2025-04-17 00:25:48,140 - INFO - --- Starting Ligand Comparison Script ---
2025-04-17 00:25:48,285 - INFO - Generating 8192 unique random pairs...
2025-04-17 00:26:00,786 - INFO - Generated 8192 unique pairs.
2025-04-17 00:26:04,266 - INFO - Saved list to unique_smiles_for_vina.txt
2025-04-17 00:26:04,284 - INFO - Saved pairs to generated_pairs.csv
2025-04-17 00:26:04,284 - INFO - --- Intermediate files generated. Run Vina using 'unique_smiles_for_vina.txt' ---
2025-04-17 00:26:04,284 - INFO - --- Update affinity_map below and set run_llm_processing=True ---
2025-04-17 00:26:04,284 - INFO - --- Starting LLM Processing ---
2025-04-17 03:00:26,964 - INFO - affinity [-9.5, -8.2, -7.6, -8.6, -7.6, -7.9, -7.4, -8.1, -7.6, -7.3, -8.0, -6.9, -7.1, -9.1, -7.3, -7.7, -6.5, -7.6, -7.2, -7.6, -8.0, -8.0, -8.7, -8.3, -7.7, -7.1, -7.6, -7.9, -8.7, -7.9, -9.9, -7.1, -6.9, -9.2, -8.4, -7.1, -7.6, -8.7, -8.0, -8.6, -7.5, -7.0, -7.5, -7.3, -8.2, -8.0, -8.1, -7.5, -8.2, -9.0, -7.8, -7.0, -8.0, -7.5, -7.9, -8.2, -9.3, -7.2, -8.0, -9.2, -8.4, -7.3, -9.0, -7.3, -7.7, -8.5, -8.1, -8.1, -7.6, -7.3, -9.2, -8.1, -9.2, -9.0, -7.4, -6.9, -7.6, -8.7, -7.7, -7.2, -7.5, -7.6, -8.3, -8.2, -8.0, -7.4, -9.0, -7.6, -6.7, -8.1, -9.4, -8.4, -7.5, -8.3, -8.5, -7.6, -7.7, -7.4, -7.4, -8.5, -7.0, -6.7, -9.5, -8.1, -7.6, -6.5, -7.9, -8.6, -9.6, -8.4, -7.9, -7.7, -8.5, -8.1, -7.7, -7.9, -8.3, -7.8, -8.2, -6.9, -8.2, -7.3, -7.6, -8.0, -7.8, -7.9, -7.9, -8.0, 0.0, -8.0, -6.5, -7.0, -7.9, -7.5, -6.4, 0.0, -8.4, -7.5, -7.8, -7.7, -7.9, -7.8, -7.5, -7.1, -8.4, -7.0, -8.4, -6.4, -7.9, -7.8, -7.9, -8.4, -8.2, -7.6, -7.5, -7.2, -7.6, -8.8, -7.8, -7.5, 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-8.0, -9.0, -8.3, 0.0, -7.2, 0.0, -8.7, -8.3, -9.9, -8.8, -8.8, -8.5, -8.4, -8.7, -10.2, -9.4, -9.6, -8.8, -10.0, -9.5, -9.3, -8.4, -10.1, -9.8, -7.7, -8.7, 0.0, -8.4, -9.7, -9.2, -8.5, -8.8, -7.0, -8.8, -9.1, -8.8, -10.3, -8.3, -9.8, -10.3, -9.5, -8.6, 0.0, -9.6, -8.4, -8.4, -11.0, -9.3, -8.3, -8.6, -7.0, -9.4, -6.5, -7.5, -7.8, -7.8, -8.7, -7.2, -7.5, -7.5, -7.9, -8.0, -7.1, -7.9, 0.0, 0.0, -9.6, -9.4, -10.2, -9.5, -9.3, -9.8, 0.0, 0.0, -8.1]
2025-04-17 03:00:26,969 - INFO - Loaded 11256 affinity values.
2025-04-17 03:00:27,095 - INFO - Prepared features for 8192 pairs.
2025-04-17 03:05:08,206 - INFO - Running LLM inference in 512 batches...
2025-04-17 03:05:08,207 - INFO - Processing batch 1/512...
2025-04-17 03:06:50,186 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (347.375 and 346.387 Da) fall comfortably within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (118.38) is slightly higher than Ligand B (113.32). Both are below the 140 A^2 threshold for good oral absorption and reasonably close to the 90 A^2 target for CNS penetration, but Ligand B is preferable.

**3. logP:** Ligand A (1.676) is within the optimal 1-3 range. Ligand B (-0.822) is slightly below 1, which *could* indicate permeability issues. This is a significant drawback for Ligand B.

**4. H-Bond Donors:** Both ligands have 3 HBD, which is within the acceptable limit of <=5.

**5. H-Bond Acceptors:** Both ligands have 6 HBA, which is within the acceptable limit of <=10.

**6. QED:** Ligand A (0.701) has a better QED score than Ligand B (0.558), indicating a more drug-like profile.

**7. DILI:** Ligand A (76.464) has a higher DILI risk than Ligand B (64.831), but both are below the concerning 60 percentile.

**8. BBB:** Ligand A (70.376) has a significantly better BBB penetration prediction than Ligand B (27.375). This is *critical* for a CNS target like DRD2.

**9. Caco-2:** Both ligands have negative Caco-2 values (-5.177 and -5.094), which is unusual and suggests poor permeability. However, these values are on a scale where negative values are possible, and direct comparison is difficult without knowing the scale's specifics.

**10. Solubility:** Both ligands have negative solubility values (-3.268 and -2.698), again suggesting poor aqueous solubility. Similar to Caco-2, interpretation is limited without knowing the scale.

**11. hERG:** Both ligands have very low hERG inhibition risk (0.115 and 0.076).

**12. Cl_mic:** Ligand B (10.266) has a lower microsomal clearance than Ligand A (17.772), suggesting better metabolic stability.

**13. t1/2:** Ligand B (-23.155) has a negative in vitro half-life, which is problematic and likely indicates rapid metabolism. Ligand A (32.642) has a reasonable half-life.

**14. Pgp:** Both ligands have very low P-gp efflux liability (0.016 and 0.047).

**15. Binding Affinity:** Ligand A (-8.6 kcal/mol) has a slightly better binding affinity than Ligand B (-7.6 kcal/mol). While both are good, the 1.0 kcal/mol difference is meaningful.

**Overall Assessment:**

Ligand A is the stronger candidate. While Ligand B has better metabolic stability (lower Cl_mic), its significantly lower BBB penetration (27.375 vs 70.376) is a major drawback for a CNS target. The slightly better affinity and QED of Ligand A, coupled with its more reasonable half-life, outweigh the slightly higher DILI risk and clearance. The negative Caco-2 and solubility values are concerning for both, but the CNS focus makes BBB the most critical factor here.



Output:
0
2025-04-17 03:06:50,187 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (397.232 Da) is slightly higher than Ligand B (345.487 Da), but both are acceptable.

**TPSA:** Ligand A (70.63) is better than Ligand B (81.99). For CNS targets, we want TPSA <= 90, so both are acceptable, but A is preferred.

**logP:** Both ligands have good logP values (A: 3.003, B: 2.764), falling within the optimal range of 1-3.

**H-Bond Donors/Acceptors:** Ligand A has 0 HBD and 5 HBA, while Ligand B has 2 HBD and 3 HBA. Both are within acceptable limits (<=5 HBD and <=10 HBA).

**QED:** Both ligands have good QED values (A: 0.633, B: 0.804), indicating good drug-like properties.

**DILI:** Ligand A (83.637) has a significantly higher DILI risk than Ligand B (29.081). This is a major concern for Ligand A.

**BBB:** Both ligands have moderate BBB penetration (A: 59.791, B: 56.921). While not ideal (>70 is desirable for CNS targets), they are comparable.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values, which is unusual and suggests poor permeability. However, the values are similar (-4.716 for A, -4.821 for B).

**Aqueous Solubility:** Both ligands have negative solubility values, indicating poor solubility. Again, the values are similar (-4.828 for A, -3.499 for B).

**hERG Inhibition:** Ligand A (0.858) has a slightly higher hERG inhibition risk than Ligand B (0.435), but both are reasonably low.

**Microsomal Clearance:** Ligand A (80.85) has a higher microsomal clearance than Ligand B (21.529), indicating lower metabolic stability.

**In vitro Half-Life:** Ligand A (11.163) has a slightly longer half-life than Ligand B (16.182).

**P-gp Efflux:** Ligand A (0.693) has a higher P-gp efflux liability than Ligand B (0.141). This is a significant disadvantage for CNS penetration.

**Binding Affinity:** Ligand B (-9.2 kcal/mol) has a *much* stronger binding affinity than Ligand A (-0.0 kcal/mol). This is a decisive factor.

**Overall Assessment:**

Ligand B is significantly better. The most important factor is the dramatically superior binding affinity. While both have issues with BBB penetration and solubility, the strong binding of Ligand B outweighs these concerns. Ligand A's high DILI risk and P-gp efflux liability are major drawbacks. The better metabolic stability of Ligand B is also a plus.

Output:
1
2025-04-17 03:06:50,187 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (443.288 Da) is higher, but still acceptable. Ligand B (369.441 Da) is preferable.

**TPSA:** Ligand A (53.16) is better than Ligand B (77.04). For CNS targets, we want TPSA <= 90, both are within this range, but A is closer to the optimal <60 for good brain penetration.

**logP:** Ligand A (4.785) is slightly high, potentially leading to solubility issues or off-target interactions. Ligand B (2.715) is within the optimal 1-3 range. This favors Ligand B.

**H-Bond Donors/Acceptors:** Ligand A (HBD=3, HBA=2) is good. Ligand B (HBD=1, HBA=6) is also acceptable, but slightly higher HBA could affect permeability.

**QED:** Both ligands have good QED scores (A: 0.393, B: 0.814). Ligand B is significantly better, indicating a more drug-like profile.

**DILI:** Ligand A (89.841) has a high DILI risk, which is concerning. Ligand B (41.411) has a much lower, and acceptable, DILI risk.

**BBB:** Ligand B (83.792) has a significantly higher BBB penetration percentile than Ligand A (69.833). This is *critical* for a CNS target like DRD2, making Ligand B strongly favored.

**Caco-2 Permeability:** Both have negative Caco-2 values (-4.858 and -4.729). This is unusual and suggests poor permeability. However, these values are on a scale where negative values are possible, and the absolute difference is small.

**Aqueous Solubility:** Both have negative solubility values (-6.296 and -3.722). This is also unusual and suggests poor solubility. Again, the difference is small.

**hERG Inhibition:** Ligand A (0.866) has a slightly higher hERG risk than Ligand B (0.296), which is preferable.

**Microsomal Clearance:** Ligand A (51.604) has higher clearance than Ligand B (37.844), indicating lower metabolic stability.

**In vitro Half-Life:** Ligand B (-13.899) has a significantly longer half-life than Ligand A (62.948). This is a major advantage for dosing convenience.

**P-gp Efflux:** Ligand A (0.341) has lower P-gp efflux than Ligand B (0.071), which is favorable for CNS exposure.

**Binding Affinity:** Ligand A (-10.2 kcal/mol) has a *much* stronger binding affinity than Ligand B (-7.8 kcal/mol). This is a substantial advantage. A >1.5 kcal/mol difference can outweigh other drawbacks.

**Overall Assessment:**

Despite Ligand A's superior binding affinity, the significant concerns regarding its DILI risk, higher logP, and lower BBB penetration make it a less desirable candidate. Ligand B has a much better overall profile, with lower DILI, better BBB penetration, better QED, better half-life, and a more favorable logP. While its affinity is lower, the difference is not so large that it completely overshadows the other advantages, particularly for a GPCR target where CNS penetration is crucial.

Output:
1
2025-04-17 03:06:50,187 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (350.384 and 348.447 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (44.29) is significantly better than Ligand B (107.11). For CNS targets, we want TPSA <= 90, and A is comfortably within this range, while B exceeds it. This is a major advantage for A.

**3. logP:** Ligand A (3.006) is optimal (1-3). Ligand B (1.461) is a bit low, potentially hindering permeation.

**4. H-Bond Donors:** Both have acceptable HBD counts (3 and 4, respectively), well below the limit of 5.

**5. H-Bond Acceptors:** Both have acceptable HBA counts (3 and 4, respectively), well below the limit of 10.

**6. QED:** Both have reasonable QED values (0.702 and 0.507), indicating good drug-like properties.

**7. DILI:** Ligand A (23.497) has a much lower DILI risk than Ligand B (33.928), suggesting better safety.

**8. BBB:** Ligand A (61.458) has a significantly better BBB penetration percentile than Ligand B (29.275). This is crucial for a CNS target like DRD2.

**9. Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and difficult to interpret without knowing the scale. However, the magnitude is similar.

**10. Aqueous Solubility:** Both have negative solubility values, again making comparison difficult.

**11. hERG:** Both have low hERG inhibition liability (0.944 and 0.455), which is good.

**12. Microsomal Clearance:** Ligand A (-13.112) has a much lower (better) microsomal clearance than Ligand B (26.317), indicating greater metabolic stability.

**13. In vitro Half-Life:** Ligand A (49.332) has a better in vitro half-life than Ligand B (-14.439).

**14. P-gp Efflux:** Ligand A (0.442) has lower P-gp efflux liability than Ligand B (0.213), which is beneficial for CNS penetration.

**15. Binding Affinity:** Ligand A (-9.5 kcal/mol) has a significantly stronger binding affinity than Ligand B (-7.5 kcal/mol). This >1.5 kcal/mol difference is substantial and can outweigh minor ADME drawbacks.

**Overall Assessment:**

Ligand A is clearly superior. It excels in critical properties for a CNS-targeting GPCR ligand: TPSA, BBB penetration, metabolic stability (Cl_mic & t1/2), P-gp efflux, and, most importantly, binding affinity. While both have acceptable QED and hERG values, Ligand A's lower DILI risk further strengthens its profile. Ligand B's lower logP and higher TPSA are significant drawbacks.

Output:
1
2025-04-17 03:06:50,187 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B based on the provided guidelines, prioritizing GPCR-specific properties (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (343.43 and 346.47 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (70.67) is higher than Ligand B (58.64). For CNS targets, TPSA should be <=90, so both are acceptable, but B is better.

**logP:** Ligand A (0.455) is quite low, potentially hindering permeability. Ligand B (1.673) is within the optimal 1-3 range. This is a significant advantage for B.

**H-Bond Donors/Acceptors:** Ligand A has 2 HBD and 4 HBA, while Ligand B has 1 HBD and 3 HBA. Both are within acceptable limits (<=5 HBD and <=10 HBA).

**QED:** Ligand A (0.836) has a higher QED than Ligand B (0.537), suggesting better overall drug-likeness.

**DILI:** Ligand A (19.66) has a higher DILI risk than Ligand B (6.36), indicating a potential liver toxicity concern.

**BBB:** Ligand A (70.34) and Ligand B (75.38) both have good BBB penetration (>70), but B is slightly better.

**Caco-2 Permeability:** Ligand A (-5.152) has poor Caco-2 permeability, while Ligand B (-4.676) is also poor, but slightly better.

**Aqueous Solubility:** Both ligands have very poor aqueous solubility (-1.616 and -2.343, respectively). This could pose formulation challenges.

**hERG Inhibition:** Both ligands show low hERG inhibition risk (0.253 and 0.497, respectively).

**Microsomal Clearance:** Ligand A (-1.993) has lower (better) microsomal clearance than Ligand B (23.983), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (31.055 hours) has a significantly longer half-life than Ligand B (0.763 hours).

**P-gp Efflux:** Ligand A (0.02) has very low P-gp efflux, which is good for CNS penetration. Ligand B (0.044) also has low P-gp efflux.

**Binding Affinity:** Ligand B (-7.7 kcal/mol) has a slightly better binding affinity than Ligand A (-8.7 kcal/mol). While both are excellent, the difference is minor.

**Overall Assessment:**

Ligand B is the more promising candidate. While Ligand A has a better QED and metabolic stability, Ligand B's superior logP, slightly better BBB, and acceptable DILI risk are crucial for a CNS-targeting GPCR ligand. The slightly better affinity of Ligand B is a bonus. Ligand A's very low logP and poor Caco-2 permeability are significant drawbacks.



Output:
1
2025-04-17 03:06:50,187 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B based on the provided guidelines, prioritizing GPCR-specific properties (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (362.495 Da) is slightly better, being closer to the lower end which can aid permeability.

**TPSA:** Both ligands have TPSA values below 90, which is good for CNS targets. Ligand A (79.03) is better than Ligand B (67.43) as lower TPSA generally correlates with better BBB penetration.

**logP:** Both ligands have logP values within the optimal range (1-3). Ligand A (2.657) is slightly better than Ligand B (3.801) as it is closer to the center of the optimal range.

**H-Bond Donors/Acceptors:** Both have 2 HBDs and 3 HBAs, which are acceptable and balance solubility and permeability.

**QED:** Ligand A (0.878) has a significantly higher QED score than Ligand B (0.53), indicating a more drug-like profile.

**DILI:** Ligand A (56.96) has a higher DILI risk than Ligand B (33.424), but both are still within acceptable limits (<60).

**BBB:** Both ligands exhibit good BBB penetration (>70%), with Ligand B (77.239) being slightly better than Ligand A (72.237).

**Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and suggests poor permeability. Ligand A (-5.362) is slightly worse than Ligand B (-4.765).

**Aqueous Solubility:** Both have negative solubility values, indicating poor aqueous solubility. Ligand A (-3.311) is slightly better than Ligand B (-4.704).

**hERG Inhibition:** Both ligands have low hERG inhibition liability (0.618 and 0.745 respectively), which is favorable.

**Microsomal Clearance:** Ligand B (76.043) has a higher microsomal clearance than Ligand A (55.466), indicating lower metabolic stability.

**In vitro Half-Life:** Ligand A (-3.516) has a longer in vitro half-life than Ligand B (33.132), which is desirable.

**P-gp Efflux:** Ligand A (0.404) has lower P-gp efflux than Ligand B (0.377), which is better for CNS exposure.

**Binding Affinity:** Ligand B (-7.9 kcal/mol) has a significantly stronger binding affinity than Ligand A (-9.7 kcal/mol). This is a substantial advantage, potentially outweighing some of the ADME drawbacks.

**Overall Assessment:**

While Ligand A has better QED, TPSA, logP, half-life, and P-gp efflux, Ligand B's significantly stronger binding affinity (-7.9 vs -9.7 kcal/mol) is a critical advantage for a GPCR target. The slightly better BBB penetration of Ligand B is also a plus. The higher DILI risk for Ligand A is a concern, but manageable. The poor Caco-2 and solubility for both are problematic, but can be addressed with formulation strategies. Given the importance of affinity for GPCRs, and the acceptable ADME profile of Ligand B, it is the more promising candidate.

Output:
1
2025-04-17 03:06:50,187 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (344.415 and 353.507 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (95.16) is slightly above the optimal <90 for CNS targets, but still reasonable. Ligand B (61.88) is well within the desired range. This favors Ligand B.

**3. logP:** Both ligands have good logP values (1.157 and 1.785), falling within the 1-3 range.

**4. H-Bond Donors:** Ligand A has 2 HBD, and Ligand B has 1. Both are acceptable (<=5).

**5. H-Bond Acceptors:** Both ligands have 4 HBA, which is within the acceptable limit of <=10.

**6. QED:** Both ligands have good QED values (0.573 and 0.642), indicating good drug-like properties.

**7. DILI:** Ligand A (36.72) has a slightly higher DILI risk than Ligand B (10.275), though both are below the 40 threshold and considered good. This favors Ligand B.

**8. BBB:** This is a critical parameter for CNS targets. Ligand A has a BBB percentile of 59.597, which is below the desirable >70. Ligand B has a BBB percentile of 70.143, meeting the threshold. This is a significant advantage for Ligand B.

**9. Caco-2 Permeability:** Ligand A (-5.353) has poor Caco-2 permeability, while Ligand B (-4.775) is also poor, but slightly better.

**10. Aqueous Solubility:** Ligand A (-1.881) has poor aqueous solubility, and Ligand B (-0.977) also has poor solubility, but is slightly better.

**11. hERG Inhibition:** Ligand A (0.11) has a slightly lower hERG inhibition risk than Ligand B (0.482), which is preferable.

**12. Microsomal Clearance:** Ligand A (-9.981) has a much lower (better) microsomal clearance than Ligand B (26.358), indicating greater metabolic stability. This favors Ligand A.

**13. In vitro Half-Life:** Ligand A (-32.771) has a much longer in vitro half-life than Ligand B (5.297), which is a significant advantage. This favors Ligand A.

**14. P-gp Efflux:** Ligand A (0.016) has significantly lower P-gp efflux than Ligand B (0.114), which is highly desirable for CNS penetration. This favors Ligand A.

**15. Binding Affinity:** Ligand A (-8.9 kcal/mol) has a significantly stronger binding affinity than Ligand B (-0.0 kcal/mol). This is the most important factor, and the >1.5 kcal/mol advantage outweighs the minor ADME drawbacks of Ligand A.

**Overall Assessment:**

While Ligand B excels in BBB penetration and has a lower DILI risk, Ligand A demonstrates a substantially superior binding affinity, significantly better metabolic stability (lower Cl_mic, longer t1/2), and lower P-gp efflux. The strong binding affinity of Ligand A is the most crucial factor, and its other properties, while not all optimal, are acceptable given the potency. The improved BBB of ligand B is not enough to overcome the huge difference in binding affinity.

Output:
1
2025-04-17 03:06:50,187 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (346.471 Da) is slightly lower, which could be beneficial for permeability. Ligand B (367.431 Da) is also good.

**TPSA:** Ligand A (49.85) is excellent, well below the 90 A^2 threshold for CNS targets. Ligand B (107.77) is higher, but still potentially acceptable, though less ideal.

**logP:** Ligand A (2.841) is optimal. Ligand B (-0.433) is significantly lower, which is a major concern as it may hinder membrane permeability and brain penetration.

**H-Bond Donors/Acceptors:** Ligand A (0 HBD, 4 HBA) is favorable. Ligand B (2 HBD, 7 HBA) is also acceptable, but slightly higher.

**QED:** Both ligands have similar QED values (0.713 and 0.699), indicating good drug-like properties.

**DILI:** Ligand A (13.339) has a much lower DILI risk than Ligand B (69.95), which is a significant advantage.

**BBB:** Ligand A (86.274) shows excellent BBB penetration potential, exceeding the desirable 70% threshold. Ligand B (39.511) is poor, indicating limited brain exposure. This is a critical drawback for a CNS target like DRD2.

**Caco-2 Permeability:** Ligand A (-4.041) is negative, which is unusual and suggests poor permeability. Ligand B (-5.606) is also negative and similarly problematic.

**Aqueous Solubility:** Both ligands have negative solubility values (-2.491 and -2.09), indicating very poor aqueous solubility. This could pose formulation challenges.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.571 and 0.134).

**Microsomal Clearance:** Ligand A (98.882) has high microsomal clearance, suggesting rapid metabolism. Ligand B (22.276) has much lower clearance, indicating better metabolic stability.

**In vitro Half-Life:** Ligand A (1.191 hours) has a short half-life, consistent with the high clearance. Ligand B (1.451 hours) is also short, but slightly better.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.056 and 0.025), which is favorable for CNS penetration.

**Binding Affinity:** Ligand B (-7.5 kcal/mol) has a 0.6 kcal/mol stronger binding affinity than Ligand A (-6.9 kcal/mol). While this is a positive, it may not be enough to overcome the significant ADME deficiencies of Ligand B.

**Overall Assessment:**

Ligand A has a superior profile for CNS drug development. Its excellent BBB penetration, low DILI risk, and optimal logP outweigh its moderate TPSA, poor Caco-2 permeability, and high clearance. Ligand B suffers from very poor BBB penetration and a concerningly high DILI risk, despite its slightly better binding affinity. The negative Caco-2 and solubility values are problematic for both, but can potentially be addressed through formulation strategies. However, the poor BBB penetration of Ligand B is a major obstacle for a CNS target.

Output:
0
2025-04-17 03:06:50,187 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (343.387 Da) is slightly lower, which could be beneficial for permeability.

**TPSA:** Both ligands have TPSA values below 140, indicating reasonable oral absorption potential. Ligand B (90.54) is closer to the preferred <90 for CNS targets, giving it a slight edge.

**logP:** Ligand A (0.259) has a very low logP, which is a significant concern. It may struggle with membrane permeability. Ligand B (1.059) is within the optimal range (1-3).

**H-Bond Donors/Acceptors:** Ligand A has 2 HBD and 5 HBA, while Ligand B has 3 HBD and 3 HBA. Both are within acceptable limits.

**QED:** Both ligands have good QED scores (A: 0.811, B: 0.699), suggesting good drug-like properties.

**DILI:** Both ligands have acceptable DILI risk (A: 65.374, B: 50.795), although A is slightly higher.

**BBB:** Ligand B (61.38%) has a better BBB percentile than Ligand A (47.499%), which is crucial for a CNS target like DRD2.

**Caco-2 Permeability:** Ligand A (-5.362) has very poor Caco-2 permeability, consistent with its low logP. Ligand B (-4.872) is also poor, but slightly better.

**Aqueous Solubility:** Both ligands have poor aqueous solubility (-2.181 and -3.323 respectively). This could pose formulation challenges, but is less critical than permeability for CNS targets.

**hERG Inhibition:** Both ligands show very low hERG inhibition risk (A: 0.02, B: 0.151).

**Microsomal Clearance:** Ligand A (-16.6 mL/min/kg) has a lower (better) microsomal clearance than Ligand B (-29.248 mL/min/kg), indicating better metabolic stability.

**In vitro Half-Life:** Ligand A (4.432 hours) has a slightly longer half-life than Ligand B (-3.907 hours).

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (A: 0.029, B: 0.009). This is favorable for CNS penetration.

**Binding Affinity:** Ligand B (-9.2 kcal/mol) has a significantly stronger binding affinity than Ligand A (0.0 kcal/mol). This is the most important factor, and the 9.2 kcal/mol difference is substantial.

**Conclusion:**

Despite Ligand A's better metabolic stability and slightly longer half-life, Ligand B is the far superior candidate. The extremely low logP and poor Caco-2 permeability of Ligand A are major liabilities, especially for a CNS target. Ligand B has a much better logP, significantly higher binding affinity, and a more favorable BBB percentile. The stronger binding affinity of Ligand B is likely to outweigh any minor drawbacks in metabolic stability or solubility.

Output:
1
2025-04-17 03:06:50,188 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (351.491 and 352.479 Da) fall comfortably within the ideal 200-500 Da range.

**TPSA:** Ligand A (53.09) is significantly better than Ligand B (81.75). For CNS targets, we want TPSA <= 90, and A is much closer to the ideal <=60 range. B is pushing the upper limit and may have reduced brain penetration.

**logP:** Ligand A (1.718) is optimal (1-3). Ligand B (0.208) is quite low, potentially hindering membrane permeability and CNS penetration.

**H-Bond Donors/Acceptors:** Ligand A (0 HBD, 4 HBA) and Ligand B (2 HBD, 4 HBA) both have acceptable numbers of H-bond donors and acceptors.

**QED:** Both ligands have reasonable QED values (0.731 and 0.612), indicating good drug-like properties.

**DILI:** Ligand A (12.214) has a much lower DILI risk than Ligand B (8.143), which is a significant advantage.

**BBB:** Ligand A (74.254) has a good BBB percentile, exceeding the desirable >70 threshold for CNS targets. Ligand B (58.821) is considerably lower, suggesting poorer brain penetration.

**Caco-2 Permeability:** Ligand A (-4.507) and Ligand B (-5.418) both have negative Caco-2 values, which is unusual and suggests poor permeability. However, the scale isn't specified, so we can't interpret this definitively.

**Aqueous Solubility:** Both ligands have negative solubility values (-0.722 and -1.365), which is also unusual and suggests poor solubility. Again, the scale is unknown.

**hERG:** Both ligands have very low hERG inhibition risk (0.434 and 0.329).

**Microsomal Clearance:** Ligand A (17.86) has higher microsomal clearance than Ligand B (5.077), indicating faster metabolism and potentially lower in vivo exposure.

**In vitro Half-Life:** Ligand B (9.46) has a significantly longer in vitro half-life than Ligand A (-2.409), which is a major advantage.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.024 and 0.006), which is favorable for CNS penetration.

**Binding Affinity:** Ligand B (-7.8 kcal/mol) has a significantly stronger binding affinity than Ligand A (-6.1 kcal/mol). This 1.7 kcal/mol difference is substantial and could outweigh some of the ADME drawbacks of Ligand B.

**Overall Assessment:**

Ligand A has superior ADME properties (TPSA, logP, BBB, DILI) making it more likely to reach the brain. However, Ligand B has a much stronger binding affinity. Given the GPCR target and the importance of CNS penetration, the stronger affinity of Ligand B is likely to be decisive. While its logP and BBB are less favorable, the substantial affinity advantage could be optimized through further structural modifications. The longer half-life of Ligand B is also a positive.

Output:
1
2025-04-17 03:06:50,188 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (351.403 Da) is slightly lower, which could be advantageous for permeability. Ligand B (416.226 Da) is still acceptable.

**TPSA:** Ligand A (99.18) is closer to the ideal range for CNS targets (<=90), but still slightly above. Ligand B (79.6) is well within the desired range. This favors Ligand B.

**logP:** Ligand A (-0.87) is a bit low, potentially hindering membrane permeability. Ligand B (1.367) is within the optimal range (1-3). This is a significant advantage for Ligand B.

**H-Bond Donors/Acceptors:** Ligand A has 2 HBD and 5 HBA, which are reasonable. Ligand B has 1 HBD and 5 HBA, also reasonable. No clear advantage here.

**QED:** Both ligands have acceptable QED values (Ligand A: 0.671, Ligand B: 0.57), indicating good drug-like properties.

**DILI:** Ligand A (23.575) has a much lower DILI risk than Ligand B (67.235). This is a substantial advantage for Ligand A.

**BBB:** Ligand B (82.474) has a significantly higher BBB penetration percentile than Ligand A (48.119). This is a critical advantage for a CNS target like DRD2.

**Caco-2 Permeability:** Both have negative values, which is unusual. Assuming these are percentile scores, Ligand B (-4.98) is slightly better than Ligand A (-5.464).

**Aqueous Solubility:** Both have negative values, which is unusual. Ligand B (-3.311) is slightly better than Ligand A (-2.028).

**hERG Inhibition:** Both ligands have very low hERG inhibition risk (Ligand A: 0.075, Ligand B: 0.165).

**Microsomal Clearance:** Ligand A (-15.391) has a much lower (better) microsomal clearance than Ligand B (43.729), indicating greater metabolic stability.

**In vitro Half-Life:** Ligand A (-10.579) has a slightly better in vitro half-life than Ligand B (-8.254).

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (Ligand A: 0.006, Ligand B: 0.061).

**Binding Affinity:** Both ligands have very similar binding affinities (Ligand A: -7.7 kcal/mol, Ligand B: -7.5 kcal/mol). The difference is less than the 1.5 kcal/mol threshold.

**Overall Assessment:**

Ligand B excels in BBB penetration and has a good logP, which are crucial for CNS GPCR targets. However, it has a higher DILI risk and a significantly higher microsomal clearance. Ligand A has a lower DILI risk, better metabolic stability, and a slightly better half-life. While its logP and BBB are less favorable, the strong affinity and lower toxicity profile are compelling. Considering the balance, and prioritizing CNS penetration *and* safety, Ligand B is the slightly more promising candidate, but the DILI risk of Ligand B is concerning.

Output:
1
2025-04-17 03:06:50,189 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (372.45 and 352.435 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (59.81) is excellent, well below the 90 A^2 threshold for CNS targets. Ligand B (107.55) is higher, but still potentially acceptable, though less ideal.

**logP:** Ligand A (4.458) is a bit high, potentially leading to solubility issues or off-target interactions. Ligand B (0.936) is quite low, which could hinder membrane permeability and CNS penetration.

**H-Bond Donors/Acceptors:** Ligand A (1 HBD, 6 HBA) is good. Ligand B (3 HBD, 5 HBA) is also acceptable.

**QED:** Both ligands have good QED scores (0.578 and 0.706), indicating generally drug-like properties.

**DILI:** Ligand A (95.929) has a very high DILI risk, a major concern. Ligand B (56.146) has a moderate DILI risk, which is preferable.

**BBB:** Ligand A (70.648) has a good BBB penetration score, crucial for a CNS target. Ligand B (48.313) has a poor BBB score, significantly reducing its potential for CNS activity.

**Caco-2 Permeability:** Both have negative Caco-2 values (-4.897 and -4.809), which is unusual and suggests poor permeability. This is a red flag for both.

**Aqueous Solubility:** Both ligands have very poor aqueous solubility (-4.601 and -2.529). This is a significant issue for formulation and bioavailability.

**hERG:** Ligand A (0.644) has a low hERG risk, which is good. Ligand B (0.265) also has a very low hERG risk.

**Microsomal Clearance:** Ligand A (50.548) has moderate clearance. Ligand B (4.813) has very low clearance, indicating better metabolic stability.

**In vitro Half-Life:** Ligand A (74.438) has a good half-life. Ligand B (-39.019) has a very short half-life, which is a major drawback.

**P-gp Efflux:** Ligand A (0.815) has moderate P-gp efflux. Ligand B (0.051) has very low P-gp efflux, which is favorable for CNS penetration.

**Binding Affinity:** Ligand A (-10.3 kcal/mol) has significantly stronger binding affinity than Ligand B (-7.7 kcal/mol). This is a substantial advantage.

**Overall Assessment:**

Ligand A excels in binding affinity and BBB penetration, which are critical for a CNS GPCR target. However, its extremely high DILI risk and poor solubility are major liabilities. Ligand B has better metabolic stability and lower P-gp efflux, but its weak binding affinity and poor BBB penetration are significant drawbacks. The difference in binding affinity (2.6 kcal/mol) is large enough to potentially overcome some of Ligand A's ADME issues with further optimization. Given the importance of affinity for GPCRs and the potential to address the DILI risk through structural modifications, Ligand A is the more promising starting point.

Output:
1
2025-04-17 03:06:50,189 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (338.411 and 345.447 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (87.04) is better than Ligand B (61.68), both are below the 90 A^2 threshold for CNS targets.

**logP:** Ligand A (3.762) is optimal (1-3), while Ligand B (-0.026) is significantly lower, potentially hindering permeation.

**H-Bond Donors:** Ligand A (2) is good, while Ligand B (0) is also acceptable.

**H-Bond Acceptors:** Ligand A (4) is good, and Ligand B (5) is also acceptable.

**QED:** Both ligands have good QED scores (0.753 and 0.772, respectively), indicating drug-like properties.

**DILI:** Ligand B (22.683) has a much lower DILI risk than Ligand A (69.911). This is a significant advantage for Ligand B.

**BBB:** Ligand B (59.093) is better than Ligand A (51.415), but both are below the desirable >70 for CNS targets.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.827 and -4.837), which is unusual and suggests poor permeability. This is a concern for both.

**Aqueous Solubility:** Both ligands have negative solubility values (-5.59 and -0.468), which is also unusual and suggests poor solubility. This is a concern for both.

**hERG Inhibition:** Ligand A (0.728) has a slightly higher hERG risk than Ligand B (0.166), but both are relatively low.

**Microsomal Clearance:** Ligand B (16.976) has significantly lower microsomal clearance than Ligand A (95.637), indicating better metabolic stability.

**In vitro Half-Life:** Ligand A (36.882) has a longer half-life than Ligand B (2.963).

**P-gp Efflux:** Ligand A (0.411) has lower P-gp efflux than Ligand B (0.017), which is better for CNS exposure.

**Binding Affinity:** Both ligands have excellent binding affinities (-8.5 and -8.2 kcal/mol). The difference of 0.3 kcal/mol is not substantial enough to outweigh other factors.

**Overall Assessment:**

Considering the GPCR-specific priorities, Ligand B is more promising. While both have issues with Caco-2 and solubility, Ligand B has a significantly better logP, lower DILI risk, and lower microsomal clearance. The slightly lower P-gp efflux of Ligand A is offset by the other advantages of Ligand B. The binding affinity difference is minimal.

Output:
1
2025-04-17 03:06:50,189 - INFO - Okay, let's analyze these two ligands for their potential as DRD2 drug candidates. DRD2 is a GPCR in the CNS, so BBB penetration, logP, Pgp efflux, TPSA, and binding affinity are paramount.

**Ligand A:** [359.897, 40.54, 4.227, 1, 3, 0.681, 15.122, 58.899, -4.784, -3.801, 0.939, 37.678, 103.601, 0.878, -9.2]
**Ligand B:** [353.419, 99.18, 0.287, 2, 5, 0.692, 33.307, 72.664, -5.132, -2.041, 0.154, -11.002, 4.716, 0.016, -7.6]

**1. Molecular Weight:** Both are within the ideal range (200-500 Da). A (359.897) and B (353.419) are comparable.

**2. TPSA:** A (40.54) is excellent for CNS penetration (well below 90). B (99.18) is higher, potentially hindering BBB penetration.

**3. logP:** A (4.227) is slightly above the optimal range but still acceptable. B (0.287) is *very* low, which is a major concern for permeability and CNS exposure.

**4. H-Bond Donors:** A (1) is good. B (2) is also acceptable.

**5. H-Bond Acceptors:** A (3) is good. B (5) is acceptable, but edging towards the upper limit.

**6. QED:** Both are similar and acceptable (A: 0.681, B: 0.692).

**7. DILI Risk:** A (15.122) is very good (low risk). B (33.307) is also relatively low risk, but higher than A.

**8. BBB Penetration:** A (58.899) is borderline for a CNS target. B (72.664) is much better, exceeding the 70% threshold. However, this benefit is likely offset by the poor logP.

**9. Caco-2 Permeability:** A (-4.784) is negative, which is unusual and suggests poor permeability. B (-5.132) is also negative and similarly concerning.

**10. Aqueous Solubility:** A (-3.801) and B (-2.041) are both negative, indicating poor aqueous solubility.

**11. hERG Inhibition:** Both are very low (A: 0.939, B: 0.154), indicating minimal cardiotoxicity risk.

**12. Microsomal Clearance:** A (37.678) is moderate. B (-11.002) is negative, which is not physically possible. This is likely an error in the data, and we should treat this value with extreme caution. It may indicate very high metabolic stability, but it's unreliable.

**13. In vitro Half-Life:** A (103.601) is good. B (4.716) is very short, suggesting rapid metabolism.

**14. P-gp Efflux:** A (0.878) is acceptable. B (0.016) is very low, indicating minimal P-gp efflux, which is good for CNS exposure.

**15. Binding Affinity:** A (-9.2) is significantly better than B (-7.6), representing a substantial potency advantage (1.6 kcal/mol difference).

**Overall Assessment:**

Ligand A has a significantly better binding affinity and a more favorable TPSA. While its BBB score is not ideal, it's still within a potentially workable range. Its logP is acceptable, and DILI risk is low. The negative Caco-2 permeability is a concern, but the strong binding affinity might compensate.

Ligand B has a better BBB score and P-gp efflux profile, but its extremely low logP is a major drawback. This will severely limit its ability to cross cell membranes and reach the CNS. The short half-life and questionable microsomal clearance data are also concerning.

Given the GPCR-specific priorities, the strong binding affinity of Ligand A outweighs its moderate BBB score and questionable permeability. The poor logP of Ligand B is a deal-breaker.

1
2025-04-17 03:06:50,190 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (369.372 and 350.459 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (63.91) is excellent, well below the 90 A^2 threshold for CNS targets. Ligand B (80.57) is still reasonable but less optimal.

**logP:** Both ligands (3.268 and 2.808) are within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A (0 HBD, 6 HBA) is favorable. Ligand B (2 HBD, 4 HBA) is also acceptable.

**QED:** Both ligands have good QED scores (0.708 and 0.68), indicating good drug-like properties.

**DILI:** Ligand A (92.633) has a high DILI risk, which is a significant concern. Ligand B (31.252) has a much lower and acceptable DILI risk.

**BBB:** Ligand A (89.104) has excellent BBB penetration, highly desirable for a CNS target. Ligand B (76.464) also shows good BBB penetration, but is less favorable than Ligand A.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.545 and -4.516). This is unusual and suggests poor permeability. However, these values are on a log scale, and negative values are not uncommon for compounds with specific efflux properties.

**Aqueous Solubility:** Both ligands have negative solubility values (-4.13 and -2.609). This suggests poor aqueous solubility, which could be a formulation challenge.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.383 and 0.38), which is good.

**Microsomal Clearance:** Ligand A (68.719) has higher microsomal clearance than Ligand B (49.299), suggesting lower metabolic stability.

**In vitro Half-Life:** Ligand B (35.341) has a longer in vitro half-life than Ligand A (21.961), which is preferable.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.607 and 0.178), which is beneficial for CNS penetration. Ligand B is better here.

**Binding Affinity:** Both ligands have strong binding affinities (-9.2 and -8.0 kcal/mol). Ligand A has a 1.2 kcal/mol advantage, which is substantial.

**Overall Assessment:**

Ligand A excels in BBB penetration and binding affinity, but suffers from a high DILI risk and higher metabolic clearance. Ligand B has a much better safety profile (lower DILI) and improved metabolic stability (longer half-life), but its binding affinity is slightly weaker and BBB is slightly lower.

Given the critical importance of safety (DILI) and metabolic stability for a CNS drug, and the fact that both ligands have good (though potentially problematic) permeability and acceptable hERG, **Ligand B is the more promising candidate.** While the affinity difference is notable, the DILI risk associated with Ligand A is a major red flag that would likely preclude further development. The slightly weaker affinity of Ligand B could potentially be optimized in subsequent iterations.

Output:
1
2025-04-17 03:06:50,190 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (338.411 and 361.471 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (69.04) is excellent, well below the 90 A^2 threshold for CNS targets. Ligand B (80.12) is still reasonable, but less optimal.

**logP:** Ligand A (3.527) is at the upper end of the optimal range (1-3), while Ligand B (1.478) is at the lower end. While a lower logP can sometimes be tolerated, it may hinder permeation.

**H-Bond Donors/Acceptors:** Both ligands have 1 HBD and a reasonable number of HBAs (5 and 6 respectively), satisfying the <5 HBD and <10 HBA guidelines.

**QED:** Both ligands have good QED scores (0.793 and 0.81), indicating drug-like properties.

**DILI:** Ligand A (74.409) has a higher DILI risk than Ligand B (48.119), which is preferable.

**BBB:** Both ligands have similar BBB penetration percentiles (52.385 and 51.493), which are not ideal for a CNS target (aim for >70). However, this is less critical if other properties are strongly favorable.

**Caco-2 Permeability:** Ligand A (-4.564) has a negative Caco-2 value, which is concerning. Ligand B (-5.381) is also negative, indicating poor intestinal absorption for both.

**Aqueous Solubility:** Ligand A (-4.494) has poor aqueous solubility, and Ligand B (-1.663) is also poor. This could pose formulation challenges.

**hERG:** Ligand A (0.848) has a slightly higher hERG inhibition risk than Ligand B (0.332), which is preferable.

**Microsomal Clearance:** Ligand B (15.685) has significantly lower microsomal clearance than Ligand A (80.36), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand B (-2.513) has a negative in vitro half-life, which is very concerning. Ligand A (22.613) is reasonable.

**P-gp Efflux:** Ligand A (0.61) has lower P-gp efflux liability than Ligand B (0.07), which is favorable for CNS penetration.

**Binding Affinity:** Both ligands have excellent binding affinities (-9.4 and -8.4 kcal/mol). Ligand A is slightly stronger, but the difference (1 kcal/mol) is not substantial enough to override other significant drawbacks.

**Overall Assessment:**

Ligand A has a better TPSA, P-gp efflux, and binding affinity, but suffers from poor Caco-2 permeability, poor aqueous solubility, higher DILI risk, and higher microsomal clearance. Ligand B has better DILI, lower microsomal clearance, and lower hERG risk, but has a lower logP, and a very concerning negative in vitro half-life.

Given the importance of metabolic stability and avoiding cardiotoxicity for a CNS drug, and the fact that both ligands have acceptable (though not ideal) BBB penetration, **Ligand B** is the more promising candidate despite the lower logP and negative half-life. The negative half-life is a significant concern, but could potentially be addressed through structural modifications. The poor solubility and permeability of both compounds are also issues that would need to be addressed.

Output:
1
2025-04-17 03:06:50,191 - INFO - Batch 1 complete. Total preferences: 16
2025-04-17 03:06:50,191 - INFO - Processing batch 2/512...
2025-04-17 03:07:31,409 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight (MW):** Both ligands (361.467 and 356.455 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (62.74) is significantly better than Ligand B (102.73). For CNS targets, TPSA should be <= 90, and A is comfortably within this range, while B is above.

**3. logP:** Both ligands have acceptable logP values (1.339 and 2.32), falling within the optimal 1-3 range.

**4. H-Bond Donors (HBD):** Both ligands are acceptable (0 and 3), staying within the limit of <=5.

**5. H-Bond Acceptors (HBA):** Both ligands are acceptable (5 and 7), staying within the limit of <=10.

**6. QED:** Both ligands have similar, good QED scores (0.743 and 0.703), indicating good drug-like properties.

**7. DILI:** Ligand A (31.563) has a much lower DILI risk than Ligand B (66.848). This is a significant advantage for A.

**8. BBB:** Ligand A (61.923) has a better BBB percentile than Ligand B (52.617), though both are below the desirable >70 for CNS targets. However, A is closer.

**9. Caco-2 Permeability:** Ligand A (-4.607) has a more negative Caco-2 value than Ligand B (-5.226). Lower values are less desirable, but the difference isn't dramatic.

**10. Aqueous Solubility:** Ligand A (-2.188) has a better solubility score than Ligand B (-4.493).

**11. hERG Inhibition:** Ligand A (0.125) has a much lower hERG inhibition liability than Ligand B (0.762), indicating a lower risk of cardiotoxicity.

**12. Microsomal Clearance:** Ligand B (29.951) has lower microsomal clearance than Ligand A (51.286), suggesting better metabolic stability.

**13. In vitro Half-Life:** Ligand B (35.02) has a significantly longer in vitro half-life than Ligand A (-0.684). This is a substantial advantage for B.

**14. P-gp Efflux:** Ligand A (0.024) has a much lower P-gp efflux liability than Ligand B (0.114), which is crucial for CNS penetration.

**15. Binding Affinity:** Ligand B (-8.2) has a slightly better binding affinity than Ligand A (-7.8). While a 1.5 kcal/mol advantage is significant, the other factors need to be considered.

**Overall Assessment:**

Ligand A is superior overall, despite Ligand B's slightly better affinity and half-life. Ligand A excels in critical areas for CNS drug development: TPSA, DILI, BBB, hERG, and P-gp efflux. Its better solubility is also a plus. While Ligand B has a better half-life and lower clearance, the risks associated with its higher TPSA, DILI, hERG, and P-gp efflux outweigh this benefit, especially for a CNS target like DRD2. The affinity difference is not large enough to compensate for these ADME/Tox liabilities.

Output:
0
2025-04-17 03:07:31,410 - INFO - Reasoning:

Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (356.407 and 352.519 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (110.25) is higher than the preferred <90 for CNS targets, while Ligand B (58.64) is well within the range. This is a significant advantage for Ligand B.

**3. logP:** Both ligands have acceptable logP values (1.684 and 3.125), falling within the 1-3 range.

**4. H-Bond Donors:** Ligand A has 3 HBD, which is acceptable. Ligand B has 1 HBD, also acceptable.

**5. H-Bond Acceptors:** Ligand A has 6 HBA, acceptable. Ligand B has 3 HBA, also acceptable.

**6. QED:** Both ligands have good QED scores (0.659 and 0.73), indicating drug-like properties.

**7. DILI:** Ligand A has a DILI risk of 88.29, which is high. Ligand B has a much lower DILI risk of 19.698, a significant advantage.

**8. BBB:** Ligand A has a BBB penetration of 63.629%, which is borderline for a CNS target. Ligand B has 71.772%, which is better and closer to the desirable >70%.

**9. Caco-2 Permeability:** Ligand A (-5.581) and Ligand B (-4.215) both have negative values, indicating poor permeability.

**10. Aqueous Solubility:** Both ligands have poor aqueous solubility (-3.441 and -2.967).

**11. hERG Inhibition:** Both ligands have low hERG inhibition risk (0.57 and 0.403).

**12. Microsomal Clearance:** Ligand A has a lower Cl_mic (25.601) than Ligand B (83.219), suggesting better metabolic stability.

**13. In vitro Half-Life:** Ligand A has a longer half-life (77.738) than Ligand B (2.6). This is a significant advantage for Ligand A.

**14. P-gp Efflux:** Ligand A (0.38) has lower P-gp efflux than Ligand B (0.209), suggesting better CNS exposure.

**15. Binding Affinity:** Ligand B (-7.2 kcal/mol) has a significantly stronger binding affinity than Ligand A (-10.4 kcal/mol). This is a substantial advantage, potentially outweighing some of the ADME drawbacks.

**Overall Assessment:**

While Ligand A has better metabolic stability and P-gp efflux, Ligand B excels in key areas for a CNS-targeting GPCR ligand. Specifically, its lower TPSA, significantly lower DILI risk, better BBB penetration, and *much* stronger binding affinity are compelling advantages. The lower half-life and higher clearance of Ligand B are concerns, but the binding affinity difference is substantial. Given the importance of affinity for GPCR ligands, and the CNS target, Ligand B is the more promising candidate.

Output:
1
2025-04-17 03:07:31,410 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 drug candidates, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (411.231 Da) is slightly higher, but still acceptable. Ligand B (347.459 Da) is also good.

**TPSA:** Ligand A (85.25) is borderline, but acceptable for a CNS target. Ligand B (69.72) is excellent, well below the 90 A^2 threshold.

**logP:** Both ligands have optimal logP values (Ligand A: 1.725, Ligand B: 0.805), falling within the 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A has 2 HBD and 5 HBA, which are within the acceptable limits. Ligand B has 1 HBD and 4 HBA, also within limits.

**QED:** Both ligands have good QED values (Ligand A: 0.734, Ligand B: 0.817), indicating good drug-like properties.

**DILI:** Ligand A has a DILI risk of 89.259, which is high and concerning. Ligand B has a much lower DILI risk of 6.049, which is excellent.

**BBB:** Ligand A has a BBB penetration of 70.803, which is desirable. Ligand B has a BBB penetration of 63.086, which is lower, but still potentially acceptable.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values, which is unusual and suggests poor permeability. However, the scale is not specified, so it's hard to interpret.

**Aqueous Solubility:** Both ligands have negative solubility values, which is also unusual. Again, the scale is not specified.

**hERG Inhibition:** Ligand A has a hERG inhibition risk of 0.61, which is moderate. Ligand B has a very low hERG risk of 0.143, which is excellent.

**Microsomal Clearance:** Ligand A has a moderate microsomal clearance of 52.818. Ligand B has a significantly lower clearance of -28.479 (potentially indicating high metabolic stability, but the negative value is concerning and requires further investigation).

**In vitro Half-Life:** Ligand A has a half-life of 10.143 hours, which is reasonable. Ligand B has a very short half-life of -9.74 hours (again, the negative value is concerning).

**P-gp Efflux:** Ligand A has a P-gp efflux liability of 0.47, which is moderate. Ligand B has a very low P-gp efflux liability of 0.006, which is excellent.

**Binding Affinity:** Both ligands have excellent binding affinities (Ligand A: -8.9 kcal/mol, Ligand B: -8.3 kcal/mol). Ligand A is slightly better, with a 0.6 kcal/mol advantage.

**Overall Assessment:**

Despite Ligand A's slightly better binding affinity, its high DILI risk (89.259) and moderate hERG risk (0.61) are major drawbacks. The negative values for Caco-2 and solubility are also concerning. Ligand B, while having slightly weaker affinity, has a significantly better safety profile (low DILI and hERG), excellent P-gp efflux properties, and a good TPSA. The negative values for Caco-2 and solubility are also concerning, but less so given the overall superior ADME profile.

Given the GPCR-specific priorities and the importance of safety for CNS drugs, Ligand B is the more promising candidate.

Output:
1
2025-04-17 03:07:31,410 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (344.411 Da) is slightly lower than Ligand B (375.579 Da), which is not a significant difference.

**TPSA:** Ligand A (88.42) is better than Ligand B (60.93) as it is closer to the ideal range for CNS targets (<=90).

**logP:** Both ligands have good logP values (A: 2.564, B: 1.873), falling within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A has 1 HBD and 5 HBA, while Ligand B has 0 HBD and 4 HBA. Both are acceptable.

**QED:** Ligand A (0.732) has a higher QED score than Ligand B (0.585), indicating better overall drug-likeness.

**DILI:** Ligand A (51.997) has a higher DILI risk than Ligand B (11.788), but both are below the concerning threshold of 60.

**BBB:** Ligand B (75.533) has a significantly better BBB penetration percentile than Ligand A (49.128). This is a crucial factor for a CNS target like DRD2.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values, which is unusual and suggests poor permeability. However, the scale is not specified, so it's hard to interpret.

**Aqueous Solubility:** Both ligands have negative solubility values, which is also unusual and suggests poor solubility.

**hERG Inhibition:** Ligand A (0.271) has a slightly higher hERG inhibition liability than Ligand B (0.816), meaning B is preferable.

**Microsomal Clearance:** Ligand B (33.929) has a lower microsomal clearance than Ligand A (60.203), indicating better metabolic stability.

**In vitro Half-Life:** Ligand B (-45.397) has a much longer in vitro half-life than Ligand A (-7.974).

**P-gp Efflux:** Ligand A (0.059) has lower P-gp efflux liability than Ligand B (0.035), which is preferable for CNS penetration.

**Binding Affinity:** Ligand A (-8.1 kcal/mol) has a slightly better binding affinity than Ligand B (-7.7 kcal/mol). While a 1.5 kcal/mol difference is not huge, it is a factor.

**Overall Assessment:**

Ligand B is the stronger candidate. While Ligand A has slightly better binding affinity and P-gp efflux, Ligand B excels in critical areas for a CNS-targeting GPCR ligand: significantly better BBB penetration, lower DILI risk, better metabolic stability (lower Cl_mic, longer t1/2), and lower hERG risk. The superior BBB penetration and metabolic stability outweigh the minor affinity difference. The unusual negative values for Caco-2 and solubility are concerning for both, but the other ADME properties of B are more favorable.

Output:
1
2025-04-17 03:07:31,411 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (369.849 and 357.41 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (84.67) is better than Ligand B (56.41) as it is closer to the optimal range for CNS targets (<=90). Ligand B is excellent.

**logP:** Both ligands have good logP values (2.278 and 2.965), falling within the 1-3 range.

**H-Bond Donors/Acceptors:** Both ligands have 1 HBD, which is good. Ligand A has 5 HBA, while Ligand B has 3. Both are acceptable (<=10).

**QED:** Both ligands have good QED scores (0.561 and 0.783), indicating drug-like properties. Ligand B is better.

**DILI:** Ligand A (60.721) is better than Ligand B (78.247) as it has a lower DILI risk.

**BBB:** Ligand B (80.845) is significantly better than Ligand A (68.67) in terms of BBB penetration, a crucial factor for CNS targets.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.834 and -4.805), which is unusual and suggests poor permeability. This is a significant concern for both.

**Aqueous Solubility:** Both ligands have negative solubility values (-3.09 and -3.86), indicating poor aqueous solubility. This is also a significant concern.

**hERG Inhibition:** Ligand A (0.286) has a lower hERG inhibition liability than Ligand B (0.765), which is preferable.

**Microsomal Clearance:** Ligand A (50.7) has a higher microsomal clearance than Ligand B (22.257), indicating lower metabolic stability.

**In vitro Half-Life:** Ligand B (5.195) has a longer in vitro half-life than Ligand A (22.227), which is desirable.

**P-gp Efflux:** Ligand A (0.295) has lower P-gp efflux liability than Ligand B (0.395), which is preferable for CNS exposure.

**Binding Affinity:** Ligand B (-9.7 kcal/mol) has a significantly stronger binding affinity than Ligand A (-7.0 kcal/mol). This is a major advantage, potentially outweighing some of the ADME drawbacks.

**Overall Assessment:**

Ligand B is superior due to its significantly higher binding affinity and better BBB penetration, both critical for a CNS-targeting GPCR like DRD2. While Ligand A has a slightly better DILI score and P-gp efflux, the substantial difference in binding affinity and BBB outweighs these advantages. The poor Caco-2 and solubility for both are concerning, but can potentially be addressed through formulation strategies.

Output:
1
2025-04-17 03:07:31,411 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (361.389 and 348.491 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (70.16) is better than Ligand B (65.54), both are below the 90 A^2 threshold for CNS targets, which is excellent.

**3. logP:** Both ligands have good logP values (1.322 and 1.626), falling within the optimal 1-3 range.

**4. H-Bond Donors:** Ligand A (0) is preferable to Ligand B (1) as fewer HBDs generally improve permeability.

**5. H-Bond Acceptors:** Both ligands have 4 HBA, which is acceptable (<=10).

**6. QED:** Both ligands have similar QED scores (0.741 and 0.737), indicating good drug-likeness.

**7. DILI:** Ligand A (47.305) has a higher DILI risk than Ligand B (13.028). This is a significant advantage for Ligand B.

**8. BBB:** Ligand A (84.102) has a significantly better BBB penetration percentile than Ligand B (59.248). This is a crucial factor for a CNS target like DRD2.

**9. Caco-2 Permeability:** Ligand A (-3.993) has better Caco-2 permeability than Ligand B (-4.827).

**10. Aqueous Solubility:** Ligand A (-1.609) has better aqueous solubility than Ligand B (-0.833).

**11. hERG Inhibition:** Both ligands have very low hERG inhibition liability (0.415 and 0.195), which is excellent.

**12. Microsomal Clearance:** Ligand B (45.637) has slightly better microsomal clearance than Ligand A (41.336), indicating better metabolic stability.

**13. In vitro Half-Life:** Ligand B (21.639) has a longer in vitro half-life than Ligand A (-23.354). This is a significant advantage for Ligand B.

**14. P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.068 and 0.011), which is excellent.

**15. Binding Affinity:** Both ligands have the same binding affinity (-7.4 kcal/mol), which is very strong.

**Overall Assessment:**

While Ligand A has better BBB penetration and Caco-2 permeability, Ligand B demonstrates a significantly lower DILI risk and a longer in vitro half-life. Given the importance of minimizing toxicity (DILI) and maximizing duration of action (half-life) in drug development, and the fact that both ligands have equal binding affinity, Ligand B is the more promising candidate. The difference in BBB is substantial, but can potentially be addressed with formulation strategies. The lower DILI and better half-life are more difficult to improve post-hoc.

Output:
1
2025-04-17 03:07:31,411 - INFO - Reasoning:

Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (353.407 and 364.433 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (96.87) is slightly above the optimal <90 for CNS targets, but still reasonable. Ligand B (87.66) is excellent, well below 90.

**3. logP:** Both ligands (1.721 and 1.609) are within the optimal 1-3 range.

**4. H-Bond Donors:** Ligand A (2) and Ligand B (3) are both acceptable, below the threshold of 5.

**5. H-Bond Acceptors:** Ligand A (6) and Ligand B (4) are both acceptable, below the threshold of 10.

**6. QED:** Ligand A (0.703) has a better QED score than Ligand B (0.55), indicating a more drug-like profile.

**7. DILI:** Ligand A (91.508) has a higher DILI risk than Ligand B (29.779). This is a significant negative for Ligand A.

**8. BBB:** Ligand B (76.619) has a substantially better BBB penetration percentile than Ligand A (24.506). This is crucial for a CNS target like DRD2.

**9. Caco-2 Permeability:** Ligand A (-5.575) has poor Caco-2 permeability, while Ligand B (-4.641) is slightly better, but still not ideal.

**10. Aqueous Solubility:** Both ligands have very poor aqueous solubility (-3.028 and -2.169 respectively). This is a concern for both, but might be mitigated by formulation strategies.

**11. hERG Inhibition:** Both ligands have low hERG inhibition risk (0.073 and 0.381).

**12. Microsomal Clearance:** Ligand A (14.358) has a lower microsomal clearance than Ligand B (38.247), suggesting better metabolic stability.

**13. In vitro Half-Life:** Ligand A (17.313) has a longer in vitro half-life than Ligand B (-16.833). This is a positive for Ligand A.

**14. P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.032 and 0.045).

**15. Binding Affinity:** Ligand A (-8.5 kcal/mol) has a slightly better binding affinity than Ligand B (-7.6 kcal/mol). This is a 0.9 kcal/mol difference, which is significant.

**Overall Assessment:**

While Ligand A has a slightly better binding affinity and metabolic stability, Ligand B is significantly better in terms of BBB penetration and DILI risk. For a CNS target like DRD2, BBB penetration is paramount. The higher DILI risk associated with Ligand A is also a major concern. Although both have poor solubility and Caco-2 permeability, these can potentially be addressed through formulation. The difference in binding affinity, while present, is likely outweighed by the superior ADME properties of Ligand B, especially its BBB score.

Output:
1
2025-04-17 03:07:31,411 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (366.845 and 349.475 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (70.08) is better than Ligand B (72.88) as both are below the 90 A^2 threshold for CNS targets, but lower is preferred.

**logP:** Ligand A (2.035) is optimal (1-3), while Ligand B (0.908) is slightly low, potentially hindering permeation.

**H-Bond Donors/Acceptors:** Both ligands have acceptable HBD (1 & 2) and HBA (4 & 4) counts, well within the recommended limits.

**QED:** Both ligands have reasonable QED scores (0.883 and 0.74), indicating good drug-likeness.

**DILI:** Both ligands have relatively low DILI risk (55.68 and 5.235 percentile), suggesting acceptable hepatic safety. Ligand B is significantly better.

**BBB:** Ligand B (57.425%) has a better BBB penetration score than Ligand A (43.699%), which is crucial for a CNS target like DRD2. While both are below the desirable >70%, B is closer.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.918 and -4.957), which is unusual and suggests poor permeability. This is a significant concern for both.

**Aqueous Solubility:** Both ligands have negative solubility values (-2.288 and -1.367), indicating poor aqueous solubility, which could hinder formulation and bioavailability.

**hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.048 and 0.155 percentile), which is excellent.

**Microsomal Clearance:** Ligand B (-6.515 mL/min/kg) has a much lower (better) microsomal clearance than Ligand A (0.243 mL/min/kg), suggesting greater metabolic stability.

**In vitro Half-Life:** Ligand B (-12.002 hours) has a significantly longer half-life than Ligand A (-2.155 hours), which is a major advantage.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.012 and 0.008), which is favorable for CNS exposure.

**Binding Affinity:** Both ligands have similar and strong binding affinities (-8.8 and -8.4 kcal/mol), both well below the -7.0 kcal/mol threshold. The difference of 0.4 kcal/mol is not substantial enough to be a deciding factor.

**Conclusion:**

Considering all factors, **Ligand B** is the more promising drug candidate. While both have issues with Caco-2 permeability and solubility, Ligand B demonstrates significantly better BBB penetration, metabolic stability (lower Cl_mic), and a longer half-life. These factors are particularly important for a CNS-targeting GPCR like DRD2. The slightly lower logP of Ligand B is a minor drawback compared to the substantial advantages in ADME properties.

Output:
1
2025-04-17 03:07:31,412 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (344.5 & 361.5 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (40.62) is significantly better than Ligand B (51.39). For CNS targets, we want TPSA <= 90, and ideally closer to 60. Ligand A is much closer to this ideal.

**3. logP:** Both ligands have good logP values (4.104 & 3.857), falling within the optimal 1-3 range, though slightly high.

**4. H-Bond Donors:** Both have 0 HBD, which is acceptable.

**5. H-Bond Acceptors:** Ligand A (2) is better than Ligand B (6). Lower HBA is generally preferred for BBB penetration.

**6. QED:** Both ligands have similar, good QED values (0.747 & 0.782), indicating good drug-like properties.

**7. DILI:** Both ligands have acceptable DILI risk (18.922 & 21.442), well below the 40% threshold.

**8. BBB:** Ligand A (97.829) has a significantly higher BBB percentile than Ligand B (80.264). This is *critical* for a CNS target like DRD2.

**9. Caco-2 Permeability:** Ligand A (-4.347) is better than Ligand B (-5.078), indicating better intestinal absorption.

**10. Aqueous Solubility:** Ligand A (-3.874) is better than Ligand B (-3.654), though both are poor. Solubility is less critical than BBB for CNS drugs.

**11. hERG Inhibition:** Both ligands have low hERG inhibition risk (0.919 & 0.794).

**12. Microsomal Clearance:** Ligand B (64.083) has lower microsomal clearance than Ligand A (70.301), suggesting better metabolic stability.

**13. In vitro Half-Life:** Ligand B (12.912) has a longer half-life than Ligand A (8.894), which is desirable.

**14. P-gp Efflux:** Ligand A (0.611) has lower P-gp efflux than Ligand B (0.438), which is beneficial for CNS exposure.

**15. Binding Affinity:** Ligand B (-7.6 kcal/mol) has a slightly better binding affinity than Ligand A (-8.2 kcal/mol). While a 1.5 kcal/mol advantage is significant, the other ADME properties are more important in this case.

**Overall Assessment:**

Ligand A is the superior candidate. Its significantly better BBB penetration (97.8% vs 80.3%), lower TPSA, and lower P-gp efflux outweigh the slightly weaker binding affinity and higher clearance. For a CNS target like DRD2, getting the drug *into* the brain is paramount, and Ligand A excels in this regard. The affinity difference is not substantial enough to overcome the ADME advantages of Ligand A.

Output:
0
2025-04-17 03:07:31,412 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (350.419 and 347.405 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (111.12) is better than Ligand B (25.61). For CNS targets, we want TPSA <= 90, so Ligand A is closer to this threshold, and Ligand B is excellent.

**logP:** Ligand A (-0.831) is suboptimal, being below the preferred 1-3 range. Ligand B (4.76) is high, potentially causing solubility issues and off-target interactions.

**H-Bond Donors/Acceptors:** Ligand A (2 HBD, 6 HBA) is reasonable. Ligand B (0 HBD, 3 HBA) is also good.

**QED:** Both ligands have good QED scores (0.601 and 0.8), indicating drug-like properties.

**DILI:** Ligand A (19.698) has a much lower DILI risk than Ligand B (33.579), which is a significant advantage.

**BBB:** Ligand B (90.617) has a significantly higher BBB penetration percentile than Ligand A (72.237). This is a crucial factor for a CNS target like DRD2.

**Caco-2 Permeability:** Ligand A (-5.401) and Ligand B (-4.458) both have negative values, which is unusual and suggests poor permeability.

**Aqueous Solubility:** Ligand A (-0.689) and Ligand B (-4.036) both have negative solubility values, which is also concerning.

**hERG Inhibition:** Ligand A (0.172) has a very low hERG risk, while Ligand B (0.969) has a moderate risk.

**Microsomal Clearance:** Ligand A (-11.173) has a negative clearance, which is not possible and likely indicates an error in the data or a very stable compound. Ligand B (28.715) has a moderate clearance.

**In vitro Half-Life:** Ligand B (63.829) has a much longer in vitro half-life than Ligand A (-18.414), which is a substantial advantage.

**P-gp Efflux:** Ligand A (0.005) has very low P-gp efflux liability, which is excellent for CNS penetration. Ligand B (0.809) has moderate P-gp efflux.

**Binding Affinity:** Ligand A (-7.8) has a slightly better binding affinity than Ligand B (-0.0).

**Overall Assessment:**

Ligand A has a better safety profile (lower DILI, lower hERG) and P-gp efflux, and slightly better binding affinity. However, its logP is poor, and its BBB penetration is lower than Ligand B. Ligand B excels in BBB penetration and has a good half-life, but suffers from a higher logP, higher DILI risk, and a significantly weaker binding affinity. The negative clearance and half-life for Ligand A are suspect and raise concerns about data quality.

Given the importance of BBB penetration for a CNS target like DRD2, and the substantial difference in binding affinity, Ligand B is the more promising candidate despite its drawbacks. The high logP could potentially be addressed through structural modifications.

Output:
1
2025-04-17 03:07:31,412 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (350.478 and 346.471 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (40.62) is significantly better than Ligand B (69.64). For CNS targets, we want TPSA <= 90, and ideally closer to 60. Ligand A is much closer to this ideal.

**logP:** Both ligands have good logP values (3.344 and 2.311), falling within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A (0 HBD, 2 HBA) is preferable to Ligand B (2 HBD, 3 HBA). Lower counts generally improve permeability.

**QED:** Both ligands have good QED scores (0.661 and 0.751), indicating good drug-like properties.

**DILI:** Ligand A (19.271) has a slightly higher DILI risk than Ligand B (14.541), but both are below the concerning threshold of 60.

**BBB:** This is a crucial parameter for a CNS target like DRD2. Ligand A has a significantly higher BBB percentile (96.937) compared to Ligand B (52.617). This is a major advantage for Ligand A.

**Caco-2 Permeability:** Ligand A (-4.347) and Ligand B (-4.866) both have negative values, indicating poor permeability. This is a concern for both, but the difference isn't substantial enough to sway the decision.

**Aqueous Solubility:** Ligand A (-3.415) and Ligand B (-2.057) both have negative values, indicating poor solubility. This is a concern for both, but the difference isn't substantial enough to sway the decision.

**hERG Inhibition:** Ligand A (0.783) has a slightly higher hERG risk than Ligand B (0.148), but both are relatively low.

**Microsomal Clearance:** Ligand A (47.744) has a higher microsomal clearance than Ligand B (20.797), suggesting lower metabolic stability. This is a drawback for Ligand A.

**In vitro Half-Life:** Ligand B (-0.513) has a slightly longer half-life than Ligand A (-6.05), which is preferable.

**P-gp Efflux:** Ligand A (0.374) has lower P-gp efflux liability than Ligand B (0.146), which is beneficial for CNS penetration.

**Binding Affinity:** Ligand B (-9.3 kcal/mol) has a slightly better binding affinity than Ligand A (-8.0 kcal/mol). However, the difference is not huge, and other factors can compensate.

**Overall Assessment:**

Ligand A is significantly better due to its superior BBB penetration (96.9% vs 52.6%), lower TPSA, and lower P-gp efflux. While Ligand B has slightly better affinity and metabolic stability, the CNS-specific requirements for DRD2 heavily favor Ligand A. The better BBB and P-gp properties of Ligand A will likely translate to higher brain exposure, which is critical for efficacy.

Output:
1
2025-04-17 03:07:31,412 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (376.513 and 349.391 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (64.35) is excellent, well below the 90 A^2 threshold for CNS targets. Ligand B (121.23) is higher, but still potentially acceptable, though less ideal.

**3. logP:** Ligand A (2.804) is optimal (1-3). Ligand B (1.329) is on the lower side, potentially impacting permeability.

**4. H-Bond Donors:** Both ligands have 2 HBD, which is within the acceptable limit of <=5.

**5. H-Bond Acceptors:** Ligand A has 4 HBA, and Ligand B has 5. Both are within the acceptable limit of <=10.

**6. QED:** Ligand A (0.774) has a better QED score than Ligand B (0.593), indicating a more drug-like profile.

**7. DILI:** Ligand A (17.449) has a much lower DILI risk than Ligand B (63.746). This is a significant advantage for Ligand A.

**8. BBB:** Ligand A (92.904) has a very good BBB penetration percentile, exceeding the desirable >70 threshold for CNS targets. Ligand B (65.18) is lower and less favorable for CNS penetration.

**9. Caco-2 Permeability:** Ligand A (-5.298) has a negative value, which is unusual and suggests poor permeability. Ligand B (-4.868) is also negative, indicating poor permeability, but slightly less so than Ligand A.

**10. Aqueous Solubility:** Both ligands have very poor aqueous solubility (-2.627 and -3.559). This is a concern for both, but may be mitigated by formulation strategies.

**11. hERG Inhibition:** Both ligands have low hERG inhibition risk (0.732 and 0.208).

**12. Microsomal Clearance:** Ligand A (17.486) has higher microsomal clearance than Ligand B (11.571), suggesting lower metabolic stability.

**13. In vitro Half-Life:** Ligand B (-5.106) has a negative half-life which is not possible. This is a red flag. Ligand A (20.262) has a reasonable half-life.

**14. P-gp Efflux:** Ligand A (0.115) exhibits lower P-gp efflux than Ligand B (0.099), which is favorable for CNS exposure.

**15. Binding Affinity:** Both ligands have the same binding affinity (-8.5 kcal/mol), which is excellent.

**Overall Assessment:**

Despite the poor Caco-2 permeability and solubility for both, Ligand A is the stronger candidate. It has a significantly better DILI score, a much higher BBB penetration, a better QED score, and lower P-gp efflux. The slightly higher microsomal clearance is a concern, but the substantial advantages in CNS penetration and safety outweigh this drawback, especially given the equal binding affinity. The negative half-life for Ligand B is a showstopper.

Output:
1
2025-04-17 03:07:31,413 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B based on the provided guidelines, prioritizing GPCR-specific properties (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (383.187 Da) is slightly higher than Ligand B (355.479 Da), but both are acceptable.

**TPSA:** Ligand A (81.91) is excellent for CNS penetration, being well below 90. Ligand B (90.9) is approaching the upper limit but still reasonable.

**logP:** Ligand A (3.789) is optimal. Ligand B (0.269) is significantly low, potentially hindering membrane permeability and CNS entry.

**H-Bond Donors/Acceptors:** Ligand A (0 HBD, 5 HBA) and Ligand B (3 HBD, 5 HBA) both fall within acceptable ranges.

**QED:** Both ligands have reasonable QED scores (Ligand A: 0.431, Ligand B: 0.552), with Ligand B being slightly more drug-like.

**DILI:** Ligand A (81.039) has a higher DILI risk than Ligand B (5.894), which is a significant concern.

**BBB:** Ligand A (78.79) has a good BBB percentile, desirable for a CNS target. Ligand B (27.375) has a very low BBB percentile, making CNS penetration unlikely.

**Caco-2 Permeability:** Ligand A (-4.559) has poor Caco-2 permeability, while Ligand B (-5.313) is also poor.

**Aqueous Solubility:** Ligand A (-5.755) has poor solubility, and Ligand B (0.048) is also poor.

**hERG:** Ligand A (0.71) has a slightly higher hERG risk than Ligand B (0.076), but both are relatively low.

**Microsomal Clearance:** Ligand A (55.274) has moderate clearance, while Ligand B (-12.405) suggests very rapid clearance and poor metabolic stability.

**In vitro Half-Life:** Ligand A (8.714 hours) has a reasonable half-life. Ligand B (1.832 hours) has a very short half-life.

**P-gp Efflux:** Ligand A (0.503) has moderate P-gp efflux, while Ligand B (0.007) suggests minimal efflux, which is favorable for CNS penetration.

**Binding Affinity:** Ligand A (-8.5 kcal/mol) has significantly stronger binding affinity than Ligand B (-7.3 kcal/mol). The 1.2 kcal/mol difference is substantial and can outweigh some ADME concerns.

**Overall Assessment:**

Despite Ligand A's higher DILI risk and poor solubility/permeability, its significantly stronger binding affinity (-8.5 vs -7.3 kcal/mol) and good BBB penetration make it the more promising candidate. The strong binding is a critical advantage for a GPCR target, and the BBB score suggests it can reach the target in the CNS. Ligand B's low logP and extremely poor metabolic stability are major drawbacks, even with its lower DILI risk. The poor BBB penetration is a dealbreaker for a CNS-targeted drug.

Output:
1
2025-04-17 03:07:31,413 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (371.216 and 342.439 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (71.84) is slightly higher than Ligand B (67.43), but both are below the 90 A^2 threshold desirable for CNS targets.

**logP:** Ligand A (3.971) is at the upper end of the optimal range (1-3), while Ligand B (2.364) is well within it. Ligand A's higher logP *could* lead to solubility issues or off-target interactions, but it's not drastically high.

**H-Bond Donors/Acceptors:** Both ligands have 2 HBD and 3-4 HBA, which are acceptable values.

**QED:** Both ligands have similar QED values (0.799 and 0.748), indicating good drug-likeness.

**DILI:** Ligand A (81.427) has a significantly higher DILI risk than Ligand B (56.844). This is a major concern for Ligand A.

**BBB:** Both ligands have good BBB penetration (69.95% and 67.623%), but neither exceeds the desirable 70% threshold.

**Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and suggests poor permeability. However, these are reported as negative values, which is not standard. We will interpret these as very low permeability.

**Aqueous Solubility:** Both ligands have very poor aqueous solubility (-4.845 and -4.67). This is a significant drawback for both.

**hERG Inhibition:** Both ligands show low hERG inhibition liability (0.416 and 0.317), which is favorable.

**Microsomal Clearance:** Ligand A (19.796) has a lower microsomal clearance than Ligand B (57.6), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand B (-10.564) has a significantly longer in vitro half-life than Ligand A (57.82).

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.06 and 0.177), which is good for CNS penetration.

**Binding Affinity:** Ligand A (-9.7 kcal/mol) has a substantially stronger binding affinity than Ligand B (-8.8 kcal/mol). This is a 0.9 kcal/mol difference, which is significant and could outweigh some of the ADME drawbacks.

**Overall Assessment:**

Ligand A has a significantly better binding affinity, and better metabolic stability. However, it has a much higher DILI risk, and a shorter half-life. Both ligands have poor solubility and permeability. Given the CNS target, the higher binding affinity of Ligand A is a strong advantage. The DILI risk is concerning, but could potentially be mitigated through structural modifications. The poor solubility and permeability are shared issues.

Output:
1
2025-04-17 03:07:31,413 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (349.435 and 350.507 Da) fall comfortably within the ideal 200-500 Da range.

**TPSA:** Ligand A (100.21) is slightly above the preferred <90 for CNS targets, but still reasonable. Ligand B (47.1) is excellent, well below the threshold.

**logP:** Both ligands have a logP around 1.0, which is optimal.

**H-Bond Donors/Acceptors:** Ligand A has 2 HBD and 5 HBA, acceptable. Ligand B has 0 HBD and 4 HBA, also acceptable.

**QED:** Both ligands have similar QED scores (0.765 and 0.759), indicating good drug-likeness.

**DILI:** Ligand A (33.85) has a much lower DILI risk than Ligand B (8.647), which is a significant advantage.

**BBB:** Both ligands have good BBB penetration (61.923% and 64.482%), but Ligand B is slightly better.

**Caco-2 Permeability:** Ligand A (-5.463) has poor Caco-2 permeability, while Ligand B (-4.956) is also poor but slightly better.

**Aqueous Solubility:** Ligand A (-1.402) has poor solubility, and Ligand B (-0.234) is also poor.

**hERG Inhibition:** Ligand A (0.077) has very low hERG inhibition risk, a major advantage. Ligand B (0.592) has a higher, though still relatively low, risk.

**Microsomal Clearance:** Ligand A (-2.67) has a negative clearance, indicating high metabolic stability, which is excellent. Ligand B (1.692) has a positive clearance, suggesting faster metabolism.

**In vitro Half-Life:** Ligand A (8.055) has a longer half-life than Ligand B (-1.088).

**P-gp Efflux:** Ligand A (0.014) has very low P-gp efflux, which is excellent for CNS penetration. Ligand B (0.026) is also low, but higher than A.

**Binding Affinity:** Ligand A (-7.4) has a slightly better binding affinity than Ligand B (0.0).

**Overall Assessment:**

Ligand A is superior due to its significantly lower DILI risk, excellent metabolic stability (negative Cl_mic), longer half-life, very low P-gp efflux, and slightly better binding affinity. While its TPSA is a bit higher and Caco-2 permeability is poor, the benefits in safety (DILI, hERG) and pharmacokinetics (Cl_mic, t1/2, Pgp) outweigh these drawbacks, especially for a CNS target like DRD2. Ligand B has slightly better BBB penetration and TPSA, but the higher DILI risk and faster metabolism are concerning.

Output:
1
2025-04-17 03:07:31,413 - INFO - Reasoning:

Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (339.439 and 338.499 Da) fall comfortably within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (47.36) is significantly better than Ligand B (33.09). For a CNS target like DRD2, a TPSA <= 90 is desirable, and A is closer to the optimal range for CNS penetration.

**3. logP:** Both ligands have good logP values (2.744 and 3.74), falling within the 1-3 range. Ligand B is slightly higher, which *could* indicate a potential for off-target interactions, but isn't a major concern.

**4. H-Bond Donors:** Both have acceptable HBD counts (0 and 1 respectively), well below the threshold of 5.

**5. H-Bond Acceptors:** Both ligands have 4 HBAs, well within the acceptable limit of 10.

**6. QED:** Both ligands have very similar and good QED values (0.86 and 0.871), indicating good drug-like properties.

**7. DILI:** Ligand A (29.042) has a slightly higher DILI risk than Ligand B (18.651), but both are below the concerning threshold of 60.

**8. BBB:** Ligand B (90.229) has a better BBB percentile than Ligand A (84.684), which is a crucial factor for CNS targets. While both are good, B is preferable.

**9. Caco-2:** Both have negative Caco-2 values (-4.634 and -4.972), which is unusual and suggests poor permeability. This is a significant drawback for both.

**10. Solubility:** Both have negative solubility values (-2.84 and -3.176), indicating poor aqueous solubility. This is another significant drawback for both.

**11. hERG:** Both ligands have low hERG inhibition liability (0.486 and 0.839), which is excellent.

**12. Cl_mic:** Ligand B (28.651) has significantly lower microsomal clearance than Ligand A (73.322), suggesting better metabolic stability.

**13. t1/2:** Ligand B (42.57) has a much longer in vitro half-life than Ligand A (-13.481), which is a major advantage.

**14. Pgp:** Both ligands have low P-gp efflux liability (0.47 and 0.467), which is good for CNS penetration.

**15. Binding Affinity:** Both ligands have very similar and strong binding affinities (-9.7 and -8.9 kcal/mol). The difference of 0.8 kcal/mol is not substantial enough to outweigh other factors.

**Overall Assessment:**

While both ligands have issues with Caco-2 permeability and solubility, Ligand B is superior due to its significantly better BBB penetration, lower microsomal clearance, and longer half-life. These factors are particularly important for a CNS target like DRD2. The slightly higher DILI risk of Ligand A is not a major concern given the other advantages of Ligand B.

Output:
1
2025-04-17 03:07:31,414 - INFO - Batch 2 complete. Total preferences: 32
2025-04-17 03:07:31,414 - INFO - Processing batch 3/512...
2025-04-17 03:08:13,341 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (348.443 and 343.431 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (59.08) is excellent, well below the 90 A^2 threshold for CNS targets. Ligand B (72.4) is still reasonable, but less optimal.

**3. logP:** Both ligands have good logP values (1.375 and 2.498), falling within the 1-3 range. Ligand B is slightly higher, potentially offering better membrane permeability.

**4. H-Bond Donors:** Ligand A (0) is ideal. Ligand B (1) is acceptable.

**5. H-Bond Acceptors:** Ligand A (4) is good. Ligand B (7) is higher, potentially impacting permeability.

**6. QED:** Both ligands have good QED scores (0.72 and 0.864), indicating drug-like properties.

**7. DILI:** Ligand A (33.812) has a lower DILI risk than Ligand B (50.058), which is preferable.

**8. BBB:** Both ligands have acceptable BBB penetration (60.644 and 66.809). However, neither exceeds the desirable >70% for CNS targets.

**9. Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and suggests poor permeability. This is a significant concern for both.

**10. Aqueous Solubility:** Both have negative solubility values, which is also concerning and suggests poor solubility.

**11. hERG Inhibition:** Both ligands exhibit very low hERG inhibition risk (0.173 and 0.84), which is excellent.

**12. Microsomal Clearance:** Ligand A (31.681) has a lower microsomal clearance, suggesting better metabolic stability than Ligand B (54.145).

**13. In vitro Half-Life:** Ligand A (-11.729) has a negative half-life, which is not possible and indicates an issue with the data. Ligand B (7.422) has a reasonable half-life.

**14. P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.028 and 0.041), which is favorable for CNS penetration.

**15. Binding Affinity:** Both ligands have very similar and strong binding affinities (-8.1 and -8.2 kcal/mol). The difference is negligible.

**Overall Assessment:**

Despite the concerning negative values for Caco-2 and Solubility, Ligand A is slightly favored. Its lower TPSA, lower DILI risk, and lower microsomal clearance are advantages. The negative half-life for Ligand A is a major red flag, however. Ligand B has a more reasonable half-life, but its higher TPSA and DILI risk are less desirable. Given the similar binding affinities, the ADME properties become the deciding factor. Because of the negative half-life, I would choose Ligand B.

Output:
1
2025-04-17 03:08:13,341 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (349.475 and 356.398 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (69.72) is excellent, well below the 90 A^2 threshold for CNS targets. Ligand B (107.61) is higher, but still potentially acceptable, though less ideal.

**logP:** Ligand A (1.398) is optimal. Ligand B (-0.904) is slightly low, potentially hindering membrane permeability.

**H-Bond Donors/Acceptors:** Ligand A (HBD=1, HBA=3) and Ligand B (HBD=3, HBA=4) both have reasonable H-bond counts, within the acceptable ranges.

**QED:** Ligand A (0.763) has a good drug-likeness score. Ligand B (0.387) is lower, indicating a less drug-like profile.

**DILI:** Both ligands have similar, low DILI risk (23.769 and 23.614 percentile).

**BBB:** Ligand B (63.862) has a better BBB penetration score than Ligand A (54.983), but both are below the desirable >70% for CNS targets.

**Caco-2 Permeability:** Ligand A (-4.785) has poor Caco-2 permeability, which is a concern. Ligand B (-5.489) is also poor, but slightly worse.

**Aqueous Solubility:** Both ligands have poor aqueous solubility (-2.553 and -1.809).

**hERG:** Both ligands have very low hERG inhibition liability (0.272 and 0.163).

**Microsomal Clearance:** Ligand B (-18.083) has significantly lower (better) microsomal clearance than Ligand A (30.777), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand B (-4.641) has a shorter half-life than Ligand A (4.191), which is less desirable.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.077 and 0.007).

**Binding Affinity:** Both ligands have very similar and strong binding affinities (-8.5 and -8.2 kcal/mol). The difference is less than 1.5 kcal/mol, so this isn't a major deciding factor.

**Overall Assessment:**

Ligand A has better TPSA and QED, but suffers from poor Caco-2 permeability and higher microsomal clearance. Ligand B has a better BBB score and significantly improved metabolic stability (lower Cl_mic), but has a lower logP and QED. Considering the GPCR-specific priorities, BBB and metabolic stability are crucial. While both BBB values are suboptimal, Ligand B's significantly improved metabolic stability is a major advantage for a CNS target. The slightly lower logP is a concern, but the strong binding affinity mitigates this to some extent.

Output:
1
2025-04-17 03:08:13,341 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (362.459 Da) and Ligand B (352.41 Da) are comparable.

**TPSA:** Ligand A (101.8) is slightly above the preferred <90 for CNS targets, but not drastically. Ligand B (84.42) is well within the desired range. This favors Ligand B.

**logP:** Both ligands have good logP values (Ligand A: 1.247, Ligand B: 1.935), falling within the optimal 1-3 range. Ligand B is slightly better.

**H-Bond Donors/Acceptors:** Ligand A (HBD=2, HBA=7) and Ligand B (HBD=1, HBA=5) both have acceptable numbers of H-bond donors and acceptors.

**QED:** Both ligands have good QED scores (Ligand A: 0.688, Ligand B: 0.811), indicating good drug-like properties. Ligand B is slightly better.

**DILI:** Ligand A (66.615) has a higher DILI risk than Ligand B (29.779). This is a significant advantage for Ligand B.

**BBB:** Ligand B (92.323) has a significantly higher BBB penetration percentile than Ligand A (53.16). This is *critical* for a CNS target like DRD2 and strongly favors Ligand B.

**Caco-2 Permeability:** Ligand A (-5.407) has poor Caco-2 permeability, while Ligand B (-4.36) is slightly better, but both are negative values indicating poor permeability.

**Aqueous Solubility:** Both ligands have poor aqueous solubility (-3.303 and -2.76 respectively).

**hERG:** Both ligands have low hERG inhibition liability (0.255 and 0.207 respectively), which is good.

**Microsomal Clearance:** Ligand A (17.712) has lower microsomal clearance than Ligand B (63.06), suggesting better metabolic stability. This favors Ligand A.

**In vitro Half-Life:** Ligand A (57.667) has a better in vitro half-life than Ligand B (-26.421). This favors Ligand A.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.134 and 0.012 respectively), which is good. Ligand B is slightly better.

**Binding Affinity:** Ligand A (-8.2 kcal/mol) has a slightly better binding affinity than Ligand B (-7.1 kcal/mol). This is a significant advantage for Ligand A. However, the difference is less than 1.5 kcal/mol, so it doesn't automatically outweigh other ADME concerns.

**Overall Assessment:**

While Ligand A has slightly better binding affinity and metabolic stability, Ligand B demonstrates a much more favorable ADME profile, particularly regarding BBB penetration (92.323 vs. 53.16) and DILI risk (29.779 vs. 66.615). For a CNS target like DRD2, BBB penetration is paramount. The lower DILI risk is also a significant advantage. The slightly weaker binding affinity of Ligand B can potentially be optimized in subsequent iterations of drug design.

Output:
1
2025-04-17 03:08:13,341 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (352.337 and 352.519 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (73.63) is significantly better than Ligand B (78.43). For CNS targets, we want TPSA <= 90, and A is closer to the optimal <= 60 range. B is pushing the upper limit.

**3. logP:** Ligand A (4.17) is higher than the optimal 1-3 range, but still potentially acceptable. Ligand B (2.19) is within the optimal range. However, for a GPCR, some lipophilicity is beneficial for membrane permeability, so A isn't severely penalized here.

**4. H-Bond Donors:** Ligand A (1) is preferable to Ligand B (3). Fewer HBDs generally improve permeability.

**5. H-Bond Acceptors:** Ligand A (5) is preferable to Ligand B (3). Fewer HBAs generally improve permeability.

**6. QED:** Ligand B (0.626) has a better QED score than Ligand A (0.416), indicating a more drug-like profile.

**7. DILI:** Ligand B (20.24) has a *much* lower DILI risk than Ligand A (76.503). This is a significant advantage for B.

**8. BBB:** Ligand A (71.074) has a better BBB penetration percentile than Ligand B (58.085). This is a critical factor for a CNS target like DRD2.

**9. Caco-2:** Both ligands have negative Caco-2 values (-4.618 and -4.725), which is unusual and suggests poor permeability. This is a concern for both.

**10. Solubility:** Both ligands have negative solubility values (-5.049 and -3.319), which is also unusual and suggests poor aqueous solubility. This is a concern for both.

**11. hERG:** Ligand A (0.875) has a slightly higher hERG risk than Ligand B (0.35). Lower is better.

**12. Cl_mic:** Ligand B (54.82) has a lower microsomal clearance than Ligand A (67.165), suggesting better metabolic stability.

**13. t1/2:** Ligand A (59.436) has a longer in vitro half-life than Ligand B (-13.125). This is a significant advantage for A.

**14. Pgp:** Ligand A (0.528) has a lower P-gp efflux liability than Ligand B (0.173), which is favorable for CNS penetration.

**15. Binding Affinity:** Both ligands have very similar and excellent binding affinities (-8.1 and -8.0 kcal/mol). The difference is negligible.

**Overall Assessment:**

Ligand B has a much better safety profile (DILI) and metabolic stability (Cl_mic). Ligand A has better BBB penetration and P-gp efflux, and a longer half-life. The TPSA for A is also more favorable. However, the substantial difference in DILI risk for Ligand B is a major advantage. While BBB is important, a high DILI risk can derail a drug candidate quickly. Given the similar affinities, the lower toxicity profile of Ligand B makes it the more promising candidate.

Output:
1
2025-04-17 03:08:13,341 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (353.463 and 348.399 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (94.81) is slightly above the preferred <90 for CNS targets, while Ligand B (88.85) is within the desirable range.

**logP:** Both ligands have a logP around 1.2-1.3, which is optimal for permeability and avoiding solubility issues.

**H-Bond Donors/Acceptors:** Ligand A has 3 HBD and 5 HBA, while Ligand B has 1 HBD and 5 HBA. Both are within acceptable limits.

**QED:** Ligand B (0.81) has a significantly better QED score than Ligand A (0.588), indicating a more drug-like profile.

**DILI:** Ligand A (11.516) has a much lower DILI risk than Ligand B (44.164), a significant advantage.

**BBB:** Ligand B (85.459) has a substantially higher BBB penetration percentile than Ligand A (25.514). This is *critical* for a CNS target like DRD2.

**Caco-2 Permeability:** Ligand A (-5.415) has a worse Caco-2 permeability than Ligand B (-4.428), indicating lower intestinal absorption.

**Aqueous Solubility:** Ligand A (-0.681) has slightly better solubility than Ligand B (-3.253).

**hERG:** Both ligands have very low hERG inhibition risk (0.438 and 0.409).

**Microsomal Clearance:** Ligand A (-9.536) exhibits much better metabolic stability (lower clearance) than Ligand B (51.527).

**In vitro Half-Life:** Ligand A (17.661) has a longer in vitro half-life than Ligand B (-8.524).

**P-gp Efflux:** Ligand A (0.031) shows lower P-gp efflux liability than Ligand B (0.133), which is beneficial for CNS exposure.

**Binding Affinity:** Both ligands have very similar and strong binding affinities (-7.7 and -8.1 kcal/mol). The difference is negligible.

**Conclusion:**

While Ligand A has advantages in DILI, metabolic stability, half-life, and P-gp efflux, Ligand B's significantly better BBB penetration (85.459 vs 25.514) is the deciding factor for a CNS target like DRD2. The higher QED score of Ligand B also contributes to its favorability. The slight drawbacks in DILI and metabolic stability of Ligand B are less concerning given the strong affinity and crucial CNS penetration.

Output:
1
2025-04-17 03:08:13,341 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (354.466 and 356.507 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (49.85) is significantly better than Ligand B (81.08). For CNS targets, we want TPSA <= 90, and A is comfortably within that range, while B is approaching the upper limit.

**3. logP:** Both ligands have acceptable logP values (2.557 and 1.641), falling within the 1-3 optimal range.

**4. H-Bond Donors:** Ligand A (0) is preferable to Ligand B (2). Fewer HBDs generally improve permeability.

**5. H-Bond Acceptors:** Ligand A (3) is preferable to Ligand B (4).

**6. QED:** Both ligands have good QED scores (0.497 and 0.658), indicating reasonable drug-likeness. Ligand B is slightly better.

**7. DILI:** Ligand A (8.298) has a slightly higher DILI risk than Ligand B (5.971), but both are below the concerning threshold of 40.

**8. BBB:** This is a critical parameter for a CNS target like DRD2. Ligand A (91.508) has a *much* higher BBB percentile than Ligand B (61.225). This is a major advantage for A.

**9. Caco-2 Permeability:** Both have negative values (-4.47 and -4.656). This is unusual and suggests poor permeability. However, the scale isn't defined, so it's hard to interpret.

**10. Aqueous Solubility:** Both have negative values (-2.15 and -1.159). Similar to Caco-2, this is concerning and suggests poor solubility.

**11. hERG:** Both ligands have low hERG risk (0.618 and 0.544), which is good.

**12. Microsomal Clearance:** Ligand A (26.994) has lower microsomal clearance than Ligand B (28.258), indicating better metabolic stability.

**13. In vitro Half-Life:** Ligand A (3.237) has a longer half-life than Ligand B (-14.011). The negative value for B is concerning and likely an error or indicates very rapid metabolism.

**14. P-gp Efflux:** Both have low P-gp efflux liability (0.128 and 0.106), which is favorable for CNS penetration.

**15. Binding Affinity:** Both ligands have excellent binding affinities (-7.3 and -7.0 kcal/mol). The difference of 0.3 kcal/mol is not substantial enough to outweigh other factors.

**Overall Assessment:**

Ligand A is significantly more promising due to its superior BBB penetration (91.5% vs 61.2%), lower TPSA (49.85 vs 81.08), fewer H-bonds, better metabolic stability (lower Cl_mic), and longer half-life. While both have issues with Caco-2 and solubility, the CNS target prioritization makes BBB the most important factor here, and A clearly wins.

Output:
1
2025-04-17 03:08:13,342 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (357.451 and 350.463 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (96.97) is slightly higher than Ligand B (78.67). Both are below the 140 A^2 threshold for oral absorption, and importantly, below the 90 A^2 threshold preferred for CNS targets. Ligand B is better here.

**3. logP:** Ligand A (-0.083) is a bit low, potentially hindering permeability. Ligand B (1.274) is within the optimal 1-3 range. Ligand B is significantly better.

**4. H-Bond Donors:** Ligand A (2) and Ligand B (1) are both acceptable (<=5). Ligand B is slightly better.

**5. H-Bond Acceptors:** Both ligands (5) are within the acceptable range (<=10).

**6. QED:** Both ligands have good QED scores (0.621 and 0.766, both >=0.5).

**7. DILI:** Both ligands have low DILI risk (25.281 and 24.234, both <40).

**8. BBB:** Ligand A (55.642) and Ligand B (50.911) are both below the desirable >70 percentile for CNS targets. This is a significant drawback for both, but they are relatively close.

**9. Caco-2:** Both have negative Caco-2 values (-4.662 and -4.926) which is unusual and suggests poor permeability.

**10. Solubility:** Both have negative solubility values (-0.694 and -0.749) which is also unusual and suggests poor solubility.

**11. hERG:** Both ligands have very low hERG risk (0.061 and 0.226).

**12. Cl_mic:** Ligand A (31.024) has a higher microsomal clearance than Ligand B (25.754), indicating lower metabolic stability. Ligand B is better.

**13. t1/2:** Ligand B (8.619) has a significantly longer in vitro half-life than Ligand A (-8.351). This is a major advantage for Ligand B.

**14. Pgp:** Both have very low Pgp efflux liability (0.006 and 0.073).

**15. Binding Affinity:** Ligand A (-7.2 kcal/mol) has a slightly better binding affinity than Ligand B (-6.8 kcal/mol). This is a 0.4 kcal/mol difference, which is notable but not overwhelmingly decisive.

**Overall Assessment:**

Considering the GPCR-specific priorities, Ligand B is the better candidate. While both have poor BBB penetration and permeability/solubility, Ligand B has a more favorable logP, better metabolic stability (lower Cl_mic, longer t1/2), and a slightly better overall profile. The slightly stronger binding affinity of Ligand A is not enough to overcome the ADME deficiencies compared to Ligand B.

Output:
1
2025-04-17 03:08:13,342 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (350.384 and 348.403 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (36.1) is excellent, well below the 90 A^2 threshold for CNS targets. Ligand B (96.69) is significantly higher, exceeding the preferred range and potentially hindering BBB penetration.

**logP:** Ligand A (4.604) is slightly high, potentially leading to solubility issues or off-target interactions, but still within a manageable range. Ligand B (0.216) is very low, which is problematic for membrane permeability and CNS penetration.

**H-Bond Donors/Acceptors:** Ligand A (1 HBD, 1 HBA) is optimal. Ligand B (2 HBD, 6 HBA) is acceptable, but the higher HBA count could slightly impact permeability.

**QED:** Both ligands have similar QED values (0.789 and 0.793), indicating good drug-likeness.

**DILI:** Ligand A (61.807) has a slightly higher DILI risk than Ligand B (58.24), but both are reasonably acceptable.

**BBB:** This is a critical parameter for a CNS target like DRD2. Ligand A shows excellent BBB penetration (96.316%), while Ligand B is very poor (13.222%).

**Caco-2 Permeability:** Ligand A (-4.731) shows poor Caco-2 permeability. Ligand B (-5.169) is also poor.

**Aqueous Solubility:** Ligand A (-5.072) has poor solubility, which is a concern given its high logP. Ligand B (-1.328) is also poor, but slightly better than Ligand A.

**hERG Inhibition:** Ligand A (0.862) has a low hERG risk, which is good. Ligand B (0.068) has a very low hERG risk, which is excellent.

**Microsomal Clearance:** Ligand A (23.344) has moderate clearance, suggesting moderate metabolic stability. Ligand B (11.525) has lower clearance, indicating better metabolic stability.

**In vitro Half-Life:** Ligand A (-2.862) has a negative half-life, which is not possible. This is likely an error in the data. Ligand B (8.421) has a reasonable half-life.

**P-gp Efflux:** Ligand A (0.641) has moderate P-gp efflux liability. Ligand B (0.019) has very low P-gp efflux liability, which is highly desirable for CNS penetration.

**Binding Affinity:** Ligand B (-8.4 kcal/mol) has significantly stronger binding affinity than Ligand A (0.0 kcal/mol). This is a substantial advantage.

**Overall Assessment:**

Ligand B is the superior candidate. While both have issues with Caco-2 permeability and solubility, Ligand B's significantly better binding affinity, lower logP, lower P-gp efflux, and vastly superior BBB penetration outweigh the slightly better DILI profile of Ligand A. The negative half-life for Ligand A is also a major red flag. The high logP of Ligand A, combined with poor solubility and Caco-2 permeability, suggests it will have poor bioavailability. Ligand B, despite its higher TPSA, is much more likely to reach the target in the brain due to its favorable BBB and P-gp properties.

Output:
1
2025-04-17 03:08:13,342 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (343.427 Da) is slightly lower, which is generally favorable for permeability.

**2. TPSA:** Ligand A (73.74) is better than Ligand B (49.15) as it is closer to the ideal range for CNS targets (<=90). Ligand B is quite low, which *could* indicate poor interactions.

**3. logP:** Ligand A (1.081) is within the optimal range (1-3). Ligand B (4.64) is high, potentially leading to solubility issues and off-target interactions.

**4. H-Bond Donors:** Ligand A (1) is good. Ligand B (0) is acceptable.

**5. H-Bond Acceptors:** Ligand A (4) is good. Ligand B (5) is acceptable.

**6. QED:** Ligand A (0.891) is excellent, indicating high drug-likeness. Ligand B (0.703) is still good, but lower.

**7. DILI:** Ligand A (25.436) has a significantly lower DILI risk than Ligand B (31.601).

**8. BBB:** Both ligands have good BBB penetration (Ligand A: 70.609, Ligand B: 76.464), exceeding the 70% threshold for CNS targets. Ligand B is slightly better.

**9. Caco-2 Permeability:** Both have negative values, which is unusual. Assuming these are logP values, they indicate poor permeability. Ligand A (-4.632) is worse than Ligand B (-4.359).

**10. Aqueous Solubility:** Ligand A (-1.798) is better than Ligand B (-5.542), indicating better solubility.

**11. hERG Inhibition:** Ligand A (0.276) has a lower hERG risk than Ligand B (0.867).

**12. Microsomal Clearance:** Ligand A (17.753) has lower clearance, suggesting better metabolic stability than Ligand B (76.525).

**13. In vitro Half-Life:** Ligand B (7.11) has a longer half-life than Ligand A (-2.48).

**14. P-gp Efflux:** Ligand A (0.118) has lower P-gp efflux, which is favorable for CNS exposure. Ligand B (0.587) is higher.

**15. Binding Affinity:** Ligand A (-9.6 kcal/mol) has a significantly stronger binding affinity than Ligand B (-7.0 kcal/mol). This is a substantial difference (>1.5 kcal/mol advantage).

**Overall Assessment:**

Ligand A is the better candidate. While Ligand B has a slightly better BBB penetration and *in vitro* half-life, Ligand A excels in most critical parameters. It has a better logP, TPSA, QED, DILI risk, solubility, hERG risk, metabolic stability, P-gp efflux, and *significantly* better binding affinity. The strong binding affinity of Ligand A can likely compensate for the slightly lower Caco-2 permeability and shorter half-life. The lower logP and TPSA of Ligand A are also more favorable for CNS penetration and reducing off-target effects.

Output:
0
2025-04-17 03:08:13,342 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (346.341 and 366.527 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (90.76) is slightly above the preferred <90 for CNS targets, but still reasonable. Ligand B (66.48) is excellent, well below 90.

**3. logP:** Both ligands have good logP values (1.957 and 2.85), falling within the optimal 1-3 range.

**4. H-Bond Donors:** Ligand A (2) and Ligand B (1) are both within the acceptable limit of <=5.

**5. H-Bond Acceptors:** Ligand A (6) and Ligand B (3) are both within the acceptable limit of <=10.

**6. QED:** Both ligands have good QED scores (0.755 and 0.807), indicating good drug-like properties.

**7. DILI:** Ligand A (82.823) has a higher DILI risk than Ligand B (38.193). This is a significant negative for Ligand A.

**8. BBB:** Ligand B (78.209) has a better BBB percentile than Ligand A (66.925). While both are reasonably good, exceeding 70 is desirable for CNS targets, and Ligand B is closer.

**9. Caco-2:** Both ligands have negative Caco-2 values, which is unusual and suggests a potential issue with the data or a very poor permeability. However, we'll proceed assuming these are percentile scores and lower is worse. Ligand A (-5.079) is worse than Ligand B (-4.441).

**10. Solubility:** Both ligands have negative solubility values, again unusual. Ligand A (-2.784) is worse than Ligand B (-3.37).

**11. hERG:** Both ligands have low hERG inhibition liability (0.416 and 0.711), which is good.

**12. Cl_mic:** Ligand A (8.264) has significantly lower microsomal clearance than Ligand B (29.645), indicating better metabolic stability.

**13. t1/2:** Ligand B (38.639) has a longer in vitro half-life than Ligand A (13.816), which is preferable.

**14. Pgp:** Ligand A (0.084) has significantly lower P-gp efflux liability than Ligand B (0.308), which is a major advantage for CNS penetration.

**15. Binding Affinity:** Ligand A (-9.1 kcal/mol) has a slightly better binding affinity than Ligand B (-8.2 kcal/mol). This 0.9 kcal/mol difference is substantial and could outweigh some ADME drawbacks.

**Overall Assessment:**

Ligand A has a better binding affinity and lower Pgp efflux, which are highly desirable for a CNS GPCR target like DRD2. However, it has a significantly higher DILI risk, worse Caco-2 and solubility, and a shorter half-life. Ligand B excels in BBB penetration, has a lower DILI risk, and a longer half-life, but its affinity is slightly weaker and Pgp efflux is higher.

Considering the GPCR-specific priorities, BBB and affinity are key. While Ligand A's affinity is better, the higher DILI risk and poorer BBB penetration are concerning. The slightly better affinity of Ligand A is likely outweighed by the more favorable ADME profile of Ligand B, particularly the lower DILI and better BBB.

Output:
1
2025-04-17 03:08:13,342 - INFO - Reasoning:

Let's analyze Ligand A and Ligand B based on the provided guidelines, prioritizing GPCR-specific properties (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (335.363 Da) is slightly lower, which could be advantageous for permeability.

**TPSA:** Ligand A (74.91) is significantly better than Ligand B (80.12). For CNS targets, TPSA should be <= 90, and both meet this, but A is closer to the optimal range.

**logP:** Both ligands have good logP values (A: 2.689, B: 1.42), falling within the 1-3 range.

**H-Bond Donors/Acceptors:** Both have acceptable HBD (1) and Ligand A has 4 HBA, while Ligand B has 6. Both are within reasonable limits.

**QED:** Both ligands have similar QED values (A: 0.798, B: 0.731), indicating good drug-likeness.

**DILI:** Ligand A (90.461) has a higher DILI risk than Ligand B (54.75). This is a significant drawback for Ligand A.

**BBB:** Ligand A (65.219) has a better BBB penetration percentile than Ligand B (45.366). This is crucial for a CNS target like DRD2.

**Caco-2 Permeability:** Ligand A (-4.889) has worse Caco-2 permeability than Ligand B (-5.322), indicating lower intestinal absorption.

**Aqueous Solubility:** Ligand A (-3.272) has worse aqueous solubility than Ligand B (-1.459).

**hERG:** Both ligands have very low hERG inhibition liability (A: 0.096, B: 0.134).

**Microsomal Clearance:** Ligand A (20.526) has a lower microsomal clearance than Ligand B (46.17), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand B (28.108) has a longer in vitro half-life than Ligand A (11.27).

**P-gp Efflux:** Both ligands have low P-gp efflux liability (A: 0.088, B: 0.014). Ligand B is slightly better.

**Binding Affinity:** Ligand B (-7.2 kcal/mol) has a significantly stronger binding affinity than Ligand A (-9.3 kcal/mol). This is a substantial advantage.

**Overall Assessment:**

Ligand B is the better candidate. While Ligand A has a slightly better TPSA and lower Cl_mic, Ligand B's significantly stronger binding affinity (-7.2 vs -9.3 kcal/mol) outweighs the minor ADME drawbacks. The improved BBB penetration, lower DILI risk, and longer half-life of Ligand B are also significant advantages for a CNS-targeting drug.

Output:
1
2025-04-17 03:08:13,343 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (344.455 and 340.387 Da) fall within the ideal range of 200-500 Da.

**TPSA:** Ligand A (61.31) is significantly better than Ligand B (85.43). For CNS targets, we want TPSA <= 90, and ideally closer to 60. Ligand A is much closer to this ideal.

**logP:** Ligand A (3.693) is optimal (1-3), while Ligand B (0.469) is quite low, potentially hindering membrane permeability.

**H-Bond Donors/Acceptors:** Both have acceptable HBD/HBA counts (A: 0/5, B: 1/5), within the guidelines.

**QED:** Both have good QED scores (A: 0.78, B: 0.878), indicating drug-like properties.

**DILI:** Ligand A (35.595) has a lower DILI risk than Ligand B (53.703), both being acceptable, but A is preferable.

**BBB:** This is critical for a CNS target. Ligand A (88.174) has excellent BBB penetration, while Ligand B (33.075) is poor.

**Caco-2 Permeability:** Ligand A (-4.937) and Ligand B (-5.036) both have negative values, which is unusual. Assuming these are logP-like scales, lower values indicate poorer permeability. However, the difference is minimal.

**Aqueous Solubility:** Both ligands have poor aqueous solubility (-3.112 and -2.719 respectively). This could pose formulation challenges, but is less critical than BBB penetration for a CNS target.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (A: 0.391, B: 0.532).

**Microsomal Clearance:** Ligand B (-4.836) has a negative clearance, which is not physically possible. This is likely an error or a different scale. Ligand A (61.659) has a reasonable clearance.

**In vitro Half-Life:** Ligand B (11.042) has a better half-life than Ligand A (-0.517). However, the negative half-life for A is likely an error.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (A: 0.396, B: 0.002). Ligand B is slightly better here.

**Binding Affinity:** Both ligands have excellent binding affinity (A: -9.5 kcal/mol, B: -8.7 kcal/mol). Ligand A is slightly better, but the difference is not huge.

**Overall Assessment:**

Ligand A is significantly better due to its superior BBB penetration (88.174 vs 33.075), optimal logP (3.693 vs 0.469), and lower DILI risk. While Ligand B has a slightly better P-gp efflux and in vitro half-life, the poor BBB penetration and low logP are major drawbacks for a CNS-targeting drug. The negative clearance and half-life values for Ligand A are suspect and should be verified, but even with those considered problematic, the other advantages of Ligand A make it the more promising candidate.

Output:
1
2025-04-17 03:08:13,343 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B based on the provided guidelines, prioritizing GPCR-specific properties (BBB, logP, Pgp, TPSA, and affinity) for DRD2.

**Molecular Weight:** Both ligands (361.471 and 343.427 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (69.95) is significantly better than Ligand B (75.44) as it is closer to the <90 A^2 threshold for CNS targets.

**logP:** Both ligands have acceptable logP values (1.068 and 2.325), falling within the optimal 1-3 range. Ligand B is slightly higher, which could potentially lead to some solubility issues, but is still within an acceptable range.

**H-Bond Donors/Acceptors:** Both ligands have 1 HBD and reasonable HBA counts (6 and 4 respectively), satisfying the <5 HBD and <10 HBA guidelines.

**QED:** Both ligands have good QED scores (0.888 and 0.805), indicating good drug-like properties.

**DILI:** Both ligands have relatively low DILI risk (47.926 and 40.403), below the 60 threshold.

**BBB:** Ligand B (70.997) has a significantly better BBB penetration score than Ligand A (43.273). This is a crucial advantage for a CNS target like DRD2.

**Caco-2 Permeability:** Both have negative Caco-2 values (-5.139 and -4.837), which is unusual and difficult to interpret without knowing the scale. However, since both are similarly negative, this doesn't strongly favor either.

**Aqueous Solubility:** Both ligands have negative solubility values (-1.542 and -3.23), again unusual. Ligand B has worse solubility.

**hERG Inhibition:** Both ligands have low hERG inhibition liability (0.588 and 0.274), which is good.

**Microsomal Clearance:** Ligand A (-16.049) has a much lower (better) microsomal clearance than Ligand B (34.784). This suggests better metabolic stability for Ligand A.

**In vitro Half-Life:** Ligand B (-3.142) has a longer in vitro half-life than Ligand A (1.758), which is favorable.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.048 and 0.131), which is good for CNS penetration.

**Binding Affinity:** Both ligands have the same binding affinity (-8.2 kcal/mol), which is excellent.

**Overall Assessment:**

While Ligand A has better TPSA and metabolic stability (lower Cl_mic), Ligand B stands out due to its significantly higher BBB penetration (70.997 vs 43.273). Given that DRD2 is a CNS target, BBB penetration is paramount. The slightly worse solubility of Ligand B is a concern, but the strong BBB score outweighs this drawback, especially given the excellent binding affinity shared by both.

Output:
1
2025-04-17 03:08:13,344 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (361.4 and 348.5 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Both ligands have TPSA values around 105, slightly above the optimal <90 for CNS targets, but not drastically so.

**3. logP:** Ligand A (2.193) is within the optimal 1-3 range. Ligand B (-0.851) is below 1, which could hinder permeation. This is a significant negative for Ligand B.

**4. H-Bond Donors:** Both ligands have 3 HBD, which is acceptable.

**5. H-Bond Acceptors:** Ligand A has 3 HBA, while Ligand B has 6. Both are within the acceptable range of <=10, but Ligand A is preferable.

**6. QED:** Both ligands have similar QED values (0.663 and 0.643), indicating good drug-likeness.

**7. DILI:** Ligand A (93.5%) has a high DILI risk, which is concerning. Ligand B (14.7%) has a very low DILI risk, a major advantage.

**8. BBB:** Ligand A (52.2%) has a moderate BBB penetration, while Ligand B (35.1%) is lower. Both are below the desirable >70% for CNS targets, but Ligand A is better.

**9. Caco-2 Permeability:** Ligand A (-5.39) and Ligand B (-6.03) both have negative Caco-2 values, which is unusual and suggests poor permeability.

**10. Aqueous Solubility:** Ligand A (-3.54) and Ligand B (-0.34) both have negative solubility values, indicating poor solubility.

**11. hERG Inhibition:** Ligand A (0.43) has a low hERG risk, while Ligand B (0.19) has an even lower risk. Both are good.

**12. Microsomal Clearance:** Ligand A (8.26) has a moderate clearance, while Ligand B (-37.1) has a very low (and likely favorable) clearance, indicating high metabolic stability.

**13. In vitro Half-Life:** Ligand A (28.9) has a moderate half-life, while Ligand B (2.1) has a very short half-life. Ligand A is significantly better.

**14. P-gp Efflux:** Ligand A (0.18) has low P-gp efflux, which is favorable for CNS penetration. Ligand B (0.004) has extremely low P-gp efflux, an even greater advantage.

**15. Binding Affinity:** Ligand A (-10.2 kcal/mol) has a significantly stronger binding affinity than Ligand B (-7.9 kcal/mol). This is a substantial advantage for Ligand A, potentially outweighing some of its ADME liabilities.

**Overall Assessment:**

Ligand A has a much stronger binding affinity, better BBB penetration, and a longer half-life. However, it has a high DILI risk and moderate clearance. Ligand B has a very low DILI risk and excellent metabolic stability (low clearance, low P-gp efflux), but its logP is suboptimal, its BBB penetration is low, and its binding affinity is significantly weaker.

Given the importance of affinity for GPCRs, and the fact that the difference in binding energy is substantial (2.3 kcal/mol), Ligand A is the more promising candidate *despite* its DILI risk. The DILI risk could potentially be mitigated through structural modifications. The low logP of Ligand B is a more difficult property to improve without significantly altering the binding pose.

Output:
1
2025-04-17 03:08:13,344 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (350.39 and 354.378 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (78.87) is significantly better than Ligand B (84.94). For CNS targets, we want TPSA <= 90, and A is closer to the ideal.

**logP:** Both ligands have good logP values (2.085 and 1.039), falling within the optimal 1-3 range. Ligand A is slightly better.

**H-Bond Donors/Acceptors:** Ligand A (HBD=2, HBA=4) and Ligand B (HBD=1, HBA=5) both have reasonable numbers of H-bond donors and acceptors, within the guidelines.

**QED:** Both ligands have acceptable QED values (0.871 and 0.705), indicating good drug-likeness.

**DILI:** Ligand A (35.983) has a lower DILI risk than Ligand B (41.993), which is preferable. Both are below the concerning threshold of 60.

**BBB:** This is a crucial parameter for a CNS target like DRD2. Ligand A (73.75) has a significantly better BBB percentile than Ligand B (66.111). A value >70 is desirable, and A is closer.

**Caco-2 Permeability:** Ligand A (-5.017) has better Caco-2 permeability than Ligand B (-4.463). Higher values indicate better absorption.

**Aqueous Solubility:** Ligand A (-3.952) has better aqueous solubility than Ligand B (-1.809).

**hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.483 and 0.153), which is excellent.

**Microsomal Clearance:** Ligand A (16.745) has a lower microsomal clearance than Ligand B (61.758), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (10.658) has a longer in vitro half-life than Ligand B (-16.526). This is a significant advantage.

**P-gp Efflux:** Ligand A (0.055) has lower P-gp efflux liability than Ligand B (0.029), which is preferable for CNS penetration.

**Binding Affinity:** Both ligands have excellent binding affinity (-8.1 and -8.0 kcal/mol). The difference is minimal.

**Overall Assessment:**

Ligand A consistently outperforms Ligand B across most key ADME properties, particularly BBB penetration, metabolic stability (Cl_mic and t1/2), and solubility. While both have good affinity, the superior ADME profile of Ligand A makes it the more promising drug candidate for targeting DRD2.

Output:
1
2025-04-17 03:08:13,345 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (366.389 and 368.459 Da) are within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (66.48) is significantly better than Ligand B (116.4). For CNS targets, we want TPSA <= 90, and A is comfortably within that range, while B exceeds it. This is a significant advantage for A.

**3. logP:** Ligand A (2.816) is optimal (1-3), while Ligand B (0.916) is a bit low, potentially hindering permeation.

**4. H-Bond Donors:** Ligand A (1) is good. Ligand B (4) is higher, potentially impacting permeability.

**5. H-Bond Acceptors:** Ligand A (3) is good. Ligand B (4) is acceptable, but slightly less favorable.

**6. QED:** Both ligands have reasonable QED values (0.905 and 0.546), with A being superior.

**7. DILI:** Ligand A (79.139) has a higher DILI risk than Ligand B (49.632), but both are below the concerning threshold of 60.

**8. BBB:** Ligand A (69.407) and Ligand B (65.452) are both reasonably good, but below the desirable >70 for CNS targets. A is slightly better.

**9. Caco-2:** Ligand A (-4.644) and Ligand B (-5.349) both have negative values, which is unusual and suggests poor Caco-2 permeability. This is a concern for both.

**10. Solubility:** Ligand A (-3.996) and Ligand B (-2.752) both have negative values, indicating poor aqueous solubility. This is a concern for both.

**11. hERG:** Ligand A (0.702) is better than Ligand B (0.242), indicating a lower risk of hERG inhibition.

**12. Cl_mic:** Ligand A (23.14) has a lower microsomal clearance than Ligand B (30.971), suggesting better metabolic stability.

**13. t1/2:** Ligand A (60.245) has a significantly longer in vitro half-life than Ligand B (-16.329). This is a major advantage for A.

**14. Pgp:** Ligand A (0.416) has lower P-gp efflux liability than Ligand B (0.01), which is beneficial for CNS penetration.

**15. Binding Affinity:** Ligand A (-9.6) has a substantially stronger binding affinity than Ligand B (-8.4). This difference of 1.2 kcal/mol is significant and can outweigh some of the ADME drawbacks.

**Overall Assessment:**

Ligand A is the stronger candidate. While both have issues with Caco-2 permeability and solubility, Ligand A excels in key areas for a CNS-targeting GPCR ligand: TPSA, logP, metabolic stability (Cl_mic, t1/2), Pgp efflux, and, crucially, binding affinity. The significantly stronger binding affinity (-9.6 vs -8.4 kcal/mol) is a decisive factor. Although Ligand A has a higher DILI risk, it's still within an acceptable range.

Output:
1
2025-04-17 03:08:13,345 - INFO - Batch 3 complete. Total preferences: 48
2025-04-17 03:08:13,345 - INFO - Processing batch 4/512...
2025-04-17 03:08:52,328 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (352.36 and 356.482 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (61.02) is slightly higher than Ligand B (58.64). Both are below the 90 A^2 threshold for CNS targets, which is good.

**3. logP:** Ligand A (4.278) is a bit high, potentially leading to solubility issues. Ligand B (2.826) is within the optimal 1-3 range. This favors Ligand B.

**4. H-Bond Donors:** Ligand A (2) and Ligand B (1) are both acceptable, well below the 5 limit.

**5. H-Bond Acceptors:** Ligand A (2) and Ligand B (3) are both acceptable, below the 10 limit.

**6. QED:** Both ligands have reasonable QED values (0.863 and 0.727), indicating good drug-like properties.

**7. DILI:** Ligand A (52.579) has a higher DILI risk than Ligand B (19.698). This strongly favors Ligand B.

**8. BBB:** Ligand B (96.161) has a significantly higher BBB penetration percentile than Ligand A (85.576). This is a crucial advantage for a CNS target like DRD2.

**9. Caco-2 Permeability:** Both have negative values, which is unusual. Assuming these are logP-like scales, lower values indicate poorer permeability. Ligand A (-4.707) is worse than Ligand B (-4.406).

**10. Aqueous Solubility:** Both have negative values, indicating very poor solubility. Ligand B (-2.69) is slightly better than Ligand A (-5.124).

**11. hERG Inhibition:** Both ligands have low hERG inhibition risk (0.611 and 0.678).

**12. Microsomal Clearance:** Ligand B (14.068) has lower microsomal clearance than Ligand A (36.725), suggesting better metabolic stability. This favors Ligand B.

**13. In vitro Half-Life:** Ligand B (-1.932) has a slightly better (less negative) in vitro half-life than Ligand A (-14.354).

**14. P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.279 and 0.193).

**15. Binding Affinity:** Ligand A (-8.8 kcal/mol) has a slightly better binding affinity than Ligand B (-8.2 kcal/mol). However, the difference is relatively small (0.6 kcal/mol) and can be overcome by other favorable ADME properties.

**Overall Assessment:**

Ligand B is the superior candidate. While Ligand A has slightly better binding affinity, Ligand B excels in crucial ADME properties for a CNS-targeting GPCR: significantly better BBB penetration, lower DILI risk, better metabolic stability (lower Cl_mic), and slightly better solubility and half-life. The logP value for Ligand B is also more optimal. The small affinity difference is outweighed by these substantial ADME advantages.

Output:
1
2025-04-17 03:08:52,329 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (349.475 and 350.463 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (78.51) is better than Ligand B (80.48). Both are below 90, which is good for CNS penetration, but A is closer to the optimal range.

**3. logP:** Both ligands have good logP values (1.777 and 1.57), falling within the 1-3 range.

**4. H-Bond Donors:** Ligand A (2) is slightly better than Ligand B (1). Both are within the acceptable limit of 5.

**5. H-Bond Acceptors:** Ligand B (6) is higher than Ligand A (3). Both are within the acceptable limit of 10.

**6. QED:** Ligand B (0.807) has a significantly better QED score than Ligand A (0.543), indicating a more drug-like profile.

**7. DILI:** Ligand A (27.724) has a lower DILI risk than Ligand B (38.813), which is favorable.

**8. BBB:** Ligand B (64.211) has a better BBB penetration percentile than Ligand A (53.121). While both are not ideal (>70), B is closer. This is a critical factor for a CNS target like DRD2.

**9. Caco-2 Permeability:** Ligand A (-5.06) has better Caco-2 permeability than Ligand B (-4.848).

**10. Aqueous Solubility:** Ligand A (-2.367) has better aqueous solubility than Ligand B (-1.891).

**11. hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.084 and 0.128).

**12. Microsomal Clearance:** Ligand B (27.521) has slightly lower microsomal clearance than Ligand A (28.504), suggesting better metabolic stability.

**13. In vitro Half-Life:** Ligand B (-9.55) has a significantly longer in vitro half-life than Ligand A (-1.955).

**14. P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.03 and 0.154).

**15. Binding Affinity:** Ligand B (-8.1) has a slightly better binding affinity than Ligand A (-7.8). While the difference is small, it's still a positive for Ligand B.

**Overall Assessment:**

Ligand B is slightly favored. While Ligand A has better solubility and Caco-2 permeability, Ligand B excels in crucial areas for CNS drug development: a significantly better QED score, better BBB penetration, longer half-life, and slightly better binding affinity. The slightly higher DILI risk for Ligand B is a concern, but the improvements in other key parameters outweigh this drawback. The improved BBB penetration and half-life are particularly important for DRD2, a CNS target.

Output:
1
2025-04-17 03:08:52,330 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 drug candidates, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (403.28 Da and 387.571 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (69.04) is slightly above the optimal <90 for CNS targets, but still reasonable. Ligand B (61.88) is well within the desired range.

**3. logP:** Ligand A (3.873) is at the higher end of the optimal 1-3 range, potentially raising concerns about solubility and off-target effects. Ligand B (1.729) is excellent, falling comfortably within the optimal range.

**4. H-Bond Donors:** Both ligands have 1 HBD, which is within the acceptable limit of <=5.

**5. H-Bond Acceptors:** Both ligands have 6 HBA, also within the acceptable limit of <=10.

**6. QED:** Both ligands have similar QED values (0.479 and 0.48), indicating moderate drug-likeness. Improvement would be desirable, but not a major concern at this stage.

**7. DILI:** Ligand A has a significantly higher DILI risk (79.721%) compared to Ligand B (21.132%). This is a major red flag for Ligand A.

**8. BBB:** Both ligands have good BBB penetration (68.903% and 64.87%), but neither exceeds the desirable >70% threshold.

**9. Caco-2 Permeability:** Both show negative values, which is unusual. Assuming these are logP-scale values, they indicate poor permeability.

**10. Aqueous Solubility:** Both ligands have negative solubility values, indicating poor solubility.

**11. hERG Inhibition:** Ligand A (0.767) shows a slightly higher risk of hERG inhibition than Ligand B (0.238), but both are relatively low.

**12. Microsomal Clearance:** Ligand A (113.21) has a much higher microsomal clearance than Ligand B (4.325), suggesting lower metabolic stability.

**13. In vitro Half-Life:** Ligand A (77.415) has a better in vitro half-life than Ligand B (20.203).

**14. P-gp Efflux:** Ligand A (0.535) has slightly lower P-gp efflux than Ligand B (0.011), which is favorable for CNS penetration.

**15. Binding Affinity:** Ligand A (-8.5 kcal/mol) has a significantly stronger binding affinity than Ligand B (-7.1 kcal/mol). This is a substantial advantage.

**Overall Assessment:**

Despite the stronger binding affinity of Ligand A, its significantly higher DILI risk and higher microsomal clearance are major drawbacks. The slightly higher logP also raises concerns. Ligand B, while having a slightly weaker affinity, presents a much more favorable ADMET profile, particularly regarding safety (DILI) and metabolic stability. For a CNS target like DRD2, a balance between potency and a good safety/ADME profile is crucial. The affinity difference of 1.4 kcal/mol, while noticeable, is likely outweighed by the substantial safety and metabolic concerns surrounding Ligand A.

Output:
1
2025-04-17 03:08:52,330 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (360.401 and 365.499 Da) fall within the ideal range of 200-500 Da.

**TPSA:** Ligand A (59.08) is significantly better than Ligand B (71.53). For CNS targets, we want TPSA <= 90, and A is much closer to the preferred <=60 range. B is still within the acceptable range, but less optimal.

**logP:** Both ligands have acceptable logP values (1.147 and 2.475, respectively), falling within the 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A (0 HBD, 4 HBA) is more favorable than Ligand B (1 HBD, 5 HBA). Lower counts are generally preferred for BBB penetration.

**QED:** Ligand B (0.87) has a higher QED score than Ligand A (0.579), indicating a more drug-like profile overall.

**DILI:** Ligand A (34.277) has a much lower DILI risk than Ligand B (48.081), suggesting a better safety profile. Both are below the concerning threshold of 60.

**BBB:** Ligand A (84.451) has a significantly higher BBB penetration percentile than Ligand B (79.372). While both are good, A is closer to the desirable >70 mark for CNS targets.

**Caco-2 Permeability:** Both have negative values (-4.258 and -4.669), which is unusual and suggests these are likely reported as logP values instead of permeability. Assuming they are logP values, they are both within the acceptable range.

**Aqueous Solubility:** Both ligands have very poor aqueous solubility (-2.04 and -3.867). This is a significant drawback for both.

**hERG Inhibition:** Both ligands show low hERG inhibition liability (0.499 and 0.507), which is good.

**Microsomal Clearance:** Ligand B (60.895) has a higher microsomal clearance than Ligand A (22.731), indicating faster metabolism and potentially lower *in vivo* exposure.

**In vitro Half-Life:** Ligand A (-31.496) has a much longer in vitro half-life than Ligand B (-18.284).

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.044 and 0.326), which is favorable for CNS penetration.

**Binding Affinity:** Ligand B (-8.4 kcal/mol) has a significantly stronger binding affinity than Ligand A (-6.7 kcal/mol). This is a substantial advantage, potentially outweighing some of the ADME drawbacks. A difference of >1.5 kcal/mol is considered significant.

**Conclusion:**

Despite Ligand B's stronger binding affinity, Ligand A is the more promising candidate. The significantly better TPSA, BBB, DILI, microsomal clearance, and half-life, coupled with acceptable logP and hERG values, make it a more balanced and potentially viable drug candidate for a CNS target like DRD2. While solubility is poor for both, the other ADME properties of Ligand A are more favorable. The affinity difference is substantial, but the other properties of A are more likely to translate to *in vivo* efficacy.

Output:
0
2025-04-17 03:08:52,330 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (341.415 and 364.833 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (87.22) is slightly higher than Ligand B (80.37), but both are below the 90 A^2 threshold desirable for CNS targets.

**logP:** Both ligands have logP values (2.316 and 2.48) within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A has 2 HBD and 5 HBA, while Ligand B has 1 HBD and 5 HBA. Both are within acceptable limits (<=5 HBD and <=10 HBA).

**QED:** Both ligands have good QED scores (0.842 and 0.903), indicating good drug-like properties.

**DILI:** Both ligands have DILI risk around 63-65, indicating moderate risk. This isn't a major differentiating factor.

**BBB:** This is a critical parameter for CNS targets. Ligand A has a BBB percentile of 58.007, while Ligand B has 35.052. Ligand A is significantly better in this regard.

**Caco-2 Permeability:** Both have negative Caco-2 values (-5.047 and -4.976) which is unusual and suggests poor permeability. This is a concern for both.

**Aqueous Solubility:** Both have negative solubility values (-3.183 and -3.847) which is also unusual and suggests poor solubility. This is a concern for both.

**hERG Inhibition:** Both ligands have low hERG inhibition liability (0.602 and 0.139), which is favorable.

**Microsomal Clearance:** Ligand B (16.298 mL/min/kg) has significantly lower microsomal clearance than Ligand A (49.427 mL/min/kg), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand B (44.171 hours) has a much longer half-life than Ligand A (17.152 hours), which is a significant advantage.

**P-gp Efflux:** Ligand A (0.093) has lower P-gp efflux than Ligand B (0.221), suggesting better CNS exposure.

**Binding Affinity:** Ligand B (-7.8 kcal/mol) has a stronger binding affinity than Ligand A (-8.3 kcal/mol). This is a substantial difference (0.5 kcal/mol), and a strong affinity is paramount.

**Overall Assessment:**

While Ligand B has superior metabolic stability (lower Cl_mic, longer t1/2) and a slightly better binding affinity, Ligand A has a considerably better BBB penetration score (58.007 vs 35.052) and lower P-gp efflux. Given DRD2 is a CNS target, BBB penetration is crucial. The affinity difference, while notable, is less important than the significant difference in BBB. The poor Caco-2 and solubility for both compounds are concerning, but can potentially be addressed through formulation strategies.

Output:
0
2025-04-17 03:08:52,330 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (364.852 and 360.439 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (62.46) is significantly better than Ligand B (88.33). For CNS targets, we want TPSA <= 90, and A is comfortably within that, while B is approaching the upper limit.

**logP:** Ligand A (3.05) is optimal (1-3), while Ligand B (1.537) is a bit low, potentially hindering membrane permeability.

**H-Bond Donors/Acceptors:** Both have 1 HBD, which is good. Ligand A has 4 HBA, and Ligand B has 6. Both are acceptable (<=10), but A is slightly preferred.

**QED:** Both ligands have good QED scores (0.767 and 0.874), indicating good drug-like properties.

**DILI:** Both have similar DILI risk (50.291 and 52.036), both being acceptable (<60).

**BBB:** Both ligands have excellent BBB penetration (71.229 and 72.896), exceeding the desirable >70 threshold for CNS targets.

**Caco-2 Permeability:** Ligand A (-4.854) and Ligand B (-5.723) both have negative values, which is unusual. Lower values indicate poorer permeability. However, the difference isn't substantial enough to be decisive.

**Aqueous Solubility:** Both have poor aqueous solubility (-2.246 and -2.161). This could pose formulation challenges, but is not a major deciding factor at this stage.

**hERG Inhibition:** Ligand A (0.935) is better than Ligand B (0.129), indicating a lower risk of cardiotoxicity.

**Microsomal Clearance:** Ligand A (33.378) has lower clearance than Ligand B (40.767), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (26.535) has a longer half-life than Ligand B (18.179), which is preferable.

**P-gp Efflux:** Ligand A (0.242) has lower P-gp efflux than Ligand B (0.044), meaning it's less likely to be pumped out of the brain, leading to higher CNS exposure.

**Binding Affinity:** Ligand B (-9.1 kcal/mol) has a significantly stronger binding affinity than Ligand A (-8.3 kcal/mol). This is a substantial advantage (>1.5 kcal/mol difference).

**Overall Assessment:**

While Ligand A has better physicochemical properties (TPSA, logP, hERG, Cl_mic, t1/2, Pgp) and comparable safety profiles (DILI), Ligand B's significantly stronger binding affinity (-9.1 vs -8.3 kcal/mol) is a critical advantage, especially for a GPCR target. The improved affinity is likely to outweigh the slightly less favorable ADME properties of Ligand B. The BBB penetration is excellent for both, mitigating some concerns about the lower logP and P-gp efflux of Ligand B.

Output:
1
2025-04-17 03:08:52,331 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (348.495 Da) is slightly lower, which could be advantageous for permeability, but both are acceptable.

**TPSA:** Ligand A (57.5) is better than Ligand B (53.43) as it is closer to the ideal TPSA for CNS targets (<=90).

**logP:** Ligand A (0.859) is a bit low, potentially hindering permeation. Ligand B (3.151) is within the optimal range (1-3). This is a significant advantage for Ligand B.

**H-Bond Donors/Acceptors:** Ligand A (0 HBD, 6 HBA) is better than Ligand B (1 HBD, 3 HBA) in terms of balancing solubility and permeability.

**QED:** Both ligands have good QED scores (A: 0.697, B: 0.791), indicating drug-like properties.

**DILI:** Ligand A (10.198) has a much lower DILI risk than Ligand B (17.449), a significant advantage.

**BBB:** Ligand B (80.962) has a considerably higher BBB penetration percentile than Ligand A (64.056). This is a crucial factor for a CNS target like DRD2.

**Caco-2 Permeability:** Ligand A (-5.161) has a worse Caco-2 permeability than Ligand B (-4.62).

**Aqueous Solubility:** Ligand A (-0.071) has a slightly better aqueous solubility than Ligand B (-3.885).

**hERG Inhibition:** Ligand A (0.277) has a much lower hERG inhibition liability than Ligand B (0.62). This is a significant safety advantage.

**Microsomal Clearance:** Ligand A (-10.298) has a much lower microsomal clearance, indicating better metabolic stability, than Ligand B (45.927).

**In vitro Half-Life:** Ligand B (23.813) has a significantly longer in vitro half-life than Ligand A (0.072). This is a positive attribute.

**P-gp Efflux:** Ligand A (0.02) has much lower P-gp efflux liability than Ligand B (0.563), which is beneficial for CNS exposure.

**Binding Affinity:** Ligand A (-7.9 kcal/mol) has a slightly better binding affinity than Ligand B (-7.5 kcal/mol). While the difference is not huge, it is still a factor.

**Overall Assessment:**

Ligand B excels in BBB penetration and in vitro half-life, both important for CNS drug development. However, it suffers from higher DILI risk, higher hERG liability, higher P-gp efflux, and a higher microsomal clearance. Ligand A, while having a slightly lower BBB score and shorter half-life, demonstrates a much more favorable safety profile (lower DILI, hERG), better metabolic stability (lower Cl_mic), and lower P-gp efflux. The affinity difference is small. Given the GPCR-specific priorities and the importance of safety and CNS penetration, and the relatively small difference in binding affinity, Ligand A is the more promising candidate.

Output:
0
2025-04-17 03:08:52,331 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 drug candidates, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (347.39 and 356.46 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (91.22) is slightly above the optimal <90 for CNS targets, but still reasonable. Ligand B (49.41) is well within the desired range. This favors Ligand B.

**3. logP:** Both ligands have good logP values (2.463 and 3.523), falling within the 1-3 optimal range. Ligand B is a bit higher, potentially leading to some solubility concerns, but not drastically.

**4. H-Bond Donors:** Ligand A has 2 HBD, and Ligand B has 1. Both are within the acceptable limit of <=5.

**5. H-Bond Acceptors:** Ligand A has 4 HBA, and Ligand B has 2. Both are within the acceptable limit of <=10.

**6. QED:** Both ligands have reasonable QED values (0.827 and 0.74), indicating good drug-like properties.

**7. DILI:** Ligand A (53.78) has a slightly higher DILI risk than Ligand B (31.33). This favors Ligand B.

**8. BBB:** Ligand B (93.76) has a significantly better BBB penetration score than Ligand A (72.24). This is a *critical* advantage for a CNS target like DRD2.

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.468 and -4.358). These values are unusual and difficult to interpret without further context, but suggest poor permeability.

**10. Aqueous Solubility:** Both ligands have negative solubility values (-4.076 and -3.838). Similar to Caco-2, these are unusual and suggest poor aqueous solubility.

**11. hERG Inhibition:** Both ligands have low hERG inhibition risk (0.524 and 0.595).

**12. Microsomal Clearance:** Ligand A (55.15) has higher microsomal clearance than Ligand B (32.68), indicating lower metabolic stability. This favors Ligand B.

**13. In vitro Half-Life:** Ligand B (-5.815) has a significantly longer in vitro half-life than Ligand A (-0.23). This is a major advantage.

**14. P-gp Efflux:** Both ligands have low P-gp efflux liability (0.117 and 0.224).

**15. Binding Affinity:** Ligand B (-9.7 kcal/mol) has a substantially stronger binding affinity than Ligand A (-7.9 kcal/mol). This is a significant advantage, potentially outweighing some of the minor ADME concerns.

**Overall Assessment:**

Ligand B is the superior candidate. While both have some concerning solubility/permeability issues (negative Caco-2 and solubility values), Ligand B excels in the key GPCR-relevant properties: significantly better BBB penetration, stronger binding affinity, longer half-life, lower DILI risk, and lower microsomal clearance. The improved affinity is particularly important.

Output:
1
2025-04-17 03:08:52,331 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 drug candidates, considering the provided guidelines and GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (345.443 and 355.479 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (78.51) is better than Ligand B (71.11), both are below the 90 A^2 threshold for CNS targets.

**logP:** Ligand A (0.987) is slightly better than Ligand B (0.487), both are within the optimal 1-3 range, but B is quite low and may have permeability issues.

**H-Bond Donors:** Ligand A (2) is slightly higher than Ligand B (1), both are within the acceptable limit of 5.

**H-Bond Acceptors:** Ligand A (3) is lower than Ligand B (5), both are within the acceptable limit of 10.

**QED:** Ligand A (0.746) is slightly better than Ligand B (0.686), both are above the 0.5 threshold, indicating good drug-likeness.

**DILI:** Ligand A (20.396) has a significantly lower DILI risk than Ligand B (9.732), both are good (<40).

**BBB:** Ligand A (67.352) has a much better BBB penetration percentile than Ligand B (39.589). This is *critical* for a CNS target like DRD2.

**Caco-2 Permeability:** Ligand A (-5.132) is better than Ligand B (-5), both are negative, indicating poor permeability.

**Aqueous Solubility:** Ligand A (-2.293) is better than Ligand B (-0.216), both are negative, indicating poor solubility.

**hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.121 and 0.227, respectively).

**Microsomal Clearance:** Ligand A (16.246) has a better (lower) microsomal clearance than Ligand B (-16.357), indicating better metabolic stability.

**In vitro Half-Life:** Ligand B (10.169) has a significantly longer half-life than Ligand A (2.556).

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.016 and 0.005, respectively).

**Binding Affinity:** Ligand A (-8.4 kcal/mol) has a significantly stronger binding affinity than Ligand B (-7.2 kcal/mol). This >1.5 kcal/mol difference is substantial.

**Overall Assessment:**

Ligand A is the stronger candidate. While both ligands have acceptable MW, QED, DILI, and hERG profiles, Ligand A excels in the most critical areas for a CNS GPCR target: **BBB penetration and binding affinity**. The significantly better BBB score is a major advantage, and the stronger binding affinity is also crucial. Although Ligand B has a longer half-life, the superior BBB and affinity of Ligand A outweigh this benefit. Both have poor solubility and permeability, which would need to be addressed in further optimization, but these are less critical than CNS penetration and target engagement.

Output:
1
2025-04-17 03:08:52,331 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B based on the provided guidelines, prioritizing GPCR-specific properties (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (353.442 and 363.527 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (79.26) is better than Ligand B (62.3), both are below the 90 A^2 threshold for CNS targets.

**logP:** Ligand B (3.251) is slightly higher than Ligand A (0.529). While 3.251 is at the upper end of the optimal range (1-3), 0.529 is quite low and may hinder permeation.

**H-Bond Donors/Acceptors:** Ligand A has 2 HBD and 5 HBA, while Ligand B has 1 HBD and 4 HBA. Both are within acceptable limits.

**QED:** Both ligands have good QED scores (0.679 and 0.809, respectively), indicating drug-like properties.

**DILI:** Ligand A (30.516) has a significantly lower DILI risk than Ligand B (47.421), which is a strong advantage.

**BBB:** Both ligands have excellent BBB penetration (83.676 and 84.064), exceeding the 70% threshold for CNS targets.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.863 and -4.995). This is unusual and suggests poor permeability. However, these values are on a scale where negative values are possible, and direct comparison is difficult without knowing the scale's specifics.

**Aqueous Solubility:** Both ligands have negative solubility values (-1.385 and -3.643). Similar to Caco-2, this is unusual and suggests poor solubility.

**hERG Inhibition:** Ligand A (0.225) has a lower hERG inhibition liability than Ligand B (0.589), indicating a lower risk of cardiotoxicity.

**Microsomal Clearance:** Ligand A (25.572) has a lower microsomal clearance than Ligand B (57.335), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (-3.915) has a more negative in vitro half-life than Ligand B (7.228). Again, this is on a scale where negative values are possible, and direct comparison is difficult without knowing the scale's specifics.

**P-gp Efflux:** Ligand A (0.01) has significantly lower P-gp efflux liability than Ligand B (0.37), which is crucial for CNS penetration.

**Binding Affinity:** Both ligands have the same binding affinity (-7.9 kcal/mol), which is excellent.

**Overall Assessment:**

Ligand A is superior due to its lower DILI risk, lower hERG inhibition, lower P-gp efflux, and lower microsomal clearance. While Ligand B has a slightly better logP, Ligand A's advantages in safety and ADME properties outweigh this. The negative values for Caco-2 and solubility are concerning for both, but the other benefits of Ligand A make it the more promising candidate.

Output:
1
2025-04-17 03:08:52,332 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (345.374 and 346.427 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (91.32) is better than Ligand B (98.66). Both are below the 140 A^2 threshold for oral absorption, and reasonably close to the 90 A^2 target for CNS penetration, but A is preferable.

**logP:** Ligand A (2.231) is optimal, while Ligand B (0.617) is a bit low, potentially hindering permeability.

**H-Bond Donors/Acceptors:** Both have 3 HBD and 4 HBA, which are within acceptable limits.

**QED:** Both ligands have similar QED values (0.572 and 0.554), indicating good drug-likeness.

**DILI:** Ligand A (54.556) has a higher DILI risk than Ligand B (29.236). This is a significant drawback for Ligand A.

**BBB:** Ligand A (53.432) has a lower BBB penetration percentile than Ligand B (36.216). While neither is ideal (>70), B is better.

**Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and suggests poor permeability. However, the scale isn't defined, so it's hard to interpret.

**Aqueous Solubility:** Both have negative solubility values, which is also unusual. Again, interpretation is difficult without knowing the scale.

**hERG:** Both ligands have very low hERG inhibition risk (0.403 and 0.187).

**Microsomal Clearance:** Ligand A (62.646) has a higher microsomal clearance than Ligand B (8.159), indicating lower metabolic stability.

**In vitro Half-Life:** Ligand B (9.44) has a longer in vitro half-life than Ligand A (-39.274). The negative value for A is concerning.

**P-gp Efflux:** Ligand A (0.133) has lower P-gp efflux liability than Ligand B (0.061), which is favorable for CNS penetration.

**Binding Affinity:** Ligand B (-7.7 kcal/mol) has a significantly stronger binding affinity than Ligand A (-9.7 kcal/mol). This is a substantial advantage.

**Overall Assessment:**

Ligand B is the better candidate. While its BBB penetration is not ideal, it's better than Ligand A's. Its significantly stronger binding affinity (-7.7 vs -9.7 kcal/mol) outweighs the slightly lower logP and the moderate P-gp efflux. Ligand B also has a much lower DILI risk and better metabolic stability (lower Cl_mic and longer t1/2). Ligand A's high DILI risk and poor metabolic stability are major concerns.

Output:
1
2025-04-17 03:08:52,332 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B based on the provided guidelines, prioritizing GPCR-specific properties (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (408.3) is slightly higher than Ligand B (345.443), but both are acceptable.

**TPSA:** Ligand A (65.18) is better than Ligand B (80.32). For CNS targets, we want TPSA <= 90, and ideally closer to 60. Ligand A is closer to this ideal.

**logP:** Both ligands have good logP values (A: 2.708, B: 1.657) falling within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A (HBD=0, HBA=6) is better than Ligand B (HBD=2, HBA=4). Lower HBD is generally preferred for BBB penetration.

**QED:** Both ligands have acceptable QED values (A: 0.784, B: 0.632), indicating good drug-like properties.

**DILI:** Ligand A (63.048) has a higher DILI risk than Ligand B (28.306). This is a negative for Ligand A.

**BBB:** Ligand A (75.107) has a significantly better BBB percentile than Ligand B (43.777). This is a *critical* advantage for a CNS target like DRD2.

**Caco-2 Permeability:** Both have negative values which is unusual. Assuming these are logP scale values, they are both poor.

**Aqueous Solubility:** Both ligands have poor aqueous solubility (-2.387 and -2.064 respectively). This could pose formulation challenges.

**hERG:** Both ligands have very low hERG inhibition liability (A: 0.306, B: 0.164), which is excellent.

**Microsomal Clearance:** Ligand B (8.354) has a much lower microsomal clearance than Ligand A (33.542), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand B (12.343) has a longer in vitro half-life than Ligand A (23.525).

**P-gp Efflux:** Both ligands have low P-gp efflux liability (A: 0.54, B: 0.022). Ligand B is slightly better.

**Binding Affinity:** Ligand A (-7.8 kcal/mol) has a slightly better binding affinity than Ligand B (-7.4 kcal/mol). While the difference is not huge (0.4 kcal/mol), it's still a positive for Ligand A.

**Overall Assessment:**

Ligand A excels in BBB penetration and binding affinity, which are paramount for a CNS GPCR target. While it has a higher DILI risk and higher clearance, the superior BBB and affinity likely outweigh these drawbacks. Ligand B has better metabolic stability and lower DILI, but its significantly lower BBB penetration is a major disadvantage. Considering the target (DRD2 in the CNS), the ability to cross the blood-brain barrier is crucial.

Output:
1
2025-04-17 03:08:52,332 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 drug candidates, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight (MW):** Both ligands (340.423 and 348.374 Da) fall comfortably within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (82.19) is better than Ligand B (91.57). Both are below the 140 A^2 threshold for oral absorption, but Ligand A is closer to the <90 A^2 target for CNS penetration.

**3. logP:** Both ligands have good logP values (3.27 and 2.981), falling within the optimal 1-3 range.

**4. H-Bond Donors (HBD):** Both ligands have 3 HBD, which is acceptable (<=5).

**5. H-Bond Acceptors (HBA):** Ligand A has 2 HBA, and Ligand B has 4 HBA, both are within the acceptable range (<=10).

**6. QED:** Both ligands have reasonable QED scores (0.755 and 0.684), indicating good drug-like properties.

**7. DILI:** Ligand A (76.735) has a higher DILI risk than Ligand B (47.926). This is a negative for Ligand A.

**8. BBB:** Ligand A (46.724) has a significantly better BBB percentile than Ligand B (31.834). This is a crucial advantage for a CNS target like DRD2.

**9. Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and suggests poor permeability. However, the values are similar (-5.54 and -5.314).

**10. Aqueous Solubility:** Both ligands have very poor aqueous solubility (-3.941 and -3.677). This is a significant drawback for both.

**11. hERG Inhibition:** Both ligands show very low hERG inhibition risk (0.085 and 0.472).

**12. Microsomal Clearance (Cl_mic):** Ligand B (28.386) has a much higher Cl_mic than Ligand A (4.114), indicating faster metabolism and lower metabolic stability.

**13. In vitro Half-Life (t1/2):** Ligand B (37.698) has a much longer half-life than Ligand A (-1.33). This is a positive for Ligand B.

**14. P-gp Efflux:** Both ligands have low P-gp efflux liability (0.135 and 0.09).

**15. Binding Affinity:** Both ligands have excellent binding affinity (-8.9 and -8.8 kcal/mol). The difference is minimal.

**Overall Assessment:**

Ligand A is superior despite the higher DILI risk. Its significantly better BBB penetration (46.724 vs 31.834) and much lower microsomal clearance (4.114 vs 28.386) are critical advantages for a CNS GPCR target. While both have poor solubility, the improved pharmacokinetic properties of Ligand A outweigh the slightly higher DILI risk, especially given the strong binding affinity.

Output:
1
2025-04-17 03:08:52,333 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (350.375 and 350.459 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (137.48) is slightly above the optimal <90 for CNS targets, but still reasonable. Ligand B (80.57) is excellent, well below 90.

**logP:** Ligand A (0.663) is a bit low, potentially hindering permeation. Ligand B (2.808) is within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A has 3 HBD and 7 HBA, which are acceptable. Ligand B has 2 HBD and 4 HBA, also acceptable.

**QED:** Ligand A (0.462) is below the desirable 0.5 threshold, suggesting a less drug-like profile. Ligand B (0.68) is above 0.5, indicating a better drug-like profile.

**DILI:** Ligand A (54.323) has a moderate DILI risk. Ligand B (31.252) has a lower, more favorable DILI risk.

**BBB:** This is critical for a CNS target. Ligand A (45.25) has a poor BBB percentile. Ligand B (76.464) is much better, exceeding the desirable >70 threshold.

**Caco-2 Permeability:** Ligand A (-5.273) shows very poor permeability. Ligand B (-4.516) is better, but still not great.

**Aqueous Solubility:** Both ligands have poor aqueous solubility (-1.942 and -2.609, respectively). This could pose formulation challenges.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.186 and 0.38, respectively).

**Microsomal Clearance:** Ligand A (-0.858) has a negative value, which is unusual and likely an error, indicating very low clearance (highly stable). Ligand B (49.299) has a moderate clearance.

**In vitro Half-Life:** Ligand A (-9.662) also has a negative value, which is unusual and likely an error, indicating a very long half-life. Ligand B (35.341) has a reasonable half-life.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.015 and 0.178, respectively), which is favorable for CNS penetration.

**Binding Affinity:** Ligand B (-8.0 kcal/mol) has a significantly stronger binding affinity than Ligand A (-7.4 kcal/mol), exceeding the 1.5 kcal/mol advantage threshold.

**Overall Assessment:**

Ligand B is clearly the superior candidate. While both have solubility issues, Ligand B excels in the critical areas for a CNS GPCR target: BBB penetration, logP, QED, and, most importantly, binding affinity. The negative values for clearance and half-life of Ligand A are concerning and likely represent errors. Ligand A's poor BBB penetration and lower affinity are significant drawbacks.

Output:
1
2025-04-17 03:08:52,333 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B based on the provided guidelines, prioritizing GPCR-specific properties (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (336.395 Da) is slightly lower, which could be advantageous for permeability.

**TPSA:** Ligand A (78.25) is significantly better than Ligand B (115.21). For CNS targets, TPSA < 90 is preferred, and Ligand A comfortably meets this, while Ligand B is pushing the limit.

**logP:** Ligand A (2.952) is optimal (1-3), while Ligand B (-0.081) is quite low. Low logP can hinder membrane permeability, a critical factor for CNS penetration.

**H-Bond Donors/Acceptors:** Ligand A (HBD=1, HBA=6) and Ligand B (HBD=2, HBA=7) are both acceptable within the guidelines.

**QED:** Both ligands have reasonable QED scores (A: 0.846, B: 0.694), indicating good drug-like properties.

**DILI:** Both ligands have similar DILI risk (A: 75.184, B: 78.868), and are within an acceptable range (<80).

**BBB:** Ligand A (64.637) has a better BBB percentile than Ligand B (42.536). A BBB > 70 is desirable for CNS targets, and Ligand A is closer to this threshold.

**Caco-2 Permeability:** Ligand A (-4.57) and Ligand B (-5.398) both have negative values, which is unusual. It's difficult to interpret without knowing the scale, but lower values generally indicate poorer permeability.

**Aqueous Solubility:** Ligand A (-5.378) and Ligand B (-1.83) both have negative values, which is also unusual. Lower values generally indicate poorer solubility.

**hERG Inhibition:** Ligand A (0.756) has a lower hERG inhibition risk than Ligand B (0.013), which is preferable.

**Microsomal Clearance:** Ligand A (103.016) has higher microsomal clearance than Ligand B (-20.126). Lower clearance is better for metabolic stability, so Ligand B is favored here.

**In vitro Half-Life:** Ligand A (26.246) has a shorter half-life than Ligand B (20.88). Longer half-life is generally preferred.

**P-gp Efflux:** Ligand A (0.328) has lower P-gp efflux than Ligand B (0.02). Lower efflux is better for CNS exposure.

**Binding Affinity:** Ligand A (-7.6 kcal/mol) has slightly better binding affinity than Ligand B (-7.4 kcal/mol). While the difference is small, it's still a positive for Ligand A.

**Overall Assessment:**

Considering the GPCR-specific priorities, Ligand A is the more promising candidate. Its superior TPSA, logP, and BBB penetration are crucial for CNS drug development. While Ligand B has better metabolic stability (lower Cl_mic), the poor logP and lower BBB penetration are significant drawbacks. The slightly better affinity of Ligand A further supports its selection.

Output:
0
2025-04-17 03:08:52,333 - INFO - Reasoning:

Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (348.447 and 368.503 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (78.53) is significantly better than Ligand B (95.16). For CNS targets, we want TPSA <= 90, so Ligand A is preferable.

**3. logP:** Both ligands have good logP values (2.157 and 1.466), falling within the optimal 1-3 range.

**4. H-Bond Donors:** Ligand A (1) and Ligand B (2) are both acceptable, being <= 5.

**5. H-Bond Acceptors:** Both ligands have 4 H-bond acceptors, well within the acceptable limit of <= 10.

**6. QED:** Ligand A (0.766) has a better QED score than Ligand B (0.611), indicating a more drug-like profile. Both are above the 0.5 threshold.

**7. DILI:** Ligand A (47.111) has a slightly higher DILI risk than Ligand B (40.985), but both are below the concerning threshold of 60.

**8. BBB:** This is a crucial parameter for CNS targets. Ligand A (69.407) has a significantly better BBB percentile than Ligand B (48.119). A value >70 is desirable, and Ligand A is closer to that target.

**9. Caco-2 Permeability:** Both have negative values, indicating poor permeability. However, the scale is not specified, making direct comparison difficult.

**10. Aqueous Solubility:** Both have negative values, indicating poor solubility. The scale is not specified, making direct comparison difficult.

**11. hERG Inhibition:** Both ligands have low hERG inhibition risk (0.386 and 0.543).

**12. Microsomal Clearance:** Ligand B (16.145) has lower microsomal clearance than Ligand A (20.684), suggesting better metabolic stability.

**13. In vitro Half-Life:** Ligand B (-43.008) has a much longer in vitro half-life than Ligand A (-12.422). This is a significant advantage.

**14. P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.094 and 0.071).

**15. Binding Affinity:** Ligand B (-7.9 kcal/mol) has a slightly better binding affinity than Ligand A (-7.1 kcal/mol). This difference of 0.8 kcal/mol is noteworthy, but not overwhelmingly decisive.

**Overall Assessment:**

While Ligand B has better metabolic stability (lower Cl_mic, longer t1/2) and slightly better binding affinity, Ligand A is superior in terms of TPSA and, critically, BBB penetration. For a CNS target like DRD2, BBB penetration is paramount. The better TPSA of Ligand A also contributes to better potential CNS exposure. The difference in affinity is not large enough to overcome the significant advantage Ligand A has in BBB.

Output:
1
2025-04-17 03:08:52,333 - INFO - Batch 4 complete. Total preferences: 64
2025-04-17 03:08:52,334 - INFO - Processing batch 5/512...
2025-04-17 03:09:34,469 - INFO - Reasoning:

Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (361.427 and 369.535 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (97.19) is slightly higher than Ligand B (88.91). Both are below the 140 A^2 threshold for oral absorption, and closer to the desirable <90 A^2 for CNS targets. Ligand B is slightly better here.

**3. logP:** Ligand A (0.468) is quite low, potentially hindering permeation. Ligand B (2.092) is within the optimal 1-3 range. This is a significant advantage for Ligand B.

**4. H-Bond Donors:** Ligand A (1) is good. Ligand B (2) is acceptable.

**5. H-Bond Acceptors:** Ligand A (7) is good. Ligand B (6) is also good.

**6. QED:** Ligand A (0.835) is excellent, indicating high drug-likeness. Ligand B (0.617) is still acceptable, above the 0.5 threshold.

**7. DILI:** Ligand A (75.184) has a higher DILI risk than Ligand B (64.521), though both are reasonably acceptable.

**8. BBB:** Both ligands have similar BBB penetration (Ligand A: 52.966, Ligand B: 54.672). Neither is above the desirable >70 for CNS targets, but this isn't a dealbreaker at this stage.

**9. Caco-2:** Both have negative Caco-2 values (-5.223 and -5.433), which is unusual and suggests poor permeability. This is a concern for both.

**10. Solubility:** Both ligands have very poor aqueous solubility (-2.397 and -3.033). This is a major drawback for both.

**11. hERG:** Ligand A (0.038) has a very low hERG risk, which is excellent. Ligand B (0.386) is slightly higher but still relatively low.

**12. Cl_mic:** Ligand A (-2.258) has a negative clearance, which is very favorable, indicating high metabolic stability. Ligand B (78.894) has a high clearance, suggesting rapid metabolism. This is a significant advantage for Ligand A.

**13. t1/2:** Ligand A (52.17 hours) has a much longer half-life than Ligand B (5.342 hours). This is a major advantage for Ligand A.

**14. Pgp:** Ligand A (0.068) has low P-gp efflux, which is good for CNS exposure. Ligand B (0.176) is slightly higher, but still acceptable.

**15. Binding Affinity:** Ligand B (-7.1 kcal/mol) has a significantly stronger binding affinity than Ligand A (-10.6 kcal/mol). This is a substantial advantage for Ligand B, potentially outweighing some of its ADME drawbacks.

**Overall Assessment:**

While Ligand A has better metabolic stability (Cl_mic, t1/2), lower hERG risk, and a better QED score, Ligand B's significantly stronger binding affinity (-7.1 vs -10.6 kcal/mol) and more favorable logP value are critical for a GPCR target, especially one in the CNS. The poor solubility and Caco-2 values are concerning for both, but can potentially be addressed with formulation strategies. The lower logP of Ligand A is a significant concern for CNS penetration.

Output:
1
2025-04-17 03:09:34,470 - INFO - Reasoning:

Let's analyze Ligand A and Ligand B for their potential as DRD2 drug candidates, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (341.411 and 374.413 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (66.65) is significantly better than Ligand B (93.21). For CNS targets, we want TPSA <= 90, so Ligand A is preferable.

**3. logP:** Ligand A (3.067) is optimal (1-3). Ligand B (1.08) is a bit low, potentially hindering permeability.

**4. H-Bond Donors:** Ligand A (0) is excellent. Ligand B (2) is acceptable, but fewer is generally better.

**5. H-Bond Acceptors:** Ligand A (4) is good. Ligand B (6) is also acceptable, but higher values can sometimes reduce permeability.

**6. QED:** Both ligands have reasonable QED values (0.86 and 0.664), indicating good drug-like properties.

**7. DILI:** Ligand A (70.376) is higher than Ligand B (55.448), suggesting a slightly increased risk of liver injury. However, both are below the concerning threshold of 60.

**8. BBB:** Both ligands have excellent BBB penetration (83.831 and 83.443), exceeding the desirable >70% threshold for CNS targets.

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 values, which is unusual and potentially problematic. However, the magnitude of negativity is similar.

**10. Aqueous Solubility:** Both ligands have negative solubility values, which is also unusual.

**11. hERG Inhibition:** Both ligands show very low hERG inhibition risk (0.277 and 0.418).

**12. Microsomal Clearance:** Ligand A (66.386) has higher clearance than Ligand B (6.575), indicating lower metabolic stability. Ligand B is significantly better here.

**13. In vitro Half-Life:** Ligand A (43.618) has a longer half-life than Ligand B (8.848). This is a positive for Ligand A.

**14. P-gp Efflux:** Both ligands show low P-gp efflux (0.283 and 0.109), which is good for CNS exposure. Ligand B is slightly better.

**15. Binding Affinity:** Ligand A (-9.5 kcal/mol) has a significantly stronger binding affinity than Ligand B (-8.4 kcal/mol). This is a substantial advantage.

**Overall Assessment:**

Ligand A excels in TPSA, logP, binding affinity, and half-life. Ligand B has better metabolic stability (lower Cl_mic) and slightly better P-gp efflux. However, the significantly stronger binding affinity of Ligand A (-9.5 vs -8.4 kcal/mol) is a major advantage, and the TPSA is more favorable. The slightly higher DILI risk for Ligand A is a minor concern compared to the substantial improvement in potency. Given the GPCR-specific priorities, the strong affinity and good BBB penetration of Ligand A make it the more promising candidate.

Output:
1
2025-04-17 03:09:34,470 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (344.323 and 377.363 Da) fall within the ideal range of 200-500 Da.

**TPSA:** Ligand A (108.63) is better than Ligand B (64.11) as it is closer to the ideal range for CNS targets (<90). Ligand B is excellent.

**logP:** Both ligands have good logP values (2.696 and 3.913), falling within the optimal 1-3 range. Ligand B is slightly higher, which *could* be a minor drawback, but not significantly.

**H-Bond Donors/Acceptors:** Ligand A has 0 HBD and 7 HBA, while Ligand B has 1 HBD and 5 HBA. Both are within acceptable limits (<=5 HBD and <=10 HBA).

**QED:** Both ligands have good QED scores (0.45 and 0.776), indicating reasonable drug-likeness. Ligand B is superior here.

**DILI:** Ligand A (86.157) has a higher DILI risk than Ligand B (75.533), which is preferable.

**BBB:** Ligand B (75.921) has a better BBB percentile than Ligand A (66.344). Both are reasonably good, but for a CNS target like DRD2, higher BBB is strongly preferred.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.429 and -4.682), which is unusual and suggests poor permeability. This is a significant concern for both.

**Aqueous Solubility:** Both ligands have negative solubility values (-5.385 and -4.125), indicating very poor aqueous solubility. This is a major drawback for both.

**hERG Inhibition:** Both ligands have low hERG inhibition liability (0.397 and 0.406), which is good.

**Microsomal Clearance:** Ligand B (54.694) has significantly lower microsomal clearance than Ligand A (121.766), indicating better metabolic stability. This is a substantial advantage for Ligand B.

**In vitro Half-Life:** Ligand B (-26.798) has a negative half-life, which is not possible. This is a red flag and suggests a problem with the data or the molecule's stability. Ligand A (15.377) has a reasonable half-life.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.405 and 0.181), which is favorable for CNS penetration. Ligand B is slightly better.

**Binding Affinity:** Both ligands have very similar and excellent binding affinities (-8.5 and -8.4 kcal/mol). The difference is negligible.

**Overall Assessment:**

While both ligands have strong binding affinity, Ligand B is the better candidate. It has a significantly better BBB score, lower DILI risk, and lower microsomal clearance (better metabolic stability). The negative Caco-2 and solubility values are concerning for both, but can potentially be addressed through formulation strategies. The negative half-life for Ligand B is a major issue, potentially indicating instability or an error in the data. Ligand A's half-life is acceptable. However, the other advantages of Ligand B outweigh this concern.

Output:
1
2025-04-17 03:09:34,470 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 drug candidates, considering the provided guidelines and GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight (MW):** Both ligands are within the ideal range (200-500 Da). Ligand A (346.427 Da) is slightly lower, which could be beneficial for permeability.

**2. TPSA:** Both ligands have TPSA values below 90, suitable for CNS targets. Ligand B (75.62) is slightly lower than Ligand A (78.87), which is a minor advantage.

**3. logP:** Ligand A (1.848) is within the optimal range (1-3). Ligand B (4.354) is higher, potentially leading to solubility issues and off-target interactions. This is a significant drawback for Ligand B.

**4. H-Bond Donors (HBD):** Both ligands have 2 HBD, which is acceptable.

**5. H-Bond Acceptors (HBA):** Ligand A has 4 HBA, and Ligand B has 8 HBA. Both are within the acceptable limit of 10, but Ligand A is preferable.

**6. QED:** Ligand A (0.824) has a better QED score than Ligand B (0.64), indicating a more drug-like profile.

**7. DILI:** Ligand A (23.497) has a significantly lower DILI risk than Ligand B (74.68). This is a major advantage for Ligand A.

**8. BBB:** Ligand A (63.862) has a better BBB percentile than Ligand B (42.73). While both are not ideal (>70 desirable), Ligand A is much closer to the target for CNS penetration.

**9. Caco-2 Permeability:** Ligand A (-4.767) has a worse Caco-2 permeability than Ligand B (-5.423), but both are poor.

**10. Aqueous Solubility:** Both ligands have similar, very poor aqueous solubility (-3.681 and -3.686). This is a concern for both, but less critical if BBB penetration is good.

**11. hERG Inhibition:** Both ligands have low hERG inhibition risk (0.379 and 0.515).

**12. Microsomal Clearance:** Ligand B (41.773) has a lower microsomal clearance than Ligand A (46.806), suggesting better metabolic stability.

**13. In vitro Half-Life:** Ligand B (67.419) has a significantly longer in vitro half-life than Ligand A (-18.174). This is a substantial advantage for Ligand B.

**14. P-gp Efflux:** Both ligands have low P-gp efflux liability (0.075 and 0.178).

**15. Binding Affinity:** Both ligands have similar binding affinities (-8.9 and -8.3 kcal/mol). The difference is less than 1.5 kcal/mol, so it's not a deciding factor.

**Overall Assessment:**

Considering the GPCR-specific priorities, Ligand A is the more promising candidate. While Ligand B has better metabolic stability and half-life, Ligand A excels in crucial areas for CNS penetration: lower logP, better BBB penetration, and significantly lower DILI risk. The higher QED score also favors Ligand A. The solubility is a concern for both, but can be addressed with formulation strategies. The slightly worse Caco-2 permeability of Ligand A is less critical given the CNS target.

Output:
0
2025-04-17 03:09:34,470 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (370.881 and 352.45 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (77.07) is slightly higher than Ligand B (67.43). Both are below the 90 A^2 threshold desirable for CNS targets, but B is better.

**logP:** Ligand A (1.18) is within the optimal 1-3 range, while Ligand B (3.341) is at the higher end. While not a major concern, higher logP can sometimes lead to off-target effects.

**H-Bond Donors/Acceptors:** Ligand A has 3 HBD and 6 HBA, while Ligand B has 2 HBD and 3 HBA. Both are within acceptable limits (<=5 HBD and <=10 HBA).

**QED:** Both ligands have good QED scores (0.596 and 0.67), indicating good drug-like properties.

**DILI:** Both have low DILI risk (44.63 and 42.885), which is positive.

**BBB:** This is a critical parameter for a CNS target like DRD2. Ligand B (73.284) has a significantly better BBB percentile than Ligand A (45.444). This is a major advantage for Ligand B.

**Caco-2 Permeability:** Ligand A (-5.007) shows poor Caco-2 permeability, while Ligand B (-4.814) is slightly better. Both are negative values, indicating low permeability.

**Aqueous Solubility:** Ligand A (-2.291) is slightly better than Ligand B (-4.052) in terms of solubility.

**hERG:** Both ligands have low hERG inhibition liability (0.886 and 0.689), which is favorable.

**Microsomal Clearance:** Ligand A (-5.246) has a negative clearance, suggesting very good metabolic stability, while Ligand B (41.639) has a moderate clearance. This is a significant advantage for Ligand A.

**In vitro Half-Life:** Ligand A (18.689 hours) has a longer half-life than Ligand B (7.143 hours). This is another advantage for Ligand A.

**P-gp Efflux:** Ligand A (0.058) has much lower P-gp efflux liability than Ligand B (0.092), which is beneficial for CNS penetration.

**Binding Affinity:** Ligand B (-8.3 kcal/mol) has a slightly better binding affinity than Ligand A (-7.6 kcal/mol). The difference is 0.7 kcal/mol, which is a meaningful advantage.

**Overall Assessment:**

Ligand B excels in BBB penetration and binding affinity, which are crucial for a CNS GPCR target. However, Ligand A demonstrates superior metabolic stability (lower Cl_mic, longer half-life), lower P-gp efflux, and better Caco-2 permeability. The difference in binding affinity (0.7 kcal/mol) is significant, but the substantial improvement in BBB for Ligand B outweighs the other benefits of Ligand A.

Output:
1
2025-04-17 03:09:34,470 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B based on the provided guidelines and GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (340.343 and 346.387 Da) fall within the ideal range of 200-500 Da.

**TPSA:** Ligand A (95.14) is significantly better than Ligand B (117.09). For CNS targets, TPSA should be <= 90, and A is closer to this threshold.

**logP:** Ligand B (1.308) is better than Ligand A (0.648). The optimal range is 1-3, and B falls comfortably within it, while A is slightly below 1, potentially hindering permeation.

**H-Bond Donors/Acceptors:** Ligand A (0 HBD, 8 HBA) is preferable to Ligand B (3 HBD, 5 HBA). Lower HBDs and HBAs generally improve permeability.

**QED:** Both ligands have similar and acceptable QED values (0.65 and 0.699, respectively).

**DILI:** Both ligands have relatively high DILI risk (79.062 and 75.184), but are still within a range that isn't immediately disqualifying.

**BBB:** Ligand A (65.374) has a significantly better BBB percentile than Ligand B (34.005). This is *critical* for a CNS target like DRD2.

**Caco-2 Permeability:** Ligand A (-4.669) has a better (more negative) Caco-2 permeability score than Ligand B (-5.508), indicating better intestinal absorption.

**Aqueous Solubility:** Ligand B (-3.007) has slightly better solubility than Ligand A (-2.111), but both are poor.

**hERG:** Both ligands have very low hERG inhibition liability (0.154 and 0.24), which is excellent.

**Microsomal Clearance:** Ligand B (10.241) has a much lower microsomal clearance than Ligand A (61.643), indicating better metabolic stability.

**In vitro Half-Life:** Ligand B (27.748) has a significantly longer in vitro half-life than Ligand A (-4.233). This is a major advantage.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.115 and 0.15), which is good.

**Binding Affinity:** Both ligands have identical binding affinities (-8.7 kcal/mol), which is excellent and removes this as a differentiating factor.

**Overall Assessment:**

While Ligand B has better logP and metabolic stability (lower Cl_mic, longer t1/2), Ligand A *strongly* outperforms it in BBB penetration and TPSA, both of which are crucial for CNS GPCR targets. The slightly better Caco-2 permeability of A is also a plus. The similar affinities mean the ADME properties become the deciding factor. Given the importance of CNS penetration for DRD2, Ligand A is the more promising candidate.

Output:
0
2025-04-17 03:09:34,470 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (340.383 and 355.435 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (79.54) is significantly better than Ligand B (93.89). For CNS targets, we want TPSA <= 90, so Ligand A is preferable.

**3. logP:** Ligand A (1.753) is within the optimal 1-3 range. Ligand B (0.878) is slightly below 1, which *could* indicate permeability issues, although not drastically.

**4. H-Bond Donors:** Ligand A (0) is better than Ligand B (1). Fewer HBDs generally improve permeability.

**5. H-Bond Acceptors:** Ligand A (5) is better than Ligand B (7). Lower HBA is generally preferred for CNS penetration.

**6. QED:** Ligand A (0.832) is significantly better than Ligand B (0.495). A higher QED suggests better overall drug-likeness.

**7. DILI:** Ligand B (38.62) is better than Ligand A (63.668). Lower DILI is crucial.

**8. BBB:** Ligand B (59.597) is better than Ligand A (44.591). This is a *critical* parameter for a CNS target like DRD2. While both are below the ideal >70, Ligand B is closer.

**9. Caco-2:** Both ligands have negative Caco-2 values (-4.879 and -4.543). This is unusual and likely indicates a problem with the prediction method or the compounds themselves. It's difficult to interpret, but suggests poor intestinal absorption.

**10. Solubility:** Ligand A (-2.306) is better than Ligand B (-0.58). Higher solubility is generally desirable.

**11. hERG:** Both ligands have very low hERG risk (0.242 and 0.252).

**12. Cl_mic:** Ligand A (25.622) is significantly better than Ligand B (77.187). Lower clearance indicates better metabolic stability.

**13. t1/2:** Ligand A (29.064) is better than Ligand B (-22.304). A positive half-life is better than a negative one.

**14. Pgp:** Both ligands have very low Pgp efflux liability (0.146 and 0.1).

**15. Binding Affinity:** Ligand A (-9.1) is *much* better than Ligand B (-6). A difference of >1.5 kcal/mol is substantial and can outweigh other drawbacks.

**Overall Assessment:**

Ligand A excels in most key properties: TPSA, logP, QED, metabolic stability (Cl_mic, t1/2), and, crucially, binding affinity. Ligand B has a better BBB score and DILI, but the significantly weaker binding affinity and poorer drug-like properties are major concerns. Given the importance of affinity for GPCRs, and the substantial difference in binding energy, Ligand A is the more promising candidate, despite its slightly lower BBB score. The negative Caco-2 values are a concern for both, but the superior binding and ADME profile of Ligand A make it the better choice for further optimization.

Output:
0
2025-04-17 03:09:34,470 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (388.965 and 362.455 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (57.7) is significantly better than Ligand B (76.46). For CNS targets, we want TPSA <= 90, and A is much closer to the optimal <=60 range. B is pushing the upper limit and could have permeability issues.

**3. logP:** Ligand A (3.742) is within the optimal 1-3 range. Ligand B (1.52) is at the lower end, potentially hindering permeability.

**4. H-Bond Donors:** Both have 1 HBD, which is acceptable.

**5. H-Bond Acceptors:** Both have 6 HBA, which is acceptable.

**6. QED:** Both ligands have good QED scores (0.804 and 0.895), indicating good drug-like properties.

**7. DILI:** Ligand A (56.572) and Ligand B (71.113) both have acceptable DILI risk, but A is better.

**8. BBB:** Ligand A (80.419) has a significantly better BBB percentile than Ligand B (64.676). This is *critical* for a CNS target like DRD2.

**9. Caco-2 Permeability:** Ligand A (-4.676) is better than Ligand B (-5.133), indicating better intestinal absorption.

**10. Aqueous Solubility:** Ligand A (-4.416) is better than Ligand B (-2.627).

**11. hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.656 and 0.367).

**12. Microsomal Clearance:** Ligand A (70.363) is higher than Ligand B (35.075), meaning B has better metabolic stability.

**13. In vitro Half-Life:** Ligand A (63.603) is better than Ligand B (35.698).

**14. P-gp Efflux:** Both ligands have low P-gp efflux liability (0.347 and 0.208).

**15. Binding Affinity:** Ligand A (-7.6) has a slightly better binding affinity than Ligand B (-0.0). This is a *major* advantage.

**Overall Assessment:**

Ligand A is clearly superior. While Ligand B has better metabolic stability (lower Cl_mic), the significant advantages of Ligand A in TPSA, logP, BBB penetration, solubility, and *especially* binding affinity outweigh this single benefit. For a CNS GPCR target, BBB penetration is paramount, and Ligand A excels in this area. The stronger binding affinity of Ligand A also suggests a higher probability of efficacy.

Output:
1
2025-04-17 03:09:34,471 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 drug candidates, considering the provided guidelines and GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (383.798 Da) is slightly higher than Ligand B (342.403 Da), but both are acceptable.

**TPSA:** Ligand A (53.09) is excellent for CNS penetration, well below the 90 A^2 threshold. Ligand B (87.12) is higher, but still potentially acceptable, though less ideal.

**logP:** Ligand A (1.063) is within the optimal range (1-3). Ligand B (0.277) is a bit low, potentially hindering permeability.

**H-Bond Donors/Acceptors:** Ligand A (0 HBD, 4 HBA) and Ligand B (1 HBD, 5 HBA) both have reasonable numbers of H-bond donors and acceptors, falling within the guidelines.

**QED:** Both ligands have good QED scores (Ligand A: 0.681, Ligand B: 0.864), indicating good drug-like properties.

**DILI:** Ligand A (45.173) has a slightly higher DILI risk than Ligand B (30.516), but both are below the concerning threshold of 60.

**BBB:** This is a critical parameter for CNS targets. Ligand A has a significantly better BBB penetration score (79.566) compared to Ligand B (36.293). This is a major advantage for Ligand A.

**Caco-2 Permeability:** Ligand A (-4.553) has poor Caco-2 permeability, while Ligand B (-5.53) is even worse. Both are very poor, but this is less critical than BBB for a CNS target.

**Aqueous Solubility:** Both ligands have poor aqueous solubility (-1.217 and -1.016 respectively). This could pose formulation challenges, but is not a dealbreaker.

**hERG Inhibition:** Both ligands show very low hERG inhibition risk (0.447 and 0.134 respectively).

**Microsomal Clearance:** Ligand A (-7.737) has significantly better metabolic stability (lower clearance) than Ligand B (2.946).

**In vitro Half-Life:** Ligand A (-11.984) has a much longer half-life than Ligand B (-29.244).

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.044 and 0.007 respectively).

**Binding Affinity:** Both ligands have the same binding affinity (-7.6 kcal/mol), which is excellent.

**Overall Assessment:**

Considering the GPCR-specific priorities, Ligand A is the more promising candidate. While both have excellent binding affinity, Ligand A's superior BBB penetration (79.6% vs 36.3%), better metabolic stability (lower Cl_mic and longer t1/2), and slightly lower DILI risk outweigh its slightly poorer Caco-2 permeability and solubility. Ligand B's low logP and poor BBB penetration are significant drawbacks for a CNS-targeted drug.

Output:
1
2025-04-17 03:09:34,471 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (338.403 Da) is slightly lower, which could be beneficial for permeability. Ligand B (364.515 Da) is also acceptable.

**TPSA:** Ligand A (52.6) is excellent, well below the 90 A^2 threshold for CNS targets. Ligand B (65.54) is still reasonable, but less optimal.

**logP:** Ligand A (3.715) is at the upper end of the optimal range (1-3), but still acceptable. Ligand B (1.73) is lower, potentially hindering permeation.

**H-Bond Donors/Acceptors:** Ligand A (0 HBD, 4 HBA) is favorable. Ligand B (1 HBD, 5 HBA) is also acceptable.

**QED:** Both ligands have good QED values (A: 0.753, B: 0.827), indicating good drug-like properties.

**DILI:** Ligand A (59.17) has a moderate DILI risk, but is still acceptable. Ligand B (19.038) has a very low DILI risk, which is a significant advantage.

**BBB:** Both ligands have good BBB penetration (A: 63.629, B: 68.282), but Ligand B is slightly better. Both are above the 70% threshold for CNS targets.

**Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and suggests a potential issue with the data or modeling. However, we can still compare their relative values. Ligand A (-4.399) is slightly better than Ligand B (-4.961).

**Aqueous Solubility:** Both have negative solubility values, which is also unusual. Ligand A (-5.52) is slightly better than Ligand B (-1.729).

**hERG Inhibition:** Both ligands have low hERG inhibition risk (A: 0.516, B: 0.478).

**Microsomal Clearance:** Ligand A (122.505) has higher clearance than Ligand B (2.89), indicating lower metabolic stability.

**In vitro Half-Life:** Ligand A (24.277 hours) has a better in vitro half-life than Ligand B (-6.007 hours).

**P-gp Efflux:** Ligand A (0.79) has slightly higher P-gp efflux than Ligand B (0.11), which is less desirable for CNS exposure.

**Binding Affinity:** Ligand B (-7.9 kcal/mol) has a significantly stronger binding affinity than Ligand A (-9.4 kcal/mol). This difference of 1.5 kcal/mol is substantial and can outweigh some ADME drawbacks.

**Overall Assessment:**

Ligand B is the stronger candidate. While Ligand A has slightly better Caco-2 permeability and in vitro half-life, Ligand B excels in key areas for a CNS-targeting GPCR ligand: significantly better binding affinity, lower DILI risk, better BBB penetration, and much lower P-gp efflux. The slightly higher logP of Ligand A is less critical given the strong affinity of Ligand B. The metabolic stability of Ligand B is also significantly better.



Output:
1
2025-04-17 03:09:34,471 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (349.387 and 355.479 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (107.11) is slightly above the optimal <90 for CNS targets, while Ligand B (92.94) is comfortably within the range. This gives a slight edge to Ligand B.

**3. logP:** Ligand A (0.039) is quite low, potentially hindering permeability. Ligand B (1.008) is within the optimal 1-3 range. This is a significant advantage for Ligand B.

**4. H-Bond Donors:** Ligand A (2) and Ligand B (1) are both acceptable, being less than 5.

**5. H-Bond Acceptors:** Ligand A (6) and Ligand B (4) are both acceptable, being less than 10.

**6. QED:** Both ligands have similar QED values (0.727 and 0.737), indicating good drug-likeness.

**7. DILI:** Ligand A (30.981) has a slightly higher DILI risk than Ligand B (24.777), but both are below the concerning threshold of 60.

**8. BBB:** Ligand B (71.035) has a significantly better BBB penetration percentile than Ligand A (40.326). This is a crucial advantage for a CNS target like DRD2.

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.846 and -4.646), which is unusual and suggests poor permeability. However, these values are on a scale where higher is better, so these are both quite poor.

**10. Aqueous Solubility:** Both ligands have negative solubility values (-1.646 and -2.257), which is also unusual and suggests poor solubility.

**11. hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.162 and 0.172).

**12. Microsomal Clearance:** Ligand A (7.4) has a much lower microsomal clearance than Ligand B (38.759), indicating better metabolic stability.

**13. In vitro Half-Life:** Ligand A (12.297) has a longer in vitro half-life than Ligand B (3.68). This is a positive for Ligand A.

**14. P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.037 and 0.027).

**15. Binding Affinity:** Ligand B (-6.5 kcal/mol) has a slightly better binding affinity than Ligand A (-8.0 kcal/mol). While Ligand A has a better affinity, the difference is not substantial enough to overcome the other deficiencies.

**Overall Assessment:**

Ligand B is the more promising candidate. While both have issues with Caco-2 and solubility, Ligand B excels in key areas for CNS GPCR targets: better logP, significantly better BBB penetration, and acceptable TPSA. Ligand A has better metabolic stability and half-life, but its poor logP and lower BBB penetration are significant drawbacks for a CNS drug. The slightly better affinity of Ligand A is not enough to offset these issues.

Output:
1
2025-04-17 03:09:34,471 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 drug candidates, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (363.889 Da and 355.478 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (84.22) is significantly better than Ligand B (20.31). For a CNS target like DRD2, a TPSA <= 90 is preferred, and Ligand A is comfortably within this range. Ligand B is *very* low, which could indicate poor interaction with the receptor despite potentially good permeability.

**3. logP:** Both ligands have acceptable logP values (3.126 and 4.851), falling within the 1-3 optimal range, though Ligand B is slightly higher.

**4. H-Bond Donors:** Ligand A has 3 HBD, which is acceptable. Ligand B has 0, which is also acceptable, but might contribute to lower binding affinity.

**5. H-Bond Acceptors:** Ligand A has 3 HBA, acceptable. Ligand B has 2, also acceptable.

**6. QED:** Ligand A (0.703) has a better QED score than Ligand B (0.412), indicating a more drug-like profile.

**7. DILI:** Both ligands have similar DILI risk (49.399 and 52.734), both being reasonably low and below the 60 threshold.

**8. BBB:** Ligand B (85.343) has a significantly better BBB percentile than Ligand A (75.727). This is a critical factor for CNS targets.

**9. Caco-2:** Both have negative Caco-2 values, which is unusual and difficult to interpret without knowing the scale. Assuming these are logP-like scales, lower values suggest poorer permeability.

**10. Solubility:** Both ligands have negative solubility values, again, difficult to interpret. Lower values suggest poor solubility.

**11. hERG:** Both ligands have low hERG inhibition liability (0.611 and 0.873), which is good.

**12. Cl_mic:** Ligand A (16.121) has a much lower microsomal clearance than Ligand B (109.217), indicating better metabolic stability.

**13. t1/2:** Ligand A (4.666) has a shorter half-life than Ligand B (9.459), but both are relatively low.

**14. Pgp:** Ligand A (0.067) has much lower P-gp efflux liability than Ligand B (0.89), which is highly desirable for CNS penetration.

**15. Binding Affinity:** Ligand B (-8.1) has a slightly better binding affinity than Ligand A (-9.0). While a 1.1 kcal/mol difference is noticeable, the other ADME properties are more concerning for Ligand B.

**Overall Assessment:**

Ligand A is the stronger candidate. While Ligand B has a slightly better binding affinity and BBB penetration, Ligand A excels in critical ADME properties like TPSA, QED, metabolic stability (Cl_mic), and P-gp efflux. The lower TPSA and P-gp efflux of Ligand A are particularly important for CNS penetration, and its better QED suggests a more balanced drug-like profile. The slightly lower BBB of Ligand A is a concern, but can potentially be addressed with further optimization. The negative solubility and Caco-2 values are concerning for both, but can be addressed during lead optimization.



Output:
1
2025-04-17 03:09:34,471 - INFO - Reasoning:

Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight (MW):** Both ligands (345.403 and 350.419 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (80.03) is significantly better than Ligand B (104.65). For CNS targets, we want TPSA <= 90, and A is comfortably within that, while B is pushing the limit.

**3. logP:** Both ligands have similar logP values (0.648 and 0.606), which are slightly below the optimal 1-3 range. This could potentially impact permeability, but isn't a major concern at this stage.

**4. H-Bond Donors (HBD):** Ligand A (0) is preferable to Ligand B (2). Lower HBD generally improves permeability.

**5. H-Bond Acceptors (HBA):** Ligand A (6) is better than Ligand B (7). Lower HBA is also generally preferable for permeability.

**6. QED:** Both ligands have acceptable QED values (0.805 and 0.724), indicating good drug-like properties.

**7. DILI:** Ligand A (47.77) has a slightly higher DILI risk than Ligand B (30.593), but both are below the concerning threshold of 60.

**8. BBB:** Both ligands have similar and good BBB penetration (65.956 and 65.374). While >70 is desirable, both are reasonably acceptable.

**9. Caco-2:** Both ligands have negative Caco-2 values (-4.617 and -4.901), which is unusual and suggests poor permeability. This is a significant drawback for both.

**10. Solubility:** Both ligands have negative solubility values (-1.75 and -1.38), indicating very poor aqueous solubility. This is a major issue for both compounds.

**11. hERG:** Both ligands have low hERG inhibition liability (0.158 and 0.23), which is good.

**12. Cl_mic:** Ligand A (22.389) has lower microsomal clearance than Ligand B (30.919), suggesting better metabolic stability.

**13. t1/2:** Ligand A (1.016) has a shorter in vitro half-life than Ligand B (-22.786). A negative half-life is not physically possible and indicates an error in the data or a very rapid degradation.

**14. Pgp:** Both ligands have very low P-gp efflux liability (0.039 and 0.006), which is excellent for CNS penetration.

**15. Binding Affinity:** Ligand A (-8.7 kcal/mol) has a slightly better binding affinity than Ligand B (-7.9 kcal/mol). A difference of 0.8 kcal/mol is meaningful, and can outweigh some ADME concerns.

**Overall Assessment:**

Ligand A is the better candidate despite the poor Caco-2 and solubility. The significantly lower TPSA, lower HBD/HBA, better metabolic stability (lower Cl_mic), and slightly better affinity outweigh the slightly higher DILI risk and shorter half-life. The negative solubility and Caco-2 values are concerning for both, but can potentially be addressed with formulation strategies. Ligand B's negative half-life is a red flag.

Output:
1
2025-04-17 03:09:34,471 - INFO - Reasoning:

Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (349.431 and 353.419 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (84.67) is excellent, falling well below the 90 A^2 threshold for CNS targets. Ligand B (113.69) is still reasonable but less optimal, being closer to the 140 A^2 threshold for oral absorption.

**3. logP:** Ligand A (1.767) is within the optimal range of 1-3. Ligand B (0.548) is slightly low, potentially hindering permeation.

**4. H-Bond Donors:** Ligand A (1) is good. Ligand B (3) is acceptable but higher.

**5. H-Bond Acceptors:** Ligand A (5) is good. Ligand B (6) is acceptable.

**6. QED:** Ligand A (0.895) is excellent, indicating a highly drug-like profile. Ligand B (0.566) is acceptable, but lower.

**7. DILI:** Ligand A (40.83) is good, indicating low liver injury risk. Ligand B (32.299) is even better.

**8. BBB:** Ligand A (77.705) is good, exceeding the 70% threshold for CNS targets. Ligand B (55.68) is considerably lower, raising concerns about CNS penetration.

**9. Caco-2:** Both ligands have negative Caco-2 values (-4.682 and -5.172), which is unusual and suggests poor permeability. This is a significant drawback for both.

**10. Solubility:** Both ligands have negative solubility values (-1.706 and -0.779), which is also unusual and suggests poor solubility. This is a significant drawback for both.

**11. hERG:** Both ligands have very low hERG inhibition liability (0.231 and 0.059), which is excellent.

**12. Cl_mic:** Ligand A (46.74) is higher than Ligand B (37.938), suggesting faster metabolism and lower metabolic stability.

**13. t1/2:** Ligand A (-25.594) is significantly worse than Ligand B (-7.248), indicating a very short half-life.

**14. Pgp:** Both ligands have very low Pgp efflux liability (0.071 and 0.031), which is excellent.

**15. Binding Affinity:** Ligand A (-9.3 kcal/mol) has a considerably stronger binding affinity than Ligand B (-6.9 kcal/mol). The difference of 2.4 kcal/mol is substantial and can outweigh some ADME drawbacks.

**Overall Assessment:**

Despite the unusual negative values for Caco-2 and Solubility, Ligand A is the more promising candidate. Its superior binding affinity (-9.3 vs -6.9 kcal/mol) is a major advantage for a GPCR target. It also has a better TPSA and QED score and a good BBB percentile. While its metabolic stability (Cl_mic) and half-life are worse than Ligand B, the strong binding affinity is likely to be more critical for efficacy. Ligand B's lower logP and significantly lower BBB penetration are major concerns for a CNS target.



Output:
0
2025-04-17 03:09:34,472 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (337.379) is slightly lower, which could be advantageous for permeability.

**TPSA:** Ligand A (78.11) is excellent for CNS penetration, well below the 90 A^2 threshold. Ligand B (130.48) is higher, but still potentially acceptable, though less ideal.

**logP:** Ligand A (3.92) is optimal. Ligand B (-1.909) is significantly lower, which is a major concern for CNS penetration. A negative logP often translates to poor membrane permeability.

**H-Bond Donors/Acceptors:** Ligand A (0 HBD, 6 HBA) is favorable. Ligand B (3 HBD, 7 HBA) is also acceptable, though slightly higher.

**QED:** Both ligands have reasonable QED values (A: 0.657, B: 0.444), suggesting drug-like properties, but A is better.

**DILI:** Ligand A (77.007) has a higher DILI risk than Ligand B (52.617), but both are below the concerning threshold of 60.

**BBB:** Both ligands have good BBB penetration (A: 70.143, B: 70.648), exceeding the 70% threshold.

**Caco-2 Permeability:** Ligand A (-4.649) has poor Caco-2 permeability, which is concerning. Ligand B (-5.418) is also poor, but slightly worse.

**Aqueous Solubility:** Ligand A (-4.465) and Ligand B (-0.977) both have poor aqueous solubility.

**hERG Inhibition:** Both ligands have very low hERG inhibition risk (A: 0.367, B: 0.086).

**Microsomal Clearance:** Ligand A (126.817) has higher microsomal clearance, indicating faster metabolism. Ligand B (-4.495) has negative clearance, which is not physically possible and likely indicates an error or extrapolation issue in the prediction. This is a significant red flag.

**In vitro Half-Life:** Ligand A (-39.811) has a negative half-life, which is not physically possible and suggests a problem with the prediction. Ligand B (21.964) has a reasonable half-life.

**P-gp Efflux:** Both ligands have low P-gp efflux (A: 0.314, B: 0.008), which is favorable for CNS exposure.

**Binding Affinity:** Ligand B (-7.2 kcal/mol) has a significantly stronger binding affinity than Ligand A (-9.4 kcal/mol). This is a substantial advantage.

**Overall Assessment:**

Ligand B has a much stronger binding affinity, which is a critical factor for GPCRs. However, its negative logP is a major drawback for CNS penetration. The negative clearance and half-life values are also highly suspicious. Ligand A has better physicochemical properties (logP, TPSA) for CNS penetration, but its Caco-2 permeability is poor, and its binding affinity is significantly weaker. The negative half-life is also a concern.

Despite the issues with the predicted values for Ligand B, the substantial difference in binding affinity is compelling. The negative logP can potentially be addressed through structural modifications. The negative clearance/half-life values are concerning, but may be prediction artifacts. Ligand A's weak affinity is harder to overcome.

Output:
1
2025-04-17 03:09:34,472 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (348.338 and 346.435 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (114.09) is slightly above the optimal <90 for CNS targets, while Ligand B (105.98) is closer to the ideal range.

**logP:** Both ligands have good logP values (1.613 and 1.36), falling within the 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A has 2 HBD and 7 HBA, while Ligand B has 1 HBD and 5 HBA. Both are within acceptable limits (<=5 HBD and <=10 HBA).

**QED:** Both ligands have similar QED scores (0.786 and 0.75), indicating good drug-likeness.

**DILI:** Ligand A has a DILI risk of 79.992, which is concerning (high risk, >60). Ligand B has a much lower DILI risk (27.608), indicating a significantly better safety profile.

**BBB:** Ligand A has a BBB penetration of 64.87%, which is below the desirable >70% for CNS targets. Ligand B has a BBB penetration of 55.991%, also below the desired threshold.

**Caco-2 Permeability:** Ligand A (-4.578) and Ligand B (-5.396) both have negative Caco-2 values, which is unusual and suggests poor permeability.

**Aqueous Solubility:** Ligand A (-4.211) and Ligand B (-1.468) both have negative solubility values, indicating poor aqueous solubility.

**hERG Inhibition:** Both ligands have low hERG inhibition liability (0.299 and 0.26), which is good.

**Microsomal Clearance:** Ligand A (61.279) has a higher microsomal clearance than Ligand B (-4.678). Negative clearance is not possible, so this is likely an error in the data, but it suggests Ligand B is more metabolically stable.

**In vitro Half-Life:** Ligand A has a half-life of 17.718 hours, while Ligand B has a half-life of -13.504 hours. Again, negative half-life is not possible, suggesting an error in the data.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.093 and 0.018), which is favorable for CNS penetration.

**Binding Affinity:** Both ligands have excellent binding affinities (-8.0 and -8.1 kcal/mol), with Ligand B being slightly better. The difference is less than 1.5 kcal/mol, so it's not a decisive factor on its own.

**Overall Assessment:**

While both ligands have good binding affinity and acceptable physicochemical properties (MW, logP, HBD/HBA, QED, P-gp), Ligand B is significantly better due to its much lower DILI risk. The BBB penetration for both is suboptimal, but the lower DILI risk of Ligand B outweighs this concern. The negative values for Caco-2 and half-life are concerning and should be investigated, but the overall profile of Ligand B is more promising.

Output:
1
2025-04-17 03:09:34,472 - INFO - Batch 5 complete. Total preferences: 80
2025-04-17 03:09:34,472 - INFO - Processing batch 6/512...
2025-04-17 03:10:15,925 - INFO - Reasoning:

Let's analyze Ligand A and Ligand B for their potential as DRD2 drug candidates, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (364.446) is slightly higher than Ligand B (339.487), but both are acceptable.

**2. TPSA:** Both ligands have TPSA values below the 90 A^2 threshold desirable for CNS targets. Ligand A (66.4) is slightly higher than Ligand B (62.73), but both are good.

**3. logP:** Ligand A (1.961) is within the optimal range (1-3). Ligand B (4.073) is a bit high, potentially leading to solubility issues and off-target interactions.

**4. H-Bond Donors:** Ligand A (0) is preferable to Ligand B (2) as fewer HBDs generally improve permeability.

**5. H-Bond Acceptors:** Both ligands have 5 HBA, which is acceptable (<=10).

**6. QED:** Both ligands have similar QED values (0.766 and 0.71), indicating good drug-likeness.

**7. DILI:** Ligand A (55.176) has a lower DILI risk than Ligand B (19.542), which is a significant advantage.

**8. BBB:** Both ligands have excellent BBB penetration (>70), with Ligand A at 84.141 and Ligand B at 83.986. This is crucial for a CNS target like DRD2.

**9. Caco-2 Permeability:** Ligand A (-4.608) has a worse Caco-2 permeability than Ligand B (-5.08). Lower values indicate lower permeability.

**10. Aqueous Solubility:** Ligand A (-2.422) has slightly better aqueous solubility than Ligand B (-3.543).

**11. hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.213 and 0.886), which is excellent.

**12. Microsomal Clearance:** Ligand A (27.567) has lower microsomal clearance than Ligand B (50.047), suggesting better metabolic stability.

**13. In vitro Half-Life:** Ligand B (28.708) has a longer in vitro half-life than Ligand A (-6.865).

**14. P-gp Efflux:** Both ligands have low P-gp efflux liability (0.122 and 0.262), which is favorable for CNS penetration.

**15. Binding Affinity:** Both ligands have very similar, strong binding affinities (-8.6 and -8.7 kcal/mol). The difference is negligible.

**Overall Assessment:**

Ligand A is the better candidate. While Ligand B has a slightly longer half-life, Ligand A excels in several critical areas: lower DILI risk, better logP, fewer H-bond donors, and better metabolic stability (lower Cl_mic). The similar binding affinity makes these differences decisive. The slightly worse Caco-2 permeability of Ligand A is less concerning given the importance of BBB penetration for a CNS target.

Output:
1
2025-04-17 03:10:15,926 - INFO - Reasoning:

Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (363.849 and 343.431 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (88.05) is excellent, well below the 90 A^2 threshold for CNS targets. Ligand B (110) is still reasonable but less optimal, exceeding the preferred threshold.

**3. logP:** Ligand A (3.42) is within the optimal 1-3 range. Ligand B (1.572) is on the lower end, potentially hindering permeability.

**4. H-Bond Donors:** Both ligands have 3 HBD, which is acceptable.

**5. H-Bond Acceptors:** Ligand A has 4 HBA, and Ligand B has 5. Both are within the acceptable limit of 10.

**6. QED:** Both ligands have QED values above 0.6, indicating good drug-likeness.

**7. DILI:** Ligand A (83.443) has a higher DILI risk than Ligand B (51.221). This is a concern for Ligand A.

**8. BBB:** Both ligands have reasonable BBB penetration (Ligand A: 60.876, Ligand B: 63.629). However, neither exceeds the desirable >70 percentile for CNS targets.

**9. Caco-2 Permeability:** Ligand A (-4.902) has poor Caco-2 permeability, while Ligand B (-5.3) is also poor. Both are significantly negative, indicating very low permeability.

**10. Aqueous Solubility:** Ligand A (-4.754) and Ligand B (-3.383) both have poor aqueous solubility.

**11. hERG Inhibition:** Both ligands show low hERG inhibition risk (Ligand A: 0.336, Ligand B: 0.189).

**12. Microsomal Clearance:** Ligand A (36.655) has higher microsomal clearance than Ligand B (19.674), suggesting lower metabolic stability.

**13. In vitro Half-Life:** Ligand A (119.734) has a longer half-life than Ligand B (-4.908).

**14. P-gp Efflux:** Both ligands show low P-gp efflux (Ligand A: 0.092, Ligand B: 0.017), which is favorable for CNS penetration.

**15. Binding Affinity:** Ligand B (-8.5 kcal/mol) has a slightly better binding affinity than Ligand A (-8.2 kcal/mol). While the difference is small, it is still a factor.

**Overall Assessment:**

Considering the GPCR-specific priorities, Ligand A has a better TPSA, but Ligand B has a better logP, lower DILI risk, lower microsomal clearance, and slightly better binding affinity. The poor Caco-2 permeability and solubility of both are concerning, but the slightly better overall profile of Ligand B, particularly its lower DILI and better affinity, makes it the more promising candidate. The slightly better half-life of Ligand A is not enough to overcome the other drawbacks.

Output:
1
2025-04-17 03:10:15,926 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (371.815 and 351.359 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (62.3) is excellent, well below the 90 A^2 threshold for CNS targets. Ligand B (110.11) is higher, but still potentially acceptable, though less ideal.

**3. logP:** Ligand A (3.003) is optimal. Ligand B (0.111) is significantly low, which could impede membrane permeability and reduce CNS exposure.

**4. H-Bond Donors:** Ligand A (1) and Ligand B (2) are both within the acceptable limit of <=5.

**5. H-Bond Acceptors:** Ligand A (3) and Ligand B (6) are both within the acceptable limit of <=10.

**6. QED:** Both ligands have similar QED values (0.782 and 0.779), indicating good drug-like properties.

**7. DILI:** Both ligands have acceptable DILI risk (52.772 and 57.929), below the 60 threshold.

**8. BBB:** Ligand A (94.339) has excellent BBB penetration, exceeding the desirable >70% for CNS targets. Ligand B (50.679) is significantly lower, raising concerns about its ability to reach the brain.

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.621 and -4.87), which is unusual and suggests poor permeability. However, these values are on a log scale and might not be directly comparable.

**10. Aqueous Solubility:** Both ligands have negative solubility values (-3.624 and -2.308), indicating poor aqueous solubility. This is a concern for formulation and bioavailability.

**11. hERG Inhibition:** Both ligands show low hERG inhibition risk (0.556 and 0.128).

**12. Microsomal Clearance:** Ligand A (45.696) has moderate clearance, while Ligand B (-40.235) has negative clearance, which is not physically possible and likely indicates an issue with the prediction or data quality.

**13. In vitro Half-Life:** Ligand A (4.266 hours) is reasonable. Ligand B (8.194 hours) is better.

**14. P-gp Efflux:** Ligand A (0.228) has low P-gp efflux, which is favorable for CNS penetration. Ligand B (0.009) also has very low P-gp efflux.

**15. Binding Affinity:** Ligand A (-8.5 kcal/mol) has a stronger binding affinity than Ligand B (-7.7 kcal/mol). The 0.8 kcal/mol difference is significant and could outweigh some of the ADME drawbacks.

**Overall Assessment:**

Ligand A is the more promising candidate. Its superior BBB penetration, optimal logP, and stronger binding affinity are crucial for a CNS-targeting GPCR like DRD2. While both ligands have solubility and permeability concerns (indicated by negative Caco-2 and solubility values), the stronger affinity and better CNS exposure profile of Ligand A make it the preferred choice. The negative clearance value for Ligand B is a red flag and suggests potential issues with its predicted properties.

Output:
1
2025-04-17 03:10:15,926 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (348.349 and 365.474 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (65.22) is higher than Ligand B (43.86). For CNS targets, we prefer TPSA <= 90, so both are acceptable, but B is better.

**3. logP:** Ligand A (3.746) is slightly higher than Ligand B (2.417), both are within the optimal 1-3 range.

**4. H-Bond Donors:** Both have 0 HBD, which is good.

**5. H-Bond Acceptors:** Ligand A has 5 HBA, and Ligand B has 4. Both are below the acceptable limit of 10.

**6. QED:** Both ligands have similar QED values (0.744 and 0.752), indicating good drug-likeness.

**7. DILI:** Ligand A (63.823) has a higher DILI risk than Ligand B (40.403). Ligand B is preferable here.

**8. BBB:** Both ligands have excellent BBB penetration (96.937 and 92.012), exceeding the desirable >70 threshold for CNS targets.

**9. Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and suggests poor permeability. However, these values are on a scale where negative values are possible, and we must consider other factors.

**10. Aqueous Solubility:** Both have negative solubility values, which is also unusual. This suggests poor aqueous solubility.

**11. hERG Inhibition:** Ligand A (0.207) has a slightly higher hERG inhibition risk than Ligand B (0.833). Ligand B is preferable.

**12. Microsomal Clearance:** Ligand A (75.804) has higher microsomal clearance than Ligand B (38.414), indicating lower metabolic stability. Ligand B is preferable.

**13. In vitro Half-Life:** Ligand B (5.596) has a longer in vitro half-life than Ligand A (-20.698). This is a significant advantage for Ligand B.

**14. P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.301 and 0.134), which is good for CNS exposure.

**15. Binding Affinity:** Both ligands have similar and strong binding affinities (-9.3 and -9.5 kcal/mol). The difference is minimal.

**Overall Assessment:**

Considering the GPCR-specific priorities, Ligand B is the better candidate. It has a lower DILI risk, better metabolic stability (lower Cl_mic, longer t1/2), and a slightly lower hERG risk. While both have similar affinity and BBB penetration, the ADME properties of Ligand B are more favorable. The negative solubility and Caco-2 values are concerning for both, but the other advantages of B outweigh this.

Output:
1
2025-04-17 03:10:15,926 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B based on the provided guidelines, prioritizing GPCR-specific properties (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (379.404) is slightly higher than Ligand B (337.402), but both are acceptable.

**TPSA:** Ligand A (101.29) is better than Ligand B (45.46) for CNS penetration, falling closer to the desired <90 A^2 for CNS targets. Ligand B is still reasonable.

**logP:** Ligand A (1.271) is within the optimal range (1-3), while Ligand B (3.734) is approaching the upper limit. While not a dealbreaker, higher logP can sometimes lead to off-target effects.

**H-Bond Donors/Acceptors:** Ligand A has 3 HBD and 4 HBA, while Ligand B has 1 HBD and 5 HBA. Both are within acceptable limits (<=5 HBD and <=10 HBA).

**QED:** Both ligands have similar QED values (0.693 and 0.721), indicating good drug-likeness.

**DILI:** Ligand A (41.877) has a significantly lower DILI risk than Ligand B (81). This is a substantial advantage for Ligand A.

**BBB:** Both ligands have good BBB penetration (Ligand A: 61.38, Ligand B: 68.437), but Ligand B is slightly better. However, both are below the desirable >70 for CNS targets.

**Caco-2 Permeability:** Ligand A (-5.433) has poor Caco-2 permeability, while Ligand B (-4.725) is also poor, but slightly better.

**Aqueous Solubility:** Both ligands have poor aqueous solubility (-2.882 and -3.902 respectively).

**hERG Inhibition:** Ligand A (0.455) has a lower hERG risk than Ligand B (0.918).

**Microsomal Clearance:** Ligand A (3.783) has lower microsomal clearance than Ligand B (50.753), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (-27.696) has a very poor in vitro half-life, while Ligand B (-2.83) is better, but still not ideal.

**P-gp Efflux:** Ligand A (0.047) has significantly lower P-gp efflux liability than Ligand B (0.691), which is crucial for CNS penetration.

**Binding Affinity:** Both ligands have similar binding affinities (-9.0 and -8.3 kcal/mol). Ligand A is slightly better, but the difference is not substantial enough to outweigh other factors.

**Overall Assessment:**

Ligand A is the stronger candidate. While it has poor Caco-2 permeability and a very short half-life, its significantly lower DILI risk, lower P-gp efflux, lower hERG risk, and better metabolic stability (lower Cl_mic) are compelling advantages, especially for a CNS target. The slightly better TPSA is also favorable. Ligand B's higher logP and DILI risk are concerning. The slightly better BBB penetration of Ligand B is not enough to offset the other drawbacks. The affinity difference is minimal.

Output:
0
2025-04-17 03:10:15,927 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B based on the provided guidelines, prioritizing GPCR-specific properties (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (392.937 Da) is slightly higher than Ligand B (354.431 Da), but both are acceptable.

**TPSA:** Both ligands have TPSA values below 90, which is favorable for CNS penetration. Ligand B (60.67) is slightly better than Ligand A (66.91).

**logP:** Both ligands have logP values within the optimal range (1-3). Ligand A (4.05) is slightly above the ideal range, potentially raising concerns about solubility and off-target effects, while Ligand B (3.55) is closer to optimal.

**H-Bond Donors & Acceptors:** Ligand A has 2 HBD and 6 HBA, while Ligand B has 0 HBD and 6 HBA. Both are within acceptable limits.

**QED:** Both ligands have QED values above 0.5, indicating good drug-likeness. Ligand B (0.658) is slightly better than Ligand A (0.594).

**DILI:** Ligand A (84.296) has a higher DILI risk than Ligand B (65.723). This is a significant negative for Ligand A.

**BBB:** Both ligands have good BBB penetration (Ligand A: 81.233, Ligand B: 79.411). Ligand A is slightly better, but both are above the 70% threshold.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values, which is unusual and suggests poor permeability. However, the scale is not defined, so it's difficult to interpret.

**Aqueous Solubility:** Both ligands have negative solubility values, indicating poor aqueous solubility. This is a concern for both.

**hERG Inhibition:** Ligand A (0.811) has a slightly higher hERG inhibition liability than Ligand B (0.264). Lower is better, so Ligand B is preferable.

**Microsomal Clearance:** Ligand A (96.819) has a higher microsomal clearance than Ligand B (101.065), meaning it's less metabolically stable.

**In vitro Half-Life:** Ligand B (-16.753) has a negative half-life, which is not possible and indicates an issue with the data. Ligand A (88.992) has a good half-life.

**P-gp Efflux:** Ligand A (0.824) has a higher P-gp efflux liability than Ligand B (0.6). Lower is better, so Ligand B is preferable.

**Binding Affinity:** Ligand B (-9.6 kcal/mol) has a significantly stronger binding affinity than Ligand A (-8.7 kcal/mol). This is a crucial advantage, potentially outweighing some of the ADME drawbacks.

**Overall Assessment:**

Ligand B is the more promising candidate. While both have solubility and permeability concerns (indicated by negative values), Ligand B exhibits a significantly stronger binding affinity, lower DILI risk, lower hERG inhibition, and lower P-gp efflux. The negative half-life for Ligand B is a data quality issue that needs to be addressed, but the other factors strongly favor it. Ligand A's higher logP and DILI risk are significant drawbacks.

Output:
1
2025-04-17 03:10:15,927 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (372.535 Da and 352.431 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (65.12) is significantly better than Ligand B (84.94). For CNS targets, we want TPSA <= 90, and ideally closer to 60. Ligand A is much closer to this ideal.

**logP:** Ligand A (-0.283) is a bit low, potentially hindering permeability. Ligand B (1.004) is within the optimal 1-3 range. This favors Ligand B slightly.

**H-Bond Donors/Acceptors:** Both have 1 HBD, which is good. Ligand A has 6 HBA, and Ligand B has 5 HBA, both acceptable.

**QED:** Both ligands have good QED scores (0.663 and 0.746), indicating drug-likeness.

**DILI:** Ligand A (21.52) has a much lower DILI risk than Ligand B (41.838). Lower is better, and Ligand A is comfortably below the 40% threshold.

**BBB:** Ligand A (34.199) has a poor BBB penetration percentile. Ligand B (54.634) is better, but still not ideal (we want >70 for CNS targets). This is a significant drawback for both, but more so for Ligand A.

**Caco-2 Permeability:** Both have negative Caco-2 values (-5.29 and -4.727), which is unusual and suggests poor permeability. This is a concern for both.

**Aqueous Solubility:** Both have negative solubility values (-1.081 and -2.037), which is also concerning.

**hERG:** Both ligands have very low hERG inhibition liability (0.205 and 0.112), which is excellent.

**Microsomal Clearance:** Ligand A (12.122) has lower microsomal clearance than Ligand B (19.806), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand B (17.56) has a significantly longer half-life than Ligand A (1.22). This is a major advantage for Ligand B.

**P-gp Efflux:** Both have very low P-gp efflux liability (0.004 and 0.027), which is good for CNS penetration.

**Binding Affinity:** Ligand B (-8.9 kcal/mol) has a significantly stronger binding affinity than Ligand A (-6.1 kcal/mol). This is a substantial advantage, potentially outweighing some of the ADME concerns. The difference is >1.5 kcal/mol.

**Overall Assessment:**

While Ligand B has a better logP, longer half-life, and *much* stronger binding affinity, Ligand A has a lower DILI risk and lower microsomal clearance. The biggest issue for both is the poor BBB penetration and permeability. However, the strong affinity of Ligand B is a major advantage for a GPCR target. Given the GPCR-specific priorities, the strong binding affinity of Ligand B is the most important factor, and can potentially be optimized through structural modifications. The poor BBB and permeability are addressable through prodrug strategies or formulation approaches.

Output:
1
2025-04-17 03:10:15,927 - INFO - Reasoning:

Let's analyze Ligand A and Ligand B based on the provided guidelines, prioritizing GPCR-specific properties (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (443.084 Da) is towards the upper end, while Ligand B (357.382 Da) is more favorably positioned.

**TPSA:** Ligand A (83.7) is better than Ligand B (102.69) as it's closer to the <90 A^2 threshold for CNS targets.

**logP:** Ligand A (4.032) is slightly high, potentially leading to solubility issues, but still within an acceptable range. Ligand B (1.135) is quite low, which could hinder membrane permeability.

**H-Bond Donors/Acceptors:** Both have 2 HBDs, which is good. Ligand A has 4 HBAs, and Ligand B has 6 HBAs. Both are within the acceptable range of <=10.

**QED:** Both ligands have similar QED values (0.638 and 0.609), indicating good drug-like properties.

**DILI:** Ligand A (90.151) has a significantly higher DILI risk than Ligand B (47.77), which is a major concern.

**BBB:** Ligand B (87.902) exhibits a much better BBB penetration potential than Ligand A (21.52). This is crucial for a CNS target like DRD2.

**Caco-2 Permeability:** Ligand A (-5.158) shows poor Caco-2 permeability, while Ligand B (-4.536) is slightly better, but still not great.

**Aqueous Solubility:** Ligand A (-4.176) has very poor aqueous solubility, which is concerning. Ligand B (-2.285) is also poor, but better than A.

**hERG Inhibition:** Ligand A (0.073) has a very low hERG inhibition risk, which is excellent. Ligand B (0.421) is slightly higher, but still relatively low.

**Microsomal Clearance:** Ligand A (7.203) has a lower microsomal clearance, suggesting better metabolic stability than Ligand B (29.387).

**In vitro Half-Life:** Ligand B (-26.528) has a significantly longer in vitro half-life than Ligand A (24.192).

**P-gp Efflux:** Ligand A (0.085) has lower P-gp efflux, which is favorable for CNS penetration. Ligand B (0.107) is slightly higher.

**Binding Affinity:** Ligand A (-9.2 kcal/mol) has a significantly stronger binding affinity than Ligand B (-7.5 kcal/mol). This is a substantial advantage.

**Overall Assessment:**

While Ligand A boasts a superior binding affinity, its extremely poor solubility, low BBB penetration, and high DILI risk are significant drawbacks. Ligand B, despite having a weaker affinity, presents a much more favorable ADME profile, particularly its excellent BBB penetration and lower DILI risk, which are critical for a CNS-targeting drug. The stronger affinity of A might overcome some ADME issues, but the combination of poor solubility and high DILI makes it a less viable candidate.

Output:
1
2025-04-17 03:10:15,927 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (349.475 and 345.443 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (72.88) is excellent, well below the 90 A^2 threshold for CNS targets. Ligand B (91.32) is slightly higher but still acceptable, though less ideal.

**3. logP:** Ligand A (0.905) is a bit low, potentially hindering permeation. Ligand B (1.781) is better, falling within the optimal 1-3 range.

**4. H-Bond Donors:** Ligand A (2) and Ligand B (3) are both within the acceptable limit of <=5.

**5. H-Bond Acceptors:** Both ligands (A: 4, B: 4) are well below the 10 limit.

**6. QED:** Ligand A (0.67) is good, indicating a strong drug-like profile. Ligand B (0.47) is lower, suggesting a less favorable overall drug-likeness.

**7. DILI:** Ligand A (8.957) has a very low DILI risk, which is excellent. Ligand B (46.452) has a moderate DILI risk, but still acceptable.

**8. BBB:** Ligand A (36.409) has a relatively low BBB penetration percentile. Ligand B (27.181) is even lower. Both are below the desirable >70 for CNS targets, but Ligand A is better.

**9. Caco-2:** Both ligands have negative Caco-2 permeability values (-4.847 and -4.997), which is unusual and suggests poor intestinal absorption. This is a significant concern.

**10. Solubility:** Both ligands have negative solubility values (-1.019 and -2.422), also unusual and concerning.

**11. hERG:** Both ligands have very low hERG inhibition risk (0.141 and 0.379).

**12. Cl_mic:** Ligand A (18.077) has lower microsomal clearance than Ligand B (24.49), indicating better metabolic stability.

**13. t1/2:** Ligand A (5.612) has a shorter in vitro half-life than Ligand B (-28.577). The negative value for Ligand B is suspect and likely indicates a very rapid clearance.

**14. Pgp:** Ligand A (0.028) has very low P-gp efflux liability, which is favorable for CNS penetration. Ligand B (0.068) is slightly higher, but still low.

**15. Binding Affinity:** Ligand A (-8.0) has a slightly better binding affinity than Ligand B (-7.8). While both are good, the 0.2 kcal/mol difference is not huge, but could be meaningful.

**Overall Assessment:**

Considering the GPCR-specific priorities, Ligand A is more promising. While both have issues with Caco-2 and solubility, Ligand A has a significantly better TPSA, DILI risk, Pgp efflux, and slightly better affinity. The lower Cl_mic also suggests better metabolic stability. The BBB penetration is low for both, but Ligand A is better. The negative solubility and Caco-2 values are red flags for both compounds and would require further investigation (e.g., experimental determination). However, given the overall profile, Ligand A appears to be the more viable candidate.

Output:
0
2025-04-17 03:10:15,928 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (363.527 and 348.487 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (53.51) is significantly better than Ligand B (78.43). For CNS targets, we want TPSA <= 90, and A is comfortably within that range, while B is approaching the upper limit.

**3. logP:** Both ligands have acceptable logP values (3.25 and 2.293, respectively), falling within the optimal 1-3 range.

**4. H-Bond Donors:** Ligand A (0) is preferable to Ligand B (3). Fewer HBDs generally improve permeability.

**5. H-Bond Acceptors:** Both ligands have a similar number of HBAs (4 and 3, respectively), which are within the acceptable range of <= 10.

**6. QED:** Ligand A (0.825) has a higher QED score than Ligand B (0.527), indicating a more drug-like profile.

**7. DILI:** Ligand A (48.623) has a slightly higher DILI risk than Ligand B (22.8), but both are below the concerning threshold of 60.

**8. BBB:** Ligand A (59.519) has a much better BBB penetration percentile than Ligand B (27.763). This is *critical* for a CNS target like DRD2. A value >70 is desirable, and A is closer to that than B.

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.873 and -4.975), which is unusual and suggests poor permeability. However, these values are on a scale where negative values are possible and don't necessarily preclude development.

**10. Aqueous Solubility:** Both ligands have negative solubility values (-2.477 and -3.107), which is also unusual. This suggests poor solubility.

**11. hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.323 and 0.225, respectively).

**12. Microsomal Clearance:** Ligand A (51.871) has higher microsomal clearance than Ligand B (3.907), meaning it's likely to be metabolized faster. This is a negative for A.

**13. In vitro Half-Life:** Ligand B (19.805) has a significantly longer in vitro half-life than Ligand A (3.996), which is a positive for B.

**14. P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.464 and 0.151, respectively).

**15. Binding Affinity:** Ligand A (0) has a weaker binding affinity than Ligand B (-). While the absolute values are not provided, the difference is significant.

**Overall Assessment:**

Despite Ligand A having a better QED, TPSA, and a slightly lower DILI risk, Ligand B is the more promising candidate. The *critical* factor is BBB penetration, where Ligand A (59.519) is significantly better than Ligand B (27.763). However, the substantially longer half-life and better binding affinity of Ligand B outweigh the slightly higher TPSA and DILI risk. The poor solubility and permeability scores are concerning for both, but can be addressed with formulation strategies.

Output:
1
2025-04-17 03:10:15,928 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (348.447 and 349.387 Da) fall comfortably within the ideal 200-500 Da range.

**TPSA:** Both ligands have TPSA values (105.48 and 104.81) that are acceptable for oral absorption, but slightly high for optimal CNS penetration (ideally <90).

**logP:** Ligand A (2.432) is within the optimal range (1-3). Ligand B (-0.671) is below 1, which could hinder permeation. This is a significant drawback for a CNS target.

**H-Bond Donors/Acceptors:** Ligand A (HBD=4, HBA=4) and Ligand B (HBD=2, HBA=5) both have reasonable numbers of H-bond donors and acceptors, unlikely to cause major issues.

**QED:** Ligand A (0.627) has a better QED score than Ligand B (0.389), indicating a more drug-like profile.

**DILI:** Both ligands have acceptable DILI risk (Ligand A: 39.667, Ligand B: 42.924), below the 60% threshold.

**BBB:** Ligand A (77.627) has a significantly better BBB percentile than Ligand B (20.512). This is a critical advantage for a CNS target like DRD2.

**Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and suggests poor permeability. However, the scale is not specified, so it's difficult to interpret.

**Aqueous Solubility:** Both ligands have negative solubility values, which is also unusual. This suggests low solubility, which could be problematic for bioavailability.

**hERG Inhibition:** Both ligands show very low hERG inhibition risk (Ligand A: 0.29, Ligand B: 0.022).

**Microsomal Clearance:** Ligand A (58.797) has a higher microsomal clearance than Ligand B (-8.94). This suggests Ligand B is more metabolically stable.

**In vitro Half-Life:** Ligand B (-15.997) has a longer in vitro half-life than Ligand A (-13.701), which is a positive.

**P-gp Efflux:** Both ligands show very low P-gp efflux liability (Ligand A: 0.016, Ligand B: 0.024).

**Binding Affinity:** Ligand A (-8.5 kcal/mol) has a significantly stronger binding affinity than Ligand B (0.0 kcal/mol). This is a major advantage.

**Overall Assessment:**

Ligand A is the stronger candidate. While both have issues with solubility and Caco-2 permeability, Ligand A's superior binding affinity, better BBB penetration, and more favorable logP outweigh its slightly higher microsomal clearance. Ligand B's very low logP is a major concern for CNS penetration, and its binding affinity is essentially non-existent. The large difference in binding affinity (-8.5 vs 0.0 kcal/mol) is a decisive factor.

Output:
1
2025-04-17 03:10:15,928 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (356.46 & 352.44 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (49.41) is excellent, well below the 90 A^2 threshold for CNS targets. Ligand B (96.69) is higher, but still potentially acceptable, though less ideal.

**3. logP:** Ligand A (3.03) is optimal. Ligand B (0.41) is quite low, which could hinder membrane permeability and CNS penetration.

**4. H-Bond Donors:** Both have acceptable HBD counts (1 and 2 respectively), well below the limit of 5.

**5. H-Bond Acceptors:** Ligand A (2) is good. Ligand B (6) is higher, but still within the acceptable limit of 10.

**6. QED:** Both ligands have similar and good QED values (0.744 and 0.741).

**7. DILI:** Ligand A (29.04) has a significantly lower DILI risk than Ligand B (47.15), indicating better predicted liver safety.

**8. BBB:** Ligand A (96.08) has excellent BBB penetration, exceeding the 70% threshold. Ligand B (30.13) is poor, suggesting limited CNS exposure. This is a critical factor for a DRD2 ligand.

**9. Caco-2:** Both have negative Caco-2 values, which is unusual and difficult to interpret without further context. However, it suggests poor intestinal absorption for both.

**10. Solubility:** Both have negative solubility values, which is also unusual.

**11. hERG:** Ligand A (0.73) has a low hERG risk. Ligand B (0.14) is even lower, but both are acceptable.

**12. Cl_mic:** Ligand A (18.57) has a lower microsomal clearance, suggesting better metabolic stability than Ligand B (22.79).

**13. t1/2:** Ligand A (-13.02) has a negative half-life, which is not possible. Ligand B (7.93) has a positive half-life.

**14. Pgp:** Ligand A (0.31) has lower P-gp efflux, which is favorable for CNS penetration. Ligand B (0.02) has very low P-gp efflux.

**15. Binding Affinity:** Ligand A (0.0) has a weaker binding affinity than Ligand B (-8.0). This is a significant advantage for Ligand B.

**Overall Assessment:**

Despite the unusual negative values for Caco-2 and solubility, the key differences lie in BBB penetration and binding affinity. Ligand A excels in BBB (96%) and has acceptable ADME properties, but its binding affinity is weak. Ligand B has a much stronger binding affinity (-8.0 kcal/mol), which could outweigh some of its ADME liabilities. However, its poor BBB penetration (30%) is a major concern for a CNS target like DRD2.

Considering the GPCR-specific priorities, BBB penetration is crucial for CNS targets. While strong binding is important, it's less valuable if the compound can't reach the brain. Ligand A's superior BBB penetration and acceptable overall profile make it the more promising candidate, despite its weaker binding affinity. The affinity difference is substantial, but optimization could potentially improve Ligand A's binding while maintaining its favorable CNS properties.

Output:
1
2025-04-17 03:10:15,928 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (350.419 and 358.523 Da) fall comfortably within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (97.56) is slightly higher than the preferred <90 for CNS targets, but still reasonable. Ligand B (76.66) is excellent, well below 90.

**3. logP:** Ligand A (1.072) is at the lower end of the optimal 1-3 range, potentially impacting permeability. Ligand B (2.367) is well within the optimal range.

**4. H-Bond Donors:** Ligand A (1) is good. Ligand B (2) is also acceptable.

**5. H-Bond Acceptors:** Ligand A (6) is good. Ligand B (4) is also good.

**6. QED:** Both ligands have acceptable QED values (0.705 and 0.628, both >0.5).

**7. DILI:** Ligand A (35.867) has a slightly higher DILI risk than Ligand B (18.418), but both are below the concerning threshold of 60.

**8. BBB:** Ligand A (77.2) is a good BBB penetration percentile, desirable for a CNS target. Ligand B (66.576) is lower, which is a significant drawback for DRD2.

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 values which is unusual and likely indicates a problem with the data.

**10. Aqueous Solubility:** Both ligands have negative solubility values, which is unusual and likely indicates a problem with the data.

**11. hERG:** Both ligands have very low hERG inhibition liability (0.1 and 0.363), which is excellent.

**12. Microsomal Clearance:** Ligand A (59.023) has lower clearance than Ligand B (86.358), suggesting better metabolic stability.

**13. In vitro Half-Life:** Ligand A (-5.847) has a negative half-life, which is unusual and likely indicates a problem with the data. Ligand B (10.323) has a reasonable half-life.

**14. P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.049 and 0.032), which is excellent for CNS penetration.

**15. Binding Affinity:** Ligand A (-7.7 kcal/mol) has a slightly better binding affinity than Ligand B (-6.9 kcal/mol). The difference of 0.8 kcal/mol is significant and could outweigh some ADME drawbacks.

**Overall Assessment:**

Despite the unusual negative values for Caco-2, solubility, and half-life, Ligand A appears to be the better candidate. The stronger binding affinity (-7.7 vs -6.9 kcal/mol) is a key advantage for a GPCR target. It also has better metabolic stability (lower Cl_mic) and acceptable BBB penetration. While its logP is slightly lower, the stronger binding and other favorable properties likely compensate. The lower DILI risk is also a plus. The negative values for Caco-2, solubility, and half-life are concerning, but the binding affinity difference is substantial.

Output:
0
2025-04-17 03:10:15,929 - INFO - Reasoning:

Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (401.45 Da) is slightly higher than Ligand B (348.487 Da), but both are acceptable.

**2. TPSA:**  Ligand A (96.44) is approaching the upper limit for CNS targets (<=90), while Ligand B (75.27) is well within the desirable range. This favors Ligand B.

**3. logP:** Both ligands have good logP values (A: 1.571, B: 2.581), falling within the optimal range of 1-3.

**4. H-Bond Donors:** Both ligands are acceptable (A: 1, B: 2), being less than or equal to 5.

**5. H-Bond Acceptors:** Both ligands are acceptable (A: 6, B: 3), being less than or equal to 10.

**6. QED:** Both ligands have similar and good QED values (A: 0.741, B: 0.708), indicating drug-like properties.

**7. DILI:** Ligand A (70.686) has a higher DILI risk than Ligand B (24.544). This is a significant advantage for Ligand B.

**8. BBB:** Ligand B (61.923) has a significantly better BBB penetration percentile than Ligand A (41.218). This is crucial for a CNS target like DRD2, and heavily favors Ligand B.

**9. Caco-2 Permeability:** Both have negative values, which is unusual. Assuming these are logP-scale values, lower values indicate poorer permeability. Both are poor, but the values are hard to interpret without knowing the scale.

**10. Aqueous Solubility:** Both have negative values, which is also unusual. Assuming these are logS values, lower values indicate poorer solubility. Both are poor, but the values are hard to interpret without knowing the scale.

**11. hERG Inhibition:** Both ligands have very low hERG inhibition risk (A: 0.167, B: 0.119), which is excellent.

**12. Microsomal Clearance:** Ligand B (9.564) has a lower microsomal clearance than Ligand A (21.08), suggesting better metabolic stability.

**13. In vitro Half-Life:** Ligand B (-7.097) has a negative half-life, which is impossible. This is a red flag and suggests an error in the data or a very rapidly metabolized compound. Ligand A (36.134) has a reasonable half-life.

**14. P-gp Efflux:** Both ligands have low P-gp efflux liability (A: 0.074, B: 0.186), which is favorable for CNS penetration.

**15. Binding Affinity:** Both ligands have excellent binding affinities (A: -8.7 kcal/mol, B: -8.8 kcal/mol). The difference is minimal.

**Overall Assessment:**

Despite the odd negative values for Caco-2 and solubility, the key differences lie in BBB penetration, DILI risk, and metabolic stability. Ligand B demonstrates superior BBB penetration (61.923 vs 41.218) and a much lower DILI risk (24.544 vs 70.686). While Ligand B has a nonsensical half-life value, the other factors strongly favor it. Ligand A has a reasonable half-life, but the poor BBB and higher DILI risk are significant drawbacks for a CNS target.

Output:
1
2025-04-17 03:10:15,929 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (369.355 and 349.435 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (138.13) is borderline for CNS penetration, just above the preferred <90, while Ligand B (98.14) is well within the ideal range. This is a significant advantage for Ligand B.

**logP:** Ligand A (0.288) is quite low, potentially hindering membrane permeability. Ligand B (0.696) is better, but still on the lower side of the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A has 1 HBD and 6 HBA, which are acceptable. Ligand B has 2 HBD and 6 HBA, also acceptable.

**QED:** Both ligands have good QED scores (0.594 and 0.684), indicating good drug-like properties.

**DILI:** Ligand A has a high DILI risk (93.37), which is concerning. Ligand B has a much lower DILI risk (43.428), a major advantage.

**BBB:** Ligand A has very poor BBB penetration (25.475), making it unlikely to be effective for a CNS target like DRD2. Ligand B has significantly better BBB penetration (60.644), although still not optimal (>70).

**Caco-2 Permeability:** Both have negative Caco-2 values (-5.066 and -5.697), which is unusual and suggests poor permeability. This is a red flag for both.

**Aqueous Solubility:** Both have negative solubility values (-3.752 and -0.77), which is also unusual and suggests poor solubility.

**hERG:** Both ligands have very low hERG inhibition liability (0.036 and 0.048), which is good.

**Microsomal Clearance:** Ligand A has a moderate clearance (21.361), while Ligand B has a lower clearance (7.55), indicating better metabolic stability.

**In vitro Half-Life:** Ligand A has a negative half-life (-20.575), which is not physically meaningful. Ligand B has a positive half-life (44.546), which is good.

**P-gp Efflux:** Both have low P-gp efflux liability (0.04 and 0.034), which is favorable for CNS penetration.

**Binding Affinity:** Ligand B (-8.8 kcal/mol) has a stronger binding affinity than Ligand A (-7.9 kcal/mol). This 0.9 kcal/mol difference is significant and can outweigh some ADME drawbacks.

**Overall Assessment:**

Ligand B is the superior candidate. While its logP is still a bit low and BBB isn't ideal, it significantly outperforms Ligand A in crucial areas: lower DILI risk, much better BBB penetration, better metabolic stability (lower Cl_mic, higher t1/2), and stronger binding affinity. Ligand A's high DILI risk and extremely poor BBB penetration are dealbreakers. The negative Caco-2 and solubility values are concerning for both, but the superior binding and ADME profile of Ligand B make it the more promising candidate.

Output:
1
2025-04-17 03:10:15,929 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 drug candidates, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (363.439 and 367.555 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (92.94) is slightly above the preferred <90 for CNS targets, but still reasonable. Ligand B (49.77) is excellent, well below 90, indicating good potential for brain penetration.

**logP:** Ligand A (0.56) is quite low, potentially hindering membrane permeability. Ligand B (3.917) is closer to the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Both ligands have acceptable HBD (1) and HBA (5/4) counts, well within the guidelines.

**QED:** Both ligands have good QED scores (0.59 and 0.72), indicating drug-like properties.

**DILI:** Ligand A (52.152) has a moderate DILI risk, while Ligand B (10.508) has a very low risk. This is a significant advantage for Ligand B.

**BBB:** Ligand A (61.613) has a moderate BBB penetration, while Ligand B (89.376) is excellent, exceeding the desirable >70 threshold for CNS targets.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values, which is unusual and suggests potential issues with in vitro permeability assays or data quality. However, the magnitude is similar.

**Aqueous Solubility:** Both ligands have negative solubility values, which is also unusual. This suggests poor aqueous solubility.

**hERG:** Ligand A (0.399) has a very low hERG risk, while Ligand B (0.875) has a moderate risk.

**Microsomal Clearance:** Ligand A (-1.563) suggests very low clearance and high metabolic stability, a significant advantage. Ligand B (94.693) indicates very high clearance and low metabolic stability.

**In vitro Half-Life:** Ligand A (-6.955) suggests a very long half-life, while Ligand B (36.655) suggests a moderate half-life.

**P-gp Efflux:** Ligand A (0.064) has very low P-gp efflux, which is favorable for CNS penetration. Ligand B (0.793) has moderate P-gp efflux.

**Binding Affinity:** Ligand A (-7.8) has a slightly better binding affinity than Ligand B (-6.4), a difference of 1.4 kcal/mol.

**Overall Assessment:**

Ligand B clearly emerges as the more promising candidate. While Ligand A has slightly better affinity and metabolic stability, Ligand B excels in crucial areas for a CNS-targeting GPCR: BBB penetration (89.376 vs 61.613), lower DILI risk (10.508 vs 52.152), and a more favorable logP (3.917 vs 0.56). The lower P-gp efflux of Ligand A is good, but the superior BBB penetration of Ligand B likely outweighs this. The unusual solubility and Caco-2 values for both compounds warrant further investigation, but the overall profile strongly favors Ligand B.

Output:
1
2025-04-17 03:10:15,929 - INFO - Batch 6 complete. Total preferences: 96
2025-04-17 03:10:15,929 - INFO - Processing batch 7/512...
2025-04-17 03:10:57,101 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (346.475 & 340.383 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (78.09) is significantly better than Ligand B (89.27). For CNS targets, we want TPSA <= 90, and A is closer to the ideal <= 60-70 range. B is pushing the upper limit.

**3. logP:** Both ligands have acceptable logP values (2.818 & 1.52), falling within the 1-3 range. Ligand A is slightly better.

**4. H-Bond Donors:** Both have 2 HBD, which is within the acceptable limit of <=5.

**5. H-Bond Acceptors:** Ligand A has 3 HBA, while Ligand B has 6. Both are within the acceptable limit of <=10, but A is preferable.

**6. QED:** Both ligands have reasonable QED scores (0.745 & 0.615), indicating good drug-like properties.

**7. DILI:** Ligand A (13.843) has a much lower DILI risk than Ligand B (62.001). This is a significant advantage for A.

**8. BBB:** Ligand A (44.591) has a lower BBB percentile than Ligand B (48.003). While neither is ideal (>70), B is slightly better. However, this is less critical than other factors given the relatively low values.

**9. Caco-2:** Both have negative Caco-2 values, which is unusual and suggests poor permeability.

**10. Solubility:** Both have negative solubility values, which is also unusual and suggests poor solubility.

**11. hERG:** Both ligands have very low hERG inhibition liability (0.317 & 0.124), which is excellent.

**12. Cl_mic:** Ligand B (5.913) has lower microsomal clearance than Ligand A (8.117), suggesting better metabolic stability.

**13. t1/2:** Ligand B (-8.618) has a slightly longer in vitro half-life than Ligand A (-17.539).

**14. Pgp:** Ligand A (0.035) has significantly lower P-gp efflux liability than Ligand B (0.103). Lower Pgp is crucial for CNS penetration.

**15. Binding Affinity:** Ligand B (-9.3) has a stronger binding affinity than Ligand A (-7.9). This is a 1.4 kcal/mol difference, which is substantial and can outweigh some ADME drawbacks.

**Overall Assessment:**

Despite Ligand B's superior binding affinity, Ligand A is the more promising candidate. The significant advantages of Ligand A in terms of DILI risk, TPSA, Pgp efflux, and a better logP profile outweigh the affinity difference. The lower TPSA and Pgp efflux of A suggest better CNS penetration potential, which is critical for a DRD2 ligand. While both have issues with Caco-2 and solubility, these can be addressed through formulation strategies.



Output:
0
2025-04-17 03:10:57,102 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (340.379 and 338.367 Da) fall within the ideal range of 200-500 Da.

**TPSA:** Ligand A (73.59) is significantly better than Ligand B (89.16). For CNS targets, we want TPSA <= 90, and A is comfortably within that range, while B is approaching the upper limit.

**logP:** Both ligands have good logP values (3.943 and 3.135), falling within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A (HBD=1, HBA=6) is slightly better than Ligand B (HBD=2, HBA=5) in terms of maintaining a balance between solubility and permeability. Both are acceptable.

**QED:** Both ligands have good QED scores (0.657 and 0.765), indicating good drug-like properties.

**DILI:** Ligand B (85.537) has a higher DILI risk than Ligand A (74.719). Both are acceptable, but A is preferable.

**BBB:** This is a critical parameter for CNS targets. Ligand A (63.746) has a better BBB percentile than Ligand B (51.803). While >70 is desirable, A is still better positioned for CNS penetration.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.554 and -4.979), which is unusual and suggests poor permeability. This is a significant concern for both.

**Aqueous Solubility:** Both ligands have negative solubility values (-5.624 and -3.94), indicating very poor aqueous solubility. This is a major drawback for both compounds.

**hERG Inhibition:** Ligand A (0.759) has a slightly higher hERG inhibition risk than Ligand B (0.542), but both are relatively low.

**Microsomal Clearance:** Ligand A (112.482) has a higher microsomal clearance than Ligand B (25.765), suggesting lower metabolic stability. This is a significant negative for Ligand A.

**In vitro Half-Life:** Ligand B (49.64) has a longer in vitro half-life than Ligand A (54.748).

**P-gp Efflux:** Ligand A (0.269) has lower P-gp efflux than Ligand B (0.172), which is beneficial for CNS exposure.

**Binding Affinity:** Ligand B (-9.7 kcal/mol) has a significantly stronger binding affinity than Ligand A (-7.5 kcal/mol). This is a substantial advantage, exceeding the 1.5 kcal/mol threshold.

**Overall Assessment:**

Despite the poor Caco-2 and solubility values for both compounds, the significantly stronger binding affinity of Ligand B (-9.7 vs -7.5 kcal/mol) is a major deciding factor. The better half-life and lower clearance of Ligand B also contribute to its favorability. While Ligand A has better TPSA and P-gp efflux, the affinity difference is substantial enough to outweigh these advantages, especially considering the GPCR target class. The DILI risk is also slightly better for Ligand A, but not enough to change the overall assessment.

Output:
1
2025-04-17 03:10:57,102 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (335.411 and 366.483 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (101.03) is better than Ligand B (87.66) as it is closer to the ideal <90 for CNS targets.

**logP:** Both ligands have good logP values (2.102 and 1.387), falling within the optimal 1-3 range. Ligand B is slightly lower, which could slightly hinder permeability, but is still acceptable.

**H-Bond Donors/Acceptors:** Both have 3 HBD and a reasonable number of HBA (4 for A, 5 for B), satisfying the <5 HBD and <10 HBA guidelines.

**QED:** Both ligands have similar QED values (0.667 and 0.68), indicating good drug-likeness.

**DILI:** Ligand A (54.091) has a slightly higher DILI risk than Ligand B (41.218), but both are below the concerning threshold of 60.

**BBB:** This is a critical parameter for a CNS target like DRD2. Ligand A has a significantly better BBB penetration percentile (81.117) compared to Ligand B (44.746). This is a major advantage for Ligand A.

**Caco-2 Permeability:** Both have negative Caco-2 values (-5.567 and -5.256), which is unusual and suggests poor permeability. However, these values are on a scale where negative values are possible and don't necessarily disqualify the compounds.

**Aqueous Solubility:** Both have negative solubility values (-3.12 and -1.961), which is also unusual and suggests poor solubility.

**hERG Inhibition:** Both ligands show low hERG inhibition liability (0.889 and 0.32), which is favorable.

**Microsomal Clearance:** Ligand A (-30.821) has a much lower (better) microsomal clearance than Ligand B (15.749), indicating greater metabolic stability.

**In vitro Half-Life:** Ligand A (-20.68) has a longer in vitro half-life than Ligand B (20.989), which is desirable.

**P-gp Efflux:** Ligand A (0.232) has lower P-gp efflux liability than Ligand B (0.078), which is beneficial for CNS exposure.

**Binding Affinity:** Both ligands have strong binding affinities (-9.8 and -8.6 kcal/mol). Ligand A is significantly more potent (1.2 kcal/mol advantage), which is a substantial difference and can outweigh some ADME drawbacks.

**Overall Assessment:**

Ligand A is the superior candidate. While both ligands have acceptable physicochemical properties and strong binding affinities, Ligand A excels in critical areas for CNS drug development: significantly better BBB penetration, lower P-gp efflux, greater metabolic stability (lower Cl_mic and longer t1/2), and a much stronger binding affinity. The slightly higher DILI risk for Ligand A is less concerning given its other advantages.

Output:
1
2025-04-17 03:10:57,102 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B based on the provided guidelines, prioritizing GPCR-specific properties (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (377.46 and 348.38 Da) fall within the ideal 200-500 Da range.

**TPSA:** Both ligands (72.27 and 71.58) are below the 90 A^2 threshold desirable for CNS targets.

**logP:** Ligand A (2.763) is optimal (1-3), while Ligand B (1.533) is at the lower end, potentially impacting permeability.

**H-Bond Donors/Acceptors:** Both have 0 HBD and 5 HBA, which are within acceptable limits.

**QED:** Both ligands have good QED scores (0.732 and 0.84), indicating drug-like properties.

**DILI:** Ligand A (42.613) has a lower DILI risk than Ligand B (53.276), both being acceptable (<60).

**BBB:** Ligand A (92.168) has a significantly better BBB penetration percentile than Ligand B (71.733). This is a critical advantage for a CNS target like DRD2.

**Caco-2 Permeability:** Both have negative Caco-2 values (-4.617 and -4.644). These values are unusual and suggest poor permeability. However, these are likely reported as logP values and indicate poor permeability.

**Aqueous Solubility:** Both have negative solubility values (-3.249 and -1.572), suggesting poor solubility.

**hERG:** Both ligands have low hERG inhibition risk (0.353 and 0.194).

**Microsomal Clearance:** Ligand A (16.618) has a higher microsomal clearance than Ligand B (14.823), suggesting lower metabolic stability.

**In vitro Half-Life:** Ligand B (15.513 hours) has a significantly longer half-life than Ligand A (3.16 hours), which is a positive attribute.

**P-gp Efflux:** Ligand A (0.304) has lower P-gp efflux liability than Ligand B (0.057), which is favorable for CNS penetration.

**Binding Affinity:** Ligand B (-8.0 kcal/mol) has a stronger binding affinity than Ligand A (-7.1 kcal/mol). This is a substantial difference (>1.5 kcal/mol) and a major advantage.

**Overall Assessment:**

While Ligand B has a superior binding affinity and longer half-life, Ligand A's significantly better BBB penetration and lower P-gp efflux are crucial for a CNS-targeted GPCR like DRD2. The slightly higher metabolic clearance of Ligand A is a concern, but the improved CNS exposure potential outweighs this drawback. The poor Caco-2 and solubility values are concerning for both, but can be addressed with formulation strategies. Considering the GPCR-specific priorities, the improved CNS penetration profile of Ligand A is more important.

Output:
1
2025-04-17 03:10:57,103 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the acceptable range (200-500 Da). Ligand A (341.411 Da) is slightly preferred as it's closer to the lower end, potentially aiding permeability.

**TPSA:** Ligand A (94.31) is excellent for CNS penetration, being well below 90. Ligand B (46.5) is also very good.

**logP:** Ligand A (2.519) is optimal. Ligand B (4.85) is higher, potentially leading to solubility issues and off-target interactions, although still within a reasonable range.

**H-Bond Donors/Acceptors:** Ligand A (2 HBD, 5 HBA) and Ligand B (1 HBD, 3 HBA) both have acceptable numbers of H-bond donors and acceptors.

**QED:** Both ligands have similar QED values (0.755 and 0.729), indicating good drug-likeness.

**DILI:** Ligand A (69.019) has a lower DILI risk than Ligand B (78.945), which is a positive.

**BBB:** Both ligands exhibit excellent BBB penetration (Ligand A: 73.401, Ligand B: 79.139), exceeding the desirable threshold of 70.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values, which is unusual and suggests a potential issue with the data or a very poor permeability. However, given the context of GPCRs and the need for CNS penetration, this is less critical than other factors.

**Aqueous Solubility:** Both ligands have negative solubility values, indicating very poor solubility. This is a significant drawback for both compounds.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.593 and 0.545).

**Microsomal Clearance:** Ligand A (68.558) has a higher microsomal clearance than Ligand B (58.923), suggesting lower metabolic stability.

**In vitro Half-Life:** Ligand B (24.751) has a significantly longer in vitro half-life than Ligand A (-15.523), which is a major advantage.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.166 and 0.595), which is excellent for CNS exposure.

**Binding Affinity:** Ligand B (-9.0 kcal/mol) has a slightly better binding affinity than Ligand A (-8.9 kcal/mol), although the difference is small.

**Overall Assessment:**

Ligand B is slightly favored due to its superior binding affinity and significantly improved in vitro half-life. While its logP is higher, the excellent BBB penetration and low P-gp efflux suggest it can still achieve sufficient CNS exposure. The poor solubility is a concern for both, but can be addressed with formulation strategies. Ligand A's lower DILI risk and slightly better MW are positives, but are outweighed by the shorter half-life and slightly weaker binding.

Output:
1
2025-04-17 03:10:57,103 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B based on the provided guidelines, prioritizing GPCR-specific properties (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (352.475 and 350.503 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (70.08) is better than Ligand B (63.45) as it is closer to the <90 A^2 threshold for CNS targets.

**logP:** Ligand A (1.435) is optimal (1-3), while Ligand B (4.421) is high and could lead to solubility issues and off-target effects.

**H-Bond Donors/Acceptors:** Ligand A has 1 HBD and 4 HBA, while Ligand B has 0 HBD and 3 HBA. Both are within acceptable limits.

**QED:** Ligand A (0.785) is better than Ligand B (0.481), indicating a more drug-like profile.

**DILI:** Ligand A (30.981) has a significantly lower DILI risk than Ligand B (16.44).

**BBB:** Ligand B (77.2) is significantly better than Ligand A (53.974) regarding BBB penetration, a crucial factor for CNS targets like DRD2.

**Caco-2 Permeability:** Ligand A (-4.279) and Ligand B (-4.692) both have negative values, which is unusual. It's difficult to interpret without knowing the scale, but we can assume lower values are less permeable.

**Aqueous Solubility:** Ligand B (-5.029) has worse solubility than Ligand A (-1.735).

**hERG:** Ligand A (0.474) has a lower hERG risk than Ligand B (0.784).

**Microsomal Clearance:** Ligand B (88.164) has a higher microsomal clearance than Ligand A (37.055), indicating lower metabolic stability.

**In vitro Half-Life:** Ligand A (23.12) has a much longer half-life than Ligand B (6.297).

**P-gp Efflux:** Ligand A (0.147) has lower P-gp efflux than Ligand B (0.791), which is favorable for CNS exposure.

**Binding Affinity:** Ligand A (-7.5 kcal/mol) has slightly better binding affinity than Ligand B (0.0 kcal/mol). While both are good, the difference is significant.

**Overall Assessment:**

Ligand A excels in most ADME properties (QED, DILI, solubility, hERG, clearance, half-life, P-gp efflux) and has comparable or better binding affinity. However, Ligand B has a much better BBB score. Given that DRD2 is a CNS target, BBB penetration is critical. The substantial difference in BBB (77.2 vs 53.974) is a major advantage for Ligand B. The higher logP of Ligand B is a concern, but the superior BBB penetration may compensate for it. The significantly better metabolic stability and half-life of Ligand A are also compelling.

Considering the balance, the better BBB penetration of Ligand B is the deciding factor for a CNS target.

Output:
1
2025-04-17 03:10:57,103 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (359.495 and 346.475 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (73.2) is better than Ligand B (76.02). Both are below the 90 A^2 threshold for CNS targets, but A is closer to the ideal.

**3. logP:** Both ligands have good logP values (3.167 and 2.919), falling within the optimal 1-3 range.

**4. H-Bond Donors:** Ligand A (1) is preferable to Ligand B (2). Lower HBD generally improves permeability.

**5. H-Bond Acceptors:** Both ligands have the same number of HBA (4), which is acceptable (<=10).

**6. QED:** Ligand A (0.775) has a better QED score than Ligand B (0.533), indicating a more drug-like profile.

**7. DILI:** Ligand A (43.117) has a lower DILI risk than Ligand B (51.532), which is favorable. Both are below the 60 threshold.

**8. BBB:** Ligand A (74.254) has significantly better BBB penetration than Ligand B (47.46). This is *critical* for a CNS target like DRD2.

**9. Caco-2 Permeability:** Ligand A (-4.864) has better Caco-2 permeability than Ligand B (-4.966), although both are negative values and require careful consideration.

**10. Aqueous Solubility:** Ligand A (-4.759) has better aqueous solubility than Ligand B (-3.172).

**11. hERG Inhibition:** Ligand A (0.693) has a lower hERG inhibition liability than Ligand B (0.232), which is a significant safety advantage.

**12. Microsomal Clearance:** Ligand B (61.287) has lower microsomal clearance (better metabolic stability) than Ligand A (75.365).

**13. In vitro Half-Life:** Ligand A (23.173) has a longer in vitro half-life than Ligand B (17.672).

**14. P-gp Efflux:** Ligand A (0.491) has lower P-gp efflux liability than Ligand B (0.125), which is beneficial for CNS exposure.

**15. Binding Affinity:** Ligand A (-7.6 kcal/mol) has slightly better binding affinity than Ligand B (-7.4 kcal/mol). While the difference is small, it's still a positive factor.

**Overall Assessment:**

Ligand A clearly outperforms Ligand B across most critical parameters, especially those prioritized for GPCRs targeting the CNS. The significantly better BBB penetration, lower hERG risk, and better QED/DILI scores make Ligand A a much more promising drug candidate. While Ligand B has slightly better metabolic stability, the other advantages of Ligand A outweigh this single benefit.

Output:
1
2025-04-17 03:10:57,103 - INFO - Reasoning:

Let's analyze Ligand A and Ligand B based on the provided guidelines, prioritizing GPCR-specific properties (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (347.459 Da) is slightly lower, which is generally favorable for permeability.

**TPSA:** Ligand A (66.65) is better than Ligand B (51.66) as it is closer to the ideal range for CNS targets (<=90).

**logP:** Both ligands have good logP values (A: 2.803, B: 3.552), falling within the optimal 1-3 range. Ligand B is slightly higher, which could potentially lead to off-target effects, but isn't a major concern.

**H-Bond Donors/Acceptors:** Both ligands have acceptable HBD (0) and HBA (A: 4, B: 5) counts.

**QED:** Both ligands have similar and good QED values (A: 0.742, B: 0.719), indicating good drug-like properties.

**DILI:** Ligand A (21.404) has a significantly lower DILI risk than Ligand B (36.06), which is a major advantage.

**BBB:** Both ligands exhibit excellent BBB penetration (A: 81.737, B: 89.957), exceeding the desirable threshold of >70. Ligand B is slightly better here.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values, which is unusual and suggests a potential issue with the data or a prediction artifact. However, we can't reliably compare based on this.

**Aqueous Solubility:** Both ligands have negative solubility values, which is also unusual and suggests a potential issue with the data or a prediction artifact.

**hERG Inhibition:** Ligand A (0.155) has a much lower hERG inhibition liability than Ligand B (0.669), making it safer from a cardiotoxicity perspective.

**Microsomal Clearance:** Ligand A (50.488) has a lower microsomal clearance than Ligand B (89.519), indicating better metabolic stability.

**In vitro Half-Life:** Ligand A (14.766) has a longer half-life than Ligand B (-14.462). The negative value for Ligand B is concerning and likely an artifact.

**P-gp Efflux:** Ligand A (0.142) has lower P-gp efflux liability than Ligand B (0.304), which is beneficial for CNS exposure.

**Binding Affinity:** Ligand A (-7.1) has a slightly stronger binding affinity than Ligand B (-6.9), although the difference is relatively small.

**Overall Assessment:**

Ligand A is clearly the superior candidate. It demonstrates a significantly lower DILI risk, lower hERG inhibition, better metabolic stability (lower Cl_mic, longer t1/2), lower P-gp efflux, and slightly better binding affinity. While Ligand B has a slightly better BBB score, the other advantages of Ligand A outweigh this. The negative solubility and Caco-2 values are concerning for both, but the other ADME properties of Ligand A are far more favorable.

Output:
1
2025-04-17 03:10:57,103 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (342.487 and 346.347 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (58.12) is excellent, well below the 90 A^2 threshold for CNS targets. Ligand B (136.47) is higher, but still potentially acceptable, though less ideal.

**logP:** Ligand A (3.842) is optimal. Ligand B (-0.524) is significantly low, which could hinder membrane permeability and CNS penetration despite a good binding affinity.

**H-Bond Donors/Acceptors:** Ligand A (1 HBD, 3 HBA) is favorable. Ligand B (2 HBD, 8 HBA) is slightly higher, but still within reasonable limits.

**QED:** Both ligands have good QED scores (0.904 and 0.545), indicating drug-like properties.

**DILI:** Ligand A (33.501) has a much lower DILI risk than Ligand B (68.786), a significant advantage.

**BBB:** Ligand A (95.502) demonstrates excellent predicted BBB penetration. Ligand B (69.523) is lower, which is concerning for a CNS target like DRD2.

**Caco-2 Permeability:** Ligand A (-4.548) is concerningly low, suggesting poor intestinal absorption. Ligand B (-5.498) is also low, but slightly better than A.

**Aqueous Solubility:** Ligand A (-4.004) is poor, while Ligand B (-2.416) is also poor, but better than A.

**hERG Inhibition:** Both ligands show low hERG inhibition risk (0.381 and 0.126).

**Microsomal Clearance:** Ligand A (52.54) is moderate, while Ligand B (5.596) is very low, indicating better metabolic stability.

**In vitro Half-Life:** Ligand A (18.801) is moderate, while Ligand B (-39.442) is very long, a significant advantage.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.146 and 0.006).

**Binding Affinity:** Both ligands have excellent binding affinity (-8.9 kcal/mol). The difference is negligible.

**Overall Assessment:**

Ligand A excels in TPSA, logP, DILI, and BBB penetration, which are critical for a CNS-targeting GPCR. However, its Caco-2 permeability and aqueous solubility are poor.

Ligand B has better metabolic stability (lower Cl_mic) and a longer half-life, but suffers from a poor logP, lower BBB penetration, and a higher DILI risk. The low logP is a major drawback for CNS penetration.

Considering the GPCR-specific priorities, the superior BBB penetration and favorable logP of Ligand A outweigh its slightly lower metabolic stability and solubility. The strong binding affinity is similar for both.

Output:
1
2025-04-17 03:10:57,104 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (345.4 & 355.4 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (98.57) is better than Ligand B (107.97). Both are below the 140 threshold for oral absorption, and Ligand A is closer to the desirable <90 for CNS targets.

**logP:** Ligand A (1.689) is within the optimal 1-3 range. Ligand B (-0.594) is slightly below 1, which could potentially hinder permeation.

**H-Bond Donors/Acceptors:** Both have 3 HBDs, which is good. Ligand A has 4 HBAs, and Ligand B has 5. Both are acceptable, being under the 10 limit.

**QED:** Ligand A (0.785) has a better QED score than Ligand B (0.512), indicating a more drug-like profile.

**DILI:** Ligand B (24.118) has a significantly lower DILI risk than Ligand A (46.801), which is a substantial advantage.

**BBB:** Ligand B (43.117) has a much better BBB penetration percentile than Ligand A (25.475). This is *critical* for a CNS target like DRD2.

**Caco-2 Permeability:** Both have negative Caco-2 values (-5.242 and -5.089), which is unusual and suggests poor permeability. This is a significant concern for both.

**Aqueous Solubility:** Both ligands have negative solubility values (-2.729 and -1.137), indicating very poor aqueous solubility. This is a major drawback for both.

**hERG:** Both have low hERG inhibition liability (0.353 and 0.082).

**Microsomal Clearance:** Ligand A (-22.433) has a much lower (better) microsomal clearance than Ligand B (12.187), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (4.943) has a slightly better in vitro half-life than Ligand B (-0.905).

**P-gp Efflux:** Ligand A (0.105) has lower P-gp efflux liability than Ligand B (0.023), which is favorable for CNS exposure.

**Binding Affinity:** Ligand A (-8.8 kcal/mol) has a significantly stronger binding affinity than Ligand B (-7.3 kcal/mol). This is a substantial advantage, potentially outweighing some of the ADME drawbacks.

**Overall Assessment:**

While Ligand A boasts superior binding affinity and metabolic stability, Ligand B shines in BBB penetration and has a much lower DILI risk. The poor Caco-2 and solubility for both are concerning, but can potentially be addressed with formulation strategies. For a CNS target like DRD2, BBB penetration is paramount. The 1.5 kcal/mol difference in binding affinity is significant, but not insurmountable, and can potentially be optimized in later stages of drug development. The lower DILI risk of Ligand B is also a major advantage.

Output:
1
2025-04-17 03:10:57,104 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (418.367 Da) is slightly higher, but acceptable. Ligand B (343.479 Da) is also good.

**TPSA:** Ligand A (46.61) is excellent, well below the 90 A^2 threshold for CNS targets. Ligand B (71.76) is still reasonable, but higher and less favorable for CNS penetration.

**logP:** Ligand A (4.755) is slightly high, potentially leading to solubility issues or off-target interactions. Ligand B (2.223) is within the optimal range (1-3).

**H-Bond Donors/Acceptors:** Ligand A (0 HBD, 4 HBA) is favorable. Ligand B (1 HBD, 7 HBA) is also acceptable, though slightly higher in HBA count.

**QED:** Both ligands have good QED scores (A: 0.636, B: 0.867), indicating drug-like properties. Ligand B is slightly better here.

**DILI:** Ligand A (67.739) has a higher DILI risk than Ligand B (52.423), though both are below the concerning threshold of 60.

**BBB:** Ligand B (63.901) has a significantly better BBB percentile than Ligand A (52.617). This is a critical factor for a CNS target like DRD2.

**Caco-2 Permeability:** Ligand A (-4.801) shows poor Caco-2 permeability, which is a concern for oral absorption. Ligand B (-5.232) is also poor, but slightly better.

**Aqueous Solubility:** Ligand A (-6.494) has very poor aqueous solubility, which is a major drawback. Ligand B (-2.295) is also poor, but better than A.

**hERG Inhibition:** Both ligands show low hERG inhibition risk (A: 0.644, B: 0.404).

**Microsomal Clearance:** Ligand A (93.182) has higher microsomal clearance, indicating faster metabolism and potentially lower bioavailability. Ligand B (17.906) has significantly lower clearance, suggesting better metabolic stability.

**In vitro Half-Life:** Ligand B (33.74 hours) has a longer in vitro half-life than Ligand A (28.305 hours), which is desirable.

**P-gp Efflux:** Ligand A (0.65) has moderate P-gp efflux, while Ligand B (0.058) has very low P-gp efflux. Lower P-gp efflux is preferred for CNS penetration.

**Binding Affinity:** Ligand B (-9.1 kcal/mol) has a significantly stronger binding affinity than Ligand A (-8.0 kcal/mol). This >1.5 kcal/mol difference is substantial and can outweigh some ADME drawbacks.

**Overall Assessment:**

Ligand B is the superior candidate. While both have issues with Caco-2 permeability and aqueous solubility, Ligand B excels in key areas for a CNS-targeting GPCR: significantly better BBB penetration, lower P-gp efflux, superior binding affinity, and improved metabolic stability (lower Cl_mic and longer t1/2). The slightly higher logP of Ligand A is a concern, and its poor solubility is a significant disadvantage. The stronger binding affinity of Ligand B is a major advantage.



Output:
1
2025-04-17 03:10:57,104 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (344.455 Da) is slightly lower, which could be advantageous for permeability.

**TPSA:** Ligand A (50.8) is better than Ligand B (59.83), falling comfortably below the 90 A^2 threshold for CNS targets.

**logP:** Both ligands have good logP values (A: 2.466, B: 1.207) within the optimal 1-3 range. Ligand A is slightly higher, which could be beneficial for membrane permeability.

**H-Bond Donors/Acceptors:** Ligand A (HBD=1, HBA=4) and Ligand B (HBD=0, HBA=6) both meet the criteria of <=5 HBD and <=10 HBA.

**QED:** Both ligands have similar, good QED values (A: 0.772, B: 0.775), indicating good drug-like properties.

**DILI:** Both ligands have low DILI risk (A: 36.254, B: 33.23), which is positive.

**BBB:** Ligand B (84.917) has a significantly higher BBB penetration percentile than Ligand A (68.748). This is a *major* advantage for a CNS target like DRD2.

**Caco-2 Permeability:** Ligand A (-5.014) has a more negative Caco-2 value than Ligand B (-4.599), suggesting potentially lower intestinal absorption.

**Aqueous Solubility:** Both ligands have very poor aqueous solubility (-1.58 and -1.489 respectively). This is a concern for both, but might be mitigated by formulation strategies.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (A: 0.434, B: 0.239).

**Microsomal Clearance:** Ligand B (-4.449) has a *much* lower (better) microsomal clearance than Ligand A (15.156), indicating greater metabolic stability.

**In vitro Half-Life:** Ligand B (19.695 hours) has a longer half-life than Ligand A (36.501 hours).

**P-gp Efflux:** Ligand A (0.145) has a lower P-gp efflux liability than Ligand B (0.041), which is preferable for CNS penetration.

**Binding Affinity:** Ligand A (-8.1 kcal/mol) has a significantly stronger binding affinity than Ligand B (-6.8 kcal/mol). This is a substantial advantage, potentially outweighing some of the ADME drawbacks. The difference is >1.5 kcal/mol.

**Overall Assessment:**

While Ligand B excels in BBB penetration and metabolic stability, the significantly stronger binding affinity of Ligand A is a decisive factor. For a GPCR target, a strong binding affinity is paramount. The slightly lower BBB and higher clearance of Ligand A are less concerning given the potency advantage. The similar solubility profiles are a shared weakness. The lower P-gp efflux for ligand A also supports its potential for CNS exposure.

Output:
1
2025-04-17 03:10:57,104 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (347.459 and 346.427 Da) fall comfortably within the ideal 200-500 Da range.

**2. TPSA:** Both ligands have TPSA values (87.3 and 87.66) that are acceptable for oral absorption (<140) and reasonably good for a CNS target (<90, though slightly above).

**3. logP:** Ligand A (0.96) is slightly lower than ideal (1-3), potentially hindering permeation. Ligand B (1.232) is better positioned within the optimal range.

**4. H-Bond Donors:** Both ligands have 3 HBD, which is within the acceptable limit of <=5.

**5. H-Bond Acceptors:** Ligand A has 3 HBA, and Ligand B has 4 HBA, both within the acceptable limit of <=10.

**6. QED:** Both ligands have similar QED values (0.692 and 0.693), indicating good drug-like properties.

**7. DILI:** Ligand A (16.557) has a significantly lower DILI risk than Ligand B (31.679). This is a major advantage for Ligand A.

**8. BBB:** Both ligands have identical BBB penetration (50.446), which is okay, but not ideal for a CNS target (desirable >70).

**9. Caco-2 Permeability:** Ligand A (-5.536) has worse Caco-2 permeability than Ligand B (-4.896), suggesting lower intestinal absorption.

**10. Aqueous Solubility:** Both ligands have poor aqueous solubility (-2.466 and -2.754), which could pose formulation challenges.

**11. hERG Inhibition:** Ligand A (0.126) has a much lower hERG inhibition liability than Ligand B (0.309), indicating a lower risk of cardiotoxicity. This is a significant advantage for Ligand A.

**12. Microsomal Clearance:** Ligand A (-14.818) has significantly lower microsomal clearance (better metabolic stability) than Ligand B (28.868). This is a substantial advantage for Ligand A.

**13. In vitro Half-Life:** Ligand A (6.902) has a shorter in vitro half-life than Ligand B (-9.825), which is a negative for Ligand A.

**14. P-gp Efflux:** Ligand A (0.016) has much lower P-gp efflux liability than Ligand B (0.06), which is beneficial for CNS penetration.

**15. Binding Affinity:** Ligand A (-10.0) has a slightly better binding affinity than Ligand B (-8.7). A 1.3 kcal/mol difference is substantial and can outweigh some ADME drawbacks.

**Overall Assessment:**

Ligand A is the more promising candidate. While both have similar TPSA, QED, and BBB, Ligand A excels in critical areas: significantly lower DILI risk, lower hERG inhibition, substantially improved metabolic stability (lower Cl_mic), lower P-gp efflux, and slightly better binding affinity. The lower Caco-2 permeability and shorter half-life of Ligand A are concerns, but the benefits in safety (DILI, hERG) and metabolic stability are more critical, especially given the CNS target. The better affinity also helps to offset the permeability issue.

Output:
0
2025-04-17 03:10:57,104 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (369.372 and 343.442 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (63.91) is higher than Ligand B (38.33). For CNS targets, we prefer TPSA <= 90, so both are acceptable, but B is significantly better.

**logP:** Both ligands have good logP values (3.268 and 4.117), falling within the optimal 1-3 range, though B is slightly higher.

**H-Bond Donors/Acceptors:** Ligand A has 0 HBD and 6 HBA, while Ligand B has 1 HBD and 2 HBA. Both are within acceptable limits (<=5 HBD and <=10 HBA).

**QED:** Both ligands have similar QED values (0.708 and 0.597), indicating good drug-likeness, with A being slightly better.

**DILI:** Ligand A (92.633) has a significantly higher DILI risk than Ligand B (24.855). This is a major concern for A.

**BBB:** Both ligands have excellent BBB penetration (89.104 and 87.67), exceeding the desirable >70 threshold for CNS targets.

**Caco-2 Permeability:** Both have negative Caco-2 values which is unusual and suggests a problem with the data. However, the values are similar.

**Aqueous Solubility:** Both ligands have very poor aqueous solubility (-4.13 and -4.377). This is a significant drawback for both, but not a deciding factor given the CNS target.

**hERG Inhibition:** Ligand A (0.383) has a slightly lower hERG inhibition risk than Ligand B (0.752), which is preferable.

**Microsomal Clearance:** Both ligands have similar microsomal clearance values (68.719 and 69.112), suggesting comparable metabolic stability.

**In vitro Half-Life:** Ligand A (21.961) has a longer half-life than Ligand B (2.353), which is desirable.

**P-gp Efflux:** Ligand A (0.607) has lower P-gp efflux liability than Ligand B (0.721), which is beneficial for CNS exposure.

**Binding Affinity:** Ligand A (-9.2 kcal/mol) has a significantly stronger binding affinity than Ligand B (-8.0 kcal/mol). This is a substantial advantage.

**Overall Assessment:**

Ligand A excels in binding affinity, BBB penetration, P-gp efflux, and half-life. However, its high DILI risk is a major concern. Ligand B has a much better safety profile (DILI) and a slightly better logP, but its binding affinity is considerably weaker.

Given the importance of binding affinity for GPCRs, and the relatively high tolerance for some ADME issues when targeting the CNS (where drug delivery is already challenging), the stronger affinity of Ligand A outweighs its DILI risk *provided* further investigation confirms the DILI prediction and potential mitigation strategies are explored. The difference in binding affinity (>1.5 kcal/mol) is substantial.

Output:
1
2025-04-17 03:10:57,105 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (360.445 and 344.503 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Both ligands have TPSA values (58.64 and 59.07) below the 90 A^2 threshold desirable for CNS targets, which is good.

**3. logP:** Ligand A (2.305) is within the optimal 1-3 range. Ligand B (4.147) is slightly above, potentially raising concerns about solubility and off-target effects, but still acceptable.

**4. H-Bond Donors:** Both ligands have acceptable HBD counts (1 and 2, respectively), well below the 5 limit.

**5. H-Bond Acceptors:** Both ligands have acceptable HBA counts (3 and 5, respectively), below the 10 limit.

**6. QED:** Both ligands have QED values (0.791 and 0.659) above 0.5, indicating good drug-like properties.

**7. DILI:** Ligand A (16.789%) has a significantly lower DILI risk than Ligand B (33.307%). This is a substantial advantage.

**8. BBB:** Ligand A (93.641%) has a considerably higher predicted BBB penetration than Ligand B (82.009%). This is a critical advantage for a CNS target like DRD2.

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.523 and -4.822), which is unusual and suggests poor permeability. However, these values are on a scale where negative values are possible and don't necessarily disqualify a compound.

**10. Aqueous Solubility:** Both ligands have negative solubility values (-2.548 and -4.432), indicating poor aqueous solubility. This is a concern, but can sometimes be overcome with formulation strategies.

**11. hERG Inhibition:** Both ligands have low hERG inhibition liability (0.561 and 0.863), which is favorable.

**12. Microsomal Clearance:** Ligand A (46.029 mL/min/kg) has a lower microsomal clearance than Ligand B (93.748 mL/min/kg), suggesting better metabolic stability.

**13. In vitro Half-Life:** Ligand A (-17.51 hours) has a negative half-life, which is unusual and likely represents a value on a scale where negative values are possible. Ligand B (38.142 hours) has a more reasonable half-life.

**14. P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.021 and 0.614), which is excellent for CNS penetration.

**15. Binding Affinity:** Ligand B (-8.1 kcal/mol) has a slightly stronger binding affinity than Ligand A (-7.8 kcal/mol). While this is a positive for Ligand B, the difference is not substantial enough to outweigh the other significant advantages of Ligand A.

**Overall Assessment:**

Ligand A is the more promising candidate. Its superior BBB penetration, lower DILI risk, and better metabolic stability (lower Cl_mic) are crucial advantages for a CNS-targeting GPCR. While Ligand B has slightly better binding affinity and a more reasonable in vitro half-life, the other ADME/Tox properties of Ligand A are significantly more favorable. The negative values for Caco-2 and solubility are concerns for both, but the overall profile of Ligand A is more balanced and suggests a higher probability of success.

Output:
0
2025-04-17 03:10:57,105 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B based on the provided guidelines, prioritizing GPCR-specific properties (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (344.5) is slightly lower, which could be beneficial for permeability, but both are acceptable.

**TPSA:** Ligand A (58.2) is better than Ligand B (32.34) regarding TPSA, falling well within the <90 A^2 range desirable for CNS targets. Ligand B is also good, but A is preferable.

**logP:** Ligand A (3.041) is within the optimal range (1-3), while Ligand B (4.458) is slightly higher. While not drastically outside the range, higher logP can sometimes lead to off-target effects and solubility issues.

**H-Bond Donors/Acceptors:** Ligand A (2 HBD, 2 HBA) and Ligand B (1 HBD, 3 HBA) both have reasonable numbers of H-bond donors and acceptors, well within the guidelines.

**QED:** Both ligands have good QED scores (A: 0.665, B: 0.78), indicating good drug-like properties.

**DILI:** Ligand A (15.2) has a significantly lower DILI risk than Ligand B (32.842). This is a substantial advantage for Ligand A.

**BBB:** Ligand B (85.072) has a considerably higher BBB penetration percentile than Ligand A (70.415). This is a critical factor for CNS targets like DRD2, and gives Ligand B a significant advantage.

**Caco-2 Permeability:** Ligand A (-4.46) has a lower Caco-2 permeability than Ligand B (-5.206). Both are negative, indicating poor permeability, but B is slightly better.

**Aqueous Solubility:** Both ligands have poor aqueous solubility (-4.026 and -4.773, respectively). This could pose formulation challenges, but isn't a dealbreaker.

**hERG Inhibition:** Ligand A (0.367) has a lower hERG inhibition liability than Ligand B (0.683), making it safer from a cardiotoxicity perspective.

**Microsomal Clearance:** Ligand A (52.068) has a lower microsomal clearance than Ligand B (100.475), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand B (14.005) has a longer in vitro half-life than Ligand A (4.763), which is generally desirable.

**P-gp Efflux:** Ligand A (0.085) has significantly lower P-gp efflux liability than Ligand B (0.532). Lower P-gp efflux is crucial for CNS penetration.

**Binding Affinity:** Ligand B (-7.7 kcal/mol) has a slightly better binding affinity than Ligand A (-8.3 kcal/mol). While A is already very good, the 0.6 kcal/mol difference is notable.

**Overall Assessment:**

Ligand B excels in BBB penetration and has a slightly better binding affinity and half-life. However, Ligand A demonstrates superior safety profiles (lower DILI and hERG) and better metabolic stability (lower Cl_mic), and lower P-gp efflux. The TPSA is also more favorable for CNS penetration. Considering the GPCR-specific priorities, the improved BBB of Ligand B is a major advantage, but the safety and metabolic properties of Ligand A are also very important. The affinity difference is not large enough to overcome the other advantages of Ligand A.

Output:
0
2025-04-17 03:10:57,105 - INFO - Batch 7 complete. Total preferences: 112
2025-04-17 03:10:57,105 - INFO - Processing batch 8/512...
2025-04-17 03:11:37,715 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (363.336 Da and 351.491 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (88.69) is better than Ligand B (61.88), both are below the 90 A^2 threshold for CNS targets.

**logP:** Both ligands have good logP values (1.94 and 1.108, respectively), falling within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Both have 1 HBD, which is good. Ligand A has 6 HBA, and Ligand B has 4 HBA, both are acceptable (<=10).

**QED:** Both ligands have reasonable QED scores (0.883 and 0.746), indicating good drug-like properties.

**DILI:** Ligand A (65.568) has a higher DILI risk than Ligand B (11.206). This is a significant negative for Ligand A.

**BBB:** Ligand A (88.872) has a significantly better BBB penetration score than Ligand B (70.26). This is a crucial advantage for a CNS target like DRD2.

**Caco-2 Permeability:** Ligand A (-4.388) has worse Caco-2 permeability than Ligand B (-4.963).

**Aqueous Solubility:** Ligand A (-2.71) has worse aqueous solubility than Ligand B (-1.06).

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.211 and 0.407).

**Microsomal Clearance:** Ligand B (31.824) has lower microsomal clearance than Ligand A (19.081), indicating better metabolic stability.

**In vitro Half-Life:** Ligand B (17.134) has a longer in vitro half-life than Ligand A (-22.602).

**P-gp Efflux:** Ligand A (0.041) has a slightly lower P-gp efflux liability than Ligand B (0.042).

**Binding Affinity:** Ligand A (-8.2 kcal/mol) has a significantly stronger binding affinity than Ligand B (0.0 kcal/mol). This is a major advantage, potentially outweighing some of the ADME drawbacks.

**Overall Assessment:**

Ligand A has a substantially better binding affinity and good BBB penetration, which are critical for a CNS GPCR target. However, it suffers from higher DILI risk, lower Caco-2 permeability, and lower solubility. Ligand B has a better safety profile (lower DILI), better metabolic stability, and longer half-life, but its binding affinity is very poor.

Given the strong preference for potency at a GPCR, especially in the CNS, and the significant affinity difference (-8.2 vs 0.0 kcal/mol), the superior binding of Ligand A is the deciding factor. While the ADME properties of Ligand A are not ideal, they could potentially be improved through further optimization. The lack of binding affinity in Ligand B is a more fundamental issue that is harder to overcome.

Output:
1
2025-04-17 03:11:37,715 - INFO - Reasoning:

Let's analyze Ligand A and Ligand B based on the provided guidelines, prioritizing GPCR-specific properties (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (352.475 and 357.435 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (67.87) is significantly better than Ligand B (84.23). For CNS targets, TPSA should be <=90, both are under this threshold, but A is much closer to the optimal range.

**logP:** Both ligands have acceptable logP values (1.725 and 2.832), falling within the 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A (HBD=1, HBA=4) is preferable to Ligand B (HBD=2, HBA=5) as it has fewer hydrogen bond donors and acceptors, potentially improving permeability. Both are within acceptable limits.

**QED:** Both ligands have good QED scores (0.758 and 0.804), indicating drug-like properties.

**DILI:** Ligand A (18.728) has a much lower DILI risk than Ligand B (75.611). This is a significant advantage.

**BBB:** Ligand A (77.511) has a significantly better BBB penetration score than Ligand B (53.432).  This is *critical* for a CNS target like DRD2. A score >70 is desirable, and A is closer.

**Caco-2 Permeability:** Ligand A (-4.459) has a slightly better (less negative) Caco-2 permeability score than Ligand B (-5.324), suggesting better intestinal absorption.

**Aqueous Solubility:** Ligand A (-1.766) has a slightly better (less negative) solubility score than Ligand B (-3.945).

**hERG:** Both ligands have very low hERG inhibition liability (0.296 and 0.277), which is excellent.

**Microsomal Clearance:** Ligand A (16.654) has a lower microsomal clearance than Ligand B (47.902), indicating better metabolic stability.

**In vitro Half-Life:** Ligand B (36.248) has a longer in vitro half-life than Ligand A (11.755). This is a positive for B, but potentially offset by its poorer metabolic stability.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.051 and 0.215).

**Binding Affinity:** Ligand B (-8.9 kcal/mol) has a significantly stronger binding affinity than Ligand A (-7.2 kcal/mol). This is a substantial advantage (1.7 kcal/mol difference).

**Overall Assessment:**

While Ligand B boasts a superior binding affinity, Ligand A has a much more favorable ADME profile, particularly regarding BBB penetration, DILI risk, and metabolic stability. For a CNS GPCR target, BBB penetration is paramount. The significantly lower DILI risk of Ligand A is also a major benefit. The difference in binding affinity, while substantial, might be overcome with further optimization of Ligand A, while fixing the ADME issues of Ligand B would be more challenging.

Output:
0
2025-04-17 03:11:37,716 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (385.421 Da) is slightly higher than Ligand B (349.435 Da), but both are acceptable.

**TPSA:** Ligand A (81.93) is better than Ligand B (101.65). For CNS targets, we want TPSA <= 90, so Ligand A is preferable.

**logP:** Ligand A (2.892) is optimal (1-3), while Ligand B (0.794) is a bit low, potentially hindering permeation. This favors Ligand A.

**H-Bond Donors/Acceptors:** Both ligands have 1 HBD, which is good. Ligand A has 8 HBA, and Ligand B has 6. Both are within the acceptable limit of <=10.

**QED:** Ligand B (0.866) has a significantly better QED score than Ligand A (0.497), indicating a more drug-like profile overall.

**DILI:** Ligand B (54.362) has a much lower DILI risk than Ligand A (95.812). This is a significant advantage for Ligand B.

**BBB:** Ligand B (77.549) has a better BBB penetration percentile than Ligand A (65.413). Both are reasonably good, but >70 is desirable for CNS targets, and Ligand B is closer.

**Caco-2 Permeability:** Ligand A (-5.093) has a negative value, which is unusual and suggests very poor permeability. Ligand B (-4.834) is also poor, but slightly better.

**Aqueous Solubility:** Both ligands have very poor aqueous solubility (-4.015 and -2.38 respectively). This is a concern for both, but less critical than BBB for CNS drugs.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.452 and 0.416 respectively).

**Microsomal Clearance:** Ligand B (20.687) has significantly lower microsomal clearance than Ligand A (67.779), indicating better metabolic stability.

**In vitro Half-Life:** Ligand B (9.158 hours) has a longer half-life than Ligand A (4.29 hours).

**P-gp Efflux:** Ligand B (0.021) has much lower P-gp efflux liability than Ligand A (0.254), which is crucial for CNS penetration.

**Binding Affinity:** Ligand A (-8.2 kcal/mol) has a significantly stronger binding affinity than Ligand B (0.0 kcal/mol). This is a major advantage for Ligand A. A >1.5 kcal/mol advantage can often outweigh other issues.

**Overall Assessment:**

Ligand B excels in ADME properties (DILI, BBB, Cl_mic, t1/2, Pgp) and has a better QED score. However, its binding affinity is very weak. Ligand A has a much stronger binding affinity, but suffers from poorer ADME properties, particularly high DILI and P-gp efflux, and poor Caco-2 permeability.

Given the GPCR target and the importance of CNS penetration, the strong affinity of Ligand A is a significant advantage. While its ADME properties are suboptimal, medicinal chemistry efforts could focus on improving these while retaining the strong binding. The extremely weak binding of Ligand B makes it a less attractive starting point, as substantial potency improvements would be needed.

Output:
1
2025-04-17 03:11:37,716 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (350.503 and 361.833 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (49.85) is excellent, well below the 90 A^2 threshold for CNS targets. Ligand B (88.08) is higher, but still acceptable, though less ideal.

**logP:** Both ligands have good logP values (2.974 and 2.114), falling within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A (0 HBD, 3 HBA) is favorable. Ligand B (1 HBD, 5 HBA) is also acceptable, but slightly higher counts could potentially impact permeability.

**QED:** Both ligands have good QED scores (0.632 and 0.851), indicating good drug-like properties.

**DILI:** Ligand A (17.759) has a much lower DILI risk than Ligand B (71.85). This is a significant advantage.

**BBB:** Ligand A (75.107) has a good BBB penetration percentile, exceeding the 70% threshold for CNS targets. Ligand B (43.932) is considerably lower, raising concerns about CNS exposure.

**Caco-2 Permeability:** Ligand A (-4.619) shows poor permeability. Ligand B (-5.052) is also poor, but slightly worse.

**Aqueous Solubility:** Both ligands have negative solubility values (-2.352 and -3.094), indicating poor aqueous solubility. This is a potential formulation challenge, but can sometimes be overcome.

**hERG Inhibition:** Ligand A (0.591) has a low hERG risk. Ligand B (0.198) also has a low hERG risk.

**Microsomal Clearance:** Ligand A (61.382) has a higher microsomal clearance than Ligand B (44.511), suggesting lower metabolic stability.

**In vitro Half-Life:** Ligand A (-8.673) has a longer in vitro half-life than Ligand B (39.98).

**P-gp Efflux:** Ligand A (0.489) has lower P-gp efflux liability than Ligand B (0.115), which is beneficial for CNS penetration.

**Binding Affinity:** Ligand B (-8.9 kcal/mol) has a slightly better binding affinity than Ligand A (-7.4 kcal/mol). The difference is 1.5 kcal/mol, which is a significant advantage.

**Overall Assessment:**

While Ligand B has a slightly better binding affinity, Ligand A is the more promising candidate. The key advantages of Ligand A are its significantly lower DILI risk, better BBB penetration, and lower P-gp efflux. These factors are crucial for a CNS-targeting drug. The slightly lower affinity of Ligand A can potentially be addressed through further optimization, while mitigating the poor solubility and permeability of both compounds will be a key focus. The poor Caco-2 values are concerning for both, but the superior CNS properties of Ligand A outweigh the small affinity difference.

Output:
0
2025-04-17 03:11:37,716 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B based on the provided guidelines, prioritizing GPCR-specific properties (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (348.407 and 352.473 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (119.43) is excellent for CNS penetration, being below 90. Ligand B (49.84) is also very good.

**logP:** Ligand A (0.337) is quite low, potentially hindering permeability. Ligand B (4.803) is high, potentially causing solubility issues and off-target effects, but acceptable.

**H-Bond Donors/Acceptors:** Both ligands have 2 HBD and 4-5 HBA, which are within acceptable limits.

**QED:** Ligand B (0.772) has a significantly better QED score than Ligand A (0.298), indicating a more drug-like profile.

**DILI:** Both ligands have acceptable DILI risk (33.773 and 43.234 percentile).

**BBB:** Ligand B (92.788) has a much higher BBB penetration score than Ligand A (46.879), which is crucial for a CNS target like DRD2.

**Caco-2 Permeability:** Ligand A (-5.453) has poor Caco-2 permeability. Ligand B (-4.663) is also poor, but slightly better than A.

**Aqueous Solubility:** Ligand A (-1.353) has poor solubility. Ligand B (-5.13) is also poor.

**hERG Inhibition:** Ligand A (0.109) has a very low hERG risk. Ligand B (0.846) has a higher, but still relatively low, hERG risk.

**Microsomal Clearance:** Ligand B (57.336 mL/min/kg) has a higher clearance than Ligand A (18.712 mL/min/kg), suggesting lower metabolic stability.

**In vitro Half-Life:** Ligand B (55.823 hours) has a significantly longer half-life than Ligand A (8.088 hours).

**P-gp Efflux:** Ligand A (0.004) has very low P-gp efflux, which is favorable for CNS penetration. Ligand B (0.436) has moderate P-gp efflux.

**Binding Affinity:** Ligand B (-9.2 kcal/mol) has a substantially stronger binding affinity than Ligand A (-7.5 kcal/mol). This difference in affinity is significant (>1.5 kcal/mol).

**Overall Assessment:**

Ligand B is the more promising candidate. While its logP is a bit high and solubility is poor, its significantly better BBB penetration, longer half-life, and *much* stronger binding affinity outweigh these drawbacks. The higher QED score also supports its drug-like potential. Ligand A's low logP and poor Caco-2 permeability are major concerns, even with its low P-gp efflux. The substantial affinity difference makes Ligand B the clear choice.

Output:
1
2025-04-17 03:11:37,716 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (361.515 and 342.483 Da) fall within the ideal range of 200-500 Da.

**TPSA:** Ligand A (59.64) is better than Ligand B (49.41). Both are below the 90 A^2 threshold for CNS targets, which is excellent.

**logP:** Ligand B (3.184) is slightly higher than Ligand A (1.665), placing it closer to the optimal 1-3 range. Ligand A is at the lower end, potentially impacting permeability.

**H-Bond Donors/Acceptors:** Ligand A has 3 HBD and 3 HBA, while Ligand B has 1 HBD and 2 HBA. Both are within acceptable limits (<=5 HBD and <=10 HBA).

**QED:** Both ligands have similar QED values (0.712 and 0.754), indicating good drug-likeness.

**DILI:** Ligand B (15.083) has a significantly lower DILI risk than Ligand A (18.651), making it more favorable from a toxicity perspective.

**BBB:** Ligand B (83.404) has a much higher BBB penetration percentile than Ligand A (66.499). This is a *critical* advantage for a CNS target like DRD2.

**Caco-2 Permeability:** Ligand A (-5.49) has better Caco-2 permeability than Ligand B (-4.924). However, both are negative values, which is unusual and requires further investigation.

**Aqueous Solubility:** Ligand A (-1.976) has better aqueous solubility than Ligand B (-3.767).

**hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.516 and 0.263).

**Microsomal Clearance:** Ligand A (-45.533) has a much lower (better) microsomal clearance than Ligand B (28.438), suggesting greater metabolic stability.

**In vitro Half-Life:** Ligand A (39.457) has a longer in vitro half-life than Ligand B (-8.252). This is a positive attribute.

**P-gp Efflux:** Ligand A (0.025) has lower P-gp efflux than Ligand B (0.108), which is beneficial for CNS exposure.

**Binding Affinity:** Both ligands have excellent binding affinities (-9.4 and -8.1 kcal/mol). Ligand A is slightly better (-9.4 kcal/mol), but the difference is less than 1.5 kcal/mol.

**Overall Assessment:**

While Ligand A has slightly better binding affinity, metabolic stability, and P-gp efflux, Ligand B significantly outperforms it in BBB penetration and DILI risk. For a CNS target like DRD2, BBB penetration is paramount. The lower DILI risk is also a significant advantage. The slightly lower affinity of Ligand B is likely surmountable with further optimization. The better logP of Ligand B also suggests better membrane permeability.

Output:
1
2025-04-17 03:11:37,717 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (383.809 Da) is slightly higher than Ligand B (354.376 Da), but both are acceptable.

**TPSA:** Ligand A (109.77) is higher than the preferred <90 for CNS targets, while Ligand B (43.18) is excellent. This is a significant advantage for Ligand B.

**logP:** Both ligands have good logP values (A: 2.555, B: 3.136), falling within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A has 2 HBD and 5 HBA, while Ligand B has 0 HBD and 5 HBA. Both are within acceptable limits.

**QED:** Both ligands have good QED scores (A: 0.742, B: 0.827), indicating good drug-like properties.

**DILI:** Ligand A has a very high DILI risk (98.953), which is a major concern. Ligand B has a much lower DILI risk (16.712), making it significantly safer.

**BBB:** Ligand B has a much higher BBB penetration (96.084) than Ligand A (15.083). This is crucial for a CNS target like DRD2.

**Caco-2 Permeability:** Ligand A has a negative Caco-2 value (-5.248), suggesting poor permeability. Ligand B also has a negative value (-4.581), but slightly better than A.

**Aqueous Solubility:** Both have negative solubility values (A: -3.954, B: -2.765), indicating poor solubility.

**hERG Inhibition:** Ligand A has very low hERG inhibition risk (0.037), while Ligand B has a moderate risk (0.841).

**Microsomal Clearance:** Ligand A has a lower clearance (2.734) than Ligand B (6.613), indicating better metabolic stability.

**In vitro Half-Life:** Ligand B has a much longer half-life (-32.665) than Ligand A (28.114), which is desirable.

**P-gp Efflux:** Ligand A has very low P-gp efflux (0.057), which is good for CNS penetration. Ligand B has moderate P-gp efflux (0.511).

**Binding Affinity:** Ligand B (-9.1 kcal/mol) has a significantly stronger binding affinity than Ligand A (-8.2 kcal/mol). This difference of 0.9 kcal/mol is substantial and can outweigh some ADME drawbacks.

**Overall Assessment:**

Ligand B is the superior candidate. While both have solubility issues, Ligand B excels in critical areas for a CNS GPCR target: significantly better BBB penetration, a much lower DILI risk, and substantially higher binding affinity. The longer half-life is also a major advantage. Although Ligand A has better metabolic stability and lower P-gp efflux, the superior BBB, DILI, and affinity of Ligand B outweigh these benefits. The TPSA of Ligand B is also much more favorable for CNS penetration.

Output:
1
2025-04-17 03:11:37,717 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 drug candidates, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (359.5 and 338.4 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (54.34) is significantly better than Ligand B (67.43). For CNS targets, we want TPSA <= 90, and ideally closer to 60. Ligand A is much closer to this ideal.

**3. logP:** Both ligands have good logP values (2.487 and 2.69), falling within the optimal 1-3 range.

**4. H-Bond Donors:** Ligand A (1) is preferable to Ligand B (2). Lower HBD generally improves permeability.

**5. H-Bond Acceptors:** Ligand A (5) is preferable to Ligand B (4). Lower HBA generally improves permeability.

**6. QED:** Both ligands have good QED scores (0.737 and 0.823), indicating good drug-like properties.

**7. DILI:** Ligand A (35.79%) has a significantly lower DILI risk than Ligand B (64.56%). This is a major advantage for Ligand A.

**8. BBB:** Ligand B (77.59%) has a better BBB penetration score than Ligand A (61.77%). While both are reasonably good, >70 is desirable for CNS targets.

**9. Caco-2 Permeability:** Ligand A (-5.056) and Ligand B (-4.907) both have negative Caco-2 permeability values, which is unusual and suggests poor permeability.

**10. Aqueous Solubility:** Both have poor aqueous solubility (-2.349 and -4.55). This is a concern, but can be addressed with formulation strategies.

**11. hERG Inhibition:** Both ligands have low hERG inhibition risk (0.776 and 0.783).

**12. Microsomal Clearance:** Ligand A (17.95) has a lower microsomal clearance than Ligand B (69.95), indicating better metabolic stability.

**13. In vitro Half-Life:** Ligand B (16.49) has a longer in vitro half-life than Ligand A (5.27). This is a slight advantage for Ligand B.

**14. P-gp Efflux:** Both ligands have similar P-gp efflux liability (0.432 and 0.467).

**15. Binding Affinity:** Ligand B (-9.5 kcal/mol) has a significantly stronger binding affinity than Ligand A (-8.2 kcal/mol). This is a substantial advantage, potentially outweighing some of the ADME drawbacks.

**Overall Assessment:**

Ligand B has a significantly better binding affinity and a better BBB score, which are crucial for a CNS GPCR target like DRD2. However, it suffers from a higher DILI risk, higher microsomal clearance, and a higher TPSA. Ligand A has a much better safety profile (lower DILI), better metabolic stability, and a lower TPSA. The difference in binding affinity is significant (1.3 kcal/mol). Given the importance of potency for GPCRs, and the potential to mitigate some of the ADME issues with formulation or further optimization, Ligand B is the more promising candidate.

Output:
1
2025-04-17 03:11:37,717 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (348.49 and 355.45 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (69.64) is significantly better than Ligand B (92.5). For CNS targets, TPSA should be <=90, so Ligand A is preferable.

**logP:** Both ligands have good logP values (2.39 and 1.83), falling within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Both have 2 HBD and 3 HBA, which are within acceptable limits.

**QED:** Ligand A (0.724) has a better QED score than Ligand B (0.462), indicating a more drug-like profile.

**DILI:** Ligand B (31.56) has a lower DILI risk than Ligand A (19.43), which is favorable.

**BBB:** Ligand B (92.94) has a much higher BBB penetration percentile than Ligand A (63.20). This is a *critical* advantage for a CNS target like DRD2.

**Caco-2 Permeability:** Both have negative values, indicating poor permeability. Ligand A (-4.75) is slightly better than Ligand B (-5.19), but both are concerning.

**Aqueous Solubility:** Both have negative values, indicating poor solubility. Ligand B (-3.18) is slightly better than Ligand A (-2.69).

**hERG:** Both ligands have low hERG inhibition risk (0.32 and 0.52).

**Microsomal Clearance:** Ligand B (23.14) has a lower microsomal clearance than Ligand A (36.91), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand B (-9.18) has a longer in vitro half-life than Ligand A (-8.04).

**P-gp Efflux:** Ligand A (0.25) has lower P-gp efflux liability than Ligand B (0.315), which is favorable for CNS penetration.

**Binding Affinity:** Ligand B (-7.6 kcal/mol) has a slightly better binding affinity than Ligand A (-8.1 kcal/mol). While A is better, the difference is not substantial enough to outweigh other factors.

**Overall Assessment:**

Ligand B excels in BBB penetration and metabolic stability, both crucial for CNS drug development. While Ligand A has a better TPSA and P-gp efflux, the significant advantage of Ligand B in BBB penetration outweighs these factors. The slightly better affinity of Ligand A is not enough to compensate for the poorer CNS exposure predicted for it.

Output:
1
2025-04-17 03:11:37,717 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B based on the provided guidelines, prioritizing GPCR-specific properties (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (339.483) is slightly lower, which is generally favorable for permeability.

**TPSA:** Ligand A (48.13) is excellent for CNS penetration, well below the 90 A^2 threshold. Ligand B (107.53) is higher, but still potentially acceptable, though less ideal.

**logP:** Ligand A (4.247) is slightly high, potentially leading to solubility issues or off-target interactions. Ligand B (0.463) is quite low, which could hinder permeation.

**H-Bond Donors/Acceptors:** Ligand A (HBD=2, HBA=1) and Ligand B (HBD=4, HBA=4) both fall within acceptable ranges.

**QED:** Both ligands have reasonable QED scores (A: 0.812, B: 0.533), indicating good drug-like properties.

**DILI:** Ligand A (40.054) has a slightly higher DILI risk than Ligand B (13.804), but both are below the concerning threshold of 60.

**BBB:** This is crucial for a CNS target like DRD2. Ligand A excels with a BBB percentile of 96.084, indicating excellent brain penetration potential. Ligand B's BBB percentile is 56.572, which is considerably lower and less desirable.

**Caco-2 Permeability:** Ligand A (-4.928) has poor Caco-2 permeability, suggesting limited intestinal absorption. Ligand B (-5.539) is also poor, but slightly worse.

**Aqueous Solubility:** Ligand A (-4.354) has poor aqueous solubility, consistent with its higher logP. Ligand B (-1.143) has better solubility, but still not ideal.

**hERG Inhibition:** Ligand A (0.9) has a slightly higher hERG risk than Ligand B (0.066), but both are relatively low.

**Microsomal Clearance:** Ligand B (-10.984) has significantly lower microsomal clearance (more negative value) than Ligand A (60.497), indicating better metabolic stability.

**In vitro Half-Life:** Ligand B (-9.88) has a longer in vitro half-life than Ligand A (4.108), which is favorable.

**P-gp Efflux:** Ligand A (0.711) has moderate P-gp efflux liability. Ligand B (0.007) has very low P-gp efflux, which is highly desirable for CNS penetration.

**Binding Affinity:** Both ligands have excellent binding affinities (A: -9.3 kcal/mol, B: -8.4 kcal/mol). Ligand A has a 0.9 kcal/mol advantage, which is significant.

**Overall Assessment:**

Ligand A has a superior binding affinity and excellent BBB penetration, which are critical for a CNS-targeting GPCR. However, its high logP, poor solubility, and moderate P-gp efflux are drawbacks. Ligand B has better metabolic stability, lower P-gp efflux, and better solubility, but its lower BBB penetration and weaker binding affinity are significant concerns.

Given the importance of CNS penetration and strong binding for DRD2, and the relatively small difference in binding affinity, **Ligand A is the more promising candidate**, despite its ADME liabilities. These liabilities could potentially be addressed through further optimization, but the core pharmacodynamic properties (affinity and BBB) are already excellent.

Output:
1
2025-04-17 03:11:37,717 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight (MW):** Both ligands are within the ideal range (200-500 Da). Ligand A (338.451) is slightly lower, which could be beneficial for permeability.

**2. TPSA:** Both ligands have TPSA values (44.12 and 45.33) that are acceptable for oral absorption (<140) and reasonably good for CNS penetration (<90, although ideally lower). They are quite similar here.

**3. logP:** Both ligands have logP values (4.841 and 4.388) that are slightly high, potentially leading to solubility issues or off-target interactions. However, for a GPCR targeting the CNS, a higher logP can be tolerated to facilitate BBB penetration.

**4. H-Bond Donors (HBD):** Ligand A (0) has fewer HBDs than Ligand B (1), which is generally preferable for BBB penetration.

**5. H-Bond Acceptors (HBA):** Ligand A (4) has more HBAs than Ligand B (2). This difference is minor.

**6. QED:** Both ligands have similar QED values (0.752 and 0.708), indicating good drug-like properties.

**7. DILI:** Ligand A (37.263) has a significantly lower DILI risk than Ligand B (73.245). This is a major advantage for Ligand A.

**8. BBB:** Both ligands have good BBB penetration (71.656 and 70.764), exceeding the desirable threshold of >70. They are very close in this metric.

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 permeability values (-4.675 and -4.714), which is unusual and suggests poor intestinal absorption. This is a concern for both.

**10. Aqueous Solubility:** Both ligands have very poor aqueous solubility (-5.627 and -4.702). This is a significant drawback, but can sometimes be overcome with formulation strategies.

**11. hERG Inhibition:** Both ligands have low hERG inhibition risk (0.657 and 0.842).

**12. Microsomal Clearance:** Ligand A (115.102) has higher microsomal clearance than Ligand B (79.541), indicating lower metabolic stability. This is a disadvantage for Ligand A.

**13. In vitro Half-Life:** Ligand B (40.671) has a much longer in vitro half-life than Ligand A (-22.7). This is a significant advantage for Ligand B.

**14. P-gp Efflux:** Both ligands have similar low P-gp efflux liability (0.755 and 0.694).

**15. Binding Affinity:** Ligand A (-9.7) has a significantly stronger binding affinity than Ligand B (-9.0). This is a substantial advantage for Ligand A, potentially outweighing some of its ADME drawbacks.

**Overall Assessment:**

Ligand A has a significantly better binding affinity and lower DILI risk, which are crucial factors. While it has higher microsomal clearance and poorer solubility than Ligand B, the strong binding affinity and lower toxicity profile are more important for a CNS-targeting GPCR. The BBB penetration is comparable for both. The negative Caco-2 values are concerning for both, but less critical for a CNS target where direct oral bioavailability isn't always paramount.

Output:
1
2025-04-17 03:11:37,717 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 drug candidates, considering the provided guidelines and GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (344.455 and 369.294 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (49.85) is excellent, well below the 90 Angstroms threshold for CNS targets. Ligand B (88.91) is higher, but still acceptable, though less optimal for CNS penetration.

**3. logP:** Both ligands have good logP values (1.689 and 1.17), falling within the optimal 1-3 range.

**4. H-Bond Donors:** Ligand A (0) is ideal. Ligand B (2) is acceptable.

**5. H-Bond Acceptors:** Ligand A (3) is good. Ligand B (5) is also acceptable.

**6. QED:** Both ligands have good QED scores (0.563 and 0.78), indicating good drug-like properties.

**7. DILI:** Ligand A (11.439) has a very low DILI risk, which is excellent. Ligand B (62.389) has a moderate DILI risk, but is still within acceptable limits.

**8. BBB:** Ligand A (86.817) has a very good BBB penetration percentile, highly desirable for a CNS target like DRD2. Ligand B (73.517) is still reasonably good, but significantly lower than Ligand A.

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.442 and -4.811), which are unusual and suggest poor permeability. This is a significant concern.

**10. Aqueous Solubility:** Both ligands have negative solubility values (-2.569 and -3.164), which is also concerning. Poor solubility can hinder bioavailability.

**11. hERG Inhibition:** Both ligands show very low hERG inhibition liability (0.387 and 0.077), which is excellent.

**12. Microsomal Clearance:** Ligand A (38.351) has moderate clearance, while Ligand B (7.558) has low clearance, suggesting better metabolic stability.

**13. In vitro Half-Life:** Ligand A (-1.495) has a short half-life, while Ligand B (-2.922) has an even shorter half-life. Both are undesirable.

**14. P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.138 and 0.029), which is favorable for CNS penetration.

**15. Binding Affinity:** Ligand B (-8.1 kcal/mol) has a slightly better binding affinity than Ligand A (-7.6 kcal/mol). This difference is >1.5 kcal/mol, which can outweigh some ADME drawbacks.

**Overall Assessment:**

Despite the concerning Caco-2 and solubility values for both, Ligand A is slightly favored due to its significantly better BBB penetration (86.8 vs 73.5) and lower DILI risk. The slightly weaker binding affinity of Ligand A is less concerning given the importance of CNS penetration for a DRD2 target. However, the poor permeability and solubility of both compounds are major red flags that would require significant optimization. Ligand B's better metabolic stability is a plus, but doesn't outweigh the other factors.

Output:
0
2025-04-17 03:11:37,717 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (356.46 and 342.44 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (49.41) is excellent, well below the 90 A^2 threshold for CNS targets. Ligand B (78.09) is higher, but still potentially acceptable, though less ideal.

**3. logP:** Ligand A (3.523) is optimal. Ligand B (1.541) is a bit low, potentially hindering membrane permeability.

**4. H-Bond Donors:** Both have acceptable HBD counts (1 and 2, respectively), well below the limit of 5.

**5. H-Bond Acceptors:** Both have acceptable HBA counts (2 and 3, respectively), well below the limit of 10.

**6. QED:** Both ligands have good QED values (0.609 and 0.815), indicating drug-like properties.

**7. DILI:** Ligand A (17.332) has a much lower DILI risk than Ligand B (36.565), which is a significant advantage.

**8. BBB:** Ligand A (89.531) has a very good BBB penetration percentile, exceeding the desirable >70% threshold for CNS targets. Ligand B (54.207) is considerably lower, raising concerns about sufficient brain exposure.

**9. Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and suggests poor permeability. However, the scale is not specified, so it's difficult to interpret.

**10. Aqueous Solubility:** Both have negative solubility values, which is also unusual and suggests poor solubility. Again, the scale is not specified.

**11. hERG Inhibition:** Both ligands have low hERG inhibition liability (0.667 and 0.115), which is positive.

**12. Microsomal Clearance:** Ligand B (7.097) has significantly lower microsomal clearance than Ligand A (44.454), suggesting better metabolic stability.

**13. In vitro Half-Life:** Ligand B (-13.094) has a very negative in vitro half-life, suggesting very rapid metabolism. Ligand A (-4.991) is better, but still indicates relatively short half-life.

**14. P-gp Efflux:** Both ligands have low P-gp efflux liability (0.102 and 0.033), which is favorable for CNS penetration.

**15. Binding Affinity:** Ligand B (-9.3 kcal/mol) has a stronger binding affinity than Ligand A (-7.7 kcal/mol) by 1.6 kcal/mol. This is a substantial difference and a major point in its favor.

**Overall Assessment:**

While Ligand B boasts a superior binding affinity, Ligand A is the more promising candidate due to its significantly better BBB penetration, lower DILI risk, and acceptable logP and TPSA values. The lower metabolic stability and half-life of Ligand B are concerning, and the weaker BBB penetration is a critical drawback for a CNS target like DRD2. The affinity difference is significant, but can potentially be addressed through further optimization, while poor BBB penetration is much harder to fix.

Output:
0
2025-04-17 03:11:37,718 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (368.5 and 348.4 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (82.78) is better than Ligand B (99.57). For CNS targets, we want TPSA <= 90, so Ligand A is preferable.

**3. logP:** Ligand A (2.059) is within the optimal 1-3 range. Ligand B (-0.546) is below 1, which could hinder permeation. This is a significant advantage for Ligand A.

**4. H-Bond Donors:** Both have 2 HBD, which is acceptable.

**5. H-Bond Acceptors:** Both have 5 HBA, which is acceptable.

**6. QED:** Both have similar QED values (0.77 and 0.746), indicating good drug-likeness.

**7. DILI:** Ligand A (61.07) has a higher DILI risk than Ligand B (39.938). This favors Ligand B.

**8. BBB:** Ligand B (63.125) has a significantly better BBB penetration percentile than Ligand A (34.548). For a CNS target like DRD2, this is a critical advantage for Ligand B.

**9. Caco-2 Permeability:** Both have negative Caco-2 values (-5.149 and -5.22), which is unusual and suggests poor permeability. However, the scale isn't specified, so it's hard to interpret.

**10. Aqueous Solubility:** Both have negative solubility values (-3.148 and -1.073), also unusual. Again, the scale is unknown.

**11. hERG Inhibition:** Ligand A (0.315) has a slightly higher hERG risk than Ligand B (0.092), favoring Ligand B.

**12. Microsomal Clearance:** Ligand A (55.44) has a higher clearance than Ligand B (14.292), meaning Ligand B is more metabolically stable.

**13. In vitro Half-Life:** Ligand A (52.235) has a longer half-life than Ligand B (11.564).

**14. P-gp Efflux:** Ligand A (0.314) has higher P-gp efflux than Ligand B (0.008). Lower P-gp efflux is preferred for CNS penetration, favoring Ligand B.

**15. Binding Affinity:** Ligand B (-7.9 kcal/mol) has a slightly better binding affinity than Ligand A (-7.7 kcal/mol). While the difference is small, it's still a positive for Ligand B.

**Overall Assessment:**

Ligand B is the stronger candidate. While Ligand A has a better TPSA and half-life, Ligand B excels in crucial areas for a CNS-targeting GPCR ligand: significantly better BBB penetration, lower DILI risk, lower hERG risk, lower P-gp efflux, and slightly better binding affinity. The logP value for Ligand A is also a significant advantage. The unusual negative values for Caco-2 and solubility are concerning for both, but the other factors strongly favor Ligand B.

Output:
1
2025-04-17 03:11:37,718 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (359.828 Da) is slightly better positioned than Ligand B (390.311 Da).

**TPSA:** Ligand A (29.54) is excellent for CNS penetration, well below the 90 A^2 threshold. Ligand B (87.3) is higher, potentially hindering BBB penetration, but still within a reasonable range.

**logP:** Ligand A (4.482) is slightly high, potentially causing solubility issues or off-target interactions. Ligand B (2.155) is optimal.

**H-Bond Donors/Acceptors:** Ligand A (0 HBD, 2 HBA) and Ligand B (3 HBD, 3 HBA) are both acceptable.

**QED:** Ligand A (0.805) has a better QED score than Ligand B (0.608), indicating a more drug-like profile.

**DILI:** Ligand B (24.234) has a significantly lower DILI risk than Ligand A (67.429), a major advantage.

**BBB:** Ligand A (88.988) has excellent BBB penetration potential. Ligand B (64.87) is lower, which is a concern for a CNS target.

**Caco-2 Permeability:** Ligand A (-4.57) has poor Caco-2 permeability, suggesting poor absorption. Ligand B (-5.606) is also poor, but slightly better than Ligand A.

**Aqueous Solubility:** Ligand A (-5.243) has very poor solubility. Ligand B (-2.59) is better, but still low.

**hERG:** Ligand A (0.796) has a slightly higher hERG risk than Ligand B (0.22), which is preferable.

**Microsomal Clearance:** Ligand A (93.202) has high microsomal clearance, indicating rapid metabolism. Ligand B (3.82) has very low clearance, suggesting good metabolic stability.

**In vitro Half-Life:** Ligand A (13.766 hours) has a reasonable half-life. Ligand B (26.194 hours) has a longer, more desirable half-life.

**P-gp Efflux:** Ligand A (0.847) has moderate P-gp efflux, which could limit CNS exposure. Ligand B (0.043) has very low P-gp efflux, a significant advantage for CNS penetration.

**Binding Affinity:** Both ligands have excellent binding affinity (-10 kcal/mol and -9.2 kcal/mol respectively), with Ligand A being slightly stronger. However, the affinity difference is not substantial enough to outweigh the other ADME/Tox concerns.

**Overall Assessment:**

Ligand A has better BBB penetration and slightly better binding affinity, but suffers from poor solubility, high DILI risk, high metabolic clearance, and moderate P-gp efflux. Ligand B, while having slightly lower BBB penetration, excels in metabolic stability (low Cl_mic, long t1/2), low DILI risk, and minimal P-gp efflux. Given the importance of metabolic stability and safety (DILI) for a CNS drug, and the relatively small difference in binding affinity, **Ligand B is the more promising candidate.** The lower P-gp efflux also supports better CNS exposure.

Output:
1
2025-04-17 03:11:37,718 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (350.434 and 365.499 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (67.43) is significantly better than Ligand B (74.58). For CNS targets, we want TPSA <= 90, and A is closer to the optimal <=60 range.

**3. logP:** Both ligands have good logP values (2.443 and 2.725), falling within the 1-3 optimal range.

**4. H-Bond Donors:** Both have 2 HBD, which is acceptable.

**5. H-Bond Acceptors:** Ligand A has 3 HBA, while Ligand B has 4. Both are within the acceptable limit of <=10.

**6. QED:** Both ligands have good QED scores (0.719 and 0.779), indicating good drug-like properties.

**7. DILI:** Ligand A (27.918) has a much lower DILI risk than Ligand B (51.028). Both are below the 60 threshold, but A is preferable.

**8. BBB:** This is a critical parameter for CNS targets. Ligand A (86.041) has a significantly higher BBB penetration percentile than Ligand B (58.627). A value >70 is desirable, and A is much closer.

**9. Caco-2 Permeability:** Ligand A (-4.341) has a more negative Caco-2 value, indicating *better* permeability than Ligand B (-5.466).

**10. Aqueous Solubility:** Ligand A (-3.237) has a slightly better solubility than Ligand B (-3.03), though both are quite poor.

**11. hERG Inhibition:** Ligand A (0.586) has a slightly better hERG profile than Ligand B (0.35), indicating lower cardiotoxicity risk.

**12. Microsomal Clearance:** Ligand A (56.876) has a higher microsomal clearance than Ligand B (43.056), meaning it's less metabolically stable. This is a negative for A.

**13. In vitro Half-Life:** Ligand B (41.874) has a significantly longer in vitro half-life than Ligand A (-14.411). This is a significant advantage for B.

**14. P-gp Efflux:** Ligand A (0.097) has lower P-gp efflux liability than Ligand B (0.082), meaning it's less likely to be pumped out of the brain.

**15. Binding Affinity:** Ligand B (-7.6 kcal/mol) has a significantly better binding affinity than Ligand A (-9.1 kcal/mol). This is a substantial advantage for B, and can outweigh some of the ADME concerns.

**Overall Assessment:**

Ligand A excels in TPSA, BBB, DILI, Caco-2 permeability, and P-gp efflux, all critical for CNS penetration and safety. However, Ligand B has a *much* stronger binding affinity and a better in vitro half-life. The superior affinity of Ligand B is a major advantage for a GPCR target, and the longer half-life is also beneficial. While Ligand A has a better safety profile (DILI, hERG), the affinity difference is substantial enough to prioritize Ligand B, especially considering optimization can address some of its ADME liabilities.

Output:
1
2025-04-17 03:11:37,718 - INFO - Batch 8 complete. Total preferences: 128
2025-04-17 03:11:37,718 - INFO - Processing batch 9/512...
2025-04-17 03:12:17,695 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (347.459 Da) is slightly lower, which could be advantageous for permeability.

**TPSA:** Both ligands are reasonably close to the ideal TPSA for CNS targets (<=90 A^2). Ligand A (91.32 A^2) is slightly higher than Ligand B (96.12 A^2), but both are acceptable.

**logP:** Both ligands have good logP values (Ligand A: 2.652, Ligand B: 3.162), falling within the optimal range of 1-3.

**H-Bond Donors/Acceptors:** Ligand A has 3 HBD and 4 HBA, while Ligand B has 0 HBD and 5 HBA. Both are within acceptable limits (<=5 HBD and <=10 HBA).

**QED:** Ligand A (0.599) has a significantly better QED score than Ligand B (0.38), indicating a more drug-like profile.

**DILI:** Both ligands have low DILI risk (Ligand A: 33.773, Ligand B: 37.999), below the 40 threshold.

**BBB:** Ligand B (72.237) has a substantially better BBB penetration percentile than Ligand A (40.946). This is a *critical* advantage for a CNS target like DRD2.

**Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and suggests poor permeability. Ligand A (-4.867) is slightly worse than Ligand B (-4.571).

**Aqueous Solubility:** Both ligands have poor aqueous solubility (-3.796 and -3.132 respectively).

**hERG Inhibition:** Both ligands have low hERG inhibition risk (Ligand A: 0.29, Ligand B: 0.404).

**Microsomal Clearance:** Ligand A (77.203) has a higher microsomal clearance than Ligand B (58.679), suggesting lower metabolic stability.

**In vitro Half-Life:** Ligand B (12.01 hours) has a significantly longer in vitro half-life than Ligand A (-32.422 hours).

**P-gp Efflux:** Both have low P-gp efflux liability (Ligand A: 0.047, Ligand B: 0.128).

**Binding Affinity:** Ligand A (-8.2 kcal/mol) has a significantly stronger binding affinity than Ligand B (-6.3 kcal/mol). This is a substantial advantage.

**Overall Assessment:**

The key differentiating factors are BBB penetration and binding affinity. Ligand B has a much better BBB score (72.237 vs 40.946), which is crucial for CNS drug development. However, Ligand A boasts a significantly stronger binding affinity (-8.2 vs -6.3 kcal/mol). The affinity difference is quite large (>1.5 kcal/mol), and can often outweigh other ADME drawbacks. Given the importance of affinity for GPCRs, and the fact that both have acceptable (though not ideal) ADME profiles, Ligand A is the more promising candidate. The poor Caco-2 and solubility of both are concerns that would need to be addressed in further optimization, but the strong binding affinity of Ligand A makes it a better starting point.

Output:
1
2025-04-17 03:12:17,695 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (352.475 and 346.431 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (98.66) is slightly above the preferred <90 for CNS targets, but still reasonable. Ligand B (72.53) is well within the optimal range. This favors Ligand B.

**3. logP:** Both ligands have good logP values (1.122 and 1.79), falling within the 1-3 range.

**4. H-Bond Donors:** Ligand A has 4 HBD, which is acceptable. Ligand B has 1 HBD, also acceptable.

**5. H-Bond Acceptors:** Ligand A has 4 HBA, acceptable. Ligand B has 6 HBA, also acceptable.

**6. QED:** Both ligands have good QED scores (0.516 and 0.863), indicating good drug-like properties. Ligand B is better here.

**7. DILI:** Ligand A (22.179) has a significantly lower DILI risk than Ligand B (35.595). This is a substantial advantage for Ligand A.

**8. BBB:** Ligand B (57.115) has a much better BBB penetration score than Ligand A (30.283). This is a critical advantage for a CNS target like DRD2.

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.096 and -5.049), which is unusual and suggests poor permeability. This is a concern for both.

**10. Aqueous Solubility:** Both ligands have negative solubility values (-2.243 and -1.627), indicating poor aqueous solubility. This is a concern for both.

**11. hERG Inhibition:** Both ligands have low hERG inhibition risk (0.096 and 0.143).

**12. Microsomal Clearance:** Ligand A (14.035) has lower microsomal clearance than Ligand B (20.99), suggesting better metabolic stability.

**13. In vitro Half-Life:** Ligand A (-12.254) has a negative half-life, which is not possible. This is a major red flag. Ligand B (54.82) has a good in vitro half-life.

**14. P-gp Efflux:** Both ligands have low P-gp efflux liability (0.092 and 0.026).

**15. Binding Affinity:** Ligand B (-7.4) has a slightly better binding affinity than Ligand A (-7.9). While the difference is small, it's still a positive for Ligand B.

**Overall Assessment:**

Ligand A has a lower DILI risk and better metabolic stability. However, the negative in vitro half-life is a critical flaw. Ligand B excels in BBB penetration, has a better QED score, and a more reasonable half-life, despite a slightly higher DILI risk. Given the importance of BBB penetration for a CNS target like DRD2, and the problematic half-life of Ligand A, Ligand B is the more promising candidate. The negative Caco-2 and solubility values are concerning for both, but can potentially be addressed through formulation strategies.

Output:
1
2025-04-17 03:12:17,695 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight (MW):** Both ligands (352.475 and 352.435 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (76.66) is excellent, well below the 90 A^2 threshold for CNS targets. Ligand B (87.78) is still acceptable, but less optimal.

**3. logP:** Ligand A (2.635) is within the optimal range of 1-3. Ligand B (-0.195) is below 1, which could hinder permeation.

**4. H-Bond Donors (HBD):** Both ligands have acceptable HBD counts (2 and 1, respectively), well below the 5 threshold.

**5. H-Bond Acceptors (HBA):** Both ligands have acceptable HBA counts (4 and 6, respectively), below the 10 threshold.

**6. QED:** Both ligands have good QED scores (0.36 and 0.795), with Ligand B being significantly better.

**7. DILI:** Ligand A (28.306) has a slightly higher DILI risk than Ligand B (21.326), but both are below the 40 threshold and considered good.

**8. BBB:** Ligand A (68.67) has a better BBB percentile than Ligand B (46.917). While both are not ideal (>70), A is closer.

**9. Caco-2 Permeability:** Ligand A (-5.258) has poor Caco-2 permeability, while Ligand B (-4.674) is also poor, but slightly better.

**10. Aqueous Solubility:** Ligand A (-1.983) has poor aqueous solubility, while Ligand B (-0.37) is also poor, but slightly better.

**11. hERG Inhibition:** Both ligands have low hERG inhibition risk (0.328 and 0.387, respectively).

**12. Microsomal Clearance:** Ligand A (30.024) has a higher microsomal clearance than Ligand B (3.917), indicating lower metabolic stability.

**13. In vitro Half-Life:** Ligand A (-1.299) has a very short in vitro half-life, while Ligand B (-15.041) is even shorter. Both are poor.

**14. P-gp Efflux:** Both ligands have low P-gp efflux liability (0.047 and 0.06, respectively).

**15. Binding Affinity:** Ligand B (-8.2 kcal/mol) has a slightly better binding affinity than Ligand A (-7.9 kcal/mol), although the difference is small.

**Overall Assessment:**

Considering the GPCR-specific priorities, Ligand A is slightly favored. While Ligand B has a better QED and affinity, Ligand A has a significantly better BBB penetration and a more favorable logP value. The poor Caco-2 and solubility of both compounds are concerning, but can potentially be addressed with formulation strategies. The slightly better metabolic stability (lower Cl_mic) of Ligand B is a positive, but the superior BBB and logP of Ligand A are more critical for a CNS target like DRD2.

Output:
1
2025-04-17 03:12:17,695 - INFO - Reasoning:

Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (343.335 and 349.427 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (112.93) is slightly above the optimal <90 for CNS targets, but still reasonable. Ligand B (77.77) is excellent, well below 90.

**3. logP:** Both ligands (2.338 and 2.741) are within the optimal 1-3 range.

**4. H-Bond Donors:** Ligand A (3) is acceptable. Ligand B (1) is also good.

**5. H-Bond Acceptors:** Ligand A (4) is acceptable. Ligand B (6) is also good.

**6. QED:** Both ligands (0.711 and 0.727) have excellent drug-likeness scores.

**7. DILI:** Ligand A (89.88) has a higher DILI risk than Ligand B (21.132). This is a significant negative for Ligand A.

**8. BBB:** Ligand B (70.609) has a good BBB penetration percentile, exceeding the 70% threshold for CNS targets. Ligand A (29.275) is quite low, indicating poor brain penetration. This is a major drawback for a DRD2 ligand.

**9. Caco-2 Permeability:** Ligand A (-5.351) has poor Caco-2 permeability. Ligand B (-4.388) is also poor, but slightly better than A.

**10. Aqueous Solubility:** Both ligands (-3.128 and -3.311) have poor aqueous solubility.

**11. hERG Inhibition:** Ligand A (0.056) has very low hERG inhibition risk. Ligand B (0.369) is slightly higher, but still relatively low.

**12. Microsomal Clearance:** Ligand A (-0.875) has a negative clearance, which is unusual and suggests very high metabolic stability. Ligand B (73.537) has high clearance, indicating rapid metabolism.

**13. In vitro Half-Life:** Ligand A (-15.95) has a negative half-life, which is also unusual and suggests extremely high stability. Ligand B (38.266) is a reasonable half-life.

**14. P-gp Efflux:** Ligand A (0.026) has very low P-gp efflux, which is favorable for CNS penetration. Ligand B (0.243) is slightly higher but still acceptable.

**15. Binding Affinity:** Ligand B (-7.6 kcal/mol) has a significantly stronger binding affinity than Ligand A (-9.2 kcal/mol). This is a substantial advantage.

**Overall Assessment:**

Ligand B is the superior candidate. While both have issues with solubility and Caco-2 permeability, Ligand B excels in the critical areas for a CNS-targeting GPCR ligand: BBB penetration and binding affinity. The lower DILI risk is also a major advantage. Ligand A's poor BBB penetration is a deal-breaker, despite its potentially interesting metabolic stability profile (negative clearance and half-life are concerning and require further investigation, but are less critical than BBB). The stronger binding affinity of Ligand B further solidifies its position as the more promising candidate.

Output:
1
2025-04-17 03:12:17,695 - INFO - Reasoning:

Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (348.49 and 364.36 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (60.85) is significantly better than Ligand B (87.66). For CNS targets, we want TPSA <= 90, and A is comfortably within that range, while B is approaching the upper limit.

**3. logP:** Both ligands have acceptable logP values (2.20 and 1.05), falling within the optimal 1-3 range.

**4. H-Bond Donors:** Ligand A (1) is preferable to Ligand B (3). Fewer HBDs generally improve permeability.

**5. H-Bond Acceptors:** Ligand A (3) is preferable to Ligand B (4). Fewer HBAs generally improve permeability.

**6. QED:** Both ligands have good QED scores (0.51 and 0.64), indicating drug-like properties.

**7. DILI:** Ligand A (5.31) has a much lower DILI risk than Ligand B (38.74). This is a significant advantage for A.

**8. BBB:** Ligand B (80.42) has a better BBB percentile than Ligand A (65.61), but both are reasonably good for a CNS target. However, the difference isn't huge.

**9. Caco-2 Permeability:** Ligand A (-4.68) is better than Ligand B (-5.07). Higher values indicate better intestinal absorption.

**10. Aqueous Solubility:** Ligand A (-1.14) is better than Ligand B (-1.77).

**11. hERG Inhibition:** Both ligands show low hERG inhibition liability (0.45 and 0.33), which is good.

**12. Microsomal Clearance:** Ligand A (35.88) is better than Ligand B (0.00). Lower clearance suggests better metabolic stability.

**13. In vitro Half-Life:** Ligand A (-1.40) is better than Ligand B (-18.09). Longer half-life is generally desirable.

**14. P-gp Efflux:** Ligand A (0.13) is better than Ligand B (0.03). Lower P-gp efflux is preferred for CNS exposure.

**15. Binding Affinity:** Ligand B (-9.2) has a significantly stronger binding affinity than Ligand A (-7.7). This is a 1.5 kcal/mol advantage, which is substantial and can outweigh some ADME drawbacks.

**Overall Assessment:**

While Ligand B has a superior binding affinity, Ligand A demonstrates a much more favorable ADME profile. Specifically, the lower DILI risk, better metabolic stability (lower Cl_mic and better t1/2), and improved permeability (Caco-2, Pgp) are crucial for drug development. The slightly lower BBB for Ligand A is a concern, but not insurmountable given its other advantages. The substantial difference in DILI risk alone is enough to favor Ligand A.

Output:
0
2025-04-17 03:12:17,696 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (341.411 and 343.339 Da) are within the ideal 200-500 Da range.

**TPSA:** Ligand A (61.88) is excellent, well below the 90 A^2 threshold for CNS targets. Ligand B (132.64) is higher, but still potentially acceptable, although less ideal.

**logP:** Ligand A (3.39) is optimal (1-3). Ligand B (0.711) is a bit low, which could hinder membrane permeability.

**H-Bond Donors/Acceptors:** Ligand A (HBD=1, HBA=3) is good. Ligand B (HBD=4, HBA=6) is also acceptable, but slightly higher counts could impact permeability.

**QED:** Both ligands have similar QED values (0.797 and 0.642), indicating good drug-likeness.

**DILI:** Ligand A (49.283) has a lower DILI risk than Ligand B (69.911), which is preferable.

**BBB:** This is a critical parameter for a CNS target like DRD2. Ligand A (86.778) has a significantly higher BBB penetration percentile than Ligand B (22.063). This is a major advantage for Ligand A.

**Caco-2 Permeability:** Ligand A (-4.458) and Ligand B (-6.084) both have negative values, indicating poor permeability. However, these values are on a scale where higher is better, so the more negative the value, the worse the permeability. Ligand A is slightly better.

**Aqueous Solubility:** Ligand A (-4.199) and Ligand B (-2.31) both have negative values, indicating poor solubility. Again, the more negative the value, the worse the solubility. Ligand B is slightly better.

**hERG Inhibition:** Ligand A (0.651) has a much lower hERG inhibition risk than Ligand B (0.011). This is a significant safety advantage for Ligand A.

**Microsomal Clearance:** Ligand A (33.483) has a higher (worse) microsomal clearance than Ligand B (-13.834). This suggests Ligand B is more metabolically stable.

**In vitro Half-Life:** Ligand A (14.788) has a longer half-life than Ligand B (-1.47), which is desirable.

**P-gp Efflux:** Ligand A (0.106) has lower P-gp efflux liability than Ligand B (0.007), which is beneficial for CNS exposure.

**Binding Affinity:** Ligand B (-9.1) has a slightly better binding affinity than Ligand A (-8.8), but the difference is relatively small (0.3 kcal/mol). Given the other ADME considerations, this difference is unlikely to be decisive.

**Overall Assessment:**

Ligand A is the stronger candidate. It excels in key properties for CNS penetration (BBB, TPSA, Pgp) and has a better safety profile (DILI, hERG). While Ligand B has slightly better metabolic stability and binding affinity, the differences are not substantial enough to outweigh Ligand A's advantages in BBB penetration, safety, and overall drug-likeness. The lower logP of Ligand B is also a concern.



Output:
0
2025-04-17 03:12:17,696 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (342.399 Da) is slightly better, being closer to the lower end which can aid permeability.

**TPSA:** Ligand A (71.58) is significantly better than Ligand B (42.43). For CNS targets, we want TPSA <= 90, and ideally lower. Ligand A is well within this range, while Ligand B is also acceptable, but less optimal.

**logP:** Ligand A (1.686) is optimal (1-3). Ligand B (4.405) is higher, potentially leading to solubility issues and off-target interactions.

**H-Bond Donors/Acceptors:** Both ligands have 0 HBD and 5 HBA, which are within acceptable limits.

**QED:** Ligand A (0.848) has a significantly better QED score than Ligand B (0.561), indicating a more drug-like profile.

**DILI:** Both ligands have acceptable DILI risk (Ligand A: 46.917, Ligand B: 40.83).

**BBB:** Ligand B (65.374) has a better BBB percentile than Ligand A (52.074). This is a crucial factor for CNS targets like DRD2, and gives Ligand B an advantage.

**Caco-2 Permeability:** Ligand A (-4.691) has a worse Caco-2 permeability than Ligand B (-5.022). Lower values suggest lower permeability.

**Aqueous Solubility:** Ligand A (-1.384) has better aqueous solubility than Ligand B (-4.43).

**hERG Inhibition:** Both ligands have low hERG inhibition risk (Ligand A: 0.248, Ligand B: 0.619).

**Microsomal Clearance:** Ligand A (34.559) has lower microsomal clearance than Ligand B (121.78), indicating better metabolic stability.

**In vitro Half-Life:** Ligand A (37.368) and Ligand B (36.56) have similar in vitro half-lives.

**P-gp Efflux:** Ligand A (0.058) has significantly lower P-gp efflux liability than Ligand B (0.473), which is highly desirable for CNS penetration.

**Binding Affinity:** Ligand A (-7.9 kcal/mol) has a significantly stronger binding affinity than Ligand B (-6.2 kcal/mol). This >1.5 kcal/mol difference is substantial and can outweigh some ADME drawbacks.

**Overall Assessment:**

Ligand A excels in most key parameters: TPSA, logP, QED, metabolic stability (Cl_mic), P-gp efflux, and, crucially, binding affinity. While Ligand B has a better BBB score, the significantly stronger binding affinity of Ligand A, combined with its superior drug-like properties and lower efflux, makes it the more promising candidate. The difference in binding affinity is large enough to compensate for the slightly lower BBB.

Output:
0
2025-04-17 03:12:17,696 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (351.447 and 357.445 Da) fall comfortably within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (101.73) is slightly above the optimal <90 for CNS targets, but still reasonable. Ligand B (52.65) is excellent, well below 90. This favors Ligand B.

**3. logP:** Ligand A (0.586) is a bit low, potentially hindering membrane permeability. Ligand B (2.037) is within the optimal 1-3 range. This significantly favors Ligand B.

**4. H-Bond Donors:** Ligand A (2) and Ligand B (1) are both acceptable, below the limit of 5.

**5. H-Bond Acceptors:** Ligand A (4) and Ligand B (3) are both acceptable, below the limit of 10.

**6. QED:** Both ligands have good QED scores (0.655 and 0.71), indicating drug-like properties.

**7. DILI:** Ligand A (18.728) has a lower DILI risk than Ligand B (22.257), which is slightly better.

**8. BBB:** This is crucial for a CNS target. Ligand A (69.833) is acceptable but not great. Ligand B (84.451) is very good, exceeding the >70 threshold. This strongly favors Ligand B.

**9. Caco-2:** Ligand A (-5.294) and Ligand B (-4.759) both have negative values, which is unusual and suggests poor permeability. The values are similar and don't differentiate the two.

**10. Solubility:** Both ligands have poor aqueous solubility (-1.894 and -2.13). This is a concern, but can potentially be addressed with formulation strategies.

**11. hERG:** Both ligands have very low hERG inhibition liability (0.08 and 0.619), which is excellent.

**12. Cl_mic:** Ligand A (7.427) has a slightly lower microsomal clearance than Ligand B (3.823), suggesting better metabolic stability. This favors Ligand A.

**13. t1/2:** Ligand B (-17.489) has a longer in vitro half-life than Ligand A (-15.302), which is desirable. This favors Ligand B.

**14. Pgp:** Both ligands have very low P-gp efflux liability (0.005 and 0.081), which is excellent for CNS penetration.

**15. Binding Affinity:** Both ligands have excellent binding affinity (-8.6 and -8.0 kcal/mol). Ligand A is slightly better (-8.6 kcal/mol), but the difference is less than the 1.5 kcal/mol threshold.

**Overall Assessment:**

Ligand B clearly emerges as the more promising candidate. While Ligand A has a slightly better affinity and lower DILI/Cl_mic, Ligand B excels in the critical GPCR-specific properties: TPSA, logP, and especially BBB penetration. The longer half-life of Ligand B is also a plus. The solubility issues are a concern for both, but can be addressed. The slightly better metabolic stability of Ligand A is less important than the superior CNS penetration profile of Ligand B for a DRD2 target.

Output:
1
2025-04-17 03:12:17,696 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (349.475 Da) is slightly lower, which could be advantageous for permeability. Ligand B (371.459 Da) is also good.

**TPSA:** Ligand A (70.67) is excellent, well below the 90 A^2 threshold for CNS targets. Ligand B (103.86) is still reasonable, but less optimal than A.

**logP:** Ligand A (1.051) is within the optimal range (1-3). Ligand B (-0.685) is slightly below 1, which could potentially hinder permeation.

**H-Bond Donors/Acceptors:** Ligand A (2 HBD, 4 HBA) and Ligand B (1 HBD, 5 HBA) both have acceptable numbers of H-bond donors and acceptors.

**QED:** Both ligands have acceptable QED values (A: 0.752, B: 0.623), indicating good drug-like properties.

**DILI:** Ligand A (11.128) has a significantly lower DILI risk than Ligand B (47.77). This is a major advantage for A.

**BBB:** Ligand A (65.801) has a better BBB penetration percentile than Ligand B (50.911), although both are not ideal (>70). However, for a CNS target, A is clearly preferable.

**Caco-2 Permeability:** Both have negative Caco-2 values (-5.19 and -5.403), which is unusual and suggests poor permeability. This is a concern for both.

**Aqueous Solubility:** Both ligands have negative solubility values (-1.704 and -1.388), which is also concerning and suggests poor solubility.

**hERG Inhibition:** Both ligands have very low hERG inhibition risk (A: 0.366, B: 0.03).

**Microsomal Clearance:** Ligand B (-8.366) has a significantly lower (better) microsomal clearance than Ligand A (2.441), indicating better metabolic stability.

**In vitro Half-Life:** Ligand A (30.958) has a longer in vitro half-life than Ligand B (12.175).

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (A: 0.014, B: 0.016).

**Binding Affinity:** Ligand A (-8.1 kcal/mol) has a slightly better binding affinity than Ligand B (-7.4 kcal/mol). While the difference is not huge, it's enough to consider, especially given the other factors.

**Overall Assessment:**

Ligand A is the stronger candidate. It has a better TPSA, logP, DILI score, BBB penetration, and binding affinity. While both have poor Caco-2 and solubility, the other advantages of A outweigh the slightly better metabolic stability of B. The improved CNS penetration potential of A is crucial for a DRD2 ligand.

Output:
1
2025-04-17 03:12:17,696 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (360.483 and 347.503 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (78.09) is higher than Ligand B (52.65). For CNS targets, TPSA should be <= 90, both are within this range, but B is preferable.

**logP:** Both ligands have good logP values (2.758 and 2.326), falling within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A has 2 HBD and 4 HBA, while Ligand B has 1 HBD and 3 HBA. Both are within acceptable limits (<=5 HBD and <=10 HBA).

**QED:** Both ligands have good QED scores (0.71 and 0.802), indicating good drug-like properties.

**DILI:** Ligand A (65.297) has a higher DILI risk than Ligand B (10.392). This is a significant advantage for Ligand B.

**BBB:** Ligand B (76.813) has a substantially better BBB penetration percentile than Ligand A (53.548). This is *critical* for a CNS target like DRD2.

**Caco-2 Permeability:** Ligand A (-5.498) has worse Caco-2 permeability than Ligand B (-4.694), indicating lower intestinal absorption.

**Aqueous Solubility:** Ligand A (-3.475) has worse aqueous solubility than Ligand B (-1.714).

**hERG Inhibition:** Both ligands have low hERG inhibition liability (0.54 and 0.441), which is good.

**Microsomal Clearance:** Ligand A (63.25) has higher microsomal clearance than Ligand B (35.663), suggesting lower metabolic stability.

**In vitro Half-Life:** Ligand B (9.619) has a slightly longer in vitro half-life than Ligand A (8.057).

**P-gp Efflux:** Ligand A (0.262) has slightly lower P-gp efflux than Ligand B (0.111), which is favorable for CNS penetration. However, both are very low.

**Binding Affinity:** Both ligands have the same binding affinity (-8.6 kcal/mol), which is excellent.

**Overall Assessment:**

Ligand B is significantly better due to its superior BBB penetration (76.813 vs 53.548), lower DILI risk (10.392 vs 65.297), better Caco-2 permeability, and better aqueous solubility. While Ligand A has slightly lower P-gp efflux, the advantages of Ligand B in BBB, DILI, and absorption outweigh this minor difference. The equal binding affinity makes these factors the deciding ones.

Output:
1
2025-04-17 03:12:17,697 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (347.331 and 354.447 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (127.49) is slightly above the optimal <90 for CNS targets, but still reasonable. Ligand B (106.94) is better, falling comfortably below 90.

**logP:** Ligand A (0.353) is quite low, potentially hindering permeability. Ligand B (0.52) is also low, but slightly better. Both are below the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Both ligands have 3 HBD and a reasonable number of HBA (7 for A, 5 for B), satisfying the <5 HBD and <10 HBA guidelines.

**QED:** Both ligands have good QED scores (0.541 and 0.56), indicating good drug-like properties.

**DILI:** Ligand A has a high DILI risk (85.576), which is a significant concern. Ligand B has a very low DILI risk (14.928), a major advantage.

**BBB:** Ligand A has a reasonable BBB penetration (65.374), but Ligand B is considerably lower (41.256). For a CNS target like DRD2, a higher BBB is strongly preferred.

**Caco-2 Permeability:** Both have negative Caco-2 values (-5.191 and -5.209), which is unusual and suggests poor permeability. This is concerning for both.

**Aqueous Solubility:** Both ligands have very poor aqueous solubility (-2.914 and -0.432). This could pose formulation challenges.

**hERG Inhibition:** Both ligands show very low hERG inhibition liability (0.051 and 0.062), which is positive.

**Microsomal Clearance:** Ligand A has a moderate clearance (28.872), while Ligand B has a negative clearance (-7.539), which is highly unusual and suggests very high metabolic stability.

**In vitro Half-Life:** Ligand A has a reasonable half-life (70.138 hours), while Ligand B has a very short half-life (-20.448 hours).

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.044 and 0.017), which is favorable for CNS penetration.

**Binding Affinity:** Both ligands have excellent binding affinities (-8.6 and -7.9 kcal/mol). The difference of 0.7 kcal/mol is not substantial enough to override other significant differences.

**Overall Assessment:**

Despite comparable binding affinities, Ligand B is the more promising candidate. Its significantly lower DILI risk is a major advantage. While its BBB penetration is lower than desired, the extremely high metabolic stability (negative Cl_mic) and low P-gp efflux could potentially compensate for this. Ligand A's high DILI risk is a deal-breaker. The poor solubility and Caco-2 permeability are concerns for both, but might be addressed through formulation strategies.

Output:
1
2025-04-17 03:12:17,697 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (347.46 and 347.42 Da) fall comfortably within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (61.88) is significantly better than Ligand B (78.95). For CNS targets, we want TPSA <= 90, and ideally closer to 60. Ligand A is much closer to this ideal.

**3. logP:** Both ligands have acceptable logP values (1.189 and 0.761), falling within the 1-3 range. Ligand A is slightly better.

**4. H-Bond Donors:** Both have 1 HBD, which is good.

**5. H-Bond Acceptors:** Both have 4 HBA, which is good.

**6. QED:** Both have good QED scores (0.599 and 0.745), indicating drug-like properties. Ligand B is slightly better.

**7. DILI:** Ligand A (22.76) has a much lower DILI risk than Ligand B (40.05). This is a significant advantage for Ligand A.

**8. BBB:** Ligand A (67.58) has a better BBB penetration percentile than Ligand B (61.92). While both are not *excellent* (>70), Ligand A is closer and more promising for a CNS target.

**9. Caco-2:** Ligand A (-5.212) has a worse Caco-2 permeability than Ligand B (-4.429). Higher is better here, so Ligand B is slightly favored.

**10. Solubility:** Both have poor aqueous solubility (-1.65 and -1.938). This is a potential issue for both, but not a deciding factor.

**11. hERG:** Both ligands have low hERG inhibition risk (0.185 and 0.233).

**12. Cl_mic:** Ligand A (7.73) has a much lower microsomal clearance than Ligand B (24.14), indicating better metabolic stability. This is a significant advantage for Ligand A.

**13. t1/2:** Ligand A (-0.797) has a worse in vitro half-life than Ligand B (-38.901). This is a significant advantage for Ligand B.

**14. Pgp:** Both have low P-gp efflux liability (0.045 and 0.025).

**15. Binding Affinity:** Ligand A (-8.4 kcal/mol) has a slightly better binding affinity than Ligand B (-7.5 kcal/mol). While both are good, the 0.9 kcal/mol difference is noteworthy.

**Overall Assessment:**

Considering the GPCR-specific priorities, Ligand A is the more promising candidate. It has a significantly better TPSA, lower DILI risk, better BBB penetration, and improved metabolic stability (lower Cl_mic). The slightly better binding affinity of Ligand A further strengthens its position. While Ligand B has a better Caco-2 permeability and in vitro half-life, the advantages of Ligand A in TPSA, DILI, BBB, and Cl_mic are more critical for a CNS-targeting GPCR ligand like DRD2.

Output:
0
2025-04-17 03:12:17,697 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (344.46 and 359.42 Da) fall within the ideal range of 200-500 Da.

**TPSA:** Ligand A (79.04) is excellent for CNS penetration, being well below 90. Ligand B (117.2) is higher, but still potentially acceptable, though less ideal.

**logP:** Ligand A (3.152) is optimal. Ligand B (-1.358) is significantly lower, which could hinder membrane permeability and brain penetration.

**H-Bond Donors/Acceptors:** Both have 3 HBD, which is good. Ligand A has 3 HBA, and Ligand B has 7 HBA. Both are within acceptable limits (<=10), but Ligand A is slightly better.

**QED:** Ligand A (0.611) is good, indicating drug-likeness. Ligand B (0.38) is below the 0.5 threshold, suggesting a less favorable drug-like profile.

**DILI:** Ligand A (38.74) has a lower DILI risk than Ligand B (24.47), both are good.

**BBB:** Ligand A (53.08) is moderate, while Ligand B (17.45) is quite low. This is a crucial difference for a CNS target like DRD2.

**Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and suggests poor permeability. However, the scale is not specified, so this is difficult to interpret.

**Aqueous Solubility:** Both have negative solubility values, which is also unusual and suggests poor solubility. Again, the scale is not specified.

**hERG Inhibition:** Both have very low hERG inhibition risk (0.822 and 0.092).

**Microsomal Clearance:** Ligand A (35.31) has higher clearance than Ligand B (19.41), suggesting lower metabolic stability.

**In vitro Half-Life:** Ligand B (-33.52) has a longer half-life than Ligand A (-29.53), which is favorable.

**P-gp Efflux:** Ligand A (0.494) has lower P-gp efflux than Ligand B (0.004), which is better for CNS penetration.

**Binding Affinity:** Ligand A (-8.5 kcal/mol) has a significantly stronger binding affinity than Ligand B (-7.3 kcal/mol). This is a substantial advantage.

**Overall Assessment:**

Ligand A is the stronger candidate. While it has slightly higher microsomal clearance, its superior logP, much better BBB penetration, lower P-gp efflux, and significantly stronger binding affinity outweigh this drawback. Ligand B's low logP and poor BBB penetration are major concerns for a CNS-targeted drug. The QED score also favors Ligand A.



Output:
1
2025-04-17 03:12:17,697 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (386.539 and 382.287 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (92.34) is slightly above the optimal <90 for CNS targets, but still reasonable. Ligand B (49.77) is excellent, well below 90.

**logP:** Both ligands have logP values (2.553 and 4.092) within the optimal 1-3 range, though Ligand B is approaching the upper limit.

**H-Bond Donors/Acceptors:** Both have acceptable HBD (2 and 1) and HBA (4 and 4) counts, well within the guidelines.

**QED:** Both ligands have good QED scores (0.682 and 0.699), indicating drug-like properties.

**DILI:** Ligand A (65.568) has a higher DILI risk than Ligand B (26.289). This is a significant negative for Ligand A.

**BBB:** Ligand A (65.529) and Ligand B (57.619) both have BBB penetration percentiles below the desirable >70 for CNS targets. However, Ligand A is slightly better.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values, which is unusual and suggests poor permeability.

**Aqueous Solubility:** Both ligands have negative solubility values, which is also unusual and suggests poor solubility.

**hERG:** Both ligands have low hERG inhibition risk (0.479 and 0.886).

**Microsomal Clearance:** Ligand A (37.321) has significantly lower microsomal clearance than Ligand B (82.26), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (51.704) has a slightly longer in vitro half-life than Ligand B (47.653).

**P-gp Efflux:** Ligand A (0.229) has much lower P-gp efflux liability than Ligand B (0.591), which is a major advantage for CNS penetration.

**Binding Affinity:** Ligand B (-7.9 kcal/mol) has a slightly better binding affinity than Ligand A (-8.3 kcal/mol). While the difference is small, it's still a factor.

**Overall Assessment:**

Considering the GPCR-specific priorities, Ligand A is the better candidate despite the slightly worse affinity. The lower P-gp efflux, significantly lower DILI risk, and better metabolic stability (lower Cl_mic) are crucial for CNS drug development. While both have issues with Caco-2 and solubility, the P-gp and DILI profiles of Ligand A are more favorable. The small difference in affinity can potentially be optimized during lead optimization.

Output:
0
2025-04-17 03:12:17,697 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (386.43 and 366.45 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (70.59) is significantly better than Ligand B (122.9). For CNS targets, we want TPSA <= 90, and A is comfortably within this range, while B is above.

**logP:** Ligand A (3.89) is good, though approaching the upper limit. Ligand B (1.2) is quite low, potentially hindering permeability.

**H-Bond Donors/Acceptors:** Ligand A (1 HBD, 7 HBA) and Ligand B (2 HBD, 9 HBA) are both acceptable, falling within the recommended ranges.

**QED:** Both ligands have similar and acceptable QED values (0.689 and 0.744, both > 0.5).

**DILI:** Ligand A (91.24) has a higher DILI risk than Ligand B (79.45), but both are reasonably acceptable.

**BBB:** Ligand A (73.63) has a better BBB penetration percentile than Ligand B (65.41). While both are above 60, a value > 70 is preferred for CNS targets, and A is closer.

**Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and suggests potential issues with the prediction method. However, the magnitude is similar.

**Aqueous Solubility:** Both have negative solubility values, also unusual. Again, the magnitudes are similar.

**hERG:** Ligand A (0.747) has a slightly higher hERG risk than Ligand B (0.231), but both are relatively low.

**Microsomal Clearance:** Both ligands have similar microsomal clearance values (30.98 and 26.54), indicating comparable metabolic stability.

**In vitro Half-Life:** Ligand A (-18.72) has a negative half-life, which is not physically possible and indicates a problem with the prediction. Ligand B (10.99) is reasonable.

**P-gp Efflux:** Ligand A (0.485) has lower P-gp efflux liability than Ligand B (0.023), which is favorable for CNS penetration.

**Binding Affinity:** Both ligands have very similar binding affinities (-8.7 and -8.5 kcal/mol), both of which are excellent.

**Overall Assessment:**

Despite the issues with the Caco-2, solubility, and half-life predictions, Ligand A is the more promising candidate. Its significantly lower TPSA and better BBB penetration are crucial for a CNS-targeting GPCR like DRD2. While Ligand B has a slightly lower DILI risk and better in vitro half-life prediction, the low logP is a significant concern for brain penetration. The small difference in binding affinity is unlikely to outweigh the ADME advantages of Ligand A. The negative half-life prediction for Ligand A is concerning, but could be an artifact of the model.

Output:
1
2025-04-17 03:12:17,697 - INFO - Reasoning:

Let's analyze Ligand A and Ligand B based on the provided guidelines, prioritizing GPCR-specific properties (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (352.479 and 349.479 Da) fall within the ideal range of 200-500 Da.

**TPSA:** Ligand A (56.33) is significantly better than Ligand B (71.54). For CNS targets, we want TPSA <= 90, and A is comfortably within that range, while B is approaching the upper limit.

**logP:** Ligand A (-0.139) is lower than the optimal 1-3 range, potentially hindering permeation. Ligand B (1.839) is within the optimal range. This favors B.

**H-Bond Donors/Acceptors:** Ligand A (0 HBD, 5 HBA) is preferable to Ligand B (2 HBD, 7 HBA) as lower counts generally improve permeability.

**QED:** Both ligands have acceptable QED values (0.708 and 0.659, both > 0.5).

**DILI:** Ligand A (8.026) has a much lower DILI risk than Ligand B (26.095). This is a significant advantage for A.

**BBB:** Both ligands have good BBB penetration (65.878 and 68.399). While both are above 60, ideally >70 is desired for CNS targets. The difference is minimal.

**Caco-2 Permeability:** Both have negative Caco-2 values (-4.637 and -5.104), which is unusual and suggests poor permeability. This is a concern for both.

**Aqueous Solubility:** Both have negative solubility values (-0.178 and -1.905), which is also unusual and suggests poor solubility. This is a concern for both.

**hERG Inhibition:** Ligand A (0.279) has a lower hERG risk than Ligand B (0.905), which is preferable.

**Microsomal Clearance:** Ligand A (11.924) has a significantly lower microsomal clearance than Ligand B (34.4), indicating better metabolic stability.

**In vitro Half-Life:** Ligand A (-22.546) has a more negative half-life, which is unusual and suggests a very short half-life. Ligand B (24.734) is better.

**P-gp Efflux:** Ligand A (0.012) has a much lower P-gp efflux liability than Ligand B (0.017), which is crucial for CNS penetration.

**Binding Affinity:** Ligand B (-8.5 kcal/mol) has a stronger binding affinity than Ligand A (-7.2 kcal/mol). This is a substantial advantage for B, potentially outweighing some ADME drawbacks.

**Overall Assessment:**

Ligand B has a better logP and significantly better binding affinity. However, Ligand A excels in TPSA, DILI risk, hERG risk, P-gp efflux, and microsomal clearance. The poor solubility and permeability for both are concerning, but the superior affinity of B is a strong driver. Given the GPCR target and the importance of CNS penetration, the lower P-gp efflux of A is valuable, but the stronger binding of B is likely to be more impactful. The lower DILI risk of A is also a positive.

Considering the balance, the stronger binding affinity of Ligand B is the deciding factor, despite its slightly less favorable ADME profile.

Output:
1
2025-04-17 03:12:17,698 - INFO - Batch 9 complete. Total preferences: 144
2025-04-17 03:12:17,698 - INFO - Processing batch 10/512...
2025-04-17 03:13:04,386 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (337.383 and 346.471 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (102.67) is slightly above the optimal <90 for CNS targets, while Ligand B (60.85) is well within the desired range. This favors Ligand B.

**logP:** Both ligands have acceptable logP values (1.429 and 2.276), falling within the 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A has 4 HBD and 3 HBA, while Ligand B has 1 HBD and 3 HBA. Both are within acceptable limits (<=5 HBD and <=10 HBA).

**QED:** Ligand A (0.566) has a slightly better QED score than Ligand B (0.472), indicating a more drug-like profile.

**DILI:** Ligand B (20.008) has a significantly lower DILI risk than Ligand A (75.649). This is a major advantage for Ligand B.

**BBB:** Ligand B (77.2) has a much better BBB penetration score than Ligand A (39.511). This is crucial for a CNS target like DRD2 and strongly favors Ligand B.

**Caco-2 Permeability:** Ligand A (-5.741) has worse Caco-2 permeability than Ligand B (-4.514), suggesting lower intestinal absorption.

**Aqueous Solubility:** Ligand A (-2.995) has worse aqueous solubility than Ligand B (-1.487).

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.294 and 0.328).

**Microsomal Clearance:** Ligand A (-7.717) has a lower (better) microsomal clearance than Ligand B (12). This suggests better metabolic stability for Ligand A.

**In vitro Half-Life:** Ligand A (22.809) has a longer in vitro half-life than Ligand B (-24.305).

**P-gp Efflux:** Ligand A (0.037) has a lower P-gp efflux liability than Ligand B (0.17), which is favorable for CNS penetration.

**Binding Affinity:** Ligand A (-9.9 kcal/mol) has a significantly stronger binding affinity than Ligand B (-8.0 kcal/mol). This is a substantial advantage for Ligand A. The difference of 1.9 kcal/mol is significant enough to potentially outweigh some ADME drawbacks.

**Overall Assessment:**

While Ligand A has superior binding affinity and metabolic stability, Ligand B excels in crucial properties for a CNS-targeting GPCR ligand: BBB penetration, lower DILI risk, and better TPSA. The significantly stronger binding affinity of Ligand A is a major plus, but the poor BBB and high DILI risk are concerning. Considering the GPCR-specific priorities, the better BBB and lower toxicity of Ligand B are more important than the slightly stronger binding of Ligand A.

Output:
1
2025-04-17 03:13:04,387 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (342.483 and 349.406 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (40.62) is significantly better than Ligand B (82.53). For CNS targets, we want TPSA <= 90, and A is comfortably within that, while B is approaching the upper limit.

**3. logP:** Both ligands have acceptable logP values (2.964 and 1.75), falling within the 1-3 optimal range.

**4. H-Bond Donors:** Both have a reasonable number of HBDs (0 and 2 respectively), well below the threshold of 5.

**5. H-Bond Acceptors:** Ligand A (2) is preferable to Ligand B (4), but both are below the 10 limit.

**6. QED:** Ligand B (0.848) has a higher QED score than Ligand A (0.502), suggesting a more drug-like profile overall.

**7. DILI:** Ligand A (13.959) has a much lower DILI risk than Ligand B (38.232). This is a significant advantage for A.

**8. BBB:** Ligand B (69.833) has a better BBB penetration percentile than Ligand A (59.325). While both are not ideal (>70 is desirable), B is closer.

**9. Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and suggests poor permeability. This is a concern for both.

**10. Aqueous Solubility:** Both have negative solubility values, indicating very poor aqueous solubility, a significant drawback.

**11. hERG Inhibition:** Both ligands show low hERG inhibition liability (0.46 and 0.378), which is good.

**12. Microsomal Clearance:** Ligand B (15.659) has significantly lower microsomal clearance than Ligand A (30.014), indicating better metabolic stability.

**13. In vitro Half-Life:** Ligand B (-36.009) has a much longer in vitro half-life than Ligand A (-5.952). This is a substantial advantage for B.

**14. P-gp Efflux:** Both ligands have low P-gp efflux liability (0.226 and 0.065), which is favorable for CNS penetration.

**15. Binding Affinity:** Ligand B (-8.6 kcal/mol) has a significantly stronger binding affinity than Ligand A (-0.0 kcal/mol). This is a *major* advantage for B, potentially outweighing some of its ADME drawbacks.

**Overall Assessment:**

While Ligand A has advantages in TPSA and DILI, Ligand B's substantially stronger binding affinity (-8.6 vs -0.0 kcal/mol) and better metabolic stability (lower Cl_mic, longer t1/2) are critical for a GPCR target. The improved BBB penetration, despite not being ideal, also contributes to its favorability. The poor solubility and Caco-2 permeability are concerns for both, but the potency advantage of B is likely to be more impactful in driving forward development, as these can be addressed through formulation strategies.

Output:
1
2025-04-17 03:13:04,387 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (351.407 and 350.482 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (120.58) is borderline for CNS penetration, being slightly above the preferred <90 threshold. Ligand B (51.02) is excellent, well below 90.

**logP:** Ligand A (-1.072) is a bit low, potentially hindering permeability. Ligand B (3.613) is excellent, falling within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A (3 HBD, 7 HBA) is acceptable. Ligand B (0 HBD, 4 HBA) is also good, with fewer H-bonds, which generally favors permeability.

**QED:** Both ligands have good QED scores (0.575 and 0.639), indicating drug-like properties.

**DILI:** Ligand A (33.812) has a low DILI risk. Ligand B (16.208) has an even lower DILI risk, which is favorable.

**BBB:** Ligand A (51.803) has a moderate BBB penetration score, which is concerning for a CNS target. Ligand B (89.066) has an excellent BBB penetration score, a significant advantage.

**Caco-2 Permeability:** Ligand A (-5.371) has poor Caco-2 permeability. Ligand B (-4.385) is also poor, but slightly better than A.

**Aqueous Solubility:** Both ligands have poor aqueous solubility (-1.442 and -4.404). This could pose formulation challenges.

**hERG Inhibition:** Both ligands show very low hERG inhibition risk (0.122 and 0.356).

**Microsomal Clearance:** Ligand A (0.321) has very low microsomal clearance, indicating good metabolic stability. Ligand B (62.102) has high microsomal clearance, suggesting rapid metabolism.

**In vitro Half-Life:** Ligand A (-7.491) has a very long in vitro half-life, which is a strong positive. Ligand B (-16.22) has a very short in vitro half-life, a significant drawback.

**P-gp Efflux:** Both ligands show very low P-gp efflux liability (0.006 and 0.09).

**Binding Affinity:** Ligand A (-7.9) has a slightly better binding affinity than Ligand B (-6.7), a difference of 1.2 kcal/mol.

**Overall Assessment:**

While Ligand A has slightly better binding affinity and metabolic stability, Ligand B is significantly better in several key areas for a CNS-targeting GPCR. Specifically, its much higher BBB penetration (89.066 vs 51.803), better logP (3.613 vs -1.072), and lower TPSA (51.02 vs 120.58) are crucial advantages. The longer half-life of Ligand A is attractive, but the poor BBB penetration is a major concern. The affinity difference of 1.2 kcal/mol is not substantial enough to overcome the ADME deficiencies of Ligand A.



Output:
1
2025-04-17 03:13:04,387 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (343.431 and 349.435 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (83.28) is excellent, falling well below the 90 A^2 threshold for CNS targets. Ligand B (100.35) is still reasonable but less optimal.

**logP:** Ligand A (1.817) is within the optimal 1-3 range. Ligand B (0.349) is slightly low, potentially hindering permeation.

**H-Bond Donors/Acceptors:** Both ligands have 2 HBD and 5/6 HBA, which are acceptable values.

**QED:** Ligand A (0.887) has a significantly better QED score than Ligand B (0.469), indicating a more drug-like profile.

**DILI:** Both ligands have similar, low DILI risk (37.922 and 37.844 percentile).

**BBB:** Ligand A (78.364) has a good BBB penetration score, exceeding the desirable 70% threshold for CNS targets. Ligand B (34.742) is quite poor, suggesting limited CNS exposure. This is a critical difference given the target.

**Caco-2 Permeability:** Ligand A (-4.776) and Ligand B (-5.376) both have negative values, which is unusual. Assuming these are logP-like scales, lower values suggest poorer permeability.

**Aqueous Solubility:** Both ligands have negative solubility values (-2.065 and -1.285), which is also unusual. This suggests poor aqueous solubility, potentially hindering formulation and bioavailability.

**hERG Inhibition:** Both ligands have very low hERG risk (0.268 and 0.091 percentile).

**Microsomal Clearance:** Both ligands have similar, moderate microsomal clearance (5.896 and 13.271 mL/min/kg).

**In vitro Half-Life:** Ligand A (13.257 hours) has a longer half-life than Ligand B (-6.383 hours). The negative value for Ligand B is concerning and likely indicates a very short half-life.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.103 and 0.017 percentile), which is favorable for CNS penetration.

**Binding Affinity:** Ligand A (-8.3 kcal/mol) has a significantly stronger binding affinity than Ligand B (-7.3 kcal/mol). This 1 kcal/mol difference is substantial and can outweigh minor ADME drawbacks.

**Overall Assessment:**

Ligand A is clearly superior. It has a better QED score, significantly better BBB penetration, a longer half-life, and a substantially stronger binding affinity. While both have poor solubility and Caco-2 permeability, the strong affinity and excellent BBB of Ligand A make it a much more promising candidate for a CNS-targeting drug like a DRD2 ligand. Ligand B's poor BBB penetration is a major drawback.



Output:
0
2025-04-17 03:13:04,387 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (346.343 and 357.357 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (116.84) is slightly above the optimal <90 for CNS targets, while Ligand B (92.51) is comfortably within the range. This gives a slight edge to Ligand B.

**logP:** Ligand A (-0.322) is a bit low, potentially hindering permeability. Ligand B (1.708) is within the optimal 1-3 range. This is a significant advantage for Ligand B.

**H-Bond Donors/Acceptors:** Ligand A has 3 HBD and 5 HBA, which are acceptable. Ligand B has 1 HBD and 5 HBA, also acceptable. No clear advantage here.

**QED:** Both ligands have good QED scores (0.51 and 0.802), indicating good drug-like properties. Ligand B is better here.

**DILI:** Ligand A (83.521) has a higher DILI risk than Ligand B (54.556). This favors Ligand B.

**BBB:** Both ligands have good BBB penetration (72.354 and 76.037), exceeding the >70% threshold for CNS targets. Ligand B is slightly better.

**Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and suggests poor permeability. However, the scale is not specified, so it's difficult to interpret.

**Aqueous Solubility:** Both ligands have negative solubility values, also unusual. Again, the scale is unspecified, making interpretation difficult.

**hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.052 and 0.187).

**Microsomal Clearance:** Ligand A (-25.89) has a more negative clearance, suggesting lower metabolic stability (better). Ligand B (18.04) has a positive value, indicating faster clearance. This favors Ligand A.

**In vitro Half-Life:** Ligand A (30.122) has a longer half-life than Ligand B (-20.927). This is a significant advantage for Ligand A.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.006 and 0.083).

**Binding Affinity:** Both ligands have similar and strong binding affinities (-8.9 and -8.2 kcal/mol). The difference of 0.7 kcal/mol is not substantial enough to be a deciding factor.

**Overall Assessment:**

Ligand B excels in key GPCR properties like logP, TPSA, and DILI. Ligand A has better metabolic stability (lower Cl_mic, longer t1/2). Considering the importance of CNS penetration (BBB is good for both) and the need for a balance between permeability and metabolic stability, Ligand A's superior metabolic profile and longer half-life, combined with acceptable TPSA and logP, outweigh the slightly higher DILI risk. The negative solubility and Caco-2 values are concerning for both, but the binding affinity is strong enough to warrant further investigation of Ligand A.

Output:
0
2025-04-17 03:13:04,388 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (349.431 Da) is slightly lower, which could be beneficial for permeability, but both are acceptable.

**TPSA:** Ligand A (86.88) is excellent for CNS penetration, well below the 90 A^2 threshold. Ligand B (55.84) is even better.

**logP:** Ligand A (1.545) is within the optimal range (1-3). Ligand B (3.314) is at the higher end, but still acceptable.

**H-Bond Donors/Acceptors:** Ligand A has 1 HBD and 5 HBA, which are reasonable. Ligand B has 0 HBD and 4 HBA, also reasonable.

**QED:** Both ligands have acceptable QED values (A: 0.72, B: 0.613), indicating good drug-like properties.

**DILI:** Ligand A (44.591) has a moderate DILI risk, but is still acceptable. Ligand B (21.908) has a significantly lower DILI risk, which is a major advantage.

**BBB:** Ligand A (60.644) is below the desirable threshold of 70% for CNS targets. Ligand B (75.339) is excellent, exceeding the 70% threshold. This is a critical difference given DRD2 is a CNS target.

**Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and suggests poor permeability. However, these values are on a strange scale and may not be directly comparable.

**Aqueous Solubility:** Both ligands have negative solubility values, indicating poor solubility. This is a concern for both.

**hERG Inhibition:** Ligand A (0.135) has a very low hERG risk, which is excellent. Ligand B (0.528) has a slightly higher, but still relatively low, hERG risk.

**Microsomal Clearance:** Ligand A (38.794) has a lower clearance, suggesting better metabolic stability. Ligand B (61.296) has a higher clearance.

**In vitro Half-Life:** Ligand A (-30.852) has a negative half-life, which is nonsensical. Ligand B (14.526) has a reasonable half-life.

**P-gp Efflux:** Ligand A (0.194) has low P-gp efflux, which is good for CNS exposure. Ligand B (0.298) also has low P-gp efflux.

**Binding Affinity:** Ligand A (-7.9 kcal/mol) has a significantly stronger binding affinity than Ligand B (-6.4 kcal/mol). This is a substantial advantage.

**Overall Assessment:**

While Ligand A has a better binding affinity and lower clearance, Ligand B is superior overall due to its significantly better BBB penetration (75.339% vs 60.644%), much lower DILI risk (21.908 vs 44.591), and a reasonable in vitro half-life. The difference in binding affinity, while significant, might be outweighed by the improved ADME properties, particularly the BBB penetration for a CNS target like DRD2. The nonsensical half-life for Ligand A is also a major red flag.

Output:
1
2025-04-17 03:13:04,388 - INFO - Reasoning:

Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (344.367 and 352.479 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (101.7) is slightly higher than Ligand B (99.33). Both are below the 140 A^2 threshold for oral absorption and reasonably close to the 90 A^2 target for CNS penetration, but Ligand B is preferable.

**3. logP:** Ligand A (3.789) is within the optimal range (1-3), but on the higher end. Ligand B (1.287) is also within the range, but closer to the lower limit. For a GPCR, a slightly higher logP can be beneficial for membrane permeability, giving a slight edge to Ligand A.

**4. H-Bond Donors:** Ligand A (2) is preferable to Ligand B (4) as fewer HBDs generally improve permeability.

**5. H-Bond Acceptors:** Ligand A (5) is preferable to Ligand B (3) as fewer HBAs generally improve permeability.

**6. QED:** Ligand A (0.585) has a better QED score than Ligand B (0.446), indicating a more drug-like profile.

**7. DILI:** Ligand B (18.108) has a significantly lower DILI risk than Ligand A (89.841), which is a major advantage.

**8. BBB:** Ligand B (74.37) has a much higher BBB penetration percentile than Ligand A (16.363). This is *critical* for a CNS target like DRD2.

**9. Caco-2 Permeability:** Ligand A (-5.058) shows poor Caco-2 permeability, while Ligand B (-4.921) is also poor, but slightly better.

**10. Aqueous Solubility:** Ligand A (-4.473) has slightly better aqueous solubility than Ligand B (-2.1).

**11. hERG Inhibition:** Both ligands show low hERG inhibition risk (0.317 and 0.406, respectively).

**12. Microsomal Clearance:** Ligand B (22.979) has lower microsomal clearance than Ligand A (34.131), suggesting better metabolic stability.

**13. In vitro Half-Life:** Ligand B (6.621) has a significantly longer in vitro half-life than Ligand A (-18.582), which is a major advantage.

**14. P-gp Efflux:** Ligand A (0.15) has lower P-gp efflux liability than Ligand B (0.019), which is beneficial for CNS exposure.

**15. Binding Affinity:** Ligand A (-9.3 kcal/mol) has a significantly stronger binding affinity than Ligand B (-7.4 kcal/mol). This is a substantial advantage, potentially outweighing some ADME drawbacks.

**Overall Assessment:**

While Ligand A has a superior binding affinity and slightly better logP, the significant advantages of Ligand B in terms of BBB penetration, DILI risk, metabolic stability (lower Cl_mic and longer t1/2), and P-gp efflux outweigh these benefits. The strong affinity of Ligand A is appealing, but its poor BBB penetration and high DILI risk make it a less viable candidate for a CNS-targeting drug. Ligand B, despite its weaker affinity, has a much more favorable ADME profile for CNS delivery and safety.

Output:
1
2025-04-17 03:13:04,388 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (356.46 and 358.43 Da) fall comfortably within the ideal 200-500 Da range.

**TPSA:** Ligand A (49.41) is significantly better than Ligand B (78.07). For CNS targets, TPSA should be <= 90, and A is much closer to the ideal <=60 range. B is pushing the upper limit and could face permeability issues.

**logP:** Ligand A (3.52) is optimal, while Ligand B (1.64) is a bit low. A logP between 1-3 is preferred, and B's value might hinder membrane permeation.

**H-Bond Donors/Acceptors:** Ligand A (1 HBD, 2 HBA) is favorable. Ligand B (0 HBD, 9 HBA) is acceptable, but the higher number of HBAs could slightly reduce permeability.

**QED:** Both ligands have similar QED values (0.74 and 0.66), indicating good drug-like properties.

**DILI:** Ligand A (24.78) has a much lower DILI risk than Ligand B (61.07). This is a significant advantage for A.

**BBB:** Ligand A (88.99) shows excellent BBB penetration, exceeding the desirable >70% threshold. Ligand B (72.78) is still reasonable but less favorable.

**Caco-2 Permeability:** Both have negative values, which is unusual. Assuming these are logP values, they are very poor.

**Aqueous Solubility:** Both have negative values, which is unusual.

**hERG:** Both ligands show low hERG inhibition risk (0.565 and 0.491).

**Microsomal Clearance:** Ligand B (70.19) has a significantly higher microsomal clearance than Ligand A (26.30), indicating faster metabolism and potentially lower *in vivo* exposure.

**In vitro Half-Life:** Ligand A (-13.81) has a longer half-life than Ligand B (-22.47), which is desirable.

**P-gp Efflux:** Ligand A (0.103) has a much lower P-gp efflux liability than Ligand B (0.298), meaning it's less likely to be pumped out of the brain, improving CNS exposure.

**Binding Affinity:** Ligand A (0.0) has a slightly better binding affinity than Ligand B (-8.5).

**Overall Assessment:**

Ligand A is clearly superior. It excels in critical areas for a CNS-targeting GPCR ligand: TPSA, BBB penetration, DILI risk, P-gp efflux, and metabolic stability (lower Cl_mic and longer t1/2). While Ligand B has acceptable properties, its higher TPSA, DILI risk, P-gp efflux, and clearance are significant drawbacks. The slightly better affinity of Ligand A further solidifies its advantage.

Output:
1
2025-04-17 03:13:04,388 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B based on the provided guidelines, prioritizing GPCR-specific properties (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (364.515 Da) is slightly better, being closer to the lower end which can aid permeability.

**TPSA:** Both ligands have TPSA values below the 90 A^2 threshold desirable for CNS targets. Ligand B (65.36 A^2) is slightly better than Ligand A (75.19 A^2).

**logP:** Both ligands have logP values within the optimal range (1-3). Ligand A (2.55) is slightly better than Ligand B (3.669), being closer to the center of the range.

**H-Bond Donors/Acceptors:** Both ligands have acceptable HBD (1) and HBA (5/4) counts.

**QED:** Ligand A (0.787) has a significantly better QED score than Ligand B (0.476), indicating a more drug-like profile.

**DILI:** Ligand B (34.82) has a much lower DILI risk than Ligand A (47.732), which is a significant advantage.

**BBB:** Ligand B (78.558) has a substantially higher BBB penetration percentile than Ligand A (61.807). This is a *critical* advantage for a CNS target like DRD2.

**Caco-2 Permeability:** Ligand A (-5.162) has a worse Caco-2 permeability than Ligand B (-4.707).

**Aqueous Solubility:** Both ligands have poor aqueous solubility (-2.675 and -3.944 respectively). This is a concern, but can potentially be addressed with formulation strategies.

**hERG Inhibition:** Ligand A (0.126) has a lower hERG inhibition liability than Ligand B (0.912), which is preferable.

**Microsomal Clearance:** Ligand B (76.958) has a higher microsomal clearance than Ligand A (50.078), suggesting faster metabolism and lower metabolic stability.

**In vitro Half-Life:** Ligand B (61.191) has a significantly longer in vitro half-life than Ligand A (-1.99). This is a significant advantage.

**P-gp Efflux:** Ligand A (0.283) has lower P-gp efflux liability than Ligand B (0.235), which is preferable for CNS penetration.

**Binding Affinity:** Ligand A (-7.2 kcal/mol) has a slightly better binding affinity than Ligand B (-6.3 kcal/mol). While the difference is less than the 1.5 kcal/mol threshold, it still contributes to its favorability.

**Overall Assessment:**

Despite Ligand A's slightly better affinity and lower P-gp efflux, Ligand B is the stronger candidate. The significantly higher BBB penetration (78.558 vs 61.807), lower DILI risk (34.82 vs 47.732), and longer half-life (61.191 vs -1.99) outweigh the minor advantages of Ligand A. The TPSA of Ligand B is also slightly better. While solubility is a concern for both, the other ADME properties of Ligand B make it more likely to achieve sufficient CNS exposure and a favorable safety profile.

Output:
1
2025-04-17 03:13:04,389 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (348.447 Da) is slightly lower, which could be advantageous for permeability. Ligand B (378.42 Da) is also good.

**TPSA:** Ligand A (96.25) is better than Ligand B (71.25) as it is closer to the ideal range for CNS targets (<=90).

**logP:** Both ligands have good logP values (A: 0.975, B: 1.3), falling within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A has 3 HBD and 5 HBA, while Ligand B has 1 HBD and 6 HBA. Both are acceptable, staying within the guidelines of <=5 HBD and <=10 HBA.

**QED:** Both ligands have good QED scores (A: 0.652, B: 0.808), indicating a drug-like profile. Ligand B is slightly better.

**DILI:** Both ligands have acceptable DILI risk (A: 29.624, B: 39.046), well below the 60 threshold.

**BBB:** This is a crucial parameter for a CNS target like DRD2. Ligand B (82.009) significantly outperforms Ligand A (55.099). A value >70 is desirable, but 82 is a strong result.

**Caco-2 Permeability:** Both have negative Caco-2 values (-4.957 and -4.799). This is unusual and suggests poor permeability. However, these values are on a log scale, and the absolute values are similar, so this isn't a major differentiator.

**Aqueous Solubility:** Both ligands have negative solubility values (-2.459 and -3.138), indicating poor solubility. This is a concern, but can be addressed through formulation.

**hERG Inhibition:** Both ligands show low hERG inhibition risk (A: 0.245, B: 0.217).

**Microsomal Clearance:** Ligand B (-5.029) has a *negative* microsomal clearance, which is highly unusual and suggests very high metabolic stability. Ligand A (36.038) has a moderate clearance.

**In vitro Half-Life:** Ligand B (-19.052) also has a negative half-life, which is impossible. This is a data error. Ligand A (10.263) is reasonable.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (A: 0.042, B: 0.105), which is good for CNS penetration.

**Binding Affinity:** Both ligands have excellent binding affinity (-8.2 kcal/mol and -8.0 kcal/mol). The difference is minimal (0.2 kcal/mol), and doesn't outweigh other factors.

**Overall Assessment:**

Ligand B is the stronger candidate. While both have good affinity, Ligand B has a significantly better BBB score (82 vs 55), and a much more favorable (though likely erroneous) metabolic stability profile. The TPSA is also better for Ligand B. The negative values for Caco-2 and solubility are concerning for both, but can potentially be addressed with formulation strategies. The negative half-life and clearance for Ligand B are data errors and should be investigated, but even without those, the BBB score is a significant advantage.

Output:
1
2025-04-17 03:13:04,389 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (352.381 Da) is slightly lower, which could be beneficial for permeability.

**TPSA:** Ligand A (53.35) is significantly better than Ligand B (83.98). For CNS targets, we want TPSA <= 90, and A is comfortably within that range, while B is approaching the upper limit.

**logP:** Both ligands have acceptable logP values (A: 3.781, B: 2.413), falling within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A (HBD=0, HBA=5) is better than Ligand B (HBD=2, HBA=5). Lower HBD is generally preferred for BBB penetration.

**QED:** Both ligands have good QED values (A: 0.536, B: 0.623), indicating drug-like properties.

**DILI:** Ligand A (64.599) has a higher DILI risk than Ligand B (47.693). This is a negative for A, but not a dealbreaker at this stage.

**BBB:** Ligand A (74.137) has a slightly better BBB percentile than Ligand B (67.701). Both are reasonably good, but A is closer to the desirable >70 threshold for CNS targets.

**Caco-2 Permeability:** Ligand A (-4.476) has a worse Caco-2 permeability than Ligand B (-5.349). Lower values indicate lower permeability.

**Aqueous Solubility:** Ligand A (-5.101) has worse aqueous solubility than Ligand B (-3.517).

**hERG Inhibition:** Ligand A (0.681) has a slightly higher hERG risk than Ligand B (0.248). Lower is better.

**Microsomal Clearance:** Ligand B (57.129) has a significantly lower microsomal clearance than Ligand A (104.472), indicating better metabolic stability.

**In vitro Half-Life:** Ligand B (-7.381) has a longer in vitro half-life than Ligand A (-14.877).

**P-gp Efflux:** Ligand A (0.568) has a lower P-gp efflux liability than Ligand B (0.163), which is favorable for CNS penetration.

**Binding Affinity:** Both ligands have excellent binding affinities (A: -7.9 kcal/mol, B: -7.7 kcal/mol). Ligand A is slightly better (-7.9 vs -7.7), but the difference is small.

**Overall Assessment:**

Considering the GPCR-specific priorities, Ligand A is the stronger candidate. Its superior TPSA, BBB, and P-gp efflux, combined with slightly better affinity, outweigh its slightly higher DILI risk, worse solubility, and clearance. The lower TPSA and P-gp efflux are particularly important for CNS penetration. While B has better metabolic stability and solubility, the CNS target profile of DRD2 makes A more promising.

Output:
0
2025-04-17 03:13:04,389 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 drug candidates, considering the provided guidelines and GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (394.421 Da) is slightly higher than Ligand B (350.547 Da), but both are acceptable.

**TPSA:** Ligand A (102.43) is higher than the preferred <90 for CNS targets, while Ligand B (49.41) is well within the range. This is a significant advantage for Ligand B.

**logP:** Ligand A (1.497) is within the optimal range (1-3). Ligand B (4.16) is slightly above, potentially raising concerns about solubility and off-target effects, but not drastically.

**H-Bond Donors/Acceptors:** Both ligands have acceptable HBD (1) and HBA (Ligand A: 7, Ligand B: 2) counts.

**QED:** Both ligands have reasonable QED scores (Ligand A: 0.777, Ligand B: 0.601), indicating good drug-like properties.

**DILI:** Ligand A (98.216) has a very high DILI risk, which is a major concern. Ligand B (20.551) has a low DILI risk, a significant advantage.

**BBB:** Both ligands have the same BBB penetration percentile (77.782), which is good for CNS targets (>70).

**Caco-2 Permeability:** Both ligands have similar, negative Caco-2 values (-4.714 and -4.711), which is unusual and suggests poor permeability. This is a drawback for both.

**Aqueous Solubility:** Both ligands have similar, negative solubility values (-3.522 and -3.787), indicating poor solubility. This is a drawback for both.

**hERG Inhibition:** Ligand A (0.234) has a lower hERG inhibition risk than Ligand B (0.808), which is preferable.

**Microsomal Clearance:** Ligand A (27.826) has lower microsomal clearance, suggesting better metabolic stability, than Ligand B (94.056).

**In vitro Half-Life:** Ligand A (41.493) has a longer half-life than Ligand B (15.054), which is desirable.

**P-gp Efflux:** Ligand A (0.302) has lower P-gp efflux, which is better for CNS exposure, than Ligand B (0.477).

**Binding Affinity:** Ligand B (-7.8 kcal/mol) has a significantly stronger binding affinity than Ligand A (-9.5 kcal/mol). This is a substantial advantage, potentially outweighing some of the ADME drawbacks.

**Overall Assessment:**

Ligand B has a much better safety profile (DILI) and significantly stronger binding affinity. While its logP is slightly higher and TPSA is lower than ideal, the affinity advantage is substantial. Ligand A's extremely high DILI risk is a major disqualifier. Both compounds have issues with solubility and Caco-2 permeability, but these can potentially be addressed through formulation or prodrug strategies. Given the GPCR-specific priorities, the strong binding affinity and lower DILI risk of Ligand B make it the more promising candidate.

Output:
1
2025-04-17 03:13:04,389 - INFO - Reasoning:

Let's analyze Ligand A and Ligand B based on the provided guidelines, prioritizing GPCR-specific properties (BBB, logP, Pgp, TPSA, and affinity).

**Ligand A:**

*   **MW:** 351.447 Da - Good. Within the ideal range.
*   **TPSA:** 92.45  - Acceptable, but pushing the limit for CNS targets.
*   **logP:** 1.475 - Good. Within the optimal range.
*   **HBD:** 3 - Good.
*   **HBA:** 4 - Good.
*   **QED:** 0.557 - Good. Above the threshold.
*   **DILI:** 47.421 - Good. Low risk.
*   **BBB:** 53.121 - Moderate. Below the desirable threshold of 70% for CNS targets.
*   **Caco-2:** -5.159 - Poor. Indicates poor intestinal absorption.
*   **Solubility:** -2.445 - Poor. Indicates low aqueous solubility.
*   **hERG:** 0.48 - Good. Low risk.
*   **Cl_mic:** 43.93 - Moderate. Not ideal, but not extremely high.
*   **t1/2:** -3.348 - Poor. Indicates a short half-life.
*   **Pgp:** 0.048 - Good. Low efflux liability.
*   **Affinity:** -7.4 kcal/mol - Excellent. Very strong binding.

**Ligand B:**

*   **MW:** 367.892 Da - Good. Within the ideal range.
*   **TPSA:** 29.54 - Excellent. Very favorable for CNS penetration.
*   **logP:** 4.905 - High. Borderline. Could lead to solubility issues and off-target effects.
*   **HBD:** 0 - Good.
*   **HBA:** 2 - Good.
*   **QED:** 0.641 - Good. Above the threshold.
*   **DILI:** 11.632 - Excellent. Very low risk.
*   **BBB:** 86.08 - Excellent. Highly desirable for a CNS target.
*   **Caco-2:** -4.243 - Poor. Indicates poor intestinal absorption.
*   **Solubility:** -5.641 - Poor. Indicates low aqueous solubility.
*   **hERG:** 0.874 - Good. Low risk.
*   **Cl_mic:** 114.961 - High. Indicates rapid metabolic clearance.
*   **t1/2:** -8.849 - Very Poor. Indicates a very short half-life.
*   **Pgp:** 0.496 - Good. Low efflux liability.
*   **Affinity:** -6.9 kcal/mol - Good. Strong binding, but not as strong as Ligand A.

**Comparison and Decision:**

Both ligands have issues with Caco-2 permeability and aqueous solubility, which would need to be addressed in further optimization. However, considering the GPCR-specific priorities for DRD2:

*   **BBB:** Ligand B is significantly better (86.08% vs. 53.121%). This is crucial for CNS penetration.
*   **TPSA:** Ligand B is much lower (29.54 vs. 92.45), further aiding CNS entry.
*   **Affinity:** Ligand A has a slightly better affinity (-7.4 vs -6.9 kcal/mol). While a 1.5 kcal/mol difference is significant, the superior BBB and TPSA of Ligand B are more critical for a CNS-targeting GPCR.
*   **Metabolic Stability:** Ligand A is better (lower Cl_mic and better t1/2), but the difference isn't overwhelming.
*   **LogP:** Ligand B's logP is higher, which is a concern, but not a deal-breaker if solubility can be improved.

Given the importance of CNS penetration for DRD2, and the significantly better BBB and TPSA values of Ligand B, I would choose **Ligand B** as the more promising starting point for drug development, despite its slightly lower affinity and higher logP. The affinity difference can potentially be addressed through further optimization, while improving BBB and TPSA is often more challenging.

Output:
1
2025-04-17 03:13:04,390 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (346.471 and 339.487 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (58.64) is better than Ligand B (62.73). Both are below the 90 A^2 threshold desirable for CNS targets, but A is closer to the optimal range.

**logP:** Ligand A (2.543) is within the optimal 1-3 range. Ligand B (4.073) is slightly higher, potentially leading to solubility issues or off-target interactions.

**H-Bond Donors/Acceptors:** Ligand A (HBD=1, HBA=3) and Ligand B (HBD=2, HBA=5) both meet the criteria of <=5 HBD and <=10 HBA.

**QED:** Both ligands have similar QED values (0.708 and 0.71), indicating good drug-likeness.

**DILI:** Ligand A (16.673) has a significantly lower DILI risk than Ligand B (19.542), indicating a safer profile. Both are below the 40 threshold.

**BBB:** Ligand B (83.986) has a better BBB penetration percentile than Ligand A (77.162), which is a critical factor for CNS targets like DRD2.

**Caco-2 Permeability:** Ligand A (-4.705) has better Caco-2 permeability than Ligand B (-5.08), suggesting better intestinal absorption.

**Aqueous Solubility:** Ligand A (-2.454) has better aqueous solubility than Ligand B (-3.543).

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.613 and 0.886).

**Microsomal Clearance:** Ligand B (50.047) has lower microsomal clearance than Ligand A (57.442), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand B (28.708) has a significantly longer in vitro half-life than Ligand A (-6.883), which is a major advantage.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.239 and 0.262).

**Binding Affinity:** Ligand B (-8.7 kcal/mol) has a slightly better binding affinity than Ligand A (-8.4 kcal/mol). While the difference is small, it's still a factor.

**Overall Assessment:**

Ligand B excels in BBB penetration and in vitro half-life, both crucial for CNS drug development. It also has slightly better binding affinity and metabolic stability. However, its logP is higher, and DILI risk is slightly elevated. Ligand A has better TPSA, solubility, and a lower DILI risk.

Considering the GPCR-specific priorities, the improved BBB penetration and half-life of Ligand B outweigh the slightly higher logP and DILI risk, especially given the small difference in binding affinity. The better ADME profile of B, particularly the longer half-life, is more valuable for a CNS target.

Output:
1
2025-04-17 03:13:04,390 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B based on the provided guidelines and GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (385.873) is slightly higher than Ligand B (347.35), but both are acceptable.

**TPSA:** Ligand A (81.62) is better than Ligand B (100.35). For CNS targets, we want TPSA <= 90, and A is closer to this threshold.

**logP:** Ligand A (2.577) is optimal (1-3), while Ligand B (0.558) is a bit low, potentially hindering permeation.

**H-Bond Donors/Acceptors:** Ligand A (0 HBD, 7 HBA) and Ligand B (2 HBD, 6 HBA) both fall within acceptable ranges (<=5 HBD, <=10 HBA).

**QED:** Both ligands have good QED scores (A: 0.535, B: 0.79), indicating drug-likeness.

**DILI:** Both ligands have relatively high DILI risk, but Ligand A (83.133) is higher than Ligand B (78.441), making B slightly preferable.

**BBB:** Ligand A (76.386) has a better BBB percentile than Ligand B (58.782). This is a crucial factor for CNS targets like DRD2.

**Caco-2 Permeability:** Ligand A (-4.616) is worse than Ligand B (-5.052), indicating lower intestinal absorption.

**Aqueous Solubility:** Ligand A (-3.395) is worse than Ligand B (-2.412), indicating lower solubility.

**hERG:** Both ligands have very low hERG inhibition risk (A: 0.288, B: 0.153).

**Microsomal Clearance:** Ligand A (57.17) has a better (lower) microsomal clearance than Ligand B (-15.317), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (1.713) has a shorter half-life than Ligand B (11.288).

**P-gp Efflux:** Ligand A (0.226) has lower P-gp efflux than Ligand B (0.003), which is favorable for CNS penetration.

**Binding Affinity:** Both ligands have excellent binding affinity (-7.7 and -7.8 kcal/mol), with Ligand B being slightly better. The affinity difference is minimal and likely less important than the ADME properties.

**Overall Assessment:**

Considering the GPCR-specific priorities, Ligand A is better overall. It has a more favorable TPSA, logP, and crucially, a significantly better BBB percentile and P-gp efflux. While Ligand B has slightly better solubility, Caco-2 permeability, and a marginally better affinity, the CNS penetration advantages of Ligand A outweigh these benefits for a DRD2 target. The metabolic stability (lower Cl_mic) of A is also a plus.

Output:
1
2025-04-17 03:13:04,390 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (367.43 and 348.49 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (89.04) is better than Ligand B (58.64). Both are below the 90 A^2 threshold for CNS targets, but Ligand B is significantly lower, which is favorable for brain penetration.

**logP:** Ligand B (2.798) is within the optimal 1-3 range. Ligand A (0.457) is quite low, potentially hindering membrane permeability and CNS penetration despite a good TPSA.

**H-Bond Donors/Acceptors:** Ligand A (0 HBD, 7 HBA) is slightly better than Ligand B (1 HBD, 3 HBA) in terms of balancing solubility and permeability.

**QED:** Both ligands have similar QED values (0.721 and 0.72), indicating good drug-likeness.

**DILI:** Ligand B (21.29) has a much lower DILI risk than Ligand A (65.57), a significant advantage.

**BBB:** Ligand B (77.47) is much better than Ligand A (64.68) in terms of predicted BBB penetration, exceeding the desirable >70% threshold. This is crucial for a CNS target like DRD2.

**Caco-2 Permeability:** Both have negative Caco-2 values (-4.394 and -4.741). This is unusual and suggests potential issues with intestinal absorption. However, these values are on a scale where negative values are possible and don't necessarily disqualify a compound.

**Aqueous Solubility:** Both have negative solubility values (-2.171 and -2.704). Similar to Caco-2, this is not necessarily disqualifying, but indicates potential formulation challenges.

**hERG Inhibition:** Ligand A (0.065) has a slightly lower hERG risk than Ligand B (0.233), which is preferable.

**Microsomal Clearance:** Ligand B (44.50) has a higher microsomal clearance than Ligand A (38.37), indicating faster metabolism and potentially lower exposure.

**In vitro Half-Life:** Ligand A (-25.01) has a significantly longer in vitro half-life than Ligand B (-13.24), which is a positive attribute.

**P-gp Efflux:** Ligand A (0.055) has lower P-gp efflux liability than Ligand B (0.123), which is favorable for CNS exposure.

**Binding Affinity:** Ligand B (-8.4 kcal/mol) has a stronger binding affinity than Ligand A (-7.6 kcal/mol). The 0.8 kcal/mol difference is substantial and can outweigh some of the ADME drawbacks of Ligand B.

**Overall Assessment:**

Ligand B is the more promising candidate. While Ligand A has better hERG and P-gp efflux profiles, Ligand B excels in the most critical areas for a CNS GPCR target: BBB penetration, DILI risk, and, most importantly, binding affinity. The stronger affinity of Ligand B (-8.4 vs -7.6 kcal/mol) is a significant advantage. The slightly higher logP of Ligand B is also more favorable for CNS penetration. The lower half-life and higher clearance of Ligand B are concerns, but these can potentially be addressed through structural modifications.



Output:
1
2025-04-17 03:13:04,390 - INFO - Batch 10 complete. Total preferences: 160
2025-04-17 03:13:04,390 - INFO - Processing batch 11/512...
2025-04-17 03:13:47,885 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (359.5 & 353.4 Da) fall comfortably within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (70.15) is higher than the preferred <90 for CNS targets, while Ligand B (56.59) is well within the range. This favors Ligand B.

**3. logP:** Both ligands have good logP values (2.48 & 1.65), falling within the optimal 1-3 range. Ligand B is slightly lower, which *could* indicate slightly better solubility, but isn't a major concern for either.

**4. H-Bond Donors:** Ligand A has 2 HBD, which is acceptable. Ligand B has 0, which is also acceptable.

**5. H-Bond Acceptors:** Ligand A has 6 HBA, acceptable. Ligand B has 5, also acceptable.

**6. QED:** Ligand A (0.855) has a significantly higher QED score than Ligand B (0.6), indicating a more drug-like profile overall.

**7. DILI:** Ligand A (54.75) has a higher DILI risk than Ligand B (11.632). This is a significant advantage for Ligand B.

**8. BBB:** Ligand B (97.25) has a *much* higher BBB penetration percentile than Ligand A (68.44). This is a critical advantage for a CNS target like DRD2.

**9. Caco-2:** Ligand A (-5.135) and Ligand B (-4.43) both have negative Caco-2 values, which is unusual and suggests poor permeability. However, the scale is not specified, so it's hard to interpret.

**10. Solubility:** Ligand A (-3.422) and Ligand B (-1.257) both have negative solubility values, which is also unusual. Again, the scale is not specified, making interpretation difficult.

**11. hERG:** Both ligands have low hERG risk (0.8 & 0.698), which is good.

**12. Cl_mic:** Ligand A (48.05) and Ligand B (53.44) have similar microsomal clearance values, suggesting comparable metabolic stability.

**13. t1/2:** Ligand A (32.24) has a longer in vitro half-life than Ligand B (22.75), which is a slight advantage.

**14. Pgp:** Ligand A (0.177) has slightly higher P-gp efflux liability than Ligand B (0.185), but the difference is minimal.

**15. Binding Affinity:** Ligand B (-6.2 kcal/mol) has a substantially stronger binding affinity than Ligand A (0.0 kcal/mol). This is a *major* advantage, potentially outweighing some of the ADME concerns.

**Overall Assessment:**

While Ligand A has a better QED and slightly longer half-life, Ligand B is significantly better in several key areas for a CNS-targeting GPCR ligand: much higher BBB penetration, lower DILI risk, and *significantly* stronger binding affinity. The TPSA is also more favorable for Ligand B. The unusual negative values for Caco-2 and solubility are concerning for both, but the affinity difference is so large that it likely outweighs these concerns.

Output:
1
2025-04-17 03:13:47,886 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (344.455 and 363.845 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (53.01) is significantly better than Ligand B (69.72). For CNS targets, we want TPSA <= 90, both are within this range, but A is much closer to the optimal value.

**logP:** Both ligands have acceptable logP values (1.576 and 2.138, respectively), falling within the 1-3 range.

**H-Bond Donors/Acceptors:** Both have 1 HBD, which is good. Ligand A has 4 HBA, and Ligand B has 3. Both are within the acceptable limit of <=10.

**QED:** Both ligands have high QED scores (0.901 and 0.894), indicating good drug-like properties.

**DILI:** Ligand A (5.855) has a lower DILI risk than Ligand B (42.458), which is preferable.

**BBB:** Both ligands have excellent BBB penetration (81.272 and 82.513), exceeding the desirable >70 threshold for CNS targets.

**Caco-2 Permeability:** Both have negative Caco-2 values (-4.554 and -4.786). This is unusual and suggests poor permeability. However, these values are on a scale where negative values are possible, and it's difficult to interpret without knowing the scale's specifics.

**Aqueous Solubility:** Both have negative solubility values (-1.568 and -3.814), indicating poor aqueous solubility. This is a concern for bioavailability.

**hERG Inhibition:** Both ligands show low hERG inhibition liability (0.766 and 0.345), which is good.

**Microsomal Clearance:** Ligand A (43.473) has a moderate clearance, while Ligand B (-17.94) has a *negative* clearance, which is not physically possible and likely an artifact of the prediction method. This is a major red flag for Ligand B.

**In vitro Half-Life:** Ligand A (13.275 hours) has a reasonable half-life, while Ligand B (19.761 hours) has a longer half-life.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.338 and 0.111), which is favorable for CNS penetration.

**Binding Affinity:** Ligand B (-8.1 kcal/mol) has a significantly stronger binding affinity than Ligand A (-9.0 kcal/mol). This is a substantial advantage.

**Overall Assessment:**

Ligand B has a significantly better binding affinity, which is a crucial factor for GPCRs. However, the negative microsomal clearance is a critical flaw. It suggests a problem with the prediction or a fundamentally unstable molecule. Ligand A, while having a slightly weaker affinity, has a more reasonable (though still not ideal) clearance, better DILI score, and a more plausible profile overall. Given the importance of metabolic stability for *in vivo* efficacy, Ligand A is the more viable candidate.

Output:
0
2025-04-17 03:13:47,886 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (352.385 and 347.415 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (83.98) is excellent, well below the 90 A^2 threshold for CNS targets. Ligand B (91.76) is slightly higher but still acceptable.

**logP:** Ligand A (2.362) is optimal (1-3). Ligand B (0.508) is a bit low, potentially hindering membrane permeability.

**H-Bond Donors:** Both ligands have 2 HBD, which is within the acceptable limit of <=5.

**H-Bond Acceptors:** Ligand A has 4 HBA, and Ligand B has 5 HBA, both within the acceptable limit of <=10.

**QED:** Both ligands have good QED scores (0.852 and 0.782), indicating good drug-like properties.

**DILI:** Ligand A (43.777) has a slightly higher DILI risk than Ligand B (29.43), but both are below the concerning threshold of 60.

**BBB:** Ligand A (87.437) has a significantly better BBB penetration percentile than Ligand B (66.266). This is a critical factor for a CNS target like DRD2.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.82 and -4.681), which is unusual and suggests poor permeability. However, these values are on a log scale and can be misleading; we must consider other factors.

**Aqueous Solubility:** Both ligands have negative solubility values (-3.197 and -1.688), indicating poor aqueous solubility.

**hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.089 and 0.145).

**Microsomal Clearance:** Ligand A (24.379) has a higher microsomal clearance than Ligand B (-8.946), suggesting lower metabolic stability.

**In vitro Half-Life:** Ligand B (7.28) has a significantly longer in vitro half-life than Ligand A (-0.988).

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.013 and 0.044).

**Binding Affinity:** Ligand A (-8.2 kcal/mol) has a slightly better binding affinity than Ligand B (-7.6 kcal/mol). While both are good, the 0.6 kcal/mol difference is noteworthy.

**Conclusion:**

Considering the GPCR-specific priorities, Ligand A is the more promising candidate. Its superior BBB penetration (87.437 vs 66.266) is a significant advantage for a CNS target. While Ligand B has a better half-life and lower clearance, the difference in binding affinity (0.6 kcal/mol) and the crucial BBB property favor Ligand A. The slightly higher DILI risk for Ligand A is less concerning than the poor BBB penetration of Ligand B. Both ligands have solubility and permeability issues, but these can be addressed through formulation strategies.



Output:
1
2025-04-17 03:13:47,886 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (373.475 and 354.47 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (103.86) is slightly above the preferred <90 for CNS targets, but still reasonable. Ligand B (81.51) is well within the desirable range. This favors Ligand B.

**logP:** Ligand A (-0.747) is a bit low, potentially hindering permeability. Ligand B (2.33) is within the optimal 1-3 range. This strongly favors Ligand B.

**H-Bond Donors/Acceptors:** Ligand A (HBD=1, HBA=5) and Ligand B (HBD=3, HBA=6) both have acceptable numbers of H-bond donors and acceptors.

**QED:** Both ligands have similar and good QED values (0.683 and 0.697).

**DILI:** Both ligands have low DILI risk (35.401 and 37.456 percentiles), indicating a low potential for liver injury.

**BBB:** Ligand A (59.364%) is below the desirable >70% for CNS targets, while Ligand B (65.025%) is closer, but still not optimal. Both would benefit from improvement here.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.238 and -4.918), which is unusual and suggests poor permeability. This is a significant concern for both.

**Aqueous Solubility:** Both ligands have negative solubility values (-1.801 and -3.156), indicating poor aqueous solubility. This is also a concern for both.

**hERG Inhibition:** Ligand A (0.067) has a very low hERG risk, which is excellent. Ligand B (0.826) has a slightly higher, but still relatively low, hERG risk. This favors Ligand A.

**Microsomal Clearance:** Ligand A (-13.077) has a negative clearance, which is not physically realistic and suggests a potential data error or unusual metabolic stability. Ligand B (24.725) has a moderate clearance.

**In vitro Half-Life:** Ligand B (34.516 hours) has a much longer half-life than Ligand A (11.036 hours). This is a significant advantage for Ligand B.

**P-gp Efflux:** Ligand A (0.028) has very low P-gp efflux liability, which is excellent for CNS penetration. Ligand B (0.266) has a slightly higher, but still reasonable, P-gp efflux. This favors Ligand A.

**Binding Affinity:** Ligand B (-8.0 kcal/mol) has a stronger binding affinity than Ligand A (-7.4 kcal/mol). This is a significant advantage for Ligand B, potentially outweighing some of its ADME drawbacks.

**Overall Assessment:**

Ligand B has a better logP, a longer half-life, and a stronger binding affinity. While its BBB penetration isn't ideal, it's better than Ligand A's. Ligand A has better hERG and P-gp profiles, but its low logP and shorter half-life are significant drawbacks. The negative Caco-2 and solubility values are concerning for both, but the stronger binding affinity of Ligand B makes it more likely to be a viable starting point for optimization, even with those issues. The negative clearance for Ligand A is also a red flag.

Output:
1
2025-04-17 03:13:47,886 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (369.408 and 360.523 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (38.33) is significantly better than Ligand B (49.41). For CNS targets, we want TPSA <= 90, and ideally lower. Ligand A is much closer to the ideal range.

**3. logP:** Both ligands have good logP values (4.122 and 3.732), falling within the optimal 1-3 range.

**4. H-Bond Donors:** Both have 1 HBD, which is acceptable.

**5. H-Bond Acceptors:** Both have 3 HBA, which is acceptable.

**6. QED:** Ligand A (0.861) has a substantially better QED score than Ligand B (0.621), indicating a more drug-like profile.

**7. DILI:** Ligand A (57.348) has a higher DILI risk than Ligand B (36.06). This is a negative for Ligand A, but not a dealbreaker at this stage.

**8. BBB:** Ligand A (86.817) has a significantly better BBB penetration percentile than Ligand B (66.111). This is *critical* for a CNS target like DRD2.

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.804 and -4.917). This is unusual and suggests poor permeability, but the scale isn't clearly defined. We'll consider this a neutral point for now.

**10. Aqueous Solubility:** Both ligands have negative solubility values (-4.564 and -4.256). Similar to Caco-2, this is concerning but the scale is unclear.

**11. hERG Inhibition:** Both ligands have low hERG inhibition risk (0.76 and 0.653).

**12. Microsomal Clearance:** Ligand A (74.067) has higher microsomal clearance than Ligand B (54.16), indicating lower metabolic stability. This is a negative for Ligand A.

**13. In vitro Half-Life:** Ligand B (5.537) has a longer in vitro half-life than Ligand A (19.278). This is a positive for Ligand B.

**14. P-gp Efflux:** Ligand A (0.664) has lower P-gp efflux than Ligand B (0.278), which is favorable for CNS penetration.

**15. Binding Affinity:** Ligand A (-9.7 kcal/mol) has a significantly stronger binding affinity than Ligand B (-8.6 kcal/mol). This is a major advantage for Ligand A, potentially outweighing some of its ADME drawbacks.

**Overall Assessment:**

Ligand A excels in the most critical areas for a CNS-targeting GPCR ligand: BBB penetration and binding affinity. While it has some ADME liabilities (higher DILI, higher Cl_mic, shorter half-life), the strong affinity and good BBB penetration are significant advantages. Ligand B has better DILI and half-life, but falls short on BBB and affinity. Given the importance of CNS penetration and potency for DRD2, Ligand A is the more promising candidate.

Output:
1
2025-04-17 03:13:47,887 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (411.34 Da) is slightly higher than Ligand B (351.491 Da), but both are acceptable.

**2. TPSA:** Ligand A (67.43) is better than Ligand B (101.29). For CNS targets, TPSA should be <= 90. Ligand A is within this range, while Ligand B exceeds it, potentially hindering BBB penetration.

**3. logP:** Ligand A (3.801) is optimal, while Ligand B (1.868) is a bit low. A logP between 1-3 is preferred, and while 1.868 isn't terrible, it might lead to permeability issues.

**4. H-Bond Donors:** Both have 2 or 3 HBD, which is acceptable (<=5).

**5. H-Bond Acceptors:** Both have 3 HBA, which is acceptable (<=10).

**6. QED:** Both ligands have good QED scores (0.53 and 0.622, respectively), indicating good drug-like properties.

**7. DILI:** Ligand A (33.424) has a slightly higher DILI risk than Ligand B (26.095), but both are below the 40 threshold, indicating low risk.

**8. BBB:** This is crucial for a CNS target. Ligand A (77.239) has a significantly better BBB percentile than Ligand B (65.723). A value >70 is desirable, and Ligand A is closer to that target.

**9. Caco-2:** Ligand A (-4.765) and Ligand B (-5.241) both have negative values, which is unusual and suggests poor permeability. However, the scale is not specified, so it's hard to interpret.

**10. Solubility:** Ligand A (-4.704) and Ligand B (-3.552) both have negative values, suggesting low solubility.

**11. hERG:** Ligand A (0.745) has a lower hERG risk than Ligand B (0.138), which is preferable.

**12. Cl_mic:** Ligand A (76.043) has a higher microsomal clearance than Ligand B (58.284), indicating faster metabolism and potentially lower *in vivo* exposure.

**13. t1/2:** Ligand B (-17.542) has a negative half-life, which is impossible. This is a significant red flag and suggests a data error or a very rapidly metabolized compound. Ligand A (33.132) has a reasonable half-life.

**14. Pgp:** Ligand A (0.377) has lower P-gp efflux liability than Ligand B (0.06), which is favorable for CNS penetration.

**15. Binding Affinity:** Ligand B (-8.1 kcal/mol) has a slightly better binding affinity than Ligand A (-7.9 kcal/mol). However, the difference is small (0.2 kcal/mol) and may not be enough to overcome the other significant differences.

**Overall Assessment:**

Ligand A is the more promising candidate. While its binding affinity is slightly lower, it excels in crucial ADME properties for a CNS-targeting GPCR: better TPSA, significantly better BBB penetration, lower Pgp efflux, and a reasonable half-life. Ligand B has a concerning negative in vitro half-life, which is a major drawback. The slightly better affinity of Ligand B is unlikely to compensate for this and its poorer BBB penetration.

Output:
1
2025-04-17 03:13:47,887 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (396.219 Da) is slightly higher than Ligand B (355.341 Da), but both are acceptable.

**TPSA:** Ligand A (54.88) is excellent for CNS penetration, well below the 90 A^2 threshold. Ligand B (87.74) is higher, but still potentially acceptable, though less ideal.

**logP:** Ligand A (4.937) is slightly high, potentially leading to solubility issues or off-target interactions. Ligand B (0.061) is very low, which could hinder membrane permeability and CNS penetration.

**H-Bond Donors/Acceptors:** Ligand A (HBD=1, HBA=3) and Ligand B (HBD=2, HBA=4) both have reasonable numbers of H-bond donors and acceptors, falling within the guidelines.

**QED:** Both ligands have good QED scores (Ligand A: 0.523, Ligand B: 0.724), indicating drug-like properties.

**DILI:** Ligand A has a very high DILI risk (99.147), which is a major concern. Ligand B has a much lower DILI risk (46.452), making it significantly safer in this regard.

**BBB:** Ligand A has a good BBB penetration score (73.168), which is desirable for a CNS target. Ligand B's BBB score (63.358) is lower, but not terrible.

**Caco-2 Permeability:** Both ligands have negative Caco-2 permeability values (-4.836 and -4.922), which is unusual and suggests poor intestinal absorption. This is likely a data artifact or indicates a problem with the model's prediction.

**Aqueous Solubility:** Both ligands have very poor aqueous solubility (-5.713 and -2.643). This is a significant drawback, especially given Ligand A's already high logP.

**hERG Inhibition:** Ligand A (0.739) has a slightly higher hERG risk than Ligand B (0.202), but both are relatively low.

**Microsomal Clearance:** Ligand A (81.086) has moderate clearance, while Ligand B has very low (and negative) clearance (-7.354), suggesting high metabolic stability.

**In vitro Half-Life:** Ligand A (124.989 hours) has a good in vitro half-life. Ligand B has a very short half-life (-35.316 hours), which is a major disadvantage.

**P-gp Efflux:** Ligand A (0.555) has moderate P-gp efflux, while Ligand B (0.01) has very low P-gp efflux, which is favorable for CNS penetration.

**Binding Affinity:** Both ligands have excellent binding affinities (Ligand A: -9.2 kcal/mol, Ligand B: -8.6 kcal/mol). Ligand A is slightly more potent.

**Overall Assessment:**

Ligand A has a superior binding affinity and acceptable BBB penetration, but its extremely high DILI risk and poor solubility are major red flags. Its high logP also raises concerns. Ligand B has a lower binding affinity, but significantly better safety profile (lower DILI), better metabolic stability (lower Cl_mic), and lower P-gp efflux. While its BBB penetration is lower and solubility is also poor, these issues might be more readily addressed through structural modifications than mitigating a high DILI risk.

Considering the GPCR-specific priorities, and the severity of the DILI risk for Ligand A, Ligand B is the more promising candidate despite its slightly lower affinity. The affinity difference (0.6 kcal/mol) is not large enough to outweigh the significant safety and metabolic advantages of Ligand B.

Output:
1
2025-04-17 03:13:47,887 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (349.5 and 350.4 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (52.65) is excellent, well below the 90 A^2 threshold for CNS targets. Ligand B (118.01) is higher, but still potentially acceptable, though less ideal.

**logP:** Ligand A (2.547) is optimal (1-3). Ligand B (-0.39) is below 1, which could hinder permeation.

**H-Bond Donors/Acceptors:** Ligand A (HBD=1, HBA=3) is favorable. Ligand B (HBD=3, HBA=6) is also acceptable, but slightly higher counts might affect permeability.

**QED:** Ligand A (0.802) is excellent, indicating high drug-likeness. Ligand B (0.414) is below the 0.5 threshold, suggesting a less favorable drug-like profile.

**DILI:** Ligand A (10.5) has a very low DILI risk. Ligand B (43.35) is moderate, but still within an acceptable range.

**BBB:** Ligand A (70.92) is good, exceeding the 70% threshold for CNS targets. Ligand B (45.52) is significantly lower and a concern for CNS penetration.

**Caco-2 Permeability:** Ligand A (-4.816) is poor, indicating low intestinal absorption. Ligand B (-5.663) is also poor.

**Aqueous Solubility:** Both ligands have very poor aqueous solubility (-1.646 and -1.548). This is a significant drawback for both.

**hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.356 and 0.033).

**Microsomal Clearance:** Ligand A (19.14) is moderate. Ligand B (23.58) is also moderate.

**In vitro Half-Life:** Ligand A (0.087) is very short. Ligand B (17.0) is much better.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.082 and 0.018).

**Binding Affinity:** Ligand B (-8.1 kcal/mol) has a slightly better binding affinity than Ligand A (-7.7 kcal/mol). However, the difference is not huge.

**Overall Assessment:**

Ligand A excels in TPSA, QED, DILI, and BBB, crucial for CNS GPCR targets. However, its poor Caco-2 permeability and very short half-life are major drawbacks.

Ligand B has a better binding affinity and half-life, but suffers from a lower BBB score, lower QED, and a less optimal logP.

Given the emphasis on BBB penetration for a CNS target like DRD2, and the overall better drug-like properties (QED, DILI), Ligand A is the more promising candidate, despite its permeability and half-life issues. These ADME properties could potentially be improved through structural modifications. The affinity difference isn't large enough to overcome Ligand A's advantages in key CNS-relevant properties.

Output:
0
2025-04-17 03:13:47,887 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (359.861 and 354.292 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (61.36) is significantly better than Ligand B (99.94). For CNS targets, we want TPSA <= 90, and A is comfortably within that, while B is above.

**logP:** Both ligands have good logP values (3.608 and 2.306), falling within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A (HBD=1, HBA=4) is preferable to Ligand B (HBD=2, HBA=5) as lower numbers generally improve permeability. Both are within acceptable limits.

**QED:** Both ligands have reasonable QED scores (0.85 and 0.749), indicating good drug-likeness.

**DILI:** Ligand A (62.699) has a much lower DILI risk than Ligand B (85.498). This is a significant advantage.

**BBB:** Ligand A (93.098) has excellent BBB penetration, exceeding the desirable >70% threshold. Ligand B (74.486) is still reasonable, but not as good.

**Caco-2 Permeability:** Ligand A (-4.805) and Ligand B (-5.137) both have negative values, which is unusual. Lower values indicate lower permeability. However, the difference isn't huge.

**Aqueous Solubility:** Ligand A (-4.994) and Ligand B (-3.401) both have negative values, indicating poor solubility. B is slightly better.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.616 and 0.302).

**Microsomal Clearance:** Ligand A (65.377) has higher microsomal clearance than Ligand B (39.655), suggesting lower metabolic stability. This favors Ligand B.

**In vitro Half-Life:** Ligand B (-4.596) has a negative half-life, which is impossible. This is a major red flag. Ligand A (24.43) is reasonable.

**P-gp Efflux:** Ligand A (0.225) has lower P-gp efflux than Ligand B (0.044), which is beneficial for CNS exposure.

**Binding Affinity:** Ligand B (-9.7 kcal/mol) has a significantly stronger binding affinity than Ligand A (-8.1 kcal/mol). This is a substantial advantage, potentially outweighing some ADME drawbacks.

**Overall Assessment:**

While Ligand B has a superior binding affinity, its problematic in vitro half-life (negative value) is a critical flaw. The negative value suggests an error in the data or a highly unstable compound. Ligand A, despite slightly weaker binding, has a much better overall profile with excellent BBB penetration, lower DILI risk, reasonable metabolic stability, and a plausible half-life. The TPSA is also significantly better for CNS penetration. Considering the GPCR-specific priorities, Ligand A is the more viable candidate.

Output:
1
2025-04-17 03:13:47,888 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (340.43 and 363.85 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (67.35) is significantly better than Ligand B (82.53). For CNS targets, we want TPSA <= 90, and Ligand A is comfortably within this range, while Ligand B is approaching the upper limit.

**3. logP:** Both ligands have good logP values (2.667 and 1.334), falling within the optimal 1-3 range. Ligand A is slightly higher, which could be beneficial for membrane permeability.

**4. H-Bond Donors:** Ligand A (1) is preferable to Ligand B (2). Lower HBD generally improves permeability.

**5. H-Bond Acceptors:** Both ligands have the same number of HBA (4), which is acceptable (<=10).

**6. QED:** Ligand A (0.878) has a higher QED score than Ligand B (0.773), indicating a more drug-like profile.

**7. DILI:** Both ligands have low DILI risk (39.67 and 38.50), which is good.

**8. BBB:** This is a critical parameter for CNS targets. Ligand A has a significantly higher BBB penetration percentile (83.83) than Ligand B (24.74). This is a major advantage for Ligand A.

**9. Caco-2 Permeability:** Ligand A (-4.213) and Ligand B (-4.69) both have negative values, which is unusual and suggests poor permeability. However, the scale isn't specified, so it's difficult to interpret.

**10. Aqueous Solubility:** Both ligands have very poor aqueous solubility (-2.891 and -2.629). This is a concern for both, but could potentially be addressed through formulation.

**11. hERG Inhibition:** Both ligands have low hERG inhibition risk (0.306 and 0.188), which is good.

**12. Microsomal Clearance:** Ligand B (-6.337) has a *negative* microsomal clearance, which is not physically possible. This is likely an error in the data and raises a significant red flag. Ligand A (73.579) has a reasonable clearance.

**13. In vitro Half-Life:** Ligand A (-20.249) has a negative half-life, which is impossible. Ligand B (-1.44) is also negative. This is another data quality issue.

**14. P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.026 and 0.033), which is favorable for CNS penetration.

**15. Binding Affinity:** Ligand B (-7.8 kcal/mol) has a slightly better binding affinity than Ligand A (-8.1 kcal/mol). However, the difference is small, and other factors are more important.

**Overall Assessment:**

Despite the slightly better affinity of Ligand B, the negative values for microsomal clearance and half-life are major concerns, suggesting a data error or a fundamentally unstable molecule. Ligand A, while having slightly lower affinity, has a much better BBB score, a more reasonable TPSA, and a higher QED. The negative half-life for Ligand A is also concerning, but less so than the negative clearance for Ligand B. Given the importance of BBB penetration for a CNS target like DRD2, and the questionable data for Ligand B, Ligand A is the more promising candidate.

Output:
1
2025-04-17 03:13:47,888 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B based on the provided guidelines, prioritizing GPCR-specific properties (BBB, logP, Pgp, TPSA, and affinity) for DRD2.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (355.435 Da) is slightly lower, which could be beneficial for permeability. Ligand B (377.467 Da) is also good.

**TPSA:** Ligand A (92.99) is excellent for CNS penetration, being well below 90. Ligand B (136.28) is above the ideal 90, but still potentially acceptable.

**logP:** Ligand A (1.306) is within the optimal range (1-3). Ligand B (-2.706) is significantly lower, which is a concern for membrane permeability and CNS penetration.

**H-Bond Donors/Acceptors:** Ligand A (0 HBD, 5 HBA) is favorable. Ligand B (3 HBD, 6 HBA) is also acceptable, though slightly higher.

**QED:** Both ligands have acceptable QED values (A: 0.507, B: 0.461), indicating reasonable drug-likeness.

**DILI:** Ligand A (15.665) has a much lower DILI risk than Ligand B (30.903), which is a significant advantage.

**BBB:** This is crucial for a CNS target. Ligand A (77.433) has a good BBB percentile. Ligand B (12.175) is very poor, indicating limited brain penetration.

**Caco-2 Permeability:** Ligand A (-4.396) is poor, while Ligand B (-5.856) is even worse. This suggests both compounds may have limited intestinal absorption.

**Aqueous Solubility:** Both have negative values, indicating very poor solubility. Ligand A (-0.888) is slightly better than Ligand B (-0.537).

**hERG Inhibition:** Both ligands show very low hERG inhibition risk (A: 0.084, B: 0.056).

**Microsomal Clearance:** Ligand A (35.41) has a moderate clearance, while Ligand B (-23.035) has a negative value, which is unusual and likely represents a very low clearance.

**In vitro Half-Life:** Ligand A (-13.95) has a negative half-life, which is also unusual and likely represents a very long half-life. Ligand B (-7.902) also has a negative half-life, suggesting a long half-life.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (A: 0.02, B: 0.001), which is favorable.

**Binding Affinity:** Ligand A (-7.5 kcal/mol) has a slightly better binding affinity than Ligand B (-7.3 kcal/mol), though the difference is small.

**Overall Assessment:**

Considering the GPCR-specific priorities, Ligand A is significantly more promising. Its superior BBB penetration, lower DILI risk, and acceptable logP outweigh its slightly poorer Caco-2 permeability. While both have solubility issues, the difference is minor. The unusual negative values for half-life and clearance require further investigation, but are less critical than the BBB and DILI profiles. Ligand B's extremely poor BBB penetration is a major drawback for a CNS target like DRD2.



Output:
0
2025-04-17 03:13:47,888 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (335.382 and 346.471 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (54.02) is excellent, well below the 90 A^2 threshold for CNS targets. Ligand B (58.64) is still acceptable but less optimal.

**logP:** Ligand A (3.795) is at the higher end of the optimal range (1-3), while Ligand B (1.958) is at the lower end. While both are within range, higher logP can sometimes be tolerated for CNS drugs to aid in BBB penetration.

**H-Bond Donors/Acceptors:** Ligand A has 2 HBD and 3 HBA, both within acceptable limits. Ligand B has 1 HBD and 3 HBA, also good.

**QED:** Both ligands have good QED scores (0.713 and 0.795, respectively), indicating drug-like properties.

**DILI:** Ligand A has a DILI risk of 66.964, which is moderately high. Ligand B has a significantly lower DILI risk (14.889), which is a major advantage.

**BBB:** Ligand A has a BBB percentile of 76.541, which is good for a CNS target. Ligand B has a lower BBB percentile (53.625), which is less desirable.

**Caco-2 Permeability:** Both have negative Caco-2 values (-4.816 and -4.602), which is unusual and suggests poor permeability. This is a significant concern for both.

**Aqueous Solubility:** Both have negative solubility values (-4.188 and -2.549), also unusual and concerning. Poor solubility can hinder bioavailability.

**hERG Inhibition:** Ligand A (0.718) has a slightly higher hERG risk than Ligand B (0.151). Lower is better here.

**Microsomal Clearance:** Ligand A has a higher microsomal clearance (20.929) than Ligand B (6.039), indicating faster metabolism and potentially lower exposure.

**In vitro Half-Life:** Ligand A has a half-life of 32.793 hours, which is good. Ligand B has a much shorter half-life (9.262 hours).

**P-gp Efflux:** Ligand A has a Pgp efflux liability of 0.23, which is relatively low. Ligand B has a very low Pgp efflux liability (0.049), which is a significant advantage for CNS penetration.

**Binding Affinity:** Ligand B (-7.9 kcal/mol) has a significantly stronger binding affinity than Ligand A (-9.9 kcal/mol). This is a substantial difference and a major factor.

**Overall Assessment:**

Ligand B is the stronger candidate despite some concerns. The significantly better binding affinity (-7.9 vs -9.9 kcal/mol) is a major advantage, and the lower DILI risk is also crucial. While both have poor Caco-2 and solubility values, the superior affinity of Ligand B could potentially overcome these issues with appropriate formulation strategies. Ligand B also has a lower Pgp efflux, which is beneficial for CNS targets. Although Ligand A has a better BBB score and half-life, the combination of higher DILI risk, weaker affinity, and higher clearance makes Ligand B the more promising candidate.

Output:
1
2025-04-17 03:13:47,888 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight (MW):** Both ligands are within the ideal range (200-500 Da). Ligand A (376.762 Da) and Ligand B (346.471 Da) are both acceptable.

**2. TPSA:** For CNS targets, we want TPSA <= 90. Ligand A (64.21) is excellent, well below the threshold. Ligand B (58.64) is also very good.

**3. logP:** Optimal range is 1-3. Ligand A (4.157) is slightly high, potentially leading to solubility issues or off-target interactions. Ligand B (2.577) is within the optimal range.

**4. H-Bond Donors (HBD):** Both ligands have 1 HBD, which is good.

**5. H-Bond Acceptors (HBA):** Ligand A has 4 HBAs, and Ligand B has 3. Both are within the acceptable limit of <= 10.

**6. QED:** Both ligands have QED values above 0.5 (A: 0.737, B: 0.752), indicating good drug-like properties.

**7. DILI:** Lower is better. Ligand A (72.509) has a higher DILI risk than Ligand B (22.334), which is a significant concern.

**8. BBB:** Higher is better, >70 is desirable for CNS targets. Ligand A (58.007) is below this threshold, while Ligand B (67.701) is closer, but still not ideal.

**9. Caco-2 Permeability:** Both have negative values, which is unusual. Assuming these represent logP-like scales, lower values indicate poorer permeability. Both are similarly poor.

**10. Aqueous Solubility:** Both have negative values, indicating poor solubility. Ligand B (-2.331) is slightly better than Ligand A (-4.645).

**11. hERG Inhibition:** Lower is better. Ligand A (0.606) has a slightly higher hERG risk than Ligand B (0.325).

**12. Microsomal Clearance (Cl_mic):** Lower is better. Ligand B (42.215) has significantly lower clearance than Ligand A (71.483), suggesting better metabolic stability.

**13. In vitro Half-Life:** Ligand A (6.394) has a better half-life than Ligand B (-19.054). However, the negative value for Ligand B is concerning and likely an error.

**14. P-gp Efflux:** Lower is better. Both have low values (A: 0.507, B: 0.178), suggesting limited P-gp efflux, which is good for CNS penetration. Ligand B is better.

**15. Binding Affinity:** Ligand B (-9.2 kcal/mol) has a significantly stronger binding affinity than Ligand A (-8.0 kcal/mol). This is a substantial advantage.

**Overall Assessment:**

Ligand B is the superior candidate. While both have issues with solubility and Caco-2 permeability, Ligand B demonstrates a significantly stronger binding affinity, lower DILI risk, better metabolic stability (lower Cl_mic), and lower P-gp efflux. The higher logP of Ligand A is a concern, and its higher DILI risk is a major drawback. The substantial affinity difference between Ligand B (-9.2 kcal/mol) and Ligand A (-8.0 kcal/mol) is likely to outweigh the minor ADME deficiencies.

Output:
1
2025-04-17 03:13:47,889 - INFO - Reasoning:

Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (348.418 and 352.475 Da) fall comfortably within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (64.79) is significantly better than Ligand B (84.5). For CNS targets, we want TPSA <= 90, and A is much closer to the optimal <=60 range. B is pushing the upper limit.

**3. logP:** Both ligands have good logP values (2.236 and 2.023), falling within the 1-3 range.

**4. H-Bond Donors:** Ligand A (1) is preferable to Ligand B (2). Lower HBD generally improves permeability.

**5. H-Bond Acceptors:** Both ligands have the same number of HBA (4), which is acceptable (<=10).

**6. QED:** Ligand A (0.906) has a significantly better QED score than Ligand B (0.716), indicating a more drug-like profile.

**7. DILI:** Ligand A (22.063) has a lower DILI risk than Ligand B (19.155), although both are quite low and acceptable.

**8. BBB:** This is a critical parameter for a CNS target like DRD2. Ligand A (93.059) has a *much* higher BBB penetration percentile than Ligand B (49.011). This is a major advantage for A.

**9. Caco-2 Permeability:** Ligand A (-4.796) is slightly better than Ligand B (-4.446), indicating better intestinal absorption.

**10. Aqueous Solubility:** Both ligands have poor aqueous solubility (-2.134 and -2.641). This could be a formulation challenge, but is not a dealbreaker.

**11. hERG Inhibition:** Ligand A (0.721) has a slightly better hERG profile than Ligand B (0.189), indicating lower cardiotoxicity risk.

**12. Microsomal Clearance:** Ligand B (69.043) has a much higher microsomal clearance than Ligand A (9.729), meaning it will be metabolized more quickly. This is a significant disadvantage for B.

**13. In vitro Half-Life:** Ligand A (34.501) has a much longer in vitro half-life than Ligand B (-21.907). This is a major advantage for A.

**14. P-gp Efflux:** Ligand A (0.066) has lower P-gp efflux liability than Ligand B (0.054), which is favorable for CNS exposure.

**15. Binding Affinity:** Ligand B (-8.7 kcal/mol) has a slightly better binding affinity than Ligand A (-7.6 kcal/mol). While affinity is important, the difference of 1.1 kcal/mol is not enough to overcome the substantial ADME advantages of Ligand A.

**Overall Assessment:**

Ligand A is clearly the superior candidate. It excels in critical properties for a CNS-targeting GPCR ligand: TPSA, BBB penetration, QED, metabolic stability (low Cl_mic, long t1/2), and P-gp efflux. While Ligand B has slightly better binding affinity, Ligand A's superior ADME profile, particularly its BBB penetration and metabolic stability, make it much more likely to be a viable drug candidate.

Output:
1
2025-04-17 03:13:47,889 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (364.471 and 345.403 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (84.42) is excellent, falling well below the 90 A^2 threshold for CNS targets. Ligand B (96.33) is still reasonable, but less optimal.

**logP:** Ligand A (1.411) is within the optimal 1-3 range. Ligand B (-0.461) is slightly below 1, which *could* indicate permeability issues, though not drastically.

**H-Bond Donors/Acceptors:** Ligand A (1 HBD, 7 HBA) and Ligand B (2 HBD, 5 HBA) both have acceptable numbers of H-bond donors and acceptors.

**QED:** Both ligands have good QED scores (0.48 and 0.682, respectively), indicating reasonable drug-likeness. Ligand B is better here.

**DILI:** Both ligands have low DILI risk (47.77 and 41.373 percentile), which is favorable.

**BBB:** Ligand A shines here with a BBB penetration of 73.943%, exceeding the desirable threshold for CNS targets. Ligand B is significantly lower at 44.668%. This is a major advantage for Ligand A.

**Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and suggests potential issues with the calculation or data. However, we can still compare them. Ligand A (-5.105) is slightly better than Ligand B (-5.641).

**Aqueous Solubility:** Both have negative solubility values, which is also unusual. Ligand A (-2.587) is slightly better than Ligand B (-1.593).

**hERG:** Both ligands have very low hERG inhibition liability (0.25 and 0.074), which is excellent.

**Microsomal Clearance:** Ligand A (81.705) has a higher microsomal clearance than Ligand B (-14.351). This suggests Ligand B is more metabolically stable, which is a plus.

**In vitro Half-Life:** Ligand B has a significantly longer in vitro half-life (5.179 hours) than Ligand A (-4.26 hours). This is a substantial advantage for Ligand B.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.038 and 0.009), which is good.

**Binding Affinity:** Ligand A (-7.8 kcal/mol) has a slightly better binding affinity than Ligand B (-8.9 kcal/mol). While both are excellent, the difference of 1.1 kcal/mol is significant and can outweigh some ADME drawbacks.

**Overall Assessment:**

Considering the GPCR-specific priorities, Ligand A is the stronger candidate. The superior BBB penetration (73.943% vs 44.668%) is critical for a CNS target like DRD2. The slightly better binding affinity (-7.8 vs -8.9 kcal/mol) further supports this choice. While Ligand B has better metabolic stability (lower Cl_mic, longer t1/2) and a slightly better QED, the BBB penetration is a crucial factor for CNS drug development, and Ligand A clearly wins in this regard. The unusual negative values for Caco-2 and solubility are concerning for both, but the relative difference isn't decisive.

Output:
0
2025-04-17 03:13:47,889 - INFO - Reasoning:

Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight (MW):** Both ligands (353.423 and 346.387 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (118.37) is better than Ligand B (120.42) as it is closer to the <90 target for CNS penetration. Both are still reasonably good.

**3. logP:** Ligand A (-0.496) is slightly lower than optimal (1-3), potentially hindering permeation. Ligand B (-0.139) is also on the lower side, but better than A.

**4. H-Bond Donors (HBD):** Ligand A (3) is within the acceptable limit of <=5. Ligand B (4) is also acceptable.

**5. H-Bond Acceptors (HBA):** Ligand A (7) is within the acceptable limit of <=10. Ligand B (5) is also acceptable.

**6. QED:** Ligand A (0.515) is good, indicating drug-likeness. Ligand B (0.282) is significantly lower, suggesting a less drug-like profile.

**7. DILI:** Both ligands have acceptable DILI risk (Ligand A: 48.468, Ligand B: 43.893), below the 60 threshold.

**8. BBB:** Ligand A (58.085) is significantly better than Ligand B (19.581) in terms of BBB penetration, crucial for a CNS target like DRD2.

**9. Caco-2:** Both ligands have negative Caco-2 values (-5.319 and -5.374), which is unusual and problematic. This suggests poor intestinal absorption.

**10. Solubility:** Both ligands have negative solubility values (-1.033 and -1.989), which is also problematic and suggests poor aqueous solubility.

**11. hERG:** Both ligands have very low hERG inhibition risk (0.048 and 0.166).

**12. Cl_mic:** Ligand A (18.911) has a higher microsomal clearance than Ligand B (5.26), indicating lower metabolic stability.

**13. t1/2:** Ligand B (-30.361) has a very negative in vitro half-life, which is concerning. Ligand A (3.385) is better, but still not ideal.

**14. Pgp:** Both ligands have very low P-gp efflux liability (0.01 and 0.019).

**15. Binding Affinity:** Ligand B (-7.8 kcal/mol) has a slightly better binding affinity than Ligand A (-7.5 kcal/mol), though the difference is relatively small.

**Overall Assessment:**

Despite the poor Caco-2 and solubility values for both, Ligand A is the more promising candidate. Its significantly better BBB penetration (58.085 vs 19.581) is critical for a CNS target. It also has a better QED score. While Ligand B has slightly better affinity and lower Cl_mic, the poor BBB score and low QED outweigh these benefits. The negative half-life for ligand B is also a major concern.

Output:
0
2025-04-17 03:13:47,889 - INFO - Batch 11 complete. Total preferences: 176
2025-04-17 03:13:47,890 - INFO - Processing batch 12/512...
2025-04-17 03:14:29,051 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (370.49 and 364.559 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (69.64) is slightly higher than Ligand B (58.12). Both are below the 90 A^2 threshold desirable for CNS targets, but B is better.

**logP:** Ligand A (1.487) is within the optimal 1-3 range. Ligand B (3.39) is at the higher end, but still acceptable.

**H-Bond Donors/Acceptors:** Ligand A has 2 HBD and 4 HBA, while Ligand B has 1 HBD and 5 HBA. Both are within acceptable limits (<=5 HBD and <=10 HBA).

**QED:** Both ligands have good QED scores (0.743 and 0.806), indicating good drug-like properties.

**DILI:** Ligand A (20.9) has a significantly lower DILI risk than Ligand B (25.359). Both are below the 40 threshold, which is good.

**BBB:** Ligand B (74.99) has a slightly better BBB penetration percentile than Ligand A (70.919). Both are above the 70% threshold, which is excellent for a CNS target.

**Caco-2 Permeability:** Ligand A (-5.148) shows poor Caco-2 permeability, while Ligand B (-4.988) is also poor, but slightly better.

**Aqueous Solubility:** Both ligands have very poor aqueous solubility (-3.073 and -3.201). This is a concern for both, but can be mitigated with formulation strategies.

**hERG Inhibition:** Both ligands show very low hERG inhibition risk (0.432 and 0.142).

**Microsomal Clearance:** Ligand A (-2.095) has a significantly lower (better) microsomal clearance than Ligand B (52.754). This suggests better metabolic stability for Ligand A.

**In vitro Half-Life:** Ligand B (32.333) has a much longer in vitro half-life than Ligand A (-1.168).

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.064 and 0.201).

**Binding Affinity:** Both ligands have the same binding affinity (-7.0 kcal/mol), which is excellent.

**Overall Assessment:**

While Ligand B has slightly better BBB penetration and a longer half-life, Ligand A is superior in several critical areas. It has a significantly lower DILI risk and a much better microsomal clearance, indicating improved safety and metabolic stability. The Caco-2 permeability is poor for both, and solubility is a concern, but these can be addressed through formulation. Given the importance of metabolic stability and safety for CNS drugs, and the equal binding affinity, Ligand A is the more promising candidate.

Output:
0
2025-04-17 03:14:29,052 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (353.419 and 364.471 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (107.97) is slightly above the optimal <90 for CNS targets, but still reasonable. Ligand B (92.57) is better, falling comfortably under 90.

**logP:** Ligand A (-0.983) is a bit low, potentially hindering permeation. Ligand B (1.562) is within the optimal 1-3 range. This is a significant advantage for Ligand B.

**H-Bond Donors/Acceptors:** Ligand A has 3 HBD and 5 HBA, acceptable values. Ligand B has 2 HBD and 5 HBA, also acceptable.

**QED:** Both ligands have good QED scores (0.602 and 0.78), indicating drug-like properties.

**DILI:** Ligand A (28.616) has a much lower DILI risk than Ligand B (64.676). This is a considerable advantage for Ligand A.

**BBB:** Ligand A (20.861) has a very poor BBB percentile, making CNS penetration unlikely. Ligand B (59.403) is still not ideal (>70 desired), but significantly better than Ligand A.

**Caco-2 Permeability:** Both have negative Caco-2 values (-5.305 and -5.091) which is unusual and suggests poor permeability.

**Aqueous Solubility:** Both have negative solubility values (-0.444 and -3.548), also unusual and suggesting poor solubility.

**hERG:** Ligand A (0.087) has a very low hERG risk, which is excellent. Ligand B (0.431) is slightly higher but still relatively low.

**Microsomal Clearance:** Ligand A (-17.759) has a negative clearance, which is not physically possible and suggests an issue with the data. Ligand B (48.142) has a high clearance, indicating rapid metabolism.

**In vitro Half-Life:** Ligand A (13.797) has a reasonable half-life. Ligand B (-26.729) has a negative half-life, which is not physically possible and suggests an issue with the data.

**P-gp Efflux:** Ligand A (0.005) has very low P-gp efflux, which is highly desirable for CNS penetration. Ligand B (0.031) is also low, but higher than Ligand A.

**Binding Affinity:** Ligand B (-9.2 kcal/mol) has a significantly stronger binding affinity than Ligand A (-7.6 kcal/mol). This >1.5 kcal/mol difference is a major advantage for Ligand B, potentially outweighing some ADME drawbacks.

**Overall Assessment:**

Ligand A has a better safety profile (lower DILI, lower hERG), and lower P-gp efflux. However, its extremely poor BBB penetration is a deal-breaker for a CNS target like DRD2. The negative clearance and half-life values are also concerning.

Ligand B, despite a higher DILI risk and faster metabolism, has a much better logP, significantly stronger binding affinity, and a reasonably better BBB penetration than Ligand A. The negative half-life is concerning, but the affinity difference is substantial.

Considering the GPCR-specific priorities, particularly BBB and affinity, and the magnitude of the affinity difference, Ligand B is the more promising candidate, assuming the negative half-life and clearance values are data errors.

Output:
1
2025-04-17 03:14:29,052 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (365.5 & 349.5 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (82.53) is slightly higher than Ligand B (70.67). Both are below the 90 A^2 threshold desirable for CNS targets, but B is better.

**3. logP:** Both ligands have good logP values (1.88 & 1.07), falling within the optimal 1-3 range.

**4. H-Bond Donors:** Both have 2 HBD, which is acceptable.

**5. H-Bond Acceptors:** Ligand A has 5 HBA, and Ligand B has 4. Both are within the acceptable limit of 10.

**6. QED:** Both have QED values above 0.7, indicating good drug-likeness.

**7. DILI:** Ligand A (55.02) has a higher DILI risk than Ligand B (15.43). This is a significant negative for Ligand A.

**8. BBB:** Ligand A (48.31) has a slightly better BBB percentile than Ligand B (39.01), but both are below the desirable >70% for CNS targets.

**9. Caco-2:** Both have negative Caco-2 values, which is unusual and suggests poor permeability. However, the scale is not defined, so it's hard to interpret.

**10. Solubility:** Both have negative solubility values, again, the scale is not defined, but suggests poor solubility.

**11. hERG:** Both ligands have very low hERG inhibition liability (0.135 & 0.108), which is excellent.

**12. Cl_mic:** Ligand B (0.73) has significantly lower microsomal clearance than Ligand A (20.98), indicating better metabolic stability.

**13. t1/2:** Ligand B (12.53) has a longer in vitro half-life than Ligand A (6.17), which is favorable.

**14. Pgp:** Both ligands show very low P-gp efflux liability (0.082 & 0.024).

**15. Binding Affinity:** Ligand B (-8.5 kcal/mol) has a *much* stronger binding affinity than Ligand A (0.0 kcal/mol). This is a decisive advantage.

**Overall Assessment:**

Ligand B is clearly superior. While both have issues with Caco-2 and solubility, Ligand B's significantly better binding affinity, lower DILI risk, and improved metabolic stability (lower Cl_mic and longer t1/2) outweigh the slightly lower BBB penetration. The substantial difference in binding affinity (-8.5 vs 0.0 kcal/mol) is a major factor, as it could compensate for minor ADME deficiencies. Given the target is a CNS GPCR, BBB is important, but strong binding is paramount.

Output:
1
2025-04-17 03:14:29,052 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (352.519 and 344.459 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (58.64) is significantly better than Ligand B (75.19). For CNS targets, we want TPSA <= 90, and A is comfortably within that, while B is approaching the upper limit.

**logP:** Both ligands have good logP values (2.839 and 2.329), falling within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Both have 1 HBD, which is good. Ligand A has 3 HBA, and Ligand B has 4. Both are acceptable (<=10).

**QED:** Both ligands have good QED scores (0.731 and 0.824), indicating drug-like properties.

**DILI:** Ligand A (14.851) has a much lower DILI risk than Ligand B (31.563). This is a significant advantage.

**BBB:** Both ligands have excellent BBB penetration (76.347 and 74.292), exceeding the desirable >70 threshold for CNS targets.

**Caco-2 Permeability:** Ligand A (-4.433) is better than Ligand B (-5.029), indicating better intestinal absorption.

**Aqueous Solubility:** Ligand A (-2.509) is better than Ligand B (-2.139), indicating better solubility.

**hERG:** Both ligands have low hERG inhibition risk (0.605 and 0.146).

**Microsomal Clearance:** Ligand A (59.694) has higher clearance than Ligand B (31.69). This means Ligand B is more metabolically stable.

**In vitro Half-Life:** Ligand B (-9.413) has a significantly longer half-life than Ligand A (1.461). This is a major advantage.

**P-gp Efflux:** Ligand A (0.182) has lower P-gp efflux than Ligand B (0.019), meaning better CNS exposure.

**Binding Affinity:** Ligand A (-7.7) has slightly better binding affinity than Ligand B (-8.5). While both are excellent, the 0.8 kcal/mol difference is noticeable.

**Overall Assessment:**

Ligand A excels in TPSA, DILI, solubility, Caco-2 permeability, and P-gp efflux. Its binding affinity is also slightly better. Ligand B shines with its significantly improved metabolic stability (lower Cl_mic and much longer half-life). However, the lower DILI risk and better CNS penetration properties of Ligand A, combined with its acceptable metabolic profile, make it the more promising candidate. The difference in binding affinity is not large enough to overcome the other advantages of Ligand A.

Output:
1
2025-04-17 03:14:29,052 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (356.463 and 346.515 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (87.15) is better than Ligand B (49.41). Both are below the 90 A^2 threshold for CNS targets, but A is closer to the upper limit.

**3. logP:** Ligand A (0.901) is slightly lower than optimal (1-3) but acceptable. Ligand B (3.524) is within the optimal range.

**4. H-Bond Donors:** Both ligands have 1 HBD, which is within the acceptable limit of <=5.

**5. H-Bond Acceptors:** Ligand A has 5 HBAs, and Ligand B has 2. Both are below the acceptable limit of <=10.

**6. QED:** Both ligands have good QED scores (0.588 and 0.748, respectively), indicating good drug-like properties.

**7. DILI:** Ligand A (14.541) has a much lower DILI risk than Ligand B (9.19). This is a significant advantage for Ligand A.

**8. BBB:** Ligand B (83.831) has a significantly better BBB penetration percentile than Ligand A (64.715). This is crucial for a CNS target like DRD2.

**9. Caco-2 Permeability:** Ligand A (-4.161) has a worse Caco-2 permeability than Ligand B (-4.752). Lower values are less favorable.

**10. Aqueous Solubility:** Ligand A (-1.256) has better aqueous solubility than Ligand B (-3.667).

**11. hERG Inhibition:** Ligand A (0.289) has a lower hERG inhibition liability than Ligand B (0.595), which is preferable.

**12. Microsomal Clearance:** Ligand B (46.378) has a lower microsomal clearance than Ligand A (94.213), indicating better metabolic stability.

**13. In vitro Half-Life:** Ligand B (-9.561) has a longer in vitro half-life than Ligand A (-36.403), which is desirable.

**14. P-gp Efflux:** Ligand A (0.07) has a lower P-gp efflux liability than Ligand B (0.134), which is beneficial for CNS penetration.

**15. Binding Affinity:** Ligand B (-8.7 kcal/mol) has a slightly better binding affinity than Ligand A (-7.0 kcal/mol). This 1.7 kcal/mol difference is substantial and could outweigh some ADME drawbacks.

**Overall Assessment:**

Ligand B excels in BBB penetration and binding affinity, which are critical for a CNS GPCR target. It also has better metabolic stability and half-life. However, it has a higher DILI risk and P-gp efflux. Ligand A has a lower DILI risk, better solubility, and lower P-gp efflux, but its BBB penetration is significantly worse.

Given the importance of BBB penetration for a CNS target like DRD2, and the relatively strong affinity advantage of Ligand B, I believe **Ligand B** is the more promising drug candidate, despite its higher DILI risk. The DILI risk can potentially be mitigated through structural modifications during lead optimization.



Output:
1
2025-04-17 03:14:29,052 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight (MW):** Both ligands (344.455 and 368.551 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (67.43) is significantly better than Ligand B (83.37). For CNS targets, we want TPSA <= 90, and A is comfortably within that range while B is approaching the upper limit.

**3. logP:** Both ligands have good logP values (2.044 and 2.582), falling within the optimal 1-3 range.

**4. H-Bond Donors (HBD):** Both ligands are acceptable (2 and 1 respectively), well below the threshold of 5.

**5. H-Bond Acceptors (HBA):** Ligand A (3) is better than Ligand B (7), keeping in mind the preference for <= 10.

**6. QED:** Both ligands have similar and good QED values (0.795 and 0.804), indicating good drug-like properties.

**7. DILI:** Ligand A (21.055) has a much lower DILI risk than Ligand B (43.117). Both are below the 40% threshold, but A is preferable.

**8. BBB:** Ligand B (93.408) has a substantially higher BBB penetration percentile than Ligand A (68.748). This is a *critical* factor for a CNS target like DRD2.

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.931 and -4.9), which is unusual and likely indicates an issue with the prediction method or the molecule's structure. It's difficult to interpret these values directly.

**10. Aqueous Solubility:** Both ligands have negative solubility values (-2.38 and -3.399), again suggesting issues with the prediction.

**11. hERG Inhibition:** Ligand A (0.416) has a lower hERG inhibition liability than Ligand B (0.801), which is favorable.

**12. Microsomal Clearance:** Ligand B (69.847) has a higher microsomal clearance than Ligand A (49.943), meaning A is more metabolically stable.

**13. In vitro Half-Life:** Both ligands have similar negative half-life values (-3.731 and -3.028), which is problematic.

**14. P-gp Efflux:** Ligand A (0.121) has lower P-gp efflux liability than Ligand B (0.205), which is beneficial for CNS penetration.

**15. Binding Affinity:** Ligand B (-7.7 kcal/mol) has a significantly better binding affinity than Ligand A (-9.2 kcal/mol). This is a substantial advantage.

**Overall Assessment:**

While Ligand A has better ADME properties (lower DILI, better TPSA, lower hERG, lower P-gp efflux, better metabolic stability), Ligand B's significantly higher BBB penetration and substantially stronger binding affinity are decisive. For a CNS GPCR target like DRD2, achieving good brain exposure and potent binding are paramount. The slightly worse ADME profile of Ligand B can potentially be addressed through further optimization, but a weak binder with good ADME is unlikely to be a viable drug. The 1.5kcal/mol advantage in binding affinity outweighs the ADME drawbacks.

Output:
1
2025-04-17 03:14:29,052 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (347.459 and 341.419 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (73.64) is slightly higher than Ligand B (70.51), but both are below the 90 A^2 threshold desirable for CNS targets.

**logP:** Ligand A (1.945) is within the optimal 1-3 range. Ligand B (0.82) is a bit low, potentially hindering permeability.

**H-Bond Donors:** Both ligands have 0 HBD, which is good.

**H-Bond Acceptors:** Ligand A has 4 HBA, while Ligand B has 8. Both are within the acceptable limit of 10, but Ligand A is preferable.

**QED:** Both ligands have high QED scores (0.736 and 0.813), indicating good drug-likeness.

**DILI:** Ligand A (22.489) has a significantly lower DILI risk than Ligand B (84.102). This is a major advantage for Ligand A.

**BBB:** Ligand A (83.404) has a better BBB penetration percentile than Ligand B (70.841). Both are reasonably good, but Ligand A is better, crucial for a CNS target.

**Caco-2 Permeability:** Both have negative values (-4.507 and -4.805), which is unusual and suggests poor permeability. However, the scale isn't specified, so it's hard to interpret.

**Aqueous Solubility:** Both have negative values (-2.738 and -2.193), again, the scale is unclear.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.546 and 0.578).

**Microsomal Clearance:** Ligand B (41.032) has lower microsomal clearance than Ligand A (49.309), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (-17.556) has a negative half-life, which is nonsensical. Ligand B (2.442) has a short half-life, which is not ideal.

**P-gp Efflux:** Ligand A (0.145) has lower P-gp efflux liability than Ligand B (0.027), which is beneficial for CNS exposure.

**Binding Affinity:** Ligand A (-7.4 kcal/mol) has a slightly better binding affinity than Ligand B (-0.0 kcal/mol). This is a significant advantage.

**Overall Assessment:**

Ligand A is clearly the better candidate. It has a significantly lower DILI risk, better BBB penetration, lower P-gp efflux, and superior binding affinity. While Ligand B has better metabolic stability, the other advantages of Ligand A, particularly the DILI and BBB scores, outweigh this benefit for a CNS-targeted GPCR like DRD2. The negative values for Caco-2 and solubility are concerning for both, but the other properties of A are much more favorable. The nonsensical half-life for Ligand A is a red flag, but the other factors strongly favor it.

Output:
1
2025-04-17 03:14:29,052 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (366.571 and 356.417 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (58.2) is significantly better than Ligand B (71.11). For CNS targets, TPSA should be <=90, both are within this range, but A is preferable.

**logP:** Both ligands have good logP values (3.359 and 2.94), falling within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A (2 HBD, 3 HBA) and Ligand B (1 HBD, 4 HBA) both have acceptable numbers of H-bond donors and acceptors.

**QED:** Both ligands have similar QED values (0.692 and 0.654), indicating good drug-likeness.

**DILI:** Ligand A (18.108) has a much lower DILI risk than Ligand B (42.924). This is a significant advantage for Ligand A.

**BBB:** Ligand B (90.035) has a better BBB penetration percentile than Ligand A (73.245), which is a crucial factor for CNS targets like DRD2.

**Caco-2 Permeability:** Ligand A (-5.379) has worse Caco-2 permeability than Ligand B (-4.523).

**Aqueous Solubility:** Both ligands have very poor aqueous solubility (-3.684 and -3.348). This is a concern for both, but not a deciding factor.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.498 and 0.395).

**Microsomal Clearance:** Ligand B (35.108) has significantly lower microsomal clearance than Ligand A (80.445), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand B (-14.366) has a negative half-life, which is not ideal. Ligand A (5.461) is better.

**P-gp Efflux:** Ligand A (0.154) has lower P-gp efflux than Ligand B (0.051), which is favorable for CNS penetration.

**Binding Affinity:** Both ligands have excellent binding affinities (-8.3 and -8.1 kcal/mol). The difference is minimal.

**Overall Assessment:**

Ligand B excels in BBB penetration and has better metabolic stability (lower Cl_mic). However, Ligand A has a significantly lower DILI risk, better TPSA, and better P-gp efflux. The binding affinity is comparable. Given the importance of minimizing toxicity (DILI) and maximizing CNS exposure (P-gp, TPSA) for a DRD2 ligand, Ligand A is the more promising candidate despite the slightly lower BBB score and worse Caco-2 permeability. The metabolic stability of B is a plus, but the DILI risk is concerning.

Output:
1
2025-04-17 03:14:29,052 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B against the provided guidelines, prioritizing GPCR-specific properties (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (361.463 Da) is slightly better positioned.

**TPSA:** Ligand A (72.47) is excellent for CNS penetration, well below 90. Ligand B (113.01) is higher, but still potentially acceptable, though less ideal.

**logP:** Ligand A (2.33) is optimal. Ligand B (-0.36) is significantly lower, potentially hindering membrane permeability and CNS entry.

**H-Bond Donors/Acceptors:** Ligand A (HBD=1, HBA=4) and Ligand B (HBD=2, HBA=7) both fall within acceptable ranges.

**QED:** Both ligands have reasonable QED scores (A: 0.857, B: 0.586), indicating good drug-like properties. Ligand A is superior.

**DILI:** Both ligands have similar DILI risk (A: 60.682, B: 59.131), categorized as moderate.

**BBB:** Ligand A (73.943) has a very good BBB percentile, exceeding the 70% threshold for CNS targets. Ligand B (32.183) is significantly lower, raising concerns about CNS exposure.

**Caco-2 Permeability:** Ligand A (-4.606) and Ligand B (-5.74) both have negative values, indicating poor permeability.

**Aqueous Solubility:** Ligand A (-3.391) and Ligand B (-1.167) both have negative values, indicating poor solubility.

**hERG:** Both ligands have low hERG risk (A: 0.591, B: 0.194).

**Microsomal Clearance:** Ligand A (40.929) has moderate clearance. Ligand B (-12.183) has a negative value, which is unusual and likely indicates very low clearance/high metabolic stability.

**In vitro Half-Life:** Ligand A (6.37) and Ligand B (5.755) have similar half-lives.

**P-gp Efflux:** Ligand A (0.328) has lower P-gp efflux liability than Ligand B (0.079), which is favorable for CNS penetration.

**Binding Affinity:** Ligand A (-8.2 kcal/mol) has significantly stronger binding affinity than Ligand B (-6.9 kcal/mol). This >1.3 kcal/mol difference is substantial.

**Conclusion:**

Considering the GPCR-specific priorities, Ligand A is the superior candidate. Its excellent BBB penetration, optimal logP, stronger binding affinity, and better P-gp efflux profile outweigh its moderate Caco-2 permeability and solubility. Ligand B's poor logP and low BBB penetration are major drawbacks for a CNS-targeting drug. While Ligand B has potentially better metabolic stability, the affinity and CNS penetration advantages of Ligand A are more critical for a DRD2 ligand.

Output:
1
2025-04-17 03:14:29,052 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (351.403 and 357.336 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (99.52) is better than Ligand B (103.79). Both are reasonably good for CNS penetration, being under 140, but closer to the 90 target is preferred.

**3. logP:** Both ligands have similar logP values (1.469 and 1.426), falling within the optimal 1-3 range.

**4. H-Bond Donors:** Ligand A (1) is better than Ligand B (3). Lower HBD generally improves permeability.

**5. H-Bond Acceptors:** Ligand A (7) is better than Ligand B (5). Both are acceptable, under the 10 threshold.

**6. QED:** Both ligands have similar QED values (0.615 and 0.651), indicating good drug-like properties.

**7. DILI:** Ligand A (60.915) is better than Ligand B (72.819). Both are moderately risky, but A is preferable.

**8. BBB:** Ligand A (68.554) is significantly better than Ligand B (47.15). This is a *critical* factor for a CNS target like DRD2.

**9. Caco-2 Permeability:** Ligand A (-4.421) is better than Ligand B (-5.363). Higher values are preferred.

**10. Aqueous Solubility:** Ligand A (-3.19) is better than Ligand B (-1.991). Higher values are preferred.

**11. hERG Inhibition:** Both ligands have very low hERG risk (0.156 and 0.131).

**12. Microsomal Clearance:** Ligand B (-13.284) is *much* better than Ligand A (51.704). Lower clearance indicates better metabolic stability.

**13. In vitro Half-Life:** Ligand B (-6.958) is *much* better than Ligand A (3.923). Longer half-life is preferable.

**14. P-gp Efflux:** Both ligands have low P-gp efflux liability (0.13 and 0.154).

**15. Binding Affinity:** Ligand B (-9.1 kcal/mol) is significantly better than Ligand A (-6.8 kcal/mol). This is a substantial difference in potency.

**Overall Assessment:**

Ligand B has a much stronger binding affinity and significantly better metabolic stability (lower Cl_mic) and half-life. However, Ligand A has a substantially better BBB penetration score and lower DILI risk. The difference in binding affinity (-9.1 vs -6.8) is a 2.3 kcal/mol advantage, which is substantial and can outweigh some of the ADME drawbacks of Ligand B. Given the importance of CNS penetration for a DRD2 ligand, and the fact that Ligand A's BBB score is only marginally acceptable, the superior binding affinity and metabolic properties of Ligand B are decisive.

Output:
1
2025-04-17 03:14:29,053 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 drug candidates, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (346.431 and 345.399 Da) fall comfortably within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (84.42) is better than Ligand B (91.64). For CNS targets, we want TPSA <= 90, so Ligand A is preferable.

**3. logP:** Ligand A (2.842) is optimal (1-3). Ligand B (0.89) is a bit low and might struggle with membrane permeability.

**4. H-Bond Donors:** Both have acceptable HBD counts (1 and 2, respectively), well below the threshold of 5.

**5. H-Bond Acceptors:** Both have the same HBA count (5), which is acceptable (<=10).

**6. QED:** Ligand A (0.89) is better than Ligand B (0.775), indicating a more drug-like profile. Both are above the 0.5 threshold.

**7. DILI:** Ligand A (39.434) has a significantly lower DILI risk than Ligand B (55.758). Both are below 60, but A is clearly better.

**8. BBB:** Ligand A (80.419) has a much better BBB penetration percentile than Ligand B (32.92). For a CNS target like DRD2, >70 is desirable, and A is closer to that goal.

**9. Caco-2 Permeability:** Ligand A (-4.418) is better than Ligand B (-4.858). Higher values indicate better absorption.

**10. Aqueous Solubility:** Ligand A (-3.299) is better than Ligand B (-2.046). Higher values are preferred.

**11. hERG Inhibition:** Both ligands have very low hERG inhibition liability (0.36 and 0.118, respectively), which is excellent.

**12. Microsomal Clearance:** Ligand B (-5.767) has a *negative* clearance, which is unusual and suggests very high metabolic stability. Ligand A (44.523) has a more typical, but higher, clearance.

**13. In vitro Half-Life:** Ligand B (-2.277) has a negative half-life, also unusual and suggesting exceptional stability. Ligand A (-5.422) has a more typical, but shorter, half-life.

**14. P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.014 and 0.037, respectively), which is good for CNS exposure.

**15. Binding Affinity:** Both ligands have very similar and strong binding affinities (-8.6 and -8.2 kcal/mol). The difference is less than 1.5 kcal/mol, so this isn't a major differentiating factor.

**Overall Assessment:**

Ligand A is significantly better overall, especially regarding crucial GPCR/CNS properties like TPSA, logP, BBB penetration, solubility, and DILI risk. While Ligand B shows extremely high metabolic stability (negative clearance and half-life, which is somewhat suspect and requires further investigation), the other ADME properties are less favorable. The improved CNS penetration and drug-like properties of Ligand A outweigh the potential benefit of Ligand B's exceptional metabolic stability.

Output:
1
2025-04-17 03:14:29,053 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (357.328 Da) is slightly lower, which could be beneficial for permeability, while Ligand B (405.34 Da) is still well within the range.

**TPSA:** Both ligands have TPSA values (55.84 and 54.04 respectively) below the 90 A^2 threshold desirable for CNS targets, indicating good potential for brain penetration.

**logP:** Both ligands have logP values within the optimal range (1-3), with Ligand A at 2.882 and Ligand B at 4.077. Ligand B is a bit higher, potentially increasing off-target interactions and decreasing solubility, but still acceptable.

**H-Bond Donors/Acceptors:** Both ligands have reasonable HBD/HBA counts (A: 0/4, B: 1/4), falling within the guidelines.

**QED:** Both ligands have good QED scores (A: 0.781, B: 0.755), indicating drug-like properties.

**DILI:** Ligand A has a significantly higher DILI risk (52.656%) compared to Ligand B (15.277%). This is a major concern for Ligand A.

**BBB:** Ligand A has a much better BBB penetration percentile (94.029%) than Ligand B (66.344%). This is a crucial advantage for a CNS target like DRD2.

**Caco-2 Permeability:** Ligand A (-4.203) has worse Caco-2 permeability than Ligand B (-5.056). Both are negative, indicating poor permeability, but Ligand A is slightly better.

**Aqueous Solubility:** Both ligands have very poor aqueous solubility (-3.532 and -3.769 respectively). This could pose formulation challenges.

**hERG Inhibition:** Both ligands have low hERG inhibition liability (A: 0.457, B: 0.804), which is good.

**Microsomal Clearance:** Both ligands have similar microsomal clearance values (A: 44.796, B: 53.984), suggesting moderate metabolic stability.

**In vitro Half-Life:** Ligand A has a significantly longer in vitro half-life (-14.832 hours) than Ligand B (-0.26 hours). This is a substantial advantage for Ligand A.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (A: 0.171, B: 0.361), which is favorable for CNS penetration.

**Binding Affinity:** Ligand B has a slightly better binding affinity (-7.6 kcal/mol) than Ligand A (-7.3 kcal/mol). This difference is relatively small (0.3 kcal/mol) but potentially meaningful.

**Overall Assessment:**

Ligand A excels in BBB penetration and in vitro half-life, both critical for CNS drug development. However, its DILI risk is concerning. Ligand B has a slightly better binding affinity and lower DILI risk, but significantly poorer BBB penetration and a much shorter half-life.

Considering the GPCR-specific priorities, BBB penetration is paramount for a DRD2 ligand. While the DILI risk for Ligand A is a drawback, the superior BBB and half-life are more important in this context. The small affinity difference can be potentially addressed in later optimization stages.

Output:
1
2025-04-17 03:14:29,053 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 drug candidates, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (345.447 and 356.396 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (91.02) is slightly above the optimal <90 for CNS targets, while Ligand B (58.87) is well within the desired range. This favors Ligand B.

**3. logP:** Ligand A (1.728) is within the optimal 1-3 range. Ligand B (3.38) is at the higher end, but still acceptable.

**4. H-Bond Donors:** Both ligands have 1 HBD, which is good.

**5. H-Bond Acceptors:** Ligand A has 5 HBA, and Ligand B has 6. Both are acceptable (<=10).

**6. QED:** Ligand A (0.85) has a better QED score than Ligand B (0.786), suggesting better overall drug-likeness.

**7. DILI:** Both ligands have similar DILI risk (42.536 and 43.66), both being acceptable (<40 is good, >60 is high risk).

**8. BBB:** Ligand B (74.719) has a significantly better BBB percentile than Ligand A (63.125). This is a crucial advantage for a CNS target like DRD2.

**9. Caco-2 Permeability:** Ligand A (-4.789) has a worse Caco-2 permeability than Ligand B (-5.018). Lower values indicate lower permeability.

**10. Aqueous Solubility:** Ligand A (-2.923) has better aqueous solubility than Ligand B (-3.529).

**11. hERG Inhibition:** Ligand A (0.367) has a lower hERG inhibition liability than Ligand B (0.728), which is favorable.

**12. Microsomal Clearance:** Ligand A (21.618) has a lower microsomal clearance than Ligand B (36.627), indicating better metabolic stability.

**13. In vitro Half-Life:** Ligand B (23.813) has a much longer in vitro half-life than Ligand A (-1.629). This is a significant advantage.

**14. P-gp Efflux:** Ligand A (0.09) has lower P-gp efflux liability than Ligand B (0.16), which is favorable for CNS penetration.

**15. Binding Affinity:** Ligand B (-8.3 kcal/mol) has a stronger binding affinity than Ligand A (-7.2 kcal/mol). This is a substantial advantage (1.1 kcal/mol difference).

**Overall Assessment:**

While Ligand A has some advantages (better QED, lower hERG, lower P-gp efflux, better solubility, and better metabolic stability), Ligand B's superior BBB penetration and significantly stronger binding affinity are decisive for a CNS GPCR target like DRD2. The longer half-life of Ligand B is also a significant benefit. The slightly higher logP and P-gp efflux of Ligand B are less concerning given the strong affinity and BBB penetration.

Output:
1
2025-04-17 03:14:29,054 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B based on the provided guidelines, prioritizing GPCR-specific properties (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (346.431 and 352.41 Da) fall within the ideal 200-500 Da range.

**TPSA:** Both ligands have TPSA values (89.53 and 83.56) below the 90 A^2 threshold desirable for CNS targets, which is excellent.

**logP:** Both ligands have logP values (1.053 and 1.677) within the optimal 1-3 range. Ligand B is slightly better here.

**H-Bond Donors/Acceptors:** Both have 2 HBD and 4 HBA, which is acceptable.

**QED:** Ligand A (0.834) has a significantly better QED score than Ligand B (0.662), indicating better overall drug-likeness.

**DILI:** Ligand A (24.661) has a much lower DILI risk than Ligand B (41.915), a significant advantage.

**BBB:** Ligand B (85.072) has a substantially higher BBB penetration percentile than Ligand A (54.983). This is a critical factor for a CNS target like DRD2.

**Caco-2 Permeability:** Ligand A (-5.02) has a worse Caco-2 permeability than Ligand B (-4.347), suggesting lower intestinal absorption.

**Aqueous Solubility:** Ligand A (-1.785) has a worse aqueous solubility than Ligand B (-2.273).

**hERG:** Both ligands have very low hERG inhibition liability (0.176 and 0.291).

**Microsomal Clearance:** Ligand A (-10.068) has significantly lower microsomal clearance than Ligand B (51.601), indicating better metabolic stability.

**In vitro Half-Life:** Ligand A (-12.808) has a worse in vitro half-life than Ligand B (-14.961).

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.01 and 0.035).

**Binding Affinity:** Both ligands have very similar binding affinities (-7.2 and -7.3 kcal/mol). The difference is negligible.

**Overall Assessment:**

Ligand B excels in BBB penetration, a crucial property for CNS drug candidates. It also has slightly better logP, Caco-2 permeability and solubility. However, Ligand A has a significantly better QED score, lower DILI risk, and much better metabolic stability (lower Cl_mic). The binding affinities are essentially the same.

Given the importance of BBB penetration for a DRD2 ligand, and the relatively small difference in binding affinity, Ligand B is the more promising candidate despite its higher DILI risk and lower QED. The improved BBB penetration is likely to outweigh the other drawbacks, especially considering the potential for further optimization to address the DILI concern.

Output:
1
2025-04-17 03:14:29,054 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight (MW):** Both ligands (345.4 and 350.4 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (84.67) is excellent, well below the 90 A^2 threshold for CNS targets. Ligand B (92.67) is still acceptable, but less optimal.

**3. logP:** Ligand A (1.142) is within the optimal range of 1-3. Ligand B (-0.083) is slightly below 1, which *could* indicate permeability issues, but isn't a dealbreaker.

**4. H-Bond Donors (HBD):** Both ligands have acceptable HBD counts (1 and 2 respectively), well below the 5 threshold.

**5. H-Bond Acceptors (HBA):** Both ligands have acceptable HBA counts (5), below the 10 threshold.

**6. QED:** Both ligands have good QED scores (0.564 and 0.702), indicating good drug-like properties.

**7. DILI:** Ligand A (49.13) has a slightly higher DILI risk than Ligand B (34.39), but both are below the concerning 60 threshold.

**8. BBB:** This is a critical parameter for a CNS target like DRD2. Ligand A (63.36) is better than Ligand B (42.96), although ideally, we'd want >70.

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.815 and -4.821), which is unusual and suggests poor permeability. This is a significant concern for both.

**10. Aqueous Solubility:** Both ligands have negative solubility values (-1.817 and -0.956), indicating very poor aqueous solubility. This is a major drawback.

**11. hERG Inhibition:** Both ligands show very low hERG inhibition risk (0.119 and 0.046).

**12. Microsomal Clearance:** Ligand A (13.095) has a higher microsomal clearance than Ligand B (0.97), indicating lower metabolic stability.

**13. In vitro Half-Life:** Ligand B (1.046) has a longer in vitro half-life than Ligand A (-0.342), which is a positive attribute.

**14. P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.093 and 0.012), which is favorable for CNS penetration.

**15. Binding Affinity:** Ligand A (-7.9 kcal/mol) has a slightly better binding affinity than Ligand B (-7.6 kcal/mol). The difference is 0.3 kcal/mol, which is not a huge advantage, but still noticeable.

**Overall Assessment:**

Despite the similar affinities, Ligand A is the better candidate. Its superior TPSA, BBB penetration, and slightly better affinity outweigh its slightly higher DILI and clearance. The biggest concern for *both* compounds is the extremely poor predicted solubility and permeability (Caco-2). However, these properties can sometimes be improved through formulation strategies. The better BBB score for Ligand A is crucial for a CNS target.

Output:
0
2025-04-17 03:14:29,054 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (352.475 Da) is slightly lower, which is generally favorable for permeability.

**TPSA:** Ligand A (78.87) is significantly better than Ligand B (113.24). For CNS targets, TPSA < 90 is preferred, and Ligand A comfortably meets this, while Ligand B is pushing the limit.

**logP:** Ligand A (1.629) is within the optimal range (1-3). Ligand B (-0.697) is below 1, which could hinder permeation.

**H-Bond Donors/Acceptors:** Both have 2 HBDs, which is good. Ligand A has 4 HBAs, and Ligand B has 8 HBAs. Both are acceptable, but Ligand A is slightly better.

**QED:** Both ligands have good QED scores (A: 0.651, B: 0.701), indicating good drug-like properties.

**DILI:** Ligand A (8.453) has a much lower DILI risk than Ligand B (56.689). This is a significant advantage for Ligand A.

**BBB:** Ligand A (65.607) has a good BBB penetration percentile, though not excellent. Ligand B (18.34) is very poor for CNS penetration. This is a crucial difference given DRD2 is a CNS target.

**Caco-2 Permeability:** Ligand A (-4.724) is poor, while Ligand B (-6.002) is even worse. Both are problematic, but Ligand B is worse.

**Aqueous Solubility:** Ligand A (-1.639) is slightly better than Ligand B (-1.28), but both are poor.

**hERG Inhibition:** Both ligands have very low hERG inhibition risk (A: 0.286, B: 0.081).

**Microsomal Clearance:** Ligand A (11.369) has a lower clearance than Ligand B (-25.729), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (-4.318) has a longer half-life than Ligand B (5.271).

**P-gp Efflux:** Ligand A (0.056) has lower P-gp efflux than Ligand B (0.005), which is favorable for CNS exposure.

**Binding Affinity:** Ligand A (-7.9 kcal/mol) has a slightly better binding affinity than Ligand B (-7.3 kcal/mol), although both are excellent. The 0.6 kcal/mol difference is meaningful.

**Overall Assessment:**

Ligand A is significantly better overall. It has a lower DILI risk, better BBB penetration, better TPSA, better logP, better metabolic stability, longer half-life, and lower P-gp efflux. While both have poor Caco-2 permeability and solubility, the CNS target makes BBB penetration and P-gp efflux more critical. The slightly better affinity of Ligand A further strengthens its position. Ligand B's poor BBB penetration is a major drawback for a DRD2 ligand.

Output:
0
2025-04-17 03:14:29,054 - INFO - Batch 12 complete. Total preferences: 192
2025-04-17 03:14:29,054 - INFO - Processing batch 13/512...
2025-04-17 03:15:10,848 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (426.332 Da) is higher, but still acceptable. Ligand B (357.46 Da) is slightly lower, potentially aiding permeability.

**TPSA:** Ligand A (64.63) is above the optimal <90 for CNS targets, but not drastically so. Ligand B (21.26) is excellent, well below the threshold. This favors Ligand B.

**logP:** Both ligands have logP values around 4.1-4.7, which is slightly high. This could lead to solubility issues or off-target interactions. However, for a GPCR, some lipophilicity is often tolerated and can aid membrane permeability.

**H-Bond Donors/Acceptors:** Both have 1 HBD, which is good. Ligand A has 5 HBA, acceptable. Ligand B has 2 HBA, which is also good.

**QED:** Both ligands have good QED scores (0.535 and 0.792), indicating drug-like properties. Ligand B is slightly better.

**DILI:** Ligand A (74.913) has a higher DILI risk than Ligand B (13.339). This is a significant advantage for Ligand B.

**BBB:** Ligand B (89.957) has a much higher BBB penetration percentile than Ligand A (54.207). This is *critical* for a CNS target like DRD2, making Ligand B highly favored.

**Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and suggests poor permeability. However, the scale is not specified, so it is difficult to interpret.

**Aqueous Solubility:** Both have negative solubility values, indicating poor solubility. This is a concern, but can be addressed through formulation.

**hERG Inhibition:** Both ligands have low hERG inhibition liability (0.63 and 0.792), which is good.

**Microsomal Clearance:** Ligand A (119.957) has higher microsomal clearance than Ligand B (13.068), indicating lower metabolic stability. This favors Ligand B.

**In vitro Half-Life:** Ligand B (24.593 hours) has a significantly longer half-life than Ligand A (12.942 hours). This is a significant advantage for Ligand B, potentially allowing for less frequent dosing.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.66 and 0.265). Ligand B is slightly better.

**Binding Affinity:** Ligand B (-9.4 kcal/mol) has a significantly stronger binding affinity than Ligand A (-8.2 kcal/mol). This is a substantial advantage, and can often outweigh minor ADME drawbacks.

**Overall:**

Ligand B consistently outperforms Ligand A across most critical parameters for a CNS-targeting GPCR. It has superior BBB penetration, lower DILI risk, better metabolic stability (lower Cl_mic, longer t1/2), and significantly stronger binding affinity. While both have issues with solubility and Caco-2 permeability, the strong affinity and favorable CNS properties of Ligand B make it the more promising drug candidate.



Output:
1
2025-04-17 03:15:10,849 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (348.447 and 347.354 Da) fall comfortably within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (67.67) is significantly better than Ligand B (125.55). For CNS targets, we want TPSA <= 90, and Ligand A is well within this range, while Ligand B exceeds it. This is a significant advantage for A.

**3. logP:** Ligand A (1.148) is within the optimal 1-3 range. Ligand B (0.55) is slightly below 1, which *could* indicate permeability issues, though not severely.

**4. H-Bond Donors:** Ligand A (0) is preferable to Ligand B (3). Fewer HBDs generally improve permeability.

**5. H-Bond Acceptors:** Ligand A (5) is better than Ligand B (6). Lower HBA counts are generally favored.

**6. QED:** Both ligands have similar QED values (0.773 and 0.701), indicating good drug-likeness.

**7. DILI:** Ligand A (30.632) has a much lower DILI risk than Ligand B (83.87). This is a substantial advantage for A.

**8. BBB:** Ligand A (69.407) and Ligand B (65.413) are both reasonably good, but below the ideal >70 for CNS targets. Ligand A is slightly better.

**9. Caco-2 Permeability:** Both have negative values (-4.506 and -4.888), which is unusual and suggests poor permeability. This is a concern for both.

**10. Aqueous Solubility:** Ligand A (-0.644) is better than Ligand B (-3.329). Higher solubility is generally preferred.

**11. hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.282 and 0.158).

**12. Microsomal Clearance:** Ligand A (28.359) has higher clearance than Ligand B (25.757), meaning B is more metabolically stable.

**13. In vitro Half-Life:** Ligand B (-20.915) has a *negative* half-life, which is impossible and indicates a significant issue. Ligand A (5.893) is reasonable.

**14. P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.026 and 0.005).

**15. Binding Affinity:** Ligand B (-8.8 kcal/mol) has a significantly stronger binding affinity than Ligand A (-7.5 kcal/mol). This is a 1.3 kcal/mol difference, which is substantial and could outweigh some ADME drawbacks.

**Overall Assessment:**

Despite the superior binding affinity of Ligand B, its negative in vitro half-life is a deal-breaker. This suggests a severe instability issue that would likely prevent it from being a viable drug candidate. Ligand A, while having slightly weaker affinity, has a much more favorable ADME profile, particularly regarding DILI risk, TPSA, solubility, and a realistic half-life. The TPSA value of Ligand A is also much better suited for CNS penetration.

Output:
0
2025-04-17 03:15:10,849 - INFO - Reasoning:

Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (344.455 and 349.431 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (49.85) is significantly better than Ligand B (95.67). For CNS targets, we want TPSA <= 90, and A is comfortably within that range, while B is above. This is a major advantage for A.

**3. logP:** Both ligands have acceptable logP values (1.832 and 1.12), falling within the optimal 1-3 range.

**4. H-Bond Donors:** Ligand A (0) is preferable to Ligand B (2). Fewer HBDs generally improve permeability.

**5. H-Bond Acceptors:** Ligand A (3) is better than Ligand B (5). Lower HBA is generally preferred for better permeability.

**6. QED:** Both ligands have good QED scores (0.565 and 0.769), indicating good drug-like properties.

**7. DILI:** Ligand A (18.147) has a lower DILI risk than Ligand B (31.563), which is favorable.

**8. BBB:** Ligand A (63.784) has a better BBB percentile than Ligand B (52.734). While >70 is desirable, A is significantly closer to that threshold, crucial for a CNS target like DRD2.

**9. Caco-2 Permeability:** Ligand A (-4.445) has a worse Caco-2 permeability than Ligand B (-5.185). However, this is less critical than BBB and TPSA for CNS penetration.

**10. Aqueous Solubility:** Ligand A (-2.246) has a worse aqueous solubility than Ligand B (-0.84). Solubility is important, but can often be addressed through formulation.

**11. hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.193 and 0.052), which is excellent.

**12. Microsomal Clearance:** Ligand A (34.559) has a higher microsomal clearance than Ligand B (10.413), suggesting lower metabolic stability. This is a drawback for A.

**13. In vitro Half-Life:** Ligand A (-7.799) has a much worse in vitro half-life than Ligand B (16.884). This is a significant disadvantage for A.

**14. P-gp Efflux:** Ligand A (0.155) has a lower P-gp efflux than Ligand B (0.045), which is favorable for CNS exposure.

**15. Binding Affinity:** Ligand B (-7.9) has a slightly better binding affinity than Ligand A (-8.2). While A is better, the difference is small and may not outweigh other factors.

**Overall Assessment:**

Ligand A excels in TPSA, H-bonding, DILI, BBB, and P-gp efflux. These are particularly important for a CNS GPCR target. However, it suffers from higher microsomal clearance and a significantly shorter half-life. Ligand B has better solubility, Caco-2 permeability, metabolic stability and half-life, but its higher TPSA and lower BBB are significant drawbacks for CNS penetration.

Considering the GPCR-specific priorities, the superior BBB penetration and lower TPSA of Ligand A are more critical than the slightly better metabolic stability of Ligand B. While the shorter half-life of A is a concern, it might be addressable through structural modifications.

Output:
0
2025-04-17 03:15:10,850 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (356.394 and 344.455 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (84.94) is excellent for CNS penetration, well below the 90 A^2 threshold. Ligand B (49.85) is even better.

**logP:** Ligand A (0.421) is a bit low, potentially hindering membrane permeability. Ligand B (2.136) is within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A has 1 HBD and 5 HBA, which is acceptable. Ligand B has 0 HBD and 3 HBA, also acceptable.

**QED:** Both ligands have good QED scores (0.57 and 0.737), indicating drug-like properties.

**DILI:** Both ligands have low DILI risk (27.685 and 22.722 percentile), which is favorable.

**BBB:** Ligand A has a BBB percentile of 75.998, which is good but Ligand B is better at 85.731. Both are above the desirable 70% threshold for CNS targets.

**Caco-2 Permeability:** Both have negative Caco-2 values (-4.511 and -4.328). This is unusual and suggests a potential issue with intestinal absorption. However, given the CNS target, this is less critical than BBB penetration.

**Aqueous Solubility:** Both have negative solubility values (-1.844 and -2.001). This is also concerning, but can be addressed through formulation strategies. Again, less critical for CNS drugs that can cross the BBB.

**hERG Inhibition:** Both have very low hERG inhibition risk (0.349 and 0.319 percentile).

**Microsomal Clearance:** Both have similar microsomal clearance values (31.844 and 32.356 mL/min/kg), indicating comparable metabolic stability.

**In vitro Half-Life:** Ligand B has a slightly better in vitro half-life (-11.731 hours) than Ligand A (-24.61 hours).

**P-gp Efflux:** Both have very low P-gp efflux liability (0.023 and 0.142 percentile), which is excellent for CNS penetration.

**Binding Affinity:** Both ligands have strong binding affinities (-8.1 and -8.9 kcal/mol). Ligand B is slightly better (-8.9 kcal/mol).

**Overall Assessment:**

Ligand B is the better candidate. While both ligands have good overall profiles, Ligand B has a more optimal logP, a better BBB percentile, and a slightly better binding affinity and in vitro half-life. Ligand A's lower logP is a concern for permeability, even with good BBB penetration. The negative Caco-2 and solubility values are concerning, but less critical for a CNS target. The small advantage in binding affinity of Ligand B, coupled with the better logP and BBB, makes it the preferred candidate.

Output:
1
2025-04-17 03:15:10,850 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (361.419 and 351.407 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (82.56) is excellent for CNS penetration, being well below 90. Ligand B (114.35) is higher, but still potentially acceptable, though less ideal.

**logP:** Ligand A (3.146) is optimal. Ligand B (-0.955) is significantly lower, which could hinder membrane permeability and CNS penetration.

**H-Bond Donors/Acceptors:** Ligand A (0 HBD, 7 HBA) is favorable. Ligand B (3 HBD, 6 HBA) is also reasonable, though the 3 HBD might slightly impact permeability.

**QED:** Both ligands have similar and good QED values (0.581 and 0.558).

**DILI:** Ligand A (69.639) has a higher DILI risk than Ligand B (44.552), but both are below the concerning threshold of 60.

**BBB:** Ligand A (81.466) has a very good BBB percentile, highly desirable for a CNS target. Ligand B (33.424) is considerably lower, indicating poor predicted brain penetration.

**Caco-2 Permeability:** Ligand A (-4.546) has poor Caco-2 permeability. Ligand B (-5.554) is even worse.

**Aqueous Solubility:** Ligand A (-4.146) has poor aqueous solubility. Ligand B (-1.08) is also poor, but slightly better than A.

**hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.149 and 0.109).

**Microsomal Clearance:** Ligand A (90.724) has high microsomal clearance, suggesting rapid metabolism. Ligand B (-8.125) has negative clearance, which is not possible and likely indicates an error in the data or a very stable compound.

**In vitro Half-Life:** Ligand A (-2.322) has a negative half-life, which is not possible. Ligand B (-6.016) also has a negative half-life.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.131 and 0.006), which is positive for CNS exposure.

**Binding Affinity:** Ligand A (-8.7 kcal/mol) has a slightly better binding affinity than Ligand B (-7.7 kcal/mol). The 1 kcal/mol difference is significant and could outweigh some ADME drawbacks.

**Overall Assessment:**

Ligand A is superior despite its poor Caco-2 permeability and aqueous solubility, and high clearance. Its excellent BBB penetration, optimal logP, and strong binding affinity are crucial for a CNS GPCR target like DRD2. The negative half-life and clearance values are suspect and would need further investigation. Ligand B's very poor logP and BBB penetration are major drawbacks that outweigh its slightly better DILI and P-gp efflux. The negative half-life and clearance values are also suspect.

Output:
1
2025-04-17 03:15:10,850 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (360.483 and 378.841 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (88.99) is excellent, falling well below the 90 A^2 threshold for CNS targets. Ligand B (115.11) is still reasonable but less optimal, exceeding the preferred threshold.

**logP:** Ligand A (2.303) is within the optimal 1-3 range. Ligand B (1.579) is slightly lower, potentially impacting permeability, but still acceptable.

**H-Bond Donors/Acceptors:** Ligand A (2 HBD, 4 HBA) and Ligand B (3 HBD, 6 HBA) both have acceptable numbers of hydrogen bond donors and acceptors.

**QED:** Both ligands have good QED scores (0.807 and 0.705), indicating good drug-like properties.

**DILI:** Both ligands have similar DILI risk (73.052 and 71.539), which is acceptable (below 80).

**BBB:** This is a critical parameter for a CNS target like DRD2. Ligand A has a BBB percentile of 29.275, which is quite low. Ligand B has a BBB percentile of 13.532, even lower. Both are poor in this regard.

**Caco-2 Permeability:** Both ligands show negative Caco-2 permeability values (-5.321 and -5.127), which is unusual and suggests poor intestinal absorption.

**Aqueous Solubility:** Both ligands have negative solubility values (-4.271 and -3.932), which is also unusual and suggests very poor solubility.

**hERG Inhibition:** Both ligands have low hERG inhibition liability (0.537 and 0.289), which is favorable.

**Microsomal Clearance:** Ligand A (33.826) has a higher microsomal clearance than Ligand B (5.257), suggesting lower metabolic stability.

**In vitro Half-Life:** Ligand B (44.897 hours) has a significantly longer half-life than Ligand A (2.841 hours), which is a major advantage.

**P-gp Efflux:** Ligand A (0.111) has lower P-gp efflux liability than Ligand B (0.06), which is favorable for CNS penetration.

**Binding Affinity:** Both ligands have excellent binding affinities (-8.6 and -8.0 kcal/mol). The difference of 0.6 kcal/mol is not large enough to overcome other significant differences.

**Overall Assessment:**

While both ligands have good binding affinity and acceptable safety profiles (DILI, hERG), their poor BBB penetration and solubility are major drawbacks. Ligand B has a significantly better half-life and lower microsomal clearance, making it more metabolically stable. However, Ligand A has slightly lower P-gp efflux. Given the importance of metabolic stability for *in vivo* efficacy, and the fact that both have poor BBB penetration, Ligand B is slightly more promising. However, the negative solubility and Caco-2 values are concerning for both.

Output:
1
2025-04-17 03:15:10,850 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (349.5 and 358.5 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (61.44) is significantly better than Ligand B (34.47). For a CNS target like DRD2, a TPSA <= 90 is preferred, and A is closer to the ideal range.

**3. logP:** Ligand A (2.306) is within the optimal 1-3 range. Ligand B (4.318) is higher, potentially leading to solubility issues and off-target interactions.

**4. H-Bond Donors:** Both ligands have acceptable HBD counts (2 for A, 0 for B), well below the threshold of 5.

**5. H-Bond Acceptors:** Both ligands have acceptable HBA counts (3 for A, 4 for B), well below the threshold of 10.

**6. QED:** Both ligands have good QED values (0.671 and 0.771), indicating drug-like properties.

**7. DILI:** Ligand A (12.02) has a much lower DILI risk than Ligand B (23.11), which is a significant advantage.

**8. BBB:** Ligand B (88.6) has a substantially better BBB penetration score than Ligand A (65.413). This is a critical factor for CNS targets.

**9. Caco-2 Permeability:** Ligand A (-5.087) has a worse Caco-2 permeability than Ligand B (-4.496), suggesting lower intestinal absorption.

**10. Aqueous Solubility:** Ligand A (-2.927) has a worse aqueous solubility than Ligand B (-4.734).

**11. hERG Inhibition:** Both ligands have low hERG inhibition risk (0.491 and 0.84).

**12. Microsomal Clearance:** Ligand A (35.079) has a lower microsomal clearance than Ligand B (119.435), indicating better metabolic stability.

**13. In vitro Half-Life:** Ligand A (-1.767) has a worse in vitro half-life than Ligand B (16.954).

**14. P-gp Efflux:** Ligand A (0.069) has a much lower P-gp efflux liability than Ligand B (0.854), which is beneficial for CNS exposure.

**15. Binding Affinity:** Both ligands have very similar and strong binding affinities (-7.9 and -7.6 kcal/mol). The difference is less than the 1.5 kcal/mol threshold.

**Overall Assessment:**

Ligand B excels in BBB penetration and has a better in vitro half-life. However, Ligand A demonstrates superior properties in terms of TPSA, logP, DILI risk, microsomal clearance, and P-gp efflux. Given the importance of BBB for CNS targets, Ligand B initially appears promising. However, the significantly higher DILI risk and P-gp efflux of Ligand B are concerning. The slightly lower BBB of Ligand A is outweighed by its better ADME properties, especially the lower DILI and P-gp efflux, which are crucial for CNS drug development. The better TPSA and logP of Ligand A also contribute to its favorability.

Output:
0
2025-04-17 03:15:10,850 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (362.417 and 341.503 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (67.87) is slightly higher than Ligand B (53.08). Both are below the 90 A^2 threshold desirable for CNS targets, but Ligand B is preferable.

**3. logP:** Ligand A (1.296) is within the optimal range (1-3). Ligand B (3.216) is at the higher end of optimal, but still acceptable.

**4. H-Bond Donors:** Ligand A (1) is good. Ligand B (2) is also acceptable.

**5. H-Bond Acceptors:** Ligand A (4) is good. Ligand B (5) is also acceptable.

**6. QED:** Both ligands have good QED scores (0.595 and 0.832), indicating drug-like properties. Ligand B is slightly better.

**7. DILI:** Ligand A (20.047) has a significantly lower DILI risk than Ligand B (32.842). This is a strong advantage for Ligand A.

**8. BBB:** Both ligands have excellent BBB penetration (94.455 and 94.029 percentile), exceeding the >70% threshold for CNS targets.

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.712 and -5.193), which is unusual and suggests poor permeability. However, these values are on a log scale, so the negative values are not directly comparable.

**10. Aqueous Solubility:** Both ligands have negative solubility values (-1.271 and -3.115), again suggesting poor solubility.

**11. hERG Inhibition:** Both ligands have low hERG inhibition liability (0.435 and 0.928).

**12. Microsomal Clearance:** Ligand A (16.449) has a lower microsomal clearance than Ligand B (39.101), indicating better metabolic stability.

**13. In vitro Half-Life:** Ligand B (27.546) has a longer in vitro half-life than Ligand A (14.892).

**14. P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.036 and 0.081).

**15. Binding Affinity:** Ligand B (-8.4 kcal/mol) has a stronger binding affinity than Ligand A (-7.8 kcal/mol). The difference of 0.6 kcal/mol is significant and could outweigh some ADME drawbacks.

**Overall Assessment:**

Ligand B has a better binding affinity and a longer half-life. However, Ligand A has a significantly lower DILI risk and better metabolic stability (lower Cl_mic). Both have good BBB penetration and low P-gp efflux. The solubility and Caco-2 permeability are concerns for both, but the affinity difference is substantial. Given the importance of potency for GPCR ligands, and the relatively good ADME properties of both, the stronger affinity of Ligand B is the deciding factor.

Output:
1
2025-04-17 03:15:10,851 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B based on the provided guidelines, prioritizing GPCR-specific properties (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (339.374) is slightly lower, which could be beneficial for permeability. Ligand B (364.471) is also good.

**TPSA:** Ligand A (82.7) is better than Ligand B (69.48) as it is closer to the ideal range for CNS targets (<=90).

**logP:** Both ligands have good logP values (A: 2.727, B: 1.908) within the optimal range of 1-3.

**H-Bond Donors/Acceptors:** Ligand A has 3 HBD and 3 HBA, while Ligand B has 0 HBD and 7 HBA. Both are acceptable, but A's profile might be slightly better for balance.

**QED:** Both ligands have good QED scores (A: 0.646, B: 0.783), indicating drug-like properties.

**DILI:** Ligand A (80.031) has a higher DILI risk than Ligand B (49.864). This is a significant negative for Ligand A.

**BBB:** Both ligands have similar BBB penetration (A: 69.833, B: 68.399). While neither exceeds the desirable >70, they are comparable.

**Caco-2 Permeability:** Both ligands have negative Caco-2 permeability values, which is unusual and suggests a potential issue with the data. However, we'll proceed assuming these are percentile scores where lower is worse.

**Aqueous Solubility:** Both ligands have negative aqueous solubility values, which is also unusual.

**hERG Inhibition:** Both ligands have very low hERG inhibition risk (A: 0.374, B: 0.264).

**Microsomal Clearance:** Ligand A (14.385) has lower microsomal clearance than Ligand B (22.245), indicating better metabolic stability.

**In vitro Half-Life:** Ligand A (16.941) has a slightly longer half-life than Ligand B (15.747).

**P-gp Efflux:** Ligand A (0.103) has lower P-gp efflux than Ligand B (0.073), which is favorable for CNS penetration.

**Binding Affinity:** Ligand A (-8.8 kcal/mol) has a significantly stronger binding affinity than Ligand B (-7.3 kcal/mol). This is a substantial advantage.

**Overall Assessment:**

Ligand A has a much stronger binding affinity, better TPSA, better metabolic stability, and lower P-gp efflux. However, it has a significantly higher DILI risk. Ligand B has a lower DILI risk. The affinity difference is >1.5 kcal/mol, which can outweigh some ADME drawbacks, *especially* given the importance of affinity for GPCRs. The DILI risk for Ligand A is concerning, but not immediately disqualifying, and could potentially be mitigated with structural modifications.

Output:
1
2025-04-17 03:15:10,851 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (360.445 and 351.451 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (69.64) is excellent, well below the 90 A^2 threshold for CNS targets. Ligand B (115.98) is higher, but still potentially acceptable, though less ideal.

**logP:** Ligand A (2.182) is optimal (1-3). Ligand B (0.901) is slightly low, potentially hindering permeability.

**H-Bond Donors/Acceptors:** Ligand A (HBD=2, HBA=3) is within the preferred ranges. Ligand B (HBD=4, HBA=4) is also acceptable.

**QED:** Ligand A (0.627) is better than Ligand B (0.469), indicating a more drug-like profile.

**DILI:** Ligand A (11.632) has a much lower DILI risk than Ligand B (41.877), a significant advantage.

**BBB:** Ligand A (78.635) has a good BBB penetration percentile, exceeding the 70% target for CNS drugs. Ligand B (36.836) is considerably lower, posing a significant hurdle for CNS activity.

**Caco-2 Permeability:** Ligand A (-4.585) and Ligand B (-5.825) both have negative values, which is unusual. Assuming these are percentile scores, lower values indicate poorer permeability. Ligand B is slightly worse here.

**Aqueous Solubility:** Both ligands have very poor aqueous solubility (-2.282 and -2.347). This is a concern for both, but can be mitigated with formulation strategies.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.337 and 0.291).

**Microsomal Clearance:** Ligand A (37.203) has a slightly higher microsomal clearance than Ligand B (29.724), suggesting potentially lower metabolic stability.

**In vitro Half-Life:** Ligand A (-8.857) has a shorter in vitro half-life than Ligand B (-6.372).

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.063 and 0.129), which is good for CNS penetration.

**Binding Affinity:** Both ligands have excellent binding affinity (-7.5 and -7.7 kcal/mol), very close to each other. The difference is negligible.

**Overall Assessment:**

Ligand A is significantly better overall. It has a much better BBB score, lower DILI risk, and a higher QED score. While its solubility and half-life are less favorable than Ligand B, the crucial CNS-related properties (BBB, TPSA, logP) and safety (DILI) are far superior. The binding affinity is comparable. Given the target is a CNS GPCR (DRD2), the superior BBB penetration and lower toxicity profile of Ligand A outweigh its slightly less favorable metabolic properties.

Output:
1
2025-04-17 03:15:10,851 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (342.4 and 350.5 Da) fall comfortably within the ideal 200-500 Da range.

**TPSA:** Ligand A (85.37) is better than Ligand B (59.08). Both are below the 90 A^2 threshold desirable for CNS targets, but Ligand B is significantly better.

**logP:** Ligand A (3.207) is optimal, while Ligand B (1.291) is a bit low, potentially hindering permeability.

**H-Bond Donors/Acceptors:** Ligand A has 2 HBD and 5 HBA, while Ligand B has 0 HBD and 4 HBA. Both are within acceptable limits.

**QED:** Ligand A (0.769) has a better QED score than Ligand B (0.489), indicating a more drug-like profile.

**DILI:** Ligand B (14.851) has a much lower DILI risk than Ligand A (53.974), a significant advantage.

**BBB:** Ligand A (74.486) has a better BBB penetration score than Ligand B (66.344), both are reasonably good, but A is preferred.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.529 and -4.482). This is unusual and suggests poor permeability.

**Aqueous Solubility:** Both ligands have negative solubility values (-3.764 and -1.541). This is also unusual and suggests poor solubility.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.47 and 0.404).

**Microsomal Clearance:** Both ligands have similar microsomal clearance values (26.581 and 27.458).

**In vitro Half-Life:** Ligand B (9.716) has a slightly longer half-life than Ligand A (8.651).

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.017 and 0.094).

**Binding Affinity:** Ligand A (-8.2 kcal/mol) has a significantly stronger binding affinity than Ligand B (-7.2 kcal/mol). This is a substantial advantage, potentially outweighing some ADME drawbacks.

**Overall Assessment:**

Ligand A excels in binding affinity and BBB penetration, and has a better QED score. However, Ligand B demonstrates a much lower DILI risk. The negative Caco-2 and solubility values are concerning for both compounds. Given the importance of CNS penetration for a DRD2 target, and the significant affinity advantage of Ligand A, I would prioritize Ligand A despite the higher DILI risk. The strong binding affinity (-8.2 kcal/mol) is a major driver, and the BBB score is acceptable. The poor solubility and permeability would need to be addressed in subsequent optimization.

Output:
1
2025-04-17 03:15:10,851 - INFO - Reasoning:

Let's analyze Ligand A and Ligand B against the provided guidelines, prioritizing GPCR-specific properties (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (346.431 and 347.375 Da) fall comfortably within the ideal 200-500 Da range.

**TPSA:** Ligand A (83.44) is excellent, falling well below the 90 A^2 threshold for CNS targets. Ligand B (118.37) is still reasonable but less optimal, being closer to the 140 A^2 limit for oral absorption.

**logP:** Ligand A (0.545) is a bit low, potentially hindering permeability. Ligand B (0.14) is even lower, raising concerns about membrane penetration. Both are below the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A (2 HBD, 5 HBA) is favorable. Ligand B (3 HBD, 7 HBA) is also acceptable, but slightly higher counts could impact permeability.

**QED:** Both ligands have acceptable QED values (0.755 and 0.625, respectively), indicating good drug-like properties.

**DILI:** Ligand A (22.451) has a significantly lower DILI risk than Ligand B (61.303), which is a considerable advantage.

**BBB:** This is crucial for a DRD2 ligand. Ligand A (58.627) is moderate, while Ligand B (34.393) is quite poor. This is a major strike against Ligand B.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.274 and -5.422), which is unusual and suggests poor permeability. This is a concern for both.

**Aqueous Solubility:** Both ligands have negative solubility values (-1.093 and -1.636), which is also unusual and suggests poor solubility.

**hERG:** Both ligands have very low hERG inhibition risk (0.199 and 0.066).

**Microsomal Clearance:** Ligand A (-17.428) has a much lower (better) microsomal clearance than Ligand B (-4.721), indicating greater metabolic stability.

**In vitro Half-Life:** Ligand A (-9.456) has a more negative (better) half-life than Ligand B (64.155).

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.007 and 0.008).

**Binding Affinity:** Ligand A (-8.5 kcal/mol) has a slightly better binding affinity than Ligand B (-7.4 kcal/mol), although both are good (below -7.0 kcal/mol). The 1.1 kcal/mol difference is significant enough to consider.

**Overall Assessment:**

Ligand A is the superior candidate. While both have issues with Caco-2 and solubility, Ligand A excels in critical areas for CNS drug development: significantly lower DILI risk, much better BBB penetration, superior metabolic stability (lower Cl_mic, better t1/2), and slightly better binding affinity. Ligand B's poor BBB penetration is a major drawback for a DRD2 ligand. The lower logP values for both are concerning, but the other advantages of Ligand A outweigh this.

Output:
1
2025-04-17 03:15:10,852 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (345.487 Da) is slightly lower, which is generally favorable for permeability, while Ligand B (392.327 Da) is a bit higher.

**TPSA:** Ligand A (54.34) is significantly better than Ligand B (61.88). For CNS targets, we want TPSA <= 90, and ideally closer to 60. Ligand A is much closer to the ideal range.

**logP:** Both ligands have good logP values (A: 2.501, B: 1.627) falling within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Both have acceptable HBD (1) and HBA (A: 3, B: 4) counts, well below the thresholds of 5 and 10 respectively.

**QED:** Both ligands have reasonable QED scores (A: 0.825, B: 0.682), indicating good drug-like properties.

**DILI:** Ligand A (12.524) has a much lower DILI risk than Ligand B (10.237), which is a significant advantage.

**BBB:** This is a crucial parameter for a CNS target like DRD2. Ligand A (82.745) has a substantially better BBB penetration percentile than Ligand B (61.768). A value >70 is desirable, and Ligand A is closer to that goal.

**Caco-2 Permeability:** Both have negative Caco-2 values (-4.897 and -4.876). This is unusual and suggests poor permeability. However, the values are very similar.

**Aqueous Solubility:** Both have negative solubility values (-2.293 and -1.769), indicating poor solubility. Again, these are similar.

**hERG Inhibition:** Both ligands show low hERG inhibition risk (A: 0.452, B: 0.443).

**Microsomal Clearance:** Ligand A (47.631) has a higher (worse) microsomal clearance than Ligand B (10.499). This suggests Ligand B is more metabolically stable.

**In vitro Half-Life:** Ligand B (4.245) has a longer in vitro half-life than Ligand A (-4.82). This is a positive for Ligand B.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (A: 0.378, B: 0.021). Ligand B is slightly better.

**Binding Affinity:** Ligand B (-7.1 kcal/mol) has a slightly better binding affinity than Ligand A (-8.0 kcal/mol). While A is better, the difference is not substantial enough to outweigh other factors.

**Overall Assessment:**

Ligand A excels in TPSA, BBB, and DILI, all critical for CNS penetration and safety. Ligand B has better metabolic stability (lower Cl_mic) and a slightly longer half-life, and a marginally better binding affinity. However, the substantial advantage of Ligand A in BBB penetration, coupled with its lower DILI risk and better TPSA, makes it the more promising candidate despite its slightly higher clearance. The similar poor solubility and Caco-2 values are concerning for both, but can be addressed through formulation strategies.

Output:
1
2025-04-17 03:15:10,852 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B based on the provided guidelines, prioritizing GPCR-specific properties (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (348.407 and 349.374 Da) fall within the ideal 200-500 Da range.

**TPSA:** Both ligands (113.93 and 112.37) are below the 140 A^2 threshold for oral absorption, and reasonably close to the 90 A^2 target for CNS penetration. Ligand B is slightly better.

**logP:** Ligand A (0.254) is quite low, potentially hindering permeation. Ligand B (0.645) is better, but still on the lower side of the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A (3 HBD, 6 HBA) is better than Ligand B (1 HBD, 10 HBA). While both are within acceptable limits, fewer H-bonds generally improve permeability.

**QED:** Both ligands have good QED scores (0.562 and 0.631), indicating drug-like properties.

**DILI:** Ligand A (51.26) has a significantly lower DILI risk than Ligand B (70.88). This is a substantial advantage for Ligand A.

**BBB:** Ligand B (79.023) has a much higher BBB penetration percentile than Ligand A (25.514). This is a *critical* advantage for a CNS target like DRD2.

**Caco-2 Permeability:** Both are negative, indicating poor permeability.

**Aqueous Solubility:** Both are negative, indicating poor solubility.

**hERG:** Both ligands have very low hERG inhibition risk (0.085 and 0.07).

**Microsomal Clearance:** Ligand A (1.211) has significantly lower microsomal clearance than Ligand B (8.009), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (-18.055) has a much longer in vitro half-life than Ligand B (11.007).

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.023 and 0.19).

**Binding Affinity:** Ligand A (-7.8 kcal/mol) has a slightly better binding affinity than Ligand B (-6.8 kcal/mol). This is a 1.0 kcal/mol difference, which is significant.

**Overall Assessment:**

Ligand B excels in BBB penetration, which is paramount for a CNS target. However, it suffers from higher DILI risk, higher clearance, and shorter half-life. Ligand A has a better safety profile (lower DILI), better metabolic stability (lower clearance, longer half-life), and slightly better affinity. The poor logP of Ligand A is a concern, but the affinity difference and superior ADME properties outweigh this.

Output:
1
2025-04-17 03:15:10,852 - INFO - Reasoning:

Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (353.394 and 358.479 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (80.76) is better than Ligand B (88.1). Both are below the 90 A^2 threshold for CNS targets, but A is closer to the ideal.

**3. logP:** Ligand A (2.359) is within the optimal range (1-3). Ligand B (0.8) is slightly low, potentially hindering permeation.

**4. H-Bond Donors:** Ligand A (1) and Ligand B (2) are both acceptable, being less than 5.

**5. H-Bond Acceptors:** Both ligands (5) are within the acceptable limit of 10.

**6. QED:** Ligand A (0.841) has a significantly better QED score than Ligand B (0.636), indicating a more drug-like profile.

**7. DILI:** Ligand A (64.172) has a higher DILI risk than Ligand B (28.616). This is a significant drawback for Ligand A.

**8. BBB:** Ligand A (59.364) has a better BBB percentile than Ligand B (39.511), which is crucial for CNS targets. However, both are below the desirable >70 threshold.

**9. Caco-2:** Both ligands have negative Caco-2 values, which is unusual and could indicate issues with the prediction method or the compounds themselves. It's difficult to interpret without further information.

**10. Solubility:** Ligand A (-3.073) has better solubility than Ligand B (-0.916).

**11. hERG:** Both ligands have low hERG risk (0.23 and 0.353).

**12. Cl_mic:** Ligand B (34.844) has significantly lower microsomal clearance than Ligand A (62.015), suggesting better metabolic stability.

**13. t1/2:** Ligand B (-5.771) has a longer in vitro half-life than Ligand A (-28.574).

**14. Pgp:** Both ligands have very low Pgp efflux liability (0.023 and 0.051).

**15. Binding Affinity:** Ligand B (-7.3 kcal/mol) has a slightly better binding affinity than Ligand A (-8.1 kcal/mol). While A is better, the difference is not substantial enough to overcome the other drawbacks.

**Overall Assessment:**

Ligand A has a better BBB penetration and binding affinity, but suffers from higher DILI risk, poorer metabolic stability (higher Cl_mic, shorter t1/2), and a lower QED score. Ligand B, while having a slightly weaker binding affinity, exhibits a much better safety profile (lower DILI), improved metabolic stability, and a better QED score. Given the GPCR-specific priorities and the importance of safety and metabolic stability for CNS drugs, Ligand B is the more promising candidate.

Output:
1
2025-04-17 03:15:10,852 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the acceptable range (200-500 Da). Ligand A (333.435 Da) is slightly lower, which is generally favorable for permeability. Ligand B (371.503 Da) is also acceptable.

**TPSA:** Ligand A (48.13) is excellent, well below the 90 A^2 threshold for CNS targets. Ligand B (73.32) is still reasonable but less optimal, potentially hindering BBB penetration.

**logP:** Ligand A (4.523) is a bit high, potentially leading to solubility issues or off-target interactions. Ligand B (-0.508) is too low, likely resulting in poor membrane permeability and reduced CNS exposure.

**H-Bond Donors/Acceptors:** Ligand A (2 HBD, 1 HBA) is excellent. Ligand B (1 HBD, 6 HBA) is acceptable, though the higher HBA count could slightly impact permeability.

**QED:** Both ligands have similar QED values (A: 0.727, B: 0.678), indicating good drug-like properties.

**DILI:** Ligand A (60.915) has a moderate DILI risk, while Ligand B (26.871) has a very low DILI risk, a significant advantage.

**BBB:** Ligand A (85.498) has excellent BBB penetration potential, exceeding the 70% threshold. Ligand B (41.605) has poor BBB penetration, a critical drawback for a CNS target.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.006 and -5.004), which is unusual and suggests issues with the prediction method or the compounds themselves. We'll need to interpret this cautiously.

**Aqueous Solubility:** Both ligands have very poor predicted aqueous solubility (-4.855 and -1.275). This is a concern for both, but potentially more problematic for Ligand A given its higher logP.

**hERG Inhibition:** Ligand A (0.88) has a slightly higher hERG risk than Ligand B (0.349), but both are relatively low.

**Microsomal Clearance:** Ligand A (59.611) has a moderate clearance, while Ligand B (12.463) has a very low clearance, indicating better metabolic stability.

**In vitro Half-Life:** Ligand B (13.512 hours) has a longer half-life than Ligand A (9.884 hours), which is desirable.

**P-gp Efflux:** Ligand A (0.632) has moderate P-gp efflux, while Ligand B (0.042) has very low P-gp efflux, which is a significant advantage for CNS penetration.

**Binding Affinity:** Ligand A (-10.2 kcal/mol) has a significantly stronger binding affinity than Ligand B (-6.8 kcal/mol). This is a substantial advantage, potentially outweighing some of the ADME drawbacks.

**Overall Assessment:**

Ligand A has a superior binding affinity and excellent BBB penetration, which are crucial for a CNS GPCR target. However, it has a higher logP, moderate DILI risk, and moderate P-gp efflux. Ligand B has a lower DILI risk, better metabolic stability, lower P-gp efflux, and a longer half-life, but suffers from very poor BBB penetration and significantly weaker binding affinity.

The strong binding affinity of Ligand A is a major advantage. While its logP and DILI are concerns, these could potentially be addressed through further optimization. The poor BBB penetration of Ligand B is a more fundamental issue that would be difficult to overcome.

Output:
1
2025-04-17 03:15:10,853 - INFO - Batch 13 complete. Total preferences: 208
2025-04-17 03:15:10,853 - INFO - Processing batch 14/512...
2025-04-17 03:15:51,524 - INFO - Reasoning:

Let's analyze Ligand A and Ligand B for their potential as DRD2 drug candidates, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (355.523 and 374.409 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (72.88) is significantly better than Ligand B (79.62). For CNS targets, we want TPSA <= 90, and A is closer to the optimal <=60 range. B is pushing the upper limit.

**3. logP:** Both ligands have good logP values (1.621 and 1.716), falling within the 1-3 optimal range.

**4. H-Bond Donors:** Ligand A (2) is slightly higher than Ligand B (1), but both are acceptable (<=5).

**5. H-Bond Acceptors:** Both ligands have 4 H-bond acceptors, which is well within the acceptable limit of <=10.

**6. QED:** Both ligands have reasonable QED scores (0.694 and 0.737), indicating good drug-like properties.

**7. DILI:** Ligand A (8.414) has a much lower DILI risk than Ligand B (60.217). This is a significant advantage for A.

**8. BBB:** Ligand B (82.164) has a substantially better BBB penetration percentile than Ligand A (42.497). This is a critical factor for a CNS target like DRD2.

**9. Caco-2 Permeability:** Ligand A (-4.863) has worse Caco-2 permeability than Ligand B (-5.05), but both are quite poor.

**10. Aqueous Solubility:** Ligand A (-1.251) has better solubility than Ligand B (-2.932).

**11. hERG Inhibition:** Both ligands have low hERG inhibition risk (0.386 and 0.451).

**12. Microsomal Clearance:** Ligand A (22.501) has lower microsomal clearance than Ligand B (31.036), indicating better metabolic stability.

**13. In vitro Half-Life:** Ligand A (23.663) has a longer in vitro half-life than Ligand B (-3.468). This is a significant advantage for A.

**14. P-gp Efflux:** Ligand A (0.037) has significantly lower P-gp efflux liability than Ligand B (0.088), which is favorable for CNS penetration.

**15. Binding Affinity:** Ligand B (-8.9 kcal/mol) has a significantly stronger binding affinity than Ligand A (-6.5 kcal/mol). This is a substantial advantage, potentially outweighing some ADME drawbacks.

**Overall Assessment:**

Ligand B has a much stronger binding affinity and better BBB penetration, which are crucial for a CNS GPCR target. However, it has a significantly higher DILI risk and higher P-gp efflux. Ligand A has better ADME properties (lower DILI, better metabolic stability, longer half-life, lower P-gp efflux, better solubility) but weaker binding affinity.

The difference in binding affinity (-8.9 vs -6.5 kcal/mol) is >1.5 kcal/mol, suggesting that the potency advantage of B could outweigh its ADME liabilities, *especially* given the good BBB penetration. While the DILI risk is concerning, it's not prohibitive at 60.217, and could potentially be mitigated through structural modifications.

Output:
1
2025-04-17 03:15:51,524 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (347.433 and 344.459 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (89.16) is better than Ligand B (68.3). Both are below the 90 A^2 threshold for CNS targets, but Ligand B is closer to optimal.

**logP:** Both ligands have good logP values (2.852 and 3.224), falling within the 1-3 range.

**H-Bond Donors:** Both have 2 HBD, which is acceptable.

**H-Bond Acceptors:** Ligand A has 5 HBA, and Ligand B has 6. Both are within the acceptable limit of 10.

**QED:** Both ligands have similar QED values (0.786 and 0.766), indicating good drug-likeness.

**DILI:** Ligand A (59.48) has a lower DILI risk than Ligand B (69.329), which is preferable.

**BBB:** Ligand A (80.419) and Ligand B (86.274) both have good BBB penetration, exceeding the 70% threshold for CNS targets. Ligand B is slightly better.

**Caco-2 Permeability:** Both have negative Caco-2 values (-4.783 and -4.823), which is unusual and suggests poor permeability. This is a significant concern for both.

**Aqueous Solubility:** Both have negative solubility values (-3.764 and -3.792), which is also concerning.

**hERG Inhibition:** Ligand A (0.225) has a much lower hERG inhibition liability than Ligand B (0.923), a crucial advantage.

**Microsomal Clearance:** Ligand B (73.998) has higher microsomal clearance than Ligand A (43.567), indicating lower metabolic stability.

**In vitro Half-Life:** Ligand A (69.621) has a slightly longer in vitro half-life than Ligand B (68.822).

**P-gp Efflux:** Ligand A (0.151) has lower P-gp efflux liability than Ligand B (0.28), which is desirable for CNS penetration.

**Binding Affinity:** Ligand B (-7.7 kcal/mol) has significantly stronger binding affinity than Ligand A (-0.0 kcal/mol). This is a substantial advantage, potentially outweighing some of the ADME concerns.

**Overall Assessment:**

Ligand B has a substantially better binding affinity, which is the most important factor for GPCRs. While it has some ADME liabilities (higher DILI, higher Pgp efflux, higher Cl_mic, negative Caco-2 and solubility), the significantly improved binding affinity (-7.7 vs -0.0 kcal/mol) is a major advantage. The BBB penetration is also slightly better for Ligand B. Ligand A has better hERG and DILI profiles, but the weak binding affinity is a critical drawback. Given the importance of potency for GPCR targets, Ligand B is the more promising candidate, despite its ADME challenges. Further optimization could focus on improving the solubility and permeability of Ligand B while maintaining its strong binding affinity.

Output:
1
2025-04-17 03:15:51,525 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (352.32 and 363.489 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (86.84) is better than Ligand B (60.77) as it is closer to the optimal range for CNS targets (<=90).

**3. logP:** Both ligands have good logP values (2.054 and 3.455), falling within the 1-3 range. Ligand B is slightly higher, which could potentially lead to some off-target effects, but isn't a major concern.

**4. H-Bond Donors:** Ligand A (1) is preferable to Ligand B (2) as lower HBD generally improves permeability.

**5. H-Bond Acceptors:** Ligand A (5) is preferable to Ligand B (3) as lower HBA generally improves permeability.

**6. QED:** Ligand A (0.892) has a significantly better QED score than Ligand B (0.694), indicating a more drug-like profile.

**7. DILI:** Ligand A (54.634) has a higher DILI risk than Ligand B (11.865). This is a significant negative for Ligand A.

**8. BBB:** Ligand B (89.104) has a much better BBB penetration score than Ligand A (64.637). This is *critical* for a CNS target like DRD2.

**9. Caco-2 Permeability:** Ligand A (-4.807) has a worse Caco-2 permeability than Ligand B (-4.273).

**10. Aqueous Solubility:** Both ligands have very poor aqueous solubility (-3.162 and -3.182). This is a concern for both, but not a deciding factor.

**11. hERG Inhibition:** Ligand A (0.344) has a lower hERG inhibition liability than Ligand B (0.853), which is favorable.

**12. Microsomal Clearance:** Ligand B (44.296) has a lower microsomal clearance than Ligand A (10.187), suggesting better metabolic stability.

**13. In vitro Half-Life:** Ligand A (14.889) has a longer in vitro half-life than Ligand B (-4.495).

**14. P-gp Efflux:** Ligand A (0.021) has significantly lower P-gp efflux liability than Ligand B (0.223), which is very important for CNS penetration.

**15. Binding Affinity:** Ligand A (-8.3) has a better binding affinity than Ligand B (-6.4). This is a substantial difference (1.9 kcal/mol) and can outweigh some ADME concerns.

**Overall Assessment:**

Despite Ligand A's superior binding affinity, lower P-gp efflux, and better QED, Ligand B is the more promising candidate. The significantly better BBB penetration (89.104 vs 64.637) and lower DILI risk (11.865 vs 54.634) are critical advantages for a CNS-targeted GPCR. The improved metabolic stability (lower Cl_mic) also contributes to its favorability. While Ligand A has a better affinity, the poor BBB and higher DILI risk are major drawbacks that are difficult to overcome.

Output:
1
2025-04-17 03:15:51,525 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B against the provided guidelines, prioritizing GPCR-specific properties (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (443.128 Da) is towards the upper end, while Ligand B (348.531 Da) is more favorably positioned.

**TPSA:** Ligand A (54.79) is higher than Ligand B (40.62). For CNS targets, TPSA should be <= 90, both are well within this limit, but B is better.

**logP:** Ligand A (4.697) is slightly high, potentially leading to solubility issues or off-target interactions. Ligand B (3.841) is closer to the optimal range of 1-3.

**H-Bond Donors/Acceptors:** Both ligands have low HBD counts (0 for A, 0 for B), which is good for permeability. Ligand A has 4 HBA, and Ligand B has 2, both are acceptable.

**QED:** Both ligands have good QED scores (0.689 and 0.732), indicating drug-like properties.

**DILI:** Ligand A (75.572) has a higher DILI risk than Ligand B (26.173). This is a significant concern.

**BBB:** Ligand B (92.71) has a much better BBB penetration score than Ligand A (79.566). This is crucial for a CNS target like DRD2.

**Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and suggests a potential issue with the data or prediction method. However, the values are similar, so this isn't a major differentiator.

**Aqueous Solubility:** Both have negative solubility values, again suggesting a potential data issue. The values are similar, so this isn't a major differentiator.

**hERG Inhibition:** Both ligands have low hERG inhibition liability (0.581 and 0.524), which is good.

**Microsomal Clearance:** Ligand B (88.465) has a higher microsomal clearance than Ligand A (42.683), indicating faster metabolism and potentially lower exposure.

**In vitro Half-Life:** Ligand A (70.04) has a longer half-life than Ligand B (28.073), which is generally desirable.

**P-gp Efflux:** Ligand A (0.643) has a slightly higher P-gp efflux liability than Ligand B (0.469), meaning B is better at avoiding efflux.

**Binding Affinity:** Ligand B (-7.4 kcal/mol) has a significantly stronger binding affinity than Ligand A (-9.4 kcal/mol). This is a substantial advantage, and can often outweigh minor ADME concerns.

**Overall Assessment:**

Ligand B is the more promising candidate. It has a better BBB score, lower DILI risk, better logP, stronger binding affinity, and lower P-gp efflux. While its metabolic clearance is higher and half-life shorter than Ligand A, the significantly improved binding affinity and CNS penetration properties are more critical for a DRD2 (CNS) target. The negative solubility and Caco-2 values are concerning, but may be data artifacts.

Output:
1
2025-04-17 03:15:51,525 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (354.403 Da) is slightly lower, which could be advantageous for permeability. Ligand B (371.702 Da) is also acceptable.

**TPSA:** Both ligands have TPSA values below the 90 A^2 threshold desirable for CNS targets. Ligand A (81.45 A^2) is better than Ligand B (84.08 A^2).

**logP:** Ligand A (0.795) is a bit low, potentially hindering permeation. Ligand B (3.398) is within the optimal range (1-3). This is a significant advantage for Ligand B.

**H-Bond Donors/Acceptors:** Ligand A (0 HBD, 7 HBA) is better than Ligand B (2 HBD, 4 HBA) in terms of balancing solubility and permeability.

**QED:** Both ligands have good QED scores (A: 0.504, B: 0.637), indicating drug-like properties. Ligand B is slightly better.

**DILI:** Ligand A (40.869) has a lower DILI risk than Ligand B (96.51). This is a substantial advantage for Ligand A.

**BBB:** Ligand A (83.288) has a significantly higher BBB penetration percentile than Ligand B (54.246). This is *critical* for a CNS target like DRD2 and heavily favors Ligand A.

**Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and suggests potential issues with the prediction method. However, Ligand A (-4.192) is slightly less negative.

**Aqueous Solubility:** Ligand A (-0.899) has better solubility than Ligand B (-5.768).

**hERG Inhibition:** Ligand A (0.766) has a lower hERG inhibition risk than Ligand B (0.263).

**Microsomal Clearance:** Ligand A (60.692) has a higher (worse) microsomal clearance than Ligand B (9.947), suggesting lower metabolic stability. This favors Ligand B.

**In vitro Half-Life:** Ligand B (44.236) has a longer in vitro half-life than Ligand A (9.155). This is a significant advantage for Ligand B.

**P-gp Efflux:** Ligand A (0.104) has lower P-gp efflux liability than Ligand B (0.286), which is favorable for CNS exposure.

**Binding Affinity:** Ligand B (-7.9 kcal/mol) has a significantly stronger binding affinity than Ligand A (-6.9 kcal/mol). The 1 kcal/mol difference is substantial and can outweigh some ADME drawbacks.

**Overall Assessment:**

While Ligand A excels in BBB, DILI, solubility, and P-gp efflux, Ligand B has a much stronger binding affinity and better metabolic stability (lower Cl_mic, longer t1/2). The strong affinity of Ligand B is a major advantage, especially for a GPCR target. The lower BBB of Ligand B is a concern, but the significantly improved binding could potentially be optimized with further structural modifications to improve brain penetration. The DILI risk for Ligand B is also higher, but not prohibitively so. Given the importance of affinity for GPCRs, and the potential to address the BBB and DILI issues through further optimization, Ligand B is the more promising candidate.

Output:
1
2025-04-17 03:15:51,525 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (381.574 and 352.431 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (82.27) is better than Ligand B (88.1), both are below the 90 A^2 threshold for CNS targets.

**logP:** Ligand A (2.133) is optimal (1-3), while Ligand B (0.203) is quite low, potentially hindering permeation. This is a significant drawback for Ligand B.

**H-Bond Donors:** Both ligands have 2 HBD, which is within the acceptable limit of <=5.

**H-Bond Acceptors:** Ligand A has 4 HBA, and Ligand B has 5 HBA, both are within the acceptable limit of <=10.

**QED:** Both ligands have similar QED values (0.767 and 0.755), indicating good drug-likeness.

**DILI:** Ligand A (44.552) has a slightly higher DILI risk than Ligand B (28.306), but both are below the concerning threshold of 60.

**BBB:** Ligand B (61.38) has a considerably better BBB penetration percentile than Ligand A (46.064). This is a crucial factor for a CNS target like DRD2.

**Caco-2 Permeability:** Ligand A (-4.915) has a worse Caco-2 permeability than Ligand B (-4.75).

**Aqueous Solubility:** Ligand A (-4.297) has a worse aqueous solubility than Ligand B (-1.68).

**hERG:** Both ligands have low hERG inhibition liability (0.243 and 0.191).

**Microsomal Clearance:** Ligand B (1.737) has a significantly lower microsomal clearance than Ligand A (18.378), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand B (18.639) has a much longer in vitro half-life than Ligand A (3.19).

**P-gp Efflux:** Ligand A (0.095) has a slightly higher P-gp efflux liability than Ligand B (0.074), but both are low.

**Binding Affinity:** Ligand B (-8.3 kcal/mol) has a substantially stronger binding affinity than Ligand A (0.0 kcal/mol). This is a major advantage for Ligand B.

**Overall Assessment:**

While Ligand A has a slightly better TPSA and DILI, Ligand B excels in several critical areas for a CNS-targeting GPCR ligand. Its significantly better BBB penetration, dramatically improved metabolic stability (lower Cl_mic and longer t1/2), and *much* stronger binding affinity outweigh the minor drawbacks in TPSA and DILI. The low logP of Ligand B is a concern, but the superior affinity could compensate for this.

Output:
1
2025-04-17 03:15:51,525 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (335.407 and 346.387 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (56.15) is excellent, well below the 90 A^2 threshold for CNS targets. Ligand B (100.46) is still reasonable but higher, potentially impacting CNS penetration.

**logP:** Ligand A (3.838) is at the upper end of the optimal range (1-3), but acceptable. Ligand B (1.186) is a bit low, potentially hindering membrane permeability.

**H-Bond Donors/Acceptors:** Ligand A (HBD=1, HBA=4) and Ligand B (HBD=2, HBA=5) both have reasonable numbers of H-bond donors and acceptors, within the guidelines.

**QED:** Both ligands have similar QED values (0.771 and 0.784), indicating good drug-like properties.

**DILI:** Ligand A (72.586) has a higher DILI risk than Ligand B (54.556), but both are below the concerning threshold of 60.

**BBB:** This is a critical factor for a CNS target like DRD2. Ligand A has a significantly better BBB percentile (69.135) than Ligand B (27.336).

**Caco-2 Permeability:** Ligand A (-4.757) and Ligand B (-5.259) both have negative Caco-2 values, indicating poor permeability. This is concerning, but can be offset by strong binding affinity.

**Aqueous Solubility:** Ligand A (-4.486) and Ligand B (-1.695) both have negative solubility values, indicating poor solubility.

**hERG Inhibition:** Ligand A (0.69) has a slightly higher hERG risk than Ligand B (0.264), but both are relatively low.

**Microsomal Clearance:** Ligand B (-13.069) has a much lower (better) microsomal clearance than Ligand A (61.293), suggesting greater metabolic stability.

**In vitro Half-Life:** Ligand B (24.392) has a longer in vitro half-life than Ligand A (16.399), which is desirable.

**P-gp Efflux:** Ligand A (0.649) has a slightly higher P-gp efflux liability than Ligand B (0.047), meaning Ligand B is less likely to be pumped out of the brain.

**Binding Affinity:** Ligand A (-9.3 kcal/mol) has a significantly stronger binding affinity than Ligand B (-7.2 kcal/mol). This is a substantial advantage (2.1 kcal/mol difference), and can potentially compensate for some of its ADME shortcomings.

**Overall Assessment:**

While Ligand B has better ADME properties (lower DILI, better metabolic stability, longer half-life, lower P-gp efflux), Ligand A's significantly stronger binding affinity (-9.3 vs -7.2 kcal/mol) and acceptable BBB penetration (69.135) are crucial for a CNS GPCR target. The stronger binding is likely to outweigh the ADME drawbacks, especially considering the importance of potency for CNS penetration and efficacy. The poor Caco-2 and solubility of A are concerns, but formulation strategies can sometimes mitigate these.



Output:
1
2025-04-17 03:15:51,525 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B based on the provided guidelines, prioritizing GPCR-specific properties (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (354.447 Da) is slightly lower, which is generally favorable for permeability.

**TPSA:** Ligand A (88.1) is excellent for CNS penetration, being well below 90. Ligand B (101.8) is still reasonable but less optimal.

**logP:** Ligand A (0.306) is quite low, potentially hindering membrane permeability. Ligand B (1.233) is better, falling within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Both ligands have 2 HBDs, which is good. Ligand A has 5 HBAs, while Ligand B has 8. Both are acceptable, but Ligand A is slightly better.

**QED:** Both ligands have similar QED values (0.687 and 0.688), indicating good drug-likeness.

**DILI:** Ligand A (14.851) has a significantly lower DILI risk than Ligand B (59.713), which is a major advantage.

**BBB:** Ligand A (38.813) has a poor BBB percentile, making CNS penetration unlikely. Ligand B (53.083) is also low, but better than Ligand A. This is a critical drawback for both, given the target is DRD2.

**Caco-2 Permeability:** Ligand A (-4.854) has very poor Caco-2 permeability, suggesting poor absorption. Ligand B (-5.785) is also poor, but slightly better.

**Aqueous Solubility:** Both ligands have negative solubility values, indicating poor solubility. Ligand A (-1.343) is slightly better than Ligand B (-2.407).

**hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.151 and 0.075).

**Microsomal Clearance:** Ligand A (5.259) has lower microsomal clearance, suggesting better metabolic stability than Ligand B (30.714).

**In vitro Half-Life:** Ligand A (14.689) has a longer half-life than Ligand B (-23.266), which is desirable.

**P-gp Efflux:** Ligand A (0.012) has very low P-gp efflux, which is excellent for CNS penetration. Ligand B (0.045) is also low, but slightly higher.

**Binding Affinity:** Ligand A (-7.5 kcal/mol) has a stronger binding affinity than Ligand B (-6.3 kcal/mol). This 1.2 kcal/mol difference is significant and could outweigh some ADME drawbacks.

**Overall Assessment:**

Despite Ligand A's superior binding affinity, lower DILI, better metabolic stability, longer half-life, and lower P-gp efflux, its extremely poor BBB penetration and Caco-2 permeability are major concerns for a CNS target like DRD2. Ligand B, while having weaker affinity, has a slightly better (though still poor) BBB score and Caco-2 permeability. The low logP of Ligand A is also a significant drawback.

Given the GPCR-specific priorities, particularly BBB penetration, and the substantial affinity difference, Ligand A is still the more promising candidate, *assuming* formulation strategies can be developed to overcome the permeability issues. However, the low BBB is a serious concern.

Output:
0
2025-04-17 03:15:51,525 - INFO - Reasoning:

Let's analyze Ligand A and Ligand B based on the provided guidelines, prioritizing GPCR-specific properties (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (350.375 and 349.435 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (104.45) is better than Ligand B (109.04). Both are reasonably good, but for a CNS target like DRD2, we ideally want TPSA <= 90. Ligand A is closer to this target.

**logP:** Ligand A (0.351) is suboptimal, being below the preferred 1-3 range. Ligand B (0.996) is better, but still on the lower end. This could impact permeability for both.

**H-Bond Donors/Acceptors:** Ligand A has 1 HBD and 6 HBA, while Ligand B has 2 HBD and 6 HBA. Both are within acceptable limits.

**QED:** Both ligands have good QED scores (0.609 and 0.691, respectively), indicating good drug-like properties.

**DILI:** Both have acceptable DILI risk (48.74 and 41.062), below the 60 threshold.

**BBB:** This is a critical parameter for DRD2. Ligand A (37.456) has a significantly lower BBB percentile than Ligand B (42.148). While neither is *ideal* (>70), Ligand B is better.

**Caco-2 Permeability:** Both have negative Caco-2 values (-4.883 and -4.993). This is unusual and suggests poor permeability.

**Aqueous Solubility:** Both have negative solubility values (-1.403 and -2.208), indicating very poor solubility.

**hERG Inhibition:** Both have low hERG inhibition risk (0.081 and 0.165).

**Microsomal Clearance:** Ligand A (31.142) has lower microsomal clearance than Ligand B (38.867), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (57.575) has a positive half-life, while Ligand B has a negative half-life (-6.218). This is a major red flag for Ligand B.

**P-gp Efflux:** Both have very low P-gp efflux liability (0.039 and 0.054), which is good for CNS penetration.

**Binding Affinity:** Ligand A (-7.9 kcal/mol) has a slightly better binding affinity than Ligand B (-7.0 kcal/mol). While both are good, the 0.9 kcal/mol difference is significant.

**Overall Assessment:**

Ligand A is better overall. While its logP is low, its superior binding affinity, lower clearance, and positive half-life outweigh the slightly lower BBB compared to Ligand B. Ligand B's negative in vitro half-life is a significant concern. Both have poor solubility and permeability, which would need to be addressed through formulation strategies. However, the combination of potency, metabolic stability, and efflux properties makes Ligand A the more promising candidate.

Output:
0
2025-04-17 03:15:51,526 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (364.511 and 350.503 Da) fall within the ideal 200-500 Da range.

**TPSA:** Both ligands have a TPSA of 58.64, which is excellent for CNS penetration, being well below the 90 A^2 threshold.

**logP:** Ligand A (3.545) is slightly higher than Ligand B (2.879), both are within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Both have 1 HBD, which is good. Ligand A has 4 HBA, while Ligand B has 3. Both are within the acceptable limit of 10.

**QED:** Both ligands have good QED scores (0.645 and 0.768, respectively), indicating drug-likeness.

**DILI:** Ligand A (42.536) has a slightly higher DILI risk than Ligand B (14.696), but both are below the concerning threshold of 60.

**BBB:** Both ligands exhibit excellent BBB penetration (89.996 and 81.194, respectively), which is crucial for a CNS target like DRD2. Ligand A is slightly better.

**Caco-2 Permeability:** Both have negative Caco-2 values (-4.754 and -4.791). This is unusual and suggests poor permeability, but the scale is not specified, so it's hard to interpret.

**Aqueous Solubility:** Both have negative solubility values (-3.708 and -2.7), which is also unusual and suggests poor solubility.

**hERG:** Both ligands have low hERG inhibition risk (0.86 and 0.504, respectively).

**Microsomal Clearance:** Ligand A (108.082) has significantly higher microsomal clearance than Ligand B (48.321), indicating lower metabolic stability.

**In vitro Half-Life:** Ligand A (42.949) has a longer in vitro half-life than Ligand B (3.086).

**P-gp Efflux:** Ligand A (0.66) has a slightly higher P-gp efflux liability than Ligand B (0.158), meaning B is less likely to be pumped out of the brain.

**Binding Affinity:** Ligand B (-8.8 kcal/mol) has a significantly stronger binding affinity than Ligand A (-7.6 kcal/mol). This is a substantial difference (1.2 kcal/mol), which can outweigh minor ADME drawbacks.

**Conclusion:**

While Ligand A has slightly better BBB penetration and in vitro half-life, Ligand B demonstrates a significantly stronger binding affinity (-8.8 vs -7.6 kcal/mol) and better metabolic stability (lower Cl_mic) and P-gp efflux. The better affinity is a major advantage for a GPCR target. The slightly lower solubility and permeability (indicated by negative Caco-2 and solubility values) are less concerning given the strong binding and good BBB penetration.

Output:
1
2025-04-17 03:15:51,526 - INFO - Reasoning:

Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (353.423 and 385.295 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (118.37) is slightly above the optimal <90 for CNS targets, but still reasonable. Ligand B (58.44) is excellent, well below 90.

**3. logP:** Ligand A (-0.496) is a bit low, potentially hindering permeability. Ligand B (2.813) is nearly ideal.

**4. H-Bond Donors:** Ligand A (3) is acceptable. Ligand B (0) is also good.

**5. H-Bond Acceptors:** Ligand A (7) is acceptable. Ligand B (4) is also good.

**6. QED:** Both ligands have good QED scores (0.515 and 0.787), indicating drug-like properties.

**7. DILI:** Ligand A (48.468) has a lower DILI risk than Ligand B (67.739), which is approaching a concerning level.

**8. BBB:** Ligand B (75.145) has a significantly better BBB penetration percentile than Ligand A (58.085). This is *critical* for a CNS target like DRD2.

**9. Caco-2 Permeability:** Both have negative values, which is unusual. Assuming these are logP-scale values, lower values indicate poorer permeability. Ligand A (-5.319) is worse than Ligand B (-4.767).

**10. Aqueous Solubility:** Both have negative values, which is also unusual. Assuming these are logS-scale values, lower values indicate poorer solubility. Ligand A (-1.033) is better than Ligand B (-3.131).

**11. hERG Inhibition:** Ligand A (0.048) has a very low hERG risk, which is excellent. Ligand B (0.354) is slightly higher, but still relatively low.

**12. Microsomal Clearance:** Both have similar, relatively high microsomal clearance (18.911 and 48.117 mL/min/kg), suggesting moderate metabolic instability.

**13. In vitro Half-Life:** Ligand A (3.385) has a slightly longer half-life than Ligand B (0.102).

**14. P-gp Efflux:** Ligand A (0.01) has very low P-gp efflux, which is excellent for CNS penetration. Ligand B (0.635) has moderate P-gp efflux.

**15. Binding Affinity:** Ligand B (-8.6 kcal/mol) has a significantly stronger binding affinity than Ligand A (-7.5 kcal/mol). This >1.5 kcal/mol difference is substantial and can outweigh some ADME drawbacks.

**Overall Assessment:**

Ligand B is the stronger candidate. While it has a slightly higher DILI risk and worse solubility, its superior BBB penetration, significantly better binding affinity, and favorable logP outweigh these concerns. The strong affinity is particularly important for a GPCR target. Ligand A's low logP and poorer BBB penetration are significant drawbacks.

Output:
1
2025-04-17 03:15:51,526 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (359.373 and 366.443 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (93.87) is better than Ligand B (104.43). Both are below the 140 A^2 threshold for oral absorption, and Ligand A is closer to the preferred <90 A^2 for CNS targets.

**3. logP:** Both ligands have low logP values (0.381 and 0.21), which is a concern. While not drastically outside the 1-3 range, they are on the low side and could hinder membrane permeability.

**4. H-Bond Donors:** Both have 1 HBD, which is acceptable.

**5. H-Bond Acceptors:** Ligand A has 5 HBA, and Ligand B has 6. Both are within the acceptable limit of <=10.

**6. QED:** Both ligands have good QED scores (0.74 and 0.82), indicating good drug-like properties.

**7. DILI:** Ligand A (26.677) has a significantly lower DILI risk than Ligand B (69.639). This is a major advantage for Ligand A.

**8. BBB:** Both ligands have similar BBB penetration (57.929 and 59.636). Neither is above the desirable 70% for CNS targets, but they are not terrible.

**9. Caco-2 Permeability:** Both have negative Caco-2 values (-4.698 and -4.963), indicating poor permeability. This is a significant drawback for both.

**10. Aqueous Solubility:** Both have negative solubility values (-0.904 and -3.29). This is problematic, suggesting poor solubility. Ligand B is worse.

**11. hERG Inhibition:** Both ligands have low hERG inhibition risk (0.501 and 0.529).

**12. Microsomal Clearance:** Ligand A (-8.018) has much lower (better) microsomal clearance than Ligand B (2.04). This indicates better metabolic stability for Ligand A.

**13. In vitro Half-Life:** Ligand A (-19.347) has a significantly longer in vitro half-life than Ligand B (-2.062).

**14. P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.031 and 0.033), which is good.

**15. Binding Affinity:** Ligand B (-8.3) has a slightly better binding affinity than Ligand A (-6.3). The difference is 2 kcal/mol, which is significant.

**Overall Assessment:**

While Ligand B has a slightly better binding affinity, Ligand A is the superior candidate overall. The key advantages of Ligand A are its significantly lower DILI risk, better metabolic stability (lower Cl_mic, longer t1/2), and better TPSA. The lower affinity of Ligand A can potentially be optimized through further medicinal chemistry efforts. The poor logP and Caco-2 permeability are concerns for both, but the ADME/Tox profile of Ligand A is much more favorable, making it a more promising starting point for drug development targeting the CNS.

Output:
1
2025-04-17 03:15:51,526 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (343.391 and 350.503 Da) fall within the ideal range of 200-500 Da.

**TPSA:** Ligand A (108.8) is better than Ligand B (69.64). Both are below the 90 A^2 threshold for CNS targets, but Ligand A is closer to the upper limit.

**logP:** Ligand B (2.186) is within the optimal range (1-3), while Ligand A (0.149) is significantly below, potentially hindering permeation.

**H-Bond Donors/Acceptors:** Both have 2 HBDs, which is good. Ligand A has 6 HBAs, while Ligand B has 3. Both are within the acceptable limit of 10.

**QED:** Both ligands have good QED scores (0.751 and 0.798), indicating drug-like properties.

**DILI:** Ligand B (4.692) has a much lower DILI risk than Ligand A (61.691). This is a significant advantage for Ligand B.

**BBB:** Ligand B (71.733) has a much better BBB penetration percentile than Ligand A (39.511). This is crucial for a CNS target like DRD2.

**Caco-2 Permeability:** Ligand A (-5.631) has a worse Caco-2 permeability than Ligand B (-4.673), indicating poorer intestinal absorption.

**Aqueous Solubility:** Ligand A (-1.487) has slightly better solubility than Ligand B (-2.752).

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.258 and 0.488).

**Microsomal Clearance:** Ligand A (-16.779) has significantly lower microsomal clearance than Ligand B (41.268), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand B (-8.622) has a longer in vitro half-life than Ligand A (-5.443).

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.019 and 0.017).

**Binding Affinity:** Both ligands have comparable and strong binding affinities (-9.5 and -9.1 kcal/mol). The difference of 0.4 kcal/mol is not substantial enough to outweigh other factors.

**Overall Assessment:**

Ligand B is the superior candidate. While Ligand A has better metabolic stability (lower Cl_mic) and slightly better solubility, Ligand B excels in the critical areas for a CNS GPCR target: BBB penetration, logP, and DILI risk. The significantly better BBB score and acceptable logP of Ligand B are major advantages. The difference in binding affinity is minimal.

Output:
1
2025-04-17 03:15:51,527 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (348.487 and 350.547 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (60.85) is better than Ligand B (43.78). Both are below the 90 A^2 threshold for CNS targets, but Ligand B is closer to optimal.

**logP:** Both ligands have good logP values (2.201 and 3.024), falling within the 1-3 range. Ligand B is slightly higher, which could be beneficial for membrane permeability.

**H-Bond Donors/Acceptors:** Both ligands have 1 HBD and 3 HBA, which are within acceptable limits.

**QED:** Both have good QED scores (0.513 and 0.616), indicating drug-like properties. Ligand B is slightly better.

**DILI:** Ligand A (5.312) has a higher DILI risk than Ligand B (1.745), which is a significant advantage for Ligand B.

**BBB:** Ligand B (74.447) has a substantially better BBB penetration score than Ligand A (65.607). This is *critical* for a CNS target like DRD2.

**Caco-2 Permeability:** Ligand A (-4.679) has better Caco-2 permeability than Ligand B (-4.457), suggesting better intestinal absorption.

**Aqueous Solubility:** Ligand A (-1.14) has better aqueous solubility than Ligand B (-2.728).

**hERG:** Ligand A (0.451) has a lower hERG inhibition liability than Ligand B (0.742), which is preferable.

**Microsomal Clearance:** Ligand B (68.425) has higher microsomal clearance than Ligand A (35.881), indicating faster metabolism and potentially lower *in vivo* exposure.

**In vitro Half-Life:** Ligand B (25.053) has a significantly longer half-life than Ligand A (-1.402). This is a major advantage.

**P-gp Efflux:** Ligand A (0.127) has lower P-gp efflux liability than Ligand B (0.251), which is desirable for CNS penetration.

**Binding Affinity:** Ligand A (-7.7) has a stronger binding affinity than Ligand B (-6.2). This is a 1.5 kcal/mol difference, which is substantial and can often outweigh minor ADME concerns.

**Overall Assessment:**

While Ligand A has better binding affinity and Caco-2 permeability, Ligand B has a significantly better safety profile (lower DILI), superior BBB penetration, and a longer half-life. For a CNS target like DRD2, BBB penetration is paramount. The 1.5 kcal/mol difference in binding affinity, while significant, is less critical than the substantial improvements in ADME properties, particularly BBB and DILI, offered by Ligand B. The longer half-life of Ligand B is also a major benefit.

Output:
1
2025-04-17 03:15:51,527 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (350.419 and 350.413 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (104.65) is higher than Ligand B (61.02). For CNS targets, we prefer TPSA <= 90. Ligand B is significantly better in this regard.

**3. logP:** Ligand A (0.996) is slightly below the optimal 1-3 range, potentially hindering permeability. Ligand B (3.063) is within the optimal range.

**4. H-Bond Donors:** Both ligands have 2 HBD, which is acceptable (<=5).

**5. H-Bond Acceptors:** Ligand A has 6 HBA, and Ligand B has 3 HBA, both within the acceptable range (<=10).

**6. QED:** Both ligands have good QED scores (0.688 and 0.731, both >= 0.5).

**7. DILI:** Ligand A (37.146) has a lower DILI risk than Ligand B (47.421), both are acceptable (<60).

**8. BBB:** This is a crucial parameter for CNS targets. Ligand B (71.811) has a significantly better BBB percentile than Ligand A (39.473). A value >70 is desirable, and Ligand B is closer to this threshold.

**9. Caco-2 Permeability:** Ligand A (-5.359) has worse Caco-2 permeability than Ligand B (-5.111). Both are negative, indicating poor permeability, but B is slightly better.

**10. Aqueous Solubility:** Ligand A (-1.658) has better solubility than Ligand B (-3.268). Solubility is important, but less critical than CNS penetration for a CNS target.

**11. hERG Inhibition:** Ligand A (0.07) has a lower hERG inhibition liability than Ligand B (0.921), which is preferable.

**12. Microsomal Clearance:** Ligand A (19.993) has lower microsomal clearance than Ligand B (22.552), indicating better metabolic stability.

**13. In vitro Half-Life:** Ligand B (8.065) has a significantly longer in vitro half-life than Ligand A (0.397). This is a significant advantage.

**14. P-gp Efflux:** Ligand A (0.016) has lower P-gp efflux liability than Ligand B (0.142), which is preferable for CNS penetration.

**15. Binding Affinity:** Ligand B (-7.9 kcal/mol) has a slightly better binding affinity than Ligand A (-7.4 kcal/mol). While both are good, the 0.5 kcal/mol difference is noticeable and can outweigh some ADME drawbacks.

**Overall Assessment:**

Ligand B is the more promising candidate. While Ligand A has slightly better solubility and lower hERG risk, Ligand B excels in the critical areas for a CNS-targeting GPCR ligand: significantly better BBB penetration, a longer half-life, and slightly improved binding affinity. The lower TPSA of Ligand B is also a significant advantage. The slightly higher logP of Ligand B is also beneficial for CNS penetration.



Output:
1
2025-04-17 03:15:51,527 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 drug candidates, considering the provided guidelines and GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (363.483 and 348.447 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (84.08) is excellent, well below the 90 A^2 threshold for CNS targets. Ligand B (107.11) is still reasonable, but less optimal, being above 90 A^2.

**logP:** Ligand A (2.629) is within the optimal 1-3 range. Ligand B (1.461) is at the lower end, potentially impacting permeability.

**H-Bond Donors/Acceptors:** Ligand A (HBD=2, HBA=5) is favorable. Ligand B (HBD=4, HBA=4) is acceptable.

**QED:** Both ligands have reasonable QED scores (0.741 and 0.507), indicating drug-like properties.

**DILI:** Ligand A (63.552) has a higher DILI risk than Ligand B (33.928), which is a significant drawback.

**BBB:** Ligand A (65.762) has a better BBB percentile than Ligand B (29.275), which is crucial for a CNS target like DRD2.

**Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and suggests a potential issue with the data or modeling. However, we'll proceed assuming these represent low permeability.

**Aqueous Solubility:** Both ligands have negative solubility values, also unusual. This suggests poor solubility, which could hinder bioavailability.

**hERG:** Both ligands have low hERG inhibition risk (0.579 and 0.455), which is positive.

**Microsomal Clearance:** Ligand A (46.174) has higher microsomal clearance than Ligand B (26.317), indicating lower metabolic stability.

**In vitro Half-Life:** Ligand B (-14.439) has a negative half-life, which is not physically possible and indicates a data issue. Ligand A (22.544) has a reasonable half-life.

**P-gp Efflux:** Ligand A (0.496) has lower P-gp efflux liability than Ligand B (0.213), which is beneficial for CNS penetration.

**Binding Affinity:** Ligand A (-8.5 kcal/mol) has a significantly stronger binding affinity than Ligand B (-7.5 kcal/mol). This 1 kcal/mol difference is substantial and can outweigh some ADME drawbacks.

**Overall Assessment:**

Ligand A is superior despite the higher DILI risk. Its significantly stronger binding affinity (-8.5 vs -7.5 kcal/mol) is a major advantage for a GPCR target. It also has better BBB penetration, lower P-gp efflux, and a reasonable half-life. While the DILI risk is concerning, it might be mitigated through structural modifications. The negative solubility and Caco-2 values are problematic, but the affinity advantage is compelling. Ligand B suffers from poor BBB penetration, a negative half-life (data issue), and weaker binding affinity.

Output:
1
2025-04-17 03:15:51,527 - INFO - Batch 14 complete. Total preferences: 224
2025-04-17 03:15:51,527 - INFO - Processing batch 15/512...
2025-04-17 03:16:32,692 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (359.455 and 359.539 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (96.87) is higher than the preferred <90 for CNS targets, but not drastically so. Ligand B (29.77) is excellent, well below the threshold. This favors Ligand B.

**3. logP:** Ligand A (1.909) is within the optimal range (1-3). Ligand B (3.623) is slightly higher, but still acceptable.

**4. H-Bond Donors:** Ligand A (2) is within the acceptable limit of <=5. Ligand B (0) is also good.

**5. H-Bond Acceptors:** Ligand A (6) is within the acceptable limit of <=10. Ligand B (5) is also good.

**6. QED:** Both ligands have reasonable QED values (0.85 and 0.788), indicating good drug-like properties.

**7. DILI:** Ligand A (76.076) has a higher DILI risk than Ligand B (30.826). This favors Ligand B.

**8. BBB:** Ligand A (45.909) has a poor BBB percentile, which is a significant drawback for a CNS target like DRD2. Ligand B (83.676) has an excellent BBB percentile. This is a major advantage for Ligand B.

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.149 and -5.293), which is unusual and suggests poor permeability. However, these values are on a different scale and difficult to interpret directly without more context.

**10. Aqueous Solubility:** Both ligands have negative solubility values (-3.145 and -2.953), also unusual and suggesting poor solubility.

**11. hERG Inhibition:** Ligand A (0.069) has a slightly lower hERG risk than Ligand B (0.957), but both are relatively low.

**12. Microsomal Clearance:** Ligand B (72.926) has a higher microsomal clearance than Ligand A (24.909), indicating lower metabolic stability. This favors Ligand A.

**13. In vitro Half-Life:** Ligand B (27.873) has a longer half-life than Ligand A (11.16), which is generally desirable. This favors Ligand B.

**14. P-gp Efflux:** Ligand A (0.033) has very low P-gp efflux, which is excellent for CNS penetration. Ligand B (0.764) is higher, but still reasonable.

**15. Binding Affinity:** Both ligands have very strong binding affinities (-8.9 and -8.4 kcal/mol). The difference of 0.5 kcal/mol is not substantial enough to outweigh other factors.

**Overall Assessment:**

Ligand B is the stronger candidate. While Ligand A has slightly better metabolic stability and P-gp efflux, Ligand B excels in the critical areas for a CNS GPCR target: TPSA, BBB penetration, and DILI risk. The significantly better BBB score for Ligand B is the most important factor, as it suggests it will reach the target in the brain more effectively. The lower DILI risk is also a significant advantage. The slightly higher logP of Ligand B is not a major concern.

Output:
1
2025-04-17 03:16:32,693 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B based on the provided guidelines, prioritizing GPCR-specific properties (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (416.272 Da) is slightly higher, but acceptable. Ligand B (346.519 Da) is also good.

**TPSA:** Ligand A (103.12) is borderline for CNS targets (ideally <90), while Ligand B (50.16) is excellent for CNS penetration. This is a significant advantage for Ligand B.

**logP:** Ligand A (0.644) is a bit low, potentially hindering permeability. Ligand B (4.034) is at the upper end of the optimal range, which could raise solubility concerns, but is still acceptable.

**H-Bond Donors/Acceptors:** Ligand A (2 HBD, 6 HBA) is good. Ligand B (1 HBD, 3 HBA) is also very good.

**QED:** Both ligands have good QED scores (A: 0.66, B: 0.895), indicating drug-like properties. Ligand B is better.

**DILI:** Ligand A (68.011) has a moderate DILI risk. Ligand B (20.279) has a very low DILI risk, a significant advantage.

**BBB:** Ligand A (66.305) is acceptable but not ideal for a CNS target. Ligand B (78.79) is very good, exceeding the 70% threshold. This is a major advantage for Ligand B.

**Caco-2 Permeability:** Ligand A (-5.094) has poor Caco-2 permeability, suggesting poor absorption. Ligand B (-4.546) is also poor, but slightly better.

**Aqueous Solubility:** Both ligands have poor aqueous solubility (-2.436 and -3.636 respectively). This could present formulation challenges.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (A: 0.361, B: 0.588).

**Microsomal Clearance:** Ligand A (1.741) has low microsomal clearance, indicating good metabolic stability. Ligand B (52.683) has high clearance, suggesting rapid metabolism. This is a significant advantage for Ligand A.

**In vitro Half-Life:** Ligand A (-36.954) has a very long in vitro half-life, which is excellent. Ligand B (23.864) has a moderate half-life.

**P-gp Efflux:** Ligand A (0.017) has very low P-gp efflux, which is desirable for CNS penetration. Ligand B (0.296) has slightly higher P-gp efflux, but still relatively low.

**Binding Affinity:** Ligand B (-9.1 kcal/mol) has a significantly stronger binding affinity than Ligand A (-6.9 kcal/mol). This is a substantial advantage, potentially outweighing some of the ADME drawbacks.

**Overall Assessment:**

Ligand B excels in key GPCR-specific properties: TPSA, BBB, and, most importantly, binding affinity. While its metabolic stability (Cl_mic) is a concern, the strong binding affinity could compensate for this, potentially allowing for a lower dose. Ligand A has better metabolic stability and half-life, but its lower affinity, higher TPSA, and lower BBB penetration make it less attractive for a CNS target like DRD2. The DILI risk is also lower for Ligand B.

Output:
1
2025-04-17 03:16:32,693 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (372.853 Da) is slightly lower, which can be advantageous for permeability.

**TPSA:** Ligand A (98.76) is better than Ligand B (57.95) as it is closer to the ideal range for CNS targets (<=90). Ligand B is quite low, which could indicate poor solubility.

**logP:** Ligand A (1.679) is optimal, while Ligand B (4.75) is high. High logP can lead to off-target effects and solubility issues.

**H-Bond Donors/Acceptors:** Both ligands have acceptable HBD (2 and 1 respectively) and HBA (5 and 4 respectively) counts.

**QED:** Both ligands have reasonable QED scores (0.822 and 0.751), indicating good drug-like properties.

**DILI:** Ligand A (70.841) has a higher DILI risk than Ligand B (25.436). This is a concern for Ligand A.

**BBB:** Ligand B (77.2) has a significantly better BBB penetration percentile than Ligand A (19.698). This is a *critical* advantage for a CNS target like DRD2.

**Caco-2 Permeability:** Ligand A (-4.786) has very poor Caco-2 permeability, suggesting poor absorption. Ligand B (-5.314) is also poor, but slightly better.

**Aqueous Solubility:** Both ligands have poor aqueous solubility (-2.565 and -3.758 respectively).

**hERG Inhibition:** Ligand A (0.287) has a lower hERG inhibition liability than Ligand B (0.848), which is favorable.

**Microsomal Clearance:** Both ligands have similar microsomal clearance rates (34.001 and 38.263 mL/min/kg).

**In vitro Half-Life:** Ligand B (38.958) has a significantly longer in vitro half-life than Ligand A (-17.353). This is a major advantage.

**P-gp Efflux:** Ligand A (0.156) has lower P-gp efflux liability than Ligand B (0.539), which is beneficial for CNS penetration.

**Binding Affinity:** Ligand B (-8.1 kcal/mol) has a *much* stronger binding affinity than Ligand A (0.0 kcal/mol). This is a decisive factor. A difference of >1.5 kcal/mol often outweighs other drawbacks.

**Overall Assessment:**

While Ligand A has a better logP and lower P-gp efflux, Ligand B excels in the most crucial areas for a CNS-targeting GPCR ligand: **BBB penetration and binding affinity**. The significantly stronger binding affinity of Ligand B (-8.1 vs 0.0 kcal/mol) is a game-changer. The improved BBB (77.2 vs 19.7) and longer half-life are also significant advantages. The higher DILI risk and slightly worse solubility of Ligand B are concerns, but can potentially be addressed through further optimization. The poor Caco-2 permeability of both is a concern, but less critical for a CNS target.

Output:
1
2025-04-17 03:16:32,694 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (340.391 and 349.519 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (113.41) is slightly above the optimal <90 for CNS targets, but still reasonable. Ligand B (61.44) is excellent, well below 90.

**logP:** Both ligands have good logP values (1.644 and 2.476), falling within the 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A has 3 HBD and 6 HBA, both acceptable. Ligand B has 2 HBD and 3 HBA, also acceptable.

**QED:** Both ligands have similar QED scores (0.631 and 0.629), indicating good drug-likeness.

**DILI:** Ligand A has a DILI risk of 63.125, which is moderately high. Ligand B has a much lower DILI risk of 14.657, a significant advantage.

**BBB:** This is a critical parameter for a CNS target. Ligand A has a BBB penetration percentile of 32.299, which is poor. Ligand B has a much better BBB penetration of 71.578, exceeding the desirable >70 threshold.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.55 and -4.95). This is unusual and suggests poor permeability. However, these values are on a log scale and negative values are not uncommon.

**Aqueous Solubility:** Both ligands have poor aqueous solubility (-2.117 and -2.159). This could pose formulation challenges.

**hERG Inhibition:** Both ligands show low hERG inhibition liability (0.165 and 0.46), which is good.

**Microsomal Clearance:** Ligand A has a negative Cl_mic (-17.754), which is excellent, indicating very high metabolic stability. Ligand B has a positive Cl_mic (40.611), suggesting faster metabolism.

**In vitro Half-Life:** Ligand A has a very short half-life (-0.938), which is a major drawback. Ligand B has a longer half-life (-11.008), but is still relatively short.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.009 and 0.084), which is favorable for CNS penetration.

**Binding Affinity:** Both ligands have similar, strong binding affinities (-8.0 and -8.4 kcal/mol). The difference is minor.

**Overall Assessment:**

Ligand B is significantly better due to its superior BBB penetration (71.578 vs 32.299), and much lower DILI risk (14.657 vs 63.125). While Ligand A has better metabolic stability (lower Cl_mic) and a slightly longer half-life, the BBB and DILI issues are more critical for a CNS-targeting drug. The similar binding affinities make these secondary factors more important. The poor solubility and Caco-2 values are concerns for both, but can potentially be addressed with formulation strategies.

Output:
1
2025-04-17 03:16:32,694 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (358.364 and 384.973 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (72.09) is significantly better than Ligand B (41.57). For a CNS target like DRD2, a TPSA <= 90 is preferred, and Ligand A is closer to the optimal range.

**3. logP:** Both ligands have good logP values (2.908 and 3.668), falling within the 1-3 range.

**4. H-Bond Donors:** Ligand A (2) is slightly higher than Ligand B (1), but both are within the acceptable limit of <= 5.

**5. H-Bond Acceptors:** Both ligands have 4 H-bond acceptors, well within the acceptable limit of <= 10.

**6. QED:** Both ligands have similar QED values (0.799 and 0.742), indicating good drug-like properties.

**7. DILI:** Both ligands have low DILI risk (39.046 and 32.803), which is favorable.

**8. BBB:** Ligand B (71.229) has a slightly better BBB penetration percentile than Ligand A (67.701). Both are above the 70% threshold for CNS targets, but B is preferable.

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.909 and -4.897). This is unusual and suggests poor permeability. However, these values are on a similar scale, so this isn't a major differentiator.

**10. Aqueous Solubility:** Both ligands have very poor aqueous solubility (-2.79 and -5.094). This is a significant drawback for both, but B is worse.

**11. hERG Inhibition:** Both ligands have low hERG inhibition risk (0.628 and 0.871), which is good.

**12. Microsomal Clearance:** Ligand B (84.344) has a much higher microsomal clearance than Ligand A (20.698), indicating faster metabolism and lower metabolic stability.

**13. In vitro Half-Life:** Ligand A (30.089) has a shorter half-life than Ligand B (52.133). However, the clearance difference is more concerning.

**14. P-gp Efflux:** Both ligands have low P-gp efflux liability (0.213 and 0.494), which is good for CNS penetration.

**15. Binding Affinity:** Ligand A (-8.4 kcal/mol) has a significantly stronger binding affinity than Ligand B (-6.5 kcal/mol). This is a substantial difference (>1.5 kcal/mol) and a major advantage for Ligand A.

**Overall Assessment:**

While Ligand B has a slightly better BBB score, Ligand A is significantly better in several key areas: TPSA, metabolic stability (lower Cl_mic), and, most importantly, binding affinity. The strong binding affinity of Ligand A (-8.4 kcal/mol) can potentially overcome its slightly lower BBB penetration. The poor solubility of both is a concern, but can be addressed with formulation strategies. The higher metabolic clearance of Ligand B is a major disadvantage. Given the GPCR-specific priorities, and the substantial affinity difference, Ligand A is the more promising candidate.

Output:
1
2025-04-17 03:16:32,694 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (347.46 and 349.43 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (61.88) is excellent, well below the 90 A^2 threshold for CNS targets. Ligand B (107.53) is higher but still potentially acceptable, though less optimal.

**logP:** Ligand A (3.48) is within the optimal 1-3 range. Ligand B (-0.007) is significantly lower, which could hinder membrane permeability and CNS penetration.

**H-Bond Donors/Acceptors:** Ligand A (1 HBD, 4 HBA) is favorable. Ligand B (4 HBD, 4 HBA) is also acceptable, but the higher HBD count could slightly impact permeability.

**QED:** Both ligands have good QED scores (0.886 and 0.541, respectively), indicating drug-like properties.

**DILI:** Ligand A (56.92) has a moderate DILI risk, but is acceptable. Ligand B (22.8) has a very low DILI risk, which is a significant advantage.

**BBB:** Ligand A (77.98) has a good BBB percentile, exceeding the 70% threshold for CNS targets. Ligand B (28.46) is quite low, suggesting poor brain penetration. This is a major drawback for a DRD2 ligand.

**Caco-2 Permeability:** Ligand A (-4.51) is poor, indicating low intestinal absorption. Ligand B (-5.28) is also poor.

**Aqueous Solubility:** Both ligands have poor aqueous solubility (-3.89 and -2.11, respectively).

**hERG Inhibition:** Both ligands show very low hERG inhibition risk (0.48 and 0.039, respectively).

**Microsomal Clearance:** Ligand A (79.48) has higher microsomal clearance, suggesting faster metabolism. Ligand B (15.70) has lower clearance, indicating better metabolic stability.

**In vitro Half-Life:** Ligand A (19.04) has a longer half-life than Ligand B (-2.46).

**P-gp Efflux:** Ligand A (0.14) has low P-gp efflux, which is good for CNS exposure. Ligand B (0.013) has very low P-gp efflux, which is excellent.

**Binding Affinity:** Ligand B (-8.3 kcal/mol) has a significantly stronger binding affinity than Ligand A (-7.7 kcal/mol). This 0.6 kcal/mol difference is substantial and could outweigh some ADME concerns.

**Overall Assessment:**

Ligand B has a significantly better binding affinity and lower DILI risk and P-gp efflux. However, its major drawback is the very poor BBB penetration and low logP. Ligand A has better BBB penetration and a more optimal logP, but its affinity is weaker, and it has higher metabolic clearance.

Given the GPCR-specific prioritization of BBB penetration for CNS targets like DRD2, and the substantial affinity advantage of Ligand B, I believe Ligand B is the more promising candidate, *provided* that strategies can be employed to improve its BBB penetration (e.g., prodrug approach, formulation strategies). The strong binding affinity is a significant advantage that could be leveraged.

Output:
1
2025-04-17 03:16:32,694 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (330.431 Da) is slightly better, being closer to the lower end which can aid permeability.

**TPSA:** Ligand A (41.99) is excellent, well below the 90 A^2 threshold for CNS targets. Ligand B (65.54) is higher, but still potentially acceptable, though less ideal.

**logP:** Ligand A (4.357) is a bit high, potentially leading to solubility issues and off-target interactions. Ligand B (0.968) is low, which could hinder permeation.

**H-Bond Donors/Acceptors:** Both have 1 HBD, which is good. Ligand A has 2 HBA, and Ligand B has 6 HBA. Ligand A is better here, as higher HBA can reduce permeability.

**QED:** Ligand A (0.73) has a good drug-likeness score. Ligand B (0.453) is lower, indicating a less favorable drug-like profile.

**DILI:** Ligand A (65.917) has a higher DILI risk than Ligand B (40.403). This is a concern for Ligand A.

**BBB:** Ligand A (67.933) has a better BBB penetration percentile than Ligand B (53.781). This is crucial for a CNS target like DRD2.

**Caco-2 Permeability:** Ligand A (-4.824) has poor Caco-2 permeability. Ligand B (-5.019) is also poor, but slightly better.

**Aqueous Solubility:** Ligand A (-5.09) has poor aqueous solubility. Ligand B (-1.936) is better, but still not great.

**hERG Inhibition:** Both ligands have low hERG risk (0.754 and 0.351 respectively), which is good.

**Microsomal Clearance:** Ligand A (49.786) has higher microsomal clearance than Ligand B (30.728), meaning it's less metabolically stable.

**In vitro Half-Life:** Ligand B (-16.058) has a significantly longer in vitro half-life than Ligand A (-4.414). This is a major advantage for Ligand B.

**P-gp Efflux:** Ligand A (0.362) has lower P-gp efflux than Ligand B (0.052), which is favorable for CNS penetration.

**Binding Affinity:** Ligand A (-10.9 kcal/mol) has *much* stronger binding affinity than Ligand B (-0.0 kcal/mol). This is a substantial advantage for Ligand A.

**Overall Assessment:**

Despite Ligand A's higher DILI risk, poor solubility, and moderate logP, its *significantly* superior binding affinity (-10.9 vs -0.0 kcal/mol) and better BBB penetration outweigh these drawbacks. The binding affinity difference is so large that it's likely to overcome permeability issues with appropriate formulation strategies. Ligand B has better ADME properties overall, but its extremely weak binding affinity makes it unlikely to be a viable candidate.

Output:
1
2025-04-17 03:16:32,695 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (395.575 Da) is slightly higher, but acceptable. Ligand B (347.463 Da) is also good.

**TPSA:**  For CNS targets, we want TPSA <= 90. Ligand A (63.58) is excellent. Ligand B (70.47) is still reasonable, but less optimal.

**logP:** Optimal is 1-3. Ligand A (4.14) is a bit high, potentially leading to solubility issues and off-target interactions. Ligand B (0.791) is quite low, which could hinder membrane permeability.

**H-Bond Donors/Acceptors:** Both have 1 HBD, which is good. Ligand A has 7 HBA, acceptable. Ligand B has 5 HBA, also acceptable.

**QED:** Both ligands have good QED scores (A: 0.564, B: 0.792), indicating drug-likeness.

**DILI:** Ligand A (63.086) has a higher DILI risk than Ligand B (19.271). This is a significant negative for Ligand A.

**BBB:**  Crucial for CNS targets. Ligand A (65.529) is borderline, while Ligand B (77.898) is very good, exceeding the 70% threshold.

**Caco-2 Permeability:** Both have negative values, which is unusual and likely indicates a scale issue where lower values represent lower permeability. However, comparing the two, Ligand B (-5.095) appears to have slightly better permeability than Ligand A (-5.5).

**Aqueous Solubility:** Both have negative values, again indicating a scale issue where lower values represent lower solubility. Ligand B (-1.162) is better than Ligand A (-3.315).

**hERG Inhibition:** Both have low hERG risk (A: 0.622, B: 0.459).

**Microsomal Clearance:** Ligand A (87.312) has significantly higher clearance than Ligand B (3.215), suggesting lower metabolic stability.

**In vitro Half-Life:** Ligand A (21.493) has a longer half-life than Ligand B (8.535).

**P-gp Efflux:** Ligand A (0.756) has slightly higher P-gp efflux than Ligand B (0.013), meaning B is less likely to be pumped out of the brain.

**Binding Affinity:** Both have excellent binding affinities (-8.6 and -8.4 kcal/mol). The difference of 0.2 kcal/mol is not substantial enough to outweigh other factors.

**Overall Assessment:**

Ligand B is the more promising candidate. While its logP is low, its superior BBB penetration, lower DILI risk, better solubility, lower P-gp efflux, and significantly better metabolic stability outweigh the slightly lower logP. Ligand A's higher logP, DILI risk, and clearance are major drawbacks. The affinity difference is minimal. Given the GPCR target and the importance of CNS penetration, Ligand B is the clear choice.

Output:
1
2025-04-17 03:16:32,695 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (356.394 and 356.507 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (104.73) is higher than Ligand B (70.08). For CNS targets, TPSA should be <= 90. Ligand B is significantly better in this regard.

**3. logP:** Ligand A (0.348) is quite low, potentially hindering permeability. Ligand B (2.048) is within the optimal range of 1-3. This is a significant advantage for Ligand B.

**4. H-Bond Donors:** Ligand A (3) is acceptable, while Ligand B (1) is even better, potentially improving permeability.

**5. H-Bond Acceptors:** Ligand A (5) and Ligand B (4) are both within the acceptable limit of <= 10.

**6. QED:** Both ligands have reasonable QED values (0.47 and 0.686), indicating drug-like properties, with Ligand B being slightly better.

**7. DILI:** Both ligands have low DILI risk (22.218 and 19.969), which is good.

**8. BBB:** Ligand A (67.352) is borderline for good CNS penetration, while Ligand B (36.293) is quite low. This is a major drawback for Ligand B.

**9. Caco-2 Permeability:** Ligand A (-5.028) has poor Caco-2 permeability, while Ligand B (-4.258) is also poor.

**10. Aqueous Solubility:** Both ligands have poor aqueous solubility (-1.968 and -1.01).

**11. hERG Inhibition:** Both ligands show low hERG inhibition risk (0.29 and 0.387).

**12. Microsomal Clearance:** Ligand A (31.331) has lower clearance than Ligand B (41.204), suggesting better metabolic stability.

**13. In vitro Half-Life:** Ligand A (19.634) has a shorter half-life than Ligand B (25.004).

**14. P-gp Efflux:** Both ligands have low P-gp efflux liability (0.018 and 0.109).

**15. Binding Affinity:** Both ligands have the same excellent binding affinity (-7.6 kcal/mol).

**Overall Assessment:**

While both ligands have excellent binding affinity, Ligand B is superior in terms of TPSA and logP, which are critical for CNS penetration and GPCR targeting. The lower TPSA and optimal logP of Ligand B suggest it will have better permeability. However, Ligand B's BBB percentile is quite low. Ligand A has a better BBB score, but suffers from a very low logP and poor Caco-2 permeability. Considering the balance, and the fact that DRD2 is a CNS target, the better logP and TPSA of Ligand B are more important than the slightly better BBB of Ligand A. The poor solubility of both compounds is a concern that would need to be addressed in further optimization.

Output:
1
2025-04-17 03:16:32,695 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (348.403 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (101.49) is better than Ligand B (110.26). For CNS targets, we want TPSA <= 90, so both are slightly above, but A is closer.

**3. logP:** Ligand A (0.591) is quite low, potentially hindering permeation. Ligand B (2.382) is within the optimal 1-3 range. This is a significant advantage for B.

**4. H-Bond Donors:** Ligand A (1) and Ligand B (2) are both acceptable (<=5).

**5. H-Bond Acceptors:** Both ligands (6) are within the acceptable range (<=10).

**6. QED:** Both ligands have similar, good QED values (0.755 and 0.758).

**7. DILI:** Ligand A (52.074) has a better DILI score than Ligand B (70.686), indicating a lower risk of liver injury.

**8. BBB:** Ligand A (69.911) has a better BBB score than Ligand B (54.517). While both are not ideal (>70), A is closer to the desired threshold for a CNS target.

**9. Caco-2 Permeability:** Both have negative values (-5.053 and -5.049), which is unusual and difficult to interpret without further context. However, we can assume they are both similarly poor in Caco-2 permeability.

**10. Aqueous Solubility:** Ligand A (-0.852) has a slightly better solubility score than Ligand B (-2.9).

**11. hERG Inhibition:** Ligand A (0.049) has a much lower hERG inhibition risk than Ligand B (0.203). This is a significant advantage for A.

**12. Microsomal Clearance:** Ligand A (18.949) has a lower microsomal clearance than Ligand B (66.417), suggesting better metabolic stability.

**13. In vitro Half-Life:** Ligand A (-7.761) has a much longer in vitro half-life than Ligand B (-22.619).

**14. P-gp Efflux:** Ligand A (0.011) has a much lower P-gp efflux liability than Ligand B (0.14). This is crucial for CNS penetration.

**15. Binding Affinity:** Both ligands have the same binding affinity (-7.8 kcal/mol), which is excellent.

**Overall Assessment:**

While Ligand B has a better logP, Ligand A excels in almost all other critical ADME properties, especially those prioritized for GPCRs targeting the CNS. Ligand A has a better BBB score, significantly lower DILI, hERG, P-gp efflux, and microsomal clearance, and a longer half-life. The lower logP of Ligand A is a concern, but the substantial advantages in other properties, particularly BBB and P-gp efflux, outweigh this drawback. The similar binding affinities make the ADME profile the deciding factor.

Output:
0
2025-04-17 03:16:32,695 - INFO - Reasoning:

Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (343.431 and 372.491 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (71.33) is excellent, well below the 90 A^2 threshold for CNS targets. Ligand B (90.03) is borderline, but still acceptable.

**3. logP:** Ligand A (1.153) is within the optimal 1-3 range. Ligand B (-0.921) is slightly below 1, which *could* indicate permeability issues, but isn't a dealbreaker.

**4. H-Bond Donors:** Both have acceptable HBD counts (0 for A, 1 for B), well under the 5 limit.

**5. H-Bond Acceptors:** Both have 5 HBAs, within the acceptable limit of 10.

**6. QED:** Both ligands have good QED scores (0.772 and 0.651), indicating drug-like properties.

**7. DILI:** Ligand A (42.458) has a slightly higher DILI risk than Ligand B (24.04), but both are below the concerning threshold of 60.

**8. BBB:** This is a critical parameter for a CNS target like DRD2. Ligand A (91.392) has a *very* good BBB percentile, exceeding the desirable >70. Ligand B (56.301) is significantly lower, indicating poorer brain penetration.

**9. Caco-2:** Ligand A (-4.767) and Ligand B (-5.239) are both negative, which is unusual and suggests very poor Caco-2 permeability. This is a concern for oral bioavailability, but less critical for a CNS target where direct delivery or other routes might be considered.

**10. Solubility:** Both ligands have poor aqueous solubility (-1.772 and -1.162). This could pose formulation challenges.

**11. hERG:** Both ligands have very low hERG risk (0.374 and 0.07).

**12. Cl_mic:** Ligand A (43.275) has a higher microsomal clearance than Ligand B (14.74), indicating lower metabolic stability.

**13. t1/2:** Ligand B (-27.149) has a much longer in vitro half-life than Ligand A (-8.113), which is a significant advantage.

**14. Pgp:** Both ligands have very low P-gp efflux liability (0.124 and 0.003).

**15. Binding Affinity:** Ligand A (-8.7 kcal/mol) has a slightly stronger binding affinity than Ligand B (-7.2 kcal/mol). This is a 1.5 kcal/mol difference, which is significant.

**Overall Assessment:**

Ligand A excels in BBB penetration and binding affinity, which are paramount for a CNS GPCR target. However, it suffers from higher metabolic clearance and poorer solubility. Ligand B has a better metabolic profile (longer half-life, lower clearance) and lower DILI risk, but its BBB penetration is significantly worse.

Given the importance of CNS penetration for DRD2, and the substantial difference in BBB scores, the stronger affinity of Ligand A, combined with its acceptable (though not ideal) other properties, makes it the more promising candidate. While the solubility and metabolic stability are concerns, these can potentially be addressed through formulation strategies or further chemical modifications. The poor BBB of Ligand B is a more difficult hurdle to overcome.

Output:
1
2025-04-17 03:16:32,696 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (350.47 and 351.49 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (92.62) is slightly above the optimal <90 for CNS targets, but still reasonable. Ligand B (53.09) is excellent, well below 90.

**logP:** Ligand A (1.726) is within the optimal 1-3 range. Ligand B (0.916) is a bit low, potentially impacting permeability.

**H-Bond Donors/Acceptors:** Both ligands have 0 HBD and 4 HBA, which are acceptable values.

**QED:** Ligand B (0.759) has a better QED score than Ligand A (0.379), indicating a more drug-like profile.

**DILI:** Both ligands have low DILI risk (Ligand A: 26.44, Ligand B: 19.58), which is good.

**BBB:** Ligand A (77.63) has a significantly better BBB percentile than Ligand B (44.98). This is a crucial factor for a CNS target like DRD2.

**Caco-2 Permeability:** Ligand A (-4.721) and Ligand B (-4.41) both have negative Caco-2 values, which is unusual and suggests poor permeability. However, the scale isn't clearly defined, so it's difficult to interpret without further context.

**Aqueous Solubility:** Both ligands have very poor aqueous solubility (-0.581 and -0.782). This is a significant drawback.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.361 and 0.406).

**Microsomal Clearance:** Ligand B (17.45) has lower microsomal clearance than Ligand A (56.29), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand B (-8.098) has a longer in vitro half-life than Ligand A (-25.633), which is desirable.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.03 and 0.053), which is favorable for CNS penetration.

**Binding Affinity:** Ligand B (-9.1 kcal/mol) has a significantly stronger binding affinity than Ligand A (-7.2 kcal/mol). This >1.5 kcal/mol difference is substantial and can outweigh some ADME drawbacks.

**Overall Assessment:**

While Ligand A has a better BBB score, Ligand B excels in almost every other critical parameter: significantly higher binding affinity, better QED, lower microsomal clearance, longer half-life, and comparable safety profiles (DILI, hERG). The slightly lower BBB score for Ligand B is a concern, but the substantial affinity advantage and improved ADME properties are likely to compensate. The poor solubility of both is a major concern that would need to be addressed through formulation strategies. However, given the choice between the two, the stronger binding and better overall ADME profile of Ligand B make it the more promising candidate.

Output:
1
2025-04-17 03:16:32,696 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B based on the provided guidelines, prioritizing GPCR-specific properties (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (340.427 and 369.481 Da) fall within the ideal range of 200-500 Da.

**TPSA:** Ligand A (65.54) is slightly above the optimal <90 for CNS targets, but still reasonable. Ligand B (56.99) is excellent, well below 90.

**logP:** Ligand A (1.522) is within the optimal 1-3 range. Ligand B (4.265) is at the upper end of acceptable, potentially raising concerns about solubility and off-target effects, but not disqualifying.

**H-Bond Donors/Acceptors:** Ligand A (1 HBD, 4 HBA) and Ligand B (0 HBD, 4 HBA) both have acceptable numbers of H-bond donors and acceptors.

**QED:** Both ligands have good QED scores (0.63 and 0.721), indicating drug-like properties.

**DILI:** Both ligands have similar, low DILI risk (32.105 and 32.842 percentile).

**BBB:** This is a critical parameter for CNS targets. Ligand B (89.608%) has a significantly higher BBB penetration score than Ligand A (56.456%). This is a major advantage for Ligand B.

**Caco-2 Permeability:** Ligand A (-4.754) has poor Caco-2 permeability, indicating poor intestinal absorption. Ligand B (-4.376) is also poor, but slightly better than A.

**Aqueous Solubility:** Ligand A (-1.833) has slightly better aqueous solubility than Ligand B (-4.809). However, solubility is less critical than BBB for a CNS target.

**hERG Inhibition:** Ligand A (0.245) has a lower hERG risk than Ligand B (0.678), which is favorable.

**Microsomal Clearance:** Ligand A (20.717 mL/min/kg) has a lower microsomal clearance, suggesting better metabolic stability, than Ligand B (69.909 mL/min/kg).

**In vitro Half-Life:** Ligand A (5.872 hours) has a shorter half-life than Ligand B (-12.859 hours - a negative value suggests a very long half-life).

**P-gp Efflux:** Ligand A (0.022) has much lower P-gp efflux liability than Ligand B (0.296), which is highly desirable for CNS penetration.

**Binding Affinity:** Ligand B (-7.2 kcal/mol) has a slightly better binding affinity than Ligand A (-8.0 kcal/mol). While A is better, the difference is not substantial enough to outweigh the other factors.

**Overall Assessment:**

Ligand B excels in BBB penetration, a crucial factor for a DRD2 (CNS target) ligand. While it has a higher logP and P-gp efflux, the significant advantage in BBB outweighs these drawbacks. Ligand A has better metabolic stability and lower P-gp efflux, but its poor BBB penetration and Caco-2 permeability are significant liabilities. The slightly better binding affinity of A is not enough to compensate for its poor CNS exposure potential.

Output:
1
2025-04-17 03:16:32,696 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (346.435 Da) is slightly lower, which could be beneficial for permeability. Ligand B (364.486 Da) is also good.

**TPSA:** Ligand A (106.14) is better than Ligand B (42.43) for CNS penetration, being closer to the ideal <90 A^2 for CNS targets. Ligand B is significantly higher, which could hinder BBB penetration.

**logP:** Ligand A (0.856) is a bit low, potentially impacting permeability. Ligand B (3.503) is closer to the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A has 2 HBD and 6 HBA, which are acceptable. Ligand B has 0 HBD and 4 HBA, also acceptable.

**QED:** Both ligands have good QED scores (A: 0.645, B: 0.725), indicating good drug-like properties.

**DILI:** Ligand A (34.277) has a lower DILI risk than Ligand B (49.399), which is preferable.

**BBB:** Ligand B (87.515) has a significantly higher BBB percentile than Ligand A (72.586). This is a crucial advantage for a CNS target like DRD2.

**Caco-2 Permeability:** Ligand A (-5.612) has poor Caco-2 permeability, while Ligand B (-4.121) is better, but still not great.

**Aqueous Solubility:** Both ligands have very poor aqueous solubility (-2.239 and -4.941 respectively). This could pose formulation challenges.

**hERG:** Ligand A (0.101) has a lower hERG risk than Ligand B (0.55), which is preferable.

**Microsomal Clearance:** Ligand B (113.513) has a much higher microsomal clearance than Ligand A (19.69), suggesting lower metabolic stability.

**In vitro Half-Life:** Ligand A (-13.484) has a much longer in vitro half-life than Ligand B (-26.949), indicating better stability.

**P-gp Efflux:** Ligand A (0.014) has very low P-gp efflux, which is good for CNS penetration. Ligand B (0.184) has slightly higher efflux, but still relatively low.

**Binding Affinity:** Both ligands have similar and good binding affinities (-7.9 kcal/mol and -6.9 kcal/mol respectively). Ligand A is slightly better, but the difference is not substantial enough to outweigh other factors.

**Overall Assessment:**

Ligand A has better TPSA, DILI, hERG, metabolic stability (lower Cl_mic and longer t1/2), and P-gp efflux. However, Ligand B has a significantly better BBB percentile and a more optimal logP. The poor Caco-2 permeability of both is a concern, but for a CNS target, BBB is paramount. The higher BBB of Ligand B, combined with acceptable logP, makes it more likely to reach the target in the brain, despite its other drawbacks. The difference in binding affinity is not large enough to overcome the better CNS penetration profile of Ligand B.

Output:
1
2025-04-17 03:16:32,696 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B based on the provided guidelines, prioritizing GPCR-specific properties (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (352.381 and 371.591 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (58.64) is significantly better than Ligand B (43.86), falling well below the 90 A^2 threshold for CNS targets. Ligand B is still reasonable, but A is preferable.

**logP:** Both ligands have good logP values (2.288 and 2.699), within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A (1 HBD, 3 HBA) is slightly better than Ligand B (0 HBD, 4 HBA) in terms of balancing solubility and permeability.

**QED:** Both ligands have acceptable QED scores (0.849 and 0.592), indicating good drug-like properties. Ligand A is better.

**DILI:** Ligand A (47.421) has a much lower DILI risk than Ligand B (11.09), placing it in the good category (<40 is ideal, <60 is good). This is a significant advantage for A.

**BBB:** Ligand A (95.192) has excellent BBB penetration, exceeding the desirable >70% threshold. Ligand B (83.56) is good, but not as high. This is a crucial factor for a CNS target like DRD2.

**Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual. Assuming these are logP values, they are both poor.

**Aqueous Solubility:** Both have negative solubility values, which is also unusual.

**hERG:** Both ligands show low hERG inhibition liability (0.588 and 0.563), which is good.

**Microsomal Clearance:** Both have similar microsomal clearance values (34.726 and 42.961), suggesting comparable metabolic stability.

**In vitro Half-Life:** Ligand A has a negative half-life (-15.825), which is unusual. Ligand B has a half-life of 12.993 hours, which is a positive.

**P-gp Efflux:** Both ligands show low P-gp efflux liability (0.332 and 0.082), which is favorable for CNS penetration. Ligand B is better.

**Binding Affinity:** Ligand A (-8.6 kcal/mol) has a significantly stronger binding affinity than Ligand B (-7.2 kcal/mol). This 1.4 kcal/mol difference is substantial and can outweigh minor ADME drawbacks.

**Overall Assessment:**

Ligand A is the stronger candidate. While Ligand B has a better P-gp efflux and in vitro half-life, Ligand A excels in critical areas for a CNS-targeting GPCR: TPSA, BBB penetration, DILI risk, and, most importantly, binding affinity. The significantly stronger binding affinity of Ligand A (-8.6 vs -7.2 kcal/mol) is a major advantage. The negative half-life of Ligand A is concerning but could be addressed with structural modifications.

Output:
1
2025-04-17 03:16:32,697 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (370.559 Da and 350.375 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (58.64) is excellent, well below the 90 A^2 threshold for CNS targets. Ligand B (118.58) is higher, but still potentially acceptable, though less ideal.

**3. logP:** Ligand A (2.688) is optimal (1-3). Ligand B (1.184) is on the lower side, potentially hindering permeability.

**4. H-Bond Donors:** Both have 1 HBD, which is good.

**5. H-Bond Acceptors:** Ligand A has 4 HBA, and Ligand B has 6. Both are within the acceptable limit of 10.

**6. QED:** Both ligands have similar QED values (0.634 and 0.629), indicating good drug-likeness.

**7. DILI:** Ligand A (31.563) has a lower DILI risk than Ligand B (49.166), which is preferable.

**8. BBB:** Ligand A (63.125) has a better BBB penetration percentile than Ligand B (59.364), though both are not ideal (>70 is desired).

**9. Caco-2 Permeability:** Both have negative Caco-2 values (-5.074 and -5.033), which is unusual and suggests poor permeability. This is a significant concern for both.

**10. Aqueous Solubility:** Both have negative solubility values (-3.37 and -2.86), which is also concerning, indicating very poor solubility.

**11. hERG Inhibition:** Ligand A (0.613) has a slightly higher hERG risk than Ligand B (0.107), which is less desirable.

**12. Microsomal Clearance:** Ligand A (79.999) has a higher microsomal clearance than Ligand B (8.985), indicating lower metabolic stability.

**13. In vitro Half-Life:** Ligand B (-4.323) has a negative half-life, which is impossible and indicates a potential data error or very rapid degradation. Ligand A (16.299) has a reasonable half-life.

**14. P-gp Efflux:** Ligand A (0.313) has lower P-gp efflux liability than Ligand B (0.069), which is favorable for CNS penetration.

**15. Binding Affinity:** Ligand B (-8.5 kcal/mol) has a significantly stronger binding affinity than Ligand A (-6.8 kcal/mol). This is a substantial advantage, potentially outweighing some of the ADME drawbacks.

**Overall Assessment:**

Ligand B has a much stronger binding affinity, which is the most critical factor for GPCRs. However, it suffers from low logP, poor solubility, and a questionable half-life. Ligand A has better ADME properties overall (better BBB, lower DILI, better P-gp efflux, reasonable half-life), but its affinity is weaker. The negative Caco-2 and solubility values for both are major red flags.

Despite the ADME concerns, the significantly stronger binding affinity of Ligand B is a decisive factor, especially considering it's a GPCR target. Optimization efforts could focus on improving its solubility and permeability. The negative half-life for Ligand B is a data quality concern that would need to be investigated.

Output:
1
2025-04-17 03:16:32,697 - INFO - Batch 15 complete. Total preferences: 240
2025-04-17 03:16:32,697 - INFO - Processing batch 16/512...
2025-04-17 03:17:15,517 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (323.4) is slightly lower, which could be beneficial for permeability, but both are acceptable.

**TPSA:** Ligand A (50.94) is better than Ligand B (58.64). For CNS targets, we want TPSA <= 90, and ideally lower. Ligand A is closer to the ideal range.

**logP:** Ligand A (4.999) is high, potentially causing solubility issues or off-target interactions. Ligand B (2.657) is much better, falling within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Both have acceptable HBD/HBA counts. Ligand A has 2/3, and Ligand B has 1/3.

**QED:** Both ligands have good QED scores (A: 0.51, B: 0.751), indicating drug-like properties. Ligand B is slightly better.

**DILI:** Ligand A (85.653) has a significantly higher DILI risk than Ligand B (18.418). This is a major concern for Ligand A.

**BBB:** Ligand B (71.772) has a much better BBB penetration score than Ligand A (52.811). Given that DRD2 is a CNS target, this is a critical advantage for Ligand B.

**Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and suggests poor permeability. However, the scale is not specified, making direct comparison difficult.

**Aqueous Solubility:** Both have negative solubility values, indicating poor solubility. Again, the scale is unspecified.

**hERG:** Ligand A (0.93) has a slightly higher hERG risk than Ligand B (0.323), but both are relatively low.

**Microsomal Clearance:** Ligand B (45.791) has a lower microsomal clearance than Ligand A (14.484), indicating better metabolic stability.

**In vitro Half-Life:** Ligand B (7.453) has a longer half-life than Ligand A (32.518).

**P-gp Efflux:** Ligand A (0.668) has a lower P-gp efflux liability than Ligand B (0.126), which is favorable for CNS penetration.

**Binding Affinity:** Ligand B (-8.1 kcal/mol) has a significantly stronger binding affinity than Ligand A (-10.8 kcal/mol). This is a substantial advantage.

**Overall Assessment:**

Ligand B is clearly the superior candidate. While both have issues with Caco-2 and solubility, Ligand B excels in the most critical areas for a CNS-targeting GPCR ligand: BBB penetration, metabolic stability, binding affinity, and DILI risk. Ligand A's high DILI risk and lower BBB penetration are significant drawbacks. The stronger binding affinity of Ligand B also outweighs the slightly higher P-gp efflux and the higher logP.

Output:
1
2025-04-17 03:17:15,518 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B based on the provided guidelines, prioritizing GPCR-specific properties (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (344.499 and 345.451 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (49.41) is excellent for CNS penetration (<90), while Ligand B (104.54) is higher, but still potentially acceptable.

**logP:** Ligand A (3.444) is optimal (1-3). Ligand B (1.442) is on the lower end, which *could* hinder permeability, but isn't a dealbreaker.

**H-Bond Donors/Acceptors:** Ligand A (1 HBD, 2 HBA) is favorable. Ligand B (3 HBD, 7 HBA) is slightly higher, but within reasonable limits.

**QED:** Both ligands (0.777 and 0.701) have good drug-likeness scores (>0.5).

**DILI:** Ligand A (22.722) has a much lower DILI risk than Ligand B (32.881), indicating better predicted liver safety.

**BBB:** This is critical for a CNS target like DRD2. Ligand A (73.711) is good, exceeding the 70% threshold. Ligand B (30.438) is significantly lower, suggesting poor brain penetration.

**Caco-2 Permeability:** Ligand A (-4.891) and Ligand B (-5.953) both have negative values, which is unusual. Assuming these are percentile scores, lower values indicate poor permeability. However, the difference isn't huge.

**Aqueous Solubility:** Ligand A (-3.669) and Ligand B (-1.224) both have negative values. Again, assuming these are percentile scores, lower values indicate poor solubility. Ligand B is better here.

**hERG Inhibition:** Ligand A (0.505) has a slightly higher hERG risk than Ligand B (0.168), but both are relatively low.

**Microsomal Clearance:** Ligand A (54.931) has higher clearance, meaning faster metabolism, than Ligand B (-31.624, a negative value suggesting very slow clearance).

**In vitro Half-Life:** Ligand A (-13.812) has a shorter half-life than Ligand B (1.437).

**P-gp Efflux:** Ligand A (0.351) has lower P-gp efflux, which is favorable for CNS penetration, compared to Ligand B (0.124).

**Binding Affinity:** Ligand B (-7.6 kcal/mol) has a significantly stronger binding affinity than Ligand A (-0.0 kcal/mol). This is a *major* advantage.

**Overall Assessment:**

Ligand B's significantly stronger binding affinity (-7.6 vs -0.0 kcal/mol) is a huge positive. While Ligand A has better BBB penetration and lower DILI risk, the difference in affinity is likely to outweigh these factors, especially given that optimizing BBB penetration and reducing DILI risk are often possible in later stages of drug development. Ligand B's lower logP and Caco-2 permeability are concerns, but the strong binding affinity suggests it's worth pursuing.

Output:
1
2025-04-17 03:17:15,518 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (344.423 Da) is slightly lower, which could be beneficial for permeability, but both are acceptable.

**TPSA:** Ligand A (118.01) is closer to the ideal range for CNS targets (<=90), but still slightly above. Ligand B (56.67) is excellent, well within the desired range. This is a significant advantage for Ligand B.

**logP:** Ligand A (0.36) is quite low, potentially hindering membrane permeability. Ligand B (2.594) is within the optimal range (1-3). This is a clear advantage for Ligand B.

**H-Bond Donors/Acceptors:** Ligand A has 3 HBD and 9 HBA, which are acceptable. Ligand B has 1 HBD and 5 HBA, also acceptable.

**QED:** Both ligands have good QED scores (A: 0.687, B: 0.785), indicating good drug-like properties.

**DILI:** Ligand A (58.705) has a higher DILI risk than Ligand B (18.883). This is a negative for Ligand A.

**BBB:** Ligand B (77.976) has a significantly better BBB penetration score than Ligand A (58.123). This is crucial for a CNS target like DRD2 and a major advantage for Ligand B.

**Caco-2 Permeability:** Ligand A (-5.639) has poor Caco-2 permeability. Ligand B (-4.804) is also poor, but slightly better than A.

**Aqueous Solubility:** Both ligands have poor aqueous solubility (-2.161 and -2.669, respectively). This could pose formulation challenges, but isn't a deciding factor.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (A: 0.458, B: 0.637).

**Microsomal Clearance:** Ligand A (16.42) has lower microsomal clearance than Ligand B (58.933), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand B (38.389) has a significantly longer in vitro half-life than Ligand A (2.819). This is a positive for Ligand B.

**P-gp Efflux:** Ligand A (0.008) shows very low P-gp efflux, which is excellent. Ligand B (0.34) has moderate P-gp efflux. This is a clear advantage for Ligand A.

**Binding Affinity:** Ligand A (-8.7 kcal/mol) has a stronger binding affinity than Ligand B (-7.0 kcal/mol). This is a substantial advantage for Ligand A, potentially outweighing some of its ADME drawbacks.

**Overall Assessment:**

While Ligand A boasts superior binding affinity and lower P-gp efflux, Ligand B excels in critical ADME properties for a CNS GPCR target. Specifically, its significantly better TPSA, logP, BBB penetration, and longer half-life are highly favorable. The lower DILI risk is also a significant benefit. The affinity difference, while substantial, might be overcome with further optimization of Ligand B. The poor Caco-2 permeability of both is a concern, but less critical for a CNS target where direct oral bioavailability isn't the primary route of administration.

Considering the GPCR-specific priorities and the overall balance of properties, Ligand B is the more promising drug candidate.

Output:
1
2025-04-17 03:17:15,518 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (340.442 and 347.375 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (33.29) is excellent, well below the 90 A^2 threshold for CNS targets. Ligand B (127.42) is higher, but still potentially acceptable, though less ideal.

**3. logP:** Ligand A (4.349) is slightly high, potentially leading to solubility issues or off-target interactions. Ligand B (-1.363) is significantly low, which could hinder membrane permeability and CNS penetration.

**4. H-Bond Donors:** Ligand A (2) and Ligand B (4) both fall within the acceptable limit of <=5.

**5. H-Bond Acceptors:** Ligand A (3) and Ligand B (5) both fall within the acceptable limit of <=10.

**6. QED:** Ligand A (0.82) is very good, indicating high drug-likeness. Ligand B (0.489) is below the 0.5 threshold, suggesting a less favorable drug-like profile.

**7. DILI:** Ligand A (39.86) has a low DILI risk. Ligand B (47.964) is slightly higher, but still within an acceptable range.

**8. BBB:** Ligand A (78.247) has a good BBB percentile, desirable for a CNS target. Ligand B (23.071) has a very low BBB percentile, a major drawback for DRD2 targeting.

**9. Caco-2:** Both ligands have negative Caco-2 values (-5.109 and -5.893), which is unusual and suggests poor permeability. These values are likely errors or indicate very poor absorption.

**10. Solubility:** Both ligands have negative solubility values (-3.575 and -2.52). These values are also unusual and suggest very poor aqueous solubility.

**11. hERG:** Ligand A (0.946) has a low hERG risk. Ligand B (0.068) also has a low hERG risk.

**12. Cl_mic:** Ligand A (35.423) has a moderate microsomal clearance. Ligand B (-20.985) has a negative clearance, which is not physically possible and likely represents an error in the data.

**13. t1/2:** Ligand A (16.149) has a reasonable in vitro half-life. Ligand B (-5.49) has a negative half-life, which is impossible and indicates a data error.

**14. Pgp:** Ligand A (0.687) has moderate P-gp efflux. Ligand B (0.004) has very low P-gp efflux, which is favorable for CNS penetration.

**15. Binding Affinity:** Ligand A (-9.7 kcal/mol) has significantly stronger binding affinity than Ligand B (-8.4 kcal/mol). This is a substantial difference.

**Overall Assessment:**

Despite the unusual negative values for Caco-2, solubility, and clearance/half-life for both compounds, Ligand A is the more promising candidate. It has a much better BBB score, a higher QED, and significantly stronger binding affinity. While its logP is slightly high, the strong affinity and good BBB penetration outweigh this concern. The negative values for B are highly suspect and make it a less viable option. The negative values for B suggest data quality issues, while A's profile, even with the questionable Caco-2/solubility, is more reasonable.

Output:
0
2025-04-17 03:17:15,518 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (343.427 and 348.407 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (65.72) is significantly better than Ligand B (104.45). For CNS targets, we want TPSA <= 90, and A is comfortably within this range, while B exceeds it.

**logP:** Ligand A (3.548) is optimal (1-3). Ligand B (-0.829) is too low, potentially hindering permeation.

**H-Bond Donors/Acceptors:** Ligand A (0 HBD, 6 HBA) and Ligand B (1 HBD, 7 HBA) both are within acceptable ranges.

**QED:** Both ligands have reasonable QED scores (0.798 and 0.673), indicating good drug-like properties.

**DILI:** Ligand A (60.915) is higher risk than Ligand B (39.279), but both are reasonably acceptable.

**BBB:** Ligand A (78.751) has a much better BBB percentile than Ligand B (27.646). This is *critical* for a CNS target like DRD2.

**Caco-2 Permeability:** Both have negative Caco-2 values which is unusual and suggests a problem with the model or data.

**Aqueous Solubility:** Both have negative solubility values which is unusual and suggests a problem with the model or data.

**hERG:** Both ligands have very low hERG inhibition liability (0.378 and 0.03), which is excellent.

**Microsomal Clearance:** Ligand A (97.175) has higher clearance than Ligand B (9.534), suggesting lower metabolic stability.

**In vitro Half-Life:** Ligand B (-17.125) has a much longer half-life than Ligand A (-9.33).

**P-gp Efflux:** Ligand A (0.512) has higher P-gp efflux liability than Ligand B (0.02), which is undesirable for CNS penetration.

**Binding Affinity:** Ligand B (-7.8 kcal/mol) has significantly stronger binding affinity than Ligand A (-0.0 kcal/mol). This is a substantial advantage.

**Overall Assessment:**

Ligand B has a much stronger binding affinity, a longer half-life, lower P-gp efflux, and lower DILI risk. However, it suffers from a low logP and a TPSA above the ideal range. Ligand A has a better TPSA and logP, better BBB penetration, but significantly weaker binding affinity and higher P-gp efflux.

Given the GPCR-specific priorities, *affinity is paramount*. The 1.8 kcal/mol difference in binding affinity is substantial enough to outweigh the drawbacks of Ligand B's logP and TPSA. While the low logP of Ligand B is a concern, it could potentially be addressed through structural modifications. The significantly improved binding affinity and CNS penetration potential (lower P-gp, better half-life) make Ligand B the more promising candidate.

Output:
1
2025-04-17 03:17:15,519 - INFO - Reasoning:

Let's analyze Ligand A and Ligand B against the provided guidelines, with a strong emphasis on GPCR-specific properties (BBB, logP, Pgp, TPSA, and affinity) for DRD2.

**Molecular Weight:** Both ligands (350.5 and 361.5 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (58.44) is significantly better than Ligand B (62.3), both are below the 90 A^2 threshold for CNS targets, but A is closer to the ideal.

**logP:** Both ligands have good logP values (2.425 and 3.191), falling within the optimal 1-3 range. Ligand B is slightly higher, which could potentially lead to some off-target effects, but it's not a major concern.

**H-Bond Donors/Acceptors:** Ligand A (0 HBD, 4 HBA) and Ligand B (1 HBD, 4 HBA) are both within acceptable limits (<=5 HBD and <=10 HBA).

**QED:** Both ligands have good QED scores (0.723 and 0.818), indicating good drug-like properties.

**DILI:** Ligand A (29.042) has a much lower DILI risk than Ligand B (57.348). This is a significant advantage for Ligand A.

**BBB:** Ligand A (64.986) has a slightly better BBB penetration percentile than Ligand B (60.062), though both are reasonably good. However, for a CNS target like DRD2, higher is better.

**Caco-2 Permeability:** Ligand A (-4.519) has a worse Caco-2 permeability than Ligand B (-5.045). Lower values indicate poorer permeability.

**Aqueous Solubility:** Ligand A (-1.915) has better aqueous solubility than Ligand B (-3.91).

**hERG:** Both ligands have similar, low hERG inhibition liability (0.312 and 0.349).

**Microsomal Clearance:** Ligand A (73.597) has higher microsomal clearance than Ligand B (66.473), indicating lower metabolic stability.

**In vitro Half-Life:** Ligand B (-3.874) has a significantly longer in vitro half-life than Ligand A (33.856), which is a major advantage.

**P-gp Efflux:** Both ligands have similar P-gp efflux liability (0.127 and 0.185).

**Binding Affinity:** Ligand B (-7.9 kcal/mol) has a slightly better binding affinity than Ligand A (-7.6 kcal/mol). While the difference is not huge, it is above the 1.5 kcal/mol threshold where it can outweigh other drawbacks.

**Overall Assessment:**

Ligand A excels in DILI risk, TPSA, solubility, and has a reasonable BBB score. However, it suffers from poorer Caco-2 permeability, higher metabolic clearance, and a shorter half-life.

Ligand B has slightly worse TPSA and solubility, but boasts a better binding affinity, a significantly longer half-life, and a lower DILI risk. The slightly better binding affinity and substantially improved metabolic stability are crucial for a GPCR target.

Considering the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity), and the overall balance of properties, Ligand B appears to be the more promising drug candidate. The improved affinity and metabolic stability are particularly important.

Output:
1
2025-04-17 03:17:15,519 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (349.475 Da) is slightly lower, which is generally favorable for permeability. Ligand B (386.901 Da) is also acceptable.

**TPSA:** Ligand A (78.51) is excellent, well below the 90 A^2 threshold for CNS targets. Ligand B (92.34) is still reasonably good, but less optimal than A.

**logP:** Both ligands have good logP values (A: 1.612, B: 1.471), falling within the 1-3 range.

**H-Bond Donors/Acceptors:** Both ligands have acceptable HBD (2) and HBA (A: 3, B: 4) counts, staying within the recommended limits.

**QED:** Both ligands have good QED scores (A: 0.565, B: 0.742), indicating good drug-like properties. Ligand B is slightly better here.

**DILI:** Ligand A (22.063) has a significantly lower DILI risk than Ligand B (65.491). This is a major advantage for Ligand A.

**BBB:** Ligand A (70.26) has a good BBB penetration score, exceeding the 70% threshold for CNS targets. Ligand B (43.001) is considerably lower and less desirable for a CNS-targeting drug.

**Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and suggests issues with the prediction method or the molecules themselves. However, the magnitude of the negative value is important. Ligand A (-5.022) is less negative than Ligand B (-5.516), suggesting slightly better permeability.

**Aqueous Solubility:** Both have negative solubility values, again indicating a potential issue with the prediction. Ligand A (-2.226) is slightly better than Ligand B (-2.823).

**hERG Inhibition:** Both ligands have very low hERG inhibition risk (A: 0.199, B: 0.102).

**Microsomal Clearance:** Ligand A (20.901) has a lower microsomal clearance than Ligand B (-9.323), indicating better metabolic stability.

**In vitro Half-Life:** Ligand A (-2.824) has a negative half-life, which is not physically possible and suggests a problem with the prediction. Ligand B (40.177) has a reasonable half-life.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (A: 0.046, B: 0.114).

**Binding Affinity:** Ligand B (-9.2 kcal/mol) has a significantly stronger binding affinity than Ligand A (0.0 kcal/mol). This is a substantial advantage for Ligand B.

**Overall Assessment:**

Ligand B has a much stronger binding affinity, which is a critical factor for GPCR ligands. However, it suffers from a higher DILI risk, significantly lower BBB penetration, and a more problematic in vitro half-life prediction. Ligand A has a better safety profile (lower DILI), better BBB penetration, and better metabolic stability. While its binding affinity is poor, the other favorable properties make it a more promising starting point for optimization. Given the importance of CNS penetration for DRD2, and the relatively large difference in BBB scores, Ligand A is the more viable candidate *at this stage*. Further optimization of Ligand A to improve its binding affinity would be a priority.

Output:
0
2025-04-17 03:17:15,519 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (343.391 Da) is slightly lower, which could be beneficial for permeability. Ligand B (360.498 Da) is also acceptable.

**TPSA:** Ligand A (111.19) is very good, being below the 140 threshold and closer to the desirable <90 for CNS targets. Ligand B (23.55) is excellent, well below the CNS target threshold.

**logP:** Ligand A (0.879) is a bit low, potentially hindering permeation. Ligand B (4.174) is higher, approaching the upper limit where solubility issues might arise, but still within an acceptable range.

**H-Bond Donors/Acceptors:** Ligand A has 2 HBD and 8 HBA, which is reasonable. Ligand B has 0 HBD and 3 HBA, also acceptable.

**QED:** Both ligands have reasonable QED values (A: 0.832, B: 0.706), indicating good drug-like properties.

**DILI:** Ligand A (70.88) has a higher DILI risk than Ligand B (57.348), but both are below the concerning 60 threshold.

**BBB:** This is crucial for a CNS target. Ligand B (81.698) has a significantly higher BBB penetration percentile than Ligand A (58.782). This is a major advantage for Ligand B.

**Caco-2 Permeability:** Ligand A (-5.352) has poor Caco-2 permeability, while Ligand B (-4.745) is slightly better, but still low.

**Aqueous Solubility:** Both have negative solubility values, which is unusual and suggests poor aqueous solubility. Ligand A (-2.492) is slightly better than Ligand B (-4.375).

**hERG Inhibition:** Both ligands have low hERG inhibition risk (A: 0.331, B: 0.95).

**Microsomal Clearance:** Ligand A (-21.004) has much lower (better) microsomal clearance than Ligand B (121.38), indicating greater metabolic stability.

**In vitro Half-Life:** Ligand A (-16.324) has a longer half-life than Ligand B (33.896).

**P-gp Efflux:** Ligand A (0.015) shows very low P-gp efflux, which is excellent for CNS penetration. Ligand B (0.728) has moderate P-gp efflux.

**Binding Affinity:** Both ligands have strong binding affinities (A: -9.2 kcal/mol, B: -8.2 kcal/mol). Ligand A is slightly better (-9.2 vs -8.2). However, the difference is less than 1.5 kcal/mol, so it's not decisive.

**Overall Assessment:**

Ligand B excels in BBB penetration and has a lower DILI risk. While its Caco-2 permeability and solubility are poor, its strong BBB penetration mitigates some of those concerns for a CNS target. Ligand A has better metabolic stability (lower Cl_mic, longer half-life) and slightly better affinity, but its significantly lower BBB penetration is a major drawback for DRD2. Given the GPCR-specific priorities, particularly BBB for CNS targets, Ligand B is the more promising candidate.

Output:
1
2025-04-17 03:17:15,519 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B against the provided guidelines, keeping in mind DRD2 is a CNS-relevant GPCR.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (345.4) is slightly lower, which could be beneficial for permeability, but both are acceptable.

**TPSA:** Ligand A (111.55) is borderline for CNS targets (<=90 is preferred) but still reasonable. Ligand B (40.62) is excellent, well below the 90 threshold, indicating better potential for brain penetration.

**logP:** Ligand A (0.881) is a bit low, potentially hindering permeation. Ligand B (3.548) is within the optimal range (1-3).

**H-Bond Donors/Acceptors:** Ligand A has 4 HBD and 5 HBA, acceptable. Ligand B has 0 HBD and 3 HBA, also acceptable and potentially beneficial for permeability.

**QED:** Both ligands have good QED scores (A: 0.605, B: 0.764), indicating drug-like properties.

**DILI:** Ligand A (50.989) has a moderate DILI risk. Ligand B (22.334) has a much lower and preferable DILI risk.

**BBB:** This is critical for a CNS target. Ligand A (25.32) has very poor predicted BBB penetration. Ligand B (82.474) has excellent predicted BBB penetration, exceeding the desirable >70 threshold.

**Caco-2 Permeability:** Ligand A (-5.315) shows poor permeability. Ligand B (-4.874) is also poor, but slightly better than A.

**Aqueous Solubility:** Both ligands have negative solubility values, which is unusual and indicates very poor solubility. This is a significant concern for both.

**hERG Inhibition:** Ligand A (0.042) has very low hERG risk, which is excellent. Ligand B (0.579) has a slightly higher, but still acceptable, hERG risk.

**Microsomal Clearance:** Ligand A (-8.961) suggests very low clearance and high metabolic stability, which is good. Ligand B (92.352) suggests high clearance and low metabolic stability, a significant drawback.

**In vitro Half-Life:** Ligand A (-29.604) suggests a very long half-life, which is positive. Ligand B (1.383) suggests a very short half-life, which is a concern.

**P-gp Efflux:** Ligand A (0.02) has very low P-gp efflux, which is favorable for CNS penetration. Ligand B (0.348) has a slightly higher P-gp efflux, but still relatively low.

**Binding Affinity:** Ligand B (-7.1) has a significantly stronger binding affinity than Ligand A (-9.4). This 1.3 kcal/mol difference is substantial and can outweigh some ADME drawbacks.

**Overall Assessment:**

While Ligand A has excellent metabolic stability and a very low hERG risk, its poor BBB penetration, low logP, and poor Caco-2 permeability are major liabilities for a CNS target. Ligand B, despite having higher DILI and lower metabolic stability, excels in BBB penetration and has a significantly stronger binding affinity. For a CNS GPCR like DRD2, BBB penetration and affinity are paramount. The stronger binding of Ligand B is also a significant advantage. The solubility issues are concerning for both, but can potentially be addressed with formulation strategies.

Output:
1
2025-04-17 03:17:15,520 - INFO - Reasoning:

Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (353.344 and 363.889 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (63.13) is higher than Ligand B (47.36). For a CNS target like DRD2, TPSA should ideally be <=90. Both are within this limit, but B is significantly better.

**3. logP:** Ligand A (3.132) is within the optimal 1-3 range. Ligand B (4.725) is a bit higher, potentially leading to solubility issues and off-target interactions, but still acceptable.

**4. H-Bond Donors:** Ligand A has 2 HBD, and Ligand B has 0. Both are within the acceptable limit of <=5.

**5. H-Bond Acceptors:** Ligand A has 3 HBA, and Ligand B has 4. Both are within the acceptable limit of <=10.

**6. QED:** Ligand A (0.867) has a better QED score than Ligand B (0.725), indicating a more drug-like profile.

**7. DILI:** Ligand A (64.288) has a slightly higher DILI risk than Ligand B (51.26), but both are reasonably low.

**8. BBB:** Both ligands have very similar BBB penetration (Ligand A: 76.813, Ligand B: 76.774). Both are above the desirable 70% threshold for CNS targets.

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.778 and -4.558). This is unusual and suggests poor permeability. However, these values are on a scale where negative values are possible, and direct comparison is difficult without knowing the scale's specifics.

**10. Aqueous Solubility:** Both ligands have negative solubility values (-3.981 and -4.931). Similar to Caco-2, this suggests poor solubility, but the scale is unknown.

**11. hERG Inhibition:** Ligand A (0.772) has a slightly higher hERG inhibition liability than Ligand B (0.512). Lower is better.

**12. Microsomal Clearance:** Ligand B (74.325) has a significantly higher microsomal clearance than Ligand A (22.051), indicating faster metabolism and lower metabolic stability.

**13. In vitro Half-Life:** Ligand A (47.872) has a longer in vitro half-life than Ligand B (31.275), which is desirable.

**14. P-gp Efflux:** Ligand A (0.431) has lower P-gp efflux liability than Ligand B (0.317). Lower is better for CNS exposure.

**15. Binding Affinity:** Ligand A (-8.2 kcal/mol) has a significantly stronger binding affinity than Ligand B (-7.4 kcal/mol). This is a >1.5 kcal/mol advantage, which can outweigh minor ADME drawbacks.

**Overall Assessment:**

Ligand A is the better candidate. While Ligand B has a slightly better TPSA, Ligand A excels in key areas: significantly stronger binding affinity, better QED, longer half-life, lower P-gp efflux, and lower microsomal clearance. The slightly higher DILI and hERG risks are less concerning given the substantial affinity advantage. Both have issues with predicted permeability and solubility, but the superior binding and pharmacokinetic properties of A make it more likely to succeed.

Output:
1
2025-04-17 03:17:15,520 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight (MW):** Both ligands (363.41 and 355.429 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (83.47) is slightly above the preferred <90 for CNS targets, but still reasonable. Ligand B (52.65) is well within the ideal range.

**3. logP:** Both ligands have good logP values (3.33 and 2.272), falling within the optimal 1-3 range.

**4. H-Bond Donors (HBD):** Both ligands have acceptable HBD counts (2 and 1, respectively), well below the limit of 5.

**5. H-Bond Acceptors (HBA):** Both ligands have acceptable HBA counts (5 and 3, respectively), below the limit of 10.

**6. QED:** Both ligands have good QED scores (0.67 and 0.778), indicating good drug-like properties.

**7. DILI:** Ligand A (62.078) has a moderate DILI risk, while Ligand B (22.489) has a very low DILI risk, which is a significant advantage.

**8. BBB:** Ligand B (75.223) has a significantly better BBB penetration percentile than Ligand A (62.35). This is a crucial factor for a CNS target like DRD2.

**9. Caco-2 Permeability:** Ligand A (-5.032) has poor Caco-2 permeability, while Ligand B (-4.591) is also poor, but slightly better.

**10. Aqueous Solubility:** Ligand A (-3.775) has poor aqueous solubility, and Ligand B (-1.028) has poor aqueous solubility.

**11. hERG Inhibition:** Both ligands have low hERG inhibition risk (0.335 and 0.659).

**12. Microsomal Clearance (Cl_mic):** Ligand A (45.495) has a higher microsomal clearance than Ligand B (18.268), indicating lower metabolic stability.

**13. In vitro Half-Life:** Ligand B (6.758) has a shorter in vitro half-life than Ligand A (53.958).

**14. P-gp Efflux:** Ligand A (0.514) has lower P-gp efflux than Ligand B (0.02), which is favorable for CNS penetration.

**15. Binding Affinity:** Ligand A (-8.8 kcal/mol) has a slightly better binding affinity than Ligand B (-7.9 kcal/mol). The difference is 0.9 kcal/mol, which is not a huge advantage.

**Overall Assessment:**

While Ligand A has slightly better binding affinity and in vitro half-life, Ligand B is significantly better in several critical ADME properties for a CNS-targeting GPCR. Specifically, its much better BBB penetration (75.223 vs 62.35), lower DILI risk (22.489 vs 62.078), and lower microsomal clearance (18.268 vs 45.495) make it a more promising candidate. The difference in binding affinity (0.9 kcal/mol) is unlikely to outweigh these substantial ADME advantages.

Output:
1
2025-04-17 03:17:15,520 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (342.355 and 345.487 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (94.82) is slightly above the optimal <90 for CNS targets, but still reasonable. Ligand B (52.65) is excellent, well below 90, suggesting better CNS penetration potential.

**logP:** Ligand A (0.521) is quite low, potentially hindering membrane permeability. Ligand B (1.485) is better, falling within the 1-3 optimal range.

**H-Bond Donors/Acceptors:** Both have acceptable HBD counts (1). Ligand A has a higher HBA count (7) compared to Ligand B (3), which is preferable.

**QED:** Both ligands have good QED scores (0.814 and 0.786), indicating good drug-like properties.

**DILI:** Ligand A (72.586) has a higher DILI risk than Ligand B (16.673). This is a significant advantage for Ligand B.

**BBB:** Both have reasonable BBB penetration (64.056 and 62.737), but neither exceeds the desirable >70 threshold.

**Caco-2 Permeability:** Both have negative Caco-2 values which is unusual and suggests poor permeability.

**Aqueous Solubility:** Both have negative solubility values, which is also unusual.

**hERG:** Both ligands have low hERG inhibition risk (0.361 and 0.237).

**Microsomal Clearance:** Ligand A (55.953) has a higher microsomal clearance than Ligand B (30.382), indicating lower metabolic stability.

**In vitro Half-Life:** Ligand A (-30.065) has a very short in vitro half-life, while Ligand B (0.688) is better, but still relatively short.

**P-gp Efflux:** Both have low P-gp efflux liability (0.14 and 0.046), which is good for CNS penetration.

**Binding Affinity:** Ligand B (-7.3 kcal/mol) has a significantly stronger binding affinity than Ligand A (-8.8 kcal/mol). This is a crucial advantage, exceeding the 1.5 kcal/mol difference threshold.

**Overall Assessment:**

Ligand B is the stronger candidate. While both have issues with Caco-2 and solubility, Ligand B excels in key areas for a CNS-targeting GPCR ligand: better logP, significantly lower DILI risk, better metabolic stability (lower Cl_mic), and, most importantly, a substantially higher binding affinity. The TPSA is also much more favorable for CNS penetration. Ligand A's low logP and poor half-life are major drawbacks.

Output:
1
2025-04-17 03:17:15,520 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 drug candidates, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (338.407 and 346.471 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Both ligands have a TPSA of 58.64, which is excellent for CNS penetration (well below the 90 A^2 threshold).

**3. logP:** Ligand A (3.519) is optimal, while Ligand B (1.673) is a bit low, potentially hindering membrane permeability.

**4. H-Bond Donors:** Both have 1 HBD, which is acceptable.

**5. H-Bond Acceptors:** Ligand A has 4 HBA, and Ligand B has 3. Both are within the acceptable range (<=10).

**6. QED:** Ligand A (0.848) has a significantly better QED score than Ligand B (0.537), indicating a more drug-like profile.

**7. DILI:** Ligand A (65.452) has a higher DILI risk than Ligand B (6.359). This is a concern for Ligand A.

**8. BBB:** Ligand A (85.459) has a much better BBB penetration percentile than Ligand B (75.378), which is crucial for a CNS target like DRD2.

**9. Caco-2 Permeability:** Ligand A (-4.479) has a worse Caco-2 permeability than Ligand B (-4.676), indicating lower intestinal absorption.

**10. Aqueous Solubility:** Ligand A (-4.867) has worse aqueous solubility than Ligand B (-2.343).

**11. hERG Inhibition:** Ligand A (0.817) has a higher hERG inhibition risk than Ligand B (0.497).

**12. Microsomal Clearance:** Ligand A (86.292) has a higher microsomal clearance than Ligand B (23.983), suggesting lower metabolic stability.

**13. In vitro Half-Life:** Ligand A (17.081) has a longer half-life than Ligand B (0.763).

**14. P-gp Efflux:** Ligand A (0.529) has lower P-gp efflux than Ligand B (0.044), which is favorable for CNS exposure.

**15. Binding Affinity:** Ligand A (-7.9 kcal/mol) has a slightly better binding affinity than Ligand B (-7.7 kcal/mol). While the difference is small, it's still a positive for Ligand A.

**Overall Assessment:**

Ligand A excels in BBB penetration, P-gp efflux, and binding affinity. However, it suffers from higher DILI risk, lower solubility, higher hERG risk, and faster clearance. Ligand B has a better safety profile (lower DILI, hERG) and better metabolic stability, but its lower logP and BBB penetration are significant drawbacks for a CNS target.

Considering the GPCR-specific priorities, the strong BBB penetration of Ligand A is a major advantage. The slight improvement in binding affinity also tips the balance. While the ADME liabilities of Ligand A are concerning, they might be addressable through further optimization. The lower BBB penetration of Ligand B is a more difficult property to improve.

Output:
1
2025-04-17 03:17:15,520 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (338.411 and 346.446 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (69.04) is moderately good, but higher than the ideal <90 for CNS targets. Ligand B (24.94) is excellent, well below the 90 threshold. This favors Ligand B.

**3. logP:** Ligand A (3.527) is at the upper end of the optimal range (1-3), potentially raising concerns about solubility and off-target effects. Ligand B (2.25) is well within the optimal range. This favors Ligand B.

**4. H-Bond Donors:** Ligand A (1) is good. Ligand B (0) is also good, potentially improving membrane permeability.

**5. H-Bond Acceptors:** Ligand A (5) is good. Ligand B (4) is also good.

**6. QED:** Ligand A (0.793) is excellent, indicating good drug-like properties. Ligand B (0.583) is acceptable, but lower than Ligand A. This favors Ligand A.

**7. DILI:** Ligand A (74.409) has a higher DILI risk than Ligand B (12.253). This strongly favors Ligand B.

**8. BBB:** Ligand A (52.385) has a moderate BBB penetration, below the desirable >70 for CNS targets. Ligand B (90.772) has excellent BBB penetration. This is a significant advantage for Ligand B.

**9. Caco-2:** Both ligands have negative Caco-2 values (-4.564 and -4.308), which is unusual and suggests poor permeability. This is a concern for both, but doesn't differentiate them.

**10. Solubility:** Both ligands have negative solubility values (-4.494 and -1.78), also unusual and concerning. Again, this is a shared issue.

**11. hERG:** Both ligands have low hERG inhibition risk (0.848 and 0.987), which is good.

**12. Cl_mic:** Ligand A (80.36) has a higher microsomal clearance, indicating lower metabolic stability. Ligand B (25.461) has much lower clearance, suggesting better metabolic stability. This favors Ligand B.

**13. t1/2:** Ligand A (22.613) has a moderate in vitro half-life. Ligand B (-31.087) has a negative half-life, which is not physically possible and likely indicates an issue with the data or model. This is a major red flag for Ligand B.

**14. Pgp:** Ligand A (0.61) has lower P-gp efflux, which is desirable for CNS exposure. Ligand B (0.57) is similar, but still good.

**15. Binding Affinity:** Ligand A (-9.4 kcal/mol) has a significantly stronger binding affinity than Ligand B (-7.9 kcal/mol). This is a substantial advantage for Ligand A, potentially outweighing some of its ADME drawbacks.

**Overall Assessment:**

Despite Ligand A's higher DILI risk and slightly less optimal logP, its *significantly* stronger binding affinity (-9.4 vs -7.9 kcal/mol) and better QED are compelling. The negative half-life for Ligand B is a critical flaw. While Ligand B excels in BBB penetration and metabolic stability, the binding affinity is insufficient to compensate for the negative half-life. The strong binding of Ligand A suggests it might be more effective at a lower dose, potentially mitigating the DILI risk.

Output:
0
2025-04-17 03:17:15,521 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (386.539 and 375.969 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (92.34) is slightly above the optimal <90 for CNS targets, but still reasonable. Ligand B (19.37) is excellent, well below 90.

**logP:** Ligand A (2.553) is within the optimal 1-3 range. Ligand B (4.77) is a bit high, potentially leading to solubility issues and off-target interactions.

**H-Bond Donors:** Ligand A (2) and Ligand B (0) are both acceptable, below the threshold of 5.

**H-Bond Acceptors:** Both ligands (A: 4, B: 4) are well below the 10 threshold.

**QED:** Both ligands have good QED values (A: 0.682, B: 0.77), indicating drug-like properties.

**DILI:** Ligand A (65.568) has a higher DILI risk than Ligand B (41.877), though both are acceptable.

**BBB:** This is crucial for a CNS target like DRD2. Ligand A (65.529) is moderately good, but Ligand B (92.051) is excellent, exceeding the desirable >70 threshold.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.871 and -4.876), which is unusual and suggests poor permeability. This is a significant concern for both.

**Aqueous Solubility:** Both ligands have negative solubility values (-4.235 and -3.411), indicating very poor aqueous solubility. This is a major drawback.

**hERG Inhibition:** Ligand A (0.479) has a slightly higher hERG risk than Ligand B (0.939), but both are relatively low.

**Microsomal Clearance:** Ligand A (37.321) has higher clearance than Ligand B (24.134), suggesting lower metabolic stability.

**In vitro Half-Life:** Ligand A (51.704) has a longer half-life than Ligand B (16.207), which is preferable.

**P-gp Efflux:** Ligand A (0.229) has lower P-gp efflux than Ligand B (0.593), which is beneficial for CNS penetration.

**Binding Affinity:** Ligand A (-8.3 kcal/mol) has significantly stronger binding affinity than Ligand B (-0.0 kcal/mol). This is a substantial advantage.

**Overall Assessment:**

Despite the poor Caco-2 and solubility values for both, Ligand A is the more promising candidate. The significantly stronger binding affinity (-8.3 vs -0.0 kcal/mol) outweighs the slightly higher DILI and clearance. The better P-gp efflux also contributes to its favorability. Ligand B's high logP and weak binding affinity are major drawbacks. The excellent BBB penetration of Ligand B is appealing, but insufficient to overcome the weak binding.

Output:
1
2025-04-17 03:17:15,521 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (357.439 and 357.485 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (76.53) is higher than the preferred <90 for CNS targets, but still potentially acceptable. Ligand B (29.54) is excellent, well below the threshold.

**3. logP:** Ligand A (2.59) is within the optimal 1-3 range. Ligand B (4.358) is slightly above, which could lead to solubility issues or off-target interactions, but not drastically.

**4. H-Bond Donors:** Both ligands have 0 HBD, which is good.

**5. H-Bond Acceptors:** Ligand A has 7 HBA, acceptable. Ligand B has 2 HBA, also acceptable.

**6. QED:** Both ligands have QED values above 0.6, indicating good drug-likeness.

**7. DILI:** Ligand A (71.152) has a higher DILI risk than Ligand B (19.31). This is a significant negative for Ligand A.

**8. BBB:** Ligand B (96.859) has excellent BBB penetration, exceeding the desirable >70 threshold. Ligand A (73.905) is also good, but not as high. This is a critical advantage for Ligand B given the CNS target.

**9. Caco-2:** Both have negative values which is unusual. Assuming these are percentile scores, Ligand A (-5.012) is very poor, while Ligand B (-4.147) is slightly better but still poor.

**10. Solubility:** Both have negative solubility values, which is also unusual. Ligand A (-2.295) is better than Ligand B (-4.81).

**11. hERG:** Both ligands have low hERG risk.

**12. Cl_mic:** Ligand A (41.054) has a lower microsomal clearance, suggesting better metabolic stability than Ligand B (91.022).

**13. t1/2:** Ligand B (19.1) has a longer in vitro half-life than Ligand A (-15.633). This is a positive for Ligand B.

**14. Pgp:** Both ligands have low Pgp efflux liability.

**15. Binding Affinity:** Ligand B (-7.6 kcal/mol) has significantly stronger binding affinity than Ligand A (-9.0 kcal/mol). This is a substantial advantage for Ligand B.

**Overall Assessment:**

Ligand B is the superior candidate. It boasts excellent BBB penetration, a significantly stronger binding affinity, a lower DILI risk, and a longer half-life. While its logP is slightly elevated and Caco-2/Solubility are poor, the strong affinity and favorable CNS properties outweigh these concerns. Ligand A suffers from a higher DILI risk and weaker binding affinity, despite better metabolic stability. For a CNS GPCR target like DRD2, BBB penetration and potency are paramount, making Ligand B the more promising candidate.

Output:
1
2025-04-17 03:17:15,521 - INFO - Batch 16 complete. Total preferences: 256
2025-04-17 03:17:15,521 - INFO - Processing batch 17/512...
2025-04-17 03:17:55,671 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (351.491 and 358.507 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (64.09) is significantly better than Ligand B (53.43). For CNS targets, we want TPSA <= 90, and lower is preferable. Ligand A is closer to the optimal range.

**3. logP:** Ligand A (0.937) is within the optimal range (1-3), but on the lower side. Ligand B (4.26) is above the optimal range, potentially leading to solubility issues and off-target effects.

**4. H-Bond Donors:** Both ligands have 1 HBD, which is acceptable (<=5).

**5. H-Bond Acceptors:** Both ligands have 4 HBA, which is acceptable (<=10).

**6. QED:** Ligand A (0.804) has a better QED score than Ligand B (0.717), indicating a more drug-like profile. Both are above the 0.5 threshold.

**7. DILI:** Both ligands have relatively low DILI risk (6.359 and 31.563, respectively), both below the 40 threshold.

**8. BBB:** Ligand A (31.214) has a significantly lower BBB percentile than Ligand B (56.65). For a CNS target like DRD2, a BBB > 70 is desirable, but >50 is a good start. Ligand B is much better in this regard.

**9. Caco-2 Permeability:** Ligand A (-4.701) has poor Caco-2 permeability. Ligand B (-5.003) is also poor, but slightly better.

**10. Aqueous Solubility:** Ligand A (-0.903) has slightly better solubility than Ligand B (-3.541).

**11. hERG Inhibition:** Both ligands have low hERG inhibition risk (0.42 and 0.598, respectively).

**12. Microsomal Clearance:** Ligand A (9.502) has lower microsomal clearance than Ligand B (88.07), suggesting better metabolic stability.

**13. In vitro Half-Life:** Ligand A (8.596) has a shorter in vitro half-life than Ligand B (25.674).

**14. P-gp Efflux:** Ligand A (0.067) has much lower P-gp efflux liability than Ligand B (0.667), which is crucial for CNS penetration.

**15. Binding Affinity:** Both ligands have very similar binding affinities (-7.5 and -7.4 kcal/mol). The difference is negligible.

**Overall Assessment:**

Ligand B has a significantly better BBB penetration (56.65 vs 31.214) and a longer half-life (25.674 vs 8.596). These are important for CNS drug development. However, Ligand B has a higher logP (4.26) which could cause solubility issues and higher P-gp efflux (0.667). Ligand A has a better TPSA, QED, metabolic stability, and lower P-gp efflux. Considering the balance, and prioritizing BBB for a CNS target, Ligand B is slightly more promising despite its higher logP, as the affinity is comparable. However, the P-gp efflux is concerning.

Output:
1
2025-04-17 03:17:55,672 - INFO - Reasoning:

Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (369.443 and 344.455 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (117.36) is borderline for CNS penetration, being above the preferred <90. Ligand B (67.43) is excellent, well below 90.

**3. logP:** Ligand A (0.793) is a bit low, potentially hindering membrane permeability. Ligand B (1.614) is better, falling within the optimal 1-3 range.

**4. H-Bond Donors:** Ligand A (3) and Ligand B (2) are both acceptable, below the limit of 5.

**5. H-Bond Acceptors:** Ligand A (6) and Ligand B (3) are both acceptable, below the limit of 10.

**6. QED:** Both ligands have good QED scores (0.524 and 0.72), indicating drug-like properties.

**7. DILI:** Ligand A (77.472) has a higher DILI risk than Ligand B (29.624), which is preferable.

**8. BBB:** This is critical for a CNS target. Ligand A (35.246) has a very low BBB penetration percentile, making it less likely to reach the target. Ligand B (48.74) is still not ideal, but significantly better than Ligand A.

**9. Caco-2:** Both ligands have negative Caco-2 values (-5.206 and -5.012), which is unusual and suggests poor permeability. However, the scale isn't specified, so it's difficult to interpret.

**10. Solubility:** Both ligands have negative solubility values (-3.113 and -3.429), which is also unusual and suggests poor solubility.

**11. hERG:** Both ligands have low hERG inhibition risk (0.089 and 0.142).

**12. Cl_mic:** Ligand A (21.935) has a higher microsomal clearance than Ligand B (2.6), suggesting lower metabolic stability.

**13. t1/2:** Ligand A (-6.497) has a negative in vitro half-life, which is not possible, and indicates a problem with the data. Ligand B (21.647) has a good in vitro half-life.

**14. Pgp:** Both ligands have low P-gp efflux liability (0.09 and 0.085).

**15. Binding Affinity:** Ligand B (-8.8 kcal/mol) has a significantly stronger binding affinity than Ligand A (0.0 kcal/mol). This is a substantial advantage, potentially outweighing some ADME drawbacks.

**Overall Assessment:**

Ligand B is clearly the more promising candidate. While its BBB penetration isn't fantastic, it's far superior to Ligand A's. Crucially, Ligand B has a much better binding affinity, lower DILI risk, better metabolic stability (lower Cl_mic), and a reasonable in vitro half-life. Ligand A's extremely poor BBB penetration and problematic half-life make it a less viable option, even if its TPSA were lower. The negative values for Caco-2 and solubility are concerning for both, but the large affinity difference favors B.

Output:
1
2025-04-17 03:17:55,672 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (350.503 and 358.467 Da) fall comfortably within the ideal 200-500 Da range.

**TPSA:** Both ligands have TPSA values (67.43 and 67.23) that are acceptable for oral absorption (<140) but slightly higher than optimal for CNS penetration (<90). This is a minor drawback, but not disqualifying.

**logP:** Both ligands have logP values (2.351 and 2.777) within the optimal 1-3 range, suggesting good permeability and reasonable solubility.

**H-Bond Donors/Acceptors:** Ligand A (2 HBD, 3 HBA) and Ligand B (1 HBD, 5 HBA) both have reasonable numbers of H-bond donors and acceptors, suggesting a balance between solubility and permeability.

**QED:** Both ligands have good QED scores (0.66 and 0.914), indicating a generally drug-like profile. Ligand B is superior here.

**DILI:** Ligand A (14.036) has a significantly lower DILI risk than Ligand B (67.623). This is a substantial advantage for Ligand A.

**BBB:** Ligand A (76.735) has a better BBB percentile than Ligand B (64.87). This is a crucial factor for a CNS target like DRD2.

**Caco-2 Permeability:** Ligand A (-4.465) has a worse Caco-2 permeability than Ligand B (-5.238).

**Aqueous Solubility:** Both ligands have poor aqueous solubility (-3.032 and -3.728). This could present formulation challenges, but is not a dealbreaker.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.422 and 0.522).

**Microsomal Clearance:** Ligand B (24.986) has a lower microsomal clearance than Ligand A (37.817), indicating better metabolic stability.

**In vitro Half-Life:** Ligand B (17.03) has a longer in vitro half-life than Ligand A (4.437), which is desirable.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.161 and 0.218).

**Binding Affinity:** Both ligands have identical binding affinities (-7.8 kcal/mol), which is excellent.

**Overall Assessment:**

Considering the GPCR-specific priorities, Ligand A is more promising. While Ligand B has slightly better metabolic stability and half-life, Ligand A's significantly lower DILI risk and better BBB penetration are more critical for a CNS-targeting drug. The similar binding affinity means the ADME properties will be the deciding factor. The poor solubility is a concern for both, but can be addressed with formulation strategies.

Output:
0
2025-04-17 03:17:55,672 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight (MW):** Both ligands are within the ideal range (200-500 Da). Ligand A (342.374 Da) is slightly better, being closer to the lower end which can aid permeability.

**2. TPSA:** Ligand A (78.09) is significantly better than Ligand B (105.39). For CNS targets, we want TPSA <= 90, and Ligand A comfortably meets this, while Ligand B is pushing the limit.

**3. logP:** Both ligands have good logP values (A: 2.104, B: 1.254) falling within the optimal 1-3 range. Ligand A is slightly more lipophilic, which could be beneficial for membrane permeability.

**4. H-Bond Donors (HBD):** Both have 2 HBD, which is acceptable.

**5. H-Bond Acceptors (HBA):** Ligand A has 3 HBA, while Ligand B has 6. Lower HBA is generally preferred for better permeability, making Ligand A more favorable.

**6. QED:** Both have similar QED values (A: 0.893, B: 0.812), indicating good drug-like properties.

**7. DILI:** Both have similar DILI risk (A: 64.327, B: 65.413), both are acceptable but not ideal.

**8. BBB:** Both have reasonable BBB penetration (A: 50.058, B: 53.974). While neither exceeds the desirable >70 percentile, they are comparable.

**9. Caco-2 Permeability:** Ligand A (-4.985) has better Caco-2 permeability than Ligand B (-5.588), indicating better intestinal absorption.

**10. Aqueous Solubility:** Both have poor aqueous solubility (A: -2.544, B: -2.917). This could pose formulation challenges, but is less critical for CNS drugs where BBB penetration is paramount.

**11. hERG Inhibition:** Both have low hERG inhibition risk (A: 0.466, B: 0.232), which is good.

**12. Microsomal Clearance:** Ligand A (27.345) has lower microsomal clearance than Ligand B (31.013), suggesting better metabolic stability.

**13. In vitro Half-Life:** Ligand A (-27.488) has a longer in vitro half-life than Ligand B (-15.854), which is desirable.

**14. P-gp Efflux:** Both have low P-gp efflux (A: 0.049, B: 0.027), which is good for CNS penetration.

**15. Binding Affinity:** Ligand A (-9.5 kcal/mol) has significantly stronger binding affinity than Ligand B (-7.6 kcal/mol). This >1.5 kcal/mol difference is a major advantage, potentially outweighing some of the ADME drawbacks.

**Overall Assessment:**

Ligand A is the superior candidate. It has a better TPSA, HBA, Caco-2 permeability, microsomal clearance, in vitro half-life, and *significantly* better binding affinity. While both have similar BBB penetration and DILI risk, the stronger binding affinity and more favorable ADME properties of Ligand A make it the more promising drug candidate for targeting DRD2.

Output:
1
2025-04-17 03:17:55,672 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (375.491 and 350.459 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (118.8) is slightly above the preferred <90 for CNS targets, but still reasonable. Ligand B (78.87) is excellent, well below 90.

**logP:** Ligand A (-0.311) is a bit low, potentially hindering permeation. Ligand B (0.926) is within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Both ligands have 2 HBD and 4-5 HBA, which are acceptable values.

**QED:** Both ligands have good QED scores (0.603 and 0.716), indicating drug-like properties.

**DILI:** Ligand A (36.758) has a slightly higher DILI risk than Ligand B (10.896), but both are below the concerning threshold of 60.

**BBB:** Both ligands show similar BBB penetration (55.021 and 55.099). While not exceeding the desirable >70, they are not disqualifying.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values, which is unusual and suggests poor permeability. However, these values are on a different scale and may not be directly comparable.

**Aqueous Solubility:** Both ligands have negative solubility values, indicating poor aqueous solubility.

**hERG:** Both ligands have very low hERG inhibition risk (0.185 and 0.28).

**Microsomal Clearance:** Ligand A (7.259) has lower microsomal clearance than Ligand B (13.715), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (-28.337) has a very negative half-life, which is concerning. Ligand B (45.261) has a more reasonable half-life.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.014 and 0.036), which is favorable for CNS penetration.

**Binding Affinity:** Ligand B (-7.9 kcal/mol) has a significantly stronger binding affinity than Ligand A (-6.8 kcal/mol). This 1.1 kcal/mol difference is substantial and can outweigh some ADME drawbacks.

**Overall Assessment:**

Ligand B is the more promising candidate. While both have issues with solubility and Caco-2 permeability, Ligand B has a significantly better logP, a more favorable half-life, and, crucially, a much stronger binding affinity for DRD2. The slightly lower DILI risk is also a benefit. The TPSA is also much better for CNS penetration. Although both have similar BBB values, the better logP and Pgp efflux of Ligand B will likely translate to better brain exposure *in vivo*.

Output:
1
2025-04-17 03:17:55,673 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (341.455 and 351.491 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (56.15) is significantly better than Ligand B (78.51). For CNS targets, we want TPSA <= 90, and A is comfortably within that, while B is approaching the upper limit.

**3. logP:** Ligand A (3.12) is optimal (1-3), while Ligand B (1.55) is on the lower side. While not terrible, lower logP can sometimes indicate permeability issues.

**4. H-Bond Donors:** Ligand A (1) and Ligand B (2) are both acceptable (<=5).

**5. H-Bond Acceptors:** Ligand A (4) and Ligand B (3) are both acceptable (<=10).

**6. QED:** Both ligands have similar QED values (0.751 and 0.73), indicating good drug-like properties.

**7. DILI:** Ligand A (20.861) has a much lower DILI risk than Ligand B (11.283), which is a significant advantage.

**8. BBB:** Ligand A (71.656) has a substantially higher BBB penetration percentile than Ligand B (57.154). This is *critical* for a CNS target like DRD2. A value >70 is desirable, and A is closer to that threshold.

**9. Caco-2:** Ligand A (-5.112) and Ligand B (-4.876) are both negative, which is unusual and suggests poor permeability. However, the scale isn't defined, so it's hard to interpret.

**10. Solubility:** Ligand A (-1.736) and Ligand B (-2.03) are both negative, indicating poor aqueous solubility. This could be a formulation challenge.

**11. hERG:** Ligand A (0.834) has a slightly higher hERG risk than Ligand B (0.231), but both are relatively low.

**12. Cl_mic:** Ligand A (38.765) has lower microsomal clearance than Ligand B (49.572), suggesting better metabolic stability.

**13. t1/2:** Ligand A (6.394) has a longer in vitro half-life than Ligand B (-7.524). The negative value for B is concerning and likely an error or indicates very rapid metabolism.

**14. Pgp:** Ligand A (0.675) has lower P-gp efflux liability than Ligand B (0.016), which is beneficial for CNS exposure.

**15. Binding Affinity:** Ligand A (-8.5 kcal/mol) has a slightly better binding affinity than Ligand B (-8.2 kcal/mol). While the difference is small, it's still a positive factor.

**Overall Assessment:**

Ligand A is significantly better than Ligand B. It has superior BBB penetration, lower DILI risk, better metabolic stability (lower Cl_mic, longer t1/2), lower P-gp efflux, and slightly better binding affinity. While both have solubility and Caco-2 permeability concerns, the CNS-specific advantages of Ligand A outweigh these drawbacks. The negative half-life value for Ligand B is a major red flag.

Output:
1
2025-04-17 03:17:55,673 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, considering the provided guidelines and GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (346.274 and 351.359 Da) fall within the ideal range of 200-500 Da.

**TPSA:** Ligand A (123.46) is slightly above the optimal <90 for CNS targets, but still reasonable. Ligand B (110.97) is better, falling comfortably below 120.

**logP:** Ligand A (1.354) is within the optimal 1-3 range. Ligand B (-0.041) is slightly below 1, which could potentially hinder permeation, but it's not drastically low.

**H-Bond Donors/Acceptors:** Both ligands have acceptable HBD (2 and 1, respectively) and HBA (7 each) counts, well within the guidelines.

**QED:** Both ligands have reasonable QED scores (0.486 and 0.565), indicating acceptable drug-likeness. Ligand B is slightly better.

**DILI:** Both ligands have high DILI risk (99.147 and 64.793), but Ligand B is significantly lower and therefore preferable.

**BBB:** Ligand A (63.474) and Ligand B (65.452) are both below the desirable >70 for CNS targets. This is a concern for both, but they are relatively close.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.92 and -4.825). This is unusual and suggests poor intestinal absorption.

**Aqueous Solubility:** Both ligands have negative solubility values (-4.093 and -2.755), indicating very poor aqueous solubility. This is a significant drawback for both.

**hERG Inhibition:** Both ligands show low hERG inhibition risk (0.207 and 0.093), which is good.

**Microsomal Clearance:** Ligand A (9.355) has a lower microsomal clearance than Ligand B (41.841), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (32.58) has a longer half-life than Ligand B (11.078), which is desirable.

**P-gp Efflux:** Ligand A (0.149) has lower P-gp efflux than Ligand B (0.03), suggesting better CNS exposure and oral bioavailability.

**Binding Affinity:** Ligand A (-10.3 kcal/mol) has a *much* stronger binding affinity than Ligand B (-6.9 kcal/mol). This is a substantial difference (>1.5 kcal/mol advantage).

**Overall Assessment:**

While both ligands have significant drawbacks (poor solubility, Caco-2 permeability, and suboptimal BBB), Ligand A is the stronger candidate due to its significantly higher binding affinity (-10.3 vs -6.9 kcal/mol). The superior affinity likely outweighs the slightly higher TPSA and lower BBB score, especially considering it also has better metabolic stability (lower Cl_mic) and a longer half-life. The lower P-gp efflux is also beneficial. The DILI risk is high for both, but lower for B. However, the substantial affinity difference of A is the deciding factor.

Output:
1
2025-04-17 03:17:55,673 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (352.479 and 368.415 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (96.25) is better than Ligand B (49.41). For CNS targets, TPSA should be <= 90, so Ligand A is closer to the threshold, but both are acceptable.

**logP:** Ligand A (1.418) is within the optimal 1-3 range. Ligand B (3.599) is at the higher end of the optimal range, potentially increasing off-target effects.

**H-Bond Donors/Acceptors:** Ligand A has 3 HBD and 5 HBA, while Ligand B has 1 HBD and 2 HBA. Both are within acceptable limits (<=5 HBD and <=10 HBA).

**QED:** Both ligands have similar QED values (0.626 and 0.666), indicating good drug-like properties.

**DILI:** Ligand A (15.238) has a significantly lower DILI risk than Ligand B (24.893). This is a substantial advantage for Ligand A.

**BBB:** Ligand B (93.874) has a much higher BBB penetration percentile than Ligand A (23.071). This is a *critical* advantage for a CNS target like DRD2.

**Caco-2 Permeability:** Ligand A (-5.307) has worse Caco-2 permeability than Ligand B (-4.415), indicating lower intestinal absorption.

**Aqueous Solubility:** Ligand A (-1.197) has slightly better aqueous solubility than Ligand B (-3.654).

**hERG Inhibition:** Ligand A (0.164) has a lower hERG inhibition liability than Ligand B (0.594), which is preferable.

**Microsomal Clearance:** Ligand B (46.486) has a lower microsomal clearance than Ligand A (21.522), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (-9.858) has a longer in vitro half-life than Ligand B (-5.476).

**P-gp Efflux:** Ligand A (0.025) has significantly lower P-gp efflux liability than Ligand B (0.09), which is crucial for CNS penetration.

**Binding Affinity:** Both ligands have very similar binding affinities (-7.8 and -7.6 kcal/mol). The difference is negligible.

**Overall Assessment:**

Ligand B excels in BBB penetration and metabolic stability. However, Ligand A has a significantly lower DILI risk and P-gp efflux, and a better hERG profile. While BBB is paramount for CNS targets, the combination of lower toxicity (DILI) and better efflux properties for Ligand A makes it a more promising candidate. The slight difference in affinity is not enough to overcome the ADME advantages of Ligand A.

Output:
0
2025-04-17 03:17:55,673 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (342.443 and 367.793 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (78.09) is significantly better than Ligand B (104.7). For CNS targets, we want TPSA <= 90, and A is comfortably within this range, while B is close to the upper limit.

**3. logP:** Both ligands have good logP values (1.541 and 1.041), falling within the optimal 1-3 range.

**4. H-Bond Donors:** Ligand A (2) is slightly higher than Ligand B (1), but both are acceptable (<=5).

**5. H-Bond Acceptors:** Ligand B (7) is higher than Ligand A (3). Both are within the acceptable range (<=10), but A is preferable.

**6. QED:** Both ligands have good QED scores (0.815 and 0.869), indicating good drug-like properties.

**7. DILI:** Ligand A (36.565) has a much lower DILI risk than Ligand B (75.184).  A score <40 is good, so A is significantly better here.

**8. BBB:** Ligand A (54.207) has a better BBB penetration percentile than Ligand B (32.299). While >70 is desirable for CNS targets, A is still better than B.

**9. Caco-2 Permeability:** Both have negative Caco-2 values (-4.949 and -4.735). This is unusual and suggests poor permeability, but the values are close enough to not be a major differentiator.

**10. Aqueous Solubility:** Both have negative solubility values (-3.039 and -2.528), indicating poor solubility. Again, the difference isn't substantial.

**11. hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.115 and 0.028).

**12. Microsomal Clearance:** Ligand B (50.871) has significantly lower microsomal clearance than Ligand A (7.097), suggesting better metabolic stability.

**13. In vitro Half-Life:** Both have negative half-life values (-13.094 and -13.185), which is not physically meaningful. This suggests the models are predicting very rapid degradation.

**14. P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.033 and 0.065).

**15. Binding Affinity:** Both ligands have excellent binding affinities (-9.3 and -8.8 kcal/mol). The difference of 0.5 kcal/mol is not large enough to outweigh other factors.

**Overall Assessment:**

Considering the GPCR-specific priorities, Ligand A is the better candidate. It has a significantly lower DILI risk, better TPSA, and better BBB penetration. While Ligand B has better metabolic stability (lower Cl_mic), the advantages of A in terms of CNS penetration and safety profile are more important for a DRD2 ligand targeting CNS disorders. The negative Caco-2 and solubility values are concerning for both, but the other properties of A make it the more promising candidate.

Output:
0
2025-04-17 03:17:55,673 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (379.47 and 366.49 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (90.21) is excellent for CNS penetration, being below the 90 threshold. Ligand B (114.18) is higher, potentially hindering BBB penetration, but still within an acceptable range for some CNS drugs.

**logP:** Ligand A (2.159) is optimal. Ligand B (1.153) is a bit low, potentially impacting permeability.

**H-Bond Donors/Acceptors:** Ligand A (0 HBD, 8 HBA) is favorable. Ligand B (3 HBD, 5 HBA) is also acceptable, though slightly higher HBD could potentially affect permeability.

**QED:** Both ligands have similar QED values (0.625 and 0.569), indicating reasonable drug-likeness.

**DILI:** Ligand A (90.733) has a significantly higher DILI risk than Ligand B (36.409). This is a major concern for Ligand A.

**BBB:** Ligand A (34.626) has poor predicted BBB penetration. Ligand B (45.056) is better, but still not ideal (target >70%).

**Caco-2 Permeability:** Ligand A (-4.96) has very poor Caco-2 permeability. Ligand B (-5.651) is also poor, but slightly better than A.

**Aqueous Solubility:** Both ligands have poor aqueous solubility (-3.621 and -2.405). This could pose formulation challenges.

**hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.118 and 0.079).

**Microsomal Clearance:** Ligand A (39.954) has higher predicted clearance than Ligand B (26.584), suggesting lower metabolic stability.

**In vitro Half-Life:** Ligand A (-26.494) has a very short predicted half-life. Ligand B (-6.662) is better, but still relatively short.

**P-gp Efflux:** Both ligands show low P-gp efflux liability (0.25 and 0.019).

**Binding Affinity:** Both ligands have very similar and excellent binding affinities (-7.6 and -6.8 kcal/mol). The difference of 0.8 kcal/mol is not substantial enough to override other ADME concerns.

**Overall Assessment:**

Ligand B is significantly more promising. While its BBB penetration isn't ideal, it's better than Ligand A's, and its DILI risk is much lower. The slightly lower logP and Caco-2 permeability are less concerning than Ligand A's poor BBB, high DILI, and poor permeability. The similar affinities mean the ADME properties are the deciding factor.

Output:
1
2025-04-17 03:17:55,673 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (348.49 & 340.43 Da) fall comfortably within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (58.64) is significantly better than Ligand B (78.09). For CNS targets, we want TPSA <= 90, and A is much closer to the ideal <60 range. B is pushing the upper limit.

**3. logP:** Both ligands have good logP values (2.35 & 2.64), falling within the optimal 1-3 range.

**4. H-Bond Donors:** Ligand A (1) is preferable to Ligand B (2). Fewer HBDs generally improve permeability.

**5. H-Bond Acceptors:** Both have 3 HBA, which is acceptable.

**6. QED:** Both ligands have good QED scores (0.685 & 0.84), indicating good drug-like properties.

**7. DILI:** Ligand A (5.78%) has a much lower DILI risk than Ligand B (65.14%). This is a significant advantage for A.

**8. BBB:** Ligand A (80.57%) has a better BBB penetration score than Ligand B (77.01%), although both are reasonably good. Since this is a CNS target, BBB is critical.

**9. Caco-2 Permeability:** Ligand A (-4.41) and Ligand B (-4.88) both have negative values, indicating poor permeability. This is a concern for both.

**10. Aqueous Solubility:** Both ligands have poor aqueous solubility (-2.51 & -4.00). This could pose formulation challenges.

**11. hERG Inhibition:** Both ligands have similar, low hERG inhibition risk (0.37 & 0.38).

**12. Microsomal Clearance:** Ligand A (25.30) has significantly lower microsomal clearance than Ligand B (61.34), indicating better metabolic stability.

**13. In vitro Half-Life:** Ligand A (1.47 hours) has a shorter half-life than Ligand B (6.75 hours). Longer half-life is generally preferred.

**14. P-gp Efflux:** Both ligands have low P-gp efflux liability (0.033 & 0.16).

**15. Binding Affinity:** Ligand B (-9.8 kcal/mol) has a significantly stronger binding affinity than Ligand A (-7.1 kcal/mol). This is a substantial advantage for B, potentially outweighing some of its ADME drawbacks.

**Overall Assessment:**

Ligand B has a significantly better binding affinity, which is a primary driver for GPCR ligands. However, Ligand A has superior ADME properties, particularly regarding DILI risk, TPSA, and metabolic stability. The difference in binding affinity is 2.7 kcal/mol, which is a substantial advantage. Considering the GPCR-specific priorities, the improved BBB and lower TPSA of Ligand A are valuable, but the significantly stronger binding of Ligand B is likely to be more impactful. The higher DILI risk for B is a concern, but could be mitigated with further structural modifications.

Output:
1
2025-04-17 03:17:55,673 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B based on the provided guidelines, prioritizing GPCR-specific properties (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (365.459 and 363.567 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (99.0) is higher than Ligand B (40.54). For CNS targets, TPSA should be <= 90. Ligand A is marginally above this, while Ligand B is well within the desired range. This favors Ligand B.

**logP:** Ligand A (1.826) is within the optimal 1-3 range. Ligand B (4.681) is slightly high, potentially leading to solubility issues and off-target effects. This favors Ligand A.

**H-Bond Donors/Acceptors:** Both have 1 HBD, which is good. Ligand A has 7 HBA, and Ligand B has 3 HBA, both are within acceptable limits (<=10).

**QED:** Both ligands have reasonable QED scores (0.838 and 0.764), indicating good drug-like properties.

**DILI:** Ligand A (74.137) has a higher DILI risk than Ligand B (16.906). This strongly favors Ligand B.

**BBB:** Ligand A (68.786) and Ligand B (86.39) both have good BBB penetration, but Ligand B is significantly better (>70), which is crucial for a CNS target like DRD2. This is a major advantage for Ligand B.

**Caco-2 Permeability:** Ligand A (-5.03) and Ligand B (-4.733) are both negative, indicating poor permeability.

**Aqueous Solubility:** Ligand A (-2.733) has slightly better solubility than Ligand B (-4.874), but both are poor.

**hERG Inhibition:** Ligand A (0.324) has a lower hERG risk than Ligand B (0.756), which is preferable. This favors Ligand A.

**Microsomal Clearance:** Ligand A (12.557) has lower clearance than Ligand B (99.791), indicating better metabolic stability. This favors Ligand A.

**In vitro Half-Life:** Ligand A (-10.897) has a longer half-life than Ligand B (5.231), which is desirable. This favors Ligand A.

**P-gp Efflux:** Ligand A (0.188) has lower P-gp efflux than Ligand B (0.884), meaning better CNS exposure. This favors Ligand A.

**Binding Affinity:** Both ligands have very good binding affinities (-8.8 and -8.1 kcal/mol). Ligand A is slightly better (-8.8 kcal/mol), but the difference is not substantial enough to outweigh other significant ADME differences.

**Overall Assessment:**

Ligand B excels in BBB penetration and has a significantly lower DILI risk. While its logP is slightly high, the superior BBB and safety profile are critical for a CNS drug targeting DRD2. Ligand A has better metabolic stability, half-life, and P-gp efflux, but the higher DILI risk and lower BBB penetration are major drawbacks. Considering the GPCR-specific priorities, Ligand B is the more promising candidate.

Output:
1
2025-04-17 03:17:55,674 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (370.431 and 347.419 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (132.46) is slightly above the optimal <90 for CNS targets, but still reasonable. Ligand B (89.35) is excellent, well below 90.

**logP:** Ligand A (-0.802) is a bit low, potentially hindering permeation. Ligand B (0.71) is within the optimal 1-3 range.

**H-Bond Donors:** Ligand A (3) is acceptable. Ligand B (1) is also good.

**H-Bond Acceptors:** Both ligands (6) are within the acceptable limit of 10.

**QED:** Both ligands have good QED scores (0.575 and 0.866), indicating drug-likeness. Ligand B is better.

**DILI:** Ligand A (78.325) has a higher DILI risk than Ligand B (47.926), though both are below the concerning threshold of 60.

**BBB:** This is crucial for a CNS target. Ligand A (27.763) has a very low BBB penetration, a significant drawback. Ligand B (73.517) is excellent, exceeding the desirable >70 threshold.

**Caco-2 Permeability:** Both have negative values, which is unusual and suggests poor permeability. However, the scale isn't specified, so it's hard to interpret.

**Aqueous Solubility:** Both have negative values, suggesting poor solubility. Again, the scale is unclear.

**hERG:** Both ligands have low hERG inhibition risk (0.062 and 0.099).

**Microsomal Clearance:** Ligand A (-12.316) has a much lower (better) microsomal clearance than Ligand B (30.776), suggesting greater metabolic stability.

**In vitro Half-Life:** Ligand A (14.083) has a longer half-life than Ligand B (5.379).

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.012 and 0.032), which is good for CNS penetration.

**Binding Affinity:** Ligand B (-8.6 kcal/mol) has a significantly stronger binding affinity than Ligand A (-7.3 kcal/mol). This >1.5 kcal/mol difference is substantial and can outweigh some ADME drawbacks.

**Overall Assessment:**

Ligand B is the superior candidate. While Ligand A has better metabolic stability and half-life, Ligand B's significantly better BBB penetration, optimal logP, stronger binding affinity, and lower DILI risk make it far more likely to succeed as a DRD2-targeting drug. The poor solubility and permeability scores are concerning for both, but can be addressed with formulation strategies. The critical factor here is CNS penetration, and Ligand B excels in that area.

Output:
1
2025-04-17 03:17:55,674 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (348.447 and 367.45 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Both ligands (89.53 and 90.98) are below the 90 A^2 threshold for CNS targets, which is excellent.

**3. logP:** Ligand A (0.729) is slightly below the optimal 1-3 range, potentially hindering permeability. Ligand B (1.164) is within the optimal range.

**4. H-Bond Donors:** Both ligands have 2 HBD, which is acceptable.

**5. H-Bond Acceptors:** Ligand A has 4 HBA, and Ligand B has 5 HBA, both within the acceptable limit of 10.

**6. QED:** Ligand A (0.839) has a significantly better QED score than Ligand B (0.558), indicating a more drug-like profile.

**7. DILI:** Ligand A (27.104) has a much lower DILI risk than Ligand B (66.421), making it safer from a liver toxicity perspective.

**8. BBB:** Ligand B (78.558) has a better BBB penetration percentile than Ligand A (54.246). This is a critical factor for CNS targets like DRD2.

**9. Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and suggests poor permeability. However, the scale is not specified, so it's difficult to interpret.

**10. Aqueous Solubility:** Both have negative solubility values, suggesting poor solubility, which is a concern.

**11. hERG Inhibition:** Both ligands have low hERG inhibition risk (0.129 and 0.386).

**12. Microsomal Clearance:** Ligand A (-13.447) has a much lower (better) microsomal clearance than Ligand B (20.47). This suggests greater metabolic stability.

**13. In vitro Half-Life:** Ligand A (-19.075) has a longer in vitro half-life than Ligand B (-26.678), which is favorable.

**14. P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.019 and 0.137), which is good for CNS penetration.

**15. Binding Affinity:** Ligand A (-9.1 kcal/mol) has a significantly stronger binding affinity than Ligand B (-7.7 kcal/mol). This is a substantial advantage.

**Overall Assessment:**

Ligand A excels in key areas: binding affinity, QED, DILI risk, metabolic stability, and in vitro half-life. While its logP is slightly suboptimal and BBB penetration is lower than Ligand B, the significantly stronger binding affinity (-9.1 vs -7.7 kcal/mol) and superior safety profile (DILI) outweigh these drawbacks, especially given the acceptable TPSA. The better QED and metabolic stability also contribute to its favorability. Ligand B's primary advantage is its better BBB penetration, but this is not enough to overcome the weaker binding and higher DILI risk.

Output:
0
2025-04-17 03:17:55,674 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (346.43 and 357.30 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (78.87) is significantly better than Ligand B (97.54). For CNS targets, we want TPSA <= 90, so Ligand A is preferable.

**logP:** Ligand A (1.601) is within the optimal 1-3 range. Ligand B (0.277) is quite low, potentially hindering membrane permeability. This favors Ligand A.

**H-Bond Donors/Acceptors:** Ligand A (2 HBD, 4 HBA) and Ligand B (1 HBD, 8 HBA) both meet the general guidelines of <=5 HBD and <=10 HBA.

**QED:** Both ligands have similar QED values (0.786 and 0.785), indicating good drug-likeness.

**DILI:** Ligand A (36.76) has a much lower DILI risk than Ligand B (71.69). This is a significant advantage for Ligand A.

**BBB:** Ligand B (88.17) has a substantially higher BBB penetration percentile than Ligand A (40.52). This is a critical factor for a CNS target like DRD2, and initially favors Ligand B.

**Caco-2 Permeability:** Both have negative Caco-2 values (-4.572 and -4.809), which is unusual and suggests poor permeability. However, these values are on a scale where negative values are possible and don't necessarily disqualify a compound.

**Aqueous Solubility:** Both ligands have negative solubility values (-2.007 and -2.625) which is also unusual.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.532 and 0.135).

**Microsomal Clearance:** Ligand B (41.72) has a slightly higher clearance than Ligand A (37.60), indicating potentially lower metabolic stability.

**In vitro Half-Life:** Ligand A (-22.865) has a more positive (longer) half-life than Ligand B (-17.587).

**P-gp Efflux:** Ligand A (0.227) has lower P-gp efflux than Ligand B (0.07), which is favorable for CNS penetration.

**Binding Affinity:** Ligand B (-9.3 kcal/mol) has a slightly better binding affinity than Ligand A (-8.6 kcal/mol). This is a 0.7 kcal/mol difference, which is not huge but still noticeable.

**Overall Assessment:**

While Ligand B has better BBB penetration and binding affinity, Ligand A demonstrates superior properties in several key areas: TPSA, logP, DILI risk, P-gp efflux, and in vitro half-life. The lower logP and higher TPSA of Ligand B raise concerns about permeability, even with the higher BBB score. The significantly lower DILI risk for Ligand A is also a major advantage. The difference in binding affinity (0.7 kcal/mol) is not substantial enough to outweigh the other benefits of Ligand A, especially considering the importance of ADME properties for CNS drugs.

Output:
1
2025-04-17 03:17:55,674 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (345.363 and 357.485 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (136.93) is borderline but acceptable for CNS penetration, while Ligand B (29.54) is excellent, well below the 90 threshold. This is a significant advantage for Ligand B.

**logP:** Ligand A (-1.596) is quite low, potentially hindering membrane permeability. Ligand B (4.358) is slightly high, potentially causing solubility issues or off-target interactions, but still within a reasonable range.

**H-Bond Donors/Acceptors:** Ligand A has 3 HBD and 8 HBA, which are acceptable. Ligand B has 0 HBD and 2 HBA, which is also good, potentially contributing to better permeability.

**QED:** Both ligands have good QED scores (0.577 and 0.646), indicating drug-like properties.

**DILI:** Ligand A (69.756) has a higher DILI risk than Ligand B (19.31), which is a significant concern.

**BBB:** Ligand B (96.859) has excellent BBB penetration, exceeding the desirable >70 threshold, while Ligand A (39.55) is poor. This is a critical advantage for a CNS target like DRD2.

**Caco-2 Permeability:** Ligand A (-6.126) has poor Caco-2 permeability. Ligand B (-4.147) is also poor, but slightly better than A.

**Aqueous Solubility:** Ligand A (-2.134) has poor solubility, while Ligand B (-4.81) is even worse. Both are problematic.

**hERG Inhibition:** Ligand A (0.072) has very low hERG risk, which is excellent. Ligand B (0.877) has a slightly elevated, but still acceptable, hERG risk.

**Microsomal Clearance:** Ligand A (-5.151) has low microsomal clearance, indicating good metabolic stability. Ligand B (91.022) has high clearance, suggesting rapid metabolism.

**In vitro Half-Life:** Ligand A (-13.92) has a short half-life, while Ligand B (19.1) has a longer half-life.

**P-gp Efflux:** Ligand A (0.004) has very low P-gp efflux, which is favorable for CNS penetration. Ligand B (0.433) has moderate P-gp efflux.

**Binding Affinity:** Ligand B (-7.6) has a significantly stronger binding affinity than Ligand A (-8.5). A >1.5 kcal/mol advantage is considered substantial.

**Overall Assessment:**

Ligand B is the superior candidate. While it has some drawbacks (high logP, poor solubility, high clearance), its *excellent* BBB penetration, significantly *stronger* binding affinity, and lower DILI risk outweigh these concerns. Ligand A's low logP, poor BBB penetration, and poor Caco-2 permeability are major liabilities. The stronger binding affinity of ligand B also provides a buffer, potentially allowing for a lower dose to achieve the desired effect, mitigating some solubility concerns.

Output:
1
2025-04-17 03:17:55,675 - INFO - Batch 17 complete. Total preferences: 272
2025-04-17 03:17:55,675 - INFO - Processing batch 18/512...
2025-04-17 03:18:37,725 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (345.4 and 363.5 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (80.76) is slightly higher than Ligand B (72.88), but both are below the 90 threshold desirable for CNS targets.

**logP:** Ligand A (0.305) is quite low, potentially hindering permeability. Ligand B (0.648) is better, but still on the lower side of the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A has 1 HBD and 5 HBA, while Ligand B has 2 HBD and 5 HBA. Both are within acceptable limits.

**QED:** Both ligands have good QED scores (0.593 and 0.698), indicating good drug-like properties.

**DILI:** Ligand A (52.152) has a higher DILI risk than Ligand B (22.451). This is a significant advantage for Ligand B.

**BBB:** Both ligands have good BBB penetration (66.615% and 67.584%), exceeding the 70% target, making them both viable for CNS targets.

**Caco-2 Permeability:** Ligand A (-4.485) has poor Caco-2 permeability, while Ligand B (-5.394) is also poor.

**Aqueous Solubility:** Both ligands have poor aqueous solubility (-1.791 and -2.037).

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.216 and 0.276).

**Microsomal Clearance:** Ligand A (-0.126) has much lower (better) microsomal clearance than Ligand B (-5.151), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (-19.811) has a much longer half-life than Ligand B (8.509).

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.047 and 0.019).

**Binding Affinity:** Ligand B (-7.9 kcal/mol) has a significantly stronger binding affinity than Ligand A (-6.6 kcal/mol) - a difference of 1.3 kcal/mol. This is a substantial advantage.

**Overall Assessment:**

Ligand B is the stronger candidate. While both have acceptable BBB penetration, Ligand B has a significantly better binding affinity, lower DILI risk, and slightly better logP. The improved affinity outweighs the slightly worse metabolic stability and solubility compared to Ligand A. Ligand A's better metabolic stability and half-life are attractive, but the weaker binding affinity is a major drawback. The poor Caco-2 and solubility for both are concerns that would need to be addressed in further optimization, but are less critical than potency and safety.

Output:
1
2025-04-17 03:18:37,726 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (347.375 and 344.459 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (129.11) is slightly above the optimal <90 for CNS targets, but still reasonable. Ligand B (77.23) is excellent, well below 90, favoring CNS penetration.

**logP:** Ligand A (-0.611) is a bit low, potentially hindering membrane permeability. Ligand B (1.645) is within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A has 4 HBD and 6 HBA, acceptable. Ligand B has 3 HBD and 3 HBA, also acceptable and potentially slightly better due to fewer hydrogen bonds.

**QED:** Both ligands have good QED scores (0.531 and 0.76), indicating drug-like properties.

**DILI:** Ligand A (52.152) has a moderate DILI risk, while Ligand B (15.355) has a very low risk. This is a significant advantage for Ligand B.

**BBB:** Ligand A (7.949) has very poor predicted BBB penetration. Ligand B (46.84) is still not ideal (>70 desirable), but significantly better than Ligand A.

**Caco-2 Permeability:** Both have negative Caco-2 values (-5.838 and -5.316), which is unusual and suggests poor permeability. This is a concern for both.

**Aqueous Solubility:** Both ligands have very poor aqueous solubility (-2.161 and -2.392). This could pose formulation challenges.

**hERG Inhibition:** Ligand A (0.032) shows very low hERG inhibition risk, which is excellent. Ligand B (0.263) is also low risk, but slightly higher than A.

**Microsomal Clearance:** Ligand A (0.663) has low microsomal clearance, indicating good metabolic stability. Ligand B (-11.8) has very high clearance, meaning it will be rapidly metabolized, a significant drawback.

**In vitro Half-Life:** Ligand A (7.342 hours) has a reasonable half-life. Ligand B (-4.536 hours) has a very short half-life, likely due to the high clearance.

**P-gp Efflux:** Ligand A (0.008) has very low P-gp efflux, which is favorable for CNS penetration. Ligand B (0.02) also shows low P-gp efflux.

**Binding Affinity:** Both ligands have excellent binding affinities (-8.4 and -8.7 kcal/mol), with Ligand B being slightly better. The affinity difference is small and likely less important than the ADME differences.

**Overall Assessment:**

Ligand B has a better logP, significantly lower DILI risk, and slightly better binding affinity. However, its major drawback is the very high microsomal clearance and resulting short half-life, and relatively poor BBB penetration. Ligand A has poor logP and BBB penetration, but better metabolic stability and a slightly lower hERG risk.

Considering the GPCR-specific priorities, BBB penetration is crucial for CNS targets like DRD2. While neither ligand is ideal, Ligand A's better metabolic stability and lower hERG risk, combined with the fact that the affinity difference is small, make it a marginally better candidate, *assuming* formulation challenges related to solubility can be addressed. The poor BBB penetration of Ligand A is a concern, but the rapid clearance of Ligand B is a more significant issue.

Output:
0
2025-04-17 03:18:37,726 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (374.706 and 363.479 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (97.16) is higher than Ligand B (64.63). For CNS targets, we prefer TPSA <= 90. Ligand B is better here.

**3. logP:** Both ligands have good logP values (3.713 and 4.073), falling within the optimal 1-3 range. Ligand B is slightly higher, which *could* be a minor concern for solubility, but not a major issue.

**4. H-Bond Donors:** Ligand A has 2 HBD, and Ligand B has 1. Both are acceptable (<=5).

**5. H-Bond Acceptors:** Both ligands have 5 HBA, which is within the acceptable range (<=10).

**6. QED:** Ligand B (0.819) has a significantly better QED score than Ligand A (0.472), indicating a more drug-like profile.

**7. DILI:** Ligand A (92.051) has a higher DILI risk than Ligand B (69.135). Both are acceptable (<40 is good, >60 is high risk), but B is preferable.

**8. BBB:** Ligand B (78.868) has a better BBB penetration percentile than Ligand A (65.335).  For a CNS target like DRD2, >70 is desirable, but B is closer to this threshold.

**9. Caco-2 Permeability:** Both have negative values, but Ligand A (-5.025) is slightly better than Ligand B (-4.536). However, these values are difficult to interpret without knowing the scale.

**10. Aqueous Solubility:** Both have negative values, indicating poor solubility. Ligand A (-5.155) is slightly worse than Ligand B (-5.33).

**11. hERG Inhibition:** Both ligands have low hERG inhibition risk (0.416 and 0.514).

**12. Microsomal Clearance:** Ligand B (107.778) has a higher microsomal clearance than Ligand A (54.257), meaning it's less metabolically stable. This is a significant drawback for Ligand B.

**13. In vitro Half-Life:** Ligand A (50.452) has a better in vitro half-life than Ligand B (59.016).

**14. P-gp Efflux:** Both ligands have low P-gp efflux liability (0.286 and 0.473).

**15. Binding Affinity:** Ligand A (-9.3 kcal/mol) has a slightly better binding affinity than Ligand B (-8.4 kcal/mol). This 0.9 kcal/mol difference is substantial and could outweigh some ADME drawbacks.

**Overall Assessment:**

While Ligand B has better QED, BBB, and lower DILI risk, Ligand A has significantly better binding affinity and metabolic stability (lower Cl_mic, longer t1/2). The improved affinity of Ligand A is a crucial factor for a GPCR target, and the metabolic stability is important for *in vivo* exposure. The slightly higher TPSA of Ligand A is a minor concern, but the strong binding affinity and better metabolic profile make it the more promising candidate.

Output:
0
2025-04-17 03:18:37,726 - INFO - Reasoning:

Let's analyze Ligand A and Ligand B for their potential as DRD2 drug candidates, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight (MW):** Both ligands (349.406 and 350.503 Da) are within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (80.32) is better than Ligand B (58.64). For CNS targets, we want TPSA <= 90, both are within this range, but A is closer to the upper limit.

**3. logP:** Ligand A (1.518) is optimal (1-3), while Ligand B (3.576) is approaching the upper end of the optimal range.

**4. H-Bond Donors (HBD):** Both ligands have acceptable HBD counts (2 and 1, respectively), well below the threshold of 5.

**5. H-Bond Acceptors (HBA):** Both ligands have acceptable HBA counts (4 and 3, respectively), well below the threshold of 10.

**6. QED:** Both ligands have good QED scores (0.816 and 0.824), indicating good drug-like properties.

**7. DILI:** Both ligands have low DILI risk (44.397 and 40.558), below the 40% threshold.

**8. BBB:** Ligand A (87.553) has a significantly better BBB penetration score than Ligand B (79.217).  This is a *critical* factor for a CNS target like DRD2.

**9. Caco-2 Permeability:** Ligand A (-4.779) has a worse Caco-2 permeability than Ligand B (-4.519).

**10. Aqueous Solubility:** Ligand A (-2.113) has a worse aqueous solubility than Ligand B (-4.237).

**11. hERG Inhibition:** Both ligands have low hERG inhibition risk (0.341 and 0.548).

**12. Microsomal Clearance (Cl_mic):** Ligand A (16.96) has a lower Cl_mic than Ligand B (67.653), suggesting better metabolic stability.

**13. In vitro Half-Life (t1/2):** Ligand A (-1.93) has a worse in vitro half-life than Ligand B (-11.24).

**14. P-gp Efflux:** Both ligands have low P-gp efflux liability (0.044 and 0.564).

**15. Binding Affinity:** Both ligands have very similar and strong binding affinities (-9.0 and -8.6 kcal/mol). The difference is less than 1.5 kcal/mol, so it's not a deciding factor.

**Overall Assessment:**

Ligand A is superior due to its significantly better BBB penetration (87.553 vs 79.217) and lower microsomal clearance (16.96 vs 67.653). While Ligand B has slightly better Caco-2 permeability and aqueous solubility, these are less critical for a CNS target. The similar binding affinities make the ADME properties the primary differentiating factors. The improved metabolic stability of Ligand A is also a significant advantage.

Output:
1
2025-04-17 03:18:37,726 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (355.459 and 348.487 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (66.4) is slightly above the optimal <90 for CNS targets, but still reasonable. Ligand B (58.64) is better, falling comfortably below 90.

**3. logP:** Both ligands have good logP values (3.284 and 2.348), within the 1-3 optimal range.

**4. H-Bond Donors:** Ligand A (2) and Ligand B (1) both meet the HBD <=5 criteria.

**5. H-Bond Acceptors:** Both ligands (3) meet the HBA <=10 criteria.

**6. QED:** Ligand A (0.763) has a significantly better QED score than Ligand B (0.541), indicating a more drug-like profile.

**7. DILI:** Ligand A (73.052) has a higher DILI risk than Ligand B (10.896). This is a significant drawback for Ligand A.

**8. BBB:** Ligand B (70.609) has a much better BBB percentile than Ligand A (25.708). This is *critical* for a CNS target like DRD2.

**9. Caco-2:** Ligand A (-5.422) and Ligand B (-4.414) both have negative values, which is unusual and suggests poor permeability. However, the scale isn't specified, so it's difficult to interpret.

**10. Solubility:** Both ligands have poor aqueous solubility (-3.242 and -2.9). This could be a formulation challenge.

**11. hERG:** Both ligands have very low hERG inhibition risk (0.023 and 0.403).

**12. Cl_mic:** Ligand A (19.152) has a lower microsomal clearance than Ligand B (36.514), suggesting better metabolic stability.

**13. t1/2:** Ligand B (-15.402) has a longer in vitro half-life than Ligand A (-13.246).

**14. Pgp:** Both ligands have very low P-gp efflux liability (0.014 and 0.063).

**15. Binding Affinity:** Ligand A (-7.7) has a slightly better binding affinity than Ligand B (-7.5), but the difference is small (0.2 kcal/mol).

**Overall Assessment:**

While Ligand A has a slightly better binding affinity and QED, the significantly higher DILI risk and *much* lower BBB penetration make it a less desirable candidate. Ligand B, despite a slightly lower affinity and QED, has a far superior safety profile (DILI) and, crucially, excellent BBB penetration. For a CNS target like DRD2, BBB penetration is paramount. The slightly longer half-life of Ligand B is also a benefit.

Output:
1
2025-04-17 03:18:37,727 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (367.471 and 349.435 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (91.76) is slightly above the preferred <90 for CNS targets, but still reasonable. Ligand B (70.91) is well within the optimal range.

**logP:** Ligand A (1.605) is within the optimal 1-3 range. Ligand B (-0.266) is slightly below 1, which *could* indicate permeability issues, but isn't a hard disqualifier.

**H-Bond Donors/Acceptors:** Ligand A has 2 HBD and 6 HBA, both acceptable. Ligand B has 0 HBD and 6 HBA, also acceptable.

**QED:** Ligand B (0.732) has a better QED score than Ligand A (0.414), indicating a more drug-like profile.

**DILI:** Ligand B (25.165) has a significantly lower DILI risk than Ligand A (50.95), a substantial advantage.

**BBB:** Ligand B (65.801) has a better BBB percentile than Ligand A (36.952). While both are not ideal (>70 is desirable), Ligand B is considerably better for a CNS target.

**Caco-2 Permeability:** Ligand A (-5.472) has poor Caco-2 permeability, a significant concern. Ligand B (-4.604) is also poor, but slightly better.

**Aqueous Solubility:** Ligand A (-0.99) has poor aqueous solubility. Ligand B (0.19) is slightly better, but still not great.

**hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.332 and 0.321).

**Microsomal Clearance:** Ligand A (-7.488) has a *much* lower (better) microsomal clearance than Ligand B (-5.968), suggesting greater metabolic stability.

**In vitro Half-Life:** Ligand A (5.844) has a better in vitro half-life than Ligand B (-2.297).

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.088 and 0.02).

**Binding Affinity:** Ligand B (-7.7 kcal/mol) has a stronger binding affinity than Ligand A (-0.0 kcal/mol). This is a *major* advantage, easily outweighing minor ADME drawbacks.

**Overall Assessment:**

Ligand B is the stronger candidate. While its solubility and Caco-2 permeability are not ideal, its significantly better BBB penetration, lower DILI risk, and *much* superior binding affinity outweigh these concerns. The strong binding affinity is particularly important for a GPCR target. Ligand A's poor Caco-2 permeability and weaker affinity are significant drawbacks.

Output:
1
2025-04-17 03:18:37,727 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (342.355 and 357.841 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (95.43) is slightly higher than the preferred <90 for CNS targets, but still reasonable. Ligand B (62.3) is excellent, well below 90.

**3. logP:** Ligand A (1.653) is within the optimal 1-3 range. Ligand B (3.2) is at the higher end of optimal, but still acceptable.

**4. H-Bond Donors:** Both ligands have 1 HBD, which is good.

**5. H-Bond Acceptors:** Ligand A has 8 HBA, acceptable. Ligand B has 3 HBA, which is also good.

**6. QED:** Both ligands have similar QED values (0.753 and 0.774), indicating good drug-like properties.

**7. DILI:** Ligand A (80.186) has a higher DILI risk than Ligand B (54.323). Ligand B is preferable here.

**8. BBB:** Both ligands have similar BBB penetration (43.699 and 45.638). Both are below the desirable >70 for CNS targets, but not drastically so.

**9. Caco-2 Permeability:** Both ligands have very negative Caco-2 values (-4.909 and -4.906). This is unusual and suggests a potential issue with permeability prediction. These values likely indicate very *high* permeability, but the negative scale is concerning.

**10. Aqueous Solubility:** Both ligands have negative solubility values (-2.878 and -3.285), again indicating a potential issue with the prediction method. These likely indicate very *low* solubility, which is a concern.

**11. hERG Inhibition:** Both ligands have low hERG inhibition risk (0.504 and 0.479).

**12. Microsomal Clearance:** Ligand A (35.347) has lower microsomal clearance than Ligand B (62.129), suggesting better metabolic stability.

**13. In vitro Half-Life:** Ligand A (7.605) has a longer half-life than Ligand B (21.327).

**14. P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.203 and 0.144). This is excellent for CNS penetration.

**15. Binding Affinity:** Ligand B (-8.6 kcal/mol) has a significantly stronger binding affinity than Ligand A (-9.0 kcal/mol). This is a substantial advantage.

**Overall Assessment:**

Ligand B is the better candidate. While both have issues with predicted solubility and permeability (negative values are concerning), Ligand B has a significantly stronger binding affinity (-8.6 vs -9.0 kcal/mol), lower DILI risk, and comparable BBB penetration. The stronger binding affinity is likely to outweigh the slightly higher logP and the questionable solubility/permeability predictions. The better metabolic stability (lower Cl_mic) of Ligand A is a positive, but the affinity difference is more critical for a GPCR target.

Output:
1
2025-04-17 03:18:37,727 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (344.415 and 347.455 Da) fall comfortably within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (100.19) is higher than the preferred <90 for CNS targets, but not drastically so. Ligand B (55.84) is excellent, well below 90. This favors Ligand B.

**3. logP:** Ligand A (1.09) is at the lower end of the optimal range (1-3), potentially impacting permeability. Ligand B (3.728) is excellent, within the optimal range. This favors Ligand B.

**4. H-Bond Donors:** Ligand A (3) is acceptable. Ligand B (0) is also acceptable, and potentially better for permeability.

**5. H-Bond Acceptors:** Both ligands have 4 HBA, which is within the acceptable limit of <=10.

**6. QED:** Both ligands have good QED scores (0.531 and 0.601), indicating drug-like properties.

**7. DILI:** Ligand A (54.556) has a moderate DILI risk. Ligand B (28.577) has a lower, more favorable DILI risk. This favors Ligand B.

**8. BBB:** Ligand A (61.109) is below the desirable >70 for CNS targets. Ligand B (79.411) is excellent, exceeding the 70% threshold. This is a significant advantage for Ligand B.

**9. Caco-2:** Both have negative values, which is unusual. Interpreting these as low permeability, Ligand A (-5.323) appears slightly better than Ligand B (-4.309), but both are poor.

**10. Solubility:** Both have negative solubility values, indicating low aqueous solubility. Ligand A (-2.423) is slightly better than Ligand B (-4.32).

**11. hERG:** Both ligands have very low hERG inhibition liability (0.138 and 0.776), which is excellent.

**12. Cl_mic:** Ligand A (4.397) has a lower microsomal clearance, suggesting better metabolic stability. Ligand B (97.637) has high clearance, a significant drawback. This favors Ligand A.

**13. t1/2:** Ligand A (14.84) has a shorter in vitro half-life than Ligand B (-17.644, which is likely an error or outlier). Assuming a positive value is preferable, this favors Ligand A.

**14. Pgp:** Ligand A (0.033) has very low P-gp efflux liability, which is excellent for CNS penetration. Ligand B (0.555) is also low, but higher than A. This favors Ligand A.

**15. Binding Affinity:** Both ligands have strong binding affinities (-9.2 and -8.7 kcal/mol). Ligand A is slightly better (-9.2 kcal/mol).

**Overall Assessment:**

While Ligand A has a slightly better binding affinity and metabolic stability, Ligand B excels in critical properties for a CNS-targeting GPCR ligand: TPSA, logP, BBB penetration, and DILI risk. The significantly better BBB penetration of Ligand B outweighs the minor advantage in affinity and metabolic stability of Ligand A. The poor Caco-2 and solubility values are concerning for both, but less critical for a CNS-focused drug.

Output:
1
2025-04-17 03:18:37,727 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (356.511 and 351.447 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (73.91) is significantly better than Ligand B (78.95). For CNS targets, we want TPSA <= 90, and A is closer to the optimal range.

**logP:** Ligand B (1.538) is slightly better than Ligand A (0.859), falling more squarely within the 1-3 range. A is a bit low, potentially hindering permeability.

**H-Bond Donors/Acceptors:** Ligand A has 2 HBD and 5 HBA, while Ligand B has 1 HBD and 4 HBA. Both are within acceptable limits (<=5 HBD and <=10 HBA).

**QED:** Ligand B (0.736) has a better QED score than Ligand A (0.568), indicating a more drug-like profile.

**DILI:** Ligand A (8.453) has a much lower DILI risk than Ligand B (28.306), a significant advantage.

**BBB:** Ligand B (71.811) has a better BBB penetration score than Ligand A (52.811). This is a critical factor for a CNS target like DRD2.

**Caco-2 Permeability:** Ligand A (-5.597) shows poor Caco-2 permeability, while Ligand B (-4.552) is slightly better, but still poor.

**Aqueous Solubility:** Both ligands have very poor aqueous solubility (-0.827 and -1.678 respectively). This could pose formulation challenges.

**hERG Inhibition:** Both ligands show very low hERG inhibition risk (0.399 and 0.198).

**Microsomal Clearance:** Ligand A (-33.829) has a much lower (better) microsomal clearance than Ligand B (1.405), suggesting greater metabolic stability.

**In vitro Half-Life:** Ligand A (-4.439) has a longer in vitro half-life than Ligand B (-18.62), which is desirable.

**P-gp Efflux:** Both ligands show minimal P-gp efflux liability (0.002 and 0.031).

**Binding Affinity:** Ligand B (-7.9) has a slightly better binding affinity than Ligand A (-7.3), but the difference is relatively small (0.6 kcal/mol).

**Overall Assessment:**

Ligand B has the advantage in BBB penetration and binding affinity, both crucial for a CNS GPCR target. However, Ligand A excels in DILI risk, metabolic stability (Cl_mic), and in vitro half-life. The poor Caco-2 permeability for both is a concern, but less critical for a CNS target where direct oral bioavailability isn't the primary concern. The lower TPSA of Ligand A is also favorable.

Given the importance of BBB penetration for DRD2, and the relatively small affinity difference, Ligand B is the slightly more promising candidate. However, the significantly better safety profile (DILI) and metabolic stability of Ligand A are very attractive. The difference in affinity is not large enough to completely override these advantages.

Output:
1
2025-04-17 03:18:37,728 - INFO - Reasoning:

Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (342.399 Da) is slightly lower, which is generally favorable for permeability.

**2. TPSA:** Ligand A (77.42) is significantly better than Ligand B (42.43). For CNS targets, we want TPSA <= 90, and ideally closer to 60. Ligand A is closer to this ideal.

**3. logP:** Both ligands have acceptable logP values (A: 2.914, B: 4.163), falling within the 1-3 range. Ligand B is slightly higher, which *could* indicate potential off-target effects or solubility issues, but is still within a reasonable range.

**4. H-Bond Donors:** Both have 0 HBD, which is good.

**5. H-Bond Acceptors:** Ligand A has 7 HBA, and Ligand B has 4 HBA. Both are within the acceptable limit of <=10.

**6. QED:** Both ligands have similar QED values (A: 0.681, B: 0.66), indicating good drug-like properties.

**7. DILI:** Ligand A (55.215) has a higher DILI risk than Ligand B (12.563). This is a significant negative for Ligand A.

**8. BBB:** Both ligands have excellent BBB penetration (A: 89.88, B: 80.574), exceeding the desirable threshold of >70.

**9. Caco-2 Permeability:** Ligand A (-5.133) has poor Caco-2 permeability, while Ligand B (-4.46) is slightly better. Both are negative values, which is unusual and suggests a potential issue with the scale used. However, relative to each other, B is better.

**10. Aqueous Solubility:** Ligand A (-2.575) has poor aqueous solubility, while Ligand B (-5.025) is even worse. Both are poor, but B is worse.

**11. hERG Inhibition:** Both ligands have low hERG inhibition liability (A: 0.808, B: 0.735), which is good.

**12. Microsomal Clearance:** Ligand A (60.818) has lower microsomal clearance than Ligand B (146.754), indicating better metabolic stability. This is a significant advantage for Ligand A.

**13. In vitro Half-Life:** Ligand A (-9.887) has a longer in vitro half-life than Ligand B (-21.958). This is a significant advantage for Ligand A.

**14. P-gp Efflux:** Both ligands have low P-gp efflux liability (A: 0.388, B: 0.325).

**15. Binding Affinity:** Ligand A (-8.4 kcal/mol) has a significantly stronger binding affinity than Ligand B (-6.8 kcal/mol). This is a >1.5 kcal/mol difference, which is a major advantage for Ligand A.

**Overall Assessment:**

Despite the higher DILI risk for Ligand A, its significantly stronger binding affinity (-8.4 vs -6.8 kcal/mol), better TPSA, lower clearance, and longer half-life outweigh the DILI concern, *especially* given the good BBB penetration. The affinity difference is substantial and could compensate for the slightly higher DILI risk. Ligand B has a better DILI profile, but its weaker binding affinity and poorer Caco-2 permeability are significant drawbacks. For a GPCR target like DRD2, strong affinity and CNS penetration are paramount.

Output:
1
2025-04-17 03:18:37,728 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (349.459 Da) is slightly preferred as it's closer to the lower end, potentially aiding permeability.

**2. TPSA:** Ligand A (36.44) is significantly better than Ligand B (32.51). Both are below 90, which is good for CNS targets. Lower TPSA generally correlates with better BBB penetration.

**3. logP:** Both ligands have logP values around 4.2-4.4, which is slightly high. While not ideal, it's not a dealbreaker, especially if other properties are favorable.

**4. H-Bond Donors:** Both have 0 HBD, which is good.

**5. H-Bond Acceptors:** Ligand A has 4 HBA, and Ligand B has 5. Both are acceptable (<=10).

**6. QED:** Both ligands have similar QED values (0.694 and 0.625), indicating reasonable drug-likeness.

**7. DILI:** Ligand A (68.282) has a significantly higher DILI risk than Ligand B (12.641). This is a major concern for Ligand A.

**8. BBB:** Ligand A (93.331) has a much better BBB penetration percentile than Ligand B (80.031). This is crucial for a CNS target like DRD2.

**9. Caco-2 Permeability:** Ligand A (-4.605) has worse Caco-2 permeability than Ligand B (-5.462). Lower values suggest poorer intestinal absorption.

**10. Aqueous Solubility:** Ligand A (-4.653) has worse aqueous solubility than Ligand B (-2.141).

**11. hERG Inhibition:** Both ligands have low hERG inhibition risk (0.812 and 0.971).

**12. Microsomal Clearance:** Ligand A (95.056) has very high microsomal clearance, indicating poor metabolic stability. Ligand B (17.6) is much better.

**13. In vitro Half-Life:** Ligand A (47.806) has a shorter half-life than Ligand B (65.806).

**14. P-gp Efflux:** Both ligands have similar P-gp efflux liability (0.775 and 0.718).

**15. Binding Affinity:** Ligand A (-9.4 kcal/mol) has a significantly stronger binding affinity than Ligand B (-8.1 kcal/mol). This is a substantial advantage.

**Overall Assessment:**

While Ligand A boasts a superior binding affinity and better BBB penetration, its significantly higher DILI risk and poor metabolic stability (high Cl_mic, short half-life) are major drawbacks. Ligand B, while having a slightly weaker affinity, presents a much more favorable ADME-Tox profile, particularly the low DILI risk and improved metabolic stability. For a CNS target, a balance between potency and safety/pharmacokinetics is critical. The 1.3 kcal/mol difference in binding affinity, while significant, may be overcome with further optimization of Ligand B. The poor ADME properties of Ligand A are harder to fix.

Output:
1
2025-04-17 03:18:37,728 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B based on the provided guidelines, prioritizing GPCR-specific properties (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (349.337) is slightly lower, which could be beneficial for permeability, but both are acceptable.

**TPSA:** Ligand A (82.53) is better than Ligand B (67.23) as it is closer to the ideal range for CNS targets (<=90).

**logP:** Both ligands have good logP values (A: 2.555, B: 2.001), falling within the optimal range of 1-3.

**H-Bond Donors/Acceptors:** Ligand A (HBD=2, HBA=4) and Ligand B (HBD=1, HBA=5) both have acceptable numbers of H-bond donors and acceptors, within the guidelines of <=5 and <=10 respectively.

**QED:** Both ligands have acceptable QED scores (A: 0.869, B: 0.783), indicating good drug-like properties.

**DILI:** Ligand A (64.909) has a higher DILI risk than Ligand B (39.434). This is a significant drawback for Ligand A.

**BBB:** Ligand B (71.733) has a significantly better BBB percentile than Ligand A (49.128). This is a crucial factor for a CNS target like DRD2.

**Caco-2 Permeability:** Ligand A (-4.837) has a worse Caco-2 permeability than Ligand B (-5.074), but both are poor.

**Aqueous Solubility:** Ligand A (-3.457) has a worse aqueous solubility than Ligand B (-2.486), but both are poor.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (A: 0.378, B: 0.311).

**Microsomal Clearance:** Ligand B (51.943) has a lower microsomal clearance than Ligand A (64.873), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand B (15.076) has a significantly longer in vitro half-life than Ligand A (-26.617). This is a major advantage for Ligand B.

**P-gp Efflux:** Ligand A (0.035) has a lower P-gp efflux liability than Ligand B (0.127), which is favorable for CNS penetration.

**Binding Affinity:** Ligand B (-7.4) has a better binding affinity than Ligand A (-8.9). While A is better, the difference is not substantial enough to overcome the other drawbacks.

**Overall Assessment:**

Ligand B is the more promising candidate. It has a significantly better BBB score, lower DILI risk, better metabolic stability (lower Cl_mic, longer t1/2), and a better binding affinity. While Ligand A has slightly better P-gp efflux, the other advantages of Ligand B outweigh this. The poor solubility and Caco-2 permeability are concerns for both, but are less critical than CNS penetration and safety for a CNS target.

Output:
1
2025-04-17 03:18:37,728 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands are within the acceptable range (200-500 Da). Ligand A (443.128 Da) is higher, but still reasonable. Ligand B (367.475 Da) is preferable.

**2. TPSA:** Ligand A (54.79) is excellent for CNS penetration, well below the 90 A^2 threshold. Ligand B (89.35) is higher, but still potentially acceptable, though less ideal.

**3. logP:** Ligand A (4.697) is slightly high, potentially leading to solubility issues or off-target interactions. Ligand B (1.411) is within the optimal range (1-3).

**4. H-Bond Donors:** Both ligands have acceptable HBD counts (0 for A, 1 for B).

**5. H-Bond Acceptors:** Both ligands have acceptable HBA counts (4 for A, 7 for B).

**6. QED:** Both ligands have good QED scores (0.689 and 0.784), indicating drug-like properties.

**7. DILI:** Both ligands have acceptable DILI risk (75.572 and 63.513), with Ligand B being slightly better.

**8. BBB:** Ligand A (79.566) has a very good BBB percentile, highly desirable for a CNS target. Ligand B (45.677) is significantly lower, raising concerns about CNS exposure. This is a major advantage for Ligand A.

**9. Caco-2:** Both have negative values, which is unusual. Assuming these are logP-scale values, lower values are worse. Ligand A (-4.518) is worse than Ligand B (-5.237).

**10. Solubility:** Both have negative values, which is unusual. Assuming these are logS values, lower values are worse. Ligand A (-5.427) is worse than Ligand B (-2.738).

**11. hERG:** Both ligands have low hERG risk (0.581 and 0.068). Ligand B is preferable.

**12. Cl_mic:** Both have similar microsomal clearance values (42.683 and 40.213), indicating comparable metabolic stability.

**13. t1/2:** Ligand A (70.04) has a much longer in vitro half-life than Ligand B (-12.192), which is a significant advantage.

**14. Pgp:** Ligand A (0.643) has lower P-gp efflux liability than Ligand B (0.062), which is preferable for CNS penetration.

**15. Binding Affinity:** Ligand A (-9.4 kcal/mol) has significantly stronger binding affinity than Ligand B (-6.6 kcal/mol). This is a substantial advantage that can outweigh some of the less ideal ADME properties.

**Overall Assessment:**

While Ligand A has a higher logP and worse Caco-2/Solubility values, its superior BBB penetration, significantly stronger binding affinity, longer half-life, and lower P-gp efflux make it the more promising candidate. The strong binding affinity is a critical factor, especially for a GPCR target, and the good BBB score is essential for CNS activity. Ligand B's lower logP and hERG are positives, but are outweighed by the significant differences in affinity and BBB.

Output:
1
2025-04-17 03:18:37,729 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (351.447 and 343.435 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (104.46) is slightly above the preferred <90 for CNS targets, but still reasonable. Ligand B (79.18) is excellent, well below 90.

**logP:** Both ligands have good logP values (1.941 and 1.152), falling within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A has 3 HBD and 5 HBA, which are acceptable. Ligand B has 1 HBD and 7 HBA, also acceptable.

**QED:** Both ligands have good QED scores (0.664 and 0.793), indicating drug-like properties.

**DILI:** Ligand A (30.361) has a significantly lower DILI risk than Ligand B (59.946). This is a substantial advantage for Ligand A.

**BBB:** Ligand A (57.774) has a lower BBB penetration percentile than Ligand B (65.839). While both are below the ideal >70, Ligand B is better.

**Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and suggests poor permeability. However, the scale is not clearly defined, so it's hard to interpret.

**Aqueous Solubility:** Both have negative solubility values, also unusual.

**hERG:** Both ligands have low hERG inhibition liability (0.256 and 0.47), which is good.

**Microsomal Clearance:** Both have similar microsomal clearance values (49.494 and 50.438), indicating comparable metabolic stability.

**In vitro Half-Life:** Ligand B has a longer in vitro half-life (2.986 hours) than Ligand A (-2.012 hours). The negative value for Ligand A is concerning.

**P-gp Efflux:** Ligand B shows P-gp efflux liability (0.026), while Ligand A has a value of 0.09. Lower is better, so Ligand B is preferable.

**Binding Affinity:** Ligand A has a significantly stronger binding affinity (-8.1 kcal/mol) than Ligand B (-0.0 kcal/mol). This is a *major* advantage for Ligand A, potentially outweighing some of its ADME drawbacks.

**Overall Assessment:**

Ligand A's primary advantage is its significantly higher binding affinity. The strong binding could compensate for the slightly higher TPSA and lower BBB. Its DILI risk is also much lower. Ligand B has better BBB and P-gp efflux, but its binding affinity is very weak. The negative in vitro half-life for Ligand A is a significant concern, but the strong binding affinity makes it a more promising starting point for optimization. Given the importance of affinity for GPCR ligands, and the relatively acceptable ADME profile of Ligand A, it is the more viable candidate.

Output:
1
2025-04-17 03:18:37,729 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (370.421 and 361.869 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (69.64) is better than Ligand B (49.77) as it is closer to the optimal range for CNS targets (<=90).

**logP:** Ligand A (2.043) is optimal (1-3), while Ligand B (4.247) is at the higher end, potentially causing solubility issues.

**H-Bond Donors/Acceptors:** Ligand A (HBD=2, HBA=4) and Ligand B (HBD=1, HBA=3) both have acceptable numbers of H-bond donors and acceptors.

**QED:** Both ligands have similar QED values (0.833 and 0.764), indicating good drug-likeness.

**DILI:** Ligand A (40.054) has a slightly better DILI score than Ligand B (15.083), indicating lower potential for liver injury.

**BBB:** Ligand A (82.241) has a significantly better BBB percentile than Ligand B (40.558). This is a critical advantage for a CNS target like DRD2.

**Caco-2 Permeability:** Ligand A (-4.944) and Ligand B (-4.671) both have negative values, which is unusual and requires further investigation. However, the difference is minimal.

**Aqueous Solubility:** Ligand A (-2.759) is slightly better than Ligand B (-4.305) in terms of solubility.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.618 and 0.872).

**Microsomal Clearance:** Ligand A (14.499) has a lower microsomal clearance than Ligand B (104.324), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (-21.057) has a negative half-life, which is not possible. This is a red flag. Ligand B (36.226) has a reasonable half-life.

**P-gp Efflux:** Ligand A (0.087) has a much lower P-gp efflux liability than Ligand B (0.333), which is favorable for CNS penetration.

**Binding Affinity:** Ligand B (-7.4 kcal/mol) has a slightly better binding affinity than Ligand A (-8.7 kcal/mol). However, the difference is not substantial enough to outweigh other significant drawbacks.

**Overall Assessment:**

Ligand A excels in BBB penetration, P-gp efflux, and metabolic stability. While its in vitro half-life is problematic (negative value), its other properties are generally more favorable for a CNS-targeting GPCR ligand. Ligand B has slightly better binding affinity, but suffers from poorer BBB penetration, higher P-gp efflux, and higher metabolic clearance. The negative half-life for Ligand A is a serious concern, but the other advantages are significant.

Output:
1
2025-04-17 03:18:37,729 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (346.427 and 348.403 Da) fall comfortably within the ideal 200-500 Da range.

**TPSA:** Ligand A (62.99) is excellent, well below the 90 A^2 threshold for CNS targets. Ligand B (116.9) is higher, but still potentially acceptable, though less ideal.

**logP:** Ligand A (1.935) is optimal. Ligand B (-1.257) is below 1, which could hinder permeation.

**H-Bond Donors/Acceptors:** Ligand A (0 HBD, 4 HBA) is favorable. Ligand B (3 HBD, 6 HBA) is also reasonable, but slightly higher counts could impact permeability.

**QED:** Both ligands have acceptable QED scores (0.836 and 0.586, respectively), indicating good drug-like properties.

**DILI:** Ligand A (28.616) has a very low DILI risk. Ligand B (47.305) is higher, but still within a reasonable range.

**BBB:** This is crucial for a CNS target. Ligand A excels with 88.057, indicating high brain penetration potential. Ligand B is very poor at 12.369, suggesting limited CNS exposure.

**Caco-2 Permeability:** Ligand A (-4.209) is concerningly low, indicating poor intestinal absorption. Ligand B (-5.166) is also poor.

**Aqueous Solubility:** Ligand A (-2.822) and Ligand B (-1.463) are both poor, which could pose formulation challenges.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.545 and 0.241, respectively).

**Microsomal Clearance:** Ligand A (73.098) is moderate, indicating reasonable metabolic stability. Ligand B (-15.041) is excellent, suggesting high metabolic stability.

**In vitro Half-Life:** Ligand A (21.108 hours) is good. Ligand B (9.32 hours) is shorter, potentially requiring more frequent dosing.

**P-gp Efflux:** Ligand A (0.288) has low P-gp efflux, which is favorable for CNS penetration. Ligand B (0.014) is even better, indicating minimal efflux.

**Binding Affinity:** Ligand A (-8.6 kcal/mol) has significantly stronger binding affinity than Ligand B (-7.0 kcal/mol). This >1.5 kcal/mol difference is substantial and can outweigh some ADME drawbacks.

**Conclusion:**

Despite Ligand A's poor Caco-2 permeability and solubility, its superior BBB penetration (88.057 vs 12.369) and significantly stronger binding affinity (-8.6 vs -7.0 kcal/mol) make it the more promising candidate for a DRD2-targeting drug, especially given the CNS focus. The lower DILI risk is also a positive factor. While the solubility and permeability issues would need to be addressed through formulation or further chemical modification, the strong affinity and BBB penetration are critical for CNS efficacy.

Output:
1
2025-04-17 03:18:37,729 - INFO - Batch 18 complete. Total preferences: 288
2025-04-17 03:18:37,729 - INFO - Processing batch 19/512...
2025-04-17 03:19:18,349 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (346.515 and 338.451 Da) fall comfortably within the ideal 200-500 Da range.

**2. TPSA:** Both ligands have a TPSA of 49.41, which is excellent for CNS penetration, being well below the 90 Angstrom threshold.

**3. logP:** Both ligands have logP values within the optimal range (3.666 and 3.154).

**4. H-Bond Donors:** Both have 1 HBD, which is acceptable.

**5. H-Bond Acceptors:** Both have 2 HBA, which is also acceptable.

**6. QED:** Ligand B (0.861) has a significantly better QED score than Ligand A (0.565), indicating a more drug-like profile.

**7. DILI:** Ligand A (23.226%) has a much lower DILI risk than Ligand B (53.548%). This is a significant advantage for Ligand A.

**8. BBB:** Ligand B (82.784%) has a substantially higher BBB penetration percentile than Ligand A (64.676%). This is a crucial factor for a CNS target like DRD2.

**9. Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and suggests poor permeability. However, the values are close enough that this isn't a major differentiator.

**10. Aqueous Solubility:** Both have negative solubility values, indicating poor aqueous solubility. This could be a formulation challenge.

**11. hERG Inhibition:** Both ligands show low hERG inhibition liability (0.549 and 0.48), which is good.

**12. Microsomal Clearance:** Ligand A (66.464) has a higher microsomal clearance than Ligand B (58.997), suggesting lower metabolic stability.

**13. In vitro Half-Life:** Ligand B (23.699 hours) has a much longer in vitro half-life than Ligand A (2.453 hours). This is a significant advantage for Ligand B.

**14. P-gp Efflux:** Ligand A (0.639) shows slightly higher P-gp efflux liability than Ligand B (0.162). Lower P-gp efflux is preferred for CNS penetration, favoring Ligand B.

**15. Binding Affinity:** Ligand B (-9.4 kcal/mol) has a significantly stronger binding affinity than Ligand A (-0.0 kcal/mol). This is a major advantage, potentially outweighing some of the ADME drawbacks.

**Overall Assessment:**

While Ligand A has a better safety profile (lower DILI), Ligand B excels in the critical areas for a CNS GPCR target: BBB penetration, binding affinity, P-gp efflux, and in vitro half-life. The substantial difference in binding affinity (-9.4 vs -0.0 kcal/mol) is a decisive factor. The better QED score of Ligand B also contributes to its favorability. The poor solubility and permeability are concerns for both, but can potentially be addressed through formulation strategies.

Output:
1
2025-04-17 03:19:18,350 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (349.297 Da) is slightly lower, which is generally favorable for permeability. Ligand B (360.479 Da) is also good.

**TPSA:** Ligand A (94.59) is better than Ligand B (60.45) for CNS penetration, being closer to the <90 threshold. Ligand B is excellent.

**logP:** Both ligands have good logP values (A: 2.85, B: 3.922), falling within the optimal 1-3 range. Ligand B is slightly higher, potentially leading to some solubility issues, but still acceptable.

**H-Bond Donors/Acceptors:** Both have 1 HBD, which is good. Ligand A has 7 HBA, while Ligand B has 5. Both are within the acceptable limit of 10.

**QED:** Both ligands have good QED scores (A: 0.543, B: 0.76), indicating good drug-like properties. Ligand B is better.

**DILI:** Ligand A (95.386) has a higher DILI risk than Ligand B (73.245). This is a significant drawback for Ligand A.

**BBB:** Ligand A (75.998) has a better BBB percentile than Ligand B (52.268). This is a crucial factor for a CNS target like DRD2.

**Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and suggests poor permeability. However, the scale is not specified, so it's difficult to interpret.

**Aqueous Solubility:** Both have negative solubility values, indicating poor solubility. This is a concern for both.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (A: 0.8, B: 0.357), which is good.

**Microsomal Clearance:** Ligand A (62.612) has a lower microsomal clearance than Ligand B (117.212), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (9.198) has a longer half-life than Ligand B (-8.183). This is a positive attribute.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (A: 0.461, B: 0.625), which is favorable for CNS penetration.

**Binding Affinity:** Both ligands have excellent binding affinities (A: -9.1 kcal/mol, B: -8.2 kcal/mol). Ligand A has a 0.9 kcal/mol advantage, which is substantial and could outweigh some of its ADME drawbacks.

**Overall Assessment:**

Ligand A has a significantly better binding affinity and metabolic stability, and a better BBB score. However, it has a higher DILI risk and worse solubility. Ligand B has better QED, lower DILI, and better TPSA.

Given the importance of BBB penetration for a CNS target like DRD2, the superior binding affinity of Ligand A, and its better metabolic stability, I believe **Ligand A** is the more promising candidate, despite its higher DILI risk. The substantial affinity difference could allow for a lower dose, potentially mitigating the DILI concern. Further optimization could focus on reducing the DILI risk and improving solubility.

Output:
0
2025-04-17 03:19:18,351 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (337.339 Da) is slightly lower, which is generally favorable for permeability. Ligand B (350.463 Da) is also good.

**TPSA:** Both ligands have TPSA values below the 140 A^2 threshold for good oral absorption, and below the 90 A^2 target for CNS penetration. Ligand B (90.54 A^2) is slightly better than Ligand A (99 A^2).

**logP:** Both ligands have logP values within the optimal range (1-3). Ligand A (1.802) is slightly higher than Ligand B (0.847), which is preferable for CNS penetration.

**H-Bond Donors/Acceptors:** Ligand A (1 HBD, 7 HBA) is better than Ligand B (3 HBD, 3 HBA). Lower HBD/HBA generally improves permeability.

**QED:** Both ligands have good QED scores (>0.5), indicating drug-like properties. Ligand B (0.702) is slightly better than Ligand A (0.576).

**DILI:** Ligand A has a very high DILI risk (99.147%), which is a major concern. Ligand B has a much lower DILI risk (25.94%), making it significantly more favorable.

**BBB:** Both ligands have acceptable BBB penetration (>70%). Ligand B (74.796%) is slightly better than Ligand A (71.501%).

**Caco-2 Permeability:** Both ligands have negative Caco-2 permeability values, which is unusual and suggests potential issues with the modeling or data.

**Aqueous Solubility:** Both ligands have negative solubility values, which is also unusual.

**hERG Inhibition:** Both ligands have low hERG inhibition risk. Ligand A (0.512) is slightly higher than Ligand B (0.224).

**Microsomal Clearance:** Ligand A (78.161 mL/min/kg) has a higher clearance than Ligand B (1.212 mL/min/kg), indicating lower metabolic stability.

**In vitro Half-Life:** Ligand A (41.515 hours) has a longer half-life than Ligand B (3.281 hours).

**P-gp Efflux:** Ligand A (0.358) has lower P-gp efflux than Ligand B (0.006), which is favorable for CNS exposure.

**Binding Affinity:** Ligand A (-9.5 kcal/mol) has a significantly stronger binding affinity than Ligand B (-8.0 kcal/mol). This is a substantial advantage.

**Overall Assessment:**

Despite Ligand A's superior binding affinity and P-gp efflux, the extremely high DILI risk is a critical drawback. The DILI risk associated with Ligand A is unacceptable for drug development. Ligand B, while having slightly weaker affinity, presents a much more favorable safety profile (low DILI) and acceptable ADME properties. The difference in binding affinity (1.5 kcal/mol) is significant but can potentially be addressed through further optimization, while mitigating a high DILI risk is often much more challenging. Given the GPCR target and the need for CNS penetration, the balance of properties favors Ligand B.

Output:
1
2025-04-17 03:19:18,351 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (360.841 and 370.455 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (72.24) is better than Ligand B (61.19). Both are below the 90 A^2 threshold desirable for CNS targets.

**3. logP:** Both ligands have good logP values (4.838 and 4.163), falling within the optimal 1-3 range, although slightly high. Ligand B is preferable here.

**4. H-Bond Donors:** Ligand A (1) is better than Ligand B (0).

**5. H-Bond Acceptors:** Ligand B (6) is better than Ligand A (3).

**6. QED:** Both ligands have similar QED values (0.54 and 0.506), indicating good drug-likeness.

**7. DILI:** Ligand A (67.003) has a significantly lower DILI risk than Ligand B (94.804). This is a major advantage for Ligand A.

**8. BBB:** Ligand A (63.125) and Ligand B (66.576) are both reasonably good, but below the >70 percentile desired for CNS targets. Ligand B is slightly better.

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.814 and -4.859), which is unusual and suggests poor permeability.

**10. Aqueous Solubility:** Both ligands have very poor aqueous solubility (-5.369 and -4.734). This is a significant concern for both.

**11. hERG Inhibition:** Ligand A (0.706) has a lower hERG inhibition liability than Ligand B (0.43), which is preferable.

**12. Microsomal Clearance:** Ligand B (36.426) has a lower microsomal clearance than Ligand A (82.416), suggesting better metabolic stability.

**13. In vitro Half-Life:** Ligand B (51.545) has a longer in vitro half-life than Ligand A (41.212), which is desirable.

**14. P-gp Efflux:** Ligand A (0.389) has lower P-gp efflux liability than Ligand B (0.681), which is better for CNS penetration.

**15. Binding Affinity:** Ligand B (-9.7 kcal/mol) has a slightly better binding affinity than Ligand A (-9.2 kcal/mol). This is a significant advantage, potentially outweighing some of the ADME drawbacks.

**Overall Assessment:**

While Ligand B has a slightly better binding affinity and metabolic stability, Ligand A demonstrates a significantly lower DILI risk and lower P-gp efflux, which are crucial for CNS drug candidates. Both have poor solubility and permeability. Considering the GPCR-specific priorities, the lower DILI risk and P-gp efflux of Ligand A are more important than the slightly better affinity of Ligand B, especially given the similar affinities.

Output:
0
2025-04-17 03:19:18,351 - INFO - Reasoning:

Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight (MW):** Both ligands (342.439 and 346.421 Da) fall comfortably within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (54.71) is higher than Ligand B (32.34). For a CNS target like DRD2, TPSA should be <= 90, so both are acceptable, but Ligand B is significantly better.

**3. logP:** Both ligands have good logP values (3.226 and 3.352), falling within the optimal 1-3 range.

**4. H-Bond Donors (HBD):** Both have 1 HBD, which is within the acceptable limit of <=5.

**5. H-Bond Acceptors (HBA):** Ligand A has 4 HBA, and Ligand B has 2. Both are below the limit of <=10.

**6. QED:** Ligand A (0.876) has a much better QED score than Ligand B (0.633), indicating a more drug-like profile.

**7. DILI:** Ligand A (8.492) has a significantly lower DILI risk than Ligand B (16.402), which is a major advantage.

**8. BBB:** Ligand B (90.112) has a substantially higher BBB penetration percentile than Ligand A (74.564). This is *critical* for a CNS target like DRD2.

**9. Caco-2 Permeability:** Both have negative Caco-2 values (-4.791 and -4.633). This is unusual and suggests poor permeability. However, the scale is not specified, and negative values may not be directly comparable.

**10. Aqueous Solubility:** Both have negative solubility values (-2.157 and -3.854). Again, the scale is unclear, but suggests poor solubility.

**11. hERG Inhibition:** Both ligands have low hERG inhibition risk (0.854 and 0.872).

**12. Microsomal Clearance:** Ligand A (-5.222) has a much lower (better) microsomal clearance than Ligand B (27.043), indicating greater metabolic stability.

**13. In vitro Half-Life:** Ligand A (34.623) has a significantly longer in vitro half-life than Ligand B (-10.448).

**14. P-gp Efflux:** Ligand A (0.187) has lower P-gp efflux liability than Ligand B (0.482), which is favorable for CNS penetration.

**15. Binding Affinity:** Both ligands have very similar and excellent binding affinities (-8.9 and -8.5 kcal/mol). The difference is less than 1.5 kcal/mol, so it's not a deciding factor.

**Overall Assessment:**

Ligand B excels in BBB penetration, which is paramount for a DRD2 ligand. However, Ligand A demonstrates superior properties in almost every other critical ADME/Tox parameter: lower DILI risk, better metabolic stability (lower Cl_mic and longer t1/2), lower P-gp efflux, and a better QED score. While both have poor Caco-2 and solubility, the strong BBB penetration of Ligand B, combined with acceptable logP and affinity, outweighs the other advantages of Ligand A.

Output:
1
2025-04-17 03:19:18,351 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B based on the provided guidelines, prioritizing GPCR-specific properties (BBB, logP, Pgp, TPSA, and affinity) for DRD2.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (347.379 Da) is slightly lower, which could be beneficial for permeability. Ligand B (391.465 Da) is also acceptable.

**TPSA:** Ligand A (129.03) is borderline for CNS penetration, being slightly above the optimal <90. Ligand B (79.37) is excellent, well within the desired range for CNS targets.

**logP:** Ligand A (0.129) is quite low, potentially hindering membrane permeability and CNS penetration. Ligand B (1.79) is within the optimal range (1-3).

**H-Bond Donors/Acceptors:** Ligand A has 3 HBD and 7 HBA, which are reasonable. Ligand B has 1 HBD and 5 HBA, also acceptable.

**QED:** Both ligands have good QED scores (A: 0.681, B: 0.75), indicating drug-like properties.

**DILI:** Ligand A (71.268) has a moderate DILI risk, while Ligand B (60.527) is slightly better. Both are acceptable, but lower is preferred.

**BBB:** This is a crucial parameter for DRD2. Ligand A has a BBB percentile of 18.147, which is very poor. Ligand B has a significantly better BBB percentile of 83.443, making it much more likely to reach the target in the CNS.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.512 and -5.095), which is unusual and suggests poor permeability. However, these values are on a scale where higher is better, and negative values indicate very low permeability.

**Aqueous Solubility:** Both ligands have poor aqueous solubility (-2.867 and -3.584). This could pose formulation challenges.

**hERG Inhibition:** Both ligands have low hERG inhibition liability (A: 0.064, B: 0.387), which is good.

**Microsomal Clearance:** Ligand A has a negative Cl_mic (-5.27), which is not physically meaningful. Ligand B (39.559) has a moderate clearance, suggesting moderate metabolic stability.

**In vitro Half-Life:** Ligand A (-27.52) has a negative half-life, which is not physically meaningful. Ligand B (-22.42) also has a negative half-life, which is not physically meaningful.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (A: 0.012, B: 0.195), which is favorable for CNS penetration.

**Binding Affinity:** Both ligands have similar binding affinities (A: -8.6 kcal/mol, B: -8.2 kcal/mol). Ligand A is slightly better, but the difference is not substantial enough to outweigh its other deficiencies.

**Conclusion:**

Ligand B is significantly more promising due to its superior BBB penetration (83.443 vs 18.147), more favorable logP (1.79 vs 0.129), and acceptable DILI risk. While both have poor solubility and permeability, the ability to cross the blood-brain barrier is paramount for a DRD2 ligand targeting CNS disorders. The slightly better affinity of Ligand A is not enough to compensate for its poor CNS penetration properties.

Output:
1
2025-04-17 03:19:18,351 - INFO - Reasoning:

Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (369.447 and 366.487 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (109.58) is higher than the preferred <90 for CNS targets, while Ligand B (74.65) is well within the range. This is a significant advantage for Ligand B.

**3. logP:** Ligand A (-0.967) is slightly low, potentially hindering permeation. Ligand B (0.106) is closer to the optimal 1-3 range.

**4. H-Bond Donors:** Ligand A (2) and Ligand B (1) both meet the HBD <=5 criteria.

**5. H-Bond Acceptors:** Ligand A (8) and Ligand B (5) both meet the HBA <=10 criteria.

**6. QED:** Both ligands have acceptable QED values (0.426 and 0.775 respectively), with Ligand B being significantly better.

**7. DILI:** Both have reasonable DILI risk (50.795 and 40.869), below the 60 threshold.

**8. BBB:** Ligand B (55.603) has a considerably better BBB percentile than Ligand A (29.546). This is *critical* for a CNS target like DRD2.

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.63 and -5.37), which is unusual and suggests poor permeability. This is a concern for both.

**10. Aqueous Solubility:** Both ligands have negative solubility values (-1.047 and -1.445), indicating very poor aqueous solubility. This is a significant drawback for both.

**11. hERG Inhibition:** Both ligands show very low hERG inhibition risk (0.04 and 0.077).

**12. Microsomal Clearance:** Ligand A (17.919) has lower microsomal clearance than Ligand B (27.905), suggesting better metabolic stability.

**13. In vitro Half-Life:** Ligand A (-16.774) has a negative half-life, which is not physically possible and indicates a problem with the data or the molecule. Ligand B (15.03) is acceptable.

**14. P-gp Efflux:** Both ligands have low P-gp efflux liability (0.037 and 0.043).

**15. Binding Affinity:** Ligand A (-7.1) has a slightly better binding affinity than Ligand B (-6.7), but the difference is less than the 1.5 kcal/mol threshold where it would clearly outweigh other drawbacks.

**Overall Assessment:**

Despite Ligand A's slightly better binding affinity, Ligand B is the more promising candidate. Ligand B excels in crucial areas for CNS drug development: TPSA, BBB penetration, and QED. Ligand A has a problematic TPSA value, a lower BBB percentile, and an impossible half-life value. The solubility and Caco-2 permeability are poor for both, but these issues might be addressed through formulation strategies. The slightly better metabolic stability of Ligand A is not enough to offset the other significant advantages of Ligand B.

Output:
1
2025-04-17 03:19:18,352 - INFO - Reasoning:

Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (350.478 and 361.511 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Both ligands have TPSA values around 49-50 A<sup>2</sup>, which is excellent for CNS penetration (well below the 90 A<sup>2</sup> threshold).

**3. logP:** Both ligands have logP values around 3.0-3.8, which is within the optimal range of 1-3.

**4. H-Bond Donors:** Ligand A has 1 HBD, and Ligand B has 0. Both are acceptable (<=5).

**5. H-Bond Acceptors:** Ligand A has 2 HBA, and Ligand B has 5. Both are acceptable (<=10), but Ligand A is slightly better.

**6. QED:** Both ligands have QED values around 0.7, indicating good drug-likeness.

**7. DILI:** Both ligands have low DILI risk (25.436 and 24.544 percentile), which is favorable.

**8. BBB:** Ligand A has a significantly higher BBB penetration percentile (85.421) compared to Ligand B (69.794). This is a *critical* advantage for a CNS target like DRD2.

**9. Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and suggests poor permeability. However, these values are on a log scale and are likely representing low permeability.

**10. Aqueous Solubility:** Both have negative solubility values, indicating poor aqueous solubility. This could be a formulation challenge.

**11. hERG Inhibition:** Both ligands have low hERG inhibition liability (0.766 and 0.727 percentile), which is good.

**12. Microsomal Clearance:** Ligand B has a higher microsomal clearance (70.964 mL/min/kg) than Ligand A (41.337 mL/min/kg). This suggests Ligand A is more metabolically stable.

**13. In vitro Half-Life:** Ligand B has a longer in vitro half-life (57.693 hours) than Ligand A (-19.734 hours). This is a significant advantage for Ligand B.

**14. P-gp Efflux:** Both ligands have low P-gp efflux liability (0.26 and 0.568 percentile), which is favorable for CNS exposure.

**15. Binding Affinity:** Both ligands have the same binding affinity (-7.2 kcal/mol), which is excellent.

**Overall Assessment:**

While Ligand B has a better in vitro half-life, Ligand A is significantly better in terms of BBB penetration, which is paramount for a CNS target. It also has slightly better HBA and lower microsomal clearance. The equal binding affinity makes the ADME properties the deciding factor. Given the importance of BBB penetration for DRD2, Ligand A is the more promising candidate.

Output:
1
2025-04-17 03:19:18,352 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (363.889 and 353.379 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (71.09) is excellent, well below the 90 A^2 threshold for CNS targets. Ligand B (139.78) is approaching the upper limit for good oral absorption (140) and is less favorable for CNS penetration.

**logP:** Ligand A (4.157) is slightly high, potentially leading to solubility issues or off-target interactions, but still within a manageable range. Ligand B (-1.903) is too low, which could hinder membrane permeability and reduce CNS exposure.

**H-Bond Donors/Acceptors:** Ligand A (2 HBD, 3 HBA) is well within the acceptable limits. Ligand B (3 HBD, 7 HBA) is also acceptable, but closer to the upper limits.

**QED:** Ligand A (0.764) has a good drug-likeness score. Ligand B (0.498) is below the 0.5 threshold, indicating a less favorable drug-like profile.

**DILI:** Both ligands have relatively low DILI risk (Ligand A: 49.632, Ligand B: 40.869), which is positive.

**BBB:** Ligand A (69.794) has a reasonable BBB penetration score, but could be better. Ligand B (27.142) has a poor BBB score, which is a significant drawback for a CNS target.

**Caco-2 Permeability:** Ligand A (-4.906) has poor Caco-2 permeability, suggesting poor intestinal absorption. Ligand B (-5.652) also has poor Caco-2 permeability.

**Aqueous Solubility:** Ligand A (-3.961) has poor aqueous solubility. Ligand B (-1.315) has slightly better, but still poor, aqueous solubility.

**hERG Inhibition:** Both ligands have very low hERG inhibition risk (Ligand A: 0.38, Ligand B: 0.073).

**Microsomal Clearance:** Ligand B (-12.901) shows significantly better metabolic stability (lower clearance) than Ligand A (64.708).

**In vitro Half-Life:** Ligand B (10.878 hours) has a better in vitro half-life than Ligand A (81.186 hours).

**P-gp Efflux:** Ligand A (0.277) has lower P-gp efflux, which is favorable for CNS exposure. Ligand B (0.006) has very low P-gp efflux, which is even more favorable.

**Binding Affinity:** Ligand A (-8.5 kcal/mol) has a significantly stronger binding affinity than Ligand B (-7.0 kcal/mol). This is a substantial advantage.

**Overall Assessment:**

While Ligand B has better metabolic stability, P-gp efflux, and a slightly better half-life, its poor BBB penetration and low logP are major concerns for a CNS-targeting drug. Ligand A, despite its higher logP and lower BBB score than ideal, has a *much* stronger binding affinity, which is a critical factor for GPCRs. The stronger binding affinity could potentially overcome some of the ADME liabilities, especially if formulation strategies can address the solubility and permeability issues. The TPSA is also much more favorable for CNS penetration.

Output:
1
2025-04-17 03:19:18,352 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (348.491 and 347.375 Da) fall comfortably within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (78.09) is significantly better than Ligand B (111.39). For CNS targets, we want TPSA <= 90, and A is well within that range, while B is pushing the limit.

**3. logP:** Ligand A (3.04) is optimal, while Ligand B (0.454) is quite low. A logP below 1 can hinder permeation, making A much more favorable.

**4. H-Bond Donors:** Both have 2 HBD, which is acceptable (<=5).

**5. H-Bond Acceptors:** Ligand A has 3 HBA, and Ligand B has 8.  Ligand A is better here, being closer to the ideal of <=10.

**6. QED:** Both ligands have similar QED values (0.72 and 0.7), indicating good drug-likeness.

**7. DILI:** Ligand A (27.142) has a much lower DILI risk than Ligand B (68.903).  A score below 40 is preferred, and A is closer to that.

**8. BBB:** Ligand A (53.083) has a better BBB penetration percentile than Ligand B (27.879). While >70 is desirable for CNS targets, A is significantly better than B.

**9. Caco-2 Permeability:** Both have negative Caco-2 values (-5.263 and -5.451), which is unusual and suggests poor permeability. However, the values are similar.

**10. Aqueous Solubility:** Both have negative solubility values (-2.727 and -2.059), also unusual, suggesting poor solubility. Again, the values are similar.

**11. hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.536 and 0.11).

**12. Microsomal Clearance:** Ligand A (26.74) has a lower (better) microsomal clearance than Ligand B (-14.873). This indicates better metabolic stability for Ligand A.

**13. In vitro Half-Life:** Ligand A (-14.259) has a worse in vitro half-life than Ligand B (30.357). This is a drawback for Ligand A.

**14. P-gp Efflux:** Both have very low P-gp efflux liability (0.089 and 0.031).

**15. Binding Affinity:** Ligand B (-8.6) has a slightly better binding affinity than Ligand A (-8.0). While a 1.5 kcal/mol advantage is significant, the other ADME properties are more concerning for Ligand B.

**Overall Assessment:**

Ligand A is significantly better overall, especially considering the GPCR-specific priorities. Its superior logP, TPSA, BBB, and DILI profile outweigh the slightly weaker binding affinity and worse half-life. Ligand B's low logP and high DILI risk are major concerns. While the affinity is slightly better, the poor ADME properties make it a less viable candidate.

Output:
1
2025-04-17 03:19:18,353 - INFO - Reasoning:

Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (335.403 and 347.463 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (58.56) is significantly better than Ligand B (82.19). For CNS targets, we want TPSA <= 90, and A is comfortably within that, while B is approaching the upper limit.

**3. logP:** Ligand A (3.774) is slightly higher than optimal (1-3), but still acceptable. Ligand B (2.002) is on the lower side, potentially hindering permeability.

**4. H-Bond Donors:** Ligand A (2) and Ligand B (1) are both within the acceptable limit of <=5.

**5. H-Bond Acceptors:** Ligand A (3) and Ligand B (4) are both within the acceptable limit of <=10.

**6. QED:** Both ligands have good QED scores (0.624 and 0.887), indicating good drug-like properties.

**7. DILI:** Both ligands have acceptable DILI risk (56.223 and 46.762), below the 60 threshold.

**8. BBB:** Ligand B (75.766) has a significantly better BBB percentile than Ligand A (46.568). This is a *critical* factor for a CNS target like DRD2.

**9. Caco-2 Permeability:** Ligand A (-5.258) has poor Caco-2 permeability, while Ligand B (-4.942) is also poor, but slightly better.

**10. Aqueous Solubility:** Ligand A (-4.358) and Ligand B (-2.934) both have poor solubility.

**11. hERG Inhibition:** Both ligands show low hERG inhibition risk (0.602 and 0.432).

**12. Microsomal Clearance:** Ligand B (34.399) has significantly lower microsomal clearance than Ligand A (81.244), suggesting better metabolic stability.

**13. In vitro Half-Life:** Ligand B (-18.644) has a longer in vitro half-life than Ligand A (-12.714).

**14. P-gp Efflux:** Ligand A (0.638) has slightly lower P-gp efflux than Ligand B (0.218), which is favorable for CNS penetration.

**15. Binding Affinity:** Ligand A (-9.6 kcal/mol) has a *much* stronger binding affinity than Ligand B (-7.5 kcal/mol). This is a >1.5 kcal/mol advantage, which can outweigh some ADME drawbacks.

**Overall Assessment:**

While Ligand B has superior BBB penetration and metabolic stability, the significantly stronger binding affinity of Ligand A is a major advantage. The slightly higher TPSA and lower BBB of Ligand A are concerns, but the substantial difference in binding affinity (-9.6 vs -7.5 kcal/mol) is likely to be decisive. The poor Caco-2 and solubility of both are drawbacks that would need to be addressed in further optimization, but the potency advantage of A is compelling. Given the GPCR target and the importance of affinity, I favor Ligand A.

Output:
1
2025-04-17 03:19:18,353 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (351.407 and 366.418 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (114.47) is better than Ligand B (108.02). Both are below the 140 A^2 threshold for oral absorption and reasonably close to the 90 A^2 target for CNS penetration.

**3. logP:** Ligand A (1.483) is within the optimal 1-3 range. Ligand B (2.706) is also acceptable, but closer to the upper limit.

**4. H-Bond Donors:** Ligand A (3) and Ligand B (2) are both acceptable, being less than 5.

**5. H-Bond Acceptors:** Ligand A (7) and Ligand B (6) are both acceptable, being less than 10.

**6. QED:** Both ligands have good QED values (0.544 and 0.661, respectively), indicating drug-like properties. Ligand B is slightly better.

**7. DILI:** Both ligands have similar DILI risk (78.054 and 77.588), indicating moderate risk. This isn't a major differentiating factor.

**8. BBB:** This is a critical parameter for DRD2. Ligand A has a significantly better BBB penetration percentile (66.188) compared to Ligand B (48.197). This is a substantial advantage for Ligand A.

**9. Caco-2 Permeability:** Ligand A (-4.833) and Ligand B (-5.392) both have negative values, indicating poor permeability. Ligand B is slightly worse.

**10. Aqueous Solubility:** Both ligands have very poor aqueous solubility (-3.119 and -3.545). This is a concern for both, but not a major differentiator.

**11. hERG Inhibition:** Ligand A (0.108) has a much lower hERG inhibition liability than Ligand B (0.724), making it safer from a cardiotoxicity perspective.

**12. Microsomal Clearance:** Ligand A (42.129) has lower microsomal clearance than Ligand B (55.946), suggesting better metabolic stability.

**13. In vitro Half-Life:** Ligand A (16.728) has a shorter half-life than Ligand B (22.815).

**14. P-gp Efflux:** Ligand A (0.018) has much lower P-gp efflux liability than Ligand B (0.242), indicating better potential for CNS exposure.

**15. Binding Affinity:** Ligand B (-8.3 kcal/mol) has a slightly better binding affinity than Ligand A (-7.9 kcal/mol). While this is a positive for Ligand B, the difference is relatively small (0.4 kcal/mol).

**Overall Assessment:**

Ligand A is the more promising candidate. While Ligand B has slightly better binding affinity and QED, Ligand A excels in critical ADME properties for a CNS-targeting GPCR: significantly better BBB penetration, lower hERG inhibition, lower P-gp efflux, and better metabolic stability. The small difference in binding affinity is likely outweighed by these substantial ADME advantages, especially considering the importance of CNS penetration for DRD2.

Output:
0
2025-04-17 03:19:18,353 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (355.391 and 351.531 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (125.04) is better than Ligand B (38.77) as it is closer to the ideal range for CNS targets (<90). Ligand B is quite low, which could indicate poor binding.

**logP:** Ligand A (-1.455) is suboptimal, being below the preferred 1-3 range. Ligand B (3.741) is excellent, falling right within the optimal range. This is a significant advantage for Ligand B regarding permeability.

**H-Bond Donors/Acceptors:** Ligand A has 3 HBD and 6 HBA, which are acceptable. Ligand B has 0 HBD and 3 HBA, also acceptable.

**QED:** Ligand B (0.669) has a better QED score than Ligand A (0.278), indicating a more drug-like profile.

**DILI:** Ligand A (21.908) has a much lower DILI risk than Ligand B (6.708). This is a positive for Ligand A.

**BBB:** Ligand B (88.251) has a significantly higher BBB penetration percentile than Ligand A (59.325). This is a crucial advantage for a CNS target like DRD2.

**Caco-2 Permeability:** Ligand A (-5.21) has poor Caco-2 permeability, while Ligand B (-4.537) is slightly better, but still not great.

**Aqueous Solubility:** Ligand A (-1.094) has slightly better solubility than Ligand B (-3.686).

**hERG Inhibition:** Ligand A (0.072) has a lower hERG inhibition risk than Ligand B (0.795).

**Microsomal Clearance:** Ligand A (-0.393) has a lower (better) microsomal clearance than Ligand B (101.616). This suggests better metabolic stability for Ligand A.

**In vitro Half-Life:** Ligand A (-25.3) has a much longer in vitro half-life than Ligand B (13.813).

**P-gp Efflux:** Ligand A (0.002) has a much lower P-gp efflux liability than Ligand B (0.427), which is very important for CNS penetration.

**Binding Affinity:** Ligand A (-7.7) has a slightly better binding affinity than Ligand B (-6.7). However, the difference is less than 1.5 kcal/mol, so it doesn't fully compensate for other deficiencies.

**Overall Assessment:**

Ligand B excels in properties critical for CNS GPCR targets: logP, BBB penetration, and QED. While its DILI and Caco-2 permeability are not ideal, the strong BBB penetration and good logP are significant advantages. Ligand A has better metabolic stability (lower Cl_mic, longer half-life) and lower DILI/hERG risk, but its poor logP, lower BBB, and poor Caco-2 permeability are major drawbacks for a CNS target. The slightly better binding affinity of Ligand A is likely outweighed by these ADME issues.

Output:
1
2025-04-17 03:19:18,353 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (357.407 Da) is slightly lower, which is generally favorable for permeability. Ligand B (394.274 Da) is also acceptable.

**TPSA:** Ligand A (108.41) is moderately above the ideal CNS target TPSA of 90, while Ligand B (71) is well below. This favors Ligand B for brain penetration.

**logP:** Ligand A (-1.797) is a bit low, potentially hindering membrane permeability. Ligand B (2.036) is within the optimal range (1-3). This is a significant advantage for Ligand B.

**H-Bond Donors/Acceptors:** Ligand A has 2 HBD and 6 HBA, which are reasonable. Ligand B has 1 HBD and 4 HBA, also acceptable.

**QED:** Both ligands have good QED scores (Ligand A: 0.543, Ligand B: 0.742), indicating drug-like properties. Ligand B is slightly better.

**DILI:** Both ligands have acceptable DILI risk (Ligand A: 34.432, Ligand B: 39.046), below the 40% threshold.

**BBB:** Ligand A (18.147) has a very low BBB penetration percentile, making it unlikely to reach the target in the CNS effectively. Ligand B (76.037) has a good BBB percentile, exceeding the 70% threshold. This is a crucial advantage for Ligand B.

**Caco-2 Permeability:** Both have negative Caco-2 values (-5.035 and -4.867), which is unusual and suggests poor permeability. However, these values are on a scale where negative values are possible and don't necessarily disqualify a compound.

**Aqueous Solubility:** Both ligands have poor aqueous solubility (-0.772 and -3.027). This could pose formulation challenges.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (Ligand A: 0.096, Ligand B: 0.335).

**Microsomal Clearance:** Ligand A (-0.365) has very low microsomal clearance, suggesting high metabolic stability. Ligand B (11.749) has higher clearance, indicating faster metabolism.

**In vitro Half-Life:** Ligand A (-14.641) has a very long in vitro half-life, which is positive. Ligand B (-1.426) has a shorter half-life.

**P-gp Efflux:** Ligand A (0.011) has very low P-gp efflux, which is excellent for CNS penetration. Ligand B (0.132) has slightly higher efflux, but still relatively low.

**Binding Affinity:** Ligand B (-8.6 kcal/mol) has a significantly stronger binding affinity than Ligand A (-6.4 kcal/mol). This >1.5 kcal/mol difference is substantial and can outweigh some ADME drawbacks.

**Conclusion:**

Considering all factors, especially the GPCR-specific priorities for a CNS target like DRD2, **Ligand B is the more promising drug candidate**. While Ligand A has excellent metabolic stability and P-gp efflux properties, its poor BBB penetration and low logP are major drawbacks. Ligand B exhibits a favorable BBB percentile, optimal logP, and a significantly stronger binding affinity, making it a more likely candidate to reach the target and exert a therapeutic effect.

Output:
1
2025-04-17 03:19:18,354 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (349.387 and 359.417 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (109.78) is higher than the preferred <90 for CNS targets, while Ligand B (78.51) is well within the range. This is a significant advantage for Ligand B.

**logP:** Ligand A (0.816) is slightly below the optimal 1-3 range, potentially hindering permeability. Ligand B (1.303) is within the optimal range.

**H-Bond Donors/Acceptors:** Ligand A has 3 HBD and 6 HBA, which are acceptable. Ligand B has 2 HBD and 3 HBA, also acceptable and slightly more favorable.

**QED:** Both ligands have good QED scores (0.629 and 0.719), indicating drug-like properties.

**DILI:** Ligand A (49.709) has a slightly higher DILI risk than Ligand B (31.795), though both are below the concerning threshold of 60.

**BBB:** Ligand B (82.706) has a significantly better BBB penetration score than Ligand A (63.203). This is crucial for a CNS target like DRD2.

**Caco-2 Permeability:** Ligand A (-5.186) and Ligand B (-4.684) both have negative values, which is unusual and suggests poor permeability. However, the scale is not specified, so it's difficult to interpret the absolute difference.

**Aqueous Solubility:** Both ligands have very poor aqueous solubility (-2.571 and -2.425). This could pose formulation challenges.

**hERG:** Both ligands have low hERG inhibition liability (0.217 and 0.323), which is good.

**Microsomal Clearance:** Ligand A (15.318) has a higher microsomal clearance than Ligand B (-4.001), indicating lower metabolic stability. This is a negative for Ligand A.

**In vitro Half-Life:** Both ligands have negative half-life values (-7.021 and -8.102), which is not possible. This is likely an error in the data.

**P-gp Efflux:** Ligand A (0.008) has very low P-gp efflux, which is favorable. Ligand B (0.027) also has low P-gp efflux, but slightly higher than A.

**Binding Affinity:** Ligand A (-8.3 kcal/mol) has a significantly stronger binding affinity than Ligand B (-0.0 kcal/mol). This is a substantial advantage for Ligand A.

**Overall Assessment:**

Despite the solubility and half-life data issues, the key factors for a CNS GPCR target are BBB penetration and binding affinity. Ligand B excels in BBB (82.706 vs 63.203) and has a better TPSA. However, Ligand A has a *much* stronger binding affinity (-8.3 vs -0.0). The difference in affinity is so large that it likely outweighs the advantages of Ligand B in other parameters, *assuming the affinity measurement is reliable*. The slightly better logP and lower DILI of Ligand B are also positives, but less critical than the binding affinity.

Output:
1
2025-04-17 03:19:18,354 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B based on the provided guidelines, prioritizing GPCR-specific properties (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (341.455 and 343.471 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (54.46) is better than Ligand B (56.41). Both are reasonably good for CNS penetration, being under 90, but A is closer to the ideal.

**logP:** Ligand A (4.277) is higher than Ligand B (2.904). While 4.277 is approaching the upper limit, it's still acceptable. Ligand B's logP is excellent.

**H-Bond Donors/Acceptors:** Both have 1 HBD, which is good. Ligand A has 4 HBA, and Ligand B has 2 HBA. Both are within acceptable limits (<=10).

**QED:** Both ligands have good QED scores (0.779 and 0.917, respectively), indicating good drug-like properties.

**DILI:** Ligand A (69.329) has a higher DILI risk than Ligand B (25.94). This is a significant negative for Ligand A.

**BBB:** Ligand B (85.343) has a significantly better BBB penetration score than Ligand A (55.991). This is a crucial advantage for a CNS target like DRD2.

**Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and suggests poor permeability. However, the values are similar (-4.539 and -4.898).

**Aqueous Solubility:** Both have negative solubility values, which is also unusual. Again, they are similar (-5.009 and -3.612).

**hERG:** Both have low hERG inhibition liability (0.803 and 0.662).

**Microsomal Clearance:** Ligand A (103.695) has higher microsomal clearance than Ligand B (46.304), indicating lower metabolic stability.

**In vitro Half-Life:** Ligand B (-18.406) has a much longer in vitro half-life than Ligand A (34.434). This is a significant positive for Ligand B.

**P-gp Efflux:** Ligand A (0.573) has lower P-gp efflux than Ligand B (0.244), which is favorable for CNS penetration.

**Binding Affinity:** Both ligands have very similar and excellent binding affinities (-8.8 and -8.6 kcal/mol). The difference is negligible.

**Overall Assessment:**

Ligand B is the superior candidate. While Ligand A has slightly better TPSA and P-gp efflux, Ligand B excels in critical areas for a CNS-targeting GPCR: significantly better BBB penetration, lower DILI risk, and a longer in vitro half-life. The similar binding affinities make these ADME properties the deciding factors.

Output:
1
2025-04-17 03:19:18,354 - INFO - Batch 19 complete. Total preferences: 304
2025-04-17 03:19:18,354 - INFO - Processing batch 20/512...
2025-04-17 03:19:58,906 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B based on the provided guidelines, prioritizing GPCR-specific properties (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (350.48 and 349.44 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (49.41) is excellent, well below the 90 A^2 threshold for CNS targets. Ligand B (108.05) is higher, but still potentially acceptable, though less ideal.

**logP:** Ligand A (3.53) is at the upper end of the optimal range (1-3), but still acceptable. Ligand B (0.91) is below 1, which could indicate poor membrane permeability.

**H-Bond Donors/Acceptors:** Ligand A (1 HBD, 2 HBA) is favorable. Ligand B (2 HBD, 5 HBA) is also reasonable, though slightly higher in HBA count.

**QED:** Both ligands have similar QED values (0.647 and 0.611), indicating good drug-likeness.

**DILI:** Ligand A (14.70) has a significantly lower DILI risk than Ligand B (53.97). This is a substantial advantage.

**BBB:** Ligand A (92.17) has excellent BBB penetration, exceeding the desirable 70% threshold. Ligand B (68.55) is lower, which is concerning for a CNS target like DRD2.

**Caco-2 Permeability:** Ligand A (-4.85) is very poor, indicating very low intestinal absorption. Ligand B (-5.20) is also poor, but slightly worse.

**Aqueous Solubility:** Ligand A (-3.71) and Ligand B (-1.9) both have poor aqueous solubility.

**hERG Inhibition:** Ligand A (0.44) has a very low risk of hERG inhibition. Ligand B (0.026) also has a very low risk.

**Microsomal Clearance:** Ligand A (21.64) has a moderate clearance. Ligand B (24.97) is slightly higher.

**In vitro Half-Life:** Ligand A (-13.95) has a very long half-life, which is highly desirable. Ligand B (-39.39) has a very long half-life, even longer than Ligand A.

**P-gp Efflux:** Ligand A (0.23) has low P-gp efflux, which is good for CNS penetration. Ligand B (0.033) has even lower P-gp efflux, which is excellent.

**Binding Affinity:** Both ligands have very similar and strong binding affinities (-7.4 and -7.6 kcal/mol). The difference is negligible.

**Overall Assessment:**

Ligand A is superior due to its significantly better BBB penetration (92.17% vs 68.55%), much lower DILI risk (14.70 vs 53.97), and acceptable TPSA. While its Caco-2 permeability is poor, this is less critical for a CNS target. The similar affinity and P-gp efflux profiles further support this conclusion. Ligand B's low logP is a significant drawback.

Output:
1
2025-04-17 03:19:58,906 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (346.431 Da) is slightly better, being closer to the lower end which can aid permeability.

**TPSA:** Ligand A (84.42) is excellent for CNS penetration, well below the 90 A^2 threshold. Ligand B (111.63) is still reasonable, but less optimal.

**logP:** Ligand A (1.207) is within the optimal range (1-3). Ligand B (-0.061) is slightly below 1, which could potentially hinder permeation.

**H-Bond Donors/Acceptors:** Ligand A (HBD=1, HBA=5) is better than Ligand B (HBD=3, HBA=7) in terms of balancing solubility and permeability.

**QED:** Ligand A (0.866) has a significantly higher QED score than Ligand B (0.573), indicating a more drug-like profile.

**DILI:** Both ligands have similar and acceptable DILI risk (Ligand A: 34.432, Ligand B: 37.844), both below the 40% threshold.

**BBB:** Ligand A (66.964) has a better BBB percentile than Ligand B (27.801). While 66.964 isn't *outstanding*, it's considerably better for a CNS target.

**Caco-2 Permeability:** Ligand A (-5.109) and Ligand B (-5.857) both have negative values, which is unusual and suggests poor permeability. However, the scale isn't defined, so it's hard to interpret.

**Aqueous Solubility:** Both ligands have poor aqueous solubility (-1.009 and -1.207 respectively).

**hERG:** Both ligands have very low hERG inhibition risk (Ligand A: 0.076, Ligand B: 0.232).

**Microsomal Clearance:** Ligand A (-1.218) has a lower (better) microsomal clearance than Ligand B (-12.279), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (7.906) has a longer half-life than Ligand B (-3.019), which is desirable.

**P-gp Efflux:** Ligand A (0.008) has a much lower P-gp efflux liability than Ligand B (0.038), which is crucial for CNS penetration.

**Binding Affinity:** Ligand A (-8.6 kcal/mol) has a slightly better binding affinity than Ligand B (-8.2 kcal/mol). While the difference is small, it's still a factor.

**Overall Assessment:**

Ligand A consistently outperforms Ligand B across most critical parameters for a CNS-targeting GPCR ligand. It has a better BBB score, lower P-gp efflux, better metabolic stability, longer half-life, higher QED, and slightly better binding affinity. While both have poor solubility and Caco-2 permeability, the other advantages of Ligand A make it the more promising candidate.



Output:
1
2025-04-17 03:19:58,907 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (344.375) is slightly lower, which is generally favorable for permeability.

**TPSA:** Ligand B (84.5) is significantly better than Ligand A (104.19). For CNS targets, we want TPSA <= 90, and Ligand B is comfortably within this range, while Ligand A is pushing the limit.

**logP:** Ligand B (1.561) is optimal, while Ligand A (-0.121) is quite low, potentially hindering membrane permeability. This is a significant drawback for Ligand A.

**H-Bond Donors/Acceptors:** Ligand A (HBD=1, HBA=6) and Ligand B (HBD=2, HBA=4) both have reasonable numbers of H-bond donors and acceptors.

**QED:** Ligand A (0.818) has a higher QED score than Ligand B (0.616), indicating better overall drug-likeness.

**DILI:** Ligand B (44.668) has a lower DILI risk than Ligand A (71.229), which is preferable.

**BBB:** Ligand B (52.966) has a significantly better BBB penetration percentile than Ligand A (27.026). This is *critical* for a CNS target like DRD2.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values, which is unusual and suggests poor permeability. However, the scale is not specified, so it's difficult to interpret.

**Aqueous Solubility:** Both ligands have negative solubility values, which is also unusual and suggests poor solubility.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (Ligand A: 0.273, Ligand B: 0.464).

**Microsomal Clearance:** Ligand A (9.969) has lower microsomal clearance than Ligand B (55.89), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand B (-50.957) has a much longer in vitro half-life than Ligand A (-4.173). This is a significant advantage for Ligand B.

**P-gp Efflux:** Ligand A (0.044) has lower P-gp efflux than Ligand B (0.074), which is desirable for CNS penetration.

**Binding Affinity:** Ligand A (-8.6 kcal/mol) has a slightly better binding affinity than Ligand B (-7.7 kcal/mol). However, the difference is not substantial enough to overcome the other significant drawbacks of Ligand A.

**Overall Assessment:**

Despite the slightly better affinity of Ligand A, Ligand B is the more promising candidate. Its superior TPSA, logP, BBB penetration, DILI risk, and in vitro half-life outweigh the minor advantage in affinity and slightly better QED and P-gp efflux of Ligand A. The poor solubility and permeability (indicated by negative Caco-2 and solubility values) are concerning for both, but are secondary to the CNS-specific requirements for a DRD2 ligand.

Output:
1
2025-04-17 03:19:58,907 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (348.374) is slightly lower, which could be beneficial for permeability, but both are acceptable.

**TPSA:** Ligand A (84.5) is excellent for CNS penetration, falling well below the 90 A^2 threshold. Ligand B (29.54) is even better, indicating potentially improved BBB penetration.

**logP:** Both ligands have logP values within the optimal range (1-3), with Ligand A at 2.882 and Ligand B at 3.988. Ligand B is pushing the upper limit, potentially raising concerns about solubility and off-target effects, but it's not drastically outside the range.

**H-Bond Donors/Acceptors:** Ligand A has 2 HBD and 4 HBA, while Ligand B has 0 HBD and 3 HBA. Both are within acceptable limits (<=5 HBD and <=10 HBA).

**QED:** Both ligands have similar QED values (0.647 and 0.63), indicating good drug-like properties.

**DILI:** Ligand A has a DILI risk of 63.086, which is moderately high. Ligand B has a significantly lower DILI risk of 39.55, making it more favorable in terms of liver toxicity.

**BBB:** Ligand A has a BBB penetration percentile of 88.096, which is very good. Ligand B has a slightly higher BBB percentile of 90.849, suggesting better CNS exposure.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.522 and -4.669), which is unusual and suggests poor intestinal absorption. This is a significant drawback for both compounds.

**Aqueous Solubility:** Both ligands have very poor aqueous solubility (-3.707 and -4.479). This could pose formulation challenges.

**hERG Inhibition:** Ligand A has a very low hERG inhibition liability (0.173), which is excellent. Ligand B has a slightly higher, but still acceptable, hERG risk (0.717).

**Microsomal Clearance:** Ligand B has a much higher microsomal clearance (95.583) than Ligand A (51.222), indicating faster metabolism and potentially lower *in vivo* exposure.

**In vitro Half-Life:** Ligand A has a longer in vitro half-life (26.051 hours) compared to Ligand B (10.076 hours), which is desirable.

**P-gp Efflux:** Ligand A has a low P-gp efflux liability (0.241), while Ligand B has a higher efflux (0.495). Lower P-gp efflux is preferred for CNS penetration.

**Binding Affinity:** Ligand A has a stronger binding affinity (-8.9 kcal/mol) than Ligand B (-7.3 kcal/mol). This is a substantial difference (over 1.5 kcal/mol) and a major advantage for Ligand A.

**Overall Assessment:**

Despite the poor Caco-2 and solubility profiles for both, Ligand A is the more promising candidate. Its significantly stronger binding affinity (-8.9 vs -7.3 kcal/mol) outweighs the slightly higher DILI risk and higher P-gp efflux. The better half-life and lower clearance are also favorable. While Ligand B has better BBB penetration, the affinity difference is critical for a GPCR target. The lower DILI risk of Ligand B is attractive, but can be addressed during lead optimization.

Output:
0
2025-04-17 03:19:58,907 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (348.491 and 351.491 Da) fall within the ideal range of 200-500 Da.

**TPSA:** Ligand A (67.23) is better than Ligand B (69.72). Both are reasonably good for CNS penetration, being below 90, but closer to the ideal <60 is preferable.

**logP:** Both ligands have good logP values (2.481 and 1.787), falling within the optimal 1-3 range. Ligand B is slightly lower, which could marginally improve solubility but might slightly hinder permeability.

**H-Bond Donors/Acceptors:** Both ligands have acceptable HBD (1) and HBA (4 and 3) counts, well within the recommended limits.

**QED:** Both ligands have good QED scores (0.522 and 0.76), indicating drug-like properties. Ligand B is better here.

**DILI:** Both ligands have low DILI risk (18.069 and 20.047), both well below the 40 threshold.

**BBB:** Ligand B (65.452) has a significantly better BBB penetration percentile than Ligand A (55.603). This is a crucial advantage for a CNS target like DRD2.

**Caco-2 Permeability:** Ligand A (-4.823) has slightly better Caco-2 permeability than Ligand B (-4.668), suggesting better intestinal absorption. However, for a CNS target, intestinal absorption is less critical than BBB penetration.

**Aqueous Solubility:** Ligand A (-1.657) has slightly better aqueous solubility than Ligand B (-2.154).

**hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.228 and 0.122).

**Microsomal Clearance:** Ligand B (54.122) has lower microsomal clearance than Ligand A (59.074), indicating better metabolic stability.

**In vitro Half-Life:** Ligand A (29.476) has a longer in vitro half-life than Ligand B (-9.486). This is a positive for Ligand A, potentially allowing for less frequent dosing.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.05 and 0.085).

**Binding Affinity:** Ligand B (-8.6 kcal/mol) has a slightly better binding affinity than Ligand A (-7.6 kcal/mol). This 1 kcal/mol difference is significant and can outweigh some ADME drawbacks.

**Overall Assessment:**

While Ligand A has slightly better Caco-2 permeability, solubility, and half-life, Ligand B excels in the most critical areas for a CNS-targeting GPCR ligand: **BBB penetration and binding affinity**. The 10% difference in BBB penetration and the 1 kcal/mol difference in binding affinity are substantial advantages. The improved metabolic stability (lower Cl_mic) of Ligand B is also a plus. The slightly better QED of Ligand B is also favorable.

Output:
1
2025-04-17 03:19:58,907 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (351.363 and 360.483 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (130.58) is slightly above the optimal <90 for CNS targets, but still reasonable. Ligand B (71.69) is excellent, well below 90.

**logP:** Ligand A (0.708) is a bit low, potentially hindering permeability. Ligand B (1.877) is better, falling within the 1-3 optimal range.

**H-Bond Donors/Acceptors:** Both have acceptable HBD counts (1). Ligand A has 8 HBA, which is at the upper limit of preference, while Ligand B has 6, which is more favorable.

**QED:** Both ligands have good QED scores (0.741 and 0.852), indicating good drug-like properties.

**DILI:** Both have acceptable DILI risk (55.448 and 36.758), below the 60 threshold. Ligand B is slightly better.

**BBB:** Ligand A has a very good BBB penetration score (71.268), exceeding the 70% threshold. Ligand B (67.08) is lower, but still potentially acceptable.

**Caco-2 Permeability:** Ligand A (-4.619) has poor Caco-2 permeability. Ligand B (-5.018) is also poor, but slightly worse.

**Aqueous Solubility:** Both have poor aqueous solubility (-1.906 and -1.769). This could pose formulation challenges.

**hERG Inhibition:** Both have very low hERG inhibition risk (0.179 and 0.627).

**Microsomal Clearance:** Ligand A (36.673) has higher microsomal clearance than Ligand B (21.747), suggesting lower metabolic stability.

**In vitro Half-Life:** Ligand B (-23.064) has a significantly longer in vitro half-life than Ligand A (7.328), which is a major advantage.

**P-gp Efflux:** Both have very low P-gp efflux liability (0.006 and 0.065), which is excellent for CNS penetration.

**Binding Affinity:** Both have excellent binding affinity (-7.0 and -8.0 kcal/mol). Ligand B is 1 kcal/mol better, which is a substantial advantage.

**Overall Assessment:**

Ligand B is the stronger candidate. While both ligands have good affinity and acceptable safety profiles, Ligand B excels in several key areas: better logP, lower microsomal clearance (better metabolic stability), significantly longer half-life, and superior binding affinity. Ligand A's low logP and poor Caco-2 permeability are concerning. Although Ligand A has a slightly better BBB score, the other advantages of Ligand B outweigh this difference, especially considering the low P-gp efflux for both.

Output:
1
2025-04-17 03:19:58,908 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (379.517 Da) is slightly higher than Ligand B (352.435 Da), but both are acceptable.

**TPSA:** Ligand A (43.86) is excellent for CNS penetration, well below the 90 A^2 threshold. Ligand B (103.53) is higher, but still potentially acceptable, though less ideal.

**logP:** Ligand A (2.164) is optimal. Ligand B (0.308) is quite low, potentially hindering membrane permeability and CNS entry.

**H-Bond Donors/Acceptors:** Ligand A (0 HBD, 4 HBA) is favorable. Ligand B (3 HBD, 4 HBA) is also acceptable, but the 3 HBD might slightly reduce permeability.

**QED:** Both ligands have reasonable QED values (Ligand A: 0.584, Ligand B: 0.416), suggesting drug-like properties. Ligand A is better here.

**DILI:** Ligand A (11.594) has a significantly lower DILI risk than Ligand B (41.024), a major advantage.

**BBB:** Ligand A (86.817) has a very good BBB percentile, highly desirable for a CNS target. Ligand B (42.264) is poor, indicating limited brain penetration.

**Caco-2 Permeability:** Ligand A (-4.685) is poor. Ligand B (-5.234) is also poor.

**Aqueous Solubility:** Both have poor aqueous solubility (-1.215 and -1.543 respectively).

**hERG:** Both ligands have low hERG inhibition liability (0.471 and 0.257 respectively).

**Microsomal Clearance:** Ligand A (16.726) has lower clearance than Ligand B (20.519), indicating better metabolic stability.

**In vitro Half-Life:** Ligand A (-12) has a very poor half-life. Ligand B (1.814) is slightly better, but still not ideal.

**P-gp Efflux:** Both ligands show low P-gp efflux liability (0.021 and 0.062 respectively).

**Binding Affinity:** Both ligands have similar binding affinities (-6.2 kcal/mol and -6.4 kcal/mol). The difference is negligible.

**Overall Assessment:**

Ligand A is significantly better due to its superior BBB penetration, lower DILI risk, optimal logP, and better metabolic stability. While both have poor Caco-2 permeability and solubility, the CNS target prioritizes BBB. The slightly better QED of Ligand A is also a plus. The similar binding affinities make the ADME properties the deciding factor.

Output:
1
2025-04-17 03:19:58,908 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (340.467 and 336.479 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (41.57) is better than Ligand B (32.34) as it is closer to the ideal <90 for CNS targets.

**logP:** Ligand A (3.394) is within the optimal 1-3 range, while Ligand B (4.714) is slightly higher, potentially increasing off-target effects and decreasing solubility.

**H-Bond Donors/Acceptors:** Both ligands have 1 HBD and a reasonable number of HBAs (3 and 1 respectively), fulfilling the criteria.

**QED:** Both ligands have good QED scores (0.917 and 0.861), indicating drug-likeness.

**DILI:** Ligand A (13.843) has a significantly lower DILI risk than Ligand B (39.628), which is a major advantage.

**BBB:** Ligand A (95.812) has excellent BBB penetration, while Ligand B (85.615) is still good but less favorable. This is crucial for a CNS target like DRD2.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values, which is unusual and suggests poor permeability. However, the scale is not specified, so it's difficult to interpret.

**Aqueous Solubility:** Both ligands have negative solubility values, which is also unusual and suggests poor solubility.

**hERG Inhibition:** Both ligands have low hERG inhibition liability (0.819 and 0.929), which is good.

**Microsomal Clearance:** Ligand A (-4.606) has a lower (better) microsomal clearance than Ligand B (75.057), indicating greater metabolic stability.

**In vitro Half-Life:** Ligand A (20.229) has a moderate half-life, while Ligand B (35.693) has a longer half-life.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.172 and 0.619), which is favorable for CNS penetration.

**Binding Affinity:** Both ligands have excellent binding affinity (-9.4 and -9.0 kcal/mol), with Ligand A being slightly more potent. The difference is less than 1.5 kcal/mol, so it's not a decisive factor on its own.

**Overall Assessment:**

Considering all factors, **Ligand A is the more promising drug candidate**. It has a lower DILI risk, significantly better BBB penetration, and better metabolic stability (lower Cl_mic). While both have similar binding affinities, the improved ADME properties of Ligand A, particularly the BBB and DILI scores, make it the superior choice for a CNS-targeting GPCR like DRD2. The negative Caco-2 and solubility values are concerning for both, but the other advantages of Ligand A outweigh this issue.

Output:
1
2025-04-17 03:19:58,908 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (352.475 and 361.519 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (84.5) is better than Ligand B (73.45). Both are below the 90 A^2 threshold desirable for CNS targets.

**logP:** Both ligands have good logP values (2.165 and 1.977), falling within the optimal 1-3 range.

**H-Bond Donors & Acceptors:** Ligand A (2 HBD, 4 HBA) is slightly better than Ligand B (1 HBD, 8 HBA) as it has fewer HBA. Both are within acceptable limits.

**QED:** Both ligands have good QED scores (0.656 and 0.725), indicating good drug-like properties.

**DILI:** Ligand A (30.748) has a significantly lower DILI risk than Ligand B (52.152). This is a substantial advantage.

**BBB:** Ligand A (64.599) has a better BBB penetration score than Ligand B (59.131), although both are below the desirable >70 threshold.

**Caco-2 Permeability:** Ligand A (-4.552) has a worse Caco-2 permeability than Ligand B (-5.809).

**Aqueous Solubility:** Ligand A (-2.807) has a worse aqueous solubility than Ligand B (-2.665).

**hERG:** Both ligands have very low hERG inhibition liability (0.154 and 0.102), which is excellent.

**Microsomal Clearance:** Ligand B (46.809) has a lower microsomal clearance than Ligand A (65.821), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand B (-5.245) has a better in vitro half-life than Ligand A (-11.17).

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.036 and 0.177), which is favorable.

**Binding Affinity:** Ligand B (-7.2 kcal/mol) has a slightly better binding affinity than Ligand A (-8.0 kcal/mol). However, the difference is not substantial enough to outweigh other factors.

**Overall Assessment:**

Ligand A excels in DILI risk and TPSA, and has a good BBB score. Ligand B has better metabolic stability, half-life, and slightly better binding affinity. However, the significantly lower DILI risk of Ligand A is a major advantage, especially considering the potential for liver toxicity with CNS drugs. While Ligand B has a slightly better binding affinity, the difference is small and can be potentially optimized later. Given the GPCR-specific priorities, the better BBB and significantly lower DILI risk of Ligand A make it the more promising candidate.

Output:
1
2025-04-17 03:19:58,908 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (361.471 and 354.416 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (78.43) is better than Ligand B (33.2). For CNS targets, we want TPSA <= 90, both are within this range, but Ligand B is significantly lower, which is favorable for BBB penetration.

**logP:** Ligand A (1.149) is within the optimal 1-3 range. Ligand B (4.671) is higher, potentially leading to solubility issues and off-target interactions.

**H-Bond Donors/Acceptors:** Ligand A (1 HBD, 6 HBA) is better balanced. Ligand B (0 HBD, 2 HBA) is quite low, which might affect solubility.

**QED:** Ligand A (0.87) has a much better QED score than Ligand B (0.667), indicating a more drug-like profile.

**DILI:** Ligand A (52.423) has a higher DILI risk than Ligand B (24.544), but both are acceptable (<60).

**BBB:** Ligand B (92.051) has a significantly higher BBB penetration percentile than Ligand A (62.233). This is a crucial advantage for a CNS target like DRD2.

**Caco-2 Permeability:** Both have negative values, which is unusual and suggests a potential issue with the data or modeling. However, the absolute value for Ligand A (-4.983) is less negative than Ligand B (-4.511), suggesting slightly better permeability.

**Aqueous Solubility:** Both have negative values, also unusual. Ligand A (-2.508) is slightly better than Ligand B (-4.698).

**hERG Inhibition:** Ligand A (0.187) has a lower hERG inhibition risk than Ligand B (0.712), which is preferable.

**Microsomal Clearance:** Ligand A (38.015) has lower microsomal clearance than Ligand B (64.995), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (6.331) has a longer half-life than Ligand B (3.649), which is desirable.

**P-gp Efflux:** Ligand A (0.064) has lower P-gp efflux liability than Ligand B (0.493), which is beneficial for CNS exposure.

**Binding Affinity:** Ligand B (-7.9 kcal/mol) has a significantly stronger binding affinity than Ligand A (-9.5 kcal/mol). This is a substantial advantage, potentially outweighing some of the ADME drawbacks of Ligand B.

**Overall Assessment:**

Ligand B has a much stronger binding affinity and excellent BBB penetration, which are the most critical factors for a CNS GPCR target. While its logP is higher and QED lower, the strong affinity could compensate for these issues. Ligand A has better ADME properties overall (QED, DILI, hERG, Cl_mic, t1/2, Pgp), but its weaker binding affinity is a significant drawback. Given the importance of potency for GPCRs, the superior affinity of Ligand B makes it the more promising candidate.

Output:
1
2025-04-17 03:19:58,908 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (347.46 and 352.43 Da) fall comfortably within the ideal 200-500 Da range.

**TPSA:** Ligand A (78.51) is significantly better than Ligand B (104.73). For CNS targets, we want TPSA <= 90, and A is closer to this threshold.

**logP:** Ligand A (1.365) is within the optimal 1-3 range, while Ligand B (0.668) is slightly below 1. This is a potential concern for permeability, although not a deal-breaker.

**H-Bond Donors/Acceptors:** Ligand A (HBD=2, HBA=3) and Ligand B (HBD=3, HBA=5) are both reasonable, falling within the acceptable limits.

**QED:** Ligand A (0.737) has a better QED score than Ligand B (0.44), indicating a more drug-like profile.

**DILI:** Ligand A (21.95) has a much lower DILI risk than Ligand B (29.78), which is a significant advantage.

**BBB:** This is crucial for a CNS target like DRD2. Ligand A (58.01) is considerably better than Ligand B (17.02). A value >70 is desirable, but A is still much more promising than B.

**Caco-2 Permeability:** Both have negative Caco-2 values (-5.156 and -5.341), which is unusual and suggests poor permeability. However, these values are on a scale where negative values are possible and don't necessarily rule out absorption.

**Aqueous Solubility:** Both have negative solubility values (-2.218 and -1.502) which is also unusual.

**hERG:** Both ligands show very low hERG inhibition risk (0.074 and 0.047).

**Microsomal Clearance:** Ligand A (21.95) has a higher clearance than Ligand B (-4.841), indicating lower metabolic stability.

**In vitro Half-Life:** Ligand A (20.154 hours) has a much longer half-life than Ligand B (1.864 hours).

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.029 and 0.022).

**Binding Affinity:** Ligand B (-8.8 kcal/mol) has a slightly better binding affinity than Ligand A (-8.2 kcal/mol). However, the difference (0.6 kcal/mol) is not substantial enough to outweigh the significant ADME advantages of Ligand A.

**Overall Assessment:**

Ligand A is the stronger candidate. While Ligand B has a slightly better binding affinity, Ligand A excels in crucial ADME properties for a CNS-targeting GPCR: significantly better TPSA, BBB penetration, DILI risk, QED, and in vitro half-life. The slightly higher clearance of Ligand A is a concern, but the other advantages are more impactful. The negative Caco-2 and solubility values are concerning for both, but the other properties of A are much more favorable.

Output:
1
2025-04-17 03:19:58,909 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (447.34 Da) is higher, but still acceptable. Ligand B (368.327 Da) is slightly better.

**TPSA:** Ligand A (126.66) is pushing the limit for CNS penetration (ideally <90), while Ligand B (70.08) is well within the desired range. This is a significant advantage for Ligand B.

**logP:** Ligand A (2.663) is optimal. Ligand B (0.348) is quite low, potentially hindering membrane permeability and CNS entry despite the good TPSA.

**H-Bond Donors/Acceptors:** Ligand A has 2 HBD and 8 HBA, which are reasonable. Ligand B has 1 HBD and 4 HBA, also acceptable.

**QED:** Both ligands have similar QED values (0.595 and 0.496), indicating reasonable drug-likeness.

**DILI:** Ligand A has a high DILI risk (96.549), which is concerning. Ligand B has a much lower DILI risk (32.881), a significant advantage.

**BBB:** Ligand A has a low BBB penetration (33.85), which is unfavorable for a CNS target. Ligand B has a much better BBB penetration (66.576), although still not ideal (>70 is preferred).

**Caco-2 Permeability:** Ligand A has a negative Caco-2 value (-5.568), which is problematic. Ligand B also has a negative Caco-2 value (-4.622), suggesting poor intestinal absorption for both.

**Aqueous Solubility:** Both ligands have negative solubility values (-3.653 and -1.591), indicating poor solubility.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.479 and 0.48).

**Microsomal Clearance:** Ligand A has a moderate clearance (30.76), while Ligand B has a negative clearance (-3.327), which is unusual and could indicate instability or an issue with the prediction method.

**In vitro Half-Life:** Ligand A has a short half-life (-1.019), while Ligand B has a very short half-life (-19.152).

**P-gp Efflux:** Both ligands have low P-gp efflux (0.262 and 0.041), which is favorable for CNS penetration.

**Binding Affinity:** Ligand A has a better binding affinity (-8.2 kcal/mol) than Ligand B (-7.4 kcal/mol). This is a substantial difference and a major point in favor of Ligand A.

**Overall Assessment:**

Despite the superior binding affinity of Ligand A, its high DILI risk, poor BBB penetration, and negative Caco-2 permeability are major drawbacks. Ligand B, while having a slightly weaker affinity, has a much better safety profile (lower DILI), better BBB penetration, and a more favorable TPSA. The low logP of Ligand B is a concern, but the stronger affinity of Ligand A might not be enough to overcome its other liabilities. Considering the GPCR-specific priorities and the overall profile, Ligand B appears to be the more promising candidate, even with the slightly weaker binding.

Output:
1
2025-04-17 03:19:58,909 - INFO - Reasoning:

Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (347.415 and 352.479 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (78.95) is better than Ligand B (56.33) as it is closer to the optimal range for CNS targets (<=90). Ligand B is excellent.

**3. logP:** Ligand A (0.736) is slightly lower than optimal (1-3), potentially hindering permeation. Ligand B (-0.138) is even lower, raising concerns about permeability.

**4. H-Bond Donors:** Ligand A (1) is good. Ligand B (0) is also good.

**5. H-Bond Acceptors:** Ligand A (4) is good. Ligand B (5) is also good.

**6. QED:** Both ligands have acceptable QED values (0.764 and 0.666, both > 0.5).

**7. DILI:** Ligand A (29.391) has a much lower DILI risk than Ligand B (4.343), which is excellent.

**8. BBB:** Ligand B (76.464) has a significantly better BBB penetration percentile than Ligand A (65.723). This is a crucial advantage for a CNS target like DRD2.

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 values, which is unusual and suggests poor permeability. Ligand A (-4.3) is slightly worse than Ligand B (-4.764).

**10. Aqueous Solubility:** Both ligands have negative solubility values, which is also unusual and suggests poor solubility. Ligand A (-2.308) is slightly better than Ligand B (-0.025).

**11. hERG Inhibition:** Ligand A (0.106) shows lower hERG inhibition risk than Ligand B (0.45).

**12. Microsomal Clearance:** Ligand A (16.027) has lower microsomal clearance, indicating better metabolic stability, than Ligand B (22.174).

**13. In vitro Half-Life:** Ligand B (-27.972) has a longer in vitro half-life than Ligand A (-22.023).

**14. P-gp Efflux:** Ligand A (0.011) has lower P-gp efflux liability than Ligand B (0.004), which is favorable for CNS exposure.

**15. Binding Affinity:** Both ligands have very similar and strong binding affinities (-7.6 and -7.0 kcal/mol). The difference of 0.6 kcal/mol is not substantial enough to be a deciding factor.

**Overall Assessment:**

Ligand B has a significantly better BBB score and longer half-life, which are critical for CNS drug development. However, Ligand A has a much lower DILI risk, better metabolic stability (lower Cl_mic), and lower P-gp efflux. Both have poor Caco-2 and solubility. The affinity is comparable. Given the importance of CNS penetration for a DRD2 ligand, and the slightly better half-life, Ligand B is the more promising candidate, despite the slightly higher DILI risk.

Output:
1
2025-04-17 03:19:58,909 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (342.418 and 358.36 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (62.46) is significantly better than Ligand B (67.43). Both are below the 90 A^2 threshold for CNS targets, but A is closer to optimal.

**3. logP:** Both ligands have acceptable logP values (1.482 and 2.662, respectively), falling within the 1-3 range.

**4. H-Bond Donors:** Ligand A (1) is preferable to Ligand B (2). Lower HBD generally improves permeability.

**5. H-Bond Acceptors:** Ligand A (5) is preferable to Ligand B (3). Lower HBA generally improves permeability.

**6. QED:** Both ligands have reasonable QED scores (0.806 and 0.751), indicating good drug-like properties.

**7. DILI:** Both ligands have similar, acceptable DILI risk (44.242 and 45.677, respectively), well below the 60 threshold.

**8. BBB:** Ligand A (84.374) has a significantly higher BBB percentile than Ligand B (78.209). This is a crucial advantage for a CNS target like DRD2.

**9. Caco-2 Permeability:** Ligand A (-5.006) is better than Ligand B (-4.566), indicating better intestinal absorption.

**10. Aqueous Solubility:** Ligand A (-2.358) is better than Ligand B (-3.31), indicating better solubility.

**11. hERG Inhibition:** Both ligands have low hERG inhibition risk (0.93 and 0.535, respectively).

**12. Microsomal Clearance:** Ligand B (22.185) has lower microsomal clearance than Ligand A (38.188), suggesting better metabolic stability.

**13. In vitro Half-Life:** Ligand A (-34.951) has a much longer in vitro half-life than Ligand B (-14.146). This is a significant advantage.

**14. P-gp Efflux:** Ligand A (0.53) has lower P-gp efflux liability than Ligand B (0.089), which is favorable for CNS penetration.

**15. Binding Affinity:** Both ligands have very similar and strong binding affinities (-9.4 and -8.8 kcal/mol). The difference is less than 1.5 kcal/mol, so it's not a deciding factor.

**Overall Assessment:**

Ligand A is superior due to its better TPSA, lower HBD/HBA, higher BBB penetration, better Caco-2 permeability, better solubility, and lower P-gp efflux. While Ligand B has better metabolic stability (lower Cl_mic), the CNS-related properties of Ligand A are more critical for a DRD2 ligand. The longer half-life of Ligand A is also a significant benefit.

Output:
1
2025-04-17 03:19:58,909 - INFO - Reasoning:

Let's analyze Ligand A and Ligand B based on the provided guidelines, prioritizing GPCR-specific properties (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (344.375 and 354.495 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (106.15) is slightly above the optimal <90 for CNS targets, but still reasonable. Ligand B (90.54) is excellent, falling right within the desired range.

**logP:** Ligand A (0.777) is a bit low, potentially hindering permeation. Ligand B (0.644) is also on the lower side, presenting a similar concern.

**H-Bond Donors/Acceptors:** Ligand A has 1 HBD and 7 HBA, well within acceptable limits. Ligand B has 3 HBD and 4 HBA, also acceptable.

**QED:** Ligand A (0.776) has a better QED score than Ligand B (0.585), indicating a more drug-like profile.

**DILI:** Ligand A (72.354) has a higher DILI risk than Ligand B (14.618). This is a significant negative for Ligand A.

**BBB:** Ligand A (47.654) has a poor BBB percentile, making CNS penetration unlikely. Ligand B (37.573) is also low, but slightly better than A. Both are below the desirable >70 for CNS targets.

**Caco-2 Permeability:** Ligand A (-5.548) and Ligand B (-5.167) both have negative Caco-2 values, indicating poor intestinal absorption.

**Aqueous Solubility:** Both ligands have very poor aqueous solubility (-1.943 and -1.34, respectively). This is a concern for formulation and bioavailability.

**hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.029 and 0.194).

**Microsomal Clearance:** Ligand A (19.53) has higher microsomal clearance than Ligand B (7.028), suggesting lower metabolic stability.

**In vitro Half-Life:** Ligand A (-16.897) has a very short in vitro half-life, while Ligand B (5.024) is slightly better, but still not ideal.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.016 and 0.004). This is favorable for CNS exposure.

**Binding Affinity:** Ligand B (-7.3 kcal/mol) has a significantly stronger binding affinity than Ligand A (-8.2 kcal/mol). This 0.9 kcal/mol difference is substantial and can outweigh some ADME concerns.

**Overall Assessment:**

While Ligand A has a slightly better QED score, Ligand B is superior due to its significantly stronger binding affinity, much lower DILI risk, and slightly better BBB penetration. The poor solubility and Caco-2 permeability are concerns for both, but the strong affinity of Ligand B makes it more likely to achieve therapeutic concentrations in the brain despite these limitations. The lower clearance and better half-life of Ligand B are also advantageous.

Output:
1
2025-04-17 03:19:58,910 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (355.394 and 342.443 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (56.15) is excellent, well below the 90 A^2 target for CNS penetration. Ligand B (67.23) is still reasonable but less optimal.

**logP:** Ligand A (4.188) is slightly high, potentially leading to solubility issues or off-target interactions. Ligand B (1.691) is good, within the 1-3 range.

**H-Bond Donors/Acceptors:** Both ligands have 1 HBD and a reasonable number of HBAs (5 and 4 respectively), satisfying the criteria.

**QED:** Both ligands have similar QED values (0.6 and 0.606), indicating good drug-likeness.

**DILI:** Ligand A (96.898) has a very high DILI risk, a significant concern. Ligand B (10.237) has a very low DILI risk, which is highly favorable.

**BBB:** Ligand A (61.342) has a moderate BBB penetration, below the desirable >70% for CNS targets. Ligand B (73.284) has good BBB penetration, exceeding the 70% threshold.

**Caco-2 Permeability:** Ligand A (-4.734) has poor Caco-2 permeability. Ligand B (-5.254) also has poor Caco-2 permeability.

**Aqueous Solubility:** Ligand A (-4.682) has poor aqueous solubility. Ligand B (-1.0) has poor aqueous solubility, but is slightly better than Ligand A.

**hERG Inhibition:** Ligand A (0.828) has a moderate hERG risk. Ligand B (0.345) has a low hERG risk, which is preferable.

**Microsomal Clearance:** Ligand A (75.964) has moderate microsomal clearance. Ligand B (15.999) has low microsomal clearance, indicating better metabolic stability.

**In vitro Half-Life:** Ligand A (16.606) has a moderate in vitro half-life. Ligand B (-11.902) has a very short in vitro half-life, a major drawback.

**P-gp Efflux:** Ligand A (0.857) has moderate P-gp efflux. Ligand B (0.037) has very low P-gp efflux, which is highly desirable for CNS penetration.

**Binding Affinity:** Ligand A (-9.2 kcal/mol) has significantly stronger binding affinity than Ligand B (-8.1 kcal/mol). This is a substantial advantage.

**Overall Assessment:**

Despite Ligand A's superior binding affinity, its high DILI risk, poor solubility, moderate BBB penetration, and moderate P-gp efflux are major concerns. Ligand B, while having a slightly weaker affinity, demonstrates a much better safety profile (low DILI, low hERG), good BBB penetration, and very low P-gp efflux. The better ADME properties of Ligand B, particularly the low DILI and good BBB, outweigh the affinity difference, making it a more promising starting point for drug development targeting the CNS.

Output:
1
2025-04-17 03:19:58,910 - INFO - Batch 20 complete. Total preferences: 320
2025-04-17 03:19:58,910 - INFO - Processing batch 21/512...
2025-04-17 03:20:42,540 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B based on the provided guidelines, prioritizing GPCR-specific properties (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (352.475 and 366.487 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (59.08) is significantly better than Ligand B (95.74). For CNS targets, TPSA should be <=90, and A is comfortably within this range, while B is approaching the upper limit. This favors A.

**logP:** Both ligands have acceptable logP values (2.191 and 1.453), falling within the 1-3 optimal range. B is slightly lower, which could potentially impact permeability, but both are reasonable.

**H-Bond Donors/Acceptors:** Ligand A (0 HBD, 4 HBA) and Ligand B (2 HBD, 4 HBA) both have acceptable numbers of H-bond donors and acceptors, well below the thresholds of 5 and 10, respectively.

**QED:** Both ligands have good QED scores (0.659 and 0.729), indicating drug-like properties.

**DILI:** Ligand A (10.818) has a much lower DILI risk than Ligand B (22.722), which is a significant advantage.

**BBB:** Ligand A (90.074) has a better BBB penetration percentile than Ligand B (77.937). While both are reasonably good, >70 is desirable for CNS targets, and A is closer to that threshold. This is a key advantage for a DRD2 ligand.

**Caco-2 Permeability:** Ligand A (-4.405) has a worse Caco-2 permeability than Ligand B (-5.227). Lower values indicate lower permeability.

**Aqueous Solubility:** Both ligands have very poor aqueous solubility (-1.877 and -1.869). This could pose formulation challenges, but is not a deciding factor here.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.322 and 0.117).

**Microsomal Clearance:** Both ligands have similar microsomal clearance values (34.158 and 31.708), indicating similar metabolic stability.

**In vitro Half-Life:** Both ligands have similar in vitro half-lives (-2.061 and -2.033).

**P-gp Efflux:** Ligand A (0.069) has a lower P-gp efflux liability than Ligand B (0.016), which is beneficial for CNS exposure.

**Binding Affinity:** Ligand A (-7.6 kcal/mol) has a significantly stronger binding affinity than Ligand B (-6.8 kcal/mol). This 0.8 kcal/mol difference is substantial and can outweigh minor ADME drawbacks.

**Overall Assessment:**

Ligand A is the superior candidate. It has better TPSA, lower DILI risk, better BBB penetration, lower P-gp efflux, and significantly stronger binding affinity. While Caco-2 permeability is slightly worse, the other advantages, particularly the strong affinity and CNS penetration, make it the more promising drug candidate for targeting DRD2.

Output:
1
2025-04-17 03:20:42,541 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B based on the provided guidelines, prioritizing GPCR-specific properties (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (350.459 Da) is slightly lower, which could be beneficial for permeability. Ligand B (376.551 Da) is also good.

**TPSA:** Ligand A (89.87) is excellent, falling well below the 90 A^2 threshold for CNS targets. Ligand B (47.09) is also very good.

**logP:** Ligand A (0.828) is a bit low, potentially hindering permeation. Ligand B (4.053) is higher, approaching the upper limit and potentially causing solubility issues, but still acceptable.

**H-Bond Donors/Acceptors:** Ligand A (3 HBD, 4 HBA) is favorable. Ligand B (0 HBD, 7 HBA) is also reasonable.

**QED:** Both ligands have acceptable QED scores (A: 0.619, B: 0.555), indicating reasonable drug-likeness.

**DILI:** Ligand A (12.369) has a significantly lower DILI risk than Ligand B (45.328), which is a major advantage.

**BBB:** Ligand B (74.874) has a considerably better BBB penetration score than Ligand A (47.344). This is *critical* for a CNS target like DRD2.

**Caco-2 Permeability:** Both have negative values, which is unusual. Assuming these are logP-scale values, they indicate poor permeability.

**Aqueous Solubility:** Both ligands have negative solubility values, which is also unusual. Assuming these are logS values, they indicate poor solubility.

**hERG Inhibition:** Both ligands have low hERG inhibition liability (A: 0.173, B: 0.79), which is good.

**Microsomal Clearance:** Ligand A (16.113 mL/min/kg) has a lower clearance, suggesting better metabolic stability than Ligand B (64.605 mL/min/kg).

**In vitro Half-Life:** Ligand B (35.838 hours) has a significantly longer half-life than Ligand A (-6.54 hours). This is a substantial advantage.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (A: 0.063, B: 0.625), which is favorable for CNS penetration.

**Binding Affinity:** Both ligands have the same binding affinity (-7.5 kcal/mol), which is excellent.

**Overall Assessment:**

Ligand B excels in BBB penetration and in vitro half-life, both crucial for CNS drug development. However, it has a higher DILI risk and significantly higher microsomal clearance. Ligand A has a much lower DILI risk and better metabolic stability but suffers from poorer BBB penetration and a shorter half-life.

Given the importance of CNS penetration for a DRD2 target, the superior BBB score of Ligand B is a decisive factor, despite its drawbacks. The longer half-life also contributes to its favorability. While the DILI risk is higher, it might be mitigated through further structural modifications.

Output:
1
2025-04-17 03:20:42,541 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (351.324 Da) is slightly better than Ligand B (408.256 Da) as it's closer to the lower end, potentially aiding permeability.

**TPSA:** Ligand A (51.47) is significantly better than Ligand B (89.35). For CNS targets, TPSA should be <=90, and A is comfortably within this range, while B is approaching the upper limit.

**logP:** Both ligands have acceptable logP values (A: 3.655, B: 2.533), falling within the optimal 1-3 range. Ligand A is slightly higher, which could be a minor concern for solubility, but not a deal-breaker.

**H-Bond Donors/Acceptors:** Both have 1 HBD, which is good. Ligand A has 3 HBA, while Ligand B has 6.  Lower HBA is generally preferred for better permeability, making Ligand A slightly better.

**QED:** Both have good QED scores (A: 0.918, B: 0.789), indicating drug-like properties. Ligand A is superior.

**DILI:** Ligand A (48.197) has a much lower DILI risk than Ligand B (89.221). This is a significant advantage for Ligand A.

**BBB:** Ligand A (94.998) has excellent BBB penetration, exceeding the desirable >70% threshold. Ligand B (80.729) is also good, but not as high. This is a crucial factor for a CNS target like DRD2.

**Caco-2 Permeability:** Both have negative Caco-2 values (-4.4 and -4.811). This is unusual and suggests poor permeability *in vitro*. However, these values are on a scale where negative values are possible and don't necessarily disqualify a compound.

**Aqueous Solubility:** Both have very poor aqueous solubility (-4.281 and -4.492). This is a concern for both, but might be mitigated by formulation strategies.

**hERG Inhibition:** Ligand A (0.71) has a slightly higher hERG risk than Ligand B (0.254). This is a minor drawback for Ligand A.

**Microsomal Clearance:** Ligand B (74.373) has a higher microsomal clearance than Ligand A (39.095), meaning it's metabolized faster. Lower clearance is preferred, giving Ligand A an advantage.

**In vitro Half-Life:** Ligand A (38.645) has a significantly longer in vitro half-life than Ligand B (9.265). This is a substantial advantage for Ligand A.

**P-gp Efflux:** Ligand A (0.347) has lower P-gp efflux than Ligand B (0.274), meaning it's less likely to be pumped out of the brain, improving CNS exposure.

**Binding Affinity:** Ligand B (-8.2 kcal/mol) has a significantly stronger binding affinity than Ligand A (-10.4 kcal/mol). This is a major advantage for Ligand B, potentially outweighing some of its ADME drawbacks.

**Overall Assessment:**

While Ligand B boasts a superior binding affinity, Ligand A demonstrates a much more favorable ADME profile, particularly regarding BBB penetration, DILI risk, metabolic stability (lower Cl_mic and longer t1/2), and P-gp efflux. The difference in binding affinity (-1.9 kcal/mol) is substantial, but the ADME advantages of Ligand A, especially for a CNS target, are compelling. The poor solubility is a concern for both, but formulation strategies could potentially address this. Given the importance of CNS penetration for DRD2, and the overall better ADME profile, Ligand A is the more promising candidate.

Output:
1
2025-04-17 03:20:42,542 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (361.511 and 353.495 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (65.36) is better than Ligand B (62.73), both are below the 90 A^2 threshold for CNS targets.

**3. logP:** Ligand A (3.39) is optimal, while Ligand B (4.751) is pushing the upper limit. Higher logP can lead to off-target effects and solubility issues.

**4. H-Bond Donors:** Ligand A (1) is preferable to Ligand B (2). Fewer HBDs generally improve permeability.

**5. H-Bond Acceptors:** Ligand A (5) is preferable to Ligand B (6). Fewer HBAs generally improve permeability.

**6. QED:** Ligand A (0.815) is significantly better than Ligand B (0.693), indicating a more drug-like profile.

**7. DILI:** Ligand A (29.857) has a much lower DILI risk than Ligand B (83.637), a significant advantage.

**8. BBB:** Ligand A (60.372) and Ligand B (67.158) are both acceptable, but neither exceeds the desirable >70 percentile for CNS targets. Ligand B is slightly better.

**9. Caco-2 Permeability:** Ligand A (-4.811) and Ligand B (-5.047) are both poor, indicating poor intestinal absorption.

**10. Aqueous Solubility:** Ligand A (-3.822) is slightly better than Ligand B (-5.015), but both are poor.

**11. hERG Inhibition:** Ligand A (0.86) is better than Ligand B (0.644), indicating lower cardiotoxicity risk.

**12. Microsomal Clearance:** Ligand A (55.34) is better than Ligand B (83.609), suggesting better metabolic stability.

**13. In vitro Half-Life:** Ligand B (55.217) is better than Ligand A (21.463), indicating a longer half-life.

**14. P-gp Efflux:** Ligand A (0.222) is significantly better than Ligand B (0.312), indicating lower P-gp efflux and better CNS exposure.

**15. Binding Affinity:** Ligand B (-8.8 kcal/mol) has a significantly stronger binding affinity than Ligand A (-7.5 kcal/mol), a difference of 1.3 kcal/mol. This is a substantial advantage and can potentially offset some ADME deficiencies.

**Overall Assessment:**

Despite the superior binding affinity of Ligand B, Ligand A demonstrates a much more favorable ADME profile, particularly regarding DILI risk, P-gp efflux, and QED. While both have poor Caco-2 and solubility, the lower DILI and P-gp efflux of Ligand A are critical for CNS drug development. The stronger affinity of Ligand B is tempting, but the higher DILI and P-gp efflux raise significant concerns about its developability. Considering the GPCR-specific priorities, the improved ADME properties of Ligand A outweigh the affinity difference.

Output:
0
2025-04-17 03:20:42,542 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (361.808 Da) and Ligand B (350.415 Da) are both acceptable.

**TPSA:** Ligand A (82.74) is excellent for CNS penetration, falling well below the 90 A^2 threshold. Ligand B (99.1) is still reasonable, but less optimal.

**logP:** Ligand A (4.615) is a bit high, potentially leading to solubility issues and off-target effects. Ligand B (0.9) is quite low, which could hinder membrane permeability and potentially reduce binding affinity.

**H-Bond Donors/Acceptors:** Ligand A (2 HBD, 4 HBA) is within acceptable limits. Ligand B (3 HBD, 5 HBA) is also acceptable.

**QED:** Both ligands have reasonable QED scores (Ligand A: 0.837, Ligand B: 0.662), indicating good drug-like properties.

**DILI:** Ligand A (85.964) has a concerningly high DILI risk. Ligand B (14.114) has a very low DILI risk, which is a significant advantage.

**BBB:** Ligand A (64.211) has a moderate BBB penetration score, while Ligand B (16.983) is very poor for CNS penetration. This is a critical factor for a DRD2 ligand.

**Caco-2 Permeability:** Ligand A (-4.397) and Ligand B (-5.37) both have negative values, which is unusual. It suggests very poor permeability.

**Aqueous Solubility:** Ligand A (-6.554) and Ligand B (-1.319) both have negative values, indicating poor solubility.

**hERG Inhibition:** Both ligands show low hERG inhibition risk (Ligand A: 0.402, Ligand B: 0.276).

**Microsomal Clearance:** Ligand A (54.083) has moderate clearance, while Ligand B (-14.208) has negative clearance, which is not possible. This is likely an error in the data.

**In vitro Half-Life:** Ligand A (76.45) has a good half-life. Ligand B (-7.713) has a negative half-life, which is not possible.

**P-gp Efflux:** Ligand A (0.168) has low P-gp efflux, which is favorable. Ligand B (0.03) also has very low P-gp efflux.

**Binding Affinity:** Ligand A (-9.1 kcal/mol) has a significantly stronger binding affinity than Ligand B (0.0 kcal/mol). This is a major advantage for Ligand A.

**Overall Assessment:**

Ligand A has a much stronger binding affinity, a better BBB score, and lower P-gp efflux. However, it has a high DILI risk and a high logP. Ligand B has a very low DILI risk, but extremely poor BBB penetration, a very weak binding affinity, and questionable ADME properties (negative clearance and half-life).

Despite the DILI risk, the significantly superior binding affinity and reasonable BBB penetration of Ligand A make it the more promising candidate. The DILI risk could potentially be mitigated through structural modifications. The poor affinity and BBB penetration of Ligand B are more difficult to overcome.

Output:
1
2025-04-17 03:20:42,542 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, considering the provided guidelines and GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (364.511 and 355.485 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (62.55) is better than Ligand B (66.91). Both are below the 90 A^2 threshold for CNS targets, which is good.

**3. logP:** Both ligands (3.088 and 3.352) are within the optimal range of 1-3.

**4. H-Bond Donors:** Ligand A (1) is better than Ligand B (2). Lower is generally preferred.

**5. H-Bond Acceptors:** Ligand A (4) is better than Ligand B (5). Lower is generally preferred.

**6. QED:** Ligand A (0.892) is significantly better than Ligand B (0.636), indicating a more drug-like profile.

**7. DILI:** Ligand A (47.732) has a lower DILI risk than Ligand B (62.582), both are acceptable but A is preferable.

**8. BBB:** Ligand B (78.519) has a significantly better BBB penetration percentile than Ligand A (68.166). This is a critical factor for a CNS target like DRD2.

**9. Caco-2 Permeability:** Both have negative values, indicating poor permeability. Ligand A (-5.181) is slightly better than Ligand B (-5.321), but both are concerning.

**10. Aqueous Solubility:** Both have negative values, indicating poor solubility. Ligand A (-3.931) is slightly better than Ligand B (-4.272), but both are concerning.

**11. hERG Inhibition:** Both ligands have low hERG inhibition risk (0.55 and 0.506).

**12. Microsomal Clearance:** Ligand B (40.416) has lower microsomal clearance than Ligand A (53.359), suggesting better metabolic stability.

**13. In vitro Half-Life:** Ligand B (26.795) has a longer half-life than Ligand A (34.996).

**14. P-gp Efflux:** Ligand A (0.453) has lower P-gp efflux than Ligand B (0.241), which is beneficial for CNS exposure.

**15. Binding Affinity:** Ligand B (-9.6 kcal/mol) has a significantly stronger binding affinity than Ligand A (-8.2 kcal/mol) - a difference of 1.4 kcal/mol. This is a substantial advantage.

**Overall Assessment:**

While Ligand A has better QED, DILI, HBD, HBA, and P-gp efflux, Ligand B excels in the most critical areas for a CNS GPCR target: **BBB penetration and binding affinity**. The 1.4 kcal/mol difference in binding affinity is significant and can outweigh the drawbacks of slightly higher P-gp efflux and lower QED. The better metabolic stability (lower Cl_mic) and longer half-life of Ligand B are also advantageous. The poor Caco-2 and solubility for both are concerning, but can be addressed with formulation strategies.

Output:
1
2025-04-17 03:20:42,542 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (359.5 and 344.4 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (81.99) is higher than Ligand B (50.28). For CNS targets, TPSA should be <= 90, so both are acceptable, but Ligand B is significantly better.

**logP:** Both ligands (3.547 and 3.863) are within the optimal 1-3 range.

**H-Bond Donors:** Ligand A (2) and Ligand B (1) are both acceptable (<=5).

**H-Bond Acceptors:** Ligand A (4) and Ligand B (5) are both acceptable (<=10).

**QED:** Both ligands have good QED scores (0.627 and 0.7), indicating drug-like properties.

**DILI:** Ligand A (53.5) has a higher DILI risk than Ligand B (29.5). Both are below the concerning threshold of 60, but B is preferable.

**BBB:** This is a critical parameter for a CNS target like DRD2. Ligand B (85.5) has a substantially higher BBB penetration percentile than Ligand A (47.6). This is a major advantage for Ligand B.

**Caco-2 Permeability:** Both have negative values, which is unusual. Assuming these are logP-scale values, lower values indicate poorer permeability. Ligand A (-4.991) is worse than Ligand B (-4.457).

**Aqueous Solubility:** Both have negative values, which is also unusual. Assuming these are logS values, lower values indicate poorer solubility. Ligand A (-4.782) is worse than Ligand B (-4.594).

**hERG:** Both ligands have low hERG inhibition risk (0.68 and 0.937), which is good.

**Microsomal Clearance:** Ligand B (98.3) has a higher microsomal clearance than Ligand A (81.7), meaning it is less metabolically stable. This is a drawback for Ligand B.

**In vitro Half-Life:** Ligand A (37.7) has a longer half-life than Ligand B (14.3), which is preferable.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.338 and 0.646), which is good for CNS penetration.

**Binding Affinity:** Both ligands have excellent binding affinity (-8.0 and -8.2 kcal/mol). Ligand B is slightly better, but the difference is small.

**Overall Assessment:**

Ligand B is clearly the better candidate. Its significantly higher BBB penetration (85.5 vs 47.6) is a crucial advantage for a CNS target. While Ligand B has a higher microsomal clearance and shorter half-life, the superior BBB penetration and slightly better affinity outweigh these drawbacks. Ligand A has a better half-life, but its poor BBB penetration is a major limitation.

Output:
1
2025-04-17 03:20:42,542 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (407.312 Da) is slightly higher, but acceptable. Ligand B (346.435 Da) is also good.

**TPSA:** Ligand A (69.04) is excellent, falling well below the 90 A^2 threshold for CNS targets. Ligand B (107.72) is still reasonable, but less optimal, being closer to the 140 A^2 threshold for oral absorption.

**logP:** Ligand A (3.503) is at the upper end of the optimal range (1-3), potentially raising concerns about solubility and off-target effects, but not critically. Ligand B (2.175) is well within the optimal range.

**H-Bond Donors/Acceptors:** Ligand A has 1 HBD and 5 HBA, which are acceptable. Ligand B has 4 HBD and 6 HBA, also acceptable, but slightly higher.

**QED:** Ligand A (0.796) has a better QED score than Ligand B (0.518), indicating a more drug-like profile.

**DILI:** Ligand A (58.511) has a higher DILI risk than Ligand B (37.456), which is a negative.

**BBB:** Ligand A (62.466) has a better BBB penetration percentile than Ligand B (56.34), which is crucial for a CNS target like DRD2.

**Caco-2 Permeability:** Ligand A (-4.75) has a worse Caco-2 permeability score than Ligand B (-5.269), indicating lower intestinal absorption.

**Aqueous Solubility:** Ligand A (-4.644) has a worse aqueous solubility score than Ligand B (-3.123).

**hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.177 and 0.649 respectively).

**Microsomal Clearance:** Ligand A (94.645) has a higher microsomal clearance than Ligand B (25.53), suggesting lower metabolic stability.

**In vitro Half-Life:** Ligand A (-22.745) has a lower in vitro half-life than Ligand B (-3.435).

**P-gp Efflux:** Ligand A (0.322) has a lower P-gp efflux liability than Ligand B (0.101), which is favorable for CNS penetration.

**Binding Affinity:** Both ligands have similar binding affinities (-8.7 kcal/mol and -8.8 kcal/mol). The difference is negligible.

**Overall Assessment:**

Ligand A excels in TPSA, QED, and BBB penetration, and P-gp efflux, which are all important for a CNS-targeting GPCR. However, it suffers from higher DILI risk, lower solubility, worse Caco-2 permeability, and poorer metabolic stability (higher Cl_mic, lower t1/2).

Ligand B has a more favorable ADME profile overall (lower DILI, better solubility, better Caco-2, better metabolic stability), but its TPSA is higher and BBB penetration is lower.

Given the importance of BBB penetration for a CNS target like DRD2, and the similar binding affinities, Ligand A is slightly favored. The higher TPSA of Ligand B is a concern, and the better BBB of Ligand A could outweigh its other drawbacks. The slightly higher DILI risk of Ligand A could be addressed through structural modifications.

Output:
0
2025-04-17 03:20:42,543 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (351.359 Da and 367.515 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (121.71) is slightly above the optimal <90 for CNS targets, but still reasonable. Ligand B (80.32) is excellent, well below 90.

**logP:** Ligand A (0.03) is quite low, potentially hindering membrane permeability. Ligand B (2.676) is within the optimal 1-3 range. This is a significant advantage for Ligand B.

**H-Bond Donors & Acceptors:** Both have 2 HBD and are within the acceptable limits. Ligand A has 6 HBA, while Ligand B has 5. Both are acceptable.

**QED:** Both ligands have similar QED values (0.738 and 0.74), indicating good drug-likeness.

**DILI:** Ligand A (58.511) has a slightly better DILI score than Ligand B (52.966), but both are acceptable.

**BBB:** Ligand A (37.495) has a poor BBB percentile, which is a major concern for a CNS target. Ligand B (49.244) is better, but still not ideal (aim for >70).

**Caco-2 Permeability:** Ligand A (-5.007) has very poor Caco-2 permeability, consistent with its low logP. Ligand B (-4.851) is also poor, but slightly better than A.

**Aqueous Solubility:** Both ligands have poor aqueous solubility (-1.796 and -2.761). This could pose formulation challenges.

**hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.085 and 0.173).

**Microsomal Clearance:** Ligand A (1.606) has significantly lower microsomal clearance than Ligand B (30.656), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (-25.339) has a very poor in vitro half-life, while Ligand B (20.222) is better, but still not great.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.01 and 0.124).

**Binding Affinity:** Ligand B (-7.9 kcal/mol) has a significantly stronger binding affinity than Ligand A (-8.4 kcal/mol). While both are good, the 0.5 kcal/mol difference is substantial.

**Overall Assessment:**

Ligand B is the more promising candidate despite its moderate BBB penetration and solubility. Its superior logP, significantly stronger binding affinity, and better (though still not ideal) Caco-2 permeability outweigh the slightly higher DILI and lower metabolic stability compared to Ligand A. Ligand A's extremely poor BBB penetration and Caco-2 permeability are major drawbacks for a CNS target, even with its slightly better metabolic stability. The affinity difference of 0.5 kcal/mol is also significant.

Output:
1
2025-04-17 03:20:42,543 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (356.403 and 362.539 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (69.9) is slightly above the optimal <90 for CNS targets, but still reasonable. Ligand B (40.62) is excellent, well below 90.

**3. logP:** Both ligands have good logP values (2.381 and 3.954), falling within the 1-3 range. Ligand B is slightly higher, potentially increasing permeability but also raising concerns about off-target effects, though it's still within acceptable limits.

**4. H-Bond Donors:** Both have 0 HBD, which is good.

**5. H-Bond Acceptors:** Ligand A has 7 HBA, and Ligand B has 3 HBA. Both are within the acceptable limit of <=10.

**6. QED:** Both ligands have acceptable QED values (0.409 and 0.737), with Ligand B being significantly better.

**7. DILI:** Ligand A has a concerningly high DILI risk (90.733), while Ligand B has a very low risk (26.057). This is a major advantage for Ligand B.

**8. BBB:** Both ligands show good BBB penetration (70.027 and 89.608), exceeding the desirable >70 threshold for CNS targets. Ligand B is better.

**9. Caco-2 Permeability:** Both have negative Caco-2 values (-4.433 and -4.744). These values are difficult to interpret without knowing the scale, but negative values are generally unfavorable.

**10. Aqueous Solubility:** Both have negative solubility values (-4.246 and -3.357). Again, scale is unknown, but negative values are unfavorable.

**11. hERG Inhibition:** Both ligands have low hERG inhibition risk (0.384 and 0.626).

**12. Microsomal Clearance:** Ligand A (88.38) has higher clearance than Ligand B (69.741), suggesting lower metabolic stability.

**13. In vitro Half-Life:** Ligand B (7.377) has a slightly longer half-life than Ligand A (11.316).

**14. P-gp Efflux:** Both have low P-gp efflux liability (0.639 and 0.61).

**15. Binding Affinity:** Both ligands have the same binding affinity (-8.5 kcal/mol), which is excellent.

**Overall Assessment:**

While both ligands exhibit excellent binding affinity, Ligand B is significantly more promising due to its superior ADME properties. Specifically, its much lower DILI risk, better QED, better BBB penetration, and lower microsomal clearance outweigh the slightly higher logP and negative Caco-2/solubility values. The TPSA is also much more favorable for CNS penetration. The negative Caco-2 and solubility values are concerning for both, but can be addressed during lead optimization. The DILI risk for Ligand A is a major red flag.

Output:
1
2025-04-17 03:20:42,543 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (343.339 and 342.443 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (109.75) is higher than the preferred <90 for CNS targets, while Ligand B (70.25) is well within the range. This is a significant advantage for Ligand B.

**3. logP:** Both ligands have good logP values (2.515 and 2.241), falling within the optimal 1-3 range.

**4. H-Bond Donors:** Ligand A (1) and Ligand B (2) both meet the HBD <=5 criteria.

**5. H-Bond Acceptors:** Ligand A (6) and Ligand B (4) both meet the HBA <=10 criteria.

**6. QED:** Both ligands have good QED scores (0.66 and 0.894), indicating good drug-like properties. Ligand B is slightly better.

**7. DILI:** Ligand A (52.191) has a moderate DILI risk, while Ligand B (11.749) has a very low risk. This is a strong advantage for Ligand B.

**8. BBB:** Ligand A (69.678) is close to the desirable >70 threshold for CNS targets, but Ligand B (82.319) exceeds it comfortably. This is a significant advantage for Ligand B.

**9. Caco-2 Permeability:** Ligand A (-4.78) and Ligand B (-5.022) both have negative values, which is unusual and suggests poor permeability. However, the scale isn't specified, so it's hard to interpret.

**10. Aqueous Solubility:** Both ligands have negative solubility values (-3.365 and -2.317), which is concerning. Solubility is a potential issue for both.

**11. hERG Inhibition:** Both ligands have low hERG inhibition risk (0.837 and 0.741).

**12. Microsomal Clearance:** Ligand A (22.768) has higher microsomal clearance than Ligand B (8.217), indicating lower metabolic stability. Ligand B is better.

**13. In vitro Half-Life:** Ligand A (-16.242) has a negative half-life, which is not possible. This is a major red flag. Ligand B (-1.245) is also negative, but less so. These values are likely errors or on a strange scale.

**14. P-gp Efflux:** Both ligands have low P-gp efflux liability (0.455 and 0.026), which is good for CNS penetration. Ligand B is better.

**15. Binding Affinity:** Both ligands have very similar and strong binding affinities (-9.3 and -9.0 kcal/mol). The difference is not substantial enough to outweigh other factors.

**Overall Assessment:**

Ligand B is significantly better than Ligand A. It has a lower TPSA, lower DILI risk, better BBB penetration, better metabolic stability (lower Cl_mic), lower P-gp efflux, and a slightly higher QED. The negative half-life values are concerning for both, but less so for Ligand B. While both have solubility issues, Ligand B's superior ADME properties and CNS penetration potential make it the more promising candidate.

Output:
1
2025-04-17 03:20:42,543 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight (MW):** Both ligands (340.39 and 346.47 Da) fall comfortably within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (88.22) is better than Ligand B (69.64). Both are below the 90 A^2 threshold for CNS targets, but A is closer to the upper limit.

**3. logP:** Both ligands have good logP values (2.48 and 1.72), falling within the optimal 1-3 range. Ligand B is slightly lower, which could potentially improve solubility.

**4. H-Bond Donors (HBD):** Both have 2 HBD, well within the acceptable limit of 5.

**5. H-Bond Acceptors (HBA):** Ligand A has 6 HBA, while Ligand B has 3. Both are below the 10 limit.

**6. QED:** Both ligands have similar QED values (0.76 and 0.72), indicating good drug-like properties.

**7. DILI:** Ligand A has a significantly higher DILI risk (83.13) than Ligand B (4.34). This is a major concern for Ligand A.

**8. BBB:** Ligand A (74.72) has a better BBB percentile than Ligand B (55.60). This is crucial for a CNS target like DRD2.

**9. Caco-2 Permeability:** Both have negative Caco-2 values (-4.98 and -4.91), which is unusual and suggests poor permeability. This is a potential issue for both.

**10. Aqueous Solubility:** Both have negative solubility values (-3.25 and -2.54), indicating very poor aqueous solubility. This is a significant drawback for both.

**11. hERG Inhibition:** Both ligands have low hERG inhibition risk (0.30 and 0.22).

**12. Microsomal Clearance:** Ligand A (39.39) has a higher microsomal clearance than Ligand B (5.92), suggesting lower metabolic stability.

**13. In vitro Half-Life:** Ligand A (48.01) has a longer half-life than Ligand B (4.69).

**14. P-gp Efflux:** Both have very low P-gp efflux liability (0.09 and 0.02). This is favorable for CNS penetration.

**15. Binding Affinity:** Ligand A (-9.7 kcal/mol) has a significantly stronger binding affinity than Ligand B (-8.3 kcal/mol). This 1.4 kcal/mol difference is substantial and could outweigh some of the ADME drawbacks.

**Overall Assessment:**

Ligand A has a much stronger binding affinity and better BBB penetration, which are critical for a CNS GPCR target. However, its significantly higher DILI risk and higher microsomal clearance are major concerns. Ligand B has a much better safety profile (DILI) and metabolic stability, but weaker binding affinity and lower BBB penetration.

Given the strong affinity advantage of Ligand A, and the fact that the DILI risk *can* sometimes be mitigated through structural modifications, I would initially favor Ligand A, but with a strong caveat that further optimization to reduce DILI is essential. The affinity difference is large enough to prioritize it for initial development, assuming further work can address the safety concerns.

Output:
1
2025-04-17 03:20:42,544 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (347.459 and 367.515 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (73.64) is significantly better than Ligand B (80.32). For CNS targets, we want TPSA <= 90, and A is closer to the optimal <= 60 range.

**logP:** Both ligands have good logP values (1.945 and 2.676), falling within the 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A (0 HBD, 4 HBA) is slightly better than Ligand B (2 HBD, 5 HBA) in terms of maintaining a balance between solubility and permeability.

**QED:** Both ligands have similar and acceptable QED values (0.736 and 0.74).

**DILI:** Ligand A (22.489) has a much lower DILI risk than Ligand B (52.966), indicating a safer profile.

**BBB:** Ligand A (83.404) has a significantly higher BBB penetration percentile than Ligand B (49.244). This is *critical* for a CNS target like DRD2.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.507 and -4.851). These values are unusual and difficult to interpret without further context. However, they suggest poor permeability.

**Aqueous Solubility:** Both ligands have negative solubility values (-2.738 and -2.761) which is also unusual and suggests poor solubility.

**hERG:** Both ligands have low hERG inhibition liability (0.546 and 0.173), which is good.

**Microsomal Clearance:** Ligand A (49.309) has a higher microsomal clearance than Ligand B (30.656), suggesting lower metabolic stability.

**In vitro Half-Life:** Ligand B (20.222) has a significantly longer in vitro half-life than Ligand A (-17.556). This is a major advantage for B.

**P-gp Efflux:** Ligand A (0.145) has lower P-gp efflux liability than Ligand B (0.124), which is favorable for CNS exposure.

**Binding Affinity:** Ligand B (-7.9 kcal/mol) has a slightly better binding affinity than Ligand A (-7.4 kcal/mol), although the difference is relatively small.

**Overall Assessment:**

While Ligand B has a better binding affinity and half-life, Ligand A is superior in several key areas for a CNS-targeting GPCR: significantly better BBB penetration, lower DILI risk, and lower P-gp efflux. The TPSA is also more favorable for A. The negative Caco-2 and Solubility values are concerning for both, but the strong BBB score for A outweighs these concerns, especially given the target. The slightly higher clearance of A is a drawback, but potentially manageable.

Output:
0
2025-04-17 03:20:42,544 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B based on the provided guidelines, prioritizing GPCR-specific properties (BBB, logP, Pgp, TPSA, and affinity) for DRD2.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (351.324 Da) is slightly lower, which could be beneficial for permeability. Ligand B (363.483 Da) is also good.

**TPSA:** Ligand A (59.42) is excellent for CNS penetration, well below the 90 A^2 threshold. Ligand B (82.53) is still reasonable, but less optimal than Ligand A.

**logP:** Ligand A (3.945) is at the higher end of the optimal range, potentially leading to solubility issues. Ligand B (1.897) is lower, closer to the bottom end of the optimal range, which is generally preferred for avoiding off-target effects.

**H-Bond Donors/Acceptors:** Ligand A (HBD=1, HBA=4) and Ligand B (HBD=2, HBA=5) both have acceptable numbers of H-bond donors and acceptors.

**QED:** Both ligands have reasonable QED scores (A: 0.851, B: 0.723), indicating good drug-like properties.

**DILI:** Ligand A (62.893) has a higher DILI risk than Ligand B (46.258), which is preferable.

**BBB:** This is a critical parameter for a CNS target like DRD2. Ligand A (83.288) has a significantly better BBB percentile than Ligand B (46.84). This is a major advantage for Ligand A.

**Caco-2 Permeability:** Ligand A (-4.52) has a negative value, which is unusual and suggests very poor permeability. Ligand B (-5.381) is also poor, but slightly less so.

**Aqueous Solubility:** Both ligands have poor aqueous solubility (-4.049 and -3.42 respectively).

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.313 and 0.34 respectively).

**Microsomal Clearance:** Ligand A (28.576) and Ligand B (21.938) have similar, relatively low, microsomal clearance values, suggesting reasonable metabolic stability.

**In vitro Half-Life:** Ligand B (-14.435) has a significantly longer in vitro half-life than Ligand A (-4.556), which is a positive attribute.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.617 and 0.076 respectively), which is good for CNS penetration. Ligand B is better.

**Binding Affinity:** Ligand A (-9.9 kcal/mol) has a substantially stronger binding affinity than Ligand B (-7.4 kcal/mol). This is a significant advantage, potentially outweighing some of the ADME drawbacks.

**Overall Assessment:**

Ligand A excels in binding affinity and BBB penetration, which are crucial for a CNS GPCR target. However, it has poor Caco-2 permeability and a higher DILI risk. Ligand B has better ADME properties (lower DILI, better half-life, lower Pgp efflux), but significantly weaker binding affinity and lower BBB penetration.

Given the strong emphasis on affinity for GPCRs, and the importance of BBB penetration for CNS targets, the superior binding affinity of Ligand A (-9.9 kcal/mol vs -7.4 kcal/mol) is the deciding factor. While its Caco-2 permeability is a concern, the strong binding and good BBB suggest it's more likely to achieve target engagement in the brain. The poor permeability might be addressed through formulation strategies.



Output:
1
2025-04-17 03:20:42,544 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (342.4 and 338.4 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (86.11) is excellent for CNS penetration, well below the 90 A^2 threshold. Ligand B (115.16) is higher, but still potentially acceptable, though less ideal.

**3. logP:** Ligand A (1.246) is within the optimal range (1-3). Ligand B (3.561) is at the higher end of the optimal range, potentially raising concerns about solubility and off-target effects, but not critically.

**4. H-Bond Donors:** Ligand A (1) and Ligand B (2) are both within the acceptable limit of <=5.

**5. H-Bond Acceptors:** Ligand A (6) and Ligand B (3) are both within the acceptable limit of <=10.

**6. QED:** Ligand A (0.657) has a better QED score than Ligand B (0.493), indicating a more drug-like profile.

**7. DILI:** Ligand A (50.6%) has a lower DILI risk than Ligand B (65.7%), which is preferable.

**8. BBB:** This is crucial for a CNS target like DRD2. Ligand A (69.4%) is significantly better than Ligand B (48.9%). Ligand A is approaching the desirable >70% threshold.

**9. Caco-2:** Both have negative values, indicating poor permeability. This is unusual and requires further investigation, but we'll proceed with relative comparison. Ligand A (-4.857) is better than Ligand B (-5.322).

**10. Solubility:** Both have negative values, indicating poor solubility. Ligand A (-2.297) is better than Ligand B (-3.209).

**11. hERG:** Both have very low hERG inhibition liability (0.14 and 0.028), which is excellent.

**12. Cl_mic:** Ligand A (20.8) has a higher (worse) microsomal clearance than Ligand B (-4.341), suggesting faster metabolism.

**13. t1/2:** Ligand B (7.749) has a longer in vitro half-life than Ligand A (-9.443), which is a significant advantage.

**14. Pgp:** Ligand A (0.145) has lower P-gp efflux than Ligand B (0.019), which is favorable for CNS penetration.

**15. Affinity:** Ligand B (-8.6 kcal/mol) has a slightly better binding affinity than Ligand A (-7.8 kcal/mol). This is a 0.8 kcal/mol difference, which is significant but not overwhelming.

**Overall Assessment:**

Ligand A excels in properties critical for CNS penetration (TPSA, BBB, Pgp) and has a better drug-like profile (QED) and lower DILI risk. While Ligand B has a slightly better binding affinity and longer half-life, the superior CNS penetration profile of Ligand A, combined with its better QED and lower DILI, makes it the more promising candidate for a DRD2-targeting drug. The slightly worse metabolic stability of Ligand A could be addressed through structural modifications.

Output:
1
2025-04-17 03:20:42,544 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (348.349 and 357.495 Da) fall within the ideal range of 200-500 Da.

**TPSA:** Ligand A (67.43) is excellent, well below the 90 A^2 threshold for CNS targets. Ligand B (90.9) is at the upper limit, but still acceptable.

**logP:** Ligand A (3.121) is optimal. Ligand B (0.515) is quite low, potentially hindering membrane permeability and CNS penetration.

**H-Bond Donors/Acceptors:** Ligand A (2 HBD, 3 HBA) is good. Ligand B (3 HBD, 5 HBA) is also acceptable.

**QED:** Ligand A (0.843) is very good, indicating high drug-likeness. Ligand B (0.589) is acceptable, but lower.

**DILI:** Ligand A (81.427) has a higher DILI risk than Ligand B (9.926). This is a significant drawback for Ligand A.

**BBB:** Ligand A (73.362) has good BBB penetration. Ligand B (24.002) has poor BBB penetration, a critical issue for a CNS target like DRD2.

**Caco-2 Permeability:** Ligand A (-4.347) has poor Caco-2 permeability. Ligand B (-5.248) also has poor Caco-2 permeability.

**Aqueous Solubility:** Ligand A (-4.308) has poor aqueous solubility. Ligand B (-0.724) has slightly better aqueous solubility, but still not ideal.

**hERG Inhibition:** Ligand A (0.625) has a low risk of hERG inhibition. Ligand B (0.216) has an even lower risk.

**Microsomal Clearance:** Ligand A (45.19) has moderate clearance. Ligand B (24.74) has lower clearance, indicating better metabolic stability.

**In vitro Half-Life:** Ligand A (8.644) has a moderate half-life. Ligand B (12.048) has a longer half-life, which is preferable.

**P-gp Efflux:** Ligand A (0.181) has low P-gp efflux, which is good for CNS penetration. Ligand B (0.01) has very low P-gp efflux, even better.

**Binding Affinity:** Ligand A (-9.2 kcal/mol) has significantly stronger binding affinity than Ligand B (-6.7 kcal/mol). This is a substantial advantage.

**Overall Assessment:**

Despite Ligand A's higher DILI risk and poor solubility/permeability, its *much* stronger binding affinity (-9.2 vs -6.7 kcal/mol) is a major advantage, especially for a GPCR target. The difference of 2.5 kcal/mol is substantial and could outweigh the ADME concerns, *provided* formulation strategies can address the solubility issues. Ligand B's poor BBB penetration is a deal-breaker for a CNS target like DRD2.

Output:
1
2025-04-17 03:20:42,545 - INFO - Batch 21 complete. Total preferences: 336
2025-04-17 03:20:42,545 - INFO - Processing batch 22/512...
2025-04-17 03:21:26,357 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (358.471 and 366.845 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (76.8) is slightly higher than Ligand B (71.78), but both are below the 90 A^2 threshold desirable for CNS targets.

**logP:** Both ligands have good logP values (3.143 and 2.779), falling within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A has 0 HBD and 7 HBA, while Ligand B has 1 HBD and 4 HBA. Both are within acceptable limits (<=5 HBD and <=10 HBA).

**QED:** Both ligands have good QED scores (0.7 and 0.813), indicating good drug-like properties.

**DILI:** Ligand A (77.472) has a higher DILI risk than Ligand B (51.842). This is a significant concern, as a lower DILI score is preferred.

**BBB:** Ligand A (61.535) has a better BBB penetration percentile than Ligand B (45.638). However, both are below the desirable >70 for CNS targets.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.269 and -4.872), which is unusual and suggests poor permeability. This is a major red flag.

**Aqueous Solubility:** Both ligands have negative solubility values (-3.146 and -3.435), indicating very poor aqueous solubility. This is also a major concern.

**hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.296 and 0.204).

**Microsomal Clearance:** Ligand A (71.179) has higher microsomal clearance than Ligand B (7.436), suggesting lower metabolic stability.

**In vitro Half-Life:** Ligand B (44.787) has a longer in vitro half-life than Ligand A (32.409).

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.446 and 0.097), which is good for CNS penetration.

**Binding Affinity:** Both ligands have very similar and strong binding affinities (-8.4 and -8.3 kcal/mol). The difference is negligible.

**Conclusion:**

Despite similar binding affinities, Ligand B is the more promising candidate. Its significantly lower DILI risk (51.842 vs 77.472) and longer half-life (44.787 vs 32.409) are major advantages. While both have poor Caco-2 and solubility, the lower DILI risk is a critical factor for drug development. The slightly better BBB of Ligand A is not enough to offset the higher DILI risk and lower half-life.

Output:
1
2025-04-17 03:21:26,358 - INFO - Reasoning:

Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, considering the provided guidelines and GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (359.813 and 361.829 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Both ligands have a TPSA of 71.53, which is acceptable for general oral absorption but slightly high for optimal CNS penetration (ideally <90, but closer to 60 is preferred).

**3. logP:** Both ligands have logP values within the optimal range (3.651 and 3.233).

**4. H-Bond Donors:** Both have 1 HBD, which is within the acceptable limit of <=5.

**5. H-Bond Acceptors:** Both have 4 HBA, also within the acceptable limit of <=10.

**6. QED:** Both ligands have QED values above 0.8, indicating a strong drug-like profile.

**7. DILI:** Ligand A (80.729) has a higher DILI risk than Ligand B (77.588), but both are reasonably acceptable.

**8. BBB:** This is a critical parameter for a CNS target like DRD2. Ligand A has a BBB percentile of 82.706, significantly higher than Ligand B's 53.276. This is a major advantage for Ligand A.

**9. Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual. It's difficult to interpret without knowing the scale, but it suggests poor permeability.

**10. Aqueous Solubility:** Both have negative solubility values, again difficult to interpret without knowing the scale.

**11. hERG Inhibition:** Both ligands show low hERG inhibition liability (0.471 and 0.34), which is good.

**12. Microsomal Clearance:** Both have similar microsomal clearance values (74.533 and 78.046), suggesting comparable metabolic stability.

**13. In vitro Half-Life:** Ligand B has a longer in vitro half-life (38.959 hours) than Ligand A (18.192 hours), which is a positive attribute.

**14. P-gp Efflux:** Both ligands exhibit low P-gp efflux liability (0.549 and 0.086), which is favorable for CNS penetration. Ligand B is significantly better here.

**15. Binding Affinity:** Both ligands have excellent binding affinities (-9.3 and -8.9 kcal/mol). Ligand A is slightly more potent, but the difference is less than 1.5 kcal/mol.

**Overall Assessment:**

Considering the GPCR-specific priorities, Ligand A is the better candidate. The significantly higher BBB penetration (82.706 vs 53.276) is crucial for a CNS-targeting drug. While Ligand B has a longer half-life and lower P-gp efflux, the BBB difference outweighs these advantages. The slightly better affinity of Ligand A is a bonus. The negative values for Caco-2 and solubility are concerning for both, but the BBB advantage of A is compelling.

Output:
1
2025-04-17 03:21:26,358 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (341.426 Da) is slightly better being closer to the lower end, which can aid permeability.

**TPSA:** Ligand A (32.7) is excellent for CNS penetration, well below the 90 A^2 threshold. Ligand B (84.3) is higher, but still acceptable, though less ideal for CNS targets.

**logP:** Ligand A (3.719) is optimal. Ligand B (2.485) is also good, but slightly lower, potentially impacting membrane permeability.

**H-Bond Donors/Acceptors:** Both ligands have 1 HBD, which is good. Ligand A has 3 HBA, and Ligand B has 5 HBA. Both are within the acceptable range of <=10.

**QED:** Both ligands have good QED scores (A: 0.924, B: 0.816), indicating drug-like properties.

**DILI:** Ligand A (9.228) has a significantly lower DILI risk than Ligand B (70.725), which is a major advantage.

**BBB:** Ligand A (90.074) has excellent BBB penetration, exceeding the 70% threshold. Ligand B (72.547) is also good, but less favorable than Ligand A.

**Caco-2 Permeability:** Both have negative Caco-2 values (-4.707 and -4.776). This is unusual and suggests poor permeability *in vitro*. However, these values are on a log scale and the negative values are likely indicating very low permeability.

**Aqueous Solubility:** Both have negative solubility values (-3.175 and -3.39). Similar to Caco-2, this indicates poor aqueous solubility.

**hERG:** Ligand A (0.994) has a slightly higher hERG risk than Ligand B (0.304), but both are relatively low.

**Microsomal Clearance:** Ligand A (40.897) has higher microsomal clearance than Ligand B (27.797), suggesting faster metabolism and potentially lower *in vivo* exposure.

**In vitro Half-Life:** Ligand B (99.968) has a significantly longer half-life than Ligand A (5.454), which is a substantial benefit.

**P-gp Efflux:** Ligand A (0.975) has slightly higher P-gp efflux than Ligand B (0.255), meaning less CNS exposure.

**Binding Affinity:** Ligand A (-10.3 kcal/mol) has a significantly stronger binding affinity than Ligand B (-9.0 kcal/mol). This is a crucial factor, as a >1.5 kcal/mol advantage can outweigh other drawbacks.

**Overall Assessment:**

Ligand A excels in binding affinity and BBB penetration, and has a much lower DILI risk. However, it suffers from higher microsomal clearance and P-gp efflux, and poorer solubility. Ligand B has a longer half-life and lower P-gp efflux, but weaker binding affinity and a higher DILI risk.

Given the importance of strong binding affinity for GPCR ligands, and the CNS target, the superior affinity and BBB penetration of Ligand A, combined with the significantly lower DILI risk, outweigh its drawbacks. The solubility and permeability issues could be addressed with formulation strategies.

Output:
1
2025-04-17 03:21:26,358 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (334.419 Da) is slightly lower, which is generally favorable for permeability. Ligand B (357.357 Da) is also good.

**TPSA:** Ligand A (44.95) is excellent, well below the 90 A^2 threshold for CNS targets. Ligand B (80.76) is higher but still acceptable, though less ideal.

**logP:** Ligand A (3.412) is within the optimal range (1-3). Ligand B (1.183) is at the lower end, potentially hindering permeation.

**H-Bond Donors/Acceptors:** Both ligands have a reasonable number of HBDs (1) and HBAs (Ligand A: 3, Ligand B: 5), falling within the guidelines.

**QED:** Both ligands have good QED values (A: 0.673, B: 0.756), indicating drug-like properties.

**DILI:** Ligand A (22.993) has a significantly lower DILI risk than Ligand B (39.201), which is a strong advantage.

**BBB:** Both ligands have excellent BBB penetration (A: 77.627, B: 78.48), exceeding the 70% threshold for CNS targets.

**Caco-2 Permeability:** Both ligands show negative Caco-2 permeability values, which is unusual and suggests a potential issue with the model or data. However, we'll proceed assuming this indicates poor permeability.

**Aqueous Solubility:** Both ligands have negative solubility values, which is also unusual and suggests a potential issue with the model or data.

**hERG Inhibition:** Both ligands have low hERG inhibition liability (A: 0.819, B: 0.29), which is positive.

**Microsomal Clearance:** Ligand A (44.082) has a higher microsomal clearance than Ligand B (16.754), suggesting lower metabolic stability.

**In vitro Half-Life:** Ligand B (-17.563) has a negative half-life, which is impossible and indicates a data issue. Ligand A (6.161) is reasonable.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (A: 0.377, B: 0.016), which is favorable for CNS exposure.

**Binding Affinity:** Ligand A (-9.0 kcal/mol) has a significantly stronger binding affinity than Ligand B (-6.9 kcal/mol). This is a substantial advantage, potentially outweighing some ADME drawbacks.

**Overall Assessment:**

Ligand A is the stronger candidate. While Ligand B has a slightly better QED and P-gp efflux profile, Ligand A excels in critical areas: significantly better binding affinity, lower DILI risk, and a reasonable half-life. The negative Caco-2 and solubility values are concerning for both, but the large affinity difference for ligand A is a compelling factor. The higher clearance of Ligand A is a concern, but could be addressed through structural modifications. Ligand B's negative half-life is a fatal flaw.

Output:
1
2025-04-17 03:21:26,359 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (356.413 and 344.375 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (71.34) is excellent, well below the 90 A^2 threshold for CNS targets. Ligand B (112.33) is higher, but still potentially acceptable, though less optimal.

**3. logP:** Ligand A (3.202) is within the optimal 1-3 range. Ligand B (0.684) is quite low, which could hinder membrane permeability and CNS penetration.

**4. H-Bond Donors:** Both ligands have acceptable HBD counts (2 and 1, respectively), well under the 5 limit.

**5. H-Bond Acceptors:** Ligand A (3) is good. Ligand B (5) is also acceptable, under the 10 limit.

**6. QED:** Ligand A (0.788) has a strong drug-like profile. Ligand B (0.258) is significantly lower, indicating a less desirable overall drug-likeness.

**7. DILI:** Both ligands have acceptable DILI risk (44.591 and 51.338, respectively), below the 60 threshold.

**8. BBB:** Ligand A (87.515) has a very good BBB penetration prediction. Ligand B (46.84) is considerably lower, raising concerns about CNS exposure.

**9. Caco-2 Permeability:** Ligand A (-4.432) and Ligand B (-4.793) both have negative values, which is unusual. It's difficult to interpret without knowing the scale. However, a lower (more negative) value suggests lower permeability.

**10. Aqueous Solubility:** Both ligands have negative solubility values (-3.779 and -1.128), also unusual. Again, without knowing the scale, it's hard to interpret, but lower values suggest lower solubility.

**11. hERG Inhibition:** Both ligands have low hERG inhibition risk (0.519 and 0.178, respectively).

**12. Microsomal Clearance:** Ligand A (42.109) has a moderate clearance. Ligand B (-3.67) is negative, which is not physically possible and indicates an issue with the data.

**13. In vitro Half-Life:** Ligand A (33.18) has a reasonable half-life. Ligand B (-5.159) is negative, again indicating a data issue.

**14. P-gp Efflux:** Ligand A (0.172) has low P-gp efflux, which is favorable. Ligand B (0.018) also has very low P-gp efflux.

**15. Binding Affinity:** Ligand A (-8.5 kcal/mol) has significantly stronger binding affinity than Ligand B (-6.7 kcal/mol). This is a substantial difference (1.8 kcal/mol), which can outweigh some ADME drawbacks.

**Overall Assessment:**

Ligand A is clearly superior. It has a better logP, QED, BBB prediction, and significantly stronger binding affinity. While both have unusual solubility and Caco-2 permeability values, the negative values for clearance and half-life for Ligand B are concerning data quality issues. Ligand A's profile aligns much better with the desired characteristics for a CNS-targeting GPCR ligand.

Output:
1
2025-04-17 03:21:26,359 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (346.471 and 354.491 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (64.36) is slightly above the optimal <90 for CNS targets, but still reasonable. Ligand B (59.08) is excellent, well below 90.

**logP:** Ligand A (4.904) is high, potentially leading to solubility issues and off-target effects. Ligand B (1.923) is within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A (1 HBD, 5 HBA) is good. Ligand B (0 HBD, 4 HBA) is also good. Both are within acceptable limits.

**QED:** Both ligands have similar QED values (0.753 and 0.656), indicating good drug-likeness.

**DILI:** Ligand A (63.746) has a concerning DILI risk, being above the 60 threshold. Ligand B (11.051) has a very low DILI risk, which is a significant advantage.

**BBB:** Ligand A (69.407) is close to the desirable >70 threshold for CNS targets. Ligand B (80.574) is excellent, well above 70.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.61 and -4.258). This is unusual and suggests poor permeability. However, these values are on a log scale and can be misleading. We'll consider this a neutral point for now, but it warrants further investigation.

**Aqueous Solubility:** Both ligands have very poor aqueous solubility (-6.344 and -0.805). This is a significant drawback, especially given Ligand A's high logP.

**hERG Inhibition:** Ligand A (0.684) shows some hERG inhibition liability, while Ligand B (0.49) is lower risk.

**Microsomal Clearance:** Ligand A (111.673) has higher clearance, indicating lower metabolic stability. Ligand B (40.189) has lower clearance, suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (99.005) has a good in vitro half-life. Ligand B (-0.897) has a very short half-life, which is a major concern.

**P-gp Efflux:** Ligand A (0.554) has moderate P-gp efflux liability. Ligand B (0.104) has very low P-gp efflux, which is highly desirable for CNS penetration.

**Binding Affinity:** Ligand A (-8.9 kcal/mol) has significantly stronger binding affinity than Ligand B (-7.5 kcal/mol). This is a substantial advantage, potentially outweighing some of its other drawbacks. The difference is >1.5 kcal/mol.

**Overall Assessment:**

Ligand A has a much stronger binding affinity, but suffers from a high DILI risk, high logP, moderate P-gp efflux, and some hERG liability. Its BBB penetration is acceptable, but solubility is poor.

Ligand B has a much better safety profile (low DILI, low hERG, low P-gp), excellent BBB penetration, and a good logP. However, its binding affinity is weaker, and its in vitro half-life is very short.

Given the GPCR-specific priorities and the significant affinity difference, **Ligand A is the more promising candidate despite its drawbacks.** The stronger binding affinity is likely to be crucial for efficacy, and the other issues might be addressable through further optimization. The poor solubility and high logP could be mitigated with formulation strategies or structural modifications. The DILI risk is concerning, but could be investigated further. The short half-life of Ligand B is a more difficult problem to solve.

Output:
1
2025-04-17 03:21:26,359 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (352.391 and 367.427 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (106.79) is slightly above the optimal <90 for CNS targets, but still reasonable. Ligand B (100.99) is better, falling closer to the desired range.

**logP:** Ligand A (0.037) is very low, potentially hindering permeability. Ligand B (-0.022) is also low, but slightly better. Both are below the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A (1 HBD, 7 HBA) is favorable. Ligand B (2 HBD, 7 HBA) is also acceptable.

**QED:** Ligand A (0.738) has a good drug-likeness score. Ligand B (0.47) is lower, indicating a less drug-like profile.

**DILI:** Ligand A (61.07) has a moderate DILI risk. Ligand B (39.473) has a lower, more favorable DILI risk.

**BBB:** This is crucial for a CNS target. Ligand A (79.566) has a good BBB percentile. Ligand B (40.403) is significantly lower, suggesting poor brain penetration.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.1 and -5.299), which is unusual and suggests poor permeability. This is concerning.

**Aqueous Solubility:** Both ligands have negative solubility values (-1.516 and -2.001), which is also unusual and suggests poor solubility.

**hERG:** Both ligands have low hERG inhibition liability (0.065 and 0.132), which is good.

**Microsomal Clearance:** Ligand A (11.32) has a moderate clearance. Ligand B (-8.277) has a negative clearance, which is not physically possible and indicates a data error or outlier.

**In vitro Half-Life:** Ligand A (10.276) has a reasonable half-life. Ligand B (-3.921) has a negative half-life, which is not physically possible and indicates a data error or outlier.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.014 and 0.032), which is favorable for CNS penetration.

**Binding Affinity:** Ligand A (-7.7 kcal/mol) has a stronger binding affinity than Ligand B (-7.1 kcal/mol). This 0.6 kcal/mol difference is significant.

**Overall Assessment:**

Ligand A is clearly superior despite its low logP. Its significantly better BBB penetration (79.6% vs 40.4%), higher QED, and stronger binding affinity outweigh the concerns about its logP. The negative values for Caco-2, solubility, clearance and half-life for Ligand B are highly suspect and make it a less viable candidate. While Ligand A's logP is suboptimal, the strong affinity and good BBB suggest it might still achieve sufficient brain exposure.

Output:
1
2025-04-17 03:21:26,359 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (341.455 and 381.473 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (56.15) is better than Ligand B (58.04), both are below the 90 A^2 threshold desirable for CNS targets.

**logP:** Ligand A (3.12) is within the optimal 1-3 range. Ligand B (4.338) is slightly higher, potentially increasing off-target effects or solubility issues, but still acceptable.

**H-Bond Donors/Acceptors:** Ligand A (HBD=1, HBA=4) and Ligand B (HBD=2, HBA=6) both have reasonable numbers of H-bond donors and acceptors, falling within the guidelines.

**QED:** Ligand A (0.751) has a better QED score than Ligand B (0.69), indicating a more drug-like profile.

**DILI:** Ligand A (20.861) has a significantly lower DILI risk than Ligand B (87.01). This is a major advantage for Ligand A.

**BBB:** Both ligands show good BBB penetration (Ligand A: 71.656, Ligand B: 77.743), exceeding the >70% threshold for CNS targets. Ligand B is slightly better.

**Caco-2 Permeability:** Both have negative Caco-2 values (-5.112 and -4.941), which is unusual and suggests poor permeability. This is a significant drawback for both.

**Aqueous Solubility:** Both ligands have negative solubility values (-1.736 and -5.032), indicating very poor aqueous solubility. This is a major issue for both.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.834 and 0.802).

**Microsomal Clearance:** Ligand A (38.765) has lower microsomal clearance than Ligand B (51.344), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand B (76.093) has a significantly longer in vitro half-life than Ligand A (6.394). This is a substantial advantage for Ligand B.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.675 and 0.713).

**Binding Affinity:** Ligand A (-8.5 kcal/mol) has a stronger binding affinity than Ligand B (-7.7 kcal/mol), exceeding the >1.5 kcal/mol advantage threshold.

**Overall Assessment:**

While both ligands have issues with Caco-2 permeability and aqueous solubility, Ligand A is the stronger candidate. Its significantly better DILI score, superior binding affinity, and lower microsomal clearance outweigh the longer half-life of Ligand B. The affinity difference is substantial. The BBB penetration is acceptable for both.

Output:
0
2025-04-17 03:21:26,360 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (349.383 and 349.475 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (85.3) is slightly above the optimal <90 for CNS targets, but acceptable. Ligand B (75.44) is well within the desired range.

**logP:** Ligand A (1.714) is within the optimal 1-3 range. Ligand B (2.888) is also within the optimal range, leaning towards the higher end, but still acceptable.

**H-Bond Donors/Acceptors:** Both ligands have 1 HBD and 5/4 HBA, respectively, which are within acceptable limits.

**QED:** Both ligands have similar QED scores (0.871 and 0.857), indicating good drug-likeness.

**DILI:** Ligand A (56.223) has a higher DILI risk than Ligand B (34.548). This is a significant advantage for Ligand B.

**BBB:** This is a critical parameter for CNS targets. Ligand B (85.731) has a significantly higher BBB penetration percentile than Ligand A (46.336). This is a major advantage for Ligand B.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values, which is unusual and suggests poor permeability. However, the scale is not specified, so it's hard to interpret.

**Aqueous Solubility:** Both ligands have negative solubility values, which is also unusual. Again, the scale is not specified.

**hERG Inhibition:** Ligand A (0.025) has a much lower hERG inhibition liability than Ligand B (0.464), which is a significant safety advantage.

**Microsomal Clearance:** Ligand A (-8.769) has a much lower (better) microsomal clearance than Ligand B (66.707), indicating greater metabolic stability.

**In vitro Half-Life:** Ligand A (-1.745) has a slightly better (longer) in vitro half-life than Ligand B (-28.023).

**P-gp Efflux:** Ligand A (0.012) has a much lower P-gp efflux liability than Ligand B (0.287), which is favorable for CNS penetration.

**Binding Affinity:** Ligand B (-8.1) has a slightly better binding affinity than Ligand A (-7.0). While the difference is less than the 1.5 kcal/mol threshold, it's still a positive for Ligand B.

**Overall Assessment:**

Ligand B excels in BBB penetration and has a lower DILI risk. These are crucial for a CNS-targeting drug. While Ligand A has advantages in hERG inhibition, microsomal clearance, P-gp efflux, and half-life, the superior BBB and lower toxicity of Ligand B outweigh these benefits. The slightly better affinity of Ligand B is also a plus. The negative values for Caco-2 and solubility are concerning for both, but the other factors strongly favor Ligand B.

Output:
1
2025-04-17 03:21:26,360 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (348.531 and 341.375 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (58.2) is excellent, well below the 90 A^2 threshold for CNS targets. Ligand B (119.7) is higher, but still potentially acceptable, though less ideal.

**logP:** Ligand A (3.509) is optimal. Ligand B (0.145) is significantly low, which could hinder membrane permeability and CNS penetration.

**H-Bond Donors:** Both ligands have 2 HBD, which is within the acceptable limit of <=5.

**H-Bond Acceptors:** Ligand A has 2 HBA, well within the limit of <=10. Ligand B has 6 HBA, still acceptable but higher.

**QED:** Ligand B (0.802) has a higher QED score than Ligand A (0.594), suggesting a more drug-like profile overall.

**DILI:** Ligand A (11.361) has a much lower DILI risk than Ligand B (73.982), indicating a safer profile.

**BBB:** Ligand A (69.678) has a good BBB percentile, desirable for a CNS target. Ligand B (21.287) has a very poor BBB percentile, a major drawback.

**Caco-2 Permeability:** Ligand A (-4.487) has a negative Caco-2 value, which is unusual and suggests poor permeability. Ligand B (-5.389) is also negative and similarly poor.

**Aqueous Solubility:** Ligand A (-4.619) and Ligand B (-3.293) both have negative solubility values, suggesting poor aqueous solubility.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.475 and 0.299 respectively).

**Microsomal Clearance:** Ligand B (-10.422) has a more negative value, indicating faster clearance and lower metabolic stability. Ligand A (59.96) has a higher clearance.

**In vitro Half-Life:** Ligand B (0.947) has a very short half-life. Ligand A (1.537) is slightly better, but still short.

**P-gp Efflux:** Ligand A (0.097) has lower P-gp efflux liability than Ligand B (0.023), which is favorable for CNS penetration.

**Binding Affinity:** Ligand B (-8.4 kcal/mol) has a slightly better binding affinity than Ligand A (-7.7 kcal/mol), a 0.7 kcal/mol difference.

**Overall Assessment:**

Despite Ligand B's slightly better binding affinity and QED, Ligand A is the more promising candidate. Ligand B's extremely low logP and poor BBB penetration are significant liabilities for a CNS-targeting drug. The higher DILI risk and faster clearance of Ligand B are also concerning. While Ligand A has poor Caco-2 permeability and solubility, these can potentially be addressed through formulation strategies. The better BBB penetration and lower DILI risk of Ligand A are crucial advantages for a DRD2 ligand.



Output:
0
2025-04-17 03:21:26,360 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (411.246 Da) is slightly higher than Ligand B (348.447 Da), but both are acceptable.

**TPSA:** Ligand A (52.57) is excellent for CNS penetration, well below the 90 A^2 threshold. Ligand B (67.67) is still reasonable, but less optimal.

**logP:** Ligand A (3.809) is at the higher end of the optimal range (1-3), potentially raising concerns about solubility and off-target effects. Ligand B (1.682) is good, within the optimal range.

**H-Bond Donors/Acceptors:** Ligand A has 2 HBD and 3 HBA, which is acceptable. Ligand B has 0 HBD and 5 HBA, also acceptable.

**QED:** Both ligands have similar QED values (0.805 and 0.812), indicating good drug-likeness.

**DILI:** Ligand A (69.794) has a higher DILI risk than Ligand B (29.934). This is a significant negative for Ligand A.

**BBB:** Ligand B (85.111) has a significantly better BBB penetration score than Ligand A (69.717). This is critical for a CNS target like DRD2.

**Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and suggests poor permeability. However, the scale is not specified, so it's hard to interpret.

**Aqueous Solubility:** Both have negative solubility values, also unusual and suggesting poor solubility.

**hERG:** Ligand A (0.887) has a slightly higher hERG risk than Ligand B (0.199).

**Microsomal Clearance:** Ligand B (35.739) has a higher microsomal clearance than Ligand A (25.223), meaning Ligand A is more metabolically stable.

**In vitro Half-Life:** Ligand A (4.563) has a longer half-life than Ligand B (-11.694). The negative value for Ligand B is concerning and likely indicates very rapid degradation.

**P-gp Efflux:** Ligand A (0.583) has lower P-gp efflux than Ligand B (0.099), which is favorable for CNS penetration.

**Binding Affinity:** Ligand A (-9.8 kcal/mol) has a significantly stronger binding affinity than Ligand B (-7.5 kcal/mol). This is a substantial advantage.

**Overall Assessment:**

Ligand A has a much stronger binding affinity and better metabolic stability (lower Cl_mic, longer t1/2) and lower P-gp efflux. However, it has a higher DILI risk, a slightly higher hERG risk, and significantly lower BBB penetration than Ligand B.

Ligand B excels in BBB penetration and has a much lower DILI risk. While its affinity is weaker and it has a shorter half-life, the strong BBB penetration and lower toxicity profile are crucial for a CNS drug. The weaker affinity *could* be improved with further optimization, but the poor ADME properties of Ligand A are harder to fix without significantly altering the core structure.

Given the GPCR-specific priorities, particularly BBB penetration for a CNS target, and the substantial difference in DILI risk, Ligand B is the more promising candidate. The affinity difference, while significant, is not insurmountable with further optimization.

Output:
1
2025-04-17 03:21:26,360 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 drug candidates, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (412.303 Da) is slightly higher than Ligand B (347.371 Da), but both are acceptable.

**TPSA:** Ligand A (70.23) is significantly better than Ligand B (97.83). For CNS targets, we want TPSA <= 90, so Ligand A is much more favorable.

**logP:** Both ligands have good logP values (A: 2.648, B: 1.115) falling within the optimal range of 1-3.

**H-Bond Donors/Acceptors:** Ligand A (HBD=3, HBA=3) is better balanced than Ligand B (HBD=1, HBA=6). While both are within acceptable limits, the higher HBA count in B might slightly hinder permeability.

**QED:** Both ligands have good QED scores (A: 0.515, B: 0.82), indicating good drug-like properties. Ligand B is slightly better here.

**DILI:** Ligand A (41.877) has a lower DILI risk than Ligand B (74.021), which is a significant advantage.

**BBB:** Ligand A (49.903) has a lower BBB penetration than Ligand B (61.38). While both are not ideal (>70 is desirable), Ligand B is better.

**Caco-2 Permeability:** Ligand A (-4.802) has worse Caco-2 permeability than Ligand B (-4.664). Both are negative, indicating poor permeability, but B is slightly better.

**Aqueous Solubility:** Ligand A (-3.63) has slightly better aqueous solubility than Ligand B (-2.738).

**hERG Inhibition:** Ligand A (0.639) has a lower hERG inhibition risk than Ligand B (0.066), which is a significant advantage.

**Microsomal Clearance:** Ligand A (15.512) has a lower microsomal clearance than Ligand B (-21.343), indicating better metabolic stability.

**In vitro Half-Life:** Ligand A (58.497) has a longer in vitro half-life than Ligand B (-13.14), which is a significant advantage.

**P-gp Efflux:** Ligand A (0.135) has lower P-gp efflux than Ligand B (0.026), which is a significant advantage for CNS penetration.

**Binding Affinity:** Ligand B (-8.6 kcal/mol) has a slightly better binding affinity than Ligand A (-7.9 kcal/mol). This is a 0.7 kcal/mol difference, which is a notable advantage.

**Overall Assessment:**

Despite Ligand B having slightly better binding affinity and BBB penetration, Ligand A is the more promising candidate. Ligand A excels in crucial ADME properties like DILI risk, hERG inhibition, metabolic stability (Cl_mic and t1/2), and P-gp efflux. Its TPSA is also significantly better, which is crucial for CNS penetration. While Ligand B has a slightly better affinity, the ADME profile of Ligand A is far more favorable, especially considering it's a GPCR target. The difference in affinity (0.7 kcal/mol) can potentially be optimized in subsequent iterations of drug design, while poor ADME properties are harder to fix later in development.

Output:
1
2025-04-17 03:21:26,361 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (343.471 and 342.403 Da) fall comfortably within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (75.43) is significantly better than Ligand B (87.12). For CNS targets, we want TPSA <= 90, and A is closer to the optimal <= 60 range. B is pushing the upper limit.

**3. logP:** Both ligands have good logP values (2.37 and 1.36), falling within the 1-3 range. Ligand A is slightly better.

**4. H-Bond Donors:** Both ligands have acceptable HBD counts (2 and 1, respectively), well below the threshold of 5.

**5. H-Bond Acceptors:** Both ligands have acceptable HBA counts (3 and 5, respectively), below the threshold of 10.

**6. QED:** Both ligands have similar and good QED values (0.885 and 0.859), indicating good drug-like properties.

**7. DILI:** Ligand A (38.93) has a much lower DILI risk than Ligand B (59.907). This is a significant advantage for A.

**8. BBB:** Ligand A (85.343) has a substantially higher BBB penetration percentile than Ligand B (51.415). This is *critical* for a CNS target like DRD2.

**9. Caco-2 Permeability:** Ligand A (-4.987) and Ligand B (-5.303) both have negative Caco-2 values, which is unusual and suggests poor permeability. However, the scale isn't specified, so it's hard to interpret.

**10. Aqueous Solubility:** Ligand A (-3.1) and Ligand B (-1.986) both have negative solubility values, suggesting poor solubility. Again, the scale is undefined.

**11. hERG Inhibition:** Both ligands have low hERG inhibition risk (0.471 and 0.507).

**12. Microsomal Clearance:** Ligand A (42.756) has higher microsomal clearance than Ligand B (18.732), indicating lower metabolic stability. This is a drawback for A.

**13. In vitro Half-Life:** Ligand B (-24.777) has a significantly longer in vitro half-life than Ligand A (1.45). This is a major advantage for B.

**14. P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.066 and 0.04).

**15. Binding Affinity:** Ligand A (-9.5 kcal/mol) has a significantly stronger binding affinity than Ligand B (-7.9 kcal/mol). This is a substantial advantage for A, potentially outweighing some of its ADME drawbacks.

**Overall Assessment:**

Ligand A excels in key areas for a CNS GPCR target: TPSA, BBB penetration, DILI risk, and *especially* binding affinity. The significantly stronger binding affinity (-9.5 vs -7.9 kcal/mol) is a major driver. While its microsomal clearance is higher (less stable) and half-life shorter, the superior affinity and BBB penetration are likely to be more critical for CNS efficacy. Ligand B has a better half-life and lower clearance, but its lower affinity and poor BBB penetration are significant drawbacks.

Output:
1
2025-04-17 03:21:26,361 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (341.411 and 357.38 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (73.48) is better than Ligand B (54.38). Both are below the 90 A^2 threshold desirable for CNS targets, but A is closer to the ideal.

**logP:** Both ligands have good logP values (1.406 and 2.062), falling within the optimal 1-3 range. Ligand B is slightly higher, which could potentially lead to some solubility issues, but is still acceptable.

**H-Bond Donors/Acceptors:** Ligand A has 1 HBD and 3 HBA, while Ligand B has 0 HBD and 6 HBA. Both are within acceptable limits (<=5 HBD and <=10 HBA).

**QED:** Both ligands have good QED scores (0.9 and 0.808), indicating good drug-like properties.

**DILI:** Ligand A (28.616) has a significantly lower DILI risk than Ligand B (62.35). This is a substantial advantage for Ligand A.

**BBB:** Ligand B (89.027) has a much higher BBB penetration percentile than Ligand A (61.38). This is a critical advantage for a CNS target like DRD2.

**Caco-2 Permeability:** Both have negative Caco-2 values (-4.796 and -4.607), which is unusual and suggests poor permeability. However, these values are on a scale where negative values are possible, and the absolute difference is small.

**Aqueous Solubility:** Both ligands have very poor aqueous solubility (-2.023 and -3.936). This is a significant drawback for both.

**hERG Inhibition:** Ligand A (0.208) has a lower hERG inhibition liability than Ligand B (0.667), indicating a lower risk of cardiotoxicity.

**Microsomal Clearance:** Ligand A (6.302) has a lower microsomal clearance than Ligand B (42.164), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (-27.704) has a much longer in vitro half-life than Ligand B (7.962).

**P-gp Efflux:** Ligand A (0.036) has lower P-gp efflux liability than Ligand B (0.032). Both are very low, which is good.

**Binding Affinity:** Ligand B (0.0 kcal/mol) has a significantly better binding affinity than Ligand A (-8.7 kcal/mol). This is a major advantage for Ligand B. The difference of 8.7 kcal/mol is substantial and can outweigh many ADME drawbacks.

**Overall Assessment:**

Ligand B excels in BBB penetration and binding affinity, the two most crucial factors for a CNS GPCR target. While it has a higher DILI risk and lower metabolic stability than Ligand A, the significantly improved binding affinity and BBB penetration are likely to outweigh these drawbacks. Ligand A has better safety (DILI, hERG) and PK properties (clearance, half-life) but lacks the potency and brain exposure needed for a CNS drug. The poor solubility is a concern for both, but formulation strategies can potentially address this.

Output:
1
2025-04-17 03:21:26,361 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (358.781 and 365.455 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (70.42) is significantly better than Ligand B (86.88). For CNS targets, we want TPSA <= 90, and A is comfortably within this range, while B is approaching the upper limit.

**3. logP:** Both ligands have good logP values (3.275 and 2.065), falling within the optimal 1-3 range.

**4. H-Bond Donors:** Ligand A (0) is preferable to Ligand B (1). Fewer HBDs generally improve permeability.

**5. H-Bond Acceptors:** Both ligands have 6 HBA, which is acceptable (<=10).

**6. QED:** Ligand B (0.812) has a higher QED score than Ligand A (0.397), indicating a more drug-like profile overall. However, QED isn't the primary driver here given the CNS target.

**7. DILI:** Ligand A (90.694) has a higher DILI risk than Ligand B (49.554). This is a significant negative for Ligand A.

**8. BBB:** Ligand A (63.746) has a better BBB percentile than Ligand B (30.748). This is crucial for a CNS target like DRD2.

**9. Caco-2:** Both have negative Caco-2 values, which is unusual and difficult to interpret without knowing the scale. However, the values are similar.

**10. Solubility:** Both have negative solubility values, which is also unusual. Again, values are similar.

**11. hERG:** Both ligands have very low hERG risk (0.205 and 0.296).

**12. Cl_mic:** Ligand B (43.844) has significantly lower microsomal clearance than Ligand A (126.773), suggesting better metabolic stability.

**13. t1/2:** Ligand B (71.526) has a significantly longer in vitro half-life than Ligand A (23.593).

**14. Pgp:** Ligand A (0.74) has lower P-gp efflux liability than Ligand B (0.283), which is favorable for CNS penetration.

**15. Binding Affinity:** Ligand A (-8.7 kcal/mol) has a slightly better binding affinity than Ligand B (-7.7 kcal/mol). This 1 kcal/mol difference is significant and can outweigh some ADME drawbacks.

**Overall Assessment:**

Despite Ligand B's better QED, lower DILI risk, and improved metabolic stability (lower Cl_mic, longer t1/2), Ligand A's superior BBB penetration, lower Pgp efflux, and slightly stronger binding affinity are more critical for a CNS GPCR target. The DILI risk for Ligand A is concerning, but the affinity advantage and CNS penetration properties are strong enough to prioritize it.

Output:
0
2025-04-17 03:21:26,361 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (359.853 and 341.419 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (58.56) is excellent, well below the 90 A^2 threshold for CNS targets. Ligand B (81.73) is still reasonable but less optimal, approaching the 140 A^2 limit for oral absorption and further from the ideal for CNS penetration.

**3. logP:** Ligand A (4.3) is slightly high, potentially leading to solubility issues or off-target interactions. Ligand B (1.173) is a bit low, which might hinder membrane permeability.

**4. H-Bond Donors:** Ligand A (2) is good. Ligand B (0) is also acceptable.

**5. H-Bond Acceptors:** Ligand A (3) is good. Ligand B (7) is higher, but still within the acceptable limit of 10.

**6. QED:** Both ligands have a QED of 0.836/0.837, indicating good drug-like properties.

**7. DILI:** Ligand A (33.191) has a lower DILI risk than Ligand B (59.519). This is a significant advantage.

**8. BBB:** Ligand A (38.813) has a very low BBB penetration percentile, making it unlikely to reach the target in the CNS. Ligand B (64.831) is better, but still not ideal (we want >70 for CNS targets).

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.795 and -5.348), which is unusual and suggests poor intestinal absorption. This is a concern for both.

**10. Aqueous Solubility:** Both ligands have negative solubility values (-4.929 and -1.405), indicating very poor aqueous solubility. This is a major drawback for both.

**11. hERG Inhibition:** Ligand A (0.543) shows a slightly higher risk of hERG inhibition than Ligand B (0.05).

**12. Microsomal Clearance:** Ligand A (72.328) has higher clearance than Ligand B (33.509), suggesting lower metabolic stability.

**13. In vitro Half-Life:** Ligand A (11.183) has a longer half-life than Ligand B (2.858).

**14. P-gp Efflux:** Ligand A (0.159) has lower P-gp efflux liability than Ligand B (0.128), which is favorable for CNS penetration.

**15. Binding Affinity:** Ligand A (-9.8 kcal/mol) has a significantly stronger binding affinity than Ligand B (-8.2 kcal/mol). This is a substantial advantage, potentially outweighing some of its other drawbacks.

**Overall Assessment:**

Despite the poor solubility and Caco-2 permeability for both, Ligand A is the more promising candidate. Its significantly stronger binding affinity (-9.8 vs -8.2 kcal/mol) is a major advantage for a GPCR target. While its BBB penetration is low, the lower DILI risk and lower P-gp efflux compared to Ligand B are also beneficial. The longer half-life is also a plus. Ligand B's lower logP and slightly better BBB are not enough to compensate for the weaker binding affinity and higher DILI risk.

Output:
0
2025-04-17 03:21:26,362 - INFO - Batch 22 complete. Total preferences: 352
2025-04-17 03:21:26,362 - INFO - Processing batch 23/512...
2025-04-17 03:22:08,599 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (346.387 and 351.451 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (106.6) is better than Ligand B (116.19). For CNS targets, we want TPSA <= 90, so both are a bit high, but A is closer.

**logP:** Ligand A (-0.23) is suboptimal, being below the preferred 1-3 range. Ligand B (2.293) is within the optimal range. This is a significant advantage for B.

**H-Bond Donors/Acceptors:** Both have 2 HBD and are within the acceptable range. Ligand A has 5 HBA, and Ligand B has 4, both are acceptable.

**QED:** Ligand A (0.716) has a much better QED score than Ligand B (0.272), indicating better overall drug-likeness.

**DILI:** Ligand A (62.078) has a higher DILI risk than Ligand B (24.622). This favors B.

**BBB:** Ligand B (54.866) has a significantly better BBB penetration percentile than Ligand A (25.475). This is *critical* for a CNS target like DRD2, making B much more promising.

**Caco-2 Permeability:** Both have negative values (-5.168 and -4.843), which is unusual and suggests poor permeability. However, the scale isn't specified, so it's hard to interpret.

**Aqueous Solubility:** Both have negative values (-2.159 and -2.267), again, the scale is not specified, so it is hard to interpret.

**hERG:** Both have very low hERG inhibition liability (0.046 and 0.291), which is excellent.

**Microsomal Clearance:** Ligand A (-8.765) has a much lower (better) microsomal clearance than Ligand B (50.925), indicating better metabolic stability.

**In vitro Half-Life:** Ligand A (-23.632) has a much longer in vitro half-life than Ligand B (-7.015), which is desirable.

**P-gp Efflux:** Ligand A (0.016) has a much lower P-gp efflux liability than Ligand B (0.069), which is beneficial for CNS penetration.

**Binding Affinity:** Both ligands have similar, strong binding affinities (-7.6 and -7.0 kcal/mol). The difference of 0.6 kcal/mol isn't enough to outweigh other significant differences.

**Overall Assessment:**

Ligand B excels in crucial areas for a CNS-targeting GPCR ligand: logP and BBB. While Ligand A has better QED, metabolic stability, half-life, and P-gp efflux, the poor logP and BBB penetration are major drawbacks. The difference in binding affinity is not substantial enough to compensate for these deficiencies.

Output:
1
2025-04-17 03:22:08,599 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (349.519 Da) is slightly lower, which could be beneficial for permeability. Ligand B (390.843 Da) is also good.

**TPSA:** Ligand A (52.65) is excellent, well below the 90 A^2 threshold for CNS targets. Ligand B (71.25) is still reasonable but less optimal.

**logP:** Both ligands have good logP values (A: 2.262, B: 3.058), falling within the 1-3 range.

**H-Bond Donors/Acceptors:** Both have acceptable HBD counts (1). Ligand B has a higher HBA count (6) compared to Ligand A (3), which might slightly affect permeability.

**QED:** Both ligands have acceptable QED scores (A: 0.847, B: 0.737), indicating good drug-like properties.

**DILI:** Ligand A (8.414) has a significantly lower DILI risk than Ligand B (62.893), a major advantage.

**BBB:** Both ligands have good BBB penetration (A: 75.107, B: 74.758), exceeding the 70% threshold for CNS targets.

**Caco-2 Permeability:** Both have negative Caco-2 values (-4.801 and -4.584) which is unusual and suggests poor permeability. This is a concern for both.

**Aqueous Solubility:** Both ligands have very poor aqueous solubility (-1.422 and -3.738). This is a significant drawback.

**hERG Inhibition:** Both ligands have low hERG risk (A: 0.492, B: 0.242).

**Microsomal Clearance:** Ligand A (-4.144) has a much lower (better) microsomal clearance than Ligand B (8.374), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (-5.055) has a negative half-life, which is not possible. Ligand B (15.011) has a reasonable half-life. The negative value for A is a red flag.

**P-gp Efflux:** Both ligands have low P-gp efflux (A: 0.046, B: 0.109), which is favorable for CNS penetration.

**Binding Affinity:** Ligand A (-8.4 kcal/mol) has a significantly stronger binding affinity than Ligand B (-7.4 kcal/mol). This 1.0 kcal/mol difference is substantial and can outweigh some ADME drawbacks.

**Overall Assessment:**

Ligand A is the better candidate despite the negative half-life. The significantly stronger binding affinity (-8.4 vs -7.4 kcal/mol), lower DILI risk, and lower microsomal clearance are major advantages. While both have poor solubility and Caco-2 permeability, the affinity difference is substantial. The negative half-life for A is a data error and should be investigated, but even ignoring that, the other properties favor A.



Output:
0
2025-04-17 03:22:08,600 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands fall within the ideal 200-500 Da range (A: 384.929, B: 353.507).

**TPSA:** Ligand A (58.64) is excellent for CNS penetration, well below the 90 A^2 threshold. Ligand B (72.88) is still reasonable but less optimal.

**logP:** Both ligands have good logP values (A: 2.957, B: 1.256), falling within the 1-3 range.

**H-Bond Donors/Acceptors:** Both ligands have acceptable HBD (A: 1, B: 2) and HBA (A: 4, B: 4) counts, well within the recommended limits.

**QED:** Both ligands have similar and acceptable QED values (A: 0.605, B: 0.644), indicating good drug-like properties.

**DILI:** Both ligands have relatively low DILI risk (A: 54.75, B: 5.235), with Ligand B being significantly better.

**BBB:** Ligand A has a much better BBB percentile (62.156) than Ligand B (33.036). This is a critical factor for a CNS target like DRD2.

**Caco-2 Permeability:** Both have negative Caco-2 values (-4.957 and -4.887), which is unusual and suggests poor permeability. This is a significant concern for both.

**Aqueous Solubility:** Both have negative solubility values (-4.796 and -0.367), indicating poor aqueous solubility. This could pose formulation challenges.

**hERG Inhibition:** Ligand A (0.567) has a slightly higher hERG risk than Ligand B (0.189), but both are relatively low.

**Microsomal Clearance:** Ligand A has a higher microsomal clearance (82.042) than Ligand B (12.261), suggesting lower metabolic stability.

**In vitro Half-Life:** Ligand B has a longer in vitro half-life (3.284 hours) than Ligand A (28.361 hours). This is a positive for Ligand B.

**P-gp Efflux:** Both ligands show very low P-gp efflux liability (A: 0.568, B: 0.015), which is favorable for CNS penetration.

**Binding Affinity:** Ligand B has a significantly better binding affinity (-6.8 kcal/mol) than Ligand A (0.0 kcal/mol). This is a major advantage.

**Overall Assessment:**

Despite the poor Caco-2 and solubility values for both, Ligand B is the more promising candidate. The significantly stronger binding affinity (-6.8 vs 0.0 kcal/mol) outweighs the slightly lower BBB and higher DILI. The improved metabolic stability (lower Cl_mic, longer t1/2) also contributes to its favorability. Ligand A's poor affinity is a major drawback. The BBB value for Ligand A is acceptable, but the affinity difference is too large to ignore.

Output:
1
2025-04-17 03:22:08,600 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (360.841 and 346.387 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (72.24) is excellent, well below the 90 A^2 threshold for CNS targets. Ligand B (125.36) is higher, but still potentially acceptable, though less ideal.

**logP:** Ligand A (4.838) is high, potentially leading to solubility issues and off-target effects. Ligand B (-0.569) is quite low, which could hinder membrane permeability and CNS penetration.

**H-Bond Donors/Acceptors:** Ligand A (1 HBD, 3 HBA) is favorable. Ligand B (3 HBD, 4 HBA) is also reasonable.

**QED:** Both ligands have good QED scores (0.54 and 0.631), indicating drug-like properties.

**DILI:** Ligand A (67.003) has a moderate DILI risk. Ligand B (35.828) has a very low DILI risk, which is a significant advantage.

**BBB:** Ligand A (63.125) has a moderate BBB penetration, which is not ideal for a CNS target. Ligand B (46.762) has poor BBB penetration, a major drawback.

**Caco-2 Permeability:** Ligand A (-4.814) shows poor permeability. Ligand B (-5.849) also shows poor permeability.

**Aqueous Solubility:** Ligand A (-5.369) has poor solubility, consistent with its high logP. Ligand B (-2.643) has slightly better solubility, but still not great.

**hERG Inhibition:** Ligand A (0.706) has a low risk of hERG inhibition. Ligand B (0.126) also has a low risk.

**Microsomal Clearance:** Ligand A (82.416) has moderate clearance. Ligand B (-17.356) has negative clearance, which is unusual and suggests very high metabolic stability.

**In vitro Half-Life:** Ligand A (41.212) has a moderate half-life. Ligand B (-14.79) has a negative half-life, which is also unusual and suggests extreme stability.

**P-gp Efflux:** Ligand A (0.389) has low P-gp efflux, which is good for CNS penetration. Ligand B (0.013) has very low P-gp efflux, even better.

**Binding Affinity:** Ligand A (-9.2 kcal/mol) has significantly stronger binding affinity than Ligand B (-8.5 kcal/mol). This is a substantial difference.

**Overall Assessment:**

Despite Ligand B's superior DILI, P-gp efflux, and metabolic stability profiles, the significantly stronger binding affinity of Ligand A (-9.2 vs -8.5 kcal/mol) is a decisive factor, especially for a GPCR target. While Ligand A has a high logP and moderate BBB penetration, the potency advantage can often be optimized through structural modifications. The poor permeability and solubility of Ligand A are concerns, but these are more readily addressed through medicinal chemistry than a large affinity gap. Ligand B's poor BBB penetration is a major limitation for a CNS target.

Output:
1
2025-04-17 03:22:08,600 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (346.515 and 347.415 Da) fall within the ideal range of 200-500 Da.

**TPSA:** Ligand A (40.62) is significantly better than Ligand B (84.67). For CNS targets, we want TPSA <= 90, and ideally closer to 60. Ligand A is well within this range, while Ligand B is approaching the upper limit and less favorable.

**logP:** Ligand A (3.312) is optimal (1-3), while Ligand B (1.767) is on the lower side. While not terrible, lower logP can sometimes hinder permeability.

**H-Bond Donors/Acceptors:** Ligand A (0 HBD, 2 HBA) is preferable to Ligand B (1 HBD, 5 HBA). Lower counts are generally better for CNS penetration.

**QED:** Both ligands have good QED scores (0.692 and 0.839), indicating good drug-like properties.

**DILI:** Ligand A (9.965) has a much lower DILI risk than Ligand B (56.572). This is a significant advantage for Ligand A.

**BBB:** Ligand A (82.086) has a considerably higher BBB penetration percentile than Ligand B (56.495). This is *critical* for a CNS target like DRD2.

**Caco-2 Permeability:** Both are negative, indicating poor permeability. However, the scale is not defined, so it is hard to interpret.

**Aqueous Solubility:** Both are negative, indicating poor solubility. However, the scale is not defined, so it is hard to interpret.

**hERG:** Both ligands have low hERG inhibition liability (0.536 and 0.23), which is good.

**Microsomal Clearance:** Ligand A (42.686) and Ligand B (47.77) are comparable, suggesting similar metabolic stability.

**In vitro Half-Life:** Ligand B (-16.948) has a much longer half-life than Ligand A (-3.49). This is a positive for Ligand B, but the negative values are concerning and the scale is not defined.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.119 and 0.138).

**Binding Affinity:** Ligand B (-7.9 kcal/mol) has a significantly stronger binding affinity than Ligand A (0.0 kcal/mol). This is a substantial advantage for Ligand B, potentially outweighing some of its ADME drawbacks.

**Overall Assessment:**

While Ligand B boasts a much stronger binding affinity, Ligand A has a significantly better safety profile (lower DILI), and crucially, much better predicted BBB penetration. For a CNS target like DRD2, BBB penetration is paramount. The lower TPSA of Ligand A also supports better CNS entry. The superior affinity of Ligand B is tempting, but the poor BBB and higher DILI risk are major concerns. Given the GPCR-specific priorities, and the importance of CNS penetration for DRD2, Ligand A is the more promising candidate.

Output:
0
2025-04-17 03:22:08,600 - INFO - Reasoning:

Let's analyze Ligand A and Ligand B based on the provided guidelines, prioritizing GPCR-specific properties (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (349.427 and 348.443 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (66.02) is significantly better than Ligand B (76.66). For CNS targets, TPSA should be <= 90, both are within this range, but A is preferable.

**logP:** Ligand A (2.801) is optimal (1-3), while Ligand B (1.163) is on the lower end, potentially hindering permeation.

**H-Bond Donors/Acceptors:** Ligand A (HBD=1, HBA=5) and Ligand B (HBD=2, HBA=4) both have acceptable numbers of H-bond donors and acceptors.

**QED:** Both ligands have good QED scores (0.52 and 0.535, respectively), indicating drug-like properties.

**DILI:** Ligand A (52.385) has a slightly higher DILI risk than Ligand B (47.693), but both are below the concerning threshold of 60.

**BBB:** This is a critical parameter for a CNS target like DRD2. Ligand A (75.107) has a significantly better BBB percentile than Ligand B (50.523). A score >70 is desirable, and A is much closer.

**Caco-2 Permeability:** Both have negative Caco-2 values which is unusual, but we can still compare. Ligand A (-4.505) is better than Ligand B (-4.892).

**Aqueous Solubility:** Both ligands have negative solubility values, which is also unusual. Ligand A (-2.425) is slightly better than Ligand B (-2.699).

**hERG:** Both ligands have very low hERG inhibition liability (0.468 and 0.154), indicating minimal cardiotoxicity risk.

**Microsomal Clearance:** Ligand A (72.74) has higher microsomal clearance than Ligand B (21.979), suggesting lower metabolic stability.

**In vitro Half-Life:** Ligand B (-1.881) has a slightly better in vitro half-life than Ligand A (-19.238).

**P-gp Efflux:** Ligand A (0.278) has lower P-gp efflux liability than Ligand B (0.118), which is favorable for CNS penetration.

**Binding Affinity:** Both ligands have very similar and strong binding affinities (-7.5 and -7.4 kcal/mol). The difference is negligible.

**Overall Assessment:**

Ligand A is the superior candidate. While Ligand B has slightly better metabolic stability and half-life, Ligand A excels in crucial areas for a CNS-targeting GPCR: significantly better BBB penetration, more optimal logP, and lower P-gp efflux. The TPSA is also more favorable for Ligand A. The small difference in binding affinity is not enough to offset the ADME advantages of Ligand A.

Output:
1
2025-04-17 03:22:08,601 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (350.375 and 340.423 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (112.07) is slightly above the optimal <90 for CNS targets, but still reasonable. Ligand B (49.85) is excellent, well below the threshold.

**logP:** Ligand A (0.202) is quite low, potentially hindering membrane permeability. Ligand B (1.547) is within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A has 2 HBD and 6 HBA, which are acceptable. Ligand B has 0 HBD and 3 HBA, also acceptable.

**QED:** Both ligands have similar QED values (0.758 and 0.73), indicating good drug-likeness.

**DILI:** Ligand A (55.758) has a moderate DILI risk, while Ligand B (28.189) has a lower, more favorable risk.

**BBB:** Ligand A (38.116) has a poor BBB penetration percentile, a significant drawback for a CNS target. Ligand B (68.282) is much better, approaching the desirable >70 threshold.

**Caco-2 Permeability:** Ligand A (-4.935) shows poor permeability. Ligand B (-4.353) is also poor, but slightly better than A.

**Aqueous Solubility:** Both ligands have negative solubility values (-1.185 and -2.714), which is unusual and suggests very poor solubility. This is a concern for both.

**hERG Inhibition:** Ligand A (0.056) has very low hERG inhibition risk, which is excellent. Ligand B (0.225) is also low risk, but slightly higher.

**Microsomal Clearance:** Ligand A (-2.78) indicates good metabolic stability (negative value). Ligand B (37.262) shows high metabolic clearance, a significant negative.

**In vitro Half-Life:** Ligand A (12.634 hours) has a reasonable half-life. Ligand B (-8.114 hours) has a very short half-life, which is problematic.

**P-gp Efflux:** Ligand A (0.005) has very low P-gp efflux, which is highly desirable for CNS penetration. Ligand B (0.073) also has low P-gp efflux, but slightly higher than A.

**Binding Affinity:** Both ligands have strong binding affinities (-7.3 and -7.7 kcal/mol), with Ligand B being slightly more potent. The difference is less than 1.5 kcal/mol, so this isn't a decisive factor.

**Overall Assessment:**

Ligand B is the more promising candidate. While both have solubility issues, Ligand B excels in key areas for a CNS GPCR target: significantly better BBB penetration, a more favorable logP, and a lower DILI risk. Although its metabolic stability and half-life are poor, these can potentially be addressed through structural modifications. Ligand A's poor BBB penetration and low logP are major liabilities that would be difficult to overcome.

Output:
1
2025-04-17 03:22:08,601 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (349.391 Da) and Ligand B (344.423 Da) are comparable.

**TPSA:** Ligand A (125.79) is slightly higher than Ligand B (85.92). For CNS targets, we want TPSA <= 90, so Ligand B is better here.

**logP:** Both ligands have very low logP values (A: 0.043, B: 0.071). This is a significant concern, as it suggests poor membrane permeability. Ideally, logP should be between 1-3.

**H-Bond Donors/Acceptors:** Ligand A has 2 HBD and 7 HBA, while Ligand B has 1 HBD and 9 HBA. Both are within acceptable limits (<=5 HBD, <=10 HBA).

**QED:** Both ligands have good QED scores (A: 0.735, B: 0.794), indicating good drug-like properties overall.

**DILI:** Ligand A has a higher DILI risk (65.762) than Ligand B (34.277). Lower DILI is preferred, making Ligand B better.

**BBB:** Ligand B (82.939) has a better BBB percentile than Ligand A (74.564). This is crucial for CNS targets like DRD2.

**Caco-2 Permeability:** Both have negative Caco-2 values (-5 for A, -5.211 for B), which is unusual and suggests very poor permeability.

**Aqueous Solubility:** Both have negative solubility values (-2.403 for A, -1.165 for B). This is also a concern, indicating very low solubility.

**hERG Inhibition:** Ligand A (0.445) has a slightly higher hERG risk than Ligand B (0.173). Lower hERG is preferred.

**Microsomal Clearance:** Ligand B (38.521) has a higher microsomal clearance than Ligand A (25.345), meaning faster metabolism and potentially lower exposure.

**In vitro Half-Life:** Ligand A (-21.097) has a more negative half-life than Ligand B (-11.693), suggesting faster degradation.

**P-gp Efflux:** Ligand A (0.087) has lower P-gp efflux than Ligand B (0.041), which is favorable for CNS penetration.

**Binding Affinity:** Ligand B (-7.5 kcal/mol) has a slightly better binding affinity than Ligand A (-8.3 kcal/mol). While both are good, the difference is not substantial enough to outweigh other factors.

**Overall Assessment:**

Despite both ligands having issues with logP and solubility, Ligand B is the more promising candidate. It has a better BBB score, lower DILI risk, lower hERG risk, and slightly better binding affinity. The lower P-gp efflux of Ligand A is a small advantage, but the other benefits of Ligand B are more significant for a CNS target. The very low logP values for both are a major concern and would need to be addressed through structural modifications.

Output:
1
2025-04-17 03:22:08,601 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (360.439 and 347.415 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (84.42) is better than Ligand B (91.76). Both are below the 90 A^2 threshold for CNS targets, but A is closer to the ideal.

**3. logP:** Both ligands have a logP around 1.3, which is optimal.

**4. H-Bond Donors:** Ligand A (1) is better than Ligand B (2). Lower is generally preferred.

**5. H-Bond Acceptors:** Ligand A (6) is better than Ligand B (5). Both are within the acceptable range.

**6. QED:** Both ligands have similar QED values (0.891 and 0.81), indicating good drug-likeness.

**7. DILI:** Ligand A (79.604) has a significantly better DILI score than Ligand B (22.683), indicating a lower risk of liver injury.

**8. BBB:** Ligand B (71.772) has a substantially better BBB penetration score than Ligand A (31.834). This is a *critical* factor for a CNS target like DRD2.

**9. Caco-2 Permeability:** Ligand A (-4.912) is better than Ligand B (-4.842). Higher values are better, indicating better intestinal absorption.

**10. Aqueous Solubility:** Ligand A (-2.093) is better than Ligand B (-2.863). Higher values are better.

**11. hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.208 and 0.183).

**12. Microsomal Clearance:** Ligand B (8.057) has lower microsomal clearance than Ligand A (11.628), suggesting better metabolic stability.

**13. In vitro Half-Life:** Ligand B (-16.972) has a longer in vitro half-life than Ligand A (-14.015).

**14. P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.039 and 0.026).

**15. Binding Affinity:** Ligand B (-8.4 kcal/mol) has a slightly better binding affinity than Ligand A (-7.3 kcal/mol). While A is still good, the 1.1 kcal/mol difference is significant.

**Overall Assessment:**

Ligand B clearly wins on BBB penetration and binding affinity, two of the most important factors for a CNS GPCR target. It also has better metabolic stability (lower Cl_mic) and a longer half-life. While Ligand A has a better DILI score and slightly better solubility, the advantages of Ligand B regarding CNS penetration and potency outweigh these benefits. The difference in binding affinity is also substantial enough to favor Ligand B.

Output:
1
2025-04-17 03:22:08,601 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the acceptable range (200-500 Da). Ligand A (369.511 Da) is slightly lower, which is generally favorable for permeability.

**TPSA:** Ligand A (37.38) is excellent for CNS penetration, well below 90. Ligand B (106) is higher, but still potentially acceptable, though less ideal.

**logP:** Ligand A (4.688) is a bit high, potentially leading to solubility issues or off-target interactions. Ligand B (-0.199) is quite low, which could hinder membrane permeability and CNS penetration.

**H-Bond Donors/Acceptors:** Ligand A (0 HBD, 3 HBA) is favorable. Ligand B (3 HBD, 7 HBA) is also acceptable, though slightly higher.

**QED:** Both ligands have reasonable QED scores (A: 0.672, B: 0.595), indicating good drug-like properties.

**DILI:** Ligand A (79.682) has a higher DILI risk than Ligand B (41.218), which is a concern.

**BBB:** Ligand A (78.907) has a significantly better BBB percentile than Ligand B (9.732). This is a *critical* factor for a CNS target like DRD2.

**Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and suggests potential issues with the data or the compounds themselves. However, we can still compare relative values. Ligand A (-5.096) is better than Ligand B (-5.393).

**Aqueous Solubility:** Both have negative solubility values, indicating very poor solubility. Ligand B (-0.805) is slightly better than Ligand A (-6.238).

**hERG Inhibition:** Ligand A (0.831) has a slightly higher hERG risk than Ligand B (0.118).

**Microsomal Clearance:** Ligand A (68.287) has a moderate clearance, while Ligand B (-28.36) has a negative clearance, which is not physically possible and indicates a data issue.

**In vitro Half-Life:** Ligand A (34.372 hours) has a reasonable half-life. Ligand B (16.02 hours) is shorter.

**P-gp Efflux:** Ligand A (0.73) shows moderate P-gp efflux, while Ligand B (0.05) shows very low P-gp efflux, which is highly desirable for CNS penetration.

**Binding Affinity:** Ligand A (-9.5 kcal/mol) has a significantly stronger binding affinity than Ligand B (-7.1 kcal/mol). The 2.4 kcal/mol difference is substantial and can often outweigh minor ADME drawbacks.

**Overall Assessment:**

Ligand A excels in binding affinity and BBB penetration, crucial for a CNS GPCR target. However, it has higher DILI risk and a slightly elevated hERG risk. Its logP is also a bit high. Ligand B has a better safety profile (lower DILI, hERG, and P-gp efflux) but suffers from very poor BBB penetration and significantly weaker binding affinity. The negative clearance and solubility values are also concerning.

Given the importance of strong binding affinity and BBB penetration for CNS GPCR targets, and the substantial difference in affinity, **Ligand A is the more promising candidate despite its drawbacks.** Optimization efforts could focus on reducing the logP and DILI risk while maintaining the strong affinity and BBB penetration.

Output:
0
2025-04-17 03:22:08,602 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (344.459 and 337.423 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (74.13) is better than Ligand B (62.61). Both are below the 90 A^2 threshold desirable for CNS targets.

**logP:** Both ligands have good logP values (3.09 and 2.366), falling within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A has 1 HBD and 4 HBA, while Ligand B has 2 HBD and 3 HBA. Both are within acceptable limits (<=5 HBD and <=10 HBA).

**QED:** Both ligands have good QED scores (0.778 and 0.845), indicating good drug-like properties.

**DILI:** Ligand A (25.436) has a significantly lower DILI risk than Ligand B (58.55). This is a substantial advantage.

**BBB:** Ligand A (84.413) has a much better BBB penetration score than Ligand B (64.211). This is critical for a CNS target like DRD2.

**Caco-2 Permeability:** Ligand A (-5.108) has worse Caco-2 permeability than Ligand B (-4.545), but both are negative values indicating poor permeability.

**Aqueous Solubility:** Both ligands have similar, very poor aqueous solubility (-3.127 and -3.272). This could pose formulation challenges.

**hERG Inhibition:** Both ligands show low hERG inhibition risk (0.252 and 0.316).

**Microsomal Clearance:** Ligand A (17.056) has lower microsomal clearance than Ligand B (4.724), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand B (33.974) has a significantly longer in vitro half-life than Ligand A (6.198).

**P-gp Efflux:** Both ligands show low P-gp efflux liability (0.106 and 0.101).

**Binding Affinity:** Ligand A (-9.3 kcal/mol) has a slightly better binding affinity than Ligand B (-8.5 kcal/mol). While both are excellent, the 0.8 kcal/mol difference is noteworthy.

**Overall Assessment:**

Considering the GPCR-specific priorities, Ligand A is the more promising candidate. Its superior BBB penetration (84.413 vs 64.211) and lower DILI risk (25.436 vs 58.55) are major advantages for a CNS drug. The slightly better binding affinity (-9.3 vs -8.5) further supports this conclusion. While Ligand B has a longer half-life and better Caco-2 permeability, the CNS target necessitates prioritizing BBB penetration and minimizing off-target effects (DILI). The solubility is a concern for both, but can be addressed with formulation strategies.

Output:
1
2025-04-17 03:22:08,602 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (339.351 Da) is slightly lower, which could be beneficial for permeability. Ligand B (350.459 Da) is also good.

**TPSA:** Ligand A (94.32) is slightly above the optimal <90 for CNS targets, but still reasonable. Ligand B (78.87) is excellent, well below 90, suggesting better CNS penetration potential.

**logP:** Both ligands have good logP values (A: 2.809, B: 1.381), falling within the 1-3 range. Ligand A is slightly higher, potentially leading to some off-target interactions, but still acceptable.

**H-Bond Donors/Acceptors:** Ligand A (HBD=1, HBA=6) and Ligand B (HBD=2, HBA=4) both have reasonable numbers of H-bond donors and acceptors, well within the guidelines.

**QED:** Both ligands have good QED scores (A: 0.735, B: 0.759), indicating good drug-like properties.

**DILI:** Ligand A has a concerningly high DILI risk (91.004 percentile). Ligand B has a very low DILI risk (22.761 percentile), a significant advantage.

**BBB:** Ligand A has a moderate BBB penetration (53.432 percentile). Ligand B has a much better BBB penetration (65.452 percentile), which is crucial for a CNS target like DRD2.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.735 and -4.394). This is unusual and suggests potential issues with the experimental setup or the compounds themselves. However, since both are similarly negative, it doesn't strongly differentiate them.

**Aqueous Solubility:** Both ligands have negative solubility values (-4.01 and -1.642). Similar to Caco-2, this is concerning and suggests poor solubility. Again, the values are comparable.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (A: 0.209, B: 0.326), which is good.

**Microsomal Clearance:** Ligand A has very high microsomal clearance (99.25 percentile) indicating rapid metabolism and low metabolic stability. Ligand B has a moderate clearance (30.991 percentile), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A has a very short in vitro half-life (-12.131 hours) consistent with the high clearance. Ligand B has a longer half-life (8.22 hours), which is preferable.

**P-gp Efflux:** Ligand A has very low P-gp efflux liability (0.129), which is good. Ligand B has very low P-gp efflux liability (0.05), even better.

**Binding Affinity:** Ligand A (-9.7 kcal/mol) has a slightly better binding affinity than Ligand B (-8.4 kcal/mol). This 1.3 kcal/mol difference is significant, but needs to be weighed against the other properties.

**Overall Assessment:**

Ligand A has a better binding affinity, but suffers from a high DILI risk, poor metabolic stability (high clearance, short half-life), and moderate BBB penetration. Ligand B, while having slightly weaker affinity, exhibits a much better safety profile (low DILI), improved metabolic stability, and better BBB penetration. Given the GPCR-specific priorities and the importance of CNS penetration and safety for a DRD2 ligand, Ligand B is the more promising candidate. The affinity difference, while notable, can potentially be optimized in further iterations of drug design.

Output:
1
2025-04-17 03:22:08,602 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight (MW):** Both ligands (344.415 and 356.373 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (93.21) is better than Ligand B (96.11), both are below the 90 A^2 threshold for CNS targets, but A is closer.

**3. logP:** Both ligands have good logP values (1.234 and 0.942), falling within the optimal 1-3 range.

**4. H-Bond Donors (HBD):** Both ligands are acceptable (2 and 3, respectively), being less than 5.

**5. H-Bond Acceptors (HBA):** Both ligands are acceptable (5 and 4, respectively), being less than 10.

**6. QED:** Both ligands have similar and good QED values (0.573 and 0.574), indicating good drug-like properties.

**7. DILI:** Ligand A (63.746) has a slightly higher DILI risk than Ligand B (54.246), but both are acceptable (<60 is good).

**8. BBB:** Ligand B (84.374) significantly outperforms Ligand A (52.579) in BBB penetration. This is a *critical* factor for a CNS target like DRD2.

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 values, which is unusual and suggests poor permeability. However, these values are on a log scale, and the absolute values are not directly comparable without knowing the scale.

**10. Aqueous Solubility:** Both ligands have negative solubility values, indicating poor solubility. This is a concern for bioavailability.

**11. hERG Inhibition:** Both ligands show very low hERG inhibition risk (0.068 and 0.095), which is excellent.

**12. Microsomal Clearance (Cl_mic):** Ligand A (10.546) has a lower microsomal clearance than Ligand B (11.283), suggesting better metabolic stability.

**13. In vitro Half-Life:** Ligand A (15.077 hours) has a significantly longer half-life than Ligand B (-20.297 hours). The negative value for B is concerning and likely an error or outlier.

**14. P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.017 and 0.025), which is favorable for CNS penetration.

**15. Binding Affinity:** Ligand A (-7.9 kcal/mol) has a slightly better binding affinity than Ligand B (-7.4 kcal/mol), although the difference is not huge.

**Overall Assessment:**

While Ligand A has slightly better affinity and metabolic stability, Ligand B's *significantly* higher BBB penetration (84.374 vs 52.579) is the deciding factor for a CNS target like DRD2. The longer half-life of Ligand A is also attractive, but the BBB is paramount. The negative half-life for Ligand B is a major red flag.

Output:
1
2025-04-17 03:22:08,602 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (352.475 and 365.543 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (59.08) is significantly better than Ligand B (62.3). Both are below the 90 A^2 threshold for CNS targets, but A is closer to the optimal range.

**logP:** Ligand A (1.818) is within the optimal 1-3 range. Ligand B (3.111) is at the higher end of the optimal range, potentially increasing off-target effects.

**H-Bond Donors/Acceptors:** Ligand A (0 HBD, 4 HBA) and Ligand B (1 HBD, 4 HBA) both have acceptable numbers of H-bond donors and acceptors.

**QED:** Both ligands have good QED scores (0.774 and 0.842), indicating good drug-like properties.

**DILI:** Ligand A (16.208) has a much lower DILI risk than Ligand B (39.201), which is a significant advantage.

**BBB:** Ligand A (85.033) has a substantially higher BBB penetration percentile than Ligand B (53.587). This is *critical* for a CNS target like DRD2.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.208 and -4.895), which is unusual and suggests poor permeability. However, Caco-2 values can be unreliable and are less important than BBB for CNS targets.

**Aqueous Solubility:** Both ligands have negative solubility values (-2.098 and -2.797), indicating poor aqueous solubility. This could be a formulation challenge, but can be overcome.

**hERG:** Both ligands have low hERG inhibition liability (0.46 and 0.406), which is good.

**Microsomal Clearance:** Ligand A (33.832) has lower microsomal clearance than Ligand B (43.985), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (12.834) has a longer in vitro half-life than Ligand B (-0.95), which is a positive attribute.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.062 and 0.319), which is favorable for CNS penetration.

**Binding Affinity:** Ligand A (-7.6 kcal/mol) has a slightly better binding affinity than Ligand B (0.0 kcal/mol). This difference in affinity is substantial.

**Overall Assessment:**

Ligand A is clearly superior. It has a better BBB score, lower DILI risk, better metabolic stability, longer half-life, and a significantly stronger binding affinity. While both have poor predicted solubility and Caco-2 permeability, the BBB score is paramount for a CNS target, and Ligand A excels in this area. The stronger binding affinity of Ligand A also outweighs the minor ADME drawbacks.

Output:
0
2025-04-17 03:22:08,602 - INFO - Reasoning:

Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (348.305 and 356.526 Da) fall comfortably within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (72.68) is better than Ligand B (49.41) in terms of TPSA. Both are below the 90 A^2 threshold for CNS targets, but Ligand B is significantly lower, which is advantageous for brain penetration.

**3. logP:** Both ligands have good logP values (3.475 and 3.942), falling within the optimal 1-3 range. Ligand B is slightly higher, which could potentially lead to some solubility issues, but is still acceptable.

**4. H-Bond Donors:** Ligand A has 0 HBD, while Ligand B has 1. Both are within the acceptable limit of <=5.

**5. H-Bond Acceptors:** Ligand A has 4 HBA, Ligand B has 2. Both are well below the 10 limit.

**6. QED:** Both ligands have good QED scores (0.629 and 0.751), indicating good drug-like properties. Ligand B is slightly better.

**7. DILI:** Ligand A has a DILI risk of 85.227, which is concerning (high risk). Ligand B has a much lower DILI risk of 9.228 (good). This is a significant advantage for Ligand B.

**8. BBB:** Ligand A has a BBB penetration of 83.521, which is good, but Ligand B is excellent at 94.029. This is a crucial factor for a CNS target like DRD2.

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.185 and -4.504). This is unusual and suggests poor permeability. However, these values are on a log scale, so they are likely representing very low permeability.

**10. Aqueous Solubility:** Both ligands have negative solubility values (-4.774 and -4.017), indicating very poor aqueous solubility. This could be a significant formulation challenge.

**11. hERG Inhibition:** Both ligands have low hERG inhibition risk (0.715 and 0.882).

**12. Microsomal Clearance:** Ligand A has a higher microsomal clearance (65.871) than Ligand B (51.484), suggesting faster metabolism and potentially lower in vivo exposure.

**13. In vitro Half-Life:** Ligand A has a longer in vitro half-life (17.621 hours) than Ligand B (-1.319 hours). This is a significant advantage for Ligand A, *however*, the negative value for Ligand B is suspect and likely indicates a very short half-life.

**14. P-gp Efflux:** Both ligands have low P-gp efflux liability (0.601 and 0.178). Ligand B is better.

**15. Binding Affinity:** Both ligands have very similar and excellent binding affinities (-8.9 and -8.7 kcal/mol). The difference is less than 1.5 kcal/mol, so it's not a decisive factor.

**Overall Assessment:**

While Ligand A has a longer in vitro half-life, its significantly higher DILI risk and lower BBB penetration are major drawbacks. Ligand B excels in the critical areas for a CNS GPCR target: excellent BBB penetration, low DILI risk, and low P-gp efflux. The slightly lower half-life of Ligand B is a concern, but potentially addressable through structural modifications. The poor solubility and permeability of both compounds are shared issues that would need to be addressed during lead optimization.

Output:
1
2025-04-17 03:22:08,603 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (373.519 and 346.431 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (118.36) is slightly above the preferred <90 for CNS targets, but still reasonable. Ligand B (93.09) is comfortably within the desired range.

**3. logP:** Both ligands have good logP values (0.889 and 1.062), falling within the optimal 1-3 range.

**4. H-Bond Donors:** Ligand A (3) and Ligand B (2) are both within the acceptable limit of <=5.

**5. H-Bond Acceptors:** Ligand A (4) and Ligand B (5) are both within the acceptable limit of <=10.

**6. QED:** Both ligands have good QED scores (0.556 and 0.753), indicating good drug-like properties.

**7. DILI:** Ligand A (33.928) has a significantly lower DILI risk than Ligand B (55.797), which is a substantial advantage. Both are below the 60 threshold, but A is much better.

**8. BBB:** Ligand A (55.176) and Ligand B (53.587) are similar, and both are below the desirable >70 for CNS targets. This is a weakness for both, but not a deciding factor *between* them.

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.346 and -4.997), which is unusual and suggests poor permeability. However, these values are on a scale where negative values are possible, and the absolute magnitude isn't directly comparable to percentile scores.

**10. Aqueous Solubility:** Both ligands have negative solubility values (-2.933 and -2.319), indicating poor aqueous solubility. This is a concern for both compounds.

**11. hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.093 and 0.086).

**12. Microsomal Clearance:** Ligand B (27.145) has a lower microsomal clearance than Ligand A (37.789), indicating better metabolic stability.

**13. In vitro Half-Life:** Ligand B (-11.52) has a significantly longer in vitro half-life than Ligand A (-52.772). This is a major advantage for Ligand B.

**14. P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.038 and 0.041).

**15. Binding Affinity:** Ligand B (-8.0) has a slightly better binding affinity than Ligand A (-7.5), although the difference is less than the 1.5 kcal/mol threshold that would strongly favor one over the other.

**Overall Assessment:**

While both ligands have weaknesses (BBB, solubility, Caco-2), Ligand B appears more promising. It has better metabolic stability (lower Cl_mic, longer t1/2), a slightly better binding affinity, and a lower DILI risk. Ligand A's main advantage is the lower DILI, but the other ADME properties of Ligand B are more favorable for a CNS-targeting GPCR ligand. The negative solubility and Caco-2 values are concerning for both and would require further investigation (e.g., salt formation, formulation strategies).

Output:
1
2025-04-17 03:22:08,603 - INFO - Batch 23 complete. Total preferences: 368
2025-04-17 03:22:08,603 - INFO - Processing batch 24/512...
2025-04-17 03:22:48,447 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (348.443 and 378.485 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (71.78) is better than Ligand B (75.27). Both are below the 90 A^2 threshold for CNS targets, which is good.

**3. logP:** Both ligands have similar logP values (2.552 and 2.567), falling within the optimal 1-3 range.

**4. H-Bond Donors:** Ligand A (1) is preferable to Ligand B (2) as lower HBD generally improves permeability.

**5. H-Bond Acceptors:** Ligand A (4) is preferable to Ligand B (3). Lower HBA generally improves permeability.

**6. QED:** Both ligands have good QED scores (0.733 and 0.772), indicating good drug-like properties.

**7. DILI:** Ligand A (17.72) has a significantly lower DILI risk than Ligand B (56.572). This is a major advantage for Ligand A.

**8. BBB:** Both ligands have good BBB penetration (78.209 and 71.384), exceeding the 70% threshold for CNS targets. Ligand A is slightly better.

**9. Caco-2 Permeability:** Ligand A (-4.607) is better than Ligand B (-4.961), indicating better intestinal absorption.

**10. Aqueous Solubility:** Ligand A (-2.067) is better than Ligand B (-4.081). Better solubility is generally desirable.

**11. hERG Inhibition:** Both ligands have low hERG inhibition risk (0.588 and 0.53).

**12. Microsomal Clearance:** Ligand B (27.299) has lower microsomal clearance than Ligand A (35.316), suggesting better metabolic stability.

**13. In vitro Half-Life:** Ligand A (11.326) has a positive half-life, while Ligand B (-14.757) has a negative half-life. This is a significant advantage for Ligand A.

**14. P-gp Efflux:** Both ligands have low P-gp efflux liability (0.211 and 0.214).

**15. Binding Affinity:** Ligand B (-8.1) has a slightly better binding affinity than Ligand A (-7.7). However, the difference is only 0.4 kcal/mol, which is not substantial enough to overcome the other significant advantages of Ligand A.

**Overall Assessment:**

Ligand A is the more promising candidate. While Ligand B has a slightly better binding affinity, Ligand A excels in crucial ADME properties, particularly DILI risk, solubility, and *in vitro* half-life. The lower DILI risk is a major advantage, and the better solubility and half-life contribute to a more favorable pharmacokinetic profile. Both have acceptable BBB penetration and logP values. The small difference in binding affinity is outweighed by the superior ADME profile of Ligand A.

Output:
0
2025-04-17 03:22:48,448 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (350.47 and 363.35 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (83.36) is better than Ligand B (55.4). Both are below the 90 A^2 threshold desirable for CNS targets, but Ligand B is significantly lower and more favorable.

**logP:** Ligand A (0.29) is quite low, potentially hindering membrane permeability. Ligand B (3.699) is within the optimal 1-3 range. This is a significant advantage for Ligand B.

**H-Bond Donors/Acceptors:** Both have acceptable HBD counts (1). Ligand A has 6 HBAs, while Ligand B has 3. Both are within the acceptable range (<=10), but Ligand B is preferable.

**QED:** Ligand A (0.692) has a better QED score than Ligand B (0.414), indicating better overall drug-likeness.

**DILI:** Ligand A (19.04) has a much lower DILI risk than Ligand B (39.51). This is a substantial advantage for Ligand A.

**BBB:** Ligand B (87.09) has a significantly higher BBB penetration percentile than Ligand A (48.74). This is *critical* for a CNS target like DRD2.

**Caco-2 Permeability:** Ligand A (-5.399) has a very poor Caco-2 permeability, indicating poor intestinal absorption. Ligand B (-4.356) is also poor, but slightly better.

**Aqueous Solubility:** Ligand A (0.001) has extremely poor solubility, which is a major concern. Ligand B (-4.261) is also poor, but better than A.

**hERG Inhibition:** Ligand A (0.087) has a very low hERG risk, which is excellent. Ligand B (0.891) is higher, but still relatively low.

**Microsomal Clearance:** Ligand A (-12.52) has a negative clearance, indicating very high metabolic stability, which is excellent. Ligand B (60.666) has a high clearance, suggesting rapid metabolism.

**In vitro Half-Life:** Ligand B (27.368 hours) has a much longer half-life than Ligand A (1.563 hours). This is a significant advantage for Ligand B.

**P-gp Efflux:** Ligand A (0.012) has very low P-gp efflux, which is favorable for CNS penetration. Ligand B (0.251) has slightly higher efflux.

**Binding Affinity:** Ligand B (-8.5 kcal/mol) has a stronger binding affinity than Ligand A (-7.5 kcal/mol). This 1 kcal/mol difference is meaningful.

**Overall Assessment:**

Ligand A has advantages in DILI risk, metabolic stability, hERG, and P-gp efflux. However, its extremely low logP, poor solubility, and poor Caco-2 permeability are major drawbacks. The low BBB penetration is also concerning for a CNS target.

Ligand B excels in BBB penetration, logP, binding affinity, and in vitro half-life. While its DILI risk and clearance are higher, the strong affinity and good CNS penetration are likely to outweigh these concerns, especially for a CNS target like DRD2. The slightly higher Pgp and hERG are manageable.

Output:
1
2025-04-17 03:22:48,448 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B based on the provided guidelines, prioritizing GPCR-specific properties (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (349.431 and 344.455 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (110.69) is higher than the preferred <90 for CNS targets, while Ligand B (58.64) is well within the optimal range. This is a significant advantage for Ligand B.

**logP:** Ligand A (0.486) is quite low, potentially hindering membrane permeability. Ligand B (2.609) is within the optimal 1-3 range. This favors Ligand B.

**H-Bond Donors/Acceptors:** Ligand A has 5 HBD and 5 HBA, acceptable but not ideal. Ligand B has 1 HBD and 3 HBA, which is more favorable for permeability.

**QED:** Both ligands have reasonable QED scores (0.492 and 0.749), indicating acceptable drug-likeness. Ligand B is better.

**DILI:** Both ligands have low DILI risk (34.781 and 29.236), below the 40 threshold.

**BBB:** Ligand A (43.311) has a poor BBB percentile, which is a major drawback for a CNS target like DRD2. Ligand B (83.443) has an excellent BBB percentile, exceeding the >70 desirable threshold. This is a critical advantage for Ligand B.

**Caco-2:** Ligand A (-5.123) and Ligand B (-4.4) have negative Caco-2 values, which is unusual and suggests poor permeability. However, the scale isn't clearly defined, so it's difficult to interpret definitively.

**Solubility:** Both ligands have poor solubility (-2.326 and -3.337).

**hERG:** Both ligands have low hERG risk (0.213 and 0.524).

**Microsomal Clearance:** Ligand A (6.743) has lower clearance than Ligand B (81.503), suggesting better metabolic stability. This favors Ligand A.

**In vitro Half-Life:** Ligand A (4.75) has a shorter half-life than Ligand B (-23.683), which is a negative.

**P-gp Efflux:** Ligand A (0.009) has very low P-gp efflux, which is good. Ligand B (0.33) has moderate P-gp efflux. This favors Ligand A.

**Binding Affinity:** Ligand B (-8.5 kcal/mol) has a slightly better binding affinity than Ligand A (-7.4 kcal/mol), a difference of 1.1 kcal/mol.

**Overall Assessment:**

Ligand B overwhelmingly outperforms Ligand A, especially considering the GPCR-specific priorities. Its superior BBB penetration, optimal logP, lower TPSA, and better binding affinity outweigh the slightly higher microsomal clearance and moderate P-gp efflux. Ligand A's poor BBB penetration and low logP are significant liabilities for a CNS drug. While Ligand A has better metabolic stability and P-gp efflux, these are less critical than CNS penetration for this target.



Output:
1
2025-04-17 03:22:48,448 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (352.425 and 347.375 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (49.41) is excellent, well below the 90 A^2 threshold for CNS targets. Ligand B (124.52) is higher, but still potentially acceptable, though less ideal.

**logP:** Ligand A (3.004) is optimal (1-3). Ligand B (-0.652) is significantly lower, which could hinder membrane permeability and CNS penetration.

**H-Bond Donors/Acceptors:** Ligand A (HBD=1, HBA=2) is favorable. Ligand B (HBD=3, HBA=6) is also acceptable, but slightly higher counts could impact permeability.

**QED:** Ligand A (0.856) is excellent, indicating high drug-likeness. Ligand B (0.622) is still reasonable, but lower than A.

**DILI:** Ligand A (26.91) has a very low DILI risk. Ligand B (59.907) is higher, suggesting a moderate risk of liver injury.

**BBB:** Ligand A (89.608) has excellent BBB penetration potential, exceeding the 70% threshold. Ligand B (28.306) is poor, suggesting limited CNS exposure.

**Caco-2 Permeability:** Ligand A (-4.628) is concerningly low, suggesting poor intestinal absorption. Ligand B (-5.296) is also low, but slightly better than A.

**Aqueous Solubility:** Ligand A (-4.146) is poor. Ligand B (-2.347) is also poor, but better than A.

**hERG Inhibition:** Both ligands (0.556 and 0.061) show low hERG inhibition risk, which is good.

**Microsomal Clearance:** Ligand A (32.033) is moderate. Ligand B (-10.724) is very low, indicating high metabolic stability.

**In vitro Half-Life:** Ligand A (-31.126) is very long, which is highly desirable. Ligand B (-3.038) is short.

**P-gp Efflux:** Both ligands (0.1 and 0.007) show very low P-gp efflux, which is excellent for CNS penetration.

**Binding Affinity:** Both ligands (-9.0 and -8.9 kcal/mol) have excellent binding affinity. The difference of 0.1 kcal/mol is not significant enough to outweigh other factors.

**Conclusion:**

Considering all factors, especially the GPCR-specific priorities, **Ligand A is the more promising drug candidate.** While its Caco-2 permeability and aqueous solubility are poor, its superior BBB penetration (89.6% vs 28.3%), optimal logP, excellent QED, and very low DILI risk outweigh these drawbacks. The excellent in vitro half-life is also a significant advantage. Ligand B's poor logP and BBB penetration are major concerns for a CNS-targeting drug, even with its better metabolic stability.

Output:
1
2025-04-17 03:22:48,449 - INFO - Reasoning:

Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (385.438 Da) is slightly higher than Ligand B (347.415 Da), but both are acceptable.

**2. TPSA:** Ligand A (97.38) is better than Ligand B (102.76) as it is closer to the <90 A^2 threshold for CNS targets.

**3. logP:** Ligand A (2.193) is optimal (1-3), while Ligand B (0.835) is slightly low, potentially hindering permeation.

**4. H-Bond Donors:** Ligand A (1) is preferable to Ligand B (3). Fewer HBDs generally improve permeability.

**5. H-Bond Acceptors:** Both ligands have 5 HBA, which is acceptable (<=10).

**6. QED:** Both ligands have acceptable QED scores (Ligand A: 0.87, Ligand B: 0.749), indicating good drug-like properties.

**7. DILI:** Ligand A (93.059) has a significantly higher DILI risk than Ligand B (35.091). This is a major concern for Ligand A.

**8. BBB:** Ligand A (65.801) has a better BBB percentile than Ligand B (23.149). This is crucial for a CNS target like DRD2.

**9. Caco-2 Permeability:** Ligand A (-4.657) is better than Ligand B (-5.06), indicating better intestinal absorption.

**10. Aqueous Solubility:** Ligand A (-3.518) is better than Ligand B (-1.985).

**11. hERG Inhibition:** Ligand A (0.574) has a lower hERG inhibition liability than Ligand B (0.169), which is favorable.

**12. Microsomal Clearance:** Ligand A (12.329) has a higher microsomal clearance than Ligand B (6.432), indicating lower metabolic stability.

**13. In vitro Half-Life:** Ligand A (176.728) has a much longer in vitro half-life than Ligand B (-24.813).

**14. P-gp Efflux:** Ligand A (0.514) has a lower P-gp efflux liability than Ligand B (0.011), which is beneficial for CNS penetration.

**15. Binding Affinity:** Both ligands have similar binding affinities (-9.5 and -8.5 kcal/mol). The difference is less than the 1.5 kcal/mol threshold.

**Overall Assessment:**

Ligand A has several advantages: better BBB penetration, better solubility, lower hERG risk, lower P-gp efflux, and a longer half-life. However, its significantly higher DILI risk is a major drawback. Ligand B has a much lower DILI risk, which is a significant advantage. While Ligand B has lower BBB penetration and a lower logP, the DILI risk associated with Ligand A is too high to ignore. The slightly better affinity of Ligand A does not outweigh the substantial safety concerns.

Output:
1
2025-04-17 03:22:48,449 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (342.447 Da) is slightly lower, which could be advantageous for permeability. Ligand B (369.462 Da) is also good.

**TPSA:** Both ligands have TPSA values (75.94 and 79.37) that are acceptable for oral absorption (<140), but a bit high for optimal CNS penetration (<90).

**logP:** Both ligands have good logP values (1.825 and 2.423), falling within the optimal range of 1-3. Ligand B is slightly higher, potentially improving membrane permeability.

**H-Bond Donors/Acceptors:** Both ligands have reasonable HBD (1) and HBA (6 & 4) counts, unlikely to cause significant issues.

**QED:** Both ligands have high QED scores (0.921 and 0.884), indicating good drug-like properties.

**DILI:** Ligand A (61.264) has a higher DILI risk than Ligand B (48.391), though both are reasonably acceptable.

**BBB:** Ligand B (79.488) has a significantly better BBB percentile than Ligand A (67.313). This is a crucial advantage for a CNS target like DRD2.

**Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and suggests a potential issue with the data or modeling. However, we can proceed assuming these are percentile scores and higher is better.

**Aqueous Solubility:** Both ligands have very poor aqueous solubility (-2.698 and -3.196). This is a significant concern for bioavailability.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.577 and 0.171).

**Microsomal Clearance:** Ligand B (-1.225) has a *negative* microsomal clearance, which is not physically possible and indicates a data issue. Ligand A (53.281) has a moderate clearance.

**In vitro Half-Life:** Ligand A (21.124 hours) has a better in vitro half-life than Ligand B (14.815 hours).

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.077 and 0.096), which is favorable for CNS penetration.

**Binding Affinity:** Ligand B (-8.8 kcal/mol) has a slightly better binding affinity than Ligand A (-8.2 kcal/mol). While the difference is not huge (0.6 kcal/mol), it's enough to be considered, especially given the other favorable properties of Ligand B.

**Overall Assessment:**

Ligand B is the more promising candidate. The primary driver is its significantly better BBB penetration (79.5% vs 67.3%). This is paramount for a CNS target. It also has a lower DILI risk and a slightly better binding affinity. While the negative microsomal clearance is a data anomaly, the other properties of Ligand B outweigh the concerns about Ligand A, especially considering the importance of CNS penetration for DRD2. The poor solubility is a concern for both, but can be addressed with formulation strategies.

Output:
1
2025-04-17 03:22:48,449 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (373.406 and 348.443 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (101.78) is better than Ligand B (67.87) as it is closer to the <90 desired for CNS targets. Ligand B is still acceptable.

**logP:** Both ligands have good logP values (1.752 and 1.316), falling within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Both have 1 HBD, which is good. Ligand A has 6 HBA, while Ligand B has 4. Both are within the acceptable limit of <=10.

**QED:** Both have good QED scores (0.552 and 0.832), indicating good drug-like properties.

**DILI:** Ligand A (57.348) has a higher DILI risk than Ligand B (27.181). This is a significant negative for Ligand A.

**BBB:** Ligand A (86.274) has a significantly better BBB penetration percentile than Ligand B (66.693). This is a critical advantage for a CNS target like DRD2.

**Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual. It's difficult to interpret without knowing the scale. However, the values are similar.

**Aqueous Solubility:** Both have negative solubility values, again making interpretation difficult. The values are similar.

**hERG:** Both ligands have low hERG inhibition liability (0.484 and 0.304), which is good.

**Microsomal Clearance:** Both have similar microsomal clearance values (33.787 and 35.813), indicating comparable metabolic stability.

**In vitro Half-Life:** Ligand A (-2.239) has a negative half-life, which is not possible. This is a major red flag. Ligand B has a half-life of 14.715 hours, which is good.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.119 and 0.035), which is excellent for CNS penetration.

**Binding Affinity:** Both ligands have excellent binding affinities (-8.0 and -8.4 kcal/mol). Ligand B is slightly better, but the difference is small.

**Overall Assessment:**

Ligand A has a better BBB score and comparable binding affinity, but suffers from a higher DILI risk and a nonsensical negative in vitro half-life. Ligand B has a lower DILI risk, a reasonable BBB score, and a positive half-life. Given the importance of metabolic stability and safety (DILI) for drug development, and the fact that the affinity difference is small, Ligand B is the more promising candidate.

Output:
1
2025-04-17 03:22:48,449 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (344.419 and 368.419 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (93.84) is better than Ligand B (119.19). For CNS targets, we want TPSA <= 90, so Ligand A is closer to this threshold.

**logP:** Ligand A (1.016) is within the optimal range (1-3), while Ligand B (-1.047) is slightly below, which *could* hinder permeation.

**H-Bond Donors/Acceptors:** Ligand A (2 HBD, 6 HBA) and Ligand B (1 HBD, 8 HBA) both have reasonable numbers of H-bonds, within the suggested limits.

**QED:** Both ligands have similar QED values (0.733 and 0.695), indicating good drug-likeness.

**DILI:** Ligand B (71.345) has a higher DILI risk than Ligand A (59.442), though both are above the preferred <40, Ligand A is better.

**BBB:** Ligand A (47.111) has a significantly better BBB penetration percentile than Ligand B (33.579). This is a *critical* factor for a CNS target like DRD2.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.167 and -5.318), which is unusual and suggests poor permeability. This is a significant concern for both.

**Aqueous Solubility:** Both ligands have negative solubility values (-2.468 and -1.573), indicating poor solubility. This is a concern for both.

**hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.033 and 0.048).

**Microsomal Clearance:** Ligand A (34.267) has a lower microsomal clearance than Ligand B (7.233), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (14.618) has a shorter half-life than Ligand B (23.402), but both are reasonable.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.052 and 0.098).

**Binding Affinity:** Both ligands have excellent binding affinity (-8.0 and -8.2 kcal/mol). The difference is minimal.

**Overall Assessment:**

Considering the GPCR-specific priorities, Ligand A is the better candidate. Its superior BBB penetration, lower DILI risk, and better metabolic stability (lower Cl_mic) outweigh the slightly shorter half-life. While both ligands have poor Caco-2 and solubility, the CNS target makes BBB penetration the most crucial factor. The binding affinity is comparable between the two.

Output:
0
2025-04-17 03:22:48,450 - INFO - Reasoning:

Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (347.434 and 383.945 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (71.09) is better than Ligand B (58.36). Both are below the 90 A^2 threshold desirable for CNS targets.

**3. logP:** Ligand A (2.407) is within the optimal 1-3 range. Ligand B (3.769) is slightly higher, but still acceptable.

**4. H-Bond Donors:** Ligand A (2) and Ligand B (1) are both within the acceptable limit of <=5.

**5. H-Bond Acceptors:** Ligand A (3) and Ligand B (5) are both within the acceptable limit of <=10.

**6. QED:** Both ligands have similar QED values (0.83 and 0.754), indicating good drug-like properties.

**7. DILI:** Both ligands have very similar, and acceptable, DILI risk (35.983 and 35.789 percentile).

**8. BBB:** This is a critical parameter for a CNS target like DRD2. Ligand A (79.256) has a significantly better BBB penetration percentile than Ligand B (60.644). This is a major advantage for Ligand A.

**9. Caco-2 Permeability:** Ligand A (-4.743) and Ligand B (-4.952) are both negative, which is unusual. It's difficult to interpret without knowing the scale. However, the values are similar.

**10. Aqueous Solubility:** Both ligands have poor aqueous solubility (-2.925 and -3.409). This is a potential drawback, but can be addressed with formulation strategies.

**11. hERG Inhibition:** Ligand A (0.473) has a lower hERG inhibition liability than Ligand B (0.848), indicating a lower risk of cardiotoxicity.

**12. Microsomal Clearance:** Ligand A (13.824) has a much lower microsomal clearance than Ligand B (53.227), suggesting better metabolic stability.

**13. In vitro Half-Life:** Ligand A (-1.007) has a shorter in vitro half-life than Ligand B (26.53). This is a negative for Ligand A.

**14. P-gp Efflux:** Ligand A (0.115) has a much lower P-gp efflux liability than Ligand B (0.824), which is crucial for CNS penetration.

**15. Binding Affinity:** Ligand A (-9.1 kcal/mol) has a significantly stronger binding affinity than Ligand B (-6.8 kcal/mol). This is a substantial advantage, potentially outweighing some of the ADME drawbacks.

**Overall Assessment:**

Ligand A is the stronger candidate. While it has a shorter in vitro half-life and poorer solubility, its superior BBB penetration, lower P-gp efflux, lower hERG inhibition, better metabolic stability (lower Cl_mic), and *significantly* stronger binding affinity outweigh these concerns. The strong binding affinity is particularly important for a GPCR target. The TPSA is also more favorable for CNS penetration.

Output:
1
2025-04-17 03:22:48,450 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (349.479 and 363.849 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (81.93) is slightly higher than Ligand B (73.14), but both are below the 90 A^2 threshold desirable for CNS targets.

**3. logP:** Both ligands have excellent logP values (2.493 and 2.383), falling within the optimal 1-3 range.

**4. H-Bond Donors:** Ligand A has 1 HBD, while Ligand B has 0. Both are within the acceptable limit of <=5.

**5. H-Bond Acceptors:** Ligand A has 7 HBA, and Ligand B has 6. Both are within the acceptable limit of <=10.

**6. QED:** Both ligands have good QED scores (0.654 and 0.673), indicating good drug-like properties.

**7. DILI:** Ligand A (35.828) has a lower DILI risk than Ligand B (50.368). This is a significant advantage.

**8. BBB:** Ligand B (80.884) has a slightly better BBB penetration percentile than Ligand A (74.254), though both are above the 70% threshold for CNS targets.

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.785 and -4.861). This is unusual and suggests poor permeability. However, these values are on a scale where negative values are possible, and direct comparison is difficult without knowing the scale's specifics.

**10. Aqueous Solubility:** Both ligands have negative solubility values (-3.311 and -2.47). Similar to Caco-2, this is unusual and requires caution.

**11. hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.164 and 0.265).

**12. Microsomal Clearance:** Ligand B (50.639) has significantly lower microsomal clearance than Ligand A (76.646), indicating better metabolic stability.

**13. In vitro Half-Life:** Ligand B (37.406) has a significantly longer in vitro half-life than Ligand A (-19.578). This is a major advantage.

**14. P-gp Efflux:** Both ligands have low P-gp efflux liability (0.229 and 0.265).

**15. Binding Affinity:** Ligand A (-7.2 kcal/mol) has a slightly better binding affinity than Ligand B (-7.1 kcal/mol), though the difference is small.

**Overall Assessment:**

While Ligand B has a better BBB score and significantly improved metabolic stability and half-life, Ligand A has a lower DILI risk and slightly better binding affinity. Given the importance of metabolic stability and half-life for *in vivo* efficacy, and the acceptable DILI risk of Ligand A, the slight advantage in binding affinity of Ligand A is not enough to overcome the superior pharmacokinetic profile of Ligand B. The negative Caco-2 and solubility values are concerning for both, but the other properties of Ligand B are more favorable for CNS drug development.

Output:
1
2025-04-17 03:22:48,450 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B based on the provided guidelines, prioritizing GPCR-specific properties (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (366.487 and 355.435 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (84.42) is excellent for CNS penetration, well below the 90 A^2 threshold. Ligand B (121.96) is higher, but still reasonably acceptable, though less ideal for CNS targets.

**logP:** Ligand A (1.853) is optimal. Ligand B (-0.466) is below 1, which could hinder permeation.

**H-Bond Donors/Acceptors:** Ligand A (HBD=1, HBA=6) is good. Ligand B (HBD=3, HBA=5) is also acceptable.

**QED:** Both ligands have reasonable QED scores (A: 0.86, B: 0.516), indicating good drug-like properties.

**DILI:** Ligand A (60.721) has a moderate DILI risk, while Ligand B (16.44) has a very low DILI risk, a significant advantage.

**BBB:** Ligand A (70.919) has good BBB penetration. Ligand B (40.403) has poor BBB penetration, a major drawback for a CNS target like DRD2.

**Caco-2 Permeability:** Ligand A (-4.859) has poor Caco-2 permeability, while Ligand B (-5.4) is also poor.

**Aqueous Solubility:** Ligand A (-3.517) has poor solubility, while Ligand B (-0.823) is slightly better, but still poor.

**hERG:** Both ligands have very low hERG inhibition risk (A: 0.15, B: 0.037).

**Microsomal Clearance:** Ligand A (34.447) has moderate clearance, while Ligand B (9.656) has low clearance, suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (4.289) has a short half-life, while Ligand B (1.41) is even shorter.

**P-gp Efflux:** Both ligands have very low P-gp efflux (A: 0.352, B: 0.006), which is favorable for CNS penetration.

**Binding Affinity:** Ligand A (-7.3 kcal/mol) has a significantly stronger binding affinity than Ligand B (-6.3 kcal/mol). This 1 kcal/mol difference is substantial and can outweigh some ADME drawbacks.

**Overall Assessment:**

Ligand A excels in binding affinity and BBB penetration, crucial for a CNS GPCR target. While its solubility and Caco-2 permeability are poor, the strong affinity might compensate. Ligand B has a much better safety profile (lower DILI, lower clearance), but suffers from poor BBB penetration and a weaker binding affinity. Given the importance of CNS penetration for DRD2, and the substantial affinity difference, Ligand A is the more promising candidate, despite its ADME liabilities. Further optimization could focus on improving solubility and permeability while maintaining the strong binding affinity.

Output:
1
2025-04-17 03:22:48,451 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (354.407 and 350.463 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (119.05) is slightly above the optimal <90 for CNS targets, but still reasonable. Ligand B (85.25) is excellent, well below 90.

**logP:** Ligand A (-1.933) is a bit low, potentially hindering permeability. Ligand B (1.446) is within the optimal 1-3 range. This is a significant advantage for Ligand B.

**H-Bond Donors/Acceptors:** Ligand A has 3 HBD and 5 HBA, acceptable. Ligand B has 2 HBD and 5 HBA, also acceptable.

**QED:** Both ligands have reasonable QED values (0.497 and 0.669), indicating drug-like properties. Ligand B is slightly better.

**DILI:** Ligand A (31.524) has a slightly higher DILI risk than Ligand B (22.8), but both are below the concerning threshold of 60.

**BBB:** This is crucial for a CNS target. Ligand A (16.945) has very poor predicted BBB penetration. Ligand B (65.839) is quite good, exceeding the desirable >70 threshold. This is a major advantage for Ligand B.

**Caco-2 Permeability:** Both have negative values (-5.173 and -4.853), which is unusual and difficult to interpret without knowing the scale. However, the negative values suggest poor permeability.

**Aqueous Solubility:** Both have negative values (-1.136 and -1.565), indicating poor solubility.

**hERG Inhibition:** Both ligands have very low predicted hERG inhibition risk (0.024 and 0.153).

**Microsomal Clearance:** Ligand A (-2.506) has a more negative value, suggesting lower clearance and better metabolic stability than Ligand B (31.068).

**In vitro Half-Life:** Ligand B (18.346) has a longer predicted half-life than Ligand A (-11.532).

**P-gp Efflux:** Both have very low P-gp efflux liability (0.003 and 0.017), which is favorable.

**Binding Affinity:** Ligand B (-7.5 kcal/mol) has a slightly better binding affinity than Ligand A (-7.3 kcal/mol), although the difference is small.

**Overall Assessment:**

Ligand B is significantly better due to its superior BBB penetration (65.839 vs 16.945), more favorable logP (1.446 vs -1.933), and slightly better binding affinity (-7.5 vs -7.3). While Ligand A has better metabolic stability, the CNS target necessitates prioritizing BBB penetration and permeability, where Ligand B excels. The slightly longer half-life of Ligand B is also a plus.

Output:
1
2025-04-17 03:22:48,451 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (367.471 and 341.419 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (71.97) is excellent, well below the 90 A^2 threshold for CNS targets. Ligand B (82.68) is still reasonable, but less optimal.

**logP:** Both ligands (2.025 and 2.047) are within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A (0 HBD, 6 HBA) is better than Ligand B (1 HBD, 8 HBA) in terms of balancing solubility and permeability, as it has fewer potential liabilities.

**QED:** Both ligands have acceptable QED scores (0.814 and 0.708), indicating good drug-like properties.

**DILI:** Ligand A (57.697) has a slightly better DILI score than Ligand B (65.917), indicating a lower risk of liver injury. Both are acceptable, but lower is preferred.

**BBB:** This is a crucial parameter for a CNS target like DRD2. Ligand A (71.501) has a significantly better BBB percentile than Ligand B (28.344). This is a major advantage for Ligand A.

**Caco-2 Permeability:** Ligand A (-4.518) and Ligand B (-5.273) both have negative values, indicating poor permeability. This is a concern for both, but the difference is not substantial.

**Aqueous Solubility:** Both ligands have poor aqueous solubility (-2.554 and -2.41). This could pose formulation challenges.

**hERG Inhibition:** Both ligands have low hERG inhibition liability (0.401 and 0.261), which is positive.

**Microsomal Clearance:** Ligand A (36.683) has a slightly higher microsomal clearance than Ligand B (29.072), meaning it might be metabolized faster.

**In vitro Half-Life:** Ligand B (-3.949) has a slightly better in vitro half-life than Ligand A (-5.036).

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.326 and 0.069), which is favorable for CNS penetration.

**Binding Affinity:** Ligand B (-8.5 kcal/mol) has a significantly stronger binding affinity than Ligand A (-7.3 kcal/mol). This is a substantial advantage, exceeding the 1.5 kcal/mol threshold.

**Overall Assessment:**

While Ligand B boasts a superior binding affinity, Ligand A has a much better BBB penetration profile, a more favorable TPSA, and a slightly better DILI score. For a CNS target like DRD2, BBB penetration is paramount. The 1.2 kcal/mol difference in binding affinity, while significant, might be overcome with further optimization of Ligand A. The poor solubility and Caco-2 permeability are concerns for both, but can be addressed with formulation strategies. Given the importance of CNS penetration for DRD2, Ligand A is the more promising candidate.

Output:
0
2025-04-17 03:22:48,451 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B based on the provided guidelines, prioritizing GPCR-specific properties (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (352.475 and 366.527 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (76.66) is better than Ligand B (67.43), both are below the 90 A^2 threshold for CNS targets.

**logP:** Both ligands have good logP values (2.635 and 2.098), falling within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Both ligands have 2 HBD and 4 HBA, which are within acceptable limits.

**QED:** Ligand B (0.724) has a significantly better QED score than Ligand A (0.36), indicating a more drug-like profile.

**DILI:** Ligand A (28.306) has a lower DILI risk than Ligand B (37.146), which is preferable.

**BBB:** Ligand A (68.67) has a substantially better BBB penetration percentile than Ligand B (45.134). This is a *critical* advantage for a CNS target like DRD2.

**Caco-2 Permeability:** Ligand A (-5.258) has a better Caco-2 permeability than Ligand B (-5.486).

**Aqueous Solubility:** Ligand A (-1.983) has a better aqueous solubility than Ligand B (-3.012).

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.328 and 0.283).

**Microsomal Clearance:** Both ligands have similar microsomal clearance (30.024 and 28.049 mL/min/kg).

**In vitro Half-Life:** Ligand B has a much longer in vitro half-life (15.368 hours) compared to Ligand A (-1.299 hours). This is a significant advantage.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.047 and 0.085).

**Binding Affinity:** Ligand A (-7.9 kcal/mol) has a slightly better binding affinity than Ligand B (-7.0 kcal/mol), although the difference is less than 1.5 kcal/mol.

**Overall Assessment:**

While Ligand B has a better QED and in vitro half-life, Ligand A's superior BBB penetration and DILI profile are decisive for a CNS-targeting GPCR like DRD2. The slightly better affinity of Ligand A is a bonus. The BBB is paramount for CNS drug candidates, and Ligand A's 68.67% percentile is much more promising than Ligand B's 45.134%.

Output:
0
2025-04-17 03:22:48,451 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (386.495 & 387.845 Da) fall comfortably within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (108.64) is better than Ligand B (113.69). Both are reasonably close to the 90 A^2 target for CNS penetration, but A is preferable.

**3. logP:** Ligand A (2.101) is slightly higher than Ligand B (1.374), placing it more optimally within the 1-3 range. Ligand B is a bit low, potentially hindering permeation.

**4. H-Bond Donors:** Both ligands have 3 HBD, which is within the acceptable limit of <=5.

**5. H-Bond Acceptors:** Ligand A has 6 HBA, and Ligand B has 7. Both are within the acceptable limit of <=10.

**6. QED:** Both ligands have good QED scores (0.579 and 0.599), indicating drug-like properties.

**7. DILI:** Ligand A (75.339) has a higher DILI risk than Ligand B (65.917). This is a negative for Ligand A.

**8. BBB:** Ligand A (11.439) has a significantly better BBB penetration percentile than Ligand B (31.989). This is a *critical* advantage for a CNS target like DRD2.

**9. Caco-2 Permeability:** Both have negative Caco-2 values (-5.749 and -5.333), which is unusual and suggests poor permeability. However, these values are on a scale where negative values are possible and don't necessarily disqualify a compound.

**10. Aqueous Solubility:** Both have negative solubility values (-2.384 and -2.427), indicating poor aqueous solubility. This is a concern for formulation.

**11. hERG Inhibition:** Both ligands show very low hERG inhibition risk (0.218 and 0.198).

**12. Microsomal Clearance:** Ligand B (21.093) has a significantly lower microsomal clearance than Ligand A (35.353), indicating better metabolic stability.

**13. In vitro Half-Life:** Ligand B (19.383) has a shorter in vitro half-life than Ligand A (60.251). This favors Ligand A.

**14. P-gp Efflux:** Both ligands have low P-gp efflux liability (0.165 and 0.241).

**15. Binding Affinity:** Ligand B (-8.1 kcal/mol) has a stronger binding affinity than Ligand A (-7.0 kcal/mol). This is a substantial advantage for Ligand B (a 1.1 kcal/mol difference).

**Overall Assessment:**

While Ligand B has superior binding affinity and metabolic stability, Ligand A's significantly better BBB penetration is crucial for a CNS-targeting drug. The difference in affinity, while substantial, might be overcome with further optimization, whereas improving BBB penetration is often more challenging. The slightly higher DILI risk for Ligand A is a concern, but not insurmountable. Considering the GPCR-specific priorities, and the importance of CNS penetration for DRD2, Ligand A is the more promising candidate.

Output:
0
2025-04-17 03:22:48,452 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (372.893 and 343.427 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Both ligands (78.87 and 75.44) are below the 90 A^2 threshold for CNS targets, which is excellent.

**3. logP:** Both ligands (2.379 and 2.164) are within the optimal 1-3 range.

**4. H-Bond Donors:** Ligand A has 2 HBD, and Ligand B has 1. Both are acceptable (<=5).

**5. H-Bond Acceptors:** Both ligands have 4 HBA, well within the acceptable limit of <=10.

**6. QED:** Ligand A (0.506) is slightly above the 0.5 threshold, indicating good drug-likeness. Ligand B (0.85) is even better.

**7. DILI:** Ligand A (33.424) has a lower DILI risk than Ligand B (48.817), both are good (<40 is preferred, but <60 is acceptable).

**8. BBB:** Ligand B (81.349) has a significantly higher BBB penetration percentile than Ligand A (67.817). This is a crucial advantage for a CNS target like DRD2.

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.058 and -5.01), which is unusual and suggests poor permeability. This is a concern for both.

**10. Aqueous Solubility:** Both ligands have negative solubility values (-2.457 and -2.784), indicating very poor aqueous solubility. This is a significant drawback for both.

**11. hERG Inhibition:** Both ligands have low hERG inhibition risk (0.402 and 0.289).

**12. Microsomal Clearance:** Ligand A (6.816) has a lower microsomal clearance than Ligand B (60.749), suggesting better metabolic stability.

**13. In vitro Half-Life:** Ligand A (1.585 hours) has a shorter half-life than Ligand B (-30.966 hours). The negative value for Ligand B is likely an error, but even if interpreted as very long, it doesn't necessarily translate to *in vivo* stability.

**14. P-gp Efflux:** Ligand A (0.125) has lower P-gp efflux liability than Ligand B (0.311), which is favorable for CNS penetration.

**15. Binding Affinity:** Ligand B (-9.0 kcal/mol) has a significantly stronger binding affinity than Ligand A (-7.5 kcal/mol). This is a substantial advantage (1.5 kcal/mol difference).

**Overall Assessment:**

While both compounds have significant drawbacks (poor solubility and Caco-2 permeability), Ligand B is the more promising candidate. Its superior BBB penetration and significantly stronger binding affinity outweigh the slightly higher DILI risk and P-gp efflux. The better QED score also contributes to its favorability. The negative half-life for Ligand B is suspect and needs further investigation, but the affinity difference is substantial.

Output:
1
2025-04-17 03:22:48,452 - INFO - Batch 24 complete. Total preferences: 384
2025-04-17 03:22:48,452 - INFO - Processing batch 25/512...
2025-04-17 03:23:29,956 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (365.474 and 353.547 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (81.99) is slightly higher than Ligand B (60.77). Both are below the 90 A^2 threshold for CNS targets, but B is preferable.

**3. logP:** Both ligands have good logP values (3.495 and 3.767), falling within the optimal 1-3 range.

**4. H-Bond Donors:** Both have 2 HBD, which is acceptable.

**5. H-Bond Acceptors:** Ligand A has 4 HBA, and Ligand B has 3. Both are within the acceptable limit of 10.

**6. QED:** Ligand A (0.756) has a slightly higher QED than Ligand B (0.588), indicating better overall drug-likeness.

**7. DILI:** Ligand A (67.623) has a higher DILI risk than Ligand B (6.359). This is a significant negative for Ligand A.

**8. BBB:** Ligand B (65.413) has a better BBB penetration percentile than Ligand A (62.117), although both are reasonably good. For a CNS target like DRD2, maximizing BBB penetration is crucial.

**9. Caco-2 Permeability:** Ligand A (-4.983) has worse Caco-2 permeability than Ligand B (-4.252). Lower values indicate lower permeability.

**10. Aqueous Solubility:** Ligand A (-5.301) has worse aqueous solubility than Ligand B (-3.375).

**11. hERG Inhibition:** Both ligands have low hERG inhibition risk (0.758 and 0.57).

**12. Microsomal Clearance:** Ligand B (75.304) has higher microsomal clearance than Ligand A (59.517), meaning it's cleared faster. This is a negative for Ligand B.

**13. In vitro Half-Life:** Ligand A (34.642) has a longer in vitro half-life than Ligand B (9.711). This is a positive for Ligand A.

**14. P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.38 and 0.3).

**15. Binding Affinity:** Ligand B (-6.6 kcal/mol) has a significantly stronger binding affinity than Ligand A (-0.0 kcal/mol). This is a major advantage for Ligand B. A difference of >1.5 kcal/mol can outweigh other drawbacks.

**Overall Assessment:**

While Ligand A has a slightly better QED and in vitro half-life, Ligand B is significantly better in almost all other critical parameters. The most important factor is the much stronger binding affinity of Ligand B. Additionally, Ligand B has a much lower DILI risk and better BBB penetration, both crucial for a CNS drug. The higher clearance of Ligand B is a concern, but the substantial affinity advantage likely compensates for this.

Output:
1
2025-04-17 03:23:29,957 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (353.467 Da) is slightly lower, which is generally favorable for permeability. Ligand B (386.539 Da) is also acceptable.

**TPSA:** Both ligands have TPSA values below 140, which is good for oral absorption. Importantly, both are also below the 90 threshold desirable for CNS targets. Ligand B (86.71) is slightly better than Ligand A (99.49).

**logP:** Ligand A (0.321) is quite low, potentially hindering membrane permeability. Ligand B (1.919) is within the optimal range (1-3). This is a significant advantage for Ligand B.

**H-Bond Donors/Acceptors:** Ligand A has 3 HBD and 6 HBA, which are acceptable. Ligand B has 2 HBD and 5 HBA, also acceptable.

**QED:** Both ligands have good QED scores (A: 0.563, B: 0.75), indicating drug-like properties. Ligand B is better.

**DILI:** Ligand A (28.655) has a much lower DILI risk than Ligand B (59.984). This is a substantial advantage for Ligand A.

**BBB:** Ligand A (27.801) has a very low BBB penetration percentile, making it unlikely to effectively reach the target in the CNS. Ligand B (51.299) is better, but still not ideal (we want >70 for CNS targets).

**Caco-2 Permeability:** Both ligands have negative Caco-2 values, which is unusual and suggests poor permeability. However, the scale isn't specified, so it's hard to interpret.

**Aqueous Solubility:** Both ligands have negative solubility values, which is also unusual and suggests poor solubility. Again, the scale isn't specified.

**hERG Inhibition:** Both ligands have low hERG inhibition liability (A: 0.184, B: 0.389), which is good.

**Microsomal Clearance:** Ligand A (19.87 mL/min/kg) has a lower microsomal clearance than Ligand B (41.212 mL/min/kg), indicating better metabolic stability.

**In vitro Half-Life:** Ligand A (11.699 hours) has a better in vitro half-life than Ligand B (-45.683 hours). The negative value for B is concerning and likely an error or outlier.

**P-gp Efflux:** Both have very low P-gp efflux liability (A: 0.01, B: 0.2).

**Binding Affinity:** Both ligands have the same excellent binding affinity (-7.4 kcal/mol).

**Overall Assessment:**

Ligand A has advantages in DILI risk and metabolic stability (Cl_mic and t1/2). However, its very poor BBB penetration and low logP are major drawbacks for a CNS target like DRD2. Ligand B has a better logP and slightly better TPSA, but a significantly higher DILI risk and questionable in vitro half-life.

Given the GPCR-specific priorities and the need for CNS penetration, Ligand B is slightly favored due to its better logP and TPSA, despite the higher DILI risk. The affinity is the same for both, so that doesn't differentiate them. The poor BBB for Ligand B is still a concern, but the low logP of Ligand A is a bigger obstacle. Further optimization of Ligand B to improve its BBB penetration and reduce DILI risk would be a reasonable next step.

Output:
1
2025-04-17 03:23:29,957 - INFO - Reasoning:

Let's analyze Ligand A and Ligand B for their potential as DRD2 drug candidates, considering the provided guidelines and GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight (MW):** Both ligands (338.411 and 344.459 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (72.94) is significantly better than Ligand B (86.88). For CNS targets, we want TPSA <= 90, and A is comfortably within that, while B is approaching the upper limit.

**3. logP:** Both ligands have good logP values (3.325 and 2.201), falling within the optimal 1-3 range.

**4. H-Bond Donors (HBD):** Both are acceptable (1 and 3 respectively), staying below the 5 threshold.

**5. H-Bond Acceptors (HBA):** Both are acceptable (5 and 3 respectively), staying below the 10 threshold.

**6. QED:** Both ligands have reasonable QED scores (0.748 and 0.663), indicating good drug-like properties.

**7. DILI:** Ligand A (84.374) has a higher DILI risk than Ligand B (44.048). This is a significant drawback for Ligand A.

**8. BBB:** Ligand B (57.619) has a considerably better BBB penetration percentile than Ligand A (32.571). This is *critical* for a CNS target like DRD2.

**9. Caco-2 Permeability:** Both have negative Caco-2 values (-5.173 and -5.156). This is unusual and suggests poor permeability. It's difficult to interpret without knowing the scale, but it's a negative for both.

**10. Aqueous Solubility:** Both have negative solubility values (-3.827 and -3.857), again unusual and suggesting poor solubility.

**11. hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.052 and 0.204).

**12. Microsomal Clearance:** Ligand B (50.831) has a higher microsomal clearance than Ligand A (23.049), suggesting faster metabolism and potentially lower exposure.

**13. In vitro Half-Life:** Ligand A (-27.521) has a longer in vitro half-life than Ligand B (-15.849). This is a positive for A.

**14. P-gp Efflux:** Both have very low P-gp efflux liability (0.113 and 0.086).

**15. Binding Affinity:** Both ligands have excellent binding affinities (-9.4 and -9.0 kcal/mol). The difference of 0.4 kcal/mol is not substantial enough to override other significant differences.

**Overall Assessment:**

While Ligand A has a slightly longer half-life, Ligand B is the superior candidate. The significantly better BBB penetration (57.619 vs 32.571) and substantially lower DILI risk (44.048 vs 84.374) are crucial advantages for a CNS-targeting drug. The slightly higher metabolic clearance of B is a lesser concern compared to the poor BBB and high DILI risk of A. The similar binding affinities make these ADME properties the deciding factors.

Output:
1
2025-04-17 03:23:29,957 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight (MW):** Both ligands (346.471 and 357.336 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (67.43) is significantly better than Ligand B (83.88). For CNS targets, we want TPSA <= 90, and A is closer to the ideal <=60. B is pushing the upper limit.

**3. logP:** Both ligands have good logP values (2.336 and 1.622), falling within the optimal 1-3 range.

**4. H-Bond Donors (HBD):** Both ligands have acceptable HBD counts (2 and 1, respectively), well below the threshold of 5.

**5. H-Bond Acceptors (HBA):** Both ligands have acceptable HBA counts (3 and 5, respectively), below the threshold of 10.

**6. QED:** Both ligands have good QED scores (0.549 and 0.816), indicating drug-like properties. Ligand B is slightly better.

**7. DILI:** Ligand A (28.926) has a much lower DILI risk than Ligand B (55.099). This is a significant advantage for A.

**8. BBB:** Ligand A (68.282) has a better BBB penetration percentile than Ligand B (56.107). While both are not ideal (>70 desirable), A is closer. This is crucial for a CNS target like DRD2.

**9. Caco-2:** Both have negative values, which is unusual. Assuming these are log scale values, lower is worse. Ligand A (-5.118) is worse than Ligand B (-4.805).

**10. Solubility:** Both have negative values, which is unusual. Assuming these are log scale values, lower is worse. Ligand A (-3.195) is worse than Ligand B (-2.387).

**11. hERG:** Ligand A (0.225) has a lower hERG inhibition liability than Ligand B (0.664), indicating a lower risk of cardiotoxicity.

**12. Cl_mic:** Ligand A (56.595) has a higher microsomal clearance than Ligand B (11.52). Higher clearance means faster metabolism and potentially lower exposure, favoring B.

**13. t1/2:** Ligand B (-21.108) has a much longer in vitro half-life than Ligand A (-11.324). This is a significant advantage for B.

**14. Pgp:** Ligand A (0.103) has lower P-gp efflux liability than Ligand B (0.079). Lower efflux is better for CNS exposure, favoring A.

**15. Binding Affinity:** Ligand A (-8.9 kcal/mol) has a significantly stronger binding affinity than Ligand B (-7.0 kcal/mol). This is a substantial advantage for A, potentially outweighing some of its ADME drawbacks.

**Overall Assessment:**

Ligand A excels in crucial areas for a CNS-targeting GPCR ligand: TPSA, DILI risk, BBB penetration, hERG, and *especially* binding affinity. While its Caco-2 and solubility are worse, and its metabolic clearance is higher, the significantly stronger binding affinity (-8.9 vs -7.0 kcal/mol) and better safety profile (lower DILI, hERG) are compelling. Ligand B has better half-life and QED, but the weaker affinity and higher DILI/hERG are concerning.

Output:
0
2025-04-17 03:23:29,957 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (350.321 and 362.539 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (77.52) is better than Ligand B (49.41) regarding TPSA. For CNS targets, we want TPSA <= 90, both are well within this range.

**logP:** Both ligands have similar logP values (2.726 and 2.673), both falling within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Both have 1 HBD, which is good. Ligand A has 5 HBA, while Ligand B has 3. Both are acceptable (<=10).

**QED:** Both ligands have high QED scores (0.811 and 0.836), indicating good drug-like properties.

**DILI:** Ligand A has a significantly higher DILI risk (85.227 percentile) compared to Ligand B (17.216 percentile). This is a major concern for Ligand A.

**BBB:** Both ligands have excellent BBB penetration (76.464 and 75.843 percentile), which is crucial for a CNS target like DRD2.

**Caco-2 Permeability:** Ligand A (-4.125) has worse Caco-2 permeability than Ligand B (-5.106). Lower values are worse.

**Aqueous Solubility:** Ligand A (-4.035) has worse aqueous solubility than Ligand B (-3.709). Lower values are worse.

**hERG:** Both ligands have low hERG inhibition liability (0.386 and 0.458), which is favorable.

**Microsomal Clearance:** Ligand A (115.16) has higher microsomal clearance than Ligand B (67.236), suggesting lower metabolic stability.

**In vitro Half-Life:** Ligand B (3.977) has a longer in vitro half-life than Ligand A (-10.291), which is desirable.

**P-gp Efflux:** Ligand A (0.205) has lower P-gp efflux than Ligand B (0.083), which is favorable for CNS penetration.

**Binding Affinity:** Both ligands have excellent binding affinity (-9.3 and -8.8 kcal/mol). Ligand A is slightly better (-9.3 vs -8.8), but the difference is less than the 1.5 kcal/mol threshold to outweigh other factors.

**Conclusion:**

Despite Ligand A having slightly better binding affinity and P-gp efflux, its significantly higher DILI risk, worse Caco-2 permeability, worse solubility, and higher microsomal clearance make it a less desirable candidate. Ligand B, with its much lower DILI risk and better metabolic stability (longer half-life), is the more promising drug candidate. The small difference in binding affinity is outweighed by the superior ADME properties of Ligand B.

Output:
1
2025-04-17 03:23:29,958 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (347.503 and 348.451 Da) fall comfortably within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (61.44) is significantly better than Ligand B (112.7). For CNS targets, we want TPSA <= 90, and Ligand A is well within this range, while Ligand B exceeds it. This is a major advantage for A.

**3. logP:** Both ligands have good logP values (2.087 and 1.387), falling within the optimal 1-3 range.

**4. H-Bond Donors:** Both have 2 HBD, which is acceptable.

**5. H-Bond Acceptors:** Ligand A has 3 HBA, and Ligand B has 6. While both are under the 10 threshold, lower is generally preferred, giving a slight edge to A.

**6. QED:** Both have similar QED values (0.693 and 0.7), indicating good drug-likeness.

**7. DILI:** Ligand A (8.53) has a much lower DILI risk than Ligand B (36.022). This is a significant advantage for A.

**8. BBB:** Ligand A (56.65) has a better BBB penetration percentile than Ligand B (42.032). While both are below the desirable >70 for CNS targets, A is closer.

**9. Caco-2 Permeability:** Both have negative Caco-2 values (-5.103 and -5.375), which is unusual and suggests poor permeability. This is a concern for both, but doesn't differentiate them.

**10. Aqueous Solubility:** Both have negative solubility values (-2.164 and -1.752), indicating poor solubility. This is a concern for both, but doesn't differentiate them.

**11. hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.472 and 0.106).

**12. Microsomal Clearance:** Ligand A (33.877) has higher microsomal clearance than Ligand B (27.216), indicating lower metabolic stability. This favors B.

**13. In vitro Half-Life:** Ligand B (15.446) has a significantly longer in vitro half-life than Ligand A (4.067). This is a substantial advantage for B.

**14. P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.04 and 0.012).

**15. Binding Affinity:** Ligand A (-9.4 kcal/mol) has a significantly stronger binding affinity than Ligand B (-7.5 kcal/mol). This is a crucial advantage for A, exceeding the 1.5 kcal/mol difference threshold.

**Overall Assessment:**

Considering the GPCR-specific priorities, Ligand A is the better candidate. The significantly stronger binding affinity (-9.4 vs -7.5 kcal/mol) is a major advantage that outweighs the slightly higher clearance. The lower TPSA and DILI risk, and better BBB penetration also contribute to its favorability. While both have poor solubility and permeability, the affinity difference is substantial enough to prioritize A.

Output:
1
2025-04-17 03:23:29,958 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (345.443 and 358.511 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (81.67) is better than Ligand B (58.12) as it is closer to the ideal <90 for CNS targets. Ligand B is excellent.

**logP:** Both ligands have good logP values (1.316 and 3.248), falling within the optimal 1-3 range. Ligand B is slightly higher, which could be beneficial for membrane permeability, but isn't a major concern.

**H-Bond Donors/Acceptors:** Ligand A has 3 HBD and 4 HBA, while Ligand B has 1 HBD and 5 HBA. Both are within acceptable limits (<=5 HBD and <=10 HBA).

**QED:** Both ligands have good QED scores (0.651 and 0.889), indicating good drug-like properties. Ligand B is better.

**DILI:** Ligand A (46.219) has a significantly lower DILI risk than Ligand B (71.384). This is a substantial advantage for Ligand A.

**BBB:** Ligand B (85.537) has a much higher BBB penetration percentile than Ligand A (54.75). This is a critical advantage for a CNS target like DRD2.

**Caco-2:** Ligand A (-4.922) and Ligand B (-5.23) are both negative, suggesting poor Caco-2 permeability. This is a concern for oral bioavailability, but less critical for a CNS target where direct delivery or other routes might be considered.

**Solubility:** Both ligands have poor aqueous solubility (-2.061 and -4.02). This could pose formulation challenges.

**hERG:** Both ligands have low hERG inhibition liability (0.5 and 0.834), which is good.

**Microsomal Clearance:** Ligand A (2.456) has a much lower microsomal clearance than Ligand B (110.634), indicating better metabolic stability. This is a significant advantage for Ligand A.

**In vitro Half-Life:** Ligand B (36.098) has a longer in vitro half-life than Ligand A (18.538), which is desirable.

**P-gp Efflux:** Ligand A (0.064) has significantly lower P-gp efflux liability than Ligand B (0.429). Lower P-gp efflux is crucial for CNS penetration.

**Binding Affinity:** Ligand A (-8.7 kcal/mol) has a significantly stronger binding affinity than Ligand B (-0.0 kcal/mol). This is a major advantage, potentially outweighing some of the ADME drawbacks.

**Overall Assessment:**

Ligand A excels in binding affinity, DILI risk, metabolic stability (low Cl_mic), and P-gp efflux. Ligand B shines in BBB penetration and has a longer half-life. However, the *massive* difference in binding affinity (-8.7 vs -0.0 kcal/mol) is the most important factor. A strong binding affinity can often compensate for less-than-ideal ADME properties, especially if alternative delivery strategies are considered. The lower DILI and P-gp efflux of Ligand A are also significant benefits. While Ligand B has better BBB penetration, the much stronger binding of Ligand A is likely to result in sufficient CNS exposure.

Output:
0
2025-04-17 03:23:29,958 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (354.397 and 340.383 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (53.76) is significantly better than Ligand B (87.32). For CNS targets, TPSA should be <=90, and A is comfortably within this range, while B is approaching the upper limit.

**3. logP:** Ligand A (2.707) is optimal (1-3), while Ligand B (0.933) is a bit low, potentially hindering permeation.

**4. H-Bond Donors:** Ligand A (0) is preferable to Ligand B (2). Fewer HBDs generally improve permeability.

**5. H-Bond Acceptors:** Ligand A (3) is better than Ligand B (4).

**6. QED:** Both ligands have similar QED values (0.757 and 0.626), indicating good drug-likeness.

**7. DILI:** Ligand A (17.72) has a much lower DILI risk than Ligand B (67.623), a significant advantage.

**8. BBB:** Ligand A (83.211) has a substantially better BBB penetration score than Ligand B (37.456). This is *critical* for a CNS target like DRD2.

**9. Caco-2:** Both have negative values, which is unusual. Assuming these are logP-scaled Caco-2 values, both are poor.

**10. Solubility:** Both have negative values, which is unusual.

**11. hERG:** Both ligands have low hERG inhibition risk (0.518 and 0.465).

**12. Cl_mic:** Ligand B (-12.279) has a *much* lower (better) microsomal clearance than Ligand A (15.261). This suggests greater metabolic stability for Ligand B.

**13. t1/2:** Ligand B (-15.475) has a longer in vitro half-life than Ligand A (16.167).

**14. Pgp:** Ligand A (0.072) has lower P-gp efflux liability than Ligand B (0.019), which is favorable for CNS exposure.

**15. Binding Affinity:** Ligand B (-8.6 kcal/mol) has a slightly better binding affinity than Ligand A (-7.5 kcal/mol). This is a 1.1 kcal/mol difference, which is significant, but needs to be weighed against other factors.

**Overall Assessment:**

While Ligand B has a slightly better binding affinity and improved metabolic stability (lower Cl_mic and longer t1/2), Ligand A is significantly superior in terms of CNS penetration (BBB), DILI risk, and TPSA. The lower logP of Ligand B is also a concern. Given that DRD2 is a CNS target, BBB penetration is paramount. The substantial difference in BBB scores, combined with the lower DILI risk and more favorable TPSA of Ligand A, outweigh the slightly better affinity of Ligand B.

Output:
1
2025-04-17 03:23:29,958 - INFO - Reasoning:

Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (349.435 and 339.443 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (98.14) is higher than the preferred <90 for CNS targets, while Ligand B (63.05) is well within the range. This is a significant advantage for Ligand B.

**3. logP:** Ligand A (0.477) is a bit low, potentially hindering membrane permeability. Ligand B (2.463) is nearly ideal.

**4. H-Bond Donors:** Ligand A (2) and Ligand B (1) are both acceptable.

**5. H-Bond Acceptors:** Ligand A (6) and Ligand B (5) are both acceptable.

**6. QED:** Both ligands have good QED scores (0.746 and 0.909), indicating drug-like properties.

**7. DILI:** Ligand A (39.201) is slightly higher than Ligand B (24.816), but both are below the concerning threshold of 60.

**8. BBB:** Ligand B (90.151) is excellent, exceeding the desirable >70 for CNS targets. Ligand A (55.176) is considerably lower and less favorable.

**9. Caco-2 Permeability:** Ligand A (-5.508) is very poor, indicating poor intestinal absorption. Ligand B (-4.933) is also poor, but slightly better.

**10. Aqueous Solubility:** Ligand A (-0.973) is poor, while Ligand B (-2.843) is even worse. Solubility is a concern for both, but less critical than BBB and TPSA for a CNS target.

**11. hERG Inhibition:** Ligand A (0.098) has a very low risk of hERG inhibition. Ligand B (0.47) is slightly higher, but still relatively low.

**12. Microsomal Clearance:** Ligand A (7.218) has lower clearance, suggesting better metabolic stability than Ligand B (32.139).

**13. In vitro Half-Life:** Ligand A (21.851) has a longer half-life than Ligand B (11.524).

**14. P-gp Efflux:** Ligand A (0.007) has very low P-gp efflux, which is excellent for CNS penetration. Ligand B (0.08) is slightly higher, but still favorable.

**15. Binding Affinity:** Ligand B (-7.9 kcal/mol) has a slightly better binding affinity than Ligand A (-8.3 kcal/mol). While both are excellent, the difference is small.

**Overall Assessment:**

Ligand B is the stronger candidate. Its superior BBB penetration (90.151 vs 55.176), lower TPSA (63.05 vs 98.14), and better logP (2.463 vs 0.477) are crucial advantages for a CNS-targeting GPCR ligand. While Ligand A has better metabolic stability (lower Cl_mic and longer t1/2) and slightly better affinity, these are outweighed by the pharmacokinetic advantages of Ligand B, especially its BBB penetration. The solubility issues of both are concerning, but can be addressed with formulation strategies.



Output:
1
2025-04-17 03:23:29,959 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B against the provided guidelines, prioritizing GPCR-specific properties (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (346.431 and 346.471 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (87.46) is excellent for CNS penetration, being well below 90. Ligand B (49.85) is even better.

**logP:** Ligand A (0.692) is a bit low, potentially hindering permeation. Ligand B (2.527) is within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A has 2 HBD and 5 HBA, which is acceptable. Ligand B has 0 HBD and 3 HBA, also acceptable.

**QED:** Both ligands have good QED scores (0.843 and 0.735, respectively), indicating drug-like properties.

**DILI:** Both ligands have low DILI risk (37.069 and 29.081 percentiles).

**BBB:** This is a critical parameter for a CNS target like DRD2. Ligand A has a BBB percentile of 27.879, which is quite low and concerning. Ligand B has a significantly higher BBB percentile of 83.172, making it much more likely to reach the brain.

**Caco-2 Permeability:** Ligand A (-4.972) has poor Caco-2 permeability. Ligand B (-4.416) is also poor, but slightly better than A.

**Aqueous Solubility:** Both ligands have poor aqueous solubility (-1.34 and -2.092). This could pose formulation challenges, but is less critical than BBB for a CNS target.

**hERG Inhibition:** Both ligands show low hERG inhibition risk (0.316 and 0.331).

**Microsomal Clearance:** Ligand A (-0.249) has very low, and therefore favorable, microsomal clearance. Ligand B (32.041) has a high microsomal clearance, indicating rapid metabolism.

**In vitro Half-Life:** Ligand A (2.641 hours) has a short half-life. Ligand B (6.955 hours) has a longer, more desirable half-life.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.025 and 0.112).

**Binding Affinity:** Ligand B (-9.2 kcal/mol) has a significantly stronger binding affinity than Ligand A (-7.5 kcal/mol). This >1.5 kcal/mol difference is substantial and can outweigh some ADME drawbacks.

**Conclusion:**

Despite Ligand A's favorable metabolic stability (low Cl_mic), its extremely poor BBB penetration is a major drawback for a CNS target. Ligand B, while having higher metabolic clearance, excels in BBB penetration, has a better logP, and a substantially stronger binding affinity. The superior affinity and BBB penetration of Ligand B outweigh its higher metabolic clearance.

Output:
1
2025-04-17 03:23:29,959 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (350.459 and 370.446 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (59.08) is significantly better than Ligand B (83.55).  For CNS targets, we want TPSA <= 90, and A is comfortably within that, while B is approaching the upper limit.

**logP:** Both ligands have similar logP values (1.291 and 1.312), falling within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A has 0 HBD and 4 HBA, while Ligand B has 1 HBD and 4 HBA. Both are within acceptable limits (<=5 HBD, <=10 HBA).

**QED:** Ligand B (0.748) has a better QED score than Ligand A (0.489), indicating a more drug-like profile.

**DILI:** Ligand A (14.851) has a much lower DILI risk than Ligand B (55.138), a significant advantage.

**BBB:** Ligand B (74.176) has a better BBB penetration percentile than Ligand A (66.344), though both are reasonably good for a CNS target.

**Caco-2 Permeability:** Ligand A (-4.482) has a worse Caco-2 permeability than Ligand B (-4.933), suggesting lower intestinal absorption.

**Aqueous Solubility:** Ligand A (-1.541) has better aqueous solubility than Ligand B (-2.739).

**hERG:** Both ligands have low hERG inhibition liability (0.404 and 0.335).

**Microsomal Clearance:** Ligand A (27.458) has higher microsomal clearance than Ligand B (-0.375), suggesting lower metabolic stability. This is a significant drawback for A.

**In vitro Half-Life:** Ligand B (19.741) has a longer in vitro half-life than Ligand A (9.716).

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.094 and 0.081).

**Binding Affinity:** Ligand B (-8.2 kcal/mol) has a significantly stronger binding affinity than Ligand A (-7.2 kcal/mol). This is a >1 kcal/mol difference, which is substantial.

**Overall Assessment:**

Ligand B is the stronger candidate. While Ligand A has advantages in TPSA, DILI, and solubility, Ligand B's superior binding affinity (-8.2 vs -7.2 kcal/mol) and better BBB penetration outweigh these benefits. The longer half-life and better QED of Ligand B are also positive factors. The slightly higher TPSA of B is not a major concern, and the DILI risk, while higher than A, is still within acceptable limits. The metabolic stability of B is also much better.

Output:
1
2025-04-17 03:23:29,959 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (356.463 and 352.431 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Both ligands have a TPSA of 104.73, which is above the optimal <90 for CNS targets, but not drastically so. This is a moderate concern for both.

**3. logP:** Ligand A (0.994) is slightly higher than Ligand B (0.668). Both are within the optimal 1-3 range, but Ligand B is closer to the lower bound, potentially impacting permeability.

**4. H-Bond Donors:** Both have 3 HBD, which is within the acceptable limit of <=5.

**5. H-Bond Acceptors:** Both have 5 HBA, also within the acceptable limit of <=10.

**6. QED:** Ligand A (0.563) has a better QED score than Ligand B (0.44), indicating a more drug-like profile.

**7. DILI:** Ligand A (19.155) has a significantly lower DILI risk than Ligand B (29.779). This is a substantial advantage for Ligand A.

**8. BBB:** Ligand A (50.679) has a much better BBB penetration percentile than Ligand B (17.022). This is *critical* for a CNS target like DRD2.

**9. Caco-2 Permeability:** Ligand A (-4.786) shows poorer Caco-2 permeability than Ligand B (-5.341), which is a slight negative for Ligand A.

**10. Aqueous Solubility:** Ligand A (-2.285) has slightly better aqueous solubility than Ligand B (-1.502).

**11. hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.14 and 0.047 respectively).

**12. Microsomal Clearance:** Ligand A (63.617) has higher microsomal clearance than Ligand B (-4.841), indicating lower metabolic stability. This is a negative for Ligand A.

**13. In vitro Half-Life:** Ligand B (1.864) has a slightly longer in vitro half-life than Ligand A (-38.056).

**14. P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.038 and 0.022 respectively).

**15. Binding Affinity:** Ligand B (-8.8 kcal/mol) has a significantly stronger binding affinity than Ligand A (-6.8 kcal/mol). This is a 2 kcal/mol difference, which is a substantial advantage.

**Overall Assessment:**

While Ligand B boasts a superior binding affinity, Ligand A is significantly better in terms of crucial ADME properties for a CNS-targeting GPCR. Specifically, the much higher BBB penetration (50.679 vs 17.022) and lower DILI risk (19.155 vs 29.779) of Ligand A are major advantages. The slightly worse metabolic stability and Caco-2 permeability of Ligand A are less concerning given the importance of CNS penetration for DRD2. The 2 kcal/mol difference in binding affinity can potentially be optimized in subsequent iterations of Ligand A, whereas improving BBB penetration is often much more challenging.

Output:
1
2025-04-17 03:23:29,959 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 drug candidates, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (348.487 and 370.837 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (58.64) is excellent, well below the 90 A^2 threshold for CNS targets. Ligand B (113.44) is higher, but still potentially acceptable, though less ideal.

**3. logP:** Ligand A (2.489) is optimal (1-3). Ligand B (0.46) is low, potentially hindering permeation.

**4. H-Bond Donors:** Ligand A (1) is good. Ligand B (3) is acceptable, but higher.

**5. H-Bond Acceptors:** Ligand A (3) is good. Ligand B (6) is higher, potentially impacting permeability.

**6. QED:** Both ligands (0.719 and 0.642) have good drug-likeness scores (>0.5).

**7. DILI:** Ligand A (13.416) has a very low DILI risk. Ligand B (50.136) is higher, indicating a moderate risk.

**8. BBB:** Ligand A (72.625) has a good BBB penetration percentile, desirable for a CNS target. Ligand B (46.064) is significantly lower, raising concerns about CNS exposure.

**9. Caco-2:** Both have negative values, which is unusual. Assuming these are logP-scale values, Ligand A (-4.831) is worse than Ligand B (-5.026), indicating poor intestinal absorption for both.

**10. Solubility:** Both have negative values, which is unusual. Assuming these are logS values, Ligand A (-2.442) is better than Ligand B (-2.103), indicating better solubility for Ligand A.

**11. hERG:** Both ligands have very low hERG risk (0.583 and 0.066).

**12. Cl_mic:** Ligand A (36.269) has a lower microsomal clearance, suggesting better metabolic stability than Ligand B (7.247).

**13. t1/2:** Ligand A (3.616) has a longer in vitro half-life than Ligand B (25.959).

**14. Pgp:** Ligand A (0.302) has lower P-gp efflux, which is favorable for CNS penetration. Ligand B (0.046) has even lower P-gp efflux, which is very favorable.

**15. Binding Affinity:** Ligand B (-7.8 kcal/mol) has a significantly stronger binding affinity than Ligand A (-8.5 kcal/mol). This is a substantial difference.

**Overall Assessment:**

Ligand B has a significantly better binding affinity, which is a major advantage. However, it suffers from a low logP, lower BBB penetration, and a higher DILI risk compared to Ligand A. Ligand A excels in TPSA, BBB, DILI, metabolic stability (Cl_mic and t1/2), and P-gp efflux.

Considering the GPCR-specific priorities, BBB penetration is crucial for CNS targets like DRD2. Ligand A's better BBB score, combined with its favorable ADME properties and acceptable affinity, makes it a more promising candidate despite the affinity difference. The affinity difference is 0.7 kcal/mol, which is not large enough to overcome the ADME liabilities of Ligand B.

Output:
0
2025-04-17 03:23:29,960 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (363.483 and 366.462 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (72.88) is slightly higher than Ligand B (66.4). Both are below the 90 A^2 threshold desirable for CNS targets, but Ligand B is preferable.

**3. logP:** Ligand A (0.648) is a bit low, potentially hindering permeability. Ligand B (1.17) is better, falling within the optimal 1-3 range.

**4. H-Bond Donors:** Ligand A (2) is acceptable, while Ligand B (0) is even better, potentially improving permeability.

**5. H-Bond Acceptors:** Both Ligand A (5) and Ligand B (5) are within the acceptable limit of 10.

**6. QED:** Both ligands have good QED scores (0.698 and 0.8), indicating drug-like properties.

**7. DILI:** Ligand A (22.451) has a significantly lower DILI risk than Ligand B (60.644), which is a substantial advantage.

**8. BBB:** Ligand B (81.466) has a much higher BBB penetration percentile than Ligand A (67.584). This is a critical factor for a CNS target like DRD2.

**9. Caco-2 Permeability:** Ligand A (-5.394) has worse Caco-2 permeability than Ligand B (-4.988), indicating lower intestinal absorption.

**10. Aqueous Solubility:** Both ligands have very poor aqueous solubility (-2.037 and -1.884). This is a concern for both, but not a deciding factor between the two.

**11. hERG Inhibition:** Both ligands show low hERG inhibition risk (0.276 and 0.261).

**12. Microsomal Clearance:** Ligand A (-5.151) has a *much* lower (better) microsomal clearance than Ligand B (17.637), suggesting greater metabolic stability.

**13. In vitro Half-Life:** Ligand A (8.509) has a better in vitro half-life than Ligand B (-14.979).

**14. P-gp Efflux:** Both ligands show very low P-gp efflux liability (0.019 and 0.043).

**15. Binding Affinity:** Ligand B (-8.1) has a slightly better binding affinity than Ligand A (-7.9), but the difference is relatively small (0.2 kcal/mol).

**Overall Assessment:**

Ligand B excels in BBB penetration and has slightly better binding affinity. However, Ligand A demonstrates a significantly lower DILI risk and much better metabolic stability (lower Cl_mic, longer t1/2). Given the importance of minimizing toxicity and ensuring sufficient drug exposure (through metabolic stability) for CNS drugs, and the relatively small difference in binding affinity, Ligand A is the more promising candidate. The lower logP of Ligand A is a concern, but the other advantages outweigh this drawback.

Output:
0
2025-04-17 03:23:29,960 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (344.459 and 349.563 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (86.88) is excellent, well below the 90 A^2 threshold for CNS targets. Ligand B (35.58) is also very good.

**3. logP:** Both ligands have good logP values (2.157 and 2.98), falling within the optimal 1-3 range.

**4. H-Bond Donors:** Ligand A has 3 HBD, acceptable. Ligand B has 1 HBD, also acceptable.

**5. H-Bond Acceptors:** Both ligands have 3 HBA, well within the acceptable limit of 10.

**6. QED:** Both ligands have good QED scores (0.663 and 0.829), indicating good drug-like properties.

**7. DILI:** Ligand A (35.556) has a slightly higher DILI risk than Ligand B (12.214), but both are below the concerning threshold of 60.

**8. BBB:** This is a critical parameter for a CNS target like DRD2. Ligand B (87.825) significantly outperforms Ligand A (60.682), exceeding the desirable >70 percentile.

**9. Caco-2 Permeability:** Both have negative values, which is unusual. However, the magnitude of the negative value for Ligand A (-5.303) is more negative than Ligand B (-4.731), suggesting potentially lower intestinal absorption for Ligand A.

**10. Aqueous Solubility:** Both ligands have negative solubility values (-2.305 and -2.863), which is also unusual and suggests poor aqueous solubility.

**11. hERG Inhibition:** Ligand A (0.135) has a lower hERG inhibition risk than Ligand B (0.895), which is preferable.

**12. Microsomal Clearance:** Ligand B (54.963) has a lower (better) microsomal clearance than Ligand A (34.289), suggesting greater metabolic stability.

**13. In vitro Half-Life:** Ligand B (11.547) has a significantly longer half-life than Ligand A (-9.948), which is a major advantage.

**14. P-gp Efflux:** Ligand A (0.094) has lower P-gp efflux liability than Ligand B (0.161), which is better for CNS exposure.

**15. Binding Affinity:** Both ligands have excellent binding affinities (-9.2 and -8.0 kcal/mol). Ligand A is slightly better (-9.2 kcal/mol), but the difference is less than 1.5 kcal/mol, so it doesn't outweigh other factors.

**Conclusion:**

While Ligand A has slightly better affinity and lower P-gp efflux, Ligand B is the superior candidate due to its significantly better BBB penetration (87.825 vs 60.682), longer half-life, and lower DILI risk. These factors are especially important for a CNS-targeting GPCR like DRD2. The slightly better affinity of Ligand A is not enough to overcome these advantages.

Output:
1
2025-04-17 03:23:29,960 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (341.451 and 352.439 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (47.56) is excellent, well below the 90 A^2 threshold for CNS targets. Ligand B (126.23) is higher, but still potentially acceptable, though less ideal.

**logP:** Ligand A (4.418) is slightly high, potentially leading to solubility issues and off-target effects, but not drastically so. Ligand B (0.24) is very low, which could hinder membrane permeability and target engagement.

**H-Bond Donors/Acceptors:** Ligand A (HBD=1, HBA=4) is good. Ligand B (HBD=3, HBA=6) is also reasonable.

**QED:** Both ligands have acceptable QED values (0.758 and 0.615, respectively), indicating good drug-like properties.

**DILI:** Both ligands have relatively low DILI risk (62.427 and 57.813), suggesting acceptable hepatic safety.

**BBB:** Both ligands have similar BBB penetration (60.993 and 62.854), which is decent but not outstanding. A value >70 would be preferred for a CNS target like DRD2.

**Caco-2 Permeability:** Ligand A (-4.594) and Ligand B (-5.657) both show poor Caco-2 permeability.

**Aqueous Solubility:** Ligand A (-6.524) and Ligand B (-2.163) both have poor aqueous solubility.

**hERG Inhibition:** Ligand A (0.823) has a slightly higher hERG risk than Ligand B (0.068), but both are relatively low.

**Microsomal Clearance:** Ligand A (134.278) has higher clearance than Ligand B (-0.064), indicating lower metabolic stability.

**In vitro Half-Life:** Ligand A (-5.168) has a shorter half-life than Ligand B (3.518).

**P-gp Efflux:** Ligand A (0.702) has moderate P-gp efflux, while Ligand B (0.022) has very low P-gp efflux, which is highly desirable for CNS penetration.

**Binding Affinity:** Ligand A (-8.9 kcal/mol) has significantly stronger binding affinity than Ligand B (-7.5 kcal/mol). This is a substantial difference (>1.5 kcal/mol) and a major advantage.

**Overall Assessment:**

Ligand A's primary advantage is its significantly higher binding affinity. However, it suffers from a higher logP, higher clearance, and moderate P-gp efflux. Ligand B has better P-gp efflux and lower clearance, but its logP is very low and its binding affinity is considerably weaker.

Given the importance of binding affinity for GPCRs, and the fact that the difference in affinity is substantial, I would prioritize Ligand A despite its drawbacks. The higher logP could potentially be mitigated through structural modifications, and the metabolic stability could be improved. The lower P-gp efflux is less concerning given the strong binding. Ligand B's low logP is a more fundamental issue that would be difficult to address without significantly altering the molecule's structure and potentially losing affinity.

Output:
1
2025-04-17 03:23:29,960 - INFO - Batch 25 complete. Total preferences: 400
2025-04-17 03:23:29,960 - INFO - Processing batch 26/512...
2025-04-17 03:24:10,994 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (343.329 and 355.395 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (53.68) is significantly better than Ligand B (129.82). For CNS targets, TPSA should be <= 90, and A is comfortably within this range, while B is considerably above.

**logP:** Ligand A (2.984) is optimal (1-3), while Ligand B (-0.434) is below 1, potentially hindering permeation.

**H-Bond Donors/Acceptors:** Ligand A (HBD=1, HBA=3) is preferable to Ligand B (HBD=3, HBA=7) as it has fewer H-bonds, which generally improves permeability. Both are within acceptable limits.

**QED:** Both ligands have reasonable QED values (0.795 and 0.605), indicating good drug-like properties.

**DILI:** Both ligands have similar, acceptable DILI risk (53.819 and 53.044).

**BBB:** Ligand A (77.2) is significantly better than Ligand B (61.225). A BBB percentile >70 is desirable for CNS targets, and A is closer to this threshold.

**Caco-2 Permeability:** Ligand A (-4.539) is much better than Ligand B (-5.238), indicating better intestinal absorption.

**Aqueous Solubility:** Ligand A (-3.483) is better than Ligand B (-1.204), suggesting better formulation potential.

**hERG Inhibition:** Ligand A (0.85) is much better than Ligand B (0.067), indicating a lower risk of cardiotoxicity.

**Microsomal Clearance:** Ligand A (37.698) is higher than Ligand B (1.199), suggesting lower metabolic stability.

**In vitro Half-Life:** Ligand A (38.36) is much better than Ligand B (6.739), suggesting a longer half-life.

**P-gp Efflux:** Ligand A (0.649) is better than Ligand B (0.014), indicating lower efflux and improved CNS exposure.

**Binding Affinity:** Ligand B (-0.0 kcal/mol) has a much better binding affinity than Ligand A (-10.4 kcal/mol). This is a substantial difference.

**Overall Assessment:**

While Ligand B has a significantly better binding affinity, Ligand A excels in almost all other critical ADME properties, especially those prioritized for GPCRs targeting the CNS (BBB, TPSA, logP, Pgp). Ligand B's poor logP, high TPSA, and low BBB penetration are major drawbacks. The substantial affinity difference (-10.4 vs 0.0) is significant, but the ADME profile of A is far superior, suggesting it's more likely to reach the target in vivo. The improved ADME properties of Ligand A could potentially compensate for the difference in binding affinity, especially with further optimization.

Output:
0
2025-04-17 03:24:10,994 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (378.529 and 370.559 Da) are within the ideal range of 200-500 Da.

**TPSA:** Ligand A (49.41) is significantly better than Ligand B (69.64). For CNS targets, we want TPSA <= 90, and ideally closer to 60. Ligand A is much closer to the ideal range.

**logP:** Ligand A (3.554) is slightly higher than Ligand B (2.568), both fall within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A (HBD=1, HBA=3) is preferable to Ligand B (HBD=2, HBA=4) as lower values generally improve permeability.

**QED:** Both ligands have similar QED values (0.719 and 0.644), indicating good drug-like properties.

**DILI:** Ligand A (23.653) has a lower DILI risk than Ligand B (33.307), which is favorable. Both are below the 40 threshold.

**BBB:** Ligand A (90.306) has a significantly higher BBB penetration percentile than Ligand B (71.074). This is a *critical* advantage for a CNS target like DRD2.

**Caco-2 Permeability:** Ligand A (-4.825) is better than Ligand B (-5.135), indicating slightly better intestinal absorption.

**Aqueous Solubility:** Both ligands have very poor aqueous solubility (-3.8 and -3.027). This is a concern, but can potentially be addressed with formulation strategies.

**hERG Inhibition:** Ligand A (0.883) shows slightly lower hERG inhibition liability than Ligand B (0.588), which is preferable.

**Microsomal Clearance:** Both ligands have similar microsomal clearance (50.899 and 50.796), suggesting comparable metabolic stability.

**In vitro Half-Life:** Ligand A (-12.977) has a shorter half-life than Ligand B (-2.871). This is a disadvantage for Ligand A.

**P-gp Efflux:** Ligand A (0.204) has lower P-gp efflux liability than Ligand B (0.397), which is favorable for CNS penetration.

**Binding Affinity:** Ligand A (-7.8 kcal/mol) has a slightly better binding affinity than Ligand B (-7.5 kcal/mol). While the difference is not huge, it's enough to potentially outweigh some of the other minor drawbacks.

**Overall Assessment:**

Ligand A is the stronger candidate. Its superior BBB penetration, lower TPSA, lower DILI risk, lower P-gp efflux, and slightly better binding affinity outweigh its slightly shorter half-life and poorer solubility. The CNS target (DRD2) makes BBB penetration a paramount concern, and Ligand A excels in this area.

Output:
1
2025-04-17 03:24:10,995 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 drug candidates, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (342.443 and 344.455 Da) fall comfortably within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (68.6) and Ligand B (67.43) are both below the 90 A^2 threshold desirable for CNS targets, which is excellent.

**3. logP:** Ligand A (2.207) and Ligand B (2.741) are both within the optimal 1-3 range.

**4. H-Bond Donors:** Ligand A (1) and Ligand B (2) are both acceptable, being less than 5.

**5. H-Bond Acceptors:** Ligand A (4) and Ligand B (3) are both acceptable, being less than 10.

**6. QED:** Ligand A (0.911) has a significantly higher QED than Ligand B (0.677), indicating a more drug-like profile.

**7. DILI:** Ligand A (41.877) has a slightly higher DILI risk than Ligand B (32.028), but both are below the concerning threshold of 60.

**8. BBB:** Ligand A (84.064) has a considerably better BBB penetration percentile than Ligand B (69.407). This is a crucial factor for a CNS target like DRD2.

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 values, which is unusual and suggests poor permeability. However, these values are on a different scale and hard to interpret without further context.

**10. Aqueous Solubility:** Both ligands have negative solubility values, again suggesting poor solubility.

**11. hERG Inhibition:** Ligand A (0.845) has a slightly higher hERG inhibition risk than Ligand B (0.149), but both are relatively low.

**12. Microsomal Clearance:** Ligand B (68.733) has a much higher microsomal clearance than Ligand A (26.086), indicating faster metabolism and potentially lower *in vivo* exposure.

**13. In vitro Half-Life:** Ligand B (-1.597) has a negative half-life, which is not possible, suggesting a data error or an extremely short half-life. Ligand A (38.756) has a good half-life.

**14. P-gp Efflux:** Ligand A (0.152) has a slightly higher P-gp efflux liability than Ligand B (0.11), but both are low.

**15. Binding Affinity:** Ligand B (-7.7 kcal/mol) has a significantly stronger binding affinity than Ligand A (-0.0 kcal/mol). This is a substantial advantage.

**Overall Assessment:**

While Ligand B boasts a much better binding affinity, several factors favor Ligand A. Ligand A has a superior QED, significantly better BBB penetration, a more reasonable half-life, and lower microsomal clearance. The negative values for Caco-2 and solubility are concerning for both, but the large difference in affinity is a major point. However, the extremely poor half-life of Ligand B and the questionable negative value raise serious concerns. The superior ADME properties of Ligand A, particularly the BBB penetration and metabolic stability, make it a more promising starting point for optimization, even with the weaker initial binding affinity. The binding affinity can be improved through medicinal chemistry efforts, while fixing poor ADME properties is often more challenging.

Output:
1
2025-04-17 03:24:10,995 - INFO - Okay, let's analyze these two ligands for their potential as DRD2 drug candidates. DRD2 is a GPCR in the CNS, so BBB penetration, logP, Pgp efflux, TPSA, and binding affinity are key.

**Ligand A:** [342.447, 74.25, 2.753, 1, 5, 0.904, 55.68, 90.655, -4.543, -2.799, 0.677, 38, 62.84, 0.115, -8]
**Ligand B:** [367.471, 84.67, 1.472, 1, 6, 0.871, 67.429, 58.123, -4.967, -3.069, 0.176, 69.68, -10.987, 0.098, 0]

**1. Molecular Weight:** Both are within the ideal range (200-500 Da). A (342.447) is slightly preferred.

**2. TPSA:** A (74.25) is excellent for CNS penetration (well below 90). B (84.67) is still reasonable, but less optimal.

**3. logP:** A (2.753) is optimal. B (1.472) is a bit low, potentially hindering membrane permeability.

**4. H-Bond Donors:** Both have 1 HBD, which is good.

**5. H-Bond Acceptors:** A has 5, B has 6. Both are acceptable (<=10).

**6. QED:** Both are high (A: 0.904, B: 0.871), indicating good drug-like properties.

**7. DILI:** A (55.68) is better than B (67.429). Lower DILI risk is always preferred.

**8. BBB:** A (90.655) is *excellent* and highly desirable for a CNS target. B (58.123) is significantly lower and a major drawback.

**9. Caco-2:** Both are negative, indicating poor permeability. This is concerning, but can be mitigated if other properties are strong.

**10. Solubility:** Both are negative, indicating poor solubility. This is also concerning.

**11. hERG:** A (0.677) is better than B (0.176). Lower hERG risk is crucial.

**12. Cl_mic:** A (38) is much better than B (69.68). Lower clearance means greater metabolic stability.

**13. t1/2:** A (62.84) is better than B (-10.987). A longer half-life is generally preferred.

**14. Pgp:** A (0.115) is much better than B (0.098). Lower Pgp efflux is crucial for CNS exposure.

**15. Binding Affinity:** A (-8) is significantly better than B (0). A difference of 8 kcal/mol is substantial and can often outweigh minor ADME issues.

**Overall Assessment:**

Ligand A is clearly superior. It has a better binding affinity, significantly better BBB penetration, lower DILI risk, better metabolic stability (lower Cl_mic), longer half-life, and lower Pgp efflux. While both have issues with Caco-2 and solubility, the strong binding affinity and CNS penetration of A make it a much more promising starting point for drug development targeting DRD2. The slight advantage in logP for A also contributes to its better profile.

Output:
1
2025-04-17 03:24:10,995 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (358.404 Da) is slightly better, being closer to the lower end, which can aid permeability.

**TPSA:** Both ligands have TPSA values (62.22 and 66.4) below the 90 A^2 threshold for CNS targets, which is good. Ligand A is slightly better.

**logP:** Both ligands have logP values within the optimal range (1-3). Ligand A (3.481) is a little higher, potentially leading to some off-target effects, but still acceptable. Ligand B (2.686) is more optimal.

**H-Bond Donors/Acceptors:** Ligand A (2 HBD, 3 HBA) is better than Ligand B (0 HBD, 6 HBA). The lower number of H-bonds in Ligand A is generally favorable for BBB penetration.

**QED:** Both ligands have acceptable QED values (0.847 and 0.675), indicating good drug-like properties. Ligand A is slightly better.

**DILI:** Ligand A (22.024) has a significantly lower DILI risk than Ligand B (56.146). This is a major advantage for Ligand A.

**BBB:** Ligand A (84.413) has a much higher BBB penetration percentile than Ligand B (64.017). This is crucial for a CNS target like DRD2.

**Caco-2 Permeability:** Both have negative values, which is unusual. However, the magnitude is similar, so this doesn't strongly favor either.

**Aqueous Solubility:** Both have negative values, which is also unusual. Again, the magnitudes are similar.

**hERG:** Both ligands have low hERG inhibition liability (0.521 and 0.197), which is good. Ligand B is slightly better.

**Microsomal Clearance:** Ligand A (18.096) has a lower microsomal clearance than Ligand B (62.124), indicating better metabolic stability.

**In vitro Half-Life:** Ligand A (-0.376) has a negative half-life, which is unusual. Ligand B (21.513) has a much longer half-life.

**P-gp Efflux:** Ligand A (0.307) has lower P-gp efflux liability than Ligand B (0.218), which is favorable for CNS exposure.

**Binding Affinity:** Ligand B (-7.3 kcal/mol) has a slightly better binding affinity than Ligand A (-8.5 kcal/mol). However, the difference is relatively small, and Ligand A already has excellent affinity.

**Overall Assessment:**

Ligand A is the stronger candidate. While Ligand B has slightly better affinity and hERG inhibition, Ligand A excels in crucial areas for a CNS GPCR target: significantly lower DILI risk, much higher BBB penetration, lower P-gp efflux, and better metabolic stability. The slightly higher logP of Ligand A is a minor concern compared to the substantial advantages in ADME properties. The unusual negative half-life for Ligand A is a red flag that would require further investigation, but the other benefits outweigh this concern at this stage.

Output:
1
2025-04-17 03:24:10,995 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (356.535 and 356.419 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (25.24) is excellent, well below the 90 A^2 threshold for CNS targets. Ligand B (96.38) is higher, but still potentially acceptable, though less ideal.

**3. logP:** Ligand A (4.867) is slightly high, potentially leading to solubility issues or off-target interactions. Ligand B (-0.069) is quite low, which could hinder membrane permeability and CNS penetration.

**4. H-Bond Donors:** Ligand A (0) is good. Ligand B (1) is also acceptable.

**5. H-Bond Acceptors:** Ligand A (3) is good. Ligand B (6) is higher, but still within the acceptable range of <=10.

**6. QED:** Both ligands have similar QED values (0.77 and 0.693), indicating good drug-like properties.

**7. DILI:** Ligand A (41.954) has a slightly higher DILI risk than Ligand B (20.822), but both are below the concerning threshold of 60.

**8. BBB:** Ligand A (92.051) has a significantly better BBB penetration score than Ligand B (66.809). This is a crucial factor for a CNS target like DRD2.

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.899 and -4.626), which is unusual and difficult to interpret without further context. However, it suggests poor permeability.

**10. Aqueous Solubility:** Both ligands have negative solubility values (-4.756 and -0.51), indicating very poor aqueous solubility. This is a significant concern.

**11. hERG Inhibition:** Ligand A (0.778) shows a slightly higher hERG inhibition risk than Ligand B (0.065).

**12. Microsomal Clearance:** Ligand A (75.59) has a higher microsomal clearance than Ligand B (24.004), suggesting lower metabolic stability.

**13. In vitro Half-Life:** Ligand B (-10.427) has a negative half-life, which is not physically possible and indicates a problem with the data or the compound's stability. Ligand A (26.204) has a reasonable half-life.

**14. P-gp Efflux:** Ligand A (0.883) has a higher P-gp efflux liability than Ligand B (0.019). Lower P-gp efflux is preferred for CNS penetration.

**15. Binding Affinity:** Ligand B (-7.1) has a significantly stronger binding affinity than Ligand A (-0). This is a major advantage.

**Overall Assessment:**

Despite Ligand B's superior binding affinity, its extremely low logP, negative half-life, and lower BBB penetration are major drawbacks. The negative half-life is a critical issue. Ligand A, while having a slightly higher logP and lower affinity, possesses a much better BBB score, more reasonable ADME properties (even with the higher clearance), and a plausible half-life. The solubility issues are a concern for both, but might be addressable with formulation strategies. Given the GPCR-specific priorities, especially BBB penetration for a CNS target, and the critical issue with Ligand B's half-life, Ligand A is the more promising candidate.

Output:
0
2025-04-17 03:24:10,996 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (356.897 and 364.555 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (32.34) is significantly better than Ligand B (58.2). For CNS targets, we want TPSA <= 90, and A is comfortably within this range, while B is approaching the upper limit.

**logP:** Ligand A (4.564) is slightly higher than the optimal 1-3 range, but still potentially acceptable. Ligand B (3.254) is within the optimal range. However, for a GPCR, a slightly higher logP isn't necessarily detrimental if other properties are favorable.

**H-Bond Donors/Acceptors:** Ligand A (HBD=1, HBA=1) is better than Ligand B (HBD=2, HBA=3) in terms of minimizing potential issues with permeability.

**QED:** Both ligands have similar QED values (0.808 and 0.761), indicating good drug-likeness.

**DILI:** Ligand A (35.556) has a slightly higher DILI risk than Ligand B (25.281), but both are below the concerning threshold of 60.

**BBB:** This is a critical parameter for a CNS target like DRD2. Ligand A (86.545) has a significantly better BBB penetration percentile than Ligand B (60.411). A value >70 is desirable, and A is closer to that mark.

**Caco-2 Permeability:** Ligand A (-4.477) and Ligand B (-5.463) both have negative values which is unusual and difficult to interpret without knowing the scale. However, lower values suggest lower permeability.

**Aqueous Solubility:** Ligand A (-5.243) and Ligand B (-3.588) both have negative values which is unusual and difficult to interpret without knowing the scale. However, lower values suggest lower solubility.

**hERG:** Ligand A (0.839) has a slightly higher hERG risk than Ligand B (0.344), but both are reasonably low.

**Microsomal Clearance:** Ligand A (82.727) has a higher microsomal clearance than Ligand B (43.492), indicating faster metabolism and potentially lower *in vivo* exposure.

**In vitro Half-Life:** Ligand A (54.282) has a longer half-life than Ligand B (0.479), which is a positive attribute.

**P-gp Efflux:** Ligand A (0.387) has lower P-gp efflux liability than Ligand B (0.168), which is favorable for CNS penetration.

**Binding Affinity:** Ligand A (-10.3 kcal/mol) has a significantly stronger binding affinity than Ligand B (-9.1 kcal/mol). This is a substantial difference (1.2 kcal/mol), and can often outweigh minor ADME deficiencies.

**Overall Assessment:**

Ligand A is the stronger candidate. While its logP is slightly elevated and its DILI risk is a bit higher, its superior BBB penetration, significantly better binding affinity, lower P-gp efflux, and longer half-life outweigh these drawbacks. The lower TPSA is also a significant advantage for CNS penetration. Ligand B, while having a more optimal logP, suffers from poorer BBB penetration, weaker binding affinity, and higher P-gp efflux, making it less likely to achieve sufficient CNS exposure and efficacy.

Output:
0
2025-04-17 03:24:10,996 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (356.463 and 358.36 Da) fall comfortably within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (76.15) is higher than Ligand B (61.8). For a CNS target like DRD2, we ideally want TPSA <= 90, so both are acceptable, but B is better.

**3. logP:** Both ligands have good logP values (1.452 and 1.699, respectively), falling within the optimal 1-3 range.

**4. H-Bond Donors:** Ligand A has 0 HBD, while Ligand B has 2. Both are within the acceptable limit of <=5.

**5. H-Bond Acceptors:** Ligand A has 5 HBA, and Ligand B has 4. Both are within the acceptable limit of <=10.

**6. QED:** Ligand B (0.813) has a significantly better QED score than Ligand A (0.51), indicating a more drug-like profile.

**7. DILI:** Ligand B (21.714) has a much lower DILI risk than Ligand A (32.067), which is a significant advantage.

**8. BBB:** Ligand B (81.698) has a substantially higher BBB penetration percentile than Ligand A (67.584). This is *critical* for a CNS target like DRD2.

**9. Caco-2 Permeability:** Both have negative values, indicating poor permeability. However, the scale is not defined, so it's hard to interpret.

**10. Aqueous Solubility:** Ligand A (-0.918) has slightly better solubility than Ligand B (-2.701), but both are quite poor.

**11. hERG Inhibition:** Both ligands have low hERG inhibition risk (0.525 and 0.597, respectively).

**12. Microsomal Clearance:** Ligand B (13.441) has a much lower microsomal clearance than Ligand A (57.81), suggesting better metabolic stability.

**13. In vitro Half-Life:** Ligand B (2.315) has a slightly longer half-life than Ligand A (-5.463).

**14. P-gp Efflux:** Both have very low P-gp efflux liability (0.094 and 0.092, respectively).

**15. Binding Affinity:** Ligand B (-7.3 kcal/mol) has a significantly stronger binding affinity than Ligand A (-0.0 kcal/mol). This is a major advantage, exceeding the 1.5 kcal/mol difference threshold.

**Overall Assessment:**

Ligand B is clearly the superior candidate. It excels in the most important parameters for a CNS-targeting GPCR ligand: BBB penetration, binding affinity, DILI risk, and metabolic stability. While Ligand A has slightly better solubility, the other advantages of Ligand B far outweigh this minor difference. The significantly stronger binding affinity of Ligand B is particularly compelling.

Output:
1
2025-04-17 03:24:10,996 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (368.411 and 347.503 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (113.01) is slightly above the optimal <90 for CNS targets, but still reasonable. Ligand B (63.13) is excellent, well below 90.

**logP:** Ligand A (-0.412) is a bit low, potentially hindering permeability. Ligand B (3.175) is within the optimal 1-3 range. This is a significant advantage for Ligand B.

**H-Bond Donors/Acceptors:** Both have 2 HBD and are within the acceptable limits. Ligand A has 6 HBA, while Ligand B has 3. Both are acceptable, but Ligand B is slightly better.

**QED:** Both ligands have similar QED values (0.699 and 0.674), indicating good drug-likeness.

**DILI:** Ligand A (61.225) has a higher DILI risk than Ligand B (25.204). This favors Ligand B.

**BBB:** Both ligands have excellent BBB penetration (70.764 and 70.919), exceeding the desirable >70 threshold for CNS targets.

**Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and suggests poor permeability. However, the scale is not specified, so it's hard to interpret.

**Aqueous Solubility:** Both have negative solubility values, which is also unusual. Again, scale is not specified.

**hERG:** Ligand A (0.2) has a very low hERG risk, which is excellent. Ligand B (0.696) is slightly higher, but still relatively low.

**Microsomal Clearance:** Ligand A (31.356) has lower clearance than Ligand B (48.947), indicating better metabolic stability.

**In vitro Half-Life:** Ligand A (-20.117) has a negative half-life, which is not possible. Ligand B (13.759) is reasonable. This is a major red flag for Ligand A.

**P-gp Efflux:** Ligand A (0.034) has very low P-gp efflux, which is excellent for CNS penetration. Ligand B (0.394) is higher, but still acceptable.

**Binding Affinity:** Ligand B (-7.7 kcal/mol) has a slightly better binding affinity than Ligand A (-8.2 kcal/mol). While the difference is small, it is still a factor.

**Overall Assessment:**

Ligand B is significantly better. It has a more favorable logP, lower DILI risk, a realistic half-life, and a slightly better binding affinity. While Ligand A has excellent P-gp efflux and hERG inhibition, its negative half-life and low logP are major drawbacks. The TPSA of Ligand B is also more favorable for CNS penetration.

Output:
1
2025-04-17 03:24:10,997 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (342.407 and 352.45 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (116.02) is higher than Ligand B (67.43). For CNS targets, TPSA should be <= 90. Ligand B is significantly better here.

**logP:** Both ligands (2.079 and 1.808) are within the optimal 1-3 range.

**H-Bond Donors:** Both have 2 HBD, which is acceptable (<=5).

**H-Bond Acceptors:** Ligand A has 8 HBA, while Ligand B has 3. Both are within the acceptable range of <=10, but Ligand B is preferable.

**QED:** Both ligands have good QED scores (0.708 and 0.734), indicating good drug-like properties.

**DILI:** Ligand A (85.692) has a considerably higher DILI risk than Ligand B (22.722). This is a significant drawback for Ligand A.

**BBB:** Ligand B (77.084) has a much better BBB penetration percentile than Ligand A (51.493). This is critical for a CNS target like DRD2.

**Caco-2 Permeability:** Ligand A (-5.241) has worse Caco-2 permeability than Ligand B (-4.999).

**Aqueous Solubility:** Ligand A (-3.265) has worse aqueous solubility than Ligand B (-2.314).

**hERG:** Both ligands have low hERG inhibition risk (0.506 and 0.484).

**Microsomal Clearance:** Ligand A (42.021) has higher microsomal clearance than Ligand B (5.689), indicating lower metabolic stability.

**In vitro Half-Life:** Ligand A (23.692) has a longer in vitro half-life than Ligand B (12.542), which is a positive.

**P-gp Efflux:** Ligand A (0.148) has slightly lower P-gp efflux liability than Ligand B (0.114), which is favorable.

**Binding Affinity:** Ligand B (-8.9 kcal/mol) has a slightly better binding affinity than Ligand A (-8.1 kcal/mol). While the difference is not huge, it is still a benefit.

**Overall Assessment:**

Ligand B is significantly better overall. It has a much lower DILI risk, superior BBB penetration, better TPSA, and better Caco-2 permeability and solubility. While Ligand A has a slightly longer half-life and lower P-gp efflux, these advantages are outweighed by the significant drawbacks of higher DILI risk and poor BBB penetration. The slightly better affinity of Ligand B further solidifies its position as the more promising candidate.

Output:
1
2025-04-17 03:24:10,997 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (352.475 and 345.399 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (67.87) is excellent, well below the 90 A^2 threshold for CNS targets. Ligand B (91.64) is slightly higher, but still potentially acceptable.

**logP:** Ligand A (1.58) is within the optimal 1-3 range. Ligand B (-0.02) is slightly below 1, which *could* indicate permeability issues, but is not a hard disqualifier.

**H-Bond Donors/Acceptors:** Ligand A (HBD=1, HBA=4) and Ligand B (HBD=2, HBA=5) both have reasonable numbers of H-bond donors and acceptors, well within the guidelines.

**QED:** Ligand A (0.788) has a strong drug-like profile. Ligand B (0.56) is acceptable, but less ideal.

**DILI:** Ligand A (9.228) has a very low DILI risk. Ligand B (35.944) is also relatively low risk.

**BBB:** This is critical for a CNS target. Ligand A (78.48) has a good BBB percentile. Ligand B (30.593) is significantly lower, indicating poor brain penetration. This is a major drawback.

**Caco-2 Permeability:** Ligand A (-4.565) and Ligand B (-5.177) both have negative Caco-2 values, which is unusual and indicates poor permeability. This is concerning, but could be due to experimental error or a specific property of the molecule.

**Aqueous Solubility:** Ligand A (-2.177) and Ligand B (-0.894) both have negative solubility values, indicating poor aqueous solubility. This could present formulation challenges.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.393 and 0.157).

**Microsomal Clearance:** Ligand A (31.603) has a moderate clearance, while Ligand B (20.539) has a lower clearance, suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (0.765) has a very short half-life. Ligand B (-6.954) has a negative half-life, which is not possible and suggests an issue with the data.

**P-gp Efflux:** Both ligands show low P-gp efflux liability (0.036 and 0.063).

**Binding Affinity:** Ligand B (-8.4 kcal/mol) has a significantly stronger binding affinity than Ligand A (-7.4 kcal/mol). This is a substantial advantage (1.0 kcal/mol difference).

**Overall Assessment:**

While Ligand B has a superior binding affinity, its poor BBB penetration (30.593) is a critical flaw for a CNS target like DRD2. The negative half-life is also a major red flag. Ligand A, despite a slightly weaker affinity, has a much better BBB score (78.48) and a more reasonable half-life. The poor Caco-2 and solubility for both are concerning, but could potentially be addressed with formulation strategies. Given the GPCR-specific priorities, the ability to cross the blood-brain barrier is paramount.

Output:
0
2025-04-17 03:24:10,997 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (370.475 and 342.443 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (104.65) is higher than the preferred <90 for CNS targets, while Ligand B (76.44) is well within the range. This is a significant advantage for Ligand B.

**logP:** Ligand A (0.223) is quite low, potentially hindering membrane permeability. Ligand B (1.539) is within the optimal 1-3 range. This favors Ligand B.

**H-Bond Donors/Acceptors:** Ligand A has 2 HBD and 7 HBA, which are acceptable. Ligand B has 1 HBD and 4 HBA, also acceptable.

**QED:** Both ligands have good QED scores (0.644 and 0.904), indicating good drug-likeness.

**DILI:** Ligand A (32.338) has a lower DILI risk than Ligand B (41.179), which is a positive.

**BBB:** Ligand A (29.973) has a very low BBB penetration percentile, making it unlikely to reach the target in the CNS effectively. Ligand B (43.815) is better, but still not ideal (we want >70).

**Caco-2 Permeability:** Both have negative Caco-2 values (-5.394 and -4.932), which is unusual and suggests poor permeability. However, these values are on a scale where negative values are possible and don't necessarily disqualify a compound.

**Aqueous Solubility:** Both have negative solubility values (-0.813 and -1.455), indicating poor solubility. This could be a formulation challenge.

**hERG Inhibition:** Ligand A (0.088) has a very low hERG risk, which is excellent. Ligand B (0.564) is slightly higher, but still relatively low.

**Microsomal Clearance:** Ligand A (-15.803) has a very low (and negative) microsomal clearance, suggesting high metabolic stability. Ligand B (-4.566) is also low, indicating good metabolic stability.

**In vitro Half-Life:** Both ligands have similar in vitro half-lives (31.3 and 29.583 hours), which are good.

**P-gp Efflux:** Ligand A (0.025) has very low P-gp efflux, which is favorable for CNS penetration. Ligand B (0.049) is also low.

**Binding Affinity:** Ligand A (-7.2 kcal/mol) has a significantly stronger binding affinity than Ligand B (-0.0 kcal/mol). This is a substantial advantage for Ligand A.

**Overall Assessment:**

Despite Ligand A's superior binding affinity, its extremely poor BBB penetration (29.973) is a major drawback for a CNS target like DRD2. The low logP also contributes to permeability concerns. Ligand B, while having weaker affinity, has a much better TPSA, logP, and a somewhat better BBB score. The slightly higher DILI risk for Ligand B is less concerning than the poor CNS penetration of Ligand A. Given the GPCR-specific priorities, particularly BBB and logP, Ligand B is the more promising candidate, even with the weaker binding affinity. The affinity difference could potentially be addressed through further optimization, but improving BBB penetration is often more challenging.

Output:
1
2025-04-17 03:24:10,997 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (341.411 and 355.389 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (83.36) is significantly better than Ligand B (110). For CNS targets, we want TPSA <= 90, so Ligand A is preferable.

**logP:** Both ligands have good logP values (1.321 and 1.426), falling within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Both have 3 HBDs, which is acceptable. Ligand B has 5 HBAs, while Ligand A has 4. Both are within the acceptable limit of <=10.

**QED:** Both ligands have similar QED values (0.767 and 0.715), indicating good drug-likeness.

**DILI:** Ligand A (38.154) has a lower DILI risk than Ligand B (54.44), which is favorable.

**BBB:** Ligand B (79.294) has a significantly better BBB penetration percentile than Ligand A (65.374). This is a *critical* factor for a CNS target like DRD2.

**Caco-2 Permeability:** Ligand A (-4.823) is better than Ligand B (-5.313), indicating better intestinal absorption. However, this is less critical for a CNS target where BBB penetration is paramount.

**Aqueous Solubility:** Both ligands have very poor aqueous solubility (-2.353 and -2.682). This could pose formulation challenges, but is not a deciding factor here.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.198 and 0.279).

**Microsomal Clearance:** Ligand A (-16.514) has *much* lower microsomal clearance than Ligand B (3.902), indicating better metabolic stability.

**In vitro Half-Life:** Ligand A (16.922 hours) has a longer half-life than Ligand B (-10.965 hours).

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.07 and 0.011).

**Binding Affinity:** Both ligands have excellent binding affinities (-9.4 and -8.3 kcal/mol). Ligand A is slightly better (-9.4 kcal/mol). The difference is >1.5 kcal/mol, which can outweigh other drawbacks.

**Overall Assessment:**

Ligand A excels in TPSA, DILI, metabolic stability (Cl_mic), and half-life, and has slightly better affinity. Ligand B's main advantage is its superior BBB penetration. However, the 1.1 kcal/mol affinity difference of Ligand A, combined with its better metabolic profile and lower DILI risk, are significant advantages. While BBB is crucial, a slightly lower BBB percentile can be compensated for with better overall ADME properties and potency.

Output:
0
2025-04-17 03:24:10,998 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (344.459 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Both ligands (75.19) are below the 90 A^2 threshold desirable for CNS targets, which is good.

**3. logP:** Both ligands (A: 2.196, B: 2.271) are within the optimal 1-3 range.

**4. H-Bond Donors:** Both ligands have 1 HBD, which is acceptable.

**5. H-Bond Acceptors:** Both ligands have 4 HBA, which is acceptable.

**6. QED:** Both ligands have good QED scores (A: 0.858, B: 0.823), indicating drug-like properties.

**7. DILI:** Ligand A (39.899) has a slightly higher DILI risk than Ligand B (15.394), but both are below the concerning threshold of 60.

**8. BBB:** This is a critical parameter for a CNS target like DRD2. Ligand B (89.104) has a significantly higher BBB percentile than Ligand A (76.541). This is a major advantage for Ligand B.

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.962 and -4.917), which is unusual and suggests poor permeability. This is a concern for both, but doesn't differentiate them.

**10. Aqueous Solubility:** Ligand B (-3.613) has better (less negative) aqueous solubility than Ligand A (-1.998).

**11. hERG Inhibition:** Ligand A (0.254) has a lower hERG inhibition liability than Ligand B (0.646), which is favorable.

**12. Microsomal Clearance:** Ligand A (40.68) has lower microsomal clearance than Ligand B (56.583), suggesting better metabolic stability.

**13. In vitro Half-Life:** Ligand B (-4.369) has a much better (less negative) in vitro half-life than Ligand A (-10.545).

**14. P-gp Efflux:** Ligand A (0.077) has lower P-gp efflux liability than Ligand B (0.02), which is favorable for CNS penetration.

**15. Binding Affinity:** Ligand B (-8.5 kcal/mol) has a slightly better binding affinity than Ligand A (-8.1 kcal/mol). While the difference is not huge, it's still a positive for Ligand B.

**Overall Assessment:**

Ligand B clearly emerges as the more promising candidate. Its superior BBB penetration (89.104 vs 76.541), better in vitro half-life, and slightly improved binding affinity outweigh the minor drawbacks of slightly higher hERG inhibition and P-gp efflux. The improved solubility is also a benefit. While both have poor Caco-2 permeability, the higher BBB score of Ligand B is critical for a CNS target.

Output:
1
2025-04-17 03:24:10,998 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (354.403 Da) is slightly lower, which is generally favorable for permeability. Ligand B (372.491 Da) is also acceptable.

**TPSA:** Both ligands have TPSA values below 140, suggesting good oral absorption potential. More importantly, both are below the 90 threshold desirable for CNS targets. Ligand B (93.53) is slightly higher than Ligand A (99.89), but both are acceptable.

**logP:** Ligand A (1.923) is within the optimal range (1-3). Ligand B (0.392) is slightly below 1, which *could* indicate potential permeability issues, although it isn't a hard cutoff.

**H-Bond Donors & Acceptors:** Both ligands have acceptable HBD (1) and HBA (7 & 6) counts, well within the recommended limits.

**QED:** Both ligands have QED values above 0.5 (0.712 and 0.677), indicating good drug-like properties.

**DILI:** Ligand A (62.272) has a higher DILI risk than Ligand B (43.622). This is a point in favor of Ligand B.

**BBB:** Ligand A (73.401) has a significantly better BBB penetration percentile than Ligand B (51.725). This is a *major* advantage for a CNS target like DRD2.

**Caco-2 Permeability:** Ligand A (-4.762) has a more negative Caco-2 value, suggesting *lower* intestinal permeability. Ligand B (-5.296) is even worse. Both are poor.

**Aqueous Solubility:** Ligand A (-1.586) has slightly better aqueous solubility than Ligand B (-0.849), though both are quite poor.

**hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.106 and 0.199).

**Microsomal Clearance:** Ligand B (37.876) has significantly lower microsomal clearance than Ligand A (66.273), indicating better metabolic stability. This is a positive for Ligand B.

**In vitro Half-Life:** Ligand B (-17.904) has a much longer in vitro half-life than Ligand A (-7.477), which is a significant advantage.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.02 and 0.038), which is good.

**Binding Affinity:** Both ligands have comparable and strong binding affinities (-7.2 and -7.3 kcal/mol). The difference is negligible.

**Overall Assessment:**

Ligand A excels in BBB penetration, a crucial factor for CNS targets. However, it suffers from lower Caco-2 permeability, higher DILI risk, and faster metabolic clearance. Ligand B has better metabolic stability (lower Cl_mic, longer t1/2), lower DILI risk, but significantly poorer BBB penetration.

Considering the GPCR-specific priorities, *BBB is paramount for a CNS target*. While Ligand B has better ADME properties in some respects, the substantial difference in BBB penetration makes Ligand A the more promising candidate. The lower Caco-2 and slightly higher DILI of Ligand A could be addressed through further optimization, but improving BBB penetration is often very difficult.

Output:
1
2025-04-17 03:24:10,998 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (360.772 and 391.877 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (82.45) is significantly better than Ligand B (110.53). For CNS targets, we want TPSA <= 90, and A is comfortably within that range, while B is above.

**3. logP:** Ligand A (4.604) is higher than optimal (1-3), potentially causing solubility issues or off-target effects. Ligand B (1.243) is a bit low, potentially hindering permeation.

**4. H-Bond Donors:** Ligand A (3) and Ligand B (2) are both acceptable (<=5).

**5. H-Bond Acceptors:** Ligand A (4) and Ligand B (6) are both acceptable (<=10).

**6. QED:** Both ligands have good QED scores (0.633 and 0.754), indicating drug-like properties.

**7. DILI:** Both ligands have high DILI risk (91.431 and 86.933), but this isn't a definitive dealbreaker at this stage.

**8. BBB:** Ligand A (11.632) has very poor BBB penetration, a critical issue for a CNS target like DRD2. Ligand B (55.913) is better, although still not ideal (we want >70).

**9. Caco-2:** Both ligands have negative Caco-2 values (-5.136 and -5.195), which is unusual and suggests poor permeability. This is a red flag for both.

**10. Solubility:** Both ligands have negative solubility values (-4.781 and -3.438), indicating very poor aqueous solubility. This is a significant concern.

**11. hERG:** Both ligands have low hERG inhibition liability (0.176 and 0.224), which is good.

**12. Cl_mic:** Ligand A (31.315) has lower microsomal clearance than Ligand B (41.477), suggesting better metabolic stability.

**13. t1/2:** Ligand A (18.886) has a positive in vitro half-life, while Ligand B (-16.471) has a negative one. This suggests Ligand A is more stable.

**14. Pgp:** Both ligands have low P-gp efflux liability (0.062 and 0.207), which is favorable for CNS penetration.

**15. Binding Affinity:** Ligand A (-8.6 kcal/mol) has significantly stronger binding affinity than Ligand B (-7.7 kcal/mol). This is a substantial advantage.

**Overall Assessment:**

Ligand A has a much stronger binding affinity and better metabolic stability (lower Cl_mic, positive t1/2). However, its major drawback is extremely poor BBB penetration. Ligand B has better BBB penetration, but significantly weaker binding affinity, and worse metabolic stability. Given the GPCR-specific priority of BBB for CNS targets, and the substantial affinity difference, the stronger affinity of Ligand A is likely to be more valuable, *if* the poor BBB penetration can be addressed through structural modifications. The poor solubility and Caco-2 permeability are also concerning for both, but can potentially be improved.

Output:
0
2025-04-17 03:24:10,999 - INFO - Batch 26 complete. Total preferences: 416
2025-04-17 03:24:10,999 - INFO - Processing batch 27/512...
2025-04-17 03:24:51,687 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (340.467 and 339.439 Da) fall comfortably within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (58.2) is significantly better than Ligand B (71.09). For CNS targets, we want TPSA <= 90, and ideally closer to 60. Ligand A is much closer to this ideal.

**3. logP:** Both ligands have acceptable logP values (3.841 and 2.064), falling within the 1-3 range. Ligand A is slightly higher, which *could* be a minor concern for solubility, but is still reasonable.

**4. H-Bond Donors:** Both have 2 HBD, which is within the acceptable limit of <= 5.

**5. H-Bond Acceptors:** Ligand A has 2 HBA, while Ligand B has 3. Both are within the acceptable limit of <= 10.

**6. QED:** Both ligands have similar, good QED values (0.741 and 0.78), indicating good drug-like properties.

**7. DILI:** Ligand A (39.667) has a slightly better DILI score than Ligand B (46.879), both are below the concerning threshold of 60.

**8. BBB:** This is a critical parameter for a CNS target like DRD2. Ligand A has a significantly higher BBB percentile (79.217) compared to Ligand B (63.086).  A value >70 is highly desirable, and Ligand A is closer to that target.

**9. Caco-2 Permeability:** Both have negative values, indicating poor permeability. This is concerning, but not a dealbreaker if other properties are strong.

**10. Aqueous Solubility:** Both have negative values, indicating poor solubility. This is concerning, but not a dealbreaker if other properties are strong.

**11. hERG Inhibition:** Both ligands have low hERG inhibition risk (0.669 and 0.263), which is excellent.

**12. Microsomal Clearance:** Ligand A (64.14) has higher clearance than Ligand B (57.766), meaning it's metabolized faster. Lower is better here.

**13. In vitro Half-Life:** Ligand B has a significantly longer in vitro half-life (-22.391) than Ligand A (0.817). This is a significant advantage for Ligand B.

**14. P-gp Efflux:** Ligand A (0.242) has lower P-gp efflux than Ligand B (0.165), which is desirable for CNS penetration.

**15. Binding Affinity:** Both ligands have excellent binding affinities (-8.7 and -8.8 kcal/mol). The difference is negligible.

**Overall Assessment:**

Ligand A excels in TPSA and BBB penetration, which are crucial for CNS GPCR targets. While its clearance is higher and half-life shorter than Ligand B, the superior CNS penetration profile, combined with comparable affinity and acceptable other properties, makes it the more promising candidate. Ligand B's longer half-life is attractive, but the lower BBB penetration is a substantial drawback for a DRD2 ligand.

Output:
1
2025-04-17 03:24:51,687 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (364.511 and 348.447 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (67.43) is significantly better than Ligand B (96.25). For CNS targets, we want TPSA <= 90, so Ligand A is preferable.

**logP:** Both ligands have acceptable logP values (3.222 and 1.752, respectively), falling within the 1-3 range. Ligand A is slightly better, being closer to the optimal range.

**H-Bond Donors/Acceptors:** Ligand A (2 HBD, 4 HBA) and Ligand B (3 HBD, 5 HBA) are both within acceptable limits (<=5 HBD and <=10 HBA).

**QED:** Both ligands have similar QED values (0.66 and 0.624), indicating good drug-likeness.

**DILI:** Ligand A (53.47) has a slightly higher DILI risk than Ligand B (39.201), but both are below the concerning threshold of 60.

**BBB:** Ligand B (73.905) has a significantly better BBB penetration percentile than Ligand A (52.423). This is a critical factor for a CNS target like DRD2.

**Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and suggests poor permeability. However, the scale isn't specified, so it's hard to interpret.

**Aqueous Solubility:** Both ligands have negative solubility values, indicating poor solubility.

**hERG:** Both ligands have very low hERG inhibition liability (0.182 and 0.191), which is excellent.

**Microsomal Clearance:** Ligand B (35.529) has lower microsomal clearance than Ligand A (44.862), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand B (19.942 hours) has a much longer in vitro half-life than Ligand A (-13.734 hours). This is a significant advantage.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.042 and 0.159), which is good.

**Binding Affinity:** Ligand B (-8.1 kcal/mol) has a slightly better binding affinity than Ligand A (-7.9 kcal/mol), although the difference is small.

**Overall Assessment:**

While Ligand A has a better TPSA and logP, Ligand B excels in crucial areas for CNS drug development: BBB penetration, metabolic stability (lower Cl_mic, longer t1/2), and slightly better binding affinity. The difference in BBB is particularly important for DRD2. The negative solubility and Caco-2 values are concerns for both, but the superior CNS penetration profile of Ligand B outweighs the minor advantages of Ligand A.

Output:
1
2025-04-17 03:24:51,687 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (346.471 and 345.403 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (70.59) is significantly better than Ligand B (95.5). For CNS targets, TPSA should be <= 90, so Ligand A is preferable.

**logP:** Ligand A (2.545) is within the optimal 1-3 range. Ligand B (-0.293) is below 1, which could hinder permeation. This is a significant advantage for Ligand A.

**H-Bond Donors/Acceptors:** Ligand A (HBD=3, HBA=3) and Ligand B (HBD=1, HBA=5) both have reasonable numbers of H-bond donors and acceptors, within the guidelines.

**QED:** Both ligands have good QED values (0.71 and 0.74), indicating good drug-like properties.

**DILI:** Ligand A (17.759) has a much lower DILI risk than Ligand B (64.754). This is a substantial advantage for Ligand A.

**BBB:** Ligand A (76.541) has a good BBB penetration percentile, exceeding the 70% threshold for CNS targets. Ligand B (53.276) is below this threshold, making it less likely to reach the target in the brain.

**Caco-2 Permeability:** Both have negative values, indicating poor permeability. However, the scale is not specified, so it's hard to interpret.

**Aqueous Solubility:** Both have negative values, indicating poor solubility. However, the scale is not specified, so it's hard to interpret.

**hERG:** Both ligands have low hERG inhibition liability (0.773 and 0.139), which is good.

**Microsomal Clearance:** Ligand A (32.513) has lower microsomal clearance than Ligand B (57.778), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (31.986) has a positive half-life, while Ligand B (-39.491) has a negative half-life. This is a significant advantage for Ligand A.

**P-gp Efflux:** Ligand A (0.285) has lower P-gp efflux liability than Ligand B (0.024), which is favorable for CNS penetration.

**Binding Affinity:** Ligand B (-7.8) has a slightly better binding affinity than Ligand A (-9.1). However, the difference is not substantial enough to outweigh the significant ADME advantages of Ligand A.

**Overall:** Considering the GPCR-specific priorities, Ligand A is clearly superior. It has better TPSA, logP, BBB penetration, DILI risk, metabolic stability, P-gp efflux, and in vitro half-life. While Ligand B has slightly better binding affinity, the ADME profile of Ligand A is far more promising for CNS drug development.

Output:
1
2025-04-17 03:24:51,688 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (350.409 and 366.531 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (32.78) is excellent, well below the 90 A^2 threshold for CNS targets. Ligand B (65.54) is higher but still acceptable, though less ideal.

**logP:** Ligand A (2.392) is optimal (1-3). Ligand B (1.771) is slightly lower, but still within an acceptable range.

**H-Bond Donors/Acceptors:** Ligand A (0 HBD, 3 HBA) is favorable. Ligand B (1 HBD, 5 HBA) is also acceptable.

**QED:** Both ligands have reasonable QED scores (0.839 and 0.761), indicating good drug-like properties.

**DILI:** Ligand A (8.763 percentile) has a significantly lower DILI risk than Ligand B (14.696 percentile). This is a substantial advantage.

**BBB:** Ligand A (91.508 percentile) has excellent predicted BBB penetration, crucial for a CNS target like DRD2. Ligand B (49.981 percentile) is considerably lower, raising concerns about sufficient brain exposure.

**Caco-2 Permeability:** Ligand A (-4.264) is poor, while Ligand B (-5.048) is even worse. Both are negative, indicating very low permeability.

**Aqueous Solubility:** Ligand A (-1.602) is poor, and Ligand B (-0.894) is also poor.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.675 and 0.272).

**Microsomal Clearance:** Ligand A (12.539 mL/min/kg) is higher than Ligand B (-1.181 mL/min/kg), suggesting Ligand B is more metabolically stable.

**In vitro Half-Life:** Ligand A (-4.906 hours) is poor, and Ligand B (10.883 hours) is better.

**P-gp Efflux:** Ligand A (0.049) has very low P-gp efflux, which is highly desirable for CNS penetration. Ligand B (0.016) also has low P-gp efflux, but slightly higher than A.

**Binding Affinity:** Ligand A (-9.4 kcal/mol) has a significantly stronger binding affinity than Ligand B (-7.1 kcal/mol). This 2.3 kcal/mol difference is substantial and can outweigh some ADME drawbacks.

**Overall Assessment:**

Ligand A is the stronger candidate. While both have poor solubility and Caco-2 permeability, Ligand A's significantly better BBB penetration, lower DILI risk, and *much* stronger binding affinity outweigh its slightly higher microsomal clearance and poorer half-life. The strong affinity is particularly important for a GPCR target. Ligand B's lower affinity and poorer BBB penetration are significant drawbacks.

Output:
1
2025-04-17 03:24:51,688 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (363.5 and 371.5 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (29.54) is excellent, well below the 90 A^2 threshold for CNS targets. Ligand B (82.97) is higher but still reasonable, though less ideal for CNS penetration.

**logP:** Ligand A (3.988) is at the upper end of the optimal range (1-3), but acceptable. Ligand B (2.338) is well within the optimal range.

**H-Bond Donors/Acceptors:** Ligand A (0 HBD, 3 HBA) is favorable. Ligand B (1 HBD, 6 HBA) is also acceptable.

**QED:** Both ligands have similar QED values (0.63 and 0.709), indicating good drug-likeness.

**DILI:** Both ligands have low DILI risk (39.55 and 38.35), which is good.

**BBB:** Ligand A has a significantly higher BBB penetration percentile (90.85) than Ligand B (71.66). This is a *critical* advantage for a CNS target like DRD2.

**Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and suggests a potential issue with the data or modeling. However, we'll proceed assuming these are percentile scores, and lower values indicate poorer permeability. Ligand A (-4.669) is slightly worse than Ligand B (-4.622), but the difference is minimal.

**Aqueous Solubility:** Both ligands have negative solubility values, which is also unusual. Assuming these are percentile scores, lower values indicate poorer solubility. Ligand A (-4.479) is slightly worse than Ligand B (-1.905).

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.717 and 0.642).

**Microsomal Clearance:** Ligand A (95.583) has a very high microsomal clearance, suggesting rapid metabolism. Ligand B (69.014) is better, but still relatively high.

**In vitro Half-Life:** Ligand A (10.076 hours) has a reasonable half-life. Ligand B (-20.298 hours) has a negative half-life, which is impossible and indicates a significant data issue.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.495 and 0.3).

**Binding Affinity:** Ligand A (-7.3 kcal/mol) has a significantly stronger binding affinity than Ligand B (-6.3 kcal/mol). This is a substantial advantage (1 kcal/mol difference).

**Overall Assessment:**

Ligand A is superior due to its significantly better BBB penetration, much stronger binding affinity, and acceptable metabolic stability despite the high clearance. The negative solubility and Caco-2 values are concerning but could be data artifacts. Ligand B has a problematic negative in vitro half-life, which is a major red flag. While Ligand B has slightly better solubility and Caco-2 permeability, the superior affinity and BBB penetration of Ligand A outweigh these minor advantages, especially for a CNS target.

Output:
1
2025-04-17 03:24:51,688 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (343.387 and 352.347 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (119.23) is better than Ligand B (127.88). Both are below the 140 A^2 threshold for oral absorption and reasonably close to the <90 A^2 target for CNS penetration, but A is closer.

**3. logP:** Ligand A (1.523) is within the optimal 1-3 range. Ligand B (-0.63) is slightly below 1, potentially hindering permeation.

**4. H-Bond Donors:** Both ligands have 3 HBDs, which is acceptable (<=5).

**5. H-Bond Acceptors:** Ligand A has 6 HBAs, and Ligand B has 7. Both are within the acceptable range (<=10).

**6. QED:** Ligand A (0.731) has a better QED score than Ligand B (0.475), indicating a more drug-like profile.

**7. DILI:** Ligand B (88.29) has a significantly higher DILI risk than Ligand A (74.176). This is a substantial negative for Ligand B.

**8. BBB:** Ligand A (55.603) has a better BBB percentile than Ligand B (48.003), although both are below the desirable >70 for CNS targets.

**9. Caco-2:** Both have negative Caco-2 values, which is unusual and difficult to interpret without knowing the scale. Assuming these are logP-like scales, lower values indicate poorer permeability. They are similarly poor.

**10. Solubility:** Both have negative solubility values, again unusual. Assuming these are logS-like scales, lower values indicate poorer solubility. They are similarly poor.

**11. hERG:** Both ligands have very low hERG inhibition liability (0.354 and 0.111), which is excellent.

**12. Cl_mic:** Ligand B (-24.411) has a *much* lower (better) microsomal clearance than Ligand A (24.021). This suggests better metabolic stability for Ligand B.

**13. t1/2:** Ligand B (3.341) has a slightly longer in vitro half-life than Ligand A (-40.386). However, the negative value for A is concerning and likely an error.

**14. Pgp:** Ligand A (0.024) has significantly lower P-gp efflux liability than Ligand B (0.007), which is favorable for CNS exposure.

**15. Binding Affinity:** Ligand A (-8.5 kcal/mol) has a substantially stronger binding affinity than Ligand B (-7.3 kcal/mol). This is a significant advantage for Ligand A.

**Overall Assessment:**

Considering the GPCR-specific priorities, Ligand A is the stronger candidate. Its superior binding affinity, better BBB penetration (even if not ideal), lower DILI risk, and lower P-gp efflux outweigh the slightly worse metabolic stability. The logP of Ligand A is also more favorable. While both have issues with solubility and Caco-2 permeability, the affinity difference is substantial enough to make Ligand A the better choice.

Output:
1
2025-04-17 03:24:51,688 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B based on the provided guidelines, prioritizing GPCR-specific properties (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (348.403 and 351.426 Da) fall within the ideal range of 200-500 Da.

**TPSA:** Ligand A (109.39) is higher than Ligand B (80.12). For CNS targets, TPSA should be <= 90. Ligand B is better here.

**logP:** Ligand A (0.779) is slightly below the optimal range (1-3), potentially hindering permeation. Ligand B (1.291) is within the optimal range. Ligand B is better.

**H-Bond Donors:** Ligand A (3) is acceptable, while Ligand B (1) is even better, minimizing potential permeability issues.

**H-Bond Acceptors:** Both ligands have acceptable HBA counts (6 and 5, respectively).

**QED:** Both ligands have good QED values (0.611 and 0.803), indicating drug-likeness. Ligand B is slightly better.

**DILI:** Ligand A (56.689) has a higher DILI risk than Ligand B (19.504). Ligand B is significantly better.

**BBB:** Ligand A (9.849) has very poor predicted BBB penetration, a critical drawback for a CNS target like DRD2. Ligand B (88.135) has excellent predicted BBB penetration. This is a major advantage for Ligand B.

**Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and difficult to interpret without further context. However, the magnitude of negativity for Ligand A (-5.415) is greater than Ligand B (-5.07), suggesting potentially lower intestinal absorption for A.

**Aqueous Solubility:** Both ligands have very poor predicted aqueous solubility (-1.528 and -1.683).

**hERG Inhibition:** Both ligands show low hERG inhibition risk (0.515 and 0.081). Ligand B is better.

**Microsomal Clearance:** Ligand A (15.822) has higher microsomal clearance than Ligand B (-1.597), indicating lower metabolic stability. Ligand B is better.

**In vitro Half-Life:** Ligand A (-6.991) has a shorter predicted half-life than Ligand B (-1.556). Ligand B is better.

**P-gp Efflux:** Ligand A (0.084) has slightly higher P-gp efflux than Ligand B (0.024). Ligand B is better.

**Binding Affinity:** Both ligands have excellent binding affinities (-7.6 and -7.0 kcal/mol). Ligand A is slightly better, but the difference is likely not enough to overcome its ADME deficiencies.

**Overall Assessment:**

Ligand B is significantly superior to Ligand A. While Ligand A has slightly better binding affinity, Ligand B excels in almost all crucial ADME properties, particularly BBB penetration, DILI risk, metabolic stability, and P-gp efflux. Given the CNS target (DRD2), BBB penetration is paramount, and Ligand B's 88.135 percentile score is highly favorable. The lower DILI risk and improved metabolic stability further strengthen its profile.

Output:
1
2025-04-17 03:24:51,689 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (346.43 and 344.46 Da) fall comfortably within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (73.99) is significantly better than Ligand B (83.98). For CNS targets, we want TPSA <= 90, and A is closer to the ideal <= 60. B is pushing the upper limit.

**3. logP:** Both ligands have acceptable logP values (1.82 and 2.17), falling within the optimal 1-3 range.

**4. H-Bond Donors:** Ligand A (1) is preferable to Ligand B (2). Lower HBD generally improves permeability.

**5. H-Bond Acceptors:** Both ligands have the same number of HBA (4), which is acceptable (<=10).

**6. QED:** Ligand A (0.902) has a much better QED score than Ligand B (0.673), indicating a more drug-like profile.

**7. DILI:** Ligand A (28.34) has a lower DILI risk than Ligand B (39.24), which is favorable. Both are below the 40 threshold.

**8. BBB:** Ligand A (64.48) is better than Ligand B (59.98), but both are below the desirable >70 for CNS targets. However, given the other properties, a slight advantage here is helpful.

**9. Caco-2:** Ligand A (-4.516) is better than Ligand B (-5.217). Higher values are better, indicating better intestinal absorption.

**10. Solubility:** Ligand A (-2.454) is better than Ligand B (-1.645). Higher values are better.

**11. hERG:** Both ligands have very low hERG risk (0.288 and 0.184), which is excellent.

**12. Cl_mic:** Ligand B (37.96) has a lower microsomal clearance than Ligand A (47.78), suggesting better metabolic stability.

**13. t1/2:** Ligand B (8.38) has a longer in vitro half-life than Ligand A (45.34). This is a significant advantage.

**14. Pgp:** Both ligands have low P-gp efflux liability (0.106 and 0.032). Ligand B is slightly better.

**15. Binding Affinity:** Ligand B (-8.1 kcal/mol) has a significantly stronger binding affinity than Ligand A (-6.8 kcal/mol). This is a >1.3 kcal/mol advantage, which can outweigh some ADME drawbacks.

**Overall Assessment:**

Ligand B has a substantially better binding affinity, a longer half-life, and slightly better Pgp efflux. However, Ligand A has a significantly better TPSA, QED, solubility, and DILI risk. While Ligand B's affinity is a major plus, the improved CNS penetration potential (lower TPSA, better solubility) and drug-likeness of Ligand A are also important for a CNS target like DRD2. The difference in affinity is significant, but not insurmountable, and can potentially be optimized in future iterations. Given the GPCR-specific priorities, and the fact that both ligands fall short of the ideal BBB penetration, the better ADME profile of Ligand A, combined with acceptable affinity, makes it the slightly more promising candidate.

Output:
0
2025-04-17 03:24:51,689 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (343.343 and 350.463 Da) fall within the ideal range of 200-500 Da.

**TPSA:** Ligand A (128.28) is slightly above the optimal <90 for CNS targets, but still reasonable. Ligand B (81.75) is excellent, well below 90.

**logP:** Both ligands (-0.012 and -0.04) are very close to zero, which is slightly concerning. While not drastically outside the 1-3 range, they are on the lower end and might indicate permeability issues.

**H-Bond Donors/Acceptors:** Ligand A (3 HBD, 6 HBA) is acceptable. Ligand B (2 HBD, 4 HBA) is also good.

**QED:** Both ligands (0.716 and 0.659) have good drug-likeness scores, exceeding the 0.5 threshold.

**DILI:** Ligand A (76.425) has a higher DILI risk than Ligand B (8.802). This is a significant negative for Ligand A.

**BBB:** Ligand B (50.058) has a better BBB penetration percentile than Ligand A (28.189), though both are below the desirable >70 for CNS targets.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.296 and -5.124), which is unusual and suggests poor permeability. This is a major concern for both.

**Aqueous Solubility:** Both ligands have negative solubility values (-3.047 and -1.106), also unusual and concerning.

**hERG:** Both ligands have very low hERG inhibition risk (0.122 and 0.107).

**Microsomal Clearance:** Ligand A (-10.662) has a lower (better) microsomal clearance than Ligand B (-15.545), indicating greater metabolic stability.

**In vitro Half-Life:** Ligand A (-5.478) has a slightly better in vitro half-life than Ligand B (-0.532).

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.005 and 0.002), which is favorable for CNS penetration.

**Binding Affinity:** Ligand A (-8.9 kcal/mol) has a significantly stronger binding affinity than Ligand B (-7.9 kcal/mol). This is a >1 kcal/mol difference, which is substantial.

**Overall Assessment:**

Ligand A has a significantly better binding affinity and better metabolic stability. However, it has a much higher DILI risk and poorer BBB penetration. Both ligands have concerningly low (negative) Caco-2 and solubility values. Ligand B has a better safety profile (lower DILI) and slightly better BBB, but weaker binding affinity.

Given the GPCR-specific priorities, and the importance of CNS penetration for a DRD2 target, the slightly better BBB and significantly lower DILI risk of Ligand B, combined with acceptable (though not ideal) affinity, make it a more promising starting point despite the permeability and solubility concerns. The affinity difference can potentially be addressed through further optimization, while fixing the permeability/solubility issues might be more challenging.

Output:
1
2025-04-17 03:24:51,689 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (349.435 and 356.373 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (116.84) is slightly higher than Ligand B (107.11). Both are below the 140 A^2 threshold for oral absorption, and closer to the desirable <90 A^2 for CNS targets, but Ligand B is better.

**3. logP:** Both ligands have similar logP values (1.103 and 1.106), falling within the optimal 1-3 range.

**4. H-Bond Donors:** Ligand A has 3 HBD, and Ligand B has 4. Both are acceptable (<=5).

**5. H-Bond Acceptors:** Ligand A has 5 HBA, and Ligand B has 4. Both are acceptable (<=10).

**6. QED:** Both ligands have similar QED values (0.617 and 0.612), indicating good drug-like properties.

**7. DILI:** Ligand A (35.479) has a significantly lower DILI risk than Ligand B (55.68). This is a crucial advantage.

**8. BBB:** Ligand B (61.962) has a substantially better BBB penetration percentile than Ligand A (36.487). This is a major advantage for a CNS target like DRD2.

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.543 and -5.262). This is unusual and suggests poor permeability, but the scale is not specified, so it's hard to interpret.

**10. Aqueous Solubility:** Both ligands have negative solubility values (-1.867 and -3.141). This is also unusual and suggests poor solubility, but the scale is not specified, so it's hard to interpret.

**11. hERG Inhibition:** Ligand A (0.033) has a slightly lower hERG inhibition liability than Ligand B (0.327), which is preferable.

**12. Microsomal Clearance:** Ligand A (-7.031) has a much lower (better) microsomal clearance than Ligand B (0.568), indicating greater metabolic stability.

**13. In vitro Half-Life:** Ligand A (-16.896) has a much longer in vitro half-life than Ligand B (-11.078), which is desirable.

**14. P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.029 and 0.042).

**15. Binding Affinity:** Both ligands have the same binding affinity (-7.8 kcal/mol), which is excellent.

**Overall Assessment:**

While Ligand B has a significantly better BBB score, Ligand A excels in several critical ADME properties: lower DILI risk, better metabolic stability (lower Cl_mic and longer t1/2), and lower hERG inhibition.  Given the importance of ADME properties for *in vivo* efficacy and safety, and the fact that both ligands have identical binding affinities, Ligand A is the more promising candidate. The better BBB of Ligand B is important, but can potentially be addressed through prodrug strategies or formulation approaches. The significantly improved safety profile and metabolic stability of Ligand A outweigh the BBB advantage of Ligand B.

Output:
0
2025-04-17 03:24:51,689 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (384.259 Da) is slightly higher than Ligand B (340.475 Da), but both are acceptable.

**TPSA:** Ligand A (67.79) is better than Ligand B (87.89). For CNS targets, we want TPSA <= 90, and ideally closer to 60. Ligand A is closer to the ideal range.

**logP:** Both ligands have good logP values (A: 3.23, B: 2.571), falling within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A (HBD=2, HBA=4) is better than Ligand B (HBD=4, HBA=6). Lower values are generally preferred for better permeability.

**QED:** Both ligands have acceptable QED values (A: 0.769, B: 0.58), indicating reasonable drug-likeness.

**DILI:** Ligand A (58.24) has a slightly better DILI score than Ligand B (47.305), both are acceptable.

**BBB:** This is critical for a CNS target like DRD2. Ligand B (70.609) has a significantly better BBB penetration percentile than Ligand A (34.626). This is a major advantage for Ligand B.

**Caco-2 Permeability:** Ligand A (-4.854) has a very poor Caco-2 permeability, while Ligand B (-5.756) is also poor, but slightly better.

**Aqueous Solubility:** Both ligands have poor aqueous solubility (A: -3.887, B: -3.344). This could pose formulation challenges.

**hERG Inhibition:** Both ligands have acceptable hERG inhibition risk (A: 0.762, B: 0.913).

**Microsomal Clearance:** Ligand B (39.032) has slightly better microsomal clearance than Ligand A (41.262), indicating better metabolic stability.

**In vitro Half-Life:** Ligand B (39.106) has a significantly longer in vitro half-life than Ligand A (23.258).

**P-gp Efflux:** Ligand A (0.605) has better P-gp efflux profile than Ligand B (0.279). Lower P-gp efflux is desirable for CNS penetration.

**Binding Affinity:** Ligand A (-8.9 kcal/mol) has a *much* stronger binding affinity than Ligand B (-0.0 kcal/mol). This is a decisive factor. A difference of >1.5 kcal/mol can often outweigh other ADME drawbacks.

**Overall Assessment:**

While Ligand B has a superior BBB score and better metabolic stability/half-life, the *massive* difference in binding affinity (-8.9 kcal/mol vs -0.0 kcal/mol) for Ligand A is overwhelming. The stronger binding is likely to translate to greater efficacy. The poor Caco-2 and solubility of Ligand A are concerns, but these can potentially be addressed through formulation strategies. The lower BBB of Ligand A is also a concern, but the strong binding might compensate for that.

Output:
1
2025-04-17 03:24:51,689 - INFO - Reasoning:

Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (357.801 and 339.439 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (106.93) is slightly above the optimal <90 for CNS targets, but still reasonable. Ligand B (65.2) is well within the desired range. This favors Ligand B.

**3. logP:** Both ligands (3.058 and 3.243) are within the optimal 1-3 range.

**4. H-Bond Donors:** Both have 2 HBD, which is acceptable.

**5. H-Bond Acceptors:** Ligand A has 6 HBA, acceptable. Ligand B has 2 HBA, also acceptable.

**6. QED:** Both ligands have good QED scores (0.726 and 0.821), indicating drug-like properties.

**7. DILI:** Ligand A (85.731) has a higher DILI risk than Ligand B (65.917). This favors Ligand B.

**8. BBB:** Ligand A (54.091) and Ligand B (62.117) both have moderate BBB penetration. While neither is >70, Ligand B is slightly better.

**9. Caco-2:** Both have negative Caco-2 values (-5.405 and -5.122), which is unusual and suggests poor permeability. This is a significant concern for both.

**10. Solubility:** Both have negative solubility values (-3.93 and -4.611), indicating very poor aqueous solubility. This is a major drawback for both.

**11. hERG:** Both have low hERG inhibition liability (0.408 and 0.521), which is good.

**12. Cl_mic:** Ligand B (50.241) has lower microsomal clearance than Ligand A (8.184), suggesting better metabolic stability. This is a significant advantage for Ligand B.

**13. t1/2:** Both have similar in vitro half-lives (53.08 and 54.021 hours).

**14. Pgp:** Both have low P-gp efflux liability (0.268 and 0.393), which is favorable for CNS penetration.

**15. Binding Affinity:** Ligand A (-9.0 kcal/mol) has a significantly stronger binding affinity than Ligand B (-8.7 kcal/mol). This is a substantial advantage for Ligand A.

**Overall Assessment:**

While both compounds have significant drawbacks (poor solubility and Caco-2 permeability), the stronger binding affinity of Ligand A (-9.0 kcal/mol vs -8.7 kcal/mol) is a major advantage, potentially outweighing some of the ADME concerns. The lower DILI risk and better metabolic stability of Ligand B are also attractive. However, for a GPCR target like DRD2, strong binding is paramount, and the difference in affinity is substantial. The slightly better BBB for Ligand B is a minor advantage. Given the importance of affinity for GPCRs, I would prioritize Ligand A despite its higher DILI risk. Further optimization would be needed to address the solubility and permeability issues.

Output:
1
2025-04-17 03:24:51,690 - INFO - Reasoning:

Let's analyze Ligand A and Ligand B against the provided guidelines, prioritizing GPCR-specific properties (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (352.36 and 344.455 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (50.16) is significantly better than Ligand B (71.34). For CNS targets, TPSA should be <=90, and A is much closer to the optimal <=60 range. B is pushing the upper limit and could hinder BBB penetration.

**logP:** Both ligands have a logP around 3.3 (3.382 and 3.349), which is optimal.

**H-Bond Donors/Acceptors:** Ligand A (HBD=1, HBA=4) is slightly better than Ligand B (HBD=2, HBA=3) in terms of maintaining a balance between solubility and permeability.

**QED:** Ligand A (0.901) has a significantly higher QED score than Ligand B (0.778), indicating better overall drug-likeness.

**DILI:** Ligand B (35.944) has a much lower DILI risk than Ligand A (65.452). This is a significant advantage for B.

**BBB:** Ligand A (85.847) has a substantially higher BBB percentile than Ligand B (65.878). This is *critical* for a CNS target like DRD2.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.718 and -4.613), which is unusual and suggests poor permeability. However, these values are on a scale where negative values are possible, and the absolute difference isn't huge.

**Aqueous Solubility:** Both ligands have negative solubility values (-3.971 and -4.057), indicating poor aqueous solubility. This is a concern for both.

**hERG:** Ligand A (0.817) has a slightly higher hERG risk than Ligand B (0.215), making B safer from a cardiotoxicity perspective.

**Microsomal Clearance:** Ligand B (64.251) has a significantly higher microsomal clearance than Ligand A (29.763), meaning it's metabolized faster and has lower metabolic stability.

**In vitro Half-Life:** Ligand A (54.663) has a longer in vitro half-life than Ligand B (40.109), which is desirable.

**P-gp Efflux:** Ligand A (0.678) has lower P-gp efflux liability than Ligand B (0.306), which is beneficial for CNS exposure.

**Binding Affinity:** Ligand A (-10 kcal/mol) has a significantly stronger binding affinity than Ligand B (-8.9 kcal/mol). This is a substantial advantage, potentially outweighing some ADME drawbacks. A difference of >1.5 kcal/mol is considered significant.

**Overall Assessment:**

While Ligand B has advantages in DILI and hERG, Ligand A is superior due to its significantly better BBB penetration, higher QED, stronger binding affinity, lower P-gp efflux, and longer half-life. The TPSA is also much more favorable for CNS penetration. The solubility and Caco-2 values are poor for both, but the strong affinity of Ligand A suggests it might overcome these issues. For a CNS GPCR target, strong binding and good brain penetration are paramount.

Output:
1
2025-04-17 03:24:51,690 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (345.443) is slightly lower, which is generally favorable for permeability.

**2. TPSA:** Ligand A (71.53) is better than Ligand B (47.36). For CNS targets, TPSA should be <=90, both are well within this range, but A is higher, potentially hindering BBB penetration slightly.

**3. logP:** Both ligands have acceptable logP values (A: 1.995, B: 3.3). Ligand B is slightly higher, which could lead to solubility issues, but is still within the optimal 1-3 range.

**4. H-Bond Donors:** Ligand A has 1 HBD, Ligand B has 0. Both are within the acceptable limit of <=5.

**5. H-Bond Acceptors:** Ligand A has 4 HBA, Ligand B has 5. Both are within the acceptable limit of <=10.

**6. QED:** Both ligands have reasonable QED values (A: 0.886, B: 0.729), indicating good drug-like properties. Ligand A is slightly better.

**7. DILI:** Both ligands have low DILI risk (A: 26.018, B: 33.501), below the 40% threshold.

**8. BBB:** Both ligands have excellent BBB penetration (A: 84.684, B: 88.29). Ligand B is marginally better, but both are above the desirable 70% threshold for CNS targets.

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.599 and -4.639). This is unusual and suggests a potential issue with intestinal absorption, but the scale is not clearly defined. It's hard to interpret without knowing the units or scale.

**10. Aqueous Solubility:** Both ligands have negative solubility values (-2.425 and -3.111). Similar to Caco-2, this is unusual and requires clarification of the scale.

**11. hERG Inhibition:** Both ligands show low hERG inhibition liability (A: 0.435, B: 0.689), which is good.

**12. Microsomal Clearance:** Ligand A has a lower microsomal clearance (25.133) than Ligand B (49.738), indicating better metabolic stability.

**13. In vitro Half-Life:** Ligand A has a significantly longer in vitro half-life (-6.274) than Ligand B (-21.991), which is a major advantage.

**14. P-gp Efflux:** Both ligands have very low P-gp efflux liability (A: 0.025, B: 0.155), which is excellent for CNS penetration.

**15. Binding Affinity:** Both ligands have similar strong binding affinities (A: -8.0, B: -6.9). Ligand A is significantly more potent.

**Overall Assessment:**

Ligand A is the superior candidate. It has a better binding affinity, longer half-life, lower microsomal clearance, slightly better QED, and a more favorable molecular weight. While Ligand B has slightly better BBB penetration and logP, the differences are not substantial enough to outweigh the advantages of Ligand A. The negative values for Caco-2 and solubility are concerning for both, but the stronger binding and improved metabolic properties of Ligand A make it the more promising drug candidate.

Output:
1
2025-04-17 03:24:51,690 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (349.431 and 362.543 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (84.67) is better than Ligand B (58.12), both are below the 90 A^2 threshold for CNS targets.

**3. logP:** Ligand A (1.722) is optimal, while Ligand B (3.573) is approaching the upper limit of the optimal range.

**4. H-Bond Donors:** Both ligands have 1 HBD, which is within the acceptable limit of <=5.

**5. H-Bond Acceptors:** Both ligands have 5 HBA, which is within the acceptable limit of <=10.

**6. QED:** Both ligands have good QED scores (0.734 and 0.805, respectively), indicating good drug-like properties.

**7. DILI:** Ligand A (28.383) has a significantly lower DILI risk than Ligand B (50.174). Both are below the 60 threshold, but A is preferable.

**8. BBB:** Ligand B (83.637) has a slightly better BBB penetration percentile than Ligand A (77.162), but both are reasonably good for a CNS target.

**9. Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and suggests poor permeability. Ligand A (-4.681) is slightly better than Ligand B (-4.761).

**10. Aqueous Solubility:** Both have negative solubility values, which is also unusual and suggests poor solubility. Ligand A (-2.318) is slightly better than Ligand B (-4.841).

**11. hERG Inhibition:** Both ligands have low hERG inhibition liability (0.155 and 0.262, respectively).

**12. Microsomal Clearance:** Ligand A (53.36) has a lower microsomal clearance than Ligand B (76.588), indicating better metabolic stability.

**13. In vitro Half-Life:** Ligand B (43.996) has a longer in vitro half-life than Ligand A (5.315).

**14. P-gp Efflux:** Ligand A (0.119) has lower P-gp efflux liability than Ligand B (0.4), which is favorable for CNS penetration.

**15. Binding Affinity:** Ligand B (-9.1 kcal/mol) has a significantly stronger binding affinity than Ligand A (-7.9 kcal/mol). This is a substantial advantage.

**Overall Assessment:**

Ligand B has a significantly better binding affinity (-9.1 vs -7.9 kcal/mol). This is a critical factor for GPCR ligands. While Ligand A has better DILI and P-gp efflux, the difference in affinity is substantial enough to outweigh these benefits. The slightly better BBB for Ligand B is also a positive. The poor Caco-2 and solubility values are concerning for both, but can be addressed with formulation strategies.

Output:
1
2025-04-17 03:24:51,690 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight (MW):** Both ligands are within the ideal range (200-500 Da). Ligand A (395.575 Da) is slightly higher than Ligand B (350.503 Da), but both are acceptable.

**2. TPSA:** Ligand A (62.3) is higher than Ligand B (58.64). For CNS targets, we want TPSA <= 90, so both are good, but B is slightly preferred.

**3. logP:** Both ligands have good logP values (A: 3.366, B: 3.189), falling within the optimal 1-3 range.

**4. H-Bond Donors (HBD):** Both have 1 HBD, which is within the acceptable limit of <=5.

**5. H-Bond Acceptors (HBA):** Ligand A has 6 HBAs, while Ligand B has 3. Both are under the limit of <=10.

**6. QED:** Both have reasonable QED values (A: 0.815, B: 0.718), indicating good drug-like properties.

**7. DILI:** Ligand A (65.413) has a significantly higher DILI risk than Ligand B (27.918). This is a major concern for Ligand A.

**8. BBB:** Ligand B (71.229) has a better BBB penetration score than Ligand A (57.154). This is crucial for a CNS target like DRD2.

**9. Caco-2 Permeability:** Ligand A (-5.228) has worse Caco-2 permeability than Ligand B (-4.441).

**10. Aqueous Solubility:** Ligand A (-3.566) has worse aqueous solubility than Ligand B (-2.529).

**11. hERG Inhibition:** Both ligands have low hERG inhibition risk (A: 0.54, B: 0.199), which is good. Ligand B is slightly better.

**12. Microsomal Clearance:** Ligand B (89.461) has higher microsomal clearance than Ligand A (78.195), meaning A is more metabolically stable.

**13. In vitro Half-Life:** Ligand A (8.853) has a longer in vitro half-life than Ligand B (0.972).

**14. P-gp Efflux:** Both have low P-gp efflux liability (A: 0.248, B: 0.249) which is good.

**15. Binding Affinity:** Ligand B (-9.0 kcal/mol) has a significantly stronger binding affinity than Ligand A (-7.6 kcal/mol). This is a substantial advantage.

**Overall Assessment:**

Ligand B is clearly the superior candidate. While Ligand A has better metabolic stability and half-life, Ligand B excels in the most critical areas for a CNS GPCR target: significantly better BBB penetration, a much lower DILI risk, and a substantially stronger binding affinity. The slightly lower metabolic stability of Ligand B is a less critical drawback compared to the issues with Ligand A.

Output:
1
2025-04-17 03:24:51,691 - INFO - Batch 27 complete. Total preferences: 432
2025-04-17 03:24:51,691 - INFO - Processing batch 28/512...
2025-04-17 03:25:32,502 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B based on the provided guidelines, prioritizing GPCR-specific properties (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (359.373 Da) is slightly higher than Ligand B (346.515 Da), but this difference isn't significant.

**TPSA:** Ligand A (87.74) is closer to the desirable threshold of 90 for CNS targets than Ligand B (58.2). This favors Ligand A.

**logP:** Ligand A (0.476) is quite low, potentially hindering permeability. Ligand B (4.457) is higher, potentially causing solubility issues but better for permeation. This favors Ligand B.

**H-Bond Donors/Acceptors:** Both have 2 HBDs, which is good. Ligand A has 4 HBAs, while Ligand B has 2. Lower HBA is generally preferred for better permeability, favoring Ligand B.

**QED:** Both ligands have good QED scores (A: 0.533, B: 0.73), indicating drug-like properties. Ligand B is slightly better.

**DILI:** Ligand A (41.915) has a slightly higher DILI risk than Ligand B (30.399), favoring Ligand B.

**BBB:** Both ligands have excellent BBB penetration (A: 80.962, B: 79.1), fulfilling the >70% requirement for CNS targets. The difference is minimal.

**Caco-2 Permeability:** Ligand A (-5.207) has poor Caco-2 permeability, while Ligand B (-4.527) is also poor but slightly better.

**Aqueous Solubility:** Both have very poor aqueous solubility (A: -2.022, B: -4.817). This is a concern for both, but Ligand B is worse.

**hERG Inhibition:** Ligand A (0.119) has a very low hERG risk, which is excellent. Ligand B (0.792) has a moderate risk, favoring Ligand A.

**Microsomal Clearance:** Ligand A (-8.345) has a very low (good) microsomal clearance, indicating good metabolic stability. Ligand B (86.359) has a high clearance, suggesting rapid metabolism, favoring Ligand A.

**In vitro Half-Life:** Ligand A (-30.239) has a very long half-life, which is excellent. Ligand B (46.544) has a moderate half-life, favoring Ligand A.

**P-gp Efflux:** Ligand A (0.01) has very low P-gp efflux, which is excellent for CNS penetration. Ligand B (0.345) has moderate P-gp efflux, favoring Ligand A.

**Binding Affinity:** Ligand B (-8.8 kcal/mol) has a slightly stronger binding affinity than Ligand A (-7.8 kcal/mol). This is a significant advantage (0.9 kcal/mol difference).

**Overall Assessment:**

While Ligand B has better logP and slightly better affinity, Ligand A excels in crucial ADME properties for a CNS-targeting GPCR drug. Specifically, its superior BBB penetration, significantly lower DILI risk, excellent metabolic stability (low Cl_mic and long t1/2), minimal P-gp efflux, and very low hERG risk are highly advantageous. The lower TPSA of Ligand A is also beneficial. The affinity difference, while notable, can potentially be optimized in subsequent iterations of drug design. The poor solubility and Caco-2 permeability are concerns for both, but can be addressed with formulation strategies.

Output:
1
2025-04-17 03:25:32,502 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (374.34 and 341.455 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (88.52) is better than Ligand B (73.2). Both are below the 90 A^2 threshold for CNS targets, which is excellent.

**logP:** Both ligands have good logP values (2.744 and 2.503), falling within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A has 2 HBD and 6 HBA, while Ligand B has 1 HBD and 3 HBA. Both are within acceptable limits (<=5 HBD and <=10 HBA).

**QED:** Both ligands have good QED scores (0.786 and 0.894), indicating good drug-like properties.

**DILI:** Ligand A (85.227) has a significantly higher DILI risk than Ligand B (27.104). This is a major concern for Ligand A.

**BBB:** Ligand B (68.941) has a better BBB penetration score than Ligand A (57.425), although both are below the desirable >70 for CNS targets.

**Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and suggests poor permeability. However, the scale is not specified, so it is difficult to interpret.

**Aqueous Solubility:** Both have negative solubility values, which is also unusual and suggests poor solubility. Again, the scale is not specified.

**hERG:** Ligand A (0.392) has a slightly better hERG profile than Ligand B (0.639), indicating lower cardiotoxicity risk.

**Microsomal Clearance:** Ligand B (39.565) has a lower microsomal clearance than Ligand A (83.787), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand B (1.975) has a slightly better in vitro half-life than Ligand A (-13.58), although both are not ideal.

**P-gp Efflux:** Ligand A (0.207) has a lower P-gp efflux liability than Ligand B (0.279), which is favorable for CNS penetration.

**Binding Affinity:** Ligand B (-7.8 kcal/mol) has a significantly stronger binding affinity than Ligand A (-8.4 kcal/mol). The difference is 0.6 kcal/mol, which is substantial.

**Overall Assessment:**

Ligand B is the more promising candidate. While both have issues with Caco-2 permeability and solubility, Ligand B has a significantly better safety profile (much lower DILI risk), better metabolic stability (lower Cl_mic), and a substantially stronger binding affinity. The slightly better BBB penetration of Ligand B also supports its selection as a CNS-targeting drug. The affinity difference outweighs the slightly worse P-gp efflux.

Output:
1
2025-04-17 03:25:32,503 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (349.431 and 346.479 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (91.65) is slightly above the optimal <90 for CNS targets, but still reasonable. Ligand B (87.89) is better, falling comfortably below 90.

**3. logP:** Ligand A (1.534) is within the optimal 1-3 range. Ligand B (3.048) is at the higher end of optimal, but still acceptable.

**4. H-Bond Donors:** Ligand A (2) and Ligand B (3) are both within the acceptable limit of <=5.

**5. H-Bond Acceptors:** Ligand A (4) and Ligand B (7) are both within the acceptable limit of <=10.

**6. QED:** Both ligands have similar QED values (0.696 and 0.647), indicating good drug-like properties.

**7. DILI:** Ligand A (38.852) has a significantly lower DILI risk than Ligand B (60.644). This is a substantial advantage for Ligand A.

**8. BBB:** Ligand B (70.803) has a better BBB penetration percentile than Ligand A (58.24). This is a crucial factor for a CNS target like DRD2.

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.008 and -5.061), which is unusual and suggests poor permeability. This is a significant concern for both.

**10. Aqueous Solubility:** Both ligands have negative solubility values (-1.567 and -4.066), indicating very poor aqueous solubility. This is a major drawback for both.

**11. hERG Inhibition:** Ligand A (0.421) shows a lower hERG inhibition liability than Ligand B (0.738), indicating a lower risk of cardiotoxicity.

**12. Microsomal Clearance:** Ligand A (-6.219) has a much lower (better) microsomal clearance than Ligand B (63.606). This suggests greater metabolic stability for Ligand A.

**13. In vitro Half-Life:** Ligand B (80.34) has a significantly longer in vitro half-life than Ligand A (21.058).

**14. P-gp Efflux:** Ligand A (0.173) has lower P-gp efflux liability than Ligand B (0.253), which is favorable for CNS penetration.

**15. Binding Affinity:** Ligand B (-7.5 kcal/mol) has a slightly better binding affinity than Ligand A (-8.2 kcal/mol). However, the difference is relatively small.

**Overall Assessment:**

While Ligand B has better BBB penetration and a longer half-life, Ligand A demonstrates superior safety profiles (lower DILI, lower hERG) and better metabolic stability (lower Cl_mic). Both have poor solubility and permeability. The slightly better affinity of Ligand B is not enough to overcome the significant safety and metabolic concerns. Given the GPCR-specific priorities, the lower DILI and better metabolic stability of Ligand A are more crucial for a CNS drug candidate.

Output:
0
2025-04-17 03:25:32,503 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (358.419 and 353.438 Da) are within the ideal 200-500 Da range.

**TPSA:** Both ligands (70.42 and 69.72) are below the 90 A^2 threshold desirable for CNS targets, which is excellent.

**logP:** Ligand A (2.974) is optimal, while Ligand B (1.243) is a bit low, potentially hindering permeability.

**H-Bond Donors/Acceptors:** Ligand A (0 HBD, 6 HBA) and Ligand B (1 HBD, 3 HBA) both have acceptable numbers of H-bond donors and acceptors.

**QED:** Both ligands have good QED scores (0.673 and 0.809), indicating drug-likeness.

**DILI:** Ligand A (77.549) has a higher DILI risk than Ligand B (23.73), which is a significant drawback.

**BBB:** Both ligands have excellent BBB penetration (57.736 and 75.998), exceeding the 70% threshold for CNS targets. Ligand B is slightly better.

**Caco-2 Permeability:** Both have negative Caco-2 values (-4.578 and -4.736) which is unusual and problematic. This suggests very poor permeability.

**Aqueous Solubility:** Both have negative solubility values (-3.536 and -2.064) which is also problematic and suggests poor solubility.

**hERG:** Both ligands have low hERG inhibition liability (0.53 and 0.189), which is good.

**Microsomal Clearance:** Ligand B (9.897) has lower microsomal clearance than Ligand A (13.841), indicating better metabolic stability.

**In vitro Half-Life:** Ligand B (9.297) has a shorter half-life than Ligand A (32.35), which is less desirable.

**P-gp Efflux:** Ligand A (0.632) has slightly higher P-gp efflux liability than Ligand B (0.032), meaning Ligand B is less likely to be pumped out of the brain. This is a significant advantage for CNS penetration.

**Binding Affinity:** Ligand B (-8.2 kcal/mol) has a significantly stronger binding affinity than Ligand A (-9.6 kcal/mol). This 1.4 kcal/mol difference is substantial and could outweigh some of the ADME drawbacks.

**Overall Assessment:**

While both ligands have issues with Caco-2 and solubility, Ligand B is the stronger candidate. Its superior binding affinity, lower DILI risk, lower P-gp efflux, and better metabolic stability outweigh the shorter half-life and slightly lower logP. The significantly improved binding affinity is a key factor, as it's a primary driver for efficacy. The lower DILI risk is also very important.

Output:
1
2025-04-17 03:25:32,503 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, considering the provided guidelines and GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (387.615 and 353.438 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (52.65) is significantly better than Ligand B (75.44). For CNS targets, we want TPSA <= 90, and ideally closer to 60. Ligand A is much closer to the ideal range.

**3. logP:** Both ligands have good logP values (2.122 and 2.407), falling within the optimal 1-3 range.

**4. H-Bond Donors:** Both have 1 HBD, which is within the acceptable limit of <= 5.

**5. H-Bond Acceptors:** Ligand A has 5 HBA, and Ligand B has 4. Both are within the acceptable limit of <= 10.

**6. QED:** Both ligands have similar and good QED values (0.757 and 0.779), indicating good drug-like properties.

**7. DILI:** Ligand A (28.112) has a slightly higher DILI risk than Ligand B (23.769), but both are below the 40 threshold and considered good.

**8. BBB:** Ligand B (86.817) has a significantly better BBB penetration percentile than Ligand A (64.482). For a CNS target like DRD2, >70 is desirable, and Ligand B is closer to this.

**9. Caco-2:** Ligand A (-5.103) and Ligand B (-4.551) both have negative Caco-2 values, which is unusual and suggests poor permeability. This is a concern for both.

**10. Solubility:** Ligand A (-3.533) and Ligand B (-2.323) both have negative solubility values, indicating poor aqueous solubility. This is a significant drawback for both.

**11. hERG:** Both ligands have low hERG inhibition liability (0.359 and 0.238), which is good.

**12. Cl_mic:** Ligand B (33.993) has significantly lower microsomal clearance than Ligand A (74.383), indicating better metabolic stability.

**13. t1/2:** Ligand B (15.072) has a much longer in vitro half-life than Ligand A (3.153), which is a significant advantage.

**14. Pgp:** Both ligands have very low P-gp efflux liability (0.072 and 0.088), which is favorable for CNS penetration.

**15. Binding Affinity:** Ligand B (-8.1 kcal/mol) has a significantly stronger binding affinity than Ligand A (-6.2 kcal/mol). This is a crucial advantage, as a >1.5 kcal/mol difference can outweigh other drawbacks.

**Overall Assessment:**

While Ligand A has a better TPSA, Ligand B excels in several critical areas for a CNS-targeting GPCR ligand: significantly better BBB penetration, much lower microsomal clearance (better metabolic stability), a longer half-life, and, most importantly, a substantially stronger binding affinity. The poor Caco-2 and solubility are concerning for both, but the strong binding affinity of Ligand B makes it more likely to overcome these issues with formulation strategies.

Output:
1
2025-04-17 03:25:32,503 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (368.434 and 349.406 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (97.11) is slightly above the ideal <90 for CNS targets, but still reasonable. Ligand B (57) is excellent, well below the threshold.

**logP:** Both ligands have good logP values (1.762 and 1.386), falling within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A has 2 HBD and 6 HBA, which are acceptable. Ligand B has 0 HBD and 4 HBA, also acceptable.

**QED:** Both ligands have identical QED scores of 0.81, indicating strong drug-like properties.

**DILI:** Ligand A has a DILI risk of 76.076, which is concerning (high risk). Ligand B has a much lower DILI risk of 15.51, which is very favorable.

**BBB:** Ligand A has a BBB penetration of 63.862, which is below the desirable >70 for CNS targets. Ligand B has a very high BBB penetration of 93.37, a significant advantage.

**Caco-2 Permeability:** Ligand A shows poor Caco-2 permeability (-5.004), suggesting poor intestinal absorption. Ligand B shows slightly poor Caco-2 permeability (-4.558).

**Aqueous Solubility:** Ligand A has a very poor aqueous solubility (-3.771). Ligand B has a slightly poor aqueous solubility (-2.017).

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.233 and 0.488).

**Microsomal Clearance:** Ligand A has a higher microsomal clearance (25.109) than Ligand B (4.371), indicating lower metabolic stability.

**In vitro Half-Life:** Ligand A has a negative half-life (-24.464), which is problematic. Ligand B has a short half-life (7.716), but is still better than Ligand A.

**P-gp Efflux:** Ligand A has a low P-gp efflux liability (0.239), which is good. Ligand B also has a low P-gp efflux liability (0.062), even better.

**Binding Affinity:** Ligand B (-9.7 kcal/mol) has a significantly stronger binding affinity than Ligand A (-7.4 kcal/mol). This >1.5 kcal/mol difference is a major advantage, potentially outweighing some ADME drawbacks.

**Overall Assessment:**

Ligand B is significantly more promising. While both ligands have acceptable MW, logP, QED, and hERG values, Ligand B excels in crucial areas for a CNS-targeting GPCR ligand: BBB penetration, DILI risk, and, most importantly, binding affinity. Ligand A's high DILI risk, poor BBB penetration, poor solubility, and negative half-life are major red flags. Although both have poor Caco-2 permeability, the strong binding affinity of Ligand B and its superior ADME properties make it the better candidate.

Output:
1
2025-04-17 03:25:32,504 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, considering the provided guidelines and GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (349.4) is slightly lower, which *could* be beneficial for permeability, but both are acceptable.

**TPSA:** Ligand A (125.8) is closer to the desirable range for CNS targets (<=90) than Ligand B (60.8), which is excellent.

**logP:** Ligand A (-0.71) is a bit low, potentially hindering membrane permeability. Ligand B (3.63) is within the optimal range (1-3). This is a significant advantage for Ligand B.

**H-Bond Donors/Acceptors:** Ligand A (1 HBD, 8 HBA) and Ligand B (2 HBD, 3 HBA) both fall within acceptable limits.

**QED:** Both ligands have similar and acceptable QED values (0.667 and 0.658).

**DILI:** Ligand A (56.8) has a higher DILI risk than Ligand B (9.3), indicating potentially greater liver toxicity. This favors Ligand B.

**BBB:** Ligand B (69.4) has a substantially better BBB penetration percentile than Ligand A (34.1). This is a *critical* advantage for a CNS target like DRD2.

**Caco-2 Permeability:** Ligand A (-5.82) shows poor Caco-2 permeability, while Ligand B (-4.41) is slightly better, but still not great.

**Aqueous Solubility:** Both ligands have very poor aqueous solubility (-0.323 and -3.676). This is a concern for both, but the lower value for Ligand B is worse.

**hERG Inhibition:** Ligand A (0.011) has a very low hERG risk, which is excellent. Ligand B (0.921) has a moderate hERG risk, which is less desirable.

**Microsomal Clearance:** Ligand A (14.78) has lower microsomal clearance than Ligand B (90.71), suggesting better metabolic stability. This favors Ligand A.

**In vitro Half-Life:** Ligand B (62.28) has a much longer in vitro half-life than Ligand A (-3.02), which is a significant advantage.

**P-gp Efflux:** Ligand A (0.011) has very low P-gp efflux, which is excellent for CNS penetration. Ligand B (0.472) has moderate P-gp efflux.

**Binding Affinity:** Ligand A (-7.2) has a slightly better binding affinity than Ligand B (-6.4), but the difference is less than 1.5 kcal/mol.

**Overall Assessment:**

Ligand B is the stronger candidate. While Ligand A has better metabolic stability and a slightly better binding affinity, Ligand B excels in key areas for CNS GPCR targets: significantly better BBB penetration, lower DILI risk, and a longer half-life. The better logP of Ligand B also supports better permeability. The poor solubility of both is a concern that would need to be addressed in formulation, but the other advantages of Ligand B outweigh the slight advantage of Ligand A in binding affinity and metabolic stability.

Output:
1
2025-04-17 03:25:32,504 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight (MW):** Both ligands (354.332 and 352.45 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (69.04) is slightly higher than Ligand B (58.64). Both are below the 90 A^2 threshold desirable for CNS targets, but B is better.

**3. logP:** Both ligands (2.497 and 2.211) are within the optimal range of 1-3.

**4. H-Bond Donors (HBD):** Both have 1 HBD, which is acceptable.

**5. H-Bond Acceptors (HBA):** Ligand A has 5 HBA, and Ligand B has 3. Both are below the 10 threshold.

**6. QED:** Ligand A (0.916) has a significantly higher QED than Ligand B (0.789), indicating better overall drug-likeness.

**7. DILI:** Ligand A (80.651) has a higher DILI risk than Ligand B (35.285). This is a significant drawback for Ligand A.

**8. BBB:** Both ligands have excellent BBB penetration (Ligand A: 87.476, Ligand B: 89.531). Ligand B is slightly better.

**9. Caco-2:** Both have negative Caco-2 values, which is unusual and suggests poor permeability. However, the scale is not specified, so it's hard to interpret.

**10. Solubility:** Both have negative solubility values, which is also unusual and suggests poor solubility. Again, the scale is not specified.

**11. hERG:** Both ligands have very low hERG inhibition risk (0.366 and 0.307).

**12. Cl_mic:** Ligand A (14.626) has a much lower microsomal clearance than Ligand B (40.197), indicating better metabolic stability.

**13. t1/2:** Ligand A (-31.162) has a negative in vitro half-life, which is not possible. Ligand B (-7.313) is also negative, indicating an issue with the data.

**14. Pgp:** Both ligands have low P-gp efflux liability (0.108 and 0.135).

**15. Binding Affinity:** Ligand B (-7.8 kcal/mol) has a slightly better binding affinity than Ligand A (-9.4 kcal/mol). Although A is better, the difference is not substantial enough to overcome its other weaknesses.

**Overall Assessment:**

Ligand B is the more promising candidate. While both have issues with Caco-2 and solubility, Ligand B has a significantly lower DILI risk, better metabolic stability (lower Cl_mic), and a slightly better binding affinity. Ligand A's high DILI risk and questionable half-life are major concerns. The slightly better TPSA and QED of Ligand A do not outweigh these drawbacks.

Output:
1
2025-04-17 03:25:32,504 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (390.452 Da) is slightly higher than Ligand B (355.429 Da), but both are acceptable.

**TPSA:** Ligand A (51.22) is better than Ligand B (61.44) for CNS penetration, being closer to the preferred <90 A^2. Ligand B is still reasonably within range, but A has an advantage.

**logP:** Ligand A (4.741) is high, potentially causing solubility issues or off-target effects. Ligand B (1.551) is much better, falling within the optimal 1-3 range. This is a significant advantage for B.

**H-Bond Donors/Acceptors:** Ligand A has 1 HBD and 5 HBA, while Ligand B has 2 HBD and 3 HBA. Both are within acceptable limits.

**QED:** Both ligands have reasonable QED scores (A: 0.742, B: 0.681), indicating good drug-like properties.

**DILI:** Ligand A (76.425) has a higher DILI risk than Ligand B (17.449). B is significantly better here.

**BBB:** Ligand A (68.864) has a moderate BBB penetration, while Ligand B (91.237) is excellent, exceeding the desirable >70 threshold. This is a major advantage for B, given the CNS target.

**Caco-2 Permeability:** Ligand A (-4.795) and Ligand B (-5.234) both have negative values, indicating poor permeability. This is a concern for both, but not a deciding factor.

**Aqueous Solubility:** Ligand A (-4.991) and Ligand B (-2.335) both have negative values, indicating poor solubility. This is a concern for both, but B is slightly better.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (A: 0.462, B: 0.65), which is good.

**Microsomal Clearance:** Ligand A (81.192) has a higher microsomal clearance, suggesting faster metabolism. Ligand B (-1.617) has a negative value, which is excellent, indicating very slow metabolism. This is a significant advantage for B.

**In vitro Half-Life:** Ligand A (-15.358) has a negative half-life, which is excellent. Ligand B (4.946) is reasonable, but not as good as A.

**P-gp Efflux:** Ligand A (0.572) has moderate P-gp efflux, while Ligand B (0.039) has very low efflux. This is a significant advantage for B, enhancing CNS exposure.

**Binding Affinity:** Ligand B (-8.2 kcal/mol) has a slightly better binding affinity than Ligand A (-7.9 kcal/mol), although the difference is small.

**Overall Assessment:**

Ligand B is the superior candidate. While Ligand A has a better in vitro half-life, Ligand B excels in critical areas for a CNS-targeting GPCR ligand: BBB penetration, logP, DILI risk, P-gp efflux, and microsomal clearance. The slightly better affinity of B further supports this conclusion. The high logP and DILI risk of Ligand A are concerning drawbacks.

Output:
1
2025-04-17 03:25:32,504 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (353.482 and 372.893 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (61.44) is significantly better than Ligand B (67.87). For CNS targets, we want TPSA <= 90, and ideally lower. Ligand A is closer to the ideal range.

**3. logP:** Both ligands have good logP values (2.383 and 2.619), falling within the optimal 1-3 range.

**4. H-Bond Donors:** Ligand A (2) is slightly higher than Ligand B (1), but both are acceptable (<=5).

**5. H-Bond Acceptors:** Ligand A (3) is slightly higher than Ligand B (4), but both are acceptable (<=10).

**6. QED:** Ligand A (0.691) has a better QED score than Ligand B (0.551), indicating a more drug-like profile.

**7. DILI:** Ligand A (13.532) has a much lower DILI risk than Ligand B (31.989). This is a significant advantage.

**8. BBB:** Ligand A (86.041) has a considerably higher BBB penetration percentile than Ligand B (73.401). This is crucial for a CNS target like DRD2.

**9. Caco-2 Permeability:** Ligand A (-4.899) has a worse Caco-2 permeability than Ligand B (-5.056). Lower values are less desirable.

**10. Aqueous Solubility:** Ligand A (-1.636) has a better aqueous solubility than Ligand B (-2.695).

**11. hERG Inhibition:** Both ligands have low hERG inhibition risk (0.607 and 0.449).

**12. Microsomal Clearance:** Ligand A (-8.323) has a much lower (better) microsomal clearance than Ligand B (20.413), suggesting better metabolic stability.

**13. In vitro Half-Life:** Ligand A (-5.671) has a better in vitro half-life than Ligand B (-4.866).

**14. P-gp Efflux:** Ligand A (0.085) has a lower P-gp efflux liability than Ligand B (0.141), which is favorable for CNS penetration.

**15. Binding Affinity:** Both ligands have excellent binding affinities (-8.0 and -7.8 kcal/mol). The difference of 0.2 kcal/mol is not substantial enough to outweigh the other advantages of Ligand A.

**Overall Assessment:**

Ligand A consistently outperforms Ligand B across several critical ADME properties, especially those prioritized for GPCRs targeting the CNS (BBB, Pgp, TPSA). It has a better QED score, significantly lower DILI risk, better metabolic stability (lower Cl_mic and better half-life), and lower P-gp efflux. While Ligand B has slightly better Caco-2 permeability, the other advantages of Ligand A are more impactful for a CNS-targeting drug. The binding affinity difference is minimal.

Output:
1
2025-04-17 03:25:32,505 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B based on the provided guidelines, prioritizing GPCR-specific properties (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (354.426 Da) is slightly preferred as it's closer to the lower end, potentially aiding permeability.

**TPSA:** Both ligands have TPSA values below 90, which is good for CNS targets. Ligand A (72.96) is slightly lower than Ligand B (69.72), a minor advantage.

**logP:** Ligand A (-0.384) is a bit low, potentially hindering permeation. Ligand B (2.324) is within the optimal range (1-3). This is a significant advantage for Ligand B.

**H-Bond Donors/Acceptors:** Both have acceptable HBD (1) and HBA (4/5) counts, falling within the guidelines.

**QED:** Both ligands have similar QED values (0.73 and 0.687), indicating good drug-likeness.

**DILI:** Ligand A (22.257) has a much lower DILI risk than Ligand B (53.044). This is a substantial advantage for Ligand A.

**BBB:** Both ligands have reasonably good BBB penetration (64.482% and 66.188%). While both are below the ideal >70%, they are comparable.

**Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and suggests poor permeability. However, the scale is not specified, so it's difficult to interpret.

**Aqueous Solubility:** Both have negative solubility values, indicating poor aqueous solubility. Ligand A (-0.939) is slightly better than Ligand B (-2.552).

**hERG:** Both ligands have low hERG inhibition liability (0.238 and 0.635), which is good.

**Microsomal Clearance:** Ligand A (-26.982) has a significantly lower (better) microsomal clearance than Ligand B (-8.816). This suggests better metabolic stability for Ligand A.

**In vitro Half-Life:** Ligand B (46.402) has a much longer in vitro half-life than Ligand A (2.678). This is a significant advantage for Ligand B.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (-8.6 and -0.065), which is favorable for CNS penetration.

**Binding Affinity:** Ligand B (-7.8 kcal/mol) has a slightly better binding affinity than Ligand A (-8.6 kcal/mol). While the difference is small, it's still a positive for Ligand B.

**Overall Assessment:**

Ligand A excels in DILI risk and microsomal clearance, suggesting a safer and more metabolically stable profile. However, its logP is suboptimal, and its in vitro half-life is very short. Ligand B has a better logP, longer half-life, and slightly better binding affinity, but it carries a higher DILI risk.

Given the GPCR target and the importance of CNS penetration, a balance is needed. The slightly better affinity and logP of Ligand B, combined with its longer half-life, outweigh the higher DILI risk, *especially* considering the relatively moderate DILI percentile (53.044). The poor solubility and Caco-2 values are concerning for both, but can potentially be addressed with formulation strategies.

Output:
1
2025-04-17 03:25:32,505 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (347.459 and 346.387 Da) fall comfortably within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (83.22) is significantly better than Ligand B (119.48). For CNS targets, we want TPSA <= 90, which Ligand A meets, while Ligand B exceeds it. This is a significant advantage for A.

**3. logP:** Both ligands have good logP values (1.788 and 1.048), falling within the optimal 1-3 range.

**4. H-Bond Donors:** Both have 3 HBD, which is acceptable.

**5. H-Bond Acceptors:** Ligand A has 3 HBA, while Ligand B has 6. Lower HBA is generally preferred for better permeability, giving a slight edge to A.

**6. QED:** Both ligands have good QED scores (0.596 and 0.645), indicating good drug-like properties.

**7. DILI:** Ligand A (38.813) has a much lower DILI risk than Ligand B (66.227). This is a substantial advantage for A.

**8. BBB:** Ligand B (72.974) has a better BBB percentile than Ligand A (47.421). While both are reasonably good, B is preferable here.

**9. Caco-2:** Ligand A (-4.719) and Ligand B (-5.237) both have negative Caco-2 values. This is unusual and suggests poor permeability. However, the scale isn't specified, so it's hard to interpret.

**10. Solubility:** Both ligands have negative solubility values (-3.071 and -3.896). Again, the scale is unclear, but negative values suggest poor solubility.

**11. hERG:** Both ligands have similar, low hERG inhibition liability (0.5 and 0.505).

**12. Cl_mic:** Ligand A (26.833) has a lower microsomal clearance than Ligand B (34.033), indicating better metabolic stability.

**13. t1/2:** Ligand A (-15.975) has a negative in vitro half-life, which is concerning. Ligand B (10.288) has a positive half-life, which is better.

**14. Pgp:** Both ligands have low Pgp efflux liability (0.193 and 0.136).

**15. Binding Affinity:** Ligand B (-8.6) has a slightly better binding affinity than Ligand A (-7.9). A difference of 0.7 kcal/mol is significant, but not overwhelming.

**Overall Assessment:**

Considering the GPCR-specific priorities, Ligand A is the better candidate. While Ligand B has a slightly better affinity and BBB penetration, Ligand A excels in TPSA, DILI risk, and metabolic stability (Cl_mic). The negative in vitro half-life of Ligand A is a concern, but the lower TPSA and DILI risk are more critical for a CNS-targeting GPCR ligand. The slightly better affinity of Ligand B might be overcome with further optimization of Ligand A.

Output:
0
2025-04-17 03:25:32,505 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (383.455 and 361.427 Da) are within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (126.07) is slightly above the optimal <90 for CNS targets, while Ligand B (106.1) is closer to the ideal range. This favors Ligand B.

**3. logP:** Both ligands have good logP values (0.985 and 1.128), falling within the 1-3 optimal range.

**4. H-Bond Donors:** Ligand A (3) and Ligand B (2) are both acceptable, being less than 5. Ligand B is slightly better.

**5. H-Bond Acceptors:** Both ligands have 7 H-bond acceptors, which is acceptable (<=10).

**6. QED:** Both ligands have good QED scores (0.679 and 0.766), indicating good drug-like properties. Ligand B is slightly better.

**7. DILI:** Ligand A (95.192) has a significantly higher DILI risk than Ligand B (69.484). This is a major drawback for Ligand A.

**8. BBB:** Both ligands have reasonable BBB penetration (54.634 and 59.403), but neither exceeds the desirable >70 for CNS targets. Ligand B is slightly better.

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.575 and -4.97), which is unusual and suggests poor permeability. This is a concern for both.

**10. Aqueous Solubility:** Both ligands have negative solubility values (-3.918 and -3.664), indicating very poor aqueous solubility. This is a significant issue for both.

**11. hERG Inhibition:** Both ligands have low hERG inhibition risk (0.198 and 0.184).

**12. Microsomal Clearance:** Ligand A (36.76) has lower microsomal clearance than Ligand B (58.375), suggesting better metabolic stability.

**13. In vitro Half-Life:** Ligand A (-35.1) has a more negative in vitro half-life than Ligand B (-25.897), which is not ideal.

**14. P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.088 and 0.027), which is favorable for CNS penetration.

**15. Binding Affinity:** Both ligands have very similar binding affinities (-8.8 and -8.3 kcal/mol), both being excellent. The difference of 0.5 kcal/mol is not enough to strongly favor one over the other.

**Overall Assessment:**

While both ligands have issues with Caco-2 permeability and aqueous solubility, Ligand B is the better candidate. It has a lower DILI risk, slightly better TPSA and QED, and a slightly better BBB score. The slightly better metabolic stability of Ligand A is outweighed by its higher DILI risk and worse TPSA. The binding affinities are comparable. Given the GPCR target and the need for CNS penetration, minimizing DILI and optimizing TPSA are crucial.

Output:
1
2025-04-17 03:25:32,506 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (350.419 and 375.491 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Both ligands have TPSA values (105.48 and 104.81) that are acceptable for oral absorption but slightly high for optimal CNS penetration (ideally <90).

**3. logP:** Ligand A (-0.174) is a bit low, potentially hindering permeation. Ligand B (0.832) is better, falling within the optimal 1-3 range.

**4. H-Bond Donors:** Ligand A (3) and Ligand B (2) are both within the acceptable limit of <=5.

**5. H-Bond Acceptors:** Ligand A (6) and Ligand B (5) are both within the acceptable limit of <=10.

**6. QED:** Both ligands have good QED scores (0.573 and 0.654), indicating drug-like properties.

**7. DILI:** Ligand A (37.069) has a lower DILI risk than Ligand B (48.313), which is preferable. Both are below the concerning threshold of 60.

**8. BBB:** Ligand B (54.866) has a significantly better BBB percentile than Ligand A (29.081). This is a *critical* advantage for a CNS target like DRD2.

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.493 and -5.205). This is unusual and suggests poor permeability. However, these values are on a scale where negative values are possible, and direct comparison is difficult without knowing the scale's specifics.

**10. Aqueous Solubility:** Both ligands have negative solubility values (-0.77 and -2.568), indicating poor solubility. This is a concern for bioavailability.

**11. hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.077 and 0.307).

**12. Microsomal Clearance:** Ligand A (-5.825) has a lower (better) microsomal clearance than Ligand B (6.791), suggesting greater metabolic stability.

**13. In vitro Half-Life:** Ligand A (27.203) has a much better in vitro half-life than Ligand B (-46.245). This is a significant advantage.

**14. P-gp Efflux:** Both ligands have very low P-gp efflux (0.006 and 0.038), which is good for CNS exposure.

**15. Binding Affinity:** Both ligands have excellent binding affinities (-7.0 and -7.6 kcal/mol). Ligand B is slightly better, but the difference is small.

**Overall Assessment:**

While Ligand A has advantages in DILI, metabolic stability (Cl_mic), and half-life, Ligand B's significantly better BBB penetration is the deciding factor for a CNS target like DRD2. The slightly better logP of Ligand B also contributes to its favorability. The poor Caco-2 and solubility for both are concerning, but the BBB is paramount for CNS drugs.

Output:
1
2025-04-17 03:25:32,506 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (364.515 Da) is slightly higher than Ligand B (345.403 Da), but both are acceptable.

**TPSA:** Ligand A (65.54) is significantly better than Ligand B (93.26). For CNS targets, we want TPSA <= 90. Ligand A is comfortably within this range, while Ligand B is slightly above, potentially hindering BBB penetration.

**logP:** Both ligands have good logP values (A: 1.84, B: 1.579), falling within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Both have 1 HBD, which is good. Ligand A has 5 HBA, and Ligand B has 6. Both are acceptable, being <= 10.

**QED:** Both have good QED scores (A: 0.764, B: 0.908), indicating good drug-like properties. Ligand B is slightly better here.

**DILI:** Ligand A (24.544) has a much lower DILI risk than Ligand B (65.568). This is a significant advantage for Ligand A.

**BBB:** Ligand A (76.309) has a considerably better BBB percentile than Ligand B (55.874). This is *critical* for a CNS target like DRD2.

**Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and suggests poor permeability. However, the scale is not specified, so it's hard to interpret.

**Aqueous Solubility:** Both have negative solubility values, which is also unusual and suggests poor solubility. Again, the scale is not specified.

**hERG:** Both ligands have very low hERG inhibition liability (A: 0.441, B: 0.145), which is excellent.

**Microsomal Clearance:** Ligand B (44.507) has a lower microsomal clearance than Ligand A (33.385), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (14.552) has a longer half-life than Ligand B (-13.133). The negative value for B is concerning.

**P-gp Efflux:** Both have very low P-gp efflux liability (A: 0.048, B: 0.032), which is excellent for CNS penetration.

**Binding Affinity:** Ligand B (-8.5 kcal/mol) has a slightly better binding affinity than Ligand A (-7.7 kcal/mol). This is a 0.8 kcal/mol difference, which is a good advantage, but not overwhelming.

**Overall Assessment:**

Considering the GPCR-specific priorities, Ligand A is the better candidate. The significantly better BBB penetration (76.3 vs 55.9), lower DILI risk (24.5 vs 65.6), and longer half-life outweigh the slightly weaker binding affinity. While Ligand B has a better QED and slightly better affinity, the poor BBB and higher DILI risk are major drawbacks for a CNS drug. The unusual negative values for Caco-2 and solubility are concerning for both, but the other factors strongly favor Ligand A.

Output:
0
2025-04-17 03:25:32,506 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (364.442 and 342.399 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (66.48) is significantly better than Ligand B (95.42). For CNS targets, we want TPSA <= 90, so Ligand A is much closer to this threshold.

**3. logP:** Both ligands have good logP values (1.946 and 1.564), falling within the optimal 1-3 range.

**4. H-Bond Donors:** Both ligands have acceptable HBD counts (1 and 2, respectively), well below the limit of 5.

**5. H-Bond Acceptors:** Ligand B (5) is better than Ligand A (3) but both are below the limit of 10.

**6. QED:** Both ligands have similar and good QED values (0.779 and 0.796), indicating good drug-like properties.

**7. DILI:** Ligand A (61.07) has a slightly higher DILI risk than Ligand B (51.493), but both are still reasonably low.

**8. BBB:** This is a critical parameter for CNS targets. Ligand A (74.292) has a significantly better BBB percentile than Ligand B (32.067). A value >70 is desirable, and Ligand A is much closer to that.

**9. Caco-2 Permeability:** Ligand A (-4.646) is better than Ligand B (-5.09). Higher values indicate better intestinal absorption.

**10. Aqueous Solubility:** Ligand A (-4.09) is better than Ligand B (-1.861). Higher values are preferred.

**11. hERG Inhibition:** Both ligands have low hERG inhibition liability (0.802 and 0.153), indicating a low risk of cardiotoxicity.

**12. Microsomal Clearance:** Ligand B (19.961) has a significantly lower microsomal clearance than Ligand A (96.234), suggesting better metabolic stability.

**13. In vitro Half-Life:** Ligand B (-16.81) has a longer half-life than Ligand A (-23.652).

**14. P-gp Efflux:** Both ligands have low P-gp efflux liability (0.238 and 0.015).

**15. Binding Affinity:** Both ligands have comparable and excellent binding affinities (-9.5 and -8.8 kcal/mol). The difference is less than 1.5 kcal/mol, so it's not a deciding factor.

**Overall Assessment:**

Ligand A clearly wins on TPSA and BBB, which are crucial for CNS GPCR targets like DRD2. While Ligand B has better metabolic stability (lower Cl_mic and longer t1/2), the superior CNS penetration potential of Ligand A outweighs this advantage. The slightly higher DILI risk for Ligand A is acceptable given its other favorable properties.

Output:
1
2025-04-17 03:25:32,507 - INFO - Batch 28 complete. Total preferences: 448
2025-04-17 03:25:32,507 - INFO - Processing batch 29/512...
2025-04-17 03:26:28,811 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (353.413 and 348.418 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (52.65) is significantly better than Ligand B (69.64). For CNS targets, we want TPSA <= 90, and A is much closer to the optimal <= 60 range. B is approaching a less desirable range.

**3. logP:** Both ligands have acceptable logP values (1.259 and 2.371), falling within the 1-3 range.

**4. H-Bond Donors:** Ligand A (1) and Ligand B (2) are both acceptable, being <= 5.

**5. H-Bond Acceptors:** Both ligands have 3 H-bond acceptors, well within the acceptable limit of <= 10.

**6. QED:** Ligand B (0.829) has a better QED score than Ligand A (0.554), indicating a more drug-like profile overall.

**7. DILI:** Both ligands have low DILI risk (18.534 and 16.712), both below the 40 threshold.

**8. BBB:** Both ligands have excellent BBB penetration (80.07 and 80.419), exceeding the desirable >70 threshold for CNS targets.

**9. Caco-2 Permeability:** Ligand A (-4.687) has a slightly better (less negative) Caco-2 permeability than Ligand B (-4.913), suggesting better intestinal absorption. However, both are quite poor, and this is not a primary concern for a CNS target.

**10. Aqueous Solubility:** Ligand A (-1.784) has better aqueous solubility than Ligand B (-3.2), which is beneficial.

**11. hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.526 and 0.328).

**12. Microsomal Clearance:** Ligand A (-18.501) has *much* better metabolic stability (lower clearance) than Ligand B (32.069). This is a significant advantage.

**13. In vitro Half-Life:** Ligand A (4.949) has a better in vitro half-life than Ligand B (-10.106).

**14. P-gp Efflux:** Ligand A (0.036) has significantly lower P-gp efflux liability than Ligand B (0.077), which is crucial for CNS penetration.

**15. Binding Affinity:** Ligand B (-9.0) has a stronger binding affinity than Ligand A (-7.4), a difference of 1.6 kcal/mol. This is a substantial advantage and can often outweigh minor ADME drawbacks.

**Overall Assessment:**

While Ligand B has a better QED and significantly stronger binding affinity, Ligand A demonstrates superior ADME properties, particularly regarding metabolic stability (Cl_mic), P-gp efflux, and TPSA. The lower TPSA and better metabolic stability of Ligand A are highly favorable for a CNS-targeting GPCR like DRD2. The difference in binding affinity is significant, but the combination of improved ADME properties, especially the lower P-gp efflux and TPSA, makes Ligand A a more promising candidate.

Output:
0
2025-04-17 03:26:28,812 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (353.482 and 352.475 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (43.86) is significantly better than Ligand B (84.5). For CNS targets, we want TPSA <= 90, and ideally closer to 60. Ligand A is well within the desirable range, while Ligand B is pushing the upper limit and could face permeability issues.

**3. logP:** Both ligands have good logP values (2.057 and 2.106), falling within the optimal 1-3 range.

**4. H-Bond Donors:** Ligand A (0) is preferable to Ligand B (2). Fewer HBDs generally improve membrane permeability.

**5. H-Bond Acceptors:** Ligand A (3) is preferable to Ligand B (4). Lower HBA counts are also generally better for permeability.

**6. QED:** Both ligands have acceptable QED values (0.777 and 0.665), indicating good drug-like properties.

**7. DILI:** Ligand A (5.894) has a much lower DILI risk than Ligand B (18.418). This is a significant advantage for Ligand A.

**8. BBB:** Ligand A (96.355) has a *much* higher BBB penetration percentile than Ligand B (56.34). This is a critical factor for a CNS target like DRD2.

**9. Caco-2:** Ligand A (-4.573) and Ligand B (-4.744) both have negative Caco-2 values, which is unusual and suggests poor permeability. However, the scale isn't specified, so it's hard to interpret.

**10. Solubility:** Both ligands have poor aqueous solubility (-1.337 and -1.825). This could be a formulation challenge, but not a deal-breaker if other properties are favorable.

**11. hERG:** Both ligands have low hERG risk (0.588 and 0.088).

**12. Cl_mic:** Ligand A (4.756) has a significantly lower microsomal clearance than Ligand B (24.288), indicating better metabolic stability.

**13. t1/2:** Ligand A (7.15) has a shorter half-life than Ligand B (8.396), but both are reasonable.

**14. Pgp:** Ligand A (0.038) has significantly lower P-gp efflux liability than Ligand B (0.06). Lower Pgp efflux is crucial for CNS penetration.

**15. Binding Affinity:** Both ligands have excellent binding affinities (-7.9 and -8.0 kcal/mol). The difference is negligible.

**Overall Assessment:**

Ligand A is clearly superior. It has better TPSA, lower HBD/HBA, significantly lower DILI risk, *much* higher BBB penetration, lower microsomal clearance, and lower P-gp efflux. While both have poor solubility, the other advantages of Ligand A, particularly its BBB penetration and lower DILI, make it the more promising drug candidate for targeting DRD2.

Output:
1
2025-04-17 03:26:28,812 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B based on the provided guidelines, prioritizing GPCR-specific properties (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (351.393 and 345.487 Da) fall within the ideal range of 200-500 Da.

**TPSA:** Ligand A (55.4) is significantly better than Ligand B (65.2). For CNS targets, TPSA should be <= 90, both are within this range, but A is closer to the optimal value.

**logP:** Both ligands have good logP values (3.606 and 3.198), falling within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A (HBD=1, HBA=3) is preferable to Ligand B (HBD=2, HBA=2) as it has fewer hydrogen bond donors, potentially improving permeability.

**QED:** Ligand B (0.831) has a higher QED score than Ligand A (0.512), suggesting a more drug-like profile overall.

**DILI:** Ligand B (27.104) has a much lower DILI risk than Ligand A (60.954). This is a significant advantage for Ligand B.

**BBB:** Ligand A (90.617) has a significantly better BBB penetration percentile than Ligand B (77.239). This is a *critical* factor for a CNS target like DRD2.

**Caco-2 Permeability:** Both have negative values, indicating poor permeability. Ligand A (-4.081) is slightly better than Ligand B (-4.796).

**Aqueous Solubility:** Both ligands have very poor aqueous solubility (-4.54 and -4.311). This could pose formulation challenges.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.445 and 0.455).

**Microsomal Clearance:** Ligand A (95.92) has a higher microsomal clearance than Ligand B (61.067), indicating lower metabolic stability.

**In vitro Half-Life:** Ligand B (-22.867) has a much longer in vitro half-life than Ligand A (-9.888). This is a significant advantage for Ligand B.

**P-gp Efflux:** Ligand A (0.329) has lower P-gp efflux than Ligand B (0.169), which is desirable for CNS penetration.

**Binding Affinity:** Ligand B (-8.4 kcal/mol) has a significantly stronger binding affinity than Ligand A (-0.0 kcal/mol). This is a major advantage, potentially outweighing some ADME drawbacks.

**Overall Assessment:**

While Ligand A has better BBB penetration and P-gp efflux, Ligand B has a much stronger binding affinity, significantly lower DILI risk, and a longer half-life. The binding affinity difference is substantial. For a GPCR target, strong binding is paramount. The lower DILI and longer half-life are also very favorable. The slightly lower BBB for Ligand B is a concern, but the superior affinity and safety profile likely compensate for this.

Output:
1
2025-04-17 03:26:28,812 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 drug candidates, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (346.515 and 346.431 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (49.41) is significantly better than Ligand B (97.12). For CNS targets, a TPSA <= 90 is preferred, and A is comfortably within this range, while B is pushing the limit.

**3. logP:** Both ligands have good logP values (3.666 and 2.204), falling within the optimal 1-3 range. Ligand A is slightly higher, which could be beneficial for membrane permeability.

**4. H-Bond Donors:** Both have acceptable HBD counts (1 and 2, respectively), well below the threshold of 5.

**5. H-Bond Acceptors:** Ligand A (2) is better than Ligand B (5), keeping within the preferred limit of 10.

**6. QED:** Both ligands have good QED scores (0.589 and 0.738), indicating good drug-like properties.

**7. DILI:** Ligand A (12.524) has a much lower DILI risk than Ligand B (45.173). This is a significant advantage for A.

**8. BBB:** Ligand A (79.721) has a better BBB penetration percentile than Ligand B (68.205). While both are reasonably good, A is closer to the desirable >70 threshold for CNS targets.

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.807 and -4.862). This is unusual and requires further investigation, but it doesn't immediately disqualify either.

**10. Aqueous Solubility:** Both ligands have negative solubility values (-3.76 and -3.254). Again, unusual and requires investigation, but not immediately disqualifying.

**11. hERG Inhibition:** Ligand A (0.434) has a lower hERG inhibition liability than Ligand B (0.048), indicating a lower risk of cardiotoxicity.

**12. Microsomal Clearance:** Ligand B (22.841) has a significantly lower microsomal clearance than Ligand A (57.464), suggesting better metabolic stability.

**13. In vitro Half-Life:** Ligand B (1.716) has a slightly longer in vitro half-life than Ligand A (-16.191). However, the negative value for A is concerning and suggests rapid degradation.

**14. P-gp Efflux:** Ligand A (0.211) has a lower P-gp efflux liability than Ligand B (0.026), which is favorable for CNS exposure.

**15. Binding Affinity:** Ligand B (-7.7 kcal/mol) has a slightly better binding affinity than Ligand A (-8.0 kcal/mol). While the difference is small, it's a positive for B.

**Overall Assessment:**

Ligand A excels in several key areas for a CNS-targeting GPCR: TPSA, BBB, DILI, hERG, and P-gp efflux. While its metabolic stability (Cl_mic and t1/2) are concerning, its superior BBB penetration, lower toxicity risk, and good binding affinity make it a more promising candidate. Ligand B has better metabolic stability and slightly better affinity, but its higher TPSA, DILI risk, and lower BBB penetration are significant drawbacks.

Output:
1
2025-04-17 03:26:28,812 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (350.463 and 353.419 Da) fall comfortably within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (83.03) is significantly better than Ligand B (104.9). For CNS targets, we want TPSA <= 90, and A is closer to this threshold.

**3. logP:** Both ligands have good logP values (1.059 and 0.737), falling within the optimal 1-3 range.

**4. H-Bond Donors:** Both have 2 HBD, which is acceptable.

**5. H-Bond Acceptors:** Ligand A has 5 HBA, while Ligand B has 6. Both are within the acceptable limit of <= 10.

**6. QED:** Both have reasonable QED scores (0.426 and 0.668), with Ligand B being slightly more drug-like.

**7. DILI:** Both have low DILI risk (27.608 and 30.748), both well below the 40 threshold.

**8. BBB:** Both have similar BBB penetration (41.993 and 43.273). While not ideal (>70 desirable), they are comparable. This is a critical factor for a CNS target like DRD2, and neither excels here.

**9. Caco-2 Permeability:** Ligand A (-5.316) has significantly better Caco-2 permeability than Ligand B (-4.727). Higher values indicate better absorption.

**10. Aqueous Solubility:** Both have poor aqueous solubility (-1.263 and -1.34). This could pose formulation challenges.

**11. hERG Inhibition:** Both have low hERG inhibition liability (0.13 and 0.466), which is good.

**12. Microsomal Clearance:** Ligand A (-4.433) has significantly lower (better) microsomal clearance than Ligand B (22.029), indicating better metabolic stability.

**13. In vitro Half-Life:** Ligand A (28.241) has a longer in vitro half-life than Ligand B (3.438).

**14. P-gp Efflux:** Ligand A (0.054) has much lower P-gp efflux than Ligand B (0.236), which is crucial for CNS penetration.

**15. Binding Affinity:** Ligand A (-7.7) has a slightly better binding affinity than Ligand B (-7.3), although both are excellent (below -7.0). The difference is 0.4 kcal/mol, which isn't huge, but is still a factor.

**Overall Assessment:**

Ligand A is superior to Ligand B. While both have acceptable MW, logP, HBD/HBA, DILI, and hERG, Ligand A demonstrates advantages in several key areas: significantly better TPSA, Caco-2 permeability, microsomal clearance, P-gp efflux, and a slightly better binding affinity. The lower TPSA and P-gp efflux are particularly important for CNS penetration, addressing a critical GPCR-specific priority. The improved metabolic stability (lower Cl_mic and longer t1/2) also contribute to its potential as a viable drug candidate.

Output:
1
2025-04-17 03:26:28,813 - INFO - Reasoning:

Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (358.873 and 392.262 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (62.46) is significantly better than Ligand B (81.33). For CNS targets, we want TPSA <= 90, and A is comfortably within that range, while B is approaching the upper limit.

**3. logP:** Both ligands have good logP values (2.664 and 1.106), falling within the optimal 1-3 range.

**4. H-Bond Donors:** Ligand A (1) and Ligand B (2) are both acceptable, being <=5.

**5. H-Bond Acceptors:** Both ligands have 4 H-bond acceptors, well within the acceptable limit of <=10.

**6. QED:** Both ligands have reasonable QED scores (0.896 and 0.736), indicating good drug-like properties.

**7. DILI:** Ligand A (59.403) has a higher DILI risk than Ligand B (47.693), but both are below the concerning threshold of 60.

**8. BBB:** Ligand A (78.48) has a significantly better BBB penetration percentile than Ligand B (63.125).  For a CNS target like DRD2, >70 is desirable, and A is closer to that goal.

**9. Caco-2 Permeability:** Both have negative values, which is unusual. Assuming these are log scale values, lower values indicate poorer permeability. Both are similarly poor.

**10. Aqueous Solubility:** Both ligands have very poor aqueous solubility (-2.36 and -2.934). This is a significant drawback for both.

**11. hERG Inhibition:** Ligand A (0.723) has a slightly higher hERG inhibition risk than Ligand B (0.341), but both are relatively low.

**12. Microsomal Clearance:** Ligand B (-30.761) has a much lower (better) microsomal clearance than Ligand A (15.652). This suggests better metabolic stability for Ligand B.

**13. In vitro Half-Life:** Ligand B (-12.708) has a much longer in vitro half-life than Ligand A (18.188). This is a significant advantage for B.

**14. P-gp Efflux:** Ligand A (0.233) has lower P-gp efflux than Ligand B (0.052), which is favorable for CNS penetration.

**15. Binding Affinity:** Ligand A (-9.9 kcal/mol) has significantly stronger binding affinity than Ligand B (-7.4 kcal/mol). This is a substantial advantage for A, potentially outweighing some of its ADME drawbacks.

**Overall Assessment:**

While Ligand B has better metabolic stability (lower Cl_mic, longer t1/2) and lower P-gp efflux, Ligand A's superior binding affinity (-9.9 vs -7.4 kcal/mol) and better BBB penetration (78.48 vs 63.125) are crucial for a CNS-targeting GPCR like DRD2. The TPSA is also more favorable for A. The solubility issues are a concern for both, but the potency advantage of A is likely to be more impactful in driving efficacy.

Output:
1
2025-04-17 03:26:28,813 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (347.342 and 344.415 Da) fall comfortably within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (84.86) is better than Ligand B (92.26). Both are below the 90 A^2 threshold for CNS targets, but A is closer to the ideal.

**3. logP:** Both ligands have good logP values (2.056 and 1.986), falling within the optimal 1-3 range.

**4. H-Bond Donors:** Ligand A (2) is slightly higher than Ligand B (1), but both are within the acceptable limit of 5.

**5. H-Bond Acceptors:** Ligand A (5) is lower than Ligand B (7), which is preferable. Both are below the 10 limit.

**6. QED:** Both ligands have good QED scores (0.592 and 0.736), indicating good drug-like properties.

**7. DILI:** Ligand A (58.589) has a higher DILI risk than Ligand B (49.128). Ligand B is preferable here.

**8. BBB:** Ligand B (63.746) has a significantly better BBB penetration percentile than Ligand A (57.852). This is a *critical* factor for a CNS target like DRD2.

**9. Caco-2 Permeability:** Ligand A (-4.841) has better Caco-2 permeability than Ligand B (-5.287), suggesting better intestinal absorption. However, for a CNS target, intestinal absorption is less critical than BBB penetration.

**10. Aqueous Solubility:** Ligand B (-1.821) has better aqueous solubility than Ligand A (-3.594).

**11. hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.694 and 0.186), which is excellent.

**12. Microsomal Clearance:** Ligand B (17.058) has significantly lower microsomal clearance than Ligand A (89.331), indicating better metabolic stability.

**13. In vitro Half-Life:** Ligand B (-8.587) has a longer in vitro half-life than Ligand A (-25.566).

**14. P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.271 and 0.354).

**15. Binding Affinity:** Both ligands have identical binding affinities (-8.5 kcal/mol), which is very strong.

**Overall Assessment:**

While Ligand A has slightly better Caco-2 permeability, Ligand B is superior in almost every other critical parameter for a CNS-targeting GPCR. Specifically, its significantly better BBB penetration (63.746 vs 57.852), lower DILI risk, lower microsomal clearance, and longer half-life make it a much more promising drug candidate. The equal binding affinity removes that as a differentiating factor.

Output:
1
2025-04-17 03:26:28,813 - INFO - Okay, let's analyze these two ligands for their potential as DRD2 drug candidates. DRD2 is a GPCR in the CNS, so BBB penetration, logP, Pgp efflux, TPSA, and binding affinity are key.

**Ligand A: [351.353, 74.69, 3.054, 2, 4, 0.839, 60.527, 76.154, -4.629, -3.538, 0.494, 43.951, 5.663, 0.076, -9.1]**

*   **MW:** 351.353 Da - Good, within the ideal range.
*   **TPSA:** 74.69 A<sup>2</sup> - Excellent, well below the 90 A<sup>2</sup> threshold for CNS targets.
*   **logP:** 3.054 - Excellent, within the optimal 1-3 range.
*   **HBD:** 2 - Good, within the acceptable limit.
*   **HBA:** 4 - Good, within the acceptable limit.
*   **QED:** 0.839 - Excellent, highly drug-like.
*   **DILI:** 60.527 - Moderate risk, slightly above the preferred <40, but not alarmingly high.
*   **BBB:** 76.154 - Very good, exceeding the 70% threshold for CNS targets.
*   **Caco-2:** -4.629 - This is a negative value, which is unusual and suggests very poor permeability. This is a significant concern.
*   **Solubility:** -3.538 - Also a negative value, indicating very poor aqueous solubility. This is a major drawback.
*   **hERG:** 0.494 - Low risk, good.
*   **Cl_mic:** 43.951 mL/min/kg - Moderate clearance, not ideal but not terrible.
*   **t1/2:** 5.663 hours - Moderate half-life.
*   **Pgp:** 0.076 - Very low efflux, excellent for CNS penetration.
*   **Affinity:** -9.1 kcal/mol - Excellent, very strong binding.

**Ligand B: [378.416, 75.27, 1.914, 2, 4, 0.821, 61.07, 75.107, -5.204, -2.903, 0.684, -11.679, -17.527, 0.176, -9.1]**

*   **MW:** 378.416 Da - Good, within the ideal range.
*   **TPSA:** 75.27 A<sup>2</sup> - Excellent, below the 90 A<sup>2</sup> threshold for CNS targets.
*   **logP:** 1.914 - Good, within the optimal range, but on the lower side.
*   **HBD:** 2 - Good, within the acceptable limit.
*   **HBA:** 4 - Good, within the acceptable limit.
*   **QED:** 0.821 - Excellent, highly drug-like.
*   **DILI:** 61.07 - Moderate risk, similar to Ligand A.
*   **BBB:** 75.107 - Very good, exceeding the 70% threshold for CNS targets.
*   **Caco-2:** -5.204 - Also a negative value, suggesting very poor permeability.
*   **Solubility:** -2.903 - Also a negative value, indicating very poor aqueous solubility.
*   **hERG:** 0.684 - Low risk, good.
*   **Cl_mic:** -11.679 mL/min/kg - Negative clearance is not physically possible and indicates a data error or unusual calculation. This is a major concern.
*   **t1/2:** -17.527 hours - Negative half-life is not physically possible and indicates a data error.
*   **Pgp:** 0.176 - Very low efflux, excellent for CNS penetration.
*   **Affinity:** -9.1 kcal/mol - Excellent, very strong binding, identical to Ligand A.

**Comparison and Decision:**

Both ligands have excellent binding affinity and good BBB penetration, which are crucial for a CNS-targeting GPCR. Both also have acceptable logP, HBD/HBA counts, QED, and Pgp efflux.  Both have moderate DILI risk. However, both ligands suffer from extremely poor predicted Caco-2 permeability and aqueous solubility (negative values). Furthermore, Ligand B has physically impossible values for clearance and half-life, indicating a significant data issue.

Despite the excellent affinity and BBB, the poor predicted permeability and solubility of both compounds are major hurdles. However, the data issues with Ligand B make it a less viable candidate. Ligand A, while also having poor predicted permeability and solubility, at least has plausible ADME properties beyond those two. It is *possible* that the negative Caco-2 and solubility values are artifacts of the prediction method, and further experimental validation might reveal better values.

Therefore, I would select **Ligand A** as the more promising candidate, but with a strong caveat that its permeability and solubility *must* be experimentally determined and improved.

1
2025-04-17 03:26:28,814 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (372.372 and 381.527 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (83.12) is better than Ligand B (80.12), both are below the 90 A^2 threshold for CNS targets, which is excellent.

**3. logP:** Ligand A (1.909) is within the optimal range (1-3), while Ligand B (2.533) is also acceptable.

**4. H-Bond Donors:** Ligand A (3) is slightly higher than Ligand B (1), but both are within the acceptable limit of <=5.

**5. H-Bond Acceptors:** Ligand A (5) is lower than Ligand B (7), both are within the acceptable limit of <=10.

**6. QED:** Both ligands have good QED scores (0.677 and 0.746, respectively), indicating good drug-like properties.

**7. DILI:** Ligand A (86.157) has a higher DILI risk than Ligand B (75.145). This is a negative for Ligand A.

**8. BBB:** Ligand A (73.75) has significantly better BBB penetration potential than Ligand B (32.416). This is a *major* advantage for a CNS target like DRD2.

**9. Caco-2 Permeability:** Ligand A (-4.627) has better Caco-2 permeability than Ligand B (-5.174), suggesting better intestinal absorption.

**10. Aqueous Solubility:** Ligand A (-3.483) has slightly better solubility than Ligand B (-3.113).

**11. hERG Inhibition:** Both ligands show low hERG inhibition risk (0.375 and 0.264, respectively).

**12. Microsomal Clearance:** Ligand B (56.106) has lower microsomal clearance than Ligand A (35.614), suggesting better metabolic stability.

**13. In vitro Half-Life:** Ligand B (51.184) has a longer in vitro half-life than Ligand A (69.445).

**14. P-gp Efflux:** Both ligands have low P-gp efflux liability (0.088 and 0.116, respectively).

**15. Binding Affinity:** Ligand A (-8.8 kcal/mol) has a significantly stronger binding affinity than Ligand B (-7.7 kcal/mol). This is a substantial advantage.

**Overall Assessment:**

While Ligand B has slightly better metabolic stability (lower Cl_mic, longer t1/2) and a lower DILI risk, Ligand A's superior BBB penetration and *much* stronger binding affinity are decisive for a CNS GPCR target like DRD2. The 1.1 kcal/mol difference in binding affinity is significant and can outweigh the minor drawbacks in DILI and metabolic stability. The excellent TPSA and logP values of both compounds are favorable.

Output:
1
2025-04-17 03:26:28,814 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (407.769 Da) is slightly higher than Ligand B (349.337 Da), but both are acceptable.

**2. TPSA:** Both ligands have TPSA values (A: 81.7, B: 85.43) that are above the optimal <90 for CNS targets, but still reasonable.

**3. logP:** Both ligands have good logP values (A: 2.861, B: 1.43), falling within the 1-3 range. Ligand A is slightly more lipophilic, which could be beneficial for membrane permeability.

**4. H-Bond Donors:** Ligand A (1 HBD) is better than Ligand B (3 HBDs). Fewer HBDs generally improve permeability.

**5. H-Bond Acceptors:** Ligand A (5 HBA) is better than Ligand B (3 HBA). Fewer HBAs generally improve permeability.

**6. QED:** Ligand B (0.781) has a better QED score than Ligand A (0.407), indicating a more drug-like profile overall.

**7. DILI Risk:** Ligand B (56.34) has a significantly lower DILI risk than Ligand A (80.962), which is a major advantage.

**8. BBB Penetration:** Ligand A (60.644) has a better BBB percentile than Ligand B (43.699). This is a critical factor for a CNS target like DRD2.

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.781 and -4.753), which is unusual and suggests poor permeability. This is a significant concern for both.

**10. Aqueous Solubility:** Both ligands have negative solubility values (-4.693 and -2.716), indicating poor aqueous solubility. This could pose formulation challenges.

**11. hERG Inhibition:** Both ligands show low hERG inhibition risk (A: 0.536, B: 0.529).

**12. Microsomal Clearance:** Ligand B (-17.779) has a significantly *lower* (better) microsomal clearance than Ligand A (74.073), indicating greater metabolic stability.

**13. In vitro Half-Life:** Ligand B (-13.164) has a longer in vitro half-life than Ligand A (10.109), which is desirable.

**14. P-gp Efflux:** Ligand A (0.211) has lower P-gp efflux than Ligand B (0.045), which is favorable for CNS exposure.

**15. Binding Affinity:** Ligand B (-9.2 kcal/mol) has a significantly stronger binding affinity than Ligand A (-7.5 kcal/mol). This is a substantial advantage, potentially outweighing some of the ADME drawbacks.

**Overall Assessment:**

While Ligand A has better BBB penetration and P-gp efflux, Ligand B has a significantly better binding affinity, lower DILI risk, better metabolic stability (lower Cl_mic, longer t1/2), and a better QED score. The strong binding affinity of Ligand B is a major advantage for a GPCR target. The poor Caco-2 and solubility for both are concerning, but can potentially be addressed with formulation strategies. The lower DILI risk for Ligand B is also a significant factor. Given the GPCR-specific priorities, the strong affinity and improved safety profile of Ligand B make it the more promising candidate despite the permeability/solubility concerns.

Output:
1
2025-04-17 03:26:28,814 - INFO - Reasoning:

Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (372.418 and 351.451 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Both ligands have TPSA values (88.1 and 82.86) below the 90 threshold for CNS targets, which is excellent.

**3. logP:** Ligand A (0.453) is slightly below the optimal 1-3 range, potentially hindering permeability. Ligand B (-0.635) is even lower, raising more concerns about membrane penetration.

**4. H-Bond Donors:** Both ligands have 2 HBD, which is within the acceptable limit of <=5.

**5. H-Bond Acceptors:** Ligand A has 5 HBA, and Ligand B has 7 HBA. Both are within the acceptable limit of <=10.

**6. QED:** Both ligands have similar QED values (0.784 and 0.751), indicating good drug-like properties.

**7. DILI:** Ligand A (45.25) has a slightly higher DILI risk than Ligand B (23.497), but both are below the concerning threshold of 60.

**8. BBB:** This is a crucial parameter for a CNS target like DRD2. Ligand A has a BBB percentile of 70.919, which is desirable (>70). Ligand B has a significantly lower BBB percentile of 31.02, which is a major drawback.

**9. Caco-2 Permeability:** Ligand A (-4.679) and Ligand B (-5.213) both have negative Caco-2 values, which is unusual and suggests poor permeability. However, these values are on a scale where negative values are possible and don't necessarily indicate a complete barrier.

**10. Aqueous Solubility:** Ligand A (-1.553) and Ligand B (0.264) both have low solubility.

**11. hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.225 and 0.201).

**12. Microsomal Clearance:** Ligand A (-8.052) has a lower (better) microsomal clearance than Ligand B (-44.356), indicating greater metabolic stability.

**13. In vitro Half-Life:** Ligand A (28.788) has a longer half-life than Ligand B (23.212).

**14. P-gp Efflux:** Ligand A (0.072) has lower P-gp efflux than Ligand B (0.007), which is favorable for CNS penetration.

**15. Binding Affinity:** Ligand A (-8.4 kcal/mol) has a significantly stronger binding affinity than Ligand B (-7.1 kcal/mol). This 1.3 kcal/mol difference is substantial and can outweigh some of the ADME drawbacks.

**Overall Assessment:**

Ligand A is the superior candidate. While both have some ADME concerns (low logP, solubility, and Caco-2 permeability), Ligand A's significantly better BBB penetration, metabolic stability (lower Cl_mic), longer half-life, lower P-gp efflux, and *much* stronger binding affinity make it the more promising drug candidate for targeting DRD2. The strong affinity is particularly important for a GPCR target, and the better BBB score is critical for CNS activity.



Output:
1
2025-04-17 03:26:28,814 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (367.431 and 375.313 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (116.42) is higher than the preferred <90 for CNS targets, while Ligand B (52.65) is excellent. This is a significant advantage for Ligand B.

**logP:** Ligand A (0.023) is quite low, potentially hindering membrane permeability. Ligand B (1.191) is within the optimal 1-3 range. This favors Ligand B.

**H-Bond Donors/Acceptors:** Ligand A has 3 HBD and 5 HBA, acceptable values. Ligand B has 1 HBD and 3 HBA, also acceptable and slightly more favorable due to lower counts.

**QED:** Both ligands have good QED scores (0.689 and 0.735), indicating good drug-like properties.

**DILI:** Ligand A (75.378) has a higher DILI risk than Ligand B (37.03). This is a clear advantage for Ligand B.

**BBB:** Both ligands have reasonably good BBB penetration (52.85% and 71.733%), but Ligand B is significantly better, exceeding the 70% threshold desirable for CNS targets.

**Caco-2 Permeability:** Ligand A (-5.346) has poor Caco-2 permeability, while Ligand B (-4.781) is better, though still not ideal.

**Aqueous Solubility:** Ligand A (-2.523) and Ligand B (-1.698) both have poor aqueous solubility.

**hERG:** Ligand A (0.139) has a slightly lower hERG risk than Ligand B (0.479), but both are relatively low.

**Microsomal Clearance:** Ligand A (-5.935) has lower (better) microsomal clearance than Ligand B (-1.583), suggesting greater metabolic stability.

**In vitro Half-Life:** Ligand A (-49.152) has a longer half-life than Ligand B (-15.485), which is a positive attribute.

**P-gp Efflux:** Ligand A (0.004) has very low P-gp efflux, which is excellent for CNS penetration. Ligand B (0.009) is also low, but slightly higher.

**Binding Affinity:** Ligand B (-9.1 kcal/mol) has a significantly stronger binding affinity than Ligand A (-8.5 kcal/mol). This >1.5 kcal/mol difference is a major advantage for Ligand B, potentially outweighing some of its ADME drawbacks.

**Overall Assessment:**

Ligand B is the superior candidate. While Ligand A has better metabolic stability and P-gp efflux, Ligand B excels in the critical GPCR-specific properties: TPSA, logP, BBB penetration, and, most importantly, binding affinity. The lower DILI risk is also a significant benefit. The slightly lower solubility and Caco-2 permeability of Ligand B are less concerning given the target is a CNS GPCR where BBB penetration is paramount.

Output:
1
2025-04-17 03:26:28,814 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (347.39 and 345.443 Da) fall comfortably within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (80.32) is better than Ligand B (75.44). Both are below the 90 A^2 threshold desirable for CNS targets, which is good.

**3. logP:** Ligand B (2.317) is within the optimal 1-3 range, while Ligand A (0.765) is slightly below 1. This is a significant drawback for Ligand A, as lower logP can hinder membrane permeability.

**4. H-Bond Donors:** Ligand A (2) is slightly higher than Ligand B (1), but both are within the acceptable limit of <=5.

**5. H-Bond Acceptors:** Both ligands have 4 H-bond acceptors, well within the acceptable limit of <=10.

**6. QED:** Both ligands have good QED scores (0.681 and 0.803), indicating good drug-like properties.

**7. DILI:** Both ligands have low DILI risk (33.695 and 34.161 percentiles), which is favorable.

**8. BBB:** Both ligands have excellent BBB penetration (76.658 and 73.905 percentiles), which is critical for a CNS target like DRD2.

**9. Caco-2 Permeability:** Ligand A (-4.528) has a worse Caco-2 permeability than Ligand B (-5.055). Both are quite poor.

**10. Aqueous Solubility:** Ligand A (-2.279) has slightly better solubility than Ligand B (-2.611), but both are poor.

**11. hERG Inhibition:** Both ligands show very low hERG inhibition risk (0.093 and 0.127 percentiles).

**12. Microsomal Clearance:** Ligand A (8.919 mL/min/kg) has significantly lower microsomal clearance than Ligand B (45.913 mL/min/kg), suggesting better metabolic stability.

**13. In vitro Half-Life:** Ligand A (-5.49 hours) has a much longer half-life than Ligand B (-14.69 hours).

**14. P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.008 and 0.185 percentiles), which is good for CNS penetration.

**15. Binding Affinity:** Ligand B (-8.6 kcal/mol) has a stronger binding affinity than Ligand A (-7.3 kcal/mol). The difference is 1.3 kcal/mol, which is substantial.

**Overall Assessment:**

While Ligand A has better metabolic stability (lower Cl_mic, longer t1/2) and slightly better solubility, its significantly lower logP is a major concern. This will likely translate to poor membrane permeability and reduced CNS exposure, despite the good BBB percentile. Ligand B, despite having higher Cl_mic and shorter half-life, has a much better logP and a significantly stronger binding affinity. The 1.3 kcal/mol difference in binding affinity is likely to outweigh the ADME drawbacks of Ligand B, especially given the acceptable BBB penetration and low P-gp efflux.

Output:
1
2025-04-17 03:26:28,815 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (379.913 and 365.455 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (71.09) is excellent, well below the 90 A^2 threshold for CNS targets. Ligand B (78.95) is still reasonable but less optimal.

**3. logP:** Ligand A (4.387) is slightly high, potentially leading to solubility issues or off-target interactions. Ligand B (2.183) is within the optimal 1-3 range.

**4. H-Bond Donors:** Ligand A (2) and Ligand B (1) are both acceptable, well below the 5 limit.

**5. H-Bond Acceptors:** Ligand A (4) and Ligand B (5) are both acceptable, below the 10 limit.

**6. QED:** Both ligands have good QED scores (0.749 and 0.83), indicating drug-like properties.

**7. DILI:** Both ligands have relatively high DILI risk (76.425 and 75.417), but these values are close and not a major differentiator.

**8. BBB:** Both ligands have good BBB penetration (61.497 and 77.705). Ligand B is better, exceeding 70% which is desirable for CNS targets.

**9. Caco-2:** Both ligands have negative Caco-2 values (-4.772 and -4.513). This is unusual and suggests poor permeability. However, these values are close and may not be reliable.

**10. Solubility:** Both ligands have very poor aqueous solubility (-5.299 and -3.274). This is a significant concern, especially given Ligand A's higher logP.

**11. hERG:** Both ligands have low hERG inhibition risk (0.562 and 0.326).

**12. Cl_mic:** Ligand A (66.061) has a lower microsomal clearance than Ligand B (75.222), suggesting better metabolic stability.

**13. t1/2:** Ligand A (89.864) has a much longer in vitro half-life than Ligand B (4.154), which is a significant advantage.

**14. Pgp:** Ligand A (0.446) has lower P-gp efflux liability than Ligand B (0.11), which is favorable for CNS penetration.

**15. Binding Affinity:** Ligand B (-8.0 kcal/mol) has a significantly stronger binding affinity than Ligand A (-7.7 kcal/mol). This 0.3 kcal/mol difference is substantial and could outweigh some of the ADME drawbacks.

**Overall Assessment:**

Ligand B has a better logP and BBB penetration, and *significantly* better binding affinity. However, Ligand A has better metabolic stability (lower Cl_mic, longer t1/2) and lower P-gp efflux. Both have poor solubility and moderate DILI risk. Given the importance of affinity for GPCRs, and the substantial difference in binding energy, Ligand B is the more promising candidate. While the solubility is a concern, it might be addressed through formulation strategies. The improved BBB and affinity are key advantages for a CNS target like DRD2.

Output:
1
2025-04-17 03:26:28,815 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (350.463 and 340.467 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (87.46) is better than Ligand B (44.12). Both are below the 90 A^2 threshold for CNS targets, but Ligand B is significantly lower, which is favorable.

**3. logP:** Ligand A (2.156) is within the optimal 1-3 range. Ligand B (4.475) is higher, potentially leading to solubility issues and off-target interactions.

**4. H-Bond Donors:** Ligand A (2) is reasonable, while Ligand B (0) is also acceptable.

**5. H-Bond Acceptors:** Ligand A (5) is good, and Ligand B (4) is also good.

**6. QED:** Both ligands have similar QED values (0.714 and 0.754), indicating good drug-like properties.

**7. DILI:** Ligand A (45.677) has a slightly higher DILI risk than Ligand B (35.595), but both are below the concerning threshold of 60.

**8. BBB:** Ligand B (75.998) has a significantly better BBB penetration percentile than Ligand A (62.621). This is a crucial advantage for a CNS target like DRD2.

**9. Caco-2 Permeability:** Ligand A (-4.748) has a worse Caco-2 permeability than Ligand B (-4.499).

**10. Aqueous Solubility:** Ligand A (-3.316) has a better aqueous solubility than Ligand B (-6.217).

**11. hERG Inhibition:** Both ligands have low hERG inhibition risk (0.187 and 0.4).

**12. Microsomal Clearance:** Ligand B (100.471) has a higher microsomal clearance than Ligand A (81.155), indicating faster metabolism and potentially lower *in vivo* exposure.

**13. In vitro Half-Life:** Ligand A (-21.582) has a longer in vitro half-life than Ligand B (-9.609).

**14. P-gp Efflux:** Ligand A (0.196) has a lower P-gp efflux liability than Ligand B (0.294), which is desirable for CNS penetration.

**15. Binding Affinity:** Ligand B (-8.4 kcal/mol) has a slightly better binding affinity than Ligand A (-7.2 kcal/mol). The difference is 1.2 kcal/mol, which is substantial enough to consider.

**Overall Assessment:**

Ligand B is the better candidate. While Ligand A has better solubility and metabolic stability, Ligand B excels in the most critical areas for a CNS GPCR target: BBB penetration and binding affinity. The higher logP of Ligand B is a minor concern, but the significantly improved BBB and binding outweigh this drawback. The difference in binding affinity is also significant.

Output:
1
2025-04-17 03:26:28,815 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (374.453 and 361.511 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (69.64) is slightly higher than Ligand B (56.67). Both are below the 90 A^2 threshold desirable for CNS targets, but Ligand B is better.

**3. logP:** Both ligands have good logP values (1.538 and 2.594), falling within the optimal 1-3 range.

**4. H-Bond Donors:** Ligand A (2) and Ligand B (1) are both within the acceptable limit of <=5. Ligand B is slightly better.

**5. H-Bond Acceptors:** Ligand A (4) and Ligand B (5) are both within the acceptable limit of <=10.

**6. QED:** Both ligands have similar QED values (0.786 and 0.785), indicating good drug-likeness.

**7. DILI:** Ligand A (39.201) has a slightly higher DILI risk than Ligand B (18.883). Ligand B is significantly better here.

**8. BBB:** Ligand B (77.976) has a significantly better BBB penetration percentile than Ligand A (69.717). This is a crucial factor for a CNS target like DRD2.

**9. Caco-2 Permeability:** Both have negative values (-4.997 and -4.804). This is unusual and suggests a potential issue with the data or the model used to predict it. We'll proceed cautiously, but it doesn't immediately disqualify either.

**10. Aqueous Solubility:** Both have negative values (-2.791 and -2.669). Similar to Caco-2, this is concerning and needs further investigation.

**11. hERG Inhibition:** Ligand A (0.287) has a slightly lower hERG inhibition liability than Ligand B (0.637), which is preferable.

**12. Microsomal Clearance:** Ligand A (-14.244) has a much lower (better) microsomal clearance than Ligand B (58.933), indicating greater metabolic stability.

**13. In vitro Half-Life:** Ligand B (38.389) has a significantly longer in vitro half-life than Ligand A (1.226).

**14. P-gp Efflux:** Ligand A (0.042) has a much lower P-gp efflux liability than Ligand B (0.34), which is highly desirable for CNS penetration.

**15. Binding Affinity:** Both ligands have excellent binding affinities (-7.1 and -7.0 kcal/mol). The difference is minimal.

**Overall Assessment:**

While Ligand A has better hERG and P-gp properties, and significantly better metabolic stability, Ligand B shines in terms of BBB penetration, DILI risk, and in vitro half-life. Given the CNS target (DRD2), BBB penetration is paramount. The lower DILI risk of Ligand B is also a significant advantage. The slightly longer half-life is also beneficial. The negative Caco-2 and solubility values are concerning for both, but the strong affinity and favorable BBB of Ligand B outweigh these concerns.

Output:
1
2025-04-17 03:26:28,815 - INFO - Batch 29 complete. Total preferences: 464
2025-04-17 03:26:28,815 - INFO - Processing batch 30/512...
2025-04-17 03:27:11,037 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (349.5 and 357.5 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (52.65) is significantly better than Ligand B (71.09). For CNS targets, we want TPSA <= 90, and A is comfortably within that range, while B is approaching the upper limit.

**logP:** Both ligands have good logP values (2.262 and 3.056), falling within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A (HBD=1, HBA=3) and Ligand B (HBD=2, HBA=4) both have acceptable numbers of H-bond donors and acceptors, well below the thresholds of 5 and 10, respectively.

**QED:** Both ligands have similar and good QED values (0.767 and 0.799), indicating good drug-like properties.

**DILI:** Ligand A (7.057) has a much lower DILI risk than Ligand B (59.287). This is a significant advantage for A.

**BBB:** Ligand A (82.9) has a substantially better BBB penetration percentile than Ligand B (68.554). This is *critical* for a CNS target like DRD2, and A is much closer to the desirable >70 threshold.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.797 and -4.968). These values are unusual, and likely represent a scaling issue or error in the data. We cannot reliably compare based on this metric.

**Aqueous Solubility:** Both ligands have negative solubility values (-2.442 and -4.585). Similar to Caco-2, these values are problematic and cannot be used for comparison.

**hERG:** Both ligands have low hERG inhibition liability (0.675 and 0.626), indicating a low risk of cardiotoxicity.

**Microsomal Clearance:** Ligand A (44.33) has lower microsomal clearance than Ligand B (65.218), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (-14.955) has a much longer in vitro half-life than Ligand B (4.817). This is a significant advantage for A.

**P-gp Efflux:** Ligand A (0.086) has significantly lower P-gp efflux liability than Ligand B (0.251), which is favorable for CNS penetration.

**Binding Affinity:** Ligand B (-9.5) has a slightly better binding affinity than Ligand A (-8.2). However, the difference is 1.3 kcal/mol, which, while noticeable, isn't large enough to overcome the substantial ADME advantages of Ligand A.

**Overall:** Considering all factors, especially the GPCR-specific priorities, Ligand A is the superior candidate. It has better TPSA, significantly lower DILI risk, much better BBB penetration, lower P-gp efflux, better metabolic stability (lower Cl_mic, longer t1/2), and while its binding affinity is slightly lower, the ADME advantages are substantial enough to outweigh this difference. The problematic solubility and Caco-2 values for both ligands are a concern, but the relative differences between the two are unknown.

Output:
0
2025-04-17 03:27:11,038 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B based on the provided guidelines, prioritizing GPCR-specific properties (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (344.411 and 348.399 Da) fall within the ideal 200-500 Da range.

**TPSA:** Both ligands have a TPSA of 82.81, which is acceptable but pushing the upper limit for CNS penetration (ideally <90).

**logP:** Ligand A (2.792) is optimal, while Ligand B (1.711) is slightly lower, potentially impacting permeability.

**H-Bond Donors/Acceptors:** Ligand A (2 HBD, 5 HBA) and Ligand B (1 HBD, 7 HBA) both have reasonable numbers of H-bond donors and acceptors.

**QED:** Ligand A (0.755) has a better QED score than Ligand B (0.658), indicating a more drug-like profile.

**DILI:** Ligand A (74.603) has a significantly higher DILI risk than Ligand B (26.483). This is a major concern for Ligand A.

**BBB:** Ligand A (51.725) has a better BBB percentile than Ligand B (38.232), which is crucial for a CNS target like DRD2.

**Caco-2 Permeability:** Ligand A (-4.849) shows poorer Caco-2 permeability than Ligand B (-4.588), suggesting lower intestinal absorption.

**Aqueous Solubility:** Ligand A (-4.517) has slightly better solubility than Ligand B (-1.879).

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.879 and 0.569, respectively).

**Microsomal Clearance:** Ligand B (56.17) has slightly higher microsomal clearance than Ligand A (52.742), suggesting potentially lower metabolic stability.

**In vitro Half-Life:** Ligand A (-17.124) has a longer in vitro half-life than Ligand B (-24.762).

**P-gp Efflux:** Ligand A (0.406) has lower P-gp efflux than Ligand B (0.304), which is favorable for CNS exposure.

**Binding Affinity:** Ligand A (-8.9 kcal/mol) has a significantly stronger binding affinity than Ligand B (-7.9 kcal/mol). This 1.0 kcal/mol difference is substantial and could outweigh some ADME drawbacks.

**Overall Assessment:**

Ligand A has a significantly better binding affinity and BBB penetration, and lower P-gp efflux, which are critical for a CNS-targeting GPCR. However, its higher DILI risk and poorer Caco-2 permeability are significant concerns. Ligand B has a much better safety profile (lower DILI) but weaker affinity and poorer BBB penetration.

Given the strong affinity advantage of Ligand A and the importance of BBB penetration for a CNS target, I would initially favor Ligand A, *with the caveat that the DILI risk needs to be thoroughly investigated and mitigated through structural modifications if possible*. The substantial binding affinity difference could allow for a lower dose, potentially reducing the DILI risk.

Output:
1
2025-04-17 03:27:11,038 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (350.478 and 367.475 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (41.57) is significantly better than Ligand B (89.87). For CNS targets, we want TPSA <= 90, and A is comfortably within that range, while B is approaching the upper limit.

**logP:** Ligand A (4.058) is good, slightly higher than optimal but acceptable. Ligand B (-0.085) is quite low, potentially hindering membrane permeability and CNS penetration.

**H-Bond Donors/Acceptors:** Both have acceptable HBD counts (1). Ligand B has a higher HBA count (7) compared to A (3), which is less ideal but not a major concern.

**QED:** Both ligands have good QED scores (0.683 and 0.8), indicating good drug-like properties.

**DILI:** Ligand A (9.151) has a much lower DILI risk than Ligand B (37.999). This is a significant advantage for A.

**BBB:** Ligand A (85.111) has a much higher BBB penetration percentile than Ligand B (64.25). This is *critical* for a CNS target like DRD2.

**Caco-2 Permeability:** Both have negative Caco-2 values (-4.668 and -4.896), which is unusual and suggests poor permeability. However, these values are on a log scale, and the absolute difference is small.

**Aqueous Solubility:** Both have negative solubility values (-2.201 and -1.724), indicating poor solubility. This is a concern, but formulation strategies can sometimes mitigate this.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.95 and 0.478).

**Microsomal Clearance:** Ligand A (16.384) has lower microsomal clearance than Ligand B (26.971), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (6.215) has a longer half-life than Ligand B (-1.548).

**P-gp Efflux:** Ligand A (0.444) has lower P-gp efflux liability than Ligand B (0.12). Lower P-gp efflux is beneficial for CNS penetration.

**Binding Affinity:** Ligand B (-7.9) has a slightly better binding affinity than Ligand A (-8.6). However, the difference is relatively small (0.7 kcal/mol) and can be outweighed by other factors.

**Overall Assessment:**

Ligand A is significantly better overall. It excels in crucial areas for a CNS-targeting GPCR ligand: TPSA, BBB penetration, DILI risk, metabolic stability, and P-gp efflux. While Ligand B has slightly better binding affinity, the differences in ADME properties, particularly BBB and logP, are substantial enough to favor Ligand A. The negative Caco-2 and solubility values are concerns for both, but these can potentially be addressed during formulation.



Output:
0
2025-04-17 03:27:11,038 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (347.419 and 353.383 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (102.05) is better than Ligand B (130.48). For CNS targets, we want TPSA <= 90, so Ligand A is closer to this threshold. Ligand B is significantly higher.

**logP:** Ligand A (1.399) is within the optimal 1-3 range. Ligand B (-1.909) is below 1, which could hinder permeation.

**H-Bond Donors/Acceptors:** Ligand A (HBD=2, HBA=6) and Ligand B (HBD=3, HBA=7) are both acceptable, within the guidelines of <=5 HBD and <=10 HBA.

**QED:** Ligand A (0.751) has a better QED score than Ligand B (0.444), indicating better overall drug-likeness.

**DILI:** Both ligands have similar DILI risk (Ligand A: 51.687, Ligand B: 52.617), and are both below the concerning threshold of 60.

**BBB:** Ligand B (70.648) has a considerably higher BBB penetration percentile than Ligand A (46.568). This is a *critical* advantage for a CNS target like DRD2.

**Caco-2 Permeability:** Both have negative Caco-2 values (-5.423 and -5.418), which is unusual and suggests poor permeability. This is a significant drawback for both.

**Aqueous Solubility:** Both have negative solubility values (-1.451 and -0.977), which is also unusual and suggests poor solubility. This is a significant drawback for both.

**hERG Inhibition:** Ligand A (0.402) has a lower hERG inhibition risk than Ligand B (0.086), which is preferable.

**Microsomal Clearance:** Ligand B (-4.495) has a *much* lower (better) microsomal clearance than Ligand A (14.059), indicating greater metabolic stability.

**In vitro Half-Life:** Ligand B (21.964) has a significantly longer half-life than Ligand A (13.116).

**P-gp Efflux:** Ligand A (0.083) has a lower P-gp efflux liability than Ligand B (0.008), which is better for CNS exposure.

**Binding Affinity:** Ligand B (-7.2 kcal/mol) has a slightly better binding affinity than Ligand A (-8.3 kcal/mol). While A is better, the difference is not substantial enough to overcome other issues.

**Overall Assessment:**

Ligand B excels in BBB penetration and metabolic stability (lower Cl_mic, longer t1/2), both crucial for CNS GPCR targets. It also has a slightly better binding affinity. However, it suffers from a lower logP and higher TPSA. Ligand A has better TPSA, logP, hERG, and P-gp efflux, but its BBB penetration is significantly lower and its metabolic stability is poor.

Given the importance of BBB penetration for a CNS target like DRD2, and the substantial difference in this parameter, Ligand B is the more promising candidate *despite* its slightly less favorable TPSA and logP. The improved metabolic stability is also a significant benefit. The poor Caco-2 and solubility are concerning for both, but can be addressed with formulation strategies.

Output:
1
2025-04-17 03:27:11,038 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (348.531 Da) is slightly lower, which could be beneficial for permeability. Ligand B (395.516 Da) is also well within range.

**TPSA:** Ligand A (49.41) is excellent, well below the 90 A^2 threshold for CNS targets. Ligand B (45.23) is also very good, falling below the threshold.

**logP:** Both ligands have logP values within the optimal range (1-3). Ligand A (3.894) is nearing the upper limit, while Ligand B (4.206) is slightly above, potentially raising concerns about solubility and off-target effects, but not critically.

**H-Bond Donors/Acceptors:** Both ligands have a reasonable number of HBD (1) and HBA (Ligand A: 2, Ligand B: 5), staying within the recommended limits.

**QED:** Both ligands have acceptable QED values (Ligand A: 0.39, Ligand B: 0.784). Ligand B's QED is significantly better, indicating a more drug-like profile.

**DILI:** Ligand A (15.471) has a much lower DILI risk than Ligand B (46.685), which is a significant advantage.

**BBB:** Both ligands exhibit good BBB penetration (Ligand A: 72.354, Ligand B: 79.992), exceeding the 70% threshold for CNS targets. Ligand B is slightly better.

**Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and suggests poor permeability. Ligand A (-4.522) is worse than Ligand B (-5.031).

**Aqueous Solubility:** Both ligands have negative solubility values, which is also unusual and suggests poor solubility. Ligand A (-3.892) is slightly better than Ligand B (-4.697).

**hERG Inhibition:** Both ligands show low hERG inhibition risk (Ligand A: 0.624, Ligand B: 0.567).

**Microsomal Clearance:** Ligand A (96.167) has a significantly higher microsomal clearance than Ligand B (30.688), suggesting lower metabolic stability. This is a major disadvantage for Ligand A.

**In vitro Half-Life:** Ligand A (-6.585) has a negative half-life, which is not possible. This is a major red flag. Ligand B (-1.335) is also negative, but less so.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (Ligand A: 0.528, Ligand B: 0.17). Ligand B is better.

**Binding Affinity:** Ligand B (-6.8 kcal/mol) has a significantly stronger binding affinity than Ligand A (-0.0 kcal/mol). This is a crucial difference, as a >1.5 kcal/mol advantage can outweigh other drawbacks.

**Overall Assessment:**

Ligand B is clearly superior. While both have issues with Caco-2 and solubility, Ligand B has a much better QED, significantly better binding affinity, lower P-gp efflux, lower microsomal clearance, and a lower DILI risk. Ligand A has a problematic negative half-life and very weak binding affinity. The strong affinity of Ligand B is the most important factor, and the other advantages outweigh the slight concerns about logP.

Output:
1
2025-04-17 03:27:11,039 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (343.431 and 350.419 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (88.91) is excellent, falling well below the 90 A^2 threshold for CNS targets. Ligand B (113.33) is still reasonable but less optimal, being above 100.

**logP:** Ligand A (2.316) is within the optimal 1-3 range. Ligand B (0.453) is quite low, potentially hindering membrane permeability and CNS penetration.

**H-Bond Donors/Acceptors:** Ligand A (HBD=2, HBA=5) and Ligand B (HBD=3, HBA=5) both have acceptable numbers of H-bond donors and acceptors.

**QED:** Both ligands have reasonable QED values (A: 0.807, B: 0.598), indicating good drug-like properties.

**DILI:** Ligand A (58.24) has a slightly higher DILI risk than Ligand B (39.046), but both are below the concerning threshold of 60.

**BBB:** Ligand A (57.193) has a better BBB penetration percentile than Ligand B (47.15), though both are below the ideal >70 for CNS targets.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values which is unusual and suggests issues with the data or modeling.

**Aqueous Solubility:** Both ligands have negative solubility values which is unusual and suggests issues with the data or modeling.

**hERG:** Both ligands have very low hERG inhibition liability (A: 0.267, B: 0.075), which is excellent.

**Microsomal Clearance:** Ligand A (29.599) has a higher microsomal clearance than Ligand B (3.734), indicating lower metabolic stability.

**In vitro Half-Life:** Ligand A (38.265) has a longer in vitro half-life than Ligand B (5.276).

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (A: 0.024, B: 0.018), which is desirable.

**Binding Affinity:** Ligand B (-8.1 kcal/mol) has a significantly stronger binding affinity than Ligand A (-7.5 kcal/mol). This >1.5 kcal/mol difference is substantial and can outweigh some ADME drawbacks.

**Overall Assessment:**

While Ligand A has better TPSA and a slightly better DILI profile, Ligand B's significantly stronger binding affinity (-8.1 vs -7.5 kcal/mol) is a major advantage, especially for a GPCR target. The lower logP of Ligand B is a concern, but the strong binding may compensate. The unusual negative values for Caco-2 and solubility are concerning and would need further investigation, but the other properties are more favorable for Ligand B. Given the GPCR-specific emphasis on affinity, Ligand B is the more promising candidate.

Output:
1
2025-04-17 03:27:11,039 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (349.435 and 352.475 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (79.7) is better than Ligand B (66.92). Both are below the 90 A^2 threshold for CNS targets, which is excellent.

**logP:** Ligand A (-0.601) is a bit low, potentially hindering permeability. Ligand B (1.866) is within the optimal 1-3 range. This is a significant advantage for Ligand B.

**H-Bond Donors/Acceptors:** Ligand A has 1 HBD and 6 HBA, while Ligand B has 0 HBD and 4 HBA. Both are within acceptable ranges.

**QED:** Both ligands have similar QED values (0.768 and 0.701), indicating good drug-likeness.

**DILI:** Ligand A (35.479) has a slightly higher DILI risk than Ligand B (12.33). Both are below the concerning 60 threshold, but lower is better.

**BBB:** This is a critical parameter for a CNS target like DRD2. Ligand B (86.002) has a significantly higher BBB penetration percentile than Ligand A (25.475). This is a major advantage for Ligand B.

**Caco-2 Permeability:** Ligand A (-4.921) shows poor Caco-2 permeability, while Ligand B (-4.397) is slightly better, but still not ideal.

**Aqueous Solubility:** Ligand A (-0.109) has slightly better solubility than Ligand B (-1.152), but both are quite poor.

**hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.082 and 0.201).

**Microsomal Clearance:** Ligand A (-24.598) has a much lower (better) microsomal clearance than Ligand B (34.66). This suggests better metabolic stability for Ligand A.

**In vitro Half-Life:** Ligand A (7.995) has a slightly longer half-life than Ligand B (-7.121).

**P-gp Efflux:** Ligand A (0.004) has very low P-gp efflux, which is excellent. Ligand B (0.041) also has low P-gp efflux, but slightly higher than Ligand A.

**Binding Affinity:** Ligand A (-7.6) has a slightly stronger binding affinity than Ligand B (-7.1). While both are good, the 0.5 kcal/mol difference is notable.

**Overall Assessment:**

Ligand B excels in key areas for a CNS-targeting GPCR ligand: BBB penetration and logP. While Ligand A has better metabolic stability (lower Cl_mic) and slightly stronger binding affinity, the poor BBB penetration and low logP are significant drawbacks. The higher BBB score of Ligand B is crucial for CNS exposure. The slightly better affinity of Ligand A is unlikely to overcome the permeability and CNS penetration issues.

Output:
1
2025-04-17 03:27:11,039 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (350.419 and 380.501 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (105.48) is higher than the preferred <90 for CNS targets, but still reasonable. Ligand B (58.64) is excellent, well below 90. This favors Ligand B.

**3. logP:** Both ligands have good logP values (1.366 and 2.402), falling within the optimal 1-3 range. Ligand B is slightly higher, potentially aiding membrane permeability.

**4. H-Bond Donors:** Ligand A has 3 HBD, acceptable. Ligand B has 1 HBD, also acceptable.

**5. H-Bond Acceptors:** Ligand A has 6 HBA, acceptable. Ligand B has 4 HBA, also acceptable.

**6. QED:** Both ligands have reasonable QED values (0.744 and 0.624), indicating good drug-like properties.

**7. DILI:** Ligand A (52.734) has a slightly higher DILI risk than Ligand B (31.291), but both are below the concerning 60 threshold.

**8. BBB:** This is a crucial parameter for a CNS target like DRD2. Ligand B (79.217) has a significantly better BBB percentile than Ligand A (53.587). This is a major advantage for Ligand B.

**9. Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and suggests potential issues with the prediction method. However, the values are similar and don't strongly differentiate the ligands.

**10. Aqueous Solubility:** Both ligands have negative solubility values, again suggesting a potential issue with the prediction method. The values are similar and don't strongly differentiate the ligands.

**11. hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.068 and 0.742), which is excellent.

**12. Microsomal Clearance:** Ligand A (11.583) has lower microsomal clearance than Ligand B (56.203), suggesting better metabolic stability. This favors Ligand A.

**13. In vitro Half-Life:** Ligand A (-20.127) has a negative half-life, which is not possible. Ligand B (8.03) is reasonable. This is a significant issue for Ligand A.

**14. P-gp Efflux:** Both have very low P-gp efflux liability (0.018 and 0.087), which is favorable for CNS penetration.

**15. Binding Affinity:** Ligand B (-7.2 kcal/mol) has a slightly better binding affinity than Ligand A (-8.0 kcal/mol). While A is better, the difference is not huge.

**Overall Assessment:**

Ligand B is the stronger candidate. It excels in BBB penetration (critical for a CNS target), has a lower DILI risk, and a better binding affinity. While Ligand A has better metabolic stability (lower Cl_mic), its negative half-life is a major red flag. Ligand A's TPSA is also higher than ideal. The slightly better affinity of Ligand A is outweighed by the other factors.

Output:
1
2025-04-17 03:27:11,039 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (348.403 and 364.833 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (98.91) is slightly higher than Ligand B (80.37). For CNS targets, we prefer TPSA <= 90, so Ligand B is better here.

**3. logP:** Ligand A (-0.313) is quite low, potentially hindering membrane permeability. Ligand B (2.123) is within the optimal 1-3 range. This is a significant advantage for Ligand B.

**4. H-Bond Donors:** Ligand A (2) and Ligand B (1) are both acceptable, below the threshold of 5.

**5. H-Bond Acceptors:** Ligand A (6) and Ligand B (5) are both acceptable, below the threshold of 10.

**6. QED:** Both ligands have good QED scores (0.684 and 0.851), indicating drug-like properties.

**7. DILI:** Ligand A (26.173) has a much lower DILI risk than Ligand B (46.297). This is a positive for Ligand A.

**8. BBB:** Ligand B (50.058) has a better BBB percentile than Ligand A (30.593). While both are not ideal (>70 desirable), Ligand B is closer.

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.511 and -5.378), which is unusual and suggests poor permeability. This is a concern for both.

**10. Aqueous Solubility:** Both ligands have negative solubility values (-0.375 and -2.563), which is also unusual and suggests poor solubility. This is a concern for both.

**11. hERG Inhibition:** Both ligands have low hERG inhibition risk (0.059 and 0.129).

**12. Microsomal Clearance:** Ligand A (17.479) has lower microsomal clearance than Ligand B (20.977), suggesting better metabolic stability.

**13. In vitro Half-Life:** Ligand B (34.796) has a significantly longer in vitro half-life than Ligand A (-6.58). This is a major advantage for Ligand B.

**14. P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.034 and 0.041).

**15. Binding Affinity:** Ligand B (-7.3 kcal/mol) has a stronger binding affinity than Ligand A (-8.6 kcal/mol). While A is stronger, the difference is small and other factors are more important.

**Overall Assessment:**

Ligand B is the better candidate. While Ligand A has a lower DILI risk and better metabolic stability, Ligand B excels in key GPCR properties: a more favorable logP, better BBB penetration, and a significantly longer half-life. The stronger binding affinity of Ligand B, combined with its better logP and BBB, outweighs the slightly higher DILI risk. The poor Caco-2 and solubility for both are concerning and would need to be addressed in further optimization, but are less critical than the CNS penetration properties for a DRD2 target.

Output:
1
2025-04-17 03:27:11,040 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (368.449 and 367.515 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (61.36) is significantly better than Ligand B (91.32). For CNS targets, we want TPSA <= 90, so Ligand A is preferable.

**logP:** Ligand A (3.949) is slightly higher than Ligand B (2.512), both are within the optimal 1-3 range, but A is closer to the upper limit.

**H-Bond Donors/Acceptors:** Both have 3 HBDs, which is good. Ligand A has 3 HBAs, while Ligand B has 5. Lower HBA is generally preferred.

**QED:** Ligand A (0.765) has a better QED score than Ligand B (0.583), indicating better overall drug-likeness.

**DILI:** Ligand A (46.801) has a lower DILI risk than Ligand B (56.146), which is favorable. Both are below the concerning threshold of 60.

**BBB:** Ligand A (83.637) has a much higher BBB penetration percentile than Ligand B (65.801). This is a critical advantage for a CNS target like DRD2, as we want >70.

**Caco-2 Permeability:** Ligand A (-4.793) has worse Caco-2 permeability than Ligand B (-5.188), but both are very poor. This isn't a major deciding factor as BBB is more important for CNS targets.

**Aqueous Solubility:** Both ligands have very poor aqueous solubility (-3.776 and -3.569 respectively). This could pose formulation challenges, but isn't a deal-breaker.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.705 and 0.601 respectively).

**Microsomal Clearance:** Ligand B (36.611) has lower microsomal clearance than Ligand A (46.82), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (30.801) has a longer half-life than Ligand B (-8.263). This is a positive attribute.

**P-gp Efflux:** Ligand A (0.446) has lower P-gp efflux than Ligand B (0.496), which is preferable for CNS penetration.

**Binding Affinity:** Both ligands have excellent binding affinity (-9.9 and -8.8 kcal/mol). Ligand A is 1.1 kcal/mol stronger, which is a significant advantage and can outweigh some of the ADME drawbacks.

**Overall:**

Ligand A is superior due to its significantly better BBB penetration, higher QED, lower DILI risk, and stronger binding affinity. While Ligand B has better metabolic stability, the CNS target necessitates prioritizing BBB and affinity. The slightly higher logP of Ligand A is acceptable given the strong affinity.

Output:
1
2025-04-17 03:27:11,040 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (366.502 and 353.507 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (49.41) is significantly better than Ligand B (61.88). For CNS targets, we want TPSA <= 90, and ideally closer to 60. Ligand A is much closer to this ideal.

**logP:** Ligand A (3.388) is within the optimal 1-3 range. Ligand B (1.639) is on the lower end, potentially hindering permeability.

**H-Bond Donors/Acceptors:** Both have acceptable HBD (1) and HBA (3 for A, 4 for B) counts, well within the guidelines.

**QED:** Both ligands have good QED scores (0.718 and 0.721), indicating good drug-like properties.

**DILI:** Ligand A (48.507) has a slightly higher DILI risk than Ligand B (4.653), but both are below the concerning threshold of 60.

**BBB:** Ligand A (85.149) has a better BBB penetration percentile than Ligand B (72.237). Both are above the desirable 70% threshold for CNS targets, but A is better.

**Caco-2 Permeability:** Ligand A (-4.954) has worse Caco-2 permeability than Ligand B (-4.626). However, the scale is not clearly defined, and the difference is small.

**Aqueous Solubility:** Ligand A (-3.622) has worse aqueous solubility than Ligand B (-0.969). Solubility is important, but can often be addressed with formulation.

**hERG Inhibition:** Ligand A (0.903) has a slightly higher hERG risk than Ligand B (0.344), but both are relatively low.

**Microsomal Clearance:** Ligand B (24.678) has significantly lower microsomal clearance than Ligand A (70.154), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand B (-12.898) has a negative half-life, which is not possible. This is likely an error in the data and is a significant red flag. Ligand A (13.44) is reasonable.

**P-gp Efflux:** Ligand A (0.614) has lower P-gp efflux than Ligand B (0.021), which is more favorable for CNS penetration.

**Binding Affinity:** Ligand A (-8.3 kcal/mol) has a stronger binding affinity than Ligand B (-7.7 kcal/mol). This difference of 0.6 kcal/mol is substantial and can outweigh minor ADME drawbacks.

**Overall Assessment:**

Ligand A is the stronger candidate. While Ligand B has better metabolic stability and solubility, the significantly stronger binding affinity of Ligand A (-8.3 vs -7.7 kcal/mol) is a major advantage. Furthermore, Ligand A's superior BBB penetration and lower P-gp efflux are crucial for a CNS-targeting drug. The negative half-life reported for Ligand B is a critical flaw. Ligand A's TPSA is also much more favorable. Although Ligand A has slightly higher DILI and hERG risk, these are manageable compared to the benefits.

Output:
1
2025-04-17 03:27:11,040 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (360.42 and 352.475 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (49.41) is significantly better than Ligand B (66.92). For CNS targets, we want TPSA <= 90, and ideally closer to 60. Ligand A is much closer to this ideal.

**logP:** Ligand A (3.117) is optimal (1-3), while Ligand B (1.866) is on the lower side. A lower logP might hinder permeation.

**H-Bond Donors/Acceptors:** Ligand A (1 HBD, 2 HBA) is preferable to Ligand B (0 HBD, 4 HBA). Both are within acceptable limits, but the slightly higher HBA count in B could potentially affect permeability.

**QED:** Both ligands have similar QED values (0.841 and 0.701), indicating good drug-like properties.

**DILI:** Ligand A (25.397) has a much lower DILI risk than Ligand B (12.33). Both are below the 40 threshold, but A is significantly safer.

**BBB:** Ligand A (93.486) has a considerably higher BBB penetration percentile than Ligand B (86.002). This is a *critical* factor for a CNS target like DRD2.

**Caco-2 Permeability:** Ligand A (-4.552) and Ligand B (-4.397) have similar, and poor, Caco-2 permeability values.

**Aqueous Solubility:** Ligand A (-4.304) and Ligand B (-1.152) have poor solubility values.

**hERG:** Both ligands have low hERG inhibition liability (0.605 and 0.201), which is good.

**Microsomal Clearance:** Ligand A (19.768) has a lower microsomal clearance than Ligand B (34.66), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (-12.69) has a *much* longer in vitro half-life than Ligand B (-7.121). This is a significant advantage.

**P-gp Efflux:** Ligand A (0.101) has lower P-gp efflux liability than Ligand B (0.041). Lower efflux is better for CNS exposure.

**Binding Affinity:** Ligand A (-8.4 kcal/mol) has a slightly better binding affinity than Ligand B (-7.1 kcal/mol). While both are good, the 1.3 kcal/mol difference is substantial and can outweigh minor ADME drawbacks.

**Overall:**

Ligand A is superior to Ligand B across most critical parameters for a CNS-targeting GPCR ligand. It has better TPSA, logP, DILI risk, BBB penetration, metabolic stability, half-life, P-gp efflux, and binding affinity. While both have poor Caco-2 permeability and solubility, the superior CNS-related properties of Ligand A make it the more promising candidate.

Output:
1
2025-04-17 03:27:11,040 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (350.415 Da) is slightly lower, which could be beneficial for permeability, while Ligand B (405.344 Da) is still well within the range.

**TPSA:** Ligand A (103.01) is better than Ligand B (67.66) as it is closer to the ideal range for CNS targets (<=90). Ligand B is quite low, which may indicate a lack of necessary interactions.

**logP:** Ligand B (3.711) is closer to the optimal range (1-3) than Ligand A (0.829). Ligand A's low logP could hinder membrane permeability.

**H-Bond Donors/Acceptors:** Ligand A has 3 HBD and 5 HBA, while Ligand B has 2 HBD and 6 HBA. Both are within acceptable limits.

**QED:** Both ligands have similar QED values (0.73 and 0.688), indicating good drug-likeness.

**DILI:** Ligand A (21.171) has a significantly lower DILI risk than Ligand B (52.462), which is a major advantage.

**BBB:** Ligand B (72.082) has a much better BBB penetration percentile than Ligand A (26.561). This is crucial for a CNS target like DRD2.

**Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and suggests potential issues with the prediction model or the compounds themselves. However, the values are similar.

**Aqueous Solubility:** Both ligands have negative solubility values, again suggesting potential issues with the prediction model. The values are similar.

**hERG Inhibition:** Ligand A (0.08) has a much lower hERG inhibition liability than Ligand B (0.853), which is a significant safety advantage.

**Microsomal Clearance:** Ligand A (-24.608) has a much lower (better) microsomal clearance than Ligand B (60.653), indicating better metabolic stability.

**In vitro Half-Life:** Ligand B (46.06) has a longer in vitro half-life than Ligand A (23.715), which is generally desirable.

**P-gp Efflux:** Ligand A (0.015) has a much lower P-gp efflux liability than Ligand B (0.499), improving CNS exposure.

**Binding Affinity:** Ligand B (-9.1 kcal/mol) has a significantly stronger binding affinity than Ligand A (0.0 kcal/mol). This is a substantial advantage, potentially outweighing some of the ADME drawbacks.

**Overall Assessment:**

Ligand B excels in binding affinity and BBB penetration, which are critical for a CNS GPCR target. However, it has concerningly high DILI risk, hERG inhibition, and P-gp efflux. Ligand A has much better safety profiles (DILI, hERG, Pgp) and metabolic stability, but its low logP and poor BBB penetration are significant drawbacks.

The difference in binding affinity is substantial (9.1 vs 0 kcal/mol). While Ligand A's affinity is poor, the other properties are far more favorable. Given the importance of potency for GPCRs, and the potential to improve ADME properties through further optimization, Ligand B is the more promising starting point.

Output:
1
2025-04-17 03:27:11,040 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (430.368 Da) is slightly higher, but acceptable. Ligand B (361.511 Da) is also good.

**TPSA:** Ligand A (115.28) is pushing the limit for CNS targets (<=90 is preferred) but might be acceptable given other favorable properties. Ligand B (62.3) is excellent, well below the 90 threshold.

**logP:** Both ligands have good logP values (Ligand A: 2.185, Ligand B: 3.246), falling within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A has 3 HBD and 4 HBA, which is reasonable. Ligand B has 1 HBD and 4 HBA, also reasonable.

**QED:** Both ligands have good QED scores (Ligand A: 0.682, Ligand B: 0.758), indicating good drug-like properties.

**DILI:** Ligand A (57.348) has a slightly higher DILI risk than Ligand B (42.148), but both are below the concerning threshold of 60.

**BBB:** This is crucial for a CNS target. Ligand A has a BBB percentile of 52.191, which is below the desirable >70. Ligand B has a significantly better BBB percentile of 68.282, although still not ideal, it is better than Ligand A.

**Caco-2 Permeability:** Both have negative values, which is unusual and suggests poor permeability. Ligand A (-5.604) is slightly better than Ligand B (-4.785).

**Aqueous Solubility:** Both have negative values, suggesting poor solubility. Ligand A (-2.996) is slightly better than Ligand B (-3.801).

**hERG Inhibition:** Both ligands have very low hERG inhibition risk (Ligand A: 0.217, Ligand B: 0.379).

**Microsomal Clearance:** Ligand A (5.58 mL/min/kg) has lower clearance and therefore better metabolic stability than Ligand B (75.421 mL/min/kg).

**In vitro Half-Life:** Ligand A (31.95 hours) has a much longer half-life than Ligand B (-5.444 hours).

**P-gp Efflux:** Ligand A (0.129) has lower P-gp efflux, which is favorable for CNS penetration, compared to Ligand B (0.272).

**Binding Affinity:** Ligand B (-7.8 kcal/mol) has a significantly stronger binding affinity than Ligand A (-9.4 kcal/mol). This is a substantial advantage.

**Overall Assessment:**

Ligand B excels in binding affinity and has a better BBB score, which are critical for a CNS GPCR target like DRD2. While Ligand A has better metabolic stability and half-life, the significantly stronger binding affinity of Ligand B, coupled with its better BBB penetration, outweighs these advantages. The lower Caco-2 and solubility for both are concerning, but can be addressed with formulation strategies.

Output:
1
2025-04-17 03:27:11,041 - INFO - Reasoning:

Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (338.411 Da) is slightly lower, which could be advantageous for permeability. Ligand B (350.375 Da) is also good.

**TPSA:** Ligand A (72.8) is excellent, well below the 90 A^2 threshold for CNS targets. Ligand B (137.48) is higher, approaching the 140 A^2 limit for oral absorption and potentially hindering BBB penetration.

**logP:** Ligand A (3.576) is at the upper end of the optimal range (1-3), but still acceptable. Ligand B (0.663) is quite low, which could significantly impair membrane permeability and CNS penetration.

**H-Bond Donors/Acceptors:** Ligand A (HBD=1, HBA=5) is favorable. Ligand B (HBD=3, HBA=7) is also within reasonable limits, but slightly higher.

**QED:** Ligand A (0.738) has a good drug-likeness score. Ligand B (0.462) is below the 0.5 threshold, indicating a less desirable drug-like profile.

**DILI:** Ligand A (62.001) has a moderate DILI risk. Ligand B (54.323) has a slightly lower DILI risk, which is positive.

**BBB:** Ligand A (63.862) has a moderate BBB penetration. Ligand B (45.25) is significantly lower, which is a major concern for a CNS target like DRD2.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.221 and -5.273), which is unusual and suggests poor permeability. This could be an artifact of the prediction method, but it's a flag.

**Aqueous Solubility:** Both ligands have negative solubility values (-3.746 and -1.942), also unusual and potentially problematic.

**hERG Inhibition:** Ligand A (0.762) has a slightly higher hERG risk than Ligand B (0.186), which is preferable.

**Microsomal Clearance:** Ligand A (79.112) has a moderate clearance. Ligand B (-0.858) has a negative clearance, which is not physically possible and likely an artifact of the prediction. This is a significant red flag.

**In vitro Half-Life:** Ligand A (18.812 hours) has a reasonable half-life. Ligand B (-9.662 hours) has a negative half-life, another prediction artifact.

**P-gp Efflux:** Ligand A (0.755) has moderate P-gp efflux. Ligand B (0.015) has very low P-gp efflux, which is a significant advantage for CNS penetration.

**Binding Affinity:** Ligand A (-9.3 kcal/mol) has a substantially stronger binding affinity than Ligand B (-7.4 kcal/mol). This difference of 1.9 kcal/mol is significant and can outweigh some ADME drawbacks.

**Overall Assessment:**

Ligand A is clearly the better candidate despite some moderate ADME liabilities. Its significantly stronger binding affinity (-9.3 vs -7.4 kcal/mol) is a major advantage. While its BBB penetration is not ideal (63.862), it's far superior to Ligand B's (45.25). Ligand B suffers from several critical issues: low logP, a QED score below 0.5, and completely unrealistic predictions for microsomal clearance and half-life. The negative values for Caco-2 and solubility are also concerning.

Output:
1
2025-04-17 03:27:11,041 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (343.427 and 345.439 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (78.51) is better than Ligand B (59.75). Both are below the 90 A^2 threshold desirable for CNS targets, but A is closer to the upper limit.

**3. logP:** Ligand A (1.617) is within the optimal 1-3 range. Ligand B (4.039) is higher, potentially leading to solubility issues and off-target interactions.

**4. H-Bond Donors:** Ligand A (2) is reasonable. Ligand B (0) is also acceptable, but too few HBDs can sometimes hinder solubility.

**5. H-Bond Acceptors:** Ligand A (3) is good. Ligand B (4) is also acceptable.

**6. QED:** Both ligands have good QED scores (0.583 and 0.711, respectively), indicating drug-like properties. Ligand B is slightly better.

**7. DILI:** Ligand A (21.52) has a significantly lower DILI risk than Ligand B (55.913). This is a major advantage for Ligand A.

**8. BBB:** Ligand B (77.898) has a much better BBB penetration percentile than Ligand A (60.876). This is crucial for a CNS target like DRD2.

**9. Caco-2 Permeability:** Ligand A (-4.852) has a worse Caco-2 permeability than Ligand B (-4.347). However, both are negative, indicating poor permeability.

**10. Aqueous Solubility:** Ligand A (-2.851) has better aqueous solubility than Ligand B (-4.673).

**11. hERG Inhibition:** Ligand A (0.386) has a lower hERG inhibition liability than Ligand B (0.878). This is a safety advantage for Ligand A.

**12. Microsomal Clearance:** Ligand A (12.148) has lower microsomal clearance, suggesting better metabolic stability, than Ligand B (112.013).

**13. In vitro Half-Life:** Ligand B (107.051) has a much longer in vitro half-life than Ligand A (1.649). This is a significant advantage for Ligand B.

**14. P-gp Efflux:** Ligand A (0.032) has significantly lower P-gp efflux liability than Ligand B (0.737). Lower P-gp efflux is desirable for CNS penetration.

**15. Binding Affinity:** Ligand B (-9.1 kcal/mol) has a stronger binding affinity than Ligand A (-8.3 kcal/mol). This is a substantial advantage, potentially outweighing some of the ADME drawbacks.

**Overall Assessment:**

Ligand B has a significantly better binding affinity and BBB penetration, and a longer half-life. However, it has a higher logP, DILI risk, and P-gp efflux. Ligand A has better solubility, lower DILI and hERG risk, lower P-gp efflux, and better metabolic stability.

Given the priority for BBB penetration for a CNS GPCR target, and the substantial affinity advantage of Ligand B (-9.1 vs -8.3 kcal/mol), I would prioritize Ligand B despite its other drawbacks. The stronger binding and better BBB penetration are likely to be more impactful for efficacy. The higher logP and DILI risk can be addressed with further optimization.

Output:
1
2025-04-17 03:27:11,041 - INFO - Batch 30 complete. Total preferences: 480
2025-04-17 03:27:11,041 - INFO - Processing batch 31/512...
2025-04-17 03:27:54,466 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (339.4 and 350.4 Da) fall comfortably within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (88.08) is excellent, being below the 90 A^2 threshold for CNS targets. Ligand B (103.01) is slightly higher but still reasonable.

**3. logP:** Both ligands have good logP values (1.43 and 0.91), falling within the optimal 1-3 range.

**4. H-Bond Donors:** Ligand A (1) is preferable to Ligand B (3) as fewer HBDs generally improve permeability.

**5. H-Bond Acceptors:** Both ligands have 5 HBA, which is acceptable (<=10).

**6. QED:** Ligand A (0.91) has a significantly better QED score than Ligand B (0.732), indicating a more drug-like profile.

**7. DILI:** Ligand A (57.66%) has a higher DILI risk than Ligand B (37.03%), but both are below the concerning 60% threshold.

**8. BBB:** Both ligands have similar BBB penetration (47.3% and 47.1%), which is acceptable but not outstanding for a CNS target. Ideally, we'd want >70%.

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 values, which is unusual and suggests poor permeability. This is a significant concern.

**10. Aqueous Solubility:** Both ligands have negative solubility values, which is also unusual and suggests poor solubility. This is a significant concern.

**11. hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.11 and 0.15), which is excellent.

**12. Microsomal Clearance:** Both ligands have negative Cl_mic values, which is unusual and suggests high metabolic stability.

**13. In vitro Half-Life:** Both ligands have negative half-life values, which is unusual.

**14. P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.003 and 0.046), which is highly desirable for CNS penetration.

**15. Binding Affinity:** Ligand A (-9.5 kcal/mol) has a slightly better binding affinity than Ligand B (-8.5 kcal/mol). While both are good, the 1 kcal/mol difference is noteworthy.

**Overall Assessment:**

Despite the unusual negative values for Caco-2, solubility, Cl_mic, and t1/2, Ligand A is the better candidate. It has a superior QED score, slightly better affinity, and fewer H-bond donors. The similar BBB values and low P-gp efflux for both are positive. The DILI risk is slightly higher for A, but still acceptable. The negative values for Caco-2, solubility, Cl_mic, and t1/2 are concerning and would require further investigation (likely experimental validation) to determine their true impact. However, based on the available data, the slight edge in affinity and drug-likeness makes Ligand A more promising.

Output:
1
2025-04-17 03:27:54,466 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (339.351 Da) is slightly lower, which could be beneficial for permeability. Ligand B (361.354 Da) is also good.

**TPSA:** Ligand A (102.66) is borderline for CNS penetration, being above the preferred <90. Ligand B (20.31) is excellent, well below the threshold. This is a significant advantage for Ligand B.

**logP:** Ligand A (0.678) is a bit low, potentially hindering membrane permeability. Ligand B (4.916) is high, potentially leading to solubility issues and off-target effects, but within an acceptable range.

**H-Bond Donors/Acceptors:** Ligand A has 2 HBD and 5 HBA, which are reasonable. Ligand B has 0 HBD and 1 HBA, which is also good, potentially improving permeability.

**QED:** Both ligands have acceptable QED values (A: 0.788, B: 0.659), indicating reasonable drug-likeness.

**DILI:** Ligand A (76.154) has a higher DILI risk than Ligand B (43.195), suggesting potential liver toxicity concerns.

**BBB:** Ligand B (96.316) has a significantly higher BBB penetration percentile than Ligand A (33.579). This is a crucial advantage for a CNS target like DRD2.

**Caco-2 Permeability:** Ligand A (-5.098) has poor Caco-2 permeability, suggesting poor absorption. Ligand B (-4.316) is also poor, but slightly better than A.

**Aqueous Solubility:** Both ligands have very poor aqueous solubility (-3.223 and -4.904 respectively). This could pose formulation challenges.

**hERG Inhibition:** Ligand A (0.306) has a slightly lower hERG risk than Ligand B (0.862), which is preferable.

**Microsomal Clearance:** Ligand A (-19.04) has a much lower (better) microsomal clearance than Ligand B (58.709), indicating greater metabolic stability.

**In vitro Half-Life:** Ligand A (-15.03) has a negative half-life, which is not physically possible and indicates a problem with the data or the molecule. Ligand B (-0.134) is also very short.

**P-gp Efflux:** Ligand A (0.035) has very low P-gp efflux, which is good for CNS exposure. Ligand B (0.23) is slightly higher, but still relatively low.

**Binding Affinity:** Ligand A (-9.6 kcal/mol) has a significantly stronger binding affinity than Ligand B (-8.0 kcal/mol). This is a substantial advantage, potentially outweighing some of the ADME drawbacks.

**Overall Assessment:**

Ligand A has a much stronger binding affinity and better metabolic stability (lower Cl_mic) and P-gp efflux. However, its BBB penetration is very poor, Caco-2 permeability is poor, and it has a higher DILI risk. The negative half-life is a major red flag.

Ligand B has excellent BBB penetration, a lower DILI risk, and a slightly better Caco-2 permeability, but its binding affinity is weaker, and it has poorer metabolic stability.

Given the GPCR-specific priorities, especially BBB penetration for a CNS target, and the significantly stronger binding affinity of Ligand A, I would lean towards **Ligand A** despite its drawbacks. The strong binding affinity could potentially be optimized through further medicinal chemistry to improve ADME properties, whereas improving the affinity of Ligand B to match A's would be more challenging. However, the negative half-life of Ligand A is a serious concern that needs investigation.

Output:
0
2025-04-17 03:27:54,467 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (378.881 Da) and Ligand B (351.441 Da) are both acceptable.

**TPSA:** Ligand A (69.64) is better than Ligand B (41.15). For CNS targets, we want TPSA <= 90, both are well within this range, but lower is preferable.

**logP:** Both ligands have good logP values (Ligand A: 2.965, Ligand B: 3.758), falling within the optimal 1-3 range. Ligand B is slightly higher, which could potentially lead to off-target effects, but is still acceptable.

**H-Bond Donors/Acceptors:** Ligand A has 2 HBD and 4 HBA, while Ligand B has 1 HBD and 3 HBA. Both are within the acceptable limits of <=5 HBD and <=10 HBA.

**QED:** Both ligands have similar and good QED values (Ligand A: 0.807, Ligand B: 0.813), indicating good drug-like properties.

**DILI:** Ligand A (47.344) has a better DILI score than Ligand B (15.626). Lower is better, and both are below the concerning threshold of 60.

**BBB:** This is a crucial parameter for CNS targets. Ligand B (86.661) significantly outperforms Ligand A (69.213) in BBB penetration. A value >70 is desirable, and Ligand B is closer to that target.

**Caco-2 Permeability:** Both have negative Caco-2 values (-4.768 and -4.801), which is unusual and suggests poor permeability. This is a significant drawback for both.

**Aqueous Solubility:** Both have negative solubility values (-4.484 and -3.354), indicating very low aqueous solubility. This is a major concern for both compounds.

**hERG Inhibition:** Ligand A (0.592) has a slightly better hERG profile than Ligand B (0.928), indicating lower cardiotoxicity risk.

**Microsomal Clearance:** Ligand B (38.972) has a lower microsomal clearance than Ligand A (14.361), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (5.717) has a longer half-life than Ligand B (0.893), which is generally desirable.

**P-gp Efflux:** Ligand A (0.453) shows lower P-gp efflux than Ligand B (0.519), which is favorable for CNS exposure.

**Binding Affinity:** Ligand B (-8.1 kcal/mol) has a significantly stronger binding affinity than Ligand A (-9.1 kcal/mol). This is a substantial advantage, potentially outweighing some of the ADME drawbacks.

**Overall Assessment:**

While Ligand A has better DILI, hERG, P-gp efflux, and in vitro half-life, Ligand B's significantly stronger binding affinity and much better BBB penetration are critical advantages for a CNS-targeting GPCR ligand. The poor Caco-2 and solubility are concerns for both, but can potentially be addressed through formulation strategies. The improved metabolic stability of Ligand B is also a plus. The difference in binding affinity (-8.1 vs -9.1) is substantial.

Output:
1
2025-04-17 03:27:54,467 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (364.515 and 348.487 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (86.88) is better than Ligand B (58.64). Both are below the 90 A^2 threshold for CNS targets, which is excellent.

**logP:** Both ligands have similar logP values (2.445 and 2.514), falling within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A has 3 HBD and 4 HBA, while Ligand B has 1 HBD and 3 HBA. Both are within acceptable limits (<=5 HBD and <=10 HBA).

**QED:** Ligand A (0.595) has a significantly better QED score than Ligand B (0.375), indicating a more drug-like profile.

**DILI:** Ligand A (29.624) has a lower DILI risk than Ligand B (19.504), both are good, but A is slightly better.

**BBB:** Ligand B (68.05) has a significantly better BBB penetration percentile than Ligand A (53.781). This is a crucial factor for a CNS target like DRD2.

**Caco-2 Permeability:** Ligand A (-5.555) has worse Caco-2 permeability than Ligand B (-4.264). Both are negative, indicating poor permeability, but B is less poor.

**Aqueous Solubility:** Ligand A (-3.25) has slightly worse aqueous solubility than Ligand B (-2.343). Both are poor.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.33 and 0.27).

**Microsomal Clearance:** Ligand A (24.474) has significantly lower microsomal clearance than Ligand B (61.98), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (2.696) has a shorter in vitro half-life than Ligand B (-2.602). B is better.

**P-gp Efflux:** Ligand A (0.064) has lower P-gp efflux liability than Ligand B (0.152), which is favorable for CNS penetration.

**Binding Affinity:** Ligand A (-7.6) has a stronger binding affinity than Ligand B (-6.9). This is a substantial difference (1.7 kcal/mol), and can often outweigh other ADME issues.

**Overall Assessment:**

Ligand A excels in binding affinity, QED, DILI, and metabolic stability (lower Cl_mic and lower Pgp efflux). However, its BBB penetration is considerably worse than Ligand B. Ligand B has a better BBB score and half-life, but suffers from lower QED, worse DILI, and weaker binding affinity.

Given the importance of BBB penetration for a CNS target like DRD2, Ligand B initially appears more promising. *However*, the 1.7 kcal/mol difference in binding affinity for Ligand A is substantial. A stronger binding ligand is more likely to achieve efficacy at a lower dose, potentially mitigating some of the ADME concerns. The lower Pgp efflux of Ligand A also supports better CNS exposure despite the lower BBB prediction. Considering these factors, the superior binding affinity and metabolic stability of Ligand A outweigh its slightly poorer BBB and solubility.

Output:
1
2025-04-17 03:27:54,467 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 drug candidates, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (341.455 Da) is slightly lower, which could be beneficial for permeability, but both are acceptable.

**TPSA:** Ligand A (53.51) is excellent for CNS penetration, well below the 90 A^2 threshold. Ligand B (66.57) is still reasonable, but less optimal.

**logP:** Both ligands have good logP values (A: 2.827, B: 3.477), falling within the 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A (HBD=0, HBA=3) is better than Ligand B (HBD=1, HBA=4) in terms of maintaining a balance between solubility and permeability.

**QED:** Both ligands have similar and acceptable QED values (A: 0.791, B: 0.774).

**DILI:** Ligand A (28.073) has a slightly higher DILI risk than Ligand B (19.504), but both are below the concerning threshold of 60.

**BBB:** Both ligands exhibit excellent BBB penetration (A: 85.072, B: 89.608), exceeding the desirable 70% threshold for CNS targets. Ligand B is slightly better.

**Caco-2 Permeability:** Both show negative Caco-2 permeability values which is unusual and suggests a potential issue with the prediction method or the compounds themselves. However, we will continue the analysis assuming these are relative values.

**Aqueous Solubility:** Both ligands have poor aqueous solubility (A: -1.726, B: -3.735). This could be a formulation challenge.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (A: 0.335, B: 0.642).

**Microsomal Clearance:** Ligand A (60.489) has higher microsomal clearance than Ligand B (27.408), implying lower metabolic stability.

**In vitro Half-Life:** Ligand B (5.738 hours) has a longer half-life than Ligand A (11.872 hours).

**P-gp Efflux:** Both ligands show very low P-gp efflux liability (A: 0.288, B: 0.231), which is favorable for CNS exposure.

**Binding Affinity:** This is the most critical parameter. Ligand B (-8.1 kcal/mol) has a significantly stronger binding affinity than Ligand A (-0.0 kcal/mol). A difference of >1.5 kcal/mol is considered substantial.

**Overall Assessment:**

While Ligand A has some advantages in TPSA and H-bonding, Ligand B is superior due to its significantly higher binding affinity, better metabolic stability (lower Cl_mic), longer half-life, and lower DILI risk. The slightly better BBB penetration of Ligand B is also a plus. The solubility issues are a concern for both, but can potentially be addressed through formulation strategies. The strong binding affinity of Ligand B outweighs the minor drawbacks.

Output:
1
2025-04-17 03:27:54,467 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (371.453 and 350.503 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (75.43) is better than Ligand B (78.43). Both are below the 90 A^2 threshold for CNS targets, which is good.

**3. logP:** Both ligands have similar logP values (2.411 and 2.376), falling within the optimal 1-3 range.

**4. H-Bond Donors:** Ligand A (2) is preferable to Ligand B (3). Lower HBD generally improves permeability.

**5. H-Bond Acceptors:** Ligand A (4) is preferable to Ligand B (3).

**6. QED:** Both ligands have good QED scores (0.57 and 0.66), indicating drug-like properties.

**7. DILI:** Ligand A (61.691) has a higher DILI risk than Ligand B (11.632). This is a significant drawback for Ligand A.

**8. BBB:** Ligand A (76.774) has a significantly better BBB penetration percentile than Ligand B (32.61). This is crucial for a CNS target like DRD2.

**9. Caco-2 Permeability:** Ligand A (-5.099) has worse Caco-2 permeability than Ligand B (-4.785), although both are negative and therefore indicate poor permeability.

**10. Aqueous Solubility:** Ligand A (-3.682) has slightly worse solubility than Ligand B (-3.316), but both are poor.

**11. hERG Inhibition:** Ligand A (0.817) has a slightly higher hERG inhibition liability than Ligand B (0.289). Lower is better here.

**12. Microsomal Clearance:** Ligand A (32.916) has lower microsomal clearance than Ligand B (44.482), indicating better metabolic stability.

**13. In vitro Half-Life:** Ligand A (8.141) has a better in vitro half-life than Ligand B (-4.076).

**14. P-gp Efflux:** Ligand A (0.078) has lower P-gp efflux liability than Ligand B (0.107), which is favorable for CNS penetration.

**15. Binding Affinity:** Ligand B (-9.0) has a significantly stronger binding affinity than Ligand A (-7.9). A difference of 1.1 kcal/mol is substantial and can often outweigh minor ADME drawbacks.

**Overall Assessment:**

Ligand A has better BBB penetration, metabolic stability, half-life, and P-gp efflux. However, it has a significantly higher DILI risk and worse Caco-2 permeability. Ligand B has a much stronger binding affinity and a much lower DILI risk, and better hERG profile. The superior binding affinity of Ligand B (-9.0 kcal/mol vs -7.9 kcal/mol) is a major advantage, especially for a GPCR target. While its BBB is lower, the strong binding could compensate. The lower DILI risk is also a significant factor.

Output:
1
2025-04-17 03:27:54,467 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (370.387 Da and 346.475 Da) fall within the ideal range of 200-500 Da.

**TPSA:** Ligand A (58.64) is significantly better than Ligand B (67.23). For CNS targets, we want TPSA <= 90, and ideally closer to 60. Ligand A is much closer to this ideal.

**logP:** Both ligands have similar logP values (2.448 and 2.373), falling within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Both have 1 HBD, which is good. Ligand A has 3 HBA, and Ligand B has 4. Both are acceptable (<=10), but lower is generally preferred.

**QED:** Both ligands have good QED scores (0.527 and 0.771), indicating drug-like properties. Ligand B is slightly better.

**DILI:** Both ligands have low DILI risk (23.963 and 21.946), which is excellent.

**BBB:** This is a crucial parameter for a CNS target like DRD2. Ligand A has a significantly higher BBB percentile (94.261) compared to Ligand B (74.874). A value >70 is desirable, and Ligand A is excellent.

**Caco-2 Permeability:** Both have negative values (-4.484 and -4.919), which is unusual and suggests poor permeability. However, these values are on a scale where negative values are possible and don't necessarily disqualify the compounds.

**Aqueous Solubility:** Both have negative values (-2.383 and -2.112), indicating poor solubility. This could be a formulation challenge.

**hERG:** Both ligands have low hERG inhibition liability (0.83 and 0.284), which is good.

**Microsomal Clearance:** Ligand A (12.499) has significantly lower microsomal clearance than Ligand B (34.988). Lower clearance indicates better metabolic stability, which is desirable.

**In vitro Half-Life:** Ligand A (-15.408) has a much longer half-life than Ligand B (-1.568). This is a significant advantage.

**P-gp Efflux:** Both have very low P-gp efflux liability (0.12 and 0.111), which is excellent for CNS penetration.

**Binding Affinity:** Both ligands have very similar and strong binding affinities (-7.8 and -7.9 kcal/mol). The difference is negligible.

**Overall Assessment:**

Ligand A is superior due to its significantly better BBB penetration (94.261 vs 74.874), lower microsomal clearance (12.499 vs 34.988), and longer in vitro half-life (-15.408 vs -1.568). While both have poor solubility and Caco-2 permeability, the improved pharmacokinetic properties of Ligand A, particularly its BBB penetration and metabolic stability, make it a more promising drug candidate for a CNS target like DRD2. The binding affinity is comparable, so the ADME advantages of Ligand A outweigh any minor differences in other properties.

Output:
1
2025-04-17 03:27:54,468 - INFO - Reasoning:

Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the acceptable range (200-500 Da). Ligand A (345.418 Da) is slightly lower, which is generally favorable for permeability.

**TPSA:** Ligand A (53.51) is significantly better than Ligand B (87.46). For CNS targets, we want TPSA <= 90, and ideally lower. Ligand A is well within this range, while Ligand B is approaching the upper limit and may have reduced brain penetration.

**logP:** Both ligands have reasonable logP values (Ligand A: 1.822, Ligand B: 0.543), falling within the 1-3 optimal range. Ligand A is better, but both are acceptable.

**H-Bond Donors/Acceptors:** Ligand A (0 HBD, 3 HBA) is preferable to Ligand B (2 HBD, 6 HBA). Lower counts generally improve permeability.

**QED:** Ligand A (0.818) has a significantly better QED score than Ligand B (0.577), indicating a more drug-like profile.

**DILI:** Ligand A (20.861) has a much lower DILI risk than Ligand B (29.159). Both are below 40, but A is better.

**BBB:** This is a crucial parameter for CNS targets. Ligand A (91.508) has excellent predicted BBB penetration, while Ligand B (57.425) is considerably lower. This is a major advantage for Ligand A.

**Caco-2 Permeability:** Ligand A (-4.629) has a more negative Caco-2 value, which is unusual and suggests poor permeability. Ligand B (-5.381) is also poor, but slightly better.

**Aqueous Solubility:** Both have negative solubility values, indicating poor solubility. Ligand A (-1.842) is slightly better than Ligand B (-1.553).

**hERG Inhibition:** Both ligands show low hERG inhibition risk (Ligand A: 0.248, Ligand B: 0.338).

**Microsomal Clearance:** Ligand A (20.151) has higher microsomal clearance than Ligand B (12.042), suggesting faster metabolism and potentially lower in vivo exposure.

**In vitro Half-Life:** Ligand B (-14.605) has a much longer in vitro half-life than Ligand A (-3.776). This is a significant advantage for Ligand B.

**P-gp Efflux:** Both ligands show low P-gp efflux (Ligand A: 0.034, Ligand B: 0.023).

**Binding Affinity:** Ligand A (-8.7 kcal/mol) has a significantly stronger binding affinity than Ligand B (-7.3 kcal/mol). This is a substantial advantage, potentially outweighing some of the ADME drawbacks.

**Overall Assessment:**

Ligand A excels in key areas for CNS GPCR targets: TPSA, BBB, QED, DILI, and, most importantly, binding affinity. While its Caco-2 permeability and microsomal clearance are concerning, the strong affinity and excellent BBB penetration are highly favorable. Ligand B has a better half-life, but suffers from higher TPSA, lower BBB, and weaker binding. The substantial difference in binding affinity (-8.7 vs -7.3 kcal/mol) is a critical factor. A 1.4 kcal/mol difference is significant and can often overcome moderate ADME liabilities.

Output:
1
2025-04-17 03:27:54,468 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (359.455 and 348.487 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (89.77) is better than Ligand B (67.43) as it is closer to the ideal range for CNS targets (<=90). Ligand B is also good.

**logP:** Both ligands have good logP values (3.215 and 2.925), falling within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A (HBD=1, HBA=6) and Ligand B (HBD=2, HBA=3) both have acceptable numbers of H-bond donors and acceptors.

**QED:** Both ligands have similar QED values (0.755 and 0.721), indicating good drug-likeness.

**DILI:** Ligand A (94.765) has a significantly higher DILI risk than Ligand B (18.651). This is a major concern for Ligand A.

**BBB:** Both ligands have reasonable BBB penetration (Ligand A: 57.58, Ligand B: 55.603). While not exceeding 70, they are comparable.

**Caco-2 Permeability:** Ligand A (-5.079) has poorer Caco-2 permeability than Ligand B (-4.592), suggesting lower intestinal absorption.

**Aqueous Solubility:** Ligand A (-3.535) has poorer aqueous solubility than Ligand B (-2.808).

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.579 and 0.406).

**Microsomal Clearance:** Ligand B (71.153) has a significantly higher microsomal clearance than Ligand A (21.625), indicating lower metabolic stability.

**In vitro Half-Life:** Ligand A (82.257) has a much longer in vitro half-life than Ligand B (7.536).

**P-gp Efflux:** Ligand A (0.282) has lower P-gp efflux than Ligand B (0.052), which is favorable for CNS exposure.

**Binding Affinity:** Both ligands have very similar, strong binding affinities (-8.8 and -8.7 kcal/mol). The difference is negligible.

**Overall Assessment:**

Ligand B is the better candidate. While Ligand A has slightly better TPSA, P-gp efflux, and half-life, its significantly higher DILI risk, poorer Caco-2 permeability, and lower solubility are major drawbacks. Ligand B has a much more favorable safety profile (DILI) and better predicted absorption (Caco-2, solubility). The small differences in other ADME properties are less critical given the strong binding affinity of both compounds.

Output:
1
2025-04-17 03:27:54,468 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (368.905 and 363.487 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (50.8) is significantly better than Ligand B (84.14). For CNS targets, we want TPSA <= 90, and A is comfortably within this range, while B is approaching the upper limit.

**3. logP:** Ligand A (4.34) is higher than the optimal range (1-3), but still potentially acceptable. Ligand B (1.336) is at the low end of the optimal range. Higher logP can sometimes be tolerated if other properties are favorable.

**4. H-Bond Donors:** Both ligands have 1 HBD, which is within the acceptable limit of <= 5.

**5. H-Bond Acceptors:** Ligand A has 4 HBAs, and Ligand B has 7. Both are within the acceptable limit of <= 10, but A is preferable.

**6. QED:** Both ligands have good QED scores (0.811 and 0.863), indicating good drug-like properties.

**7. DILI:** Both ligands have low DILI risk (44.048 and 42.885), which is good.

**8. BBB:** Ligand A (85.072) has a significantly higher BBB percentile than Ligand B (73.517). This is a *critical* advantage for a CNS target like DRD2.

**9. Caco-2 Permeability:** Ligand A (-4.637) and Ligand B (-4.976) both have negative values, indicating poor permeability.

**10. Aqueous Solubility:** Ligand A (-3.984) and Ligand B (-2.08) both have negative values, indicating poor solubility.

**11. hERG Inhibition:** Both ligands show low hERG inhibition risk (0.905 and 0.767).

**12. Microsomal Clearance:** Ligand B (21.776) has significantly lower microsomal clearance than Ligand A (45.231), indicating better metabolic stability.

**13. In vitro Half-Life:** Ligand B (14.36) has a longer half-life than Ligand A (29.046).

**14. P-gp Efflux:** Ligand A (0.492) has a lower P-gp efflux than Ligand B (0.081), suggesting better CNS exposure.

**15. Binding Affinity:** Ligand B (-8.8 kcal/mol) has a *much* stronger binding affinity than Ligand A (-0.0 kcal/mol). This is a substantial advantage.

**Overall Assessment:**

While Ligand B has superior metabolic stability (lower Cl_mic, longer t1/2) and significantly better binding affinity, Ligand A has a much more favorable TPSA and BBB penetration. Given the CNS target (DRD2), BBB penetration is paramount. The significantly stronger binding affinity of Ligand B is a major plus, but the lower BBB penetration is a serious drawback. The higher TPSA of Ligand B is also less desirable. Ligand A's P-gp efflux is also better. Considering the balance, the superior BBB penetration and TPSA of Ligand A, combined with acceptable binding and P-gp efflux, make it the more promising candidate.

Output:
0
2025-04-17 03:27:54,468 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (335.407 and 357.435 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (69.22) is better than Ligand B (72.7), both are below the 90 A^2 threshold for CNS targets, but A is closer to optimal.

**logP:** Both ligands have good logP values (3.067 and 2.351), falling within the 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A (2 HBD, 3 HBA) is slightly better than Ligand B (1 HBD, 6 HBA) in terms of balancing solubility and permeability.

**QED:** Both ligands have similar and acceptable QED values (0.773 and 0.776).

**DILI:** Ligand A (52.423) has a significantly lower DILI risk than Ligand B (61.962). This is a substantial advantage.

**BBB:** Ligand B (49.244) has a better BBB penetration score than Ligand A (38.813). This is a critical factor for a CNS target like DRD2.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values which is unusual and suggests poor permeability.

**Aqueous Solubility:** Both ligands have negative solubility values which is unusual and suggests poor solubility.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.872 and 0.579).

**Microsomal Clearance:** Ligand A (5.333) has much lower microsomal clearance than Ligand B (24.878), indicating better metabolic stability.

**In vitro Half-Life:** Ligand B (22.731) has a significantly longer in vitro half-life than Ligand A (4.207).

**P-gp Efflux:** Ligand A (0.382) has lower P-gp efflux liability than Ligand B (0.278), which is favorable for CNS penetration.

**Binding Affinity:** Ligand B (-9.2 kcal/mol) has a slightly better binding affinity than Ligand A (-8.6 kcal/mol). This 0.6 kcal/mol difference is noteworthy, but not overwhelming.

**Overall Assessment:**

Ligand B has a better BBB score and a longer half-life, both positives for CNS drug development. However, Ligand A excels in several key areas: lower DILI risk, significantly better metabolic stability (lower Cl_mic), and lower P-gp efflux. While Ligand B has a slightly better binding affinity, the difference isn't large enough to outweigh the ADME advantages of Ligand A, especially considering the importance of metabolic stability and reduced toxicity for a CNS-targeting drug. The negative Caco-2 and solubility values for both are concerning and would require further investigation.

Output:
1
2025-04-17 03:27:54,469 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (345.403 and 348.443 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (109.04) is higher than Ligand B (67.87). For CNS targets, we prefer TPSA <= 90. Ligand B is significantly better here.

**3. logP:** Both ligands (1.224 and 1.316) are within the optimal range of 1-3.

**4. H-Bond Donors:** Ligand A (2) and Ligand B (1) are both acceptable (<=5). Ligand B is slightly better.

**5. H-Bond Acceptors:** Ligand A (6) and Ligand B (4) are both acceptable (<=10). Ligand B is better.

**6. QED:** Both ligands have good QED values (0.78 and 0.832), indicating drug-likeness.

**7. DILI:** Ligand A (43.389) has a slightly higher DILI risk than Ligand B (27.181), but both are below the concerning threshold of 60.

**8. BBB:** Ligand A (80.07) has a significantly better BBB penetration percentile than Ligand B (66.693). This is a crucial factor for a CNS target like DRD2.

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.776 and -4.755), which is unusual and suggests poor permeability. This is a significant drawback for both.

**10. Aqueous Solubility:** Both ligands have negative solubility values (-2.349 and -2.726), also unusual and indicating poor solubility. This is a significant drawback for both.

**11. hERG:** Both ligands have low hERG inhibition liability (0.337 and 0.304), which is good.

**12. Microsomal Clearance:** Ligand A (27.481) has lower microsomal clearance than Ligand B (35.813), suggesting better metabolic stability.

**13. In vitro Half-Life:** Ligand A (21.375) has a longer in vitro half-life than Ligand B (14.715), which is desirable.

**14. P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.076 and 0.035), which is excellent for CNS penetration.

**15. Binding Affinity:** Ligand B (-8.4 kcal/mol) has a slightly stronger binding affinity than Ligand A (-7.6 kcal/mol). This difference of 0.8 kcal/mol is substantial and can outweigh some ADME drawbacks.

**Overall Assessment:**

While Ligand A has better BBB penetration and metabolic stability, Ligand B excels in TPSA, H-bond characteristics, and, most importantly, binding affinity. The stronger binding affinity of Ligand B (-8.4 vs -7.6) is a significant advantage for a GPCR target. The lower TPSA of Ligand B is also beneficial for CNS penetration. Both compounds have concerningly low Caco-2 and solubility values, but the superior affinity of Ligand B makes it the more promising candidate, assuming these solubility/permeability issues can be addressed through formulation or further structural modifications.

Output:
1
2025-04-17 03:27:54,469 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (368.503 and 344.419 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Both ligands have TPSA values (98.32 and 95.91) that are acceptable for oral absorption (<140), but a bit high for optimal CNS penetration (<90).

**3. logP:** Ligand A (0.809) is slightly below the optimal 1-3 range, potentially hindering permeation. Ligand B (0.527) is even lower, raising more concern for permeability.

**4. H-Bond Donors:** Ligand A (3) and Ligand B (2) are both within the acceptable limit of <=5.

**5. H-Bond Acceptors:** Both ligands (5) are within the acceptable limit of <=10.

**6. QED:** Both ligands have good QED scores (0.631 and 0.766), suggesting good drug-like properties.

**7. DILI:** Ligand A (37.456) has a lower DILI risk than Ligand B (49.942), indicating a safer profile. Both are below the concerning threshold of 60.

**8. BBB:** Ligand B (38.465) has a significantly better BBB penetration percentile than Ligand A (17.332). This is a crucial factor for a CNS target like DRD2.

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.677 and -5.597), which is unusual and suggests very poor permeability. This is a significant drawback for both.

**10. Aqueous Solubility:** Both ligands have negative solubility values (-2.566 and -1.642), indicating very poor aqueous solubility. This is a major concern for formulation and bioavailability.

**11. hERG Inhibition:** Both ligands have low hERG inhibition risk (0.187 and 0.195).

**12. Microsomal Clearance:** Ligand B (-7.487) has a negative clearance, which is not physically possible and likely indicates a very stable compound. Ligand A (18.964) has a moderate clearance.

**13. In vitro Half-Life:** Ligand B (-2.759) has a negative half-life, which is also not physically possible and suggests an extremely stable compound. Ligand A (-15.605) has a negative half-life as well.

**14. P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.071 and 0.014), which is favorable for CNS penetration.

**15. Binding Affinity:** Ligand B (-8.4 kcal/mol) has a stronger binding affinity than Ligand A (-7.4 kcal/mol) by a margin of 1 kcal/mol. This difference is significant and could outweigh some of the ADME drawbacks.

**Overall Assessment:**

Despite both compounds having significant ADME liabilities (poor solubility, permeability), Ligand B is more promising. Its superior BBB penetration, stronger binding affinity, and extremely low P-gp efflux make it a better candidate for a CNS-targeting drug like a DRD2 ligand. The negative values for clearance and half-life are concerning and likely represent data errors, but the binding affinity advantage is substantial. Ligand A's slightly better DILI profile is overshadowed by its weaker affinity and lower BBB penetration.

Output:
1
2025-04-17 03:27:54,470 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (357.405 and 368.459 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (88.91) is excellent, falling well below the 90 A^2 threshold for CNS targets. Ligand B (92.58) is slightly higher but still acceptable.

**logP:** Ligand A (1.409) is within the optimal 1-3 range. Ligand B (-0.276) is slightly below 1, which *could* indicate permeability issues, though not drastically.

**H-Bond Donors/Acceptors:** Ligand A has 2 HBD and 5 HBA, both within acceptable limits. Ligand B has 0 HBD and 6 HBA, also acceptable.

**QED:** Both ligands have good QED scores (0.736 and 0.689, respectively), indicating good drug-like properties.

**DILI:** Both ligands have low DILI risk (49.205 and 45.638), which is favorable.

**BBB:** Ligand A (72.237) has a good BBB percentile, but Ligand B (86.351) is significantly better, exceeding 80% and being more desirable for a CNS target like DRD2.

**Caco-2 Permeability:** Ligand A (-4.726) has poor Caco-2 permeability, which is a concern. Ligand B (-5.017) is also poor, but comparable to A.

**Aqueous Solubility:** Both ligands have very poor aqueous solubility (-2.529 and -1.244). This could pose formulation challenges.

**hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.092 and 0.282), which is excellent.

**Microsomal Clearance:** Ligand A (24.817) has higher microsomal clearance than Ligand B (2.542), suggesting lower metabolic stability.

**In vitro Half-Life:** Ligand A (-26.839) has a very short in vitro half-life, which is a major drawback. Ligand B (9.214) has a better, though still relatively short, half-life.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.028 and 0.058), which is good for CNS penetration.

**Binding Affinity:** Ligand B (-7.8 kcal/mol) has a slightly better binding affinity than Ligand A (-8.1 kcal/mol). While both are excellent, the difference is enough to consider.

**Overall Assessment:**

Ligand B is the more promising candidate. While both have solubility issues, Ligand B has a significantly better BBB penetration score, better metabolic stability (lower Cl_mic, longer t1/2), and slightly better binding affinity. The slightly lower logP of Ligand B is a minor concern, but the superior BBB and metabolic properties outweigh this. Ligand A's very poor in vitro half-life is a significant negative.



Output:
1
2025-04-17 03:27:54,470 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (330.347 and 343.515 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (87.9) is better than Ligand B (37.27). For CNS targets, TPSA should be <= 90, both are within this range, but A is closer to the upper limit.

**3. logP:** Both ligands have good logP values (3.276 and 3.758), falling within the optimal 1-3 range.

**4. H-Bond Donors:** Both have 1 HBD, which is acceptable.

**5. H-Bond Acceptors:** Ligand A has 5 HBA, and Ligand B has 3. Both are within the acceptable limit of <= 10.

**6. QED:** Both ligands have good QED scores (0.793 and 0.854), indicating good drug-like properties.

**7. DILI:** Ligand A has a high DILI risk (98.876%), while Ligand B has a low DILI risk (11.09%). This is a significant advantage for Ligand B.

**8. BBB:** Ligand B has a much better BBB penetration percentile (91.198%) compared to Ligand A (48.042%). This is critical for a CNS target like DRD2.

**9. Caco-2 Permeability:** Both have negative Caco-2 values (-4.888 and -4.655). These values are unusual and likely indicate poor permeability. However, the absolute values are similar.

**10. Aqueous Solubility:** Both have negative solubility values (-5.748 and -3.886), which is also unusual and suggests poor solubility. Again, the values are similar.

**11. hERG Inhibition:** Both ligands have low hERG inhibition liability (0.746 and 0.638), which is good.

**12. Microsomal Clearance:** Ligand B has a higher microsomal clearance (59.149) than Ligand A (52.373), indicating faster metabolism and potentially lower in vivo exposure.

**13. In vitro Half-Life:** Ligand B has a much longer in vitro half-life (43.993 hours) than Ligand A (14.193 hours). This is a significant advantage.

**14. P-gp Efflux:** Ligand A has a higher P-gp efflux liability (0.322) than Ligand B (0.165). Lower efflux is preferred, making Ligand B better.

**15. Binding Affinity:** Ligand A has a significantly stronger binding affinity (-9.4 kcal/mol) compared to Ligand B (-7.0 kcal/mol). This is a substantial advantage for Ligand A.

**Overall Assessment:**

While Ligand A boasts a superior binding affinity, the significant drawbacks of high DILI risk, poor BBB penetration, and higher P-gp efflux liability are major concerns. Ligand B, despite a slightly weaker binding affinity, presents a much more favorable ADME-Tox profile, with low DILI risk, excellent BBB penetration, longer half-life, and lower P-gp efflux. For a CNS target like DRD2, achieving sufficient brain exposure is paramount, and Ligand B is far better positioned to do so. The 2.4 kcal/mol difference in binding affinity, while substantial, can potentially be overcome with further optimization of Ligand B, whereas mitigating the severe ADME liabilities of Ligand A would be considerably more challenging.

Output:
1
2025-04-17 03:27:54,470 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (347.459 and 370.837 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (82.43) is significantly better than Ligand B (113.33). For CNS targets, we want TPSA <= 90, and A is comfortably within that range, while B is pushing the limit.

**3. logP:** Both ligands have good logP values (2.016 and 1.259), falling within the optimal 1-3 range.

**4. H-Bond Donors:** Ligand A (1) is preferable to Ligand B (3). Fewer HBDs generally improve permeability.

**5. H-Bond Acceptors:** Ligand A (4) is preferable to Ligand B (5). Fewer HBAs generally improve permeability.

**6. QED:** Both ligands have acceptable QED values (0.484 and 0.566), indicating reasonable drug-likeness. Ligand B is slightly better.

**7. DILI:** Ligand A (12.718) has a much lower DILI risk than Ligand B (45.25). This is a significant advantage for A.

**8. BBB:** Ligand A (65.801) has a slightly better BBB penetration percentile than Ligand B (61.729), though both are somewhat below the desired >70 for CNS targets.

**9. Caco-2 Permeability:** Ligand A (-4.455) has a better Caco-2 permeability than Ligand B (-5.454).

**10. Aqueous Solubility:** Ligand A (-1.524) has better aqueous solubility than Ligand B (-2.402).

**11. hERG Inhibition:** Both ligands have very low hERG inhibition liability (0.421 and 0.2), which is excellent.

**12. Microsomal Clearance:** Ligand A (38.036) has a lower microsomal clearance than Ligand B (5.754), suggesting better metabolic stability.

**13. In vitro Half-Life:** Ligand B (30.341) has a significantly longer in vitro half-life than Ligand A (2.61). This is a positive for B.

**14. P-gp Efflux:** Ligand A (0.135) has lower P-gp efflux liability than Ligand B (0.093), which is favorable for CNS penetration.

**15. Binding Affinity:** Ligand B (-7.8) has a slightly better binding affinity than Ligand A (-7.0). While A's affinity is good, the 0.8 kcal/mol advantage of B is notable.

**Overall Assessment:**

While Ligand B has a slightly better binding affinity and longer half-life, Ligand A demonstrates superior ADME properties, particularly regarding TPSA, DILI risk, solubility, and metabolic stability. Given the GPCR-specific priorities, the lower TPSA and DILI risk of Ligand A are crucial. The slightly lower BBB penetration of A is a concern, but the other ADME advantages outweigh this. The better permeability and reduced toxicity profile of Ligand A make it a more promising drug candidate.

Output:
0
2025-04-17 03:27:54,471 - INFO - Batch 31 complete. Total preferences: 496
2025-04-17 03:27:54,471 - INFO - Processing batch 32/512...
2025-04-17 03:28:35,026 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (352.475 and 364.383 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (81.08) is significantly better than Ligand B (49.41), falling well below the 90 A^2 threshold for CNS targets. Ligand B is also good, but A is preferable.

**logP:** Both ligands have acceptable logP values (1.172 and 2.759), within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A (HBD=2, HBA=4) and Ligand B (HBD=1, HBA=2) both have low numbers of H-donors and acceptors, which is favorable for permeability.

**QED:** Both ligands have good QED scores (0.728 and 0.78), indicating good drug-like properties.

**DILI:** Ligand A (13.843) has a much lower DILI risk than Ligand B (21.946), indicating a safer profile.

**BBB:** Ligand B (89.725) has a significantly higher BBB penetration score than Ligand A (50.679). This is a *critical* advantage for a CNS target like DRD2.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.65 and -4.591). These values are unusual and likely indicate issues with the prediction method, but suggest poor permeability.

**Aqueous Solubility:** Both ligands have negative solubility values (-0.856 and -3.728), again suggesting issues with the prediction method and potential solubility concerns.

**hERG Inhibition:** Ligand A (0.183) has a lower hERG inhibition liability than Ligand B (0.657), which is preferable.

**Microsomal Clearance:** Ligand A (-0.336) has a lower (better) microsomal clearance than Ligand B (21.621), suggesting greater metabolic stability.

**In vitro Half-Life:** Ligand B (13.836) has a longer in vitro half-life than Ligand A (-2.752).

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.024 and 0.025), which is good.

**Binding Affinity:** Ligand B (-8.9 kcal/mol) has a slightly better binding affinity than Ligand A (-8.0 kcal/mol). While the difference is not huge, it is still a positive for Ligand B.

**Overall Assessment:**

Ligand B excels in BBB penetration and has a slightly better binding affinity and longer half-life. However, Ligand A has a much better safety profile (lower DILI), lower hERG risk, and better metabolic stability (lower Cl_mic). Given the importance of BBB penetration for a CNS target, and the relatively small difference in binding affinity, Ligand B is the more promising candidate. The negative solubility and Caco-2 values for both are concerning, but can be addressed through formulation or further chemical modification.

Output:
1
2025-04-17 03:28:35,026 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (379.287 Da) is slightly higher than Ligand B (344.411 Da), but both are acceptable.

**TPSA:** Ligand A (61.36) is better than Ligand B (67.87). For CNS targets, we want TPSA <= 90, both are well within this limit.

**logP:** Ligand A (4.968) is high, potentially causing solubility issues and off-target effects. Ligand B (1.578) is within the optimal range (1-3). This is a significant advantage for Ligand B.

**H-Bond Donors/Acceptors:** Ligand A (3 HBD, 2 HBA) and Ligand B (1 HBD, 4 HBA) are both reasonable, falling within the acceptable limits.

**QED:** Both ligands have similar QED values (0.703 and 0.763), indicating good drug-like properties.

**DILI:** Ligand A (42.691) has a slightly higher DILI risk than Ligand B (35.285), but both are below the concerning threshold of 60.

**BBB:** Ligand B (87.515) has a significantly better BBB penetration percentile than Ligand A (41.373). This is a *critical* advantage for a CNS target like DRD2.

**Caco-2 Permeability:** Ligand A (-5.032) has poor Caco-2 permeability, while Ligand B (-4.722) is also poor, but slightly better.

**Aqueous Solubility:** Ligand A (-5.138) has very poor aqueous solubility, which is a major concern. Ligand B (-2.333) is also poor, but better than Ligand A.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.558 and 0.379).

**Microsomal Clearance:** Ligand B (24.156) has much lower microsomal clearance than Ligand A (55.737), indicating better metabolic stability.

**In vitro Half-Life:** Ligand B (15.983 hours) has a longer half-life than Ligand A (35.998 hours).

**P-gp Efflux:** Ligand A (0.114) has higher P-gp efflux than Ligand B (0.059), meaning less CNS exposure.

**Binding Affinity:** Ligand B (-7.6 kcal/mol) has a significantly stronger binding affinity than Ligand A (-9.4 kcal/mol). This is a substantial advantage.

**Overall Assessment:**

Ligand B is clearly the superior candidate. While both ligands have acceptable MW and QED, Ligand B excels in the critical areas for a CNS GPCR target: BBB penetration, metabolic stability (lower Cl_mic and longer t1/2), lower P-gp efflux, and significantly stronger binding affinity. Ligand A suffers from poor solubility, high logP, and lower BBB penetration, making it less likely to succeed as a CNS drug. The affinity difference is also substantial, and a 1.6 kcal/mol advantage can often outweigh minor ADME drawbacks.

Output:
1
2025-04-17 03:28:35,026 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (348.447) is slightly better, being closer to the lower end which can aid permeability.

**2. TPSA:** Ligand A (73.91) is significantly better than Ligand B (108.49). For CNS targets, we want TPSA <= 90, and Ligand A comfortably meets this, while Ligand B exceeds it.

**3. logP:** Ligand A (1.902) is optimal, falling within the 1-3 range. Ligand B (-0.175) is quite low, potentially hindering permeation.

**4. H-Bond Donors:** Both ligands have acceptable HBD counts (2 and 1 respectively), well below the threshold of 5.

**5. H-Bond Acceptors:** Both ligands have acceptable HBA counts (6 and 7 respectively), below the threshold of 10.

**6. QED:** Both ligands have reasonable QED values (0.818 and 0.547), indicating good drug-like properties. Ligand A is superior.

**7. DILI:** Ligand A (36.565) has a much lower DILI risk than Ligand B (57.387). Both are below 60, but A is preferable.

**8. BBB:** This is a critical parameter for CNS targets. Ligand A (86.739) has excellent BBB penetration, exceeding the desirable >70 threshold. Ligand B (25.126) is very poor, indicating limited CNS exposure.

**9. Caco-2 Permeability:** Ligand A (-5.149) and Ligand B (-5.425) both have negative values. This is unusual and suggests poor permeability. However, the scale is not specified, so it's difficult to interpret.

**10. Aqueous Solubility:** Both ligands have negative solubility values (-2.251 and -2.034). This is also unusual and suggests poor solubility.

**11. hERG:** Both ligands have very low hERG inhibition risk (0.444 and 0.023).

**12. Microsomal Clearance:** Ligand A (-15.893) has significantly lower (better) microsomal clearance than Ligand B (29.186), indicating greater metabolic stability.

**13. In vitro Half-Life:** Ligand A (-30.936) has a longer half-life than Ligand B (-23.055), which is desirable.

**14. P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.014 and 0.01).

**15. Binding Affinity:** Ligand A (-8.4 kcal/mol) has a significantly stronger binding affinity than Ligand B (-6.5 kcal/mol). This >1.5 kcal/mol difference is substantial and can outweigh minor ADME drawbacks.

**Overall Assessment:**

Ligand A is clearly superior. It excels in crucial parameters for a CNS-targeting GPCR ligand: TPSA, logP, BBB penetration, metabolic stability, and binding affinity. While both have issues with solubility and Caco-2 permeability, the significantly better CNS penetration and affinity of Ligand A make it the far more promising candidate. Ligand B's low logP and poor BBB penetration are major drawbacks.

Output:
1
2025-04-17 03:28:35,027 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (341.411 and 348.487 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (63.69) is significantly better than Ligand B (75.27). For CNS targets, we want TPSA <= 90, and A is much closer to the optimal <=60 range. B is approaching a less desirable range.

**logP:** Both ligands have good logP values (3.257 and 2.581), falling within the 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A (HBD=1, HBA=4) is slightly better than Ligand B (HBD=2, HBA=3) in terms of balancing solubility and permeability, though both are acceptable.

**QED:** Ligand A (0.907) has a superior QED score compared to Ligand B (0.708), indicating a more drug-like profile.

**DILI:** Ligand B (24.544) has a much lower DILI risk than Ligand A (56.727), which is a significant advantage.

**BBB:** Ligand A (73.594) has a better BBB percentile than Ligand B (61.923). While both are not exceptional, A is closer to the desirable >70 for CNS targets.

**Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and suggests potential issues with permeability prediction. However, the magnitude is similar, so this isn't a major differentiator.

**Aqueous Solubility:** Both have negative solubility values, also unusual. Again, the magnitude is similar.

**hERG:** Ligand A (0.62) has a slightly higher hERG risk than Ligand B (0.119), which is preferable for B.

**Microsomal Clearance:** Ligand B (9.564) has a significantly lower microsomal clearance than Ligand A (28.96), indicating better metabolic stability.

**In vitro Half-Life:** Ligand B (-7.097) has a longer in vitro half-life than Ligand A (8.772), which is a positive attribute.

**P-gp Efflux:** Ligand A (0.05) shows lower P-gp efflux than Ligand B (0.186), which is favorable for CNS penetration.

**Binding Affinity:** Ligand B (-8.8 kcal/mol) has a slightly better binding affinity than Ligand A (-8.1 kcal/mol). The difference is 0.7 kcal/mol, which is a meaningful advantage.

**Overall Assessment:**

Ligand B has several advantages: lower DILI risk, better metabolic stability (lower Cl_mic, longer t1/2), and slightly better binding affinity. Ligand A has a better BBB score and lower P-gp efflux. However, the difference in binding affinity (0.7 kcal/mol) combined with the significantly improved safety profile (DILI) and metabolic stability of Ligand B outweigh the slight advantage of Ligand A in BBB and P-gp. The TPSA of Ligand A is better, but not dramatically so. Considering the GPCR-specific priorities, the improved affinity, safety, and metabolic stability of Ligand B make it the more promising candidate.

Output:
1
2025-04-17 03:28:35,027 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (338.407) is slightly lower, which could be beneficial for permeability.

**TPSA:** Ligand A (82.35) is better than Ligand B (60.85) as it is closer to the ideal range for CNS targets (<90).

**logP:** Both ligands have good logP values (A: 3.969, B: 2.362), falling within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A has 2 HBD and 4 HBA, while Ligand B has 1 HBD and 3 HBA. Both are within acceptable limits.

**QED:** Both ligands have good QED scores (A: 0.781, B: 0.837), indicating good drug-like properties.

**DILI:** Ligand B (20.9) has a significantly lower DILI risk than Ligand A (50.33), which is a major advantage.

**BBB:** Ligand B (75.727) has a much better BBB penetration percentile than Ligand A (32.416). This is *critical* for a CNS target like DRD2.

**Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and suggests potential issues with absorption prediction. However, the magnitude is similar.

**Aqueous Solubility:** Both have negative solubility values, again suggesting prediction issues. The values are similar.

**hERG Inhibition:** Both ligands show low hERG inhibition liability (A: 0.678, B: 0.348), which is good.

**Microsomal Clearance:** Ligand B (-13.188) has a *much* lower (better) microsomal clearance than Ligand A (89.114), indicating greater metabolic stability.

**In vitro Half-Life:** Ligand B (-19.679) has a significantly longer in vitro half-life than Ligand A (0.055), which is highly desirable.

**P-gp Efflux:** Ligand B (0.019) has a lower P-gp efflux liability than Ligand A (0.141), which is beneficial for CNS exposure.

**Binding Affinity:** Ligand B (-8.2) has a slightly better binding affinity than Ligand A (-7.7), although the difference is not huge.

**Overall Assessment:**

Ligand B is clearly superior. While Ligand A has a slightly lower molecular weight and comparable logP, Ligand B excels in the most important parameters for a CNS-targeting GPCR ligand: BBB penetration, metabolic stability (low Cl_mic, long t1/2), P-gp efflux, and DILI risk. The slightly better affinity of Ligand B further solidifies its position as the more promising candidate. The negative solubility and Caco-2 values are concerning for both, but the other advantages of Ligand B outweigh these issues.

Output:
1
2025-04-17 03:28:35,027 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (346.431 Da) is slightly lower, which could be beneficial for permeability. Ligand B (378.841 Da) is also acceptable.

**TPSA:** Ligand A (76.46) is excellent, well below the 90 A^2 threshold for CNS targets. Ligand B (80.48) is also good, but slightly higher.

**logP:** Ligand A (1.52) is within the optimal range (1-3). Ligand B (3.331) is at the higher end of optimal, potentially raising concerns about solubility and off-target effects, but still acceptable.

**H-Bond Donors/Acceptors:** Both ligands have 1 HBD and are within the acceptable range (<=5). Ligand A has 5 HBA, and Ligand B has 7 HBA, both are within the acceptable range (<=10).

**QED:** Both ligands have acceptable QED values (Ligand A: 0.44, Ligand B: 0.544), indicating reasonable drug-likeness. Ligand B is slightly better.

**DILI:** Ligand A (43.66) has a lower DILI risk than Ligand B (93.718), which is a significant advantage.

**BBB:** Ligand A (82.513) has a significantly better BBB penetration score than Ligand B (54.634). This is *crucial* for a CNS target like DRD2.

**Caco-2 Permeability:** Ligand A (-5.262) has a negative Caco-2 value, which is unusual and suggests poor permeability. Ligand B (-4.992) is also negative, but slightly less so.

**Aqueous Solubility:** Both ligands have very poor aqueous solubility (-1.582 and -3.326 respectively). This is a concern for both, but might be manageable with formulation strategies.

**hERG Inhibition:** Both ligands show low hERG inhibition risk (0.656 and 0.276 respectively).

**Microsomal Clearance:** Ligand A (19.777) has a lower microsomal clearance, indicating better metabolic stability, than Ligand B (37.128).

**In vitro Half-Life:** Ligand A (-25.689) has a negative half-life, which is not physically possible and suggests an issue with the data or the model. Ligand B (1.564) has a very short half-life, which is less than ideal.

**P-gp Efflux:** Both ligands show low P-gp efflux liability (0.089 and 0.348 respectively).

**Binding Affinity:** Ligand B (-8.3 kcal/mol) has a significantly stronger binding affinity than Ligand A (-7.6 kcal/mol). This is a substantial advantage.

**Overall Assessment:**

While Ligand B has a better binding affinity, Ligand A is significantly better in terms of BBB penetration, DILI risk, and metabolic stability. The negative Caco-2 value and half-life for Ligand A are concerning, but the strong BBB and low DILI are very attractive for a CNS drug. Ligand B's poor BBB and high DILI are major drawbacks. The affinity difference is 0.7 kcal/mol, which is significant, but the ADME advantages of Ligand A, particularly the BBB score, outweigh this difference for a CNS target.

Output:
0
2025-04-17 03:28:35,027 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (368.543 and 366.527 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (75.27) is slightly higher than Ligand B (62.66). Both are below the 90 A^2 threshold for CNS targets, but Ligand B is preferable.

**3. logP:** Ligand A (2.283) and Ligand B (3.297) are both within the optimal 1-3 range. Ligand B is slightly higher, which could be beneficial for membrane permeability.

**4. H-Bond Donors:** Ligand A (2) and Ligand B (1) are both acceptable, being less than 5. Ligand B is slightly better.

**5. H-Bond Acceptors:** Ligand A (3) and Ligand B (5) are both acceptable, being less than 10.

**6. QED:** Both ligands have good QED values (0.69 and 0.767, respectively), indicating good drug-like properties.

**7. DILI:** Both ligands have low DILI risk (41.024 and 38.852 percentile), which is good.

**8. BBB:** This is a critical parameter for CNS targets. Ligand A has a BBB penetration of 66.615%, while Ligand B has 56.378%. Ligand A is better, but both are below the desirable >70% threshold.

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.058 and -4.774). This is unusual and suggests poor permeability.

**10. Aqueous Solubility:** Both ligands have negative solubility values (-3.997 and -3.242). This is also unusual and suggests poor aqueous solubility.

**11. hERG Inhibition:** Both ligands have low hERG inhibition liability (0.427 and 0.56), which is good.

**12. Microsomal Clearance:** Ligand A (69.633) has higher clearance than Ligand B (63.063), indicating lower metabolic stability. Ligand B is preferable.

**13. In vitro Half-Life:** Ligand B (45.977) has a significantly longer half-life than Ligand A (-23.771). This is a major advantage for Ligand B.

**14. P-gp Efflux:** Both ligands have low P-gp efflux liability (0.262 and 0.478), which is good.

**15. Binding Affinity:** Ligand B (-7.2 kcal/mol) has a significantly stronger binding affinity than Ligand A (-9.3 kcal/mol). This is a substantial advantage.

**Overall Assessment:**

While Ligand A has a better BBB score, Ligand B excels in several crucial areas: stronger binding affinity, longer half-life, lower microsomal clearance, and a slightly better logP. The negative Caco-2 and solubility values are concerning for both, but the significantly improved affinity and PK properties of Ligand B outweigh the slightly lower BBB. Given the GPCR-specific priorities, the stronger affinity and improved PK profile of Ligand B make it the more promising candidate.

Output:
1
2025-04-17 03:28:35,028 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight (MW):** Both ligands (344.459 and 346.402 Da) fall comfortably within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (79.53) is slightly higher than Ligand B (60.85). Both are below the 90 A^2 threshold desirable for CNS targets, but Ligand B is significantly better.

**3. logP:** Both ligands have a logP around 1.87, which is optimal (1-3).

**4. H-Bond Donors (HBD):** Both have 1 HBD, which is within the acceptable limit of <=5.

**5. H-Bond Acceptors (HBA):** Ligand A has 4 HBA, and Ligand B has 3. Both are below the acceptable limit of <=10.

**6. QED:** Both ligands have high QED scores (0.904 and 0.909), indicating good drug-like properties.

**7. DILI:** Ligand A (21.753) has a much lower DILI risk than Ligand B (35.673). This is a significant advantage for Ligand A.

**8. BBB:** Both ligands have excellent BBB penetration (94.378 and 91.508), exceeding the >70% threshold for CNS targets.

**9. Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and suggests poor permeability. However, the scale is not specified, so it's difficult to interpret these values.

**10. Aqueous Solubility:** Both have negative solubility values, which is also unusual and suggests poor solubility. Again, the scale is not specified.

**11. hERG Inhibition:** Both ligands have low hERG inhibition risk (0.772 and 0.592).

**12. Microsomal Clearance (Cl_mic):** Ligand A (15.792) has significantly lower microsomal clearance than Ligand B (33.88), indicating better metabolic stability.

**13. In vitro Half-Life:** Ligand A (-12.694) has a longer in vitro half-life than Ligand B (-17.829).

**14. P-gp Efflux:** Ligand A (0.041) has much lower P-gp efflux liability than Ligand B (0.228), which is crucial for CNS penetration.

**15. Binding Affinity:** Ligand B (-7.9) has a slightly better binding affinity than Ligand A (-8.2). While a 0.3 kcal/mol difference is not huge, it's noticeable.

**Overall Assessment:**

While Ligand B has a slightly better binding affinity, Ligand A is the superior candidate. Ligand A demonstrates significantly better ADMET properties: lower DILI risk, lower microsomal clearance (better metabolic stability), longer half-life, and dramatically lower P-gp efflux. These factors are particularly important for a CNS-targeting GPCR like DRD2. The slightly better TPSA of Ligand B is outweighed by the substantial advantages of Ligand A in other crucial parameters. The negative values for Caco-2 and solubility are concerning for both, but the other benefits of Ligand A make it the more promising candidate.

Output:
1
2025-04-17 03:28:35,028 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (360.5) is slightly higher than Ligand B (347.5).

**TPSA:** Ligand A (41.13) is significantly better than Ligand B (64.86). For CNS targets, we want TPSA <= 90, and ideally closer to 60. Ligand A is much closer to this ideal.

**logP:** Ligand A (4.813) is a bit high, potentially causing solubility issues or off-target interactions. Ligand B (3.063) is within the optimal range (1-3).

**H-Bond Donors/Acceptors:** Ligand A (2 HBD, 2 HBA) and Ligand B (1 HBD, 6 HBA) both fall within acceptable limits.

**QED:** Both ligands have good QED scores (A: 0.696, B: 0.857), indicating drug-like properties.

**DILI:** Ligand A (56.15) has a higher DILI risk than Ligand B (37.30). Both are acceptable, but B is preferable.

**BBB:** Ligand B (85.033) has a significantly better BBB penetration percentile than Ligand A (70.454). This is a crucial factor for a CNS target like DRD2.

**Caco-2 Permeability:** Both have negative values, indicating poor permeability. Ligand A (-4.91) is slightly better than Ligand B (-5.309), but both are concerning.

**Aqueous Solubility:** Ligand A (-5.586) has slightly better aqueous solubility than Ligand B (-3.239), but both are poor.

**hERG Inhibition:** Ligand A (0.858) has a slightly higher hERG risk than Ligand B (0.356).

**Microsomal Clearance:** Ligand A (97.17) has higher microsomal clearance than Ligand B (27.217), meaning it's less metabolically stable.

**In vitro Half-Life:** Ligand B (10.223) has a much longer in vitro half-life than Ligand A (52.876).

**P-gp Efflux:** Ligand A (0.423) has lower P-gp efflux than Ligand B (0.209), suggesting better CNS exposure.

**Binding Affinity:** Ligand A (-9.6 kcal/mol) has a significantly stronger binding affinity than Ligand B (-8.5 kcal/mol). This is a substantial advantage.

**Overall Assessment:**

While Ligand A has a superior binding affinity, Ligand B presents a more favorable ADME profile, particularly regarding BBB penetration (critical for CNS targets), lower DILI risk, and longer half-life. The higher logP and lower TPSA of Ligand A are concerning, potentially hindering its ability to reach the target in the brain. The significantly better affinity of Ligand A *could* outweigh the ADME concerns, but the combination of better BBB, lower DILI, and longer half-life makes Ligand B a more promising starting point for optimization.

Output:
1
2025-04-17 03:28:35,028 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (362.55 and 365.396 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (66.4) is better than Ligand B (72.88). Both are below the 90 A^2 threshold desirable for CNS targets, but A is closer to optimal.

**logP:** Ligand A (2.362) is within the optimal 1-3 range. Ligand B (0.749) is slightly below 1, which could hinder permeation.

**H-Bond Donors & Acceptors:** Ligand A has 0 HBD and 4 HBA, while Ligand B has 2 HBD and 4 HBA. Both are within acceptable limits.

**QED:** Both ligands have similar QED values (0.771 and 0.729), indicating good drug-likeness.

**DILI:** Ligand A (37.999) has a slightly higher DILI risk than Ligand B (21.946), but both are below the concerning threshold of 60.

**BBB:** Ligand A (68.864) and Ligand B (64.831) are both reasonably good, but below the >70 desirable for CNS targets.

**Caco-2 Permeability:** Both have negative Caco-2 values (-4.481 and -4.859), which is unusual and suggests poor permeability. This is a significant concern.

**Aqueous Solubility:** Both have negative solubility values (-2.95 and -1.259), indicating very poor aqueous solubility. This is also a significant concern.

**hERG Inhibition:** Ligand A (0.223) has a lower hERG risk than Ligand B (0.655), which is preferable.

**Microsomal Clearance:** Ligand B (-9.151) has significantly lower (better) microsomal clearance than Ligand A (67.178), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand B (-9.644) has a much longer in vitro half-life than Ligand A (7.68), which is a major advantage.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.062 and 0.023), which is good for CNS penetration.

**Binding Affinity:** Ligand B (-8.5 kcal/mol) has a substantially stronger binding affinity than Ligand A (-0.0 kcal/mol). This is a crucial difference. A >1.5 kcal/mol advantage often outweighs other drawbacks.

**Overall Assessment:**

While Ligand A has slightly better TPSA and hERG inhibition, Ligand B is significantly superior due to its much higher binding affinity, lower microsomal clearance, longer half-life, and lower DILI risk. The poor Caco-2 and solubility for both are concerning, but the strong binding affinity of Ligand B makes it more likely to be optimized to overcome these issues. The difference in binding affinity is so large it outweighs the other concerns.

Output:
1
2025-04-17 03:28:35,028 - INFO - Reasoning:

Let's analyze Ligand A and Ligand B based on the provided guidelines, prioritizing GPCR-specific properties (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (336.405 Da) is slightly preferred due to being closer to the lower end, potentially aiding permeability.

**TPSA:** Ligand A (38.77) is excellent for CNS penetration, well below 90. Ligand B (86.71) is higher, but still potentially acceptable, though less ideal.

**logP:** Ligand A (4.764) is a bit high, potentially leading to solubility issues or off-target effects. Ligand B (1.78) is within the optimal range (1-3). This favors Ligand B.

**H-Bond Donors/Acceptors:** Ligand A (0 HBD, 3 HBA) is very favorable. Ligand B (2 HBD, 5 HBA) is also acceptable.

**QED:** Both ligands have good QED scores (A: 0.651, B: 0.748), indicating drug-like properties.

**DILI:** Ligand A (77.511) has a higher DILI risk than Ligand B (46.219). This favors Ligand B.

**BBB:** Ligand A (72.237) has a good BBB penetration score, slightly better than Ligand B (67.352), but both are reasonably good for a CNS target.

**Caco-2 Permeability:** Ligand A (-4.224) has poor Caco-2 permeability, indicating potential absorption issues. Ligand B (-5.319) is also poor, but slightly worse.

**Aqueous Solubility:** Ligand A (-6.05) has very poor aqueous solubility. Ligand B (-3.014) is better, but still poor.

**hERG:** Both ligands have low hERG inhibition risk (A: 0.852, B: 0.522).

**Microsomal Clearance:** Both ligands have similar microsomal clearance (A: 30.058, B: 33.834), suggesting comparable metabolic stability.

**In vitro Half-Life:** Both ligands have negative in vitro half-lives (-36.219 and -34.812), which is unusual and suggests rapid degradation. The values are similar.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (A: 0.498, B: 0.055). Ligand B is significantly better.

**Binding Affinity:** Ligand A (-9.5 kcal/mol) has a significantly stronger binding affinity than Ligand B (-8.3 kcal/mol). This is a substantial advantage.

**Overall Assessment:**

The key differentiating factors are affinity and logP. Ligand A has a much stronger binding affinity, which is a major advantage for a GPCR target. However, its high logP and poor solubility are concerning. Ligand B has a more balanced profile with a good logP, lower DILI risk, and better P-gp efflux, but its affinity is weaker.

Given the GPCR-specific priorities, the strong affinity of Ligand A is likely to outweigh its drawbacks, *provided* solubility can be addressed through formulation strategies. The difference in binding affinity (1.2 kcal/mol) is significant.

Output:
1
2025-04-17 03:28:35,028 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (345.487 and 347.375 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (64.41) is excellent, well below the 90 A^2 threshold for CNS targets. Ligand B (124.35) is higher, but still potentially acceptable, though less ideal.

**3. logP:** Ligand A (2.813) is optimal (1-3). Ligand B (0.029) is very low, potentially hindering permeation. This is a significant drawback.

**4. H-Bond Donors:** Ligand A (0) is good. Ligand B (3) is acceptable, but higher HBDs can sometimes reduce permeability.

**5. H-Bond Acceptors:** Ligand A (3) is good. Ligand B (6) is acceptable, but higher HBAs can sometimes reduce permeability.

**6. QED:** Both ligands have similar QED values (0.79 and 0.677), indicating good drug-like properties.

**7. DILI:** Ligand A (16.673) has a much lower DILI risk than Ligand B (69.523). This is a significant advantage for Ligand A.

**8. BBB:** Ligand A (81.776) has excellent BBB penetration, exceeding the 70% threshold for CNS targets. Ligand B (25.94) has very poor predicted BBB penetration, a major concern for a DRD2 ligand.

**9. Caco-2 Permeability:** Ligand A (-4.605) has poor Caco-2 permeability. Ligand B (-5.637) has even worse Caco-2 permeability.

**10. Aqueous Solubility:** Ligand A (-2.186) has poor aqueous solubility. Ligand B (-1.328) has slightly better aqueous solubility.

**11. hERG Inhibition:** Ligand A (0.639) has a low hERG risk. Ligand B (0.029) also has a low hERG risk.

**12. Microsomal Clearance:** Ligand A (27.378) has moderate clearance. Ligand B (-3.144) has negative clearance, which is not physically possible and likely indicates an issue with the prediction or the molecule itself.

**13. In vitro Half-Life:** Ligand A (0.12) has a very short half-life. Ligand B (-3.376) has a negative half-life, which is not physically possible.

**14. P-gp Efflux:** Ligand A (0.223) has low P-gp efflux, which is favorable for CNS penetration. Ligand B (0.008) has very low P-gp efflux, which is also favorable.

**15. Binding Affinity:** Ligand A (-8.4 kcal/mol) has a significantly stronger binding affinity than Ligand B (-7.1 kcal/mol). This 1.3 kcal/mol difference is substantial and can outweigh some ADME drawbacks.

**Overall Assessment:**

Ligand A is the superior candidate. While it has poor Caco-2 permeability and aqueous solubility, its excellent BBB penetration, low DILI risk, strong binding affinity, and acceptable logP outweigh these concerns. Ligand B suffers from a very low logP, poor BBB penetration, and unrealistic clearance/half-life predictions. The significantly stronger binding affinity of Ligand A makes it a much more promising starting point for further optimization.

Output:
1
2025-04-17 03:28:35,029 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (343.387 and 349.519 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (100.21) is slightly above the optimal <90 for CNS targets, but still reasonable. Ligand B (43.86) is excellent, well below 90.

**logP:** Ligand A (0.566) is a bit low, potentially hindering membrane permeability. Ligand B (2.382) is within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A has 2 HBD and 5 HBA, which are acceptable. Ligand B has 0 HBD and 3 HBA, also acceptable.

**QED:** Both ligands have reasonable QED scores (0.765 and 0.692), indicating good drug-like properties.

**DILI:** Ligand A (55.874) has a moderate DILI risk, while Ligand B (8.918) has a very low risk. This is a significant advantage for Ligand B.

**BBB:** Ligand A (45.56) has a poor BBB penetration percentile, which is a major concern for a CNS target like DRD2. Ligand B (82.047) has excellent BBB penetration, a crucial advantage.

**Caco-2 Permeability:** Ligand A (-5.396) has very poor Caco-2 permeability. Ligand B (-4.584) is also poor, but slightly better than Ligand A.

**Aqueous Solubility:** Both ligands have poor aqueous solubility (-1.923 and -1.278). This could pose formulation challenges, but is less critical than BBB for CNS drugs.

**hERG Inhibition:** Ligand A (0.239) has a slightly elevated hERG risk, while Ligand B (0.723) has a higher risk.

**Microsomal Clearance:** Ligand A (-13.721) has very low microsomal clearance, indicating good metabolic stability. Ligand B (28.297) has higher clearance, suggesting faster metabolism.

**In vitro Half-Life:** Ligand A (-8.895) has a very long in vitro half-life, consistent with low clearance. Ligand B (-11.262) has a shorter half-life.

**P-gp Efflux:** Ligand A (0.004) has very low P-gp efflux, which is excellent for CNS penetration. Ligand B (0.149) has slightly higher efflux.

**Binding Affinity:** Ligand A (-8.7 kcal/mol) has a slightly stronger binding affinity than Ligand B (-7.7 kcal/mol), but the difference is less than 1.5 kcal/mol.

**Overall Assessment:**

Ligand B is significantly more promising due to its excellent BBB penetration (82.047), low DILI risk (8.918), and acceptable logP (2.382). While Ligand A has slightly better affinity and metabolic stability, these advantages are outweighed by its poor BBB penetration and moderate DILI risk, which are critical factors for a CNS-targeting drug. The slightly better TPSA of Ligand B is also beneficial.

Output:
1
2025-04-17 03:28:35,029 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (339.355 and 347.346 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (110.0) is slightly above the optimal <90 for CNS targets, but still reasonable. Ligand B (95.4) is well within the desired range.

**logP:** Both ligands have good logP values (1.179 and 1.65), falling within the 1-3 range.

**H-Bond Donors/Acceptors:** Both have 2 HBD and acceptable HBA counts (6 and 4 respectively).

**QED:** Both ligands have good QED scores (0.698 and 0.822), indicating good drug-like properties.

**DILI:** Ligand A (90.229) has a higher DILI risk than Ligand B (77.86), but both are still relatively acceptable.

**BBB:** This is a critical parameter for a CNS target like DRD2. Ligand B (64.017) has a significantly better BBB penetration percentile than Ligand A (44.668).

**Caco-2 Permeability:** Both ligands have negative Caco-2 values, which is unusual and indicates poor permeability. This is a significant concern for both.

**Aqueous Solubility:** Both ligands have very poor aqueous solubility (-3.126 and -2.93). This is a major drawback.

**hERG Inhibition:** Both ligands show very low hERG inhibition risk (0.031 and 0.101).

**Microsomal Clearance:** Ligand A (-7.339) has a much lower (better) microsomal clearance than Ligand B (-16.473), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (10.769 hours) has a significantly longer half-life than Ligand B (-30.702 hours). The negative value for Ligand B is concerning and likely an error or indicates very rapid degradation.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.051 and 0.012), which is favorable for CNS penetration.

**Binding Affinity:** Both ligands have excellent binding affinities (-9.4 and -9.8 kcal/mol). The difference is minimal.

**Overall Assessment:**

While both ligands have excellent binding affinity, Ligand B is the more promising candidate due to its significantly better BBB penetration (64.017 vs 44.668), and lower DILI risk. Ligand A has better metabolic stability (lower Cl_mic) and a longer half-life, but the BBB penetration is a critical factor for CNS targets. The poor solubility and Caco-2 permeability are concerns for both, but can potentially be addressed through formulation strategies.

Output:
1
2025-04-17 03:28:35,029 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (345.4 and 362.5 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (76.71) is better than Ligand B (53.43). Both are below 90, which is favorable for CNS penetration.

**3. logP:** Ligand A (2.853) is optimal (1-3), while Ligand B (4.375) is slightly higher, potentially leading to solubility issues and off-target effects.

**4. H-Bond Donors:** Both ligands have 1 HBD, which is within the acceptable limit of 5.

**5. H-Bond Acceptors:** Ligand A has 5 HBA, and Ligand B has 4. Both are within the acceptable limit of 10.

**6. QED:** Both ligands have similar QED values (0.865 and 0.83), indicating good drug-likeness.

**7. DILI:** Ligand A (56.65) has a slightly higher DILI risk than Ligand B (32.261), but both are below the concerning threshold of 60.

**8. BBB:** Ligand A (75.805) has a significantly better BBB percentile than Ligand B (69.833). This is a crucial factor for CNS targets like DRD2.

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.513 and -4.592), which is unusual and suggests poor permeability. This is a significant drawback for both.

**10. Aqueous Solubility:** Both ligands have negative solubility values (-3.56 and -5.321), which is also concerning.

**11. hERG Inhibition:** Both ligands have low hERG inhibition risk (0.421 and 0.628).

**12. Microsomal Clearance:** Ligand A (95.865) has higher microsomal clearance than Ligand B (90.067), suggesting lower metabolic stability.

**13. In vitro Half-Life:** Ligand B (-14.426) has a significantly *shorter* in vitro half-life than Ligand A (43.703). This is a major disadvantage for Ligand B.

**14. P-gp Efflux:** Both ligands have low P-gp efflux liability (0.239 and 0.303).

**15. Binding Affinity:** Ligand A (-8.1 kcal/mol) has a slightly better binding affinity than Ligand B (-7.5 kcal/mol). While both are good, the 0.6 kcal/mol difference is noticeable.

**Overall Assessment:**

Considering the GPCR-specific priorities, Ligand A is the more promising candidate. It has better BBB penetration, slightly better binding affinity, and a significantly longer in vitro half-life. While both have poor Caco-2 and solubility, the superior CNS penetration and binding of Ligand A outweigh the slightly higher DILI and clearance. The slightly better logP of Ligand A also contributes to its favorability.

Output:
1
2025-04-17 03:28:35,029 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (355.316 and 368.371 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (87.3) is better than Ligand B (69.64). Both are below the 90 A^2 threshold for CNS targets, which is excellent.

**logP:** Both ligands have good logP values (2.351 and 1.959), falling within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A has 3 HBD and 4 HBA, while Ligand B has 2 HBD and 3 HBA. Both are within acceptable limits (<=5 HBD and <=10 HBA).

**QED:** Both ligands have similar QED scores (0.572 and 0.508), indicating good drug-likeness.

**DILI:** Ligand A (70.105) has a higher DILI risk than Ligand B (33.695). This is a significant advantage for Ligand B.

**BBB:** Ligand A (83.947) has a much better BBB penetration percentile than Ligand B (54.478). This is crucial for a CNS target like DRD2.

**Caco-2 Permeability:** Ligand A (-5.183) has worse Caco-2 permeability than Ligand B (-4.833), indicating lower intestinal absorption.

**Aqueous Solubility:** Ligand A (-4.18) has worse aqueous solubility than Ligand B (-1.505).

**hERG Inhibition:** Both ligands have low hERG inhibition liability (0.298 and 0.499), which is good.

**Microsomal Clearance:** Ligand A (-9.167) has significantly lower microsomal clearance than Ligand B (0.544), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (14.924) has a longer in vitro half-life than Ligand B (-2.894).

**P-gp Efflux:** Ligand A (0.064) has lower P-gp efflux than Ligand B (0.066), which is favorable for CNS penetration.

**Binding Affinity:** Ligand A (-10.6 kcal/mol) has a significantly stronger binding affinity than Ligand B (0.0 kcal/mol). This is a major advantage, potentially outweighing some of the ADME drawbacks.

**Overall Assessment:**

Ligand A excels in binding affinity and BBB penetration, and has better metabolic stability. However, it has poorer solubility, Caco-2 permeability, and a higher DILI risk. Ligand B has a much better safety profile (lower DILI) and better solubility/permeability, but its binding affinity is extremely weak.

Given the strong emphasis on affinity for GPCRs, and the substantial difference in binding energy (-10.6 vs 0.0 kcal/mol), Ligand A is the more promising candidate despite its ADME liabilities. The strong binding could potentially be optimized through further structural modifications to address the solubility and DILI concerns. The poor affinity of Ligand B is a major hurdle that would be difficult to overcome.

Output:
1
2025-04-17 03:28:35,030 - INFO - Batch 32 complete. Total preferences: 512
2025-04-17 03:28:35,030 - INFO - Processing batch 33/512...
2025-04-17 03:29:16,624 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (347.434 and 350.419 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (52.65) is significantly better than Ligand B (85.69). For CNS targets, we want TPSA <= 90, and A is comfortably within this range, while B is approaching the upper limit.

**3. logP:** Both ligands have acceptable logP values (1.941 and 0.777), falling within the 1-3 range. Ligand A is slightly preferred.

**4. H-Bond Donors:** Both have 1 HBD, which is good.

**5. H-Bond Acceptors:** Ligand A has 3 HBA, and Ligand B has 6. Lower is generally better, and A is preferable here.

**6. QED:** Both ligands have similar QED values (0.82 and 0.819), indicating good drug-likeness.

**7. DILI:** Ligand A (29.236) has a much lower DILI risk than Ligand B (54.634). This is a significant advantage for A.

**8. BBB:** Ligand A (81.815) has a better BBB penetration percentile than Ligand B (73.905). While both are reasonably good, A is closer to the desirable >70 threshold for CNS targets.

**9. Caco-2:** Both have negative Caco-2 values (-4.719 and -4.856), which is unusual and difficult to interpret without further context. It suggests poor permeability.

**10. Solubility:** Both have negative solubility values (-1.715 and -1.75), also unusual. This suggests poor aqueous solubility.

**11. hERG:** Ligand A (0.769) has a slightly better hERG profile than Ligand B (0.156), indicating lower cardiotoxicity risk.

**12. Cl_mic:** Ligand A (33.456) has a higher microsomal clearance than Ligand B (14.062), meaning it's metabolized faster. This is a disadvantage for A.

**13. t1/2:** Ligand B (22.553) has a longer in vitro half-life than Ligand A (9.051), which is preferable.

**14. Pgp:** Ligand A (0.067) has significantly lower P-gp efflux liability than Ligand B (0.038), meaning it is less likely to be pumped out of the brain, which is crucial for CNS targets.

**15. Binding Affinity:** Both ligands have very similar and excellent binding affinities (-8.6 and -8.0 kcal/mol). The difference of 0.6 kcal/mol is not substantial enough to override other significant differences.

**Overall Assessment:**

Considering the GPCR-specific priorities, Ligand A is the better candidate. It has a significantly lower DILI risk, better TPSA, better BBB penetration, lower P-gp efflux, and a slightly better hERG profile. While Ligand B has a longer half-life and lower Cl_mic, the advantages of A in terms of CNS penetration and safety are more critical for a DRD2 target. The unusual Caco-2 and solubility values are concerning for both, but can be addressed with formulation strategies.



Output:
1
2025-04-17 03:29:16,625 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (359.411 and 350.511 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (90.09) is borderline, but acceptable for a CNS target, while Ligand B (59.31) is well within the desired range (<90). This favors Ligand B.

**logP:** Ligand A (0.643) is a bit low, potentially hindering permeation. Ligand B (1.92) is within the optimal 1-3 range. This favors Ligand B.

**H-Bond Donors:** Both have 0 HBD, which is good.

**H-Bond Acceptors:** Both have 7 HBA, which is acceptable.

**QED:** Both ligands have good QED scores (0.67 and 0.749), indicating drug-likeness.

**DILI:** Ligand A has a high DILI risk (85.149), while Ligand B has a very low risk (15.2). This is a significant advantage for Ligand B.

**BBB:** Both ligands show good BBB penetration (69.678 and 87.553), but Ligand B is better, exceeding 70%. This favors Ligand B.

**Caco-2 Permeability:** Both have negative Caco-2 values (-5.026 and -4.761). This is unusual and suggests poor permeability, but the scale isn't specified, so it's hard to interpret.

**Aqueous Solubility:** Both have negative solubility values (-3.513 and -1.58). Similar to Caco-2, the scale is unclear, making interpretation difficult.

**hERG Inhibition:** Both have low hERG inhibition risk (0.208 and 0.546).

**Microsomal Clearance:** Ligand A (67.096) has higher clearance than Ligand B (25.838), indicating lower metabolic stability. This favors Ligand B.

**In vitro Half-Life:** Ligand A has a negative half-life (-26.307), which is problematic. Ligand B has a short half-life (7.331), but it's a positive value. This strongly favors Ligand B.

**P-gp Efflux:** Both have low P-gp efflux liability (0.207 and 0.073), which is good for CNS penetration.

**Binding Affinity:** Ligand A (-8.8 kcal/mol) has significantly better binding affinity than Ligand B (-5.9 kcal/mol). This is a substantial advantage for Ligand A.

**Overall Assessment:**

While Ligand A has a much stronger binding affinity, its significantly higher DILI risk, higher microsomal clearance, and negative in vitro half-life are major drawbacks. Ligand B, despite the weaker affinity, displays a much more favorable ADME-Tox profile, with lower DILI risk, better BBB penetration, lower clearance, and a positive half-life. Considering the GPCR-specific emphasis on BBB and the importance of avoiding toxicity, Ligand B is the more promising candidate. The affinity difference, while substantial, might be overcome with further optimization of Ligand B.

Output:
1
2025-04-17 03:29:16,625 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (364.421 and 349.435 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (58.12) is excellent, well below the 90 A^2 threshold for CNS targets. Ligand B (89.35) is higher but still acceptable, though less ideal.

**3. logP:** Ligand A (2.838) is optimal. Ligand B (0.824) is a bit low, potentially hindering membrane permeability.

**4. H-Bond Donors:** Both ligands have 1 HBD, which is within the acceptable limit of <=5.

**5. H-Bond Acceptors:** Ligand A has 5 HBAs, and Ligand B has 6. Both are within the acceptable limit of <=10.

**6. QED:** Ligand A (0.906) has a very strong drug-like profile. Ligand B (0.667) is still reasonable, exceeding the 0.5 threshold.

**7. DILI:** Ligand A (62.001) has a moderate DILI risk. Ligand B (45.715) has a lower, more favorable DILI risk.

**8. BBB:** Ligand A (80.225) has good BBB penetration potential. Ligand B (56.534) is significantly lower, which is a major concern for a CNS target like DRD2.

**9. Caco-2 Permeability:** Both have negative values, which is unusual. Assuming these are logP values, Ligand A (-4.916) is worse than Ligand B (-5.075).

**10. Aqueous Solubility:** Both have negative values, which is unusual. Ligand A (-4.11) is better than Ligand B (-1.235).

**11. hERG Inhibition:** Ligand A (0.314) has very low hERG inhibition risk. Ligand B (0.076) has even lower risk, which is excellent.

**12. Microsomal Clearance:** Ligand A (33.348) has moderate clearance. Ligand B (24.93) has lower clearance, indicating better metabolic stability.

**13. In vitro Half-Life:** Ligand A (16.609) has a reasonable half-life. Ligand B (3.214) has a very short half-life, which is a significant drawback.

**14. P-gp Efflux:** Ligand A (0.282) has low P-gp efflux, which is good. Ligand B (0.012) has very low P-gp efflux, which is even better.

**15. Binding Affinity:** Ligand A (-8.6 kcal/mol) has a significantly stronger binding affinity than Ligand B (-7.1 kcal/mol). This >1.5 kcal/mol difference is substantial and can outweigh some ADME concerns.

**Overall Assessment:**

Ligand A is superior due to its significantly better binding affinity and good BBB penetration. While Ligand B has slightly better DILI, hERG, and P-gp profiles, the substantial difference in affinity and the poor BBB penetration make it less promising. The slightly higher DILI risk of Ligand A is a manageable concern given its strong potency. The short half-life of Ligand B is also a major drawback.

Output:
1
2025-04-17 03:29:16,626 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (344.39 and 346.439 Da) fall comfortably within the ideal 200-500 Da range.

**TPSA:** Ligand A (67.23) is significantly better than Ligand B (126.8). For CNS targets, we want TPSA <= 90, and A is well within that, while B is exceeding it. This is a significant advantage for A.

**logP:** Both ligands have acceptable logP values (1.636 and 0.723), falling within the 1-3 range. A is slightly better.

**H-Bond Donors/Acceptors:** Ligand A (1 HBD, 4 HBA) is better than Ligand B (4 HBD, 9 HBA). Lower values are generally preferred for better permeability.

**QED:** Ligand A (0.897) has a substantially higher QED score than Ligand B (0.578), indicating a more drug-like profile.

**DILI:** Ligand A (31.795) has a much lower DILI risk than Ligand B (48.623), both are below 60, but A is preferable.

**BBB:** Ligand A (76.231) has a significantly better BBB penetration score than Ligand B (54.634). For a CNS target like DRD2, >70 is desirable, but A is closer to that threshold than B.

**Caco-2 Permeability:** Ligand A (-4.979) is better than Ligand B (-5.589), both are negative, but A is less negative.

**Aqueous Solubility:** Both ligands have similar and poor aqueous solubility (-2.066 and -2.103). This could be a formulation challenge for both.

**hERG Inhibition:** Both ligands have similar hERG inhibition liability (0.259 and 0.343), indicating relatively low cardiotoxicity risk.

**Microsomal Clearance:** Ligand A (10.66) has a lower microsomal clearance than Ligand B (14.482), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (-19.818) has a much longer in vitro half-life than Ligand B (16.983), which is a significant advantage.

**P-gp Efflux:** Ligand A (0.071) has a lower P-gp efflux liability than Ligand B (0.011), indicating better CNS exposure.

**Binding Affinity:** Both ligands have very similar binding affinities (-8.6 and -8.4 kcal/mol). The difference is less than 1.5 kcal/mol, so it's not a deciding factor.

**Overall Assessment:**

Ligand A consistently outperforms Ligand B across most crucial ADME properties, especially TPSA, BBB, QED, DILI, metabolic stability (Cl_mic and t1/2), and P-gp efflux. While both have similar binding affinities and solubility concerns, the superior ADME profile of Ligand A makes it a much more promising drug candidate for targeting DRD2 in the CNS.

Output:
0
2025-04-17 03:29:16,626 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (353.413 and 350.459 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (71.09) is significantly better than Ligand B (84.5). For CNS targets, TPSA should be <= 90, and A is comfortably within this range, while B is approaching the upper limit.

**3. logP:** Both ligands have good logP values (2.694 and 1.572), falling within the optimal 1-3 range. Ligand A is slightly higher, potentially aiding membrane permeability.

**4. H-Bond Donors:** Both have 2 HBD, which is acceptable.

**5. H-Bond Acceptors:** Ligand A has 3 HBA, Ligand B has 4. Both are within the acceptable limit of <=10.

**6. QED:** Both have reasonable QED scores (0.855 and 0.762), indicating good drug-like properties.

**7. DILI:** Ligand A (37.301) has a slightly higher DILI risk than Ligand B (20.744), but both are below the concerning threshold of 60.

**8. BBB:** This is a crucial parameter for CNS targets. Ligand A has a significantly better BBB penetration percentile (84.374) compared to Ligand B (70.531). A value >70 is desirable, and A is clearly superior.

**9. Caco-2 Permeability:** Ligand A (-4.633) has worse Caco-2 permeability than Ligand B (-5.037). Lower (more negative) values indicate lower permeability.

**10. Aqueous Solubility:** Ligand A (-3.695) has worse aqueous solubility than Ligand B (-2.204). Higher values are preferred.

**11. hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.279 and 0.101).

**12. Microsomal Clearance:** Ligand A (32.813) has higher microsomal clearance than Ligand B (17.129), suggesting lower metabolic stability.

**13. In vitro Half-Life:** Ligand B (7.998) has a longer in vitro half-life than Ligand A (-24.255). A longer half-life is generally preferred.

**14. P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.022 and 0.027).

**15. Binding Affinity:** Ligand B (-7.8 kcal/mol) has a slightly better binding affinity than Ligand A (-8.0 kcal/mol). While the difference is small, it's still a factor.

**Overall Assessment:**

Ligand A excels in BBB penetration and TPSA, which are critical for CNS GPCR targets. However, it suffers from lower Caco-2 permeability, lower aqueous solubility, and higher microsomal clearance. Ligand B has slightly better affinity, half-life, and solubility, but its TPSA is less favorable and its BBB penetration is lower.

Considering the GPCR-specific priorities, the superior BBB penetration of Ligand A outweighs its slightly less favorable ADME properties. The small difference in binding affinity is less important than achieving good CNS exposure.

Output:
1
2025-04-17 03:29:16,626 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the acceptable range (200-500 Da). Ligand A (363.527 Da) is slightly lower than Ligand B (412.372 Da), which is generally favorable for permeability.

**TPSA:** Both ligands have TPSA values below 90, which is good for CNS penetration. Ligand A (61.44) is slightly higher than Ligand B (58.36), but both are acceptable.

**logP:** Both ligands have logP values within the optimal range (1-3). Ligand A (2.722) and Ligand B (3.171) are both suitable.

**H-Bond Donors & Acceptors:** Ligand A has 2 HBD and 4 HBA, while Ligand B has 1 HBD and 4 HBA. Both are within the recommended limits (HBD <= 5, HBA <= 10).

**QED:** Both ligands have similar QED values (Ligand A: 0.764, Ligand B: 0.731), indicating good drug-like properties.

**DILI:** Ligand A has a DILI risk of 25.126%, while Ligand B has 13.377%. Ligand B is significantly better in terms of potential liver toxicity.

**BBB:** This is a critical parameter for CNS targets. Ligand B (75.533%) has a much higher BBB penetration prediction than Ligand A (57.154%). This is a major advantage for Ligand B.

**Caco-2 Permeability:** Ligand A (-5.139) and Ligand B (-4.745) both have negative values, indicating poor permeability.

**Aqueous Solubility:** Both ligands have negative solubility values, which is concerning. Ligand A (-2.082) is slightly better than Ligand B (-3.89).

**hERG Inhibition:** Both ligands have low hERG inhibition risk (Ligand A: 0.412, Ligand B: 0.566).

**Microsomal Clearance:** Ligand B (57.787) has a higher microsomal clearance than Ligand A (26.445), indicating faster metabolism and potentially lower exposure.

**In vitro Half-Life:** Ligand A (40.054 hours) has a longer in vitro half-life than Ligand B (22.27 hours), which is desirable.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (Ligand A: 0.109, Ligand B: 0.383).

**Binding Affinity:** Ligand A (-8.2 kcal/mol) has a significantly stronger binding affinity than Ligand B (-7.0 kcal/mol). This is a substantial advantage for Ligand A, potentially outweighing some of its ADME drawbacks. The difference is >1.5 kcal/mol.

**Overall Assessment:**

While Ligand A has a superior binding affinity, Ligand B has a much better predicted BBB penetration and a lower DILI risk. Considering the GPCR-specific priorities, BBB penetration is crucial for CNS targets like DRD2. The stronger binding of Ligand A is attractive, but the significantly improved CNS exposure predicted for Ligand B, coupled with reduced toxicity, makes it the more promising candidate. The lower half-life and higher clearance of Ligand B are concerns, but these could potentially be addressed through structural modifications.

Output:
1
2025-04-17 03:29:16,626 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (372.447 and 381.929 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (110.6) is higher than the preferred <90 for CNS targets, while Ligand B (53.51) is well within the range. This is a significant advantage for Ligand B.

**logP:** Ligand A (-0.191) is quite low, potentially hindering membrane permeability. Ligand B (3.407) is optimal.

**H-Bond Donors/Acceptors:** Ligand A has 1 HBD and 7 HBA, which are acceptable. Ligand B has 0 HBD and 4 HBA, also acceptable.

**QED:** Both ligands have good QED scores (0.717 and 0.803), indicating good drug-like properties.

**DILI:** Both ligands have similar, acceptable DILI risk (40.946 and 42.458).

**BBB:** Ligand B (74.796) has a significantly better BBB percentile than Ligand A (64.482), which is crucial for a CNS target like DRD2.

**Caco-2 Permeability:** Both have negative Caco-2 values (-4.827 and -4.786), which is unusual and suggests poor permeability. However, these values are on a scale where negative values are possible, and the absolute values are similar.

**Aqueous Solubility:** Both have negative solubility values (-2.156 and -2.9), indicating poor aqueous solubility.

**hERG:** Both ligands have low hERG risk (0.151 and 0.613).

**Microsomal Clearance:** Both have similar microsomal clearance values (43.07 and 45.749), suggesting comparable metabolic stability.

**In vitro Half-Life:** Ligand B (-3.176) has a slightly better (less negative) in vitro half-life than Ligand A (-32.78).

**P-gp Efflux:** Ligand A (0.028) has a much lower P-gp efflux liability than Ligand B (0.215), which is favorable for CNS penetration.

**Binding Affinity:** Ligand B (-8.8 kcal/mol) has a significantly stronger binding affinity than Ligand A (-7.7 kcal/mol). This 1.1 kcal/mol difference is substantial and can outweigh some of the ADME drawbacks.

**Overall Assessment:**

Ligand B is the superior candidate. While both have issues with Caco-2 permeability and aqueous solubility, Ligand B excels in key areas for a CNS-targeting GPCR: significantly better TPSA, optimal logP, higher BBB penetration, and substantially improved binding affinity. The lower P-gp efflux for Ligand A is a positive, but the other advantages of Ligand B are more impactful.

Output:
1
2025-04-17 03:29:16,627 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (349.431 and 352.431 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (72.8) is significantly better than Ligand B (84.94). For CNS targets, we want TPSA <= 90, and A is comfortably within that range, while B is approaching the upper limit.

**logP:** Both ligands have acceptable logP values (1.839 and 0.884), falling within the 1-3 range.

**H-Bond Donors/Acceptors:** Both have 1 HBD and 5 HBA, which are within acceptable limits.

**QED:** Ligand A (0.842) has a higher QED score than Ligand B (0.543), indicating better overall drug-likeness.

**DILI:** Both ligands have similar, acceptable DILI risk (47.693 and 48.662 percentile).

**BBB:** Ligand A (88.755) has a much higher BBB penetration percentile than Ligand B (41.528). This is *critical* for a CNS target like DRD2.

**Caco-2 Permeability:** Both have negative Caco-2 values (-4.66 and -4.637), which is unusual and suggests poor permeability. However, these values are on a similar scale, so the difference isn't decisive.

**Aqueous Solubility:** Both have negative solubility values (-1.929 and -2.021), indicating poor solubility. Again, the difference isn't substantial.

**hERG Inhibition:** Both ligands show low hERG inhibition liability (0.364 and 0.088).

**Microsomal Clearance:** Ligand A (57.875) has higher microsomal clearance than Ligand B (32.1), meaning it's likely to be metabolized faster.

**In vitro Half-Life:** Ligand B (-4.608) has a more negative half-life, which is counterintuitive and likely indicates a very short half-life. Ligand A (29.961) has a much more reasonable half-life.

**P-gp Efflux:** Both have low P-gp efflux liability (0.084 and 0.051).

**Binding Affinity:** Ligand A (-8.5 kcal/mol) has a significantly stronger binding affinity than Ligand B (-7.3 kcal/mol). This 1.2 kcal/mol difference is substantial and can outweigh some ADME drawbacks.

**Conclusion:**

Considering all factors, **Ligand A is the more promising drug candidate.** It has superior BBB penetration, a higher QED score, a significantly stronger binding affinity, and a more reasonable in vitro half-life. While both have poor solubility and Caco-2 permeability, the strong affinity and BBB penetration of Ligand A are particularly important for a CNS GPCR target like DRD2. The slightly higher clearance of Ligand A is a concern, but potentially addressable through structural modifications.

Output:
1
2025-04-17 03:29:16,627 - INFO - Reasoning:
Let's analyze both ligands against the provided guidelines, prioritizing GPCR-specific properties (BBB, logP, Pgp, TPSA, and affinity).

**Ligand A:**

*   **MW:** 348.443 Da - Good (within 200-500 range)
*   **TPSA:** 89.87 - Excellent (below 90 for CNS targets)
*   **logP:** 1.681 - Good (within 1-3)
*   **HBD:** 3 - Good (<=5)
*   **HBA:** 4 - Good (<=10)
*   **QED:** 0.755 - Excellent (>=0.5)
*   **DILI:** 24.312 - Excellent (low risk, <40)
*   **BBB:** 43.389 - Moderate (below the desired 70 for CNS, but not terrible)
*   **Caco-2:** -4.75 - Poor (negative value suggests very low permeability)
*   **Solubility:** -2.163 - Poor (negative value suggests very low solubility)
*   **hERG:** 0.317 - Good (low risk)
*   **Cl_mic:** 9.043 - Moderate (relatively low, suggesting reasonable metabolic stability)
*   **t1/2:** 6.724 - Moderate (acceptable, but could be better)
*   **Pgp:** 0.06 - Excellent (low efflux, good for CNS penetration)
*   **Affinity:** -8.2 kcal/mol - Excellent (strong binding)

**Ligand B:**

*   **MW:** 362.417 Da - Good (within 200-500 range)
*   **TPSA:** 89.87 - Excellent (below 90 for CNS targets)
*   **logP:** 1.052 - Good (within 1-3)
*   **HBD:** 3 - Good (<=5)
*   **HBA:** 4 - Good (<=10)
*   **QED:** 0.602 - Good (>=0.5)
*   **DILI:** 25.165 - Excellent (low risk, <40)
*   **BBB:** 70.182 - Excellent (above 70, highly desirable for CNS)
*   **Caco-2:** -4.826 - Poor (negative value suggests very low permeability)
*   **Solubility:** -1.876 - Poor (negative value suggests very low solubility)
*   **hERG:** 0.451 - Good (low risk)
*   **Cl_mic:** -10.196 - Excellent (very low, suggesting high metabolic stability)
*   **t1/2:** 5.724 - Moderate (acceptable, but could be better)
*   **Pgp:** 0.037 - Excellent (low efflux, good for CNS penetration)
*   **Affinity:** -7.7 kcal/mol - Good (strong binding, but not as strong as Ligand A)

**Comparison and Decision:**

Both ligands have similar desirable properties (MW, TPSA, logP, HBD, HBA, QED, DILI, hERG, Pgp). However, Ligand A has a significantly better binding affinity (-8.2 kcal/mol vs -7.7 kcal/mol). While both have poor Caco-2 and solubility, the difference in affinity is substantial enough to outweigh these drawbacks, especially for a CNS target like DRD2. Ligand B has a better BBB score, but the affinity difference is more critical. The improved metabolic stability of Ligand B is a plus, but the slightly lower half-life isn't a dealbreaker given the stronger binding of Ligand A.

Output:
1
2025-04-17 03:29:16,627 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (344.415 and 350.375 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (108.02) is better than Ligand B (133.56). For CNS targets, TPSA should be <= 90, so Ligand A is closer to this threshold. Ligand B is significantly higher and less favorable.

**logP:** Ligand A (2.067) is within the optimal 1-3 range. Ligand B (-0.62) is below 1, which could hinder permeation.

**H-Bond Donors/Acceptors:** Ligand A (HBD=2, HBA=5) and Ligand B (HBD=4, HBA=6) are both acceptable, within the guidelines of <=5 HBD and <=10 HBA.

**QED:** Both ligands have reasonable QED values (0.787 and 0.54), indicating drug-like properties.

**DILI:** Both ligands have low DILI risk (49.593 and 41.45), below the 60 threshold.

**BBB:** Both ligands have good BBB penetration (62.233 and 60.566). While >70 is desirable, both are reasonably good for a CNS target.

**Caco-2 Permeability:** Ligand A (-4.897) is worse than Ligand B (-5.453), indicating lower intestinal absorption. However, this is less critical for a CNS target where BBB penetration is more important.

**Aqueous Solubility:** Ligand A (-3.383) is better than Ligand B (-1.204), indicating better solubility.

**hERG:** Both ligands have very low hERG inhibition risk (0.253 and 0.056).

**Microsomal Clearance:** Ligand A (44.88) is better than Ligand B (-9.104). Lower clearance is preferred for better metabolic stability.

**In vitro Half-Life:** Ligand A (-30.249) is worse than Ligand B (-10.572), indicating a shorter half-life.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.131 and 0.003).

**Binding Affinity:** Ligand A (-8.0) has a significantly better binding affinity than Ligand B (-8.8). A difference of 0.8 kcal/mol is substantial.

**Overall Assessment:**

Ligand A is superior due to its better TPSA, logP, solubility, and significantly stronger binding affinity. While its Caco-2 permeability and in vitro half-life are worse than Ligand B, these are less critical for a CNS-targeting GPCR like DRD2. The improved logP and TPSA of Ligand A are particularly important for brain penetration, and the stronger binding affinity is a major advantage.

Output:
1
2025-04-17 03:29:16,627 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (351.491 and 350.547 Da) fall comfortably within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (78.51) is higher than Ligand B (58.2). For a CNS target like DRD2, TPSA should ideally be <=90. Both are under this threshold, but B is significantly better.

**3. logP:** Ligand A (1.979) and Ligand B (3.894) are both within the optimal 1-3 range, but B is approaching the upper limit.

**4. H-Bond Donors:** Both ligands have 2 HBD, which is acceptable (<=5).

**5. H-Bond Acceptors:** Ligand A has 3 HBA, and Ligand B has 2. Both are within the acceptable range (<=10).

**6. QED:** Both ligands have similar QED values (0.632 and 0.628), indicating good drug-likeness.

**7. DILI:** Ligand A (16.712) has a much lower DILI risk than Ligand B (33.307). This is a significant advantage for A.

**8. BBB:** Ligand A (72.586) has a better BBB penetration percentile than Ligand B (67.546). While both are reasonably good, A is closer to the desirable >70 threshold for CNS targets.

**9. Caco-2 Permeability:** Ligand A (-4.973) has worse Caco-2 permeability than Ligand B (-4.687). Lower values indicate poorer permeability.

**10. Aqueous Solubility:** Ligand A (-2.474) has better aqueous solubility than Ligand B (-5.032).

**11. hERG Inhibition:** Both ligands have similar and low hERG inhibition liability (0.174 and 0.39).

**12. Microsomal Clearance:** Ligand B (72.73) has higher microsomal clearance than Ligand A (37.823), indicating lower metabolic stability.

**13. In vitro Half-Life:** Ligand B (7.66) has a longer in vitro half-life than Ligand A (-11.01). This is a positive for B, but the negative value for A is concerning.

**14. P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.058 and 0.271).

**15. Binding Affinity:** Both ligands have the same binding affinity (-7.6 kcal/mol), which is excellent.

**Overall Assessment:**

While Ligand B has a slightly better logP and in vitro half-life, Ligand A is superior in several crucial areas for a CNS-targeting GPCR ligand. Specifically, Ligand A exhibits a significantly lower DILI risk, better BBB penetration, and better aqueous solubility. The Caco-2 permeability is slightly worse for A, but the other advantages outweigh this. The negative half-life for A is concerning, but the strong binding affinity might compensate for that. Given the GPCR-specific priorities, the better BBB, lower DILI, and better solubility of Ligand A make it the more promising candidate.

Output:
0
2025-04-17 03:29:16,627 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (350.5 & 354.5 Da) fall comfortably within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (79.04) is slightly higher than Ligand B (67.87). Both are below the 90 A^2 threshold for CNS targets, but Ligand B is preferable.

**3. logP:** Ligand A (3.769) is slightly higher than Ligand B (2.69), both are within the optimal 1-3 range. Ligand B is slightly better.

**4. H-Bond Donors:** Ligand A (3) is higher than Ligand B (1). Lower is generally better for BBB penetration, so Ligand B is favored.

**5. H-Bond Acceptors:** Both ligands have 4 HBA, which is within the acceptable limit of 10.

**6. QED:** Ligand A (0.654) has a better QED score than Ligand B (0.413), indicating better overall drug-likeness.

**7. DILI:** Ligand B (26.41) has a significantly lower DILI risk than Ligand A (17.72), making it safer.

**8. BBB:** Ligand B (80.07) has a slightly better BBB penetration percentile than Ligand A (76.85), which is crucial for a CNS target like DRD2.

**9. Caco-2:** Both have negative values, indicating poor permeability. Ligand A (-5.089) is slightly worse than Ligand B (-4.914).

**10. Solubility:** Both have negative values, indicating poor solubility. Ligand A (-2.697) is slightly worse than Ligand B (-2.742).

**11. hERG:** Ligand A (0.835) has a slightly higher hERG inhibition liability than Ligand B (0.587), indicating a slightly higher risk of cardiotoxicity.

**12. Cl_mic:** Ligand A (29.2) has a higher microsomal clearance than Ligand B (23.39), suggesting lower metabolic stability.

**13. t1/2:** Ligand B (-1.868) has a much better in vitro half-life than Ligand A (-17.9).

**14. Pgp:** Ligand A (0.328) has lower P-gp efflux liability than Ligand B (0.063), which is favorable for CNS penetration.

**15. Binding Affinity:** Ligand A (-7.9 kcal/mol) has a significantly stronger binding affinity than Ligand B (-6.9 kcal/mol). This is a substantial advantage.

**Overall Assessment:**

While Ligand A has a better binding affinity and Pgp efflux profile, Ligand B demonstrates superior ADME properties, particularly concerning safety (DILI), BBB penetration, and metabolic stability (t1/2). The difference in binding affinity (1 kcal/mol) is significant, but the improved ADME profile of Ligand B, especially its better BBB penetration and lower DILI risk, makes it a more promising drug candidate for a CNS target like DRD2. The slightly weaker binding could potentially be optimized in later stages of drug development.

Output:
1
2025-04-17 03:29:16,628 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B based on the provided guidelines, prioritizing GPCR-specific properties (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (367.471 Da) is slightly lower, which could be beneficial for permeability.

**TPSA:** Ligand A (75.88) is significantly better than Ligand B (113.08). For CNS targets, TPSA should be <= 90, so Ligand A is preferable.

**logP:** Both ligands have acceptable logP values (Ligand A: 1.7, Ligand B: 2.161), falling within the optimal range of 1-3.

**H-Bond Donors/Acceptors:** Ligand A (0 HBD, 6 HBA) is better than Ligand B (3 HBD, 7 HBA). Lower values generally improve permeability.

**QED:** Ligand A (0.774) has a higher QED score than Ligand B (0.552), indicating a more drug-like profile.

**DILI:** Ligand B (96.006) has a significantly higher DILI risk than Ligand A (50.485). This is a major concern.

**BBB:** Ligand A (88.135) has a much better BBB penetration percentile than Ligand B (59.364). This is critical for a CNS target like DRD2.

**Caco-2 Permeability:** Ligand A (-4.776) has a worse Caco-2 permeability than Ligand B (-5.618), but both are very poor.

**Aqueous Solubility:** Both ligands have poor aqueous solubility (-3.146 and -3.48, respectively).

**hERG:** Both ligands have low hERG inhibition risk (0.823 and 0.682, respectively).

**Microsomal Clearance:** Ligand B (72.042) has higher microsomal clearance than Ligand A (65.98), suggesting faster metabolism and lower metabolic stability.

**In vitro Half-Life:** Ligand A (6.317) has a longer in vitro half-life than Ligand B (46.401).

**P-gp Efflux:** Ligand A (0.202) exhibits lower P-gp efflux than Ligand B (0.174), which is favorable for CNS penetration.

**Binding Affinity:** Ligand B (-9.3 kcal/mol) has a significantly stronger binding affinity than Ligand A (-7.5 kcal/mol). This is a substantial advantage.

**Overall Assessment:**

While Ligand B boasts a superior binding affinity, the significant drawbacks in DILI risk, BBB penetration, and metabolic stability are major concerns. Ligand A, despite its weaker binding, presents a much more favorable ADME-Tox profile, especially regarding CNS penetration (high BBB, low P-gp efflux, lower TPSA) and safety (lower DILI). The difference in binding affinity (-1.8 kcal/mol) is substantial, but not insurmountable, and could potentially be optimized in further iterations of drug design. Given the importance of CNS penetration for DRD2, and the high DILI risk of Ligand B, Ligand A is the more promising candidate.

Output:
0
2025-04-17 03:29:16,628 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (381.929 Da) is slightly higher than Ligand B (343.427 Da), but both are acceptable.

**TPSA:** Ligand A (63.25) is much better than Ligand B (86.34). For CNS targets, we want TPSA <= 90, and ideally lower. Ligand A is comfortably within this range, while Ligand B is approaching the upper limit.

**logP:** Ligand A (4.492) is a bit high, potentially leading to solubility issues or off-target effects. Ligand B (2.286) is within the optimal range (1-3).

**H-Bond Donors/Acceptors:** Ligand A (HBD=2, HBA=4) and Ligand B (HBD=1, HBA=4) both have reasonable numbers of H-bond donors and acceptors, falling within the acceptable limits.

**QED:** Both ligands have good QED values (Ligand A: 0.742, Ligand B: 0.858), indicating good drug-like properties.

**DILI:** Ligand A has a significantly higher DILI risk (64.521) than Ligand B (22.838). This is a major concern for Ligand A.

**BBB:** Ligand B (63.009) has a much better BBB penetration score than Ligand A (33.579). For a CNS target like DRD2, >70 is desirable, but 63 is still significantly better than 33.

**Caco-2 Permeability:** Both have negative values (-4.759 and -4.991), which is unusual and likely indicates poor permeability. However, the scale isn't specified, so it's difficult to interpret.

**Aqueous Solubility:** Both have negative values (-5.104 and -2.284), indicating poor solubility. This is a concern, especially given Ligand A's high logP.

**hERG:** Both ligands have low hERG inhibition liability (Ligand A: 0.254, Ligand B: 0.425), which is good.

**Microsomal Clearance:** Ligand B (-5.692) has a *negative* microsomal clearance, which is not physically possible and suggests an error in the data. Ligand A (82.358) has a moderate clearance.

**In vitro Half-Life:** Ligand B (22.843) has a shorter half-life than Ligand A (33.802).

**P-gp Efflux:** Ligand A (0.294) has lower P-gp efflux liability than Ligand B (0.066), which is favorable for CNS penetration.

**Binding Affinity:** Ligand A (-8.7 kcal/mol) has a significantly stronger binding affinity than Ligand B (-7.7 kcal/mol). This is a substantial advantage (1 kcal/mol difference).

**Overall Assessment:**

Despite Ligand A's superior binding affinity, its high DILI risk, poor BBB penetration, and high logP are significant drawbacks. Ligand B, while having a slightly weaker affinity, has a much better safety profile (lower DILI), better BBB penetration, and a more favorable logP. The negative microsomal clearance for Ligand B is a data quality issue, but the other factors strongly favor Ligand B. The affinity difference, while notable, might be overcome with further optimization of Ligand B.

Output:
1
2025-04-17 03:29:16,628 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (357.475 and 350.478 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (46.61) is better than Ligand B (49.41). Both are below the 90 A^2 threshold desirable for CNS targets, but A is closer to optimal.

**3. logP:** Ligand A (4.229) is slightly higher than the optimal range (1-3), while Ligand B (3.512) is within the optimal range. This favors Ligand B.

**4. H-Bond Donors:** Ligand A (0) is preferable to Ligand B (1). Fewer HBDs generally improve permeability.

**5. H-Bond Acceptors:** Ligand A (3) is preferable to Ligand B (2).

**6. QED:** Both ligands have similar, good QED values (0.777 and 0.797, both > 0.5).

**7. DILI:** Ligand A (75.611) has a significantly higher DILI risk than Ligand B (20.822). This is a major drawback for Ligand A.

**8. BBB:** Ligand B (96.161) has a much higher BBB penetration percentile than Ligand A (63.94). This is crucial for a CNS target like DRD2 and strongly favors Ligand B.

**9. Caco-2 Permeability:** Ligand A (-4.281) has worse Caco-2 permeability than Ligand B (-4.674), indicating lower intestinal absorption.

**10. Aqueous Solubility:** Ligand A (-5.824) has worse aqueous solubility than Ligand B (-3.903).

**11. hERG Inhibition:** Both ligands have relatively low hERG inhibition risk (0.79 and 0.644).

**12. Microsomal Clearance:** Ligand A (87.877) has higher microsomal clearance than Ligand B (31.187), suggesting lower metabolic stability.

**13. In vitro Half-Life:** Ligand B (-1.145) has a better in vitro half-life than Ligand A (-19.732).

**14. P-gp Efflux:** Ligand A (0.601) has lower P-gp efflux than Ligand B (0.27), which is favorable for CNS penetration.

**15. Binding Affinity:** Ligand B (-7.9 kcal/mol) has a significantly stronger binding affinity than Ligand A (-9.4 kcal/mol). This is a substantial advantage.

**Overall Assessment:**

Ligand B is the superior candidate. While Ligand A has slightly better TPSA and P-gp efflux, Ligand B excels in critical areas: significantly better BBB penetration, lower DILI risk, better metabolic stability (lower Cl_mic, longer t1/2), and *much* stronger binding affinity. The higher logP of Ligand B is acceptable, and its overall profile aligns better with the requirements for a CNS-active GPCR ligand. The strong affinity of Ligand B can compensate for minor ADME drawbacks.

Output:
1
2025-04-17 03:29:16,628 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (358.36 and 376.503 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (49.85) is significantly better than Ligand B (53.76). For CNS targets, we want TPSA <= 90, and ideally lower. Ligand A is closer to the ideal range.

**3. logP:** Both ligands have acceptable logP values (1.733 and 2.98), falling within the optimal 1-3 range.

**4. H-Bond Donors:** Both have 0 HBD, which is good.

**5. H-Bond Acceptors:** Ligand A has 3 HBA, and Ligand B has 5. Both are acceptable (<=10), but A is slightly better.

**6. QED:** Both ligands have good QED scores (0.707 and 0.753), indicating drug-like properties.

**7. DILI:** Both ligands have low DILI risk (38.309 and 36.06), which is favorable.

**8. BBB:** This is a critical parameter for CNS targets. Ligand A has a significantly higher BBB penetration percentile (97.363) compared to Ligand B (66.344). This is a major advantage for Ligand A.

**9. Caco-2 Permeability:** Ligand A (-4.24) is worse than Ligand B (-5.218). Lower values indicate lower permeability, but both are quite poor.

**10. Aqueous Solubility:** Both have very poor aqueous solubility (-2.886 and -3.626). This is a concern for both, but not a deciding factor given the other parameters.

**11. hERG Inhibition:** Both ligands have low hERG inhibition risk (0.365 and 0.626).

**12. Microsomal Clearance:** Ligand B has a much higher microsomal clearance (75.805) than Ligand A (23.3). Lower clearance is preferred for better metabolic stability.

**13. In vitro Half-Life:** Ligand B has a longer in vitro half-life (31.254 hours) than Ligand A (-21.386 hours). This is a positive for Ligand B, but the negative value for A is concerning.

**14. P-gp Efflux:** Both ligands have low P-gp efflux liability (0.089 and 0.4).

**15. Binding Affinity:** Both ligands have identical binding affinities (-8.8 kcal/mol), which is excellent.

**Overall Assessment:**

Ligand A is significantly better due to its superior BBB penetration (97.363 vs 66.344) and lower microsomal clearance (23.3 vs 75.805). While Ligand B has a better in vitro half-life, the dramatic difference in BBB and clearance outweighs this benefit. The TPSA is also more favorable for Ligand A. Both have excellent binding affinity and acceptable safety profiles. Given the CNS target (DRD2), BBB penetration is paramount.

Output:
1
2025-04-17 03:29:16,629 - INFO - Batch 33 complete. Total preferences: 528
2025-04-17 03:29:16,629 - INFO - Processing batch 34/512...
2025-04-17 03:30:00,734 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (345.487 and 360.445 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (52.65) is significantly better than Ligand B (60.85). For CNS targets, we want TPSA <= 90, both are within this range, but A is closer to the optimal value.

**3. logP:** Both ligands have acceptable logP values (1.483 and 2.134, respectively), falling within the 1-3 range.

**4. H-Bond Donors:** Both have 1 HBD, which is good.

**5. H-Bond Acceptors:** Both have 3 HBA, which is good.

**6. QED:** Both ligands have similar QED values (0.768 and 0.721), indicating good drug-likeness.

**7. DILI:** Both have low DILI risk (23.032 and 25.087 percentiles), which is favorable.

**8. BBB:** Ligand B (82.047) has a significantly better BBB penetration percentile than Ligand A (73.827). This is a critical factor for CNS targets like DRD2.

**9. Caco-2 Permeability:** Ligand A (-4.871) has a worse Caco-2 permeability than Ligand B (-4.384).

**10. Aqueous Solubility:** Ligand A (-1.26) has better aqueous solubility than Ligand B (-2.271).

**11. hERG Inhibition:** Both ligands have low hERG inhibition risk (0.48 and 0.541), which is good.

**12. Microsomal Clearance:** Ligand A (6.785) has a much lower microsomal clearance than Ligand B (38.896), indicating better metabolic stability.

**13. In vitro Half-Life:** Ligand A (16.756 hours) has a significantly longer in vitro half-life than Ligand B (-18.744 hours - negative value suggests rapid degradation).

**14. P-gp Efflux:** Both ligands have low P-gp efflux liability (0.075 and 0.13).

**15. Binding Affinity:** Ligand A (-7.8 kcal/mol) has a slightly better binding affinity than Ligand B (-7.1 kcal/mol). While both are good, the 0.7 kcal/mol difference is noteworthy.

**Overall Assessment:**

Ligand A excels in metabolic stability (lower Cl_mic, longer t1/2), solubility, and binding affinity. Ligand B's primary advantage is its superior BBB penetration. However, the difference in BBB is not substantial enough to outweigh the significant advantages of Ligand A in metabolic stability and half-life, especially considering the slightly better binding affinity. For a CNS target, metabolic stability is crucial to ensure sufficient drug exposure in the brain.

Output:
0
2025-04-17 03:30:00,735 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (350.459 Da) is slightly lower, which could be advantageous for permeability.

**TPSA:** Ligand A (78.87) is better than Ligand B (53.43) as it's closer to the ideal range for CNS targets (<=90). Ligand B is excellent.

**logP:** Ligand A (0.79) is a bit low, potentially hindering membrane permeability. Ligand B (3.501) is within the optimal range (1-3).

**H-Bond Donors/Acceptors:** Ligand A (2 HBD, 4 HBA) and Ligand B (1 HBD, 3 HBA) both have acceptable numbers of H-bond donors and acceptors.

**QED:** Both ligands have good QED scores (A: 0.635, B: 0.697), indicating drug-like properties.

**DILI:** Both ligands have low DILI risk (A: 12.369, B: 11.283), which is positive.

**BBB:** Ligand B (79.062) significantly outperforms Ligand A (46.84) in BBB penetration, a crucial factor for CNS targets like DRD2.

**Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and suggests a potential issue with the data or modeling. However, we must proceed with the available information.

**Aqueous Solubility:** Both have negative solubility values, which is also unusual and suggests a potential issue with the data or modeling.

**hERG Inhibition:** Ligand A (0.205) has a lower hERG risk than Ligand B (0.61), which is preferable.

**Microsomal Clearance:** Ligand B (44.853) has lower microsomal clearance than Ligand A (14.475), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand B (46.898) has a longer in vitro half-life than Ligand A (12.562), which is desirable.

**P-gp Efflux:** Ligand A (0.017) has much lower P-gp efflux liability than Ligand B (0.49), which is a significant advantage for CNS penetration.

**Binding Affinity:** Both ligands have the same binding affinity (-7.7 kcal/mol), which is excellent.

**Overall Assessment:**

While Ligand A has a slightly better MW, lower hERG risk, and significantly lower P-gp efflux, Ligand B excels in crucial areas for a CNS-targeting GPCR ligand: BBB penetration and metabolic stability (lower Cl_mic and longer t1/2). The more favorable logP of Ligand B also contributes to better permeability. The unusual negative values for Caco-2 and solubility are concerning for both, but the differences in BBB and metabolic stability are more decisive. Given the importance of BBB penetration for DRD2, Ligand B is the more promising candidate.

Output:
1
2025-04-17 03:30:00,735 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (343.471 Da) is slightly better being closer to the lower end, which can aid permeability.

**TPSA:** Ligand A (63.13) is better than Ligand B (51.02). Both are below the 90 A^2 threshold for CNS targets, but A is closer to the optimal range.

**logP:** Ligand A (2.634) is within the optimal 1-3 range. Ligand B (4.066) is slightly above, potentially leading to solubility issues and off-target interactions.

**H-Bond Donors/Acceptors:** Ligand A has 2 HBD and 3 HBA, while Ligand B has 0 HBD and 4 HBA. Both are acceptable, but Ligand A's HBD count might contribute to better solubility.

**QED:** Both ligands have similar QED values (0.642 and 0.653), indicating good drug-likeness.

**DILI:** Ligand A (28.383) has a significantly lower DILI risk than Ligand B (38.736), which is a major advantage.

**BBB:** Ligand B (87.088) has a much higher BBB penetration percentile than Ligand A (58.976). This is a critical factor for a CNS target like DRD2.

**Caco-2 Permeability:** Ligand A (-4.874) has significantly worse Caco-2 permeability than Ligand B (-5.07). Both are negative values, indicating poor permeability.

**Aqueous Solubility:** Ligand A (-2.732) has slightly better solubility than Ligand B (-3.857), though both are quite poor.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.127 and 0.341).

**Microsomal Clearance:** Ligand B (81.261) has a higher microsomal clearance than Ligand A (38.023), suggesting lower metabolic stability.

**In vitro Half-Life:** Ligand B (5.061) has a longer half-life than Ligand A (0.124), which is desirable.

**P-gp Efflux:** Ligand A (0.255) has lower P-gp efflux liability than Ligand B (0.623), which is beneficial for CNS exposure.

**Binding Affinity:** Ligand B (-7.7 kcal/mol) has a slightly better binding affinity than Ligand A (-8.0 kcal/mol). While the difference is small, it's still a positive for Ligand B.

**Overall Assessment:**

Ligand B excels in BBB penetration and binding affinity, which are crucial for a CNS GPCR target. However, it has a higher DILI risk, higher P-gp efflux, and faster metabolic clearance. Ligand A has better DILI and P-gp properties, and better solubility, but suffers from significantly poorer BBB penetration and Caco-2 permeability.

Considering the GPCR-specific priorities, BBB is paramount for CNS targets. The substantial difference in BBB penetration (87.088 vs 58.976) outweighs Ligand A's advantages in DILI and P-gp efflux. The slightly better affinity of Ligand B is also a contributing factor. While the solubility and permeability are concerns for Ligand B, these can potentially be addressed through formulation strategies.

Output:
1
2025-04-17 03:30:00,735 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight (MW):** Both ligands (342.403 and 344.411 Da) fall comfortably within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (100.94) is slightly higher than Ligand B (75.71). For CNS targets, we ideally want TPSA <= 90. Ligand B is better here.

**3. logP:** Both ligands have good logP values (1.662 and 1.835), falling within the optimal 1-3 range.

**4. H-Bond Donors (HBD):** Ligand A has 3 HBD, and Ligand B has 1. Both are within the acceptable limit of <=5.

**5. H-Bond Acceptors (HBA):** Ligand A has 5 HBA, and Ligand B has 4. Both are within the acceptable limit of <=10.

**6. QED:** Ligand A (0.769) has a significantly better QED score than Ligand B (0.354), indicating a more drug-like profile.

**7. DILI:** Both ligands have acceptable DILI risk (68.05 and 63.048), below the concerning threshold of 60.

**8. BBB:** Ligand A (67.584) has a better BBB percentile than Ligand B (44.785). This is a crucial factor for a CNS target like DRD2.

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 values, which is unusual and requires further investigation. However, the magnitude is similar, so it doesn't strongly differentiate them.

**10. Aqueous Solubility:** Both ligands have negative solubility values, also unusual. Again, the values are similar.

**11. hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.081 and 0.158).

**12. Microsomal Clearance (Cl_mic):** Ligand A (14.489) has a lower Cl_mic than Ligand B (61.898), suggesting better metabolic stability.

**13. In vitro Half-Life:** Ligand A (29.523 hours) has a significantly longer half-life than Ligand B (-36.595 hours - a negative value is concerning).

**14. P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.01 and 0.174).

**15. Binding Affinity:** Both ligands have excellent binding affinities (-8.7 and -8.9 kcal/mol). The difference of 0.2 kcal/mol is not substantial enough to outweigh other factors.

**Overall Assessment:**

Ligand A is superior due to its better BBB penetration, significantly better QED score, lower microsomal clearance (better metabolic stability), and longer in vitro half-life. While Ligand B has a slightly lower TPSA, the benefits of Ligand A in terms of CNS penetration and drug-likeness are more important for a DRD2 ligand.

Output:
1
2025-04-17 03:30:00,735 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (369.487 and 355.479 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (78.95) is excellent, well below the 90 A^2 threshold for CNS targets. Ligand B (93.11) is still acceptable but closer to the upper limit.

**logP:** Ligand A (0.68) is a bit low, potentially hindering permeability. Ligand B (-0.187) is even lower, raising concerns about membrane penetration.

**H-Bond Donors/Acceptors:** Ligand A (1 HBD, 5 HBA) is favorable. Ligand B (3 HBD, 5 HBA) is also acceptable, though slightly higher HBD count could be a minor issue.

**QED:** Both ligands have good QED scores (0.729 and 0.636), indicating good drug-like properties.

**DILI:** Ligand A (52.113) has a moderate DILI risk, while Ligand B (7.871) has a very low DILI risk, a significant advantage.

**BBB:** Ligand A excels with a BBB percentile of 81.698, highly desirable for a CNS target. Ligand B is very poor at 11.012, a major drawback.

**Caco-2 Permeability:** Ligand A (-4.754) shows poor permeability. Ligand B (-5.169) is also poor, but slightly worse.

**Aqueous Solubility:** Ligand A (-2.737) has poor solubility. Ligand B (-0.77) is also poor, but slightly better.

**hERG:** Both ligands have low hERG inhibition liability (0.533 and 0.321), which is good.

**Microsomal Clearance:** Ligand A (52.916) has moderate clearance. Ligand B (-2.28) has negative clearance, which is unusual and likely an error, but suggests very high metabolic stability.

**In vitro Half-Life:** Ligand A (-51.47) has a very long half-life, which is excellent. Ligand B (-2.638) has a short half-life.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.077 and 0.019), which is favorable for CNS penetration.

**Binding Affinity:** Ligand A (-8.1 kcal/mol) has significantly stronger binding affinity than Ligand B (-7.2 kcal/mol). This 0.9 kcal/mol difference is substantial and can outweigh some ADME deficiencies.

**Overall Assessment:**

Ligand A is the stronger candidate despite its lower logP and solubility. Its superior BBB penetration (81.7% vs 11.0%), significantly higher binding affinity (-8.1 vs -7.2 kcal/mol), and excellent in vitro half-life are critical advantages for a CNS-targeting GPCR. While the logP is suboptimal, the strong affinity and good BBB penetration suggest it can still achieve sufficient brain exposure. Ligand B's extremely low BBB penetration is a deal-breaker, even with its lower DILI risk. The negative clearance value for Ligand B is suspect and warrants further investigation, but even if it's a measurement error, the low BBB penetration remains a critical flaw.

Output:
1
2025-04-17 03:30:00,735 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (345.487 and 341.411 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (54.46) is excellent, well below the 90 A^2 threshold for CNS targets. Ligand B (85.43) is still reasonable but less optimal, approaching the 90 A^2 limit.

**logP:** Ligand A (3.07) is optimal (1-3). Ligand B (1.517) is on the lower side, potentially impacting permeability.

**H-Bond Donors/Acceptors:** Ligand A (1 HBD, 4 HBA) is favorable. Ligand B (3 HBD, 3 HBA) is also acceptable.

**QED:** Both ligands have good QED scores (0.891 and 0.788), indicating good drug-like properties.

**DILI:** Ligand A (29.624) has a very low DILI risk. Ligand B (45.522) is slightly higher but still acceptable.

**BBB:** This is crucial for a CNS target. Ligand A excels with a BBB percentile of 92.361. Ligand B is significantly lower at 43.001, which is a major drawback.

**Caco-2 Permeability:** Both have negative values, indicating poor permeability. However, the scale is not specified, so it's hard to interpret these values.

**Aqueous Solubility:** Both have negative values, indicating poor solubility. Again, the scale is not specified.

**hERG:** Both ligands have low hERG inhibition liability (0.706 and 0.404), which is good.

**Microsomal Clearance:** Ligand A (63.404) has higher clearance than Ligand B (10.532), suggesting lower metabolic stability.

**In vitro Half-Life:** Ligand B (-10.259) has a negative half-life, which is not possible. This is likely an error in the data. Ligand A (9.596) has a reasonable half-life.

**P-gp Efflux:** Ligand A (0.391) has lower P-gp efflux liability than Ligand B (0.061), which is beneficial for CNS penetration.

**Binding Affinity:** Ligand A (-9.3 kcal/mol) has a significantly stronger binding affinity than Ligand B (-8.5 kcal/mol). This 0.8 kcal/mol difference is substantial and can outweigh some ADME drawbacks.

**Overall Assessment:**

Ligand A is the stronger candidate. While it has slightly higher microsomal clearance, its significantly better BBB penetration, lower P-gp efflux, and substantially improved binding affinity outweigh this concern. Ligand B's poor BBB penetration is a critical flaw for a CNS-targeted drug. The questionable half-life value for Ligand B further reduces its viability.



Output:
1
2025-04-17 03:30:00,736 - INFO - Reasoning:

Let's analyze Ligand A and Ligand B based on the provided guidelines, prioritizing GPCR-specific properties (BBB, logP, Pgp, TPSA, and affinity) for DRD2.

**Molecular Weight:** Both ligands (342.414 and 349.475 Da) fall within the ideal range of 200-500 Da.

**TPSA:** Ligand A (41.57) is significantly better than Ligand B (72.88). For CNS targets, TPSA should be <= 90, both are within this range, but A is much closer to the optimal <60 for good CNS penetration.

**logP:** Ligand A (2.787) is optimal (1-3). Ligand B (0.596) is quite low, potentially hindering permeation.

**H-Bond Donors/Acceptors:** Ligand A (HBD=1, HBA=3) and Ligand B (HBD=2, HBA=4) both have acceptable numbers of H-bond donors and acceptors.

**QED:** Both ligands have reasonable QED values (0.878 and 0.782), indicating good drug-like properties.

**DILI:** Ligand A (35.944) has a much lower DILI risk than Ligand B (4.498), which is preferable.

**BBB:** Ligand A (88.949) has a significantly higher BBB percentile than Ligand B (34.238). This is *critical* for a CNS target like DRD2.

**Caco-2 Permeability:** Ligand A (-4.696) and Ligand B (-5.071) both have negative values, indicating poor permeability. This is a concern for both, but less critical than BBB for a CNS target.

**Aqueous Solubility:** Ligand A (-3.651) and Ligand B (-0.991) both have negative values, indicating poor solubility. This is a concern for both, but can be mitigated with formulation strategies.

**hERG:** Both ligands have low hERG risk (0.944 and 0.145).

**Microsomal Clearance:** Ligand B (-19.054) has a much lower (better) microsomal clearance than Ligand A (15.201), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand B (7.341) has a longer half-life than Ligand A (-1.162), which is preferable.

**P-gp Efflux:** Ligand A (0.312) has lower P-gp efflux liability than Ligand B (0.007), which is better for CNS exposure.

**Binding Affinity:** Both ligands have very similar and strong binding affinities (-9.3 and -8.4 kcal/mol). The difference is less than the 1.5 kcal/mol threshold.

**Overall Assessment:**

Ligand A is significantly better due to its superior BBB penetration (88.949 vs 34.238), lower DILI risk, and better logP. While Ligand B has better metabolic stability and half-life, these are less critical for a CNS GPCR target compared to BBB and permeability. The slightly better P-gp profile of Ligand A also contributes to its favorability. The similar binding affinities make the ADME properties the deciding factor.



Output:
1
2025-04-17 03:30:00,736 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (350.419 and 344.543 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (95.86) is higher than the ideal <90 for CNS targets, but still potentially acceptable. Ligand B (32.34) is excellent, well below the threshold.

**logP:** Ligand A (0.282) is quite low, potentially hindering permeability. Ligand B (4.282) is slightly high, potentially causing solubility issues or off-target effects, but closer to the optimal range.

**H-Bond Donors/Acceptors:** Both have 1 HBD, which is good. Ligand A has 6 HBA, acceptable. Ligand B has 2 HBA, also acceptable.

**QED:** Both ligands have similar QED values (0.792 and 0.729), indicating good drug-likeness.

**DILI:** Ligand A (55.797) has a moderate DILI risk. Ligand B (8.569) has a very low DILI risk, a significant advantage.

**BBB:** Ligand A (56.805) has a poor BBB penetration percentile. Ligand B (87.127) has excellent BBB penetration, crucial for a CNS target like DRD2.

**Caco-2 Permeability:** Both have negative Caco-2 values, suggesting poor permeability. However, this scale can be tricky to interpret and may not be directly comparable.

**Aqueous Solubility:** Both have negative solubility values, suggesting poor solubility. This is a concern for both.

**hERG:** Ligand A (0.227) has a very low hERG risk. Ligand B (0.71) has a moderate hERG risk.

**Microsomal Clearance:** Ligand A (35.48) has lower clearance, indicating better metabolic stability. Ligand B (53.214) has higher clearance.

**In vitro Half-Life:** Ligand A (0.75) has a short half-life. Ligand B (-4.81) has a very short half-life.

**P-gp Efflux:** Ligand A (0.027) has very low P-gp efflux, which is favorable for CNS penetration. Ligand B (0.26) has low P-gp efflux, also favorable.

**Binding Affinity:** Ligand B (-7.6 kcal/mol) has a slightly better binding affinity than Ligand A (-7.2 kcal/mol). While the difference is not huge, it's enough to consider, especially given other factors.

**Overall Assessment:**

Ligand B is the stronger candidate. Its excellent BBB penetration (87.127) is a major advantage for a CNS target. While its logP is slightly high and hERG risk is moderate, the significantly lower DILI risk, and slightly better binding affinity outweigh these drawbacks. Ligand A's poor BBB penetration is a critical flaw. Both have solubility and permeability concerns, but these can potentially be addressed through formulation strategies.

Output:
1
2025-04-17 03:30:00,736 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (360.435 and 364.412 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (85.36) is better than Ligand B (52.41). For CNS targets, TPSA should be <= 90, both are within this range, but A is closer to the upper limit.

**3. logP:** Both ligands have good logP values (1.878 and 2.494), falling within the optimal 1-3 range.

**4. H-Bond Donors:** Ligand A has 1 HBD, while Ligand B has 0. Both are acceptable (<=5).

**5. H-Bond Acceptors:** Ligand A has 5 HBA, and Ligand B has 6. Both are within the acceptable limit of <=10.

**6. QED:** Ligand A (0.88) has a significantly better QED score than Ligand B (0.639), indicating a more drug-like profile.

**7. DILI:** Ligand A (72.199) has a higher DILI risk than Ligand B (27.181). This is a significant drawback for Ligand A.

**8. BBB:** Ligand B (95.502) has a much higher BBB penetration score than Ligand A (64.211). This is a *critical* advantage for a CNS target like DRD2.

**9. Caco-2 Permeability:** Ligand A (-5.018) has worse Caco-2 permeability than Ligand B (-4.543).

**10. Aqueous Solubility:** Ligand A (-3.372) has worse aqueous solubility than Ligand B (-2.665).

**11. hERG Inhibition:** Ligand B (0.744) has a slightly higher hERG inhibition risk than Ligand A (0.22), but both are relatively low.

**12. Microsomal Clearance:** Both ligands have similar microsomal clearance values (30.878 and 32.872 mL/min/kg).

**13. In vitro Half-Life:** Ligand A (78.384) has a significantly longer in vitro half-life than Ligand B (8.17).

**14. P-gp Efflux:** Ligand A (0.326) has lower P-gp efflux than Ligand B (0.255), which is favorable for CNS penetration.

**15. Binding Affinity:** Ligand A (-9.5 kcal/mol) has a substantially stronger binding affinity than Ligand B (-6.8 kcal/mol). This is a significant advantage, potentially outweighing some ADME concerns.

**Overall Assessment:**

While Ligand A has a superior binding affinity and longer half-life, Ligand B is the more promising candidate due to its significantly better BBB penetration (95.502 vs. 64.211), lower DILI risk (27.181 vs. 72.199), and acceptable QED score. The strong binding affinity of Ligand A is attractive, but the poor BBB and higher DILI risk are major concerns for a CNS-targeted drug. The difference in binding affinity (2.7 kcal/mol) is substantial, but not insurmountable, and could potentially be addressed through further optimization of Ligand B.

Output:
1
2025-04-17 03:30:00,736 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (342.286 Da and 348.487 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (111.16) is slightly above the optimal <90 for CNS targets, but still reasonable. Ligand B (49.85) is excellent, well below 90.

**logP:** Both ligands have good logP values (2.6 and 2.465), falling within the 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A has 1 HBD and 6 HBA, which is acceptable. Ligand B has 0 HBD and 3 HBA, also acceptable.

**QED:** Ligand B (0.693) has a better QED score than Ligand A (0.433), indicating better overall drug-likeness.

**DILI:** Ligand A has a very high DILI risk (99.147), which is a major concern. Ligand B has a low DILI risk (13.494), a significant advantage.

**BBB:** Ligand B (80.07) has a significantly better BBB penetration percentile than Ligand A (66.576). Both are above 70, but B is preferable.

**Caco-2 Permeability:** Ligand A (-5.061) has poor Caco-2 permeability, suggesting poor intestinal absorption. Ligand B (-4.651) is also poor, but slightly better.

**Aqueous Solubility:** Both ligands have very poor aqueous solubility (-4.128 and -3.142). This could pose formulation challenges.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.421 and 0.493).

**Microsomal Clearance:** Both ligands have similar microsomal clearance values (62.435 and 60.947), indicating moderate metabolic stability.

**In vitro Half-Life:** Ligand A (69.034) has a better in vitro half-life than Ligand B (0.643).

**P-gp Efflux:** Ligand A (0.327) has lower P-gp efflux than Ligand B (0.214), which is beneficial for CNS penetration.

**Binding Affinity:** Ligand B (-7.1 kcal/mol) has a significantly stronger binding affinity than Ligand A (-10.0 kcal/mol). This is a substantial advantage, potentially outweighing some of the ADME drawbacks.

**Overall Assessment:**

Ligand B is the superior candidate. While both have solubility issues, Ligand B has a significantly better safety profile (much lower DILI), better BBB penetration, a substantially higher binding affinity, and a better QED score. The slightly lower P-gp efflux of Ligand A is less important than the other advantages of Ligand B. The longer half-life of ligand A is a plus, but the superior binding affinity of ligand B is critical for a GPCR target.



Output:
1
2025-04-17 03:30:00,736 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight (MW):** Both ligands (336.439 and 353.409 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (77.81) is higher than Ligand B (58.56). For a CNS target like DRD2, we ideally want TPSA <= 90. Both are acceptable, but B is better.

**3. logP:** Both ligands have good logP values (4.049 and 3.495), falling within the optimal 1-3 range. Ligand B is slightly better.

**4. H-Bond Donors (HBD):** Both have 2 HBDs, which is within the acceptable limit of <=5.

**5. H-Bond Acceptors (HBA):** Both have 3 HBAs, also within the acceptable limit of <=10.

**6. QED:** Both ligands have high QED scores (0.835 and 0.851), indicating good drug-like properties.

**7. DILI:** Ligand A (47.15) has a slightly higher DILI risk than Ligand B (37.34), but both are below the concerning threshold of 60.

**8. BBB:** This is a critical parameter for CNS targets. Ligand B (75.805) has a significantly higher BBB percentile than Ligand A (56.65). This is a major advantage for Ligand B.

**9. Caco-2 Permeability:** Both have negative Caco-2 values (-4.719 and -4.872). This is unusual and suggests poor permeability. However, the values are similar.

**10. Aqueous Solubility:** Both have negative solubility values (-3.806 and -3.001). This is also concerning, indicating poor aqueous solubility. Again, the values are similar.

**11. hERG Inhibition:** Both ligands show low hERG inhibition liability (0.773 and 0.325), which is good. Ligand B is slightly better.

**12. Microsomal Clearance:** Ligand A (9.067) has higher microsomal clearance than Ligand B (3.826), indicating lower metabolic stability. Ligand B is preferable.

**13. In vitro Half-Life:** Ligand A (58.412) has a longer in vitro half-life than Ligand B (5.388). This is a positive for Ligand A.

**14. P-gp Efflux:** Ligand A (0.079) has lower P-gp efflux than Ligand B (0.06), which is favorable for CNS penetration.

**15. Binding Affinity:** Both ligands have excellent binding affinities (-9.4 and -9.6 kcal/mol). The difference is minimal.

**Overall Assessment:**

Ligand B is the better candidate. While Ligand A has a longer half-life and slightly lower P-gp efflux, Ligand B excels in key GPCR-specific properties: significantly better BBB penetration, lower DILI risk, lower microsomal clearance (better metabolic stability), and slightly better logP and hERG inhibition. The similar binding affinities make these ADME properties the deciding factors. The poor Caco-2 and solubility are concerning for both, but can be addressed with formulation strategies.

Output:
1
2025-04-17 03:30:00,737 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (395.262 Da) is slightly higher than Ligand B (351.447 Da), but both are acceptable.

**TPSA:** Ligand A (76.58) is significantly better than Ligand B (100.44). For CNS targets, we want TPSA <= 90, which Ligand A meets, while Ligand B exceeds this.

**logP:** Ligand A (3.913) is at the upper end of the optimal range (1-3), while Ligand B (1.906) is towards the lower end. While both are within the range, higher logP can sometimes lead to off-target effects, but is generally acceptable for CNS targets.

**H-Bond Donors/Acceptors:** Ligand A has 1 HBD and 6 HBA, while Ligand B has 3 HBD and 4 HBA. Both are within acceptable limits (<=5 HBD and <=10 HBA).

**QED:** Both ligands have good QED scores (Ligand A: 0.473, Ligand B: 0.599), indicating reasonable drug-likeness. Ligand B is slightly better here.

**DILI:** Ligand A (70.803) has a higher DILI risk than Ligand B (21.946). This is a significant drawback for Ligand A.

**BBB:** Ligand A (76.037) has a much better BBB penetration score than Ligand B (32.765). This is a crucial factor for a CNS target like DRD2.

**Caco-2 Permeability:** Ligand A (-4.652) has a worse Caco-2 permeability than Ligand B (-5.279). Lower values indicate poorer permeability.

**Aqueous Solubility:** Ligand A (-4.775) has worse aqueous solubility than Ligand B (-1.717).

**hERG:** Ligand A (0.369) has a slightly higher hERG risk than Ligand B (0.09), though both are relatively low.

**Microsomal Clearance:** Ligand A (63.539) has higher microsomal clearance than Ligand B (35.441), indicating lower metabolic stability.

**In vitro Half-Life:** Ligand B (32.058) has a longer in vitro half-life than Ligand A (13.523).

**P-gp Efflux:** Ligand A (0.177) has lower P-gp efflux than Ligand B (0.006), which is favorable for CNS penetration.

**Binding Affinity:** Ligand A (-8.7 kcal/mol) has a significantly better binding affinity than Ligand B (-7.7 kcal/mol). This is a substantial advantage. The difference of 1 kcal/mol is significant enough to potentially overcome some ADME deficiencies.

**Overall Assessment:**

Ligand A excels in binding affinity and BBB penetration, which are critical for a CNS GPCR target. However, it suffers from higher DILI risk, lower solubility, and faster clearance. Ligand B has better ADME properties (lower DILI, better solubility, longer half-life) but significantly weaker binding affinity and poor BBB penetration.

Given the importance of strong binding affinity for GPCRs and the CNS target, the superior affinity of Ligand A is a decisive factor, even considering its ADME liabilities. The better BBB penetration also supports its potential. While the DILI risk is a concern, it might be mitigated through structural modifications in further optimization.

Output:
1
2025-04-17 03:30:00,737 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (349.475 and 344.375 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (78.51) is significantly better than Ligand B (114.91). For CNS targets, TPSA < 90 is preferred, and A is comfortably within this range, while B is approaching the upper limit.

**3. logP:** Both ligands have good logP values (1.755 and 1.096), falling within the optimal 1-3 range.

**4. H-Bond Donors:** Both have 2 HBD, which is acceptable.

**5. H-Bond Acceptors:** Ligand A has 3 HBA, while Ligand B has 7. Ligand A is preferable here, as higher HBA can sometimes hinder permeability.

**6. QED:** Both ligands have good QED scores (0.794 and 0.853), indicating drug-like properties.

**7. DILI:** Ligand A (25.281) has a much lower DILI risk than Ligand B (85.498). This is a significant advantage for A.

**8. BBB:** Ligand A (63.862) has a better BBB percentile than Ligand B (57.968), although both are below the desirable >70 for CNS targets. However, A is closer.

**9. Caco-2 Permeability:** Ligand A (-4.935) has a worse Caco-2 permeability than Ligand B (-5.632). Lower values indicate poorer permeability.

**10. Aqueous Solubility:** Both have poor aqueous solubility (-2.52 and -2.152). This is a concern for both, but not a deciding factor.

**11. hERG Inhibition:** Both ligands show very low hERG inhibition risk (0.143 and 0.036).

**12. Microsomal Clearance:** Ligand A (10.749) has lower microsomal clearance than Ligand B (-25.561), suggesting better metabolic stability.

**13. In vitro Half-Life:** Ligand A (-7.535) has a better in vitro half-life than Ligand B (17.916).

**14. P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.026 and 0.027).

**15. Binding Affinity:** Ligand B (-9.4 kcal/mol) has a significantly stronger binding affinity than Ligand A (-7.5 kcal/mol). This is a substantial advantage for B.

**Overall Assessment:**

While Ligand B has a superior binding affinity, Ligand A demonstrates a much more favorable ADME-Tox profile. Specifically, the lower DILI risk, better BBB penetration, and improved metabolic stability (lower Cl_mic, better half-life) of Ligand A are crucial for a CNS-targeting drug. The TPSA is also significantly better for A. The difference in binding affinity (-9.4 vs -7.5) is substantial (1.9 kcal/mol), but the ADME advantages of A are compelling, especially considering the challenges associated with CNS drug development. Given the GPCR-specific priorities and the importance of CNS penetration and safety, I believe Ligand A is the more viable candidate.

Output:
0
2025-04-17 03:30:00,737 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (355.41 and 342.414 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (96.53) is better than Ligand B (42.43). For CNS targets, we want TPSA <= 90, and A is closer to this threshold.

**3. logP:** Both ligands have acceptable logP values (1.331 and 3.828, respectively), falling within the 1-3 range. Ligand B is slightly higher, which *could* be a minor concern for solubility, but isn't a dealbreaker.

**4. H-Bond Donors:** Ligand A has 3 HBDs, and Ligand B has 0. Both are within the acceptable limit of <=5.

**5. H-Bond Acceptors:** Ligand A has 4 HBAs, and Ligand B has 3. Both are within the acceptable limit of <=10.

**6. QED:** Both ligands have good QED scores (0.6 and 0.749), indicating good drug-like properties.

**7. DILI:** Both ligands have relatively low DILI risk (48.507 and 43.738), both well below the concerning threshold of 60.

**8. BBB:** This is a critical parameter for a CNS target like DRD2. Ligand B (85.033) has a significantly higher BBB percentile than Ligand A (65.917). This is a major advantage for Ligand B.

**9. Caco-2 Permeability:** Ligand A (-5.164) has a negative value, indicating poor permeability. Ligand B (-4.356) is also negative, but less so. Neither is ideal, but A is worse.

**10. Aqueous Solubility:** Ligand A (-2.329) has poor solubility, while Ligand B (-4.463) is even worse. Both are problematic, but B is worse.

**11. hERG Inhibition:** Ligand A (0.087) has a very low hERG risk, which is excellent. Ligand B (0.696) is slightly higher, but still relatively low.

**12. Microsomal Clearance:** Ligand A (-2.441) has a negative value, indicating good metabolic stability. Ligand B (110.164) has high clearance, suggesting rapid metabolism. This is a significant drawback for Ligand B.

**13. In vitro Half-Life:** Ligand A (-6.03) has a negative value, indicating a long half-life. Ligand B (-1.813) has a shorter half-life.

**14. P-gp Efflux:** Ligand A (0.038) has very low P-gp efflux, which is desirable for CNS penetration. Ligand B (0.52) has moderate P-gp efflux, which is less favorable.

**15. Binding Affinity:** Ligand B (-9.6 kcal/mol) has a significantly stronger binding affinity than Ligand A (-8.1 kcal/mol). This is a substantial advantage, potentially outweighing some of the ADME drawbacks.

**Overall Assessment:**

Ligand B excels in binding affinity and BBB penetration, which are crucial for a CNS GPCR target. However, it suffers from higher microsomal clearance, lower Caco-2 permeability, and worse solubility. Ligand A has better metabolic stability, lower P-gp efflux, and a lower hERG risk, but its BBB penetration and binding affinity are significantly weaker.

The stronger binding affinity and superior BBB penetration of Ligand B are likely to be more impactful for *in vivo* efficacy at the DRD2 receptor, despite its ADME liabilities. The difference in binding affinity (-9.6 vs -8.1 kcal/mol) is a 1.5 kcal/mol advantage, which, as per the guidelines, can outweigh minor ADME drawbacks.

Output:
1
2025-04-17 03:30:00,738 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (361.471 and 366.502 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (78.43) is higher than Ligand B (46.34). For a CNS target like DRD2, TPSA < 90 is preferred, so both are acceptable, but B is significantly better.

**3. logP:** Ligand A (1.149) is within the optimal range (1-3). Ligand B (4.879) is higher, potentially leading to solubility issues and off-target interactions.

**4. H-Bond Donors:** Ligand A (1) is good. Ligand B (0) is also acceptable.

**5. H-Bond Acceptors:** Ligand A (6) is within the acceptable range (<=10). Ligand B (4) is also good.

**6. QED:** Ligand A (0.87) is excellent, indicating high drug-likeness. Ligand B (0.563) is acceptable, but lower.

**7. DILI:** Ligand A (52.423) has a moderate DILI risk. Ligand B (27.375) has a lower, more favorable DILI risk.

**8. BBB:** Ligand A (62.233) is below the desirable threshold of >70 for CNS targets. Ligand B (91.314) is excellent, indicating good brain penetration. This is a *major* advantage for a DRD2 ligand.

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.983 and -4.979), which is unusual and suggests poor permeability. This is concerning for both.

**10. Aqueous Solubility:** Both ligands have negative solubility values (-2.508 and -4.061), indicating very poor aqueous solubility. This is a significant drawback.

**11. hERG Inhibition:** Ligand A (0.187) has a very low hERG risk. Ligand B (0.862) has a slightly higher, but still relatively low, hERG risk.

**12. Microsomal Clearance:** Ligand A (38.015) has moderate clearance. Ligand B (97.973) has high clearance, suggesting poor metabolic stability.

**13. In vitro Half-Life:** Ligand A (6.331) has a shorter half-life. Ligand B (54.025) has a much longer half-life, which is desirable.

**14. P-gp Efflux:** Ligand A (0.064) has very low P-gp efflux, which is good for CNS exposure. Ligand B (0.815) has higher P-gp efflux, which could limit brain penetration.

**15. Binding Affinity:** Ligand A (-9.5 kcal/mol) has significantly stronger binding affinity than Ligand B (-6.6 kcal/mol). This is a substantial advantage, potentially outweighing some of the ADME concerns.

**Overall Assessment:**

While Ligand A has superior binding affinity and better P-gp efflux, Ligand B is significantly better in terms of BBB penetration, which is crucial for a DRD2 ligand. Ligand B also has a lower DILI risk and a longer half-life. Both have poor solubility and permeability, but the strong affinity of Ligand A might compensate for these issues. However, the exceptionally high BBB value of Ligand B is a strong indicator of its potential for CNS efficacy. The difference in affinity (2.9 kcal/mol) is substantial, but the BBB advantage of B is too significant to ignore for a CNS target.

Output:
1
2025-04-17 03:30:00,738 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (407.895 Da) is slightly higher, but acceptable. Ligand B (349.431 Da) is also good.

**TPSA:** Ligand A (55.2) is excellent for CNS penetration, well below the 90 A^2 threshold. Ligand B (91.23) is higher, but still potentially acceptable, though less ideal.

**logP:** Ligand A (2.958) is optimal. Ligand B (0.528) is quite low, potentially hindering membrane permeability and CNS penetration.

**H-Bond Donors/Acceptors:** Ligand A (0 HBD, 5 HBA) and Ligand B (2 HBD, 5 HBA) both have reasonable numbers of H-bond donors and acceptors, falling within the acceptable ranges.

**QED:** Both ligands have acceptable QED values (Ligand A: 0.782, Ligand B: 0.572), indicating good drug-like properties.

**DILI:** Ligand A (83.87) has a higher DILI risk than Ligand B (22.257). This is a concern for Ligand A.

**BBB:** Ligand A (69.058) has a good BBB percentile, desirable for a CNS target. Ligand B (39.318) has a significantly lower BBB percentile, which is a major drawback.

**Caco-2 Permeability:** Ligand A (-5.024) and Ligand B (-4.593) both have negative values, which is unusual. It's difficult to interpret without knowing the scale, but suggests poor permeability.

**Aqueous Solubility:** Both ligands have very poor aqueous solubility (-5.4 for A, -1.271 for B). This could pose formulation challenges.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.446 for A, 0.371 for B).

**Microsomal Clearance:** Ligand A (60.976) has higher microsomal clearance than Ligand B (1.87), suggesting lower metabolic stability.

**In vitro Half-Life:** Ligand B (-9.696) has a significantly longer in vitro half-life than Ligand A (-31.332).

**P-gp Efflux:** Ligand A (0.293) has lower P-gp efflux than Ligand B (0.071), meaning it's less likely to be pumped out of the brain.

**Binding Affinity:** Ligand B (-8.0) has a significantly stronger binding affinity than Ligand A (0.0). This is a crucial advantage.

**Overall Assessment:**

Ligand B has a much stronger binding affinity, a longer half-life, lower DILI risk, and lower P-gp efflux. However, it suffers from a low logP and a lower BBB percentile. Ligand A has a better logP and BBB, but weaker binding affinity, higher DILI risk, and faster clearance.

Given the GPCR-specific priorities, *binding affinity is paramount*. The 1.5 kcal/mol advantage of ligand B is substantial and likely outweighs its lower logP and BBB. While the low logP is a concern, it might be addressed through prodrug strategies. The lower BBB could also be mitigated with formulation techniques. The higher DILI risk of Ligand A is a significant concern.

Output:
1
2025-04-17 03:30:00,738 - INFO - Batch 34 complete. Total preferences: 544
2025-04-17 03:30:00,738 - INFO - Processing batch 35/512...
2025-04-17 03:30:43,378 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (352.519 and 373.45 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (69.64) is excellent, well below the 90 A^2 threshold for CNS targets. Ligand B (118.36) is higher, but still potentially acceptable, though less ideal.

**3. logP:** Ligand A (2.574) is optimal (1-3). Ligand B (0.775) is a bit low, potentially hindering permeability.

**4. H-Bond Donors:** Ligand A (2) and Ligand B (3) are both within the acceptable limit of <=5.

**5. H-Bond Acceptors:** Ligand A (3) and Ligand B (4) are both within the acceptable limit of <=10.

**6. QED:** Both ligands have similar QED values (0.67 and 0.592), indicating good drug-like properties.

**7. DILI:** Ligand A (10.237) has a very low DILI risk, significantly better than Ligand B (50.989), which is moderate.

**8. BBB:** Ligand A (70.26) has a good BBB penetration percentile, exceeding the 70% threshold for CNS targets. Ligand B (59.054) is lower, suggesting poorer brain penetration. This is a critical difference for a DRD2 ligand.

**9. Caco-2 Permeability:** Ligand A (-4.476) has poor Caco-2 permeability. Ligand B (-5.57) is even worse. Both are quite low, but the difference isn't huge.

**10. Aqueous Solubility:** Ligand A (-2.847) and Ligand B (-2.073) both have poor aqueous solubility.

**11. hERG Inhibition:** Both ligands have low hERG inhibition risk (0.621 and 0.31).

**12. Microsomal Clearance:** Ligand A (77.884) has higher microsomal clearance, indicating faster metabolism. Ligand B (3.691) has much lower clearance, suggesting better metabolic stability.

**13. In vitro Half-Life:** Ligand A (10.769) has a moderate half-life. Ligand B (-20.503) has a very short half-life, which is concerning.

**14. P-gp Efflux:** Ligand A (0.28) has lower P-gp efflux, which is favorable for CNS exposure. Ligand B (0.091) has even lower efflux, which is even more favorable.

**15. Binding Affinity:** Ligand B (-8.3 kcal/mol) has a slightly better binding affinity than Ligand A (-7.4 kcal/mol). This is a 0.9 kcal/mol difference, which is significant but not overwhelming.

**Overall Assessment:**

While Ligand B has a slightly better binding affinity and lower P-gp efflux, Ligand A is the more promising candidate. The key factors driving this decision are:

*   **BBB Penetration:** Ligand A's significantly higher BBB percentile (70.26 vs. 59.054) is crucial for a CNS target like DRD2.
*   **DILI Risk:** Ligand A has a much lower DILI risk.
*   **Metabolic Stability:** Ligand B's very low half-life and low clearance are concerning.

The lower logP and Caco-2 permeability of Ligand A are drawbacks, but these can potentially be addressed through further optimization. The superior BBB penetration and safety profile of Ligand A outweigh the slightly weaker affinity and permeability issues.

Output:
0
2025-04-17 03:30:43,379 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (353.463 and 344.459 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (92.71) is slightly higher than the ideal <90 for CNS targets, but still reasonable. Ligand B (66.4) is excellent, well below 90.

**3. logP:** Both ligands (2.154 and 2.286) are within the optimal 1-3 range.

**4. H-Bond Donors:** Ligand A (3) is acceptable. Ligand B (0) is also good, potentially improving permeability.

**5. H-Bond Acceptors:** Ligand A (6) is acceptable. Ligand B (4) is also good.

**6. QED:** Both ligands have good QED scores (0.589 and 0.825), indicating drug-like properties. Ligand B is slightly better.

**7. DILI:** Ligand A (11.594) has a lower DILI risk than Ligand B (35.789), which is a significant advantage.

**8. BBB:** Ligand B (80.574) has a significantly better BBB penetration score than Ligand A (43.583). This is *critical* for a CNS target like DRD2.

**9. Caco-2:** Both ligands have negative Caco-2 values (-4.705 and -4.692), which is unusual and suggests poor permeability. This is a concern for both.

**10. Solubility:** Both have negative solubility values (-2.139 and -2.035), also unusual and problematic.

**11. hERG:** Both ligands have low hERG risk (0.609 and 0.436).

**12. Cl_mic:** Ligand B (39.753) has a lower microsomal clearance than Ligand A (46.985), indicating better metabolic stability.

**13. t1/2:** Ligand B (-0.653) has a slightly better (less negative) in vitro half-life than Ligand A (-14.541).

**14. Pgp:** Ligand A (0.067) has a lower P-gp efflux liability than Ligand B (0.196), which is favorable for CNS penetration.

**15. Binding Affinity:** Ligand B (-8.9 kcal/mol) has a significantly stronger binding affinity than Ligand A (-7.1 kcal/mol). This >1.5 kcal/mol difference is substantial and can outweigh some ADME drawbacks.

**Overall Assessment:**

While Ligand A has a better DILI score and lower Pgp efflux, Ligand B's superior BBB penetration, significantly stronger binding affinity, and better metabolic stability are more important for a CNS GPCR target. The negative Caco-2 and solubility values are concerning for both, but the strong affinity of Ligand B suggests it might overcome these issues. The difference in binding affinity is substantial enough to prioritize Ligand B despite the slightly higher Pgp and DILI.

Output:
1
2025-04-17 03:30:43,379 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (362.495 and 342.355 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (69.64) is excellent, well below the 90 A^2 threshold for CNS targets. Ligand B (104.65) is higher, but still potentially acceptable, although less ideal.

**3. logP:** Ligand A (2.434) is optimal (1-3). Ligand B (0.232) is quite low, potentially hindering membrane permeability and CNS penetration.

**4. H-Bond Donors:** Both ligands have 2 HBD, which is within the acceptable limit of <=5.

**5. H-Bond Acceptors:** Ligand A has 4 HBA, and Ligand B has 6 HBA, both are within the acceptable limit of <=10.

**6. QED:** Both ligands have good QED scores (0.791 and 0.806), indicating good drug-like properties.

**7. DILI:** Ligand A (32.61) has a much lower DILI risk than Ligand B (77.394). This is a significant advantage for Ligand A.

**8. BBB:** Ligand A (60.333) has a moderate BBB penetration, while Ligand B (21.985) is quite low. For a CNS target like DRD2, a higher BBB value is highly desirable.

**9. Caco-2:** Both ligands have negative Caco-2 values (-5.034 and -4.985), which is unusual and suggests poor permeability. However, these values are on a scale where negative values are possible and don't necessarily disqualify a compound.

**10. Solubility:** Both ligands have negative solubility values (-3.824 and -2.736), which is also unusual. This suggests poor aqueous solubility.

**11. hERG:** Both ligands have very low hERG risk (0.405 and 0.141).

**12. Cl_mic:** Ligand A (53.497) has a higher microsomal clearance than Ligand B (-10.905). This suggests Ligand B is more metabolically stable.

**13. t1/2:** Ligand B (9.522) has a longer in vitro half-life than Ligand A (6.695).

**14. Pgp:** Ligand A (0.107) has lower P-gp efflux liability than Ligand B (0.059). Lower Pgp is favorable for CNS penetration.

**15. Binding Affinity:** Ligand B (-9.2 kcal/mol) has a significantly stronger binding affinity than Ligand A (-7.5 kcal/mol). This is a substantial advantage for Ligand B, potentially outweighing some of its ADME drawbacks.

**Overall Assessment:**

Ligand B has a significantly better binding affinity, which is crucial for GPCR targets. However, it suffers from poor logP, low BBB penetration, and higher DILI risk. Ligand A has better ADME properties (logP, BBB, DILI, Pgp), but its binding affinity is weaker.

Considering the GPCR-specific priorities, the strong affinity of Ligand B is a major advantage. While its ADME profile is less ideal, optimization strategies could potentially address the logP and BBB issues. The difference in binding affinity (1.7 kcal/mol) is large enough to potentially overcome the ADME liabilities.

Output:
1
2025-04-17 03:30:43,380 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (348.363 and 342.443 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (127.24) is higher than the preferred <90 for CNS targets, while Ligand B (76.02) is well within the range. This is a significant advantage for Ligand B.

**logP:** Ligand A (-0.897) is a bit low, potentially hindering permeability. Ligand B (1.945) is within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A has 3 HBD and 7 HBA, while Ligand B has 2 HBD and 4 HBA. Both are acceptable, falling within the guidelines.

**QED:** Both ligands have similar QED values (0.608 and 0.587), indicating good drug-likeness.

**DILI:** Ligand A (78.48) has a higher DILI risk than Ligand B (30.516). This is a concern for Ligand A.

**BBB:** Ligand A (58.821) has a lower BBB penetration percentile than Ligand B (63.629). While neither is >70, Ligand B is better.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.353 and -5.129), which is unusual and suggests poor permeability. However, these values are on a log scale, so the absolute difference isn't huge.

**Aqueous Solubility:** Both ligands have negative solubility values (-2.191 and -1.663), indicating poor solubility.

**hERG:** Both ligands have very low hERG inhibition liability (0.029 and 0.26), which is excellent.

**Microsomal Clearance:** Ligand A (-19.11) has lower (better) microsomal clearance than Ligand B (33.197), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (31.811) has a longer half-life than Ligand B (-17.808).

**P-gp Efflux:** Ligand A (0.002) has very low P-gp efflux, which is highly desirable for CNS penetration. Ligand B (0.142) is slightly higher, but still relatively low.

**Binding Affinity:** Ligand B (-8.5 kcal/mol) has a slightly better binding affinity than Ligand A (-7.4 kcal/mol). While the difference is less than 1.5 kcal/mol, it's still a positive.

**Overall Assessment:**

Considering the GPCR-specific priorities, Ligand B is the more promising candidate. It has a significantly lower TPSA, a better logP, lower DILI risk, and slightly better BBB penetration. While Ligand A has better metabolic stability (lower Cl_mic) and a longer half-life, the advantages of Ligand B in terms of TPSA, logP, and DILI outweigh these benefits, especially for a CNS target like DRD2. The slightly better affinity of Ligand B further supports this conclusion.

Output:
1
2025-04-17 03:30:43,380 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (351.447 Da) is slightly better, being closer to the lower end which can aid permeability.

**TPSA:** Ligand A (84.67) is excellent, falling well below the 90 A^2 threshold for CNS targets. Ligand B (134.93) is higher, but still acceptable, though less optimal for brain penetration.

**logP:** Ligand A (2.512) is within the optimal range (1-3). Ligand B (-1.208) is significantly lower, which could hinder membrane permeability and brain penetration.

**H-Bond Donors/Acceptors:** Ligand A (HBD=1, HBA=6) and Ligand B (HBD=2, HBA=7) both have reasonable numbers of H-bond donors and acceptors, falling within acceptable limits.

**QED:** Both ligands have acceptable QED values (A: 0.626, B: 0.479), suggesting reasonable drug-likeness. Ligand A is better.

**DILI:** Both ligands have acceptable DILI risk (A: 41.411, B: 52.036), below the concerning threshold of 60.

**BBB:** Ligand A (71.229) shows good BBB penetration potential, exceeding the desirable 70% threshold. Ligand B (53.044) is considerably lower, raising concerns about CNS exposure.

**Caco-2 Permeability:** Ligand A (-4.772) and Ligand B (-5.574) both have negative values, which is unusual. This suggests very poor permeability. However, the scale is not defined, so it is hard to interpret.

**Aqueous Solubility:** Both ligands have poor aqueous solubility (A: -2.599, B: -1.047).

**hERG Inhibition:** Both ligands show low hERG inhibition risk (A: 0.408, B: 0.185).

**Microsomal Clearance:** Ligand B (32.658) has significantly lower microsomal clearance than Ligand A (82.125), indicating better metabolic stability.

**In vitro Half-Life:** Ligand B (-1.968) has a slightly longer in vitro half-life than Ligand A (-6.876), though both are negative, which is unusual.

**P-gp Efflux:** Both ligands show low P-gp efflux liability (A: 0.27, B: 0.012). Ligand B is better.

**Binding Affinity:** Ligand B (-7.1 kcal/mol) has a significantly stronger binding affinity than Ligand A (-0.0 kcal/mol). This is a substantial advantage.

**Overall Assessment:**

Ligand B possesses a much stronger binding affinity, which is a critical factor for GPCR ligands. However, its logP is quite low, and its BBB penetration is concerningly low. Ligand A has better physicochemical properties (logP, TPSA, BBB) but significantly weaker binding affinity.

Considering the GPCR-specific priorities, the strong affinity of Ligand B is a major advantage that could potentially be optimized through structural modifications to improve its logP and BBB penetration. The very weak binding of Ligand A makes it a less attractive starting point, even with its better ADME properties.

Output:
1
2025-04-17 03:30:43,380 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (360.445 and 356.423 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (58.64) is excellent, well below the 90 A^2 threshold for CNS targets. Ligand B (108.05) is higher, but still potentially acceptable, though less ideal.

**logP:** Ligand A (2.448) is optimal (1-3). Ligand B (-1.419) is significantly lower, which could hinder membrane permeability and CNS penetration.

**H-Bond Donors/Acceptors:** Ligand A (HBD=1, HBA=3) and Ligand B (HBD=2, HBA=5) both have reasonable numbers of hydrogen bond donors and acceptors, within the suggested limits.

**QED:** Both ligands have acceptable QED values (0.643 and 0.527, both > 0.5).

**DILI:** Both ligands have low DILI risk (20.861 and 18.224 percentiles), which is favorable.

**BBB:** This is a critical parameter for a CNS target like DRD2. Ligand A excels with a BBB percentile of 94.106. Ligand B is much lower at 47.111, which is a significant concern.

**Caco-2 Permeability:** Ligand A (-4.696) has poor Caco-2 permeability, while Ligand B (-5.337) is also poor.

**Aqueous Solubility:** Ligand A (-2.8) and Ligand B (-0.495) both have poor aqueous solubility.

**hERG:** Both ligands have very low hERG inhibition liability (0.69 and 0.055), which is excellent.

**Microsomal Clearance:** Ligand A (62.083) has higher clearance than Ligand B (-2.143), suggesting Ligand B might be more metabolically stable.

**In vitro Half-Life:** Ligand B (-10.281) has a significantly longer in vitro half-life than Ligand A (-1.116), which is a major advantage.

**P-gp Efflux:** Ligand A (0.091) has lower P-gp efflux than Ligand B (0.001), which is favorable for CNS penetration.

**Binding Affinity:** Ligand A (-8.1 kcal/mol) has a slightly better binding affinity than Ligand B (-7.4 kcal/mol), but the difference is not substantial enough to overcome other significant drawbacks.

**Overall Assessment:**

Ligand A has a significantly better BBB score and a slightly better binding affinity. However, Ligand B has a much longer half-life, lower microsomal clearance, and lower P-gp efflux. The low logP and BBB penetration of Ligand B are major concerns for a CNS target. While Ligand A has poor Caco-2 permeability, the superior BBB penetration is crucial for DRD2. The slightly better affinity of Ligand A, combined with its excellent BBB score, outweighs its other drawbacks.

Output:
0
2025-04-17 03:30:43,380 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B based on the provided guidelines, prioritizing GPCR-specific properties (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (356.769 Da) is slightly lower, which could be advantageous for permeability. Ligand B (404.304 Da) is also good.

**TPSA:** Ligand A (92.92) is better than Ligand B (47.56) for CNS penetration, being closer to the <90 A^2 target.

**logP:** Both ligands have logP values (3.605 and 4.446) within the optimal range (1-3), but Ligand B is pushing the upper limit.

**H-Bond Donors/Acceptors:** Ligand A has 2 HBD and 5 HBA, while Ligand B has 1 HBD and 3 HBA. Both are within acceptable limits.

**QED:** Ligand B (0.801) has a higher QED score than Ligand A (0.584), indicating a more drug-like profile.

**DILI:** Ligand A (98.371) has a significantly higher DILI risk than Ligand B (62.699). This is a major concern for Ligand A.

**BBB:** Ligand B (65.801) has a better BBB penetration percentile than Ligand A (36.371). For a CNS target like DRD2, this is a critical advantage.

**Caco-2 Permeability:** Ligand A (-5.297) has a worse Caco-2 permeability than Ligand B (-4.773).

**Aqueous Solubility:** Ligand A (-5.361) has worse aqueous solubility than Ligand B (-4.504).

**hERG:** Ligand A (0.47) has a slightly better hERG profile than Ligand B (0.73).

**Microsomal Clearance:** Ligand B (79.015) has a higher microsomal clearance than Ligand A (36.595), indicating faster metabolism and potentially lower exposure.

**In vitro Half-Life:** Ligand A (139.823) has a longer in vitro half-life than Ligand B (71.892).

**P-gp Efflux:** Ligand A (0.476) has a lower P-gp efflux liability than Ligand B (0.776), which is favorable for CNS penetration.

**Binding Affinity:** Ligand B (-9.4 kcal/mol) has a significantly stronger binding affinity than Ligand A (-8.7 kcal/mol). This 1.7 kcal/mol difference is substantial and can outweigh some ADME drawbacks.

**Overall Assessment:**

Ligand B is the stronger candidate. While it has a slightly higher logP and P-gp efflux, its significantly better BBB penetration, much lower DILI risk, and substantially improved binding affinity outweigh these concerns. The improved QED score also supports its drug-likeness. Ligand A's high DILI risk and poor BBB penetration are major drawbacks for a CNS-targeted drug. The better half-life and P-gp profile of Ligand A are not enough to compensate for these critical issues.



Output:
1
2025-04-17 03:30:43,381 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (341.411 and 358.515 Da) fall within the ideal range of 200-500 Da.

**TPSA:** Ligand A (68.46) is better than Ligand B (59.73). Both are below the 90 A^2 threshold desirable for CNS targets, indicating good potential for brain penetration.

**logP:** Both ligands have good logP values (2.725 and 3.435), falling within the optimal 1-3 range. Ligand B is slightly higher, which could potentially lead to some off-target effects, but is still acceptable.

**H-Bond Donors/Acceptors:** Both ligands have a reasonable number of HBDs (0) and HBAs (5 and 7 respectively), satisfying the <5 HBDs and <10 HBA guidelines.

**QED:** Both ligands have similar QED values (0.808 and 0.819), indicating good drug-likeness.

**DILI:** Ligand A (43.117) has a slightly higher DILI risk than Ligand B (35.285), but both are below the concerning threshold of 60.

**BBB:** Ligand B (86.196) has a significantly better BBB percentile than Ligand A (79.992). This is a crucial factor for a CNS target like DRD2.

**Caco-2 Permeability:** Ligand A (-4.905) has better Caco-2 permeability than Ligand B (-5.485), indicating better intestinal absorption.

**Aqueous Solubility:** Both ligands have poor aqueous solubility (-2.827 and -3.04). This could pose formulation challenges, but is less critical for CNS drugs that rely on BBB penetration.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.171 and 0.32).

**Microsomal Clearance:** Ligand B (13.405) has a lower microsomal clearance than Ligand A (41.986), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (-16.285) has a longer in vitro half-life than Ligand B (-3.152).

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.494 and 0.369).

**Binding Affinity:** Ligand A (-9.1 kcal/mol) has a significantly stronger binding affinity than Ligand B (-6.7 kcal/mol). This is a substantial difference (2.4 kcal/mol), which can outweigh some ADME drawbacks.

**Overall Assessment:**

While Ligand B has a better BBB score and metabolic stability, the significantly stronger binding affinity of Ligand A (-9.1 vs -6.7 kcal/mol) is a decisive advantage, especially for a GPCR target where potency is paramount. The slightly higher DILI risk and lower BBB for Ligand A are less concerning given the substantial affinity difference. The longer half-life of Ligand A is also a positive.

Output:
1
2025-04-17 03:30:43,381 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (348.45 and 362.54 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (78.68) is better than Ligand B (40.62). Both are below the 90 A^2 threshold desirable for CNS targets, but Ligand A is closer to the upper limit.

**logP:** Ligand A (1.298) is within the optimal 1-3 range. Ligand B (3.342) is at the higher end of the optimal range, potentially increasing off-target interactions.

**H-Bond Donors/Acceptors:** Ligand A has 1 HBD and 5 HBA, while Ligand B has 0 HBD and 3 HBA. Both are within acceptable limits.

**QED:** Both ligands have similar QED values (0.838 and 0.806), indicating good drug-likeness.

**DILI:** Ligand A (18.34) has a significantly lower DILI risk than Ligand B (24.234), which is a strong advantage.

**BBB:** Ligand B (86.351) has a much higher BBB penetration percentile than Ligand A (66.576). This is a critical factor for a CNS target like DRD2.

**Caco-2 Permeability:** Both have negative values (-5.106 and -4.917), which is unusual and suggests poor permeability. The values are close enough that this isn't a major differentiator.

**Aqueous Solubility:** Ligand A (-0.846) is slightly better than Ligand B (-3.187), but both are poor. Solubility could be a formulation challenge for both.

**hERG Inhibition:** Ligand A (0.342) has a lower hERG inhibition liability than Ligand B (0.749), indicating a lower risk of cardiotoxicity.

**Microsomal Clearance:** Ligand A (-13.499) has a much lower (better) microsomal clearance than Ligand B (66.937), suggesting greater metabolic stability.

**In vitro Half-Life:** Ligand A (13.938 hours) has a significantly longer half-life than Ligand B (0.354 hours).

**P-gp Efflux:** Ligand A (0.047) has a much lower P-gp efflux liability than Ligand B (0.631), which is beneficial for CNS exposure.

**Binding Affinity:** Ligand B (-9.4 kcal/mol) has a significantly stronger binding affinity than Ligand A (-7.8 kcal/mol). This is a substantial advantage, potentially outweighing some of the ADME drawbacks.

**Overall Assessment:**

Ligand B has a significantly better binding affinity and BBB penetration, which are crucial for a CNS GPCR target. However, it suffers from higher DILI risk, higher P-gp efflux, faster clearance, and shorter half-life. Ligand A has a better safety profile (lower DILI, hERG), better metabolic stability, and lower efflux, but its affinity and BBB penetration are weaker.

The difference in binding affinity (-9.4 vs -7.8 kcal/mol) is substantial (1.6 kcal/mol). For a GPCR, this potency difference is likely to be the deciding factor, especially if further optimization can address the ADME liabilities of Ligand B. The improved BBB penetration of Ligand B is also a significant advantage.

Output:
1
2025-04-17 03:30:43,381 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (344.459 Da) is slightly lower, which is generally favorable for permeability.

**TPSA:** Ligand A (68.18) is significantly better than Ligand B (83.98). For CNS targets, TPSA should be <= 90, and lower is preferred. Ligand A is well within this range, while Ligand B is approaching the upper limit.

**logP:** Both ligands have good logP values (A: 3.469, B: 2.721), falling within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Both have acceptable HBD (2) and Ligand A has 4 HBA and Ligand B has 6 HBA, both within the guidelines.

**QED:** Both ligands have reasonable QED scores (A: 0.879, B: 0.596), indicating good drug-like properties. Ligand A is superior.

**DILI:** Ligand B (72.005) has a higher DILI risk than Ligand A (45.25). Both are acceptable, but A is preferable.

**BBB:** Both ligands have excellent BBB penetration (A: 76.192, B: 73.827), exceeding the >70% threshold for CNS targets.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values, which is unusual and suggests a potential issue with the data or modeling. However, we'll proceed assuming these represent low permeability.

**Aqueous Solubility:** Both ligands have negative solubility values, which is also unusual and suggests a potential issue with the data or modeling.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (A: 0.576, B: 0.651).

**Microsomal Clearance:** Both ligands have similar microsomal clearance values (A: 49.873, B: 49.37).

**In vitro Half-Life:** Ligand B (61.234) has a longer half-life than Ligand A (38.205), which is generally desirable.

**P-gp Efflux:** Ligand B (0.316) has lower P-gp efflux than Ligand A (0.121), which is favorable for CNS penetration.

**Binding Affinity:** Ligand A (-9.0 kcal/mol) has significantly stronger binding affinity than Ligand B (-0.0 kcal/mol). This is a crucial advantage, as a >1.5 kcal/mol difference can outweigh other drawbacks.

**Overall Assessment:**

Ligand A is the stronger candidate. Its superior TPSA, QED, DILI, and *especially* its dramatically better binding affinity outweigh the slightly shorter half-life and slightly higher P-gp efflux compared to Ligand B. The negative Caco-2 and solubility values are concerning for both, but the binding affinity difference is so large that it makes Ligand A the clear choice for further investigation.

Output:
1
2025-04-17 03:30:43,381 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (348.491 and 380.901 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Both ligands have a TPSA of 67.23, which is acceptable for oral absorption but slightly high for optimal CNS penetration (ideally <90, but closer to 60 is better).

**3. logP:** Both ligands have logP values (2.522 and 2.756) within the optimal range of 1-3.

**4. H-Bond Donors:** Both have 1 HBD, which is good.

**5. H-Bond Acceptors:** Ligand A has 4 HBA, and Ligand B has 5. Both are acceptable (<=10).

**6. QED:** Both ligands have high QED scores (0.859 and 0.867), indicating good drug-like properties.

**7. DILI:** Ligand A (24.351) has a significantly lower DILI risk than Ligand B (59.093). This is a major advantage for Ligand A.

**8. BBB:** Ligand A (72.043) has a much better BBB percentile than Ligand B (61.419). This is *critical* for a CNS target like DRD2.

**9. Caco-2 Permeability:** Ligand A (-4.788) and Ligand B (-5.072) both have negative Caco-2 values, indicating poor permeability. This is a concern for both.

**10. Aqueous Solubility:** Both ligands have poor aqueous solubility (-2.346 and -3.147). This could pose formulation challenges.

**11. hERG Inhibition:** Both ligands have low hERG inhibition risk (0.637 and 0.682).

**12. Microsomal Clearance:** Ligand B (36.902) has lower microsomal clearance than Ligand A (42.371), suggesting better metabolic stability.

**13. In vitro Half-Life:** Ligand B (-8.993) has a longer in vitro half-life than Ligand A (-0.545), which is desirable.

**14. P-gp Efflux:** Ligand A (0.218) has lower P-gp efflux liability than Ligand B (0.471), which is beneficial for CNS exposure.

**15. Binding Affinity:** Ligand B (-8.4 kcal/mol) has a slightly better binding affinity than Ligand A (-7.8 kcal/mol). This 0.6 kcal/mol difference is noticeable but not overwhelming.

**Overall Assessment:**

While Ligand B has slightly better affinity and metabolic stability (lower Cl_mic, longer t1/2), Ligand A is significantly better in terms of safety (DILI) and, crucially, BBB penetration. For a CNS target like DRD2, BBB penetration is paramount. The lower P-gp efflux for Ligand A also supports better CNS exposure. The affinity difference is not large enough to overcome the substantial advantages of Ligand A in terms of safety and CNS penetration. The poor Caco-2 and solubility are concerns for both, but can be addressed with formulation strategies.

Output:
0
2025-04-17 03:30:43,381 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (347.459 Da) is slightly lower, which could be beneficial for permeability. Ligand B (361.431 Da) is also good.

**TPSA:** Ligand A (90.46) is excellent, falling well below the 90 A^2 threshold for CNS targets. Ligand B (119.03) is higher, but still reasonable, though less optimal for CNS penetration.

**logP:** Ligand A (3.345) is within the optimal range (1-3). Ligand B (0.233) is significantly lower, which is a major concern for CNS penetration as it may struggle to cross the blood-brain barrier.

**H-Bond Donors/Acceptors:** Ligand A (HBD=4, HBA=3) and Ligand B (HBD=2, HBA=8) both have acceptable numbers of H-bond donors and acceptors.

**QED:** Both ligands have good QED scores (A: 0.636, B: 0.787), indicating drug-like properties.

**DILI:** Both ligands have acceptable DILI risk (A: 32.61, B: 62.001). Ligand A is better, but both are below the concerning threshold of 60.

**BBB:** Ligand A (63.125) has a moderate BBB penetration score. Ligand B (70.88) is better, exceeding the 70% threshold for CNS targets. However, this is heavily influenced by the low logP.

**Caco-2 Permeability:** Ligand A (-4.658) has poor Caco-2 permeability. Ligand B (-5.389) is also poor.

**Aqueous Solubility:** Both ligands have poor aqueous solubility (A: -3.949, B: -3.216).

**hERG:** Both ligands have low hERG inhibition risk (A: 0.616, B: 0.294). Ligand B is slightly better.

**Microsomal Clearance:** Ligand A (32.475) has moderate clearance, while Ligand B (-5.209) has negative clearance, which is unusual and suggests very high metabolic stability.

**In vitro Half-Life:** Ligand A (27.425) has a reasonable half-life. Ligand B (6.263) has a very short half-life.

**P-gp Efflux:** Both ligands have low P-gp efflux (A: 0.069, B: 0.043), which is good for CNS exposure.

**Binding Affinity:** Both ligands have excellent binding affinity (A: -8.9 kcal/mol, B: -8.5 kcal/mol). Ligand A is slightly better, with a 0.4 kcal/mol advantage.

**Overall Assessment:**

While Ligand B has better BBB penetration and metabolic stability, its extremely low logP is a significant drawback for CNS drug development. It's likely to have poor oral absorption and limited ability to cross the blood-brain barrier despite the BBB percentile score. The negative clearance is also a red flag. Ligand A, despite having slightly lower BBB penetration and moderate clearance, has a much more favorable logP, better Caco-2 permeability, and a slightly stronger binding affinity. The combination of these factors makes Ligand A the more promising candidate.

Output:
0
2025-04-17 03:30:43,382 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (450.244 Da) is higher, but still acceptable. Ligand B (348.447 Da) is lower, potentially favoring permeability.

**2. TPSA:** Both ligands have TPSA values around 103-104, which is slightly above the optimal <90 for CNS targets, but not disqualifying.

**3. logP:** Both ligands have good logP values (1.639 and 1.336), falling within the 1-3 range.

**4. H-Bond Donors:** Ligand A (2) is preferable to Ligand B (4). Fewer HBDs generally improve permeability.

**5. H-Bond Acceptors:** Ligand A (6) is slightly higher than Ligand B (3), but both are within the acceptable limit of 10.

**6. QED:** Both ligands have similar QED values (0.591 and 0.513), indicating good drug-likeness.

**7. DILI:** Ligand A (84.994) has a significantly higher DILI risk than Ligand B (31.601). This is a major concern for Ligand A.

**8. BBB:** Ligand B (57.464) has a substantially better BBB penetration percentile than Ligand A (43.117). This is crucial for a CNS target like DRD2.

**9. Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and suggests poor permeability. However, the scale isn't specified, so it's hard to interpret.

**10. Aqueous Solubility:** Both have negative solubility values, indicating poor aqueous solubility. This is a concern for both.

**11. hERG Inhibition:** Both ligands show low hERG inhibition risk (0.347 and 0.134).

**12. Microsomal Clearance:** Ligand A (31.978) has a higher microsomal clearance than Ligand B (5.178), suggesting lower metabolic stability.

**13. In vitro Half-Life:** Ligand B (-9.332) has a much longer in vitro half-life than Ligand A (-1.787).

**14. P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.037 and 0.013), which is favorable for CNS penetration.

**15. Binding Affinity:** Ligand A (-9.5 kcal/mol) has a stronger binding affinity than Ligand B (-7.5 kcal/mol). This is a significant advantage. However, the difference is partially offset by the other ADME properties.

**Overall Assessment:**

While Ligand A boasts a stronger binding affinity, its significantly higher DILI risk, lower BBB penetration, and poorer metabolic stability are major drawbacks. Ligand B, despite having slightly weaker affinity, presents a much more favorable ADME profile, particularly its lower DILI risk and better BBB penetration, which are critical for a CNS-targeting drug. The difference in affinity (2 kcal/mol) is not large enough to overcome the ADME liabilities of Ligand A.

Output:
1
2025-04-17 03:30:43,382 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (351.403 and 344.459 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (111.99) is better than Ligand B (67.23) as it is closer to the optimal range for CNS targets (<=90). Ligand B is still acceptable.

**3. logP:** Ligand B (2.081) is optimal (1-3), while Ligand A (0.155) is quite low, potentially hindering membrane permeability. This is a significant drawback for Ligand A.

**4. H-Bond Donors:** Ligand A (3) is acceptable, while Ligand B (1) is even better.

**5. H-Bond Acceptors:** Ligand A (6) is acceptable, while Ligand B (4) is even better.

**6. QED:** Both ligands have good QED scores (0.575 and 0.832), indicating good drug-like properties. Ligand B is slightly better.

**7. DILI:** Both ligands have low DILI risk (33.346 and 19.426), which is favorable. Ligand B is better.

**8. BBB:** Ligand B (67.08) is significantly better than Ligand A (17.72) for CNS penetration, a critical factor for DRD2 targeting.

**9. Caco-2 Permeability:** Ligand A (-5.118) is very poor, while Ligand B (-4.912) is also poor, but slightly better.

**10. Aqueous Solubility:** Both ligands have poor aqueous solubility (-1.127 and -1.491). This could pose formulation challenges, but isn't a dealbreaker.

**11. hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.187 and 0.218).

**12. Microsomal Clearance:** Ligand A (-13.955) has much lower (better) microsomal clearance than Ligand B (27.991), suggesting greater metabolic stability.

**13. In vitro Half-Life:** Both ligands have similar and poor in vitro half-lives (-12.02 and -13.175).

**14. P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.008 and 0.049).

**15. Binding Affinity:** Ligand B (-8.2) has a stronger binding affinity than Ligand A (-7.0). This is a substantial advantage.

**Overall Assessment:**

While Ligand A has better metabolic stability (lower Cl_mic) and a slightly better TPSA, Ligand B is superior in almost every other critical aspect. Specifically, its significantly better logP, BBB penetration, and binding affinity outweigh the slightly higher metabolic clearance. The low logP of Ligand A is a major concern for CNS penetration, and its poor Caco-2 permeability further diminishes its potential. The stronger binding affinity of Ligand B is also a significant advantage.

Output:
1
2025-04-17 03:30:43,382 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (363.889 and 358.507 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (62.3) is significantly higher than the preferred <90 for CNS targets, while Ligand B (34.47) is excellent. This is a major advantage for Ligand B.

**3. logP:** Ligand A (3.026) is within the optimal 1-3 range. Ligand B (4.318) is slightly above, potentially hinting at solubility issues or off-target interactions, but not drastically so.

**4. H-Bond Donors:** Ligand A (1) is good. Ligand B (0) is also acceptable.

**5. H-Bond Acceptors:** Ligand A (3) is good. Ligand B (4) is also acceptable.

**6. QED:** Both ligands have reasonable QED values (0.874 and 0.771), indicating good drug-like properties.

**7. DILI:** Both ligands have very similar and low DILI risk (23.187 and 23.11), which is positive.

**8. BBB:** Ligand B (88.6) shows excellent BBB penetration, exceeding the desirable >70 threshold. Ligand A (74.796) is good, but not as promising. This is a significant advantage for Ligand B, given the CNS target.

**9. Caco-2:** Both ligands have negative Caco-2 values (-4.867 and -4.496). These values are unusual and difficult to interpret without further context. It is possible these are logPapp values, and lower values indicate poorer permeability.

**10. Solubility:** Both ligands have negative solubility values (-3.306 and -4.734). Similar to Caco-2, these are unusual and require more context.

**11. hERG:** Ligand A (0.404) has a lower hERG risk than Ligand B (0.84). This is a slight advantage for Ligand A.

**12. Cl_mic:** Ligand A (46.031) has a lower microsomal clearance, indicating better metabolic stability, than Ligand B (119.435). This is a significant advantage for Ligand A.

**13. t1/2:** Ligand A (-8.097) has a negative in vitro half-life which is not possible. Ligand B (16.954) has a reasonable half-life.

**14. Pgp:** Ligand A (0.057) has significantly lower P-gp efflux liability than Ligand B (0.854). This is a major advantage for Ligand A, enhancing CNS exposure.

**15. Binding Affinity:** Ligand A (-8.6 kcal/mol) has a slightly better binding affinity than Ligand B (-7.6 kcal/mol). The 1 kcal/mol difference is meaningful and can outweigh some ADME drawbacks.

**Overall Assessment:**

Ligand B excels in BBB penetration and has a reasonable half-life. However, it suffers from higher P-gp efflux and a higher logP. Ligand A has a better binding affinity, lower P-gp efflux, lower microsomal clearance, and a lower hERG risk. While Ligand A's TPSA is higher, the superior affinity, P-gp, and metabolic stability, coupled with the CNS target, make it the more promising candidate. The negative values for Caco-2 and solubility are concerning for both, but the other advantages of Ligand A are more impactful.

Output:
0
2025-04-17 03:30:43,382 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (351.422 Da) is slightly higher, but acceptable. Ligand B (276.38 Da) is also good.

**TPSA:** Ligand A (91.32) is borderline for CNS targets (ideally <90), but still reasonable. Ligand B (45.33) is excellent, well below the 90 threshold.

**logP:** Both ligands have good logP values (A: 1.844, B: 1.963), falling within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A (HBD=3, HBA=4) and Ligand B (HBD=1, HBA=3) both have acceptable numbers of H-bond donors and acceptors.

**QED:** Both ligands have good QED scores (A: 0.755, B: 0.918), indicating good drug-like properties.

**DILI:** Ligand A (44.862) has a slightly higher DILI risk than Ligand B (24.971), but both are below the concerning threshold of 60.

**BBB:** This is a critical parameter for CNS targets. Ligand A has a BBB percentile of 60.45, which is below the desirable >70. Ligand B has a significantly higher BBB percentile of 93.137, making it much more likely to penetrate the brain.

**Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and suggests a potential issue with the data or modeling. However, we can still compare them relatively; Ligand A (-4.72) is slightly worse than Ligand B (-4.423).

**Aqueous Solubility:** Both ligands have negative solubility values, again suggesting a potential issue with the data. Ligand A (-1.898) is slightly worse than Ligand B (-1.308).

**hERG Inhibition:** Ligand A (0.189) has a slightly higher hERG risk than Ligand B (0.619), but both are relatively low.

**Microsomal Clearance:** Ligand B (9.066) has a considerably higher microsomal clearance than Ligand A (2.851), indicating lower metabolic stability.

**In vitro Half-Life:** Ligand B (-4.895) has a negative half-life, which is not physically possible and indicates a data issue. Ligand A (1.431) has a short half-life, but it is at least a positive value.

**P-gp Efflux:** Ligand A (0.031) has very low P-gp efflux, which is favorable for CNS penetration. Ligand B (0.383) has slightly higher P-gp efflux.

**Binding Affinity:** Ligand A (-8.3 kcal/mol) has a slightly better binding affinity than Ligand B (-7.9 kcal/mol). The difference is 0.4 kcal/mol, which is not huge, but still noticeable.

**Overall Assessment:**

Ligand B is the stronger candidate despite the slightly weaker binding affinity. The significantly better BBB penetration (93.137 vs. 60.45) is a major advantage for a CNS target like DRD2. The lower DILI risk and lower P-gp efflux also contribute to its favorability. While the negative values for Caco-2 and solubility are concerning, the difference between the two ligands is similar. The biggest drawback for Ligand B is the higher microsomal clearance and the impossible half-life value, but the difference in binding affinity can potentially be optimized during lead optimization. The questionable data points for Ligand B are a concern, but the overall profile is more promising for CNS penetration.

Output:
1
2025-04-17 03:30:43,383 - INFO - Batch 35 complete. Total preferences: 560
2025-04-17 03:30:43,383 - INFO - Processing batch 36/512...
2025-04-17 03:31:25,155 - INFO - Reasoning:

Let's analyze Ligand A and Ligand B against the provided guidelines, prioritizing GPCR-specific properties (BBB, logP, Pgp, TPSA, and affinity) for DRD2.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (343.354 Da) is slightly preferable as it's closer to the lower end, potentially aiding permeability.

**TPSA:** Ligand A (66.84) is significantly better than Ligand B (109.57). For CNS targets, TPSA < 90 is desired, and Ligand A comfortably meets this, while Ligand B is pushing the limit.

**logP:** Ligand A (3.192) is optimal (1-3), while Ligand B (0.989) is a bit low, potentially hindering permeation.

**H-Bond Donors/Acceptors:** Both ligands have acceptable HBD (1 & 2) and HBA (4 & 4) counts, well within the guidelines.

**QED:** Both ligands have reasonable QED scores (0.869 & 0.661), indicating good drug-like properties.

**DILI:** Ligand A (68.282) has a higher DILI risk than Ligand B (19.969). This is a significant drawback for Ligand A.

**BBB:** Ligand A (79.721) has a much better BBB percentile than Ligand B (61.535).  This is *critical* for a CNS target like DRD2.

**Caco-2 Permeability:** Ligand A (-4.64) is worse than Ligand B (-5.278), indicating lower intestinal absorption.

**Aqueous Solubility:** Ligand A (-4.552) is worse than Ligand B (-2.615).

**hERG:** Ligand A (0.67) has a slightly higher hERG risk than Ligand B (0.241), but both are relatively low.

**Microsomal Clearance:** Ligand A (77.343) has higher clearance than Ligand B (39.217), suggesting lower metabolic stability.

**In vitro Half-Life:** Ligand B (-39.866) has a much longer half-life than Ligand A (-12.558), which is a significant advantage.

**P-gp Efflux:** Ligand A (0.411) has lower P-gp efflux than Ligand B (0.006), which is favorable for CNS penetration.

**Binding Affinity:** Ligand A (-9.7 kcal/mol) has a significantly stronger binding affinity than Ligand B (-7.5 kcal/mol). This is a substantial advantage, potentially outweighing some of the ADME drawbacks.

**Overall Assessment:**

Ligand A excels in BBB penetration and binding affinity, which are paramount for a DRD2 ligand. However, it suffers from higher DILI risk, lower solubility, and faster clearance. Ligand B has better ADME properties (lower DILI, better solubility, longer half-life) but weaker binding affinity and poorer BBB penetration.

The strong binding affinity and good BBB of Ligand A are compelling. The difference in affinity (2.2 kcal/mol) is substantial enough to potentially overcome the ADME liabilities, *especially* given the importance of target engagement for DRD2. While the DILI risk is concerning, it could be mitigated through structural modifications during lead optimization.

Output:
1
2025-04-17 03:31:25,155 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (353.482 and 336.399 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (43.86) is excellent, well below the 90 Angstroms threshold for CNS targets. Ligand B (94.8) is higher, but still potentially acceptable, though less ideal.

**3. logP:** Both ligands have good logP values (1.917 and 1.432), falling within the optimal 1-3 range.

**4. H-Bond Donors:** Both ligands have acceptable HBD counts (0 and 1, respectively), well below the 5 threshold.

**5. H-Bond Acceptors:** Ligand A (3) and Ligand B (6) are both within the acceptable range of <=10.

**6. QED:** Both ligands have good QED scores (0.733 and 0.802), indicating good drug-like properties.

**7. DILI:** Ligand A (6.01) has a very favorable DILI score, indicating low liver injury risk. Ligand B (44.552) is higher, but still within a reasonable range.

**8. BBB:** This is a critical parameter for a CNS target like DRD2. Ligand A excels with a BBB percentile of 95.657, suggesting excellent brain penetration. Ligand B's BBB percentile is significantly lower at 46.336, which is a major drawback.

**9. Caco-2 Permeability:** Ligand A (-4.631) and Ligand B (-5.302) both have negative values, which is not ideal. However, the scale is not specified, so it's difficult to interpret the significance.

**10. Aqueous Solubility:** Both ligands have poor aqueous solubility (-1.204 and -1.817). This could pose formulation challenges, but might be mitigated by other factors.

**11. hERG Inhibition:** Both ligands have low hERG inhibition risk (0.702 and 0.502).

**12. Microsomal Clearance:** Ligand A (0.082) has very low microsomal clearance, indicating high metabolic stability. Ligand B (3.662) has higher clearance, suggesting faster metabolism.

**13. In vitro Half-Life:** Ligand A (1.189) has a short half-life, while Ligand B (-3.726) has a very long half-life.

**14. P-gp Efflux:** Ligand A (0.042) has very low P-gp efflux, which is excellent for CNS penetration. Ligand B (0.007) also shows low P-gp efflux.

**15. Binding Affinity:** Ligand B (-8.6 kcal/mol) has a slightly better binding affinity than Ligand A (-7.9 kcal/mol). However, the difference is less than 1.5 kcal/mol, and can be outweighed by other factors.

**Overall Assessment:**

Ligand A is the stronger candidate. While Ligand B has slightly better binding affinity, Ligand A's significantly superior BBB penetration (95.657 vs 46.336), lower DILI risk, and better metabolic stability (lower Cl_mic) are crucial advantages for a CNS-targeting drug. The slightly shorter half-life of Ligand A is less concerning than the poor BBB penetration of Ligand B.

Output:
0
2025-04-17 03:31:25,156 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (350.419 Da and 348.403 Da) fall within the ideal range of 200-500 Da.

**TPSA:** Ligand A (96.69) is better than Ligand B (104.39), both are below the 140 A^2 threshold for oral absorption and reasonably close to the <90 A^2 target for CNS penetration.

**logP:** Ligand A (-0.009) is slightly better than Ligand B (0.162), both are within the optimal 1-3 range, but closer to the lower end.

**H-Bond Donors/Acceptors:** Both ligands have 2 HBD and similar HBA counts (6 and 5 respectively), satisfying the <5 HBD and <10 HBA guidelines.

**QED:** Both ligands have good QED scores (0.796 and 0.807), indicating drug-like properties.

**DILI:** Ligand A (31.02) has a significantly lower DILI risk than Ligand B (66.421). This is a substantial advantage.

**BBB:** Ligand A (44.746) has a better BBB penetration percentile than Ligand B (38.038), though both are below the desirable >70% for CNS targets.

**Caco-2 Permeability:** Ligand B (-5.226) is better than Ligand A (-4.96) but both are negative values, indicating poor permeability.

**Aqueous Solubility:** Ligand B (-2.423) is worse than Ligand A (-1.235), indicating lower solubility.

**hERG:** Both ligands have very low hERG inhibition liability (0.235 and 0.111).

**Microsomal Clearance:** Ligand B (-11.413) has much lower (better) microsomal clearance than Ligand A (-8.848), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand B (-9.534) has a longer in vitro half-life than Ligand A (5.147), which is desirable.

**P-gp Efflux:** Ligand B (0.021) has a lower P-gp efflux liability than Ligand A (0.03).

**Binding Affinity:** Ligand A (-8.6 kcal/mol) has a significantly better binding affinity than Ligand B (-0.0 kcal/mol). This is a critical advantage, as a difference of >1.5 kcal/mol can outweigh other drawbacks.

**Overall Assessment:**

Ligand A is the stronger candidate. While Ligand B has better metabolic stability (lower Cl_mic, longer t1/2) and P-gp efflux, the significantly better binding affinity of Ligand A (-8.6 vs -0.0 kcal/mol) is a decisive factor, especially for a GPCR target. The lower DILI risk and slightly better BBB penetration of Ligand A are also beneficial. The Caco-2 permeability is poor for both, but the affinity difference is paramount.

Output:
1
2025-04-17 03:31:25,156 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (343.391 and 348.531 Da) fall within the ideal range of 200-500 Da.

**TPSA:** Ligand A (135.78) is excellent, being below the 90 A^2 threshold for CNS targets. Ligand B (49.41) is also very good, well below the threshold.

**logP:** Ligand A (0.372) is quite low, potentially hindering permeability. Ligand B (3.75) is within the optimal range of 1-3. This is a significant advantage for Ligand B.

**H-Bond Donors/Acceptors:** Ligand A has 3 HBD and 7 HBA, which are acceptable. Ligand B has 1 HBD and 2 HBA, also acceptable and potentially favoring permeability due to fewer hydrogen bonds.

**QED:** Both ligands have reasonable QED values (0.689 and 0.536), indicating good drug-like properties.

**DILI:** Ligand A has a DILI risk of 66.421, which is concerning (high risk). Ligand B has a much lower DILI risk of 14.075, which is excellent.

**BBB:** Both ligands have similar BBB penetration (57.736 and 58.162). While not exceeding the ideal >70, they are reasonably good for a GPCR target.

**Caco-2:** Ligand A shows poor Caco-2 permeability (-5.602), indicating poor absorption. Ligand B also shows poor Caco-2 permeability (-4.72), but is slightly better than A.

**Solubility:** Both ligands have negative solubility values (-2.629 and -3.733), suggesting poor aqueous solubility. This is a concern for both.

**hERG:** Ligand A has a very low hERG risk (0.17), which is excellent. Ligand B has a moderate hERG risk (0.615).

**Microsomal Clearance:** Ligand A has a moderate Cl_mic (26.668), while Ligand B has a higher Cl_mic (45.309), suggesting faster metabolism and lower metabolic stability for B.

**In vitro Half-Life:** Ligand A has a negative half-life (-10.663), which is unusual and likely indicates rapid degradation. Ligand B has a slightly negative half-life (-1.085), also indicating rapid degradation, but less severe than A.

**P-gp Efflux:** Ligand A has very low P-gp efflux (0.003), which is excellent for CNS penetration. Ligand B has moderate P-gp efflux (0.463).

**Binding Affinity:** Ligand A has a significantly stronger binding affinity (-7.7 kcal/mol) compared to Ligand B (0.0 kcal/mol). This is a substantial advantage for Ligand A.

**Overall Assessment:**

Ligand A has a much stronger binding affinity and excellent P-gp efflux, but suffers from poor Caco-2 permeability, a high DILI risk, and a very short in vitro half-life. Its low logP is also a concern. Ligand B has a better logP and a much lower DILI risk, but its binding affinity is very weak, and it has a higher microsomal clearance.

Given the GPCR-specific priorities, and the substantial difference in binding affinity, Ligand A is the more promising candidate *despite* its drawbacks. The strong binding affinity could potentially outweigh the ADME issues, and optimization efforts could focus on improving its logP, solubility, and metabolic stability. The DILI risk is a serious concern that would need to be addressed, but is less critical than a lack of potency.

Output:
0
2025-04-17 03:31:25,156 - INFO - Reasoning:

Let's analyze Ligand A and Ligand B based on the provided guidelines, prioritizing GPCR-specific properties (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (362.455 and 370.465 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (80.82) is significantly better than Ligand B (42.41). For CNS targets, TPSA should be <=90, both satisfy this, but A is closer to the upper limit.

**logP:** Ligand A (3.086) is optimal (1-3). Ligand B (4.913) is slightly higher, potentially leading to solubility issues and off-target effects, but still within a tolerable range.

**H-Bond Donors/Acceptors:** Ligand A (0 HBD, 7 HBA) and Ligand B (0 HBD, 5 HBA) both have acceptable numbers.

**QED:** Ligand A (0.756) is better than Ligand B (0.594), indicating a more drug-like profile.

**DILI:** Ligand A (66.576) has a higher DILI risk than Ligand B (19.465). This is a significant drawback for Ligand A.

**BBB:** Ligand B (94.145) is *much* better than Ligand A (61.729). This is a critical factor for a CNS target like DRD2. A BBB percentile >70 is desirable, and Ligand B exceeds this, while A falls short.

**Caco-2 Permeability:** Ligand A (-5.054) is worse than Ligand B (-4.852), indicating lower intestinal absorption.

**Aqueous Solubility:** Ligand A (-2.458) is worse than Ligand B (-4.933), potentially causing formulation challenges.

**hERG Inhibition:** Ligand A (0.127) has a slightly lower hERG risk than Ligand B (0.919), which is favorable.

**Microsomal Clearance:** Ligand A (51.404) has lower clearance than Ligand B (86.446), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (-8.915) has a much longer half-life than Ligand B (19.055), which is a positive attribute.

**P-gp Efflux:** Ligand A (0.26) has lower P-gp efflux than Ligand B (0.578), which is beneficial for CNS exposure.

**Binding Affinity:** Ligand A (-7.6 kcal/mol) has a slightly better binding affinity than Ligand B (-6.4 kcal/mol). This 1.2 kcal/mol difference is substantial and could outweigh some of the ADME drawbacks.

**Overall Assessment:**

Despite Ligand A's better affinity, longer half-life, and lower P-gp efflux, Ligand B is the more promising candidate. The significantly higher BBB penetration (94.145 vs 61.729) is a crucial advantage for a CNS-targeting drug.  The lower DILI risk for Ligand B is also a major positive. While Ligand A has better metabolic stability, the BBB and safety profiles of Ligand B are more favorable for development. The affinity difference, while notable, isn't large enough to overcome these significant ADME/Tox advantages.

Output:
1
2025-04-17 03:31:25,156 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (415.253 and 404.312 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (41.99) is significantly better than Ligand B (83.6). For CNS targets, we want TPSA <= 90, and A is comfortably within that range, while B is approaching the upper limit and is less desirable.

**3. logP:** Both ligands have good logP values (4.788 and 3.268), falling within the optimal range of 1-3. Ligand B is slightly better here, being closer to the middle of the range.

**4. H-Bond Donors:** Both have 1 HBD, which is acceptable.

**5. H-Bond Acceptors:** Ligand A has 2 HBA, and Ligand B has 5.  Ligand A is preferable as it is closer to the ideal of <=10.

**6. QED:** Both ligands have similar QED values (0.69 and 0.685), indicating good drug-likeness.

**7. DILI:** Ligand A (52.423) has a slightly lower DILI risk than Ligand B (57.697), which is favorable. Both are below the concerning threshold of 60.

**8. BBB:** Ligand A (87.67) has a significantly better BBB penetration percentile than Ligand B (50.717). This is *critical* for a CNS target like DRD2.

**9. Caco-2 Permeability:** Both have negative Caco-2 values (-5.105 and -5.283). This is unusual and suggests poor permeability. However, the values are very similar.

**10. Aqueous Solubility:** Both have negative solubility values (-5.246 and -3.937), indicating poor aqueous solubility. Again, the values are similar.

**11. hERG Inhibition:** Both ligands have low hERG inhibition risk (0.859 and 0.713).

**12. Microsomal Clearance:** Ligand A (62.507) has a higher microsomal clearance than Ligand B (47.949), indicating lower metabolic stability. This is a negative for Ligand A.

**13. In vitro Half-Life:** Ligand A (41.755) and Ligand B (43.677) have similar in vitro half-lives.

**14. P-gp Efflux:** Ligand A (0.742) has lower P-gp efflux than Ligand B (0.517), which is favorable for CNS penetration.

**15. Binding Affinity:** Ligand A (-10 kcal/mol) has a significantly stronger binding affinity than Ligand B (-8.6 kcal/mol). This is a substantial advantage, potentially outweighing some of the ADME drawbacks.

**Overall Assessment:**

Ligand A is the stronger candidate. While it has slightly higher microsomal clearance, its superior BBB penetration, lower TPSA, better HBA count, and *much* stronger binding affinity outweigh this drawback. The strong binding affinity is particularly important for a GPCR target. The similar poor solubility and Caco-2 values are a concern for both, but can be addressed through formulation strategies.

Output:
1
2025-04-17 03:31:25,157 - INFO - Reasoning:

Let's analyze Ligand A and Ligand B based on the provided guidelines, prioritizing GPCR-specific properties (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (347.46 and 348.49 Da) fall comfortably within the ideal 200-500 Da range.

**TPSA:** Ligand A (78.51) is slightly higher than Ligand B (67.43). Both are below the 90 A^2 threshold desirable for CNS targets, but Ligand B is better.

**logP:** Both ligands have good logP values (1.365 and 2.108), falling within the optimal 1-3 range. Ligand B is slightly higher, which could be beneficial for membrane permeability.

**H-Bond Donors/Acceptors:** Both ligands have 2 HBD and 3 HBA, meeting the criteria of <=5 and <=10 respectively.

**QED:** Ligand A (0.737) has a slightly better QED score than Ligand B (0.66), indicating slightly better overall drug-likeness.

**DILI:** Both ligands have low DILI risk (21.95 and 20.86), well below the 40 threshold.

**BBB:** Both ligands demonstrate good BBB penetration (58.01% and 59.67%), but are below the 70% target. Ligand B is marginally better.

**Caco-2 Permeability:** Ligand A (-5.156) has significantly *better* Caco-2 permeability than Ligand B (-4.779). A more negative value indicates higher permeability.

**Aqueous Solubility:** Ligand A (-2.218) has slightly better aqueous solubility than Ligand B (-3.066).

**hERG Inhibition:** Both ligands show very low hERG inhibition risk (0.074 and 0.225), which is excellent.

**Microsomal Clearance:** Ligand A (21.95) has lower microsomal clearance than Ligand B (24.38), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (20.154 hours) has a significantly longer in vitro half-life than Ligand B (7.573 hours), which is a major advantage.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.029 and 0.046), which is favorable for CNS penetration.

**Binding Affinity:** Ligand B (-7.9 kcal/mol) has a slightly better binding affinity than Ligand A (-8.2 kcal/mol). While the difference is small, it's still a positive.

**Overall Assessment:**

Considering all factors, and prioritizing GPCR properties, Ligand A is the more promising candidate. While Ligand B has a slightly better affinity and logP, Ligand A excels in crucial ADME properties: significantly better Caco-2 permeability, substantially longer half-life, and lower microsomal clearance. The slightly better QED and solubility of Ligand A also contribute to its favorability. The small affinity difference can likely be optimized during lead optimization.

Output:
0
2025-04-17 03:31:25,157 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (344.411 and 360.483 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (66.92) is significantly better than Ligand B (71.25). For CNS targets, we want TPSA <= 90, and A is closer to the optimal <=60 range.

**3. logP:** Both ligands have good logP values (1.589 and 2.295), falling within the 1-3 range.

**4. H-Bond Donors:** Ligand A (0) is preferable to Ligand B (1). Fewer HBDs generally improve permeability.

**5. H-Bond Acceptors:** Ligand A (4) is better than Ligand B (6). Lower HBA counts are generally favored for CNS penetration.

**6. QED:** Both ligands have good QED scores (0.778 and 0.888), indicating good drug-like properties.

**7. DILI:** Ligand A (34.393) has a much lower DILI risk than Ligand B (53.625). This is a significant advantage.

**8. BBB:** Ligand A (86.002) has a substantially better BBB penetration percentile than Ligand B (63.474). This is *critical* for a CNS target like DRD2.

**9. Caco-2 Permeability:** Ligand A (-4.353) is better than Ligand B (-5.067), indicating better intestinal absorption.

**10. Aqueous Solubility:** Both ligands have poor aqueous solubility (-2.211 and -2.138). This could pose formulation challenges, but is less critical than BBB for a CNS target.

**11. hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.368 and 0.274).

**12. Microsomal Clearance:** Ligand B (16.845) has lower microsomal clearance than Ligand A (30.946), suggesting better metabolic stability.

**13. In vitro Half-Life:** Ligand B (9.445) has a longer in vitro half-life than Ligand A (-10.692). This is a positive attribute.

**14. P-gp Efflux:** Ligand A (0.12) has lower P-gp efflux than Ligand B (0.296), which is favorable for CNS exposure.

**15. Binding Affinity:** Ligand A (-9.8 kcal/mol) has a slightly better binding affinity than Ligand B (-8.3 kcal/mol). While both are good, the 1.5 kcal/mol difference is significant.

**Overall Assessment:**

Ligand A is the superior candidate. Its significantly better BBB penetration, lower DILI risk, lower TPSA, fewer H-bonds, and slightly better binding affinity outweigh Ligand B's better metabolic stability and half-life. For a CNS target like DRD2, BBB penetration is paramount, and Ligand A excels in this area. The improved safety profile (lower DILI) is also a major advantage.

Output:
1
2025-04-17 03:31:25,157 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (343.427 and 346.475 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (91.32) is slightly above the optimal <90 for CNS targets, but still reasonably close. Ligand B (78.09) is well within the desired range.

**3. logP:** Both ligands have good logP values (1.342 and 2.274), falling within the 1-3 range.

**4. H-Bond Donors:** Ligand A has 3 HBD, and Ligand B has 2. Both are acceptable (<=5).

**5. H-Bond Acceptors:** Ligand A has 4 HBA, and Ligand B has 3. Both are acceptable (<=10).

**6. QED:** Both ligands have good QED scores (0.68 and 0.829), indicating good drug-like properties.

**7. DILI:** Ligand A (34.277) has a slightly higher DILI risk than Ligand B (21.055), but both are below the concerning threshold of 60.

**8. BBB:** This is a critical parameter for CNS targets like DRD2. Ligand B (69.019) has a significantly better BBB percentile than Ligand A (36.177).

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 values, which is unusual and suggests poor permeability. However, these values are on a log scale, so the magnitude of the negative value is important. Ligand A (-5.104) is slightly less negative than Ligand B (-5.297), suggesting marginally better permeability.

**10. Aqueous Solubility:** Both ligands have very poor aqueous solubility (-2.044 and -2.618). This is a significant drawback.

**11. hERG Inhibition:** Both ligands have low hERG inhibition risk (0.114 and 0.283).

**12. Microsomal Clearance:** Ligand A (-7.361) has a much lower (better) microsomal clearance than Ligand B (4.365), indicating greater metabolic stability.

**13. In vitro Half-Life:** Ligand A (3.859) has a shorter half-life than Ligand B (-28.288). Note the negative value for B indicates a very long half-life.

**14. P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.038 and 0.081).

**15. Binding Affinity:** Both ligands have excellent binding affinities (-8.2 and -8.4 kcal/mol). The difference is minimal.

**Overall Assessment:**

Ligand B is superior due to its significantly better BBB penetration (69.019 vs 36.177). While Ligand A has slightly better permeability and metabolic stability, the BBB is paramount for a CNS target. The longer half-life of Ligand B is also a benefit. The poor solubility of both is a concern, but can potentially be addressed with formulation strategies.

Output:
1
2025-04-17 03:31:25,157 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (370.377 and 343.391 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (76.66) is excellent, well below the 90 A^2 threshold for CNS targets. Ligand B (127.82) is higher, but still potentially acceptable, though less ideal.

**logP:** Ligand A (3.072) is optimal. Ligand B (0.552) is quite low, which could hinder membrane permeability and CNS penetration.

**H-Bond Donors/Acceptors:** Ligand A (HBD=2, HBA=5) and Ligand B (HBD=3, HBA=7) both have reasonable numbers of H-bond donors and acceptors, falling within the guidelines.

**QED:** Both ligands have acceptable QED values (0.766 and 0.63), indicating good drug-like properties.

**DILI:** Ligand A (86.739) has a higher DILI risk than Ligand B (62.815), which is a concern. However, DILI prediction is not always reliable.

**BBB:** Ligand A (73.905) has a good BBB percentile, while Ligand B (61.38) is lower. This is a critical factor for a CNS target like DRD2.

**Caco-2 Permeability:** Ligand A (-4.485) has poor Caco-2 permeability, which is concerning. Ligand B (-5.656) is even worse.

**Aqueous Solubility:** Ligand A (-4.29) and Ligand B (-2.814) both have poor aqueous solubility.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.456 and 0.336).

**Microsomal Clearance:** Ligand A (91.62) has higher microsomal clearance, indicating faster metabolism. Ligand B (12.583) has much lower clearance, suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (40.201) has a moderate half-life, while Ligand B (-2.961) has a very short half-life.

**P-gp Efflux:** Ligand A (0.223) has lower P-gp efflux, which is favorable for CNS penetration. Ligand B (0.021) has even lower P-gp efflux, which is even more favorable.

**Binding Affinity:** Both ligands have excellent binding affinities (-8.1 and -8.0 kcal/mol), with Ligand A being slightly better. The affinity difference is small and likely less important than the ADME properties.

**Overall Assessment:**

Ligand A has a better BBB score and slightly better affinity, but suffers from poor Caco-2 permeability and higher metabolic clearance. Ligand B has better metabolic stability and lower P-gp efflux, but a significantly lower logP and a lower BBB score. The low logP of Ligand B is a major concern for CNS penetration. While Ligand A's Caco-2 permeability is poor, the better BBB score and slightly better affinity make it a more promising starting point, assuming permeability can be improved through structural modifications.

Output:
0
2025-04-17 03:31:25,158 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (336.355 Da) is slightly lower, which *could* be beneficial for permeability, but both are acceptable.

**TPSA:** Both ligands have TPSA values below the 90 A^2 threshold for CNS targets. Ligand B (85.43 A^2) is slightly better than Ligand A (95.34 A^2).

**logP:** Both ligands have logP values within the optimal range (1-3). Ligand A (1.445) is slightly lower, while Ligand B (2.353) is closer to the middle of the range.

**H-Bond Donors/Acceptors:** Ligand A (HBD=1, HBA=7) is better than Ligand B (HBD=3, HBA=4) in terms of H-bond properties. Fewer H-bonds generally improve permeability.

**QED:** Both ligands have similar QED values (A: 0.768, B: 0.743), indicating good drug-like properties.

**DILI:** Ligand A (98.565) has a significantly higher DILI risk than Ligand B (55.642). This is a major concern for Ligand A.

**BBB:** Ligand B (25.708) has a better BBB penetration percentile than Ligand A (19.349), although both are relatively low. For a CNS target like DRD2, higher BBB penetration is highly desirable.

**Caco-2 Permeability:** Ligand A (-4.991) has a better Caco-2 permeability than Ligand B (-5.198), suggesting better intestinal absorption. However, both are negative values, indicating poor permeability.

**Aqueous Solubility:** Both ligands have poor aqueous solubility (-3.148 and -3.521 respectively).

**hERG Inhibition:** Ligand A (0.098) has a lower hERG inhibition liability than Ligand B (0.525), which is preferable.

**Microsomal Clearance:** Ligand B (8.096) has a significantly lower microsomal clearance than Ligand A (22.997), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand B (-12.121) has a much longer in vitro half-life than Ligand A (-4.208), which is a significant advantage.

**P-gp Efflux:** Ligand A (0.006) has a lower P-gp efflux liability than Ligand B (0.241), suggesting better CNS exposure.

**Binding Affinity:** Both ligands have very similar and strong binding affinities (-8.8 kcal/mol and -8.3 kcal/mol). The difference of 0.5 kcal/mol is not substantial enough to outweigh other factors.

**Overall Assessment:**

Ligand B is the more promising candidate. While it has slightly higher TPSA and P-gp efflux, its significantly lower DILI risk, better BBB penetration, lower microsomal clearance, and longer half-life are crucial advantages for a CNS-targeting drug. The binding affinity difference is minimal. Ligand A's high DILI risk is a major red flag.

Output:
1
2025-04-17 03:31:25,158 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (370.467 and 351.447 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (89.9) is excellent, falling well below the 90 A^2 threshold for CNS targets. Ligand B (100.44) is slightly higher but still acceptable.

**logP:** Both ligands have good logP values (2.473 and 1.906), within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A (1 HBD, 6 HBA) is better than Ligand B (3 HBD, 4 HBA) in terms of balancing solubility and permeability.

**QED:** Ligand A (0.742) has a higher QED score than Ligand B (0.599), indicating better overall drug-likeness.

**DILI:** Ligand A (45.522) has a slightly higher DILI risk than Ligand B (21.946), but both are below the concerning threshold of 60.

**BBB:** This is a critical parameter for a CNS target like DRD2. Ligand A (71.578) has a good BBB percentile, while Ligand B (32.765) is significantly lower. This is a major advantage for Ligand A.

**Caco-2 Permeability:** Ligand A (-4.508) has a lower Caco-2 permeability than Ligand B (-5.279). Lower values indicate lower permeability.

**Aqueous Solubility:** Ligand A (-3.175) has a slightly better solubility than Ligand B (-1.717).

**hERG Inhibition:** Both ligands show very low hERG inhibition risk (0.261 and 0.09).

**Microsomal Clearance:** Ligand A (45.656) has a higher microsomal clearance than Ligand B (35.441), suggesting lower metabolic stability.

**In vitro Half-Life:** Ligand B (32.058) has a significantly longer in vitro half-life than Ligand A (5.107).

**P-gp Efflux:** Ligand A (0.561) shows slightly higher P-gp efflux than Ligand B (0.006). Lower P-gp efflux is preferred for CNS penetration.

**Binding Affinity:** Ligand A (-8.6 kcal/mol) has a slightly better binding affinity than Ligand B (-7.7 kcal/mol). While both are good, the 0.9 kcal/mol difference is significant.

**Overall Assessment:**

Ligand A excels in key areas for a CNS-targeting GPCR ligand: TPSA, logP, QED, BBB, and binding affinity. While its DILI is slightly higher and its metabolic stability (Cl_mic) and half-life are worse than Ligand B, the superior BBB penetration and binding affinity outweigh these drawbacks. Ligand B has a better half-life and lower DILI, but its significantly lower BBB penetration is a major concern for CNS activity. The difference in binding affinity is also substantial.

Output:
1
2025-04-17 03:31:25,158 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (341.371 and 351.487 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (120.91) is slightly above the preferred <90 for CNS targets, but still reasonable. Ligand B (73.91) is excellent, well below 90.

**logP:** Ligand A (1.419) is within the optimal 1-3 range. Ligand B (3.437) is at the higher end of optimal, but still acceptable.

**H-Bond Donors/Acceptors:** Both ligands have 2 HBD and a reasonable number of HBA (6 and 4 respectively), satisfying the <5 HBD and <10 HBA guidelines.

**QED:** Ligand A (0.819) has a superior QED score compared to Ligand B (0.677), indicating better overall drug-likeness.

**DILI:** Ligand A (72.974) has a higher DILI risk than Ligand B (11.322). This is a significant negative for Ligand A.

**BBB:** Ligand B (62.233) has a substantially better BBB penetration score than Ligand A (47.964). This is crucial for a CNS target like DRD2.

**Caco-2 Permeability:** Ligand A (-5.05) has a worse Caco-2 permeability than Ligand B (-4.476).

**Aqueous Solubility:** Both ligands have poor aqueous solubility (-3.683 and -3.357 respectively). This could pose formulation challenges, but is less critical than BBB for CNS drugs.

**hERG Inhibition:** Ligand A (0.112) has a slightly lower hERG risk than Ligand B (0.821), which is favorable.

**Microsomal Clearance:** Ligand B (58.417) has a lower microsomal clearance than Ligand A (49.23), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand B (40.524) has a longer in vitro half-life than Ligand A (0.648), which is desirable.

**P-gp Efflux:** Ligand A (0.058) has a much lower P-gp efflux liability than Ligand B (0.871), which is a significant advantage for CNS penetration.

**Binding Affinity:** Ligand A (-8.7 kcal/mol) has a stronger binding affinity than Ligand B (-7.6 kcal/mol). This is a substantial difference (1.1 kcal/mol), and a key factor.

**Overall Assessment:**

While Ligand A boasts a superior binding affinity and lower P-gp efflux, its significantly higher DILI risk and lower BBB penetration are major drawbacks for a CNS drug. Ligand B, despite slightly weaker binding, presents a much more favorable ADME profile, particularly its excellent BBB penetration, low DILI risk, and better metabolic stability. The difference in binding affinity, while notable, might be overcome with further optimization of Ligand B. Given the GPCR-specific priorities, the better ADME profile of Ligand B outweighs the affinity advantage of Ligand A.

Output:
1
2025-04-17 03:31:25,158 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 drug candidates, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (370.881 and 349.519 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (76.58) is higher than Ligand B (52.65). For a CNS target like DRD2, a TPSA <= 90 is preferred. Both are under this threshold, but B is significantly better.

**3. logP:** Both ligands have good logP values (3.265 and 2.57), falling within the optimal 1-3 range.

**4. H-Bond Donors:** Both have 1 HBD, which is within the acceptable limit of <= 5.

**5. H-Bond Acceptors:** Ligand A has 6 HBAs, and Ligand B has 3. Both are below the limit of <= 10.

**6. QED:** Ligand A (0.823) has a better QED score than Ligand B (0.685), indicating a more drug-like profile.

**7. DILI:** Ligand A (59.519) has a higher DILI risk than Ligand B (8.414). This is a significant advantage for Ligand B.

**8. BBB:** Both ligands have good BBB penetration (70.609 and 79.566), exceeding the 70% threshold desirable for CNS targets. Ligand B is slightly better.

**9. Caco-2 Permeability:** Both have negative Caco-2 values (-4.514 and -4.653). This is unusual and suggests poor permeability, but the scale is not specified. We'll assume these are percentile scores, and lower is worse.

**10. Aqueous Solubility:** Both have negative solubility values (-3.763 and -1.764). Again, assuming percentile scores, lower is worse.

**11. hERG Inhibition:** Both ligands have low hERG inhibition risk (0.214 and 0.431).

**12. Microsomal Clearance:** Ligand A (61.489) has a higher microsomal clearance than Ligand B (34.887), indicating lower metabolic stability. This favors Ligand B.

**13. In vitro Half-Life:** Ligand A (2.689) has a shorter half-life than Ligand B (-0.452). The negative value for B is concerning and might be an error, but even assuming it's a low value, A is better.

**14. P-gp Efflux:** Both ligands have low P-gp efflux liability (0.05 and 0.053).

**15. Binding Affinity:** Ligand B (-7.9 kcal/mol) has a slightly better binding affinity than Ligand A (-7.1 kcal/mol). A difference of 0.8 kcal/mol is meaningful, and can outweigh some ADME drawbacks.

**Overall Assessment:**

Ligand B is the more promising candidate. While Ligand A has a better QED and in vitro half-life, Ligand B excels in critical areas for CNS GPCR targets: lower DILI risk, better BBB penetration, lower microsomal clearance (better metabolic stability), and slightly better binding affinity. The TPSA is also significantly lower for Ligand B. The negative Caco-2 and solubility values are concerning for both, but the other advantages of Ligand B are more impactful for this target.

Output:
1
2025-04-17 03:31:25,158 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (346.431 and 343.467 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (76.46) is better than Ligand B (46.61), both are below the 90 A^2 threshold for CNS targets.

**logP:** Ligand A (0.581) is suboptimal, being below the preferred 1-3 range. Ligand B (4.287) is high, potentially causing solubility issues and off-target effects, but acceptable.

**H-Bond Donors/Acceptors:** Ligand A has 1 HBD and 5 HBA, while Ligand B has 0 HBD and 3 HBA. Both are within acceptable limits.

**QED:** Both ligands have reasonable QED scores (0.792 and 0.605), indicating good drug-like properties.

**DILI:** Both ligands have similar DILI risk (49.321 and 52.385), both are acceptable.

**BBB:** Ligand B (71.656) is significantly better than Ligand A (60.76) in terms of BBB penetration, which is crucial for a CNS target like DRD2.

**Caco-2 Permeability:** Ligand A (-5.012) is very poor, while Ligand B (-4.5) is also poor.

**Aqueous Solubility:** Ligand A (-1.342) is very poor, while Ligand B (-5.116) is even worse.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.166 and 0.308).

**Microsomal Clearance:** Ligand A (10.98) is much better than Ligand B (95.521) indicating better metabolic stability.

**In vitro Half-Life:** Ligand A (18.918) is better than Ligand B (-16.985) indicating a longer half-life.

**P-gp Efflux:** Ligand A (0.047) is significantly better than Ligand B (0.411), indicating lower efflux and potentially better CNS exposure.

**Binding Affinity:** Ligand B (-9.5 kcal/mol) has a significantly stronger binding affinity than Ligand A (-7.8 kcal/mol). The difference of 1.7 kcal/mol is substantial and can outweigh some ADME drawbacks.

**Overall Assessment:**

Ligand B has a much stronger binding affinity and better BBB penetration, which are the most important factors for a CNS GPCR target. While its logP is high and solubility is poor, the strong binding affinity and good BBB penetration are likely to compensate. Ligand A has better metabolic stability and P-gp efflux, but its weak binding affinity and poor BBB penetration are major drawbacks.

Output:
1
2025-04-17 03:31:25,159 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B based on the provided guidelines, prioritizing GPCR-specific properties (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (356.817 and 347.434 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (68.84) is slightly above the optimal <90 for CNS targets, while Ligand B (54.46) is well within. This favors Ligand B.

**logP:** Both ligands (2.284 and 2.099) are within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A has 0 HBD and 6 HBA, while Ligand B has 1 HBD and 4 HBA. Both are acceptable.

**QED:** Both ligands have good QED scores (0.722 and 0.801), indicating good drug-likeness.

**DILI:** Ligand A (87.631) has a higher DILI risk than Ligand B (6.669). This is a significant advantage for Ligand B.

**BBB:** Ligand B (96.743) has a significantly higher BBB penetration score than Ligand A (67.313). This is *critical* for a CNS target like DRD2 and heavily favors Ligand B.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.135 and -4.705), which is unusual and suggests poor permeability. However, these values are on a scale where negative values are possible.

**Aqueous Solubility:** Both ligands have negative solubility values (-2.409 and -2.575), which also suggests poor solubility.

**hERG:** Ligand A (0.213) has a lower hERG risk than Ligand B (0.723).

**Microsomal Clearance:** Ligand A (7.305) has a lower microsomal clearance than Ligand B (19.805), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand B (-14.276) has a much longer in vitro half-life than Ligand A (-8.551).

**P-gp Efflux:** Ligand A (0.308) has lower P-gp efflux liability than Ligand B (0.109), which is favorable for CNS penetration.

**Binding Affinity:** Ligand A (-9.3 kcal/mol) has a stronger binding affinity than Ligand B (-7.1 kcal/mol). This is a substantial difference (2.2 kcal/mol) and a major point in favor of Ligand A.

**Overall Assessment:**

While Ligand A has superior binding affinity and better metabolic stability, Ligand B excels in crucial areas for a CNS-targeting GPCR: significantly higher BBB penetration, much lower DILI risk, and a longer half-life. The difference in binding affinity, while substantial, can potentially be overcome with further optimization. The poor ADME properties (Caco-2 and solubility) are concerning for both, but the BBB score is paramount for DRD2. Given the GPCR-specific priorities, the improved CNS exposure profile of Ligand B outweighs the affinity advantage of Ligand A.

Output:
1
2025-04-17 03:31:25,159 - INFO - Batch 36 complete. Total preferences: 576
2025-04-17 03:31:25,159 - INFO - Processing batch 37/512...
2025-04-17 03:32:07,522 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 drug candidates, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (348.487 Da) is slightly lower, which is generally favorable for permeability.

**2. TPSA:** Ligand A (58.64) is significantly better than Ligand B (104.21). For CNS targets, TPSA < 90 is preferred, and Ligand A is well within this range, while Ligand B is approaching the upper limit.

**3. logP:** Both ligands have acceptable logP values (A: 2.655, B: 1.532), falling within the optimal 1-3 range.

**4. H-Bond Donors:** Ligand A (1) is preferable to Ligand B (3). Fewer HBDs generally improve permeability.

**5. H-Bond Acceptors:** Ligand A (3) is better than Ligand B (7). Lower HBA counts are generally preferred for CNS penetration.

**6. QED:** Both ligands have similar QED values (A: 0.751, B: 0.699), both above the 0.5 threshold, indicating good drug-likeness.

**7. DILI:** Ligand A (9.965) has a much lower DILI risk than Ligand B (57.038). This is a significant advantage for Ligand A.

**8. BBB:** Ligand A (72.392) has a considerably higher BBB penetration percentile than Ligand B (61.38). This is a critical factor for a CNS target like DRD2, and Ligand A is much closer to the desirable >70 threshold.

**9. Caco-2:** Ligand A (-4.441) shows better Caco-2 permeability than Ligand B (-5.463), although both are negative values which is unusual and requires further investigation.

**10. Solubility:** Ligand A (-2.939) has slightly better solubility than Ligand B (-3.28), although both are negative values which is unusual and requires further investigation.

**11. hERG:** Ligand A (0.317) has a lower hERG inhibition liability than Ligand B (0.594), indicating a lower risk of cardiotoxicity.

**12. Cl_mic:** Ligand A (75.684) has a higher microsomal clearance than Ligand B (28.712), suggesting lower metabolic stability. This is a drawback for Ligand A.

**13. t1/2:** Ligand B (33.888) has a significantly longer in vitro half-life than Ligand A (-8.493). This is a substantial advantage for Ligand B.

**14. Pgp:** Ligand A (0.147) has lower P-gp efflux liability than Ligand B (0.015), which is favorable for CNS exposure.

**15. Binding Affinity:** Both ligands have the same binding affinity (-8.4 kcal/mol), which is excellent.

**Overall Assessment:**

Despite Ligand B having a better half-life and lower clearance, Ligand A is the more promising candidate. The key advantages of Ligand A are its significantly better TPSA, lower DILI risk, and much higher BBB penetration, all of which are crucial for a CNS-targeting GPCR like DRD2. The lower Pgp efflux also contributes positively. While Ligand A's metabolic stability is a concern, this can potentially be addressed through structural modifications during lead optimization. The similar binding affinity means that the ADME properties are the deciding factors here.

Output:
0
2025-04-17 03:32:07,523 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (363.483 and 375.559 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (88.16) is better than Ligand B (29.54) as it is closer to the <90 A^2 threshold for CNS targets. Ligand B is very low, which *could* indicate poor interactions, but isn't necessarily a dealbreaker.

**3. logP:** Ligand A (2.067) is within the optimal 1-3 range. Ligand B (4.551) is slightly higher, potentially leading to solubility issues or off-target effects, but still within a reasonable range.

**4. H-Bond Donors:** Ligand A (2) and Ligand B (0) are both acceptable, being less than 5.

**5. H-Bond Acceptors:** Both ligands (A: 4, B: 4) are within the ideal range of <=10.

**6. QED:** Both ligands have similar QED values (A: 0.776, B: 0.678), indicating good drug-like properties.

**7. DILI:** Ligand A (59.519) has a slightly higher DILI risk than Ligand B (42.691), but both are below the concerning 60 threshold.

**8. BBB:** This is a critical parameter for CNS targets. Ligand B (92.555) significantly outperforms Ligand A (59.364) in predicted BBB penetration. This is a major advantage for Ligand B.

**9. Caco-2 Permeability:** Both have negative values, which is unusual. Assuming these are percentile scores, Ligand A (-4.97) is slightly better than Ligand B (-5.054), but both are very low, indicating poor intestinal absorption. This is less critical for a CNS target where direct delivery is possible.

**10. Aqueous Solubility:** Both ligands have very low solubility scores (A: -3.131, B: -4.732). This could pose formulation challenges.

**11. hERG Inhibition:** Ligand A (0.154) has a lower hERG inhibition risk than Ligand B (0.769), which is preferable.

**12. Microsomal Clearance:** Ligand B (107.866) has a higher clearance than Ligand A (45.235), suggesting lower metabolic stability.

**13. In vitro Half-Life:** Ligand A (-48.83) has a negative half-life, which is concerning. Ligand B (39.258) has a positive half-life.

**14. P-gp Efflux:** Ligand A (0.071) has lower P-gp efflux than Ligand B (0.732), which is favorable for CNS penetration.

**15. Binding Affinity:** Ligand B (-7.0) has a significantly stronger binding affinity than Ligand A (-9.1). This is a substantial advantage, potentially outweighing some of the ADME drawbacks.

**Overall Assessment:**

While Ligand A has a slightly better safety profile (lower DILI, hERG), Ligand B is superior due to its significantly higher BBB penetration (92.555 vs 59.364) and much stronger binding affinity (-7.0 vs -9.1). The better BBB penetration is crucial for a CNS target like DRD2. The higher clearance and P-gp efflux of Ligand B are concerns, but the strong affinity could compensate for these. The negative half-life of Ligand A is a major red flag.

Output:
1
2025-04-17 03:32:07,523 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 drug candidates, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (374.388 Da and 343.471 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (83.98) is slightly above the preferred <90 for CNS targets, but still reasonable. Ligand B (64.41) is well within the ideal range.

**3. logP:** Both ligands have good logP values (2.813 and 2.732), falling within the optimal 1-3 range.

**4. H-Bond Donors:** Ligand A has 2 HBD, which is acceptable. Ligand B has 0, also acceptable.

**5. H-Bond Acceptors:** Ligand A has 6 HBA, within the limit of 10. Ligand B has 3, also within the limit.

**6. QED:** Both ligands have similar and good QED values (0.725 and 0.737), indicating good drug-like properties.

**7. DILI:** Ligand A has a DILI risk of 70.88, which is approaching the higher risk threshold (>60). Ligand B has a much lower DILI risk of 17.41, which is excellent.

**8. BBB:** This is a crucial parameter for CNS targets. Ligand A has a BBB penetration of 63.474%, which is below the desirable >70%. Ligand B has a significantly higher BBB penetration of 81.543%, making it more promising for CNS activity.

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.184 and -4.542). This is unusual and suggests poor permeability. However, these values are on a log scale, and the negative values indicate very low permeability.

**10. Aqueous Solubility:** Both ligands have negative solubility values (-3.886 and -3.527). This is also unusual and indicates very low aqueous solubility.

**11. hERG Inhibition:** Ligand A has a hERG inhibition risk of 0.767, which is acceptable. Ligand B has a lower risk of 0.406, which is preferable.

**12. Microsomal Clearance:** Ligand A has a lower microsomal clearance (11.897) than Ligand B (49.441), suggesting better metabolic stability.

**13. In vitro Half-Life:** Ligand A has a longer half-life (72.126) than Ligand B (-4.651). The negative value for Ligand B is concerning and indicates very rapid degradation.

**14. P-gp Efflux:** Ligand A has a Pgp efflux liability of 0.341, which is relatively low. Ligand B has a very low Pgp efflux liability of 0.09, which is even better.

**15. Binding Affinity:** Ligand A has a stronger binding affinity (-8.8 kcal/mol) than Ligand B (-7.4 kcal/mol). This is a substantial difference (1.4 kcal/mol), and is a significant advantage for Ligand A.

**Overall Assessment:**

While Ligand A has a significantly better binding affinity, its higher DILI risk, lower BBB penetration, and shorter half-life are concerning. Ligand B, despite the slightly weaker affinity, exhibits a much more favorable ADME profile, particularly its excellent BBB penetration, low DILI risk, and very low P-gp efflux. The poor permeability and solubility of both compounds are a concern, but the superior ADME properties of Ligand B, combined with its strong BBB penetration, make it the more promising candidate for CNS drug development. The affinity difference, while substantial, might be overcome with further optimization of Ligand B.

Output:
1
2025-04-17 03:32:07,523 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (331.379) is slightly lower, which could be beneficial for permeability, but both are acceptable.

**TPSA:** Ligand A (85.07) is excellent for CNS penetration, well below the 90 A^2 threshold. Ligand B (96.45) is still reasonable, but less optimal.

**logP:** Ligand A (2.898) is within the optimal range (1-3). Ligand B (0.949) is a bit low, potentially hindering membrane permeability.

**H-Bond Donors/Acceptors:** Both ligands have 2 HBD and 6/5 HBA, respectively, which are within acceptable limits.

**QED:** Both ligands have good QED scores (A: 0.767, B: 0.845), indicating drug-like properties.

**DILI:** Ligand A (84.025) has a higher DILI risk than Ligand B (47.538). This is a concern for Ligand A.

**BBB:** Ligand B (78.48) has a significantly better BBB penetration percentile than Ligand A (36.797). This is a *critical* advantage for a CNS target like DRD2.

**Caco-2 Permeability:** Ligand A (-5.312) shows poor Caco-2 permeability, indicating poor intestinal absorption. Ligand B (-5.044) is also poor, but slightly better.

**Aqueous Solubility:** Both ligands have very poor aqueous solubility (-4.624 and -1.703). This could pose formulation challenges.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.9 and 0.201).

**Microsomal Clearance:** Ligand B (-30.206) has significantly lower (better) microsomal clearance than Ligand A (54.977), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand B (24.286) has a longer in vitro half-life than Ligand A (12.602).

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.11 and 0.008).

**Binding Affinity:** Ligand B (-9.2 kcal/mol) has slightly better binding affinity than Ligand A (-8.9 kcal/mol). While the difference is not huge, it's a positive factor.

**Overall Assessment:**

Ligand B is the stronger candidate. While both have solubility issues, Ligand B excels in the critical areas for a CNS GPCR target: BBB penetration, metabolic stability (lower Cl_mic and longer t1/2), and has slightly better affinity. Ligand A's higher DILI risk and poor Caco-2 permeability are significant drawbacks. The superior BBB score of Ligand B is the deciding factor.

Output:
1
2025-04-17 03:32:07,523 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (375.376 and 352.391 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (83.28) is better than Ligand B (105.92). For CNS targets, we want TPSA <= 90. Ligand A is within this range, while Ligand B is slightly above.

**3. logP:** Ligand A (2.327) is optimal (1-3). Ligand B (-0.636) is below 1, which may impede permeation. This is a significant disadvantage for Ligand B.

**4. H-Bond Donors:** Both ligands have 2 HBD, which is within the acceptable limit of <=5.

**5. H-Bond Acceptors:** Ligand A has 6 HBA, and Ligand B has 7. Both are within the acceptable limit of <=10.

**6. QED:** Ligand A (0.863) has a higher QED than Ligand B (0.676), indicating a more drug-like profile.

**7. DILI:** Ligand A (63.746) has a higher DILI risk than Ligand B (40.597). While both are acceptable, Ligand B is preferable here.

**8. BBB:** Ligand A (64.211) and Ligand B (62.854) are both reasonably good, but below the desirable >70 for CNS targets. The difference is minimal.

**9. Caco-2:** Both ligands have negative Caco-2 values (-4.881 and -4.876). This is unusual and suggests poor permeability.

**10. Solubility:** Both ligands have negative solubility values (-2.757 and -1.851), suggesting poor aqueous solubility.

**11. hERG:** Both ligands have very low hERG inhibition risk (0.26 and 0.102).

**12. Cl_mic:** Ligand A (-2.284) has a lower (better) microsomal clearance than Ligand B (-5.545), indicating greater metabolic stability.

**13. t1/2:** Ligand A (13.373) has a longer half-life than Ligand B (0.899). This is a significant advantage.

**14. Pgp:** Ligand A (0.143) has lower P-gp efflux liability than Ligand B (0.008), which is preferable for CNS exposure.

**15. Binding Affinity:** Ligand A (-7.5 kcal/mol) has a slightly better binding affinity than Ligand B (-7.2 kcal/mol). While the difference is not huge, it's enough to consider.

**Overall Assessment:**

Ligand A is the better candidate. While both have issues with Caco-2 and solubility, Ligand A has a more optimal logP, better QED, better metabolic stability (lower Cl_mic, longer t1/2), lower Pgp efflux, and slightly better binding affinity. The TPSA is also more favorable for CNS penetration. The slightly higher DILI risk for Ligand A is less concerning than the poor logP of Ligand B.

Output:
1
2025-04-17 03:32:07,524 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (353.507 and 346.387 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (70.67) is significantly better than Ligand B (122.55). For CNS targets, we want TPSA <= 90, and A is comfortably within that, while B is above.

**3. logP:** Ligand A (1.687) is optimal (1-3), while Ligand B (0.454) is a bit low, potentially hindering permeation.

**4. H-Bond Donors:** Ligand A (2) and Ligand B (4) are both acceptable (<=5), but A is preferable.

**5. H-Bond Acceptors:** Ligand A (4) and Ligand B (5) are both acceptable (<=10).

**6. QED:** Both ligands have reasonable QED values (0.697 and 0.577), indicating good drug-like properties.

**7. DILI:** Ligand A (6.398) has a much lower DILI risk than Ligand B (67.119). This is a significant advantage for A.

**8. BBB:** Both ligands have similar BBB penetration (62.582 and 62.544). While not exceeding the ideal >70, they are comparable.

**9. Caco-2 Permeability:** Both have negative Caco-2 values (-5.254 and -5.478), which is unusual and suggests poor permeability. However, the values are similar.

**10. Aqueous Solubility:** Both have negative solubility values (-0.949 and -3.053), indicating poor solubility. B is worse than A.

**11. hERG Inhibition:** Both ligands have low hERG inhibition risk (0.31 and 0.197).

**12. Microsomal Clearance:** Ligand A (11.513) has higher clearance than Ligand B (-4.178), suggesting lower metabolic stability. This is a drawback for A.

**13. In vitro Half-Life:** Ligand B (-15.896) has a much longer half-life than Ligand A (4.748), which is a significant advantage.

**14. P-gp Efflux:** Both ligands show very low P-gp efflux liability (0.011 and 0.008).

**15. Binding Affinity:** Ligand B (-9.1 kcal/mol) has a significantly stronger binding affinity than Ligand A (-7.7 kcal/mol). This is a substantial advantage for B, potentially outweighing some of its ADME drawbacks.

**Overall Assessment:**

Ligand A has advantages in TPSA, logP, and DILI risk. However, Ligand B boasts a substantially stronger binding affinity (-9.1 vs -7.7 kcal/mol) and a longer half-life. While Ligand B's TPSA is higher and logP lower, the significantly improved affinity and half-life, coupled with comparable BBB penetration, make it the more promising candidate. The DILI risk is a concern for B, but can be addressed during optimization.

Output:
1
2025-04-17 03:32:07,524 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (349.406 and 350.507 Da) fall comfortably within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (85.43) is better than Ligand B (50.6). For CNS targets, TPSA < 90 is preferred, both meet this.

**3. logP:** Both ligands have good logP values (1.734 and 2.294), falling within the optimal 1-3 range.

**4. H-Bond Donors:** Ligand A has 3 HBD, which is acceptable. Ligand B has 0, also acceptable.

**5. H-Bond Acceptors:** Ligand A has 3 HBA, which is acceptable. Ligand B has 5, also acceptable.

**6. QED:** Both ligands have similar and good QED values (0.708 and 0.722), indicating good drug-like properties.

**7. DILI:** Ligand A (47.77) has a slightly higher DILI risk than Ligand B (11.322), but both are below the concerning threshold of 60.

**8. BBB:** This is a critical parameter for CNS targets like DRD2. Ligand B (83.482) has a significantly higher BBB penetration percentile than Ligand A (63.28). This is a major advantage for Ligand B.

**9. Caco-2 Permeability:** Ligand A (-5.239) has a lower Caco-2 permeability than Ligand B (-4.381), suggesting potentially poorer intestinal absorption.

**10. Aqueous Solubility:** Ligand A (-2.909) has lower aqueous solubility than Ligand B (-1.797).

**11. hERG Inhibition:** Both ligands show low hERG inhibition liability (0.412 and 0.507), which is favorable.

**12. Microsomal Clearance:** Ligand B (74.642) has a much higher microsomal clearance than Ligand A (10.887), indicating faster metabolism and potentially lower *in vivo* exposure.

**13. In vitro Half-Life:** Ligand B (13.498) has a much longer in vitro half-life than Ligand A (0.051). This is a significant advantage for Ligand B.

**14. P-gp Efflux:** Ligand A (0.085) has lower P-gp efflux than Ligand B (0.343), which is favorable for CNS penetration.

**15. Binding Affinity:** Ligand A (-9.1 kcal/mol) has a significantly stronger binding affinity than Ligand B (-6.3 kcal/mol). This is a substantial advantage for Ligand A. A 2.8 kcal/mol difference is quite significant.

**Overall Assessment:**

While Ligand B excels in BBB penetration, half-life, and has a lower DILI risk, Ligand A's substantially superior binding affinity (-9.1 vs -6.3 kcal/mol) is the deciding factor. The affinity difference is large enough to potentially overcome the slightly lower BBB and shorter half-life of Ligand A, especially considering optimization strategies can be employed to improve those parameters. The lower P-gp efflux of Ligand A is also a positive.

Output:
0
2025-04-17 03:32:07,524 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (350.415 Da) is slightly better, being closer to the lower end which can aid permeability.

**TPSA:** Both ligands are reasonably close to the desired threshold of 90 A^2 for CNS targets. Ligand A (99.1 A^2) is slightly better than Ligand B (100.55 A^2).

**logP:** Ligand A (0.9) is slightly lower than optimal (1-3), but still acceptable. Ligand B (2.013) is within the optimal range.

**H-Bond Donors/Acceptors:** Both have 3 HBDs and acceptable HBA counts (5 and 6 respectively).

**QED:** Both ligands have acceptable QED values (0.662 and 0.557 respectively), indicating reasonable drug-likeness.

**DILI:** Ligand A (14.114) has a significantly lower DILI risk than Ligand B (64.288), which is a major advantage.

**BBB:** Ligand A (16.983) has a very poor BBB penetration percentile, while Ligand B (35.324) is still low, it is better than Ligand A. This is a critical drawback for a CNS target like DRD2.

**Caco-2 Permeability:** Both have negative Caco-2 values, indicating poor permeability.

**Aqueous Solubility:** Both have negative solubility values, indicating poor solubility.

**hERG:** Both ligands have very low hERG inhibition liability, which is good.

**Microsomal Clearance:** Ligand A (-14.208) has significantly lower (better) microsomal clearance than Ligand B (19.591), indicating greater metabolic stability.

**In vitro Half-Life:** Ligand B (64.778) has a much longer in vitro half-life than Ligand A (-7.713).

**P-gp Efflux:** Both ligands have very low P-gp efflux liability, which is good.

**Binding Affinity:** Ligand B (-7.7 kcal/mol) has a slightly better binding affinity than Ligand A (-0.0 kcal/mol). This is a substantial difference.

**Overall Assessment:**

Ligand B has a significantly better binding affinity and a much longer half-life. However, Ligand A has a much lower DILI risk and better metabolic stability. The biggest issue for Ligand A is its very poor BBB penetration. Ligand B's BBB penetration is also not ideal, but significantly better than Ligand A. Considering DRD2 is a CNS target, BBB penetration is crucial. While Ligand B's affinity is better, the poor BBB penetration of both compounds is concerning. However, the significantly better affinity of Ligand B, combined with a better (though still not great) BBB score, and a longer half-life, makes it the more promising candidate. The DILI risk of Ligand B is a concern, but could potentially be mitigated through structural modifications.

Output:
1
2025-04-17 03:32:07,524 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (344.411 Da) is slightly lower, which could be advantageous for permeability.

**TPSA:** Both are below the 140 A^2 threshold for oral absorption, and importantly, below the 90 A^2 target for CNS penetration. Ligand B (75.35 A^2) is slightly better than Ligand A (82.81 A^2).

**logP:** Both ligands have logP values within the optimal range (1-3). Ligand A (2.792) is slightly lower, while Ligand B (3.633) is a bit higher. Both are acceptable, but closer to the upper end of the range.

**H-Bond Donors/Acceptors:** Ligand A has 2 HBD and 5 HBA, while Ligand B has 3 HBD and 3 HBA. Both are within acceptable limits (<=5 HBD and <=10 HBA).

**QED:** Both ligands have similar QED values (0.755 and 0.713), indicating good drug-like properties.

**DILI:** Ligand B (41.218) has a significantly lower DILI risk than Ligand A (74.603), which is a major advantage.

**BBB:** Ligand A (51.725) has a slightly better BBB penetration percentile than Ligand B (43.273). However, both are below the desirable >70% for CNS targets.

**Caco-2 Permeability:** Ligand A (-4.849) shows better Caco-2 permeability than Ligand B (-5.182), suggesting better intestinal absorption.

**Aqueous Solubility:** Ligand A (-4.517) has better aqueous solubility than Ligand B (-3.649).

**hERG Inhibition:** Both ligands have low hERG inhibition liability (0.879 and 0.782), which is good.

**Microsomal Clearance:** Ligand B (12.761) has significantly lower microsomal clearance than Ligand A (52.742), indicating better metabolic stability.

**In vitro Half-Life:** Ligand B (12.142 hours) has a significantly longer in vitro half-life than Ligand A (-17.124 hours). This is a substantial advantage.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.406 and 0.236). Ligand B is slightly better.

**Binding Affinity:** Both ligands have very similar and strong binding affinities (-8.9 kcal/mol and -8.5 kcal/mol). The difference of 0.4 kcal/mol is not substantial enough to outweigh other factors.

**Overall Assessment:**

While Ligand A has slightly better BBB penetration and Caco-2 permeability, Ligand B demonstrates superior ADME properties, particularly regarding DILI risk, metabolic stability (lower Cl_mic, longer t1/2), and P-gp efflux. Given the GPCR-specific priorities, and the importance of CNS penetration and minimizing off-target effects, Ligand B is the more promising candidate. The lower DILI and improved metabolic stability are significant advantages.

Output:
1
2025-04-17 03:32:07,525 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 drug candidates, considering the provided guidelines and GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (360.435 and 375.519 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (77.52) is higher than Ligand B (66.32). For a CNS target like DRD2, TPSA should be <=90. Both are within this range, but B is preferable.

**3. logP:** Both ligands (2.513 and 2.834) are within the optimal 1-3 range.

**4. H-Bond Donors:** Both have 1 HBD, which is acceptable (<=5).

**5. H-Bond Acceptors:** Both have 6 HBA, acceptable (<=10).

**6. QED:** Ligand A (0.848) has a better QED score than Ligand B (0.754), indicating a more drug-like profile.

**7. DILI:** Ligand A (82.241) has a higher DILI risk than Ligand B (54.478). B is significantly better here, falling well below the 60 threshold.

**8. BBB:** This is a critical parameter for CNS targets. Ligand A (55.254) has a moderate BBB penetration, while Ligand B (29.934) is quite low. This is a major drawback for Ligand B.

**9. Caco-2 Permeability:** Ligand A (-4.464) shows better Caco-2 permeability than Ligand B (-5.32). Higher values are better.

**10. Aqueous Solubility:** Ligand A (-3.61) has slightly better solubility than Ligand B (-2.953). Higher values are better.

**11. hERG:** Both ligands have low hERG inhibition liability (0.23 and 0.323), which is good.

**12. Microsomal Clearance:** Ligand A (71.856) has higher microsomal clearance than Ligand B (60.834), meaning B is more metabolically stable. Lower is better.

**13. In vitro Half-Life:** Ligand A (8.787) has a shorter half-life than Ligand B (11.032). B is preferable.

**14. P-gp Efflux:** Both ligands have low P-gp efflux liability (0.276 and 0.269), which is good.

**15. Binding Affinity:** Ligand B (-7.3 kcal/mol) has a significantly stronger binding affinity than Ligand A (-8.7 kcal/mol). This is a substantial advantage.

**Overall Assessment:**

Ligand B has a significantly better binding affinity (-7.3 vs -8.7 kcal/mol) and lower DILI risk (54.478 vs 82.241), and better metabolic stability (lower Cl_mic and longer t1/2). However, its BBB penetration is significantly lower than Ligand A (29.934 vs 55.254). While a higher BBB is preferred, the superior affinity of Ligand B is a major advantage for a GPCR target. The lower DILI risk and better metabolic stability also contribute to its favorability. The difference in affinity is likely to outweigh the lower BBB, especially with potential formulation strategies to improve brain penetration.

Output:
1
2025-04-17 03:32:07,525 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (345.4 and 341.5 Da) fall comfortably within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (104.5) is slightly above the preferred <90 for CNS targets, while Ligand B (92.9) is closer to the ideal range. This gives a slight edge to Ligand B.

**3. logP:** Ligand A (0.775) is a bit low, potentially hindering membrane permeability. Ligand B (3.155) is within the optimal 1-3 range. This is a significant advantage for Ligand B.

**4. H-Bond Donors:** Both ligands have 3 HBD, which is acceptable.

**5. H-Bond Acceptors:** Both ligands have 5 HBA, which is acceptable.

**6. QED:** Both ligands have QED values above 0.5 (0.574 and 0.686), indicating good drug-like properties. Ligand B is slightly better.

**7. DILI:** Ligand A (39.98) has a lower DILI risk than Ligand B (53.08), which is preferable.

**8. BBB:** This is crucial for a CNS target. Ligand A (27.3) has a very low BBB penetration percentile, making it unlikely to reach the target in the brain. Ligand B (90.2) has excellent predicted BBB penetration. This is a *major* advantage for Ligand B.

**9. Caco-2 Permeability:** Both have negative values, which is unusual. However, the magnitude of the negative value is important. Ligand A (-4.962) is slightly better than Ligand B (-5.007), suggesting slightly better permeability.

**10. Aqueous Solubility:** Both have negative values, indicating poor solubility. Ligand A (-2.112) is slightly better than Ligand B (-4.591).

**11. hERG Inhibition:** Ligand A (0.132) has a lower hERG risk than Ligand B (0.796), which is preferable.

**12. Microsomal Clearance:** Ligand A (15.5) has a lower Cl_mic, indicating better metabolic stability, than Ligand B (92.2). This is a significant advantage for Ligand A.

**13. In vitro Half-Life:** Ligand A (-14.4) has a negative half-life, which is not possible. This is a red flag. Ligand B (22.6) has a reasonable half-life.

**14. P-gp Efflux:** Ligand A (0.052) has lower P-gp efflux, which is favorable for CNS penetration, compared to Ligand B (0.169).

**15. Binding Affinity:** Ligand B (-8.8 kcal/mol) has a stronger binding affinity than Ligand A (-7.8 kcal/mol). This is a significant advantage for Ligand B, potentially outweighing some of the ADME drawbacks.

**Overall Assessment:**

While Ligand A has some advantages (lower DILI, lower Cl_mic, lower P-gp efflux, slightly better Caco-2 and solubility), its *extremely* poor predicted BBB penetration (27.3%) is a deal-breaker for a CNS target like DRD2. The negative in vitro half-life is also a major concern. Ligand B, despite having a slightly higher DILI and P-gp efflux, has excellent BBB penetration (90.2%), a good half-life, and significantly better binding affinity. The logP is also within the optimal range. Given the GPCR-specific priorities, especially BBB penetration and affinity, Ligand B is the far more promising candidate.

Output:
1
2025-04-17 03:32:07,525 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (349.475 and 364.515 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (75.44) is better than Ligand B (88.32). For CNS targets, we want TPSA <= 90, and A is closer to the optimal range.

**logP:** Both ligands have good logP values (3.378 and 2.162), falling within the 1-3 range. Ligand A is slightly higher, which could be beneficial for membrane permeability.

**H-Bond Donors/Acceptors:** Ligand A (HBD=1, HBA=4) is slightly better than Ligand B (HBD=2, HBA=5) as it has fewer H-bonds overall, potentially improving permeability. Both are within acceptable limits.

**QED:** Both ligands have similar QED values (0.819 and 0.807), indicating good drug-likeness.

**DILI:** Ligand A (40.054) has a slightly better DILI score than Ligand B (50.291), indicating a lower risk of liver injury. Both are below the concerning threshold of 60.

**BBB:** Both ligands have excellent BBB penetration (78.868 and 73.866), exceeding the desirable >70% threshold for CNS targets.

**Caco-2 Permeability:** Ligand A (-4.489) has a slightly better (less negative) Caco-2 value than Ligand B (-5.419), suggesting better intestinal absorption.

**Aqueous Solubility:** Ligand A (-3.409) has a slightly better (less negative) solubility value than Ligand B (-2.972).

**hERG:** Ligand A (0.242) has a lower hERG inhibition liability than Ligand B (0.584), which is preferable.

**Microsomal Clearance:** Ligand B (-1.182) has a significantly lower (better) microsomal clearance than Ligand A (74.96), indicating greater metabolic stability.

**In vitro Half-Life:** Ligand B (-7.317) has a significantly longer (better) in vitro half-life than Ligand A (-22.574).

**P-gp Efflux:** Ligand A (0.189) has a lower P-gp efflux liability than Ligand B (0.043), which is preferable for CNS penetration.

**Binding Affinity:** Both ligands have identical binding affinities (-8.1 kcal/mol), which is excellent.

**Overall Assessment:**

While Ligand B has superior metabolic stability and half-life, Ligand A is better across several key parameters for a CNS-targeting GPCR ligand: TPSA, solubility, hERG, and P-gp efflux. The difference in metabolic stability is significant, but the superior BBB, TPSA, and P-gp properties of Ligand A are more critical for CNS penetration and target engagement. The slightly better DILI score and Caco-2 permeability of Ligand A are also positive factors. Given the equal binding affinity, the ADME properties tip the balance in favor of Ligand A.

Output:
1
2025-04-17 03:32:07,525 - INFO - Reasoning:

Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (363.849 and 350.478 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (102.04) is higher than the optimal <90 for CNS targets, while Ligand B (40.62) is excellent. This is a significant advantage for Ligand B.

**3. logP:** Both ligands (3.597 and 3.014) are within the optimal 1-3 range.

**4. H-Bond Donors:** Ligand A has 3 HBD, acceptable. Ligand B has 0, also acceptable.

**5. H-Bond Acceptors:** Ligand A has 4 HBA, acceptable. Ligand B has 2, also acceptable.

**6. QED:** Both ligands have reasonable QED values (0.773 and 0.662), indicating good drug-like properties.

**7. DILI:** Ligand A (78.247) has a higher DILI risk than Ligand B (15.859). This favors Ligand B.

**8. BBB:** Ligand B (96.084) has a significantly higher BBB penetration percentile than Ligand A (64.095). This is a crucial advantage for a CNS target like DRD2.

**9. Caco-2 Permeability:** Both have negative values, which is unusual. However, the magnitude of the negative value is less important than the other parameters.

**10. Aqueous Solubility:** Both have negative values, which is unusual. However, the magnitude of the negative value is less important than the other parameters.

**11. hERG Inhibition:** Ligand A (0.341) has slightly lower hERG inhibition risk than Ligand B (0.649), but both are relatively low.

**12. Microsomal Clearance:** Ligand A (56.676) has higher microsomal clearance than Ligand B (21.283), suggesting lower metabolic stability. Ligand B is favored.

**13. In vitro Half-Life:** Ligand B (-13.89) has a negative half-life, which is not possible. This is a major red flag. Ligand A (85.904) has a good in vitro half-life.

**14. P-gp Efflux:** Ligand A (0.218) has lower P-gp efflux than Ligand B (0.335), which is favorable for CNS penetration.

**15. Binding Affinity:** Ligand A (-8.4 kcal/mol) has a slightly better binding affinity than Ligand B (-7.6 kcal/mol). However, the difference is less than 1.5 kcal/mol, so it doesn't completely overshadow the ADME advantages of Ligand B.

**Overall Assessment:**

Despite the slightly better binding affinity of Ligand A, Ligand B is the stronger candidate. Ligand B excels in key GPCR-relevant properties: TPSA, BBB, DILI, and microsomal clearance. The negative half-life for Ligand B is a major concern, but if this is an experimental error, it would be the better candidate.

Output:
1
2025-04-17 03:32:07,526 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (347.394 and 344.415 Da) fall comfortably within the ideal range of 200-500 Da.

**2. TPSA:** Both ligands have TPSA values (88.91 and 89.53) below the 90 A^2 threshold desirable for CNS targets, which is excellent.

**3. logP:** Ligand A (1.27) is within the optimal range of 1-3. Ligand B (0.173) is slightly below 1, which *could* indicate permeability issues, but is not a dealbreaker given the other parameters.

**4. H-Bond Donors:** Both ligands have 2 HBD, which is within the acceptable limit of <=5.

**5. H-Bond Acceptors:** Ligand A has 5 HBA, and Ligand B has 4 HBA, both within the acceptable limit of <=10.

**6. QED:** Both ligands have good QED scores (0.704 and 0.815), indicating good drug-like properties.

**7. DILI:** Ligand A (54.168) has a higher DILI risk than Ligand B (29.236). This is a significant advantage for Ligand B.

**8. BBB:** Ligand A has a much better BBB penetration score (70.531) than Ligand B (38.193). This is *crucial* for a CNS target like DRD2.

**9. Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and difficult to interpret without knowing the scale. However, the values are similar.

**10. Aqueous Solubility:** Both have negative solubility values, again unusual. The values are similar.

**11. hERG Inhibition:** Both ligands show very low hERG inhibition risk (0.138 and 0.156).

**12. Microsomal Clearance:** Ligand A (43.877) has a higher microsomal clearance than Ligand B (3.389), suggesting lower metabolic stability. Ligand B is significantly better here.

**13. In vitro Half-Life:** Ligand A (4.649) has a shorter half-life than Ligand B (-11.311). The negative value for B is suspect, but even if it's a scaling issue, the trend is clear.

**14. P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.061 and 0.011).

**15. Binding Affinity:** Ligand B (-8.6 kcal/mol) has a significantly stronger binding affinity than Ligand A (-7.1 kcal/mol). This >1.5 kcal/mol difference is a major advantage.

**Overall Assessment:**

While Ligand A has a better BBB score, Ligand B excels in almost every other critical parameter. It has a lower DILI risk, significantly better metabolic stability (lower Cl_mic), a potentially longer half-life, and, most importantly, a much stronger binding affinity. The slightly lower logP of Ligand B is a minor concern, but the superior affinity and ADME properties outweigh this. For a GPCR target like DRD2, strong binding and good CNS penetration (which is aided by the other ADME properties) are paramount.

Output:
1
2025-04-17 03:32:07,526 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (378.705 and 371.503 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (55.76) is significantly better than Ligand B (93.11). For CNS targets, we want TPSA <= 90, so Ligand A is preferable.

**3. logP:** Ligand A (4.326) is high, potentially causing solubility issues, but within a range that *could* be acceptable. Ligand B (-0.868) is too low, likely hindering membrane permeability and CNS penetration.

**4. H-Bond Donors:** Ligand A (1) is good. Ligand B (3) is acceptable but less ideal.

**5. H-Bond Acceptors:** Ligand A (4) is good. Ligand B (6) is acceptable.

**6. QED:** Both ligands have similar QED values (0.621 and 0.539), indicating reasonable drug-likeness.

**7. DILI:** Ligand A (61.962) has a higher DILI risk than Ligand B (10.741). This is a concern for Ligand A.

**8. BBB:** Ligand A (48.662) is moderately good, while Ligand B (13.92) is very poor. Given DRD2 is a CNS target, BBB penetration is crucial, making Ligand A much more promising.

**9. Caco-2:** Ligand A (-4.82) and Ligand B (-5.731) both have negative values, which is unusual and suggests poor permeability. However, the scale is not specified, so it's hard to interpret.

**10. Solubility:** Ligand A (-4.894) and Ligand B (-1.513) both have negative values, indicating poor solubility.

**11. hERG:** Ligand A (0.635) has a slightly higher hERG risk than Ligand B (0.139), but both are relatively low.

**12. Cl_mic:** Ligand B (-9.196) has significantly better metabolic stability (lower clearance) than Ligand A (84.451).

**13. t1/2:** Ligand A (23.745) has a slightly longer half-life than Ligand B (21.033).

**14. Pgp:** Ligand A (0.539) has lower P-gp efflux than Ligand B (0.007), which is favorable for CNS penetration.

**15. Binding Affinity:** Ligand A (-9.3 kcal/mol) has a significantly stronger binding affinity than Ligand B (-7.8 kcal/mol). This is a major advantage for Ligand A.

**Overall Assessment:**

While Ligand A has a higher DILI risk, its superior BBB penetration, significantly better binding affinity, and lower P-gp efflux outweigh this concern, especially for a CNS target like DRD2. Ligand B suffers from very poor BBB penetration and a significantly weaker binding affinity, making it a less promising candidate despite its better metabolic stability and lower DILI risk. The TPSA of Ligand A is also much more favorable.

Output:
1
2025-04-17 03:32:07,526 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (349.471 and 351.451 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (59.0) is excellent, well below the 90 target for CNS drugs. Ligand B (97.6) is higher, but still potentially acceptable, though less ideal.

**logP:** Ligand A (2.857) is optimal (1-3). Ligand B (0.368) is low, potentially hindering membrane permeability.

**H-Bond Donors:** Ligand A (1) and Ligand B (2) are both within the acceptable limit of <=5.

**H-Bond Acceptors:** Ligand A (4) and Ligand B (6) are both within the acceptable limit of <=10.

**QED:** Both ligands have reasonable QED scores (0.822 and 0.692), indicating good drug-like properties.

**DILI:** Ligand A (18.224) has a significantly lower DILI risk than Ligand B (8.414), which is a strong advantage.

**BBB:** Ligand A (41.528) has a moderate BBB penetration, while Ligand B (27.84) is quite low. This is a critical factor for a CNS target like DRD2.

**Caco-2:** Ligand A (-4.422) and Ligand B (-5.44) both have negative values, indicating poor permeability.

**Solubility:** Ligand A (-2.676) and Ligand B (-0.339) both have negative values, indicating poor solubility.

**hERG:** Ligand A (0.749) has a lower hERG risk than Ligand B (0.066).

**Cl_mic:** Ligand A (70.92) has a higher microsomal clearance than Ligand B (-18.876), indicating lower metabolic stability.

**t1/2:** Ligand A (15.195) has a longer in vitro half-life than Ligand B (-2.398).

**Pgp:** Ligand A (0.497) has lower P-gp efflux liability than Ligand B (0.002), which is favorable for CNS penetration.

**Binding Affinity:** Ligand B (-7.7) has a slightly better binding affinity than Ligand A (-7.4), but the difference is small (0.3 kcal/mol).

**Overall Assessment:**

Ligand A is significantly better overall. While Ligand B has slightly better binding affinity, Ligand A excels in crucial ADME properties for a CNS drug targeting a GPCR. Specifically, its much better BBB penetration, lower DILI risk, lower Pgp efflux, and longer half-life are substantial advantages. Ligand B's low logP and poor BBB penetration are major drawbacks. The slightly higher Cl_mic of Ligand A is a concern, but potentially addressable through structural modifications.

Output:
1
2025-04-17 03:32:07,526 - INFO - Batch 37 complete. Total preferences: 592
2025-04-17 03:32:07,526 - INFO - Processing batch 38/512...
2025-04-17 03:32:49,581 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (356.419 and 347.415 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (102.96) is slightly above the preferred <90 for CNS targets, but still reasonable. Ligand B (91.76) is better, falling comfortably under 90.

**3. logP:** Both ligands have a logP of around 1.3, which is optimal for permeability and solubility.

**4. H-Bond Donors:** Both have 2 HBD, which is within the acceptable limit of <=5.

**5. H-Bond Acceptors:** Ligand A has 6 HBA, and Ligand B has 5. Both are within the acceptable limit of <=10.

**6. QED:** Ligand B (0.776) has a significantly better QED score than Ligand A (0.452), indicating a more drug-like profile.

**7. DILI:** Ligand A (59.403) has a higher DILI risk than Ligand B (28.655). This is a significant advantage for Ligand B.

**8. BBB:** Both ligands have a BBB penetration of 49.515 and 59.403 respectively. While neither is exceptional (>70), Ligand B is slightly better.

**9. Caco-2 Permeability:** Both have negative Caco-2 values (-5.222 and -4.987). This is unusual and suggests poor permeability. However, these values are on a strange scale and may not be directly comparable.

**10. Aqueous Solubility:** Both ligands have negative solubility values (-1.826 and -1.774), which is also unusual and suggests poor solubility. Again, the scale is unclear.

**11. hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.212 and 0.145).

**12. Microsomal Clearance:** Ligand A (56.375) has a much higher microsomal clearance than Ligand B (2.942), indicating lower metabolic stability. This is a major drawback for Ligand A.

**13. In vitro Half-Life:** Ligand B (0.068) has a very short half-life, while Ligand A (-8.747) has a negative half-life, which is not physically possible. This suggests a problem with the data for Ligand A.

**14. P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.129 and 0.011).

**15. Binding Affinity:** Ligand B (-8.5 kcal/mol) has a slightly better binding affinity than Ligand A (-7.1 kcal/mol). While the difference is not huge (1.4 kcal/mol), it's enough to be considered, especially in light of the other advantages of Ligand B.

**Overall Assessment:**

Ligand B is significantly better than Ligand A. It has a higher QED score, lower DILI risk, better metabolic stability (lower Cl_mic, although the half-life is concerningly short), and slightly better binding affinity. While both have issues with Caco-2 and solubility, the data for Ligand A is particularly problematic (negative half-life). Given the GPCR-specific priorities, the combination of better ADME properties and comparable binding affinity makes Ligand B the more promising candidate.

Output:
1
2025-04-17 03:32:49,582 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the acceptable range (200-500 Da). Ligand A (350.438 Da) is slightly preferred as it's closer to the ideal range.

**TPSA:** Ligand A (78.09) is excellent for CNS penetration, well below the 90 A^2 threshold. Ligand B (133.83) is higher, potentially hindering BBB penetration, though still within a reasonable range.

**logP:** Ligand A (2.592) is optimal. Ligand B (-2.253) is significantly lower, which could lead to poor membrane permeability and bioavailability.

**H-Bond Donors/Acceptors:** Ligand A (HBD=2, HBA=3) is well within acceptable limits. Ligand B (HBD=4, HBA=8) is also acceptable, but closer to the upper limits, potentially impacting permeability.

**QED:** Ligand A (0.828) has a strong drug-like profile. Ligand B (0.328) is considerably lower, indicating a less favorable drug-like profile.

**DILI:** Both ligands have similar DILI risk (Ligand A: 60.527, Ligand B: 59.829), both being moderately risky, but not prohibitive.

**BBB:** This is a critical parameter for a CNS target. Ligand A has a good BBB percentile (56.223), while Ligand B is very low (15.083), severely limiting its potential for CNS activity.

**Caco-2 Permeability:** Ligand A (-4.916) is poor, while Ligand B (-6.374) is even worse. Both are negative, indicating low permeability.

**Aqueous Solubility:** Ligand A (-3.334) is poor, while Ligand B (-1.802) is slightly better, but still poor.

**hERG Inhibition:** Both ligands have very low hERG inhibition risk (Ligand A: 0.574, Ligand B: 0.1), which is favorable.

**Microsomal Clearance:** Ligand A (41.652) has moderate clearance, while Ligand B (18.474) has lower clearance, suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (-6.411) has a negative half-life, which is unusual and suggests rapid metabolism or instability. Ligand B (-16.763) is even worse.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (Ligand A: 0.223, Ligand B: 0.006), which is favorable for CNS penetration.

**Binding Affinity:** Ligand A (-8.5 kcal/mol) has a significantly stronger binding affinity than Ligand B (-7.2 kcal/mol). This 1.3 kcal/mol difference is substantial and can outweigh some ADME drawbacks.

**Overall Assessment:**

Ligand A is clearly the more promising candidate. While its solubility and Caco-2 permeability are poor, its superior binding affinity, better BBB penetration, and more favorable QED score outweigh these drawbacks. Ligand B's very poor BBB penetration and low logP are major liabilities for a CNS-targeting drug. The better metabolic stability of Ligand B is a plus, but not enough to compensate for its other weaknesses.

Output:
1
2025-04-17 03:32:49,582 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B based on the provided guidelines, prioritizing GPCR-specific properties (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (356.423 Da) and Ligand B (347.463 Da) are comparable.

**TPSA:** Ligand A (122.21) is borderline for CNS targets (<=90 is preferred) but still acceptable. Ligand B (63.49) is excellent, well below the 90 threshold. This favors Ligand B.

**logP:** Ligand A (-1.503) is quite low, potentially hindering permeability. Ligand B (1.312) is within the optimal range (1-3). This is a significant advantage for Ligand B.

**H-Bond Donors/Acceptors:** Ligand A (4 HBD, 5 HBA) is reasonable. Ligand B (0 HBD, 6 HBA) is also acceptable.

**QED:** Both ligands have reasonable QED scores (A: 0.488, B: 0.63), indicating drug-like properties. Ligand B is slightly better.

**DILI:** Ligand A (19.698) has a lower DILI risk than Ligand B (23.846), which is favorable.

**BBB:** Ligand B (69.407) has a much better BBB percentile than Ligand A (16.557). This is *critical* for a CNS target like DRD2 and strongly favors Ligand B.

**Caco-2 Permeability:** Ligand A (-5.448) has poor Caco-2 permeability. Ligand B (-4.933) is also poor, but slightly better.

**Aqueous Solubility:** Both have poor aqueous solubility (-0.332 and -0.542 respectively).

**hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.102 and 0.224 respectively).

**Microsomal Clearance:** Ligand A (-32.834) has significantly lower (better) microsomal clearance than Ligand B (35.121), indicating better metabolic stability.

**In vitro Half-Life:** Ligand A (-11.445) has a shorter half-life than Ligand B (10.543), which is less desirable.

**P-gp Efflux:** Ligand A (0.003) has very low P-gp efflux, which is excellent. Ligand B (0.06) is also low, but higher than A.

**Binding Affinity:** Ligand B (-7.6 kcal/mol) has a slightly better binding affinity than Ligand A (-8.4 kcal/mol). While A is better, the difference is not substantial enough to outweigh the ADME issues.

**Overall Assessment:**

Ligand B clearly outperforms Ligand A, particularly regarding crucial GPCR properties for CNS targets. Its superior BBB penetration, optimal logP, and acceptable TPSA are major advantages. While Ligand A has better metabolic stability (lower Cl_mic), the poor BBB penetration and low logP are significant drawbacks. The slightly better affinity of A is not enough to compensate for these issues.

Output:
1
2025-04-17 03:32:49,582 - INFO - Reasoning:

Let's analyze Ligand A and Ligand B based on the provided guidelines, prioritizing GPCR-specific properties (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (348.403 and 352.475 Da) fall within the ideal range of 200-500 Da.

**TPSA:** Ligand A (101.58) is slightly above the optimal <90 for CNS targets, while Ligand B (81.08) is comfortably within the range. This favors Ligand B.

**logP:** Ligand A (0.86) is a bit low, potentially hindering permeation. Ligand B (1.004) is slightly better, but still on the lower side of the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A has 3 HBD and 7 HBA, while Ligand B has 2 HBD and 4 HBA. Both are within acceptable limits.

**QED:** Both ligands have good QED scores (0.548 and 0.791), indicating good drug-like properties. Ligand B is slightly better.

**DILI:** Ligand A (61.07) has a higher DILI risk than Ligand B (10.12). This is a significant advantage for Ligand B.

**BBB:** Ligand B (65.839) has a significantly better BBB penetration percentile than Ligand A (55.603). This is crucial for a CNS target like DRD2 and strongly favors Ligand B.

**Caco-2 Permeability:** Both have negative values, which is unusual. Assuming these are percentile scores, Ligand B (-4.612) is slightly better than Ligand A (-5.133), indicating marginally better intestinal absorption.

**Aqueous Solubility:** Both ligands have very poor aqueous solubility (-2.42 and -2.477). This is a concern for both, but not a deciding factor.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.412 and 0.24), which is good.

**Microsomal Clearance:** Ligand A (-14.165) has a lower (better) microsomal clearance than Ligand B (31.604), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand B (-4.958) has a negative half-life, which is problematic. Ligand A (32.309) has a reasonable half-life.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.01 and 0.016), which is favorable for CNS penetration.

**Binding Affinity:** Ligand A (-8.5 kcal/mol) has a stronger binding affinity than Ligand B (-6.5 kcal/mol). This is a substantial difference (2 kcal/mol), and is a major point in favor of Ligand A.

**Overall Assessment:**

While Ligand A has a superior binding affinity and better metabolic stability, Ligand B excels in crucial CNS-related properties: significantly lower DILI risk and much better BBB penetration. The affinity difference is substantial, but for a CNS target, achieving brain exposure is paramount. The poor solubility of both is a concern that would need to be addressed in formulation, but the BBB advantage of Ligand B is more critical.

Output:
1
2025-04-17 03:32:49,582 - INFO - Reasoning:

Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (351.491 and 350.459 Da) fall comfortably within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (101.29) is slightly higher than the preferred <90 for CNS targets, but still reasonable. Ligand B (78.87) is excellent, well below 90. This favors Ligand B.

**3. logP:** Both ligands have good logP values (1.868 and 1.095), falling within the optimal 1-3 range. Ligand B is slightly lower, which *could* indicate slightly better solubility, but isn't a major concern for either.

**4. H-Bond Donors:** Ligand A (3) and Ligand B (2) are both within the acceptable limit of <=5. Ligand B is slightly better.

**5. H-Bond Acceptors:** Ligand A (3) and Ligand B (4) are both within the acceptable limit of <=10.

**6. QED:** Both ligands have good QED scores (0.622 and 0.703), indicating good drug-like properties. Ligand B is slightly better.

**7. DILI:** Ligand A (26.095) has a slightly higher DILI risk than Ligand B (14.618), both are good, but B is preferable.

**8. BBB:** Both ligands have good BBB penetration (65.723 and 72.819). Ligand B is better, exceeding 70%, which is desirable for a CNS target like DRD2.

**9. Caco-2 Permeability:** Ligand A (-5.241) has poor Caco-2 permeability, indicating poor intestinal absorption. Ligand B (-4.525) is also poor, but slightly better.

**10. Aqueous Solubility:** Both ligands have poor aqueous solubility (-3.552 and -1.909). This is a potential issue for both, but not a dealbreaker if other properties are strong.

**11. hERG Inhibition:** Both ligands show low hERG inhibition risk (0.138 and 0.253).

**12. Microsomal Clearance:** Ligand A (58.284) has higher microsomal clearance than Ligand B (34.442), suggesting lower metabolic stability. Ligand B is preferable.

**13. In vitro Half-Life:** Ligand A (-17.542) has a negative half-life, which is concerning. Ligand B (1.315) has a very short half-life, but is still better than a negative value.

**14. P-gp Efflux:** Both ligands have low P-gp efflux liability (0.06 and 0.04), which is good for CNS penetration.

**15. Binding Affinity:** Both ligands have very similar and excellent binding affinities (-8.1 and -8.2 kcal/mol). The difference is negligible.

**Overall Assessment:**

Ligand B consistently outperforms Ligand A in several key areas: TPSA, DILI, BBB, microsomal clearance, and in vitro half-life. While both have poor solubility and Caco-2 permeability, the superior ADME profile of Ligand B, particularly its better BBB penetration and metabolic stability, makes it the more promising drug candidate for targeting DRD2. The slightly better QED score also supports this conclusion.

Output:
1
2025-04-17 03:32:49,582 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (364.408 and 352.45 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (58.64) is significantly better than Ligand B (78.43). For CNS targets, we want TPSA <= 90, and ideally closer to 60. Ligand A is much closer to the ideal range.

**3. logP:** Both ligands have good logP values (2.089 and 1.876), falling within the optimal 1-3 range.

**4. H-Bond Donors:** Ligand A (1) is preferable to Ligand B (3). Fewer HBDs generally improve permeability.

**5. H-Bond Acceptors:** Both ligands have 3 HBA, which is acceptable.

**6. QED:** Both ligands have similar QED values (0.604 and 0.584), indicating good drug-likeness.

**7. DILI:** Ligand A (28.383) has a slightly higher DILI risk than Ligand B (14.424), but both are below the concerning threshold of 60.

**8. BBB:** This is a critical parameter for a CNS target like DRD2. Ligand A (93.563) has a much higher BBB penetration percentile than Ligand B (67.08). A value >70 is desirable, and Ligand A is very close.

**9. Caco-2 Permeability:** Ligand A (-4.598) is better than Ligand B (-4.939), indicating better intestinal absorption.

**10. Aqueous Solubility:** Both ligands have very poor aqueous solubility (-2.303 and -2.559). This is a concern, but can sometimes be mitigated with formulation strategies.

**11. hERG:** Both ligands show low hERG inhibition liability (0.651 and 0.26), which is positive.

**12. Microsomal Clearance:** Ligand B (18.77) has lower microsomal clearance than Ligand A (35.77), suggesting better metabolic stability.

**13. In vitro Half-Life:** Ligand B (-2.802) has a better in vitro half-life than Ligand A (-4.503).

**14. P-gp Efflux:** Ligand A (0.205) has lower P-gp efflux than Ligand B (0.063), which is beneficial for CNS exposure.

**15. Binding Affinity:** Ligand B (-8.2) has a slightly better binding affinity than Ligand A (-7.8). However, the difference is only 0.4 kcal/mol, which is not substantial enough to outweigh the other advantages of Ligand A.

**Overall Assessment:**

Ligand A is the more promising candidate. While Ligand B has slightly better affinity and metabolic stability, Ligand A excels in critical GPCR/CNS-related properties: significantly lower TPSA, much higher BBB penetration, and lower P-gp efflux. The slightly higher DILI risk for Ligand A is acceptable given the other benefits. The poor solubility of both compounds is a concern that would need to be addressed during formulation.

Output:
1
2025-04-17 03:32:49,582 - INFO - Reasoning:

Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (352.475 and 347.459 Da) fall comfortably within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (59.08) is excellent, well below the 90 A^2 threshold for CNS targets. Ligand B (84.23) is still reasonable, but higher and less favorable.

**3. logP:** Both ligands have good logP values (1.82 and 2.612), falling within the optimal 1-3 range.

**4. H-Bond Donors:** Ligand A (0) is preferable to Ligand B (2). Fewer HBDs generally improve permeability.

**5. H-Bond Acceptors:** Both ligands have 4 HBA, which is acceptable.

**6. QED:** Ligand A (0.701) has a significantly better QED score than Ligand B (0.503), indicating a more drug-like profile.

**7. DILI:** Ligand A (8.647) has a much lower DILI risk than Ligand B (18.224), a significant advantage.

**8. BBB:** Ligand A (83.908) has a substantially higher BBB penetration percentile than Ligand B (67.468). This is *critical* for a CNS target like DRD2.

**9. Caco-2 Permeability:** Ligand A (-4.483) and Ligand B (-4.969) both have negative values, which is unusual. Lower values indicate lower permeability. However, the difference is small.

**10. Aqueous Solubility:** Ligand A (-0.912) is slightly better than Ligand B (-1.844), but both are quite poor. Solubility could be a formulation challenge for both.

**11. hERG Inhibition:** Both ligands show very low hERG inhibition liability (0.324 and 0.14), which is excellent.

**12. Microsomal Clearance:** Ligand A (28.218) has a lower microsomal clearance than Ligand B (59.619), suggesting better metabolic stability.

**13. In vitro Half-Life:** Ligand A (-0.069) has a slightly longer half-life than Ligand B (-18.614).

**14. P-gp Efflux:** Ligand A (0.084) has lower P-gp efflux liability than Ligand B (0.027), which is favorable for CNS penetration.

**15. Binding Affinity:** Both ligands have the same binding affinity (-7.8 kcal/mol), which is excellent.

**Overall Assessment:**

Ligand A is clearly superior. It excels in crucial areas for a CNS-targeting GPCR ligand: TPSA, BBB penetration, DILI risk, QED, and metabolic stability. While both have comparable affinity and acceptable logP, Ligand A's better ADME properties, particularly its higher BBB score and lower DILI risk, make it the more promising drug candidate.

Output:
1
2025-04-17 03:32:49,583 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (350.39 and 350.459 Da) fall comfortably within the ideal 200-500 Da range.

**TPSA:** Ligand A (78.87) is slightly higher than Ligand B (70.08). Both are below the 90 A^2 threshold desirable for CNS targets, but Ligand B is preferable.

**logP:** Ligand A (2.77) is within the optimal 1-3 range. Ligand B (0.881) is a bit low, potentially hindering permeation. This favors Ligand A.

**H-Bond Donors:** Ligand A (2) and Ligand B (1) are both acceptable, being less than 5. Ligand B is slightly better.

**H-Bond Acceptors:** Both ligands (4) are within the acceptable range of <=10.

**QED:** Both ligands have good QED values (0.819 and 0.772), indicating good drug-like properties.

**DILI:** Ligand A (44.591) has a moderate DILI risk, while Ligand B (11.361) has a very low risk. This is a significant advantage for Ligand B.

**BBB:** Ligand A (76.735) has a good BBB penetration percentile, exceeding the 70% threshold for CNS targets. Ligand B (61.535) is below this threshold, which is a major drawback. This strongly favors Ligand A.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.639 and -4.466), which is unusual and suggests poor permeability. However, the scale isn't specified, so it's hard to interpret.

**Aqueous Solubility:** Both ligands have negative solubility values (-3.568 and -0.643), also unusual and suggesting poor solubility. Again, the scale is unknown.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.7 and 0.215). Ligand B is slightly better.

**Microsomal Clearance:** Ligand A (33.783) has a higher clearance than Ligand B (4.442), indicating lower metabolic stability. This favors Ligand B.

**In vitro Half-Life:** Ligand A (42.479) has a longer half-life than Ligand B (2.997). This is a significant advantage for Ligand A.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.138 and 0.072), which is excellent for CNS penetration. Ligand B is slightly better.

**Binding Affinity:** Ligand A (-8.1 kcal/mol) has a slightly stronger binding affinity than Ligand B (-7.8 kcal/mol). While the difference is small, it is within the range where it could outweigh minor ADME drawbacks.

**Overall Assessment:**

Ligand A excels in BBB penetration, binding affinity, and in vitro half-life. However, it has a higher DILI risk and higher microsomal clearance. Ligand B has a much lower DILI risk and better metabolic stability, but its BBB penetration is suboptimal and its binding affinity is slightly weaker.

Given the importance of BBB penetration for a CNS target like DRD2, and the relatively small difference in binding affinity, **Ligand A is the more promising candidate**. The slightly higher DILI risk and lower metabolic stability might be manageable with further optimization, but poor BBB penetration is a more difficult hurdle to overcome.

Output:
1
2025-04-17 03:32:49,583 - INFO - Reasoning:

Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (371.825 and 350.409 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (96.77) is slightly above the optimal <90 for CNS targets, but still reasonably acceptable. Ligand B (64.33) is well within the desired range. This favors Ligand B.

**3. logP:** Ligand A (0.236) is quite low, potentially hindering permeability. Ligand B (3.252) is within the optimal 1-3 range. This is a significant advantage for Ligand B.

**4. H-Bond Donors:** Both ligands have 1 HBD, which is within the acceptable limit of <=5.

**5. H-Bond Acceptors:** Ligand A has 6 HBAs, while Ligand B has 3. Both are below the limit of <=10.

**6. QED:** Both ligands have good QED scores (0.66 and 0.743), indicating drug-like properties.

**7. DILI:** Ligand A (56.572) has a moderate DILI risk, while Ligand B (13.959) has a very low risk. This strongly favors Ligand B.

**8. BBB:** Both ligands have excellent BBB penetration (81.388 and 88.29), exceeding the desirable >70 threshold for CNS targets. Ligand B is slightly better.

**9. Caco-2 Permeability:** Ligand A (-4.801) has poor Caco-2 permeability, suggesting poor intestinal absorption. Ligand B (-4.187) is also poor, but slightly better than Ligand A.

**10. Aqueous Solubility:** Both ligands have very poor aqueous solubility (-2.261 and -3.501). This is a concern for both, but more so for Ligand A.

**11. hERG Inhibition:** Ligand A (0.06) has very low hERG inhibition risk, while Ligand B (0.907) has a slightly higher, but still acceptable risk. This favors Ligand A, but the difference isn't huge.

**12. Microsomal Clearance:** Ligand A (10.843) has lower microsomal clearance, suggesting better metabolic stability than Ligand B (44.152). This favors Ligand A.

**13. In vitro Half-Life:** Ligand A (-2.825) has a negative half-life, which is not physically possible and indicates a problem with the data or the molecule's stability. Ligand B (18.859) has a good in vitro half-life. This is a major advantage for Ligand B.

**14. P-gp Efflux:** Ligand A (0.013) has very low P-gp efflux, which is desirable for CNS exposure. Ligand B (0.409) has moderate P-gp efflux. This favors Ligand A.

**15. Binding Affinity:** Both ligands have very similar and strong binding affinities (-6.7 and -6.9 kcal/mol). The difference is negligible.

**Overall Assessment:**

While Ligand A has advantages in P-gp efflux and hERG inhibition, its extremely low logP, poor Caco-2 permeability, and problematic half-life are significant drawbacks. Ligand B, despite slightly higher P-gp efflux, excels in crucial areas for a CNS-targeting GPCR ligand: TPSA, logP, DILI risk, and BBB penetration. The more reasonable half-life is also a major benefit. The slightly better BBB penetration and significantly lower DILI risk of Ligand B outweigh the minor advantages of Ligand A.

Output:
1
2025-04-17 03:32:49,583 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight (MW):** Both ligands (349.563 and 355.467 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (26.79) is excellent, well below the 90 A^2 threshold for CNS targets. Ligand B (63.91) is higher but still potentially acceptable, though less ideal.

**3. logP:** Both ligands (3.079 and 3.665) are within the optimal 1-3 range.

**4. H-Bond Donors (HBD):** Both have 0 HBD, which is fine.

**5. H-Bond Acceptors (HBA):** Ligand A has 3 HBA, and Ligand B has 6 HBA. Both are below the 10 threshold.

**6. QED:** Both ligands have similar QED scores (0.763 and 0.7), indicating good drug-like properties.

**7. DILI:** Ligand A (4.188) has a very favorable DILI risk, well below the 40 threshold. Ligand B (76.464) has a significantly higher DILI risk, which is a major concern.

**8. BBB:** Ligand A (93.408) has excellent BBB penetration, exceeding the 70% threshold for CNS targets. Ligand B (73.711) is still reasonable, but considerably lower.

**9. Caco-2:** Both have negative values, which is unusual. Assuming these are logP-scale values, they suggest poor permeability.

**10. Solubility:** Ligand A (-1.136) has slightly better solubility than Ligand B (-3.47), though both are quite poor.

**11. hERG:** Ligand A (0.883) has a low hERG risk. Ligand B (0.397) also has a low hERG risk.

**12. Cl_mic:** Ligand A (24.93) has a lower microsomal clearance, suggesting better metabolic stability than Ligand B (62.597).

**13. t1/2:** Ligand A (-15.027) has a negative half-life, which is impossible. This is a data error. Ligand B (34.516) has a reasonable in vitro half-life.

**14. Pgp:** Ligand A (0.125) has lower P-gp efflux, which is favorable for CNS penetration. Ligand B (0.545) has higher P-gp efflux.

**15. Binding Affinity:** Ligand B (-8.2 kcal/mol) has a slightly better binding affinity than Ligand A (-7.4 kcal/mol). This difference is 0.8 kcal/mol, which is significant but not overwhelming.

**Overall Assessment:**

Ligand A is significantly more promising despite the half-life error. It exhibits superior BBB penetration, a much lower DILI risk, better metabolic stability, and lower P-gp efflux. While Ligand B has slightly better binding affinity, the substantial advantages of Ligand A in ADME properties, particularly for a CNS target, outweigh this difference. The negative half-life for Ligand A is a data quality issue that would need to be resolved, but the other properties are compelling.

Output:
1
2025-04-17 03:32:49,583 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B based on the provided guidelines, prioritizing GPCR-specific properties (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (351.407 and 344.371 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (88.93) is excellent for CNS penetration, being well below 90. Ligand B (104.65) is still reasonable but less optimal.

**logP:** Ligand A (-0.086) is slightly low, potentially hindering permeation, but not drastically. Ligand B (-0.792) is also on the lower side, but slightly better than A.

**H-Bond Donors/Acceptors:** Ligand A (1 HBD, 7 HBA) and Ligand B (2 HBD, 6 HBA) both have acceptable numbers of H-bond donors and acceptors.

**QED:** Both ligands (0.763 and 0.696) have good drug-likeness scores, exceeding the 0.5 threshold.

**DILI:** Ligand A (49.942) has a lower DILI risk than Ligand B (62.156), indicating a better safety profile. Both are acceptable, but A is preferable.

**BBB:** This is a critical parameter for a CNS target like DRD2. Ligand A (76.037) has a good BBB percentile, exceeding the desirable >70 threshold. Ligand B (19.038) is very poor, suggesting limited CNS exposure.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.6 and -4.851), which is unusual and suggests poor permeability. However, these values are on a scale where negative values are possible and don't necessarily indicate a complete lack of permeability.

**Aqueous Solubility:** Both ligands have negative solubility values (-1.109 and -1.976), indicating poor aqueous solubility. This could pose formulation challenges.

**hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.174 and 0.129).

**Microsomal Clearance:** Ligand A (32.478) has a higher microsomal clearance than Ligand B (-6.606), meaning it's likely to be metabolized faster. Ligand B shows negative clearance, which is unusual and could indicate very high stability.

**In vitro Half-Life:** Ligand B (-12.643) has a negative in vitro half-life, which is not physically possible and suggests an issue with the data. Ligand A (23.5) is reasonable.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.007 and 0.056), which is favorable for CNS penetration.

**Binding Affinity:** Both ligands have similar binding affinities (-8.0 and -7.7 kcal/mol), both of which are excellent. The difference is less than the 1.5 kcal/mol threshold.

**Conclusion:**

Despite similar binding affinities, Ligand A is significantly more promising due to its superior BBB penetration (76.04% vs 19.04%), lower DILI risk, and a reasonable in vitro half-life. Ligand B's extremely poor BBB penetration and nonsensical half-life make it a less viable candidate, even with potentially higher metabolic stability. The slightly lower logP of Ligand A is a minor concern compared to the significant advantages in CNS penetration and safety.

Output:
0
2025-04-17 03:32:49,583 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (350.503 and 346.471 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (69.64) is better than Ligand B (62.55) as it is closer to the <90 A^2 threshold for CNS targets.

**3. logP:** Both ligands have good logP values (2.469 and 3.23), falling within the optimal 1-3 range. Ligand B is slightly higher, which could potentially lead to solubility issues, but it's not a major concern.

**4. H-Bond Donors:** Both ligands have acceptable HBD counts (2 and 1, respectively), well below the limit of 5.

**5. H-Bond Acceptors:** Both ligands have acceptable HBA counts (3), below the limit of 10.

**6. QED:** Both ligands have good QED scores (0.741 and 0.786), indicating good drug-like properties.

**7. DILI:** Ligand A (12.369) has a significantly lower DILI risk than Ligand B (21.908), which is a substantial advantage.

**8. BBB:** Ligand A (61.497) has a better BBB penetration percentile than Ligand B (55.874), although neither are above the desirable >70 threshold. This is a critical factor for a CNS target like DRD2.

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.582 and -4.615). These values are unusual and suggest poor permeability, but the scale is not defined.

**10. Aqueous Solubility:** Both ligands have negative solubility values (-2.694 and -2.289). These values are unusual and suggest poor solubility, but the scale is not defined.

**11. hERG Inhibition:** Both ligands have low hERG inhibition risk (0.231 and 0.441).

**12. Microsomal Clearance:** Ligand B (68.798) has a higher microsomal clearance than Ligand A (36.77), indicating lower metabolic stability.

**13. In vitro Half-Life:** Ligand B (73.259) has a much longer in vitro half-life than Ligand A (-1.553), which is a significant advantage.

**14. P-gp Efflux:** Both ligands have low P-gp efflux liability (0.116 and 0.259).

**15. Binding Affinity:** Both ligands have excellent binding affinities (-8.4 and -8.0 kcal/mol), with Ligand A being slightly better. The difference of 0.4 kcal/mol is not substantial enough to outweigh other factors.

**Overall Assessment:**

Considering the GPCR-specific priorities, Ligand A is the more promising candidate. While Ligand B has a better half-life, Ligand A demonstrates superior BBB penetration, significantly lower DILI risk, and slightly better binding affinity. The lower TPSA of Ligand A is also favorable for CNS penetration. The negative Caco-2 and solubility values are concerning for both, but the other advantages of Ligand A make it the better choice.

Output:
0
2025-04-17 03:32:49,583 - INFO - Reasoning:

Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, considering the provided guidelines and GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight (MW):** Both ligands (358.429 and 337.423 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (78.43) is slightly higher than Ligand B (62.61). Both are below the 90 A^2 threshold for CNS targets, which is good. Ligand B is preferable here.

**3. logP:** Both ligands have good logP values (1.984 and 2.366), falling within the optimal 1-3 range.

**4. H-Bond Donors (HBD):** Both ligands are acceptable (3 and 2 respectively), being less than 5.

**5. H-Bond Acceptors (HBA):** Both ligands are acceptable (3 each), being less than 10.

**6. QED:** Both ligands have good QED scores (0.679 and 0.845), indicating good drug-like properties. Ligand B is slightly better.

**7. DILI:** Ligand A (20.706) has a significantly lower DILI risk than Ligand B (58.55). This is a major advantage for Ligand A.

**8. BBB:** Ligand A (69.252) has a better BBB penetration score than Ligand B (64.211), although both are reasonably good. For a CNS target like DRD2, maximizing BBB penetration is crucial.

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.928 and -4.545), which is unusual and suggests poor permeability. This is a concern for both.

**10. Aqueous Solubility:** Both ligands have negative solubility values (-2.17 and -3.272), indicating very poor aqueous solubility. This is a significant drawback for both.

**11. hERG Inhibition:** Both ligands have low hERG inhibition risk (0.403 and 0.316).

**12. Microsomal Clearance (Cl_mic):** Ligand A (-15.466) has a much lower (better) microsomal clearance than Ligand B (4.724), indicating greater metabolic stability.

**13. In vitro Half-Life:** Ligand A (18.147 hours) has a better in vitro half-life than Ligand B (33.974 hours).

**14. P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.024 and 0.101).

**15. Binding Affinity:** Both ligands have similar, excellent binding affinities (-8.7 and -8.5 kcal/mol). The difference is negligible.

**Overall Assessment:**

While both ligands have good binding affinity, Ligand A is the stronger candidate. It has a significantly lower DILI risk, better metabolic stability (lower Cl_mic), and a slightly better BBB score. Although both have poor solubility and Caco-2 permeability, the improved safety profile and metabolic stability of Ligand A outweigh these drawbacks. The slightly better BBB penetration also favors Ligand A for a CNS target.

Output:
1
2025-04-17 03:32:49,583 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (347.463 and 346.515 Da) fall comfortably within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (80.12) is better than Ligand B (49.41). For a CNS target like DRD2, a TPSA <= 90 is preferred, and both meet this criterion, but A is closer to the upper limit.

**3. logP:** Ligand A (1.458) is within the optimal 1-3 range. Ligand B (3.214) is at the higher end of optimal, potentially increasing off-target interactions.

**4. H-Bond Donors:** Both ligands have 1 HBD, which is acceptable.

**5. H-Bond Acceptors:** Ligand A has 5 HBA, and Ligand B has 2 HBA. Both are below the acceptable limit of 10.

**6. QED:** Both ligands have similar QED values (0.845 and 0.831), indicating good drug-likeness.

**7. DILI:** Ligand A (41.062) has a slightly higher DILI risk than Ligand B (32.648), but both are below the concerning threshold of 60.

**8. BBB:** Ligand B (80.496) has a significantly better BBB penetration percentile than Ligand A (68.67). This is a crucial factor for CNS targets.

**9. Caco-2 Permeability:** Ligand A (-5.334) has a worse Caco-2 permeability than Ligand B (-4.892).

**10. Aqueous Solubility:** Ligand A (-1.984) has a worse aqueous solubility than Ligand B (-3.964).

**11. hERG Inhibition:** Ligand A (0.171) has a lower hERG inhibition risk than Ligand B (0.584), which is favorable.

**12. Microsomal Clearance:** Ligand B (63.065) has a higher microsomal clearance than Ligand A (16.126), suggesting lower metabolic stability.

**13. In vitro Half-Life:** Ligand A (-8.906) has a longer in vitro half-life than Ligand B (-1.605).

**14. P-gp Efflux:** Ligand A (0.032) has a much lower P-gp efflux liability than Ligand B (0.426), which is highly desirable for CNS penetration.

**15. Binding Affinity:** Ligand B (-10.2 kcal/mol) has a significantly stronger binding affinity than Ligand A (-7.7 kcal/mol). This is a substantial advantage, exceeding the 1.5 kcal/mol difference that can outweigh other drawbacks.

**Overall Assessment:**

While Ligand A has better hERG and P-gp efflux profiles, and a longer half-life, Ligand B's superior BBB penetration and *much* stronger binding affinity are decisive. The difference in binding affinity is substantial and likely to overcome the slightly higher P-gp efflux and clearance. The better BBB penetration is critical for a CNS target.

Output:
1
2025-04-17 03:32:49,584 - INFO - Reasoning:

Let's analyze Ligand A and Ligand B based on the provided guidelines, prioritizing GPCR-specific properties (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (358.419 and 346.395 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (69.68) is excellent for CNS penetration, well below the 90 A^2 threshold. Ligand B (119.57) is higher, but still potentially acceptable, though less ideal.

**logP:** Ligand A (3.712) is at the upper end of the optimal range (1-3), potentially raising concerns about solubility and off-target effects. Ligand B (0.782) is quite low, potentially hindering permeation.

**H-Bond Donors/Acceptors:** Ligand A (HBD=1, HBA=7) and Ligand B (HBD=2, HBA=9) both have reasonable numbers of H-bond donors and acceptors.

**QED:** Both ligands have acceptable QED values (0.678 and 0.583, respectively), indicating reasonable drug-likeness.

**DILI:** Both ligands show acceptable DILI risk (96.51 and 63.397 percentile), with Ligand A being slightly better.

**BBB:** This is crucial for a DRD2 ligand. Ligand A has a significantly better BBB penetration score (63.358%) than Ligand B (40.558%). While 63.358% isn't *outstanding*, it's much more promising than 40.558%.

**Caco-2 Permeability:** Ligand A (-4.676) and Ligand B (-5.878) both have negative values, suggesting poor permeability. However, the scale is not specified, so it's hard to interpret the absolute difference.

**Aqueous Solubility:** Ligand A (-5.843) and Ligand B (-1.561) both have negative solubility values, indicating poor solubility. Ligand B is slightly better.

**hERG Inhibition:** Ligand A (0.685) has a slightly higher hERG risk than Ligand B (0.1), but both are relatively low.

**Microsomal Clearance:** Ligand A (154.848 mL/min/kg) has a higher clearance, suggesting lower metabolic stability, compared to Ligand B (-2.369 mL/min/kg), which is excellent.

**In vitro Half-Life:** Ligand A (2.317 hours) has a shorter half-life than Ligand B (23.003 hours).

**P-gp Efflux:** Ligand A (0.257) has lower P-gp efflux liability than Ligand B (0.042), which is favorable for CNS penetration.

**Binding Affinity:** Ligand A (-8.3 kcal/mol) has a significantly stronger binding affinity than Ligand B (-7.0 kcal/mol). This >1.5 kcal/mol difference is a major advantage.

**Overall Assessment:**

Ligand A is the stronger candidate. Its superior binding affinity and better BBB penetration outweigh its slightly higher logP and clearance. While both have solubility issues, the difference isn't substantial enough to favor Ligand B. The significantly longer half-life of Ligand B is a plus, but the weaker binding and poorer BBB penetration are critical drawbacks for a CNS target like DRD2.



Output:
1
2025-04-17 03:32:49,584 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (344.415 Da) and Ligand B (335.495 Da) are comparable.

**TPSA:** Ligand A (89.01) is excellent for CNS penetration, being well below 90. Ligand B (27.3) is even better, indicating potentially improved brain exposure.

**logP:** Ligand A (1.536) is within the optimal range (1-3). Ligand B (3.799) is slightly higher, approaching the upper limit, which *could* lead to solubility issues, but is still acceptable.

**H-Bond Donors/Acceptors:** Both ligands have 2 HBD and 5/3 HBA, respectively, which are within acceptable limits.

**QED:** Both ligands have similar QED values (0.805 and 0.806), indicating good drug-likeness.

**DILI:** Ligand A (57.348) has a moderate DILI risk, while Ligand B (11.594) has a very low risk. This is a significant advantage for Ligand B.

**BBB:** Ligand A (54.207) has a moderate BBB penetration, while Ligand B (97.945) has excellent BBB penetration. This is a crucial factor for a CNS target like DRD2, favoring Ligand B.

**Caco-2 Permeability:** Both have negative Caco-2 values (-5.076 and -4.918), which is unusual and suggests poor permeability. However, these values are on a log scale, and the absolute values are close, so this difference is less impactful.

**Aqueous Solubility:** Both ligands have poor aqueous solubility (-2.862 and -3.039). This could be a formulation challenge, but is not a dealbreaker.

**hERG Inhibition:** Ligand A (0.404) has a slightly lower hERG risk than Ligand B (0.981), which is a minor advantage.

**Microsomal Clearance:** Ligand A (37.426) has a higher microsomal clearance than Ligand B (23.766), indicating lower metabolic stability. Ligand B is preferable here.

**In vitro Half-Life:** Ligand B (54.755) has a significantly longer in vitro half-life than Ligand A (7.987), which is a substantial advantage.

**P-gp Efflux:** Ligand A (0.165) has lower P-gp efflux than Ligand B (0.217), suggesting better CNS exposure.

**Binding Affinity:** Ligand B (-9.1 kcal/mol) has a significantly stronger binding affinity than Ligand A (-8.3 kcal/mol). This 1.8 kcal/mol difference is substantial and can outweigh minor ADME drawbacks.

**Overall Assessment:**

Ligand B is clearly superior. While both have poor solubility and Caco-2 permeability, Ligand B excels in the most important parameters for a CNS-targeting GPCR: BBB penetration, binding affinity, DILI risk, and metabolic stability (half-life and clearance). The stronger binding affinity of Ligand B is a major advantage. The slightly higher P-gp efflux and hERG risk are less concerning given the other benefits.

Output:
1
2025-04-17 03:32:49,584 - INFO - Batch 38 complete. Total preferences: 608
2025-04-17 03:32:49,584 - INFO - Processing batch 39/512...
2025-04-17 03:33:30,380 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (354.397 and 370.515 Da) fall within the ideal range of 200-500 Da.

**TPSA:** Ligand A (73.58) is significantly better than Ligand B (78.87), both are below the 90 A^2 threshold for CNS targets, but A is closer to the ideal.

**logP:** Ligand A (3.185) is optimal, while Ligand B (1.189) is a bit low, potentially hindering membrane permeability.

**H-Bond Donors:** Both ligands have 2 HBD, which is within the acceptable limit of <=5.

**H-Bond Acceptors:** Ligand A has 4 HBA, and Ligand B has 5. Both are within the acceptable limit of <=10.

**QED:** Ligand A (0.789) has a much better QED score than Ligand B (0.496), indicating a more drug-like profile.

**DILI:** Both ligands have low DILI risk (33.307 and 31.059, respectively), which is good.

**BBB:** This is a critical parameter for a CNS target like DRD2. Ligand A has a very high BBB penetration percentile (91.857), while Ligand B is significantly lower (46.336). This is a major advantage for Ligand A.

**Caco-2 Permeability:** Ligand A (-4.734) has a lower Caco-2 permeability than Ligand B (-5.093), but both are negative values, indicating poor permeability.

**Aqueous Solubility:** Both ligands have poor aqueous solubility (-3.166 and -3.032, respectively).

**hERG Inhibition:** Both ligands have low hERG inhibition liability (0.853 and 0.357, respectively).

**Microsomal Clearance:** Ligand A (20.254 mL/min/kg) has lower microsomal clearance than Ligand B (52.054 mL/min/kg), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (-18.836 hours) has a longer in vitro half-life than Ligand B (-13.108 hours), which is desirable.

**P-gp Efflux:** Ligand A (0.175) has lower P-gp efflux liability than Ligand B (0.074), indicating better potential for CNS exposure.

**Binding Affinity:** Ligand A (-8.2 kcal/mol) has a slightly better binding affinity than Ligand B (-7.0 kcal/mol). While both are good, the 1.2 kcal/mol difference is significant enough to consider.

**Overall Assessment:**

Ligand A is clearly the superior candidate. It excels in key GPCR-relevant properties like BBB penetration, metabolic stability (lower Cl_mic, longer t1/2), P-gp efflux, QED, and has a slightly better binding affinity. While both have poor solubility and Caco-2 permeability, the strong CNS-related advantages of Ligand A outweigh these drawbacks. Ligand B's low logP and poor BBB penetration are significant liabilities for a CNS-targeting drug.

Output:
1
2025-04-17 03:33:30,381 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (355.435 and 353.413 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (110.01) is higher than the preferred <90 for CNS targets, while Ligand B (61.44) is well within the range. This is a significant advantage for Ligand B.

**3. logP:** Ligand A (-0.055) is quite low, potentially hindering membrane permeability. Ligand B (2.096) is within the optimal 1-3 range. This favors Ligand B.

**4. H-Bond Donors:** Ligand A (1) and Ligand B (2) are both acceptable, being less than 5.

**5. H-Bond Acceptors:** Ligand A (5) and Ligand B (3) are both acceptable, being less than 10.

**6. QED:** Both ligands have good QED values (0.623 and 0.669), indicating drug-like properties.

**7. DILI:** Both ligands have low DILI risk (34.277 and 36.06), which is good.

**8. BBB:** Ligand B (70.027) is desirable for a CNS target like DRD2, being above the 70% threshold. Ligand A (60.838) is below this threshold. This is a major advantage for Ligand B.

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.347 and -4.772), which is unusual and suggests poor permeability. However, these values are on a scale where negative values are possible, and their relative comparison isn't straightforward.

**10. Aqueous Solubility:** Both ligands have negative solubility values (-1.037 and -1.397), indicating poor aqueous solubility. This could pose formulation challenges.

**11. hERG Inhibition:** Both ligands have low hERG inhibition risk (0.104 and 0.463).

**12. Microsomal Clearance:** Ligand A (25.767) has higher microsomal clearance than Ligand B (21.366), suggesting lower metabolic stability. This favors Ligand B.

**13. In vitro Half-Life:** Ligand B (4.605) has a longer in vitro half-life than Ligand A (-3.472), which is desirable.

**14. P-gp Efflux:** Ligand A (0.012) shows very little P-gp efflux, which is good. Ligand B (0.055) also shows low P-gp efflux, but slightly higher than A.

**15. Binding Affinity:** Ligand B (-8) has significantly stronger binding affinity than Ligand A (0). This is a critical advantage, potentially outweighing some of the ADME concerns.

**Overall Assessment:**

Ligand B is the stronger candidate. While both have solubility and permeability concerns (indicated by negative Caco-2 and solubility values), Ligand B excels in key areas for a CNS-targeting GPCR ligand: better logP, significantly better BBB penetration, longer half-life, and *much* stronger binding affinity. The TPSA is also significantly better for Ligand B. The slightly higher P-gp efflux of Ligand B is a minor concern compared to the other advantages.

Output:
1
2025-04-17 03:33:30,382 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (346.471 and 364.475 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (69.64) is significantly better than Ligand B (86.03). For CNS targets, TPSA should be <= 90, and A is comfortably within that range, while B is approaching the upper limit.

**3. logP:** Both ligands have good logP values (1.999 and 1.834), falling within the optimal 1-3 range.

**4. H-Bond Donors:** Ligand A (2) is slightly higher than Ligand B (1), but both are acceptable (<=5).

**5. H-Bond Acceptors:** Ligand B (8) is higher than Ligand A (3). Both are within the acceptable range of <=10, but A is preferable.

**6. QED:** Ligand A (0.821) has a substantially better QED score than Ligand B (0.568), indicating a more drug-like profile.

**7. DILI:** Ligand B (65.491) has a higher DILI risk than Ligand A (16.479). A lower DILI risk is preferred.

**8. BBB:** Ligand A (63.746) has a slightly better BBB penetration percentile than Ligand B (60.101). While both are below the desirable >70 for CNS targets, A is closer.

**9. Caco-2 Permeability:** Ligand A (-4.921) shows better Caco-2 permeability than Ligand B (-5.058), although both are negative values indicating poor permeability.

**10. Aqueous Solubility:** Ligand A (-3.081) has better aqueous solubility than Ligand B (-1.958), although both are negative values indicating poor solubility.

**11. hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.271 and 0.156).

**12. Microsomal Clearance:** Ligand A (6.615) has a significantly lower microsomal clearance than Ligand B (35.794), suggesting better metabolic stability.

**13. In vitro Half-Life:** Ligand A (19.201) has a longer in vitro half-life than Ligand B (23.033).

**14. P-gp Efflux:** Ligand A (0.087) has lower P-gp efflux liability than Ligand B (0.176), which is beneficial for CNS exposure.

**15. Binding Affinity:** Ligand A (-8.9 kcal/mol) has a significantly stronger binding affinity than Ligand B (-6.8 kcal/mol). This >1.5 kcal/mol difference is a major advantage, potentially outweighing some ADME drawbacks.

**Overall Assessment:**

Ligand A is superior to Ligand B across most critical parameters. It has a better QED, lower DILI risk, better BBB penetration (though still suboptimal), better metabolic stability (lower Cl_mic, longer t1/2), lower P-gp efflux, and *significantly* stronger binding affinity. While both have issues with Caco-2 permeability and solubility, the strong affinity of Ligand A makes it a more promising starting point for optimization.

Output:
0
2025-04-17 03:33:30,382 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (362.461 and 341.455 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (58.64) is better than Ligand B (54.34). Both are below the 90 A^2 threshold desirable for CNS targets.

**3. logP:** Both ligands have good logP values (2.979 and 2.59), falling within the optimal 1-3 range.

**4. H-Bond Donors:** Both have 1 HBD, which is acceptable.

**5. H-Bond Acceptors:** Both have 3 HBA, which is acceptable.

**6. QED:** Both ligands have good QED scores (0.686 and 0.895), indicating drug-like properties. Ligand B is slightly better.

**7. DILI:** Ligand A (38.542) has a slightly higher DILI risk than Ligand B (26.095), but both are below the concerning 40 threshold.

**8. BBB:** Ligand A (88.29) has significantly better BBB penetration potential than Ligand B (65.607). This is a *critical* factor for a CNS target like DRD2.

**9. Caco-2 Permeability:** Ligand A (-4.362) has better Caco-2 permeability than Ligand B (-4.923).

**10. Aqueous Solubility:** Ligand A (-2.766) has better aqueous solubility than Ligand B (-3.134).

**11. hERG Inhibition:** Ligand A (0.696) has a slightly higher hERG risk than Ligand B (0.39), but both are relatively low.

**12. Microsomal Clearance:** Ligand B (25.281) exhibits lower microsomal clearance than Ligand A (43.78), suggesting better metabolic stability.

**13. In vitro Half-Life:** Ligand B (7.055) has a significantly longer in vitro half-life than Ligand A (1.677). This is a major advantage.

**14. P-gp Efflux:** Ligand A (0.22) has lower P-gp efflux liability than Ligand B (0.103), which is favorable for CNS penetration.

**15. Binding Affinity:** Ligand B (-8.9 kcal/mol) has a substantially stronger binding affinity than Ligand A (-7.4 kcal/mol). This difference of 1.5 kcal/mol is significant and can outweigh some ADME drawbacks.

**Overall Assessment:**

While Ligand B has better metabolic stability (lower Cl_mic, longer t1/2) and a significantly stronger binding affinity, Ligand A has a better BBB score and P-gp efflux. For a CNS target like DRD2, the BBB penetration is paramount. However, the 1.5 kcal/mol difference in binding affinity is substantial. Considering the balance, the stronger affinity of Ligand B, coupled with acceptable BBB penetration, makes it the more promising candidate. The longer half-life is also a significant benefit.

Output:
1
2025-04-17 03:33:30,382 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (350.5 and 389.5 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (78.43) is significantly better than Ligand B (88.4), being closer to the desirable <90 for CNS targets.

**logP:** Ligand A (2.683) is optimal (1-3), while Ligand B (0.975) is slightly low, potentially hindering permeation.

**H-Bond Donors/Acceptors:** Ligand A (HBD=3, HBA=3) is better balanced. Ligand B (HBD=0, HBA=7) has a lower number of donors, which isn't necessarily bad, but a higher number of acceptors. Both are within acceptable limits.

**QED:** Both ligands have similar and acceptable QED values (0.645 and 0.691, respectively).

**DILI:** Ligand A (13.3) has a much lower DILI risk than Ligand B (55.021), indicating a safer profile.

**BBB:** Ligand B (68.554) has a better BBB penetration percentile than Ligand A (57.542), but both are below the desirable >70 for CNS targets.

**Caco-2 Permeability:** Ligand A (-4.691) has a more negative Caco-2 value, suggesting poorer permeability than Ligand B (-5.242). However, these values are on a strange scale and hard to interpret without knowing the units.

**Aqueous Solubility:** Both ligands have similar and poor aqueous solubility (-2.487 and -2.526).

**hERG:** Both ligands have very low hERG inhibition risk (0.137 and 0.106).

**Microsomal Clearance:** Ligand A (23.826) has lower microsomal clearance than Ligand B (37.663), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (-18.827) has a much longer in vitro half-life than Ligand B (-57.593), which is a significant advantage.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.045 and 0.038).

**Binding Affinity:** Ligand B (-7.3) has a slightly better binding affinity than Ligand A (-8.2). However, the difference is only 0.9 kcal/mol, which is not substantial enough to outweigh the other ADME deficiencies of Ligand B.

**Overall Assessment:**

Ligand A is the more promising candidate. While Ligand B has slightly better binding affinity and BBB penetration, Ligand A excels in crucial areas like DILI risk, metabolic stability (lower Cl_mic, longer t1/2), and TPSA. The lower logP of Ligand B is also a concern. Given the GPCR-specific priorities, the combination of acceptable TPSA, lower DILI, better metabolic stability, and a reasonably good binding affinity makes Ligand A the better choice.

Output:
1
2025-04-17 03:33:30,383 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (356.438 and 386.949 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (78.87) is better than Ligand B (57.58), both are below the 90 A^2 threshold desirable for CNS targets.

**logP:** Both ligands have acceptable logP values (1.019 and 1.838), falling within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A (HBD=2, HBA=4) is slightly better than Ligand B (HBD=1, HBA=6) in terms of balancing solubility and permeability.

**QED:** Both ligands have good QED scores (0.788 and 0.838), indicating drug-like properties.

**DILI:** Both ligands have low DILI risk (23.769 and 21.908), which is favorable.

**BBB:** Ligand A (74.176) has a slightly better BBB percentile than Ligand B (70.415), both are reasonably good for a CNS target, but >70 is preferred.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.705 and -4.846), which is unusual and suggests poor permeability. This is a significant concern.

**Aqueous Solubility:** Both ligands have negative solubility values (-1.63 and -3.053), indicating very poor aqueous solubility. This is a major drawback.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.315 and 0.477).

**Microsomal Clearance:** Ligand A (-6.212) has significantly lower (better) microsomal clearance than Ligand B (-0.348), indicating better metabolic stability.

**In vitro Half-Life:** Ligand A (7.505) has a better in vitro half-life than Ligand B (33.458), suggesting a longer duration of action.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.042 and 0.06), which is excellent for CNS penetration.

**Binding Affinity:** Ligand A (-8.2 kcal/mol) has a significantly stronger binding affinity than Ligand B (-6.2 kcal/mol). This is a substantial advantage.

**Overall Assessment:**

Despite the poor Caco-2 and solubility values for both compounds, Ligand A is the stronger candidate. The significantly better binding affinity (-8.2 vs -6.2 kcal/mol) is a major advantage, and it's coupled with better metabolic stability (lower Cl_mic) and a slightly better BBB score. The poor solubility and permeability would need to be addressed through formulation strategies or further chemical modifications, but the potency and pharmacokinetic properties of Ligand A make it more promising.

Output:
1
2025-04-17 03:33:30,383 - INFO - Reasoning:

Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (414.348 Da) is slightly higher than Ligand B (355.435 Da), but both are acceptable.

**2. TPSA:** Ligand A (72.28) is excellent, falling well below the 90 A^2 threshold for CNS targets. Ligand B (105.76) is still reasonable but less optimal, being closer to the 140 A^2 limit for oral absorption.

**3. logP:** Ligand A (2.952) is within the optimal range (1-3). Ligand B (0.845) is a bit low, potentially hindering membrane permeability.

**4. H-Bond Donors:** Ligand A (1) is good. Ligand B (3) is acceptable but slightly higher.

**5. H-Bond Acceptors:** Ligand A (6) is good. Ligand B (5) is also good.

**6. QED:** Both ligands have acceptable QED values (Ligand A: 0.82, Ligand B: 0.568), suggesting reasonable drug-likeness.

**7. DILI:** Both ligands have relatively low DILI risk (Ligand A: 27.453, Ligand B: 37.611), which is positive.

**8. BBB:** This is a critical parameter for a CNS target like DRD2. Ligand A has a significantly better BBB penetration percentile (77.976) compared to Ligand B (44.668).

**9. Caco-2 Permeability:** Ligand A (-4.927) shows poor permeability, while Ligand B (-5.467) is also poor. This is a concern for both.

**10. Aqueous Solubility:** Ligand A (-2.607) and Ligand B (-1.569) both have poor aqueous solubility.

**11. hERG Inhibition:** Both ligands show low hERG inhibition risk (Ligand A: 0.309, Ligand B: 0.122).

**12. Microsomal Clearance:** Ligand B (-12.832) has significantly lower (better) microsomal clearance than Ligand A (32.383), indicating better metabolic stability.

**13. In vitro Half-Life:** Ligand A (14.508) has a longer half-life than Ligand B (5.789).

**14. P-gp Efflux:** Both ligands have low P-gp efflux liability (Ligand A: 0.038, Ligand B: 0.022).

**15. Binding Affinity:** Ligand B (-7.8 kcal/mol) has a slightly better binding affinity than Ligand A (-7.4 kcal/mol). This 0.4 kcal/mol difference is significant, but needs to be weighed against other factors.

**Overall Assessment:**

Ligand A excels in BBB penetration and has a longer half-life. However, it suffers from poor Caco-2 permeability and higher microsomal clearance. Ligand B has better metabolic stability and slightly better binding affinity, but its BBB penetration is significantly lower, which is a major drawback for a CNS target. Considering the GPCR-specific priorities, particularly BBB, Ligand A is the more promising candidate *despite* its permeability and clearance issues. The superior BBB penetration is likely to result in higher CNS exposure, which is crucial for efficacy at the DRD2 receptor. The slight affinity difference can potentially be optimized in subsequent iterations of drug design.

Output:
1
2025-04-17 03:33:30,384 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (362.821 Da) and Ligand B (344.499 Da) are both acceptable.

**TPSA:** Ligand A (93.36) is slightly above the optimal <90 for CNS targets, but still reasonable. Ligand B (40.62) is excellent, well below the threshold.

**logP:** Ligand A (0.646) is a bit low, potentially hindering permeability. Ligand B (2.92) is nearly ideal.

**H-Bond Donors/Acceptors:** Ligand A has 3 HBD and 5 HBA, acceptable. Ligand B has 0 HBD and 2 HBA, also acceptable.

**QED:** Both ligands have good QED scores (A: 0.694, B: 0.769), indicating drug-like properties.

**DILI:** Ligand A (76.89) has a moderately high DILI risk. Ligand B (10.702) has a very low DILI risk, a significant advantage.

**BBB:** Ligand A (50.523) has a moderate BBB penetration, which is concerning for a CNS target. Ligand B (85.459) has excellent BBB penetration, a major positive.

**Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and suggests a potential issue with the data or modeling. However, the magnitude is similar, so it doesn't strongly differentiate them.

**Aqueous Solubility:** Both ligands have negative solubility values, which is also unusual. Again, the values are similar.

**hERG:** Both ligands have low hERG inhibition risk (A: 0.584, B: 0.688).

**Microsomal Clearance:** Ligand A (-5.076) has a negative clearance, which is not physically possible and indicates a data issue. Ligand B (57.055) has a moderate clearance.

**In vitro Half-Life:** Ligand A (-33.863) has a negative half-life, which is not physically possible and indicates a data issue. Ligand B (1.918) has a short half-life, which is a potential drawback.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (A: 0.043, B: 0.229), which is good for CNS penetration.

**Binding Affinity:** Both ligands have similar, strong binding affinities (A: -8.9 kcal/mol, B: -8.8 kcal/mol). The difference is negligible.

**Conclusion:**

Despite similar binding affinities, Ligand B is significantly more promising. It has superior BBB penetration, a much lower DILI risk, a better logP value, and a more favorable TPSA. While its half-life is shorter and clearance is higher than ideal, the issues with Ligand A's clearance and half-life (negative values) are far more concerning and suggest data quality problems. The better ADME profile of Ligand B outweighs the slight difference in binding affinity.

Output:
1
2025-04-17 03:33:30,384 - INFO - Reasoning:

Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (355.479 and 368.543 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (90.9) is better than Ligand B (78.43). Both are below the 90 A^2 threshold desirable for CNS targets.

**3. logP:** Ligand B (3.258) is optimal (1-3), while Ligand A (0.127) is significantly low, potentially hindering membrane permeability.

**4. H-Bond Donors:** Both ligands have 3 HBD, which is acceptable (<=5).

**5. H-Bond Acceptors:** Ligand A has 5 HBA, and Ligand B has 4. Both are within the acceptable range (<=10).

**6. QED:** Both ligands have similar QED values (0.576 and 0.555), indicating good drug-like properties.

**7. DILI:** Ligand A (5.933) has a much lower DILI risk than Ligand B (38.387). This is a significant advantage for Ligand A.

**8. BBB:** Ligand B (39.162) has a better BBB penetration percentile than Ligand A (23.265), but both are below the desirable >70% for CNS targets.

**9. Caco-2 Permeability:** Ligand A (-5.341) shows poor Caco-2 permeability, while Ligand B (-5.046) is also poor, but slightly better.

**10. Aqueous Solubility:** Ligand A (-0.263) has slightly better solubility than Ligand B (-3.024).

**11. hERG Inhibition:** Ligand A (0.106) has a much lower hERG inhibition liability than Ligand B (0.687). This is a critical advantage for Ligand A.

**12. Microsomal Clearance:** Ligand A (-8.299) has significantly lower microsomal clearance (better metabolic stability) than Ligand B (54.788).

**13. In vitro Half-Life:** Ligand B (49.749) has a longer in vitro half-life than Ligand A (12.77).

**14. P-gp Efflux:** Ligand A (0.008) has much lower P-gp efflux liability than Ligand B (0.659). This is a significant advantage for CNS penetration.

**15. Binding Affinity:** Ligand B (-8.0) has a slightly better binding affinity than Ligand A (-7.4), but the difference is less than 1.5 kcal/mol and can be compensated for by other factors.

**Overall Assessment:**

While Ligand B has slightly better binding affinity and half-life, Ligand A is clearly superior due to its significantly better ADME-Tox profile. Specifically, its lower DILI risk, hERG inhibition, P-gp efflux, and microsomal clearance are crucial advantages. The low logP of Ligand A is a concern, but the other benefits outweigh this drawback, especially considering the importance of a clean safety profile for CNS drugs. The slightly better BBB of Ligand B is not enough to overcome the other issues.

Output:
0
2025-04-17 03:33:30,384 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (380.901 Da) is slightly higher than Ligand B (345.403 Da), but both are acceptable.

**2. TPSA:** Ligand A (75.19) is better than Ligand B (80.56) as it is closer to the ideal <90 for CNS targets.

**3. logP:** Ligand A (2.596) is optimal (1-3). Ligand B (0.082) is quite low, potentially hindering membrane permeability.

**4. H-Bond Donors:** Ligand A (1) is good. Ligand B (0) is also acceptable.

**5. H-Bond Acceptors:** Ligand A (5) is good. Ligand B (6) is also acceptable.

**6. QED:** Both ligands have similar, good QED values (A: 0.749, B: 0.758).

**7. DILI:** Both ligands have acceptable DILI risk (A: 54.75, B: 50.33), both below the 60 threshold.

**8. BBB:** Ligand B (65.995) has a significantly better BBB penetration percentile than Ligand A (39.822). This is a crucial factor for a CNS target like DRD2.

**9. Caco-2 Permeability:** Ligand A (-5.012) is better than Ligand B (-4.619), indicating better intestinal absorption.

**10. Aqueous Solubility:** Ligand A (-2.38) is better than Ligand B (-1.26), indicating better solubility.

**11. hERG Inhibition:** Both ligands have very low hERG inhibition risk (A: 0.064, B: 0.187).

**12. Microsomal Clearance:** Ligand B (26.296) has a lower microsomal clearance than Ligand A (44.021), suggesting better metabolic stability.

**13. In vitro Half-Life:** Ligand A (26.071) has a longer half-life than Ligand B (8.246).

**14. P-gp Efflux:** Both ligands have very low P-gp efflux liability (A: 0.042, B: 0.104).

**15. Binding Affinity:** Ligand B (-8.7 kcal/mol) has a slightly better binding affinity than Ligand A (-8.3 kcal/mol). While the difference is not huge, it's a positive for Ligand B.

**Overall Assessment:**

Ligand B excels in BBB penetration and has a slightly better binding affinity and metabolic stability. However, its low logP is a significant concern. Ligand A has a better logP, solubility, Caco-2 permeability, and half-life, but its BBB penetration is considerably lower.

Considering the GPCR-specific priorities, BBB is paramount for a CNS target. While a low logP can be addressed through prodrug strategies or formulation, poor BBB penetration is much harder to overcome. The slightly stronger binding affinity of Ligand B, combined with its better BBB, outweighs the logP concern.

Output:
1
2025-04-17 03:33:30,385 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (349.475 and 352.431 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (72.88) is significantly better than Ligand B (87.15). For CNS targets, we want TPSA <= 90, and A is comfortably within that range, while B is approaching the upper limit.

**logP:** Both ligands have acceptable logP values (0.459 and 0.55), falling within the 1-3 range. However, they are on the lower end, which *could* indicate permeability issues, but isn't a major concern at this stage.

**H-Bond Donors/Acceptors:** Ligand A (2 HBD, 4 HBA) is slightly better than Ligand B (1 HBD, 5 HBA) in terms of balancing solubility and permeability. Both are within acceptable limits.

**QED:** Both ligands have good QED scores (0.593 and 0.73), indicating a generally drug-like profile.

**DILI:** Ligand A (4.149%) has a much lower DILI risk than Ligand B (37.03%). This is a significant advantage for A.

**BBB:** Ligand A (48.313%) has a better, though still not great, BBB penetration score than Ligand B (57.193%). Both are below the desirable >70% for CNS targets, but A is closer.

**Caco-2 Permeability:** Ligand A (-5.065) has a worse Caco-2 permeability than Ligand B (-4.413). Lower values indicate lower permeability.

**Aqueous Solubility:** Ligand A (-0.958) has a slightly better aqueous solubility than Ligand B (-1.603).

**hERG:** Ligand A (0.447) has a lower hERG inhibition liability than Ligand B (0.157), indicating a lower risk of cardiotoxicity.

**Microsomal Clearance:** Ligand A (-5.963) has a significantly lower (better) microsomal clearance than Ligand B (40.565). This suggests greater metabolic stability for Ligand A.

**In vitro Half-Life:** Ligand A (15.648 hours) has a much longer in vitro half-life than Ligand B (-0.597 hours). This is a substantial advantage for A.

**P-gp Efflux:** Ligand A (0.014) has a much lower P-gp efflux liability than Ligand B (0.053). This is crucial for CNS penetration, favoring A.

**Binding Affinity:** Ligand B (-8.3 kcal/mol) has a slightly better binding affinity than Ligand A (-7.3 kcal/mol). This is a 0.9 kcal/mol difference, which is significant, but needs to be weighed against the other factors.

**Overall Assessment:**

While Ligand B has a slightly better binding affinity, Ligand A is superior in almost all other critical ADME-Tox properties, especially those prioritized for GPCRs targeting the CNS. Ligand A has a much better safety profile (DILI, hERG), better metabolic stability (Cl_mic, t1/2), lower P-gp efflux, and a more favorable TPSA. The slightly lower BBB penetration of A is a concern, but the other advantages likely outweigh this. The difference in binding affinity (0.9 kcal/mol) is not enough to overcome the substantial ADME advantages of Ligand A.

Output:
0
2025-04-17 03:33:30,385 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B based on the provided guidelines, prioritizing GPCR-specific properties (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands fall within the ideal range (200-500 Da). Ligand A (352.475 Da) is slightly lower, which could be beneficial for permeability.

**TPSA:** Both ligands have TPSA values below the 90 A^2 threshold desirable for CNS targets. Ligand B (83.9) is slightly lower than Ligand A (89.87), which is a small advantage.

**logP:** Both ligands have logP values within the optimal range (1-3). Ligand A (1.196) is closer to the lower end, while Ligand B (2.698) is more centered.

**H-Bond Donors/Acceptors:** Ligand A has 3 HBD and 4 HBA, while Ligand B has 1 HBD and 6 HBA. Both are within acceptable limits (<=5 HBD and <=10 HBA).

**QED:** Both ligands have similar QED values (0.693 and 0.68), indicating good drug-like properties.

**DILI:** Ligand A (10.934) has a significantly lower DILI risk than Ligand B (57.774). This is a major advantage for Ligand A.

**BBB:** Ligand B (83.715) has a considerably higher BBB penetration percentile than Ligand A (52.966). Given that DRD2 is a CNS target, this is a crucial advantage for Ligand B.

**Caco-2 Permeability:** Ligand A (-4.971) shows poor Caco-2 permeability, while Ligand B (-5.177) is similarly poor.

**Aqueous Solubility:** Both ligands have negative solubility values, indicating poor aqueous solubility. Ligand A (-2.067) is slightly better than Ligand B (-2.897).

**hERG Inhibition:** Both ligands have low hERG inhibition liability (0.144 and 0.565).

**Microsomal Clearance:** Ligand A (3.338) has a significantly lower microsomal clearance than Ligand B (66.402), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (11.816 hours) has a shorter half-life than Ligand B (32.451 hours), which is less desirable.

**P-gp Efflux:** Ligand A (0.012) has a much lower P-gp efflux liability than Ligand B (0.105), which is beneficial for CNS exposure.

**Binding Affinity:** Ligand B (-8.2 kcal/mol) has a slightly stronger binding affinity than Ligand A (-7.3 kcal/mol). This 0.9 kcal/mol difference is significant, potentially outweighing some ADME drawbacks.

**Overall Assessment:**

Ligand B excels in BBB penetration and binding affinity, which are critical for a CNS GPCR target like DRD2. However, it suffers from higher DILI risk and P-gp efflux. Ligand A has a better safety profile (lower DILI, lower P-gp efflux) and metabolic stability, but its BBB penetration is significantly lower.

The stronger binding affinity of Ligand B, combined with its superior BBB penetration, are the most important factors. While the DILI risk is a concern, it might be manageable with further optimization. The lower P-gp efflux is also a positive.

Output:
1
2025-04-17 03:33:30,385 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (338.37 and 349.39 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (115.16) is slightly above the optimal <90 for CNS targets, while Ligand B (105.56) is closer to the ideal range.

**logP:** Ligand A (3.561) is within the optimal 1-3 range. Ligand B (-1.106) is significantly lower, which could hinder membrane permeability and CNS penetration.

**H-Bond Donors/Acceptors:** Both ligands have acceptable HBD counts (2). Ligand B has a higher HBA count (6) compared to Ligand A (3), but both are within the acceptable limit of 10.

**QED:** Both ligands have reasonable QED values (0.493 and 0.678), suggesting drug-like properties. Ligand B is better here.

**DILI:** Both ligands have similar DILI risk (65.72 and 62.23), which is acceptable (below 60 is preferred, but these are not alarming).

**BBB:** Ligand A (48.895) has a moderate BBB penetration, while Ligand B (27.336) is quite low. This is a significant drawback for a CNS target like DRD2.

**Caco-2 Permeability:** Both have negative Caco-2 values (-5.322 and -5.552), which is unusual and suggests poor permeability. However, these values are on a log scale and negative values are not uncommon. The absolute values are similar.

**Aqueous Solubility:** Both have negative solubility values (-3.209 and -0.572), indicating poor aqueous solubility. Ligand B is slightly better.

**hERG:** Both ligands have very low hERG inhibition liability (0.028 and 0.071), which is excellent.

**Microsomal Clearance:** Ligand A (-4.341) has a lower (better) microsomal clearance than Ligand B (-16.642), indicating greater metabolic stability.

**In vitro Half-Life:** Ligand A (7.749) has a shorter half-life than Ligand B (22.785).

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.019 and 0.024), which is favorable for CNS penetration.

**Binding Affinity:** Ligand A (-8.6 kcal/mol) has a significantly stronger binding affinity than Ligand B (-7.3 kcal/mol). This is a substantial advantage (1.3 kcal/mol difference).

**Conclusion:**

Considering the GPCR-specific priorities, Ligand A is the more promising candidate. Its significantly higher binding affinity outweighs its slightly higher TPSA and shorter half-life. The major drawback for Ligand B is its poor BBB penetration and low logP, which are critical for CNS drug development. While both have solubility issues, the stronger binding and better metabolic stability of Ligand A make it the better choice.

Output:
0
2025-04-17 03:33:30,386 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (340.423 and 351.447 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (82.19) is better than Ligand B (78.95) as it is closer to the <90 target for CNS penetration. Both are acceptable.

**3. logP:** Ligand A (3.27) is optimal (1-3), while Ligand B (0.387) is quite low, potentially hindering permeation. This is a significant disadvantage for Ligand B.

**4. H-Bond Donors:** Ligand A (3) is acceptable, while Ligand B (1) is also good.

**5. H-Bond Acceptors:** Ligand A (2) is acceptable, and Ligand B (4) is also within the limit of 10.

**6. QED:** Both ligands have similar QED values (0.755 and 0.741), indicating good drug-like properties.

**7. DILI:** Ligand A (76.735) has a higher DILI risk than Ligand B (26.095). This is a negative for Ligand A.

**8. BBB:** Ligand A (46.724) has a slightly better BBB penetration percentile than Ligand B (32.648), but both are below the desirable >70 for CNS targets.

**9. Caco-2 Permeability:** Ligand A (-5.54) has a negative Caco-2 value, suggesting poor permeability, while Ligand B (-4.677) is also poor, but less so.

**10. Aqueous Solubility:** Ligand A (-3.941) and Ligand B (-1.691) both have poor solubility.

**11. hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.085 and 0.091).

**12. Microsomal Clearance:** Ligand A (4.114) has a lower (better) microsomal clearance than Ligand B (23.716), indicating better metabolic stability.

**13. In vitro Half-Life:** Ligand B (11.159) has a significantly longer half-life than Ligand A (-1.33).

**14. P-gp Efflux:** Ligand A (0.135) has lower P-gp efflux than Ligand B (0.009), which is favorable for CNS exposure.

**15. Binding Affinity:** Ligand A (-8.9 kcal/mol) has a *much* stronger binding affinity than Ligand B (0.0 kcal/mol). This is a decisive advantage for Ligand A.

**Overall Assessment:**

Despite the higher DILI risk and poorer BBB penetration for Ligand A, its significantly superior binding affinity (-8.9 vs 0.0 kcal/mol) and lower P-gp efflux outweigh the drawbacks, especially considering the low logP of Ligand B. The low logP of Ligand B is a major concern for CNS penetration, even if its DILI risk is lower. The better metabolic stability of Ligand A is also a plus. While both have solubility and permeability issues, the binding affinity is the most important factor here.

Output:
1
2025-04-17 03:33:30,386 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 drug candidates, considering the provided guidelines and GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (350.365 and 345.399 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (71.34) is significantly better than Ligand B (91.76). For CNS targets, we want TPSA <= 90, so Ligand A is preferable.

**3. logP:** Ligand A (2.482) is optimal (1-3), while Ligand B (0.933) is slightly low, potentially hindering permeation.

**4. H-Bond Donors:** Both have 2 HBD, which is within the acceptable limit of <=5.

**5. H-Bond Acceptors:** Ligand A has 3 HBA, and Ligand B has 5. Both are acceptable (<=10).

**6. QED:** Both ligands have good QED values (0.768 and 0.85), indicating drug-likeness.

**7. DILI:** Ligand A (52.113) has a lower DILI risk than Ligand B (41.877), indicating a better safety profile.

**8. BBB:** Ligand A (77.976) has a significantly better BBB penetration percentile than Ligand B (54.634).  For a CNS target like DRD2, >70 is desirable, and Ligand A is closer to this threshold.

**9. Caco-2 Permeability:** Ligand A (-4.664) and Ligand B (-4.875) both have negative values, indicating poor permeability.

**10. Aqueous Solubility:** Both have negative solubility values, indicating poor solubility.

**11. hERG Inhibition:** Ligand A (0.814) has a slightly higher hERG risk than Ligand B (0.131). This is a point in favor of Ligand B.

**12. Microsomal Clearance:** Ligand A (35.04) has a lower (better) microsomal clearance than Ligand B (7.476), suggesting greater metabolic stability.

**13. In vitro Half-Life:** Ligand A (42.447) has a much longer half-life than Ligand B (-14.252), which is a significant advantage.

**14. P-gp Efflux:** Ligand A (0.366) has lower P-gp efflux liability than Ligand B (0.019), which is favorable for CNS penetration.

**15. Binding Affinity:** Ligand A (-9.2 kcal/mol) has a significantly stronger binding affinity than Ligand B (-7.5 kcal/mol). This is a crucial advantage, as a >1.5 kcal/mol difference can outweigh other drawbacks.

**Overall Assessment:**

Considering the GPCR-specific priorities, Ligand A is the stronger candidate. It has superior BBB penetration, better metabolic stability (lower Cl_mic, longer t1/2), lower P-gp efflux, and, most importantly, significantly higher binding affinity. While Ligand B has a slightly lower hERG risk, the substantial advantages of Ligand A in terms of CNS penetration and potency outweigh this concern. The poor Caco-2 and solubility of both are concerning, but can be addressed with formulation strategies.

Output:
1
2025-04-17 03:33:30,387 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (362.767 Da and 351.466 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Both ligands have TPSA values (58.95 and 58.36) below the 90 A^2 threshold desirable for CNS targets, which is excellent.

**3. logP:** Ligand A (4.126) is slightly above the optimal range (1-3), potentially leading to solubility issues. Ligand B (2.945) is within the optimal range.

**4. H-Bond Donors:** Ligand A (2) and Ligand B (1) both meet the HBD criteria (<=5).

**5. H-Bond Acceptors:** Ligand A (3) and Ligand B (4) both meet the HBA criteria (<=10).

**6. QED:** Both ligands have QED values (0.733 and 0.696) above 0.5, indicating good drug-like properties.

**7. DILI:** Ligand A (96.859) has a very high DILI risk, which is a significant concern. Ligand B (19.969) has a low DILI risk, a major advantage.

**8. BBB:** Ligand A (66.305) has a moderate BBB penetration, while Ligand B (78.79) has a good BBB penetration. Both are acceptable, but B is better.

**9. Caco-2:** Both have negative Caco-2 values, which is unusual and suggests poor permeability. However, the scale isn't specified, so it's hard to interpret.

**10. Solubility:** Both have negative solubility values, which is also unusual. Again, the scale is unknown, making interpretation difficult.

**11. hERG:** Ligand A (0.424) has a slightly elevated hERG risk, while Ligand B (0.718) is higher. This isn't a major concern for either, but B is slightly better.

**12. Cl_mic:** Ligand A (44.482) has a lower microsomal clearance than Ligand B (51.681), suggesting better metabolic stability.

**13. t1/2:** Ligand A (78.026) has a longer in vitro half-life than Ligand B (-6.967). The negative value for B is concerning and likely an error or indicates very rapid degradation.

**14. Pgp:** Ligand A (0.197) has lower P-gp efflux liability than Ligand B (0.344), which is favorable for CNS penetration.

**15. Binding Affinity:** Ligand B (-7.4 kcal/mol) has a significantly stronger binding affinity than Ligand A (-10.3 kcal/mol). This is a substantial advantage.

**Overall Assessment:**

While Ligand A has better metabolic stability (Cl_mic and t1/2) and Pgp efflux, its extremely high DILI risk is a major red flag. The slightly better BBB penetration of Ligand B, combined with its significantly stronger binding affinity and much lower DILI risk, outweighs the slightly less favorable metabolic properties. The negative values for Caco-2 and solubility are concerning for both, but the affinity difference is significant. Given the GPCR-specific priorities, the stronger affinity and lower toxicity of Ligand B make it the more promising candidate.

Output:
1
2025-04-17 03:33:30,387 - INFO - Batch 39 complete. Total preferences: 624
2025-04-17 03:33:30,387 - INFO - Processing batch 40/512...
2025-04-17 03:34:10,581 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (355.395 and 345.443 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (118.82) is better than Ligand B (73.74) as it is closer to the ideal <90 for CNS targets. Ligand B is excellent.

**logP:** Both ligands have good logP values (1.026 and 1.234), falling within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A has 2 HBD and 7 HBA, while Ligand B has 1 HBD and 4 HBA. Both are within acceptable limits (<=5 HBD and <=10 HBA).

**QED:** Both ligands have good QED scores (0.749 and 0.871), indicating good drug-like properties.

**DILI:** Ligand A has a DILI risk of 60.333, which is borderline high. Ligand B has a much lower DILI risk (19.426), a significant advantage.

**BBB:** Ligand A has a very good BBB penetration percentile (91.508), exceeding the desirable >70 threshold. Ligand B's BBB penetration (55.487) is considerably lower, a major drawback for a CNS target.

**Caco-2 Permeability:** Both have negative Caco-2 values, indicating poor permeability. This is unusual and could indicate issues with the prediction method or the molecules themselves.

**Aqueous Solubility:** Both ligands have negative solubility values, again indicating poor solubility.

**hERG:** Both ligands have very low hERG inhibition liability (0.091 and 0.225), which is excellent.

**Microsomal Clearance:** Ligand A has a negative Cl_mic (-11.44), which is highly favorable (lower is better). Ligand B has a positive Cl_mic (13.321), indicating faster metabolism and lower stability.

**In vitro Half-Life:** Ligand A has a half-life of 4.61 hours, while Ligand B has a half-life of -10.098 hours. Again, the negative value for Ligand B is concerning.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.006 and 0.036), which is excellent.

**Binding Affinity:** Ligand B (-8.1 kcal/mol) has a slightly better binding affinity than Ligand A (-7.2 kcal/mol). The difference is 0.9 kcal/mol, which is not huge, but noticeable.

**Overall Assessment:**

Ligand A excels in BBB penetration and metabolic stability (negative Cl_mic). However, its DILI risk is borderline high, and its solubility and Caco-2 permeability are poor. Ligand B has a slightly better binding affinity and a much lower DILI risk, but significantly worse BBB penetration and metabolic stability.

Given the GPCR-specific priorities, BBB penetration is crucial for a CNS target like DRD2. While Ligand B has slightly better affinity, Ligand A's superior BBB penetration and metabolic stability are more important. The DILI risk of Ligand A is a concern but could potentially be addressed through further structural modifications. The poor solubility and permeability of both compounds are concerning and would need to be addressed regardless of which is chosen.

Output:
1
2025-04-17 03:34:10,582 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (345.403 and 354.491 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (101.22) is better than Ligand B (67.87), both are below the 90 A^2 threshold for CNS targets.

**logP:** Both ligands have acceptable logP values (1.291 and 2.114, respectively), falling within the 1-3 range. Ligand B is slightly higher, potentially aiding membrane permeability.

**H-Bond Donors/Acceptors:** Both have 1 HBD, which is good. Ligand A has 6 HBA, while Ligand B has 4. Both are within the acceptable limit of 10.

**QED:** Both ligands have good QED scores (0.811 and 0.76), indicating good drug-like properties.

**DILI:** Ligand A (54.207) has a higher DILI risk than Ligand B (7.794). This is a significant drawback for Ligand A.

**BBB:** Both ligands have good BBB penetration (64.25 and 69.523), but Ligand B is slightly better. Both are above the 70% desirable threshold for CNS targets.

**Caco-2 Permeability:** Ligand A (-5.024) has poor Caco-2 permeability, while Ligand B (-4.544) is also poor, but slightly better.

**Aqueous Solubility:** Both ligands have poor aqueous solubility (-0.868 and -1.711).

**hERG Inhibition:** Ligand A (0.124) has a lower hERG inhibition risk than Ligand B (0.366), which is favorable.

**Microsomal Clearance:** Ligand A (41.66) has a lower microsomal clearance than Ligand B (7.029), indicating better metabolic stability.

**In vitro Half-Life:** Ligand A (-27.591) has a significantly longer in vitro half-life than Ligand B (5.244). This is a major advantage for Ligand A.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.024 and 0.029).

**Binding Affinity:** Ligand B (-8.0) has a slightly better binding affinity than Ligand A (-7.6). However, the difference is less than 1.5 kcal/mol.

**Overall Assessment:**

Ligand B has a significantly better safety profile (lower DILI) and slightly better binding affinity and Caco-2 permeability. Ligand A has better metabolic stability (lower Cl_mic, longer t1/2) and lower hERG risk. Considering the GPCR-specific priorities, BBB is important, and both ligands meet the threshold. However, the significantly lower DILI risk for Ligand B outweighs the advantages of Ligand A, especially given the relatively small difference in binding affinity.

Output:
1
2025-04-17 03:34:10,582 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (371.384 and 385.957 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (73.2) is better than Ligand B (60.77). Both are below the 90 A^2 threshold desirable for CNS targets, but Ligand A is slightly higher.

**3. logP:** Ligand A (2.222) is within the optimal 1-3 range. Ligand B (3.854) is pushing the upper limit, potentially increasing off-target effects or solubility issues.

**4. H-Bond Donors:** Ligand A (1) is preferable to Ligand B (2). Lower HBD generally improves permeability.

**5. H-Bond Acceptors:** Both ligands have 4 HBA, which is acceptable (<=10).

**6. QED:** Ligand A (0.863) has a significantly better QED score than Ligand B (0.7), indicating a more drug-like profile.

**7. DILI:** Ligand A (55.68) has a higher DILI risk than Ligand B (35.789). This is a negative for Ligand A.

**8. BBB:** Ligand A (81.582) has a much better BBB penetration percentile than Ligand B (61.962). This is *critical* for a CNS target like DRD2.

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 values, which is unusual and suggests poor permeability. However, the magnitude of the negative value is similar.

**10. Aqueous Solubility:** Both ligands have negative solubility values, indicating poor aqueous solubility. Again, the magnitudes are similar.

**11. hERG Inhibition:** Both ligands have low hERG inhibition risk (0.656 and 0.67, respectively).

**12. Microsomal Clearance:** Ligand A (4.112) has a lower microsomal clearance than Ligand B (54.964), suggesting better metabolic stability.

**13. In vitro Half-Life:** Ligand A (-11.308) has a significantly longer in vitro half-life than Ligand B (30.859).

**14. P-gp Efflux:** Ligand A (0.107) has lower P-gp efflux liability than Ligand B (0.808), which is favorable for CNS penetration.

**15. Binding Affinity:** Ligand A (-9.0) has a significantly stronger binding affinity than Ligand B (-0.0). This is a major advantage.

**Overall Assessment:**

Despite Ligand A's slightly higher DILI risk, its superior BBB penetration, metabolic stability (lower Cl_mic, longer t1/2), lower P-gp efflux, and *much* stronger binding affinity outweigh the drawbacks. The affinity difference is substantial (>7 kcal/mol difference), and this is the most important factor for GPCRs. The better QED and lower P-gp efflux also contribute to its favorability. While both have solubility and permeability concerns, the affinity and CNS penetration profile of Ligand A make it the more promising candidate.

Output:
1
2025-04-17 03:34:10,582 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B based on the provided guidelines, prioritizing GPCR-specific properties (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (370.475) is slightly higher than Ligand B (348.531), but both are acceptable.

**TPSA:** Ligand A (93.65) is borderline for CNS targets (<=90), while Ligand B (41.57) is well within the desirable range. This is a significant advantage for Ligand B.

**logP:** Ligand A (0.945) is a bit low, potentially hindering membrane permeability. Ligand B (3.353) is optimal.

**H-Bond Donors/Acceptors:** Both ligands have acceptable HBD (1) and HBA (Ligand A: 7, Ligand B: 3) counts.

**QED:** Both ligands have good QED scores (Ligand A: 0.768, Ligand B: 0.828), indicating drug-like properties.

**DILI:** Ligand A (68.786) has a higher DILI risk than Ligand B (5.157). This is a significant advantage for Ligand B.

**BBB:** Ligand A (48.119) has a moderate BBB penetration, while Ligand B (88.91) is excellent, exceeding the >70% threshold for CNS targets. This is a major advantage for Ligand B.

**Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and suggests a potential issue with the data or modeling. However, the magnitude of negativity is similar.

**Aqueous Solubility:** Both have negative solubility values, again suggesting a potential data issue. The values are similar.

**hERG:** Both ligands have low hERG inhibition risk (Ligand A: 0.173, Ligand B: 0.581).

**Microsomal Clearance:** Ligand A (28.448) and Ligand B (32.177) have similar, relatively low, microsomal clearance values, suggesting reasonable metabolic stability.

**In vitro Half-Life:** Ligand B (15.026) has a significantly longer half-life than Ligand A (4.924), which is desirable.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (Ligand A: 0.083, Ligand B: 0.125), which is good for CNS penetration.

**Binding Affinity:** Ligand B (-7.7 kcal/mol) has a 1.0 kcal/mol stronger binding affinity than Ligand A (-6.7 kcal/mol). This is a substantial difference and a key factor.

**Overall Assessment:**

Ligand B consistently outperforms Ligand A across several critical parameters for a CNS-targeting GPCR ligand. It has a much better BBB score, lower DILI risk, optimal logP, a superior binding affinity, and a longer half-life. While both have questionable solubility and Caco-2 permeability values, the other advantages of Ligand B outweigh these concerns. The lower TPSA of Ligand B is also a significant benefit.

Output:
1
2025-04-17 03:34:10,582 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (384.395 and 354.397 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (49.85) is significantly better than Ligand B (58.64). For CNS targets, we want TPSA <= 90, and A is closer to the optimal range.

**logP:** Both ligands have good logP values (2.021 and 1.238), falling within the 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A (0 HBD, 4 HBA) is slightly better than Ligand B (1 HBD, 3 HBA) in terms of balancing solubility and permeability. Both are within acceptable limits.

**QED:** Both ligands have good QED scores (0.696 and 0.773), indicating good drug-like properties.

**DILI:** Both ligands have acceptable DILI risk (35.983 and 41.334), well below the 60 threshold.

**BBB:** Both ligands exhibit excellent BBB penetration (93.912 and 90.772), which is crucial for a CNS target like DRD2.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.462 and -4.647). This is unusual and suggests a potential issue with intestinal absorption, but the negative values are not directly comparable without knowing the scale.

**Aqueous Solubility:** Both ligands have negative solubility values (-3.401 and -2.753). Again, the scale is unclear, but this suggests potential formulation challenges.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.588 and 0.38), which is favorable.

**Microsomal Clearance:** Ligand A (51.715) has a higher microsomal clearance than Ligand B (7.174), indicating potentially lower metabolic stability.

**In vitro Half-Life:** Ligand B (4.955) has a better in vitro half-life than Ligand A (-26.136).

**P-gp Efflux:** Ligand A (0.054) has a lower P-gp efflux liability than Ligand B (0.154), which is desirable for CNS penetration.

**Binding Affinity:** Both ligands have very similar binding affinities (-8.7 and -8.6 kcal/mol). The difference is negligible.

**Overall Assessment:**

Ligand A has a lower TPSA, lower P-gp efflux, and better solubility (less negative value). However, Ligand B has a better half-life and lower microsomal clearance. The BBB penetration is excellent for both. The binding affinity is almost identical. Given the importance of CNS penetration and the slightly better ADME profile (lower TPSA, lower P-gp efflux) of Ligand A, I would favor it.

Output:
0
2025-04-17 03:34:10,582 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (366.45 & 346.52 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (122.03) is higher than the preferred <90 for CNS targets, while Ligand B (59.07) is excellent. This is a significant advantage for Ligand B.

**logP:** Ligand A (-0.088) is quite low, potentially hindering membrane permeability. Ligand B (4.334) is high, bordering on problematic, but within an acceptable range.

**H-Bond Donors/Acceptors:** Ligand A has 3 HBD and 8 HBA, which are acceptable. Ligand B has 2 HBD and 5 HBA, also acceptable.

**QED:** Both ligands have good QED scores (0.505 and 0.652), indicating good drug-like properties.

**DILI:** Ligand A (62.23) has a higher DILI risk than Ligand B (24.93), indicating a potential liver toxicity concern.

**BBB:** This is crucial for a CNS target. Ligand A has a BBB percentile of 24.39, which is poor. Ligand B has a very good BBB percentile of 84.14, a major advantage.

**Caco-2 Permeability:** Ligand A (-6.294) shows poor permeability. Ligand B (-4.845) is also not great, but better than Ligand A.

**Aqueous Solubility:** Ligand A (-1.101) has poor solubility. Ligand B (-4.483) also has poor solubility.

**hERG Inhibition:** Ligand A (0.064) has very low hERG risk, which is excellent. Ligand B (0.911) has a slightly elevated hERG risk, but still within a manageable range.

**Microsomal Clearance:** Ligand A (15.15) has lower clearance, suggesting better metabolic stability than Ligand B (86.61).

**In vitro Half-Life:** Ligand B (36.20) has a significantly longer half-life than Ligand A (10.6), a positive attribute.

**P-gp Efflux:** Ligand A (0.047) shows low P-gp efflux, which is good for CNS penetration. Ligand B (0.298) shows moderate P-gp efflux, which is less desirable.

**Binding Affinity:** Ligand B (-8.5 kcal/mol) has a stronger binding affinity than Ligand A (-7.5 kcal/mol), a 1 kcal/mol difference which is significant.

**Overall Assessment:**

Ligand B is the stronger candidate. While its logP is a bit high and solubility is poor, its excellent BBB penetration, superior binding affinity, longer half-life, and lower DILI risk outweigh these drawbacks. Ligand A's poor BBB penetration and low logP are significant liabilities for a CNS-targeting drug. The TPSA difference is also a key factor favoring Ligand B.

Output:
1
2025-04-17 03:34:10,583 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (367.921 and 351.407 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (73.99) is excellent, well below the 90 A^2 threshold for CNS targets. Ligand B (134.58) is higher, but still potentially acceptable, although less desirable.

**logP:** Ligand A (3.898) is optimal. Ligand B (0.315) is significantly low, potentially hindering membrane permeability and CNS penetration.

**H-Bond Donors/Acceptors:** Both have 3 HBD, which is good. Ligand A has 2 HBA, while Ligand B has 7. Ligand A is better here, as excessive HBA can negatively impact permeability.

**QED:** Both ligands have acceptable QED values (0.738 and 0.695, respectively), indicating good drug-like properties.

**DILI:** Both have similar, acceptable DILI risk (41.877 and 43.622 percentile).

**BBB:** Ligand A (68.592) is reasonable, but could be better. Ligand B (80.031) is excellent, exceeding the 70% threshold for CNS targets. However, this advantage is likely offset by its poor logP.

**Caco-2 Permeability:** Ligand A (-4.956) is poor, indicating low intestinal absorption. Ligand B (-5.261) is also poor, but similar to A.

**Aqueous Solubility:** Ligand A (-4.697) is poor. Ligand B (-2.355) is also poor, but slightly better than A.

**hERG Inhibition:** Both ligands show low hERG inhibition liability (0.506 and 0.402 percentile).

**Microsomal Clearance:** Ligand A (40.196 mL/min/kg) is moderate. Ligand B (-2.74 mL/min/kg) is *very* low, suggesting excellent metabolic stability.

**In vitro Half-Life:** Ligand A (6.672 hours) is moderate. Ligand B (-21.69 hours) is exceptionally long, a significant advantage.

**P-gp Efflux:** Ligand A (0.224) is low, indicating minimal P-gp efflux. Ligand B (0.016) is even lower, suggesting very little efflux.

**Binding Affinity:** Ligand A (-8.6 kcal/mol) has significantly stronger binding affinity than Ligand B (0.0 kcal/mol). This is a crucial factor.

**Overall Assessment:**

Ligand A excels in binding affinity and has a good TPSA and acceptable HBD/HBA. Its main drawbacks are moderate Caco-2 permeability, poor aqueous solubility, and a BBB percentile that could be higher.

Ligand B has a very long half-life, low P-gp efflux, and excellent BBB penetration. However, its extremely low logP is a major concern, likely hindering its ability to cross cell membranes and reach the target. Its binding affinity is also essentially non-existent.

Given the importance of binding affinity for GPCR ligands, and the fact that a >1.5 kcal/mol advantage can outweigh other drawbacks, **Ligand A is the more promising candidate**. While its ADME properties aren't perfect, the strong binding affinity suggests it has a higher probability of achieving efficacy. The poor logP of Ligand B is a critical flaw that is unlikely to be overcome.

Output:
1
2025-04-17 03:34:10,583 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (378.219 and 348.491 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (92.41) is slightly above the optimal <90 for CNS targets, but still reasonable. Ligand B (67.23) is well within the desired range.

**3. logP:** Both ligands have good logP values (2.813 and 2.512), falling within the 1-3 range.

**4. H-Bond Donors:** Ligand A (2) and Ligand B (1) both meet the HBD criteria of <=5.

**5. H-Bond Acceptors:** Ligand A (6) and Ligand B (4) both meet the HBA criteria of <=10.

**6. QED:** Both ligands have acceptable QED values (0.731 and 0.661), indicating good drug-like properties.

**7. DILI:** Ligand A (94.106) has a high DILI risk, being significantly above the 60 threshold. Ligand B (35.479) has a much lower and acceptable DILI risk. This is a major drawback for Ligand A.

**8. BBB:** Ligand A (33.036) has very poor BBB penetration, far below the desirable >70 for CNS targets. Ligand B (55.176) is better, but still not ideal, though significantly improved over Ligand A.

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.18 and -4.807), which is unusual and suggests poor permeability. However, these values are on a scale where negative values are possible and don't necessarily disqualify a compound.

**10. Aqueous Solubility:** Both ligands have very poor aqueous solubility (-4.492 and -1.974). This could pose formulation challenges.

**11. hERG Inhibition:** Both ligands have low hERG inhibition risk (0.291 and 0.153).

**12. Microsomal Clearance:** Ligand A (26.973) has lower microsomal clearance than Ligand B (48.533), suggesting better metabolic stability.

**13. In vitro Half-Life:** Ligand B (28.607) has a longer in vitro half-life than Ligand A (12.893).

**14. P-gp Efflux:** Both ligands have low P-gp efflux liability (0.106 and 0.1).

**15. Binding Affinity:** Ligand B (-7.3 kcal/mol) has a significantly stronger binding affinity than Ligand A (-10.1 kcal/mol). This is a substantial advantage.

**Overall Assessment:**

While Ligand A has better metabolic stability and a slightly better binding affinity, its extremely poor BBB penetration and high DILI risk are major concerns for a CNS target like DRD2. Ligand B, despite a slightly lower affinity, has a much better safety profile (lower DILI) and significantly better BBB penetration, making it more likely to reach the target in the brain. The difference in binding affinity (-7.3 vs -10.1) is likely surmountable with further optimization, while addressing the severe BBB and DILI issues of Ligand A would be far more challenging.

Output:
1
2025-04-17 03:34:10,583 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (369.447 and 378.495 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (126.65) is slightly above the optimal <90 for CNS targets, but still reasonable. Ligand B (107.1) is better, falling comfortably below 90.

**logP:** Ligand A (0.637) is quite low, potentially hindering membrane permeability. Ligand B (-0.901) is also low, but slightly better than A. Both are below the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A has 3 HBD and 7 HBA, which are acceptable. Ligand B has 1 HBD and 5 HBA, also acceptable.

**QED:** Both ligands have reasonable QED scores (0.605 and 0.53), indicating good drug-like properties.

**DILI:** Ligand A (64.831) has a higher DILI risk than Ligand B (39.046). This is a significant negative for Ligand A.

**BBB:** Ligand A (64.637) has a moderate BBB penetration, while Ligand B (51.842) is lower. Both are below the desirable >70 for CNS targets, but A is better.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.343 and -5.416), which is unusual and suggests poor permeability.

**Aqueous Solubility:** Both ligands have negative solubility values (-2.704 and -0.712), which is also unusual and suggests poor solubility.

**hERG:** Both ligands have very low hERG inhibition risk (0.301 and 0.167), which is excellent.

**Microsomal Clearance:** Ligand A (13.081) has lower microsomal clearance than Ligand B (42.771), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (-11.135) has a negative half-life, which is impossible and indicates a potential data error. Ligand B (-45.584) also has a negative half-life, also indicating a potential data error.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.072 and 0.006), which is favorable for CNS penetration.

**Binding Affinity:** Ligand A (-7.0) has a slightly better binding affinity than Ligand B (-6.9). While the difference is small, it's within the range where it could outweigh some ADME drawbacks.

**Overall Assessment:**

Despite the slightly better affinity of Ligand A, its higher DILI risk and the impossible half-life value are major concerns. The negative Caco-2 and solubility values for both ligands are also problematic. However, Ligand B's lower DILI risk and better TPSA make it slightly more promising, *assuming* the negative half-life is a data error. The low logP values for both are a concern, but could potentially be addressed through structural modifications. Given the available data and prioritizing the GPCR-specific properties, especially BBB and DILI, Ligand B is the more viable candidate.

Output:
1
2025-04-17 03:34:10,583 - INFO - Reasoning:

Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight (MW):** Both ligands (343.343 and 364.412 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (110.49) is slightly above the optimal <90 for CNS targets, but still reasonable. Ligand B (52.41) is excellent, well below 90. This favors Ligand B.

**3. logP:** Both ligands have good logP values (1.782 and 2.494), falling within the 1-3 range.

**4. H-Bond Donors (HBD):** Both ligands are acceptable (1 and 0 respectively), being less than or equal to 5.

**5. H-Bond Acceptors (HBA):** Both ligands are acceptable (7 and 6 respectively), being less than or equal to 10.

**6. QED:** Both ligands have similar QED values (0.665 and 0.639), indicating good drug-likeness.

**7. DILI:** Ligand A has a significantly higher DILI risk (95.774 percentile) than Ligand B (27.181 percentile). This is a major concern for Ligand A.

**8. BBB:** Both ligands have excellent BBB penetration (61.342 and 95.502 percentile), which is crucial for a CNS target like DRD2. Ligand B is superior here.

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.706 and -4.543). This is unusual and suggests poor permeability, but the scale isn't defined, so it's hard to interpret.

**10. Aqueous Solubility:** Both ligands have negative solubility values (-3.537 and -2.665). Similar to Caco-2, the scale isn't defined, making interpretation difficult.

**11. hERG Inhibition:** Both ligands show low hERG inhibition liability (0.324 and 0.744), which is good.

**12. Microsomal Clearance:** Both ligands have similar microsomal clearance values (33.417 and 32.872), suggesting comparable metabolic stability.

**13. In vitro Half-Life:** Ligand B has a much longer in vitro half-life (8.17 hours) compared to Ligand A (-4.917 hours), which is a significant advantage.

**14. P-gp Efflux:** Both ligands have low P-gp efflux liability (0.058 and 0.255), which is favorable for CNS penetration.

**15. Binding Affinity:** Ligand A has a stronger binding affinity (-9.5 kcal/mol) than Ligand B (-6.8 kcal/mol). This is a substantial difference.

**Overall Assessment:**

While Ligand A boasts a significantly better binding affinity, its extremely high DILI risk is a major red flag. The slightly better TPSA and BBB of Ligand B, combined with a much improved safety profile (DILI) and longer half-life, outweigh the affinity difference. The negative values for Caco-2 and solubility are concerning for both, but the affinity advantage of A might overcome these if the scale is not truly negative. However, the DILI risk is too high to ignore.

Output:
1
2025-04-17 03:34:10,584 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (370.475 and 350.434 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (94.89) is slightly above the optimal <90 for CNS targets, but still reasonable. Ligand B (58.64) is well within the desired range. This favors Ligand B.

**3. logP:** Both ligands have good logP values (1.445 and 1.824), falling within the 1-3 range.

**4. H-Bond Donors:** Ligand A has 2 HBD, and Ligand B has 1. Both are acceptable (<=5).

**5. H-Bond Acceptors:** Ligand A has 4 HBA, and Ligand B has 3. Both are acceptable (<=10).

**6. QED:** Both ligands have reasonable QED scores (0.838 and 0.744), indicating good drug-like properties.

**7. DILI:** Ligand A (40.869) is slightly higher than Ligand B (29.159), but both are below the concerning threshold of 60. Ligand B is preferred.

**8. BBB:** This is a critical parameter for CNS targets. Ligand B (93.098) has a significantly higher BBB percentile than Ligand A (61.923). This is a major advantage for Ligand B.

**9. Caco-2 Permeability:** Ligand A (-5.066) and Ligand B (-4.524) both have negative values, which is unusual and suggests poor permeability. However, the scale isn't specified, so it's hard to interpret.

**10. Aqueous Solubility:** Both ligands have negative solubility values (-1.788 and -2.848), indicating poor solubility. This is a concern for both.

**11. hERG Inhibition:** Both ligands have low hERG inhibition risk (0.309 and 0.443).

**12. Microsomal Clearance:** Ligand A (-25.021) has a lower (better) microsomal clearance than Ligand B (39.571), suggesting better metabolic stability.

**13. In vitro Half-Life:** Ligand A (32.875) has a longer half-life than Ligand B (-17.455). This is a positive for Ligand A.

**14. P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.015 and 0.193), which is good for CNS penetration.

**15. Binding Affinity:** Both ligands have similar, strong binding affinities (-8.7 and -8.9 kcal/mol). The difference is negligible.

**Overall Assessment:**

Ligand B is the stronger candidate. While Ligand A has better metabolic stability (lower Cl_mic and longer t1/2), Ligand B excels in the most critical areas for a CNS-targeting GPCR ligand: significantly better BBB penetration (93.098 vs 61.923) and a lower TPSA (58.64 vs 94.89). The slightly lower DILI risk for Ligand B is also a plus. The similar binding affinities mean that the superior ADME properties of Ligand B outweigh the minor advantage of Ligand A in metabolic stability.

Output:
1
2025-04-17 03:34:10,584 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (357.426 and 338.499 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (71.11) is better than Ligand B (41.05). For CNS targets, we want TPSA <= 90, both are well within this range, but A is slightly higher.

**logP:** Ligand A (-0.059) is suboptimal, being slightly below the ideal 1-3 range. Ligand B (3.97) is excellent, falling right within the optimal range. This is a significant advantage for B, as good logP is crucial for GPCRs.

**H-Bond Donors/Acceptors:** Both have 1 HBD and are acceptable. Ligand A has 5 HBA, while Ligand B has 4. Both are within the acceptable limit of <=10.

**QED:** Both ligands have acceptable QED values (0.747 and 0.651, both >= 0.5).

**DILI:** Ligand A (20.24) has a much lower DILI risk than Ligand B (52.85). This is a considerable advantage for A.

**BBB:** Both ligands exhibit good BBB penetration (79.217 and 83.288, both >70), which is critical for a CNS target like DRD2. Ligand B is slightly better.

**Caco-2 Permeability:** Both have negative values, indicating poor permeability. This is a drawback for both, but the scale is different, and it's hard to compare directly.

**Aqueous Solubility:** Both have negative values indicating poor solubility. This is a drawback for both, but the scale is different, and it's hard to compare directly.

**hERG Inhibition:** Ligand A (0.396) has a lower hERG risk than Ligand B (0.839), which is preferable.

**Microsomal Clearance:** Ligand A (-12.99) has a negative value, suggesting very low clearance and high metabolic stability, which is excellent. Ligand B (80.902) has high clearance, indicating poor metabolic stability. This is a significant advantage for A.

**In vitro Half-Life:** Ligand A (10.002) has a reasonable half-life, while Ligand B (29.886) has a longer half-life.

**P-gp Efflux:** Ligand A (0.02) has very low P-gp efflux, which is excellent for CNS penetration. Ligand B (0.461) has moderate P-gp efflux. This is a significant advantage for A.

**Binding Affinity:** Ligand A (-7.0) has a slightly better binding affinity than Ligand B (-0.0). This is a substantial advantage for A.

**Overall Assessment:**

Ligand A excels in key areas for a CNS-targeting GPCR ligand: excellent binding affinity, very low DILI risk, low P-gp efflux, low hERG inhibition, and exceptional metabolic stability. While its logP is slightly suboptimal, its superior affinity and ADME properties outweigh this. Ligand B has a good logP and BBB penetration, but suffers from higher DILI risk, poor metabolic stability, and moderate P-gp efflux. The binding affinity is also significantly weaker.

Output:
0
2025-04-17 03:34:10,584 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (349.431 and 354.451 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (95.67) is better than Ligand B (116.48). For CNS targets, we want TPSA <= 90, so Ligand A is closer to this threshold.

**logP:** Ligand A (1.389) is within the optimal 1-3 range. Ligand B (-0.03) is slightly below 1, which could hinder permeation.

**H-Bond Donors/Acceptors:** Ligand A (HBD=2, HBA=5) and Ligand B (HBD=4, HBA=6) both have reasonable numbers of H-bond donors and acceptors, within the suggested limits.

**QED:** Ligand A (0.837) has a significantly higher QED score than Ligand B (0.549), indicating better overall drug-likeness.

**DILI:** Ligand A (29.042) has a much lower DILI risk than Ligand B (20.163), suggesting a safer profile.

**BBB:** Ligand A (51.919) has a better BBB percentile than Ligand B (19.426). While both are below the desirable >70 for CNS targets, A is significantly better.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values, which is unusual and suggests poor permeability. However, the scale is not specified, so it's hard to interpret.

**Aqueous Solubility:** Both ligands have negative solubility values, which is also unusual and suggests poor solubility.

**hERG:** Both ligands have low hERG inhibition liability (0.099 and 0.134), which is good.

**Microsomal Clearance:** Ligand A (2.352) has a much lower microsomal clearance than Ligand B (27.372), indicating better metabolic stability.

**In vitro Half-Life:** Ligand A (8.782) has a positive half-life, while Ligand B (-14.468) has a negative half-life, which is problematic.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.064 and 0.02), which is favorable for CNS penetration.

**Binding Affinity:** Ligand A (-9.1 kcal/mol) has a significantly stronger binding affinity than Ligand B (-6.9 kcal/mol). This is a substantial advantage (2.2 kcal/mol difference).

**Overall Assessment:**

Ligand A is clearly superior. It has better TPSA, logP, QED, DILI risk, BBB penetration, metabolic stability, half-life, and *significantly* stronger binding affinity. While both have issues with Caco-2 and solubility, the superior affinity and ADME properties of Ligand A outweigh these concerns, especially given the importance of BBB penetration for a CNS target like DRD2. The large difference in binding affinity (-9.1 vs -6.9) is a critical factor.

Output:
1
2025-04-17 03:34:10,584 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (378.877 Da) is slightly higher than Ligand B (346.435 Da), but both are acceptable.

**TPSA:** Ligand A (60.44) is excellent for CNS penetration, well below the 90 A^2 threshold. Ligand B (97.88) is higher, but still potentially acceptable, though less ideal for CNS targets.

**logP:** Ligand A (3.989) is at the upper end of the optimal range (1-3), potentially raising concerns about solubility and off-target effects. Ligand B (1.14) is at the lower end, which could hinder permeation.

**H-Bond Donors/Acceptors:** Ligand A has 0 HBD and 4 HBA, which is favorable. Ligand B has 1 HBD and 8 HBA, still within acceptable limits, but slightly less optimal.

**QED:** Both ligands have similar QED values (A: 0.755, B: 0.705), indicating good drug-likeness.

**DILI:** Ligand A (84.917) has a higher DILI risk than Ligand B (37.922). This is a significant drawback for Ligand A.

**BBB:** Ligand B (70.919) has a better BBB percentile than Ligand A (61.962), which is crucial for a CNS target like DRD2.

**Caco-2 Permeability:** Ligand A (-4.74) has poor Caco-2 permeability, suggesting poor intestinal absorption. Ligand B (-5.465) is also poor, but slightly better than A.

**Aqueous Solubility:** Ligand A (-5.065) has very poor aqueous solubility, a major concern. Ligand B (-1.96) is also poor, but better than A.

**hERG Inhibition:** Both ligands show low hERG inhibition risk (A: 0.351, B: 0.256).

**Microsomal Clearance:** Ligand B (2.802) has significantly lower microsomal clearance than Ligand A (49.217), indicating better metabolic stability.

**In vitro Half-Life:** Ligand B (-5.729) has a longer in vitro half-life than Ligand A (14.111), which is preferable.

**P-gp Efflux:** Both ligands show low P-gp efflux liability (A: 0.353, B: 0.086), which is good for CNS exposure.

**Binding Affinity:** Ligand A (-9.4 kcal/mol) has a significantly stronger binding affinity than Ligand B (-7.1 kcal/mol). This is a substantial advantage.

**Overall Assessment:**

Despite the superior binding affinity of Ligand A, its poor solubility, Caco-2 permeability, high DILI risk, and moderate BBB penetration are major concerns. Ligand B, while having a weaker affinity, exhibits a much more favorable ADME profile, particularly regarding BBB penetration, metabolic stability, and DILI risk. Given the GPCR-specific priorities, and the importance of CNS penetration for a DRD2 target, Ligand B is the more promising candidate. The 1.5 kcal/mol difference in binding affinity is unlikely to overcome the significant ADME liabilities of Ligand A.

Output:
1
2025-04-17 03:34:10,585 - INFO - Reasoning:

Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (343.427 and 343.431 Da) fall comfortably within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (71.53) is significantly better than Ligand B (101.21). For CNS targets, we want TPSA <= 90, so Ligand A is much closer to this threshold.

**3. logP:** Both ligands have good logP values (1.848 and 1.214), falling within the optimal 1-3 range.

**4. H-Bond Donors:** Ligand A (1) is better than Ligand B (2). Lower HBD is generally preferred for better permeability.

**5. H-Bond Acceptors:** Ligand A (4) is better than Ligand B (5). Lower HBA is generally preferred for better permeability.

**6. QED:** Both ligands have similar and good QED values (0.847 and 0.837), indicating good drug-like properties.

**7. DILI:** Ligand A (30.942) has a significantly lower DILI risk than Ligand B (47.964). Both are below the 60 threshold, but A is preferable.

**8. BBB:** Both ligands have good BBB penetration (79.488 and 73.866). Ligand A is slightly better, but both are reasonably good for a CNS target.

**9. Caco-2:** Both ligands have negative Caco-2 values (-4.598 and -5.009). These values are unusual and suggest poor permeability. However, the scale isn't specified, so it's difficult to interpret.

**10. Solubility:** Both ligands have negative solubility values (-2.593 and -2.964). Similar to Caco-2, the scale is unknown, making interpretation difficult.

**11. hERG:** Both ligands have very low hERG inhibition risk (0.261 and 0.223).

**12. Cl_mic:** Ligand A (13.831) has a lower microsomal clearance than Ligand B (27.112), indicating better metabolic stability.

**13. t1/2:** Ligand A (15.517) has a longer in vitro half-life than Ligand B (-10.268). The negative value for B is concerning and suggests rapid degradation.

**14. Pgp:** Both ligands have very low P-gp efflux liability (0.076 and 0.006).

**15. Binding Affinity:** Ligand A (-8.8 kcal/mol) has a slightly better binding affinity than Ligand B (-8.3 kcal/mol). While both are excellent, the 0.5 kcal/mol difference is notable.

**Overall Assessment:**

Ligand A consistently outperforms Ligand B across most crucial parameters. It has a lower TPSA, lower DILI risk, better metabolic stability (lower Cl_mic, longer t1/2), and slightly better binding affinity. While both have issues with Caco-2 and solubility (due to the unknown scale), the other advantages of Ligand A make it the more promising candidate. The GPCR-specific priorities of BBB, logP, Pgp, TPSA, and affinity all favor Ligand A.

Output:
1
2025-04-17 03:34:10,585 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (356.375 and 363.487 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (134.19) is borderline for CNS penetration, being slightly above the preferred <90, while Ligand B (76.3) is excellent.

**logP:** Ligand A (-1.925) is quite low, potentially hindering membrane permeability. Ligand B (1.338) is within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A has 4 HBD and 7 HBA, acceptable values. Ligand B has 1 HBD and 8 HBA, also acceptable.

**QED:** Ligand B (0.758) has a significantly better QED score than Ligand A (0.322), indicating a more drug-like profile.

**DILI:** Ligand B (45.715) has a lower DILI risk than Ligand A (64.482), which is preferable.

**BBB:** Ligand B (53.703) has a much better BBB penetration percentile than Ligand A (23.187). This is *critical* for a CNS target like DRD2.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.446 and -5.374), which is unusual and suggests poor permeability. However, these values are on a log scale, and the absolute value is more important. They are similar in this regard.

**Aqueous Solubility:** Both ligands have negative solubility values (-1.264 and -2.469), indicating poor aqueous solubility. This is a concern for both.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.142 and 0.215).

**Microsomal Clearance:** Ligand A (24.151) has lower microsomal clearance than Ligand B (28.688), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (-16.363) has a negative half-life, which is not physically possible and suggests an issue with the data. Ligand B (15.784) has a reasonable half-life.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.089 and 0.194).

**Binding Affinity:** Ligand A (-7.0) has slightly better binding affinity than Ligand B (-6.3), but the difference is only 0.7 kcal/mol.

**Overall Assessment:**

Ligand B is significantly better overall, especially considering the GPCR-specific priorities. Its superior BBB penetration, better QED, lower DILI risk, and acceptable logP outweigh the slightly weaker binding affinity and solubility concerns. Ligand A's very low logP and questionable half-life are major drawbacks. The negative solubility and Caco-2 values are concerning for both, but can potentially be addressed through formulation strategies.

Output:
1
2025-04-17 03:34:10,585 - INFO - Batch 40 complete. Total preferences: 640
2025-04-17 03:34:10,585 - INFO - Processing batch 41/512...
2025-04-17 03:34:55,237 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (368.302 and 357.426 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (51.66) is significantly better than Ligand B (78.95). For CNS targets, we want TPSA <= 90, and ideally closer to 60. Ligand A is much closer to this ideal.

**logP:** Ligand A (3.143) is optimal (1-3). Ligand B (1.03) is a bit low, potentially hindering permeation.

**H-Bond Donors/Acceptors:** Ligand A (0 HBD, 5 HBA) is preferable to Ligand B (1 HBD, 4 HBA). Both are within acceptable limits, but fewer H-bonds generally improve permeability.

**QED:** Both ligands have good QED scores (0.57 and 0.72), indicating good drug-like properties.

**DILI:** Both ligands have low DILI risk (39.434 and 33.773), which is good.

**BBB:** Both ligands have excellent BBB penetration (85.731 and 89.608), exceeding the desirable >70 threshold for CNS targets.

**Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and difficult to interpret without knowing the scale. However, we can assume they are relatively low permeability.

**Aqueous Solubility:** Both have negative solubility values, which is also unusual. This suggests poor solubility.

**hERG:** Both ligands have very low hERG inhibition risk (0.561 and 0.19).

**Microsomal Clearance:** Ligand A (53.576) has higher clearance than Ligand B (-8.87). A negative value for Ligand B suggests very high metabolic stability, which is a significant advantage.

**In vitro Half-Life:** Ligand A (-16.802) has a negative half-life, which is problematic. Ligand B (-12.013) also has a negative half-life, but is slightly better.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.131 and 0.011), which is excellent for CNS exposure.

**Binding Affinity:** Ligand B (-7.1 kcal/mol) has a slightly better binding affinity than Ligand A (-8.0 kcal/mol). However, the difference is not substantial enough to outweigh other factors.

**Overall Assessment:**

Ligand A has a better TPSA and logP, which are critical for CNS penetration. However, Ligand B has significantly better metabolic stability (lower Cl_mic, negative value) and a slightly better binding affinity. The negative half-life values for both are concerning, but the metabolic stability of Ligand B is a major advantage. Given the importance of metabolic stability for CNS drugs, and the relatively small difference in binding affinity, Ligand B is the more promising candidate.

Output:
1
2025-04-17 03:34:55,238 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (360.317 and 347.375 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (113.62) is better than Ligand B (124.52). Both are below the 140 A^2 threshold for oral absorption, and importantly, below the 90 A^2 target for CNS penetration.

**logP:** Ligand A (0.1) is slightly below the optimal 1-3 range, while Ligand B (-0.422) is even lower. Both are potentially problematic for membrane permeability, but the difference isn't huge.

**H-Bond Donors/Acceptors:** Both have 3 HBD and 6 HBA, which are acceptable.

**QED:** Ligand A (0.527) is slightly better than Ligand B (0.454), indicating a marginally more drug-like profile.

**DILI:** Both ligands have the same DILI risk (59.519%), which is acceptable (below 60).

**BBB:** Ligand A (69.794%) has a significantly better BBB penetration score than Ligand B (53.742%). This is a crucial factor for a CNS target like DRD2.

**Caco-2 Permeability:** Ligand A (-5.34) is better than Ligand B (-6.015), indicating better intestinal absorption.

**Aqueous Solubility:** Ligand A (-2.536) is better than Ligand B (-1.185), suggesting better solubility.

**hERG:** Both ligands have very low hERG inhibition liability (0.144 and 0.022), which is excellent.

**Microsomal Clearance:** Ligand B (-5.876) has a *negative* clearance, which is unusual and likely an error or indicates extremely high metabolic stability. Ligand A (29.014) is more typical.

**In vitro Half-Life:** Ligand B (16.773) has a better half-life than Ligand A (-19.414). A negative half-life is not possible, so this is likely an error.

**P-gp Efflux:** Both ligands show very low P-gp efflux liability (0.046 and 0.003), which is favorable for CNS exposure.

**Binding Affinity:** Ligand B (-8.5 kcal/mol) has a significantly stronger binding affinity than Ligand A (-6.8 kcal/mol). This is a substantial difference (>1.5 kcal/mol advantage).

**Overall Assessment:**

Despite Ligand A having better TPSA, BBB, solubility and Caco-2 permeability, the significantly stronger binding affinity of Ligand B (-8.5 vs -6.8 kcal/mol) is a decisive advantage, especially for a GPCR target. The negative values for clearance and half-life of Ligand B are concerning and likely errors, but the binding affinity difference is so large that it outweighs these concerns. The slightly lower BBB for Ligand B is a drawback, but the potency advantage is likely to compensate.

Output:
1
2025-04-17 03:34:55,238 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (346.431 Da) is slightly lower, which could be advantageous for permeability. Ligand B (389.815 Da) is still acceptable.

**TPSA:** Both ligands have TPSA values below 140, suggesting reasonable oral absorption. Ligand A (93.09) is better, falling closer to the preferred <90 for CNS targets. Ligand B (100.03) is still acceptable but less optimal.

**logP:** Both ligands have logP values within the optimal range (1-3). Ligand A (1.062) is slightly lower, while Ligand B (2.85) is closer to the ideal.

**H-Bond Donors/Acceptors:** Ligand A (2 HBD, 5 HBA) and Ligand B (3 HBD, 7 HBA) both fall within acceptable ranges.

**QED:** Both ligands have QED values above 0.5, indicating good drug-like properties. Ligand A (0.753) is slightly better than Ligand B (0.673).

**DILI:** Ligand A (55.797) has a significantly lower DILI risk than Ligand B (81.66), which is a substantial advantage.

**BBB:** Both ligands have similar BBB penetration percentiles (Ligand A: 53.587, Ligand B: 58.356). Neither is outstanding (>70), but they are both reasonable.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values, which is unusual and suggests poor permeability. Ligand A (-4.997) is slightly better (less negative) than Ligand B (-5.211).

**Aqueous Solubility:** Both ligands have negative solubility values, indicating very poor aqueous solubility. Ligand A (-2.319) is slightly better than Ligand B (-4.566).

**hERG Inhibition:** Both ligands have very low hERG inhibition risk (Ligand A: 0.086, Ligand B: 0.311).

**Microsomal Clearance:** Both ligands have similar microsomal clearance values (Ligand A: 27.145, Ligand B: 24.997).

**In vitro Half-Life:** Ligand A (-11.52) has a negative half-life, which is not possible. This is a major red flag. Ligand B (2.487) is a more reasonable value.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (Ligand A: 0.041, Ligand B: 0.053).

**Binding Affinity:** Both ligands have strong binding affinities (Ligand A: -8.0 kcal/mol, Ligand B: -8.5 kcal/mol). Ligand B is slightly more potent.

**Overall Assessment:**

Ligand B has a slightly better binding affinity and a reasonable in vitro half-life. However, Ligand A has a significantly lower DILI risk, better TPSA, and a slightly better QED. The negative half-life for Ligand A is a critical issue, suggesting a severe instability problem. The poor Caco-2 and solubility for both are concerning, but could potentially be addressed with formulation strategies. Given the importance of metabolic stability and the unphysical half-life of Ligand A, Ligand B is the more promising candidate.

Output:
1
2025-04-17 03:34:55,238 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (368.849 and 362.861 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (59.29) is significantly better than Ligand B (88.32). For CNS targets, we want TPSA <= 90, and A is comfortably within that range, while B is approaching the upper limit.

**3. logP:** Ligand A (4.287) is slightly higher than the optimal 1-3 range, but still potentially acceptable. Ligand B (2.396) is well within the optimal range. However, for a GPCR, a slightly higher logP can be tolerated if other properties are favorable.

**4. H-Bond Donors:** Ligand A (1) and Ligand B (2) are both acceptable, being <=5.

**5. H-Bond Acceptors:** Ligand A (5) and Ligand B (4) are both acceptable, being <=10.

**6. QED:** Both ligands have good QED scores (A: 0.584, B: 0.787), indicating good drug-like properties.

**7. DILI:** Ligand A (90.229) has a higher DILI risk than Ligand B (53.625). This is a significant negative for Ligand A.

**8. BBB:** Ligand B (72.237) has a better BBB penetration percentile than Ligand A (65.374). Both are above the 70% threshold, but B is closer. This is crucial for a CNS target like DRD2.

**9. Caco-2:** Both have negative Caco-2 values, which is unusual and likely indicates a data error or a very poor permeability. This is a concern for both, but the negative values make direct comparison difficult.

**10. Solubility:** Both have negative solubility values, which is also concerning. Again, direct comparison is difficult.

**11. hERG:** Both ligands have low hERG inhibition risk (A: 0.686, B: 0.611).

**12. Cl_mic:** Ligand B (13.683) has significantly lower microsomal clearance than Ligand A (72.304), indicating better metabolic stability. This is a major advantage for Ligand B.

**13. t1/2:** Ligand A (51.612) has a longer in vitro half-life than Ligand B (-21.623). However, the negative value for B is suspect and likely an error.

**14. Pgp:** Ligand A (0.676) has lower P-gp efflux than Ligand B (0.078), which is favorable for CNS penetration.

**15. Binding Affinity:** Ligand A (-10.1) has a significantly stronger binding affinity than Ligand B (-9.0). This is a substantial advantage, potentially outweighing some of the ADME drawbacks.

**Overall Assessment:**

While Ligand A has a superior binding affinity, Ligand B demonstrates a much better ADME profile, particularly regarding DILI risk, BBB penetration, and metabolic stability (Cl_mic). The lower DILI and better BBB are critical for CNS drug development. The questionable Caco-2 and solubility values for both are concerning, but the other factors favor Ligand B. The strong affinity of A is tempting, but the higher DILI risk and lower BBB are significant liabilities.

Output:
1
2025-04-17 03:34:55,238 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B based on the provided guidelines, prioritizing GPCR-specific properties (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (341.543 and 351.447 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (18.51) is excellent, well below the 90 A^2 threshold for CNS targets. Ligand B (98.74) is significantly higher, potentially hindering BBB penetration.

**logP:** Ligand A (3.824) is within the optimal 1-3 range. Ligand B (0.171) is quite low, which could severely limit its ability to cross cell membranes, including the BBB.

**H-Bond Donors/Acceptors:** Ligand A (1 HBD, 3 HBA) and Ligand B (3 HBD, 4 HBA) both have acceptable numbers of hydrogen bond donors and acceptors.

**QED:** Ligand A (0.878) has a very good QED score, indicating high drug-likeness. Ligand B (0.58) is acceptable, but lower than Ligand A.

**DILI:** Ligand A (8.647) has a very low DILI risk. Ligand B (12.796) is slightly higher, but still relatively low.

**BBB:** Ligand A (98.022) has excellent BBB penetration potential. Ligand B (35.052) is poor, a major drawback for a CNS target like DRD2.

**Caco-2 Permeability:** Ligand A (-4.882) has poor Caco-2 permeability. Ligand B (-5.157) is also poor.

**Aqueous Solubility:** Ligand A (-2.884) has poor aqueous solubility. Ligand B (-1.8) is also poor.

**hERG Inhibition:** Ligand A (0.983) has a low risk of hERG inhibition. Ligand B (0.086) has a very low risk.

**Microsomal Clearance:** Ligand A (1.062) has low microsomal clearance, suggesting good metabolic stability. Ligand B (13.551) has higher clearance, indicating faster metabolism.

**In vitro Half-Life:** Ligand A (31.781 hours) has a good in vitro half-life. Ligand B (11.524 hours) is shorter, potentially requiring more frequent dosing.

**P-gp Efflux:** Ligand A (0.14) has low P-gp efflux, which is favorable for CNS penetration. Ligand B (0.02) also has low P-gp efflux.

**Binding Affinity:** Ligand A (-9.3 kcal/mol) has a significantly stronger binding affinity than Ligand B (-8.1 kcal/mol). This 1.2 kcal/mol difference is substantial and can outweigh some ADME drawbacks.

**Conclusion:**

Considering the GPCR-specific priorities, Ligand A is the much more promising candidate. Its excellent BBB penetration, favorable logP, strong binding affinity, and low DILI risk outweigh its poor Caco-2 permeability and aqueous solubility. Ligand B's poor BBB penetration and low logP are significant liabilities for a CNS-targeting drug, despite its acceptable safety profile and good hERG inhibition. The substantial difference in binding affinity further solidifies Ligand A as the better choice.

Output:
1
2025-04-17 03:34:55,239 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (423.694 Da) is slightly higher, but still acceptable. Ligand B (371.384 Da) is also good.

**TPSA:**  For CNS targets, we want TPSA <= 90. Ligand A (59.5) is excellent, well below the threshold. Ligand B (73.2) is still reasonable, but less optimal than A.

**logP:** Optimal is 1-3. Ligand A (4.186) is a bit high, potentially leading to solubility issues or off-target interactions. Ligand B (2.222) is within the ideal range.

**H-Bond Donors/Acceptors:** Ligand A (0 HBD, 4 HBA) and Ligand B (1 HBD, 4 HBA) both have acceptable counts.

**QED:** Both ligands have good QED scores (A: 0.68, B: 0.863), indicating drug-like properties.

**DILI:** Ligand A (77.2) has a higher DILI risk than Ligand B (55.68), which is preferable. Both are below the concerning threshold of 60.

**BBB:** Both ligands show excellent BBB penetration (A: 83.288, B: 81.582), exceeding the desirable >70 threshold for CNS targets.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.371 and -4.859), which is unusual and suggests poor permeability. This is a significant concern for both.

**Aqueous Solubility:** Both ligands have very poor aqueous solubility (-5.972 and -3.611). This is a major drawback, especially given Ligand A's higher logP.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (A: 0.582, B: 0.656), which is positive.

**Microsomal Clearance:** Ligand A (130.754) has significantly higher microsomal clearance than Ligand B (4.112), indicating faster metabolism and potentially lower *in vivo* exposure.

**In vitro Half-Life:** Ligand B (-11.308) has a very short half-life, which is a significant concern. Ligand A (51.713) is better, but still not ideal.

**P-gp Efflux:** Both ligands have low P-gp efflux (A: 0.6, B: 0.107), which is favorable for CNS penetration.

**Binding Affinity:** Ligand A (-8.6 kcal/mol) has a significantly stronger binding affinity than Ligand B (-9.0 kcal/mol). This is a substantial advantage.

**Overall Assessment:**

While both ligands have issues with Caco-2 permeability and solubility, Ligand A's superior binding affinity (-8.6 vs -9.0 kcal/mol) and better TPSA, combined with acceptable BBB penetration, outweigh its slightly higher logP and DILI risk. Ligand B's faster clearance and very short half-life are major drawbacks. The significantly better affinity of Ligand A is crucial for a GPCR target, and can potentially be optimized to improve solubility and permeability.

Output:
1
2025-04-17 03:34:55,239 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight (MW):** Both ligands are within the ideal range (200-500 Da). Ligand A (337.467 Da) is slightly lower, which could be beneficial for permeability, but both are acceptable.

**2. TPSA:** Ligand A (42.99) is significantly better than Ligand B (53.51). For CNS targets, we want TPSA <= 90, and ideally lower. Ligand A is much closer to the ideal range.

**3. logP:** Ligand A (4.796) is a bit high, potentially leading to solubility issues or off-target interactions. Ligand B (3.098) is within the optimal 1-3 range.

**4. H-Bond Donors (HBD):** Both ligands have acceptable HBD counts (Ligand A: 1, Ligand B: 0).

**5. H-Bond Acceptors (HBA):** Both ligands have acceptable HBA counts (Ligand A: 4, Ligand B: 4).

**6. QED:** Both ligands have similar and good QED values (Ligand A: 0.571, Ligand B: 0.598), indicating good drug-like properties.

**7. DILI:** Both ligands have low DILI risk (Ligand A: 49.128, Ligand B: 41.062), both well below the 60 threshold.

**8. BBB:** Ligand B (70.764) has a significantly better BBB percentile than Ligand A (40.481). This is a *critical* factor for a CNS target like DRD2.

**9. Caco-2 Permeability:** Ligand A (-5.506) has poor Caco-2 permeability, while Ligand B (-4.921) is slightly better, but still not great.

**10. Aqueous Solubility:** Ligand A (-3.686) has poor aqueous solubility, which is concerning given its high logP. Ligand B (-2.88) is better, but still not ideal.

**11. hERG Inhibition:** Both ligands have low hERG inhibition risk (Ligand A: 0.935, Ligand B: 0.632).

**12. Microsomal Clearance:** Ligand B (59.672) has a higher microsomal clearance than Ligand A (42.671), suggesting Ligand A is more metabolically stable.

**13. In vitro Half-Life:** Ligand A (66.547) has a much longer in vitro half-life than Ligand B (-3.9). This is a significant advantage.

**14. P-gp Efflux:** Ligand A (0.922) shows moderate P-gp efflux, while Ligand B (0.626) has lower efflux. Lower P-gp efflux is preferred for CNS penetration.

**15. Binding Affinity:** Ligand A (-8.9 kcal/mol) has a *much* stronger binding affinity than Ligand B (-0.0 kcal/mol). This is a substantial advantage, potentially outweighing some of its ADME drawbacks.

**Overall Assessment:**

Ligand A has a significantly better binding affinity and metabolic stability (lower Cl_mic, longer t1/2). However, it suffers from poor BBB penetration, poor solubility, and poor Caco-2 permeability. Ligand B has better BBB penetration, slightly better solubility and Caco-2 permeability, and lower P-gp efflux, but its binding affinity is very weak.

Given the strong emphasis on affinity for GPCRs, and the fact that the affinity difference is so large (8.9 vs 0.0 kcal/mol), the superior binding of Ligand A is likely to be the dominant factor. While its ADME properties are not ideal, optimization strategies could potentially address these issues without sacrificing potency. The very weak binding of Ligand B makes it unlikely to be a viable candidate, even with better ADME properties.

Output:
1
2025-04-17 03:34:55,239 - INFO - Reasoning:

Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (369.462 and 354.479 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (62.74) is better than Ligand B (59.81). Both are below the 90 A^2 threshold desirable for CNS targets, indicating good potential for brain penetration.

**3. logP:** Both ligands have logP values (3.525 and 3.831) within the optimal 1-3 range.

**4. H-Bond Donors:** Ligand A (0) is preferable to Ligand B (1). Fewer HBDs generally improve permeability.

**5. H-Bond Acceptors:** Both ligands have 5 HBAs, which is acceptable (<=10).

**6. QED:** Ligand A (0.815) has a slightly better QED score than Ligand B (0.701), suggesting a more drug-like profile.

**7. DILI:** Ligand B (70.919) has a higher DILI risk than Ligand A (50.174). This is a significant negative for Ligand B.

**8. BBB:** Ligand A (83.443) has a significantly higher BBB percentile than Ligand B (64.948). This is crucial for a CNS target like DRD2.

**9. Caco-2 Permeability:** Ligand A (-4.273) has better Caco-2 permeability than Ligand B (-5.444).

**10. Aqueous Solubility:** Ligand A (-3.979) has better solubility than Ligand B (-4.639).

**11. hERG Inhibition:** Both ligands have similar, low hERG inhibition risk (0.424 and 0.421).

**12. Microsomal Clearance:** Ligand B (92.969) has higher microsomal clearance than Ligand A (85.547), indicating lower metabolic stability.

**13. In vitro Half-Life:** Ligand A (-4.79) has a longer in vitro half-life than Ligand B (5.004).

**14. P-gp Efflux:** Ligand A (0.322) has lower P-gp efflux liability than Ligand B (0.607), which is beneficial for CNS penetration.

**15. Binding Affinity:** Ligand B (-9.3 kcal/mol) has a significantly stronger binding affinity than Ligand A (-8.1 kcal/mol). This is a substantial advantage.

**Overall Assessment:**

While Ligand B boasts a superior binding affinity, Ligand A demonstrates a much more favorable ADME-Tox profile, particularly regarding BBB penetration (critical for a CNS target), lower DILI risk, better Caco-2 permeability, solubility, metabolic stability, and P-gp efflux. The 1.2 kcal/mol difference in binding affinity, while notable, can potentially be overcome with further optimization of Ligand A, while mitigating the ADME liabilities of Ligand B would be more challenging. Given the GPCR-specific priorities and the importance of CNS penetration for DRD2, Ligand A is the more promising candidate.

Output:
0
2025-04-17 03:34:55,239 - INFO - Reasoning:

Let's analyze Ligand A and Ligand B for their potential as DRD2 drug candidates, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (345.443 and 356.482 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (80.2) is slightly above the preferred <90 for CNS targets, but still reasonable. Ligand B (67.43) is excellent, well below 90.

**3. logP:** Ligand A (1.755) is within the optimal 1-3 range. Ligand B (3.45) is at the higher end of optimal, potentially raising concerns about solubility and off-target effects, but still acceptable.

**4. H-Bond Donors:** Both ligands have 2 HBD, which is within the acceptable limit of <=5.

**5. H-Bond Acceptors:** Ligand A has 4 HBA, and Ligand B has 3. Both are within the acceptable limit of <=10.

**6. QED:** Ligand A (0.705) has a good drug-likeness score. Ligand B (0.358) is significantly lower, indicating a less drug-like profile.

**7. DILI:** Both ligands have very similar DILI risk (35.091 and 35.285 percentile), both are low risk.

**8. BBB:** This is a crucial parameter for a CNS target like DRD2. Ligand A has a BBB penetration of 55.176%, which is below the desirable >70%. Ligand B has a much better BBB penetration of 91.198%, which is excellent.

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.92 and -4.791), which is unusual and suggests poor permeability. However, these values are on a log scale, and the negative values suggest very low permeability.

**10. Aqueous Solubility:** Both ligands have negative solubility values (-2.199 and -3.825), indicating poor aqueous solubility.

**11. hERG Inhibition:** Ligand A (0.161) has a very low hERG risk. Ligand B (0.621) has a slightly higher, but still relatively low, hERG risk.

**12. Microsomal Clearance:** Ligand A (4.285) has lower microsomal clearance, suggesting better metabolic stability. Ligand B (50.85) has significantly higher clearance, indicating faster metabolism.

**13. In vitro Half-Life:** Ligand A (-9.257) has a negative half-life, which is not physically possible and indicates a problem with the data or the model. Ligand B (-12.209) also has a negative half-life, indicating a similar issue.

**14. P-gp Efflux:** Ligand A (0.088) has very low P-gp efflux, which is favorable for CNS penetration. Ligand B (0.373) has slightly higher P-gp efflux, but still relatively low.

**15. Binding Affinity:** Ligand A (-8.2 kcal/mol) has a slightly better binding affinity than Ligand B (-7.6 kcal/mol). However, the difference is not substantial enough to outweigh other significant drawbacks.

**Overall Assessment:**

Despite having slightly better binding affinity, Ligand A suffers from a poor BBB penetration, questionable half-life data, and lower QED. Ligand B, while having a slightly weaker affinity, exhibits excellent BBB penetration, lower P-gp efflux, and a more favorable TPSA. The negative half-life values for both are concerning and would require further investigation, but the other properties of Ligand B make it a more promising candidate for a CNS-targeting drug like a DRD2 modulator. The superior BBB penetration of Ligand B is the deciding factor, given the target.

Output:
1
2025-04-17 03:34:55,240 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B based on the provided guidelines, prioritizing GPCR-specific properties (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (347.46 and 343.38 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (70.67) is significantly better than Ligand B (104.46). For CNS targets, TPSA should be <= 90, and A is comfortably within this range, while B exceeds it.

**logP:** Both ligands have acceptable logP values (0.817 and 1.5), falling within the 1-3 optimal range. Ligand B is slightly higher, which could be beneficial for membrane permeability.

**H-Bond Donors/Acceptors:** Ligand A (2 HBD, 4 HBA) is better than Ligand B (3 HBD, 5 HBA) in terms of balancing solubility and permeability. Both are within acceptable limits.

**QED:** Both ligands have reasonable QED scores (0.766 and 0.661), indicating good drug-like properties.

**DILI:** Ligand A (22.33) has a much lower DILI risk than Ligand B (55.45), which is a significant advantage.

**BBB:** Ligand A (44.90) has a better BBB percentile than Ligand B (36.64), though neither are >70. This is a critical factor for CNS targets like DRD2.

**Caco-2 Permeability:** Both have negative values, which is unusual. Assuming these are logP-like scales, lower values indicate poorer permeability. They are similarly poor.

**Aqueous Solubility:** Both have negative values, indicating poor solubility. Ligand B is worse (-2.693 vs -1.014).

**hERG:** Both ligands have low hERG inhibition liability (0.144 and 0.336), which is good.

**Microsomal Clearance:** Ligand A (-5.442) has much lower (better) microsomal clearance than Ligand B (48.298), indicating better metabolic stability.

**In vitro Half-Life:** Ligand A (1.512 hours) has a shorter half-life than Ligand B (7.951 hours). Longer half-life is generally preferred.

**P-gp Efflux:** Ligand A (0.008) has significantly lower P-gp efflux liability than Ligand B (0.216), which is a major advantage for CNS penetration.

**Binding Affinity:** Ligand B (-7.9 kcal/mol) has a slightly better binding affinity than Ligand A (-8.0 kcal/mol). While this is a small difference, it's still a positive for Ligand B.

**Overall Assessment:**

Despite the slightly better affinity of Ligand B, Ligand A is the superior candidate. The key advantages of Ligand A are its significantly better TPSA, lower DILI risk, lower P-gp efflux, and much better metabolic stability (lower Cl_mic). The better BBB penetration of Ligand A is also crucial for a CNS target. While Ligand B has a slightly longer half-life, the other ADME properties of Ligand A outweigh this benefit.

Output:
0
2025-04-17 03:34:55,240 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight (MW):** Both ligands (370.503 and 370.566 Da) are within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (80.9) is slightly above the optimal <90 for CNS targets, but still reasonable. Ligand B (59.08) is excellent, well below 90.

**3. logP:** Ligand A (3.658) is at the upper end of the optimal range (1-3), but acceptable. Ligand B (2.102) is well within the optimal range.

**4. H-Bond Donors (HBD):** Both ligands have acceptable HBD counts (Ligand A: 2, Ligand B: 0), well below the threshold of 5.

**5. H-Bond Acceptors (HBA):** Both ligands have acceptable HBA counts (Ligand A: 6, Ligand B: 4), below the threshold of 10.

**6. QED:** Both ligands have similar and good QED values (Ligand A: 0.687, Ligand B: 0.696), indicating good drug-like properties.

**7. DILI:** Ligand A (82.28) has a concerningly high DILI risk (above 60). Ligand B (22.102) has a very low DILI risk, which is a significant advantage.

**8. BBB:** Ligand A (64.056) has a moderate BBB penetration, below the desirable >70 for CNS targets. Ligand B (78.907) has a good BBB penetration, exceeding 70.

**9. Caco-2:** Both ligands have negative Caco-2 values, which is unusual and hard to interpret. Assuming these are percentile scores, lower values are worse. Ligand A (-5.199) is worse than Ligand B (-4.375).

**10. Solubility:** Both ligands have negative solubility values, which is also unusual. Ligand A (-4.154) is worse than Ligand B (-2.86).

**11. hERG:** Both ligands have low hERG inhibition liability (Ligand A: 0.673, Ligand B: 0.377), indicating low cardiotoxicity risk.

**12. Cl_mic:** Ligand A (33.577) has a lower microsomal clearance than Ligand B (54.406), suggesting better metabolic stability.

**13. t1/2:** Ligand A (21.662) has a longer in vitro half-life than Ligand B (13.697), which is desirable.

**14. Pgp:** Ligand A (0.505) has a lower P-gp efflux liability than Ligand B (0.099), suggesting better CNS exposure.

**15. Binding Affinity:** Ligand A (-9.8) has a significantly stronger binding affinity than Ligand B (-0.0). This is a substantial advantage.

**Overall Assessment:**

Ligand A has a much stronger binding affinity and better metabolic stability and Pgp efflux properties. However, its high DILI risk and moderate BBB penetration are major concerns. Ligand B has a much better safety profile (low DILI, good BBB), but its binding affinity is extremely weak.

Given the GPCR-specific priorities, BBB penetration is crucial for CNS targets like DRD2. While Ligand A's affinity is excellent, the high DILI risk and suboptimal BBB are significant drawbacks. Ligand B, despite its weak affinity, presents a much cleaner safety profile and better BBB penetration. The substantial difference in affinity (-9.8 vs -0.0) is a large hurdle for Ligand B, but the safety profile is compelling.

Considering the balance, and the potential for optimization of Ligand B's affinity, I would choose Ligand B as the more viable drug candidate. The safety profile is paramount, and affinity can be improved through further medicinal chemistry efforts.

Output:
1
2025-04-17 03:34:55,240 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (361.825 and 345.403 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (75.63) is significantly better than Ligand B (93.26). For CNS targets, we want TPSA <= 90, so Ligand A is preferable.

**logP:** Ligand A (4.506) is higher than the optimal 1-3 range, potentially causing solubility issues, but still within a reasonable range. Ligand B (1.566) is a bit low, potentially hindering permeation.

**H-Bond Donors/Acceptors:** Ligand A (2 HBD, 3 HBA) and Ligand B (1 HBD, 6 HBA) both have acceptable counts.

**QED:** Both ligands have good QED scores (0.725 and 0.822), indicating good drug-like properties.

**DILI:** Ligand A (77.588) has a higher DILI risk than Ligand B (56.689). This is a negative for Ligand A.

**BBB:** Ligand B (74.758) has a significantly better BBB penetration percentile than Ligand A (25.126). This is a *critical* advantage for a CNS target like DRD2.

**Caco-2 Permeability:** Both ligands have the same Caco-2 permeability (-4.945).

**Aqueous Solubility:** Both ligands have the same Aqueous Solubility (-4.156).

**hERG:** Both ligands have similar, low hERG inhibition liability (0.118 and 0.147).

**Microsomal Clearance:** Ligand A (-12.367) has a much lower (better) microsomal clearance than Ligand B (35.797), indicating greater metabolic stability.

**In vitro Half-Life:** Ligand B (-6.526) has a negative half-life, which is not possible. This is a red flag and suggests a data error or a very rapidly metabolized compound. Ligand A (22.992) has a reasonable half-life.

**P-gp Efflux:** Both ligands have similar, low P-gp efflux liability (0.055 and 0.11).

**Binding Affinity:** Ligand A (-8.7 kcal/mol) has a slightly better binding affinity than Ligand B (-7.9 kcal/mol). While the difference is not huge, it's a positive for Ligand A.

**Overall Assessment:**

Ligand B has a *much* better BBB score, which is paramount for a CNS target. However, it has a concerning negative in vitro half-life. Ligand A has a better TPSA, metabolic stability (lower Cl_mic), and slightly better affinity. While its logP is higher and DILI risk is greater, the BBB issue with Ligand B is a major drawback. Considering the importance of CNS penetration for DRD2, and the questionable half-life of Ligand B, I would favor Ligand A.

Output:
1
2025-04-17 03:34:55,240 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (350.503 and 375.563 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (58.64) is significantly better than Ligand B (48.99). Both are below the 90 A^2 threshold desirable for CNS targets, but A is closer to the optimal range.

**3. logP:** Ligand A (2.759) is within the optimal 1-3 range. Ligand B (4.093) is slightly higher, potentially leading to solubility issues and off-target interactions, although still acceptable.

**4. H-Bond Donors:** Both ligands have 1 HBD, which is within the acceptable limit of <=5.

**5. H-Bond Acceptors:** Ligand A has 3 HBAs, and Ligand B has 4. Both are below the acceptable limit of <=10.

**6. QED:** Ligand A (0.685) has a better QED score than Ligand B (0.53), indicating a more drug-like profile.

**7. DILI:** Ligand A (17.255) has a much lower DILI risk than Ligand B (39.667), which is a significant advantage.

**8. BBB:** Ligand A (75.921) has a substantially higher BBB penetration percentile than Ligand B (39.822). This is *critical* for a CNS target like DRD2.

**9. Caco-2 Permeability:** Ligand A (-4.37) and Ligand B (-5.32) both have negative values, indicating poor Caco-2 permeability. This is a concern for oral bioavailability, but less critical for a CNS target where direct delivery or other routes may be considered.

**10. Aqueous Solubility:** Ligand A (-2.798) and Ligand B (-3.495) both have poor aqueous solubility.

**11. hERG Inhibition:** Ligand A (0.445) has a lower hERG inhibition liability than Ligand B (0.834), which is preferable.

**12. Microsomal Clearance:** Ligand B (89.125) has a higher microsomal clearance than Ligand A (76.671), suggesting lower metabolic stability.

**13. In vitro Half-Life:** Ligand A (3.863) has a longer in vitro half-life than Ligand B (-0.024), which is a positive attribute.

**14. P-gp Efflux:** Ligand A (0.119) has a much lower P-gp efflux liability than Ligand B (0.469), which is important for CNS exposure.

**15. Binding Affinity:** Ligand B (-7.7) has a slightly better binding affinity than Ligand A (-7.5), but the difference is relatively small (0.2 kcal/mol).

**Overall Assessment:**

Ligand A is significantly better than Ligand B. While Ligand B has slightly better binding affinity, Ligand A excels in crucial ADME properties for a CNS-targeting GPCR. Specifically, its superior BBB penetration, lower DILI risk, lower P-gp efflux, and better metabolic stability (lower Cl_mic, longer t1/2) are highly advantageous. The TPSA is also more favorable for CNS penetration. The small affinity difference is easily outweighed by the substantial improvements in ADME properties.

Output:
0
2025-04-17 03:34:55,241 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (366.443 and 347.455 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (122.46) is slightly above the optimal <90 for CNS targets, but still reasonable. Ligand B (55.84) is excellent, well below the threshold.

**logP:** Ligand A (-0.491) is a bit low, potentially hindering permeability. Ligand B (3.98) is very good, falling within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A has 2 HBD and 5 HBA, which are acceptable. Ligand B has 0 HBD and 4 HBA, also acceptable.

**QED:** Both ligands have similar QED values (0.728 and 0.73), indicating good drug-like properties.

**DILI:** Ligand A (48.43) has a slightly higher DILI risk than Ligand B (31.989), but both are below the concerning threshold of 60.

**BBB:** This is critical for a CNS target. Ligand A (47.615) has a moderate BBB penetration, while Ligand B (84.374) is excellent, exceeding the desirable >70 threshold.

**Caco-2 Permeability:** Ligand A (-5.517) shows poor permeability, which is concerning. Ligand B (-4.301) is also not ideal, but better than A.

**Aqueous Solubility:** Both ligands have poor aqueous solubility (-1.984 and -4.638). This could pose formulation challenges.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.096 and 0.773).

**Microsomal Clearance:** Ligand A (-12.618) has a lower (better) microsomal clearance than Ligand B (97.086), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (-17.925) has a shorter half-life than Ligand B (-13.602), which is less desirable.

**P-gp Efflux:** Ligand A (0.008) has very low P-gp efflux, which is excellent for CNS penetration. Ligand B (0.393) has moderate P-gp efflux.

**Binding Affinity:** Both ligands have comparable binding affinities (-8.1 and -8.7 kcal/mol), both being strong binders. The difference is less than 1.5 kcal/mol, so this doesn't significantly sway the decision.

**Overall Assessment:**

Ligand B is the stronger candidate. While both have poor solubility, Ligand B excels in key areas for CNS GPCR targets: significantly better BBB penetration, a more favorable logP, and better Caco-2 permeability. Although Ligand A has better metabolic stability (lower Cl_mic) and lower P-gp efflux, the superior BBB penetration and logP of Ligand B outweigh these advantages. The similar binding affinities make these ADME properties the deciding factors.

Output:
1
2025-04-17 03:34:55,241 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (342.359 Da and 359.861 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (93.45) is better than Ligand B (64.34). For CNS targets, we want TPSA <= 90, so Ligand A is close to the threshold, while Ligand B is well within.

**3. logP:** Ligand A (-0.042) is suboptimal, being slightly below the preferred 1-3 range. Ligand B (4.084) is high, potentially causing solubility issues and off-target effects.

**4. H-Bond Donors:** Both ligands have acceptable HBD counts (0 for A, 1 for B), well below the limit of 5.

**5. H-Bond Acceptors:** Both ligands have acceptable HBA counts (7 for A, 6 for B), below the limit of 10.

**6. QED:** Both ligands have similar QED values (0.777 and 0.718), indicating good drug-like properties.

**7. DILI:** Both ligands have similar DILI risk (75.572 and 77.705), indicating moderate risk. This isn't a major differentiating factor.

**8. BBB:** Ligand B (62.699) has a significantly better BBB percentile than Ligand A (47.189). For a CNS target like DRD2, BBB penetration is crucial, making Ligand B more attractive.

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 values, which is unusual and suggests poor permeability. However, the values are similar (-4.474 and -4.702), so this isn't a major differentiator.

**10. Aqueous Solubility:** Both ligands have negative solubility values, which is also unusual and suggests poor solubility. Again, the values are similar (-1.749 and -4.403).

**11. hERG Inhibition:** Both ligands have low hERG inhibition risk (0.189 and 0.833).

**12. Microsomal Clearance:** Ligand A (28.465) has a lower microsomal clearance than Ligand B (75.657), suggesting better metabolic stability.

**13. In vitro Half-Life:** Ligand B (64.847) has a significantly longer in vitro half-life than Ligand A (-15.715). This is a significant advantage for dosing convenience.

**14. P-gp Efflux:** Both ligands have low P-gp efflux liability (0.054 and 0.665).

**15. Binding Affinity:** Ligand B (-7.8 kcal/mol) has a slightly better binding affinity than Ligand A (-8.1 kcal/mol). While the difference is small, it's still favorable.

**Overall Assessment:**

Ligand B is the more promising candidate. While its logP is high, its significantly better BBB penetration and longer half-life outweigh the slightly higher logP and lower affinity compared to Ligand A. The TPSA is also better for Ligand B. The similar DILI and hERG values don't sway the decision. Given the GPCR target and the need for CNS penetration, Ligand B is the better choice.

Output:
1
2025-04-17 03:34:55,241 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (350.463 and 341.411 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Both ligands (85.25 and 82.53) are below the 90 A^2 threshold for CNS targets, which is excellent.

**3. logP:** Both ligands (1.697 and 1.381) are within the optimal 1-3 range.

**4. H-Bond Donors:** Both ligands have 2 HBD, which is acceptable (<=5).

**5. H-Bond Acceptors:** Ligand A has 5 HBA, and Ligand B has 4. Both are below the 10 threshold.

**6. QED:** Both ligands have QED values (0.818 and 0.766) above 0.5, indicating good drug-likeness.

**7. DILI:** Ligand A (25.359) has a significantly lower DILI risk than Ligand B (48.468). This is a substantial advantage.

**8. BBB:** Ligand B (59.325) has a better BBB penetration percentile than Ligand A (40.093). While both are not ideal (>70), Ligand B is closer to the desired range for a CNS target.

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.77 and -4.982). This is unusual and suggests poor permeability, but the scale isn't fully defined here, so it's hard to interpret.

**10. Aqueous Solubility:** Ligand A (-1.424) has better aqueous solubility than Ligand B (-3.033).

**11. hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.124 and 0.168).

**12. Microsomal Clearance:** Ligand A (7.374) has a higher microsomal clearance than Ligand B (3.84). This suggests Ligand B is more metabolically stable.

**13. In vitro Half-Life:** Ligand B (-4.983) has a significantly longer in vitro half-life than Ligand A (0.5).

**14. P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.014 and 0.03).

**15. Binding Affinity:** Ligand B (-7.7 kcal/mol) has a stronger binding affinity than Ligand A (-7.1 kcal/mol). This is a 0.6 kcal/mol difference, which is a meaningful advantage.

**Overall Assessment:**

Ligand B is superior in terms of binding affinity and BBB penetration, and has better metabolic stability (lower Cl_mic and longer t1/2). However, Ligand A has a significantly lower DILI risk and better aqueous solubility. Considering the GPCR-specific priorities, the stronger binding affinity of Ligand B is a key advantage, and the slightly better BBB is also beneficial. The DILI risk of Ligand A is concerning, and while solubility is important, it can often be addressed with formulation strategies. The longer half-life of Ligand B is also a significant plus.

Output:
1
2025-04-17 03:34:55,241 - INFO - Batch 41 complete. Total preferences: 656
2025-04-17 03:34:55,242 - INFO - Processing batch 42/512...
2025-04-17 03:35:37,580 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (358.869 and 344.499 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (62.22) is higher than Ligand B (41.57). For a CNS target like DRD2, TPSA should be <= 90, so both are acceptable, but B is significantly better.

**3. logP:** Both ligands have similar logP values (4.073 and 4.096), which are within the optimal 1-3 range, although slightly on the higher end.

**4. H-Bond Donors:** Ligand A (2) and Ligand B (1) are both within the acceptable limit of <=5.

**5. H-Bond Acceptors:** Ligand A (3) and Ligand B (2) are both within the acceptable limit of <=10.

**6. QED:** Both ligands have good QED values (0.818 and 0.897), indicating good drug-like properties.

**7. DILI:** Ligand A (46.297) has a higher DILI risk than Ligand B (22.722). Lower is better, so B is preferable.

**8. BBB:** This is a critical parameter for CNS targets. Ligand B (89.492) has a much higher BBB penetration percentile than Ligand A (66.615). This is a significant advantage for B.

**9. Caco-2 Permeability:** Both have negative values, which is unusual and suggests poor permeability. However, the scale is not specified, making direct comparison difficult.

**10. Aqueous Solubility:** Both ligands have negative values, indicating poor solubility.

**11. hERG Inhibition:** Both ligands have similar low hERG inhibition liability (0.571 and 0.567).

**12. Microsomal Clearance:** Ligand B (52.215) has a lower microsomal clearance than Ligand A (30.609), indicating better metabolic stability.

**13. In vitro Half-Life:** Ligand B (6.76) has a lower half-life than Ligand A (26.226). While longer is generally preferred, the difference isn't massive.

**14. P-gp Efflux:** Ligand A (0.374) has lower P-gp efflux than Ligand B (0.193), which is better for CNS exposure.

**15. Binding Affinity:** Ligand A (-9.6 kcal/mol) has a slightly better binding affinity than Ligand B (-8.5 kcal/mol). This is a 1.1 kcal/mol difference, which is significant.

**Overall Assessment:**

While Ligand A has a slightly better binding affinity, Ligand B excels in several key areas crucial for a CNS-targeting GPCR ligand: significantly better BBB penetration, lower DILI risk, and better metabolic stability. The P-gp efflux is better for A, but the difference is not huge. The TPSA is also much more favorable for B. The binding affinity difference, while noticeable, might be overcome with further optimization of Ligand B. Given the importance of CNS penetration and safety for DRD2, Ligand B is the more promising candidate.

Output:
1
2025-04-17 03:35:37,581 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (376.418 Da) is slightly higher than Ligand B (343.387 Da), but both are acceptable.

**TPSA:** Ligand A (66.48) is significantly better than Ligand B (104.6). For CNS targets, TPSA should be <= 90. Ligand A is well within this range, while Ligand B is above. This is a significant advantage for Ligand A.

**logP:** Ligand A (3.143) is optimal (1-3), while Ligand B (0.238) is quite low, potentially hindering membrane permeability and CNS penetration. This favors Ligand A.

**H-Bond Donors/Acceptors:** Ligand A (HBD=1, HBA=4) is preferable to Ligand B (HBD=3, HBA=5). Both are within acceptable limits, but fewer H-bonds generally improve permeability.

**QED:** Both ligands have reasonable QED values (Ligand A: 0.816, Ligand B: 0.699), indicating good drug-like properties.

**DILI:** Both ligands have relatively high DILI risk (Ligand A: 60.721, Ligand B: 67.507), but are still within an acceptable range.

**BBB:** Ligand A (66.227) has a much better BBB percentile than Ligand B (41.605).  For a CNS target like DRD2, BBB penetration is crucial, making Ligand A significantly more promising.

**Caco-2 Permeability:** Both have negative values, which is unusual and suggests issues with the data or modeling. However, the magnitude of the negative value is larger for Ligand B (-5.561 vs -4.9), suggesting lower permeability.

**Aqueous Solubility:** Both have negative values, which is also unusual. Ligand A (-3.005) is slightly better than Ligand B (-2.431).

**hERG Inhibition:** Ligand A (0.554) has a lower hERG inhibition liability than Ligand B (0.168), which is preferable.

**Microsomal Clearance:** Ligand A (53.856) has a higher (worse) microsomal clearance than Ligand B (0.932), indicating faster metabolism. This is a drawback for Ligand A.

**In vitro Half-Life:** Ligand A (42.464) has a longer half-life than Ligand B (21.971), which is a positive attribute.

**P-gp Efflux:** Ligand A (0.451) shows lower P-gp efflux liability than Ligand B (0.008), which is highly desirable for CNS penetration.

**Binding Affinity:** Ligand B (-8.8 kcal/mol) has a slightly better binding affinity than Ligand A (-8.4 kcal/mol). While a 1.5 kcal/mol advantage is significant, the other ADME properties of Ligand B are considerably worse.

**Overall Assessment:**

Ligand A is the superior candidate. While Ligand B has slightly better binding affinity, Ligand A excels in critical ADME properties for a CNS-targeting GPCR ligand: TPSA, logP, BBB penetration, and P-gp efflux. The lower TPSA and higher logP of Ligand A will likely translate to better brain exposure, outweighing the minor difference in binding affinity. The higher metabolic clearance of Ligand A is a concern, but can potentially be addressed through structural modifications.



Output:
1
2025-04-17 03:35:37,581 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (345.443 Da) is slightly lower, which could be beneficial for permeability. Ligand B (362.415 Da) is also good.

**TPSA:** Ligand A (62.74) is excellent, well below the 90 A^2 threshold for CNS targets. Ligand B (125.8) is higher, but still potentially acceptable, though less ideal for brain penetration.

**logP:** Both ligands have good logP values (A: 1.947, B: 1.118), falling within the 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A (HBD=0, HBA=4) is better in this regard. Ligand B (HBD=3, HBA=8) is at the upper limit of acceptable HBA count.

**QED:** Both ligands have similar and acceptable QED values (A: 0.584, B: 0.595).

**DILI:** Ligand A (21.946) has a significantly lower DILI risk than Ligand B (98.061). This is a major advantage for Ligand A.

**BBB:** Ligand A (63.784) has a much better BBB percentile than Ligand B (49.011). This is critical for a CNS target like DRD2.

**Caco-2 Permeability:** Ligand A (-3.916) has a worse Caco-2 permeability than Ligand B (-5.539), but both are negative, indicating poor permeability.

**Aqueous Solubility:** Ligand A (-1.885) has slightly better solubility than Ligand B (-3.486), but both are poor.

**hERG:** Ligand A (0.192) has a lower hERG risk than Ligand B (0.527).

**Microsomal Clearance:** Ligand B (39.565) has a lower microsomal clearance than Ligand A (74.57), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand B (24.073) has a longer half-life than Ligand A (-15.945). This is a positive for Ligand B.

**P-gp Efflux:** Ligand A (0.024) has lower P-gp efflux liability than Ligand B (0.026), which is favorable for CNS penetration.

**Binding Affinity:** Ligand B (-8.1) has a significantly stronger binding affinity than Ligand A (-6.8). This is a substantial advantage for Ligand B, potentially outweighing some of its ADME drawbacks.

**Overall Assessment:**

While Ligand B has a superior binding affinity, Ligand A demonstrates a much more favorable safety profile (lower DILI) and significantly better predicted BBB penetration. The lower TPSA of Ligand A also supports better CNS entry. The slightly better solubility and lower P-gp efflux of Ligand A are also beneficial. The improved metabolic stability and half-life of Ligand B are positives, but the high DILI and poor BBB penetration are significant concerns for a CNS drug. Given the GPCR-specific priorities, particularly BBB penetration for a CNS target, and the importance of avoiding liver toxicity, Ligand A is the more promising candidate despite the weaker binding affinity. The affinity difference, while notable, is not so large that it completely overrides the ADME/Tox advantages of Ligand A.

Output:
0
2025-04-17 03:35:37,581 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (386.42 and 395.26 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (50.69) is better than Ligand B (59.81). Both are below 90, which is favorable for CNS penetration, but A is closer to the optimal range.

**3. logP:** Both ligands have logP values around 4.2, which is slightly above the optimal range of 1-3. This could lead to solubility issues or off-target interactions, but is not a dealbreaker.

**4. H-Bond Donors:** Both have 1 HBD, which is within the acceptable limit of <=5.

**5. H-Bond Acceptors:** Ligand A has 5 HBA, and Ligand B has 4. Both are within the acceptable limit of <=10.

**6. QED:** Ligand A (0.838) has a significantly better QED score than Ligand B (0.563), indicating a more drug-like profile.

**7. DILI:** Ligand A (75.301) has a lower DILI risk than Ligand B (87.786), which is preferable.

**8. BBB:** Ligand A (81.621) has a much better BBB penetration percentile than Ligand B (64.211). This is *critical* for a CNS target like DRD2.

**9. Caco-2 Permeability:** Both have negative Caco-2 values (-4.924 and -5.18), indicating poor permeability. This is a concern for oral bioavailability.

**10. Aqueous Solubility:** Both have negative solubility values (-5.255 and -3.741), indicating poor aqueous solubility. This is a concern for formulation and bioavailability.

**11. hERG Inhibition:** Both ligands have low hERG inhibition risk (0.637 and 0.671).

**12. Microsomal Clearance:** Ligand B (91.372) has a higher microsomal clearance than Ligand A (62.364), meaning it's metabolized faster and has lower metabolic stability.

**13. In vitro Half-Life:** Ligand B (94.894) has a much longer in vitro half-life than Ligand A (1.893). This is a positive for Ligand B.

**14. P-gp Efflux:** Both ligands have low P-gp efflux liability (0.718 and 0.497).

**15. Binding Affinity:** Ligand B (-9.9 kcal/mol) has a slightly better binding affinity than Ligand A (-9.3 kcal/mol). However, the difference is not substantial enough to outweigh the other significant differences.

**Overall Assessment:**

Ligand A is the better candidate. While both have issues with Caco-2 and solubility, Ligand A excels in crucial areas for a CNS-targeting GPCR: significantly better BBB penetration (81.621 vs 64.211), a much higher QED score (0.838 vs 0.563), and lower DILI risk. The slightly weaker binding affinity of Ligand A is less concerning given its superior ADME properties, especially BBB penetration. The longer half-life of Ligand B is a plus, but the other deficiencies are more critical.

Output:
0
2025-04-17 03:35:37,581 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (345.4) is slightly higher than Ligand B (328.5), but both are acceptable.

**TPSA:** Ligand A (84.66) is excellent for CNS penetration, being well below 90. Ligand B (15.71) is *exceptionally* low, which is generally favorable for BBB penetration but could potentially indicate a lack of necessary interactions.

**logP:** Ligand A (2.287) is within the optimal range (1-3). Ligand B (4.496) is a bit high, potentially leading to solubility issues and off-target interactions.

**H-Bond Donors/Acceptors:** Ligand A has 1 HBD and 5 HBA, which is reasonable. Ligand B has 0 HBD and 4 HBA, also acceptable.

**QED:** Both ligands have good QED scores (A: 0.754, B: 0.803), indicating good drug-like properties.

**DILI:** Ligand A (76.425) has a higher DILI risk than Ligand B (37.573). This is a negative for Ligand A.

**BBB:** Ligand B (96.355) has a *very* high BBB penetration score, significantly better than Ligand A (40.675). This is a major advantage for a CNS target like DRD2.

**Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual. This suggests poor permeability.

**Aqueous Solubility:** Both have negative solubility values, which is also unusual. This suggests poor solubility.

**hERG Inhibition:** Ligand A (0.032) has a very low hERG risk, which is excellent. Ligand B (0.984) has a higher, though not alarming, hERG risk.

**Microsomal Clearance:** Ligand A (29.294) has lower microsomal clearance, indicating better metabolic stability than Ligand B (60.162).

**In vitro Half-Life:** Ligand A (-21.963) has a negative half-life, which is impossible. Ligand B (-0.162) also has a negative half-life, which is impossible.

**P-gp Efflux:** Ligand A (0.059) has low P-gp efflux, which is favorable for CNS exposure. Ligand B (0.77) has a moderate P-gp efflux.

**Binding Affinity:** Ligand B (-7.6) has a slightly better binding affinity than Ligand A (-7.8), although the difference is small.

**Overall Assessment:**

Ligand B is the stronger candidate. Its exceptionally high BBB penetration is a crucial advantage for a CNS target. While its logP is slightly elevated, the superior BBB score, lower DILI risk, and comparable affinity outweigh this drawback. The negative values for Caco-2 and Solubility are concerning for both, but the difference in BBB is significant. The negative half-life values are likely errors in the data.

Output:
1
2025-04-17 03:35:37,581 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (349.475) is slightly preferred due to being closer to the lower end, potentially aiding permeability.

**TPSA:** Ligand A (72.88) is excellent for CNS penetration, well below the 90 A^2 threshold. Ligand B (111.24) is still reasonable, but less ideal.

**logP:** Ligand A (0.595) is a bit low, potentially hindering membrane permeability. Ligand B (-0.879) is even lower, raising concerns about absorption. Both are below the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A (2 HBD, 4 HBA) and Ligand B (1 HBD, 7 HBA) are both within acceptable limits.

**QED:** Both ligands have reasonable QED scores (A: 0.762, B: 0.546), indicating drug-like properties.

**DILI:** Ligand A (6.282) has a very favorable DILI score. Ligand B (45.677) is significantly higher, suggesting a greater risk of liver injury.

**BBB:** Ligand A (33.85) has a low BBB percentile, which is a major drawback for a CNS target. Ligand B (42.226) is slightly better, but still not ideal.

**Caco-2 Permeability:** Both have negative Caco-2 values (-5.096 and -5.035), which is unusual and suggests poor permeability. This is concerning for both.

**Aqueous Solubility:** Both have negative solubility values (-0.953 and -1.252), which is also unusual and suggests poor solubility. This is concerning for both.

**hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.13 and 0.104).

**Microsomal Clearance:** Ligand A (-9.874) has a very low (and negative) microsomal clearance, indicating excellent metabolic stability. Ligand B (17.555) has a higher clearance, suggesting faster metabolism.

**In vitro Half-Life:** Ligand A (14.784 hours) has a reasonable half-life. Ligand B (-41.572 hours) has a negative half-life, which is impossible and indicates a problem with the data.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.013 and 0.009), which is positive for CNS penetration.

**Binding Affinity:** Ligand A (-8.7 kcal/mol) has a significantly stronger binding affinity than Ligand B (-7.5 kcal/mol). This 1.2 kcal/mol difference is substantial.

**Overall Assessment:**

Despite the low logP and BBB values for both, Ligand A is the better candidate. Its significantly stronger binding affinity, excellent metabolic stability (low Cl_mic), favorable DILI score, and better TPSA outweigh the concerns about logP and BBB. The negative half-life for Ligand B is a critical flaw, making it a non-starter. The unusual Caco-2 and solubility values for both are concerning and would require further investigation, but the other properties of Ligand A are more promising.

Output:
0
2025-04-17 03:35:37,581 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (355.479 and 360.483 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (82.11) is better than Ligand B (76.14) as it is closer to the ideal <90 for CNS targets. Both are acceptable.

**logP:** Ligand B (2.757) is optimal (1-3), while Ligand A (0.223) is significantly low, potentially hindering membrane permeability. This is a major drawback for Ligand A.

**H-Bond Donors:** Both ligands have 2 HBD, which is within the acceptable limit of <=5.

**H-Bond Acceptors:** Ligand A has 5 HBA, while Ligand B has 6. Both are within the acceptable limit of <=10.

**QED:** Both ligands have similar QED values (0.683 and 0.67), indicating good drug-likeness.

**DILI:** Ligand A (7.445) has a much lower DILI risk than Ligand B (63.746), which is a significant advantage.

**BBB:** Ligand B (59.325) has a better BBB penetration percentile than Ligand A (29.508). However, both are below the desirable >70 for CNS targets.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.117 and -5.162), which is unusual and suggests poor permeability.

**Aqueous Solubility:** Both ligands have negative solubility values (-0.094 and -3.746), indicating poor aqueous solubility.

**hERG Inhibition:** Ligand A (0.231) shows lower hERG inhibition liability than Ligand B (0.466), which is preferable.

**Microsomal Clearance:** Ligand A (-2.141) has a lower (better) microsomal clearance than Ligand B (94.451), indicating greater metabolic stability.

**In vitro Half-Life:** Ligand A (9.658) has a longer half-life than Ligand B (-1.152), which is desirable.

**P-gp Efflux:** Ligand A (0.019) has significantly lower P-gp efflux liability than Ligand B (0.185), which is crucial for CNS penetration.

**Binding Affinity:** Ligand B (-7.8) has a significantly stronger binding affinity than Ligand A (-0). This is a substantial advantage, potentially outweighing some of the ADME concerns.

**Overall Assessment:**

Ligand B has a much better binding affinity, which is the most important factor. However, it suffers from higher DILI risk, poorer metabolic stability, and higher P-gp efflux. Ligand A has better ADME properties (lower DILI, better metabolic stability, lower P-gp efflux, longer half-life), but its very low logP and weaker binding affinity are major concerns.

Given the GPCR target and the importance of CNS penetration, the binding affinity is paramount. While Ligand B has ADME liabilities, the ~7.8 kcal/mol difference in binding affinity is substantial and could be optimized through further medicinal chemistry. The low logP of Ligand A is a significant hurdle to overcome.

Output:
1
2025-04-17 03:35:37,581 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B based on the provided guidelines, prioritizing GPCR-specific properties (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (352.337 and 366.889 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (73.63) is higher than Ligand B (58.64). For CNS targets, we want TPSA <= 90, so both are acceptable, but B is better.

**logP:** Ligand A (4.17) is slightly higher than the optimal range (1-3), potentially leading to solubility issues. Ligand B (2.974) is within the optimal range. This favors B.

**H-Bond Donors/Acceptors:** Both have 1 HBD, which is good. Ligand A has 5 HBA, while Ligand B has 3. Both are within the acceptable limit of <=10, but B is preferable.

**QED:** Ligand B (0.815) has a significantly better QED score than Ligand A (0.416), indicating a more drug-like profile.

**DILI:** Ligand A (76.503) has a higher DILI risk than Ligand B (29.818). B is much better here.

**BBB:** Both ligands have good BBB penetration (A: 71.074, B: 78.402), exceeding the 70% threshold for CNS targets. B is slightly better.

**Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and potentially problematic. However, the magnitude of negativity is similar, so this isn't a major differentiator.

**Aqueous Solubility:** Both have very poor aqueous solubility (A: -5.049, B: -3.046). This is a concern, but not a deciding factor given the other properties.

**hERG Inhibition:** Ligand A (0.875) has a slightly higher hERG risk than Ligand B (0.237). B is preferable.

**Microsomal Clearance:** Ligand A (67.165) has higher microsomal clearance than Ligand B (28.514), indicating lower metabolic stability. B is better.

**In vitro Half-Life:** Ligand A (59.436) has a longer half-life than Ligand B (33.346). This favors A, but the difference isn't huge.

**P-gp Efflux:** Ligand A (0.528) has higher P-gp efflux than Ligand B (0.068). Lower efflux is better for CNS exposure, so B is favored.

**Binding Affinity:** Ligand B (-8.5 kcal/mol) has a slightly better binding affinity than Ligand A (-8.1 kcal/mol). While the difference is small, it's still a positive for B.

**Overall Assessment:**

Ligand B consistently outperforms Ligand A across most critical ADME properties (logP, QED, DILI, hERG, Cl_mic, Pgp) and has slightly better affinity and BBB penetration. While Ligand A has a slightly longer half-life, the other advantages of Ligand B, particularly its superior drug-likeness and safety profile, make it the more promising drug candidate for a CNS target like DRD2.

Output:
1
2025-04-17 03:35:37,581 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (349.519 Da) is slightly lower, which is generally favorable for permeability.

**2. TPSA:** Ligand A (52.65) is significantly better than Ligand B (94.22). For CNS targets, TPSA < 90 is preferred, and Ligand A is comfortably within this range, while Ligand B is close to the upper limit.

**3. logP:** Both ligands have acceptable logP values (A: 2.26, B: 1.373), falling within the optimal range of 1-3.

**4. H-Bond Donors:** Both ligands have a reasonable number of HBDs (A: 1, B: 2), well below the threshold of 5.

**5. H-Bond Acceptors:** Ligand A (3) is better than Ligand B (6), keeping within the preferred range of <=10.

**6. QED:** Both ligands have similar, good QED values (A: 0.828, B: 0.812), indicating good drug-like properties.

**7. DILI:** Ligand A (8.414) has a much lower DILI risk than Ligand B (42.613). This is a significant advantage for Ligand A.

**8. BBB:** This is a critical parameter for CNS targets. Ligand A (88.174) has a very good BBB penetration percentile, exceeding the desirable >70 threshold. Ligand B (17.642) is very poor, indicating limited CNS exposure.

**9. Caco-2 Permeability:** Ligand A (-4.709) is better than Ligand B (-5.123), but both are negative values, which is unusual and requires further investigation.

**10. Aqueous Solubility:** Ligand A (-1.885) is better than Ligand B (-2.183), but both are negative values, which is unusual and requires further investigation.

**11. hERG Inhibition:** Both ligands have low hERG inhibition risk (A: 0.355, B: 0.208).

**12. Microsomal Clearance:** Ligand A (24.163) has a lower (better) microsomal clearance than Ligand B (-11.285).

**13. In vitro Half-Life:** Ligand A (-4.447) has a better in vitro half-life than Ligand B (52.5).

**14. P-gp Efflux:** Ligand A (0.069) has a much lower P-gp efflux liability than Ligand B (0.16). This is crucial for CNS penetration.

**15. Binding Affinity:** Ligand B (-8.9 kcal/mol) has a slightly better binding affinity than Ligand A (-7.9 kcal/mol). However, the difference is less than 1.5 kcal/mol, and the other ADME properties of Ligand A are significantly superior.

**Overall Assessment:**

Ligand A is the far superior candidate. While Ligand B has slightly better binding affinity, Ligand A excels in almost all other critical parameters, especially those prioritized for GPCRs targeting the CNS: BBB penetration, TPSA, DILI risk, P-gp efflux, and metabolic stability. The significantly better BBB and lower P-gp efflux of Ligand A will likely translate to much higher brain exposure, which is essential for a CNS drug. The lower DILI risk is also a major advantage.



Output:
0
2025-04-17 03:35:37,582 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (365.543 and 353.463 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (61.44) is significantly better than Ligand B (87.74). For CNS targets, we want TPSA <= 90, and A is comfortably within this range, while B is approaching the upper limit.

**3. logP:** Ligand A (2.319) is optimal (1-3), while Ligand B (0.683) is a bit low, potentially hindering permeation.

**4. H-Bond Donors:** Both ligands have 2 HBD, which is acceptable (<=5).

**5. H-Bond Acceptors:** Both ligands have 4 HBA, which is acceptable (<=10).

**6. QED:** Both ligands have QED values above 0.6, indicating good drug-likeness.

**7. DILI:** Ligand A (38.542) has a slightly higher DILI risk than Ligand B (10.702), but both are below the concerning threshold of 60.

**8. BBB:** Ligand B (64.25) has a better BBB percentile than Ligand A (52.811). However, both are below the desirable >70 for CNS targets.

**9. Caco-2 Permeability:** Ligand A (-5.096) is significantly worse than Ligand B (-4.843). However, both are negative, indicating poor permeability.

**10. Aqueous Solubility:** Ligand A (-2.949) is slightly better than Ligand B (-1.427), but both are poor.

**11. hERG Inhibition:** Ligand A (0.817) has a slightly higher hERG risk than Ligand B (0.2), but both are relatively low.

**12. Microsomal Clearance:** Ligand B (-3.423) has a much lower (better) microsomal clearance than Ligand A (34.955), indicating greater metabolic stability.

**13. In vitro Half-Life:** Ligand B (-16.652) has a longer half-life than Ligand A (-20.377), which is favorable.

**14. P-gp Efflux:** Ligand A (0.056) has a much lower P-gp efflux liability than Ligand B (0.012), which is crucial for CNS penetration.

**15. Binding Affinity:** Ligand A (-8.3 kcal/mol) has a significantly stronger binding affinity than Ligand B (-7.5 kcal/mol). This >1.5 kcal/mol difference is substantial and can outweigh some ADME drawbacks.

**Overall Assessment:**

While Ligand B has better BBB penetration and metabolic stability, Ligand A's significantly stronger binding affinity and lower P-gp efflux are critical advantages for a CNS-targeting GPCR like DRD2. The lower TPSA of Ligand A is also beneficial. Although Ligand A has slightly worse Caco-2 permeability and a higher DILI risk, the strong binding affinity is a major driver. The P-gp efflux is a critical factor for CNS drugs, and Ligand A performs better in this regard.

Output:
1
2025-04-17 03:35:37,582 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (345.443 and 362.348 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (76.38) is better than Ligand B (78.87), both are below the 90 A^2 threshold for CNS targets, which is good.

**3. logP:** Ligand A (3.236) is slightly better than Ligand B (1.78), both are within the optimal 1-3 range, but Ligand B is on the lower end, which *could* indicate permeability issues.

**4. H-Bond Donors:** Both ligands have 2 HBD, which is within the acceptable limit of <=5.

**5. H-Bond Acceptors:** Ligand A has 6 HBA, and Ligand B has 4. Both are within the acceptable limit of <=10.

**6. QED:** Both ligands have similar QED values (0.754 and 0.739), indicating good drug-likeness.

**7. DILI:** Both ligands have low DILI risk (32.377 and 31.02), which is favorable.

**8. BBB:** This is a critical parameter for a CNS target like DRD2. Ligand B (70.609) has a significantly better BBB percentile than Ligand A (57.619). This is a major advantage for Ligand B.

**9. Caco-2:** Ligand A (-4.846) is better than Ligand B (-5.141), indicating better intestinal absorption.

**10. Solubility:** Ligand A (-2.991) is better than Ligand B (-2.246), indicating better aqueous solubility.

**11. hERG:** Both ligands have low hERG inhibition liability (0.65 and 0.595), which is good.

**12. Cl_mic:** Ligand A (41.113) has lower microsomal clearance than Ligand B (43.044), suggesting better metabolic stability.

**13. t1/2:** Ligand B (-31.417) has a *much* longer in vitro half-life than Ligand A (56.311). This is a significant advantage for Ligand B.

**14. Pgp:** Ligand A (0.165) has lower P-gp efflux liability than Ligand B (0.062), which is favorable for CNS penetration.

**15. Binding Affinity:** Both ligands have identical binding affinities (-7.7 kcal/mol), which is excellent.

**Overall Assessment:**

While Ligand A has advantages in TPSA, Caco-2 permeability, solubility, and Pgp efflux, Ligand B's significantly better BBB penetration (70.609 vs 57.619) and substantially longer half-life (-31.417 vs 56.311) outweigh these benefits for a CNS target. The similar binding affinity means potency is not a differentiating factor. The slightly lower logP of Ligand B is a minor concern, but the strong BBB and half-life profiles make it the more promising candidate.

Output:
1
2025-04-17 03:35:37,582 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (368.861 and 355.869 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (87.66) is better than Ligand B (46.09). For CNS targets, TPSA should be <= 90, both are within this range, but A is closer to the upper limit.

**3. logP:** Ligand A (2.629) is optimal (1-3), while Ligand B (4.193) is slightly higher. While still acceptable, higher logP can sometimes lead to off-target effects.

**4. H-Bond Donors:** Ligand A (3) is acceptable, while Ligand B (0) is also good.

**5. H-Bond Acceptors:** Ligand A (4) and Ligand B (3) are both within the acceptable limit of <=10.

**6. QED:** Both ligands have good QED scores (0.585 and 0.755, respectively), indicating good drug-like properties. Ligand B is slightly better.

**7. DILI:** Ligand A (34.393) has a lower DILI risk than Ligand B (55.37), which is preferable.

**8. BBB:** Ligand B (69.213) has a significantly better BBB penetration percentile than Ligand A (46.336). This is a *critical* factor for a CNS target like DRD2.

**9. Caco-2 Permeability:** Ligand A (-5.216) and Ligand B (-4.671) both have negative values, which is unusual and suggests poor permeability.

**10. Aqueous Solubility:** Both ligands have very poor aqueous solubility (-3.4 and -4.635 respectively). This is a significant drawback.

**11. hERG Inhibition:** Both ligands show very low hERG inhibition risk (0.256 and 0.596, respectively).

**12. Microsomal Clearance:** Ligand A (30.464) has lower microsomal clearance than Ligand B (87.502), suggesting better metabolic stability.

**13. In vitro Half-Life:** Both ligands have similar in vitro half-lives (20.377 and 20.032 hours).

**14. P-gp Efflux:** Ligand A (0.098) has lower P-gp efflux liability than Ligand B (0.356), which is beneficial for CNS penetration.

**15. Binding Affinity:** Both ligands have identical and excellent binding affinities (-7.7 kcal/mol).

**Overall Assessment:**

Ligand B clearly wins on BBB penetration (69.213 vs 46.336), which is paramount for a CNS target. It also has a slightly better QED score. However, Ligand A has a lower DILI risk and better metabolic stability (lower Cl_mic) and lower P-gp efflux. Both have poor solubility and Caco-2 permeability. Given the importance of BBB for CNS targets, and the equal affinity, Ligand B is the more promising candidate.

Output:
1
2025-04-17 03:35:37,582 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (360.483 and 349.431 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (69.04) is excellent, well below the 90 A^2 threshold for CNS targets. Ligand B (83.66) is still reasonable but less optimal, approaching the 100 A^2 limit.

**logP:** Ligand A (3.602) is at the higher end of the optimal range (1-3), while Ligand B (1.263) is at the lower end. While both are within the range, a higher logP can sometimes be beneficial for CNS penetration, but needs to be balanced with solubility.

**H-Bond Donors/Acceptors:** Ligand A (1 HBD, 6 HBA) and Ligand B (2 HBD, 4 HBA) both have acceptable numbers of H-bond donors and acceptors.

**QED:** Both ligands have similar QED values (0.729 and 0.692), indicating good drug-likeness.

**DILI:** Ligand A (60.915) has a higher DILI risk than Ligand B (42.652). This is a significant drawback for Ligand A.

**BBB:** Ligand A (80.845) has a considerably better BBB penetration percentile than Ligand B (58.434). This is a crucial advantage for a CNS target like DRD2.

**Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and suggests a potential issue with the data or modeling. However, the values are similar.

**Aqueous Solubility:** Both ligands have negative solubility values, which is also unusual. Again, the values are similar.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.13 and 0.389).

**Microsomal Clearance:** Ligand A (78.198) has a significantly higher microsomal clearance than Ligand B (24.776), indicating lower metabolic stability.

**In vitro Half-Life:** Ligand A (11.801) has a longer half-life than Ligand B (3.169).

**P-gp Efflux:** Ligand A (0.407) has lower P-gp efflux liability than Ligand B (0.07), which is favorable for CNS penetration.

**Binding Affinity:** Ligand B (-7.7 kcal/mol) has a slightly better binding affinity than Ligand A (-8.1 kcal/mol). While the difference is small, it is still relevant.

**Overall Assessment:**

Ligand A excels in BBB penetration, P-gp efflux, and in vitro half-life. However, it has a higher DILI risk and a higher microsomal clearance. Ligand B has a better binding affinity and lower DILI risk, but poorer BBB penetration and higher P-gp efflux.

Given the importance of BBB penetration for a CNS target like DRD2, and the relatively small difference in binding affinity, Ligand A is the more promising candidate. The higher DILI risk is a concern, but could potentially be mitigated through structural modifications. The lower metabolic stability is also a concern but could be addressed through prodrug strategies or structural modifications.

Output:
1
2025-04-17 03:35:37,582 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (364.917 and 365.308 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (41.57) is significantly better than Ligand B (93.9). For CNS targets, TPSA should be <= 90, so Ligand A is much more favorable.

**logP:** Ligand A (4.526) is higher than the optimal 1-3 range, but still potentially manageable. Ligand B (1.469) is a bit low, potentially hindering membrane permeability.

**H-Bond Donors/Acceptors:** Both have 1 HBD, which is good. Ligand A has 3 HBA, while Ligand B has 6. Both are within the acceptable limit of <=10, but Ligand A is preferable.

**QED:** Both ligands have reasonable QED values (0.856 and 0.736), indicating drug-like properties.

**DILI:** Ligand A (11.283) has a much lower DILI risk than Ligand B (58.511). This is a significant advantage for Ligand A.

**BBB:** Ligand A (89.608) has a very good BBB penetration percentile, exceeding the desirable >70 threshold for CNS targets. Ligand B (77.317) is lower, though still not terrible.

**Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and suggests poor permeability. However, the scale is not clearly defined, so we can't draw strong conclusions.

**Aqueous Solubility:** Both have negative solubility values, indicating poor solubility. This is a concern for both, but might be addressable with formulation strategies.

**hERG:** Ligand A (0.852) has a slightly higher hERG risk than Ligand B (0.14), but both are relatively low.

**Microsomal Clearance:** Ligand A (35.436) has higher clearance than Ligand B (20.052), indicating lower metabolic stability. Ligand B is preferable here.

**In vitro Half-Life:** Ligand A (17.907 hours) has a longer half-life than Ligand B (-34.6 hours). The negative value for Ligand B is suspect and likely indicates a very short half-life.

**P-gp Efflux:** Ligand A (0.512) has lower P-gp efflux liability than Ligand B (0.036), which is favorable for CNS penetration.

**Binding Affinity:** Ligand A (-9.2 kcal/mol) has significantly stronger binding affinity than Ligand B (-6.7 kcal/mol). This is a major advantage for Ligand A, potentially outweighing some of its ADME drawbacks.

**Overall Assessment:**

Ligand A is clearly the more promising candidate. It has superior BBB penetration, significantly lower DILI risk, and much stronger binding affinity. While its logP is a bit high and clearance is higher than Ligand B, the substantial benefit in affinity and CNS penetration makes it the better choice. Ligand B's low logP and questionable half-life are significant drawbacks.

Output:
1
2025-04-17 03:35:37,582 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (340.339 Da) is slightly lower, which could be beneficial for permeability.

**TPSA:** Both ligands have TPSA values around 105-110, which is above the optimal <90 for CNS targets, but not drastically so. This is a moderate concern for both.

**logP:** Ligand A (0.272) has a very low logP, which is a significant drawback. It suggests poor membrane permeability and potential issues with absorption. Ligand B (3.137) has a much more favorable logP, falling within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A has 3 HBD and 5 HBA, while Ligand B has 2 HBD and 5 HBA. Both are acceptable within the guidelines.

**QED:** Both ligands have similar QED values (0.697 and 0.654), indicating good drug-like properties.

**DILI:** Ligand A (81.427) has a higher DILI risk than Ligand B (63.591), although both are within an acceptable range.

**BBB:** Both ligands have reasonable BBB penetration (Ligand A: 53.974, Ligand B: 57.619). However, for a CNS target like DRD2, higher is better, and neither is above 70.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.136 and -5.141), which is unusual and suggests very poor permeability. This is a major concern for both.

**Aqueous Solubility:** Both ligands have negative solubility values (-3.863 and -3.486), indicating very poor solubility. This is a significant issue for formulation and bioavailability.

**hERG Inhibition:** Ligand A (0.13) has a very low hERG risk, which is excellent. Ligand B (0.648) has a slightly higher, but still relatively low, hERG risk.

**Microsomal Clearance:** Ligand A (-7.149) has a much lower (better) microsomal clearance than Ligand B (46.795), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (41.944) has a longer half-life than Ligand B (6.06), which is preferable.

**P-gp Efflux:** Ligand A (0.043) has very low P-gp efflux, which is excellent for CNS penetration. Ligand B (0.332) has a higher, but still moderate, P-gp efflux.

**Binding Affinity:** Ligand A (-10.7 kcal/mol) has a significantly stronger binding affinity than Ligand B (-8.3 kcal/mol). This is a substantial advantage.

**Overall Assessment:**

Despite Ligand A's excellent affinity and low P-gp efflux, its extremely low logP and poor solubility are major liabilities. The negative Caco-2 values for both are concerning, but the low logP of Ligand A is particularly problematic for getting the drug to the target in the brain. Ligand B, while having a weaker affinity, has a much better logP, which is critical for CNS penetration. The better metabolic stability (lower Cl_mic) and acceptable hERG risk are also positives.

Considering the GPCR-specific priorities, especially BBB, logP, and affinity, and the fact that the affinity difference is substantial (-10.7 vs -8.3 kcal/mol), Ligand A is the more promising candidate *if* the solubility and permeability issues can be addressed through formulation or structural modifications. However, given the current data, the better overall profile leans towards Ligand A.

Output:
0
2025-04-17 03:35:37,582 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (352.435 and 344.375 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (96.55) is better than Ligand B (111.03). For CNS targets, we want TPSA <= 90, so Ligand A is closer to this threshold.

**3. logP:** Ligand A (0.8) is slightly lower than optimal (1-3), but still acceptable. Ligand B (1.688) is within the optimal range.

**4. H-Bond Donors:** Both ligands have 2 HBD, which is within the acceptable limit of <=5.

**5. H-Bond Acceptors:** Ligand A has 5 HBA, and Ligand B has 7 HBA. Both are within the acceptable limit of <=10.

**6. QED:** Both ligands have similar QED values (0.607 and 0.584), both above the 0.5 threshold, indicating good drug-like properties.

**7. DILI:** Ligand A (40.597) has a significantly lower DILI risk than Ligand B (82.862). This is a major advantage for Ligand A.

**8. BBB:** Ligand A (54.246) has a lower BBB penetration than Ligand B (79.333). While both are not ideal (>70), Ligand B is much better for CNS penetration.

**9. Caco-2 Permeability:** Ligand A (-5.258) has worse Caco-2 permeability than Ligand B (-4.849). Higher values are better, so Ligand B is slightly better here.

**10. Aqueous Solubility:** Ligand A (-1.142) has better aqueous solubility than Ligand B (-3.193). Higher values are better.

**11. hERG Inhibition:** Ligand A (0.64) has a higher hERG inhibition risk than Ligand B (0.046). Lower values are preferred, giving Ligand B an advantage.

**12. Microsomal Clearance:** Ligand A (19.869) has lower microsomal clearance, indicating better metabolic stability, than Ligand B (40.273).

**13. In vitro Half-Life:** Ligand A (-17.358) has a much longer in vitro half-life than Ligand B (-3.263). This is a significant advantage for Ligand A.

**14. P-gp Efflux:** Ligand A (0.048) has lower P-gp efflux liability than Ligand B (0.102). Lower efflux is better, especially for CNS targets.

**15. Binding Affinity:** Ligand B (-9.1 kcal/mol) has a significantly stronger binding affinity than Ligand A (-7.3 kcal/mol). This is a substantial advantage for Ligand B, potentially outweighing some ADME drawbacks.

**Overall Assessment:**

Ligand B has a significantly better binding affinity and BBB penetration, which are crucial for a CNS-targeting GPCR like DRD2. However, it has a higher DILI risk and hERG inhibition liability. Ligand A has better metabolic stability (lower Cl_mic, longer t1/2), lower DILI and P-gp efflux, and better solubility. The difference in binding affinity (-1.8 kcal/mol) is substantial, and a stronger binding ligand is often prioritized. Considering the GPCR-specific priorities, the stronger affinity of Ligand B is the deciding factor, despite its slightly less favorable ADME profile.

Output:
1
2025-04-17 03:35:37,583 - INFO - Batch 42 complete. Total preferences: 672
2025-04-17 03:35:37,583 - INFO - Processing batch 43/512...
2025-04-17 03:36:26,890 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (344.386 and 346.446 Da) fall comfortably within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (67.43) is higher than Ligand B (49.41). For a CNS target like DRD2, TPSA < 90 is preferred, and ideally <60. Ligand B is significantly better here.

**3. logP:** Both ligands have good logP values (3.285 and 3.042), falling within the optimal 1-3 range.

**4. H-Bond Donors:** Ligand A (2) and Ligand B (1) are both acceptable, being less than 5.

**5. H-Bond Acceptors:** Ligand A (3) and Ligand B (2) are both acceptable, being less than 10.

**6. QED:** Both ligands have similar, good QED values (0.845 and 0.833), indicating good drug-like properties.

**7. DILI:** Ligand A (75.378) has a higher DILI risk than Ligand B (36.293). Lower DILI is preferred, making Ligand B more favorable.

**8. BBB:** This is critical for a CNS target. Ligand B (82.668) has a significantly higher BBB percentile than Ligand A (61.225).  >70 is desirable, and Ligand B is closer to that threshold.

**9. Caco-2:** Both have negative values, which is unusual. Assuming these are logP values, they are similar and don't strongly differentiate the two.

**10. Solubility:** Ligand B (-2.884) has a better (higher) solubility score than Ligand A (-4.463).

**11. hERG:** Both ligands have similar, low hERG risk (0.712 and 0.759).

**12. Cl_mic:** Ligand B (29.776) has a lower (better) microsomal clearance than Ligand A (65.841), indicating better metabolic stability.

**13. t1/2:** Ligand A (14.14) has a longer half-life than Ligand B (-4.86). However, the negative value for Ligand B is concerning and likely an error. Assuming the absolute value, Ligand A still has a better in vitro half-life.

**14. Pgp:** Ligand A (0.392) has lower P-gp efflux liability than Ligand B (0.293), which is favorable for CNS penetration.

**15. Binding Affinity:** Ligand B (-8.2 kcal/mol) has a slightly better (more negative) binding affinity than Ligand A (-9.5 kcal/mol). While A is stronger, the difference isn't large enough to overcome the other ADME deficiencies.

**Overall Assessment:**

Ligand B is the more promising candidate. While Ligand A has a slightly better binding affinity and in vitro half-life, Ligand B excels in crucial areas for a CNS-targeting GPCR: significantly better TPSA, DILI risk, BBB penetration, solubility, and metabolic stability. The lower Pgp efflux also contributes to better CNS exposure. The negative half-life for Ligand B is a red flag, but the other benefits are substantial.

Output:
1
2025-04-17 03:36:26,890 - INFO - Okay, let's analyze these two ligands for their potential as DRD2 drug candidates. DRD2 is a GPCR in the CNS, so BBB penetration, logP, Pgp efflux, TPSA, and binding affinity are paramount.

**Ligand A: [391.827, 81.06, 3.54, 1, 5, 0.864, 91.431, 47.538, -4.581, -4.81, 0.304, 37.543, 90.035, 0.155, -8.9]**

*   **MW:** 391.827 Da - Acceptable.
*   **TPSA:** 81.06  - Good, but borderline for CNS targets (ideally <90).
*   **logP:** 3.54 - Excellent. Within the optimal range.
*   **HBD:** 1 - Good.
*   **HBA:** 5 - Good.
*   **QED:** 0.864 - Excellent. Highly drug-like.
*   **DILI:** 91.431 - Very high risk of liver injury. This is a significant concern.
*   **BBB:** 47.538 - Poor BBB penetration.  This is a major drawback for a CNS target.
*   **Caco-2:** -4.581 - Very poor permeability.
*   **Solubility:** -4.81 - Very poor solubility.
*   **hERG:** 0.304 - Low risk of hERG inhibition.
*   **Cl_mic:** 37.543 - Moderate clearance.
*   **t1/2:** 90.035 - Excellent in vitro half-life.
*   **Pgp:** 0.155 - Low P-gp efflux.
*   **Affinity:** -8.9 kcal/mol - Excellent binding affinity.

**Ligand B: [349.435, 80.56, 0.704, 0, 6, 0.782, 49.942, 72.082, -4.704, -1.57, 0.25, 28.05, 2.212, 0.139, -8]**

*   **MW:** 349.435 Da - Acceptable.
*   **TPSA:** 80.56 - Good, borderline for CNS targets.
*   **logP:** 0.704 - Low. Could hinder permeation.
*   **HBD:** 0 - Good.
*   **HBA:** 6 - Good.
*   **QED:** 0.782 - Good drug-like properties.
*   **DILI:** 49.942 - Acceptable DILI risk.
*   **BBB:** 72.082 - Good BBB penetration.  This is a major advantage.
*   **Caco-2:** -4.704 - Very poor permeability.
*   **Solubility:** -1.57 - Very poor solubility.
*   **hERG:** 0.25 - Low risk of hERG inhibition.
*   **Cl_mic:** 28.05 - Relatively low clearance.
*   **t1/2:** 2.212 - Short in vitro half-life.
*   **Pgp:** 0.139 - Low P-gp efflux.
*   **Affinity:** -8 kcal/mol - Excellent binding affinity, very close to Ligand A.

**Comparison and Decision:**

While Ligand A has a slightly better binding affinity (-8.9 vs -8 kcal/mol), its extremely high DILI risk (91.431) and poor BBB penetration (47.538) are deal-breakers for a CNS drug. The poor solubility and permeability also contribute to its unsuitability.

Ligand B, despite a slightly lower affinity, has a significantly better safety profile (DILI 49.942) and crucially, much better BBB penetration (72.082).  The low logP is a concern, but the strong affinity might compensate. The short half-life is a drawback, but could potentially be addressed through structural modifications. The poor permeability and solubility are also concerns, but may be less critical than the CNS penetration and safety profile.

Considering the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity), and the importance of safety for CNS drugs, **Ligand B is the more viable drug candidate.**

1
2025-04-17 03:36:26,891 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (351.443 and 344.419 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Both ligands (87.85 and 85.05) are below the 90 A^2 threshold for CNS targets, which is excellent.

**3. logP:** Ligand A (3.08) is optimal, while Ligand B (0.411) is quite low, potentially hindering membrane permeability. This is a significant drawback for a CNS target.

**4. H-Bond Donors:** Both have 1 HBD, well within the acceptable limit of 5.

**5. H-Bond Acceptors:** Both have 6 HBA, also within the acceptable limit of 10.

**6. QED:** Both ligands have good QED scores (0.648 and 0.851), indicating drug-like properties. Ligand B is slightly better here.

**7. DILI:** Ligand A (60.915) is approaching a concerning DILI risk, while Ligand B (56.689) is better.

**8. BBB:** Ligand A (77.162) has a good BBB percentile, exceeding the 70% threshold. Ligand B (44.32) is significantly lower, which is a major concern for a CNS target like DRD2.

**9. Caco-2:** Both have negative values, which is unusual and suggests poor permeability. However, the scale is not specified, making direct comparison difficult.

**10. Solubility:** Both have negative values, indicating poor solubility. Again, the scale is unspecified.

**11. hERG:** Both have low hERG inhibition liability (0.657 and 0.253), which is positive.

**12. Cl_mic:** Ligand B (30.756) has a much lower microsomal clearance than Ligand A (108.576), suggesting better metabolic stability.

**13. t1/2:** Ligand B (8.193) has a longer in vitro half-life than Ligand A (-27.49), which is a strong advantage.

**14. Pgp:** Ligand B (0.036) has significantly lower P-gp efflux liability than Ligand A (0.163), which is crucial for CNS penetration.

**15. Binding Affinity:** Both ligands have very similar and strong binding affinities (-7.6 and -7.7 kcal/mol). The difference is negligible.

**Overall Assessment:**

While Ligand B has better metabolic stability (lower Cl_mic) and half-life, and lower Pgp efflux, its significantly lower logP and poor BBB penetration are major drawbacks for a CNS-targeting drug. Ligand A, despite a slightly higher DILI risk and higher Cl_mic, has a much more favorable logP and, critically, a good BBB percentile. For a GPCR in the CNS, achieving adequate brain exposure is paramount. The slightly higher metabolic clearance of Ligand A can potentially be addressed through structural modifications later in the optimization process. The poor logP of Ligand B is a more difficult property to improve without significantly altering the binding affinity.

Output:
1
2025-04-17 03:36:26,891 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (335.386 and 359.417 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (47.67) is excellent, well below the 90 A^2 threshold for CNS targets. Ligand B (78.51) is higher but still reasonably good, though approaching the upper limit for CNS penetration.

**3. logP:** Ligand A (3.569) is optimal. Ligand B (1.013) is on the lower side, which *could* hinder permeation, but isn't drastically outside the acceptable range.

**4. H-Bond Donors:** Ligand A (1) and Ligand B (2) are both within the acceptable limit of <=5.

**5. H-Bond Acceptors:** Ligand A (5) and Ligand B (3) are both within the acceptable limit of <=10.

**6. QED:** Both ligands have good QED scores (0.606 and 0.743), indicating good drug-like properties.

**7. DILI:** Ligand A (65.568) has a higher DILI risk than Ligand B (29.779). This is a significant concern for Ligand A.

**8. BBB:** Both ligands show good BBB penetration (Ligand A: 76.696, Ligand B: 82.047), exceeding the 70% threshold for CNS targets. Ligand B is slightly better.

**9. Caco-2 Permeability:** Both have negative Caco-2 values (-5.282 and -4.927). This is unusual and suggests poor permeability *in vitro*. However, these values are on a scale where negative values are possible and don't necessarily disqualify the compounds.

**10. Aqueous Solubility:** Both have negative solubility values (-3.559 and -2.156). Similar to Caco-2, these values are on a scale where negative values are possible and don't necessarily disqualify the compounds.

**11. hERG Inhibition:** Ligand A (0.92) has a slightly higher hERG risk than Ligand B (0.348), but both are relatively low.

**12. Microsomal Clearance:** Ligand A (49.906) has higher clearance than Ligand B (-5.441). Ligand B shows *negative* clearance, which is highly unusual and suggests exceptional metabolic stability.

**13. In vitro Half-Life:** Ligand A (31.559) has a reasonable half-life. Ligand B (-31.244) has a negative half-life, which is not physically possible and indicates a potential issue with the data or assay.

**14. P-gp Efflux:** Ligand A (0.821) has moderate P-gp efflux, while Ligand B (0.014) has very low efflux. Lower P-gp efflux is preferable for CNS exposure.

**15. Binding Affinity:** Ligand A (-10.4 kcal/mol) has significantly stronger binding affinity than Ligand B (-8.3 kcal/mol). This is a substantial advantage (over 2 kcal/mol difference).

**Overall Assessment:**

Ligand A has superior binding affinity, which is a major plus. However, its higher DILI risk and higher P-gp efflux are concerning. Ligand B, while having weaker affinity, exhibits significantly better metabolic stability (negative clearance), lower DILI risk, and lower P-gp efflux. The negative values for Caco-2 and solubility are concerning for both, but not necessarily disqualifying.

Given the GPCR-specific priorities, the strong affinity of Ligand A is tempting. However, the DILI risk is a major drawback. The exceptional metabolic stability and low efflux of Ligand B, coupled with acceptable BBB penetration, make it a more promising starting point for optimization, even with the weaker initial affinity. The negative half-life for Ligand B is a data quality concern, but the other favorable properties are compelling.

Output:
1
2025-04-17 03:36:26,891 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (335.411 and 342.439 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (101.03) is better than Ligand B (58.64). For CNS targets, we want TPSA <= 90, so Ligand B is preferable.

**logP:** Both ligands have good logP values (2.102 and 2.691), falling within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A has 3 HBD and 4 HBA, while Ligand B has 1 HBD and 3 HBA. Both are within acceptable limits (<=5 HBD and <=10 HBA).

**QED:** Both ligands have good QED scores (0.667 and 0.856), indicating good drug-like properties.

**DILI:** Ligand B (40.83) has a slightly better DILI score than Ligand A (54.091), but both are acceptable (<60).

**BBB:** Ligand A (81.117) has a significantly better BBB penetration score than Ligand B (64.948). This is a crucial factor for a CNS target like DRD2.

**Caco-2 Permeability:** Ligand A (-5.567) has worse Caco-2 permeability than Ligand B (-4.488). Higher values are better, but both are negative and therefore indicate poor permeability.

**Aqueous Solubility:** Both ligands have very poor aqueous solubility (-3.12 and -3.255). This is a concern for both.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.889 and 0.443).

**Microsomal Clearance:** Ligand A (-30.821) has a significantly lower (better) microsomal clearance than Ligand B (52.7). Lower clearance indicates greater metabolic stability.

**In vitro Half-Life:** Ligand A (-20.68) has a slightly better in vitro half-life than Ligand B (-18.841).

**P-gp Efflux:** Both ligands have low P-gp efflux (0.232 and 0.274), which is good for CNS penetration.

**Binding Affinity:** Both ligands have similar binding affinities (-9.8 and -9.6 kcal/mol), which are both excellent and well below the -7.0 kcal/mol threshold. The difference is negligible.

**Overall Assessment:**

Considering the GPCR-specific priorities, Ligand A is slightly favored due to its significantly better BBB penetration (81.117 vs 64.948) and lower microsomal clearance (-30.821 vs 52.7). While Ligand B has a slightly better TPSA and DILI score, the BBB penetration is paramount for a CNS target. The slight advantage in metabolic stability of Ligand A is also beneficial. The poor solubility and Caco-2 permeability are concerns for both, but can potentially be addressed through formulation strategies.

Output:
0
2025-04-17 03:36:26,891 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (367.515 and 349.337 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (101.29) is slightly above the optimal <90 for CNS targets, but still reasonable. Ligand B (85.43) is well within the desired range.

**3. logP:** Both ligands have good logP values (1.186 and 1.43), falling within the 1-3 range.

**4. H-Bond Donors:** Both have 3 HBD, which is acceptable.

**5. H-Bond Acceptors:** Ligand A has 4 HBA, and Ligand B has 3. Both are within the acceptable limit of <=10.

**6. QED:** Both ligands have good QED scores (0.57 and 0.781), indicating good drug-like properties.

**7. DILI:** Ligand A (14.696) has a much lower DILI risk than Ligand B (56.34). This is a significant advantage for Ligand A.

**8. BBB:** Ligand A (61.419) has a better BBB percentile than Ligand B (43.699), although neither are >70. This favors Ligand A for a CNS target.

**9. Caco-2:** Both have negative Caco-2 values, which is unusual and suggests poor permeability.

**10. Solubility:** Both have negative solubility values, indicating poor aqueous solubility.

**11. hERG:** Ligand A (0.165) has a lower hERG risk than Ligand B (0.529).

**12. Cl_mic:** Ligand B (-17.779) has a significantly *lower* (better) microsomal clearance than Ligand A (43.265), indicating greater metabolic stability.

**13. t1/2:** Ligand B (-13.164) has a significantly *longer* in vitro half-life than Ligand A (0.127).

**14. Pgp:** Ligand A (0.011) has a much lower Pgp efflux liability than Ligand B (0.045), which is beneficial for CNS penetration.

**15. Binding Affinity:** Ligand B (-9.2 kcal/mol) has a slightly stronger binding affinity than Ligand A (-7.9 kcal/mol). This is a 1.3 kcal/mol difference, which is significant.

**Overall Assessment:**

Ligand B has a superior binding affinity and significantly better metabolic stability (lower Cl_mic, longer t1/2). However, Ligand A demonstrates a much more favorable safety profile (lower DILI, lower hERG) and better BBB penetration and Pgp efflux properties. Given the CNS target (DRD2), BBB penetration and minimizing off-target effects are critical. The affinity difference, while notable, might be overcome with further optimization. The poor Caco-2 and solubility for both are concerning, but can be addressed with formulation strategies.

Considering the balance of properties, and prioritizing CNS penetration and safety for a GPCR target, Ligand A is the more promising candidate.

Output:
0
2025-04-17 03:36:26,891 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (360.47 and 348.443 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (70.08) and Ligand B (67.87) are both below the 90 A^2 threshold desirable for CNS targets, indicating good potential for brain penetration.

**3. logP:** Both ligands have optimal logP values (1.752 and 1.564), falling within the 1-3 range.

**4. H-Bond Donors:** Both have 1 HBD, which is within the acceptable limit of <=5.

**5. H-Bond Acceptors:** Both have 4 HBA, which is within the acceptable limit of <=10.

**6. QED:** Both ligands have good QED scores (0.603 and 0.74), indicating drug-like properties.

**7. DILI:** Ligand A (18.883) has a lower DILI risk than Ligand B (23.11), both are below the 40 threshold, indicating low risk.

**8. BBB:** Ligand A (83.366) has a slightly higher BBB percentile than Ligand B (76.037). Both are above 70, which is desirable for CNS targets.

**9. Caco-2:** Both ligands have negative Caco-2 values (-4.345 and -4.809). This is unusual and suggests poor permeability. However, the scale is not defined, so it's hard to interpret.

**10. Solubility:** Both ligands have negative solubility values (-1.325 and -2.277). This is also unusual and suggests poor solubility. Again, the scale is undefined.

**11. hERG:** Both ligands have very low hERG inhibition risk (0.655 and 0.263).

**12. Cl_mic:** Ligand B (22.786) has a lower microsomal clearance than Ligand A (47.442), suggesting better metabolic stability.

**13. t1/2:** Ligand B (-0.85) has a slightly longer in vitro half-life than Ligand A (-3.143).

**14. Pgp:** Both ligands have low Pgp efflux liability (0.291 and 0.058).

**15. Binding Affinity:** Ligand B (-8.6 kcal/mol) has a significantly stronger binding affinity than Ligand A (-6.2 kcal/mol). This is a >1.5 kcal/mol advantage, which is substantial.

**Conclusion:**

While Ligand A has a slightly better BBB score and lower DILI risk, Ligand B's significantly stronger binding affinity (-8.6 vs -6.2 kcal/mol) outweighs the minor drawbacks in those parameters. The lower Cl_mic and longer t1/2 of Ligand B are also beneficial. The negative values for Caco-2 and Solubility are concerning for both, but the affinity difference is the most important factor here, especially for a GPCR target where achieving sufficient receptor occupancy is crucial.

Output:
1
2025-04-17 03:36:26,891 - INFO - Reasoning:

Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight (MW):** Both ligands (361.873 and 344.455 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (56.15) is excellent, well below the 90 A^2 threshold for CNS targets. Ligand B (67.43) is still reasonable, but less optimal.

**3. logP:** Ligand A (3.771) is at the higher end of the optimal range (1-3), but acceptable. Ligand B (2.741) is well within the optimal range.

**4. H-Bond Donors (HBD):** Both ligands have acceptable HBD counts (1 and 2, respectively), well below the limit of 5.

**5. H-Bond Acceptors (HBA):** Both ligands have acceptable HBA counts (5 and 3, respectively), below the limit of 10.

**6. QED:** Both ligands have good QED scores (0.602 and 0.677), indicating drug-like properties.

**7. DILI:** Ligand A (42.458) has a slightly higher DILI risk than Ligand B (32.028), but both are below the concerning threshold of 60.

**8. BBB:** Both ligands show good BBB penetration (62.233 and 69.407), but Ligand B is better, exceeding 60%. This is crucial for a CNS target like DRD2.

**9. Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and suggests poor permeability. This is a significant concern for both.

**10. Aqueous Solubility:** Both have negative solubility values, which is also unusual and suggests poor solubility. This is a significant concern for both.

**11. hERG Inhibition:** Ligand A (0.508) has a slightly higher hERG risk than Ligand B (0.149), but both are relatively low.

**12. Microsomal Clearance:** Ligand A (87.09) has a higher microsomal clearance than Ligand B (68.733), indicating lower metabolic stability.

**13. In vitro Half-Life:** Ligand B (-1.597) has a negative half-life, which is not possible and indicates a problem with the data. Ligand A (19.851) has a reasonable half-life.

**14. P-gp Efflux:** Ligand A (0.366) has lower P-gp efflux than Ligand B (0.11), which is favorable for CNS penetration.

**15. Binding Affinity:** Ligand A (-8.8 kcal/mol) has a significantly stronger binding affinity than Ligand B (-7.7 kcal/mol). This is a substantial advantage.

**Overall Assessment:**

While both ligands have issues with Caco-2 permeability and solubility, Ligand A has a significantly better binding affinity (-8.8 vs -7.7 kcal/mol). The difference in affinity is substantial enough to potentially overcome the permeability/solubility issues, especially considering the importance of potency for GPCR ligands. Ligand B has better BBB penetration and lower P-gp efflux, but the weaker affinity is a major drawback. The negative half-life for Ligand B is also a red flag. Ligand A's better metabolic stability (lower Cl_mic) is also a plus.

Output:
1
2025-04-17 03:36:26,892 - INFO - Reasoning:

Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (364.47 & 342.44 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Both ligands (93.61 & 94.88) are slightly above the optimal <90 for CNS targets, but still reasonably acceptable.

**3. logP:** Ligand A (1.766) is closer to the optimal 1-3 range than Ligand B (2.556). Ligand B is still within the acceptable range, but slightly higher logP could potentially lead to off-target effects.

**4. H-Bond Donors:** Ligand A (1) is preferable to Ligand B (2). Fewer HBDs generally improve permeability.

**5. H-Bond Acceptors:** Ligand A (5) is preferable to Ligand B (4).

**6. QED:** Both ligands have similar QED values (0.835 and 0.759), indicating good drug-likeness.

**7. DILI:** Ligand B (37.15%) has a significantly lower DILI risk than Ligand A (53.35%), making it more favorable from a toxicity perspective.

**8. BBB:** Both ligands have reasonably good BBB penetration (67.93% and 63.24%), but Ligand A is slightly better. A value >70 is desirable for CNS targets, and both are below this.

**9. Caco-2 Permeability:** Ligand A (-5.157) shows better Caco-2 permeability than Ligand B (-4.735), indicating better intestinal absorption. However, both are negative values, which is unusual and requires further investigation.

**10. Aqueous Solubility:** Both ligands have very poor aqueous solubility (-3.007 and -3.295). This is a significant drawback for both compounds, potentially hindering bioavailability.

**11. hERG Inhibition:** Both ligands have low hERG inhibition risk (0.673 and 0.366), which is positive.

**12. Microsomal Clearance:** Ligand B (13.079) has a significantly lower microsomal clearance than Ligand A (30.589), suggesting better metabolic stability.

**13. In vitro Half-Life:** Ligand A (-23.499) has a longer in vitro half-life than Ligand B (-2.245), which is desirable.

**14. P-gp Efflux:** Ligand A (0.205) has lower P-gp efflux than Ligand B (0.032), which is beneficial for CNS exposure.

**15. Binding Affinity:** Both ligands have very similar and strong binding affinities (-8.7 and -8.3 kcal/mol). The difference is less than the 1.5 kcal/mol threshold.

**Overall Assessment:**

While Ligand A has slightly better BBB penetration, Caco-2 permeability, and in vitro half-life, Ligand B demonstrates a substantially lower DILI risk and significantly improved metabolic stability (lower Cl_mic). Given the GPCR-specific focus and the importance of minimizing toxicity and maximizing CNS exposure, Ligand B is the more promising candidate. The solubility issues are a concern for both, but can potentially be addressed through formulation strategies. The lower DILI and better metabolic stability of Ligand B outweigh the slight advantages of Ligand A.

Output:
1
2025-04-17 03:36:26,892 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (344.5 and 352.4 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (72.86) is excellent, well below the 90 A^2 threshold for CNS targets. Ligand B (93.19) is approaching the upper limit but still acceptable.

**logP:** Ligand A (3.624) is optimal. Ligand B (-1.194) is significantly low, which could hinder membrane permeability and CNS penetration despite a good TPSA.

**H-Bond Donors/Acceptors:** Ligand A (HBD=1, HBA=6) is favorable. Ligand B (HBD=2, HBA=5) is also acceptable.

**QED:** Ligand A (0.703) is good, indicating strong drug-likeness. Ligand B (0.562) is acceptable but less optimal.

**DILI:** Ligand A (30.671) has a very low DILI risk. Ligand B (6.475) also has a very low DILI risk.

**BBB:** Ligand A (95.541) shows excellent BBB penetration. Ligand B (20.512) is poor, a major concern for a CNS target like DRD2.

**Caco-2 Permeability:** Both have negative values (-5.444 and -5.491), which is unusual and difficult to interpret without further context. However, given the logP values, it's likely Ligand B would have lower permeability.

**Aqueous Solubility:** Both have negative values (-2.181 and 0.062), also unusual.

**hERG Inhibition:** Ligand A (0.985) has a low risk of hERG inhibition. Ligand B (0.059) has a very low risk.

**Microsomal Clearance:** Ligand A (20.078) has moderate clearance. Ligand B (-11.77) has negative clearance, which is not physically possible and indicates an issue with the data.

**In vitro Half-Life:** Ligand A (3.406) has a short half-life. Ligand B (-28.676) has a negative half-life, which is not physically possible and indicates an issue with the data.

**P-gp Efflux:** Ligand A (0.757) has moderate P-gp efflux. Ligand B (0.001) has very low P-gp efflux, which is favorable.

**Binding Affinity:** Both ligands have strong binding affinities (-8.0 and -7.4 kcal/mol). Ligand A has a slightly better affinity.

**Overall Assessment:**

Ligand A is significantly more promising. It has a better logP, a much higher BBB score, a more reasonable metabolic profile (even with moderate clearance), and slightly better binding affinity. The negative values for Caco-2 and solubility are concerning, but less critical than the poor BBB penetration of Ligand B. Ligand B's extremely low logP and the impossible values for clearance and half-life make it a less viable candidate. The superior BBB penetration of Ligand A is crucial for a CNS target like DRD2.

Output:
1
2025-04-17 03:36:26,892 - INFO - Reasoning:

Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight (MW):** Both ligands (359.853 and 398.26 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (58.56) is significantly better than Ligand B (64.97). For CNS targets, we want TPSA <= 90, and A is closer to the ideal.

**3. logP:** Both ligands have similar logP values (4.3 and 4.33), slightly above the optimal 1-3 range, but not drastically so. This could potentially lead to some solubility issues, but isn't a major concern.

**4. H-Bond Donors (HBD):** Ligand A (2) is better than Ligand B (0). While both are acceptable, a small number of HBDs can improve solubility without significantly impacting permeability.

**5. H-Bond Acceptors (HBA):** Ligand A (3) is better than Ligand B (5). Similar to HBD, lower HBA is generally preferred for CNS penetration.

**6. QED:** Ligand A (0.836) has a substantially better QED score than Ligand B (0.612), indicating a more drug-like profile.

**7. DILI:** Ligand A (33.191) has a much lower DILI risk than Ligand B (75.766). This is a significant advantage for Ligand A.

**8. BBB:** Ligand A (38.813) has a significantly lower BBB percentile than Ligand B (87.67). This is a *critical* difference, as BBB penetration is paramount for CNS targets like DRD2. Ligand B is excellent here.

**9. Caco-2 Permeability:** Both have negative values (-4.795 and -4.791), which is unusual and suggests poor permeability. This is a concern for both.

**10. Aqueous Solubility:** Both have negative values (-4.929 and -4.425), indicating very poor aqueous solubility. This is a significant drawback for both.

**11. hERG Inhibition:** Ligand A (0.543) has a slightly better hERG profile than Ligand B (0.305), meaning lower risk of cardiotoxicity.

**12. Microsomal Clearance:** Ligand A (72.328) has lower microsomal clearance than Ligand B (102.599), suggesting better metabolic stability.

**13. In vitro Half-Life:** Ligand A (11.183) has a shorter half-life than Ligand B (14.197), but both are reasonable.

**14. P-gp Efflux:** Ligand A (0.159) has lower P-gp efflux than Ligand B (0.285), which is favorable for CNS exposure.

**15. Binding Affinity:** Ligand A (-9.8 kcal/mol) has a slightly better binding affinity than Ligand B (-8.6 kcal/mol). This difference is substantial (over 1.2 kcal/mol) and can outweigh some ADME drawbacks.

**Overall Assessment:**

While Ligand A has better overall drug-like properties (QED, DILI, metabolic stability, P-gp efflux, and a slightly better hERG profile), the *major* advantage of Ligand B is its significantly higher BBB penetration (87.67 vs. 38.813). For a CNS target like DRD2, this is the most important factor. The slightly better affinity of Ligand A is helpful, but cannot overcome the poor BBB prediction. The poor solubility and Caco-2 permeability are concerns for both, but could potentially be addressed with formulation strategies.

Output:
1
2025-04-17 03:36:26,892 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (350.415 and 339.395 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (103.01) is borderline for CNS penetration, being above the preferred <90, but still potentially acceptable. Ligand B (54.78) is excellent, well below 90, and highly favorable for CNS penetration.

**3. logP:** Ligand A (0.829) is a bit low, potentially hindering permeability. Ligand B (0.65) is also low, with similar concerns. Both are below the optimal 1-3 range.

**4. H-Bond Donors:** Ligand A (3) is acceptable. Ligand B (0) is also good, potentially improving permeability.

**5. H-Bond Acceptors:** Ligand A (5) is acceptable. Ligand B (4) is also good.

**6. QED:** Both ligands (0.73 and 0.74) have good drug-likeness scores.

**7. DILI:** Ligand A (21.171) has a lower DILI risk than Ligand B (32.842), indicating a better safety profile.

**8. BBB:** Ligand A (26.561) has a poor BBB penetration percentile. Ligand B (62.97) is significantly better, exceeding 60 and indicating reasonable CNS exposure. This is a crucial factor for a DRD2 ligand.

**9. Caco-2:** Ligand A (-5.313) has very poor Caco-2 permeability. Ligand B (-4.341) is also poor, but slightly better than A.

**10. Solubility:** Both ligands have poor aqueous solubility (-1.131 and -2.404). This could pose formulation challenges.

**11. hERG:** Both ligands have very low hERG inhibition risk (0.08 and 0.102).

**12. Cl_mic:** Ligand A (-24.608) has a very low (and negative) microsomal clearance, suggesting high metabolic stability. Ligand B (10.347) has a moderate clearance, indicating less metabolic stability.

**13. t1/2:** Ligand A (23.715) has a longer in vitro half-life than Ligand B (8.157).

**14. Pgp:** Ligand A (0.015) has very low P-gp efflux, which is excellent for CNS penetration. Ligand B (0.025) also has low P-gp efflux, but slightly higher than A.

**15. Binding Affinity:** Ligand A (0.0) has a significantly weaker binding affinity than Ligand B (-8.0). The difference of 8 kcal/mol is substantial and outweighs many of the ADME drawbacks of Ligand B.

**Overall Assessment:**

While Ligand A has better metabolic stability (Cl_mic, t1/2) and lower DILI risk, Ligand B is significantly superior in terms of BBB penetration and, critically, binding affinity. The strong binding affinity of Ligand B (-8.0 kcal/mol) is a major advantage, especially for a GPCR target. The improved BBB penetration (62.97) compared to Ligand A (26.561) is also crucial for CNS activity. The slightly higher Pgp efflux and lower metabolic stability of Ligand B are less concerning given the substantial gain in binding affinity and improved BBB penetration.

Output:
1
2025-04-17 03:36:26,892 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (350.507 and 351.401 Da) fall within the ideal range of 200-500 Da.

**TPSA:** Ligand A (55.89) is significantly better than Ligand B (77.93). For CNS targets, TPSA should be <= 90, both are within this range, but A is preferred.

**logP:** Ligand A (0.943) is slightly lower than optimal (1-3), but still acceptable. Ligand B (2.307) is within the optimal range.

**H-Bond Donors/Acceptors:** Ligand A (HBD=1, HBA=4) and Ligand B (HBD=2, HBA=5) both have reasonable H-bond characteristics, falling within the suggested limits.

**QED:** Ligand B (0.763) has a better QED score than Ligand A (0.497), indicating a more drug-like profile.

**DILI:** Ligand A (4.382) has a slightly higher DILI risk than Ligand B (32.299), but both are relatively low.

**BBB:** Ligand B (75.456) has a significantly better BBB penetration percentile than Ligand A (62.233). This is a crucial factor for a CNS target like DRD2.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.223 and -5.133), which is unusual and suggests poor permeability. This is a significant concern for both.

**Aqueous Solubility:** Ligand A (0.103) has very poor solubility, while Ligand B (-2.384) is also poor, but slightly better.

**hERG Inhibition:** Ligand A (0.452) has a lower hERG inhibition liability than Ligand B (0.636), which is favorable.

**Microsomal Clearance:** Ligand A (-19.859) has much lower (better) microsomal clearance than Ligand B (9.79). This indicates better metabolic stability for Ligand A.

**In vitro Half-Life:** Ligand A (-5.788) has a longer half-life than Ligand B (-17.05), which is desirable.

**P-gp Efflux:** Ligand A (0.009) has significantly lower P-gp efflux liability than Ligand B (0.08), which is very important for CNS penetration.

**Binding Affinity:** Ligand B (-7.5 kcal/mol) has a slightly better binding affinity than Ligand A (-7.3 kcal/mol), although the difference is small.

**Overall Assessment:**

While Ligand B has better QED, BBB, and binding affinity, Ligand A has superior metabolic stability (lower Cl_mic, longer t1/2), lower P-gp efflux, lower hERG risk, and a significantly better TPSA. The poor Caco-2 permeability is a concern for both, but the strong BBB penetration of Ligand B, combined with its slightly better affinity, outweighs the other advantages of Ligand A, especially considering the GPCR-specific priorities. However, the very poor solubility of both is a major drawback.

Output:
1
2025-04-17 03:36:26,892 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (337.423 and 357.38 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (63.13) is slightly above the optimal <90 for CNS targets, but still reasonable. Ligand B (54.38) is excellent, well below 90.

**3. logP:** Both ligands have good logP values (2.549 and 2.062), falling within the 1-3 optimal range.

**4. H-Bond Donors:** Ligand A (2) is good. Ligand B (0) is also good.

**5. H-Bond Acceptors:** Ligand A (3) is good. Ligand B (6) is acceptable, but higher.

**6. QED:** Both ligands have good QED scores (0.763 and 0.808), indicating drug-like properties.

**7. DILI:** Ligand A (52.772) has a lower DILI risk than Ligand B (62.35), both are acceptable, but A is preferred.

**8. BBB:** This is a critical parameter for a CNS target like DRD2. Ligand B (89.027) has a significantly better BBB penetration percentile than Ligand A (36.409). This is a major advantage for Ligand B.

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.021 and -4.607), which is unusual and suggests poor permeability. However, these values are on a scale where negative values are possible, and the absolute magnitude isn't necessarily directly comparable.

**10. Aqueous Solubility:** Both ligands have very poor aqueous solubility (-3.343 and -3.936). This is a significant drawback for both.

**11. hERG Inhibition:** Both ligands have low hERG inhibition risk (0.369 and 0.667).

**12. Microsomal Clearance:** Ligand A (32.907) has lower microsomal clearance than Ligand B (42.164), indicating better metabolic stability.

**13. In vitro Half-Life:** Ligand A (13.479) has a longer half-life than Ligand B (7.962).

**14. P-gp Efflux:** Ligand A (0.161) has lower P-gp efflux than Ligand B (0.032), meaning it is less likely to be pumped out of the brain, improving CNS exposure.

**15. Binding Affinity:** Ligand A (-8.7 kcal/mol) has a significantly stronger binding affinity than Ligand B (-0.0 kcal/mol). This is a substantial advantage for Ligand A.

**Overall Assessment:**

Ligand B excels in BBB penetration, a crucial factor for CNS drug development. However, its binding affinity is extremely weak. Ligand A has a much stronger binding affinity, better metabolic stability (lower Cl_mic, longer t1/2), and lower P-gp efflux. While Ligand A's BBB penetration is lower, the significantly improved binding affinity (-8.7 vs -0.0 kcal/mol) is likely to outweigh the moderate BBB concern, especially considering the potential for further optimization to improve BBB penetration. The poor solubility of both is a concern, but can be addressed with formulation strategies.

Output:
1
2025-04-17 03:36:26,893 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (359.809 and 352.475 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (71.55) is significantly better than Ligand B (87.66). For CNS targets, we want TPSA <= 90, and A is closer to the ideal <= 60. B is pushing the upper limit and may have reduced brain penetration.

**logP:** Ligand A (3.649) is optimal (1-3), while Ligand B (1.84) is on the lower side. While not terrible, lower logP can hinder membrane permeability.

**H-Bond Donors/Acceptors:** Ligand A (2 HBD, 4 HBA) and Ligand B (3 HBD, 4 HBA) are both acceptable, falling within the recommended limits.

**QED:** Both ligands have reasonable QED values (0.659 and 0.524), indicating good drug-like properties.

**DILI:** Ligand A (73.362) has a higher DILI risk than Ligand B (16.092). This is a significant drawback for A.

**BBB:** Ligand B (61.846) has a much better BBB percentile than Ligand A (37.96). For a CNS target like DRD2, >70 is desirable, but B is significantly better than A.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.991 and -4.795). This is unusual and suggests potential issues with permeability prediction. However, the values are similar.

**Aqueous Solubility:** Both ligands have negative solubility values (-5.14 and -2.16). Again, this is unusual and suggests potential issues with solubility prediction. However, B is better than A.

**hERG Inhibition:** Ligand A (0.63) has a slightly higher hERG risk than Ligand B (0.146). Lower is better here.

**Microsomal Clearance:** Ligand B (49.702) has a slightly lower Cl_mic than Ligand A (41.837), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand B (-14.621) has a negative half-life, which is concerning. Ligand A (25.341) is positive and more reasonable.

**P-gp Efflux:** Ligand A (0.575) has lower P-gp efflux than Ligand B (0.076), which is favorable for CNS penetration.

**Binding Affinity:** Ligand A (-9.7 kcal/mol) has a significantly stronger binding affinity than Ligand B (-7.3 kcal/mol). This is a substantial advantage, potentially outweighing some of the ADME drawbacks.

**Overall Assessment:**

Ligand A has a much stronger binding affinity, which is crucial for GPCRs. However, it suffers from higher DILI risk, lower BBB penetration, and higher hERG risk. Ligand B has better ADME properties (lower DILI, better BBB, lower hERG, better metabolic stability), but its binding affinity is considerably weaker.

Given the importance of BBB penetration for a CNS target, and the substantial difference in binding affinity, the stronger affinity of Ligand A is likely to be more important. While the ADME properties of A are less ideal, optimization could potentially address these issues. The weaker binding of B might require a much larger structural modification to improve, potentially losing the favorable ADME properties.

Output:
1
2025-04-17 03:36:26,893 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (383.279 Da) is slightly higher than Ligand B (347.419 Da), but both are acceptable.

**TPSA:** Ligand A (69.04) is excellent for CNS penetration, well below the 90 A^2 threshold. Ligand B (110.32) is higher, but still potentially acceptable, though less optimal.

**logP:** Ligand A (3.429) is within the optimal range (1-3). Ligand B (-0.358) is significantly below this, which could hinder membrane permeability and brain penetration.

**H-Bond Donors/Acceptors:** Ligand A (HBD=1, HBA=5) and Ligand B (HBD=2, HBA=5) both have reasonable numbers of H-bond donors and acceptors, falling within the guidelines.

**QED:** Both ligands have similar QED values (A: 0.796, B: 0.702), indicating good drug-like properties.

**DILI:** Ligand A (60.14) has a moderate DILI risk, while Ligand B (18.922) has a very low DILI risk, which is a significant advantage.

**BBB:** Ligand A (81.97) has a good BBB penetration percentile, exceeding the 70% threshold. Ligand B (64.676) is lower, which is a concern for a CNS target.

**Caco-2 Permeability:** Ligand A (-4.455) and Ligand B (-5.735) both have negative Caco-2 values, which is unusual and suggests poor permeability. However, these values are on a scale where negative values are possible, and direct comparison is difficult without knowing the scale's origin.

**Aqueous Solubility:** Ligand A (-4.646) and Ligand B (-1.722) both have negative solubility values, which is also unusual and suggests poor solubility.

**hERG Inhibition:** Ligand A (0.599) has a low hERG risk, while Ligand B (0.045) has an even lower risk, which is a positive.

**Microsomal Clearance:** Ligand A (56.985) has a moderate clearance, while Ligand B (-12.548) has a negative clearance, suggesting very high metabolic stability.

**In vitro Half-Life:** Ligand A (10.35) has a reasonable half-life, while Ligand B (-6.918) has a negative half-life, which is not physically possible and indicates a potential issue with the data or assay.

**P-gp Efflux:** Ligand A (0.181) has low P-gp efflux, which is favorable for CNS penetration. Ligand B (0.004) has extremely low P-gp efflux, which is even more favorable.

**Binding Affinity:** Ligand A (-8.5 kcal/mol) has a significantly stronger binding affinity than Ligand B (-7.4 kcal/mol). This 1.1 kcal/mol difference is substantial and could outweigh some of the ADME drawbacks of Ligand A.

**Overall Assessment:**

Ligand A has a superior binding affinity and good BBB penetration, which are critical for a CNS GPCR target. However, it has a moderate DILI risk and moderate metabolic clearance. Ligand B has a very low DILI risk, excellent P-gp efflux, and potentially very high metabolic stability, but suffers from a significantly weaker binding affinity and lower BBB penetration, and a problematic logP.

Given the importance of binding affinity for GPCRs, and the fact that the difference is substantial (1.1 kcal/mol), Ligand A is the more promising candidate despite its slightly less favorable ADME profile. The stronger binding is likely to translate to greater efficacy.

Output:
1
2025-04-17 03:36:26,893 - INFO - Batch 43 complete. Total preferences: 688
2025-04-17 03:36:26,893 - INFO - Processing batch 44/512...
2025-04-17 03:37:08,350 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (345.487 Da) and Ligand B (339.439 Da) are comparable.

**TPSA:** Ligand A (43.86) is significantly better than Ligand B (65.2). For CNS targets, TPSA < 90 is preferred, and A is much closer to the optimal <60 range. B is higher, potentially hindering BBB penetration.

**logP:** Both ligands have good logP values (A: 1.91, B: 2.151), falling within the 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A (HBD=0, HBA=3) is better than Ligand B (HBD=2, HBA=2) in terms of minimizing potential issues with permeability.

**QED:** Both ligands have good QED scores (A: 0.731, B: 0.886), indicating good drug-like properties.

**DILI:** Ligand A (12.485) has a much lower DILI risk than Ligand B (43.622). This is a significant advantage.

**BBB:** Ligand A (79.411) has a much better BBB penetration percentile than Ligand B (54.13). This is crucial for a CNS target like DRD2.

**Caco-2 Permeability:** Ligand A (-4.456) is worse than Ligand B (-5.236), but both are negative, indicating poor permeability.

**Aqueous Solubility:** Ligand A (-1.633) is better than Ligand B (-3.406).

**hERG Inhibition:** Both ligands have low hERG inhibition risk (A: 0.281, B: 0.449).

**Microsomal Clearance:** Ligand A (13.984) has a lower microsomal clearance than Ligand B (28.565), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (-11.664) has a worse in vitro half-life than Ligand B (4.268).

**P-gp Efflux:** Ligand A (0.048) has a lower P-gp efflux liability than Ligand B (0.071), which is favorable for CNS penetration.

**Binding Affinity:** Ligand B (-9.1) has a slightly better binding affinity than Ligand A (-8.7), but the difference is not substantial enough to outweigh the other significant advantages of Ligand A.

**Overall Assessment:**

Ligand A is significantly better overall, particularly regarding CNS penetration (BBB, TPSA, Pgp), safety (DILI), and metabolic stability (Cl_mic). While Ligand B has slightly better affinity and half-life, the other ADME/Tox properties of Ligand A make it a more promising drug candidate for DRD2. The difference in binding affinity is not large enough to overcome the substantial advantages of Ligand A in other critical parameters.

Output:
0
2025-04-17 03:37:08,350 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (342.399 Da) is slightly better than Ligand B (380.413 Da) as it's closer to the lower end, potentially aiding permeability.

**TPSA:** Both ligands have TPSA values (A: 100.02, B: 104.73) that are above the optimal <90 for CNS targets, but still within a reasonable range for oral absorption (<140).

**logP:** Ligand A (2.071) is optimal (1-3), while Ligand B (0.228) is quite low, potentially hindering membrane permeability and CNS penetration. This is a significant drawback for Ligand B.

**H-Bond Donors/Acceptors:** Both have acceptable HBD counts (3). Ligand B has a slightly higher HBA count (6) compared to Ligand A (4), but both are below the guideline of 10.

**QED:** Both ligands have similar QED values (A: 0.349, B: 0.37), indicating moderate drug-likeness.

**DILI:** Ligand A (63.164) has a higher DILI risk than Ligand B (35.285), but both are below the concerning threshold of 60.

**BBB:** Ligand A (61.535) has a better BBB percentile than Ligand B (59.364), though both are below the desirable >70 for CNS targets.

**Caco-2 Permeability:** Ligand A (-5.549) shows better Caco-2 permeability than Ligand B (-5.384), suggesting better intestinal absorption.

**Aqueous Solubility:** Ligand A (-3.138) has slightly better aqueous solubility than Ligand B (-1.71).

**hERG Inhibition:** Both ligands show low hERG inhibition liability (A: 0.544, B: 0.108), which is favorable.

**Microsomal Clearance:** Ligand A (48.729) has a higher microsomal clearance than Ligand B (31.616), indicating potentially lower metabolic stability.

**In vitro Half-Life:** Ligand B (-31.826) has a significantly longer in vitro half-life than Ligand A (-4.43), which is a substantial advantage.

**P-gp Efflux:** Ligand A (0.376) shows lower P-gp efflux liability than Ligand B (0.022), meaning better CNS exposure.

**Binding Affinity:** Ligand A (-8.1 kcal/mol) has a significantly stronger binding affinity than Ligand B (-6.2 kcal/mol). This is a crucial advantage, exceeding the 1.5 kcal/mol difference threshold.

**Overall Assessment:**

While Ligand B has a better half-life and lower DILI risk, Ligand A is superior due to its significantly stronger binding affinity, better logP, better Caco-2 permeability, and lower P-gp efflux. The stronger binding affinity is the most important factor, and the favorable logP and P-gp values will contribute to better CNS penetration despite the moderate BBB scores. The slightly higher clearance of Ligand A is a concern, but could potentially be addressed through structural modifications.



Output:
1
2025-04-17 03:37:08,351 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (372.447 and 355.463 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (93.11) is slightly above the optimal <90 for CNS targets, but still reasonable. Ligand B (72.36) is well within the desired range.

**logP:** Ligand A (-0.615) is a bit low, potentially hindering permeation. Ligand B (3.82) is excellent, falling within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Both have 1 HBD, which is good. Ligand A has 7 HBA, while Ligand B has 5. Both are acceptable (<=10).

**QED:** Both ligands have similar QED values (0.67 and 0.682), indicating good drug-likeness.

**DILI:** Both have relatively high DILI risk (51.26 and 65.762), but below the concerning >60 threshold.

**BBB:** Ligand B (76.696) has a significantly better BBB percentile than Ligand A (66.344), which is crucial for a CNS target like DRD2.

**Caco-2 Permeability:** Ligand A (-4.936) has poor Caco-2 permeability. Ligand B (-5.252) is also poor, but slightly better.

**Aqueous Solubility:** Both have poor aqueous solubility (-1.39 and -3.712). This could present formulation challenges.

**hERG Inhibition:** Both have low hERG inhibition risk (0.351 and 0.769), which is good.

**Microsomal Clearance:** Ligand A (46.653) has lower microsomal clearance than Ligand B (86.074), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (18.674) has a longer half-life than Ligand B (-24.899, which is unusual and likely an error or outlier).

**P-gp Efflux:** Ligand A (0.014) has very low P-gp efflux, which is highly desirable for CNS penetration. Ligand B (0.495) has moderate P-gp efflux.

**Binding Affinity:** Ligand B (-8.1 kcal/mol) has a stronger binding affinity than Ligand A (-7.5 kcal/mol). This 0.6 kcal/mol difference is substantial and can outweigh some ADME drawbacks.

**Overall Assessment:**

Ligand B is the stronger candidate. While both have some issues (solubility, Caco-2), Ligand B excels in the most critical areas for a CNS-targeting GPCR: BBB penetration and binding affinity. The significantly better BBB score and stronger binding affinity outweigh the slightly higher P-gp efflux and higher clearance. Ligand A's low logP and poor Caco-2 permeability are significant drawbacks. The negative half-life for Ligand B is concerning and may indicate an error in the data, but even without considering that, the other factors favor Ligand B.

Output:
1
2025-04-17 03:37:08,351 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (367.515 and 384.933 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (81.06) is slightly above the optimal <90 for CNS targets, but still reasonable. Ligand B (67.23) is excellent, well below 90.

**3. logP:** Both ligands (2.46 and 2.26) are within the optimal 1-3 range.

**4. H-Bond Donors:** Both have 1 HBD, which is good.

**5. H-Bond Acceptors:** Both have 5 HBA, which is good.

**6. QED:** Ligand A (0.886) has a superior QED score compared to Ligand B (0.764), indicating better overall drug-likeness.

**7. DILI:** Ligand A (60.45) has a higher DILI risk than Ligand B (47.693), but both are acceptable (below 60 is preferred).

**8. BBB:** Ligand A (72.78) has a significantly better BBB penetration percentile than Ligand B (31.912). This is *critical* for a CNS target like DRD2.

**9. Caco-2 Permeability:** Ligand A (-4.781) and Ligand B (-5.025) both have negative values, which is unusual and likely indicates low permeability. However, the scale isn't fully defined, so it's hard to interpret.

**10. Aqueous Solubility:** Both ligands have very poor aqueous solubility (-4.025 and -3.697). This is a concern, but can sometimes be mitigated with formulation strategies.

**11. hERG Inhibition:** Both ligands show very low hERG inhibition risk (0.319 and 0.089).

**12. Microsomal Clearance:** Ligand A (27.197) has a lower microsomal clearance than Ligand B (56.629), suggesting better metabolic stability.

**13. In vitro Half-Life:** Ligand A (39.196) has a longer in vitro half-life than Ligand B (8.653), which is desirable.

**14. P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.102 and 0.074), which is good for CNS penetration.

**15. Binding Affinity:** Ligand A (-8.4 kcal/mol) has a slightly better binding affinity than Ligand B (-7.7 kcal/mol). While both are good, the 0.7 kcal/mol difference is notable.

**Overall Assessment:**

Ligand A is the stronger candidate. While both have solubility issues, Ligand A excels in the most critical areas for a CNS GPCR target: BBB penetration (72.78 vs 31.912), metabolic stability (lower Cl_mic, longer t1/2), and slightly better binding affinity. The higher QED score also supports its drug-likeness. Ligand B's lower TPSA is a positive, but it's overshadowed by its poor BBB penetration.

Output:
1
2025-04-17 03:37:08,351 - INFO - Reasoning:

Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (346.471 and 378.885 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (49.85) is excellent, well below the 90 A^2 threshold for CNS targets. Ligand B (97.11) is higher, but still potentially acceptable, though less ideal.

**3. logP:** Both ligands have good logP values (2.841 and 2.707), falling within the optimal 1-3 range.

**4. H-Bond Donors:** Ligand A (0) is good. Ligand B (3) is acceptable, within the limit of 5.

**5. H-Bond Acceptors:** Ligand A (4) is good, well below 10. Ligand B (5) is also acceptable.

**6. QED:** Both ligands have acceptable QED values (0.713 and 0.673), indicating good drug-like properties.

**7. DILI:** Ligand A (13.339) has a much lower DILI risk than Ligand B (65.801), which is a significant advantage.

**8. BBB:** Ligand A (86.274) has a significantly better BBB penetration percentile than Ligand B (67.546). This is crucial for a CNS target like DRD2.

**9. Caco-2 Permeability:** Ligand A (-4.041) and Ligand B (-5.017) both have negative values, indicating poor permeability. This is a concern for both, but the value for Ligand B is worse.

**10. Aqueous Solubility:** Both ligands have very poor aqueous solubility (-2.491 and -4.152). This is a significant drawback for both.

**11. hERG Inhibition:** Both ligands have low hERG inhibition risk (0.571 and 0.462).

**12. Microsomal Clearance:** Ligand A (98.882) has a much higher microsomal clearance than Ligand B (11.015), indicating lower metabolic stability. This is a disadvantage for Ligand A.

**13. In vitro Half-Life:** Ligand B (13.036) has a much longer in vitro half-life than Ligand A (1.191), which is a significant advantage.

**14. P-gp Efflux:** Ligand A (0.056) has much lower P-gp efflux liability than Ligand B (0.109), which is favorable for CNS penetration.

**15. Binding Affinity:** Ligand B (-8.4 kcal/mol) has a significantly stronger binding affinity than Ligand A (-6.9 kcal/mol). This is a substantial advantage, potentially outweighing some ADME drawbacks.

**Overall Assessment:**

Ligand B has a significantly better binding affinity, a longer half-life, and a lower P-gp efflux. However, it has a higher DILI risk, lower BBB penetration, and worse Caco-2 permeability. Ligand A has excellent TPSA, low DILI, and good BBB penetration, but suffers from poor metabolic stability (high clearance) and weaker binding affinity.

Given the importance of binding affinity for GPCRs, and the fact that the difference in affinity (-8.4 vs -6.9) is substantial (greater than 1.5 kcal/mol), Ligand B is the more promising candidate, despite its drawbacks. The lower half-life and higher DILI risk could potentially be addressed through further optimization. The improved affinity is a key driver.

Output:
1
2025-04-17 03:37:08,351 - INFO - Reasoning:

Let's analyze Ligand A and Ligand B against the provided guidelines, prioritizing GPCR-specific properties (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (348.403 and 374.434 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (118.53) is slightly higher than Ligand B (112.57), but both are below the 140 A^2 threshold for oral absorption and reasonably close to the 90 A^2 target for CNS penetration.

**logP:** Ligand A (0.709) is a bit low, potentially hindering permeation. Ligand B (1.579) is better, falling within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A has 2 HBD and 5 HBA, while Ligand B has 3 HBD and 5 HBA. Both are within acceptable limits.

**QED:** Ligand A (0.734) has a better QED score than Ligand B (0.607), indicating a more drug-like profile.

**DILI:** Both ligands have acceptable DILI risk (43.428 and 47.77 percentiles, respectively), below the 60% threshold.

**BBB:** This is a crucial parameter for a CNS target like DRD2. Ligand A has a significantly better BBB penetration percentile (64.327) than Ligand B (50.407). While ideally >70, Ligand A is closer.

**Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and suggests poor permeability. This is a concern for both.

**Aqueous Solubility:** Both have negative solubility values, indicating very poor solubility, which is a significant drawback.

**hERG Inhibition:** Both ligands show low hERG inhibition liability (0.147 and 0.417), which is good.

**Microsomal Clearance:** Ligand A (0.837) has much lower microsomal clearance than Ligand B (19.023), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (-6.825) has a more negative in vitro half-life, which is unusual and suggests a very short half-life. Ligand B (10.792) has a more reasonable half-life.

**P-gp Efflux:** Ligand A (0.057) has significantly lower P-gp efflux liability than Ligand B (0.093), which is beneficial for CNS exposure.

**Binding Affinity:** Ligand B (-7.8 kcal/mol) has a slightly better binding affinity than Ligand A (-8.2 kcal/mol). However, the difference is relatively small.

**Overall Assessment:**

Ligand A is preferable despite the poor solubility and unusual half-life. Its superior BBB penetration, lower P-gp efflux, and lower microsomal clearance are critical advantages for a CNS-targeting GPCR. The slightly weaker binding affinity is less of a concern given the other favorable ADME properties. Ligand B's better half-life is offset by its poorer BBB, higher P-gp efflux, and higher clearance. The solubility issues are a major concern for both, but can potentially be addressed through formulation strategies.

Output:
0
2025-04-17 03:37:08,351 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (349.46 and 350.42 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (36.44) is excellent, well below the 90 A^2 threshold for CNS targets. Ligand B (103.79) is higher, but still potentially acceptable, though less ideal.

**logP:** Ligand A (4.234) is slightly high, potentially leading to solubility issues or off-target interactions. Ligand B (1.843) is within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A (0 HBD, 4 HBA) is favorable. Ligand B (3 HBD, 5 HBA) is also acceptable.

**QED:** Both ligands have similar QED values (0.694 and 0.769), indicating good drug-like properties.

**DILI:** Ligand A (68.282) has a higher DILI risk than Ligand B (32.183). This is a significant negative for Ligand A.

**BBB:** Ligand A (93.331) has excellent BBB penetration, a crucial factor for a CNS target like DRD2. Ligand B (52.811) has poor BBB penetration, a major drawback.

**Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and suggests a potential issue with the data or modeling. However, we can still compare them relatively.

**Aqueous Solubility:** Both have negative solubility values, which is also unusual.

**hERG Inhibition:** Ligand A (0.812) has a slightly higher hERG risk than Ligand B (0.171), but both are relatively low.

**Microsomal Clearance:** Ligand A (95.056) has high microsomal clearance, indicating poor metabolic stability. Ligand B (4.785) has very low clearance, suggesting good metabolic stability.

**In vitro Half-Life:** Ligand A (47.806) has a moderate half-life. Ligand B (-15.594) has a very short, and likely unrealistic, half-life.

**P-gp Efflux:** Ligand A (0.775) has moderate P-gp efflux, while Ligand B (0.006) has very low P-gp efflux, which is highly desirable for CNS penetration.

**Binding Affinity:** Ligand A (-9.4 kcal/mol) has a significantly stronger binding affinity than Ligand B (-8.0 kcal/mol). This is a substantial advantage.

**Overall Assessment:**

Despite Ligand A's higher logP and DILI risk, its *significantly* stronger binding affinity (-9.4 vs -8.0 kcal/mol) and *excellent* BBB penetration (93.331) are compelling advantages for a CNS-targeting GPCR. The difference in binding affinity is substantial enough to potentially overcome the slightly higher logP and DILI risk. Ligand B's poor BBB penetration is a critical flaw for a CNS drug. Ligand B's metabolic stability is good, but the weak binding and poor CNS exposure are dealbreakers.

Output:
1
2025-04-17 03:37:08,352 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B based on the provided guidelines, prioritizing GPCR-specific properties (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (341.455 and 347.415 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (73.99) is excellent, well below the 90 A^2 threshold for CNS targets. Ligand B (91.76) is still reasonable but closer to the 90 A^2 limit.

**logP:** Ligand A (2.763) is optimal (1-3). Ligand B (0.72) is a bit low, potentially hindering permeability.

**H-Bond Donors/Acceptors:** Both ligands have acceptable HBD (2-3) and HBA (2-5) counts.

**QED:** Both ligands have good QED scores (0.636 and 0.723), indicating drug-likeness.

**DILI:** Ligand A (26.173) has a lower DILI risk than Ligand B (33.695), both are acceptable.

**BBB:** Ligand A (65.374) has a significantly better BBB percentile than Ligand B (51.26). This is *critical* for a CNS target like DRD2.

**Caco-2 Permeability:** Ligand A (-5.171) has a negative value, suggesting poor permeability. Ligand B (-4.5) is also poor, but slightly better.

**Aqueous Solubility:** Both ligands have negative solubility values, indicating poor solubility.

**hERG Inhibition:** Both ligands have very low hERG inhibition liability (0.312 and 0.061), which is excellent.

**Microsomal Clearance:** Ligand A (23.075) has a higher microsomal clearance than Ligand B (-3.438), suggesting lower metabolic stability.

**In vitro Half-Life:** Ligand A (-20.267) has a negative half-life, which is concerning. Ligand B (25.353) has a better half-life.

**P-gp Efflux:** Ligand A (0.12) has lower P-gp efflux liability than Ligand B (0.011), which is favorable for CNS penetration.

**Binding Affinity:** Ligand A (-8.6 kcal/mol) has a slightly better binding affinity than Ligand B (-7.4 kcal/mol). This 1.2 kcal/mol difference is significant.

**Overall Assessment:**

Ligand A excels in TPSA, logP, BBB, P-gp efflux, and binding affinity. The superior BBB penetration and affinity are particularly important for a CNS GPCR target. While its Caco-2 permeability and in vitro half-life are concerning, the strong binding affinity might compensate for these issues. Ligand B has better metabolic stability and half-life, but suffers from a lower logP and significantly worse BBB penetration.

Given the importance of CNS penetration for DRD2, and the relatively strong affinity of Ligand A, it is the more promising candidate.

Output:
1
2025-04-17 03:37:08,352 - INFO - Reasoning:

Let's analyze Ligand A and Ligand B based on the provided guidelines, prioritizing GPCR-specific properties (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (346.427 Da) is slightly lower than Ligand B (381.851 Da), which is acceptable.

**TPSA:** Both ligands have TPSA values below the 90 A^2 threshold desirable for CNS targets. Ligand B (72.88 A^2) is better than Ligand A (89.87 A^2).

**logP:** Both ligands have optimal logP values (1-3). Ligand B (0.669) is a bit lower, but still acceptable. Ligand A (1.6) is slightly better.

**H-Bond Donors/Acceptors:** Both ligands have reasonable HBD and HBA counts. Ligand A (HBD=3, HBA=4) and Ligand B (HBD=2, HBA=4) both fall within acceptable limits.

**QED:** Both ligands have QED values above 0.5, indicating good drug-likeness. Ligand A (0.707) is slightly higher than Ligand B (0.686).

**DILI:** Both ligands have low DILI risk (below 40). Ligand B (33.579) is slightly better than Ligand A (39.473).

**BBB:** This is a crucial parameter for CNS targets. Ligand B (53.083) has a significantly better BBB percentile than Ligand A (42.226). This is a major advantage for Ligand B.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values, indicating poor permeability. This is concerning for both, but the values are similar.

**Aqueous Solubility:** Both ligands have negative solubility values, indicating poor solubility. This is concerning for both, but the values are similar.

**hERG Inhibition:** Both ligands have low hERG inhibition risk. Ligand A (0.347) is slightly higher than Ligand B (0.322).

**Microsomal Clearance:** Ligand B (-7.08 mL/min/kg) has a significantly *lower* (better) microsomal clearance than Ligand A (20.475 mL/min/kg), indicating greater metabolic stability.

**In vitro Half-Life:** Ligand B (-9.656 hours) has a significantly longer half-life than Ligand A (-5.106 hours).

**P-gp Efflux:** Both ligands have low P-gp efflux liability. Ligand A (0.273) is slightly higher than Ligand B (0.055).

**Binding Affinity:** Both ligands have strong binding affinities. Ligand A (-8.3 kcal/mol) is slightly better than Ligand B (-7.8 kcal/mol), but the difference is less than 1.5 kcal/mol.

**Overall Assessment:**

While Ligand A has a slightly better binding affinity and QED, Ligand B demonstrates superior ADME properties crucial for CNS penetration. Specifically, its significantly better BBB penetration, lower microsomal clearance, and longer half-life outweigh the minor difference in binding affinity. The TPSA is also more favorable for Ligand B. Given the target is a CNS GPCR (DRD2), these ADME properties are paramount.

Output:
1
2025-04-17 03:37:08,352 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (355.454 and 345.359 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (92.5) is excellent, being below the 90 threshold for CNS targets. Ligand B (112.4) is higher, but still potentially acceptable, though less ideal.

**3. logP:** Ligand A (1.235) is within the optimal range of 1-3. Ligand B (0.443) is slightly low, potentially hindering permeation.

**4. H-Bond Donors:** Both ligands have acceptable HBD counts (2 and 1, respectively), well below the threshold of 5.

**5. H-Bond Acceptors:** Ligand A (3) is good. Ligand B (6) is also acceptable, being below the 10 threshold.

**6. QED:** Both ligands have good QED scores (0.686 and 0.845), indicating good drug-like properties.

**7. DILI:** Ligand A (16.324) has a significantly lower DILI risk than Ligand B (79.449), which is a major concern.

**8. BBB:** Ligand A (92.827) has excellent BBB penetration, exceeding the desirable 70% threshold for CNS targets. Ligand B (34.975) has very poor predicted BBB penetration. This is a critical difference for a DRD2 ligand.

**9. Caco-2 Permeability:** Both have negative values, which is unusual. However, the magnitude of the negative value for Ligand A (-5.219) is less extreme than for Ligand B (-5.181).

**10. Aqueous Solubility:** Both have negative values, which is also unusual. The values are similar.

**11. hERG Inhibition:** Both ligands have low hERG inhibition risk (0.492 and 0.142).

**12. Microsomal Clearance:** Both have similar microsomal clearance values (10.623 and 10.204).

**13. In vitro Half-Life:** Ligand A (-17.146) has a worse (more negative) in vitro half-life than Ligand B (-22.483).

**14. P-gp Efflux:** Ligand A (0.028) has very low P-gp efflux, which is favorable for CNS penetration. Ligand B (0.047) also has low P-gp efflux, but slightly higher than A.

**15. Binding Affinity:** Ligand A (-7.2) has a slightly better binding affinity than Ligand B (-0.0).

**Overall Assessment:**

Ligand A is clearly the superior candidate. While Ligand B has a slightly better QED and P-gp efflux, the critical advantages of Ligand A are its significantly lower DILI risk and *much* better predicted BBB penetration. The affinity is also substantially better. The slightly worse half-life for Ligand A is less concerning than the poor BBB penetration of Ligand B for a CNS target like DRD2. The logP for Ligand A is also more favorable.

Output:
1
2025-04-17 03:37:08,352 - INFO - Reasoning:

Let's analyze Ligand A and Ligand B based on the provided guidelines, prioritizing GPCR-specific properties (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (351.447 and 361.467 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (87.74) is better than Ligand B (68.46), both are below the 90 A^2 threshold for CNS targets.

**logP:** Ligand B (3.056) is optimal (1-3), while Ligand A (0.599) is quite low, potentially hindering permeability. This is a significant drawback for Ligand A.

**H-Bond Donors/Acceptors:** Ligand A (2 HBD, 4 HBA) and Ligand B (0 HBD, 6 HBA) both are within acceptable limits.

**QED:** Both ligands have good QED scores (0.658 and 0.709, respectively), indicating drug-likeness.

**DILI:** Ligand A (22.838) has a much lower DILI risk than Ligand B (55.642), which is a positive for Ligand A.

**BBB:** Ligand B (71.733) has a significantly better BBB penetration percentile than Ligand A (53.083). This is a crucial factor for a CNS target like DRD2.

**Caco-2 Permeability:** Ligand A (-4.919) has a very poor Caco-2 permeability, while Ligand B (-5.185) is also poor, but slightly better.

**Aqueous Solubility:** Both ligands have poor aqueous solubility (-1.156 and -2.878 respectively).

**hERG:** Ligand A (0.061) has a lower hERG inhibition liability than Ligand B (0.403), which is favorable.

**Microsomal Clearance:** Ligand B (89.365) has a higher microsomal clearance than Ligand A (22.6), indicating lower metabolic stability.

**In vitro Half-Life:** Ligand B (17.717) has a longer in vitro half-life than Ligand A (3.223).

**P-gp Efflux:** Ligand A (0.016) has a much lower P-gp efflux liability than Ligand B (0.546), which is a significant advantage for CNS penetration.

**Binding Affinity:** Ligand B (-7.8 kcal/mol) has a slightly better binding affinity than Ligand A (-7.3 kcal/mol), but the difference is not substantial enough to overcome the other ADME issues.

**Overall Assessment:**

Ligand B has a better BBB score and binding affinity, which are critical for a CNS GPCR target. However, it suffers from higher DILI risk, higher P-gp efflux, and higher microsomal clearance. Ligand A has a better safety profile (lower DILI and hERG) and lower P-gp efflux, but its low logP and poor Caco-2 permeability are major concerns.

Considering the GPCR-specific priorities, the *slightly* better BBB and affinity of Ligand B are important, but the significantly better P-gp efflux and lower DILI of Ligand A, coupled with the critical logP issue for Ligand A, make Ligand B the more promising candidate. The poor permeability of Ligand A is a difficult hurdle to overcome.

Output:
1
2025-04-17 03:37:08,352 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 drug candidates, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (407.308 Da) is slightly higher than Ligand B (364.921 Da), but both are acceptable.

**TPSA:** Ligand A (58.64) is excellent for CNS penetration, well below the 90 A^2 threshold. Ligand B (65.04) is still reasonable, but less optimal.

**logP:** Both ligands have good logP values (A: 3.514, B: 3.793), falling within the 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A (HBD=1, HBA=3) and Ligand B (HBD=2, HBA=4) both have acceptable numbers of hydrogen bond donors and acceptors.

**QED:** Both ligands have similar and good QED values (A: 0.764, B: 0.784), indicating good drug-like properties.

**DILI:** Ligand A (54.789) has a moderate DILI risk, while Ligand B (13.92) has a very low DILI risk. This is a significant advantage for Ligand B.

**BBB:** Ligand A (89.027) has excellent BBB penetration, exceeding the desirable 70% threshold. Ligand B (45.599) is considerably lower, which is a major drawback for a CNS target.

**Caco-2 Permeability:** Ligand A (-4.663) and Ligand B (-5.363) both have negative Caco-2 values, indicating poor permeability. This is concerning, but not a dealbreaker if other properties are favorable.

**Aqueous Solubility:** Both ligands have very poor aqueous solubility (A: -4.493, B: -3.456). This could pose formulation challenges.

**hERG Inhibition:** Both ligands have low hERG inhibition liability (A: 0.77, B: 0.718), which is good.

**Microsomal Clearance:** Ligand A (104.677) has higher microsomal clearance than Ligand B (16.791), suggesting lower metabolic stability. This is a negative for Ligand A.

**In vitro Half-Life:** Ligand B (59.505) has a significantly longer in vitro half-life than Ligand A (36.851).

**P-gp Efflux:** Both ligands have low P-gp efflux liability (A: 0.5, B: 0.26), which is favorable for CNS penetration.

**Binding Affinity:** Ligand A (-8.7 kcal/mol) has a substantially stronger binding affinity than Ligand B (-7.5 kcal/mol). This is a significant advantage for Ligand A, potentially outweighing some of its ADME drawbacks. The difference is >1.5 kcal/mol.

**Overall Assessment:**

Ligand A excels in binding affinity and BBB penetration, crucial for a CNS GPCR target. However, it has higher DILI risk, higher clearance, and shorter half-life. Ligand B has a much better safety profile (lower DILI) and improved metabolic stability (lower clearance, longer half-life), but suffers from significantly lower BBB penetration and weaker binding affinity.

Given the importance of strong binding affinity for GPCRs and the relatively large difference in affinity (-8.7 vs -7.5 kcal/mol), I believe Ligand A is the more promising candidate, *despite* its ADME liabilities. The strong binding may allow for a lower dose, potentially mitigating some of the toxicity concerns. Further optimization could focus on improving Ligand A's metabolic stability and solubility.

Output:
0
2025-04-17 03:37:08,353 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (389.405 and 368.543 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (90.41) is slightly above the optimal <90 for CNS targets, but still reasonable. Ligand B (75.27) is excellent, well below 90.

**logP:** Both ligands have good logP values (2.795 and 2.592), falling within the 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A has 1 HBD and 8 HBA, while Ligand B has 2 HBD and 3 HBA. Both are within acceptable limits (<=5 HBD and <=10 HBA).

**QED:** Both ligands have good QED scores (0.548 and 0.614), indicating good drug-like properties.

**DILI:** Ligand A has a concerningly high DILI risk (93.059), while Ligand B has a very low risk (39.046). This is a significant advantage for Ligand B.

**BBB:** Ligand A has excellent BBB penetration (84.955), while Ligand B is lower (65.025). This is a significant advantage for Ligand A, crucial for a CNS target like DRD2.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.911 and -5.071), which is unusual and suggests poor permeability. This is a concern for both.

**Aqueous Solubility:** Both ligands have negative solubility values (-4.862 and -3.77), suggesting poor aqueous solubility. This is a concern for both.

**hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.321 and 0.324).

**Microsomal Clearance:** Ligand A has very high microsomal clearance (98.647), indicating rapid metabolism. Ligand B has moderate clearance (57.385). This is a significant advantage for Ligand B.

**In vitro Half-Life:** Ligand A has a very short half-life (-6.058), while Ligand B has a longer half-life (-14.3). This is a significant advantage for Ligand B.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.37 and 0.181).

**Binding Affinity:** Both ligands have excellent binding affinities (-7.6 and -7.8 kcal/mol). Ligand B is slightly better, but the difference is small.

**Overall Assessment:**

Ligand A has better BBB penetration and comparable affinity, but suffers from very high DILI risk, high metabolic clearance, and short half-life. Ligand B has a much better safety profile (DILI), improved metabolic stability (lower Cl_mic, longer t1/2), and slightly better affinity. While both have poor Caco-2 and solubility, the ADME/Tox profile of Ligand B is significantly more favorable, particularly the low DILI risk and improved metabolic stability. For a CNS target, a good safety profile and reasonable metabolic stability are critical.

Output:
1
2025-04-17 03:37:08,353 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (352.825 and 364.917 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (50.16) is better than Ligand B (41.57) as it is closer to the <90 A^2 threshold for CNS targets.

**logP:** Both ligands have good logP values (3.462 and 4.467), falling within the optimal 1-3 range, although Ligand B is slightly higher.

**H-Bond Donors/Acceptors:** Both have 1 HBD, which is good. Ligand A has 4 HBA, while Ligand B has 2. Both are within the acceptable limits.

**QED:** Both ligands have good QED scores (0.782 and 0.809), indicating good drug-like properties.

**DILI:** Ligand A has a significantly higher DILI risk (84.839 percentile) than Ligand B (18.845 percentile). This is a major concern for Ligand A.

**BBB:** Ligand B has a much better BBB penetration score (95.851 percentile) compared to Ligand A (72.703 percentile). This is crucial for a CNS target like DRD2.

**Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and suggests poor permeability. However, the scale isn't specified, so it's hard to interpret.

**Aqueous Solubility:** Both have negative solubility values, suggesting poor solubility. Again, the scale is unclear.

**hERG:** Both have relatively low hERG inhibition liability (0.773 and 0.897), which is favorable.

**Microsomal Clearance:** Ligand B has higher microsomal clearance (62.036) than Ligand A (44.702), meaning Ligand A is more metabolically stable.

**In vitro Half-Life:** Ligand B has a significantly longer in vitro half-life (58.083) than Ligand A (-1.012). This is a major advantage for Ligand B.

**P-gp Efflux:** Both have low P-gp efflux liability (0.303 and 0.306), which is good for CNS penetration.

**Binding Affinity:** Ligand B has a better binding affinity (-8.3 kcal/mol) than Ligand A (-10.6 kcal/mol). While Ligand A has a better affinity, the difference isn't large enough to overcome the other significant drawbacks.

**Overall Assessment:**

Ligand B is the better candidate. While Ligand A has slightly better binding affinity, Ligand B excels in critical areas for a CNS-targeting GPCR: significantly better BBB penetration, lower DILI risk, and a much longer in vitro half-life. The higher logP of Ligand B is not a major concern, and the other parameters are comparable or favorable. The poor Caco-2 and solubility values are concerning for both, but can be addressed through formulation strategies.

Output:
1
2025-04-17 03:37:08,353 - INFO - Reasoning:

Let's analyze Ligand A and Ligand B for their potential as DRD2 drug candidates, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight (MW):** Both ligands (375.441 and 364.873 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (75.44) is better than Ligand B (60.85). Both are below the 90 A^2 threshold for CNS targets, which is excellent.

**3. logP:** Both ligands have good logP values (1.735 and 2.707), falling within the optimal 1-3 range. Ligand B is slightly higher, which could be beneficial for membrane permeability.

**4. H-Bond Donors (HBD):** Both have 1 HBD, which is within the acceptable limit of <=5.

**5. H-Bond Acceptors (HBA):** Ligand A has 5 HBA, and Ligand B has 3. Both are below the acceptable limit of <=10.

**6. QED:** Both ligands have good QED scores (0.749 and 0.789), indicating good drug-like properties.

**7. DILI:** Ligand A (37.65) has a slightly better DILI score than Ligand B (43.66), indicating a lower risk of liver injury. Both are below the 40 threshold.

**8. BBB:** Ligand A (73.711) and Ligand B (71.307) both have good BBB penetration, but Ligand A is slightly better. Both are above the 70% threshold for CNS targets.

**9. Caco-2 Permeability:** Ligand A (-5.042) has a worse Caco-2 permeability score than Ligand B (-4.757).

**10. Aqueous Solubility:** Ligand A (-2.115) has a worse aqueous solubility score than Ligand B (-3.57).

**11. hERG Inhibition:** Ligand A (0.253) has a much lower hERG inhibition liability than Ligand B (0.812), which is a significant advantage.

**12. Microsomal Clearance:** Both ligands have similar microsomal clearance values (33.902 and 33.726 mL/min/kg).

**13. In vitro Half-Life:** Ligand A (-42.967) has a much worse in vitro half-life than Ligand B (30.882).

**14. P-gp Efflux:** Ligand A (0.144) has a lower P-gp efflux liability than Ligand B (0.691), which is favorable for CNS exposure.

**15. Binding Affinity:** Ligand A (-8.1 kcal/mol) has a significantly stronger binding affinity than Ligand B (-7.0 kcal/mol). This is a substantial advantage, potentially outweighing some of the ADME drawbacks.

**Overall Assessment:**

Ligand A has a significantly better binding affinity and lower hERG and P-gp efflux liabilities. While it has slightly worse Caco-2 permeability and in vitro half-life, the strong binding affinity and improved safety profile (hERG, P-gp, DILI) are crucial for a GPCR target, especially in the CNS. The TPSA and BBB values are also excellent for both. The difference in binding affinity is >1.5 kcal/mol, which is a significant advantage.

Output:
1
2025-04-17 03:37:08,353 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (346.45 and 351.403 Da) fall comfortably within the ideal 200-500 Da range.

**TPSA:** Ligand A (70.39) is significantly better than Ligand B (111.88). For CNS targets, we want TPSA <= 90, and A is well within that, while B is pushing the limit.

**logP:** Ligand A (1.117) is optimal, while Ligand B (-0.326) is a bit low, potentially hindering permeation.

**H-Bond Donors/Acceptors:** Both have 3 HBD and acceptable HBA counts (4 and 5 respectively).

**QED:** Both ligands have reasonable QED values (0.764 and 0.594), indicating drug-like properties.

**DILI:** Ligand A (8.647) has a much lower DILI risk than Ligand B (19.155), which is a significant advantage.

**BBB:** Ligand A (75.029) has a good BBB percentile, exceeding the 70% threshold for CNS targets. Ligand B (25.475) is poor, indicating limited brain penetration. This is a critical factor for DRD2.

**Caco-2 Permeability:** Both have negative values, which is unusual. Assuming these are logP-like scales, lower values indicate lower permeability. The values are similar (-5.61 and -5.781).

**Aqueous Solubility:** Both ligands have negative solubility values, which is also unusual. Again, assuming a logS-like scale, lower values indicate lower solubility. The values are similar (-0.855 and -0.827).

**hERG Inhibition:** Both ligands have very low hERG inhibition liability (0.08 and 0.007), which is excellent.

**Microsomal Clearance:** Ligand A (-24.158) has a lower (better) microsomal clearance than Ligand B (-22.728), suggesting greater metabolic stability.

**In vitro Half-Life:** Ligand B (31.773) has a longer half-life than Ligand A (17.346), which is generally desirable.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.018 and 0.007), which is excellent for CNS penetration.

**Binding Affinity:** Ligand A (-9.9 kcal/mol) has a slightly better binding affinity than Ligand B (-7.9 kcal/mol). The difference is substantial (2 kcal/mol), and this can outweigh some ADME drawbacks.

**Overall Assessment:**

Ligand A is significantly better overall. Its superior TPSA, logP, BBB penetration, and DILI risk profile, combined with comparable binding affinity and excellent safety properties (hERG, Pgp), make it a much more promising drug candidate for a CNS target like DRD2. While Ligand B has a longer half-life, the poor BBB penetration is a deal-breaker for a CNS-acting drug.

Output:
0
2025-04-17 03:37:08,353 - INFO - Batch 44 complete. Total preferences: 704
2025-04-17 03:37:08,353 - INFO - Processing batch 45/512...
2025-04-17 03:37:50,063 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (385.421 and 378.904 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (81.93) is slightly above the optimal <90 for CNS targets, but still reasonable. Ligand B (53.6) is well within the desired range.

**logP:** Ligand A (2.892) is within the optimal 1-3 range. Ligand B (4.967) is slightly high, potentially leading to solubility issues and off-target interactions.

**H-Bond Donors/Acceptors:** Ligand A (HBD=1, HBA=8) and Ligand B (HBD=2, HBA=4) both have acceptable numbers of H-bond donors and acceptors.

**QED:** Both ligands have reasonable QED values (0.497 and 0.659), indicating decent drug-likeness. Ligand B is slightly better.

**DILI:** Ligand A (95.812) has a high DILI risk, which is a significant concern. Ligand B (70.221) is also elevated, but less so than Ligand A.

**BBB:** Ligand A (65.413) has a moderate BBB penetration, while Ligand B (43.001) is lower. For a CNS target like DRD2, higher BBB penetration is crucial.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.093 and -4.914), which is unusual and suggests poor permeability. This is a red flag for both.

**Aqueous Solubility:** Both ligands have very poor aqueous solubility (-4.015 and -5.183).

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.452 and 0.658).

**Microsomal Clearance:** Ligand A (67.779) has higher microsomal clearance than Ligand B (36.812), indicating lower metabolic stability.

**In vitro Half-Life:** Ligand B (39.47) has a significantly longer in vitro half-life than Ligand A (4.29).

**P-gp Efflux:** Ligand A (0.254) has lower P-gp efflux than Ligand B (0.483), which is favorable for CNS penetration.

**Binding Affinity:** Ligand B (-9.2 kcal/mol) has a significantly stronger binding affinity than Ligand A (-8.2 kcal/mol). This 1 kcal/mol difference is substantial and can outweigh many other ADME drawbacks.

**Overall Assessment:**

Despite the poor Caco-2 and solubility profiles of both compounds, Ligand B is the more promising candidate. Its significantly stronger binding affinity (-9.2 vs -8.2 kcal/mol) is a major advantage for a GPCR target. It also has a longer half-life and lower microsomal clearance, indicating better metabolic stability. While its logP is a bit high and BBB penetration is not ideal, the superior affinity and metabolic properties make it more likely to succeed. Ligand A's high DILI risk is a major drawback.

Output:
1
2025-04-17 03:37:50,063 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (368.5) is slightly higher than Ligand B (342.4).

**TPSA:** Both ligands have TPSA values below the 90 A^2 threshold desirable for CNS targets. Ligand B (71.34) is better than Ligand A (83.55).

**logP:** Ligand A (0.97) is a bit low, potentially hindering permeation. Ligand B (3.492) is within the optimal range (1-3). This is a significant advantage for Ligand B.

**H-Bond Donors/Acceptors:** Ligand A (1 HBD, 4 HBA) and Ligand B (2 HBD, 3 HBA) both fall within acceptable limits.

**QED:** Both ligands have good QED scores (A: 0.536, B: 0.874), indicating drug-like properties. Ligand B is better.

**DILI:** Ligand A (19.43) has a much lower DILI risk than Ligand B (49.79), which is a substantial advantage.

**BBB:** Ligand A (57.74) is below the desirable threshold of 70% for CNS targets, while Ligand B (61.23) is also below, but closer.

**Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and suggests poor permeability. However, the scale is not specified, so we can't interpret these values accurately.

**Aqueous Solubility:** Both have negative solubility values, which is also unusual and suggests poor solubility. Again, the scale is not specified.

**hERG Inhibition:** Both ligands show low hERG inhibition liability (A: 0.239, B: 0.373), which is good.

**Microsomal Clearance:** Ligand A (-13.97) has a much lower (better) microsomal clearance than Ligand B (29.38), indicating better metabolic stability.

**In vitro Half-Life:** Ligand B (82.96) has a significantly longer half-life than Ligand A (2.42), which is a major advantage.

**P-gp Efflux:** Ligand A (0.055) has much lower P-gp efflux liability than Ligand B (0.109), which is favorable for CNS penetration.

**Binding Affinity:** Ligand B (-9.2 kcal/mol) has a stronger binding affinity than Ligand A (-8.4 kcal/mol). This is a crucial advantage, as a 0.8 kcal/mol difference is significant.

**Overall Assessment:**

Ligand B is superior in terms of logP, QED, binding affinity, and in vitro half-life. Ligand A has advantages in DILI risk and P-gp efflux, and microsomal clearance. However, the stronger binding affinity of Ligand B, combined with its acceptable logP and QED, outweighs the benefits of Ligand A's lower DILI and better metabolic stability. The BBB values are both suboptimal, but the affinity difference is the deciding factor.

Output:
1
2025-04-17 03:37:50,063 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 drug candidates, considering the provided guidelines and GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (359.495 and 364.515 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (63.13) is significantly better than Ligand B (76.02). For CNS targets, TPSA should be <=90, both are within this range, but A is closer to the optimal <60 range.

**3. logP:** Both ligands have good logP values (3.513 and 2.129), falling within the optimal 1-3 range.

**4. H-Bond Donors:** Both have 2 HBD, which is within the acceptable limit of <=5.

**5. H-Bond Acceptors:** Ligand A has 4 HBA, and Ligand B has 5. Both are within the acceptable limit of <=10.

**6. QED:** Both ligands have similar QED values (0.709 and 0.741), indicating good drug-likeness.

**7. DILI:** Ligand B (41.838) has a lower DILI risk than Ligand A (53.432), making it slightly preferable in terms of liver safety.

**8. BBB:** Ligand A (49.826) has a slightly better BBB penetration percentile than Ligand B (45.56). While both are below the desirable >70 for CNS targets, A is closer.

**9. Caco-2 Permeability:** Ligand A (-5.251) has a worse Caco-2 permeability than Ligand B (-5.616). Lower values are less favorable.

**10. Aqueous Solubility:** Ligand A (-3.648) has a worse aqueous solubility than Ligand B (-1.884). Lower values are less favorable.

**11. hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.499 and 0.251), which is excellent.

**12. Microsomal Clearance:** Ligand B (11.373) has significantly lower microsomal clearance than Ligand A (77.078), indicating better metabolic stability.

**13. In vitro Half-Life:** Ligand B (-7.947) has a negative half-life, which is not possible. This is likely an error in the data, but it is a significant negative indicator. Ligand A (54.44) has a reasonable half-life.

**14. P-gp Efflux:** Ligand A (0.264) has lower P-gp efflux liability than Ligand B (0.065), which is favorable for CNS penetration.

**15. Binding Affinity:** Both ligands have excellent binding affinities (-8.3 and -7.8 kcal/mol). Ligand A is slightly better (-8.3 kcal/mol).

**Overall Assessment:**

Considering the GPCR-specific priorities, Ligand A is slightly favored due to its better binding affinity and slightly better BBB penetration. However, Ligand B has better metabolic stability (lower Cl_mic), lower DILI risk, and better solubility. The negative half-life for Ligand B is a major concern and likely an error, but even ignoring that, the significantly higher clearance is a drawback. Ligand A's slightly better affinity and P-gp efflux profile outweigh its slightly higher DILI risk and lower solubility.

Output:
0
2025-04-17 03:37:50,064 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (361.47 and 352.48 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (73.22) is better than Ligand B (78.87). Both are below the 90 A^2 threshold desirable for CNS targets, but A is closer to optimal.

**logP:** Both ligands have good logP values (2.649 and 1.458), falling within the 1-3 range. Ligand A is slightly higher, potentially aiding membrane permeability.

**H-Bond Donors/Acceptors:** Ligand A has 1 HBD and 6 HBA, while Ligand B has 2 HBD and 4 HBA. Both are within acceptable limits (<=5 HBD and <=10 HBA).

**QED:** Both ligands have good QED scores (0.606 and 0.727), indicating good drug-like properties.

**DILI:** Ligand A (63.862) has a higher DILI risk than Ligand B (8.414). This is a significant drawback for Ligand A.

**BBB:** Both ligands have similar BBB penetration (59.093 and 60.838). Neither is above the desirable 70 percentile, but they are reasonably close.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.96 and -4.65), which is unusual and suggests poor permeability. This is a concern for both.

**Aqueous Solubility:** Both ligands have negative solubility values (-3.583 and -2.089), indicating very poor aqueous solubility. This is a major issue for both.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.36 and 0.24).

**Microsomal Clearance:** Ligand A (133.729) has significantly higher microsomal clearance than Ligand B (7.892), indicating lower metabolic stability.

**In vitro Half-Life:** Ligand A (-27.471) has a very short in vitro half-life, while Ligand B (-1.021) is slightly better but still poor.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.363 and 0.078), which is favorable for CNS penetration.

**Binding Affinity:** Both ligands have the same binding affinity (-8.7 kcal/mol), which is excellent.

**Overall Assessment:**

Ligand B is the better candidate. While both have issues with solubility and Caco-2 permeability, Ligand B has a much lower DILI risk and significantly better metabolic stability (lower Cl_mic and longer t1/2). The similar BBB values and equal binding affinity make the ADME properties the deciding factor. Ligand A's high DILI and poor metabolic stability are major liabilities.

Output:
1
2025-04-17 03:37:50,064 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (332.367 Da) is slightly lower, which could be beneficial for permeability.

**TPSA:** Ligand A (77.11) is much better than Ligand B (44.76) for CNS penetration, falling well below the 90 A^2 threshold. Ligand B is excellent.

**logP:** Ligand A (1.982) is optimal, while Ligand B (4.269) is pushing the upper limit. High logP can lead to solubility issues and off-target effects.

**H-Bond Donors/Acceptors:** Ligand A (1 HBD, 6 HBA) and Ligand B (0 HBD, 4 HBA) both have acceptable numbers.

**QED:** Both ligands have good QED scores (A: 0.62, B: 0.771), indicating drug-like properties.

**DILI:** Ligand A (79.333) is better than Ligand B (86.623), but both are relatively high, suggesting potential liver toxicity risk.

**BBB:** Ligand B (84.529) has a significantly better BBB percentile than Ligand A (39.279). This is a *critical* factor for a CNS target like DRD2.

**Caco-2 Permeability:** Ligand A (-5.41) has a very poor Caco-2 permeability, which is a major red flag. Ligand B (-4.296) is also poor, but better than A.

**Aqueous Solubility:** Ligand A (-2.737) has poor solubility, while Ligand B (-5.294) is even worse.

**hERG:** Ligand A (0.199) has a slightly better hERG profile than Ligand B (0.634).

**Microsomal Clearance:** Ligand A (29.57) has a lower clearance than Ligand B (55.364), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (31.588) has a longer half-life than Ligand B (-1.255), which is desirable.

**P-gp Efflux:** Ligand A (0.091) has a much lower P-gp efflux liability than Ligand B (0.755), meaning it's less likely to be pumped out of the brain.

**Binding Affinity:** Ligand B (-9.1 kcal/mol) has a stronger binding affinity than Ligand A (-8.6 kcal/mol). This is a significant advantage, potentially outweighing some of the ADME drawbacks. The difference is >1.5 kcal/mol.

**Overall Assessment:**

While Ligand A has better metabolic stability and P-gp efflux, its extremely poor Caco-2 permeability and low BBB penetration are major concerns. Ligand B, despite its higher logP and DILI risk, possesses a significantly stronger binding affinity *and* much better BBB penetration, which is paramount for a CNS-targeting drug. The stronger binding affinity is a significant advantage. The solubility and logP issues of Ligand B might be addressable with formulation strategies.

Output:
1
2025-04-17 03:37:50,064 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (372.734 Da and 381.263 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (83.81) is slightly above the preferred <90 for CNS targets, but still reasonable. Ligand B (67.23) is excellent, well below 90.

**logP:** Ligand A (4.023) is at the upper end of the optimal range (1-3) and could potentially cause solubility issues or off-target effects. Ligand B (1.83) is well within the optimal range.

**H-Bond Donors/Acceptors:** Ligand A has 2 HBD and 4 HBA, which are acceptable. Ligand B has 1 HBD and 4 HBA, also acceptable.

**QED:** Both ligands have good QED values (0.727 and 0.81), indicating good drug-like properties.

**DILI:** Ligand A has a very high DILI risk (98.255), which is a major concern. Ligand B has a much lower, though still not ideal, DILI risk (53.354).

**BBB:** Ligand A has a good BBB penetration percentile (70.997), meeting the >70 threshold for CNS targets. Ligand B has an excellent BBB penetration percentile (82.862).

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.016 and -4.797), which is unusual and suggests poor permeability. This is a significant drawback for both.

**Aqueous Solubility:** Both ligands have very poor aqueous solubility (-4.761 and -4.377). This is a concern, especially given Ligand A's high logP.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.353 and 0.272).

**Microsomal Clearance:** Ligand A has a moderate microsomal clearance (51.721), while Ligand B has a very low clearance (14.139), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A has a moderate half-life (20.539), while Ligand B has a very short half-life (0.886).

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.197 and 0.166), which is favorable for CNS penetration.

**Binding Affinity:** Ligand A has a significantly stronger binding affinity (-9.2 kcal/mol) than Ligand B (-6.8 kcal/mol). This is a substantial advantage.

**Overall Assessment:**

Ligand A has a much stronger binding affinity and acceptable BBB penetration, but its extremely high DILI risk and poor solubility are major red flags. The high logP also raises concerns. Ligand B has a better safety profile (lower DILI), better logP, and better metabolic stability, but its binding affinity is significantly weaker and its half-life is very short. The Caco-2 permeability is poor for both.

Despite the superior affinity of Ligand A, the unacceptable DILI risk outweighs this benefit. While affinity is crucial, a high risk of liver injury is a non-starter for drug development. Ligand B, while weaker in binding, presents a much more favorable safety and pharmacokinetic profile. Further optimization of Ligand B to improve its affinity and half-life would be a more promising path forward.

Output:
1
2025-04-17 03:37:50,064 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (352.381 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (69.64) is slightly above the optimal <90 for CNS targets, but still reasonable. Ligand B (58.64) is well within the desired range.

**3. logP:** Both ligands have good logP values (A: 2.548, B: 2.112), falling within the 1-3 optimal range.

**4. H-Bond Donors:** Ligand A (2) and Ligand B (1) are both acceptable, being less than 5.

**5. H-Bond Acceptors:** Both ligands have 3 H-bond acceptors, well within the acceptable limit of 10.

**6. QED:** Both ligands have good QED scores (A: 0.741, B: 0.903), indicating drug-like properties. Ligand B is slightly better.

**7. DILI:** Both ligands have low DILI risk (A: 37.65, B: 35.867), both below the 40 threshold.

**8. BBB:** Both ligands show excellent BBB penetration (A: 82.745, B: 86.274), exceeding the desirable >70 threshold for CNS targets. Ligand B is slightly better.

**9. Caco-2:** Both ligands have negative Caco-2 values (-5.139 and -4.504). This is unusual and suggests potential issues with intestinal absorption. However, these values are on a scale where negative values are possible and don't necessarily disqualify the compounds.

**10. Solubility:** Both ligands have negative solubility values (-3.338 and -2.405). Similar to Caco-2, this is not ideal but doesn't automatically eliminate them.

**11. hERG:** Both ligands have low hERG inhibition risk (A: 0.782, B: 0.535).

**12. Cl_mic:** Ligand A (30.193) has a higher microsomal clearance than Ligand B (-16.965). A negative value for Ligand B indicates higher metabolic stability, which is preferable.

**13. t1/2:** Ligand A (-9.222) has a negative in vitro half-life, which is concerning. Ligand B (17.878) has a positive and reasonable half-life.

**14. Pgp:** Both ligands have low P-gp efflux liability (A: 0.136, B: 0.052), which is beneficial for CNS penetration. Ligand B is slightly better.

**15. Binding Affinity:** Ligand B (-9.8 kcal/mol) has a slightly stronger binding affinity than Ligand A (-8.6 kcal/mol). While both are excellent (below -7.0), the 1.2 kcal/mol difference is significant and could outweigh minor ADME drawbacks.

**Overall Assessment:**

Ligand B is the better candidate. It demonstrates superior metabolic stability (lower Cl_mic, positive t1/2), slightly better BBB penetration, slightly better Pgp efflux, and a stronger binding affinity. While both have unusual Caco-2 and solubility values, Ligand B's overall profile is more favorable for development as a CNS-targeting drug.

Output:
1
2025-04-17 03:37:50,064 - INFO - Reasoning:

Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight (MW):** Both ligands (348.443 and 359.499 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Both ligands have TPSA values (75.71 and 74.07) below the 90 A^2 threshold for CNS targets, which is good.

**3. logP:** Ligand A (2.446) is within the optimal range of 1-3. Ligand B (3.514) is slightly higher but still acceptable.

**4. H-Bond Donors (HBD):** Both ligands have 1 HBD, which is within the acceptable limit of <=5.

**5. H-Bond Acceptors (HBA):** Ligand A has 4 HBA, and Ligand B has 7 HBA. Both are within the acceptable limit of <=10.

**6. QED:** Both ligands have good QED scores (0.52 and 0.815), indicating drug-like properties. Ligand B is better here.

**7. DILI:** Ligand A (43.35) has a slightly higher DILI risk than Ligand B (59.364), but both are below the concerning threshold of 60.

**8. BBB:** Ligand B (83.288) has a significantly better BBB penetration percentile than Ligand A (65.801). This is a crucial advantage for a CNS target like DRD2.

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.65 and -4.595). This is unusual and suggests poor permeability. However, these values are on a log scale and may not be directly comparable without knowing the base of the log.

**10. Aqueous Solubility:** Both ligands have very poor aqueous solubility (-2.677 and -5.037). This is a significant drawback.

**11. hERG Inhibition:** Both ligands show low hERG inhibition risk (0.297 and 0.916).

**12. Microsomal Clearance:** Both have relatively high microsomal clearance (86.252 and 89.107), indicating faster metabolism.

**13. In vitro Half-Life:** Ligand B (57.899) has a much better in vitro half-life than Ligand A (-11.183).

**14. P-gp Efflux:** Both ligands have low P-gp efflux liability (0.163 and 0.195), which is good for CNS penetration.

**15. Binding Affinity:** Ligand A (-7.7 kcal/mol) has a slightly better binding affinity than Ligand B (-6.9 kcal/mol). However, the difference is less than 1.5 kcal/mol, so it's not a decisive factor.

**Overall Assessment:**

Considering the GPCR-specific priorities, Ligand B is the more promising candidate. Its significantly better BBB penetration (83.288 vs. 65.801) and longer in vitro half-life (57.899 vs -11.183) are major advantages for a CNS-targeting drug. While both have poor solubility and high clearance, the improved CNS exposure potential of Ligand B outweighs the slightly better affinity of Ligand A.

Output:
1
2025-04-17 03:37:50,064 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 drug candidates, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (353.419 Da) is slightly lower, which could be advantageous for permeability. Ligand B (386.945 Da) is also acceptable.

**TPSA:** Ligand A (104.9) is better than Ligand B (66.48) for CNS penetration, being closer to the <90 threshold. Ligand B is still reasonable.

**logP:** Ligand A (1.093) is within the optimal range, but on the lower side. Ligand B (3.211) is also within the optimal range and closer to the ideal.

**H-Bond Donors/Acceptors:** Ligand A has 2 HBD and 6 HBA, while Ligand B has 1 HBD and 4 HBA. Both are within acceptable limits.

**QED:** Both ligands have good QED scores (A: 0.678, B: 0.744), indicating drug-like properties.

**DILI:** Both ligands have low DILI risk (A: 33.695, B: 38.852), which is positive.

**BBB:** Ligand B (70.609) has a significantly better BBB percentile than Ligand A (52.268). This is a crucial advantage for a CNS target like DRD2.

**Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and requires further investigation. However, we'll proceed with relative comparison.

**Aqueous Solubility:** Both have negative solubility values, which is also unusual.

**hERG:** Both ligands have low hERG inhibition liability (A: 0.364, B: 0.611).

**Microsomal Clearance:** Ligand A (6.77) has significantly lower microsomal clearance than Ligand B (35.611), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand B (45.088) has a much longer in vitro half-life than Ligand A (5.164).

**P-gp Efflux:** Ligand A (0.17) shows lower P-gp efflux liability than Ligand B (0.248), which is favorable for CNS exposure.

**Binding Affinity:** Ligand B (-7.8 kcal/mol) has a slightly better binding affinity than Ligand A (-7.4 kcal/mol), although the difference is relatively small.

**Overall Assessment:**

Ligand B excels in BBB penetration and has a significantly longer half-life, both critical for CNS drug development. While Ligand A has better metabolic stability (lower Cl_mic) and lower P-gp efflux, the superior BBB and half-life of Ligand B outweigh these advantages. The slightly better affinity of Ligand B further solidifies its position. The unusual negative values for Caco-2 and solubility are concerning for both, but the overall profile of Ligand B is more promising for DRD2 targeting.

Output:
1
2025-04-17 03:37:50,064 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (493.221 Da) is at the higher end, while Ligand B (345.443 Da) is more favorably positioned.

**2. TPSA:** Both ligands have TPSA values below 140, which is good for oral absorption. Ligand B (84.66) is better than Ligand A (93.45), and closer to the preferred <90 for CNS targets.

**3. logP:** Both ligands have logP values within the optimal range (1-3). Ligand A (3.331) is slightly higher, potentially increasing off-target effects, while Ligand B (2.37) is well within the range.

**4. H-Bond Donors:** Both are acceptable (<=5). Ligand A has 3, and Ligand B has 2.

**5. H-Bond Acceptors:** Both are acceptable (<=10). Ligand A has 5, and Ligand B has 3.

**6. QED:** Both have reasonable QED scores, with Ligand B (0.859) being significantly better than Ligand A (0.388).

**7. DILI:** Ligand B (28.616) has a much lower DILI risk than Ligand A (75.339), making it safer.

**8. BBB:** This is crucial for a CNS target. Ligand B (90.151) has excellent BBB penetration, while Ligand A (61.923) is less favorable, though still above 50%.

**9. Caco-2 Permeability:** Both have negative values, indicating poor permeability. This is unusual and could indicate issues with the prediction method or the molecules themselves. However, the negative value for Ligand A (-5.291) is worse than Ligand B (-4.866).

**10. Aqueous Solubility:** Both have negative values, indicating poor solubility. This is also concerning. Ligand B (-2.74) is slightly better than Ligand A (-4.236).

**11. hERG Inhibition:** Both ligands have low hERG inhibition risk. Ligand A (0.853) is slightly higher than Ligand B (0.451).

**12. Microsomal Clearance:** Ligand B (7.689) has significantly lower microsomal clearance than Ligand A (59.788), suggesting better metabolic stability.

**13. In vitro Half-Life:** Ligand B (-14.531) has a negative half-life, which is not physically possible and suggests a problem with the prediction. Ligand A (10.322) is reasonable.

**14. P-gp Efflux:** Ligand A (0.326) has lower P-gp efflux than Ligand B (0.066), which is favorable for CNS exposure.

**15. Binding Affinity:** Ligand B (-8.9 kcal/mol) has a slightly better binding affinity than Ligand A (-8.4 kcal/mol). While the difference is relatively small, it's still a positive factor.

**Overall Assessment:**

Ligand B is the superior candidate. It has a better BBB score, lower DILI risk, better QED, lower microsomal clearance (better metabolic stability), and slightly better binding affinity. While both have issues with predicted Caco-2 permeability and solubility, Ligand B is better on both counts. The negative half-life prediction for Ligand B is a major red flag, but the overall profile is still more promising than Ligand A. The P-gp efflux is better for Ligand A, but the other factors outweigh this advantage.

Output:
1
2025-04-17 03:37:50,064 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, prioritizing GPCR-specific properties (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (346.431 and 347.415 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (81.27) is significantly better than Ligand B (100.55). For CNS targets, we want TPSA <= 90, so Ligand A is preferable.

**3. logP:** Ligand A (3.315) is optimal (1-3), while Ligand B (0.96) is a bit low, potentially hindering permeation.

**4. H-Bond Donors:** Ligand A (0) is excellent. Ligand B (3) is acceptable, but higher HBD can sometimes reduce permeability.

**5. H-Bond Acceptors:** Both ligands (5) are within the acceptable range (<=10).

**6. QED:** Both ligands (0.621 and 0.638) are good, indicating drug-like properties.

**7. DILI:** Ligand A (22.8) has a much lower DILI risk than Ligand B (44.591). Both are below the 60 threshold, but A is significantly safer.

**8. BBB:** This is crucial for a CNS target like DRD2. Ligand A (83.055) is excellent (>70), while Ligand B (43.273) is poor.

**9. Caco-2 Permeability:** Both are negative, indicating poor permeability. However, the scale is not provided, so it is difficult to interpret.

**10. Aqueous Solubility:** Both are negative, indicating poor solubility. The scale is not provided, so it is difficult to interpret.

**11. hERG:** Both ligands have low hERG inhibition liability (0.434 and 0.08), which is good.

**12. Microsomal Clearance:** Ligand A (23.244) has higher clearance than Ligand B (13.245), meaning it is less metabolically stable.

**13. In vitro Half-Life:** Ligand B (-20.863) has a much longer half-life than Ligand A (6.959). This is a significant advantage for dosing frequency.

**14. P-gp Efflux:** Ligand A (0.142) has lower P-gp efflux than Ligand B (0.076), which is desirable for CNS exposure.

**15. Binding Affinity:** Both ligands have strong binding affinities (-9.7 and -8.1 kcal/mol). Ligand A is 1.6 kcal/mol better, which is a substantial advantage.

**Overall Assessment:**

Ligand A is the stronger candidate. While Ligand B has a better half-life, Ligand A excels in critical areas for a CNS-targeting GPCR: TPSA, logP, BBB penetration, and significantly lower DILI risk. The superior binding affinity of Ligand A further strengthens its position. The higher clearance of Ligand A is a drawback, but can potentially be addressed through structural modifications. The difference in binding affinity is likely to outweigh the metabolic stability concern.

Output:
1
2025-04-17 03:37:50,065 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (354.5 and 361.5 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (104.53) is higher than Ligand B (81.99). For CNS targets, TPSA < 90 is preferred. Ligand B is better here.

**3. logP:** Both ligands have good logP values (1.614 and 3.02), falling within the optimal 1-3 range. Ligand B is slightly better, being closer to the upper end of the range.

**4. H-Bond Donors:** Ligand A has 3 HBD, and Ligand B has 2. Both are acceptable (<=5).

**5. H-Bond Acceptors:** Ligand A has 3 HBA, and Ligand B has 4. Both are acceptable (<=10).

**6. QED:** Both ligands have good QED scores (0.605 and 0.747), indicating drug-like properties. Ligand B is slightly better.

**7. DILI:** Ligand A (19.39%) has a lower DILI risk than Ligand B (22.33%), both are good.

**8. BBB:** This is a critical parameter for CNS targets. Ligand A has a BBB percentile of 81.7%, which is excellent (>70). Ligand B has 65.8%, which is acceptable but less desirable.

**9. Caco-2 Permeability:** Both have negative values, which is unusual. Assuming these are logP values, they indicate poor permeability.

**10. Aqueous Solubility:** Both have negative values, which is also unusual. Assuming these are logS values, they indicate poor solubility.

**11. hERG Inhibition:** Both ligands have low hERG inhibition risk (0.359 and 0.276).

**12. Microsomal Clearance:** Ligand A (24.33) has lower clearance than Ligand B (30.668), suggesting better metabolic stability.

**13. In vitro Half-Life:** Ligand A (-9.71) has a significantly longer half-life than Ligand B (-3.934).

**14. P-gp Efflux:** Both have very low P-gp efflux liability (0.011 and 0.084).

**15. Binding Affinity:** Ligand B (-7.9 kcal/mol) has a slightly better binding affinity than Ligand A (-7.2 kcal/mol). The difference is 0.7 kcal/mol, which is significant.

**Overall Assessment:**

While Ligand B has slightly better logP, QED, and binding affinity, Ligand A has a significantly better BBB penetration (81.7% vs 65.8%), longer half-life, and lower microsomal clearance. Given the CNS target (DRD2), BBB penetration is paramount. The 0.7 kcal/mol difference in binding affinity can potentially be overcome with further optimization, while poor BBB penetration is harder to fix. The longer half-life and lower clearance of Ligand A are also significant advantages.

Output:
0
2025-04-17 03:37:50,065 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (349.519 and 346.475 Da) fall comfortably within the ideal 200-500 Da range.

**TPSA:** Ligand A (61.44) is significantly better than Ligand B (78.09). For CNS targets, we want TPSA <= 90, and A is much closer to the optimal <=60 range. B is pushing the upper limit.

**logP:** Both ligands (2.308 and 2.679) are within the optimal 1-3 range.

**H-Bond Donors & Acceptors:** Both have 2 HBD and 3 HBA, which is acceptable.

**QED:** Both have good QED scores (0.636 and 0.805), indicating drug-like properties.

**DILI:** Ligand A (7.484) has a much lower DILI risk than Ligand B (37.611). This is a significant advantage.

**BBB:** Ligand B (70.221) has a better BBB penetration score than Ligand A (58.511). While both are reasonably good, B is preferable here.

**Caco-2 Permeability:** Both have negative Caco-2 values (-4.952 and -4.868), which is unusual and suggests poor permeability. This is a concern for both, but the values are similar.

**Aqueous Solubility:** Both have negative solubility values (-1.742 and -3.262), indicating poor aqueous solubility. This is a significant drawback for both, but B is worse.

**hERG Inhibition:** Both have low hERG inhibition liability (0.4 and 0.557), which is good.

**Microsomal Clearance:** Ligand A (16.106) has significantly lower microsomal clearance than Ligand B (35.33), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (48.662) has a much longer in vitro half-life than Ligand B (-18.87). This is a substantial advantage.

**P-gp Efflux:** Both have very low P-gp efflux liability (0.033 and 0.168), which is excellent for CNS penetration.

**Binding Affinity:** Ligand B (-8.2 kcal/mol) has a slightly better binding affinity than Ligand A (-7.7 kcal/mol). This 0.5 kcal/mol difference is notable, but not overwhelmingly decisive.

**Overall Assessment:**

Considering the GPCR-specific priorities, Ligand A is the better candidate. While Ligand B has a slightly better binding affinity and BBB score, Ligand A excels in critical areas like DILI risk, metabolic stability (lower Cl_mic, longer t1/2), and TPSA. The poor Caco-2 and solubility are concerns for both, but the other advantages of A outweigh the slight affinity benefit of B. The lower DILI risk is particularly important.

Output:
0
2025-04-17 03:37:50,065 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 drug candidates, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (365.455 and 352.45 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (109.57) is higher than Ligand B (69.64). For CNS targets, TPSA should be <= 90. Ligand B is much better in this regard.

**3. logP:** Ligand A (0.261) is quite low, potentially hindering membrane permeability. Ligand B (3.925) is within the optimal 1-3 range. This is a significant advantage for Ligand B.

**4. H-Bond Donors:** Both have 2 HBD, which is acceptable.

**5. H-Bond Acceptors:** Ligand A has 5 HBA, acceptable. Ligand B has 3 HBA, also acceptable.

**6. QED:** Both ligands have reasonably good QED scores (0.778 and 0.627), indicating good drug-like properties.

**7. DILI:** Both ligands have low DILI risk (37.03 and 31.291), which is positive.

**8. BBB:** Both ligands have good BBB penetration (75.184 and 72.78), exceeding the 70% threshold for CNS targets.

**9. Caco-2 Permeability:** Ligand A (-5.354) has very poor Caco-2 permeability, indicating poor intestinal absorption. Ligand B (-4.747) is also poor, but slightly better than A.

**10. Aqueous Solubility:** Both ligands have poor aqueous solubility (-2.536 and -3.855). This could pose formulation challenges, but isn't a dealbreaker if other properties are favorable.

**11. hERG Inhibition:** Both ligands have low hERG inhibition risk (0.36 and 0.857).

**12. Microsomal Clearance:** Ligand A (-10.367) has a negative clearance, which is unusual and suggests very high metabolic stability. Ligand B (92.211) has high clearance, indicating rapid metabolism.

**13. In vitro Half-Life:** Ligand A (27.679) has a moderate half-life. Ligand B (4.416) has a very short half-life.

**14. P-gp Efflux:** Both ligands have very low P-gp efflux (0.013 and 0.514), which is favorable for CNS exposure.

**15. Binding Affinity:** Both ligands have very similar binding affinities (-8.3 kcal/mol and -8.2 kcal/mol). The difference is negligible.

**Overall Assessment:**

Ligand B is the more promising candidate. While both have acceptable BBB penetration and binding affinity, Ligand B excels in key areas for GPCRs: a more optimal logP, significantly lower TPSA, and a slightly better Caco-2 permeability. Although Ligand B has higher microsomal clearance and a shorter half-life, the more favorable ADME profile regarding permeability and lipophilicity is more critical for a CNS-targeting GPCR ligand. Ligand A's extremely low logP and poor Caco-2 permeability are major drawbacks. The negative clearance for Ligand A is also suspect and warrants further investigation.

Output:
1
2025-04-17 03:37:50,065 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (343.515 Da) is slightly better, being closer to the lower end which can aid permeability.

**TPSA:** Ligand A (35.58) is excellent, well below the 90 A^2 threshold for CNS targets. Ligand B (51.02) is still reasonable but less optimal.

**logP:** Ligand A (2.603) is within the optimal range (1-3). Ligand B (4.616) is higher, potentially leading to solubility issues and off-target interactions.

**H-Bond Donors/Acceptors:** Ligand A (HBD=1, HBA=3) and Ligand B (HBD=0, HBA=5) both fall within acceptable limits.

**QED:** Both ligands have reasonable QED scores (A: 0.862, B: 0.702), indicating good drug-like properties.

**DILI:** Ligand A (2.637) has a much lower DILI risk than Ligand B (45.328), which is a significant advantage.

**BBB:** Ligand A (80.962) has a significantly higher BBB penetration percentile than Ligand B (66.731). This is crucial for a CNS target like DRD2.

**Caco-2 Permeability:** Ligand A (-5.086) has a negative value which is unusual, and suggests poor permeability. Ligand B (-4.852) is also poor, but slightly better.

**Aqueous Solubility:** Ligand A (-1.805) and Ligand B (-4.544) both have poor aqueous solubility.

**hERG Inhibition:** Both ligands show low hERG inhibition risk (A: 0.923, B: 0.737).

**Microsomal Clearance:** Ligand A (-2.235) has a negative clearance, which is unusual and suggests very high metabolic stability. Ligand B (74.005) has high clearance, indicating faster metabolism.

**In vitro Half-Life:** Ligand A (-12.896) has a negative half-life which is unusual, and suggests very high stability. Ligand B (55.584) is reasonable.

**P-gp Efflux:** Ligand A (0.118) has much lower P-gp efflux liability than Ligand B (0.699), which is beneficial for CNS exposure.

**Binding Affinity:** Ligand B (-7.2) has a significantly stronger binding affinity than Ligand A (-9.0). This is a substantial advantage, potentially outweighing some of the ADME drawbacks. However, the negative values suggest the binding affinity is reported in a different scale. Assuming the scale is consistent, a more negative value indicates stronger binding.

**Overall Assessment:**

Ligand A excels in several key areas for a CNS-targeting GPCR: TPSA, BBB, DILI, P-gp efflux, and metabolic stability. However, it has poor Caco-2 permeability and aqueous solubility, and a weaker binding affinity. Ligand B has a much better binding affinity, but suffers from higher logP, higher DILI risk, lower BBB penetration, and higher P-gp efflux.

Given the importance of CNS penetration for DRD2, and the relatively large affinity difference (-7.2 vs -9.0), Ligand B is the more promising candidate, *assuming* the binding affinity scale is consistent. The higher logP and DILI risk are concerns, but may be addressable through further optimization. The stronger binding is a significant advantage.

Output:
1
2025-04-17 03:37:50,065 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands fall within the ideal 200-500 Da range (A: 446.252, B: 370.515).

**TPSA:** Ligand A (77.11) is better than Ligand B (81.08) as it is closer to the <90 A^2 threshold desirable for CNS targets.

**logP:** Ligand A (3.264) is within the optimal 1-3 range. Ligand B (0.712) is slightly low, potentially hindering permeation.

**H-Bond Donors/Acceptors:** Ligand A (HBD=1, HBA=6) and Ligand B (HBD=2, HBA=5) both have acceptable numbers of H-bond donors and acceptors.

**QED:** Both ligands have good QED values (A: 0.491, B: 0.72), suggesting drug-like properties, with B being better.

**DILI:** Ligand A has a high DILI risk (93.602), which is a significant concern. Ligand B has a very low DILI risk (14.424), a major advantage.

**BBB:** Ligand A (62.699) shows moderate BBB penetration, while Ligand B (43.117) is quite low. For a CNS target like DRD2, a higher BBB value is crucial.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.192 and -5.085), which is unusual and suggests poor permeability. This is a red flag for both.

**Aqueous Solubility:** Both ligands have very poor aqueous solubility (-3.955 and -1.725).

**hERG Inhibition:** Ligand A (0.802) has a slightly higher hERG risk than Ligand B (0.299), but both are relatively low.

**Microsomal Clearance:** Ligand A (67.099) has higher clearance than Ligand B (33.75), indicating lower metabolic stability.

**In vitro Half-Life:** Ligand A (109.451) has a longer half-life than Ligand B (-4.576).

**P-gp Efflux:** Ligand A (0.722) shows moderate P-gp efflux, while Ligand B (0.022) has very low efflux, which is favorable for CNS penetration.

**Binding Affinity:** Ligand A (-9.1 kcal/mol) has a significantly stronger binding affinity than Ligand B (-7.3 kcal/mol). This is a substantial advantage for Ligand A.

**Overall Assessment:**

Despite the superior binding affinity of Ligand A, its high DILI risk, moderate BBB penetration, and higher P-gp efflux are major drawbacks. Ligand B, while having a weaker binding affinity, possesses a much more favorable safety profile (low DILI), lower P-gp efflux, and a better QED score. The poor Caco-2 and solubility for both are concerning, but can potentially be addressed through formulation strategies. Given the CNS target and the importance of safety, Ligand B is the more promising candidate. The affinity difference, while significant, might be overcome with further optimization of Ligand B.

Output:
1
2025-04-17 03:37:50,065 - INFO - Batch 45 complete. Total preferences: 720
2025-04-17 03:37:50,065 - INFO - Processing batch 46/512...
2025-04-17 03:38:31,337 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (344.415 and 348.531 Da) fall comfortably within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (98.32) is higher than Ligand B (58.2). For CNS targets, we prefer TPSA <= 90. Ligand A is slightly above this, while Ligand B is well below, giving it an advantage.

**3. logP:** Ligand A (0.459) is quite low, potentially hindering membrane permeability. Ligand B (3.506) is within the optimal 1-3 range. This is a significant advantage for Ligand B.

**4. H-Bond Donors:** Ligand A (3) is acceptable, while Ligand B (2) is even better, contributing to improved permeability.

**5. H-Bond Acceptors:** Ligand A (4) and Ligand B (2) are both within the acceptable limit of <=10.

**6. QED:** Both ligands have similar QED values (0.694 and 0.67), indicating good drug-like properties.

**7. DILI:** Both ligands have low DILI risk (35.324 and 32.842), which is favorable.

**8. BBB:** This is a crucial parameter for CNS targets. Ligand B (70.182) is significantly better than Ligand A (39.473), exceeding the desirable >70 threshold.

**9. Caco-2 Permeability:** Ligand A (-5.048) shows very poor permeability. Ligand B (-4.806) is also poor, but slightly better than Ligand A.

**10. Aqueous Solubility:** Both ligands have poor aqueous solubility (-2.496 and -4.909). This could pose formulation challenges, but is less critical than permeability for CNS drugs.

**11. hERG Inhibition:** Both ligands show low hERG inhibition liability (0.168 and 0.495), which is good.

**12. Microsomal Clearance:** Ligand A (-19.727) has a much lower (better) microsomal clearance than Ligand B (74.457), indicating greater metabolic stability.

**13. In vitro Half-Life:** Ligand A (-37.562) has a much longer half-life than Ligand B (11.227), which is a significant advantage.

**14. P-gp Efflux:** Ligand A (0.024) shows very low P-gp efflux, which is excellent for CNS penetration. Ligand B (0.431) shows moderate P-gp efflux.

**15. Binding Affinity:** Both ligands have very similar binding affinities (-7.4 and -7.3 kcal/mol). The difference is negligible.

**Overall Assessment:**

While Ligand A has better metabolic stability (lower Cl_mic, longer t1/2) and lower P-gp efflux, Ligand B significantly outperforms it in key GPCR/CNS-relevant properties: logP and BBB. The low logP of Ligand A is a major concern, likely hindering its ability to cross cell membranes and reach the brain. Ligand B's higher logP and much better BBB penetration make it a more promising candidate despite the slightly higher P-gp efflux and lower metabolic stability. The similar binding affinities mean these factors become the deciding ones.

Output:
1
2025-04-17 03:38:31,338 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 drug candidates, considering the provided guidelines and GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (342.443 and 345.334 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (67.23) is significantly better than Ligand B (108.05). For CNS targets, we want TPSA <= 90, and A is comfortably within that range, while B exceeds it.

**3. logP:** Ligand A (2.049) is optimal (1-3), while Ligand B (0.196) is quite low, potentially hindering permeation.

**4. H-Bond Donors:** Both ligands have acceptable HBD counts (1 and 2 respectively), well below the threshold of 5.

**5. H-Bond Acceptors:** Both ligands have acceptable HBA counts (4 and 5 respectively), well below the threshold of 10.

**6. QED:** Both ligands have similar and good QED values (0.833 and 0.823), indicating good drug-like properties.

**7. DILI:** Ligand A (35.983) has a much lower DILI risk than Ligand B (69.756). Both are below 60, but A is preferable.

**8. BBB:** Ligand A (83.443) has a significantly higher BBB penetration percentile than Ligand B (55.603). For a CNS target like DRD2, >70 is desirable, and A is closer to this threshold.

**9. Caco-2 Permeability:** Both have negative values (-4.97 and -4.913), indicating poor permeability. This is concerning, but we'll consider it alongside other factors.

**10. Aqueous Solubility:** Both have negative values (-2.695 and -2.983), indicating poor solubility. This is also concerning.

**11. hERG Inhibition:** Both ligands have low hERG inhibition risk (0.175 and 0.29).

**12. Microsomal Clearance:** Ligand A (31.164) has a higher (worse) microsomal clearance than Ligand B (-15.203). Lower clearance is preferred for metabolic stability.

**13. In vitro Half-Life:** Ligand A (24.6) has a shorter half-life than Ligand B (-21.238). Longer half-life is generally desirable.

**14. P-gp Efflux:** Ligand A (0.114) has a much lower P-gp efflux liability than Ligand B (0.008). Lower efflux is crucial for CNS exposure.

**15. Binding Affinity:** Ligand B (-9.3 kcal/mol) has a slightly better binding affinity than Ligand A (-7.7 kcal/mol). This is a 1.6 kcal/mol difference, which is significant.

**Overall Assessment:**

While Ligand B has a slightly better binding affinity, Ligand A is significantly better across several critical ADME properties, particularly those prioritized for GPCRs targeting the CNS. Ligand A has superior TPSA, logP, BBB penetration, and P-gp efflux properties. The lower DILI risk is also a major advantage. The slightly worse metabolic stability and half-life of Ligand A could potentially be addressed through structural modifications, whereas improving the CNS penetration of Ligand B would be far more challenging given its poor logP and high P-gp efflux. The binding affinity difference, while notable, is likely outweighed by the substantial ADME advantages of Ligand A.

Output:
1
2025-04-17 03:38:31,338 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (351.793 and 348.487 Da) fall comfortably within the ideal 200-500 Da range.

**TPSA:** Ligand A (71.09) is slightly higher than Ligand B (58.64). Both are below the 90 A^2 threshold desirable for CNS targets, but Ligand B is better.

**logP:** Ligand A (3.723) is at the upper end of the optimal range (1-3), while Ligand B (2.655) is well within it. Ligand B is preferable here.

**H-Bond Donors/Acceptors:** Ligand A has 2 HBD and 4 HBA, while Ligand B has 1 HBD and 3 HBA. Both are within acceptable limits (<=5 HBD and <=10 HBA).

**QED:** Ligand B (0.751) has a higher QED score than Ligand A (0.543), indicating a more drug-like profile.

**DILI:** Both ligands have high DILI risk, but Ligand B (9.965) is significantly lower than Ligand A (96.82). This is a major advantage for Ligand B.

**BBB:** Ligand B (72.392) has a better BBB percentile than Ligand A (55.487). This is crucial for a CNS target like DRD2.

**Caco-2 Permeability:** Ligand A (-4.864) has worse Caco-2 permeability than Ligand B (-4.441).

**Aqueous Solubility:** Ligand A (-5.877) has worse aqueous solubility than Ligand B (-2.939).

**hERG:** Both ligands have low hERG inhibition liability (0.279 and 0.317).

**Microsomal Clearance:** Ligand A (34.48) has lower microsomal clearance than Ligand B (75.684), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (101.147) has a much longer in vitro half-life than Ligand B (-8.493). This is a significant advantage for Ligand A.

**P-gp Efflux:** Ligand A (0.289) has lower P-gp efflux than Ligand B (0.147), which is desirable for CNS penetration.

**Binding Affinity:** Ligand A (-9.4 kcal/mol) has a significantly stronger binding affinity than Ligand B (-7.9 kcal/mol). This is a substantial advantage, potentially outweighing some ADME drawbacks.

**Overall Assessment:**

Ligand B excels in key properties for a CNS-targeting GPCR ligand: BBB penetration, lower DILI risk, better logP, and higher QED. However, Ligand A has a significantly stronger binding affinity and better metabolic stability (lower Cl_mic and longer t1/2), and lower P-gp efflux. The difference in binding affinity (-1.5 kcal/mol) is substantial. While Ligand B has better ADME properties overall, the strong binding affinity of Ligand A is a critical factor for DRD2, and the lower P-gp efflux will help with CNS exposure.

Output:
1
2025-04-17 03:38:31,338 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (349.406 and 364.408 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (72.88) and Ligand B (69.64) are both below the 90 A^2 threshold desirable for CNS targets, which is excellent.

**3. logP:** Both ligands have logP values (1.869 and 2.091) within the optimal 1-3 range.

**4. H-Bond Donors:** Both have 2 HBD, which is within the acceptable limit of <=5.

**5. H-Bond Acceptors:** Both have 3 HBA, also within the acceptable limit of <=10.

**6. QED:** Ligand A (0.852) has a better QED score than Ligand B (0.758), indicating a more drug-like profile.

**7. DILI:** Ligand A (24.622) has a slightly higher DILI risk than Ligand B (18.418), but both are well below the concerning threshold of 60.

**8. BBB:** Both ligands have excellent BBB penetration (74.176 and 74.486 percentile), exceeding the 70% threshold for CNS targets.

**9. Caco-2:** Both have negative Caco-2 values, which is unusual and potentially problematic. However, the negative scale is not well defined and may not be directly comparable.

**10. Solubility:** Both have negative solubility values, again unusual and potentially problematic. Similar to Caco-2, the negative scale is not well defined.

**11. hERG:** Both ligands have very low hERG inhibition liability (0.325 and 0.541), which is excellent.

**12. Cl_mic:** Ligand A (24.715) has a lower microsomal clearance than Ligand B (25.451), suggesting better metabolic stability.

**13. t1/2:** Ligand A (-4.7 hours) has a significantly *worse* in vitro half-life than Ligand B (-18.313 hours). This is a major drawback for Ligand A. Negative values here are unusual and likely indicate very rapid degradation.

**14. Pgp:** Both ligands have very low P-gp efflux liability (0.022 and 0.147), which is desirable for CNS penetration.

**15. Binding Affinity:** Both ligands have very strong binding affinities (-8.8 and -8.6 kcal/mol). The difference of 0.2 kcal/mol is not substantial enough to outweigh other factors.

**Overall Assessment:**

Ligand B is the better candidate. While Ligand A has a slightly better QED and lower Cl_mic, the significantly longer in vitro half-life of Ligand B (-18.313 vs -4.7) is a critical advantage. A longer half-life translates to potentially less frequent dosing and more sustained therapeutic effect. The DILI score is also slightly better for Ligand B. The similar affinities and excellent BBB penetration for both compounds make the half-life the deciding factor.

Output:
1
2025-04-17 03:38:31,338 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (426.332 Da) is slightly higher, but acceptable. Ligand B (356.463 Da) is also good.

**TPSA:** Ligand A (55.84) is excellent for CNS penetration, well below the 90 A^2 threshold. Ligand B (95.94) is higher, but still potentially acceptable, though less ideal for CNS targets.

**logP:** Ligand A (3.603) is within the optimal range (1-3). Ligand B (1.09) is at the lower end, which could hinder permeability.

**H-Bond Donors/Acceptors:** Ligand A (0 HBD, 4 HBA) is favorable. Ligand B (2 HBD, 5 HBA) is also reasonable, but slightly higher.

**QED:** Both ligands have similar QED values (A: 0.709, B: 0.666), indicating good drug-likeness.

**DILI:** Ligand A (70.841) has a higher DILI risk than Ligand B (21.598). This is a significant drawback for Ligand A.

**BBB:** Ligand A (52.191) has a moderate BBB penetration, while Ligand B (40.171) is lower. Both are below the desirable >70 for CNS targets, but A is better.

**Caco-2 Permeability:** Both have negative Caco-2 values (-4.814 and -4.699), which is unusual and suggests poor permeability. This is a concern for both.

**Aqueous Solubility:** Both have negative solubility values (-5.722 and -2.304), indicating very poor solubility. This is a major issue for both compounds.

**hERG Inhibition:** Ligand A (0.753) has a slightly higher hERG risk than Ligand B (0.196).

**Microsomal Clearance:** Ligand A (106.457) has higher microsomal clearance, indicating faster metabolism, than Ligand B (60.656).

**In vitro Half-Life:** Ligand B (-19.393) has a negative half-life, which is not possible. This is a major red flag. Ligand A (19.242) has a reasonable half-life.

**P-gp Efflux:** Ligand A (0.555) has lower P-gp efflux, which is favorable for CNS penetration, compared to Ligand B (0.044).

**Binding Affinity:** Ligand A (-8.1 kcal/mol) has significantly stronger binding affinity than Ligand B (-6.6 kcal/mol). This is a substantial advantage, potentially outweighing some of the ADME drawbacks.

**Overall Assessment:**

Ligand A has a significantly better binding affinity and better P-gp efflux, which are key for a CNS GPCR target. While its DILI risk is higher, and BBB is not ideal, the strong binding and lower efflux are compelling. Ligand B has a problematic negative half-life, poor logP, and weaker binding. The lower DILI is a plus, but the other issues are more critical. The negative values for Caco-2 and solubility are concerning for both, but can potentially be addressed with formulation strategies.

Output:
1
2025-04-17 03:38:31,338 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (343.427 and 338.411 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (65.79) is significantly better than Ligand B (94.04). For CNS targets, we want TPSA <= 90, so Ligand A is preferable.

**3. logP:** Ligand A (1.768) is within the optimal range (1-3). Ligand B (3.117) is at the higher end, potentially leading to solubility issues, but still acceptable.

**4. H-Bond Donors:** Ligand A (1) and Ligand B (2) are both acceptable, being <= 5.

**5. H-Bond Acceptors:** Ligand A (4) and Ligand B (5) are both acceptable, being <= 10.

**6. QED:** Both ligands have good QED values (0.868 and 0.897), indicating good drug-like properties.

**7. DILI:** Ligand A (32.028) has a lower DILI risk than Ligand B (51.105), which is preferable. Both are below the 60 threshold, but A is better.

**8. BBB:** Ligand A (62.931) has a better BBB penetration percentile than Ligand B (55.021). While both are below the desirable >70 for CNS targets, A is closer.

**9. Caco-2 Permeability:** Both ligands have very poor Caco-2 permeability (-5.014 and -5.019), indicating poor intestinal absorption. This is a significant drawback for both, but doesn't disqualify them for CNS targets if BBB penetration is sufficient.

**10. Aqueous Solubility:** Both ligands have poor aqueous solubility (-1.17 and -3.427). This is a concern, but can be mitigated with formulation strategies.

**11. hERG Inhibition:** Both ligands have low hERG inhibition risk (0.423 and 0.521).

**12. Microsomal Clearance:** Ligand A (2.763) has a lower microsomal clearance than Ligand B (39.556), indicating better metabolic stability. This is a significant advantage for A.

**13. In vitro Half-Life:** Ligand A (58.931) has a much longer in vitro half-life than Ligand B (-36.288). This is a major advantage for A.

**14. P-gp Efflux:** Both ligands have low P-gp efflux (0.041 and 0.036), which is good for CNS exposure.

**15. Binding Affinity:** Ligand B (-9.7 kcal/mol) has a slightly better binding affinity than Ligand A (-8.7 kcal/mol). This is a 1.0 kcal/mol difference, which is significant, but needs to be weighed against the other ADME properties.

**Overall Assessment:**

Ligand A is significantly better overall. While Ligand B has a slightly better binding affinity, Ligand A excels in crucial ADME properties for a CNS-targeting GPCR ligand: TPSA, DILI, BBB, microsomal clearance, and in vitro half-life. The better TPSA and BBB are particularly important for CNS penetration. The improved metabolic stability (lower Cl_mic and longer t1/2) also makes Ligand A more promising. The slight difference in binding affinity can potentially be optimized in future iterations of Ligand A.

Output:
1
2025-04-17 03:38:31,338 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (347.415 Da) is slightly lower, which is generally favorable for permeability.

**TPSA:** Ligand A (83.92) is significantly better than Ligand B (119.67). For CNS targets, a TPSA <= 90 is preferred, and Ligand A comfortably meets this, while Ligand B is pushing the limit.

**logP:** Ligand A (1.011) is within the optimal range (1-3), while Ligand B (-0.25) is below 1, potentially hindering permeation.

**H-Bond Donors/Acceptors:** Both have acceptable HBD (2) counts. Ligand B has a higher HBA count (8) compared to Ligand A (5), which could slightly impact permeability.

**QED:** Both ligands have reasonable QED values (A: 0.853, B: 0.709), indicating good drug-like properties.

**DILI:** Ligand B (63.823) has a higher DILI risk than Ligand A (38.426), although both are below the concerning threshold of 60.

**BBB:** Ligand B (83.792) shows significantly better BBB penetration than Ligand A (60.876). This is a crucial factor for CNS targets like DRD2.

**Caco-2 Permeability:** Ligand A (-4.719) has better Caco-2 permeability than Ligand B (-5.045).

**Aqueous Solubility:** Ligand A (-1.641) has better aqueous solubility than Ligand B (-2.779).

**hERG:** Both ligands have very low hERG inhibition risk (A: 0.166, B: 0.211).

**Microsomal Clearance:** Ligand A (-18.868) has much lower microsomal clearance than Ligand B (10.658), indicating better metabolic stability.

**In vitro Half-Life:** Ligand A (25.872) has a longer in vitro half-life than Ligand B (-13.565).

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (A: 0.014, B: 0.035).

**Binding Affinity:** Ligand B (-7.4 kcal/mol) has a significantly stronger binding affinity than Ligand A (0 kcal/mol). This is a major advantage, potentially outweighing some of its ADME drawbacks.

**Overall Assessment:**

Ligand B has a substantially better binding affinity, which is paramount for GPCR targets. However, it suffers from a higher TPSA, lower logP, and a higher DILI risk. Ligand A has superior ADME properties (TPSA, logP, solubility, metabolic stability, half-life) but significantly weaker binding.

Given the strong binding affinity of Ligand B, I believe it is the more promising candidate *despite* its ADME liabilities. Optimization efforts could focus on improving its logP and TPSA while retaining its potent binding. The substantial affinity advantage (-7.4 vs 0) is likely to be more impactful than the ADME differences, particularly in the context of a CNS target where BBB penetration is also reasonably good.

Output:
1
2025-04-17 03:38:31,338 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (346.43 and 345.44 Da) fall comfortably within the ideal 200-500 Da range.

**TPSA:** Ligand A (83.73) is slightly higher than Ligand B (71.41). Both are below the 90 A^2 threshold for CNS targets, which is good. Ligand B is preferable here.

**logP:** Ligand A (2.925) is within the optimal 1-3 range. Ligand B (1.595) is at the lower end, potentially impacting permeability. Ligand A is preferable.

**H-Bond Donors:** Ligand A (3) and Ligand B (1) both meet the <=5 criteria. Ligand B is preferable.

**H-Bond Acceptors:** Both ligands (4) are well below the 10 threshold.

**QED:** Both ligands have good QED values (0.72 and 0.843), indicating drug-like properties.

**DILI:** Ligand A (47.421) has a slightly higher DILI risk than Ligand B (36.836), but both are below the concerning threshold of 60. Ligand B is preferable.

**BBB:** This is a crucial parameter for a CNS target like DRD2. Ligand B (63.629) has a significantly better BBB percentile than Ligand A (41.915). This is a major advantage for Ligand B.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.764 and -4.748). This is unusual and suggests poor permeability.

**Aqueous Solubility:** Both ligands have negative solubility values (-3.029 and -2.546), again indicating poor solubility.

**hERG Inhibition:** Both ligands have low hERG inhibition liability (0.72 and 0.183), which is excellent. Ligand B is preferable.

**Microsomal Clearance:** Ligand A (46.905) has a higher microsomal clearance than Ligand B (24.359), indicating lower metabolic stability. Ligand B is preferable.

**In vitro Half-Life:** Ligand B (-19.795) has a negative half-life, which is not possible. Ligand A (55.766) has a reasonable half-life. This is a significant advantage for Ligand A.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.417 and 0.114), which is good for CNS penetration. Ligand B is preferable.

**Binding Affinity:** Both ligands have excellent binding affinities (-9.0 and -9.2 kcal/mol). The difference is negligible.

**Overall Assessment:**

Ligand B clearly excels in several key areas for a CNS-targeting GPCR ligand: BBB penetration, DILI risk, hERG inhibition, microsomal clearance, and P-gp efflux. While Ligand A has a better in vitro half-life and logP, the superior CNS penetration profile of Ligand B outweighs these advantages. The negative Caco-2 and solubility values are concerning for both, but could potentially be addressed through formulation strategies.

Output:
1
2025-04-17 03:38:31,339 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (423.38 Da) is slightly higher, but acceptable. Ligand B (355.41 Da) is also good.

**2. TPSA:** Ligand A (61.02) is better than Ligand B (84.67). For CNS targets, we want TPSA <= 90, both are within this range, but A is preferable.

**3. logP:** Ligand A (3.841) is optimal (1-3), while Ligand B (1.853) is on the lower side. Lower logP can hinder permeation, making A more promising.

**4. H-Bond Donors:** Both ligands have acceptable HBD counts (A: 2, B: 1).

**5. H-Bond Acceptors:** Both ligands have acceptable HBA counts (A: 3, B: 5).

**6. QED:** Both ligands have good QED scores (A: 0.735, B: 0.842), indicating good drug-like properties.

**7. DILI:** Ligand A (65.335) has a higher DILI risk than Ligand B (33.191). This is a negative for A.

**8. BBB:** Ligand B (88.096) has a significantly better BBB penetration score than Ligand A (72.78). This is a crucial factor for a CNS target like DRD2, strongly favoring B.

**9. Caco-2 Permeability:** Ligand A (-5.209) has poor Caco-2 permeability, while Ligand B (-4.39) is slightly better, but still not ideal.

**10. Aqueous Solubility:** Ligand A (-4.329) has poor solubility, while Ligand B (-2.605) is better.

**11. hERG Inhibition:** Ligand A (0.834) has a slightly higher hERG risk than Ligand B (0.323).

**12. Microsomal Clearance:** Ligand B (11.848) has much lower microsomal clearance than Ligand A (66.881), indicating better metabolic stability.

**13. In vitro Half-Life:** Ligand B (-29.226) has a longer half-life than Ligand A (26.123).

**14. P-gp Efflux:** Ligand A (0.57) has higher P-gp efflux than Ligand B (0.166), meaning B will have better CNS exposure.

**15. Binding Affinity:** Ligand B (-8.4 kcal/mol) has a significantly stronger binding affinity than Ligand A (0.0 kcal/mol). This is a major advantage for B, potentially outweighing some of its other drawbacks.

**Overall Assessment:**

While Ligand A has a better logP, Ligand B excels in almost all other critical parameters for a CNS-targeting GPCR ligand. Specifically, its superior BBB penetration, significantly better binding affinity, lower DILI risk, better metabolic stability (lower Cl_mic, longer t1/2), and lower P-gp efflux make it a much more promising candidate. The slightly lower logP of B is a minor concern compared to the substantial advantages it offers.

Output:
1
2025-04-17 03:38:31,339 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (346.471 and 354.491 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (58.64) is significantly better than Ligand B (78.87). For CNS targets, we want TPSA <= 90, and A is much closer to the optimal <=60 range. B is approaching a less desirable range.

**logP:** Both ligands have good logP values (1.958 and 1.563), falling within the 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A (HBD=1, HBA=3) is preferable to Ligand B (HBD=2, HBA=4) as lower numbers generally improve permeability. Both are within acceptable limits.

**QED:** Both ligands have acceptable QED scores (0.748 and 0.693), indicating good drug-like properties.

**DILI:** Ligand A (16.402) has a slightly higher DILI risk than Ligand B (11.361), but both are well below the concerning threshold of 60.

**BBB:** Both ligands have good BBB penetration (60.45% and 67.662%). While >70 is desirable, these are acceptable, and not a major differentiating factor.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.716 and -4.608), which is unusual and potentially problematic. It suggests poor permeability. However, these values are close, so it's not a major differentiator.

**Aqueous Solubility:** Both ligands have negative solubility values (-2.999 and -1.786), which is also concerning and suggests poor aqueous solubility. Again, the difference isn't substantial.

**hERG:** Both ligands show low hERG inhibition risk (0.284 and 0.366).

**Microsomal Clearance:** Ligand A (33.833) has a higher microsomal clearance than Ligand B (17.388), suggesting lower metabolic stability. B is preferable here.

**In vitro Half-Life:** Ligand B (-5.921) has a negative half-life, which is impossible. This is a significant red flag. Ligand A (17.189) has a reasonable half-life.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.075 and 0.077), which is good for CNS penetration.

**Binding Affinity:** Ligand A (-7.9 kcal/mol) has a slightly better binding affinity than Ligand B (-7.7 kcal/mol), although the difference is small.

**Overall Assessment:**

Ligand A is the better candidate. While both have concerning negative Caco-2 and solubility values, Ligand B has an impossible negative in vitro half-life, making it immediately unsuitable. Ligand A has a better TPSA, and slightly better binding affinity, and a reasonable half-life, making it the more promising option despite the shared solubility/permeability concerns. The TPSA value for A is particularly important for a CNS target like DRD2.

Output:
0
2025-04-17 03:38:31,339 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (337.467 Da) is slightly lower, which could be beneficial for permeability.

**TPSA:** Ligand A (38.56) is excellent for CNS penetration, well below the 90 A^2 threshold. Ligand B (64.86) is still reasonable but less optimal.

**logP:** Both ligands have good logP values (A: 4.057, B: 3.256), falling within the 1-3 range. Ligand B is slightly more favorable.

**H-Bond Donors/Acceptors:** Both have 1 HBD, which is good. Ligand A has 4 HBA, and Ligand B has 6 HBA. Both are acceptable, but lower is generally preferred.

**QED:** Both ligands have good QED scores (A: 0.599, B: 0.896), indicating drug-like properties. Ligand B is better.

**DILI:** Ligand A (17.449) has a significantly lower DILI risk than Ligand B (74.99). This is a major advantage for Ligand A.

**BBB:** Ligand B (88.833) has a much higher BBB penetration percentile than Ligand A (68.554). This is a critical advantage for a CNS target like DRD2.

**Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and suggests poor permeability. However, the scale isn't specified, so it's hard to interpret.

**Aqueous Solubility:** Both ligands have very poor aqueous solubility (A: -2.15, B: -5.362). This is a significant drawback for both.

**hERG Inhibition:** Ligand A (0.977) has a slightly higher hERG risk than Ligand B (0.143). Ligand B is much better here.

**Microsomal Clearance:** Ligand A (26.644) has lower microsomal clearance, indicating better metabolic stability, than Ligand B (44.892).

**In vitro Half-Life:** Ligand A (29.77) has a longer half-life than Ligand B (0.861).

**P-gp Efflux:** Ligand A (0.717) has lower P-gp efflux than Ligand B (0.185), which is favorable for CNS exposure.

**Binding Affinity:** Ligand A (-8.7 kcal/mol) has a slightly better binding affinity than Ligand B (-8.1 kcal/mol). While the difference is small, it's still a positive for Ligand A.

**Overall Assessment:**

Ligand B excels in BBB penetration and has a better QED score and lower hERG risk. However, it suffers from a significantly higher DILI risk and poorer metabolic stability. Ligand A has a better safety profile (lower DILI), better metabolic stability, longer half-life, and slightly better affinity, but its BBB penetration is lower.

Considering the GPCR-specific priorities, BBB is crucial for CNS targets. While Ligand A's BBB is acceptable (68.554), Ligand B's (88.833) is much more desirable. The slightly better affinity of Ligand A is unlikely to overcome the substantial advantage of Ligand B in BBB penetration. The DILI risk of Ligand B is concerning, but could potentially be mitigated with further optimization.

Output:
1
2025-04-17 03:38:31,339 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (360.435 and 342.403 Da) are within the ideal 200-500 Da range.

**TPSA:** Ligand A (76.66) is excellent, falling well below the 90 A^2 threshold for CNS targets. Ligand B (93.01) is slightly higher but still acceptable, though less optimal.

**logP:** Ligand A (3.219) is within the optimal 1-3 range. Ligand B (1.337) is at the lower end, potentially impacting permeability.

**H-Bond Donors/Acceptors:** Ligand A (2 HBD, 6 HBA) and Ligand B (1 HBD, 6 HBA) both have reasonable numbers of H-bond donors and acceptors, well within the guidelines.

**QED:** Both ligands have good QED scores (0.801 and 0.908), indicating drug-like properties.

**DILI:** Ligand A (87.825) has a higher DILI risk than Ligand B (60.721), which is still moderately high but better.

**BBB:** Ligand A (65.258) has a lower BBB penetration percentile than Ligand B (75.649). This is a significant drawback for a CNS target like DRD2. Ligand B is desirable (>70).

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.808 and -4.998), which is unusual and suggests poor permeability. However, these values are on a log scale, and a more negative value indicates *lower* permeability.

**Aqueous Solubility:** Both ligands have negative solubility values (-4.641 and -2.722) which indicates poor solubility.

**hERG Inhibition:** Ligand A (0.56) has a slightly higher hERG risk than Ligand B (0.361), but both are relatively low.

**Microsomal Clearance:** Ligand A (94.629) has a high microsomal clearance, suggesting rapid metabolism and lower metabolic stability. Ligand B (17.112) has a much lower clearance, indicating better metabolic stability.

**In vitro Half-Life:** Ligand A (35.76) has a shorter half-life than Ligand B (4.43), further supporting the idea that Ligand A is metabolized more quickly.

**P-gp Efflux:** Ligand A (0.553) has lower P-gp efflux liability than Ligand B (0.023), which is favorable for CNS penetration.

**Binding Affinity:** Ligand B (-8.7 kcal/mol) has a significantly stronger binding affinity than Ligand A (-9.3 kcal/mol). This is a crucial advantage.

**Overall Assessment:**

While Ligand A has a slightly better P-gp efflux profile, Ligand B is superior in almost every other critical parameter for a CNS-targeting GPCR ligand. Specifically, Ligand B has better BBB penetration, lower DILI risk, significantly better metabolic stability (lower Cl_mic, longer t1/2), and a stronger binding affinity. The slightly lower logP of Ligand B is a minor concern that could potentially be addressed with further optimization, but the benefits outweigh this drawback.

Output:
1
2025-04-17 03:38:31,339 - INFO - Reasoning:

Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (359.348 and 342.403 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (71.53) is significantly better than Ligand B (93.01). For CNS targets, we want TPSA <= 90, so Ligand A is preferable.

**3. logP:** Both ligands have good logP values (1.959 and 1.337), falling within the optimal 1-3 range.

**4. H-Bond Donors:** Both have 1 HBD, which is acceptable.

**5. H-Bond Acceptors:** Ligand A has 4 HBAs, and Ligand B has 6. Both are within the acceptable limit of <=10, but Ligand A is slightly better.

**6. QED:** Both ligands have high QED scores (0.808 and 0.908), indicating good drug-like properties.

**7. DILI:** Ligand A (52.772) has a slightly better DILI score than Ligand B (60.721), indicating a lower risk of liver injury, although both are acceptable (<60 is preferred).

**8. BBB:** Ligand A (85.964) has a significantly better BBB score than Ligand B (75.649). For a CNS target like DRD2, a BBB percentile >70 is desirable, and Ligand A is closer to that threshold.

**9. Caco-2:** Both have negative Caco-2 values (-4.548 and -4.998), which is unusual and suggests poor permeability. This is a significant drawback for both.

**10. Solubility:** Both have negative solubility values (-2.686 and -2.722), indicating poor aqueous solubility. This is also a significant drawback for both.

**11. hERG:** Both ligands have very low hERG risk (0.472 and 0.361).

**12. Cl_mic:** Both have similar microsomal clearance values (17.816 and 17.112 mL/min/kg), suggesting comparable metabolic stability.

**13. t1/2:** Ligand A has a negative in vitro half-life (-16.82), which is problematic. Ligand B has a positive, though low, half-life (4.43). This is a significant advantage for Ligand B.

**14. Pgp:** Both have very low Pgp efflux liability (0.036 and 0.023), which is good for CNS penetration.

**15. Binding Affinity:** Both ligands have excellent binding affinities (-8.5 and -8.7 kcal/mol). The difference is minimal.

**Overall Assessment:**

While both ligands have excellent binding affinity, Ligand A is superior due to its lower TPSA and significantly better BBB penetration. The negative Caco-2 and solubility values are concerning for both, but can potentially be addressed through formulation strategies. The negative half-life for Ligand A is a major concern, while Ligand B has a slightly positive value. Considering the GPCR-specific priorities, particularly BBB for a CNS target, Ligand A is the more promising candidate despite the negative half-life.

Output:
1
2025-04-17 03:38:31,339 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (346.431 and 345.443 Da) fall comfortably within the ideal 200-500 Da range.

**TPSA:** Ligand A (76.46) is significantly better than Ligand B (80.32). For CNS targets, we want TPSA <= 90, and A is closer to the ideal range.

**logP:** Both ligands have good logP values (1.52 and 1.904), falling within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A has 1 HBD and 5 HBA, while Ligand B has 2 HBD and 4 HBA. Both are within acceptable limits (<=5 HBD and <=10 HBA).

**QED:** Both ligands have reasonable QED scores (0.44 and 0.501). Ligand B is slightly better, exceeding 0.5.

**DILI:** Ligand A (43.66) has a slightly higher DILI risk than Ligand B (27.181), but both are below the concerning threshold of 60.

**BBB:** This is a critical parameter for a CNS target like DRD2. Ligand A has a much higher BBB penetration percentile (82.513) compared to Ligand B (44.979). This is a major advantage for Ligand A.

**Caco-2 Permeability:** Ligand A (-5.262) has worse Caco-2 permeability than Ligand B (-4.652), but both are negative values which are difficult to interpret without knowing the scale.

**Aqueous Solubility:** Ligand A (-1.582) has slightly better solubility than Ligand B (-2.408), both are negative values which are difficult to interpret without knowing the scale.

**hERG Inhibition:** Both ligands show low hERG inhibition liability (0.656 and 0.329), which is favorable.

**Microsomal Clearance:** Ligand A (19.777) has lower microsomal clearance than Ligand B (27.669), indicating better metabolic stability.

**In vitro Half-Life:** Ligand A (-25.689) has a much longer in vitro half-life than Ligand B (5.136). This is a significant advantage for Ligand A.

**P-gp Efflux:** Ligand A (0.089) has lower P-gp efflux liability than Ligand B (0.051), suggesting better CNS exposure.

**Binding Affinity:** Ligand B (-7.8) has a slightly better binding affinity than Ligand A (-7.6), but the difference is relatively small (0.2 kcal/mol).

**Overall Assessment:**

Ligand A is the stronger candidate. While Ligand B has slightly better affinity and QED, Ligand A excels in crucial areas for a CNS-targeting GPCR ligand: significantly better BBB penetration, longer half-life, lower microsomal clearance, and lower P-gp efflux. The small difference in binding affinity is likely outweighed by these superior ADME properties, particularly the BBB penetration.

Output:
1
2025-04-17 03:38:31,339 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (379.913 and 332.407 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (71.09) is higher than Ligand B (50.16). For CNS targets, we prefer TPSA <= 90, so both are acceptable, but B is better.

**3. logP:** Both ligands have similar logP values (4.387 and 4.358), which are slightly above the optimal 1-3 range, but not drastically so. This could potentially lead to some non-specific binding or solubility issues, but it's not a major concern at this stage.

**4. H-Bond Donors:** Ligand A has 2 HBD, and Ligand B has 1. Both are within the acceptable limit of <=5.

**5. H-Bond Acceptors:** Ligand A has 4 HBA, and Ligand B has 3. Both are within the acceptable limit of <=10.

**6. QED:** Both ligands have good QED scores (0.749 and 0.755), indicating good drug-like properties.

**7. DILI:** Both ligands have similar DILI risk (76.425 and 75.184), which is moderately high, but not alarming.

**8. BBB:** Ligand B (70.919) has a significantly better BBB percentile than Ligand A (61.497). This is a crucial factor for a CNS target like DRD2.

**9. Caco-2 Permeability:** Both have negative Caco-2 values (-4.772 and -4.743), which is unusual and suggests poor permeability. This is a significant drawback for both.

**10. Aqueous Solubility:** Both have negative solubility values (-5.299 and -4.796), which is also concerning and suggests poor aqueous solubility.

**11. hERG Inhibition:** Ligand A (0.562) has a slightly lower hERG inhibition risk than Ligand B (0.882), which is preferable.

**12. Microsomal Clearance:** Ligand B (74.192) has a higher microsomal clearance than Ligand A (66.061), meaning it's metabolized faster. Ligand A has better metabolic stability.

**13. In vitro Half-Life:** Ligand A (89.864) has a much longer in vitro half-life than Ligand B (-6.508). This is a significant advantage for Ligand A.

**14. P-gp Efflux:** Ligand A (0.446) has lower P-gp efflux than Ligand B (0.482), which is better for CNS penetration.

**15. Binding Affinity:** Ligand B (-9.0) has a significantly stronger binding affinity than Ligand A (-7.7). A difference of 1.3 kcal/mol is substantial and can often outweigh minor ADME drawbacks.

**Overall Assessment:**

While Ligand A has better metabolic stability, longer half-life, lower P-gp efflux, and slightly lower hERG risk, Ligand B's significantly stronger binding affinity (-9.0 vs -7.7 kcal/mol) and better BBB penetration are critical advantages for a CNS GPCR target. The poor Caco-2 and solubility for both are concerning, but the potency advantage of B is likely to be more impactful in initial optimization.

Output:
1
2025-04-17 03:38:31,339 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B based on the provided guidelines, prioritizing GPCR-specific properties (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (467.117 Da) is higher, but still acceptable. Ligand B (351.451 Da) is slightly lower, potentially aiding permeability.

**TPSA:** Ligand A (68.34) is excellent for CNS penetration, well below the 90 A^2 threshold. Ligand B (99.49) is higher, but still reasonable, though less favorable for CNS targets.

**logP:** Ligand A (3.559) is optimal. Ligand B (-0.571) is significantly low, potentially hindering membrane permeability and bioavailability.

**H-Bond Donors/Acceptors:** Ligand A (0 HBD, 5 HBA) is good. Ligand B (3 HBD, 6 HBA) is also acceptable, but the higher number of H-bonds could slightly reduce permeability.

**QED:** Both ligands have good QED scores (A: 0.549, B: 0.611), indicating drug-like properties.

**DILI:** Ligand A (88.717) has a higher DILI risk than Ligand B (10.741). This is a significant drawback for Ligand A.

**BBB:** Ligand A (72.664) has a good BBB penetration score, desirable for a CNS target. Ligand B (23.187) has a very low BBB score, making it unlikely to effectively reach the brain.

**Caco-2 Permeability:** Ligand A (-4.94) has poor Caco-2 permeability. Ligand B (-5.73) is also poor, but slightly worse.

**Aqueous Solubility:** Ligand A (-4.391) has poor solubility. Ligand B (-0.658) has slightly better solubility.

**hERG Inhibition:** Ligand A (0.507) has a low hERG risk. Ligand B (0.079) has a very low hERG risk.

**Microsomal Clearance:** Ligand A (57.138) has moderate clearance. Ligand B (-24.526) has negative clearance, which is not physically possible and indicates an issue with the data or prediction method.

**In vitro Half-Life:** Ligand A (83.074) has a good half-life. Ligand B (19.793) has a shorter half-life.

**P-gp Efflux:** Ligand A (0.843) has moderate P-gp efflux. Ligand B (0.003) has very low P-gp efflux, which is highly desirable for CNS penetration.

**Binding Affinity:** Ligand A (-9.0 kcal/mol) has significantly stronger binding affinity than Ligand B (-7.8 kcal/mol). This is a substantial advantage for Ligand A, potentially outweighing some of its ADME drawbacks.

**Overall Assessment:**

Ligand A has a superior binding affinity and acceptable BBB penetration, which are crucial for a CNS-targeting GPCR. However, it suffers from higher DILI risk, poor Caco-2 permeability and solubility. Ligand B has a much better safety profile (DILI, hERG) and lower P-gp efflux, but its extremely low BBB penetration and significantly weaker binding affinity are major concerns. The negative microsomal clearance for Ligand B is also a red flag.

Despite the drawbacks, the strong binding affinity of Ligand A, coupled with acceptable BBB, makes it the more promising candidate, assuming the DILI risk can be mitigated through structural modifications. The poor ADME properties of Ligand A are areas for optimization, but the potency advantage is significant.

Output:
1
2025-04-17 03:38:31,340 - INFO - Batch 46 complete. Total preferences: 736
2025-04-17 03:38:31,340 - INFO - Processing batch 47/512...
2025-04-17 03:39:12,895 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (359.348 and 363.414 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Both ligands have a TPSA of 91.32, which is slightly above the optimal <90 for CNS targets, but still reasonably acceptable.

**3. logP:** Both ligands have logP values (2.002 and 2.369) within the optimal 1-3 range.

**4. H-Bond Donors:** Both ligands have 3 HBD, which is within the acceptable limit of <=5.

**5. H-Bond Acceptors:** Ligand A has 4 HBA, and Ligand B has 5 HBA, both within the acceptable limit of <=10.

**6. QED:** Ligand A (0.75) has a better QED score than Ligand B (0.628), indicating a more drug-like profile.

**7. DILI:** Ligand A (41.062) has a significantly lower DILI risk than Ligand B (62.505). This is a substantial advantage.

**8. BBB:** Ligand A (67.623) has a better BBB penetration percentile than Ligand B (39.007). This is *critical* for a CNS target like DRD2.

**9. Caco-2 Permeability:** Ligand A (-4.76) has better Caco-2 permeability than Ligand B (-5.344), suggesting better intestinal absorption.

**10. Aqueous Solubility:** Ligand A (-3.459) has slightly better aqueous solubility than Ligand B (-3.321).

**11. hERG Inhibition:** Both ligands have similar, low hERG inhibition risk (0.328 and 0.445).

**12. Microsomal Clearance:** Ligand A (27.148) has significantly lower microsomal clearance than Ligand B (50.11), indicating better metabolic stability.

**13. In vitro Half-Life:** Ligand A (-46.438) has a much longer in vitro half-life than Ligand B (-18.002).

**14. P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.014 and 0.178).

**15. Binding Affinity:** Both ligands have the same binding affinity (-8.1 kcal/mol), which is excellent.

**Overall Assessment:**

Ligand A is clearly superior. While both ligands have excellent binding affinity, Ligand A demonstrates significantly better ADME properties, particularly regarding BBB penetration, DILI risk, metabolic stability (lower Cl_mic and longer t1/2), and Caco-2 permeability. These factors are crucial for a CNS-targeting drug, and the differences between the two ligands are substantial enough to outweigh any potential minor advantages Ligand B might have.

Output:
1
2025-04-17 03:39:12,895 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the acceptable range (200-500 Da). Ligand A (356.375) is slightly lower, which could be advantageous for permeability.

**TPSA:** Ligand A (134.19) is closer to the upper limit for good oral absorption but still reasonable for a CNS target. Ligand B (97.39) is excellent, falling well below the 90 A^2 threshold for CNS penetration.

**logP:** Ligand A (-1.925) is a bit low, potentially hindering membrane permeability. Ligand B (2.078) is within the optimal range (1-3), which is a significant advantage.

**H-Bond Donors/Acceptors:** Ligand A (4 HBD, 7 HBA) and Ligand B (2 HBD, 6 HBA) both have acceptable numbers of H-bond donors and acceptors.

**QED:** Both ligands have reasonable QED scores (A: 0.322, B: 0.63). Ligand B's score is considerably better, indicating a more drug-like profile.

**DILI:** Both ligands have similar DILI risk (A: 64.482, B: 65.723), and are within an acceptable range.

**BBB:** Ligand B (59.558) has a significantly better BBB percentile than Ligand A (23.187). This is a *critical* advantage for a CNS target like DRD2.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.446 and -4.763), which is unusual and suggests poor permeability. However, these values are on a log scale and can be difficult to interpret directly.

**Aqueous Solubility:** Both ligands have negative solubility values (-1.264 and -3.071), indicating poor aqueous solubility. This could be a formulation challenge.

**hERG Inhibition:** Both ligands show low hERG inhibition risk (A: 0.142, B: 0.381).

**Microsomal Clearance:** Ligand A (24.151) has a lower microsomal clearance than Ligand B (61.645), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand B (-45.79) has a much longer in vitro half-life than Ligand A (-16.363). This is a significant advantage.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (A: 0.089, B: 0.441).

**Binding Affinity:** Ligand B (-7.9 kcal/mol) has a slightly better binding affinity than Ligand A (-7.0 kcal/mol), although both are good. The 0.9 kcal/mol difference is notable.

**Overall Assessment:**

Ligand B is the more promising candidate. While Ligand A has a slightly lower molecular weight and better metabolic stability, Ligand B excels in key areas for a CNS-targeting GPCR ligand: significantly better BBB penetration, a more favorable logP, a better QED score, and a longer half-life. The slightly improved binding affinity of Ligand B further supports this conclusion. The poor Caco-2 and solubility values are concerns for both, but can potentially be addressed through formulation strategies.



Output:
1
2025-04-17 03:39:12,895 - INFO - Reasoning:

Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (335.363 and 356.438 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (81.06) is slightly above the ideal <90 for CNS targets, but acceptable. Ligand B (75.71) is well within the desired range.

**3. logP:** Both ligands (2.029 and 1.823) are within the optimal 1-3 range.

**4. H-Bond Donors:** Both have 1 HBD, which is good.

**5. H-Bond Acceptors:** Ligand A has 5 HBA, and Ligand B has 4 HBA, both acceptable.

**6. QED:** Both ligands have QED values above 0.6, indicating good drug-likeness.

**7. DILI:** Ligand A (90.694) has a significantly higher DILI risk than Ligand B (12.834). This is a major concern for Ligand A.

**8. BBB:** Ligand B (88.6) has a much better BBB penetration percentile than Ligand A (65.607). This is crucial for a CNS target like DRD2.

**9. Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and suggests poor permeability. However, the scale isn't specified, so it's difficult to interpret.

**10. Aqueous Solubility:** Both have negative solubility values, again making interpretation difficult without knowing the scale.

**11. hERG:** Both ligands have very low hERG inhibition liability, which is good.

**12. Microsomal Clearance:** Ligand B (53.8) has lower microsomal clearance than Ligand A (58.76), suggesting better metabolic stability.

**13. In vitro Half-Life:** Ligand B (-21.019) has a significantly longer in vitro half-life than Ligand A (5.512).

**14. P-gp Efflux:** Ligand B (0.018) has much lower P-gp efflux liability than Ligand A (0.421). Lower P-gp efflux is highly desirable for CNS penetration.

**15. Binding Affinity:** Ligand A (-10.4 kcal/mol) has a significantly stronger binding affinity than Ligand B (-6.8 kcal/mol). This is a substantial advantage.

**Overall Assessment:**

While Ligand A boasts a superior binding affinity, its significantly higher DILI risk, lower BBB penetration, higher P-gp efflux, and shorter half-life are major drawbacks. Ligand B, despite the weaker binding affinity, presents a much more favorable ADME-Tox profile, particularly regarding CNS penetration (high BBB, low P-gp efflux) and safety (low DILI). The difference in binding affinity (3.6 kcal/mol) is substantial, but the ADME/Tox profile of Ligand A is concerning enough to outweigh this benefit. For a CNS target, achieving adequate brain exposure is paramount, and Ligand B is far more likely to achieve this.

Output:
1
2025-04-17 03:39:12,895 - INFO - Reasoning:

Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (366.462 and 347.371 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (66.4) is excellent, well below the 90 A^2 threshold for CNS targets. Ligand B (110.53) is higher, but still potentially acceptable, though less ideal.

**3. logP:** Both ligands have good logP values (1.17 and 0.927), falling within the optimal 1-3 range.

**4. H-Bond Donors:** Ligand A (0) is preferable to Ligand B (2). Fewer HBDs generally improve permeability.

**5. H-Bond Acceptors:** Both ligands have a reasonable number of HBAs (5 and 6, respectively), below the 10 threshold.

**6. QED:** Both ligands have similar QED values (0.8 and 0.784), indicating good drug-likeness.

**7. DILI:** Both ligands have similar DILI risk (60.644 and 67.507), placing them in a moderate risk category. This isn't a major differentiator.

**8. BBB:** This is a critical parameter for CNS targets. Ligand A has a significantly higher BBB penetration percentile (81.466) compared to Ligand B (43.001). This is a major advantage for Ligand A.

**9. Caco-2 Permeability:** Both have negative values, which is unusual. Assuming these are negative log values, they indicate poor permeability. Ligand A (-4.988) is slightly better than Ligand B (-5.064).

**10. Aqueous Solubility:** Both ligands have poor aqueous solubility (-1.884 and -3.027). This could pose formulation challenges, but is less critical than BBB penetration for a CNS target.

**11. hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.261 and 0.078).

**12. Microsomal Clearance:** Ligand B (1.004) has much lower microsomal clearance than Ligand A (17.637), suggesting better metabolic stability.

**13. In vitro Half-Life:** Ligand B (19.346) has a significantly longer in vitro half-life than Ligand A (-14.979). This is a substantial advantage for Ligand B.

**14. P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.043 and 0.023).

**15. Binding Affinity:** Both ligands have excellent binding affinity (-8.1 and -8.7 kcal/mol). Ligand B is slightly better (-8.7 kcal/mol).

**Overall Assessment:**

While Ligand B has better metabolic stability (lower Cl_mic, longer t1/2) and slightly better binding affinity, Ligand A's significantly higher BBB penetration (81.5% vs 43.0%) is the deciding factor for a CNS target like DRD2. The lower TPSA and HBD count of Ligand A are also favorable. The solubility and Caco-2 permeability are concerns for both, but can potentially be addressed through formulation strategies.

Output:
1
2025-04-17 03:39:12,896 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (413.272 Da) is slightly higher than Ligand B (351.451 Da), but both are acceptable.

**TPSA:** Both ligands have TPSA values below 140, suggesting reasonable oral absorption. Ligand A (103.79) and Ligand B (99.49) are both below the 90 threshold desirable for CNS targets, which is good.

**logP:** Ligand A (0.506) is a bit low, potentially hindering permeation. Ligand B (-0.714) is even lower, raising concerns about membrane permeability. Both are suboptimal, but Ligand A is slightly better.

**H-Bond Donors/Acceptors:** Both ligands have 3 HBDs and 6 HBAs, which are within acceptable limits (<=5 and <=10, respectively).

**QED:** Both ligands have similar QED values (0.622 and 0.602), indicating good drug-likeness.

**DILI:** Ligand A (70.221) has a higher DILI risk than Ligand B (8.957). This is a significant drawback for Ligand A.

**BBB:** Ligand B (13.455) has a very low BBB penetration percentile, making it unlikely to effectively reach the target in the CNS. Ligand A (46.84) is also not ideal, but significantly better than Ligand B.

**Caco-2 Permeability:** Ligand A (-4.927) has poor Caco-2 permeability, while Ligand B (-5.582) is also poor. Both are negative, indicating low permeability.

**Aqueous Solubility:** Ligand A (-2.239) has poor aqueous solubility, and Ligand B (-0.915) is also poor.

**hERG Inhibition:** Both ligands have very low hERG inhibition liability (0.236 and 0.05), which is excellent.

**Microsomal Clearance:** Ligand A (-12.348) has lower (better) microsomal clearance than Ligand B (-8.51). This suggests Ligand A is more metabolically stable.

**In vitro Half-Life:** Ligand A (18.454 hours) has a longer half-life than Ligand B (9.924 hours), which is favorable.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.012 and 0.001), which is excellent for CNS penetration.

**Binding Affinity:** Ligand A (-8.2 kcal/mol) has a significantly stronger binding affinity than Ligand B (-7.0 kcal/mol). This is a substantial advantage for Ligand A, potentially outweighing some of its ADME drawbacks.

**Overall Assessment:**

Ligand A has a much stronger binding affinity and better metabolic stability (lower Cl_mic, longer t1/2) and a moderately better BBB score. However, it has a higher DILI risk and poorer solubility/permeability. Ligand B has a much lower DILI risk, but suffers from extremely poor BBB penetration and a weaker binding affinity.

Given the target is a CNS GPCR (DRD2), BBB penetration is critical. While neither ligand is ideal, Ligand A's significantly better binding affinity and moderately better BBB score, combined with its improved metabolic stability, make it the more promising candidate despite its higher DILI risk and poor solubility. The affinity difference is substantial (>1.2 kcal/mol) and could be addressed with further optimization.

Output:
0
2025-04-17 03:39:12,896 - INFO - Reasoning:

Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (362.769 Da and 349.475 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (98.54) is higher than the preferred <90 for CNS targets, while Ligand B (63.57) is well within the desired range. This is a significant advantage for Ligand B.

**3. logP:** Ligand A (3.777) is at the higher end of the optimal range (1-3), while Ligand B (1.975) is closer to the lower end. Both are acceptable, but Ligand A's higher logP could potentially lead to off-target interactions or solubility issues.

**4. H-Bond Donors:** Both ligands have 1 HBD, which is within the acceptable limit of <=5.

**5. H-Bond Acceptors:** Ligand A has 5 HBAs and Ligand B has 4, both within the acceptable limit of <=10.

**6. QED:** Ligand B (0.884) has a significantly better QED score than Ligand A (0.495), indicating a more drug-like profile.

**7. DILI:** Ligand A (96.278) has a very high DILI risk, which is a major concern. Ligand B (34.238) has a low DILI risk, a substantial advantage.

**8. BBB:** Ligand B (65.413) has a better BBB percentile than Ligand A (55.293), although both are not ideal (>70 is preferred).

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.548 and -4.538), which is unusual and suggests poor permeability. This is a drawback for both.

**10. Aqueous Solubility:** Both ligands have negative solubility values (-5.681 and -1.899), indicating poor aqueous solubility. This is a concern for both, but less so for Ligand B.

**11. hERG Inhibition:** Both ligands have low hERG inhibition risk (0.459 and 0.371).

**12. Microsomal Clearance:** Ligand A (105.649) has higher microsomal clearance than Ligand B (59.942), suggesting lower metabolic stability.

**13. In vitro Half-Life:** Ligand B (18.137) has a slightly longer half-life than Ligand A (20.805).

**14. P-gp Efflux:** Ligand A (0.191) has slightly higher P-gp efflux than Ligand B (0.156), which is not ideal.

**15. Binding Affinity:** Ligand A (-9.0) has a significantly stronger binding affinity than Ligand B (-0.0). This is a major advantage for Ligand A.

**Overall Assessment:**

Despite the significantly better binding affinity of Ligand A, its high DILI risk, higher TPSA, and lower QED score are major drawbacks. The poor Caco-2 and solubility for both are concerning but can potentially be addressed with formulation strategies. However, the DILI risk is harder to mitigate. Ligand B, while having a weaker binding affinity, presents a much more favorable ADME-Tox profile, with a lower DILI risk, better QED, and a more appropriate TPSA for CNS penetration. Given the GPCR-specific priorities and the importance of a safe and drug-like profile, Ligand B is the more promising candidate. The affinity difference, while substantial, might be overcome with further optimization of Ligand B.

Output:
1
2025-04-17 03:39:12,896 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (387.238 and 376.475 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (59.59) is excellent, well below the 90 A^2 threshold for CNS targets. Ligand B (110.8) is higher, but still potentially acceptable, though less ideal.

**logP:** Ligand A (4.019) is at the upper end of the optimal range (1-3), potentially leading to solubility issues. Ligand B (-0.374) is too low, suggesting poor membrane permeability.

**H-Bond Donors/Acceptors:** Both have 2 HBDs, which is good. Ligand A has 3 HBAs, and Ligand B has 6 HBAs. Both are within the acceptable range, but Ligand A is preferable.

**QED:** Both ligands have reasonable QED values (0.706 and 0.568), indicating good drug-like properties.

**DILI:** Ligand A (68.088) has a higher DILI risk than Ligand B (39.046). This is a negative for Ligand A.

**BBB:** Ligand A (74.99) has a good BBB percentile, exceeding the 70% threshold for CNS targets. Ligand B (63.784) is lower, which is a concern for CNS penetration.

**Caco-2 Permeability:** Ligand A (-4.554) is very poor, indicating poor intestinal absorption. Ligand B (-5.563) is also poor.

**Aqueous Solubility:** Ligand A (-4.998) is very poor, consistent with its high logP. Ligand B (-1.497) is also poor, but less so than Ligand A.

**hERG Inhibition:** Ligand A (0.86) has a slightly higher hERG risk than Ligand B (0.134).

**Microsomal Clearance:** Ligand A (71.882) has higher clearance, indicating lower metabolic stability. Ligand B (-1.488) has negative clearance, which is unusual and suggests very high metabolic stability.

**In vitro Half-Life:** Ligand A (33.68) has a moderate half-life. Ligand B (17.689) has a shorter half-life.

**P-gp Efflux:** Ligand A (0.537) has moderate P-gp efflux liability. Ligand B (0.013) has very low P-gp efflux liability, which is highly desirable for CNS penetration.

**Binding Affinity:** Ligand B (-7.2 kcal/mol) has a significantly stronger binding affinity than Ligand A (-9.3 kcal/mol). This is a substantial advantage.

**Overall Assessment:**

While Ligand A has a better BBB score, its high logP, poor solubility, poor Caco-2 permeability, and higher DILI risk are significant drawbacks. Ligand B, despite a slightly lower BBB score, has a much better logP, significantly stronger binding affinity, very low P-gp efflux, and lower DILI risk. The superior binding affinity of Ligand B is a critical factor, and the other ADME properties, while not perfect, are more favorable overall. The negative clearance for Ligand B is a flag, but could be an artifact of the prediction method.

Output:
1
2025-04-17 03:39:12,896 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 drug candidates, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (425.689 Da) is slightly higher than Ligand B (380.861 Da), but both are acceptable.

**TPSA:** Ligand A (63.13) is significantly better than Ligand B (111.06). For CNS targets, we want TPSA <= 90, and Ligand A is comfortably within this range, while Ligand B exceeds it. This is a significant advantage for Ligand A regarding BBB penetration.

**logP:** Both ligands have good logP values (Ligand A: 3.399, Ligand B: 2.466), falling within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Both have 1 HBD, which is good. Ligand A has 3 HBA, while Ligand B has 5. Both are within the acceptable limit of <=10, but Ligand A is slightly preferred.

**QED:** Ligand A (0.82) has a much higher QED score than Ligand B (0.376), indicating a more drug-like profile.

**DILI:** Both ligands have similar DILI risk (Ligand A: 74.176, Ligand B: 75.301), and are in the acceptable range (< 40 is good, >60 is high risk).

**BBB:** Ligand A (78.984) has a significantly better BBB percentile than Ligand B (41.722). This is a critical factor for a CNS target like DRD2.

**Caco-2 Permeability:** Both have negative Caco-2 values (-4.803 and -4.759), which is unusual and suggests poor permeability. However, these values are on a scale where negative values are possible and don't necessarily preclude development.

**Aqueous Solubility:** Both have negative solubility values (-5.326 and -3.42), which is also unusual. Similar to Caco-2, this doesn't automatically disqualify them, but it's a potential issue for formulation.

**hERG:** Ligand A (0.956) has a slightly higher hERG risk than Ligand B (0.261), but both are relatively low.

**Microsomal Clearance:** Ligand A (29.759) has higher microsomal clearance than Ligand B (6.711), meaning it's metabolized faster. This is a disadvantage for Ligand A.

**In vitro Half-Life:** Ligand A (-15.392) has a negative half-life, which is not physically possible and indicates a problem with the data or the molecule's stability. Ligand B (-14.786) also has a negative half-life.

**P-gp Efflux:** Ligand A (0.609) has lower P-gp efflux than Ligand B (0.26), which is favorable for CNS penetration.

**Binding Affinity:** Ligand A (-7.7 kcal/mol) has a slightly better binding affinity than Ligand B (-7.3 kcal/mol). While both are excellent, the 0.4 kcal/mol difference is noticeable.

**Overall Assessment:**

Ligand A is significantly better overall, despite the issues with clearance and half-life. Its superior TPSA, BBB penetration, QED, and P-gp efflux, combined with slightly better affinity, outweigh the higher clearance. The negative half-life values for both are concerning and require further investigation, but the other properties strongly favor Ligand A. Ligand B's high TPSA and poor BBB penetration are major drawbacks for a CNS target.

Output:
1
2025-04-17 03:39:12,896 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (350.503 and 369.487 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (67.43) is significantly better than Ligand B (86.79). For CNS targets, we want TPSA <= 90, and A is comfortably within this range, while B is approaching the upper limit.

**logP:** Ligand A (2.927) is optimal (1-3), while Ligand B (-0.128) is quite low. A logP below 1 can hinder permeation. This is a significant advantage for A.

**H-Bond Donors/Acceptors:** Ligand A (2 HBD, 3 HBA) and Ligand B (1 HBD, 4 HBA) both have acceptable numbers.

**QED:** Both ligands have similar and good QED values (0.742 and 0.751).

**DILI:** Both ligands have similar and acceptable DILI risk (15.936 and 16.402).

**BBB:** Ligand A (76.735) has a much better BBB percentile than Ligand B (58.55). For a CNS target like DRD2, >70 is desirable, and A is closer to that threshold.

**Caco-2 Permeability:** Ligand A (-5.017) and Ligand B (-4.96) have similar, and poor, Caco-2 permeability.

**Aqueous Solubility:** Ligand A (-2.569) and Ligand B (-2.234) have similar, and poor, aqueous solubility.

**hERG:** Both ligands have very low hERG inhibition risk (0.493 and 0.076).

**Microsomal Clearance:** Ligand A (36.452) has higher microsomal clearance than Ligand B (10.004), suggesting lower metabolic stability. This favors B.

**In vitro Half-Life:** Ligand A (17.029) has a longer half-life than Ligand B (-5.058), which is favorable.

**P-gp Efflux:** Ligand A (0.112) has lower P-gp efflux than Ligand B (0.009), which is a significant advantage for CNS penetration.

**Binding Affinity:** Ligand A (-8.3 kcal/mol) has a slightly better binding affinity than Ligand B (-7.5 kcal/mol). While both are good, the 0.8 kcal/mol difference is meaningful.

**Overall Assessment:**

Ligand A is significantly better overall. Its superior logP, TPSA, and BBB penetration are crucial for a CNS-targeting GPCR ligand. The slightly better affinity and lower P-gp efflux further strengthen its case. While Ligand B has better metabolic stability (lower Cl_mic), the ADME advantages of A, particularly for CNS penetration, outweigh this drawback. The poor Caco-2 and solubility are concerning for both, but less critical for a CNS target where direct administration or specialized formulations can be considered.

Output:
1
2025-04-17 03:39:12,896 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (356.4 and 349.5 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (33.2) is excellent, well below the 90 A^2 threshold for CNS targets. Ligand B (52.65) is still reasonable but less optimal.

**logP:** Ligand A (4.583) is slightly high, potentially leading to solubility issues or off-target interactions. Ligand B (2.406) is within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A (0 HBD, 3 HBA) and Ligand B (1 HBD, 3 HBA) both have acceptable numbers of H-bond donors and acceptors.

**QED:** Both ligands have similar and good QED values (0.673 and 0.695, respectively), indicating good drug-like properties.

**DILI:** Ligand A (92.982) has a high DILI risk, which is a significant concern. Ligand B (6.049) has a very low DILI risk, a major advantage.

**BBB:** Ligand A (77.821) has a good BBB penetration percentile. Ligand B (81.776) is even better, exceeding 80%. Both are promising for a CNS target.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.239 and -4.991), which is unusual and suggests poor permeability. However, these values are on a log scale and can be difficult to interpret without knowing the base.

**Aqueous Solubility:** Both ligands have very poor aqueous solubility (-4.973 and -1.631). This is a concern, especially given Ligand A's higher logP.

**hERG Inhibition:** Ligand A (0.488) has a lower hERG risk than Ligand B (0.65).

**Microsomal Clearance:** Ligand A (55.902) has a higher microsomal clearance than Ligand B (26.273), indicating lower metabolic stability.

**In vitro Half-Life:** Ligand A (56.603) has a longer in vitro half-life than Ligand B (-7.827). However, the negative value for ligand B is concerning and likely indicates a very short half-life.

**P-gp Efflux:** Ligand A (0.779) has higher P-gp efflux liability than Ligand B (0.024). Lower P-gp efflux is preferred for CNS penetration.

**Binding Affinity:** Ligand A (-10.4 kcal/mol) has significantly stronger binding affinity than Ligand B (-7.5 kcal/mol). This is a substantial advantage.

**Overall Assessment:**

Ligand A has a much stronger binding affinity and acceptable BBB penetration, but suffers from a high DILI risk, poor solubility, higher P-gp efflux, and lower metabolic stability. Ligand B has a lower affinity but exhibits a significantly better safety profile (low DILI), better P-gp efflux, and better BBB penetration. The solubility is poor for both, but the DILI risk for Ligand A is a major red flag.

Given the GPCR-specific priorities and the importance of safety for CNS drugs, Ligand B is the more promising candidate despite its lower affinity. The affinity difference, while substantial, might be overcome with further optimization, while mitigating the high DILI risk of Ligand A would be much more challenging.

Output:
1
2025-04-17 03:39:12,896 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight (MW):** Both ligands (365.474 and 349.519 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (43.86) is significantly better than Ligand B (52.65). For CNS targets, we want TPSA <= 90, and ideally closer to 60. Ligand A is much closer to this ideal.

**3. logP:** Both ligands have good logP values (2.417 and 2.691), falling within the optimal 1-3 range.

**4. H-Bond Donors (HBD):** Both ligands are acceptable (0 and 1, respectively), well below the limit of 5.

**5. H-Bond Acceptors (HBA):** Both ligands are acceptable (4 and 3, respectively), well below the limit of 10.

**6. QED:** Both ligands have similar and good QED values (0.752 and 0.719), indicating good drug-like properties.

**7. DILI:** Ligand A (40.403) has a slightly higher DILI risk than Ligand B (11.671), but both are below the concerning threshold of 60. Ligand B is significantly better here.

**8. BBB:** Ligand A (92.012) has a *much* better BBB penetration percentile than Ligand B (77.084). This is a critical factor for a CNS target like DRD2.

**9. Caco-2 Permeability:** Both have negative values (-4.855 and -4.957), which is unusual and suggests very poor permeability. This is a significant drawback for both.

**10. Aqueous Solubility:** Both have negative values (-3.717 and -2.46), indicating poor solubility. This is also a significant drawback for both.

**11. hERG Inhibition:** Both ligands have low hERG inhibition risk (0.833 and 0.554).

**12. Microsomal Clearance:** Ligand A (38.414) has lower microsomal clearance than Ligand B (48.983), implying better metabolic stability.

**13. In vitro Half-Life:** Ligand A (5.596) has a longer half-life than Ligand B (0.559).

**14. P-gp Efflux:** Both ligands show low P-gp efflux liability (0.134 and 0.116).

**15. Binding Affinity:** Ligand B (-0.0 kcal/mol) has *significantly* weaker binding affinity than Ligand A (-9.5 kcal/mol). This is a massive difference. A difference of >1.5 kcal/mol often outweighs other issues.

**Overall Assessment:**

While both ligands have issues with Caco-2 permeability and aqueous solubility, the difference in binding affinity is the deciding factor. Ligand A has a substantially stronger binding affinity (-9.5 kcal/mol vs -0.0 kcal/mol), and a significantly better BBB penetration (92.012 vs 77.084). Although Ligand B has a lower DILI risk, the superior affinity and BBB score of Ligand A are more important for a CNS GPCR target. The better metabolic stability and half-life of Ligand A are also beneficial.

Output:
1
2025-04-17 03:39:12,896 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 drug candidates, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (351.447) is slightly lower, which could be beneficial for permeability, but both are acceptable.

**TPSA:** Ligand A (104.46) is better than Ligand B (62.3). For CNS targets, TPSA should be <= 90, both are within this range, but Ligand B is significantly better.

**logP:** Both ligands have good logP values (A: 1.659, B: 2.652), falling within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A has 3 HBD and 5 HBA, while Ligand B has 1 HBD and 5 HBA. Both are within acceptable limits (<=5 HBD and <=10 HBA).

**QED:** Both ligands have similar QED values (A: 0.628, B: 0.647), indicating good drug-likeness.

**DILI:** Ligand A (44.591) has a much lower DILI risk than Ligand B (66.576). This is a significant advantage for Ligand A.

**BBB:** Both ligands have similar BBB penetration (A: 56.999, B: 57.852). While not exceptional (>70 is desirable), they are reasonably good, suggesting some CNS exposure.

**Caco-2 Permeability:** Ligand A (-4.9) has a worse Caco-2 permeability than Ligand B (-5.429). Lower values indicate lower permeability.

**Aqueous Solubility:** Ligand A (-1.569) has better aqueous solubility than Ligand B (-2.171).

**hERG Inhibition:** Both ligands have low hERG inhibition risk (A: 0.177, B: 0.32).

**Microsomal Clearance:** Ligand A (35.308) has lower microsomal clearance than Ligand B (60.94), indicating better metabolic stability.

**In vitro Half-Life:** Ligand A (-29.538) has a significantly longer in vitro half-life than Ligand B (-0.053). This is a major advantage for Ligand A.

**P-gp Efflux:** Ligand A (0.164) has lower P-gp efflux than Ligand B (0.343), which is favorable for CNS penetration and oral bioavailability.

**Binding Affinity:** Ligand B (-8.6) has a slightly better binding affinity than Ligand A (-7.8). This is a 0.8 kcal/mol difference, which is significant, but not overwhelming.

**Overall Assessment:**

Ligand A demonstrates a superior ADME profile, with lower DILI risk, better metabolic stability (lower Cl_mic, longer t1/2), lower P-gp efflux, and better solubility. While Ligand B has a slightly better binding affinity, the ADME advantages of Ligand A, particularly its lower DILI and improved metabolic stability, are crucial for a CNS drug candidate. The difference in binding affinity (0.8 kcal/mol) is likely surmountable with further optimization, while poor ADME properties are much harder to fix later in development.

Output:
0
2025-04-17 03:39:12,897 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (342.443 and 349.475 Da) fall comfortably within the ideal 200-500 Da range.

**TPSA:** Ligand A (67.35) is significantly better than Ligand B (78.51). For CNS targets, we want TPSA <= 90, and ideally closer to 60. Ligand A is much closer to this ideal.

**logP:** Both ligands have good logP values (2.166 and 1.59), falling within the optimal 1-3 range. Ligand A is slightly higher, which could be beneficial for membrane permeability.

**H-Bond Donors/Acceptors:** Ligand A (HBD=1, HBA=4) is slightly better than Ligand B (HBD=2, HBA=3) in terms of maintaining a balance between solubility and permeability.

**QED:** Ligand A (0.894) has a much better QED score than Ligand B (0.685), indicating a more drug-like profile.

**DILI:** Ligand A (29.546) has a significantly lower DILI risk than Ligand B (15.083), which is a major advantage.

**BBB:** Ligand A (90.229) has a much higher BBB penetration percentile than Ligand B (69.407). This is *critical* for a CNS target like DRD2.

**Caco-2 Permeability:** Ligand A (-4.73) and Ligand B (-5.023) both have negative values, which is unusual. Lower values suggest poor permeability. However, the scale isn't specified, so it's difficult to interpret.

**Aqueous Solubility:** Both ligands have very poor aqueous solubility (-1.818 and -1.96). This is a concern for both, but might be mitigated by formulation strategies.

**hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.192 and 0.262), which is excellent.

**Microsomal Clearance:** Ligand B (17.404) has a slightly higher microsomal clearance than Ligand A (13.731), suggesting potentially lower metabolic stability.

**In vitro Half-Life:** Ligand A (25.693) has a longer in vitro half-life than Ligand B (-5.891). This is a significant advantage.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.051 and 0.019), which is good for CNS exposure.

**Binding Affinity:** Ligand A (-9.1 kcal/mol) has a significantly stronger binding affinity than Ligand B (-7.5 kcal/mol). This is a substantial difference (1.6 kcal/mol), and can often outweigh minor ADME drawbacks.

**Overall:**

Ligand A is clearly superior. It has better TPSA, QED, DILI, BBB, in vitro half-life, and *significantly* better binding affinity. While both have poor solubility, the other advantages of Ligand A, particularly its superior BBB penetration and binding affinity, make it the more promising drug candidate for a CNS target like DRD2.

Output:
1
2025-04-17 03:39:12,897 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (354.407 and 361.511 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (114.2) is slightly above the optimal <90 for CNS targets, but still reasonable. Ligand B (62.3) is excellent, well below the 90 threshold.

**3. logP:** Ligand A (-0.948) is a bit low, potentially hindering permeability. Ligand B (3.331) is within the optimal 1-3 range. This is a significant advantage for Ligand B.

**4. H-Bond Donors:** Ligand A (2) and Ligand B (1) are both acceptable, below the threshold of 5.

**5. H-Bond Acceptors:** Ligand A (5) and Ligand B (4) are both acceptable, below the threshold of 10.

**6. QED:** Both ligands (0.638 and 0.646) have good drug-likeness scores, exceeding the 0.5 threshold.

**7. DILI:** Ligand A (32.842) has a lower DILI risk than Ligand B (45.677), which is preferable.

**8. BBB:** Both ligands have good BBB penetration (Ligand A: 75.184, Ligand B: 70.027), exceeding the 70% threshold for CNS targets. Ligand A is slightly better here.

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 values, which is unusual and suggests poor permeability. This is a concern for both.

**10. Aqueous Solubility:** Both ligands have negative solubility values, which is also unusual and suggests poor solubility. This is a concern for both.

**11. hERG Inhibition:** Ligand A (0.093) has a very low hERG risk, which is excellent. Ligand B (0.488) is slightly higher, but still relatively low.

**12. Microsomal Clearance:** Ligand A (-18.087) has a negative clearance, which is not physically possible and suggests an issue with the data. Ligand B (72.336) has a high clearance, indicating rapid metabolism. This is a significant drawback for Ligand B.

**13. In vitro Half-Life:** Ligand A (6.005) has a short half-life. Ligand B (15.557) has a longer half-life, which is preferable.

**14. P-gp Efflux:** Ligand A (0.004) has very low P-gp efflux, which is excellent for CNS penetration. Ligand B (0.339) has slightly higher efflux, but still reasonable.

**15. Binding Affinity:** Ligand B (-7.8) has a significantly stronger binding affinity than Ligand A (-0). This is a major advantage for Ligand B, potentially outweighing some of its ADME drawbacks.

**Overall Assessment:**

Ligand B has a much better logP and significantly stronger binding affinity, both crucial for a GPCR target like DRD2. While its metabolic clearance is high, the strong binding could compensate. Ligand A has a better DILI score and P-gp efflux, but its low logP and significantly weaker binding affinity are major concerns. The negative values for Caco-2 and solubility are concerning for both, but the binding affinity is the most important factor here.

Output:
1
2025-04-17 03:39:12,897 - INFO - Reasoning:

Let's analyze Ligand A and Ligand B against the provided guidelines, prioritizing GPCR-specific properties (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (348.462 and 368.543 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (49.41) is significantly better than Ligand B (67.43). For CNS targets, TPSA should be <= 90, both are within this range, but A is much closer to the optimal value.

**logP:** Both ligands have good logP values (2.812 and 2.512), falling within the 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A (HBD=1, HBA=2) is preferable to Ligand B (HBD=2, HBA=4) as lower values generally improve permeability.

**QED:** Both ligands have acceptable QED scores (0.853 and 0.51), with A being significantly better.

**DILI:** Both ligands have low DILI risk (28.383 and 29.779 percentile), indicating minimal liver injury potential.

**BBB:** Ligand A (79.062) has a substantially better BBB penetration score than Ligand B (60.411). This is *critical* for a CNS target like DRD2.

**Caco-2 Permeability:** Ligand A (-4.743) has a better Caco-2 permeability value than Ligand B (-5.254). Higher values are better.

**Aqueous Solubility:** Ligand A (-4.232) has a better aqueous solubility than Ligand B (-2.453).

**hERG:** Both ligands have low hERG inhibition liability (0.59 and 0.325), which is good.

**Microsomal Clearance:** Ligand A (24.589) has a lower microsomal clearance than Ligand B (50.312), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (6.954) has a better in vitro half-life than Ligand B (-11.343).

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.205 and 0.19).

**Binding Affinity:** Ligand A (-8.6 kcal/mol) has a stronger binding affinity than Ligand B (-7.4 kcal/mol). The difference is 1.2 kcal/mol, which is significant.

**Overall Assessment:**

Ligand A consistently outperforms Ligand B across most key parameters, especially those crucial for CNS GPCR targets: BBB penetration, TPSA, metabolic stability, and binding affinity. The significantly stronger binding affinity of Ligand A (-8.6 vs -7.4 kcal/mol) further strengthens its position as the more promising candidate. While both have acceptable ADME properties, Ligand A's profile is more favorable for CNS drug development.

Output:
1
2025-04-17 03:39:12,897 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the acceptable range (200-500 Da). Ligand A (342.414 Da) is slightly preferred as it's closer to the ideal range.

**TPSA:** Ligand A (42.43) is excellent for CNS penetration, well below 90. Ligand B (69.72) is still reasonable but less optimal.

**logP:** Ligand A (3.828) is at the higher end of the optimal range (1-3), but still acceptable. Ligand B (2.324) is good, falling comfortably within the optimal range.

**H-Bond Donors/Acceptors:** Ligand A (0 HBD, 3 HBA) is favorable. Ligand B (1 HBD, 5 HBA) is also acceptable.

**QED:** Both ligands have similar QED values (A: 0.749, B: 0.687), indicating good drug-likeness.

**DILI:** Ligand A (43.738) has a slightly better DILI risk profile than Ligand B (53.044), both being reasonably low risk.

**BBB:** This is crucial for a CNS target like DRD2. Ligand A (85.033) has a significantly better BBB penetration prediction than Ligand B (66.188).

**Caco-2 Permeability:** Ligand A (-4.356) shows poor permeability, while Ligand B (-5.366) is even worse. This is a concern for both, but less critical for CNS targets if BBB is good.

**Aqueous Solubility:** Ligand A (-4.463) and Ligand B (-2.552) both have poor solubility.

**hERG Inhibition:** Both ligands show low hERG inhibition risk (A: 0.696, B: 0.635).

**Microsomal Clearance:** Ligand A (110.164) has higher metabolic clearance than Ligand B (-8.816), indicating lower metabolic stability. This is a significant drawback for Ligand A.

**In vitro Half-Life:** Ligand A (-1.813) has a shorter half-life than Ligand B (46.402), further reinforcing the metabolic stability concern.

**P-gp Efflux:** Ligand A (0.52) has slightly lower P-gp efflux liability than Ligand B (0.065), which is favorable for CNS penetration.

**Binding Affinity:** Ligand A (-9.6 kcal/mol) has a substantially stronger binding affinity than Ligand B (-7.8 kcal/mol). This is a major advantage, potentially outweighing some of the ADME drawbacks.

**Overall Assessment:**

Ligand A's superior binding affinity and better BBB penetration are strong positives. However, its higher metabolic clearance, shorter half-life, and poor Caco-2 permeability are concerning. Ligand B has better metabolic stability and permeability, but significantly weaker binding affinity and lower BBB penetration. Given the importance of affinity for GPCRs, and the CNS target, the stronger binding of Ligand A is likely to be more impactful, *provided* the metabolic issues can be addressed through medicinal chemistry optimization.

Output:
1
2025-04-17 03:39:12,898 - INFO - Batch 47 complete. Total preferences: 752
2025-04-17 03:39:12,898 - INFO - Processing batch 48/512...
2025-04-17 03:39:53,361 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (339.403 and 350.459 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (90.08) is better than Ligand B (95.5). Both are below the 90 A^2 threshold for CNS targets, but A is closer.

**3. logP:** Both ligands have similar logP values (1.39 and 1.308), falling within the optimal range of 1-3.

**4. H-Bond Donors:** Ligand A (1) is better than Ligand B (3). Lower HBD generally improves permeability.

**5. H-Bond Acceptors:** Ligand A (6) is better than Ligand B (4). Lower HBA generally improves permeability.

**6. QED:** Ligand A (0.889) is significantly better than Ligand B (0.645), indicating a more drug-like profile.

**7. DILI:** Ligand A (55.448) has a lower DILI risk than Ligand B (18.651), indicating a better safety profile.

**8. BBB:** Ligand A (65.413) has a better BBB penetration percentile than Ligand B (49.632). While both are not ideal (>70), A is closer, which is critical for a CNS target like DRD2.

**9. Caco-2 Permeability:** Both ligands have similar, very poor Caco-2 permeability (-5.101 and -5.105).

**10. Aqueous Solubility:** Both ligands have similar, very poor aqueous solubility (-2.451 and -2.236).

**11. hERG Inhibition:** Ligand A (0.73) has a slightly better hERG profile than Ligand B (0.103).

**12. Microsomal Clearance:** Ligand A (3.342) has a lower microsomal clearance than Ligand B (15.86), suggesting better metabolic stability.

**13. In vitro Half-Life:** Ligand A (15.159) has a slightly better in vitro half-life than Ligand B (17.527).

**14. P-gp Efflux:** Ligand A (0.017) has a much lower P-gp efflux liability than Ligand B (0.053), which is crucial for CNS penetration.

**15. Binding Affinity:** Both ligands have the same binding affinity (-8.1 kcal/mol), which is excellent.

**Overall Assessment:**

Ligand A consistently outperforms Ligand B across most ADME-Tox properties, particularly those prioritized for GPCRs targeting the CNS. Specifically, Ligand A has a better BBB score, lower P-gp efflux, lower DILI risk, better QED, and better metabolic stability. While both have poor Caco-2 and solubility, the superior CNS penetration properties of Ligand A make it the more promising candidate. The equal binding affinity removes that as a differentiating factor.

Output:
0
2025-04-17 03:39:53,361 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (358.473 and 372.401 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (41.57) is significantly better than Ligand B (85.17). For CNS targets, TPSA should be <= 90, and lower is preferred. Ligand A is well within this range, while Ligand B is approaching the upper limit and less desirable.

**logP:** Ligand A (4.049) is slightly higher than the optimal 1-3 range, but still acceptable. Ligand B (1.718) is on the lower side, potentially hindering permeability.

**H-Bond Donors/Acceptors:** Both have reasonable HBD (1) and HBA (3 for A, 7 for B) counts, staying within the guidelines.

**QED:** Both ligands have good QED scores (0.824 and 0.864), indicating drug-likeness.

**DILI:** Ligand A (6.592) has a much lower DILI risk than Ligand B (73.943). This is a significant advantage for Ligand A.

**BBB:** Ligand A (91.586) has excellent BBB penetration, exceeding the desirable >70% threshold. Ligand B (78.247) is lower, although still reasonably good, but not as favorable for a CNS target.

**Caco-2 Permeability:** Both have negative Caco-2 values (-4.425 and -4.879), which is unusual and suggests poor permeability. This is a concern for both, but the negative values make direct comparison difficult.

**Aqueous Solubility:** Both have negative solubility values (-3.222 and -2.616), indicating poor aqueous solubility. This could pose formulation challenges.

**hERG Inhibition:** Ligand A (0.848) has a slightly higher hERG risk than Ligand B (0.076), but both are relatively low.

**Microsomal Clearance:** Both have similar microsomal clearance values (27.805 and 27.436), suggesting comparable metabolic stability.

**In vitro Half-Life:** Ligand B (26.366) has a significantly longer half-life than Ligand A (5.529). This is a positive for Ligand B.

**P-gp Efflux:** Ligand A (0.114) has lower P-gp efflux liability than Ligand B (0.084), which is favorable for CNS exposure.

**Binding Affinity:** Both ligands have very similar and excellent binding affinities (-8.8 and -8.9 kcal/mol). The difference is negligible.

**Overall Assessment:**

Considering the GPCR-specific priorities, Ligand A is the better candidate. Its superior BBB penetration, lower DILI risk, and lower P-gp efflux, combined with a more favorable TPSA, outweigh the slightly higher logP and shorter half-life. While both have poor solubility and Caco-2 permeability, the CNS target makes BBB and P-gp more critical. The binding affinity is essentially the same.

Output:
1
2025-04-17 03:39:53,361 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (353.413 and 345.487 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (62.3) is slightly above the optimal <90 for CNS targets, but still reasonable. Ligand B (54.34) is excellent, well below 90.

**3. logP:** Both ligands have good logP values (2.763 and 3.144), falling within the 1-3 optimal range.

**4. H-Bond Donors:** Both ligands have 1 HBD, which is acceptable.

**5. H-Bond Acceptors:** Both ligands have 3 HBA, which is acceptable.

**6. QED:** Both ligands have high QED scores (0.855 and 0.891), indicating good drug-like properties.

**7. DILI:** Ligand A (39.899) has a slightly higher DILI risk than Ligand B (20.434), but both are below the concerning threshold of 60.

**8. BBB:** This is a critical parameter for a CNS target like DRD2. Ligand A has a BBB percentile of 90.617, which is excellent. Ligand B has 78.054, still good but lower than A.

**9. Caco-2 Permeability:** Ligand A (-3.915) has worse Caco-2 permeability than Ligand B (-4.67), indicating potentially lower intestinal absorption.

**10. Aqueous Solubility:** Ligand A (-3.377) has worse aqueous solubility than Ligand B (-2.628).

**11. hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.405 and 0.382).

**12. Microsomal Clearance:** Ligand A (67.094) has higher microsomal clearance than Ligand B (40.455), suggesting lower metabolic stability.

**13. In vitro Half-Life:** Ligand B (9.216 hours) has a significantly longer in vitro half-life than Ligand A (26.676 hours).

**14. P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.057 and 0.148).

**15. Binding Affinity:** Both ligands have very similar and excellent binding affinities (-9.3 and -9.1 kcal/mol). The difference of 0.2 kcal/mol is unlikely to be decisive given the other factors.

**Overall Assessment:**

Ligand A has a superior BBB penetration, which is crucial for a CNS target. However, Ligand B demonstrates better ADME properties across the board (lower DILI, better Caco-2 permeability, better solubility, lower clearance, longer half-life). The slight advantage in BBB for Ligand A is outweighed by the more favorable overall ADME profile of Ligand B.

Output:
1
2025-04-17 03:39:53,361 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (353.482 and 346.406 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (43.86) is significantly better than Ligand B (78.09). For CNS targets, we want TPSA <= 90, and ideally closer to 60. Ligand A is much closer to this ideal. Ligand B is pushing the upper limit and could have permeability issues.

**3. logP:** Both ligands have good logP values (2.057 and 1.984), falling within the optimal 1-3 range.

**4. H-Bond Donors:** Ligand A (0) is preferable to Ligand B (2). Fewer HBDs generally improve permeability.

**5. H-Bond Acceptors:** Both ligands have 3 HBA, which is within the acceptable limit of <=10.

**6. QED:** Both ligands have similar QED values (0.777 and 0.718), indicating good drug-likeness.

**7. DILI:** Ligand A (5.894) has a much lower DILI risk than Ligand B (55.874). This is a significant advantage for Ligand A.

**8. BBB:** Ligand A (96.355) has excellent BBB penetration, far exceeding the desirable >70% threshold for CNS targets. Ligand B (67.352) is lower, and while not terrible, is significantly worse than Ligand A.

**9. Caco-2:** Ligand A (-4.573) is better than Ligand B (-5.144), indicating better intestinal absorption.

**10. Solubility:** Ligand A (-1.337) is better than Ligand B (-2.651).

**11. hERG:** Both ligands have low hERG inhibition risk (0.588 and 0.478).

**12. Cl_mic:** Ligand A (4.756) has lower microsomal clearance than Ligand B (33.657), suggesting better metabolic stability.

**13. t1/2:** Ligand A (7.15) has a shorter half-life than Ligand B (58.409). However, the difference in binding affinity is more important.

**14. Pgp:** Ligand A (0.038) has much lower P-gp efflux liability than Ligand B (0.083), which is crucial for CNS exposure.

**15. Binding Affinity:** Ligand A (-7.9 kcal/mol) has a slightly better binding affinity than Ligand B (-7.7 kcal/mol). While the difference is small, it's enough to tip the scales considering the superior ADME properties of Ligand A.

**Overall:** Ligand A is clearly superior. It has significantly better BBB penetration, lower DILI risk, lower P-gp efflux, and better metabolic stability, all while maintaining comparable binding affinity and drug-likeness. The lower TPSA is also a significant benefit for CNS penetration.

Output:
1
2025-04-17 03:39:53,361 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (346.431 and 349.41 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (87.47) is better than Ligand B (91.81). Both are below the 90 A^2 threshold desirable for CNS targets, but A is closer to the ideal.

**3. logP:** Both ligands have acceptable logP values (1.163 and 1.609), falling within the optimal 1-3 range.

**4. H-Bond Donors:** Ligand A (2) is preferable to Ligand B (3). Lower HBD generally improves permeability.

**5. H-Bond Acceptors:** Ligand A (5) is preferable to Ligand B (4). Lower HBA generally improves permeability.

**6. QED:** Both ligands have reasonable QED values (0.724 and 0.676), indicating good drug-like properties.

**7. DILI:** Ligand A (35.789) has a significantly lower DILI risk than Ligand B (58.434). This is a substantial advantage.

**8. BBB:** Ligand A (36.72) has a lower BBB penetration percentile than Ligand B (47.926). While neither are *high* (above 70), B is better. This is a critical factor for a CNS target.

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.099 and -5.406). This is unusual and suggests poor permeability. However, these values are on a scale where negative values can occur, and direct comparison is difficult without knowing the scale's specifics.

**10. Aqueous Solubility:** Both ligands have negative solubility values (-1.801 and -2.829) which is also unusual and suggests poor solubility.

**11. hERG Inhibition:** Both ligands show low hERG inhibition liability (0.153 and 0.42). This is good.

**12. Microsomal Clearance:** Ligand A (-11.331) has a much lower (better) microsomal clearance than Ligand B (13.278), indicating greater metabolic stability.

**13. In vitro Half-Life:** Ligand A (-21.426) has a much longer in vitro half-life than Ligand B (6.434). This is a significant advantage.

**14. P-gp Efflux:** Both ligands have low P-gp efflux liability (0.035 and 0.05). This is good.

**15. Binding Affinity:** Ligand B (-7.9) has a slightly better binding affinity than Ligand A (-7.2). The difference is 0.7 kcal/mol, which is a reasonable advantage.

**Overall Assessment:**

While Ligand B has slightly better binding affinity and BBB penetration, Ligand A is superior overall. The significantly lower DILI risk, improved metabolic stability (lower Cl_mic and longer t1/2), and lower HBD/HBA counts of Ligand A outweigh the small advantage in binding affinity and BBB. The poor Caco-2 and solubility values are concerning for both, but the other ADME properties of A are much more favorable. For a CNS target, metabolic stability and minimizing toxicity (DILI) are crucial.

Output:
0
2025-04-17 03:39:53,361 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B based on the provided guidelines, prioritizing GPCR-specific properties (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (355.781 and 353.463 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (96.03) is excellent for CNS penetration, being well below the 90 A^2 threshold. Ligand B (107.53) is still reasonable but less optimal.

**logP:** Ligand A (3.468) is within the optimal 1-3 range. Ligand B (0.75) is quite low, potentially hindering membrane permeability and CNS entry.

**H-Bond Donors/Acceptors:** Ligand A (HBD=1, HBA=4) and Ligand B (HBD=4, HBA=4) both have acceptable numbers of H-bond donors and acceptors.

**QED:** Both ligands have reasonable QED scores (0.656 and 0.516), indicating good drug-like properties.

**DILI:** Ligand A (74.021) has a higher DILI risk than Ligand B (15.898). This is a significant drawback for Ligand A.

**BBB:** Ligand A (73.478) has a good BBB percentile, desirable for a CNS target. Ligand B (46.568) has a lower BBB percentile, which is concerning.

**Caco-2 Permeability:** Ligand A (-4.517) has poor Caco-2 permeability. Ligand B (-5.325) is also poor, but slightly worse.

**Aqueous Solubility:** Ligand A (-5.722) has poor aqueous solubility. Ligand B (-1.396) is also poor, but better than Ligand A.

**hERG Inhibition:** Ligand A (0.498) has a low hERG risk, which is good. Ligand B (0.047) has a very low hERG risk, even better.

**Microsomal Clearance:** Ligand A (48.285) has moderate clearance, while Ligand B (16.955) has lower clearance, suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (-4.707) has a short half-life. Ligand B (-2.495) has a slightly longer half-life.

**P-gp Efflux:** Ligand A (0.142) has low P-gp efflux, which is favorable for CNS penetration. Ligand B (0.006) has very low P-gp efflux, even more favorable.

**Binding Affinity:** Ligand A (-9.5 kcal/mol) has significantly stronger binding affinity than Ligand B (-7.4 kcal/mol). This is a substantial advantage.

**Overall Assessment:**

Ligand A has a much stronger binding affinity and good BBB penetration, but suffers from poor solubility, permeability, and a higher DILI risk. Ligand B has better safety profiles (DILI, hERG) and metabolic stability, but its low logP and lower BBB penetration are concerning for a CNS target. The affinity difference is substantial (>2 kcal/mol), which can often outweigh ADME drawbacks, *especially* for a GPCR where achieving sufficient target engagement is critical. However, the poor solubility and permeability of Ligand A are significant hurdles.

Considering the GPCR-specific priorities, the strong affinity of Ligand A is a major advantage. While its ADME properties are not ideal, optimization efforts could potentially address these issues. The lower affinity of Ligand B, combined with its poor logP and BBB, makes it less likely to be a viable candidate despite its better safety profile.

Output:
1
2025-04-17 03:39:53,362 - INFO - Reasoning:

Let's analyze Ligand A and Ligand B against the provided guidelines, prioritizing GPCR-specific properties (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (350.463 and 349.431 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (96.11) is slightly higher than Ligand B (84.67). Both are below the 140 threshold for oral absorption and reasonably close to the 90 target for CNS penetration, but B is better.

**logP:** Ligand A (1.578) and Ligand B (2.229) are both within the optimal 1-3 range.

**H-Bond Donors & Acceptors:** Ligand A has 3 HBD and 4 HBA, while Ligand B has 1 HBD and 5 HBA. Both are within acceptable limits (<=5 HBD, <=10 HBA).

**QED:** Both ligands have good QED scores (0.663 and 0.816, respectively), indicating drug-like properties. Ligand B is slightly better.

**DILI:** Both ligands have acceptable DILI risk (38.581 and 44.126, both <40).

**BBB:** This is a critical parameter for a CNS target like DRD2. Ligand A has a BBB percentile of 65.374, while Ligand B has 52.268. Ligand A is significantly better here, exceeding the desirable >70% threshold.

**Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and suggests poor permeability. This is a concern for both.

**Aqueous Solubility:** Both ligands have very poor aqueous solubility (-3.209 and -1.408). This is a significant drawback.

**hERG Inhibition:** Both ligands exhibit low hERG inhibition risk (0.288 and 0.24).

**Microsomal Clearance:** Ligand B (60.574) has higher microsomal clearance than Ligand A (43.973), suggesting lower metabolic stability.

**In vitro Half-Life:** Ligand A (-1.304) has a negative half-life, which is not physically possible and indicates a data error. Ligand B (7.877) has a reasonable half-life.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.053 and 0.1).

**Binding Affinity:** Both ligands have excellent binding affinity (-8.3 and -8.1 kcal/mol). The difference is minor (0.2 kcal/mol), and unlikely to outweigh other factors.

**Overall Assessment:**

Ligand A is superior in BBB penetration, which is paramount for a CNS target. It also has better metabolic stability (lower Cl_mic). However, its reported negative in vitro half-life is a major red flag and likely an error. Ligand B has a more reasonable half-life, but significantly worse BBB penetration. The solubility for both is very poor. Given the importance of BBB for CNS drugs, and assuming the negative half-life for A is an error, I would lean towards Ligand A.

Output:
1
2025-04-17 03:39:53,362 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (350.503 and 380.432 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (61.8) is significantly better than Ligand B (78.43). For CNS targets, we want TPSA <= 90, and A is comfortably within that range, while B is approaching the upper limit.

**logP:** Ligand A (3.204) is optimal, while Ligand B (1.762) is a bit low, potentially hindering membrane permeability.

**H-Bond Donors/Acceptors:** Ligand A (HBD=2, HBA=3) and Ligand B (HBD=3, HBA=4) are both acceptable, within the guidelines of <=5 HBD and <=10 HBA.

**QED:** Ligand A (0.719) has a better QED score than Ligand B (0.614), indicating a more drug-like profile.

**DILI:** Ligand A (12.059) has a much lower DILI risk than Ligand B (29.081), which is a significant advantage.

**BBB:** Ligand A (72.237) has a substantially better BBB penetration score than Ligand B (60.644).  This is *critical* for a CNS target like DRD2.

**Caco-2 Permeability:** Ligand A (-4.271) and Ligand B (-5.239) both have negative values, indicating poor permeability. However, the scale isn't specified, so it's hard to interpret the absolute difference.

**Aqueous Solubility:** Both ligands have very poor aqueous solubility (-2.663 and -2.924). This is a concern for both, but can be addressed with formulation strategies.

**hERG Inhibition:** Ligand A (0.847) has a lower hERG risk than Ligand B (0.158).

**Microsomal Clearance:** Ligand A (79.299) has a higher microsomal clearance than Ligand B (6.972), meaning it's likely to be metabolized more quickly. This is a disadvantage for A.

**In vitro Half-Life:** Ligand B (-14.67) has a negative half-life, which is not possible. This is likely an error in the data. Ligand A (14.482) has a reasonable half-life.

**P-gp Efflux:** Ligand A (0.167) has lower P-gp efflux than Ligand B (0.11), which is favorable for CNS exposure.

**Binding Affinity:** Ligand B (-8.7 kcal/mol) has a slightly better binding affinity than Ligand A (-7.6 kcal/mol). However, the difference is 1.1 kcal/mol, which is not a huge advantage given the other ADME properties.

**Overall Assessment:**

Ligand A is significantly better overall. Its superior BBB penetration, lower DILI risk, better QED, and lower P-gp efflux outweigh the slightly weaker binding affinity and higher clearance. The poor solubility is a concern for both, but formulation strategies can be employed. Ligand B's problematic half-life data also raises concerns about its reliability. Given the GPCR-specific priorities, particularly BBB for a CNS target, Ligand A is the more promising candidate.

Output:
1
2025-04-17 03:39:53,363 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (346.471 and 342.359 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (67.43) is significantly better than Ligand B (121.89). For CNS targets, we want TPSA <= 90, and A is comfortably within this range, while B exceeds it.

**3. logP:** Ligand A (2.009) is optimal (1-3), while Ligand B (0.81) is a bit low, potentially hindering permeation.

**4. H-Bond Donors:** Ligand A (2) and Ligand B (3) are both acceptable (<=5).

**5. H-Bond Acceptors:** Ligand A (3) and Ligand B (6) are both acceptable (<=10).

**6. QED:** Ligand A (0.693) is better than Ligand B (0.458), indicating a more drug-like profile.

**7. DILI:** Ligand A (20.279) has a much lower DILI risk than Ligand B (79.333). This is a significant advantage for A.

**8. BBB:** Ligand A (50.523) has a better BBB percentile than Ligand B (39.55), although both are below the desirable >70 for CNS targets. However, A is closer.

**9. Caco-2:** Ligand A (-4.507) and Ligand B (-6.108) both have negative values, which is unusual and suggests poor permeability. However, the scale isn't specified, so it's hard to interpret.

**10. Solubility:** Ligand A (-3.173) and Ligand B (-2.157) both have negative values, suggesting poor solubility.

**11. hERG:** Ligand A (0.238) has a lower hERG risk than Ligand B (0.072), which is preferable.

**12. Cl_mic:** Ligand A (33.92) has a higher (worse) microsomal clearance than Ligand B (-7.819). This suggests Ligand B is more metabolically stable.

**13. t1/2:** Ligand A (-5.579) has a shorter in vitro half-life than Ligand B (18.911). This is a disadvantage for A.

**14. Pgp:** Ligand A (0.032) has lower P-gp efflux liability than Ligand B (0.021), which is favorable for CNS penetration.

**15. Binding Affinity:** Ligand B (-8.0) has a slightly better binding affinity than Ligand A (-7.6), but the difference is less than 1.5 kcal/mol, so it's not a decisive factor.

**Overall Assessment:**

Considering the GPCR-specific priorities, Ligand A is the more promising candidate. Its significantly lower TPSA, DILI risk, and better BBB penetration outweigh the slightly worse metabolic stability and shorter half-life. The slightly weaker affinity is not a major concern given the other advantages. Ligand B's higher TPSA and DILI risk are significant drawbacks.

Output:
1
2025-04-17 03:39:53,363 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (350.369 and 367.833 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (86.88) is better than Ligand B (95.67). Both are below the 90 A^2 threshold desirable for CNS targets, but A is closer to the optimal range.

**3. logP:** Both ligands have good logP values (2.067 and 1.744), falling within the optimal 1-3 range.

**4. H-Bond Donors:** Ligand A (3) is slightly higher than Ligand B (2), but both are within the acceptable limit of <=5.

**5. H-Bond Acceptors:** Ligand B (5) is higher than Ligand A (3), but both are within the acceptable limit of <=10.

**6. QED:** Both ligands have good QED scores (0.745 and 0.845), indicating good drug-like properties.

**7. DILI:** Ligand B (49.67) has a significantly lower DILI risk than Ligand A (70.803). This is a substantial advantage for Ligand B.

**8. BBB:** Ligand B (62.97) has a better BBB penetration score than Ligand A (59.093), although both are below the desirable >70 for CNS targets.

**9. Caco-2 Permeability:** Ligand A (-5.123) has slightly better Caco-2 permeability than Ligand B (-4.904).

**10. Aqueous Solubility:** Both ligands have similar and poor aqueous solubility (-3.193 and -3.1).

**11. hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.432 and 0.143).

**12. Microsomal Clearance:** Ligand B (-5.128) has a significantly *lower* (better) microsomal clearance than Ligand A (32.016), indicating better metabolic stability.

**13. In vitro Half-Life:** Ligand B (14.745) has a longer in vitro half-life than Ligand A (-11.497).

**14. P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.091).

**15. Binding Affinity:** Ligand B (-9.0) has a significantly stronger binding affinity than Ligand A (-8.8). This difference of 0.2 kcal/mol is meaningful.

**Overall Assessment:**

Ligand B is the stronger candidate. While Ligand A has slightly better Caco-2 permeability, Ligand B excels in several critical areas: significantly lower DILI risk, better metabolic stability (lower Cl_mic, longer t1/2), better BBB penetration, and most importantly, a stronger binding affinity. The affinity difference is enough to outweigh the slight disadvantage in Caco-2. Given the GPCR target and the need for CNS penetration, the combination of better BBB, lower toxicity, and higher affinity makes Ligand B the more promising drug candidate.

Output:
1
2025-04-17 03:39:53,363 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 drug candidates, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (352.375 and 347.459 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (107.97) is higher than the preferred <90 for CNS targets, while Ligand B (78.51) is well within the range. This is a significant advantage for Ligand B.

**logP:** Ligand A (3.432) is at the upper end of the optimal 1-3 range, while Ligand B (1.365) is slightly below. While both are acceptable, Ligand A's higher logP could potentially lead to off-target interactions.

**H-Bond Donors/Acceptors:** Ligand A has 3 HBD and 5 HBA, while Ligand B has 2 HBD and 3 HBA. Both are within acceptable limits.

**QED:** Ligand B (0.737) has a better QED score than Ligand A (0.523), indicating a more drug-like profile.

**DILI:** Ligand A has a very high DILI risk (99.147%), which is a major red flag. Ligand B has a much lower, and acceptable, DILI risk (21.946%).

**BBB:** Ligand A (11.322%) has extremely poor predicted BBB penetration, making it unlikely to be effective for a CNS target like DRD2. Ligand B (58.007%) has moderate BBB penetration, which is better, though still not ideal (>70%).

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.66 and -5.156), which is unusual and suggests poor permeability. However, these values are on a log scale and can be misleading.

**Aqueous Solubility:** Both ligands have negative solubility values (-4.454 and -2.218), indicating poor aqueous solubility. This could pose formulation challenges.

**hERG Inhibition:** Both ligands show very low hERG inhibition risk (0.182 and 0.074).

**Microsomal Clearance:** Ligand A (-9.994) has a negative clearance, which is not physically possible and suggests an issue with the prediction method. Ligand B (21.95) has a relatively high clearance, indicating faster metabolism.

**In vitro Half-Life:** Ligand B (20.154 hours) has a longer half-life than Ligand A (10.977 hours), which is favorable.

**P-gp Efflux:** Both ligands show very low P-gp efflux liability (0.037 and 0.029).

**Binding Affinity:** Ligand A (-9.6 kcal/mol) has a slightly better binding affinity than Ligand B (-8.2 kcal/mol). However, the 1.4 kcal/mol difference might not be enough to overcome the significant ADME liabilities of Ligand A.

**Overall Assessment:**

Ligand A suffers from extremely poor predicted BBB penetration, a very high DILI risk, and an implausible negative microsomal clearance. While its binding affinity is slightly better, these drawbacks are too significant to ignore.

Ligand B, while not perfect, has a much more favorable profile. It has a lower DILI risk, better TPSA, a better QED score, and a longer half-life. Its BBB penetration is moderate and could potentially be improved with further optimization. The higher clearance and lower logP are concerns, but less critical than the severe issues with Ligand A.

Output:
1
2025-04-17 03:39:53,363 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (367.249 and 344.411 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (68.02) is slightly higher than Ligand B (66.92), but both are comfortably below the 90 A^2 threshold for CNS targets.

**3. logP:** Ligand A (3.528) is optimal, while Ligand B (1.589) is on the lower side. While still acceptable, lower logP can sometimes hinder permeability.

**4. H-Bond Donors:** Ligand A (1) is preferable to Ligand B (0) as it provides some hydrogen bonding potential.

**5. H-Bond Acceptors:** Both ligands have 4 HBA, which is within the acceptable range.

**6. QED:** Both ligands have good QED scores (0.627 and 0.778, respectively), indicating drug-like properties.

**7. DILI:** Ligand B (34.393) has a significantly lower DILI risk than Ligand A (70.88), which is a major advantage.

**8. BBB:** Both ligands have excellent BBB penetration (Ligand A: 90.074, Ligand B: 86.002), exceeding the desirable >70% threshold for CNS targets.

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 values, which is unusual and suggests poor permeability. However, the scale is not specified, so it is hard to interpret.

**10. Aqueous Solubility:** Both ligands have negative solubility values, which is also unusual and suggests poor solubility. Again, the scale is not specified.

**11. hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.565 and 0.368), which is excellent.

**12. Microsomal Clearance:** Ligand B (30.946) has slightly lower microsomal clearance than Ligand A (35.71), suggesting better metabolic stability.

**13. In vitro Half-Life:** Ligand B (-10.692) has a negative half-life, which is not possible. Ligand A (23.6) is a reasonable value.

**14. P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.387 and 0.12), which is highly desirable for CNS penetration.

**15. Binding Affinity:** Both ligands have the same binding affinity (-9.8 kcal/mol), which is excellent.

**Overall Assessment:**

While Ligand A has a slightly better logP and in vitro half-life, Ligand B is significantly better in terms of DILI risk and has slightly better metabolic stability. The negative values for Caco-2 and solubility are concerning for both, but the binding affinity is the most important factor here, and it is identical for both. Given the importance of minimizing toxicity (DILI) for CNS drugs, and the comparable binding affinity, Ligand B is the more promising candidate.

Output:
1
2025-04-17 03:39:53,363 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (358.435 and 354.466 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (108.33) is higher than Ligand B (67.43). For CNS targets, TPSA should be <=90, so Ligand B is significantly better here.

**logP:** Ligand A (-0.72) is below the optimal 1-3 range, potentially hindering permeation. Ligand B (2.508) is within the optimal range. This favors Ligand B.

**H-Bond Donors/Acceptors:** Ligand A has 3 HBD and 6 HBA, while Ligand B has 2 HBD and 3 HBA. Both are within acceptable limits (<=5 HBD and <=10 HBA).

**QED:** Both ligands have good QED scores (0.528 and 0.593), indicating drug-like properties.

**DILI:** Ligand A (14.889) has a lower DILI risk than Ligand B (22.8), which is preferable.

**BBB:** Ligand A (40.597) has a poor BBB penetration percentile, while Ligand B (87.941) is excellent, exceeding the >70 desirable threshold for CNS targets. This is a major advantage for Ligand B.

**Caco-2 Permeability:** Ligand A (-5.001) has very poor Caco-2 permeability, while Ligand B (-4.597) is slightly better, but still not great.

**Aqueous Solubility:** Ligand A (-0.637) has poor aqueous solubility, and Ligand B (-3.18) is even worse. This could pose formulation challenges for both.

**hERG Inhibition:** Ligand A (0.126) has a lower hERG risk than Ligand B (0.533), which is preferable.

**Microsomal Clearance:** Ligand A (4.32) has significantly lower microsomal clearance than Ligand B (55.247), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (27.741) has a longer half-life than Ligand B (-4.367), which is desirable.

**P-gp Efflux:** Ligand A (0.005) has very low P-gp efflux, while Ligand B (0.243) has moderate efflux. Lower efflux is better for CNS exposure, favoring Ligand A.

**Binding Affinity:** Ligand B (-7.8 kcal/mol) has a significantly stronger binding affinity than Ligand A (-6.8 kcal/mol). This 1 kcal/mol difference is substantial and can outweigh some ADME drawbacks.

**Overall Assessment:**

Ligand B excels in BBB penetration and binding affinity, which are critical for a CNS GPCR target like DRD2. While its solubility and Caco-2 permeability are not ideal, the strong affinity and excellent BBB penetration are likely to compensate. Ligand A has better metabolic stability and lower P-gp efflux, but its poor BBB penetration and lower affinity are significant drawbacks. The logP of Ligand A is also concerning.

Output:
1
2025-04-17 03:39:53,363 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (350.419 and 338.411 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (87.76) is better than Ligand B (94.88). Both are below the 90 A^2 threshold desirable for CNS targets, but A is closer to the ideal.

**3. logP:** Ligand B (1.995) is slightly better than Ligand A (0.713). Both are within the optimal 1-3 range, but A is a bit low, potentially hindering permeation.

**4. H-Bond Donors:** Ligand A (1) is better than Ligand B (2). Lower HBD generally improves permeability.

**5. H-Bond Acceptors:** Ligand A (5) is better than Ligand B (4). Both are within the acceptable limit of 10.

**6. QED:** Both ligands have similar, good QED values (0.808 and 0.821 respectively).

**7. DILI:** Ligand A (43.971) is significantly better than Ligand B (59.519), indicating a lower risk of drug-induced liver injury.

**8. BBB:** Ligand A (68.554) is much better than Ligand B (35.324). This is a *critical* factor for a CNS target like DRD2. A value >70 is desirable, and A is closer to that.

**9. Caco-2 Permeability:** Ligand A (-4.633) is better than Ligand B (-4.874). Higher values indicate better absorption.

**10. Aqueous Solubility:** Ligand A (-2.107) is better than Ligand B (-3.658). Higher solubility is generally preferred.

**11. hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.238 and 0.295).

**12. Microsomal Clearance:** Ligand A (13.895) is better than Ligand B (19.099), suggesting greater metabolic stability.

**13. In vitro Half-Life:** Ligand A (-12.188) is better than Ligand B (-13.631). Longer half-life is generally preferred.

**14. P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.019 and 0.041).

**15. Binding Affinity:** Both ligands have the same binding affinity (-8.0 kcal/mol), which is excellent.

**Overall Assessment:**

While both ligands have good binding affinity, Ligand A is significantly superior in several key ADME properties crucial for a CNS-targeting GPCR. Specifically, its much better BBB penetration, lower DILI risk, and improved metabolic stability make it the more promising candidate. The slightly lower logP of Ligand A is a minor concern, but is outweighed by the substantial advantages in BBB and safety.

Output:
1
2025-04-17 03:39:53,363 - INFO - Reasoning:

Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (404.308 Da and 382.247 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (56.15) is significantly better than Ligand B (84.22). For CNS targets, we want TPSA <= 90, and A is comfortably within that range while B is approaching the upper limit.

**3. logP:** Both ligands have good logP values (3.725 and 3.035), falling within the optimal 1-3 range.

**4. H-Bond Donors:** Ligand A (1) is better than Ligand B (2). Lower is generally preferred.

**5. H-Bond Acceptors:** Both ligands have the same number of H-bond acceptors (4), which is acceptable (<=10).

**6. QED:** Both ligands have reasonable QED values (0.827 and 0.721), indicating good drug-like properties.

**7. DILI:** Ligand A (53.548) is significantly better than Ligand B (87.786). Lower DILI risk is crucial. Ligand B is quite high, suggesting potential liver toxicity.

**8. BBB:** Ligand A (65.529) is much better than Ligand B (36.022). For a CNS target like DRD2, a high BBB penetration is *critical*. Ligand A is reasonably good, while Ligand B is poor.

**9. Caco-2 Permeability:** Ligand A (-4.965) is better than Ligand B (-5.542), although both are negative, indicating poor permeability.

**10. Aqueous Solubility:** Ligand A (-4.294) is better than Ligand B (-3.058), though both are negative, suggesting poor solubility.

**11. hERG Inhibition:** Ligand A (0.329) is much better than Ligand B (0.029). Lower hERG inhibition is preferred to avoid cardiotoxicity.

**12. Microsomal Clearance:** Ligand A (81.022) is higher than Ligand B (17.902), meaning faster clearance and lower metabolic stability. This is a disadvantage for Ligand A.

**13. In vitro Half-Life:** Ligand A (42.928) is better than Ligand B (-4.287). Longer half-life is generally desirable.

**14. P-gp Efflux:** Ligand A (0.677) is better than Ligand B (0.052). Lower P-gp efflux is preferred, especially for CNS targets.

**15. Binding Affinity:** Ligand B (-8.7) has a slightly better binding affinity than Ligand A (-8.2). However, the difference is only 0.5 kcal/mol, which is less crucial given the significant ADME advantages of Ligand A.

**Overall Assessment:**

Ligand A clearly outperforms Ligand B in almost all critical ADME properties, particularly BBB penetration, DILI risk, and hERG inhibition. While Ligand B has slightly better binding affinity, the substantial improvements in safety and CNS penetration offered by Ligand A outweigh this minor difference. The lower metabolic stability of Ligand A (higher Cl_mic) is a concern, but can be addressed through structural modifications in subsequent optimization stages.

Output:
1
2025-04-17 03:39:53,364 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (341.455 and 338.419 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (53.51) is significantly better than Ligand B (93.44). For CNS targets, TPSA should be <= 90, and A is comfortably within this range, while B is close to the upper limit. This favors A.

**logP:** Both ligands have acceptable logP values (2.667 and 1.802), falling within the optimal 1-3 range. B is slightly lower, which *could* indicate slightly poorer membrane permeability, but it's not a major concern.

**H-Bond Donors/Acceptors:** Ligand A (0 HBD, 3 HBA) is preferable to Ligand B (2 HBD, 8 HBA). Lower HBA generally improves CNS penetration.

**QED:** Both ligands have similar QED values (0.831 and 0.803), indicating good drug-like properties.

**DILI:** Ligand A (47.421) has a lower DILI risk than Ligand B (59.636), which is desirable.

**BBB:** Both ligands have excellent BBB penetration (73.711 and 74.486), exceeding the 70% threshold for CNS targets. This is a strong positive for both.

**Caco-2 Permeability:** Ligand A (-4.626) has a *much* better Caco-2 permeability than Ligand B (-5.605). Higher values indicate better absorption, and A is significantly better.

**Aqueous Solubility:** Both ligands have very poor aqueous solubility (-2.009 and -2.708). This is a concern for both, but could be mitigated with formulation strategies.

**hERG Inhibition:** Ligand A (0.425) has a lower hERG inhibition risk than Ligand B (0.125). Lower is better.

**Microsomal Clearance:** Ligand A (55.036) has higher microsomal clearance than Ligand B (47.449), suggesting faster metabolism and potentially lower in vivo exposure. This favors B.

**In vitro Half-Life:** Ligand B (4.18) has a slightly longer half-life than Ligand A (-7.759). Longer half-life is generally preferred.

**P-gp Efflux:** Ligand A (0.289) has lower P-gp efflux than Ligand B (0.096). Lower P-gp efflux is crucial for CNS exposure, favoring A.

**Binding Affinity:** Ligand B (-9.6 kcal/mol) has a significantly stronger binding affinity than Ligand A (-7.759 kcal/mol). This is a substantial advantage, potentially outweighing some of the ADME drawbacks of Ligand B. A difference of >1.5 kcal/mol is considered significant.

**Overall Assessment:**

Ligand B has a substantially better binding affinity. However, Ligand A has better TPSA, Caco-2 permeability, DILI risk, and P-gp efflux. The TPSA and P-gp are particularly important for CNS penetration. While B has a slightly better half-life and lower clearance, the significant affinity advantage of B, combined with acceptable BBB, outweighs the ADME concerns.

Output:
1
2025-04-17 03:39:53,364 - INFO - Batch 48 complete. Total preferences: 768
2025-04-17 03:39:53,364 - INFO - Processing batch 49/512...
2025-04-17 03:40:34,606 - INFO - Reasoning:

Let's analyze Ligand A and Ligand B for their potential as DRD2 drug candidates, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight (MW):** Both ligands (381.929 and 351.491 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (71.09) is better than Ligand B (72.88), both are below the 90 A^2 threshold for CNS targets, but closer to the upper limit.

**3. logP:** Ligand A (3.392) is optimal, while Ligand B (1.176) is on the lower side, potentially hindering permeation.

**4. H-Bond Donors (HBD):** Both ligands have 2 HBD, which is within the acceptable limit of <=5.

**5. H-Bond Acceptors (HBA):** Both ligands have 4 HBA, which is within the acceptable limit of <=10.

**6. QED:** Ligand A (0.821) has a significantly higher QED score than Ligand B (0.534), indicating better overall drug-likeness.

**7. DILI:** Ligand B (5.933) has a much lower DILI risk than Ligand A (49.942). This is a significant advantage for Ligand B.

**8. BBB:** Both ligands have good BBB penetration (Ligand A: 56.495, Ligand B: 57.774). While both are above 50, they are not exceeding 70, which is desirable for CNS targets.

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.076 and -4.966), which is unusual and suggests poor permeability. This is a concern for both.

**10. Aqueous Solubility:** Both ligands have negative solubility values (-4.253 and -0.691) which is also unusual and suggests poor solubility. This is a concern for both.

**11. hERG Inhibition:** Ligand A (0.337) has a slightly higher hERG inhibition risk than Ligand B (0.169), but both are relatively low.

**12. Microsomal Clearance (Cl_mic):** Ligand B (-1.649) has a negative Cl_mic, suggesting very high metabolic stability, which is a major advantage. Ligand A (36.87) has a higher clearance.

**13. In vitro Half-Life:** Ligand B (-22.935) has a negative half-life, suggesting extremely long half-life, which is a major advantage. Ligand A (25.43) has a shorter half-life.

**14. P-gp Efflux:** Ligand A (0.362) has a lower P-gp efflux liability than Ligand B (0.005), which is favorable for CNS penetration.

**15. Binding Affinity:** Ligand A (-9.2 kcal/mol) has a significantly stronger binding affinity than Ligand B (-7.6 kcal/mol). This is a substantial advantage, potentially outweighing some ADME drawbacks.

**Overall Assessment:**

Ligand B excels in ADME properties (DILI, Cl_mic, t1/2), while Ligand A has a much stronger binding affinity. Given the GPCR-specific priorities, the strong affinity of Ligand A is a significant factor. While Ligand B has better ADME properties, the difference in binding affinity is substantial (>1.5 kcal/mol). The poor Caco-2 and solubility values are concerning for both, but can potentially be addressed through formulation strategies. The lower P-gp efflux for Ligand A is also beneficial for CNS exposure.

Output:
1
2025-04-17 03:40:34,606 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (344.415 and 348.443 Da) fall comfortably within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (76.46) is slightly higher than Ligand B (67.87). Both are below the 90 A^2 threshold desirable for CNS targets, but Ligand B is preferable.

**3. logP:** Ligand A (0.835) is a bit low, potentially hindering permeability. Ligand B (1.745) is better, falling within the optimal 1-3 range.

**4. H-Bond Donors:** Both ligands have 1 HBD, which is within the acceptable limit of <=5.

**5. H-Bond Acceptors:** Ligand A has 5 HBAs, and Ligand B has 4. Both are below the acceptable limit of <=10.

**6. QED:** Both ligands have good QED scores (0.56 and 0.844), indicating drug-like properties. Ligand B is better.

**7. DILI:** Ligand A (39.434) has a slightly higher DILI risk than Ligand B (32.261), but both are below the concerning threshold of 60.

**8. BBB:** Ligand B (74.758) has a significantly better BBB penetration percentile than Ligand A (65.452). This is crucial for a CNS target like DRD2.

**9. Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and suggests poor permeability. Ligand A (-4.652) is slightly better than Ligand B (-4.78).

**10. Aqueous Solubility:** Both have negative solubility values, which is also unusual and suggests poor solubility.

**11. hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.219 and 0.155).

**12. Microsomal Clearance:** Ligand A (0.421) has much lower microsomal clearance than Ligand B (14.79), indicating better metabolic stability.

**13. In vitro Half-Life:** Ligand A (-0.787) has a longer in vitro half-life than Ligand B (1.832), which is desirable.

**14. P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.054 and 0.048).

**15. Binding Affinity:** Ligand B (-8.2 kcal/mol) has a slightly better binding affinity than Ligand A (-7.7 kcal/mol). While both are good, the 0.5 kcal/mol difference is meaningful.

**Overall Assessment:**

While Ligand A has better metabolic stability and half-life, Ligand B excels in crucial areas for a CNS-targeting GPCR ligand: significantly better BBB penetration, a slightly better logP, and slightly improved binding affinity. The difference in binding affinity, coupled with the superior BBB score, outweighs the advantages of Ligand A. The poor Caco-2 and solubility values are concerning for both, but can be addressed through formulation strategies.

Output:
1
2025-04-17 03:40:34,606 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (340.43 and 347.46 Da) fall comfortably within the ideal 200-500 Da range.

**TPSA:** Ligand A (67.23) is better than Ligand B (75.44). For CNS targets, we want TPSA <= 90, both are within this range, but A is closer to the optimal value.

**logP:** Both ligands have similar logP values (2.76 and 2.69), falling within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Both have 1 HBD and 4 HBA, which are acceptable.

**QED:** Ligand A (0.91) has a significantly better QED score than Ligand B (0.55), indicating a more drug-like profile.

**DILI:** Ligand A (47.34) has a higher DILI risk than Ligand B (26.87). Lower is better, so B is preferable here.

**BBB:** Both ligands have excellent BBB penetration (75.11 and 75.53), exceeding the desirable threshold of >70.

**Caco-2 Permeability:** Both have negative Caco-2 values which is unusual. However, the magnitude of the negative value for Ligand A (-4.35) is worse than Ligand B (-4.73).

**Aqueous Solubility:** Ligand A (-3.11) has worse solubility than Ligand B (-1.83). Higher solubility is preferred.

**hERG:** Both ligands have very low hERG inhibition risk (0.21 and 0.25).

**Microsomal Clearance:** Ligand B (66.33) has a significantly higher microsomal clearance than Ligand A (46.15), indicating lower metabolic stability. Lower is better.

**In vitro Half-Life:** Ligand A (34.53) has a much longer in vitro half-life than Ligand B (3.37). Longer half-life is generally preferred.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.018 and 0.335).

**Binding Affinity:** Both ligands have very similar and excellent binding affinities (-8.3 and -8.1 kcal/mol). The difference is negligible.

**Overall Assessment:**

Ligand A is superior in terms of QED, metabolic stability (lower Cl_mic, longer t1/2), and TPSA. Ligand B has a lower DILI risk and slightly better solubility. However, the strong advantages of Ligand A in QED and metabolic stability, coupled with comparable affinity and excellent BBB penetration, outweigh the slightly higher DILI risk. The negative Caco-2 values are concerning for both, but the difference is minimal.

Output:
1
2025-04-17 03:40:34,606 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (362.426 Da) and Ligand B (344.375 Da) are both acceptable.

**TPSA:** Ligand A (57.69) is excellent, well below the 90 A^2 threshold for CNS targets. Ligand B (115.05) is higher, but still potentially acceptable, though less ideal.

**logP:** Ligand A (2.815) is optimal (1-3). Ligand B (0.116) is quite low, which could hinder membrane permeability and CNS penetration.

**H-Bond Donors/Acceptors:** Ligand A (0 HBD, 3 HBA) is good. Ligand B (2 HBD, 5 HBA) is also acceptable.

**QED:** Both ligands have similar and good QED values (Ligand A: 0.84, Ligand B: 0.82).

**DILI:** Ligand A (79.837) has a higher DILI risk than Ligand B (54.207), but both are reasonably low.

**BBB:** This is critical for a CNS target. Ligand A (85.033) has excellent BBB penetration potential. Ligand B (23.381) has very poor predicted BBB penetration.

**Caco-2 Permeability:** Ligand A (-4.392) is poor, while Ligand B (-5.058) is even worse. Both are significantly negative, suggesting very low intestinal absorption. This is less critical for a CNS target if BBB penetration is good.

**Aqueous Solubility:** Ligand A (-4.365) and Ligand B (-2.494) both have poor predicted aqueous solubility.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (Ligand A: 0.802, Ligand B: 0.311).

**Microsomal Clearance:** Ligand A (37.832) has moderate clearance, while Ligand B (-17.007) has negative clearance, which is not physically possible and indicates a potential issue with the prediction method or the molecule's structure.

**In vitro Half-Life:** Ligand A (9.345 hours) has a reasonable half-life. Ligand B (0.857 hours) has a very short half-life.

**P-gp Efflux:** Ligand A (0.377) has low P-gp efflux, which is good. Ligand B (0.023) has very low P-gp efflux, which is excellent.

**Binding Affinity:** Ligand A (-9.6 kcal/mol) has significantly stronger binding affinity than Ligand B (-8.5 kcal/mol). This 1.1 kcal/mol difference is substantial.

**Overall Assessment:**

Ligand A is the superior candidate. While its Caco-2 permeability and aqueous solubility are poor, its excellent BBB penetration, strong binding affinity, and acceptable ADME properties (DILI, hERG, P-gp) make it more promising for a CNS-targeting drug. Ligand B suffers from extremely poor BBB penetration and a very short half-life, which are major drawbacks for a CNS drug, even with its low P-gp efflux. The significantly stronger binding affinity of Ligand A further solidifies its advantage.

Output:
1
2025-04-17 03:40:34,607 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (441.332 Da) is higher, but still acceptable. Ligand B (361.471 Da) is slightly better.

**TPSA:** Both ligands have TPSA values around 101, which is above the ideal <90 for CNS targets, but not drastically so. This is a minor concern for both.

**logP:** Ligand A (3.179) is optimal, while Ligand B (1.975) is a bit low, potentially hindering permeability.

**H-Bond Donors/Acceptors:** Both have 2 HBD and 6 HBA, which are within acceptable limits.

**QED:** Both have good QED scores (A: 0.648, B: 0.731), indicating drug-like properties. Ligand B is slightly better.

**DILI:** Ligand A (95.192) has a significantly higher DILI risk than Ligand B (71.811). This is a major drawback for Ligand A.

**BBB:** Ligand A (70.803) has a good BBB penetration percentile, meeting the >70 threshold for CNS targets. Ligand B (48.003) is considerably lower, which is a significant concern for CNS activity.

**Caco-2 Permeability:** Both have negative Caco-2 values (-5.15 and -5.236), which is unusual and suggests poor permeability. This is a concern for both.

**Aqueous Solubility:** Both have negative solubility values (-4.085 and -2.636), indicating very poor solubility, a significant issue for bioavailability.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.338 and 0.316).

**Microsomal Clearance:** Ligand B (40.994) has lower microsomal clearance than Ligand A (29.97), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand B (23.269) has a longer in vitro half-life than Ligand A (141.393). This is a positive for Ligand B.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.353 and 0.112), which is favorable for CNS penetration. Ligand B is better.

**Binding Affinity:** Both ligands have strong binding affinities (-9 kcal/mol and -8.6 kcal/mol). Ligand A has a slightly better affinity, but the difference is not substantial enough to outweigh other factors.

**Overall Assessment:**

Ligand A has better affinity and BBB penetration, but suffers from a very high DILI risk and poor metabolic stability. Ligand B has a lower DILI risk, better metabolic stability, a longer half-life, and lower P-gp efflux, but has poorer BBB penetration and a slightly lower logP. Given the CNS target (DRD2), the BBB is crucial. However, the high DILI risk of Ligand A is a major red flag. While Ligand B's BBB is suboptimal, it is a more tractable issue to address through structural modifications than a high DILI risk.

Output:
1
2025-04-17 03:40:34,607 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (348.403 and 346.475 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (95.75) is slightly higher than Ligand B (78.09). Both are below the 140 threshold for oral absorption, and Ligand B is closer to the preferred <90 for CNS targets.

**logP:** Ligand A (0.385) is quite low, potentially hindering permeation. Ligand B (2.679) is within the optimal 1-3 range. This is a significant advantage for Ligand B.

**H-Bond Donors/Acceptors:** Ligand A has 1 HBD and 5 HBA, while Ligand B has 2 HBD and 3 HBA. Both are within acceptable limits.

**QED:** Both ligands have similar QED values (0.83 and 0.805), indicating good drug-likeness.

**DILI:** Both ligands have low DILI risk (42.807 and 37.611), which is favorable.

**BBB:** Both ligands show good BBB penetration (76.27% and 70.221%), but Ligand A is slightly better. This is crucial for a CNS target like DRD2.

**Caco-2 Permeability:** Ligand A (-4.983) has very poor Caco-2 permeability, while Ligand B (-4.868) is also poor but slightly better.

**Aqueous Solubility:** Ligand A (-0.888) has slightly better solubility than Ligand B (-3.262).

**hERG Inhibition:** Ligand A (0.052) has very low hERG inhibition risk, while Ligand B (0.557) is slightly higher.

**Microsomal Clearance:** Ligand A (31.928) and Ligand B (35.33) have comparable microsomal clearance, suggesting similar metabolic stability.

**In vitro Half-Life:** Ligand B (-18.87) has a significantly longer in vitro half-life than Ligand A (-7.672). This is a substantial advantage.

**P-gp Efflux:** Ligand A (0.023) shows very low P-gp efflux, which is excellent for CNS penetration. Ligand B (0.168) is slightly higher, but still reasonable.

**Binding Affinity:** Both ligands have the same binding affinity (-8.2 kcal/mol), which is excellent.

**Overall Assessment:**

While Ligand A has slightly better BBB penetration and lower P-gp efflux, its significantly lower logP and poor Caco-2 permeability are major drawbacks. The low logP suggests poor membrane permeability, hindering its ability to reach the target in the CNS. Ligand B, despite slightly lower BBB and higher P-gp, has a much more favorable logP, better Caco-2 permeability, and a significantly longer half-life. Given the GPCR-specific priorities, the improved logP and half-life of Ligand B outweigh the minor differences in BBB and P-gp.

Output:
1
2025-04-17 03:40:34,607 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (366.799 Da) is slightly lower, which is generally favorable for permeability.

**2. TPSA:** Ligand A (58.12) is significantly better than Ligand B (79.46). For CNS targets, TPSA < 90 is preferred, and A is comfortably within this range while B is approaching the upper limit.

**3. logP:** Both ligands have good logP values (A: 3.247, B: 3.746), falling within the optimal 1-3 range.

**4. H-Bond Donors:** Ligand A (1) is better than Ligand B (3). Lower HBD generally improves permeability.

**5. H-Bond Acceptors:** Ligand A (4) is slightly better than Ligand B (3). Both are within the acceptable limit of 10.

**6. QED:** Ligand A (0.844) has a significantly higher QED score than Ligand B (0.656), indicating better overall drug-likeness.

**7. DILI:** Ligand B (71.772) has a lower DILI risk than Ligand A (85.653), which is a positive attribute.

**8. BBB:** Both ligands have excellent BBB penetration (A: 80.07, B: 77.821), exceeding the desirable >70 threshold for CNS targets.

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 values, which is unusual and suggests poor permeability. However, the scale is not specified, so it's hard to interpret.

**10. Aqueous Solubility:** Both ligands have negative solubility values, which is also unusual and suggests poor solubility.

**11. hERG Inhibition:** Both ligands have low hERG inhibition risk (A: 0.566, B: 0.694).

**12. Microsomal Clearance:** Ligand B (40.769) has significantly lower microsomal clearance than Ligand A (66.513), indicating better metabolic stability.

**13. In vitro Half-Life:** Ligand B (75.308) has a longer in vitro half-life than Ligand A (31.202), which is desirable.

**14. P-gp Efflux:** Both ligands have low P-gp efflux liability (A: 0.236, B: 0.21).

**15. Binding Affinity:** Ligand B (-9.5 kcal/mol) has a slightly better binding affinity than Ligand A (-8.9 kcal/mol). This difference of 0.6 kcal/mol is significant and could outweigh some of the ADME drawbacks of Ligand B.

**Overall Assessment:**

While Ligand A has better TPSA, HBD, HBA, and QED, Ligand B demonstrates superior metabolic stability (lower Cl_mic, longer t1/2), a slightly better binding affinity, and lower DILI risk. Given the GPCR target and the importance of CNS penetration, the slightly improved binding affinity and metabolic stability of Ligand B are more critical. The negative Caco-2 and solubility values are concerning for both, but the affinity advantage of B is substantial.

Output:
1
2025-04-17 03:40:34,607 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 drug candidates, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (349.435 Da) is slightly lower, which could be beneficial for permeability, but both are acceptable.

**TPSA:** Ligand B (98.77) is significantly better than Ligand A (120), falling well below the 90 A^2 threshold for CNS targets. Ligand A is above the preferred threshold.

**logP:** Ligand B (2.908) is optimal, while Ligand A (0.829) is quite low, potentially hindering membrane permeability and CNS penetration.

**H-Bond Donors/Acceptors:** Ligand A has 4 HBD and 5 HBA, while Ligand B has 1 HBD and 6 HBA. Both are within acceptable limits, but Ligand B's lower HBD count is generally preferred.

**QED:** Both ligands have similar QED values (0.587 and 0.586), indicating good drug-likeness.

**DILI:** Ligand B (75.184) has a higher DILI risk than Ligand A (60.799), but both are reasonably acceptable.

**BBB:** This is a critical parameter for a CNS target like DRD2. Ligand B (81.466) has a significantly higher BBB percentile than Ligand A (27.142). This is a major advantage for Ligand B.

**Caco-2 Permeability:** Both have negative values, indicating poor permeability. Ligand A (-5.467) is slightly better than Ligand B (-4.439), but both are concerning.

**Aqueous Solubility:** Both have negative solubility values, which is concerning. Ligand A (-2.737) is slightly better than Ligand B (-3.899).

**hERG Inhibition:** Ligand A (0.05) has a very low hERG risk, while Ligand B (0.323) is slightly higher, but still acceptable.

**Microsomal Clearance:** Ligand B (63.698) has a higher clearance than Ligand A (14.217), suggesting lower metabolic stability. This is a drawback for Ligand B.

**In vitro Half-Life:** Ligand A (-4.477) has a slightly better half-life than Ligand B (-5.34), though both are negative and concerning.

**P-gp Efflux:** Ligand A (0.099) has a slightly higher P-gp efflux liability than Ligand B (0.244), meaning Ligand B may have better CNS exposure.

**Binding Affinity:** Ligand B (-8.9 kcal/mol) has a significantly stronger binding affinity than Ligand A (0.0 kcal/mol). This is a substantial advantage that can outweigh some of the ADME drawbacks.

**Overall Assessment:**

Ligand B is the stronger candidate. Its superior BBB penetration and significantly improved binding affinity are critical for a CNS GPCR target. While it has a higher DILI risk and worse metabolic stability (higher Cl_mic), the strong affinity and BBB penetration are likely to be more impactful for *in vivo* efficacy. Ligand A's low logP and poor BBB penetration are significant liabilities. The Caco-2 and solubility issues are shared by both, and would need to be addressed in further optimization.

Output:
1
2025-04-17 03:40:34,607 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 drug candidates, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (346.471 and 365.905 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (58.64) is significantly better than Ligand B (47.79) regarding TPSA, falling well below the 90 A^2 threshold for CNS targets. Ligand B is still reasonable, but A is preferred.

**logP:** Ligand A (2.924) is within the optimal 1-3 range. Ligand B (4.621) is higher, potentially leading to solubility issues and off-target interactions. This favors Ligand A.

**H-Bond Donors/Acceptors:** Both ligands have acceptable HBD (1) and HBA (3 for A, 5 for B) counts, well within the guidelines.

**QED:** Both ligands have good QED scores (0.721 and 0.803), indicating good drug-like properties.

**DILI:** Ligand A (41.411) has a slightly better DILI percentile than Ligand B (53.354), indicating lower potential for liver injury.

**BBB:** Ligand B (77.898) has a significantly better BBB percentile than Ligand A (65.103). This is a crucial factor for CNS targets like DRD2, making Ligand B more attractive.

**Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and suggests poor permeability. However, the scale is not specified, so it's hard to interpret.

**Aqueous Solubility:** Both ligands have poor aqueous solubility (-3.21 and -4.525). This is a concern, but can potentially be addressed through formulation.

**hERG Inhibition:** Ligand A (0.271) has a much lower hERG inhibition liability than Ligand B (0.91), which is a significant safety advantage.

**Microsomal Clearance:** Ligand A (93.491) has higher microsomal clearance than Ligand B (43.291), indicating lower metabolic stability. This favors Ligand B.

**In vitro Half-Life:** Ligand B (90.867) has a much longer in vitro half-life than Ligand A (-17.625), suggesting better duration of action. This strongly favors Ligand B.

**P-gp Efflux:** Ligand A (0.412) has lower P-gp efflux liability than Ligand B (0.699), which is favorable for CNS penetration.

**Binding Affinity:** Ligand B (-7.6 kcal/mol) has a slightly better binding affinity than Ligand A (-8.6 kcal/mol). While A is better, the difference is not huge.

**Overall Assessment:**

Ligand B excels in BBB penetration and in vitro half-life, both critical for a CNS GPCR target. Its binding affinity is also slightly better. While it has a higher logP and P-gp efflux, the superior BBB and half-life outweigh these drawbacks. Ligand A has better TPSA, hERG inhibition, and P-gp efflux, but its significantly lower BBB and shorter half-life are major concerns for a CNS drug.

Output:
1
2025-04-17 03:40:34,607 - INFO - Reasoning:

Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (349.435 and 353.467 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Both ligands (112.65 and 113.49) are close to the 140 A^2 threshold for oral absorption, but slightly above the preferred <90 A^2 for CNS targets. This is a minor concern, but not disqualifying.

**3. logP:** Ligand A (0.532) is a bit low, potentially hindering membrane permeability. Ligand B (1.248) is better, falling within the optimal 1-3 range. This is a significant advantage for Ligand B.

**4. H-Bond Donors:** Ligand A (2) and Ligand B (3) are both acceptable, being less than 5.

**5. H-Bond Acceptors:** Both ligands (6) are within the acceptable limit of 10.

**6. QED:** Both ligands (0.775 and 0.583) have reasonable drug-likeness scores, with Ligand A being slightly better.

**7. DILI:** Ligand A (34.354%) has a lower DILI risk than Ligand B (41.915%), making it slightly more favorable from a toxicity perspective.

**8. BBB:** Ligand A (68.554%) and Ligand B (70.26%) both have good BBB penetration, exceeding the 70% threshold for CNS targets. Ligand B is marginally better.

**9. Caco-2 Permeability:** Both have negative values (-5.034 and -5.358), which is unusual and suggests poor permeability. This is a significant drawback for both compounds.

**10. Aqueous Solubility:** Both have negative values (-1.485 and -1.989), indicating low solubility. This is a concern for both compounds, potentially impacting bioavailability.

**11. hERG Inhibition:** Both ligands have low hERG inhibition risk (0.487 and 0.391), which is good.

**12. Microsomal Clearance:** Ligand A (1.604 mL/min/kg) has much lower microsomal clearance than Ligand B (39.334 mL/min/kg), indicating better metabolic stability. This is a significant advantage for Ligand A.

**13. In vitro Half-Life:** Ligand A (-3.254 hours) and Ligand B (-3.689 hours) both have negative half-lives, which is not physically possible. This indicates an issue with the data or the modeling used to generate these values.

**14. P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.011 and 0.017), which is excellent for CNS penetration.

**15. Binding Affinity:** Ligand B (-7.6 kcal/mol) has a significantly stronger binding affinity than Ligand A (-6.9 kcal/mol). This 0.7 kcal/mol difference is substantial and can outweigh some of the ADME drawbacks.

**Overall Assessment:**

Ligand B has a better logP and a significantly stronger binding affinity, which are crucial for GPCR targets. While Ligand A has better metabolic stability (lower Cl_mic) and a slightly lower DILI risk, the affinity difference is substantial. The negative Caco-2 and solubility values are concerning for both, but can potentially be addressed through formulation strategies. Given the importance of binding affinity for GPCRs, and the acceptable BBB penetration of both, Ligand B is the more promising candidate.

Output:
1
2025-04-17 03:40:34,607 - INFO - Reasoning:

Let's analyze Ligand A and Ligand B based on the provided guidelines, with a focus on GPCR properties (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (348.418 and 355.435 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (69.64) is significantly better than Ligand B (113.6). For CNS targets, TPSA should be <= 90, and A is comfortably within this, while B exceeds it.

**logP:** Ligand A (2.688) is optimal (1-3). Ligand B (-0.092) is below 1, which may hinder permeation.

**H-Bond Donors/Acceptors:** Ligand A (HBD=2, HBA=3) and Ligand B (HBD=3, HBA=5) both have reasonable numbers, within the suggested limits.

**QED:** Both ligands have acceptable QED values (A: 0.83, B: 0.535), indicating good drug-like properties.

**DILI:** Both ligands have low DILI risk (A: 31.175, B: 30.981), below the 40 threshold.

**BBB:** Ligand A (70.88) is much better than Ligand B (46.336).  A BBB percentile >70 is desirable for CNS targets, and A meets this criterion, while B does not.

**Caco-2 Permeability:** Ligand A (-4.752) and Ligand B (-5.157) both have negative Caco-2 values, which is unusual and suggests poor permeability. However, the scale is not defined, so it's difficult to interpret the absolute impact.

**Aqueous Solubility:** Ligand A (-3.638) and Ligand B (-1.222) both have negative solubility values, indicating poor solubility. Again, the scale is unclear.

**hERG:** Both ligands have very low hERG risk (A: 0.469, B: 0.011).

**Microsomal Clearance:** Ligand A (42.085) has higher clearance than Ligand B (23.469). Lower clearance is preferred for better metabolic stability, giving a slight edge to B.

**In vitro Half-Life:** Ligand B (-6.554) has a longer half-life than Ligand A (-4.605).

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (A: 0.063, B: 0.006).

**Binding Affinity:** Ligand A (-7.8 kcal/mol) has a slightly better binding affinity than Ligand B (-7.3 kcal/mol). While both are good, the 0.5 kcal/mol difference is significant.

**Overall Assessment:**

Considering the GPCR-specific priorities, Ligand A is significantly better. Its superior TPSA, logP, and, crucially, BBB penetration make it more likely to reach the target in the CNS. While Ligand B has slightly better metabolic stability and half-life, the differences are not substantial enough to overcome the significant advantages of Ligand A in terms of CNS penetration. The slightly better affinity of Ligand A further supports its selection.

Output:
1
2025-04-17 03:40:34,607 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (358.873 and 351.451 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (57.26) is excellent, well below the 90 A^2 threshold for CNS targets. Ligand B (99.49) is higher, but still potentially acceptable, though less ideal.

**logP:** Ligand A (3.693) is within the optimal 1-3 range. Ligand B (-0.264) is significantly below this, which is a major concern for brain penetration.

**H-Bond Donors/Acceptors:** Ligand A (HBD=2, HBA=3) and Ligand B (HBD=3, HBA=6) both have reasonable numbers of H-bond donors and acceptors.

**QED:** Both ligands have acceptable QED values (0.801 and 0.628, respectively), indicating good drug-like properties.

**DILI:** Ligand A (41.954) has a low DILI risk. Ligand B (13.92) also has a low DILI risk.

**BBB:** Ligand A (81.388) has a good BBB percentile, exceeding the 70% threshold for CNS targets. Ligand B (31.601) is significantly lower and is a major drawback.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.05 and -5.402), which is unusual and suggests poor permeability. However, these values are on a log scale and may not be directly comparable.

**Aqueous Solubility:** Both ligands have negative solubility values (-4.498 and -1.188), indicating poor aqueous solubility. This could pose formulation challenges.

**hERG:** Ligand A (0.865) has a low hERG risk. Ligand B (0.218) also has a low hERG risk.

**Microsomal Clearance:** Ligand A (53.337) has moderate clearance. Ligand B (-20.396) has negative clearance, which is not physically possible and suggests an issue with the data.

**In vitro Half-Life:** Ligand A (40.935) has a reasonable half-life. Ligand B (8.749) has a very short half-life.

**P-gp Efflux:** Ligand A (0.45) has low P-gp efflux, which is favorable for CNS penetration. Ligand B (0.008) also has very low P-gp efflux.

**Binding Affinity:** Ligand A (-9.8 kcal/mol) has significantly better binding affinity than Ligand B (-7.8 kcal/mol). The difference of 2 kcal/mol is substantial and can outweigh some ADME drawbacks.

**Overall Assessment:**

Ligand A is clearly superior. While both have solubility and Caco-2 permeability concerns, Ligand A excels in BBB penetration, logP, and, crucially, binding affinity. Ligand B's very low logP and poor BBB penetration are significant liabilities for a CNS-targeting drug. The negative clearance value for Ligand B is also a red flag, suggesting data quality issues. The superior affinity of Ligand A further solidifies its position as the more promising candidate.

Output:
1
2025-04-17 03:40:34,608 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (390.481 Da) is slightly higher than Ligand B (347.459 Da), but both are acceptable.

**TPSA:** Both ligands have TPSA values below 90 (Ligand A: 76.88, Ligand B: 73.74), which is favorable for CNS penetration.

**logP:** Both ligands have logP values within the optimal range (1-3). Ligand A (2.808) is slightly higher than Ligand B (1.931), but both are good.

**H-Bond Donors/Acceptors:** Both ligands have acceptable HBD (1) and HBA (Ligand A: 6, Ligand B: 4) counts.

**QED:** Both ligands have good QED scores (Ligand A: 0.852, Ligand B: 0.818), indicating drug-like properties.

**DILI:** Ligand A (78.325) has a higher DILI risk than Ligand B (12.951). This is a significant negative for Ligand A.

**BBB:** Ligand A (82.047) has a significantly better BBB penetration percentile than Ligand B (61.225). This is a crucial advantage for a CNS target like DRD2.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values, which is unusual and suggests poor permeability. However, the scale isn't specified, so it's difficult to interpret.

**Aqueous Solubility:** Both ligands have negative solubility values, indicating poor solubility. Again, the scale is unspecified, making interpretation difficult.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (Ligand A: 0.491, Ligand B: 0.426).

**Microsomal Clearance:** Ligand A (28.516) has lower microsomal clearance than Ligand B (52.234), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (35.83) has a longer in vitro half-life than Ligand B (-5.086). The negative value for Ligand B is concerning.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (Ligand A: 0.499, Ligand B: 0.085). Ligand B is slightly better here.

**Binding Affinity:** Ligand A (-9.1 kcal/mol) has a significantly stronger binding affinity than Ligand B (-7.8 kcal/mol). This is a substantial advantage.

**Overall Assessment:**

Ligand A excels in BBB penetration and binding affinity, both critical for a CNS GPCR target. It also has better metabolic stability and half-life. However, its DILI risk is concerning. Ligand B has a much lower DILI risk and slightly better P-gp efflux, but its BBB penetration is significantly worse, and its binding affinity is weaker.

Given the importance of CNS penetration and strong binding for DRD2, and the fact that the affinity difference is substantial (over 1.3 kcal/mol), the benefits of Ligand A outweigh its higher DILI risk, *provided* that the DILI risk can be mitigated through structural modifications. The negative solubility and Caco-2 values are concerning for both, but can be addressed during lead optimization.

Output:
1
2025-04-17 03:40:34,608 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (347.5) is slightly preferred as it's closer to the lower end, potentially aiding permeability.

**TPSA:** Ligand A (52.57) is excellent for CNS penetration, well below the 90 A^2 threshold. Ligand B (64.63) is still reasonable, but less optimal.

**logP:** Ligand A (2.046) is within the optimal range (1-3). Ligand B (4.113) is pushing the upper limit and could present solubility issues or off-target interactions.

**H-Bond Donors/Acceptors:** Both ligands have acceptable HBD/HBA counts (A: 0/5, B: 1/5), falling within the guidelines.

**QED:** Ligand A (0.788) has a higher QED score than Ligand B (0.535), indicating better overall drug-likeness.

**DILI:** Ligand A (16.751) has a significantly lower DILI risk than Ligand B (74.913), a major advantage.

**BBB:** Ligand A (88.29) shows excellent BBB penetration potential, exceeding the 70% threshold. Ligand B (54.207) is considerably lower, raising concerns about CNS exposure.

**Caco-2 Permeability:** Both show negative values, which is unusual. Assuming these are percentile scores, Ligand A (-4.772) is slightly better than Ligand B (-4.838), but both are poor.

**Aqueous Solubility:** Both ligands have negative solubility values, which is also unusual. Assuming these are percentile scores, Ligand A (-1.343) is slightly better than Ligand B (-4.886), but both are poor.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (A: 0.66, B: 0.63).

**Microsomal Clearance:** Ligand A (23.919) has lower microsomal clearance than Ligand B (119.957), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (5.504) has a shorter half-life than Ligand B (12.942), but this is less critical given the other favorable properties of Ligand A.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (A: 0.244, B: 0.66).

**Binding Affinity:** Ligand B (-8.2 kcal/mol) has a slightly better binding affinity than Ligand A (-9.0 kcal/mol). However, the difference is not substantial enough to overcome the significant ADME advantages of Ligand A.

**Overall:** Ligand A is significantly more promising. It has superior BBB penetration, lower DILI risk, better metabolic stability, a higher QED score, and a more favorable logP. While Ligand B has slightly better binding affinity, the ADME profile of Ligand A is far more conducive to successful CNS drug development.

Output:
0
2025-04-17 03:40:34,608 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (354.5 and 371.5 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (41.99) is excellent for CNS penetration (<90 is preferred), while Ligand B (69.72) is higher but still potentially acceptable.

**logP:** Ligand A (4.842) is at the upper end of the optimal range (1-3) and could present solubility challenges. Ligand B (1.741) is well within the optimal range.

**H-Bond Donors & Acceptors:** Both ligands have acceptable HBD (1) and HBA (3 & 4) counts.

**QED:** Both ligands have reasonable QED scores (0.835 and 0.635), indicating good drug-likeness.

**DILI:** Ligand A (44.281) has a moderate DILI risk, while Ligand B (25.165) has a much lower risk, which is a significant advantage.

**BBB:** Ligand A (72.547) has a good BBB penetration score, exceeding the 70% threshold for CNS targets. Ligand B (61.225) is lower, which is a concern for CNS activity.

**Caco-2 Permeability:** Ligand A (-4.894) has poor Caco-2 permeability, suggesting poor intestinal absorption. Ligand B (-5.148) is also poor, but similar to A.

**Aqueous Solubility:** Both ligands have very poor aqueous solubility (-5.218 and -2.44). This is a major concern, especially given Ligand A's high logP.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.517 and 0.404).

**Microsomal Clearance:** Ligand A (85.169) has higher microsomal clearance, indicating faster metabolism. Ligand B (56.11) has lower clearance, suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (25.969) has a shorter half-life, while Ligand B (2.529) has a very short half-life.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.366 and 0.09).

**Binding Affinity:** Ligand A (-10.3 kcal/mol) has significantly stronger binding affinity than Ligand B (-7.0 kcal/mol). The difference of 3.3 kcal/mol is substantial and can often outweigh other ADME concerns.

**Overall Assessment:**

Ligand A excels in binding affinity and BBB penetration, which are crucial for a CNS-targeting GPCR. However, it suffers from poor Caco-2 permeability, high logP, moderate DILI risk, and faster metabolism. Ligand B has a better safety profile (lower DILI), better metabolic stability, and a more favorable logP, but its binding affinity is significantly weaker and its BBB penetration is lower.

Given the substantial difference in binding affinity, and the importance of CNS penetration for DRD2, Ligand A is the more promising candidate, *despite* its ADME liabilities. Optimization efforts could focus on improving its solubility and permeability while retaining its potent binding.

Output:
1
2025-04-17 03:40:34,608 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (340.43 and 356.41 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (81.51) is better than Ligand B (49.85). Both are below the 90 A^2 threshold for CNS targets, but A is slightly higher and could potentially impact BBB penetration less favorably.

**logP:** Both ligands have good logP values (1.898 and 2.423), falling within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A has 3 HBD and 6 HBA, while Ligand B has 0 HBD and 3 HBA. Both are within acceptable limits (<=5 HBD and <=10 HBA).

**QED:** Both ligands have similar QED scores (0.792 and 0.704), indicating good drug-like properties.

**DILI:** Ligand A (49.321) has a higher DILI risk than Ligand B (22.722). This is a significant negative for Ligand A.

**BBB:** Ligand B (97.131) has a substantially better BBB penetration score than Ligand A (71.074). This is a critical advantage for a CNS target like DRD2.

**Caco-2 Permeability:** Ligand A (-5.11) has worse Caco-2 permeability than Ligand B (-4.241). While both are negative, B is better.

**Aqueous Solubility:** Both ligands have very poor aqueous solubility (-2.865 and -2.694). This could pose formulation challenges, but is less critical than BBB for CNS drugs.

**hERG Inhibition:** Both ligands have low hERG inhibition liability (0.562 and 0.461), which is good.

**Microsomal Clearance:** Ligand A (16.19) has lower microsomal clearance than Ligand B (42.444), suggesting better metabolic stability. This is a positive for Ligand A.

**In vitro Half-Life:** Ligand B (-9.142) has a negative half-life, which is a significant concern. Ligand A (18.824) has a much more reasonable half-life.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.063 and 0.124), which is favorable for CNS penetration.

**Binding Affinity:** Ligand A (-10.1 kcal/mol) has a significantly stronger binding affinity than Ligand B (-6.7 kcal/mol). This is a substantial advantage, potentially outweighing some of the ADME drawbacks.

**Overall Assessment:**

Ligand A has a much stronger binding affinity and better metabolic stability (lower Cl_mic, better t1/2). However, it has a higher DILI risk and significantly worse BBB penetration than Ligand B. Ligand B excels in BBB penetration and has a lower DILI risk, but its binding affinity is considerably weaker and its half-life is concerning.

Given the GPCR-specific priorities, particularly the importance of BBB penetration for CNS targets, and the substantial difference in binding affinity, the stronger affinity of Ligand A is likely to be more important. While the DILI risk is a concern, it can be addressed through further structural modifications. The poor BBB of Ligand A is a more difficult property to improve. The negative half-life of Ligand B is a major red flag.

Output:
1
2025-04-17 03:40:34,608 - INFO - Batch 49 complete. Total preferences: 784
2025-04-17 03:40:34,609 - INFO - Processing batch 50/512...
2025-04-17 03:41:18,312 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (349.435 and 350.507 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (100.21) is slightly above the optimal <90 for CNS targets, but still reasonable. Ligand B (68.3) is well within the desired range. This favors Ligand B.

**logP:** Ligand A (0.66) is a bit low, potentially hindering membrane permeability. Ligand B (3.485) is within the optimal 1-3 range. This strongly favors Ligand B.

**H-Bond Donors/Acceptors:** Both have 2 HBD and 5-6 HBA, which are acceptable.

**QED:** Both ligands have similar QED values (0.786 and 0.711), indicating good drug-likeness.

**DILI:** Ligand A (41.877) and Ligand B (35.905) both have low DILI risk, which is good. Ligand B is slightly better.

**BBB:** This is crucial for a CNS target. Ligand A (48.662) is below the desirable >70 percentile, while Ligand B (76.774) is excellent. This is a major advantage for Ligand B.

**Caco-2 Permeability:** Ligand A (-5.318) has poor Caco-2 permeability, suggesting poor absorption. Ligand B (-4.81) is also poor, but slightly better than A.

**Aqueous Solubility:** Ligand A (-1.296) and Ligand B (-3.771) both have poor solubility.

**hERG:** Both ligands show low hERG inhibition liability (0.099 and 0.854), which is favorable.

**Microsomal Clearance:** Ligand A (-15.59) has a much lower (better) microsomal clearance than Ligand B (59.453), indicating greater metabolic stability. This favors Ligand A.

**In vitro Half-Life:** Ligand B (49.569) has a significantly longer half-life than Ligand A (12.386), which is desirable. This favors Ligand B.

**P-gp Efflux:** Ligand A (0.013) shows very low P-gp efflux, which is excellent for CNS penetration. Ligand B (0.275) shows moderate P-gp efflux. This favors Ligand A.

**Binding Affinity:** Both ligands have the same binding affinity (-7.7 kcal/mol), which is excellent.

**Overall Assessment:**

Ligand B excels in key GPCR properties: logP, BBB, and half-life. While its Caco-2 and solubility are poor, its superior BBB penetration and logP outweigh these concerns for a CNS target. Ligand A has better metabolic stability (lower Cl_mic) and P-gp efflux, but its low logP and poor BBB penetration are significant drawbacks. The difference in BBB penetration is particularly important for DRD2.

Output:
1
2025-04-17 03:41:18,313 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (360.523 and 353.495 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (41.9) is significantly better than Ligand B (62.73). For CNS targets, we want TPSA <= 90, and A is much closer to the ideal <= 60 range. B is higher and could hinder BBB penetration.

**3. logP:** Both ligands have logP values (4.462 and 4.751) slightly above the optimal 1-3 range, but still within acceptable limits. The difference isn't substantial.

**4. H-Bond Donors:** Ligand A (0) is preferable to Ligand B (2). Fewer HBDs generally improve permeability.

**5. H-Bond Acceptors:** Ligand A (4) is better than Ligand B (6). Lower HBA counts are generally favored for CNS penetration.

**6. QED:** Both ligands have reasonable QED values (0.782 and 0.693), indicating good drug-like properties.

**7. DILI:** Ligand A (49.128) has a significantly lower DILI risk than Ligand B (77.549). This is a strong advantage for A.

**8. BBB:** Ligand A (91.508) has a much higher predicted BBB penetration than Ligand B (73.866). This is *critical* for a CNS target like DRD2.

**9. Caco-2 Permeability:** Ligand A (-4.96) is better than Ligand B (-5.255). While both are negative, a less negative value suggests better permeability.

**10. Aqueous Solubility:** Ligand A (-4.384) is slightly better than Ligand B (-4.742). Both are poor, but A is marginally better.

**11. hERG Inhibition:** Both ligands have low hERG inhibition risk (0.787 and 0.633).

**12. Microsomal Clearance:** Ligand B (90.875) has lower microsomal clearance than Ligand A (102.64), suggesting better metabolic stability.

**13. In vitro Half-Life:** Ligand B (59.643) has a significantly longer in vitro half-life than Ligand A (-12.213). This is a substantial advantage for B.

**14. P-gp Efflux:** Ligand A (0.906) has slightly lower P-gp efflux than Ligand B (0.46), which is preferable.

**15. Binding Affinity:** Ligand B (-8.8) has a slightly stronger binding affinity than Ligand A (-8.1). While a 0.7 kcal/mol difference is noticeable, it's not a huge advantage given the other factors.

**Overall Assessment:**

Ligand A is clearly superior. While Ligand B has a slightly better binding affinity and half-life, Ligand A excels in crucial properties for a CNS-targeting GPCR ligand: TPSA, BBB penetration, DILI risk, and P-gp efflux. The lower TPSA and higher BBB are particularly important, outweighing the small affinity difference. The lower DILI risk is also a significant benefit.

Output:
1
2025-04-17 03:41:18,313 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (346.39 and 362.41 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (104.39) is slightly higher than Ligand B (98.51), but both are below the 140 threshold for oral absorption and reasonably close to the 90 target for CNS penetration.

**logP:** Ligand A (-0.305) is significantly lower than the optimal 1-3 range, potentially hindering membrane permeability. Ligand B (2.534) is within the optimal range. This is a substantial advantage for Ligand B.

**H-Bond Donors/Acceptors:** Both ligands have 2 HBDs, which is acceptable. Ligand B has 8 HBAs, while Ligand A has 5. Both are within the acceptable limit of 10.

**QED:** Both ligands have similar QED values (0.688 and 0.594), indicating reasonable drug-likeness.

**DILI:** Ligand A (50.33) has a much lower DILI risk than Ligand B (89.763). This is a positive for Ligand A.

**BBB:** Ligand B (68.205) has a significantly better BBB penetration percentile than Ligand A (33.85). This is a critical advantage for a CNS target like DRD2.

**Caco-2 Permeability:** Ligand A (-4.82) shows poor Caco-2 permeability, while Ligand B (-5.143) is also poor, but slightly better.

**Aqueous Solubility:** Both ligands have very poor aqueous solubility (-2.582 and -4.292). This could pose formulation challenges.

**hERG Inhibition:** Ligand A (0.164) has a slightly lower hERG inhibition liability than Ligand B (0.866), which is preferable.

**Microsomal Clearance:** Ligand A (-4.862) has a lower (better) microsomal clearance than Ligand B (91.518), suggesting greater metabolic stability.

**In vitro Half-Life:** Ligand A (-26.21) has a shorter in vitro half-life than Ligand B (6.874).

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.015 and 0.534), which is good.

**Binding Affinity:** Both ligands have the same binding affinity (-8.4 kcal/mol), which is excellent.

**Overall Assessment:**

Ligand B is superior due to its optimal logP, significantly better BBB penetration, and acceptable DILI risk. While Ligand A has better metabolic stability and lower hERG risk, the poor logP and BBB penetration are major drawbacks for a CNS-targeting drug. The strong binding affinity is shared by both, so it doesn't differentiate them. The GPCR-specific priorities clearly favor Ligand B.

Output:
1
2025-04-17 03:41:18,313 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (362.495 and 370.566 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (58.64) is better than Ligand B (59.08), both are below the 90 A^2 threshold for CNS targets, which is good.

**3. logP:** Both ligands have good logP values (2.335 and 1.685), falling within the optimal 1-3 range. Ligand B is slightly lower, which could slightly improve solubility but might compromise permeability.

**4. H-Bond Donors:** Ligand A has 1 HBD, while Ligand B has 0. Both are within the acceptable limit of <=5.

**5. H-Bond Acceptors:** Both ligands have 4 HBAs, which is within the acceptable limit of <=10.

**6. QED:** Ligand A (0.894) has a significantly better QED score than Ligand B (0.691), indicating a more drug-like profile.

**7. DILI:** Ligand A (27.336) has a lower DILI risk than Ligand B (30.748), both are below the 40 threshold.

**8. BBB:** Ligand A (81.737) has a substantially better BBB penetration percentile than Ligand B (63.668). This is *critical* for a CNS target like DRD2.

**9. Caco-2 Permeability:** Ligand A (-5.061) has a worse Caco-2 permeability than Ligand B (-4.516).

**10. Aqueous Solubility:** Ligand A (-2.771) has worse aqueous solubility than Ligand B (-1.871).

**11. hERG Inhibition:** Both ligands have very low hERG inhibition liability (0.385 and 0.357), which is excellent.

**12. Microsomal Clearance:** Ligand A (26.383) has lower microsomal clearance than Ligand B (64.09), suggesting better metabolic stability.

**13. In vitro Half-Life:** Ligand A (9.81) has a longer in vitro half-life than Ligand B (3.811), which is preferable.

**14. P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.191 and 0.183), which is good for CNS penetration.

**15. Binding Affinity:** Ligand A (-8.3 kcal/mol) has a significantly stronger binding affinity than Ligand B (-0.0 kcal/mol). This is a major advantage.

**Overall Assessment:**

Ligand A is clearly the superior candidate. While Ligand B has slightly better Caco-2 permeability and solubility, Ligand A excels in the most important parameters for a CNS-targeting GPCR ligand: **BBB penetration, binding affinity, metabolic stability (lower Cl_mic, longer t1/2), and QED**. The significantly stronger binding affinity of Ligand A (-8.3 vs -0.0 kcal/mol) is a decisive factor, easily outweighing the minor drawbacks in permeability and solubility. The higher BBB value (81.7 vs 63.7) is also a significant advantage.

Output:
1
2025-04-17 03:41:18,313 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (384.929 and 377.507 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (58.64) is excellent, well below the 90 A^2 threshold for CNS targets. Ligand B (127.59) is higher, but still potentially acceptable, though less ideal.

**3. logP:** Ligand A (3.326) is optimal. Ligand B (0.268) is quite low, potentially hindering membrane permeability and CNS penetration.

**4. H-Bond Donors:** Ligand A (1) is good. Ligand B (3) is acceptable, but higher.

**5. H-Bond Acceptors:** Ligand A (4) is good. Ligand B (5) is acceptable, but higher.

**6. QED:** Both ligands have reasonable QED values (0.847 and 0.559), indicating good drug-like properties.

**7. DILI:** Both ligands have low DILI risk (40.869 and 36.603), which is favorable.

**8. BBB:** Ligand A (78.829) has a good BBB percentile, desirable for a CNS target. Ligand B (56.495) is significantly lower, raising concerns about CNS penetration.

**9. Caco-2:** Ligand A (-4.828) and Ligand B (-5.479) both have negative values, which is unusual. These values are likely on a log scale and indicate poor permeability.

**10. Solubility:** Ligand A (-4.02) and Ligand B (-1.72) both have negative solubility values, suggesting poor aqueous solubility.

**11. hERG:** Both ligands have low hERG risk (0.451 and 0.189).

**12. Cl_mic:** Both ligands have similar microsomal clearance values (32.655 and 31.223 mL/min/kg), suggesting comparable metabolic stability.

**13. t1/2:** Ligand A (10.22) has a reasonable in vitro half-life. Ligand B (-35.912) has a negative half-life, which is not possible and likely represents an outlier or error in the data.

**14. Pgp:** Ligand A (0.298) has low P-gp efflux liability, which is good for CNS penetration. Ligand B (0.016) has very low P-gp efflux, which is also good.

**15. Binding Affinity:** Ligand A (-7.9 kcal/mol) has a slightly better binding affinity than Ligand B (-7.4 kcal/mol), though both are excellent.

**Overall Assessment:**

Ligand A is significantly more promising. It has a better logP, a much better BBB score, and a reasonable in vitro half-life. While both have poor Caco-2 and solubility values, the superior CNS penetration profile of Ligand A, coupled with its slightly better affinity, makes it the preferred candidate for a DRD2 target. The negative half-life for Ligand B is a major red flag.

Output:
1
2025-04-17 03:41:18,314 - INFO - Reasoning:

Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (345.447 and 353.507 Da) fall comfortably within the ideal 200-500 Da range.

**2. TPSA:** Both ligands have TPSA values (88.91 and 87.3) below the 90 A^2 threshold for CNS targets, which is excellent.

**3. logP:** Both ligands have logP values (2.038 and 2.273) within the optimal 1-3 range.

**4. H-Bond Donors:** Ligand A (2 HBD) and Ligand B (3 HBD) both meet the <=5 criteria.

**5. H-Bond Acceptors:** Ligand A (5 HBA) and Ligand B (3 HBA) both meet the <=10 criteria.

**6. QED:** Both ligands have good QED scores (0.529 and 0.556), indicating good drug-like properties.

**7. DILI:** Ligand A (49.709) has a slightly higher DILI risk than Ligand B (19.736). This is a point in favor of Ligand B.

**8. BBB:** Ligand B (61.225) has a better BBB percentile than Ligand A (56.805). While both are reasonably good, a higher BBB is crucial for CNS targets like DRD2.

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.243 and -4.896), which is unusual and suggests poor permeability. This is a significant concern for both.

**10. Aqueous Solubility:** Both ligands have negative solubility values (-2.473 and -2.768), indicating poor aqueous solubility. This is a concern for formulation and bioavailability.

**11. hERG Inhibition:** Both ligands show very low hERG inhibition risk (0.043 and 0.158), which is excellent.

**12. Microsomal Clearance:** Both ligands have similar microsomal clearance values (48.412 and 46.986), indicating moderate metabolic stability.

**13. In vitro Half-Life:** Ligand B (2.256 hours) has a slightly longer half-life than Ligand A (-13.645 hours). However, the negative value for Ligand A is concerning and likely an error.

**14. P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.026 and 0.027), which is favorable for CNS penetration.

**15. Binding Affinity:** Both ligands have very similar binding affinities (-7.7 and -7.6 kcal/mol), which are both excellent and above the -7.0 kcal/mol threshold. The difference is negligible.

**Overall Assessment:**

Ligand B is slightly more favorable due to its lower DILI risk and better BBB penetration. The negative Caco-2 and solubility values are concerning for both, but the binding affinity is strong enough that these issues might be addressable through formulation or further optimization. The negative half-life for Ligand A is a red flag.

Output:
1
2025-04-17 03:41:18,314 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (352.475 and 363.483 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (78.87) is significantly better than Ligand B (91.32). For CNS targets, we want TPSA <= 90, so Ligand A is preferable.

**3. logP:** Both ligands have acceptable logP values (1.458 and 1.945, respectively), falling within the optimal 1-3 range.

**4. H-Bond Donors:** Ligand A (2) and Ligand B (3) are both acceptable, being <= 5.

**5. H-Bond Acceptors:** Ligand A (4) and Ligand B (5) are both acceptable, being <= 10.

**6. QED:** Both ligands have reasonable QED scores (0.727 and 0.674), indicating good drug-like properties.

**7. DILI:** Ligand A (8.414) has a much lower DILI risk than Ligand B (54.75). This is a significant advantage for Ligand A.

**8. BBB:** Ligand A (60.838) has a better BBB percentile than Ligand B (41.45), but ideally, we want >70 for CNS targets. Ligand A is still preferable here.

**9. Caco-2 Permeability:** Ligand A (-4.65) is better than Ligand B (-5.006). Higher values are better.

**10. Aqueous Solubility:** Ligand A (-2.089) is better than Ligand B (-2.403). Higher values are better.

**11. hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.24 and 0.08, respectively).

**12. Microsomal Clearance:** Ligand A (7.892) has significantly lower microsomal clearance than Ligand B (37.512), indicating better metabolic stability.

**13. In vitro Half-Life:** Ligand A (-1.021) has a better in vitro half-life than Ligand B (-5.556).

**14. P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.078 and 0.108, respectively).

**15. Binding Affinity:** Both ligands have excellent binding affinities (-8.7 and -8.3 kcal/mol). The difference of 0.4 kcal/mol is not substantial enough to outweigh the other advantages of Ligand A.

**Overall:** Ligand A is superior to Ligand B across most ADME-Tox properties, including DILI, BBB, metabolic stability (Cl_mic and t1/2), and solubility. While both have good binding affinity and acceptable logP/TPSA, the improved ADME profile of Ligand A makes it the more promising drug candidate for a CNS target like DRD2.

Output:
0
2025-04-17 03:41:18,314 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (348.531 and 345.359 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (40.62) is excellent, well below the 90 A^2 threshold for CNS targets. Ligand B (132.13) is higher, but still within a reasonable range, though less optimal for CNS penetration.

**3. logP:** Ligand A (3.698) is within the optimal range of 1-3. Ligand B (-0.18) is significantly below this, which could hinder membrane permeability and potentially reduce CNS exposure.

**4. H-Bond Donors:** Ligand A (0) is favorable. Ligand B (5) is at the upper limit of acceptable, potentially impacting permeability.

**5. H-Bond Acceptors:** Ligand A (2) is good. Ligand B (5) is acceptable.

**6. QED:** Ligand A (0.734) is excellent, indicating good drug-like properties. Ligand B (0.524) is acceptable, but less favorable.

**7. DILI:** Ligand A (13.61) has a very low DILI risk. Ligand B (79.915) has a considerably higher DILI risk, which is concerning.

**8. BBB:** Ligand A (92.71) has excellent predicted BBB penetration, highly desirable for a CNS target. Ligand B (25.979) has poor predicted BBB penetration, a major drawback.

**9. Caco-2 Permeability:** Ligand A (-4.604) is negative, which is unusual and suggests poor permeability. Ligand B (-5.651) is also negative, indicating poor permeability.

**10. Aqueous Solubility:** Both ligands have negative values (-3.075 and -3.166), suggesting poor aqueous solubility. This could impact bioavailability.

**11. hERG Inhibition:** Ligand A (0.633) has a low risk of hERG inhibition. Ligand B (0.124) also has a low risk.

**12. Microsomal Clearance:** Ligand A (75.343) has moderate clearance. Ligand B (-19.769) has negative clearance, which is impossible and likely an error in the data.

**13. In vitro Half-Life:** Ligand A (-21.609) has a negative half-life, which is impossible and likely an error in the data. Ligand B (35.907) has a reasonable half-life.

**14. P-gp Efflux:** Ligand A (0.288) has low P-gp efflux, which is favorable for CNS penetration. Ligand B (0.014) also has low P-gp efflux.

**15. Binding Affinity:** Both ligands have strong binding affinities (-8.2 and -9.3 kcal/mol). Ligand B is slightly better, but the difference is unlikely to overcome its other significant drawbacks.

**Overall Assessment:**

Ligand A is the better candidate despite the negative Caco-2 and half-life values, which are likely data errors. It has superior BBB penetration, a much lower DILI risk, a better QED score, and a favorable logP. Ligand B's very poor logP and low BBB penetration are significant liabilities for a CNS-targeted drug. The negative clearance and half-life values for Ligand A are concerning, but the other properties are more favorable.

Output:
0
2025-04-17 03:41:18,314 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (364.364 Da and 351.451 Da) fall within the ideal range of 200-500 Da.

**TPSA:** Ligand A (87.66) is excellent, falling well below the 90 A^2 threshold for CNS targets. Ligand B (118.4) is still reasonable but less optimal, being closer to the 140 A^2 limit for oral absorption.

**logP:** Both ligands have logP values within the optimal range (1.046 and 1.98 respectively).

**H-Bond Donors/Acceptors:** Both ligands have acceptable HBD (3 and 2) and HBA (4 and 4) counts.

**QED:** Ligand A (0.637) has a better QED score than Ligand B (0.414), indicating a more drug-like profile.

**DILI:** Ligand A (38.736) has a slightly higher DILI risk than Ligand B (20.279), but both are below the concerning threshold of 60.

**BBB:** This is a critical parameter for a CNS target like DRD2. Ligand A (80.419) has a significantly better BBB penetration percentile than Ligand B (36.758). This is a major advantage for Ligand A.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.065 and -5.057), which is unusual and suggests poor permeability. This is a concern for both, but doesn't strongly differentiate them.

**Aqueous Solubility:** Both ligands have negative solubility values (-1.771 and -1.833) which is also unusual and suggests poor solubility. This is a concern for both, but doesn't strongly differentiate them.

**hERG:** Both ligands have very low hERG inhibition liability (0.334 and 0.243), which is excellent.

**Microsomal Clearance:** Ligand A has zero clearance, which is ideal. Ligand B has a clearance of -7.512, which is also very good.

**In vitro Half-Life:** Ligand A has a very long half-life (-18.091), which is extremely favorable. Ligand B has a shorter half-life (-4.747), but still good.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.031 and 0.024), which is beneficial for CNS penetration.

**Binding Affinity:** Ligand A (-9.2 kcal/mol) has a significantly stronger binding affinity than Ligand B (-6.4 kcal/mol). This is a substantial advantage, exceeding the 1.5 kcal/mol difference threshold.

**Conclusion:**

Considering all factors, especially the GPCR-specific priorities, **Ligand A is the more promising drug candidate.** Its superior BBB penetration, significantly stronger binding affinity, and better QED score outweigh the slightly higher DILI risk. The excellent metabolic stability (zero clearance) and long half-life are also very attractive. While both ligands have issues with Caco-2 permeability and solubility, the large difference in binding affinity and BBB penetration makes Ligand A the clear choice.

Output:
1
2025-04-17 03:41:18,315 - INFO - Reasoning:

Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, considering the provided guidelines and GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight (MW):** Both ligands (375.376 and 344.371 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (83.28) is significantly better than Ligand B (113.18). For CNS targets, we want TPSA <= 90, and A is comfortably within that range, while B exceeds it.

**3. logP:** Both ligands have good logP values (2.327 and 1.493), falling within the optimal 1-3 range.

**4. H-Bond Donors (HBD):** Both are acceptable (2 and 3, respectively), staying below the 5 threshold.

**5. H-Bond Acceptors (HBA):** Both are acceptable (6 and 5, respectively), staying below the 10 threshold.

**6. QED:** Ligand A (0.863) has a significantly higher QED score than Ligand B (0.543), indicating better overall drug-likeness.

**7. DILI:** Both have relatively high DILI risk (63.746 and 67.39), but are still below the concerning >60 threshold. This isn't a major differentiator here.

**8. BBB:** Both ligands have similar BBB penetration (64.211 and 65.258). While not exceptional (>70 is desirable), they are reasonable for a CNS target.

**9. Caco-2 Permeability:** Ligand A (-4.881) has better Caco-2 permeability than Ligand B (-5.101). Higher values are better, so A is slightly preferred.

**10. Aqueous Solubility:** Ligand A (-2.757) has better aqueous solubility than Ligand B (-3.36). Higher values are better, so A is preferred.

**11. hERG Inhibition:** Both ligands have low hERG inhibition risk (0.26 and 0.295), which is good.

**12. Microsomal Clearance (Cl_mic):** Ligand A (-2.284) has significantly lower (better) microsomal clearance than Ligand B (18.725). This suggests greater metabolic stability for Ligand A.

**13. In vitro Half-Life:** Ligand A (13.373) has a much longer in vitro half-life than Ligand B (-11.046). This is a significant advantage for Ligand A.

**14. P-gp Efflux:** Both ligands have low P-gp efflux liability (0.143 and 0.041), which is good for CNS penetration.

**15. Binding Affinity:** Ligand B (-8.2 kcal/mol) has a slightly better binding affinity than Ligand A (-7.5 kcal/mol). This is a 0.7 kcal/mol difference, which is significant but may be outweighed by other factors.

**Overall Assessment:**

Ligand A is the stronger candidate. While Ligand B has slightly better binding affinity, Ligand A excels in several critical ADME properties, particularly TPSA, QED, Cl_mic, and t1/2. The lower TPSA is crucial for CNS penetration, and the improved metabolic stability (lower Cl_mic and longer t1/2) will likely translate to better *in vivo* exposure. The higher QED score also suggests a more generally "drug-like" molecule. The slight difference in binding affinity is unlikely to overcome the substantial advantages of Ligand A in ADME/Tox properties, especially for a GPCR target where CNS penetration is important.

Output:
1
2025-04-17 03:41:18,315 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (384.431 and 352.431 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (95.97) is slightly above the optimal <90 for CNS targets, but still reasonable. Ligand B (81.01) is well within the desired range.

**3. logP:** Both ligands have good logP values (2.095 and 1.785), falling within the 1-3 range.

**4. H-Bond Donors:** Ligand A has 0 HBD, which is good. Ligand B has 1 HBD, also acceptable.

**5. H-Bond Acceptors:** Ligand A has 8 HBA, within the acceptable limit of 10. Ligand B has 5 HBA, also within the limit.

**6. QED:** Both ligands have reasonable QED values (0.41 and 0.771), with Ligand B being significantly better.

**7. DILI:** Ligand A has a high DILI risk (97.945), which is concerning. Ligand B has a much lower DILI risk (40.869), which is preferable.

**8. BBB:** Both ligands have acceptable BBB penetration (62.737 and 65.452). While >70 is desirable, these are not disqualifying, and are similar.

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.844 and -4.592). This is unusual and suggests poor permeability. However, negative values are sometimes artifacts of the prediction method.

**10. Aqueous Solubility:** Both ligands have very poor aqueous solubility (-3.239 and -1.905). This is a significant drawback.

**11. hERG Inhibition:** Both ligands have low hERG inhibition risk (0.178 and 0.232).

**12. Microsomal Clearance:** Ligand A has higher microsomal clearance (64.554) than Ligand B (24.962), indicating lower metabolic stability.

**13. In vitro Half-Life:** Ligand A has a longer half-life (49.261) than Ligand B (19.874).

**14. P-gp Efflux:** Both ligands have low P-gp efflux liability (0.454 and 0.065). Ligand B is better.

**15. Binding Affinity:** Ligand A has a slightly better binding affinity (-7.3 kcal/mol) than Ligand B (-6.9 kcal/mol). This is a 0.4 kcal/mol difference, which is not huge, but potentially important.

**Overall Assessment:**

Ligand A has better affinity and half-life, but suffers from a very high DILI risk, higher clearance, and slightly higher TPSA. Ligand B has a better QED score, significantly lower DILI risk, lower clearance, and lower P-gp efflux. Both have poor solubility and permeability.

Given the GPCR-specific priorities, and the importance of minimizing toxicity (DILI) for a CNS drug, Ligand B is the more promising candidate despite the slightly weaker binding affinity. The lower DILI risk and better metabolic stability are crucial advantages. The affinity difference is not large enough to overcome the significant toxicity concern with Ligand A.

Output:
1
2025-04-17 03:41:18,315 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (355.435 Da) and Ligand B (343.471 Da) are comparable.

**TPSA:** Ligand A (88.18) is better than Ligand B (64.41). Both are below the 90 A^2 threshold for CNS targets, but Ligand B is closer to the optimal range.

**logP:** Ligand A (-0.234) is suboptimal, being below 1, which might hinder permeation. Ligand B (2.589) is within the optimal 1-3 range. This is a significant advantage for Ligand B.

**H-Bond Donors/Acceptors:** Ligand A has 1 HBD and 5 HBA, while Ligand B has 0 HBD and 3 HBA. Both are within acceptable limits.

**QED:** Both ligands have similar QED values (0.711 and 0.721), indicating good drug-likeness.

**DILI:** Ligand A (24.622) has a lower DILI risk than Ligand B (17.449), which is favorable.

**BBB:** Ligand B (83.443) has a significantly higher BBB penetration percentile than Ligand A (55.021). This is a crucial advantage for a CNS target like DRD2.

**Caco-2 Permeability:** Ligand A (-4.977) has poor Caco-2 permeability, while Ligand B (-4.467) is slightly better, but still not great.

**Aqueous Solubility:** Ligand A (-0.682) has slightly better aqueous solubility than Ligand B (-2.657).

**hERG Inhibition:** Ligand A (0.072) has a lower hERG inhibition liability than Ligand B (0.462), which is preferable.

**Microsomal Clearance:** Ligand A (3.245) has a lower microsomal clearance than Ligand B (41.617), indicating better metabolic stability.

**In vitro Half-Life:** Ligand A (-2.888) has a longer in vitro half-life than Ligand B (-16.833), which is a significant advantage.

**P-gp Efflux:** Ligand A (0.005) has much lower P-gp efflux liability than Ligand B (0.063), which is highly desirable for CNS penetration.

**Binding Affinity:** Ligand B (-8.2 kcal/mol) has a slightly better binding affinity than Ligand A (-7.1 kcal/mol), exceeding the >1.5 kcal/mol advantage threshold.

**Overall Assessment:**

Ligand B excels in BBB penetration and binding affinity, which are paramount for a CNS GPCR target. While Ligand A has advantages in DILI, metabolic stability, half-life, and P-gp efflux, the superior BBB and affinity of Ligand B outweigh these factors. The logP of Ligand A is a concern. The slightly higher hERG risk for Ligand B is manageable given its strong affinity.

Output:
1
2025-04-17 03:41:18,315 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (359.41 and 345.422 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Both ligands (64.11 and 64.86) are slightly above the optimal <90 for CNS targets, but still reasonably acceptable.

**3. logP:** Ligand A (3.524) is slightly higher than Ligand B (2.221). Both are within the 1-3 optimal range, but A is approaching the upper limit where solubility issues could arise.

**4. H-Bond Donors:** Both have 1 HBD, which is good.

**5. H-Bond Acceptors:** Ligand A has 5 HBA, and Ligand B has 6. Both are acceptable (<=10).

**6. QED:** Ligand B (0.92) has a significantly better QED score than Ligand A (0.548), indicating a more drug-like profile.

**7. DILI:** Ligand A (31.718) has a lower DILI risk than Ligand B (40.132), which is preferable.

**8. BBB:** Ligand B (94.455) has a much higher BBB penetration percentile than Ligand A (87.127). This is a *critical* advantage for a CNS target like DRD2.

**9. Caco-2 Permeability:** Ligand A (-4.892) has worse Caco-2 permeability than Ligand B (-5.005). Both are negative, which is unusual and suggests poor permeability.

**10. Aqueous Solubility:** Ligand A (-3.472) has worse aqueous solubility than Ligand B (-2.853). This is a concern, especially given Ligand A's higher logP.

**11. hERG Inhibition:** Ligand A (0.835) has a slightly higher hERG risk than Ligand B (0.353).

**12. Microsomal Clearance:** Ligand A (70.983) has higher microsomal clearance than Ligand B (26.465), indicating lower metabolic stability.

**13. In vitro Half-Life:** Ligand B (-0.202) has a longer in vitro half-life than Ligand A (7.3).

**14. P-gp Efflux:** Ligand A (0.326) has lower P-gp efflux than Ligand B (0.47), which is beneficial for CNS exposure.

**15. Binding Affinity:** Ligand B (-8.9 kcal/mol) has a slightly better binding affinity than Ligand A (-8.5 kcal/mol). While the difference is not huge, it's still a positive for Ligand B.

**Overall Assessment:**

Ligand B is the stronger candidate. While Ligand A has a slightly better DILI score and P-gp efflux, Ligand B excels in the most critical areas for a CNS GPCR target: **BBB penetration, QED, binding affinity, and metabolic stability (lower Cl_mic and longer t1/2)**. The superior BBB penetration of Ligand B is a decisive factor. The better QED score also suggests a more developable molecule. The slightly better affinity of B also helps.

Output:
1
2025-04-17 03:41:18,316 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (364.324 and 348.447 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (107.55) is slightly above the preferred <90 for CNS targets, but still reasonable. Ligand B (78.68) is excellent, well below 90.

**3. logP:** Both ligands have similar logP values (1.182 and 1.197), falling within the optimal 1-3 range.

**4. H-Bond Donors:** Ligand A has 3 HBD, acceptable. Ligand B has 1 HBD, also acceptable.

**5. H-Bond Acceptors:** Ligand A has 6 HBA, acceptable. Ligand B has 5 HBA, also acceptable.

**6. QED:** Both ligands have good QED scores (0.744 and 0.865), indicating drug-likeness.

**7. DILI:** Ligand A has a DILI risk of 51.881, which is acceptable (below 60). Ligand B has a significantly lower DILI risk of 18.651, which is highly desirable.

**8. BBB:** Ligand A has a BBB penetration of 52.656, which is below the desirable >70 for CNS targets. Ligand B has a much better BBB penetration of 62.97, approaching the desired threshold.

**9. Caco-2 Permeability:** Ligand A has a negative Caco-2 value (-4.735), suggesting poor permeability. Ligand B has a negative Caco-2 value (-5.228), also suggesting poor permeability.

**10. Aqueous Solubility:** Ligand A has a solubility of -2.768, indicating poor solubility. Ligand B has a solubility of -1.021, also indicating poor solubility, but slightly better than Ligand A.

**11. hERG Inhibition:** Ligand A has a hERG inhibition risk of 0.401, which is low and favorable. Ligand B has a very low hERG inhibition risk of 0.108, even more favorable.

**12. Microsomal Clearance:** Ligand A has a high microsomal clearance (7.567), suggesting poor metabolic stability. Ligand B has a very low (negative) clearance (-0.586), indicating excellent metabolic stability.

**13. In vitro Half-Life:** Ligand A has a negative half-life (-35.032), which is not physically meaningful and suggests a very rapid clearance. Ligand B has a short half-life (5.658), but is still better than Ligand A.

**14. P-gp Efflux:** Ligand A has a P-gp efflux of 0.041, indicating low efflux. Ligand B has a very low P-gp efflux (0.033), even more favorable.

**15. Binding Affinity:** Ligand A has a binding affinity of -8.9 kcal/mol, which is excellent. Ligand B has a binding affinity of 0.0 kcal/mol, which is very poor.

**Overall Assessment:**

Ligand A has a significantly better binding affinity, which is a major advantage. However, its poor BBB penetration, high microsomal clearance, and negative half-life are major drawbacks for a CNS-targeting drug. Ligand B has better ADME properties (lower DILI, better BBB, excellent metabolic stability, lower P-gp efflux), but its binding affinity is essentially non-existent.

Given the GPCR-specific priorities, and the fact that a >1.5 kcal/mol advantage in affinity can outweigh ADME drawbacks, Ligand A is the more promising candidate *if* its ADME issues can be addressed through further optimization. The extremely poor affinity of Ligand B makes it unlikely to be a viable starting point, regardless of its ADME profile.

Output:
1
2025-04-17 03:41:18,316 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (359.461 and 354.466 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (52.65) is significantly better than Ligand B (67.43). For CNS targets, we want TPSA <= 90, and ideally closer to 60. Ligand A is much closer to this ideal.

**3. logP:** Both ligands (2.115 and 2.483) are within the optimal 1-3 range.

**4. H-Bond Donors:** Ligand A (1) is preferable to Ligand B (2). Lower HBD generally improves permeability.

**5. H-Bond Acceptors:** Both ligands have 3 HBA, which is acceptable.

**6. QED:** Both ligands have similar QED values (0.79 and 0.77), indicating good drug-likeness.

**7. DILI:** Ligand A (9.965) has a much lower DILI risk than Ligand B (34.471). This is a significant advantage.

**8. BBB:** Ligand A (92.943) has a substantially better BBB penetration percentile than Ligand B (70.803). This is *critical* for a CNS target like DRD2.

**9. Caco-2:** Both ligands have negative Caco-2 values (-4.632 and -4.753), which is unusual and suggests poor permeability. However, the values are similar.

**10. Solubility:** Ligand A (-1.456) is slightly better than Ligand B (-3.005), but both are poor. Solubility is less critical than BBB for CNS drugs, but still a factor.

**11. hERG:** Both ligands have low hERG inhibition risk (0.39 and 0.512).

**12. Cl_mic:** Ligand A (-1.42) has a much lower (better) microsomal clearance than Ligand B (14.724). This indicates better metabolic stability.

**13. t1/2:** Ligand A (-15.171) has a very negative in vitro half-life, which is concerning. Ligand B (22.399) is better, but still not ideal.

**14. Pgp:** Ligand A (0.018) has a much lower P-gp efflux liability than Ligand B (0.202). Lower Pgp is highly desirable for CNS penetration.

**15. Affinity:** Ligand B (-7.4) has a slightly better binding affinity than Ligand A (-8.3). While affinity is important, the difference of 0.9 kcal/mol is not large enough to overcome the significant ADME advantages of Ligand A.

**Overall Assessment:**

Ligand A is significantly superior to Ligand B. It has a much better BBB score, lower DILI risk, lower Pgp efflux, and lower microsomal clearance. While Ligand B has slightly better affinity and in vitro half-life, the ADME properties of Ligand A are far more favorable for a CNS-targeting drug, especially considering the importance of BBB penetration for DRD2. The negative in vitro half-life for Ligand A is a concern, but could potentially be addressed through structural modifications.

Output:
1
2025-04-17 03:41:18,316 - INFO - Reasoning:

Let's analyze Ligand A and Ligand B for their potential as DRD2 drug candidates, considering the provided guidelines and GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (343.431 and 366.571 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (76.18) is better than Ligand B (49.41), both are below the 90 A^2 threshold for CNS targets.

**3. logP:** Ligand A (2.378) is within the optimal 1-3 range. Ligand B (3.638) is slightly higher, but still acceptable.

**4. H-Bond Donors:** Both ligands have 1 HBD, which is within the acceptable limit of <=5.

**5. H-Bond Acceptors:** Ligand A has 6 HBAs, and Ligand B has 3. Both are below the acceptable limit of <=10.

**6. QED:** Ligand A (0.922) has a significantly better QED score than Ligand B (0.474), indicating a more drug-like profile.

**7. DILI:** Both ligands have low DILI risk (35.595 and 31.601 percentiles, respectively), which is good.

**8. BBB:** Ligand B (66.499) has a better BBB penetration score than Ligand A (50.523). While both are not ideal (>70), Ligand B is closer to the desired threshold for a CNS target.

**9. Caco-2 Permeability:** Ligand A (-5.476) has a worse Caco-2 permeability than Ligand B (-4.747), indicating lower intestinal absorption.

**10. Aqueous Solubility:** Ligand A (-1.845) has a worse aqueous solubility than Ligand B (-4.336).

**11. hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.148 and 0.208, respectively).

**12. Microsomal Clearance:** Ligand A (-6.197) has a significantly lower (better) microsomal clearance than Ligand B (82.786), indicating greater metabolic stability.

**13. In vitro Half-Life:** Ligand A (15.805 hours) has a shorter half-life than Ligand B (22.402 hours).

**14. P-gp Efflux:** Ligand A (0.025) has a much lower P-gp efflux liability than Ligand B (0.156), which is crucial for CNS penetration.

**15. Binding Affinity:** Ligand B (-7.1 kcal/mol) has a slightly better binding affinity than Ligand A (-8.0 kcal/mol). However, the difference is small.

**Overall Assessment:**

Considering the GPCR-specific priorities, Ligand A is the better candidate. While Ligand B has a better BBB score and binding affinity, Ligand A excels in crucial areas like QED, metabolic stability (Cl_mic), and P-gp efflux. The lower P-gp efflux of Ligand A is particularly important for CNS targets, as it will lead to higher brain exposure. The significantly better QED score suggests a more developable molecule. The slightly lower binding affinity of Ligand A is less concerning given its superior ADME properties.

Output:
1
2025-04-17 03:41:18,316 - INFO - Batch 50 complete. Total preferences: 800
2025-04-17 03:41:18,316 - INFO - Processing batch 51/512...
2025-04-17 03:41:59,361 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (340.47 and 356.39 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (46.34) is significantly better than Ligand B (58.2).  For CNS targets, we want TPSA <= 90, and ideally closer to 60. Ligand A is much closer to the ideal.

**logP:** Both ligands have acceptable logP values (4.375 and 3.005, respectively), falling within the 1-3 range. Ligand B is slightly better here.

**H-Bond Donors/Acceptors:** Ligand A (0 HBD, 3 HBA) is preferable to Ligand B (2 HBD, 2 HBA) as fewer hydrogen bonds generally improve BBB penetration.

**QED:** Both ligands have similar QED values (0.833 and 0.789), indicating good drug-likeness.

**DILI:** Both ligands have low DILI risk (34.82 and 30.05 percentiles), which is good.

**BBB:** Both ligands have excellent BBB penetration (88.872 and 85.964 percentiles), exceeding the desirable >70 threshold.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.588 and -4.58), which is unusual and suggests poor permeability. This is a significant concern for both.

**Aqueous Solubility:** Both ligands have very poor aqueous solubility (-5.23 and -3.831). This is a major drawback.

**hERG Inhibition:** Ligand A (0.854) is slightly better than Ligand B (0.544), indicating a lower risk of cardiotoxicity.

**Microsomal Clearance:** Ligand A (102.548) has higher clearance than Ligand B (43.405). Higher clearance means faster metabolism and potentially lower exposure. Ligand B is better here.

**In vitro Half-Life:** Ligand A (-16.562) has a shorter half-life than Ligand B (-9.266). This is unfavorable.

**P-gp Efflux:** Both ligands show good P-gp efflux profiles (0.796 and 0.07). Lower values are better, so Ligand B is preferable.

**Binding Affinity:** Both ligands have similar, strong binding affinities (-9.9 and -8.9 kcal/mol). The difference of 1 kcal/mol is not substantial enough to override other factors.

**Overall Assessment:**

Ligand A excels in TPSA and H-bonding, but suffers from higher clearance and shorter half-life. Ligand B has better logP, P-gp efflux, and metabolic stability. However, the TPSA is higher, and the H-bonding profile is less favorable. Both have poor solubility and Caco-2 permeability. Given the importance of BBB penetration for a CNS target like DRD2, and the relatively small difference in binding affinity, the slightly better TPSA and H-bonding of Ligand A, combined with acceptable BBB, make it marginally more promising. However, the poor solubility and permeability of both are serious concerns.

Output:
0
2025-04-17 03:41:59,362 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (346.5 and 351.4 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (49.41) is excellent, well below the 90 target for CNS drugs. Ligand B (87.74) is higher, but still potentially acceptable, though less ideal.

**logP:** Ligand A (3.524) is optimal. Ligand B (0.435) is quite low, potentially hindering membrane permeability and CNS penetration.

**H-Bond Donors/Acceptors:** Ligand A (HBD=1, HBA=2) and Ligand B (HBD=2, HBA=4) both have reasonable numbers of H-bond donors and acceptors, falling within the acceptable limits.

**QED:** Both ligands (A=0.513, B=0.68) have good drug-likeness scores.

**DILI:** Ligand A (11.13) has a very low DILI risk, significantly better than Ligand B (20.98).

**BBB:** Ligand A (76.31) has a good BBB penetration score, exceeding the 70% threshold for CNS targets. Ligand B (59.75) is lower, which is a significant concern for a CNS target like DRD2.

**Caco-2 Permeability:** Ligand A (-4.966) has poor Caco-2 permeability. Ligand B (-5.102) is similarly poor.

**Aqueous Solubility:** Both ligands have very poor aqueous solubility (-3.418 and -1.32 respectively). This could pose formulation challenges.

**hERG:** Ligand A (0.63) has a low hERG risk, while Ligand B (0.117) has a very low hERG risk. Both are acceptable.

**Microsomal Clearance:** Ligand A (68.215) has moderate clearance. Ligand B (-9.038) has *negative* clearance, which is unrealistic and likely an artifact of the prediction method, and suggests very high metabolic stability.

**In vitro Half-Life:** Ligand A (-15.275) has a negative half-life, which is unrealistic. Ligand B (7.285) has a reasonable half-life.

**P-gp Efflux:** Ligand A (0.405) has low P-gp efflux, which is good. Ligand B (0.007) has very low P-gp efflux, even better.

**Binding Affinity:** Ligand A (-8.5 kcal/mol) has a significantly stronger binding affinity than Ligand B (-7.7 kcal/mol). This 1.8 kcal/mol difference is substantial and can outweigh some ADME drawbacks.

**Overall Assessment:**

Ligand A is superior despite the poor Caco-2 and unrealistic half-life. Its strong affinity, good BBB penetration, low DILI risk, and acceptable logP and TPSA make it a more promising candidate. The negative half-life and Caco-2 values are concerning, but could be addressed through structural modifications. Ligand B's low logP is a major drawback for CNS penetration, and while it has excellent P-gp properties and low DILI, the weaker binding affinity and unrealistic clearance/half-life values are problematic.

Output:
1
2025-04-17 03:41:59,362 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (381.929 Da) is slightly higher than Ligand B (347.379 Da), but both are acceptable.

**TPSA:** Ligand A (63.25) is excellent for CNS penetration, well below the 90 A^2 threshold. Ligand B (137.82) is higher, approaching the 140 A^2 limit for oral absorption and potentially hindering BBB penetration.

**logP:** Ligand A (4.492) is a bit high, potentially leading to solubility issues or off-target interactions. Ligand B (-0.621) is too low, which could impede membrane permeability and reduce CNS exposure.

**H-Bond Donors/Acceptors:** Ligand A (2 HBD, 4 HBA) and Ligand B (4 HBD, 7 HBA) are both within acceptable limits.

**QED:** Both ligands have reasonable QED values (Ligand A: 0.742, Ligand B: 0.527), indicating good drug-like properties.

**DILI:** Both ligands have similar DILI risk (Ligand A: 64.521, Ligand B: 60.644), placing them in the moderate risk category.

**BBB:** This is a critical parameter for a CNS target. Ligand A has a much better BBB percentile (33.579) than Ligand B (13.222), although both are below the desirable >70 threshold. Ligand A is significantly more likely to cross the BBB.

**Caco-2 Permeability:** Ligand A (-4.759) and Ligand B (-5.844) both have negative Caco-2 values, indicating poor permeability.

**Aqueous Solubility:** Both ligands have poor aqueous solubility (Ligand A: -5.104, Ligand B: -1.907).

**hERG Inhibition:** Both ligands show very low hERG inhibition liability (Ligand A: 0.254, Ligand B: 0.031).

**Microsomal Clearance:** Ligand B (-29.997) has significantly lower (better) microsomal clearance than Ligand A (82.358), suggesting greater metabolic stability.

**In vitro Half-Life:** Ligand B (4.362) has a slightly longer half-life than Ligand A (33.802), but both are relatively short.

**P-gp Efflux:** Ligand A (0.294) has lower P-gp efflux than Ligand B (0.005), which is favorable for CNS exposure.

**Binding Affinity:** Ligand B (-9.0 kcal/mol) has a significantly stronger binding affinity than Ligand A (-8.7 kcal/mol). This is a substantial advantage.

**Overall Assessment:**

Ligand B has a much stronger binding affinity and better metabolic stability. However, its low logP and poor BBB penetration are major drawbacks for a CNS-targeting drug. Ligand A, while having a weaker affinity, has a much better TPSA and BBB percentile, and a more reasonable (though still high) logP. Considering the GPCR-specific priorities, especially BBB penetration for a CNS target like DRD2, Ligand A is the more promising candidate, despite its weaker binding. The affinity difference (0.3 kcal/mol) is not large enough to overcome the significant permeability and CNS exposure issues of Ligand B. Further optimization of Ligand A to improve its affinity could yield a viable drug candidate.

Output:
0
2025-04-17 03:41:59,362 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (342.443 Da) is slightly better positioned.

**TPSA:** Ligand A (89.78) is excellent for CNS penetration, falling well below 90. Ligand B (104.45) is still reasonable, but less optimal.

**logP:** Ligand A (3.014) is optimal. Ligand B (-0.207) is significantly lower, which could hinder membrane permeability and CNS entry.

**H-Bond Donors/Acceptors:** Ligand A (4 HBD, 2 HBA) and Ligand B (1 HBD, 8 HBA) both fall within acceptable ranges, although Ligand B has a higher HBA count.

**QED:** Both ligands have good QED scores (A: 0.691, B: 0.787), indicating drug-like properties.

**DILI:** Both ligands have acceptable DILI risk (A: 54.207, B: 47.421), below the 60 threshold.

**BBB:** Ligand A (61.613) is better than Ligand B (32.92), though both are not ideal. For a CNS target like DRD2, a BBB percentile >70 is highly desirable.

**Caco-2 Permeability:** Ligand A (-4.89) is poor, indicating low intestinal absorption. Ligand B (-5.023) is also poor.

**Aqueous Solubility:** Ligand A (-4.611) and Ligand B (-1.769) are both poor, which could present formulation challenges.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (A: 0.491, B: 0.103).

**Microsomal Clearance:** Ligand A (4.832) has lower clearance, suggesting better metabolic stability than Ligand B (9.46).

**In vitro Half-Life:** Ligand A (24.757 hours) has a longer half-life than Ligand B (20.927 hours).

**P-gp Efflux:** Both ligands show very low P-gp efflux liability (A: 0.303, B: 0.152), which is favorable for CNS penetration.

**Binding Affinity:** Ligand B (-7.8 kcal/mol) has significantly stronger binding affinity than Ligand A (0 kcal/mol). This is a substantial advantage.

**Overall Assessment:**

Ligand B's significantly stronger binding affinity (-7.8 kcal/mol vs 0 kcal/mol) is a major advantage that could potentially outweigh some of its ADME drawbacks. However, its low logP (-0.207) is a serious concern for CNS penetration. Ligand A has better logP and BBB, but its binding affinity is very weak. Considering the GPCR-specific priorities, and the importance of affinity, the stronger binding of Ligand B is the deciding factor, despite its lower logP. Optimization of Ligand B to improve its logP would be a logical next step.

Output:
1
2025-04-17 03:41:59,362 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (362.415 and 352.435 Da) are within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (114.1) is slightly above the preferred <90 for CNS targets, but still reasonable. Ligand B (85.69) is well within the ideal range. This favors Ligand B.

**3. logP:** Ligand A (1.4) is within the optimal range (1-3). Ligand B (0.692) is a bit low, potentially hindering permeability. This favors Ligand A.

**4. H-Bond Donors:** Both ligands have 1 HBD, which is acceptable.

**5. H-Bond Acceptors:** Ligand A has 8 HBAs, within the acceptable limit. Ligand B has 6 HBAs, also acceptable.

**6. QED:** Ligand A (0.855) has a significantly better QED score than Ligand B (0.696), indicating better overall drug-likeness. This favors Ligand A.

**7. DILI:** Ligand A (86.972) has a higher DILI risk than Ligand B (31.02). This strongly favors Ligand B.

**8. BBB:** Ligand A (29.508) has a very poor BBB percentile, making CNS penetration unlikely. Ligand B (64.831) is better, but still not ideal (target >70). This *strongly* favors Ligand B.

**9. Caco-2:** Ligand A (-5.577) has a very poor Caco-2 permeability, suggesting poor absorption. Ligand B (-4.848) is also poor, but slightly better.

**10. Solubility:** Ligand A (-2.962) has poor solubility. Ligand B (-0.933) is also poor, but better than Ligand A. This favors Ligand B.

**11. hERG:** Both ligands have very low hERG inhibition risk (0.004 and 0.133, respectively).

**12. Cl_mic:** Ligand A (3.154) has a lower microsomal clearance, indicating better metabolic stability, than Ligand B (42.585). This favors Ligand A.

**13. t1/2:** Ligand A (-6.723) has a negative in vitro half-life, which is not possible. This is a significant red flag. Ligand B (-2.395) is also negative, but less so.

**14. Pgp:** Both ligands have very low P-gp efflux liability (0.049 and 0.024, respectively).

**15. Binding Affinity:** Both ligands have very similar and excellent binding affinities (-7.5 and -7.4 kcal/mol). The difference is negligible.

**Overall Assessment:**

Despite Ligand A having a slightly better QED and metabolic stability, the critical issues of extremely poor BBB penetration, poor Caco-2 permeability, poor solubility, and a nonsensical half-life make it a very poor candidate. Ligand B, while not perfect, has a significantly better profile, particularly regarding BBB penetration and DILI risk, which are crucial for a CNS-targeting GPCR. The slightly lower logP and solubility are less concerning than the severe issues with Ligand A.

Output:
1
2025-04-17 03:41:59,363 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (375.255 Da) is slightly better, being closer to the lower end which can aid permeability.

**TPSA:** Ligand A (75.35) is better than Ligand B (62.3). For CNS targets, we want TPSA <= 90, both are within range, but A is slightly higher.

**logP:** Both ligands have good logP values (A: 4.192, B: 3.887) falling within the optimal 1-3 range, though A is slightly higher.

**H-Bond Donors/Acceptors:** Ligand A (HBD=3, HBA=3) is slightly better than Ligand B (HBD=1, HBA=6). Both are acceptable, but A's profile is more balanced.

**QED:** Both ligands have good QED scores (A: 0.599, B: 0.706), indicating good drug-like properties. B is slightly better here.

**DILI:** Both ligands have relatively high DILI risk (A: 75.339, B: 82.823). This is a concern for both, but B is slightly higher.

**BBB:** Ligand B (68.282) has a better BBB percentile than Ligand A (57.58). This is a *critical* factor for a CNS target like DRD2.

**Caco-2 Permeability:** Ligand A (-4.844) has better Caco-2 permeability than Ligand B (-5.355).

**Aqueous Solubility:** Both ligands have poor aqueous solubility (A: -4.745, B: -4.854). This could pose formulation challenges.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (A: 0.885, B: 0.795).

**Microsomal Clearance:** Ligand A (20.496) has significantly lower microsomal clearance than Ligand B (61.913), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (97.124) has a much longer in vitro half-life than Ligand B (31.928), which is a significant advantage.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (A: 0.615, B: 0.567).

**Binding Affinity:** Ligand A (-9.5 kcal/mol) has a slightly better binding affinity than Ligand B (-8.8 kcal/mol). This difference of 0.7 kcal/mol is meaningful.

**Overall Assessment:**

While Ligand B has a better BBB score and QED, Ligand A demonstrates superior metabolic stability (lower Cl_mic, longer t1/2), better Caco-2 permeability, and a slightly stronger binding affinity. The difference in binding affinity, combined with the improved ADME properties, outweighs the slightly lower BBB score of Ligand A. Given the GPCR-specific focus on BBB, logP, Pgp, TPSA, and affinity, the combination of strong affinity and favorable ADME properties makes Ligand A the more promising candidate.

Output:
0
2025-04-17 03:41:59,363 - INFO - Okay, let's analyze these two ligands for their potential as DRD2 drug candidates.

**Step-by-step comparison:**

1. **MW:** Both ligands (A: 366.849 Da, B: 363.384 Da) fall within the ideal 200-500 Da range. No significant difference here.

2. **TPSA:** Both are reasonably good (A: 97.55, B: 98.17).  For a CNS target like DRD2, we ideally want <90, but these are close enough and not disqualifying.

3. **logP:** Ligand A (2.447) is slightly better than Ligand B (3.019). Both are within the optimal 1-3 range, but B is edging towards the higher end, potentially increasing off-target interactions.

4. **HBD:** Ligand A (2) is slightly higher than Ligand B (1). Both are acceptable, below the threshold of 5.

5. **HBA:** Ligand A (5) is higher than Ligand B (3). Both are below the threshold of 10.

6. **QED:** Ligand A (0.783) is significantly better than Ligand B (0.279). A higher QED suggests a more drug-like profile. This is a substantial advantage for A.

7. **DILI:** Ligand A (47.77) has a higher DILI risk than Ligand B (27.181). B is preferable here, being well below the 40% threshold.

8. **BBB:** Ligand B (88.91) has a much better BBB penetration score than Ligand A (70.609). For a CNS target, this is *critical*. B is excellent (>70), while A is just acceptable.

9. **Caco-2:** Ligand A (-4.842) is better than Ligand B (-4.651). Higher values are better, suggesting better intestinal absorption.

10. **Solubility:** Ligand A (-4.024) is better than Ligand B (-2.519). Higher values are better.

11. **hERG:** Ligand A (0.318) is better than Ligand B (0.602). Lower values are preferred to reduce cardiotoxicity risk.

12. **Cl_mic:** Ligand A (13.274) has a significantly lower (better) microsomal clearance than Ligand B (30.165). This indicates better metabolic stability for A.

13. **t1/2:** Ligand A (-7.704) has a much longer in vitro half-life than Ligand B (-12.412). This is a significant advantage for A, potentially allowing for less frequent dosing.

14. **Pgp:** Ligand A (0.015) has a much lower Pgp efflux liability than Ligand B (0.059). Lower efflux is crucial for CNS exposure.

15. **Binding Affinity:** Ligand A (-8.1) has a slightly better binding affinity than Ligand B (-7.0). While both are good, A has a clear advantage.

**GPCR-Specific Priorities:**

For DRD2 (a GPCR), BBB, logP, Pgp, TPSA, and affinity are paramount. Ligand B excels in BBB penetration, which is a major advantage. However, Ligand A has a significantly better QED, metabolic stability (Cl_mic, t1/2), Pgp efflux, hERG risk, and a slightly better binding affinity. The combination of these factors outweighs the BBB advantage of Ligand B.

**Conclusion:**

Considering the overall profile, particularly the crucial CNS-related properties and the strong drug-like characteristics of Ligand A, it is the more promising drug candidate.

Output:
1
2025-04-17 03:41:59,363 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (346.402 and 349.431 Da) fall comfortably within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (58.64) is significantly better than Ligand B (84.67). For CNS targets, we ideally want TPSA <= 90, and A is much closer to the optimal <=60 range. B is pushing the upper limit.

**3. logP:** Both ligands have similar logP values (2.202 and 2.23), falling within the optimal 1-3 range.

**4. H-Bond Donors:** Both have 1 HBD, which is good.

**5. H-Bond Acceptors:** Ligand A has 3 HBA, while Ligand B has 5. Both are acceptable (<=10), but A is slightly better.

**6. QED:** Ligand B (0.881) has a higher QED score than Ligand A (0.635), suggesting a more generally drug-like profile. However, QED is less critical than other factors for CNS targets.

**7. DILI:** Ligand A (37.96) has a lower DILI risk than Ligand B (49.477), which is preferable. Both are below the concerning threshold of 60.

**8. BBB:** Both ligands have excellent BBB penetration (84.529 and 80.651). This is a crucial factor for DRD2, and they are both above the desirable 70% threshold.

**9. Caco-2 Permeability:** Both have negative Caco-2 values (-4.646 and -4.547). This is unusual and suggests poor permeability. However, the absolute value is similar for both.

**10. Aqueous Solubility:** Both have negative solubility values (-2.486 and -3.032), indicating poor aqueous solubility. This is a concern, but can sometimes be mitigated with formulation strategies.

**11. hERG Inhibition:** Ligand A (0.769) has a slightly lower hERG inhibition risk than Ligand B (0.38), which is preferred.

**12. Microsomal Clearance:** Ligand A (31.456) has a higher microsomal clearance than Ligand B (21.677), indicating lower metabolic stability. This is a disadvantage for A.

**13. In vitro Half-Life:** Ligand B (-7.435) has a significantly longer in vitro half-life than Ligand A (-0.624). This is a major advantage for B.

**14. P-gp Efflux:** Ligand A (0.299) has lower P-gp efflux than Ligand B (0.14), which is beneficial for CNS exposure.

**15. Binding Affinity:** Ligand B (-8.7 kcal/mol) has a slightly better binding affinity than Ligand A (-9.4 kcal/mol). While both are excellent, the difference is small.

**Overall Assessment:**

Ligand A excels in TPSA, P-gp efflux, and DILI risk. However, Ligand B has a significantly longer half-life, better QED, and slightly better binding affinity. The biggest drawback of Ligand A is its higher microsomal clearance. Given the importance of metabolic stability for *in vivo* efficacy, and the fact that both ligands have good BBB penetration and acceptable logP values, **Ligand B is the more promising drug candidate.**

Output:
1
2025-04-17 03:41:59,363 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (335.407 and 345.359 Da) fall within the ideal range of 200-500 Da.

**TPSA:** Ligand A (61.44) is excellent, well below the 90 A^2 threshold for CNS targets. Ligand B (112.4) is higher, but still potentially acceptable, though less ideal.

**logP:** Ligand A (2.898) is optimal (1-3). Ligand B (0.443) is quite low, potentially hindering permeation.

**H-Bond Donors/Acceptors:** Ligand A (HBD=2, HBA=3) is good. Ligand B (HBD=1, HBA=6) is also reasonable.

**QED:** Both ligands have good QED scores (A: 0.907, B: 0.845), indicating drug-like properties.

**DILI:** Both have elevated DILI risk (A: 71.268, B: 79.449), but below the concerning >60 threshold.

**BBB:** Ligand A (75.145) has a good BBB percentile, desirable for a CNS target. Ligand B (34.975) has a very low BBB percentile, a significant drawback.

**Caco-2 Permeability:** Ligand A (-4.803) and Ligand B (-5.181) both have negative values, which is unusual and suggests very poor permeability. This is a red flag for both.

**Aqueous Solubility:** Ligand A (-4.831) and Ligand B (-2.238) both have negative solubility values, indicating poor solubility.

**hERG Inhibition:** Ligand A (0.598) has a low hERG risk, which is good. Ligand B (0.142) also shows a low hERG risk.

**Microsomal Clearance:** Ligand A (2.846) has a lower clearance, suggesting better metabolic stability, which is preferable. Ligand B (10.204) has a higher clearance, indicating faster metabolism.

**In vitro Half-Life:** Ligand A (21.506 hours) has a longer half-life, which is beneficial. Ligand B (-22.483 hours) has a negative half-life, which is not physically possible and indicates a problem with the data or the molecule's stability.

**P-gp Efflux:** Ligand A (0.221) has lower P-gp efflux, which is good for CNS penetration. Ligand B (0.047) also has low P-gp efflux.

**Binding Affinity:** Ligand A (-9.6 kcal/mol) has a significantly stronger binding affinity than Ligand B (0.0 kcal/mol). This is a crucial advantage.

**Overall Assessment:**

Ligand A is clearly superior. While both have issues with Caco-2 permeability and solubility, Ligand A's significantly better BBB penetration, metabolic stability, longer half-life, and *much* stronger binding affinity outweigh its drawbacks. Ligand B's extremely low BBB penetration and negative half-life are dealbreakers. The large difference in binding affinity is also a major factor.

Output:
1
2025-04-17 03:41:59,363 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (344.365 and 346.475 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (51.97) is significantly better than Ligand B (58.44). For CNS targets, we want TPSA <= 90, and ideally lower. Ligand A is closer to the ideal range.

**3. logP:** Ligand A (3.653) is slightly higher than Ligand B (2.452), both are within the optimal 1-3 range, but A is closer to the upper limit.

**4. H-Bond Donors:** Ligand A (1) is better than Ligand B (0). While both are acceptable, fewer HBDs generally improve permeability.

**5. H-Bond Acceptors:** Ligand A (5) is slightly higher than Ligand B (4). Both are within the acceptable limit of <= 10.

**6. QED:** Both ligands have good QED values (0.694 and 0.823, respectively), indicating good drug-like properties.

**7. DILI:** Ligand B (38.503) has a much lower DILI risk than Ligand A (78.829). This is a significant advantage for Ligand B.

**8. BBB:** Ligand B (86.157) has a substantially higher BBB penetration percentile than Ligand A (61.846). This is *critical* for a CNS target like DRD2.

**9. Caco-2 Permeability:** Both have negative values (-4.697 and -4.525), which is unusual and difficult to interpret without further context. However, the values are very similar.

**10. Aqueous Solubility:** Both have negative values (-4.022 and -2.76). Again, unusual and difficult to interpret. Ligand B is slightly better.

**11. hERG Inhibition:** Both ligands have low hERG inhibition risk (0.786 and 0.721).

**12. Microsomal Clearance:** Ligand B (66.712) has lower microsomal clearance than Ligand A (96.389), suggesting better metabolic stability.

**13. In vitro Half-Life:** Ligand B (-6.135) has a much longer in vitro half-life than Ligand A (1.279). This is a significant advantage.

**14. P-gp Efflux:** Ligand A (0.598) has lower P-gp efflux than Ligand B (0.385), which is favorable for CNS penetration.

**15. Binding Affinity:** Ligand A (-9.8 kcal/mol) has a significantly stronger binding affinity than Ligand B (-7.0 kcal/mol). This is a substantial advantage, potentially outweighing some ADME drawbacks.

**Overall Assessment:**

While Ligand A has a superior binding affinity, Ligand B demonstrates a much more favorable ADME profile, particularly regarding BBB penetration (86.157 vs 61.846), DILI risk (38.503 vs 78.829), and metabolic stability (lower Cl_mic and longer t1/2). For a CNS target like DRD2, BBB penetration is paramount. The 2.8 kcal/mol difference in binding affinity, while significant, might be overcome with further optimization of Ligand B. The lower DILI and better metabolic properties of Ligand B also contribute to its higher probability of success.

Output:
1
2025-04-17 03:41:59,364 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (358.341 and 346.475 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (95.94) is slightly above the preferred <90 for CNS targets, while Ligand B (87.46) is comfortably below. This gives a slight edge to Ligand B.

**3. logP:** Both ligands have good logP values (1.309 and 1.885), falling within the optimal 1-3 range.

**4. H-Bond Donors:** Ligand A (2) and Ligand B (3) are both acceptable, being less than 5.

**5. H-Bond Acceptors:** Ligand A (5) and Ligand B (4) are both acceptable, being less than 10.

**6. QED:** Both ligands have similar QED values (0.611 and 0.596), indicating good drug-like properties.

**7. DILI:** Ligand A (57.348) has a higher DILI risk than Ligand B (28.577). This is a significant advantage for Ligand B.

**8. BBB:** Ligand B (71.307) has a substantially better BBB penetration percentile than Ligand A (43.311). This is *critical* for a CNS target like DRD2.

**9. Caco-2 Permeability:** Ligand A (-4.352) has a worse Caco-2 permeability than Ligand B (-5.358). Lower values indicate lower permeability.

**10. Aqueous Solubility:** Ligand A (-2.313) has a worse aqueous solubility than Ligand B (-1.602). Lower values indicate lower solubility.

**11. hERG Inhibition:** Both ligands have similar, low hERG inhibition liabilities (0.331 and 0.641).

**12. Microsomal Clearance:** Ligand B (-10.08) has significantly lower (better) microsomal clearance than Ligand A (60.092), indicating greater metabolic stability.

**13. In vitro Half-Life:** Ligand B (7.077) has a longer in vitro half-life than Ligand A (24.536).

**14. P-gp Efflux:** Both ligands have very low P-gp efflux liabilities (0.047 and 0.032).

**15. Binding Affinity:** Both ligands have identical binding affinities (-8.2 kcal/mol), so this parameter doesn't differentiate them.

**Overall Assessment:**

Ligand B consistently outperforms Ligand A in several key ADME properties crucial for a CNS-targeting GPCR ligand. Specifically, its superior BBB penetration, lower DILI risk, improved metabolic stability (lower Cl_mic and longer t1/2), and better solubility are significant advantages. While Ligand A's TPSA is slightly better, the other benefits of Ligand B outweigh this minor difference.

Output:
1
2025-04-17 03:41:59,364 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (364.417 Da) is slightly higher than Ligand B (347.423 Da), but both are acceptable.

**TPSA:** Ligand A (40.62) is excellent for CNS penetration, well below the 90 Angstrom threshold. Ligand B (116.11) is higher, but still potentially acceptable, though less ideal.

**logP:** Both ligands have good logP values (A: 2.942, B: 2.295), falling within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A (0 HBD, 3 HBA) is better than Ligand B (1 HBD, 6 HBA) in terms of balancing solubility and permeability. Lower counts are generally preferred.

**QED:** Ligand A (0.84) has a significantly better QED score than Ligand B (0.498), indicating a more drug-like profile.

**DILI:** Ligand B (38.736) has a lower DILI risk than Ligand A (61.884), which is a positive attribute.

**BBB:** Ligand A (89.841) has a much higher BBB penetration percentile than Ligand B (44.591). This is *critical* for a CNS target like DRD2.

**Caco-2 Permeability:** Ligand A (-4.484) has a negative Caco-2 value, which is unusual and suggests poor permeability. Ligand B (-5.011) is also negative and similarly poor.

**Aqueous Solubility:** Ligand A (-3.632) and Ligand B (-1.11) both have negative solubility values, indicating poor aqueous solubility.

**hERG:** Both ligands have low hERG risk (A: 0.668, B: 0.355).

**Microsomal Clearance:** Ligand B (-1.301) has a negative clearance, which is not physically possible and likely an error in the data. Ligand A (49.72) is a reasonable value, suggesting moderate metabolic stability.

**In vitro Half-Life:** Ligand A (-32.462) has a negative half-life, which is not physically possible and likely an error in the data. Ligand B (2.467) has a very short half-life, which is undesirable.

**P-gp Efflux:** Ligand A (0.522) has lower P-gp efflux liability than Ligand B (0.009), which is favorable for CNS exposure.

**Binding Affinity:** Ligand B (-7.5 kcal/mol) has a significantly better binding affinity than Ligand A (-9.5 kcal/mol). This is a substantial advantage.

**Overall Assessment:**

Despite the strong affinity of Ligand B, the issues with its calculated properties (negative clearance and half-life) are concerning and suggest potential data errors. Ligand A has a much better predicted BBB penetration, QED, and P-gp efflux profile, which are crucial for CNS drug development. While its solubility and Caco-2 permeability are poor, these can potentially be addressed through formulation strategies. The negative half-life for Ligand A is also a data quality concern. However, given the critical importance of BBB penetration for a DRD2 ligand, and the more reasonable overall profile of Ligand A (despite its flaws), it is the more promising candidate.

Output:
0
2025-04-17 03:41:59,364 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (366.799 and 362.792 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (72.11) is significantly better than Ligand B (90.04). For CNS targets, we want TPSA <= 90, so Ligand A is preferable.

**3. logP:** Both ligands have acceptable logP values (3.21 and 3.621), falling within the 1-3 range.

**4. H-Bond Donors:** Ligand A (1) is better than Ligand B (4). Fewer HBDs generally improve permeability.

**5. H-Bond Acceptors:** Ligand A (4) is slightly better than Ligand B (3). Both are within the acceptable range.

**6. QED:** Both ligands have good QED values (0.905 and 0.571), indicating drug-likeness. Ligand A is superior.

**7. DILI:** Ligand A (61.07) has a slightly higher DILI risk than Ligand B (72.082), but both are reasonably acceptable.

**8. BBB:** This is a crucial parameter for CNS targets. Ligand A (86.545) has a much higher BBB percentile than Ligand B (26.483). This is a major advantage for Ligand A.

**9. Caco-2 Permeability:** Ligand A (-4.915) is better than Ligand B (-5.325), indicating better intestinal absorption.

**10. Aqueous Solubility:** Ligand A (-4.155) is better than Ligand B (-3.846).

**11. hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.567 and 0.577).

**12. Microsomal Clearance:** Ligand A (10.418) has lower microsomal clearance than Ligand B (22.92), suggesting better metabolic stability.

**13. In vitro Half-Life:** Ligand A (-13.678) has a longer in vitro half-life than Ligand B (-5.731).

**14. P-gp Efflux:** Ligand A (0.094) has lower P-gp efflux than Ligand B (0.155), which is beneficial for CNS exposure.

**15. Binding Affinity:** Ligand B (-9.6 kcal/mol) has a slightly better binding affinity than Ligand A (-7.9 kcal/mol). However, the difference is not substantial enough to outweigh the significant advantages of Ligand A in ADME properties, especially BBB penetration.

**Overall Assessment:**

Ligand A is significantly better overall due to its superior TPSA, BBB, HBD, QED, metabolic stability (lower Cl_mic, longer t1/2), lower P-gp efflux, and better solubility. While Ligand B has slightly better binding affinity, the ADME profile of Ligand A is far more favorable for a CNS-targeting drug. The substantial difference in BBB penetration is the deciding factor.

Output:
0
2025-04-17 03:41:59,364 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (346.519 and 344.459 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (48.47) is excellent, well below the 90 Angstroms threshold for CNS targets. Ligand B (75.19) is higher but still acceptable, though less ideal.

**logP:** Ligand A (3.265) is optimal (1-3). Ligand B (2.046) is slightly lower, but still within a reasonable range.

**H-Bond Donors/Acceptors:** Both ligands have 1 HBD and a reasonable number of HBAs (3 and 4 respectively), satisfying the <5 HBD and <10 HBA guidelines.

**QED:** Both ligands have good QED scores (0.707 and 0.857), indicating good drug-like properties.

**DILI:** Ligand A (5.777) has a very low DILI risk, significantly better than Ligand B (29.042).

**BBB:** Both ligands have good BBB penetration (84.8% and 75.3%), both exceeding the 70% threshold for CNS targets. Ligand A is slightly better.

**Caco-2 Permeability:** Ligand A (-4.611) has poor Caco-2 permeability, which is concerning. Ligand B (-5.021) is also poor, but slightly worse.

**Aqueous Solubility:** Both ligands have very poor aqueous solubility (-0.872 and -1.571). This is a significant drawback for both.

**hERG Inhibition:** Ligand A (0.809) has a low hERG risk. Ligand B (0.286) has an even lower risk, which is excellent.

**Microsomal Clearance:** Both ligands have similar microsomal clearance (22.676 and 22.837 mL/min/kg), suggesting comparable metabolic stability.

**In vitro Half-Life:** Ligand A (74.493 hours) has a much longer in vitro half-life than Ligand B (-11.131 hours). This is a major advantage for Ligand A.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.022 and 0.034), which is favorable for CNS penetration.

**Binding Affinity:** Ligand A (-7.6 kcal/mol) has a significantly stronger binding affinity than Ligand B (-8.9 kcal/mol). This is a substantial advantage.

**Overall Assessment:**

Ligand A is the stronger candidate. While both have poor solubility and Caco-2 permeability, Ligand A's significantly better binding affinity (-7.6 vs -8.9 kcal/mol), lower DILI risk, and substantially longer half-life outweigh the slightly higher TPSA and slightly lower BBB. The strong binding affinity is particularly important for a GPCR target, and the longer half-life could translate to less frequent dosing.

Output:
1
2025-04-17 03:41:59,365 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (364.383 and 356.348 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (41.57) is significantly better than Ligand B (60.25). For CNS targets, we want TPSA <= 90, and ideally closer to 60. Ligand A is much closer to this ideal.

**3. logP:** Ligand A (4.372) is slightly higher than the optimal 1-3 range, but still potentially acceptable. Ligand B (2.108) is within the optimal range. However, for a GPCR, a slightly higher logP can be tolerated if other properties are favorable.

**4. H-Bond Donors:** Ligand A (1) is preferable to Ligand B (0) as it provides some hydrogen bonding potential.

**5. H-Bond Acceptors:** Ligand A (3) is preferable to Ligand B (6). Fewer HBA is generally better for CNS penetration.

**6. QED:** Both ligands have good QED scores (0.627 and 0.711, respectively), indicating drug-like properties.

**7. DILI:** Ligand A (31.02) has a significantly lower DILI risk than Ligand B (53.936). Both are below the 60 threshold, but A is clearly better.

**8. BBB:** Both ligands have excellent BBB penetration (87.088 and 88.135 percentile). This is a critical factor for CNS targets, and both perform well.

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.673 and -4.475). This is unusual and suggests poor permeability. However, these values are on a scale where negative values are possible, and the absolute value isn't as important as the relative comparison.

**10. Aqueous Solubility:** Both ligands have very poor aqueous solubility (-3.752 and -2.719). This is a significant drawback, but can sometimes be overcome with formulation strategies.

**11. hERG Inhibition:** Both ligands have low hERG inhibition risk (0.933 and 0.387).

**12. Microsomal Clearance:** Ligand A (55.391) has a higher microsomal clearance than Ligand B (50.968). This suggests Ligand B is more metabolically stable.

**13. In vitro Half-Life:** Ligand B (-13.844) has a significantly longer in vitro half-life than Ligand A (27.854). This is a major advantage for Ligand B.

**14. P-gp Efflux:** Both ligands have low P-gp efflux liability (0.279 and 0.259).

**15. Binding Affinity:** Both ligands have excellent binding affinity (-8.5 and -8.6 kcal/mol). The difference is negligible.

**Overall Assessment:**

Ligand A excels in TPSA, DILI, and H-bonding. Ligand B has better metabolic stability (lower Cl_mic, longer t1/2) and a slightly better logP. The solubility is poor for both, but the TPSA of Ligand A is significantly more favorable for CNS penetration. Given the importance of BBB penetration and lower TPSA for CNS GPCRs, and the relatively small difference in binding affinity, Ligand A is the slightly better candidate.

Output:
0
2025-04-17 03:41:59,365 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (352.475 Da and 382.595 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (59.08) is significantly better than Ligand B (41.57), both being well below the 90 A^2 threshold for CNS targets.

**3. logP:** Ligand A (1.842) is within the optimal 1-3 range. Ligand B (3.694) is approaching the upper limit, but still acceptable.

**4. H-Bond Donors:** Both ligands have acceptable HBD counts (0 for A, 1 for B), well below the 5 threshold.

**5. H-Bond Acceptors:** Both ligands have acceptable HBA counts (4 for A, 5 for B), below the 10 threshold.

**6. QED:** Both ligands have similar and good QED values (0.685 and 0.696), indicating good drug-like properties.

**7. DILI:** Both ligands have low DILI risk (24.855 and 23.032), both well below the 40 threshold.

**8. BBB:** Ligand B (80.884) has a significantly better BBB penetration percentile than Ligand A (71.035). This is a crucial advantage for a CNS target like DRD2.

**9. Caco-2 Permeability:** Ligand A (-4.205) has a worse Caco-2 permeability than Ligand B (-5.37). Lower values indicate poorer permeability.

**10. Aqueous Solubility:** Ligand A (-2.039) has better aqueous solubility than Ligand B (-3.984).

**11. hERG Inhibition:** Both ligands have low hERG inhibition risk (0.322 and 0.872).

**12. Microsomal Clearance:** Ligand A (60.236) has lower microsomal clearance than Ligand B (75.674), suggesting better metabolic stability.

**13. In vitro Half-Life:** Ligand B (32.054) has a significantly longer in vitro half-life than Ligand A (6.883).

**14. P-gp Efflux:** Ligand A (0.07) has much lower P-gp efflux liability than Ligand B (0.647), which is beneficial for CNS penetration.

**15. Binding Affinity:** Ligand B (-7.3 kcal/mol) has a stronger binding affinity than Ligand A (-6.9 kcal/mol). The difference is 0.4 kcal/mol, which is significant.

**Overall Assessment:**

While Ligand A has advantages in TPSA, solubility, metabolic stability, and P-gp efflux, Ligand B excels in BBB penetration, half-life, and crucially, binding affinity. For a CNS GPCR target, BBB penetration and strong binding are paramount. The 0.4 kcal/mol difference in binding affinity is substantial enough to outweigh the slight drawbacks of Ligand B in other areas. The improved half-life of Ligand B is also a significant advantage.

Output:
1
2025-04-17 03:41:59,365 - INFO - Batch 51 complete. Total preferences: 816
2025-04-17 03:41:59,365 - INFO - Processing batch 52/512...
2025-04-17 03:42:46,519 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (374.434 and 352.475 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (92.78) is slightly above the optimal <90 for CNS targets, but still reasonable. Ligand B (59.08) is excellent, well below 90.

**3. logP:** Ligand A (0.732) is a bit low, potentially hindering permeability. Ligand B (1.844) is better, falling within the 1-3 optimal range.

**4. H-Bond Donors:** Ligand A (1) is good. Ligand B (0) is also good.

**5. H-Bond Acceptors:** Ligand A (5) is good. Ligand B (4) is also good.

**6. QED:** Ligand A (0.741) is excellent, indicating good drug-likeness. Ligand B (0.469) is lower, suggesting a less ideal drug-like profile.

**7. DILI:** Ligand A (47.421) has a moderate DILI risk, but is still acceptable. Ligand B (18.379) has a very low DILI risk, which is favorable.

**8. BBB:** Ligand A (62.35) is below the desirable >70 for CNS targets. Ligand B (73.517) is excellent, exceeding the 70% threshold. This is a significant advantage for Ligand B.

**9. Caco-2:** Both ligands have negative Caco-2 values (-4.329 and -4.447), which is unusual and suggests poor permeability. This is a significant concern for both.

**10. Solubility:** Both ligands have negative solubility values (-2.208 and -1.399), which is also unusual and suggests poor solubility. This is a significant concern for both.

**11. hERG:** Both ligands have low hERG inhibition liability (0.332 and 0.556), which is good.

**12. Cl_mic:** Ligand A (49.455) has a moderate microsomal clearance, while Ligand B (41.334) has a slightly lower clearance, indicating better metabolic stability.

**13. t1/2:** Ligand B (9.373) has a significantly longer in vitro half-life than Ligand A (0.206), which is a major advantage.

**14. Pgp:** Both ligands exhibit low P-gp efflux liability (0.076 and 0.084), which is good for CNS penetration.

**15. Binding Affinity:** Ligand A (-8.1 kcal/mol) has a significantly stronger binding affinity than Ligand B (-6.6 kcal/mol). This is a substantial advantage for Ligand A.

**Overall Assessment:**

While Ligand A has a superior binding affinity, Ligand B has several advantages crucial for a CNS-targeting GPCR drug: a much better BBB penetration (73.5% vs 62.3%), a longer half-life (9.373 vs 0.206), and a lower DILI risk. The lower logP of Ligand A is a concern, and the negative Caco-2 and solubility values for both are problematic. However, the strong affinity of Ligand A might overcome some of these issues. Given the importance of BBB penetration for CNS targets, and the substantial difference in half-life, I believe Ligand B is the more promising candidate, *despite* the weaker binding affinity. Further optimization of Ligand B could potentially improve its affinity while retaining its favorable ADME properties.

Output:
1
2025-04-17 03:42:46,519 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (355.391 Da) is slightly lower, which could be beneficial for permeability. Ligand B (376.469 Da) is also acceptable.

**TPSA:** Ligand A (111.4) is better than Ligand B (62.66). For CNS targets, we want TPSA <= 90, so Ligand B is preferable here.

**logP:** Ligand A (-1.647) is low, potentially hindering permeation. Ligand B (3.245) is within the optimal range (1-3). This is a significant advantage for Ligand B.

**H-Bond Donors:** Both have 1 HBD, which is acceptable (<=5).

**H-Bond Acceptors:** Ligand A has 6 HBA, and Ligand B has 5 HBA, both are within the acceptable limit of <=10.

**QED:** Both ligands have good QED values (A: 0.611, B: 0.719), indicating drug-like properties.

**DILI:** Both ligands have low DILI risk (A: 34.742, B: 35.169), below the 40 threshold.

**BBB:** Ligand B (80.419) has a significantly better BBB percentile than Ligand A (62.195). This is crucial for a CNS target like DRD2.

**Caco-2 Permeability:** Ligand A (-5.28) and Ligand B (-4.617) both have negative values, which is unusual and suggests poor permeability. However, the scale isn't specified, so it's difficult to interpret.

**Aqueous Solubility:** Ligand A (-1.627) and Ligand B (-3.05) both have negative solubility values, which is also unusual and suggests poor solubility.

**hERG Inhibition:** Ligand A (0.067) has a very low hERG risk. Ligand B (0.686) is slightly higher, but still relatively low.

**Microsomal Clearance:** Ligand A (-12.873) has a much lower (better) microsomal clearance than Ligand B (45.86). This suggests better metabolic stability for Ligand A.

**In vitro Half-Life:** Ligand A (-0.625) has a very short half-life. Ligand B (4.8) has a better half-life.

**P-gp Efflux:** Ligand A (0.006) has very low P-gp efflux, which is highly desirable for CNS penetration. Ligand B (0.404) has moderate P-gp efflux.

**Binding Affinity:** Ligand A (-7.5) has a slightly better binding affinity than Ligand B (-6.7). However, the difference is less than 1.5 kcal/mol, so it's not a decisive factor.

**Overall Assessment:**

Ligand B is the more promising candidate. While Ligand A has slightly better affinity and metabolic stability, Ligand B excels in crucial areas for a CNS-targeting GPCR ligand: logP, BBB penetration, and a reasonable half-life. The lower TPSA of Ligand B is also beneficial. The poor solubility and permeability values for both are concerning, but the other advantages of Ligand B outweigh these drawbacks.

Output:
1
2025-04-17 03:42:46,520 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B based on the provided guidelines, prioritizing GPCR-specific properties (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (365.5 and 348.5 Da) fall within the ideal 200-500 Da range.

**TPSA:** Both ligands have TPSA values (71 and 69.64) below the 90 A^2 threshold desirable for CNS targets, which is excellent.

**logP:** Both ligands have logP values (1.792 and 2.083) within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A (1 HBD, 5 HBA) and Ligand B (2 HBD, 3 HBA) both satisfy the <5 HBD and <10 HBA guidelines.

**QED:** Both ligands have QED values (0.825 and 0.722) above 0.5, indicating good drug-likeness.

**DILI:** Ligand A (28.27%) has a significantly lower DILI risk than Ligand B (13.07%), indicating a safer profile.

**BBB:** Ligand A (59.4%) has a better BBB penetration percentile than Ligand B (47.15%), although neither are above the desirable 70% threshold for CNS targets. This is a critical factor for DRD2.

**Caco-2 Permeability:** Ligand A (-5.127) and Ligand B (-4.623) both have negative Caco-2 values, which is unusual and suggests poor permeability. However, these values are on a scale where negative values are possible and don't necessarily disqualify a compound.

**Aqueous Solubility:** Both ligands have very poor aqueous solubility (-2.906 and -2.829). This is a concern but can sometimes be mitigated with formulation strategies.

**hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.152 and 0.141).

**Microsomal Clearance:** Ligand A (30.73 mL/min/kg) has a higher microsomal clearance than Ligand B (22.69 mL/min/kg), suggesting lower metabolic stability.

**In vitro Half-Life:** Ligand B (-11.59 hours) has a longer in vitro half-life than Ligand A (-8.595 hours), which is favorable.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.07 and 0.032).

**Binding Affinity:** Both ligands have identical binding affinities (-8.8 kcal/mol), which is excellent and strong.

**Conclusion:**

While both ligands have excellent binding affinity, Ligand A is preferable due to its significantly lower DILI risk and better BBB penetration, despite slightly higher microsomal clearance and shorter half-life. The lower DILI risk is a major advantage, and the better BBB is crucial for a CNS target like DRD2. The solubility issues are a concern for both, but the other advantages of Ligand A outweigh this drawback.

Output:
1
2025-04-17 03:42:46,520 - INFO - Okay, let's analyze these two ligands for their potential as DRD2 drug candidates. DRD2 is a GPCR in the CNS, so BBB penetration, logP, Pgp efflux, TPSA, and binding affinity are paramount.

**Ligand A: [369.849, 102.68 ,   2.071,   3.   ,   4.   ,   0.64 ,  43.622,  81.815, -4.894,  -3.306,   0.339,  26.306,   2.991,   0.074,  -8.4  ]**
**Ligand B: [359.495,  53.51 ,   2.65 ,   0.   ,   4.   ,   0.78 ,  53.742,  72.586, -4.877,  -2.294,   0.312,  47.667, -22.15 ,   0.294,  -9.   ]**

**1. Molecular Weight:** Both ligands are within the ideal range (200-500 Da). A (369.849) and B (359.495) are comparable.

**2. TPSA:** Ligand A (102.68) is higher than the preferred <90 for CNS targets, but not drastically so. Ligand B (53.51) is excellent, well below the threshold. This is a significant advantage for B.

**3. logP:** Both ligands have good logP values (A: 2.071, B: 2.65), falling within the optimal 1-3 range. B is slightly better.

**4. H-Bond Donors:** Ligand A (3) is acceptable. Ligand B (0) is even better, potentially improving permeability.

**5. H-Bond Acceptors:** Both ligands have 4 HBA, which is within the acceptable range.

**6. QED:** Both ligands have reasonable QED scores (A: 0.64, B: 0.78), indicating good drug-like properties. B is slightly better.

**7. DILI:** Both ligands have acceptable DILI risk (A: 43.622, B: 53.742), below the 60 threshold. A is slightly better.

**8. BBB:** Ligand A (81.815) has excellent BBB penetration, exceeding the 70% threshold. Ligand B (72.586) is still good, but less favorable. This is a major advantage for A.

**9. Caco-2:** Both have negative Caco-2 values, which is unusual and suggests a potential issue with the data or modeling. However, we can interpret this as very low permeability.

**10. Solubility:** Both have negative solubility values, which is also unusual. This suggests poor aqueous solubility.

**11. hERG:** Both ligands have low hERG risk (A: 0.339, B: 0.312).

**12. Cl_mic:** Ligand A (26.306) has lower microsomal clearance, indicating better metabolic stability compared to Ligand B (47.667). This is a positive for A.

**13. t1/2:** Ligand A (2.991) has a slightly better in vitro half-life than Ligand B (-22.15).

**14. Pgp:** Ligand A (0.074) has lower P-gp efflux, which is beneficial for CNS penetration, compared to Ligand B (0.294). This favors A.

**15. Binding Affinity:** Ligand B (-9.0) has a significantly stronger binding affinity than Ligand A (-8.4). This is a substantial advantage for B, potentially outweighing some of the ADME drawbacks.

**Overall Assessment:**

While Ligand A has better BBB penetration, metabolic stability, and Pgp efflux, Ligand B boasts a significantly stronger binding affinity (-9.0 vs -8.4 kcal/mol). For a GPCR target, especially in the CNS, strong binding is crucial. The lower TPSA of Ligand B is also a significant advantage. The unusual Caco-2 and solubility values are concerning for both, but the binding affinity difference is substantial enough to prioritize B, assuming these values are modeling artifacts.

1
2025-04-17 03:42:46,520 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (368.594 and 348.378 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (49.85) is excellent, well below the 90 A^2 threshold for CNS targets. Ligand B (98.22) is higher, but still potentially acceptable, though less ideal.

**logP:** Ligand A (2.91) is optimal (1-3). Ligand B (0.9) is a bit low, potentially hindering permeability.

**H-Bond Donors/Acceptors:** Ligand A (0 HBD, 3 HBA) is favorable. Ligand B (2 HBD, 4 HBA) is also acceptable.

**QED:** Both ligands have good QED scores (0.701 and 0.845), indicating drug-like properties.

**DILI:** Ligand A (15.936) has a much lower DILI risk than Ligand B (62.893), a significant advantage.

**BBB:** Ligand A (81.892) has a good BBB penetration score, exceeding the 70% threshold for CNS targets. Ligand B (53.083) is significantly lower, raising concerns about CNS exposure.

**Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and requires further investigation. However, the magnitude of the negative value for Ligand A (-4.284) is smaller than that of Ligand B (-4.905), suggesting slightly better permeability.

**Aqueous Solubility:** Both ligands have negative solubility values, which is also unusual. This suggests poor aqueous solubility, which could be a formulation challenge.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.608 and 0.516).

**Microsomal Clearance:** Ligand A (69.843) has higher microsomal clearance than Ligand B (-28.704), indicating lower metabolic stability. This is a drawback for Ligand A.

**In vitro Half-Life:** Ligand B (-1.504) has a more negative half-life, which is unusual. Ligand A (-11.098) is also negative, but less so.

**P-gp Efflux:** Both ligands show very low P-gp efflux liability (0.447 and 0.031), which is positive for CNS penetration.

**Binding Affinity:** Ligand B (-7.8 kcal/mol) has a significantly stronger binding affinity than Ligand A (-0.0 kcal/mol). This is a major advantage for Ligand B.

**Overall Assessment:**

While Ligand A has better TPSA, BBB, and DILI scores, the significantly stronger binding affinity of Ligand B (-7.8 vs -0.0 kcal/mol) is a decisive factor. The 1.5 kcal/mol advantage threshold is easily exceeded here. Although Ligand B has a lower logP and higher DILI, the potency advantage is likely to outweigh these drawbacks, especially given the importance of affinity for GPCR ligands. The negative Caco-2 and solubility values are concerning for both, but can be addressed with formulation strategies.

Output:
1
2025-04-17 03:42:46,520 - INFO - Reasoning:

Let's analyze Ligand A and Ligand B based on the provided guidelines, prioritizing GPCR-specific properties (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (356.407 and 348.422 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (107.71) is slightly higher than Ligand B (88.32). Both are below the 140 A^2 threshold for oral absorption, and closer to the desirable <90 A^2 for CNS targets, but Ligand B is better.

**logP:** Both ligands (1.607 and 1.96) are within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A has 3 HBD and 5 HBA, while Ligand B has 2 HBD and 4 HBA. Both are within acceptable limits.

**QED:** Both have good QED scores (0.645 and 0.851).

**DILI:** Ligand A (87.631) has a significantly higher DILI risk than Ligand B (41.877). This is a major concern for Ligand A.

**BBB:** Ligand B (89.027) has a much better BBB penetration score than Ligand A (21.171). This is *critical* for a CNS target like DRD2.

**Caco-2 Permeability:** Ligand A (-5.402) has poor Caco-2 permeability, while Ligand B (-4.939) is slightly better, but still low.

**Aqueous Solubility:** Both have negative solubility values (-3.21 and -2.679), indicating poor solubility.

**hERG:** Both ligands have low hERG inhibition liability (0.13 and 0.493).

**Microsomal Clearance:** Ligand A (-1.797) has lower (better) microsomal clearance than Ligand B (4.295), suggesting greater metabolic stability.

**In vitro Half-Life:** Ligand A (-9.643) has a longer half-life than Ligand B (-16.744).

**P-gp Efflux:** Ligand A (0.127) has lower P-gp efflux than Ligand B (0.023), which is favorable for CNS penetration.

**Binding Affinity:** Both ligands have very similar and excellent binding affinities (-9.5 and -9.1 kcal/mol). The difference is not significant enough to outweigh other factors.

**Overall Assessment:**

Ligand B is clearly the more promising candidate. While both have similar binding affinities, Ligand B exhibits significantly better BBB penetration and a much lower DILI risk. These are the most important factors for a CNS-targeting GPCR. The slightly better TPSA and Caco-2 permeability of Ligand B are also beneficial. Although Ligand A has better metabolic stability and P-gp efflux, the superior CNS properties of Ligand B outweigh these advantages.

Output:
1
2025-04-17 03:42:46,521 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (347.346 and 368.331 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (89.95) is slightly higher than Ligand B (80.49), but both are below the 90 Angstroms threshold desirable for CNS targets.

**3. logP:** Ligand A (0.867) is a bit low, potentially hindering permeability. Ligand B (2.086) is within the optimal 1-3 range. This favors Ligand B.

**4. H-Bond Donors:** Ligand A (2) and Ligand B (1) are both acceptable, being less than 5.

**5. H-Bond Acceptors:** Ligand A (4) and Ligand B (6) are both acceptable, being less than 10.

**6. QED:** Both ligands have similar QED values (0.777 and 0.775), indicating good drug-like properties.

**7. DILI:** Ligand A (62.893) has a slightly higher DILI risk than Ligand B (58.705), but both are reasonably low.

**8. BBB:** Ligand B (88.755) has a significantly better BBB percentile than Ligand A (64.676). This is a crucial advantage for a CNS target like DRD2.

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.658 and -4.675), which is unusual and suggests poor permeability. This is a significant concern for both.

**10. Aqueous Solubility:** Both ligands have negative solubility values (-2.88 and -2.928), suggesting very poor aqueous solubility. This is a major drawback for both.

**11. hERG Inhibition:** Both ligands show very low hERG inhibition risk (0.146 and 0.314).

**12. Microsomal Clearance:** Ligand A (-14.488) has a much lower (better) microsomal clearance than Ligand B (19.595), indicating greater metabolic stability.

**13. In vitro Half-Life:** Ligand A (38.027) has a longer half-life than Ligand B (-15.881).

**14. P-gp Efflux:** Both ligands show very low P-gp efflux liability (0.012 and 0.073).

**15. Binding Affinity:** Ligand A (-9.6 kcal/mol) has a slightly better binding affinity than Ligand B (-8.2 kcal/mol). This is a 1.4 kcal/mol difference, which is substantial and could outweigh some ADME drawbacks.

**Overall Assessment:**

Despite the poor Caco-2 and solubility values for both, Ligand A's superior binding affinity and metabolic stability (lower Cl_mic, longer t1/2) are compelling. However, Ligand B's significantly better BBB penetration is a major advantage for a CNS target. Given the emphasis on BBB for CNS GPCRs, and the fact that the affinity difference, while notable, isn't enormous, Ligand B is the more promising candidate. The poor permeability and solubility would need to be addressed through formulation or prodrug strategies, but the improved CNS exposure potential is critical.

Output:
1
2025-04-17 03:42:46,521 - INFO - Reasoning:

Let's analyze Ligand A and Ligand B based on the provided guidelines, prioritizing GPCR-specific properties (BBB, logP, Pgp, TPSA, and affinity) for DRD2.

**Molecular Weight:** Both ligands (359.348 and 361.383 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (91.32) is excellent for CNS penetration, being below 90. Ligand B (136.81) is above the ideal 90, potentially hindering BBB penetration.

**logP:** Ligand A (2.002) is within the optimal 1-3 range. Ligand B (-0.021) is slightly below 1, which could impede permeability.

**H-Bond Donors/Acceptors:** Ligand A (HBD=3, HBA=4) and Ligand B (HBD=4, HBA=6) both have reasonable numbers of H-bond donors and acceptors, generally within acceptable limits.

**QED:** Ligand A (0.75) has a better QED score than Ligand B (0.555), indicating a more drug-like profile.

**DILI:** Ligand A (41.062) has a much lower DILI risk than Ligand B (90.074), which is a significant advantage.

**BBB:** Ligand A (67.623) has a moderate BBB penetration score, while Ligand B (32.067) is quite low, a major drawback for a CNS target like DRD2.

**Caco-2 Permeability:** Ligand A (-4.76) and Ligand B (-5.502) both have negative values, which is unusual and suggests poor permeability. However, the scale is not specified, so it's hard to interpret.

**Aqueous Solubility:** Both ligands have very poor aqueous solubility (-3.459 and -3.741 respectively). This could pose formulation challenges.

**hERG:** Both ligands have low hERG inhibition liability (0.328 and 0.286), which is good.

**Microsomal Clearance:** Ligand A (27.148) has a higher microsomal clearance than Ligand B (19.805), indicating potentially lower metabolic stability.

**In vitro Half-Life:** Ligand A (-46.438) has a much longer in vitro half-life than Ligand B (-9.33), which is a significant advantage.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.014 and 0.047), which is favorable for CNS penetration.

**Binding Affinity:** Both ligands have similar and strong binding affinities (-8.1 and -8.4 kcal/mol). The difference is minimal.

**Overall Assessment:**

Considering the GPCR-specific priorities, Ligand A is significantly more promising. Its superior BBB penetration, lower DILI risk, better QED score, and longer half-life outweigh its slightly higher microsomal clearance. While both have poor solubility, the other advantages of Ligand A make it a better candidate. Ligand B's low BBB score is a critical flaw for a DRD2 ligand.

Output:
1
2025-04-17 03:42:46,521 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (368.459 and 346.431 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (84) and Ligand B (78.53) are both below the 90 A^2 threshold for CNS targets, which is excellent.

**3. logP:** Both ligands have logP values within the optimal range (1.043 and 1.476).

**4. H-Bond Donors:** Both have 1 HBD, which is acceptable.

**5. H-Bond Acceptors:** Ligand A has 6 HBA, and Ligand B has 4. Both are below the 10 threshold.

**6. QED:** Both ligands have high QED scores (0.859 and 0.899), indicating good drug-like properties.

**7. DILI:** Ligand A (67.546) has a higher DILI risk than Ligand B (35.285). This is a significant negative for Ligand A.

**8. BBB:** Ligand A (78.79) has a better BBB penetration percentile than Ligand B (55.874). This is a crucial advantage for a CNS target like DRD2.

**9. Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and requires further investigation. However, the values are similar.

**10. Aqueous Solubility:** Both have negative solubility values, which is also unusual. Again, values are similar.

**11. hERG:** Both ligands have very low hERG inhibition liability (0.195 and 0.176).

**12. Microsomal Clearance:** Ligand A (4.284) has significantly lower microsomal clearance than Ligand B (36.771), suggesting better metabolic stability.

**13. In vitro Half-Life:** Ligand A (-8.701) has a more negative in vitro half-life, which is better (longer half-life). Ligand B (-4.434) is still reasonable.

**14. P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.045 and 0.021).

**15. Binding Affinity:** Both ligands have excellent binding affinities (-8.1 and -8.4 kcal/mol), with Ligand B being slightly better. The difference is less than 1.5 kcal/mol, so it's not a decisive factor on its own.

**Overall Assessment:**

Ligand A has a significant advantage in BBB penetration and metabolic stability (lower Cl_mic and better half-life). However, it has a higher DILI risk. Ligand B has a slightly better binding affinity and a much lower DILI risk.

Considering the GPCR-specific priorities, BBB is paramount for a CNS target. While Ligand A's BBB is good, the lower DILI risk of Ligand B is a strong advantage, especially given that the binding affinity difference is small. The slightly better metabolic stability of Ligand A is valuable, but the DILI risk is a major concern.

Output:
1
2025-04-17 03:42:46,522 - INFO - Reasoning:

Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (379.551 Da) is slightly higher than Ligand B (345.399 Da), but both are acceptable.

**2. TPSA:** This is a critical parameter for CNS penetration. Ligand A (52.65) is significantly better than Ligand B (91.76).  A TPSA under 90 is preferred for CNS targets, and Ligand A is much closer to this threshold.

**3. logP:** Both ligands have good logP values (A: 2.795, B: 1.475), falling within the optimal 1-3 range.

**4. H-Bond Donors:** Both have acceptable HBD counts (A: 1, B: 2), well below the limit of 5.

**5. H-Bond Acceptors:** Both ligands also have acceptable HBA counts (A: 5, B: 5), below the limit of 10.

**6. QED:** Both ligands have good QED scores (A: 0.729, B: 0.807), indicating good drug-like properties.

**7. DILI:** Ligand A (31.718) has a lower DILI risk than Ligand B (48.158), which is preferable.

**8. BBB:** Ligand A (56.572) and Ligand B (59.597) are both below the desirable >70 percentile for CNS targets. However, given the other parameters, this is less of a differentiating factor.

**9. Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and suggests poor permeability. However, the scale is not specified, so it's difficult to interpret.

**10. Aqueous Solubility:** Both have negative solubility values, again making interpretation difficult.

**11. hERG Inhibition:** Both ligands have very low hERG risk (A: 0.425, B: 0.229), which is excellent.

**12. Microsomal Clearance:** Ligand A (68.771) has a higher microsomal clearance than Ligand B (27.095), suggesting lower metabolic stability. This is a negative for Ligand A.

**13. In vitro Half-Life:** Ligand B (-4.176) has a negative half-life, which is not possible. This is a major red flag. Ligand A (35.559) is reasonable.

**14. P-gp Efflux:** Both ligands have very low P-gp efflux liability (A: 0.041, B: 0.02), which is favorable for CNS penetration.

**15. Binding Affinity:** Ligand B (-8.8 kcal/mol) has a significantly stronger binding affinity than Ligand A (-7.3 kcal/mol). This is a substantial advantage (1.5 kcal/mol difference).

**Overall Assessment:**

While Ligand B has a superior binding affinity, the negative in vitro half-life is a critical flaw. A negative half-life is not physically possible and indicates a problem with the data or the compound itself. Ligand A, despite having a slightly higher clearance, has more reasonable ADME properties, especially a positive half-life and a much lower TPSA. The TPSA difference is particularly important for CNS targets like DRD2.

Output:
1
2025-04-17 03:42:46,522 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (374.522 and 348.447 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (58.64) is excellent, well below the 90 A^2 threshold for CNS targets. Ligand B (88.76) is still reasonable but closer to the upper limit.

**3. logP:** Both ligands have good logP values (2.39 and 1.399), falling within the optimal 1-3 range.

**4. H-Bond Donors:** Both have 1 HBD, which is within the acceptable limit of <=5.

**5. H-Bond Acceptors:** Ligand A has 4 HBAs, and Ligand B has 5. Both are below the 10 limit.

**6. QED:** Both ligands have good QED scores (0.709 and 0.869), indicating good drug-like properties.

**7. DILI:** Ligand A (26.095) has a significantly lower DILI risk than Ligand B (38.852). Both are below the 40 threshold, but A is preferable.

**8. BBB:** Ligand A (93.68) has a very high BBB penetration percentile, which is excellent for a CNS target like DRD2. Ligand B (78.209) is still good, but substantially lower. This is a major advantage for Ligand A.

**9. Caco-2 Permeability:** Both have negative Caco-2 values (-4.814 and -4.926), which is unusual and suggests poor permeability. This is a concern for both.

**10. Aqueous Solubility:** Both have negative solubility values (-2.969 and -0.708), indicating poor aqueous solubility. This is a concern for both.

**11. hERG Inhibition:** Both ligands have low hERG inhibition risk (0.642 and 0.396).

**12. Microsomal Clearance:** Ligand A (41.811) has a higher microsomal clearance than Ligand B (0.917), indicating lower metabolic stability. This is a drawback for Ligand A.

**13. In vitro Half-Life:** Ligand A (-7.43) has a much longer in vitro half-life than Ligand B (12.775). This is a significant advantage for Ligand A.

**14. P-gp Efflux:** Ligand A (0.291) has lower P-gp efflux liability than Ligand B (0.015), which is favorable for CNS penetration.

**15. Binding Affinity:** Both ligands have excellent binding affinities (-7.9 and -8.1 kcal/mol). The difference is minimal.

**Overall Assessment:**

Ligand A is the better candidate. While it has a higher microsomal clearance, its significantly better BBB penetration (93.68 vs. 78.209), lower DILI risk, and longer half-life outweigh this drawback. Both ligands have issues with Caco-2 permeability and aqueous solubility, which would need to be addressed during optimization, but these are less critical for a CNS target where BBB penetration is paramount. The similar binding affinities mean that the ADME properties are the deciding factors.

Output:
1
2025-04-17 03:42:46,522 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 drug candidates, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (353.463 and 349.519 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (71.11) is higher than Ligand B (52.65). For a CNS target like DRD2, TPSA should be <= 90, so both are acceptable, but B is better.

**3. logP:** Ligand A (0.382) is quite low, potentially hindering permeability. Ligand B (2.428) is within the optimal 1-3 range. This is a significant advantage for B.

**4. H-Bond Donors:** Both have 1 HBD, which is good.

**5. H-Bond Acceptors:** Ligand A has 5 HBA, and Ligand B has 3. Both are acceptable (<=10).

**6. QED:** Both ligands have similar QED values (0.774 and 0.776), indicating good drug-likeness.

**7. DILI:** Ligand A (15.781) has a higher DILI risk than Ligand B (6.049). Lower is better, so B is preferable.

**8. BBB:** Ligand B (83.637) has a significantly higher BBB penetration percentile than Ligand A (61.729). This is *critical* for a CNS target like DRD2, making B much more promising.

**9. Caco-2 Permeability:** Both have negative Caco-2 values (-4.849 and -4.731), which is unusual and suggests poor permeability. However, these values are on a scale where negative values are possible and don't necessarily disqualify a compound.

**10. Aqueous Solubility:** Ligand A (-0.627) has slightly better solubility than Ligand B (-2.27), but both are poor. Solubility can be improved with formulation.

**11. hERG Inhibition:** Ligand A (0.162) shows slightly lower hERG inhibition liability than Ligand B (0.687), which is favorable.

**12. Microsomal Clearance:** Ligand B (26.521) has a much higher microsomal clearance than Ligand A (0.32), meaning it's metabolized more quickly. This is a disadvantage for B.

**13. In vitro Half-Life:** Ligand A (13.334) has a longer in vitro half-life than Ligand B (-5.189). This is a significant advantage for A.

**14. P-gp Efflux:** Ligand A (0.008) has very low P-gp efflux, which is excellent for CNS penetration. Ligand B (0.065) is also low, but A is better.

**15. Binding Affinity:** Ligand B (-8.0 kcal/mol) has a slightly better binding affinity than Ligand A (-7.8 kcal/mol). While both are good, the 0.2 kcal/mol difference is not substantial enough to outweigh other factors.

**Overall Assessment:**

Ligand B is significantly better due to its superior BBB penetration (83.637 vs 61.729) and more favorable logP (2.428 vs 0.382). While Ligand A has better metabolic stability (lower Cl_mic and longer t1/2) and slightly lower hERG risk, the BBB and logP are paramount for a CNS GPCR target. The slight affinity difference is not enough to overcome these ADME deficiencies in Ligand A.

Output:
1
2025-04-17 03:42:46,522 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (357.454) is slightly higher than Ligand B (345.487), but both are acceptable.

**TPSA:** Ligand A (47.34) is excellent, well below the 90 A^2 threshold for CNS targets. Ligand B (81.99) is higher, but still potentially acceptable, though less ideal.

**logP:** Ligand A (3.349) is optimal (1-3). Ligand B (2.764) is also good, falling within the optimal range.

**H-Bond Donors/Acceptors:** Ligand A (0 HBD, 4 HBA) and Ligand B (2 HBD, 3 HBA) both have reasonable numbers of H-bond donors and acceptors, well below the thresholds of 5 and 10, respectively.

**QED:** Both ligands have similar QED values (Ligand A: 0.843, Ligand B: 0.804), indicating good drug-like properties.

**DILI:** Ligand A (66.809) has a higher DILI risk than Ligand B (29.081). This is a significant drawback for Ligand A.

**BBB:** Ligand A (86.468) has a much better BBB penetration percentile than Ligand B (56.921). This is a critical advantage for a CNS target like DRD2.

**Caco-2 Permeability:** Both have negative Caco-2 values (-4.741 and -4.821), which is unusual and suggests poor permeability. This is a concern for both.

**Aqueous Solubility:** Both have negative solubility values (-4.274 and -3.499), indicating poor aqueous solubility. This is a concern for both.

**hERG Inhibition:** Ligand A (0.86) has a slightly higher hERG inhibition risk than Ligand B (0.435), but both are relatively low.

**Microsomal Clearance:** Ligand A (72.852) has higher microsomal clearance than Ligand B (21.529), indicating lower metabolic stability.

**In vitro Half-Life:** Ligand B (16.182) has a longer in vitro half-life than Ligand A (-14.022). This is a significant advantage for Ligand B.

**P-gp Efflux:** Ligand A (0.753) has lower P-gp efflux than Ligand B (0.141), which is favorable for CNS penetration.

**Binding Affinity:** Ligand B (-9.2 kcal/mol) has a significantly stronger binding affinity than Ligand A (-8.0 kcal/mol). This is a substantial advantage for Ligand B.

**Overall Assessment:**

Ligand A excels in BBB penetration and P-gp efflux, crucial for CNS targets. However, it suffers from higher DILI risk, lower metabolic stability (higher Cl_mic, shorter t1/2), and significantly weaker binding affinity.

Ligand B, despite lower BBB penetration, has a much stronger binding affinity, lower DILI risk, better metabolic stability, and a longer half-life. The stronger binding affinity is a major advantage, and the lower DILI risk is also important. While the BBB penetration isn't ideal, it's not a complete barrier, and further optimization could potentially improve it.

Given the GPCR-specific priorities and the significant advantage in binding affinity and safety (DILI), Ligand B is the more promising candidate.

Output:
1
2025-04-17 03:42:46,523 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (368.459 and 348.487 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (90.98) is slightly above the preferred <90 for CNS targets, while Ligand B (69.64) is well within the range. This favors Ligand B.

**logP:** Ligand A (-0.447) is a bit low, potentially hindering membrane permeability. Ligand B (2.413) is optimal. This strongly favors Ligand B.

**H-Bond Donors/Acceptors:** Both have 2 HBD and a reasonable number of HBA (6 and 3 respectively), satisfying the criteria.

**QED:** Both ligands have acceptable QED scores (0.707 and 0.523), indicating good drug-like properties.

**DILI:** Ligand A (54.207) has a moderate DILI risk, while Ligand B (19.814) has a very low risk. This favors Ligand B.

**BBB:** Both ligands have similar BBB penetration (55.176 and 57.193), which is acceptable but not outstanding. A score >70 would be preferable, but they are comparable.

**Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and suggests poor permeability. However, the scale is not specified, so it's hard to interpret.

**Aqueous Solubility:** Both have negative solubility values, which is also unusual and suggests poor solubility. Again, the scale is not specified.

**hERG Inhibition:** Both ligands show low hERG inhibition liability (0.339 and 0.188), which is good.

**Microsomal Clearance:** Ligand A (-8.859) has a negative clearance, which is not physically possible and likely an error. Ligand B (55.754) has a high clearance, indicating rapid metabolism. This favors Ligand A, assuming the negative value is an error.

**In vitro Half-Life:** Ligand A (-22.047) has a negative half-life, which is not physically possible and likely an error. Ligand B (-10.976) has a short half-life. This favors Ligand A, assuming the negative value is an error.

**P-gp Efflux:** Both ligands show low P-gp efflux liability (0.003 and 0.161), which is favorable for CNS penetration.

**Binding Affinity:** Both ligands have strong binding affinities (-8.0 and -7.6 kcal/mol). Ligand A is slightly better (-8.0 vs -7.6).

**Overall Assessment:**

Ligand B has superior physicochemical properties (logP, TPSA, DILI) and is more likely to have good permeability and solubility. However, Ligand A has a slightly better binding affinity and potentially better metabolic stability (assuming the negative values for clearance and half-life are errors). Given the GPCR-specific emphasis on BBB, logP, and Pgp, and the fact that both have acceptable BBB and Pgp values, the better physicochemical profile of Ligand B outweighs the small affinity advantage of Ligand A. The negative values for clearance and half-life of Ligand A are concerning and suggest potential data errors.

Output:
1
2025-04-17 03:42:46,523 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B based on the provided guidelines, prioritizing GPCR-specific properties (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (363.849 and 365.459 Da) fall within the ideal range of 200-500 Da.

**TPSA:** Ligand A (72.28) is significantly better than Ligand B (101.22). For CNS targets, TPSA should be <= 90. Ligand A is within this range, while Ligand B exceeds it.

**logP:** Both ligands have acceptable logP values (1.354 and 1.608), falling within the optimal range of 1-3.

**H-Bond Donors/Acceptors:** Both ligands have 1 HBD and a reasonable number of HBAs (6 and 7 respectively), satisfying the guidelines.

**QED:** Both ligands have acceptable QED values (0.804 and 0.724), indicating good drug-likeness.

**DILI:** Ligand A (51.338) has a lower DILI risk than Ligand B (63.823), which is preferable. Both are below the concerning threshold of 60, but lower is always better.

**BBB:** This is a critical parameter for CNS targets. Ligand A has a significantly higher BBB percentile (75.107) than Ligand B (47.189). A value >70 is desirable, and Ligand A meets this criterion, while Ligand B does not.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.092 and -5.126), which is unusual and potentially problematic. However, the values are very similar.

**Aqueous Solubility:** Both ligands have negative solubility values (-2.557 and -2.523), also unusual.  Again, the values are comparable.

**hERG Inhibition:** Both ligands show very low hERG inhibition liability (0.49 and 0.143), which is excellent.

**Microsomal Clearance:** Ligand A (25.545) has a lower microsomal clearance than Ligand B (64.491), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (11.877) has a shorter half-life than Ligand B (38.387), but both are reasonable.

**P-gp Efflux:** Ligand A (0.055) has a much lower P-gp efflux liability than Ligand B (0.128), which is crucial for CNS penetration.

**Binding Affinity:** Ligand B (-7.7 kcal/mol) has a slightly better binding affinity than Ligand A (-8.2 kcal/mol). While a 1.5 kcal/mol advantage can sometimes outweigh other factors, in this case, the ADME advantages of Ligand A are substantial.

**Overall Assessment:**

Ligand A is the superior candidate. It excels in key GPCR-specific properties like TPSA and BBB penetration, has lower DILI and P-gp efflux, and better metabolic stability. The slightly weaker binding affinity of Ligand A is outweighed by its significantly improved ADME profile, especially its superior BBB penetration, which is critical for a CNS-targeting drug.

Output:
1
2025-04-17 03:42:46,523 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B based on the provided guidelines, prioritizing GPCR-specific properties (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (360.405 and 376.444 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (67.67) is higher than Ligand B (49.41). For CNS targets, TPSA should be <= 90, so both are acceptable, but B is better.

**logP:** Ligand A (2.269) and Ligand B (3.091) are both within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A has 0 HBD and 5 HBA, while Ligand B has 1 HBD and 3 HBA. Both are within acceptable limits (<=5 HBD and <=10 HBA).

**QED:** Both ligands have similar QED values (0.78 and 0.75), indicating good drug-likeness.

**DILI:** Ligand A (35.324) has a slightly higher DILI risk than Ligand B (21.598), but both are below the concerning threshold of 60.

**BBB:** This is a critical parameter for CNS targets. Ligand B (92.555) has a significantly higher BBB penetration percentile than Ligand A (76.851). This is a major advantage for Ligand B.

**Caco-2 Permeability:** Ligand A (-4.174) and Ligand B (-4.885) both have negative values, indicating poor permeability. This is a concern for both.

**Aqueous Solubility:** Ligand A (-1.011) is slightly better than Ligand B (-4.626).

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.519 and 0.499).

**Microsomal Clearance:** Ligand B (32.169) has lower microsomal clearance than Ligand A (63.769), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand B (-9.648) has a longer in vitro half-life than Ligand A (-15.925).

**P-gp Efflux:** Ligand A (0.079) has lower P-gp efflux than Ligand B (0.169), which is favorable for CNS exposure.

**Binding Affinity:** Ligand B (-8.1 kcal/mol) has a stronger binding affinity than Ligand A (-6.8 kcal/mol). The difference of 1.3 kcal/mol is significant and can outweigh some of the ADME drawbacks of Ligand B.

**Conclusion:**

Considering the GPCR-specific priorities, Ligand B is the more promising candidate. Its superior BBB penetration, stronger binding affinity, better metabolic stability (lower Cl_mic, longer t1/2), and lower DILI risk outweigh the slightly higher P-gp efflux and lower solubility compared to Ligand A. While both have poor Caco-2 permeability, the strong affinity and CNS penetration profile of Ligand B make it more likely to be a viable drug candidate for a CNS target like DRD2.

Output:
1
2025-04-17 03:42:46,524 - INFO - Batch 52 complete. Total preferences: 832
2025-04-17 03:42:46,524 - INFO - Processing batch 53/512...
2025-04-17 03:43:43,129 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (334.463 Da) is slightly preferred as it's closer to the lower end, potentially aiding permeability.

**TPSA:** Ligand A (32.34) is excellent for CNS penetration, well below the 90 A^2 threshold. Ligand B (56.33) is still reasonable, but less optimal.

**logP:** Ligand A (3.681) is within the optimal range (1-3). Ligand B (-0.177) is significantly below this, which is a major concern for permeability and CNS penetration.

**H-Bond Donors/Acceptors:** Ligand A (1 HBD, 2 HBA) is ideal. Ligand B (0 HBD, 5 HBA) is acceptable, but the higher number of acceptors could slightly hinder permeability.

**QED:** Ligand A (0.929) is excellent, indicating high drug-likeness. Ligand B (0.575) is acceptable but less favorable.

**DILI:** Ligand A (37.456) has a low DILI risk. Ligand B (5.739) is even lower, which is positive.

**BBB:** Ligand A (91.121) is excellent, exceeding the 70% threshold for CNS targets. Ligand B (65.839) is below this threshold, raising concerns about brain exposure.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values which is unusual and likely indicates a problem with the prediction method. However, the magnitude suggests Ligand A (-4.788) is slightly better than Ligand B (-4.735).

**Aqueous Solubility:** Both ligands have negative solubility values, which is also unusual and suggests prediction issues. Ligand A (-4.246) is slightly better.

**hERG:** Ligand A (0.922) has a low hERG risk. Ligand B (0.499) is also low risk.

**Microsomal Clearance:** Ligand A (45.81) has moderate clearance. Ligand B (20.089) has lower clearance, indicating better metabolic stability.

**In vitro Half-Life:** Ligand A (-7.953) has a long half-life, which is favorable. Ligand B (-12.742) has an even longer half-life.

**P-gp Efflux:** Ligand A (0.686) has moderate P-gp efflux. Ligand B (0.003) has very low P-gp efflux, which is highly desirable for CNS penetration.

**Binding Affinity:** Ligand A (-10.1 kcal/mol) has significantly stronger binding affinity than Ligand B (-6.6 kcal/mol). This is a substantial advantage.

**Overall Assessment:**

Ligand A excels in key areas for a CNS-targeting GPCR ligand: TPSA, BBB, and, crucially, binding affinity. While Ligand B has better metabolic stability (lower Cl_mic) and lower P-gp efflux, its significantly lower logP and lower BBB penetration are major drawbacks. The substantial difference in binding affinity (-10.1 vs -6.6 kcal/mol) is a decisive factor. A 3.5 kcal/mol difference is large enough to overcome minor ADME concerns.

Output:
1
2025-04-17 03:43:43,130 - INFO - Okay, let's analyze these two ligands for their potential as DRD2 drug candidates. DRD2 is a GPCR in the CNS, so BBB penetration, logP, Pgp efflux, TPSA, and binding affinity are paramount.

**Ligand A: [348.491, 79.19, 3.157, 3, 4, 0.738, 15.743, 84.529, -5.242, -1.766, 0.47, -6.936, 24.109, 0.099, -9.6]**

*   **MW:** 348.491 Da - Good, within the ideal range.
*   **TPSA:** 79.19  - Good, below the 90 threshold for CNS targets.
*   **logP:** 3.157 - Excellent, within the optimal 1-3 range.
*   **HBD:** 3 - Acceptable, within the limit of 5.
*   **HBA:** 4 - Acceptable, within the limit of 10.
*   **QED:** 0.738 - Excellent, well above the 0.5 threshold.
*   **DILI:** 15.743 - Very good, low risk of liver injury.
*   **BBB:** 84.529 - Excellent, high BBB penetration, very desirable for a CNS target.
*   **Caco-2:** -5.242 - Concerningly low, suggesting poor intestinal absorption.
*   **Solubility:** -1.766 - Poor solubility, could be a formulation challenge.
*   **hERG:** 0.47 - Low risk of hERG inhibition.
*   **Cl_mic:** -6.936 - Very good, indicates high metabolic stability.
*   **t1/2:** 24.109 - Good, reasonable in vitro half-life.
*   **Pgp:** 0.099 - Very low Pgp efflux, excellent for CNS exposure.
*   **Affinity:** -9.6 kcal/mol - Excellent, very strong binding.

**Ligand B: [349.475, 84.23, 3.078, 2, 4, 0.792, 35.091, 80.419, -4.745, -3.593, 0.376, 76.391, -23.047, 0.166, -7.6]**

*   **MW:** 349.475 Da - Good, within the ideal range.
*   **TPSA:** 84.23 - Acceptable, slightly above the ideal 90 for CNS, but not a major concern.
*   **logP:** 3.078 - Excellent, within the optimal 1-3 range.
*   **HBD:** 2 - Acceptable, within the limit of 5.
*   **HBA:** 4 - Acceptable, within the limit of 10.
*   **QED:** 0.792 - Excellent, well above the 0.5 threshold.
*   **DILI:** 35.091 - Good, relatively low risk of liver injury.
*   **BBB:** 80.419 - Good, acceptable BBB penetration.
*   **Caco-2:** -4.745 - Concerningly low, suggesting poor intestinal absorption.
*   **Solubility:** -3.593 - Poor solubility, could be a formulation challenge.
*   **hERG:** 0.376 - Low risk of hERG inhibition.
*   **Cl_mic:** 76.391 - Concerningly high, indicates lower metabolic stability.
*   **t1/2:** -23.047 - Very poor in vitro half-life.
*   **Pgp:** 0.166 - Very low Pgp efflux, excellent for CNS exposure.
*   **Affinity:** -7.6 kcal/mol - Good, strong binding.

**Comparison and Decision:**

Both ligands have good MW, logP, QED, HBD/HBA counts, and low Pgp efflux, which are all positive attributes. Both also have poor Caco-2 and solubility. However, Ligand A significantly outperforms Ligand B in several critical areas for a CNS GPCR target.

*   **BBB:** Ligand A has a much higher BBB percentile (84.529) than Ligand B (80.419).
*   **Metabolic Stability:** Ligand A has a much lower (better) microsomal clearance (-6.936) and a significantly longer in vitro half-life (24.109) compared to Ligand B (76.391 and -23.047 respectively). This is crucial for maintaining therapeutic concentrations.
*   **DILI:** Ligand A has a lower DILI risk.
*   **Affinity:** Ligand A has a substantially stronger binding affinity (-9.6 kcal/mol vs -7.6 kcal/mol).  The 2 kcal/mol difference is significant and can outweigh some of the ADME drawbacks.

While both have solubility and Caco-2 issues, these can potentially be addressed with formulation strategies. The superior BBB penetration, metabolic stability, lower toxicity risk, and stronger binding affinity of Ligand A make it the more promising drug candidate.

1
2025-04-17 03:43:43,130 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (366.286 and 346.515 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (69.64) is better than Ligand B (49.41). Both are below the 90 A^2 threshold desirable for CNS targets.

**logP:** Ligand A (1.55) is within the optimal 1-3 range. Ligand B (3.522) is at the higher end, potentially causing solubility issues, but still acceptable.

**H-Bond Donors/Acceptors:** Ligand A has 2 HBD and 3 HBA, while Ligand B has 1 HBD and 2 HBA. Both are within acceptable limits (<=5 HBD and <=10 HBA).

**QED:** Both ligands have good QED scores (0.777 and 0.8), suggesting good drug-like properties.

**DILI:** Ligand A (37.767) has a slightly higher DILI risk than Ligand B (15.626), but both are below the concerning 60 percentile.

**BBB:** Ligand B (79.062) has a significantly better BBB penetration score than Ligand A (67.701). This is a critical advantage for a CNS target like DRD2.

**Caco-2 Permeability:** Ligand A (-5.059) has worse Caco-2 permeability than Ligand B (-4.507), indicating lower intestinal absorption.

**Aqueous Solubility:** Ligand A (-1.87) has better aqueous solubility than Ligand B (-4.23).

**hERG Inhibition:** Both ligands have low hERG inhibition liability (0.46 and 0.561), which is good.

**Microsomal Clearance:** Ligand B (86.007) has a much higher microsomal clearance than Ligand A (6.351). This suggests Ligand A is more metabolically stable.

**In vitro Half-Life:** Ligand A (-10.373) has a significantly longer in vitro half-life than Ligand B (-0.728).

**P-gp Efflux:** Ligand A (0.115) has lower P-gp efflux liability than Ligand B (0.236), which is beneficial for CNS exposure.

**Binding Affinity:** Ligand B (-7.5 kcal/mol) has a slightly better binding affinity than Ligand A (-8.2 kcal/mol). While A is better, the difference is not substantial enough to overcome other ADME deficiencies.

**Overall Assessment:**

Ligand B excels in BBB penetration and binding affinity, two crucial factors for a DRD2 ligand. While its metabolic stability is a concern (high Cl_mic, short t1/2), the superior BBB penetration and acceptable logP, TPSA, and DILI scores make it a more promising candidate. Ligand A has better metabolic stability and solubility, but its lower BBB penetration is a significant drawback for a CNS target.

Output:
1
2025-04-17 03:43:43,130 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (342.403 and 347.415 Da) fall within the ideal range of 200-500 Da.

**TPSA:** Ligand A (93.01) is excellent, falling well below the 90 A^2 threshold for CNS targets. Ligand B (121.52) is higher, but still potentially acceptable, though less ideal.

**logP:** Ligand A (1.247) is within the optimal range (1-3). Ligand B (0.459) is slightly low, potentially hindering permeation.

**H-Bond Donors/Acceptors:** Ligand A (1 HBD, 6 HBA) is good. Ligand B (4 HBD, 4 HBA) is also acceptable.

**QED:** Ligand A (0.853) has a very strong drug-like profile. Ligand B (0.546) is still above the 0.5 threshold, but less favorable than A.

**DILI:** Ligand A (58.627) has a moderate DILI risk, but is acceptable. Ligand B (32.222) has a lower, more favorable DILI risk.

**BBB:** Ligand A (60.838) has a moderate BBB penetration, which is a concern for a CNS target. Ligand B (41.218) is even lower, making CNS penetration a significant hurdle.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.033 and -5.478), which is unusual and suggests poor permeability. This is a major red flag for both.

**Aqueous Solubility:** Both ligands have negative solubility values (-2.689 and -2.898), indicating very poor solubility. This is a significant formulation challenge.

**hERG:** Both ligands have very low hERG inhibition liability (0.078 and 0.16), which is excellent.

**Microsomal Clearance:** Ligand A (33.401) has a moderate clearance, while Ligand B (6.712) has a very low clearance, suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (1.624) has a short half-life. Ligand B (5.943) has a longer half-life, which is preferable.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.047 and 0.035), which is good for CNS exposure.

**Binding Affinity:** Ligand B (-9.1 kcal/mol) has a significantly stronger binding affinity than Ligand A (-8.3 kcal/mol), a difference of 0.8 kcal/mol. This is a substantial advantage.

**Overall Assessment:**

Despite the poor Caco-2 and solubility values for both, the stronger binding affinity of Ligand B, combined with its lower DILI risk, better metabolic stability (lower Cl_mic), and longer half-life, make it the more promising candidate. While the BBB penetration is low for both, the affinity difference is substantial enough to potentially overcome this with formulation strategies. Ligand A's slightly better TPSA and QED are outweighed by the significantly weaker binding and less favorable metabolic profile.

Output:
1
2025-04-17 03:43:43,130 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (353.375 and 386.945 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (129.75) is better than Ligand B (69.64). For CNS targets, TPSA < 90 is preferred, and both meet this criterion, but A is closer to the upper limit.

**3. logP:** Ligand B (2.668) is optimal (1-3), while Ligand A (-1.224) is too low, potentially hindering permeation. This is a significant drawback for A.

**4. H-Bond Donors:** Ligand A (4) is acceptable, while Ligand B (2) is also good.

**5. H-Bond Acceptors:** Ligand A (6) is acceptable, and Ligand B (4) is also good.

**6. QED:** Both ligands have reasonable QED scores (0.433 and 0.606), suggesting drug-like properties. Ligand B is slightly better.

**7. DILI:** Ligand B (30.71) has a much lower DILI risk than Ligand A (54.323), indicating better safety.

**8. BBB:** Ligand B (34.742) has a better BBB penetration score than Ligand A (18.185). While neither is >70, B is significantly better, which is crucial for a CNS target like DRD2.

**9. Caco-2 Permeability:** Ligand A (-5.624) has very poor Caco-2 permeability, while Ligand B (-4.944) is also poor, but slightly better.

**10. Aqueous Solubility:** Ligand A (-1.744) has poor solubility, while Ligand B (-3.279) is also poor, but slightly better.

**11. hERG Inhibition:** Ligand A (0.087) has a very low hERG risk, while Ligand B (0.708) has a slightly higher risk.

**12. Microsomal Clearance:** Ligand A (-19.626) has a much lower (better) microsomal clearance than Ligand B (60.305), indicating better metabolic stability.

**13. In vitro Half-Life:** Ligand B (20.979) has a significantly longer half-life than Ligand A (1.872).

**14. P-gp Efflux:** Ligand A (0.009) has very low P-gp efflux, which is highly desirable for CNS penetration. Ligand B (0.212) has higher efflux.

**15. Binding Affinity:** Ligand A (-7.8) has a slightly better binding affinity than Ligand B (-7.3), but the difference is not substantial enough to overcome the significant ADME deficiencies of Ligand A.

**Overall Assessment:**

Ligand B is the more promising candidate. While its solubility and Caco-2 permeability are not ideal, it excels in key areas for a CNS-targeting GPCR ligand: better logP, significantly lower DILI risk, better BBB penetration, longer half-life, and lower P-gp efflux. Ligand A's very low logP and poor permeability are major red flags, despite its slightly better affinity and lower clearance. The affinity difference is unlikely to overcome the ADME issues.

Output:
1
2025-04-17 03:43:43,130 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal 200-500 Da range (A: 347.459, B: 364.417).

**TPSA:** Ligand A (92.5) is better than Ligand B (53.33). For CNS targets, we want TPSA <= 90, so A is acceptable, and B is excellent.

**logP:** Ligand A (1.352) is within the optimal range (1-3). Ligand B (4.123) is slightly above, potentially leading to solubility issues or off-target interactions, but not drastically.

**H-Bond Donors/Acceptors:** Ligand A has 2 HBD and 3 HBA, which are both acceptable. Ligand B has 0 HBD and 5 HBA, also acceptable.

**QED:** Both ligands have similar QED values (A: 0.71, B: 0.661), indicating good drug-likeness.

**DILI:** Ligand A (20.822) has a significantly lower DILI risk than Ligand B (47.654). This is a major advantage for Ligand A.

**BBB:** Ligand B (80.574) has a substantially better BBB penetration score than Ligand A (65.839). This is critical for a CNS target like DRD2.

**Caco-2 Permeability:** Ligand A (-5.246) has poor Caco-2 permeability, while Ligand B (-4.508) is slightly better, but still poor.

**Aqueous Solubility:** Ligand A (-2.717) has poor aqueous solubility, while Ligand B (-4.462) is even worse.

**hERG Inhibition:** Ligand A (0.121) has a very low hERG risk, while Ligand B (0.885) has a higher, though still relatively low, risk.

**Microsomal Clearance:** Ligand A (26.677) has lower microsomal clearance than Ligand B (105.97), indicating better metabolic stability.

**In vitro Half-Life:** Ligand A (8.835) has a slightly longer half-life than Ligand B (5.715).

**P-gp Efflux:** Ligand A (0.022) has very low P-gp efflux, which is favorable for CNS penetration. Ligand B (0.361) has higher P-gp efflux.

**Binding Affinity:** Ligand B (-7.7) has a slightly stronger binding affinity than Ligand A (-7.3), a difference of 0.4 kcal/mol.

**Overall Assessment:**

Ligand B excels in BBB penetration and binding affinity, both crucial for a CNS GPCR target. However, it suffers from higher DILI risk, worse metabolic stability, and higher P-gp efflux. Ligand A has a much better safety profile (DILI, hERG, P-gp) and metabolic stability, but its BBB penetration is lower and affinity is slightly weaker.

The 0.4 kcal/mol difference in affinity is not substantial enough to overcome the significant advantages Ligand A has in terms of safety and metabolic stability, especially considering the challenges of getting a drug across the BBB. While Ligand B's affinity is better, optimizing Ligand A's structure to improve affinity is more likely to yield a viable candidate than mitigating Ligand B's ADME liabilities.

Output:
0
2025-04-17 03:43:43,130 - INFO - Reasoning:

Let's analyze Ligand A and Ligand B for their potential as DRD2 drug candidates, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (342.378 and 362.316 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (67.98) is significantly better than Ligand B (122.76). For CNS targets, we want TPSA <= 90, and A is comfortably within that range, while B exceeds it.

**3. logP:** Both ligands have good logP values (2.624 and 1.085), falling within the optimal 1-3 range.

**4. H-Bond Donors:** Ligand A (1) is preferable to Ligand B (3). Fewer HBDs generally improve permeability.

**5. H-Bond Acceptors:** Ligand A (5) is better than Ligand B (9). Lower HBA is generally preferred for better permeability.

**6. QED:** Both ligands have acceptable QED values (0.792 and 0.601), both above the 0.5 threshold.

**7. DILI:** Ligand A (75.262) has a higher DILI risk than Ligand B (68.825), but both are reasonably low.

**8. BBB:** Ligand A (78.868) has a significantly better BBB penetration percentile than Ligand B (61.535).  This is *critical* for a CNS target like DRD2.

**9. Caco-2 Permeability:** Ligand A (-4.853) has a more favorable Caco-2 permeability than Ligand B (-5.478), although both are negative and thus require careful interpretation.

**10. Aqueous Solubility:** Ligand A (-3.353) has slightly better solubility than Ligand B (-2.787), but both are quite poor.

**11. hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.429 and 0.138).

**12. Microsomal Clearance:** Ligand A (36.977) has higher microsomal clearance than Ligand B (18.132), indicating faster metabolism and potentially lower *in vivo* exposure.

**13. In vitro Half-Life:** Ligand B (-23.202) has a significantly longer *in vitro* half-life than Ligand A (19.588). This is a positive for B.

**14. P-gp Efflux:** Ligand A (0.155) has lower P-gp efflux liability than Ligand B (0.012), which is favorable for CNS penetration.

**15. Binding Affinity:** Ligand A (-9.8 kcal/mol) has a substantially better binding affinity than Ligand B (-8.0 kcal/mol). This is a >1.5 kcal/mol difference, which can outweigh some ADME drawbacks.

**Overall Assessment:**

Ligand A is the stronger candidate. While Ligand B has a better half-life and slightly lower DILI, Ligand A excels in the most important parameters for a CNS-targeting GPCR: TPSA, BBB penetration, P-gp efflux, and, crucially, binding affinity. The significantly stronger binding affinity of Ligand A (-9.8 vs -8.0 kcal/mol) is a major advantage. The slightly higher clearance of A is a concern, but can potentially be addressed through structural modifications.



Output:
1
2025-04-17 03:43:43,131 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 drug candidates, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (363.435 and 344.411 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (81.7) is slightly higher than Ligand B (75.8), but both are below the 90 Angstroms threshold desirable for CNS targets.

**3. logP:** Both ligands have good logP values (3.171 and 2.795 respectively), falling within the optimal 1-3 range.

**4. H-Bond Donors:** Both have 1 HBD, which is acceptable.

**5. H-Bond Acceptors:** Ligand A has 6 HBAs, and Ligand B has 5. Both are within the acceptable limit of 10.

**6. QED:** Ligand B (0.903) has a significantly better QED score than Ligand A (0.642), indicating a more drug-like profile.

**7. DILI:** Ligand A (77.123) has a higher DILI risk than Ligand B (44.746). Ligand B is well below the 60 threshold, while Ligand A is approaching it.

**8. BBB:** Ligand A (73.672) has a slightly better BBB percentile than Ligand B (68.941), but both are reasonably good for a CNS target, though ideally >70.

**9. Caco-2 Permeability:** Both have negative Caco-2 values (-4.341 and -4.55), which is unusual and suggests poor permeability. This is a significant concern.

**10. Aqueous Solubility:** Both have negative solubility values (-5.212 and -3.221), indicating very poor aqueous solubility. This is a major drawback.

**11. hERG Inhibition:** Both ligands have low hERG inhibition risk (0.467 and 0.54), which is good.

**12. Microsomal Clearance:** Ligand A (102.928) has a higher microsomal clearance than Ligand B (12.174), indicating lower metabolic stability.

**13. In vitro Half-Life:** Ligand B (1.117 hours) has a very short half-life, while Ligand A (40.425 hours) has a much more desirable half-life.

**14. P-gp Efflux:** Ligand A (0.246) has lower P-gp efflux liability than Ligand B (0.729), which is beneficial for CNS penetration.

**15. Binding Affinity:** Both ligands have excellent binding affinities (-8.3 and -8.5 kcal/mol). The difference is negligible.

**Overall Assessment:**

Despite both ligands having excellent binding affinity, their poor Caco-2 permeability and aqueous solubility are major concerns. However, considering the GPCR-specific priorities, Ligand B is slightly more favorable. It has a better QED score, lower DILI risk, and a significantly longer in vitro half-life. While its BBB is slightly lower, the lower P-gp efflux of Ligand A isn't enough to offset the other advantages of Ligand B. The poor solubility and permeability would need to be addressed through formulation or further chemical modification for either compound.

Output:
1
2025-04-17 03:43:43,131 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B based on the provided guidelines, prioritizing GPCR-specific properties (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (384.351) is slightly higher than Ligand B (364.427), but both are acceptable.

**TPSA:** Both ligands have TPSA values (86.71 and 87.38) that are reasonably good for CNS penetration, being below the 90 A^2 threshold.

**logP:** Both ligands have logP values within the optimal range (1-3), with Ligand A (1.137) being slightly lower and Ligand B (1.738) slightly higher. Both are acceptable.

**H-Bond Donors/Acceptors:** Ligand A (HBD=2, HBA=4) is slightly better than Ligand B (HBD=1, HBA=7) in terms of balancing solubility and permeability.

**QED:** Both ligands have QED values (0.72 and 0.645) indicating good drug-like properties.

**DILI:** Ligand A (63.513) has a lower DILI risk than Ligand B (87.282). This is a significant advantage.

**BBB:** Ligand B (68.67) has a better BBB penetration percentile than Ligand A (55.797). This is a crucial factor for a CNS target like DRD2.

**Caco-2 Permeability:** Ligand A (-5.273) has worse Caco-2 permeability than Ligand B (-4.829), suggesting lower intestinal absorption.

**Aqueous Solubility:** Ligand A (-3.556) has slightly worse aqueous solubility than Ligand B (-2.867).

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.486 and 0.514).

**Microsomal Clearance:** Ligand B (17.689) has lower microsomal clearance than Ligand A (26.653), indicating better metabolic stability.

**In vitro Half-Life:** Ligand B (22.673) has a longer in vitro half-life than Ligand A (11.229), which is desirable.

**P-gp Efflux:** Ligand A (0.103) has lower P-gp efflux liability than Ligand B (0.285), which is beneficial for CNS exposure.

**Binding Affinity:** Ligand B (-7.8 kcal/mol) has a significantly stronger binding affinity than Ligand A (-8.8 kcal/mol). This is a substantial advantage, potentially outweighing some ADME drawbacks.

**Overall Assessment:**

Ligand B is superior due to its significantly better binding affinity (-7.8 vs -8.8 kcal/mol) and improved BBB penetration (68.67 vs 55.797). While Ligand A has a lower DILI risk and P-gp efflux, the stronger binding and better CNS penetration of Ligand B are more critical for a DRD2 target. Ligand B also shows better metabolic stability and half-life.



Output:
1
2025-04-17 03:43:43,131 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (390.398 and 342.403 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (102.87) is slightly above the optimal <90 for CNS targets, but still reasonable. Ligand B (93.01) is better, falling comfortably under 90.

**logP:** Both ligands have good logP values (2.686 and 1.337), within the 1-3 range. Ligand B is slightly lower, which could potentially impact permeability, but isn't a major concern.

**H-Bond Donors/Acceptors:** Ligand A (0 HBD, 8 HBA) and Ligand B (1 HBD, 6 HBA) both have acceptable numbers of H-bond donors and acceptors, well within the guidelines.

**QED:** Both ligands have good QED scores (0.401 and 0.908). Ligand B's score is significantly higher, indicating a more drug-like profile.

**DILI:** Both ligands have similar DILI risk (62.156 and 60.721), which is acceptable (below 60 is preferred, but these are borderline).

**BBB:** Both ligands exhibit good BBB penetration (70.105 and 75.649), exceeding the 70% threshold for CNS targets. Ligand B is slightly better here.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.596 and -4.998). This is unusual and suggests poor permeability. However, these values are on a log scale, so the negative values indicate very low permeability.

**Aqueous Solubility:** Both ligands have negative solubility values (-2.587 and -2.722), indicating very poor aqueous solubility. This is a significant drawback.

**hERG Inhibition:** Both ligands show low hERG inhibition risk (0.106 and 0.361), which is good.

**Microsomal Clearance:** Ligand A has a higher microsomal clearance (109.965) than Ligand B (17.112), suggesting lower metabolic stability. This is a significant negative for Ligand A.

**In vitro Half-Life:** Ligand B has a much longer in vitro half-life (4.43 hours) than Ligand A (-18.984 hours). The negative value for Ligand A is concerning and likely an artifact or error in the data.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.225 and 0.023), which is favorable for CNS penetration. Ligand B is better here.

**Binding Affinity:** Ligand B (-8.7 kcal/mol) has a significantly stronger binding affinity than Ligand A (-6.1 kcal/mol). This >1.5 kcal/mol difference is a major advantage for Ligand B, potentially outweighing some of its other drawbacks.

**Overall Assessment:**

Ligand B is the superior candidate. While both have issues with solubility and Caco-2 permeability, Ligand B's significantly stronger binding affinity, better QED, lower microsomal clearance, longer half-life, and slightly better BBB penetration make it the more promising drug candidate. The poor solubility and permeability would need to be addressed through formulation strategies, but the improved potency and pharmacokinetic properties of Ligand B are more readily optimized. Ligand A's negative half-life is a major red flag.

Output:
1
2025-04-17 03:43:43,131 - INFO - Reasoning:

Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (347.459 and 348.491 Da) fall comfortably within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (71.41) is slightly higher than Ligand B (65.54). Both are below the 90 Angstroms threshold desirable for CNS targets, but B is closer to the optimal range.

**3. logP:** Both ligands have excellent logP values (1.724 and 1.626), falling within the optimal 1-3 range.

**4. H-Bond Donors:** Both have 1 HBD, which is acceptable.

**5. H-Bond Acceptors:** Both have 4 HBA, which is acceptable.

**6. QED:** Ligand B (0.737) has a noticeably better QED score than Ligand A (0.575), indicating a more drug-like profile.

**7. DILI:** Ligand B (13.028) has a significantly lower DILI risk than Ligand A (30.787), a substantial advantage.

**8. BBB:** Both ligands have similar BBB penetration (57.736 and 59.248). Neither exceeds the desirable >70 percentile, but they are reasonably close.

**9. Caco-2 Permeability:** Both have negative Caco-2 values (-4.81 and -4.827). This is unusual and suggests poor permeability. However, the values are very similar.

**10. Aqueous Solubility:** Both have negative solubility values (-1.202 and -0.833), indicating very poor aqueous solubility. This is a significant drawback for both.

**11. hERG Inhibition:** Both ligands show very low hERG inhibition liability (0.355 and 0.195).

**12. Microsomal Clearance:** Ligand B (45.637) has a slightly lower microsomal clearance than Ligand A (50.559), suggesting better metabolic stability.

**13. In vitro Half-Life:** Ligand B (21.639) has a significantly longer in vitro half-life than Ligand A (-0.154), a major advantage.

**14. P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.205 and 0.011). Ligand B is better here.

**15. Binding Affinity:** Ligand A (-7.9 kcal/mol) has a stronger binding affinity than Ligand B (-7.4 kcal/mol). This is a 0.5 kcal/mol difference, which is significant.

**Overall Assessment:**

While Ligand A has a slightly better binding affinity, Ligand B is superior in almost all other crucial ADME-Tox properties. Specifically, its lower DILI risk, better QED, longer half-life, and lower P-gp efflux are compelling advantages. The similar BBB values and acceptable logP for both are positive. The poor Caco-2 and solubility are concerning for both, but the other benefits of Ligand B outweigh the slightly weaker binding. Given the GPCR target and the need for CNS penetration, the improved ADME profile of Ligand B is more likely to translate into a viable drug candidate.

Output:
1
2025-04-17 03:43:43,131 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (341.411 and 344.367 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (74.08) is excellent, well below the 90 A^2 threshold for CNS targets. Ligand B (113.86) is higher, but still potentially acceptable, though less ideal.

**logP:** Ligand A (2.89) is optimal (1-3). Ligand B (0.609) is a bit low, potentially hindering permeation.

**H-Bond Donors/Acceptors:** Ligand A (0 HBD, 6 HBA) is favorable. Ligand B (4 HBD, 4 HBA) is also acceptable, though the 4 HBD is approaching the upper limit.

**QED:** Both ligands have acceptable QED scores (0.782 and 0.651, both > 0.5).

**DILI:** Ligand A (63.086) has a slightly higher DILI risk than Ligand B (56.456), but both are below the concerning 60 percentile.

**BBB:** This is critical for a CNS target like DRD2. Ligand A (77.627) has a good BBB percentile. Ligand B (21.326) is very poor, indicating limited brain penetration.

**Caco-2 Permeability:** Ligand A (-4.326) is poor, while Ligand B (-5.521) is even worse. Both are negative values, suggesting very low permeability.

**Aqueous Solubility:** Ligand A (-4.173) and Ligand B (-2.441) both have poor solubility.

**hERG Inhibition:** Both ligands show very low hERG inhibition risk (0.201 and 0.065).

**Microsomal Clearance:** Ligand A (78.69) has a higher clearance, indicating lower metabolic stability. Ligand B (-37.743) has a negative value, which is unusual and likely indicates very high stability.

**In vitro Half-Life:** Ligand A (-24.45) is negative, which is unusual and likely indicates very high stability. Ligand B (-10.838) is also negative, suggesting high stability.

**P-gp Efflux:** Both ligands show low P-gp efflux liability (0.291 and 0.002).

**Binding Affinity:** Both ligands have the same binding affinity (-8.8 kcal/mol), which is excellent.

**Overall Assessment:**

The most significant difference is the BBB penetration. Ligand A has a good BBB percentile (77.627), while Ligand B's is very low (21.326). Given that DRD2 is a CNS target, this is a decisive factor. While Ligand B has better metabolic stability and lower P-gp efflux, the poor BBB penetration makes it much less likely to be a viable drug candidate. Ligand A's slightly higher DILI risk and lower Caco-2 permeability are less concerning than the poor brain penetration of Ligand B.

Output:
0
2025-04-17 03:43:43,131 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (340.379 and 347.415 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (75.8) is significantly better than Ligand B (111.55). For CNS targets, we want TPSA <= 90, and A is comfortably within that range, while B is above.

**logP:** Both ligands have good logP values (2.392 and 1.443), falling within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A (HBD=1, HBA=5) is better than Ligand B (HBD=4, HBA=5). Lower HBD is generally preferred.

**QED:** Ligand A (0.925) has a much higher QED score than Ligand B (0.532), indicating a more drug-like profile.

**DILI:** Ligand A (65.568) has a higher DILI risk than Ligand B (21.791). This favors Ligand B.

**BBB:** Ligand A (63.203) has a better BBB penetration percentile than Ligand B (23.808). This is a *critical* factor for a CNS target like DRD2, and heavily favors Ligand A.

**Caco-2 Permeability:** Ligand A (-4.572) and Ligand B (-5.372) both have negative values, which is unusual. Lower values suggest poor permeability.

**Aqueous Solubility:** Ligand A (-2.943) and Ligand B (-2.277) both have negative solubility values, indicating poor solubility.

**hERG:** Ligand A (0.474) has a lower hERG risk than Ligand B (0.065), which is preferable.

**Microsomal Clearance:** Ligand A (54.031) has a higher microsomal clearance than Ligand B (9.326), meaning it is less metabolically stable. This favors Ligand B.

**In vitro Half-Life:** Ligand A (4.363) has a shorter half-life than Ligand B (-10.92). The negative value for B is unusual, but suggests a very long half-life. This favors Ligand B.

**P-gp Efflux:** Ligand A (0.598) has a lower P-gp efflux liability than Ligand B (0.024), which is better for CNS exposure.

**Binding Affinity:** Ligand A (-8.5 kcal/mol) has a slightly better binding affinity than Ligand B (-7.6 kcal/mol). The difference is 0.9 kcal/mol, which is significant.

**Overall Assessment:**

Ligand A excels in key GPCR properties: TPSA, BBB, P-gp efflux, and binding affinity. While its DILI and Cl_mic are less favorable, the strong BBB penetration and affinity are crucial for CNS targets. Ligand B has better DILI, metabolic stability and half-life, but suffers from a higher TPSA and significantly lower BBB penetration. Given the importance of CNS penetration for DRD2, Ligand A is the more promising candidate.

Output:
1
2025-04-17 03:43:43,131 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (347.411 and 344.455 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (81.7) is slightly above the optimal <90 for CNS targets, but still reasonable. Ligand B (69.64) is excellent, well below 90.

**3. logP:** Ligand A (3.09) is right in the sweet spot (1-3). Ligand B (1.801) is a bit low, potentially hindering permeability.

**4. H-Bond Donors:** Ligand A (1) is good. Ligand B (2) is also acceptable.

**5. H-Bond Acceptors:** Ligand A (5) is good. Ligand B (3) is also good.

**6. QED:** Ligand A (0.828) is excellent, indicating strong drug-likeness. Ligand B (0.454) is below the desirable threshold of 0.5, suggesting potential issues.

**7. DILI:** Ligand A (72.043) has a moderate DILI risk. Ligand B (14.696) has a very low DILI risk, a significant advantage.

**8. BBB:** Ligand A (83.986) has excellent BBB penetration potential, exceeding the 70% threshold. Ligand B (58.86) is significantly lower and less desirable for a CNS target.

**9. Caco-2:** Ligand A (-4.036) is concerningly low, indicating poor intestinal absorption. Ligand B (-5.091) is also poor.

**10. Solubility:** Ligand A (-4.5) is very poor. Ligand B (-2.257) is also poor, but slightly better than A.

**11. hERG:** Both ligands (0.305 and 0.166) have low hERG inhibition liability, which is good.

**12. Cl_mic:** Ligand A (104.545) has a relatively high microsomal clearance, suggesting lower metabolic stability. Ligand B (39.77) has much lower clearance and better metabolic stability.

**13. t1/2:** Ligand A (-9.486) has a very short in vitro half-life, which is undesirable. Ligand B (-31.12) has a very long in vitro half-life, a major advantage.

**14. Pgp:** Ligand A (0.164) has low P-gp efflux, which is good for CNS penetration. Ligand B (0.091) has even lower P-gp efflux, a further advantage.

**15. Binding Affinity:** Ligand B (-8.5 kcal/mol) has a significantly stronger binding affinity than Ligand A (-7.8 kcal/mol). This 0.7 kcal/mol difference is substantial and can outweigh some ADME concerns.

**Overall Assessment:**

While Ligand A has good BBB penetration and P-gp efflux, its poor solubility, Caco-2 permeability, short half-life, and higher DILI risk are significant drawbacks. Ligand B, despite a slightly lower logP and QED, exhibits a much better safety profile (low DILI), superior metabolic stability (lower Cl_mic, longer t1/2), and, most importantly, a substantially higher binding affinity. The strong binding affinity of Ligand B is a critical factor, especially for a GPCR target.

Output:
1
2025-04-17 03:43:43,132 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (346.395 and 350.463 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (121.69) is slightly above the optimal <90 for CNS targets, but still reasonable. Ligand B (96.67) is excellent, well within the desired range.

**logP:** Ligand A (-0.238) is a bit low, potentially hindering membrane permeability. Ligand B (0.346) is better, within the acceptable range, but still on the lower side.

**H-Bond Donors/Acceptors:** Both ligands have 2 HBDs, which is good. Ligand A has 7 HBAs, while Ligand B has 5. Both are acceptable, being under the 10 HBA limit.

**QED:** Both ligands have QED values above 0.6, indicating good drug-likeness.

**DILI:** Ligand A (72.47) has a higher DILI risk than Ligand B (4.459). This is a significant advantage for Ligand B.

**BBB:** Ligand A (54.634) has a moderate BBB penetration, while Ligand B (43.777) is lower. Both are below the desirable >70 for CNS targets, but Ligand A is better.

**Caco-2 Permeability:** Both have negative Caco-2 values which is unusual. Assuming these are percentile scores, both are very poor.

**Aqueous Solubility:** Both ligands have negative solubility values, which is also unusual. Assuming these are percentile scores, both are very poor.

**hERG:** Ligand A (0.038) has a very low hERG risk, which is excellent. Ligand B (0.212) is slightly higher, but still relatively low.

**Microsomal Clearance:** Ligand A (-5.385) has a negative clearance, which is not possible. Ligand B (-32.992) also has a negative clearance, which is not possible. Assuming these are percentile scores, both are very good.

**In vitro Half-Life:** Ligand A (-4.909) and Ligand B (-10.911) both have negative half-lives, which is not possible. Assuming these are percentile scores, both are very good.

**P-gp Efflux:** Ligand A (0.056) shows very low P-gp efflux, which is favorable for CNS penetration. Ligand B (0.002) is even lower, which is excellent.

**Binding Affinity:** Both ligands have very similar and strong binding affinities (-7.7 and -7.5 kcal/mol). The difference is less than 1.5 kcal/mol, so it's not a deciding factor.

**Overall Assessment:**

Considering the GPCR-specific priorities, Ligand B is more promising. It has a significantly lower DILI risk, a better TPSA, and a slightly better logP. While both have poor Caco-2 and solubility, and negative clearance/half-life values (which are likely errors in the data), the lower DILI risk and better TPSA of Ligand B are key advantages for a CNS-targeting drug. The P-gp efflux is also slightly better for Ligand B. The binding affinity is comparable.

Output:
1
2025-04-17 03:43:43,132 - INFO - Reasoning:

Let's analyze Ligand A and Ligand B, considering the provided guidelines and the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (406.232 Da) is slightly higher than Ligand B (359.466 Da), but both are acceptable.

**TPSA:** Ligand A (88.78) is closer to the desirable threshold of 90 for CNS targets than Ligand B (29.54). Ligand B is significantly better here.

**logP:** Both ligands have logP values within the optimal range (1-3). Ligand A (3.187) is slightly higher than Ligand B (4.137), but both are acceptable.

**H-Bond Donors/Acceptors:** Ligand A has 1 HBD and 6 HBA, while Ligand B has 0 HBD and 3 HBA. Both are within acceptable limits.

**QED:** Both ligands have good QED scores (Ligand A: 0.742, Ligand B: 0.803), indicating drug-like properties.

**DILI:** Ligand A (69.252) has a higher DILI risk than Ligand B (37.611). This favors Ligand B.

**BBB:** Ligand B (95.696) has a significantly better BBB penetration percentile than Ligand A (35.246). This is a *critical* advantage for a CNS target like DRD2.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.586 and -4.557). This is unusual and suggests poor permeability. However, these values are on the same scale, so it doesn't differentiate the two.

**Aqueous Solubility:** Both ligands have negative solubility values (-5.294 and -4.885). This is also unusual and suggests poor solubility. Again, these values are similar.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (Ligand A: 0.705, Ligand B: 0.861).

**Microsomal Clearance:** Ligand A (94.99) has a higher microsomal clearance than Ligand B (86.453), indicating lower metabolic stability. This favors Ligand B.

**In vitro Half-Life:** Ligand B (17.471) has a longer in vitro half-life than Ligand A (26.659). This favors Ligand B.

**P-gp Efflux:** Ligand A (0.665) has lower P-gp efflux liability than Ligand B (0.81). This is a slight advantage for Ligand A.

**Binding Affinity:** Ligand B (-7.9 kcal/mol) has a slightly better binding affinity than Ligand A (-7.6 kcal/mol). While the difference is relatively small, it's still a positive for Ligand B.

**Overall Assessment:**

Ligand B is clearly superior. Its significantly better BBB penetration, lower DILI risk, longer half-life, and slightly better binding affinity outweigh the minor disadvantages in P-gp efflux. The similar issues with Caco-2 and solubility are concerning for both, but the CNS target prioritizes BBB penetration. The slightly better affinity of Ligand B further solidifies its advantage.

Output:
1
2025-04-17 03:43:43,132 - INFO - Batch 53 complete. Total preferences: 848
2025-04-17 03:43:43,132 - INFO - Processing batch 54/512...
2025-04-17 03:44:24,735 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (365.543 and 360.435 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (71.09) is better than Ligand B (81.43). For CNS targets, we want TPSA <= 90, both are within this range, but A is closer to the ideal.

**3. logP:** Both ligands have good logP values (3.015 and 3.17), falling within the optimal 1-3 range.

**4. H-Bond Donors:** Ligand A (2) is slightly higher than Ligand B (1), but both are acceptable (<=5).

**5. H-Bond Acceptors:** Ligand A (4) is lower than Ligand B (6), which is preferable. We want <=10, both are within range, but A is better.

**6. QED:** Both ligands have good QED values (0.744 and 0.828), indicating good drug-like properties.

**7. DILI:** Both ligands have relatively high DILI risk (32.881 and 63.707), but Ligand A is significantly better. Ideally, we want <40.

**8. BBB:** Both ligands have acceptable BBB penetration (63.048 and 64.172), but neither exceeds the desirable >70 threshold. This is a critical factor for CNS targets.

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.922 and -4.673), which is unusual and suggests poor permeability. This is a significant drawback.

**10. Aqueous Solubility:** Both ligands have negative solubility values (-3.829 and -3.57), indicating very poor solubility. This is a major concern for bioavailability.

**11. hERG Inhibition:** Both ligands have low hERG inhibition liability (0.219 and 0.098), which is good.

**12. Microsomal Clearance:** Ligand A (71.371) has a higher microsomal clearance than Ligand B (64.054), indicating potentially lower metabolic stability. Lower is better.

**13. In vitro Half-Life:** Ligand B (1.375) has a slightly longer half-life than Ligand A (-5.97), which is preferable.

**14. P-gp Efflux:** Both ligands have low P-gp efflux liability (0.1 and 0.207), which is good for CNS penetration.

**15. Binding Affinity:** Ligand B (-9.0) has a significantly stronger binding affinity than Ligand A (-7.3). A difference of >1.5 kcal/mol is considered substantial.

**Overall Assessment:**

Ligand B has a substantially better binding affinity, which is a major advantage. However, both ligands suffer from poor Caco-2 permeability and aqueous solubility. Ligand A has a better DILI score and TPSA, while Ligand B has a better half-life. Considering the GPCR-specific priorities, the strong binding affinity of Ligand B is the most important factor. While the poor permeability and solubility are concerns, these can potentially be addressed through formulation strategies or further chemical modifications. The improved affinity could outweigh these drawbacks.

Output:
1
2025-04-17 03:44:24,736 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (372.921 and 365.499 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (41.13) is significantly better than Ligand B (75.44). For CNS targets, we want TPSA <= 90, and ideally closer to 60. Ligand A is much closer to this ideal.

**logP:** Ligand A (4.675) is slightly higher than optimal (1-3), but still potentially acceptable. Ligand B (2.805) is within the optimal range. However, for a GPCR, a slightly higher logP can be tolerated if other properties are favorable.

**H-Bond Donors/Acceptors:** Ligand A (2 HBD, 3 HBA) and Ligand B (1 HBD, 5 HBA) both have reasonable numbers of H-bonds.

**QED:** Both ligands have similar QED values (0.819 and 0.804), indicating good drug-like properties.

**DILI:** Ligand A (60.682) is slightly higher risk than Ligand B (53.819), but both are within an acceptable range (<60 is good, >60 is high risk).

**BBB:** Ligand A (80.419) has a significantly better BBB penetration prediction than Ligand B (70.997).  This is *critical* for a CNS target like DRD2.

**Caco-2 Permeability:** Both have negative Caco-2 values (-5.083 and -5.074). This is unusual and suggests poor permeability, but the scale isn't clearly defined, so it's difficult to interpret.

**Aqueous Solubility:** Both have negative solubility values (-4.798 and -3.846). Similar to Caco-2, this is concerning and suggests poor solubility.

**hERG:** Ligand A (0.809) has a slightly higher hERG risk than Ligand B (0.162). This is a point in favor of Ligand B.

**Microsomal Clearance:** Ligand B (60.12) has a higher microsomal clearance than Ligand A (6.687), indicating faster metabolism and potentially lower *in vivo* exposure.

**In vitro Half-Life:** Ligand A (41.686) has a longer half-life than Ligand B (0.565), which is desirable.

**P-gp Efflux:** Ligand A (0.474) has lower P-gp efflux liability than Ligand B (0.068), which is beneficial for CNS penetration.

**Binding Affinity:** Ligand B (-8.5 kcal/mol) has a significantly stronger binding affinity than Ligand A (-10.1 kcal/mol). This is a substantial advantage.

**Overall Assessment:**

While Ligand B has a better binding affinity and lower hERG risk, Ligand A's superior BBB penetration, lower P-gp efflux, longer half-life, and significantly lower TPSA make it the more promising candidate for a CNS-targeting drug like a DRD2 ligand. The slightly higher logP of Ligand A is less concerning than the poorer CNS penetration of Ligand B. The solubility and permeability issues are shared by both, and would need to be addressed through formulation or further chemical modification. The affinity difference is significant, but the ADME properties are more crucial for CNS drugs.

Output:
0
2025-04-17 03:44:24,736 - INFO - Reasoning:

Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (404.312 Da) is slightly higher than Ligand B (364.471 Da), but both are acceptable.

**2. TPSA:**  Ligand A (83.6) is better than Ligand B (93.21). For CNS targets, we want TPSA <= 90. Ligand A is closer to this threshold.

**3. logP:** Ligand A (3.268) is optimal (1-3), while Ligand B (1.51) is at the lower end of the acceptable range.  Lower logP can hinder permeation.

**4. H-Bond Donors:** Ligand A (1) is preferable to Ligand B (2). Fewer HBDs generally improve permeability.

**5. H-Bond Acceptors:** Ligand A (5) is better than Ligand B (6). Lower HBA counts are generally favored.

**6. QED:** Both ligands have good QED scores (A: 0.685, B: 0.798), indicating good drug-like properties.

**7. DILI:** Ligand A (57.697) has a lower DILI risk than Ligand B (66.344), making it more favorable. Both are acceptable, but lower is better.

**8. BBB:** Ligand A (50.717) has a lower BBB penetration percentile than Ligand B (61.342). While both are not ideal (>70 is desirable for CNS targets), Ligand B is better.

**9. Caco-2:** Both have negative Caco-2 values (-5.283 and -5.434), which is unusual and suggests poor permeability. This is a significant concern for both.

**10. Solubility:** Both have negative solubility values (-3.937 and -3.106), indicating poor aqueous solubility. This is a major drawback for both compounds.

**11. hERG:** Ligand A (0.713) has a slightly higher hERG risk than Ligand B (0.163). Lower is better here, so Ligand B is preferable.

**12. Cl_mic:** Ligand A (47.949) has significantly better metabolic stability (lower clearance) than Ligand B (17.735). This is a substantial advantage for Ligand A.

**13. t1/2:** Ligand A (43.677) has a longer in vitro half-life than Ligand B (19.241), which is desirable.

**14. Pgp:** Ligand A (0.517) has lower P-gp efflux liability than Ligand B (0.099). Lower Pgp is preferable, especially for CNS targets.

**15. Binding Affinity:** Ligand B (-9.3 kcal/mol) has a significantly stronger binding affinity than Ligand A (-8.6 kcal/mol). This is a crucial advantage, potentially outweighing some of the ADME drawbacks.

**Overall Assessment:**

Ligand B has a significantly better binding affinity and slightly better BBB penetration and hERG risk. However, Ligand A has better TPSA, logP, DILI, metabolic stability (Cl_mic), and in vitro half-life, and Pgp efflux. Both compounds have poor Caco-2 and solubility.

Given the GPCR-specific priorities, and the substantial difference in binding affinity, Ligand B is the more promising candidate *despite* its slightly worse ADME profile. The stronger binding affinity is likely to be more impactful for efficacy, and the other issues might be addressable through further optimization.

Output:
1
2025-04-17 03:44:24,736 - INFO - Reasoning:

Let's analyze Ligand A and Ligand B against the provided guidelines, prioritizing GPCR-specific properties (BBB, logP, Pgp, TPSA, and affinity) for DRD2.

**Molecular Weight:** Both ligands (342.439 and 346.431 Da) fall comfortably within the ideal 200-500 Da range.

**TPSA:** Ligand A (78.43) is slightly higher than Ligand B (73.39), but both are below the 90 A^2 threshold desirable for CNS targets.

**logP:** Ligand A (2.087) is within the optimal 1-3 range. Ligand B (3.28) is at the higher end but still acceptable.

**H-Bond Donors/Acceptors:** Ligand A has 3 HBD and 3 HBA, while Ligand B has 0 HBD and 6 HBA. Both are within acceptable limits (<=5 HBD and <=10 HBA).

**QED:** Both ligands have good QED scores (0.664 and 0.849, respectively), indicating drug-like properties.

**DILI:** Ligand A (23.769) has a significantly lower DILI risk than Ligand B (47.421), which is a substantial advantage.

**BBB:** Ligand B (66.499) has a considerably better BBB penetration score than Ligand A (45.095). This is a *critical* factor for a DRD2 ligand targeting CNS disorders.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.868 and -4.523), which is unusual and suggests poor permeability. However, the scale is not defined, so we cannot interpret this value accurately.

**Aqueous Solubility:** Both ligands have negative solubility values (-2.727 and -3.243), which is also unusual and suggests poor solubility. Again, the scale is not defined.

**hERG Inhibition:** Both ligands show low hERG inhibition liability (0.104 and 0.184).

**Microsomal Clearance:** Ligand A (29.891) has lower microsomal clearance than Ligand B (35.947), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand B (11.517) has a longer in vitro half-life than Ligand A (7.556).

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.094 and 0.078).

**Binding Affinity:** Ligand B (-8.1 kcal/mol) has a slightly better binding affinity than Ligand A (-9.8 kcal/mol). While the difference is not huge, it's still a positive for Ligand B.

**Overall Assessment:**

The key trade-offs are: Ligand B has superior BBB penetration and binding affinity, while Ligand A has a much lower DILI risk and better metabolic stability. Given that this is a CNS target (DRD2), BBB penetration is paramount. The slightly better affinity of Ligand B further strengthens its position. The lower DILI of Ligand A is attractive, but can potentially be addressed through further structural modifications. The unusual Caco-2 and solubility values are concerning for both, but we lack the scale to interpret them.

Output:
1
2025-04-17 03:44:24,736 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (348.487 and 346.471 Da) fall comfortably within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (69.64) is better than Ligand B (71.34). Both are below the 90 Angstrom threshold desirable for CNS targets, but A is closer to the optimal range.

**3. logP:** Ligand A (2.272) is within the optimal 1-3 range. Ligand B (3.608) is slightly higher, pushing towards potential solubility issues, but still acceptable.

**4. H-Bond Donors:** Both ligands have 2 HBD, which is within the acceptable limit of <=5.

**5. H-Bond Acceptors:** Both ligands have 3 HBA, also within the acceptable limit of <=10.

**6. QED:** Ligand B (0.755) has a higher QED score than Ligand A (0.522), indicating a more drug-like profile overall.

**7. DILI:** Ligand A (16.867) has a significantly lower DILI risk than Ligand B (39.744). This is a substantial advantage for Ligand A.

**8. BBB:** Ligand A (70.182) has a better BBB penetration score than Ligand B (63.94). This is *critical* for a CNS target like DRD2.

**9. Caco-2 Permeability:** Ligand A (-4.898) has a worse Caco-2 permeability than Ligand B (-4.673). However, Caco-2 is less important than BBB for CNS targets.

**10. Aqueous Solubility:** Ligand A (-2.537) has a worse aqueous solubility than Ligand B (-4.227). This is a potential drawback for Ligand A, but can be mitigated with formulation strategies.

**11. hERG Inhibition:** Ligand A (0.324) has a lower hERG inhibition risk than Ligand B (0.505), which is favorable.

**12. Microsomal Clearance:** Ligand A (58.332) has a lower microsomal clearance than Ligand B (54.107), suggesting better metabolic stability.

**13. In vitro Half-Life:** Ligand B (61.612) has a longer in vitro half-life than Ligand A (-5.753). This is a positive for Ligand B.

**14. P-gp Efflux:** Ligand A (0.068) has a lower P-gp efflux liability than Ligand B (0.291). Lower P-gp efflux is beneficial for CNS penetration.

**15. Binding Affinity:** Ligand B (-7.8) has a slightly better binding affinity than Ligand A (-8.2). While a 1.5 kcal/mol advantage is significant, the other ADME properties are more critical in this case.

**Overall Assessment:**

Ligand A is the stronger candidate. While Ligand B has a slightly better binding affinity and half-life, Ligand A excels in the crucial properties for a CNS-targeting GPCR ligand: significantly lower DILI risk, better BBB penetration, lower P-gp efflux, and lower hERG inhibition. The slightly lower solubility of Ligand A is a manageable concern compared to the potential liabilities of Ligand B.

Output:
0
2025-04-17 03:44:24,737 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (368.79 and 356.423 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (50.7) is excellent, well below the 90 A^2 threshold for CNS targets. Ligand B (108.05) is higher, but still potentially acceptable, though less ideal.

**logP:** Ligand A (3.811) is optimal. Ligand B (-1.419) is significantly lower, which could hinder membrane permeability and CNS penetration.

**H-Bond Donors/Acceptors:** Ligand A (HBD=1, HBA=4) and Ligand B (HBD=2, HBA=5) both have reasonable numbers of H-bond donors and acceptors, falling within the acceptable ranges.

**QED:** Ligand A (0.834) has a very good QED score, indicating high drug-likeness. Ligand B (0.527) is acceptable, but lower.

**DILI:** Ligand A (56.495) has a moderate DILI risk, but is still acceptable. Ligand B (18.224) has a very low DILI risk, which is a positive.

**BBB:** Ligand A (88.096) has excellent BBB penetration potential. Ligand B (47.111) has poor BBB penetration, a major drawback for a CNS target like DRD2.

**Caco-2 Permeability:** Ligand A (-4.807) has poor Caco-2 permeability. Ligand B (-5.337) also has poor Caco-2 permeability.

**Aqueous Solubility:** Ligand A (-4.174) and Ligand B (-0.495) both have poor aqueous solubility.

**hERG:** Both ligands have very low hERG inhibition liability (0.332 and 0.055 respectively).

**Microsomal Clearance:** Ligand A (25.114) has moderate microsomal clearance. Ligand B (-2.143) has negative clearance, which is not physically possible and likely indicates an issue with the data or prediction method.

**In vitro Half-Life:** Ligand A (3.298 hours) has a short half-life. Ligand B (-10.281 hours) also has a negative half-life, which is not physically possible.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.204 and 0.001 respectively).

**Binding Affinity:** Ligand A (-9.6 kcal/mol) has significantly stronger binding affinity than Ligand B (-7.4 kcal/mol). This is a substantial difference.

**Overall Assessment:**

Ligand A is the superior candidate. While it has moderate DILI risk and poor Caco-2 permeability, its excellent BBB penetration, optimal logP, strong binding affinity, and good QED score outweigh these drawbacks. Ligand B's poor logP and, critically, its very poor BBB penetration make it a less attractive candidate for a CNS target. The negative values for clearance and half-life for Ligand B raise serious concerns about the reliability of its predicted ADME properties. The large difference in binding affinity (-9.6 vs -7.4 kcal/mol) is also a significant factor favoring Ligand A.

Output:
1
2025-04-17 03:44:24,737 - INFO - Reasoning:

Let's analyze Ligand A and Ligand B based on the provided guidelines, prioritizing GPCR-specific properties (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (374.392) is slightly higher than Ligand B (347.459), but both are acceptable.

**TPSA:** Ligand A (84.73) is better than Ligand B (61.88) as it is closer to the ideal range for CNS targets (<=90). Ligand B is also good, but A has a slight edge.

**logP:** Ligand A (3.341) is optimal (1-3), while Ligand B (0.781) is a bit low, potentially hindering permeation. This is a significant advantage for Ligand A.

**H-Bond Donors/Acceptors:** Ligand A (HBD=2, HBA=6) and Ligand B (HBD=1, HBA=4) both fall within acceptable limits.

**QED:** Both ligands have similar QED values (A: 0.784, B: 0.747), indicating good drug-likeness.

**DILI:** Ligand A (70.841) has a higher DILI risk than Ligand B (4.692). This is a significant drawback for Ligand A.

**BBB:** Ligand B (77.007) has a substantially better BBB penetration percentile than Ligand A (56.611). This is a critical advantage for a CNS target like DRD2.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.203 and -5.055), which is unusual and suggests poor permeability. However, these values are on a scale where negative values are possible, and direct comparison is difficult without knowing the scale's specifics.

**Aqueous Solubility:** Both ligands have negative solubility values (-4.257 and -1.202). Similar to Caco-2, interpretation is limited without knowing the scale.

**hERG:** Both ligands have very low hERG inhibition liability (A: 0.076, B: 0.339), which is excellent.

**Microsomal Clearance:** Ligand B (11.057) has a lower microsomal clearance than Ligand A (20.879), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (15.345) has a longer half-life than Ligand B (5.851), which is generally desirable.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (A: 0.04, B: 0.013), which is favorable for CNS penetration.

**Binding Affinity:** Ligand A (-8.7 kcal/mol) has a slightly better binding affinity than Ligand B (-8.3 kcal/mol). While the difference is not huge, it's a positive for Ligand A.

**Overall Assessment:**

Ligand A has advantages in logP, TPSA, and binding affinity, and a longer half-life. However, it suffers from a significantly higher DILI risk and lower BBB penetration. Ligand B excels in BBB penetration, has a much lower DILI risk, and better metabolic stability. Given the CNS target (DRD2), BBB penetration and safety (DILI) are paramount. The slightly better affinity of Ligand A is unlikely to overcome these significant drawbacks.

Output:
1
2025-04-17 03:44:24,737 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (349.427 and 346.471 Da) fall comfortably within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (66.02) is slightly higher than Ligand B (58.64). Both are below the 90 A^2 threshold desirable for CNS targets, but B is preferable.

**3. logP:** Both ligands have good logP values (2.801 and 2.102), falling within the optimal 1-3 range.

**4. H-Bond Donors:** Both have 1 HBD, which is acceptable.

**5. H-Bond Acceptors:** Ligand A has 5 HBA, and Ligand B has 3. Both are below the 10 threshold.

**6. QED:** Ligand B (0.793) has a significantly better QED score than Ligand A (0.52), indicating a more drug-like profile.

**7. DILI:** Ligand B (22.8) has a much lower DILI risk than Ligand A (52.385), a significant advantage.

**8. BBB:** Both ligands have excellent BBB penetration (75.107), exceeding the 70% threshold for CNS targets.

**9. Caco-2 Permeability:** Both have negative Caco-2 values (-4.505 and -4.514). This is unusual and suggests poor permeability. However, as these are negative values, it's difficult to directly compare.

**10. Aqueous Solubility:** Both have negative solubility values (-2.425 and -3.5). Again, this is unusual and suggests poor solubility. Ligand B is slightly worse.

**11. hERG Inhibition:** Both have low hERG inhibition risk (0.468 and 0.233). Ligand B is slightly better.

**12. Microsomal Clearance:** Ligand A (72.74) has a higher microsomal clearance than Ligand B (3.366), meaning it's less metabolically stable.

**13. In vitro Half-Life:** Ligand B (10.954) has a significantly longer in vitro half-life than Ligand A (-19.238), a substantial benefit.

**14. P-gp Efflux:** Both have very low P-gp efflux liability (0.278 and 0.039), which is good for CNS penetration. Ligand B is better.

**15. Binding Affinity:** Ligand B (-7.8 kcal/mol) has a slightly better binding affinity than Ligand A (-7.5 kcal/mol). While the difference is small, it's within the range where it could outweigh minor ADME drawbacks.

**Overall Assessment:**

Ligand B is the superior candidate. It has a better QED score, significantly lower DILI risk, better metabolic stability (lower Cl_mic, longer t1/2), lower P-gp efflux, and slightly better binding affinity. While both have issues with Caco-2 and solubility, the other advantages of Ligand B are more critical for a CNS-targeting GPCR like DRD2.

Output:
1
2025-04-17 03:44:24,737 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (378.259 and 348.447 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (58.37) is excellent, well below the 90 A^2 threshold for CNS targets. Ligand B (93.09) is slightly higher but still acceptable, though less optimal.

**3. logP:** Ligand A (4.173) is a bit high, potentially leading to solubility issues or off-target interactions. Ligand B (2.101) is within the optimal 1-3 range.

**4. H-Bond Donors:** Both ligands have acceptable HBD counts (1 and 2, respectively), well below the limit of 5.

**5. H-Bond Acceptors:** Both ligands have acceptable HBA counts (4 and 5, respectively), well below the limit of 10.

**6. QED:** Both ligands have similar and good QED values (0.724 and 0.704), indicating good drug-like properties.

**7. DILI:** Ligand A (78.17) has a higher DILI risk than Ligand B (69.794), though both are reasonably low.

**8. BBB:** Ligand A (76.386) has a better BBB penetration percentile than Ligand B (81.698), which is crucial for a CNS target like DRD2.

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.829 and -4.7), which is unusual and suggests poor permeability. This is a significant concern for both.

**10. Aqueous Solubility:** Both ligands have negative solubility values (-5.101 and -3.763), indicating very poor aqueous solubility. This is a major drawback.

**11. hERG Inhibition:** Ligand A (0.853) has a slightly higher hERG inhibition risk than Ligand B (0.129).

**12. Microsomal Clearance:** Ligand B (55.265) has significantly lower microsomal clearance than Ligand A (88.317), suggesting better metabolic stability.

**13. In vitro Half-Life:** Ligand A (171.3) has a much longer in vitro half-life than Ligand B (3.614), which is a positive attribute.

**14. P-gp Efflux:** Ligand A (0.73) has lower P-gp efflux liability than Ligand B (0.217), which is favorable for CNS penetration.

**15. Binding Affinity:** Ligand B (-9.0 kcal/mol) has a significantly stronger binding affinity than Ligand A (-8.2 kcal/mol). This >1.5 kcal/mol difference is substantial and can outweigh some ADME drawbacks.

**Overall Assessment:**

While Ligand A has better BBB penetration and a longer half-life, Ligand B's significantly stronger binding affinity (-9.0 vs -8.2 kcal/mol) is a major advantage, especially for a GPCR target. The lower microsomal clearance of Ligand B is also beneficial. Both compounds suffer from poor solubility and permeability, but the superior affinity of Ligand B makes it the more promising candidate, assuming these solubility/permeability issues can be addressed through formulation or further chemical modifications.

Output:
1
2025-04-17 03:44:24,737 - INFO - Reasoning:

Let's analyze Ligand A and Ligand B based on the provided guidelines, prioritizing GPCR-specific properties (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (350.5 & 376.6 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (69.64) is significantly better than Ligand B (51.02) regarding TPSA, falling well below the 90 A^2 threshold for CNS targets. Ligand B is also good, but A is superior.

**logP:** Both ligands have acceptable logP values (2.183 & 3.536), within the optimal 1-3 range. Ligand B is slightly higher, which *could* be a minor concern for solubility, but isn't a dealbreaker.

**H-Bond Donors/Acceptors:** Ligand A (2 HBD, 3 HBA) and Ligand B (0 HBD, 6 HBA) both fall within acceptable limits (<=5 HBD, <=10 HBA).

**QED:** Ligand A (0.705) has a much better QED score than Ligand B (0.362), indicating a more drug-like profile.

**DILI:** Ligand A (20.4%) has a significantly lower DILI risk than Ligand B (57.9%). This is a major advantage for Ligand A.

**BBB:** Ligand A (77.2%) has a better BBB penetration percentile than Ligand B (67.2%), which is crucial for a CNS target like DRD2. Both are reasonably good, but A is preferred.

**Caco-2 Permeability:** Ligand A (-4.852) shows poor Caco-2 permeability, while Ligand B (-5.503) is also poor. This is not ideal, but not a primary concern given the focus on CNS penetration.

**Aqueous Solubility:** Both ligands have poor aqueous solubility (-3.057 and -2.191 respectively). This could pose formulation challenges, but is less critical for CNS drugs that rely on BBB penetration.

**hERG:** Both ligands have low hERG inhibition liability (0.541 & 0.662), which is good.

**Microsomal Clearance:** Ligand B (95.5) has a significantly higher microsomal clearance than Ligand A (27.4), indicating lower metabolic stability. This is a significant drawback for Ligand B.

**In vitro Half-Life:** Ligand B (6.8) has a longer in vitro half-life than Ligand A (-1.3), which is preferable. However, the negative value for A is concerning and suggests rapid metabolism or instability.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.344 & 0.658), which is favorable for CNS penetration.

**Binding Affinity:** Ligand A (-7.7 kcal/mol) has a slightly better binding affinity than Ligand B (-6.8 kcal/mol). While the difference is less than the 1.5 kcal/mol threshold, it contributes to the overall preference for A.

**Overall Assessment:**

Ligand A is the stronger candidate. It excels in crucial areas for a CNS-targeting GPCR ligand: TPSA, BBB, DILI, QED, and binding affinity. While its Caco-2 permeability and in vitro half-life are concerning, the superior BBB penetration, lower DILI risk, and better QED outweigh these drawbacks. Ligand B's higher metabolic clearance and lower QED are significant liabilities.

Output:
1
2025-04-17 03:44:24,737 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 drug candidates, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (352.519 and 367.515 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (58.64) is significantly better than Ligand B (80.32). For CNS targets, we want TPSA <= 90, and A is comfortably within that range, while B is approaching the upper limit.

**logP:** Both ligands have good logP values (3.125 and 2.753), falling within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A (HBD=1, HBA=3) is preferable to Ligand B (HBD=2, HBA=5) as it has fewer hydrogen bond donors and acceptors, generally improving permeability. Both are within acceptable limits.

**QED:** Both ligands have reasonable QED scores (0.73 and 0.658), indicating good drug-like properties.

**DILI:** Ligand A (19.698) has a much lower DILI risk than Ligand B (40.83). This is a significant advantage for A.

**BBB:** Ligand A (71.772) has a better BBB penetration percentile than Ligand B (61.38). While both are not exceptionally high, A is closer to the desirable >70 threshold for CNS targets.

**Caco-2 Permeability:** Ligand A (-4.215) and Ligand B (-4.966) both have negative Caco-2 values, which is unusual and suggests poor permeability. However, the scale is not specified, so it's hard to interpret.

**Aqueous Solubility:** Both ligands have similar, very poor aqueous solubility (-2.967 and -2.864). This could be a formulation challenge for both.

**hERG:** Both ligands have low hERG inhibition liability (0.403 and 0.436), which is good.

**Microsomal Clearance:** Ligand B (52.962) has lower microsomal clearance than Ligand A (83.219), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand B (8.429) has a significantly longer in vitro half-life than Ligand A (2.6). This is a substantial advantage for B.

**P-gp Efflux:** Both ligands have similar P-gp efflux liability (0.209 and 0.276), which is relatively low, suggesting reasonable efflux control.

**Binding Affinity:** Ligand B (-7.8 kcal/mol) has a slightly better binding affinity than Ligand A (-7.2 kcal/mol). This 0.6 kcal/mol difference is notable, but not overwhelmingly decisive.

**Overall Assessment:**

Considering the GPCR-specific priorities, Ligand A is the stronger candidate. Its superior TPSA, lower DILI risk, and better BBB penetration are crucial for a CNS-targeting drug. While Ligand B has better metabolic stability and slightly higher affinity, the advantages of A in terms of CNS penetration and safety outweigh these factors. The poor solubility is a concern for both, but can potentially be addressed through formulation strategies.

Output:
0
2025-04-17 03:44:24,738 - INFO - Reasoning:

Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (341.455 and 348.447 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (73.99) is significantly better than Ligand B (106.34). For CNS targets, we want TPSA <= 90, so Ligand A is preferable.

**3. logP:** Ligand A (3.75) is within the optimal range (1-3), while Ligand B (1.556) is at the lower end, potentially hindering permeation.

**4. H-Bond Donors:** Both have 3 HBD, which is acceptable.

**5. H-Bond Acceptors:** Ligand A has 2 HBA, while Ligand B has 5. Both are within the acceptable range of <=10, but Ligand A is better.

**6. QED:** Both ligands have similar QED values (0.684 and 0.661), indicating good drug-likeness.

**7. DILI:** Ligand A (65.917) has a higher DILI risk than Ligand B (45.095). This favors Ligand B.

**8. BBB:** Ligand B (70.027) has a slightly better BBB penetration percentile than Ligand A (68.748), but both are above the desirable 70% threshold for CNS targets.

**9. Caco-2 Permeability:** Ligand A (-4.983) has significantly better Caco-2 permeability than Ligand B (-5.241).

**10. Aqueous Solubility:** Ligand A (-5.168) has better aqueous solubility than Ligand B (-2.296).

**11. hERG Inhibition:** Ligand A (0.738) has a lower hERG inhibition risk than Ligand B (0.238), which is preferable.

**12. Microsomal Clearance:** Ligand A (55.85) has higher microsomal clearance than Ligand B (25.946), indicating lower metabolic stability. Ligand B is preferred.

**13. In vitro Half-Life:** Ligand A (24.074) has a longer in vitro half-life than Ligand B (-1.398), which is preferable.

**14. P-gp Efflux:** Ligand A (0.44) has lower P-gp efflux liability than Ligand B (0.031), which is preferable for CNS exposure.

**15. Binding Affinity:** Ligand B (-8.6 kcal/mol) has a slightly better binding affinity than Ligand A (-7.9 kcal/mol). This is a significant advantage.

**Overall Assessment:**

While Ligand B has a better binding affinity and lower DILI risk, Ligand A excels in several key properties for CNS penetration: TPSA, logP, Caco-2 permeability, solubility, hERG inhibition, and P-gp efflux. The difference in binding affinity (0.7 kcal/mol) is not substantial enough to outweigh the significant advantages of Ligand A in terms of CNS penetration and safety. The better TPSA and logP of Ligand A will likely translate to better brain exposure.

Output:
1
2025-04-17 03:44:24,738 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (349.383 Da) is slightly lower, which could be beneficial for permeability, but both are acceptable.

**TPSA:** Ligand A (85.3) is better than Ligand B (60.77). For CNS targets, TPSA should be <= 90, so both are good, but Ligand B is closer to the optimal range.

**logP:** Ligand A (1.714) is within the optimal range (1-3), while Ligand B (3.412) is at the upper end. While still acceptable, higher logP can sometimes lead to off-target effects.

**H-Bond Donors/Acceptors:** Ligand A has 1 HBD and 5 HBA, while Ligand B has 2 HBD and 4 HBA. Both are within the acceptable limits (<=5 HBD and <=10 HBA).

**QED:** Both ligands have similar QED values (0.871 and 0.812), indicating good drug-like properties.

**DILI:** Ligand A (56.223) has a higher DILI risk than Ligand B (17.526). This is a significant advantage for Ligand B.

**BBB:** Ligand B (77.239) has a substantially better BBB penetration score than Ligand A (46.336). This is *critical* for a CNS target like DRD2.

**Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and suggests poor permeability. However, the scale is not specified, so it's hard to interpret.

**Aqueous Solubility:** Both ligands have negative solubility values, which is also unusual and suggests poor solubility. Again, the scale is not specified.

**hERG Inhibition:** Ligand A (0.025) has a very low hERG inhibition risk, while Ligand B (0.572) is higher, but still relatively low.

**Microsomal Clearance:** Ligand A (-8.769) has a much lower (better) microsomal clearance than Ligand B (70.889). This indicates greater metabolic stability for Ligand A.

**In vitro Half-Life:** Ligand A (-1.745) has a negative half-life, which is not possible and suggests an issue with the data. Ligand B (8.538) has a reasonable half-life.

**P-gp Efflux:** Ligand A (0.012) has very low P-gp efflux, which is desirable for CNS penetration. Ligand B (0.572) is higher, but still acceptable.

**Binding Affinity:** Both ligands have similar and good binding affinities (-7.0 and -7.2 kcal/mol). The difference is minimal.

**Overall Assessment:**

Ligand B is the stronger candidate. While Ligand A has better metabolic stability (lower Cl_mic) and lower P-gp efflux, the significantly better BBB penetration (77.239 vs 46.336) and lower DILI risk of Ligand B are crucial for a CNS-targeting drug. The questionable values for Caco-2 and solubility for both are concerning but don't outweigh the advantages of Ligand B. The negative half-life for Ligand A is a major red flag.

Output:
1
2025-04-17 03:44:24,738 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (348.491 and 369.897 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (76.02) is excellent, well below the 90 A^2 threshold for CNS targets. Ligand B (96.01) is still reasonable but less optimal, approaching the upper limit.

**3. logP:** Both ligands have good logP values (2.313 and 2.233), falling within the optimal 1-3 range.

**4. H-Bond Donors:** Ligand A (2) and Ligand B (3) are both acceptable, being less than 5.

**5. H-Bond Acceptors:** Ligand A (4) and Ligand B (5) are both acceptable, being less than 10.

**6. QED:** Ligand A (0.828) has a significantly better QED score than Ligand B (0.62), indicating a more drug-like profile.

**7. DILI:** Ligand A (26.561) has a much lower DILI risk than Ligand B (58.434), suggesting better hepatotoxicity potential. Both are below the 60 threshold, but A is preferable.

**8. BBB:** Ligand A (70.88) has a good BBB penetration percentile, exceeding the 70% threshold for CNS targets. Ligand B (58.123) is considerably lower, raising concerns about CNS exposure.

**9. Caco-2:** Both have negative Caco-2 values, which is unusual and likely indicates poor permeability. However, the scale is not specified, so it's hard to interpret.

**10. Solubility:** Both ligands have negative solubility values, which is also unusual.

**11. hERG:** Both have low hERG inhibition liability (0.151 and 0.356), which is good.

**12. Cl_mic:** Ligand B (50.886) has a lower microsomal clearance than Ligand A (58.298), suggesting better metabolic stability.

**13. t1/2:** Ligand B (45.527) has a longer in vitro half-life than Ligand A (8.855), which is desirable.

**14. Pgp:** Ligand A (0.034) has significantly lower P-gp efflux liability than Ligand B (0.085), which is crucial for CNS penetration.

**15. Binding Affinity:** Ligand A (-9.3 kcal/mol) has a slightly better binding affinity than Ligand B (-8.3 kcal/mol). While both are excellent, the 1 kcal/mol difference is meaningful.

**Overall Assessment:**

Ligand A is the stronger candidate. It excels in crucial areas for CNS GPCR targets: TPSA, BBB penetration, Pgp efflux, and DILI risk. While Ligand B has better metabolic stability (lower Cl_mic and longer t1/2), the superior CNS penetration profile of Ligand A, combined with its better QED and slightly better affinity, outweigh these benefits. The unusual negative values for Caco-2 and solubility are concerning for both, but the other factors heavily favor Ligand A.

Output:
1
2025-04-17 03:44:24,738 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (364.471 Da) is slightly higher than Ligand B (338.455 Da), but both are acceptable.

**2. TPSA:** Ligand A (84.3) is better than Ligand B (62.98). For CNS targets, we want TPSA <= 90, and both are well within this range. Ligand B is preferable here.

**3. logP:** Ligand A (1.565) is within the optimal range (1-3), while Ligand B (4.586) is higher. While not drastically high, Ligand B's logP is approaching a level that could cause solubility issues or off-target interactions. Ligand A is preferable.

**4. H-Bond Donors:** Ligand A (1) is better than Ligand B (2). Lower HBD is generally preferred for better permeability.

**5. H-Bond Acceptors:** Both ligands have the same number of HBA (5), which is acceptable (<=10).

**6. QED:** Ligand A (0.835) has a higher QED than Ligand B (0.755), indicating a more drug-like profile.

**7. DILI:** Both ligands have similar DILI risk (Ligand A: 49.477, Ligand B: 51.028), and both are below the 60 threshold, indicating low risk.

**8. BBB:** This is a crucial parameter for CNS targets. Ligand A has a significantly higher BBB penetration percentile (85.343) compared to Ligand B (69.484). This is a major advantage for Ligand A.

**9. Caco-2 Permeability:** Ligand A (-4.954) has a worse Caco-2 permeability than Ligand B (-5.097), but both are very poor.

**10. Aqueous Solubility:** Ligand A (-1.891) has better solubility than Ligand B (-4.885).

**11. hERG Inhibition:** Both ligands have very low hERG inhibition risk (Ligand A: 0.539, Ligand B: 0.696).

**12. Microsomal Clearance:** Ligand B (69.34) has a higher clearance than Ligand A (21.561), suggesting lower metabolic stability.

**13. In vitro Half-Life:** Ligand B (68.399) has a longer half-life than Ligand A (22.121).

**14. P-gp Efflux:** Both ligands show no P-gp efflux liability (0.169 and 0.237).

**15. Binding Affinity:** Both ligands have similar binding affinity (Ligand A: 0, Ligand B: 0).

**Overall Assessment:**

Considering the GPCR-specific priorities, Ligand A is the better candidate. It has a significantly better BBB penetration (85.343 vs. 69.484), a more optimal logP (1.565 vs. 4.586), better solubility, and a lower microsomal clearance, indicating better metabolic stability. While Ligand B has a longer half-life, the superior CNS penetration and drug-like properties of Ligand A outweigh this benefit. The similar binding affinity means that the ADME properties are the deciding factors.

Output:
1
2025-04-17 03:44:24,738 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (348.487 and 362.539 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (60.85) is better than Ligand B (49.41). Both are below the 90 A^2 threshold for CNS targets, but A is slightly higher.

**3. logP:** Both ligands have good logP values (2.484 and 3.989), falling within the optimal 1-3 range. Ligand B is closer to the upper limit, which could potentially raise solubility concerns, but it's not a major issue.

**4. H-Bond Donors:** Both have 1 HBD, which is within the acceptable limit of <=5.

**5. H-Bond Acceptors:** Both have 3 HBA, which is within the acceptable limit of <=10.

**6. QED:** Both ligands have good QED values (0.797 and 0.832), indicating good drug-like properties.

**7. DILI:** Ligand A (19.465) has a significantly lower DILI risk than Ligand B (39.201). This is a substantial advantage for Ligand A.

**8. BBB:** Ligand B (74.952) has a much better BBB penetration percentile than Ligand A (50.523). This is a critical factor for a CNS target like DRD2.

**9. Caco-2 Permeability:** Both have negative values (-4.671 and -4.616), which is unusual and suggests poor permeability. This is a concern for both, but doesn't differentiate them.

**10. Aqueous Solubility:** Both have negative values (-1.941 and -4.105), indicating poor aqueous solubility. Ligand B is worse.

**11. hERG Inhibition:** Both have very low hERG inhibition risk (0.088 and 0.248).

**12. Microsomal Clearance:** Ligand A (19.313) has significantly lower microsomal clearance than Ligand B (63.311), indicating better metabolic stability.

**13. In vitro Half-Life:** Ligand B (30.948) has a longer in vitro half-life than Ligand A (23.345).

**14. P-gp Efflux:** Both have very low P-gp efflux liability (0.151 and 0.31).

**15. Binding Affinity:** Both ligands have the same binding affinity (-8 kcal/mol), which is excellent.

**Overall Assessment:**

Ligand B has a significantly better BBB penetration (74.952 vs 50.523) and longer half-life (30.948 vs 23.345). However, Ligand A has a much lower DILI risk (19.465 vs 39.201) and better metabolic stability (lower Cl_mic). Given the importance of BBB penetration for a CNS target like DRD2, and the equal binding affinity, Ligand B is slightly favored. The lower DILI risk of Ligand A is attractive, but can potentially be addressed with further structural modifications.

Output:
1
2025-04-17 03:44:24,738 - INFO - Batch 54 complete. Total preferences: 864
2025-04-17 03:44:24,738 - INFO - Processing batch 55/512...
2025-04-17 03:45:06,024 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (348.447 and 349.475 Da) fall comfortably within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (88.76) is better than Ligand B (65.79) in terms of TPSA. Both are below the 90 A^2 threshold for CNS targets, but A is closer to the ideal.

**3. logP:** Ligand A (1.399) and Ligand B (2.203) are both within the optimal 1-3 range.

**4. H-Bond Donors:** Both have 1 HBD, which is acceptable.

**5. H-Bond Acceptors:** Ligand A has 5 HBA, and Ligand B has 4. Both are below the 10 threshold.

**6. QED:** Both ligands have similar QED values (0.869 and 0.855), indicating good drug-likeness.

**7. DILI:** Ligand A (38.852) has a slightly higher DILI risk than Ligand B (21.093), but both are below the concerning 60 threshold.

**8. BBB:** Ligand A (78.209) has a significantly better BBB penetration percentile than Ligand B (63.94). This is a critical factor for a CNS target like DRD2.

**9. Caco-2 Permeability:** Ligand A (-4.926) has better Caco-2 permeability than Ligand B (-4.866), indicating better intestinal absorption.

**10. Aqueous Solubility:** Ligand A (-0.708) has better aqueous solubility than Ligand B (-1.347).

**11. hERG Inhibition:** Ligand A (0.396) has a lower hERG inhibition liability than Ligand B (0.746), which is preferable.

**12. Microsomal Clearance:** Ligand A (0.917) has lower microsomal clearance than Ligand B (0.305), suggesting better metabolic stability.

**13. In vitro Half-Life:** Ligand A (12.775) has a longer in vitro half-life than Ligand B (27.795).

**14. P-gp Efflux:** Ligand A (0.015) has significantly lower P-gp efflux liability than Ligand B (0.194), which is crucial for CNS penetration.

**15. Binding Affinity:** Both ligands have the same binding affinity (-8.0 kcal/mol), which is excellent.

**Overall Assessment:**

Ligand A consistently outperforms Ligand B in key ADME properties relevant for a CNS-targeting GPCR. Specifically, its superior BBB penetration, lower P-gp efflux, lower hERG inhibition, better solubility, and better metabolic stability make it a more promising candidate despite a slightly higher DILI risk. The equal binding affinity removes that as a differentiating factor.

Output:
1
2025-04-17 03:45:06,024 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (347.365 and 364.433 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (61.44) is significantly better than Ligand B (76.66). For CNS targets, we want TPSA <= 90, and A is comfortably within that range, while B is approaching the upper limit.

**logP:** Ligand A (3.63) is optimal, while Ligand B (1.873) is a bit low. A logP between 1-3 is preferred, and B is on the lower end, potentially hindering permeation.

**H-Bond Donors/Acceptors:** Both have 2 HBDs, which is good. Ligand A has 2 HBAs, while Ligand B has 4. Both are acceptable (<=10), but A is slightly preferable.

**QED:** Both ligands have similar QED values (0.868 and 0.655), both above the 0.5 threshold, indicating good drug-like properties.

**DILI:** Ligand A (75.921) has a higher DILI risk than Ligand B (38.736). This is a significant drawback for A.

**BBB:** Ligand B (82.241) has a better BBB penetration percentile than Ligand A (78.054). Both are good (>70), but B is slightly better, which is crucial for a CNS target like DRD2.

**Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and suggests poor permeability. However, the scale is not specified, so it's hard to interpret.

**Aqueous Solubility:** Both have negative solubility values, which is also unusual. Again, the scale is unknown.

**hERG:** Ligand A (0.623) has a slightly higher hERG risk than Ligand B (0.436), but both are relatively low.

**Microsomal Clearance:** Ligand B (30.075) has significantly lower microsomal clearance than Ligand A (69.552), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (49.186) has a longer half-life than Ligand B (-8.785). The negative value for B is concerning and likely an error.

**P-gp Efflux:** Ligand A (0.192) has lower P-gp efflux than Ligand B (0.089), which is favorable for CNS penetration.

**Binding Affinity:** Ligand A (-9.5 kcal/mol) has a significantly stronger binding affinity than Ligand B (-7.5 kcal/mol). This is a substantial advantage, potentially outweighing some of the ADME drawbacks. The difference is >1.5 kcal/mol.

**Overall Assessment:**

While Ligand A has a superior binding affinity and better P-gp efflux, its higher DILI risk and higher TPSA are concerning. Ligand B has a better safety profile (lower DILI) and slightly better BBB penetration, and significantly better metabolic stability. The stronger binding affinity of A is a significant advantage, but the DILI risk is a major concern. Given the CNS target and the importance of safety, I lean towards Ligand B. The negative values for Caco-2 and solubility are concerning for both, but the affinity difference is large enough that A could still be worth pursuing with further optimization. However, considering all factors, especially the DILI and metabolic stability, B is more likely to be a viable drug candidate.

Output:
1
2025-04-17 03:45:06,025 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (361.427 and 348.403 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (106.1) is slightly above the optimal <90 for CNS targets, while Ligand B (91.84) is closer to the ideal range.

**logP:** Ligand A (0.693) is a bit low, potentially hindering permeability. Ligand B (-0.174) is even lower, raising concerns about membrane penetration.

**H-Bond Donors/Acceptors:** Ligand A has 2 HBD and 7 HBA, which are acceptable. Ligand B has 1 HBD and 5 HBA, also acceptable.

**QED:** Ligand A (0.812) has a better QED score than Ligand B (0.545), indicating better overall drug-likeness.

**DILI:** Ligand A (83.404) has a higher DILI risk than Ligand B (39.162). This is a significant negative for Ligand A.

**BBB:** Ligand B (59.093) has a significantly better BBB penetration percentile than Ligand A (30.787). This is crucial for a CNS target like DRD2.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.479 and -5.01), which is unusual and suggests poor permeability. This is a major concern for both.

**Aqueous Solubility:** Both ligands have negative solubility values (-1.556 and -0.903), also unusual and concerning.

**hERG Inhibition:** Ligand A (0.07) has a slightly lower hERG risk than Ligand B (0.27), which is preferable.

**Microsomal Clearance:** Ligand B (10.179) has a lower microsomal clearance than Ligand A (-11.344), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (21.157) has a longer in vitro half-life than Ligand B (-15.869), which is desirable.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.006 and 0.015), which is good for CNS penetration.

**Binding Affinity:** Ligand B (-8.4 kcal/mol) has a slightly better binding affinity than Ligand A (-7.8 kcal/mol). While the difference isn't huge, it's a positive for Ligand B.

**Overall Assessment:**

Ligand B is the more promising candidate despite the low logP and Caco-2/Solubility values. Its significantly better BBB penetration (59.093 vs 30.787) and lower DILI risk (39.162 vs 83.404) are crucial advantages for a CNS-targeting GPCR. The slightly better binding affinity of Ligand B also contributes. While the negative Caco-2 and solubility values are concerning for both, the improved CNS exposure potential of Ligand B outweighs the slightly better QED and half-life of Ligand A. The low logP of both compounds would need to be addressed in further optimization.

Output:
1
2025-04-17 03:45:06,025 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (373.494 Da and 365.453 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (60.93) is better than Ligand B (49.22), both are below the 90 A^2 threshold for CNS targets.

**logP:** Ligand B (3.865) is closer to the optimal 1-3 range than Ligand A (0.248), which is quite low and could hinder membrane permeability. This is a significant advantage for Ligand B.

**H-Bond Donors/Acceptors:** Ligand A (0 HBD, 4 HBA) and Ligand B (1 HBD, 5 HBA) both have acceptable numbers of H-bond donors and acceptors.

**QED:** Both ligands have similar QED values (0.693 and 0.692), indicating good drug-likeness.

**DILI:** Ligand A (13.649) has a much lower DILI risk than Ligand B (44.281). This is a substantial advantage for Ligand A.

**BBB:** Ligand A (80.264) has a slightly better BBB penetration percentile than Ligand B (76.619), both are above 70, which is desirable for CNS targets.

**Caco-2 Permeability:** Ligand A (-4.685) has a worse Caco-2 permeability than Ligand B (-4.988).

**Aqueous Solubility:** Ligand A (-1.345) has slightly better aqueous solubility than Ligand B (-3.571).

**hERG Inhibition:** Ligand A (0.382) has a lower hERG inhibition liability than Ligand B (0.954), indicating a lower risk of cardiotoxicity.

**Microsomal Clearance:** Ligand A (5.987) has a significantly lower microsomal clearance than Ligand B (17.778), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (-2.144) has a worse in vitro half-life than Ligand B (4.817).

**P-gp Efflux:** Ligand A (0.011) has a much lower P-gp efflux liability than Ligand B (0.397), which is crucial for CNS penetration.

**Binding Affinity:** Ligand A (-7.5 kcal/mol) has a slightly better binding affinity than Ligand B (-7.1 kcal/mol). While both are good, the 0.4 kcal/mol difference is noteworthy.

**Overall Assessment:**

Ligand A excels in metabolic stability (low Cl_mic), P-gp efflux (very low), DILI risk, and binding affinity. However, its low logP is a major concern for permeability. Ligand B has a better logP, but suffers from higher DILI risk, higher P-gp efflux, and lower metabolic stability.

Considering the GPCR-specific priorities, BBB is important, but logP and P-gp efflux are critical for CNS penetration. Ligand A's very low P-gp efflux and slightly better BBB are strong advantages. The affinity difference is small enough that it can be potentially overcome with further optimization. While the low logP is a concern, it might be addressed through structural modifications. The lower DILI risk for Ligand A is also a significant safety advantage.

Output:
0
2025-04-17 03:45:06,025 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (346.43 and 354.52 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (73.99) is significantly better than Ligand B (44.81). For CNS targets, we want TPSA <= 90, and lower is preferable. Ligand A is borderline, while Ligand B is excellent.

**logP:** Ligand A (1.456) is within the optimal 1-3 range. Ligand B (4.236) is higher, potentially leading to solubility issues and off-target interactions.

**H-Bond Donors/Acceptors:** Both ligands have 1 HBD and 4 HBA, which are within acceptable limits.

**QED:** Ligand A (0.759) has a better QED score than Ligand B (0.625), indicating a more drug-like profile.

**DILI:** Ligand A (21.95) has a much lower DILI risk than Ligand B (42.54). This is a significant advantage.

**BBB:** Ligand A (62.20) has a better BBB penetration percentile than Ligand B (55.10), although both are below the desirable >70 for CNS targets.

**Caco-2 Permeability:** Ligand A (-4.638) has better Caco-2 permeability than Ligand B (-5.656).

**Aqueous Solubility:** Ligand A (-1.092) has better aqueous solubility than Ligand B (-3.677).

**hERG Inhibition:** Ligand A (0.222) has a lower hERG inhibition liability than Ligand B (0.853).

**Microsomal Clearance:** Ligand B (54.68) has a lower microsomal clearance than Ligand A (26.74), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand B (35.70) has a longer half-life than Ligand A (21.41).

**P-gp Efflux:** Ligand A (0.168) has lower P-gp efflux liability than Ligand B (0.438), which is favorable for CNS penetration.

**Binding Affinity:** Both ligands have similar binding affinities (-8.7 and -8.3 kcal/mol), with Ligand A being slightly better. The difference is less than 1.5 kcal/mol, so this isn't a deciding factor.

**Overall Assessment:**

Ligand A is superior due to its better TPSA, logP, DILI risk, BBB, Caco-2 permeability, aqueous solubility, hERG inhibition, and P-gp efflux. While Ligand B has better metabolic stability (lower Cl_mic) and half-life, the ADME properties of Ligand A are more favorable for a CNS-targeting GPCR like DRD2. The slightly better binding affinity of Ligand A further supports this conclusion.

Output:
1
2025-04-17 03:45:06,025 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (353.419 and 349.406 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (113.17) is better than Ligand B (57). While both are reasonably low, Ligand B is significantly lower and more favorable for CNS penetration, falling well below the 90 A^2 threshold. Ligand A is still acceptable, but less ideal.

**logP:** Ligand A (-0.735) is a bit low, potentially hindering membrane permeability. Ligand B (1.386) is within the optimal 1-3 range. This is a significant advantage for Ligand B.

**H-Bond Donors/Acceptors:** Ligand A has 2 HBD and 5 HBA, which is acceptable. Ligand B has 0 HBD and 4 HBA, also acceptable.

**QED:** Both ligands have good QED scores (0.632 and 0.81), indicating good drug-like properties.

**DILI:** Ligand A (22.451) has a lower DILI risk than Ligand B (15.51), which is favorable.

**BBB:** Ligand B (93.37) has a much higher BBB penetration percentile than Ligand A (63.474). This is a crucial factor for a CNS target like DRD2, making Ligand B significantly more promising.

**Caco-2 Permeability:** Both have negative values, indicating low permeability. However, the scale is not defined, making direct comparison difficult.

**Aqueous Solubility:** Both ligands have negative solubility values, indicating poor solubility.

**hERG:** Ligand A (0.178) has a lower hERG inhibition liability than Ligand B (0.488), which is preferable.

**Microsomal Clearance:** Ligand A (-0.583) has lower (better) microsomal clearance than Ligand B (4.371), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (-25.607) has a longer (better) in vitro half-life than Ligand B (7.716).

**P-gp Efflux:** Ligand A (0.029) has lower P-gp efflux liability than Ligand B (0.062), which is beneficial for CNS exposure.

**Binding Affinity:** Ligand B (-9.7 kcal/mol) has a significantly stronger binding affinity than Ligand A (-7.9 kcal/mol). This is a substantial advantage, potentially outweighing some of the ADME drawbacks of Ligand B. The difference is >1.5 kcal/mol.

**Overall Assessment:**

Ligand B excels in the most critical areas for a CNS-targeting GPCR ligand: BBB penetration and binding affinity. While Ligand A has advantages in DILI, metabolic stability, and P-gp efflux, the superior affinity and BBB penetration of Ligand B are more important. The slightly higher logP of Ligand B is also beneficial.

Output:
1
2025-04-17 03:45:06,026 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (349.435 Da) is slightly lower, which could be beneficial for permeability. Ligand B (370.559 Da) is also good.

**TPSA:** Ligand A (102.42) is borderline for CNS penetration, being slightly above the preferred <90. Ligand B (58.64) is excellent, well below 90, and highly favorable for CNS penetration.

**logP:** Ligand A (0.953) is a bit low, potentially hindering membrane permeability. Ligand B (2.544) is within the optimal range (1-3).

**H-Bond Donors/Acceptors:** Ligand A has 2 HBD and 5 HBA, which is acceptable. Ligand B has 1 HBD and 4 HBA, also acceptable.

**QED:** Both ligands have reasonable QED values (A: 0.824, B: 0.678), indicating good drug-like properties.

**DILI:** Ligand A (43.622) has a slightly higher DILI risk than Ligand B (21.714), but both are below the concerning threshold of 60.

**BBB:** This is a critical parameter for CNS targets. Ligand A (38.348) has a poor BBB percentile, while Ligand B (75.998) is very good, exceeding the desirable >70 threshold.

**Caco-2 Permeability:** Ligand A (-5.271) shows poor Caco-2 permeability, while Ligand B (-4.89) is slightly better, though still not ideal.

**Aqueous Solubility:** Both ligands have poor aqueous solubility (-2.167 and -2.851 respectively). This could pose formulation challenges.

**hERG:** Both ligands have low hERG inhibition risk (0.208 and 0.496 respectively).

**Microsomal Clearance:** Ligand A (-6.068) has a lower (better) microsomal clearance than Ligand B (60.465), suggesting better metabolic stability.

**In vitro Half-Life:** Both have similar in vitro half-lives (8.022 and 8.227 hours).

**P-gp Efflux:** Ligand A (0.083) has very low P-gp efflux, which is excellent for CNS exposure. Ligand B (0.161) also has low P-gp efflux, but slightly higher than Ligand A.

**Binding Affinity:** Both ligands have the same binding affinity (-7.3 kcal/mol), which is excellent and a primary driver of potency.

**Overall Assessment:**

While both ligands have excellent binding affinity, Ligand B is significantly better suited as a CNS drug candidate due to its superior BBB penetration (75.998 vs 38.348) and more favorable logP (2.544 vs 0.953). The lower TPSA of Ligand B also contributes to better CNS penetration. Although Ligand A has better metabolic stability (lower Cl_mic) and slightly lower P-gp efflux, the BBB and logP advantages of Ligand B outweigh these benefits, especially for a DRD2 target.

Output:
1
2025-04-17 03:45:06,026 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (343.431 and 364.471 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Both ligands have TPSA values (80.12 and 84.3) below the 90 A^2 threshold for CNS targets, which is good.

**3. logP:** Ligand A (1.025) is slightly better than Ligand B (0.641). Both are within the optimal 1-3 range, but Ligand B is closer to the lower limit, potentially impacting permeability.

**4. H-Bond Donors:** Both have 1 HBD, which is acceptable.

**5. H-Bond Acceptors:** Ligand A has 5 HBA, and Ligand B has 6. Both are below the 10 threshold.

**6. QED:** Both ligands have high QED scores (0.81 and 0.829), indicating good drug-like properties.

**7. DILI:** Ligand A (41.373) has a slightly better DILI percentile than Ligand B (59.984), suggesting a lower risk of liver injury.

**8. BBB:** Ligand A (64.831) has a significantly better BBB percentile than Ligand B (51.881). This is *critical* for a CNS target like DRD2.

**9. Caco-2 Permeability:** Both have negative Caco-2 values (-5.031 and -5.287). This is unusual and suggests poor permeability. However, these values are on a scale where negative values are possible, and direct comparison is difficult without knowing the scale's specifics.

**10. Aqueous Solubility:** Both have negative solubility values (-2.404 and -2.256), indicating poor aqueous solubility. This could pose formulation challenges.

**11. hERG Inhibition:** Both ligands show very low hERG inhibition liability (0.028 and 0.146), which is excellent.

**12. Microsomal Clearance:** Ligand B (24.216) has significantly lower microsomal clearance than Ligand A (44.829), indicating better metabolic stability.

**13. In vitro Half-Life:** Ligand B (4.944) has a longer in vitro half-life than Ligand A (-13.177), which is favorable.

**14. P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.089 and 0.046), which is beneficial for CNS penetration.

**15. Binding Affinity:** Both ligands have the same binding affinity (-8.0 kcal/mol), which is excellent and strong.

**Overall Assessment:**

While Ligand B has better metabolic stability (lower Cl_mic) and a longer half-life, the significantly superior BBB penetration of Ligand A (64.831 vs 51.881) is the deciding factor for a CNS target. The slightly better DILI score of Ligand A is also a plus. The poor Caco-2 and solubility are concerns for both, but can potentially be addressed with formulation strategies. Given the importance of BBB penetration for DRD2, Ligand A is the more promising candidate.

Output:
0
2025-04-17 03:45:06,026 - INFO - Reasoning:

Let's analyze Ligand A and Ligand B against the provided guidelines, prioritizing GPCR-specific properties (BBB, logP, Pgp, TPSA, and affinity) for DRD2.

**Molecular Weight:** Both ligands (345.403 and 369.575 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (93.25) is better than Ligand B (47.36). For CNS targets, TPSA should be <=90, so Ligand A is marginally better, while Ligand B is excellent.

**logP:** Ligand A (1.619) is within the optimal 1-3 range. Ligand B (3.747) is approaching the upper limit, potentially raising solubility concerns, but still acceptable.

**H-Bond Donors/Acceptors:** Ligand A has 1 HBD and 6 HBA, while Ligand B has 0 HBD and 5 HBA. Both are within acceptable limits.

**QED:** Ligand A (0.889) has a significantly better QED score than Ligand B (0.589), indicating a more drug-like profile.

**DILI:** Ligand B (27.608) has a much lower DILI risk than Ligand A (78.247), which is a significant advantage.

**BBB:** Ligand B (70.725) has a much better BBB penetration score than Ligand A (30.089). This is *critical* for a CNS target like DRD2.

**Caco-2 Permeability:** Ligand A (-5.401) has poor Caco-2 permeability, while Ligand B (-4.746) is slightly better, but still poor.

**Aqueous Solubility:** Both ligands have very poor aqueous solubility (-2.024 and -3.574 respectively).

**hERG Inhibition:** Ligand A (0.013) has a very low hERG inhibition risk, which is excellent. Ligand B (0.762) has a moderate risk.

**Microsomal Clearance:** Ligand A (-8.837) has significantly better metabolic stability (lower clearance) than Ligand B (130.425).

**In vitro Half-Life:** Ligand A (-2.976) has a longer half-life than Ligand B (4.384).

**P-gp Efflux:** Ligand A (0.034) has very low P-gp efflux, which is favorable for CNS penetration. Ligand B (0.519) has moderate P-gp efflux.

**Binding Affinity:** Ligand B (-6.3 kcal/mol) has a significantly stronger binding affinity than Ligand A (0.0 kcal/mol). This is a major advantage, potentially outweighing some ADME drawbacks.

**Overall Assessment:**

Ligand B is the stronger candidate despite some ADME liabilities. The significantly improved BBB penetration (70.725 vs 30.089) and *much* stronger binding affinity (-6.3 vs 0.0 kcal/mol) are decisive for a CNS GPCR target. While Ligand B has a higher DILI risk and poorer metabolic stability, these can potentially be addressed through structural modifications. Ligand A's poor affinity and BBB penetration are more difficult to overcome. The poor solubility and Caco-2 permeability are concerns for both, but can be addressed with formulation strategies.



Output:
1
2025-04-17 03:45:06,026 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (360.401 and 347.346 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (87.66) is better than Ligand B (93.46). Both are below the 90 A^2 threshold desirable for CNS targets, but A is closer to the optimal range.

**logP:** Ligand A (0.973) is slightly lower than ideal (1-3), but still acceptable. Ligand B (2.513) is within the optimal range.

**H-Bond Donors/Acceptors:** Ligand A has 3 HBD and 4 HBA, while Ligand B has 2 HBD and 5 HBA. Both are within acceptable limits (<=5 HBD, <=10 HBA).

**QED:** Both ligands have good QED scores (0.659 and 0.751, respectively), indicating good drug-like properties.

**DILI:** Both ligands have relatively high DILI risk (26.018 and 76.154). Ligand A is significantly better here.

**BBB:** Ligand A (76.347) has a significantly better BBB penetration percentile than Ligand B (60.644). This is a *critical* factor for a CNS target like DRD2.

**Caco-2 Permeability:** Ligand A (-5.13) is worse than Ligand B (-4.543), indicating lower intestinal absorption.

**Aqueous Solubility:** Ligand A (-1.409) is better than Ligand B (-3.989), suggesting better solubility.

**hERG Inhibition:** Both ligands show low hERG inhibition risk (0.276 and 0.324).

**Microsomal Clearance:** Ligand A (-4.673) has significantly lower (better) microsomal clearance than Ligand B (43.2). This suggests better metabolic stability.

**In vitro Half-Life:** Ligand A (14.039 hours) has a better in vitro half-life than Ligand B (20.546 hours).

**P-gp Efflux:** Ligand A (0.015) has much lower P-gp efflux liability than Ligand B (0.051), which is crucial for CNS penetration.

**Binding Affinity:** Ligand B (-8.8 kcal/mol) has a slightly better binding affinity than Ligand A (-7.8 kcal/mol). While a 1 kcal/mol difference is noticeable, the ADME properties are more concerning.

**Overall Assessment:**

Ligand A is the stronger candidate. While Ligand B has a slightly better binding affinity, Ligand A excels in crucial ADME properties for a CNS-targeting GPCR. Specifically, its significantly better BBB penetration, lower P-gp efflux, lower DILI risk, and improved metabolic stability (lower Cl_mic) outweigh the minor affinity difference. The better solubility of A is also a plus.



Output:
0
2025-04-17 03:45:06,026 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (354.407 and 354.451 Da) fall comfortably within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (108.05) is better than Ligand B (110.77). Both are reasonably close to the 90 A^2 threshold for CNS targets, but A is preferable.

**3. logP:** Ligand A (-1.669) is lower than ideal (1-3), potentially hindering permeability. Ligand B (-0.18) is closer to the optimal range. This favors Ligand B.

**4. H-Bond Donors:** Ligand A (2) is better than Ligand B (4). Lower HBD generally improves permeability.

**5. H-Bond Acceptors:** Ligand A (6) is better than Ligand B (4). Lower HBA generally improves permeability.

**6. QED:** Both ligands have similar QED values (0.552 and 0.508), indicating good drug-like properties.

**7. DILI:** Ligand A (26.755) has a significantly lower DILI risk than Ligand B (20.279), which is a substantial advantage.

**8. BBB:** Ligand B (40.132) has a much better BBB penetration percentile than Ligand A (29.74). This is *critical* for a CNS target like DRD2 and heavily favors Ligand B.

**9. Caco-2 Permeability:** Both have negative values (-5.175 and -5.309), which is unusual and difficult to interpret without knowing the scale. However, they are very similar.

**10. Aqueous Solubility:** Both have negative values (-0.425 and -0.905), again unusual and difficult to interpret. They are similar.

**11. hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.021 and 0.089).

**12. Microsomal Clearance:** Ligand B (-4.937) has lower (better) microsomal clearance than Ligand A (3.252), suggesting better metabolic stability.

**13. In vitro Half-Life:** Ligand B (12.201) has a significantly longer in vitro half-life than Ligand A (-20.296). This is a major advantage.

**14. P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.003).

**15. Binding Affinity:** Ligand B (-8.2 kcal/mol) has a stronger binding affinity than Ligand A (-6.9 kcal/mol). This is a significant advantage, potentially outweighing some of Ligand A's better ADME properties.

**Overall Assessment:**

While Ligand A has advantages in TPSA, HBD, HBA, and DILI, Ligand B is superior in almost all other critical parameters for a CNS-targeting GPCR. Specifically, its significantly better BBB penetration, longer half-life, stronger binding affinity, and lower microsomal clearance are decisive. The slightly less optimal logP of Ligand B is a concern, but the strong affinity may compensate.

Output:
1
2025-04-17 03:45:06,027 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (330.347 Da) is slightly better than Ligand B (364.389 Da) as it's closer to the lower end, potentially aiding permeability.

**TPSA:** Ligand A (87.9) is excellent, falling well below the 90 A^2 threshold for CNS targets. Ligand B (104.73) is still acceptable but less optimal.

**logP:** Ligand A (3.276) is within the optimal range (1-3). Ligand B (0.457) is significantly lower, which is a major concern for CNS penetration as it may struggle to cross cell membranes.

**H-Bond Donors/Acceptors:** Ligand A (1 HBD, 5 HBA) and Ligand B (3 HBD, 5 HBA) both have reasonable numbers of H-bond donors and acceptors, unlikely to be major issues.

**QED:** Ligand A (0.793) has a better QED score than Ligand B (0.569), indicating a more drug-like profile.

**DILI:** Ligand A (98.876) has a very high DILI risk, which is a significant red flag. Ligand B (36.448) has a much lower and acceptable DILI risk.

**BBB:** Ligand A (48.042) has a moderate BBB penetration, while Ligand B (67.197) is better, though still not ideal (aim for >70).

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.888 and -4.938), which is unusual and suggests poor permeability. These values are likely errors or indicate very poor absorption.

**Aqueous Solubility:** Both ligands have very negative solubility values (-5.748 and -2.17), suggesting extremely poor aqueous solubility. This is a major formulation challenge.

**hERG Inhibition:** Ligand A (0.746) has a slightly higher hERG risk than Ligand B (0.279), but both are relatively low.

**Microsomal Clearance:** Ligand A (52.373) and Ligand B (44.89) have similar microsomal clearance values, suggesting comparable metabolic stability.

**In vitro Half-Life:** Ligand A (14.193 hours) has a better in vitro half-life than Ligand B (-53.462 hours, which is nonsensical).

**P-gp Efflux:** Ligand A (0.322) has lower P-gp efflux liability than Ligand B (0.025), which is favorable for CNS exposure.

**Binding Affinity:** Ligand A (-9.4 kcal/mol) has a significantly stronger binding affinity than Ligand B (-7.7 kcal/mol). This is a substantial advantage.

**Overall Assessment:**

Ligand A has a much stronger binding affinity and better TPSA, QED, P-gp efflux, and in vitro half-life. However, its extremely high DILI risk and moderate BBB penetration are major concerns. Ligand B has a lower DILI risk and better BBB penetration, but its weak logP and significantly weaker binding affinity are problematic.

Given the GPCR-specific priorities, affinity is paramount. The 1.7 kcal/mol difference in binding affinity is substantial and could outweigh the DILI risk, *if* the DILI risk can be mitigated through structural modifications. The poor solubility and permeability of both compounds are serious issues that would need to be addressed regardless. However, the potency advantage of Ligand A is compelling.

Output:
1
2025-04-17 03:45:06,027 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (342.399 and 351.407 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (78.53) is excellent, well below the 90 A^2 threshold for CNS targets. Ligand B (129.37) is still reasonable but higher, potentially impacting BBB penetration.

**logP:** Ligand A (1.391) is within the optimal 1-3 range. Ligand B (-1.015) is slightly below 1, which could hinder permeability.

**H-Bond Donors/Acceptors:** Ligand A (1 HBD, 4 HBA) is favorable. Ligand B (4 HBD, 7 HBA) is acceptable but higher, potentially affecting permeability.

**QED:** Ligand A (0.824) has a very strong drug-like profile. Ligand B (0.451) is below the 0.5 threshold, indicating a less desirable overall drug-likeness.

**DILI:** Ligand A (68.088) has a moderate DILI risk, but is acceptable. Ligand B (27.801) has a very low DILI risk, which is excellent.

**BBB:** Ligand A (65.413) is reasonable but not ideal for a CNS target, being below the >70 percentile. Ligand B (23.769) is significantly lower, suggesting poor BBB penetration.

**Caco-2 Permeability:** Both have negative values, which is unusual. Assuming these are percentile scores, Ligand A (-4.9) is slightly better than Ligand B (-5.659), suggesting marginally better absorption.

**Aqueous Solubility:** Ligand A (-3.301) and Ligand B (-1.033) both have negative solubility values. This is concerning, and needs further investigation.

**hERG:** Both ligands have very low hERG inhibition risk (0.279 and 0.034 respectively).

**Microsomal Clearance:** Ligand A (59.315) has moderate clearance, while Ligand B (-5.026) has negative clearance, which is unusual and suggests very high metabolic stability.

**In vitro Half-Life:** Ligand A (-13.926) has a negative half-life, which is not possible. Ligand B (6.536) has a short half-life.

**Pgp Efflux:** Both ligands have very low Pgp efflux liability (0.11 and 0.002 respectively).

**Binding Affinity:** Ligand B (-7.8 kcal/mol) has a significantly stronger binding affinity than Ligand A (0.0 kcal/mol). This is a substantial advantage.

**Overall Assessment:**

While Ligand B has a significantly better binding affinity and lower DILI risk, its poor BBB penetration, low QED, and negative solubility and half-life values are major concerns. Ligand A has better predicted BBB penetration, TPSA, QED, and a reasonable DILI risk. However, its binding affinity is very weak.

Given the importance of BBB penetration for a CNS target like DRD2, and the fact that a >1.5 kcal/mol affinity advantage can outweigh other drawbacks, Ligand B is the more promising candidate *if* the solubility and half-life issues can be addressed through structural modifications. The negative values for solubility and half-life are likely errors in the modeling and require experimental validation. However, the strong binding affinity is a significant driver.

Output:
1
2025-04-17 03:45:06,027 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight (MW):** Both ligands (340.427 and 361.511 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (67.23) is slightly above the optimal <90 for CNS targets, but still reasonable. Ligand B (63.25) is better, comfortably under 90.

**3. logP:** Ligand A (1.827) is within the optimal 1-3 range. Ligand B (3.877) is at the higher end of the optimal range, potentially raising concerns about solubility and off-target effects, but not critically.

**4. H-Bond Donors (HBD):** Both ligands have acceptable HBD counts (1 and 2, respectively), well below the limit of 5.

**5. H-Bond Acceptors (HBA):** Both ligands have acceptable HBA counts (5 and 4, respectively), well below the limit of 10.

**6. QED:** Both ligands have good QED scores (0.902 and 0.666), indicating drug-like properties. Ligand A is superior here.

**7. DILI:** Both ligands have similar DILI risk (61.07 and 59.907), both are acceptable, below the 60 threshold.

**8. BBB:** Ligand B (86.817) has a significantly better BBB percentile than Ligand A (75.107). This is a *critical* advantage for a CNS target like DRD2.

**9. Caco-2 Permeability:** Both have negative Caco-2 values which is unusual and suggests poor permeability. Ligand A (-4.983) is slightly worse than Ligand B (-5.135).

**10. Aqueous Solubility:** Both ligands have poor aqueous solubility (-3.456 and -3.036). This could be a formulation challenge.

**11. hERG Inhibition:** Both ligands have low hERG inhibition risk (0.592 and 0.722).

**12. Microsomal Clearance:** Ligand A (48.176) has lower microsomal clearance than Ligand B (58.25), suggesting better metabolic stability.

**13. In vitro Half-Life:** Ligand A (-6.87) has a significantly longer in vitro half-life than Ligand B (49.238). This is a substantial advantage.

**14. P-gp Efflux:** Ligand A (0.211) has lower P-gp efflux than Ligand B (0.61), which is favorable for CNS penetration.

**15. Binding Affinity:** Ligand B (-9.0) has a significantly stronger binding affinity than Ligand A (-8.7). This is a major advantage, potentially outweighing some of the ADME concerns.

**Overall Assessment:**

While Ligand A has better metabolic stability (lower Cl_mic, longer t1/2), QED, and P-gp efflux, Ligand B excels in the most critical areas for a CNS GPCR target: **BBB penetration and binding affinity**. The substantial difference in binding affinity (-9.0 vs -8.7 kcal/mol) is a significant driver. The improved BBB penetration (86.8 vs 75.1) is also very important. The slightly higher logP of Ligand B is a minor concern compared to these advantages. The poor Caco-2 and solubility are shared issues.

Output:
1
2025-04-17 03:45:06,027 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (352.475 Da and 355.435 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (75.71) is significantly better than Ligand B (91.34). For CNS targets, we want TPSA <= 90, so Ligand A is preferable.

**logP:** Ligand A (1.831) is within the optimal 1-3 range. Ligand B (-1.036) is below 1, which could hinder permeation. This favors Ligand A.

**H-Bond Donors/Acceptors:** Ligand A (HBD=1, HBA=4) and Ligand B (HBD=2, HBA=6) both have acceptable numbers of H-bond donors and acceptors.

**QED:** Ligand A (0.766) has a better QED score than Ligand B (0.567), indicating a more drug-like profile.

**DILI:** Ligand A (21.908) has a much lower DILI risk than Ligand B (11.206), which is a significant advantage.

**BBB:** Ligand A (83.094) has a much higher BBB penetration percentile than Ligand B (44.203). This is *critical* for a CNS target like DRD2, making Ligand A strongly favored.

**Caco-2 Permeability:** Ligand A (-4.522) and Ligand B (-5.118) both have negative Caco-2 values, which is unusual and suggests poor permeability. However, the scale isn't specified, so it's hard to interpret.

**Aqueous Solubility:** Ligand A (-2.312) and Ligand B (0.092) both have poor solubility.

**hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.268 and 0.215 respectively).

**Microsomal Clearance:** Ligand A (51.327) has a higher microsomal clearance than Ligand B (12.36), meaning it's likely to be metabolized more quickly. This favors Ligand B.

**In vitro Half-Life:** Ligand A (-21.522) has a negative half-life which is not possible. This is a major red flag. Ligand B (26.113) has a reasonable half-life.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.047 and 0.005 respectively).

**Binding Affinity:** Ligand A (-8.0) has a significantly stronger binding affinity than Ligand B (-6.6). A 1.4 kcal/mol difference is substantial and can outweigh some ADME drawbacks.

**Overall Assessment:**

Despite Ligand A's superior binding affinity, TPSA, logP, QED, DILI, and BBB, the negative in vitro half-life is a dealbreaker. A negative half-life is physically impossible and indicates a problem with the data or the molecule itself. Ligand B, while having less favorable ADME properties overall, has a reasonable half-life. Given the importance of CNS penetration for DRD2, and the fact that Ligand A's half-life is impossible, I would choose Ligand B.

Output:
1
2025-04-17 03:45:06,028 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (359.495 and 350.507 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (54.34) is significantly better than Ligand B (68.3). For CNS targets, we want TPSA <= 90, and ideally closer to 60. Ligand A is much closer to this ideal.

**3. logP:** Both ligands have good logP values (2.487 and 3.485), falling within the optimal 1-3 range. Ligand B is slightly higher, which *could* be a minor concern for solubility, but is not a major drawback.

**4. H-Bond Donors:** Ligand A (1) and Ligand B (2) are both acceptable, being <= 5.

**5. H-Bond Acceptors:** Ligand A (5) and Ligand B (6) are both acceptable, being <= 10.

**6. QED:** Both ligands have similar QED values (0.737 and 0.711), indicating good drug-like properties.

**7. DILI:** Both ligands have similar, and acceptable, DILI risk (35.789 and 35.905 percentile). Both are well below the 60% threshold.

**8. BBB:** Ligand B (76.774) has a substantially better BBB penetration score than Ligand A (61.768). For a CNS target like DRD2, >70% is desirable. Ligand B is closer to this target.

**9. Caco-2 Permeability:** Ligand A (-5.056) shows poor Caco-2 permeability, while Ligand B (-4.81) is slightly better, but still poor. This is a concern for both, but more so for A.

**10. Aqueous Solubility:** Both ligands have very poor aqueous solubility (-2.349 and -3.771). This is a significant drawback for both, potentially hindering formulation and bioavailability.

**11. hERG Inhibition:** Both ligands have low hERG inhibition risk (0.776 and 0.854 percentile).

**12. Microsomal Clearance:** Ligand A (17.947) has significantly lower microsomal clearance than Ligand B (59.453), indicating better metabolic stability.

**13. In vitro Half-Life:** Ligand B (49.569) has a much longer in vitro half-life than Ligand A (5.269). This is a significant advantage for B, potentially allowing for less frequent dosing.

**14. P-gp Efflux:** Ligand A (0.432) has lower P-gp efflux than Ligand B (0.275), suggesting better CNS exposure.

**15. Binding Affinity:** Ligand A (-8.2 kcal/mol) has a significantly stronger binding affinity than Ligand B (-7.7 kcal/mol). This 0.5 kcal/mol difference is substantial and can outweigh some ADME drawbacks.

**Overall Assessment:**

Ligand A has a superior binding affinity and better TPSA, lower clearance, and lower P-gp efflux. However, Ligand B has a significantly better BBB score and a much longer half-life. Both have poor solubility and Caco-2 permeability. Given the CNS target (DRD2), BBB penetration is crucial. The 0.5 kcal/mol difference in binding affinity is significant, but the improved BBB and half-life of Ligand B are compelling. The lower clearance of A is good, but the longer half-life of B is more valuable.

Output:
1
2025-04-17 03:45:06,028 - INFO - Batch 55 complete. Total preferences: 880
2025-04-17 03:45:06,028 - INFO - Processing batch 56/512...
2025-04-17 03:45:51,650 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (343.383 and 344.371 Da) fall comfortably within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (87.74) is excellent, being below the 90 A^2 threshold for CNS targets. Ligand B (100.46) is slightly higher but still acceptable.

**3. logP:** Ligand A (-0.551) is a bit low, potentially hindering permeation. Ligand B (1.115) is within the optimal 1-3 range. This is a significant advantage for Ligand B.

**4. H-Bond Donors:** Both ligands have 2 HBD, which is within the acceptable limit of <=5.

**5. H-Bond Acceptors:** Ligand A has 4 HBA, and Ligand B has 5 HBA, both within the acceptable limit of <=10.

**6. QED:** Both ligands have good QED scores (0.721 and 0.865), indicating drug-like properties.

**7. DILI:** Ligand A (44.591) has a lower DILI risk than Ligand B (60.915), which is preferable.

**8. BBB:** Ligand A (62.97) has a moderate BBB penetration, while Ligand B (32.803) is significantly lower. This is a major drawback for Ligand B, given DRD2 is a CNS target.

**9. Caco-2 Permeability:** Both have negative values which is unusual. Assuming these are logP values, both are poor.

**10. Aqueous Solubility:** Both have negative values which is unusual. Assuming these are logS values, both are poor.

**11. hERG:** Both ligands have low hERG inhibition risk (0.109 and 0.318).

**12. Microsomal Clearance:** Ligand A (23.316) has higher clearance than Ligand B (12.414), suggesting lower metabolic stability. Ligand B is better here.

**13. In vitro Half-Life:** Ligand B (-27.17) has a very negative half-life, which is not possible. Ligand A (0.207) has a very short half-life, which is also not ideal.

**14. P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.015 and 0.033).

**15. Binding Affinity:** Ligand A (-9.8 kcal/mol) has a significantly stronger binding affinity than Ligand B (-8.2 kcal/mol). This is a substantial advantage for Ligand A.

**Overall Assessment:**

Despite Ligand B having a better logP and lower clearance, Ligand A is the more promising candidate. The significantly stronger binding affinity (-9.8 vs -8.2 kcal/mol) is a major advantage that can outweigh some of the ADME drawbacks. While Ligand A's BBB penetration is only moderate, it's still better than Ligand B's, and the strong affinity suggests it might still achieve sufficient CNS exposure. Ligand B's poor BBB penetration is a critical flaw for a DRD2 ligand. The unusual values for Caco-2, solubility, and half-life are concerning for both, but the binding affinity difference is the deciding factor.

Output:
0
2025-04-17 03:45:51,650 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 drug candidates, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (352.431 and 351.378 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (96.89) is slightly higher than Ligand B (91.5). Both are below the 140 threshold for oral absorption and reasonably close to the 90 threshold for CNS targets, but Ligand B is preferable.

**3. logP:** Ligand A (0.132) is quite low, potentially hindering permeability. Ligand B (1.031) is within the optimal 1-3 range. This is a significant advantage for Ligand B.

**4. H-Bond Donors:** Ligand A (3) is acceptable, while Ligand B (2) is even better, minimizing potential permeability issues.

**5. H-Bond Acceptors:** Ligand A (5) and Ligand B (4) are both within the acceptable range (<=10).

**6. QED:** Ligand B (0.749) has a significantly better QED score than Ligand A (0.405), indicating a more drug-like profile.

**7. DILI:** Ligand A (13.959) has a much lower DILI risk than Ligand B (67.313). This is a strong point in favor of Ligand A.

**8. BBB:** Ligand B (67.158) has a better BBB penetration score than Ligand A (44.668), which is crucial for a CNS target like DRD2.

**9. Caco-2 Permeability:** Ligand A (-5.365) has a very poor Caco-2 permeability, while Ligand B (-4.893) is slightly better, but still not great.

**10. Aqueous Solubility:** Ligand A (-1.39) and Ligand B (-2.739) both have poor aqueous solubility.

**11. hERG Inhibition:** Ligand A (0.188) has a lower hERG inhibition liability than Ligand B (0.35), which is favorable.

**12. Microsomal Clearance:** Ligand B (47.55) has a lower microsomal clearance than Ligand A (22.176), suggesting better metabolic stability.

**13. In vitro Half-Life:** Ligand B (-34.847) has a significantly longer in vitro half-life than Ligand A (11.954).

**14. P-gp Efflux:** Ligand A (0.01) has very low P-gp efflux, which is excellent for CNS penetration. Ligand B (0.071) is slightly higher, but still reasonably low.

**15. Binding Affinity:** Ligand A (-8.2) has a slightly better binding affinity than Ligand B (-7.9). However, the difference is less than 1.5 kcal/mol, so it's not a decisive factor.

**Overall Assessment:**

Ligand B clearly has a more favorable profile for a CNS-targeting GPCR. Its better logP, QED, BBB penetration, metabolic stability (lower Cl_mic, longer t1/2), and acceptable P-gp efflux outweigh the higher DILI risk and slightly weaker affinity. Ligand A's low logP and poor Caco-2 permeability are major drawbacks. While Ligand A has lower DILI and hERG, these are less critical than CNS penetration and metabolic stability for this target.

Output:
1
2025-04-17 03:45:51,651 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (409.259 Da) is slightly higher, but acceptable. Ligand B (348.399 Da) is also good.

**TPSA:** Ligand A (58.56) is excellent, well below the 90 A^2 threshold for CNS targets. Ligand B (79.31) is still reasonable, but less optimal.

**logP:** Ligand A (2.408) is within the optimal range (1-3). Ligand B (-0.622) is below 1, which could hinder permeation. This is a significant drawback for a CNS target.

**H-Bond Donors/Acceptors:** Ligand A (0 HBD, 5 HBA) is good. Ligand B (1 HBD, 5 HBA) is also acceptable.

**QED:** Both ligands have good QED values (A: 0.777, B: 0.673), indicating drug-like properties.

**DILI:** Ligand A (78.402) has a higher DILI risk than Ligand B (52.734), but both are below the concerning threshold of 60.

**BBB:** Ligand A (94.455) has excellent BBB penetration, exceeding the desirable >70% threshold. Ligand B (65.529) is lower, which is a major concern for a CNS target like DRD2.

**Caco-2 Permeability:** Both are negative, suggesting poor permeability. However, the scale is not specified, so it is hard to interpret.

**Aqueous Solubility:** Both ligands have negative solubility values, indicating poor solubility.

**hERG Inhibition:** Ligand A (0.593) has a slightly higher hERG risk than Ligand B (0.16), but both are relatively low.

**Microsomal Clearance:** Ligand A (95.74) has a higher clearance than Ligand B (3.564), suggesting lower metabolic stability.

**In vitro Half-Life:** Ligand B (-11.788) has a shorter half-life than Ligand A (-17.462), but both are negative, suggesting very short half-lives.

**P-gp Efflux:** Ligand A (0.356) has lower P-gp efflux than Ligand B (0.066), which is favorable for CNS penetration.

**Binding Affinity:** Ligand A (-9.1 kcal/mol) has a significantly stronger binding affinity than Ligand B (-7.9 kcal/mol). This is a substantial advantage, potentially outweighing some of the ADME drawbacks.

**Conclusion:**

Considering the GPCR-specific priorities, Ligand A is the more promising candidate. Its superior BBB penetration, better logP value, lower P-gp efflux, and *significantly* stronger binding affinity outweigh its slightly higher DILI risk and clearance. Ligand B's poor logP and BBB penetration are major drawbacks for a CNS-targeting drug.

Output:
1
2025-04-17 03:45:51,651 - INFO - Reasoning:

Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (354.491 and 349.435 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (67.87) is significantly better than Ligand B (97.19). For CNS targets, we want TPSA <= 90, so Ligand A is preferable.

**3. logP:** Both ligands have acceptable logP values (1.968 and 0.768), falling within the 1-3 range. Ligand A is slightly better.

**4. H-Bond Donors:** Both have 1 HBD, which is good.

**5. H-Bond Acceptors:** Ligand A has 4 HBA, and Ligand B has 6. Both are within the acceptable limit of <=10, but Ligand A is preferable.

**6. QED:** Both ligands have similar QED values (0.687 and 0.747), indicating good drug-likeness.

**7. DILI:** Ligand A (12.912) has a much lower DILI risk than Ligand B (42.924). This is a significant advantage for Ligand A.

**8. BBB:** Both ligands have similar BBB penetration (65.801 and 65.103). While both are reasonably good, ideally we want >70 for CNS targets. Neither is outstanding, but they are comparable.

**9. Caco-2:** Both have negative Caco-2 values (-4.355 and -4.814). This is unusual and suggests poor permeability. However, these values are on a scale where negative values are possible, and the absolute magnitude isn't directly interpretable without knowing the scale's specifics.

**10. Solubility:** Both have negative solubility values (-2.302 and -1.36). Similar to Caco-2, this indicates poor aqueous solubility.

**11. hERG:** Both ligands have very low hERG inhibition risk (0.275 and 0.011). This is excellent.

**12. Cl_mic:** Ligand A (70.78) has a higher microsomal clearance than Ligand B (37.938), indicating lower metabolic stability. This is a drawback for Ligand A.

**13. t1/2:** Ligand B (-5.007) has a longer *in vitro* half-life than Ligand A (-2.04). This is a significant advantage for Ligand B.

**14. Pgp:** Both have very low P-gp efflux liability (0.046 and 0.03). This is excellent for CNS penetration.

**15. Binding Affinity:** Ligand B (-7.7 kcal/mol) has a slightly better binding affinity than Ligand A (-7.4 kcal/mol). While the difference is small, it's within the range where it could outweigh minor ADME drawbacks.

**Overall Assessment:**

Ligand A excels in TPSA, DILI risk, and logP. Ligand B has better metabolic stability (lower Cl_mic, longer t1/2) and slightly better binding affinity. Both have similar BBB and Pgp properties. The poor Caco-2 and solubility for both are concerning, but may be addressable with formulation strategies.

Given the GPCR-specific priorities, the lower TPSA and DILI risk of Ligand A are crucial. While Ligand B has a slight affinity advantage and better metabolic stability, the lower TPSA and DILI of Ligand A are more important for a CNS-targeting drug.

Output:
1
2025-04-17 03:45:51,651 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (346.427) is slightly better positioned.

**TPSA:** Ligand A (64.8) is excellent, falling well below the 90 A^2 threshold for CNS targets. Ligand B (121.18) is higher, but still potentially acceptable, though less ideal.

**logP:** Ligand A (3.404) is optimal. Ligand B (0.376) is quite low, which could hinder membrane permeability and CNS penetration despite its other properties.

**H-Bond Donors/Acceptors:** Both ligands have reasonable HBD/HBA counts (A: 0/6, B: 3/6), falling within acceptable limits.

**QED:** Both ligands have good QED scores (A: 0.539, B: 0.681), indicating drug-like properties. Ligand B is slightly better here.

**DILI:** Ligand A (39.046) has a much lower DILI risk than Ligand B (83.443), which is a significant advantage.

**BBB:** Ligand A (68.748) has a better BBB percentile than Ligand B (45.909). While 68.748 isn't *outstanding*, it's more promising for a CNS target than 45.909.

**Caco-2 Permeability:** Ligand A (-4.6) has a better Caco-2 permeability than Ligand B (-5.595).

**Aqueous Solubility:** Ligand A (-4.319) has better aqueous solubility than Ligand B (-3.135).

**hERG:** Both ligands have low hERG inhibition liability (A: 0.824, B: 0.385), which is good.

**Microsomal Clearance:** Ligand A (106.372) has higher microsomal clearance than Ligand B (-6.554). This means Ligand B is likely more metabolically stable.

**In vitro Half-Life:** Ligand B (-26.371) has a longer in vitro half-life than Ligand A (-20.726).

**P-gp Efflux:** Ligand A (0.832) has lower P-gp efflux than Ligand B (0.017). Lower P-gp efflux is better for CNS exposure.

**Binding Affinity:** Both ligands have excellent binding affinity (A: -8.1 kcal/mol, B: -8.6 kcal/mol), with Ligand B being slightly more potent. However, the difference of 0.5 kcal/mol is not substantial enough to override the significant ADME advantages of Ligand A.

**Overall Assessment:**

Considering the GPCR-specific priorities, Ligand A is the more promising candidate. Its superior BBB penetration, logP, lower DILI risk, better solubility, and lower P-gp efflux outweigh the slightly weaker affinity and higher clearance compared to Ligand B. The low logP of Ligand B is a major concern for CNS penetration, and its higher DILI risk is also unfavorable. While Ligand B has a slightly better half-life, the other factors strongly favor Ligand A.

Output:
0
2025-04-17 03:45:51,651 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (372.481 and 344.459 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (49.41) is significantly better than Ligand B (67.23). For CNS targets, we want TPSA <= 90, and ideally closer to 60. Ligand A is much closer to this ideal.

**3. logP:** Both ligands have good logP values (3.798 and 2.541), falling within the optimal 1-3 range.

**4. H-Bond Donors:** Both have 1 HBD, which is acceptable.

**5. H-Bond Acceptors:** Ligand A has 2 HBA, and Ligand B has 4. Both are acceptable (<=10), but Ligand A is preferable.

**6. QED:** Both ligands have similar QED values (0.826 and 0.807), indicating good drug-likeness.

**7. DILI:** Both have acceptable DILI risk (40.713 and 43.66), below the 60 threshold.

**8. BBB:** Ligand A (90.229) has a significantly higher BBB percentile than Ligand B (73.517). This is *critical* for a CNS target like DRD2.

**9. Caco-2 Permeability:** Both have negative Caco-2 values (-4.908 and -4.798), which is unusual and suggests poor permeability. However, these values are on a log scale and difficult to interpret without knowing the base.

**10. Aqueous Solubility:** Both have negative solubility values (-4.597 and -3.321), again suggesting poor solubility. Similar to Caco-2, the scale is unknown.

**11. hERG Inhibition:** Both ligands have low hERG risk (0.921 and 0.429).

**12. Microsomal Clearance:** Ligand A (32.013) has a lower (better) microsomal clearance than Ligand B (63.613), indicating better metabolic stability.

**13. In vitro Half-Life:** Ligand A (-2.39) has a negative half-life, which is concerning. Ligand B (8.736) has a reasonable half-life.

**14. P-gp Efflux:** Ligand A (0.377) has lower P-gp efflux than Ligand B (0.068), which is favorable for CNS penetration.

**15. Binding Affinity:** Ligand A (-7.9 kcal/mol) has a slightly better binding affinity than Ligand B (-7.3 kcal/mol). While both are good, the 0.6 kcal/mol difference is notable.

**Overall Assessment:**

Ligand A is the stronger candidate. It excels in key GPCR properties: TPSA, BBB, P-gp efflux, and binding affinity. While its in vitro half-life is concerning (negative value), the significantly better BBB penetration and binding affinity outweigh this drawback, especially given the importance of CNS penetration for a DRD2 target. The lower microsomal clearance is also a positive. Ligand B has a better half-life, but falls short in TPSA and BBB, which are crucial for CNS drug development.

Output:
1
2025-04-17 03:45:51,651 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (432.271 Da) is slightly higher, but acceptable. Ligand B (352.431 Da) is also good.

**2. TPSA:** Both ligands have TPSA values below the 90 A^2 threshold desirable for CNS targets. Ligand A (89.55 A^2) is excellent, while Ligand B (77.1 A^2) is also very good.

**3. logP:** Ligand A (3.723) is within the optimal range (1-3), but approaching the upper limit. Ligand B (1.187) is also within the range, but closer to the lower limit.

**4. H-Bond Donors:** Both ligands have acceptable HBD counts (Ligand A: 2, Ligand B: 1), well below the 5 threshold.

**5. H-Bond Acceptors:** Both ligands have acceptable HBA counts (Ligand A: 6, Ligand B: 5), below the 10 threshold.

**6. QED:** Both ligands have QED values above 0.5, indicating good drug-like properties (Ligand A: 0.703, Ligand B: 0.457). Ligand A is significantly better.

**7. DILI:** Ligand A has a high DILI risk (97.596%), which is a major concern. Ligand B has a much lower DILI risk (45.483%), which is preferable.

**8. BBB:** Ligand A has a good BBB penetration percentile (61.613%), but not outstanding. Ligand B has a better BBB percentile (68.36%). Both are acceptable, but higher is better for a CNS target.

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 values, which is unusual and suggests poor permeability. Ligand A (-4.419) is slightly better than Ligand B (-4.861).

**10. Aqueous Solubility:** Both ligands have negative solubility values, indicating poor aqueous solubility. Ligand A (-4.846) is slightly better than Ligand B (-1.704).

**11. hERG Inhibition:** Both ligands have low hERG inhibition liability (Ligand A: 0.276, Ligand B: 0.211), which is good.

**12. Microsomal Clearance:** Ligand A has a high microsomal clearance (91.581), indicating poor metabolic stability. Ligand B has a much lower clearance (11.247), suggesting better metabolic stability.

**13. In vitro Half-Life:** Ligand A has a moderate half-life (42.2 hours). Ligand B has a very short half-life (-3.876 hours), which is a significant drawback.

**14. P-gp Efflux:** Both ligands have low P-gp efflux liability (Ligand A: 0.309, Ligand B: 0.032). Ligand B is better.

**15. Binding Affinity:** Both ligands have excellent binding affinities (Ligand A: -7.8 kcal/mol, Ligand B: -7.6 kcal/mol). Ligand A has a slight advantage in binding affinity.

**Overall Assessment:**

Ligand A has a better binding affinity, QED, and TPSA, but suffers from a very high DILI risk, high microsomal clearance, and poor solubility. Ligand B has a lower DILI risk, better metabolic stability, and lower P-gp efflux, but has a weaker binding affinity and a very short half-life.

Given the GPCR-specific priorities and the importance of safety (DILI) and metabolic stability, **Ligand B** is the more promising candidate despite the slightly lower affinity. The high DILI risk of Ligand A is a major red flag that would likely preclude further development. While the short half-life of Ligand B is a concern, it might be addressable through structural modifications. The slightly lower affinity can also be optimized.

Output:
1
2025-04-17 03:45:51,651 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 drug candidates, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (358.404 and 356.423 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (58.2) is excellent, well below the 90 A^2 threshold for CNS targets. Ligand B (116.93) is higher, but still potentially acceptable, though less ideal.

**logP:** Ligand A (4.298) is slightly high, potentially leading to solubility issues or off-target interactions, but still within a workable range. Ligand B (0.482) is quite low, which could hinder membrane permeability and CNS penetration.

**H-Bond Donors/Acceptors:** Ligand A (2 HBD, 2 HBA) is optimal. Ligand B (3 HBD, 7 HBA) is acceptable, but the higher HBA count could affect permeability.

**QED:** Ligand A (0.764) is good, indicating a strong drug-like profile. Ligand B (0.412) is lower, suggesting potential issues.

**DILI:** Ligand A (57.425) has a moderate DILI risk, acceptable. Ligand B (35.285) has a low DILI risk, which is favorable.

**BBB:** Ligand A (81.233) has excellent BBB penetration potential, exceeding the 70% threshold. Ligand B (24.622) has very poor predicted BBB penetration, a significant drawback for a CNS target.

**Caco-2 Permeability:** Ligand A (-4.659) is poor. Ligand B (-5.6) is even worse. Both are very negative, indicating poor intestinal absorption.

**Aqueous Solubility:** Ligand A (-4.839) is poor. Ligand B (-1.03) is also poor, but slightly better than Ligand A.

**hERG Inhibition:** Ligand A (0.814) has a low risk of hERG inhibition. Ligand B (0.159) also has a low risk.

**Microsomal Clearance:** Ligand A (50.154) has moderate clearance. Ligand B (-0.652) has negative clearance, which is not physically possible and likely indicates an issue with the prediction or data.

**In vitro Half-Life:** Ligand A (22.103 hours) is reasonable. Ligand B (18.76 hours) is also reasonable.

**P-gp Efflux:** Ligand A (0.186) has low P-gp efflux, which is good for CNS penetration. Ligand B (0.019) has very low P-gp efflux, which is even better.

**Binding Affinity:** Ligand A (-9.6 kcal/mol) has significantly stronger binding affinity than Ligand B (-6.6 kcal/mol). This is a substantial advantage, potentially outweighing some of the ADME drawbacks.

**Overall Assessment:**

Ligand A is the stronger candidate. While its logP is slightly high and Caco-2 permeability is poor, its excellent BBB penetration, strong binding affinity, and good QED make it more promising for a CNS-targeting GPCR like DRD2. The moderate DILI risk is acceptable. Ligand B's extremely poor BBB penetration is a deal-breaker, despite its lower DILI risk and better P-gp efflux. The negative microsomal clearance is also a red flag. The large difference in binding affinity (-9.6 vs -6.6 kcal/mol) is a critical factor.

Output:
1
2025-04-17 03:45:51,651 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (346.35 and 366.45 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (136.47) is slightly above the optimal <90 for CNS targets, but still reasonable. Ligand B (114.94) is excellent, well within the desired range.

**logP:** Ligand A (-0.524) is quite low, potentially hindering membrane permeability. Ligand B (0.588) is better, falling within the acceptable range, but still on the lower side.

**H-Bond Donors/Acceptors:** Both ligands have 2 HBD and 8 HBA, which are acceptable values.

**QED:** Both ligands have good QED scores (0.545 and 0.702), indicating good drug-like properties.

**DILI:** Ligand A (68.79) and Ligand B (74.72) both have DILI risk in the acceptable range (<80), but Ligand B is slightly higher.

**BBB:** Ligand A (69.52) is borderline for good CNS penetration. Ligand B (47.42) is significantly lower, raising concerns about reaching the target in the brain.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.498 and -5.78), which is unusual and suggests poor permeability. However, these values are on a scale where negative values are possible and don't necessarily preclude activity.

**Aqueous Solubility:** Both ligands have negative solubility values (-2.416 and -1.925), which is also unusual, but doesn't necessarily preclude activity.

**hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.126 and 0.035).

**Microsomal Clearance:** Ligand A (5.60) has significantly lower microsomal clearance than Ligand B (33.02), indicating better metabolic stability.

**In vitro Half-Life:** Ligand A (-39.44) has a very negative half-life, which is concerning. Ligand B (-0.162) is also negative, but less so.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.006 and 0.017).

**Binding Affinity:** Ligand B (-7.5 kcal/mol) has a significantly stronger binding affinity than Ligand A (-8.8 kcal/mol). This is a substantial difference.

**Overall Assessment:**

While Ligand A has better metabolic stability and a slightly better (though still suboptimal) BBB score, its low logP and very negative half-life are major drawbacks. Ligand B, despite a higher DILI risk and lower BBB, possesses a considerably stronger binding affinity (-7.5 vs -8.8 kcal/mol). For a GPCR target, strong affinity is paramount, and can often compensate for moderate ADME issues. The lower logP of Ligand B is a concern, but not as critical as the significantly weaker binding of Ligand A. The negative Caco-2 and solubility values are concerning for both, but may not be insurmountable with formulation strategies.

Output:
1
2025-04-17 03:45:51,651 - INFO - Okay, let's analyze these two ligands for their potential as DRD2 drug candidates. DRD2 is a GPCR in the CNS, so BBB penetration, logP, Pgp efflux, TPSA, and binding affinity are paramount.

**Ligand A:** [339.439, 45.67, 2.46, 0, 4, 0.862, 47.421, 81.815, -4.326, -1.293, 0.632, 23.548, 36.545, 0.187, 0]
**Ligand B:** [343.427, 73.74, 1.44, 1, 4, 0.648, 28.616, 33.424, -4.643, -1.12, 0.292, 10.421, -2.274, 0.086, 0]

**1. Molecular Weight:** Both ligands are within the ideal range (200-500 Da). A is 339.439, B is 343.427 - very similar.

**2. TPSA:** Ligand A (45.67) is excellent, well below the 90 A^2 threshold for CNS targets. Ligand B (73.74) is higher, but still potentially acceptable, though less desirable.

**3. logP:** Ligand A (2.46) is optimal. Ligand B (1.44) is a bit low, potentially hindering membrane permeability.

**4. H-Bond Donors:** Ligand A (0) is good. Ligand B (1) is acceptable.

**5. H-Bond Acceptors:** Both ligands have 4 HBA, which is within the acceptable range.

**6. QED:** Ligand A (0.862) is very good, indicating high drug-likeness. Ligand B (0.648) is still acceptable, but lower.

**7. DILI Risk:** Ligand A (47.421) is better than Ligand B (28.616), indicating a lower risk of drug-induced liver injury.

**8. BBB Penetration:** Ligand A (81.815) is excellent, exceeding the 70% threshold for CNS targets. Ligand B (33.424) is significantly lower and a major concern for CNS activity.

**9. Caco-2 Permeability:** Both have negative values, which is unusual and suggests a potential issue with the data or a very poor permeability. However, we'll proceed assuming the scale is inverted.  Ligand A (-4.326) is better than Ligand B (-4.643).

**10. Aqueous Solubility:** Both ligands have negative values, which is unusual. Assuming inverted scale, A (-1.293) is slightly better than B (-1.12).

**11. hERG Inhibition:** Both ligands have very low hERG risk (0.632 and 0.292).

**12. Microsomal Clearance:** Ligand A (23.548) has higher clearance than Ligand B (10.421), suggesting lower metabolic stability.

**13. In vitro Half-Life:** Ligand B (-2.274) has a negative half-life, which is impossible. This is a significant data quality issue. Ligand A (36.545) is good.

**14. P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.187 and 0.086).

**15. Binding Affinity:** Both ligands have the same binding affinity (0 kcal/mol).

**Overall Assessment:**

Ligand A is significantly better. Its superior BBB penetration, lower DILI risk, better QED, and more reasonable half-life outweigh the slightly higher microsomal clearance. Ligand B's poor BBB penetration is a critical flaw for a CNS target. The negative half-life for ligand B is a red flag indicating a data issue. While both have similar binding affinity, the ADME properties of Ligand A make it a much more promising candidate.

Output:
1
2025-04-17 03:45:51,652 - INFO - Reasoning:

Let's analyze Ligand A and Ligand B based on the provided guidelines, prioritizing GPCR properties (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (401.272) is slightly higher, but acceptable. Ligand B (386.001) is also good.

**TPSA:** Ligand A (107.85) is borderline for CNS targets (ideally <90), but not drastically outside. Ligand B (32.7) is excellent for CNS penetration.

**logP:** Ligand A (1.687) is within the optimal range (1-3). Ligand B (4.702) is slightly high, potentially leading to solubility issues and off-target interactions.

**H-Bond Donors/Acceptors:** Both ligands have acceptable HBD (1) and HBA (8 for A, 4 for B) counts.

**QED:** Both ligands have reasonable QED scores (0.775 and 0.632), indicating good drug-like properties.

**DILI:** Ligand A (84.18) has a higher DILI risk than Ligand B (11.439). This is a significant negative for Ligand A.

**BBB:** Ligand A (71.268) has a good BBB penetration percentile. Ligand B (69.833) is also acceptable, but slightly lower.

**Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and suggests a potential issue with the data or modeling. However, we'll proceed assuming these represent low permeability.

**Aqueous Solubility:** Both have negative solubility values, again suggesting a potential issue with the data or modeling.

**hERG Inhibition:** Ligand A (0.65) shows a lower hERG risk than Ligand B (0.976).

**Microsomal Clearance:** Ligand B (78.922) has a higher microsomal clearance than Ligand A (34.246), indicating lower metabolic stability.

**In vitro Half-Life:** Ligand B (46.974) has a longer half-life than Ligand A (-11.225), which is a positive.

**P-gp Efflux:** Ligand A (0.03) has much lower P-gp efflux liability than Ligand B (0.836), which is crucial for CNS penetration.

**Binding Affinity:** Ligand A (-8.2 kcal/mol) has a significantly stronger binding affinity than Ligand B (-6.9 kcal/mol). This is a substantial advantage, potentially outweighing some ADME drawbacks.

**Overall Assessment:**

Despite Ligand A's higher DILI risk and borderline TPSA, its significantly stronger binding affinity (-8.2 vs -6.9 kcal/mol) and much lower P-gp efflux liability are compelling advantages for a CNS-targeting GPCR like DRD2. The lower metabolic clearance is also beneficial. While the negative solubility and Caco-2 values are concerning, the affinity difference is substantial enough to prioritize Ligand A, assuming these values are not definitive dealbreakers. Ligand B's higher logP and DILI risk are significant drawbacks.

Output:
1
2025-04-17 03:45:51,652 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (347.459) is slightly lower, which could be beneficial for permeability. Ligand B (375.313) is also acceptable.

**TPSA:** Ligand A (64.09) is excellent, well below the 90 A^2 threshold for CNS targets. Ligand B (52.65) is even better, indicating potentially improved brain penetration.

**logP:** Ligand A (0.16) is quite low, potentially hindering membrane permeability and CNS penetration. Ligand B (1.191) is much better, falling within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Both ligands have acceptable HBD (1) and HBA (4 for A, 3 for B) counts, well within the guidelines.

**QED:** Both ligands have good QED scores (0.72 and 0.735), indicating drug-like properties.

**DILI:** Ligand A (13.843) has a very low DILI risk, significantly better than Ligand B (37.03).

**BBB:** Ligand B (71.733) has a significantly better BBB percentile than Ligand A (44.94). This is a crucial advantage for a CNS target like DRD2.

**Caco-2 Permeability:** Both have negative Caco-2 values (-4.701 and -4.781), which is unusual and suggests poor permeability. However, these values are on a log scale, and the negative values are likely indicating very low permeability.

**Aqueous Solubility:** Both ligands have very poor aqueous solubility (-0.647 and -1.698). This could pose formulation challenges.

**hERG Inhibition:** Ligand A (0.27) has a lower hERG risk than Ligand B (0.479), which is preferable.

**Microsomal Clearance:** Ligand A (-5.562) has a much lower (better) microsomal clearance than Ligand B (-1.583), suggesting greater metabolic stability.

**In vitro Half-Life:** Ligand A (-8.495) has a substantially longer in vitro half-life than Ligand B (-15.485), which is a significant advantage.

**P-gp Efflux:** Ligand A (0.066) has a lower P-gp efflux liability than Ligand B (0.009), meaning it is less likely to be pumped out of the brain, improving CNS exposure.

**Binding Affinity:** Ligand B (-9.1 kcal/mol) has a significantly stronger binding affinity than Ligand A (-7.8 kcal/mol). This is a substantial advantage, potentially outweighing some of the ADME drawbacks. The difference is >1.5 kcal/mol.

**Overall Assessment:**

Ligand B excels in binding affinity and BBB penetration, both critical for a CNS GPCR target. While it has a higher DILI risk and lower metabolic stability than Ligand A, the strong binding affinity is a major advantage. Ligand A has better safety (DILI, hERG) and PK (clearance, half-life, Pgp), but its poor logP and lower BBB penetration are significant drawbacks for a CNS target. The superior binding affinity of Ligand B is likely to drive efficacy and can be optimized further with medicinal chemistry.

Output:
1
2025-04-17 03:45:51,652 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (348.451 and 364.471 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Both ligands have TPSA values (94.22 and 92.26) below the 140 threshold for oral absorption, but slightly above the preferred <90 for CNS targets. This is a minor concern, but not disqualifying.

**3. logP:** Ligand A (0.599) is a bit low, potentially hindering permeation. Ligand B (1.254) is better, falling within the optimal 1-3 range. This favors Ligand B.

**4. H-Bond Donors:** Ligand A (2) and Ligand B (1) are both within the acceptable limit of <=5.

**5. H-Bond Acceptors:** Ligand A (5) and Ligand B (6) are both within the acceptable limit of <=10.

**6. QED:** Both ligands have good QED scores (0.813 and 0.82), indicating drug-like properties.

**7. DILI:** Ligand A (29.081) has a significantly lower DILI risk than Ligand B (45.909). This is a significant advantage for Ligand A.

**8. BBB:** Ligand B (62.35) has a better BBB penetration percentile than Ligand A (55.797), although neither are above the desirable >70 for CNS targets. This favors Ligand B, given DRD2's role in CNS disorders.

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.208 and -5.279), which is unusual and suggests poor permeability. This is a concern for both.

**10. Aqueous Solubility:** Both ligands have negative solubility values (-1.898 and -1.881), indicating poor aqueous solubility. This is a concern for both.

**11. hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.128 and 0.041).

**12. Microsomal Clearance:** Ligand A (-18.025) has a much lower (better) microsomal clearance than Ligand B (24.871), indicating greater metabolic stability. This is a substantial advantage for Ligand A.

**13. In vitro Half-Life:** Ligand B (-22.53) has a much longer in vitro half-life than Ligand A (1.229). This is a significant advantage for Ligand B.

**14. P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.016 and 0.063).

**15. Binding Affinity:** Both ligands have excellent binding affinity (-8.7 and -8.0 kcal/mol). Ligand A has a 0.7 kcal/mol advantage, which is significant.

**Overall Assessment:**

Ligand A has advantages in DILI risk, metabolic stability (Cl_mic), and binding affinity. Ligand B has advantages in BBB penetration and in vitro half-life. The logP of Ligand A is a concern, while the Caco-2 and solubility issues are shared by both. Given the importance of CNS penetration for a DRD2 ligand, and the relatively small difference in BBB values, the superior binding affinity and lower DILI risk of Ligand A, combined with its better metabolic stability, outweigh the slightly lower logP and BBB.

Output:
0
2025-04-17 03:45:51,652 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (352.366 Da) is slightly lower, which could be advantageous for permeability. Ligand B (406.28 Da) is still acceptable.

**TPSA:** Ligand A (104.39) is better than Ligand B (68.46) as it is closer to the ideal range for CNS targets (<=90). Ligand B is still acceptable.

**logP:** Ligand B (3.112) is optimal (1-3), while Ligand A (0.34) is quite low, potentially hindering membrane permeability and CNS penetration. This is a significant drawback for Ligand A.

**H-Bond Donors:** Ligand A (2) and Ligand B (0) are both within the acceptable limit of <=5.

**H-Bond Acceptors:** Both Ligand A (5) and Ligand B (5) are within the acceptable limit of <=10.

**QED:** Both ligands have similar QED values (Ligand A: 0.744, Ligand B: 0.69), indicating good drug-like properties.

**DILI:** Ligand B (44.824) has a lower DILI risk than Ligand A (63.862), making it preferable from a safety perspective.

**BBB:** Ligand B (83.831) has a significantly higher BBB penetration percentile than Ligand A (68.282). This is a critical advantage for a CNS target like DRD2.

**Caco-2 Permeability:** Ligand A (-4.911) and Ligand B (-4.453) are both negative, which is unusual and suggests very poor permeability. However, the scale is not specified, so it's difficult to interpret.

**Aqueous Solubility:** Both ligands have very poor aqueous solubility (-2.566 and -4.189, respectively). This could pose formulation challenges.

**hERG Inhibition:** Ligand A (0.215) has a lower hERG inhibition liability than Ligand B (0.78), which is favorable.

**Microsomal Clearance:** Ligand A (16.78) has a lower microsomal clearance than Ligand B (77.297), indicating better metabolic stability.

**In vitro Half-Life:** Ligand A (-27.417) has a negative half-life, which is not possible. This is likely an error in the data. Ligand B (26.264) has a reasonable half-life.

**P-gp Efflux:** Ligand A (0.016) has much lower P-gp efflux liability than Ligand B (0.426), which is beneficial for CNS exposure.

**Binding Affinity:** Both ligands have very similar and strong binding affinities (Ligand A: -7.1 kcal/mol, Ligand B: -7.2 kcal/mol). The difference is negligible.

**Overall Assessment:**

Ligand B is the more promising candidate. While Ligand A has lower P-gp efflux and better metabolic stability, Ligand B excels in key areas for CNS GPCR targeting: significantly better BBB penetration, a more optimal logP, and lower DILI risk. The questionable half-life value for Ligand A is also concerning. The slightly lower logP of Ligand A is a major drawback. Despite similar affinities, the superior ADME properties of Ligand B make it the better choice.

Output:
1
2025-04-17 03:45:51,652 - INFO - Reasoning:

Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the acceptable range (200-500 Da). Ligand A (415.332) is slightly higher, but not concerning.

**TPSA:** Ligand A (81.75) is above the ideal <90 for CNS targets, but still potentially acceptable. Ligand B (29.54) is excellent, well below 90.

**logP:** Ligand A (0.604) is a bit low, potentially hindering membrane permeability. Ligand B (4.234) is at the upper end of the optimal range, potentially leading to solubility issues, but still acceptable.

**H-Bond Donors/Acceptors:** Ligand A (2 HBD, 4 HBA) and Ligand B (0 HBD, 2 HBA) both fall within the desirable ranges.

**QED:** Both ligands have good QED scores (A: 0.666, B: 0.703), indicating good drug-like properties.

**DILI:** Both ligands have low DILI risk (A: 29.236, B: 26.134), which is positive.

**BBB:** This is a critical factor for a CNS target like DRD2. Ligand B (96.123) has excellent BBB penetration, significantly better than Ligand A (63.164).

**Caco-2 Permeability:** Ligand A (-5.341) has poor Caco-2 permeability, which is a concern. Ligand B (-4.136) is also poor, but better than A.

**Aqueous Solubility:** Both ligands have poor aqueous solubility (A: -2.081, B: -5.232). This could present formulation challenges.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (A: 0.187, B: 0.834), which is good.

**Microsomal Clearance:** Ligand A (26.413) has lower microsomal clearance than Ligand B (58.674), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand B (-9.777) has a longer in vitro half-life than Ligand A (-0.64), which is favorable.

**P-gp Efflux:** Ligand A (0.015) has very low P-gp efflux, which is excellent for CNS penetration. Ligand B (0.253) has slightly higher efflux, but still relatively low.

**Binding Affinity:** Both ligands have comparable and strong binding affinities (A: -7.6, B: -7.7). The difference is minimal and doesn't significantly favor one over the other.

**Overall Assessment:**

Ligand B is the stronger candidate. While both have poor solubility, Ligand B's significantly higher BBB penetration (96.123 vs 63.164) is a major advantage for a CNS target. It also has a longer half-life. Although Ligand A has better metabolic stability and lower P-gp efflux, the BBB score is the deciding factor for DRD2.

Output:
1
2025-04-17 03:45:51,652 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (404.308 Da) is slightly higher than Ligand B (344.419 Da), but both are acceptable.

**2. TPSA:** Ligand A (56.15) is excellent for CNS penetration, well below the 90 A^2 threshold. Ligand B (104.7) is higher, but still potentially acceptable, though less ideal.

**3. logP:** Ligand A (3.725) is at the upper end of the optimal range (1-3), but still acceptable. Ligand B (0.988) is a bit low, potentially hindering membrane permeability.

**4. H-Bond Donors:** Ligand A (1) and Ligand B (3) both fall within the acceptable limit of <=5.

**5. H-Bond Acceptors:** Ligand A (4) and Ligand B (5) both fall within the acceptable limit of <=10.

**6. QED:** Both ligands have reasonable QED scores (Ligand A: 0.827, Ligand B: 0.664), indicating good drug-like properties.

**7. DILI:** Both ligands have acceptable DILI risk (Ligand A: 53.548, Ligand B: 40.364), below the 60 threshold.

**8. BBB:** This is critical for a CNS target. Ligand A (65.529) is reasonably good, while Ligand B (25.475) is quite low, suggesting poor brain penetration.

**9. Caco-2 Permeability:** Ligand A (-4.965) and Ligand B (-5.882) both have negative values, indicating poor permeability.

**10. Aqueous Solubility:** Ligand A (-4.294) and Ligand B (-0.915) both have negative values, indicating poor solubility.

**11. hERG Inhibition:** Both ligands show low hERG inhibition risk (Ligand A: 0.329, Ligand B: 0.219).

**12. Microsomal Clearance:** Ligand A (81.022) has a higher clearance than Ligand B (-22.023), suggesting lower metabolic stability.

**13. In vitro Half-Life:** Ligand A (42.928) has a longer half-life than Ligand B (-5.432).

**14. P-gp Efflux:** Ligand A (0.677) shows moderate P-gp efflux, while Ligand B (0.014) shows very low efflux. This is a significant advantage for Ligand B.

**15. Binding Affinity:** Ligand A (-8.2 kcal/mol) has a significantly stronger binding affinity than Ligand B (-7.3 kcal/mol). This is a substantial advantage, potentially outweighing some ADME concerns.

**Overall Assessment:**

Ligand A has a superior binding affinity and better BBB penetration, which are crucial for a CNS GPCR target like DRD2. However, it has higher microsomal clearance and a slightly higher logP. Ligand B has better P-gp efflux, but suffers from significantly poorer BBB penetration and a weaker binding affinity.

Given the importance of CNS penetration for DRD2, and the substantial difference in binding affinity, Ligand A is the more promising candidate despite its slightly less favorable ADME profile. The stronger binding affinity could be optimized through further medicinal chemistry efforts, while improving BBB penetration for Ligand B would be a more significant challenge.

Output:
1
2025-04-17 03:45:51,653 - INFO - Batch 56 complete. Total preferences: 896
2025-04-17 03:45:51,653 - INFO - Processing batch 57/512...
2025-04-17 03:46:33,271 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (362.455 and 368.861 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (101.05) is slightly above the optimal <90 for CNS targets, but still reasonable. Ligand B (68.73) is well within the desired range.

**logP:** Ligand A (1.468) is within the optimal 1-3 range. Ligand B (3.331) is at the higher end of the optimal range, but still acceptable.

**H-Bond Donors/Acceptors:** Ligand A has 2 HBD and 5 HBA, which are acceptable. Ligand B has 0 HBD and 5 HBA, also acceptable.

**QED:** Both ligands have reasonable QED scores (0.839 and 0.762), indicating good drug-like properties.

**DILI:** Ligand A (83.288) has a higher DILI risk than Ligand B (46.297). This is a significant negative for Ligand A.

**BBB:** Ligand B (73.672) has a much better BBB percentile than Ligand A (63.978). This is crucial for a CNS target like DRD2.

**Caco-2 Permeability:** Ligand A (-5.249) has poor Caco-2 permeability. Ligand B (-4.438) is also poor, but slightly better than A.

**Aqueous Solubility:** Both ligands have very poor aqueous solubility (-3.346 and -3.553). This could pose formulation challenges.

**hERG:** Both ligands have low hERG inhibition risk (0.306 and 0.418).

**Microsomal Clearance:** Ligand A (32.588) has lower microsomal clearance, suggesting better metabolic stability than Ligand B (66.133).

**In vitro Half-Life:** Ligand B (6.431) has a significantly longer in vitro half-life than Ligand A (-0.646).

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.056 and 0.149).

**Binding Affinity:** Ligand B (-7.9 kcal/mol) has a significantly stronger binding affinity than Ligand A (-9.4 kcal/mol). This is a substantial advantage.

**Overall Assessment:**

Ligand B is the stronger candidate. While both have poor solubility, Ligand B excels in the most important areas for a CNS-targeting GPCR: BBB penetration, binding affinity, and in vitro half-life. The lower DILI risk is also a major advantage. Ligand A's higher DILI risk and lower BBB penetration are significant drawbacks. Although Ligand A has better metabolic stability, the affinity difference and CNS penetration of Ligand B outweigh this benefit.

Output:
1
2025-04-17 03:46:33,272 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (372.45 Da) is slightly higher than Ligand B (348.403 Da), but both are acceptable.

**TPSA:** Ligand A (59.81) is excellent for CNS penetration, well below the 90 A^2 threshold. Ligand B (114.69) is higher, but still potentially acceptable, though less ideal.

**logP:** Ligand A (4.458) is a bit high, potentially leading to solubility issues or off-target interactions. Ligand B (0.935) is quite low, which could hinder membrane permeability and CNS penetration.

**H-Bond Donors/Acceptors:** Ligand A (HBD=1, HBA=6) and Ligand B (HBD=3, HBA=6) are both within acceptable limits.

**QED:** Both ligands have good QED scores (A: 0.578, B: 0.644), indicating good drug-like properties.

**DILI:** Ligand A has a very high DILI risk (95.929), which is a major red flag. Ligand B has a much lower and acceptable DILI risk (25.436).

**BBB:** Ligand A has excellent BBB penetration (70.648), which is crucial for a CNS target. Ligand B's BBB penetration (40.132) is significantly lower and concerning.

**Caco-2 Permeability:** Ligand A (-4.897) has poor Caco-2 permeability, which is concerning. Ligand B (-5.573) is also poor, but similar to A.

**Aqueous Solubility:** Ligand A (-4.601) has poor aqueous solubility, consistent with its high logP. Ligand B (-3.09) is better, but still not ideal.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (A: 0.644, B: 0.514).

**Microsomal Clearance:** Ligand A (50.548) has moderate clearance, while Ligand B (32.761) has lower clearance, suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (74.438) has a good in vitro half-life. Ligand B (4.758) has a very short half-life, which is a significant drawback.

**P-gp Efflux:** Both ligands show low P-gp efflux (A: 0.815, B: 0.015), which is favorable for CNS penetration.

**Binding Affinity:** Ligand A (-10.3 kcal/mol) has significantly stronger binding affinity than Ligand B (-7.0 kcal/mol). This is a substantial advantage.

**Overall Assessment:**

Ligand A has a very strong binding affinity and acceptable BBB penetration, but suffers from a very high DILI risk, poor solubility, and poor Caco-2 permeability. Ligand B has a lower DILI risk, better metabolic stability, but significantly weaker binding affinity and poor BBB penetration.

Despite the strong affinity of Ligand A, the extremely high DILI risk is a deal-breaker. DILI is a major cause of drug failure. While the affinity difference is substantial, it is unlikely to overcome the safety concerns. Ligand B, while weaker in affinity, presents a much more favorable safety profile and better metabolic stability.

Output:
1
2025-04-17 03:46:33,272 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (346.43 and 360.46 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (88.41) is better than Ligand B (66.91). Both are below the 90 A^2 threshold desirable for CNS targets, but A is closer to the upper limit.

**logP:** Both ligands have good logP values (2.36 and 2.92), falling within the optimal 1-3 range.

**H-Bond Donors:** Both have 2 HBD, which is within the acceptable limit of <=5.

**H-Bond Acceptors:** Ligand A has 4 HBA, and Ligand B has 5. Both are below the 10 limit.

**QED:** Both ligands have good QED scores (0.756 and 0.821), indicating good drug-like properties.

**DILI:** Ligand A (41.18%) has a significantly lower DILI risk than Ligand B (89.65%). This is a major advantage for Ligand A.

**BBB:** Ligand B (70.65%) has a better BBB penetration score than Ligand A (60.84%). While both are reasonably good, B is above the 70% threshold.

**Caco-2 Permeability:** Both have negative Caco-2 values (-4.895 and -4.717), which is unusual and indicates poor permeability. This is a significant concern for both.

**Aqueous Solubility:** Both have negative solubility values (-2.401 and -4.69), which is also unusual and indicates poor solubility. This is a significant concern for both.

**hERG Inhibition:** Ligand A (0.091) has a much lower hERG inhibition liability than Ligand B (0.849). This is a substantial advantage for Ligand A.

**Microsomal Clearance:** Ligand A (6.113) has lower microsomal clearance than Ligand B (57.764), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand B (27.513 hours) has a longer half-life than Ligand A (14.392 hours).

**P-gp Efflux:** Ligand A (0.157) has lower P-gp efflux liability than Ligand B (0.313), which is favorable for CNS penetration.

**Binding Affinity:** Both ligands have very similar and strong binding affinities (-8.9 and -8.6 kcal/mol). The difference is less than the 1.5 kcal/mol threshold.

**Overall Assessment:**

Ligand A is significantly better due to its lower DILI risk, lower hERG inhibition, and lower P-gp efflux. While Ligand B has slightly better BBB penetration and a longer half-life, the safety and permeability advantages of Ligand A are more critical, especially given the similar binding affinities. The poor Caco-2 and solubility for both are concerning and would require further investigation/optimization, but the other factors make A the more promising candidate.

Output:
0
2025-04-17 03:46:33,273 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 drug candidates, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (356.491 and 362.539 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Both ligands have TPSA values around 49-50 A<sup>2</sup>, which is excellent for CNS penetration (well below the 90 A<sup>2</sup> threshold).

**3. logP:** Both ligands have logP values in the optimal range (3.886 and 3.127), suggesting good permeability and reasonable solubility.

**4. H-Bond Donors:** Ligand A has 0 HBD, while Ligand B has 1. Both are acceptable.

**5. H-Bond Acceptors:** Both ligands have 3 HBA, which is within the acceptable range.

**6. QED:** Both ligands have high QED scores (0.816 and 0.836), indicating good drug-like properties.

**7. DILI:** Ligand A has a DILI risk of 44.009%, while Ligand B has 31.059%. Both are good (below 40% is preferred, and both are below 60%). Ligand B is slightly better here.

**8. BBB:** Both ligands exhibit excellent BBB penetration (78.209% and 76.89%), which is crucial for a CNS target like DRD2.

**9. Caco-2 Permeability:** Ligand A (-4.38) and Ligand B (-5.142) both have negative values, which is unusual. Lower values suggest poor permeability. However, given the good logP and TPSA values, this might not be a major concern.

**10. Aqueous Solubility:** Both ligands have poor aqueous solubility (-4.435 and -3.669). This could be a formulation challenge.

**11. hERG Inhibition:** Both ligands have low hERG inhibition risk (0.663 and 0.55), which is positive.

**12. Microsomal Clearance:** Ligand A (71.399) has lower microsomal clearance than Ligand B (84.212), suggesting better metabolic stability.

**13. In vitro Half-Life:** Ligand A (13.795 hours) has a longer half-life than Ligand B (6.619 hours), which is desirable.

**14. P-gp Efflux:** Both ligands have low P-gp efflux liability (0.411 and 0.275), which is favorable for CNS exposure.

**15. Binding Affinity:** Ligand B (-9.4 kcal/mol) has a significantly stronger binding affinity than Ligand A (-8.4 kcal/mol). This difference of 1.0 kcal/mol is substantial and can outweigh some of the ADME drawbacks.

**Overall Assessment:**

While Ligand A has better metabolic stability and half-life, Ligand B's significantly stronger binding affinity (-9.4 vs -8.4 kcal/mol) is a decisive advantage, especially for a GPCR target. The slight improvements in DILI and P-gp efflux for Ligand B are also beneficial. The poor solubility and Caco-2 permeability are concerns for both, but the strong affinity of Ligand B makes it more likely to be a viable candidate, as potency can sometimes compensate for less-than-ideal ADME properties, particularly if formulation strategies can address the solubility issue.

Output:
1
2025-04-17 03:46:33,273 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (374.937 Da) and Ligand B (355.479 Da) are both acceptable.

**2. TPSA:** Ligand A (41.13) is excellent, well below the 90 A^2 threshold for CNS targets. Ligand B (93.11) is higher, approaching the upper limit for CNS penetration and potentially hindering BBB permeability.

**3. logP:** Ligand A (4.044) is at the higher end of the optimal range, potentially leading to solubility issues, but still acceptable. Ligand B (-0.187) is significantly low, which could impede membrane permeability and reduce CNS exposure.

**4. H-Bond Donors:** Both ligands have acceptable HBD counts (Ligand A: 2, Ligand B: 3).

**5. H-Bond Acceptors:** Both ligands have acceptable HBA counts (Ligand A: 3, Ligand B: 5).

**6. QED:** Both ligands have reasonable QED scores (Ligand A: 0.847, Ligand B: 0.533), suggesting good drug-like properties. Ligand A is superior.

**7. DILI:** Ligand A (35.595) has a very low DILI risk, which is excellent. Ligand B (4.769) also has a low DILI risk, but slightly higher than Ligand A.

**8. BBB:** Ligand A (80.38) has a good BBB percentile, desirable for a CNS target. Ligand B (43.699) is significantly lower, indicating poor predicted brain penetration. This is a major drawback.

**9. Caco-2 Permeability:** Both have negative Caco-2 values which is unusual. Assuming these are logP-like scales, both are poor.

**10. Aqueous Solubility:** Both have negative solubility values which is unusual. Assuming these are logS-like scales, both are poor.

**11. hERG Inhibition:** Ligand A (0.719) has a low hERG risk. Ligand B (0.149) also has a low hERG risk.

**12. Microsomal Clearance:** Ligand A (68.803) has moderate clearance. Ligand B (-5.728) has a negative clearance which is impossible and indicates an issue with the data.

**13. In vitro Half-Life:** Ligand A (37.055) has a reasonable half-life. Ligand B (8.43) has a very short half-life, which is undesirable.

**14. P-gp Efflux:** Ligand A (0.567) has moderate P-gp efflux. Ligand B (0.008) has very low P-gp efflux, which is favorable for CNS penetration.

**15. Binding Affinity:** Ligand A (-8.7 kcal/mol) has significantly stronger binding affinity than Ligand B (-7.0 kcal/mol). This difference of 1.7 kcal/mol is substantial and can outweigh some ADME drawbacks.

**Overall Assessment:**

Ligand A is the superior candidate. It has a better BBB score, more favorable logP, better binding affinity, lower DILI risk, and a reasonable half-life. While Ligand B has lower P-gp efflux, its poor BBB penetration, very short half-life, and significantly weaker binding affinity make it a less promising drug candidate. The negative clearance value for Ligand B is also a major red flag.



Output:
1
2025-04-17 03:46:33,273 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (374.478 and 350.419 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (84.5) is excellent for CNS penetration, being well below 90. Ligand B (94.05) is still reasonable but less optimal.

**logP:** Ligand A (1.573) is within the optimal 1-3 range. Ligand B (0.459) is slightly low, potentially hindering membrane permeability.

**H-Bond Donors/Acceptors:** Both have acceptable HBD (2 and 1 respectively) and HBA (5 each) counts.

**QED:** Both ligands have good QED scores (0.63 and 0.804), indicating drug-like properties.

**DILI:** Ligand A (35.789) has a slightly higher DILI risk than Ligand B (24.583), but both are below the concerning threshold of 60.

**BBB:** This is critical for a CNS target. Ligand A scores very well (74.254), while Ligand B is significantly lower (34.083).

**Caco-2 Permeability:** Ligand A (-4.823) and Ligand B (-5.009) both have negative values, which is unusual and requires careful interpretation. Lower values suggest poor permeability. However, the scale isn't defined, so it's hard to know the exact implications.

**Aqueous Solubility:** Both ligands have very poor aqueous solubility (-2.953 and -0.499). This could pose formulation challenges.

**hERG Inhibition:** Both ligands show very low hERG inhibition risk (0.171 and 0.024).

**Microsomal Clearance:** Ligand B (30.229) has a lower microsomal clearance than Ligand A (57.048), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (-8.436) has a slightly longer in vitro half-life than Ligand B (-6.575).

**P-gp Efflux:** Both ligands exhibit very low P-gp efflux liability (0.025 and 0.005), which is favorable for CNS penetration.

**Binding Affinity:** Ligand B (-7.2 kcal/mol) has a slightly better binding affinity than Ligand A (-7.0 kcal/mol). While the difference is small, it's within the range where it could be decisive.

**Overall Assessment:**

Ligand A excels in TPSA and BBB penetration, crucial for CNS targets. However, it has a slightly higher DILI risk, lower metabolic stability, and poorer solubility. Ligand B has better metabolic stability, lower DILI risk, and slightly better binding affinity, but its BBB penetration is significantly worse and logP is suboptimal. Given the importance of BBB penetration for a CNS GPCR target like DRD2, and the relatively small difference in binding affinity, **Ligand A is the more promising candidate.** The slightly lower affinity can be optimized in subsequent rounds of drug design, while improving BBB penetration is often more challenging.

Output:
1
2025-04-17 03:46:33,273 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (343.427 Da) is slightly lower, which could be beneficial for permeability, but both are acceptable.

**TPSA:** Ligand A (75.44) is better than Ligand B (46.84). For CNS targets, we want TPSA <= 90, and ideally lower. Ligand B is significantly lower, which is very favorable for brain penetration.

**logP:** Both ligands have good logP values (Ligand A: 2.17, Ligand B: 3.388), falling within the optimal 1-3 range. Ligand B is slightly higher, which could potentially lead to off-target effects, but is still acceptable.

**H-Bond Donors/Acceptors:** Ligand A has 1 HBD and 4 HBA, while Ligand B has 0 HBD and 6 HBA. Both are within acceptable limits (<=5 HBD and <=10 HBA).

**QED:** Both ligands have similar QED values (Ligand A: 0.77, Ligand B: 0.745), indicating good drug-like properties.

**DILI:** Ligand A (35.634) has a slightly higher DILI risk than Ligand B (29.197), but both are below the 40 threshold, indicating low risk.

**BBB:** This is a critical parameter for CNS targets. Ligand B (92.633) has a significantly higher BBB percentile than Ligand A (82.784). This is a major advantage for Ligand B.

**Caco-2 Permeability:** Ligand A (-4.982) has a worse Caco-2 permeability than Ligand B (-5.55). Lower values are less desirable.

**Aqueous Solubility:** Both ligands have poor aqueous solubility (-3.54 and -4.147). This could pose formulation challenges, but is not a deal-breaker if other properties are favorable.

**hERG Inhibition:** Ligand A (0.346) has a slightly lower hERG inhibition risk than Ligand B (0.603), which is preferable.

**Microsomal Clearance:** Ligand B (55.725) has a higher microsomal clearance than Ligand A (29.342), suggesting faster metabolism and potentially lower in vivo exposure.

**In vitro Half-Life:** Ligand B (-13.018) has a much longer in vitro half-life than Ligand A (-5.601). This is a significant advantage.

**P-gp Efflux:** Ligand A (0.164) has lower P-gp efflux than Ligand B (0.533), which is favorable for CNS penetration.

**Binding Affinity:** Ligand A (-8.6 kcal/mol) has a slightly better binding affinity than Ligand B (-7.4 kcal/mol). This is a 1.2 kcal/mol difference, which is significant.

**Overall Assessment:**

While Ligand A has a slightly better binding affinity and lower P-gp efflux, Ligand B excels in key GPCR/CNS-relevant parameters: significantly better BBB penetration, a longer half-life, and lower DILI risk. The TPSA is also much more favorable for CNS penetration. The difference in binding affinity (1.2 kcal/mol) is likely outweighed by the substantial improvements in ADME properties, particularly BBB and half-life, which will translate to greater in vivo exposure and efficacy.

Output:
1
2025-04-17 03:46:33,273 - INFO - Reasoning:

Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (342.403 and 362.499 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (111.06) is better than Ligand B (74.33). For CNS targets, we want TPSA <= 90, so Ligand B is preferable here.

**3. logP:** Both ligands (1.915 and 1.994) are within the optimal 1-3 range.

**4. H-Bond Donors:** Ligand A (1) is better than Ligand B (2). Lower is generally preferred for CNS penetration.

**5. H-Bond Acceptors:** Ligand A (4) is better than Ligand B (5).

**6. QED:** Ligand B (0.52) is better than Ligand A (0.353), indicating a more drug-like profile.

**7. DILI:** Both ligands have relatively low DILI risk (36.06 and 31.563), both below the 40 threshold.

**8. BBB:** Ligand A (64.444) is better than Ligand B (40.675). A BBB percentile >70 is desirable for CNS targets, and Ligand A is closer to this threshold.

**9. Caco-2 Permeability:** Ligand A (-5.131) is better than Ligand B (-5.585). Higher values indicate better absorption.

**10. Aqueous Solubility:** Ligand A (-1.086) is better than Ligand B (-1.382). Higher values are preferred.

**11. hERG Inhibition:** Both ligands have very low hERG inhibition liability (0.339 and 0.149).

**12. Microsomal Clearance:** Ligand A (1.11) is much better than Ligand B (8.619). Lower clearance is preferred for metabolic stability.

**13. In vitro Half-Life:** Ligand A (-21.193) is better than Ligand B (17.789). A more negative value indicates a longer half-life.

**14. P-gp Efflux:** Ligand A (0.026) is better than Ligand B (0.025). Lower efflux is preferred for CNS exposure.

**15. Binding Affinity:** Ligand B (-7.4) is better than Ligand A (-8.1). A more negative value indicates stronger binding. The difference of 0.7 kcal/mol is significant, and can outweigh some ADME drawbacks.

**Overall Assessment:**

Ligand B has a better QED and significantly better binding affinity. However, Ligand A has a much better BBB score, lower microsomal clearance, longer half-life, and better TPSA. Considering DRD2 is a CNS target, BBB penetration is crucial. While Ligand B's affinity is better, the substantial advantage in BBB penetration, metabolic stability (lower Cl_mic and longer t1/2), and TPSA for Ligand A makes it a more promising candidate.

Output:
0
2025-04-17 03:46:33,274 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (356.857 Da) is slightly higher than Ligand B (337.379 Da), but both are acceptable.

**TPSA:** Ligand A (50.16) is significantly better than Ligand B (77.25). For CNS targets, we want TPSA <= 90, and ideally closer to 60. Ligand A is much closer to this ideal.

**logP:** Both ligands have good logP values (3.462 and 3.39, respectively), falling within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Both have 1 HBD, which is good. Ligand A has 4 HBA, while Ligand B has 6. Both are within the acceptable limit of <=10, but Ligand A is preferable.

**QED:** Both ligands have acceptable QED scores (0.735 and 0.666, respectively), indicating good drug-like properties.

**DILI:** Both have relatively high DILI risk (68.786 and 77.045). This is a concern, but not a deal-breaker at this stage.

**BBB:** Ligand A (72.315) has a better BBB percentile than Ligand B (65.452). For a CNS target like DRD2, >70 is desirable, and A is closer to this threshold.

**Caco-2 Permeability:** Both have negative Caco-2 values (-5.051 and -4.869). This is unusual and suggests poor permeability. However, these values are on a log scale, so the actual permeability is very low.

**Aqueous Solubility:** Both have very poor aqueous solubility (-3.189 and -4.992). This is a significant drawback.

**hERG:** Both ligands have low hERG inhibition risk (0.596 and 0.576).

**Microsomal Clearance:** Ligand A (82.76) has lower microsomal clearance than Ligand B (128.705), indicating better metabolic stability.

**In vitro Half-Life:** Ligand A (144.164) has a significantly longer in vitro half-life than Ligand B (-11.554). This is a major advantage.

**P-gp Efflux:** Both have low P-gp efflux liability (0.445 and 0.46).

**Binding Affinity:** Both ligands have very similar and strong binding affinities (-9.3 and -9.4 kcal/mol). This is excellent, and the difference is not substantial enough to be a deciding factor.

**Overall Assessment:**

Considering the GPCR-specific priorities, Ligand A is the better candidate. It has a significantly lower TPSA, better BBB penetration, lower microsomal clearance, and a longer in vitro half-life. While both have poor solubility and DILI risk, the ADME properties of Ligand A are more favorable for CNS penetration and duration of action. The similar binding affinities make the ADME differences the key deciding factors.

Output:
1
2025-04-17 03:46:33,274 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (363.487 and 344.455 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (99.81) is higher than Ligand B (60.85). For CNS targets, TPSA should be <= 90. Ligand A is borderline, while Ligand B is well within the desired range.

**logP:** Both ligands have good logP values (2.048 and 1.873), falling within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A has 2 HBD and 6 HBA, while Ligand B has 1 HBD and 3 HBA. Both are within acceptable limits (<=5 HBD and <=10 HBA).

**QED:** Both ligands have good QED scores (0.736 and 0.795), indicating good drug-like properties.

**DILI:** Ligand A (40.752) has a slightly higher DILI risk than Ligand B (13.339). Both are below the concerning threshold of 60, but B is preferable.

**BBB:** Ligand A (76.503) has a better BBB percentile than Ligand B (63.552). A value >70 is desirable for CNS targets, and A is closer to that threshold. This is a significant advantage for Ligand A.

**Caco-2 Permeability:** Ligand A (-5.073) has poorer Caco-2 permeability than Ligand B (-4.707). Higher values are better, but both are negative, indicating poor permeability.

**Aqueous Solubility:** Ligand A (-3.885) has poorer aqueous solubility than Ligand B (-1.723). Higher values are better.

**hERG:** Both ligands have low hERG inhibition liability (0.363 and 0.23), which is good.

**Microsomal Clearance:** Ligand A (50.02) has higher microsomal clearance than Ligand B (23.688), suggesting lower metabolic stability. Lower is better.

**In vitro Half-Life:** Ligand A (34.927) has a longer half-life than Ligand B (13.739). This is a positive attribute for A.

**P-gp Efflux:** Ligand A (0.153) has lower P-gp efflux than Ligand B (0.081), which is favorable for CNS penetration. Lower is better.

**Binding Affinity:** Ligand B (-8.7 kcal/mol) has a significantly stronger binding affinity than Ligand A (-7.5 kcal/mol). This is a >1.2 kcal/mol advantage, which is substantial and can outweigh some ADME drawbacks.

**Overall Assessment:**

While Ligand A has advantages in BBB, in vitro half-life, and P-gp efflux, Ligand B's significantly stronger binding affinity (-8.7 vs -7.5 kcal/mol) is a major advantage, especially for a GPCR target. Ligand B also has better TPSA, DILI, solubility, and metabolic stability. The lower BBB score for Ligand B is a concern, but the superior affinity and other ADME properties are likely to compensate, especially with further optimization.

Output:
1
2025-04-17 03:46:33,274 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (345.4) is slightly lower, which could be beneficial for permeability.

**TPSA:** Ligand A (91.64) is slightly above the optimal 90 for CNS targets, but still reasonable. Ligand B (74.77) is well within the desired range.

**logP:** Ligand A (-0.106) is quite low, potentially hindering membrane permeability and CNS penetration. Ligand B (1.236) is within the optimal 1-3 range. This is a significant advantage for Ligand B.

**H-Bond Donors/Acceptors:** Ligand A (2 HBD, 5 HBA) and Ligand B (1 HBD, 6 HBA) both have acceptable numbers of H-bond donors and acceptors.

**QED:** Both ligands have good QED scores (A: 0.729, B: 0.796), indicating good drug-like properties.

**DILI:** Ligand A (34.432) has a lower DILI risk than Ligand B (51.881), which is favorable.

**BBB:** Ligand A (36.836) has a low BBB penetration percentile, which is a major drawback for a CNS target like DRD2. Ligand B (43.699) is also not ideal, but better than Ligand A.

**Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and suggests potential issues with the prediction method or the compounds themselves. However, the values are similar, so this isn't a major differentiator.

**Aqueous Solubility:** Both ligands have negative solubility values, again suggesting potential issues with the prediction. The values are similar.

**hERG Inhibition:** Ligand A (0.044) shows very low hERG inhibition risk, which is excellent. Ligand B (0.367) is slightly higher but still relatively low.

**Microsomal Clearance:** Ligand A (-8.551) has a very negative clearance, suggesting very slow metabolism and high metabolic stability. Ligand B (-4.425) is less stable, but still reasonable.

**In vitro Half-Life:** Ligand A (-3.784) has a negative half-life, which is not physically possible and indicates a problem with the prediction. Ligand B (33.411) has a good half-life.

**P-gp Efflux:** Ligand A (0.017) has very low P-gp efflux, which is excellent for CNS penetration. Ligand B (0.126) is slightly higher, but still acceptable.

**Binding Affinity:** Both ligands have good binding affinities (A: -8 kcal/mol, B: -7.5 kcal/mol). Ligand A is slightly more potent, but the difference is less than 1.5 kcal/mol, so it's not decisive.

**Overall Assessment:**

Ligand A has a better binding affinity, lower DILI risk, and lower P-gp efflux. However, its very low logP and poor BBB penetration are major concerns for a CNS target. The negative half-life is also a red flag.

Ligand B has a better logP, TPSA, and a reasonable half-life, making it more likely to cross the BBB and reach the target. While its DILI risk is higher and its affinity slightly lower, the improvements in ADME properties are more critical for a CNS-active drug.

Output:
1
2025-04-17 03:46:33,274 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (353.409 and 349.479 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (46.61) is significantly better than Ligand B (70.47). For CNS targets, we want TPSA <= 90, and ideally closer to 60. Ligand A is much closer to this ideal. Ligand B is pushing the upper limit and could have reduced brain penetration.

**3. logP:** Ligand A (3.89) is within the optimal range (1-3), while Ligand B (1.527) is on the lower end. Lower logP can hinder permeation, especially across the BBB.

**4. H-Bond Donors:** Ligand A (0) is preferred over Ligand B (1). Fewer H-bond donors generally improve membrane permeability.

**5. H-Bond Acceptors:** Ligand A (3) is better than Ligand B (5). Lower HBA counts are generally favorable for permeability.

**6. QED:** Both ligands have similar QED values (0.755 and 0.695), indicating good drug-like properties.

**7. DILI:** Ligand B (20.434) has a significantly lower DILI risk than Ligand A (35.014), which is a major advantage.

**8. BBB:** Ligand A (92.323) has a much higher BBB percentile than Ligand B (64.017). This is *critical* for a CNS target like DRD2.

**9. Caco-2 Permeability:** Ligand A (-4.372) is better than Ligand B (-4.974), indicating better intestinal absorption.

**10. Aqueous Solubility:** Ligand A (-4.068) is better than Ligand B (-1.146), suggesting better solubility.

**11. hERG Inhibition:** Ligand A (0.681) has a lower hERG risk than Ligand B (0.26), which is preferable.

**12. Microsomal Clearance:** Ligand B (23.092) has lower microsomal clearance than Ligand A (69.01), meaning it's more metabolically stable.

**13. In vitro Half-Life:** Ligand A (-25.726) has a longer in vitro half-life than Ligand B (12.582), which is desirable.

**14. P-gp Efflux:** Ligand A (0.387) has lower P-gp efflux than Ligand B (0.007), which is better for CNS exposure.

**15. Binding Affinity:** Ligand B (-7.3) has a slightly better binding affinity than Ligand A (-8.3). While affinity is crucial, the difference of 1.0 kcal/mol isn't substantial enough to outweigh the significant ADME advantages of Ligand A.

**Overall Assessment:**

Ligand A excels in properties crucial for CNS penetration (BBB, TPSA, logP, Pgp) and has acceptable DILI and hERG risk. While Ligand B has slightly better affinity and metabolic stability, its lower BBB penetration, higher TPSA, and lower logP are significant drawbacks for a DRD2 ligand. The superior CNS penetration profile of Ligand A makes it the more promising candidate.

Output:
1
2025-04-17 03:46:33,274 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (349.519 Da) is slightly lower, which could be advantageous for permeability.

**TPSA:** Ligand A (61.44) is significantly better than Ligand B (90.98). For CNS targets, a TPSA <= 90 is desirable, and Ligand A is comfortably within this range, while Ligand B is close to the upper limit.

**logP:** Both ligands have acceptable logP values (A: 3.292, B: 2.607), falling within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Both have 2 HBD, which is good. Ligand B has 4 HBA, while Ligand A has 2. Both are acceptable, but lower is generally preferred.

**QED:** Both ligands have reasonable QED scores (A: 0.741, B: 0.663), indicating good drug-like properties.

**DILI:** Ligand A (13.106) has a much lower DILI risk than Ligand B (38.736). This is a significant advantage.

**BBB:** Ligand A (81.776) has a substantially better BBB penetration score than Ligand B (43.001). Given DRD2 is a CNS target, this is a critical factor. A score >70 is desirable, and Ligand A is closer to that target.

**Caco-2 Permeability:** Ligand A (-4.682) has a worse Caco-2 permeability score than Ligand B (-5.266), but both are negative and thus indicate poor permeability.

**Aqueous Solubility:** Ligand A (-3.681) has a slightly better solubility score than Ligand B (-2.374), but both are negative and thus indicate poor solubility.

**hERG Inhibition:** Both ligands have very low hERG inhibition risk (A: 0.482, B: 0.088), which is excellent.

**Microsomal Clearance:** Ligand B (32.64) has a lower microsomal clearance than Ligand A (44.346), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand B (22.252) has a significantly longer in vitro half-life than Ligand A (-0.272). This is a major advantage.

**P-gp Efflux:** Ligand A (0.095) has lower P-gp efflux liability than Ligand B (0.058), which is favorable for CNS exposure.

**Binding Affinity:** Ligand B (-7.3) has a slightly better binding affinity than Ligand A (-9.0). However, the difference is relatively small, and Ligand A already has very strong binding.

**Overall Assessment:**

Considering the GPCR-specific priorities, Ligand A is the more promising candidate. Its superior BBB penetration, lower DILI risk, and better TPSA outweigh the slightly lower half-life and Caco-2 permeability. The binding affinity difference is not substantial enough to favor Ligand B, especially given Ligand A's other advantages for CNS penetration and safety.

Output:
0
2025-04-17 03:46:33,275 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (350.459 and 347.419 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (73.59) is excellent, well below the 90 A^2 threshold for CNS targets. Ligand B (96.33) is still reasonable but approaching the upper limit for good CNS penetration.

**logP:** Ligand A (3.06) is optimal (1-3). Ligand B (-0.404) is significantly below the optimal range and could have permeability issues.

**H-Bond Donors/Acceptors:** Ligand A (1 HBD, 5 HBA) and Ligand B (2 HBD, 5 HBA) both have acceptable numbers of H-bond donors and acceptors.

**QED:** Both ligands have reasonable QED values (0.883 and 0.774), indicating good drug-like properties.

**DILI:** Ligand A (46.995) has a slightly higher DILI risk than Ligand B (34.277), but both are below the concerning threshold of 60.

**BBB:** This is a critical factor for a CNS target. Ligand A (77.821) has a good BBB percentile, exceeding the 70% target. Ligand B (32.648) is significantly lower and would likely have poor brain penetration.

**Caco-2 Permeability:** Ligand A (-4.771) and Ligand B (-5.484) both have negative Caco-2 values, which is unusual and suggests poor permeability. However, the scale is not specified, so it's difficult to interpret these values precisely.

**Aqueous Solubility:** Ligand A (-2.571) and Ligand B (-0.931) both have negative solubility values, which is also unusual and suggests poor solubility.

**hERG:** Both ligands have very low hERG inhibition liability (0.545 and 0.058), which is excellent.

**Microsomal Clearance:** Ligand A (56.644) has moderate clearance, while Ligand B (-26.612) has a negative clearance, which is not physically possible and indicates an issue with the data.

**In vitro Half-Life:** Ligand A (11.736 hours) has a reasonable half-life. Ligand B (10.834 hours) is comparable.

**P-gp Efflux:** Ligand A (0.339) has low P-gp efflux, which is favorable. Ligand B (0.009) has very low P-gp efflux, which is even better.

**Binding Affinity:** Ligand A (-8.3 kcal/mol) has significantly better binding affinity than Ligand B (-0.0 kcal/mol). A difference of >1.5 kcal/mol is a strong indicator of superiority, even if other properties are slightly less favorable.

**Conclusion:**

Considering all factors, especially the GPCR-specific priorities, **Ligand A is the much more promising candidate.** Its superior binding affinity, good BBB penetration, acceptable TPSA and logP, and low hERG risk outweigh the slightly higher DILI risk and questionable solubility/permeability values. Ligand B's extremely low logP and poor BBB penetration are major drawbacks that are unlikely to be overcome. The negative clearance value for Ligand B also raises concerns about data quality.

Output:
1
2025-04-17 03:46:33,275 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (351.451 Da) is slightly lower, which is generally favorable for permeability. Ligand B (373.551 Da) is also good.

**TPSA:** Ligand A (89.35) is excellent, falling well below the 90 Angstroms threshold for CNS targets. Ligand B (62.73) is even better, suggesting improved BBB penetration potential.

**logP:** Ligand A (0.956) is at the lower end of the optimal range (1-3), potentially hindering permeability. Ligand B (4.854) is significantly higher, which could lead to solubility issues and off-target interactions, but is a common trade-off for CNS penetration.

**H-Bond Donors/Acceptors:** Ligand A (HBD=1, HBA=6) is within acceptable limits. Ligand B (HBD=2, HBA=7) is also acceptable.

**QED:** Both ligands have similar QED values (A: 0.634, B: 0.619), indicating good drug-like properties.

**DILI:** Ligand A (35.983) has a much lower DILI risk than Ligand B (74.176), which is a significant advantage.

**BBB:** Ligand B (76.541) has a much better BBB percentile than Ligand A (53.083). This is crucial for a CNS target like DRD2.

**Caco-2 Permeability:** Ligand A (-4.957) has a very poor Caco-2 permeability score, which is concerning. Ligand B (-5.205) is also poor, but slightly better.

**Aqueous Solubility:** Ligand A (-0.937) has slightly better solubility than Ligand B (-4.99).

**hERG:** Ligand A (0.022) has a very low hERG risk, a major advantage. Ligand B (0.662) has a moderate hERG risk, which needs consideration.

**Microsomal Clearance:** Ligand A (29.63) has a lower microsomal clearance, indicating better metabolic stability, than Ligand B (84.249).

**In vitro Half-Life:** Ligand B (51.352) has a significantly longer in vitro half-life than Ligand A (-0.846), which is desirable.

**P-gp Efflux:** Ligand A (0.016) exhibits very low P-gp efflux, which is beneficial for CNS penetration. Ligand B (0.457) has moderate P-gp efflux.

**Binding Affinity:** Ligand B (-8.3 kcal/mol) has a substantially stronger binding affinity than Ligand A (-7.2 kcal/mol). This difference of 1.1 kcal/mol is significant and can potentially outweigh some of the ADME drawbacks.

**Overall Assessment:**

Ligand B excels in binding affinity and BBB penetration, both critical for a CNS GPCR target. Its longer half-life is also a plus. However, it has higher DILI risk, higher logP, and moderate P-gp efflux. Ligand A has a better safety profile (lower DILI, hERG), better metabolic stability, and lower P-gp efflux, but suffers from weaker binding affinity and poor Caco-2 permeability, and lower BBB.

Given the importance of affinity for GPCRs and the need for CNS penetration, the stronger binding affinity and better BBB of Ligand B are more compelling, even with its ADME liabilities. Optimization efforts could focus on mitigating the DILI and logP issues of Ligand B.

Output:
1
2025-04-17 03:46:33,275 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (356.455 and 363.483 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (75.94) is better than Ligand B (83.71). Both are below the 90 A^2 threshold for CNS targets, but A is closer to the ideal.

**3. logP:** Both ligands have good logP values (2.795 and 1.344), falling within the 1-3 optimal range. Ligand A is slightly better.

**4. H-Bond Donors:** Both have 1 HBD, which is acceptable.

**5. H-Bond Acceptors:** Ligand A has 7 HBAs, while Ligand B has 4. Both are within the acceptable limit of 10.

**6. QED:** Both ligands have good QED scores (0.735 and 0.773), indicating drug-like properties.

**7. DILI:** Ligand A has a DILI risk of 79.256, which is concerning (approaching the high-risk threshold of >60). Ligand B has a much lower DILI risk (33.695), a significant advantage.

**8. BBB:** Ligand A (69.523) is below the desirable threshold of >70 for CNS targets, while Ligand B (77.123) is closer, but still not ideal.

**9. Caco-2:** Both have negative Caco-2 values, which is unusual and suggests poor permeability. This is a red flag for both.

**10. Solubility:** Both have negative solubility values, indicating poor aqueous solubility. This is also a concern for both.

**11. hERG:** Both ligands have very low hERG inhibition liability (0.51 and 0.097), which is excellent.

**12. Cl_mic:** Ligand A (53.647) has a slightly better (lower) microsomal clearance than Ligand B (47.522), suggesting better metabolic stability.

**13. t1/2:** Ligand A (64.578) has a significantly longer in vitro half-life than Ligand B (-14.179). This is a major advantage for Ligand A.

**14. Pgp:** Ligand A (0.04) has much lower P-gp efflux liability than Ligand B (0.032), which is favorable for CNS penetration.

**15. Binding Affinity:** Ligand A (-8.3 kcal/mol) has a significantly stronger binding affinity than Ligand B (-7.2 kcal/mol). This is a substantial advantage, potentially outweighing some of the ADME concerns.

**Overall Assessment:**

While Ligand A has a concerning DILI score and suboptimal BBB penetration, its significantly stronger binding affinity (-8.3 vs -7.2 kcal/mol), longer half-life, and lower P-gp efflux liability are compelling advantages, especially for a CNS target like DRD2. Ligand B's lower DILI is attractive, but its weaker affinity and shorter half-life are significant drawbacks. The negative Caco-2 and solubility values are concerning for both, but can potentially be addressed with formulation strategies. Given the importance of affinity for GPCR ligands, and the potential to mitigate the DILI risk through further optimization, Ligand A appears to be the more promising candidate.

Output:
1
2025-04-17 03:46:33,275 - INFO - Batch 57 complete. Total preferences: 912
2025-04-17 03:46:33,275 - INFO - Processing batch 58/512...
2025-04-17 03:47:14,523 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (349.39 and 344.46 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (106.08) is higher than Ligand B (76.02). For CNS targets, TPSA should be <= 90. Both are within this range, but B is significantly better.

**logP:** Ligand A (0.622) is below the optimal 1-3 range, potentially hindering permeability. Ligand B (2.506) is within the optimal range. This is a significant advantage for B.

**H-Bond Donors/Acceptors:** Ligand A has 1 HBD and 5 HBA, while Ligand B has 2 HBD and 4 HBA. Both are within acceptable limits.

**QED:** Both ligands have good QED scores (0.727 and 0.779), indicating good drug-like properties.

**DILI:** Ligand A (33.58) has a lower DILI risk than Ligand B (51.65), which is preferable.

**BBB:** Ligand A (63.78) has a better BBB penetration percentile than Ligand B (58.51), although both are below the desirable >70 for CNS targets.

**Caco-2 Permeability:** Both have negative values, indicating poor permeability. Ligand A (-5.07) is slightly better than Ligand B (-4.8).

**Aqueous Solubility:** Both have negative values, indicating poor solubility. Ligand A (-2.005) is slightly better than Ligand B (-3.33).

**hERG:** Both ligands have very low hERG inhibition liability (0.24 and 0.137), which is excellent.

**Microsomal Clearance:** Ligand A (-6.313) has a lower (better) microsomal clearance than Ligand B (26.848), suggesting greater metabolic stability.

**In vitro Half-Life:** Ligand A (27.69) has a longer half-life than Ligand B (11.09), which is desirable.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.023 and 0.075), which is excellent.

**Binding Affinity:** Ligand B (-8.7 kcal/mol) has a significantly stronger binding affinity than Ligand A (-7.3 kcal/mol). This >1.5 kcal/mol difference is a major advantage for B, potentially outweighing some of its ADME drawbacks.

**Overall Assessment:**

Ligand B has a superior logP, which is crucial for GPCR ligands. Its binding affinity is also significantly stronger. While Ligand A has better DILI and BBB, the stronger binding and better logP of Ligand B are more important for a CNS-targeting GPCR ligand like DRD2. The slightly worse BBB of B is a concern, but the strong affinity might compensate for that.

Output:
1
2025-04-17 03:47:14,523 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (342.527 Da) is slightly better, being closer to the lower end which can aid permeability.

**TPSA:** Ligand A (23.55) is excellent, well below the 90 A^2 threshold for CNS targets. Ligand B (92.79) is significantly higher, potentially hindering BBB penetration.

**logP:** Ligand A (4.634) is slightly high, potentially leading to solubility issues or off-target interactions, but still within a manageable range. Ligand B (3.411) is optimal.

**H-Bond Donors/Acceptors:** Ligand A (0 HBD, 2 HBA) is favorable. Ligand B (2 HBD, 6 HBA) is also acceptable, though slightly higher.

**QED:** Both ligands have similar QED values (A: 0.508, B: 0.571), indicating good drug-like properties.

**DILI:** Ligand A (5.894) has a much lower DILI risk than Ligand B (99.147), a significant advantage.

**BBB:** Ligand A (93.757) has excellent BBB penetration, crucial for a CNS target like DRD2. Ligand B (49.128) is considerably lower, raising concerns about reaching the target in the brain.

**Caco-2 Permeability:** Ligand A (-4.827) and Ligand B (-5.08) both have negative Caco-2 values, which is unusual and suggests poor permeability. However, the scale is not specified, so it's hard to interpret.

**Aqueous Solubility:** Both ligands have poor aqueous solubility (-3.043 and -4.714 respectively).

**hERG:** Both ligands have low hERG inhibition liability (A: 0.962, B: 0.652).

**Microsomal Clearance:** Both ligands have similar microsomal clearance (A: 45.907, B: 44.13).

**In vitro Half-Life:** Ligand A (-8.894) has a much longer in vitro half-life than Ligand B (21.375), suggesting better metabolic stability.

**P-gp Efflux:** Ligand A (0.663) has lower P-gp efflux liability than Ligand B (0.496), which is beneficial for CNS penetration.

**Binding Affinity:** Ligand B (-9.3 kcal/mol) has a slightly better binding affinity than Ligand A (-8.2 kcal/mol). However, the difference is not substantial enough to outweigh the significant ADME advantages of Ligand A.

**Conclusion:**

Considering the GPCR-specific priorities, Ligand A is the more promising candidate. Its superior BBB penetration, lower DILI risk, longer half-life, and lower P-gp efflux liability are crucial for a CNS-targeting drug. While Ligand B has slightly better binding affinity, the ADME profile of Ligand A is far more favorable, making it more likely to succeed as a drug candidate.

Output:
0
2025-04-17 03:47:14,523 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (355.479 and 352.475 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (118.36) is slightly above the preferred <90 for CNS targets, while Ligand B (89.87) is well within the range. This favors Ligand B.

**logP:** Both ligands have excellent logP values (1.15 and 1.053) falling within the optimal 1-3 range.

**H-Bond Donors & Acceptors:** Both have 3 HBD and 4 HBA, which are acceptable.

**QED:** Both ligands have good QED scores (0.509 and 0.69), indicating drug-like properties. Ligand B is slightly better.

**DILI:** Ligand A (27.104) has a lower DILI risk than Ligand B (19.736), which is favorable.

**BBB:** Both ligands have reasonable BBB penetration (50.795 and 54.517), but neither exceeds the desirable >70 threshold. Ligand B is slightly better.

**Caco-2 Permeability:** Both have negative Caco-2 values (-5.278 and -4.837), which is unusual and suggests poor permeability. This is a significant concern for both.

**Aqueous Solubility:** Both have negative solubility values (-2.856 and -2.083), indicating very poor solubility. This is a major drawback for both.

**hERG:** Both ligands have low hERG inhibition liability (0.116 and 0.308), which is good.

**Microsomal Clearance:** Ligand A (42.959) has higher microsomal clearance than Ligand B (-4.631). This means Ligand B is likely more metabolically stable, which is a significant advantage.

**In vitro Half-Life:** Ligand B (2.931) has a slightly longer in vitro half-life than Ligand A (-30.48), which is preferable.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.006 and 0.056), which is excellent for CNS penetration.

**Binding Affinity:** Ligand B (-8.1 kcal/mol) has a slightly better binding affinity than Ligand A (-7.8 kcal/mol). While the difference is small, it's within the range where it could outweigh minor ADME drawbacks.

**Overall Assessment:**

Ligand B is the better candidate. While both have issues with solubility and Caco-2 permeability, Ligand B has a lower TPSA, better metabolic stability (lower Cl_mic), a slightly longer half-life, and a slightly better binding affinity. The lower DILI risk for Ligand A is a positive, but the other ADME properties of Ligand B are more favorable for a CNS-targeting GPCR ligand. The small affinity difference is a bonus.

Output:
1
2025-04-17 03:47:14,523 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (405.336 Da) is slightly higher than Ligand B (361.467 Da), but both are acceptable.

**2. TPSA:** Ligand A (50.36) is better than Ligand B (68.46). For CNS targets, we want TPSA <= 90, and ideally closer to 60. Ligand A is closer to the ideal range.

**3. logP:** Both ligands have good logP values (A: 4.277, B: 3.056), falling within the optimal 1-3 range. Ligand B is slightly better here.

**4. H-Bond Donors:** Ligand A (2) is preferable to Ligand B (0). While both are acceptable, a small number of HBDs can aid solubility.

**5. H-Bond Acceptors:** Ligand A (2) is preferable to Ligand B (6). Higher HBA can sometimes hinder permeability.

**6. QED:** Both ligands have similar QED values (A: 0.723, B: 0.709), indicating good drug-likeness.

**7. DILI:** Ligand A (49.438) has a slightly better DILI score than Ligand B (55.642), both are acceptable, but lower is better.

**8. BBB:** Both ligands have good BBB penetration (A: 69.252, B: 71.733), but ligand B is slightly better. A value >70 is desirable for CNS targets.

**9. Caco-2:** Both have negative Caco-2 values which is unusual and suggests poor permeability. Ligand A (-4.882) is slightly better than Ligand B (-5.185).

**10. Solubility:** Both have negative solubility values which is also unusual and suggests poor solubility. Ligand A (-4.952) is slightly better than Ligand B (-2.878).

**11. hERG:** Both ligands have low hERG inhibition liability (A: 0.912, B: 0.403). Ligand B is better here.

**12. Cl_mic:** Ligand B (89.365) has lower microsomal clearance than Ligand A (105.162), indicating better metabolic stability.

**13. t1/2:** Both have similar in vitro half-lives (A: 19.449, B: 17.717).

**14. Pgp:** Both ligands have low P-gp efflux liability (A: 0.507, B: 0.546).

**15. Binding Affinity:** Ligand B (-7.8 kcal/mol) has significantly better binding affinity than Ligand A (-9.6 kcal/mol). This is a substantial advantage.

**Overall Assessment:**

While Ligand A has better TPSA and H-bonding characteristics, Ligand B's significantly stronger binding affinity (-7.8 vs -9.6 kcal/mol) is a major advantage, especially for a GPCR target. The slightly better BBB penetration of Ligand B and lower Cl_mic are also beneficial. The negative Caco-2 and solubility values for both are concerning, but the affinity difference is likely to outweigh these issues in initial optimization.

Output:
1
2025-04-17 03:47:14,523 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (345.345 and 344.455 Da) fall comfortably within the ideal 200-500 Da range.

**TPSA:** Ligand A (46.61) is excellent, well below the 90 A^2 threshold for CNS targets. Ligand B (78.43) is higher, but still reasonable, though less favorable for CNS penetration.

**logP:** Both ligands have logP values (3.214 and 3.504) within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A has 0 HBD and 3 HBA, which is very good. Ligand B has 3 HBD and 3 HBA, also acceptable.

**QED:** Both ligands have good QED scores (0.597 and 0.662), indicating drug-like properties.

**DILI:** Ligand A has a DILI risk of 88.523, which is concerningly high. Ligand B has a much lower DILI risk of 24.467, a significant advantage.

**BBB:** Ligand A has a BBB penetration percentile of 77.898, which is good for a CNS target. Ligand B has a BBB percentile of 64.25, which is less desirable.

**Caco-2 Permeability:** Both show poor Caco-2 permeability (-4.009 and -4.974). This is a concern for oral bioavailability but less critical for a CNS target where direct delivery or other routes might be considered.

**Aqueous Solubility:** Both ligands have very poor aqueous solubility (-4.419 and -4.094). This could pose formulation challenges.

**hERG Inhibition:** Both ligands show low hERG inhibition risk (0.603 and 0.523).

**Microsomal Clearance:** Ligand A has a higher microsomal clearance (96.545) than Ligand B (53.337), indicating faster metabolism and potentially lower in vivo exposure.

**In vitro Half-Life:** Ligand B has a significantly longer in vitro half-life (-5.768 hours) than Ligand A (-1.404 hours).

**P-gp Efflux:** Ligand A has lower P-gp efflux (0.335) than Ligand B (0.096), which is favorable for CNS penetration.

**Binding Affinity:** Ligand B has a better binding affinity (-9.3 kcal/mol) than Ligand A (-8.5 kcal/mol). This 0.8 kcal/mol difference is substantial and can outweigh some ADME drawbacks.

**Overall Assessment:**

Ligand B is the stronger candidate. While both have poor solubility and Caco-2 permeability, Ligand B has a significantly better binding affinity, lower DILI risk, and a longer half-life. The lower P-gp efflux of Ligand A is a benefit, but the superior affinity and safety profile of Ligand B are more important for a CNS GPCR target like DRD2. The slightly lower BBB score for Ligand B is less concerning given its improved overall profile.

Output:
1
2025-04-17 03:47:14,524 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (366.414 and 362.417 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (85.36) is slightly higher than Ligand B (78.87). Both are below the 90 A^2 threshold desirable for CNS targets, but Ligand B is preferable.

**3. logP:** Both ligands have good logP values (1.584 and 1.172), falling within the optimal 1-3 range.

**4. H-Bond Donors:** Ligand A has 1 HBD, while Ligand B has 2. Both are within the acceptable limit of <=5.

**5. H-Bond Acceptors:** Ligand A has 6 HBA, and Ligand B has 4. Both are within the acceptable limit of <=10.

**6. QED:** Both ligands have reasonable QED values (0.809 and 0.713), indicating good drug-like properties.

**7. DILI:** Ligand A has a DILI risk of 75.029, which is concerning, placing it in the higher risk category (>60). Ligand B has a much lower DILI risk of 16.402, which is excellent.

**8. BBB:** Both ligands exhibit good BBB penetration (82.164 and 87.67), exceeding the >70 percentile desirable for CNS targets. Ligand B is slightly better.

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.624 and -4.754), which is unusual and suggests poor permeability. This is a significant drawback for both.

**10. Aqueous Solubility:** Both ligands have negative solubility values (-3.071 and -1.768), indicating very poor aqueous solubility, which is a major concern for bioavailability.

**11. hERG Inhibition:** Both ligands show low hERG inhibition liability (0.629 and 0.469), which is favorable.

**12. Microsomal Clearance:** Ligand A has a Cl_mic of 35.862, while Ligand B has a negative value (-8.685). Negative clearance is not physically meaningful, but suggests very high metabolic stability. Ligand A's clearance is moderate.

**13. In vitro Half-Life:** Ligand A has a half-life of 28.533 hours, which is good. Ligand B has a very short half-life (-24.64 hours), which is a significant drawback.

**14. P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.144 and 0.027), which is excellent for CNS exposure.

**15. Binding Affinity:** Both ligands have very strong binding affinities (-8.8 and -8.1 kcal/mol). Ligand A is slightly more potent.

**Overall Assessment:**

Despite both ligands having strong binding affinities and good BBB penetration, Ligand B is significantly better due to its much lower DILI risk and potentially higher metabolic stability (indicated by the negative Cl_mic). While Ligand A has a slightly better binding affinity and half-life, the high DILI risk is a major concern. The poor Caco-2 and solubility are problematic for both, but can potentially be addressed with formulation strategies. Given the GPCR-specific prioritization, the lower DILI risk and better metabolic stability of Ligand B outweigh the slight advantage in affinity and half-life of Ligand A.

Output:
1
2025-04-17 03:47:14,524 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (346.391 and 343.387 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Both ligands (121.89 and 127.74) are below the 140 A^2 threshold for good oral absorption, but slightly above the more stringent <90 A^2 for CNS targets. This isn't a major concern, as other factors can compensate.

**3. logP:** Ligand A (0.922) is slightly better than Ligand B (0.564), falling comfortably within the 1-3 range. Ligand B is a bit low, potentially hindering permeation.

**4. H-Bond Donors:** Both ligands have 3 HBD, which is acceptable (<=5).

**5. H-Bond Acceptors:** Ligand A has 6 HBA, and Ligand B has 5 HBA. Both are below the 10 threshold.

**6. QED:** Both ligands have similar QED values (0.653 and 0.65), indicating good drug-like properties.

**7. DILI:** Ligand A (63.94) has a slightly higher DILI risk than Ligand B (56.495), but both are within an acceptable range (<60 is good).

**8. BBB:** Both ligands have similar BBB penetration (47.15% and 48.236%), which is below the desirable >70% for CNS targets. This is a significant drawback for both.

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.163 and -5.123). This is unusual and suggests poor permeability.

**10. Aqueous Solubility:** Both ligands have negative solubility values (-2.564 and -3.603), indicating very poor aqueous solubility. This is a major concern for bioavailability.

**11. hERG Inhibition:** Both ligands have low hERG inhibition risk (0.199 and 0.344).

**12. Microsomal Clearance:** Ligand A (12.974) has lower microsomal clearance than Ligand B (16.355), suggesting better metabolic stability.

**13. In vitro Half-Life:** Ligand A (-23.32) has a more negative half-life than Ligand B (-15.314), which is counterintuitive. A more negative value here likely indicates a very *short* half-life, which is unfavorable.

**14. P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.004 and 0.021), which is good for CNS exposure.

**15. Binding Affinity:** Ligand B (-8.5 kcal/mol) has a slightly better binding affinity than Ligand A (-8.1 kcal/mol). This difference of 0.4 kcal/mol is notable.

**Overall Assessment:**

Both compounds have significant drawbacks (poor solubility, permeability, and BBB penetration). However, Ligand B has a slightly better binding affinity and a lower DILI risk. The slightly better metabolic stability of Ligand A is offset by its shorter in vitro half-life. Given the importance of binding affinity for GPCRs, and the relatively small difference in other parameters, Ligand B is marginally more promising. However, both would require substantial optimization to address the solubility and permeability issues.

Output:
1
2025-04-17 03:47:14,524 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (367.793 and 346.435 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (104.7) is slightly higher than Ligand B (97.98). Both are below the 140 threshold for oral absorption and reasonably close to the 90 threshold for CNS targets, but Ligand B is preferable.

**3. logP:** Both ligands have good logP values (1.041 and 1.152), falling within the optimal 1-3 range.

**4. H-Bond Donors:** Ligand A (1) is better than Ligand B (2) as fewer HBDs generally improve permeability.

**5. H-Bond Acceptors:** Ligand A (7) is better than Ligand B (8). Lower HBA is generally preferred.

**6. QED:** Both ligands have similar and good QED values (0.869 and 0.809), indicating good drug-like properties.

**7. DILI:** Ligand A (75.184) has a significantly higher DILI risk than Ligand B (31.563). This is a major concern for Ligand A.

**8. BBB:** Ligand B (34.548) has a slightly better BBB penetration percentile than Ligand A (32.299), though both are relatively low. For a CNS target like DRD2, higher BBB penetration is crucial.

**9. Caco-2 Permeability:** Ligand A (-4.735) has a worse Caco-2 permeability than Ligand B (-5.211). Lower values indicate poorer permeability.

**10. Aqueous Solubility:** Ligand A (-2.528) has better aqueous solubility than Ligand B (-1.374).

**11. hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.028 and 0.066).

**12. Microsomal Clearance:** Ligand B (-17.754) has a significantly lower (better) microsomal clearance than Ligand A (50.871), suggesting better metabolic stability.

**13. In vitro Half-Life:** Ligand B (9.129) has a much longer in vitro half-life than Ligand A (-13.185).

**14. P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.065 and 0.043).

**15. Binding Affinity:** Ligand A (-8.8 kcal/mol) has a slightly better binding affinity than Ligand B (-7.4 kcal/mol). This is a 1.4 kcal/mol difference, which is significant.

**Overall Assessment:**

While Ligand A has a slightly better binding affinity, the significant drawbacks in DILI risk, metabolic stability (high Cl_mic, short t1/2), and Caco-2 permeability make it a less desirable candidate. Ligand B, despite slightly weaker binding, presents a much more favorable ADME-Tox profile, with lower DILI risk, better metabolic stability, and reasonable BBB penetration. The affinity difference, while noticeable, can potentially be optimized during lead optimization. For a CNS target, the improved ADME properties of Ligand B outweigh the small difference in binding affinity.

Output:
1
2025-04-17 03:47:14,524 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (351.407) is slightly lower, which could be beneficial for permeability, but both are acceptable.

**TPSA:** Ligand A (118.37) is borderline for CNS targets (ideally <90), while Ligand B (29.54) is excellent, well below the threshold. This is a significant advantage for Ligand B.

**logP:** Ligand A (-0.534) is too low, potentially hindering membrane permeability. Ligand B (4.065) is slightly high, but still within an acceptable range, though it could lead to off-target effects.

**H-Bond Donors/Acceptors:** Ligand A has 3 HBD and 8 HBA, which are reasonable. Ligand B has 0 HBD and 3 HBA, also reasonable.

**QED:** Both ligands have similar QED values (0.589 and 0.609), indicating good drug-likeness.

**DILI:** Ligand A (43.311) has a moderate DILI risk, while Ligand B (25.514) has a low DILI risk. This favors Ligand B.

**BBB:** Ligand A (53.432) has a moderate BBB penetration, which is not ideal for a CNS target. Ligand B (97.635) has excellent BBB penetration, a major advantage.

**Caco-2 Permeability:** Ligand A (-5.311) has poor Caco-2 permeability, which is concerning. Ligand B (-4.703) also has poor Caco-2 permeability, but is slightly better than Ligand A.

**Aqueous Solubility:** Both ligands have poor aqueous solubility (-0.837 and -4.814). This could pose formulation challenges, but is not a deal-breaker.

**hERG Inhibition:** Ligand A (0.124) has a very low hERG risk, which is excellent. Ligand B (0.886) has a slightly higher, but still acceptable, hERG risk.

**Microsomal Clearance:** Ligand A (-11.806) has a very low (and negative) microsomal clearance, suggesting high metabolic stability. Ligand B (84.363) has a high microsomal clearance, indicating rapid metabolism. This is a significant drawback for Ligand B.

**In vitro Half-Life:** Ligand A (8.525) has a moderate in vitro half-life. Ligand B (39.212) has a long in vitro half-life, which is favorable.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.008 and 0.438), which is good for CNS penetration.

**Binding Affinity:** Ligand B (-7.8 kcal/mol) has significantly stronger binding affinity than Ligand A (-8.0 kcal/mol). The difference is 0.8 kcal/mol, which is substantial and can outweigh some ADME drawbacks.

**Overall Assessment:**

Ligand B excels in BBB penetration and binding affinity, both critical for a CNS-targeting GPCR. While its logP is slightly high and its microsomal clearance is high, the strong affinity and excellent BBB penetration are compelling. Ligand A has a better hERG profile and metabolic stability, but suffers from poor BBB penetration and a significantly weaker binding affinity. Given the GPCR-specific priorities, the superior affinity and BBB penetration of Ligand B outweigh its drawbacks.

Output:
1
2025-04-17 03:47:14,524 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (344.5) is slightly better, being closer to the middle of the range.

**TPSA:** Ligand A (49.41) is excellent for CNS penetration, well below the 90 A^2 threshold. Ligand B (96.09) is higher, but still potentially acceptable, though less ideal.

**logP:** Ligand A (3.132) is optimal. Ligand B (0.747) is quite low, potentially hindering membrane permeability and CNS entry.

**H-Bond Donors:** Both have 1 HBD, which is good.

**H-Bond Acceptors:** Ligand A has 2 HBA, and Ligand B has 8. Ligand A is preferable here, as excessive HBAs can reduce permeability.

**QED:** Both ligands have similar QED values (0.855 and 0.774), indicating good drug-likeness.

**DILI:** Ligand A (25.785) has a much lower DILI risk than Ligand B (79.604). This is a significant advantage.

**BBB:** Ligand A (84.606) has excellent predicted BBB penetration, exceeding the 70% threshold. Ligand B (59.054) is considerably lower, raising concerns about CNS exposure.

**Caco-2 Permeability:** Ligand A (-4.776) has better Caco-2 permeability than Ligand B (-5.051).

**Aqueous Solubility:** Ligand A (-4.179) has better aqueous solubility than Ligand B (-2.471).

**hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.48 and 0.145).

**Microsomal Clearance:** Ligand A (72.056) has higher microsomal clearance than Ligand B (13.654), indicating faster metabolism and potentially lower exposure.

**In vitro Half-Life:** Ligand B (26.786) has a significantly longer in vitro half-life than Ligand A (-4.436). This is a positive for Ligand B.

**P-gp Efflux:** Ligand A (0.22) has lower P-gp efflux than Ligand B (0.164), which is favorable for CNS penetration.

**Binding Affinity:** Both ligands have comparable and strong binding affinities (-8.4 and -8.2 kcal/mol). The difference is small enough to be less important than other factors.

**Overall Assessment:**

Ligand A is significantly better overall. Its superior TPSA, logP, DILI, BBB, solubility, and P-gp efflux properties outweigh the slightly higher microsomal clearance and shorter half-life. The strong binding affinity is comparable between the two. Given the CNS target (DRD2), maximizing BBB penetration and minimizing efflux are critical, and Ligand A excels in these areas. Ligand B's low logP is a major concern.

Output:
0
2025-04-17 03:47:14,524 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (356.463 and 343.471 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (107.89) is higher than the preferred <90 for CNS targets, but still potentially acceptable. Ligand B (54.34) is excellent, well below the 90 threshold.

**3. logP:** Ligand A (0.336) is quite low, potentially hindering membrane permeability. Ligand B (2.823) is within the optimal 1-3 range.

**4. H-Bond Donors:** Ligand A (4) is acceptable. Ligand B (1) is also good.

**5. H-Bond Acceptors:** Ligand A (5) is acceptable. Ligand B (3) is also good.

**6. QED:** Both ligands have acceptable QED values (0.476 and 0.611, respectively), indicating reasonable drug-likeness.

**7. DILI:** Ligand A (15.238) has a much lower DILI risk than Ligand B (41.605), which is a significant advantage.

**8. BBB:** Ligand B (67.352) has a better BBB penetration percentile than Ligand A (35.595). While both are not ideal (>70), Ligand B is closer.

**9. Caco-2 Permeability:** Ligand A (-5.019) has poor Caco-2 permeability. Ligand B (-4.886) also has poor Caco-2 permeability.

**10. Aqueous Solubility:** Both ligands have poor aqueous solubility (-2.218 and -2.75, respectively).

**11. hERG Inhibition:** Ligand A (0.148) has a lower hERG inhibition risk than Ligand B (0.394).

**12. Microsomal Clearance:** Both ligands have similar microsomal clearance rates (42.318 and 45.738 mL/min/kg).

**13. In vitro Half-Life:** Ligand A (-7.253) has a longer in vitro half-life than Ligand B (-5.107).

**14. P-gp Efflux:** Ligand A (0.035) shows significantly lower P-gp efflux than Ligand B (0.375), which is crucial for CNS penetration.

**15. Binding Affinity:** Ligand B (-8.6 kcal/mol) has a significantly stronger binding affinity than Ligand A (-7.5 kcal/mol). This difference of 1.1 kcal/mol is substantial and can outweigh some ADME drawbacks.

**Overall Assessment:**

Despite Ligand A's lower DILI risk and P-gp efflux, Ligand B is the more promising candidate. The significantly stronger binding affinity (-8.6 vs -7.5 kcal/mol) is a major advantage for a GPCR target. While Ligand B's BBB penetration isn't ideal, it's better than Ligand A's. The logP value of Ligand B is also much more favorable. The poor Caco-2 and solubility of both are concerns, but can be addressed with formulation strategies.

Output:
1
2025-04-17 03:47:14,524 - INFO - Reasoning:

Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (362.411 and 347.415 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (112.44) is slightly above the optimal <90 for CNS targets, but still reasonable. Ligand B (75.02) is excellent, well below 90.

**3. logP:** Ligand A (2.662) is within the optimal 1-3 range. Ligand B (1.125) is on the lower side, potentially impacting permeability.

**4. H-Bond Donors:** Both have acceptable HBD counts (0 for A, 1 for B), well below the threshold of 5.

**5. H-Bond Acceptors:** Both ligands have 5 HBAs, which is acceptable (<=10).

**6. QED:** Ligand B (0.864) has a significantly better QED score than Ligand A (0.354), indicating a more drug-like profile.

**7. DILI:** Ligand B (30.632) has a much lower DILI risk than Ligand A (65.646), a significant advantage.

**8. BBB:** Both ligands have good BBB penetration (78.558 and 65.762), but Ligand A is better. Both are above 60, making them reasonable for CNS targets.

**9. Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and suggests poor permeability. However, the scale is not specified, so it's difficult to interpret.

**10. Aqueous Solubility:** Both have negative solubility values, again unusual and suggesting poor solubility.

**11. hERG Inhibition:** Both ligands show low hERG inhibition risk (0.466 and 0.497).

**12. Microsomal Clearance:** Ligand B (10.169) has significantly lower microsomal clearance than Ligand A (70.414), indicating better metabolic stability.

**13. In vitro Half-Life:** Ligand B (59.814) has a much longer in vitro half-life than Ligand A (-20.81), a substantial advantage.

**14. P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.197 and 0.046), which is favorable for CNS penetration.

**15. Binding Affinity:** Both ligands have strong binding affinities (-8.5 and -9.2 kcal/mol). Ligand B is slightly better (-9.2 kcal/mol).

**Overall Assessment:**

While Ligand A has slightly better BBB penetration, Ligand B is superior in almost every other critical aspect. It has a much better QED score, significantly lower DILI risk, substantially improved metabolic stability (lower Cl_mic and longer t1/2), and a slightly better binding affinity. The lower logP of Ligand B is a minor concern, but the other advantages outweigh this. Given the GPCR-specific priorities, the combination of lower DILI, better metabolic stability, and a good BBB score makes Ligand B the more promising drug candidate.

Output:
1
2025-04-17 03:47:14,524 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (365.455 and 360.332 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (116.82) is higher than the preferred <90 for CNS targets, but not drastically so. Ligand B (79.82) is well within the desired range. This favors Ligand B.

**3. logP:** Ligand A (0.227) is quite low, potentially hindering membrane permeability. Ligand B (2.133) is within the optimal 1-3 range. This is a significant advantage for Ligand B.

**4. H-Bond Donors:** Ligand A (4) is at the upper limit of the preferred range, while Ligand B (3) is better.

**5. H-Bond Acceptors:** Ligand A (7) and Ligand B (4) are both acceptable.

**6. QED:** Both ligands have good QED scores (0.593 and 0.696), indicating drug-like properties.

**7. DILI:** Ligand A (37.65) has a lower DILI risk than Ligand B (47.693), which is favorable.

**8. BBB:** Ligand B (78.868) has a significantly better BBB percentile than Ligand A (53.974). This is crucial for a CNS target like DRD2, making Ligand B more promising.

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 values, which is unusual and requires further investigation. However, the magnitude is similar.

**10. Aqueous Solubility:** Both ligands have negative solubility values, which is also unusual.

**11. hERG Inhibition:** Both ligands have low hERG inhibition risk (0.688 and 0.594).

**12. Microsomal Clearance:** Ligand A (-9.101) has a much lower (better) microsomal clearance than Ligand B (11.104), suggesting greater metabolic stability.

**13. In vitro Half-Life:** Ligand A (34.392) has a longer half-life than Ligand B (15.567), which is desirable.

**14. P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.072 and 0.046).

**15. Binding Affinity:** Ligand B (-7.9) has a slightly better binding affinity than Ligand A (-8.0). While the difference is small, it is still a positive for Ligand B.

**Overall Assessment:**

Ligand B is the more promising candidate. While Ligand A has better DILI and metabolic stability, Ligand B excels in key areas for CNS GPCR targets: better logP, significantly better BBB penetration, and a more favorable TPSA. The slightly better affinity of Ligand B further supports this conclusion. The unusual negative values for Caco-2 and solubility would need to be investigated experimentally, but the overall profile of Ligand B is superior for DRD2 targeting.

Output:
1
2025-04-17 03:47:14,525 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (348.359 and 350.463 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (105.02) is better than Ligand B (107.11). Both are reasonably close to the <90 A^2 target for CNS penetration, but A is preferable.

**logP:** Ligand A (0.466) is quite low, potentially hindering permeability. Ligand B (1.599) is better, falling within the optimal 1-3 range. This is a significant advantage for B.

**H-Bond Donors/Acceptors:** Ligand A has 1 HBD and 7 HBA, while Ligand B has 4 HBD and 4 HBA. Both are within acceptable limits, but B's profile is slightly more balanced.

**QED:** Both ligands have similar QED values (0.468 and 0.507), indicating reasonable drug-likeness.

**DILI:** Ligand A (61.148) has a higher DILI risk than Ligand B (13.61). This is a substantial advantage for B.

**BBB:** Ligand A (53.897) shows moderate BBB penetration, while Ligand B (29.12) is significantly lower. This is a critical disadvantage for B, given DRD2 is a CNS target.

**Caco-2 Permeability:** Ligand A (-4.915) has better Caco-2 permeability than Ligand B (-5.426), suggesting better intestinal absorption.

**Aqueous Solubility:** Ligand A (-2.679) has poor aqueous solubility, while Ligand B (-0.968) is better, though still not ideal.

**hERG:** Both ligands have low hERG inhibition risk (0.432 and 0.237).

**Microsomal Clearance:** Ligand A (12.395) has a lower microsomal clearance than Ligand B (-18.144), indicating better metabolic stability.

**In vitro Half-Life:** Ligand A (-8.761) has a longer in vitro half-life than Ligand B (-22.326).

**P-gp Efflux:** Both ligands show very low P-gp efflux liability (0.035 and 0.03).

**Binding Affinity:** Both ligands have the same binding affinity (-8.3 kcal/mol), which is excellent.

**Overall Assessment:**

Despite Ligand B having a better logP and lower DILI risk, Ligand A's superior BBB penetration and metabolic stability are crucial for a CNS-targeting drug like a DRD2 ligand. The affinity is identical, so the ADME properties become the deciding factor. While Ligand A's logP and solubility are not ideal, these can potentially be addressed through further optimization. The low BBB penetration of Ligand B is a major hurdle that is harder to overcome.

Output:
0
2025-04-17 03:47:14,525 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight (MW):** Both ligands (350.463 and 348.531 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (85.25) is slightly above the optimal <90 for CNS targets, but still reasonable. Ligand B (58.2) is excellent, well below 90. This favors Ligand B.

**3. logP:** Both ligands have good logP values (2.285 and 3.506), falling within the 1-3 range. Ligand B is a bit higher, potentially offering better membrane permeability, but also a slightly increased risk of off-target interactions.

**4. H-Bond Donors (HBD):** Both have 2 HBD, which is within the acceptable limit of <=5.

**5. H-Bond Acceptors (HBA):** Ligand A has 5 HBA, and Ligand B has 2 HBA, both within the acceptable limit of <=10.

**6. QED:** Both ligands have similar QED values (0.634 and 0.67), indicating good drug-like properties.

**7. DILI:** Ligand A (52.966) has a slightly higher DILI risk than Ligand B (22.8). This favors Ligand B.

**8. BBB:** Ligand B (77.007) has a significantly better BBB percentile than Ligand A (68.399). This is a *critical* advantage for a CNS target like DRD2.

**9. Caco-2:** Both have negative Caco-2 values (-5.075 and -4.745), which is unusual and suggests poor permeability. However, these values are on a scale where negative values are possible, and direct comparison is difficult without knowing the scale's specifics.

**10. Solubility:** Both ligands have poor aqueous solubility (-2.963 and -4.842). This is a concern, but can potentially be addressed through formulation.

**11. hERG:** Both ligands have low hERG inhibition risk (0.34 and 0.658).

**12. Cl_mic:** Ligand A (32.365) has a lower microsomal clearance than Ligand B (70.526), suggesting better metabolic stability. This favors Ligand A.

**13. t1/2:** Ligand A (6.155) has a shorter in vitro half-life than Ligand B (21.511). This favors Ligand B.

**14. Pgp:** Ligand A (0.065) has significantly lower P-gp efflux liability than Ligand B (0.434). This is a major advantage for CNS penetration, as it means more drug will reach the brain. This favors Ligand A.

**15. Binding Affinity:** Both ligands have identical binding affinities (-7.8 kcal/mol), which is excellent and removes this as a differentiating factor.

**Overall Assessment:**

While Ligand A has advantages in metabolic stability (Cl_mic) and P-gp efflux, the significantly better BBB penetration (77.007 vs 68.399) and lower DILI risk of Ligand B are crucial for a CNS-targeting drug. The longer half-life of Ligand B is also beneficial. The slightly higher logP of Ligand B is acceptable given the strong affinity. The poor Caco-2 and solubility are drawbacks for both, but formulation strategies could potentially mitigate these issues. Given the GPCR-specific priorities, the improved CNS exposure profile of Ligand B outweighs the benefits of Ligand A.

Output:
1
2025-04-17 03:47:14,525 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (344.411 and 355.37 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (78.87) is significantly better than Ligand B (113.53). For CNS targets, we want TPSA <= 90, and A is comfortably within this range, while B is above.

**3. logP:** Ligand A (2.157) is optimal (1-3), while Ligand B (0.698) is slightly low, potentially hindering permeation.

**4. H-Bond Donors:** Both ligands have 2 HBD, which is acceptable (<=5).

**5. H-Bond Acceptors:** Ligand A has 4 HBA, and Ligand B has 7. Both are within the acceptable range (<=10), but A is preferable.

**6. QED:** Ligand A (0.821) has a better QED score than Ligand B (0.55), indicating a more drug-like profile.

**7. DILI:** Ligand A (39.667) has a lower DILI risk than Ligand B (59.984), which is desirable. Both are below the 60 threshold, but A is better.

**8. BBB:** Ligand A (33.385) has a significantly lower BBB penetration percentile than Ligand B (72.276). This is a critical factor for a CNS target like DRD2, and B is much better here.

**9. Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and suggests poor permeability. However, the scale is not specified, so it's difficult to interpret.

**10. Aqueous Solubility:** Both have negative solubility values, which is also unusual. Again, the scale is unclear.

**11. hERG Inhibition:** Both ligands have low hERG inhibition risk (0.276 and 0.327).

**12. Microsomal Clearance:** Ligand A (22.211) has a higher microsomal clearance than Ligand B (11.297), suggesting lower metabolic stability. B is preferable.

**13. In vitro Half-Life:** Ligand A (-19.624) has a negative half-life, which is not possible. Ligand B (-12.705) also has a negative half-life. These values are suspect.

**14. P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.063 and 0.064).

**15. Binding Affinity:** Ligand B (-6.8 kcal/mol) has a significantly stronger binding affinity than Ligand A (0.0 kcal/mol). This is a major advantage for B.

**Overall Assessment:**

While Ligand A has better physicochemical properties (TPSA, logP, QED, DILI), Ligand B excels in crucial areas for a CNS GPCR target: **BBB penetration and binding affinity**. The significantly stronger binding affinity of Ligand B (-6.8 vs 0.0 kcal/mol) is a substantial advantage that can potentially overcome some of its less favorable physicochemical properties. The higher BBB value (72.276) is also critical for CNS exposure. The negative half-life values are concerning for both, but the affinity difference is too large to ignore.

Output:
1
2025-04-17 03:47:14,525 - INFO - Batch 58 complete. Total preferences: 928
2025-04-17 03:47:14,525 - INFO - Processing batch 59/512...
2025-04-17 03:47:56,679 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight (MW):** Both ligands are within the ideal range (200-500 Da). Ligand A (381.326 Da) is slightly higher than Ligand B (364.49 Da), but both are acceptable.

**2. TPSA:** Ligand A (59.23) is significantly better than Ligand B (69.02). For CNS targets, we want TPSA <= 90, and ideally closer to 60. Ligand A is much closer to the ideal range.

**3. logP:** Both ligands have good logP values (Ligand A: 3.805, Ligand B: 3.273), falling within the optimal 1-3 range.

**4. H-Bond Donors (HBD):** Both ligands are acceptable (Ligand A: 0, Ligand B: 1).

**5. H-Bond Acceptors (HBA):** Both ligands are acceptable (Ligand A: 5, Ligand B: 5).

**6. QED:** Both ligands have good QED scores (Ligand A: 0.759, Ligand B: 0.804), indicating good drug-like properties.

**7. DILI:** Ligand A (74.952) has a higher DILI risk than Ligand B (50.95). This is a concern for Ligand A, but not disqualifying.

**8. BBB:** Ligand A (85.537) has a significantly better BBB penetration percentile than Ligand B (63.784). This is *critical* for a CNS target like DRD2.

**9. Caco-2 Permeability:** Both have negative values, which is unusual. Assuming these are logP-scale values, lower values indicate poorer permeability. Both are poor, but Ligand A (-4.633) is slightly better than Ligand B (-4.835).

**10. Aqueous Solubility:** Both have negative values, indicating poor solubility. Ligand A (-4.04) is slightly better than Ligand B (-4.193).

**11. hERG Inhibition:** Both ligands have low hERG inhibition risk (Ligand A: 0.372, Ligand B: 0.805).

**12. Microsomal Clearance:** Ligand A (38.456) has lower microsomal clearance than Ligand B (57.48), suggesting better metabolic stability.

**13. In vitro Half-Life:** Ligand A (-32.554) has a significantly longer in vitro half-life than Ligand B (6.402). This is a major advantage.

**14. P-gp Efflux:** Ligand A (0.169) has lower P-gp efflux than Ligand B (0.439), which is desirable for CNS penetration.

**15. Binding Affinity:** Ligand B (-7.7 kcal/mol) has a stronger binding affinity than Ligand A (-9.3 kcal/mol). This is a substantial difference.

**Overall Assessment:**

Ligand B has a better binding affinity, which is a significant advantage. However, Ligand A excels in several key areas crucial for CNS drug development: TPSA, BBB penetration, metabolic stability (lower Cl_mic and longer t1/2), and P-gp efflux. The slightly higher DILI risk for Ligand A is a concern, but the superior CNS properties, particularly the BBB score, outweigh this risk, especially given the substantial binding affinity (-9.3 kcal/mol) is still very good. The affinity difference between -7.7 and -9.3 kcal/mol, while significant, may be surmountable with further optimization, whereas improving BBB penetration is often very difficult.

Output:
0
2025-04-17 03:47:56,679 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (345.359 and 345.403 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (108.33) is higher than Ligand B (82.78). For CNS targets, TPSA should be <=90, so Ligand B is preferable.

**logP:** Ligand A (2.66) is within the optimal 1-3 range. Ligand B (-0.14) is below 1, which could hinder permeation. This favors Ligand A.

**H-Bond Donors:** Ligand A (1) and Ligand B (0) are both acceptable (<=5).

**H-Bond Acceptors:** Ligand A (9) is close to the upper limit, while Ligand B (6) is well within the limit (<=10).

**QED:** Both ligands have reasonable QED values (0.659 and 0.52), indicating good drug-likeness.

**DILI:** Ligand A (85.576) has a higher DILI risk than Ligand B (38.116). This favors Ligand B.

**BBB:** Ligand A (61.962) and Ligand B (59.636) are both below the desirable threshold of >70 for CNS targets. However, this is less critical than other factors given the moderate values.

**Caco-2 Permeability:** Ligand A (-5.148) has significantly worse Caco-2 permeability than Ligand B (-4.541). This favors Ligand B.

**Aqueous Solubility:** Ligand A (-3.003) has worse solubility than Ligand B (-0.681). This favors Ligand B.

**hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.251 and 0.025).

**Microsomal Clearance:** Ligand A (11.449) has higher clearance than Ligand B (6.737), indicating lower metabolic stability. This favors Ligand B.

**In vitro Half-Life:** Ligand A (5.343) has a shorter half-life than Ligand B (-25.846, which is a very long half-life). This strongly favors Ligand B.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.086 and 0.02).

**Binding Affinity:** Ligand B (-9.5 kcal/mol) has a significantly stronger binding affinity than Ligand A (-8.6 kcal/mol). This is a crucial advantage, exceeding the 1.5 kcal/mol threshold.

**Overall Assessment:**

Ligand B is superior due to its significantly better binding affinity, lower DILI risk, better solubility, better Caco-2 permeability, and improved metabolic stability (lower Cl_mic and longer half-life). While Ligand A has a better logP, the other advantages of Ligand B outweigh this single benefit, especially considering the importance of affinity for GPCR ligands. Both ligands have suboptimal BBB penetration, but the stronger binding of Ligand B increases the likelihood of achieving sufficient target engagement *in vivo*.

Output:
1
2025-04-17 03:47:56,679 - INFO - Reasoning:

Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (340.398 and 343.387 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (55.13) is excellent, well below the 90 A^2 threshold for CNS targets. Ligand B (101.22) is higher but still potentially acceptable, though less ideal.

**3. logP:** Ligand A (4.659) is slightly high, potentially leading to solubility issues or off-target interactions. Ligand B (1.961) is excellent, falling within the optimal 1-3 range.

**4. H-Bond Donors:** Both ligands have 1 HBD, which is within the acceptable limit of <=5.

**5. H-Bond Acceptors:** Ligand A (3) is good. Ligand B (6) is also acceptable, within the <=10 limit.

**6. QED:** Both ligands have high QED scores (0.884 and 0.914), indicating good drug-like properties.

**7. DILI:** Both ligands have elevated DILI risk (71.113 and 79.333), but are still below the concerning >60 threshold. This will need to be investigated further.

**8. BBB:** Ligand A (88.29) has a very good BBB penetration score, highly desirable for a CNS target like DRD2. Ligand B (70.997) is acceptable, but less favorable.

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.797 and -4.819), which is unusual and suggests poor permeability. This is a significant concern.

**10. Aqueous Solubility:** Both ligands have negative solubility values (-4.951 and -3.378), indicating very poor aqueous solubility. This is a major drawback.

**11. hERG Inhibition:** Ligand A (0.776) has a slightly elevated hERG risk, while Ligand B (0.158) is very low, making it safer from a cardiotoxicity perspective.

**12. Microsomal Clearance:** Ligand A (64.671) has moderate clearance, while Ligand B (18.734) has very low clearance, suggesting better metabolic stability.

**13. In vitro Half-Life:** Ligand A (76.441) has a reasonable half-life. Ligand B (-2.286) has a negative half-life, which is not physically possible and indicates a problem with the data or the compound itself.

**14. P-gp Efflux:** Ligand A (0.882) has moderate P-gp efflux, while Ligand B (0.016) has very low efflux, which is favorable for CNS penetration.

**15. Binding Affinity:** Ligand A (-9.5 kcal/mol) has a significantly stronger binding affinity than Ligand B (-7.8 kcal/mol). This is a substantial advantage.

**Overall Assessment:**

Despite the poor solubility and permeability of both compounds, Ligand A is the more promising candidate. Its significantly stronger binding affinity (-9.5 vs -7.8 kcal/mol) is a major advantage, and its BBB penetration is excellent. While its logP is a bit high, the affinity difference could outweigh this drawback. Ligand B has better logP and hERG, but its negative half-life is a critical flaw, and its affinity is considerably weaker. The poor Caco-2 and solubility for both compounds are concerning and would require significant optimization.

Output:
0
2025-04-17 03:47:56,680 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 drug candidates, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (349.479 Da) is slightly lower, which could be advantageous for permeability.

**TPSA:** Ligand A (78.43) is better than Ligand B (84.5). Both are below the 90 A^2 threshold desirable for CNS targets, but A is closer to the optimal range.

**logP:** Both ligands have acceptable logP values (A: 1.482, B: 2.02), falling within the 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A (HBD=1, HBA=5) is slightly better than Ligand B (HBD=2, HBA=4) regarding the number of hydrogen bond donors and acceptors, although both are within acceptable limits.

**QED:** Both ligands have reasonable QED scores (A: 0.769, B: 0.647), indicating good drug-like properties.

**DILI:** Ligand A (24.855) has a significantly lower DILI risk than Ligand B (31.718), which is a major advantage. Both are below the 40 threshold.

**BBB:** Ligand B (79.062) has a substantially better BBB penetration score than Ligand A (57.736). This is a critical factor for a CNS target like DRD2.

**Caco-2 Permeability:** Ligand A (-5.023) shows better Caco-2 permeability than Ligand B (-4.619).

**Aqueous Solubility:** Ligand A (-0.595) has better aqueous solubility than Ligand B (-2.457).

**hERG Inhibition:** Both ligands have very low hERG inhibition risk (A: 0.199, B: 0.286).

**Microsomal Clearance:** Ligand A (18.348) has a lower microsomal clearance than Ligand B (58.641), indicating better metabolic stability.

**In vitro Half-Life:** Ligand A (13.361) has a positive half-life, while Ligand B (-27.39) has a negative half-life, which is concerning.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (A: 0.01, B: 0.037).

**Binding Affinity:** Ligand B (-7.5) has a slightly better binding affinity than Ligand A (-7.4), but the difference is minimal (0.1 kcal/mol).

**Overall Assessment:**

While Ligand B has a superior BBB score and slightly better binding affinity, Ligand A demonstrates a more favorable overall profile. Its lower DILI risk, better solubility, lower clearance, positive half-life, and better Caco-2 permeability are significant advantages. The difference in binding affinity is small and can potentially be optimized in later stages of drug development. Given the importance of ADME properties for CNS drugs, and the substantial benefits of Ligand A in these areas, it is the more promising candidate.

Output:
0
2025-04-17 03:47:56,680 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 drug candidates, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (344.415 and 345.422 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (108.02) is slightly above the optimal <90 for CNS targets, but still reasonable. Ligand B (64.86) is excellent, well below 90. This favors Ligand B.

**3. logP:** Both ligands (2.067 and 2.372) are within the optimal 1-3 range.

**4. H-Bond Donors:** Ligand A (2) and Ligand B (1) are both acceptable, below the threshold of 5. Ligand B is slightly better.

**5. H-Bond Acceptors:** Ligand A (5) and Ligand B (6) are both acceptable, below the threshold of 10.

**6. QED:** Both ligands have good QED scores (0.787 and 0.871), indicating drug-like properties. Ligand B is slightly better.

**7. DILI:** Both ligands have low DILI risk (49.593 and 41.838), both below the 60 threshold. Ligand B is slightly better.

**8. BBB:** This is crucial for a CNS target. Ligand A has a BBB percentile of 62.233, which is okay, but not great. Ligand B has a significantly higher BBB percentile of 88.096, which is very desirable. This is a major advantage for Ligand B.

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.897 and -4.947). These values are unusual and suggest poor permeability, but are likely reported as logP values, where negative values indicate low permeability.

**10. Aqueous Solubility:** Both ligands have negative solubility values (-3.383 and -2.717). These values are unusual and suggest poor solubility.

**11. hERG Inhibition:** Both ligands have low hERG inhibition risk (0.253 and 0.345).

**12. Microsomal Clearance:** Ligand A (44.88) has a higher clearance than Ligand B (21.58), indicating lower metabolic stability. Ligand B is favored.

**13. In vitro Half-Life:** Ligand A (-30.249) has a very short half-life, while Ligand B (10.049) has a more reasonable half-life. Ligand B is favored.

**14. P-gp Efflux:** Both ligands have low P-gp efflux liability (0.131 and 0.264).

**15. Binding Affinity:** Both ligands have comparable binding affinities (-8.0 and -8.3 kcal/mol), both excellent. Ligand B is slightly better.

**Overall Assessment:**

Ligand B consistently outperforms Ligand A in key areas for a CNS-targeting GPCR drug. Specifically, its significantly higher BBB penetration, lower microsomal clearance, better in vitro half-life, and slightly better DILI and QED scores make it a more promising candidate. While both have issues with Caco-2 and solubility, the BBB is the most important factor here.

Output:
1
2025-04-17 03:47:56,680 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (354.466 and 348.487 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (58.64) is significantly better than Ligand B (78.43). For CNS targets, we want TPSA <= 90, and ideally closer to 60. Ligand A is much closer to the ideal range.

**3. logP:** Both ligands have good logP values (2.44 and 1.983), falling within the optimal 1-3 range.

**4. H-Bond Donors:** Ligand A (1) is preferable to Ligand B (3). Lower HBD generally improves permeability.

**5. H-Bond Acceptors:** Both ligands have 3 HBA, which is acceptable (<=10).

**6. QED:** Both ligands have similar and good QED values (0.681 and 0.711), indicating good drug-like properties.

**7. DILI:** Ligand A (10.469) has a much lower DILI risk than Ligand B (16.247). Lower is better, and Ligand A is well below the 40% threshold.

**8. BBB:** This is a critical parameter for CNS targets. Ligand A (94.455) has excellent BBB penetration, exceeding the desirable >70% threshold. Ligand B (62.156) is significantly lower and less desirable.

**9. Caco-2 Permeability:** Both have negative values, which is unusual. It's difficult to interpret without knowing the scale, but we can assume lower values are worse.

**10. Aqueous Solubility:** Both have negative values, which is unusual. It's difficult to interpret without knowing the scale, but we can assume lower values are worse.

**11. hERG Inhibition:** Ligand A (0.678) has a slightly higher hERG risk than Ligand B (0.135), but both are relatively low.

**12. Microsomal Clearance:** Ligand A (32.814) has higher microsomal clearance than Ligand B (20.138), indicating lower metabolic stability.

**13. In vitro Half-Life:** Ligand B (3.138) has a longer half-life than Ligand A (-7.276).

**14. P-gp Efflux:** Ligand A (0.275) has lower P-gp efflux than Ligand B (0.03), which is favorable for CNS penetration.

**15. Binding Affinity:** Ligand B (-8.6) has a slightly better binding affinity than Ligand A (-7.8). However, the difference is less than 1.5 kcal/mol, and can be outweighed by other factors.

**Overall Assessment:**

Ligand A is the stronger candidate. Its superior BBB penetration (94.455 vs. 62.156), lower DILI risk (10.469 vs. 16.247), lower P-gp efflux (0.275 vs. 0.03), and more favorable TPSA (58.64 vs. 78.43) are significant advantages for a CNS-targeting GPCR ligand. While Ligand B has slightly better affinity and half-life, the ADME properties of Ligand A are far more promising for *in vivo* efficacy and safety.

Output:
1
2025-04-17 03:47:56,680 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (345.403 and 361.877 Da) fall comfortably within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (109.04) is higher than the preferred <90 for CNS targets, but not drastically so. Ligand B (52.57) is excellent, well below the threshold. This is a significant advantage for Ligand B.

**3. logP:** Both ligands (1.224 and 1.509) are within the optimal 1-3 range.

**4. H-Bond Donors:** Ligand A (2) is acceptable. Ligand B (0) is also good, potentially improving membrane permeability.

**5. H-Bond Acceptors:** Ligand A (6) is acceptable. Ligand B (5) is also good.

**6. QED:** Both ligands have good QED scores (0.78 and 0.816), indicating good drug-like properties.

**7. DILI:** Both ligands have low DILI risk (43.389 and 38.387), which is favorable.

**8. BBB:** Ligand B (93.253) has a significantly higher BBB percentile than Ligand A (80.07). This is a crucial advantage for a CNS target like DRD2.

**9. Caco-2 Permeability:** Both have negative values, indicating a percentile score. Ligand A (-4.776) is slightly better than Ligand B (-4.911).

**10. Aqueous Solubility:** Both have negative values, indicating a percentile score. Ligand A (-2.349) is slightly better than Ligand B (-2.433).

**11. hERG Inhibition:** Both ligands have low hERG inhibition risk (0.337 and 0.803).

**12. Microsomal Clearance:** Ligand A (27.481) has lower microsomal clearance than Ligand B (43.492), suggesting better metabolic stability.

**13. In vitro Half-Life:** Ligand A (21.375) has a longer in vitro half-life than Ligand B (-1.076). This is a significant advantage for Ligand A.

**14. P-gp Efflux:** Both ligands have low P-gp efflux liability (0.076 and 0.069).

**15. Binding Affinity:** Ligand A (-7.6) has a slightly stronger binding affinity than Ligand B (-7.3). While both are excellent, the 0.3 kcal/mol difference is notable.

**Overall Assessment:**

Ligand B excels in TPSA and BBB penetration, both critical for CNS GPCR targets. While Ligand A has a slightly better affinity and metabolic stability (lower Cl_mic, longer t1/2), the superior CNS penetration profile of Ligand B outweighs these advantages. The difference in binding affinity is not large enough to overcome the substantial benefit of better BBB penetration.

Output:
1
2025-04-17 03:47:56,680 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (347.459 and 354.447 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (72.88) is excellent, well below the 90 A^2 threshold for CNS targets. Ligand B (88.1) is still reasonable but less optimal.

**logP:** Ligand A (0.515) is a bit low, potentially hindering permeability. Ligand B (0.306) is even lower, raising more concerns about permeability.

**H-Bond Donors/Acceptors:** Both have 2 HBD and are within the acceptable range. Ligand A has 4 HBA, and Ligand B has 5 HBA, both are within the acceptable range of <=10.

**QED:** Both ligands have reasonable QED scores (0.711 and 0.622), indicating good drug-like properties.

**DILI:** Ligand A (6.398) has a very low DILI risk, which is excellent. Ligand B (13.339) is higher, but still relatively low.

**BBB:** This is critical for a CNS target. Ligand A (19.387) has a very poor BBB penetration score. Ligand B (57.425) is significantly better, although still not ideal (aim for >70).

**Caco-2 Permeability:** Both have negative Caco-2 values (-5.178 and -5.011), which is unusual and suggests poor permeability. This aligns with the low logP values.

**Aqueous Solubility:** Both have negative solubility values (-1.042 and -1.407), which is also unusual and suggests poor solubility.

**hERG:** Both ligands have very low hERG inhibition liability (0.106 and 0.177), which is a positive.

**Microsomal Clearance:** Ligand A (-6.374) has very low clearance, indicating high metabolic stability. Ligand B (23.404) has much higher clearance, suggesting faster metabolism.

**In vitro Half-Life:** Ligand A (-5.98) has a very long half-life, consistent with low clearance. Ligand B (17.244) has a shorter half-life.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.018 and 0.011), which is favorable for CNS penetration.

**Binding Affinity:** Ligand A (-7.6) has a slightly better binding affinity than Ligand B (-7.2). While both are good, the 0.4 kcal/mol difference is notable.

**Overall Assessment:**

Ligand A has a better binding affinity and significantly better metabolic stability (lower Cl_mic, longer t1/2) and lower DILI risk. However, its biggest weakness is extremely poor BBB penetration. Ligand B has a better BBB score, but suffers from higher clearance, a slightly weaker binding affinity, and a higher DILI risk.

Given the GPCR-specific priorities, BBB penetration is crucial for a CNS target like DRD2. While Ligand B's BBB score isn't ideal, it's substantially better than Ligand A's. The affinity difference is relatively small, and the better metabolic stability of Ligand A might be overcome with formulation strategies. The poor solubility of both is a concern, but could be addressed.

Output:
1
2025-04-17 03:47:56,680 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (368.415 and 343.387 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Both ligands (109.86 and 110.00) are slightly above the optimal <90 for CNS targets, but not drastically so. This is a moderate concern for both.

**3. logP:** Ligand A (0.369) is quite low, potentially hindering membrane permeability. Ligand B (1.819) is much better, falling within the optimal 1-3 range. This is a significant advantage for Ligand B.

**4. H-Bond Donors:** Both have 2 HBD, which is within the acceptable limit of <=5.

**5. H-Bond Acceptors:** Ligand A has 7 HBA, and Ligand B has 6 HBA, both within the acceptable limit of <=10.

**6. QED:** Both ligands have similar QED values (0.751 and 0.708), indicating good drug-like properties.

**7. DILI:** Ligand A has a DILI risk of 84.606, which is concerningly high (>60). Ligand B's DILI risk is 70.958, still elevated but lower than Ligand A.

**8. BBB:** Ligand A has a BBB penetration of 51.105, which is below the desirable >70 for CNS targets. Ligand B has a BBB penetration of 27.646, even lower. Both are suboptimal, but Ligand A is slightly better.

**9. Caco-2:** Both ligands have negative Caco-2 values (-5.127 and -5.41), which is unusual and suggests poor permeability.

**10. Solubility:** Both ligands have negative solubility values (-2.659 and -2.026), indicating poor aqueous solubility.

**11. hERG:** Both ligands have very low hERG inhibition risk (0.095 and 0.008).

**12. Cl_mic:** Ligand A has a lower (better) microsomal clearance (-14.831) than Ligand B (20.948), suggesting greater metabolic stability.

**13. t1/2:** Ligand A has a shorter in vitro half-life (-15.246) than Ligand B (-30.843).

**14. Pgp:** Both ligands have very low Pgp efflux liability (0.021 and 0.023).

**15. Binding Affinity:** Ligand B (-8.1 kcal/mol) has a slightly better binding affinity than Ligand A (-7.8 kcal/mol). While the difference is not huge, it's still a positive for Ligand B.

**Overall Assessment:**

Ligand B is the more promising candidate. While both have issues with BBB penetration and solubility, Ligand B has a significantly better logP value, which is crucial for CNS penetration. It also has a slightly better binding affinity and a lower DILI risk. Ligand A's high DILI risk and lower logP are major drawbacks. Although Ligand A has better metabolic stability (lower Cl_mic), the other factors weigh more heavily in favor of Ligand B for a CNS target like DRD2.

Output:
1
2025-04-17 03:47:56,680 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (410.268 Da) is slightly higher than Ligand B (347.459 Da), but both are acceptable.

**TPSA:** Ligand A (100.45) is slightly above the optimal <90 for CNS targets, but still reasonable. Ligand B (84.23) is well within the desired range.

**logP:** Both ligands have similar logP values (A: 2.799, B: 2.803), falling within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Both ligands have 2 HBD and 5/4 HBA, respectively, which are within acceptable limits.

**QED:** Both ligands have good QED scores (A: 0.798, B: 0.708), indicating drug-like properties.

**DILI:** Ligand A has a significantly higher DILI risk (74.99%) compared to Ligand B (25.397%). This is a major concern for Ligand A.

**BBB:** Ligand A shows better BBB penetration (57.193%) than Ligand B (46.646%), but both are below the desirable >70% for CNS targets.

**Caco-2 Permeability:** Ligand A (-4.636) shows better Caco-2 permeability than Ligand B (-4.954), suggesting better intestinal absorption.

**Aqueous Solubility:** Ligand A (-4.514) has slightly better solubility than Ligand B (-2.499).

**hERG Inhibition:** Both ligands have low hERG inhibition risk (A: 0.563, B: 0.097). Ligand B is slightly better.

**Microsomal Clearance:** Ligand A (50.135) has higher microsomal clearance than Ligand B (19.158), indicating lower metabolic stability.

**In vitro Half-Life:** Ligand A (14.494 hours) has a significantly longer half-life than Ligand B (1.629 hours).

**P-gp Efflux:** Ligand A (0.096) has lower P-gp efflux than Ligand B (0.056), which is favorable for CNS penetration.

**Binding Affinity:** Ligand B (-8.3 kcal/mol) has a significantly stronger binding affinity than Ligand A (-7.1 kcal/mol). This is a substantial advantage, exceeding the 1.5 kcal/mol threshold.

**Overall Assessment:**

While Ligand A has better BBB, Caco-2 permeability, solubility, half-life, and P-gp efflux, its significantly higher DILI risk and lower binding affinity are major drawbacks. Ligand B, despite having slightly less favorable BBB and permeability, exhibits a much stronger binding affinity and a significantly lower DILI risk. For a CNS target like DRD2, a strong binding affinity and a low toxicity profile are paramount. The difference in affinity is substantial enough to outweigh the slight disadvantages in BBB and permeability.

Output:
1
2025-04-17 03:47:56,680 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B against the provided guidelines, prioritizing GPCR-specific properties (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (364.364 Da) is slightly higher than Ligand B (349.431 Da), but this difference isn't critical.

**TPSA:** Ligand A (78.87) is excellent for CNS penetration, falling well below the 90 A^2 threshold. Ligand B (110.69) is still reasonable, but less optimal, being above 100.

**logP:** Ligand A (1.14) is within the optimal range (1-3). Ligand B (0.486) is a bit low, potentially impacting permeability.

**H-Bond Donors/Acceptors:** Ligand A (2 HBD, 4 HBA) and Ligand B (5 HBD, 5 HBA) both fall within acceptable limits.

**QED:** Ligand A (0.734) has a better QED score than Ligand B (0.492), indicating a more drug-like profile.

**DILI:** Both ligands have low DILI risk (Ligand A: 39.318, Ligand B: 34.781), which is favorable.

**BBB:** This is a crucial parameter for a CNS target like DRD2. Ligand A has a significantly better BBB penetration percentile (69.833) than Ligand B (43.311). Ligand A is approaching the desirable >70 threshold.

**Caco-2 Permeability:** Both have negative values, which is unusual and suggests issues with the modeling or data. However, the magnitude is important. Ligand A (-4.848) is less negative than Ligand B (-5.123), potentially indicating slightly better absorption.

**Aqueous Solubility:** Both have negative values, which is also unusual. Again, Ligand A (-1.896) is slightly better than Ligand B (-2.326).

**hERG:** Both ligands have very low hERG inhibition liability (Ligand A: 0.359, Ligand B: 0.213), which is excellent.

**Microsomal Clearance:** Ligand A (8.888) has a higher clearance than Ligand B (6.743), meaning it's likely to be metabolized faster.

**In vitro Half-Life:** Ligand B (4.75) has a longer half-life than Ligand A (-28.993). The negative value for A is concerning and likely an artifact of the modeling.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (Ligand A: 0.107, Ligand B: 0.009), which is good for CNS exposure.

**Binding Affinity:** Ligand B (-7.4 kcal/mol) has a significantly stronger binding affinity than Ligand A (-0.0 kcal/mol). This is a substantial advantage.

**Overall Assessment:**

While Ligand B has a superior binding affinity, Ligand A demonstrates a much more favorable ADME profile, particularly regarding BBB penetration and TPSA. The significantly better BBB score for Ligand A is crucial for a CNS-targeting drug. The negative half-life for Ligand A is a major red flag, but the other ADME properties are more favorable. The binding affinity difference is substantial, but a difference of >1.5 kcal/mol can be overcome with optimization. Given the importance of CNS penetration for DRD2, and the better overall ADME profile (excluding the half-life issue), Ligand A is the more promising starting point.

Output:
1
2025-04-17 03:47:56,680 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (364.398 Da) is slightly lower, which is generally favorable for permeability.

**2. TPSA:** Ligand A (92.34) is better than Ligand B (51.66) for CNS penetration, being closer to the <90 threshold.

**3. logP:** Both ligands have acceptable logP values (Ligand A: 1.663, Ligand B: 3.154), falling within the 1-3 range. Ligand B is closer to the upper limit, potentially raising concerns about solubility and off-target effects, but is still acceptable.

**4. H-Bond Donors:** Ligand A (2) is preferable to Ligand B (0) as it provides better solubility.

**5. H-Bond Acceptors:** Ligand A (4) is preferable to Ligand B (6) as it provides better permeability.

**6. QED:** Ligand A (0.815) has a significantly better QED score than Ligand B (0.612), indicating a more drug-like profile.

**7. DILI:** Ligand B (43.117) has a much lower DILI risk than Ligand A (80.923), which is a significant advantage.

**8. BBB:** Ligand B (82.551) has a substantially higher BBB penetration percentile than Ligand A (67.119). This is *critical* for a CNS target like DRD2.

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.922 and -4.902), which is unusual and suggests poor permeability. This is a concern for both.

**10. Aqueous Solubility:** Both ligands have negative solubility values (-3.502 and -2.468), indicating very poor aqueous solubility. This is a significant drawback for both.

**11. hERG Inhibition:** Both ligands have low hERG inhibition liability (Ligand A: 0.344, Ligand B: 0.436), which is good.

**12. Microsomal Clearance:** Ligand A (37.246) has lower microsomal clearance than Ligand B (55.209), suggesting better metabolic stability.

**13. In vitro Half-Life:** Ligand A (63.649) has a much longer in vitro half-life than Ligand B (-2.402), which is a major advantage.

**14. P-gp Efflux:** Both ligands show low P-gp efflux liability (Ligand A: 0.294, Ligand B: 0.243).

**15. Binding Affinity:** Ligand A (-10.2 kcal/mol) has a significantly stronger binding affinity than Ligand B (-6.8 kcal/mol). This is a substantial advantage that can potentially offset some of the ADME drawbacks.

**Overall Assessment:**

While Ligand A has superior QED, metabolic stability, and binding affinity, Ligand B excels in BBB penetration and has a lower DILI risk. The poor Caco-2 and solubility for both are concerning. However, for a CNS target like DRD2, BBB penetration is paramount. The significantly higher BBB score of Ligand B, combined with the lower DILI risk, outweighs the advantages of Ligand A, especially considering the strong binding affinity of Ligand A might be sufficient to overcome permeability issues with appropriate formulation strategies.

Output:
1
2025-04-17 03:47:56,681 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (347.419 and 356.482 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (112.04) is higher than the preferred <90 for CNS targets, but not drastically so. Ligand B (49.85) is excellent, well below the threshold.

**3. logP:** Ligand A (0.735) is a bit low, potentially hindering permeability. Ligand B (2.781) is within the optimal 1-3 range.

**4. H-Bond Donors:** Ligand A (4) is acceptable. Ligand B (0) is also good.

**5. H-Bond Acceptors:** Ligand A (5) is acceptable. Ligand B (3) is also good.

**6. QED:** Both ligands have good QED scores (0.564 and 0.597), indicating drug-like properties.

**7. DILI:** Ligand A (50.33) has a moderate DILI risk. Ligand B (13.959) has a very low DILI risk, which is a significant advantage.

**8. BBB:** This is crucial for a CNS target. Ligand A (15.82) has very poor predicted BBB penetration. Ligand B (98.022) has excellent predicted BBB penetration.

**9. Caco-2 Permeability:** Ligand A (-5.573) has poor Caco-2 permeability. Ligand B (-4.13) has better, but still not great, Caco-2 permeability.

**10. Aqueous Solubility:** Both ligands have poor aqueous solubility (-2.388 and -2.299). This could pose formulation challenges.

**11. hERG Inhibition:** Ligand A (0.315) has a slightly elevated hERG risk, while Ligand B (0.918) is better.

**12. Microsomal Clearance:** Ligand A (-3.118) has a negative value, suggesting low clearance and good metabolic stability. Ligand B (46.011) has a high clearance, indicating poor metabolic stability.

**13. In vitro Half-Life:** Ligand A (35.982) has a good in vitro half-life. Ligand B (1.421) has a very short half-life.

**14. P-gp Efflux:** Ligand A (0.061) has low P-gp efflux, which is desirable. Ligand B (0.47) has moderate P-gp efflux.

**15. Binding Affinity:** Ligand A (-8.8) has significantly stronger binding affinity than Ligand B (-7.3), a difference of 1.5 kcal/mol.

**Overall Assessment:**

While Ligand A has a substantially better binding affinity, its poor BBB penetration is a major drawback for a CNS target like DRD2. The low logP and Caco-2 permeability also contribute to concerns about brain exposure. Ligand B, despite its weaker affinity, possesses excellent BBB penetration, a low DILI risk, and acceptable P-gp efflux. Its metabolic stability and half-life are concerns, but these could potentially be addressed through structural modifications. The significant advantage in BBB penetration outweighs the affinity difference, especially given the GPCR-specific priorities.

Output:
1
2025-04-17 03:47:56,681 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight (MW):** Both ligands (346.431 & 345.443 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (96.25) is slightly above the optimal <90 for CNS targets, but still reasonable. Ligand B (54.04) is excellent, well below 90.

**3. logP:** Ligand A (0.45) is quite low, potentially hindering membrane permeability. Ligand B (0.95) is better, but still on the lower side of the optimal 1-3 range.

**4. H-Bond Donors (HBD):** Ligand A (3) is within the acceptable limit of <=5. Ligand B (1) is also good.

**5. H-Bond Acceptors (HBA):** Both ligands (A: 5, B: 5) are within the acceptable limit of <=10.

**6. QED:** Ligand B (0.861) has a significantly higher QED score than Ligand A (0.536), indicating better overall drug-likeness.

**7. DILI:** Ligand A (19.232) has a lower DILI risk than Ligand B (15.704), which is favorable.

**8. BBB:** Ligand B (62.233) has a substantially better BBB penetration score than Ligand A (40.558). This is *critical* for a CNS target like DRD2.

**9. Caco-2 Permeability:** Ligand A (-5.091) shows poor permeability. Ligand B (-4.831) is also poor, but slightly better.

**10. Aqueous Solubility:** Both ligands have very poor aqueous solubility (-1.669 and -1.479 respectively). This could pose formulation challenges.

**11. hERG Inhibition:** Ligand A (0.075) has a very low hERG risk, which is excellent. Ligand B (0.68) is slightly higher, but still relatively low.

**12. Microsomal Clearance:** Ligand B (44.267) has a significantly lower microsomal clearance than Ligand A (9.145), suggesting better metabolic stability.

**13. In vitro Half-Life:** Ligand B (16.285) has a much longer in vitro half-life than Ligand A (5.46), which is desirable.

**14. P-gp Efflux:** Ligand A (0.012) has very low P-gp efflux, which is excellent for CNS penetration. Ligand B (0.032) is slightly higher, but still very good.

**15. Binding Affinity:** Ligand B (-7.7 kcal/mol) has a slightly better binding affinity than Ligand A (-7.0 kcal/mol), although both are quite good. The 0.7 kcal/mol difference is significant enough to consider.

**Overall Assessment:**

While Ligand A has a lower DILI risk and better P-gp efflux, Ligand B is superior overall, especially considering the GPCR-specific priorities. The significantly better BBB penetration (62.233 vs 40.558), higher QED (0.861 vs 0.536), improved metabolic stability (lower Cl_mic), and longer half-life make Ligand B a much more promising drug candidate. The slightly better binding affinity further strengthens this conclusion. The low logP for both is a concern, but the other advantages of Ligand B outweigh this drawback.

Output:
1
2025-04-17 03:47:56,681 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (403.649 Da) is slightly higher, but still acceptable. Ligand B (350.423 Da) is also good.

**TPSA:** Ligand A (81.47) is excellent, falling well below the 90 A^2 threshold for CNS targets. Ligand B (121.64) is higher, but still within a reasonable range, though less optimal for CNS penetration.

**logP:** Ligand A (4.293) is a bit high, potentially leading to solubility issues and off-target interactions. Ligand B (0.248) is very low, which could hinder membrane permeability and binding.

**H-Bond Donors/Acceptors:** Ligand A (HBD=1, HBA=4) is favorable. Ligand B (HBD=2, HBA=5) is also acceptable.

**QED:** Both ligands have similar, relatively low QED values (A: 0.425, B: 0.419), indicating moderate drug-likeness.

**DILI:** Ligand A (77.007) has a higher DILI risk than Ligand B (12.99), which is a significant concern.

**BBB:** Ligand A (60.14) has a moderate BBB penetration, while Ligand B (30.671) is quite low. This is a critical factor for a CNS target like DRD2.

**Caco-2 Permeability:** Ligand A (-4.835) shows poor permeability, while Ligand B (-5.428) is also poor.

**Aqueous Solubility:** Ligand A (-5.684) has very poor solubility, likely due to its high logP. Ligand B (-0.775) is slightly better, but still not ideal.

**hERG Inhibition:** Ligand A (0.769) has a low hERG risk, which is good. Ligand B (0.059) has a very low hERG risk, even better.

**Microsomal Clearance:** Ligand A (51.628) has moderate clearance, while Ligand B (-12.466) has negative clearance, which is unusual and could indicate issues with the prediction or a very stable compound.

**In vitro Half-Life:** Ligand A (13.691) has a moderate half-life. Ligand B (12.777) is similar.

**P-gp Efflux:** Ligand A (0.492) has moderate P-gp efflux, while Ligand B (0.004) has very low P-gp efflux, which is highly desirable for CNS penetration.

**Binding Affinity:** Ligand A (-8.8 kcal/mol) has significantly stronger binding affinity than Ligand B (-7.4 kcal/mol). This is a substantial advantage.

**Overall Assessment:**

Despite Ligand A's strong binding affinity, its high logP, poor solubility, moderate BBB penetration, and elevated DILI risk are major drawbacks. Ligand B, while having weaker affinity, has a much better safety profile (low DILI, low hERG, very low P-gp efflux) and a more reasonable TPSA. The low logP and permeability are concerning, but the affinity difference is 1.4 kcal/mol, which might be overcome with further optimization. Given the GPCR-specific priorities, especially BBB penetration and safety, and the substantial affinity difference, Ligand A is the better starting point, but requires significant optimization to address its ADME/Tox liabilities.

Output:
1
2025-04-17 03:47:56,681 - INFO - Reasoning:

Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (348.374 and 344.371 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (84.5) is excellent, well below the 90 A^2 threshold for CNS targets. Ligand B (113.18) is higher but still reasonable, though less optimal.

**3. logP:** Ligand A (2.882) is within the optimal 1-3 range. Ligand B (1.493) is on the lower side, potentially impacting permeability.

**4. H-Bond Donors:** Ligand A (2) and Ligand B (3) are both acceptable, under the 5 limit.

**5. H-Bond Acceptors:** Ligand A (4) and Ligand B (5) are both acceptable, under the 10 limit.

**6. QED:** Both ligands have reasonable QED scores (0.647 and 0.543), indicating good drug-like properties.

**7. DILI:** Both ligands have relatively high DILI risk (63.086 and 67.39), but are still within a range that isn't immediately disqualifying.

**8. BBB:** Ligand A (88.096) has a significantly better BBB penetration percentile than Ligand B (65.258). This is a crucial factor for a CNS target like DRD2.

**9. Caco-2 Permeability:** Ligand A (-4.522) has a more favorable Caco-2 permeability value than Ligand B (-5.101), suggesting better intestinal absorption.

**10. Aqueous Solubility:** Ligand A (-3.707) has a more favorable solubility value than Ligand B (-3.36).

**11. hERG Inhibition:** Both ligands have low hERG inhibition risk (0.173 and 0.295).

**12. Microsomal Clearance:** Ligand A (51.222) has a higher microsomal clearance than Ligand B (18.725), indicating faster metabolism and potentially lower in vivo exposure.

**13. In vitro Half-Life:** Ligand B (-11.046) has a negative half-life, which is not possible and likely indicates an error or an extremely short half-life. Ligand A (26.051) has a reasonable half-life.

**14. P-gp Efflux:** Both ligands have low P-gp efflux liability (0.241 and 0.041).

**15. Binding Affinity:** Ligand A (-8.9 kcal/mol) has a slightly better binding affinity than Ligand B (-8.2 kcal/mol). While both are strong binders, the 0.7 kcal/mol difference is noteworthy.

**Overall Assessment:**

Ligand A is the superior candidate. It has a better BBB score, more favorable Caco-2 permeability and solubility, a more reasonable half-life, and slightly better binding affinity. While both have acceptable ADME properties, Ligand A's improved CNS penetration profile and metabolic stability make it more likely to succeed as a DRD2-targeting drug. The negative half-life value for Ligand B is a major red flag.

Output:
1
2025-04-17 03:47:56,681 - INFO - Batch 59 complete. Total preferences: 944
2025-04-17 03:47:56,681 - INFO - Processing batch 60/512...
2025-04-17 03:48:39,224 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B based on the provided guidelines, prioritizing GPCR-specific properties (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (355.366 and 346.402 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (111.88) is slightly above the optimal <90 for CNS targets, but acceptable. Ligand B (69.64) is well within the desired range. This favors Ligand B.

**logP:** Ligand A (-0.116) is quite low, potentially hindering permeability. Ligand B (1.794) is within the optimal 1-3 range. This is a significant advantage for Ligand B.

**H-Bond Donors/Acceptors:** Ligand A has 3 HBD and 5 HBA, while Ligand B has 2 HBD and 3 HBA. Both are within acceptable limits.

**QED:** Both ligands have good QED scores (0.659 and 0.799, respectively), indicating drug-likeness.

**DILI:** Ligand A (54.517) has a moderate DILI risk, while Ligand B (23.032) has a low DILI risk. This favors Ligand B.

**BBB:** Ligand A (36.371) has a poor BBB percentile, which is a major drawback for a CNS target like DRD2. Ligand B (75.378) has a very good BBB percentile, a significant advantage.

**Caco-2:** Both have negative Caco-2 values, which is unusual and difficult to interpret. However, the magnitude of the negative value for Ligand A (-5.194) is larger than that for Ligand B (-4.52), suggesting potentially lower absorption for Ligand A.

**Solubility:** Both ligands have negative solubility values, which is also unusual. Again, the magnitude for Ligand A (-1.015) is worse than Ligand B (-2.095).

**hERG:** Both ligands have low hERG risk (0.218 and 0.452).

**Microsomal Clearance:** Ligand A (0.352) has very low clearance, indicating high metabolic stability. Ligand B (26.91) has higher clearance, suggesting faster metabolism. This favors Ligand A.

**In vitro Half-Life:** Ligand A (27.972) has a reasonable half-life, while Ligand B (-17.541) has a negative half-life, which is not physically meaningful and suggests potential issues with the assay or compound stability. This strongly favors Ligand A.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.021 and 0.091).

**Binding Affinity:** Ligand B (-9.3 kcal/mol) has a significantly stronger binding affinity than Ligand A (-8.2 kcal/mol). This is a substantial advantage for Ligand B, potentially outweighing some ADME concerns.

**Overall Assessment:**

While Ligand A has better metabolic stability and half-life, Ligand B excels in crucial areas for a CNS-targeting GPCR: BBB penetration, logP, and significantly, binding affinity. The poor BBB of Ligand A is a major concern. The negative solubility and Caco-2 values are concerning for both, but the larger negative values for Ligand A suggest it might be worse. The significantly stronger binding affinity of Ligand B (-9.3 vs -8.2 kcal/mol) is a compelling factor.

Output:
1
2025-04-17 03:48:39,224 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (346.427 Da) is slightly lower, which could be advantageous for permeability.

**2. TPSA:** Both ligands have TPSA values below 90, which is good for CNS penetration. Ligand B (72.7) is slightly lower than Ligand A (80.57), potentially indicating better CNS penetration.

**3. logP:** Both ligands have logP values within the optimal range (1-3). Ligand A (2.263) is slightly lower than Ligand B (3.299). While both are acceptable, a logP closer to 3 can sometimes improve binding, but also increases the risk of off-target effects.

**4. H-Bond Donors:** Ligand A (2) and Ligand B (1) both fall within the acceptable limit of <=5. Ligand B is slightly better.

**5. H-Bond Acceptors:** Ligand A (4) and Ligand B (7) are both within the acceptable limit of <=10.

**6. QED:** Both ligands have similar, good QED values (0.708 and 0.709), indicating good drug-like properties.

**7. DILI:** Ligand A (39.977) has a significantly lower DILI risk than Ligand B (79.837). This is a substantial advantage for Ligand A.

**8. BBB:** Both ligands have good BBB penetration, but Ligand B (75.921) is slightly better than Ligand A (65.568). This is important for a CNS target like DRD2.

**9. Caco-2 Permeability:** Both have negative values, which is unusual. Assuming these are logP values, they indicate poor permeability. Ligand B (-5.082) is worse than Ligand A (-4.706).

**10. Aqueous Solubility:** Both ligands have negative values, which is also unusual. Assuming these are logS values, they indicate poor solubility. Ligand B (-2.979) is worse than Ligand A (-2.87).

**11. hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.185 and 0.518).

**12. Microsomal Clearance:** Ligand A (40.181) has higher microsomal clearance than Ligand B (31.222), suggesting faster metabolism and potentially lower exposure.

**13. In vitro Half-Life:** Ligand B (16.911) has a longer in vitro half-life than Ligand A (39.41), indicating better metabolic stability.

**14. P-gp Efflux:** Both ligands have low P-gp efflux liability (0.129 and 0.59). Ligand A is slightly better.

**15. Binding Affinity:** Ligand B (-8.1 kcal/mol) has a significantly stronger binding affinity than Ligand A (-6.9 kcal/mol). This is a crucial advantage, as a 1.2 kcal/mol difference is substantial.

**Overall Assessment:**

Ligand B has a superior binding affinity and slightly better BBB penetration and in vitro half-life. However, it has a much higher DILI risk, worse Caco-2 permeability and aqueous solubility. Ligand A has a lower DILI risk, better P-gp efflux, and slightly better Caco-2 permeability and aqueous solubility, but weaker binding affinity.

Given the importance of binding affinity for GPCRs, and the substantial difference (-1.2 kcal/mol), the stronger binding of Ligand B is likely to outweigh its drawbacks, *provided* the DILI risk can be mitigated through further structural modifications. The poor solubility and permeability of Ligand B are also concerning, but potentially addressable.

Output:
1
2025-04-17 03:48:39,224 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 drug candidates, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (352.431 and 352.41 Da) fall comfortably within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (85.89) is slightly above the optimal <90 for CNS targets, but still reasonable. Ligand B (76.46) is excellent, well below 90.

**3. logP:** Both ligands have logP values (0.538 and 0.614) that are quite low. While not immediately disqualifying, this could indicate permeability issues. Ideally, we want 1-3.

**4. H-Bond Donors:** Ligand A has 2 HBD, which is good. Ligand B has 1 HBD, also good. Both are within the acceptable limit of <=5.

**5. H-Bond Acceptors:** Both ligands have 5 HBA, which is within the acceptable limit of <=10.

**6. QED:** Both ligands have good QED scores (0.653 and 0.814), indicating good drug-like properties. Ligand B is slightly better.

**7. DILI:** Ligand A (25.553) has a significantly lower DILI risk than Ligand B (41.566). This is a substantial advantage for Ligand A.

**8. BBB:** This is a critical parameter for CNS targets. Ligand B (94.184) has excellent BBB penetration, exceeding the desirable >70 threshold. Ligand A (61.923) is below this threshold, which is a major drawback.

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.334 and -4.66). This is unusual and suggests poor intestinal absorption. However, for a CNS target, intestinal absorption is less critical than BBB penetration.

**10. Aqueous Solubility:** Both ligands have negative solubility values (-1.294 and -2.21). This is also unusual and suggests poor aqueous solubility.

**11. hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.133 and 0.537), which is excellent.

**12. Microsomal Clearance:** Ligand A (3.962) has lower microsomal clearance than Ligand B (5.082), suggesting better metabolic stability.

**13. In vitro Half-Life:** Both ligands have similar in vitro half-lives (16.395 and 16.227 hours).

**14. P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.012 and 0.128), which is favorable for CNS penetration.

**15. Binding Affinity:** Both ligands have very similar and strong binding affinities (-8.2 and -8.4 kcal/mol). The difference is negligible.

**Overall Assessment:**

Ligand B is clearly superior due to its significantly higher BBB penetration (94.184 vs 61.923). While Ligand A has a better DILI score and slightly better metabolic stability, the BBB is the most crucial factor for a CNS-targeting drug like one for DRD2. The low logP values are a concern for both, but the excellent affinity might compensate. The negative Caco-2 and solubility values are concerning but less important given the CNS target.

Output:
1
2025-04-17 03:48:39,224 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (367.877 and 351.447 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (81.67) is better than Ligand B (95.67). For CNS targets, we want TPSA <= 90, so Ligand A is closer to the ideal.

**logP:** Both ligands have good logP values (2.717 and 1.606), falling within the optimal 1-3 range. Ligand A is slightly higher, which could be beneficial for membrane permeability.

**H-Bond Donors & Acceptors:** Ligand A (HBD=3, HBA=3) is slightly better than Ligand B (HBD=2, HBA=5) in terms of balancing solubility and permeability.

**QED:** Both ligands have good QED scores (0.748 and 0.812), indicating good drug-like properties.

**DILI:** Ligand A (34.471) has a lower DILI risk than Ligand B (21.055), which is preferable.

**BBB:** Both ligands have similar BBB penetration (60.915 and 61.187). While both are above 50%, they are below the desirable >70% for CNS targets.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.78 and -4.827), which is unusual and suggests poor permeability. This is a significant concern.

**Aqueous Solubility:** Both ligands have negative solubility values (-3.663 and -1.632), indicating very poor aqueous solubility. This is a major drawback.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.452 and 0.276), which is good.

**Microsomal Clearance:** Ligand A (-11.91) has significantly lower (better) microsomal clearance than Ligand B (25.173), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (32.85) has a better in vitro half-life than Ligand B (-25.229).

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.059 and 0.111), which is favorable for CNS penetration.

**Binding Affinity:** Ligand A (-8.6 kcal/mol) has a significantly stronger binding affinity than Ligand B (-6.7 kcal/mol). This is a substantial advantage.

**Overall Assessment:**

Despite the poor Caco-2 and solubility for both, Ligand A is the superior candidate. Its stronger binding affinity (-8.6 vs -6.7 kcal/mol) is a major advantage, and it has better DILI, microsomal clearance, and in vitro half-life. The slightly lower TPSA is also beneficial. While both have suboptimal BBB, the improved ADME properties of Ligand A, coupled with its significantly better affinity, make it more likely to be a viable drug candidate, assuming solubility and permeability can be addressed through formulation or further chemical modifications.

Output:
1
2025-04-17 03:48:39,224 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (342.4 and 347.5 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (78.15) is higher than Ligand B (61.44). For a CNS target like DRD2, TPSA should ideally be <= 90. Both are acceptable, but B is better.

**3. logP:** Ligand A (0.941) is slightly lower than the optimal 1-3 range, potentially hindering permeability. Ligand B (1.918) is within the optimal range. This favors B.

**4. H-Bond Donors:** Ligand A (1) is good. Ligand B (2) is also acceptable.

**5. H-Bond Acceptors:** Ligand A (6) is good. Ligand B (3) is excellent.

**6. QED:** Both ligands have reasonable QED values (0.897 and 0.799), indicating good drug-like properties.

**7. DILI:** Ligand A (62.8%) has a higher DILI risk than Ligand B (21.9%). B is significantly better here.

**8. BBB:** Ligand A (73.7%) has a better BBB penetration percentile than Ligand B (55.1%). This is a critical factor for a CNS target.

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.253 and -5.164). These values are unusual and suggest poor permeability. However, the absolute values are similar.

**10. Aqueous Solubility:** Both ligands have negative solubility values (-2.618 and -3.004), indicating poor aqueous solubility. This is a concern for bioavailability.

**11. hERG Inhibition:** Both ligands have low hERG inhibition risk (0.104 and 0.341).

**12. Microsomal Clearance:** Ligand A (40.7) has a higher microsomal clearance than Ligand B (22.0), suggesting lower metabolic stability. B is better.

**13. In vitro Half-Life:** Ligand A (4.6) has a shorter half-life than Ligand B (15.1), indicating faster metabolism. B is better.

**14. P-gp Efflux:** Both ligands have low P-gp efflux liability (0.303 and 0.136). B is better.

**15. Binding Affinity:** Ligand A (-9.7 kcal/mol) has a slightly better binding affinity than Ligand B (-8.4 kcal/mol). This is a significant advantage.

**Overall Assessment:**

While Ligand A has a slightly better binding affinity and BBB penetration, Ligand B demonstrates superior ADME properties. Specifically, it has a lower DILI risk, better logP, lower microsomal clearance, longer half-life, and lower P-gp efflux. The difference in binding affinity (1.3 kcal/mol) is substantial, but the significantly improved ADME profile of Ligand B, particularly its lower DILI and better metabolic stability, makes it the more promising drug candidate. The negative Caco-2 and solubility values are concerning for both, but can be addressed with formulation strategies.

Output:
1
2025-04-17 03:48:39,224 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (345.531 and 349.347 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (44.37) is excellent, well below the 90 A^2 threshold for CNS targets. Ligand B (136.65) is higher, but still potentially acceptable, though less ideal.

**3. logP:** Ligand A (3.673) is within the optimal range of 1-3. Ligand B (-1.21) is significantly below this, which could hinder membrane permeability and CNS penetration.

**4. H-Bond Donors:** Ligand A (2) and Ligand B (4) are both within the acceptable limit of <=5.

**5. H-Bond Acceptors:** Ligand A (2) and Ligand B (6) are both within the acceptable limit of <=10.

**6. QED:** Ligand A (0.792) has a strong drug-like profile. Ligand B (0.381) is considerably lower, indicating a less favorable overall drug-likeness.

**7. DILI:** Ligand A (7.445) has a very low DILI risk. Ligand B (68.941) has a higher, but not critically high, DILI risk.

**8. BBB:** Ligand A (89.492) has excellent predicted BBB penetration. Ligand B (18.961) has very poor predicted BBB penetration, a major drawback for a CNS target.

**9. Caco-2:** Ligand A (-4.48) and Ligand B (-5.765) both have negative values, which is unusual. It suggests very poor permeability.

**10. Solubility:** Ligand A (-2.916) and Ligand B (-2.128) both have negative values, which is unusual. It suggests very poor solubility.

**11. hERG:** Ligand A (0.838) has a low hERG risk. Ligand B (0.107) also has a low hERG risk.

**12. Cl_mic:** Ligand A (16.962) has a moderate clearance. Ligand B (-12.191) has a negative clearance, which is not possible and likely represents an extrapolation error, but suggests very high metabolic stability.

**13. t1/2:** Ligand A (25.526) has a reasonable in vitro half-life. Ligand B (21.836) also has a reasonable in vitro half-life.

**14. Pgp:** Ligand A (0.149) has low P-gp efflux liability. Ligand B (0.011) has very low P-gp efflux liability.

**15. Binding Affinity:** Both ligands have a binding affinity of -8.0 and -8.2 kcal/mol, respectively. These are excellent and very similar.

**Overall Assessment:**

Ligand A is clearly superior. While both have excellent binding affinity, Ligand A's significantly better logP, TPSA, QED, and *especially* BBB penetration make it a much more promising candidate for a CNS-targeting drug like a DRD2 ligand. Ligand B's poor logP and extremely low BBB penetration are major liabilities. The unusual negative values for Caco-2 and Solubility are concerning for both, but the other properties of A outweigh this.

Output:
1
2025-04-17 03:48:39,224 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (359.323 Da) is slightly preferred as it's closer to the lower end, potentially aiding permeability.

**TPSA:** Ligand A (71.09) is excellent for CNS penetration, well below the 90 A^2 threshold. Ligand B (84.32) is still reasonable, but less optimal.

**logP:** Ligand A (2.299) is within the optimal range (1-3). Ligand B (-0.333) is significantly lower, which could hinder membrane permeability and brain penetration.

**H-Bond Donors/Acceptors:** Both ligands have acceptable HBD (2) and HBA (3 for A, 5 for B) counts.

**QED:** Both ligands have good QED scores (0.734 and 0.641, both > 0.5).

**DILI:** Ligand A (49.283) has a moderate DILI risk, but is much better than Ligand B (23.885), which is very low risk.

**BBB:** Ligand A (83.482) has a very good BBB percentile, exceeding the 70% threshold. Ligand B (22.8) is very poor for CNS penetration. This is a critical difference given the target.

**Caco-2 Permeability:** Ligand A (-4.884) is poor, while Ligand B (-5.003) is also poor. This isn't a dealbreaker, but not ideal.

**Aqueous Solubility:** Ligand A (-2.991) and Ligand B (-0.935) are both poor.

**hERG Inhibition:** Both ligands show low hERG inhibition liability (0.343 and 0.146).

**Microsomal Clearance:** Ligand B (-12.327) has a much lower (better) microsomal clearance than Ligand A (2.281), indicating greater metabolic stability.

**In vitro Half-Life:** Both ligands have poor in vitro half-lives (-5.879 and -9.475).

**P-gp Efflux:** Ligand A (0.049) has lower P-gp efflux than Ligand B (0.02), which is better for CNS exposure.

**Binding Affinity:** Ligand A (-9.0 kcal/mol) has a slightly better binding affinity than Ligand B (-7.6 kcal/mol). While both are good, the 1.4 kcal/mol difference is significant.

**Overall Assessment:**

Ligand A is significantly more promising. Its superior BBB penetration, better logP, and slightly better binding affinity outweigh the drawbacks of its higher clearance and poorer Caco-2 permeability. The DILI risk is acceptable. Ligand B's very poor BBB penetration and low logP are major liabilities for a CNS target like DRD2, even with its better metabolic stability. The affinity difference, while not huge, further favors Ligand A.

Output:
1
2025-04-17 03:48:39,225 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (332.407 Da) is slightly better than Ligand B (351.447 Da) as it's closer to the lower end, potentially aiding permeability.

**TPSA:** Ligand A (80.9) is excellent, well below the 90 A^2 threshold for CNS targets. Ligand B (113.66) is still reasonable, but less favorable.

**logP:** Ligand A (3.158) is optimal. Ligand B (0.555) is quite low, potentially hindering membrane permeability and CNS penetration.

**H-Bond Donors/Acceptors:** Ligand A (HBD=2, HBA=4) and Ligand B (HBD=3, HBA=5) both fall within acceptable limits.

**QED:** Both ligands have similar QED values (A: 0.719, B: 0.62), indicating good drug-like properties.

**DILI:** Ligand A (77.782) has a higher DILI risk than Ligand B (16.092), which is a significant drawback.

**BBB:** Ligand A (71.966) has a good BBB percentile, exceeding the 70% threshold for CNS targets. Ligand B (26.91) is significantly lower, raising concerns about CNS exposure.

**Caco-2 Permeability:** Both have negative values, which is unusual. Assuming these are logP-scale values, they indicate poor permeability. Ligand A (-5.489) is slightly better than Ligand B (-5.266).

**Aqueous Solubility:** Both have negative values, again unusual. Assuming these are logS values, they indicate poor solubility. Ligand A (-2.964) is slightly better than Ligand B (-1.726).

**hERG Inhibition:** Ligand A (0.72) has a lower hERG risk than Ligand B (0.189), which is preferable.

**Microsomal Clearance:** Ligand B (-12.347) has a much lower (better) microsomal clearance than Ligand A (61.323), suggesting greater metabolic stability.

**In vitro Half-Life:** Ligand B (6.406) has a longer half-life than Ligand A (2.939), which is desirable.

**P-gp Efflux:** Ligand A (0.414) has lower P-gp efflux than Ligand B (0.007), which is beneficial for CNS penetration.

**Binding Affinity:** Ligand B (-7.1 kcal/mol) has a slightly better binding affinity than Ligand A (-10.4 kcal/mol). However, the difference is not substantial enough to outweigh other significant drawbacks.

**Overall Assessment:**

Ligand A has a better TPSA, logP, BBB, hERG, and P-gp profile, all critical for a CNS-targeting GPCR ligand. However, its DILI risk is high, and its metabolic stability is poor. Ligand B has a better DILI, metabolic stability, and half-life, but suffers from poor logP and BBB penetration, making CNS exposure unlikely.

Considering the GPCR-specific priorities, BBB penetration and logP are paramount for CNS targets like DRD2. Ligand A's superior BBB and logP, combined with acceptable hERG and P-gp efflux, outweigh its higher DILI risk and lower metabolic stability, *provided* the DILI risk can be mitigated through structural modifications. The affinity difference is not large enough to favor Ligand B.

Output:
1
2025-04-17 03:48:39,225 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (349.475 and 359.539 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (74.57) is higher than Ligand B (38.13). For CNS targets, TPSA < 90 is preferred, so both are acceptable, but Ligand B is significantly better.

**3. logP:** Ligand A (1.936) is within the optimal 1-3 range. Ligand B (3.669) is slightly higher but still acceptable.

**4. H-Bond Donors:** Ligand A has 2 HBD, and Ligand B has 0. Both are within the acceptable limit of <=5.

**5. H-Bond Acceptors:** Both ligands have 4 HBA, which is within the acceptable limit of <=10.

**6. QED:** Both ligands have good QED scores (0.634 and 0.753, respectively), indicating drug-like properties.

**7. DILI:** Ligand A (16.053) has a lower DILI risk than Ligand B (27.336), which is favorable.

**8. BBB:** This is a critical parameter for CNS targets. Ligand A (55.021) is moderate, while Ligand B (91.508) is excellent (>70). This is a major advantage for Ligand B.

**9. Caco-2 Permeability:** Both have negative values, indicating poor permeability. Ligand A (-4.888) is slightly better than Ligand B (-5.288), but both are concerning.

**10. Aqueous Solubility:** Both have negative values, indicating poor solubility. Ligand A (-2.1) is slightly better than Ligand B (-3.755), but both are concerning.

**11. hERG Inhibition:** Both ligands have low hERG inhibition risk (0.757 and 0.849, respectively).

**12. Microsomal Clearance:** Ligand A (45.354) has lower clearance than Ligand B (82.034), suggesting better metabolic stability.

**13. In vitro Half-Life:** Ligand B (12.11) has a longer half-life than Ligand A (8.333), which is preferable.

**14. P-gp Efflux:** Ligand A (0.218) has lower P-gp efflux than Ligand B (0.82), which is favorable for CNS penetration.

**15. Binding Affinity:** Ligand B (-8.3 kcal/mol) has a significantly stronger binding affinity than Ligand A (-7.8 kcal/mol). This >1.5 kcal/mol difference is substantial and can outweigh some ADME drawbacks.

**Overall Assessment:**

While Ligand A has advantages in DILI, microsomal clearance, and P-gp efflux, Ligand B excels in the most critical areas for a CNS-targeting GPCR ligand: **BBB penetration and binding affinity**. The significantly higher BBB score and stronger binding affinity of Ligand B are compelling. The slightly higher logP and clearance are less concerning given the substantial benefits in these key parameters. The poor Caco-2 and solubility are drawbacks, but can be addressed with formulation strategies.

Output:
1
2025-04-17 03:48:39,225 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B based on the provided guidelines, prioritizing GPCR-specific properties (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (344.371 Da) is slightly lower, which could be beneficial for permeability.

**TPSA:** Ligand A (101.47) is better than Ligand B (47.36) as it is closer to the desired threshold of <=90 for CNS targets. Ligand B is quite low, potentially impacting binding.

**logP:** Ligand A (1.536) is optimal, while Ligand B (3.932) is approaching the upper limit. Higher logP can lead to off-target effects and solubility issues.

**H-Bond Donors/Acceptors:** Ligand A has 1 HBD and 6 HBA, while Ligand B has 0 HBD and 4 HBA. Both are within acceptable limits.

**QED:** Ligand A (0.903) has a significantly better QED score than Ligand B (0.713), indicating a more drug-like profile.

**DILI:** Ligand A (63.513) has a higher DILI risk than Ligand B (36.681). This is a concern for Ligand A.

**BBB:** Ligand B (77.162) has a much better BBB penetration percentile than Ligand A (65.374). This is a critical advantage for a CNS target like DRD2.

**Caco-2 Permeability:** Ligand A (-5.128) has a negative value, indicating poor permeability. Ligand B (-4.537) is also poor, but slightly better.

**Aqueous Solubility:** Ligand A (-2.344) has slightly better solubility than Ligand B (-3.88).

**hERG:** Both ligands have low hERG inhibition liability, which is positive. Ligand A (0.136) is slightly better.

**Microsomal Clearance:** Ligand B (92.816) has significantly higher microsomal clearance than Ligand A (31.041), indicating lower metabolic stability.

**In vitro Half-Life:** Ligand B (63.864) has a longer in vitro half-life than Ligand A (-18.198).

**P-gp Efflux:** Ligand A (0.076) has lower P-gp efflux liability than Ligand B (0.512), which is favorable for CNS penetration.

**Binding Affinity:** Ligand B (-7.2 kcal/mol) has a significantly stronger binding affinity than Ligand A (-9.1 kcal/mol). This is a substantial advantage.

**Overall Assessment:**

Ligand B excels in the most crucial areas for a CNS-targeting GPCR: BBB penetration and binding affinity. While it has a higher logP and clearance, the strong affinity and good BBB penetration likely outweigh these drawbacks. Ligand A has a better QED and lower P-gp efflux, but its poor Caco-2 permeability and weaker binding affinity are significant concerns. The DILI risk for Ligand A is also higher.

Output:
1
2025-04-17 03:48:39,225 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (407.312 Da) is slightly higher than Ligand B (347.463 Da), but both are acceptable.

**TPSA:** Both ligands have TPSA values below 90, which is favorable for CNS penetration. Ligand A (79.9) is slightly higher than Ligand B (72.28), but both are good.

**logP:** Ligand A (3.346) is within the optimal range (1-3), while Ligand B (1.316) is at the lower end. While still acceptable, lower logP can sometimes hinder permeability.

**H-Bond Donors/Acceptors:** Ligand A has 2 HBD and 4 HBA, while Ligand B has 1 HBD and 6 HBA. Both are within acceptable limits (<=5 HBD and <=10 HBA).

**QED:** Both ligands have similar QED values (0.77 and 0.753), indicating good drug-likeness.

**DILI:** Ligand A (53.432) has a higher DILI risk than Ligand B (33.307). This is a negative for Ligand A.

**BBB:** Both ligands have excellent BBB penetration (Ligand A: 74.952, Ligand B: 72.043), exceeding the desirable threshold of >70.

**Caco-2 Permeability:** Both ligands have negative Caco-2 permeability values, which is unusual and suggests a potential issue with the data or a very poor permeability. However, we'll proceed with the rest of the analysis.

**Aqueous Solubility:** Both ligands have negative solubility values, which is also unusual and suggests a potential issue with the data.

**hERG Inhibition:** Ligand A (0.541) has a slightly higher hERG inhibition liability than Ligand B (0.073). Lower is better, so Ligand B is preferred.

**Microsomal Clearance:** Ligand A (61.149) has a higher microsomal clearance than Ligand B (32.939), indicating lower metabolic stability. Ligand B is preferred.

**In vitro Half-Life:** Ligand B (32.573) has a longer in vitro half-life than Ligand A (22.184), which is a positive for Ligand B.

**P-gp Efflux:** Ligand A (0.559) has higher P-gp efflux liability than Ligand B (0.067), meaning less CNS exposure is expected for Ligand A. Ligand B is preferred.

**Binding Affinity:** Ligand B (-8.3 kcal/mol) has a significantly stronger binding affinity than Ligand A (-7.9 kcal/mol). This >1.5 kcal/mol difference is a major advantage for Ligand B and can outweigh minor ADME drawbacks.

**Overall Assessment:**

Ligand B consistently outperforms Ligand A across most critical ADME properties (DILI, hERG, Cl_mic, t1/2, Pgp) and crucially, has a significantly better binding affinity. While the negative Caco-2 and solubility values are concerning, the superior affinity and favorable ADME profile of Ligand B make it the more promising drug candidate for targeting DRD2.

Output:
1
2025-04-17 03:48:39,225 - INFO - Reasoning:

Let's analyze Ligand A and Ligand B based on the provided guidelines, prioritizing GPCR-specific properties (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (366.487 and 352.385 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (74.65) is better than Ligand B (78.09). Both are reasonably good for CNS penetration, being below 90, but A is closer to the optimal <60 range.

**logP:** Ligand B (1.584) is better than Ligand A (0.106). A's logP is quite low, potentially hindering membrane permeability. B is within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A (HBD=1, HBA=5) is slightly better than Ligand B (HBD=2, HBA=3) in terms of adhering to the <5 HBD and <10 HBA guidelines.

**QED:** Both ligands have similar, good QED values (0.775 and 0.763).

**DILI:** Ligand A (40.869) has a slightly better DILI profile than Ligand B (56.727), both are acceptable, but A is preferable.

**BBB:** Ligand B (80.729) is significantly better than Ligand A (55.603). For a CNS target like DRD2, a high BBB percentile is crucial. This is a major advantage for Ligand B.

**Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and suggests poor permeability. This is a concern for both.

**Aqueous Solubility:** Both have negative solubility values, which is also unusual and suggests poor solubility. This is a concern for both.

**hERG Inhibition:** Ligand A (0.077) has a much lower hERG inhibition liability than Ligand B (0.247), indicating a lower risk of cardiotoxicity.

**Microsomal Clearance:** Ligand B (21.538) has a lower microsomal clearance than Ligand A (27.905), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand B (-25.087) has a negative half-life, which is impossible. This is a significant red flag. Ligand A has a half-life of 15.03 hours, which is reasonable.

**P-gp Efflux:** Ligand A (0.043) has a much lower P-gp efflux liability than Ligand B (0.066), which is favorable for CNS penetration.

**Binding Affinity:** Ligand B (-8.4 kcal/mol) has a significantly stronger binding affinity than Ligand A (-6.7 kcal/mol). This is a substantial advantage, potentially outweighing some of the ADME concerns.

**Overall Assessment:**

Ligand B has a superior binding affinity and BBB penetration, which are critical for a CNS-targeting GPCR. However, it has a negative in vitro half-life, which is a showstopper. Ligand A has a more reasonable ADME profile, with acceptable DILI, hERG, and P-gp efflux, and a reasonable half-life. While its logP is low and BBB is not ideal, its overall profile is more balanced and plausible as a drug candidate. The negative half-life for Ligand B makes it a non-starter.

Output:
0
2025-04-17 03:48:39,225 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (350.419 and 359.499 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (96.69) is slightly above the optimal <90 for CNS targets, but still reasonable. Ligand B (72.7) is well within the desired range.

**3. logP:** Ligand A (-0.009) is quite low, potentially hindering membrane permeability. Ligand B (3.533) is excellent, falling within the optimal 1-3 range.

**4. H-Bond Donors:** Ligand A (2) and Ligand B (1) are both acceptable, below the threshold of 5.

**5. H-Bond Acceptors:** Both Ligand A (6) and Ligand B (6) are within the acceptable limit of 10.

**6. QED:** Both ligands have good QED scores (0.796 and 0.906), indicating drug-like properties.

**7. DILI:** Ligand A (31.02) has a much lower DILI risk than Ligand B (72.043), which is approaching a higher risk level.

**8. BBB:** Ligand B (60.993) is better than Ligand A (44.746), but both are below the desirable >70 for CNS targets. However, given the other factors, this isn't a dealbreaker.

**9. Caco-2:** Both have negative values, which is unusual. Assuming these are percentile scores, Ligand A (-4.96) is worse than Ligand B (-5.118), meaning lower intestinal absorption.

**10. Solubility:** Ligand A (-1.235) has slightly better solubility than Ligand B (-4.04).

**11. hERG:** Both ligands have very low hERG risk (0.235 and 0.155).

**12. Cl_mic:** Ligand A (-8.848) has significantly lower (better) microsomal clearance than Ligand B (35.885), suggesting better metabolic stability.

**13. t1/2:** Ligand B (14.41) has a longer half-life than Ligand A (5.147).

**14. Pgp:** Both ligands have low P-gp efflux liability (0.03 and 0.429).

**15. Binding Affinity:** Ligand B (-9.4) has a significantly stronger binding affinity than Ligand A (-8.6). This is a >1 kcal/mol difference, which is substantial.

**Overall Assessment:**

Ligand B excels in key areas for a CNS GPCR target: logP, binding affinity, and half-life. While its BBB penetration isn't ideal, its strong affinity might compensate. The higher DILI risk is a concern, but not disqualifying given the affinity advantage. Ligand A has better metabolic stability and lower DILI, but its poor logP is a significant drawback, likely hindering brain penetration and overall bioavailability. The weaker binding affinity is also a major disadvantage.

Output:
1
2025-04-17 03:48:39,225 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (357.885 and 352.41 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (37.27) is excellent, well below the 90 A^2 threshold for CNS targets. Ligand B (95.42) is higher, exceeding the preferred range, which could hinder BBB penetration.

**3. logP:** Ligand A (3.735) is within the optimal 1-3 range. Ligand B (0.946) is slightly low, potentially impacting membrane permeability.

**4. H-Bond Donors:** Both ligands have acceptable HBD counts (1 and 2, respectively), well below the limit of 5.

**5. H-Bond Acceptors:** Both ligands have acceptable HBA counts (3 and 5, respectively), well below the limit of 10.

**6. QED:** Both ligands have similar and good QED values (0.781 and 0.795), indicating good drug-like properties.

**7. DILI:** Ligand A (43.195) has a slightly higher DILI risk than Ligand B (26.871), but both are below the concerning threshold of 60.

**8. BBB:** Ligand A (87.864) has a significantly better BBB penetration prediction than Ligand B (71.19). This is a critical advantage for a CNS target like DRD2.

**9. Caco-2 Permeability:** Ligand A (-4.692) has poor Caco-2 permeability. Ligand B (-4.791) also has poor Caco-2 permeability.

**10. Aqueous Solubility:** Both ligands have very poor aqueous solubility (-3.409 and -1.394). This is a concern for formulation.

**11. hERG Inhibition:** Both ligands show low hERG inhibition liability (0.906 and 0.462).

**12. Microsomal Clearance:** Ligand A (31.626) has a moderate clearance, while Ligand B (-14.217) has a negative clearance, which is not physically possible and likely indicates a very stable compound.

**13. In vitro Half-Life:** Ligand A (46.17) has a reasonable half-life. Ligand B (-13.059) has a negative half-life, which is not physically possible and likely indicates a very stable compound.

**14. P-gp Efflux:** Both ligands show low P-gp efflux liability (0.469 and 0.021), which is favorable for CNS penetration.

**15. Binding Affinity:** Both ligands have very similar and strong binding affinities (-8.8 and -8.6 kcal/mol). The difference is negligible.

**Conclusion:**

Considering the GPCR-specific priorities, Ligand A is the more promising candidate. While both have strong binding affinities, Ligand A's superior TPSA and BBB penetration scores, coupled with a more realistic clearance and half-life, outweigh its slightly higher DILI risk and poor Caco-2 permeability. Ligand B's negative clearance and half-life values are highly suspect. The lower logP of Ligand B is also a disadvantage.

Output:
1
2025-04-17 03:48:39,225 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (342.483 and 367.515 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (40.62) is significantly better than Ligand B (80.32). For CNS targets, TPSA should be <= 90, and A is comfortably within this range, while B is approaching the upper limit. This favors A.

**logP:** Both ligands have good logP values (2.964 and 2.676), falling within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A (0 HBD, 2 HBA) is preferable to Ligand B (2 HBD, 5 HBA). Lower HBD/HBA generally improves permeability.

**QED:** Both ligands have good QED scores (0.502 and 0.74), indicating drug-like properties. Ligand B is slightly better.

**DILI:** Ligand A (13.959) has a much lower DILI risk than Ligand B (52.966). This is a significant advantage for A.

**BBB:** Ligand A (59.325) has a better BBB penetration percentile than Ligand B (49.244), though both are below the desirable >70 for CNS targets. Still, A is closer.

**Caco-2 Permeability:** Both have negative Caco-2 values (-4.59 and -4.851). This is unusual and suggests poor permeability *in vitro*. However, the values are similar.

**Aqueous Solubility:** Ligand A (-4.668) and Ligand B (-2.761) both have poor aqueous solubility, but B is slightly better.

**hERG Inhibition:** Both ligands show very low hERG inhibition liability (0.46 and 0.173), which is excellent.

**Microsomal Clearance:** Both ligands have similar microsomal clearance (30.014 and 30.656 mL/min/kg).

**In vitro Half-Life:** Ligand A (-5.952 hours) has a negative half-life, which is not possible. This is a major red flag. Ligand B (20.222 hours) has a reasonable half-life.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.226 and 0.124).

**Binding Affinity:** Ligand B (-7.9 kcal/mol) has a significantly stronger binding affinity than Ligand A (0.0 kcal/mol). This is a crucial difference. A binding advantage of >1.5 kcal/mol can often outweigh other drawbacks.

**Overall Assessment:**

Despite Ligand A having better TPSA, DILI, and BBB, the negative *in vitro* half-life is a critical flaw. A negative half-life is physically impossible and suggests a significant issue with the data or the molecule's stability. Ligand B, while having a higher TPSA and DILI risk, exhibits a much stronger binding affinity and a reasonable half-life. For a GPCR target, strong binding is paramount. While the BBB penetration isn't ideal for either, the superior affinity of Ligand B makes it the more promising candidate.

Output:
1
2025-04-17 03:48:39,226 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (351.403 and 356.417 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (96.97) is better than Ligand B (76.14). Both are below the 90 A^2 threshold desirable for CNS targets.

**logP:** Ligand B (2.863) is optimal (1-3), while Ligand A (-0.307) is too low, potentially hindering permeation. This is a significant drawback for Ligand A.

**H-Bond Donors/Acceptors:** Both ligands have 2 HBD and 5 HBA, which are within acceptable limits.

**QED:** Both ligands have good QED scores (0.614 and 0.674, respectively), indicating drug-like properties.

**DILI:** Ligand A (35.789) has a slightly better DILI score than Ligand B (41.915), but both are below the concerning threshold of 60.

**BBB:** Ligand B (89.027) is significantly better than Ligand A (48.895) in terms of BBB penetration, which is crucial for a CNS target like DRD2.

**Caco-2 Permeability:** Ligand A (-5.323) is worse than Ligand B (-4.428), indicating lower intestinal absorption.

**Aqueous Solubility:** Ligand A (-1.413) is worse than Ligand B (-4.241), indicating lower solubility.

**hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.096 and 0.481), which is excellent.

**Microsomal Clearance:** Ligand A (-5.143) has much lower (better) microsomal clearance than Ligand B (79.398), suggesting greater metabolic stability.

**In vitro Half-Life:** Ligand A (-12.63) has a worse half-life than Ligand B (-33.047).

**P-gp Efflux:** Ligand A (0.022) has significantly lower P-gp efflux than Ligand B (0.078), which is favorable for CNS exposure.

**Binding Affinity:** Ligand B (-7.6 kcal/mol) has a significantly stronger binding affinity than Ligand A (-9.3 kcal/mol). This is a substantial advantage for Ligand B.

**Overall Assessment:**

While Ligand A has advantages in terms of P-gp efflux and metabolic stability, its poor logP and BBB penetration are major drawbacks for a CNS-targeting GPCR. Ligand B, despite slightly higher DILI and P-gp efflux, excels in BBB penetration, logP, and crucially, binding affinity. The stronger binding affinity of Ligand B (-7.6 vs -9.3 kcal/mol) is a significant advantage that outweighs the minor ADME concerns.

Output:
1
2025-04-17 03:48:39,226 - INFO - Batch 60 complete. Total preferences: 960
2025-04-17 03:48:39,226 - INFO - Processing batch 61/512...
2025-04-17 03:49:30,613 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (344.386 and 352.312 Da) fall within the ideal range of 200-500 Da.

**TPSA:** Ligand A (59.59) is significantly better than Ligand B (81.42). For CNS targets, we want TPSA <= 90, and A is comfortably within that range, while B is approaching the upper limit.

**logP:** Both ligands have similar logP values (2.511 and 2.468), both falling within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Both have 2 HBD and 4 HBA, which are acceptable.

**QED:** Ligand A (0.845) has a much better QED score than Ligand B (0.492), indicating a more drug-like profile.

**DILI:** Ligand A (62.001) is slightly better than Ligand B (80.651), both are above the preferred <40, but A is closer.

**BBB:** Both ligands have excellent BBB penetration (76.968 and 78.092), exceeding the desirable >70 threshold for CNS targets.

**Caco-2 Permeability:** Both have negative Caco-2 values (-4.879 and -4.643), which is unusual and suggests poor permeability. This is a significant concern for both.

**Aqueous Solubility:** Both have very poor aqueous solubility (-3.445 and -4.751). This is a major drawback.

**hERG:** Both ligands show low hERG inhibition liability (0.675 and 0.695), which is good.

**Microsomal Clearance:** Ligand B (80.303) has a significantly higher microsomal clearance than Ligand A (23.855), indicating faster metabolism and lower metabolic stability.

**In vitro Half-Life:** Ligand A (36.573) has a much longer in vitro half-life than Ligand B (2.8), which is a substantial advantage.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.172 and 0.158), which is favorable for CNS penetration.

**Binding Affinity:** Ligand B (-9.9 kcal/mol) has a stronger binding affinity than Ligand A (-8.6 kcal/mol). This is a 1.3 kcal/mol difference, which is significant and could potentially outweigh some of the ADME drawbacks.

**Overall Assessment:**

While Ligand B has a better binding affinity, Ligand A is superior in most ADME properties. Specifically, Ligand A has a much better QED, lower microsomal clearance, and a significantly longer half-life. The poor Caco-2 and solubility are concerning for both, but the better overall profile of Ligand A, especially its metabolic stability and drug-likeness, makes it the more promising candidate. The affinity difference, while notable, isn't large enough to overcome the substantial ADME advantages of Ligand A, particularly for a GPCR target where CNS penetration is crucial.

Output:
0
2025-04-17 03:49:30,614 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (353.419 and 362.499 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (96.97) is slightly higher than Ligand B (83.98), but both are below the 90 A^2 threshold desirable for CNS targets.

**logP:** Ligand A (-0.717) is significantly lower than the optimal 1-3 range and is a concern for permeability. Ligand B (2.155) is within the optimal range. This is a major advantage for Ligand B.

**H-Bond Donors/Acceptors:** Both ligands have 2 HBD and 5-6 HBA, which are within acceptable limits.

**QED:** Both ligands have good QED scores (0.612 and 0.812), indicating good drug-like properties.

**DILI:** Ligand A (26.444) has a much lower DILI risk than Ligand B (54.517), which is a positive for Ligand A.

**BBB:** Ligand B (65.374) has a significantly higher BBB penetration percentile than Ligand A (29.12). This is a critical advantage for a CNS target like DRD2.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.247 and -5.071), which is unusual and suggests poor permeability. However, these values are on a scale where negative values are possible, and direct comparison is difficult without knowing the scale's specifics.

**Aqueous Solubility:** Both ligands have negative solubility values (-1.146 and -3.662), which is also unusual and suggests poor solubility. Again, the scale is unknown.

**hERG:** Both ligands have low hERG inhibition liability (0.101 and 0.297).

**Microsomal Clearance:** Ligand A (-28.518) has much lower microsomal clearance than Ligand B (51.759), indicating better metabolic stability.

**In vitro Half-Life:** Ligand B (25.273) has a significantly longer in vitro half-life than Ligand A (2.229).

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.006 and 0.48).

**Binding Affinity:** Both ligands have the same binding affinity (-8.4 kcal/mol), which is excellent.

**Overall Assessment:**

Ligand B is superior due to its favorable logP, significantly higher BBB penetration, and longer half-life. While Ligand A has a lower DILI risk and better metabolic stability, the poor logP and low BBB penetration are major drawbacks for a CNS-targeting drug. The similar binding affinity means the ADME properties will be the deciding factor. The higher BBB penetration of Ligand B is crucial for CNS efficacy.

Output:
1
2025-04-17 03:49:30,614 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (348.403 and 338.459 Da) fall comfortably within the ideal 200-500 Da range.

**TPSA:** Ligand A (113.44) is slightly above the optimal <90 for CNS targets, but still reasonable. Ligand B (86.52) is excellent, well below 90.

**logP:** Ligand A (-0.102) is quite low, potentially hindering membrane permeability. Ligand B (3.746) is near the upper end of the optimal range (1-3) but still acceptable.

**H-Bond Donors/Acceptors:** Ligand A (3 HBD, 6 HBA) and Ligand B (2 HBD, 6 HBA) both have reasonable numbers of H-bond donors and acceptors, falling within the suggested limits.

**QED:** Both ligands have good QED scores (0.565 and 0.762), indicating drug-like properties.

**DILI:** Both ligands have acceptable DILI risk (56.689 and 47.77), below the 60 threshold.

**BBB:** This is critical for a CNS target. Ligand A (45.56) is concerningly low, suggesting poor brain penetration. Ligand B (59.325) is better, but still not ideal (aim for >70).

**Caco-2 Permeability:** Both ligands show poor Caco-2 permeability (-5.457 and -5.229). This is a negative for both.

**Aqueous Solubility:** Both ligands have poor aqueous solubility (-1.638 and -3.778). This could pose formulation challenges.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.111 and 0.883).

**Microsomal Clearance:** Ligand A (2.569) has much lower clearance than Ligand B (67.29), indicating better metabolic stability.

**In vitro Half-Life:** Ligand B (61.817) has a significantly longer half-life than Ligand A (15.332).

**P-gp Efflux:** Ligand A (0.019) has very low P-gp efflux, which is excellent for CNS penetration. Ligand B (0.196) has moderate P-gp efflux.

**Binding Affinity:** Both ligands have very good binding affinity (-7.9 and -7.7 kcal/mol). The difference of 0.2 kcal/mol is not substantial enough to outweigh other factors.

**Overall Assessment:**

Ligand A has a major drawback: very poor BBB penetration (45.56). While it has excellent P-gp efflux properties and better metabolic stability, the inability to cross the blood-brain barrier is a significant hurdle for a CNS target like DRD2. Ligand B has better BBB penetration (59.325) and a longer half-life, but suffers from higher P-gp efflux and faster metabolism. Considering the GPCR-specific priorities, BBB penetration is paramount. While Ligand B's BBB score isn't ideal, it's significantly better than Ligand A's.

Output:
1
2025-04-17 03:49:30,614 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (386.627 and 358.482 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (49.41) is better than Ligand B (33.2). Both are below the 90 A^2 threshold for CNS targets, which is excellent.

**3. logP:** Ligand A (3.547) is within the optimal 1-3 range. Ligand B (4.866) is slightly above, potentially leading to solubility issues or off-target interactions, but not drastically so.

**4. H-Bond Donors:** Ligand A (1) is preferable to Ligand B (0). A small number of HBDs are generally favorable.

**5. H-Bond Acceptors:** Ligand A (4) is slightly higher than Ligand B (3), but both are within the acceptable limit of 10.

**6. QED:** Both ligands have good QED scores (0.616 and 0.691), indicating good drug-like properties.

**7. DILI:** Both ligands have acceptable DILI risk (30.361 and 39.201 percentiles), below the 40% threshold.

**8. BBB:** Ligand B (84.374) has a significantly better BBB penetration score than Ligand A (67.468). This is a *critical* factor for a CNS target like DRD2.

**9. Caco-2 Permeability:** Ligand A (-5.124) shows poor Caco-2 permeability, while Ligand B (-4.7) is slightly better, but still poor.

**10. Aqueous Solubility:** Ligand A (-3.535) has slightly better aqueous solubility than Ligand B (-4.888), but both are poor.

**11. hERG Inhibition:** Both ligands have low hERG inhibition liability (0.63 and 0.598), which is good.

**12. Microsomal Clearance:** Ligand A (77.811) and Ligand B (74.562) have similar microsomal clearance values, indicating moderate metabolic stability.

**13. In vitro Half-Life:** Ligand B (3.819) has a significantly longer in vitro half-life than Ligand A (0.217). This is a major advantage.

**14. P-gp Efflux:** Both ligands have low P-gp efflux liability (0.456 and 0.582), which is favorable for CNS penetration.

**15. Binding Affinity:** Ligand B (-8.7 kcal/mol) has a substantially stronger binding affinity than Ligand A (-7.5 kcal/mol). This difference of 1.2 kcal/mol is significant and can outweigh some of the ADME drawbacks.

**Overall Assessment:**

While Ligand A has slightly better TPSA and solubility, Ligand B is superior in almost every other critical aspect. The significantly better BBB penetration (84.374 vs 67.468), longer half-life (3.819 vs 0.217), and *much* stronger binding affinity (-8.7 vs -7.5 kcal/mol) make Ligand B the more promising drug candidate for targeting DRD2. The slightly higher logP of Ligand B is a minor concern, but the substantial affinity advantage and improved CNS properties outweigh this.

Output:
1
2025-04-17 03:49:30,614 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (349.431 and 344.499 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (95.58) is higher than Ligand B (49.41). For CNS targets, TPSA should be <= 90, so Ligand A is marginally above the ideal, while Ligand B is well within the desired range. This favors Ligand B.

**logP:** Ligand A (0.75) is a bit low, potentially hindering permeation. Ligand B (2.827) is closer to the optimal 1-3 range. This favors Ligand B.

**H-Bond Donors/Acceptors:** Ligand A has 2 HBD and 4 HBA, while Ligand B has 1 HBD and 2 HBA. Both are within acceptable limits (<=5 HBD and <=10 HBA).

**QED:** Ligand B (0.654) has a better QED score than Ligand A (0.474), indicating a more drug-like profile. This favors Ligand B.

**DILI:** Ligand A (32.261) has a slightly higher DILI risk than Ligand B (6.204), but both are below the concerning threshold of 40.

**BBB:** Both ligands have excellent BBB penetration (79.062 and 78.945), exceeding the desirable >70 threshold for CNS targets.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values, which is unusual and could indicate issues with the prediction method. However, the values are similar.

**Aqueous Solubility:** Both ligands have negative solubility values, again suggesting potential issues with the prediction method. The values are similar.

**hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.087 and 0.549).

**Microsomal Clearance:** Ligand A (14.574) has a lower microsomal clearance than Ligand B (28.831), suggesting better metabolic stability. This favors Ligand A.

**In vitro Half-Life:** Ligand A (-31.562) has a much lower in vitro half-life than Ligand B (10.386). This is a significant drawback for Ligand A.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.025 and 0.063).

**Binding Affinity:** Both ligands have similar and strong binding affinities (-8.4 and -8.1 kcal/mol). The difference is less than 1.5 kcal/mol, so it's not a deciding factor.

**Overall Assessment:**

Ligand B is the stronger candidate. While Ligand A has better metabolic stability (lower Cl_mic), Ligand B excels in several key areas for GPCRs, particularly its lower TPSA and better logP, and QED. The significantly longer in vitro half-life of Ligand B is also a major advantage. The similar binding affinities mean the ADME properties are the primary differentiators.



Output:
1
2025-04-17 03:49:30,614 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (341.43 Da) is slightly lower, which could be advantageous for permeability, but both are acceptable.

**TPSA:** Ligand A (46.09) is excellent for CNS penetration, well below the 90 A^2 threshold. Ligand B (41.93) is also very good.

**logP:** Both ligands have logP values (3.857 and 4.237) within the optimal range of 1-3, suggesting good permeability and reasonable solubility. Ligand B is slightly higher, which *could* hint at potential off-target effects, but is still acceptable.

**H-Bond Donors/Acceptors:** Ligand A (0 HBD, 3 HBA) is favorable, minimizing potential issues with permeability. Ligand B (1 HBD, 6 HBA) is also reasonable.

**QED:** Both ligands have acceptable QED scores (0.801 and 0.625), indicating good drug-like properties.

**DILI:** Ligand A (31.369) has a lower DILI risk than Ligand B (25.165), which is a positive attribute.

**BBB:** Ligand A (89.066) has a significantly better BBB penetration percentile than Ligand B (79.294). This is a critical factor for a CNS target like DRD2.

**Caco-2 Permeability:** Ligand A (-4.589) has a lower Caco-2 permeability than Ligand B (-5.282). This is not ideal for either, but Ligand B is slightly worse.

**Aqueous Solubility:** Both ligands have poor aqueous solubility (-3.401 and -3.041). This could pose formulation challenges, but is not a dealbreaker if other properties are strong.

**hERG Inhibition:** Both ligands show low hERG inhibition risk (0.754 and 0.89), which is good.

**Microsomal Clearance:** Both ligands have similar microsomal clearance (63.66 and 62.831), suggesting comparable metabolic stability.

**In vitro Half-Life:** Ligand A (-0.914) has a shorter in vitro half-life than Ligand B (54.501). This is a disadvantage for Ligand A.

**P-gp Efflux:** Ligand A (0.218) exhibits lower P-gp efflux liability than Ligand B (0.749), which is favorable for CNS exposure.

**Binding Affinity:** Ligand A (-7.8 kcal/mol) has a stronger binding affinity than Ligand B (-6.6 kcal/mol). This is a substantial difference (1.2 kcal/mol), and a key driver in the decision.

**Overall Assessment:**

Ligand A is superior due to its significantly better BBB penetration, lower P-gp efflux, stronger binding affinity, and lower DILI risk. While its Caco-2 permeability and in vitro half-life are less favorable, the strong affinity and CNS-relevant properties outweigh these drawbacks for a DRD2 target. Ligand B's slightly higher logP and lower BBB are concerning.

Output:
1
2025-04-17 03:49:30,614 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (350.375 and 348.403 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (122.13) is slightly above the optimal <90 for CNS targets, while Ligand B (104.53) is closer to the ideal range. This favors Ligand B.

**logP:** Both ligands (-0.671 and -0.463) are a bit low, potentially hindering permeation. However, they are not excessively low.

**H-Bond Donors/Acceptors:** Both have 2 HBDs and a reasonable number of HBAs (7 and 6 respectively), falling within acceptable limits.

**QED:** Both ligands have good QED scores (0.722 and 0.694), indicating drug-like properties.

**DILI:** Ligand A (45.25) has a slightly higher DILI risk than Ligand B (35.634), but both are below the concerning threshold of 60.

**BBB:** This is a critical parameter for CNS targets. Ligand A has a BBB percentile of 70.027, which is desirable. Ligand B, however, has a significantly lower BBB percentile of 31.214, making it less likely to reach the target in the brain. This is a major advantage for Ligand A.

**Caco-2 Permeability:** Both have negative Caco-2 values (-5.095 and -5.257), which is unusual and suggests poor permeability. However, these values are on a scale where negative values are possible and don't necessarily disqualify the compounds.

**Aqueous Solubility:** Both ligands have very poor aqueous solubility (-0.752 and -1.138). This could pose formulation challenges.

**hERG Inhibition:** Both ligands exhibit very low hERG inhibition risk (0.235 and 0.037).

**Microsomal Clearance:** Ligand A (-4.324) has a much lower (better) microsomal clearance than Ligand B (21.802), indicating better metabolic stability.

**In vitro Half-Life:** Ligand A (-12.858) has a negative half-life, which is unusual. Ligand B (-7.207) also has a negative half-life, but is slightly better. These values are likely on a scale where negative values are possible.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.004 and 0.009), which is favorable for CNS penetration.

**Binding Affinity:** Ligand B (-8.1 kcal/mol) has a slightly stronger binding affinity than Ligand A (-7.0 kcal/mol). The difference is 1.1 kcal/mol, which is significant.

**Overall Assessment:**

While Ligand B has a slightly better TPSA and a stronger binding affinity, Ligand A is significantly better in terms of BBB penetration and metabolic stability (lower Cl_mic). Given that DRD2 is a CNS target, BBB penetration is paramount. The 1.1 kcal/mol difference in binding affinity might be overcome with further optimization, but poor BBB penetration is a more difficult property to fix. The better metabolic stability of Ligand A is also a significant advantage.

Output:
0
2025-04-17 03:49:30,615 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (346.43 and 368.50 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (73.99) is better than Ligand B (76.46). Both are below the 90 A^2 threshold for CNS targets, which is good.

**3. logP:** Both ligands have good logP values (1.456 and 1.29), falling within the optimal 1-3 range.

**4. H-Bond Donors:** Both have 1 HBD, which is acceptable.

**5. H-Bond Acceptors:** Ligand A has 4 HBA, while Ligand B has 6. Both are below the 10 threshold, but A is preferable.

**6. QED:** Both ligands have similar QED values (0.759 and 0.734), indicating good drug-likeness.

**7. DILI:** Ligand A (21.95) has a significantly lower DILI risk than Ligand B (35.29). This is a major advantage for Ligand A.

**8. BBB:** Ligand A (62.20) has a better BBB percentile than Ligand B (56.65), although neither is above the desirable >70 threshold. However, for a CNS target like DRD2, maximizing BBB penetration is crucial.

**9. Caco-2 Permeability:** Ligand A (-4.638) has a better Caco-2 permeability than Ligand B (-5.107).

**10. Aqueous Solubility:** Both have negative values, indicating poor solubility. Ligand A (-1.092) is slightly better than Ligand B (-1.392).

**11. hERG Inhibition:** Both ligands show very low hERG inhibition liability (0.222 and 0.158), which is excellent.

**12. Microsomal Clearance:** Ligand A (26.74) has a lower Cl_mic than Ligand B (55.22), indicating better metabolic stability.

**13. In vitro Half-Life:** Ligand A (21.41) has a longer in vitro half-life than Ligand B (-3.45).

**14. P-gp Efflux:** Both ligands have low P-gp efflux liability (0.168 and 0.094).

**15. Binding Affinity:** Ligand A (-8.7 kcal/mol) has a significantly stronger binding affinity than Ligand B (-7.0 kcal/mol). This is a substantial advantage, exceeding the 1.5 kcal/mol difference that can outweigh other drawbacks.

**Overall Assessment:**

Ligand A is clearly superior. It has a better safety profile (lower DILI), better BBB penetration, better metabolic stability (lower Cl_mic, longer t1/2), better Caco-2 permeability, and *significantly* stronger binding affinity. While both have issues with aqueous solubility, the other advantages of Ligand A outweigh this concern. The strong binding affinity of Ligand A is particularly important for a GPCR target.

Output:
1
2025-04-17 03:49:30,615 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 drug candidates, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (349.431 and 354.466 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (96.87) is slightly above the preferred <90 for CNS targets, but still reasonable. Ligand B (49.85) is excellent, well below 90.

**3. logP:** Ligand A (0.383) is quite low, potentially hindering membrane permeability. Ligand B (2.557) is within the optimal 1-3 range. This is a significant advantage for Ligand B.

**4. H-Bond Donors:** Ligand A (3) is acceptable. Ligand B (0) is also good, potentially improving permeability.

**5. H-Bond Acceptors:** Both ligands have a reasonable number of H-bond acceptors (Ligand A: 4, Ligand B: 3).

**6. QED:** Both ligands have acceptable QED values (Ligand A: 0.692, Ligand B: 0.497), indicating reasonable drug-likeness. Ligand A is slightly better here.

**7. DILI:** Ligand A (31.02) has a much lower DILI risk than Ligand B (8.298), which is a significant advantage.

**8. BBB:** Ligand B (91.508) has a very high BBB penetration percentile, which is crucial for a CNS target like DRD2. Ligand A (22.412) is quite low, making CNS penetration unlikely. This is a major advantage for Ligand B.

**9. Caco-2 Permeability:** Ligand A (-5.118) has poor Caco-2 permeability, consistent with its low logP. Ligand B (-4.47) is also not great, but slightly better.

**10. Aqueous Solubility:** Both ligands have poor aqueous solubility (-1.707 and -2.15). This might pose formulation challenges, but is less critical than BBB for a CNS target.

**11. hERG Inhibition:** Both ligands have low hERG inhibition risk (Ligand A: 0.278, Ligand B: 0.618).

**12. Microsomal Clearance:** Ligand A (-12.906) has significantly lower (better) microsomal clearance than Ligand B (26.994), indicating better metabolic stability.

**13. In vitro Half-Life:** Ligand A (10.664) has a longer half-life than Ligand B (3.237).

**14. P-gp Efflux:** Both ligands have low P-gp efflux liability (Ligand A: 0.055, Ligand B: 0.128).

**15. Binding Affinity:** Ligand A (-7.7) has a slightly better binding affinity than Ligand B (-7.3), but the difference is relatively small (0.4 kcal/mol).

**Overall Assessment:**

While Ligand A has better DILI, metabolic stability, and slightly better affinity, Ligand B significantly outperforms it in crucial properties for a CNS-targeting GPCR: **BBB penetration and logP**. The high BBB value of Ligand B is a decisive factor. The slightly lower affinity can potentially be optimized in later stages of drug development. The poor logP of Ligand A is a major hurdle that is difficult to overcome.

Output:
1
2025-04-17 03:49:30,615 - INFO - Okay, let's analyze these two ligands for their potential as DRD2 drug candidates. DRD2 is a GPCR in the CNS, so BBB penetration, logP, Pgp efflux, TPSA, and binding affinity are paramount.

**Ligand A: [374.34 ,  78.26 ,   2.732,   0.   ,   6.   ,   0.769,  82.784,  89.725, -4.351,  -3.976,   0.203,  15.559,  30.16 ,   0.475,  -9.4  ]**

*   **MW:** 374.34 Da - Good, within the ideal range.
*   **TPSA:** 78.26  - Good, below the 90 threshold for CNS targets.
*   **logP:** 2.732 - Excellent, within the optimal 1-3 range.
*   **HBD:** 0 - Acceptable.
*   **HBA:** 6 - Acceptable.
*   **QED:** 0.769 - Excellent, highly drug-like.
*   **DILI:** 82.784 - Concerning, high risk of liver injury.
*   **BBB:** 89.725 - Excellent, very good CNS penetration predicted.
*   **Caco-2:** -4.351 - Poor, suggests very limited intestinal absorption.
*   **Solubility:** -3.976 - Poor, suggests very low aqueous solubility.
*   **hERG:** 0.203 - Very low risk of hERG inhibition.
*   **Cl_mic:** 15.559 - Moderate, could be better.
*   **t1/2:** 30.16 - Good, reasonable in vitro half-life.
*   **Pgp:** 0.475 - Low efflux, favorable for CNS exposure.
*   **Affinity:** -9.4 kcal/mol - Excellent, very strong binding.

**Ligand B: [365.499,  80.32 ,   1.687,   2.   ,   5.   ,   0.77 ,  36.681,  64.25 , -5.373,  -1.531,   0.217,   2.742,  15.045,   0.072,  -8.6  ]**

*   **MW:** 365.499 Da - Good, within the ideal range.
*   **TPSA:** 80.32 - Acceptable, slightly above the ideal 90 for CNS, but still reasonable.
*   **logP:** 1.687 - Acceptable, but on the lower end of the optimal range.
*   **HBD:** 2 - Acceptable.
*   **HBA:** 5 - Acceptable.
*   **QED:** 0.77 - Excellent, highly drug-like.
*   **DILI:** 36.681 - Good, low risk of liver injury.
*   **BBB:** 64.25 - Moderate, could be better for a CNS target.
*   **Caco-2:** -5.373 - Very poor, suggests extremely limited intestinal absorption.
*   **Solubility:** -1.531 - Poor, suggests very low aqueous solubility.
*   **hERG:** 0.217 - Very low risk of hERG inhibition.
*   **Cl_mic:** 2.742 - Very low, excellent metabolic stability.
*   **t1/2:** 15.045 - Moderate, could be better.
*   **Pgp:** 0.072 - Very low efflux, highly favorable for CNS exposure.
*   **Affinity:** -8.6 kcal/mol - Excellent, strong binding.

**Comparison and Decision:**

Both compounds have excellent binding affinity and drug-like scores (QED). Both also suffer from poor Caco-2 permeability and aqueous solubility. However, Ligand A has a significantly higher predicted BBB penetration (89.725 vs 64.25) and a better logP. While Ligand A has a higher DILI risk, the extremely strong binding affinity (-9.4 kcal/mol) is a significant advantage. Ligand B has better metabolic stability (lower Cl_mic) and lower DILI risk, but the lower BBB penetration is a major drawback for a CNS target.

Given the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity), and the fact that the affinity difference is substantial (1.5 kcal/mol or more), **Ligand A is the more promising candidate**. The high BBB penetration and strong binding outweigh the higher DILI risk, which can be further investigated and potentially mitigated through structural modifications.

1
2025-04-17 03:49:30,615 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B based on the provided guidelines, prioritizing GPCR-specific properties (BBB, logP, Pgp, TPSA, and affinity).

**Ligand A:**

*   **MW:** 347.371 Da - Good (within 200-500 range)
*   **TPSA:** 104.81 - Acceptable, but approaching the upper limit for CNS targets (ideally <90).
*   **logP:** 0.81 - Low. May have permeability issues.
*   **HBD:** 2 - Good.
*   **HBA:** 5 - Good.
*   **QED:** 0.585 - Good, drug-like.
*   **DILI:** 73.052 - Moderate risk.
*   **BBB:** 65.219 - Below the desirable threshold of 70 for CNS targets.
*   **Caco-2:** -4.883 - Poor permeability.
*   **Solubility:** -3.192 - Poor solubility.
*   **hERG:** 0.084 - Very low risk.
*   **Cl_mic:** 40.094 - Moderate clearance.
*   **t1/2:** 0.67 - Short half-life.
*   **Pgp:** 0.005 - Low efflux, good.
*   **Affinity:** -8.4 kcal/mol - Excellent binding affinity.

**Ligand B:**

*   **MW:** 407.505 Da - Good (within 200-500 range)
*   **TPSA:** 9.72 - Excellent, very favorable for CNS penetration.
*   **logP:** 4.946 - High. Potential solubility and off-target issues.
*   **HBD:** 0 - Good, but potentially impacts solubility.
*   **HBA:** 4 - Good.
*   **QED:** 0.709 - Good, drug-like.
*   **DILI:** 50.523 - Good, low risk.
*   **BBB:** 98.216 - Excellent, highly desirable for CNS targets.
*   **Caco-2:** -4.534 - Poor permeability.
*   **Solubility:** -4.747 - Poor solubility.
*   **hERG:** 0.994 - Moderate risk.
*   **Cl_mic:** 14.347 - Low clearance, good metabolic stability.
*   **t1/2:** -3.513 - Very short half-life.
*   **Pgp:** 0.905 - Moderate efflux.
*   **Affinity:** -8.7 kcal/mol - Excellent binding affinity, slightly better than Ligand A.

**Comparison & Decision:**

Both ligands have excellent binding affinity. However, for a CNS target like DRD2, BBB penetration is crucial. Ligand B significantly outperforms Ligand A in BBB (98.216 vs 65.219). Ligand B also has a lower DILI risk and better metabolic stability (lower Cl_mic). While Ligand B has a higher logP and moderate hERG risk, the substantial improvement in BBB and metabolic stability outweigh these drawbacks. Both have poor Caco-2 and solubility, but these can be addressed with formulation strategies. Ligand A's low logP is a more fundamental issue for CNS penetration.

Output:
1
2025-04-17 03:49:30,615 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 drug candidates, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (352.475 Da and 363.868 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (81.08) is better than Ligand B (55.63). Both are below the 90 A^2 threshold desirable for CNS targets, but A is closer to the upper limit.

**logP:** Ligand A (1.294) is within the optimal 1-3 range. Ligand B (3.588) is at the higher end of the optimal range, potentially increasing off-target interactions and decreasing solubility.

**H-Bond Donors/Acceptors:** Ligand A has 2 HBD and 4 HBA, while Ligand B has 1 HBD and 5 HBA. Both are within acceptable limits (<=5 HBD and <=10 HBA).

**QED:** Both ligands have good QED scores (0.755 and 0.901), indicating good drug-like properties.

**DILI:** Ligand A (13.067) has a significantly lower DILI risk than Ligand B (47.305). This is a major advantage for Ligand A.

**BBB:** Ligand B (88.445) has a much better BBB penetration score than Ligand A (66.499). This is a critical factor for a CNS target like DRD2.

**Caco-2 Permeability:** Ligand A (-4.69) has worse Caco-2 permeability than Ligand B (-5.055). Both are quite poor, but B is slightly better.

**Aqueous Solubility:** Ligand A (-2.067) has better aqueous solubility than Ligand B (-4.104).

**hERG:** Both ligands have similar, low hERG inhibition liability (0.3 and 0.337).

**Microsomal Clearance:** Both ligands have similar microsomal clearance (34.733 and 33.779).

**In vitro Half-Life:** Ligand B (22.859) has a significantly longer in vitro half-life than Ligand A (-7.658). This is a substantial advantage for Ligand B.

**P-gp Efflux:** Both ligands have similar P-gp efflux liability (0.052 and 0.557).

**Binding Affinity:** Ligand B (-8.4) has a stronger binding affinity than Ligand A (-7.0). This is a significant advantage for Ligand B, potentially outweighing some ADME concerns.

**Overall Assessment:**

Ligand B excels in BBB penetration and binding affinity, two crucial factors for a CNS GPCR target. Its longer half-life is also beneficial. However, it has a higher DILI risk and a logP value that is slightly concerning. Ligand A has a much lower DILI risk and better solubility, but its BBB penetration is considerably lower, and its binding affinity is weaker.

Given the importance of CNS penetration and strong binding for DRD2, the advantages of Ligand B outweigh its drawbacks. The 1.4 kcal/mol difference in binding affinity is substantial, and the higher BBB score is critical. While the DILI risk is higher, it might be mitigated through structural modifications in further optimization.

Output:
1
2025-04-17 03:49:30,615 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (337.354 Da) is slightly lower, which could be advantageous for permeability.

**TPSA:** Ligand A (50.75) is significantly better than Ligand B (66.56). For a CNS target like DRD2, TPSA should be below 90, and ideally closer to 60. Ligand A is much closer to this ideal.

**logP:** Both ligands have good logP values (A: 3.687, B: 4.235), falling within the optimal 1-3 range. Ligand B is slightly higher, potentially increasing off-target interactions.

**H-Bond Donors/Acceptors:** Ligand A (0 HBD, 4 HBA) is preferable to Ligand B (2 HBD, 3 HBA). Fewer hydrogen bonds generally improve BBB penetration.

**QED:** Both ligands have good QED scores (A: 0.522, B: 0.786), indicating drug-like properties. Ligand B is slightly better here.

**DILI:** Ligand A (62.466) has a higher DILI risk than Ligand B (32.842). This is a significant drawback for Ligand A.

**BBB:** Ligand A (82.474) has a substantially better BBB percentile than Ligand B (64.87). This is *critical* for a CNS target like DRD2.

**Caco-2 Permeability:** Ligand A (-4.844) has a worse Caco-2 permeability than Ligand B (-4.922). Both are poor, but B is slightly better.

**Aqueous Solubility:** Ligand A (-3.409) has better aqueous solubility than Ligand B (-5.138).

**hERG Inhibition:** Both ligands have low hERG inhibition risk (A: 0.872, B: 0.883).

**Microsomal Clearance:** Ligand B (76.145) has lower microsomal clearance than Ligand A (86.93), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand B (-0.86) has a longer in vitro half-life than Ligand A (38.746).

**P-gp Efflux:** Ligand A (0.841) has lower P-gp efflux than Ligand B (0.389), which is favorable for CNS penetration.

**Binding Affinity:** Ligand B (-8.2 kcal/mol) has a significantly stronger binding affinity than Ligand A (-9.2 kcal/mol). A difference of 1.0 kcal/mol is substantial and can often outweigh minor ADME concerns.

**Overall Assessment:**

Ligand A excels in BBB penetration, TPSA, and P-gp efflux, all crucial for CNS GPCR targeting. However, it suffers from a higher DILI risk and worse metabolic stability. Ligand B has a significantly stronger binding affinity, better metabolic stability, lower DILI risk, and a longer half-life. While its BBB penetration is lower, its superior affinity and more favorable ADME profile (excluding Caco-2) make it the more promising candidate. The binding affinity difference is large enough to compensate for the slightly lower BBB.

Output:
1
2025-04-17 03:49:30,615 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (356.5 and 355.5 Da) fall comfortably within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (76.66) is better than Ligand B (53.94). For a CNS target like DRD2, a TPSA below 90 is desirable, and both meet this criterion. Ligand A is slightly higher, but still acceptable.

**3. logP:** Ligand A (2.262) is within the optimal 1-3 range. Ligand B (3.735) is pushing the upper limit, potentially leading to solubility issues or off-target interactions.

**4. H-Bond Donors:** Ligand A (2) and Ligand B (1) are both acceptable, being less than 5.

**5. H-Bond Acceptors:** Ligand A (4) and Ligand B (6) are both acceptable, being less than 10.

**6. QED:** Both ligands have good QED values (0.629 and 0.764, respectively), indicating drug-like properties.

**7. DILI:** Ligand A (16.44) has a significantly lower DILI risk than Ligand B (77.549). This is a major advantage for Ligand A.

**8. BBB:** Ligand A (72.276) is good, but Ligand B (85.149) is excellent, exceeding the >70% threshold for CNS targets. This is a significant advantage for Ligand B.

**9. Caco-2 Permeability:** Ligand A (-4.337) and Ligand B (-5.166) are both negative, which is unusual and suggests poor permeability. However, the scale isn't clearly defined, so it's hard to interpret.

**10. Aqueous Solubility:** Ligand A (-2.022) and Ligand B (-4.249) are both negative, indicating poor solubility.

**11. hERG Inhibition:** Ligand A (0.374) has a lower hERG risk than Ligand B (0.695), which is preferable.

**12. Microsomal Clearance:** Ligand A (35.098) has lower microsomal clearance than Ligand B (78.095), suggesting better metabolic stability.

**13. In vitro Half-Life:** Ligand A (-8.705) has a longer in vitro half-life than Ligand B (22.035), which is desirable.

**14. P-gp Efflux:** Ligand A (0.022) has much lower P-gp efflux liability than Ligand B (0.398), which is very important for CNS penetration.

**15. Binding Affinity:** Both ligands have very similar and strong binding affinities (-7.3 and -8.0 kcal/mol, respectively). Ligand B is slightly better, but the difference is not substantial enough to outweigh other factors.

**Overall Assessment:**

While Ligand B has a superior BBB score and slightly better binding affinity, Ligand A demonstrates a much more favorable safety profile (lower DILI, lower hERG, lower P-gp efflux) and better metabolic stability (lower Cl_mic, longer t1/2). Given the CNS target and the importance of minimizing off-target effects and maximizing brain exposure, Ligand A appears to be the more promising candidate. The slightly lower BBB score of Ligand A is less concerning given its significantly improved ADME properties.

Output:
0
2025-04-17 03:49:30,615 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (354.401 and 367.515 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (78.09) is significantly better than Ligand B (91.22). For CNS targets, we want TPSA <= 90, so Ligand A is preferable.

**3. logP:** Both ligands have similar logP values (1.862 and 1.851), falling within the optimal 1-3 range.

**4. H-Bond Donors:** Both have 2 HBD, which is acceptable.

**5. H-Bond Acceptors:** Ligand A has 3 HBA, while Ligand B has 5. Both are within the acceptable limit of <=10, but Ligand A is slightly better.

**6. QED:** Ligand A (0.766) has a significantly better QED score than Ligand B (0.575), indicating a more drug-like profile.

**7. DILI:** Ligand A (49.011) has a much lower DILI risk than Ligand B (15.936). This is a significant advantage for Ligand A.

**8. BBB:** Ligand A (73.517) has a considerably higher BBB penetration percentile than Ligand B (62.466).  For a CNS target like DRD2, BBB penetration is crucial; Ligand A is much better here.

**9. Caco-2 Permeability:** Both have negative Caco-2 values (-5.063 and -5.017), which is unusual and suggests poor permeability. This is a concern for both, but doesn't differentiate them significantly.

**10. Aqueous Solubility:** Both have negative solubility values (-3.069 and -2.908), suggesting poor aqueous solubility. This is a concern for both, but doesn't differentiate them significantly.

**11. hERG Inhibition:** Both ligands have low hERG inhibition risk (0.473 and 0.631).

**12. Microsomal Clearance:** Ligand A (1.665) has much lower microsomal clearance than Ligand B (68.637), indicating better metabolic stability.

**13. In vitro Half-Life:** Ligand A (-22.488) has a negative half-life, which is not physically possible and likely an error in the data. Ligand B (17.639) has a reasonable half-life. However, the negative value for A is a major red flag.

**14. P-gp Efflux:** Both have very low P-gp efflux liability (0.064 and 0.068).

**15. Binding Affinity:** Ligand A (-8.1 kcal/mol) has a significantly stronger binding affinity than Ligand B (-7.0 kcal/mol). This is a substantial advantage, potentially outweighing some of the ADME concerns.

**Overall Assessment:**

Despite the negative half-life for Ligand A, its superior BBB penetration, lower DILI risk, better QED, and significantly stronger binding affinity make it the more promising candidate. The strong binding affinity is a major factor, and the other advantages, particularly BBB and DILI, are critical for a CNS drug. The negative half-life is concerning, but could be an artifact of the prediction method. Ligand B's higher DILI risk and lower BBB penetration are significant drawbacks.

Output:
1
2025-04-17 03:49:30,616 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (346.431 and 369.571 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (72.65) is significantly better than Ligand B (38.77). For CNS targets, we want TPSA <= 90, and ideally lower. Ligand A is well within this range, while Ligand B is excellent.

**3. logP:** Both ligands have good logP values (2.345 and 3.733), falling within the optimal 1-3 range. Ligand B is slightly higher, which *could* indicate a potential for off-target interactions, but isn't a major concern.

**4. H-Bond Donors:** Ligand A has 1 HBD, and Ligand B has 0. Both are acceptable (<=5).

**5. H-Bond Acceptors:** Ligand A has 7 HBA, and Ligand B has 4. Both are within the acceptable range (<=10).

**6. QED:** Ligand A (0.708) has a better QED score than Ligand B (0.588), indicating a more drug-like profile.

**7. DILI:** Ligand A (38.193) has a slightly higher DILI risk than Ligand B (21.869), but both are below the concerning threshold of 60.

**8. BBB:** Both ligands have excellent BBB penetration (80.962% and 80.613%), exceeding the desirable >70% threshold for CNS targets.

**9. Caco-2:** Both ligands have negative Caco-2 values (-5.073 and -5.102). This is unusual and suggests poor permeability. However, these values are on a scale where negative values are possible, and don't necessarily disqualify the compounds.

**10. Solubility:** Both ligands have very poor aqueous solubility (-2.104 and -3.83). This is a significant drawback.

**11. hERG:** Both ligands have low hERG inhibition risk (0.684 and 0.731).

**12. Cl_mic:** Ligand A (13.018) has a much lower microsomal clearance than Ligand B (79.7), indicating better metabolic stability.

**13. t1/2:** Ligand A (5.276) has a shorter in vitro half-life than Ligand B (18.824). Longer half-life is generally preferred.

**14. Pgp:** Both ligands have low P-gp efflux liability (0.092 and 0.685).

**15. Binding Affinity:** Ligand A (-8.1 kcal/mol) has a significantly stronger binding affinity than Ligand B (-6.9 kcal/mol). This >1.5 kcal/mol difference is substantial and can outweigh some ADME drawbacks.

**Overall Assessment:**

Ligand A is the stronger candidate. While both have poor solubility and Caco-2 permeability, Ligand A's significantly superior binding affinity (-8.1 vs -6.9 kcal/mol) and lower microsomal clearance are decisive advantages. The better QED score also supports its selection. The slightly higher DILI risk is less concerning given the excellent BBB penetration and strong affinity. The longer half-life of Ligand B is a plus, but the difference in affinity is more critical for a GPCR target.

Output:
0
2025-04-17 03:49:30,616 - INFO - Batch 61 complete. Total preferences: 976
2025-04-17 03:49:30,616 - INFO - Processing batch 62/512...
2025-04-17 03:50:14,495 - INFO - Reasoning:

Let's analyze Ligand A and Ligand B for their potential as DRD2 drug candidates, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (405.34 Da) is slightly higher than Ligand B (362.455 Da), but both are acceptable.

**2. TPSA:** Ligand A (58.95) is significantly better than Ligand B (96.6). For CNS targets, we want TPSA <= 90, so Ligand A is much more favorable.

**3. logP:** Ligand A (4.121) is higher than the optimal range (1-3), potentially leading to solubility issues. Ligand B (0.81) is below the optimal range and could have permeability problems. However, for a GPCR, some lipophilicity is needed for membrane interactions, and Ligand A's value isn't drastically high.

**4. H-Bond Donors:** Both ligands have acceptable HBD counts (Ligand A: 2, Ligand B: 1).

**5. H-Bond Acceptors:** Both ligands have acceptable HBA counts (Ligand A: 3, Ligand B: 5).

**6. QED:** Both ligands have good QED values (Ligand A: 0.76, Ligand B: 0.802), indicating good drug-like properties.

**7. DILI:** Ligand A (37.728) has a lower DILI risk than Ligand B (47.964), which is preferable. Both are below the concerning threshold of 60.

**8. BBB:** Ligand A (66.576) has a better BBB percentile than Ligand B (62.699), although both are below the desirable >70 for CNS targets. This is a critical factor for DRD2.

**9. Caco-2:** Ligand A (-4.847) has a very poor Caco-2 permeability, indicating poor intestinal absorption. Ligand B (-5.22) is also poor, but slightly better.

**10. Solubility:** Ligand A (-3.537) has poor aqueous solubility, consistent with its higher logP. Ligand B (-2.12) is also poor, but better than Ligand A.

**11. hERG:** Ligand A (0.819) has a lower hERG risk than Ligand B (0.132), which is preferable.

**12. Cl_mic:** Ligand A (15.895) has a higher microsomal clearance than Ligand B (-8.199), meaning it's less metabolically stable. Ligand B is significantly more stable.

**13. t1/2:** Ligand A (36.647) has a longer in vitro half-life than Ligand B (-10.237), which is a positive attribute.

**14. Pgp:** Ligand A (0.226) has lower P-gp efflux liability than Ligand B (0.061), which is better for CNS exposure.

**15. Binding Affinity:** Ligand A (-8.6 kcal/mol) has a slightly better binding affinity than Ligand B (-7.7 kcal/mol). This 0.9 kcal/mol difference is significant, and can often outweigh some ADME liabilities.

**Overall Assessment:**

Ligand A has a better binding affinity, lower DILI risk, better BBB penetration, and lower Pgp efflux. However, it suffers from poor solubility, poor Caco-2 permeability, and higher metabolic clearance. Ligand B has better metabolic stability and slightly better permeability/solubility, but weaker binding affinity and a higher DILI risk.

Given the GPCR-specific priorities for DRD2 (BBB, logP, Pgp, TPSA, and affinity), the stronger binding affinity and better BBB penetration of Ligand A are crucial. While its ADME properties are not ideal, the binding affinity advantage is substantial. Optimization efforts could focus on improving its solubility and metabolic stability.

Output:
1
2025-04-17 03:50:14,496 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight (MW):** Both ligands (338.411 and 363.439 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (68.44) is significantly better than Ligand B (84.67). For CNS targets, we want TPSA <= 90, and A is comfortably within this range, while B is approaching the upper limit.

**3. logP:** Both ligands have good logP values (1.327 and 2.15), falling within the optimal 1-3 range.

**4. H-Bond Donors (HBD):** Both ligands are acceptable (2 and 1 respectively), being less than 5.

**5. H-Bond Acceptors (HBA):** Both ligands are acceptable (3 and 6 respectively), being less than 10.

**6. QED:** Both ligands have similar, good QED values (0.868 and 0.88), indicating good drug-like properties.

**7. DILI:** Ligand A (44.048) has a slightly better DILI score than Ligand B (66.615). Both are acceptable, but A is preferable.

**8. BBB:** Both ligands have excellent BBB penetration (73.827 and 76.309), exceeding the desirable >70 threshold for CNS targets.

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.901 and -4.905). This is unusual and suggests poor permeability. However, these values are very similar and don't differentiate the two.

**10. Aqueous Solubility:** Both ligands have negative solubility values (-3.141 and -3.46). This is also unusual and suggests poor solubility. Again, the values are similar.

**11. hERG Inhibition:** Ligand A (0.757) has a slightly better hERG profile than Ligand B (0.3). Lower is better, indicating less cardiotoxicity risk.

**12. Microsomal Clearance (Cl_mic):** Ligand A (14.8) has significantly lower microsomal clearance than Ligand B (33.549). Lower clearance is preferred for better metabolic stability.

**13. In vitro Half-Life:** Ligand A (-24.866) has a much longer in vitro half-life than Ligand B (13.83). This is a significant advantage.

**14. P-gp Efflux:** Ligand A (0.074) has significantly lower P-gp efflux liability than Ligand B (0.116). Lower efflux is crucial for CNS exposure.

**15. Binding Affinity:** Ligand B (-7.5) has a significantly stronger binding affinity than Ligand A (-10.2). This is a substantial advantage, exceeding the >1.5 kcal/mol threshold where potency can outweigh other drawbacks.

**Overall Assessment:**

While Ligand A excels in ADME properties (TPSA, DILI, Cl_mic, t1/2, P-gp efflux), Ligand B boasts a considerably stronger binding affinity (-7.5 vs -10.2 kcal/mol). Given that we are targeting a GPCR, and a strong affinity can often compensate for minor ADME issues, Ligand B is the more promising candidate. The difference in binding affinity is substantial enough to outweigh the advantages of Ligand A's better ADME profile.

Output:
1
2025-04-17 03:50:14,496 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B based on the provided guidelines, prioritizing GPCR-specific properties (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (372.868 Da) is slightly higher than Ligand B (345.491 Da), but both are acceptable.

**TPSA:** Ligand A (67.43) is better than Ligand B (73.31). For CNS targets, we want TPSA <= 90, and ideally lower. Both are within range, but A is closer to the optimal value.

**logP:** Ligand A (3.819) is slightly higher than Ligand B (2.334). Both are within the optimal 1-3 range, but A is approaching the upper limit.

**H-Bond Donors/Acceptors:** Ligand A (HBD=2, HBA=3) is preferable to Ligand B (HBD=3, HBA=6). Lower HBD/HBA generally improves permeability.

**QED:** Both ligands have good QED values (A: 0.682, B: 0.735), indicating good drug-like properties.

**DILI:** Ligand A (49.787) has a higher DILI risk than Ligand B (29.857). This is a significant advantage for Ligand B.

**BBB:** Ligand A (80.884) has a better BBB percentile than Ligand B (70.143). This is a crucial factor for a CNS target like DRD2, and favors Ligand A.

**Caco-2 Permeability:** Ligand A (-4.563) has a worse Caco-2 permeability than Ligand B (-5.222). Lower values are less favorable.

**Aqueous Solubility:** Ligand A (-4.753) has worse solubility than Ligand B (-2.228). Solubility is important for formulation, and B is better here.

**hERG:** Both ligands have very low hERG inhibition liability (A: 0.812, B: 0.784), indicating minimal cardiotoxicity risk.

**Microsomal Clearance:** Ligand A (56.31) has higher microsomal clearance than Ligand B (-4.071). Lower clearance is preferred for better metabolic stability, favoring Ligand B.

**In vitro Half-Life:** Ligand A (46.83) has a shorter half-life than Ligand B (65.85). Longer half-life is generally desirable, favoring Ligand B.

**P-gp Efflux:** Ligand A (0.549) has lower P-gp efflux liability than Ligand B (0.022). Lower efflux is preferred for CNS exposure, favoring Ligand A.

**Binding Affinity:** Both ligands have excellent binding affinity (A: -8.1 kcal/mol, B: -8.3 kcal/mol). Ligand B is slightly better, but the difference is small.

**Overall Assessment:**

Ligand A excels in BBB penetration and P-gp efflux, critical for CNS targets. However, it has higher DILI risk, worse solubility, and higher clearance. Ligand B has a better safety profile (lower DILI), better solubility, and improved metabolic stability (lower clearance, longer half-life), but slightly lower BBB penetration.

Considering the GPCR-specific priorities and the relatively small difference in binding affinity, the improved safety and pharmacokinetic properties of Ligand B outweigh the slightly lower BBB value.

Output:
1
2025-04-17 03:50:14,496 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (344.455 and 348.506 Da) fall comfortably within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (58.64) is significantly better than Ligand B (32.34). For a CNS target like DRD2, a TPSA <= 90 is desirable, and Ligand A is much closer to the optimal range for CNS penetration.

**3. logP:** Ligand A (1.283) is within the optimal 1-3 range. Ligand B (4.793) is high, potentially leading to solubility issues and off-target interactions.

**4. H-Bond Donors:** Both ligands have 1 HBD, which is acceptable.

**5. H-Bond Acceptors:** Ligand A has 3 HBA, and Ligand B has 2. Both are within the acceptable limit of <= 10.

**6. QED:** Both ligands have similar QED values (0.782 and 0.801), indicating good drug-like properties.

**7. DILI:** Both ligands have low DILI risk (32.493 and 31.291 percentile), which is positive.

**8. BBB:** Ligand B (92.672) has a significantly higher BBB percentile than Ligand A (78.79). This is a crucial factor for CNS targets, and Ligand B excels here.

**9. Caco-2 Permeability:** Both have negative values, indicating poor permeability. This is unusual and requires further investigation, but the values are similar.

**10. Aqueous Solubility:** Both have negative values, indicating poor solubility. Again, this is unusual and requires further investigation, but the values are similar.

**11. hERG Inhibition:** Ligand A (0.508) has a lower hERG risk than Ligand B (0.962), which is preferable.

**12. Microsomal Clearance:** Ligand A (28.854) has a lower microsomal clearance than Ligand B (48.177), suggesting better metabolic stability.

**13. In vitro Half-Life:** Ligand A (-7.326) has a much longer in vitro half-life than Ligand B (15.1). This is a significant advantage.

**14. P-gp Efflux:** Ligand A (0.157) has lower P-gp efflux liability than Ligand B (0.663), which is favorable for CNS penetration.

**15. Binding Affinity:** Both ligands have very similar and strong binding affinities (-8.4 and -8.5 kcal/mol). The difference is negligible.

**Overall Assessment:**

While Ligand B has a superior BBB percentile, Ligand A is better across several other critical ADME properties, especially TPSA, logP, metabolic stability (Cl_mic and t1/2), and P-gp efflux. The higher logP of Ligand B is a concern, potentially leading to poor solubility and increased off-target effects. The lower TPSA of Ligand A is also beneficial for CNS penetration. Given the importance of ADME properties for CNS drugs, and the relatively similar binding affinities, Ligand A appears to be the more promising candidate.

Output:
0
2025-04-17 03:50:14,496 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (353.5 and 368.5 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (53.09) is significantly better than Ligand B (67.43). For CNS targets, we want TPSA <= 90, and ideally closer to 60. Ligand A is much closer to this ideal.

**3. logP:** Both ligands have acceptable logP values (1.593 and 2.656, respectively), falling within the 1-3 range. Ligand B is slightly higher, which could potentially lead to off-target effects, but isn't a major concern.

**4. H-Bond Donors:** Ligand A has 0 HBD, while Ligand B has 2. Both are within the acceptable limit of <=5.

**5. H-Bond Acceptors:** Both ligands have 4 HBA, well within the acceptable limit of <=10.

**6. QED:** Ligand A (0.728) has a better QED score than Ligand B (0.582), indicating a more drug-like profile.

**7. DILI:** Ligand A (11.2%) has a significantly lower DILI risk than Ligand B (23.9%). This is a substantial advantage.

**8. BBB:** Ligand A (81.6%) has a much better BBB penetration score than Ligand B (71.8%). This is *critical* for a CNS target like DRD2.

**9. Caco-2 Permeability:** Ligand A (-4.326) has a slightly better Caco-2 permeability than Ligand B (-4.977), though both are negative values which are difficult to interpret without knowing the scale.

**10. Aqueous Solubility:** Ligand A (-0.683) has better aqueous solubility than Ligand B (-3.174). This is important for formulation and bioavailability.

**11. hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.414 and 0.194, respectively).

**12. Microsomal Clearance:** Ligand B (76.35) has a higher microsomal clearance than Ligand A (33.53), indicating lower metabolic stability.

**13. In vitro Half-Life:** Ligand A (-17.99) has a better in vitro half-life than Ligand B (12.05).

**14. P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.052 and 0.106, respectively).

**15. Binding Affinity:** Both ligands have the same binding affinity (-7.5 kcal/mol), which is excellent.

**Overall Assessment:**

Ligand A is clearly superior. It has better TPSA, QED, DILI risk, BBB penetration, solubility, metabolic stability, and half-life. While both ligands have good logP and binding affinity, the ADME properties of Ligand A are significantly more favorable, especially its superior BBB penetration, which is paramount for a DRD2 ligand targeting CNS disorders.

Output:
1
2025-04-17 03:50:14,496 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (347.455 and 365.455 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (75.63) is significantly better than Ligand B (90.77). For CNS targets, we want TPSA <= 90, so Ligand A is preferable.

**3. logP:** Ligand A (3.27) is within the optimal 1-3 range, while Ligand B (0.661) is below 1, which could hinder permeation. This is a significant advantage for Ligand A.

**4. H-Bond Donors:** Both have acceptable HBD counts (2 and 1 respectively), well below the threshold of 5.

**5. H-Bond Acceptors:** Both have acceptable HBA counts (3 and 5 respectively), well below the threshold of 10.

**6. QED:** Both ligands have good QED scores (0.828 and 0.849), indicating good drug-like properties.

**7. DILI:** Ligand A (52.074) has a slightly higher DILI risk than Ligand B (38.503), but both are below the concerning threshold of 60.

**8. BBB:** Ligand B (53.47) has a better BBB penetration percentile than Ligand A (46.762), but both are below the desirable >70 for CNS targets.

**9. Caco-2 Permeability:** Ligand A (-4.635) has a much worse Caco-2 permeability than Ligand B (-5.113). Lower values are worse.

**10. Aqueous Solubility:** Ligand A (-3.346) has slightly better aqueous solubility than Ligand B (-1.667).

**11. hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.052 and 0.173).

**12. Microsomal Clearance:** Ligand B (-18.472) has significantly lower microsomal clearance than Ligand A (35.811), indicating better metabolic stability.

**13. In vitro Half-Life:** Ligand B (38.654) has a much longer in vitro half-life than Ligand A (-22.921).

**14. P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.018 and 0.024).

**15. Binding Affinity:** Both ligands have excellent binding affinities (-8.7 and -8.8 kcal/mol), with a negligible difference.

**Overall Assessment:**

While Ligand B has better BBB penetration and metabolic stability, Ligand A is superior in terms of logP and TPSA, both critical for CNS GPCR targets. The significantly better logP and TPSA of Ligand A are likely to outweigh the slightly lower BBB and higher clearance. The Caco-2 permeability is worse for Ligand A, but the primary route of exposure is expected to be CNS, so this is less critical. The binding affinities are essentially identical.

Output:
1
2025-04-17 03:50:14,496 - INFO - Reasoning:

Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (349.475 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (78.51) is higher than Ligand B (63.69). For CNS targets, we prefer TPSA <= 90, so both are acceptable, but B is better.

**3. logP:** Both ligands have good logP values (A: 1.755, B: 2.467), falling within the optimal 1-3 range.

**4. H-Bond Donors:** Ligand A (2) is slightly higher than Ligand B (1), both are within the acceptable limit of <=5.

**5. H-Bond Acceptors:** Ligand A (3) is lower than Ligand B (5), both are within the acceptable limit of <=10.

**6. QED:** Both ligands have good QED values (A: 0.717, B: 0.781), indicating good drug-like properties.

**7. DILI:** Ligand B (23.575) has a significantly lower DILI risk than Ligand A (32.299). This is a substantial advantage for B.

**8. BBB:** Ligand B (70.299) has a much better BBB penetration percentile than Ligand A (55.487).  This is *critical* for a CNS target like DRD2.

**9. Caco-2 Permeability:** Ligand A (-4.844) has better Caco-2 permeability than Ligand B (-4.255).

**10. Aqueous Solubility:** Both ligands have similar poor aqueous solubility (-2.393 and -2.213). This isn't ideal, but not a dealbreaker if other properties are strong.

**11. hERG Inhibition:** Both ligands have low hERG inhibition risk (A: 0.089, B: 0.176).

**12. Microsomal Clearance:** Ligand A (32.449) has lower microsomal clearance (better metabolic stability) than Ligand B (79.543).

**13. In vitro Half-Life:** Ligand B (-5.767) has a longer in vitro half-life than Ligand A (-2.615).

**14. P-gp Efflux:** Both ligands have very low P-gp efflux liability (A: 0.028, B: 0.147).

**15. Binding Affinity:** Ligand A (-8.1 kcal/mol) has a slightly better binding affinity than Ligand B (-7.0 kcal/mol). However, the difference is less than 1.5 kcal/mol, and can be overcome by better ADME properties.

**Overall Assessment:**

Ligand B is the superior candidate. While Ligand A has slightly better affinity and Caco-2 permeability, Ligand B excels in critical areas for a CNS-targeting GPCR: significantly lower DILI risk, *much* better BBB penetration, and a longer half-life. The TPSA is also more favorable in Ligand B. The difference in affinity is not substantial enough to outweigh these advantages.



Output:
1
2025-04-17 03:50:14,497 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (348.531 and 340.431 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (58.2) is significantly better than Ligand B (106.75). For CNS targets, TPSA should be <= 90, and A comfortably meets this, while B is pushing the limit.

**logP:** Both ligands have good logP values (3.674 and 2.705), falling within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A (HBD=2, HBA=2) is preferable to Ligand B (HBD=3, HBA=7). Lower HBA is generally preferred for better membrane permeability.

**QED:** Both ligands have similar QED scores (0.625 and 0.602), indicating good drug-likeness.

**DILI:** Ligand A (13.61) has a much lower DILI risk than Ligand B (55.176), indicating a safer profile.

**BBB:** Ligand A (67.623) and Ligand B (71.733) both have reasonably good BBB penetration, but B is slightly better. However, the TPSA of B is concerning.

**Caco-2 Permeability:** Ligand A (-4.666) has a worse Caco-2 permeability than Ligand B (-5.243). Lower values indicate lower permeability.

**Aqueous Solubility:** Ligand A (-4.01) has better aqueous solubility than Ligand B (-3.098).

**hERG Inhibition:** Ligand A (0.469) shows a lower hERG inhibition liability than Ligand B (0.939), suggesting a lower risk of cardiotoxicity.

**Microsomal Clearance:** Ligand A (68.839) has a higher microsomal clearance than Ligand B (38.309), meaning it's metabolized faster and has lower metabolic stability.

**In vitro Half-Life:** Ligand A (-7.184) has a longer in vitro half-life than Ligand B (53.672).

**P-gp Efflux:** Ligand A (0.271) has lower P-gp efflux liability than Ligand B (0.138), which is desirable for CNS penetration.

**Binding Affinity:** Ligand B (-7.3) has a slightly better binding affinity than Ligand A (-8.7). However, the difference is not substantial enough to outweigh the other significant ADME advantages of Ligand A.

**Overall Assessment:**

Ligand A is the stronger candidate. While Ligand B has slightly better binding affinity and BBB penetration, Ligand A excels in crucial areas like TPSA, DILI risk, hERG inhibition, and P-gp efflux. The lower TPSA of Ligand A is particularly important for CNS penetration. The better solubility and longer half-life are also beneficial. The higher clearance of A is a concern, but the other advantages are more impactful for a GPCR target.

Output:
1
2025-04-17 03:50:14,497 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (351.491 and 347.419 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (69.72) is excellent, well below the 90 A^2 threshold for CNS targets. Ligand B (102.05) is still reasonable, but less optimal, exceeding the preferred threshold.

**logP:** Both ligands have good logP values (1.787 and 1.399), falling within the 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A (HBD=1, HBA=3) is better than Ligand B (HBD=2, HBA=6) in terms of balancing solubility and permeability.

**QED:** Both ligands have good QED scores (0.678 and 0.751), indicating drug-like properties.

**DILI:** Ligand A (11.128) has a significantly lower DILI risk than Ligand B (51.687), which is a substantial advantage.

**BBB:** This is critical for a CNS target. Ligand A has a very good BBB penetration percentile (81.892), exceeding the desirable >70 threshold. Ligand B (46.568) is considerably lower, raising concerns about CNS exposure.

**Caco-2 Permeability:** Ligand A (-4.886) and Ligand B (-5.423) both have negative Caco-2 values, which is unusual and suggests poor permeability. However, the scale isn't clearly defined, so this is difficult to interpret.

**Aqueous Solubility:** Both ligands have very poor aqueous solubility (-2.118 and -1.451), which could pose formulation challenges.

**hERG:** Both ligands have low hERG inhibition liability (0.495 and 0.402), which is positive.

**Microsomal Clearance:** Ligand A (26.756) has a higher microsomal clearance than Ligand B (14.059), indicating lower metabolic stability.

**In vitro Half-Life:** Ligand B (13.116) has a longer in vitro half-life than Ligand A (-2.827), which is a positive.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.079 and 0.083), which is favorable for CNS penetration.

**Binding Affinity:** Ligand B (-8.3 kcal/mol) has a slightly better binding affinity than Ligand A (-7.6 kcal/mol). However, the difference is only 0.7 kcal/mol, which is not a huge advantage considering the other factors.

**Overall Assessment:**

Ligand A is the stronger candidate. While Ligand B has slightly better affinity and half-life, Ligand A excels in crucial areas for a CNS-targeting GPCR: significantly lower DILI risk, much better BBB penetration, and a more favorable TPSA. The solubility issues are a concern for both, but can be addressed with formulation strategies. The higher clearance of Ligand A is a drawback, but the substantial advantages in safety and CNS penetration outweigh this.

Output:
1
2025-04-17 03:50:14,497 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight (MW):** Both ligands (348.447 and 352.337 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (85.25) is better than Ligand B (74.45). Both are below the 90 A^2 threshold for CNS targets, which is excellent.

**3. logP:** Ligand A (1.48) is within the optimal range (1-3), while Ligand B (3.231) is at the higher end. This suggests Ligand A might have better solubility, while Ligand B might have better membrane permeability.

**4. H-Bond Donors (HBD):** Both ligands have acceptable HBD counts (2 and 0, respectively), well below the limit of 5.

**5. H-Bond Acceptors (HBA):** Both ligands have acceptable HBA counts (5 and 6, respectively), well below the limit of 10.

**6. QED:** Both ligands have similar and good QED values (0.662 and 0.679), indicating good drug-like properties.

**7. DILI:** Ligand A (35.479) has a significantly lower DILI risk than Ligand B (63.28). This is a major advantage for Ligand A.

**8. BBB:** Ligand B (90.772) has a substantially higher BBB penetration percentile than Ligand A (71.811). Given DRD2 is a CNS target, this is a crucial factor favoring Ligand B.

**9. Caco-2 Permeability:** Ligand A (-4.743) has a lower Caco-2 permeability than Ligand B (-4.33). This suggests Ligand B may have better intestinal absorption.

**10. Aqueous Solubility:** Ligand A (-1.852) has better aqueous solubility than Ligand B (-4.115).

**11. hERG Inhibition:** Both ligands have low hERG inhibition risk (0.226 and 0.254).

**12. Microsomal Clearance:** Ligand A (31.15) has a lower microsomal clearance than Ligand B (65.307), indicating better metabolic stability.

**13. In vitro Half-Life:** Ligand A (29.318) has a longer in vitro half-life than Ligand B (7). This is a significant advantage for Ligand A.

**14. P-gp Efflux:** Ligand A (0.029) has a much lower P-gp efflux liability than Ligand B (0.238). This is crucial for CNS penetration and oral bioavailability, favoring Ligand A.

**15. Binding Affinity:** Ligand B (-8.9 kcal/mol) has a significantly stronger binding affinity than Ligand A (-6.7 kcal/mol). This is a substantial advantage for Ligand B, potentially outweighing some ADME drawbacks.

**Overall Assessment:**

Ligand B excels in binding affinity and BBB penetration, which are critical for a CNS-targeting GPCR like DRD2. However, it suffers from higher DILI risk, higher P-gp efflux, faster clearance, and shorter half-life. Ligand A has a better safety profile (lower DILI), better metabolic stability (lower Cl_mic, longer t1/2), and lower P-gp efflux, but its affinity is weaker and BBB penetration is lower.

The difference in binding affinity (-8.9 vs -6.7 kcal/mol) is substantial (2.2 kcal/mol), and is likely to be the dominant factor. While Ligand A has a better ADME profile, a strong affinity is often prioritized, especially in early-stage drug discovery. The improved BBB of Ligand B also supports its potential.

Output:
1
2025-04-17 03:50:14,497 - INFO - Reasoning:

Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (346.471 and 365.905 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (67.43) is better than Ligand B (47.79) as it is closer to the ideal range for CNS targets (<=90). Ligand B is quite low, which *could* indicate reduced hydrogen bonding and potentially lower specificity.

**3. logP:** Ligand A (1.864) is optimal (1-3), while Ligand B (4.621) is higher, potentially leading to solubility issues and off-target interactions.

**4. H-Bond Donors:** Ligand A (2) is acceptable, and Ligand B (1) is also good.

**5. H-Bond Acceptors:** Ligand A (3) is acceptable, and Ligand B (5) is also within the reasonable limit of 10.

**6. QED:** Both ligands have good QED scores (0.546 and 0.803), indicating drug-like properties. Ligand B is slightly better.

**7. DILI:** Both ligands have relatively low DILI risk (12.485 and 53.354), with Ligand A being preferable.

**8. BBB:** Ligand B (77.898) has a significantly better BBB penetration score than Ligand A (53.703). This is a crucial advantage for a CNS target like DRD2.

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 values, which is unusual and suggests poor permeability. However, these values are on a different scale and hard to interpret directly.

**10. Aqueous Solubility:** Both ligands have negative solubility values, suggesting poor aqueous solubility.

**11. hERG Inhibition:** Ligand A (0.336) has a much lower hERG inhibition risk than Ligand B (0.91). This is a significant safety advantage.

**12. Microsomal Clearance:** Ligand A (10.277) has a lower microsomal clearance than Ligand B (43.291), indicating better metabolic stability.

**13. In vitro Half-Life:** Ligand B (90.867) has a significantly longer in vitro half-life than Ligand A (22.101). This is a desirable property.

**14. P-gp Efflux:** Ligand A (0.061) has a much lower P-gp efflux liability than Ligand B (0.699), which is beneficial for CNS exposure.

**15. Binding Affinity:** Ligand B (-7.6) has a slightly better binding affinity than Ligand A (-7.3), but the difference is relatively small (0.3 kcal/mol).

**Overall Assessment:**

Ligand B excels in BBB penetration and in vitro half-life, and has slightly better binding affinity and QED. However, it suffers from higher logP, higher hERG risk, higher P-gp efflux, and higher microsomal clearance. Ligand A has a better safety profile (lower hERG, DILI, and P-gp efflux), better metabolic stability, and a more optimal logP. The improved BBB of Ligand B is a significant advantage, but the other drawbacks are concerning. Given the relatively small difference in binding affinity, the better ADME/Tox profile of Ligand A makes it the more promising candidate.

Output:
0
2025-04-17 03:50:14,497 - INFO - Reasoning:

Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (368.455 and 354.451 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (96.69) is slightly above the optimal <90 for CNS targets, while Ligand B (90.98) is closer to the threshold. This gives a slight edge to Ligand B.

**3. logP:** Ligand A (1.134) is within the optimal 1-3 range. Ligand B (-0.659) is slightly below 1, which *could* indicate permeability issues, but isn't a hard disqualifier.

**4. H-Bond Donors:** Ligand A (1) is good. Ligand B (2) is acceptable, but slightly higher.

**5. H-Bond Acceptors:** Both ligands have 5 HBA, which is within the acceptable limit of <=10.

**6. QED:** Ligand A (0.863) has a significantly better QED score than Ligand B (0.565), indicating a more drug-like profile.

**7. DILI:** Ligand A (63.862) has a higher DILI risk than Ligand B (9.616). This is a significant negative for Ligand A.

**8. BBB:** Both ligands have similar BBB penetration (Ligand A: 61.225, Ligand B: 61.07). Both are acceptable, but not stellar.

**9. Caco-2:** Ligand A (-4.991) has a very poor Caco-2 permeability, indicating poor absorption. Ligand B (-5.388) is also poor, but slightly better.

**10. Solubility:** Ligand A (-1.602) has poor solubility. Ligand B (-0.134) is slightly better.

**11. hERG:** Both ligands have very low hERG inhibition risk (Ligand A: 0.153, Ligand B: 0.107).

**12. Cl_mic:** Ligand A (5.786) has a lower (better) microsomal clearance than Ligand B (7.342), suggesting better metabolic stability.

**13. t1/2:** Ligand A (43.558) has a significantly longer in vitro half-life than Ligand B (-12.969). This is a major advantage for Ligand A.

**14. Pgp:** Both ligands have very low P-gp efflux liability (Ligand A: 0.076, Ligand B: 0.003). Ligand B is slightly lower.

**15. Binding Affinity:** Ligand A (-8.4) has a *much* stronger binding affinity than Ligand B (-0). This is a substantial advantage that can potentially outweigh some of its ADME liabilities.

**Overall Assessment:**

Ligand A has a significantly better binding affinity and a longer half-life. However, it suffers from poor Caco-2 permeability, solubility, and a higher DILI risk. Ligand B has better TPSA, DILI, and slightly better Caco-2 and solubility, but its binding affinity is very weak.

Given the importance of binding affinity for GPCRs, and the fact that the affinity difference is so large (8.4 vs 0 kcal/mol), I believe Ligand A is the more promising candidate *despite* its ADME liabilities. The strong binding could potentially be optimized through further structural modifications, and the ADME issues might be mitigated with appropriate formulation strategies. The very weak binding of Ligand B is a more fundamental issue that would be harder to overcome.

Output:
1
2025-04-17 03:50:14,497 - INFO - Reasoning:

Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (345.447 and 342.443 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (70.47) is significantly better than Ligand B (88.32). For CNS targets, we want TPSA <= 90, and A is closer to the ideal <=60. B is pushing the upper limit.

**3. logP:** Ligand A (0.939) is slightly lower than optimal (1-3), but still acceptable. Ligand B (2.131) is within the optimal range.

**4. H-Bond Donors:** Ligand A (1) and Ligand B (2) are both acceptable (<=5).

**5. H-Bond Acceptors:** Ligand A (5) and Ligand B (4) are both acceptable (<=10).

**6. QED:** Both ligands have good QED scores (0.833 and 0.877), indicating good drug-like properties.

**7. DILI:** Ligand A (16.285) has a much lower DILI risk than Ligand B (48.895). This is a significant advantage for A.

**8. BBB:** Ligand A (91.043) has a considerably higher BBB penetration percentile than Ligand B (81.621). This is crucial for a CNS target like DRD2.

**9. Caco-2:** Both have negative values, which is unusual. Assuming these are logP values, they are both poor.

**10. Solubility:** Both have negative values, which is unusual.

**11. hERG:** Both ligands have very low hERG inhibition risk (0.549 and 0.565).

**12. Cl_mic:** Both ligands have similar microsomal clearance values (22.882 and 23.759 mL/min/kg), suggesting comparable metabolic stability.

**13. t1/2:** Ligand A (17.193 hours) has a longer in vitro half-life than Ligand B (-25.77 hours). The negative value for B is concerning and likely an error.

**14. Pgp:** Both ligands have low P-gp efflux liability (0.08 and 0.052).

**15. Binding Affinity:** Ligand B (-8.4 kcal/mol) has a slightly better binding affinity than Ligand A (-7.8 kcal/mol). However, the difference is less than 1.5 kcal/mol, meaning it doesn't automatically outweigh other factors.

**Overall Assessment:**

Ligand A is the stronger candidate. While Ligand B has slightly better binding affinity, Ligand A excels in crucial areas for CNS drug development: TPSA, BBB penetration, and DILI risk. The longer half-life and lower DILI risk are also significant advantages. The slightly lower logP of A is not a major concern. The negative values for Caco-2 and Solubility are concerning for both, but the other advantages of A make it the better choice.

Output:
1
2025-04-17 03:50:14,498 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (350.419 and 345.407 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (107.61) is slightly above the optimal <90 for CNS targets, but still reasonable. Ligand B (97.94) is better, falling comfortably under 100.

**3. logP:** Ligand A (0.13) is quite low, potentially hindering membrane permeability. Ligand B (0.089) is similarly low, presenting the same concern. Both are below the optimal 1-3 range.

**4. H-Bond Donors:** Ligand A (3) is acceptable. Ligand B (1) is even better.

**5. H-Bond Acceptors:** Ligand A (4) is acceptable. Ligand B (7) is also within the acceptable range of <=10.

**6. QED:** Both ligands have good QED scores (0.514 and 0.767, respectively), indicating drug-likeness. Ligand B is slightly better.

**7. DILI:** Ligand A (36.293) has a lower DILI risk than Ligand B (53.47), both being under the 60 threshold.

**8. BBB:** This is crucial for a CNS target. Ligand A shows a much better BBB penetration (78.868%) than Ligand B (43.583%).

**9. Caco-2:** Both have negative Caco-2 values, which is unusual and suggests poor permeability.

**10. Solubility:** Both ligands have negative solubility values, which is also unusual and suggests poor solubility.

**11. hERG:** Both ligands have very low hERG inhibition risk (0.106 and 0.03, respectively).

**12. Cl_mic:** Ligand A (-8.258) has a significantly *lower* (better) microsomal clearance than Ligand B (-11.556), indicating greater metabolic stability.

**13. t1/2:** Ligand B (26.275 hours) has a much longer in vitro half-life than Ligand A (1.983 hours).

**14. Pgp:** Both ligands have very low P-gp efflux liability (0.014 and 0.007, respectively).

**15. Binding Affinity:** Ligand A (-8.3 kcal/mol) has a slightly better binding affinity than Ligand B (-7.8 kcal/mol). While the difference is less than the desired 1.5 kcal/mol, it's still a factor.

**Overall Assessment:**

Despite the low logP and unusual Caco-2/Solubility values for both, Ligand A is the more promising candidate. Its significantly better BBB penetration (78.87% vs 43.58%), combined with a slightly stronger binding affinity and better metabolic stability (lower Cl_mic), outweigh the longer half-life of Ligand B. The low logP is a concern for both, but could potentially be addressed through structural modifications. The negative solubility and Caco-2 values are concerning and would require further investigation, but the other factors lean towards A being the better starting point.

Output:
0
2025-04-17 03:50:14,498 - INFO - Reasoning:

Let's analyze Ligand A and Ligand B for their potential as DRD2 drug candidates, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (360.431 and 364.471 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (61.83) is significantly better than Ligand B (97.27). For CNS targets, TPSA < 90 is preferred, and A is comfortably within this range, while B is approaching the upper limit.

**3. logP:** Ligand A (3.163) is optimal (1-3), while Ligand B (1.748) is at the lower end, potentially hindering permeability.

**4. H-Bond Donors:** Both have acceptable HBD counts (0 for A, 1 for B), well below the limit of 5.

**5. H-Bond Acceptors:** Both ligands have 5 HBAs, which is within the acceptable limit of 10.

**6. QED:** Both ligands have good QED scores (0.767 and 0.88), indicating drug-like properties.

**7. DILI:** Ligand A (58.705) has a slightly higher DILI risk than Ligand B (46.917), but both are below the concerning threshold of 60.

**8. BBB:** This is a critical parameter for CNS targets. Ligand A (83.443) has a significantly better BBB percentile than Ligand B (45.366). A value > 70 is desirable, and A is closer to this mark.

**9. Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and difficult to interpret without more context. However, the magnitude is similar.

**10. Aqueous Solubility:** Both have negative solubility values, again unusual. The magnitude of A (-4.242) is slightly less negative than B (-2.6), suggesting potentially better solubility.

**11. hERG Inhibition:** Both ligands show low hERG inhibition risk (0.428 and 0.331).

**12. Microsomal Clearance:** Ligand B (-20.871) exhibits significantly lower (better) microsomal clearance than Ligand A (27.461), indicating greater metabolic stability.

**13. In vitro Half-Life:** Ligand B (10.028 hours) has a longer half-life than Ligand A (48.731 hours).

**14. P-gp Efflux:** Ligand A (0.335) has lower P-gp efflux liability than Ligand B (0.069), which is favorable for CNS penetration.

**15. Binding Affinity:** Ligand A (-8.7 kcal/mol) has a stronger binding affinity than Ligand B (-7.2 kcal/mol). The difference of 1.5 kcal/mol is substantial and can outweigh some ADME drawbacks.

**Overall Assessment:**

Considering the GPCR-specific priorities, Ligand A is the more promising candidate. Its superior BBB penetration, better TPSA, optimal logP, and significantly stronger binding affinity outweigh its slightly higher DILI risk and higher microsomal clearance. The lower P-gp efflux is also a significant advantage for CNS exposure. While Ligand B has better metabolic stability and a slightly lower DILI risk, its poor BBB penetration and weaker affinity are major drawbacks for a CNS-targeted drug.

Output:
1
2025-04-17 03:50:14,498 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight (MW):** Both ligands (352.519 and 343.471 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (67.43) is slightly higher than Ligand B (62.3). Both are below the 90 A^2 threshold desirable for CNS targets, which is good.

**3. logP:** Both ligands have excellent logP values (3.171 and 3.078) falling within the optimal 1-3 range.

**4. H-Bond Donors (HBD):** Ligand A has 2 HBDs, and Ligand B has 1. Both are within the acceptable limit of <=5.

**5. H-Bond Acceptors (HBA):** Both ligands have 3 HBAs, well within the acceptable limit of <=10.

**6. QED:** Both ligands have good QED scores (0.626 and 0.894), indicating good drug-like properties. Ligand B is slightly better.

**7. DILI:** Ligand A (16.169) has a significantly lower DILI risk than Ligand B (33.695). This is a substantial advantage for Ligand A.

**8. BBB:** Both ligands have excellent BBB penetration (72.586 and 74.952), exceeding the >70% threshold for CNS targets. Ligand B is marginally better.

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.504 and -4.556). These values are unusual and suggest poor permeability. However, these are likely reported as logP values and are negative, indicating very low permeability.

**10. Aqueous Solubility:** Both ligands have negative solubility values (-2.996 and -3.7). These are also unusual and indicate very poor solubility.

**11. hERG Inhibition:** Both ligands have low hERG inhibition risk (0.554 and 0.225). Ligand B is slightly better here.

**12. Microsomal Clearance (Cl_mic):** Ligand A (41.151) has lower microsomal clearance than Ligand B (54.232), suggesting better metabolic stability.

**13. In vitro Half-Life:** Ligand A (-5.42) has a more negative half-life value than Ligand B (0.406). This is unusual and suggests a shorter half-life for Ligand A.

**14. P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.16 and 0.075). Ligand B is slightly better.

**15. Binding Affinity:** Ligand B (-8.2 kcal/mol) has a slightly stronger binding affinity than Ligand A (-7.9 kcal/mol). This is a 0.3 kcal/mol difference, which is notable.

**Overall Assessment:**

While Ligand B has a slightly better binding affinity and BBB penetration, Ligand A has a significantly lower DILI risk and better metabolic stability (lower Cl_mic). The poor Caco-2 and solubility for both ligands are concerning. However, for a CNS target, BBB penetration is paramount, and both ligands meet this criterion. The lower DILI risk of Ligand A is a significant advantage, as liver toxicity is a common issue in drug development. The slightly stronger binding of Ligand B could be overcome with further optimization.

Output:
1
2025-04-17 03:50:14,498 - INFO - Batch 62 complete. Total preferences: 992
2025-04-17 03:50:14,498 - INFO - Processing batch 63/512...
2025-04-17 03:50:56,930 - INFO - Reasoning:

Let's analyze Ligand A and Ligand B based on the provided guidelines, prioritizing GPCR-specific properties (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (352.362 and 363.933 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (104.73) is better than Ligand B (41.29). For CNS targets, TPSA should be <= 90, and Ligand B is significantly better in this regard.

**logP:** Both ligands have acceptable logP values (1.468 and 3.965), falling within the 1-3 range. Ligand B is closer to the upper limit, which could potentially lead to off-target effects, but is still within acceptable bounds.

**H-Bond Donors/Acceptors:** Ligand A has 3 HBD and 4 HBA, while Ligand B has 1 HBD and 4 HBA. Both are within the recommended limits.

**QED:** Both ligands have good QED scores (0.553 and 0.733), indicating good drug-like properties.

**DILI:** Ligand A has a DILI risk of 57.348%, considered moderate. Ligand B has a very low DILI risk of 8.104%, which is a significant advantage.

**BBB:** Ligand B (74.952%) is significantly better than Ligand A (60.14%) in terms of BBB penetration, a critical factor for CNS targets like DRD2.

**Caco-2 Permeability:** Ligand A (-5.045) has poor Caco-2 permeability. Ligand B (-4.89) is also poor, but slightly better than A.

**Aqueous Solubility:** Both ligands have poor aqueous solubility (-2.29 and -3.901).

**hERG Inhibition:** Ligand A (0.08) has a very low hERG inhibition risk, while Ligand B (0.947) has a moderate risk. This is a significant advantage for Ligand A.

**Microsomal Clearance:** Ligand B (51.71) has a lower microsomal clearance than Ligand A (15.406), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand B (97.181) has a much longer in vitro half-life than Ligand A (-29.74), indicating better stability.

**P-gp Efflux:** Ligand A (0.014) has very low P-gp efflux, which is favorable for CNS penetration. Ligand B (0.759) has moderate P-gp efflux.

**Binding Affinity:** Ligand B (-7.1 kcal/mol) has a slightly better binding affinity than Ligand A (-8.1 kcal/mol). While A has a better affinity, the difference is not substantial enough to outweigh the other significant advantages of Ligand B.

**Overall Assessment:**

Ligand B is the more promising candidate. While Ligand A has a slightly better binding affinity and lower hERG risk, Ligand B excels in crucial areas for a CNS-targeting GPCR drug: significantly better BBB penetration, lower DILI risk, better metabolic stability (lower Cl_mic and longer t1/2), and acceptable logP and TPSA. The moderate P-gp efflux is a minor concern that could be addressed with further optimization. The poor solubility and Caco-2 permeability are drawbacks for both, but are less critical for a CNS target where direct absorption isn't the primary route of entry.



Output:
1
2025-04-17 03:50:56,930 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (347.375 and 344.459 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (133.14) is borderline for CNS penetration, slightly above the preferred <90, but acceptable. Ligand B (69.04) is excellent, well below 90, suggesting better CNS penetration potential.

**logP:** Ligand A (0.753) is a bit low, potentially hindering permeability. Ligand B (3.355) is within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A has 4 HBD and 6 HBA, which are acceptable. Ligand B has 1 HBD and 5 HBA, also acceptable.

**QED:** Both ligands have good QED scores (0.609 and 0.836), indicating drug-like properties.

**DILI:** Ligand A (71.307) has a higher DILI risk than Ligand B (64.444), though both are reasonably acceptable.

**BBB:** Ligand A (40.597) has a low BBB percentile, which is a significant drawback for a CNS target. Ligand B (38.542) is also low, but slightly better than A. Both are far from the desired >70.

**Caco-2 Permeability:** Ligand A (-5.61) and Ligand B (-4.666) both have negative Caco-2 values, which is unusual and suggests poor permeability.

**Aqueous Solubility:** Both ligands have very poor aqueous solubility (-2.58 and -4.554). This is a major concern for formulation and bioavailability.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.143 and 0.316).

**Microsomal Clearance:** Ligand A (11.883) has lower microsomal clearance than Ligand B (81.558), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (-16.28) has a very short in vitro half-life, while Ligand B (-4.11) is better, but still not ideal.

**P-gp Efflux:** Both ligands show low P-gp efflux liability (0.036 and 0.21).

**Binding Affinity:** Ligand B (-9.0) has significantly stronger binding affinity than Ligand A (-8.2). This >1.5 kcal/mol difference is substantial and can outweigh some ADME drawbacks.

**Overall Assessment:**

While both ligands have issues (poor solubility, permeability), Ligand B is the more promising candidate. Its superior binding affinity, better logP, lower DILI risk, and slightly improved BBB penetration outweigh the slightly higher clearance. The biggest concern for both is the poor solubility and permeability, but the strong binding affinity of Ligand B makes it more likely to achieve sufficient target engagement *in vivo* despite these limitations. Ligand A's very low BBB penetration is a major disqualifier.

Output:
1
2025-04-17 03:50:56,930 - INFO - Reasoning:

Let's analyze Ligand A and Ligand B for their potential as DRD2 drug candidates, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (385.335 and 366.458 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (49.41) is excellent, well below the 90 A^2 threshold for CNS targets. Ligand B (66.48) is still reasonable but less optimal, approaching the 140 A^2 limit for oral absorption.

**3. logP:** Ligand A (3.997) is at the upper end of the optimal range (1-3), while Ligand B (1.916) is at the lower end. While both are within range, higher logP can sometimes be beneficial for BBB penetration, but needs to be balanced with solubility.

**4. H-Bond Donors:** Both ligands have 1 HBD, which is within the acceptable limit of <=5.

**5. H-Bond Acceptors:** Ligand A has 2 HBA, and Ligand B has 3 HBA, both are within the acceptable limit of <=10.

**6. QED:** Both ligands have good QED scores (0.779 and 0.81), indicating drug-like properties.

**7. DILI:** Ligand A (39.977) has a slightly better DILI score than Ligand B (55.176), indicating a lower risk of liver injury. Both are below the concerning 60 threshold.

**8. BBB:** Both ligands show good BBB penetration (Ligand A: 71.307, Ligand B: 79.217). Ligand B is slightly better, exceeding 70%. This is crucial for a CNS target like DRD2.

**9. Caco-2:** Both have negative Caco-2 values, which is unusual. Assuming these are percentile scores, lower values indicate poor permeability. Ligand A (-4.633) is slightly better than Ligand B (-4.895), but both are concerning.

**10. Solubility:** Both ligands have negative solubility values, which is also unusual. Assuming these are percentile scores, lower values indicate poor solubility. Ligand A (-4.572) is slightly better than Ligand B (-3.645), but both are concerning.

**11. hERG:** Both ligands have low hERG inhibition risk (0.555 and 0.65).

**12. Cl_mic:** Ligand A (62.28) has lower microsomal clearance than Ligand B (65.379), suggesting better metabolic stability.

**13. t1/2:** Ligand B (-37.622) has a significantly *longer* in vitro half-life than Ligand A (25.895). This is a major advantage.

**14. Pgp:** Both ligands have low P-gp efflux liability (0.23 and 0.255).

**15. Binding Affinity:** Ligand B (-9.9 kcal/mol) has a *significantly* stronger binding affinity than Ligand A (-7.8 kcal/mol). This difference of 2.1 kcal/mol is substantial and can outweigh some of the ADME drawbacks.

**Overall Assessment:**

While Ligand A has a slightly better TPSA and DILI score, Ligand B is superior due to its significantly stronger binding affinity (-9.9 vs -7.8 kcal/mol) and longer half-life. The slightly better BBB penetration of Ligand B is also a plus. The poor Caco-2 and solubility values are concerning for both, but the strong affinity of Ligand B suggests it might overcome these issues with appropriate formulation strategies. Given the GPCR-specific emphasis on affinity, Ligand B is the more promising candidate.

Output:
1

2025-04-17 03:50:56,930 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (362.367 and 367.471 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (125.88) is slightly above the optimal <90 for CNS targets, but still reasonable. Ligand B (100.55) is better, falling comfortably below 90.

**3. logP:** Both ligands have good logP values (0.742 and 0.689), within the 1-3 range.

**4. H-Bond Donors:** Ligand A has 1 HBD, which is good. Ligand B has 3, still acceptable but less ideal.

**5. H-Bond Acceptors:** Ligand A has 8 HBA, within the limit. Ligand B has 6, also good.

**6. QED:** Both ligands have similar QED values (0.663 and 0.658), indicating good drug-likeness.

**7. DILI:** Ligand A has a high DILI risk (98.759), which is a significant concern. Ligand B has a much lower DILI risk (54.323), making it more favorable.

**8. BBB:** Ligand A has a BBB penetration of 47.615, which is below the desirable >70 for CNS targets. Ligand B is also below 70 (41.024), but slightly better.

**9. Caco-2:** Both have negative Caco-2 values (-5.019 and -5.36), which is unusual and suggests poor permeability. This is a red flag for both.

**10. Solubility:** Both have negative solubility values (-3.226 and -1.048), indicating very poor aqueous solubility. This is a major issue for both compounds.

**11. hERG:** Both ligands have very low hERG inhibition risk (0.128 and 0.059).

**12. Cl_mic:** Ligand A has a higher microsomal clearance (57.007) than Ligand B (9.56), indicating lower metabolic stability.

**13. t1/2:** Ligand B has a significantly longer in vitro half-life (24.223 hours) compared to Ligand A (-2.929 hours).

**14. Pgp:** Both have very low Pgp efflux liability (0.17 and 0.016).

**15. Binding Affinity:** Ligand B has a better binding affinity (-7.5 kcal/mol) than Ligand A (-8.2 kcal/mol). While A is slightly better, the difference is not substantial enough to overcome its other weaknesses.

**Overall Assessment:**

Despite Ligand A having a slightly better binding affinity, Ligand B is a significantly better candidate. The primary reason is the drastically lower DILI risk. The improved metabolic stability (lower Cl_mic, longer t1/2) and slightly better BBB penetration also favor Ligand B. Both compounds suffer from poor solubility and Caco-2 permeability, which would need to be addressed through formulation or structural modifications, but the DILI risk for Ligand A is a major obstacle.

Output:
1
2025-04-17 03:50:56,931 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (456.215 Da) is higher, but still acceptable. Ligand B (344.411 Da) is lower, potentially aiding permeability.

**2. TPSA:** Both ligands have TPSA values below the 90 A^2 threshold for CNS targets. Ligand A (93.04 A^2) is slightly higher, while Ligand B (88.41 A^2) is better.

**3. logP:** Both ligands have optimal logP values (1-3). Ligand A (2.959) is closer to the upper limit, while Ligand B (1.89) is closer to the lower limit.

**4. H-Bond Donors:** Both have 2 HBD, which is within the acceptable limit of <=5.

**5. H-Bond Acceptors:** Both have 5 and 4 HBA respectively, which is within the acceptable limit of <=10.

**6. QED:** Both ligands have good QED scores (>0.5), indicating drug-likeness. Ligand B (0.854) is slightly better than Ligand A (0.557).

**7. DILI:** Ligand A (88.639) has a higher DILI risk than Ligand B (42.148). This is a significant negative for Ligand A.

**8. BBB:** Ligand B (67.584) has a better BBB penetration percentile than Ligand A (58.278). While neither is >70, Ligand B is closer and more desirable for a CNS target.

**9. Caco-2 Permeability:** Ligand A (-5.383) has a negative Caco-2 value, indicating poor permeability. Ligand B (-4.808) is also poor, but slightly better.

**10. Aqueous Solubility:** Ligand A (-4.388) and Ligand B (-2.058) both have negative solubility values, indicating poor solubility. Ligand B is slightly better.

**11. hERG Inhibition:** Ligand A (0.535) has a slightly higher hERG inhibition risk than Ligand B (0.123).

**12. Microsomal Clearance:** Ligand B (6.673 mL/min/kg) has significantly lower microsomal clearance than Ligand A (52.715 mL/min/kg), indicating better metabolic stability.

**13. In vitro Half-Life:** Ligand B (58.999 hours) has a much longer in vitro half-life than Ligand A (8.855 hours).

**14. P-gp Efflux:** Ligand A (0.466) has lower P-gp efflux than Ligand B (0.152), which is favorable for CNS penetration.

**15. Binding Affinity:** Ligand A (-10.2 kcal/mol) has a significantly stronger binding affinity than Ligand B (-9.0 kcal/mol). This is a substantial advantage.

**Overall Assessment:**

Ligand A has a much better binding affinity, which is a major plus. However, it suffers from higher DILI risk, poorer BBB penetration, poor Caco-2 permeability, high microsomal clearance, and shorter half-life. Ligand B, while having a weaker affinity, presents a much more favorable ADME profile, particularly with respect to BBB, metabolic stability, and DILI.

Given the GPCR-specific priorities, and especially the importance of BBB penetration for a CNS target like DRD2, Ligand B is the more promising candidate despite the slightly weaker binding affinity. The difference in affinity (1.2 kcal/mol) is not large enough to overcome the significant ADME liabilities of Ligand A.

Output:
1
2025-04-17 03:50:56,931 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (344.5 & 366.5 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (58.2) is significantly better than Ligand B (75.27). For CNS targets, TPSA should be <=90, and A is much closer to the ideal <=60 range. B is approaching a less desirable range.

**logP:** Both ligands have good logP values (3.489 and 2.56), falling within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Both have 2 HBDs, which is good. Ligand A has 2 HBAs, while Ligand B has 3. Both are acceptable, being <=10.

**QED:** Both ligands have good QED scores (0.75 and 0.841), indicating good drug-like properties.

**DILI:** Ligand A (26.871) has a much lower DILI risk than Ligand B (61.497). This is a significant advantage for A.

**BBB:** Ligand B (74.06) has a better BBB penetration percentile than Ligand A (64.25), but both are reasonably good for a CNS target.

**Caco-2 Permeability:** Ligand A (-4.785) has slightly better Caco-2 permeability than Ligand B (-4.682), though both are negative values which is a bit unusual and requires further investigation.

**Aqueous Solubility:** Ligand A (-4.204) has slightly better aqueous solubility than Ligand B (-3.762), both are negative values which is a bit unusual and requires further investigation.

**hERG:** Both ligands have very low hERG inhibition liability (0.126 and 0.252), which is excellent.

**Microsomal Clearance:** Ligand A (49.391) has lower microsomal clearance than Ligand B (58.82), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand B (-6.541) has a longer in vitro half-life than Ligand A (7.668), which is a positive.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.153 and 0.305), which is excellent.

**Binding Affinity:** Ligand B (-9.7) has a significantly stronger binding affinity than Ligand A (-9.0). This is a 0.7 kcal/mol difference, which is substantial and can outweigh some ADME drawbacks.

**Overall Assessment:**

While Ligand A has better TPSA, DILI, solubility, and clearance, Ligand B's significantly stronger binding affinity (-9.7 vs -9.0 kcal/mol) is a major advantage, especially for a GPCR target. The slightly better BBB for B is also beneficial. The longer half-life of B is also a plus. The DILI risk for A is lower, but the difference isn't dramatic enough to overcome the affinity difference.

Output:
1
2025-04-17 03:50:56,931 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (343.362 Da) is slightly lower, which could be beneficial for permeability.

**TPSA:** Ligand A (77.05) is significantly better than Ligand B (90.7), falling well below the 90 A^2 threshold for CNS targets. Ligand B is pushing the upper limit and could suffer from reduced brain penetration.

**logP:** Both ligands have good logP values (A: 2.79, B: 3.419) within the optimal range of 1-3. Ligand B is slightly higher, which *could* lead to some solubility issues, but isn't a major concern.

**H-Bond Donors/Acceptors:** Ligand A (0 HBD, 6 HBA) and Ligand B (2 HBD, 6 HBA) both meet the criteria of <=5 HBD and <=10 HBA.

**QED:** Both ligands have good QED scores (A: 0.712, B: 0.753), indicating drug-like properties.

**DILI:** Ligand A (83.443) has a higher DILI risk than Ligand B (70.221), though both are reasonably acceptable.

**BBB:** This is a crucial parameter for a CNS target. Ligand A (81.698) has a significantly better BBB percentile than Ligand B (70.531). This is a major advantage for Ligand A.

**Caco-2 Permeability:** Ligand A (-4.303) shows poor Caco-2 permeability, while Ligand B (-5.085) is even worse. Both are quite poor, but A is slightly better.

**Aqueous Solubility:** Both ligands have very poor aqueous solubility (-3.399 and -3.93, respectively). This is a concern for both, but not a deciding factor.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (A: 0.26, B: 0.77). Ligand A is preferable here.

**Microsomal Clearance:** Ligand A (91.711) has a higher microsomal clearance than Ligand B (82.588), suggesting faster metabolism and potentially lower in vivo exposure.

**In vitro Half-Life:** Ligand B (75.099) has a significantly longer in vitro half-life than Ligand A (-22.063). This is a substantial advantage for Ligand B.

**P-gp Efflux:** Ligand A (0.186) has lower P-gp efflux than Ligand B (0.339), which is favorable for CNS penetration.

**Binding Affinity:** Ligand B (-7.9 kcal/mol) has a significantly stronger binding affinity than Ligand A (-9.5 kcal/mol). This is a substantial advantage for Ligand B.

**Overall Assessment:**

While Ligand B has a superior binding affinity and better half-life, Ligand A demonstrates a much more favorable profile regarding CNS penetration (higher BBB, lower P-gp efflux, and lower TPSA). The significantly better affinity of Ligand B is a strong point, but the poor CNS penetration characteristics are a major drawback for a DRD2 ligand. The poor Caco-2 permeability for both is a concern, but can sometimes be overcome with formulation strategies. Given the importance of BBB penetration for CNS targets like DRD2, and the substantial difference in BBB percentile, Ligand A is the more promising candidate.

Output:
0
2025-04-17 03:50:56,931 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (408.286 Da) is slightly higher, but still acceptable. Ligand B (347.415 Da) is also good.

**TPSA:** Ligand A (20.31) is excellent for CNS penetration, well below the 90 A^2 threshold. Ligand B (102.76) is higher, but still potentially acceptable, though less ideal for CNS targets.

**logP:** Ligand A (4.997) is slightly above the optimal range (1-3), potentially leading to solubility issues or off-target interactions. Ligand B (-0.138) is significantly below the optimal range and may struggle with membrane permeability.

**H-Bond Donors/Acceptors:** Ligand A (0 HBD, 1 HBA) is very favorable, minimizing potential permeability issues. Ligand B (3 HBD, 5 HBA) is acceptable, but higher than ideal.

**QED:** Both ligands have similar QED values (A: 0.7, B: 0.688), indicating good drug-like properties.

**DILI:** Ligand A (54.75) has a higher DILI risk than Ligand B (37.96), but both are below the concerning threshold of 60.

**BBB:** This is a critical parameter for a CNS target like DRD2. Ligand A (93.331) exhibits excellent BBB penetration, exceeding the 70% threshold. Ligand B (41.722) has poor predicted BBB penetration.

**Caco-2 Permeability:** Ligand A (-4.644) has poor Caco-2 permeability, which is concerning. Ligand B (-5.338) is also poor.

**Aqueous Solubility:** Ligand A (-6.424) has poor aqueous solubility, which is a concern given its higher logP. Ligand B (-1.632) is also poor, but less so than Ligand A.

**hERG Inhibition:** Both ligands have very low hERG inhibition risk (A: 0.912, B: 0.074).

**Microsomal Clearance:** Ligand B (-13.378) has significantly lower (better) microsomal clearance than Ligand A (76.386), indicating better metabolic stability.

**In vitro Half-Life:** Ligand B (4.93) has a shorter half-life than Ligand A (38.567).

**P-gp Efflux:** Both ligands show low P-gp efflux liability (A: 0.711, B: 0.014), which is favorable for CNS exposure.

**Binding Affinity:** Both ligands have similar binding affinity (-9 kcal/mol).

**Overall Assessment:**

Ligand A excels in BBB penetration and has a reasonable QED and low hERG risk. However, it suffers from poor Caco-2 permeability, poor solubility, and relatively high DILI risk. Its logP is also slightly high.

Ligand B has better metabolic stability (lower Cl_mic) and lower DILI risk, but its major drawback is extremely poor BBB penetration. Its logP is also very low, which could hinder permeability.

Given the CNS target (DRD2), **BBB penetration is paramount**. Ligand A's significantly higher BBB score (93.331 vs 41.722) outweighs its other drawbacks, especially considering the similar binding affinities. While its solubility and permeability are concerns, these can potentially be addressed through formulation strategies. The poor BBB penetration of Ligand B is a more fundamental issue that is harder to overcome.

Output:
0
2025-04-17 03:50:56,931 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (356.463 Da) is slightly lower, which could be beneficial for permeability.

**TPSA:** Ligand A (68.31) is significantly better than Ligand B (100.11). For CNS targets, we want TPSA <= 90, and A is comfortably within this range, while B is above.

**logP:** Both ligands have acceptable logP values (A: 0.771, B: 1.854), falling within the 1-3 optimal range. B is slightly better.

**H-Bond Donors/Acceptors:** Ligand A (0 HBD, 5 HBA) is more favorable than Ligand B (2 HBD, 8 HBA). Lower counts generally improve permeability.

**QED:** Both ligands have similar and good QED values (A: 0.703, B: 0.716), indicating good drug-like properties.

**DILI:** Ligand B (65.917) has a higher DILI risk than Ligand A (21.326). This is a significant concern.

**BBB:** Ligand A (64.831) has a much better BBB penetration percentile than Ligand B (38.736). This is *critical* for a CNS target like DRD2.

**Caco-2 Permeability:** Ligand A (-4.125) has a better Caco-2 permeability than Ligand B (-5.366).

**Aqueous Solubility:** Ligand A (-0.373) has better aqueous solubility than Ligand B (-2.537).

**hERG Inhibition:** Both ligands have low hERG inhibition liability (A: 0.23, B: 0.31).

**Microsomal Clearance:** Ligand B (47.84) has a higher microsomal clearance than Ligand A (27.935), suggesting lower metabolic stability.

**In vitro Half-Life:** Ligand B (-11.11) has a longer in vitro half-life than Ligand A (-7.867).

**P-gp Efflux:** Both ligands have low P-gp efflux liability (A: 0.012, B: 0.039).

**Binding Affinity:** Ligand B (-8.0 kcal/mol) has a slightly better binding affinity than Ligand A (-6.6 kcal/mol). While a 1.4 kcal/mol difference is good, it needs to be weighed against the other factors.

**Overall Assessment:**

Ligand A is significantly better overall, particularly concerning CNS penetration (BBB) and safety (DILI). While Ligand B has slightly better affinity and half-life, the poor BBB penetration and higher DILI risk are major drawbacks for a CNS-targeted GPCR. The TPSA and solubility are also better for Ligand A. The affinity difference, while present, is not large enough to overcome these significant ADME/Tox concerns.

Output:
0
2025-04-17 03:50:56,931 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (345.4 and 356.5 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (98.74) is better than Ligand B (110.1). For CNS targets, we want TPSA <= 90, so A is closer to this threshold.

**logP:** Ligand A (0.777) is slightly better than Ligand B (0.192). Both are a bit low, potentially hindering permeation, but A is closer to the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A (HBD=3, HBA=4) and Ligand B (HBD=4, HBA=5) are both acceptable, within the recommended limits.

**QED:** Ligand A (0.709) has a significantly better QED score than Ligand B (0.441), indicating a more drug-like profile.

**DILI:** Ligand A (32.261) has a much lower DILI risk than Ligand B (7.445), which is a significant advantage. Both are below the 40 threshold, but A is preferable.

**BBB:** Ligand A (63.629) has a substantially higher BBB penetration percentile than Ligand B (29.003). This is *critical* for a CNS target like DRD2. While >70 is desirable, A is significantly better.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.22 and -5.212), which is unusual and suggests poor permeability. This is a concern for both.

**Aqueous Solubility:** Both ligands have negative solubility values (-2.394 and -1.194), also unusual and concerning.

**hERG:** Both ligands have very low hERG inhibition liability (0.126 and 0.222), which is excellent.

**Microsomal Clearance:** Ligand A (-22.081) has a lower (better) microsomal clearance than Ligand B (-18.757), suggesting greater metabolic stability.

**In vitro Half-Life:** Ligand A (15.313 hours) has a significantly longer half-life than Ligand B (5.41 hours), which is desirable.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.016 and 0.018), which is good for CNS exposure.

**Binding Affinity:** Ligand A (-8.7 kcal/mol) has a significantly stronger binding affinity than Ligand B (-7.4 kcal/mol). This is a substantial advantage, exceeding the 1.5 kcal/mol difference threshold.

**Overall Assessment:**

Ligand A is clearly superior. It has better TPSA, logP, QED, DILI risk, BBB penetration, metabolic stability, half-life, and *significantly* better binding affinity. While both have concerning Caco-2 and solubility values, the stronger affinity and improved CNS penetration of Ligand A outweigh these drawbacks. The substantial difference in binding affinity (-8.7 vs -7.4 kcal/mol) is a major factor.

Output:
1
2025-04-17 03:50:56,931 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (344.411 and 350.419 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (71.63) is significantly better than Ligand B (91.31). For CNS targets, we want TPSA <= 90, so Ligand A is preferable.

**logP:** Ligand A (2.524) is optimal (1-3). Ligand B (0.664) is a bit low, potentially hindering permeation.

**H-Bond Donors/Acceptors:** Both have 1 HBD, which is good. Ligand A has 4 HBA, and Ligand B has 5. Both are acceptable (<=10).

**QED:** Both ligands have reasonable QED scores (0.818 and 0.736), indicating good drug-like properties.

**DILI:** Ligand A (58.744) has a moderate DILI risk, while Ligand B (27.181) has a very low risk. This favors Ligand B.

**BBB:** Ligand A (70.182) is good, exceeding the 70% threshold for CNS targets. Ligand B (66.576) is close but slightly below the desirable threshold.

**Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and difficult to interpret without further context. However, the magnitude of the negative value for Ligand A (-4.63) is smaller than that of Ligand B (-4.919), suggesting slightly better permeability.

**Aqueous Solubility:** Both have negative solubility values, which is also unusual. The value for Ligand B (-1.907) is worse than Ligand A (-4.028).

**hERG Inhibition:** Ligand A (0.677) has a slightly higher hERG risk than Ligand B (0.142). This favors Ligand B.

**Microsomal Clearance:** Ligand A (73.728) has a higher clearance than Ligand B (8.348), indicating lower metabolic stability. This favors Ligand B.

**In vitro Half-Life:** Ligand B (-6.284) has a negative half-life, which is not possible. This is a significant red flag. Ligand A (7.618) has a reasonable half-life.

**P-gp Efflux:** Ligand A (0.362) has lower P-gp efflux liability than Ligand B (0.013), which is favorable for CNS penetration.

**Binding Affinity:** Ligand A (-8.5 kcal/mol) has a significantly stronger binding affinity than Ligand B (-7.4 kcal/mol). This is a substantial advantage, potentially outweighing some of the ADME drawbacks.

**Overall Assessment:**

Ligand A excels in binding affinity, TPSA, BBB, and P-gp efflux. Its main drawbacks are moderate DILI risk, higher microsomal clearance, and slightly higher hERG risk. Ligand B has lower DILI and hERG risks, and better metabolic stability, but suffers from a weaker binding affinity, higher TPSA, and a problematic negative in vitro half-life. The significantly stronger binding affinity of Ligand A, combined with acceptable BBB penetration and P-gp efflux, makes it the more promising candidate, despite its other shortcomings. The negative half-life for Ligand B is a dealbreaker.

Output:
1
2025-04-17 03:50:56,931 - INFO - Reasoning:

Let's analyze Ligand A and Ligand B against the provided guidelines, prioritizing GPCR-specific properties (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (345.49 and 347.50 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (52.65) is significantly better than Ligand B (63.13). For CNS targets, we want TPSA <= 90, and ideally closer to 60. Ligand A is much closer to this ideal.

**logP:** Ligand A (1.94) is within the optimal 1-3 range. Ligand B (3.28) is at the higher end of the optimal range, potentially increasing off-target interactions.

**H-Bond Donors/Acceptors:** Ligand A (1 HBD, 3 HBA) and Ligand B (2 HBD, 3 HBA) both have acceptable numbers of H-bond donors and acceptors.

**QED:** Both ligands have good QED scores (0.749 and 0.795), indicating good drug-like properties.

**DILI:** Ligand A (4.92) has a much lower DILI risk than Ligand B (13.22). This is a significant advantage for Ligand A.

**BBB:** Ligand A (83.29) has a substantially better BBB penetration score than Ligand B (74.29).  For a CNS target like DRD2, >70 is desirable, and Ligand A is closer to this threshold.

**Caco-2 Permeability:** Ligand A (-4.97) and Ligand B (-4.67) both have negative Caco-2 values, which is unusual and suggests poor permeability. However, the scale is not specified, so it's difficult to interpret.

**Aqueous Solubility:** Ligand A (-1.43) and Ligand B (-3.67) both have negative solubility values, indicating poor aqueous solubility. Ligand B is slightly worse.

**hERG:** Ligand A (0.7) has a lower hERG inhibition liability than Ligand B (0.34), which is preferable.

**Microsomal Clearance:** Ligand A (9.37) has a lower microsomal clearance than Ligand B (56.61), indicating better metabolic stability.

**In vitro Half-Life:** Ligand A (-3.55) has a negative half-life, which is unusual. Ligand B (20.51) has a much better in vitro half-life.

**P-gp Efflux:** Ligand A (0.056) has a significantly lower P-gp efflux liability than Ligand B (0.03). Lower is better for CNS exposure.

**Binding Affinity:** Ligand A (-9.4) has a significantly stronger binding affinity than Ligand B (-7.0). A >1.5 kcal/mol advantage in binding is considered substantial.

**Overall Assessment:**

Ligand A is clearly superior. It has a better TPSA, lower DILI risk, significantly better BBB penetration, lower P-gp efflux, and a much stronger binding affinity. While both have poor Caco-2 and solubility, the superior CNS properties and binding affinity of Ligand A outweigh these drawbacks for a DRD2 target. The better metabolic stability (lower Cl_mic) is also a plus. The unusual negative half-life for Ligand A is a concern, but the much stronger binding affinity suggests it might still be a better starting point for optimization.

Output:
1
2025-04-17 03:50:56,931 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight (MW):** Both ligands (348.487 and 350.503 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (69.64) is better than Ligand B (49.85). For CNS targets, we want TPSA <= 90, both are well within this range, but lower is generally preferred.

**3. logP:** Both ligands have good logP values (2.247 and 2.543), falling within the optimal 1-3 range.

**4. H-Bond Donors (HBD):** Both ligands have acceptable HBD counts (2 and 0, respectively), well below the threshold of 5.

**5. H-Bond Acceptors (HBA):** Both ligands have acceptable HBA counts (3 each), below the threshold of 10.

**6. QED:** Both ligands have similar QED values (0.749 and 0.709), indicating good drug-like properties.

**7. DILI:** Ligand A (20.9) has a significantly lower DILI risk than Ligand B (11.632), which is a major advantage.

**8. BBB:** Ligand B (88.329) has a much higher BBB penetration percentile than Ligand A (65.297). This is a *critical* factor for a CNS target like DRD2.

**9. Caco-2 Permeability:** Ligand A (-5.074) has worse Caco-2 permeability than Ligand B (-4.311). Higher values are better.

**10. Aqueous Solubility:** Both ligands have poor aqueous solubility (-2.543 and -2.609). This could pose formulation challenges, but is less critical than BBB for CNS targets.

**11. hERG Inhibition:** Both ligands have similar, low hERG inhibition liability (0.361 and 0.367), which is good.

**12. Microsomal Clearance:** Ligand A (37.22) has lower microsomal clearance than Ligand B (66.738), suggesting better metabolic stability.

**13. In vitro Half-Life:** Ligand A (3.573) has a longer in vitro half-life than Ligand B (0.062), which is desirable.

**14. P-gp Efflux:** Ligand A (0.204) has lower P-gp efflux liability than Ligand B (0.113), meaning more drug will reach the brain.

**15. Binding Affinity:** Ligand B (-7.0) has a significantly stronger binding affinity than Ligand A (-9.2). A 1.5 kcal/mol advantage is substantial and can outweigh other drawbacks.

**Overall Assessment:**

Ligand B excels in BBB penetration and binding affinity, which are the most important factors for a CNS GPCR target. While Ligand A has better DILI, metabolic stability, and P-gp efflux, the superior affinity and BBB penetration of Ligand B are more critical. The difference in affinity (-7.0 vs -9.2) is significant. The slightly higher DILI risk of Ligand B can be addressed in later optimization stages.

Output:
1
2025-04-17 03:50:56,932 - INFO - Reasoning:

Let's analyze Ligand A and Ligand B based on the provided guidelines, prioritizing GPCR-specific properties (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (347.5 and 356.4 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (63.13) is significantly better than Ligand B (75.71). For CNS targets, we want TPSA <= 90, and ideally closer to 60. Ligand A is much closer to this ideal.

**logP:** Ligand A (3.175) is within the optimal 1-3 range, while Ligand B (1.823) is at the lower end. While not terrible, lower logP can sometimes hinder permeability.

**H-Bond Donors/Acceptors:** Ligand A has 2 HBD and 3 HBA, while Ligand B has 1 HBD and 4 HBA. Both are within acceptable limits (<=5 HBD and <=10 HBA).

**QED:** Both ligands have similar QED values (0.674 and 0.673), indicating good drug-likeness.

**DILI:** Ligand A (25.2) has a slightly higher DILI risk than Ligand B (12.8), but both are well below the concerning threshold of 60.

**BBB:** Ligand B (88.6) has a significantly better BBB penetration percentile than Ligand A (70.9). This is a crucial factor for a CNS target like DRD2.

**Caco-2 Permeability:** Ligand A (-4.758) has worse Caco-2 permeability than Ligand B (-4.413). Lower (more negative) values indicate lower permeability.

**Aqueous Solubility:** Ligand A (-3.218) has slightly worse solubility than Ligand B (-2.259).

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.696 and 0.449).

**Microsomal Clearance:** Ligand B (53.8) has a slightly better microsomal clearance than Ligand A (48.9), meaning it is likely more metabolically stable.

**In vitro Half-Life:** Ligand B (-21.019) has a significantly longer in vitro half-life than Ligand A (13.759). This is a major advantage.

**P-gp Efflux:** Ligand A (0.394) has lower P-gp efflux than Ligand B (0.018), which is desirable for CNS penetration.

**Binding Affinity:** Ligand A (-7.7) has a slightly better binding affinity than Ligand B (-6.8). This is a 0.9 kcal/mol difference, which is significant.

**Overall Assessment:**

Ligand B excels in BBB penetration and in vitro half-life, both critical for CNS drug development. It also has better Caco-2 permeability and metabolic stability. While Ligand A has slightly better affinity and lower P-gp efflux, the difference in affinity (0.9 kcal/mol) is outweighed by the substantial advantages of Ligand B in terms of CNS penetration and metabolic stability. The lower TPSA of Ligand A is a plus, but the superior BBB and half-life of Ligand B are more important for this target.

Output:
1
2025-04-17 03:50:56,932 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (347.415 and 341.419 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (102.68) is slightly higher than Ligand B (81.73). For CNS targets, we prefer TPSA <= 90, so Ligand B is better here.

**3. logP:** Both ligands have good logP values (1.28 and 1.173), falling within the optimal 1-3 range.

**4. H-Bond Donors:** Ligand A has 3 HBD, while Ligand B has 0. Both are acceptable (<=5).

**5. H-Bond Acceptors:** Ligand A has 5 HBA, and Ligand B has 7. Both are within the acceptable range (<=10).

**6. QED:** Both ligands have good QED scores (0.719 and 0.837), indicating a drug-like profile.

**7. DILI:** Both ligands have similar DILI risk (60.45 and 59.519), placing them in a moderate risk category. This isn't a major differentiator.

**8. BBB:** Both ligands show good BBB penetration (64.599 and 64.831). While >70 is desirable, these are reasonably good for a CNS target.

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.241 and -5.348), which is unusual and suggests poor permeability. This is a concern for both.

**10. Aqueous Solubility:** Both ligands have negative solubility values (-2.263 and -1.405), indicating very poor aqueous solubility. This is a significant drawback for both.

**11. hERG Inhibition:** Both ligands have low hERG inhibition risk (0.387 and 0.05).

**12. Microsomal Clearance:** Ligand A has a lower (better) microsomal clearance (-26.375) than Ligand B (33.509), suggesting better metabolic stability.

**13. In vitro Half-Life:** Ligand A has a longer half-life (9.629 hours) than Ligand B (2.858 hours).

**14. P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.016 and 0.128), which is excellent for CNS penetration.

**15. Binding Affinity:** Ligand B (-8.2 kcal/mol) has a slightly better binding affinity than Ligand A (-7.8 kcal/mol). A difference of 0.4 kcal/mol is meaningful, but not enormous.

**Overall Assessment:**

Both ligands have significant drawbacks regarding solubility and Caco-2 permeability. However, considering the GPCR-specific priorities, Ligand B is slightly favored. It has a lower TPSA, which is important for CNS penetration, and a slightly better binding affinity. The improved metabolic stability and longer half-life of Ligand A are positives, but the slightly better affinity of Ligand B, coupled with the lower TPSA, makes it a marginally better candidate. The solubility and permeability issues would need to be addressed through formulation or further chemical modifications for either compound.

Output:
1
2025-04-17 03:50:56,932 - INFO - Reasoning:

Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (342.374 and 334.354 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (58.87) is better than Ligand B (61.4). Both are below the 90 A^2 threshold desirable for CNS targets, but A is closer to the optimal range.

**3. logP:** Both ligands have good logP values (2.796 and 3.184), falling within the 1-3 range.

**4. H-Bond Donors:** Ligand A has 1 HBD, while Ligand B has 0. Both are acceptable.

**5. H-Bond Acceptors:** Ligand A has 5 HBA, and Ligand B has 4. Both are below the 10 threshold.

**6. QED:** Both ligands have acceptable QED values (0.775 and 0.687), indicating good drug-like properties.

**7. DILI:** Both ligands have elevated DILI risk (68.244 and 72.509). This is a concern, but not a dealbreaker at this stage.

**8. BBB:** Ligand B (79.217) has a significantly better BBB percentile than Ligand A (70.686). This is a crucial advantage for a CNS target like DRD2.

**9. Caco-2 Permeability:** Both have negative Caco-2 values (-4.539 and -4.347). This is unusual and suggests poor permeability. However, these values are on a strange scale and may not be directly comparable.

**10. Aqueous Solubility:** Both have negative solubility values (-3.175 and -4.682). Again, this is unusual and problematic. Poor solubility could hinder bioavailability.

**11. hERG Inhibition:** Both ligands have low hERG inhibition risk (0.868 and 0.922).

**12. Microsomal Clearance:** Ligand A (34.338) has a lower microsomal clearance than Ligand B (62.168), indicating better metabolic stability.

**13. In vitro Half-Life:** Ligand B (20.95) has a longer half-life than Ligand A (12.163).

**14. P-gp Efflux:** Both ligands have low P-gp efflux liability (0.348 and 0.68).

**15. Binding Affinity:** Ligand B (-8.8 kcal/mol) has a slightly better binding affinity than Ligand A (-8.5 kcal/mol). While the difference is small, it's still a positive.

**Overall Assessment:**

While Ligand A has better TPSA and metabolic stability, Ligand B excels in BBB penetration and has a slightly better binding affinity. Given the importance of BBB penetration for a CNS target like DRD2, and the small advantage in affinity, Ligand B is the more promising candidate. The poor solubility and permeability are concerning for both, but can be addressed with formulation strategies. The DILI risk is also a concern for both, but can be investigated further.

Output:
1
2025-04-17 03:50:56,932 - INFO - Batch 63 complete. Total preferences: 1008
2025-04-17 03:50:56,932 - INFO - Processing batch 64/512...
2025-04-17 03:51:46,682 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (386.543 Da) is slightly higher than Ligand B (351.447 Da), but both are acceptable.

**TPSA:** Both ligands have TPSA values below 140 (Ligand A: 101.05, Ligand B: 98.74), which is good for oral absorption. They are also both below the 90 threshold desirable for CNS targets, which is excellent.

**logP:** Ligand A (1.482) is within the optimal range (1-3). Ligand B (0.48) is a bit low, potentially hindering permeation.

**H-Bond Donors & Acceptors:** Ligand A (HBD=2, HBA=7) and Ligand B (HBD=3, HBA=4) both have reasonable numbers of H-bond donors and acceptors, falling within the acceptable limits.

**QED:** Both ligands have QED values above 0.5 (Ligand A: 0.795, Ligand B: 0.606), indicating good drug-like properties.

**DILI:** Ligand A (66.382) has a higher DILI risk than Ligand B (28.306). This is a significant drawback for Ligand A.

**BBB:** Ligand A (70.803) has a better BBB penetration percentile than Ligand B (28.81). This is a crucial advantage for a CNS target like DRD2.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.635 and -5.327), which is unusual and suggests poor permeability. However, these values are on a scale where negative values are possible and don't necessarily disqualify a compound.

**Aqueous Solubility:** Both ligands have negative solubility values (-2.769 and -1.815), indicating poor aqueous solubility. This could pose formulation challenges.

**hERG Inhibition:** Both ligands have very low hERG inhibition risk (Ligand A: 0.256, Ligand B: 0.05).

**Microsomal Clearance:** Ligand B (10.441 mL/min/kg) has a higher microsomal clearance than Ligand A (3.16 mL/min/kg), suggesting Ligand A is more metabolically stable.

**In vitro Half-Life:** Ligand A (25.948 hours) has a significantly longer in vitro half-life than Ligand B (12.982 hours).

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (Ligand A: 0.118, Ligand B: 0.033).

**Binding Affinity:** Both ligands have very similar and strong binding affinities (-8.5 kcal/mol and -8.4 kcal/mol). The difference is negligible.

**Overall Assessment:**

Ligand A excels in BBB penetration and metabolic stability (lower Cl_mic, longer t1/2), which are crucial for CNS GPCR targets. However, it has a higher DILI risk. Ligand B has a lower DILI risk but suffers from poorer BBB penetration and metabolic stability. Given the importance of CNS penetration for DRD2, and the comparable binding affinities, Ligand A is the more promising candidate, despite the higher DILI risk. The DILI risk could potentially be mitigated through structural modifications.

Output:
1
2025-04-17 03:51:46,682 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (352.431 and 336.399 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (104.73) is slightly above the optimal <90 for CNS targets, but still reasonable. Ligand B (94.8) is better, falling comfortably under 90.

**3. logP:** Ligand A (0.668) is a bit low, potentially hindering permeability. Ligand B (1.432) is better, within the optimal 1-3 range.

**4. H-Bond Donors:** Ligand A (3) is acceptable. Ligand B (1) is even better, minimizing potential permeability issues.

**5. H-Bond Acceptors:** Ligand A (5) is acceptable. Ligand B (6) is also acceptable.

**6. QED:** Ligand B (0.802) has a significantly better QED score than Ligand A (0.44), indicating a more drug-like profile.

**7. DILI:** Ligand A (29.779) has a much lower DILI risk than Ligand B (44.552), which is a significant advantage.

**8. BBB:** Ligand B (46.336) has a better BBB percentile than Ligand A (17.022). This is *critical* for a CNS target like DRD2.

**9. Caco-2:** Both ligands have negative Caco-2 values (-5.341 and -5.302), which is unusual and suggests poor permeability. This is a concern for both.

**10. Solubility:** Both ligands have negative solubility values (-1.502 and -1.817), indicating very poor aqueous solubility. This is a major drawback.

**11. hERG:** Both ligands have very low hERG inhibition risk (0.047 and 0.502).

**12. Cl_mic:** Ligand A (-4.841) has a lower (better) microsomal clearance than Ligand B (3.662), suggesting greater metabolic stability.

**13. t1/2:** Ligand B (-3.726) has a longer in vitro half-life than Ligand A (1.864), which is desirable.

**14. Pgp:** Ligand A (0.022) has a much lower P-gp efflux liability than Ligand B (0.007), suggesting better CNS exposure.

**15. Binding Affinity:** Both ligands have very similar and strong binding affinities (-8.8 and -8.6 kcal/mol). The difference is negligible.

**Overall Assessment:**

Ligand B excels in BBB penetration and in vitro half-life, which are crucial for CNS drug development. However, it suffers from a higher DILI risk and a slightly higher P-gp efflux. Ligand A has a much better safety profile (lower DILI, lower P-gp efflux) and better metabolic stability, but its BBB penetration is significantly worse.

Considering the GPCR-specific priorities, the *most* important factor here is BBB penetration. While Ligand A's lower DILI and P-gp efflux are attractive, the substantial difference in BBB (17.022 vs 46.336) heavily favors Ligand B. The poor solubility and Caco-2 values are concerning for both, but can potentially be addressed through formulation strategies.

Output:
1
2025-04-17 03:51:46,682 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (345.403 and 343.391 Da) fall comfortably within the ideal 200-500 Da range.

**TPSA:** Ligand A (129.18) is slightly above the optimal <90 for CNS targets, but still reasonable. Ligand B (108.8) is better, falling well below 90.

**logP:** Ligand A (0.492) is quite low, potentially hindering membrane permeability. Ligand B (0.149) is even lower, raising significant concerns about permeability. Both are below the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Both have 2 HBD and are within the acceptable limits (<=5). Ligand A has 5 HBA, while Ligand B has 6. Both are within the acceptable limits (<=10).

**QED:** Both ligands have similar, good QED values (0.743 and 0.751), indicating generally drug-like properties.

**DILI:** Ligand A (53.858) has a lower DILI risk than Ligand B (61.691), which is preferable. Both are acceptable, but A is better.

**BBB:** Both ligands have similar, relatively low BBB penetration (40.52 and 39.511). This is a significant drawback for a CNS target like DRD2.

**Caco-2 Permeability:** Both have negative Caco-2 values (-5.291 and -5.631), which is unusual and suggests poor permeability.

**Aqueous Solubility:** Both have negative solubility values (-2.68 and -1.487), also unusual and indicating poor solubility.

**hERG Inhibition:** Both have very low hERG inhibition risk (0.208 and 0.258), which is excellent.

**Microsomal Clearance:** Ligand A (21.82) has a higher microsomal clearance than Ligand B (-16.779), meaning Ligand B is likely more metabolically stable.

**In vitro Half-Life:** Ligand A (20.371) has a longer in vitro half-life than Ligand B (-5.443), which is desirable.

**P-gp Efflux:** Both have very low P-gp efflux liability (0.037 and 0.019), which is good for CNS penetration.

**Binding Affinity:** Ligand A (-7.6 kcal/mol) has a significantly stronger binding affinity than Ligand B (-9.5 kcal/mol). This is a substantial advantage.

**Overall Assessment:**

While both compounds have issues, Ligand A is the better candidate. The biggest concerns are the low logP and BBB values for both. However, Ligand A's significantly stronger binding affinity (-7.6 vs -9.5 kcal/mol) is a major advantage that could potentially overcome some of the ADME deficiencies. The better DILI score and longer half-life further support choosing Ligand A. Ligand B's better metabolic stability isn't enough to offset the weaker binding. The negative solubility and Caco-2 values are concerning for both, and would need to be addressed through formulation or structural modification.

Output:
0
2025-04-17 03:51:46,683 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B based on the provided guidelines, prioritizing GPCR-specific properties (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (348.447 Da) is slightly lower, which could be beneficial for permeability.

**TPSA:** Ligand A (76.46) is significantly better than Ligand B (40.54). For CNS targets, TPSA < 90 is preferred, and Ligand B is much closer to the upper limit.

**logP:** Ligand A (1.325) is optimal (1-3), while Ligand B (4.516) is high, potentially leading to solubility issues and off-target interactions.

**H-Bond Donors/Acceptors:** Both ligands have acceptable HBD (1) and HBA (Ligand A: 5, Ligand B: 3) counts.

**QED:** Ligand A (0.894) has a significantly better QED score than Ligand B (0.73), indicating a more drug-like profile.

**DILI:** Ligand A (33.618) has a much lower DILI risk than Ligand B (14.385), which is a significant advantage.

**BBB:** Ligand B (92.943) has excellent BBB penetration, while Ligand A (52.811) is moderate. This is a critical factor for CNS targets like DRD2.

**Caco-2 Permeability:** Ligand A (-4.898) has a negative Caco-2 value which is unusual and suggests poor permeability. Ligand B (-4.569) is also negative, but slightly less so.

**Aqueous Solubility:** Ligand A (-1.271) has poor solubility, while Ligand B (-4.043) is even worse.

**hERG Inhibition:** Ligand A (0.249) has a lower hERG risk than Ligand B (0.746).

**Microsomal Clearance:** Ligand B (55.042) has a higher microsomal clearance than Ligand A (33.587), indicating faster metabolism and potentially lower in vivo exposure.

**In vitro Half-Life:** Ligand A (9.024) has a slightly longer half-life than Ligand B (7.789).

**P-gp Efflux:** Ligand A (0.031) shows very low P-gp efflux, which is highly desirable for CNS penetration. Ligand B (0.414) shows moderate P-gp efflux.

**Binding Affinity:** Ligand B (-6.5 kcal/mol) has a significantly stronger binding affinity than Ligand A (0.0 kcal/mol). This is a substantial advantage, potentially outweighing some of the ADME drawbacks.

**Overall Assessment:**

Ligand B's strong binding affinity and excellent BBB penetration are very attractive for a CNS target like DRD2. However, its high logP, poor solubility, higher DILI risk, and moderate P-gp efflux are concerns. Ligand A has a better ADME profile (lower DILI, better QED, lower P-gp efflux, better TPSA), but its binding affinity is extremely weak and Caco-2 permeability is poor.

Given the importance of binding affinity for GPCRs, and the fact that the difference in affinity (-6.5 vs 0.0 kcal/mol) is so large, Ligand B is the more promising candidate *despite* its ADME liabilities. Optimization efforts could focus on improving Ligand B's solubility and reducing its logP while maintaining its strong binding affinity.

Output:
1
2025-04-17 03:51:46,683 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B based on the provided guidelines, prioritizing GPCR-specific properties (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (350.321 and 348.487 Da) fall within the ideal range of 200-500 Da.

**TPSA:** Ligand A (96.77) is better than Ligand B (58.64) as it is closer to the ideal range for CNS targets (<=90). Ligand B is excellent.

**logP:** Both ligands have good logP values (1.644 and 2.348), falling within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A has 2 HBD and 4 HBA, while Ligand B has 1 HBD and 3 HBA. Both are within acceptable limits (<=5 HBD and <=10 HBA).

**QED:** Both ligands have reasonable QED scores (0.876 and 0.719), indicating good drug-like properties.

**DILI:** Ligand A (54.634) has a higher DILI risk than Ligand B (22.024). This is a significant advantage for Ligand B.

**BBB:** Ligand A (82.047) has a better BBB penetration score than Ligand B (66.886), exceeding the desirable threshold of 70.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.585 and -4.338) which is unusual and indicates poor permeability.

**Aqueous Solubility:** Both ligands have negative solubility values (-3.13 and -2.915) which is also unusual and indicates poor solubility.

**hERG:** Both ligands have low hERG inhibition liability (0.603 and 0.376), which is good.

**Microsomal Clearance:** Ligand A (-1.434) has a lower (better) microsomal clearance than Ligand B (29.555), indicating better metabolic stability.

**In vitro Half-Life:** Ligand A (-9.211) has a longer (better) in vitro half-life than Ligand B (8.138).

**P-gp Efflux:** Ligand A (0.238) has lower P-gp efflux liability than Ligand B (0.105), which is beneficial for CNS penetration.

**Binding Affinity:** Ligand B (-7.1 kcal/mol) has a slightly better binding affinity than Ligand A (-8.8 kcal/mol). While A is better, the difference is not substantial enough to outweigh other factors.

**Overall Assessment:**

Considering the GPCR-specific priorities, Ligand B emerges as the more promising candidate. While Ligand A has a slightly better BBB score and affinity, Ligand B demonstrates significantly lower DILI risk, better metabolic stability (lower Cl_mic), and lower P-gp efflux. The lower DILI risk is a critical advantage, and the lower P-gp efflux will help ensure sufficient CNS exposure. The affinity difference is not large enough to overcome these benefits. The negative Caco-2 and solubility values are concerning for both, but can be addressed with formulation strategies.

Output:
1
2025-04-17 03:51:46,683 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (362.813 and 347.463 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (76.66) is better than Ligand B (78.43). Both are reasonably good for CNS penetration, being below 90, but A is closer to the optimal range.

**3. logP:** Ligand A (3.337) is optimal, while Ligand B (1.06) is a bit low, potentially hindering membrane permeability.

**4. H-Bond Donors:** Ligand A (2) is preferable to Ligand B (1). Both are within the acceptable limit of 5.

**5. H-Bond Acceptors:** Ligand A (4) is preferable to Ligand B (5). Both are within the acceptable limit of 10.

**6. QED:** Both ligands have similar QED values (0.818 and 0.832), indicating good drug-like properties.

**7. DILI:** Ligand A (85.537) has a significantly higher DILI risk than Ligand B (16.13). This is a major concern for Ligand A.

**8. BBB:** Ligand A (82.009) has a much better BBB penetration percentile than Ligand B (60.527). This is crucial for a CNS target like DRD2.

**9. Caco-2 Permeability:** Ligand A (-4.703) has a worse Caco-2 permeability than Ligand B (-5.174). Lower values are less desirable.

**10. Aqueous Solubility:** Ligand A (-4.788) has a worse aqueous solubility than Ligand B (-1.243). Lower values are less desirable.

**11. hERG Inhibition:** Ligand A (0.443) has a slightly higher hERG inhibition risk than Ligand B (0.119), but both are relatively low.

**12. Microsomal Clearance:** Ligand B (-10.276) exhibits significantly lower (better) microsomal clearance than Ligand A (57.81). This suggests better metabolic stability for Ligand B.

**13. In vitro Half-Life:** Ligand B (-2.853) has a much longer in vitro half-life than Ligand A (54.204).

**14. P-gp Efflux:** Ligand A (0.171) has lower P-gp efflux liability than Ligand B (0.006), which is favorable for CNS exposure.

**15. Binding Affinity:** Ligand A (-8.3 kcal/mol) has a stronger binding affinity than Ligand B (-7.5 kcal/mol). This is a significant advantage.

**Overall Assessment:**

Ligand A has a superior binding affinity and better BBB penetration and P-gp efflux. However, it suffers from a significantly higher DILI risk, poorer solubility, and worse metabolic stability (higher clearance, shorter half-life). Ligand B, while having a slightly weaker affinity, presents a much better safety profile (lower DILI), improved metabolic stability, and better solubility.

Considering the GPCR-specific priorities and the overall balance of properties, the lower DILI risk and improved ADME properties of Ligand B outweigh the slightly weaker binding affinity, especially in the early stages of drug development. The higher DILI risk of Ligand A is a major red flag.

Output:
1
2025-04-17 03:51:46,683 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 drug candidates, considering the provided guidelines and GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight (MW):**
* Ligand A: 348.491 Da - Within the ideal range (200-500 Da).
* Ligand B: 375.563 Da - Also within the ideal range.
* *Both are acceptable.*

**2. Topological Polar Surface Area (TPSA):**
* Ligand A: 76.02 A^2 - Excellent, well below the 90 A^2 threshold for CNS targets.
* Ligand B: 48.99 A^2 - Excellent, even better for CNS penetration.
* *Both are excellent, but B is slightly better.*

**3. Lipophilicity (logP):**
* Ligand A: 2.145 - Optimal (1-3).
* Ligand B: 4.093 - Borderline high, potentially leading to solubility issues or off-target interactions.
* *Ligand A is preferred.*

**4. H-Bond Donors (HBD):**
* Ligand A: 2 - Acceptable (<=5).
* Ligand B: 1 - Acceptable (<=5).
* *Both are acceptable.*

**5. H-Bond Acceptors (HBA):**
* Ligand A: 4 - Acceptable (<=10).
* Ligand B: 4 - Acceptable (<=10).
* *Both are acceptable.*

**6. QED:**
* Ligand A: 0.793 - Excellent (>=0.5).
* Ligand B: 0.53 - Acceptable, but less ideal than A.
* *Ligand A is preferred.*

**7. DILI Risk:**
* Ligand A: 23.187 - Very low risk (<40).
* Ligand B: 39.667 - Low risk, but higher than A.
* *Ligand A is preferred.*

**8. BBB Penetration:**
* Ligand A: 68.67 - Good, but could be better for a CNS target (>70 desirable).
* Ligand B: 39.822 - Poor for a CNS target.
* *Ligand A is significantly preferred.*

**9. Caco-2 Permeability:**
* Ligand A: -4.727 - Indicates poor permeability.
* Ligand B: -5.32 - Indicates poor permeability.
* *Both are poor, but B is slightly worse.*

**10. Aqueous Solubility:**
* Ligand A: -2.179 - Poor solubility.
* Ligand B: -3.495 - Very poor solubility.
* *Ligand A is preferred.*

**11. hERG Inhibition:**
* Ligand A: 0.099 - Very low risk.
* Ligand B: 0.834 - Moderate risk.
* *Ligand A is preferred.*

**12. Microsomal Clearance:**
* Ligand A: 41.446 mL/min/kg - Moderate clearance.
* Ligand B: 89.125 mL/min/kg - High clearance, indicating lower metabolic stability.
* *Ligand A is preferred.*

**13. In vitro Half-Life:**
* Ligand A: 3.619 hours - Relatively short half-life.
* Ligand B: -0.024 hours - Extremely short half-life.
* *Ligand A is preferred.*

**14. P-gp Efflux:**
* Ligand A: 0.042 - Low efflux, favorable for CNS exposure.
* Ligand B: 0.469 - Moderate efflux, potentially limiting CNS exposure.
* *Ligand A is preferred.*

**15. Binding Affinity:**
* Ligand A: -9.2 kcal/mol - Excellent, very strong binding.
* Ligand B: -7.7 kcal/mol - Good, but significantly weaker than A.
* *Ligand A is strongly preferred.*

**Overall Assessment:**

Ligand A consistently outperforms Ligand B across most critical parameters, particularly BBB penetration, DILI risk, metabolic stability, hERG inhibition, P-gp efflux, and crucially, binding affinity. While both have issues with Caco-2 permeability and solubility, Ligand A is better in both regards. The significantly stronger binding affinity of Ligand A (-9.2 vs -7.7 kcal/mol) is a major advantage that can outweigh some of its ADME drawbacks. Given the GPCR target and the need for CNS penetration, Ligand A is the far more promising candidate.

Output:
1
2025-04-17 03:51:46,684 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (340.423 and 347.371 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (58.64) is excellent, well below the 90 A^2 threshold for CNS targets. Ligand B (97.81) is higher, but still potentially acceptable, though less optimal.

**3. logP:** Ligand A (2.588) is within the optimal 1-3 range. Ligand B (0.705) is slightly low, potentially hindering permeation.

**4. H-Bond Donors:** Both ligands have 1 HBD, which is acceptable.

**5. H-Bond Acceptors:** Ligand A has 3 HBA, and Ligand B has 6 HBA. Both are within the acceptable limit of <=10, but Ligand A is preferable.

**6. QED:** Both ligands have good QED scores (0.677 and 0.855), indicating good drug-like properties.

**7. DILI:** Ligand A (61.807) has a slightly higher DILI risk than Ligand B (57.076), but both are reasonably acceptable.

**8. BBB:** Ligand A (67.313) has a better BBB percentile than Ligand B (48.701). This is a *critical* factor for a CNS target like DRD2.

**9. Caco-2 Permeability:** Ligand A (-4.461) has a more negative Caco-2 value, indicating lower permeability. Ligand B (-5.164) is also low, but slightly worse.

**10. Aqueous Solubility:** Ligand A (-3.902) has a more negative solubility value, indicating lower solubility. Ligand B (-1.54) is better.

**11. hERG:** Ligand A (0.65) has a higher hERG risk than Ligand B (0.119), which is a significant concern.

**12. Microsomal Clearance:** Ligand A (47.274) has higher microsomal clearance than Ligand B (20.419), meaning faster metabolism and potentially lower exposure.

**13. In vitro Half-Life:** Ligand A (-6.669) has a negative half-life, indicating a very short half-life. Ligand B (22.581) has a much longer, and more desirable, half-life.

**14. P-gp Efflux:** Ligand A (0.429) has a lower P-gp efflux liability than Ligand B (0.041), which is favorable for CNS penetration.

**15. Binding Affinity:** Ligand A (-7.8) has significantly better binding affinity than Ligand B (-0.0). This is a substantial advantage.

**Overall Assessment:**

Despite Ligand A's superior binding affinity, Ligand B appears to be the more promising candidate. Ligand A has significant drawbacks in hERG risk, metabolic stability (high Cl_mic, low t1/2), solubility, and Caco-2 permeability. The strong binding affinity of Ligand A might be overcome with further optimization, but the ADME properties are concerning. Ligand B, while having weaker affinity, has a much better ADME profile, particularly its BBB penetration, longer half-life, and lower hERG risk. For a CNS target, these factors are crucial.

Output:
1
2025-04-17 03:51:46,684 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands fall within the ideal range (200-500 Da). Ligand A (403.28 Da) is slightly higher than Ligand B (337.402 Da), but both are acceptable.

**2. TPSA:** Ligand A (69.04) is higher than Ligand B (45.46). For CNS targets, we prefer TPSA <= 90. Both are below this threshold, but Ligand B is significantly better.

**3. logP:** Both ligands have good logP values (A: 3.873, B: 3.734), falling within the optimal range of 1-3.

**4. H-Bond Donors:** Both ligands have 1 HBD, which is within the acceptable limit of <= 5.

**5. H-Bond Acceptors:** Ligand A has 6 HBAs, and Ligand B has 5. Both are below the acceptable limit of <= 10.

**6. QED:** Both ligands have good QED scores (A: 0.479, B: 0.721), indicating drug-like properties. Ligand B is significantly better.

**7. DILI:** Both ligands have relatively high DILI risk (A: 79.721, B: 81.0). This is a concern, but we'll consider it alongside other factors.

**8. BBB:** Both ligands have similar BBB penetration (A: 68.903, B: 68.437). While not ideal (>70 is preferred), they are reasonably good, suggesting some CNS exposure.

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.061 and -4.725). This is unusual and suggests poor intestinal absorption.

**10. Aqueous Solubility:** Both ligands have negative solubility values (-3.528 and -3.902). This is also concerning and could hinder formulation and bioavailability.

**11. hERG Inhibition:** Both ligands have low hERG inhibition risk (A: 0.767, B: 0.918), which is favorable.

**12. Microsomal Clearance:** Ligand A has significantly higher microsomal clearance (113.21) than Ligand B (50.753). This indicates Ligand B is more metabolically stable.

**13. In vitro Half-Life:** Ligand B has a negative half-life (-2.83), which is problematic. Ligand A has a half-life of 77.415, which is good.

**14. P-gp Efflux:** Both ligands have low P-gp efflux liability (A: 0.535, B: 0.691), which is desirable for CNS penetration.

**15. Binding Affinity:** Both ligands have excellent binding affinity (A: -8.5 kcal/mol, B: -8.3 kcal/mol). The difference is small (0.2 kcal/mol), and likely not decisive.

**Overall Assessment:**

Ligand B has several advantages: lower TPSA, better QED, and significantly better metabolic stability (lower Cl_mic). However, it has a negative in vitro half-life, which is a major drawback. Ligand A has a good half-life, but suffers from higher metabolic clearance and a slightly higher TPSA. Considering the GPCR-specific priorities, BBB is reasonable for both, logP is good for both, Pgp efflux is low for both, and affinity is excellent for both. The biggest differentiating factors are metabolic stability and half-life. While the negative half-life of B is concerning, the significantly improved metabolic stability is a strong advantage for CNS penetration. The negative Caco-2 and solubility values are concerning for both, but these can potentially be addressed through formulation strategies.

Output:
1
2025-04-17 03:51:46,684 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (366.527 Da) and Ligand B (356.419 Da) are comparable.

**TPSA:** Ligand A (61.8) is better than Ligand B (110.8). For CNS targets, we want TPSA <= 90, so Ligand A is much closer to that threshold. Ligand B is significantly higher and could hinder BBB penetration.

**logP:** Ligand A (3.37) is optimal (1-3). Ligand B (0.682) is a bit low and could lead to poor membrane permeability.

**H-Bond Donors:** Both ligands have 2 HBDs, which is within the acceptable limit of <=5.

**H-Bond Acceptors:** Ligand A has 4 HBAs, and Ligand B has 6. Both are within the acceptable limit of <=10.

**QED:** Ligand A (0.727) is better than Ligand B (0.557), indicating a more drug-like profile.

**DILI:** Ligand A (35.867) and Ligand B (58.666) are both reasonably low risk, but Ligand A is preferable.

**BBB:** Ligand A (60.372) is better than Ligand B (46.026). While both are below the desirable >70 for CNS targets, Ligand A is closer. This is a critical factor for DRD2.

**Caco-2 Permeability:** Ligand A (-4.68) and Ligand B (-5.13) both have negative values, which is unusual. However, the values are similar, and it's difficult to draw a strong conclusion without knowing the scale.

**Aqueous Solubility:** Ligand A (-3.428) and Ligand B (-2.115) both have negative values, suggesting poor solubility. Ligand B is slightly better.

**hERG Inhibition:** Ligand A (0.756) is better than Ligand B (0.104), indicating lower cardiotoxicity risk.

**Microsomal Clearance:** Ligand A (61.731) has higher clearance than Ligand B (19.655), suggesting lower metabolic stability. Ligand B is preferable here.

**In vitro Half-Life:** Ligand A (9.585) has a longer half-life than Ligand B (-0.508). This is a significant advantage for Ligand A.

**P-gp Efflux:** Ligand A (0.55) is better than Ligand B (0.064), indicating lower P-gp efflux and potentially better CNS exposure.

**Binding Affinity:** Ligand B (-7.4) has a significantly better binding affinity than Ligand A (-0.0). A >1.5 kcal/mol advantage can outweigh ADME drawbacks.

**Overall Assessment:**

Ligand B has a significantly better binding affinity, which is a major advantage. However, it suffers from a higher TPSA, lower logP, and lower BBB penetration, all critical for a CNS-targeting GPCR like DRD2. Ligand A has better TPSA, logP, BBB, QED, and P-gp efflux, but its binding affinity is very weak.

Considering the importance of CNS penetration for DRD2, and the substantial affinity difference, Ligand B is the more promising candidate *despite* its less favorable TPSA and logP. The strong binding affinity could potentially be optimized with further modifications to improve ADME properties.

Output:
1
2025-04-17 03:51:46,684 - INFO - Reasoning:

Let's analyze Ligand A and Ligand B for their potential as DRD2 drug candidates, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight (MW):** Both ligands are within the ideal range (200-500 Da). Ligand A (389.901 Da) is slightly higher than Ligand B (350.547 Da), but both are acceptable.

**2. TPSA:** Ligand A (80.75) is above the preferred <90 for CNS targets, but still reasonable. Ligand B (58.2) is excellent, well below the 90 threshold. This favors Ligand B.

**3. logP:** Both ligands have good logP values (A: 2.936, B: 4.04), falling within the optimal 1-3 range, although B is pushing the upper limit.

**4. H-Bond Donors (HBD):** Both are low (A: 0, B: 2), which is good for permeability.

**5. H-Bond Acceptors (HBA):** Both are reasonable (A: 5, B: 2).

**6. QED:** Both have acceptable QED scores (A: 0.723, B: 0.694), indicating good drug-like properties.

**7. DILI:** Ligand A (66.615) has a higher DILI risk than Ligand B (18.302). This is a significant advantage for Ligand B.

**8. BBB:** Ligand B (84.219) has a much better BBB penetration score than Ligand A (56.34). This is *critical* for a CNS target like DRD2, and heavily favors Ligand B.

**9. Caco-2 Permeability:** Ligand A (-4.376) and Ligand B (-4.542) both have negative Caco-2 values, which is unusual. It suggests very low permeability.

**10. Aqueous Solubility:** Both ligands have poor aqueous solubility (A: -2.964, B: -4.76). This could pose formulation challenges.

**11. hERG Inhibition:** Both ligands show low hERG inhibition risk (A: 0.123, B: 0.533).

**12. Microsomal Clearance:** Ligand A (67.392) has lower microsomal clearance than Ligand B (82.7), suggesting better metabolic stability.

**13. In vitro Half-Life:** Ligand A (76.498) has a longer in vitro half-life than Ligand B (4.045). This is a positive for Ligand A.

**14. P-gp Efflux:** Both ligands show low P-gp efflux liability (A: 0.232, B: 0.161).

**15. Binding Affinity:** Ligand B (-8.1 kcal/mol) has a significantly stronger binding affinity than Ligand A (-7.6 kcal/mol). This >1.5 kcal/mol difference is substantial and outweighs many of the minor drawbacks.

**Overall Assessment:**

Ligand B is the stronger candidate. The superior BBB penetration (84.219 vs 56.34), significantly lower DILI risk (18.302 vs 66.615), and substantially improved binding affinity (-8.1 vs -7.6 kcal/mol) are decisive advantages. While both have poor solubility and Caco-2 permeability, the CNS target prioritization makes BBB and affinity paramount. The longer half-life of Ligand A is a benefit, but not enough to overcome the other significant advantages of Ligand B.

Output:
1
2025-04-17 03:51:46,685 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (350.419 and 348.403 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (104.39) is better than Ligand B (113.33). For CNS targets, we want TPSA <= 90, so both are above this ideal, but A is closer.

**3. logP:** Ligand A (1.596) is within the optimal range (1-3), while Ligand B (0.522) is slightly below, potentially hindering permeation.

**4. H-Bond Donors:** Ligand A (2) and Ligand B (3) are both acceptable (<=5).

**5. H-Bond Acceptors:** Both ligands (A: 5, B: 5) are within the acceptable range (<=10).

**6. QED:** Both ligands have good QED scores (A: 0.843, B: 0.734), indicating drug-like properties.

**7. DILI:** Both ligands have similar DILI risk (A: 59.636, B: 56.572), and are within an acceptable range (<60 is good).

**8. BBB:** Ligand A (55.642) has a significantly better BBB percentile than Ligand B (37.456). This is *critical* for a CNS target like DRD2.

**9. Caco-2 Permeability:** Ligand A (-4.758) has better Caco-2 permeability than Ligand B (-5.416), suggesting better intestinal absorption.

**10. Aqueous Solubility:** Ligand A (-2.901) has better solubility than Ligand B (-2.335).

**11. hERG Inhibition:** Both ligands have low hERG inhibition risk (A: 0.301, B: 0.051).

**12. Microsomal Clearance:** Ligand A (-2.256) has lower (better) microsomal clearance than Ligand B (-1.761), suggesting greater metabolic stability.

**13. In vitro Half-Life:** Ligand A (-27.428) has a much longer in vitro half-life than Ligand B (15.458).

**14. P-gp Efflux:** Ligand A (0.038) has lower P-gp efflux than Ligand B (0.02), which is favorable for CNS exposure.

**15. Binding Affinity:** Ligand B (-8.0) has a slightly better binding affinity than Ligand A (-7.7), but the difference is less than 1.5 kcal/mol.

**Overall Assessment:**

While Ligand B has a marginally better binding affinity, Ligand A is significantly superior in several key ADME properties crucial for a CNS-targeting GPCR. Specifically, its much better BBB penetration, longer half-life, lower clearance, and better solubility outweigh the small difference in binding affinity. The logP value for Ligand A is also more optimal.

Output:
1
2025-04-17 03:51:46,685 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (350.419 and 347.415 Da) are within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (111.12) is better than Ligand B (100.55). Both are below the 140 A^2 threshold for oral absorption, and Ligand B is closer to the preferred <90 A^2 for CNS targets.

**3. logP:** Ligand B (0.797) is within the optimal range (1-3), while Ligand A (-0.831) is slightly below, potentially hindering permeation.

**4. H-Bond Donors:** Ligand A (2) is preferable to Ligand B (3).

**5. H-Bond Acceptors:** Ligand A (6) is preferable to Ligand B (5).

**6. QED:** Both ligands have similar QED values (0.601 and 0.604), indicating good drug-like properties.

**7. DILI:** Ligand A (19.698) has a significantly lower DILI risk than Ligand B (41.915). This is a substantial advantage.

**8. BBB:** Ligand A (72.237) has a much higher BBB penetration percentile than Ligand B (43.505). This is *critical* for a CNS target like DRD2.

**9. Caco-2 Permeability:** Both have negative values, which is unusual. However, the magnitude is similar, so this is less of a differentiating factor.

**10. Aqueous Solubility:** Both have negative values, which is unusual. However, the magnitude is similar, so this is less of a differentiating factor.

**11. hERG:** Both ligands have very low hERG inhibition liability (0.172 and 0.047), which is excellent.

**12. Microsomal Clearance:** Ligand A (-11.173) has a much lower (better) microsomal clearance than Ligand B (3.904), indicating greater metabolic stability.

**13. In vitro Half-Life:** Ligand A (-18.414) has a much longer in vitro half-life than Ligand B (-32.27), which is a significant advantage.

**14. P-gp Efflux:** Both ligands show very low P-gp efflux liability (0.005 and 0.046).

**15. Binding Affinity:** Both ligands have comparable binding affinities (-7.8 and -8.3 kcal/mol), with Ligand B being slightly better. However, the difference is likely not enough to overcome the substantial ADME advantages of Ligand A.

**Conclusion:**

Considering the GPCR-specific priorities, Ligand A is the more promising drug candidate. While Ligand B has a slightly better binding affinity, Ligand A excels in crucial ADME properties: significantly lower DILI risk, much better BBB penetration, improved metabolic stability (lower Cl_mic, longer t1/2), and better logP. These factors are particularly important for CNS drug development, outweighing the minor affinity difference.

Output:
0
2025-04-17 03:51:46,685 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (356.5 & 367.5 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (57.26) is significantly better than Ligand B (81.7). For CNS targets, TPSA should be <= 90, and A is comfortably within this range, while B is approaching the upper limit.

**logP:** Ligand A (3.39) is optimal, while Ligand B (1.883) is a bit low, potentially hindering membrane permeability.

**H-Bond Donors/Acceptors:** Ligand A has 2 HBD and 5 HBA, while Ligand B has 1 HBD and 5 HBA. Both are within acceptable limits.

**QED:** Ligand A (0.882) has a higher QED score than Ligand B (0.71), indicating better overall drug-likeness.

**DILI:** Ligand A (59.83) is slightly higher than Ligand B (49.24), but both are reasonably low risk.

**BBB:** Ligand A (94.18) is *excellent* for CNS penetration, exceeding the desirable >70% threshold. Ligand B (67.55) is lower, which is a significant drawback for a CNS target.

**Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and suggests a potential issue with the data or modeling. However, the magnitude is similar.

**Aqueous Solubility:** Both have negative solubility values, again indicating potential data issues. The values are similar.

**hERG:** Both ligands have low hERG inhibition liability (0.867 and 0.393, respectively), which is good.

**Microsomal Clearance:** Ligand A (4.60) has a much lower (better) microsomal clearance than Ligand B (70.71). This suggests greater metabolic stability for Ligand A.

**In vitro Half-Life:** Ligand A (40.18 hours) has a significantly longer half-life than Ligand B (-35.55 hours - which is likely an error or indicates very rapid degradation).

**P-gp Efflux:** Ligand A (0.421) has lower P-gp efflux liability than Ligand B (0.092), which is favorable for CNS exposure.

**Binding Affinity:** Both ligands have the same binding affinity (-8.4 kcal/mol), which is excellent.

**Overall Assessment:**

Ligand A is superior to Ligand B. The key advantages of Ligand A are its significantly better BBB penetration, lower microsomal clearance (better metabolic stability), longer half-life, and lower P-gp efflux. While both have good affinity, the ADME properties of Ligand A are far more favorable for a CNS-targeting drug, particularly for a GPCR like DRD2. The TPSA and logP values for Ligand A are also more optimal. The negative solubility and Caco-2 values are concerning for both, but the other differences are more impactful.

Output:
1
2025-04-17 03:51:46,685 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B based on the provided guidelines, prioritizing GPCR-specific properties (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (346.471 and 342.483 Da) fall within the ideal range of 200-500 Da.

**TPSA:** Ligand A (69.64) is better than Ligand B (49.41). Both are below the 90 A^2 threshold for CNS targets, but Ligand B is closer to the optimal range.

**logP:** Ligand A (1.999) is within the optimal range (1-3), while Ligand B (3.49) is at the higher end, potentially increasing off-target effects.

**H-Bond Donors/Acceptors:** Ligand A has 2 HBD and 3 HBA, while Ligand B has 1 HBD and 2 HBA. Both are within acceptable limits.

**QED:** Both ligands have good QED scores (0.821 and 0.852), indicating good drug-like properties.

**DILI:** Ligand A (16.479) has a significantly lower DILI risk than Ligand B (40.054), which is a substantial advantage.

**BBB:** Ligand B (72.586) has a better BBB penetration score than Ligand A (63.746). This is crucial for a CNS target like DRD2.

**Caco-2 Permeability:** Ligand A (-4.921) has a worse Caco-2 permeability than Ligand B (-4.547).

**Aqueous Solubility:** Ligand A (-3.081) has better aqueous solubility than Ligand B (-4.276).

**hERG Inhibition:** Ligand A (0.271) shows lower hERG inhibition liability than Ligand B (0.653), indicating a lower risk of cardiotoxicity.

**Microsomal Clearance:** Ligand B (70.085) has higher microsomal clearance than Ligand A (6.615), suggesting lower metabolic stability.

**In vitro Half-Life:** Ligand A (19.201) has a longer in vitro half-life than Ligand B (-5.398).

**P-gp Efflux:** Ligand A (0.087) has lower P-gp efflux liability than Ligand B (0.377), which is beneficial for CNS penetration.

**Binding Affinity:** Ligand B (-9.3 kcal/mol) has a slightly better binding affinity than Ligand A (-8.9 kcal/mol). While a 1.5 kcal/mol difference is significant, other factors need to be considered.

**Overall Assessment:**

Ligand B has a better BBB score and binding affinity, which are critical for a CNS GPCR target. However, it suffers from higher DILI risk, higher P-gp efflux, higher hERG inhibition, and lower metabolic stability (higher clearance, shorter half-life). Ligand A, while having slightly weaker affinity, presents a much more favorable ADMET profile, particularly regarding safety (DILI, hERG) and CNS penetration (P-gp, BBB). The slightly weaker affinity of Ligand A can potentially be optimized in subsequent iterations, whereas mitigating the ADMET liabilities of Ligand B would be more challenging.

Output:
0
2025-04-17 03:51:46,686 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (354.397 Da) is slightly lower, which could be beneficial for permeability. Ligand B (384.523 Da) is also acceptable.

**TPSA:** Ligand A (67.43) is excellent, well below the 90 A^2 threshold for CNS targets. Ligand B (82.78) is still reasonable, but less optimal.

**logP:** Both ligands have good logP values (A: 2.262, B: 1.805), falling within the 1-3 range.

**H-Bond Donors/Acceptors:** Both have 2 HBD, which is good. Ligand A has 3 HBA, and Ligand B has 6 HBA. Higher HBA can sometimes reduce permeability, so A is slightly favored here.

**QED:** Both ligands have good QED scores (A: 0.789, B: 0.806), indicating good drug-like properties.

**DILI:** Both have acceptable DILI risk (A: 40.054, B: 45.25), below the concerning threshold of 60.

**BBB:** This is critical for a CNS target. Ligand A has a significantly better BBB percentile (82.823) compared to Ligand B (36.216). This is a major advantage for Ligand A.

**Caco-2 Permeability:** Ligand A (-4.254) is better than Ligand B (-5.163), suggesting better intestinal absorption.

**Aqueous Solubility:** Both have poor aqueous solubility (A: -2.761, B: -3.438). This is a potential issue for both, but might be mitigated by formulation strategies.

**hERG Inhibition:** Both have low hERG risk (A: 0.518, B: 0.167). Ligand B is slightly better here.

**Microsomal Clearance:** Ligand B (23.872) has lower microsomal clearance than Ligand A (31.297), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (28.185) has a longer half-life than Ligand B (10.306), which is desirable.

**P-gp Efflux:** Ligand A (0.084) has lower P-gp efflux than Ligand B (0.038), which is favorable for CNS penetration.

**Binding Affinity:** Ligand A (-8.8 kcal/mol) has a significantly stronger binding affinity than Ligand B (-7.6 kcal/mol). The 1.2 kcal/mol difference is substantial and can outweigh some ADME drawbacks.

**Overall Assessment:**

Ligand A is the stronger candidate. While Ligand B has slightly better metabolic stability and hERG inhibition, Ligand A excels in the most critical areas for a CNS-targeting GPCR: significantly better BBB penetration, superior binding affinity, and better Caco-2 permeability. The lower P-gp efflux is also beneficial. The slightly lower solubility is a concern for both, but the strong affinity and BBB penetration of Ligand A make it the more promising drug candidate.

Output:
0
2025-04-17 03:51:46,686 - INFO - Batch 64 complete. Total preferences: 1024
2025-04-17 03:51:46,686 - INFO - Processing batch 65/512...
2025-04-17 03:52:33,240 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (343.354 and 351.491 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (72.47) is better than Ligand B (64.09) as it is closer to the <90 cutoff for CNS targets.

**logP:** Ligand A (3.522) is optimal (1-3), while Ligand B (0.937) is slightly low, potentially impacting permeability.

**H-Bond Donors/Acceptors:** Both have 1 HBD and 4 HBA, which are within acceptable limits.

**QED:** Both ligands have good QED scores (0.643 and 0.804, respectively), indicating drug-like properties.

**DILI:** Ligand A (85.111) has a significantly higher DILI risk than Ligand B (6.359). This is a major concern for Ligand A.

**BBB:** Ligand A (69.058) has a better BBB penetration percentile than Ligand B (31.214), which is crucial for a CNS target like DRD2.

**Caco-2 Permeability:** Ligand A (-4.428) has a worse Caco-2 permeability than Ligand B (-4.701).

**Aqueous Solubility:** Ligand A (-5.143) has a worse aqueous solubility than Ligand B (-0.903).

**hERG:** Both ligands have low hERG inhibition liability (0.333 and 0.42, respectively).

**Microsomal Clearance:** Ligand B (9.502) has a lower microsomal clearance than Ligand A (83.727), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand B (8.596) has a longer in vitro half-life than Ligand A (23.034).

**P-gp Efflux:** Ligand A (0.385) has a better P-gp efflux profile than Ligand B (0.067).

**Binding Affinity:** Ligand A (-9.4 kcal/mol) has a significantly stronger binding affinity than Ligand B (-7.5 kcal/mol). This is a substantial advantage.

**Overall Assessment:**

Despite Ligand A's superior binding affinity and BBB penetration, its high DILI risk and poor metabolic stability (high Cl_mic, short t1/2) are major drawbacks. Ligand B, while having a weaker affinity, presents a much more favorable ADMET profile (low DILI, better metabolic stability, longer half-life). The difference in binding affinity (1.9 kcal/mol) is significant, but the ADMET liabilities of Ligand A are too concerning for it to be a viable candidate. Ligand B's lower logP is a slight concern, but could be addressed with further optimization.

Output:
1
2025-04-17 03:52:33,241 - INFO - Reasoning:

Let's analyze Ligand A and Ligand B based on the provided guidelines, prioritizing GPCR-specific properties (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (340.335 and 346.431 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (94.57) is slightly above the preferred <90 for CNS targets, while Ligand B (76.46) is well within the range. This favors Ligand B.

**logP:** Ligand A (2.58) is optimal (1-3). Ligand B (0.826) is a bit low, potentially impacting permeability. This favors Ligand A.

**H-Bond Donors/Acceptors:** Both ligands have acceptable HBD (1) and HBA (6/5) counts.

**QED:** Both ligands have reasonable QED scores (0.693 and 0.559), indicating drug-likeness.

**DILI:** Ligand A (85.692) has a higher DILI risk than Ligand B (44.242). This strongly favors Ligand B.

**BBB:** Both ligands have reasonably good BBB penetration (66.111 and 63.901), but neither exceeds the desirable >70 threshold.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values, which is unusual and suggests poor permeability. This is a significant concern for both.

**Aqueous Solubility:** Both ligands have negative solubility values, which is also a concern.

**hERG:** Both ligands have low hERG inhibition liability (0.275 and 0.257), which is good.

**Microsomal Clearance:** Ligand A (77.973) has a higher microsomal clearance than Ligand B (68.51), suggesting lower metabolic stability. This favors Ligand B.

**In vitro Half-Life:** Ligand A (26.314) has a longer half-life than Ligand B (2.628). This favors Ligand A.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.455 and 0.103), which is good, with Ligand B being slightly better.

**Binding Affinity:** Ligand A (-9.3 kcal/mol) has a significantly stronger binding affinity than Ligand B (-6.3 kcal/mol) - a difference of 3 kcal/mol. This is a substantial advantage for Ligand A, potentially outweighing some of its ADME drawbacks.

**Overall Assessment:**

Ligand A has a much stronger binding affinity, a reasonable logP, and a longer half-life. However, it has a higher DILI risk, higher microsomal clearance, and a slightly higher TPSA. Ligand B has better DILI, TPSA, and P-gp efflux, but a weaker binding affinity and lower logP.

Given the importance of binding affinity for GPCRs, and the significant 3 kcal/mol difference, the stronger binding of Ligand A is a major advantage. While the DILI risk is a concern, it might be mitigated through structural modifications. The slightly higher TPSA is also less concerning than the weaker binding of Ligand B.

Output:
1
2025-04-17 03:52:33,241 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (336.351 and 348.447 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (107.71) is slightly above the optimal <90 for CNS targets, but still reasonable. Ligand B (88.76) is excellent, well below 90.

**logP:** Both ligands (1.419 and 1.399) are within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A has 3 HBD and 4 HBA, which is acceptable. Ligand B has 1 HBD and 5 HBA, also acceptable.

**QED:** Both ligands have good QED scores (0.658 and 0.869), indicating good drug-like properties.

**DILI:** Ligand A (82.435) has a higher DILI risk than Ligand B (38.852). This is a significant negative for Ligand A.

**BBB:** Ligand B (78.209) has a substantially better BBB penetration score than Ligand A (26.638). This is *critical* for a CNS target like DRD2.

**Caco-2 Permeability:** Ligand A (-5.367) has poor Caco-2 permeability, while Ligand B (-4.926) is slightly better, but still not great.

**Aqueous Solubility:** Ligand A (-4.39) has slightly better solubility than Ligand B (-0.708).

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.188 and 0.396).

**Microsomal Clearance:** Ligand A (-13.166) has significantly lower (better) microsomal clearance than Ligand B (0.917), indicating better metabolic stability.

**In vitro Half-Life:** Ligand A (41.792) has a longer half-life than Ligand B (12.775).

**P-gp Efflux:** Ligand A (0.071) has lower P-gp efflux than Ligand B (0.015), which is favorable for CNS penetration.

**Binding Affinity:** Ligand B (-8.1) has a significantly stronger binding affinity than Ligand A (-10.5). This is a substantial advantage.

**Overall Assessment:**

Ligand B clearly emerges as the more promising candidate. While Ligand A has better metabolic stability and P-gp efflux, Ligand B's superior BBB penetration, significantly stronger binding affinity, and lower DILI risk outweigh these advantages. The BBB score is particularly important for a CNS target. The Caco-2 permeability is a concern for both, but can be addressed with formulation strategies.

Output:
1
2025-04-17 03:52:33,241 - INFO - Reasoning:

Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight (MW):** Both ligands (360.376 and 346.515 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (58.64) is better than Ligand B (49.41). Both are below the 90 A^2 threshold desirable for CNS targets, which is excellent.

**3. logP:** Ligand A (1.746) is within the optimal range (1-3), while Ligand B (3.668) is towards the higher end. While still acceptable, higher logP can sometimes lead to off-target effects.

**4. H-Bond Donors (HBD):** Both ligands have 1 HBD, which is well within the acceptable limit of <=5.

**5. H-Bond Acceptors (HBA):** Ligand A has 3 HBAs, and Ligand B has 2. Both are below the limit of <=10.

**6. QED:** Both ligands have reasonable QED scores (0.408 and 0.538, respectively), indicating acceptable drug-likeness. Ligand B is slightly better.

**7. DILI:** Ligand A (22.218) has a significantly lower DILI risk than Ligand B (11.128), which is a major advantage.

**8. BBB:** Both ligands have excellent BBB penetration (80.264 and 79.721, respectively), exceeding the 70% threshold for CNS targets.

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.668 and -4.949). This is unusual and suggests poor permeability. However, these values are on a log scale and are likely representing very low permeability.

**10. Aqueous Solubility:** Both ligands have very poor aqueous solubility (-2.627 and -3.22). This is a significant concern for bioavailability.

**11. hERG Inhibition:** Both ligands show low hERG inhibition risk (0.56 and 0.632).

**12. Microsomal Clearance (Cl_mic):** Ligand A (24.778) has a lower microsomal clearance than Ligand B (61.648), suggesting better metabolic stability.

**13. In vitro Half-Life:** Ligand A (-1.697) has a shorter half-life than Ligand B (-18.213). This is a disadvantage.

**14. P-gp Efflux:** Both ligands have low P-gp efflux liability (0.107 and 0.294), which is good for CNS exposure.

**15. Binding Affinity:** Both ligands have very similar and strong binding affinities (-8.4 and -8.0 kcal/mol). The difference is less than 0.5 kcal/mol, so it's not a major deciding factor.

**Overall Assessment:**

Ligand A is preferable despite the slightly shorter half-life. It has a substantially lower DILI risk, better metabolic stability (lower Cl_mic), and a more optimal logP. While both have poor solubility and permeability, the lower DILI and improved metabolic profile of Ligand A are more critical for a CNS-targeting drug. The affinity is comparable between the two.

Output:
0
2025-04-17 03:52:33,241 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (362.417 Da) is slightly higher than Ligand B (337.471 Da), but both are acceptable.

**2. TPSA:** Ligand A (87.66) is closer to the upper limit for CNS targets (<=90), while Ligand B (62.73) is well within the optimal range. This favors Ligand B.

**3. logP:** Both ligands have logP values within the optimal range (1-3). Ligand A (1.734) is slightly lower, while Ligand B (3.739) is at the higher end. While higher logP can sometimes cause issues, it's not a major concern here.

**4. H-Bond Donors:** Ligand A (3) and Ligand B (2) are both within the acceptable limit of <=5.

**5. H-Bond Acceptors:** Ligand A (4) and Ligand B (5) are both within the acceptable limit of <=10.

**6. QED:** Both ligands have good QED scores, with Ligand B (0.841) being slightly better than Ligand A (0.583).

**7. DILI:** Both ligands have acceptable DILI risk, with Ligand B (48.623) being slightly lower (better) than Ligand A (37.263).

**8. BBB:** This is a crucial parameter for CNS targets. Ligand B (82.047) has a significantly higher BBB percentile than Ligand A (52.268). This is a major advantage for Ligand B.

**9. Caco-2 Permeability:** Both have negative values, which is unusual and likely indicates a scaling issue. However, the values are similar and don't strongly differentiate the two.

**10. Aqueous Solubility:** Both have negative values, again likely a scaling issue. The values are similar and don't strongly differentiate the two.

**11. hERG Inhibition:** Both ligands have low hERG inhibition risk, with Ligand A (0.507) being slightly lower (better) than Ligand B (0.722).

**12. Microsomal Clearance:** Ligand B (75.095) has a higher microsomal clearance than Ligand A (33.677), indicating lower metabolic stability. This favors Ligand A.

**13. In vitro Half-Life:** Ligand A (-12.089) has a negative half-life, which is impossible. This is a significant red flag. Ligand B (36.36) has a reasonable half-life.

**14. P-gp Efflux:** Both ligands have low P-gp efflux liability (Ligand A: 0.15, Ligand B: 0.171), which is good.

**15. Binding Affinity:** Ligand B (-8.5 kcal/mol) has a slightly better binding affinity than Ligand A (-7.5 kcal/mol). While both are good, the 1 kcal/mol difference is noteworthy.

**Overall Assessment:**

Ligand B is the stronger candidate. It has a significantly better BBB score, a better QED score, and a slightly better binding affinity. While Ligand A has better metabolic stability and slightly lower hERG risk, the negative and unrealistic in vitro half-life is a major concern. The superior BBB penetration of Ligand B is critical for a CNS target like DRD2, outweighing the minor advantages of Ligand A.

Output:
1
2025-04-17 03:52:33,242 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (385.551 and 368.503 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (63.68) is better than Ligand B (75.63). For CNS targets, we want TPSA <= 90, both are within this range, but A is closer to the optimal value.

**3. logP:** Both ligands have good logP values (3.322 and 2.531), falling within the 1-3 range.

**4. H-Bond Donors:** Both have 0 HBD, which is acceptable.

**5. H-Bond Acceptors:** Ligand A has 5 HBA, and Ligand B has 6. Both are within the acceptable limit of <=10.

**6. QED:** Both ligands have similar QED values (0.676 and 0.691), indicating good drug-like properties.

**7. DILI:** Ligand A (47.77) has a slightly better DILI score than Ligand B (52.462), both are acceptable (<60).

**8. BBB:** Ligand A (89.492) has a significantly better BBB score than Ligand B (75.611). This is *critical* for a CNS target like DRD2. A score >70 is desirable, and A is closer.

**9. Caco-2 Permeability:** Both have negative Caco-2 values (-5.054 and -5.036). This is unusual and suggests poor permeability, but the scale isn't specified, so it's hard to interpret.

**10. Aqueous Solubility:** Both have negative solubility values (-4.01 and -2.456). Similar to Caco-2, the scale is unclear, but suggests poor solubility.

**11. hERG Inhibition:** Both ligands show low hERG inhibition liability (0.438 and 0.357), which is good.

**12. Microsomal Clearance:** Ligand A (72.936) has a higher microsomal clearance than Ligand B (22.911). This means Ligand B is more metabolically stable, which is preferable.

**13. In vitro Half-Life:** Ligand B (17.477) has a significantly longer in vitro half-life than Ligand A (-28.358). This is a major advantage for Ligand B.

**14. P-gp Efflux:** Ligand A (0.603) has slightly higher P-gp efflux than Ligand B (0.284), meaning Ligand B will have better CNS exposure.

**15. Binding Affinity:** Ligand A (-9.3 kcal/mol) has a significantly stronger binding affinity than Ligand B (-5.7 kcal/mol). This is a substantial advantage, potentially outweighing some ADME drawbacks. A difference of >1.5 kcal/mol is considered significant.

**Overall Assessment:**

While Ligand B has better metabolic stability (lower Cl_mic, longer t1/2) and P-gp efflux, the *much* stronger binding affinity of Ligand A (-9.3 vs -5.7 kcal/mol) and significantly better BBB penetration (89.492 vs 75.611) are decisive. For a CNS GPCR target, strong binding and good brain penetration are paramount. The slightly worse metabolic stability of Ligand A can potentially be addressed through further optimization.

Output:
1
2025-04-17 03:52:33,242 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (349.431 and 361.389 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (71.44) is significantly better than Ligand B (107.53). For CNS targets, we want TPSA <= 90, and A is comfortably within that range, while B is above.

**logP:** Ligand A (0.887) is slightly lower than optimal (1-3), but still acceptable. Ligand B (-0.352) is below 1, which could hinder permeation.

**H-Bond Donors/Acceptors:** Ligand A (0 HBD, 5 HBA) is preferable to Ligand B (4 HBD, 4 HBA). Both are within acceptable limits, but fewer H-bonds generally improve permeability.

**QED:** Ligand A (0.61) has a better QED score than Ligand B (0.35), indicating a more drug-like profile.

**DILI:** Both ligands have low DILI risk (A: 35.712, B: 33.773), both below the 40 threshold.

**BBB:** Ligand A (73.866) has a significantly higher BBB penetration percentile than Ligand B (40.326). This is a *critical* advantage for a CNS target like DRD2.

**Caco-2 Permeability:** Ligand A (-4.492) is better than Ligand B (-4.966), suggesting better intestinal absorption.

**Aqueous Solubility:** Ligand A (-2.258) is slightly better than Ligand B (-2.069), though both are quite poor.

**hERG:** Both ligands have low hERG risk (A: 0.363, B: 0.587).

**Microsomal Clearance:** Ligand A (40.201) has higher clearance than Ligand B (13.18), meaning B is more metabolically stable.

**In vitro Half-Life:** Ligand B (-16.12) has a much longer half-life than Ligand A (-4.036). This is a significant advantage.

**P-gp Efflux:** Ligand A (0.163) has lower P-gp efflux than Ligand B (0.034), which is favorable for CNS exposure.

**Binding Affinity:** Ligand B (-7.4) has a slightly better binding affinity than Ligand A (-7.1), but the difference is relatively small (0.3 kcal/mol).

**Overall Assessment:**

Ligand A excels in key GPCR properties like TPSA and BBB penetration. Its logP is acceptable, and its QED score is good. While its metabolic stability and half-life are weaker than Ligand B, the superior BBB penetration and TPSA, coupled with acceptable affinity, make it a more promising candidate for a CNS-targeting drug like a DRD2 ligand. The slight affinity advantage of Ligand B is unlikely to overcome the significant drawbacks in TPSA and BBB.

Output:
0
2025-04-17 03:52:33,242 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (350.503 and 386.283 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (49.85) is significantly better than Ligand B (110). For CNS targets, we want TPSA <= 90, and A is well within this range, while B is considerably above.

**logP:** Both ligands have good logP values (2.709 and 2.173), falling within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A (0 HBD, 3 HBA) is more favorable than Ligand B (3 HBD, 5 HBA). Lower values generally improve permeability.

**QED:** Both ligands have acceptable QED scores (0.733 and 0.665), indicating good drug-like properties.

**DILI:** Ligand A (14.889) has a much lower DILI risk than Ligand B (57.542). This is a significant advantage.

**BBB:** Ligand A (68.592) is acceptable but not great for a CNS target. Ligand B (81.698) is better, exceeding the 70% threshold, which is highly desirable for CNS penetration.

**Caco-2 Permeability:** Ligand A (-4.108) has poor Caco-2 permeability, while Ligand B (-5.437) is also poor, but slightly worse.

**Aqueous Solubility:** Both ligands have very poor aqueous solubility (-2.122 and -3.472). This could pose formulation challenges.

**hERG:** Both ligands have low hERG inhibition risk (0.215 and 0.454).

**Microsomal Clearance:** Ligand A (47.912) has higher microsomal clearance than Ligand B (20.771), indicating lower metabolic stability.

**In vitro Half-Life:** Ligand B (3.612) has a slightly longer half-life than Ligand A (-19.853), which is a positive.

**P-gp Efflux:** Both ligands show low P-gp efflux (0.071 and 0.076), which is good for CNS exposure.

**Binding Affinity:** Both ligands have excellent binding affinity (-8.0 and -8.1 kcal/mol), with Ligand B being marginally better. However, the difference is small and may not be decisive.

**Overall Assessment:**

Considering the GPCR-specific priorities, Ligand A is more promising despite the lower BBB penetration. Its significantly lower TPSA, DILI risk, and better metabolic stability (lower Cl_mic) outweigh the slightly lower BBB score. While both have poor solubility and Caco-2 permeability, these can potentially be addressed with formulation strategies. The marginal affinity difference isn't enough to favor Ligand B given the other factors.

Output:
0
2025-04-17 03:52:33,242 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (340.471 Da) is slightly better, being closer to the lower end which can aid permeability.

**TPSA:** Ligand A (50.16) is significantly better than Ligand B (96.01). For CNS targets, we want TPSA <= 90, and Ligand A comfortably meets this, while Ligand B exceeds it.

**logP:** Both ligands have good logP values (A: 2.743, B: 1.668) falling within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A (HBD=1, HBA=4) is preferable to Ligand B (HBD=3, HBA=5) as lower values generally improve permeability. Both are within acceptable limits.

**QED:** Both ligands have reasonable QED values (A: 0.91, B: 0.666), indicating good drug-like properties. Ligand A is better.

**DILI:** Ligand A (18.573) has a much lower DILI risk than Ligand B (41.838). This is a significant advantage.

**BBB:** Ligand A (78.092) has a better BBB percentile than Ligand B (63.086). Both are reasonably good, but >70 is desirable for CNS targets, and A is closer.

**Caco-2 Permeability:** Ligand A (-4.997) has a better Caco-2 permeability than Ligand B (-5.241), indicating better intestinal absorption.

**Aqueous Solubility:** Both ligands have poor aqueous solubility (-2.46 and -2.631, respectively). This could be a formulation challenge, but is not a deciding factor here.

**hERG Inhibition:** Ligand A (0.544) has a slightly better hERG profile than Ligand B (0.076), indicating lower cardiotoxicity risk.

**Microsomal Clearance:** Both ligands have similar microsomal clearance (A: 21.077, B: 21.989).

**In vitro Half-Life:** Ligand B (25.156) has a longer in vitro half-life than Ligand A (13.685). This is a positive for Ligand B, potentially allowing for less frequent dosing.

**P-gp Efflux:** Ligand A (0.282) has lower P-gp efflux liability than Ligand B (0.013), which is crucial for CNS penetration.

**Binding Affinity:** Ligand B (-8.8 kcal/mol) has a slightly better binding affinity than Ligand A (-7.7 kcal/mol). This is a 1.1 kcal/mol difference, which is significant, but needs to be weighed against other factors.

**Overall Assessment:**

Ligand A is superior overall. While Ligand B has a slightly better binding affinity and half-life, Ligand A excels in critical properties for a CNS-targeting GPCR ligand: TPSA, BBB penetration, DILI risk, and P-gp efflux. The better TPSA and BBB are particularly important for DRD2, and the lower DILI risk is a significant safety advantage. The affinity difference, while noticeable, is not large enough to outweigh these substantial ADME/Tox benefits.

Output:
1
2025-04-17 03:52:33,242 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (360.414 Da) is slightly higher than Ligand B (339.363 Da), but both are acceptable.

**TPSA:** Ligand A (64.16) is excellent for CNS penetration, well below the 90 A^2 threshold. Ligand B (118.37) is higher, but still potentially acceptable, though less ideal.

**logP:** Ligand A (3.114) is optimal. Ligand B (0.173) is quite low, potentially hindering membrane permeability and CNS entry.

**H-Bond Donors/Acceptors:** Ligand A (0 HBD, 6 HBA) is favorable. Ligand B (1 HBD, 8 HBA) is also reasonable, but slightly higher counts could affect permeability.

**QED:** Both ligands have good QED scores (A: 0.672, B: 0.72), indicating drug-like properties.

**DILI:** Ligand A (85.615) has a higher DILI risk than Ligand B (78.247), but both are below the concerning 60 percentile.

**BBB:** Ligand A (84.839) shows excellent BBB penetration, exceeding the 70% threshold. Ligand B (50.95) is significantly lower, which is a major concern for a CNS target like DRD2.

**Caco-2 Permeability:** Ligand A (-4.727) is poor, while Ligand B (-5.554) is even worse. Both are quite low, indicating poor intestinal absorption. This is less critical for CNS targets where direct delivery or BBB penetration are key.

**Aqueous Solubility:** Both ligands have very poor aqueous solubility (A: -3.237, B: -2.144). This could pose formulation challenges.

**hERG Inhibition:** Both ligands have very low hERG inhibition risk (A: 0.379, B: 0.043).

**Microsomal Clearance:** Ligand A (73.855) has moderate clearance, while Ligand B (3.282) has very low clearance, suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (26.821 hours) has a reasonable half-life. Ligand B (-9.294 hours) has a negative half-life, which is not physically possible and indicates a significant issue with the data or the molecule itself.

**P-gp Efflux:** Ligand A (0.271) shows low P-gp efflux, which is good for CNS penetration. Ligand B (0.037) also shows very low P-gp efflux.

**Binding Affinity:** Both ligands have excellent binding affinities (A: -8.9 kcal/mol, B: -9.1 kcal/mol), with Ligand B being slightly better. However, the difference is small and likely less important than the other ADME properties.

**Conclusion:**

Despite the slightly better binding affinity of Ligand B, its extremely poor in vitro half-life and significantly lower BBB penetration make it a far less viable candidate. Ligand A, while having a higher DILI risk and poor Caco-2 permeability, possesses a much more favorable profile overall, especially regarding BBB penetration, which is crucial for a CNS target like DRD2. The moderate clearance and reasonable half-life of Ligand A are also advantageous.

Output:
1
2025-04-17 03:52:33,242 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (350.503 and 349.431 Da) fall comfortably within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (69.64) is excellent, well below the 90 A^2 threshold for CNS targets. Ligand B (111.45) is higher, but still potentially acceptable, though less ideal.

**3. logP:** Ligand A (2.637) is optimal (1-3). Ligand B (0.477) is a bit low, potentially hindering membrane permeability.

**4. H-Bond Donors:** Ligand A (2) and Ligand B (3) are both within the acceptable limit of <=5.

**5. H-Bond Acceptors:** Ligand A (3) and Ligand B (5) are both within the acceptable limit of <=10.

**6. QED:** Both ligands have good QED values (0.628 and 0.59), indicating drug-like properties.

**7. DILI:** Ligand A (23.769) has a significantly lower DILI risk than Ligand B (16.906), which is a positive attribute.

**8. BBB:** This is crucial for a CNS target. Ligand A (65.529) has a good BBB percentile, while Ligand B (32.687) is considerably lower, suggesting poorer brain penetration.

**9. Caco-2 Permeability:** Ligand A (-4.66) shows poor permeability, while Ligand B (-5.125) is also poor.

**10. Aqueous Solubility:** Ligand A (-3.253) and Ligand B (-1.872) both show poor solubility.

**11. hERG Inhibition:** Both ligands have low hERG inhibition risk (0.338 and 0.217).

**12. Microsomal Clearance:** Ligand A (62.565) has higher clearance than Ligand B (-9.857), indicating lower metabolic stability.

**13. In vitro Half-Life:** Ligand B (31.594) has a longer half-life than Ligand A (-29.73), which is a positive.

**14. P-gp Efflux:** Ligand A (0.488) has lower P-gp efflux than Ligand B (0.017), which is favorable for CNS penetration.

**15. Binding Affinity:** Both ligands have very good binding affinities (-7.5 and -7.2 kcal/mol). The difference of 0.3 kcal/mol is not substantial enough to override other significant ADME differences.

**Overall Assessment:**

Ligand A is the better candidate. While both have good affinity, Ligand A has a significantly better BBB percentile, lower DILI risk, and lower P-gp efflux. Although its Caco-2 permeability and solubility are poor, the BBB is the most important factor for a CNS target like DRD2. Ligand B's lower logP and poor BBB penetration are significant drawbacks. The longer half-life of Ligand B is a plus, but not enough to overcome the other deficiencies.

Output:
1
2025-04-17 03:52:33,242 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (369.443 and 362.459 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (117.36) is slightly above the optimal <90 for CNS targets, but still reasonable. Ligand B (93.01) is better, falling comfortably under 90.

**3. logP:** Ligand A (0.793) is a bit low, potentially hindering permeability. Ligand B (1.488) is better, falling within the optimal 1-3 range.

**4. H-Bond Donors:** Ligand A (3) is acceptable. Ligand B (1) is even better, potentially improving permeability.

**5. H-Bond Acceptors:** Ligand A (6) is acceptable. Ligand B (7) is also acceptable.

**6. QED:** Both ligands have good QED scores (0.524 and 0.87), indicating good drug-like properties. Ligand B is superior here.

**7. DILI:** Ligand A (77.472) has a higher DILI risk than Ligand B (72.819), although both are reasonably low.

**8. BBB:** Ligand A (35.246) has a poor BBB percentile, a significant drawback for a CNS target. Ligand B (43.932) is better, but still not ideal (aim for >70).

**9. Caco-2:** Both have negative Caco-2 values (-5.206 and -5.147), which is unusual and suggests poor permeability. This is a concern for both.

**10. Solubility:** Both have negative solubility values (-3.113 and -3.016), indicating very poor aqueous solubility. This is a major issue for both.

**11. hERG:** Both have very low hERG inhibition liability (0.089 and 0.191), which is excellent.

**12. Cl_mic:** Ligand A (21.935) has a lower microsomal clearance than Ligand B (30.104), suggesting better metabolic stability.

**13. t1/2:** Ligand A (-6.497) has a negative in vitro half-life, which is concerning. Ligand B (-1.062) is also negative, but less so.

**14. Pgp:** Both have low P-gp efflux liability (0.09 and 0.05), which is good for CNS penetration.

**15. Binding Affinity:** Ligand B (-8.4 kcal/mol) has a significantly stronger binding affinity than Ligand A (0.0 kcal/mol). This is a substantial advantage.

**Overall Assessment:**

Ligand B is clearly the better candidate. While both have issues with solubility and Caco-2 permeability, Ligand B excels in key areas for a CNS GPCR target: better logP, a significantly stronger binding affinity, a slightly better BBB percentile, and a higher QED score. The lower DILI risk is also a plus. Ligand A's extremely poor BBB penetration and very weak binding affinity are major drawbacks. The negative half-life values for both are concerning and would require further investigation, but the affinity difference is the most critical factor here.

Output:
1
2025-04-17 03:52:33,243 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (396.171 and 369.29 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (45.23) is excellent, well below the 90 A^2 threshold for CNS targets. Ligand B (74.43) is higher, but still potentially acceptable, though less ideal.

**logP:** Ligand A (4.621) is slightly high, potentially leading to solubility issues or off-target interactions. Ligand B (1.259) is low, which might hinder membrane permeability.

**H-Bond Donors/Acceptors:** Ligand A (HBD=1, HBA=3) and Ligand B (HBD=2, HBA=3) both have reasonable numbers of H-bond donors and acceptors, falling within the guidelines.

**QED:** Both ligands have good QED scores (0.606 and 0.768), indicating drug-like properties.

**DILI:** Ligand A (79.333) has a higher DILI risk than Ligand B (58.434). This is a negative for Ligand A.

**BBB:** Both ligands have excellent BBB penetration (75.649 and 74.292), which is crucial for a CNS target like DRD2.

**Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and suggests potential issues with intestinal absorption prediction. However, this is less critical for a CNS target where direct delivery is possible.

**Aqueous Solubility:** Both ligands have poor predicted aqueous solubility (-5.406 and -2.624). This is a concern, but can sometimes be mitigated with formulation strategies.

**hERG Inhibition:** Both ligands show low hERG inhibition liability (0.575 and 0.504), which is good.

**Microsomal Clearance:** Ligand A (60.522) has a higher microsomal clearance than Ligand B (-1.369), suggesting lower metabolic stability. This is a significant drawback for Ligand A.

**In vitro Half-Life:** Ligand A (77.539) has a longer in vitro half-life than Ligand B (-22.45), which is a positive. However, the negative value for Ligand B is concerning and likely an artifact of the prediction.

**P-gp Efflux:** Ligand A (0.412) shows moderate P-gp efflux, while Ligand B (0.024) shows very low P-gp efflux. Lower P-gp efflux is preferred for CNS penetration, giving an edge to Ligand B.

**Binding Affinity:** Ligand A (-9.4 kcal/mol) has a significantly stronger binding affinity than Ligand B (0.0 kcal/mol). This is a *major* advantage for Ligand A, potentially outweighing some of its ADME drawbacks.

**Overall Assessment:**

Despite Ligand A's higher DILI risk and higher logP, its *exceptionally* strong binding affinity (-9.4 kcal/mol) is a decisive factor. The strong binding is likely to overcome some of the ADME liabilities. Ligand B has better ADME properties overall, but its binding affinity is essentially non-existent. For a GPCR, strong binding is paramount, and the CNS-relevant properties (BBB, TPSA, Pgp) are reasonably well-addressed by both compounds.

Output:
1
2025-04-17 03:52:33,243 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (458.26 Da) is higher, but still acceptable. Ligand B (346.475 Da) is lower, potentially aiding permeability.

**TPSA:** Ligand A (105.14) is above the ideal 90 for CNS targets, which is a concern. Ligand B (78.35) is well within the desired range for CNS penetration.

**logP:** Both ligands have good logP values (A: 2.255, B: 1.898), falling within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Both have 2 HBD and a reasonable number of HBA (A: 6, B: 5), satisfying the criteria.

**QED:** Both ligands have good QED scores (A: 0.687, B: 0.752), indicating drug-like properties.

**DILI:** Ligand A has a significantly higher DILI risk (81.427%) than Ligand B (13.532%). This is a major red flag for Ligand A.

**BBB:** Ligand B has a much better BBB penetration percentile (68.282%) than Ligand A (36.06%). This is critical for a CNS target like DRD2.

**Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and suggests a potential issue with the data or modeling. However, the magnitude is similar.

**Aqueous Solubility:** Both have negative solubility values, also unusual. Again, the magnitude is similar.

**hERG:** Both have low hERG inhibition liability (A: 0.342, B: 0.281), which is good.

**Microsomal Clearance:** Ligand B has a higher microsomal clearance (33.473) than Ligand A (21.501), suggesting Ligand A may have better metabolic stability.

**In vitro Half-Life:** Ligand A has a significantly longer half-life (-7.766 hours) than Ligand B (5.019 hours), which is a positive attribute.

**P-gp Efflux:** Both have low P-gp efflux liability (A: 0.049, B: 0.103).

**Binding Affinity:** Ligand A (-8.6 kcal/mol) has a slightly better binding affinity than Ligand B (-7.5 kcal/mol). This 1.1 kcal/mol difference is significant, but needs to be weighed against other factors.

**Overall Assessment:**

Ligand B is the more promising candidate. While Ligand A has slightly better affinity and metabolic stability, its significantly higher DILI risk and poor BBB penetration are major drawbacks for a CNS-targeting drug. Ligand B's superior BBB penetration, much lower DILI risk, and acceptable affinity make it the preferred choice. The unusual negative values for Caco-2 and solubility warrant further investigation, but do not outweigh the other critical differences.

Output:
1
2025-04-17 03:52:33,243 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the acceptable range (200-500 Da). Ligand A (443.75 Da) is towards the higher end, while Ligand B (339.439 Da) is more ideal.

**TPSA:** Ligand A (66.48) is higher than the ideal <90 for CNS targets, but still potentially acceptable. Ligand B (43.86) is excellent, well below the threshold.

**logP:** Ligand A (4.339) is slightly high, potentially leading to solubility issues or off-target interactions. Ligand B (1.355) is within the optimal range.

**H-Bond Donors/Acceptors:** Both have reasonable HBD/HBA counts (A: 1/3, B: 0/3), well within the guidelines.

**QED:** Both ligands have similar, good QED values (A: 0.764, B: 0.778).

**DILI:** Ligand A has a high DILI risk (90.423), which is a significant concern. Ligand B has a much lower DILI risk (19.426), a major advantage.

**BBB:** Both ligands have good BBB penetration (A: 66.344, B: 61.691), but neither exceeds the desirable >70 threshold.

**Caco-2 Permeability:** Both show poor Caco-2 permeability (A: -4.72, B: -4.421), indicating potential absorption issues.

**Aqueous Solubility:** Both ligands exhibit very poor aqueous solubility (A: -5.29, B: -1.331).

**hERG Inhibition:** Both ligands have low hERG inhibition risk (A: 0.679, B: 0.319).

**Microsomal Clearance:** Ligand A has a higher microsomal clearance (17.658) than Ligand B (4.425), suggesting lower metabolic stability.

**In vitro Half-Life:** Ligand A has a longer in vitro half-life (78.287) than Ligand B (4.73).

**P-gp Efflux:** Both ligands show low P-gp efflux (A: 0.526, B: 0.045), which is favorable for CNS penetration.

**Binding Affinity:** Both ligands have excellent binding affinity (A: -9.9 kcal/mol, B: -9.0 kcal/mol). Ligand A is slightly better, but the difference is less than 1.5 kcal/mol.

**Overall Assessment:**

While Ligand A has slightly better binding affinity and a longer half-life, its significantly higher DILI risk and higher logP are major drawbacks. The poor solubility and Caco-2 permeability are also concerning for both. However, the DILI risk for Ligand A is a critical issue that would likely halt its development. Ligand B, despite its slightly weaker affinity, has a much more favorable safety profile (lower DILI) and a better logP, making it the more promising candidate.

Output:
1
2025-04-17 03:52:33,243 - INFO - Okay, let's analyze these two ligands for their potential as DRD2 drug candidates. DRD2 is a GPCR in the CNS, so BBB penetration, logP, Pgp efflux, TPSA, and binding affinity are key.

**Ligand A: [349.391, 108.77 ,   1.393,   3.   ,   6.   ,   0.548,  62.35 ,  59.48 , -5.093,  -2.802,   0.432, -10.01 ,  25.887,   0.018,  -9.6  ]**
**Ligand B: [350.419, 107.61 ,  -0.711,   3.   ,   4.   ,   0.569,  33.346,  51.221, -4.938,  -2.601,   0.055,   0.556,  -3.663,   0.008,  -8.2  ]**

1. **MW:** Both are within the ideal range (349-350 Da). No significant difference.
2. **TPSA:** Both are reasonably good (108.77 and 107.61), but slightly above the optimal <90 for CNS targets. Ligand B is marginally better.
3. **logP:** Ligand A (1.393) is better than Ligand B (-0.711).  A logP between 1-3 is preferred, and Ligand B is a bit low, potentially hindering permeability.
4. **HBD:** Both have 3 HBD, which is acceptable.
5. **HBA:** Ligand A has 6 HBA, Ligand B has 4. Both are within the acceptable range of <=10.
6. **QED:** Both are good (0.548 and 0.569), indicating drug-like properties.
7. **DILI:** Ligand A (62.35) has a higher DILI risk than Ligand B (33.346). This is a significant negative for Ligand A.
8. **BBB:** Ligand A (59.48) has a lower BBB percentile than Ligand B (51.221). Both are below the desirable >70 for CNS targets, but Ligand B is closer.
9. **Caco-2:** Ligand A (-5.093) has a worse Caco-2 permeability than Ligand B (-4.938). Lower values suggest poorer absorption.
10. **Solubility:** Ligand A (-2.802) has slightly worse solubility than Ligand B (-2.601).
11. **hERG:** Both are very low (0.432 and 0.055), indicating low cardiotoxicity risk. Ligand B is slightly better.
12. **Cl_mic:** Ligand A (-10.01) has a much lower (better) microsomal clearance than Ligand B (0.556), suggesting better metabolic stability. This is a major advantage for Ligand A.
13. **t1/2:** Ligand A (25.887) has a much longer half-life than Ligand B (-3.663). This is a significant advantage for Ligand A.
14. **Pgp:** Both are very low (0.018 and 0.008), indicating low P-gp efflux. Ligand B is slightly better.
15. **Binding Affinity:** Ligand A (-9.6) has a significantly stronger binding affinity than Ligand B (-8.2). This is a substantial advantage for Ligand A, potentially outweighing some ADME concerns.

**Overall Assessment:**

Ligand A has a significantly better binding affinity and metabolic stability (lower Cl_mic, longer t1/2). While its DILI risk and BBB penetration are less favorable than Ligand B, the strong binding affinity is a critical factor for GPCR targets. The difference in affinity (>1.5 kcal/mol) is substantial enough to potentially overcome the ADME liabilities, especially considering optimization could address the DILI and BBB issues. Ligand B has better ADME properties overall, but its weaker binding affinity makes it less likely to be a successful drug candidate.

Output:
1
2025-04-17 03:52:33,243 - INFO - Batch 65 complete. Total preferences: 1040
2025-04-17 03:52:33,243 - INFO - Processing batch 66/512...
2025-04-17 03:53:14,583 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B based on the provided guidelines, prioritizing GPCR-specific properties (BBB, logP, Pgp, TPSA, and affinity) for DRD2.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (342.374) is slightly lower, which could be beneficial for permeability.

**TPSA:** Ligand A (58.87) is excellent for CNS penetration, well below the 90 A^2 threshold. Ligand B (99.77) is higher, but still potentially acceptable, though less ideal.

**logP:** Both ligands have good logP values (A: 2.796, B: 2.341), falling within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A (HBD=1, HBA=5) and Ligand B (HBD=3, HBA=5) both have reasonable H-bond characteristics, within the acceptable limits.

**QED:** Both ligands have acceptable QED scores (A: 0.775, B: 0.705), indicating good drug-like properties.

**DILI:** Ligand A (68.244) has a slightly higher DILI risk than Ligand B (59.403), but both are below the concerning threshold of 60.

**BBB:** This is a crucial parameter for a CNS target like DRD2. Ligand A has a significantly better BBB percentile (70.686) compared to Ligand B (37.379). This is a major advantage for Ligand A.

**Caco-2 Permeability:** Ligand A (-4.539) has a worse Caco-2 permeability score than Ligand B (-5.671). However, this is a negative score and lower values are worse.

**Aqueous Solubility:** Ligand A (-3.175) has slightly better solubility than Ligand B (-2.8).

**hERG:** Both ligands have low hERG inhibition liability (A: 0.868, B: 0.123), indicating a low risk of cardiotoxicity.

**Microsomal Clearance:** Ligand B (-4.148) has a *negative* microsomal clearance, which is highly unusual and suggests very high metabolic stability. Ligand A (34.338) has a moderate clearance.

**In vitro Half-Life:** Ligand B (6.01) has a shorter half-life than Ligand A (12.163).

**P-gp Efflux:** Ligand A (0.348) has lower P-gp efflux liability than Ligand B (0.088), which is favorable for CNS exposure.

**Binding Affinity:** Both ligands have excellent binding affinities (A: -8.5 kcal/mol, B: -8.6 kcal/mol). The difference is minimal.

**Conclusion:**

Considering all factors, especially the GPCR-specific priorities, **Ligand A is the more promising drug candidate.** While Ligand B has better metabolic stability (negative Cl_mic) and slightly better Caco-2 permeability, Ligand A's significantly superior BBB penetration (70.686 vs 37.379) and lower P-gp efflux outweigh these advantages for a CNS target like DRD2. The comparable binding affinity and acceptable ADME properties further support this conclusion.

Output:
1
2025-04-17 03:53:14,583 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (348.443 and 347.415 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (77.52) is significantly better than Ligand B (88.6). For CNS targets, we want TPSA <= 90, and A is closer to the optimal <= 60 range. B is pushing the upper limit.

**3. logP:** Both ligands have good logP values (3.109 and 1.881), falling within the 1-3 range. Ligand A is slightly better, being closer to the optimal value.

**4. H-Bond Donors:** Both have 1 HBD, which is good.

**5. H-Bond Acceptors:** Both have 5 HBA, which is good.

**6. QED:** Both ligands have similar QED values (0.799 and 0.761), indicating good drug-likeness.

**7. DILI:** Both ligands have acceptable DILI risk (54.866 and 64.444), below the 60 threshold. Ligand A is slightly better.

**8. BBB:** Ligand A (65.413) has a better BBB percentile than Ligand B (59.093), although neither are above the desirable >70 threshold. This is a critical factor for CNS targets.

**9. Caco-2 Permeability:** Both have negative Caco-2 values (-4.13 and -4.448), which is unusual and suggests poor permeability. This is a significant drawback for both.

**10. Aqueous Solubility:** Both have negative solubility values (-4.701 and -3.382), indicating very poor aqueous solubility. This is a major concern for both.

**11. hERG Inhibition:** Ligand A (0.077) has a much lower hERG inhibition liability than Ligand B (0.236). This is a significant advantage for A.

**12. Microsomal Clearance:** Ligand A (95.125) has higher microsomal clearance than Ligand B (44.758), indicating lower metabolic stability. This is a drawback for A.

**13. In vitro Half-Life:** Ligand B (-30.892) has a better (less negative) in vitro half-life than Ligand A (-44.706), indicating better stability.

**14. P-gp Efflux:** Ligand A (0.035) has a much lower P-gp efflux liability than Ligand B (0.095). This is a significant advantage for A, especially for CNS penetration.

**15. Binding Affinity:** Ligand A (-7.9 kcal/mol) has a slightly better binding affinity than Ligand B (-7.3 kcal/mol). While both are good, the 0.6 kcal/mol difference is notable.

**Overall Assessment:**

Ligand A is the better candidate. While both have poor Caco-2 and solubility, A excels in crucial GPCR-relevant properties: lower TPSA, better BBB penetration, significantly lower hERG risk, and lower P-gp efflux. The slightly better binding affinity also contributes. Although A has higher microsomal clearance, the other advantages outweigh this drawback, particularly for a CNS target where BBB penetration and minimizing efflux are paramount.

Output:
0
2025-04-17 03:53:14,583 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (350.478 and 349.391 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (49.41) is excellent, well below the 90 A^2 threshold for CNS targets. Ligand B (125.79) is higher, but still potentially acceptable, though less ideal.

**3. logP:** Ligand A (3.512) is optimal. Ligand B (0.043) is very low, which is a significant concern for permeability and CNS penetration.

**4. H-Bond Donors:** Both ligands have acceptable HBD counts (1 and 2, respectively), well below the limit of 5.

**5. H-Bond Acceptors:** Ligand A (2) is good. Ligand B (7) is higher, but still within the acceptable limit of 10.

**6. QED:** Both ligands have similar and good QED values (0.797 and 0.735), indicating good drug-like properties.

**7. DILI:** Ligand A (20.822) has a much lower DILI risk than Ligand B (65.762), which is a substantial advantage.

**8. BBB:** Ligand A (96.161) has excellent BBB penetration potential, exceeding the desirable >70% threshold. Ligand B (74.564) is lower, but still reasonable.

**9. Caco-2 Permeability:** Ligand A (-4.674) has poor Caco-2 permeability, which is concerning. Ligand B (-5) is also poor.

**10. Aqueous Solubility:** Ligand A (-3.903) and Ligand B (-2.403) both have poor aqueous solubility.

**11. hERG Inhibition:** Both ligands have low hERG inhibition risk (0.644 and 0.445, respectively).

**12. Microsomal Clearance:** Ligand A (31.187) has higher microsomal clearance than Ligand B (25.345), suggesting lower metabolic stability.

**13. In vitro Half-Life:** Ligand B (-21.097) has a significantly longer in vitro half-life than Ligand A (-1.145), which is a major advantage.

**14. P-gp Efflux:** Ligand A (0.27) has lower P-gp efflux liability than Ligand B (0.087), which is favorable for CNS exposure.

**15. Binding Affinity:** Ligand B (-8.3 kcal/mol) has a slightly stronger binding affinity than Ligand A (-7.9 kcal/mol). While the difference is not huge, it is noticeable.

**Overall Assessment:**

Ligand A excels in TPSA, logP, BBB, and P-gp efflux, which are critical for a CNS-targeting GPCR ligand. However, its Caco-2 permeability is poor and its metabolic stability is lower. Ligand B has a better half-life and slightly better affinity, but suffers from a very low logP, which will severely hinder its ability to cross the blood-brain barrier and reach the target. The higher DILI risk for Ligand B is also concerning.

Considering the GPCR-specific priorities, the strong BBB penetration and favorable logP of Ligand A outweigh its other drawbacks, especially compared to Ligand B's poor logP. While both have solubility and permeability issues, the CNS target makes BBB penetration paramount.

Output:
0
2025-04-17 03:53:14,584 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B based on the provided guidelines, prioritizing GPCR-specific properties (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (350.507 Da) is slightly preferred as it's closer to the lower end, potentially aiding permeability.

**TPSA:** Ligand A (76.14) is significantly better than Ligand B (50.28). For CNS targets, TPSA should be <= 90, and A is well within this range, while B is also acceptable.

**logP:** Both ligands have good logP values (A: 3.594, B: 4.323), falling within the optimal 1-3 range. B is slightly higher, which *could* indicate potential off-target effects or solubility issues, but is still within an acceptable range.

**H-Bond Donors/Acceptors:** Ligand A (HBD=2, HBA=5) and Ligand B (HBD=1, HBA=6) both have reasonable numbers of H-bond donors and acceptors.

**QED:** Both ligands have similar and good QED values (A: 0.735, B: 0.736), indicating good drug-like properties.

**DILI:** Ligand A (23.769) has a much lower DILI risk than Ligand B (58.434). This is a significant advantage for A.

**BBB:** Ligand A (73.905) and Ligand B (83.676) both have excellent BBB penetration, exceeding the desirable >70 threshold for CNS targets. B is slightly better, but A is still very good.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.754 and -4.92). This is unusual and requires careful consideration. Negative values often indicate issues with the assay or the compound's behavior. However, since both are similarly negative, it doesn't differentiate them.

**Aqueous Solubility:** Both ligands have negative solubility values (-2.88 and -3.901). Similar to Caco-2, this is concerning and suggests poor solubility. Again, the values are similar and don't differentiate the two.

**hERG Inhibition:** Ligand A (0.553) has a lower hERG inhibition liability than Ligand B (0.866), which is preferable.

**Microsomal Clearance:** Ligand A (47.234) has a higher (worse) microsomal clearance than Ligand B (12.752). This suggests that B is more metabolically stable.

**In vitro Half-Life:** Ligand B (2.073) has a slightly longer half-life than Ligand A (21.344), which is a minor advantage.

**P-gp Efflux:** Ligand A (0.057) has significantly lower P-gp efflux liability than Ligand B (0.42). This is a major advantage for A, as lower efflux improves CNS exposure.

**Binding Affinity:** Ligand B (-8.2 kcal/mol) has a stronger binding affinity than Ligand A (-7.2 kcal/mol). This is a substantial advantage for B (1.0 kcal/mol difference).

**Overall Assessment:**

While Ligand B has a better binding affinity and metabolic stability, Ligand A demonstrates a significantly better safety profile (lower DILI, lower hERG, lower P-gp efflux) and a more favorable TPSA. The difference in binding affinity (1.0 kcal/mol) is substantial, but the combined advantages of A in terms of safety and CNS penetration are compelling, especially given the target is a CNS GPCR. The negative Caco-2 and solubility values are concerning for both, but don't differentiate them.

Output:
0
2025-04-17 03:53:14,584 - INFO - Reasoning:

Let's analyze Ligand A and Ligand B based on the provided guidelines, prioritizing GPCR-specific properties (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (398.937 Da) is slightly higher, but acceptable. Ligand B (350.423 Da) is also good.

**TPSA:** Ligand A (57.69) is excellent, well below the 90 A^2 threshold for CNS targets. Ligand B (121.36) is higher, but still potentially acceptable, though less ideal for CNS penetration.

**logP:** Ligand A (2.786) is optimal. Ligand B (0.986) is a bit low, potentially hindering permeability.

**H-Bond Donors/Acceptors:** Ligand A (0 HBD, 4 HBA) is favorable. Ligand B (3 HBD, 6 HBA) is also within acceptable limits.

**QED:** Both ligands have similar QED values (A: 0.795, B: 0.706), indicating good drug-likeness.

**DILI:** Ligand A (70.958) has a higher DILI risk than Ligand B (57.193), but both are below the concerning threshold of 60.

**BBB:** This is a critical parameter for DRD2. Ligand A (68.127) shows good BBB penetration, while Ligand B (20.822) is significantly lower, suggesting poor CNS exposure.

**Caco-2 Permeability:** Ligand A (-4.918) and Ligand B (-5.589) both have negative values, indicating low permeability. However, this scale is not well-defined, so the absolute difference is hard to interpret.

**Aqueous Solubility:** Ligand A (-4.771) and Ligand B (-1.578) both have negative values, indicating low solubility.

**hERG:** Both ligands show very low hERG inhibition risk (A: 0.734, B: 0.037).

**Microsomal Clearance:** Ligand A (60.375) has a higher clearance than Ligand B (4.633), suggesting lower metabolic stability.

**In vitro Half-Life:** Ligand B (-4.942) has a shorter half-life than Ligand A (-31.631).

**P-gp Efflux:** Ligand A (0.464) has lower P-gp efflux liability than Ligand B (0.014), which is beneficial for CNS penetration.

**Binding Affinity:** Ligand B (-7.9 kcal/mol) has a significantly stronger binding affinity than Ligand A (-9.3 kcal/mol). The difference of 1.4 kcal/mol is substantial.

**Conclusion:**

Despite Ligand B having a superior binding affinity, Ligand A is the more promising candidate. The critical factor is the significantly better BBB penetration (68.127 vs 20.822) and lower P-gp efflux. For a CNS target like DRD2, achieving sufficient brain exposure is paramount. While Ligand B's affinity is better, it's unlikely to translate into *in vivo* efficacy if it can't effectively cross the blood-brain barrier. Ligand A's slightly higher DILI risk and clearance are less concerning than the poor BBB penetration of Ligand B.

Output:
0
2025-04-17 03:53:14,584 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (339.374 Da) is slightly lower, which is generally favorable for permeability.

**2. TPSA:** Ligand A (71.84) is better than Ligand B (49.41) as it is closer to the ideal range for CNS targets (<=90).

**3. logP:** Both ligands have good logP values (A: 3.921, B: 2.536), falling within the optimal 1-3 range.

**4. H-Bond Donors:** Ligand A (2) and Ligand B (1) are both acceptable.

**5. H-Bond Acceptors:** Ligand A (4) and Ligand B (2) are both acceptable.

**6. QED:** Both ligands have reasonable QED values (A: 0.757, B: 0.602), indicating good drug-like properties.

**7. DILI:** Ligand A (93.951) has a significantly higher DILI risk than Ligand B (32.261). This is a major concern for Ligand A.

**8. BBB:** Ligand B (70.376) has a better BBB penetration percentile than Ligand A (51.842). This is crucial for a CNS target like DRD2.

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 values, which is unusual and suggests a potential issue with the data or modeling. However, the values are similar (-4.79 for A, -4.666 for B).

**10. Aqueous Solubility:** Both ligands have negative solubility values, again suggesting a potential data issue. The values are similar (-5.418 for A, -3.407 for B).

**11. hERG Inhibition:** Both ligands have similar, low hERG inhibition risk (A: 0.567, B: 0.56).

**12. Microsomal Clearance:** Ligand B (-0.197) has significantly lower (better) microsomal clearance than Ligand A (44.083), indicating greater metabolic stability.

**13. In vitro Half-Life:** Ligand B (-29.697) has a much longer in vitro half-life than Ligand A (74.139), which is highly desirable.

**14. P-gp Efflux:** Ligand A (0.2) has lower P-gp efflux liability than Ligand B (0.052), which is favorable for CNS exposure.

**15. Binding Affinity:** Ligand A (-10.2 kcal/mol) has a slightly better binding affinity than Ligand B (-9.9 kcal/mol). However, the difference is relatively small.

**Overall Assessment:**

While Ligand A has a slightly better binding affinity and lower P-gp efflux, Ligand B is significantly better overall. The major advantages of Ligand B are its much lower DILI risk, better BBB penetration, significantly improved metabolic stability (lower Cl_mic and longer t1/2), and acceptable TPSA. The negative solubility and Caco-2 values are concerning for both, but the other ADME properties of Ligand B are far superior, making it a more promising drug candidate for DRD2. The high DILI risk associated with Ligand A is a significant red flag.

Output:
1
2025-04-17 03:53:14,584 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (367.519 and 364.471 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (68.78) is significantly better than Ligand B (92.57). For CNS targets, we want TPSA <= 90, so Ligand A is preferable.

**logP:** Both ligands have acceptable logP values (0.747 and 1.562), falling within the 1-3 range. Ligand B is slightly higher, potentially aiding membrane permeability.

**H-Bond Donors/Acceptors:** Ligand A has 1 HBD and 6 HBA, while Ligand B has 2 HBD and 5 HBA. Both are within acceptable limits (<=5 HBD and <=10 HBA).

**QED:** Both ligands have good QED scores (0.734 and 0.78), indicating drug-like properties.

**DILI:** Both ligands show low DILI risk (27.801 and 64.676), with Ligand A being slightly better. Both are below the concerning threshold of 60.

**BBB:** Ligand A (64.482) has a better BBB percentile than Ligand B (59.403). While both are not ideal (>70 desirable), Ligand A is closer. This is a critical factor for a CNS target like DRD2.

**Caco-2 Permeability:** Both have negative Caco-2 values (-5.301 and -5.091), which is unusual and suggests poor permeability. However, the scale isn't explicitly defined, so it's hard to interpret.

**Aqueous Solubility:** Both ligands have poor aqueous solubility (-0.785 and -3.548). This could pose formulation challenges.

**hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.558 and 0.431).

**Microsomal Clearance:** Ligand A (22.571) has significantly lower microsomal clearance than Ligand B (48.142), indicating better metabolic stability.

**In vitro Half-Life:** Ligand A (15.043) has a positive half-life, while Ligand B (-26.729) has a negative half-life. This is a significant advantage for Ligand A.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.007 and 0.031).

**Binding Affinity:** Ligand B (-9.2 kcal/mol) has a significantly stronger binding affinity than Ligand A (-7.2 kcal/mol). This is a substantial advantage, exceeding the 1.5 kcal/mol threshold.

**Overall Assessment:**

While Ligand B boasts a superior binding affinity, Ligand A demonstrates a more favorable ADME profile, particularly regarding BBB penetration, metabolic stability (lower Cl_mic, positive t1/2), and TPSA. The difference in binding affinity (-2 kcal/mol) is significant, but the improved ADME properties of Ligand A, especially the better BBB and metabolic stability, are crucial for a CNS-targeting GPCR like DRD2. Poor solubility is a concern for both, but can be addressed with formulation strategies.

Output:
0
2025-04-17 03:53:14,584 - INFO - Reasoning:

Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (339.403 and 347.459 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (111.48) is slightly above the optimal <90 for CNS targets, but still reasonable. Ligand B (80.32) is excellent, well below 90.

**3. logP:** Both ligands have good logP values (1.338 and 1.983), falling within the 1-3 range.

**4. H-Bond Donors:** Ligand A (4) is at the upper end of the preferred range (<=5), while Ligand B (2) is ideal.

**5. H-Bond Acceptors:** Both ligands (A: 5, B: 4) are well within the acceptable limit of <=10.

**6. QED:** Both ligands have good QED scores (A: 0.563, B: 0.753), indicating drug-like properties. Ligand B is better.

**7. DILI:** Ligand A (63.862) has a higher DILI risk than Ligand B (27.879). This is a significant negative for Ligand A.

**8. BBB:** Ligand A (57.968) has a moderate BBB penetration, while Ligand B (51.725) is also moderate. Both are below the desirable >70 for CNS targets, but not drastically so.

**9. Caco-2 Permeability:** Ligand A (-6.015) has poor Caco-2 permeability. Ligand B (-5.213) is also poor, but slightly better than A.

**10. Aqueous Solubility:** Both ligands have very poor aqueous solubility (-2.369 and -2.065). This is a concern for both, but could be mitigated with formulation strategies.

**11. hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.364 and 0.123).

**12. Microsomal Clearance:** Ligand A (-7.993) has a significantly lower (better) microsomal clearance than Ligand B (9.008), indicating better metabolic stability.

**13. In vitro Half-Life:** Ligand A (73.845) has a much longer in vitro half-life than Ligand B (27.755). This is a major advantage for Ligand A.

**14. P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.039 and 0.019).

**15. Binding Affinity:** Ligand A (-9.5 kcal/mol) has a significantly stronger binding affinity than Ligand B (-8.1 kcal/mol). This is a substantial advantage for Ligand A.

**Overall Assessment:**

While Ligand A has a higher DILI risk and poorer Caco-2 permeability, its *significantly* stronger binding affinity (-9.5 vs -8.1 kcal/mol) and substantially better metabolic stability (lower Cl_mic, longer t1/2) outweigh these drawbacks, especially considering the GPCR target class. The affinity difference is >1.5 kcal/mol, making it a critical factor. The TPSA is slightly higher, and BBB is moderate for both, but the potency and metabolic stability of A are key.

Output:
1
2025-04-17 03:53:14,585 - INFO - Reasoning:

Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight (MW):** Both ligands (418.316 and 403.324 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (84.22) is higher than the preferred <90 for CNS targets, but still reasonable. Ligand B (52.39) is excellent, well below 90.

**3. logP:** Ligand A (4.393) is slightly high, potentially leading to solubility issues or off-target effects. Ligand B (3.045) is optimal.

**4. H-Bond Donors (HBD):** Ligand A (3) is within the acceptable limit of <=5. Ligand B (0) is also good.

**5. H-Bond Acceptors (HBA):** Ligand A (3) is within the acceptable limit of <=10. Ligand B (5) is also good.

**6. QED:** Both ligands have good QED scores (0.587 and 0.712), indicating drug-like properties.

**7. DILI:** Ligand A (82.551) has a higher DILI risk than Ligand B (42.846). This is a significant concern for Ligand A.

**8. BBB:** Ligand B (91.121) has a significantly better BBB penetration score than Ligand A (79.488). This is crucial for a CNS target like DRD2.

**9. Caco-2 Permeability:** Ligand A (-5.083) and Ligand B (-4.691) both have negative values, indicating poor permeability. This is a concern for both, but the scale isn't clearly defined, so the difference may not be substantial.

**10. Aqueous Solubility:** Ligand A (-5.07) and Ligand B (-2.47) both have negative values, indicating poor solubility. This is a concern for both, but Ligand B is better.

**11. hERG Inhibition:** Ligand A (0.687) and Ligand B (0.965) are both relatively low, indicating a low risk of cardiotoxicity.

**12. Microsomal Clearance:** Ligand A (64.923) has a lower clearance than Ligand B (47.116), suggesting better metabolic stability.

**13. In vitro Half-Life:** Ligand A (81.075) has a longer half-life than Ligand B (56.37), which is desirable.

**14. P-gp Efflux:** Ligand A (0.48) has lower P-gp efflux than Ligand B (0.355), suggesting better CNS exposure.

**15. Binding Affinity:** Ligand B (-7.2 kcal/mol) has a significantly stronger binding affinity than Ligand A (-10.1 kcal/mol). This is a major advantage for Ligand B.

**Overall Assessment:**

Ligand B is the more promising candidate. While both have issues with Caco-2 and solubility, Ligand B excels in the key GPCR properties: significantly better BBB penetration, optimal logP, and a much stronger binding affinity. It also has a lower DILI risk. Ligand A's higher logP and DILI risk are significant drawbacks, despite its slightly better metabolic stability and half-life. The substantial affinity advantage of Ligand B outweighs the minor ADME differences.

Output:
1
2025-04-17 03:53:14,585 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (344.411 and 365.865 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (68.82) is excellent, well below the 90 A^2 threshold for CNS targets. Ligand B (101.21) is still reasonable, but less optimal, being above 90 A^2.

**3. logP:** Both ligands have good logP values (1.022 and 2.013), falling within the optimal 1-3 range.

**4. H-Bond Donors:** Both have 2 HBD, which is within the acceptable limit of <=5.

**5. H-Bond Acceptors:** Both have 5 HBA, also within the acceptable limit of <=10.

**6. QED:** Both ligands have similar QED values (0.781 and 0.777), indicating good drug-likeness.

**7. DILI:** Ligand A (38.503) has a lower DILI risk than Ligand B (49.864), which is preferable. Both are below the concerning 60 threshold.

**8. BBB:** This is critical for a CNS target. Ligand A (48.352) has a moderate BBB penetration, while Ligand B (78.364) shows significantly better BBB penetration, exceeding the desirable >70 threshold.

**9. Caco-2 Permeability:** Both have negative Caco-2 values (-4.969 and -5.169), which is unusual and suggests poor permeability. This is a significant drawback for both.

**10. Aqueous Solubility:** Both have negative solubility values (-2.234 and -3.349), indicating very poor aqueous solubility. This is a major concern for bioavailability.

**11. hERG Inhibition:** Both ligands show low hERG inhibition risk (0.244 and 0.404).

**12. Microsomal Clearance:** Ligand A (15.304) has lower microsomal clearance than Ligand B (22.482), suggesting better metabolic stability.

**13. In vitro Half-Life:** Ligand A (12.935) has a longer in vitro half-life than Ligand B (0.433), which is desirable.

**14. P-gp Efflux:** Both have very low P-gp efflux liability (0.038 and 0.021), which is excellent for CNS penetration.

**15. Binding Affinity:** Ligand B (-7.9 kcal/mol) has a slightly better binding affinity than Ligand A (-8.0 kcal/mol). While the difference is small, it is still a factor.

**Overall Assessment:**

Ligand B has a clear advantage in BBB penetration, which is paramount for a CNS-targeting drug. It also has a slightly better binding affinity. However, Ligand A has better metabolic stability (lower Cl_mic, longer t1/2), lower DILI risk, and better TPSA. Both suffer from poor solubility and permeability. The improved BBB penetration of Ligand B is the most important factor, outweighing the other benefits of Ligand A.

Output:
1
2025-04-17 03:53:14,585 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (342.483 Da) is slightly better, being closer to the lower end which can aid permeability.

**TPSA:** Ligand A (49.41) is significantly better than Ligand B (82.7). For CNS targets, we want TPSA <= 90, and ideally lower. Ligand A is well within this range, while Ligand B is approaching the upper limit and may have reduced brain penetration.

**logP:** Both ligands have logP values within the optimal range (1-3), but Ligand B (4.374) is higher. While not drastically outside the range, higher logP can lead to solubility issues and off-target interactions. Ligand A (3.029) is preferable.

**H-Bond Donors/Acceptors:** Ligand A (HBD=1, HBA=2) has fewer H-bonds than Ligand B (HBD=3, HBA=5). This is generally favorable for permeability.

**QED:** Both ligands have reasonable QED values (A: 0.854, B: 0.595), indicating good drug-like properties. Ligand A is superior.

**DILI:** Ligand A (40.054) has a much lower DILI risk than Ligand B (84.839). This is a significant advantage for Ligand A.

**BBB:** Ligand A (69.523) has a better BBB percentile than Ligand B (40.403). For a CNS target like DRD2, this is crucial. Ligand A is more likely to reach the target in the brain.

**Caco-2 Permeability:** Ligand A (-4.996) has a better Caco-2 permeability than Ligand B (-5.316).

**Aqueous Solubility:** Both ligands have similar, poor aqueous solubility (-4.541 and -4.423 respectively).

**hERG:** Both ligands have low hERG inhibition liability (A: 0.294, B: 0.623).

**Microsomal Clearance:** Ligand B (38.435) has a lower microsomal clearance than Ligand A (51.015), suggesting better metabolic stability. This is a slight advantage for Ligand B.

**In vitro Half-Life:** Ligand B (138.501) has a significantly longer in vitro half-life than Ligand A (5.24). This is a substantial advantage for Ligand B.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (A: 0.408, B: 0.409), which is good.

**Binding Affinity:** Both ligands have very similar binding affinities (A: -9.0 kcal/mol, B: -8.8 kcal/mol). The difference is minimal.

**Overall Assessment:**

Considering all factors, and prioritizing BBB, logP, TPSA, and affinity for a CNS GPCR target, **Ligand A is the more promising candidate**. The significantly better BBB penetration, lower TPSA, lower DILI risk, and slightly better logP outweigh the advantages of Ligand B's longer half-life and lower clearance. The binding affinities are comparable, so the ADME properties are the deciding factors.

Output:
1
2025-04-17 03:53:14,585 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands fall within the ideal range (200-500 Da). Ligand A (348.403 Da) is slightly lower, which could be beneficial for permeability, while Ligand B (370.871 Da) is still well within the acceptable range.

**TPSA:** Ligand A (113.44) is closer to the desirable threshold of 90 for CNS targets, while Ligand B (32.34) is excellent, well below 90. This favors Ligand B.

**logP:** Ligand A (0.623) is a bit low, potentially hindering permeation. Ligand B (4.261) is slightly high, potentially leading to solubility issues or off-target interactions, but still within the acceptable range.

**H-Bond Donors/Acceptors:** Ligand A has 3 HBD and 6 HBA, which are acceptable. Ligand B has 1 HBD and 2 HBA, which is also good.

**QED:** Both ligands have good QED scores (A: 0.666, B: 0.759), indicating drug-like properties.

**DILI:** Ligand A (34.548) has a slightly higher DILI risk than Ligand B (17.449), which is preferable.

**BBB:** This is a critical parameter for CNS targets. Ligand A has a BBB percentile of 42.924, which is below the desirable >70 threshold. Ligand B has a much higher BBB percentile of 93.098, making it significantly more likely to cross the blood-brain barrier. This is a major advantage for Ligand B.

**Caco-2 Permeability:** Ligand A (-5.058) shows poor permeability, while Ligand B (-4.816) is also poor but slightly better.

**Aqueous Solubility:** Both ligands have very poor aqueous solubility (-2.624 and -4.782 respectively). This is a concern for both, but might be addressable with formulation strategies.

**hERG Inhibition:** Ligand A (0.085) has a very low hERG risk, which is excellent. Ligand B (0.942) has a slightly higher hERG risk, but it's still relatively low.

**Microsomal Clearance:** Ligand A (6.408) has lower clearance, suggesting better metabolic stability than Ligand B (39.717).

**In vitro Half-Life:** Ligand A (8.935) has a slightly better in vitro half-life than Ligand B (9.481).

**P-gp Efflux:** Ligand A (0.006) has very low P-gp efflux, which is highly desirable for CNS penetration. Ligand B (0.569) has a higher, but still relatively low, P-gp efflux.

**Binding Affinity:** Ligand B (-8.5 kcal/mol) has a significantly stronger binding affinity than Ligand A (-7.4 kcal/mol). This >1.5 kcal/mol difference is substantial and can outweigh some of the ADME drawbacks.

**Overall Assessment:**

Ligand B is the stronger candidate. Its superior BBB penetration and significantly improved binding affinity are crucial for a CNS-targeting GPCR like DRD2. While Ligand A has slightly better metabolic stability and lower hERG risk, the substantial advantage in BBB and binding affinity of Ligand B outweighs these minor benefits. The slightly higher logP of Ligand B is a manageable concern, and the poor solubility of both compounds could be addressed through formulation.

Output:
1
2025-04-17 03:53:14,585 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (347.419 and 351.451 Da) fall within the ideal 200-500 Da range.

**TPSA:** Both ligands have TPSA values (87.54 and 89.35) below the 90 A^2 threshold desirable for CNS targets.

**logP:** Ligand A (0.019) is quite low, potentially hindering permeability. Ligand B (0.97) is better, falling within the optimal 1-3 range, though on the lower end.

**H-Bond Donors/Acceptors:** Both have 1 HBD, which is good. Ligand A has 5 HBA, and Ligand B has 6 HBA, both acceptable (<=10).

**QED:** Both ligands have similar QED values (0.705 and 0.716), indicating good drug-likeness.

**DILI:** Ligand A (44.126) has a slightly higher DILI risk than Ligand B (29.43), but both are below the concerning 60 threshold.

**BBB:** This is a crucial parameter for a CNS target. Ligand B (70.997) is significantly better, exceeding the 70% threshold, while Ligand A (58.821) is below.

**Caco-2 Permeability:** Both have negative Caco-2 values (-5.224 and -5.111), which is unusual and suggests poor permeability. However, these values are on a log scale and might not be directly comparable without knowing the experimental setup.

**Aqueous Solubility:** Both have negative solubility values (-0.996 and -1.102), indicating poor solubility. This is a concern for bioavailability.

**hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.049 and 0.135).

**Microsomal Clearance:** Ligand A (10.739) has a lower microsomal clearance than Ligand B (19.564), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (15.894 hours) has a significantly longer half-life than Ligand B (3.802 hours).

**P-gp Efflux:** Both have very low P-gp efflux liability (0.019 and 0.06).

**Binding Affinity:** Both ligands have the same excellent binding affinity (-7.4 kcal/mol).

**Conclusion:**

While both ligands have comparable affinity and acceptable QED, DILI, and hERG profiles, Ligand B is the more promising candidate. The primary driver is its significantly better BBB penetration (70.997% vs 58.821%). Although Ligand A has better metabolic stability (lower Cl_mic and longer t1/2), the BBB is paramount for CNS drug development. The slightly better logP of Ligand B also contributes to its favorability. The poor Caco-2 and solubility are concerns for both, but can be addressed with formulation strategies.

Output:
1
2025-04-17 03:53:14,586 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (354.288 and 348.407 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (94.05) is better than Ligand B (105.28). For CNS targets, we want TPSA <= 90, so Ligand A is closer to this threshold.

**3. logP:** Ligand A (3.283) is optimal (1-3). Ligand B (0.122) is significantly low, potentially hindering membrane permeability and CNS penetration.

**4. H-Bond Donors:** Ligand A (1) and Ligand B (2) are both acceptable (<=5).

**5. H-Bond Acceptors:** Ligand A (6) and Ligand B (7) are both acceptable (<=10).

**6. QED:** Both ligands have similar QED values (0.773 and 0.67), indicating good drug-like properties.

**7. DILI:** Ligand A (92.012) has a higher DILI risk than Ligand B (42.769). This is a negative for Ligand A.

**8. BBB:** Ligand A (69.523) has significantly better BBB penetration potential than Ligand B (35.091). This is a crucial factor for a CNS target like DRD2.

**9. Caco-2 Permeability:** Ligand A (-4.725) is better than Ligand B (-5.395), indicating better intestinal absorption.

**10. Aqueous Solubility:** Ligand A (-4.166) is better than Ligand B (-1.178), which is important for formulation.

**11. hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.263 and 0.076).

**12. Microsomal Clearance:** Ligand A (67.584) has higher clearance than Ligand B (27.142), indicating lower metabolic stability. This is a negative for Ligand A.

**13. In vitro Half-Life:** Ligand B (50.72) has a longer half-life than Ligand A (-5.345), which is desirable.

**14. P-gp Efflux:** Ligand A (0.156) has lower P-gp efflux liability than Ligand B (0.026), which is favorable for CNS exposure.

**15. Binding Affinity:** Ligand B (-7.1) has a slightly better binding affinity than Ligand A (-9.4). However, the difference is not substantial enough to outweigh the other significant ADME differences.

**Overall Assessment:**

Ligand A has a better logP and BBB, which are critical for CNS GPCR targets. While its DILI and clearance are worse than Ligand B, the significantly better BBB penetration and acceptable logP outweigh these drawbacks. Ligand B's very low logP is a major concern, likely resulting in poor CNS exposure despite its slightly better affinity.

Output:
1
2025-04-17 03:53:14,586 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B based on the provided guidelines, prioritizing GPCR-specific properties (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (374.388 and 385.555 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (76.35) is better than Ligand B (82.53). Both are below the 90 A^2 threshold for CNS targets, but A is closer to the ideal.

**logP:** Both ligands have good logP values (3.174 and 2.513), falling within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A (HBD=1, HBA=5) is slightly better than Ligand B (HBD=2, HBA=6) regarding the number of hydrogen bond donors and acceptors, being closer to the ideal thresholds.

**QED:** Both ligands have acceptable QED values (0.873 and 0.754), indicating good drug-like properties.

**DILI:** Both ligands have relatively high DILI risk (69.639 and 61.342), but are still below the concerning >60 threshold.

**BBB:** This is a critical parameter for CNS targets. Ligand A (72.664) has a significantly better BBB percentile than Ligand B (39.007). This is a major advantage for Ligand A.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values, which is unusual. It's difficult to interpret without knowing the scale. However, since both are negative, it doesn't differentiate them.

**Aqueous Solubility:** Both ligands have similar, very poor aqueous solubility (-3.9 and -3.944). This is a potential issue for both.

**hERG Inhibition:** Both ligands show low hERG inhibition liability (0.562 and 0.428), which is good.

**Microsomal Clearance:** Ligand B (53.689) has lower microsomal clearance than Ligand A (19.877), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand B (-7.368) has a negative half-life, which is impossible. This is a significant red flag for Ligand B. Ligand A (58.524) has a reasonable half-life.

**P-gp Efflux:** Ligand A (0.304) has lower P-gp efflux than Ligand B (0.281), indicating better potential for CNS exposure.

**Binding Affinity:** Both ligands have excellent binding affinities (-8.8 and -7.7 kcal/mol), well below the -7.0 kcal/mol threshold. Ligand A has a 1.1 kcal/mol advantage, which is substantial.

**Overall Assessment:**

Ligand A is the stronger candidate. While both ligands have good potency, Ligand A has a significantly better BBB percentile, a more reasonable half-life, and slightly better TPSA and P-gp efflux. The difference in BBB is particularly important for a CNS target like DRD2. The negative half-life for Ligand B is a critical flaw. Although Ligand B has better metabolic stability, the other advantages of Ligand A outweigh this benefit.

Output:
1
2025-04-17 03:53:14,586 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (349.431 and 352.519 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (78.95) is slightly higher than Ligand B (69.64). Both are below the 90 A^2 threshold desirable for CNS targets, but B is better.

**3. logP:** Ligand A (0.143) is significantly lower than the optimal 1-3 range and is concerning for permeability. Ligand B (2.861) is within the optimal range. This is a major advantage for B.

**4. H-Bond Donors:** Ligand A (1) is good. Ligand B (2) is also acceptable.

**5. H-Bond Acceptors:** Ligand A (4) is good. Ligand B (3) is also good.

**6. QED:** Both ligands (0.683 and 0.706) have good drug-likeness scores.

**7. DILI:** Ligand A (23.032) has a much lower DILI risk than Ligand B (7.949), which is excellent.

**8. BBB:** Ligand B (74.37) has a significantly better BBB penetration percentile than Ligand A (54.944). This is crucial for a CNS target like DRD2.

**9. Caco-2 Permeability:** Ligand A (-4.727) has a very poor Caco-2 permeability, suggesting poor intestinal absorption. Ligand B (-4.649) is also poor, but slightly better than A.

**10. Aqueous Solubility:** Both ligands have poor aqueous solubility (-1.939 and -2.498).

**11. hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.148 and 0.454).

**12. Microsomal Clearance:** Ligand A (6.138) has a lower microsomal clearance, indicating better metabolic stability, than Ligand B (37.674).

**13. In vitro Half-Life:** Ligand A (9.696) has a longer in vitro half-life than Ligand B (-5.031).

**14. P-gp Efflux:** Ligand A (0.011) has very low P-gp efflux, which is favorable for CNS penetration. Ligand B (0.184) is slightly higher, but still relatively low.

**15. Binding Affinity:** Both ligands have excellent binding affinity (-8.8 and -8.0 kcal/mol). The difference of 0.8 kcal/mol is not large enough to overcome the significant ADME deficiencies of Ligand A.

**Overall Assessment:**

Ligand B is the superior candidate. While Ligand A has a slightly better DILI score and metabolic stability, Ligand B excels in crucial areas for a CNS-targeting GPCR: logP, BBB penetration, and acceptable Caco-2 permeability. The slightly lower BBB and higher logP of Ligand A are significant drawbacks. The similar binding affinities make the ADME properties the deciding factor.

Output:
1
2025-04-17 03:53:14,586 - INFO - Batch 66 complete. Total preferences: 1056
2025-04-17 03:53:14,586 - INFO - Processing batch 67/512...
2025-04-17 03:53:57,440 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (378.705 and 370.4 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (55.76) is significantly better than Ligand B (80.04). For CNS targets, we want TPSA <= 90, and A is comfortably within that range, while B is approaching the upper limit.

**3. logP:** Both ligands have a logP around 4.1-4.3, which is slightly high. While not ideal, it's not a dealbreaker, and the benefit of good binding could outweigh this.

**4. H-Bond Donors:** Ligand A (1) is preferable to Ligand B (3). Fewer HBDs generally improve permeability.

**5. H-Bond Acceptors:** Both have 4 HBA, which is acceptable.

**6. QED:** Both ligands have good QED scores (0.621 and 0.692), indicating drug-like properties.

**7. DILI:** Both ligands have DILI risk around 62-68, which is moderately high, but not drastically concerning.

**8. BBB:** Ligand B (76.425) has a significantly better BBB percentile than Ligand A (48.662). This is a *critical* factor for a CNS target like DRD2.

**9. Caco-2 Permeability:** Ligand A (-4.82) has better Caco-2 permeability than Ligand B (-5.007), indicating better intestinal absorption.

**10. Aqueous Solubility:** Both ligands have very poor aqueous solubility (-4.894 and -4.914). This is a significant drawback, potentially hindering bioavailability.

**11. hERG Inhibition:** Both ligands have low hERG inhibition risk (0.635 and 0.561).

**12. Microsomal Clearance:** Ligand B (53.211) has lower microsomal clearance than Ligand A (84.451), suggesting better metabolic stability.

**13. In vitro Half-Life:** Ligand B (18.365) has a slightly longer half-life than Ligand A (23.745).

**14. P-gp Efflux:** Ligand A (0.539) has lower P-gp efflux than Ligand B (0.24), which is favorable for CNS penetration.

**15. Binding Affinity:** Both ligands have very similar and excellent binding affinities (-9.3 and -9.1 kcal/mol). The difference is negligible.

**Overall Assessment:**

Ligand B excels in BBB penetration and metabolic stability, which are crucial for CNS drug development. While Ligand A has better TPSA and Caco-2 permeability, the superior BBB score of Ligand B outweighs these advantages. Both have poor solubility, which needs to be addressed in formulation. The similar affinities mean that the ADME properties become the deciding factor.

Output:
1
2025-04-17 03:53:57,440 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 drug candidates, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (377.315 Da) is slightly higher than Ligand B (346.387 Da), but both are acceptable.

**2. TPSA:** Ligand A (72.47) is significantly better than Ligand B (133.36). For CNS targets, we want TPSA <= 90, and Ligand A is comfortably within this range, while Ligand B exceeds it. This is a significant advantage for Ligand A.

**3. logP:** Ligand A (3.139) is optimal (1-3). Ligand B (-0.378) is too low, potentially hindering permeation. This is a major drawback for Ligand B.

**4. H-Bond Donors:** Ligand A (1) and Ligand B (2) are both acceptable (<=5).

**5. H-Bond Acceptors:** Ligand A (4) and Ligand B (5) are both acceptable (<=10).

**6. QED:** Both ligands have good QED scores (Ligand A: 0.505, Ligand B: 0.7).

**7. DILI:** Ligand A (96.704) has a high DILI risk, while Ligand B (33.695) has a low DILI risk. This is a significant advantage for Ligand B.

**8. BBB:** Both ligands have similar BBB penetration (Ligand A: 54.556, Ligand B: 54.091). While not exceptional (>70), they are reasonable.

**9. Caco-2 Permeability:** Ligand A (-4.43) and Ligand B (-5.556) both have negative values, indicating poor permeability.

**10. Aqueous Solubility:** Ligand A (-4.188) and Ligand B (-2.64) both have negative values, indicating poor solubility.

**11. hERG Inhibition:** Ligand A (0.447) and Ligand B (0.072) both have low hERG inhibition risk.

**12. Microsomal Clearance:** Ligand A (54.713) has a moderate clearance, while Ligand B (-10.77) has a negative clearance, which is unusual and potentially indicates very high metabolic stability. This is a strong advantage for Ligand B.

**13. In vitro Half-Life:** Ligand A (42.944) has a reasonable half-life, while Ligand B (-2.708) has a negative half-life, which is not realistic and suggests a potential data error.

**14. P-gp Efflux:** Ligand A (0.429) and Ligand B (0.002) both have low P-gp efflux liability.

**15. Binding Affinity:** Ligand A (-9.2) has a significantly stronger binding affinity than Ligand B (-8.5). This is a substantial advantage for Ligand A, potentially outweighing some of its ADME drawbacks.

**Overall Assessment:**

Ligand A has a much better TPSA and significantly stronger binding affinity. However, it has a high DILI risk. Ligand B has a lower DILI risk, better metabolic stability, but a poor logP and TPSA. Given the importance of BBB penetration and logP for CNS GPCR targets, and the substantial affinity advantage of Ligand A, I believe Ligand A is the more promising candidate *despite* the DILI risk. The strong binding affinity could potentially allow for a lower dose, mitigating the DILI concern. The negative half-life and clearance for Ligand B are also concerning and suggest data quality issues.

Output:
0
2025-04-17 03:53:57,440 - INFO - Reasoning:

Let's analyze Ligand A and Ligand B for their potential as DRD2 drug candidates, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight (MW):** Both ligands (366.49 and 346.43 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (83.56) is better than Ligand B (92.15). For CNS targets, we want TPSA <= 90, so Ligand A is preferable.

**3. logP:** Both ligands have good logP values (1.43 and 1.84), falling within the optimal 1-3 range.

**4. H-Bond Donors (HBD):** Both ligands have 2 HBD, which is within the acceptable limit of <= 5.

**5. H-Bond Acceptors (HBA):** Ligand A has 6 HBA, and Ligand B has 5. Both are below the acceptable limit of <= 10.

**6. QED:** Both ligands have good QED scores (0.51 and 0.72), indicating good drug-like properties.

**7. DILI:** Both ligands have acceptable DILI risk (33.5 and 36.3 percentile), well below the 60% threshold.

**8. BBB:** Ligand B (66.77%) is significantly better than Ligand A (47.96%). For a CNS target like DRD2, a BBB penetration > 70% is highly desirable. While neither is optimal, Ligand B is better.

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.59 and -5.42), which is unusual and suggests poor permeability. This is a significant drawback for both.

**10. Aqueous Solubility:** Both ligands have negative solubility values (-1.68 and -2.01), indicating very poor aqueous solubility. This is a major concern for bioavailability.

**11. hERG Inhibition:** Both ligands have low hERG inhibition risk (0.38 and 0.13 percentile), which is excellent.

**12. Microsomal Clearance (Cl_mic):** Ligand A (-11.95) has a much lower (better) microsomal clearance than Ligand B (13.74). Lower clearance indicates greater metabolic stability.

**13. In vitro Half-Life:** Ligand B (28.10) has a longer half-life than Ligand A (15.14), which is generally preferred.

**14. P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.035 and 0.048), which is good for CNS exposure.

**15. Binding Affinity:** Ligand B (-8.3 kcal/mol) has a slightly better binding affinity than Ligand A (-7.4 kcal/mol). The difference is 0.9 kcal/mol, which is significant.

**Overall Assessment:**

Ligand B has a better BBB score and binding affinity, which are crucial for a CNS GPCR target. However, Ligand A has a better TPSA and significantly better metabolic stability (lower Cl_mic). Both have poor Caco-2 and solubility. The binding affinity difference is substantial enough to outweigh the better metabolic stability of Ligand A, especially considering the importance of CNS penetration. The better BBB score of Ligand B is also a significant advantage.

Output:
1
2025-04-17 03:53:57,441 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (341.367 and 359.499 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Both ligands have TPSA values (89.55 and 90.7) close to the upper limit for CNS targets (90). Ligand A is slightly better.

**3. logP:** Both ligands have good logP values (2.703 and 3.419), falling within the optimal 1-3 range. Ligand B is slightly higher, which could potentially lead to reduced solubility.

**4. H-Bond Donors:** Both have 2 HBD, which is within the acceptable limit of <=5.

**5. H-Bond Acceptors:** Both have 6 HBA, which is within the acceptable limit of <=10.

**6. QED:** Both have similar QED values (0.785 and 0.753), indicating good drug-like properties.

**7. DILI:** Ligand A (89.763) has a higher DILI risk than Ligand B (70.221). This is a significant drawback for Ligand A.

**8. BBB:** Ligand B (70.531) has a better BBB percentile than Ligand A (61.38). This is crucial for a CNS target like DRD2.

**9. Caco-2 Permeability:** Ligand A (-4.41) has a significantly worse Caco-2 permeability than Ligand B (-5.085). Lower values indicate poorer permeability.

**10. Aqueous Solubility:** Ligand A (-4.9) has slightly better aqueous solubility than Ligand B (-3.93), but both are very poor.

**11. hERG Inhibition:** Ligand A (0.347) has a lower hERG inhibition liability than Ligand B (0.77), which is preferable.

**12. Microsomal Clearance:** Ligand B (82.588) has a higher microsomal clearance than Ligand A (58.313), indicating faster metabolism and potentially lower exposure.

**13. In vitro Half-Life:** Ligand B (75.099) has a longer in vitro half-life than Ligand A (-7.197), which is desirable.

**14. P-gp Efflux:** Ligand A (0.052) has significantly lower P-gp efflux liability than Ligand B (0.339). Lower P-gp efflux is highly desirable for CNS penetration.

**15. Binding Affinity:** Ligand B (-7.9) has a slightly better binding affinity than Ligand A (-8.6). While both are excellent, the difference is not substantial enough to outweigh other factors.

**Overall Assessment:**

Ligand B is the more promising candidate. While Ligand A has a slightly better TPSA and hERG profile, Ligand B excels in crucial areas for CNS drug development: BBB penetration, in vitro half-life, and Caco-2 permeability. The lower DILI risk for Ligand B is also a significant advantage. The slightly better affinity of Ligand B further supports this conclusion. The lower P-gp efflux of Ligand A is a positive, but the superior BBB and permeability of Ligand B are more critical for a CNS target.

Output:
1
2025-04-17 03:53:57,441 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (383.809 Da) is slightly higher than Ligand B (344.459 Da), but both are acceptable.

**TPSA:** Ligand A (109.77) is higher than the preferred <90 for CNS targets, while Ligand B (67.23) is well within the range. This is a significant advantage for Ligand B.

**logP:** Both ligands have similar logP values around 2.5, which is optimal.

**H-Bond Donors/Acceptors:** Ligand A has 2 HBD and 5 HBA, while Ligand B has 1 HBD and 4 HBA. Both are within acceptable limits.

**QED:** Both ligands have good QED scores (0.742 and 0.773), indicating good drug-like properties.

**DILI:** Ligand A has a very high DILI risk (98.953), which is a major concern. Ligand B has a much lower DILI risk (32.377), making it significantly safer.

**BBB:** Ligand A has a very low BBB penetration (15.083), which is problematic for a CNS target. Ligand B has a much better BBB penetration (74.719), which is highly desirable.

**Caco-2 Permeability:** Ligand A has a negative Caco-2 value (-5.248), suggesting poor permeability. Ligand B also has a negative value (-4.872), suggesting poor permeability.

**Aqueous Solubility:** Both ligands have negative solubility values (-3.954 and -3.118), which is concerning. However, this is less critical if permeability is good.

**hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.037 and 0.34), which is excellent.

**Microsomal Clearance:** Ligand A has a lower Cl_mic (2.734) than Ligand B (31.552), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand B has a longer half-life (-1.39 hours) than Ligand A (28.114 hours), which is desirable. Note the units are inconsistent here.

**P-gp Efflux:** Ligand A has very low P-gp efflux (0.057), which is good for CNS exposure. Ligand B also has low P-gp efflux (0.048).

**Binding Affinity:** Ligand B (-7.9 kcal/mol) has a slightly better binding affinity than Ligand A (-8.2 kcal/mol). While the difference is small, it's still a positive point for Ligand B.

**Overall Assessment:**

Ligand A suffers from a very high DILI risk and poor BBB penetration, making it a poor candidate despite its reasonable affinity and metabolic stability. Ligand B has a much better safety profile (lower DILI), significantly better BBB penetration, and comparable affinity. While both have poor Caco-2 permeability and solubility, the CNS target prioritization makes BBB and safety paramount.

Output:
1
2025-04-17 03:53:57,441 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (348.261 and 343.427 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (95.35) is slightly higher than Ligand B (91.32), but both are below the 90-140 threshold for oral absorption and acceptable for a CNS target.

**3. logP:** Ligand A (2.593) is optimal, while Ligand B (1.567) is a bit low, potentially impacting membrane permeability.

**4. H-Bond Donors:** Ligand A (0) is preferable to Ligand B (3), as fewer HBDs generally improve permeability.

**5. H-Bond Acceptors:** Ligand A (6) is slightly higher than Ligand B (4), but both are within the acceptable range of <=10.

**6. QED:** Both ligands have good QED scores (0.522 and 0.708, respectively), indicating drug-like properties. Ligand B is slightly better.

**7. DILI:** Ligand A (89.88) has a higher DILI risk than Ligand B (35.75). This is a significant advantage for Ligand B.

**8. BBB:** Ligand A (74.874) has a better BBB penetration percentile than Ligand B (53.315). This is crucial for a CNS target like DRD2.

**9. Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and indicates poor permeability. Ligand A (-4.246) is slightly better than Ligand B (-4.976).

**10. Aqueous Solubility:** Both have negative solubility values, indicating poor solubility. Ligand A (-4.279) is slightly better than Ligand B (-2.301).

**11. hERG Inhibition:** Ligand A (0.392) has a lower hERG inhibition liability than Ligand B (0.059), which is preferable.

**12. Microsomal Clearance:** Ligand A (60.575) has higher microsomal clearance than Ligand B (7.74), indicating lower metabolic stability. Ligand B is significantly better here.

**13. In vitro Half-Life:** Ligand A (22.768) has a longer half-life than Ligand B (-7.752), which is desirable.

**14. P-gp Efflux:** Ligand A (0.586) has higher P-gp efflux than Ligand B (0.014). This is a significant advantage for Ligand B, as lower efflux improves CNS exposure.

**15. Binding Affinity:** Ligand B (-7.9 kcal/mol) has a slightly better binding affinity than Ligand A (-9.4 kcal/mol). While A is better, the difference isn't substantial enough to outweigh other factors.

**Overall Assessment:**

Ligand B demonstrates a superior ADME profile, particularly regarding DILI risk, P-gp efflux, and microsomal clearance. While Ligand A has a better BBB score and slightly longer half-life, the lower DILI risk and P-gp efflux of Ligand B are more critical for a CNS-targeting GPCR. The affinity difference is small. The poor Caco-2 and solubility for both are concerning, but can be addressed with formulation strategies.

Output:
1
2025-04-17 03:53:57,441 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (352.41 and 348.403 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (107.11) is better than Ligand B (119.89). For CNS targets, we want TPSA <= 90, so both are above this ideal, but A is closer.

**3. logP:** Ligand A (1.197) is within the optimal range (1-3). Ligand B (-0.715) is slightly below 1, which *could* indicate permeability issues.

**4. H-Bond Donors:** Both have 4 HBD, which is acceptable (<=5).

**5. H-Bond Acceptors:** Ligand A has 4 HBA, while Ligand B has 5. Both are within the acceptable range (<=10).

**6. QED:** Ligand A (0.639) has a better QED score than Ligand B (0.474), indicating better overall drug-likeness.

**7. DILI:** Both have acceptable DILI risk (Ligand A: 61.691, Ligand B: 52.036), although A is slightly higher. Both are below the concerning threshold of 60.

**8. BBB:** Ligand A (53.664) has a significantly better BBB percentile than Ligand B (40.054). This is *critical* for a CNS target like DRD2.

**9. Caco-2:** Both have negative Caco-2 values (-5.316 and -5.264), which is unusual and suggests poor permeability. This is a significant concern for both.

**10. Solubility:** Both have negative solubility values (-3.142 and -2.275), which is also concerning. Poor solubility can hinder bioavailability.

**11. hERG:** Both have low hERG inhibition risk (Ligand A: 0.34, Ligand B: 0.099).

**12. Cl_mic:** Ligand A (-12.363) has a much lower (better) microsomal clearance than Ligand B (0.756), suggesting better metabolic stability.

**13. t1/2:** Ligand A (-2.006) has a slightly better (less negative) in vitro half-life than Ligand B (-28.965).

**14. Pgp:** Both have very low Pgp efflux liability (Ligand A: 0.06, Ligand B: 0.01).

**15. Binding Affinity:** Ligand A (-9.7 kcal/mol) has a slightly better binding affinity than Ligand B (-8.3 kcal/mol). While both are good, the 1.4 kcal/mol difference is substantial and can outweigh some ADME drawbacks.

**Overall Assessment:**

Ligand A is the superior candidate. While both have issues with Caco-2 and solubility, Ligand A has a significantly better BBB penetration (53.664 vs 40.054), better metabolic stability (lower Cl_mic), a slightly longer half-life, and a better binding affinity. The better QED score also supports its selection. For a CNS GPCR target, BBB penetration and affinity are paramount, and Ligand A excels in these areas.

Output:
1
2025-04-17 03:53:57,441 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (349.431 and 354.491 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (98.74) is slightly higher than Ligand B (81.08). For CNS targets, we want TPSA <= 90, so both are acceptable, but B is better.

**logP:** Ligand A (-0.216) is quite low, potentially hindering membrane permeability. Ligand B (1.536) is within the optimal 1-3 range. This is a significant advantage for B.

**H-Bond Donors/Acceptors:** Ligand A has 3 HBD and 4 HBA, while Ligand B has 2 HBD and 4 HBA. Both are within acceptable limits (<=5 HBD and <=10 HBA).

**QED:** Both ligands have reasonable QED values (0.437 and 0.693), indicating drug-like properties, with B being better.

**DILI:** Ligand A (21.946) has a slightly higher DILI risk than Ligand B (14.967), but both are below the concerning threshold of 40.

**BBB:** This is crucial for a CNS target like DRD2. Ligand A (32.726) has a poor BBB percentile, while Ligand B (65.607) is much better, exceeding 50% and indicating reasonable brain penetration potential.

**Caco-2 Permeability:** Both have negative values (-4.851 and -4.653). This is unusual and suggests poor permeability.

**Aqueous Solubility:** Both ligands have negative solubility values (-1.612 and -2.048). This is also unusual and suggests poor solubility.

**hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.108 and 0.193).

**Microsomal Clearance:** Ligand A (22.558) has lower clearance than Ligand B (41.305), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (-38.56) has a very negative half-life, which is not possible. Ligand B (1.369) has a very short half-life.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.018 and 0.03).

**Binding Affinity:** Ligand A (-7.7 kcal/mol) has a significantly stronger binding affinity than Ligand B (-6.5 kcal/mol). This is a substantial advantage for A, potentially outweighing some of its ADME drawbacks.

**Overall Assessment:**

Ligand B is superior in terms of logP, TPSA, and crucially, BBB penetration. However, Ligand A boasts a substantially stronger binding affinity. The poor solubility and permeability of both compounds are concerning, but the affinity difference is significant. Given the importance of CNS penetration for a DRD2 ligand, and the better profile of Ligand B in that regard, combined with its better logP and TPSA, it is the more promising candidate despite the weaker binding. The very negative half-life value for ligand A is also a major concern.

Output:
1
2025-04-17 03:53:57,441 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (346.431 and 358.438 Da) fall within the ideal range of 200-500 Da.

**TPSA:** Ligand A (85.25) is better than Ligand B (40.62). Both are below the 90 A^2 threshold for CNS targets, but Ligand B is significantly lower, which is advantageous for brain penetration.

**logP:** Ligand A (1.442) is within the optimal range (1-3), while Ligand B (3.245) is approaching the upper limit. This suggests Ligand B might have some solubility issues.

**H-Bond Donors/Acceptors:** Ligand A has 2 HBD and 5 HBA, while Ligand B has 0 HBD and 3 HBA. Both are within acceptable limits.

**QED:** Both ligands have good QED scores (0.708 and 0.827), indicating good drug-like properties.

**DILI:** Ligand A (23.614) has a much lower DILI risk than Ligand B (49.593), which is a significant advantage.

**BBB:** Ligand B (87.127) has a significantly higher BBB penetration percentile than Ligand A (54.013). This is a crucial factor for a CNS target like DRD2.

**Caco-2 Permeability:** Ligand A (-5.309) has worse Caco-2 permeability than Ligand B (-4.687), suggesting lower intestinal absorption.

**Aqueous Solubility:** Ligand A (-1.611) has better solubility than Ligand B (-3.433).

**hERG Inhibition:** Ligand A (0.077) has a lower hERG inhibition liability than Ligand B (0.719), which is a safety advantage.

**Microsomal Clearance:** Ligand A (10.191) has lower microsomal clearance than Ligand B (32.962), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (12.638) has a longer in vitro half-life than Ligand B (4.15), which is desirable.

**P-gp Efflux:** Ligand A (0.023) has lower P-gp efflux liability than Ligand B (0.436), which is important for CNS exposure.

**Binding Affinity:** Ligand B (-9.3 kcal/mol) has a significantly stronger binding affinity than Ligand A (-7.8 kcal/mol). This is a substantial advantage, potentially outweighing some of the ADME drawbacks. The difference is >1.5 kcal/mol.

**Overall Assessment:**

Ligand B excels in binding affinity and BBB penetration, which are critical for a CNS GPCR target. While it has some drawbacks in DILI risk, solubility, and metabolic stability, the strong binding affinity and excellent BBB penetration are likely to be decisive. Ligand A has a better safety profile and ADME properties, but its weaker binding affinity is a significant limitation.

Output:
1
2025-04-17 03:53:57,442 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands are within the acceptable range (200-500 Da). Ligand A (415.328 Da) is higher, but not excessively so. Ligand B (347.419 Da) is slightly better.

**2. TPSA:**  For CNS targets, we want TPSA <= 90. Ligand A (71.03) is excellent. Ligand B (78.87) is still reasonable, but less optimal.

**3. logP:** Optimal is 1-3. Ligand A (1.972) is ideal. Ligand B (0.069) is quite low, potentially hindering permeation. This is a significant drawback for Ligand B.

**4. H-Bond Donors:**  <= 5 is preferred. Ligand A (2) and Ligand B (0) both meet this criterion.

**5. H-Bond Acceptors:** <= 10 is preferred. Ligand A (5) and Ligand B (6) both meet this criterion.

**6. QED:** Both ligands have similar QED values (0.68 and 0.669), indicating good drug-likeness.

**7. DILI:** Lower is better. Ligand A (7.057) is significantly better than Ligand B (62.195), indicating a much lower risk of liver injury.

**8. BBB:**  >70 is desirable for CNS targets. Ligand A (51.105) is moderate, while Ligand B (63.784) is better, but still not ideal.

**9. Caco-2:** Higher is better. Both are negative, which is unusual. This suggests poor intestinal absorption for both, but the scale is unclear.

**10. Solubility:** Higher is better. Both are negative, suggesting poor solubility. Again, the scale is unclear.

**11. hERG:** Lower is better. Ligand A (0.716) is better than Ligand B (0.266), indicating a lower risk of cardiotoxicity.

**12. Cl_mic:** Lower is better. Ligand A (-5.238) is much better than Ligand B (25.04), suggesting greater metabolic stability.

**13. t1/2:** Longer is better. Ligand A (28.001) is much better than Ligand B (-13.511), indicating a longer half-life.

**14. Pgp:** Lower is better. Ligand A (0.08) is much better than Ligand B (0.018), indicating lower P-gp efflux.

**15. Binding Affinity:**  More negative is better. Ligand A (-7.9) is slightly better than Ligand B (-7.6), but the difference is relatively small.

**Overall Assessment:**

Ligand A is significantly better overall. While Ligand B has a slightly better BBB score, Ligand A excels in almost every other critical parameter, especially logP, DILI, metabolic stability (Cl_mic and t1/2), P-gp efflux, and hERG inhibition. The low logP of Ligand B is a major concern for CNS penetration and overall bioavailability. The superior ADME properties of Ligand A, combined with comparable binding affinity, make it the more promising drug candidate.

Output:
1
2025-04-17 03:53:57,442 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (343.471 and 350.467 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (60.18) is excellent, well below the 90 A^2 threshold for CNS targets. Ligand B (114.93) is higher but still potentially acceptable, though less ideal.

**logP:** Ligand A (3.95) is at the upper end of the optimal range (1-3), but still acceptable. Ligand B (1.23) is low, potentially hindering permeability.

**H-Bond Donors/Acceptors:** Ligand A (1 HBD, 5 HBA) is favorable. Ligand B (3 HBD, 6 HBA) is also reasonable, but slightly higher.

**QED:** Ligand A (0.825) has a very good drug-likeness score. Ligand B (0.684) is still acceptable, but lower.

**DILI:** Both ligands have low DILI risk (44.552 and 38.581, respectively), which is positive.

**BBB:** Ligand A (74.176) has a good BBB percentile, exceeding the 70% threshold for CNS targets. Ligand B (58.938) is significantly lower, which is a major concern for CNS penetration.

**Caco-2 Permeability:** Ligand A (-4.949) has poor Caco-2 permeability. Ligand B (-5.465) is also poor.

**Aqueous Solubility:** Both ligands have poor aqueous solubility (-3.194 and -2.16, respectively).

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.82 and 0.112, respectively).

**Microsomal Clearance:** Ligand A (32.417) has moderate clearance, while Ligand B (18.963) has lower clearance, indicating better metabolic stability.

**In vitro Half-Life:** Ligand A (10.386 hours) has a reasonable half-life. Ligand B (-8.516 hours) has a negative half-life, which is not possible and likely indicates a very short half-life.

**P-gp Efflux:** Ligand A (0.516) has moderate P-gp efflux liability. Ligand B (0.016) has very low P-gp efflux, which is highly desirable for CNS penetration.

**Binding Affinity:** Ligand A (-8.8 kcal/mol) has significantly stronger binding affinity than Ligand B (-7.3 kcal/mol). The difference of 1.5 kcal/mol is substantial.

**Overall Assessment:**

Ligand A excels in binding affinity and BBB penetration, crucial for a CNS-targeting GPCR. While its Caco-2 permeability and solubility are poor, the strong affinity might compensate for these issues. Ligand B has better metabolic stability and lower P-gp efflux, but its significantly lower BBB penetration and weaker binding affinity are major drawbacks. Given the importance of CNS penetration for DRD2, and the substantial affinity difference, Ligand A is the more promising candidate.

Output:
1
2025-04-17 03:53:57,442 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (383.279 and 381.9 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (67.23) is better than Ligand B (37.38). For CNS targets, we want TPSA <= 90, both are well within this range, but A is closer to the upper limit.

**3. logP:** Ligand A (1.965) is optimal (1-3), while Ligand B (4.812) is slightly high, potentially leading to solubility issues or off-target interactions.

**4. H-Bond Donors:** Ligand A (1) is good, while Ligand B (0) is also acceptable.

**5. H-Bond Acceptors:** Ligand A (6) is good, while Ligand B (3) is also acceptable.

**6. QED:** Both ligands have good QED values (0.469 and 0.625, respectively), indicating drug-like properties. Ligand B is slightly better.

**7. DILI:** Ligand A (60.682) has a higher DILI risk than Ligand B (35.673). This is a significant negative for Ligand A.

**8. BBB:** Ligand A (85.498) has a better BBB penetration score than Ligand B (73.401). This is crucial for a CNS target like DRD2.

**9. Caco-2:** Both have negative values, which is unusual and difficult to interpret without knowing the scale. However, the values are similar.

**10. Solubility:** Both have negative values, again making direct comparison difficult. The values are similar.

**11. hERG:** Both ligands have low hERG inhibition liability (0.747 and 0.666), which is good.

**12. Cl_mic:** Ligand A (21.071) has a lower microsomal clearance than Ligand B (76.77), indicating better metabolic stability.

**13. t1/2:** Ligand A (42.553) has a shorter in vitro half-life than Ligand B (60.908).

**14. Pgp:** Ligand A (0.536) has lower P-gp efflux liability than Ligand B (0.811), which is favorable for CNS penetration.

**15. Binding Affinity:** Ligand B (-7.2 kcal/mol) has a significantly stronger binding affinity than Ligand A (-8.5 kcal/mol). This is a substantial advantage, potentially outweighing some ADME drawbacks.

**Overall Assessment:**

Ligand B has a stronger binding affinity, lower DILI risk, and a longer half-life. While its logP is slightly higher, the significantly improved affinity and reduced toxicity make it the more promising candidate. Ligand A has better BBB penetration and Pgp efflux, but the higher DILI risk and weaker binding are concerning. Given the GPCR-specific priorities, the stronger binding affinity of Ligand B is the most important factor.

Output:
1
2025-04-17 03:53:57,442 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (343.347 and 343.402 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (139.89) is close to the upper limit for good oral absorption and acceptable for CNS targets, while Ligand B (62.3) is excellent, well below the 90 A^2 threshold for CNS penetration. This favors Ligand B.

**3. logP:** Ligand A (-0.942) is slightly low, potentially hindering permeation. Ligand B (2.594) is within the optimal 1-3 range. This significantly favors Ligand B.

**4. H-Bond Donors:** Ligand A (4) is acceptable, while Ligand B (1) is even better, potentially improving permeability.

**5. H-Bond Acceptors:** Ligand A (6) is acceptable, and Ligand B (3) is also good.

**6. QED:** Both ligands have good QED scores (0.528 and 0.877), indicating drug-like properties. Ligand B is better.

**7. DILI:** Both have acceptable DILI risk (60.217 and 52.617), though Ligand B is slightly better.

**8. BBB:** This is critical for a CNS target. Ligand A (27.026) has poor BBB penetration, while Ligand B (75.145) is very good, exceeding the desirable >70 threshold. This is a major advantage for Ligand B.

**9. Caco-2 Permeability:** Both have negative values, which is unusual and suggests poor permeability. However, the scale isn't specified, so it's hard to interpret.

**10. Aqueous Solubility:** Both have negative values, indicating poor solubility.

**11. hERG Inhibition:** Both have low hERG risk (0.103 and 0.605).

**12. Microsomal Clearance:** Ligand A (-31.334) has a negative clearance, which is not physically possible and suggests an error in the data. Ligand B (55.112) indicates faster clearance, which is less desirable.

**13. In vitro Half-Life:** Ligand A (-9.194) has a negative half-life, which is impossible and indicates a data error. Ligand B (29.72) is a reasonable half-life.

**14. P-gp Efflux:** Both ligands have very low P-gp efflux (0.031 and 0.164), which is favorable for CNS exposure.

**15. Binding Affinity:** Both ligands have similar binding affinities (-9.0 and -9.3 kcal/mol), which are excellent and comparable.

**Overall Assessment:**

Ligand B is significantly better due to its superior logP, TPSA, and, crucially, BBB penetration. While Ligand A has comparable affinity, the negative values for clearance and half-life are highly suspect and likely indicate data errors. Even if those values were corrected, Ligand B's better ADME properties, particularly BBB, make it the more promising candidate for a CNS-targeting drug like a DRD2 ligand.

Output:
1
2025-04-17 03:53:57,442 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (343.431 and 354.407 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (110.0) is significantly better than Ligand B (138.78). For CNS targets, TPSA should be <=90, so Ligand A is closer to this threshold.

**logP:** Ligand A (1.572) is within the optimal 1-3 range. Ligand B (-1.421) is below 1, which could hinder permeation.

**H-Bond Donors/Acceptors:** Ligand A (3 HBD, 5 HBA) and Ligand B (5 HBD, 6 HBA) are both acceptable, though Ligand B is slightly higher in both counts.

**QED:** Ligand A (0.651) has a better QED score than Ligand B (0.327), indicating better overall drug-likeness.

**DILI:** Ligand A (51.221) has a higher DILI risk than Ligand B (15.083), but both are below the concerning threshold of 60.

**BBB:** Ligand A (63.629) has a significantly better BBB percentile than Ligand B (11.439). This is *critical* for a CNS target like DRD2.

**Caco-2:** Both have negative Caco-2 values, which is unusual and suggests poor permeability. However, these values are on a scale where negative values are possible.

**Solubility:** Ligand A (-3.383) has slightly better solubility than Ligand B (-0.014), though both are quite poor.

**hERG:** Both ligands have very low hERG inhibition risk (0.189 and 0.045).

**Microsomal Clearance:** Ligand A (19.674) has higher microsomal clearance than Ligand B (-1.767), suggesting lower metabolic stability.

**In vitro Half-Life:** Ligand B (-18.103) has a much longer in vitro half-life than Ligand A (-4.908).

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.017 and 0.007).

**Binding Affinity:** Ligand A (-8.5 kcal/mol) has a significantly stronger binding affinity than Ligand B (-6.7 kcal/mol). The difference of 1.8 kcal/mol is substantial and can outweigh some ADME drawbacks.

**Overall Assessment:**

Ligand A is the better candidate. While it has a slightly higher DILI risk and worse metabolic stability, its superior BBB penetration, TPSA, logP, QED, and *significantly* better binding affinity are decisive. For a CNS GPCR target, BBB penetration is paramount, and Ligand A excels in this area. The stronger binding affinity also provides a considerable advantage. The poor solubility and Caco-2 values are concerning for both, but can potentially be addressed with formulation strategies.

Output:
1
2025-04-17 03:53:57,442 - INFO - Reasoning:

Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight (MW):** Both ligands are within the ideal range (200-500 Da). Ligand A (404.304 Da) is slightly higher than Ligand B (348.447 Da), but both are acceptable.

**2. TPSA:** Ligand A (55.4) is significantly better than Ligand B (77.32). For CNS targets, we want TPSA <= 90, and ideally closer to 60. Ligand A is much closer to this ideal.

**3. logP:** Both ligands have good logP values (Ligand A: 3.843, Ligand B: 2.103), falling within the optimal 1-3 range. Ligand A is slightly higher, which could potentially lead to off-target effects, but is still acceptable.

**4. H-Bond Donors (HBD):** Both ligands are within the acceptable limit of <=5. Ligand A has 1 HBD, and Ligand B has 0.

**5. H-Bond Acceptors (HBA):** Both ligands are within the acceptable limit of <=10. Ligand A has 3 HBA, and Ligand B has 6.

**6. QED:** Both ligands have similar QED values (Ligand A: 0.714, Ligand B: 0.615), both above the 0.5 threshold, indicating good drug-likeness.

**7. DILI:** Ligand A (64.366) has a higher DILI risk than Ligand B (48.701). Both are below 60, so the risk is moderate, but Ligand B is preferable.

**8. BBB:** Both ligands have similar BBB penetration (Ligand A: 52.734, Ligand B: 51.066). These are borderline for a CNS target; ideally, we want >70.

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 values, which is unusual and suggests poor permeability. This is a significant concern for both.

**10. Aqueous Solubility:** Both ligands have negative solubility values, indicating very poor aqueous solubility. This is a major drawback for both compounds.

**11. hERG Inhibition:** Ligand A (0.707) has a slightly higher hERG risk than Ligand B (0.097). Ligand B is much preferable here.

**12. Microsomal Clearance:** Ligand B (98.404) has a higher microsomal clearance than Ligand A (86.857), meaning it's metabolized faster. Ligand A is preferable here.

**13. In vitro Half-Life:** Ligand A (24.865) has a significantly longer half-life than Ligand B (-13.979). This is a major advantage for Ligand A.

**14. P-gp Efflux:** Ligand A (0.283) has lower P-gp efflux than Ligand B (0.066), which is favorable for CNS penetration.

**15. Binding Affinity:** Ligand A (-9.5 kcal/mol) has a significantly stronger binding affinity than Ligand B (-7.8 kcal/mol). This is a substantial advantage, potentially outweighing some of the ADME drawbacks.

**Overall Assessment:**

While both compounds have significant issues with solubility and Caco-2 permeability, Ligand A is the more promising candidate. Its superior binding affinity (-9.5 vs -7.8 kcal/mol) is a key advantage for a GPCR target. It also has a longer half-life, lower P-gp efflux, and a slightly better TPSA. While Ligand B has a lower DILI risk and hERG inhibition, the substantial difference in binding affinity makes Ligand A the better choice, assuming further optimization can address the solubility and permeability issues.

Output:
1
2025-04-17 03:53:57,442 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (359.344 and 370.475 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (59.0) is excellent, well below the 90 target for CNS drugs. Ligand B (75.21) is still reasonable, but less optimal.

**logP:** Ligand A (1.876) is within the optimal 1-3 range. Ligand B (0.401) is a bit low, potentially hindering membrane permeability.

**H-Bond Donors/Acceptors:** Ligand A (1 HBD, 4 HBA) and Ligand B (0 HBD, 7 HBA) both have acceptable numbers of hydrogen bond donors and acceptors.

**QED:** Both ligands have good QED scores (0.895 and 0.722), indicating drug-like properties.

**DILI:** Ligand A (38.077) has a lower DILI risk than Ligand B (55.138), which is preferable.

**BBB:** This is critical for a CNS target like DRD2. Ligand A (81.698) has a significantly better BBB percentile than Ligand B (57.968).

**Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and suggests a potential issue with the data or modeling. However, the values are similar.

**Aqueous Solubility:** Both ligands have negative solubility values, which is also unusual. Again, the values are similar.

**hERG:** Ligand A (0.766) has a lower hERG risk than Ligand B (0.281), which is favorable.

**Microsomal Clearance:** Ligand B (39.332) has a higher microsomal clearance than Ligand A (14.661), suggesting faster metabolism and potentially lower exposure.

**In vitro Half-Life:** Ligand A (-7.455) has a much longer in vitro half-life than Ligand B (-16.219).

**P-gp Efflux:** Ligand A (0.325) has lower P-gp efflux liability than Ligand B (0.061), which is beneficial for CNS penetration.

**Binding Affinity:** Ligand A (-8.6 kcal/mol) has a slightly better binding affinity than Ligand B (-7.1 kcal/mol). While both are good, the 1.5 kcal/mol difference is significant.

**Overall Assessment:**

Ligand A consistently outperforms Ligand B across the most important parameters for a CNS-targeting GPCR ligand. It has better BBB penetration, lower DILI risk, lower P-gp efflux, a longer half-life, and a slightly stronger binding affinity. While both have unusual solubility and Caco-2 values, the other advantages of Ligand A make it the more promising candidate.

Output:
1
2025-04-17 03:53:57,443 - INFO - Batch 67 complete. Total preferences: 1072
2025-04-17 03:53:57,443 - INFO - Processing batch 68/512...
2025-04-17 03:54:38,164 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B based on the provided guidelines, prioritizing GPCR properties (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (350.419 and 359.543 Da) fall within the ideal range of 200-500 Da.

**TPSA:** Ligand A (96.69) is better than Ligand B (44.29). For CNS targets, TPSA should be <= 90, and both meet this criterion, but A is closer to the upper limit.

**logP:** Ligand B (3.545) is higher than Ligand A (-0.009). While both are within the acceptable range, Ligand B is closer to the optimal 1-3 range, and A is very close to 0, which could hinder permeation.

**H-Bond Donors:** Ligand A (2) is slightly better than Ligand B (1), both are within the acceptable limit of <=5.

**H-Bond Acceptors:** Both ligands have 6 HBA, which is within the acceptable limit of <=10.

**QED:** Both ligands have good QED scores (0.796 and 0.854 respectively), indicating good drug-like properties.

**DILI:** Ligand A (31.02) has a significantly lower DILI risk than Ligand B (57.58). This is a substantial advantage for Ligand A.

**BBB:** Ligand B (83.637) has a much higher BBB penetration percentile than Ligand A (44.746). This is a *critical* advantage for a CNS target like DRD2.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.96 and -5.085), which is unusual and suggests poor permeability. However, these values are on a scale where negative values are possible and don't necessarily disqualify a compound.

**Aqueous Solubility:** Both ligands have negative solubility values (-1.235 and -3.535), which is also unusual. Similar to Caco-2, these values don't automatically disqualify a compound, but are not ideal.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.235 and 0.955).

**Microsomal Clearance:** Ligand A (-8.848) has a much lower (better) microsomal clearance than Ligand B (78.369), indicating better metabolic stability.

**In vitro Half-Life:** Ligand A (5.147) has a slightly better half-life than Ligand B (-5.647).

**P-gp Efflux:** Ligand A (0.03) has a significantly lower P-gp efflux liability than Ligand B (0.515). This is a significant advantage for CNS penetration.

**Binding Affinity:** Both ligands have very similar and strong binding affinities (-8.6 and -8.3 kcal/mol). The difference of 0.3 kcal/mol is not substantial enough to outweigh other factors.

**Overall Assessment:**

Ligand B excels in BBB penetration, which is paramount for a CNS target. However, it suffers from higher DILI risk, higher P-gp efflux, and higher microsomal clearance. Ligand A has better DILI, P-gp, and metabolic stability profiles. While Ligand A's BBB is lower, the combination of its improved safety and pharmacokinetic properties, coupled with comparable binding affinity, makes it the more promising candidate.

Output:
0
2025-04-17 03:54:38,165 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (345.447) is slightly lower, which can be advantageous for permeability. Ligand B (360.845) is also good.

**TPSA:** Both ligands have TPSA values below 90 (Ligand A: 80.12, Ligand B: 78.09), which is excellent for CNS penetration.

**logP:** Ligand A (1.067) is at the lower end of the optimal range (1-3), while Ligand B (2.471) is more centrally located. While Ligand A's logP isn't *bad*, Ligand B's is preferable for better membrane permeability.

**H-Bond Donors/Acceptors:** Ligand A (HBD=1, HBA=5) and Ligand B (HBD=2, HBA=3) both have reasonable numbers of H-bond donors and acceptors, well within the guidelines.

**QED:** Both ligands have good QED scores (Ligand A: 0.75, Ligand B: 0.869), indicating good drug-like properties.

**DILI:** Ligand A (23.575) has a significantly lower DILI risk than Ligand B (56.844). This is a major advantage for Ligand A.

**BBB:** Ligand A (85.731) has a much higher BBB penetration percentile than Ligand B (60.372). This is crucial for a CNS target like DRD2.

**Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and potentially problematic. However, the scale is not specified, so it's hard to interpret.

**Aqueous Solubility:** Both have negative solubility values, which is also unusual and potentially problematic.

**hERG Inhibition:** Both ligands have very low hERG inhibition risk (Ligand A: 0.061, Ligand B: 0.167).

**Microsomal Clearance:** Ligand A (26.152) has a higher microsomal clearance than Ligand B (-1.368). This suggests Ligand B is more metabolically stable.

**In vitro Half-Life:** Ligand B (-38.719) has a much longer in vitro half-life than Ligand A (-9.467). This is a significant advantage for Ligand B.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (Ligand A: 0.022, Ligand B: 0.09).

**Binding Affinity:** Ligand A (-7.7) has slightly better binding affinity than Ligand B (0.0). This is a substantial advantage.

**Overall Assessment:**

Ligand A excels in BBB penetration, DILI risk, and binding affinity. Ligand B has better metabolic stability (lower Cl_mic, longer t1/2) and a more optimal logP. The significantly better BBB and binding affinity of Ligand A, coupled with the lower DILI risk, outweigh the slightly higher clearance. The negative solubility and Caco-2 values are concerning for both, but the strong affinity and CNS penetration profile of Ligand A make it the more promising candidate.

Output:
1
2025-04-17 03:54:38,165 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (402.519 Da) is slightly higher, but still acceptable. Ligand B (353.375 Da) is also good.

**TPSA:**  Both ligands exceed the optimal TPSA for CNS targets (<90 A^2). Ligand A (109.41 A^2) is closer to the threshold than Ligand B (114.04 A^2), suggesting potentially better CNS penetration.

**logP:** Ligand A (2.014) is within the optimal range (1-3). Ligand B (-0.453) is significantly below this range, which could hinder membrane permeability and bioavailability.

**H-Bond Donors/Acceptors:** Both ligands have 2 HBD and 6 HBA, which are within acceptable limits.

**QED:** Both ligands have reasonable QED values (A: 0.768, B: 0.625), indicating good drug-like properties.

**DILI:** Ligand A (96.045) has a high DILI risk, which is a significant concern. Ligand B (34.471) has a much lower DILI risk, making it more favorable.

**BBB:** Ligand B (76.696) has a considerably higher BBB percentile than Ligand A (39.046). This is a critical advantage for a CNS target like DRD2.

**Caco-2 Permeability:** Ligand A (-5.613) has poor Caco-2 permeability, while Ligand B (-4.889) is also poor, but slightly better.

**Aqueous Solubility:** Both ligands have poor aqueous solubility (-2.833 and -1.331 respectively).

**hERG Inhibition:** Both ligands show low hERG inhibition liability (A: 0.229, B: 0.056), which is positive.

**Microsomal Clearance:** Ligand A (-4.102) has a negative value, indicating good metabolic stability. Ligand B (17.885) has a higher clearance, suggesting faster metabolism.

**In vitro Half-Life:** Ligand A (89.177) has a longer half-life than Ligand B (-23.167), which is desirable.

**P-gp Efflux:** Ligand A (0.207) has lower P-gp efflux liability than Ligand B (0.005), which is favorable for CNS penetration.

**Binding Affinity:** Ligand A (-8.4 kcal/mol) has a slightly better binding affinity than Ligand B (-7.8 kcal/mol), but the difference is not substantial enough to overcome the other significant drawbacks.

**Overall Assessment:**

Ligand B is the more promising candidate despite its lower binding affinity. Its significantly better BBB penetration, lower DILI risk, and lower P-gp efflux outweigh the slightly weaker binding. Ligand A's high DILI risk and poor BBB penetration are major liabilities. While Ligand A has better metabolic stability and half-life, these are secondary considerations compared to the CNS penetration and safety profile.



Output:
1
2025-04-17 03:54:38,165 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (352.475 and 344.455 Da) fall within the ideal range of 200-500 Da.

**TPSA:** Ligand A (89.87) is better than Ligand B (69.64) as it is closer to the ideal range for CNS targets (<=90).

**logP:** Both ligands have good logP values (1.363 and 1.782), falling within the optimal range of 1-3.

**H-Bond Donors/Acceptors:** Ligand A has 3 HBD and 4 HBA, while Ligand B has 2 HBD and 3 HBA. Both are within acceptable limits (<=5 HBD and <=10 HBA).

**QED:** Ligand A (0.652) has a better QED score than Ligand B (0.464), indicating a more drug-like profile.

**DILI:** Ligand B (40.752) has a significantly lower DILI risk than Ligand A (10.896), which is a substantial advantage.

**BBB:** Ligand B (70.531) has a significantly better BBB penetration score than Ligand A (52.036). This is *critical* for a CNS target like DRD2.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values, indicating poor permeability. Ligand A (-4.85) is slightly better than Ligand B (-4.565).

**Aqueous Solubility:** Both ligands have negative solubility values, indicating poor solubility. Ligand A (-1.887) is slightly better than Ligand B (-2.518).

**hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.162 and 0.192).

**Microsomal Clearance:** Ligand A (7.827) has significantly lower microsomal clearance than Ligand B (21.902), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand B (-46.538) has a much longer in vitro half-life than Ligand A (-12.432), which is a significant advantage.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.024 and 0.109).

**Binding Affinity:** Both ligands have excellent binding affinities (-8.9 and -8.3 kcal/mol). Ligand A is slightly better (-8.9 kcal/mol).

**Overall Assessment:**

While Ligand A has slightly better affinity and TPSA, Ligand B excels in crucial areas for a CNS-targeting GPCR ligand: significantly better BBB penetration (70.531 vs 52.036), lower DILI risk (40.752 vs 10.896), and a much longer in vitro half-life (-46.538 vs -12.432). The difference in BBB penetration is particularly important. The slightly better metabolic stability of Ligand A is overshadowed by the other advantages of Ligand B.

Output:
1
2025-04-17 03:54:38,165 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (350.459 Da and 345.418 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (98.66) is slightly above the optimal <90 for CNS targets, while Ligand B (73.2) is well within the desired range. This favors Ligand B.

**logP:** Ligand A (0.71) is a bit low, potentially hindering permeability. Ligand B (2.689) is closer to the optimal 1-3 range. This favors Ligand B.

**H-Bond Donors/Acceptors:** Ligand A has 4 HBD and 4 HBA, which are acceptable. Ligand B has 1 HBD and 3 HBA, also acceptable. No clear advantage here.

**QED:** Both ligands have good QED scores (0.567 and 0.861), indicating drug-like properties. Ligand B is slightly better.

**DILI:** Ligand A (17.604) has a significantly lower DILI risk than Ligand B (43.195). This favors Ligand A.

**BBB:** Ligand B (81.698) has a much higher BBB penetration percentile than Ligand A (45.677). This is a *critical* advantage for a CNS target like DRD2.

**Caco-2 Permeability:** Ligand A (-5.11) has poor Caco-2 permeability, while Ligand B (-4.597) is slightly better, but still not great.

**Aqueous Solubility:** Both ligands have very poor aqueous solubility (-2.387 and -3.764). This is a concern for both, but might be manageable with formulation strategies.

**hERG Inhibition:** Ligand A (0.13) has a very low hERG inhibition risk, significantly lower than Ligand B (0.848). This is a strong advantage for Ligand A.

**Microsomal Clearance:** Ligand B (51.88) has higher microsomal clearance than Ligand A (14.535), suggesting faster metabolism and potentially lower *in vivo* exposure. This favors Ligand A.

**In vitro Half-Life:** Ligand A (20.765) has a longer in vitro half-life than Ligand B (-3.249). This favors Ligand A.

**P-gp Efflux:** Ligand A (0.019) has very low P-gp efflux liability, which is excellent for CNS penetration. Ligand B (0.234) is higher, but still relatively low. This favors Ligand A.

**Binding Affinity:** Ligand B (-9.1) has a significantly stronger binding affinity than Ligand A (-8.3). This is a substantial advantage, potentially outweighing some of the ADME drawbacks of Ligand B. A difference of 0.8 kcal/mol is meaningful.

**Overall Assessment:**

Ligand B excels in BBB penetration and binding affinity, which are paramount for a CNS GPCR target. However, it has a higher DILI risk, higher hERG risk, faster metabolism, and lower P-gp efflux. Ligand A has better ADME properties (lower DILI, hERG, clearance, P-gp efflux, longer half-life) but weaker binding affinity.

The stronger binding affinity of Ligand B is a significant advantage. While its ADME profile isn't ideal, the difference in affinity (0.8 kcal/mol) is substantial enough to potentially overcome those issues through further optimization. The improved BBB penetration is also critical.

Output:
1
2025-04-17 03:54:38,165 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (347.415 and 349.475 Da) fall comfortably within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (100.29) is higher than Ligand B (61.88). For a CNS target like DRD2, TPSA should ideally be <=90. Ligand B is much closer to this threshold, giving it an advantage.

**3. logP:** Both ligands have good logP values (1.355 and 1.006), falling within the optimal 1-3 range.

**4. H-Bond Donors:** Ligand A has 3 HBD, while Ligand B has 1. Both are acceptable (<=5).

**5. H-Bond Acceptors:** Both ligands have 4 HBA, which is also acceptable (<=10).

**6. QED:** Both ligands have similar QED values (0.676 and 0.664), indicating good drug-like properties.

**7. DILI:** Ligand A (45.793) has a slightly higher DILI risk than Ligand B (5.312). Lower is better, so Ligand B is preferable.

**8. BBB:** Ligand B (65.297) has a significantly higher BBB penetration percentile than Ligand A (59.209). This is a *critical* advantage for a CNS target like DRD2. A value >70 is desirable, and Ligand B is closer.

**9. Caco-2 Permeability:** Ligand A (-5.058) has worse Caco-2 permeability than Ligand B (-4.96). Higher is better, so Ligand B is slightly favored.

**10. Aqueous Solubility:** Ligand A (-2.964) has slightly worse solubility than Ligand B (-1.156). Higher is better, so Ligand B is slightly favored.

**11. hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.335 and 0.328).

**12. Microsomal Clearance:** Ligand B (-12.736) has a much lower (better) microsomal clearance than Ligand A (3.063), indicating greater metabolic stability.

**13. In vitro Half-Life:** Ligand B (-19.681) has a much longer in vitro half-life than Ligand A (-10.525), which is highly desirable.

**14. P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.045 and 0.019).

**15. Binding Affinity:** Ligand A (-8.9 kcal/mol) has a slightly better binding affinity than Ligand B (-7.8 kcal/mol). While a 1.1 kcal/mol difference is noticeable, the ADME advantages of Ligand B are substantial.

**Overall Assessment:**

Ligand B consistently outperforms Ligand A in key ADME properties crucial for CNS drug development, particularly BBB penetration, metabolic stability (Cl_mic and t1/2), and DILI risk. While Ligand A has a slightly better binding affinity, the ADME profile of Ligand B is far more promising, making it a more viable drug candidate. The difference in affinity is unlikely to overcome the significant ADME advantages of Ligand B.

Output:
1
2025-04-17 03:54:38,165 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (344.419 and 352.387 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (84.22) is excellent, well below the 90 A^2 threshold for CNS targets. Ligand B (106.87) is still reasonable but less optimal.

**logP:** Ligand A (0.2) is quite low, potentially hindering permeability. Ligand B (0.973) is better, closer to the optimal 1-3 range, but still on the lower side.

**H-Bond Donors/Acceptors:** Ligand A (0 HBD, 6 HBA) is favorable. Ligand B (2 HBD, 6 HBA) is also acceptable.

**QED:** Both ligands have similar QED values (0.689 and 0.675), indicating good drug-likeness.

**DILI:** Ligand A (31.059) has a significantly lower DILI risk than Ligand B (58.976), which is a considerable advantage.

**BBB:** Ligand A (76.309) has a better BBB percentile than Ligand B (69.446), which is crucial for a CNS target like DRD2.

**Caco-2 Permeability:** Ligand A (-4.918) has worse Caco-2 permeability than Ligand B (-4.574), but both are poor.

**Aqueous Solubility:** Ligand A (-1.225) has better solubility than Ligand B (-2.865).

**hERG Inhibition:** Ligand A (0.045) has a much lower hERG risk than Ligand B (0.24).

**Microsomal Clearance:** Ligand B (68.834) has a much higher microsomal clearance than Ligand A (1.89), indicating lower metabolic stability.

**In vitro Half-Life:** Ligand B (1.935) has a slightly longer half-life than Ligand A (-1.227).

**P-gp Efflux:** Ligand A (0.02) shows lower P-gp efflux liability than Ligand B (0.068), which is beneficial for CNS penetration.

**Binding Affinity:** Ligand A (-7.7 kcal/mol) has a slightly better binding affinity than Ligand B (-7.3 kcal/mol). While both are good, the 0.4 kcal/mol difference is noteworthy.

**Overall Assessment:**

Ligand A is superior due to its significantly better BBB penetration, lower DILI risk, lower hERG risk, lower P-gp efflux, and slightly better binding affinity. While its logP and Caco-2 permeability are less ideal, the strong advantages in CNS-relevant properties and safety outweigh these drawbacks. Ligand B's higher metabolic clearance is also a concern.

Output:
0
2025-04-17 03:54:38,166 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (346.391 and 353.507 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (116.14) is higher than the preferred <90 for CNS targets, but not drastically so. Ligand B (61.88) is well within the desired range. This favors Ligand B.

**logP:** Ligand A (-0.196) is quite low, potentially hindering membrane permeability. Ligand B (1.5) is within the optimal 1-3 range. This is a significant advantage for Ligand B.

**H-Bond Donors/Acceptors:** Ligand A has 3 HBD and 6 HBA, which are acceptable. Ligand B has 1 HBD and 4 HBA, also acceptable.

**QED:** Both ligands have similar QED values (0.67 and 0.682), indicating good drug-likeness.

**DILI:** Ligand A (47.266) has a moderate DILI risk, while Ligand B (5.584) has a very low risk. This strongly favors Ligand B.

**BBB:** Ligand A (8.143) has extremely poor predicted BBB penetration. Ligand B (61.962) has a reasonably good BBB penetration, although not exceptional. This is a critical advantage for Ligand B, given the CNS target.

**Caco-2:** Ligand A (-5.695) and Ligand B (-4.866) both have negative Caco-2 values, which is unusual and suggests poor permeability. However, the scale isn't specified, so it's difficult to interpret definitively.

**Solubility:** Ligand A (-1.205) and Ligand B (-0.513) both have negative solubility values, which is also unusual and suggests poor solubility.

**hERG:** Both ligands have low hERG risk (0.244 and 0.348).

**Microsomal Clearance:** Ligand A (-22.296) has a very low (good) microsomal clearance, indicating high metabolic stability. Ligand B (5.622) has a moderate clearance. This favors Ligand A.

**In vitro Half-Life:** Ligand A (-0.586) has a negative half-life, which is not physically possible and indicates an issue with the prediction. Ligand B (4.039) has a reasonable half-life.

**Pgp Efflux:** Both ligands have very low Pgp efflux liability (0.005 and 0.007).

**Binding Affinity:** Ligand B (-7.7 kcal/mol) has a slightly better binding affinity than Ligand A (-8.1 kcal/mol). While the difference isn't huge, it's still a positive for Ligand B.

**Overall Assessment:**

Ligand B is significantly more promising. It has a much better logP, lower DILI risk, substantially better BBB penetration, and a slightly better binding affinity. While Ligand A has better metabolic stability, the poor BBB penetration and low logP are major drawbacks for a CNS-targeting GPCR ligand. The unusual negative solubility and Caco-2 values for both compounds raise concerns, but the overall profile of Ligand B is far superior.

Output:
1
2025-04-17 03:54:38,166 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 drug candidates, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (335.382) is slightly lower, which could be advantageous for permeability. Ligand B (351.451) is also good.

**TPSA:** Ligand A (37.61) is excellent, well below the 90 A^2 threshold for CNS targets. Ligand B (99.35) is higher, but still potentially acceptable, though less ideal for CNS penetration.

**logP:** Ligand A (3.946) is within the optimal range (1-3), though approaching the upper limit. Ligand B (0.278) is quite low, which is a significant concern for membrane permeability and CNS penetration.

**H-Bond Donors/Acceptors:** Ligand A (0 HBD, 3 HBA) is favorable. Ligand B (3 HBD, 5 HBA) is also acceptable, but slightly higher counts could impact permeability.

**QED:** Both ligands have similar QED values (A: 0.675, B: 0.684), indicating good drug-like properties.

**DILI:** Ligand A (68.05) has a higher DILI risk than Ligand B (44.009), but both are below the concerning 60 percentile.

**BBB:** This is critical for a CNS target. Ligand A (93.408) has excellent predicted BBB penetration. Ligand B (35.44) has very poor predicted BBB penetration.

**Caco-2 Permeability:** Ligand A (-4.488) has poor Caco-2 permeability, which is concerning. Ligand B (-5.274) is also poor.

**Aqueous Solubility:** Ligand A (-4.786) has poor solubility. Ligand B (-1.963) has slightly better solubility, but still not ideal.

**hERG Inhibition:** Ligand A (0.821) has a slightly higher hERG risk than Ligand B (0.191), but both are relatively low.

**Microsomal Clearance:** Ligand A (90.221) has high microsomal clearance, suggesting rapid metabolism. Ligand B (14.441) has much lower clearance, indicating better metabolic stability.

**In vitro Half-Life:** Ligand A (39.911) has a moderate half-life. Ligand B (-1.849) has a very short half-life, which is a major drawback.

**P-gp Efflux:** Ligand A (0.585) has moderate P-gp efflux. Ligand B (0.005) has very low P-gp efflux, which is favorable for CNS exposure.

**Binding Affinity:** Ligand B (-7.3) has a significantly stronger binding affinity than Ligand A (-9.4). This is a substantial advantage.

**Overall Assessment:**

Despite Ligand B's superior binding affinity, the poor logP and BBB penetration are major liabilities for a CNS-targeting drug. The short half-life and poor Caco-2 permeability are also concerning. Ligand A, while having a weaker affinity, possesses much better predicted BBB penetration and a more reasonable logP. The higher DILI and clearance are less concerning than the permeability issues with Ligand B. The poor Caco-2 and solubility of Ligand A would need to be addressed through formulation or further chemical modification, but the core pharmacokinetic properties are more promising.

Output:
0
2025-04-17 03:54:38,166 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (345.443 and 349.352 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (78.6) is better than Ligand B (30.49). For CNS targets, TPSA should be <= 90, both are well within this range, but Ligand B is significantly lower, potentially aiding BBB penetration.

**logP:** Both ligands have good logP values (2.955 and 3.967), falling within the optimal 1-3 range. Ligand B is slightly higher, which could be a minor concern for solubility but is still acceptable.

**H-Bond Donors/Acceptors:** Ligand A has 2 HBD and 5 HBA, while Ligand B has 1 HBD and 3 HBA. Both are within acceptable limits (<=5 HBD and <=10 HBA).

**QED:** Ligand A (0.871) has a better QED score than Ligand B (0.606), indicating a more drug-like profile.

**DILI:** Ligand A (63.086) has a slightly higher DILI risk than Ligand B (54.789), but both are below the concerning threshold of 60.

**BBB:** Ligand A (85.459) has a significantly better BBB percentile than Ligand B (77.239). This is a crucial factor for a CNS target like DRD2.

**Caco-2 Permeability:** Both have negative Caco-2 values (-4.439 and -4.504), which is unusual and suggests poor permeability. This is a significant drawback for both.

**Aqueous Solubility:** Both ligands have very poor aqueous solubility (-4.204 and -5.035). This is a major concern for bioavailability.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.81 and 0.946), which is good.

**Microsomal Clearance:** Ligand A (53.191) has lower microsomal clearance than Ligand B (67.92), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (87.277) has a longer in vitro half-life than Ligand B (0.991), which is desirable.

**P-gp Efflux:** Ligand A (0.461) has lower P-gp efflux than Ligand B (0.738), which is favorable for CNS penetration.

**Binding Affinity:** Ligand B (-8.6 kcal/mol) has a significantly stronger binding affinity than Ligand A (-7.7 kcal/mol). This is a substantial advantage, potentially outweighing some of the ADME drawbacks.

**Overall Assessment:**

While Ligand A has better QED, BBB, metabolic stability, half-life, and P-gp efflux, Ligand B's significantly stronger binding affinity (-8.6 vs -7.7 kcal/mol) is a major advantage for a GPCR target. The improved affinity could compensate for the slightly higher logP and lower BBB. Both compounds suffer from poor solubility and permeability. However, given the importance of potency for GPCRs, and the CNS target, the stronger affinity of Ligand B is the deciding factor.

Output:
1
2025-04-17 03:54:38,166 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, considering the provided guidelines and GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (361.291 and 353.463 Da) fall within the ideal range of 200-500 Da.

**TPSA:** Ligand A (55.84) is excellent, well below the 90 A^2 threshold for CNS targets. Ligand B (78.95) is still reasonable but less optimal, approaching the 140 A^2 limit for oral absorption.

**logP:** Ligand A (2.087) is within the optimal range of 1-3. Ligand B (0.633) is slightly low, potentially hindering permeation.

**H-Bond Donors/Acceptors:** Both ligands have acceptable HBD (0/1) and HBA (4/4) counts, well within the guidelines.

**QED:** Both ligands have good QED scores (0.568 and 0.76), indicating drug-like properties.

**DILI:** Ligand A (72.392) has a higher DILI risk than Ligand B (23.187), which is a significant concern.

**BBB:** Ligand A (92.672) has excellent BBB penetration, crucial for a CNS target like DRD2. Ligand B (54.905) has poor BBB penetration, severely limiting its potential for CNS activity.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.48 and -4.724), which is unusual and suggests poor permeability. However, these values are on a log scale and can be difficult to interpret without further context.

**Aqueous Solubility:** Both ligands have very poor aqueous solubility (-3.294 and -1.266). This is a significant drawback, potentially impacting bioavailability.

**hERG Inhibition:** Ligand A (0.521) shows a slightly higher hERG inhibition risk than Ligand B (0.17), but both are relatively low.

**Microsomal Clearance:** Ligand A (24.212) has a higher microsomal clearance than Ligand B (19.822), meaning it's less metabolically stable.

**In vitro Half-Life:** Ligand B (1.753 hours) has a very short half-life, while Ligand A (8.115 hours) is better, but still not ideal.

**P-gp Efflux:** Both ligands have very low P-gp efflux (0.259 and 0.015), which is favorable for CNS penetration.

**Binding Affinity:** Ligand B (-7.2 kcal/mol) has significantly stronger binding affinity than Ligand A (-0.0 kcal/mol). This is a substantial advantage.

**Overall Assessment:**

Despite the poor solubility and Caco-2 values for both, Ligand B stands out due to its significantly superior binding affinity (-7.2 kcal/mol vs -0.0 kcal/mol). The strong binding affinity can potentially overcome some of the ADME liabilities. However, the poor BBB penetration is a major concern. Ligand A has excellent BBB penetration, but its binding affinity is very weak, making it unlikely to be effective. The higher DILI risk for Ligand A is also a significant negative.

Considering the GPCR-specific priorities, BBB penetration and binding affinity are paramount. While Ligand B's BBB is poor, its binding affinity is substantially better. The poor solubility of both is a concern that could be addressed with formulation strategies.

Output:
1
2025-04-17 03:54:38,166 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (346.471 and 351.451 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (58.64) is excellent, well below the 90 A^2 threshold for CNS targets. Ligand B (89.35) is still reasonable but closer to the upper limit.

**logP:** Ligand A (2.409) is optimal (1-3). Ligand B (0.528) is a bit low, potentially hindering membrane permeability.

**H-Bond Donors/Acceptors:** Both have acceptable HBD counts (1). Ligand A has 3 HBA, and Ligand B has 6 HBA. Both are within the acceptable range of <=10.

**QED:** Both ligands have good QED values (0.85 and 0.701), indicating drug-like properties.

**DILI:** Ligand A (18.108) has a much lower DILI risk than Ligand B (39.899), which is a significant advantage.

**BBB:** Ligand A (79.217) has a good BBB percentile, exceeding the desirable >70 threshold for CNS targets. Ligand B (55.642) is considerably lower and less favorable for CNS penetration.

**Caco-2 Permeability:** Ligand A (-4.535) and Ligand B (-5.068) both have negative Caco-2 permeability values, which is unusual and suggests poor intestinal absorption. However, for a CNS target, intestinal absorption is less critical than BBB penetration.

**Aqueous Solubility:** Both have negative solubility values, which is also unusual. This could pose formulation challenges.

**hERG:** Both ligands have very low hERG inhibition risk (0.245 and 0.069).

**Microsomal Clearance:** Ligand A (27.244) has a higher microsomal clearance than Ligand B (16.505), suggesting lower metabolic stability.

**In vitro Half-Life:** Ligand B (9.177) has a slightly longer half-life than Ligand A (14.582).

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.038 and 0.027).

**Binding Affinity:** Ligand A (-8.4 kcal/mol) has a significantly stronger binding affinity than Ligand B (-7.5 kcal/mol). This 0.9 kcal/mol difference is substantial and can outweigh some ADME drawbacks.

**Overall Assessment:**

Ligand A is the stronger candidate. Its superior BBB penetration, lower DILI risk, and significantly better binding affinity are key advantages for a CNS-targeting GPCR like DRD2. While its microsomal clearance is higher, the strong binding affinity and favorable BBB properties are more critical in this context. Ligand B's lower logP and lower BBB penetration are significant drawbacks.

Output:
1
2025-04-17 03:54:38,166 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (358.404 and 351.535 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (61.36) is higher than Ligand B (47.36). For CNS targets, we prefer TPSA <= 90, so both are acceptable, but B is better.

**3. logP:** Ligand A (4.467) is slightly higher than Ligand B (3.895). Both are above the optimal 1-3 range, potentially causing solubility issues or off-target effects. However, for a GPCR, slightly higher logP can be tolerated if other properties are favorable.

**4. H-Bond Donors:** Ligand A (3) is higher than Ligand B (0). Both are within the acceptable limit of <=5.

**5. H-Bond Acceptors:** Ligand A (2) is lower than Ligand B (4). Both are within the acceptable limit of <=10.

**6. QED:** Ligand A (0.727) has a better QED score than Ligand B (0.642), indicating a more drug-like profile.

**7. DILI:** Ligand A (30.399) has a significantly lower DILI risk than Ligand B (15.2). This is a major advantage for Ligand A.

**8. BBB:** Ligand A (85.072) has a better BBB penetration percentile than Ligand B (75.921). This is crucial for a CNS target like DRD2.

**9. Caco-2 Permeability:** Ligand A (-4.509) has worse Caco-2 permeability than Ligand B (-4.449). Both are negative, indicating poor permeability.

**10. Aqueous Solubility:** Ligand A (-4.906) has worse aqueous solubility than Ligand B (-3.41). Both are negative, indicating poor solubility.

**11. hERG Inhibition:** Ligand A (0.865) has a slightly higher hERG inhibition liability than Ligand B (0.664). Lower is better, so B is slightly preferred.

**12. Microsomal Clearance:** Ligand B (91.161) has significantly higher microsomal clearance than Ligand A (36.924), meaning it's metabolized faster. A is preferred.

**13. In vitro Half-Life:** Ligand B (38.977) has a slightly longer in vitro half-life than Ligand A (34.47).

**14. P-gp Efflux:** Ligand A (0.779) has lower P-gp efflux liability than Ligand B (0.392). Lower is better for CNS exposure, so A is preferred.

**15. Binding Affinity:** Ligand A (-9.3 kcal/mol) has a significantly stronger binding affinity than Ligand B (-6.7 kcal/mol). This is a substantial advantage, potentially outweighing some of the ADME drawbacks.

**Overall Assessment:**

Ligand A is the stronger candidate. While both have issues with solubility and permeability, Ligand A's significantly better binding affinity (-9.3 vs -6.7 kcal/mol), lower DILI risk, better BBB penetration, lower P-gp efflux, and better metabolic stability (lower Cl_mic) outweigh the slightly less favorable logP and TPSA. The strong binding affinity is particularly important for a GPCR target.

Output:
1
2025-04-17 03:54:38,167 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (363.439 and 349.519 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (101.15) is higher than Ligand B (61.44). For a CNS target like DRD2, TPSA should be <=90. Ligand B is much better here.

**3. logP:** Both ligands have good logP values (1.787 and 2.476), falling within the optimal 1-3 range.

**4. H-Bond Donors:** Both have 2 HBD, which is acceptable (<=5).

**5. H-Bond Acceptors:** Ligand A has 6 HBA, and Ligand B has 3. Both are within the acceptable range of <=10.

**6. QED:** Both ligands have good QED scores (0.55 and 0.662), indicating drug-like properties.

**7. DILI:** Both have relatively high DILI risk, but Ligand B (7.832) is significantly lower than Ligand A (76.774). This is a major advantage for Ligand B.

**8. BBB:** Ligand B (70.88) is much better than Ligand A (45.56) regarding BBB penetration, which is crucial for a CNS target. Ligand B exceeds the desirable threshold of >70.

**9. Caco-2 Permeability:** Both have negative Caco-2 values (-5.49 and -5.048). This is unusual and suggests poor permeability, but the scale isn't fully defined here.

**10. Aqueous Solubility:** Both have negative solubility values (-2.403 and -2.049), indicating poor solubility.

**11. hERG Inhibition:** Ligand A (0.262) has a slightly lower hERG risk than Ligand B (0.457), but both are relatively low.

**12. Microsomal Clearance:** Ligand B (27.006) has significantly lower microsomal clearance than Ligand A (47.262), indicating better metabolic stability.

**13. In vitro Half-Life:** Ligand B (-6.717) has a negative half-life, which is concerning. Ligand A (11.771) is reasonable.

**14. P-gp Efflux:** Both have very low P-gp efflux liability (0.164 and 0.032), which is good.

**15. Binding Affinity:** Both ligands have excellent binding affinities (-8.0 and -7.8 kcal/mol). The difference of 0.2 kcal/mol is not substantial enough to outweigh other factors.

**Overall Assessment:**

Ligand B is the stronger candidate. While both have good affinity and P-gp efflux, Ligand B excels in crucial areas for CNS drug development: significantly lower DILI risk, much better BBB penetration, and improved metabolic stability (lower Cl_mic). The negative half-life is a concern, but the other advantages are substantial. Ligand A's higher TPSA and DILI risk are significant drawbacks.

Output:
1
2025-04-17 03:54:38,167 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B based on the provided guidelines, prioritizing GPCR-specific properties (BBB, logP, Pgp, TPSA, and affinity) for DRD2.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (347.459 Da) is slightly lower, which could be beneficial for permeability. Ligand B (385.335 Da) is also good.

**TPSA:** Ligand A (66.65) is better than Ligand B (34.59) as it is closer to the ideal range for CNS targets (<=90). Ligand B is quite low, which might indicate a lack of necessary interactions.

**logP:** Both ligands have acceptable logP values (Ligand A: 2.799, Ligand B: 4.354). Ligand A is optimal, while Ligand B is approaching the upper limit, potentially raising concerns about solubility and off-target effects.

**H-Bond Donors/Acceptors:** Both have 0 HBD and 4 HBA, which are within acceptable limits.

**QED:** Ligand A (0.725) has a better QED score than Ligand B (0.468), indicating a more drug-like profile.

**DILI:** Ligand A (28.228) has a significantly lower DILI risk than Ligand B (11.71), which is a major advantage.

**BBB:** Both ligands exhibit excellent BBB penetration (Ligand A: 89.066, Ligand B: 87.476), exceeding the desirable threshold of >70.

**Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and potentially problematic. However, the values are similar (-4.413 for A, -4.867 for B).

**Aqueous Solubility:** Both have negative solubility values, which is also unusual and suggests poor aqueous solubility. Ligand B (-3.823) is slightly better than Ligand A (-2.297).

**hERG:** Both ligands have low hERG inhibition risk (Ligand A: 0.425, Ligand B: 0.854). Ligand A is preferable.

**Microsomal Clearance:** Ligand B (73.34) has lower microsomal clearance than Ligand A (84.001), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (-31.723) has a negative half-life, which is not possible. Ligand B (34.181) has a positive half-life, which is better.

**P-gp Efflux:** Ligand A (0.372) has lower P-gp efflux liability than Ligand B (0.632), which is favorable for CNS exposure.

**Binding Affinity:** Ligand A (-7.8 kcal/mol) has a slightly better binding affinity than Ligand B (-7.3 kcal/mol). This difference of 0.5 kcal/mol is significant.

**Overall Assessment:** Ligand A is the better candidate. It has a better QED score, lower DILI risk, better TPSA, better logP, lower P-gp efflux, and a slightly better binding affinity. While both have issues with Caco-2 permeability and aqueous solubility, the other advantages of Ligand A outweigh these drawbacks, especially considering the CNS target. The negative half-life for Ligand A is a serious concern and needs investigation, but the other properties make it more promising.

Output:
0
2025-04-17 03:54:38,167 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (346.435 and 346.431 Da) fall comfortably within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (123.56) is higher than Ligand B (76.46). For CNS targets, TPSA < 90 is preferred. Ligand B is significantly better here.

**3. logP:** Both ligands have good logP values (1.028 and 0.904), falling within the optimal 1-3 range.

**4. H-Bond Donors:** Ligand A has 3 HBD, and Ligand B has 1. Both are acceptable (<=5).

**5. H-Bond Acceptors:** Both ligands have 5 HBA, which is within the acceptable limit of <=10.

**6. QED:** Both ligands have good QED scores (0.546 and 0.588), indicating good drug-like properties.

**7. DILI:** Both ligands have low DILI risk (36.758 and 33.695), both well below the 40 threshold.

**8. BBB:** This is a crucial parameter for a CNS target like DRD2. Ligand B (83.443) has a substantially higher BBB percentile than Ligand A (41.838). This is a major advantage for Ligand B.

**9. Caco-2 Permeability:** Ligand A (-5.751) and Ligand B (-4.973) both have negative values, which is unusual and suggests poor permeability. However, the scale isn't specified, so it's difficult to interpret precisely.

**10. Aqueous Solubility:** Both ligands have very poor aqueous solubility (-1.691 and -2.057). This is a concern for both, but might be mitigated by formulation strategies.

**11. hERG Inhibition:** Both ligands show low hERG inhibition liability (0.13 and 0.319), which is good.

**12. Microsomal Clearance:** Ligand A (0.463) has significantly lower microsomal clearance than Ligand B (26.154), suggesting better metabolic stability.

**13. In vitro Half-Life:** Ligand A (12.8 hours) has a much longer half-life than Ligand B (3.55 hours). This is a significant advantage for Ligand A.

**14. P-gp Efflux:** Ligand A (0.016) has much lower P-gp efflux liability than Ligand B (0.076), which is desirable for CNS penetration.

**15. Binding Affinity:** Ligand B (-8.2 kcal/mol) has a stronger binding affinity than Ligand A (-7.1 kcal/mol). The difference is 1.1 kcal/mol, which is substantial and can outweigh some ADME drawbacks.

**Overall Assessment:**

Ligand B has a significantly better BBB score and a stronger binding affinity, both critical for a CNS GPCR target. While Ligand A has better metabolic stability (lower Cl_mic, longer t1/2) and lower P-gp efflux, the superior CNS penetration and binding of Ligand B are more important in this context. The solubility issues are a concern for both, but can potentially be addressed. The TPSA of Ligand B is also much more favorable.

Output:
1
2025-04-17 03:54:38,167 - INFO - Batch 68 complete. Total preferences: 1088
2025-04-17 03:54:38,167 - INFO - Processing batch 69/512...
2025-04-17 03:55:23,066 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (358.467 and 357.426 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (61.94) is significantly better than Ligand B (98.74).  For CNS targets, we want TPSA <= 90, so Ligand A is much closer to this threshold. Ligand B is quite high and could hinder BBB penetration.

**3. logP:** Ligand A (3.368) is optimal (1-3). Ligand B (-0.022) is too low, potentially causing permeability issues.

**4. H-Bond Donors:** Ligand A (0) is preferable to Ligand B (3). Fewer HBDs generally improve permeability.

**5. H-Bond Acceptors:** Ligand A (7) is good, while Ligand B (4) is also acceptable. Both are below the 10 threshold.

**6. QED:** Both ligands have reasonable QED values (0.333 and 0.532), with Ligand B being slightly better.

**7. DILI:** Ligand A (65.607) has a higher DILI risk than Ligand B (45.25). This is a negative for Ligand A.

**8. BBB:** Ligand A (60.838) has a better BBB percentile than Ligand B (47.809), but ideally, we want >70 for CNS targets. Both are suboptimal, but A is better.

**9. Caco-2:** Ligand A (-5.233) is very poor, suggesting poor intestinal absorption. Ligand B (-4.749) is also poor, but slightly better.

**10. Solubility:** Ligand A (-2.802) and Ligand B (-1.751) both have poor aqueous solubility.

**11. hERG:** Both ligands have low hERG risk (0.846 and 0.493).

**12. Cl_mic:** Ligand B (40.732) has significantly lower microsomal clearance than Ligand A (135.832), indicating better metabolic stability.

**13. t1/2:** Ligand B (-31.209) has a much longer in vitro half-life than Ligand A (-10.607). This is a significant advantage for Ligand B.

**14. Pgp:** Ligand A (0.84) has a slightly higher P-gp efflux liability than Ligand B (0.216). Lower Pgp is preferred for CNS penetration.

**15. Binding Affinity:** Ligand A (-7.5) has a slightly better binding affinity than Ligand B (-7.2). However, the difference is relatively small (0.3 kcal/mol) and may not be enough to overcome the other significant drawbacks of Ligand A.

**Overall Assessment:**

Ligand A has a better binding affinity and TPSA, but suffers from poor Caco-2 permeability, high DILI risk, higher Pgp efflux, and significantly higher microsomal clearance. Ligand B, while having a slightly weaker affinity, exhibits better predicted CNS penetration (lower TPSA, lower Pgp, better BBB), better metabolic stability (lower Cl_mic, longer t1/2), and lower DILI risk. Given the GPCR-specific priorities for CNS targets (BBB, logP, Pgp, TPSA, and affinity), Ligand B is the more promising candidate despite the slightly weaker binding. The difference in affinity is small enough that optimizing the other ADME properties of Ligand B is likely to yield a better overall drug candidate.

Output:
1
2025-04-17 03:55:23,066 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (364.4 and 340.5 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (106.33) is higher than Ligand B (41.57). For CNS targets, TPSA should be <= 90. Ligand B is significantly better in this regard.

**logP:** Ligand A (1.464) is within the optimal 1-3 range. Ligand B (4.039) is at the higher end, potentially leading to solubility issues and off-target effects.

**H-Bond Donors/Acceptors:** Ligand A has 2 HBD and 4 HBA, while Ligand B has 1 HBD and 3 HBA. Both are within acceptable limits.

**QED:** Both ligands have similar QED values (0.757 and 0.749), indicating good drug-likeness.

**DILI:** Ligand A (77.55) has a higher DILI risk than Ligand B (34.78). Lower DILI is preferred.

**BBB:** Ligand B (92.71) has a much higher BBB penetration percentile than Ligand A (63.94). This is a critical advantage for a CNS target like DRD2.

**Caco-2 Permeability:** Ligand A (-5.023) has worse Caco-2 permeability than Ligand B (-4.521).

**Aqueous Solubility:** Both ligands have poor aqueous solubility (-3.299 and -3.494). This could be a formulation challenge.

**hERG Inhibition:** Ligand A (0.33) has a slightly lower hERG inhibition risk than Ligand B (0.937).

**Microsomal Clearance:** Ligand B (68.349) has significantly higher microsomal clearance than Ligand A (0.959), indicating lower metabolic stability.

**In vitro Half-Life:** Ligand B (65.785) has a much longer in vitro half-life than Ligand A (-0.253).

**P-gp Efflux:** Ligand A (0.24) has lower P-gp efflux liability than Ligand B (0.347), which is favorable for CNS penetration.

**Binding Affinity:** Ligand A (-8.2 kcal/mol) has slightly better binding affinity than Ligand B (-7.9 kcal/mol). While the difference is not huge, it's a positive for Ligand A.

**Overall Assessment:**

Ligand B excels in BBB penetration, a crucial factor for DRD2. It also has a longer half-life and lower DILI risk. While its logP is higher and clearance is higher, the substantial benefit of high BBB penetration outweighs these drawbacks. Ligand A has slightly better affinity and lower P-gp efflux, but its significantly lower BBB penetration makes it less attractive for a CNS target.

Output:
1
2025-04-17 03:55:23,067 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (361.389 and 350.434 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (70.16) is better than Ligand B (67.43), both are below the 90 A^2 threshold for CNS targets, which is excellent.

**logP:** Ligand A (-0.009) is slightly below the optimal 1-3 range, but still reasonable. Ligand B (2.894) is within the optimal range. This gives a slight edge to Ligand B.

**H-Bond Donors/Acceptors:** Ligand A (0 HBD, 4 HBA) is preferable to Ligand B (2 HBD, 3 HBA) as fewer hydrogen bonds generally improve BBB penetration.

**QED:** Both ligands have good QED scores (0.667 and 0.858 respectively), indicating good drug-like properties. Ligand B is slightly better.

**DILI:** Ligand A (32.842) has a significantly lower DILI risk than Ligand B (43.079), which is a substantial advantage.

**BBB:** Both ligands have excellent BBB penetration (76.347 and 75.029), exceeding the >70% threshold for CNS targets.

**Caco-2 Permeability:** Both ligands have similar, poor Caco-2 permeability (-4.441 and -4.231). This is a concern for oral bioavailability, but less critical for a CNS target where direct delivery or other routes are possible.

**Aqueous Solubility:** Both ligands have very poor aqueous solubility (-0.655 and -3.77). This could pose formulation challenges.

**hERG Inhibition:** Ligand A (0.141) has a much lower hERG inhibition liability than Ligand B (0.497), which is a significant safety advantage.

**Microsomal Clearance:** Ligand A (17.426) has a considerably lower microsomal clearance than Ligand B (49.9), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (0.184) has a very short half-life, while Ligand B (-2.422) is also short, but less so. Both are poor.

**P-gp Efflux:** Ligand A (0.025) has very low P-gp efflux liability, which is excellent for CNS penetration. Ligand B (0.109) is higher, but still relatively low.

**Binding Affinity:** Ligand B (-8.4 kcal/mol) has a significantly stronger binding affinity than Ligand A (-7.2 kcal/mol). This is a substantial advantage, potentially outweighing some of the ADME drawbacks.

**Overall Assessment:**

Ligand B has a better logP and significantly higher binding affinity. However, Ligand A demonstrates superior safety (lower DILI, lower hERG), better metabolic stability (lower Cl_mic), and lower P-gp efflux. The difference in binding affinity is significant (1.2 kcal/mol), but the combined advantages of Ligand A regarding safety and metabolic properties make it the more promising candidate, especially considering the challenges of CNS drug development where minimizing off-target effects and ensuring sufficient brain exposure are critical.

Output:
0
2025-04-17 03:55:23,067 - INFO - Reasoning:

Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (341.415 and 356.507 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (98.17) is slightly above the optimal <90 for CNS targets, but still reasonable. Ligand B (70.08) is excellent, well below 90.

**3. logP:** Ligand A (3.729) is at the upper end of the optimal 1-3 range, while Ligand B (2.192) is comfortably within the range. Both are acceptable, but Ligand B is slightly preferred.

**4. H-Bond Donors:** Both ligands have 1 HBD, which is within the acceptable limit of <=5.

**5. H-Bond Acceptors:** Ligand A has 3 HBAs, and Ligand B has 4. Both are within the acceptable limit of <=10.

**6. QED:** Both ligands have good QED scores (0.513 and 0.687, respectively), indicating good drug-like properties. Ligand B is slightly better.

**7. DILI:** Ligand A (47.848) has a moderate DILI risk, while Ligand B (12.253) has a very low DILI risk. This is a significant advantage for Ligand B.

**8. BBB:** Both ligands have excellent BBB penetration (78.79% and 79.566%), exceeding the desirable >70% threshold for CNS targets.

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 values, which is unusual and requires further investigation. However, we'll proceed with the comparison assuming these represent low permeability.

**10. Aqueous Solubility:** Both ligands have negative solubility values, which is also unusual and suggests poor aqueous solubility.

**11. hERG Inhibition:** Both ligands show very low hERG inhibition risk (0.49 and 0.243), which is excellent.

**12. Microsomal Clearance:** Ligand A (-14.933) has a negative clearance value, which is not physically possible and suggests an error or unusual behavior. Ligand B (74.952) has a high clearance, indicating rapid metabolism.

**13. In vitro Half-Life:** Ligand A (-1.809) has a negative half-life, which is not physically possible. Ligand B (-4.874) also has a negative half-life.

**14. P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.063 and 0.096), which is favorable for CNS penetration.

**15. Binding Affinity:** Ligand A (-9.1 kcal/mol) has a significantly stronger binding affinity than Ligand B (-6.7 kcal/mol). This is a substantial advantage for Ligand A, potentially outweighing some of its ADME drawbacks.

**Overall Assessment:**

Ligand A has a significantly better binding affinity, which is paramount for GPCR targets. However, its DILI risk is higher, and its clearance and half-life values are physically impossible. Ligand B has better ADME properties (lower DILI, better logP, TPSA, and QED), but its binding affinity is considerably weaker.

Given the importance of potency for GPCRs, and the fact that both ligands have acceptable BBB penetration, I will prioritize the ligand with the stronger binding affinity, *assuming the negative clearance and half-life values for Ligand A are data errors*. If those values are accurate, Ligand A is immediately disqualified.

Output:
1
2025-04-17 03:55:23,067 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (352.431 and 356.438 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (106.94) is slightly above the optimal <90 for CNS targets, but still reasonable. Ligand B (59.08) is excellent, well below 90.

**logP:** Ligand A (0.154) is quite low, potentially hindering permeability. Ligand B (1.403) is within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A has 3 HBD and 5 HBA, acceptable. Ligand B has 0 HBD and 4 HBA, also acceptable.

**QED:** Both ligands have good QED scores (0.566 and 0.675), indicating drug-like properties.

**DILI:** Both ligands have low DILI risk (22.102 and 24.544), which is positive.

**BBB:** This is a critical parameter for CNS targets. Ligand A has a BBB percentile of 27.957, which is poor. Ligand B has a significantly better BBB percentile of 86.817, exceeding the desirable >70 threshold.

**Caco-2 Permeability:** Ligand A (-5.174) has very poor Caco-2 permeability. Ligand B (-4.257) is also poor, but better than A.

**Aqueous Solubility:** Both ligands have poor aqueous solubility (-0.773 and -1.056). This could pose formulation challenges, but is less critical than BBB for a CNS target.

**hERG:** Both ligands have very low hERG risk (0.036 and 0.338), which is excellent.

**Microsomal Clearance:** Ligand A (3.656) has lower clearance than Ligand B (24.41), indicating better metabolic stability.

**In vitro Half-Life:** Ligand B (8.343) has a longer half-life than Ligand A (6.936), which is preferable.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.021 and 0.062), which is beneficial for CNS penetration.

**Binding Affinity:** Ligand B (-7.0) has a significantly stronger binding affinity than Ligand A (0.0). This is a major advantage, exceeding the >1.5 kcal/mol difference threshold.

**Overall Assessment:**

Ligand B is clearly the superior candidate. While both have poor solubility, Ligand B's significantly better BBB penetration, higher binding affinity, and acceptable logP outweigh the drawbacks. Ligand A's extremely low logP and poor BBB penetration make it unlikely to reach the target in the brain. The better metabolic stability of Ligand A is a minor advantage compared to the substantial benefits of Ligand B.

Output:
1
2025-04-17 03:55:23,067 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (351.491 and 375.313 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (78.51) is better than Ligand B (52.65). For CNS targets, we want TPSA <= 90, both are within this range, but A is closer to the upper limit.

**3. logP:** Both ligands have good logP values (1.979 and 1.191), falling within the optimal 1-3 range.

**4. H-Bond Donors:** Ligand A (2) is slightly higher than Ligand B (1), but both are acceptable (<=5).

**5. H-Bond Acceptors:** Both ligands have 3 H-bond acceptors, well within the acceptable limit of <=10.

**6. QED:** Both ligands have good QED scores (0.667 and 0.735), indicating good drug-like properties.

**7. DILI:** Ligand A (13.067) has a significantly lower DILI risk than Ligand B (37.03). This is a major advantage for Ligand A.

**8. BBB:** Ligand B (71.733) has a better BBB penetration percentile than Ligand A (52.579). This is crucial for a CNS target like DRD2.

**9. Caco-2 Permeability:** Ligand A (-5.059) has worse Caco-2 permeability than Ligand B (-4.781), indicating lower intestinal absorption.

**10. Aqueous Solubility:** Ligand A (-2.233) has worse aqueous solubility than Ligand B (-1.698).

**11. hERG Inhibition:** Both ligands have low hERG inhibition risk (0.221 and 0.479).

**12. Microsomal Clearance:** Ligand B (-1.583) has a lower (better) microsomal clearance than Ligand A (15.47). This suggests better metabolic stability for Ligand B.

**13. In vitro Half-Life:** Ligand A (3.879) has a better in vitro half-life than Ligand B (-15.485).

**14. P-gp Efflux:** Ligand A (0.032) has a much lower P-gp efflux liability than Ligand B (0.009), which is favorable for CNS penetration.

**15. Binding Affinity:** Ligand B (-9.1 kcal/mol) has a significantly stronger binding affinity than Ligand A (-7.3 kcal/mol). This is a substantial advantage, exceeding the 1.5 kcal/mol threshold.

**Overall Assessment:**

Ligand B has a significantly better binding affinity and BBB penetration, which are critical for a CNS GPCR target. It also has better metabolic stability (lower Cl_mic). However, Ligand A has a much lower DILI risk and lower P-gp efflux. The affinity difference is substantial (-9.1 vs -7.3 kcal/mol), and the improved BBB penetration of Ligand B outweighs the slightly higher DILI risk and P-gp efflux. The solubility and Caco-2 permeability are both poor for both compounds, but these can be addressed with formulation strategies.

Output:
1
2025-04-17 03:55:23,067 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (349.435 Da) is slightly lower, which could be beneficial for permeability. Ligand B (362.39 Da) is also acceptable.

**TPSA:** Both ligands have TPSA values below 140 (Ligand A: 116.84, Ligand B: 109.76), suggesting reasonable oral absorption. Both are also below the 90 threshold desirable for CNS targets, which is excellent.

**logP:** Ligand A (1.103) is within the optimal range (1-3). Ligand B (0.338) is slightly below 1, which *could* indicate potential permeability issues, but is not a dealbreaker.

**H-Bond Donors/Acceptors:** Ligand A has 3 HBD and 5 HBA, well within the guidelines. Ligand B has 2 HBD and 7 HBA, also acceptable.

**QED:** Both ligands have QED values above 0.5 (Ligand A: 0.617, Ligand B: 0.655), indicating good drug-like properties.

**DILI:** Ligand A (35.479) has a much lower DILI risk than Ligand B (81.892). This is a significant advantage for Ligand A.

**BBB:** Ligand A (36.487) has a very poor BBB penetration percentile. Ligand B (64.87) is better, but still not ideal (we want >70 for CNS targets). This is a major drawback for both, but more so for Ligand A.

**Caco-2 Permeability:** Both have negative Caco-2 values (-5.543 and -5.08), which is unusual and suggests poor permeability. However, these values are on a scale where negative values are possible and do not necessarily preclude development.

**Aqueous Solubility:** Both have negative solubility values (-1.867 and -2.323), also unusual, suggesting poor solubility. This could present formulation challenges.

**hERG Inhibition:** Both ligands have very low hERG inhibition risk (Ligand A: 0.033, Ligand B: 0.131).

**Microsomal Clearance:** Ligand A (-7.031) has significantly lower (better) microsomal clearance than Ligand B (20.295), indicating greater metabolic stability.

**In vitro Half-Life:** Ligand A (-16.896) has a negative half-life, which is not physically possible. This is a red flag. Ligand B (-12.539) is also negative, but slightly less so. These values are likely errors or represent a very rapid degradation.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (Ligand A: 0.029, Ligand B: 0.033), which is favorable for CNS penetration.

**Binding Affinity:** Both ligands have excellent binding affinity (Ligand A: -7.8 kcal/mol, Ligand B: -8.2 kcal/mol). Ligand B is slightly better, but the difference is small.

**Overall Assessment:**

Ligand A has a better DILI profile and significantly better metabolic stability (lower Cl_mic). However, its BBB penetration is extremely poor, and its in vitro half-life is nonsensical. Ligand B has a higher DILI risk and worse metabolic stability, but a better (though still suboptimal) BBB penetration and a slightly better binding affinity. The negative half-life values for both are concerning.

Given the GPCR-specific priorities, BBB penetration is crucial for a CNS target like DRD2. While neither ligand is great in this regard, Ligand B is marginally better. The significantly better metabolic stability of Ligand A is appealing, but the extremely poor BBB and impossible half-life are major drawbacks. The slightly better affinity of Ligand B, combined with a less problematic (though still not ideal) BBB, makes it the slightly more promising candidate. However, both require significant optimization.

Output:
1
2025-04-17 03:55:23,067 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B based on the provided guidelines, prioritizing GPCR-specific properties (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (364.442 and 368.503 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (65.22) is significantly better than Ligand B (103.35). For CNS targets, TPSA should be <= 90, and A is comfortably within this range, while B is above.

**logP:** Ligand A (4.209) is higher than Ligand B (1.752). While both are within the 1-3 range, A is approaching the upper limit, potentially raising solubility concerns. B is lower, which could impact permeability.

**H-Bond Donors/Acceptors:** Ligand A (0 HBD, 6 HBA) and Ligand B (4 HBD, 6 HBA) both have reasonable H-bond characteristics.

**QED:** Both ligands have similar QED values (0.585 and 0.504), indicating good drug-like properties.

**DILI:** Ligand A (63.086) has a higher DILI risk than Ligand B (44.552). This is a negative for A.

**BBB:** Ligand A (87.98) has a significantly better BBB penetration percentile than Ligand B (54.634). This is a *critical* advantage for a CNS target like DRD2.

**Caco-2 Permeability:** Ligand A (-4.362) has a worse Caco-2 permeability than Ligand B (-5.142). Both are negative, indicating poor permeability, but B is slightly worse.

**Aqueous Solubility:** Ligand A (-6.053) has worse solubility than Ligand B (-2.803).

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.317 and 0.461).

**Microsomal Clearance:** Ligand A (98.868) has higher microsomal clearance than Ligand B (49.457), indicating lower metabolic stability. This is a negative for A.

**In vitro Half-Life:** Ligand A (-16.062) has a shorter in vitro half-life than Ligand B (44.698). This is a negative for A.

**P-gp Efflux:** Ligand A (0.588) has slightly higher P-gp efflux than Ligand B (0.105), which is unfavorable.

**Binding Affinity:** Ligand B (-7.4 kcal/mol) has a significantly stronger binding affinity than Ligand A (-9.5 kcal/mol). This is a substantial advantage for B.

**Overall Assessment:**

Despite Ligand A's better TPSA and BBB, Ligand B is the stronger candidate. The significantly improved binding affinity (-7.4 vs -9.5 kcal/mol) of Ligand B is a major advantage. While Ligand A has better BBB, the affinity difference is substantial enough to outweigh this. Additionally, Ligand B demonstrates superior ADME properties (lower DILI, better metabolic stability, longer half-life, lower P-gp efflux) and better solubility. Ligand A's high clearance and short half-life are significant drawbacks.

Output:
1
2025-04-17 03:55:23,067 - INFO - Reasoning:

Let's analyze Ligand A and Ligand B for their potential as DRD2 drug candidates, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (370.827 and 353.463 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (49.41) is significantly better than Ligand B (80.23). For CNS targets, we want TPSA <= 90, and ideally closer to 60. Ligand A is well within this range, while Ligand B is approaching the upper limit and could potentially have reduced brain penetration.

**3. logP:** Both ligands have good logP values (2.178 and 1.854), falling within the optimal 1-3 range.

**4. H-Bond Donors:** Both have 1 HBD, which is acceptable.

**5. H-Bond Acceptors:** Ligand A has 2 HBA, while Ligand B has 5. While both are under the 10 threshold, Ligand A is preferable.

**6. QED:** Both have similar QED values (0.609 and 0.676), indicating good drug-likeness.

**7. DILI:** Ligand A (35.75) has a much lower DILI risk than Ligand B (8.104). This is a significant advantage for Ligand A.

**8. BBB:** Ligand A (83.56) has a substantially higher BBB penetration percentile than Ligand B (65.258).  For a CNS target like DRD2, >70 is desirable, and Ligand A is closer to this threshold.

**9. Caco-2 Permeability:** Both have negative Caco-2 values (-4.919 and -4.931), which is unusual and suggests poor permeability. This is a concern for both, but doesn't differentiate them.

**10. Aqueous Solubility:** Both have negative solubility values (-3.606 and -1.064), suggesting poor solubility. Ligand B is slightly better, but both are problematic.

**11. hERG Inhibition:** Both ligands have low hERG inhibition risk (0.381 and 0.289).

**12. Microsomal Clearance:** Ligand B (-13.873) has a significantly lower (better) microsomal clearance than Ligand A (10.833). This indicates greater metabolic stability for Ligand B.

**13. In vitro Half-Life:** Ligand B (-1.178) has a slightly longer in vitro half-life than Ligand A (1.883).

**14. P-gp Efflux:** Both ligands have low P-gp efflux liability (0.056 and 0.033).

**15. Binding Affinity:** Ligand A (-8.5 kcal/mol) has a significantly stronger binding affinity than Ligand B (-7.3 kcal/mol). This 1.2 kcal/mol difference is substantial and can outweigh some ADME drawbacks.

**Overall Assessment:**

While Ligand B has better metabolic stability and half-life, Ligand A is superior due to its significantly better BBB penetration, lower DILI risk, and *much* stronger binding affinity.  The TPSA is also considerably better for Ligand A. The solubility and Caco-2 permeability are concerns for both, but the superior potency and CNS penetration of Ligand A make it the more promising candidate.

Output:
1
2025-04-17 03:55:23,067 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (358.429 and 364.808 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (58.64) is excellent, well below the 90 A^2 threshold for CNS targets. Ligand B (86.88) is still acceptable but less optimal.

**3. logP:** Both ligands (2.656 and 2.198) are within the optimal 1-3 range.

**4. H-Bond Donors:** Ligand A (1) is good. Ligand B (3) is acceptable, but higher HBD can sometimes reduce permeability.

**5. H-Bond Acceptors:** Both ligands (3) are within the acceptable limit of 10.

**6. QED:** Ligand A (0.743) is better than Ligand B (0.542), indicating a more drug-like profile.

**7. DILI:** Ligand A (41.334) has a lower DILI risk than Ligand B (69.562), which is a significant advantage.

**8. BBB:** Ligand A (90.151) has a much higher BBB penetration percentile than Ligand B (77.007). This is *critical* for a CNS target like DRD2.

**9. Caco-2 Permeability:** Ligand A (-4.548) has a worse Caco-2 permeability than Ligand B (-5.305). While both are negative, B is slightly better.

**10. Aqueous Solubility:** Ligand A (-2.803) has better aqueous solubility than Ligand B (-3.447).

**11. hERG Inhibition:** Both ligands (0.425 and 0.489) have low hERG inhibition risk.

**12. Microsomal Clearance:** Ligand B (22.169) has significantly lower microsomal clearance than Ligand A (39.915), suggesting better metabolic stability.

**13. In vitro Half-Life:** Ligand B (25.031) has a much longer in vitro half-life than Ligand A (-2.742). This is a substantial advantage.

**14. P-gp Efflux:** Both ligands (0.15 and 0.091) have low P-gp efflux, which is good for CNS penetration.

**15. Binding Affinity:** Ligand B (-9.1) has a *much* stronger binding affinity than Ligand A (0). This is a major advantage, potentially outweighing some of the ADME drawbacks. A difference of >1.5 kcal/mol is considered significant.

**Overall Assessment:**

Ligand B has a significantly better binding affinity, longer half-life, and lower clearance. These are crucial factors. While Ligand A has better TPSA, QED, DILI, and BBB, the substantial affinity advantage of Ligand B, combined with acceptable (though not ideal) ADME properties, makes it the more promising candidate. The higher BBB of Ligand A is attractive, but the binding affinity difference is too large to ignore.

Output:
1
2025-04-17 03:55:23,067 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (345.443 Da) is slightly lower, which could be beneficial for permeability. Ligand B (368.459 Da) is also acceptable.

**TPSA:** Ligand A (75.44) is significantly better than Ligand B (100.63). For CNS targets, TPSA should be <= 90, so Ligand A is preferable.

**logP:** Ligand A (3.052) is optimal (1-3). Ligand B (0.492) is quite low, potentially hindering permeation. This is a significant drawback for Ligand B.

**H-Bond Donors/Acceptors:** Ligand A (HBD=1, HBA=4) and Ligand B (HBD=2, HBA=6) both fall within acceptable ranges.

**QED:** Both ligands have similar and good QED values (A: 0.832, B: 0.785), indicating good drug-like properties.

**DILI:** Ligand A (42.536) has a slightly better DILI score than Ligand B (59.946), indicating a lower risk of liver injury. Both are acceptable (<60 is good).

**BBB:** Ligand A (80.031) has a much better BBB percentile than Ligand B (65.452).  A value >70 is desirable for CNS targets, and Ligand A is closer to this threshold. This is a crucial advantage for a DRD2 ligand.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.824 and -4.917). This is unusual and suggests poor permeability. However, the values are similar.

**Aqueous Solubility:** Both ligands have negative solubility values (-3.406 and -2.982). This is also unusual and suggests poor solubility. The values are similar.

**hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.218 and 0.201).

**Microsomal Clearance:** Ligand A (67.817) has a higher microsomal clearance than Ligand B (27.801), indicating lower metabolic stability. Ligand B is preferable here.

**In vitro Half-Life:** Both ligands have negative half-life values (-24.543 and -24.228). This is not physically meaningful and suggests issues with the prediction method.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.139 and 0.016).

**Binding Affinity:** Both ligands have excellent binding affinities (-8.2 and -8.3 kcal/mol). The difference is negligible.

**Overall Assessment:**

Considering the GPCR-specific priorities, Ligand A is the stronger candidate. While Ligand B has better metabolic stability (lower Cl_mic), Ligand A excels in crucial areas for CNS penetration: TPSA, logP, and BBB. The slightly better DILI score for Ligand A is also a positive. The unusual Caco-2 and solubility values are concerning for both, but the significant differences in TPSA, logP, and BBB outweigh the metabolic stability advantage of Ligand B.

Output:
1
2025-04-17 03:55:23,068 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B based on the provided guidelines, prioritizing GPCR-specific properties (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (354.491 Da) is slightly lower, which is generally favorable for permeability.

**TPSA:** Ligand A (75.71) is significantly better than Ligand B (108.55). For CNS targets, TPSA < 90 is preferred, and Ligand A is comfortably within this range, while Ligand B is approaching the upper limit.

**logP:** Both ligands have acceptable logP values (A: 2.221, B: 1.006), falling within the optimal 1-3 range. Ligand A is slightly better.

**H-Bond Donors/Acceptors:** Ligand A (HBD=1, HBA=4) is better than Ligand B (HBD=3, HBA=5) in terms of maintaining a balance between solubility and permeability.

**QED:** Both ligands have similar QED values (A: 0.61, B: 0.646), indicating good drug-likeness.

**DILI:** Ligand A (24.622) has a significantly lower DILI risk than Ligand B (35.983), which is a major advantage. Both are below the 40 threshold, but A is much safer.

**BBB:** Ligand A (72.625) has a much better BBB penetration percentile than Ligand B (54.75). For a CNS target like DRD2, >70 is desirable, and A is closer to that threshold. This is a critical factor.

**Caco-2 Permeability:** Ligand A (-4.301) has a worse Caco-2 permeability than Ligand B (-5.102). However, given the importance of BBB penetration for a CNS target, this is less critical.

**Aqueous Solubility:** Ligand A (-2.493) has slightly better aqueous solubility than Ligand B (-2.236).

**hERG Inhibition:** Both ligands have similar, low hERG inhibition liability (A: 0.332, B: 0.341).

**Microsomal Clearance:** Ligand B (-9.799) has a *much* lower (better) microsomal clearance than Ligand A (93.86). This suggests better metabolic stability for Ligand B.

**In vitro Half-Life:** Ligand B (-13.643) has a significantly longer in vitro half-life than Ligand A (-5.898).

**P-gp Efflux:** Both ligands have similar P-gp efflux liability (A: 0.039, B: 0.011).

**Binding Affinity:** Ligand B (-8.1 kcal/mol) has a slightly better binding affinity than Ligand A (-7.5 kcal/mol). While a 0.6 kcal/mol difference is noticeable, the other ADME properties are more decisive.

**Overall Assessment:**

Ligand A excels in crucial properties for a CNS-targeting GPCR ligand: TPSA, BBB penetration, and DILI risk. While Ligand B has better metabolic stability (lower Cl_mic, longer t1/2) and slightly better affinity, the significantly poorer BBB penetration and higher DILI risk are major drawbacks. The improved TPSA and BBB of Ligand A are more important for CNS penetration and reducing potential side effects.

Output:
0
2025-04-17 03:55:23,068 - INFO - Reasoning:

Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (343.354 and 336.435 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (66.84) is higher than Ligand B (49.41). For a CNS target like DRD2, we ideally want TPSA <= 90, so both are acceptable, but B is better.

**3. logP:** Both ligands have good logP values (3.192 and 2.663), falling within the optimal 1-3 range.

**4. H-Bond Donors:** Both have 1 HBD, which is within the acceptable limit of <=5.

**5. H-Bond Acceptors:** Ligand A has 4 HBAs, and Ligand B has 2. Both are below the acceptable limit of <=10.

**6. QED:** Both ligands have reasonable QED scores (0.869 and 0.679), indicating good drug-like properties.

**7. DILI:** Ligand A (68.282) has a higher DILI risk than Ligand B (42.264).  B is significantly better here, falling well below the 60% threshold.

**8. BBB:** Ligand A (79.721) has a better BBB penetration score than Ligand B (63.203). This is a critical factor for CNS targets, and A has a clear advantage.

**9. Caco-2 Permeability:** Both have negative Caco-2 values (-4.64 and -4.603). This is unusual and suggests poor permeability.

**10. Aqueous Solubility:** Both have negative solubility values (-4.552 and -4.153). This is also unusual and suggests poor solubility.

**11. hERG Inhibition:** Ligand A (0.67) has a slightly higher hERG risk than Ligand B (0.223). B is preferable.

**12. Microsomal Clearance:** Ligand A (77.343) has significantly higher microsomal clearance than Ligand B (16.808), meaning it's less metabolically stable. B is much better.

**13. In vitro Half-Life:** Ligand A (-12.558) has a negative half-life, which is not possible. Ligand B (5.396) has a reasonable half-life. This is a major red flag for Ligand A.

**14. P-gp Efflux:** Ligand A (0.411) has lower P-gp efflux than Ligand B (0.109), which is favorable for CNS penetration.

**15. Binding Affinity:** Ligand A (-9.7 kcal/mol) has a significantly stronger binding affinity than Ligand B (-8.5 kcal/mol). This is a substantial advantage for A.

**Overall Assessment:**

While Ligand A boasts a superior binding affinity and better BBB penetration and P-gp efflux, its extremely poor in vitro half-life, higher DILI risk, and higher microsomal clearance are major concerns. The negative half-life is a showstopper. Ligand B, while having a slightly weaker affinity, presents a much more favorable ADME-Tox profile, with lower DILI, better metabolic stability (lower Cl_mic, better t1/2), and lower hERG risk. Given the GPCR-specific priorities and the importance of a viable pharmacokinetic profile, Ligand B is the more promising candidate.

Output:
1
2025-04-17 03:55:23,068 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (344.46 and 342.40 Da) fall comfortably within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (67.23) is significantly better than Ligand B (84.42). For CNS targets, we want TPSA <= 90, and A is closer to the ideal <=60 range. B is pushing the upper limit.

**3. logP:** Both ligands have good logP values (2.42 and 1.06), falling within the optimal 1-3 range.

**4. H-Bond Donors:** Both have 1 HBD, which is acceptable.

**5. H-Bond Acceptors:** Ligand A has 4 HBA, and Ligand B has 5. Both are within the acceptable limit of <=10.

**6. QED:** Both ligands have good QED scores (0.7 and 0.885), indicating good drug-like properties.

**7. DILI:** Ligand A (28.89) has a much lower DILI risk than Ligand B (52.04). Both are below the concerning threshold of 60, but A is preferable.

**8. BBB:** Both ligands have excellent BBB penetration (71.89% and 79.49%). Both exceed the desirable 70% threshold for CNS targets.

**9. Caco-2 Permeability:** Both have negative Caco-2 values (-4.642 and -4.803). This is unusual and suggests poor permeability. However, these values are on a log scale, and the negative values are likely indicating very low permeability.

**10. Aqueous Solubility:** Both have negative solubility values (-2.444 and -1.606), indicating poor aqueous solubility.

**11. hERG Inhibition:** Both ligands show low hERG inhibition risk (0.48 and 0.12).

**12. Microsomal Clearance:** Ligand B (23.19) has significantly lower microsomal clearance than Ligand A (43.74), suggesting better metabolic stability.

**13. In vitro Half-Life:** Ligand B (1.37) has a slightly better in vitro half-life than Ligand A (-13.65). However, the negative value for A is concerning and suggests rapid degradation.

**14. P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.104 and 0.032). This is good for CNS exposure.

**15. Binding Affinity:** Ligand B (-8.5 kcal/mol) has a significantly stronger binding affinity than Ligand A (-7.0 kcal/mol). This is a substantial advantage (>1.5 kcal/mol difference).

**Overall Assessment:**

While both ligands have good QED, BBB, and P-gp properties, Ligand B stands out due to its superior binding affinity (-8.5 vs -7.0 kcal/mol) and better metabolic stability (lower Cl_mic and better t1/2). Ligand A has a lower DILI risk and better TPSA, but the significantly stronger binding of Ligand B outweighs these advantages, especially for a GPCR target where potency is crucial. The poor Caco-2 and solubility for both are concerning, but can potentially be addressed with formulation strategies.

Output:
1
2025-04-17 03:55:23,068 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B based on the provided guidelines, prioritizing GPCR-specific properties (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (338.43 and 347.50 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (38.06) is significantly better than Ligand B (47.56). For CNS targets, we want TPSA <= 90, and ideally lower. Ligand A is much closer to the ideal range.

**logP:** Both ligands have acceptable logP values (4.89 and 3.15), falling within the 1-3 range, though Ligand A is a bit high.

**H-Bond Donors/Acceptors:** Both have 1 HBD, which is good. Ligand A has 3 HBA, and Ligand B has 4. Both are within the acceptable limit of <=10.

**QED:** Both ligands have good QED scores (0.666 and 0.776), indicating drug-likeness.

**DILI:** Ligand A (37.77) has a slightly higher DILI risk than Ligand B (7.14), but both are below the concerning threshold of 60.

**BBB:** Ligand A (71.38) has a better BBB percentile than Ligand B (64.64), which is crucial for a CNS target like DRD2. Both are above 70, which is desirable.

**Caco-2 Permeability:** Ligand A (-5.193) shows poor Caco-2 permeability, while Ligand B (-4.641) is slightly better, but still poor.

**Aqueous Solubility:** Both ligands have very poor aqueous solubility (-4.242 and -3.161). This could pose formulation challenges.

**hERG Inhibition:** Both ligands show low hERG inhibition risk (0.926 and 0.612).

**Microsomal Clearance:** Ligand A (65.32) has higher microsomal clearance than Ligand B (40.72), suggesting lower metabolic stability.

**In vitro Half-Life:** Ligand B (16.30) has a longer in vitro half-life than Ligand A (24.64).

**P-gp Efflux:** Ligand A (0.844) has slightly higher P-gp efflux than Ligand B (0.127). Lower P-gp efflux is preferred for CNS penetration.

**Binding Affinity:** Ligand B (-9.4 kcal/mol) has a significantly stronger binding affinity than Ligand A (-8.8 kcal/mol). This >1.5 kcal/mol difference is substantial and can outweigh some ADME drawbacks.

**Conclusion:**

While Ligand A has a better TPSA and BBB, Ligand B's significantly stronger binding affinity (-9.4 vs -8.8 kcal/mol) is a major advantage, especially for a GPCR target. The lower P-gp efflux and longer half-life of Ligand B are also beneficial. The slightly worse TPSA and BBB can potentially be addressed with further optimization, but the affinity difference is harder to recover. The solubility is a concern for both, but not a deciding factor at this stage.

Output:
1
2025-04-17 03:55:23,068 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (358.364 and 349.439 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (67.23) is significantly better than Ligand B (110.76). For CNS targets, we want TPSA <= 90, so Ligand A is much closer to this threshold. Ligand B is considerably higher, potentially hindering BBB penetration.

**3. logP:** Both ligands have good logP values (2.053 and 1.102), falling within the optimal 1-3 range.

**4. H-Bond Donors:** Ligand A (1) is preferable to Ligand B (2). Lower HBD generally improves permeability.

**5. H-Bond Acceptors:** Ligand A (4) is better than Ligand B (8). Lower HBA also favors permeability.

**6. QED:** Both ligands have reasonable QED values (0.896 and 0.734), indicating good drug-like properties.

**7. DILI:** Ligand A (47.964) has a lower DILI risk than Ligand B (59.131), making it safer. Both are below the concerning threshold of 60.

**8. BBB:** Ligand A (93.874) shows excellent BBB penetration, exceeding the desirable >70% threshold. Ligand B (47.964) is significantly lower, a major drawback for a CNS target.

**9. Caco-2 Permeability:** Ligand A (-4.628) is better than Ligand B (-5.334). Higher values are better, and while both are negative, A is less negative.

**10. Aqueous Solubility:** Ligand A (-2.984) is better than Ligand B (-1.882). Higher values are better.

**11. hERG Inhibition:** Both ligands show very low hERG inhibition risk (0.284 and 0.041).

**12. Microsomal Clearance:** Ligand A (7.407) has a lower microsomal clearance than Ligand B (50.088), indicating better metabolic stability.

**13. In vitro Half-Life:** Ligand A (-11.123) has a longer in vitro half-life than Ligand B (22.651).

**14. P-gp Efflux:** Ligand A (0.125) has lower P-gp efflux than Ligand B (0.047), suggesting better CNS exposure.

**15. Binding Affinity:** Ligand A (-8.8 kcal/mol) has a stronger binding affinity than Ligand B (-6.4 kcal/mol). This is a substantial difference (>1.5 kcal/mol) and can outweigh minor ADME drawbacks.

**Overall Assessment:**

Ligand A is clearly superior. It excels in critical GPCR properties like TPSA, BBB penetration, metabolic stability, and binding affinity. While Ligand B has acceptable logP and hERG, its poor TPSA, BBB, and higher P-gp efflux are significant liabilities for a CNS-targeting drug. The much stronger binding affinity of Ligand A further solidifies its position as the more promising candidate.

Output:
1
2025-04-17 03:55:23,069 - INFO - Batch 69 complete. Total preferences: 1104
2025-04-17 03:55:23,069 - INFO - Processing batch 70/512...
2025-04-17 03:56:04,685 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (370.739 and 351.403 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (76.66) is significantly better than Ligand B (110.53). For CNS targets, we want TPSA <= 90, and A is comfortably within this range, while B exceeds it.

**logP:** Both ligands have acceptable logP values (2.71 and 1.053), falling within the 1-3 optimal range. Ligand A is slightly better.

**H-Bond Donors/Acceptors:** Both have 2 HBDs, which is good. Ligand A has 4 HBAs, and Ligand B has 6. Both are acceptable (<=10), but A is slightly preferred.

**QED:** Both ligands have reasonable QED values (0.811 and 0.711), indicating good drug-like properties.

**DILI:** Ligand A (98.216) has a very high DILI risk, which is a major concern. Ligand B (47.421) has a much lower, and acceptable, DILI risk.

**BBB:** Ligand A (52.423) has a moderate BBB penetration, while Ligand B (59.636) is also moderate. Ideally, we want >70 for CNS targets, but both are relatively low.

**Caco-2 Permeability:** Both have negative Caco-2 values (-4.341 and -4.712), which is unusual and suggests poor permeability. However, these values are on a log scale, and the absolute values are close.

**Aqueous Solubility:** Both have negative solubility values (-4.234 and -2.647), indicating poor aqueous solubility.

**hERG:** Both ligands have very low hERG inhibition liability (0.382 and 0.105), which is excellent.

**Microsomal Clearance:** Ligand A (26.662) has lower microsomal clearance than Ligand B (56.539), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (12.434) has a longer half-life than Ligand B (-7.675), which is desirable.

**P-gp Efflux:** Ligand A (0.237) has lower P-gp efflux than Ligand B (0.047), which is beneficial for CNS exposure.

**Binding Affinity:** Ligand A (-9.3 kcal/mol) has a significantly stronger binding affinity than Ligand B (-8.2 kcal/mol). This is a substantial advantage (>1.5 kcal/mol difference).

**Overall Assessment:**

Despite Ligand A's superior affinity, TPSA, metabolic stability, half-life, and P-gp efflux, its extremely high DILI risk is a major red flag. The DILI score alone is enough to disqualify it as a viable candidate. Ligand B, while having a weaker affinity and less favorable TPSA, has a much more acceptable safety profile (DILI) and comparable BBB penetration. Given the importance of safety in drug development, especially for CNS targets, Ligand B is the more promising candidate.

Output:
1
2025-04-17 03:56:04,686 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (374.491 and 350.459 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (76.14) is better than Ligand B (78.87), both are below the 90 A^2 threshold for CNS targets, which is good.

**logP:** Ligand A (2.807) is optimal, while Ligand B (1.07) is slightly low, potentially hindering permeation.

**H-Bond Donors:** Both ligands have 2 HBD, which is within the acceptable limit of <=5.

**H-Bond Acceptors:** Ligand A has 6 HBA, and Ligand B has 4. Both are below the acceptable limit of <=10.

**QED:** Both ligands have good QED scores (0.629 and 0.798, respectively), indicating drug-like properties.

**DILI:** Ligand A (79.721) has a higher DILI risk than Ligand B (26.444). This is a significant drawback for Ligand A.

**BBB:** Ligand B (34.626) has a better BBB penetration percentile than Ligand A (23.42). While neither is above the desirable 70, Ligand B is significantly better.

**Caco-2 Permeability:** Ligand A (-4.953) has a lower Caco-2 permeability than Ligand B (-4.866), suggesting poorer intestinal absorption.

**Aqueous Solubility:** Ligand A (-4.032) has lower solubility than Ligand B (-2.165).

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.452 and 0.213, respectively).

**Microsomal Clearance:** Ligand B (1.139) has much lower microsomal clearance than Ligand A (66.805), indicating better metabolic stability.

**In vitro Half-Life:** Ligand B (25.118) has a significantly longer in vitro half-life than Ligand A (-4.396).

**P-gp Efflux:** Ligand A (0.325) has slightly lower P-gp efflux than Ligand B (0.099), which is favorable for CNS exposure.

**Binding Affinity:** Ligand B (-8.7 kcal/mol) has a significantly stronger binding affinity than Ligand A (-7.7 kcal/mol). This >1.5 kcal/mol difference is substantial and can outweigh some ADME drawbacks.

**Overall Assessment:**

Ligand B is the superior candidate. While its BBB penetration isn't ideal, it's significantly better than Ligand A's. More importantly, Ligand B exhibits a much stronger binding affinity, improved metabolic stability (lower Cl_mic, longer t1/2), better solubility, lower DILI risk, and better Caco-2 permeability. Ligand A's higher DILI risk and poorer ADME profile are significant concerns. The stronger binding affinity of Ligand B is a critical advantage for a GPCR target.

Output:
1
2025-04-17 03:56:04,686 - INFO - Reasoning:

Let's analyze Ligand A and Ligand B against the provided guidelines, prioritizing GPCR-specific properties (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (346.475 and 359.495 Da) fall within the ideal 200-500 Da range.

**TPSA:** Both ligands (58.44 and 59.23) are below the 90 A^2 threshold desirable for CNS targets, which is excellent.

**logP:** Ligand A (2.488) is optimal (1-3). Ligand B (4.534) is slightly above the optimal range, potentially leading to solubility issues or off-target interactions, but still within a reasonable range.

**H-Bond Donors/Acceptors:** Both ligands have acceptable HBD (0) and HBA (4 & 5) counts, well within the guidelines.

**QED:** Both ligands have good QED scores (0.68 and 0.804), indicating drug-like properties.

**DILI:** Ligand A (23.032) has a significantly lower DILI risk than Ligand B (55.68), which is a substantial advantage.

**BBB:** Ligand B (84.917) has a better BBB penetration percentile than Ligand A (75.921), which is critical for a CNS target like DRD2.

**Caco-2 Permeability:** Ligand A (-4.423) has a lower Caco-2 permeability than Ligand B (-5.092), suggesting potentially poorer intestinal absorption.

**Aqueous Solubility:** Ligand A (-1.887) has better aqueous solubility than Ligand B (-4.075).

**hERG Inhibition:** Both ligands show low hERG inhibition liability (0.391 and 0.448), which is good.

**Microsomal Clearance:** Ligand A (55.374) has lower microsomal clearance than Ligand B (66.462), indicating better metabolic stability.

**In vitro Half-Life:** Ligand A (2.165) has a shorter half-life than Ligand B (-32.372), which is a negative.

**P-gp Efflux:** Ligand A (0.072) has lower P-gp efflux than Ligand B (0.453), which is favorable for CNS penetration.

**Binding Affinity:** Both ligands have very similar and excellent binding affinities (-7.8 and -7.9 kcal/mol). The difference is negligible.

**Overall Assessment:**

Ligand B excels in BBB penetration, which is paramount for a CNS target. However, it has a significantly higher DILI risk and poorer metabolic stability. Ligand A has a much better safety profile (DILI) and metabolic stability, and acceptable BBB penetration, and better solubility. While Ligand B has slightly better Caco-2 permeability, the other factors lean towards Ligand A being the more promising candidate. The slight advantage in BBB for Ligand B is outweighed by the higher DILI risk and lower metabolic stability.

Output:
0
2025-04-17 03:56:04,687 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B based on the provided guidelines, prioritizing GPCR-specific properties (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (346.39 and 359.50 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (101.47) is better than Ligand B (64.86). For CNS targets, TPSA should be <= 90, so Ligand B is preferable here.

**logP:** Both ligands have good logP values (2.32 and 3.37), falling within the optimal 1-3 range. Ligand B is slightly higher, which could be a minor concern for solubility, but not a dealbreaker.

**H-Bond Donors/Acceptors:** Both have 1 HBD and a reasonable number of HBAs (6 and 7, respectively), satisfying the <5 HBD and <10 HBA guidelines.

**QED:** Both ligands have similar, good QED values (0.736 and 0.744), indicating good drug-like properties.

**DILI:** Ligand B (49.01) has a significantly lower DILI risk than Ligand A (63.16), which is a substantial advantage.

**BBB:** Ligand B (77.51) has a much higher BBB penetration percentile than Ligand A (61.50). This is *critical* for a CNS target like DRD2, making Ligand B significantly more promising.

**Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and suggests poor permeability. This is a concern for both, but the scale is not defined, so it's hard to interpret.

**Aqueous Solubility:** Both have negative solubility values, which is also unusual and suggests poor solubility. This is a concern for both, but the scale is not defined, so it's hard to interpret.

**hERG:** Both ligands have low hERG inhibition liability (0.338 and 0.261), which is good.

**Microsomal Clearance:** Ligand B (47.81) has a higher microsomal clearance than Ligand A (33.75), indicating faster metabolism and potentially lower in vivo exposure. This favors Ligand A.

**In vitro Half-Life:** Ligand A (-14.34) has a much longer in vitro half-life than Ligand B (-3.77), which is a significant advantage.

**P-gp Efflux:** Both have very low P-gp efflux liability (0.152 and 0.267), which is favorable for CNS penetration.

**Binding Affinity:** Ligand A (-7.9 kcal/mol) has a slightly better binding affinity than Ligand B (-6.9 kcal/mol). While a 1 kcal/mol difference is noticeable, the ADME advantages of Ligand B are more compelling.

**Overall Assessment:**

Ligand B is the more promising candidate. Its significantly better BBB penetration and lower DILI risk outweigh the slightly weaker affinity and higher clearance. The TPSA is also more favorable for CNS penetration. While both ligands have concerning negative values for Caco-2 and solubility, the other factors strongly favor Ligand B for development as a DRD2 ligand.

Output:
1
2025-04-17 03:56:04,687 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (355.356 and 350.459 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (46.61) is excellent, well below the 90 A^2 threshold for CNS targets. Ligand B (81.08) is higher, but still potentially acceptable, though less ideal.

**logP:** Ligand A (2.838) is optimal (1-3). Ligand B (0.619) is quite low, potentially hindering membrane permeability and CNS penetration.

**H-Bond Donors/Acceptors:** Ligand A (0 HBD, 3 HBA) is favorable. Ligand B (2 HBD, 4 HBA) is also acceptable.

**QED:** Both ligands have good QED scores (0.603 and 0.731, respectively), indicating drug-like properties.

**DILI:** Both ligands have low DILI risk (32.493 and 27.336, respectively).

**BBB:** Ligand A shines with a very high BBB penetration percentile (97.635), crucial for a CNS target like DRD2. Ligand B's BBB penetration (36.371) is very poor.

**Caco-2 Permeability:** Both show poor Caco-2 permeability (-4 and -4.451). This is less concerning given the focus on BBB for CNS targets.

**Aqueous Solubility:** Both ligands have poor aqueous solubility (-2.961 and -0.877).

**hERG:** Both ligands show low hERG inhibition liability (0.6 and 0.428).

**Microsomal Clearance:** Ligand A (81.838) has higher clearance than Ligand B (-2.799), suggesting lower metabolic stability.

**In vitro Half-Life:** Both have negative half-lives (-15.742 and -14.613), which is unusual and suggests rapid degradation.

**P-gp Efflux:** Both ligands show low P-gp efflux liability (0.226 and 0.079), which is good for CNS penetration.

**Binding Affinity:** Both ligands have comparable, strong binding affinities (-9.5 and -8.2 kcal/mol). The difference is less than 1.5 kcal/mol, so it's not a deciding factor.

**Conclusion:**

Considering the GPCR-specific priorities, Ligand A is significantly more promising. Its excellent BBB penetration (97.635) and optimal logP (2.838) are major advantages for a CNS-targeting drug. While its metabolic stability (Cl_mic) is a concern, the superior BBB penetration and logP outweigh this drawback. Ligand B's extremely poor BBB penetration makes it a less viable candidate despite its slightly better QED and lower clearance.

Output:
1
2025-04-17 03:56:04,687 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (347.415 and 352.308 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (88.6) is better than Ligand B (44.76). For CNS targets, TPSA should be <= 90, both meet this criteria, but A is closer to the upper limit.

**logP:** Ligand A (2.09) is optimal (1-3), while Ligand B (4.269) is pushing the upper limit. Higher logP can lead to solubility issues and off-target effects.

**H-Bond Donors/Acceptors:** Ligand A has 1 HBD and 5 HBA, while Ligand B has 0 HBD and 4 HBA. Both are within acceptable limits (<=5 HBD and <=10 HBA).

**QED:** Ligand A (0.843) has a better QED score than Ligand B (0.771), indicating a more drug-like profile.

**DILI:** Ligand B (86.623) has a significantly higher DILI risk than Ligand A (67.003). This is a major concern.

**BBB:** Ligand B (84.529) has a better BBB penetration percentile than Ligand A (62.466). This is a critical factor for a CNS target like DRD2.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.399 and -4.296), which is unusual and suggests poor permeability. This is a red flag for both.

**Aqueous Solubility:** Both ligands have negative solubility values (-3.203 and -5.294), indicating very poor solubility. This is a significant issue for bioavailability.

**hERG Inhibition:** Ligand A (0.26) has a lower hERG inhibition liability than Ligand B (0.634), making it safer from a cardiotoxicity perspective.

**Microsomal Clearance:** Ligand A (48.089) has a lower microsomal clearance than Ligand B (55.364), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (-15.982) has a negative half-life, which is impossible and indicates a data error or an extremely unstable compound. Ligand B (-1.255) also has a negative half-life, but is closer to zero.

**P-gp Efflux:** Ligand A (0.047) has lower P-gp efflux liability than Ligand B (0.755), which is beneficial for CNS exposure.

**Binding Affinity:** Ligand B (-9.1 kcal/mol) has a significantly stronger binding affinity than Ligand A (-8.5 kcal/mol). This is a substantial advantage.

**Overall Assessment:**

Ligand B has a much stronger binding affinity and better BBB penetration, which are crucial for a CNS GPCR target. However, it suffers from a significantly higher DILI risk, worse logP, and questionable half-life data. Ligand A has better ADME properties (lower DILI, better logP, lower P-gp efflux, better metabolic stability), but its binding affinity is weaker and BBB penetration is lower. The negative half-life values are concerning for both.

Despite the better affinity and BBB of Ligand B, the high DILI risk and questionable half-life make it a less attractive candidate. The poor solubility and permeability of both compounds are major drawbacks. However, the difference in binding affinity is substantial (1.6 kcal/mol). Given the importance of affinity for GPCRs, and the possibility of addressing the ADME issues through further optimization, I would cautiously favor Ligand B.

Output:
1
2025-04-17 03:56:04,687 - INFO - Okay, let's analyze these two ligands for their potential as DRD2 drug candidates.

**Step-by-step comparison:**

1. **MW:** Ligand A (455.384 Da) is within the ideal range. Ligand B (348.422 Da) is also within range, but closer to the lower limit.
2. **TPSA:** Ligand A (46.92) is excellent for CNS penetration, well below 90. Ligand B (83.12) is higher, but still potentially acceptable, though less optimal.
3. **logP:** Ligand A (4.577) is a bit high, potentially leading to solubility issues or off-target interactions. Ligand B (1.888) is excellent, within the optimal range.
4. **HBD:** Ligand A (1) is good. Ligand B (3) is acceptable.
5. **HBA:** Ligand A (3) is good. Ligand B (4) is acceptable.
6. **QED:** Both ligands (A: 0.679, B: 0.67) have good drug-likeness scores.
7. **DILI:** Ligand A (41.024) has a slightly higher DILI risk than Ligand B (29.624), but both are considered relatively low risk.
8. **BBB:** Both ligands have good BBB penetration (A: 74.758, B: 79.294), exceeding the 70% threshold for CNS targets. Ligand B is slightly better.
9. **Caco-2:** Both have negative Caco-2 values, which is unusual and suggests a potential issue with the data or modeling. However, we can still compare them relatively.
10. **Solubility:** Both have negative solubility values, again suggesting a potential data issue.
11. **hERG:** Both ligands have low hERG inhibition risk (A: 0.497, B: 0.459).
12. **Cl_mic:** Ligand A (84.907) has a higher microsomal clearance than Ligand B (24.844), indicating lower metabolic stability.
13. **t1/2:** Ligand A (64.764) has a longer in vitro half-life than Ligand B (15.982).
14. **Pgp:** Ligand A (0.382) has lower P-gp efflux liability than Ligand B (0.013), which is favorable for CNS penetration.
15. **Binding Affinity:** Ligand B (-7.6 kcal/mol) has a significantly stronger binding affinity than Ligand A (-8.3 kcal/mol). The difference is 0.7 kcal/mol, which is substantial.

**GPCR-Specific Priorities:**

For DRD2 (a GPCR), BBB, logP, Pgp, TPSA, and affinity are crucial. Ligand B excels in logP, Pgp, and significantly in binding affinity. Ligand A has better metabolic stability (longer t1/2) and lower Pgp efflux, but its higher logP is a concern. The affinity difference is the most important factor here.

**Conclusion:**

Despite the unusual negative values for Caco-2 and solubility, the significantly stronger binding affinity of Ligand B (-7.6 kcal/mol vs -8.3 kcal/mol) and its more favorable logP outweigh the slightly higher metabolic clearance. The better Pgp profile also supports its potential for CNS exposure.

Output:
1
2025-04-17 03:56:04,688 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (403.28 Da) is slightly higher than Ligand B (350.419 Da), but both are acceptable.

**2. TPSA:** Ligand A (59.73) is excellent for CNS penetration, well below the 90 A^2 threshold. Ligand B (103.71) is higher, but still potentially acceptable, though less ideal.

**3. logP:** Ligand A (3.335) is within the optimal range (1-3). Ligand B (0.82) is a bit low, potentially hindering membrane permeability.

**4. H-Bond Donors:** Both ligands have acceptable HBD counts (Ligand A: 0, Ligand B: 1).

**5. H-Bond Acceptors:** Both ligands have acceptable HBA counts (Ligand A: 5, Ligand B: 7).

**6. QED:** Both ligands have good QED scores (Ligand A: 0.656, Ligand B: 0.857), indicating drug-like properties.

**7. DILI:** Ligand A (72.043) has a moderate DILI risk, while Ligand B (15.82) has very low risk. This is a significant advantage for Ligand B.

**8. BBB:** Both ligands have excellent BBB penetration (Ligand A: 73.594, Ligand B: 74.758), exceeding the 70% threshold.

**9. Caco-2 Permeability:** Ligand A (-4.728) has poor Caco-2 permeability, which is concerning. Ligand B (-5.252) is also poor, but similar to Ligand A.

**10. Aqueous Solubility:** Both ligands have very poor aqueous solubility (Ligand A: -3.656, Ligand B: -1.305). This could present formulation challenges.

**11. hERG Inhibition:** Ligand A (0.755) has a slightly higher hERG risk than Ligand B (0.171), which is a significant advantage for Ligand B.

**12. Microsomal Clearance:** Ligand A (107.195) has higher microsomal clearance, indicating lower metabolic stability. Ligand B (-9.016) has negative clearance, which is excellent and suggests high metabolic stability.

**13. In vitro Half-Life:** Ligand A (37.57) has a moderate in vitro half-life. Ligand B (9.385) has a low in vitro half-life.

**14. P-gp Efflux:** Ligand A (0.775) has moderate P-gp efflux. Ligand B (0.011) has very low P-gp efflux, which is highly desirable for CNS penetration.

**15. Binding Affinity:** Ligand A (-7.9 kcal/mol) has a slightly better binding affinity than Ligand B (-8.2 kcal/mol). While the difference is small, it is still a factor.

**Overall Assessment:**

Ligand B is the more promising candidate. While Ligand A has a slightly better binding affinity, Ligand B excels in crucial ADME properties: significantly lower DILI risk, much better metabolic stability (negative Cl_mic), very low P-gp efflux, and lower hERG risk. The slightly lower logP of Ligand B is a concern, but the other advantages outweigh this drawback, especially considering the importance of BBB penetration for a CNS target like DRD2. The poor Caco-2 and solubility are shared concerns, but can be addressed with formulation strategies.

Output:
1
2025-04-17 03:56:04,688 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (350.503 and 346.427 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (78.43) is slightly higher than Ligand B (71.78), but both are below the 90 A^2 threshold desirable for CNS targets.

**logP:** Ligand A (2.517) and Ligand B (1.743) are both within the optimal 1-3 range. Ligand B is a bit lower, which *could* slightly hinder permeability, but isn't a major concern.

**H-Bond Donors/Acceptors:** Ligand A has 3 HBD and 3 HBA, while Ligand B has 1 HBD and 4 HBA. Both are within acceptable limits (<=5 HBD and <=10 HBA).

**QED:** Both ligands have good QED scores (0.66 and 0.882, respectively), indicating good drug-like properties.

**DILI:** Both ligands have relatively low DILI risk (24.622 and 29.314), which is favorable.

**BBB:** This is a critical parameter for a CNS target like DRD2. Ligand B (58.938) has a significantly better BBB percentile than Ligand A (40.558). This is a major advantage for Ligand B.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.926 and -4.967). This is unusual and suggests poor permeability. However, these values are on a log scale and may not be directly comparable.

**Aqueous Solubility:** Both ligands have negative solubility values (-3.654 and -1.511). This is also unusual and suggests poor solubility.

**hERG:** Both ligands have low hERG inhibition liability (0.359 and 0.17), which is good.

**Microsomal Clearance:** Ligand A (26.961) has a higher microsomal clearance than Ligand B (-0.955). This suggests Ligand B is more metabolically stable.

**In vitro Half-Life:** Ligand B (50.661) has a significantly longer in vitro half-life than Ligand A (13.641), which is a positive attribute.

**P-gp Efflux:** Ligand A (0.282) has lower P-gp efflux liability than Ligand B (0.029), which is preferable for CNS penetration.

**Binding Affinity:** Both ligands have excellent binding affinities (-8.7 and -8.9 kcal/mol). The difference of 0.2 kcal/mol is not substantial enough to override other factors.

**Overall Assessment:**

While both ligands have good potency, Ligand B is the more promising candidate due to its significantly better BBB penetration (58.938 vs 40.558), improved metabolic stability (lower Cl_mic and longer t1/2), and better overall ADME profile. The slightly lower logP of Ligand B is a minor concern, but the substantial advantage in BBB penetration outweighs this. The negative Caco-2 and solubility values are concerning for both, but might be artifacts of the prediction method or require further investigation.

Output:
1
2025-04-17 03:56:04,688 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (353.394 and 344.459 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (93.46) is slightly above the preferred <90 for CNS targets, but still reasonable. Ligand B (70.39) is excellent, well below 90.

**3. logP:** Both ligands have good logP values (1.74 and 2.616), falling within the optimal 1-3 range.

**4. H-Bond Donors:** Both have 2 HBD, which is within the acceptable limit of <=5.

**5. H-Bond Acceptors:** Both have 5 HBA, also within the acceptable limit of <=10.

**6. QED:** Both have similar QED values (0.76 and 0.772), indicating good drug-likeness.

**7. DILI:** Ligand A (65.917) has a higher DILI risk than Ligand B (22.334). This is a significant drawback for Ligand A.

**8. BBB:** Ligand A (74.913) has a better BBB percentile than Ligand B (27.646). This is a crucial advantage for a CNS target like DRD2.

**9. Caco-2 Permeability:** Ligand A (-4.945) has worse Caco-2 permeability than Ligand B (-5.15), indicating lower intestinal absorption.

**10. Aqueous Solubility:** Ligand A (-1.856) has better aqueous solubility than Ligand B (-3.154).

**11. hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.149 and 0.179).

**12. Microsomal Clearance:** Ligand B (75.227) has higher microsomal clearance than Ligand A (31.252), suggesting lower metabolic stability.

**13. In vitro Half-Life:** Ligand B (13.262) has a longer in vitro half-life than Ligand A (-11.105).

**14. P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.053 and 0.032).

**15. Binding Affinity:** Ligand B (-7.3) has a slightly better binding affinity than Ligand A (-8.0). While A is better, the difference is not substantial enough to override other factors.

**Overall Assessment:**

Ligand A has a better BBB score and solubility, but suffers from a significantly higher DILI risk and worse Caco-2 permeability. Ligand B has a lower DILI risk, better Caco-2 permeability, and a longer half-life, but a lower BBB score. Given the importance of minimizing toxicity (DILI) and ensuring reasonable absorption (Caco-2) for a drug candidate, and the relatively small difference in binding affinity, Ligand B appears to be the more promising candidate. The slightly lower BBB score can potentially be addressed through further optimization, whereas a high DILI risk is a major hurdle.

Output:
1
2025-04-17 03:56:04,688 - INFO - Reasoning:

Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (347.459 and 341.415 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (72.88) is significantly better than Ligand B (88.91). For CNS targets, we want TPSA <= 90, and A is closer to the optimal <= 60 range. B is pushing the upper limit.

**3. logP:** Both ligands have good logP values (1.98 and 1.135), falling within the 1-3 range.

**4. H-Bond Donors:** Both have 2 HBD, which is acceptable.

**5. H-Bond Acceptors:** Ligand A has 3 HBA, while Ligand B has 5. Both are within the acceptable limit of <=10, but A is preferable.

**6. QED:** Both ligands have similar QED values (0.826 and 0.824), indicating good drug-likeness.

**7. DILI:** Ligand A (13.3) has a much lower DILI risk than Ligand B (35.634). This is a significant advantage for A.

**8. BBB:** Ligand A (72.431) has a substantially better BBB percentile than Ligand B (61.846). For a CNS target like DRD2, >70 is desirable, and A is closer to that threshold.

**9. Caco-2 Permeability:** Ligand A (-4.823) has better Caco-2 permeability than Ligand B (-5.068), though both are negative values, indicating poor permeability.

**10. Aqueous Solubility:** Ligand A (-1.541) has better solubility than Ligand B (-1.794), although both are poor.

**11. hERG Inhibition:** Ligand A (0.425) has a lower hERG inhibition risk than Ligand B (0.218), which is preferable.

**12. Microsomal Clearance:** Ligand A (-4.79) has a lower (better) microsomal clearance than Ligand B (18.337). This suggests better metabolic stability for A.

**13. In vitro Half-Life:** Ligand A (-0.436) has a better in vitro half-life than Ligand B (-20.294).

**14. P-gp Efflux:** Ligand A (0.024) has lower P-gp efflux than Ligand B (0.018), which is preferable for CNS penetration.

**15. Binding Affinity:** Ligand B (-7.7) has a slightly better binding affinity than Ligand A (-7.3), but the difference is only 0.4 kcal/mol. Given the other significant advantages of A, this difference is unlikely to outweigh them.

**Overall Assessment:**

Ligand A consistently outperforms Ligand B across most critical ADME-Tox properties, particularly BBB penetration, DILI risk, metabolic stability, and hERG inhibition. While Ligand B has slightly better binding affinity, the other advantages of Ligand A, especially its superior predicted CNS penetration, make it the more promising drug candidate for a DRD2 target.

Output:
1
2025-04-17 03:56:04,688 - INFO - Reasoning:

Let's analyze Ligand A and Ligand B against the provided guidelines, prioritizing GPCR-specific properties (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (410.268 Da) is slightly higher than Ligand B (346.387 Da), but both are acceptable.

**TPSA:** Both ligands have TPSA values around 100, which is acceptable for general oral absorption, but a bit high for optimal CNS penetration (ideally <90).

**logP:** Ligand A (2.799) is within the optimal range (1-3). Ligand B (-0.736) is significantly below this range, which could hinder permeation and bioavailability. This is a major drawback for Ligand B.

**H-Bond Donors/Acceptors:** Both ligands have 2 HBD and 5 HBA, which are within acceptable limits.

**QED:** Both ligands have QED values above 0.5, indicating good drug-likeness.

**DILI:** Ligand A (74.99) has a higher DILI risk than Ligand B (52.617), but both are reasonably acceptable.

**BBB:** Ligand A (57.193) has a slightly better BBB percentile than Ligand B (51.105), but both are not ideal for a CNS target (ideally >70).

**Caco-2 Permeability:** Ligand A (-4.636) has a worse Caco-2 permeability than Ligand B (-5.153), indicating lower intestinal absorption.

**Aqueous Solubility:** Ligand A (-4.514) has worse aqueous solubility than Ligand B (-1.4).

**hERG Inhibition:** Both ligands have very low hERG inhibition risk.

**Microsomal Clearance:** Ligand A (50.135) has higher microsomal clearance than Ligand B (-0.955), suggesting lower metabolic stability.

**In vitro Half-Life:** Ligand A (14.494 hours) has a longer half-life than Ligand B (2.083 hours).

**P-gp Efflux:** Ligand A (0.096) has slightly higher P-gp efflux than Ligand B (0.017), suggesting lower CNS exposure.

**Binding Affinity:** Ligand B (-8.7 kcal/mol) has a significantly stronger binding affinity than Ligand A (-7.1 kcal/mol) - a difference of 1.6 kcal/mol. This is a substantial advantage.

**Overall Assessment:**

Ligand B has a significantly better binding affinity and a more favorable logP value, despite having a shorter half-life and slightly lower BBB penetration. The poor logP of Ligand A is a major concern, potentially leading to poor absorption and bioavailability. The stronger binding of Ligand B can likely overcome its slightly lower BBB and shorter half-life, especially given the importance of potency for GPCR ligands.

Output:
1
2025-04-17 03:56:04,689 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 drug candidates, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (369.776 and 369.487 Da) fall comfortably within the ideal 200-500 Da range.

**TPSA:** Ligand A (85.46) is better than Ligand B (100.29). For CNS targets, we want TPSA <= 90, so Ligand A is preferable.

**logP:** Ligand A (3.418) is optimal (1-3 range), while Ligand B (1.178) is on the lower side, potentially hindering permeability.

**H-Bond Donors/Acceptors:** Ligand A (HBD=1, HBA=5) is better than Ligand B (HBD=3, HBA=4) in terms of balancing solubility and permeability.

**QED:** Both ligands have reasonable QED scores (0.756 and 0.672), indicating good drug-like properties.

**DILI:** Ligand A (85.537) has a higher DILI risk than Ligand B (58.511). This is a significant drawback for Ligand A.

**BBB:** Ligand A (74.564) has a better BBB penetration score than Ligand B (54.246). Given DRD2 is a CNS target, this is a crucial advantage for Ligand A.

**Caco-2 Permeability:** Ligand A (-4.435) has a worse Caco-2 permeability than Ligand B (-5.315). Lower values indicate lower permeability.

**Aqueous Solubility:** Ligand A (-4.447) has worse solubility than Ligand B (-3.092).

**hERG Inhibition:** Both ligands have similar, low hERG inhibition liabilities (0.291 and 0.389).

**Microsomal Clearance:** Ligand A (82.919) has a higher microsomal clearance than Ligand B (26.133), indicating lower metabolic stability.

**In vitro Half-Life:** Ligand B (-31.083) has a significantly longer in vitro half-life than Ligand A (57.615), which is very desirable.

**P-gp Efflux:** Ligand A (0.551) has slightly higher P-gp efflux than Ligand B (0.053). Lower is better for CNS penetration.

**Binding Affinity:** Both ligands have excellent binding affinities (-8.1 and -8.3 kcal/mol). The difference is minimal.

**Overall Assessment:**

Ligand A excels in BBB penetration and TPSA, and has a good logP. However, it suffers from higher DILI risk, lower solubility, higher clearance, and higher P-gp efflux.

Ligand B has a lower DILI risk, better solubility, significantly better metabolic stability (longer half-life), and lower P-gp efflux. Its BBB penetration is lower, and logP is less optimal, but these are less critical given the strong affinity.

Considering the GPCR-specific priorities, the improved ADME properties of Ligand B (lower DILI, better metabolic stability, lower P-gp efflux) outweigh the slight disadvantage in BBB penetration and logP, especially given both ligands have excellent binding affinity.

Output:
1
2025-04-17 03:56:04,689 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (345.487 and 344.499 Da) fall comfortably within the ideal 200-500 Da range.

**TPSA:** Ligand A (84.22) is better than Ligand B (40.62). Both are below the 90 A^2 threshold for CNS targets, but Ligand B is significantly lower, which is advantageous for brain penetration.

**logP:** Both ligands have good logP values (2.649 and 3.941), falling within the optimal 1-3 range. Ligand B is slightly higher, potentially leading to some solubility concerns, but still acceptable.

**H-Bond Donors/Acceptors:** Ligand A has 3 HBD and 3 HBA, while Ligand B has 0 HBD and 2 HBA. Both are within acceptable limits (<=5 HBD and <=10 HBA).

**QED:** Ligand B (0.703) has a better QED score than Ligand A (0.421), indicating a more drug-like profile.

**DILI:** Ligand B (23.885) has a significantly lower DILI risk than Ligand A (41.024), which is a major advantage.

**BBB:** Ligand B (96.782) has a much higher BBB penetration percentile than Ligand A (74.758). This is *critical* for a CNS target like DRD2.

**Caco-2 Permeability:** Both have negative values (-4.956 and -4.323), which is unusual and suggests poor permeability. However, these values are on a scale where negative values are possible, and the absolute value is what matters. Ligand A is slightly worse.

**Aqueous Solubility:** Both have negative values (-3.749 and -3.367), indicating poor solubility.

**hERG:** Both ligands have low hERG inhibition liability (0.585 and 0.878), which is good.

**Microsomal Clearance:** Ligand B (96.621) has a much higher microsomal clearance than Ligand A (55.064), suggesting faster metabolism and potentially lower in vivo exposure.

**In vitro Half-Life:** Ligand B (11.998) has a significantly longer in vitro half-life than Ligand A (-4.513), which is a positive.

**P-gp Efflux:** Both have low P-gp efflux liability (0.376 and 0.674), which is good for CNS penetration.

**Binding Affinity:** Both ligands have excellent binding affinities (-9.1 and -9.0 kcal/mol), with Ligand A being slightly better. The difference is less than 1.5 kcal/mol, so it's not a decisive factor.

**Overall Assessment:**

Ligand B is the stronger candidate. While Ligand A has slightly better binding affinity, Ligand B excels in crucial ADME properties for a CNS-targeting GPCR: significantly better BBB penetration, lower DILI risk, better QED, and a longer half-life. The lower TPSA of Ligand B is also beneficial. The higher logP of Ligand B is a minor concern, but the benefits outweigh this drawback.



Output:
1
2025-04-17 03:56:04,689 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B based on the provided guidelines, prioritizing GPCR-specific properties (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands fall within the ideal range (200-500 Da). Ligand A (358.454 Da) is slightly preferred as it's closer to the lower end, potentially aiding permeability.

**TPSA:** Ligand A (67.87) is significantly better than Ligand B (35.58). For a CNS target like DRD2, a TPSA under 90 is desirable, and Ligand A is well within that range, while Ligand B is excellent.

**logP:** Ligand A (1.677) is optimal (1-3), while Ligand B (5.305) is quite high. High logP can lead to solubility issues and off-target interactions. This favors Ligand A.

**H-Bond Donors/Acceptors:** Both ligands have acceptable HBD (1) and HBA (4 for A, 3 for B) counts.

**QED:** Both ligands have similar QED values (0.603 and 0.503), indicating reasonable drug-likeness.

**DILI:** Ligand A (12.33) has a much lower DILI risk than Ligand B (38.542), which is a significant advantage.

**BBB:** Ligand A (88.096) shows excellent BBB penetration, exceeding the desirable >70% threshold. Ligand B (68.825) is lower, which is a concern for a CNS target.

**Caco-2 Permeability:** Ligand A (-4.445) and Ligand B (-5.16) both have negative Caco-2 values. This is unusual and suggests poor permeability. However, the scale is not specified, so it's difficult to interpret the absolute impact.

**Aqueous Solubility:** Ligand A (-2.01) and Ligand B (-5.061) both have negative solubility values. This is a significant drawback for both compounds, but B is worse.

**hERG Inhibition:** Ligand A (0.569) has a lower hERG risk than Ligand B (0.983), which is preferable.

**Microsomal Clearance:** Both ligands have similar microsomal clearance values (33.748 and 34.768), indicating comparable metabolic stability.

**In vitro Half-Life:** Ligand B (25.813 hours) has a significantly longer half-life than Ligand A (5.84 hours), which is a positive attribute.

**P-gp Efflux:** Ligand A (0.045) has much lower P-gp efflux liability than Ligand B (0.933), which is crucial for CNS penetration.

**Binding Affinity:** Ligand B (-9.7 kcal/mol) has a substantially stronger binding affinity than Ligand A (-6.9 kcal/mol). This is a significant advantage, potentially outweighing some of the ADME drawbacks. A difference of 2.8 kcal/mol is substantial.

**Overall Assessment:**

While Ligand B boasts a superior binding affinity, Ligand A has a much more favorable ADME profile, especially regarding BBB penetration, DILI risk, and P-gp efflux. The high logP of Ligand B is also a concern. For a CNS target like DRD2, achieving sufficient brain exposure is paramount. The significantly better BBB and lower P-gp efflux of Ligand A, combined with acceptable TPSA and logP, make it a more promising candidate despite the weaker binding affinity. The improved safety profile (lower DILI) also contributes to its favorability. The longer half-life of B is a plus, but can potentially be optimized in Ligand A.

Output:
0
2025-04-17 03:56:04,689 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (356.43 and 355.51 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (139.66) is excellent, just under the 140 threshold for oral absorption and very good for CNS penetration. Ligand B (38.25) is also very good, well below the 90 threshold for CNS targets.

**logP:** Ligand A (-0.222) is a bit low, potentially hindering permeation. Ligand B (4.061) is at the upper end of the optimal range, potentially leading to solubility issues or off-target effects, but acceptable.

**H-Bond Donors/Acceptors:** Ligand A (3 HBD, 6 HBA) is well within acceptable limits. Ligand B (0 HBD, 5 HBA) is also good.

**QED:** Both ligands have reasonable QED scores (0.313 and 0.751), with Ligand B being significantly better.

**DILI:** Ligand A (8.65) has a very low DILI risk, which is excellent. Ligand B (24.54) is also relatively low risk.

**BBB:** Ligand A (17.80) has a poor BBB penetration score, a major drawback for a CNS target. Ligand B (88.83) has an excellent BBB score, a significant advantage.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.293 and -5.194), which is unusual and suggests poor permeability. This is concerning for both.

**Aqueous Solubility:** Both ligands have negative solubility values (0.077 and -3.152), which is also concerning.

**hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.039 and 0.869).

**Microsomal Clearance:** Ligand A (11.58) has a lower clearance, indicating better metabolic stability than Ligand B (57.94).

**In vitro Half-Life:** Ligand B (16.82) has a longer half-life than Ligand A (-2.252).

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.002 and 0.654).

**Binding Affinity:** Ligand B (-7.2 kcal/mol) has a slightly better binding affinity than Ligand A (-6.9 kcal/mol). While the difference is not huge, it is within the range where it could outweigh some ADME drawbacks.

**Overall Assessment:**

For a CNS target like DRD2, BBB penetration is critical. Ligand B excels in this area (88.83%), while Ligand A fails miserably (17.80%). Ligand B also has a better QED, longer half-life, and slightly better binding affinity. While Ligand B's logP is a little high and its solubility is poor, the excellent BBB penetration and binding affinity are decisive. Ligand A's low logP and poor BBB penetration are significant liabilities. The negative Caco-2 and solubility values are concerning for both, but can be addressed during lead optimization.

Output:
1
2025-04-17 03:56:04,690 - INFO - Batch 70 complete. Total preferences: 1120
2025-04-17 03:56:04,690 - INFO - Processing batch 71/512...
2025-04-17 03:56:45,666 - INFO - Reasoning:

Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (347.419 and 362.455 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (101.56) is slightly above the optimal <90 for CNS targets, but still reasonable. Ligand B (97.43) is better, falling comfortably under 90.

**3. logP:** Ligand A (-0.682) is a bit low, potentially hindering permeability. Ligand B (1.708) is within the optimal 1-3 range. This is a significant advantage for Ligand B.

**4. H-Bond Donors:** Ligand A (3) is acceptable. Ligand B (0) is even better, potentially improving permeability.

**5. H-Bond Acceptors:** Ligand A (5) is acceptable. Ligand B (6) is also within the reasonable limit of 10.

**6. QED:** Both ligands have good QED scores (0.613 and 0.764), indicating drug-like properties.

**7. DILI:** Ligand A (37.146) has a lower DILI risk than Ligand B (64.56). This is a positive for Ligand A.

**8. BBB:** Ligand B (66.188) has a significantly better BBB penetration percentile than Ligand A (33.734). This is crucial for a CNS target like DRD2, and a major advantage for Ligand B.

**9. Caco-2 Permeability:** Ligand A (-5.709) has poor Caco-2 permeability, indicating poor intestinal absorption. Ligand B (-4.456) is also poor, but slightly better than A.

**10. Aqueous Solubility:** Both ligands have very poor aqueous solubility (-1.404 and -4.074). This is a concern for both, but potentially more so for Ligand B given its higher logP.

**11. hERG Inhibition:** Ligand A (0.173) has a lower hERG inhibition risk than Ligand B (0.674). This favors Ligand A.

**12. Microsomal Clearance:** Ligand A (-10.674) has much lower microsomal clearance (better metabolic stability) than Ligand B (44.83). This is a significant advantage for Ligand A.

**13. In vitro Half-Life:** Ligand A (20.312) has a better in vitro half-life than Ligand B (-31.683). This is a strong positive for Ligand A.

**14. P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.067 and 0.109), which is good for CNS penetration.

**15. Binding Affinity:** Both ligands have similar binding affinity (-8.0 and -7.6 kcal/mol), which is excellent. The difference is not substantial enough to be a deciding factor.

**Overall Assessment:**

While Ligand A has advantages in DILI, metabolic stability (Cl_mic), and half-life, Ligand B excels in crucial GPCR-specific properties: logP and BBB penetration. The poor logP of Ligand A is a significant drawback, potentially limiting its ability to cross cell membranes and reach the CNS target. The substantially better BBB score for Ligand B outweighs the slightly higher DILI risk and worse metabolic stability. The slightly better Caco-2 permeability of Ligand B is also a minor positive.

Output:
1
2025-04-17 03:56:45,667 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (346.431 and 348.495 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (87.32) is better than Ligand B (66.29) as it is closer to the ideal range for CNS targets (<=90). Ligand B is also good, but A is slightly preferred.

**3. logP:** Both ligands have good logP values (1.887 and 1.19), falling within the optimal range of 1-3.

**4. H-Bond Donors:** Ligand A (2) and Ligand B (1) are both acceptable, being less than 5.

**5. H-Bond Acceptors:** Ligand A (4) and Ligand B (6) are both acceptable, being less than 10.

**6. QED:** Both ligands have similar and good QED values (0.738 and 0.782), indicating good drug-like properties.

**7. DILI:** Ligand B (7.29) is significantly better than Ligand A (46.064) regarding DILI risk, indicating a much lower potential for liver injury. This is a substantial advantage for Ligand B.

**8. BBB:** Ligand B (64.327) is slightly better than Ligand A (57.774) but both are below the desirable threshold of >70 for CNS targets.

**9. Caco-2 Permeability:** Ligand A (-4.482) is better than Ligand B (-5.199). Higher values indicate better intestinal absorption.

**10. Aqueous Solubility:** Ligand A (-3.283) is better than Ligand B (-0.814). Higher values indicate better solubility.

**11. hERG Inhibition:** Ligand A (0.242) is better than Ligand B (0.497), indicating a lower risk of cardiotoxicity.

**12. Microsomal Clearance:** Ligand B (0.779) is much better than Ligand A (64.248), indicating significantly greater metabolic stability.

**13. In vitro Half-Life:** Ligand B (4.925) is better than Ligand A (-44.409), indicating a longer half-life.

**14. P-gp Efflux:** Ligand A (0.09) is better than Ligand B (0.075), indicating lower P-gp efflux and potentially better CNS exposure.

**15. Binding Affinity:** Ligand A (-8.4) has a significantly stronger binding affinity than Ligand B (-7.3). This is a >1.1 kcal/mol advantage, which can outweigh some ADME drawbacks.

**Overall Assessment:**

Ligand B excels in safety (DILI, hERG) and ADME properties (Cl_mic, t1/2). However, Ligand A possesses a substantially stronger binding affinity. Considering DRD2 is a CNS target, BBB penetration is important, but the affinity difference is significant. The better metabolic stability and lower DILI risk of Ligand B are very attractive. However, the substantial affinity advantage of Ligand A is likely to be more impactful, especially given that both compounds have acceptable, though not optimal, BBB scores.

Output:
1
2025-04-17 03:56:45,667 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (357.401 and 362.495 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (61.88) is slightly higher than Ligand B (58.64), but both are below the 90 A^2 threshold desirable for CNS targets.

**logP:** Ligand A (1.022) is a bit low, potentially hindering permeation. Ligand B (2.661) is within the optimal 1-3 range. This favors Ligand B.

**H-Bond Donors/Acceptors:** Both have 1 HBD and 4 HBA, which are acceptable values.

**QED:** Both ligands have good QED scores (0.721 and 0.876), indicating good drug-like properties.

**DILI:** Ligand A (22.644) has a significantly lower DILI risk than Ligand B (35.052), which is a strong advantage for Ligand A.

**BBB:** Ligand A (96.743) has excellent BBB penetration, while Ligand B (78.558) is still reasonable but lower. This is a critical factor for a CNS target like DRD2, heavily favoring Ligand A.

**Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and suggests poor permeability. However, the scale is not specified, so it's hard to interpret.

**Aqueous Solubility:** Both have negative solubility values, also unusual. Again, the scale is unknown.

**hERG:** Both ligands have low hERG inhibition liability (0.6 and 0.497), which is good.

**Microsomal Clearance:** Ligand A (-5.923) has a much lower (better) microsomal clearance than Ligand B (32.552), indicating greater metabolic stability.

**In vitro Half-Life:** Ligand A (-9.005) has a much longer in vitro half-life than Ligand B (2.585), which is highly desirable.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.028 and 0.198), which is favorable for CNS penetration.

**Binding Affinity:** Ligand B (-8.5 kcal/mol) has a slightly better binding affinity than Ligand A (-7.6 kcal/mol). This 0.9 kcal/mol difference is noticeable, but not overwhelming given the other factors.

**Overall Assessment:**

While Ligand B has slightly better binding affinity and a more optimal logP, Ligand A excels in crucial areas for a CNS-targeting GPCR: significantly better BBB penetration, lower DILI risk, much better metabolic stability (lower Cl_mic, longer t1/2). The differences in BBB and metabolic stability are substantial enough to outweigh the modest affinity difference.

Output:
0
2025-04-17 03:56:45,667 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (348.487 and 341.411 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (69.64) is excellent, well below the 90 A^2 threshold for CNS targets. Ligand B (73.48) is still acceptable, but less optimal.

**3. logP:** Both ligands have good logP values (2.103 and 1.547), falling within the 1-3 range. Ligand A is slightly better.

**4. H-Bond Donors:** Ligand A (2) and Ligand B (1) are both within the acceptable limit of <=5.

**5. H-Bond Acceptors:** Both ligands have 3 H-bond acceptors, well below the 10 limit.

**6. QED:** Both ligands have good QED scores (0.748 and 0.83), indicating good drug-like properties.

**7. DILI:** Ligand A (23.614) has a significantly lower DILI risk than Ligand B (49.787). This is a major advantage.

**8. BBB:** Ligand A (65.452) has a better BBB percentile than Ligand B (53.044), although ideally, we'd want >70 for a CNS target. Ligand A is closer.

**9. Caco-2:** Both have negative Caco-2 values, which is unusual and suggests poor permeability. Ligand A (-4.756) is slightly better than Ligand B (-5.009).

**10. Solubility:** Both have negative solubility values, which is also unusual and suggests poor solubility. Ligand A (-2.407) is slightly better than Ligand B (-3.225).

**11. hERG:** Both ligands have very low hERG risk (0.212 and 0.257).

**12. Cl_mic:** Ligand B (15.928) has a significantly lower microsomal clearance than Ligand A (41.909), indicating better metabolic stability.

**13. t1/2:** Ligand B (-29.464) has a longer in vitro half-life than Ligand A (-37.687), which is desirable.

**14. Pgp:** Ligand B (0.092) has a lower P-gp efflux liability than Ligand A (0.168), which is favorable for CNS penetration.

**15. Binding Affinity:** Ligand A (-8.3 kcal/mol) has a significantly stronger binding affinity than Ligand B (-0.0 kcal/mol). This is a critical advantage, outweighing many of the ADME concerns.

**Overall Assessment:**

While Ligand B has better metabolic stability (lower Cl_mic) and Pgp efflux, the significantly stronger binding affinity of Ligand A (-8.3 vs -0.0 kcal/mol) is a decisive factor. The lower DILI risk and better BBB penetration of Ligand A also contribute to its favorability. The negative Caco-2 and solubility values are concerning for both, but can be addressed with formulation strategies. The substantial difference in binding affinity makes Ligand A the more promising candidate.

Output:
1
2025-04-17 03:56:45,667 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (363.929 Da and 367.877 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (49.33) is significantly better than Ligand B (65.64). For CNS targets, we want TPSA <= 90, and ideally closer to 60. Ligand A is much closer to this ideal.

**3. logP:** Ligand A (4.66) is slightly higher than the optimal 1-3 range, but still potentially acceptable. Ligand B (2.548) is well within the optimal range. However, for a GPCR, a slightly higher logP can be tolerated if other properties are favorable.

**4. H-Bond Donors:** Ligand A (2) and Ligand B (1) are both acceptable, being <= 5.

**5. H-Bond Acceptors:** Ligand A (2) and Ligand B (3) are both acceptable, being <= 10.

**6. QED:** Both ligands have good QED scores (0.772 and 0.869), indicating good drug-like properties.

**7. DILI:** Ligand A (22.257) has a much lower DILI risk than Ligand B (35.324). Both are below the 40 threshold, but A is preferable.

**8. BBB:** Both ligands have good BBB penetration (76.774% and 71.501%). Both are above the 70% threshold, which is critical for CNS targets.

**9. Caco-2:** Both have negative Caco-2 values, which is unusual and difficult to interpret without knowing the scale. This parameter is less critical than others.

**10. Solubility:** Both have negative solubility values, again making interpretation difficult. Solubility is important, but can be addressed through formulation.

**11. hERG:** Both ligands have low hERG inhibition liability (0.653 and 0.578), which is good.

**12. Cl_mic:** Ligand B (10.418) has significantly lower microsomal clearance than Ligand A (68.24). Lower clearance is better for metabolic stability.

**13. t1/2:** Ligand A (16.75) has a longer in vitro half-life than Ligand B (0.729). A longer half-life is generally preferred.

**14. Pgp:** Ligand A (0.707) has lower P-gp efflux than Ligand B (0.141). Lower P-gp efflux is highly desirable for CNS penetration.

**15. Binding Affinity:** Ligand B (-8.3 kcal/mol) has a significantly stronger binding affinity than Ligand A (-10.0 kcal/mol). This is a substantial advantage.

**Overall Assessment:**

While Ligand B has a superior binding affinity and better metabolic stability (lower Cl_mic), Ligand A has a much better TPSA, lower DILI risk, and lower P-gp efflux. The lower TPSA and P-gp efflux of Ligand A are particularly important for CNS penetration, and the lower DILI risk is a significant safety advantage. The affinity difference is 1.7 kcal/mol, which is substantial, but the combination of favorable ADME properties in Ligand A makes it a more promising candidate.

Output:
1
2025-04-17 03:56:45,667 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (350.463 and 385.511 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (87.46) is better than Ligand B (101.77). Both are below the 140 A^2 threshold for oral absorption, and Ligand A is closer to the more stringent <90 A^2 for CNS targets.

**3. logP:** Ligand A (1.483) is within the optimal range (1-3), while Ligand B (0.531) is slightly below, potentially hindering permeation.

**4. H-Bond Donors:** Both ligands have 2 HBD, which is acceptable (<=5).

**5. H-Bond Acceptors:** Ligand A has 5 HBA, and Ligand B has 6, both within the acceptable limit of <=10.

**6. QED:** Both ligands have good QED scores (0.743 and 0.789, respectively), indicating drug-like properties.

**7. DILI:** Both ligands have the same DILI risk (35.285 percentile), which is good (low risk).

**8. BBB:** This is a critical parameter for a CNS target like DRD2. Ligand A has a BBB penetration percentile of 66.227, which is reasonably good, but not exceptional. Ligand B has a significantly lower BBB penetration percentile of 20.279, which is a major drawback.

**9. Caco-2 Permeability:** Ligand A (-4.945) shows better Caco-2 permeability than Ligand B (-5.692), suggesting better intestinal absorption.

**10. Aqueous Solubility:** Ligand A (-1.849) is slightly better than Ligand B (-1.034), although both are negative, indicating poor solubility.

**11. hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.259 and 0.059, respectively).

**12. Microsomal Clearance:** Ligand B (-10.734) has a much lower (better) microsomal clearance than Ligand A (23.124), suggesting greater metabolic stability.

**13. In vitro Half-Life:** Ligand B (33.297) has a significantly longer in vitro half-life than Ligand A (-5.478), which is a positive attribute.

**14. P-gp Efflux:** Ligand A (0.068) has lower P-gp efflux liability than Ligand B (0.042), which is favorable for CNS exposure.

**15. Binding Affinity:** Both ligands have very similar binding affinities (-7.8 and -7.0 kcal/mol). While Ligand A is slightly better, the difference is not substantial enough to outweigh other significant differences.

**Overall Assessment:**

Ligand A is preferable due to its better TPSA, logP, Caco-2 permeability, and P-gp efflux. Most importantly, its BBB penetration is significantly better than Ligand B's, which is crucial for a CNS-targeting drug. Although Ligand B has better metabolic stability and half-life, the poor BBB penetration is a major limiting factor for a DRD2 ligand. The slight advantage in binding affinity of Ligand A is a bonus.

Output:
0
2025-04-17 03:56:45,667 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (356.466 and 343.431 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (33.2) is excellent, well below the 90 A^2 threshold for CNS targets. Ligand B (71.33) is higher, but still potentially acceptable, though less ideal.

**logP:** Ligand A (4.805) is high, potentially leading to solubility issues and off-target interactions. Ligand B (1.327) is within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Both ligands have a reasonable number of HBD (0) and HBA (3 for A, 5 for B), staying within the guidelines.

**QED:** Both ligands have good QED values (0.74 and 0.773), indicating drug-like properties.

**DILI:** Ligand A (56.883) has a higher DILI risk than Ligand B (43.932), but both are below the concerning 60 threshold.

**BBB:** This is a critical parameter for a CNS target like DRD2. Ligand A excels with a BBB percentile of 91.702, while Ligand B is lower at 79.488.

**Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and potentially indicates an issue with the prediction method or the compounds themselves. However, we proceed with caution.

**Aqueous Solubility:** Both ligands have very poor predicted aqueous solubility (-5.581 and -3.053). This is a significant concern, especially given Ligand A's high logP.

**hERG Inhibition:** Both ligands show low hERG inhibition risk (0.75 and 0.13).

**Microsomal Clearance:** Ligand A (102.08) has higher microsomal clearance than Ligand B (75.587), suggesting faster metabolism and potentially lower in vivo exposure.

**In vitro Half-Life:** Ligand B (-24.989) has a negative half-life, which is not physically possible and suggests a problem with the prediction. Ligand A (33.97) is reasonable.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.631 and 0.171), which is favorable for CNS penetration.

**Binding Affinity:** Both ligands have strong binding affinities (-8.9 and -8.6 kcal/mol). The difference of 0.3 kcal/mol is not substantial enough to override other considerations.

**Overall Assessment:**

Ligand A has a superior BBB score and a reasonable half-life, but suffers from a high logP, poor solubility, and higher metabolic clearance. Ligand B has a better logP, lower DILI risk, and lower P-gp efflux, but its predicted half-life is nonsensical. Given the importance of BBB penetration for a CNS target, and the relatively small difference in binding affinity, Ligand A is slightly favored, *assuming* the negative half-life prediction for Ligand B is an artifact of the model. However, the poor solubility of Ligand A is a major concern that would need to be addressed through formulation or structural modification.

Output:
1
2025-04-17 03:56:45,668 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (346.471 Da) is slightly higher than Ligand B (337.335 Da), but both are acceptable.

**TPSA:** Ligand A (49.85) is excellent for CNS penetration, well below the 90 A^2 threshold. Ligand B (104.46) is higher, but still potentially acceptable, though less ideal.

**logP:** Ligand A (2.505) is optimal. Ligand B (1.196) is a bit low, potentially hindering permeability.

**H-Bond Donors/Acceptors:** Ligand A (0 HBD, 3 HBA) is favorable. Ligand B (3 HBD, 5 HBA) is also reasonable, but the higher number of donors/acceptors could slightly impact permeability.

**QED:** Both ligands have similar QED values (A: 0.789, B: 0.727), indicating good drug-like properties.

**DILI:** Ligand A (34.354) has a significantly lower DILI risk than Ligand B (64.521). This is a substantial advantage for Ligand A.

**BBB:** Ligand A (91.431) has excellent predicted BBB penetration, exceeding the 70% threshold. Ligand B (24.855) is very poor, making CNS exposure unlikely. This is a critical difference given the target is DRD2.

**Caco-2 Permeability:** Ligand A (-4.366) has poor Caco-2 permeability, while Ligand B (-5.126) is also poor.

**Aqueous Solubility:** Both ligands have poor aqueous solubility (A: -2.673, B: -3.958). This could pose formulation challenges, but is less critical than BBB for a CNS target.

**hERG Inhibition:** Both ligands have very low hERG inhibition risk (A: 0.553, B: 0.144).

**Microsomal Clearance:** Ligand A (54.624) has moderate clearance, while Ligand B (-28.535) has negative clearance, which is unusual and potentially indicates very high metabolic stability.

**In vitro Half-Life:** Ligand A (-11.954) has a very short half-life, while Ligand B (28.545) has a longer half-life.

**P-gp Efflux:** Ligand A (0.376) has low P-gp efflux, which is favorable for CNS penetration. Ligand B (0.024) has very low P-gp efflux, which is even better.

**Binding Affinity:** Both ligands have excellent binding affinity (A: -9.2 kcal/mol, B: -8.1 kcal/mol), with Ligand A being slightly stronger. The 1.1 kcal/mol difference is significant.

**Overall Assessment:**

Ligand A is the stronger candidate. While it has poor Caco-2 permeability and a short half-life, its superior BBB penetration (91.431% vs 24.855%), lower DILI risk, and slightly better binding affinity (-9.2 vs -8.1 kcal/mol) are decisive advantages for a CNS-targeting GPCR like DRD2. The lower logP of Ligand B is also a concern. The metabolic stability of Ligand B is questionable given the negative clearance value.

Output:
1
2025-04-17 03:56:45,668 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (359.411 and 357.376 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (108.09) is higher than the preferred <90 for CNS targets, while Ligand B (44.81) is well within the optimal range. This is a significant advantage for Ligand B.

**logP:** Ligand A (0.746) is a bit low, potentially hindering permeability. Ligand B (3.047) is within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Both have 1 HBD, which is good. Ligand A has 6 HBA, acceptable. Ligand B has 3 HBA, which is also good.

**QED:** Both ligands have acceptable QED scores (0.847 and 0.728, both >0.5).

**DILI:** Ligand A (79.915) has a higher DILI risk than Ligand B (42.924). While both are below 60, lower is better.

**BBB:** Ligand B (78.054) has a significantly better BBB penetration score than Ligand A (46.646). This is crucial for a CNS target like DRD2.

**Caco-2 Permeability:** Ligand A (-5.105) has poor Caco-2 permeability. Ligand B (-4.474) is slightly better, but still not ideal.

**Aqueous Solubility:** Both have poor aqueous solubility (-4.02 and -3.087).

**hERG Inhibition:** Ligand A (0.367) has a lower hERG inhibition risk than Ligand B (0.857).

**Microsomal Clearance:** Ligand A (46.211) has a higher microsomal clearance than Ligand B (35.309), indicating lower metabolic stability.

**In vitro Half-Life:** Ligand B (4.183) has a slightly better in vitro half-life than Ligand A (13.221).

**P-gp Efflux:** Ligand A (0.194) has lower P-gp efflux, which is favorable for CNS penetration. Ligand B (0.092) has even lower P-gp efflux, which is even more favorable.

**Binding Affinity:** Ligand A (-8.8 kcal/mol) has a significantly stronger binding affinity than Ligand B (-7.5 kcal/mol). This is a substantial advantage.

**Overall Assessment:**

Ligand A has a significantly better binding affinity, but struggles with TPSA, logP, Caco-2 permeability, and has a higher DILI risk and microsomal clearance. Ligand B excels in TPSA, BBB, P-gp efflux, and DILI, with acceptable logP and a reasonable half-life. The superior affinity of Ligand A is tempting, however, the poor ADME properties, especially the TPSA and BBB, are concerning for CNS penetration. The difference in binding affinity (1.3 kcal/mol) is substantial, but not insurmountable, and can potentially be optimized in subsequent iterations. Ligand B's favorable ADME profile, particularly its BBB penetration, makes it a more promising starting point for a CNS-targeted drug.

Output:
1
2025-04-17 03:56:45,668 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (366.389 and 362.813 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (66.48) is significantly better than Ligand B (71.78). For CNS targets, we want TPSA <= 90, and ideally closer to 60. Ligand A is much closer to this ideal.

**3. logP:** Ligand A (2.816) is optimal (1-3), while Ligand B (4.008) is pushing the upper limit and could potentially lead to solubility issues or off-target interactions.

**4. H-Bond Donors:** Both ligands have 1 HBD, which is within the acceptable limit of <=5.

**5. H-Bond Acceptors:** Ligand A has 3 HBAs, and Ligand B has 4. Both are within the acceptable limit of <=10.

**6. QED:** Both ligands have good QED scores (0.905 and 0.819, both >=0.5).

**7. DILI:** Both ligands have similar and relatively high DILI risk (79.139 and 79.992). This is a concern for both, but not a deciding factor between them.

**8. BBB:** Ligand B (73.129) has a slightly better BBB penetration percentile than Ligand A (69.407), but both are above the desirable 70% threshold for CNS targets.

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.644 and -4.528). This is unusual and suggests poor intestinal absorption. However, for a CNS target, intestinal absorption is less critical than BBB penetration.

**10. Aqueous Solubility:** Ligand A (-3.996) is better than Ligand B (-5.742). Higher solubility is generally preferred.

**11. hERG Inhibition:** Both ligands have low hERG inhibition risk (0.702 and 0.474).

**12. Microsomal Clearance:** Ligand A (23.14) has significantly lower microsomal clearance than Ligand B (111.834), indicating better metabolic stability.

**13. In vitro Half-Life:** Ligand B (71.001) has a longer in vitro half-life than Ligand A (60.245). This is a slight advantage for Ligand B.

**14. P-gp Efflux:** Ligand A (0.416) has lower P-gp efflux than Ligand B (0.342), meaning it's less likely to be pumped out of the brain, improving CNS exposure.

**15. Binding Affinity:** Ligand A (-9.6 kcal/mol) has *significantly* stronger binding affinity than Ligand B (-0.0 kcal/mol). This is a massive difference, and a >1.5 kcal/mol advantage can often outweigh minor ADME drawbacks.

**Overall Assessment:**

Ligand A is the superior candidate. While both have concerning DILI scores, Ligand A excels in key areas for a CNS-targeting GPCR ligand: lower TPSA, optimal logP, significantly better binding affinity, lower microsomal clearance (better metabolic stability), and lower P-gp efflux. The slightly lower BBB score is less concerning given the much stronger affinity and other favorable properties. The negative Caco-2 values are a shared issue, but less critical for a CNS drug.

Output:
1
2025-04-17 03:56:45,668 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B based on the provided guidelines, prioritizing properties relevant for a GPCR target like DRD2 (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the acceptable range (200-500 Da). Ligand A (361.467 Da) is preferable as it's lower.

**TPSA:** Ligand A (82.53) is better than Ligand B (64.09) as it is closer to the ideal range for CNS targets (<=90).

**logP:** Both ligands have logP values within the optimal range (1-3), but Ligand A (2.884) is slightly better than Ligand B (4.024). Ligand B is approaching the upper limit where solubility issues can arise.

**H-Bond Donors/Acceptors:** Ligand A (HBD=2, HBA=5) and Ligand B (HBD=1, HBA=6) both fall within the acceptable ranges.

**QED:** Ligand A (0.829) has a significantly better QED score than Ligand B (0.622), indicating a more drug-like profile.

**DILI:** Ligand B (39.783) has a lower DILI risk than Ligand A (54.517), which is a positive attribute.

**BBB:** Ligand B (79.915) has a substantially better BBB penetration score than Ligand A (34.548). This is a *critical* advantage for a CNS target like DRD2.

**Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and suggests poor permeability. However, the scale is not specified, so it's difficult to interpret.

**Aqueous Solubility:** Both have negative solubility values, again, difficult to interpret without knowing the scale.

**hERG:** Ligand A (0.225) has a lower hERG inhibition liability than Ligand B (0.975), which is favorable.

**Microsomal Clearance:** Ligand B (64.717) has a slightly higher clearance than Ligand A (62.37), indicating slightly lower metabolic stability.

**In vitro Half-Life:** Ligand A (2.748) has a better in vitro half-life than Ligand B (-26.212).

**P-gp Efflux:** Ligand A (0.046) has much lower P-gp efflux liability than Ligand B (0.759), which is crucial for CNS penetration.

**Binding Affinity:** Ligand B (-8.9 kcal/mol) has a slightly better binding affinity than Ligand A (-8.5 kcal/mol). While this is a positive, the difference is relatively small.

**Overall Assessment:**

Ligand B excels in BBB penetration and binding affinity, which are key for DRD2. However, Ligand A demonstrates superior drug-likeness (QED), lower P-gp efflux, lower hERG risk, and a better half-life. The significantly better BBB score of Ligand B outweighs the other advantages of Ligand A, making it the more promising candidate, despite its slightly higher logP and DILI risk.

Output:
1
2025-04-17 03:56:45,668 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (368.503 and 346.439 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (81.75) is excellent, well below the 90 A^2 threshold for CNS targets. Ligand B (97.79) is still reasonable but less optimal, nearing the 100 A^2 mark.

**logP:** Ligand A (0.156) is quite low, potentially hindering membrane permeability. Ligand B (0.874) is better, but still on the lower side of the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A (2 HBD, 5 HBA) is good. Ligand B (1 HBD, 9 HBA) is also acceptable, although the higher HBA count could slightly impact permeability.

**QED:** Both ligands have good QED scores (0.722 and 0.823), indicating generally drug-like properties.

**DILI:** Ligand A (15.626) has a significantly lower DILI risk than Ligand B (29.818), a substantial advantage.

**BBB:** Ligand B (86.39) has a much better BBB penetration percentile than Ligand A (55.642). This is a critical factor for a CNS target like DRD2.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.625 and -5.659), which is unusual and suggests poor permeability. This is concerning for both.

**Aqueous Solubility:** Both ligands have negative solubility values (-1.595 and -1.193), indicating very poor aqueous solubility. This is a major drawback for both.

**hERG Inhibition:** Ligand A (0.048) has a very low hERG risk, while Ligand B (0.136) is slightly higher, but still low.

**Microsomal Clearance:** Ligand A (0.978) has lower microsomal clearance, suggesting better metabolic stability than Ligand B (-4.598).

**In vitro Half-Life:** Ligand B (-6.789) has a more negative half-life, indicating faster metabolism and a shorter half-life than Ligand A (-0.783).

**P-gp Efflux:** Ligand A (0.009) has a very low P-gp efflux liability, which is favorable for CNS penetration. Ligand B (0.025) is also low, but higher than Ligand A.

**Binding Affinity:** Ligand B (-7.9 kcal/mol) has a slightly better binding affinity than Ligand A (-7.0 kcal/mol). This 1.9 kcal/mol difference is significant and could potentially outweigh some of the ADME drawbacks.

**Overall Assessment:**

Ligand B has a significantly better BBB penetration and binding affinity, which are crucial for a CNS GPCR target. However, Ligand A has a much lower DILI risk and better metabolic stability. Both have poor solubility and permeability. The improved affinity of Ligand B is a substantial advantage. Given the importance of CNS penetration for DRD2, and the relatively small difference in other parameters, Ligand B is the more promising candidate, despite its slightly higher DILI risk. The solubility and permeability issues would need to be addressed through formulation or further chemical modification.

Output:
1
2025-04-17 03:56:45,668 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (350.503 and 349.475 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (69.64) is higher than Ligand B (53.09). For a CNS target like DRD2, we ideally want TPSA <= 90, so both are acceptable, but B is better.

**3. logP:** Both ligands have good logP values (2.469 and 1.098), falling within the optimal 1-3 range. Ligand A is slightly better.

**4. H-Bond Donors:** Ligand A has 2 HBD, and Ligand B has 0. Both are within the acceptable limit of <=5.

**5. H-Bond Acceptors:** Ligand A has 3 HBA, and Ligand B has 4. Both are within the acceptable limit of <=10.

**6. QED:** Both ligands have similar QED values (0.741 and 0.763), indicating good drug-likeness.

**7. DILI:** Ligand A (12.369) has a slightly higher DILI risk than Ligand B (10.896), but both are below the 40 threshold, indicating low risk.

**8. BBB:** This is a crucial parameter for CNS targets. Ligand B (83.055) has a significantly higher BBB penetration percentile than Ligand A (61.497). This is a major advantage for Ligand B.

**9. Caco-2 Permeability:** Ligand A (-4.582) and Ligand B (-4.734) both have negative values, suggesting poor permeability.

**10. Aqueous Solubility:** Ligand A (-2.694) and Ligand B (-0.931) both have negative values, suggesting poor solubility. Ligand B is slightly better.

**11. hERG Inhibition:** Ligand A (0.231) and Ligand B (0.46) have low hERG inhibition liability, which is good.

**12. Microsomal Clearance:** Ligand A (36.77) has higher microsomal clearance than Ligand B (-4.719). This means Ligand B is likely more metabolically stable.

**13. In vitro Half-Life:** Ligand A (-1.553) has a shorter in vitro half-life than Ligand B (10.096). This is a significant advantage for Ligand B.

**14. P-gp Efflux:** Ligand A (0.116) has lower P-gp efflux than Ligand B (0.047), which is better.

**15. Binding Affinity:** Ligand A (-8.4 kcal/mol) has a slightly better binding affinity than Ligand B (-7.5 kcal/mol). This is a 0.9 kcal/mol difference, which is substantial.

**Overall Assessment:**

While Ligand A has a slightly better binding affinity and lower P-gp efflux, Ligand B demonstrates superior ADME properties crucial for CNS penetration. Specifically, its significantly higher BBB penetration (83.055 vs 61.497), better metabolic stability (lower Cl_mic, higher t1/2), and slightly better solubility are compelling advantages. The 0.9 kcal/mol difference in binding affinity can potentially be overcome with further optimization, while improving the ADME profile is often more challenging. Given the GPCR-specific priorities, the improved CNS penetration profile of Ligand B makes it the more promising candidate.

Output:
1
2025-04-17 03:56:45,668 - INFO - Reasoning:

Let's analyze Ligand A and Ligand B based on the provided guidelines, prioritizing GPCR-specific properties (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (367.442 and 363.399 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (63.68) is significantly better than Ligand B (127.08). For CNS targets, TPSA should be <= 90. Ligand A is well within this range, while Ligand B is considerably higher, potentially hindering BBB penetration.

**3. logP:** Ligand A (2.182) is optimal (1-3), while Ligand B (0.87) is slightly low, potentially impacting permeability.

**4. H-Bond Donors:** Ligand A (0) is preferable to Ligand B (2). Fewer HBDs generally improve permeability.

**5. H-Bond Acceptors:** Ligand A (4) is better than Ligand B (8). Lower HBA counts are generally favored for CNS penetration.

**6. QED:** Both ligands have similar QED values (0.765 and 0.699), indicating good drug-likeness.

**7. DILI:** Ligand A (45.715) has a lower DILI risk than Ligand B (74.021), which is preferable.

**8. BBB:** Ligand A (82.009) has a significantly higher BBB percentile than Ligand B (53.742). This is a crucial advantage for a CNS target like DRD2.

**9. Caco-2:** Ligand A (-4.557) and Ligand B (-5.283) both have negative values, indicating poor Caco-2 permeability. This is a concern for oral bioavailability, but less critical for a CNS target where direct delivery or other routes might be considered.

**10. Solubility:** Both ligands have similar, very poor aqueous solubility (-3.073 and -3.047). This could pose formulation challenges.

**11. hERG:** Both ligands have very low hERG inhibition risk (0.359 and 0.024).

**12. Cl_mic:** Ligand A (10.839) has a significantly lower microsomal clearance than Ligand B (37.371), indicating better metabolic stability.

**13. t1/2:** Ligand A (15.862) has a longer in vitro half-life than Ligand B (2.89), which is desirable.

**14. Pgp:** Ligand A (0.388) has lower P-gp efflux liability than Ligand B (0.079), which is favorable for CNS exposure.

**15. Binding Affinity:** Ligand A (-8.8 kcal/mol) has a slightly better binding affinity than Ligand B (-8.3 kcal/mol). While both are strong binders, the 0.5 kcal/mol difference is noticeable.

**Overall Assessment:**

Ligand A is clearly superior. It excels in critical properties for a CNS-targeting GPCR ligand: TPSA, BBB, metabolic stability (Cl_mic, t1/2), Pgp efflux, and has a slightly better binding affinity. While both have poor solubility and Caco-2 permeability, these are less critical for a CNS target. Ligand A also exhibits a lower DILI risk.



Output:
1
2025-04-17 03:56:45,668 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (345.407 and 347.375 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (117.59) is better than Ligand B (124.52). Both are below the 140 A^2 threshold for oral absorption, and closer to the desirable <90 A^2 for CNS targets.

**3. logP:** Ligand B (-0.422) is slightly outside the optimal 1-3 range, being somewhat hydrophilic. Ligand A (0.19) is also on the lower side, but closer to the range. This is a slight advantage for A.

**4. H-Bond Donors:** Both ligands have 3 HBD, which is within the acceptable limit of <=5.

**5. H-Bond Acceptors:** Both ligands have 6 HBA, which is within the acceptable limit of <=10.

**6. QED:** Ligand A (0.631) has a better QED score than Ligand B (0.454), indicating a more drug-like profile.

**7. DILI:** Both ligands have DILI risk around the 50-60 percentile, suggesting moderate risk. Ligand B (59.519) is slightly higher than Ligand A (54.75), making A slightly preferable.

**8. BBB:** Ligand B (53.742) has a better BBB penetration percentile than Ligand A (43.117). This is a significant advantage for B, given DRD2 is a CNS target.

**9. Caco-2 Permeability:** Ligand A (-5.715) has significantly worse Caco-2 permeability than Ligand B (-6.015). Both are negative, indicating poor permeability, but A is slightly better.

**10. Aqueous Solubility:** Ligand A (-1.881) has slightly better aqueous solubility than Ligand B (-1.185).

**11. hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.08 and 0.022).

**12. Microsomal Clearance:** Ligand A (-16.471) has significantly lower (better) microsomal clearance than Ligand B (-5.876), indicating better metabolic stability.

**13. In vitro Half-Life:** Ligand B (16.773) has a much longer in vitro half-life than Ligand A (7.29). This is a significant advantage for B.

**14. P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.018 and 0.003).

**15. Binding Affinity:** Both ligands have excellent binding affinities (-9.2 and -8.5 kcal/mol). Ligand A is 0.7 kcal/mol better, which is a substantial advantage.

**Overall Assessment:**

While Ligand B has a better BBB and longer half-life, Ligand A has a better QED, lower DILI, better metabolic stability (lower Cl_mic), and, crucially, a significantly stronger binding affinity. For a GPCR target like DRD2, binding affinity is paramount. The 0.7 kcal/mol difference in affinity is likely to outweigh the slightly lower BBB penetration of Ligand A, especially considering the other favorable properties. The slightly better solubility and permeability of A also contribute to its advantage.

Output:
0
2025-04-17 03:56:45,669 - INFO - Reasoning:

Let's analyze Ligand A and Ligand B against the provided guidelines, prioritizing GPCR-specific properties (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (359.312 and 353.467 Da) fall within the ideal 200-500 Da range.

**TPSA:** Both ligands (106.85 and 107.4) are slightly above the optimal <90 for CNS targets, but still reasonable.

**logP:** Ligand A (1.3) is within the optimal range, while Ligand B (2.779) is approaching the upper limit.

**H-Bond Donors/Acceptors:** Ligand A has 2 HBD and 7 HBA, while Ligand B has 1 HBD and 4 HBA. Both are within acceptable limits.

**QED:** Ligand A (0.722) has a significantly better QED score than Ligand B (0.37), indicating a more drug-like profile.

**DILI:** Ligand A (72.043) has a higher DILI risk than Ligand B (21.442), which is a negative for Ligand A.

**BBB:** Ligand A (83.715) has a much better BBB penetration score than Ligand B (65.529). This is a *critical* advantage for a CNS target like DRD2.

**Caco-2 Permeability:** Ligand A (-5.183) has worse Caco-2 permeability than Ligand B (-4.513).

**Aqueous Solubility:** Ligand A (-2.19) has worse aqueous solubility than Ligand B (-1.202).

**hERG:** Both ligands have very low hERG inhibition risk (0.115 and 0.235 respectively).

**Microsomal Clearance:** Ligand A (26.632) has significantly lower microsomal clearance than Ligand B (50.203), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (-10.423) has a longer in vitro half-life than Ligand B (13.341).

**P-gp Efflux:** Ligand A (0.124) has lower P-gp efflux liability than Ligand B (0.027), which is beneficial for CNS penetration.

**Binding Affinity:** Ligand A (-8.2 kcal/mol) has a significantly stronger binding affinity than Ligand B (-6.1 kcal/mol). This is a substantial advantage, potentially outweighing some of the ADME drawbacks.

**Overall Assessment:**

Ligand A is the stronger candidate. While it has a higher DILI risk and slightly worse solubility and Caco-2 permeability, its *significantly* better BBB penetration, metabolic stability (lower Cl_mic, longer t1/2), lower P-gp efflux, and *much* stronger binding affinity outweigh these concerns. The strong affinity is particularly important for GPCRs, and the improved CNS penetration properties are crucial for a DRD2 target. Ligand B's lower DILI is good, but the weaker binding and poorer CNS properties are more detrimental.

Output:
1
2025-04-17 03:56:45,669 - INFO - Batch 71 complete. Total preferences: 1136
2025-04-17 03:56:45,669 - INFO - Processing batch 72/512...
2025-04-17 03:57:26,426 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (350.503 and 347.463 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (49.85) is significantly better than Ligand B (99.77). For CNS targets, TPSA should be <=90, and A is comfortably within this range, while B is pushing the limit.

**logP:** Ligand A (2.831) is optimal (1-3), while Ligand B (1.742) is at the lower end, potentially impacting permeability.

**H-Bond Donors/Acceptors:** Ligand A (0 HBD, 3 HBA) is preferable to Ligand B (3 HBD, 4 HBA). Lower values generally improve permeability.

**QED:** Ligand A (0.766) has a better QED score than Ligand B (0.561), indicating a more drug-like profile.

**DILI:** Ligand A (13.3) has a much lower DILI risk than Ligand B (22.8), which is a significant advantage.

**BBB:** Ligand A (89.531) has a substantially better BBB penetration percentile than Ligand B (64.017).  This is *critical* for a CNS target like DRD2.

**Caco-2 Permeability:** Ligand A (-4.226) has a more negative Caco-2 value than Ligand B (-5.417), which suggests better permeability.

**Aqueous Solubility:** Both ligands have similar, very poor aqueous solubility (-2.404 and -2.38). This could be a formulation challenge for both.

**hERG:** Both ligands have very low hERG inhibition liability (0.482 and 0.046), which is excellent.

**Microsomal Clearance:** Ligand A (67.885) has a higher (worse) microsomal clearance than Ligand B (27.571), meaning it's metabolized more quickly.

**In vitro Half-Life:** Ligand B (-19.949) has a negative half-life, which is unusual and likely indicates very rapid degradation. Ligand A (0.313) has a very short half-life, but it is still positive.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.113 and 0.008), which is favorable for CNS penetration.

**Binding Affinity:** Ligand B (-8.2 kcal/mol) has a slightly better binding affinity than Ligand A (-6.9 kcal/mol). However, the difference is less than 1.5 kcal/mol, and can be outweighed by other factors.

**Overall Assessment:**

Ligand A is the stronger candidate. While Ligand B has slightly better binding affinity, Ligand A excels in crucial ADME properties for a CNS-targeting GPCR, particularly BBB penetration, TPSA, DILI risk, and QED. The poor solubility is a concern for both, but the other advantages of Ligand A make it more likely to succeed as a drug candidate. The very short half-life and negative in vitro half-life of Ligand B are also concerning.

Output:
1
2025-04-17 03:57:26,426 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B based on the provided guidelines, prioritizing GPCR-specific properties (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (366.334 and 383.627 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (39.68) is better than Ligand B (38.13), both are below the 90 A^2 threshold for CNS targets.

**logP:** Ligand A (2.928) is within the optimal 1-3 range, while Ligand B (4.157) is slightly higher. While still acceptable, higher logP can sometimes lead to off-target effects.

**H-Bond Donors/Acceptors:** Ligand A (0 HBD, 3 HBA) and Ligand B (0 HBD, 5 HBA) both have reasonable numbers of H-bond donors and acceptors.

**QED:** Ligand A (0.773) has a better QED score than Ligand B (0.608), indicating a more drug-like profile.

**DILI:** Ligand A (38.93) has a higher DILI risk than Ligand B (14.23). This is a significant drawback for Ligand A.

**BBB:** Both ligands have good BBB penetration (Ligand A: 88.445, Ligand B: 83.133), exceeding the >70 percentile threshold for CNS targets. Ligand A is slightly better.

**Caco-2 Permeability:** Both have negative Caco-2 values which is unusual and suggests poor permeability.

**Aqueous Solubility:** Both ligands have negative solubility values which is also unusual and suggests poor solubility.

**hERG:** Both ligands have low hERG inhibition liability (Ligand A: 0.485, Ligand B: 0.556).

**Microsomal Clearance:** Ligand A (29.915 mL/min/kg) has significantly lower microsomal clearance than Ligand B (110.074 mL/min/kg), indicating better metabolic stability.

**In vitro Half-Life:** Ligand A (11.297 hours) has a shorter half-life than Ligand B (21.498 hours).

**P-gp Efflux:** Ligand A (0.064) has much lower P-gp efflux liability than Ligand B (0.421), which is highly desirable for CNS penetration.

**Binding Affinity:** Ligand A (-7.9 kcal/mol) has a significantly stronger binding affinity than Ligand B (-6.0 kcal/mol). This is a substantial advantage, potentially outweighing some of the ADME drawbacks.

**Overall Assessment:**

Ligand A excels in binding affinity, P-gp efflux, and metabolic stability. However, it has a higher DILI risk and a shorter half-life. Ligand B has a better DILI profile and longer half-life, but weaker binding affinity and higher P-gp efflux. Given the importance of strong binding for GPCRs, and the relatively good BBB penetration of both, the superior affinity of Ligand A is the deciding factor. The lower P-gp efflux is also a significant advantage for CNS targets. While the DILI risk is a concern, it might be mitigated through structural modifications during lead optimization.

Output:
1
2025-04-17 03:57:26,426 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (378.539 and 364.515 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (112.81) is better than Ligand B (74.41). Both are below the 90 A^2 threshold desirable for CNS targets, but Ligand A is slightly higher and could present a minor permeability issue.

**logP:** Ligand B (2.846) is optimal (1-3), while Ligand A (-0.148) is too low, potentially hindering membrane permeability. This is a significant drawback for A.

**H-Bond Donors/Acceptors:** Both have 2 HBDs, which is good. Ligand A has 5 HBAs, and Ligand B has 7. Both are acceptable (<=10).

**QED:** Both ligands have good QED values (0.549 and 0.667, respectively), indicating drug-like properties.

**DILI:** Ligand A (25.204) has a lower DILI risk than Ligand B (19.93), which is positive.

**BBB:** Ligand A (48.972) has a better BBB penetration percentile than Ligand B (32.92). While neither is above the ideal >70, A is significantly better.

**Caco-2 Permeability:** Both have negative Caco-2 values (-5.522 and -5.406). These are unusual and suggest poor permeability.

**Aqueous Solubility:** Both have negative solubility values (-0.511 and -2.858). These are also unusual and suggest poor solubility.

**hERG:** Both ligands have low hERG inhibition liability (0.089 and 0.632), which is good.

**Microsomal Clearance:** Ligand A (41.524) has slightly higher microsomal clearance than Ligand B (36.242), suggesting lower metabolic stability.

**In vitro Half-Life:** Ligand B (23.716) has a better in vitro half-life than Ligand A (-36.317).

**P-gp Efflux:** Both have very low P-gp efflux liability (0.002 and 0.233), which is excellent for CNS penetration.

**Binding Affinity:** Ligand B (-6.9 kcal/mol) has a slightly better binding affinity than Ligand A (-6.4 kcal/mol). While the difference is not huge, it is still a factor.

**Overall Assessment:**

Despite Ligand A's better BBB and lower DILI, Ligand B is the more promising candidate. The primary reason is Ligand A's very low logP, which will severely limit its ability to cross cell membranes, even with good BBB prediction. The slightly better affinity of Ligand B, combined with its acceptable logP, makes it more likely to reach the target in the CNS. The negative Caco-2 and solubility values are concerning for both, but can be addressed with formulation strategies.

Output:
1
2025-04-17 03:57:26,427 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (341.455 and 344.459 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (62.3) is significantly better than Ligand B (78.09). For CNS targets, we want TPSA <= 90, and A is comfortably within this range, while B is approaching the upper limit.

**3. logP:** Both ligands have good logP values (3.348 and 2.409), falling within the optimal 1-3 range.

**4. H-Bond Donors:** Ligand A (1) is preferable to Ligand B (2). Lower HBD generally improves permeability.

**5. H-Bond Acceptors:** Both ligands have the same number of HBA (3), which is acceptable (<=10).

**6. QED:** Both ligands have good QED values (0.774 and 0.884), indicating good drug-like properties.

**7. DILI:** Ligand A (21.753) has a much lower DILI risk than Ligand B (38.852). Both are below the 40 threshold, but A is significantly better.

**8. BBB:** This is a crucial parameter for CNS targets. Ligand A (83.831) has a much higher BBB penetration percentile than Ligand B (61.031). A value >70 is desirable, and A is closer to that target.

**9. Caco-2 Permeability:** Ligand A (-4.799) has better Caco-2 permeability than Ligand B (-5.28), although both are negative values, which is unusual.

**10. Aqueous Solubility:** Both ligands have very poor aqueous solubility (-3.233 and -3.198). This is a concern, but can potentially be addressed with formulation strategies.

**11. hERG Inhibition:** Both ligands show low hERG inhibition liability (0.415 and 0.377), which is good.

**12. Microsomal Clearance:** Ligand B (20.564) has lower microsomal clearance than Ligand A (41.972), suggesting better metabolic stability.

**13. In vitro Half-Life:** Ligand B (-18.644) has a longer in vitro half-life than Ligand A (-10.023). This is a positive attribute.

**14. P-gp Efflux:** Ligand B (0.17) has lower P-gp efflux than Ligand A (0.093), which is favorable for CNS penetration.

**15. Binding Affinity:** Ligand A (-9.1 kcal/mol) has a significantly stronger binding affinity than Ligand B (-0.0 kcal/mol). This is a substantial advantage. The difference in affinity is >1.5 kcal/mol, and can outweigh minor ADME drawbacks.

**Overall Assessment:**

Ligand A is the superior candidate. While Ligand B has better metabolic stability and P-gp efflux, Ligand A excels in critical areas for a CNS-targeting GPCR ligand: TPSA, BBB penetration, and, most importantly, binding affinity. The significantly stronger binding affinity of Ligand A (-9.1 vs -0.0 kcal/mol) is a decisive factor. The lower DILI risk is also a significant benefit. The poor solubility of both compounds is a concern, but is a formulation issue that can be addressed.

Output:
1
2025-04-17 03:57:26,427 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 drug candidates, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (351.535 and 356.482 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (52.65) is significantly better than Ligand B (69.64). For CNS targets, we want TPSA <= 90, and A is comfortably within that range, while B is approaching the upper limit.

**logP:** Both ligands have good logP values (2.815 and 2.707), falling within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A (HBD=1, HBA=3) and Ligand B (HBD=2, HBA=3) both have acceptable numbers of hydrogen bond donors and acceptors, well below the thresholds of 5 and 10 respectively.

**QED:** Ligand B (0.702) has a better QED score than Ligand A (0.486), indicating a more drug-like profile.

**DILI:** Ligand A (14.618) has a significantly lower DILI risk than Ligand B (17.138). Both are below the concerning threshold of 60, but A is preferable.

**BBB:** Ligand B (91.935) has a much higher BBB penetration percentile than Ligand A (69.678). This is a *critical* advantage for a CNS target like DRD2.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.704 and -4.814), which is unusual and suggests poor permeability. This is a potential red flag for both.

**Aqueous Solubility:** Both ligands have very poor aqueous solubility (-2.748 and -2.933). This is a significant drawback.

**hERG Inhibition:** Both ligands show low hERG inhibition liability (0.438 and 0.486), which is good.

**Microsomal Clearance:** Ligand B (27.772) has a lower microsomal clearance than Ligand A (46.091), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (10.313 hours) has a longer in vitro half-life than Ligand B (-36.716 hours). The negative value for B is concerning and likely an error or outlier.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.108 and 0.117), which is favorable for CNS penetration.

**Binding Affinity:** Ligand B (-8.5 kcal/mol) has a significantly stronger binding affinity than Ligand A (-6.6 kcal/mol). This is a substantial advantage (a >1.5 kcal/mol difference).

**Overall Assessment:**

While Ligand A has better TPSA and DILI, the superior BBB penetration and *much* stronger binding affinity of Ligand B are decisive. The improved QED and lower clearance of Ligand B are also beneficial. The poor solubility and Caco-2 permeability are concerns for both, but can potentially be addressed with formulation strategies. The negative half-life for Ligand B is a major concern, but the affinity difference is so large that it is likely worth investigating further. Given the GPCR-specific priorities, the strong binding affinity and excellent BBB penetration of Ligand B outweigh its other drawbacks.

Output:
1
2025-04-17 03:57:26,427 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (365.817 and 355.471 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (100.44) is slightly above the optimal <90 for CNS targets, but acceptable. Ligand B (82.62) is well within the desired range.

**logP:** Both ligands have good logP values (1.392 and 3.014), falling within the 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A has 3 HBD and 4 HBA, which is good. Ligand B has 2 HBD and 7 HBA, also acceptable.

**QED:** Both ligands have similar QED values (0.702 and 0.749), indicating good drug-likeness.

**DILI:** Ligand A (64.288) has a moderate DILI risk, while Ligand B (84.451) has a higher risk.

**BBB:** Ligand B (68.786) has a significantly better BBB penetration score than Ligand A (46.801). This is a critical factor for a CNS target like DRD2.

**Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and suggests poor permeability. However, the scale is not specified, so it's difficult to interpret.

**Aqueous Solubility:** Both ligands have negative solubility values, indicating poor aqueous solubility. This could be a formulation challenge.

**hERG:** Ligand A (0.091) has a very low hERG risk, while Ligand B (0.737) has a moderate risk.

**Microsomal Clearance:** Ligand A (-29.248) has a much lower (better) microsomal clearance than Ligand B (39.303), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (19.751) has a longer half-life than Ligand B (0.981).

**P-gp Efflux:** Ligand A (0.071) has a lower P-gp efflux liability than Ligand B (0.108), which is favorable for CNS penetration.

**Binding Affinity:** Ligand B (-9.9 kcal/mol) has a significantly stronger binding affinity than Ligand A (0.0 kcal/mol). This is a substantial advantage.

**Overall Assessment:**

While Ligand A has better metabolic stability, lower DILI, lower hERG risk, and lower P-gp efflux, the significantly stronger binding affinity of Ligand B (-9.9 vs 0.0 kcal/mol) and its superior BBB penetration (68.79 vs 46.80) outweigh the drawbacks of higher DILI, moderate hERG risk, and faster clearance. The affinity difference is substantial enough to potentially overcome ADME liabilities through further optimization. The BBB penetration is crucial for CNS targets.

Output:
1
2025-04-17 03:57:26,427 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B based on the provided guidelines, prioritizing GPCR-specific properties (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (393.531 Da) is slightly higher than Ligand B (349.431 Da), but both are acceptable.

**TPSA:** Ligand A (117.85) is slightly above the optimal <90 for CNS targets, while Ligand B (96.87) is closer to the ideal range. This favors Ligand B.

**logP:** Ligand A (-0.584) is a bit low, potentially hindering permeation. Ligand B (0.459) is better, falling within the 0-3 range, but still on the lower side.

**H-Bond Donors/Acceptors:** Ligand A (HBD=1, HBA=5) is better than Ligand B (HBD=3, HBA=4) in terms of these parameters, being closer to the ideal values.

**QED:** Both ligands have good QED scores (A: 0.621, B: 0.736), indicating good drug-like properties. Ligand B is slightly better.

**DILI:** Both ligands have low DILI risk (A: 31.718, B: 30.632), which is favorable.

**BBB:** This is a critical parameter for CNS targets. Ligand A has a BBB percentile of 58.511, while Ligand B has 49.748. Ligand A is significantly better in BBB penetration.

**Caco-2 Permeability:** Both have negative values (-5.501 and -4.957), which is unusual and suggests poor permeability. However, these values are on a scale where higher is better, so we can interpret these as very low permeability.

**Aqueous Solubility:** Both have negative solubility values (-1.894 and -2.166), indicating poor solubility.

**hERG Inhibition:** Both ligands show low hERG inhibition liability (A: 0.125, B: 0.272), which is good.

**Microsomal Clearance:** Ligand A (-1.033) has a lower (better) microsomal clearance than Ligand B (0.638), indicating better metabolic stability.

**In vitro Half-Life:** Ligand A (-17.072) has a lower half-life than Ligand B (-14.883), which is less desirable.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (A: 0.02, B: 0.014).

**Binding Affinity:** Both ligands have similar strong binding affinities (A: -7.3 kcal/mol, B: -7.1 kcal/mol). The difference is less than 1.5 kcal/mol, so it's not a major deciding factor.

**Overall Assessment:**

Ligand A excels in BBB penetration and metabolic stability (lower Cl_mic), while Ligand B has a slightly better TPSA and QED. However, the significantly better BBB score for Ligand A is crucial for a CNS-targeting drug. While both have poor solubility and Caco-2 permeability, the improved CNS exposure potential of Ligand A outweighs the minor advantages of Ligand B.

Output:
1
2025-04-17 03:57:26,428 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (348.443 and 347.459 Da) fall comfortably within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (71.78) is slightly above the preferred <90 for CNS targets, but still reasonable. Ligand B (62.74) is excellent, well below 90.

**3. logP:** Both ligands have good logP values (2.512 and 1.89), falling within the optimal 1-3 range. Ligand B is slightly better, being closer to 1.

**4. H-Bond Donors:** Ligand A has 1 HBD, which is acceptable. Ligand B has 0, which is also good.

**5. H-Bond Acceptors:** Both ligands have 4 HBAs, which is within the acceptable limit of <=10.

**6. QED:** Ligand A (0.911) has a superior QED score compared to Ligand B (0.756), indicating better overall drug-likeness.

**7. DILI:** Ligand A (44.591) has a slightly higher DILI risk than Ligand B (27.142), but both are below the concerning threshold of 60.

**8. BBB:** Both ligands exhibit excellent BBB penetration (70.648 and 76.541), exceeding the desirable >70 threshold for CNS targets. Ligand B is slightly better.

**9. Caco-2:** Both have negative Caco-2 values, which is unusual. Assuming these are percentile scores, this indicates poor permeability.

**10. Solubility:** Both ligands have negative solubility values, which is also unusual. Assuming these are percentile scores, this indicates poor solubility.

**11. hERG:** Both ligands have low hERG inhibition liability (0.225 and 0.296), which is favorable.

**12. Cl_mic:** Ligand A (24.673) has a lower microsomal clearance than Ligand B (55.372), suggesting better metabolic stability.

**13. t1/2:** Ligand A (28.098) has a longer in vitro half-life than Ligand B (20.613), which is desirable.

**14. Pgp:** Ligand A (0.278) has lower P-gp efflux liability than Ligand B (0.06), indicating better potential for CNS exposure.

**15. Binding Affinity:** Ligand A (-8.5 kcal/mol) has a significantly stronger binding affinity than Ligand B (-0.0 kcal/mol). This is a crucial advantage.

**Overall Assessment:**

Ligand A is the stronger candidate. While Ligand B has slightly better TPSA and BBB, the significantly superior binding affinity of Ligand A (-8.5 vs -0.0 kcal/mol) outweighs these minor differences. Furthermore, Ligand A demonstrates better metabolic stability (lower Cl_mic, longer t1/2) and lower P-gp efflux. The QED score is also higher for Ligand A. The unusual negative values for Caco-2 and solubility are concerning for both, but the strong binding affinity of A makes it more likely to overcome these issues with further optimization.

Output:
1
2025-04-17 03:57:26,428 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (350.423 and 347.419 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (112.85) is slightly above the preferred <90 for CNS targets, but not drastically so. Ligand B (90.56) is excellent, falling right within the desired range.

**logP:** Ligand A (0.345) is quite low, potentially hindering membrane permeability. Ligand B (-0.23) is also low, but marginally better than A. Both are below the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A has 1 HBD and 5 HBA, which is acceptable. Ligand B has 2 HBD and 5 HBA, also acceptable.

**QED:** Ligand B (0.788) has a significantly better QED score than Ligand A (0.438), indicating a more drug-like profile.

**DILI:** Ligand A (16.673) has a much lower DILI risk than Ligand B (35.285), which is a significant advantage.

**BBB:** Ligand B (45.444) has a better BBB percentile than Ligand A (27.84), which is crucial for a CNS target like DRD2.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values, which is unusual and suggests poor permeability.

**Aqueous Solubility:** Both ligands have negative solubility values, indicating poor solubility.

**hERG:** Both ligands show low hERG inhibition liability (0.236 and 0.273), which is good.

**Microsomal Clearance:** Ligand A (-19.318) shows significantly lower (better) microsomal clearance than Ligand B (-12.688), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (18.49 hours) has a much longer half-life than Ligand B (-12.198 hours), which is a major advantage.

**P-gp Efflux:** Both ligands show very low P-gp efflux liability (0.008 and 0.012), which is favorable for CNS penetration.

**Binding Affinity:** Ligand B (-8.1 kcal/mol) has a slightly better binding affinity than Ligand A (-7.0 kcal/mol). The difference is 1.1 kcal/mol, which is substantial.

**Overall Assessment:**

Ligand B has a better BBB, QED, and binding affinity. However, Ligand A has a much lower DILI risk, significantly better metabolic stability (lower Cl_mic), and a longer half-life. The low logP values for both are concerning, but the superior binding affinity of Ligand B, coupled with the better BBB, makes it more promising. The difference in binding affinity is large enough to potentially overcome the slightly higher DILI risk and worse metabolic stability.

Output:
1
2025-04-17 03:57:26,428 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (363.37 and 356.423 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (105.32) is better than Ligand B (134.82). For CNS targets, we want TPSA <= 90, so Ligand A is closer to this threshold.

**logP:** Ligand A (2.928) is optimal (1-3). Ligand B (-0.45) is significantly below this, potentially hindering permeation.

**H-Bond Donors/Acceptors:** Ligand A (HBD=2, HBA=6) is preferable to Ligand B (HBD=4, HBA=7) as it has fewer potential issues with permeability. Both are within acceptable limits.

**QED:** Ligand A (0.738) is better than Ligand B (0.49), indicating a more drug-like profile.

**DILI:** Ligand A (98.371) has a higher DILI risk than Ligand B (15.2). This is a significant drawback for Ligand A.

**BBB:** Ligand A (21.946) has a very poor BBB penetration percentile, while Ligand B (29.12) is also low, but better than A. Both are far from the desirable >70 for CNS targets.

**Caco-2 Permeability:** Both have negative Caco-2 values (-5.09 and -5.649), which is unusual and suggests poor permeability.

**Aqueous Solubility:** Both have negative solubility values (-4.144 and -1.192), which is also unusual and concerning.

**hERG:** Ligand A (0.634) has a slightly higher hERG risk than Ligand B (0.038), but both are relatively low.

**Microsomal Clearance:** Ligand B (-11.859) has a lower (better) microsomal clearance than Ligand A (31.098), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand B (3.962) has a better half-life than Ligand A (-13.296).

**P-gp Efflux:** Ligand A (0.232) has lower P-gp efflux than Ligand B (0.003), which is favorable for CNS exposure.

**Binding Affinity:** Ligand A (-10.5 kcal/mol) has a significantly stronger binding affinity than Ligand B (-6.9 kcal/mol). This is a substantial advantage.

**Overall Assessment:**

While Ligand A has a much better binding affinity, its poor BBB penetration, high DILI risk, and negative solubility/permeability are major concerns. Ligand B has better ADME properties (lower DILI, better metabolic stability, better half-life, lower P-gp efflux), but its logP is quite low and its affinity is significantly weaker.

Given the GPCR-specific priorities, BBB penetration is crucial for CNS targets. However, the large difference in binding affinity (-10.5 vs -6.9 kcal/mol) is a significant factor. A 3.6 kcal/mol difference is substantial and could potentially overcome some of the ADME liabilities, *if* formulation strategies can address the solubility and permeability issues. The DILI risk for Ligand A is also a major concern.

Considering all factors, and prioritizing affinity, I lean towards Ligand A, but with a strong caveat that significant medicinal chemistry work would be needed to address its ADME shortcomings.

Output:
1
2025-04-17 03:57:26,428 - INFO - Reasoning:

Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (364.515 and 388.515 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (86.88) is excellent, well below the 90 A^2 threshold for CNS targets. Ligand B (121.18) is still reasonable, but higher and less favorable for CNS penetration.

**3. logP:** Both ligands have good logP values (2.445 and 1.655), within the optimal 1-3 range.

**4. H-Bond Donors:** Ligand A (3) and Ligand B (2) are both within the acceptable limit of <=5.

**5. H-Bond Acceptors:** Ligand A (4) and Ligand B (7) are both within the acceptable limit of <=10.

**6. QED:** Both ligands have good QED scores (0.595 and 0.629), indicating drug-like properties.

**7. DILI:** Ligand A (29.624) has a significantly lower DILI risk than Ligand B (58.395), which is a substantial advantage.

**8. BBB:** Ligand A (53.781) has a much better BBB percentile than Ligand B (38.038). This is *critical* for a CNS target like DRD2.

**9. Caco-2:** Both have negative Caco-2 values, which is unusual. Assuming these are logP values, they are similar and suggest moderate permeability.

**10. Solubility:** Both have negative solubility values, which is unusual. Assuming these are logS values, they are similar and suggest moderate solubility.

**11. hERG:** Both ligands have low hERG risk (0.33 and 0.284).

**12. Cl_mic:** Ligand A (24.474) has a lower microsomal clearance than Ligand B (41.793), suggesting better metabolic stability.

**13. t1/2:** Ligand A (2.696) has a shorter in vitro half-life than Ligand B (12.488). This is a drawback for Ligand A.

**14. Pgp:** Both have very low Pgp efflux liability (0.064 and 0.105).

**15. Binding Affinity:** Ligand A (-7.6 kcal/mol) has a slightly better binding affinity than Ligand B (-7.1 kcal/mol). While the difference is less than the 1.5 kcal/mol threshold to override significant ADME issues, it's still a positive factor.

**Overall Assessment:**

Ligand A is significantly better due to its superior BBB penetration, lower DILI risk, and lower microsomal clearance. While Ligand B has a longer half-life, the CNS target demands high BBB penetration, and Ligand A clearly excels in this area. The slightly better binding affinity of Ligand A further supports its selection.

Output:
1
2025-04-17 03:57:26,428 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (343.431 and 346.387 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (72.28) is significantly better than Ligand B (93.65). For CNS targets, we want TPSA <= 90, so Ligand A is preferable.

**logP:** Ligand A (2.914) is optimal (1-3), while Ligand B (0.383) is quite low, potentially hindering membrane permeability. This favors Ligand A.

**H-Bond Donors:** Both have 1 HBD, which is acceptable.

**H-Bond Acceptors:** Ligand A has 5 HBA, and Ligand B has 6. Both are within the acceptable limit of <= 10.

**QED:** Both ligands have good QED scores (0.906 and 0.829, respectively), indicating good drug-like properties.

**DILI:** Ligand A (49.787) has a slightly better DILI score than Ligand B (57.813), but both are reasonably low risk.

**BBB:** Both ligands have similar BBB penetration (60.76% and 62.117%). While neither exceeds the desirable >70% for CNS targets, they are comparable.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.707 and -4.581), which is unusual and suggests poor permeability. However, these values are on a logarithmic scale, so small differences can be significant.

**Aqueous Solubility:** Both ligands have negative solubility values (-2.189 and -1.967), indicating poor aqueous solubility.

**hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.125 and 0.103).

**Microsomal Clearance:** Ligand A (28.963) has a higher microsomal clearance than Ligand B (12.417), indicating faster metabolism and potentially lower *in vivo* exposure. This favors Ligand B.

**In vitro Half-Life:** Ligand B (-0.412) has a slightly longer in vitro half-life than Ligand A (-12.898), which is desirable.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.013 and 0.005), which is good for CNS penetration.

**Binding Affinity:** Ligand B (-8.5 kcal/mol) has a slightly better binding affinity than Ligand A (-8.2 kcal/mol). This difference of 0.3 kcal/mol is potentially significant, and could outweigh some of the ADME drawbacks of Ligand B.

**Overall Assessment:**

Considering the GPCR-specific priorities, Ligand A has a better TPSA and logP, which are crucial for CNS penetration. However, Ligand B has a slightly better binding affinity, lower microsomal clearance, and a slightly longer half-life. The low logP of Ligand B is a significant concern, potentially hindering its ability to cross the blood-brain barrier despite the acceptable BBB percentile. The slightly better affinity of Ligand B is not enough to overcome the permeability concerns.

Output:
0
2025-04-17 03:57:26,429 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (346.471 and 350.369 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (58.64) is significantly better than Ligand B (83.98). For CNS targets, we want TPSA <= 90, and A is comfortably within that range, while B is approaching the upper limit.

**3. logP:** Both ligands have good logP values (2.289 and 2.157), falling within the optimal 1-3 range.

**4. H-Bond Donors:** Ligand A (1) is preferable to Ligand B (2). Lower HBD generally improves permeability.

**5. H-Bond Acceptors:** Ligand A (3) is preferable to Ligand B (4). Lower HBA generally improves permeability.

**6. QED:** Ligand B (0.75) has a better QED score than Ligand A (0.437), indicating a more drug-like profile overall.

**7. DILI:** Ligand A (23.459) has a much lower DILI risk than Ligand B (54.052). This is a significant advantage for A.

**8. BBB:** Both ligands have good BBB penetration (Ligand A: 75.107, Ligand B: 80.962), exceeding the >70 threshold for CNS targets. Ligand B is slightly better.

**9. Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and potentially problematic. However, the absolute value is smaller for Ligand A (-5.058 vs -4.808), suggesting slightly better permeability.

**10. Aqueous Solubility:** Both have negative solubility values, which is also unusual and problematic. Ligand B (-3.316) is slightly worse than Ligand A (-1.973).

**11. hERG Inhibition:** Both have low hERG inhibition risk (Ligand A: 0.36, Ligand B: 0.689), which is good. Ligand A is better.

**12. Microsomal Clearance:** Ligand A (39.88) has lower microsomal clearance than Ligand B (45.26), indicating better metabolic stability.

**13. In vitro Half-Life:** Ligand B (4.533) has a significantly longer half-life than Ligand A (0.974). This is a substantial advantage for B.

**14. P-gp Efflux:** Ligand A (0.139) has lower P-gp efflux than Ligand B (0.059), indicating better CNS exposure.

**15. Binding Affinity:** Ligand B (-8.8 kcal/mol) has a slightly better binding affinity than Ligand A (-8.1 kcal/mol). While the difference is not huge, it is over the 0.7 kcal/mol threshold.

**Overall Assessment:**

Ligand A excels in TPSA, DILI, hERG, and P-gp efflux, and has slightly better Caco-2 and solubility. Ligand B has a better QED score, BBB penetration, and a significantly longer half-life, and slightly better binding affinity. Given the importance of BBB penetration and affinity for a CNS GPCR target like DRD2, and the substantial half-life advantage of Ligand B, I would favor Ligand B despite the higher DILI risk. The slightly better affinity and half-life of B likely outweigh the drawbacks, especially as the DILI risk is still not excessively high.

Output:
1
2025-04-17 03:57:26,429 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (362.333 and 359.861 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (116.93) is better than Ligand B (64.34). For CNS targets, TPSA should be <=90, so Ligand B is preferable here.

**logP:** Ligand A (1.079) is within the optimal 1-3 range, while Ligand B (4.084) is slightly high. High logP can lead to solubility issues and off-target effects. Ligand A is better.

**H-Bond Donors:** Ligand A (3) is higher than Ligand B (1), but both are acceptable (<=5).

**H-Bond Acceptors:** Both ligands have 6 HBA, which is within the acceptable limit of <=10.

**QED:** Both ligands have similar QED values (0.722 and 0.718), indicating good drug-likeness.

**DILI:** Ligand A (49.321) has a significantly lower DILI risk than Ligand B (77.705). This is a major advantage for Ligand A.

**BBB:** Ligand A (82.435) has a much better BBB penetration percentile than Ligand B (62.699). For a CNS target like DRD2, this is critical.

**Caco-2 Permeability:** Both show poor Caco-2 permeability (-4.786 and -4.702). This suggests potential absorption issues, but is less critical for CNS targets where direct delivery is possible.

**Aqueous Solubility:** Both ligands have very poor aqueous solubility (-2.223 and -4.403). This could be a formulation challenge.

**hERG Inhibition:** Ligand A (0.374) has a lower hERG inhibition liability than Ligand B (0.833), indicating a lower risk of cardiotoxicity.

**Microsomal Clearance:** Ligand A (-11.399) has a lower (better) microsomal clearance than Ligand B (75.657), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (-35.643) has a shorter in vitro half-life than Ligand B (64.847). This is a drawback for Ligand A.

**P-gp Efflux:** Ligand A (0.029) has significantly lower P-gp efflux liability than Ligand B (0.665), which is crucial for CNS penetration.

**Binding Affinity:** Ligand B (-7.8) has a slightly better binding affinity than Ligand A (-8.2). However, the difference is relatively small (0.4 kcal/mol).

**Overall Assessment:**

Ligand A is clearly superior. While Ligand B has slightly better binding affinity, Ligand A excels in critical ADME properties for a CNS drug targeting a GPCR: significantly lower DILI risk, much better BBB penetration, lower P-gp efflux, lower hERG inhibition, and better metabolic stability. The slightly shorter half-life of Ligand A is a concern, but can potentially be addressed through structural modifications. The TPSA is also better for Ligand A. The logP of Ligand A is also more optimal.

Output:
0
2025-04-17 03:57:26,429 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands fall within the ideal range (200-500 Da). Ligand A (342.443 Da) is slightly preferable as it's closer to the lower end, potentially aiding permeability.

**TPSA:** Ligand A (65.54) is significantly better than Ligand B (84.5). For CNS targets, we want TPSA <= 90, and A is comfortably within this range, while B is approaching the upper limit.

**logP:** Both ligands have acceptable logP values (A: 1.518, B: 3.164), falling within the optimal 1-3 range. B is slightly higher, which could potentially lead to off-target effects, but isn't a major concern.

**H-Bond Donors/Acceptors:** Both have reasonable HBD/HBA counts (A: 1/4, B: 2/4), well within the guidelines.

**QED:** Both ligands have acceptable QED values (A: 0.728, B: 0.663), indicating good drug-like properties.

**DILI:** Ligand A (19.659) has a much lower DILI risk than Ligand B (70.958). This is a significant advantage for A.

**BBB:** This is a critical parameter for CNS targets. Ligand A (89.957) has a very good BBB penetration percentile, while Ligand B (42.032) is considerably lower. This is a major advantage for A.

**Caco-2 Permeability:** Both have negative Caco-2 values (-4.945 and -4.809), indicating poor permeability. This is a concern for both, but doesn't necessarily disqualify them, as other factors can compensate.

**Aqueous Solubility:** Both have negative solubility values (-1.24 and -4.139), indicating poor solubility. This is a concern for both, and may require formulation strategies.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (A: 0.276, B: 0.536), which is good.

**Microsomal Clearance:** Ligand A (31.268) has lower microsomal clearance than Ligand B (65.568), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (35.974) has a slightly longer in vitro half-life than Ligand B (28.56), which is preferable.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (A: 0.024, B: 0.241), which is excellent for CNS penetration.

**Binding Affinity:** Ligand B (-8.4 kcal/mol) has a slightly better binding affinity than Ligand A (-7.9 kcal/mol). While a 0.5 kcal/mol difference is noticeable, it's not a massive advantage, especially considering the other factors.

**Overall Assessment:**

Ligand A is significantly better overall. It has a much lower DILI risk, substantially better BBB penetration, lower microsomal clearance, and a slightly longer half-life. While Ligand B has a marginally better binding affinity, the ADME properties of Ligand A are far superior, especially for a CNS target like DRD2. The poor Caco-2 and solubility for both are drawbacks, but can be addressed with formulation. The superior BBB penetration and safety profile of A outweigh the small difference in binding affinity.

Output:
0
2025-04-17 03:57:26,429 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 drug candidates, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (351.403 and 344.455 Da) fall within the ideal range of 200-500 Da.

**TPSA:** Ligand A (106.62) is better than Ligand B (49.85). Both are below the 90 A^2 threshold for CNS targets, but A is closer to the upper limit.

**logP:** Both ligands have good logP values (1.901 and 2.303), falling within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A has 2 HBD and 6 HBA, while Ligand B has 0 HBD and 3 HBA. Both are within acceptable limits (<=5 HBD and <=10 HBA).

**QED:** Ligand A (0.758) has a significantly better QED score than Ligand B (0.437), indicating a more drug-like profile.

**DILI:** Ligand B (44.591) has a lower DILI risk than Ligand A (64.366), which is favorable.

**BBB:** Ligand B (82.202) has a substantially better BBB penetration score than Ligand A (64.87). This is a *critical* advantage for a CNS target like DRD2.

**Caco-2 Permeability:** Ligand A (-4.528) has slightly better Caco-2 permeability than Ligand B (-4.494), but the difference is minimal.

**Aqueous Solubility:** Ligand A (-3.467) has slightly better solubility than Ligand B (-2.557).

**hERG:** Both ligands have very low hERG inhibition liability (0.29 and 0.168), which is excellent.

**Microsomal Clearance:** Ligand B (65.258) has lower microsomal clearance than Ligand A (81.736), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (-17.441) has a longer in vitro half-life than Ligand B (-11.803), which is generally preferred.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.036 and 0.138), which is favorable for CNS penetration.

**Binding Affinity:** Both ligands have the same binding affinity (-8.0 kcal/mol), which is excellent and strong.

**Overall Assessment:**

While Ligand A has a slightly better QED, solubility, and half-life, Ligand B significantly outperforms it in BBB penetration (82.202 vs 64.87) and has a lower DILI risk and better metabolic stability. For a CNS target like DRD2, BBB penetration is paramount. The difference in BBB is substantial enough to outweigh the minor advantages of Ligand A. The equal binding affinity removes that as a differentiating factor.

Output:
1
2025-04-17 03:57:26,430 - INFO - Batch 72 complete. Total preferences: 1152
2025-04-17 03:57:26,430 - INFO - Processing batch 73/512...
2025-04-17 03:58:08,476 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (351.447 and 365.543 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (78.95) is better than Ligand B (45.67). For CNS targets, we want TPSA <= 90, both are well within this range, but A is slightly higher.

**logP:** Ligand A (0.241) is quite low, potentially hindering permeability. Ligand B (3.017) is within the optimal 1-3 range. This is a significant advantage for Ligand B.

**H-Bond Donors:** Ligand A (1) is good. Ligand B (0) is also good.

**H-Bond Acceptors:** Ligand A (4) is good. Ligand B (5) is also acceptable.

**QED:** Both ligands have similar QED values (0.787 and 0.777), indicating good drug-likeness.

**DILI:** Ligand A (29.236) has a lower DILI risk than Ligand B (15.2), which is preferable.

**BBB:** Ligand B (88.29) has a significantly higher BBB penetration percentile than Ligand A (68.748). This is a crucial advantage for a CNS target like DRD2.

**Caco-2 Permeability:** Ligand A (-4.57) and Ligand B (-4.657) both have negative Caco-2 permeability values, which is not ideal. However, the scale is not specified, so it's hard to interpret.

**Aqueous Solubility:** Both ligands have very poor aqueous solubility (-2.271 and -2.99). This could be a formulation challenge.

**hERG Inhibition:** Ligand A (0.106) has a lower hERG inhibition liability than Ligand B (0.601), which is better.

**Microsomal Clearance:** Ligand B (76.663) has a higher microsomal clearance than Ligand A (17.126), suggesting faster metabolism and lower metabolic stability.

**In vitro Half-Life:** Ligand A (10.591) has a longer in vitro half-life than Ligand B (-0.049), which is preferable.

**P-gp Efflux:** Ligand A (0.021) has much lower P-gp efflux liability than Ligand B (0.17), which is a significant advantage for CNS penetration.

**Binding Affinity:** Ligand A (-8.0) has a slightly better binding affinity than Ligand B (-6.2). A difference of 1.8 kcal/mol is substantial.

**Overall Assessment:**

Ligand B excels in BBB penetration and has an acceptable logP. However, it suffers from higher DILI risk, higher P-gp efflux, faster metabolism (higher Cl_mic), and lower in vitro half-life. Ligand A has better metabolic stability, lower P-gp efflux, lower DILI, and a superior binding affinity. While Ligand A has a low logP, the significantly better affinity and favorable ADME properties (BBB, P-gp, metabolic stability) outweigh this drawback, especially considering the importance of potency for GPCR ligands.

Output:
0
2025-04-17 03:58:08,476 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (406.848 Da) is slightly higher than Ligand B (361.431 Da), but both are acceptable.

**TPSA:** Ligand A (103.18) is better than Ligand B (116.76). For CNS targets, we want TPSA <= 90, so both are slightly above the ideal, but A is closer.

**logP:** Ligand A (1.441) is optimal (1-3), while Ligand B (0.318) is a bit low, potentially hindering permeation.

**H-Bond Donors/Acceptors:** Ligand A (HBD=1, HBA=8) and Ligand B (HBD=2, HBA=7) both fall within acceptable limits (<=5 HBD, <=10 HBA).

**QED:** Both ligands have good QED scores (A: 0.749, B: 0.792), indicating good drug-like properties.

**DILI:** Ligand A (99.147) has a very high DILI risk, which is a significant concern. Ligand B (68.088) has a moderate DILI risk, which is preferable.

**BBB:** Both ligands have reasonably good BBB penetration (A: 51.415, B: 54.634), but neither exceeds the desirable threshold of >70.

**Caco-2 Permeability:** Ligand A (-4.64) has poor Caco-2 permeability. Ligand B (-5.743) is also poor, but slightly better than A.

**Aqueous Solubility:** Ligand A (-4.774) has poor solubility. Ligand B (-3.064) is also poor, but better than A.

**hERG:** Both ligands have very low hERG inhibition risk (A: 0.024, B: 0.046).

**Microsomal Clearance:** Ligand A (102.582) has higher clearance than Ligand B (21.428), indicating lower metabolic stability.

**In vitro Half-Life:** Ligand A (4.824) has a shorter half-life than Ligand B (7.412).

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (A: 0.145, B: 0.043).

**Binding Affinity:** Both ligands have excellent binding affinity (A: -8.6 kcal/mol, B: -8.0 kcal/mol). Ligand A is slightly better (-8.6 vs -8.0).

**Overall Assessment:**

Ligand A has a slightly better binding affinity and TPSA, but suffers from a very high DILI risk, poor Caco-2 permeability, poor solubility, and higher clearance. Ligand B, while having a slightly lower affinity and higher TPSA, exhibits a much more favorable safety profile (lower DILI) and better ADME properties (lower clearance, longer half-life, slightly better solubility and permeability). Given the importance of safety and ADME properties in drug development, especially for CNS targets, Ligand B is the more promising candidate. The small difference in binding affinity is unlikely to outweigh the significant ADME/Tox advantages of Ligand B.

Output:
1
2025-04-17 03:58:08,477 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (329.403 Da) is slightly lower, which could be advantageous for permeability. Ligand B (352.519 Da) is also good.

**TPSA:** Both ligands have TPSA values above the optimal 90 A^2 for CNS targets. Ligand A (47.04 A^2) is better than Ligand B (49.85 A^2), but both are acceptable.

**logP:** Ligand A (4.845) is higher than the optimal range (1-3), potentially leading to solubility issues and off-target interactions. Ligand B (2.792) is within the optimal range. This is a significant advantage for Ligand B.

**H-Bond Donors/Acceptors:** Ligand A has 1 HBD and 4 HBA, which are within acceptable limits. Ligand B has 0 HBD and 3 HBA, also good.

**QED:** Both ligands have QED values above 0.5 (Ligand A: 0.727, Ligand B: 0.675), indicating good drug-like properties.

**DILI:** Ligand A has a high DILI risk (84.684%), which is concerning. Ligand B has a very low DILI risk (6.475%), a major advantage.

**BBB:** Ligand B has a significantly better BBB penetration percentile (90.074%) compared to Ligand A (74.06%). This is crucial for a CNS target like DRD2.

**Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and likely indicates an issue with the model or data. However, the values are similar, so this doesn't strongly favor either.

**Aqueous Solubility:** Both ligands have poor aqueous solubility (-5.857 and -1.958 respectively). Ligand B is slightly better.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.751 and 0.709 respectively).

**Microsomal Clearance:** Both ligands have relatively high microsomal clearance (Ligand A: 79.597, Ligand B: 72.824), suggesting moderate metabolic instability.

**In vitro Half-Life:** Ligand B has a longer in vitro half-life (-17.616 hours) compared to Ligand A (-13.213 hours), which is preferable.

**P-gp Efflux:** Ligand A has a higher P-gp efflux liability (0.447) than Ligand B (0.184), meaning Ligand B is less likely to be pumped out of the brain.

**Binding Affinity:** Ligand B has a significantly better binding affinity (-7.6 kcal/mol) than Ligand A (-10.8 kcal/mol). This is a substantial advantage, potentially outweighing some of the ADME drawbacks.

**Overall Assessment:**

Ligand B is the stronger candidate. While both have some issues with solubility and metabolic stability, Ligand B excels in the critical areas for a CNS GPCR target: BBB penetration, P-gp efflux, and, most importantly, binding affinity. The significantly lower DILI risk is also a major benefit. Ligand A's high DILI risk and lower BBB penetration are significant drawbacks. The higher logP of Ligand A is also a concern.

Output:
1
2025-04-17 03:58:08,477 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (347.342 and 356.457 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (84.86) is better than Ligand B (49.41), both are below the 90 A^2 threshold for CNS targets.

**3. logP:** Both ligands have good logP values (2.056 and 3.354), falling within the optimal 1-3 range. Ligand B is slightly higher, which could potentially lead to lower solubility.

**4. H-Bond Donors:** Ligand A (2) and Ligand B (1) are both within the acceptable limit of <=5.

**5. H-Bond Acceptors:** Ligand A (5) and Ligand B (2) are both within the acceptable limit of <=10.

**6. QED:** Both ligands have good QED scores (0.592 and 0.821), indicating good drug-like properties. Ligand B is slightly better.

**7. DILI:** Ligand A (58.589) has a higher DILI risk than Ligand B (33.579). This is a significant advantage for Ligand B.

**8. BBB:** Ligand B (91.702) has a significantly better BBB penetration score than Ligand A (57.852). This is *crucial* for a CNS target like DRD2.

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.841 and -4.583), which is unusual and suggests poor permeability. However, these values are on a scale where negative values are possible, and direct comparison is difficult without knowing the scale's specifics.

**10. Aqueous Solubility:** Both ligands have very poor aqueous solubility (-3.594 and -4.499). This is a concern for both, but could be mitigated with formulation strategies.

**11. hERG Inhibition:** Both ligands have low hERG inhibition risk (0.694 and 0.586).

**12. Microsomal Clearance:** Ligand A (89.331) has higher microsomal clearance than Ligand B (46.544), meaning it is less metabolically stable.

**13. In vitro Half-Life:** Ligand B (-10.124) has a longer in vitro half-life than Ligand A (-25.566).

**14. P-gp Efflux:** Ligand A (0.271) has lower P-gp efflux than Ligand B (0.111), which is better for CNS exposure.

**15. Binding Affinity:** Ligand B (-7.7 kcal/mol) has a significantly stronger binding affinity than Ligand A (-9.3 kcal/mol). This is a substantial advantage.

**Overall Assessment:**

Ligand B is the superior candidate. While both have solubility issues and poor Caco-2 permeability, Ligand B excels in the most critical areas for a CNS GPCR target: BBB penetration (91.702 vs 57.852), binding affinity (-7.7 vs -9.3 kcal/mol), lower DILI risk (33.579 vs 58.589), and better metabolic stability (lower Cl_mic and longer half-life). The stronger binding affinity could potentially offset the permeability concerns.

Output:
1
2025-04-17 03:58:08,477 - INFO - Reasoning:

Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (358.427 and 352.475 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (94.82) is higher than Ligand B (67.87). For a CNS target like DRD2, TPSA should ideally be <= 90. Ligand A is slightly above this, while Ligand B is well within the range. This favors Ligand B.

**3. logP:** Both ligands have good logP values (1.837 and 1.441), falling within the optimal 1-3 range.

**4. H-Bond Donors:** Both have 1 HBD, which is acceptable.

**5. H-Bond Acceptors:** Ligand A has 8 HBAs, while Ligand B has 4. Both are within the acceptable limit of <=10, but Ligand B is preferable.

**6. QED:** Both ligands have reasonable QED scores (0.618 and 0.504), indicating good drug-like properties.

**7. DILI:** Ligand A has a significantly higher DILI risk (89.259%) compared to Ligand B (29.74%). This is a major concern for Ligand A.

**8. BBB:** Both ligands have moderate BBB penetration (58.007% and 54.634%). While not exceptional, they are comparable. A higher value is preferred, but neither is a standout.

**9. Caco-2 Permeability:** Ligand A (-5.419) has poorer Caco-2 permeability than Ligand B (-4.402). Lower values indicate poorer permeability.

**10. Aqueous Solubility:** Ligand A (-2.723) has poorer solubility than Ligand B (-1.737).

**11. hERG Inhibition:** Both ligands show low hERG inhibition risk (0.262 and 0.397).

**12. Microsomal Clearance:** Ligand A (48.016) has higher microsomal clearance than Ligand B (13.282), indicating lower metabolic stability.

**13. In vitro Half-Life:** Ligand A (-17.189) has a shorter in vitro half-life than Ligand B (-3.623).

**14. P-gp Efflux:** Both ligands have low P-gp efflux liability (0.358 and 0.089). Ligand B is slightly better.

**15. Binding Affinity:** Ligand B (-7.5 kcal/mol) has a significantly stronger binding affinity than Ligand A (-9.1 kcal/mol). This is a substantial advantage.

**Overall Assessment:**

Ligand B is clearly the more promising candidate. It has a lower TPSA, lower DILI risk, better Caco-2 permeability, better solubility, better metabolic stability (lower Cl_mic, longer t1/2), and significantly stronger binding affinity. While BBB penetration is similar for both, the other factors strongly favor Ligand B. The improved ADME properties and substantially better binding affinity outweigh any minor drawbacks.

Output:
1
2025-04-17 03:58:08,477 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (341.455 and 349.395 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (71.09) is excellent, well below the 90 A^2 threshold for CNS targets. Ligand B (118.03) is higher, but still potentially acceptable, though less ideal.

**logP:** Ligand A (2.669) is optimal (1-3). Ligand B (0.312) is low, which could hinder membrane permeability and CNS penetration.

**H-Bond Donors/Acceptors:** Both ligands have 2 HBDs, which is good. Ligand A has 3 HBAs, and Ligand B has 7 HBAs. Both are within the acceptable range (<=10), but Ligand B is approaching the upper limit.

**QED:** Both ligands have good QED scores (0.617 and 0.673), indicating drug-like properties.

**DILI:** Ligand A (39.318) has a lower DILI risk than Ligand B (72.703), which is a significant advantage.

**BBB:** Ligand A (63.125) has a moderate BBB penetration, while Ligand B (30.787) has poor BBB penetration. This is a critical difference for a CNS target like DRD2.

**Caco-2 Permeability:** Both have negative values, indicating poor permeability. However, the scale is not specified, so it's hard to interpret.

**Aqueous Solubility:** Both have negative values, indicating poor solubility. Again, the scale is not specified.

**hERG:** Both ligands have very low hERG inhibition risk (0.173 and 0.13), which is excellent.

**Microsomal Clearance:** Ligand A (41.978) has lower microsomal clearance than Ligand B (58.4), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (-7.113) has a significantly longer half-life than Ligand B (-26.847).

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.128 and 0.046), which is good.

**Binding Affinity:** Ligand A (-8.9 kcal/mol) has a slightly better binding affinity than Ligand B (-7.8 kcal/mol). While both are good, the 1.1 kcal/mol difference is meaningful.

**Overall Assessment:**

Ligand A is clearly superior. It has better logP, significantly better BBB penetration, lower DILI risk, better metabolic stability (lower Cl_mic and longer t1/2), and slightly better binding affinity. While both have issues with Caco-2 and solubility, the CNS-related properties are paramount for a DRD2 ligand. Ligand B's low logP and poor BBB penetration are major drawbacks.

Output:
0
2025-04-17 03:58:08,478 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B based on the provided guidelines, prioritizing GPCR-specific properties (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (386.42) is slightly higher than Ligand B (344.459), but both are acceptable.

**TPSA:** Ligand A (59.06) is excellent for CNS penetration, well below the 90 A^2 threshold. Ligand B (67.35) is still reasonable, but less optimal.

**logP:** Ligand A (4.547) is a bit high, potentially leading to solubility issues and off-target interactions. Ligand B (2.015) is within the optimal range (1-3).

**H-Bond Donors/Acceptors:** Both ligands have 1 HBD and 5 HBA, which are within acceptable limits.

**QED:** Ligand B (0.908) has a significantly better QED score than Ligand A (0.675), indicating a more drug-like profile.

**DILI:** Ligand A (95.347) has a very high DILI risk, which is a major concern. Ligand B (26.173) has a low DILI risk, a significant advantage.

**BBB:** Both ligands have good BBB penetration, with Ligand B (77.627) being slightly better than Ligand A (67.701). Both exceed the 70% threshold for CNS targets.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values, which is unusual and suggests a potential issue with the data or the model. However, we'll proceed assuming these represent low permeability.

**Aqueous Solubility:** Both ligands have negative solubility values, which is also unusual. This suggests poor solubility, but we'll proceed with caution.

**hERG Inhibition:** Ligand A (0.69) has a slightly higher hERG risk than Ligand B (0.326), but both are relatively low.

**Microsomal Clearance:** Ligand B (11.141) has a much lower microsomal clearance than Ligand A (42.26), indicating better metabolic stability.

**In vitro Half-Life:** Ligand A (74.994) has a longer in vitro half-life than Ligand B (4.195), which is desirable.

**P-gp Efflux:** Ligand A (0.622) has a lower P-gp efflux liability than Ligand B (0.053), which is beneficial for CNS exposure.

**Binding Affinity:** Ligand B (-8.7 kcal/mol) has a slightly better binding affinity than Ligand A (-9.0 kcal/mol). While the difference is small, it's still a positive for Ligand B.

**Overall Assessment:**

Despite Ligand A's slightly better binding affinity and P-gp efflux, its extremely high DILI risk and higher logP are major drawbacks. Ligand B has a superior drug-like profile (QED), lower DILI risk, better metabolic stability (lower Cl_mic), and a more optimal logP. While the Caco-2 and Solubility values are concerning for both, the other factors strongly favor Ligand B. Given the CNS target and GPCR nature, BBB penetration is good for both, but the other ADME properties of Ligand B are much more favorable.

Output:
1
2025-04-17 03:58:08,478 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (347.419 and 361.467 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (109.14) is higher than the preferred <90 for CNS targets, while Ligand B (67.6) is well within the range. This is a significant advantage for Ligand B.

**logP:** Ligand A (0.15) is quite low, potentially hindering membrane permeability. Ligand B (2.478) is within the optimal 1-3 range. This favors Ligand B.

**H-Bond Donors/Acceptors:** Ligand A has 3 HBD and 6 HBA, which are acceptable. Ligand B has 1 HBD and 6 HBA, also acceptable.

**QED:** Both ligands have good QED scores (0.58 and 0.817, respectively), indicating good drug-like properties.

**DILI:** Both ligands have acceptable DILI risk (45.25 and 52.423, respectively), below the 60 threshold.

**BBB:** Ligand A (29.003) has a very low BBB penetration percentile, making it unlikely to effectively reach the DRD2 receptor in the CNS. Ligand B (49.942) is better, but still not ideal (aim for >70). However, given the other factors, this is less of a dealbreaker than Ligand A's extremely low BBB.

**Caco-2:** Both have negative Caco-2 values, which is unusual and suggests potential issues with intestinal absorption. However, these values are on a scale where negative values are possible, and direct comparison is difficult without knowing the scale's specifics.

**Solubility:** Both ligands have negative solubility values, which is also unusual. Similar to Caco-2, direct comparison is difficult.

**hERG:** Ligand A (0.049) has a very low hERG risk, which is excellent. Ligand B (0.42) is slightly higher, but still relatively low.

**Microsomal Clearance:** Ligand A (-7.516) has a very negative clearance, which is not physically meaningful and suggests a potential data error. Ligand B (61.544) has a higher clearance, indicating faster metabolism.

**In vitro Half-Life:** Ligand A (6.949) has a moderate half-life. Ligand B (9.163) has a slightly longer half-life.

**P-gp Efflux:** Ligand A (0.011) has very low P-gp efflux, which is favorable for CNS penetration. Ligand B (0.192) has a slightly higher efflux, but still relatively low.

**Binding Affinity:** Ligand B (-8.1 kcal/mol) has a slightly better binding affinity than Ligand A (-7.9 kcal/mol). While the difference is small, it's still a positive for Ligand B.

**Overall Assessment:**

Ligand B is significantly better. Its lower TPSA, optimal logP, and better (though still not ideal) BBB penetration are crucial advantages for a CNS-targeting GPCR ligand. While Ligand A has a lower hERG risk and P-gp efflux, its very low logP and extremely poor BBB penetration are major drawbacks. The questionable values for clearance and solubility for both compounds are concerning, but the differences in TPSA, logP, and BBB are more decisive.



Output:
1
2025-04-17 03:58:08,478 - INFO - Reasoning:

Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (352.475 and 345.363 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (59.08) is excellent, well below the 90 A^2 threshold for CNS targets. Ligand B (119.04) is higher, but still potentially acceptable, though less ideal.

**3. logP:** Ligand A (1.533) is within the optimal 1-3 range. Ligand B (0.165) is quite low, potentially hindering membrane permeability and CNS penetration.

**4. H-Bond Donors:** Both have acceptable HBD counts (0 for A, 1 for B), well below the 5 threshold.

**5. H-Bond Acceptors:** Ligand A (4) is good. Ligand B (8) is approaching the upper limit of 10, but still acceptable.

**6. QED:** Both ligands have good QED scores (0.697 and 0.792), indicating drug-like properties.

**7. DILI:** Ligand A (9.771) has a very low DILI risk. Ligand B (61.07) is higher, indicating a moderate risk of liver injury.

**8. BBB:** Ligand A (89.066) has excellent BBB penetration potential, exceeding the 70% threshold. Ligand B (58.938) is significantly lower, which is a major concern for a CNS target.

**9. Caco-2 Permeability:** Ligand A (-4.37) is poor, while Ligand B (-5.426) is even worse. Both are very low.

**10. Aqueous Solubility:** Both have very poor aqueous solubility (-1.294 and -1.615 respectively). This could pose formulation challenges.

**11. hERG Inhibition:** Both ligands show very low hERG inhibition risk (0.34 and 0.021).

**12. Microsomal Clearance:** Ligand A (41.132) has moderate clearance. Ligand B (13.667) has lower clearance, suggesting better metabolic stability.

**13. In vitro Half-Life:** Ligand A (-3.119) has a negative half-life, which is not possible and likely an error in the data. Ligand B (-4.176) also has a negative half-life, also likely an error.

**14. P-gp Efflux:** Both ligands show very low P-gp efflux liability (0.052 and 0.017).

**15. Binding Affinity:** Ligand B (-8.4 kcal/mol) has a slightly better binding affinity than Ligand A (-7.5 kcal/mol). The difference is 0.9 kcal/mol, which is significant but not overwhelming.

**Overall Assessment:**

Despite Ligand B having slightly better binding affinity, Ligand A is the more promising candidate. The critical factor is the significantly higher predicted BBB penetration (89.066% vs. 58.938%). For a CNS target like DRD2, this is paramount. Ligand A also has a much lower DILI risk. While both have poor solubility and Caco-2 permeability, these can potentially be addressed through formulation strategies. The negative half-life values are concerning and require further investigation, but do not negate the other favorable properties of Ligand A.



Output:
1
2025-04-17 03:58:08,478 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (346.471 and 365.474 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (58.64) is better than Ligand B (43.86), both are well below the 90 A^2 threshold for CNS targets.

**logP:** Both ligands have good logP values (2.29 and 1.902), falling within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A has 1 HBD and 3 HBA, while Ligand B has 0 HBD and 4 HBA. Both are within acceptable limits.

**QED:** Both ligands have good QED scores (0.614 and 0.822), indicating good drug-like properties.

**DILI:** Both ligands have low DILI risk (23.614 and 23.187 percentiles), which is favorable.

**BBB:** Ligand B (93.68%) significantly outperforms Ligand A (69.794%) in BBB penetration. This is a *critical* advantage for a CNS target like DRD2.

**Caco-2 Permeability:** Ligand A (-4.9) is worse than Ligand B (-4.647), but both are negative, suggesting poor permeability.

**Aqueous Solubility:** Ligand A (-2.162) is slightly better than Ligand B (-1.976), but both are quite poor.

**hERG Inhibition:** Ligand A (0.156) is much better than Ligand B (0.781), indicating a lower risk of cardiotoxicity.

**Microsomal Clearance:** Ligand B (8.062) has significantly lower microsomal clearance than Ligand A (48.933), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand B (10.043 hours) has a much longer half-life than Ligand A (-16.531 hours).

**P-gp Efflux:** Ligand A (0.102) has lower P-gp efflux than Ligand B (0.324), which is favorable for CNS penetration.

**Binding Affinity:** Ligand B (-8.4 kcal/mol) has a *much* stronger binding affinity than Ligand A (0.0 kcal/mol). This is a substantial difference.

**Overall Assessment:**

Ligand B is the stronger candidate. While Ligand A has better hERG inhibition, the significant advantages of Ligand B in BBB penetration, binding affinity, metabolic stability (lower Cl_mic and longer t1/2), and P-gp efflux outweigh this single benefit. The strong binding affinity of Ligand B is particularly important. The poor solubility and Caco-2 permeability are concerns for both, but can be addressed with formulation strategies. For a CNS target, maximizing BBB penetration and target engagement are paramount.

Output:
1
2025-04-17 03:58:08,479 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (357.451 and 352.523 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (102.34) is higher than the preferred <90 for CNS targets, while Ligand B (55.89) is well within the range. This is a significant advantage for Ligand B.

**logP:** Ligand A (-1.055) is quite low, potentially hindering permeability. Ligand B (1.188) is within the optimal 1-3 range. This favors Ligand B.

**H-Bond Donors/Acceptors:** Ligand A has 3 HBD and 6 HBA, acceptable values. Ligand B has 1 HBD and 4 HBA, also acceptable and potentially better for permeability due to fewer hydrogen bonds.

**QED:** Both ligands have good QED scores (0.58 and 0.748, respectively), indicating drug-like properties.

**DILI:** Ligand A (15.51) has a slightly higher DILI risk than Ligand B (8.957), but both are reasonably low.

**BBB:** This is crucial for a CNS target like DRD2. Ligand A has a BBB percentile of 27.918, which is poor. Ligand B has a much better BBB percentile of 66.344, exceeding the desirable >70 threshold. This is a major advantage for Ligand B.

**Caco-2 Permeability:** Both have negative Caco-2 values (-5.37 and -4.907), which is unusual and suggests poor permeability. However, these values are on a log scale, and the absolute difference isn't huge.

**Aqueous Solubility:** Both have very low solubility (0.023 and -0.739). This is a concern for both, but Ligand B is slightly worse.

**hERG Inhibition:** Both ligands show very low hERG inhibition risk (0.038 and 0.447).

**Microsomal Clearance:** Ligand A (2.049) has a lower (better) microsomal clearance than Ligand B (36.659), indicating better metabolic stability.

**In vitro Half-Life:** Both have similar in vitro half-lives (6.838 and 6.693 hours).

**P-gp Efflux:** Ligand A (0.003) shows minimal P-gp efflux, which is good. Ligand B (-6.4) shows significant P-gp efflux, which is a major drawback for CNS penetration.

**Binding Affinity:** Ligand A (0.0) has no binding affinity reported, while Ligand B (-6.4) has a strong binding affinity. This is a critical advantage for Ligand B.

**Overall Assessment:**

Ligand B is significantly more promising. While both have solubility issues, Ligand B excels in key areas for a CNS GPCR target: TPSA, logP, BBB penetration, and, crucially, binding affinity. The P-gp efflux liability of Ligand B is a concern, but the strong binding affinity might compensate for this to some extent. Ligand A's extremely low logP, poor BBB penetration, and lack of reported binding affinity make it a less attractive candidate.

Output:
1
2025-04-17 03:58:08,479 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (341.455 and 347.463 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (62.3) is significantly better than Ligand B (80.12). For CNS targets, we want TPSA <= 90, and A is comfortably within that range, while B is approaching the upper limit.

**3. logP:** Both ligands have good logP values (2.788 and 1.354), falling within the optimal 1-3 range. Ligand A is slightly better.

**4. H-Bond Donors:** Both have 1 HBD, which is acceptable (<=5).

**5. H-Bond Acceptors:** Ligand A has 3 HBA, and Ligand B has 5. Both are within the acceptable range of <=10, but A is preferable.

**6. QED:** Both ligands have good QED scores (0.613 and 0.72), indicating good drug-like properties.

**7. DILI:** Ligand A (20.24) has a much lower DILI risk than Ligand B (30.826). Both are below 40, which is good, but A is significantly better.

**8. BBB:** This is a critical parameter for CNS targets. Ligand A (66.615) has a much better BBB penetration percentile than Ligand B (51.803). A value >70 is desirable, and A is closer to that threshold.

**9. Caco-2:** Both have negative Caco-2 values (-4.843 and -4.866), which is unusual and suggests poor permeability. This is a significant drawback for both.

**10. Solubility:** Both have negative solubility values (-2.29 and -1.47), indicating poor aqueous solubility. This is also a significant drawback for both.

**11. hERG:** Both ligands have very low hERG inhibition liability (0.48 and 0.069), which is excellent.

**12. Cl_mic:** Ligand B (21.44) has lower microsomal clearance than Ligand A (31.22), suggesting better metabolic stability.

**13. t1/2:** Ligand A (-6.88) has a longer in vitro half-life than Ligand B (-0.682).

**14. Pgp:** Both have very low P-gp efflux liability (0.098 and 0.018), which is excellent for CNS penetration.

**15. Binding Affinity:** Ligand A (-8.8 kcal/mol) has a significantly stronger binding affinity than Ligand B (-7.6 kcal/mol). This 1.2 kcal/mol difference is substantial and can outweigh some of the ADME drawbacks.

**Overall Assessment:**

Ligand A is the stronger candidate. While both have issues with Caco-2 and solubility, Ligand A excels in the most critical areas for a CNS-targeting GPCR ligand: BBB penetration, binding affinity, and lower DILI risk. The significantly stronger binding affinity of Ligand A is a major advantage. Although Ligand B has better metabolic stability (lower Cl_mic), the superior BBB and affinity of Ligand A are more important for this target class.

Output:
1
2025-04-17 03:58:08,479 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (350.394 and 357.445 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Both ligands have TPSA values (68.96 and 69.22) below the 90 A^2 threshold for CNS targets, which is excellent.

**3. logP:** Ligand A (1.469) is within the optimal 1-3 range. Ligand B (3.287) is at the higher end of optimal, but still acceptable.

**4. H-Bond Donors:** Ligand A (0) is good. Ligand B (2) is also acceptable.

**5. H-Bond Acceptors:** Ligand A (6) is within the acceptable limit of 10. Ligand B (3) is also good.

**6. QED:** Both ligands have good QED values (0.721 and 0.75), indicating drug-like properties.

**7. DILI:** Ligand A (51.842) has a moderate DILI risk, but is still acceptable. Ligand B (18.263) has a very low DILI risk, which is a significant advantage.

**8. BBB:** Ligand A (89.919) has excellent BBB penetration, exceeding the 70% threshold. Ligand B (68.476) is below the 70% threshold, which is a concern for a CNS target.

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.632 and -4.578), which is unusual and suggests poor permeability. However, these values are on a log scale, so a value close to zero is better.

**10. Aqueous Solubility:** Both ligands have negative solubility values (-2.24 and -3.244), indicating poor aqueous solubility. This is a potential issue for formulation.

**11. hERG Inhibition:** Both ligands have low hERG inhibition risk (0.509 and 0.794).

**12. Microsomal Clearance:** Ligand A (59.162) has a moderate clearance, while Ligand B (19.011) has a lower clearance, suggesting better metabolic stability.

**13. In vitro Half-Life:** Ligand A (12.739) has a reasonable half-life. Ligand B (-11.256) has a negative half-life, which is not physically possible and indicates a problem with the data or the molecule.

**14. P-gp Efflux:** Both ligands have low P-gp efflux liability (0.111 and 0.294), which is favorable for CNS penetration.

**15. Binding Affinity:** Ligand B (-7.3 kcal/mol) has a significantly stronger binding affinity than Ligand A (-6.7 kcal/mol). This 0.6 kcal/mol difference is substantial and could outweigh some of the ADME drawbacks.

**Overall Assessment:**

Ligand B has a much better binding affinity and lower DILI risk, and better metabolic stability. However, its BBB penetration is significantly lower than Ligand A, and its in vitro half-life is nonsensical. Ligand A has excellent BBB penetration, but its binding affinity is weaker and its DILI risk is higher. Given the importance of binding affinity for GPCRs, and the fact that the difference is substantial, I would lean towards Ligand B *if* the half-life data can be corrected or explained. The negative half-life is a major red flag. Assuming the half-life is an error, the stronger binding and lower DILI risk of Ligand B make it the more promising candidate, despite the lower BBB score.

Output:
1
2025-04-17 03:58:08,479 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (360.282 Da and 364.486 Da) fall comfortably within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (51.22) is slightly higher than Ligand B (49.41). Both are below the 90 Angstroms threshold desirable for CNS targets, which is good.

**3. logP:** Both ligands have a logP around 3.8 (3.878 and 3.844), which is optimal.

**4. H-Bond Donors:** Both have 1 HBD, which is within the acceptable limit of <=5.

**5. H-Bond Acceptors:** Both have 3 HBA, which is within the acceptable limit of <=10.

**6. QED:** Both ligands have high QED scores (0.842 and 0.882), indicating good drug-like properties.

**7. DILI:** Ligand A (70.299) has a higher DILI risk than Ligand B (43.622). Ligand B is well below the 60 threshold, while A is approaching it.

**8. BBB:** This is a crucial parameter for a CNS target like DRD2. Ligand B (95.735) has a significantly higher BBB percentile than Ligand A (70.609). This is a major advantage for Ligand B.

**9. Caco-2 Permeability:** Both have negative values, which is unusual. Lower values indicate poorer permeability. Ligand A (-4.387) is slightly worse than Ligand B (-4.927).

**10. Aqueous Solubility:** Both have negative values, suggesting poor solubility. Ligand A (-4.555) is slightly better than Ligand B (-4.392).

**11. hERG Inhibition:** Both ligands have low hERG inhibition risk (0.672 and 0.739).

**12. Microsomal Clearance:** Both have similar microsomal clearance values (43.842 and 40.922). Lower is better, so Ligand B is slightly preferable.

**13. In vitro Half-Life:** Ligand B (14.888 hours) has a significantly longer half-life than Ligand A (-1.691 hours). This is a substantial advantage for Ligand B.

**14. P-gp Efflux:** Both ligands have low P-gp efflux liability (0.244 and 0.43).

**15. Binding Affinity:** Ligand A (-9.3 kcal/mol) has a slightly better binding affinity than Ligand B (-8.0 kcal/mol). This is a 1.3 kcal/mol difference, which is significant.

**Overall Assessment:**

While Ligand A has a slightly better binding affinity, Ligand B is significantly better in several critical ADME properties for a CNS-targeting GPCR. Specifically, the much higher BBB penetration (95.735 vs 70.609) and longer half-life (14.888 vs -1.691) are major advantages. The lower DILI risk of Ligand B is also a positive factor. The slight difference in binding affinity is likely outweighed by the superior pharmacokinetic profile of Ligand B.

Output:
1
2025-04-17 03:58:08,480 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (345.403 and 361.471 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (92.52) is slightly higher than Ligand B (78.43). Both are below the 90 A^2 threshold desirable for CNS targets, but Ligand B is better.

**logP:** Both ligands have good logP values (1.256 and 1.149), falling within the optimal 1-3 range.

**H-Bond Donors:** Ligand A has 2 HBD, and Ligand B has 1. Both are within the acceptable limit of <=5.

**H-Bond Acceptors:** Both ligands have 6 HBA, which is within the acceptable limit of <=10.

**QED:** Both ligands have high QED scores (0.819 and 0.87), indicating good drug-like properties.

**DILI:** Ligand A (57.425) has a slightly better DILI score than Ligand B (52.423), but both are reasonably low risk.

**BBB:** Ligand A (78.868) has a significantly better BBB penetration score than Ligand B (62.233). This is a critical factor for a CNS target like DRD2.

**Caco-2 Permeability:** Both have negative Caco-2 values (-4.996 and -4.983). This is unusual and suggests potential issues with intestinal absorption, but the values are very similar.

**Aqueous Solubility:** Both ligands have negative solubility values (-1.586 and -2.508). This is also concerning, and may require formulation strategies to improve bioavailability. Ligand B is slightly worse.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.521 and 0.187). Ligand B is better.

**Microsomal Clearance:** Ligand A (2.483) has a much lower microsomal clearance than Ligand B (38.015), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (-3.302) has a better (longer) in vitro half-life than Ligand B (6.331).

**P-gp Efflux:** Ligand A (0.01) has a much lower P-gp efflux liability than Ligand B (0.064), indicating better potential for CNS exposure.

**Binding Affinity:** Both ligands have excellent binding affinities (-9.2 and -9.5 kcal/mol). Ligand B is slightly better, but the difference is small.

**Overall Assessment:**

While Ligand B has a slightly better binding affinity and hERG profile, Ligand A significantly outperforms it in crucial areas for a CNS-targeting GPCR ligand: BBB penetration, metabolic stability (lower Cl_mic), longer half-life, and lower P-gp efflux. The TPSA is also slightly more favorable for Ligand A. The solubility and Caco-2 permeability are poor for both, but the ADME advantages of Ligand A are more compelling given the target.

Output:
1
2025-04-17 03:58:08,480 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (344.346 and 362.455 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (100.19) is slightly above the optimal <90 for CNS targets, but still reasonable. Ligand B (80.82) is well within the desired range.

**logP:** Both ligands have acceptable logP values (1.014 and 3.086), falling within the 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A has 3 HBD and 4 HBA, which is good. Ligand B has 0 HBD and 7 HBA, also acceptable.

**QED:** Both ligands have reasonable QED scores (0.428 and 0.756), with Ligand B being significantly better.

**DILI:** Ligand A (84.102) has a higher DILI risk than Ligand B (66.576), though both are below the concerning >60 threshold.

**BBB:** Ligand A (56.417) has a lower BBB penetration percentile than Ligand B (61.729). While neither is >70, Ligand B is better.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.026 and -5.054), which is unusual and suggests poor permeability. This is a significant drawback for both.

**Aqueous Solubility:** Both ligands have negative solubility values (-3.726 and -2.458), indicating very poor aqueous solubility. This is a major concern for bioavailability.

**hERG Inhibition:** Both ligands have low hERG inhibition liability (0.439 and 0.127), which is favorable.

**Microsomal Clearance:** Ligand A (41.907) has lower microsomal clearance than Ligand B (51.404), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (17.014) has a longer half-life than Ligand B (-8.915). The negative value for B is concerning.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.061 and 0.26), which is good for CNS penetration.

**Binding Affinity:** Ligand A (-9.6 kcal/mol) has a significantly stronger binding affinity than Ligand B (-7.6 kcal/mol). This is a substantial advantage.

**Overall Assessment:**

Ligand A's primary strength is its significantly better binding affinity. However, it suffers from a slightly higher DILI risk, lower BBB, and a negative Caco-2 and solubility. Ligand B has better QED, DILI, BBB, and a more reasonable half-life, but its affinity is considerably weaker.

Given the GPCR-specific priorities, BBB and affinity are crucial. While neither ligand excels in BBB, the substantial difference in binding affinity (-9.6 vs -7.6 kcal/mol) is likely to outweigh the other drawbacks of Ligand A, *provided* solubility and permeability can be addressed through formulation or further chemical modification. The negative Caco-2 and solubility are serious issues, but a strong starting point with high affinity is valuable.

Output:
1
2025-04-17 03:58:08,480 - INFO - Batch 73 complete. Total preferences: 1168
2025-04-17 03:58:08,480 - INFO - Processing batch 74/512...
2025-04-17 03:58:51,622 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (340.423 and 374.819 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (62.55) is significantly better than Ligand B (76.02). For CNS targets, we want TPSA <= 90, and A is comfortably within that range, while B is approaching the upper limit.

**logP:** Ligand A (3.8) is slightly higher than the optimal range (1-3), but still acceptable. Ligand B (2.056) is closer to the lower end, which could hinder permeability.

**H-Bond Donors/Acceptors:** Ligand A (1 HBD, 3 HBA) and Ligand B (2 HBD, 4 HBA) both have reasonable numbers of H-bond donors and acceptors, well below the thresholds of 5 and 10 respectively.

**QED:** Both ligands have acceptable QED values (0.9 and 0.513), indicating reasonable drug-likeness.

**DILI:** Ligand A (38.348) has a slightly better DILI score than Ligand B (48.468), both are acceptable (<60).

**BBB:** Both ligands have excellent BBB penetration (82.164 and 83.443), exceeding the desirable >70 threshold for CNS targets.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.428 and -4.916). This is unusual and problematic, indicating poor intestinal absorption. However, for a CNS target, intestinal absorption is less critical than BBB penetration, so this is not a deal-breaker, but a concern.

**Aqueous Solubility:** Both ligands have negative solubility values (-4.072 and -3.188), indicating poor aqueous solubility. This could pose formulation challenges.

**hERG:** Both ligands have low hERG risk (0.598 and 0.26), which is favorable.

**Microsomal Clearance:** Ligand A (54.099) has higher microsomal clearance than Ligand B (32.541), suggesting lower metabolic stability.

**In vitro Half-Life:** Ligand B (4.079 hours) has a significantly shorter half-life than Ligand A (104.95 hours). This is a major advantage for Ligand A.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.238 and 0.123), which is good for CNS exposure.

**Binding Affinity:** Both ligands have excellent binding affinity (-8.9 and -8.0 kcal/mol). Ligand A is slightly better (-8.9 kcal/mol).

**Overall Assessment:**

Ligand A is superior due to its lower TPSA, better in vitro half-life, and slightly better binding affinity. While both have poor Caco-2 and solubility, these are less critical for a CNS target with good BBB penetration. Ligand B's shorter half-life is a significant drawback.

Output:
1
2025-04-17 03:58:51,622 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (347.371 and 352.431 Da) fall within the ideal range of 200-500 Da.

**TPSA:** Ligand A (117.51) is slightly above the optimal <90 for CNS targets, but still reasonable. Ligand B (104.73) is better, falling comfortably below 90.

**logP:** Both ligands (0.385 and 0.358) are quite low, potentially hindering membrane permeability. This is a concern for both.

**H-Bond Donors/Acceptors:** Both have 3 HBD and 5 HBA, which are within acceptable limits.

**QED:** Ligand A (0.666) has a better QED score than Ligand B (0.473), indicating a more drug-like profile.

**DILI:** Ligand A (63.978) has a higher DILI risk than Ligand B (23.769). This is a significant negative for Ligand A.

**BBB:** Ligand A (41.218) has a very low BBB penetration percentile, making it unlikely to effectively reach the DRD2 receptor in the brain. Ligand B (27.104) is also low, but slightly better than A. Both are far from the desirable >70.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.413 and -5.107), which is unusual and suggests very poor intestinal absorption.

**Aqueous Solubility:** Both ligands have negative solubility values (-2.602 and -1.381), indicating poor aqueous solubility, which is problematic for formulation and bioavailability.

**hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.035 and 0.102).

**Microsomal Clearance:** Ligand A (-2.684) has a negative clearance, which is not physically possible and likely indicates an error or unusual behavior in the prediction. Ligand B (17.823) has a higher clearance, suggesting faster metabolism.

**In vitro Half-Life:** Ligand A (5.849) has a slightly longer half-life than Ligand B (-3.654). However, the negative half-life for B is concerning.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.025 and 0.027), which is favorable for CNS penetration.

**Binding Affinity:** Both ligands have very strong binding affinities (-8.7 and -8.3 kcal/mol). The difference of 0.4 kcal/mol is not substantial enough to overcome other significant differences.

**Overall Assessment:**

Ligand A has a better QED and slightly better half-life, but suffers from a significantly higher DILI risk and, critically, extremely poor predicted BBB penetration. The negative clearance is also a major red flag. Ligand B, while having a lower QED and higher clearance, has a much lower DILI risk. Both have poor solubility and permeability.

Given the GPCR-specific emphasis on BBB penetration and the importance of minimizing toxicity (DILI), Ligand B is the slightly more promising candidate, despite its drawbacks. The extremely poor BBB prediction for Ligand A is a deal-breaker for a CNS target like DRD2. The negative clearance for ligand A is also a significant concern.

Output:
1
2025-04-17 03:58:51,623 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (347.463 and 343.471 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (62.63) is significantly better than Ligand B (71.09). For CNS targets, we want TPSA <= 90, and ideally closer to 60. Ligand A is much closer to the ideal.

**3. logP:** Ligand B (3.209) is better than Ligand A (0.354). The optimal range is 1-3, and Ligand B falls within this, while Ligand A is too low, potentially hindering permeation.

**4. H-Bond Donors:** Ligand A (1) is better than Ligand B (2). Lower is generally preferred.

**5. H-Bond Acceptors:** Ligand A (6) is better than Ligand B (3). Lower is generally preferred.

**6. QED:** Both ligands have the same QED (0.833), indicating good drug-likeness.

**7. DILI:** Ligand A (11.206) has a much lower DILI risk than Ligand B (36.758). This is a significant advantage for Ligand A.

**8. BBB:** Ligand A (75.533) has a better BBB penetration percentile than Ligand B (63.746). Both are reasonably good, but Ligand A is closer to the desirable >70 threshold for CNS targets.

**9. Caco-2:** Both ligands have very poor Caco-2 permeability (-4.846 and -4.85). This is a concern for oral bioavailability, but less critical for a CNS target where direct delivery or other routes might be considered.

**10. Solubility:** Ligand A (-0.102) is slightly better than Ligand B (-3.567), but both are very poor. Solubility is a concern, but can be addressed with formulation strategies.

**11. hERG:** Ligand A (0.719) has a lower hERG inhibition liability than Ligand B (0.524). Lower is better.

**12. Cl_mic:** Ligand A (9.636) has a significantly lower microsomal clearance than Ligand B (25.449), indicating better metabolic stability.

**13. t1/2:** Ligand A (33.213) has a much longer in vitro half-life than Ligand B (1.242). This is a major advantage for Ligand A.

**14. Pgp:** Ligand A (0.018) has significantly lower P-gp efflux liability than Ligand B (0.19). This is crucial for CNS penetration.

**15. Binding Affinity:** Ligand B (-8.9) has a stronger binding affinity than Ligand A (-7.6). This is a 1.3 kcal/mol difference, which is substantial and could potentially outweigh some of the ADME drawbacks of Ligand B.

**Overall Assessment:**

While Ligand B has a better binding affinity, Ligand A demonstrates superior ADME properties, particularly those critical for CNS drug development (BBB, Pgp, metabolic stability, DILI). The significantly better BBB, lower Pgp efflux, lower DILI risk, and longer half-life of Ligand A make it a more promising candidate, despite the slightly weaker binding. The poor Caco-2 and solubility are concerns, but can potentially be addressed through formulation. The logP of Ligand A is a concern, but not insurmountable. The affinity difference, while significant, may be overcome with further optimization of Ligand A.

Output:
0
2025-04-17 03:58:51,623 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (349.475) is slightly better, being closer to the lower end which can aid permeability.

**TPSA:** Both ligands have TPSA values below 90, which is good for CNS penetration. Ligand B (60.93) is significantly lower than Ligand A (84.64), making it more favorable for crossing the blood-brain barrier.

**logP:** Both ligands have logP values within the optimal range (1-3). Ligand A (1.784) and Ligand B (1.873) are comparable.

**H-Bond Donors/Acceptors:** Ligand A has 1 HBD and 4 HBA, while Ligand B has 0 HBD and 4 HBA. Both are within acceptable limits.

**QED:** Ligand A (0.792) has a higher QED score than Ligand B (0.585), indicating a more drug-like profile.

**DILI:** Both ligands have low DILI risk, with Ligand A (12.369) being slightly better than Ligand B (11.788).

**BBB:** Ligand B (75.533) has a significantly higher BBB percentile than Ligand A (66.925), which is a crucial advantage for a CNS target like DRD2.

**Caco-2 Permeability:** Both have negative values, indicating poor permeability. Ligand A (-4.52) is slightly better than Ligand B (-4.829).

**Aqueous Solubility:** Both have negative values, indicating poor solubility. Ligand A (-1.779) is slightly better than Ligand B (-1.377).

**hERG Inhibition:** Both ligands have low hERG inhibition risk, with Ligand A (0.381) being slightly better than Ligand B (0.816).

**Microsomal Clearance:** Ligand A (11.012) has a much lower microsomal clearance than Ligand B (33.929), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand B (-45.397) has a significantly worse in vitro half-life than Ligand A (-0.868).

**P-gp Efflux:** Both ligands have very low P-gp efflux liability. Ligand A (0.032) is slightly better than Ligand B (0.035).

**Binding Affinity:** Ligand B (-7.7 kcal/mol) has a stronger binding affinity than Ligand A (-6.8 kcal/mol). The difference of 0.9 kcal/mol is substantial and can outweigh some of the ADME drawbacks of Ligand B.

**Overall Assessment:**

Ligand B excels in BBB penetration and binding affinity, which are the most critical factors for a CNS GPCR target. While it has some drawbacks in metabolic stability (higher Cl_mic, lower t1/2) and solubility, the significantly improved binding affinity and BBB penetration are likely to be more impactful for *in vivo* efficacy. Ligand A has a better QED, DILI, and metabolic stability, but its lower affinity and BBB penetration are significant disadvantages.

Output:
1
2025-04-17 03:58:51,623 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (348.487 Da) is slightly better positioned.

**TPSA:** Ligand A (58.64) is excellent for CNS penetration, well below the 90 A^2 threshold. Ligand B (118.56) is higher, but still potentially acceptable, though less ideal.

**logP:** Ligand A (2.511) is optimal. Ligand B (0.263) is quite low, potentially hindering membrane permeability and CNS entry.

**H-Bond Donors/Acceptors:** Both have 1 HBD, which is good. Ligand A has 3 HBA, while Ligand B has 8 HBA. Ligand A is preferable here.

**QED:** Both ligands have acceptable QED scores (0.686 and 0.633, both >0.5).

**DILI:** Ligand A (29.081) has a much lower DILI risk than Ligand B (75.688). This is a significant advantage for Ligand A.

**BBB:** Ligand A (73.866) has a good BBB percentile, exceeding the 70% threshold. Ligand B (62.97) is lower, which is concerning for a CNS target.

**Caco-2 Permeability:** Ligand A (-4.941) and Ligand B (-5.272) both have negative values, which is unusual and difficult to interpret without knowing the scale. However, they are similar.

**Aqueous Solubility:** Both ligands have similar, very poor aqueous solubility (-2.844 and -2.824). This could pose formulation challenges.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.477 and 0.2).

**Microsomal Clearance:** Both ligands have similar microsomal clearance (51.525 and 52.735), suggesting comparable metabolic stability.

**In vitro Half-Life:** Ligand A (2.06 hours) has a better in vitro half-life than Ligand B (-26.42 hours - a negative value is unusual and suggests very rapid degradation).

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.202 and 0.044).

**Binding Affinity:** Ligand A (-7.9 kcal/mol) has a slightly better binding affinity than Ligand B (-7.3 kcal/mol). While the difference is not huge, it's enough to be a factor.

**Overall Assessment:**

Ligand A is significantly better. It has a more favorable logP, lower DILI risk, better BBB penetration, and a slightly better binding affinity. While both have poor solubility, the other advantages of Ligand A outweigh this drawback. Ligand B's low logP and higher DILI risk are major concerns for a CNS-targeting drug.

Output:
1
2025-04-17 03:58:51,624 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (373.446 and 381.395 Da) fall within the ideal range of 200-500 Da.

**TPSA:** Ligand A (72.91) is better than Ligand B (62.3). Both are below 90, which is favorable for CNS penetration.

**logP:** Both ligands have good logP values (1.847 and 2.187), falling within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A (0 HBD, 5 HBA) and Ligand B (1 HBD, 4 HBA) both have acceptable numbers of H-bond donors and acceptors, well within the guidelines.

**QED:** Both ligands have good QED scores (0.562 and 0.702), indicating good drug-like properties.

**DILI:** Both ligands have low DILI risk (40.054 and 38.62), which is positive.

**BBB:** Ligand A (91.663) has a significantly higher BBB percentile than Ligand B (71.229). This is a critical advantage for a CNS target like DRD2.

**Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and requires further investigation. However, the values are similar (-4.406 and -4.943) and don't strongly differentiate the two.

**Aqueous Solubility:** Both ligands have very poor aqueous solubility (-2.44 and -2.526). This is a significant drawback for both, but may be manageable with formulation strategies.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.429 and 0.367).

**Microsomal Clearance:** Ligand A (11.308 mL/min/kg) has lower microsomal clearance than Ligand B (13.183 mL/min/kg), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (21.803 hours) has a significantly longer half-life than Ligand B (-4.816 hours). This is a major advantage.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.244 and 0.077).

**Binding Affinity:** Ligand A (-8.7 kcal/mol) has a slightly better binding affinity than Ligand B (-8.1 kcal/mol), though the difference is relatively small.

**Overall Assessment:**

Ligand A is superior due to its significantly better BBB penetration (91.663 vs 71.229), longer in vitro half-life (21.803 vs -4.816), and slightly better binding affinity (-8.7 vs -8.1). While both have poor solubility, the improved pharmacokinetic properties of Ligand A make it a more promising drug candidate for a CNS target like DRD2.

Output:
1
2025-04-17 03:58:51,624 - INFO - Reasoning:

Let's analyze Ligand A and Ligand B against the provided guidelines, prioritizing GPCR-specific properties (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (369.45 & 386.50 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (105.55) is higher than the preferred <90 for CNS targets, while Ligand B (75.62) is well within the range. This is a significant advantage for Ligand B.

**logP:** Ligand A (-2.059) is too low, potentially hindering membrane permeability. Ligand B (3.964) is near the upper limit of optimal (1-3), but still acceptable.

**H-Bond Donors/Acceptors:** Both ligands have 2 HBD and 7-8 HBA, which are within acceptable limits.

**QED:** Both ligands have good QED scores (0.558 and 0.711), indicating drug-like properties.

**DILI:** Ligand A (41.30) has a lower DILI risk than Ligand B (80.61), which is a positive for Ligand A.

**BBB:** This is crucial for a CNS target like DRD2. Ligand A (12.87) has a very poor BBB percentile, making it unlikely to reach the target in the brain. Ligand B (77.59) is excellent, exceeding the >70 desirable threshold. This is a major advantage for Ligand B.

**Caco-2 Permeability:** Both have negative values, indicating poor permeability.

**Aqueous Solubility:** Both have negative values, indicating poor solubility.

**hERG:** Both ligands have very low hERG inhibition liability (0.091 and 0.43), which is good.

**Microsomal Clearance:** Ligand A (-18.93) suggests very low clearance (highly metabolically stable), which is good. Ligand B (63.18) is higher, indicating faster metabolism.

**In vitro Half-Life:** Ligand A (23.67) has a longer half-life than Ligand B (12.33), which is favorable.

**P-gp Efflux:** Ligand A (0.003) has very low P-gp efflux, suggesting good CNS exposure. Ligand B (0.218) is higher, meaning it's more likely to be pumped out of the brain.

**Binding Affinity:** Ligand B (-8.5 kcal/mol) has a slightly better binding affinity than Ligand A (-7.5 kcal/mol). While the difference is not huge, it's a contributing factor.

**Overall Assessment:**

Ligand B is significantly better suited as a drug candidate for DRD2. Its excellent BBB penetration, acceptable logP, and better binding affinity outweigh the slightly higher DILI risk and faster metabolism. Ligand A's extremely poor BBB penetration is a deal-breaker for a CNS target, despite its favorable metabolic stability and lower DILI. The TPSA of Ligand B is also much more favorable.

Output:
1
2025-04-17 03:58:51,624 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B based on the provided guidelines, prioritizing GPCR-specific properties (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (335.407) is slightly preferred as it's closer to the lower end, potentially aiding permeability, but the difference isn't substantial.

**TPSA:** Ligand A (54.46) is excellent for CNS penetration, well below the 90 A^2 threshold. Ligand B (89.87) is still reasonable, but less ideal.

**logP:** Ligand A (2.966) is optimal (1-3). Ligand B (0.389) is quite low, potentially hindering membrane permeability and CNS entry. This is a significant drawback.

**H-Bond Donors/Acceptors:** Ligand A (HBD=1, HBA=4) and Ligand B (HBD=3, HBA=4) both fall within acceptable ranges.

**QED:** Both ligands have good QED scores (A: 0.937, B: 0.623), indicating drug-like properties.

**DILI:** Ligand A (43.04) has a slightly higher DILI risk than Ligand B (18.922), but both are below the concerning threshold of 60.

**BBB:** Ligand A (88.29) has excellent BBB penetration, exceeding the desirable 70% threshold. Ligand B (78.79) is still good, but less favorable.

**Caco-2 Permeability:** Ligand A (-4.818) and Ligand B (-5.082) both have negative values, which is unusual. Assuming these are logP-like scales, lower values indicate lower permeability. Both are poor.

**Aqueous Solubility:** Ligand A (-3.403) and Ligand B (-1.171) both have negative values, indicating poor solubility.

**hERG:** Both ligands have low hERG inhibition risk (A: 0.726, B: 0.332).

**Microsomal Clearance:** Ligand A (21.53) has a higher clearance than Ligand B (-21.896). This suggests Ligand B is more metabolically stable.

**In vitro Half-Life:** Ligand A (-2.816) has a shorter half-life than Ligand B (-4.949).

**P-gp Efflux:** Ligand A (0.212) has lower P-gp efflux than Ligand B (0.063), indicating better potential for CNS exposure.

**Binding Affinity:** Ligand A (-10.1 kcal/mol) has significantly stronger binding affinity than Ligand B (-8.8 kcal/mol). This is a substantial advantage.

**Overall Assessment:**

Ligand A is the stronger candidate. While Ligand B has better metabolic stability and lower DILI risk, Ligand A's superior BBB penetration, optimal logP, and *much* stronger binding affinity outweigh these drawbacks, especially considering the target is a CNS GPCR (DRD2). The lower logP of Ligand B is a major concern for CNS penetration. The significantly better affinity of Ligand A (-10.1 vs -8.8) is a decisive factor.

Output:
1
2025-04-17 03:58:51,624 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (399.204 Da) is slightly higher than Ligand B (360.479 Da), but both are acceptable.

**2. TPSA:** Ligand A (100.88) is borderline for CNS targets (ideally <90), while Ligand B (68.17) is well within the desired range. This is a significant advantage for Ligand B.

**3. logP:** Both ligands have good logP values (A: 3.008, B: 3.13), falling within the optimal 1-3 range.

**4. H-Bond Donors:** Ligand A (2) and Ligand B (1) are both acceptable, being less than 5.

**5. H-Bond Acceptors:** Ligand A (5) and Ligand B (4) are both acceptable, being less than 10.

**6. QED:** Both ligands have good QED scores (A: 0.552, B: 0.911). Ligand B's score is considerably higher, indicating a more drug-like profile.

**7. DILI:** Ligand A (98.953) has a very high DILI risk, which is concerning. Ligand B (74.021) has a moderate DILI risk, which is much better.

**8. BBB:** Ligand A (61.342) has a moderate BBB penetration, while Ligand B (76.27) is better, though still not ideal (aim for >70).

**9. Caco-2:** Both show poor Caco-2 permeability (-5.55 and -4.68 respectively). This suggests potential absorption issues.

**10. Solubility:** Both have poor aqueous solubility (-5.019 and -3.352 respectively).

**11. hERG:** Both ligands have low hERG inhibition risk (A: 0.688, B: 0.386).

**12. Cl_mic:** Both ligands have similar microsomal clearance (A: 29.063, B: 29.061).

**13. t1/2:** Ligand A (90.982) has a much longer in vitro half-life than Ligand B (-8.43). This is a significant advantage for Ligand A.

**14. Pgp:** Both ligands have low P-gp efflux liability (A: 0.425, B: 0.454).

**15. Binding Affinity:** Ligand A (-10.2 kcal/mol) has a significantly stronger binding affinity than Ligand B (-8.9 kcal/mol). This is a substantial advantage for Ligand A, potentially outweighing some of its ADME drawbacks.

**Overall Assessment:**

Ligand A has a much stronger binding affinity and a longer half-life, which are highly desirable. However, its very high DILI risk and borderline TPSA are major concerns. Ligand B has a better safety profile (lower DILI), better TPSA, and a higher QED score, but its binding affinity is weaker.

Given the GPCR-specific priorities, the balance tips towards Ligand B. While the affinity difference is significant, the high DILI risk associated with Ligand A is a substantial hurdle. The slightly better BBB and TPSA of Ligand B, combined with its superior QED, make it the more promising candidate, despite the weaker binding. Further optimization of Ligand B to improve its affinity would be a logical next step.

Output:
1
2025-04-17 03:58:51,624 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (354.422 and 356.482 Da) fall comfortably within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (59.08) is slightly higher than Ligand B (49.85). Both are below the 90 A^2 threshold desirable for CNS targets, making both favorable.

**3. logP:** Ligand A (1.155) is at the lower end of the optimal 1-3 range, while Ligand B (2.637) is closer to the middle. Ligand B is slightly preferred here as it has better potential for membrane permeability.

**4. H-Bond Donors:** Both ligands have 0 HBD, which is good.

**5. H-Bond Acceptors:** Ligand A has 4 HBA, Ligand B has 3. Both are below the 10 threshold.

**6. QED:** Both ligands have similar QED values (0.672 and 0.628), indicating good drug-likeness.

**7. DILI:** Ligand A (25.165) has a significantly lower DILI risk than Ligand B (11.439). This is a substantial advantage for Ligand A.

**8. BBB:** Both ligands have excellent BBB penetration (89.376 and 90.617), exceeding the >70% threshold for CNS targets.

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.298 and -4.237). This is unusual and suggests poor permeability. However, these values are on a scale where negative values are possible, and the absolute value is more important. They are very similar.

**10. Aqueous Solubility:** Both ligands have negative solubility values (-1.835 and -1.722). Similar to Caco-2, these are on a scale where negative values are possible.

**11. hERG Inhibition:** Ligand A (0.355) has a lower hERG inhibition liability than Ligand B (0.811), indicating a lower risk of cardiotoxicity.

**12. Microsomal Clearance:** Ligand B (48.086) has a lower microsomal clearance than Ligand A (34.731), suggesting better metabolic stability.

**13. In vitro Half-Life:** Ligand B (9.105) has a significantly longer in vitro half-life than Ligand A (0.296). This is a major advantage for Ligand B.

**14. P-gp Efflux:** Ligand A (0.061) has lower P-gp efflux liability than Ligand B (0.307), which is favorable for CNS exposure.

**15. Binding Affinity:** Both ligands have very similar and strong binding affinities (-7.2 and -7.3 kcal/mol). The difference is negligible.

**Overall Assessment:**

Ligand A excels in DILI risk, hERG inhibition, and P-gp efflux. Ligand B has better metabolic stability (lower Cl_mic and longer t1/2) and a slightly better logP. The Caco-2 and solubility values are similar and problematic for both. Given the importance of metabolic stability for *in vivo* efficacy, and the similar binding affinities, Ligand B appears slightly more promising. However, the significantly lower DILI risk of Ligand A is a strong consideration. Considering the balance, the longer half-life and better logP of Ligand B are more critical for a CNS drug.

Output:
1
2025-04-17 03:58:51,625 - INFO - Reasoning:

Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (353.403 Da) and Ligand B (338.382 Da) are both acceptable.

**TPSA:** Ligand A (92.18) is slightly above the optimal <90 for CNS targets, but still reasonable. Ligand B (40.62) is excellent, well below the 90 threshold.

**logP:** Both ligands have good logP values (A: 3.151, B: 2.222), falling within the 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A (HBD=2, HBA=5) and Ligand B (HBD=0, HBA=2) both have acceptable numbers of H-bond donors and acceptors.

**QED:** Both ligands have good QED scores (A: 0.71, B: 0.776), indicating good drug-like properties.

**DILI:** Ligand A (94.804) has a high DILI risk, exceeding the 60 threshold. Ligand B (47.926) has a much lower, acceptable DILI risk. This is a significant negative for Ligand A.

**BBB:** Ligand A (22.993) has very poor predicted BBB penetration. Ligand B (87.476) has excellent predicted BBB penetration, exceeding the desirable >70 threshold for CNS targets. This is a critical advantage for Ligand B.

**Caco-2 Permeability:** Ligand A (-5.485) has poor Caco-2 permeability. Ligand B (-4.36) is also poor, but slightly better than A.

**Aqueous Solubility:** Both ligands have poor aqueous solubility (A: -3.171, B: -3.585).

**hERG Inhibition:** Ligand A (0.028) has very low hERG inhibition risk. Ligand B (0.473) has a slightly higher, but still relatively low, hERG risk.

**Microsomal Clearance:** Ligand A (-3.565) has good metabolic stability (negative value). Ligand B (18.828) has relatively high metabolic clearance, which is a negative.

**In vitro Half-Life:** Ligand A (-1.605) has good in vitro half-life. Ligand B (-11.122) has poor in vitro half-life.

**P-gp Efflux:** Both ligands have very low P-gp efflux (A: 0.023, B: 0.202), which is good for CNS penetration.

**Binding Affinity:** Both ligands have the same binding affinity (-9.4 kcal/mol), which is excellent.

**Overall Assessment:**

While both ligands have excellent binding affinity, Ligand B is significantly more promising due to its superior BBB penetration (87.5% vs 23%), lower DILI risk (47.9% vs 94.8%), and better TPSA (40.6 vs 92.2). Ligand A's high DILI risk and poor BBB penetration are major drawbacks for a CNS-targeting drug. Ligand B's metabolic clearance and half-life are less favorable, but these can potentially be addressed through structural modifications without significantly impacting the key properties.

Output:
1
2025-04-17 03:58:51,625 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the acceptable range (200-500 Da). Ligand A (462.332 Da) is higher, but not excessively so. Ligand B (345.359 Da) is lower, potentially aiding permeability.

**TPSA:** Ligand A (87.32) is excellent for CNS penetration, being well below 90. Ligand B (120.32) is higher, but still potentially acceptable, though less ideal.

**logP:** Ligand A (3.17) is optimal. Ligand B (-0.294) is significantly low, which could hinder membrane permeability and potentially reduce binding affinity.

**H-Bond Donors/Acceptors:** Ligand A (HBD=2, HBA=4) is well within the guidelines. Ligand B (HBD=3, HBA=6) is also acceptable, but slightly higher.

**QED:** Both ligands have good QED scores (A: 0.662, B: 0.703), indicating good drug-like properties.

**DILI:** Both ligands have similar DILI risk (A: 61.303, B: 56.146), indicating moderate risk.

**BBB:** Ligand A (55.913) has a moderate BBB penetration score, while Ligand B (19.349) has a very low score. This is a critical difference for a CNS target like DRD2.

**Caco-2 Permeability:** Ligand A (-4.899) has poor Caco-2 permeability, which is concerning. Ligand B (-5.408) is also poor, but slightly worse.

**Aqueous Solubility:** Both have very poor aqueous solubility (A: -4.402, B: -2.832). This could pose formulation challenges.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (A: 0.541, B: 0.202).

**Microsomal Clearance:** Ligand A (39.454) has moderate clearance, while Ligand B (-18.016) has negative clearance (highly desirable, indicating excellent metabolic stability).

**In vitro Half-Life:** Ligand B (-35.024) has a very long half-life, which is a significant advantage. Ligand A (6.102) has a shorter half-life.

**P-gp Efflux:** Both have very low P-gp efflux (A: 0.218, B: 0.013), which is favorable for CNS penetration.

**Binding Affinity:** Ligand B (-8.6 kcal/mol) has a significantly stronger binding affinity than Ligand A (0 kcal/mol). This is a substantial advantage.

**Overall Assessment:**

Ligand B is the better candidate despite its low logP and poor Caco-2 permeability. The significantly stronger binding affinity (-8.6 kcal/mol vs 0 kcal/mol) and the exceptionally long in vitro half-life and low P-gp efflux outweigh the drawbacks. The poor logP could be addressed with structural modifications, but a strong starting affinity is crucial. The very low BBB score is a concern, but not insurmountable if other properties are favorable. Ligand A's poor affinity makes it a less attractive starting point, even with a slightly better TPSA and BBB score.



Output:
1
2025-04-17 03:58:51,625 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (431.352 Da) is higher, but still acceptable. Ligand B (351.403 Da) is slightly lower, potentially aiding permeability.

**2. TPSA:** Ligand A (86.71) is excellent, falling well below the 90 A^2 threshold for CNS targets. Ligand B (109.66) is higher, but still within a reasonable range, though less optimal for CNS penetration.

**3. logP:** Ligand A (2.848) is optimal. Ligand B (0.133) is significantly low, which could hinder membrane permeability and potentially reduce binding affinity.

**4. H-Bond Donors:** Both ligands have acceptable HBD counts (Ligand A: 2, Ligand B: 3).

**5. H-Bond Acceptors:** Both ligands have acceptable HBA counts (Ligand A: 3, Ligand B: 6).

**6. QED:** Both ligands have similar, acceptable QED values (Ligand A: 0.718, Ligand B: 0.647).

**7. DILI:** Both ligands have acceptable DILI risk (Ligand A: 64.327, Ligand B: 54.827), below the 60 threshold.

**8. BBB:** Ligand A (59.984) is borderline for good CNS penetration, while Ligand B (45.909) is lower. This is a crucial factor for DRD2.

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.389 and -5.169), which is unusual and suggests poor intestinal absorption. This is a concern for oral bioavailability.

**10. Aqueous Solubility:** Both ligands have negative solubility values (-3.376 and -1.589), indicating very poor aqueous solubility. This is a significant drawback for formulation and bioavailability.

**11. hERG Inhibition:** Both ligands have very low hERG inhibition risk (Ligand A: 0.261, Ligand B: 0.124).

**12. Microsomal Clearance:** Ligand A (8.251) has a lower clearance, suggesting better metabolic stability than Ligand B (-2.645).

**13. In vitro Half-Life:** Ligand A (30.773 hours) has a significantly longer half-life than Ligand B (15.408 hours).

**14. P-gp Efflux:** Both ligands have very low P-gp efflux liability (Ligand A: 0.114, Ligand B: 0.034).

**15. Binding Affinity:** Ligand B (-8.2 kcal/mol) has a significantly stronger binding affinity than Ligand A (0 kcal/mol). This is a substantial advantage.

**Overall Assessment:**

While Ligand B has a much superior binding affinity, its very low logP and lower BBB penetration are major concerns for a CNS target like DRD2. The poor solubility and permeability (Caco-2) are also problematic. Ligand A, despite its weaker binding affinity, has a much better logP, TPSA, and a reasonable BBB score. Its better metabolic stability (lower Cl_mic and longer half-life) is also advantageous. The significantly stronger binding of Ligand B *could* potentially overcome the ADME issues, but the low logP is a substantial hurdle for CNS penetration. Given the GPCR-specific priorities, and the importance of BBB penetration for DRD2, I believe Ligand A is the more viable candidate, as it has a better balance of properties. Further optimization of Ligand A to improve its binding affinity would be a more promising strategy than attempting to fix the severe ADME issues of Ligand B.

Output:
0
2025-04-17 03:58:51,625 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (352.435 and 351.447 Da) fall comfortably within the ideal 200-500 Da range.

**TPSA:** Ligand A (105.48) is slightly above the preferred <90 for CNS targets, but still reasonable. Ligand B (89.95) is excellent, falling well below 90.

**logP:** Ligand A (2.068) is optimal (1-3). Ligand B (0.123) is quite low, potentially hindering membrane permeability.

**H-Bond Donors/Acceptors:** Ligand A (HBD=3, HBA=6) and Ligand B (HBD=2, HBA=4) both have acceptable numbers of H-bond donors and acceptors, within the guidelines.

**QED:** Both ligands have good QED scores (0.752 and 0.756), indicating drug-like properties.

**DILI:** Ligand A (48.623) has a moderate DILI risk, but is acceptable. Ligand B (18.922) has a very low DILI risk, which is a significant advantage.

**BBB:** Ligand A (78.558) has a good BBB percentile, exceeding the 70% threshold for CNS targets. Ligand B (59.829) is below this threshold, which is a major drawback for a CNS target like DRD2.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.466 and -4.763), which is unusual and suggests poor permeability. However, these values are on a log scale and are likely indicating very low permeability.

**Aqueous Solubility:** Both ligands have negative solubility values (-2.925 and -1.537), suggesting poor solubility.

**hERG:** Both ligands have very low hERG inhibition risk (0.118 and 0.164).

**Microsomal Clearance:** Ligand A (44.697) has moderate clearance, while Ligand B (-0.87) has very low clearance, indicating better metabolic stability.

**In vitro Half-Life:** Ligand A (-10.841) has a negative half-life, which is not physically possible and likely indicates a very rapid degradation. Ligand B (7.099) has a reasonable half-life.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.023 and 0.01).

**Binding Affinity:** Ligand A (-8.5 kcal/mol) has slightly better binding affinity than Ligand B (-7.8 kcal/mol), but the difference is not huge.

**Overall Assessment:**

Ligand A has a better BBB score and slightly better binding affinity. However, it has a concerning negative in vitro half-life and moderate microsomal clearance. Ligand B has a significantly lower DILI risk, much better metabolic stability (very low Cl_mic), a reasonable half-life, and a better TPSA. The biggest drawback for Ligand B is its low logP and resulting poor BBB penetration. However, the DRD2 is a GPCR, and while BBB is important, a strong binding affinity and favorable ADME properties can sometimes compensate. Given the issues with Ligand A's stability and the superior safety profile of Ligand B, I would prioritize Ligand B, hoping that formulation strategies could mitigate the low logP and improve BBB penetration.

Output:
1
2025-04-17 03:58:51,626 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (344.455 and 356.501 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (58.64) is excellent for CNS penetration, well below the 90 A^2 threshold. Ligand B (23.55) is even better.

**logP:** Ligand A (2.021) is optimal. Ligand B (4.028) is at the higher end of the optimal range, potentially raising concerns about solubility and off-target effects, but still acceptable.

**H-Bond Donors/Acceptors:** Ligand A has 1 HBD and 3 HBA, which is good. Ligand B has 0 HBD and 2 HBA, also good. Both are within the recommended limits.

**QED:** Both ligands have good QED values (0.613 and 0.717, respectively), indicating drug-like properties.

**DILI:** Both ligands have relatively low DILI risk (12.136 and 13.532 percentiles), which is favorable.

**BBB:** Ligand A (70.648) has a good BBB penetration score, meeting the >70% threshold for CNS targets. Ligand B (97.635) is *excellent* with very high predicted BBB penetration. This is a significant advantage.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.785 and -4.547). This is unusual and suggests poor intestinal absorption. However, for a CNS target, intestinal absorption is less critical than BBB penetration.

**Aqueous Solubility:** Both ligands have negative solubility values (-2.956 and -3.393). This is concerning, but can sometimes be overcome with formulation strategies, *especially* if BBB penetration is high.

**hERG Inhibition:** Ligand A (0.109) shows very low hERG inhibition risk, which is excellent. Ligand B (0.963) is slightly higher, but still relatively low risk.

**Microsomal Clearance:** Ligand A (1.012) has very low microsomal clearance, indicating good metabolic stability. Ligand B (24.165) has significantly higher clearance, suggesting faster metabolism and potentially lower exposure.

**In vitro Half-Life:** Ligand A (-2.238) has a negative half-life, which is not physically meaningful and suggests a very rapid clearance. Ligand B (-1.544) is also negative, but less so.

**P-gp Efflux:** Ligand A (0.048) has very low P-gp efflux, which is ideal for CNS penetration. Ligand B (0.632) has moderate P-gp efflux, which is less desirable.

**Binding Affinity:** Ligand A (-8.4 kcal/mol) has a significantly stronger binding affinity than Ligand B (-7.5 kcal/mol). This 1.9 kcal/mol difference is substantial and could outweigh some of the ADME drawbacks.

**Overall Assessment:**

Ligand B excels in BBB penetration and has acceptable logP, DILI, and hERG values. However, its higher microsomal clearance, P-gp efflux, and weaker affinity are drawbacks. Ligand A has excellent metabolic stability and P-gp properties, and a *much* stronger binding affinity. While its solubility and Caco-2 permeability are poor, the strong affinity and excellent BBB penetration are crucial for a CNS-targeting GPCR like DRD2. The negative half-life values are concerning, but could be due to modeling limitations. The superior binding affinity of Ligand A is likely to be a decisive factor.

Output:
0
2025-04-17 03:58:51,626 - INFO - Reasoning:

Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (342.483 and 345.443 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (40.62) is significantly better than Ligand B (75.44). For CNS targets, we want TPSA <= 90, and ideally closer to 60. Ligand A is well within this range, while Ligand B is approaching the upper limit and less favorable.

**3. logP:** Both ligands have acceptable logP values (3.13 and 2.54), falling within the optimal 1-3 range.

**4. H-Bond Donors:** Ligand A (0) is preferable to Ligand B (1). Fewer HBDs generally improve permeability.

**5. H-Bond Acceptors:** Ligand A (2) is better than Ligand B (4). Lower HBA counts are generally preferred for CNS penetration.

**6. QED:** Both ligands have good QED scores (0.582 and 0.804), indicating good drug-like properties. Ligand B is slightly better.

**7. DILI:** Ligand A (24.234) has a lower DILI risk than Ligand B (35.479), which is a positive attribute.

**8. BBB:** Both ligands have excellent BBB penetration (77.937 and 83.404), exceeding the desirable >70 threshold for CNS targets. Ligand B is slightly better.

**9. Caco-2 Permeability:** Ligand A (-4.639) is worse than Ligand B (-5.057). Lower values here are less desirable.

**10. Aqueous Solubility:** Ligand A (-3.139) is worse than Ligand B (-2.55). Lower values here are less desirable.

**11. hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.348 and 0.306), which is excellent.

**12. Microsomal Clearance:** Ligand A (68.818) has higher microsomal clearance than Ligand B (40.382), indicating lower metabolic stability. This is a negative for Ligand A.

**13. In vitro Half-Life:** Ligand A (-26.421) has a shorter in vitro half-life than Ligand B (-18.047), which is unfavorable.

**14. P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.324 and 0.276), which is excellent for CNS exposure.

**15. Binding Affinity:** Both ligands have identical binding affinities (-8.1 kcal/mol), which is very strong and exceeds the desired < -7.0 kcal/mol.

**Overall Assessment:**

While both ligands have strong binding affinity and good BBB penetration, Ligand A is superior in terms of TPSA, HBD, HBA, and DILI risk. However, Ligand B has better Caco-2 permeability, solubility, metabolic stability (lower Cl_mic), and a longer in vitro half-life. Given the GPCR-specific focus on BBB, logP, Pgp, TPSA, and affinity, and the importance of metabolic stability for *in vivo* efficacy, Ligand B is the slightly better candidate. The lower TPSA and better ADME properties of Ligand B outweigh the slightly worse Caco-2 and solubility.

Output:
1
2025-04-17 03:58:51,626 - INFO - Batch 74 complete. Total preferences: 1184
2025-04-17 03:58:51,626 - INFO - Processing batch 75/512...
2025-04-17 03:59:33,851 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (464.117 Da) is higher, but still acceptable. Ligand B (345.399 Da) is lower, potentially aiding permeability.

**TPSA:** Ligand A (71.42) is better than Ligand B (101.3). For CNS targets, we want TPSA <= 90, so Ligand A is closer to this threshold.

**logP:** Ligand A (4.602) is high, potentially causing solubility and off-target issues. Ligand B (1.889) is within the optimal range (1-3).

**H-Bond Donors/Acceptors:** Both have 2 HBDs, which is good. Ligand A has 4 HBAs, and Ligand B has 5. Both are acceptable, being <=10.

**QED:** Both ligands have good QED scores (A: 0.466, B: 0.627), indicating reasonable drug-likeness. Ligand B is slightly better.

**DILI:** Ligand A (96.82) has a very high DILI risk, which is a significant concern. Ligand B (60.915) is also elevated, but considerably lower than Ligand A.

**BBB:** Ligand A (48.119) has a low BBB penetration percentile, which is a major drawback for a CNS target like DRD2. Ligand B (57.115) is also not ideal, but better than Ligand A.

**Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and suggests poor permeability.

**Aqueous Solubility:** Both have negative solubility values, indicating very poor solubility.

**hERG:** Ligand A (0.898) has a slightly elevated hERG risk, while Ligand B (0.031) shows very low risk.

**Microsomal Clearance:** Ligand A (45.254) has moderate clearance, while Ligand B (29.42) has lower clearance, indicating better metabolic stability.

**In vitro Half-Life:** Ligand A (63.127) has a reasonable half-life, while Ligand B (-31.621) has a negative half-life, which is impossible and suggests a data error or significant instability.

**P-gp Efflux:** Ligand A (0.867) has moderate P-gp efflux, while Ligand B (0.11) has very low efflux, which is favorable for CNS penetration.

**Binding Affinity:** Ligand A (-9.3 kcal/mol) has significantly stronger binding affinity than Ligand B (0.0 kcal/mol). This is a substantial advantage.

**Overall Assessment:**

Despite the strong binding affinity of Ligand A, its extremely high DILI risk and poor BBB penetration are major red flags. The high logP also raises concerns. Ligand B has better ADME properties (lower DILI, better P-gp efflux, better logP, lower hERG), but its binding affinity is essentially zero, making it unlikely to be effective. The negative half-life for ligand B is also a critical issue.

However, the difference in binding affinity is so large (-9.3 vs 0.0 kcal/mol) that it *could* potentially outweigh the ADME issues of Ligand A, *if* those issues could be addressed through further optimization. The poor ADME properties of Ligand A would require significant medicinal chemistry effort to improve. Ligand B, with no binding affinity, is not a viable starting point.

Output:
1
2025-04-17 03:59:33,851 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (342.483 and 356.455 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (49.41) is excellent, well below the 90 A^2 threshold for CNS targets. Ligand B (103.59) is higher, but still potentially acceptable, though less optimal for CNS penetration.

**3. logP:** Both ligands have good logP values (3.262 and 2.575), falling within the 1-3 range.

**4. H-Bond Donors:** Both ligands have acceptable HBD counts (1 and 2 respectively), below the threshold of 5.

**5. H-Bond Acceptors:** Ligand A (2) is excellent. Ligand B (7) is higher, but still within the acceptable range of 10.

**6. QED:** Both ligands have good QED scores (0.827 and 0.872), indicating good drug-like properties.

**7. DILI:** Ligand A (36.293) has a much lower DILI risk than Ligand B (85.072). This is a significant advantage for Ligand A.

**8. BBB:** Ligand A (67.817) has a significantly better BBB penetration percentile than Ligand B (51.066). This is crucial for a CNS target like DRD2.

**9. Caco-2:** Both ligands have negative Caco-2 values (-4.623 and -4.963), which is unusual and difficult to interpret without further context. It suggests poor permeability, but could be an artifact of the prediction method.

**10. Solubility:** Both ligands have negative solubility values (-4.354 and -4.689), again suggesting poor solubility. This is a concern, but can be addressed through formulation.

**11. hERG:** Both ligands have low hERG risk (0.54 and 0.464).

**12. Cl_mic:** Ligand B (34.468) has a lower microsomal clearance, indicating better metabolic stability than Ligand A (69.561).

**13. t1/2:** Ligand B (17.318) has a longer in vitro half-life than Ligand A (-11.085). This is a significant advantage for Ligand B.

**14. Pgp:** Ligand A (0.438) has lower P-gp efflux liability than Ligand B (0.046). Lower Pgp is preferred for CNS exposure.

**15. Binding Affinity:** Both ligands have excellent binding affinities (-8.6 and -8.1 kcal/mol). The difference of 0.5 kcal/mol is not substantial enough to outweigh other factors.

**Overall Assessment:**

Ligand A is the better candidate. While Ligand B has better metabolic stability and half-life, Ligand A excels in critical areas for a CNS GPCR target: significantly lower DILI risk, much better BBB penetration, and lower P-gp efflux. Its TPSA is also considerably lower, which favors CNS penetration. The negative Caco-2 and solubility values are concerning for both, but formulation strategies could potentially mitigate these issues. The slightly weaker affinity of Ligand A is not a major drawback given its superior ADME properties.

Output:
0
2025-04-17 03:59:33,852 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (392.815 and 370.559 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (88.33) is slightly above the optimal <90 for CNS targets, but still reasonable. Ligand B (69.64) is well within the desired range.

**3. logP:** Both ligands have good logP values (3.004 and 2.568), falling within the 1-3 optimal range.

**4. H-Bond Donors:** Ligand A (1) and Ligand B (2) are both acceptable, being less than 5.

**5. H-Bond Acceptors:** Ligand A (6) and Ligand B (4) are both acceptable, being less than 10.

**6. QED:** Both ligands have similar QED values (0.697 and 0.644), indicating good drug-like properties.

**7. DILI:** Ligand A (77.2) has a higher DILI risk than Ligand B (33.307). This is a significant negative for Ligand A.

**8. BBB:** Both ligands have good BBB penetration (81.078 and 71.074), exceeding the 70% threshold for CNS targets. Ligand A has a slightly better BBB score.

**9. Caco-2 Permeability:** Ligand A (-4.848) and Ligand B (-5.135) both have negative values, indicating poor permeability. This is a concern for both.

**10. Aqueous Solubility:** Both ligands have poor aqueous solubility (-3.685 and -3.027).

**11. hERG Inhibition:** Both ligands have low hERG inhibition risk (0.595 and 0.588).

**12. Microsomal Clearance:** Ligand A (59.301) has a higher microsomal clearance than Ligand B (50.796), suggesting lower metabolic stability.

**13. In vitro Half-Life:** Ligand B (-2.871) has a significantly longer in vitro half-life than Ligand A (23.512). This is a major advantage for Ligand B.

**14. P-gp Efflux:** Both ligands have low P-gp efflux liability (0.369 and 0.397).

**15. Binding Affinity:** Ligand B (-7.5 kcal/mol) has a stronger binding affinity than Ligand A (-8.0 kcal/mol). While A is slightly better, the difference is not substantial enough to overcome other issues.

**Overall Assessment:**

Ligand B is the more promising candidate. While both have poor Caco-2 permeability and solubility, Ligand B demonstrates a significantly better safety profile (lower DILI risk) and improved metabolic stability (longer half-life). The slightly better binding affinity of Ligand A is outweighed by its higher DILI risk and lower half-life. Given the GPCR target and the need for CNS penetration, the improved safety and pharmacokinetic properties of Ligand B make it the more viable option.

Output:
1
2025-04-17 03:59:33,852 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (372.531 & 343.471 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (87.66) is better than Ligand B (61.44). Both are below the 90 A^2 threshold desirable for CNS targets, but A is slightly higher and could potentially impact BBB penetration less favorably than B.

**3. logP:** Both ligands have good logP values (1.483 & 2.174), falling within the optimal 1-3 range.

**4. H-Bond Donors:** Ligand A (3) and Ligand B (2) are both within the acceptable limit of <= 5.

**5. H-Bond Acceptors:** Ligand A (5) and Ligand B (3) are both within the acceptable limit of <= 10.

**6. QED:** Ligand B (0.76) has a significantly better QED score than Ligand A (0.506), indicating a more drug-like profile.

**7. DILI:** Ligand B (15.394) has a much lower DILI risk than Ligand A (19.038), a significant advantage.

**8. BBB:** Ligand B (69.794) has a better BBB percentile than Ligand A (51.26). While both are not ideal (>70), B is considerably better for CNS penetration. This is a critical factor for a DRD2 ligand.

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.045 and -5.011), which is unusual and suggests poor permeability. This is a concern for both.

**10. Aqueous Solubility:** Both ligands have negative solubility values (-2.858 and -2.544), indicating very poor aqueous solubility. This is a significant drawback for both.

**11. hERG Inhibition:** Ligand A (0.145) has a slightly lower hERG inhibition liability than Ligand B (0.611), which is preferable.

**12. Microsomal Clearance:** Ligand B (2.708) has a much lower microsomal clearance than Ligand A (46.961), indicating better metabolic stability.

**13. In vitro Half-Life:** Ligand B (2.483) has a longer in vitro half-life than Ligand A (-1.2), which is desirable.

**14. P-gp Efflux:** Ligand A (0.098) has lower P-gp efflux liability than Ligand B (0.036), which is preferable for CNS exposure.

**15. Binding Affinity:** Ligand B (-9.0) has a significantly stronger binding affinity than Ligand A (-7.2). This >1.5 kcal/mol difference is substantial and can outweigh some ADME drawbacks.

**Overall Assessment:**

Ligand B is the superior candidate. While both have poor Caco-2 and solubility, Ligand B excels in crucial areas for a CNS-targeting GPCR ligand: significantly better BBB penetration, lower DILI risk, much better metabolic stability (lower Cl_mic, longer t1/2), and *much* stronger binding affinity. The improved QED score also supports its drug-likeness. Although Ligand A has slightly better hERG and P-gp profiles, the substantial advantages of Ligand B in BBB, affinity, and metabolic stability outweigh these minor differences.

Output:
1
2025-04-17 03:59:33,852 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (363.527 and 352.435 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (71.09) is excellent, well below the 90 A^2 threshold for CNS targets. Ligand B (85.69) is still reasonable, but less optimal.

**3. logP:** Ligand A (3.142) is within the optimal 1-3 range. Ligand B (0.64) is quite low, potentially hindering membrane permeability and CNS penetration.

**4. H-Bond Donors:** Both ligands have acceptable HBD counts (2 and 1, respectively), well below the 5 threshold.

**5. H-Bond Acceptors:** Both ligands have acceptable HBA counts (4 and 6, respectively), below the 10 threshold.

**6. QED:** Both ligands have good QED scores (0.697 and 0.778), indicating good drug-like properties.

**7. DILI Risk:** Both have low DILI risk, with Ligand B slightly better (34.781 vs 40.52).

**8. BBB Penetration:** Ligand B (62.582) has a better BBB percentile than Ligand A (54.672), but both are below the desirable >70 for CNS targets.

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.016 and -5.015). This is unusual and suggests poor permeability.

**10. Aqueous Solubility:** Both ligands have negative solubility values (-3.193 and -0.773). This is also unusual and suggests poor solubility.

**11. hERG Inhibition:** Both ligands have very low hERG risk (0.111 and 0.066).

**12. Microsomal Clearance:** Ligand B (19.572) has significantly lower microsomal clearance than Ligand A (52.846), indicating better metabolic stability.

**13. In vitro Half-Life:** Ligand B (33.399 hours) has a much longer half-life than Ligand A (13.732 hours).

**14. P-gp Efflux:** Both ligands have low P-gp efflux liability (0.25 and 0.015). Ligand B is better.

**15. Binding Affinity:** Ligand A (-8.1 kcal/mol) has a significantly stronger binding affinity than Ligand B (-6.6 kcal/mol). This is a substantial advantage.

**Overall Assessment:**

While Ligand B has better BBB penetration, metabolic stability, half-life, and P-gp efflux, Ligand A's significantly stronger binding affinity (-8.1 vs -6.6 kcal/mol) is a critical advantage, especially for a GPCR target. The 1.5 kcal/mol difference can often outweigh minor ADME drawbacks. Both ligands have concerning negative Caco-2 and solubility values, which would need to be addressed through further optimization. However, the potency advantage of Ligand A makes it the more promising candidate *at this stage*.

Output:
1
2025-04-17 03:59:33,852 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (404.279 Da) is slightly higher than Ligand B (346.471 Da), but both are acceptable.

**TPSA:** Ligand A (29.54) is excellent for CNS penetration, well below the 90 A^2 threshold. Ligand B (69.64) is higher, but still potentially acceptable, though less ideal.

**logP:** Ligand A (4.427) is a bit high, potentially leading to solubility issues and off-target interactions. Ligand B (2.148) is within the optimal range (1-3).

**H-Bond Donors/Acceptors:** Ligand A (0 HBD, 2 HBA) is favorable. Ligand B (2 HBD, 3 HBA) is also acceptable.

**QED:** Ligand A (0.704) has a better QED score than Ligand B (0.572), indicating a more drug-like profile.

**DILI:** Ligand A (59.636) has a moderate DILI risk, while Ligand B (13.339) has a very low risk, which is a significant advantage.

**BBB:** Ligand A (82.474) has a good BBB penetration percentile, exceeding the 70% threshold. Ligand B (61.497) is below this threshold, which is a concern for a CNS target.

**Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and suggests potential issues with permeability prediction. However, we can still compare relative values. Ligand A (-4.634) is slightly better than Ligand B (-4.655).

**Aqueous Solubility:** Both have negative solubility values, which is also unusual. Ligand A (-4.995) is slightly better than Ligand B (-2.67).

**hERG Inhibition:** Ligand A (0.861) has a slightly higher hERG risk than Ligand B (0.136), which is a significant advantage for Ligand B.

**Microsomal Clearance:** Ligand A (96.752) has a higher microsomal clearance, indicating lower metabolic stability. Ligand B (33.236) has a much lower clearance, suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (42.097) has a reasonable in vitro half-life. Ligand B (-15.288) has a negative half-life, which is not physically possible and indicates a problem with the prediction.

**P-gp Efflux:** Ligand A (0.883) has moderate P-gp efflux, while Ligand B (0.051) has very low efflux, which is highly desirable for CNS penetration.

**Binding Affinity:** Ligand A (-9.7 kcal/mol) has significantly stronger binding affinity than Ligand B (-7.9 kcal/mol). This is a substantial advantage, potentially outweighing some of the ADME drawbacks.

**Overall Assessment:**

Ligand A has a superior binding affinity and good BBB penetration, but suffers from a higher logP, moderate DILI risk, higher microsomal clearance, and moderate P-gp efflux. Ligand B has better ADME properties (lower DILI, lower clearance, lower P-gp efflux, better hERG), but weaker binding affinity and lower BBB penetration.

Given the importance of binding affinity for GPCRs, and the substantial difference (-1.8 kcal/mol), Ligand A is the more promising candidate, *despite* its less ideal ADME profile. The strong binding could allow for lower dosing, potentially mitigating some of the ADME concerns. The BBB penetration is acceptable.

Output:
1
2025-04-17 03:59:33,852 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (337.423 and 346.431 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (61.44) is significantly better than Ligand B (84.42). For CNS targets, we want TPSA <= 90, and A is comfortably within this range, while B is approaching the upper limit.

**logP:** Both ligands have acceptable logP values (2.978 and 1.5), falling within the 1-3 optimal range. Ligand A is slightly preferred due to being closer to the ideal range.

**H-Bond Donors/Acceptors:** Ligand A (HBD=2, HBA=3) and Ligand B (HBD=1, HBA=5) both meet the criteria of <=5 HBD and <=10 HBA.

**QED:** Both ligands have good QED scores (0.847 and 0.873), indicating good drug-like properties.

**DILI:** Ligand A (85.653) has a considerably higher DILI risk than Ligand B (43.428). This is a significant drawback for Ligand A.

**BBB:** Ligand B (70.531) has a better BBB percentile than Ligand A (62.699). While both are above 70, which is desirable for CNS targets, B is better.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.847 and -4.701), which is unusual and suggests poor permeability. This is a concern for both, but the values are similar.

**Aqueous Solubility:** Both ligands have negative solubility values (-4.542 and -2.912), indicating poor aqueous solubility. This is a concern for both.

**hERG Inhibition:** Ligand A (0.622) has a slightly higher hERG risk than Ligand B (0.19). Lower is better, so B is preferred.

**Microsomal Clearance:** Ligand B (43.862) has a significantly higher microsomal clearance than Ligand A (15.686). This means Ligand A is more metabolically stable, which is a positive.

**In vitro Half-Life:** Ligand A (30.666) has a longer in vitro half-life than Ligand B (-13.989). This is a significant advantage for Ligand A.

**P-gp Efflux:** Ligand A (0.27) has a lower P-gp efflux liability than Ligand B (0.075). Lower is better, so A is preferred.

**Binding Affinity:** Ligand A (-9.5 kcal/mol) has a significantly stronger binding affinity than Ligand B (-7.8 kcal/mol). This is a substantial advantage for Ligand A, potentially outweighing some of its ADME drawbacks.

**Overall Assessment:**

Ligand A has a much stronger binding affinity and better metabolic stability (lower Cl_mic, longer t1/2) and lower P-gp efflux. However, it has a significantly higher DILI risk and a lower BBB percentile. Ligand B has a better safety profile (lower DILI, hERG) and better BBB penetration, but weaker binding affinity and poorer metabolic stability.

Given the importance of binding affinity for GPCRs, and the fact that the difference in affinity is substantial (1.7 kcal/mol), I believe Ligand A is the more promising candidate *despite* its higher DILI risk. The DILI risk could potentially be mitigated through structural modifications, but improving the binding affinity of Ligand B would be more challenging. The better BBB and P-gp properties of Ligand A are also favorable.

Output:
1
2025-04-17 03:59:33,853 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (352.435 and 359.289 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (87.91) is excellent, falling well below the 90 A^2 threshold for CNS targets. Ligand B (129.93) is still acceptable but less optimal, nearing the 140 A^2 threshold for oral absorption.

**logP:** Ligand A (0.209) is quite low, potentially hindering permeability. Ligand B (0.377) is also low, but slightly better. Both are below the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A has 1 HBD and 6 HBA, which are reasonable. Ligand B has 2 HBD and 6 HBA, also acceptable.

**QED:** Ligand A (0.72) has a good drug-likeness score. Ligand B (0.431) is lower, indicating a less favorable drug-like profile.

**DILI:** Ligand A (15.936) has a very low DILI risk, which is excellent. Ligand B (74.952) has a significantly higher DILI risk, which is concerning.

**BBB:** Ligand A (56.301) has a moderate BBB penetration score. Ligand B (64.482) is slightly better, but both are below the desirable >70 percentile for CNS targets.

**Caco-2 Permeability:** Ligand A (-4.867) has poor Caco-2 permeability. Ligand B (-5.173) is also poor.

**Aqueous Solubility:** Ligand A (-0.389) has poor solubility. Ligand B (-2.675) has even worse solubility.

**hERG Inhibition:** Ligand A (0.127) has very low hERG inhibition risk. Ligand B (0.349) is slightly higher, but still relatively low.

**Microsomal Clearance:** Ligand A (10.922) has moderate clearance. Ligand B (-5.026) has negative clearance, which is unusual and likely an artifact or error in the data, but suggests very high metabolic stability.

**In vitro Half-Life:** Ligand A (3.831) has a short half-life. Ligand B (-14.633) has a very long half-life, again likely an artifact given the negative value.

**P-gp Efflux:** Ligand A (0.007) has very low P-gp efflux, which is excellent for CNS penetration. Ligand B (0.049) also has low P-gp efflux.

**Binding Affinity:** Ligand A (-7.7 kcal/mol) has a slightly better binding affinity than Ligand B (-7.3 kcal/mol). While both are good, the 1.5 kcal/mol difference is significant.

**Overall Assessment:**

Ligand A is superior despite its lower BBB and logP values. Its significantly lower DILI risk, excellent P-gp efflux profile, and slightly better binding affinity are crucial advantages. The negative values for clearance and half-life of Ligand B are highly suspect and suggest potential data quality issues. While Ligand A's logP is suboptimal, it can potentially be addressed through structural modifications. The poor solubility and permeability of both compounds are drawbacks that would need to be addressed, but are less critical than safety concerns.

Output:
0
2025-04-17 03:59:33,853 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (368.909 Da and 353.438 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (69.3) is slightly above the optimal <90 for CNS targets, but still reasonable. Ligand B (61.88) is well within the desired range.

**3. logP:** Ligand A (3.343) is at the upper end of the optimal 1-3 range, while Ligand B (0.566) is quite low. Low logP can hinder membrane permeability.

**4. H-Bond Donors:** Both ligands have 1 HBD, which is within the acceptable limit of <=5.

**5. H-Bond Acceptors:** Ligand A has 3 HBAs, and Ligand B has 4. Both are below the limit of <=10.

**6. QED:** Ligand A (0.837) has a significantly better QED score than Ligand B (0.56), indicating a more drug-like profile.

**7. DILI:** Ligand A (30.593) has a much lower DILI risk than Ligand B (16.13), suggesting better potential for liver safety.

**8. BBB:** Ligand B (70.88) has a better BBB penetration percentile than Ligand A (64.831), which is crucial for a CNS target like DRD2.

**9. Caco-2 Permeability:** Ligand A (-4.992) has a negative Caco-2 value which is concerning. Ligand B (-4.442) also has a negative value, but is slightly better.

**10. Aqueous Solubility:** Ligand A (-3.68) and Ligand B (-1.18) both have negative solubility values, indicating poor solubility.

**11. hERG Inhibition:** Ligand A (0.751) has a slightly higher hERG inhibition risk than Ligand B (0.371), but both are relatively low.

**12. Microsomal Clearance:** Ligand A (35.45) has a higher microsomal clearance than Ligand B (10.269), meaning it's metabolized faster.

**13. In vitro Half-Life:** Ligand B (-28.1) has a much longer in vitro half-life than Ligand A (-2.958), suggesting better metabolic stability.

**14. P-gp Efflux:** Ligand A (0.237) has a lower P-gp efflux liability than Ligand B (0.029), which is beneficial for CNS penetration.

**15. Binding Affinity:** Both ligands have similar binding affinities (-8.0 kcal/mol and -7.4 kcal/mol respectively). The difference of 0.6 kcal/mol is not substantial enough to be a deciding factor.

**Overall Assessment:**

Ligand B has a better BBB score and longer half-life, which are important for CNS targets. However, it has a significantly lower logP, which could hinder permeability. Ligand A has a better QED, lower DILI risk, and lower P-gp efflux, but a worse BBB score and faster clearance. Considering the importance of CNS penetration for DRD2, and the relatively small difference in binding affinity, Ligand B is slightly more promising. The low logP of Ligand B is a concern, but could potentially be addressed through structural modifications.

Output:
1
2025-04-17 03:59:33,853 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (352.519 and 349.519 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (78.43) is higher than Ligand B (52.65). For a CNS target like DRD2, TPSA should ideally be <=90. Both are within this range, but B is significantly better.

**3. logP:** Both ligands have good logP values (2.622 and 2.548), falling within the optimal 1-3 range.

**4. H-Bond Donors:** Ligand A has 3 HBD, while Ligand B has 1. Both are acceptable (<=5).

**5. H-Bond Acceptors:** Both ligands have 3 HBA, which is well within the acceptable range (<=10).

**6. QED:** Ligand B (0.768) has a higher QED than Ligand A (0.565), indicating a more drug-like profile.

**7. DILI:** Ligand B (4.653) has a much lower DILI risk than Ligand A (10.237). This is a significant advantage for B.

**8. BBB:** Ligand B (79.217) has a better BBB penetration percentile than Ligand A (65.839). Both are reasonably good, but B is preferable for a CNS target.

**9. Caco-2 Permeability:** Ligand A (-4.715) has better Caco-2 permeability than Ligand B (-5.027).

**10. Aqueous Solubility:** Ligand A (-2.988) has better aqueous solubility than Ligand B (-1.546).

**11. hERG Inhibition:** Both ligands have similar, low hERG inhibition liability (0.386 and 0.585).

**12. Microsomal Clearance:** Ligand B (-2.043) has significantly lower microsomal clearance than Ligand A (58.628), suggesting better metabolic stability.

**13. In vitro Half-Life:** Ligand B (-2.044) has a much longer in vitro half-life than Ligand A (-25.857).

**14. P-gp Efflux:** Ligand A (0.231) has lower P-gp efflux than Ligand B (0.035), which is better for CNS exposure.

**15. Binding Affinity:** Both ligands have very similar and strong binding affinities (-8.6 and -8.2 kcal/mol). The difference is less than 1.5 kcal/mol, so this is not a major differentiating factor.

**Overall Assessment:**

Ligand B is the stronger candidate. While Ligand A has slightly better Caco-2 permeability and solubility, Ligand B excels in crucial areas for a CNS-targeting GPCR ligand: lower DILI risk, better BBB penetration, significantly improved metabolic stability (lower Cl_mic and longer t1/2), and a higher QED score. The similar binding affinities make these ADME properties the deciding factors.

Output:
1
2025-04-17 03:59:33,853 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (345.403 and 346.427 Da) fall comfortably within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (83.73) is better than Ligand B (70.83). Both are below the 90 A^2 threshold for CNS targets, which is favorable.

**3. logP:** Ligand A (1.61) and Ligand B (2.266) are both within the optimal 1-3 range.

**4. H-Bond Donors:** Ligand A (1) is better than Ligand B (0). Fewer HBDs generally improve permeability.

**5. H-Bond Acceptors:** Ligand A (8) is higher than Ligand B (4). Ligand B is preferable here.

**6. QED:** Both ligands have good QED scores (0.791 and 0.842), indicating good drug-like properties.

**7. DILI:** Ligand B (34.432) has a significantly lower DILI risk than Ligand A (68.205). This is a major advantage for Ligand B.

**8. BBB:** Ligand A (85.537) has a better BBB penetration percentile than Ligand B (70.57). This is critical for a CNS target like DRD2.

**9. Caco-2 Permeability:** Ligand A (-4.581) has better Caco-2 permeability than Ligand B (-4.461).

**10. Aqueous Solubility:** Ligand A (-2.846) has better aqueous solubility than Ligand B (-1.974).

**11. hERG Inhibition:** Both ligands have low hERG inhibition liability (0.626 and 0.086). Ligand B is slightly better.

**12. Microsomal Clearance:** Ligand B (40.314) has a slightly lower microsomal clearance than Ligand A (49.072), suggesting better metabolic stability.

**13. In vitro Half-Life:** Ligand B (20.65) has a much longer in vitro half-life than Ligand A (8.902). This is a significant advantage.

**14. P-gp Efflux:** Ligand A (0.083) has lower P-gp efflux than Ligand B (0.157). Lower P-gp efflux is favorable for CNS penetration.

**15. Binding Affinity:** Both ligands have excellent binding affinities (-8.3 and -8.5 kcal/mol). The difference is negligible.

**Overall Assessment:**

While Ligand A has better BBB penetration and Caco-2 permeability, Ligand B excels in several critical ADME properties: significantly lower DILI risk, longer half-life, and lower microsomal clearance. The slightly lower P-gp efflux of Ligand A is a minor advantage compared to the more substantial improvements in safety (DILI) and PK (half-life, clearance) offered by Ligand B. Given the GPCR-specific priorities, the improved ADME profile of Ligand B outweighs the slightly better BBB score of Ligand A.

Output:
1
2025-04-17 03:59:33,854 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (369.531 and 354.439 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (61.88) is significantly better than Ligand B (94.8). For CNS targets, we want TPSA <= 90, so Ligand A is preferable.

**3. logP:** Ligand A (0.958) is slightly below the optimal 1-3 range, but acceptable. Ligand B (2.158) is within the optimal range.

**4. H-Bond Donors:** Both have 1 HBD, which is good.

**5. H-Bond Acceptors:** Ligand A has 5, and Ligand B has 7. Both are acceptable (<=10), but Ligand A is slightly better.

**6. QED:** Ligand B (0.907) has a better QED score than Ligand A (0.69), indicating a more drug-like profile.

**7. DILI:** Ligand A (14.23) has a much lower DILI risk than Ligand B (80.07). This is a significant advantage for Ligand A.

**8. BBB:** Ligand A (67.119) is better than Ligand B (62.97), but both are below the desirable >70 percentile for CNS targets. However, given the other parameters, this isn't a dealbreaker.

**9. Caco-2 Permeability:** Both have negative values (-5.082 and -5.27), which is unusual and suggests poor permeability.

**10. Aqueous Solubility:** Both have negative values (-1.781 and -4.625), indicating poor solubility.

**11. hERG Inhibition:** Ligand A (0.315) has a much lower hERG risk than Ligand B (0.787), which is a crucial safety consideration.

**12. Microsomal Clearance:** Both have similar microsomal clearance (31.285 and 32.769 mL/min/kg).

**13. In vitro Half-Life:** Ligand B (17.962) has a longer half-life than Ligand A (11.37), which is generally desirable.

**14. P-gp Efflux:** Ligand A (0.018) has significantly lower P-gp efflux liability than Ligand B (0.121). Lower P-gp efflux is crucial for CNS penetration.

**15. Binding Affinity:** Ligand A (-7.6) has a significantly stronger binding affinity than Ligand B (0). A difference of >1.5 kcal/mol is a major advantage, and can outweigh some ADME drawbacks.

**Overall Assessment:**

Ligand A is the better candidate. While Ligand B has a better QED and half-life, Ligand A excels in the critical areas for a CNS-targeting GPCR ligand: significantly better TPSA, much lower DILI risk, lower hERG risk, lower P-gp efflux, and *much* stronger binding affinity. The slightly lower logP of Ligand A is less concerning than the higher DILI and P-gp efflux of Ligand B. The poor Caco-2 and solubility are concerning for both, but can be addressed through formulation strategies. The superior binding affinity of Ligand A is the deciding factor.

Output:
1
2025-04-17 03:59:33,854 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (344.5) is slightly lower, which is generally favorable for permeability.

**2. TPSA:** Ligand A (49.41) is better than Ligand B (30.29) as it is still within the desirable range for CNS targets (<90). Ligand B is excellent.

**3. logP:** Both ligands have good logP values (A: 3.275, B: 4.081), falling within the optimal 1-3 range. Ligand B is slightly higher, which *could* present solubility issues, but isn't a major concern at this level.

**4. H-Bond Donors:** Ligand A (1) is preferable to Ligand B (0). While both are acceptable, having at least one HBD can improve solubility.

**5. H-Bond Acceptors:** Ligand A (2) is preferable to Ligand B (4). Lower HBA is generally better for CNS penetration.

**6. QED:** Both ligands have acceptable QED scores (A: 0.796, B: 0.643), indicating reasonable drug-likeness. Ligand A is slightly better.

**7. DILI:** Ligand A (30.322) has a significantly lower DILI risk than Ligand B (47.77), making it safer.

**8. BBB:** Ligand B (87.98) has a substantially better BBB penetration score than Ligand A (74.758). This is a *critical* advantage for a CNS target like DRD2.

**9. Caco-2 Permeability:** Both have negative values, which is unusual and suggests poor permeability. However, the scale is not specified, so it's difficult to interpret.

**10. Aqueous Solubility:** Both ligands have very poor aqueous solubility (-4.454 and -4.557). This is a significant drawback for both.

**11. hERG Inhibition:** Both ligands have low hERG inhibition risk (A: 0.348, B: 0.906), which is good.

**12. Microsomal Clearance:** Ligand B (53.773) has lower microsomal clearance than Ligand A (72.355), suggesting better metabolic stability.

**13. In vitro Half-Life:** Ligand B (18.292) has a significantly longer in vitro half-life than Ligand A (-3.473), which is a major advantage.

**14. P-gp Efflux:** Both ligands have low P-gp efflux liability (A: 0.367, B: 0.694), which is favorable for CNS exposure.

**15. Binding Affinity:** Both ligands have excellent binding affinities (A: -9.2 kcal/mol, B: -8.0 kcal/mol). Ligand A is significantly more potent.

**Overall Assessment:**

Ligand A has a better safety profile (lower DILI), better drug-likeness (QED), and *significantly* stronger binding affinity. However, Ligand B excels in BBB penetration and has better metabolic stability (lower Cl_mic and longer t1/2). Given that DRD2 is a CNS target, BBB penetration is paramount. The difference in affinity (1.2 kcal/mol) is substantial, but the superior BBB score of Ligand B, coupled with its improved metabolic stability, outweighs the affinity difference. Solubility is a concern for both, but can be addressed with formulation strategies.

Output:
1
2025-04-17 03:59:33,854 - INFO - Reasoning:

Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (347.375 and 367.406 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Both ligands (111.79 and 113.48) are slightly above the optimal <90 for CNS targets, but still reasonably acceptable.

**3. logP:** Ligand A (-1.786) is lower than the optimal 1-3 range, potentially hindering permeation. Ligand B (0.066) is closer to the optimal range.

**4. H-Bond Donors:** Ligand A (2) and Ligand B (3) are both within the acceptable limit of <=5.

**5. H-Bond Acceptors:** Both ligands (7) are within the acceptable limit of <=10.

**6. QED:** Both ligands have good QED scores (0.623 and 0.707), indicating drug-like properties.

**7. DILI:** Ligand A (46.452) has a much lower DILI risk than Ligand B (68.941), which is a significant advantage.

**8. BBB:** Ligand B (55.642) has a considerably better BBB penetration percentile than Ligand A (16.479). This is a *critical* factor for a CNS target like DRD2.

**9. Caco-2 Permeability:** Both have negative values (-5.14 and -5.377), which is unusual and suggests poor permeability. However, the scale isn't specified, so it's difficult to interpret.

**10. Aqueous Solubility:** Both have negative values (-1.218 and -2.431), again, scale is unspecified.

**11. hERG Inhibition:** Ligand A (0.017) has a very low hERG risk, while Ligand B (0.409) has a slightly elevated risk.

**12. Microsomal Clearance:** Ligand A (-18.907) has a lower (better) microsomal clearance than Ligand B (-16.766), suggesting greater metabolic stability.

**13. In vitro Half-Life:** Ligand B (12.125) has a longer half-life than Ligand A (5.044), which is generally desirable.

**14. P-gp Efflux:** Ligand A (0.009) has very low P-gp efflux, which is excellent for CNS penetration. Ligand B (0.058) is slightly higher but still relatively low.

**15. Binding Affinity:** Ligand B (-8.3 kcal/mol) has a significantly stronger binding affinity than Ligand A (-6.7 kcal/mol). This is a substantial advantage, potentially outweighing some of its ADME drawbacks.

**Overall Assessment:**

While Ligand A has a better safety profile (lower DILI, lower hERG, lower P-gp efflux, better metabolic stability) and a slightly better logP, Ligand B's *much* stronger binding affinity (-8.3 vs -6.7 kcal/mol) and significantly improved BBB penetration (55.642 vs 16.479) are decisive for a CNS GPCR target. The difference in affinity is substantial (>1.5 kcal/mol), and the BBB is paramount. The slightly higher DILI and hERG risk of Ligand B are acceptable given the potency and CNS penetration.

Output:
1
2025-04-17 03:59:33,854 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (344.411 and 339.439 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (66.9) is slightly higher than Ligand B (64.41). Both are below the 90 A^2 threshold desirable for CNS targets, which is good.

**3. logP:** Both ligands have good logP values (2.944 and 2.328), falling within the optimal 1-3 range.

**4. H-Bond Donors:** Both have 0 HBD, which is acceptable.

**5. H-Bond Acceptors:** Ligand A has 4 HBA, and Ligand B has 3. Both are below the 10 threshold.

**6. QED:** Both ligands have good QED scores (0.774 and 0.846), indicating good drug-like properties.

**7. DILI:** Both ligands have low DILI risk (32.648 and 30.787 percentile), which is favorable.

**8. BBB:** Both ligands exhibit excellent BBB penetration (75.107 and 73.827 percentile), crucial for a CNS target like DRD2.

**9. Caco-2 Permeability:** Ligand A (-4.187) is slightly better than Ligand B (-4.377), indicating better intestinal absorption. However, both are negative values, which is unusual and requires further investigation in a real-world scenario.

**10. Aqueous Solubility:** Both ligands have poor aqueous solubility (-2.399 and -2.885). This is a potential issue, but can be mitigated with formulation strategies.

**11. hERG Inhibition:** Both ligands have low hERG inhibition risk (0.278 and 0.489), which is good.

**12. Microsomal Clearance:** Ligand A (71.23) has higher microsomal clearance than Ligand B (47.062), suggesting lower metabolic stability. This is a significant drawback for Ligand A.

**13. In vitro Half-Life:** Ligand B (-9.694) has a significantly longer in vitro half-life than Ligand A (36.012). This is a major advantage for Ligand B.

**14. P-gp Efflux:** Ligand A (0.221) has lower P-gp efflux than Ligand B (0.093), meaning it is less likely to be pumped out of the brain, which is desirable for CNS penetration.

**15. Binding Affinity:** Both ligands have very similar and excellent binding affinities (-7.2 and -7.3 kcal/mol). The difference is negligible.

**Overall Assessment:**

While both ligands have good overall profiles, Ligand B is more favorable due to its significantly better metabolic stability (lower Cl_mic, longer t1/2). The slightly lower P-gp efflux of Ligand A is a minor advantage that is outweighed by the metabolic concerns. Both have good BBB penetration, logP, TPSA, and affinity. Solubility is a concern for both, but manageable.

Output:
1
2025-04-17 03:59:33,855 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the acceptable range (200-500 Da). Ligand A (425.304 Da) is higher, but still reasonable. Ligand B (352.435 Da) is slightly lower.

**TPSA:** Ligand A (76.57) is excellent for CNS penetration, being well below 90. Ligand B (90.98) is borderline, potentially hindering BBB penetration, but not dramatically.

**logP:** Ligand A (2.289) is optimal. Ligand B (0.098) is quite low, which could significantly impede membrane permeability and reduce CNS exposure.

**H-Bond Donors/Acceptors:** Both ligands have acceptable HBD (0/2) and HBA (5/5) counts.

**QED:** Both ligands have good QED scores (0.735 and 0.634), indicating generally drug-like properties.

**DILI:** Ligand A (84.296) has a higher DILI risk than Ligand B (35.944). This is a concern for Ligand A.

**BBB:** Ligand A (67.003) has a moderate BBB percentile, which is acceptable but not ideal. Ligand B (38.426) has a low BBB percentile, making CNS penetration a significant concern.

**Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and suggests a potential issue with the data or prediction method. However, the magnitude of the negative value is similar.

**Aqueous Solubility:** Both have negative solubility values, which is also unusual and suggests a potential issue with the data or prediction method. The magnitude of the negative value is similar.

**hERG Inhibition:** Ligand A (0.361) has a very low hERG risk. Ligand B (0.061) also has a very low hERG risk.

**Microsomal Clearance:** Ligand A (7.693) has a reasonable microsomal clearance. Ligand B (-22.927) has a *negative* clearance, which is physically impossible and indicates a severe issue with the prediction.

**In vitro Half-Life:** Ligand A (49.97) has a reasonable half-life. Ligand B (-7.097) has a negative half-life, which is impossible and indicates a severe issue with the prediction.

**P-gp Efflux:** Ligand A (0.285) has low P-gp efflux, which is favorable for CNS penetration. Ligand B (0.003) has very low P-gp efflux, also favorable.

**Binding Affinity:** Both ligands have excellent binding affinities (-7.4 and -7.6 kcal/mol), with Ligand B being slightly better. The affinity difference is small enough that it won't likely overcome other significant ADME issues.

**Overall Assessment:**

Ligand B has a slightly better binding affinity, but suffers from critical issues: a very low logP, a low BBB percentile, and *impossible* negative values for microsomal clearance and half-life. These issues suggest significant problems with its predicted ADME profile and make it a very unlikely drug candidate. Ligand A, while having a higher DILI risk, has a much more reasonable ADME profile, particularly its logP and BBB penetration, and its predicted clearance and half-life are plausible.

Output:
1
2025-04-17 03:59:33,855 - INFO - Batch 75 complete. Total preferences: 1200
2025-04-17 03:59:33,855 - INFO - Processing batch 76/512...
2025-04-17 04:00:15,964 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (346.515 and 348.491 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (49.41) is significantly better than Ligand B (79.3). For CNS targets, TPSA should be <=90, and A is comfortably within that range, while B is approaching the upper limit.

**logP:** Both ligands have good logP values (3.831 and 3.118), within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A (HBD=1, HBA=2) is better than Ligand B (HBD=3, HBA=6). Lower values are generally preferred for better permeability.

**QED:** Both ligands have acceptable QED values (0.645 and 0.595), indicating reasonable drug-likeness.

**DILI:** Ligand A (20.706) has a much lower DILI risk than Ligand B (27.104). Both are below the 40 threshold, but A is preferable.

**BBB:** Ligand A (74.913) has a significantly better BBB penetration percentile than Ligand B (60.644). For a CNS target like DRD2, >70 is desirable, but A is closer to that threshold.

**Caco-2 Permeability:** Ligand A (-4.735) is better than Ligand B (-4.951), indicating better intestinal absorption.

**Aqueous Solubility:** Ligand A (-4.014) is better than Ligand B (-2.639), indicating better solubility.

**hERG Inhibition:** Ligand A (0.323) has a lower hERG inhibition liability than Ligand B (0.812), which is crucial for avoiding cardiotoxicity.

**Microsomal Clearance:** Ligand A (69.607) has higher microsomal clearance than Ligand B (22.119), meaning B is more metabolically stable.

**In vitro Half-Life:** Ligand B (45.928) has a much longer in vitro half-life than Ligand A (-1.979). This is a significant advantage for dosing frequency.

**P-gp Efflux:** Ligand A (0.329) has lower P-gp efflux liability than Ligand B (0.174), which is beneficial for CNS exposure.

**Binding Affinity:** Both ligands have excellent binding affinities (-8.3 and -8.5 kcal/mol). The difference is minimal.

**Overall Assessment:**

Ligand A excels in most key properties, particularly TPSA, BBB, DILI, hERG, solubility, and P-gp efflux. While Ligand B has a better half-life and lower clearance, the superior CNS penetration profile (BBB, TPSA, Pgp) and safety profile (DILI, hERG) of Ligand A are more critical for a DRD2 ligand targeting CNS disorders. The similar binding affinities make the ADME/Tox differences the deciding factor.

Output:
1
2025-04-17 04:00:15,964 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 drug candidates, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight (MW):** Both ligands (342.374 and 353.551 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (111.77) is better than Ligand B (52.65). For CNS targets, we want TPSA <= 90, and Ligand B is comfortably within this range, while Ligand A is slightly above.

**3. logP:** Both ligands have good logP values (2.033 and 3.447), falling within the optimal 1-3 range. Ligand B is slightly higher, which could potentially lead to some off-target effects, but is still acceptable.

**4. H-Bond Donors (HBD):** Both ligands have acceptable HBD counts (3 and 1, respectively), well below the threshold of 5.

**5. H-Bond Acceptors (HBA):** Both ligands have acceptable HBA counts (4 and 3, respectively), well below the threshold of 10.

**6. QED:** Both ligands have reasonable QED values (0.772 and 0.691), indicating good drug-like properties.

**7. DILI:** Ligand B (38.503) has a significantly lower DILI risk than Ligand A (61.07). This is a substantial advantage for Ligand B.

**8. BBB:** Both ligands have acceptable BBB penetration (54.13 and 55.797). While >70 is desirable, these values are reasonably good for a GPCR target.

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.258 and -4.778). This is unusual and suggests poor permeability. However, these values are on a scale where negative values are possible, and direct comparison is difficult without knowing the scale's specifics.

**10. Aqueous Solubility:** Both ligands have negative solubility values (-3.476 and -3.362). Similar to Caco-2, this is unusual and requires careful interpretation.

**11. hERG Inhibition:** Both ligands have low hERG inhibition risk (0.759 and 0.693).

**12. Microsomal Clearance (Cl_mic):** Ligand A (-26.476) has a much lower (better) microsomal clearance than Ligand B (51.616). This suggests greater metabolic stability for Ligand A.

**13. In vitro Half-Life:** Ligand B (39.203) has a longer in vitro half-life than Ligand A (33.24). This is a positive for Ligand B.

**14. P-gp Efflux:** Both ligands have low P-gp efflux liability (0.18 and 0.26).

**15. Binding Affinity:** Ligand A (-8.7 kcal/mol) has a significantly stronger binding affinity than Ligand B (-6.9 kcal/mol). This is a 1.8 kcal/mol difference, which is substantial and can outweigh some ADME drawbacks.

**Overall Assessment:**

Ligand A has a significantly better binding affinity and metabolic stability. However, Ligand B exhibits a much lower DILI risk and a longer half-life. Both have similar BBB penetration and P-gp efflux. The TPSA is better for Ligand B. Given the importance of binding affinity for GPCRs, and the substantial difference in affinity (-8.7 vs -6.9 kcal/mol), I would favor Ligand A despite its higher DILI risk. The DILI risk is still within a manageable range (61%), and further optimization could potentially address this. The strong binding affinity is a key advantage.

Output:
0
2025-04-17 04:00:15,965 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (433.274 Da) is higher, but still acceptable. Ligand B (344.371 Da) is lower, potentially aiding permeability.

**TPSA:** Ligand A (59.5) is excellent, well below the 90 Angstrom threshold for CNS targets. Ligand B (117.25) is higher, but still reasonable, though less favorable for CNS penetration.

**logP:** Ligand A (3.439) is optimal. Ligand B (0.915) is a bit low, potentially hindering membrane permeability and CNS entry.

**H-Bond Donors/Acceptors:** Ligand A (0 HBD, 4 HBA) is favorable. Ligand B (2 HBD, 6 HBA) is also acceptable.

**QED:** Both ligands have similar and good QED values (0.696 and 0.741, respectively).

**DILI:** Ligand A (74.68) has a slightly higher DILI risk than Ligand B (69.484), but both are reasonably low.

**BBB:** Ligand A (76.115) has a significantly better BBB penetration percentile than Ligand B (56.495). This is a critical advantage for a CNS target like DRD2.

**Caco-2 Permeability:** Ligand A (-4.426) shows poor Caco-2 permeability, which is a concern. Ligand B (-5.11) is also poor, but slightly worse.

**Aqueous Solubility:** Ligand A (-5.713) has very poor solubility. Ligand B (-3.144) is also poor, but better than Ligand A.

**hERG:** Ligand A (0.755) has a slightly higher hERG risk than Ligand B (0.147). This is a significant advantage for Ligand B.

**Microsomal Clearance:** Ligand A (87.289) has higher microsomal clearance, indicating faster metabolism. Ligand B (13.045) has much lower clearance, suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (14.561 hours) has a moderate half-life. Ligand B (-6.267 hours) has a negative half-life, which is not physically possible and indicates an issue with the data or model.

**P-gp Efflux:** Ligand A (0.496) has lower P-gp efflux, which is favorable for CNS penetration. Ligand B (0.036) has very low P-gp efflux, which is even more favorable.

**Binding Affinity:** Ligand A (-9.2 kcal/mol) has a significantly stronger binding affinity than Ligand B (-8.1 kcal/mol). This is a substantial advantage that could outweigh some of the ADME drawbacks.

**Overall Assessment:**

Ligand A has a superior binding affinity and acceptable BBB penetration, but suffers from poor solubility and Caco-2 permeability, and higher metabolic clearance. Ligand B has better solubility, lower hERG risk, and lower P-gp efflux, but significantly weaker binding affinity and lower BBB penetration.

Given the GPCR-specific priorities, *binding affinity and BBB penetration are paramount*. The 1.1 kcal/mol difference in binding affinity is substantial. While Ligand A's solubility and permeability are concerns, these can potentially be addressed through formulation strategies. The improved BBB penetration is also a major plus. The negative half-life for Ligand B is a showstopper.

Output:
1
2025-04-17 04:00:15,965 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (343.471 Da) is slightly better, being closer to the lower end which can aid permeability.

**TPSA:** Ligand A (52.65) is significantly better than Ligand B (109.57). For CNS targets, we want TPSA <= 90, and Ligand A comfortably meets this, while Ligand B is pushing the limit.

**logP:** Both ligands have acceptable logP values (Ligand A: 2.724, Ligand B: 0.989), falling within the optimal 1-3 range. Ligand A is slightly preferred as it's closer to the middle of the range.

**H-Bond Donors/Acceptors:** Ligand A (HBD=1, HBA=3) is better than Ligand B (HBD=2, HBA=4) in terms of balancing solubility and permeability.

**QED:** Ligand A (0.914) has a much higher QED score than Ligand B (0.661), indicating a more drug-like profile.

**DILI:** Ligand A (30.399) has a significantly lower DILI risk than Ligand B (19.969), which is a major advantage.

**BBB:** Ligand A (87.127) has a much higher BBB penetration percentile than Ligand B (61.535). This is *critical* for a CNS target like DRD2.

**Caco-2 Permeability:** Ligand A (-4.685) and Ligand B (-5.278) both have negative values, which is unusual and suggests poor permeability. However, the scale isn't specified, so it's difficult to interpret.

**Aqueous Solubility:** Both ligands have poor aqueous solubility (-2.419 and -2.615 respectively). This could pose formulation challenges, but is less critical than BBB penetration for a CNS target.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.845 and 0.241 respectively).

**Microsomal Clearance:** Ligand A (-11.848) has a much lower (better) microsomal clearance than Ligand B (39.217), indicating better metabolic stability.

**In vitro Half-Life:** Ligand A (17.316 hours) has a significantly longer half-life than Ligand B (-39.866 hours). The negative value for Ligand B is concerning and likely an error or indicates very rapid degradation.

**P-gp Efflux:** Ligand A (0.117) has a lower P-gp efflux liability than Ligand B (0.006), which is favorable for CNS exposure.

**Binding Affinity:** Ligand B (-7.5 kcal/mol) has a slightly better binding affinity than Ligand A (-8.4 kcal/mol). While affinity is important, the difference of 0.9 kcal/mol is not substantial enough to outweigh the significant ADME advantages of Ligand A.

**Overall:** Ligand A is the far superior candidate. It excels in crucial properties for a CNS-targeting GPCR ligand: BBB penetration, TPSA, metabolic stability, DILI risk, and QED. While Ligand B has slightly better binding affinity, Ligand A's overall profile is much more promising for development.

Output:
0
2025-04-17 04:00:15,965 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (344.5 and 349.4 Da) fall comfortably within the ideal 200-500 Da range.

**TPSA:** Ligand A (49.41) is significantly better than Ligand B (93.46). For CNS targets, we want TPSA <= 90, so Ligand A is much more favorable.

**logP:** Ligand A (3.136) is within the optimal 1-3 range. Ligand B (1.739) is at the lower end, potentially impacting permeability.

**H-Bond Donors/Acceptors:** Ligand A (1 HBD, 2 HBA) and Ligand B (2 HBD, 5 HBA) both have reasonable values, well within the recommended limits.

**QED:** Both ligands have good QED scores (0.615 and 0.782), indicating good drug-like properties.

**DILI:** Ligand A (22.489) has a much lower DILI risk than Ligand B (51.338), which is a significant advantage.

**BBB:** Both ligands have good BBB penetration (67.701 and 70.105), but Ligand B is slightly better. However, the TPSA of Ligand A is much better, which will also help with BBB penetration.

**Caco-2 Permeability:** Both have negative Caco-2 values, indicating poor permeability. This is concerning, but we must consider other factors.

**Aqueous Solubility:** Both have negative solubility values, indicating poor solubility. This is concerning, but we must consider other factors.

**hERG:** Both ligands have low hERG risk (0.392 and 0.289).

**Microsomal Clearance:** Ligand A (40.341) has slightly better metabolic stability (lower clearance) than Ligand B (42.167).

**In vitro Half-Life:** Ligand A (-13.123) has a significantly longer half-life than Ligand B (7.814). This is a major advantage.

**P-gp Efflux:** Ligand A (0.185) has lower P-gp efflux liability than Ligand B (0.051), which is beneficial for CNS exposure.

**Binding Affinity:** Ligand B (-8.4) has a slightly better binding affinity than Ligand A (-7.9). However, the difference is only 0.5 kcal/mol, and other ADME properties are more concerning for Ligand B.

**Overall Assessment:**

Ligand A is the superior candidate. While Ligand B has slightly better binding affinity, Ligand A excels in crucial ADME properties, especially TPSA, DILI, metabolic stability (Cl_mic and t1/2), and P-gp efflux. The lower TPSA of Ligand A is particularly important for CNS penetration, aligning with the GPCR-specific priorities. The lower DILI risk is also a major benefit. The negative Caco-2 and solubility values are concerning for both, but the other advantages of Ligand A outweigh this drawback.

Output:
1
2025-04-17 04:00:15,965 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 drug candidates, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (361.873 and 365.455 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (62.3) is excellent, well below the 90 A^2 threshold for CNS targets. Ligand B (105.64) is higher but still potentially acceptable, though less desirable.

**3. logP:** Ligand A (3.633) is optimal. Ligand B (0.456) is quite low, potentially hindering membrane permeability and CNS penetration.

**4. H-Bond Donors:** Ligand A (1) and Ligand B (2) are both within the acceptable limit of 5.

**5. H-Bond Acceptors:** Ligand A (3) and Ligand B (5) are both within the acceptable limit of 10.

**6. QED:** Both ligands have good QED scores (0.814 and 0.73), suggesting good drug-like properties.

**7. DILI:** Ligand A (48.623) has a lower DILI risk than Ligand B (22.451), indicating a safer profile.

**8. BBB:** Ligand A (80.031) has a significantly better BBB percentile than Ligand B (54.478). This is crucial for a CNS target like DRD2.

**9. Caco-2 Permeability:** Ligand A (-4.994) and Ligand B (-5.659) both have negative values, indicating poor permeability. However, the scale is not specified, so it's hard to interpret the magnitude of the difference.

**10. Aqueous Solubility:** Ligand A (-4.15) and Ligand B (-1.921) both have negative values, indicating poor solubility. Again, the scale is not specified.

**11. hERG Inhibition:** Ligand A (0.59) shows a lower hERG inhibition risk than Ligand B (0.045), which is a significant advantage.

**12. Microsomal Clearance:** Ligand A (43.409) has a higher microsomal clearance than Ligand B (0.937), suggesting lower metabolic stability.

**13. In vitro Half-Life:** Ligand B (-8.628) has a much longer in vitro half-life than Ligand A (35.767). This is a significant advantage.

**14. P-gp Efflux:** Ligand A (0.126) shows lower P-gp efflux liability than Ligand B (0.014), which is favorable for CNS penetration.

**15. Binding Affinity:** Both ligands have excellent binding affinities (-7.7 and -8.1 kcal/mol), with Ligand B being slightly stronger. However, the difference is likely not enough to overcome the significant ADME deficiencies of Ligand B.

**Overall Assessment:**

Ligand A is the more promising candidate. While Ligand B has slightly better binding affinity and a longer half-life, Ligand A excels in crucial areas for a CNS-targeting GPCR: TPSA, logP, BBB penetration, and DILI risk. The lower logP and BBB of Ligand B are major drawbacks, potentially limiting its ability to reach the target in the brain. The lower hERG risk for Ligand A is also a significant safety advantage. The higher clearance of Ligand A is a concern, but could potentially be addressed through structural modifications.

Output:
1
2025-04-17 04:00:15,966 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (356.3 Da) is slightly higher than Ligand B (333.439 Da), but both are acceptable.

**TPSA:** Ligand A (80.68) is better than Ligand B (59.39) for CNS penetration, being closer to the <90 A^2 target for CNS targets.

**logP:** Ligand A (2.667) is optimal, while Ligand B (4.073) is approaching the upper limit and could potentially cause solubility issues or off-target interactions.

**H-Bond Donors/Acceptors:** Ligand A (2 HBD, 5 HBA) and Ligand B (1 HBD, 4 HBA) both fall within acceptable ranges.

**QED:** Both ligands have good QED scores (Ligand A: 0.832, Ligand B: 0.783), indicating drug-like properties.

**DILI:** Ligand A (66.421) has a higher DILI risk than Ligand B (41.954), which is preferable.

**BBB:** Ligand A (71.229) has a significantly better BBB penetration score than Ligand B (53.703), a crucial factor for a CNS target like DRD2.

**Caco-2 Permeability:** Ligand A (-4.733) and Ligand B (-5.229) both have negative values, indicating poor permeability. However, the scale is not specified, so it's difficult to assess the relative impact.

**Aqueous Solubility:** Both ligands have very poor aqueous solubility (-4.148 and -4.395 respectively).

**hERG Inhibition:** Both ligands have similar, low hERG inhibition liability (Ligand A: 0.55, Ligand B: 0.602).

**Microsomal Clearance:** Ligand A (23.34) has a higher clearance than Ligand B (20.667), meaning Ligand B is more metabolically stable.

**In vitro Half-Life:** Ligand B (-52.107) has a much longer in vitro half-life than Ligand A (-3.426), which is a significant advantage.

**P-gp Efflux:** Ligand A (0.304) has lower P-gp efflux liability than Ligand B (0.469), which is favorable for CNS exposure.

**Binding Affinity:** Ligand B (-10.1 kcal/mol) has a substantially stronger binding affinity than Ligand A (-8.8 kcal/mol). This difference of 1.3 kcal/mol is significant and can outweigh some of the ADME drawbacks.

**Overall Assessment:**

While Ligand A has better BBB penetration and lower P-gp efflux, Ligand B's significantly stronger binding affinity (-10.1 vs -8.8 kcal/mol) and longer half-life are compelling advantages. The higher DILI risk for Ligand A is also concerning. Although Ligand B has a higher logP, the substantial affinity difference makes it a more promising candidate. The poor solubility and Caco-2 permeability are concerns for both, but can be addressed with formulation strategies.

Output:
1
2025-04-17 04:00:15,966 - INFO - Reasoning:

Let's analyze Ligand A and Ligand B based on the provided guidelines, prioritizing GPCR-specific properties (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (343.358 and 346.475 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (75.48) is slightly higher than Ligand B (69.3). Both are below the 90 A^2 threshold desirable for CNS targets, but Ligand B is preferable.

**logP:** Both ligands have good logP values (3.133 and 2.615), falling within the 1-3 range. Ligand A is slightly higher, which could potentially lead to off-target effects, but both are acceptable.

**H-Bond Donors/Acceptors:** Both ligands have 1 HBD and a reasonable number of HBAs (4 and 3 respectively), satisfying the <5 HBD and <10 HBA guidelines.

**QED:** Both ligands have good QED scores (0.683 and 0.861), indicating good drug-like properties. Ligand B is better.

**DILI:** Ligand A (78.945) has a significantly higher DILI risk than Ligand B (36.177). This is a major concern for Ligand A.

**BBB:** Ligand A (81.582) has a better BBB percentile than Ligand B (65.839). This is a crucial factor for a CNS target like DRD2.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.921 and -4.886), which is unusual and suggests poor permeability. However, these values are on a scale where negative values are possible, and direct comparison is difficult without knowing the scale's specifics.

**Aqueous Solubility:** Both ligands have negative solubility values (-4.566 and -3.102), indicating poor aqueous solubility. This could pose formulation challenges.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.785 and 0.479).

**Microsomal Clearance:** Ligand B (57.995) has a significantly higher microsomal clearance than Ligand A (14.789), indicating lower metabolic stability.

**In vitro Half-Life:** Ligand A (18.308 hours) has a longer half-life than Ligand B (-14.476 hours). The negative value for Ligand B is concerning and suggests very rapid degradation.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.29 and 0.317), which is good for CNS penetration.

**Binding Affinity:** Ligand A (-9.7 kcal/mol) has a significantly stronger binding affinity than Ligand B (-7.6 kcal/mol). This is a substantial advantage.

**Overall Assessment:**

Ligand A has a much stronger binding affinity and better BBB penetration, which are critical for a CNS GPCR target. However, it has a significantly higher DILI risk and lower metabolic stability. Ligand B has a lower DILI risk, better QED, and better TPSA, but weaker binding affinity and poorer BBB penetration.

Given the importance of affinity for GPCRs and the significant difference in binding energy (-9.7 vs -7.6 kcal/mol), the stronger binding of Ligand A likely outweighs its drawbacks, *provided* the DILI risk can be mitigated through structural modifications. The poor solubility of both is a concern, but can be addressed through formulation strategies. The negative Caco-2 and solubility values are concerning but less critical than the affinity and DILI.

Output:
1
2025-04-17 04:00:15,966 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (381.574 and 370.515 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (82.27) is slightly higher than Ligand B (67.87). Both are below the 90 A^2 threshold desirable for CNS targets, but B is better.

**3. logP:** Both ligands have good logP values (2.133 and 1.288), falling within the optimal 1-3 range. Ligand B is slightly lower, which could potentially affect permeability, but it's not a major concern.

**4. H-Bond Donors:** Ligand A has 2 HBD, and Ligand B has 1. Both are within the acceptable limit of <=5.

**5. H-Bond Acceptors:** Ligand A has 4 HBA, and Ligand B has 5. Both are within the acceptable limit of <=10.

**6. QED:** Both ligands have similar QED values (0.767 and 0.731), indicating good drug-like properties.

**7. DILI:** Ligand A (44.552) has a slightly higher DILI risk than Ligand B (23.575). Both are below the concerning threshold of 60, but B is preferable.

**8. BBB:** This is a critical parameter for CNS targets. Ligand B (68.554) has a significantly better BBB penetration percentile than Ligand A (46.064). This is a major advantage for Ligand B.

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.915 and -4.92), which is unusual and suggests poor permeability. This is a concern for both.

**10. Aqueous Solubility:** Both ligands have negative solubility values (-4.297 and -2.347), indicating poor solubility. This is a concern for both.

**11. hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.243 and 0.285), which is excellent.

**12. Microsomal Clearance:** Ligand B (37.679) has a higher microsomal clearance than Ligand A (18.378), suggesting faster metabolism and potentially lower in vivo exposure. This favors Ligand A.

**13. In vitro Half-Life:** Ligand B (5.936) has a longer in vitro half-life than Ligand A (3.19), which is generally desirable.

**14. P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.095 and 0.039), which is favorable for CNS penetration.

**15. Binding Affinity:** Ligand B (-7.5 kcal/mol) has a significantly stronger binding affinity than Ligand A (-0.0 kcal/mol). This is a substantial advantage, potentially outweighing some of the ADME drawbacks.

**Overall Assessment:**

Ligand B is the stronger candidate. While both have issues with Caco-2 permeability and solubility, Ligand B's significantly better BBB penetration and *much* stronger binding affinity are critical advantages for a CNS-targeting GPCR like DRD2. The longer half-life of B is also a plus. Although Ligand A has better metabolic stability, the difference isn't large enough to overcome B's superior affinity and BBB penetration.

Output:
1
2025-04-17 04:00:15,966 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (351.407 and 344.499 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (119.55) is better than Ligand B (40.62), both are below the 90 A^2 threshold for CNS targets.

**logP:** Ligand A (-0.138) is suboptimal, being below 1, which could hinder permeation. Ligand B (3.801) is within the optimal 1-3 range. This is a significant advantage for Ligand B.

**H-Bond Donors/Acceptors:** Ligand A (2 HBD, 6 HBA) and Ligand B (0 HBD, 2 HBA) both fall within acceptable limits.

**QED:** Both ligands have good QED scores (0.642 and 0.815, respectively), indicating good drug-like properties.

**DILI:** Both ligands have low DILI risk (39.434 and 37.728), which is favorable.

**BBB:** Ligand B (81.892) has a substantially better BBB percentile than Ligand A (69.833). This is a crucial advantage for a CNS target like DRD2.

**Caco-2 Permeability:** Ligand A (-5.315) and Ligand B (-4.256) both have negative values, which is unusual. It's difficult to interpret without knowing the scale, but lower values are generally less favorable.

**Aqueous Solubility:** Both ligands have poor aqueous solubility (-2.321 and -4.073). This could pose formulation challenges.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.095 and 0.648).

**Microsomal Clearance:** Ligand A (16.407) has a lower microsomal clearance than Ligand B (68.8), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand B (15.392) has a significantly longer in vitro half-life than Ligand A (5.527).

**P-gp Efflux:** Ligand A (0.013) has very low P-gp efflux liability, which is excellent. Ligand B (0.501) is also relatively low, but higher than A.

**Binding Affinity:** Ligand B (-7.6 kcal/mol) has a slightly better binding affinity than Ligand A (-7.1 kcal/mol), although the difference is not huge.

**Overall Assessment:**

Ligand B is the more promising candidate. While Ligand A has better P-gp efflux and metabolic stability, Ligand B excels in key GPCR-specific properties: a more favorable logP, significantly better BBB penetration, and a longer half-life. The slightly better binding affinity of Ligand B further supports this conclusion. The poor solubility of both is a concern, but can potentially be addressed through formulation strategies. The logP value of Ligand A is a major drawback.

Output:
1
2025-04-17 04:00:15,966 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B based on the provided guidelines, prioritizing GPCR-specific properties (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (356.379 and 346.431 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (129.56) is borderline for CNS targets, slightly above the preferred <90, while Ligand B (76.46) is excellent, well below 90.

**logP:** Ligand A (-2.151) is quite low, potentially hindering permeation. Ligand B (0.965) is better, though still on the lower side of the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A (3 HBD, 7 HBA) is reasonable. Ligand B (1 HBD, 5 HBA) is even better, suggesting a good balance of solubility and permeability.

**QED:** Both ligands have acceptable QED values (0.455 and 0.779), with Ligand B being significantly better.

**DILI:** Ligand A (60.217) is approaching a concerning DILI risk, while Ligand B (45.173) is much lower and safer.

**BBB:** This is crucial for a CNS target like DRD2. Ligand A (14.23) has very poor predicted BBB penetration. Ligand B (65.374) is significantly better, although still not ideal (aim for >70).

**Caco-2 Permeability:** Both have negative values (-5.535 and -5.082), which is unusual and difficult to interpret without knowing the scale. However, we can assume lower values mean lower permeability.

**Aqueous Solubility:** Both ligands have negative values (-1.211 and -1.186), which is also unusual and suggests poor solubility.

**hERG Inhibition:** Both ligands have low hERG risk (0.133 and 0.166).

**Microsomal Clearance:** Ligand A (1.517) has lower clearance, indicating better metabolic stability than Ligand B (2.928).

**In vitro Half-Life:** Ligand A (-2.308) has a very negative half-life, which is not possible. Ligand B (6.32) is a reasonable half-life.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.008 and 0.03).

**Binding Affinity:** Ligand B (-7.8 kcal/mol) has a significantly stronger binding affinity than Ligand A (-6.9 kcal/mol), exceeding the 1.5 kcal/mol advantage threshold.

**Overall Assessment:**

Ligand B is the superior candidate. While its logP is a bit low and BBB is not optimal, it excels in crucial areas for a CNS GPCR target: significantly better BBB penetration, much lower DILI risk, a substantially stronger binding affinity, and better QED. The issues with solubility and Caco-2 permeability are concerning for both, but the affinity advantage of Ligand B, coupled with its better safety profile and BBB, outweigh the drawbacks. Ligand A's very poor BBB penetration and borderline DILI risk are major red flags.

Output:
1
2025-04-17 04:00:15,967 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (344.46 and 344.50 Da) fall comfortably within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (74.33) is higher than Ligand B (40.62). For a CNS target like DRD2, TPSA < 90 is preferred, so both are acceptable, but Ligand B is significantly better.

**3. logP:** Both ligands have good logP values (2.14 and 3.23), falling within the optimal 1-3 range. Ligand B is slightly higher, which *could* be beneficial for membrane permeability, but isn't a major concern for either.

**4. H-Bond Donors:** Ligand A has 2 HBD, and Ligand B has 0. Both are within the acceptable limit of <=5.

**5. H-Bond Acceptors:** Ligand A has 4 HBA, Ligand B has 2. Both are within the acceptable limit of <=10.

**6. QED:** Both ligands have good QED scores (0.532 and 0.567), indicating good drug-like properties.

**7. DILI:** Ligand A (33.23) has a slightly higher DILI risk than Ligand B (11.28). Both are below 40, indicating low risk, but Ligand B is preferable.

**8. BBB:** Both ligands have good BBB penetration (71.07 and 76.31). Both are above the desirable 70% threshold for CNS targets. Ligand B is slightly better.

**9. Caco-2 Permeability:** Ligand A (-5.021) has poorer Caco-2 permeability than Ligand B (-4.505). Higher values are better, so Ligand B is preferred.

**10. Aqueous Solubility:** Ligand A (-2.794) has poorer aqueous solubility than Ligand B (-3.546). Higher values are better, so Ligand B is preferred.

**11. hERG Inhibition:** Both ligands have low hERG inhibition risk (0.65 and 0.452).

**12. Microsomal Clearance:** Ligand A (50.012) has higher microsomal clearance than Ligand B (42.029), suggesting lower metabolic stability. Lower is better, so Ligand B is preferred.

**13. In vitro Half-Life:** Ligand A (58.995) has a shorter in vitro half-life than Ligand B (-7.607). Longer is better, so Ligand B is preferred.

**14. P-gp Efflux:** Ligand A (0.06) has lower P-gp efflux than Ligand B (0.206), which is better for CNS exposure.

**15. Binding Affinity:** Ligand B (-8.1 kcal/mol) has a slightly better binding affinity than Ligand A (-7.9 kcal/mol). While both are excellent, the 0.2 kcal/mol difference, while not huge, is enough to be a deciding factor.

**Overall Assessment:**

Ligand B consistently outperforms Ligand A across most ADME properties crucial for CNS drug development, including TPSA, DILI, BBB, Caco-2 permeability, solubility, microsomal clearance, and in vitro half-life. While Ligand A has slightly better P-gp efflux, the other advantages of Ligand B, especially its superior binding affinity, outweigh this.

Output:
1
2025-04-17 04:00:15,967 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (361.511 and 377.507 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (71.09) is significantly better than Ligand B (127.59). For CNS targets, TPSA should be <= 90, and A is comfortably within this range, while B is pushing the limit.

**3. logP:** Ligand A (2.976) is optimal (1-3), while Ligand B (0.268) is quite low, potentially hindering membrane permeability.

**4. H-Bond Donors:** Ligand A (2) and Ligand B (3) are both acceptable (<=5).

**5. H-Bond Acceptors:** Ligand A (4) and Ligand B (5) are both acceptable (<=10).

**6. QED:** Ligand A (0.734) is better than Ligand B (0.559), indicating a more drug-like profile.

**7. DILI:** Both ligands have low DILI risk (A: 37.999, B: 36.603), both under the 40 threshold.

**8. BBB:** Ligand A (52.656) and Ligand B (56.495) are both below the ideal >70 for CNS targets, but not drastically so. This is an area where neither ligand excels, but it's not a dealbreaker on its own.

**9. Caco-2:** Both have negative values (-5.233 and -5.479), which is unusual and difficult to interpret without knowing the scale. Assuming these are logP-like scales, lower values suggest poorer permeability.

**10. Solubility:** Both have negative values (-2.224 and -1.72), again unusual. Lower values suggest lower solubility.

**11. hERG:** Both ligands have very low hERG risk (0.155 and 0.189).

**12. Cl_mic:** Ligand A (20.299) has a lower microsomal clearance than Ligand B (31.223), suggesting better metabolic stability.

**13. t1/2:** Ligand A (4.623) has a shorter in vitro half-life than Ligand B (-35.912). The negative value for B is concerning and likely an error or indicates very rapid degradation.

**14. Pgp:** Both ligands have low P-gp efflux liability (0.249 and 0.016).

**15. Binding Affinity:** Ligand A (-8.8 kcal/mol) has a significantly stronger binding affinity than Ligand B (-7.4 kcal/mol). This >1.5 kcal/mol difference is substantial and can outweigh minor ADME drawbacks.

**Overall Assessment:**

Ligand A is the superior candidate. It has a better TPSA, logP, QED, and significantly better binding affinity. While its BBB penetration isn't ideal, it's comparable to Ligand B. The lower microsomal clearance of Ligand A is also favorable. The negative values for Caco-2 and Solubility are concerning for both, but the overall profile of A is more promising, especially given the strong binding affinity. The negative half-life for ligand B is a major red flag.

Output:
1
2025-04-17 04:00:15,967 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B based on the provided guidelines, prioritizing GPCR-specific properties (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (346.431 Da) is slightly lower, which *could* be beneficial for permeability, but both are acceptable.

**TPSA:** Ligand A (67.67) is significantly better than Ligand B (78.35). For CNS targets, we want TPSA <= 90, and ideally closer to 60. Ligand A is much closer to the ideal range.

**logP:** Both ligands have acceptable logP values (Ligand A: 1.031, Ligand B: 2.463), falling within the optimal 1-3 range. Ligand B is slightly higher, which could potentially lead to off-target effects, but isn't a major concern.

**H-Bond Donors/Acceptors:** Ligand A (0 HBD, 5 HBA) is preferable to Ligand B (2 HBD, 7 HBA). Lower HBD/HBA generally improves permeability.

**QED:** Both ligands have similar and good QED scores (Ligand A: 0.772, Ligand B: 0.787), indicating good drug-like properties.

**DILI:** Ligand A (26.483) has a significantly lower DILI risk than Ligand B (67.003). This is a substantial advantage for Ligand A.

**BBB:** Both ligands have good BBB penetration (Ligand A: 76.309, Ligand B: 73.517), exceeding the desirable threshold of 70 for CNS targets. Ligand A is slightly better.

**Caco-2 Permeability:** Ligand A (-4.839) has a much better Caco-2 permeability than Ligand B (-5.46). Higher values are better, and while both are negative, Ligand A is less negative.

**Aqueous Solubility:** Ligand A (-0.741) has better aqueous solubility than Ligand B (-3.719).

**hERG Inhibition:** Both ligands have very low hERG inhibition liability (Ligand A: 0.23, Ligand B: 0.495), which is excellent.

**Microsomal Clearance:** Ligand A (28.068) has lower microsomal clearance than Ligand B (37.463), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand B (33.813) has a longer in vitro half-life than Ligand A (10.582). This is a positive for Ligand B, but not enough to offset other issues.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (Ligand A: 0.057, Ligand B: 0.094), which is excellent for CNS penetration.

**Binding Affinity:** Both ligands have the same binding affinity (-8.0 kcal/mol), which is excellent. This removes affinity as a differentiating factor.

**Overall Assessment:**

Ligand A consistently outperforms Ligand B in most crucial ADME properties, especially TPSA, DILI, solubility, and Caco-2 permeability. While Ligand B has a slightly longer half-life, the significant advantages of Ligand A in terms of safety (DILI), brain penetration (TPSA, BBB), and absorption (Caco-2, solubility) make it the more promising drug candidate for a CNS target like DRD2.

Output:
1
2025-04-17 04:00:15,967 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B based on the provided guidelines, prioritizing GPCR-specific properties (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (402.288 Da) is slightly higher than Ligand B (347.423 Da), but both are acceptable.

**TPSA:** Ligand A (55.4) is significantly better than Ligand B (118.06). For CNS targets, we want TPSA <= 90, and Ligand A is comfortably within this range, while Ligand B is well above. This is a substantial advantage for Ligand A.

**logP:** Both ligands have good logP values (A: 3.513, B: 2.051), falling within the optimal range of 1-3. Ligand A is slightly higher, which *could* be a minor concern, but not a dealbreaker.

**H-Bond Donors/Acceptors:** Both have acceptable HBD (1) and HBA (A: 3, B: 4) counts.

**QED:** Ligand A (0.779) has a better QED score than Ligand B (0.482), indicating a more drug-like profile.

**DILI:** Ligand A (61.303) has a higher DILI risk than Ligand B (34.587). This is a negative for Ligand A, but still within an acceptable range.

**BBB:** Ligand A (70.88) has a significantly better BBB percentile than Ligand B (31.252). This is *critical* for a CNS target like DRD2, and a major advantage for Ligand A.

**Caco-2 Permeability:** Ligand A (-4.722) has a worse Caco-2 permeability than Ligand B (-5.281). Both are negative values, which is unusual.

**Aqueous Solubility:** Ligand A (-4.236) has a worse aqueous solubility than Ligand B (-1.588). Both are negative values, which is unusual.

**hERG Inhibition:** Ligand A (0.492) has a slightly higher hERG inhibition risk than Ligand B (0.108). Lower is better, so this favors Ligand B.

**Microsomal Clearance:** Ligand A (99.114) has a much higher microsomal clearance than Ligand B (1.988). This suggests Ligand A is less metabolically stable, a significant drawback.

**In vitro Half-Life:** Ligand A (58.638) has a longer half-life than Ligand B (3.784). This is a positive for Ligand A.

**P-gp Efflux:** Ligand A (0.358) has lower P-gp efflux than Ligand B (0.008), which is favorable for CNS penetration.

**Binding Affinity:** Ligand A (-8.6 kcal/mol) has a significantly stronger binding affinity than Ligand B (-6.8 kcal/mol). This is a substantial advantage for Ligand A, and can often outweigh minor ADME concerns.

**Overall Assessment:**

Ligand A excels in key areas for a CNS GPCR target: TPSA, BBB, P-gp efflux, and, most importantly, binding affinity. While it has some drawbacks (DILI, Cl_mic, solubility), the strong affinity and good BBB penetration are compelling. Ligand B has better DILI and hERG, but its poor TPSA and significantly lower BBB penetration make it a less attractive candidate for a CNS target. The difference in binding affinity (-8.6 vs -6.8) is also substantial.

Output:
1
2025-04-17 04:00:15,968 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight (MW):** Both ligands (344.459 and 368.543 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (75.19) is better than Ligand B (51.66). For CNS targets, we want TPSA <= 90, and ideally closer to 60. Both are within the acceptable range, but A is slightly higher, potentially impacting BBB penetration less favorably.

**3. logP:** Ligand B (3.637) is higher than Ligand A (2.196). Both are within the optimal 1-3 range, but B is approaching the upper limit.

**4. H-Bond Donors (HBD):** Ligand A (1) is better than Ligand B (0). Lower HBD is generally preferred for BBB penetration.

**5. H-Bond Acceptors (HBA):** Ligand A (4) is better than Ligand B (5). Lower HBA is also generally preferred for BBB penetration.

**6. QED:** Ligand A (0.858) is significantly better than Ligand B (0.668), indicating a more drug-like profile.

**7. DILI:** Ligand A (39.899) is slightly higher than Ligand B (31.834), but both are well below the concerning threshold of 60.

**8. BBB:** Ligand B (79.449) is slightly better than Ligand A (76.541). Both are above the desirable 70% threshold for CNS targets, but B has a slightly higher predicted penetration.

**9. Caco-2:** Both ligands have negative Caco-2 values (-4.962 and -4.817), which is unusual and suggests poor permeability. This is a significant drawback for both.

**10. Solubility:** Both ligands have negative solubility values (-1.998 and -3.994), which is also unusual and suggests poor aqueous solubility. This is another significant drawback for both.

**11. hERG:** Ligand A (0.254) is significantly better than Ligand B (0.781), indicating a lower risk of cardiotoxicity.

**12. Cl_mic:** Ligand B (80.597) has a higher microsomal clearance than Ligand A (40.68), meaning it's metabolized faster. Lower is better for metabolic stability.

**13. t1/2:** Ligand B (57.788) has a significantly longer in vitro half-life than Ligand A (-10.545). This is a major advantage for B.

**14. Pgp:** Ligand A (0.077) is significantly better than Ligand B (0.765), suggesting lower P-glycoprotein efflux and better CNS exposure.

**15. Affinity:** Ligand A (-8.1) has a better (more negative) binding affinity than Ligand B (-7.0). This is a substantial advantage, potentially outweighing some of the ADME drawbacks.

**Overall Assessment:**

While both ligands have significant drawbacks (poor Caco-2 and solubility), Ligand A has a superior binding affinity, better QED, lower DILI, lower hERG risk, and lower Pgp efflux. The slightly better BBB of Ligand B is not enough to offset these advantages. The significantly longer half-life of Ligand B is a positive, but the stronger binding of A is crucial for a GPCR target.

Output:
0
2025-04-17 04:00:15,968 - INFO - Batch 76 complete. Total preferences: 1216
2025-04-17 04:00:15,968 - INFO - Processing batch 77/512...
2025-04-17 04:00:58,080 - INFO - Reasoning:

Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (347.419 and 346.475 Da) fall comfortably within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (100.16) is slightly higher than Ligand B (67.23). For CNS targets, we ideally want TPSA <= 90. Ligand B is better here.

**3. logP:** Both ligands have good logP values (2.275 and 2.1), falling within the optimal 1-3 range.

**4. H-Bond Donors:** Both have 1 HBD, which is acceptable.

**5. H-Bond Acceptors:** Ligand A has 6 HBAs, and Ligand B has 4. Both are within the acceptable limit of <= 10.

**6. QED:** Both ligands have good QED scores (0.729 and 0.888), indicating good drug-like properties.

**7. DILI:** Ligand A (43.622) has a slightly higher DILI risk than Ligand B (21.908). Both are below the concerning threshold of 60, but lower is better.

**8. BBB:** Ligand B (73.245) has a significantly better BBB percentile than Ligand A (65.374). This is a critical factor for a CNS target like DRD2.

**9. Caco-2 Permeability:** Ligand A (-5.186) has worse Caco-2 permeability than Ligand B (-4.518). Higher values are better, so ligand B is preferable.

**10. Aqueous Solubility:** Ligand A (-1.494) has slightly better aqueous solubility than Ligand B (-2.573).

**11. hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.126 and 0.103).

**12. Microsomal Clearance:** Ligand A (34.391) has lower microsomal clearance than Ligand B (57.456), suggesting better metabolic stability.

**13. In vitro Half-Life:** Ligand A (20.555) has a longer in vitro half-life than Ligand B (11.421).

**14. P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.041 and 0.023).

**15. Binding Affinity:** Both ligands have very similar and excellent binding affinities (-7.5 and -7.4 kcal/mol). The difference is negligible.

**Overall Assessment:**

Considering the GPCR-specific priorities, Ligand B is the better candidate. While Ligand A has slightly better metabolic stability and solubility, Ligand B excels in BBB penetration (73.245 vs 65.374) and has a lower DILI risk. The TPSA is also significantly lower for Ligand B, which is beneficial for CNS penetration. The binding affinities are essentially identical, so the ADME properties become the deciding factors.

Output:
1
2025-04-17 04:00:58,081 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 drug candidates, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (367.475 and 378.885 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (89.87) is excellent, being below the 90 threshold for CNS targets. Ligand B (97.11) is slightly higher, but still acceptable.

**3. logP:** Ligand A (-0.085) is a bit low, potentially hindering permeation. Ligand B (2.707) is within the optimal 1-3 range. This is a significant advantage for Ligand B.

**4. H-Bond Donors:** Ligand A (1) is good. Ligand B (3) is also acceptable, staying under the 5 limit.

**5. H-Bond Acceptors:** Ligand A (7) is good. Ligand B (5) is also good, below the 10 limit.

**6. QED:** Both ligands have reasonable QED values (0.8 and 0.673), indicating good drug-like properties.

**7. DILI:** Both ligands have elevated DILI risk (37.999 and 65.801), but Ligand B is higher. This is a concern for both, but more so for Ligand B.

**8. BBB:** Ligand A (64.25) is borderline for good CNS penetration. Ligand B (67.546) is also borderline, but slightly better. Both are below the desirable >70 for CNS targets.

**9. Caco-2:** Both have negative Caco-2 values (-4.896 and -5.017), which is unusual and suggests poor permeability. This is a significant drawback for both.

**10. Solubility:** Both have negative solubility values (-1.724 and -4.152), indicating very poor aqueous solubility. This is a major concern for both.

**11. hERG:** Both ligands have low hERG risk (0.478 and 0.462).

**12. Cl_mic:** Ligand A (26.971) has a higher microsomal clearance than Ligand B (11.015), suggesting lower metabolic stability. This favors Ligand B.

**13. t1/2:** Ligand B (13.036) has a longer in vitro half-life than Ligand A (-1.548), which is a significant advantage.

**14. Pgp:** Both ligands have low P-gp efflux liability (0.12 and 0.109), which is favorable for CNS penetration.

**15. Binding Affinity:** Ligand B (-8.4 kcal/mol) has a slightly better binding affinity than Ligand A (-7.9 kcal/mol). While the difference is not huge, it's enough to potentially outweigh some of the ADME drawbacks.

**Overall Assessment:**

Ligand B is the more promising candidate. While both have significant issues with solubility and Caco-2 permeability, Ligand B has a more favorable logP, better metabolic stability (lower Cl_mic), longer half-life, and slightly better binding affinity. The slightly higher DILI risk is a concern, but the other factors outweigh this. Ligand A's low logP is a significant disadvantage, and its higher Cl_mic is also unfavorable. The BBB values for both are suboptimal, but this can potentially be addressed with prodrug strategies or formulation approaches.

Output:
1
2025-04-17 04:00:58,081 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (364.515 and 341.411 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Both ligands have TPSA values (79.18 and 79.37) that are acceptable for oral absorption (<140) but slightly high for optimal CNS penetration (<90).

**3. logP:** Both ligands have logP values (1.708 and 1.601) within the optimal range of 1-3, suggesting good permeability and reasonable solubility.

**4. H-Bond Donors:** Ligand A (3) is slightly higher than Ligand B (1), but both are within the acceptable limit of <=5.

**5. H-Bond Acceptors:** Ligand A (5) is slightly higher than Ligand B (4), but both are within the acceptable limit of <=10.

**6. QED:** Both ligands have QED values (0.743 and 0.652) above 0.5, indicating good drug-like properties.

**7. DILI:** Ligand A (33.385) has a lower DILI risk than Ligand B (44.668), which is preferable.

**8. BBB:** Ligand A (61.962) and Ligand B (67.08) are both below the desirable threshold of >70 for CNS targets, but Ligand B is slightly better.

**9. Caco-2 Permeability:** Ligand A (-5.296) has worse Caco-2 permeability than Ligand B (-4.655).

**10. Aqueous Solubility:** Both ligands have very poor aqueous solubility (-2.514 and -2.456). This is a concern, but potentially manageable with formulation strategies.

**11. hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.144 and 0.096).

**12. Microsomal Clearance:** Ligand A (0.742) has significantly lower microsomal clearance than Ligand B (59.22), indicating better metabolic stability.

**13. In vitro Half-Life:** Ligand A (39.201) has a longer in vitro half-life than Ligand B (-25.841), which is highly desirable.

**14. P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.043 and 0.045).

**15. Binding Affinity:** Both ligands have similar and excellent binding affinities (-8.5 and -8.3 kcal/mol). The difference is minor.

**Overall Assessment:**

Considering the GPCR-specific priorities, Ligand A is the better candidate. While both have similar affinities, Ligand A has a significantly lower DILI risk and much better metabolic stability (lower Cl_mic and longer t1/2). The slightly better BBB penetration of Ligand B is not enough to offset these advantages. The poor solubility of both is a concern, but can be addressed during formulation.

Output:
0
2025-04-17 04:00:58,081 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (367.56 and 380.80 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (48.72) is significantly better than Ligand B (76.02). For CNS targets, we want TPSA <= 90, and ideally closer to 60. Ligand A is much closer to this ideal.

**logP:** Ligand A (3.81) is slightly higher than Ligand B (2.29), both within the optimal 1-3 range, but A is closer to the upper limit.

**H-Bond Donors/Acceptors:** Ligand A has 1 HBD and 4 HBA, while Ligand B has 2 HBD and 4 HBA. Both are acceptable, within the guidelines of <=5 HBD and <=10 HBA.

**QED:** Both ligands have good QED scores (0.639 and 0.762), indicating good drug-like properties.

**DILI:** Ligand A (18.11) has a considerably lower DILI risk than Ligand B (59.40). This is a significant advantage for Ligand A.

**BBB:** Both ligands have excellent BBB penetration (78.21% and 83.83%), exceeding the desirable >70% threshold for CNS targets.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.11 and -4.83), which is unusual and suggests poor permeability. However, these values are on a log scale, and the negative values are likely indicating very low permeability.

**Aqueous Solubility:** Both ligands have negative solubility values (-3.26 and -3.91), indicating poor aqueous solubility. This could pose formulation challenges.

**hERG Inhibition:** Ligand A (0.92) has a slightly higher hERG risk than Ligand B (0.22), but both are relatively low.

**Microsomal Clearance:** Ligand A (84.71) has a much higher microsomal clearance than Ligand B (28.43), suggesting lower metabolic stability. This is a drawback for Ligand A.

**In vitro Half-Life:** Ligand A (86.61) has a longer half-life than Ligand B (0.66), which is a positive attribute.

**P-gp Efflux:** Ligand A (0.38) has lower P-gp efflux liability than Ligand B (0.14), which is favorable for CNS penetration.

**Binding Affinity:** Ligand B (-8.4 kcal/mol) has a significantly stronger binding affinity than Ligand A (-6.9 kcal/mol). This is a substantial advantage, exceeding the 1.5 kcal/mol difference threshold.

**Overall Assessment:**

Ligand B has a significantly better binding affinity, which is paramount for GPCR ligands. While Ligand A has advantages in DILI risk, P-gp efflux, and in vitro half-life, the substantial difference in binding affinity (-1.5 kcal/mol) outweighs these benefits. The poor Caco-2 and solubility for both are concerning, but can potentially be addressed with formulation strategies. The higher metabolic clearance of Ligand A is also a concern. Given the GPCR target and the importance of brain penetration, the strong affinity of Ligand B makes it the more promising candidate.

Output:
1
2025-04-17 04:00:58,081 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (377.422 and 357.801 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (76.34) is slightly higher than Ligand B (71.76), but both are below the 90 A^2 threshold desirable for CNS targets.

**3. logP:** Ligand A (4.099) is at the upper end of the optimal range (1-3), while Ligand B (2.472) is well within it. Ligand A's higher logP *could* lead to solubility issues or off-target interactions, but it isn't drastically outside the acceptable range.

**4. H-Bond Donors:** Ligand A (0) is preferable to Ligand B (1) as fewer HBDs generally improve membrane permeability.

**5. H-Bond Acceptors:** Both ligands have 6 HBA, which is acceptable (<=10).

**6. QED:** Ligand B (0.779) has a significantly better QED score than Ligand A (0.38), indicating a more drug-like profile.

**7. DILI:** Both ligands have high DILI risk (98.178 and 97.674), which is a concern. However, this is a prediction and needs experimental validation.

**8. BBB:** Ligand A (83.055) has a much better BBB percentile than Ligand B (53.587). This is a *critical* advantage for a CNS target like DRD2.

**9. Caco-2:** Both ligands have negative Caco-2 values (-4.734 and -4.567), which is unusual and suggests poor permeability. This is a significant drawback for both.

**10. Solubility:** Both ligands have very poor predicted aqueous solubility (-4.903 and -3.961). This is a major concern for bioavailability.

**11. hERG:** Both ligands have low hERG inhibition risk (0.517 and 0.318).

**12. Cl_mic:** Ligand B (17.558) has a significantly lower microsomal clearance than Ligand A (122.009), indicating better metabolic stability.

**13. t1/2:** Ligand B (31.809) has a longer in vitro half-life than Ligand A (43.567). This is a positive attribute.

**14. Pgp:** Ligand A (0.668) has a slightly lower P-gp efflux liability than Ligand B (0.114), which is favorable for CNS penetration.

**15. Binding Affinity:** Both ligands have very similar and strong binding affinities (-9.3 and -9.4 kcal/mol). The difference is negligible.

**Overall Assessment:**

Despite the poor solubility and Caco-2 permeability predictions for both, Ligand A is more promising due to its significantly better BBB penetration (83.055 vs 53.587) and lower P-gp efflux. While Ligand B has better QED and metabolic stability, the BBB is paramount for a CNS-targeting drug. The similar binding affinities mean that the ADME properties become the deciding factor. The high DILI risk is a concern for both, but can be investigated further.

Output:
0
2025-04-17 04:00:58,081 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B based on the provided guidelines, prioritizing GPCR-specific properties (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (344.46 and 352.48 Da) fall within the ideal range of 200-500 Da.

**TPSA:** Ligand A (67.23) is better than Ligand B (70.08). Both are below 90, which is good for CNS targets.

**logP:** Both ligands have good logP values (1.84 and 1.27), falling within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Both ligands have 1 HBD and 4 HBA, which are within acceptable limits.

**QED:** Both ligands have good QED scores (0.732 and 0.809), indicating good drug-like properties.

**DILI:** Ligand A (26.52) has a significantly lower DILI risk than Ligand B (7.87). This is a major advantage for Ligand A.

**BBB:** Ligand B (67.16) has a slightly better BBB penetration percentile than Ligand A (57.46). However, both are below the desirable >70 for CNS targets.

**Caco-2 Permeability:** Ligand A (-5.01) has a worse Caco-2 permeability than Ligand B (-4.45).

**Aqueous Solubility:** Both ligands have very poor aqueous solubility (-1.24 and -1.11).

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.151 and 0.358).

**Microsomal Clearance:** Ligand B (15.91) has a significantly lower microsomal clearance than Ligand A (29.21), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand B (1.53) has a slightly better in vitro half-life than Ligand A (-8.19).

**P-gp Efflux:** Ligand A (0.039) has a much lower P-gp efflux liability than Ligand B (0.061), which is beneficial for CNS penetration.

**Binding Affinity:** Ligand B (-8.3) has a slightly better binding affinity than Ligand A (-7.6). The difference is 0.7 kcal/mol, which is a significant advantage.

**Overall Assessment:**

While Ligand B has a slightly better binding affinity and metabolic stability, Ligand A has a much lower DILI risk and significantly lower P-gp efflux. The lower P-gp efflux is crucial for CNS penetration, and the lower DILI risk is a major safety advantage. The slightly lower BBB for Ligand A is a concern, but the lower P-gp efflux can partially compensate for this. The affinity difference, while notable, might be overcome with further optimization, while mitigating DILI and improving CNS penetration are often more challenging. Given the GPCR target and CNS focus, prioritizing BBB, logP, Pgp, and safety (DILI) is critical.

Output:
0
2025-04-17 04:00:58,081 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (351.447 and 350.394 Da) fall comfortably within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (84.67) is better than Ligand B (76.98) but both are below the 90 A^2 threshold for CNS targets, which is excellent.

**3. logP:** Ligand A (2.163) is optimal (1-3). Ligand B (-0.04) is slightly below 1, which could potentially hinder permeation.

**4. H-Bond Donors:** Both ligands have 1 HBD, which is within the acceptable limit of <=5.

**5. H-Bond Acceptors:** Both ligands have 5 HBA, which is within the acceptable limit of <=10.

**6. QED:** Both ligands have good QED scores (0.737 and 0.825, respectively), indicating drug-like properties.

**7. DILI:** Ligand A (30.787) has a lower DILI risk than Ligand B (25.436), both are very good.

**8. BBB:** Ligand A (87.088) has a significantly better BBB penetration percentile than Ligand B (60.76). This is *crucial* for a CNS target like DRD2.

**9. Caco-2 Permeability:** Ligand A (-4.317) is better than Ligand B (-4.441). Both are negative, but A is less negative.

**10. Aqueous Solubility:** Ligand A (-1.849) is better than Ligand B (-0.195). Both are negative, but A is less negative.

**11. hERG Inhibition:** Both ligands have low hERG inhibition risk (0.133 and 0.282, respectively).

**12. Microsomal Clearance:** Ligand B (-3.75) has a lower (better) microsomal clearance than Ligand A (76.93). This suggests better metabolic stability for Ligand B.

**13. In vitro Half-Life:** Ligand B (-9.133) has a longer half-life than Ligand A (-33.291).

**14. P-gp Efflux:** Both ligands have low P-gp efflux liability (0.044 and 0.023, respectively).

**15. Binding Affinity:** Ligand A (-7.3 kcal/mol) has a slightly better binding affinity than Ligand B (-8.1 kcal/mol). Although the difference is relatively small, it is still a positive for Ligand A.

**Overall Assessment:**

While Ligand B shows advantages in metabolic stability (lower Cl_mic) and half-life, the significantly superior BBB penetration of Ligand A (87.088 vs 60.76) is the deciding factor for a CNS-targeting drug. The slightly better affinity of Ligand A also contributes. The logP of Ligand B is a concern. Given the GPCR-specific priorities, particularly for CNS targets, BBB penetration is paramount.

Output:
1
2025-04-17 04:00:58,081 - INFO - Reasoning:

Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (346.435 and 361.419 Da) fall within the ideal 200-500 Da range.

**TPSA:** Both ligands (80.41 and 82.56) are below the 90 A^2 threshold desirable for CNS targets, which is excellent.

**logP:** Ligand A (1.453) is within the optimal 1-3 range. Ligand B (3.146) is at the upper end of the optimal range, but still acceptable.

**H-Bond Donors/Acceptors:** Both ligands have acceptable HBD (0) and HBA (8 & 7) counts, well within the guidelines.

**QED:** Ligand A (0.745) has a better QED score than Ligand B (0.581), indicating a more drug-like profile.

**DILI:** Both ligands have relatively high DILI risk (63.397 and 69.639), but are still below the concerning >60 threshold. This is something to investigate further, but not a dealbreaker at this stage.

**BBB:** Ligand A (92.827) has a significantly better BBB penetration score than Ligand B (81.466). This is a *critical* factor for a CNS target like DRD2.

**Caco-2 Permeability:** Both have negative Caco-2 values (-4.824 and -4.546), which is unusual and suggests poor permeability. This is a significant concern for both.

**Aqueous Solubility:** Both ligands have very poor aqueous solubility (-2.394 and -4.146). This is a major drawback that would require formulation strategies.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.742 and 0.149), which is positive.

**Microsomal Clearance:** Ligand A (66.517) has lower microsomal clearance than Ligand B (90.724), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (-5.375) has a longer in vitro half-life than Ligand B (-2.322).

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.143 and 0.131), which is favorable for CNS penetration.

**Binding Affinity:** Ligand B (-8.7 kcal/mol) has a significantly stronger binding affinity than Ligand A (-7.5 kcal/mol). This is a substantial advantage (1.2 kcal/mol difference).

**Overall Assessment:**

While Ligand B boasts a superior binding affinity, Ligand A has a significantly better BBB score, better metabolic stability (lower Cl_mic, longer t1/2), and a better QED score. The poor Caco-2 and solubility are concerning for both, but the strong affinity of Ligand B is a compelling advantage. However, for a CNS target, BBB penetration is paramount. The difference in BBB (92.8% vs 81.5%) is substantial enough to outweigh the affinity difference, especially considering the other favorable properties of Ligand A.

Output:
0
2025-04-17 04:00:58,081 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (346.427 Da and 346.391 Da) fall comfortably within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (78.87) is significantly better than Ligand B (107.09). For CNS targets, we want TPSA <= 90, so Ligand A is preferable.

**3. logP:** Ligand A (1.504) is within the optimal 1-3 range. Ligand B (-0.087) is slightly below 1, which *could* indicate permeability issues, though not drastically.

**4. H-Bond Donors:** Both ligands have 2 HBD, which is acceptable (<=5).

**5. H-Bond Acceptors:** Ligand A has 4 HBA, and Ligand B has 5. Both are within the acceptable limit of <=10.

**6. QED:** Both ligands have QED values above 0.75, indicating good drug-like properties.

**7. DILI:** Ligand A (21.753) has a much lower DILI risk than Ligand B (41.024). Lower is better, and Ligand A is well below the concerning threshold of 60.

**8. BBB:** Ligand A (51.183) has a better BBB penetration percentile than Ligand B (36.06). While both are below the desirable >70 for CNS targets, Ligand A is closer.

**9. Caco-2 Permeability:** Ligand A (-5.336) and Ligand B (-5.318) have similar, and poor, Caco-2 permeability.

**10. Aqueous Solubility:** Both ligands have very poor aqueous solubility (-1.257 and -1.793 respectively). This is a concern for both.

**11. hERG Inhibition:** Ligand A (0.068) has a significantly lower hERG inhibition risk than Ligand B (0.201). Lower is better.

**12. Microsomal Clearance:** Ligand A (-7.21) has a much lower (better) microsomal clearance than Ligand B (-8.758). This suggests better metabolic stability for Ligand A.

**13. In vitro Half-Life:** Ligand A (1.842) has a shorter half-life than Ligand B (-15.308). However, the negative value for Ligand B is suspect and likely indicates a very long half-life, which is good.

**14. P-gp Efflux:** Ligand A (0.008) has very low P-gp efflux, which is excellent for CNS penetration. Ligand B (0.03) is also low, but slightly higher.

**15. Binding Affinity:** Ligand B (-8.758) has a significantly stronger binding affinity than Ligand A (-7.21). This is a substantial advantage (over 1.5 kcal/mol difference).

**Overall Assessment:**

Ligand B has a much better binding affinity, which is a crucial factor. However, Ligand A demonstrates superior properties in several key areas for CNS drug development: TPSA, DILI, BBB, hERG, and P-gp efflux. The solubility and Caco-2 permeability are poor for both. The improved metabolic stability of Ligand A is also a plus.

The affinity difference is significant. While Ligand A is better optimized for CNS penetration and safety, the stronger affinity of Ligand B could potentially outweigh the ADME drawbacks, *especially* if further optimization can address the solubility and permeability issues.

Output:
1
2025-04-17 04:00:58,081 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 drug candidates, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (345.487 Da) is slightly lower, which could be advantageous for permeability, while Ligand B (427.412 Da) is closer to the upper limit.

**TPSA:** Ligand A (64.41) is significantly better than Ligand B (43.18) regarding TPSA. For CNS targets, we want TPSA <= 90, and ideally closer to 60. Ligand A is much closer to this ideal.

**logP:** Both ligands have good logP values (A: 3.122, B: 4.019), falling within the optimal 1-3 range. Ligand B is slightly higher, which *could* lead to solubility issues, but isn't a major concern.

**H-Bond Donors/Acceptors:** Both ligands have reasonable HBD/HBA counts (A: 0/3, B: 0/6). Ligand B has more HBA, but still within acceptable limits.

**QED:** Both ligands have acceptable QED scores (A: 0.735, B: 0.67), indicating good drug-like properties.

**DILI:** Ligand A (11.128) has a much lower DILI risk than Ligand B (35.75), which is a significant advantage.

**BBB:** Both ligands have excellent BBB penetration (A: 75.843, B: 78.79), exceeding the desirable threshold of >70.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values, which is unusual and suggests a potential issue with the data or modeling. However, we can still compare them relatively. Ligand A (-4.403) is slightly better than Ligand B (-5.173).

**Aqueous Solubility:** Both ligands have negative solubility values, again indicating a potential data issue. Ligand A (-2.641) is slightly better than Ligand B (-3.266).

**hERG:** Both ligands have low hERG inhibition risk (A: 0.587, B: 0.796).

**Microsomal Clearance:** Ligand A (42.776) has lower microsomal clearance than Ligand B (50.503), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (-10.595) has a negative half-life, which is problematic. Ligand B (13.803) has a positive half-life, indicating better stability.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (A: 0.04, B: 0.575), which is good for CNS exposure. Ligand A is significantly lower.

**Binding Affinity:** Ligand B (-7.2 kcal/mol) has a slightly better binding affinity than Ligand A (-6.4 kcal/mol). This 0.8 kcal/mol difference is significant, potentially outweighing some of the ADME drawbacks of Ligand B.

**Overall Assessment:**

Ligand A excels in TPSA, DILI, P-gp efflux, and microsomal clearance. However, its in vitro half-life is a major concern. Ligand B has a better binding affinity and a positive half-life, but has a higher DILI risk and a less favorable TPSA. Given the importance of CNS penetration for DRD2 targeting, the lower TPSA and DILI of Ligand A are compelling. The slightly better affinity of Ligand B is a benefit, but the negative half-life of Ligand A is a significant drawback. Considering the potential for optimization of the half-life of Ligand A, it appears to be the more promising starting point.

Output:
0
2025-04-17 04:00:58,082 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 drug candidates, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (346.471 and 352.435 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (57.69) is excellent, well below the 90 A^2 threshold for CNS targets. Ligand B (90.98) is at the upper limit, but still acceptable.

**logP:** Ligand A (2.385) is optimal (1-3). Ligand B (0.51) is a bit low, potentially hindering membrane permeability.

**H-Bond Donors/Acceptors:** Ligand A (0 HBD, 3 HBA) is favorable. Ligand B (2 HBD, 4 HBA) is also acceptable.

**QED:** Both ligands have similar QED values (0.665 and 0.538), indicating reasonable drug-likeness.

**DILI:** Ligand A (25.165) has a significantly lower DILI risk than Ligand B (46.762), which is a substantial advantage.

**BBB:** Ligand A (88.019) shows excellent BBB penetration, exceeding the desirable 70% threshold. Ligand B (70.88) is acceptable but less favorable.

**Caco-2:** Ligand A (-4.654) has a negative Caco-2 value which is unusual and concerning, suggesting poor permeability. Ligand B (-5.035) is similarly poor.

**Solubility:** Both ligands have negative solubility values (-2.778 and -1.657), indicating very poor aqueous solubility, a major drawback.

**hERG:** Both ligands show low hERG inhibition liability (0.199 and 0.476), which is positive.

**Microsomal Clearance:** Ligand A (58.399) has a higher microsomal clearance than Ligand B (-12.633), suggesting faster metabolism and potentially lower *in vivo* exposure.

**In vitro Half-Life:** Ligand B (5.208) has a longer half-life than Ligand A (13.325), which is preferable.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.092 and 0.01), which is good for CNS penetration.

**Binding Affinity:** Ligand B (-8.8 kcal/mol) has a significantly stronger binding affinity than Ligand A (-6.3 kcal/mol) - a difference of 2.5 kcal/mol. This is a major advantage that can potentially offset some of its ADME liabilities.

**Overall Assessment:**

Despite the poor solubility and Caco-2 values for both compounds, Ligand B stands out due to its significantly stronger binding affinity (-8.8 vs -6.3 kcal/mol). The higher affinity, coupled with acceptable BBB penetration and lower DILI risk than Ligand A, makes it the more promising candidate. The lower logP is a concern, but the strong binding could compensate. The longer half-life is also a plus. While the solubility and permeability need to be addressed through formulation or structural modification, the superior potency of Ligand B makes it the better starting point for further optimization.

Output:
1
2025-04-17 04:00:58,082 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (358.511 and 342.443 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (57.26) is significantly better than Ligand B (75.19). For CNS targets, we want TPSA <= 90, and A is much closer to the preferred <= 60 range. B is pushing the upper limit.

**logP:** Both ligands have good logP values (2.969 and 2.225), falling within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A (2 HBD, 5 HBA) is slightly more favorable than Ligand B (1 HBD, 4 HBA), but both are within acceptable limits.

**QED:** Both ligands have high QED scores (0.882 and 0.91), indicating good drug-like properties.

**DILI:** Ligand A (71.152) has a higher DILI risk than Ligand B (38.969). This is a negative for A.

**BBB:** Ligand A (66.576) and Ligand B (69.252) are both reasonably good, but below the desirable >70 for CNS targets. B is slightly better.

**Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and suggests poor permeability. This is a significant concern for both.

**Aqueous Solubility:** Both have negative solubility values, indicating very poor solubility. This is a major drawback for both compounds.

**hERG Inhibition:** Ligand A (0.79) has a slightly higher hERG risk than Ligand B (0.164), which is preferable.

**Microsomal Clearance:** Ligand B (50.048) has a higher microsomal clearance than Ligand A (30.221), indicating lower metabolic stability. A is better here.

**In vitro Half-Life:** Ligand A (36.654) has a significantly longer half-life than Ligand B (1.322), which is a substantial advantage.

**P-gp Efflux:** Ligand A (0.498) has lower P-gp efflux than Ligand B (0.024), which is favorable for CNS penetration.

**Binding Affinity:** Both ligands have very similar, excellent binding affinities (-7.8 and -7.7 kcal/mol). The difference is negligible.

**Overall Assessment:**

Considering the GPCR-specific priorities, Ligand A is slightly more favorable. While it has a higher DILI risk, its superior TPSA, lower P-gp efflux, longer half-life, and better metabolic stability outweigh this concern. Both compounds suffer from poor solubility and permeability, which are major hurdles. However, the slightly better ADME profile of Ligand A, especially regarding CNS penetration, makes it the more promising candidate.

Output:
1
2025-04-17 04:00:58,082 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (344.459 Da) is slightly better being closer to the middle of the range.

**TPSA:** Ligand A (66.4) is significantly better than Ligand B (104.39). For CNS targets, we want TPSA <= 90, and Ligand A is comfortably within this range, while Ligand B exceeds it.

**logP:** Both ligands have acceptable logP values (Ligand A: 2.286, Ligand B: 0.619), but Ligand A is more optimal (1-3). Ligand B's logP is relatively low, which could hinder permeation.

**H-Bond Donors/Acceptors:** Ligand A (0 HBD, 4 HBA) is preferable to Ligand B (2 HBD, 5 HBA). Lower counts are generally better for permeability.

**QED:** Both ligands have reasonable QED values (Ligand A: 0.825, Ligand B: 0.664), indicating good drug-like properties. Ligand A is slightly better.

**DILI:** Ligand A (35.789) has a lower DILI risk than Ligand B (49.593), which is desirable.

**BBB:** This is a crucial parameter for CNS targets. Ligand A (80.574) has a significantly higher BBB penetration percentile than Ligand B (47.266). This is a major advantage for Ligand A.

**Caco-2 Permeability:** Ligand A (-4.692) has a higher Caco-2 permeability than Ligand B (-5.29), indicating better intestinal absorption.

**Aqueous Solubility:** Both ligands have poor aqueous solubility (-2.035 and -2.532 respectively). This is a concern for both, but not a deciding factor.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.436 and 0.25 respectively).

**Microsomal Clearance:** Ligand B (-10.488) has a lower (better) microsomal clearance than Ligand A (39.753), indicating greater metabolic stability. This is a point in favor of Ligand B.

**In vitro Half-Life:** Ligand B (-10.123) has a longer in vitro half-life than Ligand A (-0.653), which is also a positive for Ligand B.

**P-gp Efflux:** Ligand A (0.196) has lower P-gp efflux liability than Ligand B (0.025), which is preferable for CNS exposure.

**Binding Affinity:** Both ligands have very similar and strong binding affinities (-8.9 kcal/mol and -8.1 kcal/mol). The difference of 0.8 kcal/mol is not substantial enough to override the other ADME differences.

**Overall Assessment:**

Ligand A is the stronger candidate. Its superior BBB penetration, lower TPSA, better logP, lower DILI risk, and lower P-gp efflux outweigh Ligand B's better metabolic stability and half-life. For a CNS target like DRD2, getting the drug into the brain is paramount, and Ligand A's higher BBB percentile is a decisive advantage. The affinity is comparable between the two.

Output:
1
2025-04-17 04:00:58,082 - INFO - Reasoning:

Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (351.387 and 345.443 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (95.13) is higher than the preferred <90 for CNS targets, while Ligand B (62.74) is well within the range. This is a significant advantage for Ligand B.

**3. logP:** Ligand A (4.026) is at the upper end of the optimal range (1-3) and could potentially lead to solubility issues. Ligand B (1.906) is excellent, right in the sweet spot.

**4. H-Bond Donors:** Ligand A (2) is acceptable, and Ligand B (0) is also good.

**5. H-Bond Acceptors:** Ligand A (5) is acceptable, and Ligand B (4) is also good.

**6. QED:** Both ligands have good QED scores (0.742 and 0.765), indicating drug-like properties.

**7. DILI:** Ligand A (93.951) has a high DILI risk, which is concerning. Ligand B (40.403) has a much lower and acceptable DILI risk.

**8. BBB:** Ligand A (27.724) has a very poor BBB penetration percentile, making it unlikely to effectively reach the target in the CNS. Ligand B (73.517) has a good BBB penetration percentile, a crucial factor for a DRD2 ligand.

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 values, which is unusual and potentially problematic. However, the scale is not specified, making it difficult to interpret.

**10. Aqueous Solubility:** Both ligands have negative solubility values, indicating poor aqueous solubility.

**11. hERG Inhibition:** Ligand A (0.613) has a slightly higher hERG risk than Ligand B (0.217), though both are relatively low.

**12. Microsomal Clearance:** Ligand A (37.87) and Ligand B (43.887) have similar microsomal clearance values, suggesting comparable metabolic stability.

**13. In vitro Half-Life:** Ligand A (132.066) has a longer half-life than Ligand B (5.885), which is a positive attribute.

**14. P-gp Efflux:** Ligand A (0.423) has lower P-gp efflux than Ligand B (0.256), which is beneficial for CNS penetration.

**15. Binding Affinity:** Ligand A (-8.7 kcal/mol) has a significantly stronger binding affinity than Ligand B (-6.8 kcal/mol). This is a substantial advantage for Ligand A.

**Overall Assessment:**

While Ligand A boasts a superior binding affinity, its poor BBB penetration, high DILI risk, and borderline high logP are major drawbacks. Ligand B, despite a weaker binding affinity, excels in crucial properties for a CNS-targeting GPCR ligand: excellent TPSA, optimal logP, good BBB penetration, and low DILI risk. The difference in binding affinity (-1.9 kcal/mol) is substantial, but the ADME/Tox profile of Ligand B is far more favorable. Given the GPCR-specific priorities, especially BBB and safety (DILI), and the potential to optimize Ligand B's affinity through further medicinal chemistry efforts, it is the more promising candidate.

Output:
1
2025-04-17 04:00:58,082 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (351.535 and 352.494 Da) fall comfortably within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (52.65) is slightly higher than Ligand B (49.41), but both are below the 90 Angstroms threshold desirable for CNS targets.

**3. logP:** Both ligands have good logP values (2.652 and 3.448), falling within the optimal 1-3 range. Ligand B is slightly higher, which could be beneficial for membrane permeability, but isn't a major concern.

**4. H-Bond Donors:** Both ligands have 1 HBD, which is within the acceptable limit of <=5.

**5. H-Bond Acceptors:** Ligand A has 3 HBAs, and Ligand B has 2. Both are below the limit of <=10.

**6. QED:** Both ligands have similar QED values (0.616 and 0.646), indicating good drug-like properties.

**7. DILI:** Ligand A (4.731) has a much lower DILI risk than Ligand B (9.771). This is a significant advantage for Ligand A.

**8. BBB:** Ligand B (95.735) has a substantially higher BBB penetration percentile than Ligand A (83.637). This is a *critical* advantage for a CNS target like DRD2.

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.729 and -4.85). These values are unusual and likely indicate poor permeability in this assay. It's difficult to interpret without knowing the scale, but they are both unfavorable.

**10. Aqueous Solubility:** Both ligands have negative solubility values (-1.673 and -3.731). Again, the scale is unknown, but negative values suggest poor aqueous solubility, which could hinder bioavailability. Ligand B appears slightly worse.

**11. hERG Inhibition:** Both ligands have low hERG inhibition risk (0.709 and 0.88).

**12. Microsomal Clearance:** Ligand A (56.538) has higher microsomal clearance than Ligand B (46.663), suggesting faster metabolism and potentially lower exposure.

**13. In vitro Half-Life:** Ligand B (-9.52) has a much longer in vitro half-life than Ligand A (-2.695). This is a significant advantage for Ligand B.

**14. P-gp Efflux:** Both ligands have low P-gp efflux liability (0.023 and 0.393).

**15. Binding Affinity:** Both ligands have identical binding affinities (-7.4 kcal/mol), which is excellent.

**Overall Assessment:**

The key differentiating factors are BBB penetration, DILI risk, and metabolic stability. Ligand B has a significantly higher BBB penetration (95.735 vs 83.637) and a much longer half-life (-9.52 vs -2.695), which are crucial for CNS drug development. While Ligand A has a lower DILI risk, the importance of CNS penetration and metabolic stability for a DRD2 ligand outweighs this benefit. The poor Caco-2 and solubility values are concerning for both, but can potentially be addressed through formulation strategies.

Output:
1
2025-04-17 04:00:58,083 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (347.415 and 339.399 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (79.9) is better than Ligand B (88.08). Both are below the 90 A^2 threshold for CNS targets, but A is closer to the optimal range.

**3. logP:** Both ligands (1.063 and 1.523) are within the optimal 1-3 range.

**4. H-Bond Donors:** Ligand A (2) is slightly higher than Ligand B (1), but both are acceptable (<=5).

**5. H-Bond Acceptors:** Ligand A (4) is lower than Ligand B (5), both are acceptable (<=10).

**6. QED:** Both ligands have good QED scores (0.854 and 0.892), indicating good drug-like properties.

**7. DILI:** Ligand A (57.348) has a higher DILI risk than Ligand B (47.15). Both are acceptable (<60).

**8. BBB:** Ligand A (71.462) has a significantly better BBB penetration score than Ligand B (56.146). This is a *critical* factor for a CNS target like DRD2.

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.927 and -4.903). This is unusual and suggests poor permeability. However, the values are very similar.

**10. Aqueous Solubility:** Both ligands have negative solubility values (-1.957 and -1.567) indicating very poor solubility. This is a significant drawback.

**11. hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.209 and 0.141).

**12. Microsomal Clearance:** Ligand A (8.341) has a higher microsomal clearance than Ligand B (6.269), meaning it is less metabolically stable.

**13. In vitro Half-Life:** Ligand B (11.873) has a longer in vitro half-life than Ligand A (27.095). This is a positive for Ligand B.

**14. P-gp Efflux:** Ligand A (0.021) has a much lower P-gp efflux liability than Ligand B (0.004), which is highly desirable for CNS penetration.

**15. Binding Affinity:** Ligand B (-8.8 kcal/mol) has a significantly stronger binding affinity than Ligand A (-0 kcal/mol). This is a *major* advantage, potentially outweighing some of the ADME drawbacks.

**Overall Assessment:**

While Ligand B has a superior binding affinity, the significantly better BBB penetration and P-gp efflux profile of Ligand A are crucial for a CNS target. The lower clearance and slightly better TPSA of Ligand A are also favorable. The poor solubility and Caco-2 permeability are concerning for both, but the strong binding affinity of Ligand B might overcome those issues. However, the substantial difference in BBB penetration is a decisive factor.

Output:
1
2025-04-17 04:00:58,083 - INFO - Batch 77 complete. Total preferences: 1232
2025-04-17 04:00:58,083 - INFO - Processing batch 78/512...
2025-04-17 04:01:42,006 - INFO - Reasoning:

Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (349.475 and 352.435 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (92.5) is significantly better than Ligand B (115.97). For CNS targets, we ideally want TPSA <= 90. Ligand A is closer to this threshold.

**logP:** Ligand A (1.599) is within the optimal 1-3 range. Ligand B (-1.184) is below 1, which could hinder permeation.

**H-Bond Donors/Acceptors:** Ligand A (HBD=2, HBA=3) and Ligand B (HBD=3, HBA=5) both have reasonable numbers of H-bond donors and acceptors, staying within the guidelines.

**QED:** Both ligands have acceptable QED scores (0.619 and 0.52), indicating good drug-like properties.

**DILI:** Ligand A (10.237) has a much lower DILI risk than Ligand B (5.894), suggesting better potential for avoiding liver toxicity.

**BBB:** Ligand A (68.127) has a significantly better BBB penetration percentile than Ligand B (35.014). This is *critical* for a CNS target like DRD2.

**Caco-2 Permeability:** Ligand A (-5.253) and Ligand B (-6.002) both have negative values, indicating poor permeability.

**Aqueous Solubility:** Ligand A (-2.407) and Ligand B (-0.871) both have negative values, indicating poor solubility.

**hERG:** Both ligands have very low hERG inhibition liability (0.167 and 0.132), which is excellent.

**Microsomal Clearance:** Ligand A (35.006) has a higher microsomal clearance than Ligand B (-21.71), suggesting lower metabolic stability. However, the negative value for Ligand B is unusual and may indicate an issue with the prediction.

**In vitro Half-Life:** Ligand A (-18.569) has a negative half-life, which is not possible. Ligand B (-16.381) also has a negative half-life. Both are problematic.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.019 and 0.001), which is favorable for CNS penetration.

**Binding Affinity:** Both ligands have comparable and strong binding affinities (-8.2 and -8.7 kcal/mol). The difference is minimal.

**Overall Assessment:**

Ligand A is significantly better than Ligand B. The key advantages of Ligand A are its superior BBB penetration, lower DILI risk, and more favorable logP and TPSA values. While both have issues with solubility and permeability, the BBB score is paramount for a CNS target. The negative half-life values are concerning for both, but the other properties of Ligand A make it the more promising candidate.

Output:
1
2025-04-17 04:01:42,006 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (356.897 and 351.491 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (32.34) is excellent, well below the 90 A^2 threshold for CNS targets. Ligand B (70.67) is higher, but still potentially acceptable, though less ideal.

**3. logP:** Ligand A (4.564) is slightly high, potentially leading to solubility issues or off-target interactions. Ligand B (1.154) is quite low, which might hinder membrane permeability.

**4. H-Bond Donors:** Ligand A (1) is good. Ligand B (2) is acceptable.

**5. H-Bond Acceptors:** Ligand A (1) is good. Ligand B (4) is acceptable.

**6. QED:** Ligand A (0.808) is excellent, indicating high drug-likeness. Ligand B (0.58) is acceptable, but lower.

**7. DILI:** Ligand A (35.556) has a low DILI risk, which is favorable. Ligand B (5.545) also has a low DILI risk.

**8. BBB:** Ligand A (86.545) has a very good BBB penetration percentile, crucial for a CNS target like DRD2. Ligand B (54.983) is significantly lower, raising concerns about CNS exposure.

**9. Caco-2:** Ligand A (-4.477) and Ligand B (-5.228) both have negative values, which is unusual and suggests poor permeability. However, these values are on a scale where negative values are possible and don't necessarily preclude absorption.

**10. Solubility:** Ligand A (-5.243) has poor aqueous solubility, consistent with its high logP. Ligand B (-0.842) has better solubility.

**11. hERG:** Ligand A (0.839) has a low hERG risk. Ligand B (0.492) also has a low hERG risk.

**12. Cl_mic:** Ligand A (82.727) has a relatively high microsomal clearance, suggesting faster metabolism. Ligand B (-8.58) has negative clearance, which is impossible and likely an error in the data. This is a major red flag.

**13. t1/2:** Ligand A (54.282) has a moderate in vitro half-life. Ligand B (8.37) has a very short half-life.

**14. Pgp:** Ligand A (0.387) has low P-gp efflux, which is good for CNS penetration. Ligand B (0.042) also has low P-gp efflux.

**15. Binding Affinity:** Ligand A (-10.3 kcal/mol) has significantly stronger binding affinity than Ligand B (-7.0 kcal/mol). This is a substantial advantage.

**Overall Assessment:**

Ligand A excels in key areas for a CNS-targeting GPCR ligand: excellent BBB penetration, strong binding affinity, low DILI risk, and low P-gp efflux. Its main drawbacks are its high logP and resulting poor solubility, and relatively high metabolic clearance. However, the strong affinity could potentially compensate for these ADME issues.

Ligand B has a lower logP and better solubility, but suffers from significantly lower BBB penetration, a very short half-life, and a highly suspect negative microsomal clearance value. The lower affinity is also a disadvantage. The negative clearance value is a critical flaw.

Given the importance of BBB penetration and binding affinity for a CNS GPCR target, and the problematic negative clearance value for Ligand B, Ligand A is the more promising candidate.

Output:
1
2025-04-17 04:01:42,006 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (433.322 Da) is slightly higher, but still acceptable. Ligand B (369.571 Da) is also good.

**2. TPSA:** Both ligands have TPSA values below the 90 A^2 threshold for CNS targets, which is positive. Ligand A (50.28 A^2) is slightly higher than Ligand B (38.77 A^2), but both are favorable.

**3. logP:** Both ligands have logP values within the optimal range (1-3). Ligand A (4.323) is a bit high, potentially leading to solubility issues or off-target interactions, while Ligand B (3.733) is better.

**4. H-Bond Donors:** Ligand A has 1 HBD, which is acceptable. Ligand B has 0 HBD, also acceptable.

**5. H-Bond Acceptors:** Ligand A has 6 HBA, within the acceptable range. Ligand B has 4 HBA, also within range.

**6. QED:** Both ligands have QED values above 0.5, indicating good drug-like properties. Ligand A (0.736) is slightly better than Ligand B (0.588).

**7. DILI:** Ligand A has a DILI risk of 58.434%, which is approaching the higher risk threshold (>60%). Ligand B has a much lower DILI risk (21.869%), a significant advantage.

**8. BBB:** Both ligands have excellent BBB penetration (>70%), with Ligand A at 83.676% and Ligand B at 80.613%. This is crucial for a CNS target like DRD2.

**9. Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and suggests poor permeability. However, the scale is not specified, so it's difficult to interpret.

**10. Aqueous Solubility:** Both have negative solubility values, suggesting poor solubility. Again, the scale is not specified.

**11. hERG Inhibition:** Both ligands show low hERG inhibition liability, which is good. Ligand A (0.866) is slightly higher than Ligand B (0.731).

**12. Microsomal Clearance:** Ligand A has a lower Cl_mic (12.752 mL/min/kg) than Ligand B (79.7 mL/min/kg), indicating better metabolic stability.

**13. In vitro Half-Life:** Ligand A has a shorter half-life (2.073 hours) than Ligand B (18.824 hours), which is less desirable.

**14. P-gp Efflux:** Both ligands have low P-gp efflux liability (Ligand A: 0.42, Ligand B: 0.685), which is favorable for CNS exposure.

**15. Binding Affinity:** Ligand A has a significantly stronger binding affinity (-8.2 kcal/mol) than Ligand B (-6.9 kcal/mol). This is a substantial advantage, potentially outweighing some of its less favorable ADME properties.

**Overall Assessment:**

Ligand A has a much stronger binding affinity, which is the most important factor for GPCRs. However, it has a higher logP, a potentially problematic DILI score, and a shorter half-life. Ligand B has better ADME properties (lower DILI, better metabolic stability, longer half-life) but weaker binding affinity.

Given the strong affinity of Ligand A and the importance of potency for GPCRs, I would prioritize Ligand A, but with a caveat. Further optimization would be needed to address the DILI risk and improve its metabolic stability/half-life. The difference in affinity (1.3 kcal/mol) is substantial enough to warrant further investigation of Ligand A despite its drawbacks.

Output:
1
2025-04-17 04:01:42,006 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the acceptable range (200-500 Da). Ligand A (354.407 Da) is slightly better positioned.

**TPSA:** Ligand B (58.2) is significantly better than Ligand A (137.32). For CNS targets, we want TPSA <= 90, and Ligand B is well within this range while Ligand A is close to the upper limit.

**logP:** Ligand A (-0.142) is quite low, potentially hindering membrane permeability. Ligand B (4.044) is high, potentially causing solubility issues or off-target interactions, but is within the acceptable range.

**H-Bond Donors/Acceptors:** Ligand A has 4 HBD and 6 HBA, while Ligand B has 2 HBD and 2 HBA. Both are acceptable, but Ligand B is more favorable due to lower counts, potentially improving permeability.

**QED:** Both ligands have good QED scores (A: 0.513, B: 0.614), indicating good drug-like properties.

**DILI:** Ligand B (27.53) has a much lower DILI risk than Ligand A (58.705), which is a significant advantage.

**BBB:** Ligand B (66.615) has a substantially better BBB penetration score than Ligand A (28.383). This is *critical* for a CNS target like DRD2.

**Caco-2 Permeability:** Both have negative values, indicating poor permeability. Ligand A (-5.608) is slightly better than Ligand B (-4.859), but both are concerning.

**Aqueous Solubility:** Both ligands have poor aqueous solubility (-1.944 and -5.158 respectively).

**hERG Inhibition:** Ligand A (0.024) shows a very slight risk of hERG inhibition, while Ligand B (0.489) is slightly higher. Both are relatively low risk.

**Microsomal Clearance:** Ligand A (-5.446) indicates lower clearance and better metabolic stability than Ligand B (72.395).

**In vitro Half-Life:** Ligand B (-6.293) has a slightly better half-life than Ligand A (-9.54).

**P-gp Efflux:** Both ligands show very low P-gp efflux liability (0.017 and 0.259 respectively).

**Binding Affinity:** Both ligands have excellent binding affinity (-8.0 and -8.2 kcal/mol respectively). The difference is minimal.

**Overall Assessment:**

Ligand B is significantly better overall, despite its higher logP and lower metabolic stability. The superior BBB penetration (66.615 vs 28.383), lower DILI risk (27.53 vs 58.705), and lower TPSA (58.2 vs 137.32) are crucial advantages for a CNS-targeting GPCR. The slightly lower metabolic stability of Ligand B can be addressed through structural modifications in later optimization stages. The affinity is comparable between the two. The poor solubility and Caco-2 permeability are concerns for both, but can be addressed through formulation or prodrug strategies.

Output:
1
2025-04-17 04:01:42,006 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (365.459 Da and 378.567 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (98.14) is slightly above the optimal <90 for CNS targets, but still reasonable. Ligand B (58.12) is excellent, well below 90.

**logP:** Ligand A (0.978) is a bit low, potentially hindering permeability. Ligand B (3.299) is within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A has 2 HBD and 7 HBA, which are acceptable. Ligand B has 1 HBD and 6 HBA, also acceptable.

**QED:** Both ligands have similar QED values (0.68 and 0.605), indicating good drug-likeness.

**DILI:** Both ligands have similar DILI risk (63.397 and 62.35), placing them in a moderate risk category. This isn't a major differentiating factor.

**BBB:** This is crucial for a CNS target. Ligand A has a BBB percentile of 49.942, which is below the desirable >70. Ligand B has a significantly better BBB percentile of 79.566.

**Caco-2 Permeability:** Both have negative Caco-2 values (-5.39 and -5.212), which is unusual and suggests poor permeability. This is a red flag for both, but doesn't necessarily disqualify them.

**Aqueous Solubility:** Both have negative solubility values (-1.824 and -4.318), indicating very poor aqueous solubility. This is a significant issue for both compounds.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.537 and 0.652).

**Microsomal Clearance:** Ligand A (28.832) has lower clearance than Ligand B (92.874), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (37.425) has a longer half-life than Ligand B (-1.491), which is preferable.

**P-gp Efflux:** Ligand A (0.184) has lower P-gp efflux than Ligand B (0.451), which is better for CNS exposure.

**Binding Affinity:** Ligand A (-7.9 kcal/mol) has a slightly better binding affinity than Ligand B (-7.1 kcal/mol), a difference of 0.8 kcal/mol.

**Overall Assessment:**

While Ligand A has slightly better affinity, half-life, and lower P-gp efflux, Ligand B is superior regarding key GPCR/CNS properties. Specifically, the significantly higher BBB penetration (79.566 vs 49.942) and more favorable logP (3.299 vs 0.978) are critical advantages. The poor solubility and Caco-2 permeability are concerns for both, but the improved CNS penetration of Ligand B outweighs the slightly better affinity of Ligand A.

Output:
1
2025-04-17 04:01:42,006 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (366.53 and 365.47 Da) fall comfortably within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (58.64) is higher than Ligand B (43.86). For a CNS target like DRD2, we ideally want TPSA <= 90, both are within this range, but B is better.

**3. logP:** Both ligands have good logP values (2.749 and 1.902), falling within the optimal 1-3 range.

**4. H-Bond Donors:** Ligand A has 1 HBD, while Ligand B has 0. Both are acceptable (<=5).

**5. H-Bond Acceptors:** Both ligands have 4 HBAs, which is within the acceptable limit of <=10.

**6. QED:** Both ligands have good QED scores (0.76 and 0.822), indicating good drug-like properties.

**7. DILI:** Ligand A (32.261) has a slightly higher DILI risk than Ligand B (23.187), but both are below the concerning threshold of 60.

**8. BBB:** This is a crucial parameter for CNS targets. Ligand B (93.68) has a significantly higher BBB penetration percentile than Ligand A (67.468). This is a major advantage for Ligand B.

**9. Caco-2 Permeability:** Ligand A (-5.533) has poorer Caco-2 permeability than Ligand B (-4.647).

**10. Aqueous Solubility:** Ligand A (-4.035) has poorer aqueous solubility than Ligand B (-1.976).

**11. hERG Inhibition:** Both ligands show low hERG inhibition risk (0.5 and 0.781).

**12. Microsomal Clearance:** Ligand B (8.062) has much lower microsomal clearance than Ligand A (40.395), suggesting better metabolic stability.

**13. In vitro Half-Life:** Ligand B (10.043) has a significantly longer in vitro half-life than Ligand A (-7.633).

**14. P-gp Efflux:** Both ligands have low P-gp efflux liability (0.162 and 0.324).

**15. Binding Affinity:** Both ligands have identical binding affinities (-8.4 kcal/mol), which is excellent.

**Overall Assessment:**

While both ligands have excellent binding affinity, Ligand B is superior due to its significantly better BBB penetration (93.68 vs 67.468), lower microsomal clearance, longer half-life, better Caco-2 permeability, and better aqueous solubility. These factors are particularly important for a CNS-targeting GPCR like DRD2. Ligand A's higher TPSA and lower BBB are significant drawbacks.

Output:
1
2025-04-17 04:01:42,007 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (349.479 and 355.395 Da) fall within the ideal range of 200-500 Da.

**TPSA:** Ligand A (83.29) is excellent, well below the 90 A^2 threshold for CNS targets. Ligand B (138.6) is higher, but still potentially acceptable, though less ideal.

**logP:** Ligand A (2.962) is optimal (1-3). Ligand B (-1.07) is significantly lower, which could hinder membrane permeability and CNS penetration despite the BBB score.

**H-Bond Donors/Acceptors:** Ligand A (HBD=2, HBA=5) is good. Ligand B (HBD=4, HBA=8) is also acceptable, but slightly higher values could potentially impact permeability.

**QED:** Ligand A (0.791) is excellent, indicating strong drug-likeness. Ligand B (0.504) is acceptable, but lower than Ligand A.

**DILI:** Ligand A (26.018) has a very low DILI risk. Ligand B (68.05) is higher, indicating a moderate risk of liver injury.

**BBB:** Ligand A (85.498) has excellent BBB penetration potential. Ligand B (26.483) has poor BBB penetration, a critical drawback for a CNS target like DRD2.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.074 and -5.116), which is unusual and suggests poor permeability. This is a concern for both, but the negative values are similar.

**Aqueous Solubility:** Both ligands have negative solubility values (-2.288 and -1.241), which is also unusual and suggests poor solubility. This is a concern for both, but Ligand B is slightly better.

**hERG:** Both ligands have very low hERG inhibition risk (0.34 and 0.032).

**Microsomal Clearance:** Ligand A (15.565) has moderate clearance, while Ligand B (-8.118) has negative clearance, which is not physically possible and likely an error. Assuming this is an outlier, we'll consider Ligand B to have very high metabolic stability.

**In vitro Half-Life:** Ligand A (20.392 hours) has a good half-life. Ligand B (34.762 hours) has a longer half-life, which is advantageous.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.076 and 0.006).

**Binding Affinity:** Both ligands have very similar and strong binding affinities (-7.8 and -7.7 kcal/mol). The difference is negligible.

**Overall Assessment:**

Ligand A is significantly better due to its superior BBB penetration (85.5% vs 26.5%), better logP (2.96 vs -1.07), and lower DILI risk (26.0% vs 68.1%). While both have issues with Caco-2 and solubility, the CNS target makes BBB penetration paramount. Ligand B's negative clearance value is also a red flag. The similar affinities are less important given the ADME advantages of Ligand A.

Output:
1
2025-04-17 04:01:42,007 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands are within the acceptable range (200-500 Da). Ligand A (415.253 Da) is slightly higher than Ligand B (346.387 Da), but neither is a concern.

**2. TPSA:** Ligand A (41.99) is excellent for CNS penetration, well below the 90 A^2 threshold. Ligand B (122.55) is higher, but still potentially acceptable, though less ideal.

**3. logP:** Ligand A (4.788) is a bit high, potentially leading to solubility issues or off-target interactions. Ligand B (0.454) is quite low, which could hinder membrane permeability and CNS penetration.

**4. H-Bond Donors:** Ligand A (1) is good. Ligand B (4) is at the upper limit of acceptable.

**5. H-Bond Acceptors:** Ligand A (2) is good. Ligand B (5) is acceptable.

**6. QED:** Both ligands have similar QED values (A: 0.69, B: 0.577), indicating reasonable drug-likeness.

**7. DILI:** Ligand A (52.423) has a lower DILI risk than Ligand B (67.119), making it more favorable.

**8. BBB:** Ligand A (87.67) has significantly better predicted BBB penetration than Ligand B (62.544). This is a critical factor for a CNS target like DRD2.

**9. Caco-2 Permeability:** Both have negative values which is unusual. Assuming these are logP values, Ligand A (-5.105) is worse than Ligand B (-5.478).

**10. Aqueous Solubility:** Both ligands have negative values which is unusual. Assuming these are logS values, Ligand A (-5.246) is worse than Ligand B (-3.053).

**11. hERG Inhibition:** Ligand A (0.859) has a lower hERG risk than Ligand B (0.197), which is preferable.

**12. Microsomal Clearance:** Ligand A (62.507) has higher clearance than Ligand B (-4.178), indicating lower metabolic stability. This is a negative for Ligand A.

**13. In vitro Half-Life:** Ligand A (41.755) has a longer half-life than Ligand B (-15.896), which is preferable.

**14. P-gp Efflux:** Ligand A (0.742) has lower P-gp efflux than Ligand B (0.008), which is favorable for CNS exposure.

**15. Binding Affinity:** Ligand A (-10.0) has a significantly stronger binding affinity than Ligand B (-9.1). This is a substantial advantage.

**Overall Assessment:**

Ligand A excels in key areas for a CNS GPCR target: strong binding affinity, good BBB penetration, lower DILI risk, and lower P-gp efflux. While its logP is slightly high and clearance is higher than ideal, the substantial affinity advantage and favorable CNS properties outweigh these drawbacks. Ligand B suffers from poor logP, lower BBB penetration, and a weaker binding affinity.

Output:
1
2025-04-17 04:01:42,007 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (350.463 Da) is slightly lower, which is generally favorable for permeability. Ligand B (385.877 Da) is also acceptable.

**TPSA:** Ligand A (76.46) is excellent, well below the 90 A^2 threshold for CNS targets. Ligand B (109.26) is still reasonable, but less optimal, being above 90.

**logP:** Both ligands have acceptable logP values (A: 1.133, B: 1.855), falling within the 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A (HBD=1, HBA=5) is better than Ligand B (HBD=3, HBA=8) in terms of balancing solubility and permeability.

**QED:** Ligand A (0.763) has a significantly better QED score than Ligand B (0.423), indicating a more drug-like profile.

**DILI:** Ligand A (27.569) has a much lower DILI risk than Ligand B (71.656), which is a significant advantage.

**BBB:** Ligand A (64.793) has a better BBB penetration score than Ligand B (28.306). This is *critical* for a CNS target like DRD2.

**Caco-2 Permeability:** Ligand A (-5.021) has a more negative Caco-2 value, which is less favorable. Ligand B (-5.538) is slightly worse. Both are poor.

**Aqueous Solubility:** Ligand A (-0.84) has slightly better solubility than Ligand B (-2.523).

**hERG:** Both ligands have very low hERG inhibition liability (A: 0.143, B: 0.2), which is excellent.

**Microsomal Clearance:** Both ligands have similar microsomal clearance (A: 25.735, B: 26.673), suggesting comparable metabolic stability.

**In vitro Half-Life:** Both ligands have similar in vitro half-lives (A: 20.098, B: 22.507).

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (A: 0.019, B: 0.198), which is favorable for CNS penetration.

**Binding Affinity:** Ligand B (-7.7 kcal/mol) has a slightly better binding affinity than Ligand A (-7.3 kcal/mol), but the difference is relatively small (0.4 kcal/mol).

**Overall Assessment:**

Ligand A is significantly better overall. While Ligand B has slightly better binding affinity, Ligand A excels in crucial ADME properties for a CNS-targeting GPCR, including TPSA, QED, DILI risk, and *especially* BBB penetration. The better BBB score of Ligand A is a major advantage. The Caco-2 permeability is poor for both, but this is less critical for a CNS target where direct oral bioavailability isn't necessarily the primary route of administration.



Output:
0
2025-04-17 04:01:42,007 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (362.423 and 373.479 Da) fall within the ideal range of 200-500 Da.

**TPSA:** Ligand A (128.56) is slightly higher than Ligand B (123.05), but both are below the 140 threshold for good oral absorption and reasonably close to the 90 target for CNS penetration.

**logP:** Ligand A (-1.892) is lower than optimal (1-3), potentially hindering permeation. Ligand B (-0.173) is closer to the optimal range, but still on the lower side.

**H-Bond Donors/Acceptors:** Ligand A has 4 HBD and 7 HBA, while Ligand B has 2 HBD and 7 HBA. Both are within acceptable limits.

**QED:** Ligand B (0.619) has a significantly better QED score than Ligand A (0.334), indicating a more drug-like profile.

**DILI:** Ligand A (8.802) has a much lower DILI risk than Ligand B (60.915), which is a significant concern.

**BBB:** Ligand B (47.228) has a better BBB percentile than Ligand A (36.099), but both are below the desirable >70 for CNS targets.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.281 and -5.372), which is unusual and suggests poor permeability.

**Aqueous Solubility:** Both ligands have negative solubility values (-1.291 and -1.72), which is also unusual and suggests poor solubility.

**hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.082 and 0.084).

**Microsomal Clearance:** Ligand A (4.55) has significantly lower microsomal clearance than Ligand B (16.904), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand B (38.474) has a much longer in vitro half-life than Ligand A (-21.653), which is a significant advantage.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.007 and 0.044).

**Binding Affinity:** Ligand B (-7.7 kcal/mol) has a significantly stronger binding affinity than Ligand A (-6.1 kcal/mol). This >1.5 kcal/mol difference is a major advantage, potentially outweighing some of its ADME drawbacks.

**Overall Assessment:**

Ligand B has a superior binding affinity and a better QED score and in vitro half-life. However, its DILI risk is concerningly high. Ligand A has a much lower DILI risk and better metabolic stability but suffers from weaker binding affinity and a lower QED score. Given the importance of binding affinity for GPCRs, and the significant difference observed (-7.7 vs -6.1 kcal/mol), Ligand B is the more promising candidate *despite* the higher DILI risk. The DILI risk could potentially be mitigated through structural modifications. The poor Caco-2 and solubility values are shared by both and would require attention during lead optimization.



Output:
1
2025-04-17 04:01:42,007 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (362.5 and 356.5 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (70.4) is excellent for CNS penetration, being well below the 90 A^2 threshold. Ligand B (101.98) is higher but still potentially acceptable, though less ideal.

**logP:** Ligand A (3.323) is within the optimal 1-3 range. Ligand B (-0.964) is significantly lower, which could hinder membrane permeability and CNS penetration.

**H-Bond Donors/Acceptors:** Both ligands have 2/5 HBD/HBA, which is acceptable.

**QED:** Ligand A (0.827) has a very good drug-likeness score, while Ligand B (0.52) is just above the minimum acceptable threshold.

**DILI:** Ligand A (28.3) has a much lower DILI risk than Ligand B (11.4).

**BBB:** Ligand A (83.2%) shows excellent predicted BBB penetration, crucial for a CNS target. Ligand B (18.96%) is very poor, making it less attractive.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values, which is unusual and difficult to interpret without further context. However, the magnitude of the negative value for Ligand A (-5.212) is smaller than that of Ligand B (-5.579).

**Aqueous Solubility:** Both ligands have negative solubility values, which is also unusual. Again, the magnitude for Ligand A (-2.288) is less negative than for Ligand B (-0.122).

**hERG:** Ligand A (0.768) has a lower hERG risk than Ligand B (0.096).

**Microsomal Clearance:** Ligand A (9.183) has a lower microsomal clearance, suggesting better metabolic stability, compared to Ligand B (-0.753).

**In vitro Half-Life:** Ligand A (15.611 hours) has a significantly longer half-life than Ligand B (-14.425 hours).

**P-gp Efflux:** Ligand A (0.196) has lower P-gp efflux liability than Ligand B (0.002).

**Binding Affinity:** Ligand A (-8.8 kcal/mol) has a significantly stronger binding affinity than Ligand B (-6.6 kcal/mol). The difference of 2.2 kcal/mol is substantial and can outweigh minor ADME drawbacks.

**Conclusion:**

Considering all factors, especially the GPCR-specific priorities, **Ligand A is significantly more promising.** It has superior BBB penetration, a better logP value, a lower DILI risk, better metabolic stability, longer half-life, lower P-gp efflux, and, most importantly, a much stronger binding affinity. While both ligands have unusual solubility and Caco-2 permeability values, the overall profile of Ligand A is far more favorable for development as a DRD2-targeting drug.

Output:
1
2025-04-17 04:01:42,007 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight (MW):** Both ligands (354.43 & 356.46 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (83.56) is better than Ligand B (58.2). For CNS targets, we want TPSA <= 90, both are within this range, but A is closer to the upper limit.

**3. logP:** Ligand B (3.57) is higher than Ligand A (0.59). While both are within the 1-3 range, Ligand B is closer to the upper limit. This could lead to solubility issues, but for a GPCR, some lipophilicity is beneficial for membrane interactions.

**4. H-Bond Donors (HBD):** Both ligands have 2 HBD, which is within the acceptable limit of <= 5.

**5. H-Bond Acceptors (HBA):** Ligand A has 5 HBA, and Ligand B has 2. Both are within the acceptable limit of <= 10.

**6. QED:** Both ligands have similar QED values (0.643 and 0.621), indicating good drug-like properties.

**7. DILI:** Ligand A (30.32) has a lower DILI risk than Ligand B (41.92), which is preferable. Both are below the 60 threshold.

**8. BBB:** Ligand B (89.61%) has a significantly higher BBB penetration score than Ligand A (78.71%). This is a *critical* advantage for a CNS target like DRD2.

**9. Caco-2 Permeability:** Both have negative values (-4.583 and -4.597), which is unusual and suggests poor permeability. This is a significant drawback for both.

**10. Aqueous Solubility:** Ligand A (-0.482) has slightly better solubility than Ligand B (-4.48), but both are very poor.

**11. hERG Inhibition:** Ligand A (0.434) has a slightly lower hERG inhibition risk than Ligand B (0.548).

**12. Microsomal Clearance:** Ligand A (29.76) has lower microsomal clearance than Ligand B (46.66), indicating better metabolic stability.

**13. In vitro Half-Life:** Ligand A (12.37) has a longer half-life than Ligand B (-3.49). This is a significant advantage.

**14. P-gp Efflux:** Ligand A (0.024) has much lower P-gp efflux liability than Ligand B (0.214). Lower P-gp efflux is highly desirable for CNS penetration.

**15. Binding Affinity:** Ligand B (-8.1 kcal/mol) has a stronger binding affinity than Ligand A (-7.6 kcal/mol). This is a substantial advantage (0.5 kcal/mol difference).

**Overall Assessment:**

While Ligand A has better metabolic stability, lower DILI risk, and lower P-gp efflux, Ligand B's *significantly* higher BBB penetration and stronger binding affinity are decisive. For a CNS GPCR target, BBB penetration is paramount. The 0.5 kcal/mol difference in binding affinity is enough to outweigh the drawbacks of slightly higher logP and P-gp efflux. The poor Caco-2 permeability is a concern for both, but less critical for a CNS target where direct oral bioavailability isn't the primary concern.

Output:
1
2025-04-17 04:01:42,007 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (340.383 Da) is slightly better positioned.

**TPSA:** Ligand A (92.35) is better than Ligand B (103.87). Both are below the 140 threshold for oral absorption, and reasonably close to the 90 threshold for CNS targets, but A is preferable.

**logP:** Ligand A (2.49) is optimal (1-3). Ligand B (0.029) is quite low, potentially hindering permeability. This is a significant drawback for B.

**H-Bond Donors/Acceptors:** Ligand A (HBD=3, HBA=5) and Ligand B (HBD=2, HBA=6) both fall within acceptable ranges.

**QED:** Both ligands have good QED scores (A: 0.587, B: 0.706), indicating good drug-like properties. B is slightly better here.

**DILI:** Ligand A (77.394) has a higher DILI risk than Ligand B (65.103), but both are acceptable.

**BBB:** Ligand A (66.421) has a better BBB percentile than Ligand B (52.191). While neither are >70, A is significantly better for a CNS target.

**Caco-2 Permeability:** Ligand A (-4.87) shows better Caco-2 permeability than Ligand B (-5.142), indicating better intestinal absorption.

**Aqueous Solubility:** Ligand A (-4.048) has better aqueous solubility than Ligand B (-1.983).

**hERG Inhibition:** Ligand A (0.319) has a lower hERG inhibition risk than Ligand B (0.05), which is preferable.

**Microsomal Clearance:** Ligand A (55.478) has higher microsomal clearance than Ligand B (29.569), meaning B is more metabolically stable.

**In vitro Half-Life:** Ligand A (26.721) has a longer half-life than Ligand B (-2.355).

**P-gp Efflux:** Ligand A (0.087) shows lower P-gp efflux than Ligand B (0.008), which is preferable for CNS penetration.

**Binding Affinity:** Ligand A (-9.5 kcal/mol) has a significantly stronger binding affinity than Ligand B (-7.6 kcal/mol). This is a substantial advantage for A.

**Overall Assessment:**

Ligand A is the stronger candidate. While Ligand B has a slightly better QED and lower microsomal clearance, Ligand A excels in crucial areas for a CNS-targeting GPCR ligand: significantly stronger binding affinity, better BBB penetration, better logP, better solubility, and lower P-gp efflux. The lower logP of Ligand B is a major concern, potentially hindering its ability to cross the blood-brain barrier and reach the target. The affinity difference is also substantial (>1.5 kcal/mol).

Output:
1
2025-04-17 04:01:42,007 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (353.423 and 346.471 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (118.37) is slightly above the preferred <90 for CNS targets, but still reasonable. Ligand B (58.64) is excellent, well below 90.

**logP:** Ligand A (-0.291) is quite low, potentially hindering membrane permeability. Ligand B (2.127) is within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A has 3 HBD and 7 HBA, acceptable values. Ligand B has 1 HBD and 3 HBA, also good.

**QED:** Ligand A (0.561) is good, indicating drug-likeness. Ligand B (0.395) is lower, suggesting a less favorable drug-like profile.

**DILI:** Ligand A (50.174) has a moderate DILI risk. Ligand B (8.375) has a very low DILI risk, which is a significant advantage.

**BBB:** Ligand A (51.183) has a low BBB penetration, which is a major concern for a CNS target. Ligand B (80.341) has excellent BBB penetration, exceeding the desirable >70 threshold.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.914 and -4.689), which is unusual and suggests poor permeability. However, these values are on a log scale and can be difficult to interpret without further context.

**Aqueous Solubility:** Both ligands have negative solubility values (-1.631 and -2.273), also unusual and suggesting poor solubility.

**hERG:** Ligand A (0.084) has a very low hERG risk. Ligand B (0.355) has a slightly higher, but still acceptable, hERG risk.

**Microsomal Clearance:** Both ligands have similar microsomal clearance values (24.613 and 23.256), indicating comparable metabolic stability.

**In vitro Half-Life:** Ligand A (-13.278) has a negative half-life, which is not physically meaningful. Ligand B (-1.137) also has a negative half-life, indicating a problem with the data.

**P-gp Efflux:** Ligand A (0.016) has very low P-gp efflux, which is favorable. Ligand B (0.122) has slightly higher P-gp efflux, but still relatively low.

**Binding Affinity:** Ligand B (-7.3 kcal/mol) has a slightly better binding affinity than Ligand A (-6.9 kcal/mol), although the difference is not huge.

**Overall Assessment:**

Ligand B is the more promising candidate. While its QED is lower, its superior logP, BBB penetration, and lower DILI risk are critical for a CNS-targeting GPCR ligand. The slightly better binding affinity further supports this conclusion. The negative values for Caco-2 and solubility are concerning for both, but the other advantages of Ligand B outweigh these issues. The negative half-life values are suspect and would need to be investigated further, but do not change the overall ranking.

Output:
1
2025-04-17 04:01:42,008 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B based on the provided guidelines, prioritizing GPCR-specific properties (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (364.877 and 354.491 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (83.62) is slightly higher than Ligand B (75.71), but both are below the 90 A^2 threshold desirable for CNS targets.

**logP:** Both ligands have good logP values (1.785 and 2.365), falling within the optimal 1-3 range. Ligand B is slightly more lipophilic.

**H-Bond Donors/Acceptors:** Ligand A has 2 HBD and 6 HBA, while Ligand B has 1 HBD and 4 HBA. Both are within acceptable limits (<=5 HBD and <=10 HBA).

**QED:** Ligand A (0.847) has a significantly higher QED score than Ligand B (0.562), indicating better overall drug-likeness.

**DILI:** Ligand A (47.887) has a higher DILI risk than Ligand B (20.202), but both are below the concerning threshold of 60.

**BBB:** Both ligands have good BBB penetration (63.784 and 65.335), but are just below the highly desirable >70 percentile. Ligand B is slightly better.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.986 and -4.212), which is unusual and suggests poor permeability. This is a significant concern for both.

**Aqueous Solubility:** Both ligands have negative solubility values (-3.348 and -2.757), indicating very poor aqueous solubility. This is a major drawback for both.

**hERG Inhibition:** Ligand A (0.906) has a slightly higher hERG inhibition risk than Ligand B (0.239), but both are relatively low.

**Microsomal Clearance:** Ligand B (86.56) has a much higher microsomal clearance than Ligand A (12.124), suggesting lower metabolic stability.

**In vitro Half-Life:** Ligand A (16.925) has a longer in vitro half-life than Ligand B (-10.22), which is a positive attribute. The negative value for Ligand B is concerning.

**P-gp Efflux:** Ligand A (0.391) has lower P-gp efflux liability than Ligand B (0.018), which is favorable for CNS penetration.

**Binding Affinity:** Ligand A (-8.6 kcal/mol) has a significantly stronger binding affinity than Ligand B (-7.0 kcal/mol). This is a substantial advantage, exceeding the 1.5 kcal/mol threshold.

**Overall Assessment:**

Despite the poor Caco-2 and solubility values for both, Ligand A is the more promising candidate. Its significantly stronger binding affinity (-8.6 vs -7.0 kcal/mol) is a major advantage for a GPCR target like DRD2, and can potentially compensate for some of the ADME deficiencies.  Ligand A also has a better QED score, longer half-life, and lower P-gp efflux. While Ligand B has slightly better BBB penetration and lower DILI risk, the difference isn't substantial enough to outweigh the benefits of Ligand A's superior affinity and drug-likeness. The poor solubility and permeability would need to be addressed through formulation or further chemical modification, but the starting point is better with Ligand A.

Output:
1
2025-04-17 04:01:42,008 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 drug candidates, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (363.483 Da) is slightly higher than Ligand B (346.515 Da), but both are acceptable.

**TPSA:** Ligand A (73.22) is higher than Ligand B (58.2). For CNS targets, we ideally want TPSA <= 90. Both are within this range, but Ligand B is preferable.

**logP:** Both ligands have good logP values (Ligand A: 2.387, Ligand B: 3.57), falling within the optimal 1-3 range. Ligand B is slightly higher, which could be beneficial for membrane permeability, but also raises a slight concern for off-target effects.

**H-Bond Donors/Acceptors:** Ligand A has 1 HBD and 5 HBA, while Ligand B has 2 HBD and 2 HBA. Both are within acceptable limits (<=5 HBD and <=10 HBA). Ligand B is slightly more favorable here due to lower HBA count.

**QED:** Both ligands have reasonable QED values (Ligand A: 0.855, Ligand B: 0.799), indicating good drug-like properties. Ligand A is slightly better.

**DILI:** Ligand A (61.497) has a higher DILI risk than Ligand B (31.563). This is a significant advantage for Ligand B.

**BBB:** Ligand B (66.499) has a better BBB percentile than Ligand A (59.325). While both are not ideal (>70 is desirable), Ligand B is closer to the target. This is a crucial factor for a CNS target like DRD2.

**Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual. However, the magnitude is similar.

**Aqueous Solubility:** Both have negative solubility values, indicating poor solubility. This is a concern for both, but the value for Ligand B (-4.42) is slightly worse than Ligand A (-3.163).

**hERG Inhibition:** Both ligands have low hERG inhibition liability (0.339 and 0.345), which is good.

**Microsomal Clearance:** Ligand A (46.245) has lower microsomal clearance than Ligand B (60.668), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (-14.976) has a significantly *longer* in vitro half-life than Ligand B (-4.272). This is a major advantage for Ligand A.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.146 and 0.294), which is favorable for CNS penetration. Ligand A is slightly better.

**Binding Affinity:** Both ligands have excellent binding affinity (-8.6 and -8.9 kcal/mol). Ligand B is slightly stronger, but the difference is small and may not be practically significant.

**Overall Assessment:**

Considering all factors, especially the GPCR-specific priorities, **Ligand B** appears to be the more promising candidate. While Ligand A has better metabolic stability (lower Cl_mic, longer t1/2) and slightly better QED and P-gp efflux, Ligand B excels in crucial areas for CNS penetration: lower DILI risk and a significantly better BBB percentile. The slightly better logP and TPSA of Ligand B also contribute to its favorability. The small advantage in binding affinity for Ligand B is a bonus.

Output:
1
2025-04-17 04:01:42,008 - INFO - Batch 78 complete. Total preferences: 1248
2025-04-17 04:01:42,008 - INFO - Processing batch 79/512...
2025-04-17 04:02:23,995 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (358.36 and 341.411 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (58.64) is excellent, well below the 90 A^2 threshold for CNS targets. Ligand B (71.53) is still reasonable but less optimal.

**logP:** Ligand A (4.273) is slightly high, potentially leading to solubility issues or off-target interactions. Ligand B (1.087) is on the low side, which could hinder permeation.

**H-Bond Donors/Acceptors:** Both ligands have acceptable HBD (1) and HBA (3 & 4) counts, well within the guidelines.

**QED:** Both ligands have good QED scores (0.878 and 0.786), indicating drug-like properties.

**DILI:** Ligand A (56.223) has a higher DILI risk than Ligand B (35.634), which is preferable.

**BBB:** Ligand A (96.006) has excellent BBB penetration, a critical factor for a CNS target like DRD2. Ligand B (54.091) has poor BBB penetration.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values, which is unusual and suggests poor permeability. This is a significant concern for both.

**Aqueous Solubility:** Both ligands have very poor aqueous solubility (-4.933 and -2.629). This is a major drawback.

**hERG:** Both ligands have very low hERG inhibition risk (0.387 and 0.178), which is good.

**Microsomal Clearance:** Ligand A (58.439) has higher microsomal clearance, suggesting faster metabolism. Ligand B (-6.375) has negative clearance, which is not physically possible and likely an error in the data.

**In vitro Half-Life:** Ligand A (-10.058) has a negative half-life, which is not physically possible. Ligand B (-0.05) is also very low.

**P-gp Efflux:** Both ligands have very low P-gp efflux (0.115 and 0.017), which is favorable for CNS penetration.

**Binding Affinity:** Ligand B (-8.1 kcal/mol) has a slightly better binding affinity than Ligand A (-7.9 kcal/mol), but the difference is relatively small.

**Overall Assessment:**

Ligand A's strong BBB penetration is a significant advantage for a CNS target. However, its higher logP, DILI risk, and problematic clearance/half-life values are concerning. Ligand B has better DILI and a slightly better binding affinity, but its extremely poor BBB penetration is a deal-breaker for a CNS drug. The negative clearance and half-life values for both are suspect and require further investigation. Despite the slightly better affinity of Ligand B, the critical importance of BBB penetration for a DRD2 ligand pushes me towards Ligand A, assuming the negative values are data errors.

Output:
1
2025-04-17 04:02:23,995 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities: BBB, logP, Pgp, TPSA, and affinity.

**Molecular Weight:** Both ligands are within the acceptable range (200-500 Da). Ligand A (357.407 Da) is slightly lower, which could be advantageous for permeability.

**TPSA:** Both ligands have TPSA values below 140, suggesting reasonable oral absorption. Ligand A (108.41) is slightly higher than Ligand B (104.37), but both are below the 90 threshold desirable for CNS targets.

**logP:** Ligand A (-1.797) is lower than the optimal 1-3 range, potentially hindering permeation. Ligand B (0.611) is closer to the optimal range. This is a significant advantage for Ligand B.

**H-Bond Donors/Acceptors:** Ligand A (2 HBD, 6 HBA) and Ligand B (3 HBD, 5 HBA) both fall within acceptable limits.

**QED:** Both ligands have similar QED values (0.543 and 0.534), indicating good drug-likeness.

**DILI:** Ligand A (34.432) has a lower DILI risk than Ligand B (43.117), which is favorable.

**BBB:** This is a critical parameter for a CNS target. Ligand A (18.147) has a very low BBB percentile, making it unlikely to effectively reach the brain. Ligand B (44.979) has a substantially better, though still not ideal, BBB percentile.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values, indicating poor permeability. This is concerning for both.

**Aqueous Solubility:** Both ligands have negative solubility values, indicating poor solubility. This is concerning for both.

**hERG Inhibition:** Both ligands show very low hERG inhibition risk (0.096 and 0.071).

**Microsomal Clearance:** Ligand A (-0.365) has a lower (better) microsomal clearance than Ligand B (40.908), suggesting greater metabolic stability.

**In vitro Half-Life:** Ligand A (-14.641) has a very negative half-life, which is not interpretable and suggests very rapid metabolism. Ligand B (-36.868) also has a negative half-life, but is less extreme.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.011 and 0.043), which is good.

**Binding Affinity:** Ligand B (-7.6 kcal/mol) has a significantly stronger binding affinity than Ligand A (-6.4 kcal/mol). This 1.2 kcal/mol difference is substantial and can outweigh some ADME drawbacks.

**Overall Assessment:**

While Ligand A has a slightly better DILI and microsomal clearance profile, its extremely poor BBB penetration is a major drawback for a CNS target like DRD2. Ligand B, despite having a slightly higher DILI risk and worse metabolic stability, possesses a significantly stronger binding affinity *and* a substantially better (though still not optimal) BBB percentile. The improved binding affinity is a significant advantage, and the better BBB penetration is critical for CNS efficacy. The negative Caco-2 and solubility values are concerning for both, but can potentially be addressed through formulation strategies.

Output:
1
2025-04-17 04:02:23,996 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (426.332 Da) is higher, but still acceptable. Ligand B (339.439 Da) is slightly preferred.

**2. TPSA:** Ligand A (55.84) is better than Ligand B (47.36) for CNS penetration, being closer to the <90 target.

**3. logP:** Both ligands have good logP values (A: 3.603, B: 2.968) within the optimal 1-3 range. Ligand B is slightly more hydrophilic, which could be beneficial for solubility, but both are good.

**4. H-Bond Donors:** Both have 0 HBD, which is favorable.

**5. H-Bond Acceptors:** Both have 4 HBA, which is within the acceptable limit of <=10.

**6. QED:** Both ligands have good QED scores (A: 0.709, B: 0.864), indicating good drug-like properties. Ligand B is slightly better.

**7. DILI:** Ligand B (42.807) has a significantly lower DILI risk than Ligand A (70.841). This is a major advantage for Ligand B.

**8. BBB:** Ligand B (91.431) has a much higher BBB penetration percentile than Ligand A (52.191). This is *critical* for a CNS target like DRD2.

**9. Caco-2 Permeability:** Both have negative Caco-2 values (-4.814 and -4.726), which is unusual and suggests poor permeability. However, these values are on a scale where negative values are possible and don't necessarily disqualify a compound.

**10. Aqueous Solubility:** Both have negative solubility values (-5.722 and -2.954), which is also unusual. Similar to Caco-2, these values don't automatically disqualify the compounds, but indicate potential formulation challenges.

**11. hERG:** Both ligands have low hERG inhibition liability (A: 0.753, B: 0.726), which is good.

**12. Microsomal Clearance:** Ligand A (106.457) has a higher microsomal clearance than Ligand B (81.263), suggesting lower metabolic stability. Ligand B is preferred.

**13. In vitro Half-Life:** Ligand B (8.979) has a slightly longer in vitro half-life than Ligand A (19.242).

**14. P-gp Efflux:** Both have similar P-gp efflux liability (A: 0.555, B: 0.614).

**15. Binding Affinity:** Ligand A (-8.1 kcal/mol) has a slightly better binding affinity than Ligand B (-7.9 kcal/mol), but the difference is small (0.2 kcal/mol). Given the other factors, this difference is unlikely to be decisive.

**Overall Assessment:**

Ligand B is significantly better overall. While Ligand A has slightly better binding affinity, Ligand B excels in crucial areas for a CNS-targeting GPCR ligand: significantly lower DILI risk, much higher BBB penetration, and better metabolic stability (lower Cl_mic). The slightly better QED score for Ligand B also contributes to its favorability. The unusual negative Caco-2 and solubility values are a concern for both, but the other advantages of Ligand B outweigh this.

Output:
1
2025-04-17 04:02:23,996 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (371.478 and 347.39 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (78.51) is slightly higher than Ligand B (69.72), but both are below the 90 A^2 threshold desirable for CNS targets.

**3. logP:** Ligand A (2.308) is within the optimal 1-3 range. Ligand B (0.942) is slightly below 1, which might slightly hinder permeability.

**4. H-Bond Donors:** Both ligands have acceptable HBD counts (2 and 1 respectively), well below the 5 limit.

**5. H-Bond Acceptors:** Both ligands have 3 HBAs, well within the limit of 10.

**6. QED:** Both ligands have good QED scores (0.805 and 0.885), indicating good drug-like properties.

**7. DILI:** Ligand A (55.68) has a slightly higher DILI risk than Ligand B (48.623), but both are below the concerning 60 threshold.

**8. BBB:** Ligand A (70.066) has a slightly better BBB penetration score than Ligand B (66.576), both are reasonably good for a CNS target, but ideally >70.

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 values, which is unusual and suggests poor permeability. However, the scale is not specified, so it's difficult to interpret.

**10. Aqueous Solubility:** Both ligands have negative solubility values, again unusual and suggesting poor solubility. The scale is not specified, so it's difficult to interpret.

**11. hERG Inhibition:** Both ligands have very low hERG inhibition liability (0.621 and 0.22), which is excellent.

**12. Microsomal Clearance:** Ligand A (38.238) has a higher microsomal clearance than Ligand B (10.254), indicating lower metabolic stability.

**13. In vitro Half-Life:** Ligand B (0.005) has a very short in vitro half-life, which is a significant drawback. Ligand A (-16.734) also has a very short half-life, but is less negative than B.

**14. P-gp Efflux:** Both ligands have low P-gp efflux liability (0.09 and 0.069), which is favorable for CNS penetration.

**15. Binding Affinity:** Both ligands have very similar binding affinities (-8.6 and -8.7 kcal/mol), which are excellent and strong.

**Overall Assessment:**

The key differences lie in metabolic stability and BBB penetration. Ligand B has significantly better metabolic stability (lower Cl_mic, longer t1/2) and slightly better BBB penetration. Although both have poor Caco-2 and solubility values, the strong binding affinity is the most important factor here. Given the importance of metabolic stability for *in vivo* efficacy, and the slightly better BBB score, Ligand B is the more promising candidate.

Output:
1
2025-04-17 04:02:23,996 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (329.359 Da and 346.471 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (71.09) is slightly above the optimal <90 for CNS targets, but still reasonable. Ligand B (62.55) is excellent, well below 90.

**logP:** Both ligands have a logP around 3.2, which is optimal.

**H-Bond Donors/Acceptors:** Ligand A has 2 HBD and 4 HBA, fitting the <5 and <10 rules. Ligand B has 1 HBD and 3 HBA, also good.

**QED:** Both ligands have good QED scores (0.721 and 0.86), indicating drug-likeness.

**DILI:** Ligand A has a high DILI risk (94.804), which is a significant concern. Ligand B has a much lower DILI risk (35.867), a major advantage.

**BBB:** Both ligands have good BBB penetration (62.97 and 70.415), but Ligand B is slightly better. A value >70 is desirable for CNS targets.

**Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and suggests poor permeability. However, the scale is not specified, so it's difficult to interpret.

**Aqueous Solubility:** Both have negative solubility values, also unusual and suggesting poor solubility. Again, the scale is not specified.

**hERG:** Both ligands have low hERG inhibition liability (0.61 and 0.602), which is good.

**Microsomal Clearance:** Ligand A (16.637) has a lower microsomal clearance than Ligand B (28.774), indicating better metabolic stability.

**In vitro Half-Life:** Ligand A (72.604) has a longer half-life than Ligand B (50.325), which is desirable.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.383 and 0.418), which is favorable for CNS penetration.

**Binding Affinity:** Ligand A (-11.2 kcal/mol) has a significantly stronger binding affinity than Ligand B (-8.7 kcal/mol). This is a substantial advantage, potentially outweighing some of the ADME drawbacks.

**Overall Assessment:**

Ligand A has a much stronger binding affinity, better metabolic stability, and longer half-life, but suffers from a very high DILI risk. Ligand B has a better safety profile (lower DILI), slightly better BBB penetration, and a good QED score, but its binding affinity is considerably weaker.

Given the GPCR target and the importance of CNS penetration, a balance between potency and safety/ADME properties is crucial. While the affinity of Ligand A is very attractive, the extremely high DILI risk is a major red flag. It's unlikely that a molecule with such a high DILI risk would progress through development. Ligand B, despite its weaker affinity, presents a much more favorable safety profile and reasonable ADME properties.

Output:
1
2025-04-17 04:02:23,996 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (342.53 & 353.51 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (23.55) is excellent, well below the 90 A^2 threshold for CNS targets. Ligand B (61.88) is higher, but still potentially acceptable, though less ideal.

**logP:** Ligand A (4.634) is slightly high, potentially leading to solubility issues or off-target interactions. Ligand B (1.497) is within the optimal range (1-3).

**H-Bond Donors/Acceptors:** Ligand A (0 HBD, 2 HBA) and Ligand B (1 HBD, 4 HBA) both have reasonable numbers of H-bond donors and acceptors, well within the guidelines.

**QED:** Both ligands have good QED scores (0.508 and 0.786), indicating drug-like properties.

**DILI:** Both ligands have low DILI risk (5.894 and 5.7), which is positive.

**BBB:** Ligand A shines here with a BBB percentile of 93.757, excellent for a CNS target. Ligand B's BBB percentile is 76.851, still reasonably good, but significantly lower than Ligand A.

**Caco-2 Permeability:** Both have negative Caco-2 values (-4.827 and -4.571). This is unusual and suggests poor permeability. However, these values are on a log scale and can be misleading without context.

**Aqueous Solubility:** Both have negative solubility values (-3.043 and -0.849), indicating poor aqueous solubility. This is a concern, especially for Ligand A with its higher logP.

**hERG Inhibition:** Both ligands show low hERG inhibition risk (0.962 and 0.319).

**Microsomal Clearance:** Ligand A (45.907) has a moderate microsomal clearance, while Ligand B (10.076) has a very low clearance, suggesting better metabolic stability.

**In vitro Half-Life:** Both have negative in vitro half-life values (-8.894 and -8.533), which is unusual and requires further investigation.

**P-gp Efflux:** Ligand A (0.663) has lower P-gp efflux liability than Ligand B (0.016), which is favorable for CNS penetration.

**Binding Affinity:** Ligand A (-8.2 kcal/mol) has a slightly better binding affinity than Ligand B (-7.3 kcal/mol). The 0.9 kcal/mol difference is significant and could outweigh some of the ADME drawbacks.

**Overall Assessment:**

Given the GPCR-specific priorities, BBB penetration is crucial. Ligand A's significantly higher BBB percentile (93.76 vs 76.85) is a major advantage. While Ligand A has a higher logP and lower solubility, its superior binding affinity and P-gp efflux profile, combined with the critical BBB value, make it the more promising candidate. The Caco-2 and half-life values are concerning for both, but the binding affinity and CNS penetration potential of Ligand A are more compelling.

Output:
1
2025-04-17 04:02:23,996 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (353.463 and 344.459 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (87.74) is better than Ligand B (65.54) as it is closer to the 90 A^2 threshold for CNS targets.

**3. logP:** Ligand B (3.037) is optimal, while Ligand A (0.681) is quite low, potentially hindering membrane permeability.

**4. H-Bond Donors:** Ligand A (2) and Ligand B (1) are both acceptable.

**5. H-Bond Acceptors:** Ligand A (5) and Ligand B (4) are both acceptable.

**6. QED:** Ligand B (0.826) has a significantly better QED score than Ligand A (0.595), indicating a more drug-like profile.

**7. DILI:** Ligand A (20.744) has a much lower DILI risk than Ligand B (44.979).

**8. BBB:** Ligand B (93.874) has a significantly higher BBB penetration percentile than Ligand A (36.603). This is *critical* for a CNS target like DRD2.

**9. Caco-2 Permeability:** Ligand A (-5.36) is worse than Ligand B (-4.839).

**10. Aqueous Solubility:** Ligand A (-0.941) is better than Ligand B (-3.987).

**11. hERG Inhibition:** Ligand A (0.156) has a lower hERG inhibition liability than Ligand B (0.548), which is preferable.

**12. Microsomal Clearance:** Ligand A (-4.372) has a lower (better) microsomal clearance than Ligand B (88.424).

**13. In vitro Half-Life:** Ligand A (-4.717) has a longer half-life than Ligand B (-4.054).

**14. P-gp Efflux:** Ligand A (0.011) has a much lower P-gp efflux liability than Ligand B (0.249), which is important for CNS penetration.

**15. Binding Affinity:** Ligand B (-8.8) has a slightly better binding affinity than Ligand A (-8.2). However, the difference is not substantial enough to overcome the other significant drawbacks.

**Overall Assessment:**

While Ligand A has some advantages in terms of DILI, hERG, clearance, and half-life, Ligand B is significantly better regarding BBB penetration, QED, and logP. The high BBB value for Ligand B is the most important factor for a CNS target like DRD2. The slightly better affinity of Ligand B is a bonus. The lower logP of Ligand A is a major concern for CNS penetration.

Output:
1
2025-04-17 04:02:23,996 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (353.438 and 349.387 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (84.23) is excellent, well below the 90 A^2 threshold for CNS targets. Ligand B (99.18) is still reasonable but less optimal, approaching the 100 A^2 limit.

**logP:** Ligand A (2.231) is within the optimal 1-3 range. Ligand B (0.35) is quite low, potentially hindering membrane permeability and CNS penetration.

**H-Bond Donors/Acceptors:** Both ligands have 2 HBD and a reasonable number of HBA (4 for A, 5 for B), satisfying the <5 HBD and <10 HBA guidelines.

**QED:** Both ligands have similar QED values (0.751 and 0.74), indicating good drug-likeness.

**DILI:** Ligand A (21.714) has a much lower DILI risk than Ligand B (31.291), which is a significant advantage.

**BBB:** Ligand A (84.064) has a significantly higher BBB penetration percentile than Ligand B (24.389). This is *critical* for a CNS target like DRD2.

**Caco-2 Permeability:** Ligand A (-4.662) has a worse Caco-2 permeability than Ligand B (-5.513), but both are quite poor.

**Aqueous Solubility:** Ligand A (-2.803) has better solubility than Ligand B (-1.651).

**hERG:** Both ligands have very low hERG inhibition liability (0.3 and 0.101), which is excellent.

**Microsomal Clearance:** Ligand B (-12.805) has a significantly lower (better) microsomal clearance than Ligand A (27.451), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand B (-8.954) has a longer in vitro half-life than Ligand A (0.105), which is desirable.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.047 and 0.016), which is good for CNS penetration.

**Binding Affinity:** Ligand A (-9.1 kcal/mol) has a slightly better binding affinity than Ligand B (-8.2 kcal/mol). While the difference isn't huge (0.9 kcal/mol), it's a positive factor.

**Overall Assessment:**

Ligand A is the stronger candidate. Its superior BBB penetration, lower DILI risk, and slightly better binding affinity outweigh its poorer Caco-2 permeability and higher microsomal clearance. The low logP of Ligand B is a major concern for CNS penetration, even with low P-gp efflux. While Ligand B has better metabolic stability and half-life, these are secondary considerations compared to getting the drug into the brain.



Output:
1
2025-04-17 04:02:23,996 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (364.515 and 364.433 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (67.23) is significantly better than Ligand B (78.87). For CNS targets, we want TPSA <= 90, and A is closer to the ideal <=60 range. B is pushing the upper limit.

**3. logP:** Both ligands have good logP values (2.063 and 1.42), falling within the optimal 1-3 range.

**4. H-Bond Donors:** Ligand A (1) is preferable to Ligand B (2). Lower HBD generally improves permeability.

**5. H-Bond Acceptors:** Ligand A (5) is preferable to Ligand B (4). Lower HBA generally improves permeability.

**6. QED:** Both ligands have acceptable QED values (0.839 and 0.683), indicating good drug-like properties.

**7. DILI:** Ligand A (29.779) has a much lower DILI risk than Ligand B (14.773). Both are below 40, which is good, but A is significantly better.

**8. BBB:** Ligand B (72.896) has a slightly better BBB penetration percentile than Ligand A (66.615). Both are above the 70% threshold, but B is closer.

**9. Caco-2 Permeability:** Ligand A (-5.3) is significantly better than Ligand B (-4.627). Higher Caco-2 values indicate better absorption.

**10. Aqueous Solubility:** Ligand A (-2.46) is better than Ligand B (-1.317). Higher solubility is generally preferred.

**11. hERG Inhibition:** Both ligands have very low hERG inhibition liability (0.605 and 0.446), which is excellent.

**12. Microsomal Clearance:** Ligand B (-1.545) has a *negative* clearance, which is highly unusual and suggests extreme metabolic stability. Ligand A (35.501) has a more typical, but higher, clearance.

**13. In vitro Half-Life:** Ligand B (-28.51) has a *negative* half-life, which is also highly unusual and suggests extreme stability. Ligand A (-8.142) has a more typical, but shorter, half-life.

**14. P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.059 and 0.027), which is excellent.

**15. Binding Affinity:** Both ligands have very similar and excellent binding affinities (-7.6 and -7.5 kcal/mol). The difference is negligible.

**Overall Assessment:**

While Ligand B has a slightly better BBB penetration and extremely favorable (and likely unrealistic) metabolic stability, Ligand A is superior in most other key ADME properties. Specifically, its lower TPSA, lower DILI risk, better Caco-2 permeability, and better solubility are all significant advantages. The slightly lower BBB score for Ligand A is less concerning given its other benefits. The negative values for clearance and half-life for Ligand B are red flags, suggesting potential issues with the data or an unusual compound behavior that may not translate well *in vivo*.

Output:
1
2025-04-17 04:02:23,996 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (352.291 and 342.399 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (59.81) is excellent, well below the 90 A^2 threshold for CNS targets. Ligand B (95.42) is higher, but still potentially acceptable, though less ideal.

**logP:** Ligand A (3.693) is optimal. Ligand B (1.767) is on the lower side, potentially impacting permeability, but not drastically.

**H-Bond Donors/Acceptors:** Ligand A (1 HBD, 4 HBA) is favorable. Ligand B (2 HBD, 5 HBA) is also acceptable.

**QED:** Both ligands have good QED scores (0.732 and 0.834), indicating drug-like properties.

**DILI:** Ligand A (91.314) has a higher DILI risk than Ligand B (67.507), which is a concern.

**BBB:** Ligand A (85.498) has a significantly better BBB penetration score than Ligand B (31.873). This is *critical* for a CNS target like DRD2.

**Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and likely indicates a data error or a very poor permeability. However, given the context of comparing two ligands, we'll proceed assuming this is a relative measure and focus on the difference. Ligand A (-4.636) is slightly better than Ligand B (-4.921).

**Aqueous Solubility:** Both have negative solubility values, again likely indicating a data issue. Ligand B (-2.893) is slightly better than Ligand A (-4.818).

**hERG:** Ligand A (0.751) has a slightly higher hERG risk than Ligand B (0.205).

**Microsomal Clearance:** Ligand A (68.571) has higher clearance than Ligand B (42.957), suggesting lower metabolic stability.

**In vitro Half-Life:** Ligand A (43.791) has a longer half-life than Ligand B (36.424).

**P-gp Efflux:** Ligand A (0.434) has lower P-gp efflux liability than Ligand B (0.08), which is favorable for CNS penetration.

**Binding Affinity:** Both ligands have excellent binding affinities (-8.6 and -8.0 kcal/mol). Ligand A is slightly better, but the difference is less than 1.5 kcal/mol, so it's not a decisive factor.

**Overall Assessment:**

Ligand A excels in BBB penetration, P-gp efflux, and binding affinity. However, it has a higher DILI risk and clearance. Ligand B has a lower DILI risk and clearance, but significantly poorer BBB penetration. For a CNS target like DRD2, BBB penetration is paramount. The superior BBB score of Ligand A, combined with its acceptable (though not ideal) other properties, makes it the more promising candidate despite the higher DILI and clearance.

Output:
1
2025-04-17 04:02:23,996 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (377.897 Da) and Ligand B (354.466 Da) are both acceptable.

**2. TPSA:** Ligand A (71.09) is slightly above the preferred <90 for CNS targets, but still reasonable. Ligand B (49.85) is excellent, well below 90. This favors Ligand B.

**3. logP:** Ligand A (4.211) is a bit high, potentially leading to solubility issues and off-target effects. Ligand B (2.104) is within the optimal 1-3 range. This strongly favors Ligand B.

**4. H-Bond Donors:** Ligand A (2) is acceptable. Ligand B (0) is also acceptable, and potentially beneficial for permeability.

**5. H-Bond Acceptors:** Ligand A (4) is acceptable. Ligand B (3) is also acceptable.

**6. QED:** Both ligands have similar, good QED values (0.759 and 0.76).

**7. DILI:** Ligand A (69.135) has a higher DILI risk than Ligand B (10.392). This is a significant advantage for Ligand B.

**8. BBB:** Ligand A (76.192) is good, exceeding the 70% threshold. Ligand B (97.635) is *excellent*, very close to 100%. This is a major advantage for Ligand B, crucial for a CNS target like DRD2.

**9. Caco-2 Permeability:** Both have negative values, which is unusual. Assuming these are logP-scaled permeability values, lower (more negative) values indicate lower permeability. Ligand A (-4.931) is slightly better than Ligand B (-4.438), but both are poor.

**10. Aqueous Solubility:** Both have negative values, which is unusual. Assuming these are logS values, lower (more negative) values indicate lower solubility. Ligand B (-2.319) is better than Ligand A (-5.049).

**11. hERG Inhibition:** Ligand A (0.379) has a slightly higher hERG risk than Ligand B (0.73). Lower is better. This favors Ligand B.

**12. Microsomal Clearance:** Both have similar clearance values (46.435 and 49.466 mL/min/kg). Neither is particularly good, indicating moderate metabolic liability.

**13. In vitro Half-Life:** Ligand B (-11.901) has a significantly *shorter* half-life than Ligand A (46.14). This is a disadvantage for Ligand B.

**14. P-gp Efflux:** Ligand A (0.29) has lower P-gp efflux, which is desirable for CNS penetration. Ligand B (0.144) has even lower efflux, a significant advantage.

**15. Binding Affinity:** Both ligands have very similar, excellent binding affinities (-8.9 and -8.7 kcal/mol). The difference is negligible.

**Overall Assessment:**

Ligand B consistently outperforms Ligand A in key areas for a CNS-targeting GPCR ligand. It has better logP, lower DILI risk, significantly better BBB penetration, lower hERG risk, and lower P-gp efflux. While its in vitro half-life is worse, the other advantages outweigh this drawback. Ligand A's slightly better Caco-2 permeability and half-life are not enough to compensate for its higher logP, DILI risk, and lower BBB.

Output:
1
2025-04-17 04:02:23,997 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (349.431 Da) is slightly lower, which could be beneficial for permeability, but both are acceptable.

**TPSA:** Ligand A (107.53) is better than Ligand B (59.07) as it is closer to the 90 A^2 threshold for CNS targets. Ligand B is very low, which might suggest reduced hydrogen bonding and potentially lower solubility.

**logP:** Ligand A (-0.168) is suboptimal, being below the ideal range of 1-3. This could hinder membrane permeability. Ligand B (4.64) is too high, potentially leading to solubility issues and off-target interactions.

**H-Bond Donors/Acceptors:** Ligand A has 4 HBD and 4 HBA, which are within acceptable limits. Ligand B has 2 HBD and 5 HBA, also acceptable.

**QED:** Both ligands have good QED scores (Ligand A: 0.5, Ligand B: 0.739), indicating a generally drug-like profile.

**DILI:** Ligand A (25.165) has a much lower DILI risk than Ligand B (69.833), a significant advantage.

**BBB:** Ligand B (63.125) has a better BBB percentile than Ligand A (30.593), which is crucial for a CNS target like DRD2. However, neither is above the desirable 70% threshold.

**Caco-2 Permeability:** Both have negative values, which is unusual. Assuming these are logP-scale values, they indicate poor permeability.

**Aqueous Solubility:** Both ligands have negative values, indicating poor aqueous solubility.

**hERG Inhibition:** Ligand A (0.05) shows very low hERG inhibition risk, which is excellent. Ligand B (0.689) has a higher, though still relatively low, risk.

**Microsomal Clearance:** Ligand A (2.733) has a significantly lower microsomal clearance than Ligand B (56.329), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand B (22.627) has a much longer in vitro half-life than Ligand A (-0.24), which is a positive attribute.

**P-gp Efflux:** Ligand A (0.009) has very low P-gp efflux liability, which is excellent for CNS penetration. Ligand B (0.172) has a slightly higher, but still relatively low, efflux.

**Binding Affinity:** Ligand B (-9.1 kcal/mol) has a significantly stronger binding affinity than Ligand A (0.0 kcal/mol). This is a major advantage, potentially outweighing some of its ADME drawbacks.

**Overall Assessment:**

Ligand B has a much stronger binding affinity, a longer half-life, and better BBB penetration. However, it suffers from a high logP, elevated DILI risk, and higher microsomal clearance. Ligand A has a better safety profile (lower DILI, hERG, and P-gp efflux) and better metabolic stability, but its binding affinity is very weak and its logP is too low.

Given the importance of binding affinity for GPCRs, and the fact that a >1.5 kcal/mol advantage can outweigh ADME drawbacks, **Ligand B is the more promising candidate**, despite its shortcomings. Optimization efforts could focus on reducing its logP and DILI risk while maintaining its strong affinity.

Output:
1
2025-04-17 04:02:23,997 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (381.215 Da) is slightly higher than Ligand B (344.459 Da), but both are acceptable.

**TPSA:** Ligand A (68.71) is better than Ligand B (88.32). For CNS targets, we want TPSA <= 90, both are under this threshold, but A is preferable.

**logP:** Ligand A (4.522) is higher than the optimal range (1-3) and could present solubility issues. Ligand B (2.128) is within the optimal range. This favors B.

**H-Bond Donors/Acceptors:** Ligand A (0 HBD, 5 HBA) is good. Ligand B (2 HBD, 4 HBA) is also acceptable.

**QED:** Both ligands have good QED values (A: 0.65, B: 0.876), indicating drug-like properties. B is slightly better.

**DILI:** Ligand A (79.604) has a higher DILI risk than Ligand B (26.871). This is a significant advantage for B.

**BBB:** Ligand A (60.915) is below the desirable threshold of >70 for CNS targets. Ligand B (89.221) is excellent, exceeding the 70% threshold. This is a *major* advantage for B.

**Caco-2 Permeability:** Both have negative values, which is unusual and suggests very poor permeability. However, the scale isn't specified, so it's hard to interpret.

**Aqueous Solubility:** Both have negative values, indicating poor solubility. This is a concern for both, but A's logP suggests it will be worse.

**hERG:** Both ligands have low hERG inhibition liability (A: 0.62, B: 0.501), which is good.

**Microsomal Clearance:** Ligand A (80.5) has higher clearance than Ligand B (2.444), indicating lower metabolic stability. B is much better.

**In vitro Half-Life:** Ligand A (62.124) has a reasonable half-life. Ligand B (-18.286) has a very short (or problematic) half-life. A is better here.

**P-gp Efflux:** Both have low P-gp efflux liability (A: 0.717, B: 0.012). B is significantly better.

**Binding Affinity:** Ligand A (-9.0 kcal/mol) has a significantly stronger binding affinity than Ligand B (-7.6 kcal/mol). This is a substantial advantage for A.

**Overall Assessment:**

While Ligand A boasts a significantly better binding affinity, its poor BBB penetration, higher DILI risk, and higher microsomal clearance are major drawbacks for a CNS-targeting drug. Ligand B, despite a weaker affinity, has excellent BBB penetration, a much lower DILI risk, better metabolic stability, and lower P-gp efflux. Given the GPCR-specific priorities, particularly BBB for CNS targets, and the substantial difference in BBB scores, Ligand B is the more promising candidate. The affinity difference, while significant, might be overcome with further optimization, whereas fixing the poor CNS penetration of Ligand A would be far more challenging.

Output:
1
2025-04-17 04:02:23,997 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (407.312 Da) is higher, but still acceptable. Ligand B (342.395 Da) is slightly lower, potentially aiding permeability.

**2. TPSA:** Ligand A (81.85) is better than Ligand B (92.43) as it is closer to the <90 threshold for CNS targets.

**3. logP:** Both ligands have good logP values (A: 3.183, B: 2.952), falling within the optimal 1-3 range.

**4. H-Bond Donors:** Both have 2 HBD, which is within the acceptable limit of <=5.

**5. H-Bond Acceptors:** Ligand A has 3 HBA, and Ligand B has 4. Both are within the acceptable limit of <=10.

**6. QED:** Both ligands have good QED scores (A: 0.799, B: 0.871), indicating good drug-like properties.

**7. DILI:** Ligand A (59.829) has a lower DILI risk than Ligand B (72.819), which is preferable.

**8. BBB:** This is a critical parameter for a CNS target like DRD2. Ligand A (62.737) has a significantly better BBB percentile than Ligand B (44.591). This is a major advantage for Ligand A.

**9. Caco-2 Permeability:** Both have negative values, indicating poor permeability. Ligand A (-5.096) is slightly better than Ligand B (-4.931).

**10. Aqueous Solubility:** Both have negative values, indicating poor solubility. Ligand A (-3.833) is slightly better than Ligand B (-3.159).

**11. hERG Inhibition:** Both ligands have very low hERG inhibition risk (A: 0.147, B: 0.015). Ligand B is slightly better.

**12. Microsomal Clearance:** Ligand B (12.439) has a much lower microsomal clearance than Ligand A (45.759), suggesting better metabolic stability.

**13. In vitro Half-Life:** Ligand B (-29.38) has a much longer in vitro half-life than Ligand A (-11.148). This is a significant advantage for Ligand B.

**14. P-gp Efflux:** Both have very low P-gp efflux liability (A: 0.278, B: 0.014). Ligand B is slightly better.

**15. Binding Affinity:** Ligand B (-8.8 kcal/mol) has a significantly stronger binding affinity than Ligand A (-7.2 kcal/mol). This is a substantial advantage, potentially outweighing some of the ADME drawbacks.

**Overall Assessment:**

While Ligand B has superior binding affinity, metabolic stability (lower Cl_mic, longer t1/2), and P-gp efflux, Ligand A has a significantly better BBB penetration and lower DILI risk. For a CNS target like DRD2, BBB penetration is paramount. The 1.6 kcal/mol difference in binding affinity, while substantial, can potentially be overcome with further optimization, whereas poor BBB penetration is a more difficult property to improve. The slightly better TPSA of Ligand A also favors it.

Output:
1
2025-04-17 04:02:23,997 - INFO - Reasoning:

Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (352.519 and 341.459 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (67.43) is better than Ligand B (71.1). Both are below the 90 A^2 threshold desirable for CNS targets, but A is closer to the ideal.

**3. logP:** Both ligands (3.173 and 2.775) are within the optimal 1-3 range.

**4. H-Bond Donors:** Ligand A (2) is preferable to Ligand B (3). Lower HBD generally improves permeability.

**5. H-Bond Acceptors:** Ligand A (3) is preferable to Ligand B (6). Lower HBA generally improves permeability.

**6. QED:** Both ligands have good QED scores (0.659 and 0.719), indicating good drug-like properties.

**7. DILI:** Ligand A (15.2) has a significantly lower DILI risk than Ligand B (63.668). This is a major advantage for Ligand A.

**8. BBB:** Ligand B (88.29) has a substantially better BBB penetration percentile than Ligand A (71.656). This is a critical factor for a CNS target like DRD2.

**9. Caco-2 Permeability:** Ligand A (-4.53) has worse Caco-2 permeability than Ligand B (-5.329). Lower (more negative) values indicate lower permeability.

**10. Aqueous Solubility:** Ligand A (-3.128) has slightly better aqueous solubility than Ligand B (-2.648).

**11. hERG Inhibition:** Ligand A (0.483) has a lower hERG inhibition liability than Ligand B (0.941), indicating a lower risk of cardiotoxicity.

**12. Microsomal Clearance:** Ligand B (31.233) has significantly lower microsomal clearance than Ligand A (65.321), suggesting better metabolic stability.

**13. In vitro Half-Life:** Ligand B (73.891) has a much longer in vitro half-life than Ligand A (-19.506). This is a significant advantage for Ligand B.

**14. P-gp Efflux:** Ligand A (0.212) has lower P-gp efflux liability than Ligand B (0.132). Lower P-gp efflux is favorable for CNS penetration.

**15. Binding Affinity:** Ligand B (-9.3) has a significantly stronger binding affinity than Ligand A (0.0). This is a decisive factor.

**Overall Assessment:**

While Ligand A has advantages in DILI risk, hERG inhibition, and P-gp efflux, Ligand B's superior BBB penetration, metabolic stability (lower Cl_mic, longer t1/2), and, crucially, *much* stronger binding affinity outweigh these benefits. The strong binding affinity of Ligand B (-9.3 kcal/mol) is a substantial advantage, and the high BBB penetration (88.29) is essential for a CNS target. The lower DILI and hERG risks of Ligand A are good, but can be addressed through further optimization.

Output:
1
2025-04-17 04:02:23,997 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 drug candidates, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (346.431 and 348.447 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (82.18) is significantly better than Ligand B (98.32). For CNS targets, TPSA should be <= 90. Ligand A is within this range, while Ligand B exceeds it.

**3. logP:** Ligand A (3.483) is optimal (1-3), while Ligand B (1.098) is on the lower end, potentially hindering permeation.

**4. H-Bond Donors:** Ligand A (1) is good, while Ligand B (3) is acceptable but less ideal.

**5. H-Bond Acceptors:** Ligand A (7) is good, while Ligand B (4) is also good.

**6. QED:** Ligand A (0.806) is excellent, indicating high drug-likeness. Ligand B (0.551) is acceptable but lower.

**7. DILI:** Ligand A (54.634) has a moderate DILI risk, while Ligand B (11.4) has a very low risk.

**8. BBB:** Ligand A (81.97) has excellent BBB penetration, crucial for a CNS target like DRD2. Ligand B (34.626) has poor BBB penetration.

**9. Caco-2:** Ligand A (-4.654) and Ligand B (-5.398) both have negative values, indicating poor Caco-2 permeability. However, the scale is not specified, so the absolute difference is hard to interpret.

**10. Solubility:** Ligand A (-4.964) and Ligand B (-1.51) both have negative values, indicating poor solubility. Again, the scale is not specified.

**11. hERG:** Both ligands (0.177 and 0.158) have low hERG inhibition liability, which is good.

**12. Cl_mic:** Ligand A (97.828) has a high microsomal clearance, suggesting lower metabolic stability. Ligand B (-2.479) has negative clearance, which is not possible and likely indicates a very stable compound.

**13. t1/2:** Ligand A (12.842) has a reasonable in vitro half-life. Ligand B (-26.739) has a negative half-life, which is not possible and indicates an issue with the data.

**14. Pgp:** Both ligands (0.286 and 0.021) have low P-gp efflux liability, which is good for CNS exposure.

**15. Binding Affinity:** Ligand A (-8.4 kcal/mol) has a significantly stronger binding affinity than Ligand B (-7.7 kcal/mol). The 0.7 kcal/mol difference is substantial and can outweigh some ADME drawbacks.

**Overall Assessment:**

Ligand A is clearly superior. It has better TPSA, logP, QED, and *significantly* better binding affinity and BBB penetration. While its DILI and Cl_mic are not ideal, the strong affinity and good BBB penetration are critical for a CNS GPCR target. Ligand B has a better DILI profile, but its poor logP, TPSA, BBB penetration, and questionable t1/2 and Cl_mic values make it a less promising candidate. The negative values for Cl_mic and t1/2 are concerning and suggest data errors.

Output:
1
2025-04-17 04:02:23,997 - INFO - Batch 79 complete. Total preferences: 1264
2025-04-17 04:02:23,998 - INFO - Processing batch 80/512...
2025-04-17 04:03:05,446 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (344.419 and 343.431 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (101.8) is higher than Ligand B (74.09). For CNS targets, TPSA < 90 is preferred. Ligand B is significantly better here.

**3. logP:** Both ligands have good logP values (1.847 and 1.725), falling within the optimal 1-3 range.

**4. H-Bond Donors:** Ligand A (2) and Ligand B (1) are both acceptable, being less than 5. Ligand B is slightly better.

**5. H-Bond Acceptors:** Ligand A (6) and Ligand B (7) are both acceptable, being less than 10.

**6. QED:** Both ligands have good QED scores (0.798 and 0.805), indicating good drug-like properties.

**7. DILI:** Ligand A (78.247) has a higher DILI risk than Ligand B (44.397). Lower is better, so Ligand B is preferred.

**8. BBB:** Ligand B (76.154) has a significantly better BBB penetration score than Ligand A (58.278). This is *critical* for a CNS target like DRD2.

**9. Caco-2:** Both have negative Caco-2 values which is unusual and hard to interpret.

**10. Solubility:** Both have negative solubility values which is unusual and hard to interpret.

**11. hERG:** Both ligands have low hERG inhibition liability (0.139 and 0.304), which is good.

**12. Cl_mic:** Ligand A (34.277) has slightly lower microsomal clearance than Ligand B (39.06), suggesting better metabolic stability.

**13. t1/2:** Ligand B (-9.142) has a negative in vitro half-life, which is concerning and likely an error. Ligand A (25.133) has a reasonable half-life.

**14. Pgp:** Ligand A (0.01) has much lower P-gp efflux liability than Ligand B (0.274). Lower is better, especially for CNS penetration.

**15. Binding Affinity:** Ligand B (-8.8 kcal/mol) has slightly better binding affinity than Ligand A (-7.8 kcal/mol). While both are good, the 1 kcal/mol difference is meaningful.

**Overall Assessment:**

Ligand B clearly wins on the most important criteria for a CNS GPCR target: BBB penetration and DILI risk. While Ligand A has better metabolic stability and Pgp efflux, the superior BBB and lower toxicity of Ligand B outweigh these advantages. The negative half-life for Ligand B is a significant concern, but the affinity difference is enough to warrant further investigation.

Output:
1
2025-04-17 04:03:05,446 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (383.86 and 347.35 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (92.51) is better than Ligand B (105.9), both are below the 140 threshold for oral absorption, and Ligand A is closer to the preferred <90 for CNS targets.

**3. logP:** Ligand A (1.995) is optimal (1-3), while Ligand B (0.054) is quite low, potentially hindering permeation.

**4. H-Bond Donors:** Both have 1 HBD, which is acceptable.

**5. H-Bond Acceptors:** Ligand A has 5 HBA, while Ligand B has 8. Both are within the acceptable limit of 10, but Ligand A is preferable.

**6. QED:** Both ligands have reasonable QED values (0.852 and 0.762), indicating good drug-like properties.

**7. DILI:** Ligand A (84.34) has a higher DILI risk than Ligand B (69.79), but both are below the concerning threshold of 60.

**8. BBB:** Ligand B (90.15) has a significantly better BBB penetration score than Ligand A (53.63). This is a crucial factor for a CNS target like DRD2.

**9. Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and suggests poor permeability. However, the scale is not specified, so it's hard to interpret.

**10. Aqueous Solubility:** Both have negative solubility values, again, the scale is not specified.

**11. hERG Inhibition:** Ligand A (0.331) has a slightly higher hERG inhibition liability than Ligand B (0.011), but both are very low risk.

**12. Microsomal Clearance:** Ligand A (69.12) has higher microsomal clearance than Ligand B (3.81), indicating lower metabolic stability.

**13. In vitro Half-Life:** Ligand B (-5.54) has a longer in vitro half-life than Ligand A (-20.13).

**14. P-gp Efflux:** Ligand A (0.245) has lower P-gp efflux liability than Ligand B (0.042), which is beneficial for CNS exposure.

**15. Binding Affinity:** Ligand B (-7.8 kcal/mol) has a significantly stronger binding affinity than Ligand A (-9.4 kcal/mol). This is a major advantage.

**Overall Assessment:**

While Ligand A has better TPSA, logP, and P-gp efflux, Ligand B excels in the most critical areas for a CNS-targeting GPCR: **BBB penetration and binding affinity**. The significantly stronger binding affinity (-7.8 vs -9.4 kcal/mol) of Ligand B is a substantial advantage that can potentially outweigh some of its ADME drawbacks (lower logP, higher clearance). The superior BBB score (90.15 vs 53.63) is also a critical factor.

Output:
1
2025-04-17 04:03:05,446 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (353.438 and 353.503 Da) fall comfortably within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (75.44) is slightly higher than Ligand B (59). Both are below the 90 Angstroms threshold desirable for CNS targets, but Ligand B is significantly better.

**3. logP:** Both ligands have logP values within the optimal range (2.407 and 2.752).

**4. H-Bond Donors:** Both have 1 HBD, which is acceptable.

**5. H-Bond Acceptors:** Both have 4 HBA, which is acceptable.

**6. QED:** Ligand A (0.779) has a slightly better QED score than Ligand B (0.682), indicating a more drug-like profile.

**7. DILI:** Ligand A (23.769) has a slightly higher DILI risk than Ligand B (13.339), but both are well below the concerning threshold of 60.

**8. BBB:** Ligand A (86.817) exhibits significantly better BBB penetration potential than Ligand B (78.558). This is a crucial factor for a CNS target like DRD2.

**9. Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and suggests poor permeability. However, the absolute value is closer to 0 for Ligand A (-4.551) than Ligand B (-4.488), suggesting slightly better permeability.

**10. Aqueous Solubility:** Both ligands have negative solubility values, indicating poor aqueous solubility. Ligand A (-2.323) is slightly better than Ligand B (-2.285).

**11. hERG Inhibition:** Ligand A (0.238) has a lower hERG inhibition liability than Ligand B (0.774), making it safer from a cardiotoxicity perspective.

**12. Microsomal Clearance:** Ligand B (54.792) has a lower microsomal clearance than Ligand A (33.993), suggesting better metabolic stability.

**13. In vitro Half-Life:** Ligand B (23.296) has a longer in vitro half-life than Ligand A (15.072), which is desirable.

**14. P-gp Efflux:** Ligand A (0.088) has lower P-gp efflux liability than Ligand B (0.675), which is beneficial for CNS exposure.

**15. Binding Affinity:** Ligand A (-8.1 kcal/mol) has a significantly stronger binding affinity than Ligand B (-6.9 kcal/mol). This is a substantial advantage, potentially outweighing some of the ADME drawbacks.

**Overall Assessment:**

While Ligand B has better metabolic stability (lower Cl_mic, longer t1/2) and slightly better TPSA, Ligand A excels in several critical areas for a CNS-targeting GPCR ligand. Specifically, its superior BBB penetration, significantly stronger binding affinity, lower hERG risk, and lower P-gp efflux liability are highly advantageous. The slightly higher DILI risk is not overly concerning given the low overall value. The negative Caco-2 and solubility values are concerning for both, but the affinity difference is large enough to prioritize Ligand A.

Output:
1
2025-04-17 04:03:05,446 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (370.739 Da and 362.499 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (76.66) is significantly better than Ligand B (83.98). For CNS targets, we want TPSA <= 90, and A is closer to the ideal <=60 range.

**3. logP:** Both ligands have good logP values (2.71 and 2.442), falling within the optimal 1-3 range.

**4. H-Bond Donors:** Both have 2 HBD, which is acceptable.

**5. H-Bond Acceptors:** Ligand A has 4 HBA, and Ligand B has 5. Both are within the acceptable limit of <=10.

**6. QED:** Both ligands have similar, good QED values (0.811 and 0.814).

**7. DILI:** Ligand A has a high DILI risk (98.216), which is a significant concern. Ligand B has a much lower, and acceptable, DILI risk (41.024).

**8. BBB:** Ligand B (61.923) has a substantially better BBB penetration percentile than Ligand A (52.423). While both are not ideal (>70), B is closer. This is *critical* for a CNS target like DRD2.

**9. Caco-2 Permeability:** Ligand A (-4.341) has better Caco-2 permeability than Ligand B (-5.043). However, both are negative values, indicating poor permeability.

**10. Aqueous Solubility:** Ligand A (-4.234) has slightly better solubility than Ligand B (-3.472), but both are poor.

**11. hERG Inhibition:** Both ligands show low hERG inhibition liability (0.382 and 0.191), which is good.

**12. Microsomal Clearance:** Ligand B (29.39) has a slightly lower microsomal clearance than Ligand A (26.662), suggesting better metabolic stability.

**13. In vitro Half-Life:** Ligand B (29.211) has a much longer in vitro half-life than Ligand A (12.434).

**14. P-gp Efflux:** Ligand A (0.237) has lower P-gp efflux than Ligand B (0.121), which is favorable for CNS penetration.

**15. Binding Affinity:** Ligand B (-8.4) has a significantly stronger binding affinity than Ligand A (-9.3). A difference of >1.5 kcal/mol is very significant.

**Overall Assessment:**

Despite Ligand A having slightly better Caco-2 permeability and P-gp efflux, the significantly higher DILI risk and lower BBB penetration are major drawbacks. Ligand B has a much better safety profile (lower DILI), better BBB penetration, superior binding affinity, and a longer half-life. The stronger binding affinity of Ligand B can potentially compensate for the slightly lower Caco-2 permeability. Given the GPCR-specific priorities, especially BBB and affinity, Ligand B is the more promising candidate.

Output:
1
2025-04-17 04:03:05,447 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (360.394 and 350.459 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Both ligands have TPSA values (67.43 and 66.92) below the 90 A^2 threshold for CNS targets, which is good.

**3. logP:** Ligand A (3.914) is at the upper end of the optimal range (1-3), while Ligand B (2.134) is well within it. Ligand A's higher logP *could* lead to off-target effects, but isn't immediately disqualifying.

**4. H-Bond Donors:** Ligand A has 2 HBD, which is acceptable. Ligand B has 0, also acceptable.

**5. H-Bond Acceptors:** Ligand A has 3 HBA, and Ligand B has 4. Both are below the 10 threshold.

**6. QED:** Ligand A (0.736) has a better QED score than Ligand B (0.563), indicating a more drug-like profile.

**7. DILI:** Ligand A (71.035) has a significantly higher DILI risk than Ligand B (21.675). This is a major concern for Ligand A.

**8. BBB:** Ligand B (77.162) has a substantially better BBB penetration percentile than Ligand A (58.899). This is *critical* for a CNS target like DRD2.

**9. Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and suggests poor permeability. However, the scale isn't specified, so it's hard to interpret.

**10. Aqueous Solubility:** Both have negative solubility values, suggesting poor solubility. Again, the scale isn't specified.

**11. hERG Inhibition:** Both ligands have low hERG inhibition liability (0.603 and 0.267), which is good.

**12. Microsomal Clearance:** Ligand B (64.986) has a slightly lower (better) microsomal clearance than Ligand A (58.34).

**13. In vitro Half-Life:** Ligand A (16.787) has a longer half-life than Ligand B (-2.161). This is a positive for Ligand A.

**14. P-gp Efflux:** Ligand A (0.307) has lower P-gp efflux liability than Ligand B (0.079), which is favorable for CNS penetration.

**15. Binding Affinity:** Ligand B (-7.9 kcal/mol) has a significantly stronger binding affinity than Ligand A (-9.2 kcal/mol). A 1.3 kcal/mol difference is substantial.

**Overall Assessment:**

While Ligand A has a better QED, longer half-life, and lower P-gp efflux, the significantly higher DILI risk and lower BBB penetration are major drawbacks. Ligand B, despite its slightly lower QED and shorter half-life, has a much better safety profile (lower DILI) and, crucially, *much* better predicted BBB penetration, and a superior binding affinity. For a CNS target like DRD2, BBB penetration and strong affinity are paramount. The superior binding affinity of Ligand B further solidifies its advantage.

Output:
1
2025-04-17 04:03:05,447 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 drug candidates, considering the provided guidelines and GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight (MW):** Both ligands (354.332 and 350.463 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Both ligands have a TPSA of approximately 85.24, which is acceptable for general oral absorption but slightly high for optimal CNS penetration (ideally <90).

**3. logP:** Ligand A (2.889) is optimal, while Ligand B (1.91) is slightly lower, potentially impacting permeability.

**4. H-Bond Donors (HBD):** Both ligands have 2 HBD, which is within the acceptable limit of <=5.

**5. H-Bond Acceptors (HBA):** Ligand A has 3 HBA, and Ligand B has 5 HBA, both within the acceptable limit of <=10.

**6. QED:** Both ligands have QED values (0.824 and 0.712) above 0.5, indicating good drug-like properties.

**7. DILI:** Ligand A (49.05%) has a moderate DILI risk, while Ligand B (30.012%) has a lower, more favorable DILI risk.

**8. BBB:** This is a crucial parameter for a CNS target like DRD2. Ligand A has a BBB percentile of 76.309%, which is good. Ligand B has a lower BBB percentile of 66.925%, which is less desirable.

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 values, which is unusual and suggests poor permeability. However, these values are on a scale where negative values are possible, and direct comparison is difficult without knowing the scale's specifics.

**10. Aqueous Solubility:** Both ligands have negative solubility values, which is also unusual. Again, direct comparison is difficult without knowing the scale.

**11. hERG Inhibition:** Both ligands have very low hERG inhibition liability (0.685 and 0.1), indicating a low risk of cardiotoxicity.

**12. Microsomal Clearance (Cl_mic):** Ligand A (1.645 mL/min/kg) has significantly lower clearance than Ligand B (73.773 mL/min/kg), suggesting better metabolic stability.

**13. In vitro Half-Life:** Ligand A (17.495 hours) has a much longer half-life than Ligand B (-10.083 hours), which is a significant advantage.

**14. P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.04 and 0.051), which is favorable for CNS exposure.

**15. Binding Affinity:** Ligand A (-7.7 kcal/mol) has a slightly better binding affinity than Ligand B (-8.3 kcal/mol). While both are excellent, the difference is meaningful.

**Overall Assessment:**

Considering the GPCR-specific priorities, Ligand A is the more promising candidate. It has a better BBB score, significantly better metabolic stability (lower Cl_mic and longer t1/2), and slightly better binding affinity. While Ligand B has a lower DILI risk, the superior CNS penetration and pharmacokinetic properties of Ligand A outweigh this advantage. The unusual negative values for Caco-2 and solubility are concerning for both, but the other factors favor Ligand A.

Output:
1
2025-04-17 04:03:05,447 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (339.366 and 347.503 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (48.3) is significantly better than Ligand B (63.13). For CNS targets, we want TPSA <= 90, and A is much closer to the ideal <=60 range. B is approaching a less desirable range.

**logP:** Both ligands (3.163 and 2.962) are within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A (0 HBD, 4 HBA) is preferable to Ligand B (2 HBD, 3 HBA). Lower HBD/HBA generally improves permeability.

**QED:** Both ligands have good QED scores (0.671 and 0.721), indicating good drug-like properties.

**DILI:** Ligand A (75.184) has a higher DILI risk than Ligand B (15.626). This is a significant drawback for A.

**BBB:** Both ligands have comparable BBB penetration (82.823 and 75.145). Both are above the 70% threshold, which is good for CNS targets.

**Caco-2 Permeability:** Both have negative Caco-2 values (-4.462 and -4.582). This is unusual and suggests poor permeability, but the scale is not clearly defined, so it's hard to interpret.

**Aqueous Solubility:** Both have negative solubility values (-4.491 and -2.914). Similar to Caco-2, the scale is unclear, but suggests poor solubility.

**hERG:** Ligand A (0.783) has a slightly higher hERG risk than Ligand B (0.344), but both are relatively low.

**Microsomal Clearance:** Ligand A (91.215) has a higher microsomal clearance than Ligand B (51.721), indicating lower metabolic stability.

**In vitro Half-Life:** Ligand B (7.433 hours) has a significantly longer half-life than Ligand A (-0.475 hours). This is a major advantage for B.

**P-gp Efflux:** Ligand A (0.545) has lower P-gp efflux than Ligand B (0.078), which is preferable for CNS penetration.

**Binding Affinity:** Ligand B (-7.9 kcal/mol) has a stronger binding affinity than Ligand A (-9.9 kcal/mol). While A is stronger, the difference is not large enough to overcome the other significant drawbacks.

**Overall Assessment:**

Ligand B is the better candidate. While Ligand A has slightly better P-gp efflux and binding affinity, Ligand B has a significantly lower DILI risk, better metabolic stability (lower Cl_mic and higher t1/2), and a more favorable TPSA. The comparable BBB penetration and logP values further support this conclusion. The negative Caco-2 and Solubility values are concerning for both, but the other advantages of B outweigh the slightly better affinity of A.

Output:
1
2025-04-17 04:03:05,447 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 drug candidates, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (353.463 and 374.884 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (96.53) is better than Ligand B (67.43), both are below the 90 A^2 threshold for CNS targets.

**3. logP:** Both ligands have good logP values (1.57 and 2.372) within the optimal 1-3 range. Ligand B is slightly better.

**4. H-Bond Donors:** Ligand A (3) is slightly higher than Ligand B (2), but both are acceptable (<=5).

**5. H-Bond Acceptors:** Ligand A (4) is slightly higher than Ligand B (3), but both are acceptable (<=10).

**6. QED:** Both ligands have good QED scores (0.519 and 0.701), indicating good drug-like properties. Ligand B is better.

**7. DILI:** Both ligands have low DILI risk (24.544 and 32.765), well below the 40 threshold.

**8. BBB:** Both ligands have excellent BBB penetration (80.419 and 84.955), exceeding the desirable >70 threshold for CNS targets. Ligand B is slightly better.

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 permeability values (-4.733 and -4.734). This is unusual and suggests a potential issue with intestinal absorption. However, negative values aren't directly comparable without understanding the scale.

**10. Aqueous Solubility:** Both ligands have negative aqueous solubility values (-2.41 and -3.886). This is also unusual and suggests poor solubility.

**11. hERG Inhibition:** Both ligands have low hERG inhibition risk (0.342 and 0.516).

**12. Microsomal Clearance:** Ligand A (52.188) has higher microsomal clearance than Ligand B (45.353), indicating lower metabolic stability.

**13. In vitro Half-Life:** Ligand B (26.64) has a longer in vitro half-life than Ligand A (-28.96), which is a significant advantage.

**14. P-gp Efflux:** Both ligands have low P-gp efflux liability (0.066 and 0.217).

**15. Binding Affinity:** Ligand B (-7.6 kcal/mol) has a slightly better binding affinity than Ligand A (-7.4 kcal/mol). While the difference is small, it's within the range where it could outweigh minor ADME drawbacks.

**Overall Assessment:**

Both ligands are promising candidates, but Ligand B is slightly more favorable. It has a better QED score, slightly better BBB penetration, a longer half-life, and a slightly better binding affinity. While both have concerning negative values for Caco-2 and solubility, the better overall profile of Ligand B makes it the preferred choice. The small improvement in binding affinity, coupled with the improved half-life, tips the balance.

Output:
1
2025-04-17 04:03:05,447 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 drug candidates, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (350.394 and 354.397 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (73.29) is higher than Ligand B (57.69). For a CNS target like DRD2, we prefer TPSA <= 90, so both are acceptable, but B is better.

**3. logP:** Ligand A (0.689) is slightly lower than the optimal 1-3 range, potentially hindering permeability. Ligand B (1.357) is within the optimal range. This favors B.

**4. H-Bond Donors:** Both ligands have 0 HBD, which is good.

**5. H-Bond Acceptors:** Ligand A has 4 HBA, and Ligand B has 3. Both are within the acceptable limit of <=10.

**6. QED:** Both ligands have similar QED values (0.735 and 0.752), indicating good drug-likeness.

**7. DILI:** Ligand A (48.623) has a slightly higher DILI risk than Ligand B (35.905). Both are below 60, so the risk is moderate, but B is preferable.

**8. BBB:** Ligand A (91.663) has a slightly better BBB penetration percentile than Ligand B (87.67). Both are good (>70), but A has a slight edge here.

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.685 and -4.651). This is unusual and suggests poor permeability, but the values are very close.

**10. Aqueous Solubility:** Both ligands have negative solubility values (-2.512 and -1.933), which is also unusual and suggests poor solubility. Again, the values are very close.

**11. hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.301 and 0.226).

**12. Microsomal Clearance:** Ligand A (-2.93) has lower (better) microsomal clearance than Ligand B (16.934). This indicates better metabolic stability for A.

**13. In vitro Half-Life:** Ligand A (-0.875) has a negative half-life, which is not physically possible and indicates an issue with the data. Ligand B (-22.695) also has a negative half-life, indicating a data quality issue for both.

**14. P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.029 and 0.114).

**15. Binding Affinity:** Both ligands have similar and strong binding affinities (-8.0 and -8.1 kcal/mol).

**Overall Assessment:**

Considering the GPCR-specific priorities, Ligand B is slightly more favorable. While Ligand A has a better BBB score and metabolic stability, Ligand B has a more optimal logP and lower DILI risk. The negative values for Caco-2 and solubility are concerning for both, but the affinity is excellent for both. Given the slightly better ADME profile of B, I would select it.

Output:
1
2025-04-17 04:03:05,447 - INFO - Reasoning:

Let's analyze Ligand A and Ligand B for their potential as DRD2 drug candidates, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (380.495 & 387.267 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (74.77) is significantly better than Ligand B (86.63). For CNS targets, we want TPSA <= 90, and A is closer to the optimal <=60 range. B is pushing the upper limit.

**3. logP:** Ligand A (2.304) is optimal (1-3), while Ligand B (0.933) is slightly low, potentially hindering permeation.

**4. H-Bond Donors:** Both have 1 HBD, which is acceptable.

**5. H-Bond Acceptors:** Ligand A has 8 HBA, which is good. Ligand B has 5, also acceptable.

**6. QED:** Both ligands have reasonable QED values (0.821 and 0.78), indicating good drug-like properties.

**7. DILI:** Ligand A (93.253) has a high DILI risk, which is a significant concern. Ligand B (57.348) has a moderate risk, but is much better than A.

**8. BBB:** Ligand A (65.529) has a moderate BBB penetration, while Ligand B (61.807) is also moderate. Both are below the desirable >70 for CNS targets, but not drastically so.

**9. Caco-2:** Both have negative Caco-2 values (-4.653 and -4.808). This is unusual and suggests poor permeability. This is a red flag for both.

**10. Solubility:** Both have negative solubility values (-3.273 and -1.998). This is also unusual and suggests poor aqueous solubility. This is another red flag for both.

**11. hERG:** Ligand A (0.69) has a slightly higher hERG risk than Ligand B (0.142). B is much better here.

**12. Cl_mic:** Ligand A (58.746) has a moderate clearance, while Ligand B (7.057) has very low clearance, indicating better metabolic stability.

**13. t1/2:** Ligand A (31.057) has a reasonable half-life. Ligand B (-20.76) has a negative half-life, which is not physically possible and indicates a problem with the data or the molecule.

**14. Pgp:** Ligand A (0.445) has lower P-gp efflux than Ligand B (0.033), which is favorable for CNS penetration.

**15. Binding Affinity:** Ligand A (-8.1 kcal/mol) has a significantly stronger binding affinity than Ligand B (-7.4 kcal/mol). This is a substantial advantage.

**Overall Assessment:**

Despite the strong affinity of Ligand A, its high DILI risk is a major drawback. The negative values for Caco-2 and solubility are also concerning. Ligand B has better ADME properties (lower DILI, better metabolic stability, lower hERG risk, lower Pgp efflux), but its lower logP and weaker affinity are disadvantages. The negative half-life for Ligand B is a fatal flaw.

Considering the GPCR-specific priorities and the overall profile, Ligand A is slightly more promising due to its significantly better binding affinity, *despite* the DILI risk. The DILI risk could potentially be mitigated through structural modifications. The negative values for solubility and Caco-2 are concerning for both, but the affinity difference is substantial.

Output:
0
2025-04-17 04:03:05,448 - INFO - Reasoning:

Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (346.431 and 351.451 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (96.11) is better than Ligand B (109.14). For CNS targets, we want TPSA <= 90, so Ligand A is closer to this threshold.

**3. logP:** Ligand A (1.705) is optimal (1-3). Ligand B (0.457) is a bit low, potentially hindering permeation.

**4. H-Bond Donors:** Both have 3 HBD, which is acceptable (<=5).

**5. H-Bond Acceptors:** Ligand A has 4 HBA, and Ligand B has 6. Both are within the acceptable range (<=10), but Ligand A is preferable.

**6. QED:** Both ligands have reasonable QED values (0.73 and 0.567), indicating good drug-like properties.

**7. DILI:** Both have relatively low DILI risk (30.748 and 35.828 percentile), which is good.

**8. BBB:** Ligand A (44.591%) and Ligand B (40.791%) both have low BBB penetration. This is a significant drawback for a CNS target like DRD2. However, we are looking for relative viability, and we need to consider all factors.

**9. Caco-2 Permeability:** Both have negative Caco-2 values (-5.216 and -5.465), which is unusual and suggests poor permeability.

**10. Aqueous Solubility:** Both have negative solubility values (-2.023 and -1.577), which is also unusual and suggests poor solubility.

**11. hERG Inhibition:** Both have very low hERG inhibition risk (0.161 and 0.034 percentile), which is excellent.

**12. Microsomal Clearance:** Ligand A (36.062 mL/min/kg) has higher clearance than Ligand B (6.947 mL/min/kg), indicating lower metabolic stability. Ligand B is significantly better here.

**13. In vitro Half-Life:** Ligand A (-31.04 hours) has a negative half-life, which is not physically possible and likely an error in the data. Ligand B (0.004 hours) is extremely short, also problematic.

**14. P-gp Efflux:** Both have very low P-gp efflux liability (0.048 and 0.018 percentile), which is good.

**15. Binding Affinity:** Ligand B (-7.6 kcal/mol) has a slightly better binding affinity than Ligand A (-7.9 kcal/mol). While the difference is small, it's still a factor.

**Overall Assessment:**

Despite both ligands having significant drawbacks (poor BBB, permeability, and solubility), Ligand B appears slightly more promising. It has better metabolic stability (lower Cl_mic), slightly better binding affinity, and a less problematic (though still very poor) in vitro half-life. Ligand A has a negative half-life which is impossible. The TPSA and logP values for Ligand A are slightly better, but the other factors weigh in favor of Ligand B.

Output:
1
2025-04-17 04:03:05,448 - INFO - Reasoning:
Let's analyze both ligands against the provided guidelines, prioritizing GPCR-specific properties (BBB, logP, Pgp, TPSA, and affinity) for DRD2.

**Ligand A:**

*   **MW:** 344.371 Da - Good (within 200-500 range)
*   **TPSA:** 117.25 - Acceptable, but pushing the limit for CNS targets (ideally <90).
*   **logP:** 0.915 - On the lower side, could potentially hinder permeability.
*   **HBD:** 2 - Good.
*   **HBA:** 6 - Good.
*   **QED:** 0.741 - Excellent.
*   **DILI:** 69.484 - Moderate risk.
*   **BBB:** 56.495 - Below the desirable threshold of >70 for CNS targets.
*   **Caco-2:** -5.11 - Poor permeability.
*   **Solubility:** -3.144 - Poor solubility.
*   **hERG:** 0.147 - Low risk.
*   **Cl_mic:** 13.045 mL/min/kg - Moderate clearance.
*   **t1/2:** -6.267 hours - Relatively short half-life.
*   **Pgp:** 0.036 - Low efflux, good.
*   **Affinity:** -8.1 kcal/mol - Excellent binding affinity.

**Ligand B:**

*   **MW:** 370.837 Da - Good (within 200-500 range)
*   **TPSA:** 113.44 - Acceptable, but pushing the limit for CNS targets (ideally <90).
*   **logP:** 0.46 - Low, potentially hindering permeability.
*   **HBD:** 3 - Good.
*   **HBA:** 6 - Good.
*   **QED:** 0.642 - Good.
*   **DILI:** 50.136 - Moderate risk, slightly better than Ligand A.
*   **BBB:** 46.064 - Below the desirable threshold of >70 for CNS targets.
*   **Caco-2:** -5.026 - Poor permeability.
*   **Solubility:** -2.103 - Poor solubility.
*   **hERG:** 0.066 - Low risk.
*   **Cl_mic:** 7.247 mL/min/kg - Lower clearance, better metabolic stability than Ligand A.
*   **t1/2:** 25.959 hours - Long half-life, desirable.
*   **Pgp:** 0.046 - Low efflux, good.
*   **Affinity:** -7.8 kcal/mol - Very good binding affinity, but slightly weaker than Ligand A.

**Comparison and Decision:**

Both ligands have significant drawbacks regarding permeability (Caco-2) and solubility. However, for a CNS target like DRD2, BBB penetration is crucial. Both are below the desired 70% threshold, but this is less critical than the binding affinity. Ligand A has a significantly better binding affinity (-8.1 kcal/mol vs -7.8 kcal/mol). While Ligand B has a better half-life and lower clearance, the 0.3 kcal/mol difference in binding affinity is substantial and can often outweigh minor ADME deficiencies, especially given the potential for further optimization. The slightly lower DILI risk for Ligand B is a minor benefit. The low logP for both is a concern, but can be addressed in later optimization stages.

Therefore, Ligand A is the more promising candidate due to its superior binding affinity.

Output:
0
2025-04-17 04:03:05,448 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (357.401 and 347.507 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (78.51) is better than Ligand B (54.26). Both are below the 90 A^2 threshold desirable for CNS targets.

**logP:** Ligand A (1.196) is within the optimal 1-3 range. Ligand B (2.659) is also within range, but closer to the upper limit.

**H-Bond Donors:** Ligand A (2) is acceptable, while Ligand B (0) is also good.

**H-Bond Acceptors:** Ligand A (3) is acceptable, while Ligand B (5) is also good.

**QED:** Ligand A (0.75) is better than Ligand B (0.645), indicating a more drug-like profile.

**DILI:** Ligand A (27.608) has a significantly lower DILI risk than Ligand B (13.532), which is a major advantage.

**BBB:** Both ligands have excellent BBB penetration (Ligand A: 83.366, Ligand B: 83.831), exceeding the >70% threshold for CNS targets.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.863 and -4.974), which is unusual and suggests poor permeability. This is a concern for both compounds.

**Aqueous Solubility:** Both ligands have negative solubility values (-2.23 and -0.914), which is also a concern.

**hERG Inhibition:** Ligand A (0.154) has a much lower hERG inhibition risk than Ligand B (0.414).

**Microsomal Clearance:** Ligand A (1.054) has significantly lower microsomal clearance than Ligand B (31.493), indicating better metabolic stability.

**In vitro Half-Life:** Ligand A (-1.634) has a negative half-life, which is unusual. Ligand B (7.66) has a reasonable half-life.

**P-gp Efflux:** Ligand A (0.01) has very low P-gp efflux, which is excellent for CNS penetration. Ligand B (0.318) has a slightly higher, but still acceptable, P-gp efflux.

**Binding Affinity:** Ligand B (-7.6 kcal/mol) has slightly better binding affinity than Ligand A (-8.2 kcal/mol), but the difference is small.

**Overall Assessment:**

Ligand A is the better candidate. While Ligand B has slightly better binding affinity, Ligand A excels in crucial ADME properties: lower DILI risk, lower microsomal clearance (better metabolic stability), lower hERG inhibition, and significantly lower P-gp efflux. The negative Caco-2 and solubility values are concerning for both, but the superior ADME profile of Ligand A, particularly its safety metrics and CNS penetration potential, outweigh the small affinity difference.

Output:
1
2025-04-17 04:03:05,448 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (347.5 & 345.5 Da) fall comfortably within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (38.77) is excellent, well below the 90 A^2 threshold for CNS targets. Ligand B (73.31) is higher, but still potentially acceptable, though less ideal.

**3. logP:** Ligand A (4.073) is at the upper end of the optimal range (1-3), potentially leading to solubility issues. Ligand B (2.334) is within the ideal range.

**4. H-Bond Donors:** Ligand A (0) is good. Ligand B (3) is acceptable.

**5. H-Bond Acceptors:** Ligand A (3) is good. Ligand B (6) is acceptable.

**6. QED:** Both ligands have good QED scores (0.599 and 0.735), indicating drug-likeness.

**7. DILI:** Both ligands have similar, low DILI risk (29.24 and 29.86 percentile).

**8. BBB:** Ligand A (64.10) is reasonable but not outstanding. Ligand B (70.14) is better, exceeding the 70% threshold for CNS targets. This is a significant advantage for Ligand B.

**9. Caco-2:** Ligand A (-4.612) is very poor. Ligand B (-5.222) is also poor, but slightly worse.

**10. Solubility:** Ligand A (-3.72) is poor. Ligand B (-2.228) is also poor, but better than Ligand A.

**11. hERG:** Both ligands have low hERG risk (0.769 and 0.784).

**12. Cl_mic:** Ligand A (88.923) has higher clearance, suggesting lower metabolic stability. Ligand B (-4.071) has negative clearance, which is unusual and suggests very high metabolic stability. This is a major advantage for Ligand B.

**13. t1/2:** Ligand A (7.884) is a reasonable half-life. Ligand B (65.85) has a very long half-life, which is highly desirable.

**14. Pgp:** Both ligands have low Pgp efflux liability (0.852 and 0.022). Ligand B is significantly better.

**15. Binding Affinity:** Ligand B (-8.3 kcal/mol) has a significantly stronger binding affinity than Ligand A (-7.7 kcal/mol). This 0.6 kcal/mol difference is substantial and can outweigh some ADME drawbacks.

**Overall Assessment:**

Ligand B is the superior candidate. While both have acceptable MW, QED, and DILI, Ligand B excels in key areas for a CNS-targeting GPCR ligand: better BBB penetration, significantly improved metabolic stability (Cl_mic and t1/2), lower Pgp efflux, and a substantially stronger binding affinity. Ligand A's higher logP and poor Caco-2 and solubility are concerning.

Output:
1
2025-04-17 04:03:05,448 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B based on the provided guidelines, prioritizing GPCR-specific properties (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (364.789 Da) and Ligand B (352.385 Da) are comparable.

**TPSA:** Ligand A (117.67) is slightly higher than the ideal <90 for CNS targets, but still reasonable. Ligand B (69.3) is excellent, well below the 90 threshold.

**logP:** Both ligands have good logP values (A: 1.812, B: 1.544), falling within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A (HBD=3, HBA=4) and Ligand B (HBD=1, HBA=3) both have acceptable numbers of H-bond donors and acceptors.

**QED:** Both ligands have good QED scores (A: 0.724, B: 0.897), indicating drug-like properties. Ligand B is slightly better.

**DILI:** Ligand A (73.517) has a higher DILI risk than Ligand B (41.566). Ligand B is clearly preferable here.

**BBB:** This is a critical parameter for CNS targets. Ligand B (80.419) has a significantly better BBB percentile than Ligand A (57.736). This is a major advantage for Ligand B.

**Caco-2 Permeability:** Ligand A (-5.307) and Ligand B (-4.852) both have negative values, which is unusual and suggests poor permeability. However, the scale isn't explicitly defined, so we can't definitively say which is worse.

**Aqueous Solubility:** Both ligands have poor aqueous solubility (A: -3.367, B: -2.154).

**hERG Inhibition:** Both ligands have low hERG inhibition risk (A: 0.162, B: 0.42).

**Microsomal Clearance:** Ligand A (18.028) has lower microsomal clearance than Ligand B (26.229), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (69.821) has a much longer in vitro half-life than Ligand B (-45.633). This is a significant advantage for Ligand A.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (A: 0.035, B: 0.063).

**Binding Affinity:** Both ligands have very similar and strong binding affinities (A: -8.7 kcal/mol, B: -8.2 kcal/mol). The difference of 0.5 kcal/mol is not substantial enough to outweigh other factors.

**Overall Assessment:**

Ligand B is the stronger candidate. Its superior BBB penetration (80.419 vs 57.736) and lower DILI risk (41.566 vs 73.517) are crucial advantages for a CNS-targeting drug. While Ligand A has a longer half-life and better metabolic stability, the improved CNS exposure potential of Ligand B is more important for a DRD2 ligand. The slightly better TPSA of Ligand B also contributes to its favorability. The similar affinities make the ADME properties the deciding factors.

Output:
1
2025-04-17 04:03:05,448 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B based on the provided guidelines, prioritizing GPCR-specific properties (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (340.463 and 344.419 Da) fall comfortably within the ideal 200-500 Da range.

**TPSA:** Ligand A (46.53) is excellent, well below the 90 A^2 threshold for CNS targets. Ligand B (103.01) is higher, but still potentially acceptable, though less ideal.

**logP:** Ligand A (4.503) is slightly high, potentially leading to solubility issues or off-target interactions. Ligand B (1.046) is low, which could hinder permeation.

**H-Bond Donors/Acceptors:** Ligand A (1 HBD, 3 HBA) is favorable. Ligand B (3 HBD, 6 HBA) is also acceptable, but higher.

**QED:** Both ligands have good QED scores (0.596 and 0.694), indicating drug-like properties.

**DILI:** Ligand A (24.195) has a much lower DILI risk than Ligand B (57.387), which is a significant advantage.

**BBB:** This is crucial for a CNS target. Ligand A (66.266) has a reasonable BBB percentile, but Ligand B (36.642) is considerably lower and less desirable.

**Caco-2 Permeability:** Ligand A (-4.505) has poor Caco-2 permeability, which is a concern. Ligand B (-5.314) is also poor.

**Aqueous Solubility:** Ligand A (-5.591) has poor solubility. Ligand B (-2.735) is better, but still not ideal.

**hERG:** Both ligands have low hERG inhibition risk (0.822 and 0.441), which is good.

**Microsomal Clearance:** Ligand A (101.222) has higher clearance than Ligand B (38.367), suggesting lower metabolic stability.

**In vitro Half-Life:** Ligand B (19.976) has a significantly longer half-life than Ligand A (1.823), a major advantage.

**P-gp Efflux:** Ligand A (0.848) has lower P-gp efflux liability than Ligand B (0.011), which is beneficial for CNS exposure.

**Binding Affinity:** Both ligands have excellent binding affinities (-9.2 and -8.8 kcal/mol). The difference of 0.4 kcal/mol is not substantial enough to outweigh other factors.

**Overall Assessment:**

Ligand A has better TPSA, DILI, and P-gp efflux. However, it suffers from poor Caco-2 permeability, solubility, and metabolic stability. Ligand B has a better BBB, longer half-life, and better solubility, but a higher DILI risk and P-gp efflux. Given the importance of BBB penetration for a CNS target like DRD2, and the substantial difference in BBB percentile, Ligand B is the more promising candidate despite its higher DILI risk. The longer half-life also contributes to its favorability.

Output:
1
2025-04-17 04:03:05,449 - INFO - Batch 80 complete. Total preferences: 1280
2025-04-17 04:03:05,449 - INFO - Processing batch 81/512...
2025-04-17 04:03:47,989 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (361.877 and 355.479 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (62.53) is excellent, well below the 90 A^2 threshold for CNS targets. Ligand B (73.32) is still reasonable, but less optimal.

**logP:** Ligand A (3.148) is within the optimal 1-3 range. Ligand B (0.728) is a bit low, potentially hindering permeability.

**H-Bond Donors/Acceptors:** Both have 1 HBD and 5 HBA, which are acceptable.

**QED:** Ligand A (0.908) has a very strong drug-like profile. Ligand B (0.711) is still good, but not as high.

**DILI:** Ligand A (55.176) has a moderate DILI risk. Ligand B (5.312) has a very low DILI risk, a significant advantage.

**BBB:** Ligand A (91.159) has excellent BBB penetration, exceeding the desirable >70% threshold. Ligand B (56.65) is considerably lower, which is a major drawback for a CNS target.

**Caco-2 Permeability:** Both have negative Caco-2 values (-5.018 and -4.998). This is unusual and suggests poor permeability, but the scale is not specified.

**Aqueous Solubility:** Both have negative solubility values (-2.969 and -0.682). Again, the scale is not specified, but suggests poor solubility.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.589 and 0.338).

**Microsomal Clearance:** Ligand A (52.54) has moderate clearance. Ligand B (-6.815) has negative clearance, which is not physically possible and likely indicates an error or an unusual data representation.

**In vitro Half-Life:** Ligand A (-0.854) has a negative half-life, which is not physically possible. Ligand B (-4.263) also has a negative half-life, indicating a data issue.

**P-gp Efflux:** Both have low P-gp efflux liability (0.439 and 0.013), which is favorable for CNS penetration.

**Binding Affinity:** Ligand A (-9.4 kcal/mol) has significantly stronger binding affinity than Ligand B (-6.9 kcal/mol). This is a substantial advantage, exceeding the >1.5 kcal/mol difference threshold.

**Overall Assessment:**

Despite the questionable solubility, permeability, half-life, and clearance data, Ligand A is the stronger candidate. Its superior BBB penetration and, critically, its much higher binding affinity outweigh the slightly higher DILI risk and the issues with the ADME properties. The large difference in binding affinity (-9.4 vs -6.9 kcal/mol) is a decisive factor. Ligand B's low logP and poor BBB penetration are significant liabilities for a CNS-targeting drug. The negative values for clearance and half-life are concerning and suggest data quality issues, but even ignoring those, the affinity difference is too large to overlook.

Output:
1
2025-04-17 04:03:47,990 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 drug candidates, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (340.442 and 350.419 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (33.29) is excellent, well below the 90 A^2 threshold for CNS targets. Ligand B (87.91) is higher, but still potentially acceptable, though less ideal.

**logP:** Ligand A (4.349) is slightly high, potentially leading to solubility issues or off-target effects. Ligand B (0.461) is quite low, which could hinder permeation.

**H-Bond Donors/Acceptors:** Ligand A (HBD=2, HBA=3) and Ligand B (HBD=1, HBA=6) both have reasonable numbers of H-bond donors and acceptors, falling within the guidelines.

**QED:** Both ligands (0.82 and 0.83) have high QED scores, indicating good drug-like properties.

**DILI:** Both ligands have low DILI risk (39.86 and 38.736), which is favorable.

**BBB:** Ligand A (78.247) has a good BBB percentile, exceeding the 70% threshold for CNS targets. Ligand B (55.138) is significantly lower, raising concerns about CNS penetration. This is a critical difference given the target.

**Caco-2 Permeability:** Ligand A (-5.109) has poor Caco-2 permeability. Ligand B (-4.776) also has poor Caco-2 permeability, but slightly better than A.

**Aqueous Solubility:** Ligand A (-3.575) has poor aqueous solubility. Ligand B (-1.322) has slightly better solubility, but still low.

**hERG Inhibition:** Ligand A (0.946) has a slightly elevated hERG risk, but acceptable. Ligand B (0.265) shows very low hERG risk, which is excellent.

**Microsomal Clearance:** Ligand A (35.423) has moderate clearance, while Ligand B (0.43) has very low clearance, indicating better metabolic stability.

**In vitro Half-Life:** Ligand A (16.149 hours) has a reasonable half-life. Ligand B (12.193 hours) has a shorter half-life.

**P-gp Efflux:** Ligand A (0.687) has moderate P-gp efflux. Ligand B (0.026) has very low P-gp efflux, which is highly desirable for CNS penetration.

**Binding Affinity:** Ligand A (-9.7 kcal/mol) has significantly stronger binding affinity than Ligand B (-8.2 kcal/mol). This is a substantial advantage (1.5 kcal/mol difference).

**Overall Assessment:**

While Ligand B has better metabolic stability (lower Cl_mic, lower Pgp, lower hERG), the significantly stronger binding affinity of Ligand A (-9.7 vs -8.2 kcal/mol) and its superior BBB penetration (78.2% vs 55.1%) are crucial for a CNS-targeting GPCR like DRD2. The slightly higher logP and lower solubility of Ligand A are concerns, but the potency advantage and better CNS penetration are likely to outweigh these drawbacks, especially with potential for further optimization. The poor Caco-2 permeability for both is a concern, but less critical for a CNS target.

Output:
0
2025-04-17 04:03:47,990 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (354.4 and 349.4 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (60.85) is significantly better than Ligand B (100.25). For CNS targets, we want TPSA <= 90, so Ligand A is much closer to this threshold.

**3. logP:** Both ligands have good logP values (2.356 and 1.074), falling within the optimal 1-3 range.

**4. H-Bond Donors:** Both have 1 HBD, which is acceptable.

**5. H-Bond Acceptors:** Ligand A has 3 HBA, while Ligand B has 6. Both are within the acceptable limit of <=10, but Ligand A is preferable.

**6. QED:** Both ligands have reasonable QED values (0.852 and 0.719), indicating good drug-like properties.

**7. DILI:** Ligand A (35.983) has a lower DILI risk than Ligand B (44.591). Both are below the concerning threshold of 60, but lower is better.

**8. BBB:** This is a crucial parameter for a CNS target like DRD2. Ligand A (83.443) has a significantly higher BBB percentile than Ligand B (58.821). A value >70 is desirable, and Ligand A is much closer.

**9. Caco-2 Permeability:** Both have negative values (-4.64 and -4.703). This is unusual and suggests poor permeability, but the scale isn't defined, so it's hard to interpret.

**10. Aqueous Solubility:** Both have negative values (-2.337 and -2.316). Similar to Caco-2, this is hard to interpret without knowing the scale.

**11. hERG Inhibition:** Both ligands have low hERG inhibition risk (0.329 and 0.351).

**12. Microsomal Clearance:** Ligand A (19.857) has a lower microsomal clearance than Ligand B (48.029), indicating better metabolic stability.

**13. In vitro Half-Life:** Ligand A (-23.482) has a more negative (longer) half-life than Ligand B (30.754). Again, the scale is unclear, but a more negative value is generally better.

**14. P-gp Efflux:** Both have very low P-gp efflux liability (0.047 and 0.141).

**15. Binding Affinity:** Both ligands have excellent binding affinities (-8.0 and -7.0 kcal/mol). Ligand A is slightly better (-8.0 kcal/mol).

**Overall Assessment:**

Ligand A is superior to Ligand B. It has a lower TPSA, lower DILI risk, significantly better BBB penetration, better metabolic stability (lower Cl_mic), longer half-life, and slightly better binding affinity. While both have similar logP and H-bond properties, the improvements in CNS penetration and ADME properties make Ligand A the more promising drug candidate for a CNS target like DRD2.

Output:
1
2025-04-17 04:03:47,990 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (360.801 and 345.399 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (104.21) is slightly above the optimal <90 for CNS targets, but still reasonable. Ligand B (88.58) is excellent, well below 90.

**3. logP:** Ligand A (0.852) is a bit low, potentially hindering membrane permeability. Ligand B (2.318) is within the optimal 1-3 range.

**4. H-Bond Donors:** Ligand A (3) is acceptable. Ligand B (1) is also good.

**5. H-Bond Acceptors:** Both ligands (A: 5, B: 5) are within the acceptable limit of <=10.

**6. QED:** Both ligands have good QED scores (A: 0.708, B: 0.898), indicating drug-like properties. Ligand B is slightly better.

**7. DILI:** Ligand A (69.794) has a higher DILI risk than Ligand B (44.591). Ligand B is preferable.

**8. BBB:** Ligand B (69.95) has a significantly better BBB penetration percentile than Ligand A (24.738). This is a *critical* advantage for a CNS target like DRD2.

**9. Caco-2 Permeability:** Both have negative Caco-2 values which is unusual and suggests poor permeability.

**10. Aqueous Solubility:** Both have negative solubility values which is also unusual.

**11. hERG Inhibition:** Both ligands have very low hERG inhibition risk (A: 0.044, B: 0.222).

**12. Microsomal Clearance:** Ligand A (-22.4) has a much lower (better) microsomal clearance than Ligand B (10.953), suggesting greater metabolic stability.

**13. In vitro Half-Life:** Ligand A (30.748) has a longer half-life than Ligand B (16.643).

**14. P-gp Efflux:** Both ligands have very low P-gp efflux liability (A: 0.011, B: 0.124).

**15. Binding Affinity:** Both ligands have excellent binding affinities (A: -8.8 kcal/mol, B: -9.4 kcal/mol). Ligand B is slightly stronger.

**Overall Assessment:**

While Ligand A has better metabolic stability (lower Cl_mic, longer t1/2) and slightly better binding affinity, Ligand B is superior overall due to its significantly better BBB penetration (69.95 vs 24.738), more optimal logP (2.318 vs 0.852), lower DILI risk, and slightly higher QED. For a CNS target like DRD2, BBB penetration is paramount. The slightly lower metabolic stability of Ligand B can potentially be addressed through structural modifications later in the optimization process. The negative Caco-2 and solubility values are concerning for both, but can be addressed during lead optimization.

Output:
1
2025-04-17 04:03:47,990 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (365.543 and 349.475 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (61.44) is significantly better than Ligand B (75.44). For CNS targets, we want TPSA <= 90, and A is much closer to the ideal <=60. B is pushing the upper limit.

**3. logP:** Both ligands have acceptable logP values (1.793 and 3.105), falling within the 1-3 range. Ligand B is slightly higher, which *could* indicate potential solubility issues, but is still within an acceptable range.

**4. H-Bond Donors:** Both have reasonable HBD counts (2 and 1 respectively), well below the threshold of 5.

**5. H-Bond Acceptors:** Both ligands have 4 HBA, which is acceptable (<=10).

**6. QED:** Both ligands have similar QED values (0.722 and 0.704), indicating good drug-like properties.

**7. DILI:** Both ligands have very similar and low DILI risk (16.44 and 16.479 percentile), indicating a low risk of liver injury.

**8. BBB:** Ligand B (88.833) has a substantially better BBB penetration score than Ligand A (70.415). This is a *critical* factor for a CNS target like DRD2.

**9. Caco-2 Permeability:** Ligand A (-5.235) has a worse Caco-2 permeability than Ligand B (-4.534), suggesting lower intestinal absorption.

**10. Aqueous Solubility:** Both have poor aqueous solubility (-2.939 and -3.327). This is a concern, but can often be addressed with formulation strategies.

**11. hERG Inhibition:** Both ligands have low hERG inhibition risk (0.348 and 0.672).

**12. Microsomal Clearance:** Both ligands have similar microsomal clearance (74.94 and 75.978 mL/min/kg), indicating similar metabolic stability.

**13. In vitro Half-Life:** Ligand A (24.657 hours) has a significantly longer half-life than Ligand B (11.044 hours). This is a positive attribute.

**14. P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.1 and 0.172).

**15. Binding Affinity:** Ligand A (-8.9 kcal/mol) has a slightly better binding affinity than Ligand B (-8.2 kcal/mol). While both are excellent, the 0.7 kcal/mol difference is noteworthy.

**Overall Assessment:**

Ligand A has a better TPSA, longer half-life, and slightly better binding affinity. However, Ligand B *significantly* outperforms Ligand A in BBB penetration, which is paramount for a CNS target. The slightly better Caco-2 permeability of Ligand B is also a plus. While Ligand A's affinity is better, the difference isn't large enough to overcome the substantial advantage of Ligand B's BBB score.

Output:
1
2025-04-17 04:03:47,990 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B against the provided guidelines, prioritizing GPCR-specific properties (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (350.415 and 364.471 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (81.01) is better than Ligand B (65.98) as it is closer to the <90 A^2 threshold for CNS targets.

**logP:** Ligand A (1.703) is optimal, while Ligand B (0.675) is slightly low, potentially hindering permeation.

**H-Bond Donors/Acceptors:** Ligand A has 1 HBD and 5 HBA, while Ligand B has 0 HBD and 6 HBA. Both are within acceptable limits.

**QED:** Both ligands have good QED scores (0.845 and 0.769, respectively), indicating drug-like properties.

**DILI:** Ligand A (37.728) has a slightly higher DILI risk than Ligand B (28.383), but both are below the concerning threshold of 60.

**BBB:** Ligand B (76.851) significantly outperforms Ligand A (63.94) in BBB penetration, which is crucial for a CNS target like DRD2.

**Caco-2 Permeability:** Ligand A (-4.672) is worse than Ligand B (-5.036), indicating lower intestinal absorption.

**Aqueous Solubility:** Ligand A (-2.304) is better than Ligand B (-1.121).

**hERG:** Both ligands have very low hERG inhibition liability (0.238 and 0.255, respectively).

**Microsomal Clearance:** Ligand B (-5.314) has a significantly *lower* (better) microsomal clearance than Ligand A (42.224), indicating greater metabolic stability.

**In vitro Half-Life:** Ligand B (1.776) has a lower half-life than Ligand A (63.909).

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.071 and 0.044, respectively).

**Binding Affinity:** Ligand B (-8.2 kcal/mol) has a stronger binding affinity than Ligand A (-7.7 kcal/mol). This 0.5 kcal/mol difference is substantial and can outweigh some ADME drawbacks.

**Conclusion:**

While Ligand A has better solubility, Ligand B excels in the most critical areas for a CNS-targeting GPCR: BBB penetration, metabolic stability (lower Cl_mic), and, most importantly, binding affinity. The stronger binding affinity of Ligand B is a significant advantage. The slightly lower logP of Ligand B is a minor concern compared to the benefits of its superior BBB and metabolic properties.

Output:
1
2025-04-17 04:03:47,990 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (370.503 and 354.431 Da) fall within the ideal range of 200-500 Da.

**TPSA:** Ligand A (80.9) is better than Ligand B (71.45). Both are below the 90 A^2 threshold for CNS targets, which is excellent.

**logP:** Both ligands have good logP values (3.658 and 4.014), falling within the optimal 1-3 range. Ligand B is slightly higher, which could potentially lead to some solubility issues, but it's not a major concern.

**H-Bond Donors/Acceptors:** Both ligands have 2 HBD and 6/5 HBA, respectively, which are within acceptable limits.

**QED:** Both ligands have good QED scores (0.687 and 0.726), indicating drug-like properties.

**DILI:** Both ligands have high DILI risk (82.28 and 82.396), which is a concern. However, this is a predictive score and doesn't necessarily disqualify either compound.

**BBB:** Ligand A (64.056) has a significantly better BBB percentile than Ligand B (43.117). This is *critical* for a CNS target like DRD2.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.199 and -5.213). This is unusual and suggests poor intestinal absorption. However, for a CNS target, intestinal absorption is less critical than BBB penetration.

**Aqueous Solubility:** Both ligands have negative solubility values (-4.154 and -5.188). This is a concern, but can be addressed through formulation strategies.

**hERG:** Both ligands have low hERG inhibition liability (0.673 and 0.622), which is good.

**Microsomal Clearance:** Ligand A (33.577) has a lower microsomal clearance than Ligand B (99.951), indicating better metabolic stability.

**In vitro Half-Life:** Ligand A (21.662) has a longer half-life than Ligand B (-23.145). The negative value for Ligand B is concerning and suggests very rapid metabolism.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.505 and 0.79).

**Binding Affinity:** Both ligands have excellent binding affinities (-9.8 and -9.5 kcal/mol). The difference of 0.3 kcal/mol is not substantial enough to outweigh other factors.

**Conclusion:**

Considering all factors, **Ligand A** is the more promising drug candidate. While both ligands have similar binding affinities and acceptable physicochemical properties, Ligand A significantly outperforms Ligand B in BBB penetration (64.056 vs 43.117) and has better metabolic stability (lower Cl_mic and longer t1/2). These are crucial factors for a CNS-targeting GPCR like DRD2. The DILI risk is a concern for both, but can be investigated further.

Output:
0
2025-04-17 04:03:47,990 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (343.358 Da) is slightly lower, which could be beneficial for permeability. Ligand B (378.822 Da) is also good.

**TPSA:** Both ligands have TPSA values below the 90 A^2 threshold for CNS targets, which is excellent. Ligand B (58.2) is significantly lower than Ligand A (75.48), making it more favorable for brain penetration.

**logP:** Both ligands have logP values between 3 and 4, which is acceptable, but leaning towards the higher end. Ligand B (3.787) is slightly higher than Ligand A (3.217).

**H-Bond Donors/Acceptors:** Ligand A has 1 HBD and 4 HBA, while Ligand B has 2 HBD and 2 HBA. Both are within acceptable limits.

**QED:** Both ligands have QED values above 0.5, indicating good drug-like properties. Ligand A (0.686) is slightly better than Ligand B (0.609).

**DILI:** Ligand A (80.729) has a higher DILI risk than Ligand B (55.176). This is a significant negative for Ligand A.

**BBB:** Both ligands have excellent BBB penetration (Ligand A: 77.898, Ligand B: 77.511), exceeding the desirable threshold of 70.

**Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and likely indicates a problem with the prediction method or the molecule's structure. It's difficult to interpret without more information.

**Aqueous Solubility:** Both ligands have very poor aqueous solubility (-4.7 and -4.594). This is a major concern for both.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.805 and 0.876), which is positive.

**Microsomal Clearance:** Both have similar microsomal clearance values (Ligand A: 47.249, Ligand B: 41.877). These are relatively moderate, suggesting moderate metabolic stability.

**In vitro Half-Life:** Both ligands have similar in vitro half-lives (Ligand A: 43.594, Ligand B: 46.725).

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.42 and 0.494), which is good for CNS penetration.

**Binding Affinity:** Both ligands have excellent binding affinities (-8.7 and -8.5 kcal/mol). The difference is small (0.2 kcal/mol) and unlikely to be decisive.

**Overall Assessment:**

Ligand B is the more promising candidate. While both have poor solubility, Ligand B has a significantly lower DILI risk and a lower TPSA, both of which are beneficial. The slightly higher logP of Ligand B is less concerning than the higher DILI risk of Ligand A. The binding affinities are comparable. Given the GPCR-specific priorities, the lower TPSA and DILI risk of Ligand B make it the better choice.

Output:
1
2025-04-17 04:03:47,990 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (362.539 Da and 387.571 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (40.62) is excellent, well below the 90 Angstroms threshold for CNS targets. Ligand B (101.29) is higher, but still potentially acceptable, though less ideal.

**3. logP:** Ligand A (2.912) is optimal (1-3). Ligand B (1.302) is on the lower end, potentially hindering permeability.

**4. H-Bond Donors:** Ligand A (0) is good. Ligand B (3) is acceptable, but higher HBD can sometimes impact permeability.

**5. H-Bond Acceptors:** Ligand A (3) is good. Ligand B (5) is also acceptable.

**6. QED:** Ligand A (0.758) is excellent, indicating strong drug-likeness. Ligand B (0.491) is lower, suggesting a less favorable drug-like profile.

**7. DILI:** Ligand A (32.105) has a low DILI risk. Ligand B (25.165) also has a low DILI risk. Both are good.

**8. BBB:** Ligand A (71.501) has a good BBB percentile, desirable for a CNS target. Ligand B (57.58) is lower, which is a significant drawback for DRD2.

**9. Caco-2:** Both ligands have negative Caco-2 values, which is unusual and indicates poor permeability. However, these values are on a different scale and hard to interpret directly.

**10. Solubility:** Both ligands have negative solubility values, which is also unusual and indicates poor solubility.

**11. hERG:** Ligand A (0.295) has very low hERG risk. Ligand B (0.086) has even lower hERG risk, but both are excellent.

**12. Cl_mic:** Ligand A (49.318) has a moderate microsomal clearance. Ligand B (39.016) has a lower clearance, suggesting better metabolic stability.

**13. t1/2:** Ligand A (3.701) has a short in vitro half-life. Ligand B (-18.157) has a negative half-life, which is not physically possible and indicates an issue with the data.

**14. Pgp:** Ligand A (0.25) has low P-gp efflux liability. Ligand B (0.033) has very low P-gp efflux liability. Both are good.

**15. Binding Affinity:** Ligand A (-7.3 kcal/mol) has a slightly better binding affinity than Ligand B (-6.9 kcal/mol). While both are good, the 1.5 kcal/mol difference is significant.

**Overall Assessment:**

Ligand A is the stronger candidate. While Ligand B has slightly better metabolic stability and P-gp efflux, Ligand A excels in crucial areas for a CNS-targeting GPCR: TPSA, logP, QED, and most importantly, BBB penetration. The slightly better binding affinity of Ligand A further strengthens its position. The negative values for Caco-2 and solubility are concerning for both, but the other properties of Ligand A make it more promising. The negative half-life for Ligand B is a clear red flag.

Output:
0
2025-04-17 04:03:47,991 - INFO - Reasoning:

Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (370.559 and 374.539 Da) fall comfortably within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (60.85) is significantly better than Ligand B (75.62). For CNS targets, we want TPSA <= 90, and ideally closer to 60. Ligand A is much closer to the ideal.

**3. logP:** Ligand A (2.23) is within the optimal 1-3 range. Ligand B (4.354) is higher, potentially leading to solubility issues and off-target interactions.

**4. H-Bond Donors:** Ligand A (1) is preferable to Ligand B (2). Fewer HBDs generally improve permeability.

**5. H-Bond Acceptors:** Ligand A (4) is better than Ligand B (8). Similar to HBDs, lower HBA counts are generally favored.

**6. QED:** Ligand A (0.806) has a much better QED score than Ligand B (0.64), indicating a more drug-like profile.

**7. DILI:** Ligand A (21.908) has a significantly lower DILI risk than Ligand B (74.68), which is a substantial concern.

**8. BBB:** Ligand A (54.362) has a better BBB penetration score than Ligand B (42.73), although both are below the desirable >70 for CNS targets. However, given the other factors, Ligand A's better BBB is a plus.

**9. Caco-2 Permeability:** Ligand A (-4.634) has a more negative Caco-2 value, which is not ideal. Ligand B (-5.423) is worse. This suggests both have poor intestinal absorption, but it's less critical for a CNS target where direct delivery is possible.

**10. Aqueous Solubility:** Ligand A (-2.59) has better solubility than Ligand B (-3.686), though both are poor.

**11. hERG Inhibition:** Ligand A (0.213) has a much lower hERG risk than Ligand B (0.515). This is a critical safety parameter.

**12. Microsomal Clearance:** Ligand B (41.773) has lower microsomal clearance than Ligand A (62.117), suggesting better metabolic stability. This is a point in favor of Ligand B.

**13. In vitro Half-Life:** Ligand B (67.419) has a significantly longer half-life than Ligand A (1.726), which is a major advantage.

**14. P-gp Efflux:** Ligand A (0.086) has a much lower P-gp efflux liability than Ligand B (0.178), which is crucial for CNS penetration.

**15. Binding Affinity:** Ligand B (-8.3) has a significantly stronger binding affinity than Ligand A (-6.5). This is a 1.8 kcal/mol difference, which is substantial and can outweigh some ADME drawbacks.

**Overall Assessment:**

While Ligand B has a superior binding affinity and metabolic stability (lower Cl_mic, longer t1/2), Ligand A is significantly better across multiple critical ADME properties, especially DILI risk, hERG inhibition, P-gp efflux, and TPSA. The higher affinity of Ligand B is attractive, but the poor ADME profile, particularly the high DILI and P-gp efflux, raise significant concerns. For a CNS target like DRD2, minimizing efflux and maximizing BBB penetration are paramount. Ligand A, despite its weaker binding, presents a more balanced and safer profile.

Output:
0
2025-04-17 04:03:47,991 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B based on the provided guidelines, prioritizing GPCR-specific properties (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (351.387 and 387.567 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (84.94) is excellent for CNS penetration, being well below 90. Ligand B (48) is even better.

**logP:** Both ligands have good logP values (3.521 and 2.879), falling within the optimal 1-3 range.

**H-Bond Donors:** Ligand A has 1 HBD, which is good. Ligand B has 0, also good.

**H-Bond Acceptors:** Both ligands have 6 HBAs, which is acceptable (<=10).

**QED:** Ligand B (0.61) has a slightly better QED score than Ligand A (0.449), indicating better overall drug-likeness.

**DILI:** Ligand A has a very high DILI risk (94.843), which is a major concern. Ligand B has a much lower DILI risk (40.752), which is preferable.

**BBB:** Ligand B (79.682) has a significantly better BBB penetration percentile than Ligand A (52.617). This is crucial for a CNS target like DRD2.

**Caco-2 Permeability:** Both have negative Caco-2 values which is unusual and suggests poor permeability.

**Aqueous Solubility:** Both ligands have negative solubility values, which is also unusual and suggests poor solubility.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.406 and 0.749).

**Microsomal Clearance:** Ligand B (105.972) has higher microsomal clearance than Ligand A (92.16), indicating faster metabolism and potentially lower exposure.

**In vitro Half-Life:** Ligand B (24.656) has a significantly longer in vitro half-life than Ligand A (-2.315), which is a major advantage.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.654 and 0.608).

**Binding Affinity:** Ligand A (-9.3 kcal/mol) has a slightly better binding affinity than Ligand B (-6.8 kcal/mol). However, the difference in affinity (2.5 kcal/mol) might be outweighed by the significant advantages of Ligand B in other ADME properties.

**Overall Assessment:**

Ligand A has better binding affinity, but its extremely high DILI risk and poor BBB penetration are major drawbacks. Ligand B, while having slightly weaker affinity, exhibits a much more favorable ADME profile, including significantly lower DILI risk, better BBB penetration, and a longer half-life. Given the GPCR-specific priorities, particularly BBB penetration for a CNS target, and the importance of avoiding hepatotoxicity, Ligand B is the more promising candidate.

Output:
1
2025-04-17 04:03:47,991 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 drug candidates, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (344.459 Da) is slightly lower, which is generally favorable for permeability.

**2. TPSA:** Ligand A (67.23) is significantly better than Ligand B (87.74). For CNS targets, TPSA should be <= 90, and A is comfortably within this range, while B is approaching the upper limit.

**3. logP:** Both ligands have good logP values (A: 1.84, B: 1.44), falling within the optimal 1-3 range.

**4. H-Bond Donors:** Ligand A (1) is preferable to Ligand B (2). Lower HBD generally improves permeability.

**5. H-Bond Acceptors:** Ligand A (4) is preferable to Ligand B (5). Lower HBA generally improves permeability.

**6. QED:** Both ligands have good QED scores (A: 0.732, B: 0.826), indicating a generally drug-like profile.

**7. DILI:** Ligand A (26.522) has a much lower DILI risk than Ligand B (69.678). This is a significant advantage for A.

**8. BBB:** Ligand A (57.464) has a better BBB percentile than Ligand B (53.044), though both are not ideal (>70 is desirable). However, given the other factors, A's slightly better BBB is a plus.

**9. Caco-2:** Both ligands have negative Caco-2 values (-5.01 and -5.072), which is unusual and suggests poor permeability. This is a significant drawback for both.

**10. Solubility:** Both ligands have negative solubility values (-1.244 and -2.019), indicating poor aqueous solubility. This is a concern for bioavailability.

**11. hERG:** Both ligands have low hERG risk (A: 0.151, B: 0.197).

**12. Cl_mic:** Ligand B (-15.687) has a much lower (better) microsomal clearance than Ligand A (29.209), indicating greater metabolic stability.

**13. t1/2:** Ligand B (12.965) has a longer in vitro half-life than Ligand A (-8.186). This is a significant advantage for B.

**14. Pgp:** Both ligands have very low Pgp efflux liability (A: 0.039, B: 0.045). This is good, as it suggests good CNS exposure.

**15. Binding Affinity:** Ligand A (-7.6) has a slightly better binding affinity than Ligand B (-8.0). While B is slightly better, the difference is not substantial enough to outweigh other factors.

**Overall Assessment:**

Ligand A is the better candidate. While Ligand B has better metabolic stability and half-life, Ligand A excels in critical areas for CNS drug development: lower TPSA, lower DILI risk, slightly better BBB penetration, and better H-bonding characteristics. The binding affinity difference is minimal. The poor Caco-2 and solubility are concerns for both, but can be addressed with formulation strategies. The lower DILI risk of A is particularly important.

Output:
0
2025-04-17 04:03:47,991 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight (MW):** Both ligands (366.38 and 372.466 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (98.66) is better than Ligand B (101.05). Both are reasonably close to the 90 A^2 threshold for CNS targets, but A is preferable.

**3. logP:** Ligand B (1.573) is better than Ligand A (0.718). Both are within the optimal range of 1-3, but B is closer to the sweet spot.

**4. H-Bond Donors (HBD):** Ligand A (4) is slightly higher than Ligand B (2), but both are acceptable (<=5).

**5. H-Bond Acceptors (HBA):** Ligand B (6) is better than Ligand A (4). Both are within the acceptable range (<=10).

**6. QED:** Ligand B (0.753) is significantly better than Ligand A (0.534), indicating a more drug-like profile.

**7. DILI:** Ligand A (25.397) is *much* better than Ligand B (55.176). This is a significant advantage for Ligand A.

**8. BBB:** Ligand B (79.992) is better than Ligand A (63.862). Both are reasonably good, but B is closer to the desirable >70 percentile for CNS targets.

**9. Caco-2 Permeability:** Ligand A (-5.032) is better than Ligand B (-4.973). Higher values are better, and A is slightly better.

**10. Aqueous Solubility:** Ligand A (-1.7) is better than Ligand B (-3.373). Higher values are better, and A is better.

**11. hERG Inhibition:** Both ligands (0.313 and 0.226) have very low hERG inhibition risk, which is excellent.

**12. Microsomal Clearance (Cl_mic):** Ligand A (-9.919) is significantly better than Ligand B (17.421). A negative value indicates very high metabolic stability.

**13. In vitro Half-Life:** Ligand A (-21.764) is significantly better than Ligand B (31.956). A negative value indicates a very long half-life.

**14. P-gp Efflux:** Both ligands (0.022 and 0.15) have low P-gp efflux liability, which is good for CNS exposure. Ligand A is slightly better.

**15. Binding Affinity:** Both ligands have the same binding affinity (-8.4 kcal/mol), which is excellent.

**Overall Assessment:**

While Ligand B has better logP, QED, and BBB penetration, Ligand A has *much* better DILI risk, metabolic stability (Cl_mic), and in vitro half-life. The superior ADME profile of Ligand A, particularly the significantly lower DILI and higher metabolic stability, outweighs the slight advantages of Ligand B, especially considering the importance of safety and duration of action for a CNS drug. The binding affinity is identical, so potency is not a differentiating factor. Given the GPCR-specific priorities, the improved BBB of Ligand B is helpful, but not enough to overcome the substantial ADME benefits of Ligand A.

Output:
0
2025-04-17 04:03:47,991 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands are within the acceptable range (200-500 Da). Ligand A (369.795 Da) is slightly higher than Ligand B (348.443 Da), but both are reasonable.

**2. TPSA:** Ligand A (47.56) is significantly better than Ligand B (71.78). For CNS targets, we want TPSA <= 90, and ideally closer to 60. Ligand A is much closer to this ideal. Ligand B is pushing the upper limit and could have permeability issues.

**3. logP:** Both ligands have good logP values (A: 3.673, B: 2.594), falling within the optimal range of 1-3.

**4. H-Bond Donors:** Both have 1 HBD, which is good.

**5. H-Bond Acceptors:** Ligand A has 3 HBA, and Ligand B has 4. Both are acceptable (<=10).

**6. QED:** Both ligands have high QED values (A: 0.81, B: 0.888), indicating good drug-like properties.

**7. DILI:** Ligand A (63.978) has a higher DILI risk than Ligand B (25.165). This is a concern for Ligand A.

**8. BBB:** Both ligands have excellent BBB penetration (A: 73.052, B: 70.919), exceeding the desirable threshold of >70.

**9. Caco-2 Permeability:** Both have negative Caco-2 values (-4.471 and -4.643). This is unusual and suggests a potential issue with the data or a predicted poor permeability. However, given the other properties, it's less of a concern than TPSA.

**10. Aqueous Solubility:** Both have negative solubility values (-4.451 and -2.317). Similar to Caco-2, this is concerning but less critical than other factors.

**11. hERG Inhibition:** Both ligands have low hERG inhibition risk (A: 0.751, B: 0.278). Ligand B is slightly better.

**12. Microsomal Clearance:** Ligand A (76.235) has higher clearance than Ligand B (11.377), indicating lower metabolic stability. This is a significant drawback for Ligand A.

**13. In vitro Half-Life:** Ligand B (25.993) has a longer half-life than Ligand A (16.977), which is preferable.

**14. P-gp Efflux:** Both have low P-gp efflux (A: 0.438, B: 0.066). Ligand B is significantly better, which is crucial for CNS penetration.

**15. Binding Affinity:** Both ligands have very similar and excellent binding affinities (A: -8.8 kcal/mol, B: -8.7 kcal/mol). The difference is negligible.

**Overall Assessment:**

Ligand B is the better candidate. While Ligand A has a slightly better QED, Ligand B excels in several key areas: lower DILI risk, significantly lower microsomal clearance (better metabolic stability), longer half-life, and lower P-gp efflux. The lower TPSA of Ligand A is a plus, but the other advantages of Ligand B outweigh this. The negative Caco-2 and solubility values are concerning for both, but the other ADME properties of Ligand B are more favorable.



Output:
1
2025-04-17 04:03:47,991 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (356.413 and 350.507 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (81.59) is higher than Ligand B (55.89). For a CNS target like DRD2, TPSA should ideally be <=90. Both are acceptable, but B is better.

**3. logP:** Ligand A (2.093) is within the optimal 1-3 range. Ligand B (0.776) is slightly below 1, which *could* indicate permeability issues, though not severely. A is better here.

**4. H-Bond Donors:** Ligand A (4) is acceptable, while Ligand B (1) is excellent.

**5. H-Bond Acceptors:** Both ligands have a reasonable number of HBA (A: 3, B: 4), well within the limit of 10.

**6. QED:** Both ligands have good QED scores (A: 0.547, B: 0.769), indicating drug-like properties. B is better.

**7. DILI:** Ligand A (27.685) and Ligand B (1.473) both have low DILI risk, with B being significantly lower. B is much better.

**8. BBB:** Ligand A (72.896) and Ligand B (83.87) both have good BBB penetration, but B is significantly better, exceeding 80%. This is a critical factor for a CNS target.

**9. Caco-2 Permeability:** Ligand A (-4.748) and Ligand B (-5.16) both have negative values, which is unusual. It suggests poor permeability.

**10. Aqueous Solubility:** Ligand A (-2.344) and Ligand B (-0.836) both have negative values, suggesting poor solubility.

**11. hERG Inhibition:** Both ligands show low hERG inhibition risk (A: 0.618, B: 0.55).

**12. Microsomal Clearance:** Ligand A (29.119) has higher clearance than Ligand B (1.396), indicating lower metabolic stability. B is better.

**13. In vitro Half-Life:** Ligand A (-5.925) and Ligand B (-5.754) both have negative values, which is unusual.

**14. P-gp Efflux:** Both ligands have low P-gp efflux (A: 0.285, B: 0.008), which is favorable for CNS penetration. B is better.

**15. Binding Affinity:** Ligand A (-8.6 kcal/mol) has a slightly better binding affinity than Ligand B (-7.6 kcal/mol). This is a 1.0 kcal/mol difference, which is significant.

**Overall Assessment:**

While Ligand A has a slightly better binding affinity, Ligand B consistently outperforms it in crucial ADME properties for a CNS-targeting GPCR. Specifically, Ligand B has a significantly better BBB score, lower DILI risk, lower microsomal clearance, and lower P-gp efflux. The slightly lower logP of Ligand B is a minor concern, but the substantial advantages in other areas outweigh this. The affinity difference, while noticeable, is not large enough to overcome the superior ADME profile of Ligand B.

Output:
1
2025-04-17 04:03:47,991 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (368.405 and 343.435 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (71.45) is significantly better than Ligand B (79.18). For CNS targets, we want TPSA <= 90, and A is closer to the optimal <= 60 range. B is pushing the upper limit.

**3. logP:** Ligand A (4.142) is higher than optimal (1-3). Ligand B (1.152) is a bit low, potentially hindering permeability. However, for a GPCR, a slightly higher logP can be tolerated if other properties are favorable.

**4. H-Bond Donors:** Ligand A (2) and Ligand B (1) are both acceptable (<=5).

**5. H-Bond Acceptors:** Ligand A (5) and Ligand B (7) are both acceptable (<=10).

**6. QED:** Both ligands (0.83 and 0.793) have good drug-likeness scores (>0.5).

**7. DILI:** Ligand A (93.37) has a significantly higher DILI risk than Ligand B (59.946). This is a major concern for Ligand A.

**8. BBB:** Ligand B (65.839) has a better BBB penetration percentile than Ligand A (50.64). While both are not ideal (>70 is preferred), B is closer. This is critical for a CNS target like DRD2.

**9. Caco-2 Permeability:** Both have negative values, which is unusual. Assuming these are logP-scale values, Ligand A (-4.897) has slightly better permeability than Ligand B (-5.169), but both are very poor.

**10. Aqueous Solubility:** Both have negative values, which is unusual. Assuming these are logS values, Ligand B (-1.72) has better solubility than Ligand A (-5.052).

**11. hERG Inhibition:** Ligand A (0.112) has a slightly higher hERG risk than Ligand B (0.47), but both are relatively low.

**12. Microsomal Clearance:** Ligand B (50.438) has a higher clearance than Ligand A (6.079), indicating lower metabolic stability.

**13. In vitro Half-Life:** Ligand A (28.108) has a much longer half-life than Ligand B (2.986).

**14. P-gp Efflux:** Ligand A (0.09) has lower P-gp efflux liability than Ligand B (0.026), which is favorable for CNS penetration.

**15. Binding Affinity:** Ligand A (-9.6 kcal/mol) has a significantly stronger binding affinity than Ligand B (0.0 kcal/mol). This is a substantial advantage.

**Overall Assessment:**

Ligand A has a much stronger binding affinity and better P-gp efflux, and longer half-life. However, its high DILI risk and lower BBB penetration are major drawbacks. Ligand B has a better safety profile (lower DILI) and better BBB penetration, but its binding affinity is extremely weak.

Considering the GPCR-specific priorities, the strong binding affinity of Ligand A is a significant advantage that *could* outweigh its other issues, *if* the DILI risk could be mitigated through structural modifications. However, the very weak binding of Ligand B makes it unlikely to be a viable starting point for drug development, even with better ADME properties.

Output:
1
2025-04-17 04:03:47,992 - INFO - Batch 81 complete. Total preferences: 1296
2025-04-17 04:03:47,992 - INFO - Processing batch 82/512...
2025-04-17 04:04:35,189 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (436.64 Da) is higher, but still acceptable. Ligand B (354.491 Da) is slightly lower, which could be beneficial for permeability.

**TPSA:** Ligand A (65.38) is better than Ligand B (89.87). For CNS targets, we want TPSA <= 90, so both are within range, but A is preferable.

**logP:** Ligand A (3.884) is optimal, while Ligand B (1.299) is a bit low. A logP between 1-3 is preferred, and B is at the lower end, potentially impacting permeability.

**H-Bond Donors/Acceptors:** Ligand A (HBD=1, HBA=5) is better than Ligand B (HBD=3, HBA=4). Both are within acceptable limits, but A has a lower HBD count.

**QED:** Both ligands have similar QED values (A: 0.742, B: 0.694), indicating good drug-like properties.

**DILI:** Ligand A (83.908) has a significantly higher DILI risk than Ligand B (10.585). This is a major concern for Ligand A.

**BBB:** Ligand A (89.027) has excellent BBB penetration, while Ligand B (63.086) is lower. For a CNS target like DRD2, this is a critical advantage for Ligand A.

**Caco-2 Permeability:** Ligand A (-4.468) has poor Caco-2 permeability, while Ligand B (-4.859) is also poor. Both are negative values, suggesting very low permeability.

**Aqueous Solubility:** Ligand A (-5.162) has poor aqueous solubility, while Ligand B (-1.66) is better. Solubility is important for formulation and bioavailability.

**hERG Inhibition:** Ligand A (0.645) has a slightly higher hERG risk than Ligand B (0.2). Lower is better.

**Microsomal Clearance:** Ligand A (46.871) has a moderate clearance, while Ligand B (4.699) has a very low clearance. This suggests better metabolic stability for Ligand B.

**In vitro Half-Life:** Ligand A (54.488) has a moderate half-life, while Ligand B (-8.51) has a very short half-life. This is a significant advantage for Ligand A.

**P-gp Efflux:** Ligand A (0.798) has moderate P-gp efflux, while Ligand B (0.037) has very low P-gp efflux. Lower P-gp efflux is better for CNS exposure, favoring Ligand B.

**Binding Affinity:** Ligand B (-8.2 kcal/mol) has a significantly stronger binding affinity than Ligand A (0.0 kcal/mol). This is a major advantage for Ligand B.

**Overall Assessment:**

Ligand A has a strong BBB penetration and a reasonable half-life, but suffers from high DILI risk, poor solubility, and very weak binding affinity. Ligand B has excellent metabolic stability, low P-gp efflux, and *much* stronger binding affinity, but has lower BBB penetration and a shorter half-life.

Given the importance of binding affinity for GPCRs, and the fact that the difference in affinity is substantial (>1.5 kcal/mol), Ligand B is the more promising candidate despite its lower BBB penetration. The strong binding is likely to outweigh the moderate BBB issue, and further optimization could address the BBB and half-life concerns. The high DILI risk of Ligand A is a significant red flag.

Output:
1
2025-04-17 04:04:35,190 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (349.475 and 340.427 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (78.51) is better than Ligand B (71.25). Both are below the 90 A^2 threshold for CNS targets, which is excellent.

**3. logP:** Ligand A (1.302) is within the optimal 1-3 range. Ligand B (2.515) is also acceptable, but slightly higher.

**4. H-Bond Donors:** Ligand A (2) and Ligand B (1) are both within the acceptable limit of <=5.

**5. H-Bond Acceptors:** Ligand A (3) and Ligand B (5) are both within the acceptable limit of <=10.

**6. QED:** Ligand B (0.928) has a significantly better QED score than Ligand A (0.759), indicating a more drug-like profile.

**7. DILI:** Ligand A (10.392) has a much lower DILI risk than Ligand B (47.15), which is a significant advantage.

**8. BBB:** Ligand A (70.997) has a better BBB penetration percentile than Ligand B (64.482). Both are reasonably good, but A is closer to the desirable >70 threshold for CNS targets.

**9. Caco-2:** Ligand A (-5.062) and Ligand B (-4.842) are both negative, indicating poor permeability. This is a concern for both, but doesn't heavily sway the decision given the CNS target.

**10. Solubility:** Ligand A (-1.961) and Ligand B (-2.536) both have negative solubility scores, which is concerning.

**11. hERG:** Both ligands have very low hERG inhibition risk (0.138 and 0.171, respectively).

**12. Cl_mic:** Ligand A (-6.955) has much lower microsomal clearance than Ligand B (18.982), suggesting better metabolic stability.

**13. t1/2:** Ligand A (-14.742) has a much longer in vitro half-life than Ligand B (2.568).

**14. Pgp:** Both ligands have very low P-gp efflux liability (0.013 and 0.16, respectively).

**15. Binding Affinity:** Ligand B (-9.4 kcal/mol) has a significantly stronger binding affinity than Ligand A (-7.5 kcal/mol). This is a substantial advantage, exceeding the 1.5 kcal/mol threshold.

**Overall Assessment:**

Ligand B has a superior binding affinity and a better QED score. However, Ligand A demonstrates significantly better ADMET properties, particularly regarding DILI risk, BBB penetration, metabolic stability (lower Cl_mic and longer t1/2). While the affinity difference is substantial, the improved safety and pharmacokinetic profile of Ligand A, crucial for CNS drug development, make it the more promising candidate. The slightly lower affinity can potentially be optimized in later stages of drug development.

Output:
0
2025-04-17 04:04:35,190 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B based on the provided guidelines, prioritizing GPCR-specific properties (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (349.391 and 348.531 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (122.28) is slightly above the optimal <90 for CNS targets, but still reasonable. Ligand B (58.2) is excellent, well below the threshold.

**logP:** Ligand A (-0.074) is quite low, potentially hindering permeability. Ligand B (4.27) is high, approaching the upper limit where solubility issues could arise, but still acceptable.

**H-Bond Donors/Acceptors:** Ligand A (3 HBD, 7 HBA) is within acceptable ranges. Ligand B (2 HBD, 2 HBA) is also good, potentially favoring permeability due to fewer hydrogen bonds.

**QED:** Both ligands have similar QED scores (0.582 and 0.508), indicating good drug-like properties.

**DILI:** Ligand A (35.169) has a slightly higher DILI risk than Ligand B (20.861), but both are below the concerning threshold of 60.

**BBB:** This is a critical parameter for a CNS target like DRD2. Ligand B (72.78) has a significantly better BBB percentile than Ligand A (11.439). This is a major advantage for Ligand B.

**Caco-2 Permeability:** Ligand A (-5.728) shows poor permeability. Ligand B (-4.702) is better, but still not ideal.

**Aqueous Solubility:** Ligand A (-1.038) has poor solubility. Ligand B (-4.283) has even worse solubility.

**hERG Inhibition:** Ligand A (0.105) has a very low hERG risk. Ligand B (0.619) has a slightly higher, but still acceptable, risk.

**Microsomal Clearance:** Ligand A (9.589) has lower clearance, suggesting better metabolic stability than Ligand B (66.252).

**In vitro Half-Life:** Ligand A (12.343) has a longer half-life than Ligand B (7.264).

**P-gp Efflux:** Ligand A (0.015) has very low P-gp efflux, which is favorable for CNS penetration. Ligand B (0.353) has moderate P-gp efflux.

**Binding Affinity:** Ligand B (-8.3) has a slightly better binding affinity than Ligand A (-7.9), although the difference is relatively small.

**Overall Assessment:**

Ligand B is the more promising candidate. While its solubility is poor, its significantly higher BBB penetration (72.78 vs. 11.439) is a decisive advantage for a CNS-targeting drug. The slightly better affinity of Ligand B further supports this conclusion. Ligand A's low logP and poor Caco-2 permeability are significant drawbacks. Although Ligand A has better metabolic stability and lower P-gp efflux, the BBB penetration of Ligand B is paramount for DRD2 targeting.

Output:
1
2025-04-17 04:04:35,190 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (353.482 and 348.531 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (52.65) is slightly higher than Ligand B (41.57). Both are below the 90 A^2 threshold for CNS targets, which is good. Ligand B is preferable here.

**3. logP:** Ligand A (1.964) and Ligand B (3.353) are both within the optimal 1-3 range. Ligand B is slightly better, being closer to the upper end of the range, which can aid in membrane permeability.

**4. H-Bond Donors:** Both ligands have 1 HBD, which is within the acceptable limit of <=5.

**5. H-Bond Acceptors:** Both ligands have 3 HBA, which is within the acceptable limit of <=10.

**6. QED:** Both ligands have QED values above 0.79, indicating good drug-likeness.

**7. DILI:** Ligand A (8.802%) has a slightly higher DILI risk than Ligand B (5.157%), but both are well below the concerning threshold of 40%.

**8. BBB:** Both ligands show excellent BBB penetration (Ligand A: 86.739%, Ligand B: 88.91%). This is crucial for a CNS target like DRD2. Ligand B is marginally better.

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.802 and -4.683). This is unusual and suggests poor intestinal absorption *in vitro*. However, this is less critical for a CNS target where direct delivery via BBB is prioritized.

**10. Aqueous Solubility:** Both ligands have very poor aqueous solubility (-2.523 and -2.565). This could pose formulation challenges, but is less critical given the good BBB penetration.

**11. hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.686 and 0.581).

**12. Microsomal Clearance:** Ligand A (23.923 mL/min/kg) has lower microsomal clearance than Ligand B (32.177 mL/min/kg), suggesting better metabolic stability.

**13. In vitro Half-Life:** Ligand A (-14.403 hours) has a negative half-life, which is not physically possible and indicates a problem with the data or the model. Ligand B (15.026 hours) has a reasonable half-life. This is a significant drawback for Ligand A.

**14. P-gp Efflux:** Both ligands have low P-gp efflux liability (0.031 and 0.125).

**15. Binding Affinity:** Ligand A (-8.6 kcal/mol) has a slightly better binding affinity than Ligand B (-7.7 kcal/mol). The difference is 0.9 kcal/mol, which is significant.

**Overall Assessment:**

While Ligand A has slightly better binding affinity and lower clearance, the negative in vitro half-life is a major red flag. This suggests a severe instability issue that would likely preclude further development. Ligand B, despite slightly weaker affinity, presents a much more favorable ADME profile, with a reasonable half-life, good BBB penetration, and acceptable DILI and hERG risks. The small difference in affinity can potentially be optimized later in the drug discovery process. Given the GPCR-specific priorities, the better overall profile of Ligand B makes it the more promising candidate.

Output:
1
2025-04-17 04:04:35,190 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (377.413 and 384.933 Da) fall within the ideal range of 200-500 Da.

**TPSA:** Ligand A (84.67) is better than Ligand B (60.25), both are below the 90 A^2 threshold for CNS targets.

**logP:** Ligand A (1.538) is within the optimal range (1-3), while Ligand B (3.686) is approaching the upper limit.

**H-Bond Donors:** Ligand A (1) is preferable to Ligand B (0) as it provides some hydrogen bonding potential.

**H-Bond Acceptors:** Both ligands have 6 HBA, which is acceptable (<=10).

**QED:** Ligand A (0.776) has a slightly better QED score than Ligand B (0.661), indicating better overall drug-likeness.

**DILI:** Ligand B (55.487) has a lower DILI risk than Ligand A (66.77), which is a positive attribute.

**BBB:** Ligand A (80.419) has significantly better BBB penetration than Ligand B (69.407). This is a crucial factor for a CNS target like DRD2.

**Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and suggests poor permeability. However, the scale is not specified, so it's difficult to interpret.

**Aqueous Solubility:** Both ligands have negative solubility values, indicating poor solubility.

**hERG Inhibition:** Ligand A (0.172) has a much lower hERG inhibition liability than Ligand B (0.632), which is a significant safety advantage.

**Microsomal Clearance:** Ligand B (69.502) has higher microsomal clearance than Ligand A (37.449), indicating faster metabolism and potentially lower exposure.

**In vitro Half-Life:** Ligand B (52.923) has a longer in vitro half-life than Ligand A (12.21), which is generally desirable.

**P-gp Efflux:** Ligand A (0.073) has much lower P-gp efflux liability than Ligand B (0.728), which is important for CNS penetration.

**Binding Affinity:** Ligand A (-8.3 kcal/mol) has a significantly stronger binding affinity than Ligand B (-6.3 kcal/mol). This is a substantial advantage, potentially outweighing some of the ADME drawbacks.

**Overall Assessment:**

Ligand A is the better candidate. While Ligand B has a slightly lower DILI risk and a longer half-life, Ligand A excels in the most critical areas for a CNS-targeting GPCR ligand: significantly better BBB penetration, much lower P-gp efflux, a much stronger binding affinity, and lower hERG inhibition. The better TPSA and QED scores also contribute to its favorability. The poor solubility and permeability are concerns for both, but the strong affinity of Ligand A suggests it might be able to overcome these issues.

Output:
1
2025-04-17 04:04:35,190 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (366.315 and 357.426 Da) fall within the ideal range of 200-500 Da.

**TPSA:** Ligand A (87.32) is better than Ligand B (98.74). Both are below the 90 A^2 threshold for CNS targets, but A is closer to the ideal.

**logP:** Ligand A (1.348) is within the optimal range (1-3). Ligand B (-0.022) is slightly below 1, which *could* hinder permeation, though not drastically.

**H-Bond Donors/Acceptors:** Ligand A (2 HBD, 4 HBA) and Ligand B (3 HBD, 4 HBA) both have acceptable numbers, well below the limits of 5 and 10 respectively.

**QED:** Ligand A (0.744) has a better QED score than Ligand B (0.532), indicating a more drug-like profile.

**DILI:** Ligand B (45.25) has a significantly lower DILI risk than Ligand A (59.946), which is a substantial advantage.

**BBB:** Ligand A (64.25) has a slightly better BBB percentile than Ligand B (47.809), but both are below the desirable >70 for CNS targets. This is a critical factor, and neither is ideal.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.9 and -4.749), which is unusual and suggests poor permeability. This is concerning for both.

**Aqueous Solubility:** Both have negative solubility values (-2.453 and -1.751) which is also concerning.

**hERG:** Both ligands have low hERG inhibition risk (0.412 and 0.493).

**Microsomal Clearance:** Ligand A (-4.792) has a *much* lower (better) microsomal clearance than Ligand B (40.732), indicating greater metabolic stability.

**In vitro Half-Life:** Ligand A (-26.919) has a longer in vitro half-life than Ligand B (-31.209), which is preferable.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.045 and 0.216).

**Binding Affinity:** Ligand B (-7.2 kcal/mol) has a slightly better binding affinity than Ligand A (-8.1 kcal/mol). While A is better, the difference is not substantial enough to overcome other issues.

**Overall Assessment:**

Ligand A has advantages in TPSA, QED, metabolic stability (Cl_mic and t1/2), and a slightly better BBB score. However, Ligand B has a significantly lower DILI risk and a slightly better binding affinity. Both have poor Caco-2 and solubility. Given the importance of BBB penetration for a CNS target like DRD2, and the relatively small difference in binding affinity, Ligand A is slightly favored due to its better metabolic stability and slightly better BBB. However, the poor Caco-2 and solubility are major drawbacks for both.

Output:
1
2025-04-17 04:04:35,190 - INFO - Okay, let's analyze these two ligands for their potential as DRD2 drug candidates. DRD2 is a GPCR in the CNS, so BBB penetration, logP, Pgp efflux, TPSA, and binding affinity are paramount.

**Ligand A: [368.349, 85.25, 2.491, 2, 5, 0.581, 68.244, 63.203, -4.972, -2.944, 0.335, 58.803, 29.802, 0.26, -8.2]**

*   **MW:** 368.349 Da - Acceptable.
*   **TPSA:** 85.25 - Acceptable, but pushing the upper limit for CNS targets.
*   **logP:** 2.491 - Excellent.
*   **HBD:** 2 - Good.
*   **HBA:** 5 - Good.
*   **QED:** 0.581 - Good, drug-like.
*   **DILI:** 68.244 - Moderate risk, but not alarming.
*   **BBB:** 63.203 - Acceptable, but could be better for a CNS target.
*   **Caco-2:** -4.972 - Poor permeability.
*   **Solubility:** -2.944 - Poor solubility.
*   **hERG:** 0.335 - Low risk.
*   **Cl_mic:** 58.803 - Moderate clearance.
*   **t1/2:** 29.802 - Moderate half-life.
*   **Pgp:** 0.26 - Low efflux, good.
*   **Affinity:** -8.2 kcal/mol - Excellent.

**Ligand B: [346.515, 49.41, 3.239, 1, 2, 0.542, 32.842, 64.715, -4.569, -3.692, 0.621, 63.321, -14.445, 0.2, -7.6]**

*   **MW:** 346.515 Da - Acceptable.
*   **TPSA:** 49.41 - Excellent for CNS penetration.
*   **logP:** 3.239 - Excellent.
*   **HBD:** 1 - Good.
*   **HBA:** 2 - Good.
*   **QED:** 0.542 - Good, drug-like.
*   **DILI:** 32.842 - Very low risk.
*   **BBB:** 64.715 - Acceptable, similar to Ligand A.
*   **Caco-2:** -4.569 - Poor permeability.
*   **Solubility:** -3.692 - Poor solubility.
*   **hERG:** 0.621 - Moderate risk.
*   **Cl_mic:** 63.321 - Moderate clearance.
*   **t1/2:** -14.445 - Very short half-life, a significant drawback.
*   **Pgp:** 0.2 - Low efflux, good.
*   **Affinity:** -7.6 kcal/mol - Very good, but not as strong as Ligand A.

**Comparison and Decision:**

Both ligands have poor Caco-2 permeability and solubility, which would require formulation strategies to address. However, Ligand A has a significantly stronger binding affinity (-8.2 vs -7.6 kcal/mol).  This 1.6 kcal/mol difference is substantial and can often outweigh minor ADME deficiencies, especially for a GPCR where high affinity is critical. While Ligand B has a slightly better DILI score and TPSA, the much shorter in vitro half-life (-14.445 hours) is a major concern.  A short half-life translates to frequent dosing and potentially lower overall exposure. Ligand A's moderate half-life (29.802 hours) is much more favorable.

Considering the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity), and the substantial affinity advantage of Ligand A, it is the more promising drug candidate.

1
2025-04-17 04:04:35,191 - INFO - Reasoning:

Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (365.813 and 346.515 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (77.02) is higher than the optimal <90 for CNS targets, but still reasonable. Ligand B (49.41) is excellent, well below 90.

**3. logP:** Both ligands have good logP values (3.428 and 3.809), falling within the 1-3 range.

**4. H-Bond Donors:** Ligand A (2) and Ligand B (1) are both within the acceptable limit of <=5.

**5. H-Bond Acceptors:** Ligand A (5) and Ligand B (2) are both within the acceptable limit of <=10.

**6. QED:** Both ligands have similar and good QED values (0.786 and 0.795), indicating good drug-like properties.

**7. DILI:** Ligand A (71.656) has a higher DILI risk than Ligand B (29.042). This is a significant negative for Ligand A.

**8. BBB:** Ligand B (73.362) has a much better BBB penetration percentile than Ligand A (46.413). This is *critical* for a CNS target like DRD2.

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 values, which is unusual and suggests a potential issue with the data or modeling. However, the values are similar (-4.739 vs -4.624).

**10. Aqueous Solubility:** Both ligands have negative solubility values, again unusual. The values are similar (-3.926 vs -3.668).

**11. hERG Inhibition:** Both ligands have low hERG inhibition risk (0.588 and 0.405).

**12. Microsomal Clearance:** Ligand A (27.587) has lower microsomal clearance than Ligand B (70.678), suggesting better metabolic stability.

**13. In vitro Half-Life:** Ligand B (-8.86) has a significantly *longer* in vitro half-life than Ligand A (26.174). This is a strong positive for Ligand B.

**14. P-gp Efflux:** Ligand A (0.55) has slightly higher P-gp efflux than Ligand B (0.404), meaning Ligand B is less likely to be pumped out of the brain.

**15. Binding Affinity:** Ligand B (-9.1) has a slightly better (more negative) binding affinity than Ligand A (-8.3). While the difference is not huge, it's still a factor.

**Overall Assessment:**

Ligand B is the superior candidate. While Ligand A has better metabolic stability (lower Cl_mic), Ligand B excels in the most critical areas for a CNS GPCR target: BBB penetration, lower DILI risk, and a longer half-life. The slightly better binding affinity of Ligand B further strengthens its position. The negative values for Caco-2 and solubility are concerning for both, but the other factors heavily favor Ligand B.

Output:
1
2025-04-17 04:04:35,191 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (356.419 and 351.447 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (105.17) is slightly higher than Ligand B (98.74). Both are below the 140 A^2 threshold for oral absorption and reasonably close to the <90 A^2 target for CNS penetration, but Ligand B is preferable.

**3. logP:** Ligand A (-0.167) is slightly below the optimal 1-3 range, potentially hindering permeability. Ligand B (0.171) is also low, but marginally better. This is a weakness for both, but less critical given the other parameters.

**4. H-Bond Donors:** Ligand A (2) and Ligand B (3) are both acceptable, being less than 5.

**5. H-Bond Acceptors:** Ligand A (6) and Ligand B (4) are both acceptable, being less than 10.

**6. QED:** Both ligands have acceptable QED scores (0.663 and 0.58), indicating good drug-like properties.

**7. DILI:** Ligand A (30.322) has a significantly lower DILI risk than Ligand B (12.796), which is a substantial advantage.

**8. BBB:** Ligand A (41.45) has a better BBB penetration percentile than Ligand B (35.052). While neither is above the desirable >70, A is better.

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.052 and -5.157), which is unusual and suggests poor permeability. This is a significant concern for both.

**10. Aqueous Solubility:** Both ligands have negative solubility values (-1.014 and -1.8), indicating very poor aqueous solubility. This is a major drawback for both.

**11. hERG Inhibition:** Both ligands have low hERG inhibition risk (0.092 and 0.086).

**12. Microsomal Clearance:** Ligand A (18.332) has a higher microsomal clearance than Ligand B (13.551), indicating lower metabolic stability.

**13. In vitro Half-Life:** Ligand B (11.524) has a significantly longer in vitro half-life than Ligand A (0.42), which is a major advantage.

**14. P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.022 and 0.02).

**15. Binding Affinity:** Ligand B (-8.1 kcal/mol) has a significantly stronger binding affinity than Ligand A (-7.1 kcal/mol) - a difference of 1.0 kcal/mol. This is a substantial advantage that can outweigh some of the ADME drawbacks.

**Overall Assessment:**

Ligand B is the better candidate. While both have issues with solubility and Caco-2 permeability, Ligand B's significantly improved binding affinity (-8.1 vs -7.1 kcal/mol) and longer half-life are critical advantages for a GPCR target. The lower DILI risk of Ligand A is appealing, but the affinity difference is more impactful. The slightly better BBB for Ligand A is overshadowed by the stronger binding of B.

Output:
1
2025-04-17 04:04:35,191 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (362.5 and 349.4 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (83.98) is better than Ligand B (89.35). Both are below the 90 A^2 threshold desirable for CNS targets, but A is closer to the optimal range.

**3. logP:** Ligand A (2.06) is better than Ligand B (0.761). Both are within the 1-3 range, but ligand B is closer to the lower limit, which could hinder permeability.

**4. H-Bond Donors:** Ligand A (2) is slightly better than Ligand B (1). Both are within the acceptable limit of <=5.

**5. H-Bond Acceptors:** Ligand A (5) is slightly worse than Ligand B (6). Both are within the acceptable limit of <=10.

**6. QED:** Both ligands have good QED scores (0.741 and 0.848), indicating good drug-like properties.

**7. DILI:** Both ligands have similar DILI risk (45.3 and 48.6 percentile), which is acceptable (below 60).

**8. BBB:** Ligand B (51.2%) is slightly better than Ligand A (46.5%). While neither is above the desirable 70% threshold, B is closer. This is a critical parameter for CNS targets like DRD2.

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.325 and -5.068), which is unusual and suggests poor permeability. This is a significant drawback for both.

**10. Aqueous Solubility:** Both ligands have negative solubility values (-2.746 and -1.711), indicating very poor aqueous solubility. This is a major issue for formulation and bioavailability.

**11. hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.078 and 0.096 percentile), which is excellent.

**12. Microsomal Clearance:** Ligand A (14.0) has lower microsomal clearance than Ligand B (17.5), indicating better metabolic stability.

**13. In vitro Half-Life:** Ligand A (13.86) has a slightly longer half-life than Ligand B (12.91), which is preferable.

**14. P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.12 and 0.019 percentile), which is excellent for CNS penetration.

**15. Binding Affinity:** Both ligands have very similar and strong binding affinities (-8.5 and -8.3 kcal/mol). The difference is negligible.

**Overall Assessment:**

Despite the similar binding affinities, Ligand A is slightly more favorable. It has a better TPSA, logP, metabolic stability (lower Cl_mic), and half-life. While Ligand B has a slightly better BBB score, the other advantages of Ligand A outweigh this difference. Both compounds suffer from poor predicted permeability and solubility, which are significant liabilities. However, given the strong binding affinity and the focus on CNS penetration for DRD2, optimizing Ligand A to improve its solubility and permeability would be a more promising path than optimizing Ligand B.

Output:
0
2025-04-17 04:04:35,191 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 drug candidates, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (348.403 Da) is slightly lower, which could be beneficial for permeability.

**TPSA:** Ligand A (87.95) is better than Ligand B (51.66) as it is closer to the optimal range for CNS targets (<=90). Ligand B is quite low, which might indicate issues with solubility.

**logP:** Ligand A (1.689) is within the optimal range (1-3). Ligand B (3.763) is at the higher end, potentially leading to solubility issues or off-target interactions, but still acceptable.

**H-Bond Donors/Acceptors:** Ligand A has 1 HBD and 5 HBA, while Ligand B has 0 HBD and 6 HBA. Both are within acceptable limits.

**QED:** Both ligands have good QED scores (A: 0.663, B: 0.813), indicating good drug-like properties.

**DILI:** Ligand A (49.283) has a lower DILI risk than Ligand B (66.615), which is a significant advantage.

**BBB:** Ligand B (85.77) has a significantly better BBB penetration score than Ligand A (59.868). This is a critical factor for a CNS target like DRD2.

**Caco-2 Permeability:** Both have negative values, which is unusual and suggests a potential issue with the data or modeling. However, the magnitude of negativity is similar.

**Aqueous Solubility:** Both ligands have negative solubility values, which is also unusual. Ligand A (-1.624) is slightly better than Ligand B (-3.696).

**hERG Inhibition:** Both ligands have very low hERG inhibition risk (A: 0.397, B: 0.326).

**Microsomal Clearance:** Ligand A (4.137) has a much lower microsomal clearance than Ligand B (64.932), indicating better metabolic stability.

**In vitro Half-Life:** Ligand A (7.955) has a longer half-life than Ligand B (4.935).

**P-gp Efflux:** Ligand A (0.037) has significantly lower P-gp efflux liability than Ligand B (0.442), which is crucial for CNS penetration.

**Binding Affinity:** Ligand B (-8.8 kcal/mol) has a slightly better binding affinity than Ligand A (-9.3 kcal/mol). While this difference is small, it's a positive for Ligand B.

**Overall Assessment:**

Ligand A excels in metabolic stability (low Cl_mic, longer t1/2), lower DILI risk, and lower P-gp efflux. Ligand B shines with its superior BBB penetration and slightly better binding affinity. Given the CNS target (DRD2), BBB penetration is paramount. While Ligand A has better ADME properties overall, the significantly better BBB score of Ligand B outweighs these advantages. The affinity difference is small enough that it is unlikely to be a deciding factor.

Output:
1
2025-04-17 04:04:35,191 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (364.406 and 365.539 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (93.84) is better than Ligand B (38.77). For CNS targets, TPSA should be <= 90, so Ligand A is preferable.

**3. logP:** Ligand B (3.902) is closer to the optimal range (1-3) than Ligand A (0.731). A logP below 1 can hinder permeation.

**4. H-Bond Donors:** Ligand A (2) is reasonable, while Ligand B (0) is also acceptable.

**5. H-Bond Acceptors:** Ligand A (7) is reasonable, while Ligand B (4) is also acceptable.

**6. QED:** Ligand A (0.816) has a better QED score than Ligand B (0.59), indicating a more drug-like profile.

**7. DILI:** Ligand A (75.262) has a higher DILI risk than Ligand B (16.751). This is a significant drawback for Ligand A.

**8. BBB:** Ligand B (77.937) has a better BBB penetration score than Ligand A (68.941), which is crucial for a CNS target like DRD2.

**9. Caco-2 Permeability:** Ligand A (-5.257) has poor Caco-2 permeability, while Ligand B (-4.522) is slightly better, but both are quite poor.

**10. Aqueous Solubility:** Both ligands have very poor aqueous solubility (-3.223 and -4.032 respectively).

**11. hERG Inhibition:** Ligand A (0.158) has a lower hERG inhibition liability than Ligand B (0.812), which is favorable.

**12. Microsomal Clearance:** Ligand B (140.273) has significantly higher microsomal clearance than Ligand A (6.454), meaning Ligand A is more metabolically stable.

**13. In vitro Half-Life:** Both ligands have similar in vitro half-lives (5.125 and 5.129 hours).

**14. P-gp Efflux:** Ligand A (0.061) has much lower P-gp efflux liability than Ligand B (0.707), which is highly desirable for CNS penetration.

**15. Binding Affinity:** Ligand A (-8.0) has a significantly stronger binding affinity than Ligand B (-6.9). A 1.1 kcal/mol difference is substantial and can outweigh some ADME drawbacks.

**Overall Assessment:**

Ligand A has a much stronger binding affinity and better metabolic stability (lower Cl_mic, lower Pgp efflux). However, it has a higher DILI risk, poorer BBB penetration, and poor Caco-2 permeability. Ligand B has better BBB penetration, lower DILI risk, and a more optimal logP, but its binding affinity is considerably weaker.

Given the importance of CNS penetration for a DRD2 target, and the substantial affinity difference, the stronger affinity of Ligand A is likely to be more important. The lower Pgp efflux also supports better CNS exposure. While the DILI risk is a concern, it might be mitigated through structural modifications during lead optimization. The poor solubility and Caco-2 permeability are also areas for improvement, but are less critical than affinity and CNS penetration at this stage.

Output:
1
2025-04-17 04:04:35,191 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 drug candidates, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (342.483 and 346.471 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (40.62) is significantly better than Ligand B (70.59). For CNS targets, we want TPSA <= 90, and ideally closer to 60. Ligand A is much closer to this ideal. Ligand B is higher and may have reduced brain penetration.

**3. logP:** Both ligands have good logP values (3.26 and 3.065), falling within the optimal range of 1-3.

**4. H-Bond Donors:** Ligand A (0) is preferable to Ligand B (3). Fewer HBDs generally improve permeability.

**5. H-Bond Acceptors:** Both ligands have 3 HBA, which is acceptable.

**6. QED:** Both ligands have similar QED values (0.825 and 0.785), indicating good drug-likeness.

**7. DILI:** Ligand A (8.414) has a much lower DILI risk than Ligand B (30.671). This is a significant advantage for Ligand A.

**8. BBB:** Ligand A (82.862) has a better BBB percentile than Ligand B (78.054), though both are reasonably good. Given DRD2 is a CNS target, maximizing BBB penetration is crucial.

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.793 and -4.789). This is unusual and requires further investigation, but it's similar for both.

**10. Aqueous Solubility:** Both ligands have negative solubility values (-2.187 and -2.663). Similar to Caco-2, this is unusual and requires further investigation.

**11. hERG Inhibition:** Both ligands have low hERG inhibition risk (0.806 and 0.529).

**12. Microsomal Clearance:** Ligand A (14.502) has a lower microsomal clearance than Ligand B (19.044), suggesting better metabolic stability.

**13. In vitro Half-Life:** Ligand A (-25.211) has a much longer in vitro half-life than Ligand B (13.654). This is a significant advantage.

**14. P-gp Efflux:** Ligand A (0.371) has lower P-gp efflux liability than Ligand B (0.364), indicating better potential for CNS exposure.

**15. Binding Affinity:** Ligand B (-9.5) has a slightly better binding affinity than Ligand A (-8.9). However, the difference is only 0.6 kcal/mol, which is less impactful than the significant ADME advantages of Ligand A.

**Overall:**

Ligand A is the superior candidate. While Ligand B has a slightly better binding affinity, Ligand A demonstrates significantly better ADME properties, particularly lower DILI risk, better BBB penetration, improved metabolic stability (lower Cl_mic and longer t1/2), and lower P-gp efflux. These factors are crucial for a CNS-targeting GPCR like DRD2. The negative Caco-2 and solubility values are concerning for both, but the overall profile of A is more favorable.

Output:
1
2025-04-17 04:04:35,191 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 drug candidates, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (361.383 Da) and Ligand B (342.527 Da) are both acceptable.

**TPSA:** Ligand A (110.8) is borderline for CNS penetration, being above the preferred <90. Ligand B (32.34) is excellent, well below 90, indicating good potential for CNS penetration.

**logP:** Both ligands have logP values within the optimal range (1-3). Ligand A (2.943) and Ligand B (3.584) are both good.

**H-Bond Donors/Acceptors:** Ligand A has 2 HBD and 7 HBA, which are acceptable. Ligand B has 1 HBD and 2 HBA, also acceptable.

**QED:** Both ligands have good QED scores (Ligand A: 0.536, Ligand B: 0.717), suggesting good drug-like properties. Ligand B is slightly better.

**DILI:** Both ligands have high DILI risk (Ligand A: 98.216, Ligand B: 9.771). However, Ligand B is *significantly* lower, indicating a much lower risk of liver injury. This is a major advantage for Ligand B.

**BBB:** Ligand A has a BBB percentile of 39.511, which is below the desirable >70 for CNS targets. Ligand B has a BBB percentile of 91.314, which is excellent.

**Caco-2 Permeability:** Both have negative Caco-2 values (-4.919 and -4.975). This is unusual and suggests poor permeability. However, these values are on a scale where negative values are possible and don't necessarily preclude development.

**Aqueous Solubility:** Both have negative solubility values (-4.169 and -4.798). Similar to Caco-2, these are on a scale where negative values are possible.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (Ligand A: 0.616, Ligand B: 0.893).

**Microsomal Clearance:** Both have similar microsomal clearance values (Ligand A: 56.769, Ligand B: 57.809), suggesting similar metabolic stability.

**In vitro Half-Life:** Both have similar in vitro half-lives (Ligand A: 5.225, Ligand B: 5.157).

**P-gp Efflux:** Both ligands show low P-gp efflux liability (Ligand A: 0.367, Ligand B: 0.363).

**Binding Affinity:** Ligand A has a significantly better binding affinity (-8.9 kcal/mol) compared to Ligand B (-7.4 kcal/mol). This is a substantial difference (1.5 kcal/mol), and a strong advantage for Ligand A.

**Overall Assessment:**

Ligand A has a much stronger binding affinity, which is a critical factor for GPCRs. However, Ligand B has a significantly better safety profile (much lower DILI risk) and superior BBB penetration, both crucial for a CNS-targeting drug. The TPSA of Ligand B is also much more favorable. While the Caco-2 and solubility values are concerning for both, the large affinity difference for Ligand A might overcome these issues. Considering the GPCR-specific priorities, the superior BBB penetration and lower DILI risk of Ligand B are very important. The 1.5 kcal/mol affinity difference is significant, but not insurmountable, and can potentially be addressed through further optimization.

Output:
1
2025-04-17 04:04:35,192 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (355.459 and 358.389 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (46.61) is significantly better than Ligand B (87.46). For CNS targets, we want TPSA <= 90, and ideally closer to 60. Ligand A is well within the desirable range, while Ligand B is approaching the upper limit and could hinder BBB penetration.

**3. logP:** Ligand A (3.295) is optimal (1-3), while Ligand B (0.774) is slightly low, potentially impacting permeability.

**4. H-Bond Donors:** Ligand A (0) is preferable to Ligand B (2). Fewer HBDs generally improve permeability.

**5. H-Bond Acceptors:** Ligand A (4) is better than Ligand B (5). Lower is generally better for permeability.

**6. QED:** Both ligands have similar QED values (0.794 and 0.672), both above the 0.5 threshold, indicating good drug-like properties.

**7. DILI:** Ligand A (56.844) has a higher DILI risk than Ligand B (20.706). This is a drawback for Ligand A, but not a dealbreaker if other properties are significantly better.

**8. BBB:** Ligand A (77.511) has a significantly higher BBB penetration percentile than Ligand B (67.235). This is *critical* for a CNS target like DRD2.

**9. Caco-2:** Ligand A (-4.733) and Ligand B (-4.61) both have negative Caco-2 values, which is unusual and suggests poor permeability. However, these values are very close and not a major differentiator.

**10. Solubility:** Ligand A (-4.087) and Ligand B (-1.004) both have negative solubility values. Ligand B is better here, but both are poor.

**11. hERG:** Both ligands have low hERG inhibition liability (0.457 and 0.267), which is good.

**12. Cl_mic:** Ligand A (121.046) has a higher microsomal clearance than Ligand B (7.776). This means Ligand B is more metabolically stable, which is desirable.

**13. t1/2:** Ligand A (12.645) has a longer in vitro half-life than Ligand B (-33.446). This is a significant advantage for Ligand A.

**14. Pgp:** Ligand A (0.644) has lower P-gp efflux liability than Ligand B (0.031). Lower Pgp efflux is crucial for CNS penetration.

**15. Binding Affinity:** Both ligands have very similar binding affinities (-8.4 and -7.4 kcal/mol). Ligand A is slightly better, but the difference is not substantial enough to outweigh other factors.

**Overall Assessment:**

Ligand A excels in the critical areas for a CNS GPCR target: TPSA, logP, BBB penetration, and Pgp efflux. While its DILI risk is higher and its metabolic stability is lower, the superior CNS penetration profile and slightly better affinity make it the more promising candidate. Ligand B's lower DILI and better metabolic stability are offset by its poorer TPSA, logP, and BBB penetration.

Output:
0
2025-04-17 04:04:35,192 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (350.394 and 388.53 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (67.67) is better than Ligand B (49.85) as it is closer to the <90 A^2 threshold for CNS targets.

**logP:** Ligand A (0.704) is a bit low, potentially hindering permeation, while Ligand B (2.637) is within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Both have 0 HBD and 5 HBA, which are acceptable.

**QED:** Both ligands have similar QED values (0.784 and 0.752), indicating good drug-likeness.

**DILI:** Ligand A (38.736) has a significantly lower DILI risk than Ligand B (58.434), which is a positive attribute.

**BBB:** Both ligands have excellent BBB penetration (90.617 and 88.678), exceeding the desirable >70 threshold for CNS targets.

**Caco-2 Permeability:** Both have negative Caco-2 values which is unusual and difficult to interpret.

**Aqueous Solubility:** Both have negative solubility values which is also unusual and difficult to interpret.

**hERG:** Ligand A (0.286) shows a much lower hERG inhibition liability than Ligand B (0.605), which is a significant advantage.

**Microsomal Clearance:** Ligand A (5.655) has a much lower microsomal clearance than Ligand B (76.861), suggesting better metabolic stability.

**In vitro Half-Life:** Both ligands have similar in vitro half-lives (9.31 and 9.349 hours).

**P-gp Efflux:** Ligand A (0.05) has significantly lower P-gp efflux liability than Ligand B (0.519), which is crucial for CNS exposure.

**Binding Affinity:** Ligand A (-8.2 kcal/mol) has a substantially stronger binding affinity than Ligand B (-6.9 kcal/mol). This >1.5 kcal/mol difference is a major advantage, potentially outweighing some of the less ideal ADME properties.

**Overall Assessment:**

Ligand A is the superior candidate. While its logP is slightly low, its significantly better binding affinity, lower DILI risk, lower hERG inhibition, lower P-gp efflux, and lower microsomal clearance outweigh this minor drawback. The excellent BBB penetration is shared by both, but the other factors strongly favor Ligand A.

Output:
1
2025-04-17 04:04:35,192 - INFO - Batch 82 complete. Total preferences: 1312
2025-04-17 04:04:35,192 - INFO - Processing batch 83/512...
2025-04-17 04:05:29,182 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (353.419 and 352.463 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (96.97) is better than Ligand B (57.95). For CNS targets, TPSA should be <= 90, so Ligand A is close to the limit, while Ligand B is well within the desired range.

**3. logP:** Ligand B (4.166) is higher than Ligand A (0.121). While optimal logP is 1-3, Ligand B is slightly above, potentially causing solubility issues. Ligand A is significantly low, which may hinder permeation.

**4. H-Bond Donors:** Ligand A (2) is slightly higher than Ligand B (1), but both are within the acceptable limit of <=5.

**5. H-Bond Acceptors:** Both ligands have 5 HBA, which is within the acceptable limit of <=10.

**6. QED:** Ligand A (0.678) has a better QED score than Ligand B (0.542), indicating a more drug-like profile.

**7. DILI:** Ligand A (33.307) has a significantly lower DILI risk than Ligand B (52.772), which is a major advantage. Both are below the 60 threshold, but A is preferred.

**8. BBB:** Ligand A (78.945) has a better BBB penetration percentile than Ligand B (68.903). Both are reasonably good, but for a CNS target like DRD2, higher BBB is preferred.

**9. Caco-2 Permeability:** Ligand A (-4.783) has worse Caco-2 permeability than Ligand B (-5.806). Lower values indicate poorer permeability.

**10. Aqueous Solubility:** Ligand A (-1.832) has better aqueous solubility than Ligand B (-3.004).

**11. hERG Inhibition:** Ligand A (0.198) has a lower hERG inhibition liability than Ligand B (0.882), which is a significant safety advantage.

**12. Microsomal Clearance:** Ligand B (49.639) has a lower microsomal clearance than Ligand A (16.918), suggesting better metabolic stability.

**13. In vitro Half-Life:** Ligand B (23.851) has a longer in vitro half-life than Ligand A (-20.584), which is desirable.

**14. P-gp Efflux:** Ligand A (0.015) has a much lower P-gp efflux liability than Ligand B (0.533), which is crucial for CNS penetration.

**15. Binding Affinity:** Ligand B (-8.3) has a slightly better binding affinity than Ligand A (-7.7). This is a 1.5 kcal/mol difference, which is significant.

**Overall Assessment:**

Ligand B has a better binding affinity and metabolic stability (lower Cl_mic, longer t1/2). However, Ligand A excels in crucial areas for CNS drug development: lower DILI risk, better BBB penetration, lower hERG inhibition, and significantly lower P-gp efflux. The lower logP of Ligand A is a concern, but the superior CNS properties and safety profile outweigh this drawback, especially given the relatively modest affinity difference. The TPSA of ligand A is slightly higher, but still acceptable.

Output:
0
2025-04-17 04:05:29,182 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight (MW):** Both ligands (354.491 and 355.435 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (78.87) is better than Ligand B (80.34), both are below the 90 A^2 threshold for CNS targets, but A is closer to the optimal range.

**3. logP:** Ligand A (1.848) is within the optimal 1-3 range. Ligand B (-0.914) is slightly below 1, which *could* hinder permeation, though not drastically.

**4. H-Bond Donors (HBD):** Both ligands have acceptable HBD counts (2 and 1 respectively), well below the 5 limit.

**5. H-Bond Acceptors (HBA):** Both ligands have acceptable HBA counts (4 and 6 respectively), below the 10 limit.

**6. QED:** Both ligands have similar QED values (0.697 and 0.637), indicating good drug-like properties.

**7. DILI:** Ligand A (6.592) has a significantly lower DILI risk than Ligand B (23.963). This is a substantial advantage for Ligand A.

**8. BBB:** Ligand B (47.654) has a better BBB penetration percentile than Ligand A (40.093). While neither are *excellent* (>70), B is better. This is a critical parameter for a CNS target like DRD2.

**9. Caco-2:** Ligand A (-4.576) has a worse Caco-2 permeability than Ligand B (-5.02). Lower values indicate poorer absorption.

**10. Solubility:** Ligand A (-1.17) has slightly better solubility than Ligand B (-0.592).

**11. hERG:** Both ligands have very low hERG inhibition risk (0.243 and 0.128), which is excellent.

**12. Cl_mic:** Ligand B (-18.924) has a much lower (better) microsomal clearance than Ligand A (19.334). Lower clearance suggests greater metabolic stability.

**13. t1/2:** Ligand B (22.477) has a longer in vitro half-life than Ligand A (8.822). This is a significant advantage.

**14. Pgp:** Both ligands have very low P-gp efflux liability (0.022 and 0.005), which is excellent.

**15. Binding Affinity:** Both ligands have very similar and strong binding affinities (-7.2 and -7.0 kcal/mol). The difference is negligible.

**Overall Assessment:**

Ligand B has advantages in BBB penetration, metabolic stability (Cl_mic), and in vitro half-life. However, Ligand A has a significantly lower DILI risk and a slightly better logP and TPSA. Given the importance of minimizing toxicity (DILI) and achieving CNS penetration for a DRD2 target, and the similar binding affinities, Ligand A is the slightly more promising candidate. The better logP and TPSA of Ligand A also contribute to better predicted CNS penetration.

Output:
1
2025-04-17 04:05:29,182 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 drug candidates, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (350.438 and 349.475 Da) fall comfortably within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (83.12) is slightly higher than Ligand B (78.51), but both are below the 90 A^2 threshold desirable for CNS targets.

**3. logP:** Ligand A (2.275) and Ligand B (1.636) are both within the optimal 1-3 range. Ligand B is slightly lower, which *could* indicate slightly reduced permeability, but it's not a major concern.

**4. H-Bond Donors:** Ligand A (3) and Ligand B (2) are both acceptable, being less than or equal to 5.

**5. H-Bond Acceptors:** Ligand A (4) and Ligand B (3) are both acceptable, being less than or equal to 10.

**6. QED:** Both ligands have similar QED values (0.672 and 0.654), indicating good drug-like properties.

**7. DILI:** Ligand A (49.864) has a higher DILI risk than Ligand B (21.908). This is a significant advantage for Ligand B.

**8. BBB:** Ligand A (77.976) has a substantially better BBB penetration percentile than Ligand B (60.954). This is *critical* for a CNS target like DRD2.

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.925 and -4.863). This is unusual and suggests poor permeability, but the scale is not specified, so it's difficult to interpret.

**10. Aqueous Solubility:** Both ligands have negative solubility values (-3.277 and -2.057). Similar to Caco-2, the scale is unclear, making interpretation difficult.

**11. hERG Inhibition:** Ligand A (0.526) shows slightly higher hERG inhibition liability than Ligand B (0.148). Lower is better, so Ligand B is preferred.

**12. Microsomal Clearance:** Ligand A (13.962) has lower microsomal clearance than Ligand B (54.579), indicating better metabolic stability.

**13. In vitro Half-Life:** Ligand A (11.506) has a longer half-life than Ligand B (-4.151). This is a significant advantage for Ligand A.

**14. P-gp Efflux:** Ligand A (0.046) has lower P-gp efflux liability than Ligand B (0.019), which is favorable for CNS penetration.

**15. Binding Affinity:** Ligand A (-8.0) has a significantly stronger binding affinity than Ligand B (-0.0). This is a *major* advantage, potentially outweighing some ADME concerns.

**Overall Assessment:**

Ligand A excels in binding affinity, metabolic stability, half-life, and P-gp efflux. Its BBB penetration is also good. However, it has a higher DILI risk and slightly higher hERG liability. Ligand B has a much lower DILI risk and hERG liability, but significantly weaker binding affinity and poorer BBB penetration.

Given the importance of binding affinity for GPCRs, and the need for BBB penetration for CNS targets, the stronger binding and better BBB of Ligand A are decisive. While the DILI risk is a concern, it might be mitigated through further structural modifications. The very weak binding of Ligand B is a major drawback that would be difficult to overcome.

Output:
1
2025-04-17 04:05:29,183 - INFO - Reasoning:

Let's analyze Ligand A and Ligand B based on the provided guidelines, prioritizing GPCR-specific properties (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (370.471 and 378.826 Da) fall within the ideal range of 200-500 Da.

**TPSA:** Ligand A (95.94) is higher than the preferred <90 for CNS targets, while Ligand B (57.26) is well within the range. This is a significant advantage for Ligand B.

**logP:** Both ligands have acceptable logP values (1.125 and 2.838), falling within the optimal 1-3 range. Ligand B is slightly better positioned.

**H-Bond Donors/Acceptors:** Both have 2 HBD and 5/4 HBA, respectively, which are acceptable.

**QED:** Both ligands have similar QED scores (0.75 and 0.716), indicating good drug-likeness.

**DILI:** Ligand A (42.303) and Ligand B (34.742) both have low DILI risk, below the 40 threshold, which is good. Ligand B is slightly better.

**BBB:** This is a crucial parameter for CNS targets. Ligand A has a BBB percentile of 27.801, which is poor. Ligand B has a much better BBB percentile of 70.997, exceeding the desirable >70 threshold. This is a major advantage for Ligand B.

**Caco-2 Permeability:** Ligand A (-4.844) shows poor permeability, while Ligand B (-5.255) is also poor, but slightly better.

**Aqueous Solubility:** Both ligands have poor aqueous solubility (-2.288 and -3.42). This could pose formulation challenges, but is less critical than BBB for a CNS target.

**hERG Inhibition:** Ligand A (0.07) and Ligand B (0.749) both have low hERG inhibition risk.

**Microsomal Clearance:** Ligand A (46.5) has higher clearance than Ligand B (15.996), indicating lower metabolic stability. Ligand B is significantly better.

**In vitro Half-Life:** Ligand A (-36.388) has a very short half-life, while Ligand B (33.182) has a longer, though still relatively short, half-life. Ligand B is better.

**P-gp Efflux:** Ligand A (0.042) has very low P-gp efflux, which is good. Ligand B (0.153) has slightly higher efflux, but still acceptable.

**Binding Affinity:** Ligand A (-8.6 kcal/mol) has a slightly better binding affinity than Ligand B (-7.9 kcal/mol). However, the difference is less than 1.5 kcal/mol, and can be outweighed by other factors.

**Overall Assessment:**

Ligand B is significantly more promising due to its superior BBB penetration (70.997 vs 27.801), lower microsomal clearance, and longer half-life. While Ligand A has slightly better binding affinity, the differences in ADME properties, especially BBB, are critical for a CNS-targeting drug. The lower TPSA of Ligand B is also a significant advantage.

Output:
1
2025-04-17 04:05:29,183 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (403.284 Da) is slightly higher than Ligand B (363.845 Da), but both are acceptable.

**TPSA:** Both ligands have TPSA values (77.63 and 76.24) that are above the optimal <90 for CNS targets, but still reasonably close. This isn't a major differentiating factor.

**logP:** Ligand A (2.511) and Ligand B (3.172) both fall within the optimal 1-3 range. Ligand B is slightly higher, which could potentially lead to some off-target effects, but is still acceptable.

**H-Bond Donors/Acceptors:** Ligand A (HBD=1, HBA=6) and Ligand B (HBD=2, HBA=5) both have reasonable numbers of H-bond donors and acceptors, well within the guidelines.

**QED:** Both ligands have similar QED values (0.71 and 0.704), indicating good drug-likeness.

**DILI:** Ligand A (65.568) has a higher DILI risk than Ligand B (52.423). This is a negative for Ligand A.

**BBB:** Ligand A (67.546) has a slightly better BBB penetration percentile than Ligand B (48.042). This is a significant advantage for a CNS target like DRD2.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values, indicating poor permeability. Ligand B (-4.553) is slightly better than Ligand A (-5.294), but both are problematic.

**Aqueous Solubility:** Both ligands have very poor aqueous solubility (-2.523 and -4.21). This is a significant drawback for both, potentially hindering bioavailability.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.157 and 0.541), which is good.

**Microsomal Clearance:** Ligand A (38.281) has significantly lower microsomal clearance than Ligand B (54.145), indicating better metabolic stability. This is a positive for Ligand A.

**In vitro Half-Life:** Ligand A (35.511) has a longer in vitro half-life than Ligand B (19.247), further supporting its better metabolic stability.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.253 and 0.236), which is favorable for CNS penetration.

**Binding Affinity:** Ligand A (-9.8 kcal/mol) has a significantly stronger binding affinity than Ligand B (-8.2 kcal/mol). This is a substantial advantage, potentially outweighing some of the ADME drawbacks. A 1.6 kcal/mol difference is considerable.

**Overall Assessment:**

Ligand A is the better candidate. While it has a higher DILI risk, its significantly stronger binding affinity (-9.8 vs -8.2 kcal/mol), better BBB penetration (67.5 vs 48.0), and improved metabolic stability (lower Cl_mic and longer t1/2) outweigh the slightly higher DILI risk and poor solubility. The stronger binding affinity is particularly important for a GPCR target. The poor Caco-2 and solubility are concerns, but can potentially be addressed with formulation strategies.



Output:
1
2025-04-17 04:05:29,183 - INFO - Reasoning:

Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (343.446 and 366.824 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (41.29) is significantly better than Ligand B (86.88). For CNS targets, we want TPSA <= 90, and A is comfortably within that, while B is approaching the upper limit.

**3. logP:** Both ligands have good logP values (3.365 and 2.839), falling within the optimal 1-3 range.

**4. H-Bond Donors:** Ligand A (1) is preferable to Ligand B (3). Fewer HBDs generally improve permeability.

**5. H-Bond Acceptors:** Ligand A (4) is preferable to Ligand B (3). Fewer HBAs generally improve permeability.

**6. QED:** Ligand A (0.929) has a much higher QED score than Ligand B (0.658), indicating a more drug-like profile.

**7. DILI:** Ligand A (12.679) has a significantly lower DILI risk than Ligand B (77.394). This is a major advantage for A.

**8. BBB:** Ligand A (86.584) has a substantially better BBB percentile than Ligand B (60.76).  For a CNS target like DRD2, >70 is desirable; A is closer to that threshold.

**9. Caco-2 Permeability:** Ligand A (-4.749) has a worse Caco-2 permeability than Ligand B (-5.238), but both are negative, indicating poor permeability.

**10. Aqueous Solubility:** Ligand A (-1.718) has better aqueous solubility than Ligand B (-4.053).

**11. hERG Inhibition:** Both ligands have low hERG inhibition risk (0.934 and 0.595).

**12. Microsomal Clearance:** Ligand A (-7.601) has much lower (better) microsomal clearance than Ligand B (43.217), indicating better metabolic stability.

**13. In vitro Half-Life:** Ligand A (13.408 hours) has a longer half-life than Ligand B (56.454 hours).

**14. P-gp Efflux:** Ligand A (0.564) has lower P-gp efflux than Ligand B (0.496), which is favorable for CNS penetration.

**15. Binding Affinity:** Both ligands have excellent binding affinities (-9.9 and -9.4 kcal/mol). The difference of 0.5 kcal/mol is not substantial enough to outweigh the significant ADME advantages of Ligand A.

**Overall Assessment:**

Ligand A is significantly better than Ligand B across most critical ADME properties, especially DILI, BBB, TPSA, QED, and metabolic stability. While both have good binding affinity and logP, Ligand A's superior ADME profile makes it a much more promising drug candidate for a CNS target like DRD2.

Output:
0
2025-04-17 04:05:29,183 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight (MW):** Both ligands (344.415 and 344.323 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (99.24) is better than Ligand B (106.87). Both are below the 140 A^2 threshold for oral absorption, and approaching the desirable <90 A^2 for CNS targets. Ligand A is preferable.

**3. logP:** Both ligands (1.225 and 1.266) are within the optimal range of 1-3, suggesting good permeability and avoiding solubility issues.

**4. H-Bond Donors (HBD):** Both have 2 HBD, which is within the acceptable limit of <=5.

**5. H-Bond Acceptors (HBA):** Both have 6 HBA, within the acceptable limit of <=10.

**6. QED:** Ligand A (0.702) is better than Ligand B (0.604), indicating a more drug-like profile.

**7. DILI:** Ligand A (43.04%) has a significantly lower DILI risk than Ligand B (90.074%), which is a substantial advantage.

**8. BBB:** Ligand A (77.821%) has a significantly better BBB penetration prediction than Ligand B (61.846%). This is *critical* for a CNS target like DRD2.

**9. Caco-2 Permeability:** Ligand A (-5.262) is better than Ligand B (-5.052), indicating better intestinal absorption.

**10. Aqueous Solubility:** Ligand A (-2.69) is better than Ligand B (-3.376), suggesting better solubility.

**11. hERG Inhibition:** Ligand A (0.453) is better than Ligand B (0.223), indicating a lower risk of cardiotoxicity.

**12. Microsomal Clearance (Cl_mic):** Ligand A (46.033) has higher clearance than Ligand B (-20.461). This is a negative for Ligand A, suggesting faster metabolism.

**13. In vitro Half-Life (t1/2):** Ligand A (-9.658) has a shorter half-life than Ligand B (-4.608), which is a negative for Ligand A.

**14. P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.091 and 0.085).

**15. Binding Affinity:** Ligand B (-8.8 kcal/mol) has a slightly better binding affinity than Ligand A (-8.0 kcal/mol). While a difference of 0.8 kcal/mol is noticeable, it's not a massive difference and can be overcome by superior ADME properties.

**Overall Assessment:**

Ligand A is significantly better overall, despite the slightly weaker binding affinity. Its superior BBB penetration, lower DILI risk, better solubility, and better Caco-2 permeability are crucial advantages for a CNS-targeting drug. While Ligand A has higher clearance and shorter half-life, these can potentially be addressed through structural modifications during lead optimization. Ligand B's high DILI risk and poor BBB penetration are major drawbacks.

Output:
1
2025-04-17 04:05:29,183 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (365.415 Da) is slightly higher than Ligand B (343.387 Da), but both are acceptable.

**2. TPSA:** Ligand A (117.43) is borderline for CNS targets (ideally <90), while Ligand B (96.41) is comfortably within the desired range. This is a significant advantage for Ligand B.

**3. logP:** Ligand A (0.57) is a bit low, potentially hindering membrane permeability. Ligand B (0.849) is also on the lower side, but slightly better. Both could benefit from increased lipophilicity.

**4. H-Bond Donors:** Both ligands have 2 HBD, which is within the acceptable limit of <=5.

**5. H-Bond Acceptors:** Ligand A has 6 HBA, and Ligand B has 7. Both are within the acceptable limit of <=10.

**6. QED:** Both ligands have reasonable QED scores (Ligand A: 0.8, Ligand B: 0.629), indicating good drug-like properties.

**7. DILI:** Ligand A (89.57) has a concerningly high DILI risk, while Ligand B (39.511) is much lower and acceptable. This is a major drawback for Ligand A.

**8. BBB:** Ligand A (79.062) has a good BBB penetration percentile, while Ligand B (25.281) is poor. This is a significant advantage for Ligand A.

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 values, which is unusual and suggests poor permeability. Ligand A (-5.186) is slightly better than Ligand B (-5.958).

**10. Aqueous Solubility:** Both ligands have negative solubility values, which is also unusual. Ligand A (-3.027) is slightly better than Ligand B (-1.129).

**11. hERG Inhibition:** Both ligands have very low hERG inhibition risk (Ligand A: 0.196, Ligand B: 0.08).

**12. Microsomal Clearance:** Ligand B (-16.254) has a lower (better) microsomal clearance than Ligand A (10.809), indicating greater metabolic stability.

**13. In vitro Half-Life:** Ligand B (27.262) has a significantly longer in vitro half-life than Ligand A (-28.167), which is a major advantage.

**14. P-gp Efflux:** Both ligands have very low P-gp efflux liability (Ligand A: 0.031, Ligand B: 0.004).

**15. Binding Affinity:** Ligand A (-9.5 kcal/mol) has a significantly stronger binding affinity than Ligand B (-7.0 kcal/mol). This is a substantial advantage for Ligand A.

**Overall Assessment:**

While Ligand A has a much better binding affinity and acceptable BBB penetration, its high DILI risk is a significant concern. Ligand B, despite weaker affinity, has a much more favorable safety profile (lower DILI), better TPSA, and improved metabolic stability (lower Cl_mic, longer t1/2). Given the GPCR-specific priorities and the importance of safety, Ligand B is the more promising candidate, even with the weaker binding. The affinity difference, while notable, might be addressable through further optimization, while mitigating a high DILI risk is often far more challenging.

Output:
1
2025-04-17 04:05:29,183 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (357.382 and 341.455 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (107.97) is higher than Ligand B (81.99). For CNS targets, we prefer TPSA <= 90, so Ligand B is significantly better here.

**3. logP:** Ligand A (-0.299) is quite low, potentially hindering membrane permeability. Ligand B (3.017) is within the optimal 1-3 range. This is a major advantage for Ligand B.

**4. H-Bond Donors:** Ligand A (3) and Ligand B (2) are both acceptable, being <= 5.

**5. H-Bond Acceptors:** Ligand A (5) and Ligand B (3) are both acceptable, being <= 10.

**6. QED:** Both ligands have good QED values (0.626 and 0.762, respectively), indicating drug-like properties.

**7. DILI:** Both ligands have acceptable DILI risk (35.828 and 41.76), both under the 40% threshold.

**8. BBB:** Ligand B (55.06) has a better BBB percentile than Ligand A (44.397), although both are below the desirable >70 for CNS targets. However, given the other factors, this difference is less critical.

**9. Caco-2 Permeability:** Ligand A (-5.061) has poor Caco-2 permeability, while Ligand B (-4.61) is slightly better but still not great.

**10. Aqueous Solubility:** Ligand A (-1.499) has poor solubility, while Ligand B (-4.189) is also poor.

**11. hERG Inhibition:** Both ligands have low hERG inhibition risk (0.184 and 0.511).

**12. Microsomal Clearance:** Ligand A (-43.723) has a lower (better) microsomal clearance than Ligand B (26.85). This suggests better metabolic stability for Ligand A.

**13. In vitro Half-Life:** Ligand A (-12.507) has a shorter half-life than Ligand B (6.12).

**14. P-gp Efflux:** Ligand A (0.018) has significantly lower P-gp efflux liability than Ligand B (0.092), which is a major advantage for CNS penetration.

**15. Binding Affinity:** Both ligands have comparable binding affinities (-8.6 and -8.8 kcal/mol). The difference is minimal.

**Overall Assessment:**

Ligand B is superior due to its more favorable logP, TPSA, and BBB values. While Ligand A has better metabolic stability (lower Cl_mic) and lower P-gp efflux, the poor logP and higher TPSA of Ligand A are significant drawbacks for a CNS-targeting GPCR ligand. The slightly better BBB penetration of Ligand B, combined with its better logP and TPSA, outweighs the advantage of Ligand A's lower P-gp efflux and better metabolic stability.

Output:
1
2025-04-17 04:05:29,183 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (364.511 and 351.447 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (62.55) is significantly better than Ligand B (86.88). For CNS targets, we want TPSA <= 90, and A is comfortably within that, while B is approaching the upper limit.

**logP:** Ligand A (3.549) is optimal (1-3), while Ligand B (2.024) is a bit low, potentially hindering permeability.

**H-Bond Donors/Acceptors:** Both have 1 HBD, which is good. Ligand A has 4 HBA, and Ligand B has 5. Both are acceptable (<=10).

**QED:** Both ligands have similar QED values (0.83 and 0.812), indicating good drug-likeness.

**DILI:** Ligand A (43.738) has a slightly higher DILI risk than Ligand B (32.959), but both are below the concerning threshold of 60.

**BBB:** Ligand A (83.249) has a much better BBB penetration percentile than Ligand B (63.086).  For a CNS target like DRD2, >70 is desirable, and A is closer to that mark.

**Caco-2 Permeability:** Ligand A (-4.951) is better than Ligand B (-4.52), indicating better intestinal absorption.

**Aqueous Solubility:** Ligand A (-4.289) is better than Ligand B (-1.281), which is important for formulation.

**hERG:** Both ligands have low hERG inhibition liability (0.553 and 0.34), which is good.

**Microsomal Clearance:** Both ligands have similar microsomal clearance values (52.539 and 50.117), indicating similar metabolic stability.

**In vitro Half-Life:** Ligand A (12.189) has a better in vitro half-life than Ligand B (-17.878).

**P-gp Efflux:** Ligand A (0.394) has lower P-gp efflux liability than Ligand B (0.224), which is beneficial for CNS exposure.

**Binding Affinity:** Ligand A (-8.6 kcal/mol) has a significantly stronger binding affinity than Ligand B (-7.8 kcal/mol). This 0.8 kcal/mol difference is substantial and can outweigh minor ADME drawbacks.

**Conclusion:**

Considering the GPCR-specific priorities, Ligand A is the superior candidate. It has a better TPSA, logP, BBB penetration, solubility, half-life, P-gp efflux, and, crucially, a significantly stronger binding affinity. While Ligand B has a slightly lower DILI risk, the advantages of Ligand A, particularly its superior CNS penetration and binding affinity, make it the more promising drug candidate for a CNS target like DRD2.

Output:
1
2025-04-17 04:05:29,183 - INFO - Reasoning:

Let's analyze Ligand A and Ligand B based on the provided guidelines, prioritizing GPCR-specific properties (BBB, logP, Pgp, TPSA, and affinity) for DRD2.

**Molecular Weight:** Both ligands (367.343 and 347.459 Da) fall within the ideal range of 200-500 Da.

**TPSA:** Ligand A (78.51) is better than Ligand B (54.78) as it is closer to the ideal range for CNS targets (<=90). Ligand B is excellent.

**logP:** Ligand A (0.766) is slightly lower than optimal (1-3), potentially hindering permeation. Ligand B (1.671) is within the optimal range.

**H-Bond Donors/Acceptors:** Ligand A (2 HBD, 3 HBA) and Ligand B (0 HBD, 4 HBA) both have acceptable numbers of H-bond donors and acceptors.

**QED:** Both ligands have good QED scores (0.681 and 0.814), indicating good drug-like properties.

**DILI:** Ligand A (34.471) has a slightly higher DILI risk than Ligand B (27.065), but both are below the concerning threshold of 60.

**BBB:** This is a crucial parameter for DRD2. Ligand A has a significantly better BBB penetration percentile (79.139) compared to Ligand B (69.407).

**Caco-2 Permeability:** Ligand A (-4.955) and Ligand B (-4.567) both have negative values, which is unusual. Assuming these are logP-like scales, lower values suggest poorer permeability.

**Aqueous Solubility:** Ligand A (-2.46) has slightly better solubility than Ligand B (-0.532), but both are poor.

**hERG:** Both ligands have very low hERG inhibition liability (0.389 and 0.267), which is excellent.

**Microsomal Clearance:** Ligand A (-8.128) has much lower microsomal clearance than Ligand B (33.179), indicating better metabolic stability. This is a significant advantage.

**In vitro Half-Life:** Ligand A (-14.888) has a much longer in vitro half-life than Ligand B (4.716), further supporting its better metabolic stability.

**P-gp Efflux:** Ligand A (0.011) has extremely low P-gp efflux liability, which is highly desirable for CNS penetration. Ligand B (0.141) also has low efflux, but not as low as ligand A.

**Binding Affinity:** Ligand B (-8.5) has a slightly better binding affinity than Ligand A (-8.1), but the difference is relatively small (0.4 kcal/mol).

**Overall Assessment:**

While Ligand B has a slightly better logP and binding affinity, Ligand A significantly outperforms it in critical areas for a CNS-targeting GPCR drug: BBB penetration, metabolic stability (lower Cl_mic, longer t1/2), and P-gp efflux. The slightly lower logP of Ligand A is a minor concern that could potentially be addressed through further optimization, but the superior ADME properties of Ligand A are more crucial for CNS drug development.

Output:
1
2025-04-17 04:05:29,184 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (349.39) is slightly better, being closer to the lower end which can aid permeability.

**TPSA:** Ligand B (66.92) is significantly better than Ligand A (93.9). For CNS targets, TPSA < 90 is preferred, and Ligand B is well within this range, while Ligand A is close to the upper limit.

**logP:** Both ligands have optimal logP values (around 1), suggesting good permeability and avoiding solubility issues. Ligand A (1.1) is marginally better.

**H-Bond Donors/Acceptors:** Ligand A has 1 HBD and 6 HBA, while Ligand B has 0 HBD and 4 HBA. Both are within acceptable limits.

**QED:** Both ligands have similar and good QED scores (0.707 and 0.7), indicating drug-like properties.

**DILI:** Ligand B (12.33) has a much lower DILI risk than Ligand A (62.35), which is a significant advantage.

**BBB:** Ligand B (82.05) has a substantially higher BBB penetration percentile than Ligand A (60.95). This is *critical* for a CNS target like DRD2.

**Caco-2 Permeability:** Ligand A (-4.658) has slightly better Caco-2 permeability than Ligand B (-4.481), but both are negative values which is not ideal.

**Aqueous Solubility:** Ligand A (-2.227) has slightly better aqueous solubility than Ligand B (-1.533), but both are negative values, indicating poor solubility.

**hERG Inhibition:** Ligand B (0.238) shows lower hERG inhibition liability than Ligand A (0.08), which is a positive attribute.

**Microsomal Clearance:** Ligand B (31.763) has a higher microsomal clearance than Ligand A (21.864), meaning Ligand A is more metabolically stable.

**In vitro Half-Life:** Ligand A (-21.539) has a much longer in vitro half-life than Ligand B (-10.286).

**P-gp Efflux:** Ligand A (0.024) has lower P-gp efflux liability than Ligand B (0.045), which is favorable for CNS penetration.

**Binding Affinity:** Both ligands have excellent binding affinities (-7.4 and -7.5 kcal/mol), with Ligand B being slightly better. The difference is minimal and unlikely to outweigh other factors.

**Overall Assessment:**

Considering the GPCR-specific priorities, Ligand B is the more promising candidate. Its superior BBB penetration (82.05 vs 60.95), significantly lower DILI risk (12.33 vs 62.35), and lower hERG liability outweigh the slight advantages of Ligand A in metabolic stability and P-gp efflux. While Ligand A has a slightly longer half-life and better Caco-2 permeability, these are less critical for a CNS target where BBB penetration is paramount. The TPSA value for Ligand B is also much more favorable.



Output:
1
2025-04-17 04:05:29,184 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B based on the provided guidelines, prioritizing GPCR-specific properties (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (356.394 and 346.406 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (84.94) is better than Ligand B (65.54), both being below the 90 A^2 threshold desirable for CNS targets.

**logP:** Ligand B (1.74) is better than Ligand A (0.279). Ligand A's logP is quite low, potentially hindering membrane permeability. Ligand B is within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Both have 1 HBD and similar HBA counts (5 and 4 respectively), which are acceptable.

**QED:** Ligand B (0.844) has a significantly higher QED score than Ligand A (0.384), indicating better overall drug-likeness.

**DILI:** Ligand A (17.798) has a much lower DILI risk than Ligand B (60.915). This is a significant advantage for Ligand A.

**BBB:** Ligand A (92.4) has a substantially better BBB penetration percentile than Ligand B (80.031). This is critical for a CNS target like DRD2.

**Caco-2 Permeability:** Ligand A (-4.717) has slightly better Caco-2 permeability than Ligand B (-4.578).

**Aqueous Solubility:** Both ligands have very poor aqueous solubility (-2.309 and -2.835 respectively). This could pose formulation challenges.

**hERG Inhibition:** Both ligands show similar, low hERG inhibition liability (0.43 and 0.431).

**Microsomal Clearance:** Ligand A (24.404) has lower microsomal clearance than Ligand B (34.223), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (-18.489) has a significantly longer in vitro half-life than Ligand B (12.196).

**P-gp Efflux:** Both ligands have similar P-gp efflux liability (0.035 and 0.027).

**Binding Affinity:** Ligand B (-8.3 kcal/mol) has a slightly better binding affinity than Ligand A (-7.5 kcal/mol). While the difference is not huge, it is a factor.

**Overall Assessment:**

Ligand A excels in BBB penetration, metabolic stability, in vitro half-life, and DILI risk. Ligand B has a slightly better binding affinity and a better logP value. However, the significant advantages of Ligand A in CNS penetration (BBB), metabolic stability, and safety (DILI) outweigh the modest affinity difference. The poor solubility of both compounds is a concern, but can potentially be addressed through formulation strategies. Given the CNS target, BBB is paramount.

Output:
0
2025-04-17 04:05:29,184 - INFO - Reasoning:

Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (341.411 and 364.511 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (85.43) is better than Ligand B (58.64). Both are below the 90 A^2 threshold desirable for CNS targets.

**3. logP:** Both ligands have good logP values (1.517 and 3.125), falling within the optimal 1-3 range. Ligand B is slightly higher, potentially improving membrane permeability.

**4. H-Bond Donors:** Ligand A (3) is higher than Ligand B (1). Both are within the acceptable limit of <=5.

**5. H-Bond Acceptors:** Ligand A (3) and Ligand B (4) are both within the acceptable limit of <=10.

**6. QED:** Both ligands have good QED scores (0.788 and 0.873), indicating good drug-like properties.

**7. DILI:** Both ligands have similar, acceptable DILI risk (45.522 and 47.15). Both are well below the 60 threshold.

**8. BBB:** This is a crucial parameter for a CNS target like DRD2. Ligand B (63.009) is significantly better than Ligand A (43.001). A value >70 is desirable, but 63 is a substantial improvement over 43.

**9. Caco-2 Permeability:** Both have negative values (-5.035 and -4.9), which is unusual. This suggests poor permeability. However, the scale isn't specified, so it's hard to interpret.

**10. Aqueous Solubility:** Both have negative values (-3.421 and -3.135), again unusual and suggesting poor solubility.

**11. hERG Inhibition:** Both ligands show low hERG inhibition risk (0.404 and 0.445).

**12. Microsomal Clearance:** Ligand A (10.532) has significantly lower microsomal clearance than Ligand B (37.291), suggesting better metabolic stability.

**13. In vitro Half-Life:** Ligand A (-10.259) has a negative half-life, which is impossible. Ligand B (20.654) is a reasonable value. This is a major red flag for Ligand A.

**14. P-gp Efflux:** Both ligands have low P-gp efflux liability (0.061 and 0.376), which is favorable for CNS penetration.

**15. Binding Affinity:** Both ligands have the same binding affinity (-8.5 kcal/mol), which is excellent.

**Overall Assessment:**

While Ligand A has better TPSA and metabolic stability (lower Cl_mic), the negative and impossible in vitro half-life is a critical flaw. Ligand B demonstrates significantly better BBB penetration, which is paramount for a DRD2 ligand targeting CNS disorders. The slightly higher logP of Ligand B is also beneficial. The Caco-2 and solubility values are concerning for both, but the BBB advantage of Ligand B outweighs the other minor benefits of Ligand A, especially considering the fatal flaw of Ligand A's half-life.

Output:
1
2025-04-17 04:05:29,184 - INFO - Okay, let's analyze these two ligands for their potential as DRD2 drug candidates. DRD2 is a GPCR in the CNS, so BBB penetration, logP, Pgp efflux, TPSA, and binding affinity are key.

**Ligand A: [342.527, 24.5, 4.067, 1, 3, 0.893, 11.4, 83.482, -5.13, -2.628, 0.952, 3.121, 28.691, 0.502, -9.2]**

*   **MW:** 342.527 Da - Good (within 200-500 range).
*   **TPSA:** 24.5  - Excellent (well below 90 for CNS targets).
*   **logP:** 4.067 - Borderline. Slightly high, could lead to solubility issues or off-target interactions, but not drastically so.
*   **HBD:** 1 - Good.
*   **HBA:** 3 - Good.
*   **QED:** 0.893 - Excellent. Highly drug-like.
*   **DILI:** 11.4 - Excellent. Very low risk of liver injury.
*   **BBB:** 83.482 - Very good. Above the 70% threshold for CNS targets.
*   **Caco-2:** -5.13 - Not interpretable. Negative values are unusual for Caco-2 permeability.
*   **Solubility:** -2.628 - Not interpretable. Negative values are unusual for solubility.
*   **hERG:** 0.952 - Good. Low risk of hERG inhibition.
*   **Cl_mic:** 3.121 - Good. Relatively low metabolic clearance.
*   **t1/2:** 28.691 - Good. Decent in vitro half-life.
*   **Pgp:** 0.502 - Good. Low P-gp efflux, favorable for CNS exposure.
*   **Affinity:** -9.2 kcal/mol - Excellent. Very strong binding.

**Ligand B: [349.45, 52.65, 1.516, 1, 3, 0.74, 12.369, 97.014, -4.881, -1.943, 0.63, 6.337, 0.944, 0.057, -8.4]**

*   **MW:** 349.45 Da - Good (within 200-500 range).
*   **TPSA:** 52.65 - Acceptable, but higher than Ligand A. Still potentially okay for CNS, but less ideal.
*   **logP:** 1.516 - Good. Within the optimal range.
*   **HBD:** 1 - Good.
*   **HBA:** 3 - Good.
*   **QED:** 0.74 - Good. Still drug-like, but slightly lower than Ligand A.
*   **DILI:** 12.369 - Good. Low risk of liver injury.
*   **BBB:** 97.014 - Excellent. Very high BBB penetration.
*   **Caco-2:** -4.881 - Not interpretable. Negative values are unusual for Caco-2 permeability.
*   **Solubility:** -1.943 - Not interpretable. Negative values are unusual for solubility.
*   **hERG:** 0.63 - Good. Low risk of hERG inhibition.
*   **Cl_mic:** 6.337 - Acceptable, but higher than Ligand A, suggesting faster metabolism.
*   **t1/2:** 0.944 - Poor. Very short in vitro half-life.
*   **Pgp:** 0.057 - Excellent. Very low P-gp efflux.
*   **Affinity:** -8.4 kcal/mol - Very good. Strong binding, but not as strong as Ligand A.

**Comparison and Decision:**

Both ligands have good MW, HBD/HBA, DILI, and hERG profiles. Ligand B has superior BBB penetration and Pgp efflux properties, but a significantly shorter half-life and higher metabolic clearance. Ligand A has a slightly higher logP, but a much better half-life and lower clearance. Most importantly, Ligand A has a substantially stronger binding affinity (-9.2 vs -8.4 kcal/mol). For a GPCR target, especially in the CNS, strong binding is paramount. The 0.8 kcal/mol difference in binding affinity is significant and likely outweighs the slightly higher logP of Ligand A. The negative Caco-2 and solubility values are concerning for both, but we can't make a definitive judgement without knowing the scale/units used.

Given the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity), and the significantly stronger binding affinity of Ligand A, I would choose **Ligand A** as the more promising drug candidate.

1
2025-04-17 04:05:29,184 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (402.969 Da) is slightly higher, but still acceptable. Ligand B (355.507 Da) is also good.

**TPSA:** Ligand A (78.43) is better than Ligand B (41.15). For CNS targets, we want TPSA <= 90, both are well within this range, but Ligand B is significantly lower, which is advantageous for brain penetration.

**logP:** Ligand A (3.495) is within the optimal range (1-3). Ligand B (4.992) is slightly above, potentially leading to solubility issues and off-target interactions, but not drastically so.

**H-Bond Donors/Acceptors:** Ligand A has 3 HBD and 5 HBA, which are acceptable. Ligand B has 1 HBD and 4 HBA, also acceptable.

**QED:** Ligand A (0.568) is better than Ligand B (0.411). A QED > 0.5 is preferred, and Ligand A is closer to this threshold.

**DILI:** Ligand A (71.772) has a higher DILI risk than Ligand B (52.074). Lower DILI is better, so Ligand B is preferable here.

**BBB:** Ligand B (65.297) has a significantly better BBB penetration percentile than Ligand A (33.85). This is *critical* for a CNS target like DRD2.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.357 and -5.216). This is unusual and suggests poor intestinal absorption. However, for a CNS target, intestinal absorption is less critical than BBB penetration.

**Aqueous Solubility:** Both ligands have negative solubility values (-3.988 and -4.428). This is also concerning, but can sometimes be overcome with formulation strategies, and is less critical for CNS targets that rely on BBB penetration.

**hERG Inhibition:** Ligand A (0.678) has a slightly lower hERG inhibition risk than Ligand B (0.933). Lower is better.

**Microsomal Clearance:** Ligand A (62.39) has a lower microsomal clearance than Ligand B (73.432), indicating better metabolic stability.

**In vitro Half-Life:** Ligand A (82.609) has a significantly longer in vitro half-life than Ligand B (-14.739). This is a major advantage for Ligand A.

**P-gp Efflux:** Ligand A (0.443) has lower P-gp efflux than Ligand B (0.788), which is favorable for CNS exposure.

**Binding Affinity:** Ligand A (-8.1 kcal/mol) has a significantly stronger binding affinity than Ligand B (-7.1 kcal/mol). This is a substantial advantage, and can often outweigh minor ADME drawbacks.

**Overall Assessment:**

Ligand A has a stronger binding affinity, better QED, lower DILI, lower P-gp efflux, and a much longer half-life. However, Ligand B has a significantly better BBB penetration, which is paramount for a CNS target. The negative Caco-2 and solubility values are concerning for both, but less critical given the focus on CNS penetration. The difference in binding affinity (1 kcal/mol) is significant and, combined with the better metabolic stability of Ligand A, makes it the more promising candidate despite the lower BBB score.

Output:
1
2025-04-17 04:05:29,184 - INFO - Batch 83 complete. Total preferences: 1328
2025-04-17 04:05:29,185 - INFO - Processing batch 84/512...
2025-04-17 04:06:13,992 - INFO - Reasoning:

Let's analyze Ligand A and Ligand B for their potential as DRD2 drug candidates, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (341.415 and 346.471 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (88.47) is better than Ligand B (58.64), both are below the 90 A^2 threshold for CNS targets.

**3. logP:** Ligand B (2.433) is optimal (1-3), while Ligand A (0.311) is quite low, potentially hindering permeation. This is a significant negative for Ligand A.

**4. H-Bond Donors:** Ligand A (2) and Ligand B (1) are both acceptable (<=5).

**5. H-Bond Acceptors:** Ligand A (5) and Ligand B (3) are both acceptable (<=10).

**6. QED:** Both ligands have good QED scores (0.756 and 0.778, respectively), indicating drug-like properties.

**7. DILI:** Ligand B (24.738) has a much lower DILI risk than Ligand A (37.999), which is preferable.

**8. BBB:** Ligand B (78.364) has a significantly better BBB penetration score than Ligand A (54.13). This is *critical* for a CNS target like DRD2.

**9. Caco-2 Permeability:** Ligand A (-5.006) has a very poor Caco-2 permeability, while Ligand B (-4.415) is slightly better, but still not ideal.

**10. Aqueous Solubility:** Both ligands have poor aqueous solubility (-2.278 and -2.915, respectively). This could pose formulation challenges, but isn't a deal-breaker if other properties are strong.

**11. hERG Inhibition:** Both ligands have low hERG inhibition risk (0.678 and 0.253, respectively).

**12. Microsomal Clearance:** Ligand A (-47.418) has a much lower (better) microsomal clearance than Ligand B (79.614), suggesting better metabolic stability.

**13. In vitro Half-Life:** Ligand A (13.349 hours) has a better in vitro half-life than Ligand B (-18.467 hours).

**14. P-gp Efflux:** Ligand A (0.003) has a much lower P-gp efflux liability than Ligand B (0.182), which is favorable for CNS penetration.

**15. Binding Affinity:** Both ligands have similar, strong binding affinities (-9.1 and -8.6 kcal/mol). The difference is less than the 1.5 kcal/mol threshold.

**Overall Assessment:**

While Ligand A has better metabolic stability (lower Cl_mic, longer t1/2) and P-gp efflux, its significantly lower logP and poor Caco-2 permeability are major drawbacks for a CNS target. Ligand B excels in the critical areas for a CNS GPCR: BBB penetration, acceptable logP, and lower DILI risk. The slightly worse metabolic stability and higher P-gp efflux of Ligand B are less concerning given its superior CNS penetration profile. The affinity difference is not substantial enough to override the ADME advantages of Ligand B.

Output:
1
2025-04-17 04:06:13,992 - INFO - Reasoning:

Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (391.249 Da) is slightly higher than Ligand B (343.471 Da), but both are acceptable.

**2. TPSA:** Ligand A (105.32) is higher than Ligand B (71.09). For CNS targets, we prefer TPSA <= 90. Ligand B is comfortably within this range, while Ligand A is slightly above. This favors Ligand B.

**3. logP:** Both ligands have good logP values (Ligand A: 2.251, Ligand B: 3.146), falling within the optimal 1-3 range. Ligand B is slightly more lipophilic, which could be beneficial for membrane permeability, but isn't a major concern for either.

**4. H-Bond Donors:** Both have 2 HBD, which is within the acceptable limit of <=5.

**5. H-Bond Acceptors:** Ligand A has 6 HBA, and Ligand B has 3 HBA, both within the acceptable limit of <=10. Ligand B is preferable here.

**6. QED:** Both ligands have good QED scores (Ligand A: 0.612, Ligand B: 0.747), indicating good drug-like properties. Ligand B is slightly better.

**7. DILI:** Ligand A has a DILI risk of 90.461, which is high. Ligand B has a DILI risk of 27.336, which is excellent. This is a significant advantage for Ligand B.

**8. BBB:** Ligand A has a BBB penetration of 33.695, which is quite low. Ligand B has a BBB penetration of 59.287, which is better, but still not ideal (we want >70 for CNS targets). However, the difference is substantial and favors Ligand B.

**9. Caco-2 Permeability:** Both have negative Caco-2 values (-5.041 and -4.938), which is unusual and suggests poor permeability. This is a concern for both, but doesn't differentiate them.

**10. Aqueous Solubility:** Both have negative solubility values (-3.434 and -2.261), indicating poor solubility. This is a concern for both, but doesn't differentiate them.

**11. hERG Inhibition:** Both ligands have low hERG inhibition risk (0.125 and 0.237), which is good.

**12. Microsomal Clearance:** Ligand A has a higher microsomal clearance (58.171) than Ligand B (24.471), indicating lower metabolic stability. Ligand B is preferable.

**13. In vitro Half-Life:** Ligand A has a negative half-life (-43.218), which is not physically meaningful and suggests a very rapid degradation. Ligand B has a half-life of 11.87 hours, which is reasonable. This is a major advantage for Ligand B.

**14. P-gp Efflux:** Both ligands have low P-gp efflux liability (0.05 and 0.055), which is good.

**15. Binding Affinity:** Ligand A has a significantly better binding affinity (-9.3 kcal/mol) than Ligand B (-8.0 kcal/mol). This is a substantial advantage for Ligand A.

**Overall Assessment:**

While Ligand A has a much stronger binding affinity, its poor BBB penetration, high DILI risk, and very short half-life are major drawbacks. Ligand B, despite having a slightly weaker affinity, exhibits a much more favorable ADME profile, particularly regarding BBB, DILI, and metabolic stability. For a CNS target like DRD2, achieving sufficient brain exposure and minimizing toxicity are critical. The affinity difference, while significant, might be overcome with further optimization of Ligand B, whereas addressing the severe ADME issues of Ligand A would be far more challenging.

Output:
1
2025-04-17 04:06:13,992 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (383.876 Da) is slightly higher than Ligand B (341.367 Da), but both are acceptable.

**TPSA:** Ligand A (44.81) is excellent for CNS penetration, well below the 90 A^2 threshold. Ligand B (121.52) is higher, but still potentially acceptable, though less ideal.

**logP:** Ligand A (3.899) is at the upper end of the optimal range (1-3), but still acceptable. Ligand B (1.53) is on the lower end, potentially hindering permeability.

**H-Bond Donors/Acceptors:** Ligand A (HBD=1, HBA=4) is good. Ligand B (HBD=4, HBA=4) is acceptable, but higher HBD count can sometimes be problematic.

**QED:** Both ligands have reasonable QED values (Ligand A: 0.87, Ligand B: 0.58), indicating good drug-like properties.

**DILI:** Ligand A (64.909) has a slightly higher DILI risk than Ligand B (56.844), but both are below the concerning 60 threshold.

**BBB:** Ligand A (84.413) has a significantly better BBB penetration score than Ligand B (59.829). This is a crucial factor for a CNS target like DRD2.

**Caco-2 Permeability:** Ligand A (-4.749) and Ligand B (-5.867) both have negative Caco-2 values. This is unusual and suggests poor permeability. However, the scale is not specified, so it's difficult to interpret.

**Aqueous Solubility:** Ligand A (-4.771) and Ligand B (-2.612) both have negative solubility values, indicating poor solubility. Again, the scale is not specified.

**hERG:** Ligand A (0.889) has a slightly higher hERG risk than Ligand B (0.113), but both are relatively low.

**Microsomal Clearance:** Ligand A (62.106) has a higher microsomal clearance than Ligand B (-8.428). This suggests Ligand B is more metabolically stable.

**In vitro Half-Life:** Both ligands have similar in vitro half-lives (Ligand A: -5.73, Ligand B: -5.775).

**P-gp Efflux:** Ligand A (0.491) has a lower P-gp efflux liability than Ligand B (0.018), which is favorable for CNS exposure.

**Binding Affinity:** Ligand B (-9.2 kcal/mol) has a significantly stronger binding affinity than Ligand A (-7.6 kcal/mol). This is a substantial advantage (1.6 kcal/mol difference).

**Overall Assessment:**

Ligand B has a superior binding affinity, better metabolic stability (lower Cl_mic), and lower P-gp efflux. However, Ligand A has a much better BBB score, a more favorable logP, and lower P-gp efflux. The superior BBB penetration of Ligand A is critical for a CNS target. While Ligand B's affinity is excellent, the poor BBB score is a significant drawback. The negative Caco-2 and solubility values for both are concerning, but the affinity difference is large enough to potentially overcome these issues with formulation strategies. Given the importance of CNS penetration for DRD2, and the substantial affinity advantage of Ligand B, I lean towards Ligand B.

Output:
1
2025-04-17 04:06:13,992 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (349.391 Da) is slightly lower, which is generally favorable for permeability. Ligand B (363.908 Da) is also good.

**TPSA:** Ligand A (110.37) is better than Ligand B (21.06) for CNS penetration, being closer to the <90 target for CNS targets. Ligand B's TPSA is very low, which could indicate a lack of necessary interactions.

**logP:** Ligand A (1.239) is within the optimal range (1-3). Ligand B (4.893) is significantly higher, potentially leading to solubility issues and off-target interactions.

**H-Bond Donors/Acceptors:** Ligand A has 1 HBD and 6 HBA, which are acceptable. Ligand B has 0 HBD and 3 HBA, also acceptable, but potentially indicating lower aqueous solubility.

**QED:** Both ligands have good QED scores (A: 0.613, B: 0.728), suggesting good drug-like properties.

**DILI:** Ligand A (47.421) has a moderate DILI risk, while Ligand B (13.804) has a very low DILI risk, which is a significant advantage.

**BBB:** Ligand A (87.476) has good BBB penetration, but Ligand B (95.967) is even better, which is crucial for a CNS target like DRD2.

**Caco-2 Permeability:** Both have negative values, which is unusual and problematic. However, the scale is not specified, so it's hard to interpret.

**Aqueous Solubility:** Both ligands have negative solubility values, which is also problematic and suggests poor solubility.

**hERG Inhibition:** Ligand A (0.352) has a low hERG risk, while Ligand B (0.94) has a slightly higher risk, but still relatively low.

**Microsomal Clearance:** Ligand A (9.966) has lower clearance than Ligand B (33.971), indicating better metabolic stability.

**In vitro Half-Life:** Ligand A (-24.469) has a negative half-life, which is impossible. Ligand B (38.97) has a reasonable half-life.

**P-gp Efflux:** Ligand A (0.091) has lower P-gp efflux, which is favorable for CNS exposure. Ligand B (0.793) has higher P-gp efflux, potentially limiting CNS penetration.

**Binding Affinity:** Ligand B (-8.0 kcal/mol) has a slightly better binding affinity than Ligand A (-7.8 kcal/mol), but the difference is marginal.

**Overall Assessment:**

Ligand B has a superior BBB score, lower DILI risk, and a slightly better binding affinity. However, it suffers from a high logP, which could lead to solubility and off-target issues. Ligand A has a better TPSA, lower logP, and better metabolic stability. The negative half-life for Ligand A is a critical flaw. Given the importance of BBB penetration for a CNS target, and the relatively small difference in binding affinity, Ligand B appears to be the more promising candidate, *despite* its higher logP. The negative solubility and Caco-2 values are concerning for both, but can be addressed through formulation strategies.

Output:
1
2025-04-17 04:06:13,993 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (348.363 Da) is slightly lower, which could be beneficial for permeability. Ligand B (361.511 Da) is also good.

**TPSA:** Ligand A (127.24) is borderline for CNS penetration, being above the preferred <90, but not drastically so. Ligand B (47.36) is excellent, well below the threshold. This is a significant advantage for Ligand B.

**logP:** Ligand A (-0.897) is a bit low, potentially hindering membrane permeability. Ligand B (4.001) is at the upper end of the optimal range, which could lead to solubility issues but is generally acceptable.

**H-Bond Donors/Acceptors:** Ligand A has 3 HBD and 7 HBA, which are reasonable. Ligand B has 0 HBD and 5 HBA, also acceptable.

**QED:** Both ligands have good QED scores (A: 0.608, B: 0.714), indicating good drug-like properties.

**DILI:** Ligand A (78.48) has a higher DILI risk than Ligand B (20.396). This is a significant concern for Ligand A.

**BBB:** Ligand B (76.696) has a much better BBB penetration score than Ligand A (58.821). This is crucial for a CNS target like DRD2.

**Caco-2 Permeability:** Ligand A (-5.353) has poor Caco-2 permeability, which is concerning. Ligand B (-4.578) is also poor, but slightly better.

**Aqueous Solubility:** Both have very poor solubility (-2.191 and -4.142). This is a potential formulation challenge for both, but might be less of an issue if the compounds are highly potent and can be administered in a suitable formulation.

**hERG Inhibition:** Ligand A (0.029) has a very low hERG risk, which is excellent. Ligand B (0.527) is slightly higher, but still relatively low.

**Microsomal Clearance:** Ligand A (-19.11) has lower (better) microsomal clearance than Ligand B (101.832), indicating better metabolic stability.

**In vitro Half-Life:** Ligand A (31.811) has a better in vitro half-life than Ligand B (20.406).

**P-gp Efflux:** Ligand A (0.002) has very low P-gp efflux, which is excellent for CNS penetration. Ligand B (0.323) is higher, which could limit CNS exposure.

**Binding Affinity:** Ligand A (-7.4) has a slightly better binding affinity than Ligand B (-6.5). However, the difference is less than 1.5 kcal/mol, so it doesn't completely outweigh other factors.

**Overall:**

Ligand B is the more promising candidate. While its solubility is poor, it excels in crucial areas for a CNS GPCR target: TPSA, BBB penetration, and P-gp efflux. Its DILI risk is also significantly lower than Ligand A. Ligand A has a better affinity and metabolic stability, but its poor BBB, higher DILI, and low Caco-2 permeability are major drawbacks. The slightly better affinity of Ligand A is unlikely to overcome these significant ADME deficiencies.

Output:
1
2025-04-17 04:06:13,993 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (340.358 Da and 362.861 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (86.02) is better than Ligand B (70.25) as it is closer to the ideal <90 A^2 for CNS targets.

**logP:** Both ligands have good logP values (2.988 and 3.155), falling within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A (4 HBD, 2 HBA) is slightly better than Ligand B (2 HBD, 3 HBA). Both are within acceptable ranges.

**QED:** Both have good QED scores (0.588 and 0.877), indicating good drug-likeness. Ligand B is better here.

**DILI:** Ligand A (90.694) has a higher DILI risk than Ligand B (64.172). This is a significant negative for Ligand A.

**BBB:** Both ligands have acceptable BBB penetration (67.313 and 68.67). However, values >70 are preferred for CNS targets.

**Caco-2 Permeability:** Ligand A (-5.148) has poor Caco-2 permeability, while Ligand B (-4.797) is slightly better, but still not great.

**Aqueous Solubility:** Both ligands have poor aqueous solubility (-4.861 and -4.227).

**hERG:** Both ligands have low hERG inhibition liability (0.69 and 0.685), which is good.

**Microsomal Clearance:** Ligand B (31.134) has significantly lower microsomal clearance than Ligand A (6.159), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (100.987) has a much longer in vitro half-life than Ligand B (24.632).

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.201 and 0.233), which is favorable for CNS penetration.

**Binding Affinity:** Ligand A (-11.0) has a significantly stronger binding affinity than Ligand B (-0.0). This is a substantial advantage.

**Overall Assessment:**

Ligand A's primary advantage is its significantly higher binding affinity. However, it suffers from poor Caco-2 permeability, higher DILI risk, and lower metabolic stability. Ligand B has better metabolic stability, lower DILI risk, and slightly better Caco-2 permeability, but its binding affinity is very weak.

Given the importance of binding affinity for GPCRs, and the fact that the affinity difference is so large (over 10 kcal/mol), the strong binding of Ligand A outweighs its other drawbacks, *provided* that the poor permeability and DILI risk can be addressed through further optimization. The higher half-life is also a positive.

Output:
1
2025-04-17 04:06:13,993 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (370.881 and 340.467 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (87.47) is better than Ligand B (49.41). For CNS targets, we want TPSA <= 90, and both meet this criterion, but A is closer to the upper limit.

**3. logP:** Both ligands have good logP values (2.217 and 3.569), falling within the optimal 1-3 range. Ligand B is slightly higher, which *could* be a minor concern for solubility, but is still acceptable.

**4. H-Bond Donors:** Ligand A (2) and Ligand B (1) are both within the acceptable limit of <=5.

**5. H-Bond Acceptors:** Ligand A (5) and Ligand B (2) are both within the acceptable limit of <=10.

**6. QED:** Both ligands have good QED scores (0.695 and 0.736), indicating good drug-like properties.

**7. DILI:** Both ligands have low DILI risk (38.038 and 30.593), both below the 40 threshold.

**8. BBB:** Both ligands have excellent BBB penetration (70.609 and 70.221), exceeding the desirable >70% threshold for CNS targets.

**9. Caco-2 Permeability:** Ligand A (-5.033) and Ligand B (-4.802) both have negative values, which is unusual. It's difficult to interpret without knowing the scale, but generally, higher values are better.

**10. Aqueous Solubility:** Both ligands have poor aqueous solubility (-2.782 and -3.797). This is a potential issue for formulation and bioavailability, but can sometimes be overcome with formulation strategies.

**11. hERG Inhibition:** Both ligands have low hERG inhibition risk (0.246 and 0.669).

**12. Microsomal Clearance:** Ligand A (43.519) has a lower microsomal clearance than Ligand B (68.455), suggesting better metabolic stability.

**13. In vitro Half-Life:** Ligand A (77.441) has a significantly longer in vitro half-life than Ligand B (3.728). This is a major advantage.

**14. P-gp Efflux:** Ligand A (0.081) has lower P-gp efflux liability than Ligand B (0.373), which is favorable for CNS exposure.

**15. Binding Affinity:** Ligand B (-8.7 kcal/mol) has a significantly stronger binding affinity than Ligand A (-7.2 kcal/mol). This is a >1.5 kcal/mol advantage, which is substantial and can outweigh some ADME drawbacks.

**Overall Assessment:**

While Ligand A has better metabolic stability (lower Cl_mic, longer t1/2) and P-gp efflux, the significantly stronger binding affinity of Ligand B (-8.7 vs -7.2 kcal/mol) is the deciding factor. The affinity difference is large enough to compensate for the slightly higher logP and worse metabolic properties. Both have acceptable BBB penetration and DILI risk. Solubility is a concern for both, but is a formulation challenge rather than a fundamental disqualifier.

Output:
1
2025-04-17 04:06:13,993 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (344.415 and 347.419 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (81.27) is excellent, well below the 90 A^2 threshold for CNS targets. Ligand B (89.35) is still acceptable, but less optimal.

**logP:** Ligand A (3.578) is within the optimal 1-3 range. Ligand B (0.088) is significantly low, potentially hindering membrane permeability and CNS penetration.

**H-Bond Donors/Acceptors:** Ligand A (0 HBD, 5 HBA) is favorable. Ligand B (1 HBD, 6 HBA) is also reasonable.

**QED:** Both ligands have good QED scores (0.568 and 0.706), indicating drug-like properties.

**DILI:** Ligand A (65.568) has a moderate DILI risk, while Ligand B (50.523) is better, indicating a lower risk of liver injury.

**BBB:** Ligand A (84.141) has a very good BBB penetration percentile, highly desirable for a CNS target. Ligand B (37.146) is poor, suggesting limited CNS exposure.

**Caco-2 Permeability:** Both have negative values (-4.474 and -4.864). This is unusual and requires further investigation, but we'll assume it indicates poor permeability for now.

**Aqueous Solubility:** Both have negative values (-5.063 and -1.615), also unusual and suggesting poor solubility.

**hERG:** Ligand A (0.602) has a low hERG risk, while Ligand B (0.103) is even lower, indicating minimal cardiotoxicity concerns.

**Microsomal Clearance:** Ligand A (74.616) has moderate clearance, while Ligand B (-2.025) has *very* low clearance, suggesting high metabolic stability.

**In vitro Half-Life:** Ligand A (22.617 hours) is reasonable. Ligand B (-8.86 hours) is problematic, indicating rapid metabolism.

**P-gp Efflux:** Ligand A (0.511) has moderate P-gp efflux, while Ligand B (0.012) has very low efflux, which is beneficial for CNS penetration.

**Binding Affinity:** Both ligands have excellent binding affinity (-7.3 and -7.1 kcal/mol). The difference of 0.2 kcal/mol is not substantial enough to override other significant differences.

**Conclusion:**

Considering the GPCR-specific priorities, Ligand A is significantly more promising. Its superior BBB penetration, acceptable logP, and reasonable metabolic stability outweigh the slightly higher DILI risk compared to Ligand B. Ligand B's extremely low logP and poor BBB penetration are major drawbacks for a CNS-targeting drug, despite its better metabolic stability and lower P-gp efflux.

Output:
1
2025-04-17 04:06:13,993 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (347.34 and 367.471 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (47.04) is excellent, well below the 90 A^2 threshold for CNS targets. Ligand B (78.95) is higher, but still acceptable, though less optimal.

**logP:** Ligand A (4.83) is slightly high, potentially leading to solubility issues or off-target interactions. Ligand B (1.046) is quite low, which might hinder permeability.

**H-Bond Donors/Acceptors:** Both ligands have acceptable HBD (1) and HBA (4 & 5) counts, within the recommended limits.

**QED:** Both ligands have good QED scores (0.734 and 0.787), indicating good drug-like properties.

**DILI:** Both ligands have relatively high DILI risk (88.019 and 71.694), but Ligand B is better.

**BBB:** Ligand A (75.107) has a good BBB percentile, desirable for a CNS target. Ligand B (68.786) is lower, making CNS penetration less likely.

**Caco-2 Permeability:** Both have negative Caco-2 values (-4.574 and -4.866), which is unusual and suggests poor permeability. This is a significant concern.

**Aqueous Solubility:** Both have very poor aqueous solubility (-5.524 and -3.391). This is a major drawback.

**hERG:** Both ligands have low hERG risk (0.792 and 0.692).

**Microsomal Clearance:** Ligand A (76.334) has higher clearance than Ligand B (68.63), suggesting lower metabolic stability.

**In vitro Half-Life:** Ligand B (21.766) has a significantly longer half-life than Ligand A (-0.49), which is a substantial advantage.

**P-gp Efflux:** Ligand A (0.427) has lower P-gp efflux liability than Ligand B (0.21), which is favorable for CNS penetration.

**Binding Affinity:** Ligand A (-9.1 kcal/mol) has a significantly stronger binding affinity than Ligand B (-8.3 kcal/mol). This 0.8 kcal/mol difference is substantial and can outweigh some ADME drawbacks.

**Overall Assessment:**

Ligand A has a superior binding affinity and better BBB penetration, which are crucial for a CNS GPCR target. However, it suffers from higher logP, higher clearance, and poor solubility. Ligand B has better metabolic stability (longer half-life) and lower DILI risk, but its lower affinity and BBB penetration are significant disadvantages.

Despite the poor solubility and permeability for both, the significantly stronger binding affinity of Ligand A, coupled with its acceptable BBB, makes it the more promising candidate. The binding affinity advantage is large enough to warrant further optimization efforts to address the solubility and permeability issues.

Output:
1
2025-04-17 04:06:13,993 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight (MW):** Both ligands (341.455 and 349.431 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (58.37) is excellent, well below the 90 A^2 threshold for CNS targets. Ligand B (100.55) is still reasonable but higher, potentially impacting BBB penetration.

**3. logP:** Both ligands have good logP values (3.041 and 2.134), falling within the optimal 1-3 range.

**4. H-Bond Donors (HBD):** Ligand A (1) and Ligand B (3) are both acceptable, being less than 5.

**5. H-Bond Acceptors (HBA):** Ligand A (4) and Ligand B (5) are both acceptable, being less than 10.

**6. QED:** Both ligands have acceptable QED scores (0.877 and 0.7), indicating good drug-like properties.

**7. DILI:** Ligand A (23.032) has a much lower DILI risk than Ligand B (50.989), which is a significant advantage.

**8. BBB:** Ligand A (76.541) has a considerably better BBB percentile than Ligand B (64.482). This is *critical* for a CNS target like DRD2.

**9. Caco-2 Permeability:** Both have negative values (-4.968 and -4.7), which is unusual. However, the scale isn't specified, so it's hard to interpret. We'll consider this a neutral point.

**10. Aqueous Solubility:** Both have negative values (-1.555 and -2.843), again, scale unspecified, but potentially problematic.

**11. hERG Inhibition:** Ligand A (0.756) has a lower hERG risk than Ligand B (0.199), which is preferable.

**12. Microsomal Clearance:** Ligand A (5.513) has a lower microsomal clearance than Ligand B (28.103), indicating better metabolic stability.

**13. In vitro Half-Life:** Ligand A (-3.266) has a longer in vitro half-life than Ligand B (-13.169).

**14. P-gp Efflux:** Ligand A (0.31) has lower P-gp efflux liability than Ligand B (0.015), which is beneficial for CNS penetration.

**15. Binding Affinity:** Ligand A (-8.6 kcal/mol) has a slightly better binding affinity than Ligand B (-9.0 kcal/mol). While both are excellent, the difference is minimal.

**Overall Assessment:**

Ligand A is clearly superior. It excels in critical areas for a CNS-targeting GPCR ligand: BBB penetration, DILI risk, metabolic stability (Cl_mic and t1/2), P-gp efflux, and hERG inhibition. While both ligands have good MW, logP, QED, and affinity, the ADME properties of Ligand A are significantly more favorable. The slightly better affinity of Ligand B is unlikely to overcome the substantial advantages of Ligand A in terms of drug-likeness and safety.

Output:
1
2025-04-17 04:06:13,993 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (367.515 and 343.471 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (78.51) is slightly higher than Ligand B (71.09). Both are below the 90 A^2 threshold desirable for CNS targets, but Ligand B is preferable.

**3. logP:** Ligand A (1.006) is at the lower end of the optimal 1-3 range, while Ligand B (2.985) is closer to the ideal. Ligand B is better here for permeability.

**4. H-Bond Donors:** Both ligands have 2 HBD, which is within the acceptable limit of <=5.

**5. H-Bond Acceptors:** Ligand A has 4 HBA, and Ligand B has 3. Both are below the acceptable limit of <=10.

**6. QED:** Both ligands have good QED scores (0.711 and 0.799, respectively), indicating good drug-like properties.

**7. DILI:** Ligand A (31.02) has a slightly higher DILI risk than Ligand B (25.94), both are below the 40 threshold, so this difference is minor.

**8. BBB:** Ligand B (76.154) has a significantly better BBB penetration percentile than Ligand A (62.233). This is a *critical* factor for a CNS target like DRD2.

**9. Caco-2 Permeability:** Ligand A (-5.245) has worse Caco-2 permeability than Ligand B (-4.704).

**10. Aqueous Solubility:** Both ligands have poor aqueous solubility (-3.371 and -3.184 respectively).

**11. hERG Inhibition:** Ligand A (0.182) has a slightly lower hERG inhibition liability than Ligand B (0.404), which is preferable.

**12. Microsomal Clearance:** Ligand B (42.216) has higher microsomal clearance than Ligand A (31.064), meaning Ligand A is more metabolically stable.

**13. In vitro Half-Life:** Ligand A (6.156) has a longer in vitro half-life than Ligand B (3.86).

**14. P-gp Efflux:** Ligand A (0.016) has significantly lower P-gp efflux liability than Ligand B (0.081), which is highly desirable for CNS penetration.

**15. Binding Affinity:** Ligand B (-8.6 kcal/mol) has a stronger binding affinity than Ligand A (-7.5 kcal/mol). The difference of 1.1 kcal/mol is substantial and can outweigh some of the ADME drawbacks of Ligand B.

**Overall Assessment:**

While Ligand A has better metabolic stability (lower Cl_mic, longer t1/2) and P-gp efflux, Ligand B excels in the most critical areas for a CNS GPCR target: **BBB penetration and binding affinity**. The 1.1 kcal/mol difference in binding affinity is significant, and the higher BBB value of Ligand B (76.154 vs 62.233) is a major advantage. The slightly higher logP of Ligand B is also favorable. The slightly higher hERG and Cl_mic of Ligand B are less concerning given the strong affinity and BBB penetration.

Output:
1
2025-04-17 04:06:13,993 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (349.475 and 348.403 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (53.09) is excellent, well below the 90 A^2 threshold for CNS targets. Ligand B (113.44) is higher, but still potentially acceptable, though less ideal.

**logP:** Ligand A (0.953) is slightly below the optimal 1-3 range, potentially hindering permeation. Ligand B (0.623) is even lower, raising more concerns about permeability.

**H-Bond Donors/Acceptors:** Ligand A (0 HBD, 4 HBA) is favorable. Ligand B (3 HBD, 6 HBA) is also within acceptable limits.

**QED:** Both ligands have reasonable QED values (0.761 and 0.666), indicating good drug-like properties.

**DILI:** Ligand A (9.035) has a very low DILI risk, which is excellent. Ligand B (34.548) is higher, but still considered relatively low risk.

**BBB:** This is critical for a CNS target. Ligand A scores very well (70.027), exceeding the desirable >70 threshold. Ligand B (42.924) is significantly lower and a major drawback.

**Caco-2 Permeability:** Ligand A (-4.438) is poor, indicating limited intestinal absorption. Ligand B (-5.058) is even worse.

**Aqueous Solubility:** Both ligands have negative solubility values (-0.556 and -2.624), indicating poor solubility. This is a concern, but can sometimes be mitigated with formulation strategies.

**hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.425 and 0.085).

**Microsomal Clearance:** Ligand A (18.649) has a higher clearance than Ligand B (6.408), suggesting lower metabolic stability.

**In vitro Half-Life:** Ligand B (8.935) has a longer half-life than Ligand A (4.518), which is favorable.

**P-gp Efflux:** Both ligands show very low P-gp efflux liability (0.022 and 0.006), which is excellent for CNS penetration.

**Binding Affinity:** Ligand B (-7.4 kcal/mol) has a significantly stronger binding affinity than Ligand A (-6.9 kcal/mol). This 0.5 kcal/mol difference is substantial and could potentially overcome some of its ADME deficiencies.

**Overall Assessment:**

Ligand A excels in TPSA, DILI, and BBB penetration, which are crucial for CNS GPCR targets. However, its logP and Caco-2 permeability are concerning, and its metabolic stability (Cl_mic) is not ideal.

Ligand B has a significantly better binding affinity, a longer half-life, and lower microsomal clearance. However, its TPSA is higher, and its BBB penetration is substantially lower than Ligand A. Its logP is also suboptimal.

Given the strong emphasis on BBB penetration for CNS targets like DRD2, and the significant affinity advantage of Ligand B, I believe **Ligand B** is the more promising candidate, *despite* the lower BBB score. The stronger binding affinity could potentially allow for a lower dose, mitigating some of the permeability issues. Further optimization could focus on improving the BBB score and logP of Ligand B.

Output:
1
2025-04-17 04:06:13,994 - INFO - Reasoning:

Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (380.388 and 347.39 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (89.31) is better than Ligand B (73.74). Both are below the 90 A^2 threshold desirable for CNS targets.

**3. logP:** Ligand A (3.718) is within the optimal 1-3 range, while Ligand B (0.951) is slightly below, potentially hindering permeation.

**4. H-Bond Donors:** Both ligands have 1 HBD, which is acceptable.

**5. H-Bond Acceptors:** Both ligands have 4 HBAs, which is acceptable.

**6. QED:** Both ligands have good QED scores (0.602 and 0.823), indicating drug-like properties.

**7. DILI:** Ligand A (67.429) has a higher DILI risk than Ligand B (35.285). This is a significant drawback for Ligand A.

**8. BBB:** Both ligands have good BBB penetration (77.2 and 72.78), but Ligand A is slightly better.

**9. Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and suggests issues with the data or modeling. However, the magnitude is similar.

**10. Aqueous Solubility:** Both have negative solubility values, which is also unusual. Again, the magnitude is similar.

**11. hERG Inhibition:** Both ligands have low hERG inhibition risk (0.744 and 0.409).

**12. Microsomal Clearance:** Ligand A (43.779) has a higher microsomal clearance than Ligand B (11.901), indicating lower metabolic stability.

**13. In vitro Half-Life:** Ligand B (-23.586) has a significantly longer in vitro half-life than Ligand A (14.34). This is a major advantage for Ligand B.

**14. P-gp Efflux:** Both ligands have low P-gp efflux liability (0.406 and 0.05). Ligand B is slightly better.

**15. Binding Affinity:** Both ligands have excellent binding affinity (-9.1 and -8.5 kcal/mol). Ligand A has a 0.6 kcal/mol advantage.

**Overall Assessment:**

While Ligand A has a slightly better BBB and binding affinity, Ligand B is superior overall due to its significantly better DILI score, lower microsomal clearance (better metabolic stability), and longer in vitro half-life. The slightly lower logP of Ligand B is a minor concern, but the other advantages outweigh this. Given the GPCR-specific priorities, metabolic stability and safety (DILI) are crucial.

Output:
1
2025-04-17 04:06:13,994 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (360.401 and 386.298 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (87.66) is better than Ligand B (41.29). For CNS targets, TPSA < 90 is preferred, and both meet this criterion, but A is closer to the upper limit.

**3. logP:** Ligand A (0.973) is slightly lower than optimal (1-3), but still acceptable. Ligand B (4.491) is higher than ideal, potentially leading to solubility issues and off-target interactions.

**4. H-Bond Donors:** Ligand A (3) is higher than Ligand B (1), but both are within the acceptable limit of <=5.

**5. H-Bond Acceptors:** Both ligands have 4 H-bond acceptors, which is within the acceptable limit of <=10.

**6. QED:** Both ligands have good QED scores (0.659 and 0.762), indicating good drug-like properties.

**7. DILI:** Ligand A (26.018) has a significantly lower DILI risk than Ligand B (18.379), indicating a better safety profile.

**8. BBB:** Both ligands have good BBB penetration (76.347 and 73.827), both above the 70% threshold for CNS targets. Ligand A is slightly better.

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.13 and -4.871). This is unusual and suggests poor intestinal absorption. However, for a CNS target, intestinal absorption is less critical than BBB penetration.

**10. Aqueous Solubility:** Both ligands have negative solubility values (-1.409 and -4.692), indicating poor aqueous solubility. This is a concern, but can be mitigated through formulation strategies.

**11. hERG Inhibition:** Ligand A (0.276) has a much lower hERG inhibition risk than Ligand B (0.902). This is a significant advantage.

**12. Microsomal Clearance:** Ligand A (-4.673) has a negative clearance, which is very good, indicating high metabolic stability. Ligand B (69.744) has high clearance, suggesting rapid metabolism.

**13. In vitro Half-Life:** Ligand A (14.039 hours) has a longer half-life than Ligand B (-2.827 hours).

**14. P-gp Efflux:** Ligand A (0.015) has very low P-gp efflux liability, which is excellent for CNS penetration. Ligand B (0.687) has moderate P-gp efflux.

**15. Binding Affinity:** Ligand A (-7.8 kcal/mol) has a slightly better binding affinity than Ligand B (-7.4 kcal/mol). While both are good, the 0.4 kcal/mol difference is noticeable.

**Overall Assessment:**

Ligand A is significantly better than Ligand B. It has a lower DILI risk, lower hERG inhibition, better metabolic stability (negative clearance and longer half-life), lower P-gp efflux, and slightly better binding affinity. While both have poor solubility and Caco-2 permeability, these are less critical for a CNS target with good BBB penetration. Ligand B's high logP and high clearance are major drawbacks.

Output:
0
2025-04-17 04:06:13,994 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (363.403 Da) is slightly higher than Ligand B (343.471 Da), but both are acceptable.

**TPSA:** Ligand A (125.99) is borderline for CNS penetration, being slightly above the preferred <90. Ligand B (54.34) is excellent, well below the threshold. This favors Ligand B.

**logP:** Ligand A (-0.307) is a bit low, potentially hindering membrane permeability. Ligand B (2.564) is optimal. This is a significant advantage for Ligand B.

**H-Bond Donors/Acceptors:** Ligand A (2 HBD, 8 HBA) is acceptable. Ligand B (1 HBD, 3 HBA) is also good, potentially slightly better due to fewer H-bonds.

**QED:** Both ligands have good QED scores (A: 0.691, B: 0.863), indicating drug-like properties. Ligand B is slightly better.

**DILI:** Ligand A (76.386) has a higher DILI risk than Ligand B (17.836). This is a substantial advantage for Ligand B.

**BBB:** Both ligands have good BBB penetration (A: 58.976, B: 74.758), but Ligand B is better. While both are not >70, Ligand B is closer.

**Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and indicates poor permeability. However, the scale is not specified, so it's difficult to interpret.

**Aqueous Solubility:** Both have negative solubility values, which is also unusual. This is a concern for both.

**hERG:** Ligand A (0.046) has a very low hERG risk, which is excellent. Ligand B (0.309) is slightly higher but still relatively low.

**Microsomal Clearance:** Ligand A (-7.849) has a negative clearance, which is not physically possible and suggests an issue with the data. Ligand B (42.071) has a moderate clearance. This is a major red flag for Ligand A.

**In vitro Half-Life:** Ligand A (-10.211) has a negative half-life, which is also not physically possible and indicates an issue with the data. Ligand B (-2.735) is also negative, suggesting data quality issues.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (A: 0.021, B: 0.157), which is favorable for CNS penetration.

**Binding Affinity:** Both ligands have excellent binding affinities (A: -8.1 kcal/mol, B: -8.4 kcal/mol). Ligand B is slightly better, but the difference is small.

**Overall Assessment:**

Ligand B is significantly more promising. It has better logP, TPSA, DILI, BBB, and a slightly better binding affinity. The negative values for clearance and half-life for both compounds are concerning and suggest data errors, but are more problematic for Ligand A. While both have issues with solubility and Caco-2 permeability, Ligand B's overall profile is superior, particularly regarding key GPCR properties like BBB penetration and reduced off-target risk (DILI).

Output:
1
2025-04-17 04:06:13,994 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B based on the provided guidelines, prioritizing GPCR-specific properties (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (351.491 and 353.369 Da) fall within the ideal range of 200-500 Da.

**TPSA:** Ligand A (78.51) is better than Ligand B (82.53). Both are below the 90 A^2 threshold desirable for CNS targets, but A is closer to optimal.

**logP:** Both ligands have good logP values (1.838 and 1.211), falling within the 1-3 range. Ligand B is slightly lower, which *could* indicate slightly reduced permeability, but it's not a major concern.

**H-Bond Donors/Acceptors:** Both have 2 HBDs, which is good. Ligand A has 3 HBAs, while Ligand B has 4. Both are acceptable (<=10).

**QED:** Both ligands have similar and good QED values (0.7 and 0.797), indicating good drug-like properties.

**DILI:** Ligand A (14.424) has a significantly lower DILI risk than Ligand B (30.942). This is a substantial advantage for Ligand A.

**BBB:** Both ligands have good BBB penetration (65.452% and 68.36%), but neither exceeds the desirable >70% threshold. Ligand B is slightly better.

**Caco-2 Permeability:** Ligand A (-5.017) has *poor* Caco-2 permeability, while Ligand B (-4.676) is also poor, but slightly better.

**Aqueous Solubility:** Both ligands have poor aqueous solubility (-1.84 and -2.012). This could pose formulation challenges.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.282 and 0.421).

**Microsomal Clearance:** Ligand A (17.558) has a better (lower) microsomal clearance than Ligand B (-16.844). This suggests better metabolic stability for Ligand A.

**In vitro Half-Life:** Ligand A (-9.81) has a much longer in vitro half-life than Ligand B (-24.549). This is a significant advantage for Ligand A.

**P-gp Efflux:** Ligand A (0.058) has lower P-gp efflux than Ligand B (0.063), which is favorable for CNS penetration.

**Binding Affinity:** Ligand B (-8.4 kcal/mol) has a significantly stronger binding affinity than Ligand A (0.0 kcal/mol). This is a *major* advantage for Ligand B, potentially outweighing some ADME concerns.

**Overall Assessment:**

The key trade-off is between Ligand B's superior binding affinity and Ligand A's better ADME properties (DILI, Cl_mic, t1/2, Pgp). Given that this is a CNS target (DRD2), BBB is important, and both are reasonably good. However, the *substantial* difference in binding affinity (-8.4 vs 0.0 kcal/mol) is likely to be the dominant factor. A strong binding affinity can often be optimized through further structural modifications, while poor ADME properties are more difficult to fix later in development. The better metabolic stability and lower DILI risk of Ligand A are attractive, but the lack of significant binding affinity is a critical flaw.

Output:
1
2025-04-17 04:06:13,994 - INFO - Batch 84 complete. Total preferences: 1344
2025-04-17 04:06:13,994 - INFO - Processing batch 85/512...
2025-04-17 04:06:55,079 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (351.447) is slightly lower, which could be beneficial for permeability, but both are acceptable.

**TPSA:** Ligand A (110.52) is borderline for CNS targets (ideally <90), while Ligand B (81.86) is well within the desired range. This is a significant advantage for Ligand B.

**logP:** Ligand A (0.49) is quite low, potentially hindering membrane permeability and CNS penetration. Ligand B (1.903) is within the optimal range (1-3). This is a substantial advantage for Ligand B.

**H-Bond Donors/Acceptors:** Ligand A has 3 HBD and 4 HBA, which are acceptable. Ligand B has 1 HBD and 5 HBA, also acceptable.

**QED:** Both ligands have good QED scores (A: 0.525, B: 0.739), indicating good drug-like properties. Ligand B is better.

**DILI:** Both have acceptable DILI risk (A: 25.63, B: 37.03), with Ligand B being slightly higher but still within a reasonable range.

**BBB:** Ligand B (82.745) has a significantly better BBB percentile than Ligand A (62.97). This is crucial for a CNS target like DRD2.

**Caco-2 Permeability:** Ligand A (-5.305) has poor Caco-2 permeability, while Ligand B (-4.998) is also poor, but slightly better.

**Aqueous Solubility:** Both have poor aqueous solubility (-2.612 and -2.98 respectively). This could pose formulation challenges.

**hERG:** Both ligands have very low hERG inhibition liability (A: 0.049, B: 0.264), which is excellent.

**Microsomal Clearance:** Ligand B (32.998) has lower microsomal clearance than Ligand A (46.727), indicating better metabolic stability.

**In vitro Half-Life:** Ligand B (10.228) has a significantly longer half-life than Ligand A (-2.276). This is a major advantage for dosing convenience.

**P-gp Efflux:** Both have very low P-gp efflux liability (A: 0.008, B: 0.14), which is good.

**Binding Affinity:** Ligand B (-7.5 kcal/mol) has a slightly better binding affinity than Ligand A (-7.1 kcal/mol). While the difference is not huge, it's a positive factor.

**Overall Assessment:**

Ligand B is clearly superior. It excels in key properties for a CNS-targeting GPCR ligand: better TPSA, significantly better logP and BBB penetration, improved metabolic stability (lower Cl_mic, longer t1/2), and slightly better binding affinity. While both have poor solubility and Caco-2 permeability, the CNS-specific properties of Ligand B outweigh these drawbacks. The low logP of Ligand A is a major concern for CNS penetration.

Output:
1
2025-04-17 04:06:55,080 - INFO - Reasoning:

Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (354.372 and 342.443 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (38.5) is significantly better than Ligand B (75.5). For CNS targets, we want TPSA <= 90, and A is comfortably within that, while B is approaching the upper limit.

**3. logP:** Ligand A (4.513) is a bit high, potentially leading to solubility issues, but still within a manageable range. Ligand B (2.397) is excellent.

**4. H-Bond Donors:** Ligand A (0) is ideal. Ligand B (2) is acceptable.

**5. H-Bond Acceptors:** Both ligands have 4 HBA, which is within the acceptable limit of <=10.

**6. QED:** Both ligands have similar QED values (0.81 and 0.773), indicating good drug-likeness.

**7. DILI:** Both ligands have low DILI risk (46.258 and 43.195), which is positive.

**8. BBB:** Ligand A (85.731) has a significantly better BBB penetration percentile than Ligand B (79.062).  For a CNS target like DRD2, >70 is desirable, and A is closer to that threshold.

**9. Caco-2 Permeability:** Both have negative values, which is unusual and suggests a potential issue with the data or modeling. However, the magnitude is similar.

**10. Aqueous Solubility:** Both have negative solubility values, which is also unusual. Ligand B (-3.49) is slightly better (less negative) than Ligand A (-4.721).

**11. hERG Inhibition:** Both ligands have low hERG inhibition risk (0.875 and 0.646).

**12. Microsomal Clearance:** Ligand B (53.535) has a lower (better) microsomal clearance than Ligand A (46.006).

**13. In vitro Half-Life:** Ligand A (-33.607) has a significantly longer (better) in vitro half-life than Ligand B (20.508).

**14. P-gp Efflux:** Both ligands have low P-gp efflux liability (0.37 and 0.067). Ligand B is slightly better.

**15. Binding Affinity:** Ligand A (-9.0 kcal/mol) has a substantially stronger binding affinity than Ligand B (-8.7 kcal/mol). This is a crucial advantage, as a >1.5 kcal/mol difference can outweigh other drawbacks.

**Overall Assessment:**

Ligand A is the stronger candidate. While its logP is slightly higher, its significantly better TPSA, BBB penetration, and *much* stronger binding affinity outweigh this concern. The longer half-life is also a significant advantage. The unusual solubility and Caco-2 values are a flag, but the other properties are more critical for a CNS GPCR target.

Output:
1
2025-04-17 04:06:55,080 - INFO - Reasoning:

Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (354.332 and 360.439 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (78.09) is significantly better than Ligand B (88.33). For CNS targets, we want TPSA <= 90, and A is closer to the optimal <=60 range. B is pushing the upper limit.

**3. logP:** Both ligands have good logP values (1.994 and 2.449), falling within the optimal 1-3 range.

**4. H-Bond Donors:** Ligand A (2) is slightly higher than Ligand B (1), but both are within the acceptable limit of <=5.

**5. H-Bond Acceptors:** Ligand A (3) is lower than Ligand B (6). Both are within the acceptable limit of <=10, but A is preferable.

**6. QED:** Both ligands have good QED scores (0.641 and 0.855), indicating good drug-like properties.

**7. DILI:** Ligand A (56.068) has a lower DILI risk than Ligand B (73.245). Both are under 60, so acceptable, but A is better.

**8. BBB:** This is critical for a CNS target. Ligand A (80.264) has a significantly better BBB penetration percentile than Ligand B (66.925). A is >70, which is desirable.

**9. Caco-2 Permeability:** Both have negative values (-4.967 and -5.014) which is unusual and suggests poor permeability. This is a concern for both, but doesn't differentiate them.

**10. Aqueous Solubility:** Both have negative values (-3.246 and -3.108) which is also unusual and suggests poor solubility. This is a concern for both, but doesn't differentiate them.

**11. hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.209 and 0.14).

**12. Microsomal Clearance:** Ligand A (4.705) has lower microsomal clearance than Ligand B (48.854), indicating better metabolic stability.

**13. In vitro Half-Life:** Ligand A (-6.525) has a much longer in vitro half-life than Ligand B (-26.524).

**14. P-gp Efflux:** Both ligands have low P-gp efflux liability (0.14 and 0.119).

**15. Binding Affinity:** Ligand B (-8.2) has a slightly better binding affinity than Ligand A (-9.1). However, the difference is less than 1.5 kcal/mol, so the ADME advantages of Ligand A are more important.

**Overall Assessment:**

Ligand A is significantly better overall. It has a lower TPSA, better BBB penetration, lower DILI risk, lower microsomal clearance, and a longer half-life. While Ligand B has slightly better binding affinity, the ADME properties of Ligand A are far more favorable for a CNS-targeting drug, especially considering the importance of BBB penetration for GPCRs in the brain. The negative Caco-2 and solubility values are concerning for both, but the other advantages of A outweigh this.

Output:
1
2025-04-17 04:06:55,080 - INFO - Reasoning:

Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (358.467 and 344.507 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (83.98) is better than Ligand B (58.87). Both are below the 90 A^2 threshold for CNS targets, but A is closer to the upper limit.

**3. logP:** Ligand A (2.216) is within the optimal 1-3 range. Ligand B (3.838) is slightly higher, potentially increasing off-target interactions, but still acceptable.

**4. H-Bond Donors:** Ligand A (2) and Ligand B (1) are both within the acceptable limit of <=5.

**5. H-Bond Acceptors:** Ligand A (5) and Ligand B (6) are both within the acceptable limit of <=10.

**6. QED:** Both ligands have similar QED values (0.758 and 0.737), indicating good drug-likeness.

**7. DILI:** Ligand A (45.522) has a lower DILI risk than Ligand B (59.131), which is preferable. Both are below the concerning threshold of 60.

**8. BBB:** Ligand B (88.949) has a significantly better BBB penetration score than Ligand A (62.117). This is a *critical* advantage for a CNS target like DRD2.

**9. Caco-2 Permeability:** Both have negative values, which is unusual. I will assume these are logP values and interpret them as poor permeability.

**10. Aqueous Solubility:** Both have negative values, indicating poor solubility.

**11. hERG Inhibition:** Ligand A (0.053) has a much lower hERG inhibition risk than Ligand B (0.964). This is a significant advantage for Ligand A.

**12. Microsomal Clearance:** Ligand B (95.928) has a much higher microsomal clearance than Ligand A (27.274), meaning it's metabolized more quickly. Lower clearance is preferred.

**13. In vitro Half-Life:** Ligand B (29.127) has a slightly longer half-life than Ligand A (24.252), which is a minor advantage.

**14. P-gp Efflux:** Ligand A (0.099) has lower P-gp efflux liability than Ligand B (0.871), which is favorable for CNS penetration.

**15. Binding Affinity:** Ligand A (-9.1 kcal/mol) has a slightly better binding affinity than Ligand B (-8.3 kcal/mol). While both are excellent, the 0.8 kcal/mol difference is noteworthy.

**Overall Assessment:**

Ligand B excels in BBB penetration, a crucial factor for CNS targets. However, it suffers from higher DILI risk, higher hERG inhibition, and higher P-gp efflux. Ligand A has better metabolic stability (lower Cl_mic), lower DILI and hERG risk, and slightly better affinity. The superior BBB of Ligand B is a strong point, but the combined advantages of Ligand A in safety (DILI, hERG) and metabolic stability, coupled with its good affinity, make it the more promising candidate.

Output:
1
2025-04-17 04:06:55,080 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (365.503 and 352.41 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (80.12) is significantly better than Ligand B (96.25). For CNS targets, we want TPSA <= 90, so Ligand A is preferable.

**logP:** Ligand A (1.307) is within the optimal 1-3 range. Ligand B (0.393) is a bit low, potentially hindering permeation.

**H-Bond Donors/Acceptors:** Ligand A (HBD=1, HBA=6) and Ligand B (HBD=3, HBA=5) both have acceptable numbers of H-bond donors and acceptors.

**QED:** Both ligands have reasonable QED values (0.788 and 0.662), indicating good drug-like properties.

**DILI:** Ligand A (44.203) and Ligand B (38.503) both have low DILI risk, below the threshold of 40 being good.

**BBB:** Ligand B (69.833) has a better BBB percentile than Ligand A (54.983), but both are below the desirable >70 for CNS targets. This is a critical factor for DRD2.

**Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and suggests a potential issue with the data or modeling. However, we can still compare relative values. Ligand A (-5.641) is slightly better than Ligand B (-5.197).

**Aqueous Solubility:** Both ligands have very poor aqueous solubility (-2.216 and -2.124). This is a significant drawback, but can sometimes be overcome with formulation strategies.

**hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.155 and 0.105).

**Microsomal Clearance:** Ligand B (-12.193) has significantly lower (better) microsomal clearance than Ligand A (27.013), indicating greater metabolic stability.

**In vitro Half-Life:** Ligand B (1.116) has a slightly better half-life than Ligand A (-8.17), though both are quite low.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.023 and 0.02).

**Binding Affinity:** Ligand B (-8.3) has a slightly better binding affinity than Ligand A (-7.7). While a 1.5 kcal/mol difference isn't huge, it's a positive for Ligand B.

**Overall Assessment:**

Ligand A excels in TPSA and logP, which are important for CNS penetration. However, Ligand B has a better BBB percentile, significantly better metabolic stability (lower Cl_mic), and slightly better binding affinity. The poor solubility of both is a concern, but the better BBB and metabolic stability of Ligand B, combined with its slightly improved affinity, make it the more promising candidate despite the slightly higher TPSA. The affinity difference, while small, could be critical for efficacy.

Output:
1
2025-04-17 04:06:55,080 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (363.483 and 365.547 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (82.53) is better than Ligand B (67.07). Both are below the 90 A^2 threshold desirable for CNS targets, but A is slightly higher and could be a minor drawback.

**3. logP:** Ligand A (1.897) is within the optimal range (1-3). Ligand B (3.321) is at the higher end of the optimal range.

**4. H-Bond Donors:** Ligand A (2) and Ligand B (1) both meet the criteria of <=5.

**5. H-Bond Acceptors:** Ligand A (5) and Ligand B (7) both meet the criteria of <=10.

**6. QED:** Both ligands have good QED scores (0.723 and 0.777, respectively), indicating good drug-like properties.

**7. DILI:** Ligand A (46.258) has a slightly higher DILI risk than Ligand B (19.349). This favors Ligand B.

**8. BBB:** Both ligands have reasonably good BBB penetration (Ligand A: 46.84%, Ligand B: 48.817%). While >70% is desirable, these are acceptable, and similar.

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 values, which is unusual and suggests poor permeability. Ligand A (-5.381) is slightly worse than Ligand B (-5.113).

**10. Aqueous Solubility:** Both ligands have negative solubility values, which is also unusual and suggests poor solubility. Ligand A (-3.42) is slightly worse than Ligand B (-3.047).

**11. hERG Inhibition:** Both ligands have low hERG inhibition risk (Ligand A: 0.34, Ligand B: 0.593).

**12. Microsomal Clearance:** Ligand A (21.938) has significantly lower microsomal clearance than Ligand B (40.882), indicating better metabolic stability.

**13. In vitro Half-Life:** Ligand A (-14.435) has a negative half-life, which is not possible and indicates a problem with the data. Ligand B (35.541) has a reasonable half-life.

**14. P-gp Efflux:** Both ligands have low P-gp efflux liability (Ligand A: 0.076, Ligand B: 0.116).

**15. Binding Affinity:** Ligand A (-7.4 kcal/mol) has a slightly better binding affinity than Ligand B (-6.8 kcal/mol). The difference is 0.6 kcal/mol, which is significant.

**Overall Assessment:**

Ligand A has a better binding affinity and lower microsomal clearance, which are key advantages. However, the negative half-life value is a major red flag, suggesting a data error or a highly unstable compound. Ligand B has a better DILI score, and a positive half-life, but a slightly worse affinity. Given the importance of metabolic stability and a reasonable half-life for *in vivo* efficacy, and the significant affinity advantage of A, I would cautiously favor Ligand A *if* the half-life data can be verified/corrected. However, the negative half-life is a serious concern. Without corrected data, I must select Ligand B.

Output:
1
2025-04-17 04:06:55,080 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B based on the provided guidelines and GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (344.499 and 347.459 Da) fall within the ideal range of 200-500 Da.

**TPSA:** Ligand A (40.62) is significantly better than Ligand B (82.53). For CNS targets, TPSA should be <= 90, and ideally lower. Ligand A is well within this range, while Ligand B is approaching the upper limit and less favorable.

**logP:** Ligand A (3.23) is optimal (1-3), while Ligand B (1.696) is on the lower side, potentially hindering permeation.

**H-Bond Donors/Acceptors:** Ligand A (0 HBD, 2 HBA) is preferable to Ligand B (2 HBD, 4 HBA). Lower values generally improve permeability.

**QED:** Both ligands have acceptable QED values (0.738 and 0.631, both > 0.5).

**DILI:** Ligand A (16.092) has a much lower DILI risk than Ligand B (28.577), indicating better potential for liver safety.

**BBB:** This is a crucial parameter for a CNS target like DRD2. Ligand A (78.558) shows excellent BBB penetration (close to the desirable >70), while Ligand B (34.238) is poor.

**Caco-2 Permeability:** Both are negative, suggesting poor permeability. However, the scale is not specified, so it's hard to interpret.

**Aqueous Solubility:** Both are negative, suggesting poor solubility. Again, the scale is not specified.

**hERG:** Both ligands have low hERG inhibition liability (0.433 and 0.367).

**Microsomal Clearance:** Ligand A (78.873) has higher clearance than Ligand B (53.339), meaning it's less metabolically stable.

**In vitro Half-Life:** Ligand B (18.698) has a significantly longer half-life than Ligand A (-5.856), which is a major advantage.

**P-gp Efflux:** Both ligands show low P-gp efflux liability (0.231 and 0.086).

**Binding Affinity:** Ligand B (-7.6 kcal/mol) has a slightly better binding affinity than Ligand A (-9.3 kcal/mol). However, the difference is not substantial enough to outweigh the significant ADME advantages of Ligand A.

**Overall Assessment:**

Considering the GPCR-specific priorities, Ligand A is the superior candidate. Its excellent BBB penetration, favorable TPSA and logP values, and low DILI risk are critical for a CNS-targeting drug. While Ligand B has slightly better affinity and half-life, the poor BBB penetration and higher DILI risk are major drawbacks. The difference in affinity is not large enough to overcome the ADME deficiencies of Ligand B.

Output:
1
2025-04-17 04:06:55,080 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (348.418 and 349.45 Da) fall comfortably within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (50.8) and Ligand B (52.65) are both below the 90 A^2 threshold for CNS targets, which is excellent.

**3. logP:** Ligand A (2.335) is within the optimal 1-3 range. Ligand B (1.492) is slightly lower but still acceptable.

**4. H-Bond Donors:** Both ligands have 1 HBD, which is well within the acceptable limit of <=5.

**5. H-Bond Acceptors:** Ligand A has 4 HBAs, and Ligand B has 3. Both are below the acceptable limit of <=10.

**6. QED:** Ligand A (0.887) has a higher QED than Ligand B (0.709), indicating a more drug-like profile.

**7. DILI:** Ligand A (13.61) has a significantly lower DILI risk than Ligand B (11.788), both are good, but A is preferable.

**8. BBB:** Both ligands have excellent BBB penetration (Ligand A: 88.057%, Ligand B: 87.321%). This is crucial for a CNS target like DRD2.

**9. Caco-2 Permeability:** Both have negative values (-4.47 and -4.953), which is unusual and suggests poor permeability. However, these values are on a scale where negative values are possible, and the absolute magnitude is important. They are relatively similar.

**10. Aqueous Solubility:** Both have negative values (-1.879 and -2.436). Similar to Caco-2, these are on a scale where negative values are possible. Ligand B has slightly worse solubility.

**11. hERG Inhibition:** Both ligands show low hERG inhibition risk (Ligand A: 0.634, Ligand B: 0.582).

**12. Microsomal Clearance:** Ligand A (41.786) has higher microsomal clearance than Ligand B (21.416), indicating lower metabolic stability. This is a significant drawback for Ligand A.

**13. In vitro Half-Life:** Ligand B (-9.805) has a much longer in vitro half-life than Ligand A (1.431), indicating better stability.

**14. P-gp Efflux:** Both ligands show low P-gp efflux liability (Ligand A: 0.061, Ligand B: 0.036).

**15. Binding Affinity:** Ligand A (-8.7 kcal/mol) has a slightly better binding affinity than Ligand B (-8.3 kcal/mol), but the difference is relatively small (0.4 kcal/mol).

**Overall Assessment:**

While Ligand A has a slightly better QED and binding affinity, Ligand B demonstrates superior ADME properties, particularly in terms of metabolic stability (lower Cl_mic, longer t1/2) and slightly better solubility. The difference in binding affinity is not substantial enough to outweigh the significant advantage of Ligand B's improved pharmacokinetic profile. For a CNS target, metabolic stability and BBB penetration are paramount.

Output:
1
2025-04-17 04:06:55,080 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (386.945 Da) is slightly higher than Ligand B (368.344 Da), but both are acceptable.

**TPSA:** Ligand A (78.43) is significantly better than Ligand B (103.59). For CNS targets, we want TPSA <= 90, and Ligand A is comfortably within this range, while Ligand B is pushing the limit.

**logP:** Both ligands have good logP values (A: 2.989, B: 2.196), falling within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A (HBD=3, HBA=4) is slightly better than Ligand B (HBD=2, HBA=7). Both are within acceptable limits, but fewer H-bonds generally improve permeability.

**QED:** Both ligands have good QED scores (A: 0.642, B: 0.857), indicating good drug-like properties. Ligand B is slightly better here.

**DILI:** Ligand A (44.63) has a much lower DILI risk than Ligand B (89.996). This is a significant advantage for Ligand A.

**BBB:** Ligand A (54.478) has a better BBB penetration percentile than Ligand B (59.17). While both are not ideal (>70 desirable), A is closer.

**Caco-2 Permeability:** Ligand A (-4.916) has a worse Caco-2 permeability than Ligand B (-5.068). Lower values indicate lower permeability.

**Aqueous Solubility:** Ligand A (-3.929) has a slightly better aqueous solubility than Ligand B (-4.339).

**hERG Inhibition:** Both ligands have low hERG inhibition risk (A: 0.471, B: 0.317), which is good.

**Microsomal Clearance:** Ligand A (57.558) has a higher microsomal clearance than Ligand B (5.673). This suggests Ligand B is more metabolically stable.

**In vitro Half-Life:** Ligand A (23.601) has a longer in vitro half-life than Ligand B (3.456).

**P-gp Efflux:** Ligand A (0.564) has a lower P-gp efflux liability than Ligand B (0.017). Lower P-gp efflux is preferable for CNS penetration.

**Binding Affinity:** Ligand B (-9.0) has a significantly stronger binding affinity than Ligand A (-8.3). This is a substantial advantage, potentially outweighing some ADME drawbacks.

**Overall Assessment:**

Ligand B has a significantly better binding affinity, which is crucial for GPCR targets. However, it suffers from a higher DILI risk, a TPSA that is pushing the limit, and a higher P-gp efflux. Ligand A has a better safety profile (lower DILI), better TPSA, and better P-gp efflux, but its affinity is weaker. Considering the GPCR-specific priorities, the strong binding affinity of Ligand B is a major advantage. While the other properties are not ideal, optimization could potentially address those issues. The affinity difference of 0.7 kcal/mol is substantial.

Output:
1
2025-04-17 04:06:55,080 - INFO - Reasoning:

Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (365.748 and 389.543 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (94.36) is slightly higher than Ligand B (88.6). Both are below the 90 A^2 threshold desirable for CNS targets, but Ligand B is preferable.

**3. logP:** Ligand A (3.723) is at the upper end of the optimal range (1-3), while Ligand B (1.784) is closer to the lower end. While both are acceptable, Ligand A's higher logP could potentially lead to off-target interactions or solubility issues.

**4. H-Bond Donors:** Both ligands have 1 HBD, which is within the acceptable limit of <=5.

**5. H-Bond Acceptors:** Ligand A has 5 HBAs, and Ligand B has 6. Both are below the acceptable limit of <=10.

**6. QED:** Ligand B (0.732) has a significantly better QED score than Ligand A (0.478), indicating a more drug-like profile.

**7. DILI:** Ligand B (61.807) has a lower DILI risk than Ligand A (87.864), which is a significant advantage.

**8. BBB:** Ligand A (76.309) has a slightly better BBB penetration percentile than Ligand B (63.862). This is a critical factor for CNS targets like DRD2.

**9. Caco-2 Permeability:** Ligand A (-4.443) has a more negative Caco-2 value, suggesting *lower* permeability than Ligand B (-5.263). This is unfavorable.

**10. Aqueous Solubility:** Ligand A (-5.347) has a more negative solubility value, indicating *lower* solubility than Ligand B (-3.124). This is unfavorable.

**11. hERG Inhibition:** Both ligands have relatively low hERG inhibition risk (0.22 and 0.41 respectively).

**12. Microsomal Clearance:** Ligand B (54.411) has a lower microsomal clearance than Ligand A (63.682), suggesting better metabolic stability.

**13. In vitro Half-Life:** Ligand B (2.146) has a slightly longer in vitro half-life than Ligand A (1.818).

**14. P-gp Efflux:** Both ligands have low P-gp efflux liability (0.19 and 0.113 respectively).

**15. Binding Affinity:** Ligand A (-9.1 kcal/mol) has a significantly stronger binding affinity than Ligand B (-7.8 kcal/mol). This is a substantial advantage.

**Overall Assessment:**

While Ligand A boasts a superior binding affinity, Ligand B has a more favorable ADME profile across several key parameters. Specifically, Ligand B exhibits lower DILI risk, better QED, improved solubility, better metabolic stability, and a slightly longer half-life. The difference in binding affinity (-1.3 kcal/mol) is substantial, but not insurmountable, and can potentially be optimized in subsequent iterations. Given the GPCR-specific emphasis on BBB penetration, the slightly better BBB score of Ligand A is a point in its favor, but is outweighed by the other ADME advantages of Ligand B. For a CNS target, a balance between potency and favorable ADME properties is crucial.

Output:
1
2025-04-17 04:06:55,081 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B based on the provided guidelines, prioritizing GPCR-specific properties (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (382.595 Da) is slightly higher than Ligand B (350.463 Da), but both are acceptable.

**TPSA:** Ligand A (58.2) is excellent for CNS penetration, well below the 90 A^2 threshold. Ligand B (65.12) is still reasonable but less optimal.

**logP:** Ligand A (3.769) is within the optimal range (1-3). Ligand B (-0.765) is significantly below this, which could hinder membrane permeability and CNS entry despite a good TPSA.

**H-Bond Donors/Acceptors:** Ligand A (2 HBD, 4 HBA) and Ligand B (1 HBD, 5 HBA) both fall within acceptable limits (<=5 HBD, <=10 HBA).

**QED:** Both ligands have acceptable QED values (Ligand A: 0.673, Ligand B: 0.521), indicating reasonable drug-likeness.

**DILI:** Ligand A (47.266) has a moderate DILI risk, but is still within acceptable limits (<60). Ligand B (8.841) has a very low DILI risk, which is favorable.

**BBB:** This is a critical parameter for CNS targets. Ligand A (71.811) has a good BBB percentile, exceeding the 70% threshold. Ligand B (53.936) is significantly lower, suggesting poorer brain penetration.

**Caco-2 Permeability:** Ligand A (-5.044) and Ligand B (-4.833) have negative values, which is unusual. These values are likely on a log scale and indicate poor permeability.

**Aqueous Solubility:** Both ligands have very poor aqueous solubility (-4.791 and -0.795 respectively). This could pose formulation challenges.

**hERG Inhibition:** Ligand A (0.683) has a low hERG risk. Ligand B (0.317) also has a low hERG risk.

**Microsomal Clearance:** Ligand A (89.83) has a relatively high microsomal clearance, suggesting faster metabolism. Ligand B (-13.983) has a negative clearance, which is impossible and likely indicates an error or an extremely stable compound.

**In vitro Half-Life:** Ligand A (37.619) has a moderate half-life. Ligand B (-15.834) has a negative half-life, which is impossible and suggests an issue with the data.

**P-gp Efflux:** Ligand A (0.395) has low P-gp efflux, which is good for CNS penetration. Ligand B (0.012) has very low P-gp efflux, which is even better.

**Binding Affinity:** Ligand A (-7.9 kcal/mol) has a significantly stronger binding affinity than Ligand B (-7.3 kcal/mol). The 1.6 kcal/mol difference is substantial and can outweigh some ADME drawbacks.

**Overall Assessment:**

Ligand A is the stronger candidate. While it has a slightly higher molecular weight and moderate DILI risk, its superior BBB penetration, excellent TPSA, stronger binding affinity, and low P-gp efflux outweigh the drawbacks. Ligand B has a better DILI profile and P-gp efflux, but its significantly lower logP and substantially worse BBB penetration are major concerns for a CNS-targeting drug. The negative values for clearance and half-life for ligand B are also red flags, suggesting data quality issues.

Output:
1
2025-04-17 04:06:55,081 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (366.575 and 346.475 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (66.91) is slightly higher than Ligand B (59.39). Both are below the 90 A^2 threshold desirable for CNS targets, which is good.

**logP:** Ligand A (3.993) is at the upper end of the optimal range (1-3), while Ligand B (1.943) is closer to the lower end. While Ligand A's logP is acceptable, it's closer to a potential issue with solubility or off-target effects.

**H-Bond Donors/Acceptors:** Ligand A has 2 HBD and 5 HBA, while Ligand B has 1 HBD and 5 HBA. Both are within acceptable limits.

**QED:** Ligand A (0.655) and Ligand B (0.82) both have good drug-likeness scores, exceeding the 0.5 threshold. Ligand B is slightly better.

**DILI:** Ligand A (45.173) has a moderate DILI risk, while Ligand B (13.532) has a very low DILI risk. This is a significant advantage for Ligand B.

**BBB:** Both ligands have good BBB penetration (Ligand A: 75.572, Ligand B: 81.349), exceeding the 70% threshold for CNS targets. Ligand B is slightly better.

**Caco-2 Permeability:** Both have negative Caco-2 values (-5.111 and -5.091), which is unusual and suggests poor permeability. This is a concern for both, but doesn't necessarily disqualify them.

**Aqueous Solubility:** Both have negative solubility values (-4.454 and -1.112), indicating poor aqueous solubility. Ligand B is better than Ligand A.

**hERG:** Both ligands have low hERG inhibition liability (0.782 and 0.655), which is good.

**Microsomal Clearance:** Ligand A (110.399) has higher microsomal clearance than Ligand B (47.985), indicating lower metabolic stability. This favors Ligand B.

**In vitro Half-Life:** Ligand A (67.207) has a longer half-life than Ligand B (7.477), which is desirable.

**P-gp Efflux:** Ligand A (0.315) has lower P-gp efflux than Ligand B (0.068), which is favorable for CNS exposure.

**Binding Affinity:** Ligand B (-7.3 kcal/mol) has a significantly stronger binding affinity than Ligand A (-8.0 kcal/mol). This is a crucial advantage, as a >1.5 kcal/mol difference can outweigh other drawbacks.

**Overall Assessment:**

Ligand B is the stronger candidate. While Ligand A has a longer half-life and lower P-gp efflux, Ligand B excels in critical areas: significantly better binding affinity, lower DILI risk, slightly better BBB penetration, and lower microsomal clearance. The solubility and Caco-2 permeability are concerns for both, but the superior affinity and safety profile of Ligand B make it more likely to succeed as a drug candidate.

Output:
1
2025-04-17 04:06:55,081 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (341.415 and 346.515 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (90.12) is better than Ligand B (40.62). For CNS targets, TPSA <= 90 is preferred, and Ligand A is right on the threshold, while Ligand B is well below.

**logP:** Both ligands have acceptable logP values (1.415 and 3.308), falling within the optimal 1-3 range. Ligand B is slightly higher, which could potentially lead to off-target effects, but it's not a major concern.

**H-Bond Donors/Acceptors:** Ligand A has 3 HBD and 3 HBA, while Ligand B has 0 HBD and 2 HBA. Both are within acceptable limits (<=5 HBD and <=10 HBA).

**QED:** Both ligands have similar QED values (0.768 and 0.766), indicating good drug-likeness.

**DILI:** Ligand A has a DILI risk of 55.138, while Ligand B has 15.471. Ligand B is significantly better, with a low DILI risk.

**BBB:** Ligand A has a BBB penetration of 80.419, and Ligand B has 90.5. Both are good, exceeding the 70% threshold for CNS targets, but Ligand B is superior.

**Caco-2 Permeability:** Ligand A (-5.154) and Ligand B (-4.731) both have negative values, indicating poor permeability. This is a concern for both.

**Aqueous Solubility:** Both ligands have poor aqueous solubility (-2.99 and -3.405). This could pose formulation challenges.

**hERG Inhibition:** Ligand A (0.418) is better than Ligand B (0.658), indicating a lower risk of cardiotoxicity.

**Microsomal Clearance:** Ligand A (-2.118) has a lower (better) microsomal clearance than Ligand B (63.064), suggesting greater metabolic stability.

**In vitro Half-Life:** Ligand A (-8.829) has a longer half-life than Ligand B (-3.015), which is desirable.

**P-gp Efflux:** Ligand A (0.024) has much lower P-gp efflux than Ligand B (0.461). Lower efflux is crucial for CNS exposure.

**Binding Affinity:** Both ligands have the same binding affinity (-8.8 kcal/mol), which is excellent.

**Overall Assessment:**

Ligand B excels in BBB penetration and DILI risk, which are critical for a CNS-targeting GPCR. However, Ligand A demonstrates superior metabolic stability (lower Cl_mic, longer t1/2), lower P-gp efflux, and lower hERG inhibition. The Caco-2 permeability is poor for both. Given the importance of CNS penetration and safety (DILI) for a DRD2 ligand, and the fact that the binding affinity is identical, Ligand B is slightly favored. However, the better metabolic profile of Ligand A is a significant advantage. Considering the balance, and the slightly better overall ADME profile (despite the BBB being slightly lower), Ligand A is the more viable candidate.

Output:
0
2025-04-17 04:06:55,081 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight (MW):** Both ligands (344.455 and 357.523 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (50.8) is better than Ligand B (54.02). Both are below the 90 A^2 threshold for CNS targets, but A is closer to the optimal range.

**3. logP:** Ligand A (3.152) is within the optimal range (1-3). Ligand B (4.553) is slightly higher, potentially leading to solubility issues and off-target interactions.

**4. H-Bond Donors (HBD):** Both ligands have acceptable HBD counts (1 and 2, respectively), well below the limit of 5.

**5. H-Bond Acceptors (HBA):** Both ligands have acceptable HBA counts (3 and 4, respectively), well below the limit of 10.

**6. QED:** Both ligands have good QED scores (0.913 and 0.825), indicating good drug-like properties.

**7. DILI:** Ligand A (22.024) has a significantly lower DILI risk than Ligand B (58.666). This is a major advantage for Ligand A.

**8. BBB:** Both ligands have excellent BBB penetration (89.531 and 84.335), exceeding the desirable threshold of 70 for CNS targets. Ligand A is slightly better.

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.472 and -4.854). This is unusual and suggests poor permeability, but the scale isn't defined, so it's hard to interpret.

**10. Aqueous Solubility:** Both ligands have negative solubility values (-2.754 and -4.321). Similar to Caco-2, this is unusual and suggests poor solubility.

**11. hERG Inhibition:** Both ligands have low hERG inhibition risk (0.647 and 0.73).

**12. Microsomal Clearance (Cl_mic):** Ligand A (30.13) has lower microsomal clearance than Ligand B (48.321), suggesting better metabolic stability.

**13. In vitro Half-Life:** Ligand B (60.656) has a significantly longer in vitro half-life than Ligand A (0.18). This is a significant advantage for Ligand B.

**14. P-gp Efflux:** Both ligands have low P-gp efflux liability (0.13 and 0.641).

**15. Binding Affinity:** Both ligands have very similar and strong binding affinities (-8.6 and -8.5 kcal/mol). The difference is negligible.

**Overall Assessment:**

Ligand A is superior due to its lower DILI risk, better logP, slightly better TPSA and BBB penetration, and lower microsomal clearance. While Ligand B has a longer half-life, the other advantages of Ligand A outweigh this benefit, particularly given the strong binding affinity of both compounds. The negative Caco-2 and solubility values are concerning for both, but the other ADME properties of A are more favorable.

Output:
0
2025-04-17 04:06:55,081 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (358.473 and 352.475 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (58.2) is excellent, well below the 90 target for CNS drugs. Ligand B (78.87) is still reasonable but less optimal.

**3. logP:** Ligand A (3.302) is within the optimal 1-3 range. Ligand B (1.034) is on the lower side, potentially hindering permeability.

**4. H-Bond Donors:** Both have 2 HBD, which is acceptable.

**5. H-Bond Acceptors:** Ligand A has 2 HBA, and Ligand B has 4 HBA, both are within the acceptable range of <=10.

**6. QED:** Ligand A (0.629) has a better QED score than Ligand B (0.48), indicating better overall drug-likeness.

**7. DILI:** Ligand A (15.316) has a significantly lower DILI risk than Ligand B (5.777), which is a major advantage.

**8. BBB:** Ligand A (85.847) has a very good BBB penetration percentile, exceeding the desirable >70 threshold for CNS targets. Ligand B (33.385) is poor for CNS penetration.

**9. Caco-2:** Both have negative Caco-2 values, which is unusual and difficult to interpret without further context. However, a more negative value generally suggests lower permeability.

**10. Solubility:** Both have negative solubility values, again unusual.

**11. hERG:** Both ligands have low hERG inhibition liability (0.504 and 0.415), which is good.

**12. Cl_mic:** Ligand A (45.326) has a higher microsomal clearance than Ligand B (34.876), meaning it's likely to be metabolized faster.

**13. t1/2:** Ligand B (-1.894) has a negative in vitro half-life, which is not possible. This is a red flag. Ligand A (6.877) has a reasonable half-life.

**14. Pgp:** Ligand A (0.122) has lower P-gp efflux liability than Ligand B (0.075), which is favorable for CNS exposure.

**15. Binding Affinity:** Ligand A (-7.3 kcal/mol) has a significantly stronger binding affinity than Ligand B (-6.8 kcal/mol). The 0.5 kcal/mol difference is substantial enough to outweigh some of the ADME drawbacks.

**Overall Assessment:**

Ligand A is clearly the superior candidate. It has a better BBB score, lower DILI risk, better QED, and significantly stronger binding affinity. While its metabolic clearance is slightly higher, the substantial advantages in CNS penetration, safety, and potency outweigh this concern. The negative values for Caco-2 and solubility are concerning but less critical than the other factors. Ligand B's negative half-life is a major disqualifier.

Output:
1
2025-04-17 04:06:55,081 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 drug candidates, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (341.451 and 359.467 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (47.56) is excellent, well below the 90 A^2 threshold for CNS targets. Ligand B (113.17) is higher but still potentially acceptable, though less ideal.

**logP:** Ligand A (3.694) is within the optimal 1-3 range. Ligand B (-0.019) is significantly outside the optimal range, being slightly negative. This is a major concern for brain penetration.

**H-Bond Donors/Acceptors:** Ligand A (1 HBD, 3 HBA) and Ligand B (2 HBD, 5 HBA) both have reasonable numbers of H-bond donors and acceptors, unlikely to cause major issues.

**QED:** Ligand A (0.708) has a better QED score than Ligand B (0.532), indicating better overall drug-likeness.

**DILI:** Ligand A (43.738) has a lower DILI risk than Ligand B (12.214), which is a positive attribute.

**BBB:** Ligand A (54.052) has a significantly better BBB percentile than Ligand B (44.591). While both are not *ideal* (>70), A is closer.

**Caco-2 Permeability:** Ligand A (-4.705) has a negative Caco-2 value, which is unusual and suggests poor permeability. Ligand B (-5.175) is also poor, but similar.

**Aqueous Solubility:** Ligand A (-4.549) and Ligand B (-0.748) both have negative solubility values, indicating poor solubility.

**hERG:** Ligand A (0.895) has a lower hERG risk than Ligand B (0.346), which is preferable.

**Microsomal Clearance:** Ligand A (102.956) has higher microsomal clearance than Ligand B (44.422), suggesting faster metabolism and potentially lower in vivo exposure.

**In vitro Half-Life:** Ligand A (-18.173) has a negative half-life, which is impossible. This is a red flag. Ligand B (-16.456) is also negative, and equally problematic.

**P-gp Efflux:** Ligand A (0.73) has lower P-gp efflux liability than Ligand B (0.058), which is beneficial for CNS penetration.

**Binding Affinity:** Ligand A (-8.7 kcal/mol) has a significantly stronger binding affinity than Ligand B (-6.2 kcal/mol). This is a substantial advantage.

**Overall Assessment:**

Ligand A has a significantly better binding affinity and a better BBB percentile, lower DILI risk, and lower P-gp efflux. However, it has a negative Caco-2 and half-life values which are concerning. Ligand B has a poor logP, which is a major drawback for CNS penetration, and a higher DILI risk. The negative half-life for both is a data quality issue. Despite the negative Caco-2 and half-life, the superior affinity and BBB of Ligand A, combined with its better overall drug-likeness profile, make it the more promising candidate *if* the negative values are data errors. The strong binding affinity could potentially outweigh some of the ADME liabilities, assuming they can be addressed through further optimization.

Output:
1
2025-04-17 04:06:55,082 - INFO - Batch 85 complete. Total preferences: 1360
2025-04-17 04:06:55,082 - INFO - Processing batch 86/512...
2025-04-17 04:07:34,561 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (338.407 and 354.441 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (53.76) is slightly higher than Ligand B (49.41), but both are below the 90 A^2 threshold desirable for CNS targets.

**logP:** Both ligands have good logP values (2.27 and 3.131), falling within the optimal 1-3 range. Ligand B is slightly higher, which could potentially lead to some off-target effects, but is still acceptable.

**H-Bond Donors/Acceptors:** Ligand A (0 HBD, 3 HBA) and Ligand B (1 HBD, 2 HBA) both have low numbers of H-bond donors and acceptors, which is favorable for permeability.

**QED:** Both ligands have similar QED values (0.792 and 0.771), indicating good drug-like properties.

**DILI:** Ligand A (31.252) has a slightly higher DILI risk than Ligand B (19.698), but both are well below the concerning threshold of 60.

**BBB:** Both ligands exhibit excellent BBB penetration (Ligand A: 85.498, Ligand B: 91.314), exceeding the desirable >70 percentile for CNS targets. Ligand B is slightly better.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.38 and -4.682), which is unusual and suggests poor permeability. This is a significant concern.

**Aqueous Solubility:** Both ligands have negative solubility values (-3.939 and -3.443), indicating very poor aqueous solubility. This is a major drawback.

**hERG:** Both ligands have low hERG inhibition liability (0.313 and 0.498), which is good.

**Microsomal Clearance:** Ligand A (13.299) has significantly lower microsomal clearance than Ligand B (30.34), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (14.306) has a longer in vitro half-life than Ligand B (-2.687), which is preferable.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.092 and 0.068), which is favorable for CNS exposure.

**Binding Affinity:** Ligand B (-8.7 kcal/mol) has a significantly stronger binding affinity than Ligand A (-7.8 kcal/mol). This 0.9 kcal/mol difference is substantial and could outweigh some of the ADME drawbacks.

**Overall Assessment:**

Despite the poor Caco-2 and solubility values for both compounds, the superior binding affinity of Ligand B is a critical factor. For a CNS target like DRD2, good BBB penetration is also essential, and both ligands meet this criterion. Ligand B also has a slightly better BBB score and lower DILI risk. While Ligand A has better metabolic stability and half-life, the potency advantage of Ligand B is more important for GPCRs. The poor solubility and permeability would need to be addressed through formulation strategies, but the strong binding affinity makes Ligand B the more promising candidate.

Output:
1
2025-04-17 04:07:34,562 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B based on the provided guidelines, prioritizing GPCR-specific properties (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (346.431 Da) is slightly lower, which could be beneficial for permeability, but both are acceptable.

**TPSA:** Ligand A (74.65) is better than Ligand B (58.64) as it is closer to the ideal range for CNS targets (<=90).

**logP:** Ligand B (2.544) is optimal (1-3), while Ligand A (0.265) is quite low, potentially hindering permeation. This is a significant drawback for Ligand A.

**H-Bond Donors/Acceptors:** Both have acceptable HBD counts (1). Ligand A has 5 HBA, while Ligand B has 3. Both are within the acceptable range (<=10).

**QED:** Both ligands have good QED scores (A: 0.613, B: 0.646), indicating drug-like properties.

**DILI:** Ligand B (10.469) has a much lower DILI risk than Ligand A (32.959), a significant advantage.

**BBB:** Ligand B (89.88) has excellent BBB penetration, exceeding the desirable threshold of >70, while Ligand A (58.782) is considerably lower. This is a critical factor for a CNS target like DRD2.

**Caco-2 Permeability:** Ligand A (-4.913) has poor Caco-2 permeability, while Ligand B (-4.54) is slightly better, but still not ideal.

**Aqueous Solubility:** Both have poor aqueous solubility (-1.01 and -2.733).

**hERG:** Both ligands have low hERG inhibition liability (A: 0.071, B: 0.772).

**Microsomal Clearance:** Ligand A (10.736) has lower microsomal clearance than Ligand B (45.339), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (-12.362) has a longer in vitro half-life than Ligand B (-2.259), which is favorable.

**P-gp Efflux:** Ligand A (0.017) has much lower P-gp efflux liability than Ligand B (0.185), which is beneficial for CNS exposure.

**Binding Affinity:** Ligand A (-7.9 kcal/mol) has a slightly better binding affinity than Ligand B (-7.4 kcal/mol). While a 0.5 kcal/mol difference is noticeable, it might not be enough to overcome the significant ADME deficiencies of Ligand A.

**Overall Assessment:**

Ligand B is the more promising candidate. While its solubility and Caco-2 permeability are not ideal, its superior BBB penetration, lower DILI risk, and acceptable logP outweigh the slightly weaker binding affinity and higher P-gp efflux compared to Ligand A. Ligand A's very low logP is a major concern for CNS penetration, despite its better P-gp efflux and slightly stronger binding. The combination of good BBB, lower DILI, and reasonable logP makes Ligand B the better choice for a DRD2 targeting drug.

Output:
1
2025-04-17 04:07:34,562 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (349.431 and 348.403 Da) are within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (100.45) is better than Ligand B (108.89). For CNS targets, we want TPSA <= 90, so both are slightly above the ideal, but A is closer.

**3. logP:** Ligand A (1.051) is within the optimal 1-3 range. Ligand B (0.024) is very low, potentially hindering permeation. This is a significant drawback for B.

**4. H-Bond Donors:** Ligand A (2) and Ligand B (3) are both acceptable (<=5).

**5. H-Bond Acceptors:** Both ligands (5) are within the acceptable range (<=10).

**6. QED:** Ligand A (0.723) has a better QED score than Ligand B (0.537), indicating a more drug-like profile.

**7. DILI:** Both ligands have similar, acceptable DILI risk (47.693 and 47.15).

**8. BBB:** Ligand A (50.679) and Ligand B (53.897) are both reasonably good, but neither exceeds the desirable >70 percentile for CNS targets. However, given the other factors, this is less critical.

**9. Caco-2:** Both have negative Caco-2 values (-5.154 and -5.611), which is unusual and difficult to interpret without further context. It suggests poor permeability.

**10. Solubility:** Both ligands have negative solubility values (-2.129 and -1.888), which is also unusual and suggests very poor aqueous solubility.

**11. hERG:** Both ligands have very low hERG risk (0.189 and 0.164).

**12. Cl_mic:** Ligand B (1.942) has a lower microsomal clearance than Ligand A (3.063), suggesting better metabolic stability.

**13. t1/2:** Ligand A (16.205) has a longer in vitro half-life than Ligand B (14.036).

**14. Pgp:** Both ligands have very low Pgp efflux liability (0.024 and 0.007).

**15. Binding Affinity:** Ligand B (-8.8 kcal/mol) has a slightly better binding affinity than Ligand A (-8.1 kcal/mol). This is a 0.7 kcal/mol difference, which is significant but not overwhelming.

**Overall Assessment:**

Ligand B has a better binding affinity and metabolic stability, but its extremely low logP is a major concern. Low logP often translates to poor membrane permeability and reduced CNS exposure, even with low Pgp efflux. Ligand A, while having slightly weaker affinity, has a much more favorable logP value, a better QED score, and a longer half-life. The unusual negative values for Caco-2 and solubility are concerning for both, but the logP issue for B is more critical given the CNS target.

Considering the GPCR-specific priorities, the balance of properties leans towards Ligand A being the more viable candidate. The slightly better affinity of Ligand B is unlikely to overcome the permeability issues caused by its low logP.

Output:
0
2025-04-17 04:07:34,562 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B based on the provided guidelines, prioritizing GPCR-specific properties (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (368.503 and 364.364 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (94.56) is slightly above the optimal <90 for CNS targets, while Ligand B (75.71) is well within the desired range. This favors Ligand B.

**logP:** Both ligands have acceptable logP values (1.003 and 1.778), falling within the 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A has 3 HBD and 6 HBA, while Ligand B has 1 HBD and 4 HBA. Both are within acceptable limits (<=5 HBD and <=10 HBA).

**QED:** Both ligands have reasonable QED scores (0.636 and 0.552), indicating good drug-like properties.

**DILI:** Ligand A (33.23) has a slightly higher DILI risk than Ligand B (29.081), but both are below the concerning threshold of 40.

**BBB:** This is a critical parameter for CNS targets. Ligand B (92.672) has a significantly higher BBB percentile than Ligand A (33.579). This is a major advantage for Ligand B.

**Caco-2 Permeability:** Ligand A (-5.55) shows poor Caco-2 permeability, while Ligand B (-4.707) is slightly better, though still not ideal.

**Aqueous Solubility:** Both ligands have negative solubility values (-1.003 and -2.622), indicating poor aqueous solubility. This could pose formulation challenges.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.174 and 0.44).

**Microsomal Clearance:** Ligand A (-29.142) has a much lower (better) microsomal clearance than Ligand B (17.343), suggesting greater metabolic stability.

**In vitro Half-Life:** Ligand A (24.156) has a longer in vitro half-life than Ligand B (-19.331).

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.039 and 0.038), which is favorable for CNS penetration.

**Binding Affinity:** Ligand A (-7.8) has a slightly better binding affinity than Ligand B (-7.3). However, the difference is only 0.5 kcal/mol, which may not be enough to overcome other ADME deficiencies.

**Overall Assessment:**

Ligand B is the more promising candidate. Its significantly higher BBB penetration (92.672 vs 33.579) is a crucial advantage for a CNS-targeting drug. While Ligand A has better metabolic stability and half-life, and slightly better affinity, Ligand B's superior TPSA and BBB outweigh these benefits. The poor Caco-2 permeability of both is a concern, but can potentially be addressed through formulation strategies.



Output:
1
2025-04-17 04:07:34,562 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (339.4) is slightly lower, which could be advantageous for permeability.

**TPSA:** Ligand A (84.83) is excellent for CNS penetration, well below the 90 A^2 threshold. Ligand B (49.41) is also very good.

**logP:** Both ligands have good logP values (A: 2.643, B: 3.616), falling within the optimal 1-3 range. Ligand B is slightly higher, which *could* present a minor solubility issue, but is still acceptable.

**H-Bond Donors/Acceptors:** Ligand A (HBD=2, HBA=6) and Ligand B (HBD=1, HBA=2) both have reasonable numbers of H-bond donors and acceptors, well within the guidelines.

**QED:** Both ligands have similar and acceptable QED values (A: 0.763, B: 0.761).

**DILI:** Ligand A (88.251) has a higher DILI risk than Ligand B (29.43). This is a significant negative for Ligand A.

**BBB:** Ligand B (96.045) has a *much* better BBB percentile than Ligand A (57.736). This is a crucial advantage for a CNS target like DRD2.

**Caco-2 Permeability:** Ligand A (-5.183) shows poor Caco-2 permeability, indicating poor intestinal absorption. Ligand B (-4.458) is better, but still not ideal.

**Aqueous Solubility:** Both ligands have poor aqueous solubility (A: -4.462, B: -3.898). This is a concern, but can sometimes be mitigated with formulation strategies.

**hERG:** Both ligands have similar and relatively low hERG risk (A: 0.756, B: 0.85).

**Microsomal Clearance:** Ligand A (32.694) has lower microsomal clearance than Ligand B (56.426), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (22.438) has a longer in vitro half-life than Ligand B (-19.105). This is a positive for Ligand A.

**P-gp Efflux:** Ligand A (0.082) has lower P-gp efflux than Ligand B (0.545), indicating better potential for CNS exposure.

**Binding Affinity:** Both ligands have excellent binding affinity (A: -8.5 kcal/mol, B: -8.6 kcal/mol). The difference is minimal.

**Overall Assessment:**

Ligand B is the superior candidate. While Ligand A has better metabolic stability and P-gp efflux, the significantly better BBB penetration, much lower DILI risk, and slightly better Caco-2 permeability of Ligand B outweigh these advantages. For a CNS target like DRD2, BBB penetration is paramount. The lower DILI risk is also a major factor. The binding affinity is comparable between the two.

Output:
1
2025-04-17 04:07:34,562 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (351.422 and 340.379 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (75.44) is excellent, well below the 90 A^2 threshold for CNS targets. Ligand B (98.66) is still reasonable but less optimal, approaching the 100 A^2 limit.

**logP:** Both ligands have good logP values (2.147 and 1.889), falling within the 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A (HBD=1, HBA=4) is better than Ligand B (HBD=4, HBA=4). Lower HBD is generally preferred, and Ligand A is closer to the ideal.

**QED:** Ligand A (0.852) has a significantly better QED score than Ligand B (0.645), indicating a more drug-like profile.

**DILI:** Ligand A (35.595) has a much lower DILI risk than Ligand B (48.623), both are acceptable, but A is preferred.

**BBB:** This is critical for a CNS target like DRD2. Ligand A (87.01) has a very good BBB percentile, exceeding the desirable >70 threshold. Ligand B (31.834) is quite poor, suggesting limited brain penetration.

**Caco-2 Permeability:** Ligand A (-4.871) and Ligand B (-5.268) both have negative values, which is unusual and suggests poor permeability. However, the scale isn't specified, so it's difficult to interpret.

**Aqueous Solubility:** Both ligands have very poor aqueous solubility (-2.051 and -3.602). This is a concern for both, but B is worse.

**hERG Inhibition:** Both ligands show low hERG inhibition risk (0.205 and 0.505).

**Microsomal Clearance:** Ligand B (-2.944) has a negative value, which is unusual and suggests very low clearance, and therefore high metabolic stability. Ligand A (19.974) has a moderate clearance.

**In vitro Half-Life:** Ligand B (-15.895) has a negative value, which is unusual and suggests a very long half-life. Ligand A (-21.574) also has a negative value, suggesting a very long half-life.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.085 and 0.045), which is good for CNS penetration.

**Binding Affinity:** Both ligands have excellent binding affinities (-8.7 and -9.4 kcal/mol). Ligand B is slightly better, but the difference is not substantial enough to overcome its other weaknesses.

**Overall Assessment:**

Ligand A is significantly better due to its superior BBB penetration (87.01 vs 31.834), better QED score (0.852 vs 0.645), and lower DILI risk (35.595 vs 48.623). While both have poor solubility, the BBB is paramount for a CNS target. The slightly better affinity of Ligand B is outweighed by its poor brain penetration.

Output:
0
2025-04-17 04:07:34,562 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (388.515 Da) is slightly higher than Ligand B (361.379 Da), but both are acceptable.

**TPSA:** Ligand A (116.4) is above the ideal <90 for CNS targets, while Ligand B (29.54) is excellent. This is a significant advantage for Ligand B.

**logP:** Ligand A (-0.192) is quite low, potentially hindering membrane permeability. Ligand B (4.072) is slightly high, but still within an acceptable range, though it could lead to off-target effects.

**H-Bond Donors/Acceptors:** Ligand A has 4 HBD and 5 HBA, which are acceptable. Ligand B has 0 HBD and 2 HBA, which is also good.

**QED:** Both ligands have good QED values (A: 0.469, B: 0.685), suggesting reasonable drug-likeness. Ligand B is better.

**DILI:** Both ligands have low DILI risk (A: 43.893, B: 32.144), which is positive. Ligand B is slightly better.

**BBB:** Ligand A (46.375) has a poor BBB percentile, which is a major drawback for a CNS target like DRD2. Ligand B (96.084) has an excellent BBB percentile, a huge advantage.

**Caco-2 Permeability:** Ligand A (-5.791) has very poor Caco-2 permeability, consistent with its low logP. Ligand B (-4.45) is also poor, but better than A.

**Aqueous Solubility:** Ligand A (-1.62) and Ligand B (-3.642) both have poor aqueous solubility.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (A: 0.112, B: 0.862).

**Microsomal Clearance:** Ligand A (30.285) has lower clearance than Ligand B (56.498), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand B (17.061) has a significantly longer half-life than Ligand A (5.847).

**P-gp Efflux:** Ligand A (0.016) has very low P-gp efflux, which is favorable for CNS penetration. Ligand B (0.574) has moderate P-gp efflux.

**Binding Affinity:** Ligand B (-7.7 kcal/mol) has a slightly better binding affinity than Ligand A (-7.5 kcal/mol), although the difference is small.

**Overall Assessment:**

Ligand B is the superior candidate. Its excellent BBB penetration, good QED, lower DILI risk, and slightly better binding affinity outweigh its slightly higher logP and moderate P-gp efflux. Ligand A's poor BBB penetration and Caco-2 permeability are major liabilities for a CNS-targeting drug. While Ligand A has better metabolic stability, the ADME profile of Ligand B is much more favorable for CNS drug development.

Output:
1
2025-04-17 04:07:34,562 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (347.371 and 361.467 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (102.16) is higher than the preferred <90 for CNS targets, while Ligand B (70.67) is well within the range. This is a significant advantage for Ligand B.

**logP:** Ligand A (0.782) is a bit low, potentially hindering permeability. Ligand B (3.24) is optimal.

**H-Bond Donors/Acceptors:** Both have 2 HBDs, which is good. Ligand A has 7 HBAs, while Ligand B has 4. Both are acceptable, but Ligand B is slightly better.

**QED:** Both ligands have good QED scores (0.749 and 0.882), indicating drug-like properties.

**DILI:** Ligand A (67.817) has a higher DILI risk than Ligand B (56.921), though both are reasonably acceptable.

**BBB:** Ligand B (91.702) shows excellent BBB penetration, a critical factor for a CNS target like DRD2. Ligand A (45.134) is considerably lower, raising concerns about CNS exposure.

**Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and suggests potential issues with the data or modeling. However, we can still compare them relatively.

**Aqueous Solubility:** Both have negative solubility values, which is also unusual.

**hERG Inhibition:** Ligand A (0.353) has a slightly lower hERG risk than Ligand B (0.716), which is a minor advantage.

**Microsomal Clearance:** Ligand B (51.013) has a lower microsomal clearance than Ligand A (35.416), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand B (11.191 hours) has a longer half-life than Ligand A (20.152 hours).

**P-gp Efflux:** Ligand A (0.053) shows lower P-gp efflux, which is favorable for CNS penetration. Ligand B (0.297) has higher P-gp efflux.

**Binding Affinity:** Ligand B (-9.7 kcal/mol) has a significantly stronger binding affinity than Ligand A (-8.3 kcal/mol). This 1.4 kcal/mol difference is substantial and can outweigh minor ADME drawbacks.

**Overall Assessment:**

Ligand B is the stronger candidate. It excels in key GPCR properties: optimal logP, excellent BBB penetration, and significantly higher binding affinity. While Ligand A has a slightly lower hERG risk and P-gp efflux, Ligand B's superior TPSA, BBB, affinity, and metabolic stability are more critical for a CNS-targeting drug. The unusual negative values for Caco-2 and solubility are concerning, but the relative comparison still favors Ligand B.

Output:
1
2025-04-17 04:07:34,563 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (360.5 and 348.5 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (23.55) is excellent, well below the 90 A^2 threshold for CNS targets. Ligand B (58.64) is higher but still reasonable, though less optimal for CNS penetration.

**3. logP:** Ligand A (4.454) is slightly high, potentially leading to solubility issues or off-target interactions. Ligand B (2.487) is within the optimal 1-3 range.

**4. H-Bond Donors:** Both ligands have a low number of HBDs (0 for A, 1 for B), which is favorable for permeability.

**5. H-Bond Acceptors:** Both ligands have 3 HBAs, which is acceptable.

**6. QED:** Both ligands have good QED scores (0.786 and 0.83), indicating drug-like properties.

**7. DILI:** Ligand A (26.02) has a very low DILI risk, significantly better than Ligand B (12.64).

**8. BBB:** This is a critical parameter for a CNS target like DRD2. Ligand A (97.325) has an excellent BBB percentile, while Ligand B (76.813) is good, but less favorable.

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 values, which is unusual and likely indicates a problem with the prediction method, or a very poor permeability.

**10. Aqueous Solubility:** Both ligands have negative solubility values, which is also unusual and likely indicates a problem with the prediction method, or a very poor solubility.

**11. hERG Inhibition:** Ligand A (0.983) has a slightly higher hERG risk than Ligand B (0.389), but both are relatively low.

**12. Microsomal Clearance:** Ligand A (51.789) has a higher microsomal clearance than Ligand B (36.255), suggesting lower metabolic stability.

**13. In vitro Half-Life:** Ligand A (16.706) has a longer half-life than Ligand B (12.142), which is desirable.

**14. P-gp Efflux:** Ligand A (0.859) has lower P-gp efflux liability than Ligand B (0.097), which is favorable for CNS exposure.

**15. Binding Affinity:** Ligand A (-9.2 kcal/mol) has a significantly stronger binding affinity than Ligand B (-8.2 kcal/mol). This 1.0 kcal/mol difference is substantial and can outweigh some ADME drawbacks.

**Overall Assessment:**

Ligand A is the stronger candidate. While its logP is slightly elevated and its clearance is higher, its significantly superior binding affinity (-9.2 vs -8.2 kcal/mol), excellent BBB penetration (97.3 vs 76.8), and very low DILI risk outweigh these concerns. The lower P-gp efflux also favors CNS exposure. The unusual negative values for Caco-2 and solubility are concerning, but the strong affinity and BBB penetration suggest further investigation of Ligand A is warranted.

Output:
1
2025-04-17 04:07:34,563 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (363.439 and 370.881 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (84.67) is better than Ligand B (87.47). Both are below the 90 A^2 threshold desirable for CNS targets, but A is closer to the ideal.

**3. logP:** Both ligands (2.15 and 2.217) are within the optimal 1-3 range.

**4. H-Bond Donors:** Ligand A (1) is preferable to Ligand B (2). Lower HBD generally improves permeability.

**5. H-Bond Acceptors:** Ligand A (6) is slightly better than Ligand B (5), both are within the acceptable range of <=10.

**6. QED:** Ligand A (0.88) is significantly better than Ligand B (0.695), indicating a more drug-like profile.

**7. DILI:** Ligand A (66.615) has a higher DILI risk than Ligand B (38.038). This is a negative for Ligand A.

**8. BBB:** Both ligands have good BBB penetration (Ligand A: 76.309, Ligand B: 70.609), exceeding the >70% threshold for CNS targets. Ligand A is slightly better.

**9. Caco-2 Permeability:** Ligand A (-4.905) has worse Caco-2 permeability than Ligand B (-5.033). Lower values are less desirable.

**10. Aqueous Solubility:** Ligand A (-3.46) has slightly worse aqueous solubility than Ligand B (-2.782).

**11. hERG Inhibition:** Both ligands have low hERG inhibition risk (0.3 and 0.246 respectively).

**12. Microsomal Clearance:** Ligand A (33.549) has lower microsomal clearance than Ligand B (43.519), suggesting better metabolic stability.

**13. In vitro Half-Life:** Ligand B (77.441) has a significantly longer in vitro half-life than Ligand A (13.83). This is a major advantage for Ligand B.

**14. P-gp Efflux:** Both ligands have low P-gp efflux liability (0.116 and 0.081 respectively).

**15. Binding Affinity:** Ligand A (-7.5 kcal/mol) has a slightly better binding affinity than Ligand B (-7.2 kcal/mol). This is a significant advantage, potentially outweighing some ADME drawbacks.

**Overall Assessment:**

Ligand A has a better QED, TPSA, BBB, and binding affinity. However, Ligand B has a significantly better in vitro half-life, lower DILI risk, and slightly better Caco-2 permeability and solubility. The difference in binding affinity (0.3 kcal/mol) is substantial enough to consider, but the improved metabolic stability (longer half-life) and reduced toxicity (lower DILI) of Ligand B are highly desirable for a CNS drug candidate. Given the GPCR-specific priorities, the longer half-life and lower toxicity of Ligand B make it the more promising candidate.

Output:
1
2025-04-17 04:07:34,563 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (341.455 and 350.503 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Both ligands have TPSA values (62.3 and 62.55) below the 90 A^2 threshold for CNS targets, which is excellent.

**3. logP:** Ligand A (2.715) is optimal, while Ligand B (3.799) is approaching the upper limit of the optimal range.

**4. H-Bond Donors:** Both ligands have 1 HBD, which is within the acceptable limit of <=5.

**5. H-Bond Acceptors:** Both ligands have 3 HBA, which is within the acceptable limit of <=10.

**6. QED:** Ligand A (0.809) has a better QED score than Ligand B (0.737), indicating a more drug-like profile.

**7. DILI:** Ligand A (27.065) has a significantly lower DILI risk than Ligand B (31.214), both are good, but A is better.

**8. BBB:** Ligand A (72.78) has a better BBB penetration percentile than Ligand B (54.75). This is a crucial factor for a CNS target like DRD2.

**9. Caco-2 Permeability:** Ligand A (-4.825) and Ligand B (-4.462) both have negative Caco-2 values, which is unusual and suggests poor permeability. However, the scale is not defined, so we can't interpret this definitively.

**10. Aqueous Solubility:** Both ligands have negative solubility values (-3.269 and -2.928), which is also unusual and suggests poor solubility. Again, the scale is not defined.

**11. hERG Inhibition:** Ligand A (0.385) has a lower hERG inhibition liability than Ligand B (0.664), indicating a lower risk of cardiotoxicity.

**12. Microsomal Clearance:** Ligand B (73.519) has a higher microsomal clearance than Ligand A (70.074), suggesting lower metabolic stability.

**13. In vitro Half-Life:** Ligand B (113.08) has a significantly longer in vitro half-life than Ligand A (-13.083). This is a major advantage for Ligand B.

**14. P-gp Efflux:** Ligand A (0.074) has a lower P-gp efflux liability than Ligand B (0.333), which is favorable for CNS penetration.

**15. Binding Affinity:** Ligand A (-9.2 kcal/mol) has a significantly stronger binding affinity than Ligand B (-6.5 kcal/mol). This is a substantial advantage.

**Overall Assessment:**

Ligand A is superior due to its significantly better binding affinity, lower DILI risk, better BBB penetration, lower hERG inhibition, and lower P-gp efflux. While Ligand B has a longer half-life, the substantial advantage in binding affinity and CNS penetration properties of Ligand A outweigh this benefit. The negative Caco-2 and solubility values are concerning for both, but the superior potency and CNS properties of A make it the more promising candidate.

Output:
1
2025-04-17 04:07:34,563 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (342.439 and 358.433 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (58.64) is better than Ligand B (47.1). Both are below the 90 Angstrom threshold desirable for CNS targets, which is excellent.

**3. logP:** Ligand A (1.891) is optimal, while Ligand B (0.337) is slightly low. A logP below 1 can hinder permeation.

**4. H-Bond Donors:** Ligand A (1) is good. Ligand B (0) is also acceptable.

**5. H-Bond Acceptors:** Ligand A (3) is good. Ligand B (4) is also acceptable.

**6. QED:** Ligand A (0.913) is excellent, indicating high drug-likeness. Ligand B (0.727) is still good, but not as strong.

**7. DILI:** Ligand A (30.826) has a significantly lower DILI risk than Ligand B (16.479), both are good.

**8. BBB:** Ligand A (76.658) has a better BBB penetration percentile than Ligand B (69.639). Both are reasonably good, but exceeding 70% is preferred for CNS targets.

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 values, which is unusual and potentially problematic. However, the scale is not specified, so it's hard to interpret.

**10. Aqueous Solubility:** Both ligands have negative solubility values, which is also unusual. Again, the scale is not specified, making interpretation difficult.

**11. hERG Inhibition:** Both ligands have low hERG inhibition risk (0.327 and 0.408).

**12. Microsomal Clearance:** Ligand A (55.584) has a higher microsomal clearance than Ligand B (-13.797). This suggests Ligand B is more metabolically stable, which is desirable.

**13. In vitro Half-Life:** Ligand A (28.776) has a longer half-life than Ligand B (-21.255). This is a positive attribute.

**14. P-gp Efflux:** Ligand A (0.139) has lower P-gp efflux liability than Ligand B (0.012), meaning it's less likely to be pumped out of the brain, improving CNS exposure.

**15. Binding Affinity:** Ligand A (-8.5 kcal/mol) has a slightly better binding affinity than Ligand B (-7.6 kcal/mol). While both are good, the 0.9 kcal/mol difference is significant and can outweigh some ADME drawbacks.

**Overall Assessment:**

Ligand A is the superior candidate. While Ligand B has better metabolic stability and slightly lower P-gp efflux, Ligand A excels in key areas for a CNS-targeting GPCR ligand: better TPSA, logP, QED, BBB penetration, binding affinity, and lower DILI risk. The slightly longer half-life of Ligand A is also beneficial. The negative values for Caco-2 and solubility are concerning for both, but the other advantages of Ligand A make it the more promising candidate.

Output:
1
2025-04-17 04:07:34,563 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B based on the provided guidelines, prioritizing GPCR properties (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (356.46 and 362.40 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (40.62) is significantly better than Ligand B (59.39). For CNS targets, we want TPSA <= 90, and ideally lower. Ligand A is much closer to the ideal range.

**logP:** Both ligands have acceptable logP values (3.31 and 2.12), falling within the 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A (0 HBD, 2 HBA) is preferable to Ligand B (1 HBD, 5 HBA) as lower counts generally improve permeability.

**QED:** Both ligands have good QED scores (0.76 and 0.90), indicating good drug-like properties.

**DILI:** Ligand A (23.2%) has a significantly lower DILI risk than Ligand B (38.3%). Both are below the 40% threshold, but A is better.

**BBB:** Ligand A (97.2%) has excellent BBB penetration, while Ligand B (84.4%) is still good, but noticeably lower. This is a critical factor for a CNS target like DRD2.

**Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and suggests a problem with the data or the model. However, the values are similar.

**Aqueous Solubility:** Both have negative solubility values, which is also unusual. Again, the values are similar.

**hERG:** Both ligands have low hERG inhibition risk (0.64 and 0.24).

**Microsomal Clearance:** Ligand A (30.4 mL/min/kg) has higher clearance than Ligand B (17.4 mL/min/kg), indicating lower metabolic stability.

**In vitro Half-Life:** Ligand A (-17.99 hours) has a negative half-life, which is impossible and suggests a data error. Ligand B (-8.48 hours) also has a negative half-life.

**P-gp Efflux:** Ligand A (0.25) has lower P-gp efflux liability than Ligand B (0.11), which is favorable for CNS penetration.

**Binding Affinity:** Ligand B (-7.1 kcal/mol) has a significantly better binding affinity than Ligand A (0.0 kcal/mol). This is a substantial advantage.

**Overall Assessment:**

Despite the issues with the half-life and solubility data, the key factors for a CNS-targeting GPCR are BBB penetration, logP, TPSA, Pgp efflux, and binding affinity. Ligand A excels in BBB penetration, TPSA, and Pgp efflux, while Ligand B has a much stronger binding affinity. The substantial difference in binding affinity (-7.1 vs 0.0 kcal/mol) is likely to outweigh the advantages of Ligand A, *assuming the binding affinity data is reliable*. The DILI risk is also lower for Ligand A. However, the negative half-life for both compounds is a major concern.

Given the importance of binding affinity for GPCRs, and the relatively good BBB score for Ligand B, I would choose Ligand B. The negative half-life would need to be investigated and addressed through structural modifications.

Output:
1
2025-04-17 04:07:34,563 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (465.193 Da) is higher, but still acceptable. Ligand B (384.801 Da) is preferable.

**TPSA:** Ligand A (36.67) is excellent for CNS penetration, well below the 90 A^2 threshold. Ligand B (116.36) is higher, but still potentially acceptable, though less ideal.

**logP:** Ligand A (4.138) is slightly high, potentially leading to solubility issues or off-target effects. Ligand B (2.335) is within the optimal range (1-3).

**H-Bond Donors/Acceptors:** Ligand A (0 HBD, 5 HBA) is good. Ligand B (1 HBD, 7 HBA) is also acceptable.

**QED:** Ligand A (0.583) is good, indicating drug-likeness. Ligand B (0.48) is slightly lower, suggesting a less ideal drug-like profile.

**DILI:** Ligand A (67.003) has a moderate DILI risk, but is still within an acceptable range. Ligand B (99.147) has a very high DILI risk, which is a significant concern.

**BBB:** Ligand A (93.563) has excellent BBB penetration, highly desirable for a CNS target. Ligand B (45.095) has poor BBB penetration, a major drawback.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.038 and -4.909), which is unusual and suggests poor permeability. This is a concern for both.

**Aqueous Solubility:** Both ligands have very poor aqueous solubility (-3.859 and -4.123). This will be a significant formulation challenge.

**hERG Inhibition:** Ligand A (0.977) has a low hERG risk. Ligand B (0.262) also has a low hERG risk.

**Microsomal Clearance:** Ligand A (55.605) has moderate clearance. Ligand B (21.634) has lower clearance, indicating better metabolic stability.

**In vitro Half-Life:** Ligand A (18.672) has a moderate half-life. Ligand B (29.022) has a longer half-life, which is preferable.

**P-gp Efflux:** Ligand A (0.888) has moderate P-gp efflux. Ligand B (0.256) has low P-gp efflux, which is beneficial for CNS exposure.

**Binding Affinity:** Both ligands have the same excellent binding affinity (-8.8 kcal/mol).

**Overall Assessment:**

Ligand A is superior due to its excellent BBB penetration, acceptable DILI risk, and good QED. While its logP is slightly high and solubility is poor, the strong BBB penetration and binding affinity outweigh these drawbacks for a CNS GPCR target. Ligand B's extremely high DILI risk and poor BBB penetration are major liabilities that cannot be easily overcome. The better metabolic stability and lower P-gp efflux of Ligand B are not enough to compensate for these critical issues.

Output:
0
2025-04-17 04:07:34,563 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (366.845 and 366.531 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (70.08) is slightly higher than Ligand B (65.54). Both are below the 90 A^2 threshold desirable for CNS targets, but B is better.

**3. logP:** Both ligands (2.035 and 1.913) are within the optimal 1-3 range.

**4. H-Bond Donors:** Both have 1 HBD, which is acceptable.

**5. H-Bond Acceptors:** Ligand A has 4 HBA, and Ligand B has 5. Both are below the 10 threshold.

**6. QED:** Ligand A (0.883) has a significantly better QED score than Ligand B (0.687), indicating a more drug-like profile.

**7. DILI:** Ligand A (55.68) has a higher DILI risk than Ligand B (16.44). This is a significant negative for Ligand A.

**8. BBB:** Ligand B (75.882) has a much better BBB penetration percentile than Ligand A (43.699). This is *critical* for a CNS target like DRD2.

**9. Caco-2 Permeability:** Ligand A (-4.918) has a worse Caco-2 permeability than Ligand B (-5.022). Both are quite poor, but similar.

**10. Aqueous Solubility:** Ligand A (-2.288) is slightly better than Ligand B (-1.726), but both are poor.

**11. hERG Inhibition:** Ligand A (0.048) has a slightly lower hERG inhibition risk than Ligand B (0.284).

**12. Microsomal Clearance:** Ligand B (60.036) has a significantly higher microsomal clearance than Ligand A (0.243), meaning faster metabolism and potentially lower exposure.

**13. In vitro Half-Life:** Ligand B (4.989) has a longer in vitro half-life than Ligand A (-2.155).

**14. P-gp Efflux:** Ligand A (0.012) has a much lower P-gp efflux liability than Ligand B (0.036), which is favorable for CNS penetration.

**15. Binding Affinity:** Ligand A (-8.8 kcal/mol) has a significantly stronger binding affinity than Ligand B (-6.4 kcal/mol). This is a substantial advantage.

**Overall Assessment:**

While Ligand A has a better QED, lower P-gp efflux, and *much* stronger binding affinity, its significantly higher DILI risk and lower BBB penetration are major drawbacks. Ligand B, despite the weaker affinity, has a much better safety profile (lower DILI) and significantly better BBB penetration, which is paramount for a CNS target. The difference in binding affinity (-8.8 vs -6.4) is substantial (2.4 kcal/mol), but the improved ADME properties of Ligand B, particularly the BBB score, outweigh this difference. The lower metabolic clearance of ligand A is a plus, but not enough to overcome the other issues.

Output:
1
2025-04-17 04:07:34,563 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (347.415 and 356.455 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (75.02) is significantly better than Ligand B (103.59). For CNS targets, we want TPSA <= 90, and A is comfortably within this range, while B is pushing the limit.

**3. logP:** Ligand A (1.125) is within the optimal 1-3 range. Ligand B (2.575) is also acceptable, but slightly higher.

**4. H-Bond Donors:** Both ligands have acceptable HBD counts (1 and 2, respectively), well below the threshold of 5.

**5. H-Bond Acceptors:** Both ligands have acceptable HBA counts (5 and 7, respectively), well below the threshold of 10.

**6. QED:** Both ligands have high QED scores (0.864 and 0.872), indicating good drug-like properties.

**7. DILI:** Ligand A (30.632) has a much lower DILI risk than Ligand B (85.072). This is a significant advantage for A.

**8. BBB:** Ligand A (65.762) has a better BBB penetration percentile than Ligand B (51.066). While >70 is desirable, A is closer to that mark, and this is a crucial factor for a CNS target like DRD2.

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.955 and -4.963). This is unusual and suggests poor permeability. However, the values are very similar.

**10. Aqueous Solubility:** Ligand A (-1.847) is better than Ligand B (-4.689). Higher solubility is generally preferred.

**11. hERG Inhibition:** Both ligands have low hERG inhibition risk (0.497 and 0.464).

**12. Microsomal Clearance:** Ligand A (10.169) has a lower microsomal clearance than Ligand B (34.468), indicating better metabolic stability.

**13. In vitro Half-Life:** Ligand A (59.814) has a significantly longer in vitro half-life than Ligand B (17.318).

**14. P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.046).

**15. Binding Affinity:** Ligand A (-9.2 kcal/mol) has a stronger binding affinity than Ligand B (-8.1 kcal/mol). This is a 1.1 kcal/mol difference, which is substantial and can outweigh minor ADME drawbacks.

**Overall Assessment:**

Ligand A is clearly superior. It excels in key areas for CNS GPCR targets: TPSA, BBB penetration, DILI risk, metabolic stability (Cl_mic and t1/2), solubility, and, most importantly, binding affinity. While both have poor Caco-2 permeability, the significantly better profile of Ligand A across other critical parameters makes it the more promising drug candidate.

Output:
1
2025-04-17 04:07:34,564 - INFO - Batch 86 complete. Total preferences: 1376
2025-04-17 04:07:34,564 - INFO - Processing batch 87/512...
2025-04-17 04:08:15,147 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (343.43 and 352.44 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (82.62) is better than Ligand B (87.91). Both are below the 90 A^2 threshold for CNS targets, which is good.

**logP:** Ligand A (2.984) is slightly better than Ligand B (1.935), falling comfortably within the 1-3 range. Ligand B is at the lower end, potentially impacting permeability.

**H-Bond Donors/Acceptors:** Ligand A has 4 HBD and 4 HBA, while Ligand B has 1 HBD and 6 HBA. Both are within acceptable limits (<=5 HBD and <=10 HBA).

**QED:** Ligand B (0.833) has a higher QED score than Ligand A (0.594), suggesting a more drug-like profile overall.

**DILI:** Both ligands have acceptable DILI risk (Ligand A: 54.36, Ligand B: 52.42), below the 60 threshold.

**BBB:** Ligand B (76.46) has a significantly better BBB penetration percentile than Ligand A (47.93). This is a crucial factor for a CNS target like DRD2.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values, which is unusual and suggests poor permeability. However, these values are on a log scale and the negative values are not directly comparable without knowing the base of the log.

**Aqueous Solubility:** Both ligands have negative solubility values, which is also unusual. Again, these values are not directly comparable without knowing the scale.

**hERG:** Both ligands have low hERG inhibition liability (Ligand A: 0.786, Ligand B: 0.343), which is favorable.

**Microsomal Clearance:** Ligand B (78.85) has a higher microsomal clearance than Ligand A (61.02), indicating faster metabolism and potentially lower *in vivo* exposure.

**In vitro Half-Life:** Ligand A (26.95) has a longer in vitro half-life than Ligand B (-12.297). The negative value for Ligand B is concerning and likely indicates a very short half-life.

**P-gp Efflux:** Ligand A (0.433) has lower P-gp efflux liability than Ligand B (0.036), which is beneficial for CNS penetration.

**Binding Affinity:** Both ligands have very similar and strong binding affinities (-8.1 and -7.9 kcal/mol). The difference is less than the 1.5 kcal/mol threshold.

**Overall Assessment:**

While Ligand B has a better QED and significantly better BBB penetration, its very short in vitro half-life and high P-gp efflux are major drawbacks. Ligand A, despite having a slightly lower QED and BBB, has a more reasonable half-life, lower P-gp efflux, and acceptable metabolic clearance. Given the importance of CNS penetration and metabolic stability for a DRD2 ligand, Ligand A appears to be the more promising candidate.

Output:
0
2025-04-17 04:08:15,147 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (344.5) is slightly better positioned.

**TPSA:** Ligand A (40.62) is excellent for CNS penetration (<90), while Ligand B (105.04) is higher, potentially hindering BBB penetration.

**logP:** Ligand A (3.374) is optimal (1-3). Ligand B (0.214) is significantly low, which could lead to poor membrane permeability and bioavailability.

**H-Bond Donors/Acceptors:** Ligand A (0 HBD, 2 HBA) and Ligand B (2 HBD, 8 HBA) both fall within acceptable ranges.

**QED:** Both ligands have good QED scores (A: 0.787, B: 0.801), indicating generally drug-like properties.

**DILI:** Ligand A (13.3) has a much lower DILI risk than Ligand B (79.333). This is a significant advantage.

**BBB:** Ligand A (83.404) has excellent BBB penetration, exceeding the desirable threshold of 70. Ligand B (50.679) is considerably lower, raising concerns for CNS exposure.

**Caco-2 Permeability:** Ligand A (-4.587) and Ligand B (-5.091) both have negative values, which is unusual. It's difficult to interpret without knowing the scale, but generally, a more negative value suggests lower permeability.

**Aqueous Solubility:** Both ligands have very poor aqueous solubility (-3.76 and -3.227 respectively). This could pose formulation challenges.

**hERG Inhibition:** Ligand A (0.56) has a lower hERG risk than Ligand B (0.34), which is preferable.

**Microsomal Clearance:** Ligand A (75.968) has higher microsomal clearance than Ligand B (4.175), indicating lower metabolic stability. This is a drawback for Ligand A.

**In vitro Half-Life:** Ligand A (-11.717) has a very short in vitro half-life, while Ligand B (28.708) is better. This is a significant disadvantage for Ligand A.

**P-gp Efflux:** Ligand A (0.222) has lower P-gp efflux than Ligand B (0.065), which is favorable for CNS exposure.

**Binding Affinity:** Ligand A (-9.7 kcal/mol) has a significantly stronger binding affinity than Ligand B (-7.7 kcal/mol). This is a substantial advantage that could outweigh some of the ADME drawbacks.

**Overall Assessment:**

Ligand A has a superior profile for a CNS-targeting GPCR ligand. The strong binding affinity (-9.7 kcal/mol) and excellent BBB penetration (83.4%) are key advantages. While its metabolic stability (Cl_mic) and half-life are concerns, the significantly lower DILI risk and P-gp efflux, combined with its optimal logP and TPSA, make it a more promising candidate. Ligand B's low logP and poor BBB penetration are major drawbacks, despite its better metabolic stability. The affinity difference is also substantial.

Output:
1
2025-04-17 04:08:15,147 - INFO - Reasoning:

Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (366.483 and 342.443 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Both ligands have TPSA values (67.87 and 67.23) that are acceptable for oral absorption but slightly high for optimal CNS penetration (ideally <90).

**3. logP:** Both ligands have good logP values (2.186 and 1.691), falling within the optimal 1-3 range.

**4. H-Bond Donors:** Both have 1 HBD, which is within the acceptable limit of <=5.

**5. H-Bond Acceptors:** Ligand A has 5 HBAs, and Ligand B has 4. Both are within the acceptable limit of <=10.

**6. QED:** Ligand A (0.751) has a better QED score than Ligand B (0.606), suggesting a more drug-like profile.

**7. DILI:** Ligand A (56.883) has a higher DILI risk than Ligand B (10.237). This is a significant drawback for Ligand A.

**8. BBB:** Ligand B (73.284) has a significantly better BBB percentile than Ligand A (69.407).  For a CNS target like DRD2, this is a crucial advantage.

**9. Caco-2 Permeability:** Ligand A (-4.974) has better Caco-2 permeability than Ligand B (-5.254), indicating better intestinal absorption.

**10. Aqueous Solubility:** Ligand A (-2.014) has better aqueous solubility than Ligand B (-1.0).

**11. hERG Inhibition:** Both ligands have low hERG inhibition risk (0.225 and 0.345).

**12. Microsomal Clearance:** Ligand B (15.999) has a lower microsomal clearance than Ligand A (48.578), indicating better metabolic stability.

**13. In vitro Half-Life:** Ligand B (-11.902) has a longer in vitro half-life than Ligand A (37.236), which is desirable.

**14. P-gp Efflux:** Both ligands have low P-gp efflux liability (0.158 and 0.037).

**15. Binding Affinity:** Ligand B (-8.1 kcal/mol) has a slightly better binding affinity than Ligand A (-7.7 kcal/mol). While the difference is not huge, it's still a positive factor.

**Overall Assessment:**

Ligand B is the more promising candidate. While Ligand A has slightly better Caco-2 permeability and solubility, Ligand B excels in the critical areas for a CNS GPCR target: significantly lower DILI risk, better BBB penetration, better metabolic stability (lower Cl_mic and longer t1/2), and slightly improved binding affinity. The QED score is slightly lower for B, but the other advantages outweigh this.

Output:
1
2025-04-17 04:08:15,148 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (374.507 Da) is slightly higher than Ligand B (344.375 Da), but both are acceptable.

**2. TPSA:** Ligand A (91.93) is better than Ligand B (123.05). For CNS targets, TPSA should be <= 90, so Ligand A is closer to the threshold, while Ligand B exceeds it.

**3. logP:** Ligand A (1.165) is within the optimal range (1-3). Ligand B (-0.158) is slightly below 1, which *could* indicate permeability issues, although not drastically.

**4. H-Bond Donors:** Ligand A (3) and Ligand B (1) are both within the acceptable limit of <=5.

**5. H-Bond Acceptors:** Ligand A (5) and Ligand B (6) are both within the acceptable limit of <=10.

**6. QED:** Ligand B (0.792) has a significantly better QED score than Ligand A (0.386), indicating a more drug-like profile.

**7. DILI:** Ligand A (37.069) has a lower DILI risk than Ligand B (49.942), both are good, but A is better.

**8. BBB:** Ligand A (63.784) has a better BBB penetration percentile than Ligand B (46.219). For a CNS target like DRD2, >70 is desirable, but A is closer.

**9. Caco-2:** Ligand A (-4.753) and Ligand B (-5.357) are both negative, indicating poor permeability. This is a concern for both.

**10. Solubility:** Ligand A (-2.801) and Ligand B (-2.085) are both negative, indicating poor solubility. This is a concern for both.

**11. hERG:** Both ligands have very low hERG risk (0.342 and 0.043 respectively).

**12. Cl_mic:** Ligand A (19.08) has a lower (better) microsomal clearance than Ligand B (-13.407). This suggests better metabolic stability for Ligand A.

**13. t1/2:** Ligand A (12.941) has a longer in vitro half-life than Ligand B (-24.332), which is desirable.

**14. Pgp:** Both ligands have very low P-gp efflux liability (0.023 and 0.013 respectively).

**15. Binding Affinity:** Ligand A (-7.9 kcal/mol) has a slightly better binding affinity than Ligand B (-7.5 kcal/mol). While both are good, the 0.4 kcal/mol difference is meaningful.

**Overall Assessment:**

Considering the GPCR-specific priorities, Ligand A is the better candidate. While Ligand B has a better QED score, Ligand A excels in crucial areas for CNS penetration and metabolic stability: TPSA, BBB, Cl_mic, and t1/2. The slightly better affinity of Ligand A further strengthens its position. The poor Caco-2 and solubility for both are concerning, but can be addressed with formulation strategies.

Output:
1
2025-04-17 04:08:15,148 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (352.316 and 357.296 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (76.02) is significantly better than Ligand B (97.54). For CNS targets, TPSA should be <= 90, and A is comfortably within that range, while B is approaching the upper limit.

**3. logP:** Ligand A (2.095) is optimal (1-3), while Ligand B (0.277) is quite low, potentially hindering membrane permeability.

**4. H-Bond Donors:** Both ligands have acceptable HBD counts (2 and 1, respectively), well below the threshold of 5.

**5. H-Bond Acceptors:** Ligand A (4) is good, while Ligand B (8) is higher, but still within the acceptable limit of 10.

**6. QED:** Both ligands have reasonable QED values (0.885 and 0.785), indicating good drug-like properties.

**7. DILI:** Both ligands have similar and acceptable DILI risk (74.952 and 71.694, both < 80).

**8. BBB:** Both ligands show excellent BBB penetration (83.482 and 88.174), exceeding the desirable >70 threshold for CNS targets.

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.896 and -4.809). This is unusual and suggests a potential issue with the data or a very poor permeability. However, given the context of comparing two ligands, we proceed assuming this is a consistent artifact.

**10. Aqueous Solubility:** Both ligands have negative solubility values (-3.799 and -2.625). Similar to Caco-2, this is unusual, but we'll proceed with the comparison.

**11. hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.462 and 0.135), which is excellent.

**12. Microsomal Clearance:** Ligand A (23.275) has lower clearance than Ligand B (41.72), indicating better metabolic stability.

**13. In vitro Half-Life:** Ligand A (44.002) has a significantly longer half-life than Ligand B (-17.587). The negative value for B is concerning and likely indicates a very rapid degradation.

**14. P-gp Efflux:** Both ligands have low P-gp efflux liability (0.442 and 0.07).

**15. Binding Affinity:** Both ligands have very similar and strong binding affinities (-9.6 and -9.3 kcal/mol). The difference of 0.3 kcal/mol is not substantial enough to outweigh other factors.

**Overall Assessment:**

Ligand A is clearly superior. While both ligands have good affinity and BBB penetration, Ligand A has a much more favorable logP, TPSA, metabolic stability (lower Cl_mic, longer t1/2), and a more reasonable profile for solubility and permeability (even considering the negative values). Ligand B's low logP and negative half-life are significant drawbacks.

Output:
1
2025-04-17 04:08:15,148 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 drug candidates, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (364.873 and 361.913 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (58.64) is significantly higher than Ligand B (29.54). For a CNS target like DRD2, TPSA should ideally be below 90, and lower is better. Ligand B is much closer to the ideal range.

**3. logP:** Ligand A (3.501) is within the optimal range (1-3), while Ligand B (4.591) is slightly above, potentially leading to solubility issues.

**4. H-Bond Donors:** Ligand A (1) and Ligand B (0) are both acceptable, being less than 5.

**5. H-Bond Acceptors:** Ligand A (3) and Ligand B (2) are both acceptable, being less than 10.

**6. QED:** Both ligands have similar QED values (0.832 and 0.767), indicating good drug-like properties.

**7. DILI:** Ligand A (37.069) has a slightly higher DILI risk than Ligand B (24.157), but both are below the concerning threshold of 60.

**8. BBB:** Both ligands exhibit excellent BBB penetration (Ligand A: 96.472, Ligand B: 91.392), which is crucial for a CNS target.

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 values, which is unusual and suggests a potential issue with the data or modeling. However, we will continue the analysis assuming these represent relative permeability, and lower values are less favorable.

**10. Aqueous Solubility:** Both ligands have negative solubility values, again suggesting a potential issue with the data. Lower values are less favorable.

**11. hERG Inhibition:** Both ligands have low hERG inhibition risk (Ligand A: 0.703, Ligand B: 0.783).

**12. Microsomal Clearance:** Ligand A (80.631) has lower microsomal clearance than Ligand B (102.754), indicating better metabolic stability.

**13. In vitro Half-Life:** Ligand A (-2.146) has a negative half-life, which is not physically possible and indicates a data issue. Ligand B (31.753) has a reasonable half-life.

**14. P-gp Efflux:** Both ligands have low P-gp efflux liability (Ligand A: 0.333, Ligand B: 0.735), which is favorable for CNS penetration.

**15. Binding Affinity:** Both ligands have strong binding affinities (Ligand A: -9.1 kcal/mol, Ligand B: -8.7 kcal/mol). Ligand A has a slightly better affinity.

**Overall Assessment:**

Despite the questionable Caco-2 and solubility data, Ligand A appears slightly more promising. It has a better binding affinity, lower microsomal clearance, and a lower P-gp efflux liability. However, its higher TPSA is a concern. Ligand B has a much lower TPSA, which is highly desirable for CNS penetration, but its slightly higher logP and higher clearance are drawbacks. The negative half-life for ligand A is a major red flag. Considering the importance of TPSA for CNS targets and the data quality issues with ligand A, I would lean towards Ligand B.

Output:
1
2025-04-17 04:08:15,148 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B based on the provided guidelines, prioritizing GPCR properties (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (347.419 and 349.475 Da) fall within the ideal range of 200-500 Da.

**TPSA:** Ligand A (89.35) is better than Ligand B (78.51), both are below the 90 Angstrom threshold for CNS targets.

**logP:** Ligand B (1.59) is better than Ligand A (0.15). A logP of 0.15 is quite low and could hinder membrane permeability. Ligand B is within the optimal 1-3 range.

**H-Bond Donors & Acceptors:** Ligand A has 1 HBD and 6 HBA, while Ligand B has 2 HBD and 3 HBA. Both are within acceptable limits (<=5 HBD and <=10 HBA).

**QED:** Both ligands have good QED scores (0.584 and 0.621, respectively), indicating drug-like properties.

**DILI:** Ligand A (38.697) has a significantly lower DILI risk than Ligand B (15.355), which is a substantial advantage.

**BBB:** Ligand A (72.664) has a slightly better BBB penetration percentile than Ligand B (69.407), though both are reasonably good for a CNS target.

**Caco-2 Permeability:** Ligand A (-5.265) has a more negative Caco-2 value than Ligand B (-5.063), indicating better intestinal absorption.

**Aqueous Solubility:** Ligand A (-0.696) has a better solubility score than Ligand B (-2.182).

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.139 and 0.269, respectively).

**Microsomal Clearance:** Ligand A (12.025 mL/min/kg) has significantly lower microsomal clearance than Ligand B (29.803 mL/min/kg), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (0.046 hours) has a very short half-life, while Ligand B (-15.962 hours) has a negative half-life, which is likely an error in the data.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.034 and 0.045, respectively).

**Binding Affinity:** Ligand B (-7.7 kcal/mol) has a slightly better binding affinity than Ligand A (-7.2 kcal/mol). The difference is 0.5 kcal/mol, which is significant.

**Overall Assessment:**

While Ligand B has a slightly better binding affinity and logP, Ligand A excels in several crucial ADME properties. Specifically, its lower DILI risk, better solubility, significantly lower microsomal clearance, and better Caco-2 permeability are highly favorable. The negative half-life for Ligand B is a major red flag. The slightly better BBB for Ligand A is also a plus for a CNS target. The difference in binding affinity (0.5 kcal/mol) is not large enough to overcome the superior ADME profile of Ligand A.

Output:
0
2025-04-17 04:08:15,148 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (344.46 and 344.42 Da) fall comfortably within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (86.88) is excellent, well below the 90 A^2 threshold for CNS targets. Ligand B (114.85) is still reasonable but higher, potentially impacting BBB penetration.

**3. logP:** Both ligands have good logP values (2.10 and 1.62), falling within the optimal 1-3 range.

**4. H-Bond Donors:** Both have 3 HBD, which is acceptable.

**5. H-Bond Acceptors:** Ligand A has 3 HBA, and Ligand B has 4 HBA. Both are within the acceptable limit of <=10.

**6. QED:** Both ligands have QED values (0.76 and 0.62) above 0.5, indicating good drug-like properties.

**7. DILI:** Ligand A (33.42) has a lower DILI risk than Ligand B (39.67), both being good (<40).

**8. BBB:** This is a critical parameter for a CNS target like DRD2. Ligand A has a significantly better BBB percentile (64.72) than Ligand B (51.73).

**9. Caco-2 Permeability:** Both have negative Caco-2 values (-5.23 and -5.24), which is unusual and difficult to interpret without further context. However, the values are very similar.

**10. Aqueous Solubility:** Both have negative solubility values (-3.36 and -3.07), which is also unusual and suggests poor solubility. Again, values are similar.

**11. hERG Inhibition:** Both ligands have low hERG inhibition risk (0.36 and 0.46).

**12. Microsomal Clearance:** Ligand A (32.79) has a higher microsomal clearance than Ligand B (-4.26). This suggests Ligand B is more metabolically stable.

**13. In vitro Half-Life:** Ligand B (-9.65) has a significantly longer in vitro half-life than Ligand A (1.84).

**14. P-gp Efflux:** Ligand A (0.17) has a lower P-gp efflux liability than Ligand B (0.06), which is favorable for CNS penetration.

**15. Binding Affinity:** Ligand A (-10.4 kcal/mol) has a significantly stronger binding affinity than Ligand B (-7.8 kcal/mol). This is a substantial difference, exceeding the 1.5 kcal/mol advantage threshold.

**Overall Assessment:**

Ligand A is the stronger candidate. While Ligand B has better metabolic stability (lower Cl_mic, longer t1/2) and slightly lower P-gp efflux, the significantly superior binding affinity (-10.4 vs -7.8 kcal/mol) and better BBB penetration (64.7 vs 51.7) of Ligand A outweigh these advantages. The TPSA is also better for Ligand A. The similar poor solubility and Caco-2 permeability are concerns for both, but these can potentially be addressed through formulation strategies. Given the importance of potency and CNS penetration for a DRD2 ligand, Ligand A is the more promising candidate.

Output:
1
2025-04-17 04:08:15,148 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (344.415 and 342.395 Da) fall comfortably within the ideal 200-500 Da range.

**TPSA:** Ligand A (89.01) is slightly higher than Ligand B (81.43), but both are below the 90 A^2 threshold desirable for CNS targets.

**logP:** Ligand A (1.336) is optimal, while Ligand B (3.607) is approaching the upper limit of the optimal range. This gives a slight edge to Ligand A.

**H-Bond Donors:** Ligand A (2) and Ligand B (1) are both acceptable, being less than 5.

**H-Bond Acceptors:** Both ligands (5) are within the acceptable limit of 10.

**QED:** Both ligands have good QED scores (0.774 and 0.811), indicating good drug-like properties.

**DILI:** Ligand A (62.854) has a lower DILI risk than Ligand B (77.2), which is preferable.

**BBB:** Ligand B (85.459) has a significantly better BBB penetration score than Ligand A (50.523). This is a *major* advantage for a CNS target like DRD2.

**Caco-2 Permeability:** Ligand A (-5.384) has a worse Caco-2 permeability than Ligand B (-4.396).

**Aqueous Solubility:** Ligand A (-2.466) has a worse aqueous solubility than Ligand B (-5.481).

**hERG:** Both ligands have low hERG inhibition liability (0.317 and 0.261).

**Microsomal Clearance:** Ligand B (94.958) has a higher microsomal clearance than Ligand A (33.209), meaning Ligand A is more metabolically stable.

**In vitro Half-Life:** Ligand A (-22.694) has a longer in vitro half-life than Ligand B (-0.424).

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.272 and 0.379).

**Binding Affinity:** Both ligands have similar, excellent binding affinities (-9.6 and -9.3 kcal/mol). The difference is negligible.

**Overall Assessment:**

Ligand B excels in BBB penetration, a critical factor for CNS drug development. While Ligand A has advantages in metabolic stability (lower Cl_mic, longer t1/2) and DILI risk, the superior BBB score of Ligand B outweighs these benefits. The slightly higher logP of Ligand B isn't a major concern given its strong affinity.

Output:
1
2025-04-17 04:08:15,148 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B against the provided guidelines, prioritizing GPCR-specific properties (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (361.47 and 349.48 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (91.92) is slightly above the preferred <90 for CNS targets, but still reasonable. Ligand B (61.88) is well within the ideal range.

**logP:** Both ligands have good logP values (1.55 and 1.17), falling within the 1-3 optimal range.

**H-Bond Donors/Acceptors:** Ligand A has 2 HBD and 4 HBA, while Ligand B has 1 HBD and 4 HBA. Both are acceptable, staying within the recommended limits.

**QED:** Both ligands have similar QED scores (0.817 and 0.809), indicating good drug-likeness.

**DILI:** Ligand A has a DILI risk of 53.5%, considered good. Ligand B has a significantly lower DILI risk of 23.6%, which is excellent.

**BBB:** Both ligands have good BBB penetration (63.9% and 65.8%), exceeding the desirable threshold of 70% for CNS targets.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values, which is unusual and suggests poor permeability. However, these values are on a strange scale, and the negative values may not be directly comparable.

**Aqueous Solubility:** Both ligands have negative solubility values, which is also unusual. Again, the scale is unclear, but suggests poor solubility.

**hERG:** Both ligands have low hERG inhibition risk (0.292 and 0.252).

**Microsomal Clearance:** Ligand A (11.08) has a higher microsomal clearance than Ligand B (7.30), suggesting lower metabolic stability.

**In vitro Half-Life:** Both ligands have similar in vitro half-lives (15.14 and 15.76 hours).

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.13 and 0.064), which is favorable for CNS penetration.

**Binding Affinity:** Ligand B (-7.3 kcal/mol) has a significantly stronger binding affinity than Ligand A (-9.9 kcal/mol). This difference of 2.6 kcal/mol is substantial and can outweigh minor ADME drawbacks.

**Conclusion:**

While both ligands have reasonable properties, Ligand B is the more promising candidate. Its significantly stronger binding affinity (-7.3 vs -9.9 kcal/mol) is a major advantage, especially for a GPCR target like DRD2. It also exhibits a lower DILI risk and slightly lower microsomal clearance, indicating potentially better safety and metabolic stability. The TPSA is also more favorable. The unusual negative values for Caco-2 and Solubility are concerning for both, but the affinity difference is the deciding factor.

Output:
1
2025-04-17 04:08:15,148 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight (MW):** Both ligands (358.47 & 351.49 Da) fall comfortably within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (76.88) is higher than the preferred <90 for CNS targets, but still reasonable. Ligand B (53.09) is excellent, well below 90.

**3. logP:** Both ligands have good logP values (1.63 & 1.23), falling within the optimal 1-3 range.

**4. H-Bond Donors (HBD):** Ligand A has 1 HBD, and Ligand B has 0. Both are acceptable (<=5).

**5. H-Bond Acceptors (HBA):** Ligand A has 5 HBA, and Ligand B has 4. Both are within the acceptable range (<=10).

**6. QED:** Ligand A (0.881) has a better QED score than Ligand B (0.699), indicating a more drug-like profile.

**7. DILI:** Ligand A (59.131) has a higher DILI risk than Ligand B (15.587). This is a significant negative for Ligand A.

**8. BBB:** Ligand B (82.047) has a substantially better BBB penetration percentile than Ligand A (59.674). This is *critical* for a CNS target like DRD2.

**9. Caco-2 Permeability:** Ligand A (-5.047) shows poor Caco-2 permeability, while Ligand B (-4.223) is slightly better, but still not great.

**10. Aqueous Solubility:** Ligand A (-3.289) has poor aqueous solubility, and Ligand B (-1.148) is also poor. Solubility is a concern for both.

**11. hERG Inhibition:** Ligand A (0.073) has very low hERG inhibition risk, while Ligand B (0.457) is slightly higher, but still acceptable.

**12. Microsomal Clearance:** Ligand A (24.895) and Ligand B (21.85) have similar, moderate microsomal clearance values.

**13. In vitro Half-Life:** Ligand B (-26.547) has a significantly longer in vitro half-life than Ligand A (1.182). This is a major advantage for Ligand B.

**14. P-gp Efflux:** Ligand A (0.115) shows lower P-gp efflux than Ligand B (0.14), which is favorable for CNS penetration.

**15. Binding Affinity:** Ligand A (-9.4 kcal/mol) has a significantly stronger binding affinity than Ligand B (-7.2 kcal/mol). This is a substantial advantage for Ligand A.

**Overall Assessment:**

While Ligand A boasts a superior binding affinity, its significantly higher DILI risk, poorer BBB penetration, and poor Caco-2 permeability are major drawbacks. Ligand B, despite a slightly weaker affinity, presents a much more favorable ADME profile, particularly its excellent BBB penetration and longer half-life, which are crucial for a CNS-targeting drug. The lower DILI risk is also a significant benefit. The difference in affinity (2.2 kcal/mol) is substantial, but the ADME advantages of Ligand B are likely to outweigh this difference, especially considering the challenges of CNS drug development.

Output:
1
2025-04-17 04:08:15,149 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (345.407 and 363.527 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (119.66) is better than Ligand B (54.46). Both are below the 90 A^2 threshold desirable for CNS targets.

**logP:** Ligand B (3.019) is optimal (1-3). Ligand A (0.518) is quite low, potentially hindering membrane permeability.

**H-Bond Donors:** Ligand A (3) is acceptable, while Ligand B (1) is even better.

**H-Bond Acceptors:** Both ligands (5) are within the acceptable limit of 10.

**QED:** Both ligands have good QED scores (0.73 and 0.684, respectively), indicating drug-like properties.

**DILI:** Ligand B (11.4) has a much lower DILI risk than Ligand A (50.136), a significant advantage.

**BBB:** Ligand B (79.566) has a substantially better BBB penetration score than Ligand A (36.487). This is *critical* for a CNS target like DRD2.

**Caco-2 Permeability:** Both have negative values, which is unusual. However, the magnitude of the negative value for Ligand A (-5.668) is larger than Ligand B (-5.065), suggesting potentially worse intestinal absorption for Ligand A.

**Aqueous Solubility:** Both have negative values, which is also unusual. The magnitude of the negative value for Ligand A (-2.013) is smaller than Ligand B (-3.481), suggesting potentially better aqueous solubility for Ligand A.

**hERG Inhibition:** Ligand A (0.105) has a slightly lower hERG risk than Ligand B (0.708).

**Microsomal Clearance:** Ligand A (-26.809) has a much lower (better) microsomal clearance than Ligand B (71.506), indicating greater metabolic stability.

**In vitro Half-Life:** Ligand A (6.905) has a better in vitro half-life than Ligand B (-3.878).

**P-gp Efflux:** Ligand A (0.018) has a much lower P-gp efflux liability than Ligand B (0.093), which is favorable for CNS penetration.

**Binding Affinity:** Ligand A (-8.3 kcal/mol) has a significantly stronger binding affinity than Ligand B (-6.9 kcal/mol).  This is a substantial advantage.

**Overall Assessment:**

Ligand A has a significantly better binding affinity, lower P-gp efflux, lower microsomal clearance, and longer half-life. However, it suffers from a very low logP, potentially hindering permeability, and a higher DILI risk and lower BBB penetration. Ligand B has a much better logP, DILI score, and, crucially, a much higher BBB penetration score. The difference in binding affinity is significant (1.4 kcal/mol), but the poor ADME properties of Ligand A, especially the low logP and BBB, are major concerns for a CNS target. While the affinity of Ligand A is attractive, the improved ADME profile of Ligand B, particularly its BBB penetration, makes it the more promising candidate.

Output:
1
2025-04-17 04:08:15,149 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (346.471 and 357.38 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (58.64) is slightly higher than Ligand B (54.38), but both are well below the 90 A^2 threshold for CNS targets.

**3. logP:** Both ligands have good logP values (2.267 and 2.062), falling within the optimal 1-3 range.

**4. H-Bond Donors:** Ligand A has 1 HBD, while Ligand B has 0. Both are acceptable (<=5).

**5. H-Bond Acceptors:** Ligand A has 3 HBA, Ligand B has 6. Both are within the acceptable range (<=10), but Ligand A is preferable.

**6. QED:** Both ligands have good QED scores (0.686 and 0.808), indicating drug-like properties.

**7. DILI:** Ligand A (15.898) has a significantly lower DILI risk than Ligand B (62.35). This is a major advantage for Ligand A.

**8. BBB:** Ligand B (89.027) has a better BBB penetration percentile than Ligand A (72.896). This is a crucial factor for a CNS target like DRD2.

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.798 and -4.607), which is unusual and suggests poor permeability. However, these values are on a scale where negative values are possible and don't necessarily disqualify a compound.

**10. Aqueous Solubility:** Both ligands have negative solubility values (-2.431 and -3.936), indicating poor solubility. This could be a formulation challenge.

**11. hERG Inhibition:** Ligand A (0.263) has a lower hERG inhibition liability than Ligand B (0.667), making it safer from a cardiotoxicity perspective.

**12. Microsomal Clearance:** Ligand A (51.9) has a higher microsomal clearance than Ligand B (42.164), suggesting faster metabolism. This is a slight disadvantage for Ligand A.

**13. In vitro Half-Life:** Ligand B (7.962) has a much longer in vitro half-life than Ligand A (-27.981). This is a significant advantage for Ligand B.

**14. P-gp Efflux:** Ligand A (0.114) has lower P-gp efflux than Ligand B (0.032), which is preferable for CNS penetration.

**15. Binding Affinity:** Ligand A (-8.0) has a significantly stronger binding affinity than Ligand B (-0.0). This is a substantial advantage that can outweigh some of the ADME drawbacks.

**Overall Assessment:**

While Ligand B has better BBB penetration and a longer half-life, Ligand A's significantly stronger binding affinity (-8.0 vs -0.0 kcal/mol) and much lower DILI risk are critical advantages. The affinity difference is so large that it's likely to overcome the slightly lower BBB and faster clearance of Ligand A. The P-gp efflux is also better for Ligand A. The solubility and Caco-2 permeability are poor for both, but these can be addressed with formulation strategies. Given the GPCR target and the importance of potency, Ligand A is the more promising candidate.

Output:
1
2025-04-17 04:08:15,149 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (375.921 and 388.021 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (29.54) is significantly better than Ligand B (30.29). Both are below the 90 A^2 threshold for CNS targets, which is excellent.

**3. logP:** Both ligands have good logP values (4.988 and 4.327), falling within the optimal 1-3 range, although slightly high. This could potentially lead to off-target effects but is not a major concern at this stage.

**4. H-Bond Donors:** Both have 0 HBD, which is acceptable.

**5. H-Bond Acceptors:** Ligand A has 3 HBA, and Ligand B has 5. Both are below the 10 threshold.

**6. QED:** Both ligands have acceptable QED values (0.666 and 0.559), indicating reasonable drug-likeness.

**7. DILI:** Ligand A (29.042) has a slightly higher DILI risk than Ligand B (21.714), but both are below the concerning threshold of 60.

**8. BBB:** This is a critical parameter for a CNS target like DRD2. Ligand B (81.698) has a significantly higher BBB percentile than Ligand A (45.793). This is a major advantage for Ligand B.

**9. Caco-2 Permeability:** Ligand A (-4.574) has a more negative Caco-2 value, indicating *better* permeability than Ligand B (-5.179). However, both are negative, which is unusual and suggests poor permeability.

**10. Aqueous Solubility:** Ligand A (-5.371) has slightly better solubility than Ligand B (-4.242), but both are poor.

**11. hERG Inhibition:** Ligand A (0.686) has a slightly lower hERG risk than Ligand B (0.913), which is preferable.

**12. Microsomal Clearance:** Ligand A (102.684) has a higher microsomal clearance than Ligand B (88.571), indicating lower metabolic stability.

**13. In vitro Half-Life:** Ligand B (37.107) has a significantly longer in vitro half-life than Ligand A (24.312), which is a significant advantage.

**14. P-gp Efflux:** Ligand A (0.5) has lower P-gp efflux liability than Ligand B (0.793), which is better for CNS exposure.

**15. Binding Affinity:** Ligand A (-7.6 kcal/mol) has a slightly better binding affinity than Ligand B (-6.9 kcal/mol). This difference of 0.7 kcal/mol is significant and could potentially outweigh some of the ADME drawbacks.

**Overall Assessment:**

While Ligand A has better affinity and lower P-gp efflux, Ligand B excels in crucial parameters for CNS drug development: **BBB penetration and in vitro half-life**. The significantly higher BBB value for Ligand B is a major advantage for targeting DRD2 in the brain. The longer half-life also contributes to a more desirable pharmacokinetic profile. Although Ligand A has slightly better solubility and hERG, the BBB and half-life advantages of Ligand B are more critical for a CNS GPCR target.

Output:
1
2025-04-17 04:08:15,149 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (353.5 and 348.4 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (53.09) is excellent, well below the 90 A^2 threshold for CNS targets. Ligand B (104.21) is higher, but still potentially acceptable, though less ideal.

**3. logP:** Both ligands have good logP values (1.593 and 1.072), falling within the optimal 1-3 range.

**4. H-Bond Donors:** Ligand A (0) is preferable to Ligand B (3) as fewer HBDs generally improve permeability.

**5. H-Bond Acceptors:** Ligand A (4) is better than Ligand B (5).

**6. QED:** Both ligands have similar QED values (0.728 and 0.652), indicating good drug-likeness.

**7. DILI:** Ligand A (11.2) has a significantly lower DILI risk than Ligand B (37.6), which is a substantial advantage.

**8. BBB:** Ligand A (81.582) has a much higher BBB penetration percentile than Ligand B (43.893). This is *critical* for a CNS target like DRD2.

**9. Caco-2 Permeability:** Ligand A (-4.326) has better Caco-2 permeability than Ligand B (-5.008).

**10. Aqueous Solubility:** Ligand A (-0.683) has better aqueous solubility than Ligand B (-1.526).

**11. hERG Inhibition:** Both ligands show very low hERG inhibition liability (0.414 and 0.066), which is excellent.

**12. Microsomal Clearance:** Ligand A (33.526) has higher microsomal clearance than Ligand B (13.162), indicating lower metabolic stability. This is a negative for Ligand A.

**13. In vitro Half-Life:** Ligand B (-5.755) has a longer in vitro half-life than Ligand A (-17.99), which is a positive for Ligand B.

**14. P-gp Efflux:** Ligand A (0.052) has lower P-gp efflux than Ligand B (0.013), which is favorable for CNS penetration.

**15. Binding Affinity:** Ligand B (-7.9) has slightly better binding affinity than Ligand A (-7.5), but the difference is relatively small (0.4 kcal/mol).

**Overall Assessment:**

Ligand A is significantly better overall, despite slightly higher Cl_mic. Its superior BBB penetration (81.6% vs 43.9%), lower DILI risk (11.2% vs 37.6%), better solubility, and lower P-gp efflux are crucial advantages for a CNS-targeting GPCR. The small difference in binding affinity (0.4 kcal/mol) is outweighed by these ADME/Tox benefits.

Output:
1
2025-04-17 04:08:15,149 - INFO - Reasoning:

Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (362.817 and 352.366 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (90.54) is excellent, falling below the 90 A^2 threshold for CNS targets. Ligand B (124.44) is higher, but still potentially acceptable, though less ideal.

**3. logP:** Ligand A (1.059) is within the optimal range (1-3). Ligand B (-1.038) is slightly below 1, which *could* indicate permeability issues, but isn't a dealbreaker.

**4. H-Bond Donors:** Ligand A (3) and Ligand B (4) are both acceptable (<=5).

**5. H-Bond Acceptors:** Ligand A (3) and Ligand B (6) are both acceptable (<=10).

**6. QED:** Ligand A (0.699) is better than Ligand B (0.443), indicating a more drug-like profile.

**7. DILI:** Both ligands have similar, acceptable DILI risk (Ligand A: 50.795, Ligand B: 46.258, both <60).

**8. BBB:** Ligand A (61.38) is better than Ligand B (36.177) regarding BBB penetration. While 61.38 isn't *outstanding*, it's significantly better for a CNS target than 36.177. This is a crucial factor for DRD2.

**9. Caco-2 Permeability:** Ligand A (-4.872) and Ligand B (-5.228) both have negative values, suggesting poor permeability. This is concerning, but not necessarily disqualifying if other properties are strong.

**10. Aqueous Solubility:** Ligand A (-3.323) and Ligand B (-1.793) both have negative values, indicating poor solubility. This could pose formulation challenges.

**11. hERG Inhibition:** Both ligands show very low hERG inhibition risk (Ligand A: 0.151, Ligand B: 0.138).

**12. Microsomal Clearance:** Ligand A (-29.248) has a much lower (better) microsomal clearance than Ligand B (-1.787), suggesting greater metabolic stability.

**13. In vitro Half-Life:** Both ligands have similar, short in vitro half-lives (Ligand A: -3.907, Ligand B: -3.92).

**14. P-gp Efflux:** Both ligands have very low P-gp efflux liability (Ligand A: 0.009, Ligand B: 0.042).

**15. Binding Affinity:** Ligand A (-9.2 kcal/mol) has a significantly stronger binding affinity than Ligand B (-7.9 kcal/mol). This 1.3 kcal/mol difference is substantial and can outweigh some ADME drawbacks.

**Overall Assessment:**

Ligand A is the superior candidate. It has better BBB penetration, a significantly stronger binding affinity, better QED, and lower microsomal clearance. While both have poor Caco-2 permeability and solubility, the stronger binding and improved CNS penetration of Ligand A are critical advantages for a DRD2 ligand. The lower clearance also suggests better *in vivo* exposure.

Output:
1
2025-04-17 04:08:15,150 - INFO - Batch 87 complete. Total preferences: 1392
2025-04-17 04:08:15,150 - INFO - Processing batch 88/512...
2025-04-17 04:08:56,046 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (346.39 and 370.48 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (95.86) is slightly higher than Ligand B (84.74). Both are below the 140 A^2 threshold for oral absorption and reasonably close to the 90 A^2 target for CNS penetration, but Ligand B is better.

**logP:** Ligand A (-0.606) is a bit low, potentially hindering permeability. Ligand B (0.601) is within the optimal 1-3 range. This is a significant advantage for Ligand B.

**H-Bond Donors/Acceptors:** Ligand A has 1 HBD and 6 HBA, while Ligand B has 0 HBD and 6 HBA. Both are within acceptable limits.

**QED:** Both ligands have similar QED values (0.731 and 0.626), indicating good drug-likeness.

**DILI:** Ligand A (60.721) has a higher DILI risk than Ligand B (46.956), although both are reasonably acceptable.

**BBB:** This is critical for a CNS target. Ligand B (77.162) has a significantly better BBB penetration percentile than Ligand A (41.295). This is a major advantage for Ligand B.

**Caco-2 Permeability:** Both have negative values (-4.881 and -4.591), which is unusual and suggests poor permeability. However, these values are on a scale where higher is better, so they are both poor.

**Aqueous Solubility:** Both ligands have poor aqueous solubility (-0.63 and -1.715).

**hERG Inhibition:** Ligand A (0.052) shows a slightly lower hERG inhibition liability than Ligand B (0.684), which is preferable.

**Microsomal Clearance:** Ligand A (-0.095) has a lower (better) microsomal clearance than Ligand B (59.511). This suggests better metabolic stability for Ligand A.

**In vitro Half-Life:** Ligand A (0.052) has a very short in vitro half-life, while Ligand B (-43.424) has a negative value which is unusual and suggests a very long half-life.

**P-gp Efflux:** Ligand A (0.006) has a much lower P-gp efflux liability than Ligand B (0.317), which is beneficial for CNS exposure.

**Binding Affinity:** Both ligands have very good binding affinity (-7.5 and -7.3 kcal/mol). The difference of 0.2 kcal/mol is not substantial enough to outweigh other factors.

**Overall Assessment:**

Ligand B clearly stands out due to its significantly better BBB penetration (77.162 vs 41.295) and more favorable logP (0.601 vs -0.606). While Ligand A has better metabolic stability (lower Cl_mic) and P-gp efflux, the BBB and logP are more critical for a CNS-targeting GPCR like DRD2. The slightly higher hERG risk for Ligand B is a minor concern compared to the poor BBB penetration of Ligand A.

Output:
1
2025-04-17 04:08:56,047 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (344.415 Da) is slightly lower, which could be advantageous for permeability.

**2. TPSA:** Ligand A (73.91) is significantly better than Ligand B (105.32). For CNS targets, we want TPSA <= 90, so Ligand A is preferable.

**3. logP:** Both ligands have good logP values (A: 2.193, B: 2.928), falling within the optimal 1-3 range.

**4. H-Bond Donors:** Both have 2 HBD, which is acceptable.

**5. H-Bond Acceptors:** Ligand A has 3 HBA, while Ligand B has 6. Lower HBA is generally preferred for better permeability, making Ligand A more favorable.

**6. QED:** Both ligands have reasonable QED values (A: 0.804, B: 0.738), indicating good drug-like properties.

**7. DILI:** Ligand A (58.511) has a much lower DILI risk than Ligand B (98.371). This is a significant advantage for Ligand A.

**8. BBB:** Ligand A (59.325) has a better BBB percentile than Ligand B (21.946). This is *critical* for a CNS target like DRD2.

**9. Caco-2 Permeability:** Both have negative Caco-2 values, indicating poor permeability. However, Ligand A (-4.983) is slightly better than Ligand B (-5.09).

**10. Aqueous Solubility:** Both have negative solubility values, indicating poor solubility. Ligand A (-2.381) is slightly better than Ligand B (-4.144).

**11. hERG Inhibition:** Both have low hERG inhibition risk (A: 0.505, B: 0.634).

**12. Microsomal Clearance:** Both have similar microsomal clearance values (A: 29.577, B: 31.098).

**13. In vitro Half-Life:** Ligand A (-9.15) has a longer in vitro half-life than Ligand B (-13.296).

**14. P-gp Efflux:** Both have low P-gp efflux liability (A: 0.088, B: 0.232), which is good.

**15. Binding Affinity:** Ligand B (-10.5 kcal/mol) has a slightly better binding affinity than Ligand A (-9.3 kcal/mol). However, the difference is not substantial enough to outweigh the significant ADME advantages of Ligand A.

**Overall Assessment:**

Ligand A is significantly better due to its superior TPSA, DILI risk, BBB penetration, and in vitro half-life. While Ligand B has slightly better binding affinity, the ADME properties of Ligand A are far more favorable for a CNS-targeting drug, especially considering the importance of BBB penetration for DRD2.

Output:
0
2025-04-17 04:08:56,047 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 drug candidates, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight (MW):** Both ligands (355.558 and 350.507 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (38.13) is excellent, well below the 90 Angstroms threshold for CNS targets. Ligand B (85.23) is higher but still acceptable, though less optimal for CNS penetration.

**3. logP:** Ligand A (4.334) is slightly high, potentially leading to solubility issues or off-target interactions. Ligand B (2.059) is within the optimal range of 1-3.

**4. H-Bond Donors (HBD):** Both ligands have acceptable HBD counts (0 for A, 2 for B), well below the limit of 5.

**5. H-Bond Acceptors (HBA):** Both ligands have acceptable HBA counts (3 for A, 4 for B), below the limit of 10.

**6. QED:** Ligand A (0.752) has a better QED score than Ligand B (0.591), indicating a more drug-like profile.

**7. DILI:** Ligand A (60.954) has a moderate DILI risk, while Ligand B (2.52) has a very low risk, which is a significant advantage.

**8. BBB:** Ligand A (77.433) has a good BBB percentile, exceeding the 70% threshold for CNS targets. Ligand B (57.852) is lower, indicating poorer predicted brain penetration.

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 values, which is unusual and suggests poor permeability. However, these values are on a different scale and difficult to interpret directly.

**10. Aqueous Solubility:** Both ligands have negative solubility values, suggesting very poor solubility.

**11. hERG Inhibition:** Both ligands show low hERG inhibition risk (0.777 and 0.708).

**12. Microsomal Clearance:** Ligand A (93.744) has high microsomal clearance, suggesting rapid metabolism and potentially low bioavailability. Ligand B (-18.871) has *very* low (negative) clearance, indicating excellent metabolic stability.

**13. In vitro Half-Life:** Ligand A (5.022) has a short half-life. Ligand B (-10.68) has a very long (negative) half-life, which is highly favorable.

**14. P-gp Efflux:** Both ligands have low P-gp efflux liability (0.793 and 0.012), which is good for CNS exposure. Ligand B is significantly better.

**15. Binding Affinity:** Ligand B (-7.5 kcal/mol) has a significantly stronger binding affinity than Ligand A (0 kcal/mol). This is a crucial difference, as a >1.5 kcal/mol advantage can outweigh other drawbacks.

**Overall Assessment:**

Despite Ligand A's better QED and BBB, Ligand B is the stronger candidate. The significantly improved binding affinity (-7.5 vs 0 kcal/mol) is paramount for a GPCR target. Furthermore, Ligand B exhibits substantially better metabolic stability (negative clearance, long half-life) and lower DILI risk. While its TPSA is higher and logP lower than ideal, the dramatic improvement in affinity and ADME properties outweighs these concerns. The negative solubility and Caco-2 values are concerning for both, but can potentially be addressed through formulation strategies.

Output:
1
2025-04-17 04:08:56,047 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (365.449 and 361.471 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (45.23) is significantly better than Ligand B (71.33). For CNS targets, we want TPSA <= 90, and ideally closer to 60. Ligand A is much closer to this ideal.

**logP:** Ligand A (3.693) is optimal (1-3), while Ligand B (2.045) is on the lower end, potentially hindering permeation.

**H-Bond Donors/Acceptors:** Ligand A (HBD=1, HBA=4) is better balanced than Ligand B (HBD=0, HBA=6). While both are acceptable, more HBA can sometimes lead to issues.

**QED:** Both ligands have similar QED values (0.879 and 0.817), indicating good drug-likeness.

**DILI:** Both ligands have acceptable DILI risk (61.07 and 58.511), below the concerning threshold of 60.

**BBB:** Ligand A (89.608) has a significantly better BBB percentile than Ligand B (71.307). For a CNS target like DRD2, >70 is desirable, and Ligand A is closer to this.

**Caco-2 Permeability:** Both have negative values (-4.634 and -4.836), which is unusual and difficult to interpret without knowing the scale. However, they are similar.

**Aqueous Solubility:** Both have negative values (-3.127 and -2.291), also unusual. Again, they are similar.

**hERG Inhibition:** Ligand A (0.893) is slightly higher than Ligand B (0.238), indicating a potentially higher risk of cardiotoxicity, but still relatively low.

**Microsomal Clearance:** Ligand A (-4.343) has a *lower* (better) clearance than Ligand B (42.61). Lower clearance indicates greater metabolic stability.

**In vitro Half-Life:** Ligand A (40.532) has a longer half-life than Ligand B (23.242), which is desirable.

**P-gp Efflux:** Ligand A (0.591) has lower P-gp efflux than Ligand B (0.195), which is beneficial for CNS exposure.

**Binding Affinity:** Both ligands have excellent binding affinities (-8.7 and -8.3 kcal/mol). Ligand A is slightly better, but the difference is small.

**Overall Assessment:**

Ligand A consistently outperforms Ligand B across several key ADME properties crucial for a CNS-targeting GPCR ligand. Specifically, its superior TPSA, logP, BBB penetration, metabolic stability (lower Cl_mic, longer t1/2), and lower P-gp efflux make it a more promising candidate. While Ligand B has a slightly lower hERG risk, the other advantages of Ligand A outweigh this minor difference. The binding affinity difference is negligible.

Output:
1
2025-04-17 04:08:56,047 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 drug candidates, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (385.555 Da) is slightly higher than Ligand B (347.434 Da), but both are acceptable.

**TPSA:** Ligand A (82.27) is higher than Ligand B (54.46). For CNS targets, we want TPSA <= 90, so both are within range, but Ligand B is significantly better.

**logP:** Both ligands have good logP values (Ligand A: 1.713, Ligand B: 2.099), falling within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A has 2 HBD and 5 HBA, while Ligand B has 1 HBD and 4 HBA. Both are within acceptable limits (<=5 HBD and <=10 HBA).

**QED:** Ligand B (0.801) has a significantly higher QED score than Ligand A (0.599), indicating a more drug-like profile.

**DILI:** Ligand B (6.669) has a much lower DILI risk than Ligand A (38.154), which is a significant advantage.

**BBB:** This is a critical parameter for CNS targets. Ligand B (96.743) exhibits excellent BBB penetration, while Ligand A (26.134) is poor. This is a major differentiating factor.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values, which is unusual and suggests poor permeability. However, the scale is not specified, so it's difficult to interpret.

**Aqueous Solubility:** Both ligands have negative solubility values, which is also unusual and suggests poor solubility. Again, the scale is not specified.

**hERG Inhibition:** Ligand A (0.204) has a slightly lower hERG inhibition risk than Ligand B (0.723), but both are relatively low.

**Microsomal Clearance:** Ligand B (19.805) has a lower microsomal clearance than Ligand A (39.118), indicating better metabolic stability.

**In vitro Half-Life:** Ligand B (-14.276) has a negative half-life, which is not physically possible and suggests an issue with the data. Ligand A (24.472) is reasonable. However, the negative value for Ligand B is a red flag.

**P-gp Efflux:** Ligand A (0.083) has lower P-gp efflux than Ligand B (0.109), which is preferable for CNS penetration.

**Binding Affinity:** Both ligands have very similar and strong binding affinities (Ligand A: -7.3 kcal/mol, Ligand B: -7.1 kcal/mol). The difference is less than 1.5 kcal/mol, so this isn't a major deciding factor.

**Overall Assessment:**

Ligand B is the superior candidate. It has a significantly better BBB score, lower DILI risk, better QED, and lower microsomal clearance. While the Caco-2 and solubility values are concerning for both, the BBB advantage of Ligand B is crucial for a CNS-targeting drug. The negative half-life for Ligand B is a major concern, but the other advantages are substantial. Ligand A's poor BBB penetration is a significant drawback.

Output:
1
2025-04-17 04:08:56,047 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 drug candidates, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (364.408 Da and 362.499 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (58.64) is significantly better than Ligand B (71.25). For CNS targets, we want TPSA <= 90, and ideally closer to 60. Ligand A is much closer to the ideal range.

**3. logP:** Both ligands have good logP values (3.013 and 2.536), falling within the optimal 1-3 range.

**4. H-Bond Donors:** Both have 1 HBD, which is acceptable.

**5. H-Bond Acceptors:** Ligand A has 3 HBA, while Ligand B has 6. Lower is generally better, and Ligand A is preferable.

**6. QED:** Both ligands have good QED scores (0.755 and 0.822), indicating good drug-like properties.

**7. DILI:** Both ligands have similar and acceptable DILI risk (39.667 and 39.201, both <40).

**8. BBB:** Ligand A (74.292) has a significantly better BBB percentile than Ligand B (54.362). A value >70 is desirable for CNS targets, and Ligand A is closer to this threshold.

**9. Caco-2:** Both have negative Caco-2 values, which is unusual and difficult to interpret without knowing the scale. However, the magnitude of the negative value for Ligand A (-4.566) is less than for Ligand B (-5.029), suggesting slightly better permeability.

**10. Solubility:** Both have negative solubility values, again unusual. Similar to Caco-2, the less negative value for Ligand A (-2.685) suggests slightly better solubility.

**11. hERG:** Both ligands have low hERG inhibition liability (0.603 and 0.233), which is good.

**12. Cl_mic:** Ligand B (34.953) has a lower microsomal clearance than Ligand A (60.59), indicating better metabolic stability.

**13. t1/2:** Ligand B (8.554) has a longer in vitro half-life than Ligand A (-11.089). This is a significant advantage.

**14. Pgp:** Both ligands have low Pgp efflux liability (0.147 and 0.128), which is good.

**15. Binding Affinity:** Ligand B (-7.8 kcal/mol) has a slightly better binding affinity than Ligand A (-8.1 kcal/mol). While the difference is small, it's a positive for Ligand B.

**Overall Assessment:**

Considering the GPCR-specific priorities, Ligand A is favored due to its significantly better TPSA and BBB penetration. While Ligand B has better metabolic stability (lower Cl_mic) and a slightly longer half-life, the importance of CNS penetration for a DRD2 target (involved in CNS disorders) outweighs these benefits. The slightly better affinity of Ligand B is not enough to overcome the significant differences in TPSA and BBB.

Output:
1
2025-04-17 04:08:56,047 - INFO - Reasoning:

Let's analyze Ligand A and Ligand B based on the provided guidelines, prioritizing GPCR-specific properties (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (364.808 and 362.495 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (82.26) is slightly higher than Ligand B (67.43). For CNS targets, we prefer TPSA <= 90, so both are acceptable, but B is better.

**logP:** Ligand A (3.366) is within the optimal range (1-3), while Ligand B (2.043) is closer to the lower bound. Both are acceptable, but A is slightly preferred.

**H-Bond Donors/Acceptors:** Ligand A has 4 HBD and 2 HBA, while Ligand B has 2 HBD and 4 HBA. Both are within acceptable limits (<=5 HBD and <=10 HBA).

**QED:** Ligand B (0.842) has a significantly better QED score than Ligand A (0.627), suggesting a more drug-like profile.

**DILI:** Ligand B (50.174) has a much lower DILI risk than Ligand A (88.329). This is a significant advantage for Ligand B.

**BBB:** Ligand B (71.384) has a better BBB penetration score than Ligand A (68.127). While both are above 70 (desirable for CNS targets), B is better.

**Caco-2 Permeability:** Ligand A (-4.69) shows poorer Caco-2 permeability compared to Ligand B (-5.367). Lower values here are worse.

**Aqueous Solubility:** Ligand A (-5.874) exhibits lower aqueous solubility than Ligand B (-3.508).

**hERG Inhibition:** Both ligands have very low hERG inhibition liability (0.481 and 0.478), which is excellent.

**Microsomal Clearance:** Ligand A (41.722) has lower microsomal clearance than Ligand B (44.014), indicating better metabolic stability.

**In vitro Half-Life:** Ligand A (87.727) has a significantly longer in vitro half-life than Ligand B (18.084). This is a major advantage for Ligand A.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.136 and 0.299), which is good.

**Binding Affinity:** Ligand B (-7.9 kcal/mol) has a substantially stronger binding affinity than Ligand A (-10.5 kcal/mol). This is a very significant advantage for Ligand B, potentially outweighing some ADME drawbacks.

**Overall Assessment:**

Ligand B clearly wins on several critical parameters for a CNS-targeting GPCR ligand: better BBB penetration, lower DILI risk, significantly improved binding affinity, and better QED. While Ligand A has better metabolic stability and half-life, the superior affinity and safety profile of Ligand B are more important. The slightly lower half-life of Ligand B can potentially be addressed through formulation or structural modifications.

Output:
1
2025-04-17 04:08:56,048 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (365.539 Da) is slightly higher than Ligand B (347.463 Da), but this isn't a major concern.

**TPSA:** Ligand A (63.24) is significantly better than Ligand B (90.98). For CNS targets, we want TPSA <= 90, so Ligand A is preferable.

**logP:** Ligand A (3.811) is optimal, while Ligand B (1.981) is on the lower side. Lower logP can hinder permeation, making Ligand A more attractive.

**H-Bond Donors/Acceptors:** Ligand A (HBD=1, HBA=3) is better than Ligand B (HBD=2, HBA=4) in terms of balancing solubility and permeability. Both are within acceptable limits.

**QED:** Both ligands have good QED scores (A: 0.686, B: 0.738), suggesting good drug-like properties.

**DILI:** Both ligands have similar, acceptable DILI risk (A: 37.456, B: 38.387).

**BBB:** This is crucial for a CNS target. Ligand A has a significantly higher BBB percentile (78.092) compared to Ligand B (41.218). This is a major advantage for Ligand A.

**Caco-2 Permeability:** Ligand A (-4.849) is worse than Ligand B (-5.493), but both are negative, indicating poor permeability. This is a drawback for both, but less critical than BBB for a CNS target.

**Aqueous Solubility:** Ligand A (-3.948) is worse than Ligand B (-1.791). Solubility is important, but can be addressed with formulation strategies.

**hERG Inhibition:** Ligand A (0.607) has a slightly higher hERG risk than Ligand B (0.086), but both are relatively low.

**Microsomal Clearance:** Ligand B (8.732) has a much lower clearance than Ligand A (62.147), suggesting better metabolic stability. This is a significant advantage for Ligand B.

**In vitro Half-Life:** Ligand A (18.627) has a longer half-life than Ligand B (-3.844). This is a positive for Ligand A.

**P-gp Efflux:** Ligand A (0.526) has lower P-gp efflux than Ligand B (0.108), which is desirable for CNS penetration.

**Binding Affinity:** Ligand A (-8.2 kcal/mol) has a significantly stronger binding affinity than Ligand B (0.0 kcal/mol). This is the most important factor, and the >1.5 kcal/mol advantage of A outweighs many of its drawbacks.

**Overall:**

Ligand A excels in the most critical areas for a CNS-targeting GPCR ligand: **BBB penetration and binding affinity**. While Ligand B has better metabolic stability (lower Cl_mic) and solubility, the superior BBB and binding affinity of Ligand A are decisive. The slightly higher TPSA and lower solubility of A can be potentially addressed through formulation or further optimization.



Output:
1
2025-04-17 04:08:56,048 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (354.491 and 360.498 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (87.66) is better than Ligand B (33.2). For CNS targets, we want TPSA <= 90, so both are acceptable, but A is closer to the upper limit.

**3. logP:** Ligand A (1.466) is within the optimal range (1-3). Ligand B (4.539) is slightly high, potentially leading to solubility issues and off-target interactions.

**4. H-Bond Donors:** Ligand A (3) is acceptable. Ligand B (0) is also acceptable, but too few HBDs can sometimes hinder solubility.

**5. H-Bond Acceptors:** Both ligands (A: 4, B: 3) are well within the acceptable limit of <= 10.

**6. QED:** Both ligands have good QED scores (A: 0.646, B: 0.805), indicating drug-like properties. B is slightly better here.

**7. DILI:** Ligand A (26.444) has a much lower DILI risk than Ligand B (56.844). This is a significant advantage for Ligand A.

**8. BBB:** Ligand B (86.817) has a significantly better BBB penetration score than Ligand A (45.754). This is *critical* for a CNS target like DRD2.

**9. Caco-2:** Both ligands have negative Caco-2 values (-5.07 and -4.749). This is unusual and suggests poor permeability.

**10. Solubility:** Ligand A (-1.941) has slightly better solubility than Ligand B (-4.642).

**11. hERG:** Both ligands have low hERG inhibition liability (A: 0.142, B: 0.642), which is good.

**12. Cl_mic:** Ligand A (31.29) has a lower microsomal clearance than Ligand B (63.126), indicating better metabolic stability.

**13. t1/2:** Ligand A (-4.315) has a negative half-life, which is concerning. Ligand B (4.245) has a positive half-life, which is more desirable.

**14. Pgp:** Ligand A (0.037) has much lower P-gp efflux liability than Ligand B (0.76). Lower Pgp is crucial for CNS penetration.

**15. Binding Affinity:** Ligand B (-8.6) has a significantly stronger binding affinity than Ligand A (-7.4). A difference of 1.2 kcal/mol is substantial and can often outweigh other drawbacks.

**Overall Assessment:**

Ligand B excels in BBB penetration and binding affinity, both critical for a DRD2 ligand. However, it has a higher logP, higher DILI risk, and higher Pgp efflux. Ligand A has better metabolic stability, lower DILI, and lower Pgp efflux, but its BBB penetration is poor, and its binding affinity is weaker.

The strong binding affinity and excellent BBB of Ligand B are compelling. While the higher logP and DILI are concerns, the 1.2 kcal/mol advantage in binding affinity is likely to be decisive, especially given the importance of potency for GPCR ligands. The poor Caco-2 values for both are concerning, but can be addressed through formulation strategies.

Output:
1
2025-04-17 04:08:56,048 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (353.403 and 356.432 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (84.12) is excellent for CNS penetration, being well below 90. Ligand B (25.36) is even better.

**logP:** Ligand A (3.295) is within the optimal 1-3 range. Ligand B (4.519) is slightly above, which could potentially lead to solubility issues or off-target interactions, but is not a dealbreaker.

**H-Bond Donors/Acceptors:** Ligand A has 1 HBD and 6 HBA, both acceptable. Ligand B has 0 HBD and 3 HBA, also acceptable.

**QED:** Both ligands have reasonable QED values (0.73 and 0.577), indicating good drug-like properties.

**DILI:** Ligand A has a high DILI risk (95.386), which is a major concern. Ligand B has a very low DILI risk (6.398), a significant advantage.

**BBB:** Ligand A (63.746) has moderate BBB penetration, while Ligand B (98.139) has excellent BBB penetration, crucial for a CNS target like DRD2.

**Caco-2 Permeability:** Both have negative Caco-2 values (-4.869 and -4.422). This is unusual and suggests a potential issue with intestinal absorption, or an error in the data. However, given the focus on CNS penetration, this is less critical than BBB.

**Aqueous Solubility:** Both have negative solubility values (-5.503 and -3.903). Similar to Caco-2, this is concerning but less critical given the CNS target.

**hERG:** Ligand A (0.544) has a slightly elevated hERG risk, while Ligand B (0.967) is higher. This is a concern for both, but manageable if the benefit outweighs the risk.

**Microsomal Clearance:** Ligand A (90.33) has a high microsomal clearance, indicating rapid metabolism. Ligand B (43.762) has lower clearance, suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (58.693) has a moderate half-life, while Ligand B (27.127) has a short half-life.

**P-gp Efflux:** Ligand A (0.545) has low P-gp efflux, which is good for CNS exposure. Ligand B (0.745) is slightly higher, but still acceptable.

**Binding Affinity:** Ligand B (-7.9 kcal/mol) has a slightly better binding affinity than Ligand A (-8.5 kcal/mol). While the difference is small, it's still a positive.

**Overall Assessment:**

Ligand B is the stronger candidate. While it has a slightly higher logP and hERG risk, its significantly lower DILI risk, excellent BBB penetration, and better metabolic stability outweigh these drawbacks. The superior binding affinity further supports this conclusion. Ligand A's high DILI risk is a major red flag.

Output:
1
2025-04-17 04:08:56,048 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B based on the provided guidelines, prioritizing GPCR-specific properties (BBB, logP, Pgp, TPSA, and affinity) for DRD2.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (346.391 Da) is slightly lower, which could be beneficial for permeability, but both are acceptable.

**TPSA:** Ligand A (127.0) is borderline for CNS targets (ideally <90), while Ligand B (29.95) is excellent. This is a significant advantage for Ligand B.

**logP:** Ligand A (0.5) is quite low, potentially hindering permeation. Ligand B (3.943) is optimal. This is a major advantage for Ligand B.

**H-Bond Donors/Acceptors:** Ligand A has 4 HBD and 5 HBA, which are acceptable. Ligand B has 1 HBD and 5 HBA, also acceptable.

**QED:** Both ligands have good QED scores (A: 0.627, B: 0.789), indicating drug-like properties.

**DILI:** Ligand A (62.001) is approaching a concerning DILI risk, while Ligand B (45.832) is much lower and safer.

**BBB:** Ligand A (24.506) has very poor predicted BBB penetration, making it less suitable for a CNS target like DRD2. Ligand B (92.168) has excellent predicted BBB penetration, a critical advantage.

**Caco-2 Permeability:** Ligand A (-5.444) has poor Caco-2 permeability, consistent with its low logP. Ligand B (-4.808) is also not great, but better than A.

**Aqueous Solubility:** Both have negative solubility values, indicating poor solubility. This is a potential issue for both, but might be manageable with formulation.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (A: 0.096, B: 0.99).

**Microsomal Clearance:** Ligand A (-17.568) has a negative clearance, which is unusual and likely an error, suggesting very high metabolic stability. Ligand B (17.797) has a moderate clearance.

**In vitro Half-Life:** Ligand A (-21.16) has a negative half-life, also likely an error, suggesting extreme stability. Ligand B (46.212) has a good half-life.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (A: 0.013, B: 0.877), which is favorable for CNS penetration.

**Binding Affinity:** Both ligands have similar and strong binding affinities (-8.6 kcal/mol). The difference is negligible.

**Overall Assessment:**

Ligand B is significantly more promising due to its superior TPSA, logP, and especially its excellent BBB penetration. While both have solubility concerns, Ligand B's better ADME properties, particularly its BBB score, outweigh the slight advantage of Ligand A's potentially erroneous metabolic stability data. Ligand A's low logP and poor BBB penetration are major drawbacks for a CNS-targeted GPCR.

Output:
1
2025-04-17 04:08:56,048 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, considering the provided guidelines and GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (355.479 and 348.422 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (87.74) is better than Ligand B (75.19). Both are below the 90 A^2 threshold for CNS targets, which is excellent.

**3. logP:** Ligand B (2.202) is better than Ligand A (0.784). Ligand B is within the optimal 1-3 range, while Ligand A is slightly below 1, which *could* indicate permeability issues.

**4. H-Bond Donors:** Ligand B (1) is better than Ligand A (2). Lower HBD generally improves permeability.

**5. H-Bond Acceptors:** Both ligands have 4 HBA, which is acceptable (<=10).

**6. QED:** Both ligands have similar QED values (0.606 and 0.577), both above the 0.5 threshold, indicating good drug-like properties.

**7. DILI:** Ligand A (19) is significantly better than Ligand B (51.493). Lower DILI risk is crucial.

**8. BBB:** Ligand B (89.027) is *much* better than Ligand A (54.711). For a CNS target like DRD2, a BBB percentile >70 is highly desirable, and Ligand B is closer to this target.

**9. Caco-2 Permeability:** Ligand A (-4.865) is better than Ligand B (-4.952), but both are negative, which is not ideal.

**10. Aqueous Solubility:** Ligand A (-1.915) is better than Ligand B (-2.746), but both are negative, which is not ideal.

**11. hERG Inhibition:** Ligand A (0.252) is better than Ligand B (0.603). Lower hERG inhibition is preferred.

**12. Microsomal Clearance:** Ligand A (36.701) is better than Ligand B (45.733). Lower clearance suggests better metabolic stability.

**13. In vitro Half-Life:** Ligand A (-6.331) is better than Ligand B (-3.8). A more negative value indicates a longer half-life.

**14. P-gp Efflux:** Ligand A (0.029) is significantly better than Ligand B (0.279). Lower P-gp efflux is crucial for CNS penetration.

**15. Binding Affinity:** Ligand B (-7.1) is slightly better than Ligand A (-6.9). While both are good, the small advantage in affinity for Ligand B is a plus.

**Overall Assessment:**

While Ligand A has advantages in DILI, metabolic stability, half-life, and P-gp efflux, Ligand B excels in the most critical areas for a CNS GPCR target: BBB penetration and logP. The substantial difference in BBB (89.027 vs 54.711) is a major factor. The slightly better affinity of Ligand B also contributes. The lower DILI risk of Ligand A is good, but can potentially be addressed with further optimization. The slightly lower logP of Ligand A is a concern for CNS penetration.

Output:
1
2025-04-17 04:08:56,048 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B based on the provided guidelines, prioritizing GPCR-specific properties (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (350.503 and 368.352 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (58.64) is excellent, well below the 90 A^2 threshold for CNS targets. Ligand B (99.1) is higher, but still potentially acceptable, though less ideal.

**logP:** Ligand A (3.047) is optimal (1-3). Ligand B (-0.338) is significantly outside the optimal range and is concerningly low, potentially hindering membrane permeability.

**H-Bond Donors/Acceptors:** Ligand A (HBD=1, HBA=3) and Ligand B (HBD=3, HBA=5) both have reasonable numbers of H-bond donors and acceptors, falling within the guidelines.

**QED:** Both ligands have similar QED values (0.65 and 0.631), indicating good drug-likeness.

**DILI:** Ligand A (9.19) has a very low DILI risk. Ligand B (16.789) is higher, but still relatively low.

**BBB:** Ligand A (81.233) has a good BBB percentile, exceeding the 70% threshold for CNS targets. Ligand B (58.976) is significantly lower, raising concerns about CNS penetration.

**Caco-2 Permeability:** Ligand A (-4.359) has poor Caco-2 permeability. Ligand B (-5.089) is even worse.

**Aqueous Solubility:** Both ligands have negative solubility values, indicating poor aqueous solubility, but Ligand A (-2.178) is better than Ligand B (-1.115).

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.387 and 0.276).

**Microsomal Clearance:** Ligand A (70.712) has moderate clearance. Ligand B (-24.064) has negative clearance, which is not possible and likely an error in the data, but suggests very high metabolic stability.

**In vitro Half-Life:** Ligand A (-1.548) has a negative half-life, which is not possible and likely an error. Ligand B (-16.782) also has a negative half-life, also likely an error.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.116 and 0.025), which is favorable.

**Binding Affinity:** Ligand A (-7.8 kcal/mol) has a slightly better binding affinity than Ligand B (-8.8 kcal/mol). While both are excellent, the difference is not substantial enough to overcome other significant issues.

**Overall Assessment:**

Ligand A is the better candidate despite the negative values for Caco-2 and half-life. Its superior logP and BBB penetration are crucial for a CNS-targeting GPCR ligand. While its solubility is poor, this can be addressed with formulation strategies. Ligand B's extremely low logP is a major drawback, severely limiting its ability to cross cell membranes and reach the CNS. The negative values for clearance and half-life are also concerning and likely indicate data errors.

Output:
0
2025-04-17 04:08:56,048 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (356.413 and 371.459 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (50.8) is excellent, well below the 90 A^2 threshold for CNS targets. Ligand B (97.83) is higher, but still potentially acceptable, though less ideal.

**logP:** Ligand A (2.102) is optimal (1-3). Ligand B (0.269) is quite low, potentially hindering permeability and CNS penetration.

**H-Bond Donors:** Both ligands have 1 HBD, which is within the acceptable limit of <=5.

**H-Bond Acceptors:** Ligand A has 4 HBAs, and Ligand B has 6. Both are within the acceptable limit of <=10.

**QED:** Both ligands have QED values around 0.6, indicating good drug-likeness.

**DILI:** Ligand A (9.616) has a very low DILI risk, excellent. Ligand B (59.131) is higher, indicating a moderate risk, but not prohibitive.

**BBB:** This is critical for a CNS target. Ligand A scores very high (95.657), indicating excellent predicted BBB penetration. Ligand B (70.376) is acceptable, but significantly lower.

**Caco-2 Permeability:** Ligand A (-4.594) and Ligand B (-5.21) both have negative values, which is unusual. A higher value is preferred.

**Aqueous Solubility:** Ligand A (-2.317) and Ligand B (-1.459) both have negative values, which is unusual. A higher value is preferred.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.89 and 0.247 respectively).

**Microsomal Clearance:** Ligand A (14.265) has a lower clearance than Ligand B (27.759), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (-13.029) has a longer half-life than Ligand B (-3.406).

**P-gp Efflux:** Ligand A (0.202) has lower P-gp efflux liability than Ligand B (0.015), which is favorable for CNS penetration.

**Binding Affinity:** Ligand B (-8.1) has a slightly better binding affinity than Ligand A (-7.6), a difference of 0.5 kcal/mol. While a 1.5 kcal/mol advantage is usually significant, this difference is small and can be overcome by superior ADME properties.

**Overall Assessment:**

Ligand A is significantly better overall due to its superior BBB penetration, lower DILI risk, better metabolic stability (lower Cl_mic, longer t1/2), and lower P-gp efflux. While Ligand B has slightly better binding affinity, the ADME properties of Ligand A are far more favorable for a CNS-targeting drug, especially given the importance of BBB penetration for GPCRs like DRD2. The low logP of Ligand B is a major concern.

Output:
1
2025-04-17 04:08:56,048 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (352.475 and 346.475 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Both ligands have TPSA values (67.87 and 67.23) below the 90 A^2 threshold for CNS targets, which is excellent.

**3. logP:** Ligand A (1.724) is within the optimal range (1-3). Ligand B (2.582) is also within the optimal range, but closer to the upper limit.

**4. H-Bond Donors:** Both ligands have 1 HBD, which is well within the acceptable limit of <=5.

**5. H-Bond Acceptors:** Both ligands have 4 HBA, also well within the acceptable limit of <=10.

**6. QED:** Both ligands have similar QED values (0.79 and 0.772), indicating good drug-likeness.

**7. DILI:** Ligand A (15.82 percentile) has a significantly lower DILI risk than Ligand B (30.787 percentile). This is a substantial advantage for Ligand A.

**8. BBB:** Ligand A (81.698 percentile) has a better BBB penetration prediction than Ligand B (74.719 percentile). This is crucial for a CNS target like DRD2.

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.452 and -4.447), which is unusual and suggests poor permeability. However, these values are very close and likely not a major differentiator.

**10. Aqueous Solubility:** Both ligands have negative solubility values (-1.98 and -2.758), suggesting poor aqueous solubility. Ligand B has slightly worse solubility.

**11. hERG Inhibition:** Both ligands have low hERG inhibition risk (0.297 and 0.122 percentile).

**12. Microsomal Clearance:** Ligand A (15.196 mL/min/kg) has significantly lower microsomal clearance than Ligand B (69.969 mL/min/kg), indicating better metabolic stability.

**13. In vitro Half-Life:** Ligand A (-0.111 hours) has a slightly worse in vitro half-life than Ligand B (8.319 hours). This is a drawback for Ligand A.

**14. P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.034 and 0.078 percentile), which is favorable.

**15. Binding Affinity:** Both ligands have very similar binding affinities (-7.7 and -7.6 kcal/mol). The difference is negligible.

**Overall Assessment:**

Ligand A is superior. While Ligand B has a slightly better in vitro half-life, Ligand A excels in critical areas for CNS drug development: significantly lower DILI risk, better BBB penetration, and substantially improved metabolic stability (lower Cl_mic). The binding affinities are nearly identical. Given the GPCR-specific priorities, the improved ADME properties of Ligand A outweigh the minor disadvantage in half-life.

Output:
1
2025-04-17 04:08:56,049 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (349.519 and 345.447 Da) fall comfortably within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (52.65) is significantly better than Ligand B (99.81). For CNS targets, TPSA should be <= 90, and A is well within this, while B is approaching the upper limit.

**3. logP:** Both ligands have good logP values (2.406 and 1.547), falling within the optimal 1-3 range.

**4. H-Bond Donors:** Ligand A (1) and Ligand B (2) are both acceptable, being less than 5.

**5. H-Bond Acceptors:** Ligand A (3) and Ligand B (5) are both acceptable, being less than 10.

**6. QED:** Both ligands have good QED scores (0.695 and 0.817), indicating good drug-like properties.

**7. DILI:** Ligand A (6.049) has a much lower DILI risk than Ligand B (38.969). This is a significant advantage for A.

**8. BBB:** Ligand A (81.776) has a substantially better BBB penetration percentile than Ligand B (57.619). This is *critical* for a CNS target like DRD2.

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.991 and -4.832). This is unusual and suggests poor permeability, but the scale isn't clearly defined, so it's hard to interpret.

**10. Aqueous Solubility:** Both ligands have negative solubility values (-1.631 and -2.923), again, the scale is unclear.

**11. hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.65 and 0.197).

**12. Microsomal Clearance:** Both ligands have similar microsomal clearance values (26.273 and 25.318 mL/min/kg), indicating comparable metabolic stability.

**13. In vitro Half-Life:** Ligand A (-7.827) has a longer in vitro half-life than Ligand B (10.762).

**14. P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.024 and 0.025).

**15. Binding Affinity:** Ligand B (-8.5 kcal/mol) has a slightly better binding affinity than Ligand A (-7.5 kcal/mol). While a 1.0 kcal/mol difference is noticeable, it's not a massive advantage, and can be overcome by better ADME properties.

**Overall Assessment:**

Ligand A is the superior candidate. Its significantly better TPSA, DILI risk, and especially BBB penetration make it much more likely to reach the target in the CNS. While Ligand B has slightly better binding affinity, the ADME advantages of Ligand A, particularly its BBB score, outweigh this difference for a CNS-targeted GPCR like DRD2.

Output:
1
2025-04-17 04:08:56,049 - INFO - Batch 88 complete. Total preferences: 1408
2025-04-17 04:08:56,049 - INFO - Processing batch 89/512...
2025-04-17 04:09:48,067 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (343.383 and 356.451 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (107.53) is better than Ligand B (66.4). For CNS targets, we want TPSA <= 90, so both are acceptable, but A is closer to the upper limit.

**logP:** Ligand A (0.684) is slightly low, potentially hindering permeation. Ligand B (2.218) is within the optimal 1-3 range. This favors B.

**H-Bond Donors/Acceptors:** Ligand A has 4 HBD and 4 HBA, which is good. Ligand B has 0 HBD and 6 HBA, also acceptable.

**QED:** Both ligands have reasonable QED values (0.476 and 0.783), with B being significantly better.

**DILI:** Ligand A (59.131) has a lower DILI risk than Ligand B (72.043), which is preferable.

**BBB:** Ligand B (76.154) has a much better BBB penetration percentile than Ligand A (59.054). This is a *critical* factor for a CNS target like DRD2.

**Caco-2 Permeability:** Both have negative Caco-2 values (-5.29 and -4.82), which is unusual and suggests poor permeability. However, these values are on a scale where negative values are possible, and direct comparison is difficult without knowing the scale's specifics.

**Aqueous Solubility:** Both have negative solubility values (-2.44 and -2.203), indicating poor solubility.

**hERG Inhibition:** Ligand A (0.051) has a very low hERG inhibition liability, which is excellent. Ligand B (0.441) is higher, posing a greater risk.

**Microsomal Clearance:** Ligand A (-4.415) has a negative clearance, which is not physically possible and likely indicates a data error or unusual experimental result. Ligand B (31.517) has a higher clearance, suggesting faster metabolism.

**In vitro Half-Life:** Ligand A (10.828 hours) has a longer half-life than Ligand B (-3.326 hours), but the negative value for B is problematic.

**P-gp Efflux:** Ligand A (0.008) has very low P-gp efflux, which is highly desirable for CNS penetration. Ligand B (0.505) has higher efflux.

**Binding Affinity:** Ligand A (-10.6 kcal/mol) has a significantly stronger binding affinity than Ligand B (-8.7 kcal/mol). This is a substantial advantage.

**Overall Assessment:**

Despite Ligand A's superior binding affinity and lower DILI/P-gp efflux, the negative values for Caco-2 permeability, solubility, and microsomal clearance are concerning. The negative clearance is a significant red flag. Ligand B, while having a weaker affinity, presents a more reasonable ADME profile, *especially* its significantly better BBB penetration (76.154 vs. 59.054). For a CNS target, BBB penetration is paramount. The better logP of Ligand B also contributes to its favorability. While the hERG risk is slightly higher for B, it's not a deal-breaker given the other advantages.

Output:
1
2025-04-17 04:09:48,067 - INFO - Reasoning:

Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (350.375 Da) is slightly lower, which *could* be beneficial for permeability, but both are acceptable.

**TPSA:** Ligand A (113.77) is better than Ligand B (74.33), falling closer to the desirable range for CNS targets (<=90). Ligand B is excellent.

**logP:** Ligand A (-0.534) is suboptimal, being below the preferred 1-3 range. This suggests potential permeability issues. Ligand B (1.725) is within the optimal range.

**H-Bond Donors/Acceptors:** Ligand A (2 HBD, 6 HBA) and Ligand B (3 HBD, 5 HBA) are both within acceptable limits.

**QED:** Both ligands have similar, good QED values (0.667 and 0.672).

**DILI:** Ligand A (52.191) has a slightly higher DILI risk than Ligand B (33.307), but both are reasonably low.

**BBB:** This is crucial for a CNS target. Ligand A (65.839) is decent, but Ligand B (36.526) is significantly lower, indicating poor predicted brain penetration.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values, which is unusual and likely indicates a problem with the prediction method or the molecule's behavior in the assay. However, the values are similar.

**Aqueous Solubility:** Both ligands have negative solubility values, again suggesting a potential issue with the prediction. The values are similar.

**hERG Inhibition:** Both ligands show very low hERG inhibition risk (0.076 and 0.185).

**Microsomal Clearance:** Ligand A (9.029) has a higher predicted clearance than Ligand B (-7.049), suggesting lower metabolic stability. The negative value for Ligand B is unusual and likely an artifact of the prediction.

**In vitro Half-Life:** Ligand A (-36.321) has a very negative half-life, which is nonsensical. Ligand B (20.164) is reasonable.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.008 and 0.014), which is favorable for CNS penetration.

**Binding Affinity:** Ligand B (-7.4 kcal/mol) has a significantly stronger binding affinity than Ligand A (-8.0 kcal/mol). This is a substantial advantage.

**Overall Assessment:**

Ligand B is the stronger candidate. While its TPSA is excellent, its logP is optimal, and its binding affinity is superior. The biggest concern with Ligand A is its poor logP, which will likely hinder its ability to cross cell membranes, including the BBB. The negative half-life for Ligand A is also a major red flag. Although Ligand B has a lower BBB score, the much stronger binding affinity and better logP outweigh this drawback. The unusual negative values for Caco-2, solubility and clearance for both ligands are concerning and would need further investigation, but the relative differences between the two compounds are clear.

Output:
1
2025-04-17 04:09:48,067 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (372.531 and 346.475 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (78.87) is slightly higher than Ligand B (58.44). Both are below the 90 A^2 threshold desirable for CNS targets, but B is better.

**3. logP:** Both ligands have good logP values (1.558 and 2.488), falling within the optimal 1-3 range.

**4. H-Bond Donors:** Ligand A has 2 HBD, and Ligand B has 0. Both are within the acceptable limit of <=5.

**5. H-Bond Acceptors:** Ligand A has 5 HBA, and Ligand B has 4. Both are within the acceptable limit of <=10.

**6. QED:** Both ligands have good QED scores (0.569 and 0.68), indicating drug-like properties.

**7. DILI:** Ligand A (14.541) has a significantly lower DILI risk than Ligand B (23.032). Both are below the 40 threshold, but A is preferred.

**8. BBB:** Ligand B (75.921) has a substantially better BBB penetration percentile than Ligand A (53.47). This is a *critical* factor for a CNS target like DRD2.

**9. Caco-2 Permeability:** Ligand A (-5.26) has poorer Caco-2 permeability than Ligand B (-4.423).

**10. Aqueous Solubility:** Both have negative solubility values, indicating poor solubility. Ligand A (-2.088) is slightly better than Ligand B (-1.887), but both are concerning.

**11. hERG Inhibition:** Both ligands have low hERG inhibition risk (0.384 and 0.391).

**12. Microsomal Clearance:** Ligand A (35.87) has lower microsomal clearance than Ligand B (55.374), suggesting better metabolic stability.

**13. In vitro Half-Life:** Ligand A (18.771) has a longer in vitro half-life than Ligand B (2.165).

**14. P-gp Efflux:** Both ligands have low P-gp efflux liability (0.11 and 0.072).

**15. Binding Affinity:** Ligand B (-7.8 kcal/mol) has a slightly better binding affinity than Ligand A (-7.2 kcal/mol). While the difference is not huge, it's a noticeable advantage.

**Overall Assessment:**

Ligand B excels in BBB penetration and binding affinity, which are paramount for a CNS GPCR target. While Ligand A has advantages in DILI risk, metabolic stability, and half-life, the superior BBB penetration of Ligand B outweighs these benefits. The slightly better affinity of B is also a plus. The solubility of both is a concern, but can be addressed with formulation strategies.

Output:
1
2025-04-17 04:09:48,067 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (364.511 and 365.547 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (58.64) is significantly better than Ligand B (67.07). For CNS targets, TPSA should be <= 90, and lower is preferred. Ligand A is much closer to the optimal range for CNS penetration.

**3. logP:** Ligand A (1.665) is within the optimal range (1-3), while Ligand B (3.321) is at the higher end, potentially leading to solubility issues or off-target interactions.

**4. H-Bond Donors:** Both ligands have 1 HBD, which is acceptable (<=5).

**5. H-Bond Acceptors:** Ligand A has 4 HBAs, and Ligand B has 7. Both are within the acceptable range (<=10), but Ligand A is preferable.

**6. QED:** Both ligands have good QED scores (0.698 and 0.777), indicating good drug-like properties.

**7. DILI:** Both ligands have similar, relatively low DILI risk (18.108 and 19.349 percentile).

**8. BBB:** Ligand A (56.534%) has a significantly better BBB penetration score than Ligand B (48.817%). This is a *critical* factor for a CNS target like DRD2.

**9. Caco-2 Permeability:** Both have negative values, indicating poor permeability. However, the scale is not specified, making direct comparison difficult.

**10. Aqueous Solubility:** Both have negative values, indicating poor solubility. Again, the scale is not specified.

**11. hERG Inhibition:** Both ligands have low hERG inhibition risk (0.265 and 0.593).

**12. Microsomal Clearance:** Ligand A (19.705) has a lower microsomal clearance than Ligand B (40.882), suggesting better metabolic stability.

**13. In vitro Half-Life:** Ligand B (35.541) has a much longer in vitro half-life than Ligand A (-1.789). This is a significant advantage for Ligand B.

**14. P-gp Efflux:** Both ligands have low P-gp efflux liability (0.102 and 0.116).

**15. Binding Affinity:** Ligand A (-7.2 kcal/mol) has a slightly better binding affinity than Ligand B (-6.8 kcal/mol). While the difference is not huge, it's a positive factor.

**Overall Assessment:**

Considering the GPCR-specific priorities, Ligand A is the better candidate. Its lower TPSA and logP values, combined with significantly better BBB penetration and lower microsomal clearance, outweigh the longer half-life of Ligand B. The slightly better binding affinity of Ligand A further supports this conclusion. While both have solubility and permeability concerns, the CNS penetration is paramount for a DRD2 ligand, and Ligand A excels in this area.

Output:
0
2025-04-17 04:09:48,067 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (351.491 and 345.447 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (56.59) is significantly better than Ligand B (61.68). For CNS targets, we want TPSA <= 90, and ideally closer to 60. Both are acceptable, but A is preferred.

**logP:** Ligand A (3.028) is optimal (1-3). Ligand B (0.723) is a bit low, potentially hindering membrane permeability. This is a significant drawback for a CNS target.

**H-Bond Donors/Acceptors:** Both have 0 HBD and 5 HBA, which are within acceptable limits.

**QED:** Both ligands have good QED scores (0.837 and 0.755), indicating good drug-like properties.

**DILI:** Ligand A (32.105) has a slightly higher DILI risk than Ligand B (26.755), but both are well below the concerning threshold of 60.

**BBB:** Ligand A (87.553) has a substantially better BBB penetration score than Ligand B (67.352). This is *critical* for a CNS target like DRD2.

**Caco-2 Permeability:** Ligand A (-4.117) is better than Ligand B (-4.741), indicating better intestinal absorption.

**Aqueous Solubility:** Ligand A (-3.606) is better than Ligand B (-0.465).

**hERG:** Both ligands have very low hERG inhibition risk (0.591 and 0.176).

**Microsomal Clearance:** Ligand A (64.125) has higher clearance than Ligand B (41.265), suggesting lower metabolic stability. This is a negative for A.

**In vitro Half-Life:** Ligand A (27.407) has a longer half-life than Ligand B (17.036).

**P-gp Efflux:** Ligand A (0.378) has lower P-gp efflux than Ligand B (0.035), which is favorable for CNS penetration.

**Binding Affinity:** Ligand B (-7.6 kcal/mol) has a slightly better binding affinity than Ligand A (-7.0 kcal/mol), but the difference is less than the 1.5 kcal/mol threshold where it would definitively outweigh other factors.

**Overall Assessment:**

Ligand A is superior due to its significantly better BBB penetration, logP, solubility, Caco-2 permeability, and P-gp efflux. While Ligand A has a higher microsomal clearance, the substantial advantages in CNS penetration and permeability outweigh this drawback. Ligand B's low logP is a significant concern for CNS delivery. The slightly better affinity of Ligand B isn't enough to overcome the ADME deficiencies.



Output:
1
2025-04-17 04:09:48,067 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight (MW):**
* Ligand A: 476.115 Da - Within the ideal range (200-500 Da).
* Ligand B: 381.837 Da - Also within the ideal range.
* *No clear advantage here.*

**2. Topological Polar Surface Area (TPSA):**
* Ligand A: 42.43 A<sup>2</sup> - Excellent, well below the 90 A<sup>2</sup> threshold for CNS targets.
* Ligand B: 74.72 A<sup>2</sup> - Still reasonable for CNS penetration, but higher than Ligand A.
* *Ligand A is better.*

**3. Lipophilicity (logP):**
* Ligand A: 4.568 - Slightly high, potentially leading to solubility issues or off-target interactions.
* Ligand B: 2.747 - Optimal range (1-3).
* *Ligand B is better.*

**4. H-Bond Donors (HBD):**
* Ligand A: 0 - Acceptable.
* Ligand B: 0 - Acceptable.
* *No clear advantage.*

**5. H-Bond Acceptors (HBA):**
* Ligand A: 3 - Acceptable.
* Ligand B: 6 - Acceptable.
* *No clear advantage.*

**6. Quantitative Estimate of Drug-likeness (QED):**
* Ligand A: 0.611 - Good, above the 0.5 threshold.
* Ligand B: 0.716 - Very good, slightly better than Ligand A.
* *Ligand B is slightly better.*

**7. DILI Risk:**
* Ligand A: 75.029 - Moderate risk.
* Ligand B: 77.162 - Moderate risk, similar to Ligand A.
* *No clear advantage.*

**8. Blood-Brain Barrier (BBB):**
* Ligand A: 89.298 - Excellent, well above the 70% threshold for CNS targets.
* Ligand B: 69.678 - Good, but below the desirable 70% threshold.
* *Ligand A is significantly better.*

**9. Caco-2 Permeability:**
* Ligand A: -4.604 - This is a negative value, which is unusual and likely indicates a very poor permeability.
* Ligand B: -4.505 - Also negative, but slightly less negative than Ligand A, suggesting slightly better permeability.
* *Ligand B is slightly better.*

**10. Aqueous Solubility:**
* Ligand A: -5.208 - Very poor solubility. This is a major concern.
* Ligand B: -4.514 - Poor solubility, but slightly better than Ligand A.
* *Ligand B is better.*

**11. hERG Inhibition:**
* Ligand A: 0.666 - Low risk.
* Ligand B: 0.266 - Very low risk.
* *Ligand B is better.*

**12. Microsomal Clearance:**
* Ligand A: 47.804 - Moderate clearance.
* Ligand B: 75.613 - High clearance, indicating faster metabolism.
* *Ligand A is better.*

**13. In vitro Half-Life:**
* Ligand A: -4.948 - This is a negative value, which is unusual and likely indicates a very short half-life.
* Ligand B: 30.35 - Good half-life.
* *Ligand B is significantly better.*

**14. P-gp Efflux:**
* Ligand A: 0.49 - Low efflux, good for CNS exposure.
* Ligand B: 0.445 - Very low efflux, even better for CNS exposure.
* *Ligand B is slightly better.*

**15. Binding Affinity:**
* Ligand A: -9.4 kcal/mol - Excellent, very strong binding.
* Ligand B: -8.5 kcal/mol - Very good, but weaker than Ligand A.
* *Ligand A is significantly better.*

**Overall Assessment:**

Ligand A has a superior binding affinity and better BBB penetration. However, it suffers from very poor solubility, poor Caco-2 permeability, and a short half-life. Ligand B has better ADME properties (solubility, permeability, half-life, P-gp efflux, hERG) and a good QED score. While its binding affinity is slightly weaker, the difference of 0.9 kcal/mol might be outweighed by the significantly improved ADME profile, especially for a CNS target where achieving adequate brain exposure is crucial. The poor solubility and permeability of Ligand A are major liabilities that would likely hinder its development.

Output:
1
2025-04-17 04:09:48,068 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (344.415 and 335.407 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (87.46) is better than Ligand B (73.2). Both are below the 90 A^2 threshold desirable for CNS targets, but A is closer to the upper limit.

**logP:** Ligand B (2.079) is optimal (1-3), while Ligand A (0.179) is quite low, potentially hindering membrane permeability. This is a significant drawback for A.

**H-Bond Donors/Acceptors:** Ligand A (2 HBD, 5 HBA) and Ligand B (1 HBD, 3 HBA) both have reasonable numbers of H-bond donors and acceptors, well within the acceptable limits.

**QED:** Both ligands have good QED scores (0.798 and 0.919), indicating good drug-like properties.

**DILI:** Both ligands have low DILI risk (33.463 and 35.789), which is favorable.

**BBB:** Ligand A (72.858) has a better BBB percentile than Ligand B (68.282). Both are above 70, which is desirable for CNS targets, but A is slightly better.

**Caco-2 Permeability:** Ligand A (-4.994) has a significantly worse Caco-2 permeability score than Ligand B (-4.787). Lower values indicate poorer permeability.

**Aqueous Solubility:** Ligand A (-2.032) has a slightly better aqueous solubility than Ligand B (-3.884).

**hERG:** Both ligands have low hERG inhibition liability (0.228 and 0.641), which is good.

**Microsomal Clearance:** Ligand B (3.501) has a lower microsomal clearance than Ligand A (6.681), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (12.984) has a longer in vitro half-life than Ligand B (-9.698).

**P-gp Efflux:** Ligand A (0.045) has a lower P-gp efflux liability than Ligand B (0.048), which is favorable for CNS penetration.

**Binding Affinity:** Both ligands have excellent binding affinity (-9.5 and -9.2 kcal/mol). The difference of 0.3 kcal/mol is not substantial enough to override other significant differences.

**Overall Assessment:**

Ligand A has a better BBB penetration and P-gp efflux profile, and a longer half-life, but suffers from a very low logP and poor Caco-2 permeability. The low logP is a major concern, as it will likely limit its ability to cross cell membranes and reach the target in the brain. Ligand B has a more optimal logP, better Caco-2 permeability, and improved metabolic stability, making it more likely to be bioavailable and reach the target. While Ligand A's slightly better BBB is a plus, the permeability issues are more critical for a GPCR target in the CNS.

Output:
1
2025-04-17 04:09:48,068 - INFO - Okay, let's analyze these two ligands for their potential as DRD2 drug candidates. DRD2 is a GPCR in the CNS, so BBB penetration, logP, Pgp efflux, TPSA, and binding affinity are paramount.

**Ligand A:** [377.463, 136.82 ,  -1.106,   3.   ,   6.   ,   0.436,  39.162,  54.246, -5.877,  -1.839,   0.069,  11.407,  -8.733,   0.01 ,  -6.9  ]
**Ligand B:** [373.909,  48.99 ,   4.966,   1.   ,   3.   ,   0.663,  59.946,  77.898, -4.932,  -5.123,   0.823,  72.87 ,  22.315,   0.636,  -7.7  ]

**Step-by-step comparison:**

1. **MW:** Both are within the ideal range (200-500 Da). A (377.463) and B (373.909) are comparable.
2. **TPSA:** A (136.82) is slightly above the optimal <90 for CNS targets, but still reasonable. B (48.99) is excellent, well below 90.
3. **logP:** A (-1.106) is quite low, potentially hindering permeability. B (4.966) is high, potentially causing solubility issues and off-target effects, but within the acceptable range.
4. **HBD:** A (3) is acceptable. B (1) is also good.
5. **HBA:** A (6) is acceptable. B (3) is also good.
6. **QED:** A (0.436) is below the desirable 0.5, indicating a less drug-like profile. B (0.663) is better, exceeding 0.5.
7. **DILI:** A (39.162) is good, low risk. B (59.946) is approaching a moderate risk, but not alarming.
8. **BBB:** A (54.246) is below the desirable >70 for CNS targets. B (77.898) is excellent, exceeding 70.
9. **Caco-2:** A (-5.877) is very poor, suggesting poor intestinal absorption. B (-4.932) is also poor, but slightly better than A.
10. **Solubility:** A (-1.839) is poor. B (-5.123) is very poor.
11. **hERG:** A (0.069) is very low risk. B (0.823) is slightly higher, but still relatively low.
12. **Cl_mic:** A (11.407) is relatively low, suggesting good metabolic stability. B (72.87) is high, indicating rapid metabolism.
13. **t1/2:** A (-8.733) is very long, which is good. B (22.315) is moderate.
14. **Pgp:** A (0.01) is very low, indicating minimal efflux. B (0.636) is higher, suggesting some efflux.
15. **Affinity:** A (-6.9) is good. B (-7.7) is *significantly* better, a 0.8 kcal/mol advantage.

**Overall Assessment:**

Ligand B is the stronger candidate despite some drawbacks. The significantly better binding affinity (-7.7 vs -6.9 kcal/mol) is a major advantage for a GPCR target, and can potentially offset some of the less ideal ADME properties. Crucially, B has excellent BBB penetration (77.898), which is essential for a CNS drug. While its logP is high and solubility is poor, these might be addressed through formulation strategies. Ligand A has a poor BBB score, poor Caco-2 permeability, and a lower QED score, making it less attractive. The longer half-life of A is a plus, but not enough to overcome its other deficiencies.

1
2025-04-17 04:09:48,068 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (409.284 Da) is slightly higher than Ligand B (342.443 Da), but both are acceptable.

**2. TPSA:** Ligand A (102.3) is above the preferred <90 for CNS targets, while Ligand B (66.4) is well within the range. This is a significant advantage for Ligand B.

**3. logP:** Both ligands have good logP values (A: 1.878, B: 2.06), falling within the optimal 1-3 range.

**4. H-Bond Donors:** Ligand A has 2 HBD, which is acceptable. Ligand B has 0, which is also good.

**5. H-Bond Acceptors:** Both ligands have 4 HBA, which is within the acceptable limit of <=10.

**6. QED:** Both ligands have similar and good QED values (A: 0.725, B: 0.768), indicating good drug-like properties.

**7. DILI:** Ligand A (64.676) has a higher DILI risk than Ligand B (24.583). This is a clear advantage for Ligand B.

**8. BBB:** Ligand B (84.684) has a significantly better BBB penetration percentile than Ligand A (51.066). This is critical for a CNS target like DRD2.

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.81 and -4.715), which is unusual and suggests very poor permeability. However, these values are on a scale where negative values are possible, and direct comparison is difficult without knowing the scale's specifics.

**10. Aqueous Solubility:** Both ligands have negative solubility values (-3.934 and -1.393), indicating poor aqueous solubility. Again, the scale is important for interpretation.

**11. hERG Inhibition:** Both ligands show very low hERG inhibition risk (A: 0.511, B: 0.221).

**12. Microsomal Clearance:** Ligand A (42.751) has higher microsomal clearance than Ligand B (16.405), indicating lower metabolic stability.

**13. In vitro Half-Life:** Ligand B (-4.168) has a negative half-life, which is concerning and likely an artifact of the modeling or scale. Ligand A (57.175) has a reasonable half-life.

**14. P-gp Efflux:** Both ligands have very low P-gp efflux liability (A: 0.088, B: 0.034).

**15. Binding Affinity:** Both ligands have the same excellent binding affinity (-7.9 kcal/mol).

**Overall Assessment:**

While both ligands have excellent binding affinity, Ligand B is significantly more promising due to its superior BBB penetration (84.7% vs 51.1%), lower DILI risk (24.6% vs 64.7%), lower TPSA (66.4 vs 102.3), and lower microsomal clearance (16.4 vs 42.8). The negative Caco-2 and solubility values are concerning for both, but the other advantages of Ligand B outweigh these drawbacks, especially given the importance of BBB penetration for a CNS target. The negative half-life for Ligand B is a red flag, but could be an artifact.

Output:
1
2025-04-17 04:09:48,068 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B based on the provided guidelines, prioritizing GPCR-specific properties (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (356.86 & 348.44 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (50.16) is significantly better than Ligand B (76.66). For CNS targets, we want TPSA <= 90, and A is comfortably within this range, while B is approaching the upper limit.

**logP:** Ligand A (3.462) is optimal (1-3), while Ligand B (1.953) is on the lower side, potentially impacting permeability.

**H-Bond Donors/Acceptors:** Both ligands have similar HBD (1 vs 2) and HBA (4 vs 4) counts, both within acceptable ranges.

**QED:** Both ligands have good QED scores (0.735 and 0.753), indicating good drug-like properties.

**DILI:** Ligand A (68.79) has a higher DILI risk than Ligand B (26.64), which is a negative for A.

**BBB:** Ligand A (72.32) has a better BBB penetration percentile than Ligand B (62.47), which is crucial for a CNS target like DRD2.

**Caco-2 Permeability:** Ligand A (-5.051) and Ligand B (-4.662) both have negative values, which is unusual. Assuming these are log scale values, lower values indicate lower permeability. Both are poor, but B is slightly better.

**Aqueous Solubility:** Both ligands have poor aqueous solubility (-3.189 and -2.505).

**hERG:** Ligand A (0.596) has a slightly higher hERG risk than Ligand B (0.088), which is a negative for A.

**Microsomal Clearance:** Ligand A (82.76) has higher microsomal clearance than Ligand B (42.89), meaning faster metabolism and potentially lower *in vivo* exposure.

**In vitro Half-Life:** Ligand A (144.16) has a much longer half-life than Ligand B (6.00), which is a significant advantage.

**P-gp Efflux:** Ligand A (0.445) has lower P-gp efflux than Ligand B (0.037), meaning better CNS exposure.

**Binding Affinity:** Ligand B (-7.7 kcal/mol) has a significantly stronger binding affinity than Ligand A (-9.3 kcal/mol). This is a substantial advantage for B, potentially outweighing some of its ADME drawbacks.

**Overall Assessment:**

Ligand B has a significantly better binding affinity, lower DILI risk, and lower hERG risk. However, Ligand A has better BBB penetration, a longer half-life, and lower P-gp efflux. The TPSA of Ligand A is also much more favorable. Considering the GPCR-specific priorities, the stronger binding affinity of Ligand B is a critical factor. While its BBB is lower, the difference isn't drastic, and the improved potency could compensate. The slightly lower logP of B is a concern, but not insurmountable. The longer half-life and lower P-gp efflux of A are beneficial, but the significantly stronger binding of B is more important for initial efficacy.

Output:
1
2025-04-17 04:09:48,068 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (363.483 and 366.403 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (95.08) is better than Ligand B (122.47). For CNS targets, TPSA should be <= 90, so Ligand A is closer to this threshold.

**logP:** Ligand A (2.222) is optimal (1-3). Ligand B (-0.399) is below 1, which could hinder permeation.

**H-Bond Donors:** Both ligands have 2-3 HBD, which is acceptable (<=5).

**H-Bond Acceptors:** Ligand A (5) is better than Ligand B (9). While both are under the 10 limit, lower is generally preferred.

**QED:** Ligand A (0.703) is significantly better than Ligand B (0.457). A QED > 0.5 is desirable.

**DILI:** Ligand B (73.284) has a higher DILI risk than Ligand A (54.207). Both are acceptable (<60 is good), but A is preferable.

**BBB:** Ligand A (52.889) has a much better BBB percentile than Ligand B (15.743). For a CNS target like DRD2, BBB penetration is crucial, and >70 is desirable. Ligand A is closer to this threshold.

**Caco-2 Permeability:** Both have negative values (-5.573 and -5.684), which is unusual and difficult to interpret without knowing the scale. However, we can assume lower values indicate poorer permeability.

**Aqueous Solubility:** Both have negative values (-2.882 and -1.78), again unusual and indicating poor solubility.

**hERG Inhibition:** Ligand A (0.557) has a slightly higher hERG risk than Ligand B (0.061). However, both are relatively low.

**Microsomal Clearance:** Ligand B (4.985) has significantly lower microsomal clearance than Ligand A (21.727), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (26.179) has a longer half-life than Ligand B (22.945), which is generally preferred.

**P-gp Efflux:** Ligand A (0.402) has lower P-gp efflux than Ligand B (0.043), which is beneficial for CNS exposure.

**Binding Affinity:** Ligand A (-9.4 kcal/mol) has a significantly stronger binding affinity than Ligand B (-6.3 kcal/mol). This is a substantial difference (>1.5 kcal/mol advantage), and can outweigh some ADME drawbacks.

**Overall Assessment:**

Ligand A is clearly superior. It has better TPSA, logP, QED, BBB, P-gp efflux, and *significantly* better binding affinity. While Ligand B has better metabolic stability (lower Cl_mic), the strong affinity of Ligand A, coupled with its more favorable CNS penetration properties, makes it the more promising drug candidate. The solubility and Caco-2 permeability are concerning for both, but can be addressed through formulation strategies.



Output:
1
2025-04-17 04:09:48,068 - INFO - Reasoning:

Let's analyze Ligand A and Ligand B based on the provided guidelines, prioritizing GPCR-specific properties (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (384.7) is slightly higher than Ligand B (358.4), but both are acceptable.

**TPSA:** Ligand A (34.15) is excellent for CNS penetration, well below 90. Ligand B (78.43) is higher, but still potentially acceptable, though less ideal.

**logP:** Ligand A (4.784) is at the upper end of the optimal range, potentially raising concerns about solubility and off-target effects. Ligand B (1.841) is closer to the lower end, which could hinder permeation, but is generally preferred over a very high logP.

**H-Bond Donors/Acceptors:** Ligand A (HBD=1, HBA=3) and Ligand B (HBD=3, HBA=3) both have reasonable numbers of H-bond donors and acceptors.

**QED:** Ligand A (0.728) has a better QED score than Ligand B (0.58), indicating a more drug-like profile.

**DILI:** Ligand A (53.548) has a higher DILI risk than Ligand B (20.163). This is a significant advantage for Ligand B.

**BBB:** Both ligands have good BBB penetration (Ligand A: 79.488, Ligand B: 77.821), exceeding the desirable threshold of 70. This is crucial for a CNS target like DRD2.

**Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and suggests a potential issue with the data or the model used to predict it. It's difficult to interpret without more context.

**Aqueous Solubility:** Both have negative solubility values, again suggesting a potential issue with the data or the model.

**hERG Inhibition:** Ligand A (0.796) has a slightly higher hERG risk than Ligand B (0.645), but both are relatively low.

**Microsomal Clearance:** Ligand A (43.342) has a higher microsomal clearance than Ligand B (15.445), indicating lower metabolic stability. This favors Ligand B.

**In vitro Half-Life:** Ligand B (34.442) has a longer in vitro half-life than Ligand A (23.075), which is desirable.

**P-gp Efflux:** Ligand A (0.553) has lower P-gp efflux liability than Ligand B (0.133), which is favorable for CNS exposure.

**Binding Affinity:** Both ligands have very similar and strong binding affinities (Ligand A: -8.9 kcal/mol, Ligand B: -8.4 kcal/mol). The difference of 0.5 kcal/mol is unlikely to outweigh other significant ADME differences.

**Overall Assessment:**

Ligand B is the more promising candidate. While Ligand A has a slightly better QED and lower P-gp efflux, Ligand B excels in crucial areas: significantly lower DILI risk, better metabolic stability (lower Cl_mic, longer t1/2), and a more favorable logP. The similar binding affinities make the ADME advantages of Ligand B decisive. The negative Caco-2 and solubility values are concerning for both, but the other benefits of Ligand B make it preferable.

Output:
1
2025-04-17 04:09:48,069 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (346.475 and 375.519 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Both ligands have TPSA values (67.23 and 66.32) below the 90 A^2 threshold desirable for CNS targets, which is excellent.

**3. logP:** Both ligands have logP values (2.582 and 2.834) within the optimal 1-3 range.

**4. H-Bond Donors:** Both ligands have 1 HBD, which is within the acceptable limit of <=5.

**5. H-Bond Acceptors:** Ligand A has 4 HBAs, and Ligand B has 6 HBAs. Both are below the 10 limit.

**6. QED:** Both ligands have QED values (0.772 and 0.754) above 0.5, indicating good drug-like properties.

**7. DILI:** Ligand A (30.787) has a significantly lower DILI risk than Ligand B (54.478). This is a substantial advantage.

**8. BBB:** Ligand A (74.719) has a much better BBB percentile than Ligand B (29.934). This is *critical* for a CNS target like DRD2.

**9. Caco-2 Permeability:** Ligand A (-4.447) has a slightly better (less negative) Caco-2 permeability than Ligand B (-5.32), suggesting better intestinal absorption.

**10. Aqueous Solubility:** Both ligands have poor aqueous solubility (-2.758 and -2.953). This could pose formulation challenges, but is less critical than BBB penetration for a CNS target.

**11. hERG Inhibition:** Both ligands have low hERG inhibition risk (0.122 and 0.323).

**12. Microsomal Clearance:** Ligand A (69.969) has a slightly higher microsomal clearance than Ligand B (60.834), meaning it might be metabolized a bit faster.

**13. In vitro Half-Life:** Ligand B (11.032) has a longer in vitro half-life than Ligand A (8.319).

**14. P-gp Efflux:** Both ligands have low P-gp efflux liability (0.078 and 0.269).

**15. Binding Affinity:** Ligand A (-7.6 kcal/mol) has a slightly stronger binding affinity than Ligand B (-7.3 kcal/mol). While the difference is not huge (0.3 kcal/mol), it's still a positive factor.

**Overall Assessment:**

Ligand A is the superior candidate. The *significant* advantage in BBB penetration (74.719 vs 29.934) and lower DILI risk are crucial for a CNS-targeting drug. The slightly better Caco-2 permeability and binding affinity further support this conclusion. While Ligand B has a slightly longer half-life, the BBB and safety profiles of Ligand A are far more important for DRD2.

Output:
0
2025-04-17 04:09:48,069 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (386.231 Da) is slightly higher than Ligand B (364.461 Da), but both are acceptable.

**2. TPSA:** Ligand A (95.86) is borderline for CNS targets, being slightly above the preferred <90. Ligand B (25.36) is excellent, well below the threshold. This is a significant advantage for Ligand B.

**3. logP:** Ligand A (2.985) is within the optimal range (1-3). Ligand B (4.529) is slightly above, potentially leading to solubility issues or off-target interactions, but not drastically.

**4. H-Bond Donors:** Ligand A (3) is acceptable. Ligand B (0) is also acceptable, and potentially beneficial for membrane permeability.

**5. H-Bond Acceptors:** Both ligands have 4 HBA, which is well within the acceptable limit of 10.

**6. QED:** Both ligands have similar and good QED values (0.74 and 0.753, respectively).

**7. DILI:** Ligand A (65.452) has a higher DILI risk than Ligand B (23.73). This is a clear advantage for Ligand B.

**8. BBB:** Ligand A (30.128) has a poor BBB percentile, indicating limited CNS penetration. Ligand B (95.58) has excellent BBB penetration, crucial for a DRD2 ligand targeting CNS disorders. This is a major advantage for Ligand B.

**9. Caco-2 Permeability:** Ligand A (-5.482) has poor Caco-2 permeability. Ligand B (-4.577) is also poor, but slightly better than A.

**10. Aqueous Solubility:** Both ligands have very poor aqueous solubility (-3.701 and -4.295, respectively). This is a concern for both, but could be addressed with formulation strategies.

**11. hERG Inhibition:** Ligand A (0.091) has a slightly lower hERG risk than Ligand B (0.894), but both are relatively low.

**12. Microsomal Clearance:** Ligand A (-2.359) has better metabolic stability (lower clearance) than Ligand B (55.065). This is a significant advantage for Ligand A.

**13. In vitro Half-Life:** Ligand A (15.983) has a longer half-life than Ligand B (2.71). This is a clear advantage for Ligand A.

**14. P-gp Efflux:** Ligand A (0.038) has much lower P-gp efflux liability than Ligand B (0.674). Lower P-gp efflux is desirable for CNS exposure, favoring Ligand A.

**15. Binding Affinity:** Both ligands have similar and strong binding affinities (-8.7 and -8.2 kcal/mol, respectively). The difference of 0.5 kcal/mol is not substantial enough to outweigh other considerations.

**Overall Assessment:**

While Ligand A has advantages in metabolic stability, half-life, and P-gp efflux, Ligand B excels in crucial properties for a CNS-targeting GPCR ligand: TPSA, BBB penetration, and DILI risk. The significantly better BBB penetration of Ligand B is the most important factor. The lower TPSA and DILI risk further solidify its advantage. The slightly higher logP and poorer metabolic stability of Ligand B are less concerning than the poor BBB penetration of Ligand A.

Output:
1
2025-04-17 04:09:48,069 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (354.382 and 366.458 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (87.91) is better than Ligand B (75.27), both are below the 90 A^2 threshold for CNS targets.

**logP:** Ligand A (-0.016) is slightly lower than optimal (1-3), potentially impacting permeability. Ligand B (2.56) is within the optimal range. This favors Ligand B.

**H-Bond Donors/Acceptors:** Ligand A (1 HBD, 6 HBA) and Ligand B (2 HBD, 3 HBA) both have acceptable numbers of H-bond donors and acceptors, well below the thresholds of 5 and 10 respectively.

**QED:** Both ligands have good QED scores (0.818 and 0.841), indicating good drug-like properties.

**DILI:** Ligand A (54.323) has a slightly better DILI score than Ligand B (61.497), both are acceptable, but lower is better.

**BBB:** Ligand A (78.713) and Ligand B (74.06) are both reasonably good for BBB penetration, but Ligand A is slightly better. A value >70 is desirable for CNS targets.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.447 and -4.682), which is unusual and indicates poor permeability. This is a significant drawback for both.

**Aqueous Solubility:** Both ligands have negative solubility values (-1.004 and -3.762), indicating very poor aqueous solubility. This is a major concern for both compounds.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.153 and 0.252).

**Microsomal Clearance:** Ligand A (0.065) has significantly lower microsomal clearance than Ligand B (58.82), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (-23.934) has a very negative half-life, which is nonsensical, and indicates a problem with the data. Ligand B (-6.541) is also negative, but less so.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.02 and 0.305), which is favorable for CNS penetration.

**Binding Affinity:** Ligand B (-9.7 kcal/mol) has a significantly stronger binding affinity than Ligand A (-7.7 kcal/mol). This is a substantial advantage, potentially outweighing some of the ADME drawbacks.

**Overall Assessment:**

Ligand B is favored due to its superior binding affinity (-9.7 vs -7.7 kcal/mol) and optimal logP (2.56). While both have poor Caco-2 and solubility, the stronger binding of Ligand B is a critical advantage for a GPCR target. Ligand A has slightly better BBB and DILI, and lower clearance, but the affinity difference is more significant. The negative half-life values are concerning for both, and would require further investigation.

Output:
1
2025-04-17 04:09:48,069 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (370.471 and 346.446 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (90.31) is borderline but acceptable for CNS penetration, while Ligand B (40.62) is excellent, well below the 90 threshold. This favors Ligand B.

**logP:** Ligand A (-0.546) is quite low, potentially hindering membrane permeability. Ligand B (3.323) is optimal. This is a significant advantage for Ligand B.

**H-Bond Donors/Acceptors:** Ligand A has 2 HBD and 6 HBA, which are reasonable. Ligand B has 0 HBD and 2 HBA, also reasonable.

**QED:** Both ligands have good QED scores (0.69 and 0.821), indicating drug-like properties.

**DILI:** Both have acceptable DILI risk (27.569 and 31.601 percentiles), below the 40 threshold.

**BBB:** Ligand B (94.378%) is excellent, exceeding the desirable >70% threshold for CNS targets. Ligand A (61.846%) is lower, though not terrible. This is a major advantage for Ligand B.

**Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and suggests poor permeability. However, the scale is not specified, so it's hard to interpret.

**Aqueous Solubility:** Both have negative solubility values, which is also unusual and suggests poor solubility.

**hERG:** Both ligands have low hERG risk (0.265 and 0.602), which is good.

**Microsomal Clearance:** Ligand A (18.458 mL/min/kg) has lower clearance than Ligand B (57.667 mL/min/kg), suggesting better metabolic stability. This favors Ligand A.

**In vitro Half-Life:** Both have similar in vitro half-lives (5.588 and 6.021 hours).

**P-gp Efflux:** Ligand A (0.053) has very low P-gp efflux liability, which is excellent for CNS penetration. Ligand B (0.254) is higher, but still reasonable.

**Binding Affinity:** Ligand B (-8.0 kcal/mol) has a significantly stronger binding affinity than Ligand A (-6.3 kcal/mol). This is a substantial advantage for Ligand B, potentially outweighing some of the ADME concerns.

**Overall Assessment:**

Ligand B clearly emerges as the more promising candidate. Its superior logP, TPSA, and especially BBB penetration, combined with a much stronger binding affinity, outweigh the slightly higher microsomal clearance and P-gp efflux. Ligand A's lower logP and BBB are significant drawbacks for a CNS target. The negative solubility and Caco-2 values are concerning for both, but the affinity difference is large enough to prioritize Ligand B.

Output:
1
2025-04-17 04:09:48,069 - INFO - Batch 89 complete. Total preferences: 1424
2025-04-17 04:09:48,070 - INFO - Processing batch 90/512...
2025-04-17 04:10:29,008 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 drug candidates, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (363.483 Da and 372.49 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (79.46) is slightly higher than Ligand B (75.27), but both are below the 90 A^2 threshold desirable for CNS targets.

**3. logP:** Both ligands have good logP values (3.54 and 3.617, respectively), falling within the optimal 1-3 range.

**4. H-Bond Donors:** Ligand A (1) is better than Ligand B (2) as we want to keep this low for good permeability.

**5. H-Bond Acceptors:** Ligand A (7) is higher than Ligand B (3). Lower is better, but both are within acceptable limits (<=10).

**6. QED:** Ligand A (0.683) has a slightly better QED score than Ligand B (0.575), indicating a more drug-like profile.

**7. DILI:** Ligand B (20.24) has a significantly lower DILI risk than Ligand A (43.971), which is a substantial advantage.

**8. BBB:** Ligand B (71.811) has a significantly better BBB penetration score than Ligand A (38.813). This is *critical* for a CNS target like DRD2.

**9. Caco-2 Permeability:** Ligand A (-5.497) has a worse Caco-2 permeability than Ligand B (-4.749).

**10. Aqueous Solubility:** Both ligands have similar, poor aqueous solubility (-3.505 and -3.438, respectively). This could pose formulation challenges, but is less critical than BBB for CNS drugs.

**11. hERG Inhibition:** Both ligands have low hERG inhibition risk (0.275 and 0.35, respectively).

**12. Microsomal Clearance:** Ligand B (83.521) has a slightly lower microsomal clearance than Ligand A (86.496), suggesting better metabolic stability.

**13. In vitro Half-Life:** Ligand B (-2.93) has a better in vitro half-life than Ligand A (-7.706).

**14. P-gp Efflux:** Both ligands have similar P-gp efflux liability (0.345 and 0.183).

**15. Binding Affinity:** Ligand A (-8.3) has a slightly better binding affinity than Ligand B (-7.4). However, the difference is 0.9 kcal/mol, which, while noticeable, isn't a massive advantage given the other factors.

**Overall Assessment:**

While Ligand A has a slightly better binding affinity and QED, Ligand B is significantly superior in terms of crucial ADME properties for a CNS-targeting GPCR. Specifically, its much better BBB penetration (71.811 vs 38.813) and lower DILI risk (20.24 vs 43.971) are major advantages. The better half-life and lower clearance also contribute to its favorability. The slight difference in binding affinity is outweighed by these more critical factors.

Output:
1
2025-04-17 04:10:29,008 - INFO - Reasoning:

Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (346.515 and 365.905 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (49.41) is better than Ligand B (47.79). Both are below the 90 A^2 threshold desirable for CNS targets, which is excellent.

**3. logP:** Ligand A (3.214) is within the optimal 1-3 range. Ligand B (4.621) is slightly higher, potentially leading to solubility issues or off-target interactions, but not drastically so.

**4. H-Bond Donors:** Both ligands have 1 HBD, which is acceptable.

**5. H-Bond Acceptors:** Ligand A has 2 HBA, and Ligand B has 5. Ligand A is preferable here as it is closer to the ideal of <=10.

**6. QED:** Both ligands have similar QED values (0.831 and 0.803), indicating good drug-likeness.

**7. DILI:** Ligand A (32.648) has a significantly lower DILI risk than Ligand B (53.354). This is a substantial advantage for Ligand A.

**8. BBB:** Ligand A (80.496) has a slightly better BBB penetration percentile than Ligand B (77.898). While both are reasonably good, DRD2 is a CNS target, so maximizing BBB penetration is important.

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 values, indicating poor permeability. This is a concern for both.

**10. Aqueous Solubility:** Both ligands have negative solubility values, indicating poor solubility. This is a concern for both.

**11. hERG Inhibition:** Ligand A (0.584) has a lower hERG inhibition liability than Ligand B (0.91). This is a positive for Ligand A.

**12. Microsomal Clearance:** Ligand B (43.291) has lower microsomal clearance than Ligand A (63.065), suggesting better metabolic stability. This favors Ligand B.

**13. In vitro Half-Life:** Ligand B (90.867) has a significantly longer in vitro half-life than Ligand A (-1.605). This is a major advantage for Ligand B.

**14. P-gp Efflux:** Ligand A (0.426) has lower P-gp efflux liability than Ligand B (0.699). Lower P-gp efflux is desirable for CNS penetration, favoring Ligand A.

**15. Binding Affinity:** Ligand B (-7.6 kcal/mol) has a significantly stronger binding affinity than Ligand A (-10.2 kcal/mol). This is a substantial advantage for Ligand B, and can often outweigh minor ADME drawbacks.

**Overall Assessment:**

While Ligand A has advantages in DILI risk, BBB, hERG, and P-gp efflux, Ligand B's significantly stronger binding affinity (-7.6 vs -10.2 kcal/mol) and longer half-life are crucial for a GPCR target like DRD2. The affinity difference is substantial. The slightly higher logP and DILI risk of Ligand B are acceptable trade-offs given its superior potency and duration of action. The poor Caco-2 and solubility are concerns for both, but can be addressed with formulation strategies.

Output:
1
2025-04-17 04:10:29,008 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (349.431 and 347.459 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (89.55) is better than Ligand B (74.43). Both are below the 90 A^2 threshold for CNS targets, which is excellent.

**3. logP:** Both ligands have good logP values (1.21 and 2.19), falling within the optimal 1-3 range. Ligand B is slightly better.

**4. H-Bond Donors:** Both have 2 HBD, which is within the acceptable limit of <=5.

**5. H-Bond Acceptors:** Ligand A has 5 HBA, while Ligand B has 3. Both are below the 10 limit.

**6. QED:** Both ligands have good QED scores (0.736 and 0.794), indicating good drug-like properties. Ligand B is slightly better.

**7. DILI:** Ligand A (49.438) has a slightly higher DILI risk than Ligand B (9.965). This favors Ligand B.

**8. BBB:** Ligand B (76.309) has a significantly better BBB penetration percentile than Ligand A (54.634). This is a *critical* advantage for a CNS target like DRD2.

**9. Caco-2 Permeability:** Ligand A (-4.921) has slightly better Caco-2 permeability than Ligand B (-4.668).

**10. Aqueous Solubility:** Ligand A (-1.9) has better aqueous solubility than Ligand B (-2.954).

**11. hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.19 and 0.528).

**12. Microsomal Clearance:** Ligand B (12.322) has lower microsomal clearance than Ligand A (23.402), suggesting better metabolic stability.

**13. In vitro Half-Life:** Ligand A (18.596) has a positive half-life, while Ligand B (-19.624) has a negative half-life. This is a significant drawback for Ligand B.

**14. P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.025 and 0.023).

**15. Binding Affinity:** Both ligands have excellent binding affinities (-7.6 and -7.5 kcal/mol). The difference is minimal.

**Overall Assessment:**

Ligand B excels in the most important parameters for a CNS-targeting GPCR ligand: BBB penetration and DILI risk. While Ligand A has better solubility and Caco-2 permeability, the superior BBB and lower DILI of Ligand B are more critical. The negative in vitro half-life of Ligand B is concerning, but can potentially be addressed through structural modifications. The slightly better metabolic stability of Ligand B is also a plus. The binding affinity is nearly identical.

Output:
1
2025-04-17 04:10:29,008 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (344.5 & 350.5 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Both ligands (49.4 & 49.85) are below the 90 A^2 threshold for CNS targets, which is excellent.

**3. logP:** Ligand A (3.417) is slightly higher than Ligand B (2.83), both are within the optimal 1-3 range.

**4. H-Bond Donors:** Ligand A (1) is preferable to Ligand B (0) as it has one H-bond donor, which can aid solubility.

**5. H-Bond Acceptors:** Ligand A (2) is preferable to Ligand B (3).

**6. QED:** Ligand A (0.777) has a better QED score than Ligand B (0.664), indicating better overall drug-likeness.

**7. DILI:** Ligand B (15.24) has a significantly lower DILI risk than Ligand A (40.05). This is a substantial advantage for Ligand B.

**8. BBB:** Ligand B (92.56) has a much higher BBB penetration percentile than Ligand A (66.38). This is *critical* for a CNS target like DRD2.

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 values, which is unusual and suggests poor permeability. However, the scale isn't specified, so we can't interpret these values definitively.

**10. Aqueous Solubility:** Both ligands have negative solubility values, which is also unusual and suggests poor solubility. Again, the scale isn't specified.

**11. hERG Inhibition:** Ligand A (0.23) has a lower hERG inhibition liability than Ligand B (0.659), which is favorable.

**12. Microsomal Clearance:** Ligand B (65.26) has slightly higher microsomal clearance than Ligand A (57.42). Lower is better for metabolic stability, so Ligand A is slightly better here.

**13. In vitro Half-Life:** Ligand B (2.7) has a slightly longer half-life than Ligand A (-14.19).

**14. P-gp Efflux:** Ligand A (0.41) has lower P-gp efflux liability than Ligand B (0.317), which is preferable for CNS penetration.

**15. Binding Affinity:** Ligand B (-7.2 kcal/mol) has a significantly stronger binding affinity than Ligand A (-9.0 kcal/mol). This is a major advantage, potentially outweighing some of the ADME drawbacks.

**Overall Assessment:**

While Ligand A has some advantages in terms of hERG and Cl_mic, Ligand B is significantly better overall, especially considering the GPCR-specific priorities. The *much* higher BBB penetration (92.6% vs 66.4%), substantially lower DILI risk, and significantly improved binding affinity (-7.2 vs -9.0 kcal/mol) make Ligand B the far more promising candidate. The slightly higher P-gp efflux is a minor concern compared to the benefits. The negative values for Caco-2 and solubility are concerning, but the strong affinity and BBB penetration suggest these might be addressable through formulation or further structural modifications.

Output:
1
2025-04-17 04:10:29,009 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (362.455 and 362.459 Da) fall comfortably within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (87.46) is better than Ligand B (93.01). Both are below the 90 A^2 threshold desirable for CNS targets, but A is closer to the optimal range.

**3. logP:** Both ligands have good logP values (1.951 and 1.488), falling within the optimal 1-3 range.

**4. H-Bond Donors:** Ligand A (2) is slightly higher than Ligand B (1), but both are within the acceptable limit of <=5.

**5. H-Bond Acceptors:** Ligand A (6) and Ligand B (7) are both within the acceptable limit of <=10.

**6. QED:** Both ligands have identical and good QED scores (0.87).

**7. DILI:** Ligand A (61.613) has a lower DILI risk than Ligand B (72.819). Both are acceptable, but A is preferable.

**8. BBB:** Both ligands have similar BBB penetration (43.273 and 43.932). These are not great, ideally >70 for CNS targets, but comparable.

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.298 and -5.147). This is unusual and indicates poor permeability.

**10. Aqueous Solubility:** Both ligands have very poor aqueous solubility (-3.128 and -3.016).

**11. hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.26 and 0.191).

**12. Microsomal Clearance:** Ligand A (-0.067) has much lower microsomal clearance than Ligand B (30.104), suggesting better metabolic stability. This is a significant advantage.

**13. In vitro Half-Life:** Ligand A (11.981) has a much longer in vitro half-life than Ligand B (-1.062). This is a substantial advantage.

**14. P-gp Efflux:** Both ligands have low P-gp efflux liability (0.1 and 0.05).

**15. Binding Affinity:** Ligand B (-8.4 kcal/mol) has a significantly stronger binding affinity than Ligand A (-7.4 kcal/mol). This is a 1 kcal/mol difference, which is substantial.

**Overall Assessment:**

While Ligand B has a better binding affinity, Ligand A demonstrates superior ADME properties, particularly in metabolic stability (lower Cl_mic) and half-life. The poor Caco-2 and solubility for both are concerning, but the significantly improved metabolic profile of Ligand A, combined with a lower DILI risk, makes it a more promising starting point for optimization. The affinity difference, while notable, can potentially be addressed through medicinal chemistry efforts, whereas improving metabolic stability is often more challenging. Given the GPCR target and the need for CNS penetration, a balance between affinity and ADME is crucial.

Output:
0
2025-04-17 04:10:29,009 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (357.801 and 352.494 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (77.05) is better than Ligand B (49.41). For CNS targets, we want TPSA <= 90, both are well within this range, but A is slightly higher.

**logP:** Ligand A (2.48) is within the optimal 1-3 range, while Ligand B (3.616) is slightly higher. Both are acceptable, but A is preferred.

**H-Bond Donors/Acceptors:** Ligand A (0 HBD, 6 HBA) and Ligand B (1 HBD, 2 HBA) both have reasonable counts, well below the thresholds of 5 and 10, respectively.

**QED:** Both ligands have good QED scores (0.719 and 0.761), indicating good drug-like properties.

**DILI:** Ligand A (72.392) has a higher DILI risk than Ligand B (29.43). This is a significant drawback for Ligand A.

**BBB:** Ligand B (96.045) has a much higher BBB penetration percentile than Ligand A (70.997). This is a crucial advantage for a CNS target like DRD2.

**Caco-2 Permeability:** Ligand A (-5.156) has worse Caco-2 permeability than Ligand B (-4.458), indicating lower intestinal absorption.

**Aqueous Solubility:** Both ligands have poor aqueous solubility (-2.417 and -3.898). This is a concern, but can potentially be addressed with formulation strategies.

**hERG Inhibition:** Ligand A (0.068) has a lower hERG inhibition liability than Ligand B (0.85), which is desirable.

**Microsomal Clearance:** Ligand A (30.632) has lower microsomal clearance than Ligand B (56.426), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (-0.192) has a shorter half-life than Ligand B (-19.105), which is not ideal.

**P-gp Efflux:** Ligand A (0.356) has lower P-gp efflux than Ligand B (0.545), which is favorable for CNS penetration.

**Binding Affinity:** Ligand A (-9.9 kcal/mol) has a slightly better binding affinity than Ligand B (-8.6 kcal/mol). This is a significant advantage, but must be weighed against other factors.

**Overall Assessment:**

Ligand A has a better binding affinity and lower P-gp efflux, but suffers from higher DILI risk, poorer BBB penetration, worse Caco-2 permeability, and a shorter half-life. Ligand B, while having slightly weaker affinity, excels in BBB penetration, has a much lower DILI risk, and better metabolic stability.

Given the GPCR-specific priorities, especially BBB penetration for a CNS target, and the significant concern of DILI, **Ligand B is the more promising drug candidate.** The affinity difference, while noticeable, is not large enough to outweigh the superior ADME properties of Ligand B.

Output:
1
2025-04-17 04:10:29,009 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (362.5 and 344.5 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (69.3) is significantly better than Ligand B (86.9). For CNS targets, we want TPSA <= 90, and A is comfortably within this range, while B is approaching the upper limit.

**logP:** Both ligands have good logP values (1.999 and 2.157), falling within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A (1 HBD, 4 HBA) is preferable to Ligand B (3 HBD, 3 HBA). While both are acceptable, fewer H-bonds generally improve permeability.

**QED:** Ligand A (0.832) has a higher QED score than Ligand B (0.663), indicating a more drug-like profile.

**DILI:** Ligand A (48.7) has a slightly higher DILI risk than Ligand B (35.6), but both are well below the concerning threshold of 60.

**BBB:** Both ligands have similar BBB penetration (60.6% and 60.7%), which is acceptable but not ideal for a CNS target. A value >70 would be preferred.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.341 and -5.303), which is unusual and suggests poor permeability. This is a significant concern for both.

**Aqueous Solubility:** Both ligands have negative solubility values (-2.832 and -2.305), indicating very poor aqueous solubility. This is a major drawback.

**hERG Inhibition:** Ligand A (0.356) has a lower hERG inhibition liability than Ligand B (0.135), which is preferable.

**Microsomal Clearance:** Ligand A (47.4) has a higher microsomal clearance than Ligand B (34.3), indicating faster metabolism and lower metabolic stability.

**In vitro Half-Life:** Ligand B (-9.9) has a slightly better in vitro half-life than Ligand A (-19.6), but both are very poor.

**P-gp Efflux:** Both ligands show very low P-gp efflux liability (0.16 and 0.094), which is good for CNS penetration.

**Binding Affinity:** Ligand B (-9.2 kcal/mol) has a significantly stronger binding affinity than Ligand A (-0.0 kcal/mol). This is a substantial advantage, potentially outweighing some of the ADME drawbacks.

**Conclusion:**

Despite the poor solubility and permeability of both compounds, Ligand B's significantly superior binding affinity (-9.2 kcal/mol vs -0.0 kcal/mol) is a decisive factor. While Ligand A has better TPSA and QED, the binding affinity difference is substantial enough to prioritize Ligand B. The slightly better half-life and lower DILI risk also contribute to its favorability. The poor solubility and permeability would need to be addressed through formulation or structural modifications, but the strong binding provides a solid starting point.

Output:
1
2025-04-17 04:10:29,009 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 drug candidates, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (344.459 Da) is slightly lower, which is generally favorable for permeability.

**2. TPSA:** Ligand A (65.54) is significantly better than Ligand B (89.87). For CNS targets, TPSA < 90 is preferred, and A is comfortably within this range, while B is approaching the upper limit.

**3. logP:** Both ligands have acceptable logP values (A: 1.662, B: 0.934), falling within the optimal range of 1-3.

**4. H-Bond Donors:** Ligand A (1) is better than Ligand B (3). Fewer HBDs generally improve permeability.

**5. H-Bond Acceptors:** Ligand A (4) is better than Ligand B (6). Fewer HBAs generally improve permeability.

**6. QED:** Ligand A (0.902) has a significantly higher QED score than Ligand B (0.551), indicating a more drug-like profile.

**7. DILI:** Ligand A (20.396) has a much lower DILI risk than Ligand B (39.511). Both are below 40, which is good, but A is considerably safer.

**8. BBB:** Ligand A (62.621) is better than Ligand B (57.736), although both are below the desirable >70 for CNS targets. However, given the other properties, A has a better chance of achieving sufficient brain penetration.

**9. Caco-2:** Ligand A (-4.735) is better than Ligand B (-5.552). Higher values indicate better intestinal absorption, and A is less negative.

**10. Solubility:** Ligand A (-1.739) is better than Ligand B (-2.539). Higher values indicate better solubility.

**11. hERG:** Both ligands have low hERG risk (A: 0.231, B: 0.466).

**12. Cl_mic:** Ligand A (3.918) has significantly lower microsomal clearance than Ligand B (32.43), suggesting better metabolic stability.

**13. t1/2:** Ligand A (5.172) has a longer in vitro half-life than Ligand B (2.133).

**14. Pgp:** Ligand A (0.025) has much lower P-gp efflux liability than Ligand B (0.075), which is crucial for CNS penetration.

**15. Binding Affinity:** Ligand A (-8.2 kcal/mol) has a significantly stronger binding affinity than Ligand B (-7.0 kcal/mol). This is a substantial advantage, exceeding the 1.5 kcal/mol threshold where it can outweigh other drawbacks.

**Overall:**

Ligand A consistently outperforms Ligand B across most crucial parameters, especially for a CNS target like DRD2. It has better TPSA, logP, QED, DILI, BBB, Caco-2, solubility, metabolic stability (Cl_mic and t1/2), P-gp efflux, and *significantly* stronger binding affinity. While both have acceptable hERG risk, the overall profile of Ligand A makes it a much more promising drug candidate.

Output:
1
2025-04-17 04:10:29,009 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (344.39 and 352.475 Da) fall within the ideal range of 200-500 Da.

**TPSA:** Ligand A (79.18) is slightly higher than the ideal <90 for CNS targets, but still reasonable. Ligand B (60.03) is excellent, well below the threshold.

**logP:** Both ligands (2.121 and 2.656) are within the optimal range of 1-3.

**H-Bond Donors:** Ligand A has 3 HBD, which is acceptable. Ligand B has 1 HBD, also acceptable.

**H-Bond Acceptors:** Both ligands have 5 HBA, which is within the acceptable limit of <=10.

**QED:** Both ligands have good QED scores (0.797 and 0.828), indicating drug-like properties.

**DILI:** Ligand A (72.082) has a moderate DILI risk, while Ligand B (20.589) has a very low DILI risk. This is a significant advantage for Ligand B.

**BBB:** Ligand A (70.648) is at the lower end of desirable for CNS targets, but still acceptable. Ligand B (91.392) is excellent, exceeding the >70 threshold. This is a major advantage for Ligand B.

**Caco-2 Permeability:** Ligand A (-5.086) has poor Caco-2 permeability. Ligand B (-4.671) also has poor Caco-2 permeability.

**Aqueous Solubility:** Both ligands have poor aqueous solubility (-3.469 and -2.495).

**hERG Inhibition:** Both ligands show low hERG inhibition risk (0.643 and 0.532).

**Microsomal Clearance:** Ligand A (5.589) has moderate clearance, while Ligand B (3.398) has lower clearance, indicating better metabolic stability. This favors Ligand B.

**In vitro Half-Life:** Ligand A (-1.889) has a short half-life, while Ligand B (19.855) has a very long half-life. This is a substantial advantage for Ligand B.

**P-gp Efflux:** Ligand A (0.151) has low P-gp efflux, which is good. Ligand B (0.059) has even lower P-gp efflux, which is excellent.

**Binding Affinity:** Ligand B (-7.6) has a significantly stronger binding affinity than Ligand A (-10). The difference of 2.6 kcal/mol is substantial and can outweigh some ADME drawbacks.

**Overall Assessment:**

Ligand B is clearly superior. While both ligands have acceptable MW, logP, H-bonds, QED, and hERG, Ligand B excels in critical areas for a CNS-targeting GPCR ligand: BBB penetration, DILI risk, metabolic stability (lower Cl_mic, longer t1/2), P-gp efflux, and, most importantly, binding affinity. Ligand A's poor Caco-2 permeability and shorter half-life are also drawbacks. The significantly better binding affinity of Ligand B (-7.6 kcal/mol vs -10 kcal/mol) further solidifies its position as the more promising candidate.

Output:
1
2025-04-17 04:10:29,009 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 drug candidates, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (340.47 and 346.43 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (45.48) is excellent, well below the 90 A^2 threshold for CNS targets. Ligand B (107.11) is higher, but still acceptable, though less optimal.

**logP:** Ligand A (3.809) is at the higher end of the optimal range (1-3), while Ligand B (1.253) is slightly below, which could hinder permeability.

**H-Bond Donors/Acceptors:** Ligand A (1 HBD, 3 HBA) is ideal. Ligand B (4 HBD, 4 HBA) is acceptable, but slightly higher counts could impact permeability.

**QED:** Ligand A (0.9) is excellent, indicating high drug-likeness. Ligand B (0.339) is significantly lower, suggesting a less favorable drug-like profile.

**DILI:** Ligand A (14.851) has a very low DILI risk. Ligand B (50.136) is higher, indicating a moderate risk.

**BBB:** This is crucial for a CNS target like DRD2. Ligand A (89.531) has a very good BBB penetration percentile. Ligand B (22.412) is poor, making it less likely to reach the target in the brain.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values, which is unusual and potentially problematic. However, we'll consider other factors.

**Aqueous Solubility:** Both ligands have negative solubility values, which is also concerning.

**hERG:** Ligand A (0.929) has a low hERG risk. Ligand B (0.247) also has a low hERG risk.

**Microsomal Clearance:** Ligand A (29.195) has moderate clearance. Ligand B (-8.229) has *negative* clearance, which is not physically possible and suggests an error in the data or a very unusual metabolic profile.

**In vitro Half-Life:** Ligand A (69.289) has a good half-life. Ligand B (-9.525) has a negative half-life, which is not physically possible.

**P-gp Efflux:** Ligand A (0.4) has low P-gp efflux, which is favorable for CNS penetration. Ligand B (0.084) also has low P-gp efflux.

**Binding Affinity:** Ligand A (-9.9 kcal/mol) has significantly stronger binding affinity than Ligand B (0.0 kcal/mol). This is a major advantage.

**Overall Assessment:**

Ligand A is significantly superior. It has better TPSA, logP, QED, DILI, BBB, half-life, and *much* stronger binding affinity. The negative values for Caco-2 and solubility are concerning for both, but the superior ADME profile and binding affinity of Ligand A outweigh these concerns. Ligand B has several concerning properties (low QED, poor BBB, negative clearance and half-life) and very weak binding affinity, making it a poor candidate.

Output:
1
2025-04-17 04:10:29,009 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (345.443 and 353.419 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (84.66) is excellent, falling well below the 90 A^2 threshold for CNS targets. Ligand B (105.76) is still reasonable but less optimal, being closer to the 140 A^2 limit for oral absorption.

**logP:** Ligand A (2.37) is within the optimal 1-3 range. Ligand B (-0.647) is below 1, which could hinder permeation.

**H-Bond Donors/Acceptors:** Ligand A (HBD=2, HBA=3) and Ligand B (HBD=3, HBA=5) both have acceptable numbers of H-bond donors and acceptors.

**QED:** Ligand A (0.859) has a very strong drug-like profile, while Ligand B (0.478) is lower, indicating less ideal drug-like characteristics.

**DILI:** Both ligands have low DILI risk (Ligand A: 28.616, Ligand B: 26.173), both well below the 40 threshold.

**BBB:** This is critical for a CNS target like DRD2. Ligand A has a very high BBB penetration percentile (90.151), while Ligand B is significantly lower (60.644).

**Caco-2 Permeability:** Ligand A (-4.866) and Ligand B (-5.368) both have negative values, which is unusual and suggests very poor permeability. However, these values are on a scale where negative values are possible, so we must consider them cautiously.

**Aqueous Solubility:** Both ligands have poor aqueous solubility (-2.74 and -1.297 respectively).

**hERG Inhibition:** Both ligands show low hERG inhibition liability (0.451 and 0.06 respectively).

**Microsomal Clearance:** Ligand A (7.689) has a lower clearance than Ligand B (20.886), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (-14.531) has a negative half-life, which is impossible. This is likely an error in the data. Ligand B (1.426) has a very short half-life.

**P-gp Efflux:** Ligand A (0.066) has low P-gp efflux, which is favorable for CNS exposure. Ligand B (0.003) also has low P-gp efflux.

**Binding Affinity:** Ligand A (-8.9 kcal/mol) has a significantly stronger binding affinity than Ligand B (-7.4 kcal/mol). This >1.5 kcal/mol difference is substantial.

**Overall Assessment:**

Ligand A is the superior candidate. It has a better TPSA, logP, QED, BBB penetration, metabolic stability (lower Cl_mic), and significantly stronger binding affinity. While both have poor solubility and Caco-2 permeability, the strong affinity and excellent BBB penetration of Ligand A outweigh these drawbacks for a CNS-targeted GPCR. The negative half-life for Ligand A is a data error that would need to be resolved, but even without that, its other properties are far more favorable. Ligand B's low logP and lower BBB penetration are significant liabilities.

Output:
1
2025-04-17 04:10:29,010 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B based on the provided guidelines, prioritizing GPCR-specific properties (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (370.877 and 350.409 Da) fall within the ideal range of 200-500 Da.

**TPSA:** Ligand A (67.87) is slightly higher than Ligand B (45.33). For CNS targets, TPSA should be <= 90, both are within this range, but B is better.

**logP:** Ligand A (1.964) is within the optimal range (1-3), while Ligand B (3.967) is approaching the upper limit. This favors A slightly.

**H-Bond Donors/Acceptors:** Both have acceptable HBD counts (1). Ligand A has 4 HBA, and Ligand B has 2. Both are within the acceptable limit of <=10.

**QED:** Both ligands have good QED scores (0.744 and 0.821), indicating drug-likeness.

**DILI:** Ligand A (37.65) has a much lower DILI risk than Ligand B (59.131). This is a significant advantage for A.

**BBB:** Ligand B (89.957) has a significantly higher BBB penetration score than Ligand A (69.135). This is a major advantage for B, given the CNS target.

**Caco-2 Permeability:** Both have negative Caco-2 values, indicating poor permeability. Ligand A (-5.033) is slightly worse than Ligand B (-4.888).

**Aqueous Solubility:** Both have negative solubility values, indicating poor solubility. Ligand A (-2.136) is slightly better than Ligand B (-4.044).

**hERG:** Both ligands have low hERG inhibition liability (0.247 and 0.898).

**Microsomal Clearance:** Ligand A (28.167) has lower microsomal clearance than Ligand B (40.803), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (30.642) has a longer in vitro half-life than Ligand B (14.314).

**P-gp Efflux:** Ligand A (0.086) has lower P-gp efflux liability than Ligand B (0.462), which is favorable for CNS penetration.

**Binding Affinity:** Ligand A (-8.8 kcal/mol) has a significantly stronger binding affinity than Ligand B (-7.8 kcal/mol). This is a substantial advantage for A, potentially outweighing some of its ADME drawbacks.

**Overall Assessment:**

Ligand B excels in BBB penetration, which is crucial for a CNS target like DRD2. However, Ligand A demonstrates superior binding affinity, lower DILI risk, better metabolic stability (lower Cl_mic, longer t1/2), and lower P-gp efflux. The difference in binding affinity (-8.8 vs -7.8 kcal/mol) is substantial. While B has better BBB, A's lower P-gp efflux and strong affinity could still lead to sufficient CNS exposure. The lower DILI risk of A is also a significant safety advantage.

Output:
0
2025-04-17 04:10:29,010 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 drug candidates, considering the provided guidelines and GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (346.435 and 347.459 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (80.41) is better than Ligand B (70.67), both are below the 90 A^2 threshold for CNS targets.

**logP:** Ligand A (1.453) is optimal, while Ligand B (0.664) is slightly low, potentially hindering permeability.

**H-Bond Donors/Acceptors:** Ligand A (0 HBD, 8 HBA) is preferable to Ligand B (2 HBD, 4 HBA) as it minimizes potential issues with permeability.

**QED:** Both ligands have similar QED values (0.745 and 0.664), indicating good drug-likeness.

**DILI:** Ligand A (63.397) has a higher DILI risk than Ligand B (18.728), which is a significant drawback.

**BBB:** Ligand A (92.827) has a significantly higher BBB penetration percentile than Ligand B (54.866). This is *critical* for a CNS target like DRD2.

**Caco-2 Permeability:** Ligand A (-4.824) and Ligand B (-5.049) both have negative values, indicating poor permeability.

**Aqueous Solubility:** Ligand A (-2.394) and Ligand B (-1.22) both have negative values, indicating poor solubility.

**hERG:** Both ligands have low hERG inhibition liability (0.742 and 0.208), which is good.

**Microsomal Clearance:** Ligand A (66.517) has a higher microsomal clearance than Ligand B (1.846), indicating lower metabolic stability.

**In vitro Half-Life:** Ligand B (6.452) has a longer half-life than Ligand A (-5.375), which is favorable.

**P-gp Efflux:** Ligand A (0.143) has lower P-gp efflux liability than Ligand B (0.014), which is beneficial for CNS penetration.

**Binding Affinity:** Ligand A (-7.5 kcal/mol) has a slightly better binding affinity than Ligand B (-6.6 kcal/mol). The difference is 0.9 kcal/mol, which is substantial.

**Overall Assessment:**

Ligand A excels in BBB penetration and binding affinity, which are paramount for a CNS GPCR target. However, it suffers from higher DILI risk and lower metabolic stability. Ligand B has a much lower DILI risk and better metabolic stability, but its BBB penetration is significantly lower, and its logP is less optimal.

Given the importance of CNS penetration for DRD2, and the substantial affinity advantage of Ligand A, I would prioritize Ligand A despite its drawbacks. The higher DILI risk and lower metabolic stability could be addressed through further optimization, but achieving good BBB penetration is often more challenging. The affinity difference is also significant enough to potentially outweigh the ADME concerns.

Output:
1
2025-04-17 04:10:29,010 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (353.507 Da) is slightly lower, which *could* be beneficial for permeability, but both are acceptable.

**TPSA:** Ligand A (70.67) is better than Ligand B (40.62). For a CNS target like DRD2, TPSA should be <=90, both are well within this range, but Ligand B is closer to the optimal range for CNS penetration.

**logP:** Ligand A (1.687) is within the optimal range (1-3). Ligand B (3.401) is at the higher end, potentially leading to solubility issues or off-target interactions, but still acceptable.

**H-Bond Donors/Acceptors:** Ligand A has 2 HBD and 4 HBA, while Ligand B has 0 HBD and 3 HBA. Both are within acceptable limits (<=5 HBD and <=10 HBA).

**QED:** Both ligands have similar QED values (0.697 and 0.684), indicating good drug-like properties.

**DILI:** Ligand A (6.398) has a significantly lower DILI risk than Ligand B (24.04). This is a substantial advantage for Ligand A.

**BBB:** Ligand B (91.663) has a much higher BBB penetration percentile than Ligand A (62.582). This is a *critical* advantage for a CNS target like DRD2.

**Caco-2 Permeability:** Ligand A (-5.254) has poor Caco-2 permeability, while Ligand B (-4.516) is better, but still poor.

**Aqueous Solubility:** Ligand A (-0.949) has poor aqueous solubility, while Ligand B (-3.395) is even worse. This is a concern for both, but more so for Ligand B.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.31 and 0.472).

**Microsomal Clearance:** Ligand A (11.513) has lower microsomal clearance (better metabolic stability) than Ligand B (54.555).

**In vitro Half-Life:** Ligand A (4.748) has a better in vitro half-life than Ligand B (-18.278).

**P-gp Efflux:** Ligand A (0.011) has very low P-gp efflux, a significant advantage for CNS penetration. Ligand B (0.132) has slightly higher efflux.

**Binding Affinity:** Both ligands have very similar and strong binding affinities (-7.7 and -7.6 kcal/mol). The difference is negligible.

**Overall Assessment:**

Ligand B excels in BBB penetration, a crucial factor for a CNS target. However, it suffers from higher DILI risk, poor solubility, and higher metabolic clearance. Ligand A has better metabolic stability, lower DILI, and lower P-gp efflux, but its BBB penetration is significantly lower. Given the importance of BBB for CNS drugs, and the similar binding affinities, Ligand B is the slightly better candidate, despite its drawbacks. However, the poor solubility of Ligand B is a significant concern that would need to be addressed through formulation strategies.

Output:
1
2025-04-17 04:10:29,010 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (339.439 and 353.383 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (53.51) is excellent, well below the 90 A^2 threshold for CNS targets. Ligand B (130.48) is higher, but still potentially acceptable, though less ideal.

**3. logP:** Ligand A (1.79) is within the optimal 1-3 range. Ligand B (-1.909) is below 1, which could hinder permeation.

**4. H-Bond Donors:** Ligand A (0) is good. Ligand B (3) is acceptable, but higher HBD can sometimes reduce permeability.

**5. H-Bond Acceptors:** Ligand A (3) is good. Ligand B (7) is acceptable, but higher HBA can sometimes reduce permeability.

**6. QED:** Ligand A (0.844) is excellent, indicating strong drug-likeness. Ligand B (0.444) is lower, suggesting a less favorable drug-like profile.

**7. DILI:** Ligand A (19.232) has a very low DILI risk. Ligand B (52.617) is higher, indicating a moderate risk.

**8. BBB:** Ligand A (86.274) has a good BBB penetration percentile. Ligand B (70.648) is acceptable, but less desirable for a CNS target.

**9. Caco-2:** Ligand A (-4.89) is poor. Ligand B (-5.418) is also poor. Both have very low Caco-2 permeability.

**10. Solubility:** Ligand A (-1.842) is poor. Ligand B (-0.977) is also poor. Both have low aqueous solubility.

**11. hERG:** Both ligands (0.169 and 0.086) have very low hERG inhibition liability, which is excellent.

**12. Cl_mic:** Ligand A (49.307) has moderate metabolic clearance. Ligand B (-4.495) has negative clearance, which is not possible. This is likely an error in the data, but it is a significant red flag.

**13. t1/2:** Ligand A (-18.568) has a negative half-life, which is not possible. This is likely an error in the data, and is a significant red flag. Ligand B (21.964) has a reasonable in vitro half-life.

**14. Pgp:** Both ligands (0.19 and 0.008) have low P-gp efflux liability, which is good.

**15. Binding Affinity:** Ligand A (-9.2) has significantly stronger binding affinity than Ligand B (-7.2). This is a >2 kcal/mol difference, which is substantial.

**Overall Assessment:**

Despite the poor Caco-2 and solubility values for both, Ligand A is the stronger candidate. Its superior affinity, excellent TPSA, good BBB penetration, low DILI risk, and high QED outweigh its permeability issues. The negative values for half-life and clearance are concerning and likely data errors, but the affinity difference is so large that it still favors Ligand A. Ligand B has a negative clearance, which is impossible, and a lower QED and BBB score.

Output:
1
2025-04-17 04:10:29,010 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (365.861 and 382.501 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (79.46) is better than Ligand B (41.99). For CNS targets, TPSA should be <= 90. Both are within this range, but A is closer to the upper limit and B is significantly lower, which is favorable for brain penetration.

**3. logP:** Ligand A (2.768) is optimal (1-3). Ligand B (4.873) is higher, potentially leading to solubility issues and off-target interactions, though still within a reasonable range.

**4. H-Bond Donors:** Ligand A (3) is acceptable. Ligand B (1) is also good.

**5. H-Bond Acceptors:** Ligand A (3) is acceptable. Ligand B (4) is also good.

**6. QED:** Both ligands have similar QED values (0.767 and 0.75), indicating good drug-likeness.

**7. DILI:** Ligand A (56.301) and Ligand B (59.442) are both acceptable, with low DILI risk (below 60).

**8. BBB:** Ligand B (89.415) is significantly better than Ligand A (73.362). A BBB percentile >70 is desirable for CNS targets, and B is closer to this threshold.

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.81 and -4.662). This is unusual and suggests poor permeability. However, these values are on a scale where negative values are possible and don't necessarily disqualify a compound.

**10. Aqueous Solubility:** Both ligands have negative solubility values (-3.774 and -5.22). Similar to Caco-2, this indicates poor aqueous solubility.

**11. hERG Inhibition:** Ligand A (0.163) has a lower hERG risk than Ligand B (0.555), which is preferable.

**12. Microsomal Clearance:** Ligand A (28.005) has lower microsomal clearance than Ligand B (55.979), indicating better metabolic stability.

**13. In vitro Half-Life:** Ligand B (38.61) has a longer half-life than Ligand A (30.229), which is generally desirable.

**14. P-gp Efflux:** Ligand A (0.132) has lower P-gp efflux than Ligand B (0.585), which is favorable for CNS exposure.

**15. Binding Affinity:** Ligand A (-8.6 kcal/mol) has significantly stronger binding affinity than Ligand B (-0.0 kcal/mol). This is a crucial difference. A >1.5 kcal/mol advantage in binding can outweigh other drawbacks.

**Overall Assessment:**

While Ligand B has better BBB penetration and a longer half-life, Ligand A's significantly stronger binding affinity (-8.6 vs -0.0 kcal/mol) is the dominant factor. The affinity difference is so large that it likely outweighs the slightly lower BBB and higher P-gp efflux of Ligand A. The similar DILI and QED scores, combined with the better metabolic stability and lower hERG risk of Ligand A, further support its selection. The poor solubility and permeability (negative Caco-2 and solubility values) are concerns for both, but can be addressed through formulation strategies.

Output:
1
2025-04-17 04:10:29,011 - INFO - Batch 90 complete. Total preferences: 1440
2025-04-17 04:10:29,011 - INFO - Processing batch 91/512...
2025-04-17 04:11:20,126 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (342.4 and 355.5 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (86.11) is better than Ligand B (61.88) as it is closer to the optimal range for CNS targets (<=90).

**logP:** Both ligands have good logP values (2.263 and 1.887), falling within the 1-3 range.

**H-Bond Donors/Acceptors:** Both have 1 HBD, which is good. Ligand A has 6 HBA, while Ligand B has 4. Both are acceptable (<=10).

**QED:** Both ligands have similar QED values (0.68 and 0.65), indicating good drug-likeness.

**DILI:** Ligand A has a significantly higher DILI risk (85.58%) compared to Ligand B (5.47%). This is a major concern for Ligand A.

**BBB:** Ligand B has a much higher BBB penetration percentile (81.23%) than Ligand A (48.51%). This is crucial for a CNS target like DRD2.

**Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and suggests potential issues with permeability prediction. However, the values are close enough to not be a major differentiator.

**Aqueous Solubility:** Both have negative solubility values, again suggesting issues with prediction. Ligand B is slightly better (-1.225 vs -3.624).

**hERG Inhibition:** Ligand A (0.126) has a slightly higher hERG inhibition risk than Ligand B (0.481), but both are relatively low.

**Microsomal Clearance:** Ligand B has a significantly lower microsomal clearance (19.90) than Ligand A (61.55), indicating better metabolic stability.

**In vitro Half-Life:** Both have similar negative half-life values (-3.776 and -3.95), which is concerning and suggests prediction issues.

**P-gp Efflux:** Ligand A (0.117) has a slightly lower P-gp efflux liability than Ligand B (0.025), which is favorable for CNS penetration.

**Binding Affinity:** Ligand B has a significantly stronger binding affinity (-6.8 kcal/mol) than Ligand A (0.0 kcal/mol). This is a decisive advantage.

**Overall Assessment:**

Ligand B is the far superior candidate. While both have some issues with predicted solubility and half-life, Ligand B excels in the most important areas for a CNS-targeting GPCR ligand: BBB penetration, metabolic stability (lower Cl_mic), and, most importantly, binding affinity. Ligand A's high DILI risk is a significant red flag. The stronger binding affinity of Ligand B can potentially outweigh any minor ADME drawbacks.

Output:
1
2025-04-17 04:11:20,126 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 drug candidates, considering the provided guidelines and GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (366.286 and 347.507 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (58.64) is better than Ligand B (53.4) and both are below the 90 A^2 threshold for CNS targets.

**3. logP:** Both ligands have similar logP values (2.257 and 2.215), falling within the optimal range of 1-3.

**4. H-Bond Donors:** Both have 1 HBD, which is acceptable.

**5. H-Bond Acceptors:** Ligand A has 3 HBA, and Ligand B has 4. Both are below the 10 threshold.

**6. QED:** Both ligands have high QED scores (0.835 and 0.912), indicating good drug-like properties.

**7. DILI:** Ligand A (54.517) has a higher DILI risk than Ligand B (5.312). This is a significant drawback for Ligand A.

**8. BBB:** Ligand A (85.847) has a significantly better BBB penetration percentile than Ligand B (72.082). This is crucial for a CNS target like DRD2.

**9. Caco-2 Permeability:** Ligand A (-4.393) has slightly better Caco-2 permeability than Ligand B (-4.749).

**10. Aqueous Solubility:** Ligand B (-0.695) has better aqueous solubility than Ligand A (-2.602).

**11. hERG Inhibition:** Both ligands have similar, low hERG inhibition risk (0.641 and 0.68).

**12. Microsomal Clearance:** Ligand B (-12.957) has a lower (better) microsomal clearance than Ligand A (1.124), suggesting greater metabolic stability.

**13. In vitro Half-Life:** Ligand B (5.494) has a longer in vitro half-life than Ligand A (-21.425).

**14. P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.082 and 0.042).

**15. Binding Affinity:** Ligand B (-8.5 kcal/mol) has a slightly better binding affinity than Ligand A (-8.0 kcal/mol). While the difference is not huge, it's a positive for Ligand B.

**Overall Assessment:**

Ligand A has a better BBB score and Caco-2 permeability. However, it suffers from a significantly higher DILI risk and poorer metabolic stability (higher Cl_mic, shorter half-life) compared to Ligand B. Ligand B has a slightly better binding affinity and a much more favorable safety profile (lower DILI) and pharmacokinetic profile (better Cl_mic and t1/2). Given the GPCR-specific priorities, the improved safety and PK properties of Ligand B outweigh the slight advantage of Ligand A in BBB and Caco-2.

Output:
1
2025-04-17 04:11:20,126 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (362.459 Da) is slightly higher than Ligand B (346.475 Da), but both are acceptable.

**TPSA:** Ligand A (95.12) is higher than Ligand B (60.25). For CNS targets, we prefer TPSA <= 90. Ligand A is slightly above this, while Ligand B is well within the range. This favors Ligand B.

**logP:** Ligand A (0.45) is quite low, potentially hindering membrane permeability. Ligand B (2.886) is within the optimal range (1-3). This is a significant advantage for Ligand B.

**H-Bond Donors/Acceptors:** Ligand A has 0 HBD and 7 HBA. Ligand B has 0 HBD and 5 HBA. Both are within acceptable limits.

**QED:** Both ligands have good QED scores (A: 0.772, B: 0.822), indicating good drug-like properties.

**DILI:** Ligand A (63.086) has a higher DILI risk than Ligand B (44.63). Both are acceptable, but B is preferable.

**BBB:** Ligand B (80.613) has a significantly better BBB penetration score than Ligand A (50.795). This is crucial for a CNS target like DRD2, making Ligand B much more promising.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.979 and -4.724). This is unusual and suggests poor permeability, but the scale isn't specified, so it's difficult to interpret.

**Aqueous Solubility:** Both ligands have negative solubility values (-3.524 and -3.204). Again, the scale is unknown, making interpretation difficult.

**hERG:** Both ligands have very low hERG inhibition liability (0.128 and 0.137), which is excellent.

**Microsomal Clearance:** Ligand A (39.186) has lower microsomal clearance than Ligand B (48.269), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand B (15.906) has a significantly longer in vitro half-life than Ligand A (-8.552). This is a major advantage for Ligand B.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.121 and 0.349).

**Binding Affinity:** Both ligands have excellent binding affinity (-7.0 and -8.3 kcal/mol). Ligand B is slightly better, but the difference is relatively small.

**Overall Assessment:**

Ligand B is clearly the more promising candidate. It has a better logP, TPSA, BBB score, and in vitro half-life. While Ligand A has slightly better metabolic stability, the advantages of Ligand B regarding CNS penetration and pharmacokinetic properties outweigh this. The binding affinity difference is minor. The negative Caco-2 and solubility values are concerning for both, but the overall profile of Ligand B is superior for a CNS-targeting GPCR.

Output:
1
2025-04-17 04:11:20,126 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (352.366 Da) is slightly lower, which could be beneficial for permeability. Ligand B (386.543 Da) is also good.

**TPSA:** Ligand A (118.53) is better than Ligand B (91.4), both are below the 140 A^2 threshold for oral absorption and importantly, below the 90 A^2 threshold for CNS targets.

**logP:** Ligand A (0.012) is quite low, potentially hindering membrane permeability. Ligand B (0.596) is better, falling within the optimal 1-3 range. This is a significant advantage for Ligand B.

**H-Bond Donors/Acceptors:** Both have 2 HBD and 5-6 HBA, which are acceptable values.

**QED:** Both ligands have similar QED scores (0.67 and 0.575), indicating reasonable drug-likeness.

**DILI:** Ligand A (46.258) has a slightly higher DILI risk than Ligand B (35.052), but both are below the concerning 60 threshold.

**BBB:** This is crucial for a CNS target like DRD2. Ligand A has a much better BBB penetration percentile (77.821) than Ligand B (52.268). This is a major advantage for Ligand A.

**Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and suggests poor permeability. However, the scale is not defined, so it's hard to interpret.

**Aqueous Solubility:** Both have negative solubility values, indicating poor solubility.

**hERG Inhibition:** Both have low hERG inhibition liability (0.179 and 0.37), which is good.

**Microsomal Clearance:** Ligand A (-0.769) has a lower (better) microsomal clearance than Ligand B (3.619), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (2.592) has a shorter half-life than Ligand B (-19.725). The negative value for Ligand B is suspect.

**P-gp Efflux:** Ligand A (0.028) has lower P-gp efflux liability than Ligand B (0.023), which is beneficial for CNS exposure.

**Binding Affinity:** Ligand B (-7.2 kcal/mol) has a slightly better binding affinity than Ligand A (-8.3 kcal/mol). While Ligand A has a better affinity, the difference is not substantial enough to outweigh other factors.

**Overall Assessment:**

Ligand A excels in BBB penetration and metabolic stability, and has a slightly better binding affinity. However, its very low logP is a significant concern, potentially hindering its ability to cross cell membranes despite the good BBB prediction. Ligand B has a more favorable logP, which is crucial for GPCR ligands. While its BBB penetration is lower, its binding affinity is still strong. Given the importance of logP and BBB for CNS GPCR targets, and the relatively small difference in binding affinity, Ligand B appears to be the more promising candidate.

Output:
1
2025-04-17 04:11:20,126 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (362.417 Da) is slightly higher than Ligand B (347.371 Da), but both are acceptable.

**TPSA:** Ligand A (59.08) is excellent for CNS penetration, well below the 90 A^2 threshold. Ligand B (112.78) is higher, but still potentially acceptable, though less ideal.

**logP:** Ligand A (1.39) is within the optimal range (1-3). Ligand B (0.944) is slightly below 1, which *could* indicate permeability issues, but is not a major concern.

**H-Bond Donors/Acceptors:** Ligand A (0 HBD, 4 HBA) is favorable. Ligand B (2 HBD, 5 HBA) is also acceptable, though slightly higher.

**QED:** Both ligands have similar QED values (A: 0.687, B: 0.587), indicating good drug-like properties.

**DILI:** Ligand A (25.436) has a significantly lower DILI risk than Ligand B (41.024), which is a substantial advantage.

**BBB:** Ligand A (85.498) has excellent BBB penetration, exceeding the 70% threshold. Ligand B (62.233) is considerably lower, which is a major drawback for a CNS target like DRD2.

**Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and suggests a potential issue with the modeling or data quality. However, the magnitude of negativity is similar.

**Aqueous Solubility:** Both ligands have negative solubility values, again suggesting potential issues with the data. The values are similar in magnitude.

**hERG:** Both ligands have low hERG risk (A: 0.579, B: 0.327).

**Microsomal Clearance:** Ligand A (24.918) has a higher clearance than Ligand B (-7.118), suggesting lower metabolic stability. This is a negative for ligand A.

**In vitro Half-Life:** Ligand B (4.977) has a longer half-life than Ligand A (-0.455), which is a positive for ligand B.

**P-gp Efflux:** Ligand A (0.04) has very low P-gp efflux, which is excellent for CNS penetration. Ligand B (0.104) is slightly higher, but still relatively low.

**Binding Affinity:** Ligand B (-9.6 kcal/mol) has a significantly stronger binding affinity than Ligand A (-8.2 kcal/mol). This >1.5 kcal/mol difference is a major advantage for Ligand B, potentially outweighing some of its ADME drawbacks.

**Overall Assessment:**

Ligand A excels in BBB penetration and P-gp efflux, and has a much lower DILI risk. However, its metabolic stability is a concern. Ligand B has a significantly higher binding affinity, a longer half-life, and a lower clearance, but its BBB penetration is considerably worse.

Given the importance of BBB penetration for a CNS target like DRD2, and the substantial difference in binding affinity, Ligand B is the more promising candidate. The stronger binding is likely to be more impactful than the slightly lower BBB score, especially if further optimization can improve its CNS exposure.

Output:
1
2025-04-17 04:11:20,127 - INFO - Reasoning:

Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands fall within the ideal range (200-500 Da). Ligand A (407.239 Da) is slightly higher, but still acceptable. Ligand B (342.439 Da) is a bit lower, which could be beneficial for permeability.

**2. TPSA:** Ligand A (72.24) is higher than Ligand B (60.45). For a CNS target like DRD2, we ideally want TPSA <= 90, so both are within range, but Ligand B is preferable.

**3. logP:** Ligand A (4.622) is a bit high, potentially leading to solubility issues and off-target interactions. Ligand B (3.63) is much better, falling within the optimal 1-3 range.

**4. H-Bond Donors:** Both ligands have 1 HBD, which is acceptable.

**5. H-Bond Acceptors:** Ligand A has 3 HBA, and Ligand B has 4 HBA, both are within the acceptable limit of <=10.

**6. QED:** Ligand B (0.835) has a significantly better QED score than Ligand A (0.581), indicating a more drug-like profile.

**7. DILI:** Ligand A (73.013) has a higher DILI risk than Ligand B (58.705), although both are reasonably low.

**8. BBB:** This is crucial for a CNS target. Ligand A (80.264) has a good BBB percentile, while Ligand B (51.415) is significantly lower. This is a major advantage for Ligand A.

**9. Caco-2 Permeability:** Both have negative values, which is unusual and suggests poor permeability. However, the scale is not specified, so it's difficult to interpret.

**10. Aqueous Solubility:** Both ligands have very poor aqueous solubility (-6.21 and -4.733 respectively). This is a significant concern for both.

**11. hERG Inhibition:** Both ligands have low hERG inhibition risk (0.549 and 0.496 respectively).

**12. Microsomal Clearance:** Ligand B (100.086) has a very high microsomal clearance, suggesting rapid metabolism and potentially low bioavailability. Ligand A (65.143) is better, but still relatively high.

**13. In vitro Half-Life:** Ligand A (61.122) has a much longer in vitro half-life than Ligand B (6.501), which is a significant advantage.

**14. P-gp Efflux:** Ligand A (0.297) has lower P-gp efflux than Ligand B (0.154), suggesting better CNS exposure.

**15. Binding Affinity:** Ligand B (-8.8 kcal/mol) has a significantly stronger binding affinity than Ligand A (-10.1 kcal/mol). This is a substantial advantage for Ligand B, potentially outweighing some of its ADME drawbacks.

**Overall Assessment:**

Ligand B has a superior binding affinity and better logP and TPSA values. However, it suffers from very high metabolic clearance, poor BBB penetration, and a lower QED score. Ligand A has a good BBB score, longer half-life, lower P-gp efflux, and a reasonable DILI score. While its logP is a bit high and solubility is poor, the strong BBB penetration and better metabolic stability are crucial for a CNS target like DRD2. The affinity difference, while significant, might be overcome with further optimization of Ligand A.

Output:
1
2025-04-17 04:11:20,127 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (352.475 and 351.491 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (59.08) is better than Ligand B (61.88). Both are below the 90 A^2 threshold desirable for CNS targets, but A is closer to optimal.

**3. logP:** Both ligands have good logP values (1.82 and 1.393), falling within the 1-3 range.

**4. H-Bond Donors:** Ligand A (0) is better than Ligand B (1). Fewer HBDs generally improve permeability.

**5. H-Bond Acceptors:** Both ligands have 4 HBA, which is acceptable (<=10).

**6. QED:** Both ligands have similar and good QED values (0.701 and 0.753), indicating good drug-like properties.

**7. DILI:** Ligand A (8.647) has a significantly lower DILI risk than Ligand B (11.09). This is a substantial advantage.

**8. BBB:** Ligand A (83.908) has a better BBB percentile than Ligand B (75.029). Both are reasonably good, but A is closer to the desirable >70 threshold for CNS targets.

**9. Caco-2:** Both have negative Caco-2 values (-4.483 and -4.691). This is unusual and suggests poor permeability. However, the values are very close.

**10. Solubility:** Both have negative solubility values (-0.912 and -1.338), which is also unusual and suggests poor solubility. Again, the values are very close.

**11. hERG:** Both ligands have low hERG inhibition liability (0.324 and 0.296), which is good.

**12. Cl_mic:** Ligand B (15.218) has a lower microsomal clearance than Ligand A (28.218), indicating better metabolic stability.

**13. t1/2:** Ligand B (34.171) has a significantly longer in vitro half-life than Ligand A (-0.069). This is a major advantage.

**14. Pgp:** Both ligands have low Pgp efflux liability (0.084 and 0.038), which is good for CNS penetration.

**15. Binding Affinity:** Ligand A (-7.8) has a slightly better binding affinity than Ligand B (-7.2). While both are good, the 0.6 kcal/mol difference is noteworthy.

**Overall Assessment:**

Ligand A excels in BBB penetration, DILI risk, and binding affinity, and has a lower TPSA and fewer HBDs. Ligand B has better metabolic stability (lower Cl_mic) and a longer half-life. The affinity difference between A and B is not large enough to outweigh the substantial advantages of A in terms of CNS penetration (BBB) and safety (DILI). While both have poor Caco-2 and solubility, these are less critical for a CNS target.

Output:
0
2025-04-17 04:11:20,127 - INFO - Reasoning:

Let's analyze Ligand A and Ligand B for their potential as DRD2 drug candidates, considering the provided guidelines and GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (341.411 and 383.901 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (63.05) is excellent, well below the 90 A^2 threshold for CNS targets. Ligand B (83.36) is still reasonable, but less optimal.

**3. logP:** Ligand A (1.864) is within the optimal 1-3 range. Ligand B (3.145) is at the higher end of optimal, but still acceptable.

**4. H-Bond Donors:** Ligand A (1) is good. Ligand B (3) is also acceptable, but approaching the upper limit.

**5. H-Bond Acceptors:** Ligand A (4) is good. Ligand B (5) is also acceptable.

**6. QED:** Ligand A (0.845) is excellent, indicating strong drug-likeness. Ligand B (0.52) is acceptable, but less desirable.

**7. DILI:** Ligand A (43.234) has a low DILI risk. Ligand B (56.572) is slightly higher, but still within an acceptable range.

**8. BBB:** This is crucial for a CNS target like DRD2. Ligand A (81.698) has a good BBB percentile. Ligand B (48.662) is significantly lower, indicating poorer brain penetration.

**9. Caco-2 Permeability:** Ligand A (-4.747) and Ligand B (-5.081) both have negative values, which is unusual. Assuming these are logP-like scales, lower values suggest poorer permeability. However, the absolute values are similar.

**10. Aqueous Solubility:** Both ligands have very poor aqueous solubility (-2.579 and -4.296). This is a significant concern for both.

**11. hERG Inhibition:** Both ligands have low hERG risk (0.378 and 0.196).

**12. Microsomal Clearance:** Ligand A (19.12) has lower clearance than Ligand B (43.814), suggesting better metabolic stability.

**13. In vitro Half-Life:** Ligand A (18.146) has a longer half-life than Ligand B (4.494), which is preferable.

**14. P-gp Efflux:** Ligand A (0.079) has very low P-gp efflux, which is excellent for CNS penetration. Ligand B (0.132) is slightly higher, but still relatively low.

**15. Binding Affinity:** Ligand A (-8.7 kcal/mol) has a significantly stronger binding affinity than Ligand B (-7.6 kcal/mol). This 1.1 kcal/mol difference is substantial and can outweigh some ADME drawbacks.

**Overall Assessment:**

Ligand A is clearly superior. It has a better TPSA, QED, BBB, metabolic stability (lower Cl_mic, longer t1/2), and significantly higher binding affinity. While both have poor solubility, the superior CNS penetration (BBB) and binding affinity of Ligand A make it the more promising candidate. The slightly higher DILI risk for Ligand B is also a minor negative.

Output:
1
2025-04-17 04:11:20,127 - INFO - Here's a step-by-step reasoning for selecting the better drug candidate between Ligand A and Ligand B, targeting DRD2 (a GPCR):

**1. Molecular Weight (MW):**
*   Ligand A: 348.443 Da - Within the ideal range (200-500 Da).
*   Ligand B: 359.535 Da - Within the ideal range (200-500 Da).
*   *Both are acceptable.*

**2. Topological Polar Surface Area (TPSA):**
*   Ligand A: 91.57  - Slightly above the preferred <90 for CNS targets, but still reasonable.
*   Ligand B: 29.54 - Excellent, well below the 90 threshold for CNS penetration.
*   *Ligand B is significantly better.*

**3. Lipophilicity (logP):**
*   Ligand A: 1.723 - Optimal (1-3).
*   Ligand B: 4.808 - High. Could lead to solubility issues and off-target interactions.
*   *Ligand A is better.*

**4. H-Bond Donors (HBD):**
*   Ligand A: 3 - Acceptable (<=5).
*   Ligand B: 0 - Acceptable (<=5).
*   *Both are acceptable.*

**5. H-Bond Acceptors (HBA):**
*   Ligand A: 4 - Acceptable (<=10).
*   Ligand B: 3 - Acceptable (<=10).
*   *Both are acceptable.*

**6. Quantitative Estimate of Drug-likeness (QED):**
*   Ligand A: 0.7 - Good, above the 0.5 threshold.
*   Ligand B: 0.593 - Acceptable, slightly above the 0.5 threshold.
*   *Ligand A is slightly better.*

**7. DILI Risk:**
*   Ligand A: 30.593 - Low risk (below 40).
*   Ligand B: 33.695 - Low risk (below 40).
*   *Both are acceptable.*

**8. Blood-Brain Barrier Penetration (BBB):**
*   Ligand A: 56.611 - Below the desirable 70% for CNS targets.
*   Ligand B: 76.037 - Excellent, above the 70% threshold.
*   *Ligand B is significantly better.*

**9. Caco-2 Permeability:**
*   Ligand A: -4.949 - Negative value is unusual and suggests poor permeability.
*   Ligand B: -5.159 - Negative value is unusual and suggests poor permeability.
*   *Both are poor, but similar.*

**10. Aqueous Solubility:**
*   Ligand A: -2.164 - Poor solubility.
*   Ligand B: -5.158 - Very poor solubility.
*   *Ligand A is slightly better.*

**11. hERG Inhibition:**
*   Ligand A: 0.377 - Low risk.
*   Ligand B: 0.552 - Low risk.
*   *Both are acceptable.*

**12. Microsomal Clearance:**
*   Ligand A: 9.697 - Relatively low, suggesting better metabolic stability.
*   Ligand B: 129.433 - High clearance, indicating rapid metabolism.
*   *Ligand A is significantly better.*

**13. In vitro Half-Life:**
*   Ligand A: 33.831 - Good half-life.
*   Ligand B: 6.619 - Short half-life.
*   *Ligand A is significantly better.*

**14. P-gp Efflux:**
*   Ligand A: 0.165 - Low efflux, favorable for CNS exposure.
*   Ligand B: 0.609 - Moderate efflux, could limit CNS exposure.
*   *Ligand A is better.*

**15. Binding Affinity:**
*   Ligand A: -8.3 kcal/mol - Excellent.
*   Ligand B: -7.1 kcal/mol - Good, but less potent than Ligand A.
*   *Ligand A is significantly better.*

**Overall Assessment:**

Given the GPCR-specific priorities (BBB, logP, Pgp, TPSA, affinity), **Ligand A** is the more promising candidate despite its slightly higher TPSA and lower solubility. Ligand B has a very high logP and poor metabolic stability. Ligand A exhibits superior BBB penetration, metabolic stability (lower Cl_mic, longer t1/2), P-gp efflux profile, and, crucially, significantly better binding affinity. The 1.2 kcal/mol difference in binding affinity is substantial and can outweigh the minor drawbacks of Ligand A.

1
2025-04-17 04:11:20,127 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (339.483 and 346.471 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (46.06) is significantly better than Ligand B (71.34). For CNS targets, we want TPSA <= 90, and ideally lower. Ligand A is well within this range, while Ligand B is approaching the upper limit and less favorable.

**logP:** Ligand A (4.218) is slightly higher than the optimal 1-3 range, but still acceptable. Ligand B (3.785) is within the optimal range.

**H-Bond Donors/Acceptors:** Both ligands have 2 HBD and a reasonable number of HBA (2 and 3 respectively), satisfying the <=5 and <=10 criteria.

**QED:** Both ligands have good QED scores (0.729 and 0.789), indicating drug-like properties.

**DILI:** Ligand A (27.918) has a lower DILI risk than Ligand B (42.071), which is preferable. Both are below the 60 threshold.

**BBB:** This is a critical parameter for a CNS target like DRD2. Ligand A has a significantly higher BBB penetration percentile (96.782) compared to Ligand B (62.854). This is a major advantage for Ligand A.

**Caco-2 Permeability:** Both have negative values, which is unusual. However, the magnitude is similar, suggesting similar absorption potential.

**Aqueous Solubility:** Both have negative values, which is also unusual. Again, the magnitude is similar, suggesting similar solubility.

**hERG:** Both ligands have low hERG inhibition liability (0.902 and 0.413), which is good.

**Microsomal Clearance:** Ligand A (48.357) has lower microsomal clearance than Ligand B (55.44), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (45.691) has a longer in vitro half-life than Ligand B (52.323).

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.692 and 0.434), which is favorable for CNS penetration.

**Binding Affinity:** Ligand A (-9.0 kcal/mol) has a significantly stronger binding affinity than Ligand B (-8.6 kcal/mol). This difference of 0.4 kcal/mol is substantial and can outweigh minor ADME drawbacks.

**Overall Assessment:**

Ligand A is superior to Ligand B. It has a much better BBB score, a lower TPSA, lower DILI risk, better metabolic stability (lower Cl_mic, longer t1/2), and significantly stronger binding affinity. While Ligand B has a slightly better logP, the advantages of Ligand A, particularly its BBB penetration and binding affinity, are far more important for a CNS-targeting GPCR like DRD2.

Output:
1
2025-04-17 04:11:20,127 - INFO - Reasoning:

Let's analyze Ligand A and Ligand B based on the provided guidelines, prioritizing GPCR-specific properties (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (349.41 and 359.495 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (88.91) is better than Ligand B (71.09) as it is closer to the ideal <90 for CNS targets.

**logP:** Both ligands (1.777 and 2.09) are within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Both ligands have 2 HBD and 5/4 HBA, respectively, which are acceptable.

**QED:** Both ligands have good QED scores (0.793 and 0.864), indicating drug-like properties.

**DILI:** Ligand A (72.819) has a slightly higher DILI risk than Ligand B (57.619), but both are below the concerning threshold of 60.

**BBB:** Ligand A (72.896) has a better BBB percentile than Ligand B (54.478), which is a crucial factor for CNS targets like DRD2.

**Caco-2 Permeability:** Ligand A (-4.94) has a worse Caco-2 permeability than Ligand B (-5.521), but both are negative values, indicating poor permeability.

**Aqueous Solubility:** Both ligands have similar and very poor aqueous solubility (-2.634 and -2.625). This is a concern for both.

**hERG Inhibition:** Ligand A (0.069) has a lower hERG inhibition liability than Ligand B (0.228), which is preferable.

**Microsomal Clearance:** Ligand A (29.962) has a higher microsomal clearance than Ligand B (11.327), indicating lower metabolic stability.

**In vitro Half-Life:** Ligand B (29.31) has a significantly longer in vitro half-life than Ligand A (6.803), which is a positive attribute.

**P-gp Efflux:** Ligand A (0.08) has a lower P-gp efflux liability than Ligand B (0.101), which is favorable for CNS penetration.

**Binding Affinity:** Both ligands have excellent binding affinities (-8.6 and -8.8 kcal/mol). The difference is negligible.

**Overall Assessment:**

Considering the GPCR-specific priorities, Ligand A is slightly favored. It has a better TPSA, lower hERG risk, and lower P-gp efflux. The most significant advantage is its better BBB penetration. While Ligand B has a longer half-life and lower DILI, BBB penetration is paramount for a DRD2 ligand targeting CNS disorders. The solubility is a concern for both, but can be addressed with formulation strategies.

Output:
0
2025-04-17 04:11:20,127 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (351.447 and 345.443 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (93.46) is slightly higher than Ligand B (62.74). For CNS targets, we prefer TPSA <= 90, so Ligand B is better here.

**3. logP:** Both ligands have good logP values (1.923 and 2.257), falling within the optimal 1-3 range.

**4. H-Bond Donors:** Ligand A has 2 HBD, and Ligand B has 0. Both are acceptable (<=5).

**5. H-Bond Acceptors:** Ligand A has 5 HBA, and Ligand B has 4. Both are acceptable (<=10).

**6. QED:** Both ligands have reasonable QED values (0.709 and 0.509), indicating good drug-like properties.

**7. DILI:** Both ligands have low DILI risk (39.667 and 31.989), which is favorable.

**8. BBB:** Both ligands have excellent BBB penetration (75.843 and 75.301), exceeding the desirable >70 threshold for CNS targets.

**9. Caco-2 Permeability:** Both have negative Caco-2 values (-4.482 and -4.371), which is unusual and suggests poor permeability. This is a significant concern.

**10. Aqueous Solubility:** Both have negative solubility values (-2.923 and -1.707), indicating very poor aqueous solubility. This is a major drawback.

**11. hERG Inhibition:** Both ligands show low hERG inhibition risk (0.317 and 0.368).

**12. Microsomal Clearance:** Ligand A (48.65) has higher microsomal clearance than Ligand B (39.578), suggesting lower metabolic stability.

**13. In vitro Half-Life:** Ligand B (12.419) has a slightly longer half-life than Ligand A (10.179).

**14. P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.133 and 0.134), which is excellent for CNS penetration.

**15. Binding Affinity:** Ligand A (-8.3 kcal/mol) has a significantly stronger binding affinity than Ligand B (-7.7 kcal/mol). This is a 0.6 kcal/mol difference, which is substantial and can outweigh some ADME concerns.

**Overall Assessment:**

Both compounds have serious solubility and permeability issues (negative Caco-2 and solubility values). However, Ligand A has a significantly better binding affinity. Given the GPCR-specific prioritization of affinity, and the acceptable BBB penetration for both, Ligand A is the more promising candidate *despite* the ADME liabilities. The stronger binding could potentially be optimized with further medicinal chemistry to address the solubility and permeability issues. Ligand B's weaker affinity makes it less likely to succeed even with optimization.

Output:
1
2025-04-17 04:11:20,127 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (351.491 and 346.431 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Both ligands have TPSA values (69.72 and 68.88) below the 90 A^2 threshold desirable for CNS targets, which is excellent.

**3. logP:** Ligand A (1.953) is within the optimal 1-3 range. Ligand B (0.418) is slightly below 1, which *could* hinder permeation, though not severely.

**4. H-Bond Donors:** Both have 1 HBD, which is within the acceptable limit of <=5.

**5. H-Bond Acceptors:** Ligand A has 3 HBAs, and Ligand B has 4 HBAs, both within the acceptable limit of <=10.

**6. QED:** Both ligands have good QED scores (0.68 and 0.727), indicating good drug-like properties.

**7. DILI:** Ligand A (42.187) has a moderate DILI risk, while Ligand B (19.426) has a very low DILI risk, which is a significant advantage for B.

**8. BBB:** Ligand A (62.466) has a moderate BBB penetration, while Ligand B (55.176) is lower. While both are not ideal (>70), A is better.

**9. Caco-2 Permeability:** Ligand A (-4.646) has better Caco-2 permeability than Ligand B (-5.304), suggesting better intestinal absorption.

**10. Aqueous Solubility:** Ligand A (-2.167) has slightly better aqueous solubility than Ligand B (-1.083).

**11. hERG Inhibition:** Both ligands have low hERG inhibition risk (0.167 and 0.227).

**12. Microsomal Clearance:** Ligand A (63.202) has higher microsomal clearance than Ligand B (-10.905), indicating lower metabolic stability. This is a significant drawback for A.

**13. In vitro Half-Life:** Ligand A (-6.682) has a negative half-life, which is concerning. Ligand B (0.683) has a short half-life, but it is positive.

**14. P-gp Efflux:** Both ligands have low P-gp efflux liability (0.133 and 0.01).

**15. Binding Affinity:** Ligand B (-8.0 kcal/mol) has a significantly stronger binding affinity than Ligand A (-7.1 kcal/mol). This 0.9 kcal/mol difference is substantial and can outweigh some ADME drawbacks.

**Overall Assessment:**

Ligand B is the more promising candidate. While its BBB penetration isn't ideal, its significantly lower DILI risk, much better metabolic stability (lower Cl_mic, better t1/2), and *substantially* stronger binding affinity outweigh the slightly lower logP and BBB. The affinity difference is large enough to be a key driver. Ligand A's poor metabolic stability and negative half-life are major concerns.

Output:
1
2025-04-17 04:11:20,128 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (343.402 and 367.471 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (63.25) is significantly better than Ligand B (91.76). For CNS targets, we want TPSA <= 90, and A is comfortably within this range, while B is close to the upper limit.

**logP:** Ligand A (3.015) is optimal (1-3), while Ligand B (1.041) is at the lower end, potentially hindering permeation.

**H-Bond Donors/Acceptors:** Both have acceptable HBD counts (2). Ligand B has a higher HBA count (6) compared to A (3), but both are within the acceptable limit of <=10.

**QED:** Both ligands have reasonable QED scores (0.812 and 0.751), indicating good drug-like properties.

**DILI:** Both ligands have low DILI risk (40.403 and 42.187), which is good.

**BBB:** Ligand A (83.831) has a significantly better BBB percentile than Ligand B (39.511).  For a CNS target like DRD2, >70 is desirable, and A is closer to this threshold.

**Caco-2 Permeability:** Both have negative Caco-2 values (-4.427 and -4.88), which is unusual and suggests poor permeability. However, these values are on a scale where negative values are possible and don't necessarily disqualify a compound.

**Aqueous Solubility:** Both have negative solubility values (-3.698 and -1.153). Similar to Caco-2, these values are on a scale where negative values are possible.

**hERG:** Both ligands have low hERG inhibition liability (0.441 and 0.245), which is favorable.

**Microsomal Clearance:** Ligand A (38.004) has a higher microsomal clearance than Ligand B (-0.578). Lower clearance is preferred for metabolic stability, so B is better here.

**In vitro Half-Life:** Ligand A (26.433) has a longer half-life than Ligand B (6.235), which is desirable.

**P-gp Efflux:** Ligand A (0.085) has lower P-gp efflux liability than Ligand B (0.029), which is better for CNS exposure.

**Binding Affinity:** Ligand A (-9.6 kcal/mol) has a significantly stronger binding affinity than Ligand B (-6.9 kcal/mol). This is a substantial difference (>1.5 kcal/mol advantage) and can outweigh minor ADME drawbacks.

**Overall Assessment:**

Ligand A is clearly superior. While both have some ADME concerns (negative Caco-2 and solubility), Ligand A excels in the most critical areas for a CNS GPCR target: BBB penetration, logP, and, most importantly, binding affinity. The significantly stronger binding affinity of Ligand A (-9.6 vs -6.9 kcal/mol) is a major advantage. The better BBB and P-gp efflux profiles of A also contribute to its potential for CNS exposure.

Output:
1
2025-04-17 04:11:20,128 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (352.475 and 337.335 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (87.66) is better than Ligand B (104.46). Both are below the 140 A^2 threshold for oral absorption, and Ligand A is closer to the desirable <90 A^2 for CNS targets.

**3. logP:** Both ligands have good logP values (1.364 and 1.196), falling within the optimal 1-3 range.

**4. H-Bond Donors:** Both have 3 HBD, which is acceptable.

**5. H-Bond Acceptors:** Ligand A has 4 HBA, and Ligand B has 5. Both are within the acceptable limit of <=10.

**6. QED:** Both ligands have similar QED values (0.713 and 0.727), indicating good drug-likeness.

**7. DILI:** Ligand A (35.285) has a significantly lower DILI risk than Ligand B (64.521). This is a major advantage for Ligand A.

**8. BBB:** Ligand A (39.395) has a better BBB percentile than Ligand B (24.855). While neither is >70, Ligand A is closer and more favorable for a CNS target like DRD2.

**9. Caco-2:** Both have negative Caco-2 values (-5.056 and -5.126), which is unusual and suggests poor permeability. This is a concern for both.

**10. Solubility:** Both have negative solubility values (-2.414 and -3.958), indicating very poor aqueous solubility. This is a significant drawback for both.

**11. hERG:** Both ligands have very low hERG risk (0.172 and 0.144).

**12. Cl_mic:** Ligand A (27.595) has a lower (better) microsomal clearance than Ligand B (-28.535). This suggests better metabolic stability for Ligand A.

**13. t1/2:** Ligand B (28.545) has a longer in vitro half-life than Ligand A (8.634). This is a positive for Ligand B, but the difference may not be substantial enough to outweigh other factors.

**14. Pgp:** Both have very low Pgp efflux liability (0.087 and 0.024).

**15. Binding Affinity:** Ligand B (-8.1) has a slightly better binding affinity than Ligand A (-7.5). The difference is 0.6 kcal/mol, which is not a huge advantage, but is noticeable.

**Overall Assessment:**

Considering the GPCR-specific priorities, Ligand A is the more promising candidate. While Ligand B has slightly better binding affinity, Ligand A excels in crucial ADME properties for CNS penetration: lower DILI risk, better BBB penetration, and lower microsomal clearance. The poor Caco-2 and solubility are concerns for both, but can be addressed with formulation strategies. The slightly stronger binding of Ligand B is unlikely to overcome the superior ADME profile of Ligand A, especially for a CNS target.

Output:
0
2025-04-17 04:11:20,128 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (339.4) is slightly preferred due to being closer to the lower end, potentially aiding permeability.

**TPSA:** Ligand A (98.98) is better than Ligand B (50.16) as it is closer to the ideal range for CNS targets (<=90). Ligand B is excellent.

**logP:** Ligand A (1.056) is within the optimal range, while Ligand B (3.494) is approaching the upper limit. While not a dealbreaker, Ligand A's lower logP is slightly favored.

**H-Bond Donors/Acceptors:** Both ligands have 1 HBD and 5 HBA, which are acceptable.

**QED:** Ligand A (0.887) has a better QED score than Ligand B (0.779), indicating a more drug-like profile.

**DILI:** Both ligands have acceptable DILI risk (Ligand A: 43.9, Ligand B: 38.1).

**BBB:** This is a critical parameter for CNS targets. Ligand B (73.79) significantly outperforms Ligand A (41.06) in BBB penetration, making it highly desirable.

**Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and suggests poor permeability. This is a significant concern for both.

**Aqueous Solubility:** Both have negative solubility values, which is also a concern.

**hERG Inhibition:** Ligand A (0.174) has a much lower hERG inhibition liability than Ligand B (0.583), which is a significant advantage.

**Microsomal Clearance:** Ligand A (-8.28) has a much lower (better) microsomal clearance than Ligand B (81.42), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand B (28.41) has a longer half-life than Ligand A (5.72), which is generally preferred.

**P-gp Efflux:** Ligand A (0.004) has a much lower P-gp efflux liability than Ligand B (0.658), which is crucial for CNS penetration.

**Binding Affinity:** Ligand A (-7.8) has a slightly better binding affinity than Ligand B (-0.0). This is a substantial difference and a major deciding factor.

**Overall Assessment:**

Ligand A excels in binding affinity, hERG, microsomal clearance, P-gp efflux, and QED. Ligand B's primary advantage is its significantly better BBB penetration and longer half-life. However, the substantial difference in binding affinity (-7.8 vs -0.0 kcal/mol) and the other favorable ADME properties of Ligand A outweigh the BBB advantage of Ligand B. The poor Caco-2 and solubility values are concerning for both, but can be addressed with formulation strategies.

Output:
1
2025-04-17 04:11:20,128 - INFO - Batch 91 complete. Total preferences: 1456
2025-04-17 04:11:20,128 - INFO - Processing batch 92/512...
2025-04-17 04:12:01,136 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (344.46 and 358.41 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (78.67) is excellent, well below the 90 A^2 threshold for CNS targets. Ligand B (95.94) is still reasonable but closer to the 90 A^2 limit.

**logP:** Ligand A (3.562) is optimal. Ligand B (0.544) is significantly low, potentially hindering membrane permeability and CNS penetration.

**H-Bond Donors/Acceptors:** Both have 2 HBD, which is good. Ligand A has 2 HBA, while Ligand B has 5 HBA. Both are within acceptable limits (<=10), but Ligand A is preferable.

**QED:** Both ligands have acceptable QED values (0.879 and 0.7), indicating good drug-like properties.

**DILI:** Ligand A (30.05) has a much lower DILI risk than Ligand B (21.171), which is a significant advantage.

**BBB:** Ligand A (88.135) has a very good BBB penetration percentile, exceeding the desirable >70% threshold for CNS targets. Ligand B (64.676) is considerably lower, raising concerns about reaching the target in the brain.

**Caco-2 Permeability:** Both have negative Caco-2 values (-4.76 and -4.716), which is unusual and suggests poor permeability. However, these values are on a log scale and are difficult to interpret without knowing the base.

**Aqueous Solubility:** Both have negative solubility values (-4.26 and -1.368), indicating poor aqueous solubility. This could pose formulation challenges.

**hERG Inhibition:** Ligand A (0.78) shows a lower hERG inhibition liability than Ligand B (0.193), which is favorable.

**Microsomal Clearance:** Ligand A (26.397) has higher microsomal clearance than Ligand B (11.516), suggesting faster metabolism and potentially lower in vivo exposure.

**In vitro Half-Life:** Ligand B (-18.57) has a negative half-life, which is impossible. This is likely an error in the data. Ligand A (10.868) has a reasonable half-life.

**P-gp Efflux:** Ligand A (0.092) has lower P-gp efflux liability than Ligand B (0.019), which is beneficial for CNS penetration.

**Binding Affinity:** Ligand A (-8.2 kcal/mol) has a slightly better binding affinity than Ligand B (-7.6 kcal/mol), although both are good. The 1.5 kcal/mol difference is not huge, but it's a plus for Ligand A.

**Overall Assessment:**

Ligand A is significantly better than Ligand B. It has superior BBB penetration, lower DILI risk, lower hERG inhibition, better logP, and slightly better binding affinity. While both have poor solubility and Caco-2 permeability, the CNS target profile makes BBB penetration and P-gp efflux particularly important, where Ligand A excels. The negative half-life for Ligand B is a major red flag.

Output:
0
2025-04-17 04:12:01,136 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (362.367 and 347.459 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (49.41) is significantly better than Ligand B (74.43). For CNS targets, we want TPSA <= 90, and ideally closer to 60. Ligand A is much closer to this ideal.

**3. logP:** Both ligands have good logP values (3.443 and 2.107), falling within the optimal 1-3 range.

**4. H-Bond Donors:** Both have acceptable HBD counts (1 and 2 respectively), well below the threshold of 5.

**5. H-Bond Acceptors:** Both have acceptable HBA counts (2 and 3 respectively), well below the threshold of 10.

**6. QED:** Both ligands have similar and good QED values (0.756 and 0.793), indicating good drug-like properties.

**7. DILI:** Ligand A (46.297) has a slightly higher DILI risk than Ligand B (25.669), but both are below the concerning threshold of 60.

**8. BBB:** Ligand A (88.096) has a significantly better BBB penetration prediction than Ligand B (70.803).  For a CNS target like DRD2, >70 is desirable, and Ligand A is closer to this.

**9. Caco-2 Permeability:** Both have negative Caco-2 values which is unusual. This suggests a potential issue with intestinal absorption, but we'll need to consider other factors.

**10. Aqueous Solubility:** Both have negative solubility values, which is also unusual and suggests poor solubility.

**11. hERG Inhibition:** Both ligands show very low hERG inhibition risk (0.694 and 0.393), which is excellent.

**12. Microsomal Clearance:** Ligand B (38.189) has lower microsomal clearance than Ligand A (52.177), suggesting better metabolic stability.

**13. In vitro Half-Life:** Ligand B (-11.978) has a negative half-life, which is nonsensical. Ligand A (14.075) has a reasonable half-life.

**14. P-gp Efflux:** Both ligands show very low P-gp efflux liability (0.145 and 0.037), which is favorable for CNS penetration.

**15. Binding Affinity:** Both ligands have the same binding affinity (-8.2 kcal/mol), which is excellent and well below the -7.0 kcal/mol threshold.

**Overall Assessment:**

Given the GPCR-specific priorities, Ligand A is the better candidate. While Ligand B has slightly better metabolic stability and lower DILI risk, Ligand A's significantly better TPSA and BBB penetration are crucial for a CNS-targeting drug. The negative values for Caco-2 and solubility are concerning for both, but the strong binding affinity and favorable CNS properties of Ligand A outweigh these concerns. The nonsensical half-life prediction for Ligand B is a major red flag.

Output:
1
2025-04-17 04:12:01,137 - INFO - Reasoning:

Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, considering the provided guidelines and GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (368.543 and 358.467 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (58.64) is significantly better than Ligand B (88.32). For CNS targets, we want TPSA <= 90, and A is comfortably within that range, while B is approaching the upper limit.

**3. logP:** Both ligands have good logP values (2.442 and 2.042), falling within the optimal 1-3 range.

**4. H-Bond Donors:** Ligand A (1) is preferable to Ligand B (2). Lower HBD generally improves permeability.

**5. H-Bond Acceptors:** Both ligands have the same number of HBA (4), which is acceptable (<=10).

**6. QED:** Both ligands have good QED scores (0.782 and 0.828), indicating good drug-like properties.

**7. DILI:** Ligand A (31.601) has a much lower DILI risk than Ligand B (58.666). Both are below 60, but A is significantly better.

**8. BBB:** Ligand A (83.831) has a better BBB penetration percentile than Ligand B (78.247). While both are reasonably good, A is closer to the desirable >70 threshold for CNS targets.

**9. Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and suggests a potential issue with the data or modeling. However, the values are similar (-4.999 vs -4.873) and don't strongly differentiate the ligands.

**10. Aqueous Solubility:** Both have negative solubility values, again suggesting a potential data issue. The values are similar (-3.357 vs -2.571).

**11. hERG Inhibition:** Ligand A (0.476) has a lower hERG inhibition liability than Ligand B (0.266), indicating a lower risk of cardiotoxicity. Lower is better.

**12. Microsomal Clearance:** Ligand A (46.03) has a higher microsomal clearance than Ligand B (26.933), suggesting lower metabolic stability. This is a negative for A.

**13. In vitro Half-Life:** Ligand B (-21.197) has a much longer in vitro half-life than Ligand A (4.573). This is a significant advantage for B.

**14. P-gp Efflux:** Ligand A (0.191) has lower P-gp efflux liability than Ligand B (0.14). Lower is better, especially for CNS targets, and A is slightly preferred.

**15. Binding Affinity:** Ligand B (-8.8 kcal/mol) has a slightly better binding affinity than Ligand A (-7.8 kcal/mol). A difference of 1 kcal/mol is significant and can outweigh some ADME drawbacks.

**Overall Assessment:**

Ligand B has a superior binding affinity and a much better in vitro half-life. However, Ligand A excels in TPSA, DILI risk, BBB penetration, and hERG inhibition. Given the GPCR-specific priorities, the lower TPSA and better BBB of Ligand A are crucial for CNS penetration. The significantly lower DILI risk is also a major advantage. While Ligand B's affinity is better, the 1 kcal/mol difference isn't enormous, and the other advantages of Ligand A make it the more promising candidate.

Output:
1
2025-04-17 04:12:01,137 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (379.865 and 392.327 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (64.63) is slightly higher than Ligand B (61.88), but both are below the 90 A^2 threshold desirable for CNS targets.

**logP:** Ligand A (4.5) is higher than the optimal 1-3 range, potentially leading to solubility issues or off-target effects. Ligand B (1.627) is within the optimal range. This is a significant advantage for Ligand B.

**H-Bond Donors/Acceptors:** Both ligands have acceptable HBD (1) and HBA (5/4) counts, well within the guidelines.

**QED:** Both ligands have good QED scores (0.591 and 0.682), indicating drug-like properties.

**DILI:** Ligand A (90.733) has a high DILI risk, which is concerning. Ligand B (10.237) has a very low DILI risk, a major advantage.

**BBB:** Ligand A (50.523) has a moderate BBB penetration, while Ligand B (61.768) is better, but still not ideal (>70 is preferred). However, given the other factors, this is less critical.

**Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and suggests poor permeability. This is a potential issue for both.

**Aqueous Solubility:** Both have negative solubility values, indicating very poor solubility. This is a significant drawback for both.

**hERG:** Both ligands have low hERG inhibition liability (0.502 and 0.443), which is good.

**Microsomal Clearance:** Ligand A (104.44) has higher microsomal clearance than Ligand B (10.499), indicating lower metabolic stability. Ligand B is much more metabolically stable.

**In vitro Half-Life:** Ligand A (12.235) has a longer half-life than Ligand B (4.245).

**P-gp Efflux:** Ligand A (0.413) has lower P-gp efflux than Ligand B (0.021), suggesting better CNS exposure.

**Binding Affinity:** Ligand A (-8.1 kcal/mol) has a significantly stronger binding affinity than Ligand B (-7.1 kcal/mol). This is a substantial advantage for Ligand A.

**Overall Assessment:**

Ligand A has a much stronger binding affinity and lower P-gp efflux, which are highly desirable for a CNS GPCR target. However, its high DILI risk, high logP, and higher metabolic clearance are significant concerns. Ligand B has a better logP, much lower DILI risk, and significantly better metabolic stability. While its binding affinity is weaker and BBB penetration is not optimal, the improved safety and pharmacokinetic profile are compelling.

Considering the balance of properties, and prioritizing safety (DILI) and pharmacokinetic properties (logP, Cl_mic) alongside affinity, Ligand B is the more promising candidate. The affinity difference, while substantial, might be overcome with further optimization, while mitigating the DILI risk of Ligand A would be much more challenging.

Output:
1
2025-04-17 04:12:01,137 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (350.503 and 352.435 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (58.64) is excellent, well below the 90 A^2 threshold for CNS targets. Ligand B (96.55) is higher but still acceptable, though less optimal.

**3. logP:** Ligand A (2.759) is within the optimal 1-3 range. Ligand B (0.881) is slightly low, potentially hindering permeability.

**4. H-Bond Donors:** Both ligands have acceptable HBD counts (1 and 2, respectively), well below the 5 limit.

**5. H-Bond Acceptors:** Ligand A (3) and Ligand B (5) are both within the acceptable limit of 10.

**6. QED:** Both ligands have good QED scores (0.651 and 0.759, respectively), indicating drug-like properties.

**7. DILI:** Ligand A (30.322) has a lower DILI risk than Ligand B (52.695), which is preferable.

**8. BBB:** This is critical for a CNS target. Ligand A (71.772) has a good BBB percentile, exceeding the 70% threshold. Ligand B (45.56) is significantly lower and concerning for CNS penetration.

**9. Caco-2 Permeability:** Ligand A (-4.725) has poor Caco-2 permeability. Ligand B (-5.033) is also poor.

**10. Aqueous Solubility:** Both ligands have poor aqueous solubility (-2.646 and -1.554 respectively).

**11. hERG:** Both ligands have a low hERG risk (0.228 and 0.226, respectively).

**12. Microsomal Clearance:** Ligand A (74.774) has a higher microsomal clearance than Ligand B (3.612), indicating lower metabolic stability.

**13. In vitro Half-Life:** Ligand B (-14.673) has a significantly longer half-life than Ligand A (-7.044).

**14. P-gp Efflux:** Both ligands show no P-gp efflux liability (0.241 and 0.012, respectively).

**15. Binding Affinity:** Ligand B (-8.1 kcal/mol) has a substantially stronger binding affinity than Ligand A (-7.044 kcal/mol). This is a >1 kcal/mol difference, which is significant.

**Overall Assessment:**

While Ligand B has a superior binding affinity and a longer half-life, its significantly lower BBB penetration is a major drawback for a CNS target like DRD2. Ligand A, despite its weaker affinity, has a much better BBB score and a lower DILI risk. The poor Caco-2 and solubility for both are concerning, but can potentially be addressed through formulation strategies. Given the GPCR-specific priorities, particularly BBB for CNS targets, and the substantial difference in BBB penetration, Ligand A is the more promising candidate. The stronger binding of Ligand B isn't enough to overcome the poor CNS penetration.

Output:
1
2025-04-17 04:12:01,137 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (350.503 and 376.45 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (69.64) is significantly better than Ligand B (99.85). For CNS targets, we want TPSA <= 90, and A is comfortably within this range, while B is slightly above.

**3. logP:** Both ligands have acceptable logP values (2.78 and 1.018), falling within the 1-3 range. Ligand A is slightly better.

**4. H-Bond Donors:** Both have 2 HBD, which is good.

**5. H-Bond Acceptors:** Ligand A has 3 HBA, while Ligand B has 5. Both are acceptable (<=10), but A is preferable.

**6. QED:** Both ligands have good QED scores (0.724 and 0.772), indicating good drug-like properties.

**7. DILI:** Ligand A (32.067) has a lower DILI risk than Ligand B (52.772), which is favorable. Both are below the concerning 60 threshold.

**8. BBB:** Ligand A (50.446) has a lower BBB penetration percentile than Ligand B (55.138). While both are not ideal (>70), B is slightly better.

**9. Caco-2 Permeability:** Ligand A (-4.623) shows poorer Caco-2 permeability compared to Ligand B (-5.048). Lower values are worse.

**10. Aqueous Solubility:** Ligand A (-2.725) has slightly better aqueous solubility than Ligand B (-3.05). Higher values are better.

**11. hERG Inhibition:** Ligand A (0.251) has a lower hERG inhibition liability than Ligand B (0.64), which is a significant advantage.

**12. Microsomal Clearance:** Ligand A (44.304) has a higher microsomal clearance than Ligand B (37.376), indicating lower metabolic stability. This favors Ligand B.

**13. In vitro Half-Life:** Ligand A (7.486) has a longer in vitro half-life than Ligand B (-2.225), which is preferable.

**14. P-gp Efflux:** Ligand A (0.105) has lower P-gp efflux liability than Ligand B (0.107), which is slightly better.

**15. Binding Affinity:** Ligand B (-7.2 kcal/mol) has a stronger binding affinity than Ligand A (-6.9 kcal/mol). This 1.5 kcal/mol difference is substantial and can outweigh some ADME drawbacks.

**Overall Assessment:**

Ligand B has a better binding affinity and slightly better BBB penetration. However, Ligand A excels in TPSA, DILI, hERG inhibition, and in vitro half-life. The lower TPSA and hERG risk of Ligand A are particularly important for a CNS-targeting GPCR. While Ligand B's affinity is stronger, the other favorable properties of Ligand A make it a more balanced and potentially viable drug candidate.

Output:
0
2025-04-17 04:12:01,137 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (373.356 and 364.511 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Both ligands (80.32 and 81.42) are below the 90 A^2 threshold desirable for CNS targets, which is good.

**3. logP:** Ligand A (2.648) is within the optimal 1-3 range. Ligand B (3.794) is slightly higher, but still acceptable.

**4. H-Bond Donors:** Both ligands have 2 HBD, well within the acceptable limit of 5.

**5. H-Bond Acceptors:** Both ligands have 5 HBA, also within the acceptable limit of 10.

**6. QED:** Both ligands have QED values above 0.7, indicating good drug-like properties.

**7. DILI:** Ligand A (81.504) has a higher DILI risk than Ligand B (42.536). This is a significant negative for Ligand A.

**8. BBB:** Ligand B (84.141) has a significantly better BBB penetration percentile than Ligand A (67.701). For a CNS target like DRD2, this is a critical advantage.

**9. Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and suggests poor permeability. However, the scale is not defined, so it is hard to interpret.

**10. Aqueous Solubility:** Both have negative solubility values, which is also unusual and suggests poor solubility.

**11. hERG:** Both ligands have low hERG inhibition liability (0.327 and 0.6), which is favorable.

**12. Microsomal Clearance:** Ligand B (57.707) has a higher microsomal clearance than Ligand A (48.25), suggesting faster metabolism. This is a slight negative for Ligand B.

**13. In vitro Half-Life:** Ligand B (61.948) has a longer in vitro half-life than Ligand A (-12.564), which is a significant advantage.

**14. P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.193 and 0.221), which is good for CNS penetration.

**15. Binding Affinity:** Ligand B (-7.9 kcal/mol) has a slightly better binding affinity than Ligand A (-8.8 kcal/mol). While both are strong binders, the difference is meaningful.

**Overall Assessment:**

Ligand B is the more promising candidate. While Ligand A has slightly better binding affinity, Ligand B excels in crucial areas for CNS drug development: significantly lower DILI risk, much better BBB penetration, and a longer in vitro half-life. The slightly higher logP and clearance of Ligand B are less concerning than the higher DILI risk and lower BBB penetration of Ligand A. The GPCR-specific priorities heavily favor Ligand B.

Output:
1
2025-04-17 04:12:01,137 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (345.531 Da) is slightly lower, which could be beneficial for permeability, but both are acceptable.

**TPSA:** Ligand A (35.58) is excellent for CNS penetration, well below the 90 A^2 threshold. Ligand B (66.92) is higher, but still reasonable, though less ideal for CNS targets.

**logP:** Ligand A (3.691) is within the optimal range (1-3). Ligand B (1.825) is at the lower end, potentially impacting permeability.

**H-Bond Donors/Acceptors:** Ligand A (HBD=1, HBA=3) and Ligand B (HBD=0, HBA=4) both have reasonable numbers of H-bond donors and acceptors, falling within the guidelines.

**QED:** Both ligands have acceptable QED values (A: 0.818, B: 0.71), indicating good drug-like properties.

**DILI:** Ligand A (14.114) has a significantly lower DILI risk than Ligand B (12.718), which is a strong advantage.

**BBB:** Ligand A (91.431) has a much higher predicted BBB penetration than Ligand B (76.541). This is *critical* for a CNS target like DRD2.

**Caco-2 Permeability:** Both ligands show negative Caco-2 permeability values, which is unusual and suggests potential issues with the prediction method. However, we can still compare them relatively. Ligand A (-4.48) is slightly better than Ligand B (-4.36).

**Aqueous Solubility:** Both have negative solubility values, again suggesting issues with the prediction. Ligand A (-2.688) is slightly better than Ligand B (-1.67).

**hERG Inhibition:** Ligand A (0.95) has a slightly higher hERG risk than Ligand B (0.283), but both are relatively low.

**Microsomal Clearance:** Ligand A (45.821) has a lower microsomal clearance than Ligand B (77.294), indicating better metabolic stability.

**In vitro Half-Life:** Ligand A (52.746) has a longer in vitro half-life than Ligand B (-19.347). The negative value for B is concerning and suggests a very short half-life.

**P-gp Efflux:** Ligand A (0.374) has a lower P-gp efflux liability than Ligand B (0.038), which is favorable for CNS exposure.

**Binding Affinity:** Ligand B (-8.2 kcal/mol) has a slightly stronger binding affinity than Ligand A (-7.0 kcal/mol). This is a significant advantage, but needs to be weighed against the other ADME properties.

**Overall Assessment:**

Ligand A is clearly superior due to its significantly better BBB penetration, lower DILI risk, better metabolic stability (lower Cl_mic, longer t1/2), and lower P-gp efflux. While Ligand B has a slightly better binding affinity, the ADME profile of Ligand A is much more promising for a CNS-targeting drug. The difference in affinity (1.2 kcal/mol) is unlikely to outweigh the substantial advantages in ADME properties, especially BBB penetration, for a DRD2 ligand.



Output:
1
2025-04-17 04:12:01,137 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (351.447 and 360.483 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (89.95) is better than Ligand B (76.14) as it is closer to the ideal <90 for CNS targets.

**logP:** Ligand B (2.757) is optimal (1-3), while Ligand A (0.123) is significantly low, potentially hindering permeability. This is a major drawback for Ligand A.

**H-Bond Donors:** Both have 2 HBD, which is within the acceptable limit of <=5.

**H-Bond Acceptors:** Ligand A (4) is better than Ligand B (6), being closer to the ideal of <=10.

**QED:** Both ligands have acceptable QED scores (0.756 and 0.67), indicating good drug-like properties.

**DILI:** Ligand A (18.922) has a much lower DILI risk than Ligand B (63.746), a significant advantage.

**BBB:** Both ligands have similar BBB penetration (59.829 and 59.325). Neither is above the desirable 70, but they are comparable.

**Caco-2:** Ligand A (-4.763) has a worse Caco-2 permeability than Ligand B (-5.162), suggesting lower intestinal absorption.

**Solubility:** Ligand A (-1.537) has better solubility than Ligand B (-3.746).

**hERG:** Ligand A (0.164) has a lower hERG risk than Ligand B (0.466), which is preferable.

**Microsomal Clearance:** Ligand B (94.451) has very high microsomal clearance, indicating poor metabolic stability. Ligand A (-0.87) has a negative value, suggesting very good metabolic stability.

**In vitro Half-Life:** Ligand A (7.099 hours) has a better in vitro half-life than Ligand B (-1.152 hours).

**P-gp Efflux:** Ligand A (0.01) has significantly lower P-gp efflux than Ligand B (0.185), which is crucial for CNS penetration.

**Binding Affinity:** Both ligands have the same binding affinity (-7.8 kcal/mol), which is excellent.

**Overall Assessment:**

While both ligands have excellent binding affinity, Ligand A is superior due to its significantly better logP, DILI, metabolic stability (Cl_mic and t1/2), and P-gp efflux. The low logP of Ligand A is a concern, but its other advantages, particularly the improved ADME profile, outweigh this drawback. Ligand B's high DILI risk and poor metabolic stability are major liabilities.

Output:
0
2025-04-17 04:12:01,137 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (383.807) is slightly higher, but acceptable. Ligand B (348.491) is also good.

**TPSA:** Ligand A (46.84) is excellent for CNS penetration, well below the 90 A^2 threshold. Ligand B (76.02) is still reasonable, but less optimal for CNS targets.

**logP:** Ligand A (4.244) is slightly high, potentially leading to solubility issues or off-target interactions. Ligand B (2.361) is within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A (0 HBD, 5 HBA) is favorable. Ligand B (2 HBD, 4 HBA) is also acceptable.

**QED:** Both ligands have similar QED values (0.679 and 0.681), indicating good drug-likeness.

**DILI:** Ligand A (86.002) has a significantly higher DILI risk than Ligand B (29.236). This is a major concern for Ligand A.

**BBB:** Ligand A (80.264) has excellent BBB penetration, exceeding the 70% threshold. Ligand B (64.482) is lower, but still potentially acceptable depending on the required CNS exposure.

**Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and suggests a potential issue with the data or modeling. However, it's likely representing poor permeability.

**Aqueous Solubility:** Both ligands have very poor aqueous solubility (-5.705 and -2.806). This is a significant drawback for both, but potentially manageable with formulation strategies.

**hERG Inhibition:** Ligand A (0.713) has a slightly higher hERG risk than Ligand B (0.146).

**Microsomal Clearance:** Both ligands have similar microsomal clearance rates (52.339 and 55.586), indicating moderate metabolic stability.

**In vitro Half-Life:** Ligand A (16.289) has a longer half-life than Ligand B (-3.689), which is a positive attribute.

**P-gp Efflux:** Ligand A (0.769) has a higher P-gp efflux liability than Ligand B (0.116), which is unfavorable for CNS penetration.

**Binding Affinity:** Ligand A (-9.1 kcal/mol) has a significantly stronger binding affinity than Ligand B (-8.3 kcal/mol). This 0.8 kcal/mol difference is substantial and could outweigh some of the ADME drawbacks.

**Overall Assessment:**

Ligand A has a much stronger binding affinity and good BBB penetration, but suffers from higher DILI risk, higher P-gp efflux, and slightly higher hERG risk. Its logP is also on the higher side. Ligand B has better ADME properties (lower DILI, P-gp, hERG, and better logP), but significantly weaker binding affinity.

Given the GPCR target and the importance of CNS penetration, the strong affinity of Ligand A is a major advantage. While the ADME properties are not ideal, the potency difference is substantial enough that optimization efforts could focus on mitigating the DILI and P-gp efflux issues. The poor solubility is a concern for both, but could be addressed through formulation.

Output:
1
2025-04-17 04:12:01,138 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 drug candidates, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (351.475 and 346.475 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (54.88) is significantly better than Ligand B (87.46). For CNS targets, we want TPSA <= 90, and A is comfortably within that range, while B is approaching the upper limit.

**3. logP:** Ligand A (4.567) is higher than the optimal 1-3 range, but still potentially acceptable. Ligand B (1.503) is on the lower side, which could hinder permeability.

**4. H-Bond Donors:** Ligand A (1) is good. Ligand B (3) is acceptable, but higher.

**5. H-Bond Acceptors:** Ligand A (4) is good. Ligand B (3) is also good.

**6. QED:** Both ligands have similar QED values (0.733 and 0.699), indicating good drug-like properties.

**7. DILI:** Ligand A (69.911) has a higher DILI risk than Ligand B (12.02). This is a significant drawback for Ligand A.

**8. BBB:** Ligand B (76.464) has a much better BBB penetration percentile than Ligand A (53.083). This is *critical* for a CNS target like DRD2.

**9. Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and suggests potential issues with the modeling or data. However, the magnitude is similar.

**10. Aqueous Solubility:** Both have negative solubility values, again unusual. The magnitude is similar.

**11. hERG:** Ligand A (0.644) shows slightly higher hERG inhibition risk than Ligand B (0.366), but both are reasonably low.

**12. Microsomal Clearance:** Ligand B (-6.933) has significantly *lower* (better) microsomal clearance than Ligand A (82.459), indicating greater metabolic stability.

**13. In vitro Half-Life:** Ligand B (3.662) has a slightly longer half-life than Ligand A (25.577).

**14. P-gp Efflux:** Ligand A (0.402) has lower P-gp efflux liability than Ligand B (0.017), which is favorable for CNS penetration.

**15. Binding Affinity:** Ligand B (-7.1) has a slightly better binding affinity than Ligand A (-9.6). While A is stronger, the difference isn't large enough to overcome its other deficiencies.

**Overall Assessment:**

Ligand B is the more promising candidate. It has a significantly better BBB score, lower DILI risk, better metabolic stability (lower Cl_mic), and a slightly longer half-life. While Ligand A has a slightly better binding affinity and lower P-gp efflux, the advantages of Ligand B in terms of CNS penetration and safety outweigh these factors. The TPSA of Ligand A is also preferable, but the other ADME properties of Ligand B are far more important for a CNS-targeting GPCR.

Output:
1
2025-04-17 04:12:01,138 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B based on the provided guidelines, prioritizing GPCR-specific properties (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (373.538 and 377.463 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (52.65) is significantly better than Ligand B (105.25). For CNS targets, TPSA should be <= 90, and A is well within that, while B is approaching the upper limit. This favors A.

**logP:** Ligand A (1.917) is optimal (1-3), while Ligand B (-1.209) is below 1, potentially hindering permeation. This is a significant advantage for A.

**H-Bond Donors/Acceptors:** Both have acceptable HBD (1) and HBA (A: 4, B: 6) counts, within the guidelines.

**QED:** Both ligands have similar QED values (A: 0.706, B: 0.645), indicating good drug-likeness.

**DILI:** Ligand A (11.943) has a much lower DILI risk than Ligand B (56.572). This is a substantial advantage for A.

**BBB:** Ligand A (70.764) is good, exceeding the 70% threshold for CNS targets. Ligand B (51.609) is considerably lower, raising concerns about brain penetration. This is a critical advantage for A.

**Caco-2 Permeability:** Both have negative values, indicating low permeability. However, A (-4.995) is less negative than B (-5.209), suggesting slightly better permeability.

**Aqueous Solubility:** Both have negative values, indicating low solubility. A (-2.416) is slightly better than B (-1.702).

**hERG Inhibition:** Both have very low hERG inhibition risk (A: 0.6, B: 0.124).

**Microsomal Clearance:** Both have similar microsomal clearance values (A: 24.389, B: 23.301), suggesting comparable metabolic stability.

**In vitro Half-Life:** Ligand A (3.804) has a shorter half-life than Ligand B (-46.171). The negative value for B is concerning and likely an outlier or error.

**P-gp Efflux:** Both have low P-gp efflux liability (A: 0.056, B: 0.011), which is good for CNS exposure.

**Binding Affinity:** Ligand B (-8.2 kcal/mol) has a slightly better binding affinity than Ligand A (-7.1 kcal/mol). While a 1.1 kcal/mol difference is notable, the significant advantages of A in other crucial ADME properties, particularly BBB and logP, likely outweigh this difference.

**Overall:** Considering the GPCR-specific priorities, Ligand A is the more promising candidate. It has better TPSA, logP, BBB, and DILI profiles, all crucial for CNS drug development. While Ligand B has slightly better affinity, the superior ADME properties of Ligand A make it a more viable drug candidate.

Output:
1
2025-04-17 04:12:01,138 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (383.382) is slightly higher than Ligand B (344.415), but both are acceptable.

**2. TPSA:** Ligand A (46.17) is excellent for CNS penetration, well below the 90 A^2 threshold. Ligand B (89.16) is higher, but still potentially acceptable, though less ideal.

**3. logP:** Ligand A (4.002) is at the upper end of the optimal range, potentially raising solubility concerns. Ligand B (2.033) is well within the optimal range.

**4. H-Bond Donors:** Both ligands have acceptable HBD counts (Ligand A: 1, Ligand B: 2).

**5. H-Bond Acceptors:** Both ligands have acceptable HBA counts (Ligand A: 2, Ligand B: 5).

**6. QED:** Both ligands have good QED values (Ligand A: 0.799, Ligand B: 0.839), indicating drug-likeness.

**7. DILI:** Both ligands have low DILI risk (Ligand A: 45.25, Ligand B: 40.326), both below the 40 percentile threshold.

**8. BBB:** Ligand A (85.459) has a significantly better BBB penetration score than Ligand B (43.583). This is a crucial advantage for a CNS target like DRD2.

**9. Caco-2 Permeability:** Ligand A (-4.618) has a negative value, indicating poor permeability. Ligand B (-5.173) is also poor, but similar to A.

**10. Aqueous Solubility:** Ligand A (-6.367) has poor aqueous solubility. Ligand B (-2.157) is slightly better, but still poor.

**11. hERG Inhibition:** Ligand A (0.785) has a slightly higher hERG risk than Ligand B (0.028).

**12. Microsomal Clearance:** Ligand A (42.829) has a higher microsomal clearance than Ligand B (8.052), indicating lower metabolic stability.

**13. In vitro Half-Life:** Ligand B (48.902) has a significantly longer in vitro half-life than Ligand A (28.642).

**14. P-gp Efflux:** Ligand A (0.274) has lower P-gp efflux liability than Ligand B (0.009), which is favorable for CNS exposure.

**15. Binding Affinity:** Ligand B (-7.5) has a significantly stronger binding affinity than Ligand A (-9). This is a substantial advantage.

**Overall Assessment:**

While Ligand A has a better BBB score and lower P-gp efflux, Ligand B's significantly stronger binding affinity (-7.5 vs -9 kcal/mol) and longer half-life are more critical for a GPCR target. The slightly higher TPSA and lower BBB of Ligand B are less concerning given the substantial affinity advantage. The lower metabolic clearance of Ligand B is also a significant plus. The solubility of both compounds is poor, but this can be addressed with formulation strategies.

Output:
1
2025-04-17 04:12:01,138 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (367.764 and 344.415 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (89.55) is excellent, falling below the 90 A^2 threshold for CNS targets. Ligand B (95.42) is slightly higher, but still acceptable.

**logP:** Ligand A (2.861) is optimal (1-3). Ligand B (1.505) is on the lower end, potentially impacting permeability.

**H-Bond Donors/Acceptors:** Both ligands have 2 HBD and 5 HBA, which are within acceptable limits.

**QED:** Both ligands have good QED scores (0.605 and 0.807), indicating drug-likeness.

**DILI:** Ligand A has a high DILI risk (95.386 percentile), which is a significant concern. Ligand B has a much lower DILI risk (45.056 percentile), a major advantage.

**BBB:** Ligand A (54.595 percentile) has moderate BBB penetration. Ligand B (57.968 percentile) is also moderate. Both are below the desirable >70% for CNS targets, but not disqualifying.

**Caco-2 Permeability:** Ligand A (-4.59) shows poor Caco-2 permeability. Ligand B (-5.111) is also poor, but slightly worse.

**Aqueous Solubility:** Ligand A (-4.754) has poor aqueous solubility. Ligand B (-2.884) is better, but still poor.

**hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.346 and 0.119), which is excellent.

**Microsomal Clearance:** Ligand A (80.03 mL/min/kg) has moderate clearance. Ligand B (14.334 mL/min/kg) has very low clearance, indicating better metabolic stability.

**In vitro Half-Life:** Ligand A (43.439 hours) has a good half-life. Ligand B (-15.137 hours) has a negative half-life, which is not possible and indicates a problem with the data or the prediction.

**P-gp Efflux:** Ligand A (0.111) has low P-gp efflux, which is good for CNS penetration. Ligand B (0.027) has extremely low P-gp efflux, even better.

**Binding Affinity:** Ligand B (-9.8 kcal/mol) has a significantly stronger binding affinity than Ligand A (-8.6 kcal/mol). This 1.2 kcal/mol difference is substantial and can outweigh some ADME drawbacks.

**Overall Assessment:**

Ligand B is the superior candidate. Despite similar BBB penetration, its significantly stronger binding affinity, much lower DILI risk, and improved metabolic stability (lower Cl_mic) are major advantages. While both have poor Caco-2 and solubility, the binding affinity difference is crucial for a GPCR target, and the lower DILI risk is a critical safety factor. The negative half-life for Ligand B is a data issue that would need to be investigated, but even ignoring this, the other advantages make it preferable.

Output:
1
2025-04-17 04:12:01,138 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (345.447 and 350.459 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (80.12) is better than Ligand B (67.87). Both are below the 90 A^2 threshold desirable for CNS targets, but A is slightly higher.

**3. logP:** Both ligands have similar logP values (1.378 and 1.339), falling within the optimal 1-3 range.

**4. H-Bond Donors:** Both have 1 HBD, which is acceptable.

**5. H-Bond Acceptors:** Ligand A has 5 HBA, and Ligand B has 4. Both are below the 10 threshold.

**6. QED:** Ligand A (0.818) has a slightly higher QED than Ligand B (0.777), indicating better overall drug-likeness.

**7. DILI:** Both ligands have low DILI risk (30.71 and 33.152 percentile), which is good.

**8. BBB:** This is a critical parameter for a CNS target like DRD2. Ligand A has a significantly higher BBB penetration (76.774%) compared to Ligand B (55.874%). This is a major advantage for Ligand A.

**9. Caco-2 Permeability:** Ligand A (-4.997) has a slightly better Caco-2 permeability than Ligand B (-4.389).

**10. Aqueous Solubility:** Ligand A (-2.96) has slightly worse solubility than Ligand B (-1.751). However, solubility is less critical than BBB for CNS targets.

**11. hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.061 and 0.272), which is excellent.

**12. Microsomal Clearance:** Ligand B (-0.93) has a *negative* Cl_mic, which is highly unusual and suggests exceptional metabolic stability. Ligand A (49.256) has a moderate clearance. This is a substantial advantage for Ligand B.

**13. In vitro Half-Life:** Ligand B (12.084 hours) has a significantly longer half-life than Ligand A (-16.662 hours). This is a major advantage for Ligand B.

**14. P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.035 and 0.087), which is good.

**15. Binding Affinity:** Ligand A (-7.8 kcal/mol) has a substantially stronger binding affinity than Ligand B (0.0 kcal/mol). This is a significant advantage for Ligand A.

**Overall Assessment:**

Ligand A excels in binding affinity and has good BBB penetration. However, Ligand B demonstrates superior metabolic stability (negative Cl_mic), a longer half-life, and acceptable BBB penetration. The substantial difference in binding affinity (-7.8 vs 0 kcal/mol) is a critical factor. While metabolic stability and half-life are important, a significantly stronger binding affinity often outweighs moderate ADME drawbacks, especially when the ADME profile isn't severely problematic. Ligand A's BBB penetration is also quite good.

Output:
1
2025-04-17 04:12:01,138 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 drug candidates, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (344.46 and 361.36 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (82.26) is better than Ligand B (63.52), both are below the 90 A^2 threshold for CNS targets.

**logP:** Both ligands have good logP values (1.84 and 3.02), falling within the optimal 1-3 range. Ligand B is slightly higher, which could be beneficial for membrane permeability but needs to be balanced against solubility.

**H-Bond Donors/Acceptors:** Ligand A has 4 HBD and 3 HBA, while Ligand B has 1 HBD and 5 HBA. Both are within acceptable limits (<=5 HBD and <=10 HBA).

**QED:** Both ligands have similar QED values (0.658 and 0.705), indicating good drug-likeness.

**DILI:** Both ligands have similar, acceptable DILI risk (35.05 and 35.79 percentile).

**BBB:** Ligand B (74.56%) has a significantly better BBB penetration score than Ligand A (62.39%). This is a crucial advantage for a CNS target like DRD2.

**Caco-2 Permeability:** Ligand A (-5.51) has worse Caco-2 permeability than Ligand B (-4.66).

**Aqueous Solubility:** Ligand A (-2.08) has better aqueous solubility than Ligand B (-3.62).

**hERG:** Ligand A (0.23) has a lower hERG inhibition liability than Ligand B (0.862), which is preferable.

**Microsomal Clearance:** Ligand B (44.64) has a much higher microsomal clearance than Ligand A (-0.285), indicating lower metabolic stability. This is a significant drawback for Ligand B.

**In vitro Half-Life:** Ligand B (18.76 hours) has a longer in vitro half-life than Ligand A (8.48 hours).

**P-gp Efflux:** Ligand A (0.041) has a lower P-gp efflux liability than Ligand B (0.472), which is favorable for CNS penetration.

**Binding Affinity:** Ligand A (-9.9 kcal/mol) has a significantly stronger binding affinity than Ligand B (-6.9 kcal/mol). This is a substantial advantage, potentially outweighing some ADME concerns.

**Overall Assessment:**

Ligand A has a superior binding affinity and better metabolic stability (lower Cl_mic, better P-gp efflux). Ligand B has a better BBB score and slightly longer half-life. However, the substantial difference in binding affinity (-9.9 vs -6.9 kcal/mol) and the concerningly high microsomal clearance of Ligand B are major factors. For a GPCR, strong binding is paramount, and the better ADME profile of Ligand A (especially metabolic stability and P-gp efflux) makes it the more promising candidate.

Output:
0
2025-04-17 04:12:01,138 - INFO - Batch 92 complete. Total preferences: 1472
2025-04-17 04:12:01,139 - INFO - Processing batch 93/512...
2025-04-17 04:12:41,344 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (344.455 Da) is slightly lower, which could be beneficial for permeability, but both are acceptable.

**TPSA:** Ligand A (78.43) is better than Ligand B (83.55) as it is closer to the desirable <90 A^2 for CNS targets.

**logP:** Both ligands have good logP values (A: 2.925, B: 1.119) within the optimal 1-3 range. Ligand A is slightly better.

**H-Bond Donors/Acceptors:** Ligand A (HBD=3, HBA=3) and Ligand B (HBD=1, HBA=4) are both within acceptable limits (<=5 HBD, <=10 HBA).

**QED:** Both ligands have good QED scores (A: 0.603, B: 0.75), indicating good drug-like properties. Ligand B is slightly better.

**DILI:** Ligand A (20.24) has a significantly lower DILI risk than Ligand B (52.074), which is a major advantage.

**BBB:** Ligand B (78.868) has a better BBB penetration score than Ligand A (67.623), which is crucial for a CNS target like DRD2.

**Caco-2 Permeability:** Ligand A (-4.647) has a worse Caco-2 permeability than Ligand B (-5.205). Lower values are worse.

**Aqueous Solubility:** Ligand A (-3.116) has better solubility than Ligand B (-2.275).

**hERG Inhibition:** Ligand A (0.526) has a lower hERG inhibition risk than Ligand B (0.167). Lower is better.

**Microsomal Clearance:** Ligand B (-8.32) has a significantly lower (better) microsomal clearance than Ligand A (48.759), indicating better metabolic stability.

**In vitro Half-Life:** Ligand B (21.39) has a much longer in vitro half-life than Ligand A (8.73), which is desirable.

**P-gp Efflux:** Ligand A (0.42) has lower P-gp efflux liability than Ligand B (0.13), which is beneficial for CNS exposure.

**Binding Affinity:** Ligand B (-9.3 kcal/mol) has a significantly stronger binding affinity than Ligand A (-8.4 kcal/mol). This is a substantial advantage, potentially outweighing some ADME drawbacks.

**Overall Assessment:**

Ligand B excels in binding affinity, BBB penetration, metabolic stability (low Cl_mic, high t1/2), and QED. However, it has a higher DILI risk and P-gp efflux. Ligand A has better solubility, lower DILI and hERG, and lower P-gp efflux, but weaker binding affinity and poorer metabolic stability.

Given the importance of strong binding affinity for GPCRs and the relatively good BBB score of Ligand B, the stronger affinity of Ligand B is the deciding factor. While the DILI and P-gp efflux are concerns, these can potentially be addressed through further optimization. The substantial binding affinity advantage is more difficult to achieve through optimization.

Output:
1
2025-04-17 04:12:41,345 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (353.463 and 367.43 Da) fall within the ideal 200-500 Da range.

**TPSA:** Both ligands (82.11 and 79.37) are below the 90 A^2 threshold desirable for CNS targets, which is excellent.

**logP:** Ligand A (-0.026) is slightly below the optimal 1-3 range, potentially hindering permeability. Ligand B (2.236) is within the optimal range. This favors Ligand B.

**H-Bond Donors/Acceptors:** Ligand A has 2 HBD and 5 HBA, while Ligand B has 1 HBD and 4 HBA. Both are within acceptable limits (<=5 HBD and <=10 HBA).

**QED:** Both ligands have similar QED values (0.701 and 0.679), indicating good drug-likeness.

**DILI:** Ligand A (5.894) has a significantly lower DILI risk than Ligand B (25.087), which is a substantial advantage.

**BBB:** Ligand B (43.273) has a much better BBB penetration percentile than Ligand A (31.097). This is crucial for a CNS target like DRD2, and strongly favors Ligand B.

**Caco-2 Permeability:** Both have negative Caco-2 values (-4.994 and -5.053), which is unusual and suggests poor permeability. This is a concern for both.

**Aqueous Solubility:** Both have negative solubility values (-0.303 and -0.942), which is also concerning and suggests poor solubility.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.159 and 0.234).

**Microsomal Clearance:** Ligand A (-12.086) has a lower (better) microsomal clearance than Ligand B (23.339), indicating greater metabolic stability.

**In vitro Half-Life:** Ligand B (30.702) has a longer half-life than Ligand A (19.702), which is generally desirable.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.004 and 0.036), which is good for CNS penetration.

**Binding Affinity:** Ligand A (-7.8) has a slightly better (more negative) binding affinity than Ligand B (-7.5). While a 0.3 kcal/mol difference is not huge, it is noticeable.

**Overall Assessment:**

Ligand B excels in BBB penetration and has a longer half-life, both critical for CNS drug development. Its logP is also more favorable. However, Ligand A has a much lower DILI risk and better metabolic stability. Both have poor predicted Caco-2 permeability and solubility. The affinity difference is relatively small. Given the importance of BBB penetration for a DRD2 ligand, and the acceptable DILI risk of Ligand B, I favor Ligand B.

Output:
1
2025-04-17 04:12:41,345 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 drug candidates, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (379.364 and 372.487 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (123.13) is slightly above the optimal <90 for CNS targets, but still reasonable. Ligand B (95.94) is better, falling comfortably below 90.

**logP:** Ligand A (0.715) is a bit low, potentially hindering permeation. Ligand B (0.427) is even lower, raising more concerns about permeability. Both are below the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A has 3 HBD and 7 HBA, which are within acceptable limits. Ligand B has 2 HBD and 5 HBA, also acceptable.

**QED:** Both ligands have similar QED values (0.679 and 0.632), indicating good drug-likeness.

**DILI:** Ligand A has a DILI risk of 65.723, which is moderately high. Ligand B has a lower DILI risk (40.752), which is preferable.

**BBB:** This is critical for a CNS target. Ligand A has a BBB penetration of 28.228, which is quite low and a significant drawback. Ligand B has a much better BBB penetration of 42.924, though still not ideal (>70 is desired).

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.517 and -5.299), which is unusual and suggests poor intestinal absorption. This is a concern for oral bioavailability.

**Aqueous Solubility:** Both ligands have very poor aqueous solubility (-1.763 and -1.521). This will likely require formulation strategies.

**hERG Inhibition:** Both ligands show very low hERG inhibition risk (0.328 and 0.123), which is excellent.

**Microsomal Clearance:** Ligand A has a very low microsomal clearance (0.073), suggesting good metabolic stability. Ligand B has a significantly higher clearance (15.32), indicating faster metabolism and potentially lower *in vivo* exposure.

**In vitro Half-Life:** Ligand A has a half-life of 5.592 hours, which is reasonable. Ligand B has a very short half-life (0.608 hours), raising concerns about dosing frequency.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.038 and 0.029), which is favorable for CNS penetration.

**Binding Affinity:** Ligand A has a significantly better binding affinity (-7.7 kcal/mol) compared to Ligand B (0.0 kcal/mol). This is a substantial advantage.

**Overall Assessment:**

Despite the poor solubility and Caco-2 permeability for both, Ligand A is the stronger candidate. The much higher binding affinity (-7.7 kcal/mol vs 0.0 kcal/mol) is a major advantage that can potentially offset some of the ADME liabilities. Ligand B's significantly worse affinity, combined with its higher microsomal clearance and shorter half-life, make it a less attractive option. While Ligand A's BBB penetration is low, it's still better than Ligand B's, and the strong binding affinity might allow for efficacy even with limited brain exposure. The DILI risk for Ligand A is a concern, but manageable.



Output:
0
2025-04-17 04:12:41,345 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B against the provided guidelines, prioritizing GPCR-specific properties (BBB, logP, Pgp, TPSA, and affinity) for DRD2.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (336.391 Da) is slightly lower, which is generally favorable for permeability. Ligand B (371.547 Da) is also acceptable.

**TPSA:** Both ligands have TPSA values below the 90 A^2 threshold for CNS targets (Ligand A: 79.19, Ligand B: 78.51). This is excellent.

**logP:** Ligand A (3.029) is within the optimal range (1-3). Ligand B (1.029) is at the lower end, which *could* potentially hinder permeation, but isn't a dealbreaker.

**H-Bond Donors/Acceptors:** Ligand A (HBD=1, HBA=4) and Ligand B (HBD=2, HBA=4) both have reasonable numbers of H-bond donors and acceptors, well within the recommended limits.

**QED:** Both ligands have acceptable QED values (Ligand A: 0.874, Ligand B: 0.731), indicating good drug-like properties.

**DILI:** Ligand A has a significantly higher DILI risk (74.409%) compared to Ligand B (14.967%). This is a major concern for Ligand A.

**BBB:** Ligand A (77.2%) has a better BBB penetration percentile than Ligand B (66.576%), which is important for a CNS target like DRD2.

**Caco-2 Permeability:** Ligand A (-4.213) shows poor Caco-2 permeability, while Ligand B (-5.089) is even worse. Both are quite low, suggesting potential absorption issues, but this is less critical than BBB for CNS targets.

**Aqueous Solubility:** Ligand A (-5.549) has slightly better solubility than Ligand B (-1.986), but both are very poor.

**hERG Inhibition:** Ligand A (0.708) has a slightly higher hERG risk than Ligand B (0.22), but both are relatively low.

**Microsomal Clearance:** Ligand B (-6.076) has a *much* lower (better) microsomal clearance than Ligand A (65.902). This suggests better metabolic stability for Ligand B.

**In vitro Half-Life:** Ligand B (-3.059) has a longer in vitro half-life than Ligand A (16.993), further supporting its better metabolic stability.

**P-gp Efflux:** Ligand A (0.246) has lower P-gp efflux liability than Ligand B (0.023), which is favorable for CNS exposure.

**Binding Affinity:** Ligand A (-8.1 kcal/mol) has a significantly stronger binding affinity than Ligand B (-7.2 kcal/mol). This is a substantial advantage (0.9 kcal/mol difference).

**Overall Assessment:**

While Ligand A has a better BBB and binding affinity, its significantly higher DILI risk and poor metabolic stability (high Cl_mic, short t1/2) are major drawbacks. Ligand B, despite slightly weaker binding, presents a much more favorable ADMET profile, with a low DILI risk, excellent metabolic stability, and acceptable BBB penetration. The affinity difference, while noticeable, may be overcome with further optimization of Ligand B. Given the CNS target and the importance of minimizing toxicity, Ligand B is the more promising candidate.

Output:
1
2025-04-17 04:12:41,345 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B based on the provided guidelines and GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (358.47 & 368.37 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (73.85) is slightly higher than Ligand B (69.64), but both are below the 90 A^2 threshold desirable for CNS targets.

**logP:** Ligand A (4.55) is higher than the optimal 1-3 range, potentially causing solubility issues. Ligand B (1.79) is within the optimal range.

**H-Bond Donors/Acceptors:** Ligand A has 0 HBD and 6 HBA, while Ligand B has 2 HBD and 3 HBA. Both are within acceptable limits.

**QED:** Both ligands have similar QED values (0.43 and 0.51), indicating reasonable drug-likeness.

**DILI:** Ligand A (60.53) is at the upper limit of acceptable DILI risk, while Ligand B (16.05) is significantly lower and preferable.

**BBB:** Ligand B (94.03) exhibits excellent BBB penetration, a crucial factor for CNS targets like DRD2. Ligand A (81.47) is good, but not as high.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values, which is unusual. Assuming these are logP-like scales, lower values indicate poorer permeability. Ligand A (-4.93) appears slightly worse than Ligand B (-5.08).

**Aqueous Solubility:** Both ligands have negative solubility values, suggesting poor aqueous solubility. Ligand B (-2.44) is slightly better than Ligand A (-5.87).

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.61 and 0.78).

**Microsomal Clearance:** Ligand A (53.08) has a higher microsomal clearance than Ligand B (17.96), indicating lower metabolic stability.

**In vitro Half-Life:** Ligand B (-6.16) has a significantly longer in vitro half-life than Ligand A (3.18), which is a positive attribute.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.63 and 0.14). Ligand B is preferable.

**Binding Affinity:** Ligand B (-8.6 kcal/mol) has a slightly better binding affinity than Ligand A (-9.2 kcal/mol). While the difference is small, it's still a factor.

**Overall Assessment:**

Considering the GPCR-specific priorities, Ligand B is the more promising candidate. Its superior BBB penetration, lower DILI risk, better metabolic stability (lower Cl_mic, longer t1/2), and slightly better binding affinity outweigh the slightly lower logP and Caco-2 permeability. Ligand A's higher logP raises concerns about solubility and potential off-target effects.

Output:
1
2025-04-17 04:12:41,345 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (374.35 and 392.204 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (58.64) is significantly better than Ligand B (29.54). For CNS targets, we want TPSA <= 90, and ideally lower. Ligand A is good, while Ligand B is excellent.

**logP:** Ligand A (2.352) is within the optimal 1-3 range. Ligand B (4.62) is higher, potentially leading to solubility issues and off-target interactions.

**H-Bond Donors/Acceptors:** Ligand A has 1 HBD and 3 HBA, while Ligand B has 0 HBD and 2 HBA. Both are within acceptable limits (<=5 HBD and <=10 HBA).

**QED:** Both ligands have similar QED values (0.696 and 0.644), indicating good drug-like properties.

**DILI:** Ligand A (31.02) has a much lower DILI risk than Ligand B (63.978). This is a significant advantage for Ligand A.

**BBB:** Ligand A (76.774) and Ligand B (82.164) both have good BBB penetration, exceeding the 70% threshold for CNS targets. Ligand B is slightly better.

**Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and suggests a potential issue with the data or modeling. However, the values are similar (-4.528 and -4.238).

**Aqueous Solubility:** Both have negative solubility values, which is also unusual. Ligand A (-2.104) is slightly better than Ligand B (-5.532).

**hERG Inhibition:** Ligand A (0.488) has a lower hERG inhibition risk than Ligand B (0.833).

**Microsomal Clearance:** Ligand A (23.818) has a lower microsomal clearance than Ligand B (94.508), indicating better metabolic stability.

**In vitro Half-Life:** Ligand A (-22.934) has a negative half-life, which is not physically possible and suggests a data issue. Ligand B (35.55) is positive and reasonable.

**P-gp Efflux:** Ligand A (0.035) has a much lower P-gp efflux liability than Ligand B (0.729), which is crucial for CNS penetration.

**Binding Affinity:** Ligand B (-8.3) has a slightly better binding affinity than Ligand A (-7.8), but the difference is less than 1.5 kcal/mol.

**Overall Assessment:**

Ligand A is superior despite the questionable half-life data. It has a significantly better safety profile (lower DILI, lower hERG), better metabolic stability (lower Cl_mic), and lower P-gp efflux, all critical for CNS drug development. While Ligand B has slightly better BBB penetration and binding affinity, the advantages of Ligand A in ADME-Tox properties outweigh these minor differences. The negative half-life for Ligand A is concerning, but the other advantages are substantial.



Output:
1
2025-04-17 04:12:41,345 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B based on the provided guidelines, prioritizing GPCR-specific properties (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (356.411 and 348.399 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (95.39) is slightly above the optimal <90 for CNS targets, but acceptable. Ligand B (81.01) is well within the desired range.

**logP:** Both ligands have good logP values (0.991 and 1.282), falling within the 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A (3 HBD, 6 HBA) and Ligand B (1 HBD, 5 HBA) both have reasonable numbers of H-bond donors and acceptors, well below the thresholds of 5 and 10 respectively.

**QED:** Both ligands have good QED scores (0.608 and 0.867), indicating good drug-like properties.

**DILI:** Ligand A (81.815) has a higher DILI risk than Ligand B (43.273). Ligand B is preferable here.

**BBB:** This is a crucial parameter for a CNS target like DRD2. Ligand B (49.748) has a significantly better BBB percentile than Ligand A (24.506). This is a major advantage for Ligand B.

**Caco-2 Permeability:** Ligand A (-5.719) shows poor Caco-2 permeability, while Ligand B (-4.589) is slightly better, but still poor.

**Aqueous Solubility:** Both ligands have very poor aqueous solubility (-3.351 and -1.937). This is a concern for both, but might be mitigated by formulation strategies.

**hERG Inhibition:** Both ligands have low hERG inhibition liability (0.436 and 0.239), which is good.

**Microsomal Clearance:** Ligand A (-5.742) has a lower (better) microsomal clearance than Ligand B (23.902), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand B (30.024 hours) has a considerably longer half-life than Ligand A (13.041 hours).

**P-gp Efflux:** Ligand A (0.095) shows slightly more P-gp efflux than Ligand B (0.035), which is preferable for CNS penetration.

**Binding Affinity:** Ligand A (-8.7 kcal/mol) has a significantly stronger binding affinity than Ligand B (-0.0 kcal/mol). This is a substantial advantage for Ligand A. The difference in affinity is >1.5 kcal/mol, and can outweigh some of the ADME drawbacks.

**Overall Assessment:**

While Ligand B excels in BBB penetration and has a better safety profile (lower DILI), Ligand A's *much* stronger binding affinity (-8.7 vs -0.0 kcal/mol) is a decisive factor, especially for a GPCR target. The improved metabolic stability (lower Cl_mic) of Ligand A is also beneficial. The poor solubility and Caco-2 permeability of both are concerns, but can potentially be addressed with formulation. The slightly higher Pgp efflux for Ligand A is a minor drawback compared to the massive difference in binding affinity.

Output:
1
2025-04-17 04:12:41,345 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (337.47 and 352.48 Da) fall within the ideal 200-500 Da range.

**TPSA:** Both ligands have TPSA values (57.78 and 56.33) below the 90 A^2 threshold desirable for CNS targets, which is excellent.

**logP:** Ligand A (4.723) is higher than optimal (1-3) but still potentially acceptable. Ligand B (-0.138) is significantly *below* the optimal range and could have permeability issues. This is a major strike against Ligand B.

**H-Bond Donors/Acceptors:** Ligand A (2 HBD, 2 HBA) and Ligand B (0 HBD, 5 HBA) both fall within acceptable ranges.

**QED:** Both ligands have reasonable QED scores (0.775 and 0.666), indicating good drug-like properties.

**DILI:** Ligand A (51.842) has a moderate DILI risk, but Ligand B (4.343) is very low, which is a positive for B.

**BBB:** Both ligands have good BBB penetration (77.162 and 76.464), exceeding the 70% threshold for CNS targets.

**Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and suggests a potential issue with the data or modeling. However, the magnitude is similar.

**Aqueous Solubility:** Both ligands have very poor aqueous solubility (-5.625 and -0.025). This is a concern for both, but may be less critical given the CNS target and potential for formulation strategies.

**hERG Inhibition:** Ligand A (0.845) has a slightly higher hERG risk than Ligand B (0.45), but both are reasonably low.

**Microsomal Clearance:** Ligand A (67.181) has higher clearance than Ligand B (22.174), suggesting lower metabolic stability. This favors Ligand B.

**In vitro Half-Life:** Ligand B (-27.972) has a significantly longer half-life than Ligand A (-9.858). This is a strong advantage for Ligand B.

**P-gp Efflux:** Ligand A (0.607) has lower P-gp efflux than Ligand B (0.004), which is favorable for CNS exposure.

**Binding Affinity:** Ligand A (-10.2 kcal/mol) has a *much* stronger binding affinity than Ligand B (-7.0 kcal/mol). This is a substantial advantage for Ligand A, potentially outweighing some of its ADME drawbacks.

**Overall Assessment:**

Ligand B has better ADME properties (lower clearance, longer half-life, lower DILI, better P-gp efflux) and solubility, but its logP is very poor, which is a significant concern for brain penetration. Ligand A has a dramatically superior binding affinity, good BBB penetration, and acceptable (though not ideal) ADME properties. The strong binding affinity of Ligand A is likely to be the dominant factor, especially for a CNS target where potency is crucial. The higher logP of Ligand A is a concern, but may be mitigated by formulation strategies.

Output:
1
2025-04-17 04:12:41,346 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (353.344 and 353.419 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (63.13) is significantly better than Ligand B (88.18). For CNS targets, we want TPSA <= 90, and A is comfortably within that range, while B is approaching the upper limit.

**3. logP:** Ligand A (3.132) is optimal (1-3), while Ligand B (0.363) is quite low, potentially hindering membrane permeability.

**4. H-Bond Donors:** Both ligands have acceptable HBD counts (2 and 1 respectively), well below the threshold of 5.

**5. H-Bond Acceptors:** Both ligands have acceptable HBA counts (3 and 5 respectively), well below the threshold of 10.

**6. QED:** Both ligands have similar and good QED values (0.867 and 0.771), indicating good drug-like properties.

**7. DILI:** Ligand A (64.288) has a higher DILI risk than Ligand B (34.161). This is a negative for A.

**8. BBB:** Ligand A (76.813) has a significantly better BBB penetration percentile than Ligand B (59.636). This is *crucial* for a CNS target like DRD2.

**9. Caco-2 Permeability:** Both have negative Caco-2 values which is unusual. Assuming these are percentile scores, Ligand A (-4.778) is slightly better than Ligand B (-4.9), but both are poor.

**10. Aqueous Solubility:** Both have negative solubility values which is also unusual. Assuming these are percentile scores, Ligand A (-3.981) is slightly better than Ligand B (-1.37), but both are poor.

**11. hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.772 and 0.173).

**12. Microsomal Clearance:** Ligand B (-35.175) has a much lower (better) microsomal clearance than Ligand A (22.051), indicating greater metabolic stability.

**13. In vitro Half-Life:** Ligand A (47.872) has a longer half-life than Ligand B (-4.699).

**14. P-gp Efflux:** Ligand A (0.431) has lower P-gp efflux liability than Ligand B (0.014), which is favorable for CNS penetration.

**15. Binding Affinity:** Both ligands have very similar and excellent binding affinities (-8.2 and -8.3 kcal/mol). The difference is negligible.

**Overall Assessment:**

Ligand A excels in key areas for a CNS GPCR target: TPSA, logP, and especially BBB penetration. While its DILI risk is higher, the superior BBB penetration and logP outweigh this concern, especially given the similar binding affinities. Ligand B has better metabolic stability (lower Cl_mic) and lower DILI, but its poor logP and significantly lower BBB penetration are major drawbacks for a CNS-acting drug.

Output:
1
2025-04-17 04:12:41,346 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B based on the provided guidelines, prioritizing GPCR-specific properties (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (429.336 Da) is slightly higher than Ligand B (380.455 Da), but both are acceptable.

**TPSA:** Ligand A (60.77) is excellent for CNS penetration, well below the 90 A^2 threshold. Ligand B (116.65) is higher, but still potentially acceptable, though less ideal for CNS targets.

**logP:** Ligand A (2.665) is optimal. Ligand B (-0.661) is significantly lower, which could hinder membrane permeability and CNS penetration.

**H-Bond Donors/Acceptors:** Ligand A (0 HBD, 6 HBA) is favorable. Ligand B (2 HBD, 8 HBA) is also acceptable, but slightly higher counts could impact permeability.

**QED:** Both ligands have good QED scores (A: 0.648, B: 0.712), indicating drug-like properties.

**DILI:** Ligand A (44.591) has a lower DILI risk than Ligand B (89.763), which is a significant advantage.

**BBB:** Ligand A (68.748) has a much better BBB percentile than Ligand B (38.348). This is a critical factor for a CNS target like DRD2.

**Caco-2 Permeability:** Ligand A (-4.778) has poor Caco-2 permeability. Ligand B (-6.074) is even worse. Both are concerning, but the negative values suggest these are percentile scores where lower is worse.

**Aqueous Solubility:** Both ligands have poor aqueous solubility (-2.583 and -2.07 respectively). This could pose formulation challenges.

**hERG Inhibition:** Ligand A (0.557) has a lower hERG risk than Ligand B (0.083), which is preferable.

**Microsomal Clearance:** Ligand A (96.582) has higher microsomal clearance, suggesting faster metabolism. Ligand B (-8.788) has *negative* clearance, which is impossible and indicates an error or unusual behavior in the prediction. This is a major red flag.

**In vitro Half-Life:** Ligand A (30.009 hours) has a reasonable half-life. Ligand B (46.415 hours) has a longer half-life, which is generally desirable.

**P-gp Efflux:** Ligand A (0.59) has lower P-gp efflux, which is good for CNS penetration. Ligand B (0.121) has even lower efflux, which is even better.

**Binding Affinity:** Ligand B (-9.4 kcal/mol) has significantly stronger binding affinity than Ligand A (-6.8 kcal/mol). This is a substantial advantage, potentially outweighing some ADME drawbacks.

**Overall Assessment:**

Despite Ligand B's superior binding affinity, its extremely problematic negative microsomal clearance makes it a highly unlikely drug candidate. The negative clearance value is a critical flaw. Ligand A has a better overall profile, with acceptable MW, TPSA, logP, QED, DILI, and a reasonable BBB score. While its Caco-2 permeability and aqueous solubility are poor, and its affinity is lower, these issues might be addressable through formulation or further optimization. The combination of a reasonable ADME profile and acceptable CNS penetration potential makes Ligand A the more viable candidate.

Output:
0
2025-04-17 04:12:41,346 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (344.459 and 348.447 Da) fall comfortably within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (66.4) is significantly better than Ligand B (76.46). For a CNS target like DRD2, TPSA should be <= 90, and ideally lower. Ligand A is closer to the ideal range.

**3. logP:** Both ligands have good logP values (2.347 and 1.346), falling within the optimal 1-3 range. Ligand A is slightly higher, which could be beneficial for membrane permeability, but both are acceptable.

**4. H-Bond Donors:** Ligand A (0) is better than Ligand B (1). Fewer H-bond donors generally improve permeability.

**5. H-Bond Acceptors:** Ligand A (4) is better than Ligand B (5). Fewer H-bond acceptors also generally improve permeability.

**6. QED:** Both ligands have similar and good QED values (0.794 and 0.807), indicating good drug-like properties.

**7. DILI:** Both ligands have low DILI risk (31.485 and 34.471), both well below the 40 threshold.

**8. BBB:** This is a critical parameter for CNS targets. Ligand A has a significantly better BBB penetration percentile (86.817) compared to Ligand B (73.866). A value >70 is desirable, and Ligand A is much closer to optimal.

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.82 and -4.774), which is unusual and suggests poor permeability. However, these values are on the same scale, so this isn't a differentiating factor.

**10. Aqueous Solubility:** Both ligands have very poor aqueous solubility (-2.283 and -1.969). This is a significant drawback for both, but not a differentiating factor.

**11. hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.371 and 0.352).

**12. Microsomal Clearance:** Ligand A (39.044) has higher microsomal clearance than Ligand B (25.866), indicating faster metabolism and potentially lower *in vivo* exposure. This favors Ligand B.

**13. In vitro Half-Life:** Ligand B (17.147) has a much longer half-life than Ligand A (-12.669). This is a substantial advantage for Ligand B.

**14. P-gp Efflux:** Both ligands have low P-gp efflux liability (0.329 and 0.025), which is good. Ligand B is slightly better.

**15. Binding Affinity:** Both ligands have excellent binding affinity (-8.4 and -8.5 kcal/mol). The difference is negligible.

**Overall Assessment:**

Ligand A excels in TPSA and BBB penetration, which are crucial for CNS GPCR targets. However, Ligand B demonstrates superior metabolic stability (lower Cl_mic, longer t1/2) and slightly better P-gp efflux. The solubility is poor for both. Considering the importance of CNS penetration for DRD2, and the relatively small difference in affinity, Ligand A is the more promising candidate.

Output:
0
2025-04-17 04:12:41,346 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (345.49 and 352.44 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (43.86) is significantly better than Ligand B (85.69). For CNS targets, we want TPSA <= 90, and A is comfortably within this range, while B is approaching the upper limit.

**logP:** Ligand A (1.295) is optimal, while Ligand B (0.692) is slightly low, potentially hindering permeation.

**H-Bond Donors/Acceptors:** Ligand A (0 HBD, 3 HBA) is preferable to Ligand B (1 HBD, 6 HBA) as it has fewer potential issues with permeability. Both are within acceptable limits.

**QED:** Both ligands have similar QED values (0.682 and 0.696), indicating good drug-like properties.

**DILI:** Ligand A (11.21) has a much lower DILI risk than Ligand B (31.02), which is a significant advantage.

**BBB:** Ligand A (80.81) has a substantially better BBB penetration percentile than Ligand B (64.83). This is *critical* for a CNS target like DRD2.

**Caco-2 Permeability:** Both are negative, indicating poor permeability. However, the scale is not specified, so it's hard to interpret.

**Aqueous Solubility:** Both are negative, indicating poor solubility. Again, the scale is not specified.

**hERG:** Ligand A (0.607) has a lower hERG inhibition liability than Ligand B (0.133), which is a positive.

**Microsomal Clearance:** Ligand A (20.93) has a lower microsomal clearance than Ligand B (42.59), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (5.29) has a longer half-life than Ligand B (-2.395), which is desirable.

**P-gp Efflux:** Ligand A (0.042) has a much lower P-gp efflux liability than Ligand B (0.024), meaning it's less likely to be pumped out of the brain, improving CNS exposure.

**Binding Affinity:** Ligand B (-7.4 kcal/mol) has a slightly better binding affinity than Ligand A (-8.0 kcal/mol). However, the difference is relatively small (0.6 kcal/mol), and the other ADME properties of Ligand A are far superior.

**Overall:** Considering the GPCR-specific priorities, Ligand A is the much more promising candidate. Its superior BBB penetration, lower TPSA, better logP, lower DILI, lower P-gp efflux, and better metabolic stability outweigh the slightly weaker binding affinity. The difference in binding affinity is not large enough to overcome the significant ADME advantages of Ligand A.

Output:
1
2025-04-17 04:12:41,346 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (341.426 and 339.399 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (32.7) is excellent, well below the 90 A^2 threshold for CNS targets. Ligand B (98.98) is higher, but still potentially acceptable, though less ideal.

**logP:** Ligand A (3.719) is at the upper end of the optimal range (1-3), but still acceptable. Ligand B (1.056) is a bit low, potentially hindering permeability.

**H-Bond Donors/Acceptors:** Both ligands have 1 HBD, which is good. Ligand A has 3 HBA, and Ligand B has 5 HBA. Both are within the acceptable limit of <=10.

**QED:** Both ligands have QED values above 0.8, indicating good drug-likeness.

**DILI:** Ligand A (9.228) has a much lower DILI risk than Ligand B (43.932). This is a significant advantage for Ligand A.

**BBB:** Ligand A (90.074) has excellent BBB penetration, exceeding the desirable >70% threshold. Ligand B (41.062) has poor BBB penetration, a major drawback for a CNS target like DRD2.

**Caco-2 Permeability:** Ligand A (-4.707) and Ligand B (-5.228) both have negative Caco-2 values, indicating poor permeability. However, the scale is not clearly defined, so this is less informative.

**Aqueous Solubility:** Ligand A (-3.175) and Ligand B (-1.663) both have negative solubility values, indicating poor solubility. Again, the scale is not defined.

**hERG:** Ligand A (0.994) has a slightly higher hERG risk than Ligand B (0.174). This is a minor concern, but Ligand B is preferable here.

**Microsomal Clearance:** Ligand A (40.897) has moderate clearance. Ligand B (-8.28) has negative clearance, which is not physically possible and likely indicates an error or an unusual data representation. This is a significant red flag for Ligand B.

**In vitro Half-Life:** Both ligands have similar in vitro half-lives (5.454 and 5.72 hours).

**P-gp Efflux:** Ligand A (0.975) has moderate P-gp efflux. Ligand B (0.004) has very low P-gp efflux, which is favorable.

**Binding Affinity:** Ligand A (-10.3 kcal/mol) has significantly stronger binding affinity than Ligand B (-7.8 kcal/mol). This is a substantial advantage, potentially outweighing some of the ADME drawbacks.

**Overall Assessment:**

Ligand A is the stronger candidate. Its superior BBB penetration, significantly lower DILI risk, and much higher binding affinity are critical advantages for a CNS-targeting GPCR. While its logP is slightly higher and hERG risk slightly elevated, these are less concerning than the poor BBB penetration and questionable clearance of Ligand B. The negative clearance value for Ligand B is a major issue. The substantial affinity difference (-10.3 vs -7.8 kcal/mol) is a decisive factor.

Output:
1
2025-04-17 04:12:41,346 - INFO - Reasoning:

Let's analyze Ligand A and Ligand B for their potential as DRD2 drug candidates, considering the provided guidelines and GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (348.407 Da) is slightly lower, which is generally favorable for permeability.

**TPSA:** Both ligands have TPSA values below 140, suggesting reasonable oral absorption. Ligand B (97.39) is better, being closer to the preferred <90 for CNS targets. Ligand A (113.14) is still acceptable but less ideal.

**logP:** Ligand A (0.108) has a very low logP, which is a significant concern as it may hinder membrane permeability and reduce brain penetration. Ligand B (0.775) is better, though still on the lower side of the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A (HBD=1, HBA=7) and Ligand B (HBD=2, HBA=5) both fall within acceptable limits.

**QED:** Both ligands have QED values above 0.5, indicating good drug-like properties. Ligand A (0.748) is slightly better.

**DILI:** Both ligands have low DILI risk (Ligand A: 48.895, Ligand B: 47.15), which is positive.

**BBB:** Both ligands have moderate BBB penetration (Ligand A: 40.791, Ligand B: 46.413). Neither is above the desirable 70% threshold for CNS targets, but this isn't a dealbreaker if other properties are strong.

**Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and suggests poor permeability. This is a red flag.

**Aqueous Solubility:** Both have very poor aqueous solubility (Ligand A: -1.641, Ligand B: -2.553). This is a significant issue for formulation and bioavailability.

**hERG Inhibition:** Both ligands show very low hERG inhibition risk (Ligand A: 0.082, Ligand B: 0.151), which is excellent.

**Microsomal Clearance:** Ligand A (-3.872) has a negative clearance, which is not physically possible and indicates an issue with the data or prediction method. Ligand B (19.263) has a moderate clearance.

**In vitro Half-Life:** Ligand A (10.281) has a reasonable half-life. Ligand B (-43.522) has a negative half-life, which is also not physically possible and indicates an issue with the data.

**P-gp Efflux:** Both ligands show very low P-gp efflux (Ligand A: 0.008, Ligand B: 0.021), which is favorable for CNS penetration.

**Binding Affinity:** Ligand B (-8.2 kcal/mol) has a significantly stronger binding affinity than Ligand A (-7.4 kcal/mol). This 0.8 kcal/mol difference is substantial and could outweigh some ADME drawbacks.

**Overall Assessment:**

Ligand A suffers from a very low logP and questionable microsomal clearance and half-life data. Ligand B has better logP and a significantly higher binding affinity. While both have poor solubility and Caco-2 permeability, the superior affinity of Ligand B, coupled with acceptable (though not ideal) BBB penetration, makes it the more promising candidate. The negative clearance and half-life for Ligand B are concerning and require further investigation, but the affinity advantage is substantial.

Output:
1
2025-04-17 04:12:41,347 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight (MW):** Both ligands (349.475 and 346.435 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (69.72) is excellent, well below the 90 A^2 threshold for CNS targets. Ligand B (85.05) is still reasonable, but less optimal.

**3. logP:** Ligand A (1.852) is within the optimal range (1-3). Ligand B (0.521) is slightly low, potentially impacting permeability.

**4. H-Bond Donors (HBD):** Both ligands have 1 HBD, which is acceptable.

**5. H-Bond Acceptors (HBA):** Ligand A has 3 HBA, and Ligand B has 6. Both are within the acceptable limit of 10, but Ligand A is preferable.

**6. QED:** Both ligands have good QED scores (0.713 and 0.755), indicating drug-like properties.

**7. DILI:** Ligand A (26.871) has a significantly lower DILI risk than Ligand B (33.812).

**8. BBB:** This is crucial for a CNS target like DRD2. Ligand A (73.672) has a good BBB percentile, exceeding the desirable >70 threshold. Ligand B (37.418) is quite low, suggesting poor brain penetration.

**9. Caco-2 Permeability:** Ligand A (-4.887) and Ligand B (-5.315) both have negative values, which is unusual and requires further investigation. However, the values are fairly similar.

**10. Aqueous Solubility:** Ligand A (-1.843) and Ligand B (-0.715) both have negative solubility values, indicating poor solubility.

**11. hERG Inhibition:** Both ligands show very low hERG inhibition risk (0.157 and 0.079).

**12. Microsomal Clearance:** Ligand A (53.04) has higher microsomal clearance than Ligand B (20.352), indicating lower metabolic stability.

**13. In vitro Half-Life:** Ligand B (27.748) has a longer in vitro half-life than Ligand A (15.371), which is desirable.

**14. P-gp Efflux:** Ligand A (0.037) has very low P-gp efflux liability, which is excellent for CNS penetration. Ligand B (0.011) is also low, but slightly higher.

**15. Binding Affinity:** Ligand B (-8.0) has a significantly stronger binding affinity than Ligand A (-0.0). This is a substantial advantage.

**Overall Assessment:**

While Ligand B has a much stronger binding affinity, Ligand A is significantly better in terms of BBB penetration, DILI risk, and P-gp efflux. The strong affinity of Ligand B is compelling, but the poor BBB penetration is a major drawback for a CNS target. The difference in binding affinity is large (>1.5 kcal/mol), but the poor ADME properties of Ligand B are concerning. Given the importance of CNS penetration for DRD2, and the relatively low affinity of Ligand A, further optimization of Ligand A would be a more promising strategy.

Output:
0
2025-04-17 04:12:41,347 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (345.418 and 363.908 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (43.86) is better than Ligand B (21.06). For CNS targets, TPSA should be <= 90, both are well within this range, but lower is preferable, giving a slight edge to B.

**logP:** Ligand A (0.837) is slightly lower than the optimal 1-3 range, potentially hindering permeability. Ligand B (4.893) is higher, which could lead to solubility issues or off-target interactions, but is more favorable for BBB penetration.

**H-Bond Donors/Acceptors:** Both have 0 HBD and 3 HBA, which is acceptable.

**QED:** Both ligands have reasonable QED values (0.431 and 0.728), with B being better.

**DILI:** Ligand A (21.055) has a slightly higher DILI risk than Ligand B (13.804), but both are below the concerning threshold of 60.

**BBB:** Ligand B (95.967) significantly outperforms Ligand A (78.79) in BBB penetration, which is *critical* for a CNS target like DRD2.

**Caco-2 Permeability:** Ligand A (-4.681) and Ligand B (-4.669) are both very poor, indicating poor intestinal absorption. This isn't a primary concern for CNS targets where direct delivery or high BBB penetration can compensate.

**Aqueous Solubility:** Ligand A (-2.102) and Ligand B (-4.788) are both poor, but B is worse.

**hERG Inhibition:** Ligand A (0.393) has a slightly lower hERG risk than Ligand B (0.94).

**Microsomal Clearance:** Ligand A (9.639) has a lower microsomal clearance than Ligand B (33.971), indicating better metabolic stability.

**In vitro Half-Life:** Ligand A (-30.593) has a much longer in vitro half-life than Ligand B (38.97), which is a significant advantage.

**P-gp Efflux:** Ligand A (0.086) shows much lower P-gp efflux than Ligand B (0.793), which is highly desirable for CNS penetration.

**Binding Affinity:** Ligand B (-8.0) has a slightly better binding affinity than Ligand A (-7.6), but the difference is not substantial enough to overcome the other ADME issues.

**Overall Assessment:**

Ligand B excels in BBB penetration and binding affinity, which are key for a CNS GPCR target. However, it suffers from higher logP, lower solubility, higher P-gp efflux, and higher microsomal clearance. Ligand A has better metabolic stability, lower P-gp efflux, and a longer half-life, but its BBB penetration is significantly lower.

Considering the importance of BBB penetration for DRD2, and the relatively small difference in binding affinity, **Ligand B is the more promising candidate**, despite its other drawbacks. The higher logP and P-gp efflux might be mitigated with formulation strategies, but poor BBB penetration is harder to overcome.

Output:
1
2025-04-17 04:12:41,347 - INFO - Batch 93 complete. Total preferences: 1488
2025-04-17 04:12:41,347 - INFO - Processing batch 94/512...
2025-04-17 04:13:24,129 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (348.443 and 348.531 Da) fall comfortably within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (59.08) is better than Ligand B (49.41). Both are below the 90 A^2 threshold desirable for CNS targets, which is excellent.

**3. logP:** Ligand A (0.919) is slightly below the optimal 1-3 range, but still acceptable. Ligand B (3.75) is within the optimal range.

**4. H-Bond Donors:** Ligand A (0) is preferable to Ligand B (1). Fewer HBDs generally improve permeability.

**5. H-Bond Acceptors:** Ligand A (4) is better than Ligand B (2). Both are below the 10 threshold.

**6. QED:** Ligand A (0.709) is better than Ligand B (0.536), indicating a more drug-like profile.

**7. DILI:** Ligand A (23.149) has a significantly lower DILI risk than Ligand B (14.075), which is a major advantage.

**8. BBB:** Ligand A (68.166) has a better BBB penetration percentile than Ligand B (58.162), although both are below the ideal >70 for CNS targets.

**9. Caco-2 Permeability:** Ligand A (-4.636) is much better than Ligand B (-4.72). Higher values indicate better absorption.

**10. Aqueous Solubility:** Ligand A (-1.425) is better than Ligand B (-3.733).

**11. hERG Inhibition:** Ligand A (0.389) is better than Ligand B (0.615), indicating a lower risk of cardiotoxicity.

**12. Microsomal Clearance:** Ligand A (33.596) has lower clearance than Ligand B (45.309), suggesting better metabolic stability.

**13. In vitro Half-Life:** Ligand A (5.931) has a longer half-life than Ligand B (-1.085), which is desirable.

**14. P-gp Efflux:** Ligand A (0.098) has lower P-gp efflux than Ligand B (0.463), which is crucial for CNS penetration.

**15. Binding Affinity:** Ligand B (0.0) has a better binding affinity than Ligand A (-8.6). This is a substantial difference.

**Overall Assessment:**

While Ligand B has a significantly better binding affinity, Ligand A demonstrates superior ADME properties across almost all parameters, particularly regarding safety (DILI, hERG) and CNS penetration (BBB, P-gp). The affinity difference is large enough to be considered, but the overall balance of properties favors Ligand A. The better ADME profile of Ligand A will likely translate to better *in vivo* efficacy, even with a slightly weaker initial binding affinity.

Output:
0
2025-04-17 04:13:24,129 - INFO - Reasoning:

Let's analyze Ligand A and Ligand B based on the provided guidelines, prioritizing GPCR-specific properties (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (354.491 and 341.371 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (67.87) is significantly better than Ligand B (101.53). For CNS targets, TPSA should be <=90, so Ligand A is preferable.

**logP:** Both ligands have good logP values (2.116 and 1.19), falling within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A (HBD=1, HBA=4) is better than Ligand B (HBD=2, HBA=6) in terms of balancing solubility and permeability.

**QED:** Both ligands have similar and acceptable QED values (0.678 and 0.701), indicating good drug-likeness.

**DILI:** Ligand A (21.908) has a much lower DILI risk than Ligand B (62.35). This is a significant advantage.

**BBB:** Ligand A (63.629) has a better BBB percentile than Ligand B (31.834). While >70 is desirable, 63.629 is still better than 31.834 for a CNS target like DRD2.

**Caco-2 Permeability:** Ligand A (-4.708) has a worse Caco-2 permeability than Ligand B (-5.351). However, this is less critical than BBB for CNS targets.

**Aqueous Solubility:** Ligand A (-1.721) has a worse aqueous solubility than Ligand B (-2.14). This is a minor drawback.

**hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.493 and 0.258).

**Microsomal Clearance:** Ligand A (26.728) has a higher microsomal clearance than Ligand B (18.4), suggesting lower metabolic stability.

**In vitro Half-Life:** Ligand B (17.514) has a longer in vitro half-life than Ligand A (10.534).

**P-gp Efflux:** Ligand A (0.158) has a lower P-gp efflux liability than Ligand B (0.027), which is favorable for CNS penetration.

**Binding Affinity:** Ligand B (-8.7) has a significantly stronger binding affinity than Ligand A (0). This is a substantial advantage.

**Overall Assessment:**

While Ligand B boasts a significantly better binding affinity, Ligand A has a much better safety profile (lower DILI), better BBB penetration, and lower P-gp efflux. The stronger affinity of Ligand B is a major plus, but the ADME properties of Ligand A are more favorable for CNS drug development. Given the importance of BBB penetration and minimizing off-target effects for CNS targets, and the substantial difference in DILI risk, Ligand A is the more promising candidate despite the weaker binding affinity. The affinity difference is large enough to potentially be optimized in subsequent rounds of medicinal chemistry.

Output:
0
2025-04-17 04:13:24,130 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (378.395) is slightly lower, which is generally favorable for permeability.

**TPSA:** Ligand A (139.8) is very good, being just at the threshold for good oral absorption and excellent for CNS penetration. Ligand B (59.81) is excellent, well below the 90 A^2 threshold for CNS targets.

**logP:** Ligand A (1.655) is optimal. Ligand B (4.082) is a bit high, potentially leading to solubility issues and off-target interactions.

**H-Bond Donors/Acceptors:** Ligand A (HBD=2, HBA=9) is acceptable. Ligand B (HBD=1, HBA=4) is also acceptable.

**QED:** Both ligands have good QED scores (A: 0.516, B: 0.682), indicating good drug-like properties.

**DILI:** Ligand A (99.069) has a very high DILI risk, which is a significant concern. Ligand B (56.185) has a moderate DILI risk, which is much better.

**BBB:** Ligand A (23.149) has a very poor BBB penetration score, making it unlikely to be effective for a CNS target like DRD2. Ligand B (55.138) has a better, though still not ideal, BBB score.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values, which is unusual and suggests poor permeability. However, these values are on a log scale, and the negative values indicate very low permeability.

**Aqueous Solubility:** Both ligands have negative solubility values, indicating very poor solubility.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (A: 0.347, B: 0.455).

**Microsomal Clearance:** Ligand A (19.387) has lower clearance than Ligand B (86.291), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand B (53.909) has a significantly longer half-life than Ligand A (14.009), which is desirable.

**P-gp Efflux:** Ligand A (0.089) has very low P-gp efflux, which is favorable for CNS penetration. Ligand B (0.56) has moderate P-gp efflux.

**Binding Affinity:** Both ligands have very similar and excellent binding affinities (-8.2 and -8.3 kcal/mol). The difference is negligible.

**Overall Assessment:**

Despite the similar binding affinities, Ligand B is the more promising candidate. Ligand A's extremely high DILI risk and very poor BBB penetration are major drawbacks for a CNS drug. While Ligand B has a moderate DILI risk and a less-than-ideal BBB score, its longer half-life and better metabolic stability are advantageous. The higher logP of Ligand B is a concern, but the difference in binding affinity is minimal, and the other ADME properties of Ligand B are superior.

Output:
1
2025-04-17 04:13:24,130 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (347.39 and 346.439 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (80.32) is significantly better than Ligand B (97.79). For CNS targets, we want TPSA <= 90, so Ligand A is preferable.

**3. logP:** Both ligands have similar logP values (0.814 and 0.874), which are within the optimal 1-3 range.

**4. H-Bond Donors:** Ligand A (2) is slightly higher than Ligand B (1), but both are acceptable (<=5).

**5. H-Bond Acceptors:** Ligand B (9) is higher than Ligand A (4). Both are within the acceptable limit of <=10, but A is better.

**6. QED:** Ligand B (0.823) has a slightly better QED score than Ligand A (0.682), indicating a more drug-like profile. However, the difference isn't substantial enough to be decisive.

**7. DILI:** Ligand B (29.818) has a much lower DILI risk than Ligand A (54.478). This is a significant advantage for Ligand B.

**8. BBB:** Ligand B (86.39) has a better BBB penetration percentile than Ligand A (79.411). Both are good (>70), but B is better for a CNS target like DRD2.

**9. Caco-2 Permeability:** Ligand A (-4.338) has better Caco-2 permeability than Ligand B (-5.659).

**10. Aqueous Solubility:** Ligand B (-1.193) has better aqueous solubility than Ligand A (-2.337).

**11. hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.206 and 0.136).

**12. Microsomal Clearance:** Ligand B (-4.598) has lower (better) microsomal clearance than Ligand A (30.678), indicating greater metabolic stability.

**13. In vitro Half-Life:** Ligand B (-6.789) has a longer in vitro half-life than Ligand A (-12.234).

**14. P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.037 and 0.025).

**15. Binding Affinity:** Both ligands have very similar and strong binding affinities (-7.7 and -7.9 kcal/mol). The difference is negligible.

**Overall Assessment:**

Ligand B is the stronger candidate. While Ligand A has slightly better Caco-2 permeability, Ligand B excels in several critical areas for a CNS-targeting GPCR: lower DILI risk, better BBB penetration, lower microsomal clearance (better metabolic stability), and longer in vitro half-life. The TPSA value for Ligand A is also more favorable. The similar binding affinities mean that the ADME advantages of Ligand B outweigh any minor differences in absorption.

Output:
1
2025-04-17 04:13:24,130 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B based on the provided guidelines, prioritizing GPCR-specific properties (BBB, logP, Pgp, TPSA, and affinity) for DRD2.

**Molecular Weight:** Both ligands (353.379 and 348.531 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (126.66) is better than Ligand B (49.41). For CNS targets, TPSA should be <= 90, and both meet this requirement, but A is closer to the upper limit, while B is significantly lower, suggesting potentially better CNS penetration.

**logP:** Ligand A (-0.795) is suboptimal, being below the preferred 1-3 range. Ligand B (3.624) is excellent, falling comfortably within the optimal range. This is a significant advantage for B.

**H-Bond Donors/Acceptors:** Ligand A (2 HBD, 7 HBA) and Ligand B (1 HBD, 2 HBA) both have acceptable numbers of H-bond donors and acceptors.

**QED:** Both ligands have similar and good QED values (0.627 and 0.647).

**DILI:** Ligand A (48.623) has a slightly higher DILI risk than Ligand B (15.936), but both are below the concerning threshold of 60.

**BBB:** Ligand B (85.033) has a much higher BBB percentile than Ligand A (57.193). This is a critical advantage for a CNS target like DRD2.

**Caco-2 Permeability:** Ligand A (-5.488) has poor Caco-2 permeability, while Ligand B (-4.495) is also poor, but slightly better.

**Aqueous Solubility:** Ligand A (-1.623) has poor aqueous solubility, while Ligand B (-3.871) is even worse.

**hERG Inhibition:** Ligand A (0.024) has very low hERG inhibition risk, while Ligand B (0.643) has a slightly higher, but still acceptable, risk.

**Microsomal Clearance:** Ligand A (11.731) has lower microsomal clearance (better metabolic stability) than Ligand B (81.906).

**In vitro Half-Life:** Ligand B (32.896) has a significantly longer in vitro half-life than Ligand A (12.45).

**P-gp Efflux:** Ligand A (0.006) has very low P-gp efflux liability, which is excellent for CNS penetration. Ligand B (0.295) has slightly higher P-gp efflux, but still relatively low.

**Binding Affinity:** Ligand B (-7.6 kcal/mol) has a slightly better binding affinity than Ligand A (-7.4 kcal/mol), though the difference is small.

**Overall Assessment:**

Ligand B is the stronger candidate. While Ligand A has better metabolic stability (lower Cl_mic) and lower P-gp efflux, Ligand B excels in the most critical areas for a CNS-targeting GPCR: logP, BBB penetration, and in vitro half-life. The slightly better affinity of Ligand B further supports this conclusion. The poor solubility and Caco-2 permeability of both compounds would need to be addressed in further optimization, but these are less critical than CNS penetration at this stage.

Output:
1
2025-04-17 04:13:24,130 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (357.479 and 389.493 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (49.05) is significantly better than Ligand B (62.3). For CNS targets, we want TPSA <= 90, and ideally closer to 60. Ligand A is much closer to this ideal.

**3. logP:** Both ligands have good logP values (3.751 and 2.855), falling within the optimal 1-3 range.

**4. H-Bond Donors:** Ligand A (0) is preferable to Ligand B (1). Fewer HBDs generally improve permeability.

**5. H-Bond Acceptors:** Both ligands have 5 HBA, which is acceptable (<=10).

**6. QED:** Both ligands have reasonable QED values (0.837 and 0.729), indicating good drug-like properties.

**7. DILI:** Ligand A (50.291) has a lower DILI risk than Ligand B (61.729), which is preferable. Both are acceptable, but lower is better.

**8. BBB:** Both ligands have excellent BBB penetration (86.08% and 82.241%), exceeding the desirable threshold of >70%.

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.226 and -5.062). This is unusual and suggests poor permeability. However, these values are on a log scale, and the absolute values are similar, so this isn't a major differentiator.

**10. Aqueous Solubility:** Both ligands have very poor aqueous solubility (-3.434 and -3.733). This is a significant concern for bioavailability.

**11. hERG Inhibition:** Ligand A (0.872) has a slightly higher hERG risk than Ligand B (0.537), but both are relatively low.

**12. Microsomal Clearance:** Ligand A (19.127) has a higher microsomal clearance than Ligand B (18.491), suggesting faster metabolism and lower metabolic stability. This is a negative for Ligand A.

**13. In vitro Half-Life:** Ligand B (-16.663) has a much longer in vitro half-life than Ligand A (40.519). This is a significant advantage for Ligand B.

**14. P-gp Efflux:** Ligand A (0.514) has lower P-gp efflux liability than Ligand B (0.173), which is preferable for CNS penetration.

**15. Binding Affinity:** Ligand A (-8.1 kcal/mol) has a significantly stronger binding affinity than Ligand B (-7.2 kcal/mol). This >1.5 kcal/mol difference is a major advantage for Ligand A, potentially outweighing some of its ADME drawbacks.

**Overall Assessment:**

Despite the poor solubility and Caco-2 permeability for both, Ligand A emerges as the more promising candidate. Its significantly stronger binding affinity (-8.1 vs -7.2 kcal/mol) is a crucial advantage for a GPCR target. It also has a lower DILI risk and lower P-gp efflux. While Ligand B has a better half-life and slightly lower hERG risk, the affinity difference is substantial. The TPSA of Ligand A is also more favorable. Given the CNS target, the good BBB penetration for both is helpful, but the stronger binding and lower P-gp efflux of Ligand A are more important.

Output:
0
2025-04-17 04:13:24,130 - INFO - Reasoning:

Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (425.689 Da) is slightly higher than Ligand B (386.283 Da), but both are acceptable.

**2. TPSA:** Ligand A (63.13) is significantly better than Ligand B (92.94). For CNS targets, we want TPSA <= 90, so Ligand A is much closer to the desired value.

**3. logP:** Both ligands have logP values within the optimal range (1-3), with Ligand A at 3.399 and Ligand B at 4.19. Ligand B is slightly higher, potentially increasing off-target effects, but still acceptable.

**4. H-Bond Donors:** Ligand A (1) is preferable to Ligand B (2). Lower HBD generally improves permeability.

**5. H-Bond Acceptors:** Ligand A (3) is preferable to Ligand B (5). Lower HBA generally improves permeability.

**6. QED:** Both ligands have similar QED values (0.82 and 0.769), indicating good drug-like properties.

**7. DILI:** Both ligands have similar DILI risk (74.176 and 78.402), and are within an acceptable range (<80).

**8. BBB:** This is a critical parameter for CNS targets. Ligand A has a BBB percentile of 78.984, which is very good. Ligand B has a significantly lower BBB percentile of 41.644, making it less likely to reach the target in the brain.

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.803 and -4.889). This is unusual and suggests poor intestinal absorption. However, for a CNS target, intestinal absorption is less critical than BBB penetration.

**10. Aqueous Solubility:** Both ligands have negative solubility values (-5.326 and -4.952), indicating poor aqueous solubility. This could pose formulation challenges.

**11. hERG Inhibition:** Ligand A (0.956) is preferable to Ligand B (0.081). Lower hERG inhibition is crucial to avoid cardiotoxicity.

**12. Microsomal Clearance:** Ligand A (29.759) has a lower (better) microsomal clearance than Ligand B (61.032), indicating better metabolic stability.

**13. In vitro Half-Life:** Ligand A (-15.392) has a negative half-life, which is unusual, but may indicate rapid metabolism. Ligand B (49.179) has a longer half-life.

**14. P-gp Efflux:** Ligand A (0.609) is preferable to Ligand B (0.029). Lower P-gp efflux is desirable for improved CNS exposure.

**15. Binding Affinity:** Ligand B (-9.0) has a significantly stronger binding affinity than Ligand A (-7.7). A 1.3 kcal/mol difference is substantial and could outweigh some of the ADME drawbacks.

**Overall Assessment:**

While Ligand B has a superior binding affinity, Ligand A is a more promising drug candidate due to its significantly better BBB penetration (78.984 vs. 41.644), lower TPSA (63.13 vs. 92.94), better hERG inhibition, and lower P-gp efflux. These factors are particularly important for a CNS-targeting GPCR like DRD2. The slightly longer half-life of Ligand B is a plus, but the poor BBB penetration is a major drawback. The negative solubility and Caco-2 values for both are concerning but less critical for a CNS drug.



Output:
0
2025-04-17 04:13:24,130 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (353.423 and 347.427 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Both ligands have TPSA values (133.63 and 130.04) that are acceptable for oral absorption (<=140), but slightly higher than optimal for CNS penetration (<=90).

**3. logP:** Ligand A (-0.766) is a bit low, potentially hindering permeation. Ligand B (-0.067) is better, falling within the acceptable range, but still on the lower side.

**4. H-Bond Donors:** Both ligands have 4 HBD, which is within the acceptable limit of <=5.

**5. H-Bond Acceptors:** Ligand A has 4 HBA, while Ligand B has 10. Ligand B is at the upper limit of acceptable HBA, potentially impacting permeability.

**6. QED:** Both ligands have reasonable QED values (0.32 and 0.466), indicating moderate drug-likeness.

**7. DILI:** Ligand A (23.885) has a significantly lower DILI risk than Ligand B (47.305), which is a major advantage.

**8. BBB:** Ligand A (71.888) has a much better BBB percentile than Ligand B (39.162). This is *critical* for a CNS target like DRD2.

**9. Caco-2:** Both have negative Caco-2 values (-5.736 and -5.782) which is unusual and suggests poor permeability.

**10. Solubility:** Both have negative solubility values (-1.289 and -1.252) which is also unusual and suggests poor solubility.

**11. hERG:** Both ligands have very low hERG inhibition risk (0.058 and 0.471).

**12. Cl_mic:** Ligand A (-8.685) has a much lower (better) microsomal clearance than Ligand B (3.775), indicating greater metabolic stability.

**13. t1/2:** Ligand A (-4.175) has a more negative in vitro half-life, which is unusual and suggests a very short half-life. Ligand B (1.891) is better, but still relatively short.

**14. Pgp:** Both ligands have very low Pgp efflux liability (0.003 and 0.002).

**15. Binding Affinity:** Ligand A (-7.6 kcal/mol) has a slightly better binding affinity than Ligand B (-6.7 kcal/mol). This 0.9 kcal/mol difference is significant, and can outweigh some ADME drawbacks.

**Overall Assessment:**

Given the GPCR-specific priorities, BBB penetration is paramount for DRD2. Ligand A has a significantly better BBB percentile (71.888) compared to Ligand B (39.162). Furthermore, Ligand A has a lower DILI risk and better metabolic stability (lower Cl_mic). While both have poor Caco-2 and solubility values, the superior BBB, DILI, Cl_mic, and slightly better affinity of Ligand A make it the more promising candidate.

Output:
1
2025-04-17 04:13:24,130 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (343.471 and 342.399 Da) fall comfortably within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (71.09) is significantly better than Ligand B (98.32). For CNS targets, we want TPSA <= 90, and A is much closer to this threshold.

**3. logP:** Ligand A (3.146) is optimal (1-3), while Ligand B (1.327) is on the lower end, potentially hindering permeation.

**4. H-Bond Donors:** Both have acceptable HBD counts (2 and 3 respectively), well below the limit of 5.

**5. H-Bond Acceptors:** Both have acceptable HBA counts (3 and 4 respectively), well below the limit of 10.

**6. QED:** Both ligands have good QED scores (0.747 and 0.78), indicating good drug-like properties.

**7. DILI:** Both have low DILI risk (27.336 and 62.35), but Ligand A is preferable.

**8. BBB:** Ligand A (59.287) is better than Ligand B (17.371), although neither are above the desirable 70% threshold for CNS targets. However, for a GPCR, maximizing BBB is crucial.

**9. Caco-2:** Ligand A (-4.938) and Ligand B (-5.421) both have negative values, which is unusual. These values are likely on a log scale, and lower values indicate lower permeability.

**10. Solubility:** Both ligands have poor aqueous solubility (-2.261 and -2.942).

**11. hERG:** Both ligands have very low hERG risk (0.237 and 0.253).

**12. Cl_mic:** Ligand B (-21.557) has a significantly *lower* (better) microsomal clearance than Ligand A (24.471), suggesting better metabolic stability.

**13. t1/2:** Both have similar in vitro half-lives (11.87 and 12.841 hours).

**14. Pgp:** Both have very low P-gp efflux liability (0.055 and 0.057).

**15. Binding Affinity:** Ligand A (-8.0) has a substantially stronger binding affinity than Ligand B (0.0). This is a critical advantage. A difference of >1.5 kcal/mol can outweigh other drawbacks.

**Overall Assessment:**

While Ligand B has better metabolic stability (lower Cl_mic), Ligand A is superior due to its significantly stronger binding affinity (-8.0 vs 0.0 kcal/mol), better TPSA (71.09 vs 98.32), and better BBB penetration (59.287 vs 17.371). The stronger binding affinity is a major advantage for a GPCR target. The slightly higher DILI risk for Ligand B is also a minor concern. The lower logP of Ligand B is a concern for brain penetration.

Output:
1
2025-04-17 04:13:24,130 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (347.375 and 345.374 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (111.79) is slightly above the optimal <90 for CNS targets, but still reasonable. Ligand B (75.44) is excellent, well below 90.

**logP:** Ligand A (-1.786) is a bit low, potentially hindering permeability. Ligand B (1.896) is within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A has 2 HBD and 7 HBA, which are acceptable. Ligand B has 1 HBD and 4 HBA, also acceptable.

**QED:** Both ligands have good QED scores (0.623 and 0.898), indicating drug-like properties.

**DILI:** Both ligands have low DILI risk (46.452 and 41.062), below the 60 threshold.

**BBB:** This is a crucial parameter for a CNS target. Ligand A has a BBB percentile of 16.479, which is quite low and concerning. Ligand B has a significantly better BBB percentile of 62.233, which is much more promising, though still not ideal (>70).

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.14 and -4.775), which is unusual and suggests poor permeability. This could be an artifact of the prediction method or indicate issues with the structures.

**Aqueous Solubility:** Both ligands have negative solubility values (-1.218 and -2.352), also unusual and potentially problematic.

**hERG:** Both ligands have very low hERG risk (0.017 and 0.426).

**Microsomal Clearance:** Ligand A has a very low (good) Cl_mic (-18.907), indicating high metabolic stability. Ligand B has a higher Cl_mic (12.641), suggesting faster metabolism.

**In vitro Half-Life:** Ligand A has a half-life of 5.044 hours, while Ligand B has a shorter half-life of 2.566 hours.

**P-gp Efflux:** Ligand A has very low P-gp efflux (0.009), which is desirable for CNS penetration. Ligand B has slightly higher P-gp efflux (0.033), but still relatively low.

**Binding Affinity:** Ligand B (-9.4 kcal/mol) has a significantly stronger binding affinity than Ligand A (-6.7 kcal/mol). This is a substantial difference (>1.5 kcal/mol advantage).

**Overall Assessment:**

Ligand B is the stronger candidate. While both have issues with predicted Caco-2 and solubility, Ligand B excels in the most crucial areas for a CNS GPCR target: significantly better BBB penetration, a much stronger binding affinity, and acceptable logP. The lower metabolic stability (higher Cl_mic) and shorter half-life of Ligand B are drawbacks, but could potentially be addressed through structural modifications. Ligand A's very poor BBB penetration is a major hurdle that is less likely to be overcome.

Output:
1
2025-04-17 04:13:24,131 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (374.547 Da) is slightly higher than Ligand B (344.499 Da), but both are acceptable.

**TPSA:** Ligand A (75.71) is higher than Ligand B (49.41). For CNS targets, we ideally want TPSA <= 90. Both are below this threshold, but Ligand B is significantly better.

**logP:** Ligand A (1.595) is within the optimal range (1-3). Ligand B (3.131) is at the higher end of the optimal range. Both are acceptable, but Ligand A might have a slight advantage in terms of potential off-target effects.

**H-Bond Donors/Acceptors:** Both ligands have 1 HBD, which is good. Ligand A has 5 HBA, while Ligand B has 2. Both are within the acceptable limits (<=10 and <=5 respectively). Ligand B is preferable here.

**QED:** Ligand A (0.74) has a better QED score than Ligand B (0.57), indicating a more drug-like profile.

**DILI:** Ligand A (8.53) has a much lower DILI risk than Ligand B (14.424). This is a significant advantage for Ligand A.

**BBB:** Ligand A (69.368) has a better BBB penetration percentile than Ligand B (61.38). While both are reasonably good, exceeding 70 is desirable for CNS targets, and Ligand A is closer.

**Caco-2 Permeability:** Ligand A (-4.806) has a worse Caco-2 permeability than Ligand B (-5.156). Lower values indicate poorer permeability.

**Aqueous Solubility:** Ligand A (-1.248) has better aqueous solubility than Ligand B (-3.683).

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.484 and 0.367 respectively).

**Microsomal Clearance:** Ligand A (5.058) has a lower microsomal clearance than Ligand B (47.406), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (-10.484) has a much longer in vitro half-life than Ligand B (-6.718).

**P-gp Efflux:** Ligand A (0.011) has significantly lower P-gp efflux liability than Ligand B (0.246), which is crucial for CNS penetration.

**Binding Affinity:** Ligand B (-7.3 kcal/mol) has a slightly better binding affinity than Ligand A (-8.0 kcal/mol). However, the difference is not substantial enough to outweigh the other significant advantages of Ligand A.

**Overall Assessment:**

Considering the GPCR-specific priorities, Ligand A is the better candidate. It has better BBB penetration, lower DILI risk, lower P-gp efflux, better metabolic stability (lower Cl_mic and longer t1/2), better aqueous solubility, and a superior QED score. While Ligand B has slightly better binding affinity and a lower TPSA, the advantages of Ligand A in ADME properties, particularly for a CNS target, are more critical.

Output:
1
2025-04-17 04:13:24,131 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (343.358 Da) is slightly lower, which could be beneficial for permeability.

**2. TPSA:** Ligand A (75.48) is significantly better than Ligand B (109). For a CNS target like DRD2, TPSA < 90 is preferred, and A is comfortably within that range, while B is above.

**3. logP:** Both ligands have acceptable logP values (A: 3.217, B: 1.151), falling within the 1-3 range. However, B is on the lower end, potentially hindering permeation.

**4. H-Bond Donors:** Ligand A (1) is better than Ligand B (3). Lower HBD generally improves permeability.

**5. H-Bond Acceptors:** Ligand A (4) is better than Ligand B (5). Lower HBA is also generally preferred for permeability.

**6. QED:** Both ligands have similar QED values (A: 0.686, B: 0.605), both above the 0.5 threshold, indicating good drug-like properties.

**7. DILI:** Ligand A (80.729) has a higher DILI risk than Ligand B (56.301). While both are below the concerning 60 threshold, B is preferable.

**8. BBB:** Ligand A (77.898) has a better BBB penetration percentile than Ligand B (52.579). For a CNS target, >70 is desirable, and A is closer to that mark. This is a crucial advantage for A.

**9. Caco-2 Permeability:** Ligand A (-4.727) has worse Caco-2 permeability than Ligand B (-5.505). Lower (more negative) values indicate lower permeability.

**10. Aqueous Solubility:** Ligand A (-4.7) has worse aqueous solubility than Ligand B (-2.587). Lower (more negative) values indicate lower solubility.

**11. hERG Inhibition:** Ligand A (0.805) has a higher hERG inhibition risk than Ligand B (0.191). B is significantly better here, minimizing cardiotoxicity concerns.

**12. Microsomal Clearance:** Ligand A (47.249) has higher microsomal clearance than Ligand B (24.871), meaning it's metabolized faster. B is preferable for metabolic stability.

**13. In vitro Half-Life:** Ligand A (43.594) has a shorter in vitro half-life than Ligand B (25.213). B is preferable for longer duration of action.

**14. P-gp Efflux:** Ligand A (0.42) has lower P-gp efflux than Ligand B (0.058). Lower P-gp efflux is better for CNS exposure.

**15. Binding Affinity:** Ligand B (-7.8) has a slightly better binding affinity than Ligand A (-8.7). While both are excellent, the 0.9 kcal/mol difference is significant.

**Overall Assessment:**

Despite Ligand B having slightly better affinity and lower DILI/hERG risk, Ligand A is the more promising candidate. The critical factors for a CNS GPCR target are BBB penetration and TPSA. Ligand A significantly outperforms Ligand B in both of these areas. While Ligand A has some drawbacks in solubility, permeability, and metabolic stability, these can potentially be addressed through further optimization. The superior BBB penetration and lower TPSA of Ligand A are likely to translate to better brain exposure and efficacy. The affinity difference, while present, is not large enough to overcome the ADME advantages of Ligand A.

Output:
1
2025-04-17 04:13:24,131 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 drug candidates, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (345.491 and 350.419 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (54.26) is significantly better than Ligand B (106.27). For CNS targets, we want TPSA <= 90, so Ligand A is much closer to this threshold. Ligand B is considerably higher, potentially hindering BBB penetration.

**3. logP:** Both ligands have good logP values (2.64 and 2.304), falling within the optimal 1-3 range.

**4. H-Bond Donors:** Ligand A (0) is preferable to Ligand B (2). Fewer HBDs generally improve permeability.

**5. H-Bond Acceptors:** Both ligands have 5 HBA, which is acceptable (<=10).

**6. QED:** Ligand A (0.646) has a better QED score than Ligand B (0.405), indicating a more drug-like profile.

**7. DILI:** Ligand A (12.796) has a much lower DILI risk than Ligand B (62.35). This is a significant advantage for Ligand A.

**8. BBB:** Ligand A (82.164) has a significantly better BBB penetration percentile than Ligand B (63.125). This is *critical* for a CNS target like DRD2. A value >70 is desirable, and Ligand A is closer.

**9. Caco-2 Permeability:** Ligand A (-5.082) and Ligand B (-4.817) are similar, and both are negative, indicating poor permeability.

**10. Aqueous Solubility:** Ligand A (-1.265) is slightly better than Ligand B (-3.238), but both are poor.

**11. hERG Inhibition:** Both ligands have similar, low hERG inhibition risk (0.299 and 0.383).

**12. Microsomal Clearance:** Ligand A (23.043) has a lower microsomal clearance than Ligand B (61.593), suggesting better metabolic stability.

**13. In vitro Half-Life:** Ligand B (23.821) has a longer half-life than Ligand A (3.222).

**14. P-gp Efflux:** Both ligands have similar, low P-gp efflux liability (0.153 and 0.185).

**15. Binding Affinity:** Ligand B (-7.5) has a slightly better binding affinity than Ligand A (-7.3), but the difference is relatively small (0.2 kcal/mol). Given the other significant advantages of Ligand A, this difference is unlikely to be decisive.

**Overall Assessment:**

Ligand A is clearly the more promising candidate. It excels in crucial properties for a CNS-targeting GPCR ligand: TPSA, BBB penetration, DILI risk, and metabolic stability. While Ligand B has slightly better affinity and half-life, the substantial advantages of Ligand A in ADME properties, particularly BBB and DILI, outweigh this minor difference in potency.

Output:
1
2025-04-17 04:13:24,131 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (350.5 and 368.5 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (55.89) is significantly better than Ligand B (67.43). For CNS targets, we want TPSA <= 90, and ideally closer to 60. Ligand A is much closer to this ideal.

**3. logP:** Ligand A (0.774) is a bit low, potentially hindering permeability, but still within an acceptable range. Ligand B (2.49) is better, falling within the optimal 1-3 range.

**4. H-Bond Donors:** Both have acceptable HBD counts (1 and 2, respectively), well below the limit of 5.

**5. H-Bond Acceptors:** Both ligands have 4 HBAs, which is acceptable (<=10).

**6. QED:** Both ligands have reasonable QED scores (0.737 and 0.646), indicating good drug-like properties.

**7. DILI:** Ligand A (2.792) has a much lower DILI risk than Ligand B (26.25). This is a significant advantage.

**8. BBB:** Both ligands have good BBB penetration (78.79% and 74.758%), exceeding the desirable threshold of 70% for CNS targets.

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.18 and -5.128). This is unusual and suggests poor permeability. However, these values are very similar, so it doesn't differentiate the two.

**10. Aqueous Solubility:** Ligand A (-0.648) is slightly better than Ligand B (-3.171), indicating better solubility.

**11. hERG Inhibition:** Both ligands have low hERG inhibition risk (0.458 and 0.463).

**12. Microsomal Clearance:** Ligand A (8.684) has a lower clearance than Ligand B (67.284), indicating better metabolic stability.

**13. In vitro Half-Life:** Ligand A (-1.709) has a negative half-life, which is not physically possible and likely indicates an issue with the data. Ligand B (19.55) has a reasonable half-life.

**14. P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.003 and 0.145).

**15. Binding Affinity:** Ligand A (-7.8 kcal/mol) has a slightly better binding affinity than Ligand B (-7.2 kcal/mol). While the difference is not huge (less than 1.5 kcal/mol), it's still a positive factor.

**Overall Assessment:**

Ligand A is superior despite the negative half-life value. It has a much lower DILI risk, better TPSA, better metabolic stability (lower Cl_mic), and slightly better binding affinity. While Ligand A's logP is a bit low, its overall profile is more favorable for a CNS-targeting drug. The negative half-life for Ligand A is a major concern, but the other advantages are significant. Ligand B's half-life is acceptable, but its higher DILI risk and worse TPSA make it less attractive.

Output:
0
2025-04-17 04:13:24,131 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (348.487 and 369.487 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (78.43) is significantly better than Ligand B (92.51). For CNS targets, we want TPSA <= 90, so Ligand A is preferable.

**3. logP:** Both ligands (2.439 and 2.253) are within the optimal 1-3 range.

**4. H-Bond Donors:** Ligand A (3) is slightly higher than Ligand B (1), but both are acceptable (<=5).

**5. H-Bond Acceptors:** Ligand A (3) is lower than Ligand B (5), both are acceptable (<=10).

**6. QED:** Both ligands have similar, good QED values (0.69 and 0.71).

**7. DILI:** Ligand A (20.9) has a much lower DILI risk than Ligand B (74.021). This is a significant advantage for Ligand A.

**8. BBB:** Ligand B (61.807) has a better BBB penetration percentile than Ligand A (44.979). While both are not ideal (>70 desirable), Ligand B is better in this regard.

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.717 and -4.895). This is unusual and suggests poor permeability. However, the values are similar.

**10. Aqueous Solubility:** Both ligands have negative solubility values (-3.182 and -3.523). This also suggests poor solubility. Again, the values are similar.

**11. hERG Inhibition:** Both ligands have low hERG inhibition liability (0.174 and 0.261), which is good.

**12. Microsomal Clearance:** Ligand B (93.358) has a much higher microsomal clearance than Ligand A (50.25). Lower clearance is preferred for better metabolic stability, favoring Ligand A.

**13. In vitro Half-Life:** Ligand A (-9.025) has a much longer in vitro half-life than Ligand B (-38.962). This is a significant advantage for Ligand A.

**14. P-gp Efflux:** Both ligands have low P-gp efflux liability (0.143 and 0.307), which is good.

**15. Binding Affinity:** Ligand A (-8.4 kcal/mol) has a slightly better binding affinity than Ligand B (-7.7 kcal/mol). While the difference is not huge, it's a positive for Ligand A.

**Overall Assessment:**

Considering the GPCR-specific priorities, Ligand A is the better candidate. It has a lower TPSA, significantly lower DILI risk, better metabolic stability (lower Cl_mic, longer t1/2), and slightly better binding affinity. While Ligand B has a better BBB score, the other advantages of Ligand A outweigh this. The poor Caco-2 and solubility values are concerning for both, but can be addressed through formulation strategies.

Output:
0
2025-04-17 04:13:24,132 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (349.431 and 357.445 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (94.66) is slightly above the preferred <90 for CNS targets, but still reasonable. Ligand B (43.86) is excellent, well below 90.

**logP:** Ligand A (0.75) is a bit low, potentially hindering permeability. Ligand B (2.155) is within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A has 3 HBD and 4 HBA, which are acceptable. Ligand B has 0 HBD and 3 HBA, also acceptable.

**QED:** Ligand A (0.748) has a good drug-likeness score. Ligand B (0.494) is lower, but not disqualifying.

**DILI:** Ligand A (37.418) shows a low risk of DILI. Ligand B (25.553) is even lower, indicating a very favorable safety profile.

**BBB:** This is crucial for a CNS target. Ligand A (22.644) has a poor BBB penetration percentile. Ligand B (90.074) is excellent, exceeding the desirable >70 threshold.

**Caco-2 Permeability:** Ligand A (-5.025) has poor Caco-2 permeability. Ligand B (-4.557) is also poor, but slightly better than A.

**Aqueous Solubility:** Both ligands have negative solubility values (-2.307 and -0.637), suggesting poor aqueous solubility. This is a concern for both.

**hERG Inhibition:** Ligand A (0.281) has a very low risk of hERG inhibition. Ligand B (0.73) is slightly higher, but still relatively low.

**Microsomal Clearance:** Ligand A (7.361) has a lower clearance, suggesting better metabolic stability. Ligand B (34.766) has a significantly higher clearance, indicating faster metabolism.

**In vitro Half-Life:** Ligand A (-6.518) has a very short half-life. Ligand B (-0.266) has a slightly longer half-life, but still short.

**P-gp Efflux:** Ligand A (0.047) has very low P-gp efflux, which is good for CNS penetration. Ligand B (0.084) also has low P-gp efflux.

**Binding Affinity:** Ligand A (-8.5 kcal/mol) has a significantly stronger binding affinity than Ligand B (-6.9 kcal/mol). This is a substantial advantage.

**Overall Assessment:**

Despite Ligand A's superior binding affinity, its poor BBB penetration and Caco-2 permeability are major drawbacks for a CNS-targeting drug. The low logP also contributes to potential permeability issues. Ligand B, while having a weaker affinity, possesses excellent BBB penetration, a favorable DILI profile, and acceptable P-gp efflux. The higher metabolic clearance and shorter half-life are concerns, but could potentially be addressed through structural modifications. Given the GPCR-specific priorities, particularly BBB penetration for CNS targets, Ligand B is the more promising candidate. The affinity difference, while significant, might be overcome with further optimization of Ligand B, whereas improving BBB penetration for Ligand A would be a much more difficult task.

Output:
1
2025-04-17 04:13:24,132 - INFO - Batch 94 complete. Total preferences: 1504
2025-04-17 04:13:24,132 - INFO - Processing batch 95/512...
2025-04-17 04:14:03,957 - INFO - Reasoning:

Let's analyze Ligand A and Ligand B against the provided guidelines, prioritizing GPCR-specific properties (BBB, logP, Pgp, TPSA, and affinity) for DRD2.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (462.309 Da) is higher, but still acceptable. Ligand B (341.411 Da) is lower, potentially aiding permeability.

**TPSA:** Ligand A (63.68) is better than Ligand B (74.69) as it is closer to the <90 A^2 threshold for CNS targets.

**logP:** Both ligands have good logP values (A: 3.294, B: 2.781), falling within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A (HBD=0, HBA=5) is better than Ligand B (HBD=2, HBA=4) in terms of minimizing potential permeability issues.

**QED:** Both ligands have good QED scores (A: 0.643, B: 0.9), indicating drug-like properties.

**DILI:** Ligand B (54.789) has a significantly lower DILI risk than Ligand A (79.527), which is a substantial advantage.

**BBB:** Both ligands have acceptable BBB penetration (A: 68.282, B: 66.848), but neither exceeds the desirable >70 threshold.

**Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and suggests potential issues with intestinal absorption. This is a concern for both.

**Aqueous Solubility:** Both have negative solubility values, which is also unusual and suggests poor solubility.

**hERG Inhibition:** Both ligands have similar, low hERG inhibition liability (A: 0.49, B: 0.491).

**Microsomal Clearance:** Ligand B (17.95) has significantly lower microsomal clearance than Ligand A (100.553), indicating better metabolic stability.

**In vitro Half-Life:** Ligand B (-26.898) has a much longer in vitro half-life than Ligand A (-3.107), which is a major advantage.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (A: 0.307, B: 0.095), which is good for CNS penetration. Ligand B is slightly better.

**Binding Affinity:** Ligand B (-10.3 kcal/mol) has a significantly stronger binding affinity than Ligand A (-8.1 kcal/mol). This is a crucial advantage, exceeding the >1.5 kcal/mol difference threshold.

**Overall Assessment:**

While Ligand A has a slightly better TPSA, Ligand B excels in several critical areas: DILI risk, metabolic stability (Cl_mic & t1/2), and, most importantly, binding affinity. The significantly stronger binding affinity of Ligand B (-10.3 vs -8.1 kcal/mol) can likely compensate for its slightly higher TPSA and lower QED. The lower DILI and improved metabolic stability are also significant benefits. Both have issues with Caco-2 and solubility, but these can potentially be addressed through formulation strategies. Given the GPCR target and the importance of CNS penetration, the improved ADME properties and superior affinity of Ligand B make it the more promising candidate.

Output:
1
2025-04-17 04:14:03,957 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (350.434 and 345.407 Da) fall within the ideal range of 200-500 Da.

**TPSA:** Ligand A (58.64) is excellent, well below the 90 A^2 threshold for CNS targets. Ligand B (97.94) is higher, but still potentially acceptable, though less ideal.

**logP:** Ligand A (1.991) is optimal. Ligand B (0.647) is a bit low, potentially hindering membrane permeability.

**H-Bond Donors:** Both ligands have 1 HBD, which is within the acceptable limit of <=5.

**H-Bond Acceptors:** Ligand A has 3 HBA, and Ligand B has 7 HBA, both within the acceptable limit of <=10.

**QED:** Both ligands have good QED scores (0.746 and 0.794, respectively), indicating drug-like properties.

**DILI:** Ligand A (32.842) has a lower DILI risk than Ligand B (62.001), which is approaching a higher risk category.

**BBB:** Ligand A (90.772) has significantly better predicted BBB penetration than Ligand B (71.772). This is a crucial advantage for a CNS target like DRD2.

**Caco-2 Permeability:** Ligand A (-4.394) has worse Caco-2 permeability than Ligand B (-5.171), but both are negative, indicating limited permeability.

**Aqueous Solubility:** Ligand A (-2.804) has better solubility than Ligand B (-2.38), although both are poor.

**hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.36 and 0.056, respectively).

**Microsomal Clearance:** Ligand A (35.585) has higher microsomal clearance than Ligand B (21.385), suggesting lower metabolic stability.

**In vitro Half-Life:** Ligand B (-0.516) has a slightly longer in vitro half-life than Ligand A (-15.167).

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.086 and 0.048, respectively), which is good for CNS penetration.

**Binding Affinity:** Ligand B (-8.1 kcal/mol) has a slightly better binding affinity than Ligand A (-7.8 kcal/mol). This 0.3 kcal/mol difference, while not huge, is a positive for Ligand B.

**Overall Assessment:**

Considering the GPCR-specific priorities, Ligand A is the more promising candidate. Its superior BBB penetration (90.772 vs 71.772) is a significant advantage for a CNS target. While Ligand B has slightly better affinity and half-life, the lower logP and higher DILI risk of Ligand B are concerning. The better TPSA and solubility of Ligand A also contribute to its favorability. The difference in binding affinity is not large enough to overcome the ADME advantages of Ligand A.

Output:
1
2025-04-17 04:14:03,958 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (345.4 & 365.5 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (80.76) is slightly higher than Ligand B (69.72). Both are below the 90 A^2 threshold desirable for CNS targets, but Ligand B is better.

**3. logP:** Both ligands have good logP values (1.587 & 1.063), falling within the optimal 1-3 range. Ligand B is slightly lower, which could slightly improve solubility.

**4. H-Bond Donors:** Both have 1 HBD, which is acceptable.

**5. H-Bond Acceptors:** Ligand A has 5 HBA, Ligand B has 4. Both are below the 10 threshold.

**6. QED:** Both ligands have high QED scores (0.847 & 0.809), indicating good drug-like properties.

**7. DILI:** Ligand A (41.411) has a slightly higher DILI risk than Ligand B (19.698). Both are below the concerning 60 percentile, but B is preferable.

**8. BBB:** This is critical for a CNS target. Ligand A has a BBB percentile of 77.898, while Ligand B is 65.839. Ligand A is significantly better here.

**9. Caco-2 Permeability:** Ligand A (-4.645) and Ligand B (-5.174) both have negative values, indicating poor permeability. This is a concern for both.

**10. Aqueous Solubility:** Both have poor solubility (-3.344 and -2.872).

**11. hERG:** Both ligands have very low hERG inhibition risk (0.24 & 0.207).

**12. Microsomal Clearance:** Ligand B (25.918) has a higher microsomal clearance than Ligand A (15.383), suggesting faster metabolism and lower metabolic stability.

**13. In vitro Half-Life:** Ligand A (-7.559) has a longer in vitro half-life than Ligand B (-4.673).

**14. P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.024 & 0.02).

**15. Binding Affinity:** Ligand A (-8.1 kcal/mol) has a slightly better binding affinity than Ligand B (-7.7 kcal/mol). While both are good, the 0.4 kcal/mol difference is notable.

**Overall Assessment:**

Ligand A is superior due to its significantly better BBB penetration (77.9% vs 65.8%), longer half-life, and slightly better binding affinity. While Ligand B has a lower DILI risk and slightly better TPSA, the BBB is the most critical factor for a CNS GPCR target like DRD2. The slightly better metabolic stability of Ligand A is also a plus. The poor Caco-2 and solubility are concerns for both, but can be addressed with formulation strategies.

Output:
1
2025-04-17 04:14:03,958 - INFO - Reasoning:

Let's analyze Ligand A and Ligand B based on the provided guidelines, prioritizing GPCR-specific properties (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (343.343 Da) is slightly lower, which could be beneficial for permeability, but both are acceptable.

**TPSA:** Ligand A (101.66) is better than Ligand B (110.28) as it is closer to the ideal <90 for CNS targets. Ligand B is still reasonably low.

**logP:** Ligand A (0.359) is quite low, potentially hindering permeation. Ligand B (1.007) is better, falling within the optimal 1-3 range. This is a significant advantage for Ligand B.

**H-Bond Donors/Acceptors:** Ligand A (0 HBD, 7 HBA) and Ligand B (2 HBD, 7 HBA) both have acceptable numbers of H-bond donors and acceptors.

**QED:** Both ligands have similar and good QED values (A: 0.79, B: 0.702), indicating good drug-like properties.

**DILI:** Ligand A (73.09) has a slightly higher DILI risk than Ligand B (63.746), but both are below the concerning threshold of 60.

**BBB:** Ligand A (61.807) and Ligand B (68.748) are both reasonably good, but below the desirable >70 for CNS targets. Ligand B is slightly better.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values, which is unusual and suggests poor permeability. However, the scale is not defined, so it's difficult to interpret.

**Aqueous Solubility:** Both ligands have negative solubility values, which is also unusual and suggests poor solubility.

**hERG:** Both ligands have very low hERG inhibition liability (A: 0.151, B: 0.219), which is excellent.

**Microsomal Clearance:** Ligand A (9.684) has significantly lower microsomal clearance than Ligand B (25.545), indicating better metabolic stability. This is a major advantage for Ligand A.

**In vitro Half-Life:** Ligand A (-5.228) has a slightly better (less negative) in vitro half-life than Ligand B (-6.2), suggesting better stability.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (A: 0.028, B: 0.024), which is favorable for CNS penetration.

**Binding Affinity:** Ligand A (-8.7 kcal/mol) has a stronger binding affinity than Ligand B (-8.2 kcal/mol). This 0.5 kcal/mol difference is significant, and could outweigh some ADME drawbacks.

**Overall Assessment:**

Ligand A has a better binding affinity and metabolic stability (lower Cl_mic, better t1/2). However, Ligand B has a much better logP, which is critical for CNS penetration, and a slightly better BBB score. The low logP of Ligand A is a significant concern. While the affinity difference is important, the ability to reach the target in the brain is paramount for a CNS-acting drug.

Considering the GPCR-specific priorities, the better logP and slightly improved BBB of Ligand B outweigh the slightly stronger binding affinity of Ligand A.

Output:
1
2025-04-17 04:14:03,958 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight (MW):** Both ligands (347.321 and 348.487 Da) fall comfortably within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (73.34) is slightly higher than Ligand B (62.55). Both are below the 90 A^2 threshold desirable for CNS targets, but Ligand B is preferable.

**3. logP:** Ligand A (2.56) is within the optimal 1-3 range. Ligand B (3.834) is at the higher end, potentially raising concerns about solubility and off-target effects, but still acceptable.

**4. H-Bond Donors (HBD):** Both ligands have 1 HBD, which is within the acceptable limit of <=5.

**5. H-Bond Acceptors (HBA):** Ligand A has 5 HBA, and Ligand B has 3. Both are below the limit of <=10.

**6. QED:** Both ligands have good QED scores (0.642 and 0.726, respectively), indicating drug-like properties.

**7. DILI:** Ligand A (76.58) has a higher DILI risk than Ligand B (28.887). This is a significant advantage for Ligand B.

**8. BBB:** Ligand A (87.67) has a slightly better BBB percentile than Ligand B (78.868), but both are reasonably good for CNS penetration.

**9. Caco-2 Permeability:** Ligand A (-4.678) has worse Caco-2 permeability than Ligand B (-4.204).

**10. Aqueous Solubility:** Ligand A (-3.172) has worse aqueous solubility than Ligand B (-3.525).

**11. hERG Inhibition:** Both ligands have low hERG inhibition risk (0.404 and 0.667, respectively).

**12. Microsomal Clearance:** Ligand A (31.176) has lower microsomal clearance than Ligand B (77.02), suggesting better metabolic stability.

**13. In vitro Half-Life:** Ligand B (74.597) has a significantly longer in vitro half-life than Ligand A (0.463), which is a major advantage.

**14. P-gp Efflux:** Ligand A (0.39) has lower P-gp efflux than Ligand B (0.588), suggesting better CNS exposure.

**15. Binding Affinity:** Ligand B (-7.1 kcal/mol) has a significantly stronger binding affinity than Ligand A (-9.3 kcal/mol). This is a crucial factor, especially for GPCRs, and a difference of 2.2 kcal/mol is substantial.

**Overall Assessment:**

While Ligand A has a slightly better BBB penetration and lower P-gp efflux, Ligand B excels in several critical areas. Its significantly lower DILI risk, longer half-life, and *much* stronger binding affinity outweigh the minor drawbacks in BBB and P-gp. The better solubility and Caco-2 permeability also contribute to its favorability. Given the GPCR-specific priorities, the superior binding affinity and safety profile of Ligand B make it the more promising drug candidate.

Output:
1
2025-04-17 04:14:03,958 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (362.411 and 368.455 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (95.86) is better than Ligand B (97.64). Both are below the 140 threshold for oral absorption and reasonably close to the 90 threshold for CNS targets, but A is preferable.

**3. logP:** Ligand A (0.506) is lower than the optimal 1-3 range, potentially hindering permeation. Ligand B (1.193) is closer to the ideal range. This favors Ligand B.

**4. H-Bond Donors:** Ligand A (1) is better than Ligand B (2). Lower HBD generally improves permeability.

**5. H-Bond Acceptors:** Ligand A (7) is better than Ligand B (5). Lower HBA generally improves permeability.

**6. QED:** Both ligands have similar and good QED values (0.832 and 0.814, respectively), indicating good drug-like properties.

**7. DILI:** Ligand A (53.315) has a lower DILI risk than Ligand B (64.831), which is preferable.

**8. BBB:** Ligand B (70.648) has a significantly better BBB penetration score than Ligand A (31.756). This is *critical* for a CNS target like DRD2, making Ligand B strongly favored.

**9. Caco-2 Permeability:** Ligand A (-4.767) has a worse Caco-2 permeability than Ligand B (-5.25). Lower values are worse.

**10. Aqueous Solubility:** Both have very poor aqueous solubility (-2.57 and -2.679). This is a concern for both, but not a deciding factor.

**11. hERG Inhibition:** Ligand A (0.18) has a lower hERG inhibition risk than Ligand B (0.543), which is preferable.

**12. Microsomal Clearance:** Ligand A (6.356) has a lower microsomal clearance than Ligand B (11.744), suggesting better metabolic stability. This favors Ligand A.

**13. In vitro Half-Life:** Ligand B (33.289) has a much longer in vitro half-life than Ligand A (-4.779), which is a significant advantage.

**14. P-gp Efflux:** Ligand A (0.087) has lower P-gp efflux than Ligand B (0.092), which is preferable.

**15. Binding Affinity:** Ligand B (-7.9) has a slightly better binding affinity than Ligand A (-8.2). While A is better, the difference is small.

**Overall Assessment:**

Ligand B is the stronger candidate. The *critical* advantage is its significantly higher BBB penetration (70.648 vs. 31.756). This outweighs the slightly better metabolic stability of Ligand A. The better half-life of Ligand B is also a significant plus. While Ligand A has some advantages in DILI and hERG, the CNS target necessitates prioritizing BBB penetration.

Output:
1
2025-04-17 04:14:03,958 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B based on the provided guidelines, prioritizing GPCR-specific properties (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (341.367 Da) is slightly lower, which could be beneficial for permeability, but both are acceptable.

**TPSA:** Ligand A (99.69) is better than Ligand B (67.23) as it is closer to the ideal range for CNS targets (<=90). Ligand B is still acceptable.

**logP:** Both ligands have acceptable logP values (A: 0.796, B: 2.619), falling within the 1-3 range. Ligand B is closer to the optimal range.

**H-Bond Donors/Acceptors:** Ligand A (HBD=2, HBA=6) and Ligand B (HBD=1, HBA=5) both have reasonable numbers of H-bond donors and acceptors, well within the guidelines.

**QED:** Both ligands have high QED scores (A: 0.838, B: 0.861), indicating good drug-like properties.

**DILI:** Both ligands have elevated DILI risk (A: 53.005, B: 58.434), but are still below the concerning threshold of 60.

**BBB:** Ligand B (52.617) has a significantly better BBB percentile than Ligand A (26.716). This is a *critical* advantage for a CNS target like DRD2.

**Caco-2 Permeability:** Ligand A (-4.904) has a more negative Caco-2 value, which is worse than Ligand B (-5.01).

**Aqueous Solubility:** Both ligands have very poor aqueous solubility (-2.316 and -3.095). This is a significant drawback for both.

**hERG Inhibition:** Both ligands have very low hERG inhibition risk (A: 0.233, B: 0.159).

**Microsomal Clearance:** Ligand A (-17.033) has a much lower (better) microsomal clearance than Ligand B (59.168), indicating greater metabolic stability.

**In vitro Half-Life:** Ligand B (66.848) has a significantly longer in vitro half-life than Ligand A (-14.33). This is a substantial advantage.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (A: 0.01, B: 0.139).

**Binding Affinity:** Ligand A (-9.5 kcal/mol) has a slightly better binding affinity than Ligand B (-8.3 kcal/mol). While both are excellent, the 1.2 kcal/mol difference is noteworthy.

**Overall Assessment:**

Ligand A has a better binding affinity and metabolic stability (lower Cl_mic). However, Ligand B demonstrates a significantly improved BBB penetration and a longer half-life, both crucial for CNS drug development. While solubility is poor for both, the superior BBB penetration of Ligand B outweighs the slightly better affinity of Ligand A, especially considering the target is DRD2 in the CNS.

Output:
1
2025-04-17 04:14:03,958 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (343.47 and 351.45 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (55.4) is excellent, well below the 90 A^2 threshold for CNS targets. Ligand B (89.35) is higher, but still potentially acceptable, though less ideal.

**logP:** Ligand A (3.81) is at the upper end of the optimal range (1-3), but still acceptable. Ligand B (0.96) is quite low, potentially hindering membrane permeability and CNS penetration.

**H-Bond Donors/Acceptors:** Both have 1 HBD, which is good. Ligand A has 3 HBA, and Ligand B has 6 HBA. Both are within the acceptable range of <=10, but Ligand B is higher.

**QED:** Both ligands have reasonable QED values (0.80 and 0.63), suggesting good drug-like properties.

**DILI:** Both ligands have low DILI risk (32.30 and 36.0), indicating minimal liver injury potential.

**BBB:** Ligand A has a significantly better BBB penetration percentile (71.0) than Ligand B (53.1). This is a crucial factor for a CNS target like DRD2.

**Caco-2 Permeability:** Ligand A (-4.31) has better Caco-2 permeability than Ligand B (-4.96), suggesting better intestinal absorption.

**Aqueous Solubility:** Ligand A (-4.61) has better aqueous solubility than Ligand B (-0.94).

**hERG Inhibition:** Ligand A (0.51) has a slightly higher hERG risk than Ligand B (0.02), but both are relatively low.

**Microsomal Clearance:** Ligand A (109.65) has higher microsomal clearance than Ligand B (29.63), suggesting faster metabolism and potentially lower in vivo exposure.

**In vitro Half-Life:** Ligand A (-18.34) has a shorter in vitro half-life than Ligand B (-0.85), which is less desirable.

**P-gp Efflux:** Ligand A (0.44) has lower P-gp efflux liability than Ligand B (0.02), which is favorable for CNS penetration.

**Binding Affinity:** Ligand B (-7.2 kcal/mol) has a slightly better binding affinity than Ligand A (-8.7 kcal/mol). However, the difference is not substantial enough to outweigh the significant ADME advantages of Ligand A.

**Conclusion:**

Considering the GPCR-specific priorities, Ligand A is the more promising candidate. Its superior BBB penetration, better logP, better Caco-2 permeability, better solubility, and lower P-gp efflux are critical for CNS drug development. While Ligand B has slightly better binding affinity, the ADME profile of Ligand A is significantly more favorable, especially for a CNS target.

Output:
1
2025-04-17 04:14:03,958 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (346.515 and 353.398 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (64.35) is excellent, well below the 90 A^2 threshold for CNS targets. Ligand B (101.53) is higher, but still reasonable, though less optimal for CNS penetration.

**logP:** Ligand A (4.117) is at the upper end of the optimal range (1-3) and could potentially cause solubility issues or off-target interactions. Ligand B (-0.146) is significantly below the optimal range, which is a major concern for permeability and CNS penetration.

**H-Bond Donors/Acceptors:** Ligand A (2 HBD, 3 HBA) is within acceptable limits. Ligand B (1 HBD, 5 HBA) is also acceptable.

**QED:** Both ligands have reasonable QED scores (0.862 and 0.737), indicating good drug-like properties.

**DILI:** Both ligands have acceptable DILI risk (31.524 and 39.511 percentile).

**BBB:** Ligand A (81.698%) has a very good BBB penetration score, exceeding the 70% threshold. Ligand B (68.941%) is lower, and while not terrible, it's less desirable for a CNS target.

**Caco-2 Permeability:** Ligand A (-4.597) has poor Caco-2 permeability. Ligand B (-5.162) also has poor Caco-2 permeability.

**Aqueous Solubility:** Both ligands have poor aqueous solubility (-4.5 and -1.217).

**hERG:** Ligand A (0.843) has a moderate hERG risk. Ligand B (0.074) has a very low hERG risk, which is a significant advantage.

**Microsomal Clearance:** Ligand A (68.881) has moderate clearance. Ligand B (-7.051) has negative clearance, which is unusual and suggests very high metabolic stability - a significant advantage.

**In vitro Half-Life:** Ligand A (30.176 hours) has a reasonable half-life. Ligand B (-4.276 hours) has a negative half-life, which is also unusual and likely indicates very high stability.

**P-gp Efflux:** Ligand A (0.435) has low P-gp efflux, which is good for CNS exposure. Ligand B (0.016) has very low P-gp efflux, an even greater advantage.

**Binding Affinity:** Both ligands have excellent binding affinity (-8.0 and -7.5 kcal/mol). The difference of 0.5 kcal/mol is not substantial enough to outweigh other factors.

**Overall Assessment:**

Ligand B is the stronger candidate. While its logP is a concern, its superior BBB penetration, extremely low hERG risk, negative clearance and half-life, and very low P-gp efflux are compelling advantages for a CNS-targeting GPCR like DRD2. Ligand A's higher logP and poor Caco-2 permeability are drawbacks. The negative clearance and half-life for Ligand B are unusual but indicate exceptional metabolic stability.



Output:
1
2025-04-17 04:14:03,958 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (336.479 and 344.415 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (32.34) is excellent, well below the 90 A^2 threshold for CNS targets. Ligand B (67.67) is still reasonable but higher, potentially impacting BBB penetration slightly.

**logP:** Ligand A (4.714) is a bit high, potentially leading to solubility issues or off-target interactions. Ligand B (0.925) is on the lower side, which could hinder membrane permeability.

**H-Bond Donors/Acceptors:** Ligand A has 1 HBD and 1 HBA, which is favorable. Ligand B has 0 HBD and 5 HBA, also acceptable.

**QED:** Both ligands have reasonable QED values (0.861 and 0.765), indicating good drug-like properties.

**DILI:** Both ligands have acceptable DILI risk (39.628 and 46.064), below the 60 threshold.

**BBB:** Both ligands have high BBB penetration (85.615 and 83.637), which is crucial for a CNS target like DRD2.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.41 and -4.391), which is unusual and could indicate issues with intestinal absorption. However, these values are close and may not be significantly different.

**Aqueous Solubility:** Both ligands have very poor aqueous solubility (-5.368 and -2.155). This is a significant concern.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.929 and 0.378).

**Microsomal Clearance:** Ligand A (75.057) has higher clearance than Ligand B (60.929), suggesting lower metabolic stability.

**In vitro Half-Life:** Ligand B (-22.568) has a negative half-life, which is not physically possible and indicates a potential issue with the data or the assay. Ligand A (35.693) has a reasonable half-life.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.619 and 0.087), which is good for CNS exposure.

**Binding Affinity:** Both ligands have the same strong binding affinity (-9 kcal/mol).

**Overall Assessment:**

Ligand A has a better TPSA and a more reasonable (though still not ideal) logP. Its half-life is also more plausible. Ligand B has slightly better metabolic stability (lower Cl_mic), but its negative half-life is a major red flag. Both have poor solubility, but this might be addressed with formulation strategies. Given the importance of BBB penetration for a CNS target and the strong binding affinity of both, the better ADME profile of Ligand A, particularly the plausible half-life, makes it the more promising candidate.

Output:
1
2025-04-17 04:14:03,958 - INFO - Reasoning:

Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (381.223 and 343.431 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (99.25) is slightly above the preferred <90 for CNS targets, while Ligand B (71.33) is well within the range. This favors Ligand B.

**3. logP:** Ligand A (3.059) is optimal, while Ligand B (1.523) is a bit low, potentially impacting permeability.

**4. H-Bond Donors:** Ligand A (3) is acceptable, and Ligand B (0) is also good.

**5. H-Bond Acceptors:** Both ligands (A: 5, B: 5) are within the acceptable limit of <=10.

**6. QED:** Both ligands have good QED scores (A: 0.707, B: 0.764), indicating drug-like properties.

**7. DILI:** Ligand A (97.829) has a very high DILI risk, which is a significant concern. Ligand B (55.758) has a moderate risk, which is much more acceptable.

**8. BBB:** Ligand B (71.811) has a good BBB percentile, exceeding the 70% threshold for CNS targets. Ligand A (60.876) is below this threshold. This is a major advantage for Ligand B.

**9. Caco-2 Permeability:** Both have negative Caco-2 values (-4.784 and -4.756), which is unusual and suggests poor permeability. However, these values are on a scale where negative values are possible, and direct comparison is difficult without knowing the scale's specifics.

**10. Aqueous Solubility:** Both ligands have very poor aqueous solubility (-5.15 and -1.975). This is a concern for both, but might be mitigated by formulation strategies.

**11. hERG Inhibition:** Both ligands have very low hERG inhibition risk (A: 0.116, B: 0.154).

**12. Microsomal Clearance:** Ligand A (10.783) has lower clearance, indicating better metabolic stability than Ligand B (56.088).

**13. In vitro Half-Life:** Ligand A (20.454) has a longer half-life than Ligand B (-13.8). The negative value for B is concerning and likely indicates very rapid degradation.

**14. P-gp Efflux:** Both ligands have very low P-gp efflux liability (A: 0.033, B: 0.152), which is favorable for CNS penetration.

**15. Binding Affinity:** Both ligands have excellent binding affinities (A: -9.5 kcal/mol, B: -8.5 kcal/mol). Ligand A is slightly better, with a 1 kcal/mol advantage.

**Overall Assessment:**

Despite Ligand A having slightly better binding affinity and metabolic stability, the extremely high DILI risk and lower BBB penetration are major drawbacks. Ligand B, while having a slightly lower affinity and worse metabolic stability, exhibits a much better safety profile (lower DILI) and significantly better BBB penetration, which is crucial for a CNS target like DRD2. The negative Caco-2 and solubility values are concerning for both, but the other advantages of Ligand B outweigh these issues.

Output:
1
2025-04-17 04:14:03,959 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (393.412 Da) is slightly higher than Ligand B (346.515 Da), but both are acceptable.

**TPSA:** Ligand A (88.16) is closer to the ideal range for CNS targets (<=90), while Ligand B (49.41) is well within this range. This favors Ligand B.

**logP:** Both ligands have good logP values (Ligand A: 2.294, Ligand B: 3.676), falling within the optimal 1-3 range. Ligand B is slightly higher, potentially leading to some solubility concerns, but still acceptable.

**H-Bond Donors/Acceptors:** Ligand A has 2 HBD and 6 HBA, while Ligand B has 1 HBD and 2 HBA. Both are within acceptable limits (<=5 HBD and <=10 HBA).

**QED:** Both ligands have similar QED values (Ligand A: 0.786, Ligand B: 0.772), indicating good drug-like properties.

**DILI:** Ligand A has a significantly higher DILI risk (88.251%) compared to Ligand B (19.969%). This is a major concern for Ligand A.

**BBB:** Ligand B has a much better BBB penetration percentile (81.388%) than Ligand A (53.742%). This is crucial for a CNS target like DRD2 and strongly favors Ligand B.

**Caco-2 Permeability:** Ligand A (-5.249) has a negative value, which is unusual and suggests poor permeability. Ligand B (-4.72) is also negative, but less so.

**Aqueous Solubility:** Both ligands have poor aqueous solubility (-3.144 and -4.175, respectively). This could pose formulation challenges.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.258 and 0.299, respectively).

**Microsomal Clearance:** Ligand B has a significantly higher microsomal clearance (54.863) than Ligand A (13.883), indicating faster metabolism and potentially lower in vivo exposure. This favors Ligand A.

**In vitro Half-Life:** Ligand A has a much longer in vitro half-life (54.995 hours) than Ligand B (-19.271 hours). This is a significant advantage for Ligand A.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.238 and 0.199, respectively).

**Binding Affinity:** Ligand A (-8.7 kcal/mol) has a stronger binding affinity than Ligand B (-7.2 kcal/mol). This is a substantial difference (1.5 kcal/mol) and a major advantage for Ligand A.

**Overall Assessment:**

Despite Ligand A's superior binding affinity and longer half-life, its significantly higher DILI risk and poorer BBB penetration are major drawbacks. Ligand B, while having a slightly weaker affinity, exhibits a much better safety profile (lower DILI) and significantly better BBB penetration, which is critical for a CNS-targeting drug. The Caco-2 permeability is poor for both, but the other factors outweigh this.

Output:
1
2025-04-17 04:14:03,959 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 drug candidates, considering the provided guidelines and GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight (MW):** Both ligands (358.467 and 352.454 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (75.19) is better than Ligand B (76.14) as both are below the 90 A^2 threshold for CNS targets, but lower is preferred.

**3. logP:** Both ligands have acceptable logP values (2.659 and 3.147), falling within the optimal 1-3 range. Ligand B is slightly higher, which *could* be a minor concern for solubility, but isn't a dealbreaker.

**4. H-Bond Donors (HBD):** Both ligands are within the acceptable limit of <=5 (Ligand A: 1, Ligand B: 2).

**5. H-Bond Acceptors (HBA):** Both ligands are within the acceptable limit of <=10 (Ligand A: 6, Ligand B: 5).

**6. QED:** Both ligands have good QED scores (0.823 and 0.714), indicating good drug-like properties.

**7. DILI:** Ligand B (51.338) has a significantly lower DILI risk than Ligand A (73.129), making it more favorable from a safety perspective.

**8. BBB:** Ligand B (87.088) has a substantially higher BBB penetration percentile than Ligand A (79.139). This is *critical* for a CNS target like DRD2.

**9. Caco-2 Permeability:** Ligand A (-5.272) has better Caco-2 permeability than Ligand B (-4.306), indicating potentially better intestinal absorption. However, for a CNS target, intestinal absorption is less critical than BBB penetration.

**10. Aqueous Solubility:** Both ligands have very poor aqueous solubility (-3.126 and -3.91). This is a significant drawback for both, but could be mitigated with formulation strategies.

**11. hERG Inhibition:** Both ligands have low hERG inhibition risk (0.532 and 0.52).

**12. Microsomal Clearance:** Ligand A (60.545) has lower microsomal clearance than Ligand B (84.457), suggesting better metabolic stability.

**13. In vitro Half-Life:** Ligand B (-4.708) has a longer in vitro half-life than Ligand A (2.698), which is desirable.

**14. P-gp Efflux:** Both ligands have similar low P-gp efflux liability (0.122 and 0.21).

**15. Binding Affinity:** Both ligands have excellent binding affinity (-8.1 and -8.2 kcal/mol). The difference is negligible.

**Overall Assessment:**

While Ligand A has slightly better Caco-2 permeability and microsomal clearance, Ligand B is significantly better in the most important areas for a CNS GPCR target: **BBB penetration and DILI risk**. The higher BBB score for Ligand B is a major advantage, as it suggests better CNS exposure. The lower DILI risk is also a significant safety benefit. The longer half-life of Ligand B is also a plus. The solubility issues are a concern for both, but can potentially be addressed.

Output:
1
2025-04-17 04:14:03,959 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (346.39 and 345.49 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (125.36) is slightly above the optimal <90 for CNS targets, but still reasonable. Ligand B (54.34) is excellent, well below 90.

**logP:** Ligand A (-0.569) is a bit low, potentially hindering permeability. Ligand B (3.282) is within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A has 3 HBD and 4 HBA, acceptable. Ligand B has 1 HBD and 3 HBA, also acceptable.

**QED:** Both ligands have good QED scores (0.631 and 0.805), indicating good drug-like properties.

**DILI:** Both ligands have similar, moderate DILI risk (35.83 and 38.89), below the concerning threshold of 60.

**BBB:** This is crucial for a CNS target. Ligand A has 46.76% BBB penetration, which is not ideal. Ligand B has a much better 71.50% BBB penetration, exceeding the desirable >70% threshold.

**Caco-2 Permeability:** Ligand A (-5.849) and Ligand B (-4.669) both have negative values, which is unusual and suggests poor permeability. However, the scale is not specified, so it's difficult to interpret.

**Aqueous Solubility:** Both ligands have poor aqueous solubility (-2.643 and -3.628). This could pose formulation challenges.

**hERG Inhibition:** Both ligands show low hERG inhibition risk (0.126 and 0.469).

**Microsomal Clearance:** Ligand A (-17.36) suggests good metabolic stability (negative value implies slow clearance). Ligand B (58.59) indicates faster clearance, which is less desirable.

**In vitro Half-Life:** Ligand A (-14.79) suggests a longer half-life. Ligand B (11.19) has a shorter half-life.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.013 and 0.299), which is excellent for CNS penetration.

**Binding Affinity:** Both ligands have similar binding affinities (-8.5 and -8.3 kcal/mol), which are both excellent and well below the -7.0 threshold. The difference is minimal.

**Conclusion:**

Considering the GPCR-specific priorities, Ligand B is the more promising candidate. While both have good affinity and low P-gp efflux, Ligand B significantly outperforms Ligand A in BBB penetration (71.5% vs 46.8%) and has a better logP value (3.28 vs -0.57). Although Ligand A has better metabolic stability and half-life, the superior BBB penetration of Ligand B is paramount for a CNS-targeting drug like a DRD2 ligand. The slightly better logP of Ligand B also contributes to better permeability.

Output:
1
2025-04-17 04:14:03,959 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (358.389 and 349.431 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (76.46) is better than Ligand B (84.67). Both are below the 90 A^2 threshold for CNS targets, but A is closer to the optimal range.

**3. logP:** Both ligands have acceptable logP values (1.055 and 1.767), falling within the 1-3 range.

**4. H-Bond Donors:** Both have 1 HBD, which is within the acceptable limit of <=5.

**5. H-Bond Acceptors:** Both have 5 HBA, also within the acceptable limit of <=10.

**6. QED:** Both ligands have good QED scores (0.754 and 0.895), indicating good drug-like properties.

**7. DILI:** Both have relatively low DILI risk (37.65 and 40.83), both below the 40 threshold.

**8. BBB:** Both ligands have excellent BBB penetration (78.635 and 77.705), which is crucial for a CNS target like DRD2.

**9. Caco-2 Permeability:** Both have negative Caco-2 values (-4.52 and -4.682), which is unusual and suggests poor permeability. This is a significant drawback.

**10. Aqueous Solubility:** Both have negative solubility values (-1.727 and -1.706), which is also a concern.

**11. hERG Inhibition:** Both have very low hERG inhibition risk (0.269 and 0.231).

**12. Microsomal Clearance:** Ligand A (20.464) has lower microsomal clearance than Ligand B (46.74), indicating better metabolic stability.

**13. In vitro Half-Life:** Ligand A (-43.268) has a more negative half-life, which is unexpected and likely indicates a very short half-life. Ligand B (-25.594) is better, but still not ideal.

**14. P-gp Efflux:** Both have low P-gp efflux liability (0.049 and 0.071).

**15. Binding Affinity:** Ligand B (-9.3 kcal/mol) has a significantly better binding affinity than Ligand A (-8.3 kcal/mol). This 1.0 kcal/mol difference is substantial and could outweigh some of the ADME drawbacks.

**Overall Assessment:**

Despite the poor Caco-2 and solubility values for both, Ligand B is the more promising candidate. The significantly stronger binding affinity (-9.3 vs -8.3 kcal/mol) is a major advantage for a GPCR target. While Ligand A has slightly better TPSA and Cl_mic, the affinity difference is more critical. The BBB penetration is good for both, satisfying a key requirement for CNS activity. The negative Caco-2 and solubility values are concerning and would require further investigation (e.g., salt formation, prodrug strategies) but are not immediately disqualifying given the strong affinity.

Output:
1
2025-04-17 04:14:03,960 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (346.475) is slightly lower, which is generally favorable for permeability.

**TPSA:** Ligand A (67.23) is better than Ligand B (41.57). For CNS targets, TPSA should be <= 90, both are well within this range, but A is slightly higher.

**logP:** Both ligands have good logP values (A: 1.918, B: 2.904), falling within the optimal 1-3 range. Ligand B is closer to the upper end, which could potentially lead to solubility issues, but is still acceptable.

**H-Bond Donors/Acceptors:** Both have 1 HBD and 4 HBA, which are within acceptable limits.

**QED:** Both ligands have good QED scores (A: 0.578, B: 0.799), indicating a generally drug-like profile. Ligand B is better here.

**DILI:** Ligand A (22.528) has a significantly lower DILI risk than Ligand B (36.138), which is a major advantage.

**BBB:** Ligand B (91.276) has a much higher BBB penetration percentile than Ligand A (53.083). This is *critical* for a CNS target like DRD2.

**Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and suggests poor permeability. However, the scale isn't specified, so it's hard to interpret.

**Aqueous Solubility:** Both have negative solubility values, indicating poor solubility.

**hERG:** Both ligands have low hERG inhibition liability (A: 0.226, B: 0.796), which is good.

**Microsomal Clearance:** Ligand A (29.13) has lower microsomal clearance than Ligand B (61.841), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand B (35.177) has a longer in vitro half-life than Ligand A (-7.429). This is a positive for Ligand B.

**P-gp Efflux:** Ligand A (0.125) has lower P-gp efflux liability than Ligand B (0.169), which is beneficial for CNS penetration.

**Binding Affinity:** Ligand A (-8.1 kcal/mol) has a significantly stronger binding affinity than Ligand B (-6.5 kcal/mol). This is a substantial advantage, potentially outweighing some ADME drawbacks.

**Overall Assessment:**

Ligand A has a better safety profile (lower DILI), better metabolic stability (lower Cl_mic), and *much* stronger binding affinity. However, Ligand B has significantly better BBB penetration and a longer half-life. Given the CNS target, BBB is paramount. The affinity difference is 1.6 kcal/mol, which is significant, but the substantial improvement in BBB for Ligand B is likely to translate to greater *in vivo* efficacy. The poor solubility and permeability are concerning for both, but can be addressed with formulation strategies.

Output:
1
2025-04-17 04:14:03,960 - INFO - Batch 95 complete. Total preferences: 1520
2025-04-17 04:14:03,960 - INFO - Processing batch 96/512...
2025-04-17 04:14:45,558 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 drug candidates, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (353.5 and 363.5 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (81.67) is better than Ligand B (62.74). Both are below the 90 A^2 threshold for CNS targets, but A is slightly higher and may present a minor permeability issue.

**logP:** Ligand A (1.423) and Ligand B (2.168) are both within the optimal 1-3 range.

**H-Bond Donors:** Ligand A (3) is acceptable, while Ligand B (0) is also good.

**H-Bond Acceptors:** Ligand A (4) and Ligand B (5) are both acceptable, below the 10 threshold.

**QED:** Ligand A (0.675) is slightly better than Ligand B (0.594), both are above the 0.5 threshold.

**DILI:** Ligand A (5.855) is significantly better than Ligand B (63.746). Ligand B's DILI risk is high (>60).

**BBB:** Ligand B (68.864) is better than Ligand A (55.952), but both are below the desirable >70 for CNS targets. This is a critical factor for DRD2.

**Caco-2 Permeability:** Ligand A (-5.059) is worse than Ligand B (-4.62). Lower values suggest poorer permeability.

**Aqueous Solubility:** Ligand A (-1.505) is better than Ligand B (-2.05).

**hERG:** Ligand A (0.174) is better than Ligand B (0.476), indicating lower cardiotoxicity risk.

**Microsomal Clearance:** Ligand A (-3.886) is much better than Ligand B (69.994), suggesting significantly improved metabolic stability.

**In vitro Half-Life:** Ligand A (-9.285) is better than Ligand B (-5.821), indicating a longer half-life.

**P-gp Efflux:** Ligand A (0.017) is significantly better than Ligand B (0.51), suggesting lower efflux and better CNS exposure.

**Binding Affinity:** Ligand B (-8.2) has a stronger binding affinity than Ligand A (-7.2) by 1 kcal/mol. This is a substantial difference.

**Overall Assessment:**

Ligand B has a better binding affinity and BBB penetration, which are crucial for a CNS target like DRD2. However, its high DILI risk and very high microsomal clearance are major concerns. Ligand A has a much better safety profile (DILI, hERG) and superior metabolic stability (Cl_mic, t1/2) and P-gp efflux. While its BBB penetration and Caco-2 permeability are not ideal, the significant advantage in safety and metabolic stability, combined with acceptable binding affinity, makes it the more promising candidate. The 1 kcal/mol difference in binding affinity can potentially be addressed through further optimization, while mitigating the DILI and clearance issues of Ligand B would be far more challenging.

Output:
0
2025-04-17 04:14:45,559 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (405.38 and 380.535 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (32.34) is excellent, well below the 90 A^2 threshold for CNS targets. Ligand B (73.66) is higher, but still potentially acceptable, though less ideal.

**3. logP:** Ligand A (4.323) is slightly high, potentially leading to solubility issues or off-target interactions. Ligand B (3.802) is better, falling comfortably within the 1-3 range.

**4. H-Bond Donors:** Both have acceptable HBD counts (1 and 2, respectively), well below the 5 limit.

**5. H-Bond Acceptors:** Ligand A (2) is good. Ligand B (6) is higher, but still within the acceptable limit of 10.

**6. QED:** Both ligands have similar and good QED values (0.791 and 0.774), indicating good drug-like properties.

**7. DILI:** Ligand A (14.618) has a significantly lower DILI risk than Ligand B (51.028). This is a substantial advantage for Ligand A.

**8. BBB:** Ligand A (89.492) has a much higher BBB penetration percentile than Ligand B (54.478). This is *critical* for a CNS target like DRD2.

**9. Caco-2 Permeability:** Both have negative Caco-2 values (-5.195 and -4.832), which is unusual and suggests poor permeability. However, these values are on a log scale and can be difficult to interpret directly without knowing the base of the log.

**10. Aqueous Solubility:** Both have negative solubility values (-3.678 and -4.335), indicating poor aqueous solubility. This is a concern, especially given Ligand A's higher logP.

**11. hERG Inhibition:** Both ligands have low hERG inhibition risk (0.918 and 0.411).

**12. Microsomal Clearance:** Ligand A (10.413) has a lower microsomal clearance than Ligand B (45.084), suggesting better metabolic stability.

**13. In vitro Half-Life:** Ligand A (13.823) has a shorter half-life than Ligand B (26.632), but both are reasonable.

**14. P-gp Efflux:** Ligand A (0.411) has lower P-gp efflux liability than Ligand B (0.559), which is favorable for CNS penetration.

**15. Binding Affinity:** Ligand A (-10.2 kcal/mol) has *significantly* stronger binding affinity than Ligand B (-0.0 kcal/mol). This is a decisive advantage, easily outweighing any minor ADME drawbacks.

**Overall Assessment:**

Ligand A is the superior candidate. Its significantly higher binding affinity, coupled with better BBB penetration, lower DILI risk, lower P-gp efflux, and better metabolic stability, make it a much more promising drug candidate for targeting DRD2. While both ligands have solubility and permeability concerns (indicated by negative Caco-2 and solubility values), the strong binding affinity of Ligand A suggests that these issues might be mitigated through formulation strategies. Ligand B's weak binding affinity makes it unlikely to be a viable candidate, regardless of its other properties.

Output:
1
2025-04-17 04:14:45,559 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (348.403 and 351.407 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (102.32) is better than Ligand B (107.77), both are reasonably close to the 90 A^2 threshold for CNS targets, but A is preferable.

**logP:** Ligand A (-0.155) is slightly below the optimal 1-3 range, potentially hindering permeability. Ligand B (-1.576) is also below the optimal range and even lower, raising more concerns about permeability.

**H-Bond Donors/Acceptors:** Both have 2 HBD and 6-7 HBA, which are within acceptable limits.

**QED:** Both ligands have similar QED values (0.636 and 0.614), indicating good drug-likeness.

**DILI:** Ligand A (59.907) has a higher DILI risk than Ligand B (30.361). This is a significant advantage for Ligand B.

**BBB:** Ligand A (47.809) has a better BBB penetration percentile than Ligand B (21.287). This is a crucial factor for a CNS target like DRD2, and favors Ligand A.

**Caco-2 Permeability:** Both have very poor Caco-2 permeability (-5.31 and -5.347).

**Aqueous Solubility:** Both have very poor aqueous solubility (-1.947 and 0.048).

**hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.084 and 0.073).

**Microsomal Clearance:** Ligand A (3.687) has significantly better metabolic stability (lower clearance) than Ligand B (-27.38). This is a major advantage for Ligand A.

**In vitro Half-Life:** Ligand A (8.184) has a longer half-life than Ligand B (6.182).

**P-gp Efflux:** Both ligands show very low P-gp efflux liability (0.024 and 0.005).

**Binding Affinity:** Ligand A (-7.9 kcal/mol) has slightly better binding affinity than Ligand B (-7.6 kcal/mol). While the difference is not huge, it's still a positive for Ligand A.

**Overall Assessment:**

Ligand A excels in BBB penetration, metabolic stability (Cl_mic), in vitro half-life, and binding affinity. Ligand B has a lower DILI risk. However, given the CNS target (DRD2), BBB penetration is paramount. The slightly better affinity and significantly better BBB of Ligand A outweigh the lower DILI score of Ligand B. Both have poor solubility and permeability, which would need to be addressed in further optimization, but the pharmacokinetic profile of A is better suited for CNS penetration.

Output:
1
2025-04-17 04:14:45,559 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (349.431 and 348.447 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (84.67) is better than Ligand B (78.68) as it is closer to the ideal TPSA for CNS targets (<90). Both are well below the 140 threshold for oral absorption.

**3. logP:** Ligand A (2.248) is within the optimal range (1-3), while Ligand B (0.975) is slightly below, potentially hindering permeation.

**4. H-Bond Donors:** Both ligands have 1 HBD, which is acceptable (<=5).

**5. H-Bond Acceptors:** Both ligands have 5 HBA, which is acceptable (<=10).

**6. QED:** Ligand B (0.829) has a higher QED than Ligand A (0.629), indicating a more drug-like profile.

**7. DILI:** Ligand B (16.867) has a significantly lower DILI risk than Ligand A (49.399), making it safer.

**8. BBB:** Ligand A (67.701) has a better BBB penetration percentile than Ligand B (55.642), which is crucial for a CNS target like DRD2.

**9. Caco-2 Permeability:** Ligand A (-5.105) has a slightly better Caco-2 permeability than Ligand B (-5.281).

**10. Aqueous Solubility:** Ligand B (-0.556) has better aqueous solubility than Ligand A (-2.761).

**11. hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.18 and 0.228).

**12. Microsomal Clearance:** Ligand B (16.539) has a lower microsomal clearance than Ligand A (25.03), indicating better metabolic stability.

**13. In vitro Half-Life:** Ligand A (-5.177) has a longer in vitro half-life than Ligand B (0.135).

**14. P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.072 and 0.04).

**15. Binding Affinity:** Ligand B (-8.8 kcal/mol) has a significantly stronger binding affinity than Ligand A (-7.5 kcal/mol). The difference of 1.3 kcal/mol is substantial and can outweigh some ADME drawbacks.

**Overall Assessment:**

While Ligand A has better BBB penetration and half-life, Ligand B demonstrates superior characteristics in several critical areas: significantly higher binding affinity, lower DILI risk, better solubility, and improved metabolic stability. The stronger binding affinity of Ligand B is a major advantage, especially for a GPCR target. The slightly lower BBB value for Ligand B is less concerning given the strong affinity and other favorable properties.

Output:
1
2025-04-17 04:14:45,559 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (416.159 Da) is slightly higher, but acceptable. Ligand B (344.342 Da) is also good.

**TPSA:** Ligand A (113.56) is approaching the upper limit for CNS targets (<=90), but still potentially acceptable given strong affinity. Ligand B (79.73) is well within the desired range for CNS penetration.

**logP:** Both ligands have good logP values (A: 2.552, B: 2.687), falling within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A has 0 HBD and 8 HBA, which is reasonable. Ligand B has 1 HBD and 4 HBA, also reasonable.

**QED:** Ligand B (0.926) has a significantly better QED score than Ligand A (0.404), indicating a more drug-like profile.

**DILI:** Both ligands have high DILI scores (A: 97.984, B: 87.01), which is a concern. However, these are predictions and need experimental validation.

**BBB:** Ligand A has a much better BBB percentile (75.107) than Ligand B (51.493). This is a critical factor for a CNS target like DRD2.

**Caco-2 Permeability:** Both have negative Caco-2 values which is unusual and likely indicates a problem with the prediction model, but we can assume poor permeability.

**Aqueous Solubility:** Both ligands have very poor predicted aqueous solubility (A: -5.149, B: -3.832). This is a significant drawback.

**hERG Inhibition:** Ligand A (0.369) has a lower hERG risk than Ligand B (0.072), which is preferable.

**Microsomal Clearance:** Ligand A (103.099) has a higher microsomal clearance than Ligand B (26.646), suggesting lower metabolic stability.

**In vitro Half-Life:** Ligand B (-19.931) has a negative half-life, which is impossible and indicates a problem with the prediction. Ligand A (43.628) is reasonable.

**P-gp Efflux:** Ligand A (0.426) has a slightly higher P-gp efflux liability than Ligand B (0.075), meaning B may have better CNS exposure.

**Binding Affinity:** Ligand B (-9.6 kcal/mol) has a significantly stronger binding affinity than Ligand A (-8.1 kcal/mol). This 1.5 kcal/mol difference is substantial and can outweigh some ADME drawbacks.

**Overall Assessment:**

Ligand B has a superior binding affinity and QED score, and lower P-gp efflux. However, its BBB penetration is significantly lower than Ligand A, and its in vitro half-life is nonsensical. Ligand A has a better BBB score, a more reasonable half-life, and lower hERG risk. The poor solubility for both is a major concern. Given the importance of BBB penetration for a CNS target, and the substantial affinity advantage of Ligand B, I would lean towards Ligand B *if* the half-life and BBB predictions can be clarified/validated. However, the prediction issues with Ligand B are concerning.

Output:
1
2025-04-17 04:14:45,559 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (345.4 and 342.5 Da) fall comfortably within the ideal 200-500 Da range.

**TPSA:** Ligand A (80.76) is better than Ligand B (58.2). Both are below the 90 A^2 threshold desirable for CNS targets, but A is closer to the upper limit.

**logP:** Ligand B (3.082) is optimal (1-3), while Ligand A (0.305) is quite low, potentially hindering membrane permeability. This is a significant drawback for A.

**H-Bond Donors/Acceptors:** Ligand A has 1 HBD and 5 HBA, while Ligand B has 2 HBD and 2 HBA. Both are within acceptable ranges.

**QED:** Both ligands have similar QED values (0.593 and 0.576), indicating good drug-like properties.

**DILI:** Ligand B (31.64) has a much lower DILI risk than Ligand A (52.152), making it safer from a liver toxicity perspective.

**BBB:** Ligand A (66.615) has a better BBB penetration percentile than Ligand B (49.67), which is important for a CNS target like DRD2. However, both are below the desirable >70 threshold.

**Caco-2 Permeability:** Ligand A (-4.485) has slightly better Caco-2 permeability than Ligand B (-4.703), but both are negative values, indicating poor permeability.

**Aqueous Solubility:** Ligand B (-4.78) has worse aqueous solubility than Ligand A (-1.791).

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.216 and 0.156).

**Microsomal Clearance:** Ligand A (-0.126) has much lower microsomal clearance than Ligand B (45.148), indicating better metabolic stability.

**In vitro Half-Life:** Ligand A (-19.811) has a much longer in vitro half-life than Ligand B (-4.11), which is a significant advantage.

**P-gp Efflux:** Ligand A (0.047) has lower P-gp efflux than Ligand B (0.185), which is favorable for CNS penetration.

**Binding Affinity:** Ligand B (-9.0 kcal/mol) has significantly stronger binding affinity than Ligand A (-6.6 kcal/mol). This is a >1.5 kcal/mol advantage, which can outweigh some ADME drawbacks.

**Overall Assessment:**

Ligand B's superior binding affinity is a major advantage. While its BBB penetration is lower than Ligand A, its significantly better logP, DILI, metabolic stability, and half-life outweigh this drawback. Ligand A suffers from a very low logP, which will severely limit its ability to cross cell membranes and reach the brain. Although A has better BBB and P-gp efflux, the poor logP is a critical issue.

Output:
1
2025-04-17 04:14:45,559 - INFO - Reasoning:

Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (354.451 and 363.845 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (99.77) is slightly higher than the preferred <90 for CNS targets, but still reasonable. Ligand B (75.44) is excellent, well below 90.

**3. logP:** Both ligands have good logP values (1.906 and 3.222), falling within the optimal 1-3 range. Ligand B is slightly higher, potentially offering better membrane permeability.

**4. H-Bond Donors:** Ligand A has 3 HBD, which is acceptable. Ligand B has 1 HBD, also acceptable.

**5. H-Bond Acceptors:** Both ligands have 4 HBA, which is within the acceptable limit of <=10.

**6. QED:** Both ligands have good QED scores (0.657 and 0.855), indicating good drug-like properties. Ligand B is better.

**7. DILI:** Ligand A (47.421) has a slightly better DILI risk profile than Ligand B (54.75), both are acceptable.

**8. BBB:** This is a critical parameter for a CNS target like DRD2. Ligand A has a BBB percentile of 70.997, which is desirable (>70). Ligand B has a significantly lower BBB percentile of 55.176, which is a major drawback.

**9. Caco-2:** Both have negative values, indicating a percentile score. Without knowing the scale, it's hard to compare directly, but these are likely similar.

**10. Solubility:** Both have negative values, indicating a percentile score. These are likely similar.

**11. hERG:** Both ligands have low hERG inhibition liability (0.198 and 0.388), which is good.

**12. Cl_mic:** Ligand A (40.431) has a lower microsomal clearance than Ligand B (62.661), suggesting better metabolic stability.

**13. t1/2:** Ligand B (51.204) has a significantly longer in vitro half-life than Ligand A (4.393). This is a positive attribute.

**14. Pgp:** Both ligands have very low Pgp efflux liability (0.021 and 0.136), which is excellent for CNS penetration.

**15. Binding Affinity:** Ligand B (-8.8 kcal/mol) has a substantially stronger binding affinity than Ligand A (-7.7 kcal/mol). This difference of 1.1 kcal/mol is significant and could outweigh some ADME drawbacks.

**Overall Assessment:**

While Ligand B has a superior binding affinity and a longer half-life, its significantly lower BBB penetration (55.176 vs 70.997 for Ligand A) is a critical concern for a CNS target.  The improved affinity of Ligand B might be offset by reduced brain exposure. Ligand A, despite a slightly weaker affinity, has a much more favorable BBB profile and better metabolic stability. Given the GPCR-specific priorities, particularly BBB penetration for CNS targets, Ligand A is the more promising candidate.

Output:
0
2025-04-17 04:14:45,559 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (432.296 Da) is slightly higher, but still acceptable. Ligand B (344.411 Da) is lower, which could be beneficial for permeability.

**2. TPSA:** Both ligands have TPSA values below 140, suggesting reasonable oral absorption. Ligand A (99.52) is slightly higher than Ligand B (88.42), but both are below the 90 threshold for CNS targets.

**3. logP:** Both ligands have logP values between 1 and 3 (Ligand A: 2.234, Ligand B: 2.564), which is optimal.

**4. H-Bond Donors:** Both have 1 HBD, which is within the acceptable limit of 5.

**5. H-Bond Acceptors:** Ligand A has 7 HBAs, and Ligand B has 5. Both are below the limit of 10.

**6. QED:** Both ligands have QED values above 0.5 (Ligand A: 0.674, Ligand B: 0.732), indicating good drug-like properties.

**7. DILI:** Both ligands have relatively high DILI risk (Ligand A: 91.47, Ligand B: 51.997). Ligand B is significantly better here, indicating lower potential for liver injury.

**8. BBB:** This is a critical parameter for CNS targets. Ligand A has a BBB percentile of 51.803, while Ligand B has 49.128. Both are below the desirable >70 threshold, but are relatively close.

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.911 and -4.1), which is unusual and suggests poor permeability. This is a significant concern.

**10. Aqueous Solubility:** Both ligands have very negative solubility values (-3.332 and -4.034), indicating very poor aqueous solubility. This is a major drawback.

**11. hERG Inhibition:** Both ligands have low hERG inhibition risk (Ligand A: 0.407, Ligand B: 0.271). Ligand B is slightly better.

**12. Microsomal Clearance:** Ligand A (51.725) has lower microsomal clearance than Ligand B (60.203), suggesting better metabolic stability.

**13. In vitro Half-Life:** Ligand A (11.908 hours) has a longer half-life than Ligand B (-7.974 hours). This is a significant advantage.

**14. P-gp Efflux:** Both ligands have low P-gp efflux liability (Ligand A: 0.378, Ligand B: 0.059). Ligand B is significantly better, which is crucial for CNS penetration.

**15. Binding Affinity:** Both ligands have excellent binding affinities (Ligand A: -8.3 kcal/mol, Ligand B: -8.1 kcal/mol). The difference is small (0.2 kcal/mol) and unlikely to outweigh other factors.

**Overall Assessment:**

Both ligands have significant drawbacks regarding solubility and Caco-2 permeability. However, considering the GPCR-specific priorities, Ligand B appears slightly more promising. It has a better DILI score, lower P-gp efflux, and slightly better hERG inhibition. While Ligand A has a longer half-life and better metabolic stability, the improvements in ADME properties for Ligand B are more critical for a CNS-targeting drug. The affinity difference is minimal.

Output:
1
2025-04-17 04:14:45,560 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 drug candidates, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (350.503 and 352.435 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (49.85) is excellent, well below the 90 A^2 threshold for CNS targets. Ligand B (118.55) is higher, but still within a reasonable range, though less optimal for CNS penetration.

**logP:** Ligand A (2.402) is optimal (1-3). Ligand B (-0.173) is below 1, which could hinder permeation.

**H-Bond Donors/Acceptors:** Ligand A (0 HBD, 3 HBA) is favorable. Ligand B (4 HBD, 5 HBA) is acceptable, but slightly higher counts could impact permeability.

**QED:** Both ligands have acceptable QED values (0.608 and 0.567, respectively), indicating reasonable drug-likeness.

**DILI:** Ligand A (6.786) has a very low DILI risk. Ligand B (31.601) is still relatively low, but higher than Ligand A.

**BBB:** This is crucial for a CNS target like DRD2. Ligand A (92.943) shows excellent BBB penetration potential. Ligand B (12.175) is very poor, suggesting limited CNS exposure.

**Caco-2 Permeability:** Ligand A (-4.409) has poor Caco-2 permeability. Ligand B (-5.564) is also poor.

**Aqueous Solubility:** Ligand A (-2.372) and Ligand B (-1.607) both have poor aqueous solubility.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.735 and 0.115, respectively).

**Microsomal Clearance:** Ligand A (77.269) has moderate clearance. Ligand B (-2.793) has negative clearance which is not possible.

**In vitro Half-Life:** Ligand A (-10.703) has negative half-life which is not possible. Ligand B (-32.047) also has negative half-life which is not possible.

**P-gp Efflux:** Ligand A (0.195) has low P-gp efflux, which is good for CNS penetration. Ligand B (0.028) also has low P-gp efflux.

**Binding Affinity:** Both ligands have strong binding affinities (-7.5 and -8.2 kcal/mol). Ligand B is slightly better (-8.2 kcal/mol).

**Overall Assessment:**

Ligand A is significantly better due to its excellent BBB penetration (92.943) and favorable TPSA (49.85) and logP (2.402). While its Caco-2 permeability and aqueous solubility are poor, the strong BBB score mitigates these concerns for a CNS target. Ligand B's extremely poor BBB penetration (12.175) is a major drawback, despite its slightly better binding affinity. The negative values for clearance and half-life are also concerning.

Output:
1
2025-04-17 04:14:45,560 - INFO - Reasoning:

Let's analyze Ligand A and Ligand B based on the provided guidelines, prioritizing GPCR-specific properties (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (351.403 and 368.405 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (104.9) is better than Ligand B (55.57). For CNS targets, TPSA should be <=90, and Ligand B is significantly better in this regard.

**logP:** Ligand A (0.408) is quite low, potentially hindering permeability. Ligand B (3.823) is within the optimal 1-3 range. This is a significant advantage for Ligand B.

**H-Bond Donors/Acceptors:** Ligand A has 2 HBD and 6 HBA, while Ligand B has 0 HBD and 5 HBA. Both are within acceptable limits.

**QED:** Both ligands have good QED scores (0.657 and 0.778, respectively), indicating good drug-like properties.

**DILI:** Both ligands have acceptable DILI risk (32.842 and 48.313, both < 40).

**BBB:** Ligand B (93.098) is *much* better than Ligand A (45.366) regarding BBB penetration, which is crucial for a CNS target like DRD2.

**Caco-2 Permeability:** Ligand A (-5.137) has poor Caco-2 permeability, while Ligand B (-4.292) is slightly better, but still not great.

**Aqueous Solubility:** Ligand A (-1.194) has poor aqueous solubility, while Ligand B (-4.753) is even worse. This could pose formulation challenges for both, but is more concerning for Ligand B.

**hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.055 and 0.506, respectively).

**Microsomal Clearance:** Ligand A (4.474) has lower microsomal clearance than Ligand B (85.029), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (23.703) has a longer half-life than Ligand B (-24.921), which is a positive attribute.

**P-gp Efflux:** Ligand A (0.037) has significantly lower P-gp efflux liability than Ligand B (0.381), meaning it is less likely to be pumped out of the brain.

**Binding Affinity:** Ligand A (-7.4) has slightly better binding affinity than Ligand B (-7.2), but the difference is relatively small (0.2 kcal/mol).

**Overall Assessment:**

While Ligand A has slightly better affinity and metabolic stability, Ligand B is significantly superior in terms of BBB penetration (93.098 vs 45.366) and logP (3.823 vs 0.408). Given that DRD2 is a CNS target, BBB penetration and appropriate lipophilicity are paramount. The lower P-gp efflux for Ligand A is a benefit, but the substantial advantage of Ligand B in BBB penetration outweighs this. The slightly lower affinity of Ligand B is unlikely to be a major issue given its improved pharmacokinetic properties.

Output:
1
2025-04-17 04:14:45,560 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B based on the provided guidelines, prioritizing GPCR-specific properties (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (350.47 and 357.49 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (114.93) is excellent for CNS penetration, being well below 90. Ligand B (20.31) is *exceptionally* low, potentially too low and might compromise binding affinity.

**logP:** Ligand A (1.23) is optimal. Ligand B (4.813) is slightly high, potentially leading to solubility issues or off-target interactions, but still within a tolerable range.

**H-Bond Donors/Acceptors:** Ligand A (3 HBD, 6 HBA) is good. Ligand B (0 HBD, 2 HBA) is also acceptable, though very low HBA might impact solubility.

**QED:** Both ligands have similar QED values (0.684 and 0.696), indicating good drug-likeness.

**DILI:** Ligand A (38.58) has a slightly higher DILI risk than Ligand B (29.97), but both are below the 40 threshold and considered good.

**BBB:** Ligand B (89.53) has a significantly better BBB penetration score than Ligand A (58.94). This is a critical advantage for a CNS target like DRD2.

**Caco-2 Permeability:** Ligand A (-5.465) has poor Caco-2 permeability, while Ligand B (-4.861) is also poor, but slightly better.

**Aqueous Solubility:** Both ligands have very poor aqueous solubility (-2.16 and -4.841). This is a concern for both, but might be mitigated by formulation strategies.

**hERG:** Ligand A (0.112) has a very low hERG risk, while Ligand B (0.808) has a slightly elevated risk, but still relatively low.

**Microsomal Clearance:** Ligand A (18.96) has a much lower microsomal clearance than Ligand B (81.19), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (-8.52) has a longer in vitro half-life than Ligand B (3.33), further supporting better metabolic stability.

**P-gp Efflux:** Ligand A (0.016) has very low P-gp efflux, which is excellent for CNS penetration. Ligand B (0.822) has higher P-gp efflux, which could limit brain exposure.

**Binding Affinity:** Both ligands have very similar binding affinities (-7.3 and -8.3 kcal/mol). The difference of 1 kcal/mol is not substantial enough to outweigh other significant differences.

**Overall Assessment:**

Ligand B excels in BBB penetration and has a lower DILI risk. However, Ligand A has superior metabolic stability (lower Cl_mic, longer t1/2), lower P-gp efflux, and a much better TPSA value for CNS penetration. The slightly lower BBB score of Ligand A is a drawback, but the combination of its other favorable properties, particularly the very low P-gp efflux and better metabolic profile, makes it a more promising candidate. The extremely low TPSA of Ligand B is also a concern.

Output:
0
2025-04-17 04:14:45,560 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (350.463 and 348.487 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (76.46) is slightly higher than Ligand B (69.64). Both are below the 90 A^2 threshold desirable for CNS targets, which is good.

**3. logP:** Both ligands have excellent logP values (2.502 and 2.415), falling within the optimal 1-3 range.

**4. H-Bond Donors:** Ligand A (1) is better than Ligand B (2). Lower HBD generally improves permeability.

**5. H-Bond Acceptors:** Ligand A (5) is better than Ligand B (3). Lower HBA generally improves permeability.

**6. QED:** Ligand A (0.905) has a significantly better QED score than Ligand B (0.662), indicating a more drug-like profile.

**7. DILI:** Ligand A (44.281) has a slightly higher DILI risk than Ligand B (13.3), but both are well below the concerning threshold of 60.

**8. BBB:** Ligand A (76.347) has a better BBB percentile than Ligand B (66.344). Both are reasonably good, but for a CNS target like DRD2, higher is preferred.

**9. Caco-2 Permeability:** Ligand A (-4.432) has a worse Caco-2 permeability than Ligand B (-4.632). Lower values are less desirable.

**10. Aqueous Solubility:** Ligand A (-2.285) has a slightly worse aqueous solubility than Ligand B (-1.981).

**11. hERG:** Both ligands have very low hERG inhibition liability (0.287 and 0.212), which is excellent.

**12. Microsomal Clearance:** Ligand A (39.334) has a lower microsomal clearance than Ligand B (44.998), suggesting better metabolic stability.

**13. In vitro Half-Life:** Ligand A (1.58) has a very short half-life, while Ligand B (-26.614) has a very long half-life. This is a significant advantage for Ligand B.

**14. P-gp Efflux:** Both ligands have low P-gp efflux liability (0.054 and 0.105), which is good for CNS penetration.

**15. Binding Affinity:** Ligand B (-8.7 kcal/mol) has a significantly stronger binding affinity than Ligand A (-7.4 kcal/mol). This is a substantial advantage, exceeding the 1.5 kcal/mol threshold where other factors can be overlooked.

**Overall Assessment:**

While Ligand A has a better QED score and slightly better BBB penetration, Ligand B's significantly stronger binding affinity (-8.7 vs -7.4 kcal/mol) and substantially longer in vitro half-life are critical advantages. The slightly lower BBB and QED of Ligand B are less concerning given the potency and improved metabolic stability. The better half-life is particularly important for a CNS target.

Output:
1
2025-04-17 04:14:45,560 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (350.434 Da) is slightly preferred.

**TPSA:** Ligand A (49.85) is excellent for CNS penetration, well below the 90 A^2 threshold. Ligand B (133.83) is higher, approaching the 140 A^2 limit for oral absorption and less ideal for CNS targets.

**logP:** Ligand A (2.842) is optimal. Ligand B (-2.253) is significantly lower, potentially hindering membrane permeability and CNS entry.

**H-Bond Donors/Acceptors:** Ligand A (0 HBD, 4 HBA) is favorable. Ligand B (4 HBD, 8 HBA) is acceptable, but higher HBD/HBA can sometimes reduce permeability.

**QED:** Ligand A (0.766) is very good, indicating high drug-likeness. Ligand B (0.328) is lower, suggesting a less favorable drug-like profile.

**DILI:** Ligand A (44.281) has a lower DILI risk than Ligand B (59.829). Both are acceptable, but A is better.

**BBB:** Ligand A (84.529) has excellent predicted BBB penetration. Ligand B (15.083) is very poor, a major drawback for a CNS target.

**Caco-2 Permeability:** Ligand A (-4.134) is poor, while Ligand B (-6.374) is worse. Both are negative values, indicating low permeability.

**Aqueous Solubility:** Ligand A (-3.266) is poor, while Ligand B (-1.802) is slightly better.

**hERG Inhibition:** Ligand A (0.745) has a slightly higher hERG risk than Ligand B (0.1), but both are relatively low.

**Microsomal Clearance:** Ligand A (84.206) has higher clearance, indicating lower metabolic stability. Ligand B (18.474) has lower clearance and better metabolic stability.

**In vitro Half-Life:** Ligand A (-10.017) has a very short half-life. Ligand B (-16.763) is even shorter. Both are poor.

**P-gp Efflux:** Ligand A (0.229) has lower P-gp efflux, which is desirable for CNS penetration. Ligand B (0.006) has very low P-gp efflux.

**Binding Affinity:** Ligand A (-8.3 kcal/mol) has a slightly better binding affinity than Ligand B (-7.2 kcal/mol). This difference is significant.

**Overall Assessment:**

Ligand A is significantly more promising. While it has some drawbacks (Caco-2, half-life, and clearance), its superior BBB penetration, optimal logP, good QED, and strong binding affinity outweigh these concerns, especially given the GPCR target. Ligand B's very poor BBB penetration and low logP are critical failures for a CNS drug candidate, despite its better metabolic stability. The affinity difference, while not enormous, further favors Ligand A.

Output:
1
2025-04-17 04:14:45,560 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (351.535 and 366.531 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (43.86) is significantly better than Ligand B (78.35). For CNS targets, we want TPSA <= 90, and A is comfortably within this, while B is approaching the upper limit.

**3. logP:** Both ligands have good logP values (2.604 and 3.006), falling within the optimal 1-3 range.

**4. H-Bond Donors:** Ligand A (0) is preferable to Ligand B (2). Fewer HBDs generally improve permeability.

**5. H-Bond Acceptors:** Ligand A (3) is better than Ligand B (6). Lower HBA counts are generally favored for CNS penetration.

**6. QED:** Both ligands have good QED scores (0.608 and 0.775), indicating good drug-like properties.

**7. DILI:** Ligand A (8.181) has a much lower DILI risk than Ligand B (43.622). This is a significant advantage for A.

**8. BBB:** Ligand A (92.672) has a better BBB penetration percentile than Ligand B (78.558). Both are reasonably good, but A is clearly superior, exceeding the desirable >70 threshold.

**9. Caco-2 Permeability:** Ligand A (-4.403) has worse Caco-2 permeability than Ligand B (-5.139). However, this is a less critical parameter than BBB for CNS targets.

**10. Aqueous Solubility:** Ligand A (-1.734) has better solubility than Ligand B (-3.179).

**11. hERG Inhibition:** Both ligands have similar, low hERG inhibition liabilities (0.669 and 0.709).

**12. Microsomal Clearance:** Ligand A (79.202) has higher microsomal clearance than Ligand B (47.432), indicating lower metabolic stability. This is a drawback for A.

**13. In vitro Half-Life:** Ligand B (9.973) has a longer in vitro half-life than Ligand A (6.444). This is an advantage for B.

**14. P-gp Efflux:** Both ligands have similar, low P-gp efflux liabilities (0.107 and 0.408).

**15. Binding Affinity:** Ligand B (-8.2) has a significantly stronger binding affinity than Ligand A (-7.1). This is a substantial advantage for B (1.1 kcal/mol difference).

**Overall Assessment:**

While Ligand B has a superior binding affinity and better metabolic stability (lower Cl_mic, longer t1/2), Ligand A excels in several key properties crucial for CNS penetration: lower TPSA, lower HBD/HBA, better BBB penetration, lower DILI risk, and better solubility. The 1.1 kcal/mol difference in binding affinity is substantial, but the improvements in ADME properties, particularly BBB and DILI, for Ligand A are compelling. Given the GPCR-specific priorities, the better CNS penetration profile of Ligand A outweighs the affinity difference.

Output:
0
2025-04-17 04:14:45,560 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (344.386 and 350.478 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (60.85) is better than Ligand B (53.43) as it is closer to the <90 target for CNS penetration.

**3. logP:** Both ligands have acceptable logP values (2.034 and 3.684), falling within the optimal 1-3 range. Ligand B is slightly higher, which *could* be a minor concern for solubility, but not a dealbreaker.

**4. H-Bond Donors:** Both have 1 HBD, which is within the acceptable limit of <=5.

**5. H-Bond Acceptors:** Both have 3 HBA, also within the acceptable limit of <=10.

**6. QED:** Ligand A (0.903) has a significantly better QED score than Ligand B (0.691), indicating a more drug-like profile.

**7. DILI:** Ligand A (53.819) has a higher DILI risk than Ligand B (13.649). This is a significant advantage for Ligand B.

**8. BBB:** Both ligands have excellent BBB penetration (81.698 and 80.574), exceeding the desirable >70 threshold for CNS targets. This is comparable between the two.

**9. Caco-2 Permeability:** Both have negative Caco-2 values (-4.327 and -4.389). This is unusual and suggests poor permeability. However, these values are on a scale where negative values are possible, and the difference is minimal.

**10. Aqueous Solubility:** Ligand A (-1.989) has better solubility than Ligand B (-3.651).

**11. hERG Inhibition:** Both ligands have low hERG inhibition risk (0.778 and 0.768).

**12. Microsomal Clearance:** Ligand B (66.218) has a higher microsomal clearance than Ligand A (24.863), suggesting lower metabolic stability. This is a significant advantage for Ligand A.

**13. In vitro Half-Life:** Ligand A (10.709) has a positive half-life, while Ligand B (-10.813) has a negative half-life. This is a significant advantage for Ligand A.

**14. P-gp Efflux:** Both ligands have low P-gp efflux liability (0.341 and 0.308).

**15. Binding Affinity:** Ligand B (-6.7 kcal/mol) has a slightly better binding affinity than Ligand A (-9.0 kcal/mol). This is a substantial advantage for Ligand B.

**Overall Assessment:**

Ligand B has a significantly better binding affinity and a much lower DILI risk. However, Ligand A has a better QED score, better metabolic stability (lower Cl_mic and positive t1/2), and better solubility. Considering the GPCR-specific priorities, the strong binding affinity of Ligand B is a major advantage, potentially outweighing the slightly higher logP and lower QED. The lower DILI risk is also a significant benefit. The negative Caco-2 values are concerning for both, but similar.

Output:
1
2025-04-17 04:14:45,561 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (371.438 and 360.523 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (111.21) is slightly above the optimal <90 for CNS targets, but still reasonable. Ligand B (49.41) is excellent, well below 90.

**logP:** Ligand A (-0.006) is very low, potentially hindering permeability. Ligand B (3.914) is close to optimal (1-3).

**H-Bond Donors/Acceptors:** Ligand A (3 HBD, 6 HBA) is acceptable. Ligand B (1 HBD, 3 HBA) is also good.

**QED:** Both ligands have good QED scores (0.649 and 0.885), indicating drug-like properties.

**DILI:** Both ligands have similar, moderate DILI risk (54.168 and 50.95).

**BBB:** Ligand B (74.176) is significantly better than Ligand A (37.65) regarding BBB penetration, a critical factor for CNS targets like DRD2.

**Caco-2 Permeability:** Ligand A (-5.867) is very poor, suggesting poor intestinal absorption. Ligand B (-4.872) is also poor, but better than A.

**Aqueous Solubility:** Ligand A (-2.215) and Ligand B (-4.409) both have poor aqueous solubility.

**hERG Inhibition:** Ligand A (0.032) has a very low hERG risk, which is excellent. Ligand B (0.46) is slightly higher but still acceptable.

**Microsomal Clearance:** Ligand A (-31.012) has a very low (good) microsomal clearance, indicating high metabolic stability. Ligand B (88.172) has a high clearance, suggesting rapid metabolism.

**In vitro Half-Life:** Ligand A (-7.587) has a very short half-life. Ligand B (3.107) has a short half-life, but is better than A.

**P-gp Efflux:** Ligand A (0.007) has very low P-gp efflux, which is favorable for CNS penetration. Ligand B (0.648) has moderate P-gp efflux.

**Binding Affinity:** Ligand B (-10.2 kcal/mol) has a significantly stronger binding affinity than Ligand A (-7.1 kcal/mol). This >1.5 kcal/mol difference is a major advantage.

**Overall Assessment:**

Ligand B is the stronger candidate. While both have solubility issues, Ligand B excels in key areas for a CNS-targeting GPCR ligand: significantly better BBB penetration, much stronger binding affinity, and a more optimal logP. The higher metabolic clearance and P-gp efflux of Ligand B are drawbacks, but the substantial affinity advantage and improved BBB penetration likely outweigh these concerns. Ligand A's very low logP and poor Caco-2 permeability are significant liabilities.

Output:
1
2025-04-17 04:14:45,561 - INFO - Batch 96 complete. Total preferences: 1536
2025-04-17 04:14:45,561 - INFO - Processing batch 97/512...
2025-04-17 04:15:25,648 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (362.543 Da and 381.929 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (61.02) is significantly better than Ligand B (71.09). For CNS targets, we want TPSA <= 90, and ideally closer to 60. Ligand A is much closer to the ideal range.

**3. logP:** Both ligands have good logP values (4.433 and 3.392), falling within the optimal 1-3 range, but Ligand A is slightly higher.

**4. H-Bond Donors:** Both have 2 HBD, which is within the acceptable limit of <=5.

**5. H-Bond Acceptors:** Ligand A has 3 HBA, and Ligand B has 4. Both are within the acceptable limit of <=10.

**6. QED:** Both ligands have good QED scores (0.73 and 0.821), indicating good drug-like properties.

**7. DILI:** Ligand A (51.725) has a slightly higher DILI risk than Ligand B (49.942), but both are reasonably low and below the concerning threshold of 60.

**8. BBB:** This is a critical parameter for a CNS target like DRD2. Ligand A has a BBB percentile of 70.958, which is excellent (>70). Ligand B has a BBB percentile of 56.495, which is considerably lower and less desirable.

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.079 and -5.076). This is unusual and suggests poor permeability. However, the absolute value is similar for both.

**10. Aqueous Solubility:** Both ligands have very poor aqueous solubility (-4.183 and -4.253). This is a significant drawback.

**11. hERG Inhibition:** Ligand A (0.9) has a slightly higher hERG inhibition risk than Ligand B (0.337), but both are relatively low.

**12. Microsomal Clearance:** Ligand B (36.87) has significantly lower microsomal clearance than Ligand A (80.682), indicating better metabolic stability.

**13. In vitro Half-Life:** Ligand A (69.005) has a much longer in vitro half-life than Ligand B (25.43), which is preferable.

**14. P-gp Efflux:** Both ligands have low P-gp efflux liability (0.366 and 0.362), which is good for CNS penetration.

**15. Binding Affinity:** Ligand B (-9.2 kcal/mol) has a significantly stronger binding affinity than Ligand A (-7.7 kcal/mol). This is a substantial advantage (1.5 kcal/mol difference).

**Overall Assessment:**

While Ligand B has superior binding affinity and metabolic stability, Ligand A is significantly better in terms of BBB penetration and has a longer half-life. Given the CNS target (DRD2), BBB penetration is paramount. The stronger affinity of Ligand B is attractive, but the poor BBB penetration is a major concern. The solubility issues are similar for both, and would require formulation strategies to address. Considering the GPCR-specific priorities, the better BBB score of Ligand A outweighs the affinity advantage of Ligand B.

Output:
0
2025-04-17 04:15:25,649 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (348.403 Da) is slightly preferred as it's closer to the lower end, potentially aiding permeability.

**TPSA:** Ligand A (87.9) is excellent for CNS penetration, being well below 90. Ligand B (115.11) is still reasonable but less optimal.

**logP:** Ligand A (0.111) is quite low, potentially hindering membrane permeability. Ligand B (1.579) is much better, falling within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A (1 HBD, 6 HBA) and Ligand B (3 HBD, 6 HBA) both have acceptable counts.

**QED:** Both ligands have decent QED scores (A: 0.816, B: 0.705), indicating good drug-like properties.

**DILI:** Ligand A (45.56) has a lower DILI risk than Ligand B (71.539), which is a positive.

**BBB:** This is crucial for a CNS target. Ligand A excels with 72.237, while Ligand B is very poor at 13.532.

**Caco-2 Permeability:** Ligand A (-4.645) and Ligand B (-5.127) both have negative values, which is unusual and suggests very poor permeability. However, the scale isn't specified, so it's hard to interpret.

**Aqueous Solubility:** Ligand A (-1.581) and Ligand B (-3.932) both have negative values, indicating poor solubility.

**hERG:** Both ligands have low hERG risk (A: 0.236, B: 0.289).

**Microsomal Clearance:** Ligand A (19.959) has a lower clearance than Ligand B (5.257), indicating better metabolic stability.

**In vitro Half-Life:** Ligand A (-4.929) has a negative half-life, which is not possible. This is likely an error in the data. Ligand B (44.897) has a reasonable half-life.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (A: 0.025, B: 0.06), which is good.

**Binding Affinity:** Ligand A (-7.8) has a slightly better binding affinity than Ligand B (-8.0). However, the difference is small.

**Overall Assessment:**

Ligand A is significantly better regarding BBB penetration, DILI risk, and metabolic stability. However, its low logP is a major concern, potentially limiting its ability to cross cell membranes. Ligand B has a better logP but suffers from poor BBB penetration and higher DILI risk. Given the importance of BBB penetration for a CNS target like DRD2, and the relatively small difference in binding affinity, Ligand A is the more promising candidate, despite the logP issue. Further optimization to increase logP while maintaining the other favorable properties would be the next step. The negative half-life for Ligand A is a data error that needs to be addressed.

Output:
0
2025-04-17 04:15:25,649 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (364.555 and 360.483 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (40.62) is significantly better than Ligand B (76.02). For CNS targets, we want TPSA <= 90, and ideally lower. Ligand A is well within this range, while Ligand B is approaching the upper limit.

**3. logP:** Both ligands have a logP of around 3, which is optimal.

**4. H-Bond Donors:** Ligand A (0) is preferable to Ligand B (2). Fewer HBDs generally improve permeability.

**5. H-Bond Acceptors:** Ligand A (3) is better than Ligand B (5). Lower HBA is also favorable for permeability.

**6. QED:** Both ligands have good QED values (0.537 and 0.675), indicating drug-like properties.

**7. DILI:** Ligand A (26.095) has a much lower DILI risk than Ligand B (60.644). This is a significant advantage for Ligand A.

**8. BBB:** Ligand A (80.38) has a substantially better BBB penetration percentile than Ligand B (65.839). This is *critical* for a CNS target like DRD2.

**9. Caco-2 Permeability:** Both have negative values, which is unusual. However, the magnitude is similar, and this metric is less important than BBB for CNS targets.

**10. Aqueous Solubility:** Both have negative values, indicating poor solubility. This could be a formulation challenge, but is less critical than BBB for CNS penetration.

**11. hERG Inhibition:** Both ligands have low hERG inhibition risk (0.735 and 0.51).

**12. Microsomal Clearance:** Ligand B (52.685) has lower microsomal clearance than Ligand A (83.052), suggesting better metabolic stability.

**13. In vitro Half-Life:** Ligand B (33.813) has a significantly longer in vitro half-life than Ligand A (-7.627). This is a strong advantage for Ligand B.

**14. P-gp Efflux:** Ligand A (0.504) has lower P-gp efflux than Ligand B (0.358), which is favorable for CNS exposure.

**15. Binding Affinity:** Ligand B (-8.4) has a stronger binding affinity than Ligand A (-6.4). This is a 2.0 kcal/mol difference, which is substantial and can outweigh some ADME drawbacks.

**Overall Assessment:**

While Ligand B has superior binding affinity and metabolic stability, Ligand A is significantly better in terms of BBB penetration, TPSA, DILI risk, and P-gp efflux. For a CNS target like DRD2, BBB penetration is paramount. The strong affinity of Ligand B is attractive, but the lower BBB and higher DILI risk are concerning. The lower TPSA of Ligand A is also a significant advantage. The difference in half-life is concerning for Ligand A, but can be addressed with prodrug strategies.

Output:
1
2025-04-17 04:15:25,649 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (355.439 and 368.499 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (108.23) is slightly above the optimal <90 for CNS targets, but still reasonable. Ligand B (75.71) is excellent, well below 90.

**3. logP:** Both ligands have good logP values (1.83 and 2.069), falling within the 1-3 range.

**4. H-Bond Donors:** Both have 1 HBD, which is within the acceptable limit of <=5.

**5. H-Bond Acceptors:** Ligand A has 8 HBAs, and Ligand B has 5. Both are within the acceptable limit of <=10.

**6. QED:** Both ligands have similar QED values (0.775 and 0.752), indicating good drug-likeness.

**7. DILI:** Both ligands have similar DILI risk (67.468 and 66.072), placing them in a moderate risk category, but not alarmingly high.

**8. BBB:** This is a critical parameter for a CNS target like DRD2. Ligand A has a BBB percentile of 74.525, which is good. Ligand B has a significantly lower BBB percentile of 46.219, which is a major drawback.

**9. Caco-2 Permeability:** Ligand A (-4.606) and Ligand B (-5.533) both have negative Caco-2 values, which is unusual. Lower values suggest poor permeability.

**10. Aqueous Solubility:** Both ligands have poor aqueous solubility (-2.492 and -3.24).

**11. hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.042 and 0.112).

**12. Microsomal Clearance:** Ligand A (94.933) has a higher microsomal clearance than Ligand B (39.62), suggesting lower metabolic stability.

**13. In vitro Half-Life:** Ligand B (-23.945) has a slightly longer in vitro half-life than Ligand A (-26.79), but both are negative values which is unusual.

**14. P-gp Efflux:** Both ligands have low P-gp efflux liability (0.082 and 0.145), which is favorable for CNS penetration.

**15. Binding Affinity:** Both ligands have excellent binding affinities (-7.0 and -7.3 kcal/mol). Ligand B is slightly better (-7.3 kcal/mol).

**Overall Assessment:**

While Ligand B has a slightly better binding affinity and lower microsomal clearance, Ligand A is significantly better regarding BBB penetration (74.525 vs 46.219). Given that DRD2 is a CNS target, BBB penetration is paramount. The slightly better affinity of Ligand B is unlikely to overcome the substantial difference in BBB penetration. Both have poor solubility and Caco-2 permeability, which would need to be addressed during optimization, but these are secondary to the BBB issue.

Output:
0
2025-04-17 04:15:25,649 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (346.387 and 351.491 Da) fall within the ideal range of 200-500 Da.

**TPSA:** Ligand A (80.93) is better than Ligand B (61.88) as it is closer to the ideal range for CNS targets (<=90).

**logP:** Both ligands have acceptable logP values (0.939 and 1.415), falling within the optimal range of 1-3. Ligand B is slightly better.

**H-Bond Donors/Acceptors:** Ligand A has 0 HBD and 7 HBA, while Ligand B has 1 HBD and 4 HBA. Both are within acceptable limits (<=5 HBD and <=10 HBA).

**QED:** Both ligands have similar QED values (0.738 and 0.705), indicating good drug-likeness.

**DILI:** Ligand A (39.667) has a lower DILI risk than Ligand B (7.135), which is preferable.

**BBB:** Ligand A (71.811) has a significantly better BBB penetration percentile than Ligand B (63.474). This is a critical factor for a CNS target like DRD2.

**Caco-2 Permeability:** Ligand A (-4.754) and Ligand B (-4.822) have similar, and poor, Caco-2 permeability.

**Aqueous Solubility:** Ligand A (-1.014) is slightly better than Ligand B (-0.345) in terms of aqueous solubility, but both are very poor.

**hERG Inhibition:** Both ligands have low hERG inhibition liability (0.399 and 0.271), which is good.

**Microsomal Clearance:** Ligand A (37.858) has higher microsomal clearance than Ligand B (-1.01), suggesting lower metabolic stability. Ligand B is better here.

**In vitro Half-Life:** Ligand B (-17) has a significantly longer in vitro half-life than Ligand A (-4.613), which is a major advantage.

**P-gp Efflux:** Ligand A (0.031) has a lower P-gp efflux liability than Ligand B (0.008), which is favorable for CNS penetration.

**Binding Affinity:** Both ligands have very similar and strong binding affinities (-7.9 and -7.6 kcal/mol). The difference is less than the 1.5 kcal/mol threshold.

**Overall Assessment:**

Considering the GPCR-specific priorities, Ligand A is more promising. While Ligand B has better metabolic stability (lower Cl_mic, longer t1/2), Ligand A has a significantly better BBB percentile (71.811 vs. 63.474) and lower DILI risk. The slightly better TPSA of Ligand A also contributes to its favorability. The binding affinity difference is minimal. The poor Caco-2 and solubility are concerns for both, but less critical for a CNS target where direct oral bioavailability isn't always essential.

Output:
0
2025-04-17 04:15:25,650 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (361.389 and 377.535 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (71.11) is better than Ligand B (53.51) as it is closer to the <90 target for CNS penetration.

**logP:** Ligand B (2.748) is optimal (1-3), while Ligand A (0.259) is quite low, potentially hindering membrane permeability.

**H-Bond Donors:** Ligand A has 1 HBD, and Ligand B has 0. Both are acceptable.

**H-Bond Acceptors:** Both ligands have 5 HBAs, which is within the acceptable limit of <=10.

**QED:** Both ligands have good QED scores (0.659 and 0.778, respectively), indicating drug-likeness.

**DILI:** Ligand A (18.728) has a significantly lower DILI risk than Ligand B (37.611). This is a substantial advantage.

**BBB:** Ligand A (86.545) has a much better BBB penetration percentile than Ligand B (66.925). This is critical for a CNS target like DRD2.

**Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and suggests poor permeability. However, the scale is not specified, so it's difficult to interpret.

**Aqueous Solubility:** Both have negative solubility values, again, difficult to interpret without knowing the scale.

**hERG Inhibition:** Both ligands show low hERG inhibition liability (0.448 and 0.295), which is good.

**Microsomal Clearance:** Ligand A (-30.546) has a much lower (better) microsomal clearance than Ligand B (42.306), indicating greater metabolic stability.

**In vitro Half-Life:** Ligand A (-14.558) has a negative half-life, which is concerning. Ligand B has a short half-life (4.054 hours).

**P-gp Efflux:** Both have very low P-gp efflux liability (0.007 and 0.232), which is favorable for CNS penetration.

**Binding Affinity:** Ligand B (-7.3 kcal/mol) has a stronger binding affinity than Ligand A (-8.7 kcal/mol). This is a significant advantage, potentially outweighing some ADME drawbacks.

**Overall Assessment:**

While Ligand B has a better binding affinity, Ligand A is superior in several critical ADME properties for a CNS-targeting GPCR. Specifically, its significantly better BBB penetration, lower DILI risk, and improved metabolic stability (lower Cl_mic) are compelling advantages. The low logP of Ligand A is a concern, but the strong affinity of Ligand B might compensate for some permeability issues. However, the negative half-life for Ligand A is a major red flag. Considering the importance of CNS penetration for DRD2, and the better overall ADME profile (except for half-life), Ligand A is the more promising candidate.

Output:
0
2025-04-17 04:15:25,650 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (349.391 and 347.375 Da) fall comfortably within the ideal 200-500 Da range.

**TPSA:** Ligand A (117.37) is slightly higher than Ligand B (113.49). Both are below the 140 A^2 threshold for oral absorption and reasonably close to the 90 A^2 target for CNS penetration, but Ligand B is preferable.

**logP:** Both ligands have similar logP values (0.595 and 0.522), which are on the low side of optimal (1-3). This could potentially hinder permeability, but isn't a dealbreaker.

**H-Bond Donors/Acceptors:** Ligand A has 4 HBD and 5 HBA, while Ligand B has 2 HBD and 7 HBA. Both are within acceptable limits (<=5 HBD, <=10 HBA).

**QED:** Ligand B (0.755) has a better QED score than Ligand A (0.596), indicating a more drug-like profile.

**DILI:** Ligand A (73.052) has a slightly higher DILI risk than Ligand B (69.756), but both are reasonably low.

**BBB:** Ligand A (71.772) has a better BBB penetration percentile than Ligand B (62.156). This is a critical factor for a CNS target like DRD2.

**Caco-2 Permeability:** Both show poor Caco-2 permeability (-5.059 and -4.892). This is a concern, especially given the already low logP values.

**Aqueous Solubility:** Both have poor aqueous solubility (-3.122 and -2.642).

**hERG:** Both ligands show very low hERG inhibition risk (0.172 and 0.071).

**Microsomal Clearance:** Ligand A (-19.65) has significantly lower microsomal clearance than Ligand B (20.729), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (49.518) has a longer in vitro half-life than Ligand B (38.117).

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.007 and 0.041).

**Binding Affinity:** Ligand A (-9.7 kcal/mol) has a significantly stronger binding affinity than Ligand B (-8.3 kcal/mol). This is a substantial advantage.

**Overall Assessment:**

The key differentiating factors are binding affinity and BBB penetration. Ligand A has a much stronger binding affinity, which is paramount for GPCR targets. While Ligand B has a better QED and slightly better BBB, the difference in binding affinity (-1.4 kcal/mol) is substantial enough to outweigh these benefits. The lower clearance and longer half-life of Ligand A are also favorable. The poor Caco-2 and solubility are shared concerns, but can be addressed through formulation strategies.

Output:
1
2025-04-17 04:15:25,650 - INFO - Reasoning:

Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (363.483 and 343.387 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (88.68) is excellent, well below the 90 A^2 threshold for CNS targets. Ligand B (99) is still reasonable but less optimal.

**3. logP:** Both ligands have good logP values (2.301 and 1.851), falling within the 1-3 range.

**4. H-Bond Donors:** Both ligands have acceptable HBD counts (2 and 1, respectively), well below the 5 limit.

**5. H-Bond Acceptors:** Both ligands have acceptable HBA counts (6 and 7, respectively), below the 10 limit.

**6. QED:** Both ligands have similar and good QED values (0.668 and 0.674), indicating good drug-like properties.

**7. DILI:** Ligand A (36.293) has a much lower DILI risk than Ligand B (83.792). This is a significant advantage for Ligand A.

**8. BBB:** Ligand B (67.701) has a substantially better BBB penetration score than Ligand A (24.661). This is a critical factor for a CNS target like DRD2.

**9. Caco-2 Permeability:** Both ligands have similar and very poor Caco-2 permeability (-4.922 and -4.912).

**10. Aqueous Solubility:** Ligand A (-0.963) has better aqueous solubility than Ligand B (-3.018).

**11. hERG Inhibition:** Ligand A (0.57) has a lower hERG inhibition liability than Ligand B (0.034), which is preferable.

**12. Microsomal Clearance:** Ligand A (-9.723) has significantly lower microsomal clearance, indicating better metabolic stability, than Ligand B (42.609).

**13. In vitro Half-Life:** Ligand A (53.449) has a longer in vitro half-life than Ligand B (2.554).

**14. P-gp Efflux:** Ligand A (0.345) has lower P-gp efflux liability than Ligand B (0.193).

**15. Binding Affinity:** Ligand B (-0.0 kcal/mol) has a slightly better binding affinity than Ligand A (-6.8 kcal/mol). However, the difference is not substantial enough to outweigh the other significant advantages of Ligand A.

**Overall Assessment:**

While Ligand B has a better BBB score and slightly better binding affinity, Ligand A is the more promising candidate. Ligand A demonstrates a significantly better safety profile (lower DILI, lower hERG), superior metabolic stability (lower Cl_mic, longer t1/2), and lower P-gp efflux. The TPSA is also more favorable. The difference in binding affinity is not large enough to offset these substantial advantages, especially considering the importance of ADME properties for CNS drug development.

Output:
1
2025-04-17 04:15:25,650 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (384.57 and 369.84 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (67.43) is higher than Ligand B (37.61). For a CNS target like DRD2, we ideally want TPSA <= 90, so both are acceptable, but B is significantly better.

**3. logP:** Ligand A (2.87) is within the optimal 1-3 range. Ligand B (4.239) is slightly above, potentially leading to solubility issues or off-target interactions, but not drastically so.

**4. H-Bond Donors:** Ligand A (2) is good. Ligand B (0) is also acceptable.

**5. H-Bond Acceptors:** Ligand A (5) is good. Ligand B (3) is also good.

**6. QED:** Both ligands have good QED values (0.609 and 0.714), indicating drug-like properties.

**7. DILI:** Ligand A (57.70) has a higher DILI risk than Ligand B (31.60). This is a significant advantage for B.

**8. BBB:** Ligand B (96.78) has a much higher BBB penetration percentile than Ligand A (64.64). This is *critical* for a CNS target like DRD2, making B far more promising.

**9. Caco-2 Permeability:** Ligand A (-5.592) has poor Caco-2 permeability. Ligand B (-4.44) is better, but still not great.

**10. Aqueous Solubility:** Ligand A (-3.468) has poor aqueous solubility. Ligand B (-4.217) is also poor.

**11. hERG Inhibition:** Ligand A (0.552) has a slightly higher hERG inhibition risk than Ligand B (0.848), but both are relatively low.

**12. Microsomal Clearance:** Ligand A (65.60) has higher microsomal clearance than Ligand B (51.71), indicating lower metabolic stability. This favors B.

**13. In vitro Half-Life:** Ligand B (4.421) has a very short half-life compared to Ligand A (20.488). This is a significant drawback for B.

**14. P-gp Efflux:** Ligand A (0.608) has slightly higher P-gp efflux than Ligand B (0.589), favoring B.

**15. Binding Affinity:** Ligand B (-7.7) has a slightly better binding affinity than Ligand A (-7.0). While the difference is not huge, it's enough to be considered.

**Overall Assessment:**

Ligand B is the stronger candidate. The superior BBB penetration (96.78 vs 64.64) is the most important factor for a CNS target. It also has lower DILI risk, better metabolic stability (lower Cl_mic), and slightly better affinity. While Ligand B has a shorter half-life and poorer Caco-2 permeability, the BBB advantage outweighs these drawbacks. Ligand A's poor BBB and higher DILI are significant liabilities.

Output:
1
2025-04-17 04:15:25,651 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (350.503 and 345.403 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (49.85) is excellent, well below the 90 A^2 threshold for CNS targets. Ligand B (109) is higher, but still potentially acceptable, though less ideal.

**logP:** Ligand A (2.709) is optimal (1-3). Ligand B (-0.008) is quite low, potentially hindering membrane permeability and CNS penetration.

**H-Bond Donors/Acceptors:** Ligand A (0 HBD, 3 HBA) is very favorable. Ligand B (3 HBD, 5 HBA) is also reasonable, though slightly higher.

**QED:** Both ligands have good QED scores (0.733 and 0.665, respectively), indicating drug-like properties.

**DILI:** Ligand A (14.889) has a significantly lower DILI risk than Ligand B (71.19), which is a substantial concern.

**BBB:** Ligand A (68.592) has a good BBB penetration percentile, although ideally >70. Ligand B (40.791) is considerably lower, raising concerns about CNS exposure.

**Caco-2 Permeability:** Ligand A (-4.108) is poor, indicating low intestinal absorption. Ligand B (-5.332) is also poor.

**Aqueous Solubility:** Both ligands have very poor aqueous solubility (-2.122 and -2.046, respectively). This could pose formulation challenges.

**hERG Inhibition:** Both ligands show very low hERG inhibition risk (0.215 and 0.043).

**Microsomal Clearance:** Ligand A (47.912) has moderate clearance, while Ligand B (-19.878) has negative clearance, which is not physically possible and indicates an error or outlier in the data. Assuming this is a data error, we should still consider the other parameters.

**In vitro Half-Life:** Ligand A (-19.853) has a negative half-life, which is not physically possible and indicates an error or outlier in the data. Ligand B (-9.691) also has a negative half-life.

**P-gp Efflux:** Both ligands show very low P-gp efflux liability (0.071 and 0.012).

**Binding Affinity:** Both ligands have excellent binding affinity (-8.0 and -8.4 kcal/mol). The difference is minor.

**Overall Assessment:**

Ligand A is significantly better due to its superior DILI risk, better BBB penetration, and more favorable logP. While both have poor solubility and Caco-2 permeability, these can potentially be addressed through formulation strategies. The negative values for clearance and half-life are concerning data quality issues, but the substantial differences in DILI and BBB make Ligand A the stronger candidate. Ligand B's very low logP and high DILI risk are major drawbacks.

Output:
1
2025-04-17 04:15:25,651 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (355.467 and 355.479 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (88.73) is slightly above the optimal <90 for CNS targets, but still reasonable. Ligand B (78.95) is well within the desired range.

**3. logP:** Ligand A (2.665) is within the optimal 1-3 range. Ligand B (1.025) is at the lower end, potentially impacting permeability.

**4. H-Bond Donors:** Ligand A (3) is acceptable. Ligand B (1) is also good.

**5. H-Bond Acceptors:** Both ligands (5) are within the acceptable limit of <=10.

**6. QED:** Both ligands (0.635 and 0.592) have good drug-likeness scores (>0.5).

**7. DILI:** Ligand A (57.774) has a moderate DILI risk, but is still acceptable. Ligand B (14.541) has a very low DILI risk, which is a significant advantage.

**8. BBB:** Ligand A (53.432) has a moderate BBB penetration, which is not ideal for a CNS target. Ligand B (63.009) shows better BBB penetration, exceeding 60% and moving closer to the desirable >70%.

**9. Caco-2:** Both ligands have negative Caco-2 values, which is unusual and suggests a potential issue with the data or modeling. However, we can still compare them relatively. Ligand A (-5.935) is worse than Ligand B (-4.531).

**10. Solubility:** Both ligands have negative solubility values, which is also unusual. Ligand A (-2.976) is worse than Ligand B (-0.218).

**11. hERG:** Both ligands have very low hERG inhibition risk (0.58 and 0.148).

**12. Cl_mic:** Ligand A (19.136) has a lower microsomal clearance, indicating better metabolic stability than Ligand B (45.226).

**13. t1/2:** Ligand A (20.118) has a longer in vitro half-life than Ligand B (-16.226). The negative value for Ligand B is concerning and likely indicates a very rapid metabolism.

**14. Pgp:** Both ligands have very low P-gp efflux liability (0.145 and 0.003). Ligand B is slightly better.

**15. Binding Affinity:** Ligand A (-8.9 kcal/mol) has a significantly stronger binding affinity than Ligand B (-6.4 kcal/mol). This is a substantial difference (2.5 kcal/mol), which can outweigh some ADME drawbacks.

**Overall Assessment:**

Ligand A has a superior binding affinity and better metabolic stability (lower Cl_mic, longer t1/2). However, Ligand B has a lower DILI risk, better BBB penetration, and slightly better Pgp efflux profile. The negative solubility and Caco-2 values are concerning for both, but the difference between the two is less critical than the affinity difference. Given the importance of binding affinity for GPCRs, and the acceptable (though not ideal) BBB penetration of Ligand A, the stronger binding of Ligand A is the deciding factor.

Output:
1
2025-04-17 04:15:25,651 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 drug candidates, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (343.43 & 362.46 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (75.44) is significantly better than Ligand B (93.01). For CNS targets, we want TPSA <= 90, so Ligand A is preferable.

**3. logP:** Both ligands have good logP values (2.45 & 1.49), falling within the optimal 1-3 range.

**4. H-Bond Donors:** Both have 1 HBD, which is acceptable.

**5. H-Bond Acceptors:** Ligand A has 4 HBA, while Ligand B has 7. Both are within the acceptable limit of <= 10, but Ligand A is better.

**6. QED:** Both ligands have similar and good QED values (0.85 & 0.87), indicating good drug-like properties.

**7. DILI:** Ligand A (41.1%) has a slightly better DILI profile than Ligand B (72.8%), but both are reasonably safe.

**8. BBB:** This is crucial for a CNS target. Ligand A has a much higher BBB penetration percentile (87.6%) compared to Ligand B (43.9%). This is a significant advantage for Ligand A.

**9. Caco-2 Permeability:** Ligand A (-4.89) has a better Caco-2 value than Ligand B (-5.15), indicating better intestinal absorption.

**10. Aqueous Solubility:** Both have very poor aqueous solubility (-3.63 & -3.02). This could be a formulation challenge for both, but isn't a deciding factor here.

**11. hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.43 & 0.19).

**12. Microsomal Clearance:** Ligand B (30.1) has significantly lower microsomal clearance than Ligand A (70.5), suggesting better metabolic stability. This is a positive for Ligand B.

**13. In vitro Half-Life:** Ligand B (-1.06) has a longer in vitro half-life than Ligand A (1.86), which is favorable.

**14. P-gp Efflux:** Ligand A (0.25) has lower P-gp efflux than Ligand B (0.05), which is desirable for CNS penetration.

**15. Binding Affinity:** Ligand A (-9.7 kcal/mol) has a slightly better binding affinity than Ligand B (-8.4 kcal/mol). While both are excellent, the 1.3 kcal/mol difference is significant.

**Overall Assessment:**

Ligand A excels in key GPCR properties: TPSA, BBB penetration, and binding affinity. While Ligand B has better metabolic stability (lower Cl_mic and longer t1/2), the superior CNS penetration (BBB) and binding affinity of Ligand A are more critical for a DRD2 target. The slightly higher metabolic clearance of Ligand A could be addressed through structural modifications during lead optimization.

Output:
1
2025-04-17 04:15:25,651 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (351.491 and 381.523 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (64.09) is significantly better than Ligand B (88.57). For CNS targets, we want TPSA <= 90, and A is comfortably within that range, while B is approaching the upper limit.

**3. logP:** Both ligands have acceptable logP values (1.081 and 2.913, respectively), falling within the optimal 1-3 range.

**4. H-Bond Donors:** Both ligands are acceptable (1 and 2, respectively), well below the threshold of 5.

**5. H-Bond Acceptors:** Both ligands are acceptable (4 and 6, respectively), well below the threshold of 10.

**6. QED:** Both ligands have good QED values (0.823 and 0.77), indicating good drug-like properties.

**7. DILI:** Ligand A (5.739) has a much lower DILI risk than Ligand B (63.746). This is a significant advantage for A.

**8. BBB:** Both ligands have the same BBB penetration (52.579 percentile). This is okay, but not great; ideally, we'd want >70 for a CNS target.

**9. Caco-2 Permeability:** Ligand A (-4.575) has worse Caco-2 permeability than Ligand B (-5.299), but both are poor.

**10. Aqueous Solubility:** Ligand A (-0.299) has better aqueous solubility than Ligand B (-3.724).

**11. hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.293 and 0.342, respectively).

**12. Microsomal Clearance:** Ligand A (-1.07) has a lower (better) microsomal clearance than Ligand B (54.169). This suggests better metabolic stability for Ligand A.

**13. In vitro Half-Life:** Ligand B (65.289) has a significantly longer in vitro half-life than Ligand A (9.55). This is a positive for B.

**14. P-gp Efflux:** Ligand A (0.021) has much lower P-gp efflux liability than Ligand B (0.151). Lower P-gp efflux is crucial for CNS penetration.

**15. Binding Affinity:** Ligand B (-7.3) has a slightly better binding affinity than Ligand A (-8.2). While a 1.5 kcal/mol advantage is usually significant, the other factors weigh heavily in this case.

**Overall Assessment:**

Ligand A is the more promising candidate. While Ligand B has a slightly better binding affinity and in vitro half-life, Ligand A excels in critical ADME properties for a CNS-targeting GPCR. Specifically, its significantly lower DILI risk, better TPSA, lower P-gp efflux, and better metabolic stability are major advantages. The comparable BBB values aren't ideal for either, but the other properties of A make it the better choice.

Output:
0
2025-04-17 04:15:25,652 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (362.5 & 365.4 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (74.33) is higher than Ligand B (54.02). For a CNS target like DRD2, TPSA should be <=90, so both are acceptable, but B is better.

**3. logP:** Ligand A (1.42) is within the optimal 1-3 range. Ligand B (4.659) is higher, potentially leading to solubility issues and off-target effects.

**4. H-Bond Donors:** Both have 2 HBD, which is within the acceptable limit of <=5.

**5. H-Bond Acceptors:** Ligand A has 5 HBA, and Ligand B has 4. Both are within the acceptable limit of <=10.

**6. QED:** Both ligands have good QED scores (0.652 & 0.715), indicating drug-like properties.

**7. DILI:** Ligand A (33.3) has a significantly lower DILI risk than Ligand B (64.5). This is a major advantage for Ligand A.

**8. BBB:** Ligand B (83.3%) has a much better BBB penetration score than Ligand A (55.9%). This is crucial for a CNS target.

**9. Caco-2 Permeability:** Ligand A (-5.1) has worse Caco-2 permeability than Ligand B (-4.714), but both are poor.

**10. Aqueous Solubility:** Ligand A (-2.239) has better aqueous solubility than Ligand B (-5.15). This is important given Ligand B's higher logP.

**11. hERG Inhibition:** Ligand A (0.212) has a lower hERG inhibition risk than Ligand B (0.483).

**12. Microsomal Clearance:** Ligand A (-1.788) has lower (better) microsomal clearance than Ligand B (61.688), indicating better metabolic stability.

**13. In vitro Half-Life:** Ligand B (35.48) has a significantly longer half-life than Ligand A (19.341).

**14. P-gp Efflux:** Ligand A (0.045) has lower P-gp efflux than Ligand B (0.38), which is favorable for CNS penetration.

**15. Binding Affinity:** Ligand B (-8.4 kcal/mol) has a stronger binding affinity than Ligand A (-7.3 kcal/mol). This is a substantial difference (>1.5 kcal/mol) and a significant advantage for Ligand B.

**Overall Assessment:**

Ligand B excels in BBB penetration and binding affinity, which are critical for a CNS GPCR target. Its longer half-life is also a plus. However, it suffers from higher logP, DILI risk, and P-gp efflux. Ligand A has better ADME properties (DILI, solubility, clearance, P-gp), but its BBB penetration and binding affinity are weaker.

The difference in binding affinity (-8.4 vs -7.3) is substantial enough to potentially overcome the ADME liabilities of Ligand B, especially considering the importance of potency for GPCRs. While the higher logP of Ligand B is a concern, it's not insurmountable with potential formulation strategies. The improved BBB penetration is a significant advantage.

Output:
1
2025-04-17 04:15:25,652 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (422.71 Da) is slightly higher than Ligand B (363.487 Da), but both are acceptable.

**TPSA:** Ligand A (62.3) is better than Ligand B (80.12). For CNS targets, we want TPSA <= 90, both are within this range, but A is preferable.

**logP:** Ligand A (3.912) is optimal, while Ligand B (2.013) is a bit low, potentially hindering permeation.

**H-Bond Donors/Acceptors:** Both have acceptable HBD counts (1). Ligand B has a higher HBA count (6) compared to Ligand A (3), which is slightly less desirable, but both are within reasonable limits.

**QED:** Both ligands have good QED scores (A: 0.6, B: 0.776), indicating good drug-like properties.

**DILI:** Ligand A (63.823) has a higher DILI risk than Ligand B (43.195). This is a negative for Ligand A.

**BBB:** Ligand A (80.109) has a significantly better BBB penetration score than Ligand B (64.793). This is a crucial factor for a CNS target like DRD2.

**Caco-2 Permeability:** Ligand A (-4.934) has better Caco-2 permeability than Ligand B (-5.04), though both are negative values which is unusual and requires further investigation.

**Aqueous Solubility:** Ligand A (-4.431) has slightly better solubility than Ligand B (-3.111), though both are negative values which is unusual and requires further investigation.

**hERG:** Ligand A (0.311) has a lower hERG inhibition liability than Ligand B (0.55), which is preferable.

**Microsomal Clearance:** Ligand B (53.175) has lower microsomal clearance than Ligand A (40.255), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand B (-18.218) has a longer in vitro half-life than Ligand A (14.025), which is a positive.

**P-gp Efflux:** Ligand A (0.427) has lower P-gp efflux liability than Ligand B (0.14), which is favorable for CNS penetration.

**Binding Affinity:** Ligand B (-7.3 kcal/mol) has a significantly stronger binding affinity than Ligand A (-10.2 kcal/mol). This is a substantial advantage.

**Overall Assessment:**

Ligand B has a significantly better binding affinity and metabolic stability. However, Ligand A has better BBB penetration, lower P-gp efflux, and lower hERG risk. The superior binding affinity of Ligand B is a major advantage, and the difference of 2.9 kcal/mol is substantial enough to outweigh the slightly lower BBB and higher P-gp efflux. The lower DILI risk of Ligand B is also a positive. While the negative Caco-2 and solubility values are concerning for both, the overall profile of Ligand B is more promising.

Output:
1
2025-04-17 04:15:25,652 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B based on the provided guidelines, prioritizing GPCR-specific properties (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (366.53 and 367.81 Da) fall within the ideal range of 200-500 Da.

**TPSA:** Ligand A (49.85) is significantly better than Ligand B (93.09). For CNS targets, TPSA should be <= 90, and A is comfortably within this range, while B is slightly above.

**logP:** Both ligands have acceptable logP values (2.49 and 1.77), falling within the optimal 1-3 range.

**H-Bond Donors & Acceptors:** Both ligands have reasonable HBD (0 & 1) and HBA (4) counts, well within the recommended limits.

**QED:** Both ligands have good QED scores (0.77 and 0.86), indicating good drug-like properties.

**DILI:** Ligand A (38.66) has a lower DILI risk than Ligand B (55.33), which is preferable. Both are below the concerning threshold of 60.

**BBB:** Ligand A (71.23) has a slightly better BBB penetration percentile than Ligand B (68.13). While both are reasonably good, exceeding 70 is desirable for CNS targets, and A is closer.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values, which is unusual and suggests poor permeability. This is a concern for both.

**Aqueous Solubility:** Both ligands have negative solubility values, indicating poor aqueous solubility. This is a significant drawback for both.

**hERG Inhibition:** Both ligands have low hERG inhibition liability (0.36 and 0.40), which is good.

**Microsomal Clearance:** Ligand A (72.77) has a higher (worse) microsomal clearance than Ligand B (-22.74). A negative value for B indicates very good metabolic stability.

**In vitro Half-Life:** Ligand A (1.71) has a shorter half-life than Ligand B (-8.38). Again, the negative value for B suggests a very long half-life.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.22 and 0.05), which is favorable for CNS penetration.

**Binding Affinity:** Both ligands have the same binding affinity (-7.1 kcal/mol), which is excellent.

**Overall Assessment:**

Given the GPCR-specific priorities, Ligand A is slightly favored due to its significantly lower TPSA and better BBB penetration, despite its higher microsomal clearance and shorter half-life. The improved TPSA and BBB are more critical for CNS penetration than the metabolic stability advantage of Ligand B. The solubility and permeability issues are concerning for both, but can be addressed with formulation strategies.

Output:
1
2025-04-17 04:15:25,652 - INFO - Batch 97 complete. Total preferences: 1552
2025-04-17 04:15:25,652 - INFO - Processing batch 98/512...
2025-04-17 04:16:06,424 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (341.455 and 342.399 Da) fall comfortably within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (62.3) is significantly better than Ligand B (84.3). For CNS targets, we want TPSA <= 90, and A is much closer to the preferred <=60 range. B is pushing the upper limit.

**3. logP:** Ligand A (2.788) is optimal (1-3). Ligand B (0.489) is quite low, potentially hindering membrane permeability and CNS penetration.

**4. H-Bond Donors:** Both ligands have 1 HBD, which is within the acceptable limit of <=5.

**5. H-Bond Acceptors:** Ligand A has 3 HBAs, and Ligand B has 5. Both are within the acceptable limit of <=10.

**6. QED:** Both ligands have good QED scores (0.613 and 0.789), indicating drug-like properties.

**7. DILI:** Ligand A (20.24) has a much lower DILI risk than Ligand B (55.293). This is a significant advantage for A.

**8. BBB:** Ligand A (66.615) has a better BBB percentile than Ligand B (63.048), though both are reasonably good. A is closer to the desirable >70 for CNS targets.

**9. Caco-2:** Both ligands have negative Caco-2 values (-4.843 and -4.816), which is unusual and difficult to interpret without further context. They suggest poor permeability.

**10. Solubility:** Both ligands have negative solubility values (-2.29 and -2.44), indicating poor aqueous solubility.

**11. hERG:** Both ligands have very low hERG inhibition risk (0.48 and 0.067), which is excellent.

**12. Cl_mic:** Ligand B (25.787) has lower microsomal clearance than Ligand A (31.22), suggesting better metabolic stability.

**13. t1/2:** Ligand B (-13.385) has a significantly longer in vitro half-life than Ligand A (-6.88). This is a substantial advantage for B.

**14. Pgp:** Both ligands have very low Pgp efflux liability (0.098 and 0.045), which is favorable for CNS penetration.

**15. Binding Affinity:** Both ligands have very similar and strong binding affinities (-8.8 and -8.0 kcal/mol). The difference of 0.8 kcal/mol is not large enough to outweigh other factors.

**Overall Assessment:**

Considering the GPCR-specific priorities, Ligand A is the better candidate. While Ligand B has a longer half-life, Ligand A excels in crucial areas for CNS penetration: TPSA, logP, and DILI risk. The slightly better BBB percentile for A also contributes. The similar binding affinities mean that the superior ADME properties of A are more important. The poor Caco-2 and solubility values are concerning for both, but can potentially be addressed with formulation strategies.

Output:
1
2025-04-17 04:16:06,424 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (362.459 and 342.443 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (103.01) is slightly above the preferred <90 for CNS targets, but still reasonable. Ligand B (75.19) is excellent, well below 90.

**3. logP:** Ligand A (1.01) is at the lower end of the optimal range (1-3), potentially leading to permeability issues. Ligand B (2.21) is well within the optimal range.

**4. H-Bond Donors:** Ligand A (3) is acceptable, within the limit of 5. Ligand B (1) is even better.

**5. H-Bond Acceptors:** Ligand A (6) is within the acceptable limit of 10. Ligand B (4) is also good.

**6. QED:** Both ligands have good QED scores (0.578 and 0.657), indicating drug-like properties.

**7. DILI:** Both ligands have similar, acceptable DILI risk (39.473 and 39.938, both <40).

**8. BBB:** Ligand B (63.862) has a significantly better BBB percentile than Ligand A (46.336). This is a critical factor for a CNS target like DRD2.

**9. Caco-2 Permeability:** Ligand A (-6.001) has poor Caco-2 permeability. Ligand B (-5.069) is slightly better, but still not great.

**10. Aqueous Solubility:** Both ligands have poor aqueous solubility (-2.396 and -1.897).

**11. hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.437 and 0.116).

**12. Microsomal Clearance:** Ligand A (-4.202) has a negative value, which is unusual and suggests very low clearance (highly metabolically stable). Ligand B (19.259) has a higher clearance.

**13. In vitro Half-Life:** Ligand A (12.181) has a reasonable half-life. Ligand B (-1.77) has a very short half-life, which is a significant drawback.

**14. P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.017 and 0.016).

**15. Binding Affinity:** Ligand B (-7.4 kcal/mol) has a slightly better binding affinity than Ligand A (-8.0 kcal/mol). While A is slightly better, the difference is not substantial enough to overcome the other issues.

**Overall Assessment:**

Ligand B is the more promising candidate. While both have solubility issues, Ligand B excels in BBB penetration, has a better logP, and a slightly better binding affinity. Ligand A has better metabolic stability (lower clearance) and a slightly better binding affinity, but its poor Caco-2 permeability and lower BBB penetration are significant drawbacks for a CNS-targeted drug. The better BBB penetration of Ligand B is crucial for DRD2, making it the preferred candidate despite the shorter half-life.

Output:
1
2025-04-17 04:16:06,425 - INFO - Reasoning:

Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (378.881 and 348.422 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (68.29) is excellent, well below the 90 A^2 threshold for CNS targets. Ligand B (74.33) is still acceptable, but less optimal.

**3. logP:** Both ligands have good logP values (2.869 and 1.414), falling within the 1-3 range. Ligand A is slightly preferred here.

**4. H-Bond Donors:** Ligand A (1) and Ligand B (2) are both within the acceptable limit of 5.

**5. H-Bond Acceptors:** Ligand A (5) and Ligand B (4) are both within the acceptable limit of 10.

**6. QED:** Both ligands have similar, good QED values (0.715 and 0.763), indicating good drug-like properties.

**7. DILI:** Ligand A (70.221) has a higher DILI risk than Ligand B (43.66). This is a significant drawback for Ligand A.

**8. BBB:** Both ligands show good BBB penetration (42.924 and 70.531). Ligand B is significantly better, exceeding the 70 percentile threshold desirable for CNS targets.

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.926 and -4.721). This is unusual and suggests poor permeability. However, these values are on a log scale, so the absolute difference is important.

**10. Aqueous Solubility:** Both ligands have negative solubility values (-3.937 and -1.698). Again, this is unusual and suggests poor solubility. Ligand B is better here.

**11. hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.373 and 0.389).

**12. Microsomal Clearance:** Ligand A (91.309) has a higher microsomal clearance than Ligand B (9.84), indicating lower metabolic stability.

**13. In vitro Half-Life:** Ligand A (-0.803) has a shorter in vitro half-life than Ligand B (0.444).

**14. P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.135 and 0.026).

**15. Binding Affinity:** Both ligands have excellent binding affinity (-8.1 and -8.2 kcal/mol), which is very similar.

**Overall Assessment:**

While both ligands have excellent binding affinity, Ligand B is the more promising candidate. It has a significantly lower DILI risk, better BBB penetration, better solubility, better metabolic stability (lower Cl_mic and longer t1/2), and lower P-gp efflux. Although both have negative Caco-2 and solubility values, Ligand B is better in both cases. The slightly lower logP of Ligand B is not a major concern given its other advantages.

Output:
1
2025-04-17 04:16:06,425 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (384.38 and 383.25 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (93.53) is slightly above the optimal <90 for CNS targets, but still reasonable. Ligand B (49.41) is excellent, well below 90.

**3. logP:** Ligand A (0.515) is quite low, potentially hindering membrane permeability. Ligand B (3.968) is closer to the optimal 1-3 range.

**4. H-Bond Donors:** Both ligands have 1 HBD, which is within the acceptable limit of <=5.

**5. H-Bond Acceptors:** Ligand A has 6 HBA, and Ligand B has 2. Both are within the acceptable limit of <=10.

**6. QED:** Both ligands have good QED scores (0.772 and 0.813), indicating good drug-like properties.

**7. DILI:** Both ligands have acceptable DILI risk (69.794 and 66.421), below the concerning threshold of 60.

**8. BBB:** Ligand A has a very good BBB penetration percentile (81.815), exceeding the desirable >70 for CNS targets. Ligand B (70.841) also meets the threshold, but is less favorable than Ligand A.

**9. Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and suggests issues with the prediction method or the compounds themselves. However, we'll proceed with caution.

**10. Aqueous Solubility:** Both ligands have very poor aqueous solubility (-2.655 and -5.101). This is a significant drawback.

**11. hERG Inhibition:** Both ligands have low hERG inhibition risk (0.337 and 0.569).

**12. Microsomal Clearance:** Ligand A (20.353) has lower clearance than Ligand B (74.937), indicating better metabolic stability.

**13. In vitro Half-Life:** Ligand A (-40.502) has a negative half-life, which is not physically possible and indicates an issue with the prediction. Ligand B (41.018) is a reasonable half-life.

**14. P-gp Efflux:** Both ligands have low P-gp efflux liability (0.113 and 0.151), which is favorable for CNS penetration.

**15. Binding Affinity:** Ligand B (-9.1 kcal/mol) has a significantly stronger binding affinity than Ligand A (-7.5 kcal/mol). This is a >1.5 kcal/mol difference, which is a substantial advantage.

**Overall Assessment:**

Ligand B is the stronger candidate despite the solubility issues. The significantly improved binding affinity (-9.1 vs -7.5 kcal/mol) outweighs the slightly lower BBB and higher clearance. The TPSA is also much better for CNS penetration. Ligand A's negative half-life is a major red flag, and its low logP is concerning. While both have poor solubility, this can be addressed with formulation strategies.



Output:
1
2025-04-17 04:16:06,425 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (385.823 Da) is slightly higher than Ligand B (349.391 Da), but both are acceptable.

**2. TPSA:** Ligand A (62.39) is excellent, falling well below the 90 A^2 threshold for CNS targets. Ligand B (125.21) is higher, but still potentially acceptable, though less ideal for CNS penetration.

**3. logP:** Ligand A (3.867) is at the upper end of the optimal range (1-3), potentially raising concerns about solubility and off-target effects. Ligand B (-0.431) is significantly lower than optimal, which could hinder membrane permeability and CNS penetration.

**4. H-Bond Donors:** Ligand A (3) and Ligand B (4) are both within the acceptable limit of <=5.

**5. H-Bond Acceptors:** Ligand A (3) and Ligand B (5) are both within the acceptable limit of <=10.

**6. QED:** Ligand A (0.659) has a better QED score than Ligand B (0.497), indicating a more drug-like profile.

**7. DILI:** Ligand A (81.078) has a higher DILI risk than Ligand B (66.615), but both are reasonably acceptable.

**8. BBB:** Ligand A (64.211) shows better BBB penetration potential than Ligand B (46.685). This is a critical factor for a CNS target like DRD2.

**9. Caco-2 Permeability:** Ligand A (-4.953) has a negative value, which is unusual and suggests very poor permeability. Ligand B (-5.06) is similarly poor.

**10. Aqueous Solubility:** Ligand A (-5.985) has very poor aqueous solubility. Ligand B (-3.347) is also poor, but slightly better than Ligand A.

**11. hERG Inhibition:** Ligand A (0.663) has a lower hERG risk than Ligand B (0.189), which is preferable.

**12. Microsomal Clearance:** Ligand A (20.726) has lower microsomal clearance than Ligand B (26.533), suggesting better metabolic stability.

**13. In vitro Half-Life:** Ligand A (65.55) has a much longer in vitro half-life than Ligand B (-26.047). This is a significant advantage.

**14. P-gp Efflux:** Ligand A (0.366) has lower P-gp efflux liability than Ligand B (0.027), which is favorable for CNS exposure.

**15. Binding Affinity:** Ligand B (-7.9 kcal/mol) has a significantly stronger binding affinity than Ligand A (-9.3 kcal/mol). This is a substantial advantage, potentially outweighing some ADME concerns.

**Overall Assessment:**

Despite Ligand B's superior binding affinity, its poor BBB penetration, low logP, and poor Caco-2 permeability are major drawbacks for a CNS target. Ligand A, while having a weaker affinity, exhibits much better BBB penetration, a more favorable logP, and better metabolic stability. The poor solubility and permeability of Ligand A are concerning, but these could potentially be addressed through formulation strategies. The combination of acceptable ADME properties and reasonable BBB penetration makes Ligand A the more promising candidate.

Output:
0
2025-04-17 04:16:06,425 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (349.391 Da) is slightly lower, which could be beneficial for permeability.

**2. TPSA:** Ligand A (122.28) is borderline for CNS targets (ideally <90), while Ligand B (71.09) is well within the desired range. This is a significant advantage for Ligand B.

**3. logP:** Ligand A (0.71) is a bit low, potentially hindering membrane permeability. Ligand B (3.278) is optimal.

**4. H-Bond Donors:** Ligand A (3) is acceptable. Ligand B (2) is also good.

**5. H-Bond Acceptors:** Ligand A (7) is acceptable. Ligand B (3) is excellent.

**6. QED:** Both ligands have good QED scores (A: 0.645, B: 0.701), indicating drug-likeness.

**7. DILI:** Ligand A (67.778) has a higher DILI risk than Ligand B (40.054), though both are reasonably acceptable.

**8. BBB:** Ligand B (83.831) has a significantly better BBB penetration prediction than Ligand A (20.085). This is *critical* for a CNS target like DRD2.

**9. Caco-2 Permeability:** Ligand A (-5.49) has poor Caco-2 permeability, while Ligand B (-4.666) is slightly better, but still not great.

**10. Aqueous Solubility:** Ligand A (-1.837) has poor solubility, while Ligand B (-4.002) is also poor.

**11. hERG Inhibition:** Ligand A (0.064) has very low hERG inhibition risk, which is excellent. Ligand B (0.381) is slightly higher, but still acceptable.

**12. Microsomal Clearance:** Ligand A (28.05) has lower clearance than Ligand B (39.138), suggesting better metabolic stability.

**13. In vitro Half-Life:** Ligand B (18.46) has a longer half-life than Ligand A (9.46), which is desirable.

**14. P-gp Efflux:** Ligand A (0.055) has very low P-gp efflux liability, which is excellent. Ligand B (0.161) is slightly higher, but still acceptable.

**15. Binding Affinity:** Both ligands have excellent binding affinities (A: -7.6 kcal/mol, B: -7.7 kcal/mol). The difference is minimal.

**Overall Assessment:**

Ligand B is the stronger candidate. While Ligand A has a slightly better metabolic profile (lower Cl_mic) and P-gp efflux, Ligand B excels in the key areas for CNS GPCR targets: TPSA, logP, and *especially* BBB penetration. The significantly higher BBB score for Ligand B outweighs the minor advantages of Ligand A. The slightly longer half-life of Ligand B is also a plus. Both have acceptable DILI and hERG risks.

Output:
1
2025-04-17 04:16:06,426 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (348.447 and 344.342 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (67.67) is significantly better than Ligand B (99.52). For CNS targets, we want TPSA <= 90, and A is comfortably within that, while B is pushing the limit.

**logP:** Both ligands have acceptable logP values (1.822 and 2.15), falling within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A (0 HBD, 5 HBA) is slightly better than Ligand B (3 HBD, 4 HBA) in terms of balancing solubility and permeability.

**QED:** Both ligands have reasonable QED scores (0.836 and 0.789), indicating good drug-like properties.

**DILI:** Ligand A (29.779) has a much lower DILI risk than Ligand B (74.176). This is a significant advantage for A.

**BBB:** Ligand A (72.005) has a considerably higher BBB penetration percentile than Ligand B (57.619). This is *critical* for a CNS target like DRD2. A score >70 is desirable, and A is close, while B is considerably lower.

**Caco-2 Permeability:** Both have negative values, which is unusual and likely indicates a scaling issue. However, the magnitude of the negative value for A (-4.403) is less extreme than for B (-4.947), suggesting slightly better permeability.

**Aqueous Solubility:** Both have negative values, indicating poor solubility. A (-1.741) is slightly better than B (-3.256).

**hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.252 and 0.049).

**Microsomal Clearance:** Ligand A (50.35) has a higher (worse) microsomal clearance than Ligand B (-7.468). This suggests B is more metabolically stable.

**In vitro Half-Life:** Ligand B (-17.699) has a much longer in vitro half-life than Ligand A (-11.29). This is a significant advantage for B.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.028 and 0.009).

**Binding Affinity:** Both ligands have similar, strong binding affinities (-8.3 and -7.9 kcal/mol). The difference is less than the 1.5 kcal/mol threshold.

**Overall Assessment:**

Considering the GPCR-specific priorities, Ligand A is the better candidate. The significantly better BBB penetration (72.005 vs 57.619) and lower DILI risk (29.779 vs 74.176) outweigh the slightly higher microsomal clearance and shorter half-life. The TPSA is also much more favorable for CNS penetration. The binding affinities are comparable, so the ADME properties become the deciding factors.

Output:
0
2025-04-17 04:16:06,426 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (353.447 Da) is slightly lower, which could be beneficial for permeability. Ligand B (398.815 Da) is also acceptable.

**TPSA:** Ligand A (54.34) is significantly better than Ligand B (94.59). For CNS targets, we want TPSA <= 90, so Ligand A is much more favorable.

**logP:** Both ligands have good logP values (A: 2.862, B: 2.143), falling within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Both have acceptable HBD (1) and HBA (A: 4, B: 6) counts, well within the guidelines.

**QED:** Both ligands have similar and acceptable QED values (A: 0.77, B: 0.763).

**DILI:** Both have relatively high DILI risk (A: 87.049, B: 81.466), but this isn't a dealbreaker at this stage.

**BBB:** Ligand B (68.166) has a better BBB percentile than Ligand A (57.736), but both are below the desirable >70 for CNS targets.

**Caco-2 Permeability:** Both have negative Caco-2 values (-4.996 and -4.793), which is unusual and indicates very poor permeability. This is a significant concern for both.

**Aqueous Solubility:** Both have negative solubility values (-3.997 and -3.31), indicating very poor aqueous solubility. This is also a significant concern.

**hERG:** Both ligands have very low hERG inhibition liability (A: 0.394, B: 0.041), which is excellent.

**Microsomal Clearance:** Ligand B (-1.179) has much better (lower) microsomal clearance than Ligand A (54.023), indicating better metabolic stability.

**In vitro Half-Life:** Ligand B (-3.328) has a longer in vitro half-life than Ligand A (26.411), which is preferable.

**P-gp Efflux:** Ligand A (0.423) has slightly higher P-gp efflux liability than Ligand B (0.098), meaning B is better at avoiding efflux.

**Binding Affinity:** Both ligands have identical binding affinities (-8.4 kcal/mol), which is excellent and a strong point in their favor.

**Overall Assessment:**

Given the GPCR-specific priorities, TPSA is critical for CNS penetration. Ligand A has a much lower TPSA (54.34) than Ligand B (94.59). While Ligand B has better BBB, clearance, and half-life, the significantly higher TPSA is a major drawback. The poor Caco-2 and solubility for both are concerning, but can potentially be addressed with formulation strategies. The strong binding affinity is a positive for both. Considering the importance of TPSA for CNS targets, Ligand A is the more promising candidate.

Output:
0
2025-04-17 04:16:06,426 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (369.447 and 350.463 Da) fall within the ideal range of 200-500 Da.

**TPSA:** Ligand A (108.49) is higher than the preferred <90 for CNS targets, while Ligand B (84.42) is closer to the ideal range. This gives a slight edge to Ligand B.

**logP:** Ligand A (-0.175) is quite low, potentially hindering membrane permeability. Ligand B (1.952) is within the optimal 1-3 range. This is a significant advantage for Ligand B.

**H-Bond Donors/Acceptors:** Both have 1 HBD, which is good. Ligand A has 7 HBA, while Ligand B has 6. Both are acceptable, being under 10.

**QED:** Both ligands have good QED scores (0.547 and 0.685), indicating drug-like properties. Ligand B is slightly better.

**DILI:** Both have acceptable DILI risk (57.387 and 52.191), below the 60 threshold.

**BBB:** Ligand A (25.126) has a very low BBB penetration percentile, making it less likely to reach the CNS target. Ligand B (44.281) is better, but still not ideal (>70 is preferred). This is a major drawback for Ligand A.

**Caco-2 Permeability:** Both have negative Caco-2 values (-5.425 and -4.735), which is unusual and suggests poor permeability. However, the scale isn't clearly defined, so this is hard to interpret.

**Aqueous Solubility:** Both have negative solubility values (-2.034 and -2.047), which is also unusual. Again, the scale is unclear.

**hERG:** Both have very low hERG inhibition liability (0.023 and 0.104), which is excellent.

**Microsomal Clearance:** Ligand A (29.186) has lower clearance than Ligand B (77.883), suggesting better metabolic stability. This is a positive for Ligand A.

**In vitro Half-Life:** Ligand A (-23.055) has a negative half-life, which is impossible. This is a major red flag. Ligand B (4.482) has a reasonable half-life.

**P-gp Efflux:** Both have low P-gp efflux liability (0.01 and 0.03), which is good for CNS penetration.

**Binding Affinity:** Ligand B (-6.9 kcal/mol) has a slightly better binding affinity than Ligand A (-6.5 kcal/mol), although the difference is not huge.

**Overall Assessment:**

Ligand B is significantly more promising. It has a better logP, TPSA, BBB penetration, and in vitro half-life. While its BBB isn't ideal, it's far superior to Ligand A's. The negative values for Caco-2 and solubility are concerning for both, but the negative half-life for Ligand A is a fatal flaw. The slightly better affinity of Ligand B further supports its selection.

Output:
1
2025-04-17 04:16:06,426 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (334.419 and 354.401 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (72.19) is excellent, well below the 90 A^2 threshold for CNS targets. Ligand B (75.19) is also good, but slightly higher.

**3. logP:** Ligand A (3.407) is at the upper end of the optimal range (1-3), while Ligand B (1.91) is towards the lower end. While both are acceptable, a higher logP can aid in membrane permeability for CNS targets, making Ligand A slightly favored.

**4. H-Bond Donors:** Ligand A (2) and Ligand B (1) both meet the <=5 criteria.

**5. H-Bond Acceptors:** Ligand A (3) and Ligand B (4) both meet the <=10 criteria.

**6. QED:** Both ligands have reasonable QED values (0.884 and 0.774), indicating good drug-like properties.

**7. DILI:** Ligand A (62.195) has a higher DILI risk than Ligand B (35.789). This is a significant drawback for Ligand A.

**8. BBB:** Both ligands exhibit excellent BBB penetration (Ligand A: 80.264, Ligand B: 84.141), exceeding the 70% threshold for CNS targets. Ligand B is slightly better.

**9. Caco-2 Permeability:** Both have negative Caco-2 values which is unusual and likely indicates poor permeability. However, the values are on a similar scale, so this doesn't significantly differentiate them.

**10. Aqueous Solubility:** Both ligands have negative solubility values, which is also unusual and likely indicates poor solubility. Again, the values are similar.

**11. hERG Inhibition:** Ligand A (0.62) has a slightly higher hERG risk than Ligand B (0.369), but both are relatively low.

**12. Microsomal Clearance:** Ligand A (17.135) has a higher microsomal clearance than Ligand B (6.977), suggesting lower metabolic stability.

**13. In vitro Half-Life:** Ligand A (28.12) has a longer half-life than Ligand B (7.527). This is a positive for Ligand A.

**14. P-gp Efflux:** Ligand A (0.671) has lower P-gp efflux than Ligand B (0.015), which is favorable for CNS penetration.

**15. Binding Affinity:** Ligand B (-8.1 kcal/mol) has a significantly stronger binding affinity than Ligand A (-10.7 kcal/mol). This is a crucial advantage, as a >1.5 kcal/mol difference can outweigh other factors.

**Overall Assessment:**

While Ligand A has a better P-gp efflux profile and a longer half-life, its higher DILI risk, higher microsomal clearance, and significantly weaker binding affinity are major concerns. Ligand B, despite a slightly less optimal logP and a slightly higher P-gp efflux, presents a much more favorable profile overall, particularly due to its superior binding affinity and lower DILI risk. The strong binding affinity of Ligand B is a critical advantage for a GPCR target.

Output:
1
2025-04-17 04:16:06,427 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (344.455 and 359.861 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (58.64) is excellent, well below the 90 A^2 threshold for CNS targets. Ligand B (75.87) is still reasonable but less optimal.

**3. logP:** Ligand A (3.785) is within the optimal 1-3 range. Ligand B (4.731) is slightly higher, potentially leading to solubility issues or off-target interactions, but not drastically so.

**4. H-Bond Donors:** Ligand A (1) is good. Ligand B (2) is also acceptable.

**5. H-Bond Acceptors:** Ligand A (3) is good. Ligand B (6) is higher, but still within the acceptable limit of 10.

**6. QED:** Both ligands have reasonable QED values (0.908 and 0.566), indicating drug-like properties. Ligand A is significantly better.

**7. DILI:** Ligand A (35.091) has a much lower DILI risk than Ligand B (73.401), which is a significant advantage.

**8. BBB:** This is crucial for a CNS target. Ligand A (87.398) has a very good BBB percentile, exceeding the desirable >70 threshold. Ligand B (60.915) is considerably lower, raising concerns about CNS penetration.

**9. Caco-2 Permeability:** Ligand A (-4.336) and Ligand B (-5.368) have negative values, which is unusual and suggests poor permeability. However, the scale is not specified, so it's difficult to interpret the absolute impact.

**10. Aqueous Solubility:** Both ligands have very poor aqueous solubility (-4.587 and -4.477). This is a concern, but could potentially be addressed with formulation strategies.

**11. hERG Inhibition:** Both ligands have similar, low hERG inhibition risk (0.519 and 0.815).

**12. Microsomal Clearance:** Ligand A (81.756) has a lower microsomal clearance than Ligand B (83.42), suggesting better metabolic stability.

**13. In vitro Half-Life:** Ligand A (-8.947) has a significantly longer in vitro half-life than Ligand B (200.222). This is a major advantage.

**14. P-gp Efflux:** Both ligands have similar, low P-gp efflux liability (0.159 and 0.511).

**15. Binding Affinity:** Both ligands have the same binding affinity (-8.7 kcal/mol), which is excellent.

**Overall Assessment:**

Ligand A is significantly better due to its superior BBB penetration, lower DILI risk, better QED, and significantly longer in vitro half-life. While both have poor solubility, the other advantages of Ligand A outweigh this drawback, especially for a CNS target like DRD2. The slightly higher logP of Ligand B is also a minor concern.

Output:
0
2025-04-17 04:16:06,427 - INFO - Reasoning:

Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (355.394 and 367.515 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (56.15) is excellent, well below the 90 A^2 threshold for CNS targets. Ligand B (78.51) is still reasonable but less optimal, nearing the upper limit.

**3. logP:** Ligand A (4.188) is slightly high, potentially leading to solubility issues or off-target interactions. Ligand B (1.173) is quite low, which could hinder membrane permeability and CNS penetration.

**4. H-Bond Donors:** Ligand A (1) is good. Ligand B (2) is also acceptable.

**5. H-Bond Acceptors:** Ligand A (5) is good. Ligand B (4) is good.

**6. QED:** Both ligands (0.6 and 0.715) have good drug-likeness scores.

**7. DILI:** Ligand A (96.898) has a very high DILI risk, which is a significant concern. Ligand B (27.608) has a low DILI risk, a major advantage.

**8. BBB:** Ligand A (61.342) has a moderate BBB penetration, which is not ideal for a CNS target. Ligand B (33.385) has poor BBB penetration.

**9. Caco-2 Permeability:** Ligand A (-4.734) has poor Caco-2 permeability. Ligand B (-5.242) also has poor Caco-2 permeability.

**10. Aqueous Solubility:** Ligand A (-4.682) has poor aqueous solubility. Ligand B (-2.351) has slightly better solubility.

**11. hERG Inhibition:** Ligand A (0.828) has a moderate hERG risk. Ligand B (0.065) has very low hERG risk, a significant advantage.

**12. Microsomal Clearance:** Ligand A (75.964) has moderate clearance. Ligand B (19.103) has low clearance, indicating better metabolic stability.

**13. In vitro Half-Life:** Ligand A (16.606) has a moderate half-life. Ligand B (-13.326) has a very short half-life, a major drawback.

**14. P-gp Efflux:** Ligand A (0.857) has moderate P-gp efflux. Ligand B (0.017) has very low P-gp efflux, a significant advantage for CNS penetration.

**15. Binding Affinity:** Both ligands have similar, strong binding affinities (-9.2 and -8.2 kcal/mol). The difference of 1 kcal/mol is not substantial enough to outweigh other factors.

**Overall Assessment:**

Ligand A has a better TPSA and comparable affinity, but suffers from high DILI risk, poor BBB penetration, poor solubility, and moderate P-gp efflux. Ligand B, while having a slightly less optimal TPSA and lower BBB penetration, excels in safety (low DILI and hERG), metabolic stability (low Cl_mic), and reduced efflux (low Pgp). Given the CNS target, minimizing safety liabilities and maximizing brain exposure are crucial. The affinity difference is not large enough to overcome the significant safety concerns with Ligand A.

Output:
1
2025-04-17 04:16:06,427 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (346.515 and 350.375 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (41.57) is significantly better than Ligand B (127.8). For CNS targets, we want TPSA <= 90, and A is well within this range, while B is considerably above.

**logP:** Ligand A (4.158) is slightly high, but still within a potentially acceptable range. Ligand B (0.812) is quite low, which could hinder membrane permeability and CNS penetration.

**H-Bond Donors/Acceptors:** Ligand A (HBD=1, HBA=3) and Ligand B (HBD=2, HBA=5) both have reasonable numbers of H-bond donors and acceptors.

**QED:** Ligand A (0.87) has a better QED score than Ligand B (0.555), indicating a more drug-like profile.

**DILI:** Ligand A (13.3) has a much lower DILI risk than Ligand B (57.58), which is a significant advantage.

**BBB:** Ligand A (93.874) shows excellent BBB penetration, exceeding the desirable >70% threshold. Ligand B (76.735) is lower, but still reasonable, though not as promising for a CNS target.

**Caco-2 Permeability:** Ligand A (-4.492) and Ligand B (-5.214) both have negative values, which is unusual and suggests poor permeability. However, the scale is not specified, so it's difficult to interpret.

**Aqueous Solubility:** Ligand A (-3.583) and Ligand B (-2.378) both have negative values, indicating poor solubility.

**hERG:** Ligand A (0.934) has a lower hERG risk than Ligand B (0.163), which is preferable.

**Microsomal Clearance:** Ligand A (30.693) has a higher microsomal clearance than Ligand B (13.311), meaning it's likely to be metabolized more quickly.

**In vitro Half-Life:** Ligand B (15.401) has a longer in vitro half-life than Ligand A (6.963), which is a positive attribute.

**P-gp Efflux:** Ligand A (0.418) has a lower P-gp efflux liability than Ligand B (0.033), which is beneficial for CNS penetration.

**Binding Affinity:** Both ligands have very similar and strong binding affinities (-8.7 and -8.5 kcal/mol). The difference is less than 1.5 kcal/mol, so it's not a deciding factor.

**Overall Assessment:**

Ligand A is significantly better overall. Its superior TPSA, BBB penetration, lower DILI risk, and lower P-gp efflux outweigh its slightly higher logP and faster clearance. Ligand B's low logP is a major concern for CNS penetration, and its higher DILI risk is also unfavorable. While Ligand B has a better half-life, the other factors strongly favor Ligand A.

Output:
1
2025-04-17 04:16:06,427 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (349.391 and 361.345 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (122.28) is slightly above the preferred <90 for CNS targets, while Ligand B (113.69) is closer to the ideal range.

**logP:** Ligand A (-0.074) is a bit low, potentially hindering permeation. Ligand B (0.394) is better, falling within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Both have 3 HBDs, which is good. Ligand A has 7 HBAs, while Ligand B has 6. Both are acceptable (<=10).

**QED:** Both ligands have good QED scores (0.582 and 0.617), indicating drug-like properties.

**DILI:** Ligand A (35.169) has a lower DILI risk than Ligand B (56.999), which is a significant advantage.

**BBB:** This is critical for a CNS target like DRD2. Ligand B (75.649) has a much higher BBB penetration percentile than Ligand A (11.439). This is a major point in favor of Ligand B.

**Caco-2 Permeability:** Both have negative values, indicating poor permeability. Ligand A (-5.728) is slightly better than Ligand B (-4.839), but both are concerning.

**Aqueous Solubility:** Both have negative values, indicating poor solubility. Ligand A (-1.038) is slightly better than Ligand B (-1.595).

**hERG Inhibition:** Both have low hERG inhibition risk (0.105 and 0.203).

**Microsomal Clearance:** Ligand A (9.589) has a lower microsomal clearance than Ligand B (35.882), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (12.343) has a positive half-life, whereas Ligand B (-12.657) has a negative half-life, which is concerning.

**P-gp Efflux:** Both have very low P-gp efflux liability (0.015 and 0.026), which is good for CNS penetration.

**Binding Affinity:** Ligand A (-7.9 kcal/mol) has a slightly better binding affinity than Ligand B (-6.9 kcal/mol). This 1.0 kcal/mol difference is substantial and could outweigh some ADME drawbacks.

**Overall Assessment:**

Ligand B excels in BBB penetration, a crucial factor for a DRD2 ligand. However, it suffers from higher DILI risk, poor Caco-2 permeability, poor solubility, and a negative in vitro half-life. Ligand A has better metabolic stability (lower Cl_mic, positive t1/2), lower DILI risk, slightly better solubility, and a significantly stronger binding affinity. While Ligand A's logP is suboptimal and TPSA is slightly high, the superior binding affinity and better safety/stability profile make it the more promising candidate. The difference in binding affinity is large enough to potentially compensate for the slightly less ideal logP and TPSA.

Output:
0
2025-04-17 04:16:06,428 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (347.327 and 347.463 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (114.04) is better than Ligand B (79.26). Both are below the 140 A^2 threshold for oral absorption and, importantly, below the 90 A^2 target for CNS penetration. Ligand B is significantly better here.

**logP:** Ligand A (-0.073) is slightly lower than optimal (1-3), potentially hindering permeation. Ligand B (0.315) is also on the lower side, but better than A.

**H-Bond Donors/Acceptors:** Both have 2 HBD and a reasonable number of HBA (6 and 5 respectively). This is acceptable.

**QED:** Both ligands have good QED scores (0.582 and 0.777), indicating good drug-like properties. Ligand B is better.

**DILI:** Ligand A (76.076) has a higher DILI risk than Ligand B (6.049). This is a significant advantage for Ligand B.

**BBB:** Ligand A (81.776) has a better BBB penetration percentile than Ligand B (64.017), which is crucial for a CNS target like DRD2.

**Caco-2 Permeability:** Ligand A (-4.764) has a worse Caco-2 permeability than Ligand B (-5.446).

**Aqueous Solubility:** Ligand A (-3.849) has a worse aqueous solubility than Ligand B (-0.71).

**hERG:** Both ligands have very low hERG inhibition risk (0.17 and 0.131).

**Microsomal Clearance:** Ligand A (10.372) has a better microsomal clearance (lower) than Ligand B (-24.681), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (-8.129) has a worse in vitro half-life than Ligand B (0.864).

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.025 and 0.004).

**Binding Affinity:** Both ligands have the same binding affinity (-8.1 kcal/mol), which is excellent.

**Overall Assessment:**

Ligand B excels in several key areas: DILI risk, QED, TPSA, and solubility. While Ligand A has a slightly better BBB score and microsomal clearance, the significantly lower DILI risk and better TPSA of Ligand B are more important for a CNS-targeting GPCR. The similar binding affinity means the ADME properties will be the deciding factor.

Output:
1
2025-04-17 04:16:06,428 - INFO - Reasoning:

Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (352.475 and 346.387 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (67.87) is significantly better than Ligand B (102.74). For CNS targets, we want TPSA <= 90, so Ligand A is closer to this threshold. Ligand B is considerably higher and may suffer from reduced brain penetration.

**3. logP:** Ligand A (1.725) is within the optimal 1-3 range. Ligand B (-0.578) is below 1, which could hinder membrane permeability.

**4. H-Bond Donors:** Both ligands have 1 HBD, which is acceptable (<=5).

**5. H-Bond Acceptors:** Ligand A has 4 HBA, and Ligand B has 5. Both are within the acceptable range (<=10).

**6. QED:** Both ligands have similar QED values (0.758 and 0.737), indicating good drug-like properties.

**7. DILI:** Ligand A (18.728) has a much lower DILI risk than Ligand B (48.275). This is a significant advantage for Ligand A.

**8. BBB:** Ligand A (77.511) has a significantly better BBB percentile than Ligand B (46.064).  For a CNS target like DRD2, >70 is desirable, and Ligand A is much closer to that threshold.

**9. Caco-2:** Both have negative values (-4.459 and -4.933). These values are difficult to interpret without knowing the scale, but the negative values suggest low permeability.

**10. Solubility:** Both have negative values (-1.766 and -1.802). Similar to Caco-2, these values are difficult to interpret without knowing the scale, but suggest low solubility.

**11. hERG:** Both ligands have very low hERG risk (0.296 and 0.114).

**12. Cl_mic:** Ligand A (16.654) has a lower (better) microsomal clearance than Ligand B (-17.681). This suggests better metabolic stability for Ligand A.

**13. t1/2:** Ligand A (11.755) has a shorter half-life than Ligand B (24.579). This is a slight advantage for Ligand B, but not a major one.

**14. Pgp:** Both ligands have very low Pgp efflux liability (0.051 and 0.011).

**15. Binding Affinity:** Ligand B (-7.8 kcal/mol) has a slightly better binding affinity than Ligand A (-7.2 kcal/mol). While a 0.6 kcal/mol difference is noticeable, it may not be enough to overcome the significant ADME advantages of Ligand A.

**Overall Assessment:**

Ligand A is the superior candidate. While Ligand B has slightly better binding affinity, Ligand A demonstrates significantly better predicted CNS penetration (higher BBB, lower TPSA, better logP), lower DILI risk, and better metabolic stability (lower Cl_mic). These factors are crucial for a GPCR target in the CNS. The slight difference in binding affinity is likely surmountable with further optimization, whereas correcting the poor ADME profile of Ligand B would be more challenging.

Output:
0
2025-04-17 04:16:06,428 - INFO - Batch 98 complete. Total preferences: 1568
2025-04-17 04:16:06,428 - INFO - Processing batch 99/512...
2025-04-17 04:16:47,291 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (350.463 and 348.491 Da) fall comfortably within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (78.68) is slightly higher than Ligand B (59.39). For a CNS target like DRD2, TPSA < 90 is preferred, so both are acceptable, but Ligand B is better.

**3. logP:** Both ligands have good logP values (1.682 and 2.267), falling within the optimal 1-3 range.

**4. H-Bond Donors:** Both have 1 HBD, which is within the acceptable limit of <=5.

**5. H-Bond Acceptors:** Both have 5 HBA, also within the acceptable limit of <=10.

**6. QED:** Both ligands have high QED scores (0.844 and 0.857), indicating good drug-like properties.

**7. DILI:** Ligand A (15.083) has a slightly higher DILI risk than Ligand B (13.532), but both are below the 40 threshold and considered good.

**8. BBB:** This is a critical parameter for CNS targets. Ligand A has a BBB percentile of 78.558, while Ligand B has 74.292. Ligand A is slightly better here, but both are reasonably good.

**9. Caco-2 Permeability:** Both have negative Caco-2 values (-4.914 and -4.81), which is unusual and suggests poor permeability. This is a concern for both.

**10. Aqueous Solubility:** Both have negative solubility values (-1.203 and -1.375), indicating very poor aqueous solubility. This is a significant drawback for both.

**11. hERG Inhibition:** Both ligands have low hERG inhibition risk (0.494 and 0.473).

**12. Microsomal Clearance:** Ligand B (44.11) has significantly lower microsomal clearance than Ligand A (24.741), suggesting better metabolic stability.

**13. In vitro Half-Life:** Ligand A (-12.927) has a longer in vitro half-life than Ligand B (-8.309), which is favorable.

**14. P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.073 and 0.06), which is good for CNS penetration.

**15. Binding Affinity:** Ligand A (-7.3 kcal/mol) has a slightly better binding affinity than Ligand B (-6.8 kcal/mol). This 0.5 kcal/mol difference is meaningful, and could outweigh some of the ADME drawbacks.

**Overall Assessment:**

While both compounds have significant solubility and permeability issues, Ligand A appears slightly more promising. It has a better BBB score, a better binding affinity, and a longer half-life. Ligand B has better metabolic stability (lower Cl_mic), but the affinity difference is more important for a GPCR target. The poor solubility and permeability are major concerns for both, but could potentially be addressed with formulation strategies. Given the slightly better overall profile, especially the affinity and BBB, Ligand A is the preferred candidate.

Output:
1
2025-04-17 04:16:47,291 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 drug candidates, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (329.403 Da) is slightly lower, which can be beneficial for permeability. Ligand B (348.447 Da) is also good.

**TPSA:** Ligand A (47.04) is excellent, well below the 90 A^2 threshold for CNS targets. Ligand B (67.67) is still reasonable, but less optimal.

**logP:** Ligand A (4.845) is a bit high, potentially leading to solubility issues or off-target interactions. Ligand B (0.938) is quite low, which could hinder permeation.

**H-Bond Donors/Acceptors:** Ligand A (1 HBD, 4 HBA) and Ligand B (0 HBD, 5 HBA) both fall within acceptable ranges.

**QED:** Both ligands have good QED scores (A: 0.727, B: 0.794), indicating drug-like properties.

**DILI:** Ligand A (84.684) has a higher DILI risk than Ligand B (40.171). This is a significant negative for Ligand A.

**BBB:** Ligand B (88.29) has a significantly better BBB penetration score than Ligand A (74.06). This is crucial for a CNS target like DRD2.

**Caco-2 Permeability:** Ligand A (-4.938) has poor Caco-2 permeability, while Ligand B (-4.348) is slightly better, but still not great.

**Aqueous Solubility:** Ligand A (-5.857) has very poor aqueous solubility, likely due to its high logP. Ligand B (-1.288) is better, but still not ideal.

**hERG Inhibition:** Ligand A (0.751) has a slightly higher hERG risk than Ligand B (0.207).

**Microsomal Clearance:** Ligand A (79.597) has higher microsomal clearance, indicating faster metabolism, compared to Ligand B (43.79).

**In vitro Half-Life:** Ligand B (12.396 hours) has a much longer in vitro half-life than Ligand A (-13.213 hours).

**P-gp Efflux:** Ligand A (0.447) has lower P-gp efflux, which is good for CNS penetration, compared to Ligand B (0.144).

**Binding Affinity:** Ligand B (-7.9 kcal/mol) has a significantly stronger binding affinity than Ligand A (-10.8 kcal/mol). This is a major advantage for Ligand B.

**Overall Assessment:**

Ligand B is the stronger candidate. While its logP is low and Caco-2 permeability is not ideal, its superior BBB penetration, significantly better binding affinity, lower DILI risk, and longer half-life outweigh these drawbacks. Ligand A's high logP, poor solubility, higher DILI risk, and weaker binding affinity make it a less attractive candidate, despite its slightly lower molecular weight and better P-gp efflux. The strong binding affinity of Ligand B can potentially compensate for some of its ADME deficiencies.

Output:
1
2025-04-17 04:16:47,292 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (358.433 and 344.423 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (65.63) is significantly better than Ligand B (100.86). For CNS targets, we want TPSA <= 90, so Ligand A is preferable.

**3. logP:** Ligand A (3.11) is optimal (1-3). Ligand B (0.993) is a bit low, potentially hindering permeability.

**4. H-Bond Donors:** Both ligands have acceptable HBD counts (3 and 2, respectively), well below the limit of 5.

**5. H-Bond Acceptors:** Ligand A (4) is better than Ligand B (8), closer to the ideal limit of 10.

**6. QED:** Both ligands have good QED scores (0.562 and 0.722), indicating drug-like properties.

**7. DILI:** Both ligands have acceptable DILI risk (41.411 and 49.864), below the 60 threshold.

**8. BBB:** Ligand A (70.415) is better than Ligand B (63.474), and both are reasonably good, but Ligand A is above the 70% threshold desirable for CNS targets.

**9. Caco-2 Permeability:** Ligand A (-4.76) is better than Ligand B (-5.542), indicating better intestinal absorption, though both are negative values which is unusual.

**10. Aqueous Solubility:** Ligand A (-2.048) is better than Ligand B (-1.862), though both are negative, indicating poor solubility.

**11. hERG Inhibition:** Ligand A (0.874) is better than Ligand B (0.431), indicating lower cardiotoxicity risk.

**12. Microsomal Clearance:** Ligand A (34.72) is higher than Ligand B (18.503), meaning it has lower metabolic stability. This is a drawback for Ligand A.

**13. In vitro Half-Life:** Ligand A (58.742) is significantly better than Ligand B (-1.824).

**14. P-gp Efflux:** Ligand A (0.097) is much better than Ligand B (0.005), indicating lower P-gp efflux and better CNS exposure.

**15. Binding Affinity:** Ligand B (-8.0) has a slightly better binding affinity than Ligand A (-7.9), but the difference is small (0.1 kcal/mol).

**Overall Assessment:**

Considering the GPCR-specific priorities, Ligand A is the better candidate. It has superior TPSA, logP, BBB penetration, P-gp efflux, hERG inhibition, and in vitro half-life. While Ligand B has a slightly better binding affinity and lower microsomal clearance, the advantages of Ligand A in CNS penetration and safety outweigh this. The slightly higher clearance of Ligand A could be addressed through structural modifications.

Output:
1
2025-04-17 04:16:47,292 - INFO - Reasoning:

Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (363.816 and 352.523 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (58.56) is slightly higher than Ligand B (55.89), but both are below the 90 A^2 threshold desirable for CNS targets.

**3. logP:** Ligand A (3.894) is within the optimal 1-3 range, while Ligand B (1.023) is at the lower end, potentially hindering permeability.

**4. H-Bond Donors:** Ligand A (2) and Ligand B (1) are both within the acceptable limit of <=5.

**5. H-Bond Acceptors:** Ligand A (3) and Ligand B (4) are both within the acceptable limit of <=10.

**6. QED:** Both ligands have reasonable QED values (0.817 and 0.709), indicating good drug-like properties.

**7. DILI:** Ligand A (59.791) has a higher DILI risk than Ligand B (2.559). This is a significant drawback for Ligand A.

**8. BBB:** Ligand A (62.233) and Ligand B (58.744) both have BBB penetration around 60%, which is not ideal for a CNS target, but acceptable.

**9. Caco-2 Permeability:** Ligand A (-4.982) and Ligand B (-5.066) have similar, poor Caco-2 permeability.

**10. Aqueous Solubility:** Ligand A (-3.905) and Ligand B (-0.581) both have poor solubility. Ligand B is slightly better.

**11. hERG Inhibition:** Both ligands show low hERG inhibition liability (0.333 and 0.477), which is good.

**12. Microsomal Clearance:** Ligand B (-5.211) has a significantly lower (better) microsomal clearance than Ligand A (10.5). This suggests better metabolic stability for Ligand B.

**13. In vitro Half-Life:** Ligand B (-7.505) has a much longer in vitro half-life than Ligand A (15.555).

**14. P-gp Efflux:** Ligand A (0.187) has lower P-gp efflux than Ligand B (0.004), which is positive for CNS penetration.

**15. Binding Affinity:** Both ligands have excellent binding affinities (-9.5 and -7.5 kcal/mol). Ligand A has a 2 kcal/mol advantage.

**Overall Assessment:**

Ligand A has a better binding affinity, and lower P-gp efflux. However, its significantly higher DILI risk, higher microsomal clearance, and shorter half-life are major concerns. Ligand B, while having a slightly lower affinity, presents a much more favorable ADME profile with a significantly lower DILI risk, better metabolic stability (lower Cl_mic, longer t1/2), and improved solubility. Considering the GPCR-specific priorities, and the importance of a clean safety profile for CNS drugs, Ligand B is the more promising candidate. The 2 kcal/mol affinity difference can likely be overcome with further optimization, whereas mitigating the DILI risk of Ligand A would be far more challenging.

Output:
1
2025-04-17 04:16:47,292 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (350.463 and 392.327 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (78.67) is slightly higher than Ligand B (61.88). Both are below the 90 A^2 threshold desirable for CNS targets, but Ligand B is preferable.

**3. logP:** Ligand A (0.821) is a bit low, potentially hindering permeability. Ligand B (1.627) is better, falling within the optimal 1-3 range.

**4. H-Bond Donors:** Both have 1 HBD, which is good.

**5. H-Bond Acceptors:** Ligand A has 5 HBA, and Ligand B has 4. Both are acceptable (<=10).

**6. QED:** Ligand A (0.824) has a higher QED than Ligand B (0.682), indicating better overall drug-likeness.

**7. DILI:** Ligand A (13.532) has a slightly higher DILI risk than Ligand B (10.237), but both are well below the concerning threshold of 60.

**8. BBB:** Ligand B (61.768) has a significantly better BBB penetration percentile than Ligand A (52.889). This is *crucial* for a CNS target like DRD2.

**9. Caco-2 Permeability:** Ligand A (-4.816) has worse Caco-2 permeability than Ligand B (-4.876), although both are negative and indicate poor permeability.

**10. Aqueous Solubility:** Ligand A (0.132) has very poor solubility, while Ligand B (-1.769) is even worse. Solubility is a concern for both, but less critical than BBB for CNS targets.

**11. hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.311 and 0.443).

**12. Microsomal Clearance:** Ligand A (9.921) has lower microsomal clearance than Ligand B (10.499), suggesting better metabolic stability.

**13. In vitro Half-Life:** Ligand A (-3.271) has a more negative half-life, indicating a shorter half-life than Ligand B (4.245).

**14. P-gp Efflux:** Ligand A (0.041) has lower P-gp efflux than Ligand B (0.021), which is favorable for CNS penetration.

**15. Binding Affinity:** Ligand B (-7.1 kcal/mol) has a slightly better binding affinity than Ligand A (-7.6 kcal/mol). While the difference is small, it's still a positive.

**Overall Assessment:**

While Ligand A has a better QED and slightly better metabolic stability, Ligand B is superior due to its significantly improved BBB penetration (61.768 vs 52.889) and slightly better binding affinity. For a CNS target like DRD2, BBB penetration is paramount. The slightly lower logP of Ligand A is also a concern.

Output:
1
2025-04-17 04:16:47,292 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (350.375 and 348.418 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (122.13) is borderline for CNS penetration, slightly above the preferred <90. Ligand B (71.34) is excellent, well below 90, suggesting better CNS penetration.

**3. logP:** Ligand A (-0.671) is a bit low, potentially hindering membrane permeability. Ligand B (3.43) is optimal, falling within the 1-3 range.

**4. H-Bond Donors:** Both ligands have 2 HBD, which is within the acceptable limit of <=5.

**5. H-Bond Acceptors:** Ligand A has 7 HBA, acceptable. Ligand B has 3 HBA, also acceptable.

**6. QED:** Both ligands have similar QED values (0.722 and 0.707), indicating good drug-likeness.

**7. DILI:** Both ligands have similar DILI risk (45.25 and 46.995), both are good (low risk).

**8. BBB:** Ligand A has 70.027% BBB penetration, which is acceptable but not outstanding. Ligand B has 86.623%, which is very good and highly desirable for a CNS target like DRD2.

**9. Caco-2 Permeability:** Ligand A (-5.095) has poor Caco-2 permeability. Ligand B (-4.476) has better, but still poor, Caco-2 permeability.

**10. Aqueous Solubility:** Ligand A (-0.752) has poor aqueous solubility. Ligand B (-4.175) has even poorer aqueous solubility.

**11. hERG Inhibition:** Both ligands have low hERG inhibition risk (0.235 and 0.457).

**12. Microsomal Clearance:** Ligand A (-4.324) has low microsomal clearance, suggesting good metabolic stability. Ligand B (68.999) has high microsomal clearance, indicating faster metabolism.

**13. In vitro Half-Life:** Ligand A (-12.858) has a long in vitro half-life, which is desirable. Ligand B (33.55) has a shorter half-life.

**14. P-gp Efflux:** Both ligands have very low P-gp efflux (0.004 and 0.371), which is excellent for CNS penetration.

**15. Binding Affinity:** Ligand B (-8.2 kcal/mol) has a significantly stronger binding affinity than Ligand A (-7.0 kcal/mol). This >1.5 kcal/mol difference is substantial and can outweigh some ADME drawbacks.

**Overall Assessment:**

Considering the GPCR-specific priorities, Ligand B is the more promising candidate. While both have acceptable DILI and P-gp efflux, Ligand B excels in BBB penetration and, crucially, binding affinity. The higher logP of Ligand B is also favorable. Although its solubility and Caco-2 permeability are poor, the strong affinity and good BBB penetration are likely to be more critical for a CNS-targeting drug. Ligand A's lower logP and poorer affinity are significant drawbacks.

Output:
1
2025-04-17 04:16:47,293 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (354.491 and 383.798 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (78.87) is higher than Ligand B (53.09). For a CNS target like DRD2, TPSA should be <=90, so both are acceptable, but B is better.

**3. logP:** Both ligands have good logP values (1.562 and 1.063), falling within the optimal 1-3 range.

**4. H-Bond Donors:** Ligand A has 2 HBD, while Ligand B has 0. Both are acceptable (<=5).

**5. H-Bond Acceptors:** Both ligands have 4 HBA, which is within the acceptable range of <=10.

**6. QED:** Both ligands have similar QED values (0.727 and 0.681), indicating good drug-likeness.

**7. DILI:** Ligand A (7.871) has a significantly lower DILI risk than Ligand B (45.173). This is a substantial advantage for Ligand A.

**8. BBB:** Ligand B (79.566) has a slightly better BBB penetration percentile than Ligand A (73.75), but both are above the desirable 70% threshold for CNS targets.

**9. Caco-2 Permeability:** Both have negative values, indicating a scale rather than a percentile. Without knowing the scale, it's hard to compare, but both are similarly poor.

**10. Aqueous Solubility:** Both have negative values, indicating a scale rather than a percentile. Without knowing the scale, it's hard to compare, but both are similarly poor.

**11. hERG Inhibition:** Both ligands have similar, very low hERG inhibition liability (0.4 and 0.447).

**12. Microsomal Clearance:** Ligand B (-7.737) has a *negative* microsomal clearance, which is not physically possible. This suggests an error in the data or a very unusual metabolic profile. Ligand A (32.334) is more reasonable.

**13. In vitro Half-Life:** Ligand B (-11.984) has a negative half-life, which is also not physically possible. This further reinforces the data quality concerns for Ligand B. Ligand A (3.333) is a reasonable half-life.

**14. P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.02 and 0.044), which is good for CNS penetration.

**15. Binding Affinity:** Both ligands have excellent binding affinities (-7.1 and -7.6 kcal/mol). Ligand B is slightly better (-7.6 vs -7.1), but the difference is less than the 1.5 kcal/mol threshold that might outweigh other drawbacks.

**Overall Assessment:**

Ligand B has a slightly better BBB and binding affinity, but suffers from impossible values for microsomal clearance and half-life, and a significantly higher DILI risk. Ligand A has a more reasonable ADME profile, with a lower DILI risk and plausible metabolic parameters. Given the data issues with Ligand B, and the importance of ADME properties for a CNS target, Ligand A is the more viable drug candidate.

Output:
0
2025-04-17 04:16:47,293 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (351.403 and 367.559 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (132.96) is better than Ligand B (61.44). For CNS targets, TPSA should be <=90, and both meet this criterion, but A is closer to the upper limit.

**logP:** Ligand A (-1.511) is lower than the optimal 1-3 range, potentially hindering permeability. Ligand B (1.728) is within the optimal range. This is a significant advantage for B.

**H-Bond Donors/Acceptors:** Ligand A has 4 HBD and 5 HBA, which are acceptable. Ligand B has 2 HBD and 4 HBA, also acceptable.

**QED:** Both ligands have reasonable QED values (0.489 and 0.686), indicating drug-like properties, with B being slightly better.

**DILI:** Ligand A (23.071) has a lower DILI risk than Ligand B (15.083), which is favorable.

**BBB:** This is crucial for a CNS target like DRD2. Ligand B (78.558) has a significantly higher BBB percentile than Ligand A (22.063). This is a major advantage for B.

**Caco-2 Permeability:** Ligand A (-6.02) and Ligand B (-5.496) both have negative values, which is unusual and suggests poor permeability. However, the scale isn't specified, so it's hard to interpret.

**Aqueous Solubility:** Both ligands have negative solubility values (-1.644 and -3.105), indicating poor solubility. This is a concern for both, but B is slightly worse.

**hERG Inhibition:** Both ligands have very low hERG inhibition liability (0.041 and 0.466), which is excellent.

**Microsomal Clearance:** Ligand A (-27.031) has a much lower (better) microsomal clearance than Ligand B (45.397), indicating greater metabolic stability.

**In vitro Half-Life:** Ligand A (4.9 hours) has a slightly longer half-life than Ligand B (3.14 hours).

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.003 and 0.058), which is good for CNS penetration.

**Binding Affinity:** Both ligands have the same binding affinity (-7.9 kcal/mol), which is excellent and meets the criteria.

**Overall Assessment:**

While Ligand A has better DILI and metabolic stability, Ligand B excels in critical areas for a CNS-targeting GPCR: significantly higher BBB penetration and a more favorable logP value. The binding affinity is identical, so these differences are paramount. The poor solubility and Caco-2 permeability are concerns for both, but the BBB is the deciding factor here.

Output:
1
2025-04-17 04:16:47,293 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (344.342 and 349.519 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (69.68) is higher than Ligand B (52.65). For CNS targets, we prefer TPSA <= 90, so both are acceptable, but B is better.

**3. logP:** Both ligands have good logP values (2.618 and 2.406), falling within the optimal 1-3 range.

**4. H-Bond Donors:** Both have 1 HBD, which is within the acceptable limit of <=5.

**5. H-Bond Acceptors:** Ligand A has 6 HBAs, and Ligand B has 3. Both are below the limit of <=10.

**6. QED:** Both ligands have good QED scores (0.642 and 0.793), indicating good drug-like properties.

**7. DILI:** Ligand A has a DILI risk of 80.729, which is high. Ligand B has a much lower DILI risk of 5.739, which is excellent. This is a significant advantage for Ligand B.

**8. BBB:** Both ligands have good BBB penetration (47.926 and 80.574). Ligand B is significantly better, exceeding the desirable >70 threshold for CNS targets.

**9. Caco-2 Permeability:** Both have negative Caco-2 values (-4.171 and -4.631), which is unusual and suggests poor permeability. However, these values are on a scale where negative values are possible and don't necessarily rule out absorption.

**10. Aqueous Solubility:** Both have negative solubility values (-4.9 and -2.659), indicating very poor aqueous solubility. This is a concern for both, but less so for B.

**11. hERG Inhibition:** Both ligands have low hERG inhibition risk (0.494 and 0.761).

**12. Microsomal Clearance:** Ligand A has a higher microsomal clearance (79.8) than Ligand B (18.453). Lower clearance is preferred for metabolic stability, giving an advantage to Ligand B.

**13. In vitro Half-Life:** Ligand A has a longer half-life (24.237) than Ligand B (9.379). This is a positive for Ligand A, but the difference isn't huge.

**14. P-gp Efflux:** Both ligands show low P-gp efflux liability (0.247 and 0.156).

**15. Binding Affinity:** Ligand B (-8.8 kcal/mol) has a slightly better binding affinity than Ligand A (-7.9 kcal/mol). While both are good, the 0.9 kcal/mol difference is significant and can outweigh some ADME drawbacks.

**Overall Assessment:**

Ligand B is the superior candidate. While Ligand A has a slightly longer half-life, Ligand B excels in critical areas for a CNS-targeting GPCR ligand: significantly lower DILI risk, much better BBB penetration, lower microsomal clearance, and slightly better binding affinity. The poor solubility and Caco-2 permeability are concerning for both, but the other advantages of Ligand B outweigh these drawbacks.

Output:
1
2025-04-17 04:16:47,294 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B based on the provided guidelines, prioritizing GPCR-specific properties (BBB, logP, Pgp, TPSA, and affinity) for DRD2.

**Molecular Weight:** Both ligands (349.475 and 363.462 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (78.51) is better than Ligand B (85) as it is closer to the optimal <90 for CNS targets.

**logP:** Both ligands have acceptable logP values (1.755 and 2.858), falling within the 1-3 range. Ligand B is slightly higher, which could potentially lead to some off-target effects, but is still within acceptable limits.

**H-Bond Donors/Acceptors:** Ligand A has 2 HBD and 3 HBA, while Ligand B has 1 HBD and 6 HBA. Both are within the acceptable ranges (<=5 HBD and <=10 HBA).

**QED:** Both ligands have good QED scores (0.794 and 0.853), indicating good drug-like properties.

**DILI:** Ligand A (25.281) has a significantly lower DILI risk than Ligand B (61.574). This is a substantial advantage for Ligand A.

**BBB:** Ligand B (85.459) has a much better BBB penetration percentile than Ligand A (63.862). This is a critical factor for a CNS target like DRD2.

**Caco-2 Permeability:** Both have negative values (-4.935 and -4.885), which is unusual and difficult to interpret without knowing the scale. However, they are similar.

**Aqueous Solubility:** Both have negative values (-2.52 and -3.93), also unusual and difficult to interpret. They are similar.

**hERG Inhibition:** Ligand A (0.143) has a lower hERG inhibition liability than Ligand B (0.454), which is favorable.

**Microsomal Clearance:** Ligand A (10.749) has a lower microsomal clearance than Ligand B (34.842), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (-7.535) has a longer in vitro half-life than Ligand B (8.19).

**P-gp Efflux:** Ligand A (0.026) has a much lower P-gp efflux liability than Ligand B (0.137), which is crucial for CNS penetration.

**Binding Affinity:** Both ligands have very similar binding affinities (-7.5 and -7.4 kcal/mol). The difference is negligible.

**Overall Assessment:**

Ligand A excels in safety (DILI, hERG), metabolic stability (Cl_mic, t1/2), and CNS penetration (P-gp efflux). While Ligand B has a better BBB percentile, the other advantages of Ligand A, especially the significantly lower DILI and P-gp efflux, outweigh this difference. The similar binding affinities make the ADME/Tox profile the deciding factor.

Output:
0
2025-04-17 04:16:47,294 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (347.415 and 368.474 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (93.46) is slightly above the preferred <90 for CNS targets, but still reasonable. Ligand B (67.43) is excellent, well below 90.

**logP:** Both ligands (1.639 and 2.281) are within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Both have 2 HBD and 5/4 HBA, which are acceptable.

**QED:** Both ligands have good QED scores (0.551 and 0.691), indicating drug-like properties.

**DILI:** Ligand A (47.693) has a slightly better DILI score than Ligand B (60.799), indicating a lower risk of liver injury. However, both are below the concerning threshold of 60.

**BBB:** Both ligands have excellent BBB penetration (71.811 and 72.005), exceeding the desirable >70% for CNS targets.

**Caco-2 Permeability:** Ligand A (-4.461) and Ligand B (-5.142) both have negative Caco-2 values, which is unusual and suggests poor permeability. This is a significant concern.

**Aqueous Solubility:** Both ligands have very poor aqueous solubility (-3.143 and -3.175). This is a major drawback for oral bioavailability.

**hERG Inhibition:** Both ligands show low hERG inhibition liability (0.339 and 0.74), which is good.

**Microsomal Clearance:** Ligand A (35.07) has a lower microsomal clearance than Ligand B (58.312), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (-11.927) has a negative in vitro half-life, which is not possible and indicates a problem with the data or prediction. Ligand B (11.345) has a reasonable half-life.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.242 and 0.297), which is favorable for CNS exposure.

**Binding Affinity:** Ligand B (-8.3 kcal/mol) has a significantly stronger binding affinity than Ligand A (-7.5 kcal/mol). This 0.8 kcal/mol difference is substantial and could outweigh some of the ADME drawbacks.

**Overall Assessment:**

While both ligands have issues with solubility and Caco-2 permeability, Ligand B is the more promising candidate. Its significantly stronger binding affinity (-8.3 vs -7.5 kcal/mol) is a major advantage for a GPCR target. The slightly higher DILI risk is less concerning than the problematic in vitro half-life of Ligand A. The better metabolic stability (lower Cl_mic) of Ligand A is a plus, but the affinity difference is more crucial.

Output:
1
2025-04-17 04:16:47,294 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (368.905 and 367.49 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (58.64) is slightly higher than Ligand B (53.51). Both are below the 90 A^2 threshold desirable for CNS targets, which is good.

**3. logP:** Both ligands have excellent logP values (2.689 and 2.734), falling within the optimal 1-3 range.

**4. H-Bond Donors:** Ligand A has 1 HBD, while Ligand B has 0. Both are within the acceptable limit of <=5.

**5. H-Bond Acceptors:** Ligand A has 3 HBA, and Ligand B has 4. Both are below the limit of <=10.

**6. QED:** Both ligands have good QED scores (0.716 and 0.803), indicating good drug-like properties.

**7. DILI:** Ligand A (18.922) has a significantly lower DILI risk than Ligand B (40.054). This is a substantial advantage for Ligand A.

**8. BBB:** Ligand B (89.725) has a better BBB penetration percentile than Ligand A (76.658). This is a crucial factor for a CNS target like DRD2.

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.591 and -4.556). These values are unusual and suggest poor permeability, but are likely on a log scale where negative values represent low permeability.

**10. Aqueous Solubility:** Both ligands have negative solubility values (-3.046 and -2.815), indicating poor aqueous solubility.

**11. hERG Inhibition:** Ligand A (0.273) has a lower hERG inhibition liability than Ligand B (0.526), which is preferable.

**12. Microsomal Clearance:** Ligand A (58.832) has a slightly higher microsomal clearance than Ligand B (56.877), suggesting slightly lower metabolic stability.

**13. In vitro Half-Life:** Ligand B (-1.609) has a better in vitro half-life than Ligand A (-4.601).

**14. P-gp Efflux:** Ligand A (0.186) has lower P-gp efflux liability than Ligand B (0.146), which is favorable for CNS penetration.

**15. Binding Affinity:** Ligand A (-8.4 kcal/mol) has a slightly better binding affinity than Ligand B (-7.8 kcal/mol). This 1.6 kcal/mol difference is significant and can outweigh some ADME drawbacks.

**Overall Assessment:**

Ligand A has a significantly better safety profile (lower DILI, lower hERG) and a better binding affinity. While Ligand B has a slightly better BBB penetration, the difference isn't large enough to overcome the advantages of Ligand A, especially considering the importance of safety and potency. Both have poor solubility and permeability, which would need to be addressed in further optimization. However, the stronger binding affinity and improved safety profile of Ligand A make it the more promising candidate.

Output:
1
2025-04-17 04:16:47,294 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (368.865 and 369.849 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (89.53) is better than Ligand B (74.87). Both are below the 90 A^2 threshold for CNS targets, but A is closer to the ideal.

**3. logP:** Both ligands have a logP of approximately 1.53, which is optimal.

**4. H-Bond Donors:** Ligand A has 2 HBD, and Ligand B has 1. Both are within the acceptable limit of <=5.

**5. H-Bond Acceptors:** Both ligands have 4 HBA, well within the acceptable limit of <=10.

**6. QED:** Both ligands have high QED scores (0.846 and 0.873), indicating good drug-like properties.

**7. DILI:** Ligand A (59.442) has a lower DILI risk than Ligand B (70.919), which is preferable. Both are below the 60 threshold, but A is better.

**8. BBB:** Ligand B (58.511) significantly outperforms Ligand A (25.32) in BBB penetration. This is a *critical* factor for a CNS target like DRD2.

**9. Caco-2 Permeability:** Ligand A (-4.997) has slightly better Caco-2 permeability than Ligand B (-4.766), but both are negative values, indicating poor permeability.

**10. Aqueous Solubility:** Both ligands have similar, very poor aqueous solubility (-3.183 and -3.079).

**11. hERG Inhibition:** Ligand A (0.394) has a slightly higher hERG inhibition liability than Ligand B (0.219), meaning B is safer.

**12. Microsomal Clearance:** Ligand B (1.568) has much lower microsomal clearance than Ligand A (6.389), indicating better metabolic stability.

**13. In vitro Half-Life:** Ligand B (16.429 hours) has a significantly longer half-life than Ligand A (-13.147 hours).

**14. P-gp Efflux:** Ligand A (0.326) has lower P-gp efflux than Ligand B (0.102), which is desirable for CNS penetration.

**15. Binding Affinity:** Ligand B (-7.8 kcal/mol) has a slightly better binding affinity than Ligand A (-8.0 kcal/mol). While A is better, the difference is small.

**Overall Assessment:**

Ligand B is the stronger candidate. While Ligand A has slightly better TPSA and P-gp efflux, Ligand B's *superior* BBB penetration, metabolic stability (lower Cl_mic, longer t1/2), lower DILI risk, and slightly better binding affinity outweigh these minor drawbacks. The BBB is a critical property for CNS targets, and Ligand B's significantly higher BBB percentile makes it the more promising candidate. The poor solubility and Caco-2 permeability are concerns for both, but can be addressed with formulation strategies.

Output:
1
2025-04-17 04:16:47,295 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 drug candidates, considering the provided guidelines and GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (372.435 and 362.459 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (105.72) is better than Ligand B (117). Both are below the 140 threshold for oral absorption, but Ligand A is closer to the preferred <90 for CNS targets.

**logP:** Both ligands have good logP values (2.335 and 1.21), falling within the 1-3 optimal range. Ligand A is slightly better.

**H-Bond Donors/Acceptors:** Ligand A (1 HBD, 9 HBA) is preferable to Ligand B (3 HBD, 6 HBA). Both are within acceptable limits, but fewer H-bonds generally improves permeability.

**QED:** Both ligands have good QED scores (0.662 and 0.756), indicating good drug-like properties.

**DILI:** Ligand A (96.084) has a significantly higher DILI risk than Ligand B (65.529). This is a major concern for Ligand A.

**BBB:** Both ligands have similar BBB penetration (48.197 and 48.391). Neither is particularly high, but acceptable for non-CNS targets. Given this is a CNS target, higher BBB is desirable.

**Caco-2 Permeability:** Both have negative Caco-2 values (-5.191 and -5.545), which is unusual and suggests poor permeability. This is a significant drawback for both.

**Aqueous Solubility:** Both have negative solubility values (-4.785 and -2.643), indicating very poor solubility. This is a major hurdle for drug development.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.315 and 0.575).

**Microsomal Clearance:** Ligand A (88.147) has a lower (better) microsomal clearance than Ligand B (-24.182). This suggests better metabolic stability for Ligand A.

**In vitro Half-Life:** Ligand A (0.257) has a very short half-life, while Ligand B (-26.19) is even worse. Both are very poor.

**P-gp Efflux:** Ligand A (0.35) has lower P-gp efflux than Ligand B (0.169), which is favorable for CNS penetration.

**Binding Affinity:** Ligand A (-8.2 kcal/mol) has a slightly better binding affinity than Ligand B (-7.9 kcal/mol). While the difference is not huge, it's a positive for Ligand A.

**Overall Assessment:**

Despite having a slightly better affinity and P-gp efflux, Ligand A is significantly hampered by its high DILI risk and very short half-life. Ligand B, while having a slightly weaker affinity, has a much lower DILI risk and a slightly better half-life. Both have poor solubility and permeability, which are major issues. Considering the GPCR-specific priorities, the lower DILI risk of Ligand B is a critical advantage, even with the slightly lower affinity. The solubility and permeability issues would need to be addressed through formulation or structural modifications, but starting with a lower toxicity profile is preferable.

Output:
1
2025-04-17 04:16:47,295 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (365.817 and 350.354 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (82.71) is excellent, well below the 90 A^2 threshold for CNS targets. Ligand B (133.15) is higher, approaching the 140 A^2 limit for oral absorption and less ideal for CNS penetration.

**3. logP:** Ligand A (1.454) is within the optimal 1-3 range. Ligand B (0.981) is slightly below 1, potentially hindering permeation, but not drastically.

**4. H-Bond Donors:** Ligand A (1) is good. Ligand B (4) is higher, potentially impacting permeability.

**5. H-Bond Acceptors:** Ligand A (4) is good. Ligand B (8) is higher, potentially impacting permeability.

**6. QED:** Ligand A (0.785) is excellent, indicating strong drug-likeness. Ligand B (0.581) is acceptable, but less ideal.

**7. DILI:** Both ligands have relatively high DILI risk (74.292 and 77.394), but are still below the concerning >60 threshold. This is a potential area for future optimization for both.

**8. BBB:** Ligand A (64.754) is moderate, while Ligand B (47.15) is lower. For a CNS target like DRD2, a higher BBB percentile is strongly preferred.

**9. Caco-2:** Both ligands have negative Caco-2 values (-4.759 and -5.448) which is unusual and suggests poor permeability.

**10. Solubility:** Both ligands have negative solubility values (-2.357 and -3.1), indicating very poor aqueous solubility. This is a significant drawback.

**11. hERG:** Both ligands have low hERG inhibition risk (0.138 and 0.372), which is positive.

**12. Cl_mic:** Ligand A (67.891) has higher metabolic clearance than Ligand B (31.381), suggesting lower metabolic stability.

**13. t1/2:** Ligand B (-15.588) has a negative in vitro half-life, which is not possible and indicates a very rapid metabolism. Ligand A (-6.935) is also negative, but less so. These values are suspect.

**14. Pgp:** Both ligands have low P-gp efflux liability (0.098 and 0.031), which is favorable for CNS penetration.

**15. Binding Affinity:** Ligand B (-8.0 kcal/mol) has a slightly better binding affinity than Ligand A (-7.8 kcal/mol). While the difference is small, it is within the range where it could outweigh minor ADME drawbacks.

**Overall Assessment:**

Despite the slightly better affinity of Ligand B, Ligand A is the more promising candidate. The key factors driving this decision are: significantly better TPSA, better QED, and a more reasonable (though still poor) BBB score compared to Ligand B. The negative Caco-2 and solubility values are concerning for both, but the TPSA advantage of Ligand A suggests it might be more amenable to structural modifications to improve these properties. The negative half-life values for both are problematic and require further investigation. Ligand B's lower BBB and higher HBD/HBA counts are less desirable for a CNS target.



Output:
0
2025-04-17 04:16:47,295 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B based on the provided guidelines, prioritizing GPCR-specific properties (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (346.431 and 350.459 Da) fall within the ideal range of 200-500 Da.

**TPSA:** Both ligands (96.11 and 98.66) are below the 140 A^2 threshold for oral absorption, but slightly above the preferred <90 A^2 for CNS targets. This isn't a major concern, but something to note.

**logP:** Ligand A (1.657) is optimal, while Ligand B (0.71) is a bit low, potentially hindering permeation.

**H-Bond Donors/Acceptors:** Both have 3/4, which is acceptable.

**QED:** Both ligands have reasonable QED scores (0.667 and 0.567), indicating good drug-like properties.

**DILI:** Ligand A (47.034) has a higher DILI risk than Ligand B (17.604). This is a significant negative for Ligand A.

**BBB:** Ligand A (62.311) has a better BBB percentile than Ligand B (45.677), which is crucial for a CNS target like DRD2. However, both are below the desirable >70.

**Caco-2 Permeability:** Both have negative Caco-2 values (-5.239 and -5.11), which is unusual and suggests poor permeability. This is a concern for both.

**Aqueous Solubility:** Both have negative solubility values (-3.439 and -2.387), which is also unusual and suggests poor solubility.

**hERG:** Both ligands have very low hERG risk (0.385 and 0.13).

**Microsomal Clearance:** Ligand B (14.535) has lower microsomal clearance than Ligand A (22.064), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand B (20.765) has a slightly longer half-life than Ligand A (22.872).

**P-gp Efflux:** Both have very low P-gp efflux liability (0.086 and 0.019), which is favorable for CNS penetration.

**Binding Affinity:** Both ligands have very similar and excellent binding affinities (-8.2 and -8.3 kcal/mol). The difference is negligible.

**Overall Assessment:**

Ligand B is preferable due to its significantly lower DILI risk and better metabolic stability (lower Cl_mic). While Ligand A has a slightly better BBB score, the DILI risk is a major concern. The similar affinities and low P-gp efflux for both compounds mean that the differences in ADME properties become the deciding factors. The negative Caco-2 and solubility values are concerning for both, but can potentially be addressed with formulation strategies.

Output:
1
2025-04-17 04:16:47,295 - INFO - Batch 99 complete. Total preferences: 1584
2025-04-17 04:16:47,295 - INFO - Processing batch 100/512...
2025-04-17 04:17:27,497 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (359.451 and 373.465 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (80.32) is better than Ligand B (38.77). For CNS targets, we want TPSA <= 90, both are within this range, but A is closer to the upper limit and B is much lower, potentially indicating better CNS penetration.

**3. logP:** Both ligands have a logP around 3.5 (3.595 and 3.543), which is optimal.

**4. H-Bond Donors:** Ligand A has 2 HBD, and Ligand B has 0. Both are acceptable (<=5).

**5. H-Bond Acceptors:** Ligand A has 6 HBA, and Ligand B has 4. Both are acceptable (<=10).

**6. QED:** Both ligands have reasonable QED values (0.816 and 0.766), indicating good drug-like properties.

**7. DILI:** Ligand A has a DILI risk of 82.241, which is concerning (high risk, >60). Ligand B has a much lower DILI risk of 36.952 (good, <40). This is a significant advantage for Ligand B.

**8. BBB:** Ligand A has a BBB penetration of 55.293, which is below the desirable threshold of >70 for CNS targets. Ligand B has a BBB penetration of 96.743, which is excellent. This is a crucial advantage for Ligand B.

**9. Caco-2:** Both ligands have negative Caco-2 values (-4.917 and -4.537). These values are difficult to interpret without knowing the scale, but negative values generally suggest poor permeability.

**10. Solubility:** Both ligands have negative solubility values (-4.449 and -3.593). Similar to Caco-2, these are difficult to interpret without the scale, but suggest poor aqueous solubility.

**11. hERG:** Ligand A (0.246) has a slightly lower hERG risk than Ligand B (0.677), which is preferable.

**12. Cl_mic:** Ligand A has a higher microsomal clearance (90.638) than Ligand B (53.172), indicating lower metabolic stability. Ligand B is better.

**13. t1/2:** Ligand A has a longer in vitro half-life (44.166) than Ligand B (22.233). This is an advantage for Ligand A.

**14. Pgp:** Ligand A (0.415) has lower P-gp efflux than Ligand B (0.332), which is preferable for CNS exposure.

**15. Binding Affinity:** Both ligands have very similar and strong binding affinities (-8.9 and -8.0 kcal/mol). The difference of 0.9 kcal/mol is not substantial enough to outweigh other significant differences.

**Overall Assessment:**

While Ligand A has a slightly longer half-life and lower Pgp efflux, Ligand B is significantly better overall, especially considering the GPCR-specific priorities for a CNS target. Ligand B has a much better BBB penetration score, a significantly lower DILI risk, and better metabolic stability (lower Cl_mic). The similar binding affinities make the ADME/Tox advantages of Ligand B decisive.

Output:
1
2025-04-17 04:17:27,498 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (348.443 and 354.411 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (67.87) is significantly better than Ligand B (131.12). For CNS targets, we want TPSA <= 90, and A is comfortably within that, while B is above.

**logP:** Ligand A (0.949) is borderline, slightly below the optimal 1-3 range, but acceptable. Ligand B (-0.287) is quite low, potentially hindering membrane permeability.

**H-Bond Donors/Acceptors:** Ligand A (1 HBD, 4 HBA) is favorable. Ligand B (3 HBD, 7 HBA) is also acceptable, but slightly higher.

**QED:** Both ligands have good QED scores (0.549 and 0.585), indicating good drug-like properties.

**DILI:** Ligand A (9.965) has a much lower DILI risk than Ligand B (72.392), a significant advantage.

**BBB:** Ligand A (55.021) has a moderate BBB penetration, while Ligand B (50.523) is also moderate but slightly lower. Both are below the desirable >70 for CNS targets, but A is better.

**Caco-2 Permeability:** Ligand A (-4.618) has poor Caco-2 permeability, while Ligand B (-5.715) is even worse.

**Aqueous Solubility:** Ligand A (-2.125) has poor aqueous solubility, while Ligand B (-1.482) is slightly better.

**hERG:** Both ligands have very low hERG inhibition risk (0.253 and 0.04).

**Microsomal Clearance:** Ligand A (28.339) has higher microsomal clearance than Ligand B (-4.211), suggesting lower metabolic stability.

**In vitro Half-Life:** Ligand B (2.729) has a slightly longer in vitro half-life than Ligand A (-5.451).

**P-gp Efflux:** Ligand A (0.059) has lower P-gp efflux liability than Ligand B (0.014), which is beneficial for CNS exposure.

**Binding Affinity:** Both ligands have comparable binding affinities (-8.0 and -7.6 kcal/mol), both are excellent. The difference of 0.4 kcal/mol is not substantial enough to override other factors.

**Overall Assessment:**

Considering the GPCR-specific priorities, Ligand A is the better candidate. While both have good affinity, Ligand A has a significantly lower DILI risk and a much more favorable TPSA. The lower logP of Ligand B is a significant concern for permeability. Although Ligand A's BBB is not ideal, it is better than Ligand B's. The better P-gp efflux profile of Ligand A is also a plus.

Output:
0
2025-04-17 04:17:27,498 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (347.463 and 352.475 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (90.12) is slightly above the preferred <90 for CNS targets, but acceptable. Ligand B (84.5) is well within the desired range.

**3. logP:** Ligand A (1.188) is at the lower end of optimal, but still acceptable. Ligand B (2.165) is better positioned within the 1-3 range.

**4. H-Bond Donors:** Ligand A (3) and Ligand B (2) are both within the acceptable limit of <=5.

**5. H-Bond Acceptors:** Both ligands (A: 4, B: 4) are well below the acceptable limit of <=10.

**6. QED:** Both ligands have similar QED values (A: 0.691, B: 0.623), indicating good drug-likeness.

**7. DILI:** Ligand A (16.867) has a significantly lower DILI risk than Ligand B (52.346), which is a major advantage.

**8. BBB:** Ligand B (64.637) has a better BBB percentile than Ligand A (47.732), which is critical for a CNS target like DRD2.

**9. Caco-2 Permeability:** Ligand A (-5.689) has poor Caco-2 permeability, suggesting poor absorption. Ligand B (-4.874) is also poor, but slightly better.

**10. Aqueous Solubility:** Ligand A (-0.65) has slightly better solubility than Ligand B (-3.631).

**11. hERG Inhibition:** Both ligands have very low hERG inhibition risk (A: 0.278, B: 0.101).

**12. Microsomal Clearance:** Ligand A (1.129) has much lower microsomal clearance, indicating better metabolic stability, compared to Ligand B (44.237).

**13. In vitro Half-Life:** Ligand A (-18.533) has a significantly longer in vitro half-life than Ligand B (-10.94).

**14. P-gp Efflux:** Both ligands have very low P-gp efflux liability (A: 0.013, B: 0.222).

**15. Binding Affinity:** Both ligands have the same binding affinity (-8.4 kcal/mol), which is excellent.

**Overall Assessment:**

While Ligand B has a better BBB penetration, the significant advantages of Ligand A in terms of DILI risk, metabolic stability (lower Cl_mic and longer t1/2), and slightly better solubility are crucial. The Caco-2 permeability is a concern for both, but the other ADME properties of Ligand A are far superior. Given the importance of minimizing toxicity and maximizing exposure for CNS drugs, Ligand A is the more promising candidate.

Output:
0
2025-04-17 04:17:27,498 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (356.413 and 350.423 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (50.8) is excellent, well below the 90 Angstroms threshold for CNS targets. Ligand B (121.36) is higher, but still potentially acceptable, though less ideal.

**3. logP:** Ligand A (3.285) is optimal. Ligand B (0.986) is a bit low, potentially hindering membrane permeability.

**4. H-Bond Donors:** Ligand A (1) is good. Ligand B (3) is acceptable, but higher.

**5. H-Bond Acceptors:** Ligand A (3) is good. Ligand B (6) is higher, potentially impacting permeability.

**6. QED:** Both ligands (0.881 and 0.706) have good drug-likeness scores.

**7. DILI:** Ligand A (47.732) has a lower DILI risk than Ligand B (57.193), both are acceptable.

**8. BBB:** This is crucial for a CNS target like DRD2. Ligand A (70.919) has a good BBB percentile. Ligand B (20.822) is very low, indicating poor brain penetration.

**9. Caco-2 Permeability:** Ligand A (-4.335) is better than Ligand B (-5.589), suggesting better intestinal absorption.

**10. Aqueous Solubility:** Ligand A (-3.605) is better than Ligand B (-1.578), which is a positive attribute.

**11. hERG Inhibition:** Ligand A (0.698) has a lower hERG risk than Ligand B (0.037).

**12. Microsomal Clearance:** Ligand A (40.697) has a higher clearance than Ligand B (4.633), indicating lower metabolic stability.

**13. In vitro Half-Life:** Ligand A (-32.929) has a longer half-life than Ligand B (-4.942).

**14. P-gp Efflux:** Ligand A (0.213) has lower P-gp efflux than Ligand B (0.014), which is favorable for CNS penetration.

**15. Binding Affinity:** Ligand B (-7.9 kcal/mol) has a slightly better binding affinity than Ligand A (-8.3 kcal/mol). While affinity is important, the difference is small.

**Overall Assessment:**

Ligand A is significantly better overall, especially considering the GPCR-specific requirements. Its superior BBB penetration, logP, P-gp efflux, and solubility outweigh the slightly weaker binding affinity compared to Ligand B. Ligand B's poor BBB penetration is a major drawback for a CNS drug candidate. While Ligand B has a slightly better binding affinity, the ADME properties of Ligand A are far more favorable for development.

Output:
1
2025-04-17 04:17:27,498 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (338.451 and 369.441 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (75.35) is better than Ligand B (79.8) as it is closer to the <90 threshold for CNS targets.

**3. logP:** Both ligands have good logP values (2.74 and 3.135), falling within the optimal 1-3 range.

**4. H-Bond Donors:** Ligand A (3) is slightly higher than Ligand B (2), but both are within the acceptable limit of <=5.

**5. H-Bond Acceptors:** Ligand B (6) is higher than Ligand A (3), but both are within the acceptable limit of <=10.

**6. QED:** Both ligands have similar and good QED values (0.758 and 0.784), indicating good drug-like properties.

**7. DILI:** Ligand A (15.626) has a significantly lower DILI risk than Ligand B (70.26), making it safer from a liver toxicity perspective.

**8. BBB:** Ligand B (84.451) has a much higher BBB penetration percentile than Ligand A (49.67). This is a crucial factor for a CNS target like DRD2.

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.936 and -4.986), which is unusual and suggests poor permeability. This is a significant drawback for both.

**10. Aqueous Solubility:** Both ligands have negative solubility values (-2.647 and -3.519), indicating poor aqueous solubility, which could hinder formulation and bioavailability.

**11. hERG Inhibition:** Both ligands have low hERG inhibition risk (0.731 and 0.642).

**12. Microsomal Clearance:** Ligand B (27.334) has a much higher microsomal clearance than Ligand A (3.31), indicating lower metabolic stability.

**13. In vitro Half-Life:** Ligand B (22.939) has a longer in vitro half-life than Ligand A (8.932), which is generally desirable.

**14. P-gp Efflux:** Ligand B (0.23) has a lower P-gp efflux liability than Ligand A (0.307), which is beneficial for CNS exposure.

**15. Binding Affinity:** Ligand A (-9.5 kcal/mol) has a slightly better binding affinity than Ligand B (-8.8 kcal/mol). While both are good, the 0.7 kcal/mol difference is notable.

**Overall Assessment:**

Ligand B excels in BBB penetration and has a longer half-life and lower P-gp efflux, which are critical for CNS drug development. However, it has a significantly higher DILI risk and a higher microsomal clearance, indicating potential safety and metabolic stability concerns. Ligand A has a lower DILI risk, better TPSA, and slightly better binding affinity, but its BBB penetration is considerably lower.

Given the importance of BBB penetration for a CNS target like DRD2, and the relatively small advantage in binding affinity for Ligand A, **Ligand B is the more promising candidate despite its higher DILI and clearance.** The poor Caco-2 and solubility for both are concerning and would need to be addressed through formulation strategies, but the CNS penetration is paramount.

Output:
1
2025-04-17 04:17:27,499 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (360.405 and 340.427 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (67.67) is slightly above the optimal <90 for CNS targets, but still reasonable. Ligand B (50.6) is well within the desired range.

**logP:** Both ligands have good logP values (2.269 and 1.479), falling within the 1-3 range.

**H-Bond Donors/Acceptors:** Both have 0 HBD and 5 HBA, which are acceptable.

**QED:** Both ligands have good QED scores (0.78 and 0.846), indicating good drug-likeness.

**DILI:** Both ligands have low DILI risk (35.324 and 38.93), both below the 40 threshold.

**BBB:** Ligand B (90.617) has a significantly higher BBB penetration percentile than Ligand A (76.851). This is a crucial advantage for a CNS target like DRD2.

**Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and suggests a potential issue with the data or modeling. However, we'll proceed assuming these represent low permeability.

**Aqueous Solubility:** Both have negative solubility values, which is also unusual and suggests a potential issue with the data or modeling.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.519 and 0.653).

**Microsomal Clearance:** Ligand B (47.385) has lower microsomal clearance than Ligand A (63.769), indicating better metabolic stability.

**In vitro Half-Life:** Both have negative half-life values, which is unusual and suggests a potential issue with the data or modeling.

**P-gp Efflux:** Ligand A (0.079) has a lower P-gp efflux liability than Ligand B (0.235), which is favorable for CNS penetration.

**Binding Affinity:** Ligand B (-9.3 kcal/mol) has a significantly stronger binding affinity than Ligand A (-6.8 kcal/mol). This difference of 2.5 kcal/mol is substantial and can outweigh minor ADME drawbacks.

**Overall Assessment:**

Ligand B is the stronger candidate. The significantly better BBB penetration and binding affinity are the most important factors, given the CNS target. While Ligand A has slightly better P-gp efflux, the difference is not enough to overcome the advantages of Ligand B. The unusual negative values for Caco-2 and solubility are concerning for both, but the overall profile of Ligand B is more promising.

Output:
1
2025-04-17 04:17:27,499 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (347.463 and 364.515 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (79.26) is better than Ligand B (65.54), both are below the 90 A^2 threshold for CNS targets, which is good.

**3. logP:** Ligand A (0.905) is slightly lower than optimal (1-3), potentially impacting permeability. Ligand B (1.921) is within the optimal range.

**4. H-Bond Donors:** Ligand A (2) is acceptable, while Ligand B (1) is even better, both are below the threshold of 5.

**5. H-Bond Acceptors:** Both ligands (A: 5, B: 5) are within the acceptable limit of 10.

**6. QED:** Both ligands have reasonable QED values (A: 0.83, B: 0.781), indicating good drug-like properties.

**7. DILI:** Both ligands have similar and acceptable DILI risk (A: 36.293, B: 36.06), both well below the 60 threshold.

**8. BBB:** Ligand B (76.464) has a significantly better BBB percentile than Ligand A (62.233). This is a critical factor for a CNS target like DRD2.

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 values, which is unusual and suggests a potential issue with the data or modeling. However, we can't definitively interpret this without more context.

**10. Aqueous Solubility:** Both ligands have negative solubility values, which is also unusual and suggests a potential issue with the data or modeling.

**11. hERG Inhibition:** Ligand A (0.134) has a lower hERG inhibition risk than Ligand B (0.79), which is preferable.

**12. Microsomal Clearance:** Ligand A (1.486) has significantly lower microsomal clearance than Ligand B (40.434), indicating better metabolic stability.

**13. In vitro Half-Life:** Ligand A (12.636 hours) has a much longer in vitro half-life than Ligand B (-22.484 hours). The negative value for ligand B is concerning and likely an artifact of the modeling.

**14. P-gp Efflux:** Ligand A (0.016) has a much lower P-gp efflux liability than Ligand B (0.14), which is favorable for CNS penetration.

**15. Binding Affinity:** Both ligands have very similar and strong binding affinities (A: -8.7 kcal/mol, B: -8.5 kcal/mol). The difference is not substantial enough to be a deciding factor.

**Overall Assessment:**

While Ligand A has a slightly better hERG profile and metabolic stability, Ligand B significantly outperforms it in BBB penetration, which is paramount for a CNS target. The negative values for Caco-2 and solubility are concerning for both, but the difference in BBB is substantial. Given the importance of CNS penetration for DRD2, and the better logP value for Ligand B, I would favor Ligand B.

Output:
1
2025-04-17 04:17:27,499 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (355.467 and 349.431 Da) fall within the ideal 200-500 Da range.

**TPSA:** Both ligands have TPSA values (81.05 and 80.76) below the 90 A^2 threshold desirable for CNS targets, which is excellent.

**logP:** Ligand A (3.422) is optimal, while Ligand B (0.884) is a bit low, potentially hindering membrane permeability.

**H-Bond Donors/Acceptors:** Both ligands have acceptable HBD (2 & 1) and HBA (5 & 5) counts.

**QED:** Ligand A (0.884) has a higher QED score than Ligand B (0.67), indicating better overall drug-likeness.

**DILI:** Ligand A (73.401) has a slightly higher DILI risk than Ligand B (31.524), but both are below the concerning threshold of 60.

**BBB:** Both ligands have very good BBB penetration (69.523% and 69.407%), fulfilling the key requirement for a CNS target.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.041 and -4.571), which is unusual and suggests poor permeability. However, these values are on a logarithmic scale, so even negative values can be meaningful.

**Aqueous Solubility:** Both ligands have very poor aqueous solubility (-4.568 and -1.432). This is a significant drawback.

**hERG Inhibition:** Both ligands show low hERG inhibition liability (0.721 and 0.395), which is positive.

**Microsomal Clearance:** Ligand A (27.853 mL/min/kg) has a higher clearance than Ligand B (10.65 mL/min/kg), suggesting lower metabolic stability.

**In vitro Half-Life:** Ligand A (45.496 hours) has a longer half-life than Ligand B (10.713 hours).

**P-gp Efflux:** Ligand A (0.234) shows lower P-gp efflux than Ligand B (0.041), which is beneficial for CNS exposure.

**Binding Affinity:** Ligand A (-8.3 kcal/mol) has a significantly stronger binding affinity than Ligand B (-7.7 kcal/mol). This 0.6 kcal/mol difference is substantial and can outweigh some ADME liabilities.

**Overall Assessment:**

While both compounds have issues with solubility and Caco-2 permeability, Ligand A is the more promising candidate. Its superior binding affinity (-8.3 vs -7.7 kcal/mol) is a major advantage, especially for a GPCR target. It also has a better QED, longer half-life, and lower P-gp efflux. Although Ligand A has a higher DILI risk and clearance, these are less critical concerns than the strong binding affinity and good BBB penetration. The low logP of Ligand B is a significant concern.

Output:
1
2025-04-17 04:17:27,499 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (342.33 and 348.42 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (85.26) is better than Ligand B (62.55) as it is closer to the ideal <90 for CNS targets.

**3. logP:** Both ligands have good logP values (3.231 and 3.541), falling within the optimal 1-3 range.

**4. H-Bond Donors:** Ligand A has 0 HBD, while Ligand B has 1. Both are acceptable (<=5).

**5. H-Bond Acceptors:** Ligand A has 6 HBA, and Ligand B has 3. Both are within the acceptable range (<=10).

**6. QED:** Both ligands have similar QED values (0.726 and 0.668), indicating good drug-likeness.

**7. DILI:** Ligand A (93.68) has a significantly higher DILI risk than Ligand B (53.005). This is a major drawback for Ligand A.

**8. BBB:** Ligand A (92.904) has a slightly better BBB penetration percentile than Ligand B (89.88), but both are good for a CNS target (>70).

**9. Caco-2 Permeability:** Ligand A (-4.764) has worse Caco-2 permeability than Ligand B (-4.823). Both are negative, indicating poor permeability.

**10. Aqueous Solubility:** Ligand A (-3.709) has slightly better aqueous solubility than Ligand B (-3.392).

**11. hERG Inhibition:** Ligand A (0.493) has a lower hERG inhibition liability than Ligand B (0.966), which is favorable.

**12. Microsomal Clearance:** Ligand B (69.921) has a higher microsomal clearance than Ligand A (34.677), meaning Ligand A is more metabolically stable.

**13. In vitro Half-Life:** Ligand B (89.388) has a significantly longer in vitro half-life than Ligand A (-16.707).

**14. P-gp Efflux:** Ligand A (0.34) has lower P-gp efflux liability than Ligand B (0.721), which is favorable for CNS penetration.

**15. Binding Affinity:** Ligand B (-7.8 kcal/mol) has a significantly stronger binding affinity than Ligand A (-9.4 kcal/mol). This is a substantial advantage.

**Overall Assessment:**

While Ligand A has slightly better TPSA and P-gp efflux, the significant drawbacks of high DILI risk, poor half-life, and weaker binding affinity outweigh these benefits. Ligand B, despite slightly higher P-gp efflux, exhibits a much more favorable profile with lower DILI risk, a significantly longer half-life, and a substantially stronger binding affinity. The affinity difference is particularly important for a GPCR target.

Output:
1
2025-04-17 04:17:27,499 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (370.739 and 353.369 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (76.66) is better than Ligand B (82.27). Both are below the 90 A^2 threshold for CNS targets, which is good.

**logP:** Both ligands have acceptable logP values (2.71 and 1.531), falling within the 1-3 range. Ligand A is slightly better.

**H-Bond Donors/Acceptors:** Both have 2 HBD and a reasonable number of HBA (4 and 3 respectively), satisfying the <5 HBD and <10 HBA guidelines.

**QED:** Both ligands have good QED scores (0.811 and 0.861), indicating good drug-like properties.

**DILI:** Ligand A has a significantly higher DILI risk (98.216 percentile) than Ligand B (36.448 percentile). This is a major concern for Ligand A.

**BBB:** Ligand B (80.419 percentile) has a much better BBB penetration score than Ligand A (52.423 percentile). This is crucial for a CNS target like DRD2.

**Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and suggests poor permeability. However, the scale is not defined, so it's hard to interpret.

**Aqueous Solubility:** Both have negative solubility values, which is also unusual and suggests poor solubility. Again, the scale is not defined.

**hERG:** Both ligands have low hERG inhibition liability (0.382 and 0.389), which is good.

**Microsomal Clearance:** Ligand B (-11.046) has a significantly lower (better) microsomal clearance than Ligand A (26.662), indicating greater metabolic stability.

**In vitro Half-Life:** Ligand B (-34.876) has a much longer in vitro half-life than Ligand A (12.434), which is desirable.

**P-gp Efflux:** Both have very low P-gp efflux liability (0.237 and 0.019), which is good for CNS penetration.

**Binding Affinity:** Both ligands have very similar and strong binding affinities (-9.3 and -8.7 kcal/mol). The difference is less than 1.5 kcal/mol, so it's not a decisive factor.

**Conclusion:**

Considering all factors, **Ligand B** is the more promising drug candidate. While both have good affinity and drug-like properties, Ligand B has significantly better BBB penetration, lower DILI risk, improved metabolic stability (lower Cl_mic and longer t1/2), and lower P-gp efflux. The higher DILI risk associated with Ligand A is a major red flag. Although both have unusual solubility and Caco-2 values, the other ADME properties of Ligand B are far superior for a CNS-targeting GPCR.

Output:
1
2025-04-17 04:17:27,500 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, considering the provided guidelines and GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (349.39 and 340.38 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (95.61) is higher than Ligand B (78.53). For CNS targets, TPSA should be <= 90, so Ligand B is preferable.

**logP:** Ligand A (0.383) is quite low, potentially hindering permeation. Ligand B (2.122) is within the optimal 1-3 range. This is a significant advantage for Ligand B.

**H-Bond Donors/Acceptors:** Both have 1 HBD, which is good. Ligand A has 7 HBA, while Ligand B has 4. Both are acceptable, but Ligand B is slightly better.

**QED:** Both ligands have good QED scores (0.826 and 0.865), indicating drug-like properties.

**DILI:** Ligand A (60.8%) has a slightly better DILI risk profile than Ligand B (74.3%), but both are acceptable.

**BBB:** Ligand B (69.76%) has a better BBB penetration percentile than Ligand A (53.08%). While >70 is desirable, 69.76% is still a reasonable value, and significantly better than Ligand A.

**Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and suggests poor permeability. However, the scale is not specified, so it's difficult to interpret.

**Aqueous Solubility:** Ligand A (-0.709) has slightly better solubility than Ligand B (-3.642).

**hERG:** Both ligands have very low hERG inhibition liability (0.302 and 0.215), which is excellent.

**Microsomal Clearance:** Ligand A (-11.912) has a much lower (better) microsomal clearance than Ligand B (29.977), suggesting greater metabolic stability.

**In vitro Half-Life:** Ligand A (-20.323) has a slightly longer half-life than Ligand B (-18.658).

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.039 and 0.091), which is excellent.

**Binding Affinity:** Ligand B (-9.0 kcal/mol) has a significantly stronger binding affinity than Ligand A (-7.5 kcal/mol). This >1.5 kcal/mol difference is a major advantage.

**Overall Assessment:**

Ligand B is superior due to its better logP, TPSA, BBB penetration, and significantly stronger binding affinity. While Ligand A has slightly better metabolic stability and solubility, the improvements in permeability and target engagement with Ligand B outweigh these factors, especially given the GPCR target class and the need for CNS penetration.

Output:
1
2025-04-17 04:17:27,500 - INFO - Reasoning:

Let's analyze Ligand A and Ligand B against the provided guidelines, prioritizing GPCR-specific properties (BBB, logP, Pgp, TPSA, and affinity) for DRD2.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (341.455 Da) is slightly lower, which could be beneficial for permeability.

**TPSA:** Ligand A (62.3) is excellent for CNS penetration, well below the 90 A^2 threshold. Ligand B (116.48) is higher, potentially hindering BBB penetration, although still within a reasonable range.

**logP:** Ligand A (2.825) is optimal. Ligand B (-1.741) is significantly lower, which is a concern for membrane permeability and CNS penetration.

**H-Bond Donors/Acceptors:** Ligand A (HBD=1, HBA=3) and Ligand B (HBD=2, HBA=8) both fall within acceptable limits, but Ligand B has a higher number of HBA, potentially impacting permeability.

**QED:** Ligand A (0.865) has a much better QED score than Ligand B (0.57), indicating a more drug-like profile.

**DILI:** Ligand A (32.261) has a lower DILI risk than Ligand B (20.706), which is preferable.

**BBB:** This is critical for DRD2. Ligand A (70.958) has a good BBB percentile, exceeding the 70% threshold. Ligand B (19.31) is very low, a major drawback for a CNS target.

**Caco-2 Permeability:** Ligand A (-4.373) has a negative value, which is unusual and suggests poor permeability. Ligand B (-5.581) is also poor.

**Aqueous Solubility:** Ligand A (-2.92) and Ligand B (0.22) both have poor solubility.

**hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.221 and 0.04 respectively).

**Microsomal Clearance:** Ligand B (-9.038) has a negative value, which is unusual and suggests very slow clearance. Ligand A (51.336) has a moderate clearance.

**In vitro Half-Life:** Both ligands have similar in vitro half-lives (12.893 and 13.828 hours).

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.027 and 0.005 respectively).

**Binding Affinity:** Both ligands have the same binding affinity (-7.8 kcal/mol), which is excellent.

**Overall Assessment:**

Despite the similar binding affinity, Ligand A is significantly more promising. Its superior BBB penetration, better logP, higher QED, and lower DILI risk outweigh the concerns regarding Caco-2 permeability and solubility. Ligand B's poor BBB penetration and low logP are major liabilities for a CNS-targeting drug. The unusual negative values for Caco-2 and Cl_mic for both compounds warrant further investigation but are less critical than the BBB and logP issues with Ligand B.

Output:
1
2025-04-17 04:17:27,500 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (350.415 and 354.523 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (96.89) is better than Ligand B (41.91). For CNS targets, we want TPSA <= 90, so Ligand A is closer to this threshold.

**logP:** Ligand B (3.981) is optimal (1-3), while Ligand A (0.392) is quite low, potentially hindering membrane permeability. This is a significant drawback for Ligand A.

**H-Bond Donors:** Ligand A (3) is acceptable, while Ligand B (0) is also good.

**H-Bond Acceptors:** Both ligands have 5 HBA, which is within the acceptable limit of <=10.

**QED:** Both ligands have good QED values (0.599 and 0.752, respectively), indicating drug-like properties.

**DILI:** Ligand A (18.108) has a much lower DILI risk than Ligand B (40.016), which is a positive for Ligand A.

**BBB:** Ligand B (81.621) has a significantly higher BBB penetration percentile than Ligand A (55.332). For a CNS target like DRD2, >70 is desirable, but Ligand B is much closer than Ligand A.

**Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and suggests poor permeability. However, the scale is not specified, so it's hard to interpret.

**Aqueous Solubility:** Both have negative solubility values, indicating poor solubility. Again, the scale is not specified.

**hERG Inhibition:** Ligand A (0.129) has a lower hERG inhibition liability than Ligand B (0.805), which is preferable.

**Microsomal Clearance:** Ligand B (65.521) has higher microsomal clearance than Ligand A (11.881), indicating lower metabolic stability. This favors Ligand A.

**In vitro Half-Life:** Ligand B (12.168) has a longer in vitro half-life than Ligand A (-5.468), which is a positive for Ligand B.

**P-gp Efflux:** Ligand A (0.02) has much lower P-gp efflux liability than Ligand B (0.495), which is crucial for CNS penetration.

**Binding Affinity:** Ligand B (-7.5 kcal/mol) has a better binding affinity than Ligand A (-8.5 kcal/mol). This is a substantial advantage for Ligand B.

**Overall Assessment:**

Ligand A has advantages in DILI, hERG, P-gp efflux, and metabolic stability. However, its low logP and BBB penetration are major concerns for a CNS target. Ligand B, despite a higher DILI and P-gp efflux, has a significantly better logP, BBB penetration, and *most importantly*, a better binding affinity. The affinity difference (-7.5 vs -8.5 kcal/mol) is substantial and likely outweighs the ADME drawbacks of Ligand B, especially considering optimization potential.

Output:
1
2025-04-17 04:17:27,500 - INFO - Reasoning:

Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (365.411 and 347.413 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (115.9) is higher than the preferred <90 for CNS targets, while Ligand B (55.63) is well within the range. This is a significant advantage for Ligand B.

**3. logP:** Ligand A (0.406) is quite low, potentially hindering membrane permeability. Ligand B (3.219) is optimal.

**4. H-Bond Donors:** Ligand A (3) is acceptable, while Ligand B (1) is even better.

**5. H-Bond Acceptors:** Ligand A (7) is acceptable, Ligand B (5) is also good.

**6. QED:** Both ligands have good QED scores (0.707 and 0.902), indicating drug-like properties.

**7. DILI:** Ligand A (70.686) has a higher DILI risk than Ligand B (54.634), though both are reasonably acceptable.

**8. BBB:** Ligand B (89.957) shows excellent BBB penetration, crucial for a CNS target like DRD2. Ligand A (9.539) is very poor. This is a decisive factor.

**9. Caco-2 Permeability:** Ligand A (-5.399) has poor Caco-2 permeability, consistent with its low logP. Ligand B (-4.767) is also not great, but better than A.

**10. Aqueous Solubility:** Both have negative solubility values, which is unusual and requires further investigation, but doesn't immediately disqualify either.

**11. hERG Inhibition:** Both ligands show low hERG inhibition risk (0.105 and 0.406).

**12. Microsomal Clearance:** Ligand A (-12.489) has significantly lower (better) microsomal clearance than Ligand B (18.162), indicating greater metabolic stability.

**13. In vitro Half-Life:** Ligand A (32.876) has a longer half-life than Ligand B (14.188).

**14. P-gp Efflux:** Ligand A (0.153) has lower P-gp efflux, which is favorable for CNS penetration. Ligand B (0.447) is higher.

**15. Binding Affinity:** Ligand B (-9.2 kcal/mol) has a significantly stronger binding affinity than Ligand A (-7.6 kcal/mol). This 1.6 kcal/mol difference is substantial and can outweigh some ADME drawbacks.

**Overall Assessment:**

Ligand B is the superior candidate. While Ligand A has better metabolic stability and P-gp efflux, Ligand B excels in the critical areas for a CNS GPCR target: TPSA, logP, and, most importantly, BBB penetration. The significantly stronger binding affinity of Ligand B further solidifies its advantage. The slightly higher P-gp efflux and clearance of Ligand B are less concerning given its superior CNS exposure potential.

Output:
1
2025-04-17 04:17:27,501 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight (MW):** Both ligands (372.531 and 343.431 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (86.71) is better than Ligand B (81.93). Both are below the 90 A^2 threshold desirable for CNS targets, but A is closer to the ideal.

**3. logP:** Both ligands (2.23 and 2.291) are within the optimal 1-3 range.

**4. H-Bond Donors (HBD):** Ligand A (2) is preferable to Ligand B (1) as it is within the acceptable range of <=5.

**5. H-Bond Acceptors (HBA):** Ligand A (4) is preferable to Ligand B (6) as it is within the acceptable range of <=10.

**6. QED:** Both ligands have good QED scores (0.648 and 0.755), indicating drug-like properties. Ligand B is slightly better.

**7. DILI:** Ligand A (31.989) has a significantly lower DILI risk than Ligand B (47.421). This is a substantial advantage for Ligand A.

**8. BBB:** Ligand B (62.854) has a much better BBB penetration score than Ligand A (36.487). This is a critical factor for a CNS target like DRD2.

**9. Caco-2 Permeability:** Ligand A (-5.528) is better than Ligand B (-4.71). Higher values indicate better intestinal absorption.

**10. Aqueous Solubility:** Ligand A (-1.791) is better than Ligand B (-2.992). Higher values indicate better solubility.

**11. hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.055 and 0.172).

**12. Microsomal Clearance (Cl_mic):** Ligand B (71.347) has a significantly higher clearance than Ligand A (5.583), meaning Ligand A is more metabolically stable.

**13. In vitro Half-Life:** Ligand A (-20.134) has a better half-life than Ligand B (-21.626).

**14. P-gp Efflux:** Ligand A (0.01) has a lower P-gp efflux liability than Ligand B (0.213), which is favorable for CNS penetration.

**15. Binding Affinity:** Ligand B (-8.1 kcal/mol) has a stronger binding affinity than Ligand A (-6.7 kcal/mol). This is a 1.4 kcal/mol difference, which is significant and can outweigh some ADME drawbacks.

**Overall Assessment:**

Ligand B has a significantly better BBB score and binding affinity, which are crucial for a CNS GPCR target. However, Ligand A demonstrates superior ADME properties, including lower DILI risk, better metabolic stability (lower Cl_mic), lower P-gp efflux, and better solubility.

The stronger binding affinity of Ligand B is a major advantage. While Ligand A has better ADME properties, the 1.4 kcal/mol difference in binding is substantial enough to prioritize Ligand B, especially given the acceptable (though not ideal) BBB score. The improved BBB penetration of B, combined with its stronger binding, is likely to translate to greater efficacy *in vivo*.

Output:
1
2025-04-17 04:17:27,501 - INFO - Reasoning:

Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight (MW):** Both ligands (369.799 and 374.897 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (64.11) is higher than Ligand B (50.5). For CNS targets, we prefer TPSA <= 90, so both are acceptable, but B is better.

**3. logP:** Ligand A (4.59) is slightly above the optimal range (1-3), potentially leading to solubility issues. Ligand B (3.777) is within the optimal range.

**4. H-Bond Donors (HBD):** Both ligands are acceptable (1 and 0 respectively), being less than 5.

**5. H-Bond Acceptors (HBA):** Both ligands are acceptable (4 and 5 respectively), being less than 10.

**6. QED:** Ligand A (0.856) has a higher QED than Ligand B (0.659), indicating better overall drug-likeness.

**7. DILI:** Ligand A (85.576) has a higher DILI risk than Ligand B (63.823). Lower is better, so B is preferable.

**8. BBB:** Ligand A (68.631) has a slightly better BBB penetration percentile than Ligand B (62.117). However, both are below the desirable >70 for CNS targets.

**9. Caco-2:** Both have negative Caco-2 values, which is unusual. Assuming these are percentile scores, lower values indicate poor permeability. Ligand A (-4.626) is worse than Ligand B (-5.063).

**10. Solubility:** Ligand A (-5.81) has worse solubility than Ligand B (-3.121).

**11. hERG:** Ligand A (0.369) has a lower hERG inhibition liability than Ligand B (0.865), which is preferable.

**12. Cl_mic:** Ligand A (72.936) has a lower microsomal clearance than Ligand B (100.742), indicating better metabolic stability.

**13. t1/2:** Ligand B (44.965) has a significantly longer in vitro half-life than Ligand A (7.52).

**14. Pgp:** Ligand A (0.182) has lower P-gp efflux liability than Ligand B (0.405), which is better for CNS exposure.

**15. Binding Affinity:** Ligand B (-7.4 kcal/mol) has a significantly stronger binding affinity than Ligand A (-9.2 kcal/mol). This is a substantial advantage.

**Overall Assessment:**

While Ligand A has a better QED and Pgp efflux profile, Ligand B excels in several crucial areas for a CNS-targeting GPCR ligand. Specifically, its superior binding affinity (-7.4 vs -9.2 kcal/mol) is a major advantage. It also has a better logP, lower DILI risk, and a significantly longer half-life. The slightly lower BBB penetration of Ligand B is a concern, but the stronger affinity and improved ADME properties likely outweigh this drawback.

Output:
1
2025-04-17 04:17:27,501 - INFO - Batch 100 complete. Total preferences: 1600
2025-04-17 04:17:27,501 - INFO - Processing batch 101/512...
2025-04-17 04:18:10,283 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (368.503 and 359.853 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (85.16) is better than Ligand B (58.56) as it is closer to the <90 A^2 threshold for CNS targets. Ligand B is excellent.

**logP:** Ligand A (1.898) is optimal, while Ligand B (4.08) is pushing the upper limit. Higher logP can lead to off-target effects and solubility issues.

**H-Bond Donors/Acceptors:** Ligand A (0 HBD, 6 HBA) and Ligand B (2 HBD, 3 HBA) both have acceptable numbers of H-bond donors and acceptors.

**QED:** Both ligands have similar QED values (0.813 and 0.783), indicating good drug-likeness.

**DILI:** Ligand A (64.87) has a slightly higher DILI risk than Ligand B (50.136), but both are acceptable.

**BBB:** Ligand A (81.272) has a significantly better BBB penetration percentile than Ligand B (43.273). This is a *critical* advantage for a CNS target like DRD2.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.602 and -4.656), which is unusual and suggests poor permeability. This is a significant concern for both.

**Aqueous Solubility:** Both ligands have negative solubility values (-3.497 and -4.707), indicating very poor aqueous solubility. This is a major drawback.

**hERG Inhibition:** Ligand A (0.161) has a much lower hERG inhibition liability than Ligand B (0.473), making it safer from a cardiotoxicity perspective.

**Microsomal Clearance:** Ligand A (30.697) and Ligand B (33.982) have similar microsomal clearance values, indicating moderate metabolic stability.

**In vitro Half-Life:** Ligand B (56.35) has a significantly longer in vitro half-life than Ligand A (34.677), which is desirable.

**P-gp Efflux:** Ligand A (0.307) has lower P-gp efflux liability than Ligand B (0.416), which is beneficial for CNS exposure.

**Binding Affinity:** Both ligands have excellent binding affinities (-8.2 and -8.5 kcal/mol). Ligand B is slightly better, but the difference is small.

**Overall Assessment:**

While Ligand B has a slightly better binding affinity and in vitro half-life, Ligand A is the superior candidate due to its significantly better BBB penetration (81.272 vs 43.273), lower hERG risk, and lower P-gp efflux. The BBB is paramount for a CNS target, and Ligand A's value is much closer to the desirable >70 percentile. The poor Caco-2 and solubility are concerning for both, but can potentially be addressed with formulation strategies.

Output:
0
2025-04-17 04:18:10,283 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (344.459 and 349.479 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (50.6) is significantly better than Ligand B (88.17). For CNS targets, we want TPSA <= 90, and A is comfortably within this range, while B is approaching the upper limit.

**logP:** Both ligands have acceptable logP values (1.685 and 2.483, respectively), falling within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A (0 HBD, 5 HBA) is slightly better than Ligand B (3 HBD, 6 HBA) regarding the balance of solubility and permeability.

**QED:** Both ligands have reasonable QED scores (0.8 and 0.635), indicating good drug-likeness.

**DILI:** Ligand A (18.651) has a much lower DILI risk than Ligand B (48.119). This is a significant advantage.

**BBB:** Ligand A (89.027) has a substantially better BBB penetration score than Ligand B (70.686). Given that DRD2 is a CNS target, this is a critical factor.

**Caco-2 Permeability:** Ligand A (-4.759) has a worse Caco-2 permeability than Ligand B (-5.104), but both are quite poor.

**Aqueous Solubility:** Ligand A (-0.503) has slightly better solubility than Ligand B (-2.98), although both are very poor.

**hERG Inhibition:** Both ligands have similar, low hERG inhibition liability (0.641 and 0.629).

**Microsomal Clearance:** Ligand B (70.359) has significantly higher microsomal clearance than Ligand A (3.742), suggesting lower metabolic stability.

**In vitro Half-Life:** Ligand B (26.793) has a slightly longer half-life than Ligand A (24.859).

**P-gp Efflux:** Both ligands have similar P-gp efflux liability (0.169 and 0.068).

**Binding Affinity:** Both ligands have very similar binding affinities (-8.4 and -8.1 kcal/mol). The difference is less than 1.5 kcal/mol, so it's not a deciding factor.

**Conclusion:**

Considering all factors, especially the GPCR-specific priorities, **Ligand A is the more promising drug candidate.** It has significantly better BBB penetration, lower DILI risk, lower microsomal clearance (better metabolic stability), and a more favorable TPSA. While Ligand B has a slightly longer half-life and slightly better Caco-2 permeability, these advantages are outweighed by the superior CNS penetration and safety profile of Ligand A. The binding affinities are comparable.

Output:
1
2025-04-17 04:18:10,283 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 drug candidates, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (360.523 and 352.519 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (40.62) is better than Ligand B (42.01), both are below the 90 A^2 threshold for CNS targets, suggesting good potential for brain penetration.

**3. logP:** Both ligands (2.952 and 2.539) are within the optimal 1-3 range.

**4. H-Bond Donors:** Both have 0 HBD, which is acceptable.

**5. H-Bond Acceptors:** Ligand A has 3 HBA, and Ligand B has 4. Both are within the acceptable limit of <=10.

**6. QED:** Ligand A (0.783) has a slightly better QED score than Ligand B (0.673), indicating a more drug-like profile.

**7. DILI:** Ligand A (39.201) has a significantly better DILI score than Ligand B (11.206). Ligand B's DILI is still acceptable, but A is preferable.

**8. BBB:** Both ligands have excellent BBB penetration (Ligand A: 82.474, Ligand B: 84.529), exceeding the >70% threshold for CNS targets.

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.953 and -4.678), which is unusual and suggests poor permeability. However, these values are on a strange scale and are difficult to interpret without knowing the scale's specifics.

**10. Aqueous Solubility:** Both ligands have negative solubility values (-3.825 and -1.666), which is also unusual and suggests poor solubility. Similar to Caco-2, the scale is unknown.

**11. hERG Inhibition:** Both ligands have low hERG inhibition risk (0.75 and 0.627).

**12. Microsomal Clearance:** Ligand A (99.262) has a much higher microsomal clearance than Ligand B (60.05), indicating lower metabolic stability. This is a significant drawback for Ligand A.

**13. In vitro Half-Life:** Ligand B (33.901) has a much longer in vitro half-life than Ligand A (1.847), which is a major advantage.

**14. P-gp Efflux:** Both ligands have low P-gp efflux liability (0.506 and 0.194).

**15. Binding Affinity:** Ligand A (-8.2 kcal/mol) has a significantly stronger binding affinity than Ligand B (-7.0 kcal/mol). This >1.5 kcal/mol difference is substantial and can outweigh some ADME concerns.

**Overall Assessment:**

Despite Ligand A's superior binding affinity, Ligand B appears to be the more promising drug candidate. Ligand A has a significantly higher microsomal clearance and shorter half-life, which are critical drawbacks. While the negative Caco-2 and solubility values are concerning for both, the difference in metabolic stability is more impactful. Ligand B's better half-life, combined with acceptable BBB penetration, logP, and a much lower DILI risk, makes it the preferred choice. The affinity difference, while significant, can potentially be addressed through further optimization of Ligand B.

Output:
1
2025-04-17 04:18:10,283 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 drug candidates, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (363.435 Da) and Ligand B (347.507 Da) are both acceptable.

**TPSA:** Ligand A (76.82) is slightly above the optimal <90 for CNS targets, but still reasonable. Ligand B (53.4) is excellent, well below 90.

**logP:** Both ligands have good logP values (A: 2.896, B: 2.2), falling within the 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A (0 HBD, 6 HBA) is favorable. Ligand B (1 HBD, 5 HBA) is also good. Both are within acceptable limits.

**QED:** Both ligands have good QED scores (A: 0.556, B: 0.887), indicating good drug-like properties. Ligand B is significantly better.

**DILI:** Ligand A has a concerning DILI risk (88.949%), indicating potential liver toxicity. Ligand B has a very low DILI risk (14.308%), a major advantage.

**BBB:** Both ligands have acceptable BBB penetration (A: 69.756%, B: 68.282%), though ideally >70% is preferred for CNS targets. They are comparable here.

**Caco-2 Permeability:** Ligand A (-4.687) has poor Caco-2 permeability, suggesting poor absorption. Ligand B (-5.108) also has poor Caco-2 permeability, but is slightly worse.

**Aqueous Solubility:** Ligand A (-3.897) and Ligand B (-1.561) both have poor aqueous solubility. Ligand B is slightly better.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (A: 0.563, B: 0.524).

**Microsomal Clearance:** Ligand A (76.23) has higher microsomal clearance, suggesting faster metabolism. Ligand B (32.57) has lower clearance, indicating better metabolic stability.

**In vitro Half-Life:** Ligand A (83.628) has a longer half-life than Ligand B (28.747).

**P-gp Efflux:** Both ligands have low P-gp efflux (A: 0.47, B: 0.02). Ligand B is significantly better.

**Binding Affinity:** Ligand A (-8.4 kcal/mol) has a significantly stronger binding affinity than Ligand B (-6.8 kcal/mol). This is a substantial advantage.

**Overall Assessment:**

While Ligand A boasts a superior binding affinity, its high DILI risk and poor Caco-2 permeability are major drawbacks. Ligand B, despite a weaker binding affinity, presents a much more favorable ADME-Tox profile: significantly lower DILI, better metabolic stability (lower Cl_mic), and lower P-gp efflux. For a GPCR target in the CNS, a balance between affinity and ADME properties is crucial. The substantial improvement in safety (DILI) and potential for CNS exposure (Pgp, Cl_mic) with Ligand B outweighs the affinity difference.

Output:
1
2025-04-17 04:18:10,284 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (381.45 and 382.408 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (72.47) is excellent, well below the 90 A^2 threshold for CNS targets. Ligand B (87.46) is still reasonable but less optimal, approaching the 90 A^2 limit.

**logP:** Ligand A (2.594) is within the optimal 1-3 range. Ligand B (0.543) is a bit low, potentially hindering membrane permeability.

**H-Bond Donors/Acceptors:** Ligand A (HBD=1, HBA=5) and Ligand B (HBD=2, HBA=6) both have acceptable numbers of H-bond donors and acceptors.

**QED:** Ligand A (0.833) has a very good QED score, indicating high drug-likeness. Ligand B (0.577) is acceptable but lower.

**DILI:** Ligand A (88.523) has a higher DILI risk than Ligand B (29.159), which is a significant drawback.

**BBB:** Both ligands have similar BBB penetration (Ligand A: 55.138, Ligand B: 57.425). Neither is ideal (>70), but acceptable given the binding affinity.

**Caco-2 Permeability:** Both have negative Caco-2 values which is unusual and suggests poor permeability.

**Aqueous Solubility:** Both have negative solubility values, which is also unusual and suggests poor solubility.

**hERG:** Both ligands have very low hERG inhibition risk (0.345 and 0.338).

**Microsomal Clearance:** Ligand A (18.534) has a higher microsomal clearance than Ligand B (12.042), suggesting lower metabolic stability.

**In vitro Half-Life:** Ligand B (-14.605) has a negative half-life, which is not possible. Ligand A (51.245) is reasonable.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.362 and 0.023).

**Binding Affinity:** Ligand A (-9.7 kcal/mol) has a significantly stronger binding affinity than Ligand B (-7.3 kcal/mol) - a difference of 2.4 kcal/mol. This is a substantial advantage.

**Overall Assessment:**

Ligand A has a significantly better binding affinity, a better TPSA, and a better QED score. However, it has a much higher DILI risk and a higher microsomal clearance. Ligand B has a lower DILI risk, but its logP is suboptimal, and its binding affinity is considerably weaker.

Given the importance of affinity for GPCR ligands, and the fact that the difference in affinity is substantial (2.4 kcal/mol), I would prioritize Ligand A despite its higher DILI risk. The DILI risk could potentially be mitigated through structural modifications during lead optimization. The lower logP of Ligand B is a more fundamental issue that would be harder to address without significantly altering the core structure and potentially losing affinity.

Output:
1
2025-04-17 04:18:10,284 - INFO - Reasoning:

Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (335.37 and 349.39 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (95.83) is excellent, being below the 90 A^2 threshold for CNS targets. Ligand B (136.28) is higher, but still potentially acceptable, though less ideal.

**3. logP:** Both ligands have good logP values (1.87 and 1.57), falling within the optimal 1-3 range.

**4. H-Bond Donors:** Both have 3 HBD, which is within the acceptable limit of <=5.

**5. H-Bond Acceptors:** Ligand A has 5 HBA, and Ligand B has 7. Both are within the acceptable limit of <=10.

**6. QED:** Both ligands have good QED scores (0.53 and 0.72), indicating good drug-like properties.

**7. DILI:** Ligand A (82.24) has a higher DILI risk than Ligand B (68.86). While both are below the concerning 60 threshold, lower is better.

**8. BBB:** This is a critical parameter for a CNS target like DRD2. Ligand A has a BBB percentile of 20.12, which is quite low. Ligand B has a significantly better BBB percentile of 56.65, making it more likely to reach the target in the brain.

**9. Caco-2:** Both have negative Caco-2 values, which is unusual and suggests poor permeability. However, these values are on a strange scale and are difficult to interpret without more context.

**10. Solubility:** Both have negative solubility values, also unusual. This suggests poor aqueous solubility.

**11. hERG:** Both ligands have low hERG inhibition liability (0.61 and 0.32), which is good.

**12. Cl_mic:** Ligand A (18.88) has lower microsomal clearance than Ligand B (20.31), suggesting better metabolic stability.

**13. t1/2:** Ligand A (70.63) has a much longer in vitro half-life than Ligand B (-2.64). This is a significant advantage.

**14. Pgp:** Ligand A (0.32) has lower P-gp efflux liability than Ligand B (0.02), meaning it's less likely to be pumped out of the brain.

**15. Binding Affinity:** Ligand A (-10.1 kcal/mol) has a significantly stronger binding affinity than Ligand B (-8.8 kcal/mol). This is a substantial advantage, potentially outweighing some of the ADME drawbacks.

**Overall Assessment:**

Ligand A has a superior binding affinity and better metabolic stability (lower Cl_mic, longer t1/2) and lower Pgp efflux, but suffers from very poor BBB penetration. Ligand B has a better BBB score and lower DILI risk, but its affinity is weaker.

Given the emphasis on BBB penetration for CNS GPCR targets, and the substantial affinity difference, the stronger binding affinity of Ligand A is likely to be more important. While the low BBB is a concern, it might be mitigated through formulation strategies or further structural modifications. The difference in affinity (-1.3 kcal/mol) is significant.

Output:
1
2025-04-17 04:18:10,284 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (339.439 and 350.459 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (47.36) is excellent, well below the 90 A^2 threshold for CNS targets. Ligand B (87.66) is higher, but still acceptable, though less optimal for CNS penetration.

**logP:** Ligand A (3.291) is within the optimal 1-3 range. Ligand B (1.26) is on the lower side, potentially hindering membrane permeability.

**H-Bond Donors/Acceptors:** Ligand A (0 HBD, 4 HBA) and Ligand B (3 HBD, 4 HBA) both have reasonable numbers of H-bond donors and acceptors, well within the guidelines.

**QED:** Both ligands have acceptable QED values (0.862 and 0.697, respectively), indicating good drug-like properties.

**DILI:** Ligand A (53.742) has a moderate DILI risk, while Ligand B (28.616) has a very low DILI risk, which is a significant advantage.

**BBB:** Ligand A (83.443) has a good BBB penetration percentile, desirable for a CNS target. Ligand B (28.81) has poor BBB penetration, a major drawback.

**Caco-2 Permeability:** Ligand A (-4.667) has poor Caco-2 permeability. Ligand B (-5.095) also has poor Caco-2 permeability.

**Aqueous Solubility:** Both ligands have poor aqueous solubility (-2.919 and -2.783, respectively). This could pose formulation challenges.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.273 and 0.136, respectively).

**Microsomal Clearance:** Ligand A (45.693) has moderate microsomal clearance, while Ligand B (28.402) has lower clearance, suggesting better metabolic stability.

**In vitro Half-Life:** Ligand B (15.624 hours) has a longer in vitro half-life than Ligand A (10.122 hours), which is preferable.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.514 and 0.046, respectively), which is good for CNS exposure.

**Binding Affinity:** Both ligands have strong binding affinities (-9.5 and -8.6 kcal/mol). Ligand A has a slightly better affinity, but the difference (0.9 kcal/mol) isn't massive enough to overcome other significant drawbacks.

**Overall Assessment:**

Ligand A excels in TPSA and has a slightly better binding affinity and BBB penetration. However, its Caco-2 permeability is very poor. Ligand B has a significantly lower DILI risk, better metabolic stability (lower Cl_mic), and a longer half-life. While its BBB penetration is poor, the lower DILI and improved metabolic properties are crucial for a CNS drug candidate. The slightly weaker binding affinity of Ligand B is less concerning given the other advantages. Considering the GPCR-specific priorities, and the importance of minimizing toxicity and maximizing metabolic stability for CNS drugs, Ligand B is the more promising candidate.

Output:
1
2025-04-17 04:18:10,284 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (349.333 and 353.507 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (59.0) is significantly better than Ligand B (87.3). For CNS targets, we want TPSA <= 90, and A is comfortably within that range, while B is approaching the upper limit.

**3. logP:** Both ligands have good logP values (2.59 and 1.986), falling within the optimal 1-3 range.

**4. H-Bond Donors:** Ligand A (1) is preferable to Ligand B (3). Fewer HBDs generally improve permeability.

**5. H-Bond Acceptors:** Ligand A (4) is slightly better than Ligand B (3), but both are acceptable.

**6. QED:** Ligand A (0.901) is significantly better than Ligand B (0.561), indicating a more drug-like profile.

**7. DILI:** Ligand A (53.315) has a higher DILI risk than Ligand B (16.324). This is a negative for Ligand A.

**8. BBB:** Ligand A (76.192) has a substantially better BBB percentile than Ligand B (64.211). This is a critical advantage for a CNS target like DRD2.

**9. Caco-2 Permeability:** Ligand A (-3.982) is better than Ligand B (-4.864), indicating better intestinal absorption.

**10. Aqueous Solubility:** Ligand A (-3.422) is better than Ligand B (-2.705), suggesting better solubility.

**11. hERG Inhibition:** Ligand A (0.728) has a slightly higher hERG risk than Ligand B (0.189). This is a negative for Ligand A.

**12. Microsomal Clearance:** Ligand B (45.518) has lower microsomal clearance than Ligand A (19.061), indicating better metabolic stability.

**13. In vitro Half-Life:** Ligand B (-3.174) has a longer in vitro half-life than Ligand A (4.106).

**14. P-gp Efflux:** Ligand A (0.377) has lower P-gp efflux than Ligand B (0.022), which is favorable for CNS penetration.

**15. Binding Affinity:** Ligand A (-9.2 kcal/mol) has a significantly stronger binding affinity than Ligand B (-8.0 kcal/mol). This is a major advantage, potentially outweighing some of the ADME drawbacks.

**Overall Assessment:**

Ligand A excels in key areas for a CNS GPCR target: TPSA, BBB, P-gp efflux, solubility, and *especially* binding affinity. While it has slightly higher DILI and hERG risk, and lower metabolic stability, the significantly stronger binding affinity and better BBB penetration are likely to be decisive. Ligand B has better metabolic stability and lower DILI/hERG, but its weaker affinity and poorer BBB penetration make it less promising.

Output:
1
2025-04-17 04:18:10,284 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 drug candidates, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (357.885 Da) is slightly lower, which is generally favorable for permeability. Ligand B (364.389 Da) is also good.

**TPSA:** Ligand A (36.44) is excellent, well below the 90 A^2 threshold for CNS targets. Ligand B (99.1) is significantly higher, potentially hindering BBB penetration.

**logP:** Ligand A (3.896) is within the optimal range (1-3). Ligand B (0.45) is quite low, which could limit its ability to cross cell membranes, including the BBB.

**H-Bond Donors/Acceptors:** Ligand A (0 HBD, 3 HBA) is favorable. Ligand B (3 HBD, 5 HBA) is acceptable, but higher values can sometimes reduce permeability.

**QED:** Ligand A (0.779) is good, indicating a drug-like profile. Ligand B (0.45) is below the desirable threshold of 0.5, suggesting potential issues.

**DILI:** Ligand A (41.838) has a moderate DILI risk, but is acceptable. Ligand B (28.228) has a lower DILI risk, which is preferable.

**BBB:** Ligand A (93.408) has excellent BBB penetration potential. Ligand B (65.607) is lower, and while not terrible, it's less desirable for a CNS target.

**Caco-2:** Ligand A (-4.68) has poor Caco-2 permeability. Ligand B (-5.105) also has poor Caco-2 permeability.

**Solubility:** Ligand A (-4.447) has poor solubility. Ligand B (-2.147) has poor solubility.

**hERG:** Both ligands have low hERG inhibition risk (Ligand A: 0.938, Ligand B: 0.565).

**Microsomal Clearance:** Ligand A (71.472) has moderate clearance. Ligand B (-17.434) has negative clearance, which is not possible and likely an error in the data, but suggests very high metabolic stability.

**In vitro Half-Life:** Ligand A (2.268 hours) has a short half-life. Ligand B (-20.407 hours) also has a negative half-life, which is not possible and likely an error in the data.

**P-gp Efflux:** Ligand A (0.768) has moderate P-gp efflux. Ligand B (0.051) has very low P-gp efflux, which is highly desirable for CNS penetration.

**Binding Affinity:** Ligand A (-10.1 kcal/mol) has significantly stronger binding affinity than Ligand B (-8.2 kcal/mol). This is a substantial difference, potentially outweighing some of the ADME drawbacks.

**Overall Assessment:**

Ligand A excels in TPSA, logP, BBB, and, most importantly, binding affinity. Its weaknesses are Caco-2 permeability, solubility, and half-life. Ligand B has better DILI and P-gp efflux, but suffers from a high TPSA, low logP, poor QED, and significantly weaker binding affinity.

Given the importance of binding affinity for GPCRs, and the need for BBB penetration for CNS targets, Ligand A is the more promising candidate *despite* its ADME liabilities. The strong binding affinity could allow for a lower dose, potentially mitigating some of the ADME issues. Further optimization would focus on improving solubility, permeability, and half-life while maintaining the high affinity. The negative values for clearance and half-life for Ligand B are concerning and suggest data errors.

Output:
1
2025-04-17 04:18:10,284 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (355.434 and 345.447 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (37.38) is excellent, well below the 90 A^2 threshold for CNS targets. Ligand B (72.28) is higher, but still reasonably acceptable, though less optimal for CNS penetration.

**logP:** Ligand A (4.256) is slightly high, potentially leading to solubility issues or off-target interactions. Ligand B (1.406) is within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A (0 HBD, 2 HBA) is favorable. Ligand B (1 HBD, 6 HBA) is also acceptable, though the higher HBA count could slightly impact permeability.

**QED:** Both ligands have good QED values (0.701 and 0.744), indicating drug-like properties.

**DILI:** Ligand A (77.627) has a higher DILI risk than Ligand B (40.403). Ligand B is well below the 60 threshold, indicating lower liver injury risk.

**BBB:** Ligand A (83.133) shows excellent BBB penetration, which is crucial for a CNS target like DRD2. Ligand B (64.482) is lower, suggesting reduced CNS exposure.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.988 and -4.896). This is unusual and suggests poor permeability. However, these values are on a log scale and can be misleading without knowing the base.

**Aqueous Solubility:** Both ligands have very poor aqueous solubility (-5.508 and -2.007). This is a significant concern for bioavailability.

**hERG Inhibition:** Both ligands show low hERG inhibition risk (0.936 and 0.407).

**Microsomal Clearance:** Ligand A (63.527) has higher microsomal clearance than Ligand B (46.962), indicating faster metabolism and potentially lower *in vivo* exposure.

**In vitro Half-Life:** Ligand B (0.34 hours) has a very short half-life, while Ligand A (-30.692 hours) is negative, which is also unusual.

**P-gp Efflux:** Ligand A (0.436) has lower P-gp efflux than Ligand B (0.206), suggesting better CNS exposure.

**Binding Affinity:** Ligand B (-7.9 kcal/mol) has a significantly stronger binding affinity than Ligand A (-11.3 kcal/mol). This is a substantial advantage.

**Overall Assessment:**

While Ligand A has excellent BBB penetration and lower P-gp efflux, its high logP, higher DILI risk, faster metabolism, and significantly weaker binding affinity are major drawbacks. Ligand B, despite having a lower BBB score, exhibits a much stronger binding affinity, lower DILI risk, and better metabolic stability. The poor solubility and permeability are concerning for both, but the potency advantage of Ligand B is likely to outweigh these issues, especially given the possibility of formulation strategies to improve solubility.

Output:
1
2025-04-17 04:18:10,284 - INFO - Reasoning:

Let's analyze Ligand A and Ligand B based on the provided guidelines, prioritizing GPCR-specific properties (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (348.487 Da) is slightly lower, which *could* be beneficial for permeability, but both are acceptable.

**TPSA:** Ligand A (62.55) is excellent for CNS penetration, well below the 90 A^2 threshold. Ligand B (78.09) is still reasonable, but less optimal.

**logP:** Ligand A (3.834) is at the higher end of the optimal range (1-3), while Ligand B (2.55) is well within the optimal range. Both are acceptable, but Ligand B is slightly preferred.

**H-Bond Donors/Acceptors:** Ligand A (HBD=1, HBA=3) and Ligand B (HBD=2, HBA=3) both have low numbers of H-bond donors and acceptors, which is favorable for permeability.

**QED:** Both ligands have good QED scores (A: 0.726, B: 0.795), indicating good drug-like properties.

**DILI:** Ligand A (28.887) has a significantly lower DILI risk than Ligand B (53.858), which is a strong advantage.

**BBB:** Ligand A (78.868) has a much better BBB penetration score than Ligand B (64.25), which is crucial for a CNS target like DRD2.

**Caco-2 Permeability:** Ligand A (-4.204) has a lower Caco-2 permeability than Ligand B (-4.901), but both are negative values which are difficult to interpret without knowing the scale.

**Aqueous Solubility:** Both ligands have similarly poor aqueous solubility (-3.525 and -3.598). This could pose formulation challenges, but is not a deciding factor.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (A: 0.667, B: 0.398), which is good.

**Microsomal Clearance:** Ligand A (77.02) has a higher microsomal clearance than Ligand B (7.842), indicating faster metabolism and potentially lower *in vivo* exposure. This is a significant disadvantage for Ligand A.

**In vitro Half-Life:** Ligand A (74.597) has a longer in vitro half-life than Ligand B (-25.565). However, the negative value for Ligand B is concerning and suggests a very short half-life.

**P-gp Efflux:** Ligand A (0.588) has lower P-gp efflux than Ligand B (0.065), which is favorable for CNS exposure.

**Binding Affinity:** Ligand B (-7.8 kcal/mol) has a slightly better binding affinity than Ligand A (-7.1 kcal/mol). While the difference is not huge, it's enough to consider, especially given the other factors.

**Overall:**

Ligand A excels in BBB penetration, DILI risk, and P-gp efflux. However, it suffers from higher microsomal clearance and lower Caco-2 permeability. Ligand B has slightly better affinity and logP, but a significantly higher DILI risk, lower BBB penetration, and higher P-gp efflux. Considering the CNS target and the importance of BBB penetration, the lower DILI risk of Ligand A is also a major benefit. The slightly better affinity of Ligand B is unlikely to outweigh the other factors.

Output:
1
2025-04-17 04:18:10,285 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (428.264 Da) is slightly higher than Ligand B (373.791 Da), but both are acceptable.

**TPSA:** Ligand A (115.32) is slightly above the optimal <90 for CNS targets, while Ligand B (99.12) is closer to the ideal range. This gives a slight edge to Ligand B.

**logP:** Ligand A (2.072) is within the optimal 1-3 range. Ligand B (4.79) is higher, potentially leading to solubility issues and off-target effects. This favors Ligand A.

**H-Bond Donors/Acceptors:** Ligand A has 1 HBD and 7 HBA, while Ligand B has 2 HBD and 3 HBA. Both are within acceptable limits.

**QED:** Ligand A (0.725) has a better QED score than Ligand B (0.408), indicating better overall drug-likeness. This favors Ligand A.

**DILI:** Ligand A (97.867) has a significantly higher DILI risk than Ligand B (59.403). This is a major concern for Ligand A.

**BBB:** Ligand B (78.868) has a better BBB percentile than Ligand A (57.968). This is crucial for a CNS target like DRD2 and strongly favors Ligand B.

**Caco-2 Permeability:** Ligand A (-4.888) has poor Caco-2 permeability, while Ligand B (-4.55) is slightly better, but both are quite poor.

**Aqueous Solubility:** Ligand A (-3.738) has very poor solubility, while Ligand B (-5.159) is even worse. Both are problematic.

**hERG Inhibition:** Ligand A (0.245) has a lower hERG inhibition risk than Ligand B (0.691). This favors Ligand A.

**Microsomal Clearance:** Ligand A (45.755) has a higher microsomal clearance than Ligand B (40.583), indicating lower metabolic stability. This favors Ligand B.

**In vitro Half-Life:** Ligand B (30.546) has a shorter in vitro half-life than Ligand A (88.756). This favors Ligand A.

**P-gp Efflux:** Ligand A (0.191) has lower P-gp efflux than Ligand B (0.229), which is beneficial for CNS penetration. This favors Ligand A.

**Binding Affinity:** Both ligands have very similar and excellent binding affinities (-7.8 and -7.9 kcal/mol). The difference is negligible.

**Overall Assessment:**

Ligand A excels in binding affinity, QED, hERG, P-gp efflux, and in vitro half-life. However, it suffers from very high DILI risk, poor solubility, poor Caco-2 permeability, and a lower BBB percentile.

Ligand B has a better BBB percentile, lower DILI risk, better TPSA, and slightly better Caco-2 permeability and microsomal clearance. However, it has a higher logP and lower QED.

Considering the GPCR-specific priorities, BBB penetration is critical for a CNS target like DRD2. While Ligand A has slightly better ADME properties in some areas, the significantly higher DILI risk and lower BBB penetration of Ligand A are major drawbacks. Ligand B's better BBB and lower DILI risk outweigh its slightly less favorable logP and QED.

Output:
1
2025-04-17 04:18:10,285 - INFO - Reasoning:

Let's analyze Ligand A and Ligand B based on the provided guidelines, prioritizing GPCR-specific properties (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (353.304 Da) is slightly lower, which could be advantageous for permeability.

**TPSA:** Both ligands have TPSA values (84.04 and 87.3) below the 90 A^2 threshold desirable for CNS targets, indicating good potential for brain penetration.

**logP:** Both ligands have logP values within the optimal range (1-3), with Ligand A (1.92) being slightly lower and Ligand B (2.942) being closer to the upper limit.

**H-Bond Donors/Acceptors:** Ligand A (0 HBD, 6 HBA) and Ligand B (3 HBD, 4 HBA) both fall within acceptable ranges.

**QED:** Ligand A (0.838) has a significantly higher QED score than Ligand B (0.621), suggesting a more drug-like profile.

**DILI:** Both ligands have acceptable DILI risk, with Ligand A (72.703) being slightly higher than Ligand B (60.876), but both are below the concerning threshold of 60.

**BBB:** Ligand A (83.443) has a significantly higher BBB percentile than Ligand B (59.248). This is a crucial advantage for a CNS target like DRD2.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values, which is unusual and suggests poor permeability. However, the scale is not defined, so it's hard to interpret.

**Aqueous Solubility:** Both ligands have negative solubility values, which is also unusual.

**hERG Inhibition:** Ligand A (0.201) shows a much lower hERG inhibition liability than Ligand B (0.646), indicating a lower risk of cardiotoxicity.

**Microsomal Clearance:** Ligand A (63.809) has a higher microsomal clearance than Ligand B (37.333), indicating potentially lower metabolic stability.

**In vitro Half-Life:** Ligand B (46.642) has a significantly longer in vitro half-life than Ligand A (-6.238), which is a substantial advantage.

**P-gp Efflux:** Ligand A (0.374) shows lower P-gp efflux liability than Ligand B (0.183), which is favorable for CNS penetration.

**Binding Affinity:** Ligand B (-7.9 kcal/mol) has a slightly stronger binding affinity than Ligand A (-8.3 kcal/mol). While the difference is small, it's still a factor.

**Overall Assessment:**

Ligand A excels in key GPCR properties like BBB penetration, P-gp efflux, and hERG inhibition. It also has a better QED score. However, Ligand B has a better in vitro half-life and slightly better binding affinity. The significantly better BBB score of Ligand A is a major advantage for a CNS target. The lower P-gp efflux also contributes to better CNS exposure. While Ligand A has higher clearance, the superior CNS penetration properties are likely more critical for DRD2.

Output:
1
2025-04-17 04:18:10,285 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (350.547 and 364.515 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (49.41) is excellent, well below the 90 A^2 threshold for CNS targets. Ligand B (76.02) is still reasonable, but higher and potentially problematic for CNS penetration.

**3. logP:** Ligand A (4.28) is slightly high, potentially leading to solubility issues or off-target interactions, but still within a tolerable range. Ligand B (2.129) is optimal.

**4. H-Bond Donors:** Both ligands have acceptable HBD counts (1 and 2, respectively), well below the 5 threshold.

**5. H-Bond Acceptors:** Ligand A (2) and Ligand B (5) are both within the acceptable range of <=10.

**6. QED:** Both ligands have similar and good QED values (0.745 and 0.741), indicating good drug-like properties.

**7. DILI:** Ligand A (21.791) has a significantly lower DILI risk than Ligand B (41.838), which is a substantial advantage.

**8. BBB:** This is crucial for a CNS target. Ligand A (83.288) has a very good BBB percentile, exceeding the desirable >70 threshold. Ligand B (45.56) is considerably lower and raises concerns about CNS exposure.

**9. Caco-2 Permeability:** Ligand A (-4.7) is poor, indicating low intestinal absorption. Ligand B (-5.616) is also poor.

**10. Aqueous Solubility:** Ligand A (-4.246) and Ligand B (-1.884) both have poor aqueous solubility, which could pose formulation challenges.

**11. hERG Inhibition:** Both ligands show low hERG inhibition risk (0.62 and 0.251, respectively).

**12. Microsomal Clearance:** Ligand A (75.869) has higher microsomal clearance than Ligand B (11.373), indicating lower metabolic stability.

**13. In vitro Half-Life:** Ligand B (-7.947) has a significantly longer in vitro half-life than Ligand A (-4.847), which is a positive attribute.

**14. P-gp Efflux:** Ligand A (0.444) has lower P-gp efflux liability than Ligand B (0.065), which is favorable for CNS exposure.

**15. Binding Affinity:** Both ligands have excellent binding affinities (-8.3 and -7.8 kcal/mol), well below the -7.0 threshold. Ligand A has a 0.5 kcal/mol advantage, which is significant.

**Overall Assessment:**

Ligand A excels in key areas for a CNS GPCR target: TPSA, BBB, DILI, and binding affinity. While its logP is slightly elevated and Caco-2 permeability is poor, the strong BBB penetration and lower DILI risk are compelling advantages. Ligand B has better metabolic stability and solubility, but its significantly lower BBB penetration is a major drawback for a CNS target like DRD2. The affinity difference, while present, is less impactful than the substantial difference in predicted brain exposure.

Output:
1
2025-04-17 04:18:10,285 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight (MW):** Both ligands (353.438 and 350.463 Da) fall comfortably within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (75.44) is better than Ligand B (85.25). For CNS targets, we want TPSA <= 90, both are within this range, but A is closer to the ideal.

**3. logP:** Both ligands have similar logP values (2.346 and 2.332), falling within the optimal 1-3 range.

**4. H-Bond Donors (HBD):** Both are acceptable (1 and 2 respectively), well below the limit of 5.

**5. H-Bond Acceptors (HBA):** Both are acceptable (4 and 5 respectively), well below the limit of 10.

**6. QED:** Both have reasonable QED scores (0.816 and 0.716), indicating good drug-like properties.

**7. DILI:** Ligand A (35.944) has a better DILI score than Ligand B (48.623), indicating a lower risk of liver injury. Both are below the 60 threshold, but A is preferable.

**8. BBB:** Both ligands have excellent BBB penetration (86.661 and 81.66), exceeding the desirable >70% threshold for CNS targets.

**9. Caco-2 Permeability:** Ligand A (-4.363) is better than Ligand B (-4.542), indicating better intestinal absorption.

**10. Aqueous Solubility:** Ligand A (-2.642) is better than Ligand B (-3.154), indicating better aqueous solubility.

**11. hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.421 and 0.266).

**12. Microsomal Clearance (Cl_mic):** Ligand A (65.055) has higher clearance than Ligand B (49.43), meaning it's less metabolically stable. This is a negative for Ligand A.

**13. In vitro Half-Life (t1/2):** Ligand B (34.082) has a longer half-life than Ligand A (-28.293), which is a significant advantage.

**14. P-gp Efflux:** Both ligands have low P-gp efflux liability (0.123 and 0.228).

**15. Binding Affinity:** Ligand B (-7.2 kcal/mol) has a significantly stronger binding affinity than Ligand A (-8.1 kcal/mol). This is a crucial advantage, potentially outweighing some of the ADME drawbacks of Ligand A.

**Overall Assessment:**

While Ligand A has better TPSA, solubility, and DILI, Ligand B's significantly stronger binding affinity (-7.2 vs -8.1 kcal/mol) and longer half-life are decisive. The slightly higher clearance of Ligand A is a concern, but the superior affinity of Ligand B is a more important factor for a GPCR target like DRD2. Both have good BBB penetration and acceptable ADME properties.

Output:
1
2025-04-17 04:18:10,285 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (362.392 and 344.455 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (49.85) is significantly better than Ligand B (58.64). For CNS targets, we want TPSA <= 90, and ideally closer to 60. Ligand A is much closer to this ideal.

**3. logP:** Both ligands have a logP around 2.0 (2.062 and 2.021), which is optimal (1-3).

**4. H-Bond Donors:** Ligand A (0) is preferable to Ligand B (1). Fewer HBDs generally improve permeability.

**5. H-Bond Acceptors:** Both ligands have 3 HBAs, which is acceptable (<=10).

**6. QED:** Both ligands have reasonable QED values (0.772 and 0.613), indicating good drug-like properties (>=0.5).

**7. DILI:** Ligand A (20.473) has a much lower DILI risk than Ligand B (12.136). Lower is better, and Ligand A is well below the 40% threshold.

**8. BBB:** Ligand A (88.872) has a significantly higher BBB penetration percentile than Ligand B (70.648). This is *crucial* for a CNS target like DRD2. >70 is desirable, and Ligand A is closer to this.

**9. Caco-2 Permeability:** Ligand A (-4.338) is better than Ligand B (-4.785), indicating better intestinal absorption.

**10. Aqueous Solubility:** Ligand A (-2.506) is better than Ligand B (-2.956), although both are quite poor. Solubility is less critical than BBB for CNS drugs.

**11. hERG Inhibition:** Ligand A (0.581) has a slightly better hERG profile than Ligand B (0.109), indicating lower cardiotoxicity risk.

**12. Microsomal Clearance:** Ligand B (1.012) has much lower microsomal clearance than Ligand A (22.039), suggesting better metabolic stability.

**13. In vitro Half-Life:** Ligand B (-2.238) has a better in vitro half-life than Ligand A (-16.858).

**14. P-gp Efflux:** Ligand A (0.073) has a lower P-gp efflux liability than Ligand B (0.048), which is favorable for CNS exposure.

**15. Binding Affinity:** Ligand B (-8.4) has a slightly better binding affinity than Ligand A (-7.9), a difference of 0.5 kcal/mol. While affinity is important, the other ADME properties are more concerning for Ligand B.

**Overall Assessment:**

Ligand A is the stronger candidate. While Ligand B has slightly better affinity and metabolic stability, Ligand A excels in crucial properties for a CNS-targeting GPCR ligand: TPSA, BBB penetration, DILI risk, and P-gp efflux. The superior BBB penetration of Ligand A is a significant advantage, outweighing the small difference in binding affinity. The lower DILI risk is also a major plus.



Output:
1
2025-04-17 04:18:10,285 - INFO - Batch 101 complete. Total preferences: 1616
2025-04-17 04:18:10,285 - INFO - Processing batch 102/512...
2025-04-17 04:18:49,618 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (351.451 and 354.378 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (120.0) is slightly above the preferred <90 for CNS targets, but still reasonable. Ligand B (87.15) is excellent, well below the threshold.

**3. logP:** Ligand A (0.923) is a bit low, potentially hindering permeability. Ligand B (0.518) is even lower and concerning for permeability.

**4. H-Bond Donors:** Ligand A (4) is acceptable. Ligand B (1) is also good.

**5. H-Bond Acceptors:** Both ligands (A: 5, B: 5) are within the acceptable limit of 10.

**6. QED:** Both ligands have similar QED values (A: 0.607, B: 0.555), indicating reasonable drug-likeness.

**7. DILI:** Both ligands have acceptable DILI risk (A: 56.146, B: 49.632), below the 60 threshold.

**8. BBB:** This is crucial for a CNS target. Ligand A (36.371) has a poor BBB percentile. Ligand B (81.698) is excellent, exceeding the desirable >70 threshold.

**9. Caco-2 Permeability:** Ligand A (-5.396) and Ligand B (-4.854) both have negative values, which is unusual and suggests very poor permeability.

**10. Aqueous Solubility:** Both ligands have poor aqueous solubility (A: -2.667, B: -2.045).

**11. hERG Inhibition:** Both ligands show low hERG inhibition risk (A: 0.06, B: 0.33).

**12. Microsomal Clearance:** Ligand A (16.629) has lower clearance than Ligand B (20.96), suggesting better metabolic stability.

**13. In vitro Half-Life:** Ligand B (-34.033) has a significantly longer in vitro half-life than Ligand A (-15.387).

**14. P-gp Efflux:** Both ligands have low P-gp efflux liability (A: 0.037, B: 0.119).

**15. Binding Affinity:** Ligand B (-8.6 kcal/mol) has a substantially stronger binding affinity than Ligand A (-7.5 kcal/mol). This >1.5 kcal/mol difference is significant.

**Overall Assessment:**

While Ligand A has slightly better metabolic stability, Ligand B is clearly superior due to its excellent BBB penetration (81.698%), significantly stronger binding affinity (-8.6 kcal/mol), and longer half-life. The lower logP values for both are a concern, but the strong affinity of Ligand B may compensate for this. The TPSA of Ligand B is also much more favorable for CNS penetration.

Output:
1
2025-04-17 04:18:49,619 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (336.395 Da) is slightly lower, which could be beneficial for permeability. Ligand B (367.515 Da) is also acceptable.

**TPSA:** Ligand A (69.04) is excellent, well below the 90 A^2 threshold for CNS targets. Ligand B (82.43) is still reasonable but less optimal.

**logP:** Ligand A (3.484) is at the upper end of the optimal range (1-3), but still acceptable. Ligand B (1.802) is towards the lower end, potentially hindering permeation.

**H-Bond Donors/Acceptors:** Both ligands have 1 HBD and 5 HBA, which are within acceptable limits.

**QED:** Ligand A (0.724) has a better QED score than Ligand B (0.596), indicating a more drug-like profile.

**DILI:** Ligand A (82.939) has a higher DILI risk than Ligand B (27.724). This is a significant drawback for Ligand A.

**BBB:** Both ligands have acceptable BBB penetration (Ligand A: 70.027, Ligand B: 64.793), but Ligand A is slightly better, exceeding the 70% threshold desirable for CNS targets.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values, which is unusual and suggests a potential issue with the data or a very poor permeability. However, we will continue the analysis.

**Aqueous Solubility:** Both ligands have negative solubility values, which is also unusual and suggests a potential issue with the data or very poor solubility.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (Ligand A: 0.772, Ligand B: 0.588).

**Microsomal Clearance:** Ligand A (67.288) has a higher microsomal clearance than Ligand B (29.66), indicating lower metabolic stability.

**In vitro Half-Life:** Ligand A (39.224) has a longer half-life than Ligand B (2.541), which is a positive attribute.

**P-gp Efflux:** Ligand A (0.594) has a lower P-gp efflux liability than Ligand B (0.137), which is beneficial for CNS exposure.

**Binding Affinity:** Ligand A (-9.8 kcal/mol) has a significantly stronger binding affinity than Ligand B (-6.5 kcal/mol). This is a substantial advantage.

**Overall Assessment:**

Ligand A has a superior binding affinity, better BBB penetration, lower P-gp efflux, and a better QED score. However, it has a significantly higher DILI risk and higher microsomal clearance. Ligand B has a lower DILI risk and better metabolic stability, but weaker binding affinity, lower BBB penetration, and higher P-gp efflux.

Given the importance of binding affinity for GPCRs, and the fact that the difference in affinity is >1.5 kcal/mol, Ligand A is more likely to be a viable drug candidate *despite* the higher DILI risk. The DILI risk could potentially be mitigated through structural modifications in subsequent optimization rounds. The stronger binding is likely to translate to greater efficacy, and the better BBB penetration and lower P-gp efflux will improve CNS exposure.

Output:
1
2025-04-17 04:18:49,619 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (336.355 Da) is slightly lower, which could be advantageous for permeability.

**TPSA:** Ligand A (86.86) is excellent for CNS penetration, well below the 90 A^2 threshold. Ligand B (49.41) is also very good.

**logP:** Ligand A (1.342) is within the optimal range. Ligand B (3.914) is approaching the upper limit, potentially raising concerns about solubility and off-target effects, but still acceptable.

**H-Bond Donors/Acceptors:** Both ligands have acceptable HBD (1) and HBA (Ligand A: 7, Ligand B: 2) counts.

**QED:** Both ligands have similar and acceptable QED values (Ligand A: 0.727, Ligand B: 0.709), indicating good drug-like properties.

**DILI:** Ligand A (83.017) has a higher DILI risk than Ligand B (13.3), which is a significant negative.

**BBB:** Ligand B (87.01) has a substantially better BBB penetration score than Ligand A (35.867). This is a critical advantage for a CNS target like DRD2.

**Caco-2 Permeability:** Ligand A (-5.059) shows poor Caco-2 permeability, while Ligand B (-4.594) is slightly better but still low.

**Aqueous Solubility:** Both ligands have very poor aqueous solubility (-2.732 and -3.938 respectively). This is a concern for formulation.

**hERG Inhibition:** Both ligands have relatively low hERG inhibition liability (Ligand A: 0.549, Ligand B: 0.663).

**Microsomal Clearance:** Ligand B (67.125) has a higher microsomal clearance than Ligand A (41.614), suggesting lower metabolic stability.

**In vitro Half-Life:** Ligand A (-27.626) has a significantly shorter in vitro half-life than Ligand B (-10.655).

**P-gp Efflux:** Both ligands have low P-gp efflux liability (Ligand A: 0.068, Ligand B: 0.133).

**Binding Affinity:** Both ligands have excellent binding affinity (Ligand A: -9.5 kcal/mol, Ligand B: -8.0 kcal/mol). Ligand A has a 1.5 kcal/mol advantage.

**Overall Assessment:**

Ligand A has a better binding affinity and lower clearance, but suffers from poor BBB penetration, poor Caco-2 permeability, a high DILI risk, and a short half-life. Ligand B, while having slightly weaker affinity, excels in BBB penetration, has a much lower DILI risk, and a longer half-life. Given the CNS target (DRD2), BBB penetration is paramount. The 1.5 kcal/mol difference in binding affinity can likely be overcome with further optimization, whereas improving BBB penetration is far more challenging. The lower DILI risk of Ligand B is also a significant advantage.

Output:
1
2025-04-17 04:18:49,619 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 drug candidates, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (350.419 and 350.459 Da) fall comfortably within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (87.91) is better than Ligand B (78.87). Both are below the 90 A^2 threshold desirable for CNS targets, but A is closer to the upper limit.

**3. logP:** Ligand B (1.237) is better than Ligand A (0.636). Both are within the optimal 1-3 range, but A is quite low, potentially hindering permeability.

**4. H-Bond Donors:** Ligand A (1) is better than Ligand B (2). Lower HBD is generally preferred for better permeability.

**5. H-Bond Acceptors:** Ligand A (6) is better than Ligand B (4). Both are within the acceptable range of <=10.

**6. QED:** Both ligands have similar QED values (0.776 and 0.677), indicating good drug-like properties.

**7. DILI:** Ligand A (29.934) is significantly better than Ligand B (12.136). A lower DILI percentile is highly desirable.

**8. BBB:** Ligand A (67.623) is slightly better than Ligand B (65.374), but both are below the 70% threshold for strong CNS penetration.

**9. Caco-2 Permeability:** Ligand A (-4.904) is better than Ligand B (-4.655), indicating better intestinal absorption.

**10. Aqueous Solubility:** Ligand A (-0.893) is better than Ligand B (-1.777). Higher solubility is preferred.

**11. hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.187 and 0.241).

**12. Microsomal Clearance:** Ligand A (9.711) is significantly better than Ligand B (27.769). Lower clearance indicates better metabolic stability.

**13. In vitro Half-Life:** Ligand A (8.624) is better than Ligand B (2.934). A longer half-life is preferred.

**14. P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.03 and 0.054).

**15. Binding Affinity:** Ligand B (-7.7) has a slightly better binding affinity than Ligand A (-7.5). While both are excellent, the 0.2 kcal/mol difference is not massive.

**Overall Assessment:**

Ligand A is superior. While Ligand B has a slightly better binding affinity, Ligand A excels in crucial ADME properties, particularly DILI, microsomal clearance, and in vitro half-life. Ligand A also has better solubility and Caco-2 permeability. The slightly lower logP of Ligand A is a concern, but the substantial advantages in safety (DILI) and metabolic stability outweigh this drawback. Given the GPCR-specific priority of BBB penetration, both ligands are somewhat lacking, but the other improvements in A make it the better candidate.

Output:
0
2025-04-17 04:18:49,619 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (354.447 and 346.427 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (68.31) is excellent, well below the 90 A^2 threshold for CNS targets. Ligand B (78.87) is still reasonable, but less optimal.

**logP:** Ligand A (0.831) is a bit low, potentially hindering permeation. Ligand B (1.848) is better, falling within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A (0 HBD, 5 HBA) is favorable. Ligand B (2 HBD, 4 HBA) is also acceptable.

**QED:** Both ligands have good QED scores (0.661 and 0.824), indicating drug-like properties.

**DILI:** Ligand A (46.064) has a slightly higher DILI risk than Ligand B (23.497), but both are below the concerning 60 threshold.

**BBB:** Both ligands show good BBB penetration (58.782 and 63.862), but neither exceeds the desirable 70% threshold.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.446 and -4.767), which is unusual and suggests poor permeability. This is a significant concern.

**Aqueous Solubility:** Both ligands have negative solubility values (-0.968 and -3.681), indicating very poor aqueous solubility. This is a major issue for bioavailability.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.132 and 0.379).

**Microsomal Clearance:** Ligand A (31.117) has lower microsomal clearance than Ligand B (46.806), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (1.058 hours) has a very short half-life, while Ligand B (-18.174 hours) has a negative half-life, which is not physically possible and indicates a problem with the data or the model.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.049 and 0.075), which is good for CNS exposure.

**Binding Affinity:** Ligand B (-8.9 kcal/mol) has significantly stronger binding affinity than Ligand A (-7.0 kcal/mol). This >1.5 kcal/mol difference is substantial and can outweigh some ADME drawbacks.

**Overall Assessment:**

Ligand B is the more promising candidate despite some concerning ADME properties. The significantly stronger binding affinity (-8.9 vs -7.0 kcal/mol) is a major advantage for a GPCR target like DRD2. While both have poor solubility and permeability (indicated by negative Caco-2 and solubility values), the better logP and lower DILI risk of Ligand B are also favorable. The negative half-life for Ligand B is a data quality issue that would need to be investigated. Ligand A's very short half-life is also problematic.

Output:
1
2025-04-17 04:18:49,619 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (358.869 and 347.419 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (56.33) is excellent, well below the 90 A^2 threshold for CNS targets. Ligand B (78.87) is still reasonable but less optimal.

**logP:** Ligand A (3.979) is at the upper end of the optimal range (1-3), but still acceptable. Ligand B (0.108) is significantly low, potentially hindering membrane permeability and CNS penetration.

**H-Bond Donors/Acceptors:** Ligand A (2 HBD, 2 HBA) is well within the desirable limits. Ligand B (0 HBD, 6 HBA) is also acceptable, though the higher number of HBAs might slightly reduce permeability.

**QED:** Both ligands have similar QED values (0.81 and 0.769), indicating good drug-likeness.

**DILI:** Ligand A (39.667) has a slightly better DILI score than Ligand B (45.095), both are acceptable.

**BBB:** Both ligands have good BBB penetration (67.352% and 68.282%), exceeding the 70% threshold.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values, which is unusual and suggests a potential issue with the data or the model. However, we can still compare their relative values. Ligand A (-4.994) is slightly better than Ligand B (-4.503).

**Aqueous Solubility:** Both ligands have negative solubility values, which is also unusual. Ligand A (-4.288) is slightly better than Ligand B (-0.668).

**hERG:** Ligand A (0.811) has a slightly better hERG score than Ligand B (0.246), indicating lower cardiotoxicity risk.

**Microsomal Clearance:** Ligand A (4.097) has a lower (better) microsomal clearance than Ligand B (-5.29), suggesting greater metabolic stability.

**In vitro Half-Life:** Ligand A (31.206 hours) has a significantly longer half-life than Ligand B (1.036 hours).

**P-gp Efflux:** Ligand A (0.369) has a lower P-gp efflux liability than Ligand B (0.021), which is favorable for CNS penetration.

**Binding Affinity:** Ligand B (-7.6 kcal/mol) has a significantly stronger binding affinity than Ligand A (-9.3 kcal/mol). This is a substantial advantage.

**Overall Assessment:**

While Ligand A has better ADME properties across the board (TPSA, logP, clearance, half-life, P-gp efflux), Ligand B's significantly stronger binding affinity (-7.6 vs -9.3 kcal/mol) is a major advantage, especially for a GPCR target. The difference in affinity is large enough to potentially overcome the less favorable logP and clearance. The negative Caco-2 and solubility values are concerning for both, but the affinity difference is the deciding factor.

Output:
1
2025-04-17 04:18:49,619 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (354.491 and 348.403 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (75.71) is excellent, well below the 90 A^2 threshold for CNS targets. Ligand B (103.53) is still reasonable, but less optimal, being above 90 A^2.

**logP:** Ligand A (2.221) is within the optimal 1-3 range. Ligand B (-0.403) is below 1, which could hinder permeation.

**H-Bond Donors/Acceptors:** Ligand A (HBD=1, HBA=4) and Ligand B (HBD=3, HBA=4) both have acceptable numbers of hydrogen bond donors and acceptors.

**QED:** Both ligands have similar QED values (0.61 and 0.609), indicating good drug-likeness.

**DILI:** Ligand A (24.622) has a much lower DILI risk than Ligand B (55.525), which is a significant advantage.

**BBB:** Ligand A (72.625) has a good BBB percentile, exceeding the 70% threshold for CNS targets. Ligand B (55.138) is considerably lower, indicating poor brain penetration. This is a critical disadvantage for a DRD2 ligand.

**Caco-2 Permeability:** Ligand A (-4.301) and Ligand B (-5.345) both have negative Caco-2 values, which is unusual and suggests poor permeability. However, the scale is not clearly defined, so it's hard to interpret.

**Aqueous Solubility:** Both ligands have very poor aqueous solubility (-2.493 and -2.219). This could pose formulation challenges.

**hERG:** Both ligands have low hERG inhibition liability (0.332 and 0.171), which is good.

**Microsomal Clearance:** Ligand A (93.86) has a higher microsomal clearance, suggesting faster metabolism. Ligand B (9.345) has much lower clearance, indicating better metabolic stability.

**In vitro Half-Life:** Ligand B (-15.756) has a much longer in vitro half-life than Ligand A (-5.898), which is desirable.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.039 and 0.028), which is favorable for CNS exposure.

**Binding Affinity:** Ligand B (-8.5 kcal/mol) has a slightly better binding affinity than Ligand A (-7.5 kcal/mol). The difference is 1 kcal/mol, which is not huge but still noticeable.

**Overall Assessment:**

Ligand A excels in TPSA, BBB, and DILI risk, which are crucial for a CNS-targeting GPCR ligand. While its solubility and metabolic stability are concerns, its strong BBB penetration and lower toxicity profile are significant advantages. Ligand B has better metabolic stability and binding affinity, but its poor BBB penetration and higher DILI risk are major drawbacks. Given the importance of brain penetration for DRD2, Ligand A is the more promising candidate. The slightly better affinity of Ligand B is unlikely to overcome its poor CNS exposure.

Output:
0
2025-04-17 04:18:49,620 - INFO - Reasoning:

Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (367.5 and 337.4 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (80.32) is better than Ligand B (73.99). Both are below the 90 A^2 threshold desirable for CNS targets, which is good.

**3. logP:** Both ligands have good logP values (2.148 and 2.546), falling within the optimal 1-3 range.

**4. H-Bond Donors:** Ligand A (2) is preferable to Ligand B (3). Lower HBD generally improves permeability.

**5. H-Bond Acceptors:** Ligand A (5) is preferable to Ligand B (2). Both are within the acceptable range.

**6. QED:** Both ligands have similar, good QED values (0.738 and 0.758), indicating good drug-like properties.

**7. DILI:** Ligand B (39.162) has a slightly lower DILI risk than Ligand A (48.391), but both are below the concerning threshold of 60.

**8. BBB:** Both ligands have excellent BBB penetration (56.999% and 59.403%), which is crucial for a CNS target like DRD2. Ligand B is slightly better.

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 values, which is unusual and suggests poor permeability. This is a significant concern for both.

**10. Aqueous Solubility:** Both ligands have negative solubility values, which is also unusual and suggests poor solubility. This is a significant concern for both.

**11. hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.252 and 0.405), which is excellent.

**12. Microsomal Clearance:** Ligand B (27.813) has significantly lower microsomal clearance than Ligand A (43.17), indicating better metabolic stability. This is a major advantage.

**13. In vitro Half-Life:** Ligand B (-3.024) has a significantly longer in vitro half-life than Ligand A (9.568), which is a substantial benefit.

**14. P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.165 and 0.1), which is favorable for CNS penetration.

**15. Binding Affinity:** Ligand B (-9.7 kcal/mol) has a substantially stronger binding affinity than Ligand A (-8.3 kcal/mol). This difference of 1.4 kcal/mol is significant and can outweigh some ADME drawbacks.

**Overall Assessment:**

While both compounds have issues with Caco-2 permeability and aqueous solubility, Ligand B is the stronger candidate. Its superior binding affinity, lower microsomal clearance, longer half-life, and slightly better BBB penetration outweigh the slightly higher DILI risk. The large difference in binding affinity is the most important factor.

Output:
1
2025-04-17 04:18:49,620 - INFO - Reasoning:

Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands are within the acceptable range (200-500 Da). Ligand A (356.369 Da) is slightly preferred as it's closer to the ideal range.

**2. TPSA:** Both ligands have TPSA values around 79, which is slightly above the optimal <90 for CNS targets, but still reasonable.

**3. logP:** Both ligands have logP values between 1 and 3 (1.286 and 1.807 respectively), which is ideal.

**4. H-Bond Donors:** Ligand A (2 HBD) is slightly better than Ligand B (1 HBD) as it provides a balance between solubility and permeability.

**5. H-Bond Acceptors:** Ligand A (4 HBA) and Ligand B (5 HBA) are both acceptable.

**6. QED:** Ligand A (0.722) has a better QED score than Ligand B (0.592), indicating a more drug-like profile.

**7. DILI:** Ligand A (36.797) has a significantly lower DILI risk than Ligand B (65.374). This is a major advantage for Ligand A.

**8. BBB:** This is a critical parameter for CNS targets. Ligand A (76.464) has a much higher BBB penetration percentile than Ligand B (44.979). This is a substantial advantage for Ligand A.

**9. Caco-2 Permeability:** Ligand A (-4.409) and Ligand B (-5.485) both have negative values, indicating poor permeability. However, this scale is not well defined, and the absolute values are less informative without context.

**10. Aqueous Solubility:** Both ligands have poor aqueous solubility (-2.062 and -2.606 respectively). This could pose formulation challenges.

**11. hERG Inhibition:** Both ligands have low hERG inhibition risk (0.329 and 0.56 respectively).

**12. Microsomal Clearance:** Ligand B (25.684) has lower microsomal clearance than Ligand A (36.338), suggesting better metabolic stability.

**13. In vitro Half-Life:** Ligand B (26.003 hours) has a significantly longer half-life than Ligand A (-20.321 hours). This is a major advantage for Ligand B.

**14. P-gp Efflux:** Both ligands have low P-gp efflux liability (0.054 and 0.165 respectively).

**15. Binding Affinity:** Both ligands have comparable and strong binding affinities (-8.2 and -8.6 kcal/mol). The difference is minimal.

**Overall Assessment:**

Ligand A is significantly better overall, despite the longer half-life of Ligand B. The key advantages of Ligand A are its superior BBB penetration, lower DILI risk, and better QED score. While Ligand B has better metabolic stability, the CNS target necessitates high BBB penetration, which Ligand A delivers. The comparable binding affinities mean that the ADME/Tox advantages of Ligand A outweigh the slightly better metabolic stability of Ligand B.

Output:
1
2025-04-17 04:18:49,620 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (376.4 and 360.443 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (58.64) is excellent, well below the 90 A^2 threshold for CNS targets. Ligand B (93.44) is higher, but still potentially acceptable, though less ideal.

**logP:** Both ligands have good logP values (2.353 and 1.743), falling within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A (1 HBD, 4 HBA) is better than Ligand B (2 HBD, 8 HBA). Both are within acceptable limits, but fewer H-bonds generally improve permeability.

**QED:** Both ligands have reasonable QED scores (0.829 and 0.565), indicating drug-like properties. Ligand A is significantly better.

**DILI:** Ligand A (31.369) has a much lower DILI risk than Ligand B (78.247), which is a significant advantage.

**BBB:** Ligand A (91.47) has excellent BBB penetration, exceeding the desirable >70% threshold. Ligand B (58.278) is considerably lower, raising concerns about CNS exposure. This is a critical factor for a DRD2 ligand.

**Caco-2 Permeability:** Ligand A (-4.949) is better than Ligand B (-5.455), indicating better intestinal absorption.

**Aqueous Solubility:** Ligand A (-2.915) is better than Ligand B (-1.937), which is important for formulation.

**hERG:** Ligand A (0.503) has a lower hERG risk than Ligand B (0.779).

**Microsomal Clearance:** Ligand A (10.128) has lower clearance than Ligand B (56.32), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (-5.702) has a longer half-life than Ligand B (12.484).

**P-gp Efflux:** Ligand A (0.103) shows lower P-gp efflux liability than Ligand B (0.121).

**Binding Affinity:** Ligand A (-8.6 kcal/mol) has a slightly better binding affinity than Ligand B (-7.9 kcal/mol). While both are good, the 1.5 kcal/mol difference is notable.

**Overall Assessment:**

Ligand A consistently outperforms Ligand B across most critical parameters, especially BBB penetration, DILI risk, metabolic stability, and P-gp efflux. While Ligand B has acceptable properties, Ligand A's superior profile makes it a much more promising drug candidate for targeting DRD2 in the CNS. The slightly better affinity of Ligand A further reinforces this conclusion.

Output:
1
2025-04-17 04:18:49,620 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (361.467 and 356.495 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (84.23) is better than Ligand B (70.67). Both are below the 90 A^2 threshold desirable for CNS targets.

**logP:** Both ligands have good logP values (3.188 and 3.469), falling within the optimal 1-3 range.

**H-Bond Donors:** Both have 2 HBD, which is acceptable.

**H-Bond Acceptors:** Ligand A has 5 HBA, and Ligand B has 4. Both are within the acceptable limit of 10.

**QED:** Both ligands have high QED scores (0.827 and 0.832), indicating good drug-likeness.

**DILI:** Ligand A (61.884) has a higher DILI risk than Ligand B (47.77). This favors Ligand B.

**BBB:** Ligand B (61.38) has a better BBB penetration percentile than Ligand A (55.293), although both are not ideal (>70). This is a significant advantage for Ligand B given the CNS target.

**Caco-2 Permeability:** Ligand A (-5.003) has better Caco-2 permeability than Ligand B (-5.22).

**Aqueous Solubility:** Ligand A (-4.971) has better aqueous solubility than Ligand B (-4.057).

**hERG:** Ligand A (0.243) has a lower hERG inhibition liability than Ligand B (0.539), indicating a lower risk of cardiotoxicity.

**Microsomal Clearance:** Ligand B (33.802) has a significantly lower microsomal clearance than Ligand A (48.021), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (55.426) has a longer in vitro half-life than Ligand B (-14.953). This is a substantial advantage for Ligand A.

**P-gp Efflux:** Ligand A (0.131) has lower P-gp efflux liability than Ligand B (0.21), which is favorable for CNS penetration.

**Binding Affinity:** Ligand B (-8.6) has a stronger binding affinity than Ligand A (-9.0). Although A is slightly better, the difference is small.

**Overall Assessment:**

Ligand B has several advantages: lower DILI risk, better BBB penetration, and significantly better metabolic stability (lower Cl_mic). Ligand A has better Caco-2 permeability, solubility, half-life and P-gp efflux. However, for a CNS target like DRD2, BBB penetration and metabolic stability are crucial. The stronger binding affinity of Ligand B, combined with its superior BBB and metabolic stability, outweigh the advantages of Ligand A.

Output:
1
2025-04-17 04:18:49,620 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (404.312 Da) is slightly higher, but acceptable. Ligand B (350.419 Da) is also good.

**TPSA:** Ligand A (83.6) is excellent, falling well below the 90 A^2 threshold for CNS targets. Ligand B (116.49) is higher, but still potentially acceptable, though less ideal.

**logP:** Ligand A (3.268) is within the optimal range (1-3). Ligand B (0.892) is a bit low, potentially hindering permeability.

**H-Bond Donors/Acceptors:** Ligand A (1 HBD, 5 HBA) is favorable. Ligand B (4 HBD, 6 HBA) is also acceptable, but slightly higher counts could impact permeability.

**QED:** Both ligands have similar QED values (A: 0.685, B: 0.605), indicating reasonable drug-likeness.

**DILI:** Both ligands have similar and acceptable DILI risk (A: 57.697, B: 57.038).

**BBB:** Ligand A (50.717) has a moderate BBB penetration score. Ligand B (38.891) has a lower BBB score, which is a significant drawback for a CNS target like DRD2.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.283 and -5.178), which is unusual and suggests poor permeability. This is a concern for both.

**Aqueous Solubility:** Both ligands have negative solubility values (-3.937 and -2.091), indicating poor aqueous solubility. This is a significant issue for bioavailability.

**hERG Inhibition:** Ligand A (0.713) has a slightly higher hERG risk than Ligand B (0.305), but both are relatively low.

**Microsomal Clearance:** Ligand A (47.949) has a higher microsomal clearance than Ligand B (7.65), suggesting lower metabolic stability.

**In vitro Half-Life:** Ligand A (43.677) has a longer half-life than Ligand B (3.08), which is preferable.

**P-gp Efflux:** Ligand A (0.517) has lower P-gp efflux liability than Ligand B (0.018), which is a positive for CNS penetration.

**Binding Affinity:** Both ligands have excellent binding affinities (A: -8.6 kcal/mol, B: -8.8 kcal/mol), with Ligand B being slightly better. However, the affinity difference is small.

**Overall Assessment:**

Given the GPCR-specific priorities, BBB penetration is crucial for a CNS target. Ligand A has a significantly better BBB score (50.717) than Ligand B (38.891). While both have issues with Caco-2 permeability and aqueous solubility, the better BBB, lower P-gp efflux, and longer half-life of Ligand A make it the more promising candidate. The slightly better affinity of Ligand B is outweighed by its poor BBB penetration and higher P-gp efflux.

Output:
0
2025-04-17 04:18:49,620 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (343.427 and 352.406 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Both ligands have TPSA values (82.62 and 82.78) that are acceptable for oral absorption (<140), but slightly higher than optimal for CNS penetration (<90). This is a minor drawback, but not disqualifying.

**3. logP:** Ligand A (2.984) is optimal, while Ligand B (1.286) is a bit low, potentially hindering membrane permeability.

**4. H-Bond Donors:** Ligand A (4) is acceptable, while Ligand B (2) is also good.

**5. H-Bond Acceptors:** Both ligands (4) are within the acceptable range.

**6. QED:** Both ligands have good QED scores (0.594 and 0.808), indicating drug-like properties. Ligand B is better here.

**7. DILI:** Ligand A (54.362) has a moderate DILI risk, while Ligand B (17.371) has a very low risk. This is a significant advantage for Ligand B.

**8. BBB:** Ligand B (63.629) has a significantly better BBB penetration percentile than Ligand A (47.926). This is crucial for a CNS target like DRD2.

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.858 and -4.87). This is unusual and suggests poor permeability. However, these values are on a scale where negative values are possible, and the absolute magnitude isn't directly comparable to positive values.

**10. Aqueous Solubility:** Both ligands have negative solubility values (-3.27 and -2.261), indicating poor aqueous solubility. This could be a formulation challenge.

**11. hERG Inhibition:** Ligand A (0.786) has a slightly higher hERG risk than Ligand B (0.285), which is preferable.

**12. Microsomal Clearance:** Ligand A (61.02) has higher microsomal clearance than Ligand B (11.481), suggesting lower metabolic stability. Ligand B is better here.

**13. In vitro Half-Life:** Ligand B (24.55) has a longer in vitro half-life than Ligand A (26.951), which is desirable.

**14. P-gp Efflux:** Ligand A (0.433) has lower P-gp efflux liability than Ligand B (0.021), which is beneficial for CNS exposure.

**15. Binding Affinity:** Ligand A (-8.1 kcal/mol) has a slightly better binding affinity than Ligand B (-7.7 kcal/mol). This is a positive for Ligand A, but the difference is not huge.

**Overall Assessment:**

Considering the GPCR-specific priorities, Ligand B is the more promising candidate. Its significantly better BBB penetration, lower DILI risk, lower microsomal clearance, and longer half-life outweigh the slightly weaker binding affinity and lower logP. While both have poor Caco-2 and solubility, these issues can potentially be addressed through formulation strategies. The improved safety profile (DILI, hERG) and CNS penetration of Ligand B are critical advantages for a DRD2 targeting drug.

Output:
1
2025-04-17 04:18:49,620 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (347.361 and 342.403 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (66.4) is significantly better than Ligand B (104.7). For CNS targets, we want TPSA <= 90, and A is comfortably within that range, while B exceeds it.

**3. logP:** Ligand A (4.034) is higher than the optimal 1-3 range, but still potentially acceptable. Ligand B (0.94) is *below* the ideal range, which could hinder permeation.

**4. H-Bond Donors:** Ligand A (2) and Ligand B (3) are both acceptable (<=5).

**5. H-Bond Acceptors:** Ligand A (2) and Ligand B (5) are both acceptable (<=10).

**6. QED:** Both ligands have similar QED values (0.829 and 0.726), indicating good drug-likeness.

**7. DILI:** Ligand A (78.247) has a higher DILI risk than Ligand B (59.907), but both are reasonably acceptable.

**8. BBB:** Ligand A (41.218) and Ligand B (39.667) are both relatively low for a CNS target. Ideally, we want >70. However, this is not a knockout factor if other properties are favorable.

**9. Caco-2:** Both have negative Caco-2 values, which is unusual and requires further investigation. However, we can still compare them. Ligand A (-4.748) is slightly better than Ligand B (-5.551).

**10. Solubility:** Both have negative solubility values, which is also unusual. Ligand A (-3.398) is slightly better than Ligand B (-2.763).

**11. hERG:** Both ligands have very low hERG inhibition risk (0.208 and 0.103).

**12. Cl_mic:** Ligand B (-4.81) has a *negative* microsomal clearance, which is not physically possible. This is a significant red flag, suggesting a potential data error or an unusual compound behavior. Ligand A (20.829) is reasonable.

**13. t1/2:** Ligand A (5.945) and Ligand B (6.873) are similar.

**14. Pgp:** Both ligands have very low P-gp efflux liability (0.074 and 0.022).

**15. Binding Affinity:** Ligand B (-9.3) has a slightly better binding affinity than Ligand A (-9.0). However, the difference is small (0.3 kcal/mol) and may not be decisive.

**Overall Assessment:**

Ligand A is superior. While its BBB penetration is not ideal, its TPSA is much better than Ligand B's, and its microsomal clearance is a realistic value. Ligand B has a problematic negative microsomal clearance, which is a major concern. The slightly better affinity of Ligand B is unlikely to overcome this significant ADME issue. Given the GPCR target and the need for CNS penetration, the lower TPSA and more reasonable ADME profile of Ligand A make it the more promising candidate.

Output:
1
2025-04-17 04:18:49,621 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (346.43 and 349.52 Da) fall comfortably within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (71.78) is higher than Ligand B (52.65). For a CNS target like DRD2, TPSA should be <= 90, so both are acceptable, but B is better.

**3. logP:** Both ligands have good logP values (2.08 and 2.262), falling within the optimal 1-3 range.

**4. H-Bond Donors:** Both have 1 HBD, which is within the acceptable limit of <=5.

**5. H-Bond Acceptors:** Ligand A has 4 HBAs, and Ligand B has 3. Both are below the acceptable limit of <=10.

**6. QED:** Both ligands have good QED scores (0.695 and 0.767), indicating good drug-like properties.

**7. DILI:** Ligand A (24.54) has a slightly higher DILI risk than Ligand B (4.81), but both are well below the concerning threshold of 60.

**8. BBB:** This is a crucial parameter for CNS targets. Ligand B (79.49) has a significantly better BBB percentile than Ligand A (58.94). This is a major advantage for B.

**9. Caco-2 Permeability:** Both have negative Caco-2 values (-4.968 and -4.942), which is unusual and suggests poor permeability. This is a concern for both.

**10. Aqueous Solubility:** Both have negative solubility values (-1.805 and -1.57), indicating very poor aqueous solubility. This is a significant drawback for both.

**11. hERG Inhibition:** Both have low hERG inhibition liability (0.323 and 0.58), which is good.

**12. Microsomal Clearance:** Ligand A (50.71) has a higher microsomal clearance than Ligand B (5.94), indicating lower metabolic stability. B is preferable here.

**13. In vitro Half-Life:** Ligand B (3.84) has a shorter half-life than Ligand A (25.98). A is preferable here.

**14. P-gp Efflux:** Both have very low P-gp efflux liability (0.064 and 0.028), which is favorable for CNS penetration.

**15. Binding Affinity:** Ligand B (-7.2 kcal/mol) has a slightly better binding affinity than Ligand A (-8.1 kcal/mol). While A is better, the difference is not substantial enough to outweigh other factors.

**Overall Assessment:**

Ligand B is the more promising candidate. Its superior BBB penetration (79.49% vs 58.94%), lower microsomal clearance, and slightly better binding affinity outweigh the longer half-life of Ligand A. The poor Caco-2 and solubility are concerns for both, but can be addressed with formulation strategies. Given the importance of BBB penetration for a CNS target like DRD2, Ligand B is the stronger choice.

Output:
1
2025-04-17 04:18:49,621 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (347.463 and 349.479 Da) fall comfortably within the ideal 200-500 Da range.

**TPSA:** Ligand A (72.54) is significantly better than Ligand B (80.12). For CNS targets, we want TPSA <= 90, and A is closer to the optimal <= 60 range. B is approaching the upper limit.

**logP:** Both ligands have acceptable logP values (0.743 and 1.782), falling within the 1-3 range. Ligand B is slightly better, being closer to the optimal range.

**H-Bond Donors/Acceptors:** Both have 1 HBD and a reasonable number of HBAs (4 and 5 respectively). This is acceptable.

**QED:** Both ligands have good QED scores (0.79 and 0.898), indicating good drug-like properties.

**DILI:** Ligand A (16.092) has a much lower DILI risk than Ligand B (35.789). This is a significant advantage for A.

**BBB:** Ligand A (68.205) is better than Ligand B (64.172), but both are below the desirable >70 threshold for CNS targets. However, given that we are comparing two ligands, A is preferable.

**Caco-2 Permeability:** Ligand A (-5.175) has worse Caco-2 permeability than Ligand B (-4.691). This suggests B might have slightly better intestinal absorption.

**Aqueous Solubility:** Ligand A (-0.948) has better aqueous solubility than Ligand B (-2.512). This is a positive for A.

**hERG:** Both ligands have very low hERG inhibition risk (0.212 and 0.264), which is excellent.

**Microsomal Clearance:** Ligand A (-3.681) has significantly lower microsomal clearance than Ligand B (50.622). This suggests A is more metabolically stable.

**In vitro Half-Life:** Ligand A (-15.57) has a worse in vitro half-life than Ligand B (-7.662).

**P-gp Efflux:** Ligand A (0.008) has much lower P-gp efflux than Ligand B (0.138). This is a crucial advantage for A, as lower efflux is vital for CNS penetration.

**Binding Affinity:** Ligand A (-7.7) has slightly better binding affinity than Ligand B (-0.0). This is a significant advantage.

**Overall Assessment:**

Considering the GPCR-specific priorities, Ligand A is the better candidate. It has a significantly lower DILI risk, better TPSA, better P-gp efflux, better metabolic stability (lower Cl_mic), and better binding affinity. While Ligand B has slightly better Caco-2 permeability and logP, the advantages of A in terms of safety (DILI), CNS penetration (P-gp, TPSA, BBB), and potency (affinity) outweigh these minor differences. The lower half-life of A is a concern, but can potentially be addressed through structural modifications.

Output:
0
2025-04-17 04:18:49,621 - INFO - Batch 102 complete. Total preferences: 1632
2025-04-17 04:18:49,621 - INFO - Processing batch 103/512...
2025-04-17 04:19:31,530 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (345.403 and 344.455 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (93.26) is better than Ligand B (67.43). Both are below the 90 A^2 threshold desirable for CNS targets, but A is slightly higher and may present a minor permeability issue.

**logP:** Ligand A (1.526) is within the optimal 1-3 range. Ligand B (3.066) is at the higher end of the optimal range, potentially increasing off-target effects.

**H-Bond Donors/Acceptors:** Ligand A has 1 HBD and 6 HBA, while Ligand B has 2 HBD and 3 HBA. Both are within acceptable limits.

**QED:** Ligand A (0.907) has a significantly better QED score than Ligand B (0.747), indicating a more drug-like profile.

**DILI:** Ligand A (38.697) has a lower DILI risk than Ligand B (45.444), both are acceptable.

**BBB:** Ligand A (84.102) has a much higher BBB penetration percentile than Ligand B (54.595). This is *critical* for a CNS target like DRD2.

**Caco-2 Permeability:** Ligand A (-5.018) shows poor Caco-2 permeability. Ligand B (-4.393) is also poor, but slightly better.

**Aqueous Solubility:** Ligand A (-2.635) has slightly better solubility than Ligand B (-4.051).

**hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.2 and 0.305, respectively).

**Microsomal Clearance:** Ligand A (12.295) has a lower microsomal clearance than Ligand B (69.138), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (-0.023) has a very short half-life, while Ligand B (-17.549) has a very long half-life. This is a significant advantage for Ligand B.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.088 and 0.207, respectively).

**Binding Affinity:** Both ligands have excellent binding affinity (-9.0 and -8.4 kcal/mol). The difference of 0.6 kcal/mol is not substantial enough to outweigh other factors.

**Overall Assessment:**

Ligand A excels in QED, DILI, BBB penetration, and metabolic stability. However, its Caco-2 permeability is quite poor and its in vitro half-life is very short. Ligand B has a better half-life, but suffers from lower BBB penetration, a higher logP, and a worse QED score. Given the CNS target, BBB penetration is paramount. The superior BBB score of Ligand A, combined with its better QED and lower DILI, outweighs its permeability and half-life concerns, especially considering optimization can address these issues.

Output:
1
2025-04-17 04:19:31,531 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (348.4) is slightly preferred due to being closer to the middle of the range.

**TPSA:** Ligand A (85.9) is excellent for CNS penetration, being well below 90. Ligand B (108.6) is still acceptable but less optimal.

**logP:** Ligand A (0.578) is a bit low, potentially hindering permeability. Ligand B (1.374) is better, falling within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A (2 HBD, 5 HBA) and Ligand B (3 HBD, 7 HBA) both have reasonable numbers of H-bond donors and acceptors, unlikely to cause major issues.

**QED:** Both ligands have acceptable QED scores (A: 0.671, B: 0.527), indicating reasonable drug-likeness.

**DILI:** Ligand A (61.1) has a moderate DILI risk, while Ligand B (82.5) has a higher risk. This favors Ligand A.

**BBB:** This is a crucial parameter for a CNS target. Ligand A (70.9) is good, exceeding the 70% threshold. Ligand B (19.5) is very poor, suggesting limited brain penetration.

**Caco-2 Permeability:** Both have negative values, indicating poor permeability. However, the scale is not defined, so we cannot interpret these values.

**Aqueous Solubility:** Both ligands have negative solubility values, which is concerning.

**hERG:** Both ligands have low hERG inhibition liability (A: 0.201, B: 0.405), which is favorable.

**Microsomal Clearance:** Ligand A (21.3) has a lower clearance than Ligand B (37.0), indicating better metabolic stability.

**In vitro Half-Life:** Ligand A (-15.254) has a negative half-life, which is not interpretable. Ligand B (56.3) is a more reasonable value.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (A: 0.062, B: 0.078), which is good.

**Binding Affinity:** Ligand A (-8.1) has a slightly better binding affinity than Ligand B (-7.9). While the difference is small, it's still a positive.

**Overall Assessment:**

Ligand A is significantly better due to its superior BBB penetration, lower DILI risk, and better metabolic stability. While its logP is slightly low, the strong affinity and excellent BBB score outweigh this drawback for a CNS-targeting GPCR like DRD2. Ligand B's poor BBB penetration is a major disqualifier.

Output:
0
2025-04-17 04:19:31,531 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (427.364 Da) is higher, but still acceptable. Ligand B (366.38 Da) is slightly better.

**2. TPSA:** Ligand A (61.8) is better than Ligand B (75.71). For CNS targets, we want TPSA <= 90, and ideally closer to 60. Ligand A is closer to the ideal.

**3. logP:** Ligand A (3.511) is optimal, while Ligand B (1.675) is on the lower side. Lower logP can hinder permeation, particularly across the BBB. This favors Ligand A.

**4. H-Bond Donors:** Both ligands have acceptable HBD counts (2 and 1, respectively), well below the threshold of 5.

**5. H-Bond Acceptors:** Both ligands have acceptable HBA counts (5 and 4, respectively), well below the threshold of 10.

**6. QED:** Both ligands have similar and good QED values (0.767 and 0.751).

**7. DILI:** Both ligands have low DILI risk (41.877 and 40.558), which is good.

**8. BBB:** Ligand A (81.311) has a significantly better BBB penetration percentile than Ligand B (73.401). This is a crucial factor for a CNS target like DRD2.

**9. Caco-2 Permeability:** Ligand A (-5.038) has worse Caco-2 permeability than Ligand B (-4.549), but both are negative values which is not ideal.

**10. Aqueous Solubility:** Ligand A (-3.219) has worse aqueous solubility than Ligand B (-2.694). Solubility is important for formulation, but can be mitigated.

**11. hERG Inhibition:** Ligand A (0.929) has slightly higher hERG inhibition risk than Ligand B (0.387). This is a concern, but not a dealbreaker if other properties are favorable.

**12. Microsomal Clearance:** Ligand A (41.084) has higher microsomal clearance than Ligand B (32.988). Lower clearance is preferred for metabolic stability, favoring Ligand B.

**13. In vitro Half-Life:** Ligand B (-25.373) has a much longer in vitro half-life than Ligand A (41.405). This is a significant advantage for Ligand B.

**14. P-gp Efflux:** Ligand A (0.737) has better P-gp efflux profile than Ligand B (0.053). Lower P-gp efflux is better, so Ligand B is favored.

**15. Binding Affinity:** Ligand A (-7.7 kcal/mol) has a slightly better binding affinity than Ligand B (-7.3 kcal/mol). While both are excellent, the 0.4 kcal/mol difference could be significant.

**Overall Assessment:**

Ligand A excels in logP, TPSA, and binding affinity, and has a good BBB score. However, it has poorer solubility, higher hERG risk, and higher clearance. Ligand B has better solubility, lower hERG, better half-life, and better P-gp efflux. The difference in binding affinity is relatively small, and the improved CNS penetration (BBB) and metabolic stability (half-life) of Ligand B, coupled with the lower hERG risk, make it the more promising candidate despite the slightly weaker binding.

Output:
1
2025-04-17 04:19:31,532 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (349.431 and 348.407 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (95.71) is better than Ligand B (113.14). For CNS targets, we want TPSA <= 90, so Ligand A is closer to this threshold.

**logP:** Ligand A (3.617) is optimal (1-3 range), while Ligand B (0.08) is significantly low, potentially hindering membrane permeability.

**H-Bond Donors/Acceptors:** Ligand A (2 HBD, 4 HBA) is better balanced than Ligand B (1 HBD, 8 HBA). High HBA can sometimes reduce permeability.

**QED:** Ligand A (0.627) has a better QED score than Ligand B (0.496), indicating a more drug-like profile.

**DILI:** Ligand B (35.169) has a significantly lower DILI risk than Ligand A (46.956), which is a positive attribute.

**BBB:** Both ligands have good BBB penetration (Ligand A: 68.36, Ligand B: 70.492). Ligand B is slightly better, but both are reasonably good for a CNS target.

**Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and suggests a potential issue with the data or modeling. However, the magnitude is similar.

**Aqueous Solubility:** Both have negative solubility values, which is also unusual. Again, the magnitude is similar.

**hERG:** Ligand A (0.757) has a slightly higher hERG risk than Ligand B (0.048). Lower hERG is preferred.

**Microsomal Clearance:** Ligand B (62.866) has significantly higher microsomal clearance than Ligand A (3.582), indicating faster metabolism and potentially lower *in vivo* exposure.

**In vitro Half-Life:** Ligand A (-1.971) has a better (longer) in vitro half-life than Ligand B (3.563).

**P-gp Efflux:** Ligand A (0.349) exhibits lower P-gp efflux than Ligand B (0.02), which is favorable for CNS penetration.

**Binding Affinity:** Ligand A (-8.6 kcal/mol) has a significantly stronger binding affinity than Ligand B (-5.9 kcal/mol). This is a crucial factor, and a difference of 2.7 kcal/mol is substantial.

**Overall Assessment:**

While Ligand B has a lower DILI risk and slightly better BBB penetration, Ligand A is superior overall. The significantly stronger binding affinity (-8.6 vs -5.9 kcal/mol) outweighs the slightly higher DILI risk and hERG liability. The better logP and TPSA values of Ligand A are also beneficial for CNS penetration. The lower P-gp efflux and improved metabolic stability (lower Cl_mic, longer t1/2) further support Ligand A as the more promising candidate. The unusual negative solubility and Caco-2 values are concerning but similar for both compounds.



Output:
1
2025-04-17 04:19:31,532 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 drug candidates, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (367.362 and 373.507 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (38.13) is excellent, well below the 90 Angstroms threshold for CNS targets. Ligand B (72.7) is higher, but still potentially acceptable, though less optimal.

**3. logP:** Both ligands have good logP values (3.835 and 3.64), falling within the 1-3 range.

**4. H-Bond Donors:** Ligand A (0) is ideal, while Ligand B (1) is also acceptable.

**5. H-Bond Acceptors:** Ligand A (3) is good, while Ligand B (7) is higher, but still within the acceptable limit of 10.

**6. QED:** Both ligands have similar, acceptable QED values (0.687 and 0.642), indicating good drug-like properties.

**7. DILI:** Ligand A (14.696) has a much lower DILI risk than Ligand B (69.484), which is a significant advantage.

**8. BBB:** This is crucial for a CNS target like DRD2. Ligand A (93.563) has a very high BBB penetration percentile, making it highly desirable. Ligand B (37.805) has a poor BBB penetration percentile, which is a major drawback.

**9. Caco-2 Permeability:** Ligand A (-4.264) has poor Caco-2 permeability, while Ligand B (-5.32) is even worse. This is not ideal, but can be mitigated with formulation strategies.

**10. Aqueous Solubility:** Ligand A (-4.569) has poor solubility, while Ligand B (-2.749) is slightly better.

**11. hERG Inhibition:** Both ligands have low hERG inhibition risk (0.711 and 0.581).

**12. Microsomal Clearance:** Ligand A (52.664) and Ligand B (47.02) have similar, acceptable microsomal clearance values.

**13. In vitro Half-Life:** Ligand A (-11.161) has a negative half-life, which is unusual and likely an error or indicates very rapid metabolism. Ligand B (8.621) has a reasonable half-life.

**14. P-gp Efflux:** Ligand A (0.339) has lower P-gp efflux liability than Ligand B (0.626), which is favorable for CNS penetration.

**15. Binding Affinity:** Ligand B (-8.3 kcal/mol) has a slightly better binding affinity than Ligand A (-7.0 kcal/mol), a difference of 1.3 kcal/mol.

**Overall Assessment:**

Despite the slightly better affinity of Ligand B, Ligand A is the more promising candidate. The significantly lower DILI risk, excellent TPSA, and *very* high BBB penetration of Ligand A outweigh the slightly weaker affinity and poorer Caco-2 permeability. The negative half-life for Ligand A is concerning and needs investigation, but the other factors strongly favor it. Ligand B's poor BBB penetration is a critical flaw for a CNS-targeting drug.

Output:
1
2025-04-17 04:19:31,532 - INFO - Reasoning:

Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (348.45 & 350.50 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (87.32) is better than Ligand B (60.85). Both are below the 90 A^2 threshold desirable for CNS targets, but A is closer to the upper limit.

**3. logP:** Both ligands have good logP values (1.265 & 2.279), falling within the optimal 1-3 range. Ligand B is slightly better.

**4. H-Bond Donors:** Ligand A (2) is slightly higher than Ligand B (1), but both are acceptable (<=5).

**5. H-Bond Acceptors:** Ligand A (4) is higher than Ligand B (3), but both are within the acceptable range (<=10).

**6. QED:** Both ligands have good QED scores (0.74 & 0.799), indicating good drug-like properties.

**7. DILI:** Ligand A (33.89%) has a significantly lower DILI risk than Ligand B (9.27%). This is a major advantage for Ligand A.

**8. BBB:** Ligand B (67.00%) has a better BBB penetration score than Ligand A (58.51%), but both are below the >70% desirable for CNS targets.

**9. Caco-2 Permeability:** Ligand A (-5.269) has a worse Caco-2 permeability than Ligand B (-4.59). Lower values indicate lower permeability.

**10. Aqueous Solubility:** Ligand A (-2.038) has a worse aqueous solubility than Ligand B (-2.56). Lower values indicate lower solubility.

**11. hERG Inhibition:** Ligand A (0.187) has a lower hERG inhibition risk than Ligand B (0.557), which is preferable.

**12. Microsomal Clearance:** Ligand A (15.59) has a lower microsomal clearance than Ligand B (29.14), suggesting better metabolic stability.

**13. In vitro Half-Life:** Ligand B (2.483) has a longer in vitro half-life than Ligand A (-1.979).

**14. P-gp Efflux:** Ligand A (0.021) has a much lower P-gp efflux liability than Ligand B (0.189), which is crucial for CNS penetration.

**15. Binding Affinity:** Ligand B (-9.2 kcal/mol) has a significantly stronger binding affinity than Ligand A (-7.6 kcal/mol). This is a substantial advantage, exceeding the 1.5 kcal/mol threshold.

**Overall Assessment:**

While Ligand B has a superior binding affinity and slightly better BBB penetration and half-life, Ligand A demonstrates a much more favorable safety profile with significantly lower DILI risk and P-gp efflux. The lower P-gp efflux is particularly important for a CNS target like DRD2. The difference in binding affinity (-9.2 vs -7.6) is substantial, but the other ADME/Tox properties of Ligand A are considerably better, especially the DILI and P-gp efflux. Given the importance of minimizing off-target effects and maximizing CNS exposure for a DRD2 ligand, Ligand A is the more promising candidate.

Output:
0
2025-04-17 04:19:31,532 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 drug candidates, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (386.543 Da) is slightly higher than Ligand B (360.479 Da), but both are acceptable.

**TPSA:** Ligand A (101.05) is better than Ligand B (68.17) for CNS penetration, being closer to the <90 A^2 target.

**logP:** Ligand A (1.482) is within the optimal range (1-3), while Ligand B (3.13) is at the higher end. While still acceptable, higher logP can sometimes lead to off-target effects.

**H-Bond Donors/Acceptors:** Ligand A (HBD=2, HBA=7) and Ligand B (HBD=1, HBA=4) both have reasonable numbers of H-bond donors and acceptors, falling within the guidelines.

**QED:** Both ligands have good QED scores (Ligand A: 0.795, Ligand B: 0.911), indicating drug-like properties. Ligand B is slightly better.

**DILI:** Both ligands have elevated DILI risk, with Ligand A at 66.382 and Ligand B at 74.021. This is a concern for both, but Ligand A is slightly better.

**BBB:** Both ligands demonstrate good BBB penetration (Ligand A: 70.803, Ligand B: 76.27). Both are above the 70% threshold for CNS targets. Ligand B is slightly better.

**Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual. This suggests poor permeability. Ligand A (-5.635) is slightly better than Ligand B (-4.68), but both are unfavorable.

**Aqueous Solubility:** Both ligands have negative solubility values, which is also unusual and indicates very poor solubility. Ligand A (-2.769) is slightly better than Ligand B (-3.352).

**hERG Inhibition:** Both ligands have low hERG inhibition risk (Ligand A: 0.256, Ligand B: 0.386), which is positive.

**Microsomal Clearance:** Ligand A (3.16 mL/min/kg) has significantly lower microsomal clearance than Ligand B (29.061 mL/min/kg), indicating better metabolic stability.

**In vitro Half-Life:** Ligand A (25.948 hours) has a much longer in vitro half-life than Ligand B (-8.43 hours). This is a significant advantage for Ligand A.

**P-gp Efflux:** Both ligands show low P-gp efflux liability (Ligand A: 0.118, Ligand B: 0.454), which is good for CNS exposure. Ligand A is slightly better.

**Binding Affinity:** Both ligands have excellent binding affinity (Ligand A: -8.5 kcal/mol, Ligand B: -8.9 kcal/mol). Ligand B is slightly better in terms of binding.

**Overall Assessment:**

While Ligand B has slightly better BBB penetration and binding affinity, Ligand A is superior in terms of metabolic stability (lower Cl_mic), longer half-life, and slightly better DILI risk, P-gp efflux, and TPSA. The poor Caco-2 and solubility for both are concerning, but these can potentially be addressed through formulation strategies. Given the GPCR-specific focus on BBB and the importance of metabolic stability for CNS drugs, Ligand A appears to be the more promising candidate.

Output:
0
2025-04-17 04:19:31,533 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (348.45 & 349.48 Da) fall comfortably within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (94.56) is slightly higher than Ligand B (81.33). Both are below the 90 A^2 threshold desirable for CNS targets, but B is better.

**3. logP:** Ligand A (0.681) is a bit low, potentially hindering permeability. Ligand B (1.418) is better, falling within the optimal 1-3 range.

**4. H-Bond Donors:** Ligand A (3) is slightly higher than Ligand B (2), but both are acceptable (<=5).

**5. H-Bond Acceptors:** Ligand A (5) is slightly higher than Ligand B (4), but both are acceptable (<=10).

**6. QED:** Both ligands have good QED scores (0.642 and 0.73), indicating good drug-like properties.

**7. DILI:** Ligand A (19.23) has a significantly lower DILI risk than Ligand B (12.76), which is a substantial advantage.

**8. BBB:** Ligand B (68.36) has a significantly better BBB penetration percentile than Ligand A (48.90). This is a critical factor for a CNS target like DRD2.

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.141 and -5.174), which is unusual and suggests poor permeability. This is a concern for both.

**10. Aqueous Solubility:** Both ligands have negative solubility values (-1.117 and -1.681), indicating very poor aqueous solubility. This is a significant drawback for both.

**11. hERG Inhibition:** Ligand A (0.079) has a much lower hERG inhibition liability than Ligand B (0.674), making it safer from a cardiotoxicity perspective.

**12. Microsomal Clearance:** Ligand B (-5.849) has a negative clearance, which is not physically possible and suggests an issue with the data or model. Ligand A (2.523) has a reasonable clearance.

**13. In vitro Half-Life:** Ligand B (-24.567) has a negative half-life, which is not physically possible and suggests an issue with the data or model. Ligand A (1.328) has a short half-life, but it's a realistic value.

**14. P-gp Efflux:** Ligand A (0.006) has very low P-gp efflux liability, which is excellent for CNS penetration. Ligand B (0.036) is also low, but higher than A.

**15. Binding Affinity:** Ligand B (-7.7 kcal/mol) has a slightly better binding affinity than Ligand A (-7.4 kcal/mol). This difference is potentially significant, but must be weighed against the other factors.

**Overall Assessment:**

While Ligand B has a better binding affinity and BBB penetration, its negative clearance and half-life values are highly suspect and indicate potential data quality issues. Ligand A, despite having a slightly lower affinity and BBB, has more reasonable ADME properties (lower DILI, better hERG, positive clearance and half-life, very low P-gp efflux). The poor Caco-2 and solubility for both are concerning, but could potentially be addressed with formulation strategies. Given the questionable data for Ligand B, and the importance of reasonable ADME properties for *in vivo* viability, Ligand A is the more promising candidate.

Output:
0
2025-04-17 04:19:31,533 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (350.459 and 365.499 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (87.66) is better than Ligand B (71.53), being closer to the desirable <90 for CNS targets.

**logP:** Ligand A (0.977) is slightly lower than optimal (1-3), but still acceptable. Ligand B (2.235) is within the optimal range.

**H-Bond Donors/Acceptors:** Ligand A (3 HBD, 4 HBA) and Ligand B (1 HBD, 5 HBA) both have reasonable numbers of H-bond donors and acceptors.

**QED:** Ligand B (0.839) has a significantly better QED score than Ligand A (0.541), indicating a more drug-like profile.

**DILI:** Ligand A (11.4) has a much lower DILI risk than Ligand B (22.761), which is a significant advantage.

**BBB:** Ligand B (82.28) has a substantially better BBB penetration score than Ligand A (49.981). This is *critical* for a CNS target like DRD2.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.632 and -4.971), which is unusual and suggests poor permeability. However, these values are on a log scale, and the absolute values are similar.

**Aqueous Solubility:** Both ligands have negative solubility values (-1.6 and -2.726), indicating poor solubility.

**hERG:** Ligand A (0.118) has a lower hERG inhibition liability than Ligand B (0.528), which is favorable.

**Microsomal Clearance:** Ligand B (17.821) has a much higher microsomal clearance than Ligand A (0.116), indicating faster metabolism and potentially lower *in vivo* exposure.

**In vitro Half-Life:** Ligand B (8.174) has a longer half-life than Ligand A (0.615), which is generally desirable.

**P-gp Efflux:** Ligand A (0.022) has a much lower P-gp efflux liability than Ligand B (0.101), which is important for CNS penetration.

**Binding Affinity:** Ligand A (-7.8 kcal/mol) has a stronger binding affinity than Ligand B (-7.1 kcal/mol). This difference of 0.7 kcal/mol is substantial and could outweigh some ADME drawbacks.

**Overall Assessment:**

Ligand A has a better binding affinity, lower DILI risk, lower hERG risk, lower P-gp efflux, and lower microsomal clearance. However, Ligand B has a significantly better BBB score and QED. The BBB score is the most important factor here, given that DRD2 is a CNS target. While Ligand A's affinity is better, the difference isn't large enough to overcome Ligand B's superior predicted brain penetration.

Output:
1
2025-04-17 04:19:31,533 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B based on the provided guidelines, prioritizing GPCR-specific properties (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (353.379) is slightly lower, which could be beneficial for permeability, but both are acceptable.

**TPSA:** Ligand A (127.92) is better than Ligand B (71.09) as it is closer to the ideal range for CNS targets (<=90). Ligand B is quite low, which might indicate a lack of necessary interactions.

**logP:** Ligand A (-2.812) is suboptimal, being below the preferred 1-3 range. Ligand B (2.769) is within the optimal range. This is a significant advantage for Ligand B regarding permeability and potential off-target effects.

**H-Bond Donors/Acceptors:** Ligand A has 3 HBD and 6 HBA, while Ligand B has 2 HBD and 5 HBA. Both are within acceptable limits.

**QED:** Ligand B (0.844) has a much higher QED score than Ligand A (0.442), indicating a more drug-like profile.

**DILI:** Ligand B (58.976) has a higher DILI risk than Ligand A (35.324), but both are below the concerning threshold of 60.

**BBB:** Ligand A (57.736) has a better BBB percentile than Ligand B (46.219). This is a crucial factor for a CNS target like DRD2.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values, which is unusual and suggests poor permeability. However, the scale is not specified, so it's difficult to interpret.

**Aqueous Solubility:** Both ligands have negative solubility values, which is also unusual and suggests poor solubility.

**hERG Inhibition:** Both ligands have very low hERG inhibition liability, which is good.

**Microsomal Clearance:** Ligand A (-18.267) has a much lower (better) microsomal clearance than Ligand B (10.415), indicating greater metabolic stability.

**In vitro Half-Life:** Ligand B (19.786) has a significantly longer in vitro half-life than Ligand A (-13.34), which is a positive attribute.

**P-gp Efflux:** Ligand A (0.001) has extremely low P-gp efflux liability, which is excellent for CNS penetration. Ligand B (0.162) is also low, but higher than A.

**Binding Affinity:** Ligand B (-8.3) has a slightly better binding affinity than Ligand A (-7.5), although both are strong binders.

**Overall Assessment:**

Ligand A excels in BBB penetration and P-gp efflux, crucial for CNS targets. It also has better metabolic stability. However, its logP is significantly suboptimal, and its QED score is low.

Ligand B has a better logP, QED, and in vitro half-life, and a slightly better binding affinity. However, its BBB penetration is lower, and its DILI risk is higher.

Considering the GPCR-specific priorities, the balance of properties favors Ligand B. While BBB is important, the significantly better logP and QED of Ligand B, coupled with its stronger binding affinity and longer half-life, outweigh the slightly lower BBB score. The negative solubility and Caco-2 values are concerning for both, but can be addressed through formulation strategies.

Output:
1
2025-04-17 04:19:31,533 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (350.394 Da) is slightly better, being closer to the lower end which can aid permeability.

**TPSA:** Ligand A (75.63) is significantly better than Ligand B (104.81). For CNS targets, we want TPSA <= 90, so Ligand A is within this range, while Ligand B is above.

**logP:** Ligand A (1.024) is optimal, while Ligand B (0.272) is a bit low, potentially hindering membrane permeability.

**H-Bond Donors/Acceptors:** Ligand A (0 HBD, 6 HBA) and Ligand B (2 HBD, 6 HBA) both have reasonable numbers of H-bonds, within the guidelines.

**QED:** Both ligands have acceptable QED values (Ligand A: 0.738, Ligand B: 0.516), indicating good drug-like properties.

**DILI:** Ligand A (55.099) and Ligand B (60.954) both have acceptable DILI risk, though Ligand A is slightly better.

**BBB:** This is a critical parameter for a CNS target like DRD2. Ligand A (92.168) has excellent BBB penetration, while Ligand B (53.703) is significantly lower, which is a major drawback.

**Caco-2 Permeability:** Ligand A (-4.327) and Ligand B (-5.571) both have negative values, which is unusual. Lower values indicate lower permeability. Ligand A is slightly better.

**Aqueous Solubility:** Both ligands have poor aqueous solubility (-1.621 and -2.865 respectively). This could pose formulation challenges, but is less critical than BBB for a CNS drug.

**hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.171 and 0.181 respectively).

**Microsomal Clearance:** Ligand A (74.281) has higher clearance than Ligand B (64.008), meaning Ligand B is more metabolically stable.

**In vitro Half-Life:** Ligand B (-30.841) has a much longer half-life than Ligand A (1.655), which is a significant advantage.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.082 and 0.022 respectively).

**Binding Affinity:** Ligand A (-8.6 kcal/mol) has a significantly stronger binding affinity than Ligand B (-6.8 kcal/mol). This >1.5 kcal/mol difference is substantial and can outweigh some ADME drawbacks.

**Overall Assessment:**

Ligand A is clearly the better candidate. Its superior BBB penetration (92.168 vs 53.703) and significantly stronger binding affinity (-8.6 vs -6.8 kcal/mol) are the most important factors, given the CNS target and GPCR class. While Ligand B has better metabolic stability and half-life, these are less critical than CNS penetration and potency for this application. The slightly better TPSA and logP of Ligand A also contribute to its favorability.



Output:
1
2025-04-17 04:19:31,534 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (359.451 and 342.403 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (63.69) is significantly better than Ligand B (95.91). For CNS targets, we want TPSA <= 90, so Ligand A is much more favorable.

**3. logP:** Both ligands have acceptable logP values (1.942 and 0.74), falling within the 1-3 range. Ligand A is slightly better.

**4. H-Bond Donors:** Both ligands have reasonable HBD counts (1 and 2, respectively), well below the threshold of 5.

**5. H-Bond Acceptors:** Both ligands have acceptable HBA counts (6 and 5, respectively), below the threshold of 10.

**6. QED:** Both ligands have good QED scores (0.884 and 0.856), indicating good drug-like properties.

**7. DILI:** Ligand A (68.476) has a higher DILI risk than Ligand B (47.15). This favors Ligand B.

**8. BBB:** Ligand A (51.454) and Ligand B (56.65) are both below the desirable >70 percentile for CNS penetration. However, BBB is less critical if other properties are excellent.

**9. Caco-2 Permeability:** Ligand A (-4.831) shows poor Caco-2 permeability, while Ligand B (-5.288) is also poor. This is a concern for both.

**10. Aqueous Solubility:** Both ligands have poor aqueous solubility (-2.037 and -2.646). This is a drawback for both, but can be mitigated with formulation strategies.

**11. hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.403 and 0.176). This is excellent for both.

**12. Microsomal Clearance:** Ligand A (11.973) has a higher microsomal clearance than Ligand B (-2.527), indicating lower metabolic stability. This favors Ligand B.

**13. In vitro Half-Life:** Ligand A (1.934) has a shorter half-life than Ligand B (-7.236), indicating lower stability. This strongly favors Ligand B.

**14. P-gp Efflux:** Ligand A (0.086) has slightly higher P-gp efflux than Ligand B (0.019). Lower efflux is preferred for CNS targets, favoring Ligand B.

**15. Binding Affinity:** Ligand B (-9.2 kcal/mol) has a significantly stronger binding affinity than Ligand A (-8.0 kcal/mol). This is a substantial advantage, potentially outweighing some of the ADME drawbacks.

**Overall Assessment:**

Ligand B is the more promising candidate. While both have poor solubility and Caco-2 permeability, Ligand B excels in key areas: significantly stronger binding affinity, better metabolic stability (lower Cl_mic, longer t1/2), lower P-gp efflux, and lower DILI risk. Ligand A has a better TPSA, but the affinity difference is substantial. Given the GPCR target and the importance of brain penetration, the superior binding affinity and ADME properties of Ligand B make it the better choice.

Output:
1
2025-04-17 04:19:31,534 - INFO - Reasoning:

Let's analyze Ligand A and Ligand B for their potential as DRD2 drug candidates, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (349.406 Da) is slightly preferred due to being closer to the lower end, potentially aiding permeability.

**2. TPSA:** Ligand A (87.3) is excellent, falling well below the 90 A^2 threshold for CNS targets. Ligand B (47.09) is also very good.

**3. logP:** Ligand A (1.884) is optimal. Ligand B (4.156) is at the higher end of the optimal range, potentially leading to solubility issues or off-target interactions, but still acceptable.

**4. H-Bond Donors:** Ligand A (3) is good. Ligand B (0) is also acceptable, though a small number of HBDs can sometimes aid solubility.

**5. H-Bond Acceptors:** Both ligands are acceptable (Ligand A: 3, Ligand B: 5), being below the 10 threshold.

**6. QED:** Both ligands have similar QED values (Ligand A: 0.657, Ligand B: 0.626), indicating good drug-like properties.

**7. DILI:** Ligand A (51.648) has a slightly higher DILI risk than Ligand B (38.62), but both are below the 40 threshold and considered good.

**8. BBB:** This is a crucial parameter for a CNS target like DRD2. Ligand B (96.355) significantly outperforms Ligand A (66.809) in BBB penetration, making it a strong contender.

**9. Caco-2 Permeability:** Ligand A (-5.124) has poor Caco-2 permeability, which is a concern. Ligand B (-4.622) is also poor, but slightly better.

**10. Aqueous Solubility:** Both ligands have very poor aqueous solubility (Ligand A: -2.749, Ligand B: -4.685). This is a significant drawback for both, but might be mitigated by formulation strategies.

**11. hERG Inhibition:** Both ligands show low hERG inhibition risk (Ligand A: 0.344, Ligand B: 0.805).

**12. Microsomal Clearance:** Ligand A (4.126) has lower microsomal clearance, suggesting better metabolic stability compared to Ligand B (49.968).

**13. In vitro Half-Life:** Ligand A (22.121 hours) has a better in vitro half-life than Ligand B (19.237 hours).

**14. P-gp Efflux:** Ligand A (0.118) shows lower P-gp efflux, which is favorable for CNS penetration. Ligand B (0.487) has higher P-gp efflux.

**15. Binding Affinity:** Ligand B (-7.5 kcal/mol) has a significantly stronger binding affinity than Ligand A (-9.2 kcal/mol). This >1.5 kcal/mol difference is a major advantage, potentially outweighing some of the ADME drawbacks.

**Overall Assessment:**

While Ligand A has better metabolic stability (lower Cl_mic) and P-gp efflux, Ligand B's superior BBB penetration and significantly higher binding affinity are decisive factors for a CNS-targeting GPCR like DRD2. The slightly higher logP of Ligand B is a minor concern, but the substantial affinity advantage is likely to be more important. The poor solubility of both is a concern that would need to be addressed during formulation.

Output:
1
2025-04-17 04:19:31,534 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (368.503 and 348.487 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (74.77) is slightly higher than Ligand B (49.85). For CNS targets, TPSA < 90 is preferred, and both meet this. Ligand B is significantly better here.

**logP:** Ligand A (1.078) is at the lower end of the optimal 1-3 range, while Ligand B (2.751) is closer to the ideal. This favors Ligand B for permeability.

**H-Bond Donors/Acceptors:** Ligand A has 1 HBD and 6 HBA, while Ligand B has 0 HBD and 3 HBA. Both are within acceptable limits (<=5 HBD and <=10 HBA).

**QED:** Both ligands have similar QED values (0.743 and 0.737), indicating good drug-likeness.

**DILI:** Ligand A (21.442) has a much lower DILI risk than Ligand B (35.905), which is a significant advantage.

**BBB:** Ligand B (70.105) has a slightly better BBB penetration percentile than Ligand A (68.282), but both are acceptable for a CNS target (>70 is desirable).

**Caco-2 Permeability:** Ligand A (-4.93) has a more negative Caco-2 value, suggesting lower intestinal absorption compared to Ligand B (-4.631).

**Aqueous Solubility:** Ligand A (-1.005) has slightly better aqueous solubility than Ligand B (-2.671).

**hERG Inhibition:** Both ligands have similar, low hERG inhibition liability (0.488 and 0.508).

**Microsomal Clearance:** Ligand A (-25.846) has significantly lower microsomal clearance than Ligand B (51.504), indicating better metabolic stability.

**In vitro Half-Life:** Ligand B (21.827) has a longer in vitro half-life than Ligand A (13.614).

**P-gp Efflux:** Ligand A (0.051) has a much lower P-gp efflux liability than Ligand B (0.256), which is crucial for CNS penetration.

**Binding Affinity:** Ligand A (-7.0) has a slightly better binding affinity than Ligand B (-0.0). This is a substantial difference.

**Overall Assessment:**

Ligand A excels in binding affinity, DILI risk, microsomal clearance, and P-gp efflux. Ligand B has a slightly better BBB and in vitro half-life, and a better logP. However, the significantly better affinity of Ligand A (-7.0 vs -0.0 kcal/mol) and lower P-gp efflux are very important for a CNS GPCR target. The lower DILI risk and better metabolic stability of Ligand A are also strong positives. While Ligand B has a slightly better logP, the difference isn't substantial enough to outweigh the other advantages of Ligand A.

Output:
1
2025-04-17 04:19:31,534 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (350.415 Da) is slightly lower, which could be beneficial for permeability, while Ligand B (380.457 Da) is also well within the range.

**TPSA:** Ligand A (110.1) is higher than the preferred <90 for CNS targets, but not drastically so. Ligand B (77.92) is excellent, well below the 90 threshold, indicating better potential for CNS penetration.

**logP:** Ligand A (0.411) is quite low, potentially hindering membrane permeability and CNS entry. Ligand B (0.913) is better, though still on the lower side of the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A has 4 HBD and 5 HBA, acceptable values. Ligand B has 1 HBD and 4 HBA, also acceptable and potentially slightly more favorable due to fewer donors.

**QED:** Both ligands have good QED scores (A: 0.615, B: 0.769), indicating good drug-like properties.

**DILI:** Ligand A (14.696) has a very low DILI risk, which is excellent. Ligand B (27.453) is still relatively low, but higher than Ligand A.

**BBB:** This is a critical parameter for CNS targets. Ligand B (80.264) has a significantly higher BBB percentile than Ligand A (14.036), making it much more likely to reach the target in the brain.

**Caco-2 Permeability:** Ligand A (-5.533) has a negative Caco-2 value, indicating very poor permeability. Ligand B (-4.798) is also poor, but slightly better than A.

**Aqueous Solubility:** Both ligands have poor aqueous solubility (-1.755 and -2.403 respectively). This could pose formulation challenges.

**hERG Inhibition:** Both ligands show low hERG inhibition liability (0.27 and 0.604 respectively), which is good.

**Microsomal Clearance:** Ligand A (-15.344) has a lower (better) microsomal clearance than Ligand B (15.311), suggesting greater metabolic stability.

**In vitro Half-Life:** Both ligands have poor in vitro half-lives (-26.563 and -33.364 respectively).

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.032 and 0.033 respectively), which is favorable for CNS penetration.

**Binding Affinity:** Both ligands have similar binding affinities (-8.1 and -8.2 kcal/mol), which are excellent and strong. The difference is negligible.

**Overall Assessment:**

Ligand B is the stronger candidate. While both have poor solubility and half-lives, Ligand B's significantly higher BBB penetration (80.264 vs 14.036) and more favorable TPSA (77.92 vs 110.1) are crucial for a CNS-targeting GPCR like DRD2. Although Ligand A has a slightly better DILI score and microsomal clearance, the BBB advantage of Ligand B outweighs these benefits. The similar binding affinities mean potency isn't a differentiating factor.



Output:
1
2025-04-17 04:19:31,535 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 drug candidates, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands fall within the ideal range (200-500 Da). Ligand A (340.339 Da) is slightly preferred as it's closer to the lower end, potentially aiding permeability.

**2. TPSA:** Ligand A (109.73) is better than Ligand B (64.28). For CNS targets, TPSA should be <= 90. Ligand B is well within this range, while Ligand A is slightly above. However, the difference isn't drastic.

**3. logP:** Both ligands have good logP values (Ligand A: 2.002, Ligand B: 3.483), falling within the optimal 1-3 range. Ligand B is slightly higher, which could potentially lead to off-target effects, but isn't a major concern.

**4. H-Bond Donors:** Ligand A (2) is preferable to Ligand B (0). Having some HBDs can improve solubility.

**5. H-Bond Acceptors:** Both ligands have the same number of HBA (6), which is within the acceptable limit of <=10.

**6. QED:** Both ligands have similar QED values (Ligand A: 0.735, Ligand B: 0.665), both above the 0.5 threshold, indicating good drug-like properties.

**7. DILI:** Ligand A (95.502) has a significantly higher DILI risk than Ligand B (75.649). This is a major drawback for Ligand A.

**8. BBB:** Ligand B (80.69) has a much better BBB penetration percentile than Ligand A (17.449). This is *critical* for a CNS target like DRD2.

**9. Caco-2 Permeability:** Ligand A (-5.318) has a worse Caco-2 permeability than Ligand B (-4.667). Both are negative, indicating poor permeability, but B is better.

**10. Aqueous Solubility:** Both ligands have similar and poor aqueous solubility (-3.294 and -3.36 respectively).

**11. hERG Inhibition:** Ligand A (0.004) has a much lower hERG inhibition liability than Ligand B (0.792), which is a significant advantage.

**12. Microsomal Clearance:** Ligand A (-11.561) has a much lower microsomal clearance than Ligand B (50.71), suggesting better metabolic stability.

**13. In vitro Half-Life:** Both ligands have similar in vitro half-lives (Ligand A: 19.201, Ligand B: 19.574).

**14. P-gp Efflux:** Ligand A (0.011) has a much lower P-gp efflux liability than Ligand B (0.498), which is beneficial for CNS exposure.

**15. Binding Affinity:** Ligand B (-9.0 kcal/mol) has a slightly better binding affinity than Ligand A (-8.5 kcal/mol). While the difference is not huge, it's still a positive for Ligand B.

**Overall Assessment:**

Despite Ligand A's better hERG and metabolic stability, the significantly higher DILI risk and *very* poor BBB penetration are major red flags. For a CNS target, BBB penetration is paramount. Ligand B, while having a slightly higher logP and P-gp efflux, has a much more favorable safety profile (lower DILI) and excellent BBB penetration. The slightly better affinity of Ligand B further supports its selection.

Output:
1
2025-04-17 04:19:31,535 - INFO - Batch 103 complete. Total preferences: 1648
2025-04-17 04:19:31,535 - INFO - Processing batch 104/512...
2025-04-17 04:20:13,316 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (350.459 and 344.411 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (87.66) is slightly above the optimal <90 for CNS targets, but still reasonable. Ligand B (71.78) is excellent, well below 90.

**3. logP:** Both ligands have good logP values (1.26 and 1.95), falling within the 1-3 range.

**4. H-Bond Donors:** Ligand A (3) is acceptable. Ligand B (1) is also good.

**5. H-Bond Acceptors:** Both ligands (4) are within the acceptable limit of <=10.

**6. QED:** Both ligands have similar QED values (0.697 and 0.695), indicating good drug-like properties.

**7. DILI:** Both ligands have low DILI risk (28.616 and 24.544), both well below the 40 threshold.

**8. BBB:** This is a crucial parameter for a CNS target like DRD2. Ligand B (68.67) is significantly better than Ligand A (28.81). While 68.67 isn't *outstanding*, it's a much more promising starting point for CNS penetration.

**9. Caco-2 Permeability:** Both have negative values, indicating poor permeability. Ligand A (-5.095) is slightly worse than Ligand B (-4.269).

**10. Aqueous Solubility:** Both have negative solubility values, indicating poor solubility. Ligand A (-2.783) is slightly worse than Ligand B (-3.207).

**11. hERG Inhibition:** Both ligands have low hERG inhibition risk (0.136 and 0.229).

**12. Microsomal Clearance:** Both have similar microsomal clearance rates (28.402 and 25.183), suggesting moderate metabolic stability.

**13. In vitro Half-Life:** Both have similar in vitro half-lives (15.624 and 14.752 hours).

**14. P-gp Efflux:** Both have low P-gp efflux liability (0.046 and 0.092), which is good for CNS exposure.

**15. Binding Affinity:** Ligand A (-8.6 kcal/mol) has a significantly stronger binding affinity than Ligand B (-7.3 kcal/mol). This is a 1.3 kcal/mol difference, which is substantial and can outweigh some ADME drawbacks.

**Overall Assessment:**

While Ligand A has a superior binding affinity, Ligand B has a significantly better BBB percentile. Given that DRD2 is a CNS target, BBB penetration is paramount. The difference in affinity (1.3 kcal/mol) is substantial, but can potentially be addressed through further optimization. The poor Caco-2 and solubility of both compounds are concerning, but can be tackled with prodrug strategies or formulation approaches. The better BBB score of Ligand B makes it a more promising starting point for development.

Output:
1
2025-04-17 04:20:13,317 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (363.483 and 354.447 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Both ligands (84.23 and 85.89) are below the 90 A^2 threshold desirable for CNS targets, which is good.

**3. logP:** Ligand A (3.32) is optimal, while Ligand B (0.618) is quite low. Low logP can hinder membrane permeability, which is a concern for CNS penetration.

**4. H-Bond Donors:** Both have 2 HBD, which is within the acceptable limit of <=5.

**5. H-Bond Acceptors:** Both have 5 HBA, also within the acceptable limit of <=10.

**6. QED:** Both ligands have similar QED values (0.753 and 0.73), indicating good drug-likeness.

**7. DILI:** Ligand A (69.678) has a slightly higher DILI risk than Ligand B (37.185), but both are below the concerning threshold of 60.

**8. BBB:** Ligand B (71.733) has a significantly better BBB penetration percentile than Ligand A (21.326). This is a crucial factor for a CNS target like DRD2.

**9. Caco-2 Permeability:** Ligand A (-5.205) has very poor Caco-2 permeability, while Ligand B (-4.89) is also poor, but slightly better.

**10. Aqueous Solubility:** Ligand A (-3.176) has slightly better solubility than Ligand B (-1.359).

**11. hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.25 and 0.176).

**12. Microsomal Clearance:** Ligand A (44.963) has a higher microsomal clearance than Ligand B (2.306), suggesting lower metabolic stability.

**13. In vitro Half-Life:** Ligand B (15.665) has a significantly longer in vitro half-life than Ligand A (55.214).

**14. P-gp Efflux:** Both ligands have low P-gp efflux liability (0.181 and 0.027).

**15. Binding Affinity:** Ligand B (-7.7 kcal/mol) has a slightly better binding affinity than Ligand A (-7.3 kcal/mol). While the difference is not huge, it is still a factor.

**Overall Assessment:**

Ligand B is the more promising candidate. While Ligand A has slightly better solubility, Ligand B excels in the critical areas for a CNS-targeting GPCR: significantly better BBB penetration, longer half-life, lower microsomal clearance, and slightly better binding affinity. The lower logP of Ligand B is a concern, but the superior BBB penetration and affinity likely outweigh this drawback. The Caco-2 permeability is poor for both, but not a primary concern for a CNS target.

Output:
1
2025-04-17 04:20:13,317 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight (MW):** Both ligands (350.39 and 355.454 Da) fall comfortably within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (81.08) is better than Ligand B (87.3). Both are below the 90 A^2 threshold for CNS targets, but A is closer to the optimal range.

**3. logP:** Both ligands have good logP values (1.365 and 1.299), falling within the 1-3 range.

**4. H-Bond Donors (HBD):** Both ligands are acceptable (2 and 3 respectively), staying under the 5 limit.

**5. H-Bond Acceptors (HBA):** Both ligands are acceptable (4 and 3 respectively), staying under the 10 limit.

**6. QED:** Ligand A (0.859) has a significantly better QED score than Ligand B (0.671), indicating higher overall drug-likeness.

**7. DILI:** Ligand A (29.042) has a much lower DILI risk than Ligand B (19.969), which is a significant advantage.

**8. BBB:** Ligand B (71.927) has a substantially better BBB penetration percentile than Ligand A (47.111). This is a *critical* factor for a DRD2 ligand targeting CNS disorders.

**9. Caco-2 Permeability:** Ligand A (-4.865) has a better Caco-2 permeability than Ligand B (-5.14), suggesting better intestinal absorption.

**10. Aqueous Solubility:** Ligand A (-1.782) has better aqueous solubility than Ligand B (-2.263).

**11. hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.523 and 0.193), which is excellent.

**12. Microsomal Clearance:** Ligand A (12.209) has lower microsomal clearance than Ligand B (24.184), suggesting better metabolic stability.

**13. In vitro Half-Life:** Ligand A (-13.339) has a much longer in vitro half-life than Ligand B (-4.452).

**14. P-gp Efflux:** Both ligands show very low P-gp efflux liability (0.161 and 0.017).

**15. Binding Affinity:** Both ligands have excellent binding affinities (-8.8 and -8.9 kcal/mol), with Ligand B being slightly better. However, the difference is small.

**Overall Assessment:**

While Ligand B has a superior BBB score and slightly better binding affinity, Ligand A demonstrates significantly better drug-like properties (QED, DILI, solubility, metabolic stability, half-life) and acceptable BBB penetration. The substantial improvements in ADME/Tox properties for Ligand A outweigh the small advantage in binding affinity and BBB penetration of Ligand B. For a GPCR target in the CNS, a balance of potency *and* good pharmacokinetic properties is crucial. Ligand A presents a more promising overall profile.

Output:
1
2025-04-17 04:20:13,317 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 drug candidates, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (357.494 and 361.467 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (20.31) is excellent, well below the 90 A^2 threshold for CNS targets. Ligand B (67.6) is higher, but still potentially acceptable, though less ideal.

**logP:** Ligand A (4.813) is slightly high, potentially leading to solubility issues or off-target interactions. Ligand B (2.478) is within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A (0 HBD, 2 HBA) is favorable. Ligand B (1 HBD, 6 HBA) is also reasonable, though slightly higher in HBA count.

**QED:** Both ligands have good QED scores (0.696 and 0.817), indicating drug-like properties.

**DILI:** Ligand A (29.973) has a significantly lower DILI risk than Ligand B (52.423), which is a strong advantage.

**BBB:** Ligand A (89.531) shows excellent BBB penetration, crucial for a CNS target like DRD2. Ligand B (49.942) is considerably lower, raising concerns about CNS exposure.

**Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and suggests poor permeability. However, the scale is not specified, so it's difficult to interpret.

**Aqueous Solubility:** Both ligands have negative solubility values, suggesting poor aqueous solubility. This is a concern, particularly for Ligand A with its higher logP.

**hERG Inhibition:** Both ligands show low hERG inhibition risk (0.808 and 0.42), which is positive.

**Microsomal Clearance:** Ligand A (81.186) has higher microsomal clearance than Ligand B (61.544), suggesting potentially lower metabolic stability.

**In vitro Half-Life:** Ligand B (9.163 hours) has a significantly longer half-life than Ligand A (3.332 hours), which is desirable.

**P-gp Efflux:** Ligand A (0.822) has slightly higher P-gp efflux than Ligand B (0.192), which is unfavorable for CNS penetration.

**Binding Affinity:** Both ligands have very similar and strong binding affinities (-8.3 and -8.1 kcal/mol). The difference is less than the 1.5 kcal/mol threshold.

**Overall Assessment:**

Considering the GPCR-specific priorities, Ligand A is more promising despite its slightly higher logP and clearance. Its significantly better BBB penetration (89.531 vs 49.942) and lower DILI risk (29.973 vs 52.423) are major advantages for a CNS drug candidate. While solubility and Caco-2 permeability are concerns for both, the superior BBB penetration of Ligand A is critical for DRD2 targeting. The slightly better half-life of Ligand B is not enough to offset the CNS exposure issues.

Output:
0
2025-04-17 04:20:13,317 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 drug candidates, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (355.404 and 343.391 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (58.36) is excellent, well below the 90 A^2 threshold for CNS targets. Ligand B (105.9) is higher, but still potentially acceptable, though less ideal.

**3. logP:** Ligand A (3.343) is optimal (1-3). Ligand B (0.186) is quite low, which could hinder membrane permeability and CNS penetration.

**4. H-Bond Donors:** Ligand A (2) and Ligand B (1) are both within the acceptable limit of <=5.

**5. H-Bond Acceptors:** Ligand A (3) and Ligand B (7) are both within the acceptable limit of <=10.

**6. QED:** Both ligands have good QED scores (0.818 and 0.83), indicating good drug-like properties.

**7. DILI:** Ligand A (21.946) has a very favorable DILI score, indicating low liver injury risk. Ligand B (80.07) is higher, suggesting a moderate risk.

**8. BBB:** Ligand A (96.278) has an excellent BBB penetration score, highly desirable for a CNS target like DRD2. Ligand B (41.024) is significantly lower, raising concerns about reaching the target in the brain.

**9. Caco-2 Permeability:** Ligand A (-4.922) and Ligand B (-5.502) both have negative values, which is unusual and suggests poor permeability. However, these values are on a scale where negative values are possible, and the absolute magnitude isn't directly comparable without knowing the scale's specifics.

**10. Aqueous Solubility:** Ligand A (-3.756) and Ligand B (-1.509) both have negative values, indicating poor aqueous solubility.

**11. hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.95 and 0.101).

**12. Microsomal Clearance:** Ligand A (-18.684) has a negative value, suggesting very low clearance and excellent metabolic stability. Ligand B (3.343) has a low clearance, but not as favorable as Ligand A.

**13. In vitro Half-Life:** Ligand A (-17.335) has a negative value, suggesting a very long half-life. Ligand B (4.695) has a shorter half-life.

**14. P-gp Efflux:** Ligand A (0.125) has very low P-gp efflux, which is excellent for CNS penetration. Ligand B (0.009) also has very low P-gp efflux.

**15. Binding Affinity:** Ligand A (-9.4 kcal/mol) has a significantly stronger binding affinity than Ligand B (-8.2 kcal/mol). This 1.2 kcal/mol difference is substantial and can outweigh some ADME drawbacks.

**Overall Assessment:**

Ligand A is the superior candidate. While both have issues with solubility and Caco-2 permeability, Ligand A excels in critical areas for a CNS-targeting GPCR: BBB penetration, metabolic stability (low Cl_mic and long t1/2), low DILI risk, and, crucially, significantly higher binding affinity. Ligand B's low logP is a major concern, likely hindering its ability to cross the blood-brain barrier despite its low P-gp efflux. The stronger affinity of Ligand A is a significant advantage.

Output:
1
2025-04-17 04:20:13,318 - INFO - Reasoning:

Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (364.829 and 364.515 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (80.57) is better than Ligand B (86.88). Both are below the 90 A^2 threshold for CNS targets, but A is closer to the ideal.

**3. logP:** Ligand A (3.645) is slightly higher than Ligand B (2.445), both are within the optimal 1-3 range.

**4. H-Bond Donors:** Ligand A (2) is preferable to Ligand B (3). Lower HBD generally improves permeability.

**5. H-Bond Acceptors:** Both ligands have 4 HBA, which is acceptable.

**6. QED:** Ligand A (0.785) has a significantly better QED score than Ligand B (0.595), indicating a more drug-like profile.

**7. DILI:** Ligand A (63.746) has a higher DILI risk than Ligand B (29.624). This is a significant drawback for Ligand A.

**8. BBB:** Ligand A (61.574) has a slightly better BBB penetration percentile than Ligand B (53.781), but both are below the desirable >70% for CNS targets.

**9. Caco-2 Permeability:** Ligand A (-4.768) has a worse Caco-2 permeability than Ligand B (-5.555). Lower values indicate poorer absorption.

**10. Aqueous Solubility:** Ligand A (-4.652) has a worse aqueous solubility than Ligand B (-3.25).

**11. hERG Inhibition:** Ligand A (0.738) has a higher hERG inhibition liability than Ligand B (0.33). Lower is better.

**12. Microsomal Clearance:** Ligand A (55.728) has a higher microsomal clearance than Ligand B (24.474), suggesting lower metabolic stability.

**13. In vitro Half-Life:** Ligand A (66.428) has a longer in vitro half-life than Ligand B (2.696).

**14. P-gp Efflux:** Ligand A (0.5) has a lower P-gp efflux liability than Ligand B (0.064), which is favorable for CNS penetration.

**15. Binding Affinity:** Ligand A (-8.9 kcal/mol) has a significantly stronger binding affinity than Ligand B (-7.6 kcal/mol). This is a substantial advantage, potentially outweighing some of the ADME concerns.

**Overall Assessment:**

Ligand A has a much better binding affinity and a better P-gp efflux profile. However, it suffers from higher DILI risk, poorer solubility, and higher hERG inhibition. Ligand B has a better safety profile (lower DILI, hERG) and better solubility, but its binding affinity is considerably weaker.

Given the importance of affinity for GPCRs, and the significant difference (-8.9 vs -7.6 kcal/mol), the stronger binding of Ligand A is likely to be the deciding factor, *provided* the DILI risk can be mitigated through further optimization. The slightly better BBB and P-gp efflux also support Ligand A.

Output:
1
2025-04-17 04:20:13,318 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (399.705 and 382.957 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (50.36) is slightly above the optimal <90 for CNS targets, but still reasonable. Ligand B (34.59) is excellent, well below 90.

**3. logP:** Both ligands have logP values around 4.7-4.9, which is slightly high. This could potentially lead to solubility issues or off-target interactions, but is not a dealbreaker given the importance of CNS penetration for DRD2.

**4. H-Bond Donors:** Ligand A has 2 HBD, which is acceptable. Ligand B has 0, which is also acceptable.

**5. H-Bond Acceptors:** Ligand A has 3 HBA, and Ligand B has 5. Both are within the acceptable limit of <=10.

**6. QED:** Ligand A (0.766) has a better QED score than Ligand B (0.583), suggesting a more drug-like profile.

**7. DILI:** Ligand A (65.491) has a higher DILI risk than Ligand B (35.44), which is a significant concern.

**8. BBB:** Both ligands have good BBB penetration (Ligand A: 74.796, Ligand B: 77.705), exceeding the desirable >70 threshold for CNS targets. Ligand B is slightly better.

**9. Caco-2:** Both have negative Caco-2 values, which is unusual and likely indicates a data error or a very poor permeability. This is a concerning point for both.

**10. Solubility:** Both ligands have very poor aqueous solubility (-5.43 and -5.098). This is a major drawback, potentially hindering bioavailability.

**11. hERG:** Both ligands show low hERG inhibition risk (0.825 and 0.853), which is positive.

**12. Cl_mic:** Ligand A (26.632) has a lower microsomal clearance than Ligand B (102.322), indicating better metabolic stability.

**13. t1/2:** Ligand A (65.435) has a longer in vitro half-life than Ligand B (46.66), which is desirable.

**14. Pgp:** Both ligands have low P-gp efflux liability (0.43 and 0.608), which is good for CNS exposure.

**15. Binding Affinity:** Ligand B (-6.9 kcal/mol) has a significantly better binding affinity than Ligand A (-10.5 kcal/mol). This is a substantial advantage.

**Overall Assessment:**

Ligand B is the better candidate despite its slightly lower QED and solubility. The significantly stronger binding affinity (-6.9 vs -10.5 kcal/mol) is a major advantage for a GPCR target and can often compensate for minor ADME deficiencies. While both have poor solubility and Caco-2 permeability, the lower DILI risk and better metabolic stability of Ligand B are also favorable. The slightly better BBB penetration of Ligand B is also a plus. Ligand A's high DILI risk is a significant red flag.

Output:
1
2025-04-17 04:20:13,318 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (349.519 and 360.38 Da) fall within the ideal range of 200-500 Da.

**TPSA:** Ligand A (43.86) is significantly better than Ligand B (81.34). For CNS targets, TPSA should be <= 90, and lower is preferred. Ligand A is well within this range, while Ligand B is approaching the upper limit.

**logP:** Both ligands have acceptable logP values (2.667 and 3.092), falling within the optimal range of 1-3.

**H-Bond Donors/Acceptors:** Ligand A (0 HBD, 3 HBA) and Ligand B (1 HBD, 5 HBA) both have reasonable numbers of H-bond donors and acceptors, well below the thresholds of 5 and 10, respectively.

**QED:** Both ligands have good QED scores (0.693 and 0.77), indicating drug-like properties.

**DILI:** Both ligands have low DILI risk (5.7 and 52.734), which is favorable.

**BBB:** Ligand A (92.323) has a significantly higher BBB penetration percentile than Ligand B (87.941). This is a crucial factor for a CNS target like DRD2.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.509 and -4.507). This is unusual and suggests poor permeability. However, the values are very similar, so this isn't a major differentiator.

**Aqueous Solubility:** Both ligands have negative solubility values (-1.509 and -3.683), indicating poor aqueous solubility. This is a concern, but again, similar for both.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.354 and 0.676).

**Microsomal Clearance:** Ligand A (45.474) has lower microsomal clearance than Ligand B (53.737), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (-8.689) has a longer in vitro half-life than Ligand B (-10.9), which is desirable.

**P-gp Efflux:** Ligand A (0.062) has much lower P-gp efflux liability than Ligand B (0.267). Lower P-gp efflux is crucial for CNS penetration.

**Binding Affinity:** Both ligands have very similar and strong binding affinities (-7.0 and -6.9 kcal/mol). The difference is negligible.

**Overall Assessment:**

Ligand A is superior due to its significantly better TPSA, BBB penetration, lower P-gp efflux, and better metabolic stability (lower Cl_mic and longer t1/2). While both have issues with Caco-2 permeability and aqueous solubility, the CNS-relevant properties of Ligand A make it the more promising candidate. The slight advantage in BBB and P-gp efflux are particularly important for DRD2, a CNS target.

Output:
0
2025-04-17 04:20:13,318 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (341.455 and 362.308 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (58.22) is excellent, well below the 90 A^2 threshold for CNS targets. Ligand B (104.65) is higher but still potentially acceptable, though less ideal.

**logP:** Ligand A (4.092) is at the upper end of the optimal range (1-3), potentially leading to solubility issues. Ligand B (0.504) is quite low, which could hinder membrane permeability and CNS penetration.

**H-Bond Donors/Acceptors:** Ligand A (1 HBD, 4 HBA) is favorable. Ligand B (2 HBD, 6 HBA) is also reasonable.

**QED:** Both ligands have similar QED values (0.851 and 0.791), indicating good drug-likeness.

**DILI:** Both ligands have elevated DILI risk (18.573 and 62.737), but Ligand A is considerably better.

**BBB:** Ligand A (62.427) is borderline for good CNS penetration, while Ligand B (63.901) is similar. Both are below the desirable >70 percentile.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.93 and -4.937), which is unusual and suggests poor permeability. This is a significant concern.

**Aqueous Solubility:** Both ligands have negative solubility values (-4.234 and -2.101), indicating very poor aqueous solubility. This is a major drawback.

**hERG Inhibition:** Ligand A (0.849) has a slightly higher hERG risk than Ligand B (0.135), but both are relatively low.

**Microsomal Clearance:** Ligand A (51.317) has a higher clearance than Ligand B (-2.638), suggesting lower metabolic stability.

**In vitro Half-Life:** Ligand A (-26.011) has a negative half-life, which is not physically possible and indicates a problem with the data or prediction. Ligand B (-23.314) also has a negative half-life.

**P-gp Efflux:** Ligand A (0.323) has lower P-gp efflux liability than Ligand B (0.012), which is favorable for CNS penetration.

**Binding Affinity:** Ligand A (-8.5 kcal/mol) has a significantly stronger binding affinity than Ligand B (-6.8 kcal/mol). This 1.7 kcal/mol difference is substantial and could outweigh some of the ADME drawbacks.

**Overall Assessment:**

Despite the poor solubility and permeability predictions for both compounds, Ligand A is the more promising candidate. Its significantly stronger binding affinity (-8.5 vs -6.8 kcal/mol) is a major advantage, especially for a GPCR target. While its logP is high and DILI risk is present, these are potentially addressable through further optimization. The negative half-life for both is a red flag, but the binding affinity difference is compelling. Ligand B's very low logP is a significant concern for CNS penetration.

Output:
0
2025-04-17 04:20:13,319 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (350.423 and 352.431 Da) fall comfortably within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (109.22) is slightly above the preferred <90 for CNS targets, while Ligand B (93.73) is closer to the ideal range. This gives a slight edge to Ligand B.

**3. logP:** Ligand A (-0.243) is quite low, potentially hindering membrane permeability. Ligand B (0.941) is within the optimal 1-3 range. This is a significant advantage for Ligand B.

**4. H-Bond Donors:** Both ligands have 2 HBD, which is within the acceptable limit of <=5.

**5. H-Bond Acceptors:** Ligand A has 6 HBA, while Ligand B has 5. Both are within the acceptable limit of <=10.

**6. QED:** Ligand A (0.688) has a better QED score than Ligand B (0.451), indicating a more drug-like profile.

**7. DILI:** Ligand A (62.233) has a higher DILI risk than Ligand B (31.291). This favors Ligand B.

**8. BBB:** Ligand A (43.583) has a lower BBB penetration percentile than Ligand B (47.15). While neither is ideal (>70), Ligand B is slightly better.

**9. Caco-2 Permeability:** Ligand A (-5.661) has poor Caco-2 permeability, while Ligand B (-4.777) is slightly better, but still not great.

**10. Aqueous Solubility:** Ligand A (-1.163) has poor aqueous solubility, while Ligand B (-2.486) is even worse. This is a concern for both, but more so for Ligand B.

**11. hERG Inhibition:** Both ligands show very low hERG inhibition liability (0.024 and 0.071 respectively), which is excellent.

**12. Microsomal Clearance:** Ligand A (2.659) has significantly lower microsomal clearance than Ligand B (63.389), suggesting better metabolic stability. This is a strong advantage for Ligand A.

**13. In vitro Half-Life:** Ligand A (25.727 hours) has a much longer in vitro half-life than Ligand B (-23.149 hours). This is a major advantage for Ligand A.

**14. P-gp Efflux:** Both ligands show very low P-gp efflux liability (0.011 and 0.03 respectively), which is excellent.

**15. Binding Affinity:** Ligand B (-6.5 kcal/mol) has a significantly stronger binding affinity than Ligand A (0.0 kcal/mol). This is a crucial advantage for Ligand B, potentially outweighing some of its ADME drawbacks.

**Overall Assessment:**

Ligand B has a superior binding affinity and a better logP value, which are critical for a GPCR target like DRD2. It also has lower DILI risk and slightly better BBB penetration. However, it suffers from poor solubility, high metabolic clearance, and a short half-life. Ligand A has better QED, metabolic stability, half-life, and lower DILI, but its low logP and weak binding affinity are major drawbacks.

Considering the importance of binding affinity for initial hit identification and the fact that the other ADME properties of Ligand B could potentially be optimized, Ligand B is the more promising candidate.

Output:
1
2025-04-17 04:20:13,319 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (373.274 Da and 364.471 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (66.02) is excellent for CNS penetration, well below the 90 A^2 threshold. Ligand B (104.53) is higher, but still potentially acceptable, though less ideal.

**logP:** Ligand A (2.578) is optimal. Ligand B (1.245) is a bit low, potentially hindering membrane permeability.

**H-Bond Donors/Acceptors:** Ligand A (HBD=1, HBA=5) is good. Ligand B (HBD=3, HBA=4) is also reasonable.

**QED:** Both ligands have acceptable QED values (0.674 and 0.54), indicating reasonable drug-likeness.

**DILI:** Ligand A (59.131) has a higher DILI risk than Ligand B (40.287), but both are below the concerning 60 percentile.

**BBB:** Ligand A (76.347) has significantly better predicted BBB penetration than Ligand B (55.874). This is a critical advantage for a CNS target like DRD2.

**Caco-2 Permeability:** Ligand A (-4.682) has poor Caco-2 permeability, which is a concern. Ligand B (-5.359) is also poor, but slightly worse.

**Aqueous Solubility:** Both ligands have very poor aqueous solubility (-3.207 and -2.389). This could present formulation challenges.

**hERG:** Both ligands have low hERG inhibition risk (0.687 and 0.067).

**Microsomal Clearance:** Ligand A (31.011) has higher microsomal clearance than Ligand B (-1.016), suggesting lower metabolic stability. Ligand B is excellent in this regard.

**In vitro Half-Life:** Ligand A (-1.821) has a shorter half-life than Ligand B (-3.029), indicating faster metabolism.

**P-gp Efflux:** Ligand A (0.17) has lower P-gp efflux liability than Ligand B (0.028), which is favorable for CNS exposure.

**Binding Affinity:** Ligand B (-8.8 kcal/mol) has a significantly stronger binding affinity than Ligand A (-7.2 kcal/mol). This is a substantial advantage, potentially outweighing some ADME drawbacks. The difference is >1.5 kcal/mol.

**Overall Assessment:**

Ligand B's significantly stronger binding affinity (-8.8 vs -7.2 kcal/mol) is the most important factor. While Ligand A has better BBB penetration and P-gp efflux, the affinity difference is substantial. Ligand B also has better metabolic stability (lower Cl_mic, longer t1/2) and lower DILI risk. The lower logP and Caco-2 permeability of Ligand B are concerns, but the strong binding affinity suggests it might still be effective *in vivo*.

Output:
1
2025-04-17 04:20:13,319 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (386.876 and 354.402 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (75.27) is better than Ligand B (43.37). For a CNS target like DRD2, a TPSA under 90 is desirable, and both meet this criterion, but A is slightly higher.

**3. logP:** Ligand A (2.227) is within the optimal 1-3 range. Ligand B (4.9) is higher, potentially leading to solubility issues and off-target interactions.

**4. H-Bond Donors:** Ligand A (2) is reasonable. Ligand B (0) is also acceptable.

**5. H-Bond Acceptors:** Ligand A (3) is good. Ligand B (4) is also acceptable.

**6. QED:** Ligand A (0.557) is better, indicating a more drug-like profile than Ligand B (0.372).

**7. DILI:** Ligand A (52.734) has a lower DILI risk than Ligand B (88.057), which is a significant advantage.

**8. BBB:** Ligand A (81.737) has a significantly better BBB penetration percentile than Ligand B (65.839). This is *critical* for a CNS target like DRD2.

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.996 and -4.147), which is unusual and suggests poor permeability. However, these values are on a different scale and hard to interpret directly.

**10. Aqueous Solubility:** Both ligands have negative solubility values (-3.668 and -6.569), again unusual and suggesting poor solubility.

**11. hERG Inhibition:** Ligand A (0.65) shows a lower hERG inhibition liability than Ligand B (0.287), which is preferable.

**12. Microsomal Clearance:** Ligand A (48.328) has a lower (better) microsomal clearance than Ligand B (129.822), indicating greater metabolic stability.

**13. In vitro Half-Life:** Ligand A (9.387) has a shorter half-life than Ligand B (30.877). While longer is generally preferred, this difference isn't decisive given the other factors.

**14. P-gp Efflux:** Ligand A (0.359) has lower P-gp efflux liability than Ligand B (0.476), which is advantageous for CNS penetration.

**15. Binding Affinity:** Ligand B (-9.1 kcal/mol) has a slightly better binding affinity than Ligand A (-8.8 kcal/mol). However, the difference is only 0.3 kcal/mol, which is less significant than the substantial ADME advantages of Ligand A.

**Overall Assessment:**

Ligand A is the superior candidate. While Ligand B has slightly better binding affinity, Ligand A demonstrates significantly better ADME properties, particularly regarding BBB penetration (81.7 vs 65.8), lower DILI risk (52.7 vs 88.1), lower P-gp efflux, and better metabolic stability. For a CNS target like DRD2, these factors are paramount. The negative Caco-2 and solubility values are concerning for both, but the other advantages of Ligand A outweigh this concern.

Output:
1
2025-04-17 04:20:13,319 - INFO - Reasoning:

Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (361.467 and 345.403 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (69.72) is significantly better than Ligand B (104.12). For CNS targets, we want TPSA <= 90, and A is comfortably within that, while B exceeds it. This is a substantial advantage for A.

**3. logP:** Both ligands have acceptable logP values (1.062 and 1.363), falling within the optimal 1-3 range.

**4. H-Bond Donors:** Ligand A (1) is preferable to Ligand B (2). Fewer HBDs generally improve permeability.

**5. H-Bond Acceptors:** Ligand A (4) is preferable to Ligand B (5). Fewer HBAs generally improve permeability.

**6. QED:** Both ligands have good QED scores (0.818 and 0.823), indicating good drug-like properties.

**7. DILI:** Ligand A (51.493) has a slightly higher DILI risk than Ligand B (41.877), but both are below the concerning threshold of 60.

**8. BBB:** Ligand B (60.256) has a better BBB penetration percentile than Ligand A (54.052). While both are not ideal (>70 is desirable), B is better.

**9. Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and suggests a potential issue with the data or modeling. However, the values are similar (-5.075 vs -5.381) and don't strongly differentiate the ligands.

**10. Aqueous Solubility:** Both have negative solubility values, which is also unusual. Again, the values are similar (-2.569 vs -1.517) and don't strongly differentiate the ligands.

**11. hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.272 and 0.029).

**12. Microsomal Clearance:** Ligand A (-12.365) has a *much* lower (better) microsomal clearance than Ligand B (-6.132). This indicates greater metabolic stability for Ligand A.

**13. In vitro Half-Life:** Ligand A (-7.531) has a negative half-life, which is not physically possible. Ligand B has a positive half-life (5.163), which is preferable. However, the negative value for A is likely an artifact of the modeling.

**14. P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.018 and 0.013).

**15. Binding Affinity:** Both ligands have the same binding affinity (-9.1 kcal/mol), which is excellent.

**Overall Assessment:**

Despite Ligand B having a slightly better BBB score, Ligand A is the stronger candidate. The significantly lower TPSA and microsomal clearance of Ligand A are crucial advantages for a CNS-targeting GPCR ligand. Lower TPSA facilitates brain penetration, and lower clearance translates to a longer duration of action. While the negative half-life for A is concerning, it's likely a modeling error and doesn't negate the other strong properties. The slightly higher DILI risk for A is acceptable given its other advantages.

Output:
1
2025-04-17 04:20:13,320 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (344.5 & 349.5 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (40.62) is significantly better than Ligand B (69.72). For CNS targets, we want TPSA <= 90, and ideally lower. Ligand A is much closer to the ideal range.

**3. logP:** Ligand A (3.232) is within the optimal 1-3 range. Ligand B (1.564) is a bit low, potentially hindering permeability.

**4. H-Bond Donors:** Both are acceptable (0 for A, 1 for B), well below the limit of 5.

**5. H-Bond Acceptors:** Both are acceptable (2 for A, 3 for B), well below the limit of 10.

**6. QED:** Both have good QED scores (0.567 and 0.74), indicating drug-like properties.

**7. DILI:** Ligand A (11.283) has a much lower DILI risk than Ligand B (18.185), which is a significant advantage.

**8. BBB:** Both ligands have good BBB penetration (76.3% and 70.6%), exceeding the desirable threshold of 70% for CNS targets. Ligand A is slightly better.

**9. Caco-2:** Both have negative Caco-2 values, which is unusual and suggests poor permeability. However, the scale is not specified, so it's difficult to interpret.

**10. Solubility:** Both have negative solubility values, also unusual and suggesting poor solubility.

**11. hERG:** Both ligands have low hERG inhibition risk (0.452 and 0.246).

**12. Cl_mic:** Ligand B (27.799) has lower microsomal clearance than Ligand A (42.029), indicating better metabolic stability.

**13. t1/2:** Ligand A (-7.607) has a significantly longer in vitro half-life than Ligand B (-2.537).

**14. Pgp:** Ligand A (0.206) has lower P-gp efflux liability than Ligand B (0.032), which is beneficial for CNS exposure.

**15. Binding Affinity:** Ligand A (-8.1 kcal/mol) has a stronger binding affinity than Ligand B (-6.8 kcal/mol). This is a substantial difference (>1.5 kcal/mol) and a major driver in the decision.

**Overall Assessment:**

Ligand A is superior due to its significantly better TPSA, lower DILI risk, stronger binding affinity, and longer half-life. While Ligand B has better metabolic stability (lower Cl_mic) and slightly lower Pgp efflux, the advantages of Ligand A in TPSA, affinity, and safety (DILI) outweigh these benefits, especially given the CNS target. The negative solubility and Caco-2 values are concerning for both, but the stronger binding and better CNS penetration profile of A make it the more promising candidate.

Output:
1
2025-04-17 04:20:13,320 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (344.39 and 351.447 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (72.36) is excellent, well below the 90 A^2 threshold for CNS targets. Ligand B (87.74) is still reasonable, but less optimal.

**logP:** Both ligands have good logP values (2.377 and 1.418), falling within the 1-3 range.

**H-Bond Donors/Acceptors:** Both ligands have acceptable HBD (1 & 2) and HBA (4 & 4) counts, well within the guidelines.

**QED:** Ligand A (0.924) has a very high QED score, indicating excellent drug-likeness. Ligand B (0.726) is still good, but less so.

**DILI:** Ligand A (64.288) has a higher DILI risk than Ligand B (17.449). This is a significant drawback for Ligand A.

**BBB:** Ligand A (84.684) has a better BBB penetration percentile than Ligand B (75.843), which is important for a CNS target like DRD2.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values, which is unusual and suggests poor permeability. This is a concern for both.

**Aqueous Solubility:** Both ligands have negative solubility values, indicating poor solubility. This is a concern for both.

**hERG Inhibition:** Ligand A (0.964) has a slightly higher hERG risk than Ligand B (0.261).

**Microsomal Clearance:** Ligand A (22.264) has lower microsomal clearance, suggesting better metabolic stability than Ligand B (25.258).

**In vitro Half-Life:** Ligand A (26.836) has a longer in vitro half-life than Ligand B (-16.815). The negative value for Ligand B is concerning and likely indicates very rapid degradation.

**P-gp Efflux:** Ligand A (0.271) has lower P-gp efflux, which is favorable for CNS penetration, compared to Ligand B (0.012).

**Binding Affinity:** Ligand B (-7.6 kcal/mol) has a significantly stronger binding affinity than Ligand A (0.0 kcal/mol). This is a major advantage for Ligand B.

**Overall Assessment:**

Ligand B is the stronger candidate. While Ligand A has better BBB penetration and metabolic stability, Ligand B's substantially higher binding affinity (-7.6 vs 0 kcal/mol) outweighs the drawbacks. The significantly lower DILI risk and better P-gp efflux of Ligand B are also important advantages. The negative half-life for Ligand B is a serious concern, but the strong binding affinity suggests that optimization could potentially address this issue. The poor Caco-2 and solubility are shared concerns that would need to be addressed for either compound.

Output:
1
2025-04-17 04:20:13,320 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight (MW):** Both ligands (362.392 and 352.463 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Both ligands have TPSA values (58.64 and 57.95) below the 90 A^2 threshold desirable for CNS targets, which is excellent.

**3. logP:** Ligand A (2.253) is within the optimal 1-3 range. Ligand B (4.166) is slightly above, potentially hinting at solubility issues or off-target interactions, but still acceptable.

**4. H-Bond Donors (HBD):** Both ligands have 1 HBD, well within the acceptable limit of 5.

**5. H-Bond Acceptors (HBA):** Ligand A has 3 HBA, and Ligand B has 5 HBA, both are within the acceptable limit of 10.

**6. QED:** Ligand A (0.835) has a significantly better QED score than Ligand B (0.542), indicating a more drug-like profile.

**7. DILI:** Ligand A (24.195) has a much lower DILI risk than Ligand B (52.772), which is a significant advantage.

**8. BBB:** Ligand A (91.198) has a substantially better BBB penetration percentile than Ligand B (68.903). This is crucial for a CNS target like DRD2.

**9. Caco-2 Permeability:** Ligand A (-4.607) has a more positive Caco-2 value than Ligand B (-5.806), suggesting better intestinal absorption.

**10. Aqueous Solubility:** Ligand A (-2.846) has a more positive solubility value than Ligand B (-3.004), suggesting better aqueous solubility.

**11. hERG Inhibition:** Both ligands have low hERG inhibition risk (0.375 and 0.882).

**12. Microsomal Clearance (Cl_mic):** Ligand A (16.395) has a lower Cl_mic than Ligand B (49.639), indicating better metabolic stability.

**13. In vitro Half-Life (t1/2):** Ligand A (-4.318) has a more positive half-life value than Ligand B (23.851), suggesting a longer half-life.

**14. P-gp Efflux:** Both ligands have low P-gp efflux liability (0.067 and 0.533).

**15. Binding Affinity:** Both ligands have the same binding affinity (-8.3 kcal/mol), which is excellent.

**Overall Assessment:**

Ligand A consistently outperforms Ligand B across most crucial ADME-Tox properties, particularly BBB penetration, DILI risk, metabolic stability, and QED. While both have good binding affinity, Ligand A's superior ADME profile makes it a much more promising drug candidate for targeting DRD2 in the CNS.

Output:
0
2025-04-17 04:20:13,320 - INFO - Batch 104 complete. Total preferences: 1664
2025-04-17 04:20:13,320 - INFO - Processing batch 105/512...
2025-04-17 04:20:53,861 - INFO - Reasoning:

Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight (MW):** Both ligands (344.459 and 350.503 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (58.44) is significantly better than Ligand B (67.43). For CNS targets, we want TPSA <= 90, and ideally closer to 60. Ligand A is much closer to the ideal range.

**3. logP:** Both ligands have acceptable logP values (1.797 and 2.947), falling within the optimal 1-3 range. Ligand B is slightly higher, which could potentially lead to some off-target interactions, but isn't a major concern.

**4. H-Bond Donors (HBD):** Both are low (0 and 2 respectively), which is good for permeability.

**5. H-Bond Acceptors (HBA):** Both are reasonable (4 and 3 respectively), within the acceptable limit of 10.

**6. QED:** Both have acceptable QED values (0.758 and 0.694), indicating good drug-like properties.

**7. DILI:** Ligand A (17.1) has a much lower DILI risk than Ligand B (29.236). This is a significant advantage.

**8. BBB:** Ligand A (77.007) has a better BBB penetration percentile than Ligand B (67.197). While both are reasonably good, exceeding 70 is desirable for CNS targets, and Ligand A is closer.

**9. Caco-2 Permeability:** Ligand A (-4.927) is better than Ligand B (-4.696). Higher values indicate better intestinal absorption.

**10. Aqueous Solubility:** Ligand A (-1.529) is better than Ligand B (-3.489). Higher solubility is preferred.

**11. hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.32 and 0.185).

**12. Microsomal Clearance:** Ligand A (37.753) has lower microsomal clearance than Ligand B (60.584), suggesting better metabolic stability.

**13. In vitro Half-Life:** Ligand A (-13.417) has a better (longer) in vitro half-life than Ligand B (-7.141).

**14. P-gp Efflux:** Both ligands have low P-gp efflux liability (0.106 and 0.186).

**15. Binding Affinity:** Both ligands have excellent binding affinity (-8.7 and -8.1 kcal/mol). The difference of 0.6 kcal/mol is not substantial enough to outweigh the numerous advantages of Ligand A.

**Overall Assessment:**

Ligand A consistently outperforms Ligand B across most crucial ADME properties (DILI, BBB, solubility, metabolic stability, half-life, Caco-2 permeability) while maintaining comparable potency and acceptable physicochemical properties. Given the target is a CNS GPCR (DRD2), the better BBB penetration and lower DILI risk of Ligand A are particularly important.

Output:
1
2025-04-17 04:20:53,861 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B based on the provided guidelines, prioritizing GPCR-specific properties (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (355.463 and 353.463 Da) fall within the ideal range of 200-500 Da.

**TPSA:** Ligand A (63.13) is excellent for CNS penetration, well below the 90 A^2 threshold. Ligand B (81.16) is still reasonable but less ideal.

**logP:** Ligand A (3.465) is optimal. Ligand B (0.321) is quite low, potentially hindering membrane permeability and CNS entry.

**H-Bond Donors/Acceptors:** Both have acceptable HBD (2 and 1 respectively) and HBA (4 each) counts.

**QED:** Both ligands have good QED scores (0.544 and 0.772), indicating drug-like properties.

**DILI:** Ligand A (73.556) has a moderate DILI risk, while Ligand B (25.514) has a very low risk.

**BBB:** Ligand A (81.97) has excellent BBB penetration, exceeding the 70% threshold. Ligand B (46.607) is significantly lower, raising concerns for CNS exposure.

**Caco-2 Permeability:** Ligand A (-5.044) has poor Caco-2 permeability. Ligand B (-4.508) is also poor, but slightly better than A.

**Aqueous Solubility:** Both ligands have very poor aqueous solubility (-4.114 and -0.438). This could pose formulation challenges.

**hERG Inhibition:** Ligand A (0.761) has a low risk of hERG inhibition. Ligand B (0.11) has a very low risk.

**Microsomal Clearance:** Ligand A (78.99) has moderate microsomal clearance, suggesting moderate metabolic stability. Ligand B (27.523) has low clearance, indicating better metabolic stability.

**In vitro Half-Life:** Ligand A (58.241) has a reasonable half-life. Ligand B (-5.097) has a very short half-life, which is a significant drawback.

**P-gp Efflux:** Ligand A (0.735) has moderate P-gp efflux. Ligand B (0.022) has very low P-gp efflux, which is favorable for CNS penetration.

**Binding Affinity:** Ligand A (-9.4 kcal/mol) has a significantly stronger binding affinity than Ligand B (-7.3 kcal/mol). The 2.1 kcal/mol difference is substantial and can often outweigh other deficiencies.

**Overall Assessment:**

Ligand A excels in binding affinity and BBB penetration, crucial for a CNS-targeting GPCR. While its Caco-2 permeability and solubility are poor, the strong binding and good BBB offset these concerns. Ligand B has better metabolic stability and lower DILI/hERG risk, but its low logP and significantly weaker binding affinity are major drawbacks, especially given the importance of potency for GPCR targets. The poor BBB penetration is also a critical issue.

Output:
1
2025-04-17 04:20:53,862 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (348.531 and 347.419 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (49.41) is excellent, well below the 90 A^2 threshold for CNS targets. Ligand B (110.32) is higher, but still potentially acceptable, though less ideal.

**3. logP:** Ligand A (3.912) is within the optimal range (1-3). Ligand B (0.041) is very low, which is a significant concern for membrane permeability and CNS penetration.

**4. H-Bond Donors:** Both have acceptable HBD counts (1 and 2, respectively), well below the threshold of 5.

**5. H-Bond Acceptors:** Ligand A (2) and Ligand B (5) are both within the acceptable range of <=10.

**6. QED:** Both ligands have good QED scores (0.723 and 0.783), indicating good drug-like properties.

**7. DILI:** Ligand A (18.883) has a much lower DILI risk than Ligand B (43.66). This is a significant advantage.

**8. BBB:** Ligand A (82.164) has a very good BBB penetration percentile, exceeding the desirable >70% for CNS targets. Ligand B (55.138) is considerably lower and less favorable for CNS activity.

**9. Caco-2:** Ligand A (-4.358) and Ligand B (-5.487) both have negative Caco-2 values, which is unusual and suggests poor permeability. However, these values are on a scale where negative values are possible, and direct comparison is difficult without knowing the scale's range.

**10. Solubility:** Ligand A (-4.229) and Ligand B (-2.339) both have negative solubility values, which is also unusual and suggests poor solubility.

**11. hERG:** Both ligands have very low hERG inhibition liability (0.562 and 0.132), which is excellent.

**12. Cl_mic:** Ligand A (90.378) has a higher microsomal clearance than Ligand B (-1.19). This suggests Ligand B is more metabolically stable, which is a positive.

**13. t1/2:** Ligand A (13.023) has a longer in vitro half-life than Ligand B (15.254). This is a positive for Ligand A.

**14. Pgp:** Ligand A (0.188) has lower P-gp efflux liability than Ligand B (0.012), which is favorable for CNS exposure.

**15. Binding Affinity:** Both ligands have excellent binding affinities (-8.0 and -8.7 kcal/mol). The difference of 0.7 kcal/mol is not substantial enough to outweigh other significant differences.

**Overall Assessment:**

Ligand A is the stronger candidate. While both have good affinity, Ligand A excels in critical areas for a CNS-targeting GPCR ligand: TPSA, logP, BBB penetration, and DILI risk. Ligand B's very low logP is a major drawback, likely hindering its ability to cross the blood-brain barrier despite its slightly better metabolic stability. The better BBB and lower DILI of Ligand A are decisive factors.

Output:
1
2025-04-17 04:20:53,862 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (360.391 and 341.455 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (97.64) is higher than the preferred <90 for CNS targets, but still potentially acceptable. Ligand B (53.51) is excellent, well below 90.

**3. logP:** Both ligands (2.602 and 2.038) are within the optimal 1-3 range.

**4. H-Bond Donors:** Ligand A has 2 HBD, which is acceptable. Ligand B has 0, also acceptable.

**5. H-Bond Acceptors:** Ligand A has 6 HBA, within the limit of 10. Ligand B has 3, also within the limit.

**6. QED:** Both ligands have good QED scores (0.679 and 0.845), indicating drug-like properties.

**7. DILI:** Ligand A has a very high DILI risk (99.031), which is a significant concern. Ligand B has a low DILI risk (10.237), a major advantage.

**8. BBB:** Ligand A has a BBB penetration of 52.811, which is below the desirable >70 for CNS targets. Ligand B has excellent BBB penetration (92.168), a crucial advantage for a DRD2 ligand.

**9. Caco-2:** Both have negative Caco-2 values which is unusual, but we can assume they represent low permeability.

**10. Solubility:** Both have negative solubility values, which is also unusual.

**11. hERG:** Both ligands have low hERG inhibition liability (0.674 and 0.315), which is good.

**12. Cl_mic:** Ligand A has a lower microsomal clearance (21.214) than Ligand B (62.4), suggesting better metabolic stability.

**13. t1/2:** Ligand A has a longer in vitro half-life (84.703) than Ligand B (-21.386), which is a positive.

**14. Pgp:** Ligand A has a low Pgp efflux liability (0.244), which is good. Ligand B also has a low Pgp efflux liability (0.149), also good.

**15. Binding Affinity:** Both ligands have excellent binding affinities (-9.7 and -9.0 kcal/mol). The difference of 0.7 kcal/mol is not substantial enough to outweigh other significant differences.

**Overall Assessment:**

While Ligand A has a slightly better half-life and metabolic stability, its extremely high DILI risk and suboptimal BBB penetration are major drawbacks. Ligand B excels in BBB penetration, has a very low DILI risk, and acceptable metabolic stability. Considering the GPCR-specific priorities, particularly BBB for a CNS target like DRD2, and the importance of minimizing toxicity (DILI), Ligand B is the more promising candidate.

Output:
1
2025-04-17 04:20:53,862 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (358.463 and 362.905 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (69.64) is higher than Ligand B (51.14). For a CNS target like DRD2, TPSA should be <=90, so both are acceptable, but B is better.

**3. logP:** Ligand A (2.513) is within the optimal range (1-3). Ligand B (4.28) is slightly above, potentially raising concerns about solubility and off-target effects, but still within a tolerable range.

**4. H-Bond Donors:** Ligand A (2) is acceptable. Ligand B (0) is also good.

**5. H-Bond Acceptors:** Ligand A (4) is acceptable. Ligand B (5) is also acceptable.

**6. QED:** Both ligands have reasonable QED values (0.834 and 0.688), indicating good drug-like properties.

**7. DILI:** Ligand A (54.556) has a higher DILI risk than Ligand B (29.546). This is a significant advantage for Ligand B.

**8. BBB:** Ligand B (74.758) has a significantly better BBB penetration percentile than Ligand A (64.793). This is crucial for a CNS target like DRD2.

**9. Caco-2 Permeability:** Both have negative values, which is unusual and suggests poor permeability. However, the scale is not specified, so it's hard to interpret.

**10. Aqueous Solubility:** Both have negative values, suggesting poor solubility. Again, the scale is not specified.

**11. hERG Inhibition:** Both ligands have low hERG inhibition risk (0.579 and 0.786).

**12. Microsomal Clearance:** Ligand B (73.896) has a higher microsomal clearance than Ligand A (43.617), indicating lower metabolic stability. This is a drawback for Ligand B.

**13. In vitro Half-Life:** Ligand A (34.829) has a longer in vitro half-life than Ligand B (21.682). This is a positive for Ligand A.

**14. P-gp Efflux:** Ligand A (0.54) shows lower P-gp efflux liability than Ligand B (0.312), which is favorable for CNS penetration.

**15. Binding Affinity:** Ligand A (-9.1 kcal/mol) has a significantly stronger binding affinity than Ligand B (-6.6 kcal/mol). This is a substantial advantage for Ligand A, potentially outweighing some of its ADME drawbacks.

**Overall Assessment:**

While Ligand B has better BBB penetration and a lower DILI risk, the significantly stronger binding affinity of Ligand A (-9.1 vs -6.6 kcal/mol) is a major advantage. For a GPCR target, strong binding is paramount. The slightly higher TPSA and lower BBB of Ligand A are less concerning given its superior affinity. The longer half-life and lower P-gp efflux also support Ligand A.

Output:
1
2025-04-17 04:20:53,862 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (351.324 and 368.587 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (51.47) is better than Ligand B (49.41) as both are below the 90 A^2 threshold for CNS targets.

**3. logP:** Both ligands have a logP around 3.6-3.7, which is within the optimal range of 1-3.

**4. H-Bond Donors:** Both have 1 HBD, which is acceptable (<=5).

**5. H-Bond Acceptors:** Both have 3 HBA, which is acceptable (<=10).

**6. QED:** Ligand A (0.918) has a significantly better QED score than Ligand B (0.64), indicating a more drug-like profile.

**7. DILI:** Ligand A (48.197) has a better DILI score than Ligand B (19.349), indicating lower potential for liver injury.

**8. BBB:** Ligand A (94.998) has a significantly higher BBB percentile than Ligand B (83.249), which is crucial for a CNS target like DRD2.

**9. Caco-2 Permeability:** Ligand A (-4.4) and Ligand B (-5.083) both have negative values, which is difficult to interpret without knowing the scale. However, lower values are generally worse.

**10. Aqueous Solubility:** Ligand A (-4.281) and Ligand B (-4.042) both have negative values, which is difficult to interpret without knowing the scale. However, lower values are generally worse.

**11. hERG Inhibition:** Both ligands have similar hERG inhibition liability (0.71 and 0.719), which is acceptable.

**12. Microsomal Clearance:** Ligand B (92.352) has a higher microsomal clearance than Ligand A (39.095), suggesting lower metabolic stability.

**13. In vitro Half-Life:** Ligand A (38.645) has a longer in vitro half-life than Ligand B (-13.037), which is desirable.

**14. P-gp Efflux:** Both ligands have similar P-gp efflux liability (0.347 and 0.327), which is acceptable.

**15. Binding Affinity:** Ligand B (-7.6 kcal/mol) has a significantly better binding affinity than Ligand A (-10.4 kcal/mol). This is a substantial advantage.

**Overall Assessment:**

While Ligand B has a better binding affinity, Ligand A excels in almost all other crucial ADME properties, particularly BBB penetration, QED, DILI, and metabolic stability (lower Cl_mic and longer t1/2). The substantial difference in BBB (94.998 vs 83.249) is a major advantage for a CNS target. The better QED and DILI scores also contribute to a more favorable drug profile. The affinity difference, while significant, might be overcome with further optimization of Ligand A, given its superior overall profile.

Output:
0
2025-04-17 04:20:53,862 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (337.467 Da) is slightly lower, which could be beneficial for permeability.

**TPSA:** Ligand A (57.78) is excellent for CNS penetration, well below the 90 A^2 threshold. Ligand B (91.76) is higher, but still potentially acceptable, though less ideal.

**logP:** Ligand A (4.723) is at the upper end of the optimal range, potentially leading to solubility issues or off-target interactions. Ligand B (1.737) is within the optimal range, favoring permeability and reducing off-target risk.

**H-Bond Donors/Acceptors:** Both ligands have 2 HBDs, which is good. Ligand A has 2 HBAs, while Ligand B has 5. Both are within acceptable limits (<=10), but Ligand A is slightly better.

**QED:** Both ligands have QED values around 0.6-0.7, indicating reasonable drug-likeness.

**DILI:** Ligand A (51.842) has a moderate DILI risk. Ligand B (20.9) has a very low DILI risk, a significant advantage.

**BBB:** Ligand A (77.162) has good BBB penetration, exceeding the 70% threshold. Ligand B (54.052) is below this threshold, which is a major drawback for a CNS target.

**Caco-2 Permeability:** Both have negative Caco-2 values which is unusual and suggests a potential issue with the data or the model.

**Aqueous Solubility:** Both have negative solubility values, which is also unusual and suggests a potential issue with the data or the model.

**hERG:** Both ligands have low hERG inhibition liability, which is good.

**Microsomal Clearance:** Ligand A (67.181) has higher clearance than Ligand B (35.544), suggesting lower metabolic stability.

**In vitro Half-Life:** Ligand B (-22.31) has a significantly longer half-life than Ligand A (-9.858).

**P-gp Efflux:** Ligand A (0.607) has lower P-gp efflux liability than Ligand B (0.065), which is favorable for CNS exposure.

**Binding Affinity:** Ligand A (-10.2 kcal/mol) has a substantially stronger binding affinity than Ligand B (-7.0 kcal/mol). This is a major advantage, potentially outweighing some of its other drawbacks.

**Overall Assessment:**

Ligand A excels in binding affinity and BBB penetration, and has acceptable TPSA and P-gp efflux. However, its higher logP and DILI risk are concerns. Ligand B has a better safety profile (lower DILI) and metabolic stability (longer half-life), but suffers from poor BBB penetration and substantially weaker binding affinity.

Given the importance of CNS penetration for a DRD2 ligand (targeting CNS disorders), and the significant advantage in binding affinity for Ligand A, I believe **Ligand A** is the more promising candidate, despite its slightly higher logP and DILI risk. The strong binding affinity could allow for a lower dose, potentially mitigating the DILI risk. The better BBB penetration is crucial for CNS efficacy.

Output:
0
2025-04-17 04:20:53,862 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 drug candidates, considering the provided guidelines and GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight (MW):** Both ligands (342.395 and 345.487 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (80.68) is better than Ligand B (52.65). For CNS targets, we want TPSA <= 90, both are within this range, but A is closer to the upper limit.

**3. logP:** Ligand A (3.75) is within the optimal range (1-3), while Ligand B (1.771) is at the lower end. Lower logP can hinder permeation.

**4. H-Bond Donors (HBD):** Both ligands have acceptable HBD counts (2 and 1, respectively), well below the threshold of 5.

**5. H-Bond Acceptors (HBA):** Both ligands have acceptable HBA counts (5 and 3, respectively), well below the threshold of 10.

**6. QED:** Both ligands have similar and good QED values (0.797 and 0.793), indicating good drug-like properties.

**7. DILI:** Ligand B (29.081) has a significantly lower DILI risk than Ligand A (71.423). This is a substantial advantage for Ligand B.

**8. BBB:** Ligand B (70.919) has a better BBB penetration percentile than Ligand A (38.426). This is *critical* for a CNS target like DRD2.

**9. Caco-2 Permeability:** Both have negative values, indicating poor permeability.

**10. Aqueous Solubility:** Both have negative values, indicating poor solubility.

**11. hERG Inhibition:** Both ligands have low hERG inhibition risk (0.12 and 0.362, respectively).

**12. Microsomal Clearance (Cl_mic):** Ligand A (23.209) has lower microsomal clearance than Ligand B (33.13), suggesting better metabolic stability.

**13. In vitro Half-Life:** Ligand A (-25.232) has a negative half-life, which is not possible. Ligand B (-4.986) also has a negative half-life, which is not possible.

**14. P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.042 and 0.066, respectively).

**15. Binding Affinity:** Ligand A (-8.2 kcal/mol) has a slightly better binding affinity than Ligand B (-7.7 kcal/mol). The difference is 0.5 kcal/mol, which is significant but not overwhelming.

**Overall Assessment:**

While Ligand A has a slightly better binding affinity and metabolic stability, Ligand B is significantly better in terms of safety (DILI) and, crucially, BBB penetration. For a CNS target like DRD2, BBB penetration is paramount. The lower DILI risk is also a major advantage. The slightly weaker binding affinity of Ligand B can potentially be optimized in subsequent iterations. The negative half-life values are concerning for both, and would require further investigation.

Output:
1
2025-04-17 04:20:53,862 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (350.503 and 367.921 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (78.43) is better than Ligand B (47.36) as it is closer to the ideal TPSA for CNS targets (<=90). Ligand B is excellent.

**3. logP:** Both ligands have good logP values (2.231 and 3.798), falling within the optimal 1-3 range. Ligand B is slightly higher, which could be a minor concern, but still acceptable.

**4. H-Bond Donors:** Ligand A has 3 HBD, which is acceptable. Ligand B has 0, which is also acceptable.

**5. H-Bond Acceptors:** Both ligands have acceptable HBA counts (3 and 4, respectively), below the threshold of 10.

**6. QED:** Both ligands have good QED scores (0.597 and 0.702), indicating good drug-like properties.

**7. DILI:** Ligand A (13.959) has a significantly lower DILI risk than Ligand B (16.092), which is a positive attribute.

**8. BBB:** This is a critical parameter for CNS targets. Ligand B (87.631) has a much higher BBB penetration percentile than Ligand A (48.003). This is a major advantage for Ligand B.

**9. Caco-2 Permeability:** Both have negative values, which is unusual. However, the magnitude of the negative value for Ligand A (-4.861) is more negative than Ligand B (-4.662), suggesting potentially worse permeability for Ligand A.

**10. Aqueous Solubility:** Both have negative values, which is also unusual. Ligand A (-3.361) is slightly worse than Ligand B (-2.874).

**11. hERG Inhibition:** Ligand A (0.278) has a lower hERG inhibition liability than Ligand B (0.661), which is preferable.

**12. Microsomal Clearance:** Ligand B (77.685) has a higher microsomal clearance than Ligand A (42.79), indicating faster metabolism and potentially lower exposure.

**13. In vitro Half-Life:** Ligand B (16.213) has a longer in vitro half-life than Ligand A (-13.256), which is a positive attribute.

**14. P-gp Efflux:** Ligand A (0.123) has lower P-gp efflux liability than Ligand B (0.685), which is beneficial for CNS exposure.

**15. Binding Affinity:** Ligand A (-8.4 kcal/mol) has a significantly stronger binding affinity than Ligand B (-7.0 kcal/mol). This is a substantial advantage for Ligand A.

**Overall Assessment:**

While Ligand B excels in BBB penetration and has a better half-life, Ligand A has a significantly better binding affinity and lower DILI risk. The stronger binding affinity of Ligand A is a major advantage, and a 1.4 kcal/mol difference can often outweigh minor ADME drawbacks, especially for a GPCR target where achieving sufficient target engagement is crucial. The lower DILI risk is also a significant positive. The slightly worse BBB and solubility of Ligand A are concerns, but might be addressable with further optimization. The P-gp efflux is also better for Ligand A.

Output:
0
2025-04-17 04:20:53,862 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (346.431 and 338.415 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (82.08) is excellent, well below the 90 A^2 threshold for CNS targets. Ligand B (95.59) is still reasonable but less optimal, approaching the 100 A^2 limit.

**logP:** Ligand A (0.77) is a bit low, potentially hindering permeability. Ligand B (2.205) is much better, falling within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A (1 HBD, 4 HBA) is good. Ligand B (3 HBD, 6 HBA) is also acceptable, though slightly higher.

**QED:** Ligand A (0.721) has a strong drug-like profile. Ligand B (0.504) is acceptable, but lower than Ligand A.

**DILI:** Ligand A (32.842) has a very low DILI risk, excellent. Ligand B (69.95) is higher, indicating a moderate risk, but still not alarming.

**BBB:** Ligand A (57.736) has a moderate BBB penetration, which is a concern for a CNS target. Ligand B (67.313) is also moderate, but slightly better. Both are below the desirable >70 percentile.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.039 and -5.453), which is unusual and suggests poor permeability. This is a significant drawback for both.

**Aqueous Solubility:** Both ligands have negative solubility values (-2.049 and -3.431), which is also unusual and suggests poor solubility. This is a significant drawback for both.

**hERG Inhibition:** Ligand A (0.102) has very low hERG inhibition risk, excellent. Ligand B (0.613) has a slightly higher risk, but still relatively low.

**Microsomal Clearance:** Ligand A (10.339) has lower clearance, suggesting better metabolic stability. Ligand B (57.708) has significantly higher clearance, indicating faster metabolism.

**In vitro Half-Life:** Ligand A (-12.301) has a negative half-life, which is impossible and indicates a data error. Ligand B (0.562) has a very short half-life, which is undesirable.

**P-gp Efflux:** Ligand A (0.01) has very low P-gp efflux, excellent. Ligand B (0.178) has slightly higher efflux, but still relatively low.

**Binding Affinity:** Ligand B (-9.3 kcal/mol) has a significantly stronger binding affinity than Ligand A (-8.3 kcal/mol). This 1 kcal/mol difference is substantial.

**Overall Assessment:**

While both ligands have issues with Caco-2 permeability and solubility, Ligand B is the more promising candidate. Its superior logP, significantly stronger binding affinity, and slightly better BBB penetration outweigh its higher DILI risk and faster clearance. The negative half-life for ligand A is a critical flaw. The lower P-gp efflux for ligand A is a plus, but not enough to overcome the affinity difference and the half-life issue.

Output:
1
2025-04-17 04:20:53,863 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 drug candidates, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (343.431 and 357.426 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (82.23) is excellent, well below the 90 A^2 threshold for CNS targets. Ligand B (98.74) is still reasonable but less optimal, approaching the 100 A^2 limit.

**logP:** Ligand A (1.363) is within the optimal 1-3 range. Ligand B (0.122) is quite low, potentially hindering membrane permeability.

**H-Bond Donors/Acceptors:** Ligand A (0 HBD, 5 HBA) is favorable. Ligand B (3 HBD, 4 HBA) is also acceptable, though the 3 HBDs are slightly higher.

**QED:** Ligand A (0.808) has a very good drug-likeness score. Ligand B (0.511) is acceptable, but lower than Ligand A.

**DILI:** Ligand A (35.479) has a low DILI risk. Ligand B (10.818) has an even lower DILI risk, which is positive.

**BBB:** Ligand A (73.827) has a good BBB penetration percentile. Ligand B (66.227) is lower, which is a significant drawback for a CNS target.

**Caco-2 Permeability:** Ligand A (-4.789) has poor Caco-2 permeability. Ligand B (-5.266) is similarly poor.

**Aqueous Solubility:** Both ligands have very poor aqueous solubility (-1.641 and -1.514 respectively). This could pose formulation challenges.

**hERG:** Both ligands have very low hERG inhibition risk (0.194 and 0.36 respectively).

**Microsomal Clearance:** Ligand A (25.218) has moderate clearance. Ligand B (-35.729) has negative clearance, which is not possible and likely indicates an error or outlier in the data. This is a major red flag.

**In vitro Half-Life:** Ligand A (-5.897) has a negative half-life, which is not possible and suggests data issues. Ligand B (9.149) has a reasonable half-life.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.04 and 0.009 respectively), which is favorable for CNS penetration.

**Binding Affinity:** Ligand A (-8.5 kcal/mol) has a significantly stronger binding affinity than Ligand B (-7.6 kcal/mol). This 0.9 kcal/mol difference is substantial.

**Overall Assessment:**

Despite the poor solubility and Caco-2 permeability for both, Ligand A is the stronger candidate. Its superior binding affinity, better BBB penetration, and higher QED outweigh the slightly higher TPSA. However, the negative values for clearance and half-life are concerning and require further investigation. Ligand B's negative clearance and half-life are highly problematic and suggest unreliable data. The lower logP is also a concern.

Output:
1
2025-04-17 04:20:53,863 - INFO - Reasoning:

Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (349.43 and 364.56 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (79.98) is better than Ligand B (49.41). Both are below the 90 A^2 threshold desirable for CNS targets, but A is closer to the upper limit.

**3. logP:** Ligand A (3.012) is within the optimal 1-3 range. Ligand B (4.518) is slightly higher, potentially increasing off-target effects and decreasing solubility.

**4. H-Bond Donors:** Both have 1 HBD, which is acceptable.

**5. H-Bond Acceptors:** Ligand A has 5 HBA, and Ligand B has 3. Both are below the 10 threshold.

**6. QED:** Both ligands have similar QED values (0.604 and 0.621), indicating good drug-likeness.

**7. DILI:** Ligand A (52.152) has a slightly higher DILI risk than Ligand B (35.479), but both are below the concerning 60 threshold.

**8. BBB:** Ligand A (70.609) and Ligand B (69.407) are both reasonably good for BBB penetration, being just above 60%. However, A is slightly better.

**9. Caco-2 Permeability:** Ligand A (-4.203) has better Caco-2 permeability than Ligand B (-4.895).

**10. Aqueous Solubility:** Ligand A (-3.241) has better aqueous solubility than Ligand B (-3.898).

**11. hERG Inhibition:** Both ligands show low hERG inhibition risk (0.265 and 0.525).

**12. Microsomal Clearance:** Ligand A (99.848) has significantly lower microsomal clearance than Ligand B (115.552), suggesting better metabolic stability.

**13. In vitro Half-Life:** Ligand A (13.725) has a shorter in vitro half-life than Ligand B (48.436). This is a drawback for Ligand A.

**14. P-gp Efflux:** Ligand A (0.325) shows lower P-gp efflux than Ligand B (0.361), which is favorable for CNS penetration.

**15. Binding Affinity:** Ligand B (-7.5 kcal/mol) has a slightly better binding affinity than Ligand A (-7.2 kcal/mol). This 0.3 kcal/mol difference is significant.

**Overall Assessment:**

While Ligand B has a slightly better binding affinity and longer half-life, Ligand A demonstrates superior properties in several key areas critical for a CNS-targeting GPCR ligand: better TPSA, logP, Caco-2 permeability, aqueous solubility, lower microsomal clearance, and lower P-gp efflux. The slightly better BBB penetration of Ligand A is also a plus. The difference in binding affinity (0.3 kcal/mol) is not substantial enough to outweigh the more favorable ADME profile of Ligand A.

Output:
1
2025-04-17 04:20:53,863 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (365.909 Da and 352.475 Da) fall within the ideal range of 200-500 Da.

**TPSA:** Ligand A (61.36) is better than Ligand B (67.87). Both are below the 90 A^2 threshold for CNS targets, but A is closer to the ideal.

**logP:** Both ligands have good logP values (2.536 and 1.891 respectively), falling within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Both have 1 HBD, which is good. Ligand A has 5 HBA, while Ligand B has 4. Both are within the acceptable limit of <=10.

**QED:** Both ligands have similar QED values (0.785 and 0.767), indicating good drug-likeness.

**DILI:** Ligand A (22.838) has a significantly lower DILI risk than Ligand B (31.989). This is a substantial advantage.

**BBB:** Ligand A (92.943) has a much higher BBB penetration percentile than Ligand B (68.786). This is *critical* for a CNS target like DRD2.

**Caco-2 Permeability:** Ligand A (-5.099) is worse than Ligand B (-4.682), indicating lower intestinal absorption. However, for a CNS target, intestinal absorption is less crucial than BBB penetration.

**Aqueous Solubility:** Ligand A (-2.577) is worse than Ligand B (-1.26), suggesting lower solubility.

**hERG Inhibition:** Ligand A (0.577) has a slightly higher hERG inhibition risk than Ligand B (0.192), but both are relatively low.

**Microsomal Clearance:** Ligand B (31.256) has a higher microsomal clearance than Ligand A (11.407), indicating lower metabolic stability.

**In vitro Half-Life:** Ligand A (26.538) has a longer in vitro half-life than Ligand B (12.691).

**P-gp Efflux:** Ligand A (0.034) exhibits lower P-gp efflux than Ligand B (0.036), which is favorable for CNS penetration.

**Binding Affinity:** Ligand A (-8.7 kcal/mol) has *significantly* stronger binding affinity than Ligand B (0.0 kcal/mol). This is a decisive advantage.

**Conclusion:**

Despite slightly worse Caco-2 permeability and aqueous solubility, Ligand A is a far superior candidate. Its substantially better BBB penetration, lower DILI risk, longer half-life, lower P-gp efflux, and *much* stronger binding affinity outweigh these minor drawbacks. The strong binding affinity is particularly important, and the excellent BBB penetration is essential for a CNS-targeting drug.

Output:
1
2025-04-17 04:20:53,863 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (358.5 & 382.6 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Both ligands have a TPSA of 58.2, which is excellent for CNS penetration (well below the 90 A^2 threshold).

**3. logP:** Both ligands have logP values (4.085 & 3.769) within the optimal 1-3 range, though slightly on the higher end. This isn't a major concern, but should be monitored.

**4. H-Bond Donors:** Both have 2 HBD, which is acceptable.

**5. H-Bond Acceptors:** Ligand A has 3 HBA, and Ligand B has 4 HBA, both are within the acceptable limit of 10.

**6. QED:** Ligand A (0.747) has a slightly better QED score than Ligand B (0.673), indicating a more drug-like profile.

**7. DILI:** Ligand A (52.97%) has a slightly higher DILI risk than Ligand B (47.27%), but both are below the concerning 60% threshold.

**8. BBB:** Ligand B (71.811%) shows better predicted BBB penetration than Ligand A (64.831%), which is a crucial factor for a CNS target like DRD2.

**9. Caco-2 Permeability:** Both have negative Caco-2 values (-5.14 and -5.044), which is unusual and suggests poor permeability. This is a significant drawback for both.

**10. Aqueous Solubility:** Both have very poor aqueous solubility (-4.15 and -4.791). This is a major formulation challenge.

**11. hERG Inhibition:** Both have low hERG inhibition risk (0.731 and 0.683).

**12. Microsomal Clearance:** Ligand B (89.83) has a higher microsomal clearance than Ligand A (78.19), suggesting faster metabolism and potentially lower *in vivo* exposure.

**13. In vitro Half-Life:** Ligand A (77.335 hours) has a significantly longer half-life than Ligand B (37.619 hours), which is a major advantage.

**14. P-gp Efflux:** Both have low P-gp efflux liability (0.518 and 0.395), which is good for CNS exposure.

**15. Binding Affinity:** Ligand B (-7.9 kcal/mol) has a substantially stronger binding affinity than Ligand A (-9.2 kcal/mol). This is a significant advantage, potentially outweighing some of the ADME concerns.

**Overall Assessment:**

While both compounds have significant ADME liabilities (poor solubility and permeability), Ligand B's much stronger binding affinity (-7.9 vs -9.2 kcal/mol) and better BBB penetration (71.8% vs 64.8%) are compelling. The longer half-life of Ligand A is attractive, but the affinity difference is substantial. Given the GPCR-specific priorities, the stronger binding and improved BBB penetration of Ligand B are more important than the slightly better QED and half-life of Ligand A.

Output:
1
2025-04-17 04:20:53,863 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (379.913 Da) is slightly higher than Ligand B (348.403 Da), but both are acceptable.

**TPSA:** Ligand A (55.2) is excellent for CNS penetration, well below the 90 A^2 threshold. Ligand B (113.44) is higher, but still potentially acceptable, though less ideal.

**logP:** Ligand A (3.069) is optimal. Ligand B (-0.05) is significantly low, which could hinder membrane permeability and potentially reduce binding affinity.

**H-Bond Donors/Acceptors:** Ligand A (0 HBD, 5 HBA) is favorable. Ligand B (3 HBD, 6 HBA) is also acceptable, but more polar.

**QED:** Both ligands have reasonable QED values (A: 0.822, B: 0.664), indicating good drug-like properties.

**DILI:** Ligand A (60.45) is approaching a concerning DILI risk, while Ligand B (42.652) is much lower and safer.

**BBB:** Ligand A (86.817) has excellent BBB penetration potential. Ligand B (45.599) is significantly lower, making CNS exposure less likely. This is a crucial factor for a DRD2 ligand.

**Caco-2:** Both have negative Caco-2 values which is unusual, but suggests poor permeability.

**Solubility:** Both ligands have negative solubility values, which is also unusual.

**hERG:** Both ligands have very low hERG inhibition risk (A: 0.61, B: 0.082).

**Cl_mic:** Ligand A (24.956) has a moderate clearance, while Ligand B (6.126) has a very low clearance, suggesting better metabolic stability.

**t1/2:** Ligand A (3.282) has a short half-life, while Ligand B (21.246) has a much longer half-life.

**Pgp:** Ligand A (0.498) has low P-gp efflux, which is good for CNS penetration. Ligand B (0.008) has extremely low P-gp efflux, which is even better.

**Binding Affinity:** Both ligands have excellent binding affinities (A: -8.7 kcal/mol, B: -8.3 kcal/mol). Ligand A is slightly stronger, but the difference is relatively small.

**Overall Assessment:**

Ligand A excels in BBB penetration, logP, and binding affinity, which are critical for a DRD2 ligand. However, its DILI risk is higher, and its metabolic clearance is faster. Ligand B has better metabolic stability (lower Cl_mic, longer t1/2) and a lower DILI risk, but its logP is poor and its BBB penetration is significantly lower.

Given the importance of CNS penetration for DRD2, and the relatively small difference in binding affinity, Ligand A is the more promising candidate *despite* the slightly elevated DILI risk and lower metabolic stability. These can be addressed in subsequent optimization rounds. The poor logP of Ligand B is a more fundamental issue that would be harder to resolve.

Output:
1
2025-04-17 04:20:53,864 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (357.479 and 364.471 Da) fall within the ideal range of 200-500 Da.

**TPSA:** Ligand A (71.09) is significantly better than Ligand B (77.53). For CNS targets, we want TPSA <= 90, and A is closer to the ideal <=60.

**logP:** Both ligands have good logP values (3.007 and 2.216), falling within the optimal 1-3 range.

**H-Bond Donors:** Both have 2 HBD, which is acceptable.

**H-Bond Acceptors:** Ligand A has 4 HBA, while Ligand B has 8.  Lower is generally better, and A is preferable.

**QED:** Ligand A (0.864) has a much better QED score than Ligand B (0.626), indicating a more drug-like profile.

**DILI:** Ligand A (48.895) has a significantly lower DILI risk than Ligand B (85.653). This is a major advantage for A.

**BBB:** Ligand A (58.278) has a lower BBB penetration than Ligand B (64.25). While both are below the desirable >70 for CNS targets, B is slightly better.

**Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and suggests poor permeability. However, the scale isn't specified, so it's hard to interpret.

**Aqueous Solubility:** Both have negative solubility values, which is also unusual and suggests poor solubility.

**hERG:** Both ligands have low hERG inhibition liability (0.414 and 0.871), which is good.

**Microsomal Clearance:** Ligand A (11.934) has a lower microsomal clearance than Ligand B (86.572), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (35.777) has a shorter half-life than Ligand B (63.875).

**P-gp Efflux:** Ligand A (0.119) has significantly lower P-gp efflux liability than Ligand B (0.191), which is crucial for CNS penetration.

**Binding Affinity:** Ligand A (-9.2 kcal/mol) has a substantially stronger binding affinity than Ligand B (-6.1 kcal/mol). This is a very significant advantage, potentially outweighing some of the ADME drawbacks.

**Overall Assessment:**

Ligand A is clearly superior. Its significantly better binding affinity, lower DILI risk, lower P-gp efflux, lower TPSA, better QED, and lower microsomal clearance outweigh its slightly lower BBB penetration and shorter half-life. The stronger binding affinity is particularly important for a GPCR target. While both ligands have issues with Caco-2 and solubility, the overall profile of A is much more promising.

Output:
1
2025-04-17 04:20:53,864 - INFO - Batch 105 complete. Total preferences: 1680
2025-04-17 04:20:53,864 - INFO - Processing batch 106/512...
2025-04-17 04:21:36,763 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 drug candidates, considering the provided guidelines and GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (350.415 and 342.483 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (96.89) is better than Ligand B (49.41). For CNS targets, TPSA should be <=90, so both are acceptable, but A is closer to the upper limit.

**logP:** Ligand B (3.029) is optimal (1-3), while Ligand A (0.263) is significantly low, potentially hindering membrane permeability. This is a major drawback for Ligand A.

**H-Bond Donors/Acceptors:** Ligand A (HBD=3, HBA=5) is slightly higher in both counts than Ligand B (HBD=1, HBA=2), but both are within acceptable limits.

**QED:** Ligand B (0.854) has a superior QED score compared to Ligand A (0.555), indicating a more drug-like profile.

**DILI:** Both ligands have acceptable DILI risk (Ligand A: 34.238, Ligand B: 40.054), below the 60 threshold.

**BBB:** Ligand B (69.523) has a significantly better BBB percentile than Ligand A (36.836). For a CNS target like DRD2, >70 is desirable, but Ligand B is a much better starting point than Ligand A.

**Caco-2 Permeability:** Both have negative Caco-2 values (-5.145 and -4.996), which is unusual and suggests poor permeability. However, these values are on a different scale and may not be directly comparable.

**Aqueous Solubility:** Both have negative solubility values (-1.376 and -4.541) which is also unusual.

**hERG:** Both ligands show low hERG inhibition liability (Ligand A: 0.334, Ligand B: 0.294).

**Microsomal Clearance:** Ligand A (15.418 mL/min/kg) has a lower (better) microsomal clearance than Ligand B (51.015 mL/min/kg), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (12.45 hours) has a longer half-life than Ligand B (5.24 hours), which is preferable.

**P-gp Efflux:** Ligand A (0.064) has significantly lower P-gp efflux liability than Ligand B (0.408), which is beneficial for CNS penetration.

**Binding Affinity:** Ligand B (-9.0 kcal/mol) has a substantially stronger binding affinity than Ligand A (-7.9 kcal/mol). This difference of 1.1 kcal/mol is significant and can outweigh some ADME drawbacks.

**Overall Assessment:**

While Ligand A has advantages in metabolic stability (Cl_mic), half-life, and P-gp efflux, its extremely low logP and poor BBB penetration are major concerns for a CNS-targeting drug. Ligand B, despite having higher P-gp efflux and lower metabolic stability, possesses a much more favorable logP, significantly better BBB penetration, and a substantially stronger binding affinity. The higher affinity of Ligand B is a critical advantage for GPCRs.

Output:
1
2025-04-17 04:21:36,764 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (368.905 and 340.431 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (69.64) is significantly better than Ligand B (106.75). For CNS targets, we want TPSA <= 90, so Ligand A is preferable.

**3. logP:** Both ligands have good logP values (2.568 and 2.705), falling within the optimal 1-3 range.

**4. H-Bond Donors:** Ligand A (2) and Ligand B (3) are both acceptable, being <= 5.

**5. H-Bond Acceptors:** Ligand A (3) is better than Ligand B (7). We prefer <= 10, and Ligand B is getting closer to the upper limit.

**6. QED:** Both ligands have reasonable QED values (0.783 and 0.602), both above the 0.5 threshold.

**7. DILI:** Ligand A (24.157) has a much lower DILI risk than Ligand B (55.176). Lower is better, and Ligand A is well below the 40% threshold.

**8. BBB:** Ligand B (71.733) has a significantly better BBB penetration score than Ligand A (60.527). For a CNS target like DRD2, >70 is desirable, but Ligand B is closer.

**9. Caco-2 Permeability:** Ligand A (-4.785) has a worse Caco-2 permeability than Ligand B (-5.243). Lower values indicate poorer permeability.

**10. Aqueous Solubility:** Both ligands have poor aqueous solubility (-3.369 and -3.098). This is a concern, but can sometimes be mitigated with formulation strategies.

**11. hERG Inhibition:** Ligand A (0.338) has a lower hERG inhibition liability than Ligand B (0.939), which is preferable.

**12. Microsomal Clearance:** Both ligands have similar microsomal clearance (38.467 and 38.309).

**13. In vitro Half-Life:** Ligand B (53.672) has a much longer in vitro half-life than Ligand A (2.357). This is a significant advantage.

**14. P-gp Efflux:** Ligand A (0.226) has lower P-gp efflux liability than Ligand B (0.138). Lower is better for CNS exposure.

**15. Binding Affinity:** Ligand B (-7.3) has a slightly better binding affinity than Ligand A (-8.3). While both are excellent, the 1.0 kcal/mol difference is notable.

**Overall Assessment:**

Ligand B has a better BBB score and a longer half-life, and slightly better binding affinity. However, Ligand A has a much lower TPSA, lower DILI risk, lower hERG risk, and lower P-gp efflux. Given the GPCR-specific priorities, the lower TPSA and lower toxicity liabilities of Ligand A are more important than the slightly better BBB and half-life of Ligand B. The affinity difference is not large enough to overcome the ADME advantages of Ligand A.

Output:
0
2025-04-17 04:21:36,764 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (427.32) is higher, but still acceptable. Ligand B (343.471) is slightly better.

**TPSA:** Both ligands have TPSA values below the 90 A^2 threshold desirable for CNS targets. Ligand B (62.3) is significantly better than Ligand A (77.85).

**logP:** Both ligands have logP values within the optimal range (1-3). Ligand A (3.557) is at the higher end, potentially raising concerns about off-target effects, while Ligand B (2.936) is more ideal.

**H-Bond Donors/Acceptors:** Ligand A (0 HBD, 5 HBA) is better than Ligand B (1 HBD, 3 HBA) in terms of balancing solubility and permeability.

**QED:** Both ligands have good QED scores (>0.5), indicating drug-like properties. Ligand B (0.914) is superior to Ligand A (0.632).

**DILI:** Ligand B (34.509) has a much lower DILI risk than Ligand A (80.031). This is a significant advantage.

**BBB:** Ligand B (73.866) has a better BBB penetration score than Ligand A (63.862), although both are reasonably good. For a CNS target like DRD2, maximizing BBB penetration is crucial.

**Caco-2 Permeability:** Both have negative Caco-2 values which is unusual and suggests a potential issue with the data.

**Aqueous Solubility:** Both ligands have negative solubility values which is unusual and suggests a potential issue with the data.

**hERG:** Both ligands have low hERG inhibition liability, which is good. Ligand B (0.512) is slightly better than Ligand A (0.463).

**Microsomal Clearance:** Ligand B (51.344) has a lower microsomal clearance than Ligand A (58.566), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand B (-19.511) has a negative half-life, which is impossible and indicates a data error. Ligand A (28.803) is reasonable.

**P-gp Efflux:** Ligand A (0.355) has lower P-gp efflux liability than Ligand B (0.193), which is favorable for CNS penetration.

**Binding Affinity:** Ligand B (-8.7 kcal/mol) has a significantly stronger binding affinity than Ligand A (-7.5 kcal/mol). This 1.2 kcal/mol difference is substantial and can outweigh minor ADME drawbacks.

**Overall Assessment:**

Despite the questionable Caco-2 and Solubility data, Ligand B is the stronger candidate. Its superior BBB penetration, lower DILI risk, better metabolic stability, and significantly higher binding affinity outweigh the slightly higher logP and P-gp efflux. The negative half-life for Ligand B is a major concern and suggests a data error, but the affinity difference is so large that it still warrants selection *if* the half-life can be verified. Ligand A's higher DILI risk and lower affinity are significant drawbacks.

Output:
1
2025-04-17 04:21:36,764 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (352.431 Da) is slightly lower, which could be beneficial for permeability, but both are acceptable.

**TPSA:** Ligand A (99.1) is better than Ligand B (63.05). For CNS targets, TPSA should be <= 90. Ligand A is close to the limit, while Ligand B is well within the desired range.

**logP:** Ligand A (-0.038) is quite low, potentially hindering membrane permeability. Ligand B (2.83) is optimal. This is a significant advantage for Ligand B.

**H-Bond Donors/Acceptors:** Ligand A has 3 HBD and 5 HBA, which are reasonable. Ligand B has 1 HBD and 7 HBA, also acceptable.

**QED:** Both ligands have good QED scores (Ligand A: 0.583, Ligand B: 0.844), indicating good drug-like properties. Ligand B is better.

**DILI:** Both ligands have low DILI risk (Ligand A: 24.544, Ligand B: 42.846), which is good.

**BBB:** Ligand A (44.397) has a concerningly low BBB penetration percentile. Ligand B (52.036) is also low, but better than A. For a CNS target like DRD2, >70 is desirable, and both fall significantly short. This is a major drawback for both, but more so for Ligand A.

**Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and suggests poor permeability.

**Aqueous Solubility:** Both have negative solubility values, which is also unusual and suggests poor solubility.

**hERG:** Both ligands have low hERG inhibition liability (Ligand A: 0.082, Ligand B: 0.14), which is excellent.

**Microsomal Clearance:** Ligand A (7.045) has a lower clearance than Ligand B (81.6), indicating better metabolic stability. This is a positive for Ligand A.

**In vitro Half-Life:** Ligand A (5.148) has a slightly longer half-life than Ligand B (0.821).

**P-gp Efflux:** Ligand A (0.015) has very low P-gp efflux, which is excellent for CNS penetration. Ligand B (0.085) is also low, but higher than A.

**Binding Affinity:** Ligand A (-7.2) has a slightly better binding affinity than Ligand B (-0.0). This is a substantial advantage for Ligand A.

**Overall Assessment:**

Ligand A has a better binding affinity, lower clearance, and lower P-gp efflux. However, it suffers from a very low logP and a very low BBB percentile. Ligand B has a better logP and slightly better BBB, but significantly weaker binding affinity and higher clearance.

Given the GPCR-specific priorities, BBB and logP are critical for CNS targets. While both ligands have poor BBB penetration, Ligand A's extremely low logP is a major concern, likely hindering its ability to cross cell membranes even if it avoids efflux. The significantly stronger binding affinity of Ligand A *could* potentially overcome some of these ADME issues, but the poor logP is a significant hurdle. Ligand B, despite its weaker affinity, has a more favorable logP, which is crucial for CNS penetration.

Considering the balance of properties, and the importance of logP for CNS GPCR targets, I would lean towards Ligand B as the more viable starting point for optimization, despite its weaker binding. The affinity can be improved through medicinal chemistry efforts, but fixing a poor logP is often more challenging.

Output:
1
2025-04-17 04:21:36,765 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (348.462 Da) is slightly preferred as it's closer to the lower end, potentially aiding permeability.

**TPSA:** Ligand A (52.57) is significantly better than Ligand B (88.16). For CNS targets, TPSA should be <= 90, and A is comfortably within this range, while B is approaching the upper limit. This is a significant advantage for A.

**logP:** Both ligands have good logP values (A: 3.656, B: 2.697), falling within the optimal 1-3 range. A is slightly higher, which *could* be a minor concern for solubility, but isn't a dealbreaker.

**H-Bond Donors/Acceptors:** Both have 2 HBD, which is good. Ligand B has 6 HBA compared to A's 2. While both are under the 10 limit, the lower HBA count of A is favorable for permeability.

**QED:** Both are reasonably drug-like (A: 0.853, B: 0.782), exceeding the 0.5 threshold.

**DILI:** Ligand A (8.026) has a much lower DILI risk than Ligand B (73.052). This is a substantial advantage for A.

**BBB:** Ligand A (87.127) has excellent BBB penetration, exceeding the desirable >70% threshold. Ligand B (54.478) is significantly lower, making it less likely to achieve sufficient CNS exposure. This is a critical advantage for A, given the CNS target.

**Caco-2 Permeability:** Ligand A (-4.575) has a worse Caco-2 value than Ligand B (-5.339), indicating lower intestinal absorption. However, for a CNS target, intestinal absorption is less critical than BBB penetration.

**Aqueous Solubility:** Both have similar, very poor aqueous solubility (-3.282 and -3.296). This could pose formulation challenges for both, but is less critical given the focus on CNS penetration.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (A: 0.854, B: 0.231). B is slightly better here, but the difference is not substantial.

**Microsomal Clearance:** Ligand A (19.166) has a higher microsomal clearance than Ligand B (7.459), indicating faster metabolism. This is a disadvantage for A.

**In vitro Half-Life:** Both have similar in vitro half-lives (A: 29.357, B: 29.556).

**P-gp Efflux:** Ligand A (0.25) has lower P-gp efflux liability than Ligand B (0.209), which is favorable for CNS exposure.

**Binding Affinity:** Ligand B (-8.2) has slightly better binding affinity than Ligand A (-8.9), but the difference is small (0.7 kcal/mol). Given the other factors, this difference is unlikely to be decisive.

**Overall:**

Ligand A is significantly better due to its superior TPSA, DILI risk, and, crucially, BBB penetration. While Ligand B has slightly better affinity and lower P-gp efflux, the substantial advantages of A in terms of CNS penetration and safety profile outweigh these minor benefits. The higher metabolic clearance of A is a concern, but could potentially be addressed through structural modifications.

Output:
0
2025-04-17 04:21:36,765 - INFO - Reasoning:

Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (379.32 and 343.431 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (130.88) is slightly above the optimal <90 for CNS targets, but still reasonable. Ligand B (79.38) is excellent, well below 90.

**3. logP:** Both ligands (2.051 and 2.013) are within the optimal 1-3 range.

**4. H-Bond Donors:** Both have 2 HBD, which is acceptable.

**5. H-Bond Acceptors:** Ligand A has 7 HBA, and Ligand B has 6. Both are within the acceptable limit of <=10.

**6. QED:** Ligand B (0.871) has a significantly better QED score than Ligand A (0.428), indicating a more drug-like profile.

**7. DILI:** Ligand A (88.057) has a higher DILI risk than Ligand B (51.028). Ligand B is well below the 60 threshold for high risk.

**8. BBB:** Ligand B (88.445) has a much better BBB penetration percentile than Ligand A (39.977). This is *critical* for a CNS target like DRD2.

**9. Caco-2 Permeability:** Ligand A (-5.457) has poor Caco-2 permeability, while Ligand B (-4.935) is slightly better, but still not great.

**10. Aqueous Solubility:** Both have very poor aqueous solubility (-4 and -3.664). This is a concern, but can sometimes be mitigated with formulation strategies.

**11. hERG Inhibition:** Both ligands have low hERG inhibition risk (0.621 and 0.61).

**12. Microsomal Clearance:** Ligand B (63.28) has a significantly higher microsomal clearance than Ligand A (11.766), indicating lower metabolic stability.

**13. In vitro Half-Life:** Ligand A (52.257) has a better in vitro half-life than Ligand B (11.466).

**14. P-gp Efflux:** Both have very low P-gp efflux liability (0.166 and 0.039), which is good for CNS penetration.

**15. Binding Affinity:** Ligand B (-9.9 kcal/mol) has a significantly stronger binding affinity than Ligand A (-8.8 kcal/mol). This >1.5 kcal/mol difference is substantial and can outweigh some ADME drawbacks.

**Overall Assessment:**

Ligand B is clearly the superior candidate. While both have poor solubility, Ligand B excels in the most critical areas for a CNS GPCR target: BBB penetration and binding affinity. The significantly better QED and lower DILI risk also favor Ligand B. The higher microsomal clearance is a concern, but the strong binding affinity might allow for a lower dose, potentially mitigating the impact of faster metabolism. Ligand A's poor BBB penetration and weaker binding affinity are significant drawbacks.

Output:
1
2025-04-17 04:21:36,765 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 drug candidates, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (359.773 and 341.415 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (110.0) is higher than the preferred <90 for CNS targets, while Ligand B (80.12) is comfortably below. This is a significant advantage for Ligand B.

**3. logP:** Ligand A (1.962) is within the optimal 1-3 range. Ligand B (0.433) is a bit low, potentially hindering membrane permeability.

**4. H-Bond Donors:** Both ligands have acceptable HBD counts (2 and 1 respectively), well below the limit of 5.

**5. H-Bond Acceptors:** Both ligands have acceptable HBA counts (6 and 5 respectively), well below the limit of 10.

**6. QED:** Both ligands have good QED values (0.72 and 0.806), indicating good drug-like properties.

**7. DILI:** Ligand A (96.782) has a high DILI risk, which is concerning. Ligand B (36.642) has a much lower, and acceptable, DILI risk.

**8. BBB:** Ligand A (33.579) has a very poor BBB penetration percentile, making it unlikely to reach the target in the CNS. Ligand B (60.644) is better, but still below the desirable >70 for CNS targets.

**9. Caco-2 Permeability:** Both have negative Caco-2 values (-5.686 and -5.212). These values are unusual and difficult to interpret without further context, but suggest poor permeability.

**10. Aqueous Solubility:** Both have negative solubility values (-3.032 and -2.021). Again, these are unusual and suggest very poor solubility.

**11. hERG Inhibition:** Both ligands show very low hERG inhibition risk (0.033 and 0.08).

**12. Microsomal Clearance:** Ligand A (-4.19) suggests lower clearance and better metabolic stability than Ligand B (0.256).

**13. In vitro Half-Life:** Ligand A (9.077) has a slightly longer half-life than Ligand B (-2.258).

**14. P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.043 and 0.035), which is positive for CNS penetration.

**15. Binding Affinity:** Both ligands have very similar and excellent binding affinities (-8.4 and -8.3 kcal/mol). The difference is negligible.

**Overall Assessment:**

Despite similar binding affinities, Ligand B is the more promising candidate. Its significantly lower TPSA, much lower DILI risk, and better (though still suboptimal) BBB penetration outweigh the slightly lower logP and higher clearance. Ligand A's high DILI risk and extremely poor BBB penetration are major drawbacks. The negative Caco-2 and solubility values are concerning for both, but could be artifacts of the prediction method.

Output:
1
2025-04-17 04:21:36,765 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (372.575 and 360.845 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (67.43) is significantly better than Ligand B (78.35). For CNS targets, we want TPSA <= 90, and A is closer to the optimal <=60 range. B is pushing the upper limit.

**3. logP:** Both ligands have good logP values (3.124 and 2.472), falling within the 1-3 range.

**4. H-Bond Donors:** Both have 2 HBD, which is acceptable.

**5. H-Bond Acceptors:** Ligand A has 4 HBA, and Ligand B has 5. Both are within the acceptable limit of <=10.

**6. QED:** Both ligands have good QED scores (0.652 and 0.875), indicating good drug-like properties.

**7. DILI:** Ligand A (29.081) has a much lower DILI risk than Ligand B (55.68). This is a significant advantage for A.

**8. BBB:** Ligand A (67.197) has a better BBB penetration percentile than Ligand B (35.13). This is *critical* for a CNS target like DRD2.

**9. Caco-2 Permeability:** Ligand A (-4.737) has better Caco-2 permeability than Ligand B (-5.282).

**10. Aqueous Solubility:** Both have poor aqueous solubility (-3.363 and -3.873). This could pose formulation challenges, but is less critical than BBB for a CNS target.

**11. hERG Inhibition:** Both ligands have low hERG inhibition risk (0.391 and 0.412).

**12. Microsomal Clearance:** Ligand A (70.15) has a slightly higher microsomal clearance than Ligand B (63.564), suggesting slightly lower metabolic stability.

**13. In vitro Half-Life:** Ligand B (-7.602) has a longer in vitro half-life than Ligand A (8.609).

**14. P-gp Efflux:** Both ligands have low P-gp efflux liability (0.079 and 0.055).

**15. Binding Affinity:** Ligand B (-9.0) has a significantly stronger binding affinity than Ligand A (-7.3). This is a substantial advantage. A difference of >1.5 kcal/mol can often outweigh other ADME concerns.

**Overall Assessment:**

While Ligand B boasts a superior binding affinity, Ligand A has a much more favorable ADME profile, particularly regarding BBB penetration (67.2% vs 35.1%) and DILI risk (29.1% vs 55.7%). For a CNS target like DRD2, BBB penetration is paramount. The difference in binding affinity, while significant, might be overcome with further optimization of Ligand A. The lower DILI risk of Ligand A is also a strong positive. Given the GPCR-specific priorities, the better BBB and lower toxicity profile of Ligand A are more important than the stronger binding of Ligand B.

Output:
0
2025-04-17 04:21:36,765 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (358.41 and 348.403 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (118.89) is slightly above the optimal <90 for CNS targets, but still reasonable. Ligand B (102.31) is better, falling comfortably under 90.

**3. logP:** Ligand A (-0.904) is a bit low, potentially hindering membrane permeability. Ligand B (-0.668) is also on the lower side, but slightly better than A. Both are below the optimal 1-3 range.

**4. H-Bond Donors:** Ligand A (5) is at the upper limit of the preferred range. Ligand B (2) is excellent.

**5. H-Bond Acceptors:** Both ligands (5) are within the acceptable range of <=10.

**6. QED:** Ligand B (0.706) has a significantly better QED score than Ligand A (0.421), indicating better overall drug-likeness.

**7. DILI:** Ligand A (19.542) has a much lower DILI risk than Ligand B (40.636), which is a significant advantage.

**8. BBB:** Ligand B (45.444) has a better BBB percentile than Ligand A (30.477), though both are not ideal. For a CNS target like DRD2, >70 is preferred.

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.664 and -5.187), which is unusual and suggests poor permeability. This is a concern for both.

**10. Aqueous Solubility:** Both ligands have negative solubility values (-1.271 and -1.833), indicating very poor aqueous solubility, which is a major drawback.

**11. hERG Inhibition:** Both ligands show low hERG inhibition risk (0.225 and 0.245).

**12. Microsomal Clearance:** Ligand A (-23.074) has a much lower (better) microsomal clearance than Ligand B (-16.636), suggesting greater metabolic stability.

**13. In vitro Half-Life:** Ligand B (16.686) has a slightly longer half-life than Ligand A (15.302).

**14. P-gp Efflux:** Both ligands show very low P-gp efflux liability (0.009 and 0.005).

**15. Binding Affinity:** Ligand B (-8.2 kcal/mol) has a stronger binding affinity than Ligand A (-7.7 kcal/mol). This 0.5 kcal/mol difference is significant.

**Overall Assessment:**

While Ligand B has a better QED, BBB, and binding affinity, Ligand A has a significantly lower DILI risk and better metabolic stability (lower Cl_mic). Both suffer from poor predicted solubility and permeability. However, the stronger binding affinity of Ligand B, coupled with its better QED and BBB, is more compelling, especially considering the GPCR target class. The DILI risk of Ligand A is a concern, but can potentially be addressed with further structural modifications. The poor solubility and permeability are significant challenges for both, but the affinity advantage of B is likely to be more impactful in initial optimization efforts.

Output:
1
2025-04-17 04:21:36,766 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (356.853 and 354.466 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (54.28) is better than Ligand B (58.64). Both are below the 90 Angstrom threshold desirable for CNS targets, but A is closer to optimal.

**3. logP:** Ligand A (4.795) is higher than the optimal range (1-3), potentially causing solubility issues and off-target effects. Ligand B (2.294) is within the optimal range. This favors B.

**4. H-Bond Donors:** Both ligands have 1 HBD, which is acceptable.

**5. H-Bond Acceptors:** Ligand A has 4 HBAs, and Ligand B has 3. Both are below the 10 threshold.

**6. QED:** Ligand B (0.843) has a significantly better QED score than Ligand A (0.491), indicating a more drug-like profile.

**7. DILI:** Ligand B (34.277) has a much lower DILI risk than Ligand A (60.682). This is a significant advantage for Ligand B.

**8. BBB:** Ligand B (88.135) has a substantially higher BBB penetration score than Ligand A (45.677). This is *critical* for a CNS target like DRD2 and strongly favors Ligand B.

**9. Caco-2 Permeability:** Ligand A (-4.829) and Ligand B (-4.401) both have negative values, which is unusual. It suggests poor permeability. However, the scale isn't specified, so it's hard to interpret.

**10. Aqueous Solubility:** Ligand A (-5.526) and Ligand B (-3.707) both have negative values, indicating poor solubility.

**11. hERG Inhibition:** Ligand A (0.88) has a slightly higher hERG risk than Ligand B (0.477), but both are relatively low.

**12. Microsomal Clearance:** Ligand A (78.853) and Ligand B (61.379) are both relatively high, suggesting moderate metabolic instability.

**13. In vitro Half-Life:** Ligand B (-15.128) has a significantly *longer* in vitro half-life than Ligand A (60.473). This is a major advantage for B.

**14. P-gp Efflux:** Ligand A (0.703) has a slightly higher P-gp efflux liability than Ligand B (0.206). Lower efflux is preferred for CNS penetration, favoring B.

**15. Binding Affinity:** Ligand B (-8.8 kcal/mol) has a slightly better binding affinity than Ligand A (-8.2 kcal/mol). While the difference is not huge, it's enough to be considered.

**Overall Assessment:**

Ligand B is clearly the superior candidate. It excels in key properties for a CNS-targeting GPCR ligand: significantly better BBB penetration, lower DILI risk, a higher QED score, a longer half-life, lower P-gp efflux, and slightly better binding affinity. While both have solubility and permeability concerns, the other advantages of Ligand B outweigh these drawbacks. Ligand A's higher logP and lower BBB are significant liabilities.

Output:
1
2025-04-17 04:21:36,766 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (362.777 and 347.459 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (116.32) is higher than the preferred <90 for CNS targets, but still potentially acceptable. Ligand B (66.65) is excellent, well below the 90 threshold.

**logP:** Ligand A (1.298) is within the optimal 1-3 range. Ligand B (2.799) is also good, falling within the optimal range.

**H-Bond Donors/Acceptors:** Ligand A has 3 HBD and 5 HBA, which are acceptable. Ligand B has 0 HBD and 4 HBA, also acceptable.

**QED:** Both ligands have similar QED values (0.711 and 0.725), indicating good drug-likeness.

**DILI:** Ligand A (96.433) has a high DILI risk, exceeding the >60 threshold. Ligand B (28.228) has a very low DILI risk, well below the 40 threshold. This is a significant advantage for Ligand B.

**BBB:** Ligand A (49.011) has a poor BBB penetration percentile. Ligand B (89.066) has excellent BBB penetration, exceeding the desirable >70 threshold for CNS targets. This is a major advantage for Ligand B.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.921 and -4.413), which is unusual and suggests poor permeability. However, these values are on a scale where negative values are possible, and direct comparison is difficult without knowing the scale's specifics.

**Aqueous Solubility:** Both ligands have negative solubility values (-4.241 and -2.297), also suggesting poor solubility. Again, interpretation is limited without knowing the scale.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.132 and 0.425).

**Microsomal Clearance:** Ligand A (1.771) has a lower (better) microsomal clearance than Ligand B (84.001), indicating greater metabolic stability.

**In vitro Half-Life:** Ligand A (57.144) has a longer half-life than Ligand B (-31.723). The negative value for Ligand B is concerning and suggests very rapid degradation.

**P-gp Efflux:** Ligand A (0.028) has very low P-gp efflux, which is good for CNS exposure. Ligand B (0.372) has slightly higher P-gp efflux, but still relatively low.

**Binding Affinity:** Ligand A (-9.1 kcal/mol) has a significantly stronger binding affinity than Ligand B (-7.8 kcal/mol). This is a substantial advantage for Ligand A.

**Overall Assessment:**

While Ligand A boasts a significantly better binding affinity, its high DILI risk, poor BBB penetration, and relatively shorter half-life are major drawbacks. Ligand B, despite a slightly weaker affinity, excels in crucial areas for a CNS-targeting GPCR ligand: low DILI risk, excellent BBB penetration, and low P-gp efflux. The negative values for Caco-2 and solubility are concerning for both, but the differences in DILI and BBB are more critical for CNS drug development. The superior ADME properties of Ligand B, particularly its BBB penetration, outweigh the affinity difference in this case.

Output:
1
2025-04-17 04:21:36,766 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (349.387 and 354.47 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (107.11) is higher than Ligand B (78.09). For CNS targets, TPSA < 90 is preferred. Ligand B is significantly better in this regard.

**3. logP:** Ligand A (-0.03) is quite low, potentially hindering permeability. Ligand B (2.457) is within the optimal 1-3 range. This is a significant advantage for Ligand B.

**4. H-Bond Donors:** Both have 2 HBD, which is acceptable.

**5. H-Bond Acceptors:** Ligand A has 6 HBA, and Ligand B has 3. Both are within the acceptable limit of 10.

**6. QED:** Both ligands have reasonable QED values (0.773 and 0.677), indicating good drug-like properties.

**7. DILI:** Both have similar DILI risk (41.76 and 42.071), both being relatively low and acceptable.

**8. BBB:** Ligand B (69.523) has a better BBB percentile than Ligand A (55.603). While neither is >70, Ligand B is closer and more desirable for a CNS target.

**9. Caco-2:** Both have negative Caco-2 values (-4.817 and -4.944), which is unusual and suggests poor permeability. However, these values are on a scale where negative values are possible and don't necessarily disqualify a compound.

**10. Solubility:** Both have negative solubility values (-1.496 and -2.739), also unusual. Similar to Caco-2, these values don't automatically disqualify the compounds.

**11. hERG:** Both have very low hERG inhibition liability (0.102 and 0.513), which is excellent.

**12. Cl_mic:** Ligand A (10.649) has lower microsomal clearance than Ligand B (54.514), suggesting better metabolic stability.

**13. t1/2:** Ligand A (-12.186) has a negative in vitro half-life, which is not physically possible and indicates a problem with the data or the compound's stability. Ligand B (-6.717) also has a negative half-life, but is less extreme.

**14. Pgp:** Ligand A (0.012) has significantly lower P-gp efflux liability than Ligand B (0.189), which is favorable for CNS penetration.

**15. Binding Affinity:** Ligand B (-8.2 kcal/mol) has a stronger binding affinity than Ligand A (-7.6 kcal/mol). This 1.6 kcal/mol difference is substantial and can outweigh some ADME drawbacks.

**Overall Assessment:**

Ligand B is the stronger candidate. While both have issues with Caco-2 and solubility, Ligand B excels in key areas for a CNS-targeting GPCR: better logP, better TPSA, better BBB penetration, and significantly stronger binding affinity. The negative half-life values are concerning for both, but less so for Ligand B. Ligand A's very low logP and higher Pgp efflux are significant drawbacks.

Output:
1
2025-04-17 04:21:36,766 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B based on the provided guidelines, prioritizing GPCR-specific properties (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (348.403 and 368.419 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (114.62) is better than Ligand B (119.31), both are below the 140 A^2 threshold for oral absorption, and closer to the <90 A^2 target for CNS penetration.

**logP:** Ligand A (0.33) is slightly better than Ligand B (-0.454), both are a bit low, potentially hindering permeation. However, they are not excessively low.

**H-Bond Donors/Acceptors:** Ligand A (2 HBD, 5 HBA) is preferable to Ligand B (1 HBD, 9 HBA).  Ligand B has a higher number of HBA, which could slightly reduce permeability.

**QED:** Both ligands have acceptable QED values (0.719 and 0.665, both > 0.5).

**DILI:** Ligand A (41.024) has a significantly lower DILI risk than Ligand B (70.376). This is a major advantage for Ligand A.

**BBB:** Ligand A (65.839) has a much better BBB penetration percentile than Ligand B (46.413). This is *critical* for a CNS target like DRD2.

**Caco-2 Permeability:** Both have negative Caco-2 values (-5.549 and -5.578) which is unusual and suggests poor permeability.

**Aqueous Solubility:** Both have negative solubility values (-1.853 and -1.092), which is also unusual and suggests poor solubility.

**hERG:** Both ligands have very low hERG inhibition liability (0.141 and 0.052).

**Microsomal Clearance:** Ligand A (-16.573) has a much lower (better) microsomal clearance than Ligand B (2.785), indicating better metabolic stability.

**In vitro Half-Life:** Ligand A (-10.055) has a more negative (better) in vitro half-life than Ligand B (3.543), suggesting a longer half-life.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.013 and 0.016).

**Binding Affinity:** Ligand B (-7.5 kcal/mol) has a slightly better binding affinity than Ligand A (-8.0 kcal/mol). While this is a positive for Ligand B, the difference is not substantial enough to outweigh the significant ADME advantages of Ligand A.

**Overall Assessment:**

Ligand A is significantly better overall. Its superior BBB penetration, lower DILI risk, better metabolic stability (lower Cl_mic, better t1/2), and acceptable TPSA and logP values make it a much more promising drug candidate for a CNS target like DRD2. While Ligand B has slightly better binding affinity, the ADME profile of Ligand A is far superior, and the affinity difference is not large enough to overcome those benefits.

Output:
1
2025-04-17 04:21:36,767 - INFO - Reasoning:

Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (352.431 and 354.495 Da) fall comfortably within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (99.1) is slightly higher than Ligand B (81.75). For CNS targets, we prefer TPSA <= 90. Ligand B is better here.

**3. logP:** Ligand A (0.167) is quite low, potentially hindering permeability. Ligand B (0.596) is better, but still on the lower side of the optimal 1-3 range.

**4. H-Bond Donors:** Ligand A (3) is acceptable. Ligand B (2) is even better, minimizing potential permeability issues.

**5. H-Bond Acceptors:** Ligand A (5) is acceptable. Ligand B (4) is slightly better.

**6. QED:** Both ligands have good QED scores (0.606 and 0.635), indicating drug-like properties.

**7. DILI:** Ligand A (24.622) has a significantly lower DILI risk than Ligand B (9.965). This is a major advantage for Ligand A.

**8. BBB:** Ligand A (52.268) has a better BBB percentile than Ligand B (36.487), although both are below the desirable >70 for CNS targets. This is a significant factor favoring Ligand A.

**9. Caco-2:** Ligand A (-4.939) and Ligand B (-5.232) both have very poor Caco-2 permeability.

**10. Solubility:** Ligand A (-1.617) and Ligand B (-0.93) both have poor aqueous solubility.

**11. hERG:** Both ligands have low hERG inhibition liability (0.206 and 0.156), which is good.

**12. Cl_mic:** Ligand B (5.362) has a lower microsomal clearance than Ligand A (15.454), indicating better metabolic stability.

**13. t1/2:** Ligand B (-1.157) has a slightly better in vitro half-life than Ligand A (-7.108).

**14. Pgp:** Both ligands have very low P-gp efflux liability (0.017 and 0.005), which is favorable for CNS penetration.

**15. Binding Affinity:** Both ligands have very similar and excellent binding affinities (-7.5 and -7.4 kcal/mol). The difference is negligible.

**Overall Assessment:**

While Ligand B has slightly better logP and metabolic stability, Ligand A has a significantly lower DILI risk and a better BBB percentile. Given the CNS target (DRD2), BBB penetration is crucial, and minimizing liver toxicity is paramount. The similar binding affinities make the ADME properties the deciding factor. The lower DILI and better BBB of Ligand A outweigh the slightly better metabolic stability of Ligand B.

Output:
0
2025-04-17 04:21:36,767 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (352.483 Da) is slightly lower, which *could* be beneficial for permeability, but both are acceptable.

**TPSA:** Both ligands have TPSA values below 140, suggesting reasonable oral absorption. Ligand B (93.9) is better, being closer to the preferred <90 for CNS targets. Ligand A (101.41) is still acceptable but less optimal.

**logP:** Both ligands have logP values within the optimal range (1-3). Ligand A (2.162) is slightly higher than Ligand B (1.469), but both are good.

**H-Bond Donors/Acceptors:** Both have 1 HBD, which is good. Ligand A has 4 HBA, and Ligand B has 6. Both are within the acceptable limit of 10, but Ligand A is slightly more favorable.

**QED:** Ligand B (0.736) has a significantly better QED score than Ligand A (0.391), indicating a more drug-like profile.

**DILI:** Ligand A (22.102) has a much lower DILI risk than Ligand B (58.511). This is a significant advantage for Ligand A.

**BBB:** Ligand B (77.317) has a substantially better BBB penetration score than Ligand A (49.011). This is *critical* for a CNS target like DRD2.

**Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and suggests poor permeability. However, the scale is not specified, so it's difficult to interpret. Ligand A (-5.107) is slightly better than Ligand B (-4.902).

**Aqueous Solubility:** Both have negative solubility values, indicating poor solubility. Again, the scale is unknown. Ligand A (-1.167) is slightly better.

**hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.525 and 0.14, respectively). This is excellent.

**Microsomal Clearance:** Ligand B (20.052) has lower microsomal clearance than Ligand A (24.371), indicating better metabolic stability.

**In vitro Half-Life:** Ligand B (-34.6) has a negative half-life, which is not possible. This is a major red flag and suggests a problem with the data or the molecule itself. Ligand A (13.02) is reasonable.

**P-gp Efflux:** Both have very low P-gp efflux liability (0.021 and 0.036, respectively). This is favorable for CNS penetration.

**Binding Affinity:** Ligand B (-6.7 kcal/mol) has a significantly stronger binding affinity than Ligand A (0.0 kcal/mol). This is a substantial advantage, potentially outweighing some ADME concerns.

**Overall Assessment:**

Ligand B has a much better binding affinity and BBB penetration, which are crucial for a CNS GPCR target. It also has better QED and metabolic stability. However, its DILI risk is higher, and its in vitro half-life is nonsensical. Ligand A has a lower DILI risk and a reasonable half-life, but its BBB penetration and binding affinity are significantly weaker.

Given the importance of binding affinity and BBB for CNS GPCRs, and acknowledging the data issue with Ligand B's half-life, the stronger affinity of Ligand B is a compelling factor. The DILI risk is concerning, but could potentially be addressed through further optimization. The negative half-life is a major issue, but assuming it's a data error, the overall profile of Ligand B is more promising.

Output:
1
2025-04-17 04:21:36,767 - INFO - Reasoning:

Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands are within the acceptable range (200-500 Da). Ligand A (369.374 Da) is slightly preferred as it's closer to the ideal range.

**2. TPSA:** Ligand A (108.22) is better than Ligand B (64.35). For CNS targets, TPSA < 90 is desirable, and both meet this criterion, but Ligand B is significantly lower.

**3. logP:** Ligand A (1.157) is within the optimal range (1-3), while Ligand B (3.941) is approaching the upper limit. While not a deal-breaker, the higher logP of B could lead to solubility issues or off-target interactions.

**4. H-Bond Donors:** Ligand A (0) is preferred. Fewer HBDs generally improve permeability. Ligand B has 2 HBDs.

**5. H-Bond Acceptors:** Ligand A (8) is acceptable. Ligand B (3) is very good.

**6. QED:** Both ligands have good QED scores (A: 0.532, B: 0.777), indicating drug-like properties. Ligand B is better here.

**7. DILI:** Ligand A (87.01) has a higher DILI risk than Ligand B (37.456). This is a significant negative for Ligand A.

**8. BBB:** Both ligands have excellent BBB penetration (A: 72.741, B: 87.553). Ligand B is better, exceeding 80%.

**9. Caco-2 Permeability:** Both have negative values, indicating poor permeability. Ligand A (-4.785) is slightly better than Ligand B (-5.028).

**10. Aqueous Solubility:** Both have negative values, indicating poor solubility. Ligand A (-2.418) is slightly better than Ligand B (-4.426).

**11. hERG Inhibition:** Ligand A (0.031) has a very low hERG risk, which is excellent. Ligand B (0.754) has a moderate risk.

**12. Microsomal Clearance:** Ligand A (45.725) has a higher clearance than Ligand B (13.412), suggesting lower metabolic stability. Ligand B is preferred.

**13. In vitro Half-Life:** Ligand B (25.973) has a longer half-life than Ligand A (14.219), which is desirable.

**14. P-gp Efflux:** Ligand A (0.335) has lower P-gp efflux liability than Ligand B (0.291), which is good for CNS penetration.

**15. Binding Affinity:** Ligand B (-9.5 kcal/mol) has a significantly stronger binding affinity than Ligand A (-7.7 kcal/mol). This >1.5 kcal/mol difference is a major advantage, potentially outweighing some ADME drawbacks.

**Overall Assessment:**

Ligand B is the stronger candidate. While Ligand A has a better hERG profile and slightly better P-gp efflux, Ligand B excels in crucial areas for a CNS GPCR target: significantly higher binding affinity, better BBB penetration, lower DILI risk, and improved metabolic stability (lower Cl_mic, longer t1/2). The higher logP of Ligand B is a minor concern that could be addressed through further optimization.

Output:
1
2025-04-17 04:21:36,767 - INFO - Batch 106 complete. Total preferences: 1696
2025-04-17 04:21:36,768 - INFO - Processing batch 107/512...
2025-04-17 04:22:17,072 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (398.304 and 381.885 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (47.04) is significantly better than Ligand B (85.43). For CNS targets, we want TPSA <= 90, and ideally closer to 60. Ligand A is much closer to this ideal. Ligand B's TPSA is relatively high and could hinder BBB penetration.

**logP:** Ligand A (4.672) is slightly higher than the optimal 1-3 range, but still potentially acceptable. Ligand B (2.353) is within the optimal range. However, for a GPCR, a slightly higher logP can be tolerated if other properties are favorable.

**H-Bond Donors/Acceptors:** Ligand A (HBD=1, HBA=4) and Ligand B (HBD=3, HBA=4) both have reasonable numbers of H-bond donors and acceptors.

**QED:** Both ligands have good QED scores (A: 0.588, B: 0.743), indicating good drug-like properties.

**DILI:** Both ligands have similar DILI risk (A: 54.944, B: 55.642), and are within an acceptable range (<60).

**BBB:** Ligand A (53.16) has a significantly better BBB percentile than Ligand B (25.708). This is a *critical* factor for a CNS target like DRD2.

**Caco-2 Permeability:** Both have negative Caco-2 values (-5.26 and -5.198), which is unusual and suggests poor permeability. However, these values are on a scale where negative values are possible, and direct comparison is difficult without knowing the scale's specifics.

**Aqueous Solubility:** Both have negative solubility values (-3.91 and -3.521), again suggesting poor solubility. Similar to Caco-2, the scale is unknown.

**hERG:** Both ligands have low hERG inhibition liability (A: 0.954, B: 0.525), which is good.

**Microsomal Clearance:** Ligand A (41.483) has a higher microsomal clearance than Ligand B (8.096), suggesting lower metabolic stability.

**In vitro Half-Life:** Ligand B (-12.121) has a negative half-life, which is impossible and indicates a problem with the data. Ligand A (14.218) has a reasonable half-life.

**P-gp Efflux:** Ligand A (0.675) has lower P-gp efflux than Ligand B (0.241), which is favorable for CNS penetration.

**Binding Affinity:** Both ligands have very similar and strong binding affinities (-8.6 and -8.3 kcal/mol). The difference is less than the 1.5 kcal/mol threshold.

**Conclusion:**

Considering all factors, **Ligand A is the more promising candidate.** While Ligand B has a slightly better logP and QED, Ligand A excels in critical areas for CNS drug development: significantly better BBB penetration, a reasonable half-life (unlike the impossible value for B), and lower P-gp efflux. The higher TPSA of Ligand B is a major drawback, and the negative half-life for Ligand B is a data quality issue. The slight difference in binding affinity is not enough to overcome these significant ADME differences.

Output:
0
2025-04-17 04:22:17,072 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (357.841 and 366.483 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (60.18) is significantly better than Ligand B (75.71). For CNS targets, we want TPSA <= 90, and A is comfortably within this range, while B is approaching the upper limit.

**3. logP:** Ligand A (4.791) is higher than the optimal 1-3 range, potentially causing solubility issues, but still within a reasonable range. Ligand B (1.378) is on the lower side, which could hinder permeation.

**4. H-Bond Donors:** Both ligands have 1 HBD, which is acceptable (<=5).

**5. H-Bond Acceptors:** Both ligands have 5 HBA, which is acceptable (<=10).

**6. QED:** Ligand A (0.683) has a better QED score than Ligand B (0.493), indicating better overall drug-likeness.

**7. DILI:** Ligand B (27.995) has a much lower DILI risk than Ligand A (80.651). This is a significant advantage for Ligand B.

**8. BBB:** Ligand A (83.986) has a much better BBB penetration percentile than Ligand B (62.737). This is *critical* for a CNS target like DRD2.

**9. Caco-2 Permeability:** Ligand A (-5.104) and Ligand B (-4.841) both have negative values, which is unusual and suggests poor permeability. However, the scale isn't defined, so it's hard to interpret.

**10. Aqueous Solubility:** Ligand A (-5.223) and Ligand B (-2.721) both have negative values, suggesting poor solubility.

**11. hERG Inhibition:** Ligand A (0.803) has a slightly higher hERG risk than Ligand B (0.124), which is preferable for B.

**12. Microsomal Clearance:** Ligand B (86.736) has a higher microsomal clearance than Ligand A (53.796), meaning it's metabolized faster. A is preferable here.

**13. In vitro Half-Life:** Ligand A (102.935) has a much longer in vitro half-life than Ligand B (-28.83). This is a significant advantage for A.

**14. P-gp Efflux:** Ligand A (0.587) has lower P-gp efflux liability than Ligand B (0.054), which is preferable for CNS exposure.

**15. Binding Affinity:** Ligand B (-7.6 kcal/mol) has a significantly stronger binding affinity than Ligand A (-10.2 kcal/mol). This is a substantial advantage for B, potentially outweighing some of its ADME drawbacks.

**Overall Assessment:**

Ligand B has a superior binding affinity and lower DILI risk and hERG inhibition. However, Ligand A has a much better BBB score, longer half-life, and lower P-gp efflux. Considering DRD2 is a CNS target, BBB penetration is paramount. While Ligand B's affinity is excellent, the lower BBB penetration is a major concern. Ligand A's slightly lower affinity is acceptable given its superior CNS penetration profile.

Output:
1
2025-04-17 04:22:17,073 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (337.423 Da) is slightly lower, which could be beneficial for permeability.

**2. TPSA:** Ligand A (47.36) is significantly better than Ligand B (107.85). For CNS targets, we want TPSA <= 90, and Ligand A is comfortably within this range, while Ligand B is above.

**3. logP:** Both ligands have acceptable logP values (Ligand A: 2.809, Ligand B: 1.687), falling within the optimal range of 1-3.

**4. H-Bond Donors:** Both are acceptable (Ligand A: 0, Ligand B: 1).

**5. H-Bond Acceptors:** Ligand A (4) is better than Ligand B (8), keeping in mind we want <=10.

**6. QED:** Both ligands have good QED scores (Ligand A: 0.601, Ligand B: 0.775), indicating good drug-like properties.

**7. DILI:** Both have relatively high DILI risk (Ligand A: 48.817, Ligand B: 84.18). Ligand A is preferable here.

**8. BBB:** Ligand A (84.762) has a significantly better BBB percentile than Ligand B (71.268).  For a CNS target like DRD2, >70 is desirable, and Ligand A is closer to this threshold.

**9. Caco-2:** Both have negative Caco-2 values, which is unusual and suggests poor permeability. However, the scale is not specified, so it's hard to interpret.

**10. Solubility:** Both have negative solubility values, which is also unusual.

**11. hERG:** Both have low hERG inhibition liability (Ligand A: 0.663, Ligand B: 0.65), which is good.

**12. Cl_mic:** Ligand B (34.246) has a much lower microsomal clearance than Ligand A (80.305), suggesting better metabolic stability.

**13. t1/2:** Both have negative in vitro half-life values, which is unusual.

**14. Pgp:** Ligand A (0.686) has slightly lower P-gp efflux liability than Ligand B (0.03), which is preferable.

**15. Binding Affinity:** Both have very similar and strong binding affinities (Ligand A: -8.4 kcal/mol, Ligand B: -8.2 kcal/mol). The difference is less than 1.5 kcal/mol, so it's not a major deciding factor.

**Overall Assessment:**

Considering the GPCR-specific priorities, Ligand A is the better candidate. Its significantly lower TPSA and higher BBB penetration are crucial for CNS drug development. While Ligand B has better metabolic stability (lower Cl_mic), the benefits of improved CNS penetration and a slightly better safety profile (lower DILI) outweigh this advantage. The unusual negative values for Caco-2 and solubility are concerning for both, but the other properties favor Ligand A.

Output:
1
2025-04-17 04:22:17,073 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (351.353 and 348.487 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (73.48) is higher than Ligand B (49.85). For a CNS target like DRD2, TPSA < 90 is preferred, so both are acceptable, but B is better.

**3. logP:** Ligand A (1.146) is slightly lower than Ligand B (2.443). Both are within the optimal 1-3 range, but B is closer to the sweet spot.

**4. H-Bond Donors:** Ligand A (1) is better than Ligand B (0). While both are acceptable (<=5), having one donor can sometimes improve solubility.

**5. H-Bond Acceptors:** Both ligands have 3 HBA, which is well within the acceptable limit of <=10.

**6. QED:** Both ligands have similar QED values (0.809 and 0.77), indicating good drug-likeness.

**7. DILI:** Ligand A (39.667) has a significantly lower DILI risk than Ligand B (11.09). This is a substantial advantage for Ligand A.

**8. BBB:** Both ligands demonstrate excellent BBB penetration (Ligand A: 90.151, Ligand B: 92.943). Both exceed the desirable >70 threshold for CNS targets.

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.723 and -4.368). This is unusual and suggests poor permeability. However, these values are on a strange scale, and may not be directly comparable.

**10. Aqueous Solubility:** Both ligands have negative solubility values (-2.326 and -2.696). Again, this is unusual and suggests poor solubility.

**11. hERG Inhibition:** Ligand A (0.249) shows a lower hERG inhibition liability than Ligand B (0.599), indicating a lower risk of cardiotoxicity.

**12. Microsomal Clearance:** Ligand A (-12.574) has a much lower (better) microsomal clearance than Ligand B (57.509), suggesting greater metabolic stability.

**13. In vitro Half-Life:** Ligand A (-37.445) has a much longer in vitro half-life than Ligand B (11.515), which is a significant advantage.

**14. P-gp Efflux:** Ligand A (0.029) has a considerably lower P-gp efflux liability than Ligand B (0.078), suggesting better CNS exposure.

**15. Binding Affinity:** Ligand B (-7.9) has a slightly better binding affinity than Ligand A (-7.1). This is a 1.5 kcal/mol difference, which is significant.

**Overall Assessment:**

While Ligand B has a slightly better binding affinity, Ligand A is superior in almost all other critical ADME-Tox properties. Specifically, Ligand A demonstrates significantly lower DILI risk, better metabolic stability (lower Cl_mic, longer t1/2), lower hERG inhibition, and lower P-gp efflux. These factors are crucial for a CNS drug candidate. The slightly weaker binding affinity of Ligand A can potentially be optimized in subsequent iterations of drug design, whereas improving the ADME profile of Ligand B would be much more challenging.

Output:
0
2025-04-17 04:22:17,073 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B based on the provided guidelines, prioritizing GPCR-specific properties (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (364.43 and 359.50 Da) fall within the ideal 200-500 Da range.

**TPSA:** Both ligands have TPSA values (93.53 and 90.70) below 140, suggesting good oral absorption potential. They are reasonably close to the 90 cutoff for CNS targets, but Ligand B is slightly better.

**logP:** Ligand A (0.489) is below the optimal 1-3 range, potentially hindering permeation. Ligand B (3.419) is within the optimal range. This is a significant advantage for Ligand B.

**H-Bond Donors/Acceptors:** Ligand A (1 HBD, 6 HBA) and Ligand B (2 HBD, 6 HBA) both meet the criteria of <=5 HBD and <=10 HBA.

**QED:** Both ligands have good QED scores (0.722 and 0.753), indicating drug-like properties.

**DILI:** Both ligands have acceptable DILI risk (73.83 and 70.22), below the 60 threshold.

**BBB:** Ligand A (59.33) has a BBB percentile below the desirable 70 for CNS targets. Ligand B (70.53) is right at the threshold and is preferable.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.816 and -5.085), which is unusual and suggests poor permeability. However, these values are on a scale where negative values are possible, and direct comparison is difficult without knowing the scale's specifics.

**Aqueous Solubility:** Both ligands have negative solubility values (-2.562 and -3.93), again suggesting poor solubility. Similar to Caco-2, interpretation is limited by the scale.

**hERG Inhibition:** Both ligands show low hERG inhibition risk (0.706 and 0.77).

**Microsomal Clearance:** Ligand A (48.44) has lower microsomal clearance than Ligand B (82.59), indicating better metabolic stability.

**In vitro Half-Life:** Ligand B (75.10) has a significantly longer in vitro half-life than Ligand A (-18.4), which is a substantial advantage.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.101 and 0.339).

**Binding Affinity:** Ligand A (-8.1 kcal/mol) has a slightly better binding affinity than Ligand B (-7.9 kcal/mol). However, the difference is less than 1.5 kcal/mol, so it's not a decisive factor.

**Overall Assessment:**

Ligand B is the more promising candidate. While Ligand A has slightly better binding affinity, Ligand B excels in crucial GPCR-specific properties: logP (optimal range), and BBB penetration (above the 70% threshold). It also has a significantly longer in vitro half-life, which is a major advantage for drug development. The negative Caco-2 and solubility values are concerning for both, but the other advantages of Ligand B outweigh this.

Output:
1
2025-04-17 04:22:17,073 - INFO - Reasoning:

Let's analyze Ligand A and Ligand B based on the provided guidelines, prioritizing GPCR-specific properties (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (346.45 & 356.39 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (41.57) is significantly better than Ligand B (92.01). For CNS targets, TPSA should be <=90, making Ligand A much more favorable.

**logP:** Ligand A (4.089) is slightly higher than optimal (1-3), but still potentially acceptable. Ligand B (0.665) is quite low, which could hinder membrane permeability and CNS penetration.

**H-Bond Donors/Acceptors:** Ligand A (HBD=1, HBA=2) is better than Ligand B (HBD=2, HBA=5) in terms of balancing solubility and permeability.

**QED:** Both ligands have similar QED values (0.876 and 0.749), indicating good drug-likeness.

**DILI:** Both ligands have low DILI risk (37.61 and 35.60), which is positive.

**BBB:** Ligand A (92.71) is *significantly* better than Ligand B (64.831). A BBB percentile >70 is highly desirable for CNS targets like DRD2. This is a major advantage for Ligand A.

**Caco-2 Permeability:** Ligand A (-4.399) and Ligand B (-4.895) both have negative Caco-2 values, which is unusual and suggests poor permeability. However, the scale is not clearly defined, so it's difficult to interpret.

**Aqueous Solubility:** Ligand A (-4.598) and Ligand B (-1.384) both have negative solubility values, which is also unusual and suggests poor solubility.

**hERG Inhibition:** Ligand A (0.713) is better than Ligand B (0.24), indicating a lower risk of cardiotoxicity.

**Microsomal Clearance:** Ligand A (85.414) has a higher clearance than Ligand B (5.048), meaning it's less metabolically stable. This is a drawback for Ligand A.

**In vitro Half-Life:** Ligand A (20.481) has a longer half-life than Ligand B (2.1), which is favorable.

**P-gp Efflux:** Ligand A (0.642) is better than Ligand B (0.027), suggesting lower P-gp efflux and improved CNS exposure.

**Binding Affinity:** Ligand B (-7.2 kcal/mol) has a significantly stronger binding affinity than Ligand A (0.0 kcal/mol). This is a substantial advantage for Ligand B, potentially outweighing some of its ADME deficiencies.

**Overall Assessment:**

While Ligand B boasts a much stronger binding affinity, Ligand A excels in crucial ADME properties for a CNS-targeting GPCR. Specifically, its superior TPSA and BBB penetration are critical. The higher logP of Ligand A is a minor concern, but the extremely low logP of Ligand B is more problematic. The better P-gp efflux profile of Ligand A is also beneficial. The metabolic stability is a concern for Ligand A, but the half-life is longer. The significantly stronger binding affinity of Ligand B is a major factor, but the poor BBB penetration and high TPSA are significant drawbacks for a CNS target. Given the importance of CNS penetration for DRD2, and the substantial difference in BBB values, I believe Ligand A is the more promising candidate.

Output:
1
2025-04-17 04:22:17,074 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (368.861 and 384.929 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (68.73) is better than Ligand B (58.64) as it is closer to the <90 A^2 threshold for CNS targets.

**logP:** Both ligands have good logP values (3.331 and 2.957), falling within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A (0 HBD, 5 HBA) is slightly better than Ligand B (1 HBD, 4 HBA) in terms of balancing solubility and permeability.

**QED:** Both ligands have acceptable QED scores (0.762 and 0.605), indicating good drug-likeness.

**DILI:** Ligand A (46.297) has a lower DILI risk than Ligand B (54.75), which is preferable.

**BBB:** Ligand A (73.672) has a significantly better BBB penetration percentile than Ligand B (62.156). This is a critical advantage for a CNS target like DRD2.

**Caco-2 Permeability:** Ligand A (-4.438) has a slightly better Caco-2 permeability than Ligand B (-4.957).

**Aqueous Solubility:** Ligand A (-3.553) has better aqueous solubility than Ligand B (-4.796).

**hERG:** Both ligands have similar hERG inhibition liability (0.418 and 0.567), indicating a relatively low risk.

**Microsomal Clearance:** Ligand A (66.133) has lower microsomal clearance than Ligand B (82.042), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand B (28.361) has a significantly longer in vitro half-life than Ligand A (6.431). This is a notable advantage.

**P-gp Efflux:** Ligand A (0.149) has lower P-gp efflux liability than Ligand B (0.568), which is desirable for CNS penetration.

**Binding Affinity:** Ligand A (-7.9 kcal/mol) has a slightly better binding affinity than Ligand B (-0.0 kcal/mol). This is a crucial factor, and the 7.9 kcal/mol difference is substantial.

**Overall Assessment:**

Considering the GPCR-specific priorities, Ligand A is the more promising candidate. It excels in BBB penetration, has a lower DILI risk, better P-gp efflux profile, and significantly stronger binding affinity. While Ligand B has a longer half-life, the superior CNS penetration and binding affinity of Ligand A outweigh this advantage, especially for a CNS target like DRD2.

Output:
1
2025-04-17 04:22:17,074 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight (MW):** Both ligands (361.511 and 360.841 Da) are within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (62.3) is slightly higher than Ligand B (53.76). Both are below the 90 A^2 threshold for CNS targets, which is good. Ligand B is preferable here.

**3. logP:** Ligand A (2.561) and Ligand B (3.556) are both within the optimal 1-3 range. Ligand B is slightly higher, which could be beneficial for membrane permeability, but also increases the risk of off-target interactions.

**4. H-Bond Donors (HBD):** Ligand A (1) and Ligand B (0) are both acceptable, being less than 5.

**5. H-Bond Acceptors (HBA):** Ligand A (4) and Ligand B (3) are both acceptable, being less than 10.

**6. QED:** Both ligands have similar QED values (0.875 and 0.841), indicating good drug-like properties.

**7. DILI:** Both ligands have acceptable DILI risk (40.287 and 47.964), below the 60 threshold.

**8. BBB:** Both ligands have excellent BBB penetration (76.696 and 75.572), exceeding the desirable >70 threshold for CNS targets.

**9. Caco-2 Permeability:** Ligand A (-5.18) and Ligand B (-4.439) both have negative values, indicating low permeability. This is a concern, but we need to consider other factors.

**10. Aqueous Solubility:** Both ligands have very poor aqueous solubility (-3.336 and -4.376). This is a significant drawback.

**11. hERG Inhibition:** Both ligands have low hERG inhibition risk (0.425 and 0.569).

**12. Microsomal Clearance (Cl_mic):** Ligand A (49.7) has a higher clearance than Ligand B (30.282). Lower clearance is preferred for metabolic stability, favoring Ligand B.

**13. In vitro Half-Life (t1/2):** Ligand A (-11.945) has a negative half-life, which is not possible and likely indicates a very rapid degradation. Ligand B (47.851) has a much more reasonable half-life. This is a major advantage for Ligand B.

**14. P-gp Efflux:** Both ligands have low P-gp efflux liability (0.154 and 0.454), which is good for CNS exposure.

**15. Binding Affinity:** Ligand B (-8.4 kcal/mol) has a significantly stronger binding affinity than Ligand A (-7.6 kcal/mol). This 0.8 kcal/mol difference is substantial and can outweigh some of the ADME drawbacks.

**Overall Assessment:**

While both ligands have good BBB penetration and acceptable safety profiles, Ligand B is clearly superior. Its stronger binding affinity, lower microsomal clearance, and significantly better *in vitro* half-life outweigh the slightly higher logP and slightly lower TPSA. The poor solubility and Caco-2 permeability are concerns for both, but can potentially be addressed with formulation strategies. The negative half-life for Ligand A is a deal-breaker.

Output:
1
2025-04-17 04:22:17,074 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 drug candidates, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (335.37 & 348.53 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (82.19) is better than Ligand B (40.62). For CNS targets, we want TPSA <= 90, both are within this range, but A is closer to the upper limit.

**3. logP:** Ligand A (1.54) is optimal, while Ligand B (3.987) is approaching the upper limit of the optimal range.

**4. H-Bond Donors:** Ligand A (1) is preferable to Ligand B (0).

**5. H-Bond Acceptors:** Ligand A (5) is preferable to Ligand B (2).

**6. QED:** Both ligands have similar QED values (0.768 and 0.754), indicating good drug-likeness.

**7. DILI:** Ligand B (31.563) has a significantly lower DILI risk than Ligand A (80.109), which is a major advantage.

**8. BBB:** Ligand B (90.733) has a much higher BBB penetration percentile than Ligand A (56.34). This is *critical* for a CNS target like DRD2.

**9. Caco-2 Permeability:** Ligand A (-5.123) has a lower Caco-2 permeability than Ligand B (-4.588).

**10. Aqueous Solubility:** Ligand A (-3.723) has a lower solubility than Ligand B (-3.5).

**11. hERG Inhibition:** Ligand A (0.425) has a lower hERG inhibition risk than Ligand B (0.733).

**12. Microsomal Clearance:** Ligand B (89.977) has a much higher microsomal clearance than Ligand A (33.62), indicating lower metabolic stability.

**13. In vitro Half-Life:** Ligand A (14.393) has a longer in vitro half-life than Ligand B (-19.952).

**14. P-gp Efflux:** Ligand A (0.103) has lower P-gp efflux than Ligand B (0.554), which is favorable for CNS penetration.

**15. Binding Affinity:** Ligand B (-7.8) has a stronger binding affinity than Ligand A (-9.4). This is a significant advantage, potentially outweighing some ADME drawbacks.

**Overall Assessment:**

While Ligand A has better metabolic stability (lower Cl_mic, longer t1/2) and lower P-gp efflux, Ligand B is significantly better in terms of BBB penetration (90.733 vs 56.34) and has a much lower DILI risk. The binding affinity of Ligand B is also substantially stronger (-7.8 vs -9.4). For a CNS GPCR target, BBB penetration is paramount, and the lower DILI risk is a major benefit. The stronger binding affinity of Ligand B further solidifies its potential. Although Ligand B has a higher Cl_mic, the improved CNS exposure and safety profile are more important in this case.

Output:
1
2025-04-17 04:22:17,075 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (351.491 and 345.487 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (78.51) is slightly higher than Ligand B (64.41). Both are below the 90 A^2 threshold desirable for CNS targets, but Ligand B is preferable.

**3. logP:** Both ligands have good logP values (1.979 and 2.812), falling within the optimal 1-3 range. Ligand B is slightly higher, which could be beneficial for membrane permeability.

**4. H-Bond Donors:** Ligand A has 2 HBD, and Ligand B has 0. Both are within the acceptable limit of <=5. Ligand B is slightly favored due to fewer potential off-target interactions.

**5. H-Bond Acceptors:** Both ligands have 3 HBA, well within the acceptable limit of <=10.

**6. QED:** Both ligands have similar QED values (0.632 and 0.679), indicating good drug-like properties.

**7. DILI:** Ligand A (16.712%) has a lower DILI risk than Ligand B (18.418%), which is a slight advantage.

**8. BBB:** Ligand B (78.984%) has a slightly better BBB penetration percentile than Ligand A (72.586%). Both are above the 70% threshold, which is critical for CNS targets.

**9. Caco-2 Permeability:** Ligand A (-4.973) has slightly better Caco-2 permeability than Ligand B (-4.591).

**10. Aqueous Solubility:** Ligand A (-2.474) has slightly better aqueous solubility than Ligand B (-3.093).

**11. hERG Inhibition:** Ligand A (0.174) has a lower hERG inhibition risk than Ligand B (0.609), a significant advantage.

**12. Microsomal Clearance:** Ligand B (58.325) has a lower microsomal clearance than Ligand A (37.823), indicating better metabolic stability.

**13. In vitro Half-Life:** Ligand B (-9.981) has a longer in vitro half-life than Ligand A (-11.01), which is desirable.

**14. P-gp Efflux:** Ligand A (0.058) has lower P-gp efflux liability than Ligand B (0.384), which is a significant advantage for CNS exposure.

**15. Binding Affinity:** Both ligands have very similar binding affinities (-7.6 and -7.7 kcal/mol), which are excellent. The difference is negligible.

**Overall Assessment:**

Ligand B has advantages in BBB penetration and metabolic stability (lower Cl_mic, longer t1/2). However, Ligand A demonstrates better solubility, Caco-2 permeability, lower hERG risk, and significantly lower P-gp efflux. Given the CNS target (DRD2), minimizing P-gp efflux and hERG risk are crucial. The slight advantage in BBB for Ligand B is outweighed by the more substantial benefits of Ligand A regarding safety and CNS penetration.

Output:
0
2025-04-17 04:22:17,075 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (370.431 and 346.431 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (94.09) is slightly above the optimal <90 for CNS targets, but still reasonable. Ligand B (89.16) is better, falling comfortably under 90.

**logP:** Ligand A (-0.357) is a bit low, potentially hindering permeation. Ligand B (2.694) is within the optimal 1-3 range. This is a significant advantage for Ligand B.

**H-Bond Donors/Acceptors:** Ligand A (0 HBD, 8 HBA) is good. Ligand B (2 HBD, 5 HBA) is also acceptable.

**QED:** Both ligands have good QED scores (0.577 and 0.807), indicating good drug-like properties.

**DILI:** Both ligands have acceptable DILI risk (53.509 and 56.146), below the concerning threshold of 60.

**BBB:** Ligand A (61.38) is borderline for good CNS penetration, while Ligand B (44.436) is significantly lower. This is a major drawback for Ligand B.

**Caco-2 Permeability:** Both have negative values (-4.933 and -4.944) which is unusual and indicates very poor permeability. This is a red flag for both.

**Aqueous Solubility:** Both have negative values (-1.251 and -3.456) which is also unusual and indicates very poor solubility. This is a red flag for both.

**hERG:** Both ligands have low hERG risk (0.167 and 0.319).

**Microsomal Clearance:** Ligand A (10.382) has lower clearance than Ligand B (48.649), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand B (58.335) has a significantly longer half-life than Ligand A (10.345).

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.038 and 0.119).

**Binding Affinity:** Ligand B (-8.9 kcal/mol) has a substantially stronger binding affinity than Ligand A (-7.4 kcal/mol). This difference of 1.5 kcal/mol is significant and can outweigh some ADME drawbacks.

**Overall Assessment:**

Ligand B has a superior binding affinity and a better logP value, which are crucial for GPCR targets. Its longer half-life is also a positive. However, its BBB penetration is significantly lower than Ligand A, and both ligands have very poor Caco-2 permeability and solubility. The strong binding affinity of Ligand B is a major advantage, and with optimization, the permeability and solubility issues might be addressed. Ligand A's lower logP and BBB are less favorable.

Output:
1
2025-04-17 04:22:17,075 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (360.391 and 377.388 Da) fall within the ideal range of 200-500 Da.

**TPSA:** Ligand A (108.58) is slightly higher than the ideal <90 for CNS targets, but still reasonable. Ligand B (88.16) is excellent, well below 90.

**logP:** Both ligands (2.042 and 2.313) are within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A has 1 HBD and 8 HBA, while Ligand B has 2 HBD and 5 HBA. Both are within acceptable limits (<=5 HBD and <=10 HBA).

**QED:** Both ligands have similar QED values (0.785 and 0.714), indicating good drug-like properties.

**DILI:** Ligand A (83.443) has a higher DILI risk than Ligand B (69.639), though both are below the concerning threshold of 60.

**BBB:** Ligand A (82.823) and Ligand B (78.364) both have good BBB penetration, exceeding the desirable >70 threshold for CNS targets. Ligand A has a slight edge here.

**Caco-2 Permeability:** Both have negative Caco-2 values (-4.955 and -4.796). This is unusual and suggests poor permeability. However, these values are on a scale where negative values are possible and don't necessarily preclude development.

**Aqueous Solubility:** Both ligands have negative solubility values (-4.69 and -3.418). Similar to Caco-2, this indicates poor solubility, which could be a formulation challenge.

**hERG:** Both ligands have low hERG inhibition risk (0.285 and 0.217).

**Microsomal Clearance:** Ligand A (53.683) has a higher microsomal clearance than Ligand B (15.391), suggesting lower metabolic stability. This is a significant drawback.

**In vitro Half-Life:** Ligand B (-14.752) has a longer in vitro half-life than Ligand A (-28.223), which is a positive attribute.

**P-gp Efflux:** Both ligands show low P-gp efflux liability (0.129 and 0.13).

**Binding Affinity:** Both ligands have excellent binding affinity (-8.4 and -8.8 kcal/mol). Ligand B has a slightly better affinity.

**Overall Assessment:**

Ligand B is the more promising candidate. While both ligands have good affinity and BBB penetration, Ligand B has a significantly better metabolic stability profile (lower Cl_mic, longer t1/2), a lower DILI risk, and slightly better binding affinity. The TPSA value is also more favorable. Although both have poor solubility and permeability, the metabolic advantage of Ligand B outweighs these concerns, especially for a CNS target where maintaining adequate brain exposure is critical.

Output:
1
2025-04-17 04:22:17,075 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (350.419 and 354.445 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (104.54) is higher than the preferred <90 for CNS targets, but still potentially acceptable. Ligand B (54.18) is excellent, well below the threshold.

**logP:** Ligand A (0.608) is quite low, potentially hindering membrane permeability. Ligand B (2.696) is within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A has 2 HBD and 5 HBA, which are reasonable. Ligand B has 1 HBD and 5 HBA, also reasonable.

**QED:** Both ligands have good QED scores (0.715 and 0.741), indicating good drug-like properties.

**DILI:** Ligand A (32.377) has a slightly higher DILI risk than Ligand B (21.442), but both are below the concerning threshold of 60.

**BBB:** This is critical for a CNS target. Ligand A (61.535) is below the desirable >70, while Ligand B (90.074) is excellent.

**Caco-2 Permeability:** Ligand A (-5.38) is very poor, suggesting poor intestinal absorption. Ligand B (-4.689) is also poor, but slightly better than Ligand A.

**Aqueous Solubility:** Ligand A (-0.355) is very poor, while Ligand B (-3.036) is also poor.

**hERG Inhibition:** Ligand A (0.034) has very low hERG risk, which is excellent. Ligand B (0.835) has a slightly elevated risk, but is still relatively low.

**Microsomal Clearance:** Ligand A (14.424) has lower clearance than Ligand B (27.121), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (-14.451) has a negative half-life, which is not possible and likely indicates a problem with the data. Ligand B (10.682) is reasonable.

**P-gp Efflux:** Ligand A (0.011) has very low P-gp efflux, which is excellent for CNS penetration. Ligand B (0.344) has moderate P-gp efflux.

**Binding Affinity:** Ligand B (-7.3 kcal/mol) has a significantly stronger binding affinity than Ligand A (-8.2 kcal/mol).

**Overall Assessment:**

Ligand B is the superior candidate. While both have issues with solubility and Caco-2 permeability, Ligand B excels in the critical areas for a CNS GPCR target: BBB penetration (90.074 vs 61.535) and binding affinity (-7.3 vs -8.2). The slightly higher DILI and hERG risk for Ligand B are less concerning than Ligand A's poor logP, Caco-2 permeability, and BBB penetration. The negative half-life for Ligand A is a major red flag.



Output:
1
2025-04-17 04:22:17,076 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (348.491 and 353.419 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (78.09) is significantly better than Ligand B (104.9). For CNS targets, we want TPSA <= 90, and Ligand A is comfortably within this range, while Ligand B is approaching the upper limit.

**3. logP:** Both ligands have acceptable logP values (2.296 and 0.878), falling within the 1-3 range. Ligand A is slightly preferred due to being closer to the optimal range.

**4. H-Bond Donors:** Both have 2 HBD, which is within the acceptable limit of <=5.

**5. H-Bond Acceptors:** Ligand A has 3 HBA, while Ligand B has 6.  Ligand A is better here, being closer to the ideal of <=10.

**6. QED:** Both ligands have similar QED values (0.757 and 0.754), indicating good drug-likeness.

**7. DILI:** Ligand A (22.102) has a lower DILI risk than Ligand B (26.134), which is preferable. Both are below the 40 threshold, indicating low risk.

**8. BBB:** Ligand A (48.236) has a slightly better BBB penetration percentile than Ligand B (43.505). While neither is above the desirable 70, Ligand A is closer.

**9. Caco-2 Permeability:** Ligand A (-5.23) has a worse Caco-2 permeability than Ligand B (-4.661). Higher values are better, so Ligand B is slightly favored here.

**10. Aqueous Solubility:** Both ligands have very poor aqueous solubility (-1.962 and -1.912). This is a concern for both, but not a deciding factor.

**11. hERG Inhibition:** Both ligands have very low hERG inhibition liability (0.569 and 0.143), which is excellent.

**12. Microsomal Clearance:** Ligand B (16.326) has lower microsomal clearance than Ligand A (31.033), indicating better metabolic stability. This is a significant advantage for Ligand B.

**13. In vitro Half-Life:** Ligand B (-8.895) has a slightly better in vitro half-life than Ligand A (-16.03).

**14. P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.11 and 0.028), which is excellent.

**15. Binding Affinity:** Both ligands have the same binding affinity (-8.0 kcal/mol), which is very strong and well below the -7.0 threshold.

**Overall Assessment:**

Ligand A excels in TPSA, logP, HBA, and DILI, and has a slightly better BBB score. However, Ligand B demonstrates superior metabolic stability (lower Cl_mic) and a slightly better half-life. The TPSA advantage of Ligand A is crucial for CNS penetration, but the metabolic stability of Ligand B is also very important. Given the equal binding affinity, the lower TPSA of Ligand A and the importance of CNS penetration for a DRD2 target, Ligand A is slightly more promising.

Output:
0
2025-04-17 04:22:17,076 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (360.336 and 369.447 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (84.42) is excellent, well below the 90 A^2 threshold for CNS targets. Ligand B (129.46) is still reasonable, but less optimal, being closer to the 140 A^2 limit for oral absorption.

**logP:** Ligand A (1.7) is within the optimal 1-3 range. Ligand B (-0.459) is slightly below 1, which *could* indicate permeability issues, although not drastically.

**H-Bond Donors & Acceptors:** Both have acceptable HBD (1 & 2) and HBA (5 & 5) counts, well within the guidelines.

**QED:** Both ligands have reasonable QED scores (0.884 and 0.742), indicating good drug-like properties.

**DILI:** Ligand A (62.35) has a slightly higher DILI risk than Ligand B (70.88), but both are acceptable.

**BBB:** This is critical for a CNS target like DRD2. Ligand A (75.301) has a good BBB percentile, exceeding the 70% threshold. Ligand B (29.12) is significantly lower and a major concern for CNS penetration.

**Caco-2 Permeability:** Ligand A (-4.377) and Ligand B (-5.375) both have negative values, which is unusual. This suggests very poor permeability. However, the scale isn't specified, so it's hard to interpret.

**Aqueous Solubility:** Both ligands have poor aqueous solubility (-2.374 and -2.529). This could pose formulation challenges.

**hERG:** Both ligands have very low hERG inhibition liability (0.119 and 0.13), which is excellent.

**Microsomal Clearance:** Ligand A (21.882) has a moderate clearance, while Ligand B (-0.356) has a *very* low (and potentially unrealistic) clearance, suggesting high metabolic stability.

**In vitro Half-Life:** Ligand A (-28.2) has a negative half-life, which is not physically possible and indicates an issue with the data. Ligand B (-39.35) also has a negative half-life.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.01 and 0.033), which is favorable for CNS exposure.

**Binding Affinity:** Both ligands have excellent binding affinities (-7.8 and -7.5 kcal/mol), with Ligand A being slightly better. The 0.3 kcal/mol difference is not enough to overcome other significant issues.

**Conclusion:**

Despite Ligand A having a slightly better binding affinity, the critical factor is the BBB penetration. Ligand A's BBB percentile (75.301) is significantly higher than Ligand B's (29.12). While both have solubility concerns, the poor BBB penetration of Ligand B makes it a much less viable candidate for a CNS-targeting drug. The negative half-life values for both are concerning and suggest data errors, but the BBB difference is the deciding factor.

Output:
0
2025-04-17 04:22:17,076 - INFO - Reasoning:

Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (355.777 and 348.443 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (76.23) is significantly better than Ligand B (91.57). For CNS targets, we want TPSA <= 90, so Ligand A is preferable.

**3. logP:** Ligand A (3.741) is slightly higher than optimal (1-3), but still acceptable. Ligand B (1.774) is on the lower side, potentially hindering permeation.

**4. H-Bond Donors:** Ligand A (1) is good. Ligand B (3) is also acceptable, but slightly less favorable.

**5. H-Bond Acceptors:** Both ligands have 4 H-bond acceptors, which is within the acceptable range of <=10.

**6. QED:** Both ligands have good QED scores (0.571 and 0.634, respectively), indicating good drug-like properties.

**7. DILI:** Ligand A (93.525) has a significantly higher DILI risk than Ligand B (24.583). This is a major concern for Ligand A.

**8. BBB:** Ligand A (44.979) has a very low BBB penetration percentile, making it unlikely to effectively reach the target in the CNS. Ligand B (30.748) is also low, but better than Ligand A.

**9. Caco-2 Permeability:** Ligand A (-4.88) and Ligand B (-5.111) both have negative values, which is unusual and suggests poor permeability.

**10. Aqueous Solubility:** Ligand A (-5.149) and Ligand B (-2.669) both have negative values, suggesting poor solubility.

**11. hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.189 and 0.108, respectively).

**12. Microsomal Clearance:** Ligand A (68.229) has higher clearance than Ligand B (20.047), indicating lower metabolic stability.

**13. In vitro Half-Life:** Ligand A (30.934) has a slightly longer half-life than Ligand B (24.608).

**14. P-gp Efflux:** Both ligands have low P-gp efflux liability (0.385 and 0.104, respectively).

**15. Binding Affinity:** Ligand A (-10.7 kcal/mol) has a significantly stronger binding affinity than Ligand B (-8.4 kcal/mol). This is a substantial advantage.

**Overall Assessment:**

Despite the significantly better binding affinity of Ligand A, its poor BBB penetration, high DILI risk, and higher metabolic clearance are major drawbacks. Ligand B, while having a weaker affinity, has a much better safety profile (lower DILI) and slightly better BBB penetration. Given the GPCR-specific priority of BBB penetration for CNS targets, and the importance of avoiding liver toxicity, Ligand B is the more promising candidate. The affinity difference, while significant, might be overcome with further optimization of Ligand B.

Output:
1
2025-04-17 04:22:17,076 - INFO - Batch 107 complete. Total preferences: 1712
2025-04-17 04:22:17,076 - INFO - Processing batch 108/512...
2025-04-17 04:22:57,591 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B based on the provided guidelines, prioritizing GPCR-specific properties (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (366.853 and 378.841 Da) fall within the ideal range of 200-500 Da.

**TPSA:** Ligand A (95.91) is better than Ligand B (115.11). For CNS targets, we want TPSA <= 90, so Ligand A is closer to this target.

**logP:** Both ligands have good logP values (1.396 and 1.579), falling within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A (HBD=2, HBA=5) is slightly better than Ligand B (HBD=3, HBA=6) in terms of maintaining a balance between solubility and permeability. Both are acceptable.

**QED:** Both ligands have similar and acceptable QED values (0.69 and 0.705).

**DILI:** Ligand B (71.539) has a higher DILI risk than Ligand A (61.807). Lower DILI is preferred.

**BBB:** This is a critical parameter for CNS targets like DRD2. Ligand A has a significantly better BBB percentile (32.532) than Ligand B (13.532). While >70 is desirable, Ligand A is substantially better.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.535 and -5.127), which is unusual and suggests poor permeability. This is a significant concern for both.

**Aqueous Solubility:** Both ligands have negative solubility values (-2.237 and -3.932), indicating very poor aqueous solubility. This is a major drawback for both.

**hERG Inhibition:** Both ligands have low hERG inhibition liability (0.224 and 0.289), which is good.

**Microsomal Clearance:** Ligand B (5.257) has much lower microsomal clearance than Ligand A (31.543), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand B (44.897 hours) has a significantly longer in vitro half-life than Ligand A (28.349 hours).

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.139 and 0.06), which is favorable for CNS penetration.

**Binding Affinity:** Ligand B (-8.0 kcal/mol) has a slightly better binding affinity than Ligand A (-7.8 kcal/mol). This 0.2 kcal/mol difference is not huge, but it's a factor.

**Overall Assessment:**

Ligand A excels in TPSA and has a much better BBB score, which are crucial for CNS GPCR targets. Ligand B has better metabolic stability (lower Cl_mic, longer t1/2) and slightly better binding affinity. However, the significantly better BBB penetration of Ligand A, coupled with its lower DILI risk, outweighs the advantages of Ligand B, despite the permeability and solubility issues shared by both. The poor permeability and solubility are serious concerns that would need to be addressed through formulation or further chemical modification, but the CNS targeting properties of Ligand A are more promising for a DRD2 ligand.

Output:
0
2025-04-17 04:22:57,591 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (443.388 and 417.965 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (76.13) is better than Ligand B (79.37), both are below the 90 A^2 threshold for CNS targets, which is good.

**3. logP:** Ligand A (3.898) is slightly higher than Ligand B (1.985). Both are within the optimal 1-3 range, but Ligand B is closer to the lower bound.

**4. H-Bond Donors:** Both have 1 HBD, which is good.

**5. H-Bond Acceptors:** Ligand A has 5 HBA, and Ligand B has 6. Both are acceptable (<=10).

**6. QED:** Both ligands have good QED scores (0.657 and 0.804), indicating good drug-like properties.

**7. DILI:** Both ligands have relatively high DILI risk (70.803 and 79.682). This is a concern for both, but not a deciding factor at this stage.

**8. BBB:** Both ligands have similar BBB penetration (54.246 and 54.634). Neither are above the desirable 70% threshold, but this is not a major differentiator.

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.172 and -5.208), indicating poor permeability. This is a significant drawback for both.

**10. Aqueous Solubility:** Both ligands have very poor aqueous solubility (-3.985 and -4.358). This is a major issue for both.

**11. hERG Inhibition:** Both ligands have low hERG inhibition risk (0.559 and 0.568).

**12. Microsomal Clearance:** Both ligands have similar microsomal clearance (41.396 and 43.864 mL/min/kg), suggesting moderate metabolic stability.

**13. In vitro Half-Life:** Ligand A has a significantly longer half-life (35.374 hours) than Ligand B (17.21 hours). This is a significant advantage for Ligand A.

**14. P-gp Efflux:** Both ligands have low P-gp efflux liability (0.357 and 0.125). Ligand B is slightly better here.

**15. Binding Affinity:** Both ligands have excellent binding affinity (-8.2 and -8.3 kcal/mol). The difference is negligible.

**Overall Assessment:**

Both compounds have significant drawbacks (poor solubility, poor Caco-2 permeability). However, Ligand A has a longer half-life, which is a crucial advantage for a CNS drug. While Ligand B has slightly better P-gp efflux, the longer half-life of Ligand A is more valuable in this context, as it suggests a potentially more sustained effect. The similar BBB values and affinities make the half-life the deciding factor.

Output:
1
2025-04-17 04:22:57,592 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (362.47 and 354.411 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (62.22) is excellent, well below the 90 A^2 threshold for CNS targets. Ligand B (136.87) is higher, but still potentially acceptable, though less ideal.

**logP:** Ligand A (3.504) is optimal. Ligand B (-2.563) is significantly lower, which could hinder membrane permeability and CNS penetration.

**H-Bond Donors/Acceptors:** Ligand A (HBD=2, HBA=4) and Ligand B (HBD=4, HBA=5) both fall within reasonable ranges.

**QED:** Ligand A (0.792) has a better QED score than Ligand B (0.43), indicating better overall drug-likeness.

**DILI:** Ligand A (48.236) has a lower DILI risk than Ligand B (22.722), suggesting a safer profile.

**BBB:** Ligand A (68.515) has a significantly better BBB penetration score than Ligand B (53.548). While both are not >70, A is closer and more promising for a CNS target.

**Caco-2 Permeability:** Ligand A (-4.412) has a negative Caco-2 value, which is unusual and suggests poor permeability. Ligand B (-5.934) is even worse. This is a significant concern for both.

**Aqueous Solubility:** Ligand A (-4.436) and Ligand B (-1.36) both have negative solubility values, indicating very poor aqueous solubility. This is a major drawback for both.

**hERG Inhibition:** Ligand A (0.569) has a lower hERG risk than Ligand B (0.027), which is a positive.

**Microsomal Clearance:** Ligand A (38.813) has a higher (worse) microsomal clearance than Ligand B (-33.85). This suggests Ligand B is more metabolically stable.

**In vitro Half-Life:** Ligand A (5.018) has a shorter half-life than Ligand B (-11.673).

**P-gp Efflux:** Ligand A (0.372) has lower P-gp efflux than Ligand B (0.0). Lower efflux is better for CNS exposure.

**Binding Affinity:** Ligand B (-8.1) has a slightly better binding affinity than Ligand A (-7.8). However, the difference is only 0.3 kcal/mol, which is not substantial enough to outweigh other significant drawbacks.

**Overall Assessment:**

Ligand A is superior despite the negative Caco-2 and solubility values. Its better BBB penetration, logP, QED, DILI, and P-gp efflux properties are crucial for a CNS-targeting GPCR ligand. Ligand B's poor logP and lower BBB penetration are major liabilities. While Ligand B has better metabolic stability and slightly higher affinity, these are less critical than the ADME properties for a CNS drug. The negative Caco-2 and solubility for both are concerning and would require significant medicinal chemistry efforts to address, but Ligand A is the better starting point.

Output:
0
2025-04-17 04:22:57,592 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (345.443 Da) is slightly lower, which could be beneficial for permeability. Ligand B (381.9 Da) is also good.

**TPSA:** Ligand A (75.44) is better than Ligand B (37.38) for CNS penetration, being closer to the <90 threshold for CNS targets.

**logP:** Both ligands have acceptable logP values (A: 2.893, B: 4.812). Ligand A is optimal (1-3), while Ligand B is pushing the upper limit, potentially leading to solubility issues and off-target interactions.

**H-Bond Donors/Acceptors:** Ligand A (HBD=1, HBA=4) and Ligand B (HBD=0, HBA=3) both have reasonable numbers of H-bond donors and acceptors, falling within the guidelines.

**QED:** Both ligands have similar QED values (A: 0.635, B: 0.625), indicating good drug-like properties.

**DILI:** Ligand B (35.673) has a significantly lower DILI risk than Ligand A (56.65), which is a major advantage.

**BBB:** Both ligands have good BBB penetration (A: 65.529, B: 73.401), but Ligand B is slightly better, exceeding 70%.

**Caco-2 Permeability:** Ligand A (-5.012) has a negative Caco-2 value, which is unusual and suggests very poor permeability. Ligand B (-4.753) is also poor, but slightly better than A.

**Aqueous Solubility:** Both ligands have poor aqueous solubility (A: -2.93, B: -4.514). This is a concern, but can sometimes be mitigated with formulation strategies.

**hERG Inhibition:** Ligand A (0.104) has a very low hERG risk, which is excellent. Ligand B (0.666) has a moderate hERG risk, which is acceptable but requires further investigation.

**Microsomal Clearance:** Ligand B (76.77) has a slightly higher microsomal clearance than Ligand A (74.608), indicating potentially lower metabolic stability.

**In vitro Half-Life:** Ligand B (60.908) has a significantly longer in vitro half-life than Ligand A (-39.813), which is a substantial advantage.

**P-gp Efflux:** Both ligands have very low P-gp efflux (A: 0.325, B: 0.811), which is favorable for CNS exposure.

**Binding Affinity:** Ligand B (-7.2 kcal/mol) has a significantly stronger binding affinity than Ligand A (-0.0 kcal/mol). This is a crucial factor, as a >1.5 kcal/mol advantage can outweigh other drawbacks.

**Overall Assessment:**

While Ligand A has a better TPSA and lower hERG risk, Ligand B is superior due to its significantly stronger binding affinity, better BBB penetration, lower DILI risk, and longer half-life. The poor Caco-2 permeability and slightly higher logP of Ligand B are concerns, but the substantial binding affinity advantage outweighs these drawbacks, especially for a CNS target like DRD2.

Output:
1
2025-04-17 04:22:57,593 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (367.471 and 370.406 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (87.74) is better than Ligand B (109.33). For CNS targets, we want TPSA <= 90, and A is comfortably within this range, while B is approaching the upper limit.

**3. logP:** Both ligands have acceptable logP values (-0.392 and -0.086), falling within the 1-3 range, though on the lower side. This isn't a major concern, but higher values would be preferable for membrane permeability.

**4. H-Bond Donors:** Ligand A (2) is slightly higher than Ligand B (1), but both are within the acceptable limit of <= 5.

**5. H-Bond Acceptors:** Both ligands have 6 H-bond acceptors, well within the limit of <= 10.

**6. QED:** Both ligands have good QED scores (0.51 and 0.719), indicating good drug-like properties. Ligand B is slightly better.

**7. DILI:** Ligand A (25.63) has a significantly lower DILI risk than Ligand B (64.676). This is a major advantage for Ligand A.

**8. BBB:** Ligand B (77.705) has a substantially better BBB penetration score than Ligand A (56.65). This is *critical* for a CNS target like DRD2.

**9. Caco-2 Permeability:** Ligand A (-5.249) has lower Caco-2 permeability than Ligand B (-4.58). This suggests potentially poorer intestinal absorption for Ligand A, but this is less important than BBB for a CNS target.

**10. Aqueous Solubility:** Both ligands have very poor aqueous solubility (-2.461 and -2.229). This is a potential issue for both, but formulation strategies might mitigate it.

**11. hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.16 and 0.066).

**12. Microsomal Clearance:** Ligand B (1.651) has much lower microsomal clearance than Ligand A (23.39), indicating better metabolic stability. This is a significant advantage for Ligand B.

**13. In vitro Half-Life:** Ligand B (12.041) has a much longer in vitro half-life than Ligand A (-3.669). This is a strong advantage for Ligand B.

**14. P-gp Efflux:** Both ligands show very low P-gp efflux liability (0.015 and 0.012).

**15. Binding Affinity:** Both ligands have the same binding affinity (-7.7 kcal/mol), which is excellent.

**Overall Assessment:**

While Ligand A has a lower DILI risk and a slightly better TPSA, Ligand B clearly wins out due to its significantly better BBB penetration (77.705 vs 56.65), lower microsomal clearance, and longer half-life. For a CNS target like DRD2, BBB penetration is paramount. The improved metabolic stability and half-life of Ligand B are also crucial for *in vivo* efficacy. The slightly worse DILI score is a concern, but potentially manageable.

Output:
1
2025-04-17 04:22:57,593 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B based on the provided guidelines, prioritizing GPCR-specific properties (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (362.461 Da and 361.511 Da) fall within the ideal range of 200-500 Da.

**TPSA:** Ligand A (78.43) is higher than Ligand B (54.46). For CNS targets, we want TPSA <= 90, so both are acceptable, but B is better.

**logP:** Both ligands have good logP values (2.642 and 2.781), falling within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A has 3 HBD and 3 HBA, while Ligand B has 1 HBD and 5 HBA. Both are within acceptable limits (<=5 HBD and <=10 HBA).

**QED:** Ligand B (0.876) has a significantly higher QED score than Ligand A (0.523), indicating a more drug-like profile.

**DILI:** Ligand A (23.73) has a lower DILI risk than Ligand B (38.775), which is preferable.

**BBB:** Ligand B (92.323) has a much higher BBB penetration percentile than Ligand A (65.374). This is a *critical* advantage for a CNS target like DRD2.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.881 and -4.873), which is unusual and doesn't provide useful information.

**Aqueous Solubility:** Both ligands have negative solubility values (-2.802 and -3.391), which is also unusual and doesn't provide useful information.

**hERG Inhibition:** Both ligands have low hERG inhibition liability (0.632 and 0.615), which is good.

**Microsomal Clearance:** Ligand B (58.647) has a higher microsomal clearance than Ligand A (39.915), indicating lower metabolic stability. This is a drawback for Ligand B.

**In vitro Half-Life:** Ligand A (10.264) has a longer in vitro half-life than Ligand B (4.567), which is preferable.

**P-gp Efflux:** Ligand B (0.362) has lower P-gp efflux liability than Ligand A (0.139), which is a benefit for CNS penetration.

**Binding Affinity:** Ligand B (-8.9 kcal/mol) has a significantly stronger binding affinity than Ligand A (-6.7 kcal/mol). This is a substantial advantage, potentially outweighing some of the ADME drawbacks.

**Overall Assessment:**

Ligand B is superior due to its significantly higher BBB penetration (92.323 vs 65.374) and much stronger binding affinity (-8.9 vs -6.7 kcal/mol). While Ligand B has a higher DILI risk and lower metabolic stability, the improved CNS penetration and potency are crucial for a DRD2 target. The higher QED score of Ligand B also supports its drug-like properties.

Output:
1
2025-04-17 04:22:57,593 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (343.431 and 361.507 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (81.07) is better than Ligand B (46.61). Both are below 90, which is good for CNS penetration.

**logP:** Both ligands have good logP values (2.548 and 3.345), falling within the optimal 1-3 range. Ligand B is slightly higher, which could be a minor concern for solubility, but not a dealbreaker.

**H-Bond Donors/Acceptors:** Ligand A has 2 HBD and 5 HBA, while Ligand B has 0 HBD and 4 HBA. Both are within acceptable limits (<=5 HBD and <=10 HBA).

**QED:** Both have similar QED values (0.897 and 0.808), indicating good drug-likeness.

**DILI:** Ligand A (62.737) has a higher DILI risk than Ligand B (28.616). This is a significant negative for Ligand A.

**BBB:** Ligand B (85.847) has a significantly better BBB penetration percentile than Ligand A (79.721). This is crucial for a CNS target like DRD2.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.88 and -4.822), which is unusual and suggests poor permeability. This is a concern for both.

**Aqueous Solubility:** Both ligands have negative solubility values (-4.089 and -3.244), indicating poor aqueous solubility. This is a concern for both, but might be less critical if BBB penetration is high.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.442 and 0.375).

**Microsomal Clearance:** Ligand A (75.515) has higher microsomal clearance than Ligand B (67.734), indicating lower metabolic stability.

**In vitro Half-Life:** Ligand B (6.948) has a longer in vitro half-life than Ligand A (35.518). This is a positive for Ligand B.

**P-gp Efflux:** Ligand A (0.242) has lower P-gp efflux liability than Ligand B (0.598), which is favorable for CNS exposure.

**Binding Affinity:** Ligand B (-7.7 kcal/mol) has a significantly stronger binding affinity than Ligand A (-10.2 kcal/mol). This is a major advantage for Ligand B, and can outweigh some of the ADME concerns.

**Overall Assessment:**

Ligand B is the more promising candidate. While both have issues with Caco-2 permeability and solubility, Ligand B has a significantly better BBB score, lower DILI risk, stronger binding affinity, and longer half-life. The stronger affinity is a substantial advantage for a GPCR target. Although Ligand A has slightly better P-gp efflux, the other factors strongly favor Ligand B.

Output:
1
2025-04-17 04:22:57,594 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B based on the provided guidelines, prioritizing GPCR-specific properties (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (339.355 and 348.399 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (123.76) is slightly above the optimal <90 for CNS targets, but still reasonable. Ligand B (81.01) is excellent, well below 90.

**logP:** Ligand A (2.044) is within the optimal 1-3 range. Ligand B (0.887) is a bit low, potentially hindering permeation.

**H-Bond Donors/Acceptors:** Ligand A has 4 HBD and 4 HBA, which are acceptable. Ligand B has 1 HBD and 5 HBA, also acceptable.

**QED:** Both ligands have good QED scores (0.579 and 0.772), indicating drug-like properties.

**DILI:** Ligand A (87.049) has a higher DILI risk than Ligand B (60.101), though both are within acceptable ranges.

**BBB:** This is critical for a CNS target. Ligand A (27.414) has a very poor BBB percentile, making it unlikely to reach the target in the brain. Ligand B (46.413) is better, but still not ideal (aim for >70).

**Caco-2 Permeability:** Ligand A (-5.886) shows poor permeability. Ligand B (-4.442) is better, but still low.

**Aqueous Solubility:** Both ligands have very poor aqueous solubility (-3.179 and -2.414). This could pose formulation challenges.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.133 and 0.158).

**Microsomal Clearance:** Ligand A (-21.936) has significantly lower (better) microsomal clearance than Ligand B (0.757), suggesting greater metabolic stability.

**In vitro Half-Life:** Ligand A (40.012) has a longer half-life than Ligand B (21.185).

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.024 and 0.072), which is favorable for CNS penetration.

**Binding Affinity:** Ligand B (-7.8 kcal/mol) has a significantly stronger binding affinity than Ligand A (-10.3 kcal/mol). This is a substantial advantage.

**Overall Assessment:**

While Ligand A has better metabolic stability and half-life, its extremely poor BBB penetration is a deal-breaker for a CNS target like DRD2. Ligand B, despite its lower logP and Caco-2 permeability, has a significantly better binding affinity and a moderately improved BBB score. The stronger binding affinity is likely to outweigh the permeability concerns, especially considering the low P-gp efflux for both. The solubility issues are a concern for both, but can potentially be addressed with formulation strategies.

Output:
1
2025-04-17 04:22:57,594 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 drug candidates, considering the provided guidelines and GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (364.555 Da and 377.455 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (49.41) is excellent, well below the 90 A^2 threshold for CNS targets. Ligand B (135.25) is higher, but still potentially acceptable, though less favorable.

**logP:** Ligand A (3.206) is optimal (1-3). Ligand B (0.475) is quite low, potentially hindering membrane permeability and CNS penetration.

**H-Bond Donors/Acceptors:** Ligand A (HBD=1, HBA=3) is well within the desirable ranges. Ligand B (HBD=3, HBA=9) is at the upper limit for HBA, but acceptable.

**QED:** Ligand A (0.815) is excellent, indicating high drug-likeness. Ligand B (0.593) is acceptable, but less optimal.

**DILI:** Ligand A (22.993) has a very low DILI risk. Ligand B (86.39) has a significantly higher DILI risk, which is concerning.

**BBB:** Ligand A (75.301) has a good BBB percentile, desirable for a CNS target. Ligand B (58.007) is lower, suggesting limited brain penetration.

**Caco-2 Permeability:** Ligand A (-5.025) has poor Caco-2 permeability. Ligand B (-6.11) also has poor Caco-2 permeability.

**Aqueous Solubility:** Ligand A (-4.313) has poor aqueous solubility. Ligand B (-2.225) has slightly better aqueous solubility.

**hERG Inhibition:** Both ligands (0.314 and 0.443) have low hERG inhibition risk.

**Microsomal Clearance:** Ligand A (62.673) has moderate clearance. Ligand B (9.813) has very low clearance, indicating good metabolic stability.

**In vitro Half-Life:** Ligand A (-4.062) has a negative half-life, which is unusual and likely indicates a very short half-life. Ligand B (-16.287) also has a negative half-life, indicating a very short half-life.

**P-gp Efflux:** Both ligands (0.185 and 0.255) have low P-gp efflux liability, which is good.

**Binding Affinity:** Both ligands have strong binding affinities (-7.0 and -8.3 kcal/mol). Ligand B has a slightly better affinity.

**Overall Assessment:**

Ligand A excels in TPSA, QED, DILI, and BBB, crucial for a CNS-targeting GPCR. However, it suffers from poor Caco-2 permeability and aqueous solubility, and a very short in vitro half-life.

Ligand B has a better binding affinity and metabolic stability (lower Cl_mic), but its low logP, higher DILI risk, and lower BBB penetration are significant drawbacks.

Considering the GPCR-specific priorities, BBB penetration is paramount for CNS targets. Ligand A's superior BBB score and lower DILI risk, combined with acceptable TPSA and logP, make it the more promising candidate despite its permeability and solubility issues, which could potentially be addressed through formulation strategies. The affinity difference is not large enough to outweigh the ADME advantages of Ligand A.

Output:
0
2025-04-17 04:22:57,594 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, considering the provided guidelines and GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (360.328 and 365.543 Da) fall within the ideal range of 200-500 Da.

**TPSA:** Ligand A (61.83) is better than Ligand B (71.09). Both are below 90, which is good for CNS penetration.

**logP:** Both ligands have good logP values (3.921 and 3.787), falling within the optimal range of 1-3.

**H-Bond Donors/Acceptors:** Ligand A (0 HBD, 5 HBA) is slightly preferable to Ligand B (2 HBD, 4 HBA) as lower HBD generally improves BBB penetration. Both are within acceptable limits.

**QED:** Both ligands have good QED scores (0.72 and 0.805), indicating good drug-likeness.

**DILI:** Both ligands have similar, acceptable DILI risk (52.074 and 51.997 percentile).

**BBB:** Both ligands have excellent BBB penetration (79.992 and 78.209 percentile), which is crucial for a CNS target like DRD2.

**Caco-2 Permeability:** Ligand A (-4.263) is better than Ligand B (-4.749). Higher values indicate better absorption.

**Aqueous Solubility:** Ligand A (-4.593) is better than Ligand B (-5.867). Higher values are preferred.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.416 and 0.545 percentile).

**Microsomal Clearance:** Ligand A (43.353) has significantly lower microsomal clearance than Ligand B (78.878), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (-0.91) has a slightly better in vitro half-life than Ligand B (-1.881).

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.29 and 0.247 percentile), which is good for CNS exposure.

**Binding Affinity:** Ligand A (-8.8 kcal/mol) has a slightly better binding affinity than Ligand B (-8.5 kcal/mol). While both are excellent, the 0.3 kcal/mol difference is noteworthy.

**Overall Assessment:**

Considering all factors, Ligand A is slightly more favorable. It has a better TPSA, Caco-2 permeability, solubility, microsomal clearance, and binding affinity. While both ligands have excellent BBB penetration and acceptable ADME properties, the combination of slightly improved pharmacokinetic parameters and binding affinity makes Ligand A the better candidate.

Output:
0
2025-04-17 04:22:57,595 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (355.43 and 352.44 Da) fall comfortably within the ideal 200-500 Da range.

**TPSA:** Ligand A (88.83) is excellent, falling below the 90 A^2 threshold for CNS targets. Ligand B (100.71) is slightly higher but still acceptable.

**logP:** Ligand A (2.232) is optimal (1-3). Ligand B (-0.022) is quite low, potentially hindering permeability and reducing the likelihood of good brain penetration.

**H-Bond Donors/Acceptors:** Both ligands have 1 HBD and 7 HBA, which are within acceptable limits (<=5 HBD and <=10 HBA).

**QED:** Both ligands have similar QED values (0.761 and 0.715), indicating good drug-like properties.

**DILI:** Ligand A (73.44) has a higher DILI risk than Ligand B (29.31), but both are below the concerning threshold of 60.

**BBB:** Ligand A (56.50) is better than Ligand B (30.75), but both are below the desirable 70% for CNS targets. However, considering the other parameters, BBB is less of a deciding factor here.

**Caco-2 Permeability:** Ligand A (-5.072) is significantly worse than Ligand B (-4.902), indicating lower intestinal absorption.

**Aqueous Solubility:** Ligand A (-2.768) is worse than Ligand B (-0.37), suggesting potential formulation challenges.

**hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.399 and 0.071), which is excellent.

**Microsomal Clearance:** Ligand A (37.12) has higher clearance than Ligand B (-13.32), indicating lower metabolic stability. Ligand B is significantly more stable.

**In vitro Half-Life:** Ligand B (5.576) has a longer half-life than Ligand A (2.057).

**P-gp Efflux:** Ligand A (0.2) has lower P-gp efflux than Ligand B (0.038), which is favorable for CNS penetration.

**Binding Affinity:** Ligand A (-9.6 kcal/mol) has a significantly stronger binding affinity than Ligand B (-8.1 kcal/mol). This is a substantial difference (1.5 kcal/mol), and is a major advantage.

**Overall Assessment:**

Despite Ligand A's better P-gp efflux, the combination of Ligand B's superior logP, metabolic stability (lower Cl_mic, longer t1/2), solubility, and acceptable DILI risk makes it a more promising candidate. The significantly stronger binding affinity of Ligand A is attractive, but the poor logP and metabolic stability are significant drawbacks for a CNS target. The difference in affinity might be overcome with further optimization of Ligand B.

Output:
1
2025-04-17 04:22:57,595 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B based on the provided guidelines, prioritizing GPCR-specific properties (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (338.411 and 351.353 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (67.23) is better than Ligand B (73.48). Both are below the 90 A^2 threshold desirable for CNS targets, but A is closer to optimal.

**logP:** Both ligands have good logP values (2.037 and 1.146), falling within the 1-3 range. Ligand A is slightly better.

**H-Bond Donors/Acceptors:** Both have acceptable HBD (1) and HBA (4/3) counts, well within the guidelines.

**QED:** Both ligands have good QED scores (0.931 and 0.809), indicating good drug-like properties.

**DILI:** Ligand A (59.713) has a higher DILI risk than Ligand B (39.667), which is preferable.

**BBB:** Ligand B (90.151) significantly outperforms Ligand A (70.415) in BBB penetration, a critical factor for CNS targets like DRD2.

**Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and suggests poor permeability. However, the scale is not specified, so this is difficult to interpret.

**Aqueous Solubility:** Both have negative solubility values, which is also unusual and suggests poor solubility. Again, the scale is not specified.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.351 and 0.249).

**Microsomal Clearance:** Ligand B (-12.574) has a much lower (better) microsomal clearance than Ligand A (26.644), indicating greater metabolic stability.

**In vitro Half-Life:** Ligand B (-37.445) has a much longer in vitro half-life than Ligand A (20.783), which is desirable.

**P-gp Efflux:** Ligand A (0.235) has lower P-gp efflux than Ligand B (0.029), suggesting better CNS exposure.

**Binding Affinity:** Ligand A (-8.6 kcal/mol) has a slightly better binding affinity than Ligand B (-7.1 kcal/mol). The difference is 1.5 kcal/mol, which is significant.

**Overall Assessment:**

While Ligand A has a slightly better binding affinity, Ligand B excels in crucial ADME properties for a CNS-targeting GPCR. Specifically, its significantly higher BBB penetration, lower microsomal clearance, and longer half-life are major advantages. The lower DILI risk is also a positive. The slightly lower P-gp efflux of Ligand A is a minor benefit compared to the other advantages of Ligand B. The negative Caco-2 and solubility values are concerning for both, but the superior CNS penetration profile of Ligand B is more critical for this target.

Output:
1
2025-04-17 04:22:57,595 - INFO - Reasoning:

Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (352.387 and 350.463 Da) fall comfortably within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (106.87) is slightly above the optimal <90 for CNS targets, but still reasonable. Ligand B (85.25) is excellent, well below 90. This favors Ligand B.

**3. logP:** Ligand A (0.76) is a bit low, potentially hindering permeability. Ligand B (1.734) is better, falling within the optimal 1-3 range. This favors Ligand B.

**4. H-Bond Donors:** Both ligands have 2 HBD, which is within the acceptable limit of <=5.

**5. H-Bond Acceptors:** Ligand A has 6 HBA, and Ligand B has 5. Both are within the acceptable limit of <=10.

**6. QED:** Both ligands have good QED scores (0.598 and 0.748, respectively), indicating good drug-like properties.

**7. DILI:** Ligand A (47.421) and Ligand B (38.736) both have low DILI risk, below the 40 threshold, which is positive. Ligand B is slightly better.

**8. BBB:** Both ligands have reasonable BBB penetration (43.311 and 48.197, respectively), but neither exceeds the desirable >70 for CNS targets. Ligand B is slightly better.

**9. Caco-2:** Both ligands have negative Caco-2 values (-4.791 and -4.978). This is unusual and suggests poor permeability.

**10. Solubility:** Both ligands have negative solubility values (-2.736 and -2.733). This is also unusual and suggests poor solubility.

**11. hERG:** Both ligands have very low hERG inhibition risk (0.139 and 0.313, respectively). This is excellent.

**12. Cl_mic:** Ligand A (59.83) has a higher microsomal clearance than Ligand B (43.662), indicating lower metabolic stability. This favors Ligand B.

**13. t1/2:** Ligand A (31.376) has a longer in vitro half-life than Ligand B (19.974). This favors Ligand A.

**14. Pgp:** Both ligands have very low P-gp efflux liability (0.023 and 0.051, respectively), which is excellent for CNS penetration.

**15. Binding Affinity:** Ligand B (-7.5 kcal/mol) has a significantly stronger binding affinity than Ligand A (-8.1 kcal/mol). This is a crucial advantage, as a >1.5 kcal/mol difference can outweigh other drawbacks.

**Overall Assessment:**

While both ligands have some concerning properties (negative Caco-2 and solubility values), Ligand B emerges as the more promising candidate. It has a better logP, lower Cl_mic, and, most importantly, a significantly stronger binding affinity for DRD2. The slightly better TPSA and DILI scores also contribute to its favorability. The longer half-life of Ligand A is a benefit, but the affinity difference is substantial.

Output:
1
2025-04-17 04:22:57,596 - INFO - Reasoning:

Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (380.901 and 398.304 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (75.19) is higher than Ligand B (57.94). For a CNS target like DRD2, TPSA should ideally be <=90. Both are acceptable, but B is better.

**3. logP:** Ligand A (2.292) and Ligand B (3.751) are both within the optimal 1-3 range. B is slightly higher, which could be beneficial for membrane permeability, but needs to be balanced with solubility.

**4. H-Bond Donors:** Both ligands have 1 HBD, which is within the acceptable limit of <=5.

**5. H-Bond Acceptors:** Ligand A has 6 HBAs, and Ligand B has 4. Both are below the limit of <=10.

**6. QED:** Both ligands have good QED scores (0.828 and 0.853), indicating good drug-like properties.

**7. DILI:** Ligand A has a DILI risk of 65.917, which is concerning as it's above the 60 threshold. Ligand B has a much lower DILI risk of 27.142, a significant advantage.

**8. BBB:** Ligand B (76.27) has a significantly better BBB penetration percentile than Ligand A (63.629). This is *critical* for a CNS target like DRD2.

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.245 and -5.019). This is unusual and suggests poor permeability. However, the scale isn't specified, so it's hard to interpret.

**10. Aqueous Solubility:** Both ligands have very poor aqueous solubility (-3.132 and -4.458). This is a significant drawback.

**11. hERG Inhibition:** Both ligands have low hERG inhibition risk (0.763 and 0.867), which is good.

**12. Microsomal Clearance:** Ligand A (8.127) has lower microsomal clearance than Ligand B (54.163), suggesting better metabolic stability.

**13. In vitro Half-Life:** Ligand A (45.928) has a longer in vitro half-life than Ligand B (20.753), which is desirable.

**14. P-gp Efflux:** Ligand A (0.202) has lower P-gp efflux than Ligand B (0.601), which is beneficial for CNS exposure.

**15. Binding Affinity:** Ligand B (-9.9 kcal/mol) has a significantly stronger binding affinity than Ligand A (-8.4 kcal/mol). This >1.5 kcal/mol difference is substantial and can outweigh some ADME drawbacks.

**Overall Assessment:**

While Ligand A has better metabolic stability and P-gp efflux, Ligand B is the superior candidate. The significantly stronger binding affinity (-9.9 vs -8.4 kcal/mol) and *much* lower DILI risk are major advantages. Critically, Ligand B also has a much better BBB penetration percentile (76.27 vs 63.629), which is paramount for a CNS-targeting drug. The solubility and Caco-2 permeability are poor for both, but the affinity and safety profile of Ligand B make it the more promising candidate.

Output:
1
2025-04-17 04:22:57,596 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 drug candidates, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (345.447 and 348.531 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (71.33) is higher than Ligand B (49.41). For a CNS target like DRD2, TPSA should ideally be <=90, so both are acceptable, but B is significantly better.

**3. logP:** Ligand A (1.482) is within the optimal range (1-3), while Ligand B (3.889) is approaching the upper limit. Both are acceptable, but A is slightly preferred.

**4. H-Bond Donors:** Ligand A (0) and Ligand B (1) are both low, which is favorable for permeability.

**5. H-Bond Acceptors:** Ligand A (5) and Ligand B (2) are both within the acceptable limit of <=10.

**6. QED:** Both ligands have similar QED values (0.775 and 0.792), indicating good drug-likeness.

**7. DILI:** Ligand A (33.075) has a slightly higher DILI risk than Ligand B (24.506), but both are below the concerning threshold of 60.

**8. BBB:** This is a critical parameter for CNS targets. Ligand B (83.172) has a significantly higher BBB penetration percentile than Ligand A (71.035). This is a major advantage for Ligand B.

**9. Caco-2 Permeability:** Both have negative values, indicating poor permeability. However, the scale is not specified, so it's hard to interpret.

**10. Aqueous Solubility:** Both have negative values, indicating poor solubility. Again, the scale is not specified.

**11. hERG Inhibition:** Ligand A (0.277) shows a lower hERG inhibition liability than Ligand B (0.578), which is preferable.

**12. Microsomal Clearance:** Ligand B (67.124) has higher microsomal clearance than Ligand A (36.838), indicating lower metabolic stability. A is preferred.

**13. In vitro Half-Life:** Ligand A (-7.276) has a much longer in vitro half-life than Ligand B (1.62). This is a significant advantage for A.

**14. P-gp Efflux:** Ligand A (0.081) has lower P-gp efflux liability than Ligand B (0.362), which is crucial for CNS penetration.

**15. Binding Affinity:** Both ligands have very similar binding affinities (-9.0 and -7.2 kcal/mol). Ligand A has a significantly better affinity.

**Overall Assessment:**

While Ligand B has a superior BBB score, Ligand A demonstrates a more favorable profile overall. It has better affinity, lower P-gp efflux, a longer half-life, lower microsomal clearance, and lower hERG inhibition. The slightly higher TPSA of Ligand A is less concerning than the higher logP and P-gp efflux of Ligand B. Considering the importance of CNS penetration and metabolic stability for a DRD2 targeting drug, Ligand A appears to be the more promising candidate.

Output:
0
2025-04-17 04:22:57,596 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (352.475 and 365.836 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (59.08) is significantly better than Ligand B (66.22). Both are below the 90 A^2 threshold desirable for CNS targets, but A is closer to optimal.

**logP:** Ligand A (1.82) is within the optimal 1-3 range. Ligand B (3.179) is at the higher end of the range, potentially raising concerns about solubility and off-target interactions.

**H-Bond Donors/Acceptors:** Both ligands have 0 HBD and 4 HBA, which are acceptable values.

**QED:** Both ligands have similar QED values (0.701 and 0.696), indicating good drug-likeness.

**DILI:** Ligand A (12.524) has a much lower DILI risk than Ligand B (21.946), a significant advantage.

**BBB:** Both ligands have excellent BBB penetration (83.831 and 86.196), exceeding the >70% threshold for CNS targets. Ligand B is slightly better.

**Caco-2 Permeability:** Both have negative Caco-2 values (-4.319 and -4.297). This is unusual and suggests poor permeability. However, these values are very close, so this is not a major differentiator.

**Aqueous Solubility:** Ligand A (-1.089) is better than Ligand B (-3.975), indicating better solubility.

**hERG:** Ligand A (0.195) has a lower hERG inhibition liability than Ligand B (0.752), which is crucial for avoiding cardiotoxicity.

**Microsomal Clearance:** Ligand A (39.353) has lower microsomal clearance than Ligand B (61.405), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (14.851) has a longer half-life than Ligand B (9.096), which is desirable.

**P-gp Efflux:** Ligand A (0.033) has significantly lower P-gp efflux liability than Ligand B (0.202), which is beneficial for CNS exposure.

**Binding Affinity:** Both ligands have the same binding affinity (-6.6 kcal/mol), which is good.

**Overall Assessment:**

Ligand A consistently outperforms Ligand B across most critical ADME properties, particularly DILI, solubility, hERG, microsomal clearance, P-gp efflux, and half-life. While both have good BBB penetration and acceptable TPSA, Ligand A's superior ADME profile makes it the more promising drug candidate. The slightly better logP of Ligand B is not enough to offset the other significant advantages of Ligand A.

Output:
0
2025-04-17 04:22:57,597 - INFO - Batch 108 complete. Total preferences: 1728
2025-04-17 04:22:57,597 - INFO - Processing batch 109/512...
2025-04-17 04:23:38,582 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (351.447 and 365.459 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (83.8) is excellent, falling well below the 90 A^2 threshold for CNS targets. Ligand B (108.09) is still reasonable but less optimal.

**logP:** Ligand A (1.016) is within the optimal 1-3 range. Ligand B (0.487) is slightly low, potentially hindering permeability, but not drastically.

**H-Bond Donors/Acceptors:** Ligand A has 2 HBD and 5 HBA, both well within acceptable limits. Ligand B has 1 HBD and 6 HBA, also acceptable.

**QED:** Both ligands have good QED scores (0.696 and 0.817), indicating drug-like properties.

**DILI:** Ligand A (33.23) has a much lower DILI risk than Ligand B (51.609), which is a significant advantage.

**BBB:** Ligand B (66.925) has a considerably better BBB penetration percentile than Ligand A (38.697). This is a crucial factor for a CNS target like DRD2.

**Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and suggests a potential issue with the data or modeling. However, we'll proceed assuming these represent relative permeability, and lower values are less favorable. Ligand A (-4.777) is slightly better than Ligand B (-5.067).

**Aqueous Solubility:** Both have negative solubility values, again suggesting a potential issue with the data. Ligand A (-1.399) is slightly better than Ligand B (-3.281).

**hERG Inhibition:** Both have low hERG inhibition risk (0.267 and 0.454).

**Microsomal Clearance:** Both have similar microsomal clearance values (27.406 and 28.044 mL/min/kg), indicating comparable metabolic stability.

**In vitro Half-Life:** Ligand A (19.824 hours) has a significantly longer half-life than Ligand B (-28.733 hours - a negative value is concerning and likely indicates poor stability).

**P-gp Efflux:** Both have low P-gp efflux liability (0.122 and 0.044), which is good for CNS penetration.

**Binding Affinity:** Ligand B (-8.1 kcal/mol) has a stronger binding affinity than Ligand A (-7.5 kcal/mol). This 0.6 kcal/mol difference is substantial and could outweigh some ADME drawbacks.

**Overall Assessment:**

Ligand B has a superior binding affinity and better BBB penetration, which are critical for a CNS GPCR target. However, it has a higher DILI risk, lower half-life, and a slightly less favorable TPSA. Ligand A has a better safety profile (lower DILI), better half-life, and TPSA, but its affinity and BBB penetration are significantly worse.

Given the importance of binding affinity for initial hit selection and the relatively high BBB for Ligand B, I lean towards **Ligand B** despite its slightly higher DILI risk. The DILI risk can be addressed in subsequent optimization rounds, but improving affinity is often more challenging.

Output:
1
2025-04-17 04:23:38,583 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 drug candidates, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (345.487 Da) is slightly lower, which is generally favorable for permeability. Ligand B (360.523 Da) is also good.

**TPSA:** Ligand A (73.2) is better than Ligand B (53.43). For CNS targets, we want TPSA <= 90, both are well within this range, but lower is better.

**logP:** Ligand A (3.172) is within the optimal range (1-3). Ligand B (4.074) is slightly higher, potentially leading to solubility issues or off-target interactions, but still acceptable.

**H-Bond Donors/Acceptors:** Both ligands have 1 HBD and 3-4 HBA, which are within the acceptable limits (<=5 HBD and <=10 HBA).

**QED:** Both ligands have similar QED values (0.795 and 0.733), indicating good drug-likeness.

**DILI:** Ligand A (20.977) has a significantly lower DILI risk than Ligand B (25.785), which is a major advantage.

**BBB:** Ligand A (65.839) has a slightly better BBB penetration percentile than Ligand B (62.117). While both are not ideal (>70), Ligand A is closer.

**Caco-2 Permeability:** Ligand A (-4.606) has better Caco-2 permeability than Ligand B (-4.855). Higher values indicate better absorption.

**Aqueous Solubility:** Ligand A (-3.096) has better aqueous solubility than Ligand B (-3.46).

**hERG Inhibition:** Ligand A (0.497) has a lower hERG inhibition liability than Ligand B (0.719), which is preferable for avoiding cardiotoxicity.

**Microsomal Clearance:** Ligand A (44.221) has lower microsomal clearance than Ligand B (74.854), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (-4.703) has a shorter in vitro half-life than Ligand B (42.315). This is a disadvantage for Ligand A.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.062 and 0.625 respectively), which is excellent for CNS penetration.

**Binding Affinity:** Ligand B (-7.4) has a significantly stronger binding affinity than Ligand A (-0.0). This is a crucial factor, as a >1.5 kcal/mol advantage can outweigh other drawbacks.

**Overall Assessment:**

Ligand B has a much stronger binding affinity, which is the most important factor for a GPCR ligand. While Ligand A has better ADME properties (lower DILI, better BBB, solubility, lower hERG, better metabolic stability), the substantial difference in binding affinity (-7.4 vs -0.0 kcal/mol) makes Ligand B the more promising candidate. The slightly higher logP and DILI risk of Ligand B could be addressed through further optimization, but the potency difference is difficult to overcome.

Output:
1
2025-04-17 04:23:38,583 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (382.595 Da) is slightly higher than Ligand B (346.427 Da), but both are acceptable.

**TPSA:** Ligand A (58.2) is excellent for CNS penetration, well below the 90 A^2 threshold. Ligand B (77.92) is still reasonable but less optimal.

**logP:** Ligand A (3.769) is within the optimal range (1-3). Ligand B (0.432) is quite low, potentially hindering membrane permeability and CNS entry.

**H-Bond Donors/Acceptors:** Both ligands have acceptable HBD (2 and 1 respectively) and HBA (4 each) counts.

**QED:** Both ligands have good QED scores (0.673 and 0.749), indicating drug-like properties.

**DILI:** Ligand A (47.266) has a slightly higher DILI risk than Ligand B (26.328), but both are below the concerning threshold of 60.

**BBB:** Ligand A (71.811) has a good BBB percentile, desirable for a CNS target. Ligand B (59.752) is significantly lower, raising concerns about brain penetration.

**Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual. Assuming these are logP-like scales, lower values indicate poorer permeability. Ligand A (-5.044) is worse than Ligand B (-4.814).

**Aqueous Solubility:** Both have negative solubility values, which is also unusual. Lower values suggest poor solubility. Ligand A (-4.791) is worse than Ligand B (-1.954).

**hERG Inhibition:** Ligand A (0.683) has a slightly higher hERG risk than Ligand B (0.043), but both are relatively low.

**Microsomal Clearance:** Ligand A (89.83) has a higher microsomal clearance than Ligand B (14.996), suggesting faster metabolism and potentially lower exposure.

**In vitro Half-Life:** Ligand A (37.619) has a longer half-life than Ligand B (10.218).

**P-gp Efflux:** Ligand A (0.395) has lower P-gp efflux than Ligand B (0.093), which is beneficial for CNS penetration.

**Binding Affinity:** Ligand A (-7.9 kcal/mol) has a significantly stronger binding affinity than Ligand B (-6.2 kcal/mol). This 1.7 kcal/mol difference is substantial and can outweigh some ADME drawbacks.

**Overall Assessment:**

Ligand A is the stronger candidate. While its Caco-2 and solubility are poor, its superior BBB penetration, lower P-gp efflux, and *much* stronger binding affinity (-7.9 vs -6.2 kcal/mol) are decisive advantages for a CNS-targeting GPCR like DRD2. The slightly higher DILI risk and clearance are less concerning given the potency. Ligand B's low logP and poor BBB penetration are significant liabilities.

Output:
1
2025-04-17 04:23:38,583 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (368.396 and 385.555 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (67.87) is significantly better than Ligand B (80.32). For CNS targets, TPSA should be <= 90, and A is comfortably within this range, while B is approaching the upper limit.

**3. logP:** Both ligands have good logP values (2.429 and 2.836), falling within the optimal 1-3 range.

**4. H-Bond Donors:** Ligand A (1) is preferable to Ligand B (2). Lower HBD generally improves permeability.

**5. H-Bond Acceptors:** Ligand A (4) is preferable to Ligand B (6). Lower HBA generally improves permeability.

**6. QED:** Both ligands have acceptable QED values (0.528 and 0.706), indicating good drug-like properties.

**7. DILI:** Ligand A (44.63) has a lower DILI risk than Ligand B (63.397), which is a significant advantage.

**8. BBB:** Ligand A (86.002) has a much higher BBB penetration percentile than Ligand B (43.079). This is *critical* for a CNS target like DRD2.

**9. Caco-2 Permeability:** Ligand A (-4.916) is better than Ligand B (-5.051), though both are negative, indicating relatively poor permeability.

**10. Aqueous Solubility:** Ligand A (-2.844) is better than Ligand B (-3.385), though both are negative, indicating poor solubility.

**11. hERG Inhibition:** Ligand A (0.537) has a lower hERG inhibition liability than Ligand B (0.123), which is a positive.

**12. Microsomal Clearance:** Ligand A (28.944) has lower microsomal clearance than Ligand B (36.134), suggesting better metabolic stability.

**13. In vitro Half-Life:** Ligand A (-5.177) has a longer in vitro half-life than Ligand B (16.517).

**14. P-gp Efflux:** Ligand A (0.102) has lower P-gp efflux liability than Ligand B (0.097).

**15. Binding Affinity:** Ligand B (-8.0) has a slightly better binding affinity than Ligand A (-7.9). However, the difference is only 0.1 kcal/mol, and the other ADME properties of Ligand A are significantly more favorable.

**Overall Assessment:**

Ligand A is the superior candidate. While Ligand B has a marginally better binding affinity, Ligand A excels in crucial ADME properties for a CNS-targeting GPCR, particularly BBB penetration, TPSA, DILI risk, and metabolic stability. The substantial difference in BBB penetration (86% vs 43%) is a decisive factor. The lower TPSA, DILI, and better metabolic profile further solidify Ligand A's position as the more promising drug candidate.

Output:
1
2025-04-17 04:23:38,584 - INFO - Reasoning:

Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (360.443 and 346.471 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (100.94) is slightly above the optimal <90 for CNS targets, but still reasonable. Ligand B (60.85) is excellent, well below the 90 threshold.

**3. logP:** Both ligands have good logP values (1.962 and 2.249), falling within the 1-3 range.

**4. H-Bond Donors:** Ligand A has 3 HBD, which is acceptable. Ligand B has 1 HBD, also acceptable.

**5. H-Bond Acceptors:** Ligand A has 6 HBA, within the limit of 10. Ligand B has 3 HBA, also within the limit.

**6. QED:** Both ligands have good QED scores (0.731 and 0.889), indicating good drug-like properties.

**7. DILI:** Ligand A (85.847) has a higher DILI risk than Ligand B (35.556). This is a significant negative for Ligand A.

**8. BBB:** Ligand B (57.193) has a significantly better BBB penetration score than Ligand A (45.366). This is crucial for a CNS target like DRD2.

**9. Caco-2 Permeability:** Ligand A (-5.629) has poor Caco-2 permeability. Ligand B (-4.369) is also poor, but slightly better.

**10. Aqueous Solubility:** Ligand A (-3.991) has poor aqueous solubility. Ligand B (-1.868) is also poor, but better than Ligand A.

**11. hERG Inhibition:** Both ligands have low hERG inhibition risk (0.156 and 0.687).

**12. Microsomal Clearance:** Ligand A (-4.223) has lower (better) microsomal clearance than Ligand B (65.161), indicating better metabolic stability.

**13. In vitro Half-Life:** Ligand A (34.629) has a longer half-life than Ligand B (-5.307).

**14. P-gp Efflux:** Ligand A (0.015) has very low P-gp efflux, which is excellent for CNS penetration. Ligand B (0.439) has moderate P-gp efflux.

**15. Binding Affinity:** Both ligands have very similar and strong binding affinities (-8.7 and -8.5 kcal/mol). The difference is negligible.

**Overall Assessment:**

Ligand B is the more promising candidate. While both have good affinity and acceptable logP/TPSA, Ligand B excels in key areas for a CNS GPCR target: significantly lower DILI risk, much better BBB penetration, and lower P-gp efflux. Although Ligand A has better metabolic stability and half-life, the superior safety profile and CNS penetration potential of Ligand B outweigh these advantages. The solubility and Caco-2 permeability are poor for both, but can be addressed with formulation strategies.

Output:
1
2025-04-17 04:23:38,584 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (352.475 and 350.419 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (78.87) is significantly better than Ligand B (93.53). For CNS targets, TPSA should be <= 90, so Ligand A is preferable.

**3. logP:** Both ligands have acceptable logP values (1.317 and 0.965), falling within the optimal range of 1-3.

**4. H-Bond Donors:** Both ligands are within the acceptable range (2 and 1, respectively).

**5. H-Bond Acceptors:** Both ligands are within the acceptable range (4 and 6, respectively).

**6. QED:** Both ligands have good QED scores (0.724 and 0.67), indicating drug-like properties.

**7. DILI:** Ligand A (9.19) has a much lower DILI risk than Ligand B (41.179). This is a significant advantage for Ligand A.

**8. BBB:** Ligand B (72.78) has a better BBB penetration percentile than Ligand A (56.805). While both are reasonably good, Ligand B is better here.

**9. Caco-2 Permeability:** Ligand A (-4.664) has slightly better Caco-2 permeability than Ligand B (-4.527), but both are negative values which is unusual and suggests poor permeability.

**10. Aqueous Solubility:** Ligand A (-2.235) has slightly better solubility than Ligand B (-1.817), but both are negative values which is unusual and suggests poor solubility.

**11. hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.253 and 0.125).

**12. Microsomal Clearance:** Ligand A (51.81) has a lower microsomal clearance than Ligand B (85.15), indicating better metabolic stability.

**13. In vitro Half-Life:** Ligand A (-4.313) has a much longer in vitro half-life than Ligand B (-22.437).

**14. P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.042 and 0.046).

**15. Binding Affinity:** Ligand A (-8.1 kcal/mol) has a significantly stronger binding affinity than Ligand B (-6.9 kcal/mol). This is a crucial advantage, exceeding the 1.5 kcal/mol difference threshold.

**Overall Assessment:**

Ligand A is clearly superior. While Ligand B has a slightly better BBB score, Ligand A excels in almost every other critical parameter, especially binding affinity, DILI risk, metabolic stability, and in vitro half-life. The substantial difference in binding affinity (-8.1 vs -6.9 kcal/mol) outweighs the slightly lower BBB score of Ligand A. The lower TPSA and DILI risk are also significant advantages.

Output:
1
2025-04-17 04:23:38,584 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (342.407 and 353.463 Da) fall within the ideal range of 200-500 Da.

**TPSA:** Ligand A (104.62) is slightly above the preferred <90 for CNS targets, but still reasonable. Ligand B (87.74) is well within the desired range.

**logP:** Ligand A (0.99) is a bit low, potentially hindering permeation. Ligand B (0.681) is also on the lower side, but similar to A.

**H-Bond Donors/Acceptors:** Both ligands have 2 HBD and a reasonable number of HBA (7 for A, 4 for B), satisfying the <5 HBD and <10 HBA guidelines.

**QED:** Both ligands have good QED scores (0.692 and 0.705), indicating drug-like properties.

**DILI:** Ligand A (58.24) has a moderate DILI risk, while Ligand B (15.2) has a very low risk, a significant advantage.

**BBB:** Ligand A (28.461) has a poor BBB penetration percentile, making it less suitable for a CNS target like DRD2. Ligand B (50.019) has a better, though still not ideal, BBB score.

**Caco-2 Permeability:** Both have negative Caco-2 values (-5.746 and -5.121) which is unusual and suggests poor permeability.

**Aqueous Solubility:** Both have negative solubility values (-2.467 and -0.862), which is also unusual and suggests poor solubility.

**hERG:** Both ligands have low hERG inhibition liability (0.272 and 0.089), which is good.

**Microsomal Clearance:** Ligand A (-5.452) has a negative clearance, which is not physically possible and likely an error in the data. Ligand B (8.858) has a moderate clearance.

**In vitro Half-Life:** Ligand A (38.84) has a reasonable half-life. Ligand B (10.292) has a very short half-life, which is a drawback.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.026 and 0.009), which is favorable for CNS penetration.

**Binding Affinity:** Ligand A (-8.8 kcal/mol) has a significantly stronger binding affinity than Ligand B (-7.8 kcal/mol). This 1.0 kcal/mol difference is substantial and could outweigh some ADME concerns.

**Overall Assessment:**

Despite Ligand A's superior binding affinity, its extremely poor BBB penetration and questionable microsomal clearance are major concerns for a CNS target. Ligand B, while having a weaker affinity, presents a much better ADME profile, particularly the significantly lower DILI risk and better (though still not great) BBB penetration. The negative solubility and Caco-2 values are concerning for both, but the affinity difference is large enough to potentially overcome these issues with formulation strategies.

Considering the GPCR-specific priorities, the better BBB and lower DILI risk of Ligand B make it the more promising candidate, despite the weaker binding affinity.

Output:
1
2025-04-17 04:23:38,584 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (348.4) is slightly better, being closer to the lower end which can aid permeability.

**TPSA:** Ligand A (93.73) is better than Ligand B (23.55). For CNS targets, we want TPSA <= 90, and Ligand A is closer to that threshold. Ligand B's very low TPSA is good for permeability but might indicate a lack of crucial interactions.

**logP:** Ligand A (2.204) is optimal (1-3). Ligand B (4.901) is higher, potentially leading to solubility issues and off-target effects.

**H-Bond Donors/Acceptors:** Ligand A (2 HBD, 6 HBA) and Ligand B (0 HBD, 4 HBA) both fall within acceptable ranges.

**QED:** Both ligands have good QED scores (A: 0.605, B: 0.745), indicating drug-like properties.

**DILI:** Ligand A (65.723) has a higher DILI risk than Ligand B (46.879), but both are acceptable.

**BBB:** Ligand B (98.876) significantly outperforms Ligand A (77.2) in BBB penetration, which is *critical* for a CNS target like DRD2.

**Caco-2 Permeability:** Both have negative values which is unusual. Assuming these are logP values, they are both poor.

**Aqueous Solubility:** Both have negative values which is unusual. Assuming these are logS values, they are both poor.

**hERG:** Ligand A (0.409) has a lower hERG risk than Ligand B (0.976), which is preferable.

**Microsomal Clearance:** Ligand A (64.562) has a higher microsomal clearance than Ligand B (22.929), indicating lower metabolic stability.

**In vitro Half-Life:** Ligand B (16.41) has a longer half-life than Ligand A (-5.012), which is desirable.

**P-gp Efflux:** Ligand A (0.064) has lower P-gp efflux than Ligand B (0.789), which is better for CNS exposure.

**Binding Affinity:** Both ligands have excellent binding affinities (-8.6 kcal/mol and -8.3 kcal/mol). The difference of 0.3 kcal/mol is not substantial enough to outweigh other factors.

**Overall Assessment:**

Ligand B excels in BBB penetration and has a longer half-life and lower DILI. While its logP is a bit high, the superior BBB penetration is a major advantage for a CNS target. Ligand A has better TPSA and lower hERG risk, but its lower BBB penetration and higher clearance are significant drawbacks. Given the GPCR-specific priorities, especially BBB, Ligand B is the more promising candidate.

Output:
1
2025-04-17 04:23:38,584 - INFO - Reasoning:

Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (414.221 Da) is slightly higher than Ligand B (361.913 Da), but both are acceptable.

**2. TPSA:**  Ligand A (38.33) is slightly higher than Ligand B (29.54). Both are well below the 90 A^2 threshold for CNS targets, which is excellent.

**3. logP:** Both ligands have good logP values (A: 4.754, B: 4.591), falling within the optimal range of 1-3, though slightly above. This could potentially lead to off-target effects, but is not a major concern at this stage.

**4. H-Bond Donors:** Ligand A has 1 HBD, and Ligand B has 0. Both are within the acceptable limit of <=5.

**5. H-Bond Acceptors:** Both ligands have 2 HBAs, well below the limit of <=10.

**6. QED:** Both ligands have similar QED values (A: 0.784, B: 0.767), indicating good drug-like properties.

**7. DILI:** Ligand A has a DILI risk of 64.909, which is moderately high. Ligand B has a much lower DILI risk (24.157), which is a significant advantage.

**8. BBB:** Ligand A has a BBB penetration percentile of 85.421, while Ligand B has 91.392. Both are excellent, exceeding the >70 threshold for CNS targets, but Ligand B is slightly better.

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.67 and -4.591), which is unusual and suggests poor permeability. This is a significant concern for both.

**10. Aqueous Solubility:** Both ligands have very poor aqueous solubility (-5.531 and -4.9). This is a major drawback for both compounds.

**11. hERG Inhibition:** Both ligands have low hERG inhibition risk (A: 0.812, B: 0.783), which is good.

**12. Microsomal Clearance:** Ligand A has a lower microsomal clearance (70.057) compared to Ligand B (102.754), indicating better metabolic stability.

**13. In vitro Half-Life:** Ligand A has a half-life of 38.075 hours, while Ligand B has 31.753 hours. Ligand A is slightly better.

**14. P-gp Efflux:** Both ligands have low P-gp efflux liability (A: 0.45, B: 0.735), which is favorable for CNS penetration.

**15. Binding Affinity:** Ligand A has a significantly better binding affinity (-10.5 kcal/mol) compared to Ligand B (-8.7 kcal/mol). This is a substantial advantage, potentially outweighing some of the ADME drawbacks.

**Overall Assessment:**

While both ligands have significant ADME issues (poor solubility and Caco-2 permeability), Ligand A's substantially stronger binding affinity (-10.5 vs -8.7 kcal/mol) is a critical advantage for a GPCR target. The slightly better metabolic stability (lower Cl_mic) and half-life also favor Ligand A. Although Ligand B has a lower DILI risk and slightly better BBB penetration, the potency difference is likely to be more impactful in driving efficacy.

Output:
1
2025-04-17 04:23:38,585 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (381.445 Da) is slightly higher than Ligand B (350.503 Da), but both are acceptable.

**TPSA:** Ligand A (95.58) is borderline for CNS penetration, being slightly above the preferred <90 threshold. Ligand B (49.85) is excellent, well below the 90 threshold.

**logP:** Ligand A (-0.576) is a bit low, potentially hindering permeability. Ligand B (2.543) is within the optimal range (1-3).

**H-Bond Donors/Acceptors:** Ligand A has 2 HBD and 5 HBA, which are reasonable. Ligand B has 0 HBD and 3 HBA, also acceptable.

**QED:** Both ligands have good QED scores (A: 0.616, B: 0.709), indicating good drug-like properties.

**DILI:** Ligand A (32.842) has a slightly higher DILI risk than Ligand B (11.632), but both are below the concerning 60 threshold.

**BBB:** Ligand B (88.329) has a significantly better BBB penetration score than Ligand A (64.831). This is a critical advantage for a CNS target like DRD2.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values, which is unusual and suggests poor permeability. However, the scale is not specified, so it's difficult to interpret.

**Aqueous Solubility:** Both ligands have negative solubility values, suggesting poor aqueous solubility. This is a concern for bioavailability.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (A: 0.113, B: 0.367).

**Microsomal Clearance:** Ligand A (-12.298) has a *negative* clearance, which is impossible and likely an error in the data. Ligand B (66.738) has a high clearance, indicating poor metabolic stability.

**In vitro Half-Life:** Ligand A (7.012) has a slightly better half-life than Ligand B (0.062).

**P-gp Efflux:** Ligand A (0.008) has very low P-gp efflux, which is excellent for CNS penetration. Ligand B (0.113) has slightly higher efflux, but still relatively low.

**Binding Affinity:** Both ligands have comparable binding affinities (-7.5 kcal/mol and -7.0 kcal/mol, respectively). Ligand A is slightly better, but the difference is less than the 1.5 kcal/mol threshold.

**Overall Assessment:**

Considering the GPCR-specific priorities, Ligand B is the more promising candidate. Its superior BBB penetration (88.329 vs. 64.831) and better logP (2.543 vs. -0.576) are crucial for CNS drug development. While Ligand A has a slightly better affinity and half-life, the negative microsomal clearance value is a major red flag, indicating a data error or a fundamentally unstable molecule. The lower TPSA of Ligand B is also beneficial.



Output:
1
2025-04-17 04:23:38,585 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (410.851 and 411.344 Da) fall within the ideal range of 200-500 Da.

**TPSA:** Ligand A (77.52) is higher than Ligand B (66.49). For a CNS target like DRD2, we prefer TPSA <= 90, so both are acceptable, but B is better.

**logP:** Both ligands have good logP values (2.949 and 3.087), falling within the optimal range of 1-3.

**H-Bond Donors/Acceptors:** Ligand A has 1 HBD and 6 HBA, while Ligand B has 2 HBD and 4 HBA. Both are within acceptable limits (<=5 HBD and <=10 HBA).

**QED:** Both ligands have reasonable QED values (0.792 and 0.748), indicating good drug-like properties.

**DILI:** Ligand A has a significantly higher DILI risk (94.959 percentile) compared to Ligand B (18.728 percentile). This is a major concern for Ligand A.

**BBB:** Ligand B (79.217 percentile) has a much better BBB penetration score than Ligand A (61.846 percentile). This is crucial for a CNS target like DRD2.

**Caco-2 Permeability:** Both have negative Caco-2 values which is unusual and suggests a potential issue with the data, but we can still compare them. Ligand A (-4.796) is slightly better than Ligand B (-4.977).

**Aqueous Solubility:** Ligand B (-1.718) has better aqueous solubility than Ligand A (-5.135).

**hERG:** Ligand A (0.29) has a lower hERG inhibition liability than Ligand B (0.679), which is favorable.

**Microsomal Clearance:** Ligand B (-17.909 mL/min/kg) has significantly lower microsomal clearance than Ligand A (37.34 mL/min/kg), indicating better metabolic stability.

**In vitro Half-Life:** Ligand B (26.926 hours) has a longer in vitro half-life than Ligand A (19.572 hours).

**P-gp Efflux:** Ligand A (0.333) has lower P-gp efflux liability than Ligand B (0.031), which is favorable for CNS penetration.

**Binding Affinity:** Both ligands have excellent binding affinities (-8.0 and -9.1 kcal/mol). Ligand B is slightly better.

**Overall Assessment:**

Ligand B is clearly the more promising candidate. While Ligand A has a slightly better hERG profile and P-gp efflux, its significantly higher DILI risk, lower BBB penetration, and higher microsomal clearance are major drawbacks. Ligand B excels in the critical areas for a CNS GPCR target: BBB penetration, metabolic stability, and lower toxicity (DILI). The slightly better binding affinity of Ligand B further strengthens its position.

Output:
1
2025-04-17 04:23:38,585 - INFO - Here's a step-by-step comparison of Ligand A and Ligand B, followed by my final decision:

**1. Molecular Weight (MW):** Both ligands (347.375 and 345.403 Da) fall comfortably within the ideal 200-500 Da range. No significant difference here.

**2. Topological Polar Surface Area (TPSA):** Ligand A (124.35) is slightly higher than Ligand B (112.91). For a CNS target like DRD2, we ideally want TPSA <= 90. Ligand B is closer to this target, which is a slight advantage.

**3. Lipophilicity (logP):** Ligand A (0.029) is quite low, potentially hindering membrane permeability. Ligand B (1.565) is within the optimal 1-3 range. This is a significant advantage for Ligand B.

**4. H-Bond Donors (HBD):** Both ligands have 3 HBD, which is acceptable (<=5).

**5. H-Bond Acceptors (HBA):** Ligand A has 6 HBA, and Ligand B has 5. Both are within the acceptable limit of <=10.

**6. QED:** Both ligands have good QED scores (0.677 and 0.735), indicating good drug-like properties.

**7. DILI:** Both ligands have relatively high DILI risk (69.523 and 67.197). This is a concern for both, but not a deciding factor between the two.

**8. BBB:** Ligand B (44.668) has a substantially better BBB penetration percentile than Ligand A (25.94). This is *critical* for a CNS target like DRD2.

**9. Caco-2 Permeability:** Ligand A (-5.637) has very poor Caco-2 permeability, while Ligand B (-5.424) is also poor, but slightly better.

**10. Aqueous Solubility:** Both ligands have poor aqueous solubility (-1.328 and -3.554). This could pose formulation challenges, but is less critical than BBB penetration for a CNS drug.

**11. hERG Inhibition:** Both ligands show very low hERG inhibition risk (0.029 and 0.212). This is positive for both.

**12. Microsomal Clearance (Cl_mic):** Ligand A (-3.144) has a negative value, suggesting very low clearance and high metabolic stability, which is good. Ligand B (7.51) has a higher clearance, indicating faster metabolism.

**13. In vitro Half-Life:** Ligand A (-3.376) has a negative value, suggesting a very long half-life, which is good. Ligand B (2.178) has a shorter half-life.

**14. P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.008 and 0.064). This is positive for both, aiding CNS exposure.

**15. Binding Affinity:** Ligand B (-9.6 kcal/mol) has a significantly stronger binding affinity than Ligand A (-7.1 kcal/mol). This >1.5 kcal/mol difference is a major advantage for Ligand B, potentially outweighing some of its ADME drawbacks.

**GPCR-Specific Considerations:** For DRD2 (a GPCR), BBB penetration, logP, Pgp efflux, TPSA, and affinity are paramount. Ligand B excels in BBB penetration and affinity, and has a more favorable logP. While Ligand A has better metabolic stability (Cl_mic and t1/2), the superior CNS penetration and binding of Ligand B are more important for this target.

**Conclusion:**

Ligand B is the more promising drug candidate.

1
2025-04-17 04:23:38,585 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (347.375 and 353.369 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (122.28) is slightly above the preferred <90 for CNS targets, but still reasonable. Ligand B (91.06) is well within the desired range. This favors Ligand B.

**3. logP:** Ligand A (0.849) is a bit low, potentially hindering membrane permeability. Ligand B (1.519) is better, falling within the optimal 1-3 range. This favors Ligand B.

**4. H-Bond Donors:** Both ligands have 3 HBD, which is acceptable.

**5. H-Bond Acceptors:** Ligand A has 7 HBA, which is acceptable. Ligand B has 3 HBA, which is also acceptable and potentially better for permeability.

**6. QED:** Both ligands have QED values > 0.5 (0.638 and 0.677), indicating good drug-like properties.

**7. DILI:** Ligand A (64.909) has a higher DILI risk than Ligand B (49.477). This favors Ligand B.

**8. BBB:** Ligand B (69.252) has a significantly better BBB percentile than Ligand A (54.634). This is a crucial advantage for a CNS target like DRD2.

**9. Caco-2:** Both have negative Caco-2 values, which is unusual and difficult to interpret without knowing the scale. Assuming these are logP-like scales, lower values indicate poorer permeability.

**10. Solubility:** Both ligands have negative solubility values, again making direct comparison difficult.

**11. hERG:** Both ligands have low hERG inhibition liability (0.332 and 0.438), which is good.

**12. Cl_mic:** Ligand B (-1.982) has a *negative* microsomal clearance, which is highly unusual and suggests very high metabolic stability. Ligand A (41.053) has a moderate clearance. This is a major advantage for Ligand B.

**13. t1/2:** Ligand B (-25.504) has a negative in vitro half-life, which is also unusual. Ligand A (-23.069) also has a negative half-life.

**14. Pgp:** Both ligands have low Pgp efflux liability (0.082 and 0.067), which is favorable for CNS penetration.

**15. Binding Affinity:** Ligand B (-9.1 kcal/mol) has a slightly better binding affinity than Ligand A (-8.6 kcal/mol). While the difference is not huge, it contributes to the overall preference for Ligand B.

**Overall Assessment:**

Ligand B is significantly more promising. It has better TPSA, logP, BBB penetration, DILI risk, and binding affinity. The negative values for Caco-2, solubility, and half-life are concerning and require further investigation, but the overall profile of Ligand B is superior, particularly regarding CNS penetration and metabolic stability. The negative clearance and half-life values are anomalous and would need to be verified experimentally, but even without that, the other factors strongly favor Ligand B.

Output:
1
2025-04-17 04:23:38,586 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight (MW):** Both ligands (345.443 and 346.431 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (70.49) is significantly better than Ligand B (87.46). For CNS targets, we want TPSA <= 90, and A is closer to the optimal <= 60 range. B is pushing the upper limit.

**3. logP:** Ligand A (2.489) is within the optimal 1-3 range. Ligand B (0.706) is a bit low, potentially hindering permeation.

**4. H-Bond Donors (HBD):** Both ligands have 2 HBD, which is acceptable (<=5).

**5. H-Bond Acceptors (HBA):** Both ligands have 5 HBA, which is acceptable (<=10).

**6. QED:** Both ligands have good QED scores (0.757 and 0.786), indicating good drug-like properties.

**7. DILI:** Ligand A (8.181) has a much lower DILI risk than Ligand B (39.24). This is a significant advantage for A.

**8. BBB:** Ligand A (79.062) has a much better BBB penetration score than Ligand B (29.508). This is *critical* for a CNS target like DRD2.

**9. Caco-2 Permeability:** Both have negative values, which is unusual. However, the magnitude of the negative value for A (-5.345) is less than that of B (-5.21), suggesting slightly better permeability.

**10. Aqueous Solubility:** Both have negative values, which is also unusual. The magnitude of the negative value for A (-3.167) is less than that of B (-1.813), suggesting slightly better solubility.

**11. hERG Inhibition:** Ligand A (0.904) has a slightly higher hERG risk than Ligand B (0.2), but both are relatively low.

**12. Microsomal Clearance:** Ligand A (7.455) has lower microsomal clearance than Ligand B (10.692), indicating better metabolic stability.

**13. In vitro Half-Life:** Ligand A (-34.235) has a much longer in vitro half-life than Ligand B (-11.564).

**14. P-gp Efflux:** Ligand A (0.079) has lower P-gp efflux than Ligand B (0.049), which is favorable for CNS penetration.

**15. Binding Affinity:** Ligand A (-8.7 kcal/mol) has a slightly better binding affinity than Ligand B (-7.9 kcal/mol). While both are good, the 0.8 kcal/mol difference is meaningful.

**Overall Assessment:**

Ligand A is significantly superior to Ligand B. It excels in crucial areas for a CNS-targeting GPCR ligand: BBB penetration, DILI risk, metabolic stability (Cl_mic and t1/2), and P-gp efflux. It also has slightly better binding affinity and acceptable physicochemical properties. While Ligand B has a slightly lower hERG risk, the advantages of Ligand A far outweigh this minor difference.

Output:
1
2025-04-17 04:23:38,586 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B based on the provided guidelines, prioritizing GPCR-specific properties (BBB, logP, Pgp, TPSA, and affinity) for DRD2.

**Molecular Weight:** Both ligands (352.435 and 344.459 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (102.74) is slightly above the optimal <90 for CNS targets, but still reasonable. Ligand B (69.87) is excellent, well below 90.

**logP:** Ligand A (-0.007) is quite low, potentially hindering permeation. Ligand B (2.137) is within the optimal 1-3 range. This is a significant advantage for Ligand B.

**H-Bond Donors/Acceptors:** Ligand A (1 HBD, 5 HBA) and Ligand B (2 HBD, 5 HBA) both have acceptable numbers of hydrogen bond donors and acceptors.

**QED:** Both ligands have good QED scores (0.724 and 0.807), indicating good drug-like properties.

**DILI:** Ligand A (39.201) has a slightly higher DILI risk than Ligand B (13.571), but both are below the concerning threshold of 60.

**BBB:** This is critical for DRD2. Ligand A (36.293) has a poor BBB percentile, suggesting limited CNS penetration. Ligand B (65.103) is much better, though ideally >70.

**Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and difficult to interpret. However, the magnitude of the negative value for Ligand A (-4.875) is larger than Ligand B (-5.048) suggesting slightly better permeability.

**Aqueous Solubility:** Both ligands have poor aqueous solubility (-1.191 and -1.654).

**hERG Inhibition:** Both ligands show low hERG inhibition risk (0.211 and 0.348).

**Microsomal Clearance:** Ligand A (21.031) has a higher microsomal clearance than Ligand B (10.366), indicating lower metabolic stability.

**In Vitro Half-Life:** Ligand B (71.545) has a significantly longer in vitro half-life than Ligand A (15.779).

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.022 and 0.024), which is favorable for CNS penetration.

**Binding Affinity:** Ligand B (-7.4 kcal/mol) has a substantially stronger binding affinity than Ligand A (-0.0 kcal/mol). This is a decisive advantage.

**Overall Assessment:**

Ligand B is significantly more promising. It has a better logP, much better BBB penetration, a longer half-life, lower clearance, and, most importantly, a dramatically superior binding affinity. While both have poor solubility, the strong affinity of Ligand B could potentially overcome this issue. Ligand A's poor logP and BBB penetration are major drawbacks for a CNS target like DRD2.

Output:
1
2025-04-17 04:23:38,586 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (352.479 Da) is slightly lower, which could be beneficial for permeability. Ligand B (380.495 Da) is also good.

**TPSA:** Ligand A (72.96) is excellent, falling well below the 90 A^2 threshold for CNS targets. Ligand B (92.26) is still reasonable but less optimal, being closer to the 90 A^2 limit.

**logP:** Ligand A (0.302) is quite low, potentially hindering membrane permeability. Ligand B (2.31) is within the optimal range (1-3). This is a significant advantage for Ligand B.

**H-Bond Donors/Acceptors:** Both ligands have 1 HBD and are within acceptable limits. Ligand B has 7 HBA, while Ligand A has 4. Both are acceptable.

**QED:** Both ligands have good QED scores (A: 0.746, B: 0.777), indicating drug-like properties.

**DILI:** Ligand A (7.445) has a very low DILI risk, which is excellent. Ligand B (77.821) has a significantly higher DILI risk, which is a concern.

**BBB:** Ligand A (54.634) has a moderate BBB penetration score, while Ligand B (40.481) is lower. For a CNS target like DRD2, a higher BBB score is highly desirable.

**Caco-2 Permeability:** Ligand A (-5.276) has poor Caco-2 permeability, which aligns with its low logP. Ligand B (-4.882) is also poor, but slightly better than A.

**Aqueous Solubility:** Ligand A (-0.207) and B (-2.773) both have poor solubility.

**hERG Inhibition:** Both ligands have very low hERG inhibition risk (A: 0.209, B: 0.239).

**Microsomal Clearance:** Ligand A (-4.342) has a negative value, suggesting very low clearance and excellent metabolic stability. Ligand B (45.104) has a high clearance, indicating faster metabolism.

**In vitro Half-Life:** Ligand A (-6.965) has a negative value, suggesting a very long half-life. Ligand B (21.697) has a moderate half-life.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (A: 0.003, B: 0.326).

**Binding Affinity:** Ligand B (-7.8 kcal/mol) has significantly stronger binding affinity than Ligand A (-0.0 kcal/mol). This is a crucial advantage, potentially outweighing some of its ADME drawbacks.

**Overall Assessment:**

Ligand B has a much stronger binding affinity, a better logP, and acceptable H-bond characteristics. However, it suffers from higher DILI risk, lower BBB penetration, and higher metabolic clearance. Ligand A has excellent safety (DILI, hERG) and metabolic stability, but its low logP and weak binding affinity are major drawbacks, especially for a CNS target.

Despite the DILI and clearance concerns, the significantly superior binding affinity of Ligand B, combined with its acceptable logP, makes it the more promising candidate. Further optimization could address the DILI and clearance issues, but the potency advantage is difficult to recover.

Output:
1
2025-04-17 04:23:38,586 - INFO - Batch 109 complete. Total preferences: 1744
2025-04-17 04:23:38,587 - INFO - Processing batch 110/512...
2025-04-17 04:24:21,116 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (350.459 and 352.475 Da) fall comfortably within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (66.92) is significantly better than Ligand B (87.66). For CNS targets, we want TPSA <= 90, and A is closer to the optimal <=60 range. B is pushing the upper limit.

**3. logP:** Both ligands have good logP values (1.991 and 1.674), falling within the 1-3 range.

**4. H-Bond Donors:** Ligand A (0) is preferable to Ligand B (3). Fewer HBDs generally improve permeability.

**5. H-Bond Acceptors:** Both have 4 HBA, which is acceptable (<=10).

**6. QED:** Both ligands have similar and good QED values (0.562 and 0.58), indicating good drug-like properties.

**7. DILI:** Ligand A (30.748) has a much lower DILI risk than Ligand B (19.969). Lower is better, and A is well below the 40% threshold.

**8. BBB:** Ligand A (73.672) has a significantly higher BBB penetration percentile than Ligand B (60.605). This is *critical* for a CNS target like DRD2. A is above the desirable 70% threshold.

**9. Caco-2 Permeability:** Ligand A (-4.481) and Ligand B (-5.048) both have negative values, which is unusual. It's difficult to interpret without knowing the scale, but lower values likely indicate poorer permeability. However, the BBB score for A is much higher, potentially mitigating this concern.

**10. Aqueous Solubility:** Ligand A (-2.342) and Ligand B (-1.644) have negative solubility values, which is also unusual. Again, difficult to interpret without the scale, but lower values suggest poorer solubility.

**11. hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.295 and 0.118).

**12. Microsomal Clearance:** Ligand A (71.137) has a higher microsomal clearance than Ligand B (20.566). This means B is more metabolically stable, which is generally desirable.

**13. In vitro Half-Life:** Ligand A (-9.274) has a much longer in vitro half-life than Ligand B (-2.978). This is a significant advantage for dosing considerations.

**14. P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.172 and 0.042).

**15. Binding Affinity:** Ligand B (-8.1) has a slightly better binding affinity than Ligand A (-6.9). However, the difference is 1.2 kcal/mol, which, while noticeable, may not be enough to overcome the significant ADME advantages of Ligand A.

**Overall Assessment:**

Ligand A is the more promising candidate. While Ligand B has slightly better binding affinity, Ligand A excels in crucial ADME properties for a CNS-targeting GPCR: significantly better BBB penetration, lower DILI risk, longer half-life, and lower TPSA. The slightly higher clearance of A is a minor drawback compared to the substantial benefits in CNS penetration and safety.

Output:
0
2025-04-17 04:24:21,126 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (386.361 and 376.766 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (41.13) is significantly better than Ligand B (71.25). For CNS targets, we want TPSA <= 90, and A is comfortably within this range, while B is approaching the upper limit.

**logP:** Ligand A (4.416) is slightly higher than the optimal 1-3 range, but still potentially acceptable. Ligand B (3.077) is within the optimal range.

**H-Bond Donors/Acceptors:** Ligand A (2 HBD, 2 HBA) and Ligand B (1 HBD, 5 HBA) both have reasonable numbers of H-bonds.

**QED:** Both ligands have good QED scores (0.753 and 0.87), indicating good drug-like properties.

**DILI:** Ligand A (53.625) has a lower DILI risk than Ligand B (60.217), which is preferable. Both are below the concerning threshold of 60.

**BBB:** Ligand A (80.264) has a substantially better BBB penetration percentile than Ligand B (68.282). This is a *critical* factor for a CNS target like DRD2.

**Caco-2 Permeability:** Ligand A (-5.148) has a worse Caco-2 permeability than Ligand B (-4.688), but both are negative values, suggesting poor permeability.

**Aqueous Solubility:** Ligand A (-4.495) has slightly worse solubility than Ligand B (-3.369), but both are poor.

**hERG:** Ligand A (0.692) has a lower hERG risk than Ligand B (0.274), which is preferable.

**Microsomal Clearance:** Ligand B (53.686) has a lower microsomal clearance than Ligand A (23.535), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand B (-24.086) has a significantly longer in vitro half-life than Ligand A (2.367). This is a major advantage.

**P-gp Efflux:** Ligand A (0.229) has lower P-gp efflux than Ligand B (0.145), which is better for CNS penetration.

**Binding Affinity:** Ligand A (-8.3 kcal/mol) has a stronger binding affinity than Ligand B (-7.8 kcal/mol). The difference of 0.5 kcal/mol is significant, and can outweigh some ADME drawbacks.

**Overall Assessment:**

Ligand A excels in binding affinity and BBB penetration, which are crucial for a CNS GPCR target. It also has a better DILI score and lower P-gp efflux. However, it has poorer Caco-2 permeability, solubility, and metabolic stability (higher Cl_mic, shorter t1/2).

Ligand B has better metabolic stability (lower Cl_mic, longer t1/2), Caco-2 permeability, and solubility, but its BBB penetration is significantly lower, and its binding affinity is weaker.

Given the importance of CNS penetration and strong binding for DRD2, Ligand A is the more promising candidate despite its ADME liabilities. The stronger affinity and better BBB are likely to be more impactful for efficacy than the slightly poorer metabolic stability, especially in the early stages of drug development where optimization can address these issues.

Output:
0
2025-04-17 04:24:21,126 - INFO - Reasoning:

Let's analyze Ligand A and Ligand B based on the provided guidelines, prioritizing GPCR-specific properties (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (346.446 Da) is slightly lower, which could be beneficial for permeability.

**TPSA:** Ligand A (41.57) is significantly better than Ligand B (66.4), falling well below the 90 A^2 threshold for CNS targets. Ligand B is higher, potentially hindering BBB penetration.

**logP:** Both ligands have acceptable logP values (A: 2.104, B: 2.686), falling within the 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A (HBD=1, HBA=3) is preferable to Ligand B (HBD=0, HBA=6) as it strikes a better balance.

**QED:** Ligand A (0.911) has a much higher QED score than Ligand B (0.675), indicating better overall drug-likeness.

**DILI:** Ligand A (20.396) has a significantly lower DILI risk than Ligand B (56.146), which is a major advantage.

**BBB:** Ligand A (89.298) has a much higher BBB percentile than Ligand B (64.017). This is *critical* for a CNS target like DRD2.

**Caco-2 Permeability:** Both have negative values, indicating poor permeability.

**Aqueous Solubility:** Both have negative values, indicating poor solubility.

**hERG:** Both ligands have low hERG inhibition liability (A: 0.763, B: 0.197), which is good.

**Microsomal Clearance:** Ligand A (34.378) has a lower microsomal clearance than Ligand B (62.124), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (-10.441) has a negative half-life, while Ligand B (21.513) is positive, indicating better in vitro stability.

**P-gp Efflux:** Ligand A (0.232) has lower P-gp efflux liability than Ligand B (0.218), which is favorable for CNS penetration.

**Binding Affinity:** Ligand B (-7.3 kcal/mol) has a slightly better binding affinity than Ligand A (-9.3 kcal/mol). While affinity is important, the other ADME properties of Ligand A are far superior.

**Overall Assessment:**

Ligand A is significantly better overall. Its superior BBB penetration, lower DILI risk, better QED, lower TPSA, and lower microsomal clearance outweigh the slightly weaker binding affinity. For a CNS GPCR target, maximizing brain exposure and minimizing toxicity are paramount. Ligand B's higher TPSA and DILI risk are significant drawbacks.

Output:
1
2025-04-17 04:24:21,127 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B based on the provided guidelines, prioritizing GPCR-specific properties (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (390.615 Da) is slightly higher than Ligand B (315.482 Da), but both are acceptable.

**TPSA:** Ligand A (49.85) is better than Ligand B (23.47) for CNS penetration, being closer to the <90 A^2 target. Ligand B is quite low, which could potentially reduce binding affinity.

**logP:** Ligand A (2.939) is within the optimal range (1-3). Ligand B (4.266) is a bit high, potentially leading to solubility issues and off-target interactions.

**H-Bond Donors/Acceptors:** Ligand A has 0 HBD and 5 HBA, which is reasonable. Ligand B has 1 HBD and 3 HBA, also acceptable.

**QED:** Both ligands have good QED scores (Ligand A: 0.597, Ligand B: 0.86), indicating drug-like properties.

**DILI:** Ligand A (49.283) has a slightly higher DILI risk than Ligand B (24.738), but both are below the concerning threshold of 60.

**BBB:** Ligand B (89.182) significantly outperforms Ligand A (57.542) in BBB penetration, a crucial factor for CNS targets like DRD2.

**Caco-2 Permeability:** Ligand A (-4.644) has a negative Caco-2 value, which is undesirable. Ligand B (-5.093) is also negative, but slightly less so. Both suggest poor intestinal absorption.

**Aqueous Solubility:** Both ligands have very poor aqueous solubility (-3.313 and -4.089 respectively). This is a significant drawback.

**hERG Inhibition:** Ligand A (0.341) has a lower hERG inhibition risk than Ligand B (0.934), which is preferable.

**Microsomal Clearance:** Ligand B (75.804) has a higher microsomal clearance than Ligand A (63.966), indicating faster metabolism and potentially lower exposure.

**In vitro Half-Life:** Ligand B (25.195 hours) has a longer half-life than Ligand A (18.492 hours), which is generally desirable.

**P-gp Efflux:** Ligand A (0.311) has lower P-gp efflux liability than Ligand B (0.375), which is beneficial for CNS exposure.

**Binding Affinity:** Ligand B (-8.9 kcal/mol) has a significantly stronger binding affinity than Ligand A (-0.0 kcal/mol). This is a major advantage, potentially outweighing some of the ADME drawbacks.

**Overall Assessment:**

While Ligand B has a higher logP and slightly worse solubility and Caco-2 permeability, its *significantly* superior binding affinity (-8.9 vs -0.0 kcal/mol) and much better BBB penetration (89.182 vs 57.542) are decisive. The stronger binding is likely to overcome minor ADME issues, and the improved BBB penetration is critical for a CNS target like DRD2. Ligand A's very weak binding affinity makes it a poor candidate despite its slightly better DILI and hERG profiles.

Output:
1
2025-04-17 04:24:21,127 - INFO - Reasoning:

Let's analyze Ligand A and Ligand B based on the provided guidelines, prioritizing GPCR-specific properties (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (356.463 and 365.375 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (99.1) is higher than the preferred <90 for CNS targets, while Ligand B (56.07) is well within the range. This is a significant advantage for Ligand B.

**logP:** Ligand A (0.288) is quite low, potentially hindering membrane permeability. Ligand B (2.698) is within the optimal 1-3 range. This favors Ligand B.

**H-Bond Donors/Acceptors:** Ligand A has 3 HBD and 5 HBA, acceptable values. Ligand B has 0 HBD and 6 HBA, also acceptable.

**QED:** Both ligands have good QED scores (0.675 and 0.751), indicating drug-like properties.

**DILI:** Both ligands have low DILI risk (30.322 and 35.867), which is good.

**BBB:** This is critical for a CNS target like DRD2. Ligand A has a BBB percentile of 35.401, which is below the desirable >70. Ligand B has a much higher BBB percentile of 95.308, a major advantage.

**Caco-2 Permeability:** Ligand A (-4.987) and Ligand B (-4.646) both have negative Caco-2 values, which is unusual and suggests poor permeability. However, the scale is not specified, so it's difficult to interpret.

**Aqueous Solubility:** Ligand A (-1.091) and Ligand B (-3.505) both have negative solubility values, again, interpretation is limited without knowing the scale.

**hERG:** Ligand A (0.134) has a very low hERG risk, excellent. Ligand B (0.595) is slightly higher, but still relatively low.

**Microsomal Clearance:** Ligand A (16.803) and Ligand B (24.522) have moderate microsomal clearance. Lower is better, so Ligand A is slightly favored here.

**In vitro Half-Life:** Ligand A (8.815) has a shorter half-life than Ligand B (-4.014, which is likely a very long half-life given the negative value). This favors Ligand B.

**P-gp Efflux:** Ligand A (0.018) has very low P-gp efflux, which is excellent for CNS penetration. Ligand B (0.215) has slightly higher efflux, but still relatively low.

**Binding Affinity:** Ligand B (-7.5 kcal/mol) has significantly stronger binding affinity than Ligand A (0.0 kcal/mol). This is a substantial advantage, potentially outweighing some of the minor ADME drawbacks.

**Overall Assessment:**

Ligand B is the stronger candidate. While Ligand A has a slightly better hERG profile and lower microsomal clearance, Ligand B excels in the most crucial areas for a CNS-targeting GPCR: TPSA, logP, BBB, and, most importantly, binding affinity. The significantly higher BBB penetration and binding affinity of Ligand B are compelling advantages. The negative values for Caco-2 and solubility are concerning for both, but the overall profile of Ligand B is much more promising.

Output:
1
2025-04-17 04:24:21,127 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (364.339 and 348.491 Da) are within the ideal 200-500 Da range.

**TPSA:** Ligand A (58.64) is excellent, well below the 90 A^2 threshold for CNS targets. Ligand B (64.68) is still reasonable, but less optimal.

**logP:** Ligand A (1.826) is within the optimal 1-3 range. Ligand B (0.6) is a bit low, potentially hindering membrane permeability.

**H-Bond Donors/Acceptors:** Ligand A (HBD=1, HBA=3) and Ligand B (HBD=2, HBA=4) both have acceptable numbers of H-bond donors and acceptors.

**QED:** Both ligands have similar QED values (0.775 and 0.714), indicating good drug-likeness.

**DILI:** Ligand A (41.179) has a slightly higher DILI risk than Ligand B (5.273), but both are below the concerning threshold of 60.

**BBB:** This is a critical parameter for a CNS target like DRD2. Ligand A (87.476) has a very good BBB percentile, exceeding the desirable >70 threshold. Ligand B (54.866) is significantly lower, suggesting poor brain penetration.

**Caco-2 Permeability:** Ligand A (-4.649) and Ligand B (-5.397) both have negative Caco-2 values, which is unusual and suggests poor permeability. However, these values are on a scale where negative values are common and don't necessarily preclude development.

**Aqueous Solubility:** Ligand A (-3.749) and Ligand B (-1.555) both have negative solubility values, which is also unusual.

**hERG Inhibition:** Both ligands have very low hERG inhibition liability (0.42 and 0.274), which is excellent.

**Microsomal Clearance:** Ligand A (35.102) has a higher microsomal clearance than Ligand B (-25.778), suggesting lower metabolic stability. Ligand B is more metabolically stable.

**In vitro Half-Life:** Ligand B (-7.256) has a slightly longer in vitro half-life than Ligand A (-10.01), but both are negative, which is unusual.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.12 and 0.006), which is favorable for CNS penetration.

**Binding Affinity:** Crucially, both ligands have the same binding affinity (-7.9 kcal/mol), which is excellent and meets the > -7.0 kcal/mol criterion.

**Overall Assessment:**

Despite the unusual negative values for Caco-2 and solubility, the key differentiator here is the BBB penetration. Ligand A has a significantly higher BBB percentile (87.476) compared to Ligand B (54.866). Given that DRD2 is a CNS target, this is a decisive advantage. While Ligand B has better metabolic stability (lower Cl_mic), the superior BBB penetration of Ligand A outweighs this benefit. The similar binding affinities mean potency is not a distinguishing factor.

Output:
1
2025-04-17 04:24:21,128 - INFO - Reasoning:

Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight (MW):** Both ligands are within the ideal range (200-500 Da). Ligand A (399.822 Da) is slightly higher than Ligand B (343.391 Da), but both are acceptable.

**2. TPSA:** Ligand A (78.51) is significantly better than Ligand B (123.95). For CNS targets, we want TPSA <= 90, and Ligand A is comfortably within this range, while Ligand B is pushing the limit.

**3. logP:** Both ligands have good logP values (Ligand A: 2.213, Ligand B: 1.313), falling within the optimal 1-3 range.

**4. H-Bond Donors (HBD):** Both ligands have acceptable HBD counts (Ligand A: 2, Ligand B: 1), well below the threshold of 5.

**5. H-Bond Acceptors (HBA):** Both ligands have acceptable HBA counts (Ligand A: 4, Ligand B: 5), below the threshold of 10.

**6. QED:** Ligand A (0.795) has a much better QED score than Ligand B (0.331). A QED >= 0.5 is desirable, and Ligand A easily meets this criterion, indicating a more drug-like profile.

**7. DILI:** Ligand A (61.264) has a higher DILI risk than Ligand B (41.915), but both are below the concerning threshold of 60.

**8. BBB:** Ligand A (44.862) and Ligand B (40.675) both have relatively low BBB penetration. While >70 is desirable for CNS targets, these values are not drastically different and are a weakness for both.

**9. Caco-2:** Both have negative Caco-2 values (-5.155 and -4.93), which is unusual and suggests poor permeability. This is a significant concern for both.

**10. Solubility:** Both have negative solubility values (-3.711 and -1.443), indicating very poor aqueous solubility. This is a major drawback for both compounds.

**11. hERG:** Both ligands have very low hERG inhibition liability (Ligand A: 0.471, Ligand B: 0.196), which is excellent.

**12. Cl_mic:** Ligand A (3.278) has a much lower microsomal clearance than Ligand B (28.233), indicating better metabolic stability.

**13. t1/2:** Ligand A (-9.67) has a more negative in vitro half-life than Ligand B (-14.109), suggesting a longer half-life.

**14. Pgp:** Both ligands have very low P-gp efflux liability (Ligand A: 0.026, Ligand B: 0.015), which is favorable for CNS penetration.

**15. Binding Affinity:** Ligand A (-8.8 kcal/mol) has a significantly stronger binding affinity than Ligand B (-7.1 kcal/mol). This is a crucial advantage, as a >1.5 kcal/mol difference can outweigh other drawbacks.

**Overall Assessment:**

Despite both ligands having issues with Caco-2 permeability and solubility, Ligand A is the superior candidate. Its significantly better TPSA, QED, metabolic stability (lower Cl_mic), longer half-life, and, most importantly, much stronger binding affinity to DRD2 outweigh the slightly higher DILI risk and similar BBB values. The strong affinity suggests that even with permeability/solubility issues, achieving therapeutic concentrations in the brain might be possible with appropriate formulation strategies.

Output:
1
2025-04-17 04:24:21,128 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (370.559 and 356.813 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (58.64) is significantly better than Ligand B (80.05). For CNS targets, we want TPSA <= 90, and A is comfortably within that, while B is approaching the upper limit.

**logP:** Both ligands have good logP values (2.976 and 3.497), falling within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A (HBD=1, HBA=4) and Ligand B (HBD=2, HBA=5) both have reasonable numbers of H-bond donors and acceptors, well within the guidelines.

**QED:** Both ligands have good QED scores (0.634 and 0.706), indicating good drug-like properties.

**DILI:** Ligand A (26.173) has a much lower DILI risk than Ligand B (82.823). This is a significant advantage for A.

**BBB:** Ligand A (77.705) and Ligand B (82.668) both have good BBB penetration, exceeding the 70% threshold for CNS targets. B is slightly better.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.957 and -4.994). This is unusual and suggests poor permeability. However, these values are on a log scale and the absolute value is more important. They are very similar.

**Aqueous Solubility:** Both ligands have negative solubility values (-3.087 and -5.037). Again, these are on a log scale and indicate poor aqueous solubility. B is worse.

**hERG:** Both ligands have low hERG inhibition liability (0.581 and 0.645), which is good.

**Microsomal Clearance:** Ligand A (79.271) has a higher microsomal clearance than Ligand B (53.673), indicating lower metabolic stability. This favors B.

**In vitro Half-Life:** Ligand B (72.058) has a significantly longer in vitro half-life than Ligand A (-9.497), which is a strong advantage for B.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.301 and 0.232), which is favorable for CNS penetration.

**Binding Affinity:** Both ligands have excellent binding affinities (-7.0 and -9.6 kcal/mol). Ligand B is significantly more potent.

**Overall Assessment:**

Ligand B has a substantially better binding affinity and a longer half-life. However, it has a significantly higher DILI risk and worse aqueous solubility. Ligand A has a much lower DILI risk and better TPSA. The difference in binding affinity (2.6 kcal/mol) is substantial and likely outweighs the slightly higher DILI risk and lower TPSA of Ligand B, especially considering the good BBB penetration of both. The longer half-life of B is also a significant advantage.

Output:
1
2025-04-17 04:24:21,128 - INFO - Reasoning:

Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (347.423 and 343.45 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (118.06) is better than Ligand B (55.63). For CNS targets, we want TPSA <= 90, so Ligand B is significantly better in this regard.

**3. logP:** Ligand A (1.738) is within the optimal range (1-3). Ligand B (4.219) is slightly high, potentially leading to solubility issues and off-target effects.

**4. H-Bond Donors:** Both ligands have 1 HBD, which is acceptable.

**5. H-Bond Acceptors:** Ligand A has 4 HBA, and Ligand B has 5. Both are within the acceptable limit of <= 10.

**6. QED:** Ligand B (0.903) has a much better QED score than Ligand A (0.479), indicating a more drug-like profile.

**7. DILI:** Both ligands have acceptable DILI risk (Ligand A: 43.622, Ligand B: 49.283), both under the 60 threshold.

**8. BBB:** Ligand B (88.174) has a significantly higher BBB penetration percentile than Ligand A (55.099). This is *critical* for a CNS target like DRD2.

**9. Caco-2 Permeability:** Both have negative values, indicating poor permeability. Ligand A (-5.157) is slightly better than Ligand B (-4.907).

**10. Aqueous Solubility:** Both have negative values, indicating poor solubility. Ligand A (-2.086) is slightly better than Ligand B (-4.618).

**11. hERG Inhibition:** Both ligands have low hERG inhibition risk (Ligand A: 0.167, Ligand B: 0.491).

**12. Microsomal Clearance:** Ligand A (11.592) has a lower (better) microsomal clearance than Ligand B (46.825), suggesting better metabolic stability.

**13. In vitro Half-Life:** Ligand A (-5.878) has a negative half-life, which is concerning. Ligand B (34.267) has a much more reasonable half-life.

**14. P-gp Efflux:** Ligand A (0.016) has a much lower P-gp efflux liability than Ligand B (0.604). Lower P-gp efflux is desirable for CNS penetration.

**15. Binding Affinity:** Ligand B (-8.2 kcal/mol) has a significantly stronger binding affinity than Ligand A (-7.3 kcal/mol). This >1.5 kcal/mol difference is substantial and can outweigh some ADME drawbacks.

**Overall Assessment:**

While Ligand A has better metabolic stability and P-gp efflux, Ligand B is superior overall, especially considering the CNS target. The significantly higher BBB penetration (88.174 vs 55.099) and substantially improved binding affinity (-8.2 vs -7.3 kcal/mol) are decisive. The better QED score also supports Ligand B. Although Ligand B has a higher logP and lower Caco-2/solubility, the strong affinity and BBB penetration are likely to overcome these issues.

Output:
1
2025-04-17 04:24:21,128 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (371.771 and 351.441 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (83.48) is slightly above the optimal <90 for CNS targets, but still reasonable. Ligand B (38.13) is excellent, well below 90.

**logP:** Both ligands (3.265 and 3.919) are within the optimal 1-3 range, with Ligand B being slightly higher.

**H-Bond Donors/Acceptors:** Ligand A has 3 HBD and 4 HBA, which is acceptable. Ligand B has 0 HBD and 3 HBA, also acceptable.

**QED:** Both ligands have good QED scores (0.704 and 0.729), indicating good drug-like properties.

**DILI:** Ligand A has a DILI risk of 83.133, which is concerning (high risk, >60). Ligand B has a much lower DILI risk of 35.285, which is very favorable.

**BBB:** This is crucial for a CNS target. Ligand A has a BBB penetration of 36.371, which is poor. Ligand B has an excellent BBB penetration of 95.192.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.781 and -4.38), which is unusual and suggests poor permeability. However, these values are on a log scale and are likely indicating very low permeability.

**Aqueous Solubility:** Both ligands have negative solubility values (-4.096 and -4.072), indicating very low solubility. This is a significant drawback.

**hERG Inhibition:** Ligand A (0.279) has a slightly higher hERG risk than Ligand B (0.796), but both are relatively low.

**Microsomal Clearance:** Ligand A (39.065) has a lower microsomal clearance than Ligand B (71.018), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (56.736) has a significantly longer half-life than Ligand B (2.502).

**P-gp Efflux:** Ligand A (0.095) has lower P-gp efflux than Ligand B (0.687), which is favorable for CNS penetration.

**Binding Affinity:** Ligand B (-7.8 kcal/mol) has a slightly better binding affinity than Ligand A (-7.4 kcal/mol), although both are excellent. The 0.4 kcal/mol difference is significant.

**Overall Assessment:**

Ligand B is the superior candidate. While both have poor solubility and permeability, Ligand B excels in the critical areas for a CNS GPCR target: significantly better BBB penetration (95.192 vs 36.371), a much lower DILI risk (35.285 vs 83.133), and slightly improved binding affinity (-7.8 vs -7.4). The longer half-life of Ligand A is a plus, but is outweighed by the significant liabilities in BBB and DILI.

Output:
1
2025-04-17 04:24:21,129 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (352.435 Da) is slightly lower, which could be beneficial for permeability. Ligand B (371.497 Da) is also good.

**TPSA:** Ligand A (104.54) is borderline for CNS penetration, being slightly above the preferred <90. Ligand B (45.23) is excellent, well below the threshold. This is a significant advantage for Ligand B.

**logP:** Ligand A (0.795) is a bit low, potentially hindering membrane permeability. Ligand B (3.919) is very good, falling within the optimal range.

**H-Bond Donors/Acceptors:** Ligand A has 2 HBD and 5 HBA, which are acceptable. Ligand B has 1 HBD and 4 HBA, also acceptable.

**QED:** Both ligands have reasonable QED values (Ligand A: 0.479, Ligand B: 0.873). Ligand B's value is significantly higher, indicating a more drug-like profile.

**DILI:** Both ligands have similar, low DILI risk (Ligand A: 24.118, Ligand B: 24.04).

**BBB:** Ligand A (46.491) has a poor BBB percentile, making CNS penetration unlikely. Ligand B (91.314) has an excellent BBB percentile, a crucial advantage for a DRD2 ligand.

**Caco-2 Permeability:** Ligand A (-5.523) has very poor Caco-2 permeability. Ligand B (-4.862) is also poor, but slightly better than Ligand A.

**Aqueous Solubility:** Both ligands have poor aqueous solubility (Ligand A: -1.032, Ligand B: -3.721).

**hERG Inhibition:** Ligand A (0.117) has a very low hERG risk, which is excellent. Ligand B (0.683) has a slightly higher, but still acceptable, hERG risk.

**Microsomal Clearance:** Ligand A (45.711) has moderate clearance, while Ligand B (23.744) has lower clearance, suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (-23.003) has a very short half-life, a major drawback. Ligand B (-1.619) has a better, but still relatively short, half-life.

**P-gp Efflux:** Ligand A (0.021) has very low P-gp efflux, which is favorable. Ligand B (0.449) has slightly higher P-gp efflux, but still reasonably low.

**Binding Affinity:** Ligand A (-7.3 kcal/mol) has slightly better binding affinity than Ligand B (-6.9 kcal/mol), but the difference is not substantial enough to outweigh the significant ADME deficiencies of Ligand A.

**Overall Assessment:**

Ligand B is significantly more promising. Its superior BBB penetration, TPSA, logP, QED, and metabolic stability outweigh the slightly weaker binding affinity and poorer solubility compared to Ligand A. Ligand A's poor BBB and Caco-2 permeability, combined with its short half-life, make it a less viable candidate despite the slightly better affinity. Given the GPCR target and the need for CNS penetration, Ligand B is the clear choice.

Output:
1
2025-04-17 04:24:21,129 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (364.555 and 344.39 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (40.62) is significantly better than Ligand B (70.25).  For CNS targets, we want TPSA <= 90, and ideally closer to 60. Ligand A is well within this range, while Ligand B is approaching the upper limit and could present permeability challenges.

**logP:** Both ligands have good logP values (2.96 and 2.818), falling within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A (0 HBD, 4 HBA) is preferable to Ligand B (2 HBD, 3 HBA). Lower HBD/HBA generally improves permeability.

**QED:** Both ligands have good QED scores (0.778 and 0.876), indicating good drug-like properties.

**DILI:** Ligand A (20.202) has a much lower DILI risk than Ligand B (38.658).  Both are below 40, which is good, but A is significantly better.

**BBB:** Ligand A (91.663) has a substantially higher BBB penetration percentile than Ligand B (75.611). This is a *critical* advantage for a CNS target like DRD2.

**Caco-2 Permeability:** Ligand A (-4.726) and Ligand B (-4.517) are both negative, indicating poor permeability, but A is slightly better.

**Aqueous Solubility:** Ligand A (-2.16) and Ligand B (-3.219) are both poor, but B is worse.

**hERG:** Both ligands have low hERG inhibition liability (0.976 and 0.538), which is good.

**Microsomal Clearance:** Ligand A (30.628) has a higher (worse) microsomal clearance than Ligand B (-14.616). This suggests Ligand B is more metabolically stable.

**In vitro Half-Life:** Ligand A (13.653) has a longer half-life than Ligand B (-16.516).

**P-gp Efflux:** Ligand A (0.634) has lower P-gp efflux liability than Ligand B (0.119). Lower P-gp efflux is desirable, especially for CNS drugs.

**Binding Affinity:** Ligand B (-8.3 kcal/mol) has a slightly better binding affinity than Ligand A (-7.8 kcal/mol). While a 0.5 kcal/mol difference is notable, it is unlikely to overcome the significant ADME advantages of Ligand A.

**Overall Assessment:**

Ligand A is the stronger candidate. Its superior BBB penetration, lower DILI risk, better TPSA, and lower P-gp efflux are crucial for a CNS-targeting GPCR ligand. While Ligand B has slightly better affinity and metabolic stability, the ADME properties of Ligand A are far more favorable for *in vivo* efficacy and safety. The difference in binding affinity is unlikely to outweigh the substantial advantages in drug-like properties of Ligand A.

Output:
0
2025-04-17 04:24:21,129 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (367.427 and 364.515 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (90.73) is slightly above the optimal <90 for CNS targets, but still reasonable. Ligand B (56.75) is well within the desired range. This favors Ligand B.

**3. logP:** Both ligands have a logP around 1.6, which is optimal (1-3).

**4. H-Bond Donors:** Both have 0 HBD, which is acceptable.

**5. H-Bond Acceptors:** Ligand A has 7 HBA, and Ligand B has 6. Both are within the acceptable limit of <=10.

**6. QED:** Both ligands have good QED scores (0.546 and 0.654, respectively), indicating good drug-like properties. Ligand B is slightly better.

**7. DILI:** Ligand A (71.811) has a higher DILI risk than Ligand B (52.85). This favors Ligand B.

**8. BBB:** This is a critical parameter for a CNS target like DRD2. Ligand B (78.519) has a significantly better BBB penetration percentile than Ligand A (29.12). This is a major advantage for Ligand B.

**9. Caco-2 Permeability:** Ligand A (-4.821) and Ligand B (-4.987) both have negative values, indicating poor permeability. This is a concern for both, but doesn't strongly differentiate them.

**10. Aqueous Solubility:** Both ligands have negative solubility values, indicating poor solubility. This is a concern for both.

**11. hERG Inhibition:** Both ligands have low hERG inhibition risk (0.394 and 0.57, respectively).

**12. Microsomal Clearance:** Both ligands have similar microsomal clearance values (57.535 and 56.625 mL/min/kg), suggesting similar metabolic stability.

**13. In vitro Half-Life:** Ligand B (10.462 hours) has a significantly longer half-life than Ligand A (-27.877 hours). This is a strong advantage for Ligand B.

**14. P-gp Efflux:** Both ligands have low P-gp efflux liability (0.14 and 0.108, respectively).

**15. Binding Affinity:** Ligand B (-7.6 kcal/mol) has a slightly better binding affinity than Ligand A (-8.0 kcal/mol). While A is slightly better, the difference is not substantial enough to outweigh the other factors.

**Overall Assessment:**

Ligand B is the more promising candidate. It demonstrates significantly better BBB penetration, a longer half-life, lower DILI risk, and a slightly better binding affinity. While both ligands have issues with Caco-2 permeability and aqueous solubility, the improved CNS penetration and pharmacokinetic properties of Ligand B make it a more viable drug candidate for a CNS target like DRD2.

Output:
1
2025-04-17 04:24:21,130 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (363.405 Da) and Ligand B (341.463 Da) are both acceptable.

**TPSA:** Ligand A (98.74) is slightly above the optimal <90 for CNS targets, but still reasonable. Ligand B (71.76) is excellent, well below 90.

**logP:** Ligand A (0.272) is quite low, potentially hindering permeability. Ligand B (2.43) is within the optimal 1-3 range. This is a significant advantage for Ligand B.

**H-Bond Donors/Acceptors:** Ligand A has 3 HBD and 4 HBA, which are acceptable. Ligand B has 1 HBD and 7 HBA, also acceptable.

**QED:** Both ligands have good QED scores (Ligand A: 0.512, Ligand B: 0.924), indicating drug-like properties. Ligand B is significantly better.

**DILI:** Both have relatively high DILI risk (Ligand A: 33.424, Ligand B: 61.419), but both are below the concerning threshold of 60.

**BBB:** Ligand A (60.295) is borderline for good CNS penetration. Ligand B (70.027) is much better, exceeding the 70% threshold. This is a crucial advantage for a DRD2 ligand.

**Caco-2 Permeability:** Ligand A (-4.846) is very poor, indicating extremely low intestinal absorption. Ligand B (-5.315) is also poor, but slightly better.

**Aqueous Solubility:** Both have poor solubility (Ligand A: -0.75, Ligand B: -2.481). This could pose formulation challenges.

**hERG Inhibition:** Both have low hERG inhibition risk (Ligand A: 0.245, Ligand B: 0.467).

**Microsomal Clearance:** Ligand A (9.172) has lower clearance, suggesting better metabolic stability than Ligand B (46.186).

**In vitro Half-Life:** Ligand A (-27.856) has a very negative half-life, which is concerning. Ligand B (20.516) is reasonable.

**P-gp Efflux:** Ligand A (0.012) has very low P-gp efflux, which is favorable for CNS penetration. Ligand B (0.073) is also low, but slightly higher.

**Binding Affinity:** Ligand A (-7.2) has slightly better binding affinity than Ligand B (-0.0). This is a substantial difference.

**Overall Assessment:**

While Ligand A has a slightly better binding affinity and lower microsomal clearance/P-gp efflux, its very low logP, poor Caco-2 permeability, and borderline BBB penetration are major drawbacks for a CNS-targeting drug. Ligand B, despite weaker binding, has a much more favorable profile with a good logP, excellent BBB penetration, and a reasonable half-life. The superior ADME properties of Ligand B, particularly its BBB penetration, outweigh the slightly weaker binding affinity in this case, given the target is DRD2.

Output:
1
2025-04-17 04:24:21,130 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B based on the provided guidelines, prioritizing GPCR-specific properties (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (421.371 Da) is slightly higher, but acceptable. Ligand B (356.423 Da) is also good.

**TPSA:** Ligand A (68.29) is excellent for CNS penetration, well below the 90 A^2 threshold. Ligand B (130.83) is higher, but still potentially acceptable, though less ideal.

**logP:** Ligand A (4.062) is at the upper end of the optimal range, potentially raising concerns about solubility and off-target effects. Ligand B (-1.245) is significantly lower, which could hinder permeability.

**H-Bond Donors/Acceptors:** Ligand A (HBD=1, HBA=5) is favorable. Ligand B (HBD=3, HBA=5) is also reasonable.

**QED:** Ligand A (0.791) is excellent, indicating good drug-likeness. Ligand B (0.475) is lower, suggesting a less drug-like profile.

**DILI:** Ligand A (81.388) has a higher DILI risk, which is a concern. Ligand B (19.542) has a very low DILI risk, which is a significant advantage.

**BBB:** Ligand A (46.413) has moderate BBB penetration, but is below the desirable >70 percentile for CNS targets. Ligand B (53.432) is also below the 70 percentile, but is still better than A.

**Caco-2 Permeability:** Ligand A (-4.672) has poor Caco-2 permeability. Ligand B (-5.748) also has poor Caco-2 permeability.

**Aqueous Solubility:** Ligand A (-5.281) has poor aqueous solubility. Ligand B (-1.434) has better aqueous solubility than A.

**hERG Inhibition:** Ligand A (0.417) has a very low hERG risk. Ligand B (0.021) has an extremely low hERG risk.

**Microsomal Clearance:** Ligand A (72.313) has moderate clearance. Ligand B (12.896) has low clearance, indicating better metabolic stability.

**In vitro Half-Life:** Ligand A (10.133) has a moderate half-life. Ligand B (-16.122) has a very short half-life, which is a major drawback.

**P-gp Efflux:** Ligand A (0.617) has moderate P-gp efflux. Ligand B (0.004) has very low P-gp efflux, which is highly desirable for CNS penetration.

**Binding Affinity:** Ligand A (-9.1 kcal/mol) has significantly stronger binding affinity than Ligand B (-7.5 kcal/mol). This is a substantial advantage, potentially outweighing some of its other drawbacks.

**Overall Assessment:**

Ligand A has a much stronger binding affinity, which is crucial for GPCR targets. However, it suffers from higher DILI risk, poor solubility, poor Caco-2 permeability, and moderate BBB penetration. Ligand B has a better safety profile (lower DILI, hERG), better metabolic stability, and lower P-gp efflux, but its affinity is weaker, its QED is lower, and its half-life is very short.

Given the GPCR-specific priorities, the strong binding affinity of Ligand A is a major factor. While its ADME properties are not ideal, optimization efforts could potentially address these issues. The weaker affinity of Ligand B, coupled with its short half-life, makes it a less promising starting point, even with its better safety profile.

Output:
1
2025-04-17 04:24:21,130 - INFO - Reasoning:

Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (366.893 and 346.475 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (86.88) is better than Ligand B (50.72) as it is closer to the ideal <90 for CNS targets. Ligand B is excellent.

**3. logP:** Both ligands (2.903 and 2.406) are within the optimal 1-3 range.

**4. H-Bond Donors:** Ligand A has 3 HBD, which is acceptable. Ligand B has 0, which is also good.

**5. H-Bond Acceptors:** Ligand A has 3 HBA, acceptable. Ligand B has 6, which is still within the acceptable limit of 10.

**6. QED:** Both ligands have good QED scores (0.693 and 0.82), indicating drug-like properties.

**7. DILI:** Ligand A (61.962) has a higher DILI risk than Ligand B (37.263). This is a negative for Ligand A.

**8. BBB:** Ligand B (86.933) has a significantly better BBB penetration percentile than Ligand A (64.482). This is a crucial advantage for a CNS target like DRD2.

**9. Caco-2 Permeability:** Ligand A (-5.188) has poor Caco-2 permeability, which is a significant drawback. Ligand B (-4.479) is also poor, but slightly better.

**10. Aqueous Solubility:** Both ligands have poor aqueous solubility (-4.517 and -3.167).

**11. hERG Inhibition:** Ligand A (0.313) has a slightly higher hERG inhibition liability than Ligand B (0.734).

**12. Microsomal Clearance:** Ligand A (33.691) has lower microsomal clearance, suggesting better metabolic stability than Ligand B (54.799).

**13. In vitro Half-Life:** Ligand A (29.222) has a longer in vitro half-life than Ligand B (8.271).

**14. P-gp Efflux:** Ligand A (0.367) has lower P-gp efflux, which is favorable for CNS penetration, compared to Ligand B (0.105).

**15. Binding Affinity:** Ligand A (-8.6 kcal/mol) has a significantly stronger binding affinity than Ligand B (-0.0 kcal/mol). This is a major advantage for Ligand A, potentially outweighing some of its ADME drawbacks.

**Overall Assessment:**

While Ligand A has a superior binding affinity and better metabolic stability (lower Cl_mic, longer t1/2) and P-gp efflux, Ligand B excels in BBB penetration and has a lower DILI risk. The poor Caco-2 permeability of both is a concern. However, for a CNS target like DRD2, BBB penetration is paramount. The significantly higher BBB score of Ligand B, combined with its lower DILI risk, makes it the more promising candidate, despite the weaker binding affinity. The large difference in binding affinity is concerning, but could be overcome with further optimization.

Output:
1
2025-04-17 04:24:21,131 - INFO - Batch 110 complete. Total preferences: 1760
2025-04-17 04:24:21,131 - INFO - Processing batch 111/512...
2025-04-17 04:25:02,882 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (359.354 and 348.487 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (106.2) is better than Ligand B (67.43). Both are below the 90 A^2 threshold for CNS targets, which is excellent.

**logP:** Ligand B (2.537) is optimal (1-3), while Ligand A (-0.492) is below 1, potentially hindering permeation. This is a significant drawback for Ligand A.

**H-Bond Donors:** Both ligands have 2 HBD, which is within the acceptable limit of <=5.

**H-Bond Acceptors:** Ligand A has 6 HBA, while Ligand B has 3. Both are below the limit of <=10.

**QED:** Both ligands have good QED scores (0.62 and 0.82, respectively), indicating drug-like properties.

**DILI:** Ligand B (23.071) has a much lower DILI risk than Ligand A (59.829). Ligand B is well below the 40% threshold, while Ligand A is approaching the 60% high-risk mark.

**BBB:** Ligand A (59.364) and Ligand B (52.036) are both below the desirable >70% for CNS targets. However, Ligand A is slightly better.

**Caco-2 Permeability:** Both have negative values (-5.228 and -4.966). This is unusual and suggests poor permeability.

**Aqueous Solubility:** Both have negative values (-2.099 and -2.691). This also suggests poor solubility.

**hERG Inhibition:** Both ligands show low hERG inhibition liability (0.104 and 0.193).

**Microsomal Clearance:** Ligand A (-31.781) has a much lower (better) microsomal clearance than Ligand B (24.804), suggesting greater metabolic stability.

**In vitro Half-Life:** Ligand A (4.168) has a slightly better half-life than Ligand B (-0.213).

**P-gp Efflux:** Ligand A (0.021) has a much lower P-gp efflux liability than Ligand B (0.091), which is crucial for CNS penetration.

**Binding Affinity:** Ligand B (-9.3 kcal/mol) has a significantly stronger binding affinity than Ligand A (-7.8 kcal/mol). This >1.5 kcal/mol difference is substantial and can outweigh some ADME drawbacks.

**Overall Assessment:**

While Ligand A has better TPSA, P-gp efflux, and metabolic stability, Ligand B excels in crucial areas for a CNS-targeting GPCR ligand: logP, DILI risk, and, most importantly, binding affinity. The significantly stronger binding affinity of Ligand B (-9.3 vs -7.8 kcal/mol) is a major advantage. The negative logP values and Caco-2/Solubility values are concerning for both, but the superior affinity of B is likely to be more impactful.

Output:
1
2025-04-17 04:25:02,883 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 drug candidates, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (353.438 and 358.873 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (78.51) is significantly better than Ligand B (51.02), being closer to the optimal <90 for CNS targets. Ligand B is excellent.

**logP:** Both ligands have acceptable logP values (1.006 and 3.086), falling within the 1-3 range. Ligand B is slightly better.

**H-Bond Donors/Acceptors:** Ligand A has 2 HBD and 3 HBA, while Ligand B has 0 HBD and 4 HBA. Both are within acceptable limits (<=5 HBD and <=10 HBA).

**QED:** Both ligands have similar and good QED scores (0.792 and 0.797), indicating good drug-likeness.

**DILI:** Ligand A (14.269) has a much lower DILI risk than Ligand B (29.973), which is a significant advantage.

**BBB:** Both ligands have excellent BBB penetration (83.831 and 83.366), exceeding the desirable >70 threshold for CNS targets.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.979 and -4.866), which is unusual and suggests poor permeability. This is a concern for both.

**Aqueous Solubility:** Both ligands have negative solubility values (-2.277 and -2.745), suggesting very poor aqueous solubility. This is a significant drawback for both.

**hERG:** Ligand A (0.245) has a lower hERG inhibition liability than Ligand B (0.537), indicating a lower risk of cardiotoxicity.

**Microsomal Clearance:** Ligand A (-4.431) has a much lower (better) microsomal clearance than Ligand B (61.646), indicating better metabolic stability.

**In vitro Half-Life:** Ligand A (0.475) has a very short half-life, while Ligand B (-16.792) has a negative half-life, which is not physically meaningful. This is a major concern for both.

**P-gp Efflux:** Ligand A (0.012) has very low P-gp efflux liability, while Ligand B (0.289) has slightly higher efflux. Lower is better for CNS exposure.

**Binding Affinity:** Both ligands have very similar and strong binding affinities (-8.2 and -8.1 kcal/mol), exceeding the desired < -7.0 kcal/mol.

**Overall Assessment:**

Ligand A is superior due to its significantly lower DILI risk, lower hERG inhibition, and much better metabolic stability (lower Cl_mic). While both have poor solubility and permeability, the ADME profile of Ligand A is considerably more favorable. The slightly better TPSA of Ligand B is not enough to offset the other disadvantages.

Output:
0
2025-04-17 04:25:02,883 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (343.387 and 343.427 Da) fall comfortably within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (99.42) is slightly higher than Ligand B (82.43). For CNS targets, we ideally want TPSA <= 90, so Ligand B is preferable.

**3. logP:** Ligand A (0.327) is quite low, potentially hindering membrane permeability. Ligand B (1.885) is better, falling within the optimal 1-3 range. This is a significant advantage for Ligand B.

**4. H-Bond Donors:** Ligand A (0) and Ligand B (1) are both acceptable, being <= 5.

**5. H-Bond Acceptors:** Ligand A (6) and Ligand B (4) are both acceptable, being <= 10.

**6. QED:** Both ligands have good QED scores (0.781 and 0.885), indicating drug-like properties.

**7. DILI:** Ligand A (42.924) and Ligand B (54.556) both have acceptable DILI risk, below the 60 threshold.

**8. BBB:** Ligand A (60.644) and Ligand B (64.87) are both below the desirable >70 percentile for CNS targets. However, Ligand B is slightly better.

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.448 and -4.617), which is unusual and suggests poor permeability. This is a concern for both.

**10. Aqueous Solubility:** Both ligands have negative solubility values (-2.516 and -3.172), which is also unusual and suggests poor solubility. This is a concern for both.

**11. hERG Inhibition:** Ligand A (0.256) and Ligand B (0.568) both have low hERG inhibition risk, which is good.

**12. Microsomal Clearance:** Ligand A (12.796) has lower clearance than Ligand B (36.802), indicating better metabolic stability. This is a positive for Ligand A.

**13. In vitro Half-Life:** Both ligands have similar in vitro half-lives (6.273 and 6.525 hours).

**14. P-gp Efflux:** Ligand A (0.029) has significantly lower P-gp efflux liability than Ligand B (0.147), which is crucial for CNS penetration. This is a strong advantage for Ligand A.

**15. Binding Affinity:** Ligand B (-8.1 kcal/mol) has a significantly stronger binding affinity than Ligand A (-7.2 kcal/mol). This >1.5 kcal/mol difference is substantial and can outweigh some ADME drawbacks.

**Overall Assessment:**

While Ligand A has better metabolic stability and lower P-gp efflux, Ligand B's superior logP and significantly stronger binding affinity are more critical for a GPCR target like DRD2. The slightly better TPSA and BBB values for Ligand B also contribute to its favorability. The poor Caco-2 and solubility values are concerning for both, but the affinity difference is likely to be the deciding factor.

Output:
1
2025-04-17 04:25:02,883 - INFO - Reasoning:

Let's analyze Ligand A and Ligand B for their potential as DRD2 drug candidates, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (411.246 Da) is slightly higher than Ligand B (350.463 Da), but both are acceptable.

**2. TPSA:** Ligand A (75.35) is better than Ligand B (85.25). For CNS targets, we want TPSA <= 90, and both are within this range, but A is closer to the optimal value.

**3. logP:** Ligand A (3.13) is within the optimal range (1-3), while Ligand B (1.734) is at the lower end. While not a dealbreaker, a slightly higher logP is generally preferred for CNS penetration.

**4. H-Bond Donors:** Ligand A (3) and Ligand B (2) are both acceptable (<=5).

**5. H-Bond Acceptors:** Ligand A (3) and Ligand B (5) are both acceptable (<=10).

**6. QED:** Both ligands have good QED values (A: 0.677, B: 0.748), indicating good drug-like properties.

**7. DILI:** Ligand A (64.754) has a higher DILI risk than Ligand B (38.736). This is a negative for Ligand A.

**8. BBB:** Ligand A (73.75) has a significantly better BBB penetration percentile than Ligand B (48.197). This is a *critical* advantage for a CNS target like DRD2.

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.006 and -4.978). These values are unusual and suggest poor permeability. However, since these are negative values, it's difficult to interpret their relative impact.

**10. Aqueous Solubility:** Both ligands have negative solubility values (-3.675 and -2.733), indicating poor aqueous solubility. This is a concern for both.

**11. hERG Inhibition:** Ligand A (0.886) has a slightly higher hERG inhibition risk than Ligand B (0.313), but both are reasonably low.

**12. Microsomal Clearance:** Ligand B (43.662) has a higher microsomal clearance than Ligand A (34.06), meaning it's metabolized faster. Lower clearance is preferred.

**13. In vitro Half-Life:** Ligand A (97.908) has a much longer in vitro half-life than Ligand B (19.974), which is a significant advantage.

**14. P-gp Efflux:** Ligand A (0.596) has lower P-gp efflux than Ligand B (0.051). Lower P-gp efflux is desirable for CNS penetration.

**15. Binding Affinity:** Ligand A (-9.3 kcal/mol) has a significantly stronger binding affinity than Ligand B (-7.5 kcal/mol). This is a substantial advantage, potentially outweighing some of the ADME drawbacks.

**Overall Assessment:**

Ligand A has a superior binding affinity, better BBB penetration, longer half-life, lower P-gp efflux, and lower microsomal clearance. While it has a higher DILI risk, the strong binding affinity and favorable CNS penetration properties are critical for a DRD2 target. Ligand B has a lower DILI risk, but its weaker affinity, poor BBB penetration, and faster metabolism make it a less attractive candidate. The negative Caco-2 and solubility values are concerning for both, but the potency and CNS properties of A are more compelling.

Output:
1
2025-04-17 04:25:02,883 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the acceptable range (200-500 Da). Ligand A (340.358 Da) is slightly preferred as it's closer to the ideal range.

**TPSA:** Ligand A (88.0) is excellent for CNS penetration, falling well below the 90 Angstrom threshold. Ligand B (29.95) is even better, suggesting very good brain penetration.

**logP:** Ligand A (2.427) is optimal. Ligand B (4.308) is a bit high, potentially leading to solubility issues and off-target interactions, though still within a reasonable range.

**H-Bond Donors/Acceptors:** Ligand A has 2 HBD and 5 HBA, which are acceptable. Ligand B has 1 HBD and 5 HBA, also acceptable.

**QED:** Both ligands have similar QED values (0.745 and 0.728), indicating good drug-likeness.

**DILI:** Ligand A (73.245) has a higher DILI risk than Ligand B (35.556). This is a significant drawback for Ligand A.

**BBB:** Ligand B (88.212) has a much better BBB percentile than Ligand A (66.576). This is crucial for a CNS target like DRD2.

**Caco-2 Permeability:** Ligand A (-5.161) has poor Caco-2 permeability, suggesting poor intestinal absorption. Ligand B (-4.826) is also poor, but slightly better.

**Aqueous Solubility:** Both ligands have very poor aqueous solubility (-3.591 and -4.107). This could pose formulation challenges.

**hERG Inhibition:** Ligand A (0.519) has a slightly higher hERG risk than Ligand B (0.996), but both are relatively low.

**Microsomal Clearance:** Ligand A (62.158) has higher microsomal clearance than Ligand B (28.983), indicating lower metabolic stability.

**In vitro Half-Life:** Ligand B (8.156 hours) has a significantly longer half-life than Ligand A (-15.735 hours). This is a major advantage for Ligand B.

**P-gp Efflux:** Ligand A (0.214) has lower P-gp efflux than Ligand B (0.949), which is favorable for CNS exposure.

**Binding Affinity:** Ligand B (-9.2 kcal/mol) has a significantly stronger binding affinity than Ligand A (-10.4 kcal/mol). This is a substantial advantage that can outweigh some of the ADME drawbacks.

**Overall Assessment:**

While Ligand A has a slightly better MW and P-gp efflux, Ligand B is significantly better in almost every other critical parameter for a CNS-targeting GPCR ligand. Specifically, its superior BBB penetration, much lower DILI risk, longer half-life, and significantly stronger binding affinity outweigh the slightly higher logP and P-gp efflux. The poor solubility and Caco-2 permeability are concerns for both, but can potentially be addressed with formulation strategies.

Output:
1
2025-04-17 04:25:02,884 - INFO - Reasoning:

Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (355.312 and 347.415 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (63.68) is significantly better than Ligand B (87.74). For CNS targets, we want TPSA <= 90, and A is much closer to the desirable threshold of <=60. B is pushing the upper limit.

**3. logP:** Both ligands have acceptable logP values (2.225 and 0.804), falling within the 1-3 range. Ligand A is slightly better.

**4. H-Bond Donors:** Ligand A (0) is preferable to Ligand B (2). Fewer HBDs generally improve permeability.

**5. H-Bond Acceptors:** Both ligands have 4 HBA, which is acceptable (<=10).

**6. QED:** Both ligands have similar QED values (0.763 and 0.737), indicating good drug-like properties.

**7. DILI:** Ligand A (63.358) has a higher DILI risk than Ligand B (32.338). This is a negative for Ligand A.

**8. BBB:** Ligand A (98.41) has a *much* better BBB penetration percentile than Ligand B (68.748). This is a critical advantage for a CNS target like DRD2.

**9. Caco-2 Permeability:** Ligand A (-4.115) is worse than Ligand B (-4.879), indicating lower intestinal absorption. However, for a CNS target, intestinal absorption is less crucial than BBB penetration.

**10. Aqueous Solubility:** Ligand A (-3.412) is better than Ligand B (-1.663), indicating better solubility.

**11. hERG Inhibition:** Ligand A (0.586) has a lower hERG inhibition liability than Ligand B (0.105), which is preferable.

**12. Microsomal Clearance:** Ligand A (35.543) has higher, and therefore worse, microsomal clearance than Ligand B (-4.62). This suggests Ligand B is more metabolically stable.

**13. In vitro Half-Life:** Ligand A (-1.7) is worse than Ligand B (-5.507), indicating a shorter half-life.

**14. P-gp Efflux:** Ligand A (0.339) has lower P-gp efflux liability than Ligand B (0.016), which is preferable for CNS exposure.

**15. Binding Affinity:** Both ligands have the same binding affinity (-8.3 kcal/mol), which is excellent.

**Overall Assessment:**

Despite Ligand B having better metabolic stability (lower Cl_mic, longer t1/2) and lower DILI risk, Ligand A is the stronger candidate due to its significantly superior BBB penetration (98.41 vs. 68.748) and lower P-gp efflux. For a CNS target like DRD2, getting the drug into the brain is paramount. The slightly worse metabolic properties of Ligand A can potentially be addressed through further optimization, but improving BBB penetration is often more challenging. The TPSA is also much better for Ligand A.

Output:
1
2025-04-17 04:25:02,884 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (361.364 and 345.403 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (83.48) is excellent, falling well below the 90 A^2 threshold for CNS targets. Ligand B (112.91) is still reasonable, but less optimal, being above 100 A^2.

**logP:** Both ligands have logP values (1.73 and 1.902) within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Both have 3 HBDs, which is good. Ligand A has 4 HBAs, and Ligand B has 5 HBAs, both acceptable.

**QED:** Both ligands have similar QED values (0.691 and 0.633), indicating good drug-likeness.

**DILI:** Ligand A (14.851) has a significantly lower DILI risk than Ligand B (69.523). This is a major advantage for Ligand A.

**BBB:** Ligand A (77.937) has a much better BBB penetration percentile than Ligand B (34.858). This is crucial for a CNS target like DRD2.

**Caco-2 Permeability:** Ligand A (-4.723) and Ligand B (-5.385) both have negative values, indicating poor permeability. However, the scale is not specified, so it's hard to interpret the absolute difference.

**Aqueous Solubility:** Both ligands have very poor aqueous solubility (-2.002 and -3.216). This is a concern, but can sometimes be mitigated with formulation strategies.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.337 and 0.15).

**Microsomal Clearance:** Ligand A (-9.116) has a much lower (better) microsomal clearance than Ligand B (38.832), suggesting greater metabolic stability.

**In vitro Half-Life:** Ligand A (16.78) has a longer half-life than Ligand B (-11.691), which is preferable.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.028 and 0.037).

**Binding Affinity:** Both ligands have excellent binding affinity (-8.6 and -8.2 kcal/mol). The difference of 0.4 kcal/mol is not substantial enough to outweigh the other significant differences.

**Overall Assessment:**

Ligand A is significantly better due to its superior BBB penetration, lower DILI risk, lower microsomal clearance, and longer half-life. While both have poor solubility and Caco-2 permeability, the ADME profile of Ligand A is considerably more favorable for CNS drug development. The slightly better affinity of Ligand A is a bonus, but the ADME advantages are the deciding factors.

Output:
1
2025-04-17 04:25:02,884 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (355.507 and 335.407 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (35.58) is significantly better than Ligand B (59.23). For CNS targets, we want TPSA <= 90, and ideally lower. Ligand A is well within this range, while Ligand B is approaching the upper limit and could pose permeability challenges.

**logP:** Both ligands have acceptable logP values (3.138 and 4.274), falling within the optimal 1-3 range, though Ligand B is slightly higher.

**H-Bond Donors/Acceptors:** Ligand A (HBD=1, HBA=2) is preferable to Ligand B (HBD=0, HBA=4). While both are reasonable, a slight increase in hydrogen bonding potential can improve solubility without drastically impacting permeability.

**QED:** Ligand A (0.808) has a better QED score than Ligand B (0.698), indicating a more drug-like profile.

**DILI:** Ligand B (75.456) has a higher DILI risk than Ligand A (47.034). Lower DILI is always preferred.

**BBB:** Ligand A (74.292) has a significantly better BBB penetration percentile than Ligand B (55.021). This is *critical* for a CNS target like DRD2. A value >70 is desirable, and Ligand A is closer to this threshold.

**Caco-2 Permeability:** Both have negative Caco-2 values (-4.824 and -4.565), which is unusual and suggests poor permeability. However, these values are on a scale where negative values are possible and don't necessarily preclude development.

**Aqueous Solubility:** Both have negative solubility values (-4.043 and -5.302), which is also unusual. This suggests poor aqueous solubility, which could be a formulation challenge.

**hERG Inhibition:** Ligand A (0.881) has a slightly higher hERG inhibition risk than Ligand B (0.374), but both are relatively low.

**Microsomal Clearance:** Ligand A (77.03) has a higher microsomal clearance than Ligand B (49.922), suggesting lower metabolic stability.

**In vitro Half-Life:** Ligand B (-1.727) has a negative half-life, which is impossible. This is a major red flag and suggests a significant issue with the data or the compound's stability. Ligand A (15.302) has a reasonable half-life.

**P-gp Efflux:** Ligand A (0.579) has lower P-gp efflux than Ligand B (0.397), which is beneficial for CNS penetration.

**Binding Affinity:** Ligand B (-10.1 kcal/mol) has a significantly stronger binding affinity than Ligand A (-8.8 kcal/mol). This is a substantial advantage (1.3 kcal/mol difference), and could potentially outweigh some of the ADME drawbacks.

**Overall Assessment:**

Despite the stronger binding affinity of Ligand B, the negative half-life is a critical flaw. It indicates instability or a problem with the assay. Ligand A, while having a weaker binding affinity, has a much more favorable ADME profile, particularly regarding BBB penetration, DILI risk, and a plausible half-life. For a CNS target like DRD2, good brain penetration is paramount. The combination of better BBB, lower DILI, and a reasonable half-life makes Ligand A the more viable candidate.

Output:
0
2025-04-17 04:25:02,884 - INFO - Reasoning:

Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (361.833 and 341.371 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (104.11) is slightly higher than Ligand B (101.53), but both are below the 140 A^2 threshold for oral absorption and reasonably close to the <90 A^2 target for CNS drugs.

**3. logP:** Both ligands have good logP values (1.928 and 1.19), falling within the optimal 1-3 range.

**4. H-Bond Donors:** Ligand A (3) is slightly higher than Ligand B (2), but both are acceptable (<=5).

**5. H-Bond Acceptors:** Ligand A (4) is lower than Ligand B (6), both are within the acceptable range (<=10).

**6. QED:** Both ligands have similar and good QED values (0.708 and 0.701), indicating good drug-like properties.

**7. DILI:** Ligand A (70.182) has a slightly higher DILI risk than Ligand B (62.35), but both are below the concerning threshold of 60, and are acceptable.

**8. BBB:** This is a critical parameter for a CNS target like DRD2. Ligand A (64.676) has a significantly better BBB penetration percentile than Ligand B (31.834). This is a major advantage for Ligand A.

**9. Caco-2 Permeability:** Both have negative Caco-2 values (-5.384 and -5.351), which is unusual and suggests poor permeability. This is a concern for both.

**10. Aqueous Solubility:** Both ligands have negative solubility values (-3.851 and -2.14), indicating poor aqueous solubility. This is a concern for both.

**11. hERG Inhibition:** Both ligands show low hERG inhibition risk (0.719 and 0.258).

**12. Microsomal Clearance:** Ligand A (-7.139) has a much lower (better) microsomal clearance than Ligand B (18.4). This suggests greater metabolic stability for Ligand A.

**13. In vitro Half-Life:** Ligand B (17.514) has a much longer in vitro half-life than Ligand A (1.628).

**14. P-gp Efflux:** Ligand A (0.068) has a lower P-gp efflux liability than Ligand B (0.027), which is favorable for CNS penetration.

**15. Binding Affinity:** Both ligands have excellent binding affinities (-9.7 and -8.7 kcal/mol). Ligand A is slightly more potent.

**Overall Assessment:**

While both ligands have good potency and acceptable physicochemical properties, Ligand A is the more promising candidate. The key advantages of Ligand A are its significantly better BBB penetration (64.676 vs 31.834), lower microsomal clearance (-7.139 vs 18.4), and lower P-gp efflux (0.068 vs 0.027). These factors are crucial for CNS drug development. The longer half-life of Ligand B is a benefit, but the poor BBB penetration is a significant drawback. The poor Caco-2 and solubility for both compounds are concerning, but can be addressed with formulation strategies.



Output:
1
2025-04-17 04:25:02,885 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 drug candidates, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (362.352 and 350.434 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (96.25) is slightly above the optimal <90 for CNS targets, but still reasonable. Ligand B (62.55) is excellent, well below 90.

**3. logP:** Ligand A (0.767) is a bit low, potentially hindering membrane permeability. Ligand B (2.806) is excellent, falling within the optimal 1-3 range.

**4. H-Bond Donors:** Ligand A (3) is acceptable. Ligand B (1) is also good.

**5. H-Bond Acceptors:** Ligand A (5) is acceptable. Ligand B (3) is also good.

**6. QED:** Both ligands have good QED scores (0.667 and 0.803), indicating drug-like properties.

**7. DILI:** Both ligands have acceptable DILI risk (52.966 and 44.009), below the concerning threshold of 60.

**8. BBB:** This is a critical parameter for a CNS target like DRD2. Ligand B (75.378) is significantly better than Ligand A (51.803), exceeding the desirable >70 threshold.

**9. Caco-2 Permeability:** Ligand A (-5.168) has poor Caco-2 permeability, suggesting poor absorption. Ligand B (-4.747) is also poor, but slightly better than Ligand A.

**10. Aqueous Solubility:** Both ligands have poor aqueous solubility (-2.107 and -2.895). This could pose formulation challenges.

**11. hERG Inhibition:** Both ligands show low hERG inhibition risk (0.176 and 0.631), which is favorable.

**12. Microsomal Clearance:** Ligand A (16.446) has lower clearance than Ligand B (27.195), indicating better metabolic stability.

**13. In vitro Half-Life:** Ligand B (3.297) has a longer half-life than Ligand A (-3.396), which is preferable.

**14. P-gp Efflux:** Ligand A (0.071) has lower P-gp efflux, which is good for CNS penetration. Ligand B (0.39) has higher P-gp efflux.

**15. Binding Affinity:** Both ligands have very similar and excellent binding affinities (-8.8 and -8.9 kcal/mol). The difference is negligible.

**Overall Assessment:**

While Ligand A has better metabolic stability (lower Cl_mic) and lower P-gp efflux, Ligand B is superior overall due to its significantly better BBB penetration (75.378 vs 51.803), more optimal logP (2.806 vs 0.767), and better TPSA (62.55 vs 96.25). The improved BBB penetration is crucial for a CNS target. The slightly longer half-life of Ligand B is also beneficial. The Caco-2 permeability is poor for both, and solubility is a concern, but these can potentially be addressed through formulation strategies.

Output:
1
2025-04-17 04:25:02,885 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (344.39 and 358.473 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (67.23) is higher than Ligand B (40.62). For a CNS target like DRD2, TPSA should ideally be <= 90, so both are acceptable, but B is significantly better.

**3. logP:** Ligand A (1.804) is within the optimal 1-3 range. Ligand B (3.696) is at the higher end, but still acceptable.

**4. H-Bond Donors:** Ligand A has 1 HBD, and Ligand B has 0. Both are within the acceptable limit of <=5.

**5. H-Bond Acceptors:** Ligand A has 4 HBA, and Ligand B has 2. Both are within the acceptable limit of <=10.

**6. QED:** Ligand A (0.864) has a higher QED than Ligand B (0.769), indicating better overall drug-likeness.

**7. DILI:** Ligand A (59.131) has a higher DILI risk than Ligand B (16.208). This is a significant advantage for Ligand B.

**8. BBB:** Ligand A (76.58) has a good BBB percentile, but Ligand B (97.402) is excellent, exceeding the >70 desirable threshold. This is a crucial factor for a CNS target.

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.71 and -4.294). While unusual, these values are on a similar scale and don't strongly differentiate the two.

**10. Aqueous Solubility:** Both ligands have negative solubility values (-2.95 and -3.915), again similar and not a major differentiator.

**11. hERG Inhibition:** Ligand A (0.263) has a slightly lower hERG risk than Ligand B (0.679), which is preferable.

**12. Microsomal Clearance:** Ligand A (46.643) and Ligand B (47.149) have similar microsomal clearance values.

**13. In vitro Half-Life:** Ligand A (6.432) has a positive half-life, while Ligand B (-21.973) has a negative half-life. This is a major red flag for Ligand B, suggesting rapid metabolism.

**14. P-gp Efflux:** Ligand A (0.179) has lower P-gp efflux than Ligand B (0.058), which is better for CNS penetration.

**15. Binding Affinity:** Ligand A (-9.7 kcal/mol) has a significantly stronger binding affinity than Ligand B (-7.9 kcal/mol). The difference of 1.8 kcal/mol is substantial and can outweigh some ADME drawbacks.

**Overall Assessment:**

Ligand B excels in BBB penetration and has a much lower DILI risk. However, its negative in vitro half-life is a major concern. Ligand A, while having a slightly higher DILI risk and P-gp efflux, has a significantly stronger binding affinity and a reasonable half-life. Given the importance of affinity for GPCRs, and the acceptable ADME profile of Ligand A, it is the more promising candidate.

Output:
1
2025-04-17 04:25:02,885 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (349.435 Da) is slightly lower, which could be beneficial for permeability. Ligand B (356.323 Da) is also good.

**TPSA:** Ligand A (81.91) is excellent, falling well below the 90 A^2 threshold for CNS targets. Ligand B (51.02) is even better, indicating potentially improved brain penetration.

**logP:** Ligand A (0.376) is quite low, potentially hindering membrane permeability and reducing CNS exposure. Ligand B (3.065) is within the optimal range (1-3), which is a significant advantage.

**H-Bond Donors/Acceptors:** Ligand A has 1 HBD and 6 HBA, which are acceptable. Ligand B has 0 HBD and 4 HBA, also acceptable.

**QED:** Both ligands have reasonable QED values (A: 0.831, B: 0.774), suggesting good drug-like characteristics.

**DILI:** Ligand A (23.226) has a much lower DILI risk than Ligand B (64.095), indicating a safer profile regarding liver toxicity.

**BBB:** Ligand B (95.812) has a significantly higher BBB penetration percentile than Ligand A (47.383). This is a crucial advantage for a CNS target like DRD2.

**Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and suggests poor permeability. However, the scale is not specified, so it's difficult to interpret.

**Aqueous Solubility:** Both ligands have negative solubility values, indicating poor aqueous solubility. This could pose formulation challenges.

**hERG Inhibition:** Ligand A (0.198) shows very low hERG inhibition risk, which is excellent. Ligand B (0.5) is slightly higher but still relatively low.

**Microsomal Clearance:** Ligand A (-2.485) has a negative clearance, which is not physically possible and likely an error. Ligand B (32.097) has a moderate clearance, suggesting moderate metabolic stability.

**In vitro Half-Life:** Ligand A (-2.514) has a negative half-life, also an error. Ligand B (-17.178) has a negative half-life, also an error.

**P-gp Efflux:** Ligand A (0.013) has very low P-gp efflux liability, which is favorable for CNS penetration. Ligand B (0.275) has slightly higher P-gp efflux, but still relatively low.

**Binding Affinity:** Ligand B (-9.8 kcal/mol) has a significantly stronger binding affinity than Ligand A (-7.7 kcal/mol). This >1.5 kcal/mol difference is a major advantage, potentially outweighing some ADME drawbacks.

**Overall Assessment:**

Despite the errors in clearance and half-life values, Ligand B is the more promising candidate. Its superior BBB penetration, optimal logP, and significantly stronger binding affinity are critical for a CNS GPCR target. While Ligand A has a lower DILI risk and P-gp efflux, the benefits of Ligand B's improved CNS exposure and potency are more important in this context. The negative values for Caco-2 and solubility are concerning for both, but can potentially be addressed through formulation strategies. The errors in clearance and half-life for both compounds suggest issues with the data or modeling.

Output:
1
2025-04-17 04:25:02,885 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (408.26 and 381.89 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (119.14) is slightly above the optimal <90 for CNS targets, but still reasonable. Ligand B (88.91) is excellent, well below 90.

**logP:** Both ligands have good logP values (1.86 and 2.32), falling within the 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A has 5 HBD and 4 HBA, which is acceptable. Ligand B has 2 HBD and 6 HBA, also acceptable.

**QED:** Both ligands have good QED scores (0.533 and 0.831), indicating good drug-like properties.

**DILI:** Both ligands have relatively high DILI risk (72.70 and 78.95), but these are percentile scores and not absolute risks. We'll consider this a neutral factor for now.

**BBB:** This is a critical parameter for a CNS target like DRD2. Ligand A has a BBB percentile of 32.18, which is poor. Ligand B has a much better BBB percentile of 50.45, which is still not ideal (>70 desirable) but significantly better than Ligand A.

**Caco-2 Permeability:** Both have negative Caco-2 values (-5.61 and -5.17), which is unusual and suggests poor permeability. This is a significant concern for both.

**Aqueous Solubility:** Both ligands have poor aqueous solubility (-3.79 and -3.68). This could pose formulation challenges.

**hERG Inhibition:** Both ligands show very low hERG inhibition risk (0.29 and 0.25). This is excellent.

**Microsomal Clearance:** Ligand A has a very low (good) Cl_mic (-0.33), indicating high metabolic stability. Ligand B has a higher Cl_mic (6.65), suggesting faster metabolism.

**In vitro Half-Life:** Ligand A has a very long half-life (-6.52), which is excellent. Ligand B has a shorter half-life (31.10), which is less desirable.

**P-gp Efflux:** Both ligands have very low P-gp efflux (0.02 and 0.21), which is good for CNS penetration.

**Binding Affinity:** Ligand B has a significantly stronger binding affinity (-7.8 kcal/mol) compared to Ligand A (-0.0 kcal/mol). This is a substantial advantage.

**Overall Assessment:**

Ligand B is the stronger candidate. While both have issues with Caco-2 permeability and solubility, Ligand B's significantly improved BBB penetration and *much* stronger binding affinity outweigh the slightly higher metabolic clearance. The superior affinity is a critical factor, and the better BBB is essential for a CNS-targeting drug. Ligand A's extremely weak binding affinity makes it unlikely to be a viable candidate despite its favorable metabolic stability and half-life.

Output:
1
2025-04-17 04:25:02,886 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (457.258 Da) is higher, but still acceptable. Ligand B (365.499 Da) is slightly better.

**TPSA:** Ligand A (29.54) is excellent for CNS penetration, well below the 90 A^2 threshold. Ligand B (73.74) is higher, but still potentially acceptable, though less ideal for CNS targets.

**logP:** Ligand A (4.182) is slightly high, potentially leading to solubility issues or off-target interactions. Ligand B (1.544) is within the optimal range (1-3).

**H-Bond Donors/Acceptors:** Ligand A (0 HBD, 2 HBA) is favorable. Ligand B (1 HBD, 5 HBA) is also acceptable.

**QED:** Both ligands have good QED scores (A: 0.645, B: 0.859), indicating good drug-like properties.

**DILI:** Ligand A (53.315) has a moderate DILI risk, while Ligand B (30.128) has a low DILI risk. This favors Ligand B.

**BBB:** Ligand A (89.492) has excellent BBB penetration, exceeding the 70% threshold. Ligand B (47.926) is significantly lower, which is a major drawback for a CNS target like DRD2.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.736 and -4.952). This is unusual and suggests poor permeability. However, these values are on a log scale, so the negative values are not directly comparable without knowing the base of the log.

**Aqueous Solubility:** Both ligands have negative solubility values (-4.648 and -0.803). Similar to Caco-2, these are on a scale where lower values indicate lower solubility. Ligand B is better here.

**hERG Inhibition:** Ligand A (0.797) has a slightly higher hERG risk than Ligand B (0.28), which is preferable.

**Microsomal Clearance:** Ligand A (52.791) has moderate clearance, while Ligand B (-5.88) has very low clearance, indicating better metabolic stability.

**In vitro Half-Life:** Ligand A (11.923 hours) has a reasonable half-life. Ligand B (9.468 hours) is also acceptable.

**P-gp Efflux:** Ligand A (0.822) has moderate P-gp efflux, while Ligand B (0.157) has low P-gp efflux, which is beneficial for CNS penetration.

**Binding Affinity:** Ligand A (-9.7 kcal/mol) has significantly stronger binding affinity than Ligand B (-8.0 kcal/mol). This is a substantial advantage.

**Overall Assessment:**

Ligand A excels in binding affinity and BBB penetration, which are crucial for a CNS GPCR target. However, its higher logP and moderate DILI risk are concerns. Ligand B has better ADME properties (lower logP, DILI, P-gp efflux, and better metabolic stability), but its significantly lower BBB penetration is a major disadvantage.

The strong binding affinity of Ligand A (-9.7 kcal/mol) is a significant advantage that likely outweighs its slightly less favorable ADME profile, especially considering the importance of potency for GPCR ligands. The excellent BBB penetration further supports its potential.

Output:
1
2025-04-17 04:25:02,886 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 drug candidates, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (346.391 and 348.487 Da) fall comfortably within the ideal 200-500 Da range.

**TPSA:** Ligand A (97.36) is slightly above the optimal <90 for CNS targets, while Ligand B (78.43) is well within the desired range. This favors Ligand B.

**logP:** Ligand A (0.328) is quite low, potentially hindering permeability. Ligand B (2.13) is within the optimal 1-3 range. This is a significant advantage for Ligand B.

**H-Bond Donors/Acceptors:** Ligand A has 0 HBD and 7 HBA, which are acceptable. Ligand B has 3 HBD and 3 HBA, also acceptable.

**QED:** Both ligands have reasonable QED scores (0.774 and 0.688), indicating good drug-like properties.

**DILI:** Ligand A (56.146) has a higher DILI risk than Ligand B (6.514). This favors Ligand B.

**BBB:** Ligand A (54.634) has a moderate BBB penetration, while Ligand B (35.595) is lower. While both are below the ideal >70 for CNS targets, Ligand A is better.

**Caco-2 Permeability:** Both have negative Caco-2 values which is unusual and suggests poor permeability.

**Aqueous Solubility:** Both ligands have negative solubility values, which is also unusual and suggests poor solubility.

**hERG:** Both ligands have very low hERG inhibition liability (0.076 and 0.241), which is excellent.

**Microsomal Clearance:** Ligand A (39.604) has a higher microsomal clearance than Ligand B (21.747), indicating lower metabolic stability. This favors Ligand B.

**In vitro Half-Life:** Ligand A (-23.601) has a negative half-life, which is not possible. Ligand B (10.33) has a reasonable half-life.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.017 and 0.019), which is good.

**Binding Affinity:** Ligand B (-9.1 kcal/mol) has a significantly stronger binding affinity than Ligand A (-7.7 kcal/mol). This is a crucial advantage for Ligand B, exceeding the 1.5 kcal/mol threshold.

**Overall Assessment:**

Ligand B consistently outperforms Ligand A across several key parameters, especially logP, DILI, metabolic stability (Cl_mic), and binding affinity. While Ligand A has slightly better BBB penetration, the other advantages of Ligand B, particularly its superior binding affinity and favorable ADME profile, outweigh this. The negative values for solubility and Caco-2 permeability are concerning for both, but the stronger binding of Ligand B suggests it might overcome these issues with further optimization.

Output:
1
2025-04-17 04:25:02,886 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 drug candidates, considering the provided guidelines and GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (349.431 and 367.833 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (80.76) is excellent, well below the 90 A^2 threshold for CNS targets. Ligand B (92.93) is still reasonable but closer to the upper limit.

**3. logP:** Both ligands have logP values (2.706 and 2.669) within the optimal 1-3 range.

**4. H-Bond Donors:** Ligand A (1) and Ligand B (2) both meet the <=5 criteria.

**5. H-Bond Acceptors:** Both ligands (5) meet the <=10 criteria.

**6. QED:** Ligand A (0.827) has a superior QED score compared to Ligand B (0.691), indicating better overall drug-likeness.

**7. DILI:** Both ligands have acceptable DILI risk, with Ligand A (49.593) being slightly lower than Ligand B (53.432). Both are well below the 60 threshold.

**8. BBB:** This is a crucial parameter for CNS targets. Ligand A exhibits a significantly higher BBB penetration percentile (79.294) than Ligand B (34.858). This is a major advantage for Ligand A.

**9. Caco-2 Permeability:** Ligand A (-4.299) and Ligand B (-5.146) both have negative values, suggesting poor permeability. However, these values are on a scale where higher is better, so the negative values are not directly comparable without knowing the scale's zero point.

**10. Aqueous Solubility:** Both ligands have negative solubility values (-3.043 and -2.954), again suggesting poor solubility. Similar to Caco-2, these values are hard to interpret without knowing the scale's zero point.

**11. hERG Inhibition:** Both ligands show low hERG inhibition risk (0.389 and 0.156), which is favorable.

**12. Microsomal Clearance:** Ligand A (86.138) has higher microsomal clearance than Ligand B (9.286), indicating lower metabolic stability. This is a drawback for Ligand A.

**13. In vitro Half-Life:** Ligand B (63.389) has a significantly longer in vitro half-life than Ligand A (-30.21), suggesting better metabolic stability.

**14. P-gp Efflux:** Ligand A (0.046) has a much lower P-gp efflux liability than Ligand B (0.195), which is beneficial for CNS penetration.

**15. Binding Affinity:** Ligand B (-8.0) has a slightly better binding affinity than Ligand A (-7.1), but the difference is less than 1.5 kcal/mol.

**Overall Assessment:**

While Ligand B has slightly better binding affinity and metabolic stability (longer half-life, lower Cl_mic), Ligand A is significantly more promising due to its superior BBB penetration (79.294 vs 34.858), lower P-gp efflux, and better QED score. For a CNS target like DRD2, BBB penetration is paramount, and Ligand A clearly excels in this regard. The difference in binding affinity is not substantial enough to outweigh the significant advantage in CNS penetration and efflux.

Output:
0
2025-04-17 04:25:02,886 - INFO - Batch 111 complete. Total preferences: 1776
2025-04-17 04:25:02,886 - INFO - Processing batch 112/512...
2025-04-17 04:25:45,490 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (344.459 and 362.499 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (69.3) is better than Ligand B (72.21). Both are below the 90 A^2 threshold for CNS targets, but A is closer to the optimal range for brain penetration.

**3. logP:** Ligand A (2.415) is within the optimal 1-3 range. Ligand B (3.955) is pushing the upper limit, potentially leading to solubility issues and off-target interactions.

**4. H-Bond Donors:** Ligand A (1) is preferable to Ligand B (2). Lower HBD generally improves permeability.

**5. H-Bond Acceptors:** Ligand A (3) is preferable to Ligand B (7). Lower HBA generally improves permeability.

**6. QED:** Both ligands have good QED scores (0.582 and 0.736), indicating good drug-like properties.

**7. DILI:** Both ligands have acceptable DILI risk (38.736 and 59.442), with Ligand A being slightly better.

**8. BBB:** Ligand A (60.411) and Ligand B (64.87) are both moderately good, but fall short of the >70 percentile desirable for CNS targets.

**9. Caco-2 Permeability:** Ligand A (-4.978) is significantly better than Ligand B (-5.23). Higher (less negative) values indicate better absorption.

**10. Aqueous Solubility:** Ligand A (-2.458) is better than Ligand B (-4.426). Higher values indicate better solubility.

**11. hERG Inhibition:** Both ligands have low hERG risk (0.73 and 0.517).

**12. Microsomal Clearance:** Ligand A (71.844) is better than Ligand B (74.694), meaning it is likely more metabolically stable.

**13. In vitro Half-Life:** Ligand B (85.205) is significantly better than Ligand A (-21.536). A longer half-life is generally preferred.

**14. P-gp Efflux:** Ligand A (0.518) is better than Ligand B (0.094). Lower P-gp efflux is crucial for CNS penetration.

**15. Binding Affinity:** Ligand B (-8.5 kcal/mol) has a significantly stronger binding affinity than Ligand A (-7.0 kcal/mol). This is a substantial advantage, potentially outweighing some of the ADME drawbacks.

**Overall Assessment:**

Ligand B has a considerably stronger binding affinity, which is a primary driver for GPCR drug candidates. While Ligand B has a slightly higher logP and lower P-gp efflux, the significant improvement in binding affinity (-8.5 vs -7.0 kcal/mol) is likely to be decisive. The longer half-life of Ligand B is also a positive factor. Ligand A has better TPSA, solubility, and metabolic stability, but the potency difference is too large to ignore.

Output:
1
2025-04-17 04:25:45,491 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (341.455 and 357.407 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (53.51) is excellent, well below the 90 A^2 threshold for CNS targets. Ligand B (122.83) is higher, but still potentially acceptable, though less ideal.

**logP:** Ligand A (2.442) is optimal (1-3). Ligand B (-0.898) is below 1, which could hinder permeation. This is a significant drawback.

**H-Bond Donors/Acceptors:** Ligand A (0 HBD, 3 HBA) is favorable. Ligand B (3 HBD, 6 HBA) is also acceptable, but slightly higher counts could impact permeability.

**QED:** Both ligands have reasonable QED values (0.512 and 0.46), indicating drug-like properties.

**DILI:** Ligand A (15.626) has a lower DILI risk than Ligand B (19.775), which is preferable. Both are below the 40 threshold.

**BBB:** Both ligands have excellent BBB penetration (73.75 and 74.758 percentile), exceeding the desirable >70% threshold for CNS targets.

**Caco-2 Permeability:** Ligand A (-4.337) has poor Caco-2 permeability. Ligand B (-5.737) is even worse. Both are quite low, suggesting absorption issues.

**Aqueous Solubility:** Both ligands have poor aqueous solubility (-1.759 and -1.723). This could pose formulation challenges.

**hERG Inhibition:** Both ligands show very low hERG inhibition risk (0.574 and 0.028).

**Microsomal Clearance:** Ligand A (31.329) has higher microsomal clearance than Ligand B (-3.724). This means Ligand B is more metabolically stable, which is a positive.

**In vitro Half-Life:** Ligand A (-1.923) has a shorter in vitro half-life than Ligand B (-5.277). This is another advantage for Ligand B.

**P-gp Efflux:** Both ligands show very low P-gp efflux liability (0.068 and 0.002).

**Binding Affinity:** Both ligands have identical and strong binding affinity (-7.7 kcal/mol).

**Overall Assessment:**

While both ligands have excellent binding affinity and BBB penetration, Ligand A suffers from poor Caco-2 permeability and higher metabolic clearance. Ligand B's biggest drawback is its low logP, which could severely limit its ability to cross cell membranes despite the good BBB score. However, the better metabolic stability and half-life of Ligand B, coupled with its slightly better DILI profile, make it marginally more promising. The poor Caco-2 values for both are concerning, but can sometimes be overcome with formulation strategies. The logP of Ligand A is much more favorable.

Considering the GPCR-specific priorities, the balance tips slightly towards Ligand A due to the more optimal logP value, which is crucial for CNS penetration and target engagement.

Output:
1
2025-04-17 04:25:45,491 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (367.475 and 342.439 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (89.35) is better than Ligand B (62.55), both are below the 90 A^2 threshold for CNS targets.

**logP:** Ligand B (3.591) is optimal (1-3), while Ligand A (0.155) is significantly low, potentially hindering membrane permeability.

**H-Bond Donors:** Both have 1 HBD, which is acceptable.

**H-Bond Acceptors:** Ligand A has 7 HBA, while Ligand B has 3. Both are within the acceptable limit of <=10.

**QED:** Both ligands have good QED scores (0.746 and 0.797, respectively), indicating drug-like properties.

**DILI:** Ligand B (31.989) has a much lower DILI risk than Ligand A (51.493), making it safer.

**BBB:** Ligand B (78.713) has a significantly better BBB penetration score than Ligand A (52.268). This is crucial for a CNS target like DRD2.

**Caco-2 Permeability:** Ligand A (-5.039) has a negative Caco-2 value, which is concerning. Ligand B (-4.566) is also negative, but less so.

**Aqueous Solubility:** Both have negative solubility values, which is not ideal, but not a primary concern if permeability is good.

**hERG Inhibition:** Ligand A (0.076) has a very low hERG risk, slightly better than Ligand B (0.769).

**Microsomal Clearance:** Ligand B (82.825) has a higher microsomal clearance than Ligand A (22.822), indicating faster metabolism and potentially lower *in vivo* exposure.

**In vitro Half-Life:** Ligand B (82.116) has a much longer half-life than Ligand A (4.367), which is a significant advantage.

**P-gp Efflux:** Ligand A (0.031) has a very low P-gp efflux liability, which is excellent for CNS penetration. Ligand B (0.202) is higher, but still relatively low.

**Binding Affinity:** Ligand B (-7.9 kcal/mol) has a slightly better binding affinity than Ligand A (-7.6 kcal/mol). While the difference is small, it's still a positive factor.

**Overall Assessment:**

Ligand B is clearly the better candidate. While Ligand A has a slightly better hERG profile and P-gp efflux, Ligand B excels in the most critical areas for a CNS-targeting GPCR: BBB penetration, DILI risk, *in vitro* half-life, and logP. The slightly better binding affinity of Ligand B further strengthens its position. The negative Caco-2 values are a concern for both, but the superior BBB and overall ADME profile of Ligand B outweigh this drawback.

Output:
1
2025-04-17 04:25:45,491 - INFO - Reasoning:
Let's analyze both ligands against the provided guidelines, prioritizing GPCR-specific properties (BBB, logP, Pgp, TPSA, and affinity).

**Ligand A:**

*   **MW:** 357.426 Da - Within the ideal range (200-500).
*   **TPSA:** 98.74 A<sup>2</sup> - Acceptable, but approaching the upper limit for CNS targets (ideally <90).
*   **logP:** 0.261 - Low. Could hinder permeability.
*   **HBD:** 3 - Acceptable.
*   **HBA:** 4 - Acceptable.
*   **QED:** 0.58 - Good drug-like properties.
*   **DILI:** 18.302 - Very low risk. Excellent.
*   **BBB:** 65.413 - Borderline for CNS, but not ideal.
*   **Caco-2:** -5.24 - Negative value is unusual and suggests very poor permeability.
*   **Solubility:** -1.105 - Very poor solubility.
*   **hERG:** 0.058 - Very low risk. Excellent.
*   **Cl_mic:** -15.58 mL/min/kg - Negative value is unusual, but suggests very high metabolic stability.
*   **t1/2:** 0.574 hours - Very short half-life.
*   **Pgp:** 0.012 - Very low efflux. Excellent.
*   **Affinity:** -7.7 kcal/mol - Excellent binding affinity.

**Ligand B:**

*   **MW:** 353.394 Da - Within the ideal range (200-500).
*   **TPSA:** 111.55 A<sup>2</sup> - Higher than ideal for CNS targets.
*   **logP:** 1.102 - Good. Within the optimal range.
*   **HBD:** 4 - Acceptable.
*   **HBA:** 5 - Acceptable.
*   **QED:** 0.559 - Good drug-like properties.
*   **DILI:** 53.781 - Moderate risk.
*   **BBB:** 39.977 - Poor BBB penetration. Not suitable for CNS targets.
*   **Caco-2:** -5.011 - Negative value is unusual and suggests very poor permeability.
*   **Solubility:** -2.552 - Very poor solubility.
*   **hERG:** 0.112 - Low risk.
*   **Cl_mic:** 9.051 mL/min/kg - Moderate metabolic clearance.
*   **t1/2:** -9.92 hours - Negative value is unusual, but suggests very short half-life.
*   **Pgp:** 0.024 - Very low efflux. Excellent.
*   **Affinity:** -7.6 kcal/mol - Excellent binding affinity, very close to Ligand A.

**Comparison & Decision:**

Both ligands have excellent binding affinity. However, Ligand A is significantly better regarding DILI risk, Pgp efflux, and metabolic stability (Cl_mic). While Ligand A's logP is low and BBB is borderline, its superior safety profile and low efflux are crucial for a CNS-targeting drug. Ligand B has a better logP, but its DILI risk is higher, and its BBB penetration is poor. Both have poor Caco-2 and solubility, but these can be addressed with formulation strategies. Given the GPCR-specific priorities, and the importance of CNS penetration and safety for DRD2 targets, Ligand A is the more promising candidate.

Output:
0
2025-04-17 04:25:45,491 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (350.459 and 352.475 Da) fall comfortably within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (67.87) is significantly better than Ligand B (89.87). For CNS targets, TPSA < 90 is preferred, and A is closer to the optimal <60 range. B is pushing the upper limit.

**3. logP:** Both ligands have good logP values (1.215 and 1.053), falling within the 1-3 range.

**4. H-Bond Donors:** Ligand A (1) is better than Ligand B (3). Lower HBD generally improves permeability.

**5. H-Bond Acceptors:** Both ligands have the same number of HBA (4), which is acceptable (<=10).

**6. QED:** Ligand A (0.75) is slightly better than Ligand B (0.69), indicating a more drug-like profile. Both are above the 0.5 threshold.

**7. DILI:** Ligand A (23.226) has a much lower DILI risk than Ligand B (19.736). Both are good, but A is preferable.

**8. BBB:** This is a critical parameter for CNS targets. Ligand A (77.743) is significantly better than Ligand B (54.517). A value >70 is desirable, and A is closer to that target.

**9. Caco-2 Permeability:** Ligand A (-4.693) is better than Ligand B (-4.837). Higher values are better, indicating better intestinal absorption.

**10. Aqueous Solubility:** Ligand A (-1.613) is better than Ligand B (-2.083). Higher values are better.

**11. hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.365 and 0.308), which is excellent.

**12. Microsomal Clearance:** Ligand B (-4.631) has a negative clearance value, which is unusual and suggests very high metabolic stability. Ligand A (35.701) has a moderate clearance. This is a significant advantage for B.

**13. In vitro Half-Life:** Ligand B (2.931) has a lower half-life than Ligand A (9.626). A is preferable.

**14. P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.039 and 0.056).

**15. Binding Affinity:** Ligand B (-8.1) has a slightly better binding affinity than Ligand A (-7.9). While a 1.5 kcal/mol advantage is significant, the other ADME properties are more concerning.

**Overall Assessment:**

Ligand A is the better candidate. While Ligand B has slightly better binding affinity and metabolic stability, Ligand A excels in crucial properties for CNS penetration and safety: TPSA, BBB, DILI, solubility, and half-life. The difference in binding affinity (0.2 kcal/mol) is not substantial enough to outweigh the significant advantages of Ligand A in terms of ADME properties, especially for a CNS target like DRD2. The lower TPSA and higher BBB of Ligand A are particularly important for ensuring sufficient brain exposure.

Output:
0
2025-04-17 04:25:45,492 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (351.793 and 367.471 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (71.09) is excellent, well below the 90 A^2 threshold for CNS targets. Ligand B (82.97) is still reasonable but less optimal.

**logP:** Ligand A (3.723) is at the upper end of the optimal range (1-3), but acceptable. Ligand B (0.532) is significantly below the optimal range and could indicate poor membrane permeability.

**H-Bond Donors/Acceptors:** Ligand A (2 HBD, 4 HBA) is good. Ligand B (1 HBD, 6 HBA) is also acceptable.

**QED:** Both ligands have good QED scores (0.543 and 0.821), indicating drug-like properties.

**DILI:** Ligand A (96.82) has a high DILI risk, which is a significant concern. Ligand B (32.842) has a very low DILI risk, a major advantage.

**BBB:** Ligand A (55.487) has a moderate BBB penetration, which is not ideal for a CNS target. Ligand B (31.214) has poor BBB penetration, a significant drawback.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.864 and -4.978), which is unusual and suggests issues with the assay or the compounds themselves. These values are difficult to interpret directly.

**Aqueous Solubility:** Both ligands have negative solubility values (-5.877 and -1.195), which is also unusual and suggests poor solubility.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.279 and 0.11).

**Microsomal Clearance:** Ligand A (34.48) has moderate clearance, while Ligand B (2.094) has very low clearance, suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (101.147) has a good in vitro half-life. Ligand B (15.702) has a short half-life.

**P-gp Efflux:** Ligand A (0.289) has low P-gp efflux, which is favorable for CNS penetration. Ligand B (0.106) also has low P-gp efflux.

**Binding Affinity:** Ligand A (-9.4 kcal/mol) has significantly stronger binding affinity than Ligand B (-7.5 kcal/mol). This is a substantial advantage.

**Overall Assessment:**

Despite the unusual Caco-2 and solubility values, Ligand A has a much stronger binding affinity and better TPSA, P-gp efflux, and in vitro half-life. However, its high DILI risk and moderate BBB penetration are major concerns. Ligand B has a much better safety profile (low DILI) and better metabolic stability, but its weak binding affinity and poor BBB penetration are significant drawbacks.

Given the GPCR-specific priorities, and the substantial difference in binding affinity, I would lean towards Ligand A, *but with a strong caveat*. The high DILI risk needs to be addressed through structural modifications. The moderate BBB penetration could potentially be improved with further optimization. The strong affinity is a key driver here, as it could potentially outweigh some of the ADME liabilities if they can be mitigated.

Output:
1
2025-04-17 04:25:45,492 - INFO - Reasoning:

Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (355.341 and 346.475 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (75.88) is better than Ligand B (66.37) as it is closer to the <90 A^2 threshold for CNS targets. Both are acceptable.

**3. logP:** Both ligands have good logP values (1.568 and 1.205), falling within the optimal 1-3 range.

**4. H-Bond Donors:** Ligand A (0) is preferable to Ligand B (2) as fewer HBDs generally improve permeability.

**5. H-Bond Acceptors:** Ligand A (5) is preferable to Ligand B (4) as both are within the acceptable range of <=10.

**6. QED:** Both ligands have similar, good QED values (0.77 and 0.78), indicating good drug-like properties.

**7. DILI:** Ligand A (60.682) has a higher DILI risk than Ligand B (10.702). This is a significant drawback for Ligand A.

**8. BBB:** Ligand A (91.043) has a much better BBB penetration percentile than Ligand B (59.131). This is a critical advantage for a CNS target like DRD2.

**9. Caco-2 Permeability:** Ligand A (-4.158) is better than Ligand B (-5.409), indicating better intestinal absorption.

**10. Aqueous Solubility:** Ligand A (-2.627) is better than Ligand B (-0.761), suggesting better solubility.

**11. hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.257 and 0.219).

**12. Microsomal Clearance:** Ligand B (-12.011) has a lower (better) microsomal clearance than Ligand A (24.521), indicating greater metabolic stability.

**13. In vitro Half-Life:** Ligand B (5.963) has a longer in vitro half-life than Ligand A (-38.715). This is a significant advantage for Ligand B.

**14. P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.066 and 0.033).

**15. Binding Affinity:** Both ligands have similar, strong binding affinities (-8.4 and -8.6 kcal/mol). The difference is negligible.

**Overall Assessment:**

Ligand A excels in BBB penetration, solubility, and Caco-2 permeability. However, its significantly higher DILI risk is a major concern. Ligand B has better metabolic stability (lower Cl_mic, longer t1/2) and a much lower DILI risk. While its BBB penetration is lower, it's still reasonably good (59.131). Given the importance of minimizing toxicity (DILI) and ensuring reasonable metabolic stability for a CNS drug, Ligand B is the more promising candidate. The slightly lower BBB score is less critical than the improved safety profile.

Output:
1
2025-04-17 04:25:45,492 - INFO - Reasoning:

Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (386.5 and 347.5 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (100.62) is slightly above the optimal <90 for CNS targets, while Ligand B (77.57) is well within the desired range. This favors Ligand B.

**3. logP:** Both ligands have acceptable logP values (0.667 and 0.724), falling within the 1-3 range.

**4. H-Bond Donors:** Ligand A has 1 HBD, and Ligand B has 2. Both are within the acceptable limit of <=5.

**5. H-Bond Acceptors:** Both ligands have 5 HBAs, which is within the acceptable limit of <=10.

**6. QED:** Both ligands have good QED scores (0.742 and 0.688), indicating good drug-like properties.

**7. DILI:** Ligand A (54.56%) has a slightly higher DILI risk than Ligand B (43.93%), but both are below the concerning threshold of 60%.

**8. BBB:** Ligand A (82.09%) shows better BBB penetration than Ligand B (73.13%), which is crucial for a CNS target like DRD2. This is a significant advantage for Ligand A.

**9. Caco-2 Permeability:** Ligand A (-4.759) and Ligand B (-4.996) both have negative Caco-2 values, which is unusual and suggests poor permeability. However, the scale is not specified, so it's difficult to interpret.

**10. Aqueous Solubility:** Both ligands have very poor aqueous solubility (-3.712 and -1.127). This is a significant drawback for both.

**11. hERG Inhibition:** Both ligands have low hERG inhibition risk (0.271 and 0.494).

**12. Microsomal Clearance:** Ligand B (23.25) has significantly lower microsomal clearance than Ligand A (49.94), indicating better metabolic stability. This favors Ligand B.

**13. In vitro Half-Life:** Ligand B (29.75) has a longer in vitro half-life than Ligand A (-21.30), suggesting better duration of action. This favors Ligand B.

**14. P-gp Efflux:** Both ligands have low P-gp efflux liability (0.121 and 0.01).

**15. Binding Affinity:** Ligand B (-7.8 kcal/mol) has a significantly stronger binding affinity than Ligand A (-9.5 kcal/mol). This is a major advantage for Ligand B. A difference of 1.7 kcal/mol is substantial.

**Overall Assessment:**

While Ligand A has a better BBB score, Ligand B excels in several critical areas: significantly higher binding affinity, lower microsomal clearance (better metabolic stability), and a longer in vitro half-life. Ligand B also has a more favorable TPSA. The solubility is poor for both, but the affinity difference is substantial enough to outweigh the slightly lower BBB score of Ligand B. Given the GPCR-specific priorities, the strong binding affinity of Ligand B is the most important factor.

Output:
1
2025-04-17 04:25:45,492 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B based on the provided guidelines, prioritizing GPCR properties (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (347.371 and 351.466 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (102.16) is higher than the preferred <90 for CNS targets, while Ligand B (56.67) is well within the range. This is a significant advantage for Ligand B.

**logP:** Ligand A (0.782) is a bit low, potentially hindering permeation. Ligand B (2.169) is within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A has 2 HBD and 7 HBA, which are acceptable. Ligand B has 1 HBD and 4 HBA, also acceptable.

**QED:** Both ligands have good QED scores (0.749 and 0.818), indicating drug-likeness.

**DILI:** Ligand A (67.817) has a higher DILI risk than Ligand B (4.459). This is a significant advantage for Ligand B.

**BBB:** Ligand B (92.749) has excellent BBB penetration, exceeding the desirable >70% threshold. Ligand A (45.134) is below this threshold, which is a major drawback for a CNS target like DRD2.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.942 and -4.658), which is unusual and difficult to interpret without further context. However, it doesn't strongly favor either ligand.

**Aqueous Solubility:** Both ligands have negative solubility values (-2.497 and -0.997), also unusual and hard to interpret.

**hERG:** Ligand A (0.353) has a slightly lower hERG risk than Ligand B (0.841), but both are relatively low.

**Microsomal Clearance:** Ligand A (35.416) has higher microsomal clearance than Ligand B (10.669), suggesting lower metabolic stability. Ligand B is preferable here.

**In vitro Half-Life:** Ligand B (-22.834) has a much longer in vitro half-life than Ligand A (20.152), which is a significant advantage.

**P-gp Efflux:** Ligand A (0.053) has lower P-gp efflux than Ligand B (0.265), which is favorable for CNS penetration.

**Binding Affinity:** Ligand A (-8.3 kcal/mol) has a slightly better binding affinity than Ligand B (-7.6 kcal/mol), but the difference (0.7 kcal/mol) isn't substantial enough to overcome the significant ADME advantages of Ligand B.

**Overall:** Considering the GPCR-specific priorities, Ligand B is the superior candidate. Its excellent BBB penetration, lower DILI risk, better metabolic stability (lower Cl_mic, longer t1/2), and acceptable logP outweigh the slightly weaker binding affinity and slightly higher P-gp efflux compared to Ligand A. The lower TPSA of Ligand B is also a significant advantage for CNS penetration.

Output:
1
2025-04-17 04:25:45,492 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (356.419 and 345.447 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (113.96) is slightly above the optimal <90 for CNS targets, but still reasonable. Ligand B (98.17) is better, falling comfortably below 90.

**logP:** Ligand A (-0.094) is quite low, potentially hindering membrane permeability. Ligand B (2.786) is within the optimal 1-3 range. This is a significant advantage for Ligand B.

**H-Bond Donors/Acceptors:** Ligand A has 3 HBD and 6 HBA, both acceptable. Ligand B has 1 HBD and 3 HBA, also acceptable.

**QED:** Both ligands have similar QED values (0.372 and 0.346), indicating moderate drug-likeness.

**DILI:** Both ligands have relatively low DILI risk (16.906 and 15.936), which is good.

**BBB:** This is a crucial parameter for a CNS target like DRD2. Ligand A has a BBB percentile of 30.71, which is quite low and concerning. Ligand B has a much higher BBB percentile of 75.262, a significant advantage.

**Caco-2 Permeability:** Both have negative Caco-2 values (-5.364 and -5.019), which is unusual and suggests poor permeability. However, these values are on a scale where negative values are possible and don't necessarily preclude development.

**Aqueous Solubility:** Both ligands have very poor aqueous solubility (-0.999 and -2.991). This could pose formulation challenges.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.106 and 0.255).

**Microsomal Clearance:** Both ligands have similar microsomal clearance values (37.519 and 37.016 mL/min/kg), indicating moderate metabolic stability.

**In vitro Half-Life:** Ligand A (-12.578) has a very short half-life, while Ligand B (-19.91) is slightly longer, but still short. Both are concerning.

**P-gp Efflux:** Both ligands show very low P-gp efflux liability (0.016 and 0.028), which is favorable for CNS penetration.

**Binding Affinity:** Ligand B (-8.3 kcal/mol) has a slightly better binding affinity than Ligand A (-7.6 kcal/mol). While the difference is not huge, it's still a positive factor.

**Overall Assessment:**

Ligand B is the more promising candidate. Its superior logP and significantly better BBB penetration are critical advantages for a CNS-targeting GPCR. While both ligands have poor solubility and short half-lives, the improved permeability and CNS exposure potential of Ligand B outweigh the slightly better affinity of Ligand A. The low logP of Ligand A is a major drawback.

Output:
1
2025-04-17 04:25:45,493 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (346.475 and 348.403 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (76.02) is excellent, well below the 90 A^2 threshold for CNS targets. Ligand B (113.44) is higher, but still potentially acceptable, though less ideal.

**logP:** Ligand A (1.862) is optimal. Ligand B (0.128) is quite low, potentially hindering membrane permeability and reducing brain exposure.

**H-Bond Donors/Acceptors:** Ligand A (2 HBD, 4 HBA) is good. Ligand B (3 HBD, 6 HBA) is also acceptable.

**QED:** Ligand A (0.791) is strong, indicating good drug-likeness. Ligand B (0.615) is still reasonable, but less favorable.

**DILI:** Ligand A (27.608) has a low DILI risk. Ligand B (38.038) is slightly higher, but still within an acceptable range.

**BBB:** Ligand A (62.233) is moderate. Ligand B (54.052) is lower, which is a significant drawback for a CNS target like DRD2.

**Caco-2 Permeability:** Both have negative values (-5.135 and -4.844), which is unusual and difficult to interpret without more context. However, it suggests poor permeability.

**Aqueous Solubility:** Both have negative values (-2.383 and -2.226), again unusual. This suggests poor solubility.

**hERG:** Both ligands have very low hERG risk (0.111 and 0.083).

**Microsomal Clearance:** Ligand A (30.236) has moderate clearance. Ligand B (24.281) has lower clearance, suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (12.332) has a reasonable half-life. Ligand B (-35.159) has a negative half-life, which is impossible and indicates a problem with the data or the prediction method.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.113 and 0.007).

**Binding Affinity:** Both ligands have excellent binding affinity (-8.0 and -8.3 kcal/mol). The difference is minimal.

**Overall Assessment:**

Ligand A is superior due to its better logP, TPSA, QED, and a more reasonable (though still problematic) half-life. The biggest issue for both is the negative Caco-2 and solubility values, which need investigation. However, the significantly lower BBB penetration for Ligand B, coupled with the impossible half-life value, makes it a less desirable candidate. While Ligand A's BBB is not ideal, it's better than Ligand B's and can potentially be improved through structural modifications. The similar binding affinities mean the ADME properties are the deciding factor.

Output:
1
2025-04-17 04:25:45,493 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B against the provided guidelines, prioritizing GPCR-specific properties (BBB, logP, Pgp, TPSA, and affinity) for DRD2.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (368.905) is slightly higher than Ligand B (346.347), but both are acceptable.

**TPSA:** Ligand A (69.64) is excellent for CNS penetration, well below the 90 A^2 threshold. Ligand B (126.38) is higher, but still potentially acceptable, though less ideal.

**logP:** Ligand A (3.704) is within the optimal range (1-3). Ligand B (-0.474) is significantly lower, which could hinder membrane permeability and CNS penetration.

**H-Bond Donors/Acceptors:** Both ligands have reasonable HBD (2) and HBA (3 for A, 8 for B) counts, staying within the suggested limits. Ligand B's higher HBA may slightly impact permeability.

**QED:** Both ligands have good QED scores (0.653 and 0.749), indicating drug-like properties.

**DILI:** Ligand A (21.714) has a much lower DILI risk than Ligand B (56.301), making it safer from a liver toxicity perspective.

**BBB:** This is a critical parameter for DRD2. Ligand A (62.854) has a moderate BBB penetration, while Ligand B (37.263) is quite low. This is a significant disadvantage for Ligand B.

**Caco-2 Permeability:** Ligand A (-4.581) and Ligand B (-5.06) both have negative values, which is unusual and suggests poor permeability. However, the scale is not specified, so it's hard to interpret.

**Aqueous Solubility:** Ligand A (-3.438) and Ligand B (-2.442) both have negative values, indicating low solubility.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.776 and 0.066), which is positive.

**Microsomal Clearance:** Ligand A (41.223) has a higher microsomal clearance than Ligand B (11.093), indicating faster metabolism and potentially lower in vivo exposure.

**In vitro Half-Life:** Ligand A (71.509) has a significantly longer in vitro half-life than Ligand B (-4.722), which is a major advantage.

**P-gp Efflux:** Ligand A (0.331) has lower P-gp efflux liability than Ligand B (0.028), meaning it's less likely to be pumped out of the brain, improving CNS exposure.

**Binding Affinity:** Ligand B (-8.9 kcal/mol) has a substantially stronger binding affinity than Ligand A (-7.0 kcal/mol). This is a significant advantage for Ligand B. However, the other ADME properties must be considered.

**Overall Assessment:**

While Ligand B boasts a superior binding affinity, its significantly lower logP and BBB penetration, coupled with higher DILI risk and lower in vitro half-life, are major drawbacks for a CNS-targeting drug. Ligand A, despite a slightly weaker affinity, presents a much more favorable ADME profile, particularly regarding BBB penetration, DILI risk, and metabolic stability. The combination of acceptable TPSA, logP, and P-gp efflux, along with a reasonable half-life, makes Ligand A a more promising candidate for further development. The affinity difference, while notable, might be overcome with further optimization of Ligand A.

Output:
0
2025-04-17 04:25:45,493 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (408.351 Da) is slightly higher than Ligand B (362.539 Da), but both are acceptable.

**2. TPSA:** Ligand A (78.51) is higher than Ligand B (40.62). For CNS targets, we prefer TPSA <= 90. Both are below this, but Ligand B is significantly better.

**3. logP:** Both ligands have good logP values (A: 2.649, B: 3.565), falling within the optimal 1-3 range. Ligand B is slightly higher, which could be beneficial for membrane permeability.

**4. H-Bond Donors:** Ligand A has 2 HBD, while Ligand B has 0. Both are within the acceptable limit of <=5.

**5. H-Bond Acceptors:** Both ligands have 3 HBA, which is well within the acceptable limit of <=10.

**6. QED:** Both ligands have good QED scores (A: 0.76, B: 0.803), indicating good drug-like properties.

**7. DILI:** Ligand A has a DILI risk of 58.744, while Ligand B has 29.236. Ligand B is significantly better, being well below the 40 threshold.

**8. BBB:** This is a crucial parameter for CNS targets. Ligand A has a BBB penetration of 71.501, while Ligand B has 93.563. Ligand B is substantially better, exceeding the desirable >70 threshold.

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.998 and -4.894). These values are difficult to interpret without knowing the scale, but suggest poor permeability.

**10. Aqueous Solubility:** Both ligands have negative solubility values (-4.602 and -3.228). Similar to Caco-2, these values are difficult to interpret.

**11. hERG Inhibition:** Both ligands have low hERG inhibition risk (A: 0.599, B: 0.382), which is favorable.

**12. Microsomal Clearance:** Ligand A has a lower Cl_mic (38.766) than Ligand B (64.44), indicating better metabolic stability.

**13. In vitro Half-Life:** Ligand A has a negative half-life (-9.295) and Ligand B has a very short half-life (1.623). These values are difficult to interpret.

**14. P-gp Efflux:** Ligand A has a Pgp efflux of 0.112, while Ligand B has 0.614. Lower is better, so Ligand A is preferable here.

**15. Binding Affinity:** Both ligands have excellent binding affinities (A: -8.8 kcal/mol, B: -8.3 kcal/mol). Ligand A is slightly better (-8.8 vs -8.3).

**Overall Assessment:**

Ligand B clearly outperforms Ligand A in several critical areas for a CNS-targeting GPCR ligand: significantly better BBB penetration (93.563 vs 71.501), lower DILI risk (29.236 vs 58.744), and a lower P-gp efflux liability. While Ligand A has slightly better affinity and metabolic stability, the improvements in BBB, DILI, and Pgp for Ligand B outweigh these minor drawbacks. The negative values for Caco-2 and solubility are concerning for both, but the superior CNS-relevant properties of Ligand B make it the more promising candidate.

Output:
1
2025-04-17 04:25:45,493 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (337.379 Da) is slightly lower than Ligand B (360.336 Da), which is acceptable.

**TPSA:** Ligand A (77.25) is better than Ligand B (85.77). For CNS targets, we want TPSA <= 90, and both are within this range, but A is closer to the optimal value.

**logP:** Ligand A (3.39) is optimal (1-3), while Ligand B (-0.123) is significantly below this range. Low logP can hinder membrane permeability and CNS penetration. This is a major strike against Ligand B.

**H-Bond Donors/Acceptors:** Ligand A (HBD=1, HBA=6) is preferable to Ligand B (HBD=2, HBA=5). Both are within acceptable limits, but A's lower HBD count is slightly better.

**QED:** Both ligands have good QED scores (A: 0.666, B: 0.782), indicating good drug-like properties.

**DILI:** Ligand A (77.045) has a higher DILI risk than Ligand B (47.344). This is a negative for Ligand A, but not a dealbreaker at this stage.

**BBB:** Ligand A (65.452) and Ligand B (63.358) are both below the desirable threshold of >70 for CNS targets. However, this is less critical if other properties are favorable.

**Caco-2 Permeability:** Ligand A (-4.869) and Ligand B (-5.088) both have negative values, which is unusual and suggests very poor permeability. This is a concern for both, but the values are similar.

**Aqueous Solubility:** Ligand A (-4.992) and Ligand B (-0.931) both have negative values, indicating poor solubility. Ligand B is slightly better.

**hERG Inhibition:** Ligand A (0.576) has a lower hERG risk than Ligand B (0.241), which is preferable.

**Microsomal Clearance:** Ligand A (128.705) has higher clearance than Ligand B (-16.484). This suggests Ligand B is more metabolically stable, which is a positive.

**In vitro Half-Life:** Ligand A (-11.554) has a shorter half-life than Ligand B (-8.589). This is a negative for Ligand A.

**P-gp Efflux:** Ligand A (0.46) has lower P-gp efflux than Ligand B (0.03). Lower efflux is better for CNS penetration, favoring Ligand A.

**Binding Affinity:** Ligand A (-9.4 kcal/mol) has significantly stronger binding affinity than Ligand B (-7.5 kcal/mol). This is a substantial advantage for Ligand A, potentially outweighing some of its ADME drawbacks. A difference of 1.9 kcal/mol is quite significant.

**Conclusion:**

Despite Ligand A's higher DILI risk and lower BBB penetration, its superior logP, P-gp efflux, and *much* stronger binding affinity make it the more promising candidate. The low logP of Ligand B is a major concern for CNS penetration, and its weaker binding affinity is difficult to overcome. While both have poor solubility and permeability, the binding affinity difference is the deciding factor.

Output:
1
2025-04-17 04:25:45,494 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 drug candidates, considering the provided guidelines and GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (362.352 and 356.413 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (93.21) is slightly above the optimal <90 for CNS targets, but still reasonable. Ligand B (78.43) is well within the desired range.

**logP:** Both ligands (2.272 and 2.93) are within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A has 2 HBD and 5 HBA, while Ligand B has 3 HBD and 3 HBA. Both are acceptable, staying within the guidelines of <=5 HBD and <=10 HBA.

**QED:** Ligand A (0.784) has a better QED score than Ligand B (0.637), indicating a more drug-like profile.

**DILI:** Ligand A (50.097) has a slightly higher DILI risk than Ligand B (38.116), but both are below the concerning threshold of 60.

**BBB:** This is a critical parameter for CNS targets like DRD2. Ligand A (78.519) has a significantly better BBB penetration percentile than Ligand B (59.248). A value >70 is desirable, and Ligand A is closer to that.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.783 and -5.067), which is unusual and suggests poor permeability. However, these values are on a scale where negative values are possible and don't necessarily disqualify the compounds.

**Aqueous Solubility:** Both ligands have negative solubility values (-2.985 and -3.301), which is also unusual and suggests poor solubility.

**hERG:** Ligand A (0.251) has a lower hERG inhibition liability than Ligand B (0.689), indicating a lower risk of cardiotoxicity.

**Microsomal Clearance:** Ligand A (49.473) has a slightly lower microsomal clearance than Ligand B (42.36), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand B (-16.006) has a significantly longer in vitro half-life than Ligand A (-1.14), which is a positive attribute.

**P-gp Efflux:** Ligand A (0.02) has a much lower P-gp efflux liability than Ligand B (0.228), which is crucial for CNS penetration.

**Binding Affinity:** Ligand B (-8.9 kcal/mol) has a slightly better binding affinity than Ligand A (-8.2 kcal/mol). While the difference is not huge, it's a factor.

**Overall Assessment:**

Considering the GPCR-specific priorities, Ligand A is the more promising candidate. While Ligand B has a slightly better affinity and half-life, Ligand A excels in BBB penetration (78.519 vs 59.248), P-gp efflux (0.02 vs 0.228), and hERG inhibition (0.251 vs 0.689). The better QED score and lower DILI risk also favor Ligand A. The negative Caco-2 and solubility values are concerning for both, but the superior CNS-related properties of Ligand A outweigh these drawbacks.

Output:
0
2025-04-17 04:25:45,494 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (342.439 and 348.422 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (49.85) is significantly better than Ligand B (75.19). For CNS targets, we want TPSA <= 90, and ideally closer to 60. Ligand A is well within this range, while Ligand B is approaching the upper limit and less desirable.

**3. logP:** Both ligands have acceptable logP values (1.132 and 2.329), falling within the optimal 1-3 range. Ligand B is slightly higher, which could potentially lead to some off-target interactions, but it's not a major concern.

**4. H-Bond Donors:** Ligand A (0) is preferable to Ligand B (1). Fewer H-bond donors generally improve membrane permeability.

**5. H-Bond Acceptors:** Ligand A (3) is better than Ligand B (4). Lower HBA count is generally favorable for permeability.

**6. QED:** Both ligands have good QED scores (0.723 and 0.829), indicating good drug-like properties.

**7. DILI:** Ligand A (31.989) has a much lower DILI risk than Ligand B (54.401). This is a significant advantage for Ligand A.

**8. BBB:** Both ligands have good BBB penetration (78.868 and 85.653), exceeding the desirable threshold of >70 for CNS targets. Ligand B is slightly better here.

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.41 and -4.421). This is unusual and suggests poor permeability. However, these values are on the same scale, so they don't differentiate the ligands.

**10. Aqueous Solubility:** Both ligands have very poor aqueous solubility (-2.821 and -2.687). This is a significant drawback for both, potentially hindering formulation and bioavailability.

**11. hERG Inhibition:** Both ligands show low hERG inhibition liability (0.398 and 0.276), which is good.

**12. Microsomal Clearance:** Ligand A (32.737) has a slightly lower microsomal clearance than Ligand B (39.051), suggesting better metabolic stability.

**13. In vitro Half-Life:** Ligand A (-2.448) has a significantly longer in vitro half-life than Ligand B (-10.98). This is a major advantage for Ligand A.

**14. P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.089 and 0.033), which is excellent for CNS exposure.

**15. Binding Affinity:** Ligand A (-8.2) has a slightly better binding affinity than Ligand B (-7.9). While the difference is small, it's still a positive for Ligand A.

**Overall Assessment:**

Ligand A is the more promising candidate. It has a lower TPSA, lower DILI risk, better metabolic stability (lower Cl_mic, longer t1/2), fewer H-bonds, and slightly better binding affinity. While both have poor solubility and Caco-2 permeability, Ligand A's other advantages, particularly the lower DILI and improved metabolic stability, make it the preferred choice for further development. The slightly better BBB penetration of Ligand B is not enough to offset the other drawbacks.

Output:
0
2025-04-17 04:25:45,494 - INFO - Batch 112 complete. Total preferences: 1792
2025-04-17 04:25:45,494 - INFO - Processing batch 113/512...
2025-04-17 04:26:26,990 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 drug candidates, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (345.443 and 361.877 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (75.44) is slightly above the optimal <90 for CNS targets, but still reasonable. Ligand B (64.86) is excellent, well below 90.

**3. logP:** Ligand A (2.559) is within the optimal 1-3 range. Ligand B (3.805) is slightly higher, approaching the upper limit, but still acceptable.

**4. H-Bond Donors:** Both ligands have 1 HBD, which is within the ideal limit of <=5.

**5. H-Bond Acceptors:** Ligand A has 4 HBAs, and Ligand B has 6 HBAs, both within the acceptable limit of <=10.

**6. QED:** Both ligands have good QED scores (0.851 and 0.897), indicating good drug-like properties.

**7. DILI:** Ligand A (53.276) has a slightly better DILI risk profile than Ligand B (62.35), but both are reasonably low risk (<60 is good).

**8. BBB:** This is a critical parameter for CNS targets. Ligand B (83.986) has a significantly better BBB penetration percentile than Ligand A (74.254). This is a major advantage for Ligand B.

**9. Caco-2 Permeability:** Ligand A (-4.769) and Ligand B (-5.152) both have negative values, indicating poor permeability. This is a concern for both.

**10. Aqueous Solubility:** Both ligands have poor aqueous solubility (-3.703 and -4.556). This could pose formulation challenges.

**11. hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.28 and 0.261).

**12. Microsomal Clearance:** Both ligands have similar microsomal clearance values (44.711 and 45.11 mL/min/kg), suggesting comparable metabolic stability.

**13. In vitro Half-Life:** Ligand B (7.162) has a significantly longer in vitro half-life than Ligand A (-3.903). This is a significant advantage for Ligand B.

**14. P-gp Efflux:** Both ligands have low P-gp efflux liability (0.287 and 0.459).

**15. Binding Affinity:** Ligand B (-7.6 kcal/mol) has a slightly better binding affinity than Ligand A (-8.4 kcal/mol). Although A is slightly better, the difference is not substantial enough to outweigh the other factors.

**Overall Assessment:**

Ligand B is the more promising candidate. While both have poor solubility and Caco-2 permeability, Ligand B excels in key areas for CNS GPCR targets: significantly better BBB penetration (83.986 vs 74.254) and a longer in vitro half-life (7.162 vs -3.903). The slightly better affinity of Ligand A is not enough to offset these advantages.

Output:
1
2025-04-17 04:26:26,990 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (356.463 and 346.475 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (79.31) is better than Ligand B (59.51) as it is closer to the ideal range for CNS targets (<=90).

**logP:** Ligand B (2.828) is optimal (1-3), while Ligand A (0.504) is below 1, which could hinder permeation. This is a significant drawback for Ligand A.

**H-Bond Donors:** Both ligands have 1 HBD, which is within the acceptable limit of <=5.

**H-Bond Acceptors:** Ligand A has 5 HBA, and Ligand B has 6, both within the acceptable limit of <=10.

**QED:** Both ligands have good QED values (0.685 and 0.731, respectively), indicating drug-like properties.

**DILI:** Both ligands have acceptable DILI risk (23.924 and 39.667, both <40).

**BBB:** Ligand B (97.286) is *significantly* better than Ligand A (38.852) regarding BBB penetration, a crucial factor for CNS targets like DRD2.

**Caco-2 Permeability:** Ligand A (-4.379) and Ligand B (-4.896) both have negative values, which is unusual. It's difficult to interpret without knowing the scale, but lower values generally indicate poorer permeability.

**Aqueous Solubility:** Ligand A (-0.664) and Ligand B (-3.169) both have negative values, indicating poor solubility.

**hERG Inhibition:** Both ligands show low hERG inhibition liability (0.408 and 0.869, respectively).

**Microsomal Clearance:** Ligand A (31.649) has lower microsomal clearance than Ligand B (73.185), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand B (33.963) has a substantially longer half-life than Ligand A (5.361), which is desirable.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.162 and 0.174, respectively).

**Binding Affinity:** Ligand A (-7.8 kcal/mol) has a slightly better binding affinity than Ligand B (-7.6 kcal/mol), but the difference is small (0.2 kcal/mol) and may not outweigh other factors.

**Overall Assessment:**

While Ligand A has slightly better binding affinity and metabolic stability, Ligand B is significantly superior in terms of BBB penetration (97.286 vs 38.852) and has a longer half-life. The low logP of Ligand A is a major concern, potentially limiting its ability to cross cell membranes and reach the target in the CNS. Given the GPCR-specific priorities for DRD2, BBB penetration and logP are paramount.

Output:
1
2025-04-17 04:26:26,991 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B based on the provided guidelines, prioritizing GPCR-specific properties (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (353.442) is slightly lower, which could be beneficial for permeability, but both are acceptable.

**TPSA:** Ligand A (90.98) is excellent for CNS penetration, falling well below the 90 threshold. Ligand B (38.77) is also very good.

**logP:** Ligand A (1.749) is optimal. Ligand B (3.594) is at the higher end of optimal, but still acceptable.

**H-Bond Donors/Acceptors:** Ligand A has 2 HBD and 4 HBA, which are good values. Ligand B has 0 HBD and 3 HBA, also acceptable.

**QED:** Ligand A (0.781) has a better QED score than Ligand B (0.597), indicating a more drug-like profile.

**DILI:** Ligand A (38.969) has a significantly lower DILI risk than Ligand B (14.385), which is a major advantage.

**BBB:** Ligand B (98.216) has a substantially higher BBB penetration score than Ligand A (73.827). This is a critical factor for a CNS target like DRD2.

**Caco-2 Permeability:** Ligand A (-5.365) has a negative Caco-2 value, which is concerning. Ligand B (-3.888) is also negative, but less so. Both suggest poor intestinal absorption, but the scale isn't fully defined.

**Aqueous Solubility:** Ligand A (-2.045) and Ligand B (-4.103) both have negative solubility values, indicating poor aqueous solubility.

**hERG Inhibition:** Ligand A (0.149) has a lower hERG inhibition liability than Ligand B (0.848), which is preferable.

**Microsomal Clearance:** Ligand A (-0.155) has a negative clearance, which is excellent, suggesting high metabolic stability. Ligand B (94.362) has very high clearance, indicating rapid metabolism.

**In vitro Half-Life:** Ligand A (-23.113) has a negative half-life, which is excellent. Ligand B (4.075) has a short half-life.

**P-gp Efflux:** Ligand A (0.042) has very low P-gp efflux liability, which is good for CNS exposure. Ligand B (0.518) has moderate P-gp efflux.

**Binding Affinity:** Ligand A (-8.6) has a significantly stronger binding affinity than Ligand B (-6.6). A difference of 2 kcal/mol is substantial.

**Overall Assessment:**

Ligand A excels in most ADME properties (DILI, metabolic stability, P-gp efflux, and binding affinity) and has a good TPSA and logP. Its main weakness is the negative Caco-2 and solubility values. However, for a CNS target, these are less critical than BBB penetration.

Ligand B's primary strength is its excellent BBB penetration. However, it suffers from high DILI risk, high metabolic clearance, moderate P-gp efflux, and weaker binding affinity.

Given the importance of BBB penetration for a CNS target like DRD2, and the substantial affinity difference, the stronger binding affinity of Ligand A, coupled with its superior safety profile (DILI) and metabolic stability, outweigh the concerns about its solubility and Caco-2 permeability. The difference in affinity is large enough to potentially overcome the absorption challenges.

Output:
0
2025-04-17 04:26:26,991 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 drug candidates, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (363.447 and 382.873 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (105.9) is slightly above the preferred <90 for CNS targets, while Ligand B (91.48) is closer to the ideal range. This gives a slight edge to Ligand B.

**3. logP:** Ligand A (0.558) is quite low, potentially hindering membrane permeability. Ligand B (1.508) is better, falling within the optimal 1-3 range. This is a significant advantage for Ligand B.

**4. H-Bond Donors:** Ligand A (1) is good. Ligand B (2) is acceptable.

**5. H-Bond Acceptors:** Ligand A (8) is good. Ligand B (7) is good.

**6. QED:** Both ligands have similar, high QED values (0.851 and 0.836), indicating good drug-like properties.

**7. DILI:** Both ligands have relatively high DILI risk (66.344 and 62.776), but are still within an acceptable range.

**8. BBB:** Ligand A (46.491) has a poor BBB percentile, making CNS penetration unlikely. Ligand B (36.371) is also low, but slightly better than A. Both are below the desirable >70 for CNS targets.

**9. Caco-2:** Both ligands have negative Caco-2 values (-5.581 and -5.181), which is unusual and suggests poor permeability. This is a concern for both.

**10. Solubility:** Both ligands have very poor aqueous solubility (-2.037 and -2.473). This is a major drawback for both.

**11. hERG:** Both ligands have very low hERG inhibition risk (0.095 and 0.105).

**12. Cl_mic:** Ligand A (14.462) has a higher microsomal clearance than Ligand B (-7.67), suggesting lower metabolic stability. This favors Ligand B.

**13. t1/2:** Ligand B (9.314) has a significantly longer in vitro half-life than Ligand A (0.543), which is a major advantage.

**14. Pgp:** Both ligands have very low P-gp efflux liability (0.042 and 0.086), which is positive for CNS exposure.

**15. Binding Affinity:** Ligand B (-7.9 kcal/mol) has a substantially stronger binding affinity than Ligand A (0.0 kcal/mol). This is a critical advantage, potentially outweighing some of its other weaknesses.

**Overall Assessment:**

Ligand B is the superior candidate. While both have issues with solubility and Caco-2 permeability, Ligand B excels in key areas for a CNS-targeting GPCR: significantly better binding affinity, a longer half-life, lower microsomal clearance, and a slightly better logP and TPSA. The slightly better BBB percentile, while still low, also contributes to its favorability. Ligand A's extremely weak binding affinity is a deal-breaker.

Output:
1
2025-04-17 04:26:26,991 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (350.463 and 342.458 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (80.48) is excellent, well below the 90 A^2 threshold for CNS targets. Ligand B (32.34) is also very good, comfortably under the threshold.

**logP:** Ligand A (1.604) is optimal. Ligand B (4.089) is approaching the upper limit of the optimal range and could potentially cause solubility issues.

**H-Bond Donors/Acceptors:** Both ligands have acceptable HBD (1) and HBA (6 for A, 2 for B) counts.

**QED:** Both ligands have good QED scores (0.808 and 0.79), indicating good drug-like properties.

**DILI:** Ligand A (26.328) has a significantly lower DILI risk than Ligand B (16.053), which is a substantial advantage.

**BBB:** Ligand B (96.278) has a *much* higher BBB penetration score than Ligand A (73.129). This is a critical factor for a CNS target like DRD2.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values, which is unusual and suggests poor permeability. However, the scale isn't specified, so it's hard to interpret.

**Aqueous Solubility:** Both ligands have negative solubility values, indicating poor aqueous solubility. This is a concern, but potentially manageable with formulation strategies.

**hERG:** Ligand A (0.239) has a lower hERG inhibition liability than Ligand B (0.787), which is preferable.

**Microsomal Clearance:** Ligand B (51.331) has higher microsomal clearance than Ligand A (40.041), meaning faster metabolism and potentially lower exposure.

**In vitro Half-Life:** Ligand B (6.813) has a longer in vitro half-life than Ligand A (-4.582), which is a positive.

**P-gp Efflux:** Ligand A (0.039) has much lower P-gp efflux liability than Ligand B (0.217), which is crucial for CNS penetration.

**Binding Affinity:** Ligand B (-8.5 kcal/mol) has a significantly stronger binding affinity than Ligand A (-6.2 kcal/mol). This is a substantial advantage, potentially outweighing some of the ADME drawbacks.

**Overall Assessment:**

Ligand B excels in BBB penetration and binding affinity, two key factors for a CNS GPCR target. However, it has higher DILI risk, higher P-gp efflux, and faster metabolism. Ligand A has better safety (DILI, hERG, P-gp) and metabolic stability, but its BBB penetration and binding affinity are considerably weaker.

The difference in binding affinity (-8.5 vs -6.2 kcal/mol) is substantial (2.3 kcal/mol), and is likely to be the deciding factor. While Ligand A has a better safety profile, the stronger binding of Ligand B is likely to translate to greater efficacy at lower doses, potentially mitigating some of the ADME concerns. The superior BBB penetration of Ligand B is also a major advantage.

Output:
1
2025-04-17 04:26:26,991 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B based on the provided guidelines, prioritizing GPCR-specific properties (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (345.4) is slightly lower, which is generally favorable for permeability.

**TPSA:** Ligand A (93.46) is borderline for CNS targets (<=90), while Ligand B (61.44) is well within the ideal range. This is a significant advantage for Ligand B regarding brain penetration.

**logP:** Both ligands have good logP values (A: 1.958, B: 2.844), falling within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Both have acceptable HBD (2) and HBA (A: 5, B: 3) counts.

**QED:** Both ligands have QED values above 0.5 (A: 0.713, B: 0.693), indicating good drug-likeness.

**DILI:** Ligand A has a higher DILI risk (75.03%) compared to Ligand B (5.58%). This is a substantial negative for Ligand A.

**BBB:** Ligand B shows a significantly better BBB penetration percentile (71.97%) than Ligand A (40.09%). This is a critical advantage for a CNS target like DRD2.

**Caco-2 Permeability:** Ligand A has a slightly better (less negative) Caco-2 value (-4.834) than Ligand B (-5.011), suggesting slightly better intestinal absorption. However, this is less important for a CNS target where BBB penetration is paramount.

**Aqueous Solubility:** Both have negative solubility values, indicating poor solubility. Ligand A (-3.222) is slightly better than Ligand B (-2.479), but both are problematic.

**hERG:** Ligand A (0.093) has a slightly higher hERG risk than Ligand B (0.639), but both are relatively low.

**Microsomal Clearance:** Ligand B has a much lower microsomal clearance (17.703) than Ligand A (92.361), indicating better metabolic stability.

**In vitro Half-Life:** Ligand B has a longer in vitro half-life (-4.231) than Ligand A (-21.69), which is desirable.

**P-gp Efflux:** Ligand B has a much lower P-gp efflux liability (0.062) than Ligand A (0.096), suggesting better CNS exposure.

**Binding Affinity:** Ligand B (-0.0 kcal/mol) has a significantly better binding affinity than Ligand A (-8.2 kcal/mol). This is a decisive advantage.

**Overall:** Considering all factors, especially the GPCR-specific priorities, Ligand B is the more promising drug candidate. It has superior BBB penetration, lower DILI risk, better metabolic stability, lower P-gp efflux, and significantly better binding affinity. While Ligand A has slightly better Caco-2 permeability and solubility, these are less critical for a CNS target, and are outweighed by the advantages of Ligand B.

Output:
1
2025-04-17 04:26:26,991 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (347.415 Da) is slightly lower, which could be beneficial for permeability. Ligand B (367.921 Da) is also good.

**TPSA:** Ligand A (84.67) is excellent, falling well below the 90 A^2 threshold for CNS targets. Ligand B (47.36) is also very good.

**logP:** Ligand A (1.305) is within the optimal range (1-3). Ligand B (3.573) is at the higher end of the optimal range, potentially increasing off-target interactions but also aiding membrane permeability.

**H-Bond Donors/Acceptors:** Ligand A has 1 HBD and 5 HBA, which are acceptable. Ligand B has 0 HBD and 4 HBA, also acceptable.

**QED:** Both ligands have similar QED values (0.784 and 0.772), indicating good drug-like properties.

**DILI:** Ligand A (48.662) has a slightly higher DILI risk than Ligand B (29.973), but both are below the concerning threshold of 60.

**BBB:** This is a critical parameter for CNS targets. Ligand B (88.29) has a significantly higher BBB penetration percentile than Ligand A (55.176). This is a major advantage for Ligand B.

**Caco-2 Permeability:** Ligand A (-4.996) has poor Caco-2 permeability, which is a concern. Ligand B (-4.873) also has poor Caco-2 permeability.

**Aqueous Solubility:** Both ligands have poor aqueous solubility (-2.104 and -3.389 respectively). This could pose formulation challenges.

**hERG Inhibition:** Ligand A (0.086) has a very low hERG risk, which is excellent. Ligand B (0.523) has a slightly higher, but still relatively low, hERG risk.

**Microsomal Clearance:** Ligand B (76.465) has a higher microsomal clearance than Ligand A (34.049), suggesting faster metabolism and potentially lower exposure.

**In vitro Half-Life:** Ligand A (-18.681) has a negative half-life, which is not possible. This is likely an error in the data. Ligand B (29.408) has a reasonable half-life.

**P-gp Efflux:** Ligand A (0.065) has very low P-gp efflux, which is favorable for CNS penetration. Ligand B (0.615) has a slightly higher P-gp efflux, but still relatively low.

**Binding Affinity:** Ligand A (-7.0) has a slightly better binding affinity than Ligand B (-0.0). This is a significant advantage.

**Overall Assessment:**

Despite the error in Ligand A's half-life, the most important factor for a CNS-targeting GPCR like DRD2 is BBB penetration. Ligand B's significantly higher BBB percentile (88.29 vs. 55.176) outweighs the slightly better affinity of Ligand A. While Ligand A has better hERG and P-gp profiles, the substantial difference in BBB penetration makes Ligand B the more promising candidate. The higher metabolic clearance of Ligand B is a concern, but could be addressed through structural modifications.

Output:
1
2025-04-17 04:26:26,992 - INFO - Reasoning:

Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (361.829 and 358.511 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (80.32) is better than Ligand B (59.07). For CNS targets, we want TPSA <= 90, both are within this range, but A is closer to the upper limit.

**3. logP:** Ligand B (3.791) is slightly higher than Ligand A (2.212), but both are within the optimal 1-3 range.

**4. H-Bond Donors:** Both ligands have 2 HBD, which is acceptable (<=5).

**5. H-Bond Acceptors:** Ligand A has 4 HBA, and Ligand B has 6. Both are within the acceptable range of <=10, but A is preferable.

**6. QED:** Ligand B (0.823) has a significantly better QED score than Ligand A (0.45), indicating a more drug-like profile.

**7. DILI:** Both ligands have relatively high DILI risk (76.464 and 63.125), but Ligand B is slightly better. Ideally, we want <40.

**8. BBB:** Ligand B (88.445) has a much higher BBB penetration percentile than Ligand A (62.117). This is *critical* for a CNS target like DRD2.

**9. Caco-2 Permeability:** Ligand A (-4.918) has better Caco-2 permeability than Ligand B (-5.159). Higher values are better.

**10. Aqueous Solubility:** Ligand A (-3.168) has better aqueous solubility than Ligand B (-4.52). Higher values are better.

**11. hERG Inhibition:** Ligand A (0.173) has a lower hERG inhibition liability than Ligand B (0.773), which is preferable.

**12. Microsomal Clearance:** Ligand B (86.287) has a higher microsomal clearance than Ligand A (65.64), meaning it's less metabolically stable. Lower is better.

**13. In vitro Half-Life:** Ligand A (68.784) has a slightly longer in vitro half-life than Ligand B (67.572).

**14. P-gp Efflux:** Ligand A (0.094) has lower P-gp efflux liability than Ligand B (0.329), which is favorable for CNS penetration.

**15. Binding Affinity:** Ligand A (-9.1 kcal/mol) has a stronger binding affinity than Ligand B (-8.5 kcal/mol). This is a significant advantage (>1.5 kcal/mol difference).

**Overall Assessment:**

While Ligand B has better QED and BBB penetration, Ligand A has a substantially better binding affinity (-9.1 vs -8.5 kcal/mol). The strong binding affinity of Ligand A can potentially outweigh some of its ADME drawbacks, especially given the importance of potency for GPCR targets. The lower P-gp efflux and hERG inhibition of Ligand A are also beneficial. The BBB penetration of Ligand A (62.117) is not ideal, but the superior binding affinity makes it a more promising candidate.

Output:
1
2025-04-17 04:26:26,992 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B based on the provided guidelines, prioritizing GPCR-specific properties (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands fall within the ideal range (200-500 Da). Ligand A (351.495 Da) is slightly preferred as it's closer to the lower end, potentially aiding permeability.

**TPSA:** Ligand A (89.38) is excellent for CNS penetration, being well below 90. Ligand B (125.69) is still acceptable but less optimal.

**logP:** Ligand A (3.743) is within the optimal range (1-3), while Ligand B (0.37) is significantly low, potentially hindering membrane permeability and CNS entry. This is a major drawback for Ligand B.

**H-Bond Donors/Acceptors:** Ligand A (0 HBD, 3 HBA) and Ligand B (3 HBD, 6 HBA) both have reasonable numbers of H-bond donors and acceptors.

**QED:** Both ligands have acceptable QED values (Ligand A: 0.26, Ligand B: 0.532). Ligand B is better here.

**DILI:** Ligand A (15.898) has a much lower DILI risk than Ligand B (65.762), which is a significant concern.

**BBB:** Ligand A (80.07) has a good BBB percentile, exceeding the 70% threshold for CNS targets. Ligand B (45.909) is considerably lower, indicating poor brain penetration. This is a critical disadvantage for a DRD2 ligand.

**Caco-2 Permeability:** Ligand A (-4.708) and Ligand B (-5.989) both have negative values, indicating poor permeability.

**Aqueous Solubility:** Both ligands have very poor solubility (-2.378 and -2.11 respectively).

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.694 and 0.065). Ligand B is better here.

**Microsomal Clearance:** Ligand A (47.261) has a moderate clearance, while Ligand B (9.402) has a very low clearance, suggesting better metabolic stability.

**In vitro Half-Life:** Ligand B (15.444) has a longer half-life than Ligand A (-21.34), which is desirable.

**P-gp Efflux:** Ligand A (0.155) shows lower P-gp efflux liability than Ligand B (0.038), which is favorable for CNS exposure.

**Binding Affinity:** Ligand B (-7.9 kcal/mol) has a slightly better binding affinity than Ligand A (-7.2 kcal/mol). While a 0.7 kcal/mol difference is not huge, it's a positive for Ligand B.

**Overall Assessment:**

Despite Ligand B's slightly better affinity and metabolic stability, Ligand A is the more promising candidate. The critical factors driving this decision are Ligand A's significantly better BBB penetration, lower DILI risk, and acceptable logP. Ligand B's very low logP and poor BBB penetration are major liabilities for a CNS-targeted drug. The slight affinity advantage of Ligand B is unlikely to overcome these significant ADME deficiencies.

Output:
0
2025-04-17 04:26:26,992 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (367.471 and 363.889 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (97.39) is slightly higher than Ligand B (81.99). Both are below the 140 threshold for oral absorption, but only Ligand B is comfortably below the 90 threshold desirable for CNS targets.

**3. logP:** Ligand A (2.044) and Ligand B (3.148) are both within the optimal 1-3 range.

**4. H-Bond Donors:** Both ligands have 2 HBD, which is acceptable.

**5. H-Bond Acceptors:** Ligand A has 5 HBA, while Ligand B has 3. Both are within the acceptable limit of 10.

**6. QED:** Ligand A (0.849) has a slightly better QED score than Ligand B (0.76), indicating a more drug-like profile.

**7. DILI:** Ligand A (56.921) has a higher DILI risk than Ligand B (32.299). This is a significant advantage for Ligand B.

**8. BBB:** Ligand A (71.035) has a better BBB penetration percentile than Ligand B (60.76). This is a crucial factor for a CNS target like DRD2.

**9. Caco-2 Permeability:** Ligand A (-4.817) has slightly better Caco-2 permeability than Ligand B (-4.799), but both are negative values which is difficult to interpret without knowing the scale.

**10. Aqueous Solubility:** Ligand A (-2.943) has slightly better aqueous solubility than Ligand B (-4.433), but both are negative values which is difficult to interpret without knowing the scale.

**11. hERG Inhibition:** Ligand A (0.216) has a lower hERG inhibition liability than Ligand B (0.451), which is favorable.

**12. Microsomal Clearance:** Ligand A (54.041) and Ligand B (57.816) have similar microsomal clearance values.

**13. In vitro Half-Life:** Ligand A (-39.207) has a significantly longer in vitro half-life than Ligand B (13.982). This is a major advantage for Ligand A.

**14. P-gp Efflux:** Ligand A (0.043) has much lower P-gp efflux liability than Ligand B (0.134), which is beneficial for CNS penetration.

**15. Binding Affinity:** Both ligands have very similar binding affinities (-8.4 and -8.5 kcal/mol). The difference is negligible.

**Overall Assessment:**

While Ligand A has a slightly better QED, longer half-life, and lower P-gp efflux, Ligand B has a significantly lower DILI risk and a TPSA value more favorable for CNS penetration. The BBB score for Ligand A is better, but the difference isn't substantial enough to outweigh the lower DILI risk of Ligand B. Given the importance of minimizing toxicity (DILI) and maximizing CNS penetration (lower TPSA) for a DRD2 ligand, Ligand B is the slightly more promising candidate.

Output:
1
2025-04-17 04:26:26,992 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight (MW):** Both ligands (363.483 and 370.519 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (80.32) is better than Ligand B (93.09). For CNS targets, we want TPSA <= 90, so Ligand A is preferable.

**3. logP:** Both ligands (1.465 and 1.525) are within the optimal range of 1-3.

**4. H-Bond Donors (HBD):** Both have 2 HBD, which is acceptable (<=5).

**5. H-Bond Acceptors (HBA):** Both have 5 HBA, which is acceptable (<=10).

**6. QED:** Both ligands have similar QED values (0.65 and 0.611), both above the desirable threshold of 0.5.

**7. DILI:** Both ligands have low DILI risk (41.024 and 39.511), below the 40% threshold.

**8. BBB:** Ligand B (54.983) has a significantly better BBB percentile than Ligand A (44.203). For a CNS target like DRD2, BBB penetration is crucial, making Ligand B more attractive.

**9. Caco-2 Permeability:** Both have negative Caco-2 values (-5.021 and -5.199). This is unusual and suggests poor permeability. However, the values are similar.

**10. Aqueous Solubility:** Ligand B (-1.593) is slightly better than Ligand A (-3.269), indicating slightly better solubility.

**11. hERG Inhibition:** Ligand A (0.29) has a lower hERG inhibition liability than Ligand B (0.617), which is desirable.

**12. Microsomal Clearance (Cl_mic):** Ligand A (30.732) has a lower Cl_mic than Ligand B (61.753), indicating better metabolic stability.

**13. In vitro Half-Life:** Ligand A (11.946) has a positive half-life, while Ligand B (-41.075) has a negative half-life. This is a significant advantage for Ligand A.

**14. P-gp Efflux:** Ligand A (0.04) has much lower P-gp efflux liability than Ligand B (0.222), which is beneficial for CNS exposure.

**15. Binding Affinity:** Ligand B (-7.8 kcal/mol) has a slightly better binding affinity than Ligand A (-7.4 kcal/mol). While a 1.5 kcal/mol difference is significant, the other ADME properties must be considered.

**Overall Assessment:**

Ligand B has a better BBB score and binding affinity, which are important for a CNS GPCR target. However, Ligand A excels in metabolic stability (lower Cl_mic, positive half-life), P-gp efflux, and hERG inhibition. The TPSA is also more favorable for Ligand A. The negative Caco-2 values for both are concerning, but the other advantages of Ligand A, particularly its better ADME profile, outweigh the slightly weaker binding affinity. Given the importance of CNS penetration and the balance of properties, I would lean towards Ligand A as the more viable candidate.

Output:
0
2025-04-17 04:26:26,992 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (358.435 and 358.427 Da) are within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (105.17) is slightly higher than Ligand B (104.03). Both are reasonably close to the 90 A^2 threshold for CNS targets, but still above it.

**3. logP:** Ligand A (0.082) is significantly lower than Ligand B (1.077). Ligand A is below the optimal 1-3 range, which could hinder permeation. Ligand B is within the acceptable range.

**4. H-Bond Donors:** Ligand A (2) is higher than Ligand B (1). Both are within the acceptable limit of <=5.

**5. H-Bond Acceptors:** Ligand A (6) is lower than Ligand B (8). Both are within the acceptable limit of <=10.

**6. QED:** Ligand B (0.872) has a considerably higher QED score than Ligand A (0.566), indicating a more drug-like profile.

**7. DILI:** Ligand A (12.136) has a much lower DILI risk than Ligand B (81.776). This is a significant advantage for Ligand A.

**8. BBB:** Ligand A (54.634) and Ligand B (53.083) are very similar in BBB penetration, and both are below the desirable >70 percentile for CNS targets. This is a weakness for both, but not a differentiating factor.

**9. Caco-2:** Ligand A (-4.755) and Ligand B (-5.221) are both very poor in Caco-2 permeability.

**10. Solubility:** Ligand A (-1.336) is better than Ligand B (-3.318).

**11. hERG:** Ligand A (0.212) has a lower hERG inhibition liability than Ligand B (0.364), indicating a lower risk of cardiotoxicity.

**12. Cl_mic:** Ligand A (25.637) and Ligand B (24.362) are very similar in microsomal clearance.

**13. t1/2:** Ligand B (9.499) has a significantly longer in vitro half-life than Ligand A (-17.857). This is a major advantage for Ligand B.

**14. Pgp:** Ligand A (0.02) has a much lower P-gp efflux liability than Ligand B (0.121). This is a significant advantage for Ligand A, particularly for CNS penetration.

**15. Binding Affinity:** Ligand A (-6.6) has a better binding affinity than Ligand B (0.0). This is a substantial advantage for Ligand A.

**Overall Assessment:**

Ligand A has a significantly better binding affinity, lower DILI risk, lower P-gp efflux, and better solubility. However, Ligand B has a much better QED score and a longer half-life. Both have poor BBB penetration and Caco-2 permeability. The most critical factors for a CNS GPCR target like DRD2 are affinity, BBB, Pgp, and logP. While both ligands fail to meet the BBB threshold, Ligand A's superior affinity and lower Pgp efflux outweigh the benefits of Ligand B's slightly better logP and half-life. The low logP of Ligand A is a concern, but the strong binding could compensate.

Output:
0
2025-04-17 04:26:26,993 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (335.407 and 345.443 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (67.16) is better than Ligand B (71), both are below the 90 A^2 threshold for CNS targets, but A is preferable.

**logP:** Ligand A (4.657) is slightly higher than the optimal 1-3 range, while Ligand B (2.147) is within the optimal range. This favors Ligand B.

**H-Bond Donors/Acceptors:** Ligand A has 2 HBD and 3 HBA, while Ligand B has 1 HBD and 4 HBA. Both are within acceptable limits (<=5 HBD and <=10 HBA).

**QED:** Both ligands have good QED scores (0.688 and 0.75), indicating good drug-like properties.

**DILI:** Ligand A (78.286) has a higher DILI risk than Ligand B (33.773). This is a significant advantage for Ligand B.

**BBB:** Ligand A (75.611) has a better BBB penetration percentile than Ligand B (68.67). This is a crucial factor for a CNS target like DRD2, favoring Ligand A.

**Caco-2 Permeability:** Ligand A (-4.805) has worse Caco-2 permeability than Ligand B (-4.855).

**Aqueous Solubility:** Ligand A (-5.347) has worse aqueous solubility than Ligand B (-3.063).

**hERG:** Ligand A (0.811) has a slightly higher hERG inhibition liability than Ligand B (0.142). This favors Ligand B.

**Microsomal Clearance:** Ligand A (92.445) has higher microsomal clearance than Ligand B (26.163), indicating lower metabolic stability. This favors Ligand B.

**In vitro Half-Life:** Ligand A (28.466) has a longer in vitro half-life than Ligand B (10.791). This favors Ligand A.

**P-gp Efflux:** Ligand A (0.657) has lower P-gp efflux liability than Ligand B (0.122), which is preferable for CNS penetration. This favors Ligand A.

**Binding Affinity:** Ligand A (-10.0) has a significantly stronger binding affinity than Ligand B (-9.1). This is a major advantage for Ligand A, potentially outweighing some ADME drawbacks.

**Overall Assessment:**

Ligand A excels in binding affinity and BBB penetration, and P-gp efflux, which are critical for a CNS GPCR target. However, it has concerning DILI risk, poor solubility, and higher clearance. Ligand B has better ADME properties (lower DILI, better solubility, lower clearance, lower hERG), but its binding affinity is weaker and BBB penetration is lower.

The strong binding affinity of Ligand A (-10.0 kcal/mol vs -9.1 kcal/mol) is a substantial advantage. Given the importance of potency for GPCR ligands, and the fact that the BBB value is still reasonably good (75.611), I believe Ligand A is the more promising candidate, despite its ADME liabilities. These liabilities could potentially be addressed through further optimization.

Output:
0
2025-04-17 04:26:26,993 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B based on the provided guidelines, prioritizing GPCR-specific properties (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (359.388 Da) is slightly preferred as it's closer to the lower end, potentially aiding permeability.

**TPSA:** Ligand A (47.56) is excellent for CNS penetration, well below the 90 A^2 threshold. Ligand B (96.01) is higher, potentially hindering BBB penetration, though still not drastically outside acceptable limits.

**logP:** Both ligands have good logP values (A: 3.796, B: 2.993), falling within the optimal 1-3 range. Ligand A is slightly higher, which could be beneficial for membrane permeability, but also raises a minor concern for off-target effects.

**H-Bond Donors/Acceptors:** Ligand A (HBD=1, HBA=3) is better than Ligand B (HBD=3, HBA=5) regarding the number of hydrogen bond donors and acceptors. Fewer H-bonds generally improve membrane permeability.

**QED:** Ligand A (0.841) has a significantly better QED score than Ligand B (0.389), indicating a more drug-like profile.

**DILI:** Ligand A (35.789) has a much lower DILI risk than Ligand B (96.045), a significant advantage.

**BBB:** Ligand A (84.064) has a very good BBB percentile, exceeding the desirable >70 threshold for CNS targets. Ligand B (54.246) is considerably lower, raising concerns about CNS exposure.

**Caco-2 Permeability:** Ligand A (-4.672) has a negative Caco-2 value, which is unusual and suggests poor permeability. Ligand B (-5.124) is also negative and similarly concerning. These values are likely on a log scale where negative values indicate low permeability.

**Aqueous Solubility:** Both ligands have very poor aqueous solubility (-3.739 and -5.0, respectively). This is a significant drawback for both, potentially impacting bioavailability.

**hERG Inhibition:** Ligand A (0.694) has a lower hERG inhibition risk than Ligand B (0.165), which is preferable.

**Microsomal Clearance:** Ligand B (28.532) has a lower microsomal clearance than Ligand A (40.857), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand B (44.85) has a significantly longer in vitro half-life than Ligand A (1.395), a major advantage for dosing convenience.

**P-gp Efflux:** Ligand A (0.396) has lower P-gp efflux liability than Ligand B (0.124), which is beneficial for CNS exposure.

**Binding Affinity:** Ligand B (-9.8 kcal/mol) has a *much* stronger binding affinity than Ligand A (-0.0 kcal/mol). This is a decisive advantage, potentially outweighing some of the ADME drawbacks.

**Overall Assessment:**

Despite Ligand A's better QED, DILI, BBB, and P-gp efflux, the overwhelmingly stronger binding affinity of Ligand B (-9.8 kcal/mol vs -0.0 kcal/mol) is the most critical factor, especially for a GPCR target. While Ligand B has poorer solubility, Caco-2 permeability, and a higher DILI risk, these issues might be addressable through formulation strategies or further chemical modifications. The significant improvement in binding affinity is a substantial advantage that outweighs the other concerns. The longer half-life of Ligand B is also a significant benefit.

Output:
1
2025-04-17 04:26:26,993 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (366.527 Da) is slightly higher than Ligand B (344.459 Da), but both are acceptable.

**TPSA:** Both ligands have TPSA values (67.43 and 69.3) slightly above the optimal 90 for CNS targets, but still reasonable.

**logP:** Ligand A (3.14) is within the optimal range (1-3), while Ligand B (1.985) is at the lower end. For a GPCR, a slightly higher logP is often preferred for membrane permeability, giving a slight edge to Ligand A.

**H-Bond Donors/Acceptors:** Ligand A has 2 HBD and 4 HBA, while Ligand B has 1 HBD and 3 HBA. Both are within acceptable limits (<=5 HBD and <=10 HBA).

**QED:** Both ligands have good QED scores (0.66 and 0.849), indicating good drug-like properties.

**DILI:** Ligand A (49.011) has a higher DILI risk than Ligand B (23.187). This is a significant drawback for Ligand A.

**BBB:** Ligand A (61.38) has a better BBB percentile than Ligand B (51.183), which is crucial for a CNS target like DRD2.

**Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and suggests poor permeability. However, the magnitude of the negative value for Ligand A (-5.284) is worse than for Ligand B (-5.01).

**Aqueous Solubility:** Both ligands have negative solubility values, indicating poor aqueous solubility. Ligand A (-2.958) is slightly worse than Ligand B (-1.836).

**hERG Inhibition:** Ligand A (0.699) has a slightly higher hERG inhibition risk than Ligand B (0.182). This is another point in favor of Ligand B.

**Microsomal Clearance:** Ligand A (47.337) has a higher microsomal clearance than Ligand B (30.424), suggesting lower metabolic stability.

**In vitro Half-Life:** Ligand B (-8.979) has a significantly *longer* in vitro half-life than Ligand A (39.966), which is a major advantage.

**P-gp Efflux:** Ligand A (0.495) has lower P-gp efflux liability than Ligand B (0.037), which is desirable for CNS penetration.

**Binding Affinity:** Ligand A (-7.6 kcal/mol) has a slightly better binding affinity than Ligand B (-7.1 kcal/mol). This 0.5 kcal/mol difference is significant and could potentially outweigh some of the ADME drawbacks of Ligand A.

**Overall Assessment:**

Ligand A has better binding affinity and BBB penetration, and lower P-gp efflux. However, it suffers from higher DILI risk, higher microsomal clearance (lower metabolic stability), worse Caco-2 permeability, and worse aqueous solubility. Ligand B has a significantly better safety profile (lower DILI, lower hERG), better metabolic stability (lower Cl_mic, longer t1/2), and slightly better solubility. The affinity difference is relatively small. Considering the GPCR-specific priorities and the overall balance of properties, Ligand B appears to be the more promising drug candidate.

Output:
1
2025-04-17 04:26:26,993 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (351.451 and 371.453 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (116.19) is better than Ligand B (59.23). For CNS targets, TPSA should be <= 90. Ligand A is slightly above, but Ligand B is well within the range.

**3. logP:** Ligand A (2.293) is optimal (1-3), while Ligand B (4.702) is high, potentially leading to solubility issues and off-target interactions.

**4. H-Bond Donors:** Ligand A (2) is acceptable, while Ligand B (0) is also good.

**5. H-Bond Acceptors:** Ligand A (4) is acceptable, while Ligand B (5) is also good.

**6. QED:** Ligand B (0.675) has a better QED score than Ligand A (0.272), indicating a more drug-like profile.

**7. DILI:** Ligand A (24.622) has a significantly lower DILI risk than Ligand B (57.697).

**8. BBB:** Ligand B (89.066) has a much higher BBB penetration percentile than Ligand A (54.866). This is a crucial factor for CNS targets like DRD2.

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.843 and -4.813), which is unusual and suggests poor permeability. This is a significant concern for both.

**10. Aqueous Solubility:** Both ligands have negative solubility values (-2.267 and -4.704), indicating poor aqueous solubility.

**11. hERG Inhibition:** Ligand A (0.291) has a lower hERG inhibition liability than Ligand B (0.762), which is preferable.

**12. Microsomal Clearance:** Ligand A (50.925) has a lower microsomal clearance than Ligand B (77.132), suggesting better metabolic stability.

**13. In vitro Half-Life:** Ligand A (-7.015) has a much longer in vitro half-life than Ligand B (23.236).

**14. P-gp Efflux:** Ligand A (0.069) has a lower P-gp efflux liability than Ligand B (0.714), which is beneficial for CNS exposure.

**15. Binding Affinity:** Ligand B (-7.7) has a slightly better binding affinity than Ligand A (-7.0). However, the difference is less than 1.5 kcal/mol, so it doesn't necessarily outweigh other factors.

**Overall Assessment:**

Ligand B excels in BBB penetration and binding affinity, which are critical for a CNS GPCR target. However, it suffers from a higher logP, higher DILI risk, and higher P-gp efflux. Ligand A has better ADME properties (lower DILI, better metabolic stability, lower P-gp efflux, longer half-life, lower hERG) and a more reasonable logP, but its BBB penetration is lower and its Caco-2 and solubility are poor.

Considering the GPCR-specific priorities, the improved BBB penetration of Ligand B is a significant advantage. While the ADME properties of Ligand A are better, the slightly improved binding affinity of Ligand B, combined with its superior BBB, makes it the more promising candidate, assuming the solubility and permeability issues can be addressed through formulation or further structural modifications.

Output:
1
2025-04-17 04:26:26,994 - INFO - Batch 113 complete. Total preferences: 1808
2025-04-17 04:26:26,994 - INFO - Processing batch 114/512...
2025-04-17 04:27:08,932 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, considering the provided guidelines and GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (352.475 and 357.451 Da) fall within the ideal range of 200-500 Da.

**TPSA:** Ligand A (98.66) is better than Ligand B (107.97). Both are below the 140 A^2 threshold for oral absorption, but Ligand A is closer to the desirable <90 A^2 for CNS targets.

**logP:** Ligand A (0.835) is within the optimal range (1-3), while Ligand B (-0.323) is slightly below 1, potentially hindering permeation.

**H-Bond Donors/Acceptors:** Ligand A has 4 HBD and 4 HBA, which is good. Ligand B has 3 HBD and 6 HBA, also acceptable, but slightly higher HBA could impact permeability.

**QED:** Ligand A (0.462) is slightly better than Ligand B (0.365), indicating a marginally more drug-like profile. Both are below the ideal 0.5.

**DILI:** Both ligands have similar DILI risk (13.571 and 13.61), both being low risk (<40).

**BBB:** Ligand A (40.481) has a significantly better BBB penetration percentile than Ligand B (30.71). This is a crucial factor for a CNS target like DRD2.

**Caco-2 Permeability:** Ligand A (-4.982) is better than Ligand B (-5.158), indicating better intestinal absorption.

**Aqueous Solubility:** Ligand A (-2.978) is better than Ligand B (-0.51), suggesting better formulation potential.

**hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.086 and 0.136).

**Microsomal Clearance:** Ligand A (34.226) has lower microsomal clearance than Ligand B (50.879), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (-12.593) has a longer in vitro half-life than Ligand B (-17.887).

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.021 and 0.005).

**Binding Affinity:** Ligand A (-8.2 kcal/mol) has a significantly stronger binding affinity than Ligand B (-6.8 kcal/mol). This >1.5 kcal/mol difference is substantial.

**Overall Assessment:**

Ligand A consistently outperforms Ligand B across most critical parameters, especially for a CNS target. Its superior BBB penetration, better logP, lower TPSA, better solubility, improved metabolic stability, longer half-life, and significantly stronger binding affinity make it the more promising candidate. While both have acceptable DILI and hERG profiles, the ADME properties and, crucially, the binding affinity of Ligand A are far more favorable.

Output:
1
2025-04-17 04:27:08,933 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (337.379 and 342.443 Da) are within the ideal range of 200-500 Da.

**TPSA:** Ligand A (99.58) is slightly above the optimal <90 for CNS targets, but still reasonable. Ligand B (69.04) is excellent, well below the threshold.

**logP:** Both ligands have good logP values (1.454 and 2.847), falling within the 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A has 2 HBD and 5 HBA, while Ligand B has 1 HBD and 5 HBA. Both are within acceptable limits.

**QED:** Both ligands have acceptable QED scores (0.86 and 0.749), indicating good drug-likeness.

**DILI:** Both ligands have relatively low DILI risk (41.024 and 47.421), below the concerning threshold of 60.

**BBB:** Ligand B (33.075) has a significantly better BBB percentile than Ligand A (24.661). This is a crucial advantage for a CNS target like DRD2.

**Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and suggests poor permeability. However, these values are on a strange scale and may not be directly comparable.

**Aqueous Solubility:** Both ligands have negative solubility values, suggesting poor aqueous solubility.

**hERG:** Both ligands show low hERG inhibition liability (0.773 and 0.113), which is favorable.

**Microsomal Clearance:** Ligand A (-35.893) has a *negative* microsomal clearance, which is not physically possible and likely an error in the data. Ligand B (80.624) has a high clearance, indicating faster metabolism.

**In vitro Half-Life:** Ligand A (28.891) has a longer half-life than Ligand B (-26.239). However, the negative half-life for Ligand B is also likely an error.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.144 and 0.099), which is good for CNS penetration.

**Binding Affinity:** Both ligands have excellent binding affinities (-9.3 and -8.4 kcal/mol). Ligand A is slightly better (-9.3 kcal/mol).

**Overall Assessment:**

Despite the slightly better affinity of Ligand A, the negative microsomal clearance and half-life values are highly suspect and raise serious concerns about data quality. Ligand B, while having a slightly weaker affinity, presents a much more plausible ADME profile, particularly its significantly better BBB penetration. The negative values for solubility and Caco-2 for both are concerning, but the BBB is a critical factor for CNS targets. Given the questionable data for Ligand A, and prioritizing BBB penetration for a CNS GPCR target, Ligand B is the more promising candidate.

Output:
1
2025-04-17 04:27:08,933 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (352.37 and 353.463 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (124.2) is slightly above the optimal <90 for CNS targets, but still reasonable. Ligand B (107.53) is better, falling comfortably under the 90 threshold.

**logP:** Ligand A (1.854) is within the optimal 1-3 range. Ligand B (0.463) is a bit low, potentially hindering permeability.

**H-Bond Donors/Acceptors:** Ligand A has 1 HBD and 5 HBA, well within acceptable limits. Ligand B has 4 HBD and 4 HBA, also acceptable.

**QED:** Both ligands have reasonable QED values (0.457 and 0.533), indicating decent drug-likeness.

**DILI:** Ligand A (48.817) has a moderate DILI risk, but is still acceptable. Ligand B (13.804) has a much lower DILI risk, which is a significant advantage.

**BBB:** Ligand A (81.776) has good BBB penetration, exceeding the 70% threshold. Ligand B (56.572) is below this threshold, which is a major concern for a CNS target like DRD2.

**Caco-2 Permeability:** Ligand A (-4.891) and Ligand B (-5.539) both have negative Caco-2 values, indicating poor permeability.

**Aqueous Solubility:** Both ligands have poor aqueous solubility (-2.005 and -1.143 respectively).

**hERG Inhibition:** Both ligands show very low hERG inhibition risk (0.278 and 0.066).

**Microsomal Clearance:** Ligand A (17.386) has a higher microsomal clearance than Ligand B (-10.984), indicating lower metabolic stability.

**In vitro Half-Life:** Ligand B (-9.88) has a longer in vitro half-life than Ligand A (-13.163).

**P-gp Efflux:** Both ligands show very low P-gp efflux liability (0.069 and 0.007).

**Binding Affinity:** Both ligands have excellent binding affinity (-7.0 and -8.4 kcal/mol). Ligand B is slightly better.

**Overall Assessment:**

While Ligand B has slightly better affinity and a lower DILI risk, the significantly lower BBB penetration (56.572%) is a critical drawback for a CNS target. Ligand A, despite its slightly higher DILI risk and lower BBB, still exceeds the 70% threshold, making it more likely to reach the brain. The similar permeability issues for both are a concern, but can be addressed through formulation strategies. Given the GPCR-specific emphasis on BBB penetration, Ligand A is the more promising candidate.

Output:
1
2025-04-17 04:27:08,933 - INFO - Reasoning:

Let's analyze Ligand A and Ligand B based on the provided guidelines, prioritizing GPCR-specific properties (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (351.447 and 380.458 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (91.76) is slightly above the optimal <90 for CNS targets, while Ligand B (86.8) is comfortably below. This gives a slight edge to Ligand B.

**logP:** Both ligands have good logP values (1.737 and 2.827), falling within the 1-3 range.

**H-Bond Donors/Acceptors:** Both have acceptable HBD counts (2) and Ligand B has a slightly higher HBA count (7 vs 5 for A), but both are within the recommended limits.

**QED:** Both ligands have good QED scores (0.627 and 0.714), indicating good drug-like properties.

**DILI:** Ligand A (20.9) has a significantly lower DILI risk than Ligand B (70.88), which is a major concern.

**BBB:** Ligand A (54.052) has a better BBB percentile than Ligand B (42.264), though neither is above the highly desirable >70. This is a crucial factor for a CNS target like DRD2.

**Caco-2 Permeability:** Ligand A (-4.864) has a worse Caco-2 permeability than Ligand B (-5.456), indicating lower intestinal absorption.

**Aqueous Solubility:** Ligand A (-1.414) has better aqueous solubility than Ligand B (-3.239).

**hERG:** Both ligands have similar hERG inhibition liability (0.557 and 0.642).

**Microsomal Clearance:** Ligand A (35.544) has a lower microsomal clearance than Ligand B (57.447), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (-22.31) has a significantly longer in vitro half-life than Ligand B (24.21).

**P-gp Efflux:** Ligand A (0.065) exhibits lower P-gp efflux than Ligand B (0.179), which is beneficial for CNS penetration.

**Binding Affinity:** Ligand B (-8.2) has a stronger binding affinity than Ligand A (-7.0). This is a 1.2 kcal/mol difference, which is significant.

**Overall Assessment:**

Ligand B has a better binding affinity and slightly better TPSA. However, Ligand A has significantly better DILI, BBB, metabolic stability, half-life, and P-gp efflux. The high DILI risk for Ligand B is a major red flag. While the affinity of Ligand B is better, the other ADME properties of Ligand A are more favorable for CNS drug development, particularly the lower DILI and better BBB penetration. The improved metabolic stability and longer half-life of Ligand A are also advantageous.



Output:
0
2025-04-17 04:27:08,933 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (363.336 and 351.491 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (78.95) is better than Ligand B (70.67). Both are below the 90 A^2 threshold desirable for CNS targets, which is good.

**logP:** Ligand A (-0.097) is slightly lower than optimal (1-3), but still acceptable. Ligand B (1.609) is within the optimal range.

**H-Bond Donors/Acceptors:** Ligand A (HBD=1, HBA=5) and Ligand B (HBD=2, HBA=4) both have reasonable H-bond characteristics, well within the recommended limits.

**QED:** Both ligands have good QED scores (A: 0.694, B: 0.731), indicating good drug-like properties.

**DILI:** Ligand A (26.483) has a significantly lower DILI risk than Ligand B (13.843), which is a major advantage. Both are below the 40 threshold, but A is much safer.

**BBB:** Ligand A (72.043) has a better BBB percentile than Ligand B (54.595). A score >70 is desirable for CNS targets, and A is closer to that threshold. This is a critical factor for DRD2.

**Caco-2 Permeability:** Ligand A (-4.859) and Ligand B (-5.012) both have poor Caco-2 permeability.

**Aqueous Solubility:** Ligand A (-2.137) and Ligand B (-0.87) both have poor aqueous solubility.

**hERG Inhibition:** Ligand A (0.447) has a lower hERG inhibition liability than Ligand B (0.153), which is preferable.

**Microsomal Clearance:** Ligand A (4.885) has a significantly lower microsomal clearance than Ligand B (12.931), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (-7.157) has a better (longer) in vitro half-life than Ligand B (6.694).

**P-gp Efflux:** Ligand A (0.011) has a much lower P-gp efflux liability than Ligand B (0.016), which is crucial for CNS penetration.

**Binding Affinity:** Ligand A (-7.3) has a slightly better binding affinity than Ligand B (0.0).

**Overall Assessment:**

Ligand A consistently outperforms Ligand B in several critical parameters for a CNS-targeting GPCR ligand. Specifically, it has a significantly lower DILI risk, better BBB penetration, lower P-gp efflux, lower microsomal clearance (better metabolic stability), a longer half-life, and a slightly better binding affinity. While both have poor Caco-2 permeability and aqueous solubility, these can potentially be addressed through formulation strategies. The superior ADME properties and safety profile of Ligand A, combined with its slightly better affinity, make it the more promising drug candidate.

Output:
1
2025-04-17 04:27:08,933 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (336.355 and 347.459 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (92.49) is slightly above the optimal <90 for CNS targets, but still reasonable. Ligand B (78.51) is well within the desired range.

**logP:** Both ligands have good logP values (1.181 and 1.078), falling within the 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A has 1 HBD and 6 HBA, while Ligand B has 2 HBD and 3 HBA. Both are within acceptable limits (<=5 HBD and <=10 HBA).

**QED:** Both ligands have acceptable QED scores (0.772 and 0.706), indicating good drug-like properties.

**DILI:** Ligand A has a DILI risk of 88.523, which is high and concerning. Ligand B has a much lower DILI risk of 16.053, a significant advantage.

**BBB:** Ligand A has a BBB penetration percentile of 71.772, which is good for a CNS target. Ligand B has a BBB penetration percentile of 63.358, which is less desirable, though not terrible.

**Caco-2 Permeability:** Both have negative Caco-2 values (-5.232 and -5.16), which is unusual and suggests poor permeability. This is a red flag for both.

**Aqueous Solubility:** Both ligands have negative solubility values (-3.059 and -1.858), indicating very poor aqueous solubility, which is a major drawback.

**hERG Inhibition:** Both ligands have very low hERG inhibition liability (0.16 and 0.104), which is excellent.

**Microsomal Clearance:** Ligand A has a moderate microsomal clearance (34.953), while Ligand B has a very low clearance (5.584), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A has a half-life of 7.355 hours, while Ligand B has a negative half-life (-1.555), which is not physically meaningful and indicates a potential issue with the data or the compound's stability.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.2 and 0.032), which is favorable for CNS penetration.

**Binding Affinity:** Ligand A has a significantly stronger binding affinity (-10.1 kcal/mol) compared to Ligand B (-8.8 kcal/mol). This is a substantial difference.

**Overall Assessment:**

Despite the strong affinity of Ligand A, its high DILI risk is a major concern. The negative Caco-2 and solubility values are also significant drawbacks. Ligand B has a lower affinity, but its significantly lower DILI risk, better metabolic stability (lower Cl_mic), and low P-gp efflux are attractive. The negative half-life for Ligand B is concerning and needs further investigation, but the other properties are more favorable. Considering the GPCR-specific priorities, the balance of properties favors Ligand B, *assuming* the negative half-life can be resolved. The strong affinity of Ligand A is tempting, but the DILI risk is likely to be a showstopper in development.

Output:
1
2025-04-17 04:27:08,933 - INFO - Reasoning:

Let's analyze Ligand A and Ligand B against the provided guidelines, prioritizing GPCR-specific properties (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (370.431 and 358.41 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (132.72) is borderline for CNS targets, slightly above the preferred <90, but acceptable. Ligand B (77.1) is excellent, well below 90.

**logP:** Ligand A (-0.202) is quite low, potentially hindering permeation. Ligand B (0.765) is better, within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A (3 HBD, 8 HBA) is reasonable. Ligand B (1 HBD, 5 HBA) is even better, suggesting a favorable balance between solubility and permeability.

**QED:** Both ligands have good QED scores (0.625 and 0.693), indicating drug-like properties.

**DILI:** Ligand A (57.348) has a moderate DILI risk. Ligand B (30.283) has a significantly lower and more favorable DILI risk.

**BBB:** Ligand A (20.357) has a very poor BBB penetration prediction. Ligand B (94.261) is excellent, highly desirable for a CNS target like DRD2. This is a major advantage for Ligand B.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.129 and -4.579). This is unusual and suggests a potential issue with the prediction method or the compounds themselves. However, given the other data, we'll proceed cautiously.

**Aqueous Solubility:** Both ligands have negative solubility values (-2.835 and -1.458). Similar to Caco-2, this is concerning, but we'll consider the overall profile.

**hERG:** Both ligands have low hERG inhibition risk (0.08 and 0.268).

**Microsomal Clearance:** Ligand A (19.698) has a higher microsomal clearance than Ligand B (8.796), indicating potentially lower metabolic stability.

**In vitro Half-Life:** Ligand B (7.743) has a longer in vitro half-life than Ligand A (-41.499), which is a significant advantage.

**P-gp Efflux:** Ligand A (0.014) has very low P-gp efflux, which is good. Ligand B (0.033) also has low P-gp efflux.

**Binding Affinity:** Ligand B (-7.6 kcal/mol) has a slightly better binding affinity than Ligand A (-7.2 kcal/mol), although the difference is relatively small.

**Overall Assessment:**

Ligand B is clearly superior. Its excellent BBB penetration, favorable logP, lower DILI risk, longer half-life, and slightly better affinity outweigh the minor concerns regarding Caco-2 and solubility. Ligand A's poor BBB prediction and low logP are major drawbacks for a CNS-targeted GPCR. While both have issues with predicted solubility and permeability, the other advantages of Ligand B make it a much more promising drug candidate.

Output:
1
2025-04-17 04:27:08,934 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (355.439 and 349.519 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (133.63) is closer to the desirable <90 for CNS targets, while Ligand B (52.65) is well within this range. This favors Ligand B.

**logP:** Ligand A (-0.687) is slightly low, potentially hindering permeation. Ligand B (2.262) is within the optimal 1-3 range. This favors Ligand B.

**H-Bond Donors/Acceptors:** Ligand A has 4 HBD and 4 HBA, which is acceptable. Ligand B has 1 HBD and 3 HBA, also acceptable.

**QED:** Both ligands have good QED scores (0.407 and 0.767, respectively), indicating drug-likeness. Ligand B is better.

**DILI:** Ligand A (19.969) has a lower DILI risk than Ligand B (7.057), which is favorable.

**BBB:** Ligand A (70.105) is at the lower end of desirable for CNS targets, while Ligand B (82.9) is excellent. This strongly favors Ligand B.

**Caco-2 Permeability:** Both have negative values, which is unusual and suggests poor permeability. However, the scale isn't specified, so it's difficult to interpret.

**Aqueous Solubility:** Both have negative values, suggesting poor solubility.

**hERG:** Ligand A (0.11) has a lower hERG risk than Ligand B (0.675), which is favorable.

**Microsomal Clearance:** Ligand A (20.215) has lower clearance than Ligand B (44.33), indicating better metabolic stability. This favors Ligand A.

**In vitro Half-Life:** Both have negative half-lives, which is impossible. This suggests an issue with the data.

**P-gp Efflux:** Ligand A (0.004) has very low P-gp efflux, which is excellent for CNS penetration. Ligand B (0.086) is also low, but higher than A. This favors Ligand A.

**Binding Affinity:** Ligand B (-8.2 kcal/mol) has a significantly stronger binding affinity than Ligand A (-7.1 kcal/mol). This is a substantial advantage, potentially outweighing some ADME drawbacks.

**Overall Assessment:**

Ligand B excels in key GPCR properties: TPSA, logP, and especially BBB and binding affinity. While Ligand A has better DILI, lower clearance, and lower P-gp efflux, the superior binding affinity and BBB penetration of Ligand B are critical for a CNS-targeting drug. The difference in binding affinity (-8.2 vs -7.1) is significant. The slightly higher DILI risk of Ligand B can be addressed during optimization.

Output:
1
2025-04-17 04:27:08,934 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (362.495 and 350.503 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (68.29) is significantly better than Ligand B (78.43). For CNS targets, we want TPSA <= 90, and A is closer to the ideal <= 60 range. B is pushing the upper limit.

**3. logP:** Ligand A (4.493) is higher than the optimal 1-3 range, potentially causing solubility issues, but still within a manageable range. Ligand B (2.375) is within the optimal range.

**4. H-Bond Donors:** Ligand A (1) is preferable to Ligand B (3). Fewer HBDs generally improve permeability.

**5. H-Bond Acceptors:** Ligand A (4) is preferable to Ligand B (3). Fewer HBAs generally improve permeability.

**6. QED:** Both ligands have similar QED values (0.702 and 0.617), indicating good drug-like properties.

**7. DILI:** Ligand A (74.99) has a higher DILI risk than Ligand B (10.198). This is a significant drawback for Ligand A.

**8. BBB:** Ligand B (53.974) has a better BBB penetration score than Ligand A (46.336). While both are not ideal (>70 is desirable), B is closer.

**9. Caco-2:** Both ligands have negative Caco-2 values (-4.683 and -4.729), which is unusual and suggests poor permeability. This is a concern for both.

**10. Solubility:** Both ligands have negative solubility values (-4.57 and -3.039), indicating very poor aqueous solubility. This is a major issue for both.

**11. hERG:** Both ligands have very low hERG inhibition liability (0.509 and 0.37). This is good.

**12. Cl_mic:** Both ligands have similar microsomal clearance (49.016 and 49.367), indicating similar metabolic stability.

**13. t1/2:** Ligand B (-18.619) has a negative in vitro half-life, which is not possible. This is a clear error or outlier. Ligand A (20.941) has a reasonable half-life.

**14. Pgp:** Ligand A (0.562) has lower P-gp efflux liability than Ligand B (0.09). Lower Pgp is better, especially for CNS targets.

**15. Binding Affinity:** Both ligands have the same binding affinity (-8.6 kcal/mol), which is excellent.

**Overall Assessment:**

Despite the strong binding affinity of both ligands, Ligand B appears to be a better candidate. The most significant advantage is the much lower DILI risk. While its BBB is not ideal, it's better than Ligand A's. The negative half-life for Ligand B is a major red flag and likely an error, but even ignoring that, the DILI risk of Ligand A is a serious concern. The slightly better TPSA and Pgp values for Ligand A are outweighed by the DILI and BBB issues. The solubility and Caco-2 values are poor for both, but these could potentially be addressed with formulation strategies.

Output:
1
2025-04-17 04:27:08,934 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (361.47 and 363.45 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (83.48) is slightly higher than Ligand B (72.88). Both are below the 90 A^2 threshold desirable for CNS targets, but B is preferable.

**logP:** Ligand A (3.395) is within the optimal 1-3 range. Ligand B (1.086) is at the lower end, potentially hindering permeability. This favors A.

**H-Bond Donors/Acceptors:** Ligand A has 3 HBD and 5 HBA, while Ligand B has 2 HBD and 4 HBA. Both are within acceptable limits.

**QED:** Both ligands have reasonable QED scores (0.706 and 0.643), indicating good drug-like properties.

**DILI:** Ligand A (64.56) has a higher DILI risk than Ligand B (10.24). This is a significant advantage for B.

**BBB:** Both ligands have good BBB penetration (63.36% and 65.84%), exceeding the 70% target, suggesting they can reach the CNS. B is slightly better.

**Caco-2 Permeability:** Both have negative Caco-2 values which is unusual and suggests issues with the prediction method.

**Aqueous Solubility:** Both ligands have negative solubility values, which is also unusual and suggests issues with the prediction method.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.367 and 0.454).

**Microsomal Clearance:** Ligand A (27.11) has a higher microsomal clearance than Ligand B (-5.41). This indicates lower metabolic stability for A, favoring B.

**In vitro Half-Life:** Ligand B (-28.99) has a much longer in vitro half-life than Ligand A (7.17), suggesting better persistence. This strongly favors B.

**P-gp Efflux:** Ligand A (0.321) has a slightly lower P-gp efflux liability than Ligand B (0.006). This is a small advantage for A.

**Binding Affinity:** Ligand A (-7.6 kcal/mol) has a slightly better binding affinity than Ligand B (-8.2 kcal/mol). While this difference is present, the other ADME properties of B are more compelling.

**Overall Assessment:**

Ligand B demonstrates a superior ADME profile. It has a significantly lower DILI risk, better metabolic stability (lower Cl_mic, longer t1/2), and comparable BBB penetration. While Ligand A has a slightly better binding affinity and P-gp efflux, the advantages of B in terms of safety (DILI) and pharmacokinetics (Cl_mic, t1/2) outweigh these minor differences. Given the CNS target, the lower DILI and improved PK profile of B are crucial.

Output:
1
2025-04-17 04:27:08,934 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (353.379 and 347.39 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (126.66) is slightly above the optimal <90 for CNS targets, but still reasonable. Ligand B (80.32) is excellent, well below 90, suggesting better CNS penetration potential.

**logP:** Ligand A (-0.795) is a bit low, potentially hindering membrane permeability. Ligand B (1.413) is within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Both have 2 HBDs, which is good. Ligand A has 7 HBAs, while Ligand B has 4. Both are acceptable (<=10), but Ligand B's lower HBA count is slightly preferable.

**QED:** Both ligands have good QED scores (0.627 and 0.844), indicating drug-like properties.

**DILI:** Both have acceptable DILI risk (48.623 and 55.525, both <60).

**BBB:** Ligand B (80.419) has a significantly better BBB percentile than Ligand A (57.193). This is a crucial advantage for a CNS target like DRD2.

**Caco-2:** Both have negative Caco-2 values, which is unusual and suggests poor permeability. However, the scale is not specified, so it's hard to interpret.

**Solubility:** Both have negative solubility values, which is also unusual. Again, the scale is not specified.

**hERG:** Both have very low hERG inhibition risk (0.024 and 0.226).

**Microsomal Clearance:** Ligand B (-8.224) has a *negative* microsomal clearance, which is not physically possible and suggests an error in the data. Ligand A (11.731) is reasonable.

**In vitro Half-Life:** Ligand B (23.056) has a longer half-life than Ligand A (12.45), which is desirable.

**P-gp Efflux:** Both have very low P-gp efflux liability (0.006 and 0.064), which is good for CNS penetration.

**Binding Affinity:** Ligand B (-8.7 kcal/mol) has a slightly better binding affinity than Ligand A (-7.4 kcal/mol). While both are good, the 1.3 kcal/mol difference is significant and could outweigh some ADME drawbacks.

**Overall:**

Ligand B is the stronger candidate. It has a better logP, significantly better BBB penetration, a longer half-life, and slightly better binding affinity. The negative microsomal clearance for Ligand B is a major red flag and likely an error, but even disregarding that, the other advantages are substantial. Ligand A's lower logP and BBB penetration are concerning for a CNS target.

Output:
1
2025-04-17 04:27:08,935 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 drug candidates, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (346.43 and 368.50 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (73.99) is significantly better than Ligand B (84.50). For CNS targets, we want TPSA <= 90, and A is closer to the optimal <=60 range. B is pushing the upper limit.

**3. logP:** Both ligands have acceptable logP values (1.21 and 1.42), falling within the 1-3 range.

**4. H-Bond Donors:** Ligand A (1) is preferable to Ligand B (2). Lower HBD generally improves permeability.

**5. H-Bond Acceptors:** Ligand A (4) is better than Ligand B (5). Lower HBA is also favorable for permeability.

**6. QED:** Both ligands have similar QED values (0.753 and 0.71), indicating good drug-likeness.

**7. DILI:** Ligand A (8.10) has a much lower DILI risk than Ligand B (40.05). This is a significant advantage for A.

**8. BBB:** Both ligands have the same BBB penetration (54.44 percentile). This is not ideal, as >70 is desirable for CNS targets, but it's the same for both.

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.786 and -5.453), which is unusual and suggests poor permeability. However, the values are similar.

**10. Aqueous Solubility:** Ligand A (-1.201) is better than Ligand B (-2.617). Higher solubility is generally preferred.

**11. hERG Inhibition:** Ligand A (0.417) shows lower hERG inhibition liability than Ligand B (0.064), which is a significant safety advantage.

**12. Microsomal Clearance:** Ligand A (-1.359) has a lower (better) microsomal clearance than Ligand B (30.239), indicating greater metabolic stability.

**13. In vitro Half-Life:** Ligand A (15.606) has a longer half-life than Ligand B (-9.98).

**14. P-gp Efflux:** Ligand A (0.131) has lower P-gp efflux liability than Ligand B (0.103), which is preferable for CNS exposure.

**15. Binding Affinity:** Both ligands have very similar and excellent binding affinities (-7.8 and -7.9 kcal/mol). The difference is negligible.

**Overall Assessment:**

Ligand A is clearly superior. It has better TPSA, lower DILI risk, better solubility, lower hERG inhibition, lower microsomal clearance, longer half-life, and lower P-gp efflux. While both have similar BBB penetration and affinity, the ADME properties of Ligand A are significantly more favorable, making it a much more promising drug candidate.

Output:
1
2025-04-17 04:27:08,935 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (341.415 and 349.475 Da) fall comfortably within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (80.12) is better than Ligand B (84.64). Both are below the 90 A^2 threshold desirable for CNS targets, but A is closer to the optimal range.

**3. logP:** Ligand A (1.47) is within the optimal 1-3 range. Ligand B (2.071) is also acceptable, but slightly higher.

**4. H-Bond Donors:** Both ligands have 1 HBD, which is good.

**5. H-Bond Acceptors:** Ligand A has 5 HBA, and Ligand B has 4. Both are below the 10 threshold.

**6. QED:** Ligand A (0.913) has a significantly better QED score than Ligand B (0.823), indicating higher drug-likeness.

**7. DILI:** Ligand A (47.77) has a moderate DILI risk, while Ligand B (20.202) is very low risk. This is a significant advantage for Ligand B.

**8. BBB:** Ligand A (67.119) has a better BBB percentile than Ligand B (57.27). This is crucial for a CNS target like DRD2.

**9. Caco-2 Permeability:** Ligand A (-4.823) has better Caco-2 permeability than Ligand B (-4.578), indicating better intestinal absorption.

**10. Aqueous Solubility:** Ligand A (-1.322) has better aqueous solubility than Ligand B (-1.794).

**11. hERG Inhibition:** Ligand A (0.253) has a lower hERG inhibition liability than Ligand B (0.586), making it safer from a cardiotoxicity perspective.

**12. Microsomal Clearance:** Ligand A (-2.953) has a much lower (better) microsomal clearance than Ligand B (14.321), indicating greater metabolic stability.

**13. In vitro Half-Life:** Ligand A (-8.5) has a longer in vitro half-life than Ligand B (-3.141).

**14. P-gp Efflux:** Ligand A (0.03) has a much lower P-gp efflux liability than Ligand B (0.15), which is essential for CNS penetration.

**15. Binding Affinity:** Ligand A (-7.4) has a slightly better binding affinity than Ligand B (-7.1). While both are good, the 1.5 kcal/mol advantage of A is noteworthy.

**Overall Assessment:**

Ligand A is superior in most key parameters for a CNS-targeting GPCR ligand. It has better BBB penetration, lower P-gp efflux, better metabolic stability (lower Cl_mic, longer t1/2), better solubility, lower hERG risk, and slightly better binding affinity. While Ligand B has a significantly lower DILI risk, the other advantages of Ligand A outweigh this concern, especially given the relatively moderate DILI risk of Ligand A. The combination of better CNS penetration properties and binding affinity makes Ligand A the more promising candidate.

Output:
1
2025-04-17 04:27:08,935 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (405.34 Da) is slightly higher than Ligand B (358.364 Da), but both are acceptable.

**TPSA:** Ligand A (58.95) is better than Ligand B (72.09). For CNS targets, we want TPSA <= 90, both are well within this range, but A is preferable.

**logP:** Ligand A (4.121) is slightly higher than the optimal range (1-3), but still potentially acceptable. Ligand B (2.908) is within the ideal range. This gives a slight edge to B.

**H-Bond Donors/Acceptors:** Both ligands have 2 HBD and 3-4 HBA, which are within acceptable limits (<=5 HBD and <=10 HBA). No significant difference here.

**QED:** Both ligands have similar QED values (0.76 and 0.799), indicating good drug-likeness.

**DILI:** Both ligands have low DILI risk (37.728 and 39.046), both are good.

**BBB:** Both ligands have good BBB penetration (66.576 and 67.701). While >70 is desirable, these are reasonably good, and similar.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.847 and -4.909). This is unusual and likely indicates poor permeability *in vitro*. This is a concern for both, but doesn't differentiate them.

**Aqueous Solubility:** Both ligands have very poor aqueous solubility (-3.537 and -2.79). This is a significant drawback for both, potentially hindering bioavailability.

**hERG:** Both ligands have low hERG inhibition liability (0.819 and 0.628), which is good.

**Microsomal Clearance:** Ligand B (20.698) has a slightly lower (better) microsomal clearance than Ligand A (15.895). Lower clearance indicates better metabolic stability.

**In vitro Half-Life:** Ligand B (30.089) has a slightly longer half-life than Ligand A (36.647). Longer half-life is generally preferred.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.226 and 0.213), which is good for CNS penetration.

**Binding Affinity:** Both ligands have excellent binding affinity (-8.6 and -8.4 kcal/mol). The difference is small (0.2 kcal/mol), and likely not decisive.

**Overall Assessment:**

Considering the GPCR-specific priorities, both ligands have some drawbacks. The poor solubility and Caco-2 permeability are concerning for both. However, Ligand B has a slight advantage in logP, microsomal clearance, and in vitro half-life. The TPSA is also slightly better for Ligand A. The binding affinity difference is minimal. Given the slightly better ADME profile of Ligand B, it is marginally more likely to be a viable drug candidate.

Output:
1
2025-04-17 04:27:08,935 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (344.419 and 344.503 Da) fall comfortably within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (95.91) is higher than Ligand B (50.16). For CNS targets, a TPSA <= 90 is preferred. Ligand A is borderline, while Ligand B is well within the desired range. This favors Ligand B.

**3. logP:** Ligand A (0.805) is a bit low, potentially hindering membrane permeability. Ligand B (2.903) is within the optimal 1-3 range. This strongly favors Ligand B.

**4. H-Bond Donors:** Ligand A (2) and Ligand B (1) are both acceptable, being <= 5.

**5. H-Bond Acceptors:** Ligand A (5) and Ligand B (4) are both acceptable, being <= 10.

**6. QED:** Both ligands have good QED scores (0.758 and 0.836), indicating good drug-like properties.

**7. DILI:** Ligand A (48.623) has a slightly higher DILI risk than Ligand B (23.226), although both are below the concerning threshold of 60. This favors Ligand B.

**8. BBB:** This is crucial for a CNS target like DRD2. Ligand A (35.983) has a poor BBB percentile, while Ligand B (58.821) is better, though still not ideal (>70 is desirable). This is a significant advantage for Ligand B.

**9. Caco-2 Permeability:** Ligand A (-5.395) has very poor Caco-2 permeability, indicating poor intestinal absorption. Ligand B (-4.753) is also poor, but slightly better than A.

**10. Aqueous Solubility:** Both ligands have poor aqueous solubility (-2.135 and -2.996). This could present formulation challenges, but isn't a dealbreaker.

**11. hERG Inhibition:** Both ligands show low hERG inhibition risk (0.193 and 0.399).

**12. Microsomal Clearance:** Ligand A (1.676) has much lower microsomal clearance than Ligand B (42.687), suggesting better metabolic stability. This favors Ligand A.

**13. In vitro Half-Life:** Ligand A (-3.554) has a negative half-life, which is not physically possible and indicates an issue with the data or prediction. Ligand B (10.041) has a reasonable half-life. This is a significant issue for Ligand A.

**14. P-gp Efflux:** Both ligands have low P-gp efflux liability (0.032 and 0.186), which is good for CNS penetration.

**15. Binding Affinity:** Ligand A (-7.9 kcal/mol) has a significantly stronger binding affinity than Ligand B (-6.6 kcal/mol). This is a substantial advantage for Ligand A.

**Overall Assessment:**

While Ligand A has a superior binding affinity and better metabolic stability, its extremely poor BBB penetration, poor Caco-2 permeability, and the unrealistic half-life are major drawbacks. Ligand B, despite a weaker affinity, has a much more favorable profile for CNS penetration (better BBB, TPSA, and logP) and a reasonable half-life. The difference in affinity (1.3 kcal/mol) is substantial, but not insurmountable, and can potentially be optimized in further iterations. Given the importance of CNS penetration for a DRD2 target, Ligand B is the more promising candidate.

Output:
1
2025-04-17 04:27:08,936 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B based on the provided guidelines, prioritizing GPCR-specific properties (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (360.43 and 366.49 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (90.31) is better than Ligand B (73.39). For CNS targets, TPSA should be <=90, and A is right at the threshold, while B is comfortably below.

**logP:** Ligand B (2.922) is optimal (1-3), while Ligand A (-0.055) is significantly below, potentially hindering permeation. This is a major drawback for A.

**H-Bond Donors/Acceptors:** Ligand A (2 HBD, 5 HBA) and Ligand B (1 HBD, 7 HBA) both fall within acceptable ranges.

**QED:** Both ligands have good QED scores (0.592 and 0.727, respectively), indicating drug-like properties.

**DILI:** Ligand A (12.524) has a much lower DILI risk than Ligand B (47.034), which is a significant advantage.

**BBB:** Ligand A (73.943) has a considerably better BBB penetration score than Ligand B (63.319). This is crucial for a CNS target like DRD2.

**Caco-2 Permeability:** Both ligands have similar, poor Caco-2 permeability scores (-4.711 and -4.627).

**Aqueous Solubility:** Both ligands have very poor aqueous solubility scores (-0.016 and -3.381).

**hERG:** Ligand A (0.348) has a lower hERG inhibition liability than Ligand B (0.704), indicating a lower risk of cardiotoxicity.

**Microsomal Clearance:** Ligand A (3.812) has a lower microsomal clearance than Ligand B (56.865), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand B (38.154) has a significantly longer in vitro half-life than Ligand A (4.007).

**P-gp Efflux:** Ligand A (0.039) has much lower P-gp efflux liability than Ligand B (0.432), which is favorable for CNS penetration.

**Binding Affinity:** Ligand A (-7.2 kcal/mol) has a slightly better binding affinity than Ligand B (-6.9 kcal/mol), although the difference is not huge.

**Overall Assessment:**

While Ligand B has a better half-life, Ligand A is significantly better in almost all other crucial aspects for a CNS-targeting GPCR ligand. Specifically, its superior BBB penetration, lower logP (though still a concern), much lower DILI risk, lower hERG risk, lower P-gp efflux, and slightly better affinity outweigh the shorter half-life. The poor solubility and Caco-2 permeability are concerns for both, but can be addressed with formulation strategies. The low logP of A is a concern, but the strong affinity and favorable ADME properties make it a more promising candidate.

Output:
0
2025-04-17 04:27:08,936 - INFO - Batch 114 complete. Total preferences: 1824
2025-04-17 04:27:08,936 - INFO - Processing batch 115/512...
2025-04-17 04:27:51,283 - INFO - Reasoning:

Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (374.34 and 342.399 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (88.52) is excellent, falling well below the 90 A^2 threshold for CNS targets. Ligand B (108.55) is still reasonable but less optimal.

**logP:** Ligand A (2.744) is within the optimal 1-3 range. Ligand B (1.455) is slightly low, potentially impacting permeability.

**H-Bond Donors/Acceptors:** Ligand A (2 HBD, 6 HBA) and Ligand B (3 HBD, 5 HBA) both have acceptable numbers of H-bond donors and acceptors.

**QED:** Both ligands have similar QED values (0.786 and 0.762), indicating good drug-likeness.

**DILI:** Ligand A (85.227) has a higher DILI risk than Ligand B (41.877). This is a significant drawback for Ligand A.

**BBB:** Ligand A (57.425) has a moderate BBB penetration, while Ligand B (27.026) is quite low. For a CNS target like DRD2, a higher BBB value is crucial.

**Caco-2 Permeability:** Ligand A (-4.815) has poor Caco-2 permeability, while Ligand B (-5.56) is also poor.

**Aqueous Solubility:** Ligand A (-4.445) has poor aqueous solubility, while Ligand B (-2.973) is slightly better.

**hERG:** Both ligands have similar, low hERG inhibition liability (0.392 and 0.285).

**Microsomal Clearance:** Ligand A (83.787) has higher microsomal clearance, indicating lower metabolic stability, compared to Ligand B (22.373).

**In vitro Half-Life:** Ligand B (-22.369) has a significantly longer in vitro half-life than Ligand A (-13.58).

**P-gp Efflux:** Both ligands exhibit low P-gp efflux liability (0.207 and 0.011).

**Binding Affinity:** Both ligands have comparable binding affinities (-8.4 and -8.9 kcal/mol), which are both excellent.

**Overall Assessment:**

While both ligands have strong binding affinity, Ligand B is the more promising candidate. Its lower DILI risk, significantly better metabolic stability (lower Cl_mic, longer t1/2), and lower P-gp efflux are major advantages. Although its BBB penetration is not ideal, it's still better than Ligand A. Ligand A's high DILI risk and poor metabolic stability are significant concerns. The slightly lower logP for Ligand B is a minor drawback compared to the other benefits.

Output:
1
2025-04-17 04:27:51,284 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, considering the provided guidelines and GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (341.5 and 348.5 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (35.58) is significantly better than Ligand B (69.64). For CNS targets, TPSA should be <= 90, and ideally lower. Ligand A is much closer to the ideal range for CNS penetration.

**logP:** Both ligands have acceptable logP values (3.759 and 2.272), falling within the 1-3 optimal range. Ligand A is slightly higher, potentially aiding membrane permeability.

**H-Bond Donors/Acceptors:** Ligand A (HBD=1, HBA=3) and Ligand B (HBD=2, HBA=3) both have reasonable numbers of H-bond donors and acceptors, well within the suggested limits.

**QED:** Ligand A (0.731) has a higher QED score than Ligand B (0.522), indicating a more drug-like profile.

**DILI:** Ligand A (33.97) has a significantly lower DILI risk than Ligand B (16.87), making it safer from a liver toxicity perspective.

**BBB:** Ligand A (81.47) has a better BBB percentile than Ligand B (70.18), which is crucial for CNS targets like DRD2. Both are above the 70% threshold, but A is preferable.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.826 and -4.898). This is unusual and suggests poor permeability. However, the values are very similar.

**Aqueous Solubility:** Both ligands have negative solubility values (-2.711 and -2.537). This is also unusual and suggests poor solubility. Again, the values are very similar.

**hERG Inhibition:** Ligand A (0.877) has a slightly higher hERG inhibition risk than Ligand B (0.324), but both are relatively low and acceptable.

**Microsomal Clearance:** Ligand B (58.33) has a higher microsomal clearance than Ligand A (29.91), meaning Ligand A is more metabolically stable.

**In vitro Half-Life:** Ligand A (5.418) has a longer in vitro half-life than Ligand B (-5.753). The negative value for B is concerning.

**P-gp Efflux:** Ligand A (0.402) has a lower P-gp efflux liability than Ligand B (0.068), which is beneficial for CNS exposure.

**Binding Affinity:** Both ligands have very similar and strong binding affinities (-8.5 and -8.2 kcal/mol). The difference is less than the 1.5 kcal/mol threshold.

**Overall Assessment:**

Considering the GPCR-specific priorities, Ligand A is the superior candidate. It has a significantly better TPSA, DILI score, BBB penetration, metabolic stability (lower Cl_mic, longer t1/2), and lower P-gp efflux. While both have similar affinities and problematic Caco-2/solubility values, the ADME properties of Ligand A are substantially more favorable for a CNS-targeting drug.

Output:
0
2025-04-17 04:27:51,284 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (350.459 Da and 369.615 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (78.87) is better than Ligand B (29.54) for CNS penetration, being closer to the <90 Angstroms threshold. Ligand B is exceptionally low, which *could* indicate poor interactions with the receptor, but isn't necessarily a dealbreaker.

**3. logP:** Ligand A (1.237) is within the optimal 1-3 range. Ligand B (4.702) is high, potentially leading to solubility issues and off-target effects.

**4. H-Bond Donors:** Ligand A (2) is acceptable. Ligand B (0) is also acceptable.

**5. H-Bond Acceptors:** Ligand A (4) is acceptable. Ligand B (3) is also acceptable.

**6. QED:** Ligand A (0.799) is excellent, indicating good drug-like properties. Ligand B (0.59) is still acceptable but less ideal.

**7. DILI:** Ligand A (17.449) has a lower DILI risk than Ligand B (13.455), which is preferable.

**8. BBB:** Ligand B (86.002) significantly outperforms Ligand A (44.591) in predicted BBB penetration, a critical factor for a CNS target like DRD2.

**9. Caco-2 Permeability:** Ligand A (-4.681) has poor Caco-2 permeability. Ligand B (-4.566) is also poor, but slightly better.

**10. Aqueous Solubility:** Ligand A (-1.759) has poor aqueous solubility. Ligand B (-5.758) has even worse aqueous solubility.

**11. hERG Inhibition:** Ligand A (0.236) has a very low hERG risk. Ligand B (0.907) has a slightly higher, but still acceptable, hERG risk.

**12. Microsomal Clearance:** Ligand A (29.709) has lower microsomal clearance, indicating better metabolic stability. Ligand B (126.777) has high clearance.

**13. In vitro Half-Life:** Ligand B (55.444) has a significantly longer in vitro half-life than Ligand A (3.347).

**14. P-gp Efflux:** Ligand A (0.039) has very low P-gp efflux, which is favorable for CNS penetration. Ligand B (0.806) has higher P-gp efflux.

**15. Binding Affinity:** Ligand A (-8.6 kcal/mol) has a *much* stronger binding affinity than Ligand B (-0.0 kcal/mol). This is a decisive advantage.

**Overall Assessment:**

While Ligand B excels in BBB penetration and has a longer half-life, its high logP, poor solubility, and *extremely* weak binding affinity are major drawbacks. Ligand A, despite its lower BBB penetration and poor Caco-2 permeability, has a significantly superior binding affinity, better metabolic stability, lower DILI risk, and lower P-gp efflux. The strong binding affinity of Ligand A is likely to outweigh its ADME deficiencies, especially given the potential for further optimization.

Output:
0
2025-04-17 04:27:51,284 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (360.351 and 357.361 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (49.41) is significantly better than Ligand B (100.35). For CNS targets, we want TPSA <= 90, so A is well within this range, while B is above.

**logP:** Ligand A (2.821) is optimal (1-3), while Ligand B (0.035) is quite low, potentially hindering membrane permeability.

**H-Bond Donors/Acceptors:** Ligand A (HBD=1, HBA=2) is favorable. Ligand B (HBD=2, HBA=6) is acceptable, but higher HBA could affect permeability.

**QED:** Both ligands have similar QED values (0.821 and 0.748), indicating good drug-likeness.

**DILI:** Ligand A (35.983) has a lower DILI risk than Ligand B (54.866), which is preferable. Both are below the concerning threshold of 60.

**BBB:** Ligand A (79.333) has a better BBB penetration percentile than Ligand B (68.903). While both are not exceptionally high, A is closer to the desirable >70 for CNS targets.

**Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and suggests a potential issue with the data or the model's prediction. However, the magnitude of the negative value for A (-4.408) is less severe than for B (-4.835), suggesting slightly better permeability.

**Aqueous Solubility:** Both have negative solubility values, which is also unusual. Again, A (-3.032) is slightly better than B (-2.394).

**hERG:** Ligand A (0.714) has a lower hERG risk than Ligand B (0.119). Lower is better.

**Microsomal Clearance:** Ligand A (8.716) has a lower microsomal clearance than Ligand B (-15.393). Lower clearance indicates better metabolic stability.

**In vitro Half-Life:** Ligand A (5.223) has a slightly longer half-life than Ligand B (4.975).

**P-gp Efflux:** Ligand A (0.027) has significantly lower P-gp efflux liability than Ligand B (0.09). Lower is better, especially for CNS penetration.

**Binding Affinity:** Ligand A (-9.4 kcal/mol) has a significantly stronger binding affinity than Ligand B (-8.0 kcal/mol). This is a substantial difference, exceeding the 1.5 kcal/mol advantage threshold.

**Overall Assessment:**

Ligand A consistently outperforms Ligand B across most critical parameters, especially those prioritized for GPCRs targeting the CNS. Its superior TPSA, logP, BBB, P-gp efflux, metabolic stability, and *significantly* stronger binding affinity make it the more promising candidate. While both have unusual solubility and Caco-2 values, A is better in both cases.



Output:
1
2025-04-17 04:27:51,285 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (351.491 and 366.487 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (72.88) is significantly better than Ligand B (100.19). For CNS targets, TPSA should be <=90, and A is comfortably within this range, while B is approaching the upper limit.

**logP:** Both ligands have similar logP values (1.297 and 1.392), falling within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A (2 HBD, 4 HBA) is preferable to Ligand B (3 HBD, 5 HBA), as lower values generally improve permeability. Both are acceptable.

**QED:** Ligand A (0.678) has a slightly better QED score than Ligand B (0.575), indicating a more drug-like profile. Both are above the 0.5 threshold.

**DILI:** Ligand A (8.026) has a much lower DILI risk than Ligand B (44.552). This is a significant advantage for A.

**BBB:** Ligand A (57.193) has a better BBB penetration percentile than Ligand B (44.513), though neither is >70, which is highly desirable for CNS targets. A is still better.

**Caco-2 Permeability:** Ligand A (-4.831) has slightly better Caco-2 permeability than Ligand B (-5.438), but both are negative values which is hard to interpret without knowing the scale.

**Aqueous Solubility:** Ligand A (-0.643) has slightly better aqueous solubility than Ligand B (-1.427), but both are negative values which is hard to interpret without knowing the scale.

**hERG Inhibition:** Both ligands have very low hERG inhibition liability (0.105 and 0.111), which is excellent.

**Microsomal Clearance:** Ligand A (8.506) has significantly lower microsomal clearance than Ligand B (34.646), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (-16.083) has a much longer in vitro half-life than Ligand B (16.215). This is a significant advantage for A.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.012 and 0.044), which is excellent.

**Binding Affinity:** Both ligands have the same binding affinity (-7.3 kcal/mol), which is excellent and meets the criteria of < -7.0 kcal/mol.

**Overall Assessment:**

Ligand A is clearly superior. While both have good affinity, Ligand A excels in crucial ADME properties: lower DILI risk, better BBB penetration, lower microsomal clearance, and a longer half-life. Its TPSA is also more favorable for CNS penetration. The slightly better QED and solubility also contribute to its overall profile.

Output:
1
2025-04-17 04:27:51,285 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (353.5 & 372.5 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (70.67) is significantly better than Ligand B (98.82). For CNS targets, we want TPSA <= 90, so Ligand A is preferable.

**logP:** Ligand A (1.687) is within the optimal 1-3 range. Ligand B (-1.017) is below 1, which could hinder permeation. This favors Ligand A.

**H-Bond Donors/Acceptors:** Both have 2 HBDs, which is good. Ligand A has 4 HBAs, while Ligand B has 5. Both are acceptable (<=10), but lower is generally better.

**QED:** Ligand A (0.731) has a better QED score than Ligand B (0.505), indicating a more drug-like profile.

**DILI:** Ligand A (10.2%) has a much lower DILI risk than Ligand B (21.4%). This is a significant advantage for Ligand A.

**BBB:** Ligand B (56.9%) has a better BBB penetration score than Ligand A (41.2%). However, both are below the desirable >70% for CNS targets.

**Caco-2 Permeability:** Both have negative values (-5.08 & -5.67), indicating poor permeability. This is a concern for both.

**Aqueous Solubility:** Both have negative solubility values (-1.58 & -1.66), suggesting poor aqueous solubility, which could impact bioavailability.

**hERG:** Both ligands have very low hERG inhibition risk (0.26 & 0.10).

**Microsomal Clearance:** Ligand A (3.83) has lower microsomal clearance than Ligand B (5.21), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (16.59 hours) has a significantly longer half-life than Ligand B (-26.44 hours - which is likely an error or indicates very rapid metabolism). This is a major advantage for Ligand A.

**P-gp Efflux:** Both have very low P-gp efflux liability (0.02 & 0.004).

**Binding Affinity:** Ligand B (-6.6 kcal/mol) has a slightly better binding affinity than Ligand A (-8.0 kcal/mol). However, the difference is not substantial enough to outweigh the numerous ADME advantages of Ligand A.

**Overall:** Considering the GPCR-specific priorities, Ligand A is the more promising candidate. It has better TPSA, logP, QED, DILI risk, metabolic stability, and half-life. While Ligand B has slightly better affinity and BBB, the other significant drawbacks make Ligand A the preferred choice.

Output:
1
2025-04-17 04:27:51,285 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 drug candidates, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (352.439 Da and 347.463 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (92.59) is slightly above the optimal <90 for CNS targets, but still reasonable. Ligand B (74.09) is well within the desired range.

**logP:** Ligand A (1.319) is within the optimal 1-3 range. Ligand B (2.586) is also within the optimal range.

**H-Bond Donors:** Both ligands have 1 HBD, which is acceptable (<=5).

**H-Bond Acceptors:** Ligand A has 6 HBA, and Ligand B has 7 HBA, both within the acceptable limit of <=10.

**QED:** Ligand A (0.825) has a better QED score than Ligand B (0.712), indicating a more drug-like profile.

**DILI:** Both ligands have acceptable DILI risk (Ligand A: 51.648, Ligand B: 43.738), both below the 60% threshold.

**BBB:** Ligand A (62.97%) has a slightly better BBB penetration score than Ligand B (47.111%), but both are below the desirable >70% for CNS targets.

**Caco-2 Permeability:** Ligand A (-4.571) and Ligand B (-5.142) both have negative Caco-2 permeability values, which is unusual and suggests poor intestinal absorption. This is a significant drawback.

**Aqueous Solubility:** Both ligands have poor aqueous solubility (Ligand A: -1.624, Ligand B: -2.243).

**hERG Inhibition:** Both ligands have low hERG inhibition risk (Ligand A: 0.191, Ligand B: 0.301).

**Microsomal Clearance:** Ligand A (40.673) has a slightly better microsomal clearance than Ligand B (35.612), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (-2.926) has a slightly better in vitro half-life than Ligand B (-1.861).

**P-gp Efflux:** Both ligands have low P-gp efflux liability (Ligand A: 0.027, Ligand B: 0.122), which is good for CNS penetration.

**Binding Affinity:** Ligand B (-7.6 kcal/mol) has a slightly better binding affinity than Ligand A (-7.4 kcal/mol). While the difference is small, it's within the range where it could outweigh minor ADME drawbacks.

**Overall Assessment:**

Ligand B has a slightly better binding affinity and TPSA, which are crucial for GPCR targets. However, Ligand A has a better QED, BBB, and metabolic stability. Both have poor Caco-2 permeability and solubility. Given the importance of CNS penetration for a DRD2 target, and the slight advantage in binding affinity, Ligand B is marginally preferred. The difference in binding affinity is small, but combined with the slightly better TPSA, it tips the balance.

Output:
1
2025-04-17 04:27:51,285 - INFO - Reasoning:

Let's analyze Ligand A and Ligand B against the provided guidelines, prioritizing GPCR-specific properties (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (336.439 Da) is slightly lower, which could be beneficial for permeability.

**TPSA:** Ligand A (58.12) is excellent for CNS penetration, well below the 90 A^2 threshold. Ligand B (85.23) is higher, but still reasonable, though less optimal for CNS targets.

**logP:** Both ligands have good logP values (A: 2.466, B: 2.059), falling within the 1-3 range.

**H-Bond Donors/Acceptors:** Both ligands have acceptable HBD (A: 1, B: 2) and HBA (A: 4, B: 4) counts, well below the limits of 5 and 10 respectively.

**QED:** Ligand A (0.935) has a significantly higher QED score than Ligand B (0.591), indicating a more drug-like profile.

**DILI:** Ligand A (45.173) has a moderate DILI risk, while Ligand B (2.52) has a very low DILI risk, which is a significant advantage.

**BBB:** Ligand A (91.663) has excellent BBB penetration, exceeding the 70% threshold. Ligand B (57.852) is considerably lower, a major drawback for a CNS target like DRD2.

**Caco-2 Permeability:** Ligand A (-4.881) has poor Caco-2 permeability, which is a concern. Ligand B (-5.261) is similarly poor.

**Aqueous Solubility:** Both ligands have poor aqueous solubility (A: -3.319, B: -1.644).

**hERG:** Both ligands have low hERG risk (A: 0.761, B: 0.708).

**Microsomal Clearance:** Ligand A (75.858) has moderate clearance, while Ligand B (-18.871) has negative clearance, suggesting very high metabolic stability. This is a substantial advantage for Ligand B.

**In vitro Half-Life:** Ligand A (-1.244) has a short half-life, while Ligand B (-10.68) has an even shorter half-life. Both are poor.

**P-gp Efflux:** Both ligands have low P-gp efflux (A: 0.305, B: 0.012), which is favorable for CNS penetration. Ligand B is slightly better.

**Binding Affinity:** Ligand A (-8.9 kcal/mol) has a stronger binding affinity than Ligand B (-7.5 kcal/mol). This is a significant advantage for Ligand A, potentially outweighing some of its ADME deficiencies. The difference is >1.5 kcal/mol.

**Overall Assessment:**

Despite Ligand A's superior binding affinity and QED, Ligand B is the more promising candidate. The critical factor is the significantly better BBB penetration (57.852 vs 91.663) and dramatically improved metabolic stability (negative Cl_mic). While Ligand A has a better binding affinity, the lower BBB and moderate clearance are major liabilities for a CNS-targeted GPCR. Ligand B's low DILI risk is also a significant benefit. The poor solubility and Caco-2 permeability are concerns for both, but can potentially be addressed with formulation strategies.



Output:
1
2025-04-17 04:27:51,285 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (347.342 and 349.475 Da) fall comfortably within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (84.86) is slightly higher than Ligand B (75.44). Both are below the 90 A^2 threshold desirable for CNS targets, but Ligand B is better.

**3. logP:** Ligand A (2.056) and Ligand B (3.105) are both within the optimal 1-3 range. Ligand B is slightly higher, potentially aiding membrane permeability.

**4. H-Bond Donors:** Ligand A (2) and Ligand B (1) are both acceptable, below the 5 limit. Ligand B is slightly better.

**5. H-Bond Acceptors:** Ligand A (5) and Ligand B (4) are both below the 10 limit. Ligand B is slightly better.

**6. QED:** Both ligands have good QED scores (0.592 and 0.704), indicating good drug-like properties. Ligand B is better.

**7. DILI:** Ligand A (58.589) has a higher DILI risk than Ligand B (16.479). This is a significant advantage for Ligand B.

**8. BBB:** Ligand A (57.852) and Ligand B (88.833) both have reasonable BBB penetration, but Ligand B is substantially better, exceeding the desirable >70 percentile for CNS targets.

**9. Caco-2 Permeability:** Both have negative Caco-2 values (-4.841 and -4.534). This is unusual and suggests poor permeability. However, these values are on a scale where negative values are possible and don't necessarily indicate a complete lack of permeability.

**10. Aqueous Solubility:** Both have negative solubility values (-3.594 and -3.327). Similar to Caco-2, these values are on a scale where negative values are possible.

**11. hERG Inhibition:** Both ligands show low hERG inhibition liability (0.694 and 0.672), which is good.

**12. Microsomal Clearance:** Ligand A (89.331) has higher microsomal clearance than Ligand B (75.978), indicating lower metabolic stability. Ligand B is better.

**13. In vitro Half-Life:** Ligand B (11.044 hours) has a significantly longer in vitro half-life than Ligand A (-25.566 hours). This is a major advantage for Ligand B.

**14. P-gp Efflux:** Both ligands have low P-gp efflux liability (0.271 and 0.172), which is favorable. Ligand B is slightly better.

**15. Binding Affinity:** Ligand A (-9.3 kcal/mol) has a slightly better binding affinity than Ligand B (-8.2 kcal/mol). This is a 1.1 kcal/mol difference, which is significant, but needs to be weighed against other factors.

**Overall Assessment:**

While Ligand A has a slightly better binding affinity, Ligand B demonstrates a significantly superior ADME profile, particularly regarding BBB penetration, DILI risk, metabolic stability (lower Cl_mic and longer t1/2), and P-gp efflux. For a CNS target like DRD2, the improved BBB penetration and reduced toxicity risk of Ligand B are crucial. The difference in binding affinity (1.1 kcal/mol) is likely outweighed by the substantial improvements in drug-like properties.

Output:
1
2025-04-17 04:27:51,286 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (348.447 and 346.515 Da) fall comfortably within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (94.56) is higher than the preferred <90 for CNS targets, but not drastically so. Ligand B (40.62) is excellent, well below the threshold. This favors Ligand B.

**3. logP:** Ligand A (0.681) is a bit low, potentially hindering permeability. Ligand B (3.332) is near the upper end of the optimal range (1-3), which is good. This favors Ligand B.

**4. H-Bond Donors:** Ligand A has 3 HBD, which is acceptable. Ligand B has 0, also acceptable. No clear advantage here.

**5. H-Bond Acceptors:** Ligand A has 5 HBA, acceptable. Ligand B has 2, also acceptable. No clear advantage here.

**6. QED:** Both ligands have good QED scores (0.642 and 0.717), indicating good drug-like properties.

**7. DILI:** Ligand A (19.232) has a slightly higher DILI risk than Ligand B (13.339), but both are below the concerning threshold of 40.

**8. BBB:** This is crucial for a CNS target like DRD2. Ligand A (48.895) has a poor BBB penetration percentile. Ligand B (82.164) is excellent, exceeding the desirable >70 threshold. This is a major advantage for Ligand B.

**9. Caco-2 Permeability:** Ligand A (-5.141) shows poor permeability. Ligand B (-4.556) is also poor, but slightly better.

**10. Aqueous Solubility:** Ligand A (-1.117) and Ligand B (-3.277) both show poor solubility.

**11. hERG Inhibition:** Ligand A (0.079) has a very low hERG risk, which is excellent. Ligand B (0.544) is also low, but slightly higher. This favors Ligand A.

**12. Microsomal Clearance:** Ligand A (2.523) has a low clearance, indicating good metabolic stability. Ligand B (60.133) has a high clearance, suggesting rapid metabolism. This strongly favors Ligand A.

**13. In vitro Half-Life:** Ligand A (1.328) has a short half-life. Ligand B (-1.014) has a negative half-life which is not possible, and indicates a data error.

**14. P-gp Efflux:** Ligand A (0.006) has very low P-gp efflux, which is excellent for CNS penetration. Ligand B (0.204) is also low, but higher than Ligand A. This favors Ligand A.

**15. Binding Affinity:** Ligand B (-7.7) has a slightly better binding affinity than Ligand A (-7.4), a difference of 0.3 kcal/mol. While a 1.5 kcal/mol advantage is significant, 0.3 kcal/mol is less impactful and can be overcome by superior ADME properties.

**Overall Assessment:**

While Ligand B has a slightly better binding affinity, Ligand A is the superior candidate. Ligand B's poor metabolic stability (high Cl_mic) and lower BBB penetration are significant drawbacks for a CNS target. Ligand A exhibits excellent P-gp efflux and hERG inhibition profiles, and acceptable metabolic stability. The slightly lower affinity is outweighed by the better ADME properties, especially the improved BBB penetration.

Output:
0
2025-04-17 04:27:51,286 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B against the provided guidelines, prioritizing GPCR-specific properties (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (342.399 Da) is slightly preferred due to being lower.

**TPSA:** Ligand A (74.74) is excellent for CNS penetration, well below 90. Ligand B (49.5) is also very good.

**logP:** Ligand A (2.076) is optimal. Ligand B (4.238) is pushing the upper limit and could potentially lead to solubility issues or off-target interactions.

**H-Bond Donors/Acceptors:** Both ligands have acceptable HBD (1) and HBA (6 for A, 4 for B) counts.

**QED:** Both ligands have good QED scores (0.742 and 0.639, respectively), indicating drug-likeness.

**DILI:** Ligand A (32.377) has a significantly lower DILI risk than Ligand B (52.074). This is a substantial advantage.

**BBB:** Ligand B (78.79) has a much better BBB penetration percentile than Ligand A (47.693). This is a critical factor for a CNS target like DRD2.

**Caco-2 Permeability:** Ligand A (-5.271) has poor Caco-2 permeability, while Ligand B (-4.931) is also poor, but slightly better.

**Aqueous Solubility:** Ligand A (-1.486) has better aqueous solubility than Ligand B (-4.357).

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.659 and 0.967, respectively).

**Microsomal Clearance:** Ligand A (19.329) has lower microsomal clearance, indicating better metabolic stability, compared to Ligand B (59.082).

**In vitro Half-Life:** Ligand B (75.157) has a longer in vitro half-life than Ligand A (38.361).

**P-gp Efflux:** Ligand A (0.127) has significantly lower P-gp efflux liability than Ligand B (0.96). Lower P-gp efflux is crucial for CNS penetration.

**Binding Affinity:** Ligand B (-9.7 kcal/mol) has a considerably stronger binding affinity than Ligand A (-7.3 kcal/mol). This is a significant advantage, potentially outweighing some ADME drawbacks.

**Overall Assessment:**

Ligand B has a superior binding affinity and BBB penetration, which are paramount for a CNS GPCR target. However, it suffers from higher logP, higher DILI risk, poorer solubility, higher P-gp efflux, and faster clearance. Ligand A has better ADME properties (lower DILI, better solubility, lower P-gp efflux, better metabolic stability) but weaker affinity and lower BBB penetration.

The difference in binding affinity (-9.7 vs -7.3 kcal/mol) is substantial (2.4 kcal/mol). Given the importance of potency for GPCRs, and the potential to mitigate some ADME issues through formulation or structural modifications, the stronger binding of Ligand B is the deciding factor. The improved BBB penetration also supports this choice.

Output:
1
2025-04-17 04:27:51,286 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (350.419 and 347.379 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (111.53) is slightly higher than Ligand B (107.17), but both are below the 140 A^2 threshold for oral absorption and reasonably close to the 90 A^2 target for CNS penetration.

**3. logP:** Ligand A (-0.061) is slightly better than Ligand B (-0.249), both are close to optimal (1-3), but a bit low. This could potentially impact permeability.

**4. H-Bond Donors:** Ligand A (2) is slightly higher than Ligand B (1), but both are within the acceptable limit of 5.

**5. H-Bond Acceptors:** Ligand A (5) is lower than Ligand B (8). Ligand B is approaching the upper limit of 10, which could slightly hinder permeability.

**6. QED:** Both ligands have good QED scores (0.668 and 0.74), indicating good drug-like properties.

**7. DILI:** Ligand A (21.908) has a significantly lower DILI risk than Ligand B (73.982). This is a major advantage for Ligand A.

**8. BBB:** Ligand B (70.997) has a better BBB penetration percentile than Ligand A (58.278). This is crucial for a CNS target like DRD2.

**9. Caco-2 Permeability:** Ligand A (-4.971) has a worse Caco-2 permeability than Ligand B (-5.434). Both are negative, indicating poor permeability.

**10. Aqueous Solubility:** Both ligands have very poor aqueous solubility (-1.362 and -1.661). This could pose formulation challenges.

**11. hERG Inhibition:** Both ligands have low hERG inhibition risk (0.073 and 0.131).

**12. Microsomal Clearance:** Ligand A (-6.492) has significantly lower (better) microsomal clearance than Ligand B (1.098), indicating better metabolic stability.

**13. In vitro Half-Life:** Ligand A (17.3) has a longer half-life than Ligand B (3.647), which is desirable.

**14. P-gp Efflux:** Ligand A (0.009) exhibits lower P-gp efflux than Ligand B (0.021), which is beneficial for CNS exposure.

**15. Binding Affinity:** Ligand B (-8.1 kcal/mol) has a significantly stronger binding affinity than Ligand A (-7.1 kcal/mol). This is a substantial advantage, exceeding the 1.5 kcal/mol threshold.

**Overall Assessment:**

While Ligand B has a better BBB score and significantly stronger binding affinity, Ligand A demonstrates a much more favorable safety profile (lower DILI) and better metabolic stability (lower Cl_mic, longer t1/2). The difference in affinity is substantial, but the poor ADME profile of Ligand B (high DILI, poor metabolic stability) is concerning. Ligand A's lower affinity could potentially be optimized through further medicinal chemistry efforts, while mitigating the ADME liabilities of Ligand B might be more challenging. Given the GPCR-specific priorities and the importance of a good safety profile for CNS drugs, I would prioritize Ligand A for further development.

Output:
0
2025-04-17 04:27:51,286 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (336.4 and 343.4 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Both ligands have TPSA values (84.7 and 79.1) below the 90 A^2 threshold desirable for CNS targets, which is excellent.

**3. logP:** Both ligands have logP values (1.81 and 1.93) within the optimal 1-3 range.

**4. H-Bond Donors:** Ligand A has 2 HBD, and Ligand B has 1. Both are acceptable (<=5).

**5. H-Bond Acceptors:** Both ligands have 5 HBA, which is also acceptable (<=10).

**6. QED:** Ligand B (0.91) has a significantly better QED score than Ligand A (0.74), indicating a more drug-like profile.

**7. DILI:** Ligand B (38.7) has a much lower DILI risk than Ligand A (65.7), making it safer from a liver toxicity perspective.

**8. BBB:** Ligand A (74.9%) has a slightly better BBB penetration prediction than Ligand B (68.7%), though both are reasonably good. This is a critical factor for a CNS target like DRD2.

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 values, which is unusual and suggests a potential issue with intestinal absorption. However, these values are on a log scale, and the absolute values are not directly comparable without knowing the scale.

**10. Aqueous Solubility:** Both ligands have negative solubility values, which is also unusual. Again, the scale is unknown, but suggests potential formulation challenges.

**11. hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.086 and 0.103), which is excellent.

**12. Microsomal Clearance:** Ligand B (2.77) has a significantly lower microsomal clearance than Ligand A (26.1), indicating better metabolic stability.

**13. In vitro Half-Life:** Ligand B (15.5) has a longer in vitro half-life than Ligand A (30.5), which is desirable.

**14. P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.101 and 0.04), which is excellent for CNS penetration.

**15. Binding Affinity:** Ligand A (-10.1 kcal/mol) has a significantly stronger binding affinity than Ligand B (-8.6 kcal/mol). This is a substantial difference (1.5 kcal/mol), and a strong affinity can often outweigh minor ADME drawbacks.

**Overall Assessment:**

While Ligand B demonstrates superior ADME properties (QED, DILI, Cl_mic, t1/2), the significantly stronger binding affinity of Ligand A (-10.1 vs -8.6 kcal/mol) is a decisive factor for a GPCR target. The difference in affinity is large enough to potentially overcome the slightly higher DILI risk and lower QED of Ligand A. The BBB penetration is also acceptable for Ligand A.

Output:
1
2025-04-17 04:27:51,287 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (362.407 and 354.422 Da) fall within the ideal range of 200-500 Da.

**TPSA:** Ligand A (87.49) is slightly above the optimal <90 for CNS targets, but acceptable. Ligand B (75.71) is well within the desired range.

**logP:** Both ligands have good logP values (1.852 and 2.112), falling within the 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A has 0 HBD and 7 HBA, while Ligand B has 1 HBD and 4 HBA. Both are within acceptable limits (<=5 HBD and <=10 HBA).

**QED:** Both ligands have relatively low QED scores (0.443 and 0.313), indicating they are not particularly drug-like. This is a potential concern, but can be overcome if other properties are excellent.

**DILI:** Ligand A has a significantly higher DILI risk (87.902 percentile) than Ligand B (44.591 percentile). This is a major drawback for Ligand A.

**BBB:** Ligand B has a better BBB penetration score (79.604%) than Ligand A (67.933%). Both are above the 70% threshold, but B is better.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.823 and -4.296). This is unusual and suggests poor permeability, which is concerning.

**Aqueous Solubility:** Both ligands have negative solubility values (-3.518 and -2.262), indicating very poor aqueous solubility. This is a significant issue for both compounds.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.238 and 0.488), which is good.

**Microsomal Clearance:** Ligand A (86.914) and Ligand B (84.462) both have high microsomal clearance, indicating rapid metabolism and potentially low bioavailability.

**In vitro Half-Life:** Ligand B has a significantly longer in vitro half-life (-19.076 hours) than Ligand A (-0.752 hours). This is a substantial advantage for Ligand B.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.422 and 0.243), which is favorable for CNS penetration.

**Binding Affinity:** Both ligands have excellent binding affinities (-8.8 kcal/mol and -8.0 kcal/mol). Ligand A has a slightly better affinity, but the difference is less than 1.5 kcal/mol.

**Overall Assessment:**

Ligand B is the more promising candidate. While both have poor solubility and permeability, Ligand B has a significantly lower DILI risk, better BBB penetration, and a much longer in vitro half-life. The slightly better affinity of Ligand A is outweighed by its higher DILI risk and shorter half-life. The poor solubility and permeability are serious issues that would need to be addressed through formulation or structural modification, but Ligand B provides a better starting point.

Output:
1
2025-04-17 04:27:51,287 - INFO - Reasoning:

Let's analyze Ligand A and Ligand B based on the provided guidelines, prioritizing GPCR-specific properties (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (343.431 and 350.503 Da) fall within the ideal range of 200-500 Da.

**TPSA:** Ligand A (80.12) is better than Ligand B (60.85), both are below the 90 A^2 threshold for CNS targets.

**logP:** Ligand B (2.567) is slightly better than Ligand A (1.13), falling more centrally within the optimal 1-3 range. Ligand A is a bit low, potentially hindering permeation.

**H-Bond Donors/Acceptors:** Both have acceptable HBD (1) and HBA (A: 5, B: 3) counts.

**QED:** Both ligands have good QED scores (A: 0.785, B: 0.833), indicating drug-like properties.

**DILI:** Ligand B (15.743) has a significantly lower DILI risk than Ligand A (51.493), a major advantage.

**BBB:** Ligand A (70.57) has a slightly better BBB penetration percentile than Ligand B (64.87), but both are reasonably good, exceeding the 70% threshold.

**Caco-2 Permeability:** Ligand A (-5.33) has a much better Caco-2 permeability than Ligand B (-4.489), suggesting better intestinal absorption.

**Aqueous Solubility:** Ligand A (-2.448) has better aqueous solubility than Ligand B (-2.13).

**hERG:** Both ligands have low hERG inhibition risk (A: 0.106, B: 0.306).

**Microsomal Clearance:** Ligand B (20.389) has lower microsomal clearance than Ligand A (33.363), indicating better metabolic stability.

**In vitro Half-Life:** Ligand B (0.967) has a slightly longer in vitro half-life than Ligand A (-1.647).

**P-gp Efflux:** Ligand A (0.071) has significantly lower P-gp efflux liability than Ligand B (0.132), which is crucial for CNS penetration.

**Binding Affinity:** Ligand B (-8.0) has a slightly better binding affinity than Ligand A (-7.8), although the difference is small.

**Overall Assessment:**

While Ligand A has better Caco-2 permeability, solubility, and P-gp efflux, Ligand B excels in several critical areas for a CNS-targeting GPCR drug: significantly lower DILI risk, better metabolic stability (lower Cl_mic), and slightly better binding affinity. The logP value of Ligand B is also more optimal. The small difference in BBB is less critical given the overall profile. The slightly lower P-gp efflux of ligand A is a benefit, but the substantial improvement in DILI and metabolic stability with ligand B outweighs this.

Output:
1
2025-04-17 04:27:51,287 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (350.419 Da) is slightly lower, which is generally favorable for permeability. Ligand B (408.304 Da) is also acceptable.

**2. TPSA:** This is crucial for CNS penetration. Ligand A (113.44) is better, being closer to the ideal <90 for CNS targets, while Ligand B (82.94) is excellent.

**3. logP:** Ligand A (0.059) is quite low, potentially hindering membrane permeability and CNS entry. Ligand B (1.3) is within the optimal 1-3 range. This is a significant advantage for Ligand B.

**4. H-Bond Donors:** Ligand A (3) is acceptable, while Ligand B (1) is even better, potentially improving permeability.

**5. H-Bond Acceptors:** Both ligands have 6 HBA, which is within the acceptable limit of <=10.

**6. QED:** Both ligands have good QED scores (A: 0.641, B: 0.81), indicating drug-like properties. Ligand B is slightly better.

**7. DILI:** Ligand A (46.219) has a lower DILI risk than Ligand B (54.323), but both are reasonably low.

**8. BBB:** Both ligands have acceptable BBB penetration (A: 43.156, B: 48.158), but neither is exceptionally high (>70).

**9. Caco-2 Permeability:** Ligand A (-4.96) has very poor Caco-2 permeability, which is a major concern. Ligand B (-5.217) is also poor, but slightly better.

**10. Aqueous Solubility:** Ligand A (-1.323) and Ligand B (-2.02) both have poor solubility.

**11. hERG Inhibition:** Both ligands have very low hERG inhibition risk (A: 0.079, B: 0.124).

**12. Microsomal Clearance:** Ligand A (7.427) has lower clearance, suggesting better metabolic stability than Ligand B (1.415).

**13. In vitro Half-Life:** Ligand A (-7.953) has a significantly longer half-life than Ligand B (17.87). This is a substantial advantage for Ligand A.

**14. P-gp Efflux:** Both ligands have very low P-gp efflux liability (A: 0.01, B: 0.092).

**15. Binding Affinity:** Ligand A (-8.4) has a significantly stronger binding affinity than Ligand B (0.0). This is a major advantage for Ligand A.

**Overall Assessment:**

Ligand A has a much stronger binding affinity and a longer half-life, which are highly desirable. However, its very low logP and poor Caco-2 permeability are significant drawbacks, potentially limiting its ability to cross the BBB and reach the target in the CNS. Ligand B has a better logP and slightly better Caco-2 permeability, but its binding affinity is extremely weak.

Considering the GPCR-specific priorities, and the fact that DRD2 is a CNS target, the balance tips towards Ligand A *despite* its permeability issues. The significantly stronger binding affinity (-8.4 kcal/mol vs 0.0 kcal/mol) is a major advantage that could potentially be overcome with formulation strategies to improve solubility and permeability. A 8.4 kcal/mol advantage is substantial and likely outweighs the ADME concerns, especially given the low P-gp efflux for both compounds.

Output:
1
2025-04-17 04:27:51,287 - INFO - Batch 115 complete. Total preferences: 1840
2025-04-17 04:27:51,287 - INFO - Processing batch 116/512...
2025-04-17 04:28:32,291 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (352.366 and 351.447 Da) are within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (100.6) is better than Ligand B (104.46). Both are reasonably close to the 90 A^2 threshold for CNS targets, but A is preferable.

**3. logP:** Ligand B (1.941) is better than Ligand A (0.237). A logP of 0.237 is quite low and may hinder membrane permeability. Ligand B falls within the optimal 1-3 range.

**4. H-Bond Donors:** Ligand A (2) is better than Ligand B (3). Fewer HBDs generally improve permeability.

**5. H-Bond Acceptors:** Ligand A (6) is better than Ligand B (5).

**6. QED:** Both ligands have similar QED values (0.673 and 0.664), indicating good drug-likeness.

**7. DILI:** Both ligands have the same DILI risk (54.556 and 30.361 percentile), which is acceptable (below 60).

**8. BBB:** Ligand B (57.774) is significantly better than Ligand A (30.361). For a CNS target like DRD2, a high BBB penetration is crucial. This is a major advantage for Ligand B.

**9. Caco-2 Permeability:** Ligand A (-5.211) is better than Ligand B (-4.856). Higher values indicate better intestinal absorption.

**10. Aqueous Solubility:** Ligand A (-1.25) is better than Ligand B (-2.804).

**11. hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.253 and 0.256).

**12. Microsomal Clearance:** Ligand A (13.472) is better than Ligand B (49.494). Lower clearance indicates better metabolic stability.

**13. In vitro Half-Life:** Ligand A (34.235) is better than Ligand B (-2.012). A longer half-life is generally preferred.

**14. P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.031 and 0.09).

**15. Binding Affinity:** Ligand B (-8.1 kcal/mol) is significantly better than Ligand A (-7.5 kcal/mol). A 0.6 kcal/mol difference in binding affinity is substantial and can outweigh some ADME drawbacks.

**Overall Assessment:**

While Ligand A has better properties in terms of metabolic stability (Cl_mic, t1/2) and solubility, Ligand B excels in the most critical areas for a CNS-targeting GPCR: BBB penetration and binding affinity. The significantly higher BBB value for Ligand B is a major advantage, and the stronger binding affinity (-8.1 vs -7.5 kcal/mol) further solidifies its potential. The slightly higher logP of Ligand B is also beneficial for membrane permeability. The lower Caco-2 and aqueous solubility of Ligand B are less concerning given the primary focus on CNS penetration.

Output:
1
2025-04-17 04:28:32,291 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B based on the provided guidelines, prioritizing GPCR-specific properties (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (341.411 and 349.435 Da) fall within the ideal range of 200-500 Da.

**TPSA:** Ligand A (82.27) is excellent for CNS penetration, being well below 90. Ligand B (126.21) is still reasonable, but less optimal.

**logP:** Ligand A (1.375) is within the optimal range. Ligand B (0.74) is slightly low, potentially impacting permeability.

**H-Bond Donors/Acceptors:** Ligand A (2 HBD, 3 HBA) and Ligand B (4 HBD, 4 HBA) both have acceptable counts.

**QED:** Both ligands have similar QED values (0.466 and 0.49), indicating moderate drug-likeness.

**DILI:** Ligand A (38.309) has a slightly higher DILI risk than Ligand B (23.885), but both are below the concerning threshold of 60.

**BBB:** This is a critical parameter for a CNS target like DRD2. Ligand A (35.673) has a poor BBB percentile, while Ligand B (71.035) is quite good, exceeding the desirable >70 threshold.

**Caco-2 Permeability:** Ligand A (-4.967) has very poor Caco-2 permeability, while Ligand B (-5.614) is also poor, but slightly better.

**Aqueous Solubility:** Both ligands have very poor aqueous solubility (-2.484 and -1.805 respectively).

**hERG Inhibition:** Both ligands show low hERG inhibition risk (0.362 and 0.134).

**Microsomal Clearance:** Ligand A (-2.243) has a negative clearance, which is unusual and suggests very high metabolic stability. Ligand B (8.182) has a moderate clearance.

**In vitro Half-Life:** Ligand A (-24.15) has a very long half-life, likely related to the negative clearance. Ligand B (3.407) has a short half-life.

**P-gp Efflux:** Both ligands show very low P-gp efflux liability (0.11 and 0.007).

**Binding Affinity:** Ligand A (-8.9 kcal/mol) has a significantly stronger binding affinity than Ligand B (-7.7 kcal/mol). The difference of 1.2 kcal/mol is substantial and can outweigh some ADME concerns.

**Conclusion:**

Despite the superior affinity of Ligand A, its extremely poor BBB penetration and Caco-2 permeability are major drawbacks for a CNS drug. While its metabolic stability is excellent, getting it into the brain will be a significant hurdle. Ligand B, while having a slightly lower affinity, possesses a much better BBB percentile and slightly better Caco-2 permeability. The difference in affinity, while significant, may be overcome with further optimization. Given the GPCR-specific priorities, particularly BBB penetration, Ligand B is the more promising candidate.

Output:
1
2025-04-17 04:28:32,291 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 drug candidates, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (363.351 and 347.463 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (47.56) is significantly better than Ligand B (80.12). For CNS targets, we want TPSA <= 90, and ideally closer to 60. Ligand A is much closer to this ideal. Ligand B is pushing the upper limit and could suffer from reduced BBB penetration.

**3. logP:** Ligand A (3.957) is at the upper end of the optimal range (1-3), but still acceptable. Ligand B (1.354) is a bit low, potentially hindering membrane permeability.

**4. H-Bond Donors:** Both ligands have 1 HBD, which is within the acceptable limit of <= 5.

**5. H-Bond Acceptors:** Ligand A has 3 HBA, and Ligand B has 5. Both are within the acceptable limit of <= 10.

**6. QED:** Both ligands have similar QED values (0.779 and 0.72), indicating good drug-like properties.

**7. DILI:** Ligand A (37.456) has a slightly higher DILI risk than Ligand B (30.826), but both are below the concerning threshold of 60.

**8. BBB:** Ligand A (92.633) has a significantly higher BBB penetration percentile than Ligand B (51.803). This is *critical* for a CNS target like DRD2.

**9. Caco-2 Permeability:** Both have negative Caco-2 values which is unusual and likely indicates an issue with the model or data.

**10. Aqueous Solubility:** Both have negative solubility values, which is also unusual.

**11. hERG Inhibition:** Ligand A (0.751) has a slightly higher hERG risk than Ligand B (0.069). This is a potential concern for Ligand A, but not a major red flag at this level.

**12. Microsomal Clearance:** Ligand A (52.737) has a higher microsomal clearance than Ligand B (21.44). This suggests Ligand B is metabolically more stable.

**13. In vitro Half-Life:** Ligand A (-15.045) has a negative half-life, which is impossible. This is a data error. Ligand B (-0.682) is also negative, indicating a data issue.

**14. P-gp Efflux:** Ligand A (0.217) has lower P-gp efflux than Ligand B (0.018), which is beneficial for CNS penetration.

**15. Binding Affinity:** Both ligands have very similar binding affinities (-7.7 and -7.6 kcal/mol), which are excellent. The difference is negligible.

**Overall Assessment:**

Despite the data quality issues with Caco-2, solubility, and half-life, the key differences lie in TPSA and BBB. Ligand A has a much lower TPSA and significantly better predicted BBB penetration, making it far more likely to reach the target in the CNS. While Ligand B has slightly better metabolic stability and lower hERG risk, the BBB advantage of Ligand A is paramount for a DRD2-targeting drug. The P-gp efflux is also slightly better for Ligand A.

Output:
1
2025-04-17 04:28:32,292 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 drug candidates, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (392.428 and 364.511 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (66.49) is slightly above the optimal <90 for CNS targets, but still reasonable. Ligand B (60.85) is better, falling comfortably below 90.

**3. logP:** Both ligands have good logP values (1.509 and 2.671), within the 1-3 range.

**4. H-Bond Donors:** Ligand A has 2 HBD, and Ligand B has 1. Both are acceptable (<=5).

**5. H-Bond Acceptors:** Ligand A has 5 HBA, and Ligand B has 4. Both are acceptable (<=10).

**6. QED:** Both ligands have good QED scores (0.741 and 0.874), indicating good drug-like properties.

**7. DILI:** Ligand A has a DILI risk of 83.947, which is high and concerning. Ligand B has a much lower DILI risk of 23.653, a significant advantage.

**8. BBB:** Ligand A has a BBB penetration of 61.38%, which is below the desirable >70% for CNS targets. Ligand B has a significantly better BBB penetration of 74.486%, making it more promising for CNS activity.

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.965 and -4.684), which is unusual and suggests poor permeability. However, these values are on a logarithmic scale, and negative values are common. The absolute values are similar, so this doesn't strongly favor either.

**10. Aqueous Solubility:** Both ligands have negative solubility values (-3.351 and -2.812), also typical for this scale, and similar in magnitude.

**11. hERG Inhibition:** Both ligands have low hERG inhibition risk (0.453 and 0.479).

**12. Microsomal Clearance:** Ligand A (20.304) has lower microsomal clearance than Ligand B (52.311), suggesting better metabolic stability.

**13. In vitro Half-Life:** Ligand A (25.847) has a longer in vitro half-life than Ligand B (5.619), which is favorable.

**14. P-gp Efflux:** Both ligands have low P-gp efflux liability (0.269 and 0.292), which is good for CNS penetration.

**15. Binding Affinity:** Ligand B (-8.7 kcal/mol) has a significantly stronger binding affinity than Ligand A (-7.7 kcal/mol). This 1 kcal/mol difference is substantial and can outweigh some ADME drawbacks.

**Overall Assessment:**

Ligand B is the more promising candidate. While Ligand A has better metabolic stability and half-life, Ligand B excels in the critical areas for a CNS-targeting GPCR: significantly lower DILI risk, much better BBB penetration, and a substantially stronger binding affinity. The slightly higher clearance and shorter half-life of Ligand B are less concerning given its superior safety profile and potency.

Output:
1
2025-04-17 04:28:32,292 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (341.382 and 351.363 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (55.4) is excellent, well below the 90 A^2 threshold for CNS targets. Ligand B (117.86) is higher, but still potentially acceptable, though less ideal.

**logP:** Ligand A (3.619) is optimal. Ligand B (-0.65) is significantly low, which could hinder membrane permeability and CNS penetration.

**H-Bond Donors/Acceptors:** Both have acceptable HBD counts (1). Ligand A has 3 HBA, while Ligand B has 8. The higher HBA count in Ligand B could impact permeability.

**QED:** Both ligands have reasonable QED scores (0.845 and 0.566), indicating drug-like properties.

**DILI:** Ligand A (67.429) has a slightly higher DILI risk than Ligand B (57.154), but both are below the concerning 60 threshold.

**BBB:** Ligand A (84.141) has a very good BBB percentile, highly desirable for a CNS target like DRD2. Ligand B (42.846) is significantly lower, raising concerns about CNS exposure.

**Caco-2 Permeability:** Both have negative Caco-2 values (-4.454 and -4.898), which is unusual and suggests poor permeability. However, these values are on a log scale and should be interpreted cautiously.

**Aqueous Solubility:** Both have negative solubility values (-5.19 and -1.283) which also suggests poor solubility.

**hERG:** Ligand A (0.577) has a lower hERG risk than Ligand B (0.038), which is preferable.

**Microsomal Clearance:** Ligand A (73.849) has higher clearance than Ligand B (24.663), indicating lower metabolic stability.

**In vitro Half-Life:** Ligand A (-10.107) has a negative half-life, which is not physically possible and indicates a problem with the data. Ligand B (0.714) is a very short half-life.

**P-gp Efflux:** Ligand A (0.242) has lower P-gp efflux liability than Ligand B (0.011), which is favorable for CNS penetration.

**Binding Affinity:** Both ligands have very similar and strong binding affinities (-8.8 and -8.9 kcal/mol). This difference is negligible.

**Conclusion:**

Considering all factors, especially the GPCR-specific priorities, **Ligand A is the more promising candidate.** While it has a higher DILI risk and lower metabolic stability, its significantly better logP, TPSA, and *especially* BBB penetration outweigh these drawbacks. The poor solubility and permeability values for both are concerning, but the superior CNS penetration profile of Ligand A is critical for a DRD2 target. The negative half-life for Ligand A is a data quality issue that would need to be resolved, but the overall profile is still more favorable.

Output:
1
2025-04-17 04:28:32,292 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (345.403 and 352.425 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (103.76) is borderline for CNS penetration, being slightly above the preferred <90 threshold. Ligand B (49.41) is well within the ideal range for CNS targets.

**logP:** Ligand A (0.487) is quite low, potentially hindering membrane permeability. Ligand B (3.051) is near the optimal range of 1-3.

**H-Bond Donors/Acceptors:** Ligand A has 2 HBD and 5 HBA, which are acceptable. Ligand B has 1 HBD and 2 HBA, also acceptable.

**QED:** Both ligands have good QED scores (0.75 and 0.791), indicating drug-like properties.

**DILI:** Ligand A has a DILI risk of 60.14, placing it at a moderate risk. Ligand B has a much lower DILI risk (21.714), which is favorable.

**BBB:** This is a critical parameter for a CNS target. Ligand A's BBB penetration is 36.177%, which is quite low. Ligand B has excellent BBB penetration at 90.035%.

**Caco-2 Permeability:** Ligand A has a negative Caco-2 value (-5.346), suggesting poor permeability. Ligand B also has a negative value (-4.694) but is slightly better.

**Aqueous Solubility:** Both ligands have negative solubility values (-2.293 and -3.003), which is concerning. However, these scales are relative, and the absolute solubility might still be adequate.

**hERG Inhibition:** Both ligands show low hERG inhibition risk (0.17 and 0.299).

**Microsomal Clearance:** Ligand A has a lower Cl_mic (8.309) than Ligand B (30.519), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A has a longer half-life (26.152 hours) than Ligand B (-15.111 hours). The negative value for Ligand B is unusual and suggests rapid metabolism or instability.

**P-gp Efflux:** Ligand A shows minimal P-gp efflux (0.02), which is excellent. Ligand B has a slightly higher P-gp efflux (0.145).

**Binding Affinity:** Ligand B (-9.4 kcal/mol) has a slightly better binding affinity than Ligand A (-8.7 kcal/mol). While the difference is not huge, it's a positive factor.

**Overall Assessment:**

Ligand B is significantly more promising. Its superior BBB penetration, better logP, lower DILI risk, and slightly better affinity outweigh the drawbacks of a higher Cl_mic and a negative Caco-2 value. Ligand A's low logP and poor BBB penetration are major concerns for a CNS-targeting drug. The negative half-life for Ligand B is a red flag, but could be addressed through structural modifications.

Output:
1
2025-04-17 04:28:32,292 - INFO - Reasoning:

Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (345.483 and 345.399 Da) fall comfortably within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (47.56) is significantly better than Ligand B (78.95). For CNS targets, TPSA < 90 is preferred, and A is much closer to the optimal <60 range. B is pushing the upper limit.

**3. logP:** Ligand A (3.858) is slightly higher than Ligand B (2.155), both are within the optimal 1-3 range, but A is closer to the upper end.

**4. H-Bond Donors:** Both ligands have 1 HBD, which is acceptable.

**5. H-Bond Acceptors:** Ligand A has 3 HBA, while Ligand B has 4. Both are within the acceptable limit of <=10.

**6. QED:** Ligand B (0.848) has a better QED score than Ligand A (0.603), indicating a more drug-like profile overall.

**7. DILI:** Ligand A (18.922) has a significantly lower DILI risk than Ligand B (57.387). This is a major advantage for A.

**8. BBB:** Both ligands have excellent BBB penetration (A: 83.288, B: 83.094). This is crucial for a CNS target like DRD2, and they are both above the desirable 70% threshold.

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.344 and -4.64). This is unusual and suggests poor permeability. However, these values are on a strange scale, and may not be directly comparable.

**10. Aqueous Solubility:** Both ligands have negative solubility values (-4.063 and -2.637). Similar to Caco-2, this is unusual and suggests poor solubility.

**11. hERG Inhibition:** Ligand A (0.605) has a slightly higher hERG risk than Ligand B (0.335), but both are relatively low.

**12. Microsomal Clearance:** Ligand B (24.841) has significantly lower microsomal clearance than Ligand A (68.27), indicating better metabolic stability.

**13. In vitro Half-Life:** Ligand B (24.124) has a much longer in vitro half-life than Ligand A (5.651). This is a significant advantage for B.

**14. P-gp Efflux:** Ligand A (0.193) has lower P-gp efflux than Ligand B (0.051), which is favorable for CNS penetration.

**15. Binding Affinity:** Both ligands have very similar and excellent binding affinities (-8.6 and -8.7 kcal/mol). The difference is negligible.

**Overall Assessment:**

While Ligand B has a better QED, longer half-life, and better metabolic stability, Ligand A's significantly lower DILI risk and lower P-gp efflux are critical advantages. The lower TPSA of Ligand A is also beneficial for CNS penetration. The Caco-2 and solubility values are concerning for both, but the other properties, particularly the DILI risk, push me towards selecting Ligand A. Given the GPCR-specific focus on BBB (which both achieve), logP, Pgp, TPSA, and affinity, Ligand A is the more promising candidate.

Output:
1
2025-04-17 04:28:32,293 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (365.459 and 372.437 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (101.22) is slightly above the optimal <90 for CNS targets, but still reasonable. Ligand B (49.85) is excellent, well below the threshold.

**logP:** Both ligands have good logP values (1.608 and 2.622), falling within the 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A has 1 HBD and 7 HBA, which are acceptable. Ligand B has 0 HBD and 4 HBA, also acceptable.

**QED:** Both ligands have good QED scores (0.724 and 0.816), indicating good drug-like properties.

**DILI:** Ligand A (63.823) has a higher DILI risk than Ligand B (43.932), though both are below the concerning >60 threshold.

**BBB:** This is a critical parameter for a CNS target like DRD2. Ligand B (92.051) has a significantly higher BBB percentile than Ligand A (47.189). This is a major advantage for Ligand B.

**Caco-2 Permeability:** Ligand A (-5.126) has poor Caco-2 permeability, suggesting poor intestinal absorption. Ligand B (-4.636) also has poor Caco-2 permeability, but is slightly better than Ligand A.

**Aqueous Solubility:** Both ligands have very poor aqueous solubility (-2.523 and -2.694). This could pose formulation challenges.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.143 and 0.442).

**Microsomal Clearance:** Ligand B (31.599) has lower microsomal clearance than Ligand A (64.491), indicating better metabolic stability.

**In vitro Half-Life:** Ligand A (38.387) has a longer in vitro half-life than Ligand B (-7.817). However, the negative value for Ligand B is concerning and likely indicates rapid degradation.

**P-gp Efflux:** Ligand A (0.128) has lower P-gp efflux liability than Ligand B (0.214), which is favorable for CNS penetration.

**Binding Affinity:** Ligand A (-7.7) has a slightly better binding affinity than Ligand B (0.0). This is a significant advantage. However, the affinity of Ligand B is not very strong.

**Overall Assessment:**

While Ligand A has a slightly better binding affinity and lower P-gp efflux, Ligand B is the more promising candidate due to its significantly better BBB penetration (92.051 vs. 47.189), lower DILI risk, and better metabolic stability (lower Cl_mic). The poor solubility and Caco-2 permeability are concerns for both, but can potentially be addressed through formulation strategies. The negative in vitro half-life for Ligand B is a significant drawback. However, the superior BBB penetration is crucial for a CNS-targeting drug, and the better metabolic stability is also a significant advantage. The affinity difference, while present, is not large enough to overcome these ADME advantages of Ligand B.

Output:
1
2025-04-17 04:28:32,293 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (349.406 and 342.403 Da) fall comfortably within the ideal 200-500 Da range.

**TPSA:** Ligand A (80.32) is excellent, falling well below the 90 A^2 threshold for CNS targets. Ligand B (95.08) is still reasonable but less optimal, nearing the upper limit.

**logP:** Ligand A (1.713) is within the optimal 1-3 range. Ligand B (0.678) is slightly low, potentially impacting permeability, but not severely.

**H-Bond Donors/Acceptors:** Ligand A has 2 HBD and 4 HBA, both well within acceptable limits. Ligand B has 1 HBD and 5 HBA, also acceptable.

**QED:** Both ligands have good QED scores (0.605 and 0.833, respectively), indicating drug-like properties. Ligand B is slightly better here.

**DILI:** Both ligands have acceptable DILI risk (47.732 and 50.795 percentiles), below the concerning threshold of 60.

**BBB:** This is a critical parameter for a CNS target. Ligand A has a significantly better BBB penetration score (69.523%) compared to Ligand B (27.724%). This is a major advantage for Ligand A.

**Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and suggests poor permeability. This is a significant concern for both.

**Aqueous Solubility:** Both ligands show poor aqueous solubility (-2.445 and -1.322). This could pose formulation challenges.

**hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.156 and 0.03), which is excellent.

**Microsomal Clearance:** Ligand A (9.474) has a slightly better (lower) microsomal clearance than Ligand B (-15.906), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (10.626 hours) has a better in vitro half-life than Ligand B (-0.768 hours).

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.024 and 0.013), which is favorable for CNS penetration.

**Binding Affinity:** Ligand B (-8.7 kcal/mol) has a slightly better binding affinity than Ligand A (-8.3 kcal/mol). However, the difference is only 0.4 kcal/mol, which, while noticeable, isn't overwhelmingly decisive given the other factors.

**Overall Assessment:**

Considering the GPCR-specific priorities, Ligand A is the more promising candidate. Its superior BBB penetration (69.523% vs 27.724%) is a crucial advantage for a CNS-targeting drug. While Ligand B has slightly better affinity and QED, Ligand A compensates with better TPSA, metabolic stability (lower Cl_mic), and half-life. The poor Caco-2 and solubility are concerns for both, but can potentially be addressed through formulation strategies. The slightly better affinity of Ligand B is unlikely to overcome the significant difference in predicted brain penetration.

Output:
0
2025-04-17 04:28:32,293 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (361.423 and 365.792 Da) fall comfortably within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (97.39) is slightly higher than Ligand B (80.32). For CNS targets, we prefer TPSA <= 90, so Ligand B is better here.

**3. logP:** Both ligands (2.001 and 2.124) are within the optimal 1-3 range.

**4. H-Bond Donors:** Both have 2 HBD, which is acceptable.

**5. H-Bond Acceptors:** Ligand A has 6 HBA, and Ligand B has 4. Both are below the limit of 10.

**6. QED:** Both ligands have similar QED values (0.627 and 0.628), indicating good drug-likeness.

**7. DILI:** Both ligands have high DILI risk (81.039 and 80.109), which is a concern. However, this is a percentile, and we're comparing two similar values, so it doesn't differentiate them significantly at this stage.

**8. BBB:** Ligand A (69.794) has a better BBB percentile than Ligand B (53.974). This is a crucial factor for CNS targets like DRD2.

**9. Caco-2:** Both have negative Caco-2 values (-4.559 and -4.737), which is unusual and suggests poor permeability. This is a significant drawback for both.

**10. Solubility:** Both have negative solubility values (-3.592 and -4.182), indicating very poor aqueous solubility. This is a major issue for oral bioavailability.

**11. hERG:** Both ligands have very low hERG inhibition liability (0.223 and 0.127), which is excellent.

**12. Cl_mic:** Ligand B (72.965) has a higher microsomal clearance than Ligand A (61.365), suggesting faster metabolism and lower metabolic stability.

**13. t1/2:** Ligand A (14.987) has a longer in vitro half-life than Ligand B (-4.817). This is a positive for Ligand A.

**14. Pgp:** Both have very low Pgp efflux liability (0.16 and 0.144), which is favorable for CNS penetration.

**15. Binding Affinity:** Ligand B (-9.0 kcal/mol) has a significantly stronger binding affinity than Ligand A (-8.7 kcal/mol). This 0.3 kcal/mol difference is substantial and could outweigh some of the ADME drawbacks.

**Overall Assessment:**

Ligand B has a superior binding affinity and a lower TPSA, but suffers from a lower BBB penetration and higher metabolic clearance. Ligand A has a better BBB and longer half-life, but weaker binding affinity and higher TPSA. Both have poor solubility and Caco-2 permeability, and high DILI risk.

Given the importance of binding affinity for GPCRs, and the 0.3 kcal/mol advantage of Ligand B, I believe **Ligand B** is the more promising candidate. While the lower BBB is a concern, the stronger binding could translate to lower doses needed for efficacy, potentially mitigating the BBB issue. The solubility and permeability issues would need to be addressed through formulation strategies.

Output:
1
2025-04-17 04:28:32,293 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (361.27 and 362.495 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (64.11) is slightly higher than Ligand B (62.66), but both are below the 90 A^2 threshold desirable for CNS targets.

**3. logP:** Both ligands have good logP values (3.396 and 3.442), falling within the optimal 1-3 range.

**4. H-Bond Donors:** Both have 1 HBD, which is acceptable.

**5. H-Bond Acceptors:** Ligand A has 4 HBAs, and Ligand B has 5. Both are within the acceptable limit of 10.

**6. QED:** Both ligands have good QED scores (0.655 and 0.742), indicating good drug-like properties.

**7. DILI:** Ligand A (68.166) has a higher DILI risk than Ligand B (37.922). This is a significant drawback for Ligand A.

**8. BBB:** Ligand A (77.821) has a significantly better BBB penetration percentile than Ligand B (52.811). This is a crucial factor for a CNS target like DRD2.

**9. Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and suggests poor permeability. However, the scale is not specified, so it's hard to interpret.

**10. Aqueous Solubility:** Both have negative solubility values, suggesting poor solubility. Again, scale is not specified.

**11. hERG Inhibition:** Ligand A (0.405) has a lower hERG inhibition risk than Ligand B (0.787), which is preferable.

**12. Microsomal Clearance:** Ligand B (84.25) has a higher microsomal clearance than Ligand A (19.684), indicating lower metabolic stability.

**13. In vitro Half-Life:** Ligand B (22.837) has a longer in vitro half-life than Ligand A (7.641).

**14. P-gp Efflux:** Ligand A (0.119) has a much lower P-gp efflux liability than Ligand B (0.749), which is beneficial for CNS penetration.

**15. Binding Affinity:** Ligand A (-9.6 kcal/mol) has a significantly stronger binding affinity than Ligand B (-7.2 kcal/mol). This is a substantial advantage.

**Overall Assessment:**

Ligand A has a superior binding affinity and better BBB penetration and P-gp efflux properties, which are critical for a CNS GPCR target. However, it has a higher DILI risk. Ligand B has a lower DILI risk and better metabolic stability (lower Cl_mic, longer t1/2), but its affinity and BBB penetration are significantly worse.

Given the importance of strong binding affinity and BBB penetration for CNS targets, and the relatively modest difference in DILI risk compared to the affinity difference, **Ligand A is the more promising candidate**. The DILI risk could potentially be mitigated through structural modifications during lead optimization.

Output:
0
2025-04-17 04:28:32,293 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 drug candidates, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (361.345 and 359.491 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (102.69) is slightly above the optimal <90 for CNS targets, but still reasonable. Ligand B (49.77) is excellent, well below 90. This favors Ligand B.

**3. logP:** Ligand A (0.871) is a bit low, potentially hindering permeability. Ligand B (3.679) is within the optimal 1-3 range. This favors Ligand B.

**4. H-Bond Donors:** Ligand A (2) and Ligand B (1) are both acceptable (<=5).

**5. H-Bond Acceptors:** Ligand A (6) and Ligand B (4) are both acceptable (<=10).

**6. QED:** Both ligands have good QED scores (0.712 and 0.856, both > 0.5).

**7. DILI:** Ligand A (63.086) has a higher DILI risk than Ligand B (46.219), both are acceptable, but B is better.

**8. BBB:** Ligand A (88.135) has a better BBB penetration percentile than Ligand B (70.997), which is still good, but A is better.

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.943 and -4.8), which is unusual and suggests poor permeability. This is a significant concern for both.

**10. Aqueous Solubility:** Both ligands have negative solubility values (-2.174 and -3.847), which is also unusual and suggests poor solubility. This is a significant concern for both.

**11. hERG Inhibition:** Ligand A (0.261) has a lower hERG inhibition risk than Ligand B (0.776). This favors Ligand A.

**12. Microsomal Clearance:** Ligand B (84.384) has a significantly higher microsomal clearance than Ligand A (17.792), indicating lower metabolic stability. This strongly favors Ligand A.

**13. In vitro Half-Life:** Ligand B (46.45) has a longer half-life than Ligand A (16.907). This favors Ligand B.

**14. P-gp Efflux:** Ligand A (0.04) shows very low P-gp efflux, which is excellent for CNS penetration. Ligand B (0.879) has moderate P-gp efflux. This strongly favors Ligand A.

**15. Binding Affinity:** Ligand B (-8.0) has a slightly better binding affinity than Ligand A (-7.8). While a 0.2 kcal/mol difference isn't huge, it's a positive for Ligand B.

**Overall Assessment:**

Despite the poor Caco-2 and solubility values for both compounds, Ligand A emerges as the more promising candidate. Its superior BBB penetration, significantly lower microsomal clearance (better metabolic stability), and very low P-gp efflux are crucial advantages for a CNS-targeting GPCR like DRD2. The slightly better hERG profile also contributes. While Ligand B has a slightly better binding affinity and half-life, the ADME properties of Ligand A are more favorable for brain exposure and drug-like behavior. The negative Caco-2 and solubility values are concerning for both, and would need to be addressed through further optimization.

Output:
0
2025-04-17 04:28:32,294 - INFO - Reasoning:

Let's analyze Ligand A and Ligand B based on the provided guidelines, prioritizing GPCR-specific properties (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (345.359 and 346.471 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (122.71) is slightly above the optimal <90 for CNS targets, but still reasonable. Ligand B (53.01) is excellent, well below 90.

**logP:** Ligand A (0.282) is quite low, potentially hindering permeation. Ligand B (2.677) is within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A has 3 HBD and 7 HBA, acceptable. Ligand B has 1 HBD and 4 HBA, also acceptable.

**QED:** Both ligands have good QED scores (0.54 and 0.914), indicating drug-like properties.

**DILI:** Ligand A (70.686) has a higher DILI risk than Ligand B (23.536).

**BBB:** This is crucial for a CNS target. Ligand A (46.995) has a moderate BBB penetration, while Ligand B (86.468) is excellent, exceeding the desirable >70 threshold.

**Caco-2 Permeability:** Ligand A (-5.705) has poor Caco-2 permeability, suggesting poor absorption. Ligand B (-4.279) is better, but still not great.

**Aqueous Solubility:** Both ligands have negative solubility values, which is unusual and suggests very poor solubility. This is a significant concern for both.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.222 and 0.849).

**Microsomal Clearance:** Ligand A (-22.151) has a negative clearance, which is not physically realistic and suggests a potential issue with the data. Ligand B (2.4) has a low clearance, indicating good metabolic stability.

**In vitro Half-Life:** Ligand A (-29.446) also has a negative half-life, indicating a data issue. Ligand B (35.391) has a reasonable half-life.

**P-gp Efflux:** Ligand A (0.008) has very low P-gp efflux, which is favorable for CNS penetration. Ligand B (0.399) has slightly higher efflux, but still relatively low.

**Binding Affinity:** Both ligands have similar strong binding affinities (-9.6 and -8.0 kcal/mol). Ligand A is slightly better, but the difference is not huge.

**Overall Assessment:**

Ligand B is the more promising candidate. While both have solubility issues, Ligand B excels in key GPCR properties: excellent BBB penetration, a good logP value, low DILI risk, and good metabolic stability. Ligand A's low logP, poor Caco-2 permeability, and questionable clearance/half-life data are significant drawbacks. The negative values for clearance and half-life are particularly concerning and suggest potential data errors. Although Ligand A has slightly better affinity, the ADME properties of Ligand B are far superior for a CNS-targeting drug.

Output:
1
2025-04-17 04:28:32,294 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (330.391 and 344.39 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (62.83) is excellent, well below the 90 A^2 threshold for CNS targets. Ligand B (82.17) is still reasonable, but less optimal.

**logP:** Ligand A (4.671) is slightly high, potentially leading to solubility issues or off-target interactions. Ligand B (2.014) is within the optimal 1-3 range.

**H-Bond Donors:** Both ligands have 2 HBD, which is acceptable.

**H-Bond Acceptors:** Ligand A has 4 HBA, and Ligand B has 5 HBA, both within the acceptable limit of 10.

**QED:** Both ligands have good QED scores (0.558 and 0.889), indicating good drug-like properties.

**DILI:** Ligand A (82.668) has a higher DILI risk than Ligand B (57.154), which is preferable.

**BBB:** Both ligands have good BBB penetration (71.074 and 78.945), exceeding the 70% threshold for CNS targets. Ligand B is slightly better.

**Caco-2 Permeability:** Both have negative Caco-2 values (-5.168 and -4.94), which is unusual and suggests poor permeability. This is a significant concern for both.

**Aqueous Solubility:** Both ligands have very poor aqueous solubility (-5.885 and -3.231). This is a major drawback.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.93 and 0.677).

**Microsomal Clearance:** Ligand A (85.796) has higher clearance than Ligand B (15.301), indicating lower metabolic stability. Ligand B is significantly better.

**In vitro Half-Life:** Ligand A (-10.457) has a very short half-life, while Ligand B (2.472) is slightly better, but still not ideal.

**P-gp Efflux:** Ligand A (0.533) has lower P-gp efflux than Ligand B (0.025), which is favorable for CNS penetration.

**Binding Affinity:** Ligand B (-8.8 kcal/mol) has significantly stronger binding affinity than Ligand A (-10.3 kcal/mol). This is a substantial advantage.

**Overall Assessment:**

While both compounds have significant drawbacks (poor solubility and Caco-2 permeability), Ligand B emerges as the more promising candidate. Its superior binding affinity (-8.8 vs -10.3 kcal/mol) is a major advantage that can potentially offset some of the ADME issues. Furthermore, Ligand B has a better DILI score, lower microsomal clearance (better metabolic stability), and lower P-gp efflux. Ligand A's higher logP and shorter half-life are also concerning.

Output:
1
2025-04-17 04:28:32,294 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (348.451 and 350.415 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (97.35) is slightly higher than Ligand B (90.31). Both are below the 140 A^2 threshold for oral absorption and reasonably close to the 90 A^2 target for CNS penetration, but Ligand B is preferable.

**logP:** Ligand A (0.914) is within the optimal range (1-3), while Ligand B (-0.31) is slightly below 1, potentially hindering permeation. This favors Ligand A.

**H-Bond Donors/Acceptors:** Ligand A (HBD=1, HBA=6) and Ligand B (HBD=2, HBA=5) both have acceptable numbers of H-bond donors and acceptors.

**QED:** Both ligands have similar QED values (0.528 and 0.507), indicating good drug-likeness.

**DILI:** Ligand A (37.03) has a slightly higher DILI risk than Ligand B (25.94), but both are below the concerning threshold of 60.

**BBB:** This is a crucial parameter for a CNS target like DRD2. Ligand A (76.696) has significantly better BBB penetration potential than Ligand B (47.111). This is a major advantage for Ligand A.

**Caco-2 Permeability:** Ligand A (-5.338) and Ligand B (-4.848) both have negative Caco-2 values, which is unusual and suggests poor permeability. However, the scale is not specified, so it's hard to interpret.

**Aqueous Solubility:** Both ligands have very poor aqueous solubility (-0.873 and -1.242, respectively). This is a concern for both, but could be mitigated with formulation strategies.

**hERG Inhibition:** Both ligands show low hERG inhibition risk (0.282 and 0.255).

**Microsomal Clearance:** Ligand A (15.434) has a higher microsomal clearance than Ligand B (4.273), indicating lower metabolic stability. This favors Ligand B.

**In vitro Half-Life:** Ligand B (9.716) has a significantly longer in vitro half-life than Ligand A (-18.597). This is a substantial advantage for Ligand B.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.036 and 0.026), which is good for CNS exposure.

**Binding Affinity:** Ligand B (-7.8 kcal/mol) has a slightly stronger binding affinity than Ligand A (-7.4 kcal/mol). While the difference is not huge, it's within the range where a 0.4 kcal/mol advantage can be meaningful.

**Overall Assessment:**

Ligand A excels in BBB penetration and logP, which are critical for CNS GPCR targets. However, it suffers from higher microsomal clearance and a shorter half-life. Ligand B has a better half-life, lower clearance, slightly better affinity, and lower DILI risk, but its BBB penetration is significantly poorer and its logP is suboptimal.

Considering the importance of CNS penetration for DRD2, and the relatively small difference in binding affinity, **Ligand A is the more promising candidate**. The poor solubility of both compounds is a concern, but formulation strategies could potentially address this. The better BBB score of Ligand A outweighs the slightly better metabolic stability of Ligand B.



Output:
0
2025-04-17 04:28:32,294 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (365.367 and 382.51 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (128.5) is better than Ligand B (49.41). For CNS targets, TPSA should be <=90. Ligand A is slightly above, but Ligand B is significantly lower and more favorable.

**logP:** Ligand A (1.662) is within the optimal 1-3 range. Ligand B (4.664) is higher, potentially leading to solubility issues and off-target effects.

**H-Bond Donors/Acceptors:** Both have acceptable HBD counts (1). Ligand A has 8 HBAs, while Ligand B has 3. Both are within the acceptable range of <=10.

**QED:** Both ligands have similar QED values (0.446 and 0.424), indicating moderate drug-likeness.

**DILI:** Ligand A (96.549) has a significantly higher DILI risk than Ligand B (28.383). This is a major concern for Ligand A.

**BBB:** Ligand B (79.294) has a better BBB penetration percentile than Ligand A (66.576). Both are reasonably good, but >70 is preferred for CNS targets.

**Caco-2 Permeability:** Both have negative Caco-2 values (-4.933 and -4.961). This is unusual and suggests poor permeability.

**Aqueous Solubility:** Both have negative solubility values (-4.578 and -3.569), indicating poor aqueous solubility.

**hERG Inhibition:** Ligand A (0.276) has a lower hERG inhibition risk than Ligand B (0.838), which is preferable.

**Microsomal Clearance:** Ligand A (75.644) has higher microsomal clearance than Ligand B (52.864), indicating lower metabolic stability.

**In vitro Half-Life:** Ligand B (-2.668) has a negative half-life, which is not possible. Ligand A (38.191) has a more reasonable half-life.

**P-gp Efflux:** Ligand A (0.224) has lower P-gp efflux liability than Ligand B (0.728), which is favorable for CNS penetration.

**Binding Affinity:** Both ligands have excellent binding affinities (-8.7 and -8.3 kcal/mol). The difference of 0.4 kcal/mol is not substantial enough to outweigh other factors.

**Overall Assessment:**

Ligand B is the better candidate. While it has a higher logP and P-gp efflux, its significantly lower DILI risk, better BBB penetration, and reasonable metabolic stability are more important for a CNS-targeting GPCR ligand. The negative Caco-2 and solubility values are concerning for both, but can potentially be addressed through formulation strategies. The negative half-life for Ligand B is a significant data quality issue. Ligand A's high DILI risk is a major red flag.

Output:
1
2025-04-17 04:28:32,294 - INFO - Batch 116 complete. Total preferences: 1856
2025-04-17 04:28:32,295 - INFO - Processing batch 117/512...
2025-04-17 04:29:16,250 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (362.451 and 352.458 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Both ligands have TPSA values (75.71 and 75.2) that are above the optimal <90 for CNS targets, but not drastically so. This is a moderate concern for both.

**3. logP:** Ligand A (1.449) is within the optimal range (1-3), while Ligand B (2.087) is also acceptable.

**4. H-Bond Donors:** Ligand A (1) and Ligand B (2) are both within the acceptable limit of <=5.

**5. H-Bond Acceptors:** Ligand A (5) and Ligand B (7) are both within the acceptable limit of <=10.

**6. QED:** Ligand B (0.812) has a significantly better QED score than Ligand A (0.487), indicating a more drug-like profile.

**7. DILI:** Ligand B (41.954) has a much lower DILI risk than Ligand A (60.915), which is a significant advantage.

**8. BBB:** Ligand B (88.135) has a substantially higher BBB penetration percentile than Ligand A (28.848). This is *critical* for a CNS target like DRD2.

**9. Caco-2 Permeability:** Both have negative values, which is unusual. Assuming these are logP-scale values, they suggest poor permeability. Ligand A (-4.969) is slightly better than Ligand B (-5.101), but both are concerning.

**10. Aqueous Solubility:** Both have negative values, suggesting very poor solubility. Ligand A (-2.745) is slightly better than Ligand B (-2.957).

**11. hERG Inhibition:** Ligand A (0.05) has a slightly lower hERG risk than Ligand B (0.669), which is a minor advantage.

**12. Microsomal Clearance:** Ligand B (30.502) has a lower microsomal clearance than Ligand A (17.927), suggesting better metabolic stability.

**13. In vitro Half-Life:** Ligand B (24.703) has a much longer in vitro half-life than Ligand A (-15.571). This is a significant advantage.

**14. P-gp Efflux:** Ligand A (0.088) has lower P-gp efflux liability than Ligand B (0.022), which is a minor advantage.

**15. Binding Affinity:** Ligand A (-7.8 kcal/mol) has a slightly better binding affinity than Ligand B (-7.6 kcal/mol). This is a small advantage, but not overwhelming.

**Overall Assessment:**

Ligand B is the superior candidate. While Ligand A has a slightly better binding affinity and P-gp efflux, Ligand B excels in crucial ADME properties for CNS drug development: significantly better BBB penetration, lower DILI risk, improved QED, and a longer half-life. The substantial difference in BBB penetration is the most important factor, outweighing the small affinity difference. The slightly better metabolic stability of Ligand B is also a positive. Both compounds have poor solubility and permeability, which would need to be addressed in further optimization, but Ligand B's profile is more promising overall.

Output:
1
2025-04-17 04:29:16,251 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (368.861 and 361.511 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (68.73) is slightly higher than Ligand B (61.44), but both are below the 90 A^2 threshold desirable for CNS targets.

**3. logP:** Ligand A (3.331) is slightly higher than Ligand B (2.803), both are within the optimal 1-3 range.

**4. H-Bond Donors:** Ligand A (0) has fewer HBDs than Ligand B (2), which is generally favorable for BBB penetration.

**5. H-Bond Acceptors:** Ligand A (5) has fewer HBAs than Ligand B (6).

**6. QED:** Both ligands have similar and good QED values (0.762 and 0.775, respectively).

**7. DILI:** Ligand A (46.297) has a lower DILI risk than Ligand B (56.301), indicating a potentially safer profile. Both are below the concerning threshold of 60.

**8. BBB:** Ligand B (78.829) has a slightly better BBB penetration percentile than Ligand A (73.672), but both are above the 70% threshold for CNS targets.

**9. Caco-2 Permeability:** Ligand A (-4.438) has a more negative Caco-2 value, implying better intestinal absorption than Ligand B (-4.971).

**10. Aqueous Solubility:** Both ligands have poor aqueous solubility (-3.553 and -4.166 respectively). This could pose formulation challenges, but is less critical for CNS drugs that can utilize alternative transport mechanisms.

**11. hERG Inhibition:** Ligand A (0.418) has a lower hERG inhibition liability than Ligand B (0.866), indicating a lower risk of cardiotoxicity.

**12. Microsomal Clearance:** Ligand A (66.133) has a higher microsomal clearance than Ligand B (13.225), indicating lower metabolic stability. This is a significant drawback for Ligand A.

**13. In vitro Half-Life:** Ligand B (63.512) has a significantly longer in vitro half-life than Ligand A (6.431), which is a major advantage.

**14. P-gp Efflux:** Ligand A (0.149) has lower P-gp efflux liability than Ligand B (0.35), which is favorable for CNS exposure.

**15. Binding Affinity:** Ligand B (-8.9 kcal/mol) has a stronger binding affinity than Ligand A (-7.9 kcal/mol), a difference of 1 kcal/mol. This is a substantial advantage.

**Overall Assessment:**

While Ligand A has some favorable properties (lower DILI, lower P-gp efflux, better Caco-2 permeability), Ligand B is the stronger candidate. The key advantages of Ligand B are its significantly better metabolic stability (lower Cl_mic, longer t1/2) and superior binding affinity. The slightly better BBB of Ligand B is also a plus. The solubility issues are present in both and can be addressed with formulation strategies. The affinity difference outweighs the minor drawbacks of Ligand B.

Output:
1
2025-04-17 04:29:16,251 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (491.585 Da) is towards the upper end, while Ligand B (352.435 Da) is comfortably within.

**TPSA:** Ligand A (54.02) is excellent for CNS penetration, well below the 90 A^2 threshold. Ligand B (96.55) is higher, but still potentially acceptable, though less ideal.

**logP:** Ligand A (4.751) is slightly high, potentially leading to solubility issues and off-target interactions. Ligand B (0.881) is quite low, which could hinder membrane permeability and CNS penetration.

**H-Bond Donors/Acceptors:** Both ligands have 2 HBD and reasonable HBA counts (3 and 5 respectively). This is acceptable.

**QED:** Both ligands have good QED scores (0.369 and 0.759), suggesting reasonable drug-likeness. Ligand B is better here.

**DILI:** Ligand A (82.241) has a higher DILI risk than Ligand B (52.695).

**BBB:** Ligand A (61.535) has a moderate BBB penetration, while Ligand B (45.56) is lower. For a CNS target like DRD2, higher BBB is strongly preferred.

**Caco-2 Permeability:** Ligand A (-4.944) has poor Caco-2 permeability, while Ligand B (-5.033) is also poor.

**Aqueous Solubility:** Ligand A (-6.293) has very poor aqueous solubility. Ligand B (-1.554) is also poor, but better than A.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.621 and 0.226).

**Microsomal Clearance:** Ligand A (28.527) has higher microsomal clearance than Ligand B (3.612), indicating lower metabolic stability.

**In vitro Half-Life:** Ligand B (-14.673) has a significantly longer in vitro half-life than Ligand A (50.772).

**P-gp Efflux:** Ligand A (0.217) has lower P-gp efflux than Ligand B (0.012), which is beneficial for CNS exposure.

**Binding Affinity:** Both ligands have excellent binding affinity (-9.7 and -8.1 kcal/mol). Ligand A is slightly better (-9.7 kcal/mol).

**Overall Assessment:**

Ligand A has a better binding affinity and lower P-gp efflux, but suffers from high logP, poor solubility, poor Caco-2 permeability, higher DILI risk, and faster metabolic clearance. Ligand B has better solubility, lower DILI, better metabolic stability, and a longer half-life, but has a lower BBB score and a lower binding affinity.

Given the GPCR-specific priorities, BBB penetration is crucial for DRD2. While Ligand A has a slightly better affinity, its poor solubility, permeability, and moderate BBB score are significant drawbacks. Ligand B, despite the lower affinity, presents a more balanced profile with better ADME properties, particularly its improved metabolic stability and lower DILI risk. The affinity difference of 1.6 kcal/mol, while noticeable, is likely outweighed by the ADME advantages of Ligand B.

Output:
1
2025-04-17 04:29:16,251 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (354.479 and 362.459 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (51.02) is excellent, well below the 90 A^2 threshold for CNS targets. Ligand B (117) is higher, but still potentially acceptable, though less ideal.

**logP:** Ligand A (3.313) is optimal. Ligand B (1.21) is a bit low, potentially hindering membrane permeability.

**H-Bond Donors/Acceptors:** Ligand A (0 HBD, 5 HBA) is good. Ligand B (3 HBD, 6 HBA) is also reasonable.

**QED:** Both ligands have good QED scores (0.661 and 0.756), indicating drug-like properties.

**DILI:** Both ligands have elevated DILI risk (60.062 and 65.529), which is a concern, but not disqualifying at this stage.

**BBB:** Ligand A excels with a BBB percentile of 73.827, very desirable for a CNS target. Ligand B's BBB percentile (48.391) is significantly lower and less favorable.

**Caco-2 Permeability:** Both have negative Caco-2 values (-5.112 and -5.545), which is unusual and suggests poor permeability. This is a significant drawback for both.

**Aqueous Solubility:** Both have negative solubility values (-2.543 and -2.643), also unusual and indicating poor aqueous solubility.

**hERG Inhibition:** Both ligands show low hERG inhibition risk (0.675 and 0.575).

**Microsomal Clearance:** Ligand A (51.876) has higher clearance than Ligand B (-24.182), suggesting lower metabolic stability. Ligand B has a negative value, which is unusual and could indicate very high stability or an issue with the prediction.

**In vitro Half-Life:** Ligand A (-19.841) has a negative half-life, which is not physically possible and indicates a problem with the prediction. Ligand B (-26.19) also has a negative half-life.

**P-gp Efflux:** Ligand A (0.705) has moderate P-gp efflux, while Ligand B (0.169) has very low P-gp efflux, which is beneficial for CNS penetration.

**Binding Affinity:** Ligand A (-8.8 kcal/mol) has a significantly stronger binding affinity than Ligand B (-7.9 kcal/mol). This 0.9 kcal/mol difference is substantial.

**Overall Assessment:**

Despite the unusual negative values for Caco-2 and solubility, the significantly better BBB penetration and substantially stronger binding affinity of Ligand A make it the more promising candidate. The lower P-gp efflux of Ligand B is a plus, but it's outweighed by the poorer BBB score and weaker binding. The negative half-life values for both are concerning and require further investigation, but the affinity difference is a major factor.

Output:
0
2025-04-17 04:29:16,251 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (384.929 Da) is slightly higher than Ligand B (345.487 Da), but both are acceptable.

**TPSA:** Ligand A (50.8) is significantly better than Ligand B (75.43). For CNS targets, we want TPSA <= 90, and ideally closer to 60. Ligand A is much closer to the ideal range.

**logP:** Both ligands have good logP values (A: 3.334, B: 3.146), falling within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A (HBD=1, HBA=4) is slightly better than Ligand B (HBD=2, HBA=3) in terms of balancing solubility and permeability. Both are within acceptable limits.

**QED:** Ligand A (0.868) has a significantly higher QED score than Ligand B (0.561), indicating a more drug-like profile.

**DILI:** Ligand B (30.826) has a much lower DILI risk than Ligand A (60.644). This is a significant advantage for Ligand B.

**BBB:** Both ligands have good BBB penetration (A: 75.533, B: 71.772), exceeding the 70% threshold for CNS targets.

**Caco-2 Permeability:** Both have negative Caco-2 values which is unusual and suggests a potential issue with the data or modeling. However, the values are similar (-4.817 vs -4.988).

**Aqueous Solubility:** Both have negative solubility values which is also unusual. The values are similar (-4.213 vs -3.625).

**hERG:** Both ligands have low hERG inhibition liability (A: 0.466, B: 0.771), which is favorable.

**Microsomal Clearance:** Both ligands have similar microsomal clearance values (A: 51.744, B: 53.532).

**In vitro Half-Life:** Ligand A (38.195 hours) has a much longer half-life than Ligand B (10.05 hours), which is a significant advantage.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (A: 0.178, B: 0.107), which is good for CNS exposure.

**Binding Affinity:** Ligand A (-8.4 kcal/mol) has a slightly better binding affinity than Ligand B (-7.9 kcal/mol). While the difference is not huge, it is still a factor.

**Overall Assessment:**

Ligand A excels in TPSA, QED, and in vitro half-life, and has slightly better binding affinity. However, Ligand B has a significantly lower DILI risk. Considering the GPCR-specific priorities, BBB is good for both, logP is good for both, and Pgp is low for both. The TPSA of Ligand A is much more favorable for CNS penetration. The binding affinity difference is relatively small, and the longer half-life of Ligand A is a significant benefit. The DILI risk of Ligand B is concerning, but could be mitigated with further structural modifications. Given the importance of CNS penetration (low TPSA) and a reasonable binding affinity, Ligand A appears to be the more promising candidate.

Output:
1
2025-04-17 04:29:16,252 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (332.363 and 368.88 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (80.04) is excellent, well below the 90 A^2 threshold for CNS targets. Ligand B (49.41) is also very good, comfortably under the threshold.

**3. logP:** Both ligands have a logP around 3.3-3.4, which is optimal for permeability and avoiding off-target effects.

**4. H-Bond Donors:** Ligand A has 2 HBD, and Ligand B has 1. Both are within the acceptable limit of <=5.

**5. H-Bond Acceptors:** Ligand A has 5 HBA, and Ligand B has 2. Both are within the acceptable limit of <=10.

**6. QED:** Both ligands have QED values above 0.5 (0.598 and 0.553), indicating good drug-like properties.

**7. DILI:** Ligand A has a high DILI risk (98.216%), which is a significant concern. Ligand B has a much lower DILI risk (28.112%), making it more favorable.

**8. BBB:** Ligand A has a very low BBB penetration (25.979%), which is a major drawback for a CNS target like DRD2. Ligand B has a significantly higher BBB penetration (90.112%), which is highly desirable.

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.361 and -4.909), which is unusual and suggests poor permeability. However, these values are on a scale where negative values are possible and don't necessarily disqualify the compounds.

**10. Aqueous Solubility:** Both ligands have negative solubility values (-4.566 and -4.276), indicating poor aqueous solubility. This could pose formulation challenges.

**11. hERG Inhibition:** Both ligands show low hERG inhibition risk (0.209 and 0.378).

**12. Microsomal Clearance:** Ligand A has a lower Cl_mic (18.694) than Ligand B (38.194), suggesting better metabolic stability.

**13. In vitro Half-Life:** Ligand A has a longer half-life (44.494) than Ligand B (-6.522), which is generally preferred.

**14. P-gp Efflux:** Both ligands have low P-gp efflux liability (0.133 and 0.171), which is good for CNS exposure.

**15. Binding Affinity:** Both ligands have excellent binding affinities (-9.1 and -8.1 kcal/mol). Ligand A is slightly more potent.

**Overall Assessment:**

Despite Ligand A's slightly better affinity and metabolic stability, its extremely high DILI risk and very poor BBB penetration are major red flags. For a CNS target like DRD2, BBB penetration is crucial. Ligand B, while having slightly weaker affinity and poorer metabolic stability, has a much more acceptable DILI risk and excellent BBB penetration. The affinity difference (1 kcal/mol) is likely outweighed by the significant improvement in safety and CNS exposure.

Output:
1
2025-04-17 04:29:16,252 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 drug candidates, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (356.354 and 357.495 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (111.54) is slightly above the optimal <90 for CNS targets, but still reasonable. Ligand B (96.53) is excellent, well below 90.

**3. logP:** Ligand A (-0.557) is a bit low, potentially hindering permeability. Ligand B (2.206) is within the optimal 1-3 range. This is a significant advantage for Ligand B.

**4. H-Bond Donors:** Ligand A (2) and Ligand B (3) are both acceptable, below the threshold of 5.

**5. H-Bond Acceptors:** Ligand A (6) and Ligand B (4) are both acceptable, below the threshold of 10.

**6. QED:** Both ligands have reasonable QED values (0.659 and 0.522), indicating good drug-like properties.

**7. DILI:** Ligand A (56.572) has a moderate DILI risk, but is acceptable. Ligand B (21.52) has a much lower DILI risk, which is highly favorable.

**8. BBB:** Ligand A (57.619) has a low BBB penetration percentile, which is a major drawback for a CNS target like DRD2. Ligand B (77.2) shows good BBB penetration, exceeding the desirable >70 threshold. This is a critical advantage for Ligand B.

**9. Caco-2:** Both ligands have negative Caco-2 values (-5.113 and -4.794), which is unusual and suggests poor permeability. However, these values are on a different scale and are difficult to interpret directly.

**10. Solubility:** Both ligands have negative solubility values (-1.81 and -2.57), which is also unusual and suggests poor solubility.

**11. hERG:** Both ligands have low hERG inhibition liability (0.19 and 0.613), which is good.

**12. Cl_mic:** Ligand A (-7.195) has a lower (better) microsomal clearance than Ligand B (59.321), indicating greater metabolic stability.

**13. t1/2:** Ligand A (-15.121) has a negative in vitro half-life, which is not possible and indicates an issue with the data. Ligand B (-23.98) also has a negative value, suggesting data quality concerns.

**14. Pgp:** Both ligands have very low Pgp efflux liability (0.029 and 0.037), which is favorable for CNS penetration.

**15. Binding Affinity:** Ligand B (-7.3) has slightly better binding affinity than Ligand A (-8.1). While the difference is small, it's in the right direction.

**Overall Assessment:**

Ligand B is significantly more promising. Its superior BBB penetration, better logP, and lower DILI risk outweigh the slightly worse metabolic stability (Cl_mic) and the small difference in binding affinity. The negative values for Caco-2 and solubility are concerning for both, but the other advantages of Ligand B make it the better candidate. The negative half-life values for both are suspect and would need to be investigated.

Output:
1
2025-04-17 04:29:16,252 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (349.431 and 342.527 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (86.88) is excellent, falling well below the 90 A^2 threshold for CNS targets. Ligand B (32.34) is also very good.

**logP:** Ligand A (1.237) is within the optimal 1-3 range. Ligand B (4.124) is slightly above, potentially raising concerns about solubility and off-target effects, but still acceptable.

**H-Bond Donors/Acceptors:** Both ligands have 1 HBD and a reasonable number of HBAs (5 for A, 2 for B), satisfying the <5 HBD and <10 HBA guidelines.

**QED:** Ligand A (0.884) has a very strong drug-like profile. Ligand B (0.732) is also good, but slightly lower.

**DILI:** Ligand A (37.922) has a low DILI risk. Ligand B (14.23) has an even lower risk, which is a significant advantage.

**BBB:** Ligand A (50.872) has moderate BBB penetration, which is not ideal for a CNS target. Ligand B (87.127) has excellent BBB penetration, exceeding the desirable >70 percentile. This is a major advantage.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.514 and -4.578), which is unusual and suggests poor permeability. However, these values are on a log scale and can be difficult to interpret without further information.

**Aqueous Solubility:** Both ligands have negative solubility values (-1.051 and -4.376), indicating poor aqueous solubility. This is a concern for both compounds.

**hERG Inhibition:** Ligand A (0.285) has a very low hERG risk. Ligand B (0.776) has a slightly higher, but still acceptable, hERG risk.

**Microsomal Clearance:** Ligand A (43.628) has moderate clearance. Ligand B (81.051) has higher clearance, suggesting lower metabolic stability.

**In vitro Half-Life:** Ligand A (-24.296) has a negative half-life, which is not physically possible and suggests an issue with the data. Ligand B (22.834) has a reasonable half-life.

**P-gp Efflux:** Ligand A (0.131) has low P-gp efflux, which is good for CNS penetration. Ligand B (0.512) has slightly higher P-gp efflux, but still acceptable.

**Binding Affinity:** Ligand B (-9.0 kcal/mol) has a significantly stronger binding affinity than Ligand A (-8.6 kcal/mol). This >1.5 kcal/mol difference is substantial and can outweigh some ADME drawbacks.

**Overall Assessment:**

Ligand B is the more promising candidate. While it has slightly higher logP and clearance, its significantly better BBB penetration and substantially stronger binding affinity are crucial for a CNS-targeting GPCR like DRD2. The lower DILI risk is also a plus. The negative half-life for Ligand A is a major red flag, and its lower BBB penetration is a significant disadvantage. The solubility issues are a concern for both, but can potentially be addressed through formulation strategies.



Output:
1
2025-04-17 04:29:16,252 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (348.45 & 349.44 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (78.68) is significantly better than Ligand B (126.21). For CNS targets, we want TPSA <= 90, and A is comfortably within that, while B is above.

**3. logP:** Both ligands have acceptable logP values (1.61 & 0.74), falling within the 1-3 range.

**4. H-Bond Donors:** Ligand A (1) is preferable to Ligand B (4). Fewer HBDs generally improve permeability.

**5. H-Bond Acceptors:** Ligand A (5) is preferable to Ligand B (4).

**6. QED:** Ligand A (0.875) is significantly better than Ligand B (0.49), indicating a more drug-like profile.

**7. DILI:** Both ligands have low DILI risk (21.13 & 23.89), both well below the 40 threshold.

**8. BBB:** Both ligands have excellent BBB penetration (71.89% & 71.04%), exceeding the desirable 70% threshold for CNS targets.

**9. Caco-2 Permeability:** Ligand A (-4.857) is better than Ligand B (-5.614), indicating better intestinal absorption.

**10. Aqueous Solubility:** Both ligands have poor aqueous solubility (-1.6 & -1.805). This is a potential issue, but less critical for CNS drugs where BBB penetration is prioritized.

**11. hERG Inhibition:** Both ligands show very low hERG inhibition risk (0.255 & 0.134).

**12. Microsomal Clearance:** Ligand A (-6.545) has a much lower (better) microsomal clearance than Ligand B (8.182), indicating greater metabolic stability.

**13. In vitro Half-Life:** Ligand A (4.346) has a slightly better in vitro half-life than Ligand B (3.407).

**14. P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.023 & 0.007).

**15. Binding Affinity:** Ligand A (-8.4 kcal/mol) has a stronger binding affinity than Ligand B (-7.7 kcal/mol). This 0.7 kcal/mol difference is significant, exceeding the 1.5 kcal/mol threshold where affinity can outweigh other drawbacks.

**Overall Assessment:**

Ligand A is superior to Ligand B across most key parameters. It has a lower TPSA, better QED, lower microsomal clearance, better Caco-2 permeability, and a significantly stronger binding affinity. While both have acceptable BBB penetration and low DILI/hERG risk, the improvements in ADME properties and binding affinity make Ligand A the more promising drug candidate.

Output:
1
2025-04-17 04:29:16,252 - INFO - Okay, let's analyze these two ligands for their potential as DRD2 drug candidates.

**Step-by-step comparison:**

1. **MW:** Both ligands (A: 355.777 Da, B: 364.515 Da) fall within the ideal 200-500 Da range. No significant difference here.

2. **TPSA:** Both ligands (A: 76.23, B: 76.44) are below the 90 A^2 threshold for CNS targets, which is excellent. Very similar values.

3. **logP:** Ligand A (3.741) is higher than Ligand B (1.25). Ligand A is at the upper end of the optimal range, while Ligand B is slightly below. For a GPCR targeting the CNS, a higher logP is generally preferred to aid in membrane permeability and BBB penetration, but we must consider other factors.

4. **HBD:** Both ligands have 1 HBD, which is within the acceptable limit of <=5.

5. **HBA:** Ligand A has 4 HBA, and Ligand B has 5. Both are within the acceptable limit of <=10.

6. **QED:** Both ligands have good QED scores (A: 0.571, B: 0.718), indicating good drug-like properties. Ligand B is slightly better.

7. **DILI:** Ligand A has a high DILI risk (93.525%), while Ligand B has a very low risk (16.712%). This is a *major* advantage for Ligand B. DILI is a significant concern in drug development.

8. **BBB:** Ligand B (57.154%) has a significantly better BBB percentile than Ligand A (44.979%). While both are below the ideal >70% for CNS targets, Ligand B is closer.

9. **Caco-2:** Ligand A (-4.88) has a worse Caco-2 permeability than Ligand B (-5.227). Lower values indicate poorer permeability.

10. **Solubility:** Ligand A (-5.149) has worse solubility than Ligand B (-2.247). Solubility is important for formulation and bioavailability.

11. **hERG:** Both ligands have low hERG inhibition liability (A: 0.189, B: 0.486), which is good.

12. **Cl_mic:** Ligand B (34.975) has a lower microsomal clearance than Ligand A (68.229), indicating better metabolic stability.

13. **t1/2:** Ligand B (-1.448) has a negative in vitro half-life, which is concerning. Ligand A (30.934) has a reasonable half-life. However, negative values are often artifacts of the prediction method and should be interpreted cautiously.

14. **Pgp:** Ligand A (0.385) has lower P-gp efflux liability than Ligand B (0.011). Lower Pgp is preferred, especially for CNS targets.

15. **Binding Affinity:** Ligand A (-10.7 kcal/mol) has a *much* stronger binding affinity than Ligand B (-7.4 kcal/mol). This is a substantial difference (3.3 kcal/mol), and a significant advantage for Ligand A.

**GPCR-Specific Priorities & Overall Assessment:**

For a GPCR like DRD2, BBB penetration, logP, Pgp efflux, TPSA, and affinity are key. While Ligand B has better BBB, solubility, metabolic stability, and a lower DILI risk, Ligand A's *significantly* stronger binding affinity is a major factor. The difference in affinity is large enough to potentially overcome some of the ADME liabilities of Ligand A. The high DILI risk of Ligand A is concerning, but could potentially be mitigated through structural modifications during lead optimization. The lower Pgp efflux of ligand A is also beneficial.

Considering the balance, the superior binding affinity of Ligand A outweighs the ADME drawbacks, especially given that those drawbacks can be addressed in subsequent optimization rounds.

Output:
1
2025-04-17 04:29:16,253 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (358.471 and 364.837 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (76.8) is significantly better than Ligand B (104.7). For CNS targets, we want TPSA <= 90, and A is comfortably within that, while B is above.

**logP:** Both ligands have acceptable logP values (3.143 and 1.653), falling within the 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A (0 HBD, 7 HBA) is slightly better than Ligand B (3 HBD, 5 HBA) in terms of balancing solubility and permeability.

**QED:** Both ligands have similar, good QED values (0.7 and 0.724).

**DILI:** Ligand A (77.472) has a higher DILI risk than Ligand B (65.374), but both are reasonably acceptable.

**BBB:** Ligand A (61.535) has a slightly better BBB penetration percentile than Ligand B (58.511), but both are below the desirable >70 for CNS targets. This is a critical factor.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.269 and -5.749), which is unusual and potentially problematic. It suggests poor permeability.

**Aqueous Solubility:** Both ligands have negative solubility values (-3.146 and -2.814), also unusual and concerning for bioavailability.

**hERG:** Both ligands have very low hERG inhibition liability (0.296 and 0.177), which is excellent.

**Microsomal Clearance:** Ligand A (71.179) has higher microsomal clearance than Ligand B (-6.109). Lower is better for metabolic stability, so B is preferable here.

**In vitro Half-Life:** Both ligands have similar in vitro half-lives (32.409 and 32.088 hours).

**P-gp Efflux:** Ligand A (0.446) has slightly better P-gp efflux liability than Ligand B (0.046), meaning less efflux and potentially better CNS exposure.

**Binding Affinity:** Ligand B (-8.8 kcal/mol) has a slightly better binding affinity than Ligand A (-8.4 kcal/mol). While the difference is small, it is still a factor.

**Overall Assessment:**

Considering the GPCR-specific priorities, TPSA is a key differentiator. Ligand A's lower TPSA is a significant advantage for CNS penetration. While Ligand B has slightly better affinity and lower clearance, the higher TPSA and slightly worse P-gp efflux are drawbacks. The negative Caco-2 and solubility values are concerning for both, but the TPSA difference is more critical for a CNS target like DRD2.

Output:
1
2025-04-17 04:29:16,253 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (351.76 and 365.50 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Both ligands have TPSA values around 98-99 A<sup>2</sup>, which is acceptable but pushing the upper limit for CNS penetration. Ideally, we'd like to be below 90 A<sup>2</sup>.

**3. logP:** Both ligands have logP values around 2.5-2.7, which is within the optimal 1-3 range.

**4. H-Bond Donors:** Both have 1 HBD, which is good.

**5. H-Bond Acceptors:** Ligand A has 7 HBA, and Ligand B has 4 HBA. Both are acceptable, being under the 10 threshold.

**6. QED:** Ligand A (0.609) has a significantly better QED score than Ligand B (0.351), indicating a more drug-like profile.

**7. DILI:** Ligand A has a very high DILI risk (99.8%), which is a major red flag. Ligand B has a much lower DILI risk (26.6%), which is favorable.

**8. BBB:** Ligand A (50.5%) and Ligand B (55.2%) both have BBB penetration scores that are not ideal for a CNS target (ideally >70%). However, they are relatively close.

**9. Caco-2:** Both ligands have negative Caco-2 values, which is unusual and suggests poor permeability.

**10. Solubility:** Both ligands have negative solubility values, indicating poor aqueous solubility.

**11. hERG:** Both ligands have low hERG inhibition liability, which is good.

**12. Cl_mic:** Ligand A (58.43 mL/min/kg) has a slightly higher microsomal clearance than Ligand B (49.26 mL/min/kg), suggesting slightly lower metabolic stability.

**13. t1/2:** Ligand A (31.6 hours) has a significantly longer in vitro half-life than Ligand B (13.7 hours), which is a positive attribute.

**14. Pgp:** Ligand A (0.145) has lower P-gp efflux liability than Ligand B (0.046), which is favorable for CNS penetration.

**15. Binding Affinity:** Ligand B (-7.3 kcal/mol) has a significantly stronger binding affinity than Ligand A (-10.1 kcal/mol). This is a substantial advantage, potentially outweighing some ADME drawbacks.

**Overall Assessment:**

While Ligand A has a better QED, longer half-life and lower Pgp efflux, its extremely high DILI risk is a deal-breaker. The DILI risk is far too high to proceed with this molecule. Ligand B, despite its lower QED and shorter half-life, has a much more acceptable DILI profile and, crucially, a significantly better binding affinity. The affinity difference of 2.8 kcal/mol is substantial. Although both ligands have suboptimal BBB and solubility, the stronger binding of Ligand B makes it more likely to achieve sufficient target engagement *in vivo*.

Output:
1
2025-04-17 04:29:16,253 - INFO - Reasoning:

Let's analyze Ligand A and Ligand B against the provided guidelines, prioritizing GPCR-specific properties (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (360.479 and 374.547 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (58.64) is significantly better than Ligand B (75.71). For CNS targets, TPSA should be <= 90, both are within this range, but A is preferable.

**logP:** Both ligands have good logP values (2.287 and 2.006), falling within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Both ligands have 1 HBD and 4 HBA, which are acceptable.

**QED:** Ligand A (0.82) has a better QED score than Ligand B (0.705), indicating a more drug-like profile.

**DILI:** Ligand A (38.503) has a slightly higher DILI risk than Ligand B (22.14), but both are below the concerning threshold of 60.

**BBB:** Both ligands exhibit excellent BBB penetration (71.617 and 76.813), exceeding the desirable >70 threshold for CNS targets.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.808 and -4.888). These values are unusual and difficult to interpret without context, but suggest poor permeability.

**Aqueous Solubility:** Both ligands have negative solubility values (-3.379 and -2.446), indicating poor aqueous solubility.

**hERG Inhibition:** Both ligands show low hERG inhibition liability (0.406 and 0.533), which is favorable.

**Microsomal Clearance:** Ligand A (-2.835) has a much lower (better) microsomal clearance than Ligand B (66.81). This suggests better metabolic stability for Ligand A.

**In vitro Half-Life:** Ligand A (13.942 hours) has a significantly longer half-life than Ligand B (-35.058 hours). The negative value for B is concerning and likely an error or indicates very rapid degradation.

**P-gp Efflux:** Ligand A (0.407) has lower P-gp efflux liability than Ligand B (0.039), which is beneficial for CNS exposure.

**Binding Affinity:** Ligand B (-7.5 kcal/mol) has a slightly better binding affinity than Ligand A (-7.3 kcal/mol), but the difference is marginal (0.2 kcal/mol).

**Overall Assessment:**

Considering the GPCR-specific priorities, Ligand A is the more promising candidate. While Ligand B has slightly better binding affinity, Ligand A demonstrates superior drug-like properties (higher QED), better metabolic stability (lower Cl_mic, longer t1/2), lower P-gp efflux, and a more favorable TPSA. The negative solubility and Caco-2 values are concerning for both, but the other advantages of A outweigh the small affinity difference. The negative half-life for Ligand B is a major red flag.

Output:
1
2025-04-17 04:29:16,253 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (343.427 and 347.459 Da) fall comfortably within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (66.65) is significantly better than Ligand B (84.23). For CNS targets, we want TPSA <= 90, and A is closer to the optimal <=60 range. B is pushing the upper limit.

**3. logP:** Both ligands have good logP values (2.322 and 2.68), falling within the 1-3 optimal range.

**4. H-Bond Donors:** Ligand A (0) is preferable to Ligand B (2). Fewer HBDs generally improve permeability.

**5. H-Bond Acceptors:** Both ligands have 4 HBA, which is acceptable (<=10).

**6. QED:** Both ligands have good QED scores (0.773 and 0.858), indicating good drug-like properties.

**7. DILI:** Ligand A (31.524) has a much lower DILI risk than Ligand B (53.47). Both are below 60, but A is significantly better.

**8. BBB:** This is crucial for a CNS target like DRD2. Ligand A (91.198) is excellent, exceeding the desirable >70 threshold. Ligand B (69.988) is lower and less favorable.

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.759 and -4.804), which is unusual and suggests poor permeability. However, these values are on a log scale, so the absolute difference is small.

**10. Aqueous Solubility:** Both ligands have very poor aqueous solubility (-1.812 and -3.727). This is a significant drawback for both.

**11. hERG:** Both ligands have low hERG inhibition liability (0.377 and 0.339), which is good.

**12. Microsomal Clearance:** Both have similar microsomal clearance (42.148 and 46.656 mL/min/kg). Neither is ideal, suggesting moderate metabolic liability.

**13. In vitro Half-Life:** Ligand A (-17.484) has a very short half-life, while Ligand B (4.674) is slightly better, but still not great.

**14. P-gp Efflux:** Both have low P-gp efflux liability (0.173 and 0.348), which is good for CNS penetration.

**15. Binding Affinity:** Ligand B (-9.4 kcal/mol) has a slightly better binding affinity than Ligand A (-8.9 kcal/mol). However, the difference is only 0.5 kcal/mol, which is not substantial enough to overcome the significant ADME advantages of Ligand A.

**Overall:**

Ligand A is the better candidate. While both have solubility and metabolic stability concerns, Ligand A excels in crucial areas for a CNS-targeting GPCR ligand: TPSA, BBB penetration, and DILI risk. The slightly better affinity of Ligand B is outweighed by these factors.

Output:
0
2025-04-17 04:29:16,254 - INFO - Reasoning:

Let's analyze Ligand A and Ligand B for their potential as DRD2 drug candidates, considering the provided guidelines and GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight (MW):** Both ligands (365.861 and 367.471 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (56.59) is significantly better than Ligand B (93.46). For CNS targets, TPSA should be <= 90, and A is comfortably within this range, while B is slightly above. This is a significant advantage for A.

**3. logP:** Ligand A (3.716) is optimal, while Ligand B (1.377) is on the lower side. While not terrible, lower logP can hinder membrane permeability.

**4. H-Bond Donors (HBD):** Both ligands have acceptable HBD counts (0 for A, 2 for B), well below the threshold of 5.

**5. H-Bond Acceptors (HBA):** Both ligands have acceptable HBA counts (5 for A, 6 for B), well below the threshold of 10.

**6. QED:** Both ligands have similar QED values (0.758 and 0.721), indicating good drug-like properties.

**7. DILI:** Both ligands have low DILI risk (49.128 and 43.195), both well below the concerning threshold of 60.

**8. BBB:** Ligand A (77.821) has a better BBB percentile than Ligand B (68.941). While both are reasonably good, a value >70 is desirable for CNS targets, and A is closer.

**9. Caco-2 Permeability:** Ligand A (-4.594) has worse Caco-2 permeability than Ligand B (-5.37). Lower values indicate lower permeability, so B is slightly better here.

**10. Aqueous Solubility:** Ligand A (-3.513) has slightly better aqueous solubility than Ligand B (-2.838).

**11. hERG Inhibition:** Both ligands show low hERG inhibition risk (0.68 and 0.269).

**12. Microsomal Clearance (Cl_mic):** Ligand B (44.479) has lower microsomal clearance than Ligand A (67.946), suggesting better metabolic stability.

**13. In vitro Half-Life:** Ligand A (28.452) has a longer in vitro half-life than Ligand B (0.562). This is a significant advantage for A.

**14. P-gp Efflux:** Ligand A (0.4) has lower P-gp efflux liability than Ligand B (0.049), which is favorable for CNS penetration.

**15. Binding Affinity:** Ligand B (-7.6 kcal/mol) has a slightly better binding affinity than Ligand A (-8.2 kcal/mol). While A is already very good, B's affinity is marginally stronger.

**Overall Assessment:**

Considering the GPCR-specific priorities, Ligand A is the more promising candidate. It excels in TPSA, logP, BBB penetration, and in vitro half-life. While Ligand B has slightly better affinity and metabolic stability, the advantages of A in CNS penetration (TPSA, BBB, P-gp) and overall drug-like properties outweigh these minor differences. The slightly better affinity of B is unlikely to overcome A's superior predicted CNS exposure.

Output:
1
2025-04-17 04:29:16,254 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (353.805 and 350.415 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (44.49) is significantly better than Ligand B (77.96). For CNS targets, we want TPSA <= 90, and A is comfortably within that range, while B is approaching the upper limit.

**logP:** Ligand A (4.894) is higher than the optimal 1-3 range, potentially causing solubility issues and off-target effects. Ligand B (1.429) is within the optimal range.

**H-Bond Donors/Acceptors:** Both have acceptable HBD counts (0). Ligand A has 4 HBA, and Ligand B has 6. Both are below the 10 threshold.

**QED:** Both ligands have good QED values (0.612 and 0.722), indicating drug-like properties.

**DILI:** Ligand A (82.668) has a higher DILI risk than Ligand B (50.679). Both are acceptable, but B is preferable.

**BBB:** Ligand B (72.586) has a significantly better BBB penetration percentile than Ligand A (54.246). This is a *critical* factor for a CNS target like DRD2.

**Caco-2 Permeability:** Both have negative Caco-2 values (-4.642 and -4.28), which is unusual and suggests poor permeability. This is a concern for both.

**Aqueous Solubility:** Both have negative solubility values (-6.229 and -1.134), indicating poor aqueous solubility. This is a significant drawback for both.

**hERG Inhibition:** Ligand A (0.629) has a slightly higher hERG inhibition risk than Ligand B (0.137), making B more favorable.

**Microsomal Clearance:** Ligand A (63.874) has a higher microsomal clearance than Ligand B (53.818), suggesting lower metabolic stability.

**In vitro Half-Life:** Ligand B (-25.288) has a negative half-life, which is impossible and indicates a significant issue with the data or the compound itself. Ligand A (35.452) is reasonable.

**P-gp Efflux:** Ligand A (0.713) has higher P-gp efflux than Ligand B (0.049). Lower P-gp efflux is preferred for CNS penetration, so B is better.

**Binding Affinity:** Ligand A (-9.4 kcal/mol) has a substantially stronger binding affinity than Ligand B (-6.6 kcal/mol). This is a >1.5 kcal/mol difference, which can outweigh some ADME drawbacks.

**Overall Assessment:**

Despite Ligand A's superior binding affinity, Ligand B presents a more balanced profile for a CNS-targeting GPCR. The significantly better BBB penetration, lower P-gp efflux, lower DILI risk, and lower hERG risk are crucial advantages. The negative half-life for Ligand B is a major red flag, making it unlikely to be a viable candidate. While both have poor solubility and permeability, the stronger affinity of Ligand A might be able to overcome these issues with formulation strategies.

Output:
1
2025-04-17 04:29:16,254 - INFO - Batch 117 complete. Total preferences: 1872
2025-04-17 04:29:16,254 - INFO - Processing batch 118/512...
2025-04-17 04:29:58,451 - INFO - Reasoning:

Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (348.443 and 374.457 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (81.43) is slightly higher than Ligand B (76.14), but both are below the 90 A^2 threshold desirable for CNS targets.

**logP:** Both ligands have logP values around 3 (2.962 and 3.011), which is optimal for permeability and avoiding solubility issues.

**H-Bond Donors/Acceptors:** Ligand A (HBD=1, HBA=5) and Ligand B (HBD=2, HBA=6) both have acceptable numbers of H-bond donors and acceptors.

**QED:** Ligand A (0.799) has a slightly higher QED score than Ligand B (0.65), indicating better overall drug-likeness.

**DILI:** Ligand A (20.396) has a significantly lower DILI risk than Ligand B (59.442). This is a substantial advantage.

**BBB:** Ligand B (85.692) has a notably higher BBB penetration percentile than Ligand A (71.694). This is a critical factor for a CNS target like DRD2.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.373 and -4.664), which is unusual and suggests poor permeability. However, these values are on a scale where negative values are possible, and a direct comparison is difficult without knowing the scale's specifics.

**Aqueous Solubility:** Both ligands have negative solubility values (-3.634 and -3.984), indicating poor aqueous solubility.

**hERG Inhibition:** Both ligands have low hERG inhibition liability (0.152 and 0.279), which is good.

**Microsomal Clearance:** Ligand A (104.646) has higher microsomal clearance than Ligand B (62.192), suggesting lower metabolic stability.

**In vitro Half-Life:** Ligand B (-7.152) has a longer in vitro half-life than Ligand A (-15.93), which is preferable.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.12 and 0.168), which is good for CNS exposure.

**Binding Affinity:** Both ligands have very similar binding affinities (-8.3 and -8.1 kcal/mol). The difference is minimal.

**Overall Assessment:**

Ligand B is superior in terms of BBB penetration and in vitro half-life. However, Ligand A has a much lower DILI risk and a slightly better QED score. Given the importance of minimizing toxicity (DILI) and the relatively small difference in binding affinity, Ligand A is the more promising candidate. The slightly better BBB of Ligand B is outweighed by the significantly higher DILI risk. The poor Caco-2 and solubility values are concerning for both, but can be addressed with formulation strategies.

Output:
0
2025-04-17 04:29:58,451 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (343.343 and 384.929 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (122.14) is better than Ligand B (49.85). For CNS targets, we want TPSA <= 90, so Ligand B is significantly better.

**3. logP:** Both ligands have similar logP values (3.15 and 3.169), falling within the optimal range of 1-3.

**4. H-Bond Donors:** Ligand A has 3 HBD, and Ligand B has 0. Both are acceptable (<=5).

**5. H-Bond Acceptors:** Ligand A has 6 HBA, and Ligand B has 5. Both are acceptable (<=10).

**6. QED:** Both ligands have good QED values (0.671 and 0.731), indicating drug-like properties.

**7. DILI:** Ligand A has a higher DILI risk (95.89%) compared to Ligand B (37.03%). This is a significant negative for Ligand A.

**8. BBB:** Ligand B (82.862%) has a much better BBB penetration percentile than Ligand A (31.834%). This is crucial for a CNS target like DRD2.

**9. Caco-2 Permeability:** Ligand A (-5.08) has worse Caco-2 permeability than Ligand B (-4.603). Higher values are better.

**10. Aqueous Solubility:** Ligand A (-4.91) has worse aqueous solubility than Ligand B (-3.573). Higher values are better.

**11. hERG:** Both ligands have similar hERG inhibition liability (0.545 and 0.678), which is acceptable.

**12. Microsomal Clearance:** Ligand B (98.981) has a significantly higher microsomal clearance than Ligand A (41.622). Lower clearance is preferred for better metabolic stability.

**13. In vitro Half-Life:** Ligand A (86.983) has a much longer in vitro half-life than Ligand B (-4.992). Longer half-life is generally desirable.

**14. P-gp Efflux:** Ligand A (0.053) has lower P-gp efflux than Ligand B (0.355). Lower efflux is preferred for CNS exposure.

**15. Binding Affinity:** Ligand B (-7.2 kcal/mol) has a slightly better binding affinity than Ligand A (-8.1 kcal/mol). While both are good, the difference is not substantial enough to outweigh other factors.

**Overall Assessment:**

Ligand B is the more promising candidate. While Ligand A has slightly better binding affinity and half-life, Ligand B excels in critical areas for a CNS-targeting GPCR: significantly better BBB penetration, lower DILI risk, and lower P-gp efflux. The lower TPSA of Ligand B is also a benefit. The higher metabolic clearance of Ligand B is a concern, but could potentially be addressed through structural modifications.

Output:
1
2025-04-17 04:29:58,451 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (382.917 and 354.422 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (67.23) is better than Ligand B (75.71). For CNS targets, we want TPSA <= 90, both are within this range, but A is closer to the optimal value.

**3. logP:** Both ligands have good logP values (1.96 and 2.112), falling within the 1-3 range.

**4. H-Bond Donors:** Both have 1 HBD, which is acceptable.

**5. H-Bond Acceptors:** Ligand A has 5 HBAs, and Ligand B has 4. Both are below the acceptable limit of 10.

**6. QED:** Ligand A (0.808) has a significantly better QED score than Ligand B (0.313), indicating a more drug-like profile.

**7. DILI:** Ligand A (59.984) has a slightly higher DILI risk than Ligand B (44.591), but both are below the concerning threshold of 60.

**8. BBB:** Ligand B (79.604) has a substantially better BBB penetration score than Ligand A (51.842). This is a *critical* factor for a CNS target like DRD2.

**9. Caco-2 Permeability:** Ligand A (-5.063) has a worse Caco-2 permeability than Ligand B (-4.296).

**10. Aqueous Solubility:** Ligand A (-3.614) has worse aqueous solubility than Ligand B (-2.262).

**11. hERG:** Both ligands have low hERG inhibition liability (0.367 and 0.488), which is good.

**12. Microsomal Clearance:** Ligand B (84.462) has a higher microsomal clearance than Ligand A (37.172), suggesting lower metabolic stability.

**13. In vitro Half-Life:** Ligand A (-26.36) has a longer in vitro half-life than Ligand B (-19.076).

**14. P-gp Efflux:** Both ligands have low P-gp efflux liability (0.207 and 0.243), which is favorable.

**15. Binding Affinity:** Both ligands have the same binding affinity (-8.0 kcal/mol), which is excellent.

**Overall Assessment:**

While Ligand A has better QED, metabolic stability (lower Cl_mic, longer t1/2), and Caco-2 permeability, Ligand B *significantly* outperforms Ligand A in BBB penetration (79.6 vs 51.8). Given that DRD2 is a CNS target, BBB penetration is paramount. The difference in BBB is substantial enough to outweigh the advantages of Ligand A in other areas. The binding affinity is identical, so potency is not a differentiating factor.

Output:
1
2025-04-17 04:29:58,451 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (348.471 and 363.395 Da) fall within the ideal range of 200-500 Da.

**TPSA:** Ligand A (36.1) is excellent, well below the 90 A^2 threshold for CNS targets. Ligand B (101.73) is higher, but still potentially acceptable, though less ideal.

**logP:** Ligand A (4.296) is slightly high, potentially leading to solubility issues or off-target interactions. Ligand B (0.664) is quite low, which could hinder membrane permeability and CNS penetration.

**H-Bond Donors/Acceptors:** Both ligands have 1 HBD, which is good. Ligand A has 2 HBA, and Ligand B has 8 HBA. Higher HBA can sometimes reduce permeability.

**QED:** Ligand A (0.654) has a good drug-likeness score. Ligand B (0.476) is lower, indicating a less favorable overall drug-like profile.

**DILI:** Both ligands have similar DILI risk (70.841 and 69.058), which is acceptable (below 80).

**BBB:** Ligand A has a significantly higher BBB penetration percentile (85.459) compared to Ligand B (36.526). This is *critical* for a CNS target like DRD2.

**Caco-2 Permeability:** Ligand A (-5.137) has poor Caco-2 permeability, while Ligand B (-4.887) is also poor, but slightly better.

**Aqueous Solubility:** Both ligands have poor aqueous solubility (-4.632 and -2.107).

**hERG Inhibition:** Ligand A (0.788) has a slightly higher hERG risk than Ligand B (0.067), but both are relatively low.

**Microsomal Clearance:** Both ligands have similar microsomal clearance (56.211 and 53.664 mL/min/kg), suggesting comparable metabolic stability.

**In vitro Half-Life:** Both ligands have negative in vitro half-lives (-11.548 and -10.786 hours), indicating rapid metabolism.

**P-gp Efflux:** Ligand A (0.753) has moderate P-gp efflux, while Ligand B (0.111) has very low P-gp efflux. Lower P-gp efflux is beneficial for CNS penetration.

**Binding Affinity:** Both ligands have excellent binding affinity (-8.7 and -8.0 kcal/mol). The difference is 0.7 kcal/mol, which is significant, but not overwhelming given the other ADME properties.

**Overall Assessment:**

Ligand A excels in BBB penetration and has a better QED score. However, it suffers from higher logP, poor Caco-2 permeability, and moderate P-gp efflux. Ligand B has a lower logP and P-gp efflux, but significantly poorer BBB penetration and a lower QED.

For a CNS target like DRD2, BBB penetration is paramount. Ligand A's significantly higher BBB score (85.459 vs 36.526) outweighs its slightly higher logP and moderate P-gp efflux. The affinity difference is not large enough to overcome the BBB disadvantage of Ligand B.

Output:
0
2025-04-17 04:29:58,451 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (356.375 and 353.507 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (111.24) is slightly above the optimal <90 for CNS targets, while Ligand B (81.67) is well within the desired range. This favors Ligand B.

**logP:** Ligand A (-0.743) is a bit low, potentially hindering permeability. Ligand B (1.447) is within the optimal 1-3 range. This is a significant advantage for Ligand B.

**H-Bond Donors/Acceptors:** Ligand A has 1 HBD and 7 HBA, which are acceptable. Ligand B has 3 HBD and 4 HBA, also acceptable.

**QED:** Both ligands have reasonable QED scores (0.363 and 0.548), but Ligand B is better.

**DILI:** Ligand A (52.191) has a moderate DILI risk, while Ligand B (5.312) has a very low risk. This strongly favors Ligand B.

**BBB:** Both ligands have reasonable BBB penetration (43.117 and 46.452), but neither is above the desirable 70% threshold for CNS targets. This isn't a decisive factor.

**Caco-2 Permeability:** Both have negative Caco-2 values (-5.018 and -5.164), which is unusual and suggests poor permeability. This is a concern for both.

**Aqueous Solubility:** Both ligands have very low aqueous solubility (-1.24 and -1.385). This could pose formulation challenges, but is not a dealbreaker.

**hERG Inhibition:** Both ligands show very low hERG inhibition risk (0.055 and 0.243).

**Microsomal Clearance:** Ligand A (34.827) has a higher microsomal clearance than Ligand B (3.305), suggesting lower metabolic stability. This favors Ligand B.

**In vitro Half-Life:** Ligand B (-7.347) has a longer in vitro half-life than Ligand A (-20.851). This is a significant advantage for Ligand B.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.014 and 0.024), which is good for CNS penetration.

**Binding Affinity:** Ligand B (-7.5 kcal/mol) has a slightly better binding affinity than Ligand A (-6.6 kcal/mol). While both are good, the difference is meaningful.

**Overall:**

Ligand B consistently outperforms Ligand A across most critical parameters, especially logP, DILI, microsomal clearance, and half-life. While both have issues with Caco-2 permeability and solubility, Ligand B's superior ADME profile and slightly better binding affinity make it the more promising drug candidate for targeting DRD2.

Output:
1
2025-04-17 04:29:58,452 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (364.873 and 341.455 Da) fall within the ideal range of 200-500 Da.

**TPSA:** Ligand A (50.8) is significantly better than Ligand B (71.09). For CNS targets, we want TPSA <= 90, and A is much closer to the ideal <= 60. B is pushing the upper limit and may have reduced brain penetration.

**logP:** Both ligands have good logP values (2.853 and 2.593), falling within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A (HBD=1, HBA=4) is preferable to Ligand B (HBD=2, HBA=3). While both are within acceptable limits, fewer H-bonds generally improve permeability.

**QED:** Ligand B (0.865) has a higher QED score than Ligand A (0.54), suggesting a more generally drug-like profile. However, QED is less critical than CNS penetration for a CNS target.

**DILI:** Ligand A (16.014) has a much lower DILI risk than Ligand B (44.397). This is a significant advantage for A.

**BBB:** Ligand A (68.399) has a substantially better BBB percentile than Ligand B (43.893). This is *critical* for a DRD2 ligand, as DRD2 is a CNS target. A score >70 is desirable, and A is closer to this threshold.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.903 and -4.861) which is unusual and suggests poor permeability. This is a concern for both, but doesn't differentiate them.

**Aqueous Solubility:** Both ligands have negative solubility values (-2.795 and -3.25), which is also unusual and suggests poor solubility. This is a concern for both, but doesn't differentiate them.

**hERG:** Ligand A (0.715) has a slightly higher hERG risk than Ligand B (0.191), but both are relatively low.

**Microsomal Clearance:** Ligand B (21.077) has a higher microsomal clearance than Ligand A (6.908), indicating faster metabolism and potentially lower exposure.

**In vitro Half-Life:** Ligand A (21.134 hours) has a significantly longer half-life than Ligand B (-3.074 hours). This is a major advantage for A, potentially allowing for less frequent dosing.

**P-gp Efflux:** Ligand A (0.243) has lower P-gp efflux than Ligand B (0.117), which is favorable for CNS penetration.

**Binding Affinity:** Ligand B (-8.9 kcal/mol) has a slightly better binding affinity than Ligand A (-7.9 kcal/mol). While a 1 kcal/mol difference is noticeable, the ADME advantages of Ligand A are substantial.

**Overall Assessment:**

Ligand A is the stronger candidate. While Ligand B has slightly better binding affinity and QED, Ligand A excels in critical areas for a CNS-targeting GPCR ligand: significantly better BBB penetration, lower DILI risk, longer half-life, and lower P-gp efflux. The TPSA value for A is also much more favorable. The unusual negative values for Caco-2 and solubility are concerning for both, but the other advantages of A outweigh this concern.



Output:
0
2025-04-17 04:29:58,452 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (352.45 Da) is slightly lower, which could be beneficial for permeability. Ligand B (380.861 Da) is also acceptable.

**TPSA:** Ligand A (66.48) is excellent, well below the 90 A^2 threshold for CNS targets. Ligand B (93.01) is still reasonable but closer to the upper limit, potentially hindering BBB penetration.

**logP:** Both ligands have good logP values (A: 2.405, B: 1.199) within the optimal 1-3 range. Ligand A is slightly higher, which could be advantageous for membrane permeability, but Ligand B is still acceptable.

**H-Bond Donors/Acceptors:** Both have 1 HBD, which is good. Ligand A has 3 HBA, while Ligand B has 7 HBA.  Ligand A is preferable here, as higher HBA can sometimes reduce permeability.

**QED:** Both ligands have good QED scores (A: 0.682, B: 0.812), indicating good drug-like properties.

**DILI:** Ligand A (17.72) has a much lower DILI risk than Ligand B (80.729), which is a significant advantage.

**BBB:** This is crucial for a CNS target. Ligand A shows excellent BBB penetration (89.531%), while Ligand B is considerably lower (51.066%). This is a major point in favor of Ligand A.

**Caco-2 Permeability:** Ligand A (-4.572) shows poor Caco-2 permeability, while Ligand B (-5.555) is also poor. This is a concern for both, but less critical given the focus on BBB for CNS targets.

**Aqueous Solubility:** Both ligands have very poor aqueous solubility (-2.615 and -2.38 respectively). This could pose formulation challenges.

**hERG:** Both ligands have low hERG inhibition liability (0.157 and 0.138), which is good.

**Microsomal Clearance:** Ligand B (-3.071) has a negative value, indicating very low clearance and excellent metabolic stability, while Ligand A (23.317) has a relatively high clearance. This is a significant advantage for Ligand B.

**In vitro Half-Life:** Ligand A (-20.759) has a negative half-life, which is unusual and likely an error or indicates very rapid metabolism. Ligand B (-0.981) has a short half-life, but is more reasonable.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.048 and 0.059), which is favorable for CNS penetration.

**Binding Affinity:** Both ligands have the same binding affinity (-7.6 kcal/mol), which is excellent.

**Overall Assessment:**

Ligand A excels in TPSA, BBB penetration, and DILI risk. However, it has poor Caco-2 permeability and high microsomal clearance, and an unrealistic half-life. Ligand B has better metabolic stability (lower Cl_mic) and a more reasonable half-life, but suffers from higher DILI risk, lower BBB penetration, and a higher TPSA.

Given the importance of BBB penetration for a CNS target like DRD2, and the significantly lower DILI risk, **Ligand A is the more promising candidate** despite its drawbacks in Caco-2 permeability and metabolic stability. The high affinity of both compounds mitigates some of the ADME concerns. Further optimization could focus on improving the solubility and metabolic stability of Ligand A.

Output:
0
2025-04-17 04:29:58,452 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (349.475 and 353.463 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (69.72) is slightly higher than Ligand B (62.32), but both are below the 90 A^2 threshold desirable for CNS targets.

**logP:** Ligand A (1.398) is within the optimal 1-3 range. Ligand B (0.051) is very low, potentially hindering membrane permeability. This is a significant drawback.

**H-Bond Donors/Acceptors:** Ligand A has 1 HBD and 3 HBA, while Ligand B has 0 HBD and 5 HBA. Both are within acceptable limits (<=5 HBD and <=10 HBA).

**QED:** Both ligands have reasonable QED scores (0.763 and 0.699), indicating good drug-like properties.

**DILI:** Ligand A (23.769) has a much lower DILI risk than Ligand B (13.106), suggesting better potential for avoiding liver toxicity.

**BBB:** Ligand A (54.983) has a moderate BBB penetration, while Ligand B (62.737) is slightly better. However, both are below the desirable >70 percentile for CNS targets.

**Caco-2 Permeability:** Ligand A (-4.785) has worse Caco-2 permeability than Ligand B (-4.423), suggesting lower intestinal absorption for Ligand A.

**Aqueous Solubility:** Ligand A (-2.553) has worse aqueous solubility than Ligand B (-0.044).

**hERG:** Both ligands have low hERG inhibition liability (0.272 and 0.283), which is good.

**Microsomal Clearance:** Ligand A (30.777) has a higher microsomal clearance than Ligand B (9.658), indicating faster metabolism and potentially lower exposure.

**In vitro Half-Life:** Ligand B (13.325) has a significantly longer in vitro half-life than Ligand A (4.191), which is a positive attribute.

**P-gp Efflux:** Both ligands have similar, low P-gp efflux liability (0.077 and 0.021).

**Binding Affinity:** Ligand A (-8.5 kcal/mol) has a significantly stronger binding affinity than Ligand B (-7.2 kcal/mol). This is a substantial advantage. The difference of 1.3 kcal/mol is large enough to potentially overcome some ADME deficiencies.

**Overall Assessment:**

While Ligand A has a better binding affinity and lower DILI risk, Ligand B has better logP, solubility, Caco-2 permeability, and *much* better metabolic stability (lower Cl_mic, longer t1/2). The very low logP of Ligand B is a major concern for CNS penetration, even with a slightly better BBB percentile. The stronger binding affinity of Ligand A is a significant advantage for a GPCR target. Considering the GPCR-specific priorities, the binding affinity is paramount, and the TPSA values are acceptable for both. Ligand A's lower metabolic stability is a concern, but potentially manageable through structural modifications.

Output:
1
2025-04-17 04:29:58,452 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (354.451 and 360.567 Da) fall within the ideal range of 200-500 Da.

**TPSA:** Ligand A (90.98) is excellent for CNS penetration, being below 90. Ligand B (33.2) is also very good.

**logP:** Ligand A (0.037) is quite low, potentially hindering membrane permeability. Ligand B (4.862) is higher, approaching the upper limit, which could raise solubility concerns but is acceptable.

**H-Bond Donors/Acceptors:** Ligand A has 2 HBD and 5 HBA, which are reasonable. Ligand B has 0 HBD and 3 HBA, also acceptable.

**QED:** Ligand A (0.657) has a better QED score than Ligand B (0.466), indicating a more drug-like profile.

**DILI:** Ligand A (29.042) has a significantly lower DILI risk than Ligand B (12.136), which is a major advantage.

**BBB:** Ligand B (83.133) has a much better BBB penetration score than Ligand A (74.292), which is critical for a CNS target like DRD2.

**Caco-2 Permeability:** Ligand A (-4.661) has poor Caco-2 permeability, likely due to its low logP. Ligand B (-4.891) is also poor, but similar to A.

**Aqueous Solubility:** Ligand A (-0.917) has poor aqueous solubility, consistent with its low logP. Ligand B (-4.497) is even worse.

**hERG Inhibition:** Ligand A (0.376) has a lower hERG risk than Ligand B (0.764), which is preferable.

**Microsomal Clearance:** Ligand B (113.273) has a much higher microsomal clearance than Ligand A (31.2), meaning it will be metabolized more quickly.

**In vitro Half-Life:** Ligand B (12.484) has a longer half-life than Ligand A (-30.573), which is a positive.

**P-gp Efflux:** Ligand A (0.016) has very low P-gp efflux, which is excellent for CNS penetration. Ligand B (0.742) has moderate P-gp efflux.

**Binding Affinity:** Ligand B (-6.7 kcal/mol) has a better binding affinity than Ligand A (-8.0 kcal/mol). The difference is substantial (1.3 kcal/mol), and this is a key factor.

**Overall Assessment:**

Ligand A has better QED, lower DILI, lower hERG, and significantly lower P-gp efflux. However, its low logP leads to poor solubility and Caco-2 permeability, and its BBB is lower than Ligand B. Ligand B has a superior binding affinity and a much better BBB score, despite having a higher DILI risk and higher P-gp efflux.

Given the GPCR-specific priorities, **binding affinity and BBB penetration are paramount**. Ligand B's significantly stronger binding affinity and superior BBB penetration outweigh its drawbacks, especially considering the potential for addressing the DILI risk through structural modifications. The higher metabolic clearance is also a concern, but potentially addressable. The low logP of Ligand A is a more fundamental issue.

Output:
1
2025-04-17 04:29:58,452 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (377.315 Da) is slightly higher than Ligand B (356.413 Da), but both are acceptable.

**TPSA:** Ligand A (41.13) is excellent for CNS penetration, well below the 90 A^2 threshold. Ligand B (66.48) is still reasonable, but less optimal than A.

**logP:** Ligand A (4.954) is a bit high, potentially leading to solubility issues and off-target effects. Ligand B (2.31) is within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A (2 HBD, 1 HBA) and Ligand B (1 HBD, 3 HBA) both have acceptable numbers of hydrogen bond donors and acceptors.

**QED:** Both ligands have similar QED values (A: 0.735, B: 0.679), indicating good drug-like properties.

**DILI:** Both ligands have low DILI risk (A: 50.33, B: 41.838), which is favorable.

**BBB:** Ligand B (87.631) has a significantly higher BBB percentile than Ligand A (78.519). This is a critical advantage for a CNS target like DRD2.

**Caco-2 Permeability:** Both have negative Caco-2 values which is unusual and suggests a potential issue with the data. However, we can still compare them relatively. Ligand A (-4.648) is slightly worse than Ligand B (-4.487).

**Aqueous Solubility:** Both ligands have very poor aqueous solubility (A: -5.859, B: -2.687). This is a concern, but can sometimes be mitigated with formulation strategies.

**hERG Inhibition:** Ligand A (0.757) has a slightly higher hERG risk than Ligand B (0.212), which is preferable.

**Microsomal Clearance:** Ligand B (15.255) has a much lower microsomal clearance than Ligand A (57.815), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand B (-14.994) has a negative half-life, which is not physically possible and suggests an issue with the data. Ligand A (59.478) is acceptable.

**P-gp Efflux:** Ligand A (0.51) has lower P-gp efflux than Ligand B (0.094), which is better for CNS exposure.

**Binding Affinity:** Ligand B (-8.1 kcal/mol) has a significantly stronger binding affinity than Ligand A (-10.4 kcal/mol). This is a substantial advantage, and can often outweigh minor ADME drawbacks.

**Overall Assessment:**

While Ligand A has a slightly better logP and P-gp efflux, Ligand B excels in the most crucial areas for a CNS-targeting GPCR: BBB penetration and binding affinity. The significantly stronger binding affinity of Ligand B (-8.1 vs -10.4 kcal/mol) is a major advantage. The lower microsomal clearance of Ligand B is also favorable. The negative half-life for Ligand B is a data quality concern, but the other advantages are substantial. The TPSA of Ligand A is better, but Ligand B's TPSA is still acceptable.

Output:
1
2025-04-17 04:29:58,453 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (372.759 Da and 344.499 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (96.11) is higher than Ligand B (40.62). For CNS targets, TPSA should be <= 90, so Ligand B is significantly better here.

**3. logP:** Both ligands have good logP values (3.053 and 3.371), falling within the optimal 1-3 range.

**4. H-Bond Donors:** Ligand A has 3 HBD, and Ligand B has 0. Both are acceptable (<=5).

**5. H-Bond Acceptors:** Ligand A has 4 HBA, and Ligand B has 2. Both are acceptable (<=10).

**6. QED:** Both ligands have good QED scores (0.555 and 0.721), indicating good drug-like properties.

**7. DILI:** Ligand A (88.251) has a higher DILI risk than Ligand B (32.183). Ligand B is much preferred.

**8. BBB:** Ligand B (65.607) has a significantly better BBB penetration percentile than Ligand A (44.552). This is a critical factor for a CNS target like DRD2.

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.701 and -4.746). These values are unusual and suggest poor permeability. However, the values are very similar.

**10. Aqueous Solubility:** Both ligands have negative solubility values (-3.896 and -3.537). These values are also unusual and suggest poor solubility. Again, the values are very similar.

**11. hERG Inhibition:** Both ligands have low hERG inhibition risk (0.388 and 0.402).

**12. Microsomal Clearance:** Ligand B (54.685) has a lower microsomal clearance than Ligand A (64.472), indicating better metabolic stability.

**13. In vitro Half-Life:** Ligand B (-6.805) has a negative half-life, which is not possible. Ligand A (29.465) has a reasonable half-life. This is a significant negative for Ligand B.

**14. P-gp Efflux:** Both ligands have low P-gp efflux liability (0.165 and 0.364).

**15. Binding Affinity:** Ligand A (-8.8 kcal/mol) has a slightly better binding affinity than Ligand B (-8.1 kcal/mol). However, the difference is relatively small.

**Overall Assessment:**

Ligand B is the more promising candidate. While both have issues with Caco-2 and solubility, Ligand B excels in crucial areas for a CNS-targeting GPCR: significantly lower DILI risk, much better BBB penetration, and improved metabolic stability. The slightly weaker binding affinity of Ligand B is likely outweighed by its superior ADME properties, particularly BBB penetration. The negative half-life for Ligand B is a major red flag.

Output:
1
2025-04-17 04:29:58,453 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (343.391) is slightly lower, which could be beneficial for permeability, but both are acceptable.

**TPSA:** Ligand A (138.68) is close to the upper limit for good oral absorption and acceptable for CNS targets, while Ligand B (95.42) is excellent for CNS penetration. This favors Ligand B.

**logP:** Ligand A (0.774) is a bit low, potentially hindering permeation. Ligand B (1.076) is better, falling within the optimal range. This favors Ligand B.

**H-Bond Donors/Acceptors:** Ligand A has 4 HBD and 6 HBA, which is reasonable. Ligand B has 2 HBD and 6 HBA, also reasonable. No strong preference here.

**QED:** Both ligands have good QED scores (A: 0.632, B: 0.706), indicating drug-like properties.

**DILI:** Ligand A has a significantly higher DILI risk (83.908) compared to Ligand B (42.924). This is a major concern for Ligand A.

**BBB:** Ligand A (64.211) has a moderate BBB penetration, while Ligand B (52.889) is lower. While both are not ideal (>70), Ligand A is better.

**Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and suggests poor permeability. However, the scale is not specified, so it's difficult to interpret.

**Aqueous Solubility:** Both have negative solubility values, indicating poor solubility. Again, the scale is not specified.

**hERG Inhibition:** Ligand A (0.217) has a slightly higher hERG risk than Ligand B (0.09), but both are relatively low.

**Microsomal Clearance:** Ligand A (8.203) has a moderate clearance, while Ligand B (-10.814) has a negative clearance, which is not possible. This is likely an error in the data for ligand B, and we should treat it with caution.

**In vitro Half-Life:** Ligand A (-7.142) has a negative half-life, which is impossible. Ligand B (-0.023) is also negative. This is another data quality issue.

**P-gp Efflux:** Ligand A (0.031) has low P-gp efflux, which is good for CNS exposure. Ligand B (0.05) is slightly higher, but still acceptable.

**Binding Affinity:** Ligand A (-9.0 kcal/mol) has a significantly stronger binding affinity than Ligand B (-8.5 kcal/mol). This is a substantial advantage for Ligand A.

**Overall Assessment:**

Despite the questionable data for half-life and clearance, the most important factors for a CNS GPCR target are affinity, BBB, TPSA, logP, and safety (DILI). Ligand A has a much better binding affinity (-9.0 vs -8.5), and a better BBB score (64.211 vs 52.889). However, Ligand A has a significantly higher DILI risk. Ligand B has better TPSA and logP values. The negative values for half-life and clearance for both compounds are concerning and suggest potential data errors.

Given the importance of strong binding for GPCRs, and the fact that the difference in affinity is >1.5 kcal/mol, I would cautiously favor Ligand A, *assuming* the DILI risk can be mitigated through structural modifications. The negative values for clearance and half-life would need to be investigated and corrected.

Output:
0
2025-04-17 04:29:58,453 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 drug candidates, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (351.487 and 356.463 Da) fall comfortably within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (56.79) is excellent, well below the 90 A^2 threshold for CNS targets. Ligand B (79.31) is still reasonable, but less optimal, approaching the 90 A^2 limit.

**3. logP:** Ligand A (3.911) is at the upper end of the optimal range (1-3), but still acceptable. Ligand B (0.648) is quite low, potentially hindering membrane permeability and CNS penetration.

**4. H-Bond Donors:** Both ligands have 1 HBD, which is within the acceptable limit of <=5.

**5. H-Bond Acceptors:** Ligand A has 4 HBAs, and Ligand B has 5. Both are within the acceptable limit of <=10.

**6. QED:** Both ligands have similar QED values (0.733 and 0.756), indicating good drug-likeness.

**7. DILI:** Ligand A (49.864) has a slightly higher DILI risk than Ligand B (30.012), but both are below the concerning threshold of 60.

**8. BBB:** Ligand A (63.358) and Ligand B (68.748) both have reasonable BBB penetration, but neither exceeds the desirable 70% threshold.

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.305 and -4.372), which is unusual and suggests poor permeability. This is a significant concern.

**10. Aqueous Solubility:** Both ligands have negative solubility values (-4.629 and -0.914), which is also concerning and suggests poor solubility.

**11. hERG Inhibition:** Ligand A (0.73) has a slightly higher hERG risk than Ligand B (0.23), but both are relatively low.

**12. Microsomal Clearance:** Ligand A (90.642) has significantly higher microsomal clearance than Ligand B (20.545), meaning it will be metabolized more quickly.

**13. In vitro Half-Life:** Ligand A (14.609) has a longer half-life than Ligand B (7.495), which is preferable.

**14. P-gp Efflux:** Ligand A (0.498) has lower P-gp efflux than Ligand B (0.046), which is beneficial for CNS penetration.

**15. Binding Affinity:** Both ligands have excellent binding affinities (-7.8 and -7.6 kcal/mol), with Ligand A being slightly stronger. The affinity difference is less than 1.5 kcal/mol, so it's not a decisive factor on its own.

**Overall Assessment:**

Considering the GPCR-specific priorities, Ligand A is more promising despite its higher DILI and clearance. Its superior TPSA, logP, and P-gp efflux profile are crucial for CNS penetration. While both have poor Caco-2 and solubility, the better logP of Ligand A suggests it might be more amenable to formulation strategies to improve these properties. Ligand B's very low logP is a major drawback, likely severely limiting its ability to cross the BBB.

Output:
0
2025-04-17 04:29:58,453 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (412.259 Da) is slightly higher, but acceptable. Ligand B (350.35 Da) is also good.

**TPSA:** Ligand A (83.48) is better than Ligand B (109.42). For CNS targets, we want TPSA <= 90, so Ligand A is preferable.

**logP:** Ligand A (2.783) is optimal (1-3). Ligand B (-0.894) is below 1, which could hinder permeation. This is a significant drawback for Ligand B.

**H-Bond Donors/Acceptors:** Both have 3 HBD and 4-5 HBA, which are within acceptable limits.

**QED:** Ligand A (0.653) has a better QED score than Ligand B (0.32), indicating a more drug-like profile.

**DILI:** Ligand A (62.893) has a higher DILI risk than Ligand B (44.126), but both are still reasonably low.

**BBB:** Ligand B (83.87) has a significantly better BBB penetration percentile than Ligand A (46.375). This is a critical factor for a CNS target like DRD2.

**Caco-2 Permeability:** Ligand A (-4.946) has a negative value, which is concerning. Ligand B (-5.473) is also negative, indicating poor intestinal absorption for both.

**Aqueous Solubility:** Both ligands have negative solubility values, indicating poor solubility.

**hERG:** Both ligands have low hERG inhibition liability (0.192 and 0.198), which is good.

**Microsomal Clearance:** Ligand B (-1.077) has a negative clearance, which is unusual and potentially indicates very high metabolic stability. Ligand A (31.93) has a higher, more typical clearance.

**In vitro Half-Life:** Ligand B (-8.999) has a negative half-life, which is also unusual and suggests exceptional stability. Ligand A (25.759) has a reasonable half-life.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.006 and 0.194), which is favorable for CNS penetration.

**Binding Affinity:** Both ligands have excellent binding affinity (-9.1 and -9.3 kcal/mol), with a very slight advantage to Ligand B. However, this small difference is unlikely to outweigh the other significant differences.

**Overall Assessment:**

Ligand B has a superior BBB score and potentially better metabolic stability (negative clearance and half-life, though these are unusual). However, its logP is significantly lower than ideal, which is a major concern for CNS penetration. Ligand A has a better TPSA, QED, and a more reasonable (though still not ideal) logP. The similar binding affinities mean that the ADME properties are the deciding factor. While the negative Caco-2 and solubility values are concerning for both, the low logP of Ligand B is a more critical issue for a CNS target.

Output:
1
2025-04-17 04:29:58,454 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (348.447 and 348.422 Da) fall comfortably within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (105.48) is higher than the preferred <90 for CNS targets, while Ligand B (58.44) is well within the range. This is a significant advantage for Ligand B.

**3. logP:** Both ligands have acceptable logP values (2.432 and 1.16), falling within the 1-3 range. Ligand B is slightly lower, potentially improving solubility.

**4. H-Bond Donors:** Ligand A has 4 HBD, which is acceptable. Ligand B has 0, which is also acceptable.

**5. H-Bond Acceptors:** Both ligands have 4 HBA, which is acceptable.

**6. QED:** Both ligands have good QED scores (0.627 and 0.82), indicating drug-like properties.

**7. DILI:** Ligand A (39.667) has a slightly higher DILI risk than Ligand B (20.783), but both are below the concerning threshold of 60.

**8. BBB:** Ligand B (86.894) has a significantly better BBB percentile than Ligand A (77.627). This is crucial for a CNS target like DRD2.

**9. Caco-2 Permeability:** Both have negative values, which is unusual. However, the magnitude of negativity is similar, so this isn't a strong differentiator.

**10. Aqueous Solubility:** Both have negative values, which is unusual. The magnitude of negativity is similar, so this isn't a strong differentiator.

**11. hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.29 and 0.287).

**12. Microsomal Clearance:** Ligand B (11.412) has a significantly lower microsomal clearance than Ligand A (58.797), indicating better metabolic stability.

**13. In vitro Half-Life:** Ligand B (-16.317) has a longer in vitro half-life than Ligand A (-13.701).

**14. P-gp Efflux:** Both have very low P-gp efflux liability (0.016 and 0.061).

**15. Binding Affinity:** Ligand B (-9.0) has a slightly stronger binding affinity than Ligand A (-8.5). While the difference is less than the 1.5 kcal/mol threshold to outweigh other issues, it contributes to its favorability.

**Overall Assessment:**

Ligand B is the superior candidate. It excels in key properties for a CNS-targeting GPCR ligand: lower TPSA, significantly better BBB penetration, lower microsomal clearance (better metabolic stability), and a slightly longer half-life. While both have acceptable logP, QED, and safety profiles, Ligand B's advantages in CNS penetration and metabolic stability are decisive. The slightly better binding affinity further supports this conclusion.

Output:
1
2025-04-17 04:29:58,454 - INFO - Reasoning:

Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (354.407) is slightly lower, which could be beneficial for permeability.

**2. TPSA:** Ligand A (113.42) is better than Ligand B (83.89) as it is still within the range for CNS targets (<90 A^2).

**3. logP:** Ligand A (-1.799) is lower than the optimal 1-3 range, potentially hindering membrane permeability. Ligand B (2.318) is within the optimal range. This is a significant advantage for Ligand B.

**4. H-Bond Donors:** Ligand A (3) is acceptable, while Ligand B (1) is even better.

**5. H-Bond Acceptors:** Ligand A (5) is acceptable, and Ligand B (6) is also acceptable.

**6. QED:** Both ligands have good QED scores (A: 0.551, B: 0.866), indicating drug-like properties. Ligand B is better.

**7. DILI:** Ligand A (29.663) has a much lower DILI risk than Ligand B (63.552). This is a significant advantage for Ligand A.

**8. BBB:** Ligand A (50.252) and Ligand B (55.525) are both below the desirable >70 percentile for CNS targets. However, this is less critical if other properties are favorable.

**9. Caco-2:** Both have negative values, which is unusual. Assuming these are percentile scores, both are poor.

**10. Solubility:** Ligand A (-0.832) has poor solubility. Ligand B (-3.581) is even worse.

**11. hERG:** Ligand A (0.07) has a very low hERG risk, which is excellent. Ligand B (0.332) is slightly higher but still relatively low.

**12. Cl_mic:** Ligand A (-10.576) has a negative clearance, which is not possible. Assuming this is a percentile score, it indicates very high metabolic stability. Ligand B (0.881) has low metabolic stability. This is a major advantage for Ligand A.

**13. t1/2:** Ligand A (5.816) has a shorter half-life than Ligand B (12.535).

**14. Pgp:** Ligand A (0.003) has very low P-gp efflux, which is excellent for CNS penetration. Ligand B (0.366) has moderate P-gp efflux.

**15. Binding Affinity:** Ligand B (-8.9 kcal/mol) has a significantly stronger binding affinity than Ligand A (-7.8 kcal/mol). This is a substantial advantage for Ligand B, potentially outweighing some ADME drawbacks.

**Overall Assessment:**

Ligand B has a better logP and significantly better binding affinity. However, Ligand A has a much lower DILI risk, better P-gp efflux, and better metabolic stability. Both have poor solubility and BBB penetration. Considering the GPCR-specific priorities, the strong binding affinity of Ligand B is a major factor. While Ligand A's ADME properties are better, the affinity difference is substantial enough to favor Ligand B, assuming the solubility issues can be addressed through formulation.

Output:
1
2025-04-17 04:29:58,454 - INFO - Batch 118 complete. Total preferences: 1888
2025-04-17 04:29:58,454 - INFO - Processing batch 119/512...
2025-04-17 04:30:39,974 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (347.419 and 354.491 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (93.26) is slightly above the preferred <90 for CNS targets, while Ligand B (75.71) is well within the range. This favors Ligand B.

**logP:** Ligand A (1.448) and Ligand B (2.365) are both within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Both ligands have 1 HBD, which is good. Ligand A has 6 HBA, and Ligand B has 4 HBA, both are acceptable (<=10).

**QED:** Ligand A (0.78) has a better QED score than Ligand B (0.562), indicating a more drug-like profile.

**DILI:** Ligand A (52.346) has a higher DILI risk than Ligand B (20.202). This is a significant advantage for Ligand B.

**BBB:** Both ligands have good BBB penetration (Ligand A: 61.535, Ligand B: 65.335). Ligand B is slightly better.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values, which is unusual. However, the magnitude is similar, so this isn't a major differentiator.

**Aqueous Solubility:** Both have negative solubility values, indicating poor solubility. Ligand A (-0.967) is slightly better than Ligand B (-2.757).

**hERG Inhibition:** Both ligands show low hERG inhibition liability (Ligand A: 0.151, Ligand B: 0.239), which is good.

**Microsomal Clearance:** Ligand A (51.236) has a lower (better) microsomal clearance than Ligand B (86.56). This suggests better metabolic stability for Ligand A.

**In vitro Half-Life:** Ligand A (-5.112) has a longer (better) in vitro half-life than Ligand B (-10.22).

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (Ligand A: 0.024, Ligand B: 0.018).

**Binding Affinity:** Ligand A (-8.3 kcal/mol) has a significantly stronger binding affinity than Ligand B (-7.0 kcal/mol). This is a substantial advantage for Ligand A, potentially outweighing some ADME drawbacks.

**Overall Assessment:**

Ligand A has a superior binding affinity and better metabolic stability (lower Cl_mic, longer t1/2). Ligand B has a lower DILI risk and a slightly better TPSA. The difference in binding affinity (1.3 kcal/mol) is significant. Given the GPCR target and the importance of potency, the stronger binding of Ligand A is the deciding factor, despite its slightly higher TPSA and DILI risk.

Output:
1
2025-04-17 04:30:39,975 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (360.46 & 350.46 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (58.12) is significantly better than Ligand B (84.42). For CNS targets, we want TPSA <= 90, and ideally closer to 60. Ligand A is much closer to this ideal.

**logP:** Ligand A (4.162) is slightly high, but acceptable. Ligand B (1.606) is a bit low, potentially hindering permeability. Optimal is 1-3.

**H-Bond Donors/Acceptors:** Both have 1 HBD, which is good. Ligand A has 4 HBA, and Ligand B has 5. Both are acceptable, being <= 10.

**QED:** Ligand A (0.89) is excellent, indicating high drug-likeness. Ligand B (0.648) is still reasonable, but less optimal.

**DILI:** Ligand A (51.26) has a moderate DILI risk, while Ligand B (25.44) has a very low risk. This favors Ligand B.

**BBB:** Ligand A (85.85) has excellent BBB penetration, exceeding the desirable >70% threshold. Ligand B (59.05) is significantly lower, which is a major drawback for a CNS target like DRD2.

**Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and suggests poor permeability. However, the scale is not specified, so this is hard to interpret.

**Aqueous Solubility:** Both have negative solubility values, also unusual and suggesting poor solubility. Again, the scale is not specified.

**hERG:** Both ligands have very low hERG risk (0.239 and 0.192).

**Microsomal Clearance:** Ligand A (34.42) and Ligand B (39.68) are comparable, both indicating moderate metabolic clearance. Lower is better.

**In vitro Half-Life:** Ligand A (1.20) has a very short half-life, while Ligand B (18.96) has a much longer half-life. This strongly favors Ligand B.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.183 and 0.016), which is good for CNS penetration.

**Binding Affinity:** Ligand A (-8.6 kcal/mol) has significantly stronger binding affinity than Ligand B (-7.5 kcal/mol). This is a substantial advantage, potentially outweighing some ADME concerns.

**Overall Assessment:**

Ligand A excels in binding affinity and BBB penetration, which are crucial for a CNS GPCR target. However, its short half-life and slightly high logP are concerns. Ligand B has a better safety profile (lower DILI) and longer half-life, but its lower BBB penetration and weaker binding affinity are significant drawbacks.

Given the importance of both strong binding and CNS penetration for DRD2, and the substantial difference in affinity (-8.6 vs -7.5 kcal/mol), I believe Ligand A is the more promising candidate *despite* its shorter half-life. The strong binding could allow for lower dosing, mitigating the half-life issue. The excellent BBB penetration is also critical.

Output:
0
2025-04-17 04:30:39,975 - INFO - Reasoning:

Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (374.482 and 373.474 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (93.09) is slightly above the preferred <90 for CNS targets, but still reasonable. Ligand B (55.84) is excellent, well below 90.

**3. logP:** Ligand A (1.432) is within the optimal 1-3 range. Ligand B (3.314) is at the higher end of optimal, but still acceptable.

**4. H-Bond Donors:** Ligand A (2) and Ligand B (0) are both within the acceptable limit of <=5.

**5. H-Bond Acceptors:** Ligand A (5) and Ligand B (4) are both within the acceptable limit of <=10.

**6. QED:** Both ligands (0.72 and 0.613) have good drug-likeness scores, exceeding the 0.5 threshold.

**7. DILI:** Ligand A (50.33) has a moderate DILI risk, but is acceptable. Ligand B (21.908) has a much lower, and more favorable, DILI risk.

**8. BBB:** Both ligands have good BBB penetration (77.976 and 75.339), exceeding the desirable >70 threshold for CNS targets.

**9. Caco-2 Permeability:** Ligand A (-5.074) and Ligand B (-4.623) both have negative values, indicating poor permeability. This is a concern for both.

**10. Aqueous Solubility:** Both ligands have poor aqueous solubility (-2.867 and -2.033). This could pose formulation challenges.

**11. hERG Inhibition:** Both ligands have low hERG inhibition risk (0.2 and 0.528).

**12. Microsomal Clearance:** Ligand A (20.213) has a lower (better) microsomal clearance than Ligand B (61.296), suggesting better metabolic stability.

**13. In vitro Half-Life:** Ligand A (-15.634) has a negative half-life, which is unusual and suggests rapid metabolism or instability. Ligand B (14.526) has a reasonable half-life.

**14. P-gp Efflux:** Both ligands have low P-gp efflux liability (0.109 and 0.298), which is favorable for CNS penetration.

**15. Binding Affinity:** Ligand A (-8.5 kcal/mol) has a significantly stronger binding affinity than Ligand B (-6.4 kcal/mol). This is a substantial advantage.

**Overall Assessment:**

While both ligands have some drawbacks (poor Caco-2 and solubility), Ligand A's significantly stronger binding affinity (-8.5 vs -6.4 kcal/mol) is a major advantage, potentially outweighing its slightly higher TPSA and the unusual negative half-life. The lower microsomal clearance is also a positive. Ligand B has a better DILI profile and half-life, but the weaker binding affinity is a significant concern for a GPCR target. Given the importance of affinity for GPCRs, and the acceptable BBB penetration for both, Ligand A is the more promising candidate.

Output:
1
2025-04-17 04:30:39,975 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (348.487 and 349.431 Da) are within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (49.85) is excellent, falling well below the 90 Angstroms threshold for CNS targets. Ligand B (94.81) is higher, but still potentially acceptable, though less ideal.

**3. logP:** Ligand A (2.607) is optimal (1-3). Ligand B (0.656) is a bit low, potentially hindering membrane permeability.

**4. H-Bond Donors:** Ligand A (0) is good. Ligand B (3) is acceptable, within the limit of 5.

**5. H-Bond Acceptors:** Ligand A (3) is good. Ligand B (5) is acceptable, within the limit of 10.

**6. QED:** Both ligands (0.693 and 0.701) have good drug-likeness scores, exceeding the 0.5 threshold.

**7. DILI:** Ligand A (7.794) has a very low DILI risk. Ligand B (42.264) is still relatively low, but higher than A.

**8. BBB:** Ligand A (85.731) has excellent BBB penetration potential, exceeding the 70% threshold. Ligand B (40.132) is significantly lower, a major drawback for a CNS target.

**9. Caco-2 Permeability:** Ligand A (-4.538) is poor. Ligand B (-5.021) is also poor. This is a negative for both, but less critical given the focus on CNS penetration.

**10. Aqueous Solubility:** Both ligands (-2.058 and -1.938) have poor aqueous solubility. This could pose formulation challenges, but is less critical than BBB penetration for a CNS target.

**11. hERG Inhibition:** Both ligands (0.326 and 0.242) have low hERG inhibition risk, which is good.

**12. Microsomal Clearance:** Ligand A (40.137) has moderate clearance. Ligand B (35.325) has slightly lower clearance, suggesting better metabolic stability.

**13. In vitro Half-Life:** Ligand B (33.941) has a significantly longer half-life than Ligand A (2.919), which is a positive.

**14. P-gp Efflux:** Both ligands (0.054 and 0.13) have low P-gp efflux, which is favorable for CNS exposure.

**15. Binding Affinity:** Ligand B (-8.2 kcal/mol) has a significantly stronger binding affinity than Ligand A (-7.3 kcal/mol). This 0.9 kcal/mol difference is substantial and could outweigh some of the ADME drawbacks of Ligand B.

**Overall Assessment:**

Ligand A excels in TPSA, BBB, and DILI, making it a good starting point for CNS penetration. However, its Caco-2 permeability is poor and its binding affinity is weaker. Ligand B has a much stronger binding affinity and better metabolic stability (lower Cl_mic, longer t1/2) but suffers from lower BBB penetration and a slightly higher DILI risk.

Given the GPCR-specific priorities, particularly the importance of BBB penetration for CNS targets, and the significant affinity advantage of Ligand B, I believe **Ligand B** is the more promising drug candidate. The stronger binding is likely to be more impactful than the slightly lower BBB score, and further optimization could potentially improve its BBB penetration.

Output:
1
2025-04-17 04:30:39,975 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (378.881 and 358.385 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (62.66) is significantly better than Ligand B (77.92). For CNS targets, we want TPSA <= 90, and A is much closer to the ideal <=60. B is pushing the upper limit.

**3. logP:** Ligand A (3.822) is within the optimal 1-3 range, while Ligand B (0.821) is slightly below, potentially hindering permeation.

**4. H-Bond Donors:** Both have 1 HBD, which is acceptable.

**5. H-Bond Acceptors:** Ligand A has 5, and Ligand B has 4, both are within the acceptable limit of <=10.

**6. QED:** Both ligands have similar QED values (0.878 and 0.731), indicating good drug-likeness.

**7. DILI:** Ligand A (56.844) has a higher DILI risk than Ligand B (30.322). This is a negative for A.

**8. BBB:** Both ligands have excellent BBB penetration (77.705 and 76.735), exceeding the desirable >70 threshold for CNS targets.

**9. Caco-2:** Both have negative Caco-2 values, which is unusual and difficult to interpret without further context. However, we can assume they are both relatively poor in this regard.

**10. Solubility:** Both have negative solubility values, again unusual. We can assume they are both relatively poorly soluble.

**11. hERG:** Ligand A (0.758) has a slightly higher hERG risk than Ligand B (0.203). Lower is better, so B is preferable.

**12. Cl_mic:** Ligand B (-10.542) has significantly lower (better) microsomal clearance than Ligand A (27.221), indicating better metabolic stability.

**13. t1/2:** Ligand B (-9.941) has a longer in vitro half-life than Ligand A (14.852).

**14. Pgp:** Both ligands have very low Pgp efflux liability (0.65 and 0.03), which is excellent for CNS penetration.

**15. Binding Affinity:** Both ligands have very strong binding affinities (-9.0 and -8.0 kcal/mol). Ligand A is slightly better, but the difference is less than 1.5 kcal/mol.

**Overall Assessment:**

While Ligand A has slightly better binding affinity and BBB penetration, Ligand B is superior in most other critical ADME properties. Specifically, Ligand B has a significantly lower DILI risk, better metabolic stability (lower Cl_mic and longer t1/2), lower hERG risk, and a more favorable logP. The TPSA is also better for Ligand A. Given the GPCR-specific priorities, the improved ADME profile of Ligand B outweighs the minor affinity advantage of Ligand A.

Output:
1
2025-04-17 04:30:39,975 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (346.391 and 347.459 Da) fall comfortably within the ideal 200-500 Da range.

**TPSA:** Ligand A (116.12) is slightly above the optimal <90 for CNS targets, but still reasonable. Ligand B (91.32) is better, falling within the preferred range.

**logP:** Ligand A (0.478) is quite low, potentially hindering permeability. Ligand B (2.686) is much better, falling within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A has 2 HBD and 6 HBA, which are acceptable. Ligand B has 3 HBD and 4 HBA, also acceptable.

**QED:** Both ligands have similar QED values (0.666 and 0.64), indicating good drug-likeness.

**DILI:** Ligand A (54.168) has a higher DILI risk than Ligand B (27.065), though both are below the concerning threshold of 60.

**BBB:** This is crucial for a CNS target. Ligand A (32.648) has a very low BBB penetration percentile, making it unlikely to reach the target in the brain. Ligand B (46.103) has a better, though still not ideal, BBB percentile.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.649 and -5.052), which is unusual and suggests poor permeability. This is a significant concern for both.

**Aqueous Solubility:** Both ligands have negative solubility values (-1.883 and -2.877), which is also concerning and suggests poor solubility.

**hERG Inhibition:** Both ligands show very low hERG inhibition risk (0.065 and 0.127).

**Microsomal Clearance:** Ligand A (-6.776) has a more negative value, suggesting lower clearance and better metabolic stability than Ligand B (26.67).

**In vitro Half-Life:** Ligand A (24.236 hours) has a better in vitro half-life than Ligand B (-10.895 hours).

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.007 and 0.049), which is favorable for CNS penetration.

**Binding Affinity:** Ligand B (-8.2 kcal/mol) has a slightly better binding affinity than Ligand A (-8.0 kcal/mol), although the difference is small.

**Overall Assessment:**

Ligand B is significantly better due to its more favorable logP, BBB penetration, and lower DILI risk. While both have poor Caco-2 and solubility, the improved CNS penetration potential of Ligand B outweighs the slightly better metabolic stability and half-life of Ligand A. The small difference in binding affinity is not enough to overcome the ADME deficiencies of Ligand A.

Output:
1
2025-04-17 04:30:39,975 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (350.375 and 347.459 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (104.98) is slightly above the optimal <90 for CNS targets, but still reasonable. Ligand B (73.74) is well within the desired range.

**logP:** Ligand A (-0.959) is a bit low, potentially hindering permeation. Ligand B (2.216) is within the optimal 1-3 range. This is a significant advantage for Ligand B.

**H-Bond Donors/Acceptors:** Both have 1 HBD, which is good. Ligand A has 6 HBA, acceptable. Ligand B has 4 HBA, also acceptable.

**QED:** Both ligands have good QED scores (0.635 and 0.821), indicating good drug-like properties.

**DILI:** Ligand A (22.024) has a much lower DILI risk than Ligand B (35.479), which is a positive.

**BBB:** Both ligands have similar BBB penetration (51.803 and 51.221). Neither is above the desirable >70, but this isn't a dealbreaker given the other factors.

**Caco-2 Permeability:** Both have negative Caco-2 values (-5.217 and -4.743), which is unusual and suggests poor permeability. This is a concern for both.

**Aqueous Solubility:** Both have negative solubility values (-1.258 and -1.884), indicating poor solubility. This could pose formulation challenges.

**hERG:** Both have low hERG inhibition risk (0.105 and 0.374).

**Microsomal Clearance:** Ligand A (5.441) has significantly lower microsomal clearance than Ligand B (47.327), indicating better metabolic stability.

**In vitro Half-Life:** Ligand A (14.644) has a longer half-life than Ligand B (8.817).

**P-gp Efflux:** Both have very low P-gp efflux liability (0.002 and 0.09).

**Binding Affinity:** Both ligands have excellent binding affinity (-7.8 and -7.9 kcal/mol), which is the most important factor. The difference is minimal.

**Overall Assessment:**

Ligand B has a better logP, which is crucial for GPCR ligands. However, Ligand A demonstrates superior metabolic stability (lower Cl_mic, longer t1/2) and a significantly lower DILI risk. Both have poor Caco-2 and solubility, which are drawbacks. Given the importance of metabolic stability and safety (DILI) for a CNS drug, and the similar binding affinities, Ligand A is slightly more promising.

Output:
0
2025-04-17 04:30:39,975 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (355.494 Da) is slightly higher than Ligand B (344.459 Da), but both are acceptable.

**TPSA:** Ligand A (46.61) is excellent for CNS penetration, well below the 90 A^2 threshold. Ligand B (78.35) is higher, but still reasonable, though less optimal for CNS targets.

**logP:** Ligand A (3.835) is at the upper end of the optimal range (1-3), while Ligand B (2.208) is closer to the lower end. While both are acceptable, a higher logP can sometimes lead to off-target effects, but is generally acceptable for GPCRs.

**H-Bond Donors/Acceptors:** Ligand A (0 HBD, 3 HBA) is preferable to Ligand B (2 HBD, 5 HBA) as fewer H-bonds generally improve BBB penetration.

**QED:** Both ligands have good QED scores (A: 0.652, B: 0.768), indicating good drug-like properties.

**DILI:** Ligand A (27.608) has a significantly lower DILI risk than Ligand B (39.085), which is a clear advantage.

**BBB:** This is a critical parameter for a CNS target like DRD2. Ligand A (93.912) has a very high BBB percentile, making it highly likely to cross the blood-brain barrier. Ligand B (47.15) has a poor BBB percentile, which is a major drawback.

**Caco-2 Permeability:** Ligand A (-3.992) has poor Caco-2 permeability, while Ligand B (-4.913) is also poor. This isn't a major concern given the CNS target, as BBB penetration is more important.

**Aqueous Solubility:** Ligand A (-4.392) and Ligand B (-1.535) both have poor solubility.

**hERG:** Both ligands have low hERG inhibition risk (A: 0.68, B: 0.512).

**Microsomal Clearance:** Ligand A (118.04) has higher microsomal clearance than Ligand B (53.208), suggesting lower metabolic stability.

**In vitro Half-Life:** Ligand B (63.478) has a significantly longer in vitro half-life than Ligand A (-4.738), which is a positive attribute.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (A: 0.462, B: 0.142), which is good for CNS penetration.

**Binding Affinity:** Both ligands have the same binding affinity (-7.1 kcal/mol), which is excellent.

**Overall Assessment:**

Ligand A is strongly favored due to its excellent BBB penetration (93.912) and lower DILI risk (27.608). While it has slightly higher clearance and lower Caco-2 permeability, the importance of BBB penetration for a CNS target outweighs these drawbacks, especially given the equal binding affinity. Ligand B's poor BBB penetration is a significant hurdle.

Output:
0
2025-04-17 04:30:39,976 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (384.57) is slightly higher than Ligand B (367.87), but both are acceptable.

**TPSA:** Both ligands have TPSA values below 90, which is good for CNS penetration. Ligand B (56.49) is better than Ligand A (67.43).

**logP:** Both ligands have logP values within the optimal range (1-3), but Ligand B (4.36) is pushing the upper limit and could potentially lead to solubility issues or off-target interactions. Ligand A (2.87) is more favorable.

**H-Bond Donors/Acceptors:** Ligand A has 2 HBD and 5 HBA, while Ligand B has 0 HBD and 6 HBA. Both are within acceptable limits (<=5 HBD and <=10 HBA).

**QED:** Both ligands have QED values above 0.5, indicating good drug-likeness. Ligand A (0.609) is slightly better than Ligand B (0.526).

**DILI:** Ligand A (57.70) has a lower DILI risk than Ligand B (85.69), which is a significant advantage.

**BBB:** Ligand A (64.64) shows significantly better BBB penetration potential than Ligand B (48.39). This is a crucial factor for a CNS target like DRD2.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values, which is unusual and suggests poor permeability. However, these values are on a scale where negative values are possible and don't necessarily disqualify a compound.

**Aqueous Solubility:** Both ligands have negative solubility values, indicating poor aqueous solubility. This is a concern, but can sometimes be mitigated through formulation strategies.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.552 and 0.539 respectively).

**Microsomal Clearance:** Ligand B (34.16) has a lower microsomal clearance than Ligand A (65.60), indicating better metabolic stability.

**In vitro Half-Life:** Ligand B (-7.94) has a longer half-life than Ligand A (20.49).

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.608 and 0.579 respectively).

**Binding Affinity:** Ligand B (-9.9 kcal/mol) has a significantly stronger binding affinity than Ligand A (-7.0 kcal/mol). This is a substantial advantage, potentially outweighing some of the ADME drawbacks.

**Overall Assessment:**

Ligand B has a superior binding affinity, better metabolic stability, and longer half-life. However, Ligand A has a better BBB score, lower DILI risk, and a more favorable logP. Given the importance of CNS penetration for a DRD2 ligand, and the substantial difference in binding affinity, Ligand B is the more promising candidate despite its slightly higher DILI risk and less favorable logP. The strong binding affinity could allow for a lower dose, potentially mitigating the DILI risk.

Output:
1
2025-04-17 04:30:39,976 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (338.415 and 356.413 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (106.75) is better than Ligand B (66.57), both are under the 90 A^2 threshold for CNS targets.

**logP:** Both ligands have good logP values (2.436 and 3.477), falling within the optimal 1-3 range. Ligand B is slightly higher, which could be beneficial for membrane permeability but needs to be balanced with solubility.

**H-Bond Donors/Acceptors:** Ligand A has 3 HBD and 7 HBA, while Ligand B has 1 HBD and 4 HBA. Both are within acceptable limits (<=5 HBD and <=10 HBA).

**QED:** Both ligands have good QED scores (0.635 and 0.774), indicating good drug-like properties.

**DILI:** Ligand A (59.907) has a higher DILI risk than Ligand B (19.504). This is a significant drawback for Ligand A.

**BBB:** Ligand B (89.608) has a much better BBB penetration percentile than Ligand A (59.519). This is *critical* for a CNS target like DRD2.

**Caco-2 Permeability:** Ligand A (-5.386) has worse Caco-2 permeability than Ligand B (-4.416).

**Aqueous Solubility:** Both ligands have poor aqueous solubility (-3.138 and -3.735). This is a concern, but can sometimes be mitigated with formulation strategies.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.828 and 0.642).

**Microsomal Clearance:** Ligand B (27.408) has significantly lower microsomal clearance than Ligand A (67.033), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand B (5.738) has a longer in vitro half-life than Ligand A (13.368).

**P-gp Efflux:** Ligand A (0.089) has lower P-gp efflux than Ligand B (0.231), which is favorable for CNS penetration.

**Binding Affinity:** Both ligands have very similar and excellent binding affinities (-8.3 and -8.1 kcal/mol). The difference is negligible.

**Overall Assessment:**

Ligand B is clearly the better candidate. While both have good potency, Ligand B excels in critical ADME properties for a CNS-targeting GPCR: significantly better BBB penetration, lower DILI risk, better metabolic stability (lower Cl_mic and longer t1/2), and better Caco-2 permeability. The slightly higher P-gp efflux is a minor concern compared to the advantages in BBB and metabolic stability. The lower HBD/HBA count in Ligand B might also contribute to better permeability.

Output:
1
2025-04-17 04:30:39,976 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (371.547 and 362.461 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (78.51) is better than Ligand B (49.85). Both are below the 90 A^2 threshold desirable for CNS targets.

**logP:** Ligand A (1.029) is within the optimal 1-3 range, while Ligand B (3.797) is approaching the upper limit.

**H-Bond Donors/Acceptors:** Ligand A has 2 HBD and 4 HBA, while Ligand B has 0 HBD and 3 HBA. Both are within acceptable limits.

**QED:** Ligand A (0.731) has a better QED score than Ligand B (0.586), indicating a more drug-like profile.

**DILI:** Ligand A (14.967) has a significantly lower DILI risk than Ligand B (23.614), which is a crucial advantage.

**BBB:** Ligand B (78.209) has a better BBB penetration score than Ligand A (66.576), which is a key consideration for a CNS target like DRD2.

**Caco-2 Permeability:** Ligand A (-5.089) has a worse Caco-2 permeability than Ligand B (-3.991).

**Aqueous Solubility:** Ligand A (-1.986) has better aqueous solubility than Ligand B (-3.244).

**hERG:** Ligand A (0.22) has a lower hERG inhibition liability than Ligand B (0.776), which is a safety advantage.

**Microsomal Clearance:** Ligand A (-6.076) has much lower microsomal clearance than Ligand B (91.091), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (-3.059) has a longer in vitro half-life than Ligand B (7.561).

**P-gp Efflux:** Ligand A (0.023) has lower P-gp efflux liability than Ligand B (0.146), which is beneficial for CNS penetration.

**Binding Affinity:** Ligand A (-7.2 kcal/mol) has a slightly better binding affinity than Ligand B (-6.4 kcal/mol). While the difference is not huge, it's still a positive factor.

**Overall Assessment:**

Ligand A demonstrates a superior ADMET profile overall. It has a lower DILI risk, better metabolic stability (lower Cl_mic and longer t1/2), lower hERG inhibition, lower P-gp efflux, better solubility, and a slightly better binding affinity. While Ligand B has a better BBB score and Caco-2 permeability, the other advantages of Ligand A, especially the safety and metabolic stability aspects, outweigh these. For a CNS target, a good BBB score is important, but it's not the only factor. A compound with poor metabolic stability or high toxicity will likely fail in development.

Output:
1
2025-04-17 04:30:39,976 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight (MW):** Both ligands (378.925 and 384.611 Da) fall comfortably within the ideal 200-500 Da range.

**2. TPSA:** Both ligands have a TPSA of 40.62, which is excellent for CNS penetration, being well below the 90 A^2 threshold.

**3. logP:** Both ligands have logP values within the optimal range (3.511 and 3.255).

**4. H-Bond Donors (HBD):** Both have 0 HBD, which is acceptable.

**5. H-Bond Acceptors (HBA):** Ligand A has 3 HBA, and Ligand B has 4 HBA, both within the acceptable limit of 10.

**6. QED:** Ligand A (0.804) has a better QED score than Ligand B (0.659), indicating a more drug-like profile.

**7. DILI:** Ligand A (37.301) has a slightly higher DILI risk than Ligand B (29.391), but both are below the concerning threshold of 60.

**8. BBB:** Ligand A (88.135) has a significantly better BBB penetration percentile than Ligand B (76.735). This is a critical advantage for a CNS target like DRD2.

**9. Caco-2 Permeability:** Both have negative Caco-2 values (-4.998 and -5.076), which is unusual and suggests poor permeability. However, these values are on a strange scale and may not be directly comparable.

**10. Aqueous Solubility:** Both have negative solubility values (-4.492 and -3.739), also unusual and suggesting poor solubility.

**11. hERG Inhibition:** Both ligands show low hERG inhibition liability (0.659 and 0.678).

**12. Microsomal Clearance (Cl_mic):** Ligand B (84.704) has a higher microsomal clearance than Ligand A (43.994), indicating faster metabolism and potentially lower *in vivo* exposure.

**13. In vitro Half-Life:** Ligand A (0.223) has a slightly longer half-life than Ligand B (0.104), but both are very short.

**14. P-gp Efflux:** Both ligands have similar P-gp efflux liability (0.584 and 0.521).

**15. Binding Affinity:** Ligand A (-8.3 kcal/mol) has a significantly stronger binding affinity than Ligand B (-7.2 kcal/mol). This is a substantial difference (1.1 kcal/mol), which can outweigh some ADME drawbacks.

**Overall Assessment:**

Ligand A is the more promising candidate. Its superior BBB penetration, significantly stronger binding affinity, better QED score, and lower microsomal clearance outweigh the slightly higher DILI risk. The poor Caco-2 and solubility values are concerning for both, but the strong affinity of Ligand A suggests it might still be effective *in vivo* despite these issues. The difference in binding affinity is substantial enough to prioritize Ligand A for further optimization.

Output:
1
2025-04-17 04:30:39,976 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 drug candidates, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (352.431 Da and 349.519 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (81.01) is better than Ligand B (52.65). Both are below the 90 A^2 threshold for CNS targets, but Ligand B is closer to optimal.

**3. logP:** Both ligands have good logP values (2.729 and 2.408), falling within the 1-3 range.

**4. H-Bond Donors:** Both have 1 HBD, which is acceptable.

**5. H-Bond Acceptors:** Ligand A has 5 HBA, while Ligand B has 3. Both are below the 10 threshold.

**6. QED:** Ligand A (0.851) has a significantly better QED score than Ligand B (0.487), indicating a more drug-like profile.

**7. DILI:** Ligand A (38.969) has a lower DILI risk than Ligand B (5.584), both are good.

**8. BBB:** Ligand A (65.529) has a slightly better BBB percentile than Ligand B (60.876), although both are below the desirable >70 for CNS targets.

**9. Caco-2:** Both have negative Caco-2 values, indicating poor permeability. Ligand A (-4.453) is slightly better than Ligand B (-4.888).

**10. Solubility:** Both have negative solubility values, indicating poor solubility. Ligand A (-2.64) is slightly better than Ligand B (-1.524).

**11. hERG:** Ligand A (0.138) has a much lower hERG risk than Ligand B (0.6).

**12. Cl_mic:** Ligand B (-15.25) has a significantly lower (better) microsomal clearance than Ligand A (48.657), suggesting better metabolic stability.

**13. t1/2:** Ligand B (-8.743) has a longer in vitro half-life than Ligand A (29.038), which is desirable.

**14. Pgp:** Ligand A (0.013) has a much lower Pgp efflux liability than Ligand B (0.051), which is crucial for CNS penetration.

**15. Binding Affinity:** Both ligands have excellent binding affinities (-7.1 and -7.2 kcal/mol). The difference is negligible.

**Overall Assessment:**

Ligand A excels in QED, DILI, hERG, and Pgp efflux. Ligand B has better metabolic stability (lower Cl_mic) and a longer half-life. While both have poor Caco-2 and solubility, the lower Pgp efflux of Ligand A is a significant advantage for CNS penetration, given that DRD2 is a CNS target. The better QED and safety profiles (DILI, hERG) of Ligand A also contribute to its favorability. The slightly better BBB score for Ligand A is also a plus.

Output:
1
2025-04-17 04:30:39,977 - INFO - Reasoning:

Let's analyze Ligand A and Ligand B based on the provided guidelines, prioritizing GPCR-specific properties (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (368.77 and 346.39 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (68.29) is significantly better than Ligand B (95.34). For CNS targets, we want TPSA <= 90, so Ligand A is preferable.

**logP:** Ligand A (4.221) is slightly higher than the optimal range (1-3), but still potentially acceptable. Ligand B (2.411) is within the optimal range. However, for a GPCR, a slightly higher logP can be tolerated if other properties are favorable.

**H-Bond Donors/Acceptors:** Both have 1 HBD, which is good. Ligand A has 4 HBA, and Ligand B has 7 HBA. Both are acceptable, but lower is generally preferred.

**QED:** Both ligands have similar QED values (0.823 and 0.807), indicating good drug-likeness.

**DILI:** Ligand A (84.413) has a higher DILI risk than Ligand B (69.717), which is less desirable.

**BBB:** Both ligands have similar BBB penetration (59.25% and 60.64%), which is below the desirable >70% for CNS targets. This is a significant drawback for both.

**Caco-2 Permeability:** Both have negative Caco-2 values (-4.11 and -4.70), which is unusual and suggests poor permeability.

**Aqueous Solubility:** Both have negative solubility values (-5.51 and -3.02), indicating very poor aqueous solubility. This is a major concern for bioavailability.

**hERG Inhibition:** Both ligands show low hERG inhibition liability (0.384 and 0.206), which is good.

**Microsomal Clearance:** Ligand A (101.45) has higher microsomal clearance than Ligand B (79.55), indicating lower metabolic stability.

**In vitro Half-Life:** Ligand B (9.79) has a significantly longer half-life than Ligand A (67.32), which is a major advantage.

**P-gp Efflux:** Both ligands show low P-gp efflux liability (0.158 and 0.049), which is good for CNS penetration.

**Binding Affinity:** Ligand B (-7.9 kcal/mol) has a slightly better binding affinity than Ligand A (-8.6 kcal/mol). While both are excellent, the difference is small.

**Overall Assessment:**

Despite Ligand A having a better TPSA, its higher DILI risk, higher clearance, and shorter half-life are significant drawbacks. Ligand B, while having a slightly higher TPSA and a less optimal logP, has a better safety profile (lower DILI), better metabolic stability (lower clearance, longer half-life), and comparable binding affinity. The similar BBB values are a concern for both, but the other ADME properties of Ligand B are more favorable.

Output:
1
2025-04-17 04:30:39,977 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (351.403 and 365.455 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (113.69) is better than Ligand B (71.97) as it is closer to the ideal range for CNS targets (<=90). Ligand B is excellent.

**logP:** Ligand A (0.716) is a bit low, potentially hindering permeability. Ligand B (1.294) is better, falling within the optimal 1-3 range.

**H-Bond Donors:** Ligand A (3) is acceptable. Ligand B (0) is excellent.

**H-Bond Acceptors:** Both ligands (6) are within the acceptable limit of <=10.

**QED:** Both ligands have good QED scores (0.667 and 0.76, respectively), indicating drug-likeness.

**DILI:** Both ligands have low DILI risk (37.922 and 43.932 percentiles), which is favorable.

**BBB:** Ligand B (78.868) is significantly better than Ligand A (49.515) in terms of BBB penetration, a crucial factor for CNS targets like DRD2.

**Caco-2 Permeability:** Ligand A (-4.592) and Ligand B (-4.957) both have negative values, which is unusual. It's difficult to interpret without knowing the scale, but generally, higher values are preferred.

**Aqueous Solubility:** Both ligands have very poor aqueous solubility (-3.268 and -2.265). This could pose formulation challenges.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.152 and 0.162), which is good.

**Microsomal Clearance:** Ligand B (28.34) has a significantly lower microsomal clearance than Ligand A (57.951), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand B (-1.988) has a slightly better in vitro half-life than Ligand A (-36.808).

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.055 and 0.121), which is excellent for CNS penetration.

**Binding Affinity:** Both ligands have the same binding affinity (-8 kcal/mol), which is excellent.

**Conclusion:**

While both ligands have good binding affinity and acceptable safety profiles (DILI, hERG), Ligand B is the more promising candidate. Its superior BBB penetration (78.868 vs. 49.515), better logP (1.294 vs. 0.716), and lower microsomal clearance (28.34 vs. 57.951) outweigh the slightly better TPSA of Ligand A. The solubility is a concern for both, but can be addressed with formulation strategies. Given the GPCR-specific priorities, Ligand B is the better choice.

Output:
1
2025-04-17 04:30:39,977 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (339.439 and 357.401 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (64.11) is significantly better than Ligand B (78.6). For CNS targets, TPSA should be <=90, both are within this range, but A is preferable.

**logP:** Both ligands have good logP values (3.467 and 2.21), falling within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A (HBD=1, HBA=4) and Ligand B (HBD=2, HBA=5) both have reasonable numbers of H-bond donors and acceptors, well below the thresholds of 5 and 10, respectively.

**QED:** Both ligands have high QED scores (0.906 and 0.864), indicating good drug-like properties.

**DILI:** Ligand A (48.468) has a slightly higher DILI risk than Ligand B (31.718), but both are below the concerning threshold of 60.

**BBB:** Ligand B (85.343) has a substantially better BBB penetration percentile than Ligand A (72.896). This is a critical factor for a CNS target like DRD2.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.389 and -4.721), which is unusual and suggests poor permeability. This is a significant drawback for both.

**Aqueous Solubility:** Both ligands have negative solubility values (-3.734 and -2.617), indicating poor aqueous solubility. This could pose formulation challenges.

**hERG:** Both ligands have low hERG inhibition liability (0.456 and 0.449), which is favorable.

**Microsomal Clearance:** Ligand A (28.261) has higher microsomal clearance than Ligand B (14.43), suggesting lower metabolic stability.

**In vitro Half-Life:** Both have negative half-lives (-2.526 and -2.06), which is not physically meaningful and indicates a problem with the data or model.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.14 and 0.089), which is good, especially for CNS penetration.

**Binding Affinity:** Ligand B (-7.6 kcal/mol) has a significantly stronger binding affinity than Ligand A (-9.4 kcal/mol). This is a major advantage, potentially outweighing some ADME concerns.

**Overall Assessment:**

While Ligand A has a better TPSA and slightly lower DILI, Ligand B excels in the most critical areas for a CNS-targeting GPCR ligand: significantly better BBB penetration and substantially stronger binding affinity. The negative Caco-2 and solubility values are concerning for both, but the strong affinity of Ligand B makes it more likely to be optimized to overcome these issues. The lower clearance of Ligand B is also a positive.

Output:
1
2025-04-17 04:30:39,977 - INFO - Batch 119 complete. Total preferences: 1904
2025-04-17 04:30:39,977 - INFO - Processing batch 120/512...
2025-04-17 04:31:21,695 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (346.471 and 345.403 Da) are within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (60.85) is significantly better than Ligand B (93.26). For CNS targets, TPSA should be <=90, and A is comfortably within this range, while B is close to the upper limit and less desirable.

**3. logP:** Both ligands have good logP values (1.816 and 1.566), falling within the optimal range of 1-3.

**4. H-Bond Donors:** Both have 1 HBD, which is acceptable.

**5. H-Bond Acceptors:** Ligand A has 3 HBA, and Ligand B has 6. Both are within the acceptable limit of <=10, but A is preferable.

**6. QED:** Ligand B (0.822) has a higher QED than Ligand A (0.565), suggesting a more drug-like profile overall. However, this is less critical than CNS penetration for a CNS target.

**7. DILI:** Ligand A (6.01) has a lower DILI risk than Ligand B (56.689), which is a significant advantage.

**8. BBB:** Ligand B (74.758) has a better BBB penetration score than Ligand A (65.374). Both are above the 70% threshold, but B is closer. This is a critical factor for DRD2, a CNS target.

**9. Caco-2:** Both have negative Caco-2 values, which is unusual and suggests poor permeability. This is a concern for both.

**10. Solubility:** Both have negative solubility values, indicating poor aqueous solubility. This is a concern for both.

**11. hERG:** Both ligands have very low hERG inhibition liability (0.205 and 0.147), which is excellent.

**12. Cl_mic:** Ligand A (24.052) has a lower microsomal clearance than Ligand B (35.797), suggesting better metabolic stability.

**13. t1/2:** Ligand B (-6.526) has a longer in vitro half-life than Ligand A (-4.71), which is a positive.

**14. Pgp:** Both ligands have very low P-gp efflux liability (0.031 and 0.11), which is favorable for CNS penetration.

**15. Binding Affinity:** Both ligands have the same binding affinity (-7.9 kcal/mol), which is excellent and removes this as a differentiating factor.

**Overall Assessment:**

While Ligand B has a slightly better BBB score and QED, Ligand A has a significantly lower DILI risk, better TPSA, and lower microsomal clearance. Given the CNS target (DRD2), BBB is crucial, but the lower TPSA and DILI risk of Ligand A are also highly valuable. The comparable binding affinity means we can prioritize the ADME properties. The lower TPSA of Ligand A is a significant advantage for CNS penetration, potentially offsetting the slightly lower BBB score.

Output:
0
2025-04-17 04:31:21,695 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (353.419 and 345.443 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (115.03) is slightly above the optimal <90 for CNS targets, but still reasonable. Ligand B (71.53) is excellent, well below 90.

**logP:** Ligand A (-0.978) is a bit low, potentially hindering permeability. Ligand B (2.175) is within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A has 4 HBD and 6 HBA, both acceptable. Ligand B has 1 HBD and 4 HBA, also acceptable.

**QED:** Both ligands have good QED scores (0.525 and 0.55), indicating drug-like properties.

**DILI:** Ligand A (21.869) has a lower DILI risk than Ligand B (29.081), both are good.

**BBB:** This is a crucial parameter for a CNS target. Ligand A (21.946) has a poor BBB penetration percentile. Ligand B (73.982) has a very good BBB penetration percentile.

**Caco-2 Permeability:** Ligand A (-5.256) has poor Caco-2 permeability. Ligand B (-4.89) is also not great, but slightly better than A.

**Aqueous Solubility:** Both have negative solubility values, indicating poor solubility. Ligand A (-0.879) is slightly better than Ligand B (-2.095).

**hERG Inhibition:** Both ligands show very low hERG inhibition risk (0.101 and 0.555).

**Microsomal Clearance:** Ligand A (-7.898) has significantly lower (better) microsomal clearance than Ligand B (7.633), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand B (10.896 hours) has a much longer half-life than Ligand A (1.087 hours).

**P-gp Efflux:** Ligand A (0.025) has very low P-gp efflux, which is excellent for CNS penetration. Ligand B (0.104) also has low P-gp efflux, but higher than A.

**Binding Affinity:** Both ligands have very similar and strong binding affinities (-7.0 and -7.7 kcal/mol). The difference is not substantial enough to override other factors.

**Overall Assessment:**

Ligand B is the stronger candidate. While Ligand A has better metabolic stability (lower Cl_mic) and lower P-gp efflux, Ligand B has a significantly better BBB penetration (73.982 vs 21.946), a more favorable logP, and a longer half-life. For a CNS target like DRD2, BBB penetration is paramount. The slightly better logP and half-life of Ligand B also contribute to its favorability. The affinity is comparable between the two.

Output:
1
2025-04-17 04:31:21,696 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (403.28 Da) is slightly higher than Ligand B (352.483 Da), but both are acceptable.

**2. TPSA:** Ligand A (69.04) is excellent, falling well below the 90 A^2 threshold for CNS targets. Ligand B (75.64) is still reasonable, but less optimal.

**3. logP:** Ligand A (3.873) is at the higher end of the optimal range (1-3), while Ligand B (1.113) is at the lower end. A logP that's too low can hinder permeation.

**4. H-Bond Donors:** Both ligands have 1 HBD, which is within the acceptable limit of <=5.

**5. H-Bond Acceptors:** Ligand A has 6 HBAs, and Ligand B has 8. Both are below the 10 limit, but Ligand A is preferable.

**6. QED:** Both ligands have good QED scores (A: 0.479, B: 0.708). Ligand B is better here.

**7. DILI:** Ligand A (79.721) has a higher DILI risk than Ligand B (42.846). This is a significant drawback for Ligand A.

**8. BBB:** Both ligands have good BBB penetration (A: 68.903, B: 79.411). Ligand B is better, exceeding 70%, which is desirable for CNS targets.

**9. Caco-2:** Both have negative Caco-2 values which is unusual and suggests poor permeability.

**10. Solubility:** Both ligands have negative solubility values, which is also unusual and suggests poor solubility.

**11. hERG:** Both ligands have low hERG inhibition risk (A: 0.767, B: 0.871).

**12. Cl_mic:** Ligand A (113.21) has higher microsomal clearance than Ligand B (45.932), indicating lower metabolic stability.

**13. t1/2:** Ligand A (77.415) has a longer in vitro half-life than Ligand B (23.473). This is a positive for Ligand A.

**14. Pgp:** Ligand A (0.535) has lower P-gp efflux liability than Ligand B (0.014), which is beneficial for CNS penetration.

**15. Binding Affinity:** Ligand A (-8.5 kcal/mol) has significantly stronger binding affinity than Ligand B (-0.0 kcal/mol). This is a major advantage for Ligand A.

**Overall Assessment:**

Ligand A has a much stronger binding affinity and better Pgp efflux properties, and a longer half-life. However, it has a higher DILI risk and higher microsomal clearance. Ligand B has better QED, lower DILI, better BBB penetration, and lower clearance, but its binding affinity is very weak.

Given the GPCR-specific priorities, strong binding affinity is crucial. The significant difference in binding affinity (-8.5 vs -0.0 kcal/mol) outweighs the drawbacks of Ligand A, *assuming* the DILI risk can be mitigated through structural modifications. The better BBB of Ligand B is less important given Ligand A's lower Pgp efflux.

Output:
1
2025-04-17 04:31:21,696 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (362.459 Da) is slightly lower, which could be beneficial for permeability.

**2. TPSA:** Ligand A (74.57) is significantly better than Ligand B (93.01). For CNS targets, TPSA < 90 is preferred, and A is closer to this threshold.

**3. logP:** Ligand B (1.199) is better than Ligand A (0.141). A logP between 1-3 is optimal, and B falls within this range, while A is quite low, potentially hindering membrane permeability.

**4. H-Bond Donors:** Both have acceptable HBD counts (A: 0, B: 1), well below the limit of 5.

**5. H-Bond Acceptors:** Both have the same HBA count (7), which is acceptable (<=10).

**6. QED:** Both have good QED values (A: 0.756, B: 0.812), indicating drug-like properties.

**7. DILI:** Ligand A (46.375) has a much lower DILI risk than Ligand B (80.729). This is a significant advantage for A.

**8. BBB:** Both ligands have similar BBB penetration (A: 50.95, B: 51.066). Neither is exceptionally high (>70), but they are comparable.

**9. Caco-2 Permeability:** Both have negative Caco-2 values (-5.222 and -5.555). This is unusual and suggests poor permeability based on this metric.

**10. Aqueous Solubility:** Both have negative solubility values (-0.446 and -2.38). This suggests poor solubility.

**11. hERG Inhibition:** Both have low hERG inhibition liability (A: 0.31, B: 0.138), which is good.

**12. Microsomal Clearance:** Ligand B (-3.071) has a negative clearance, which is not physically possible. This is likely an error in the data, and we should treat this with caution. Ligand A (22.38) has a higher, but still reasonable, clearance.

**13. In vitro Half-Life:** Ligand A (-6.785) has a negative half-life, which is not physically possible. This is likely an error in the data, and we should treat this with caution. Ligand B (-0.981) also has a negative half-life.

**14. P-gp Efflux:** Both have very low P-gp efflux liability (A: 0.024, B: 0.059), which is favorable for CNS penetration.

**15. Binding Affinity:** Ligand B (-7.6) has slightly better binding affinity than Ligand A (-7.4). While the difference is small (0.2 kcal/mol), it's still a positive for B.

**Overall Assessment:**

Despite the slightly better affinity of Ligand B, Ligand A is the more promising candidate. The primary drivers are its significantly lower DILI risk and better TPSA. The negative values for Caco-2 and half-life are concerning for both, but the errors in the data make these less reliable. Ligand B's logP is better, but the DILI risk is a major concern. Given the GPCR-specific focus on BBB, logP, Pgp, TPSA, and affinity, the combination of lower DILI risk and better TPSA for Ligand A outweighs the slight affinity advantage of Ligand B.

Output:
0
2025-04-17 04:31:21,696 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (342.355 Da and 350.375 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (120.16) is slightly higher than Ligand B (115.97), but both are below the 140 A^2 threshold for oral absorption and reasonably close to the 90 A^2 target for CNS penetration.

**logP:** Ligand A (-1.085) is slightly hydrophilic, potentially hindering permeability. Ligand B (-1.803) is also on the hydrophilic side, but slightly better than A. Both are below the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A has 4 HBD and 4 HBA, while Ligand B has 2 HBD and 7 HBA. Both are within acceptable limits (<=5 HBD and <=10 HBA).

**QED:** Ligand B (0.662) has a better QED score than Ligand A (0.388), indicating a more drug-like profile.

**DILI:** Both ligands have similar DILI risk (47.887 and 49.399), and are both considered good (below 60).

**BBB:** Ligand A (29.12) has a significantly better BBB penetration percentile than Ligand B (25.863). This is a critical factor for a CNS target like DRD2.

**Caco-2 Permeability:** Both ligands have very poor Caco-2 permeability (-5.495 and -5.025). This is a major concern for oral bioavailability.

**Aqueous Solubility:** Both ligands have very poor aqueous solubility (-2.779 and -0.965). This could pose formulation challenges.

**hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.031 and 0.104).

**Microsomal Clearance:** Ligand A (-22.606) has a much lower (better) microsomal clearance than Ligand B (-11.228), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand B (21.205) has a significantly longer in vitro half-life than Ligand A (-19.905).

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.009 and 0.026).

**Binding Affinity:** Ligand A (-8.7 kcal/mol) has a significantly stronger binding affinity than Ligand B (-7.7 kcal/mol). This is a substantial advantage.

**Overall Assessment:**

While Ligand B has a better QED and in vitro half-life, Ligand A is superior due to its significantly stronger binding affinity (-8.7 vs -7.7 kcal/mol) and better BBB penetration (29.12 vs 25.863). The improved metabolic stability (lower Cl_mic) of Ligand A is also a positive. The poor Caco-2 and solubility are concerns for both, but can be addressed with formulation strategies. For a CNS target, strong affinity and BBB penetration are paramount, and Ligand A excels in these areas.

Output:
1
2025-04-17 04:31:21,696 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (346.431 and 350.415 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (76.46) is better than Ligand B (79.31), both are below the 90 A^2 threshold desirable for CNS targets.

**logP:** Ligand A (0.829) is slightly better than Ligand B (-0.374), falling within the optimal 1-3 range. Ligand B is a bit low, which *could* hinder permeability.

**H-Bond Donors/Acceptors:** Both have 1 HBD and 5 HBA, which are acceptable.

**QED:** Ligand A (0.774) has a slightly better QED score than Ligand B (0.661), indicating better overall drug-likeness.

**DILI:** Ligand A (39.201) has a significantly lower DILI risk than Ligand B (15.51), which is a substantial advantage.

**BBB:** Ligand A (55.642) has a better BBB penetration percentile than Ligand B (46.724), although both are below the desired >70 for CNS targets.

**Caco-2 Permeability:** Ligand A (-5.105) has a worse Caco-2 permeability than Ligand B (-4.73), indicating potentially lower intestinal absorption.

**Aqueous Solubility:** Both ligands have very poor aqueous solubility (-1.086 and -1.063 respectively). This is a concern for both, but can be addressed with formulation strategies.

**hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.095 and 0.125 respectively).

**Microsomal Clearance:** Ligand B (-6.165) has a *much* lower (better) microsomal clearance than Ligand A (12.632), suggesting greater metabolic stability.

**In vitro Half-Life:** Both have similar in vitro half-lives (19.037 and 18.433 hours).

**P-gp Efflux:** Both have low P-gp efflux liability (0.022 and 0.031 respectively).

**Binding Affinity:** Ligand B (-7.1 kcal/mol) has a slightly better binding affinity than Ligand A (-8.0 kcal/mol). While Ligand A's affinity is better, the difference is not substantial enough to outweigh other factors.

**Overall Assessment:**

Ligand A has advantages in TPSA, logP, QED, and DILI risk, and a better binding affinity. However, Ligand B has a significantly better microsomal clearance and a slightly better binding affinity. The biggest drawback of Ligand A is its higher DILI risk and worse metabolic stability. Given the CNS target and the importance of BBB penetration, a lower DILI risk and better metabolic stability are crucial. While both have poor solubility, this is a formulation challenge.

Output:
1
2025-04-17 04:31:21,696 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 drug candidates, considering the provided guidelines and GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (358.291 and 357.445 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (70.59) is higher than the preferred <90 for CNS targets, but still potentially acceptable. Ligand B (45.67) is excellent, well below the threshold.

**3. logP:** Both ligands (3.075 and 3.113) are within the optimal 1-3 range.

**4. H-Bond Donors:** Ligand A has 3 HBD, which is acceptable. Ligand B has 0, also acceptable.

**5. H-Bond Acceptors:** Both ligands have 4 HBA, within the acceptable limit of <=10.

**6. QED:** Both ligands have good QED scores (0.568 and 0.681), indicating drug-like properties. Ligand B is slightly better.

**7. DILI:** Ligand A (68.592) has a higher DILI risk than Ligand B (13.571). This is a significant negative for Ligand A.

**8. BBB:** Ligand B (92.4) has a very high BBB penetration score, which is excellent for a CNS target like DRD2. Ligand A (66.421) is lower, but still reasonably good, though not ideal.

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 values, which is unusual and suggests poor permeability. However, these values are on a scale where negative values are possible, and the absolute magnitude matters less than the relative comparison.

**10. Aqueous Solubility:** Both ligands have negative solubility values, indicating poor aqueous solubility.

**11. hERG Inhibition:** Both ligands have low hERG inhibition risk (0.716 and 0.747).

**12. Microsomal Clearance:** Ligand A (31.593) has lower microsomal clearance, suggesting better metabolic stability than Ligand B (55.093).

**13. In vitro Half-Life:** Ligand A (-23.504) has a negative half-life, which is unusual. Ligand B (8.419) has a positive half-life.

**14. P-gp Efflux:** Both ligands have low P-gp efflux liability (0.168 and 0.065), which is favorable for CNS penetration. Ligand B is slightly better.

**15. Binding Affinity:** Ligand A (-9.9) has a significantly stronger binding affinity than Ligand B (-6.4). This difference of 3.5 kcal/mol is substantial and could outweigh some of the ADME drawbacks.

**Overall Assessment:**

Ligand B clearly excels in ADME properties, particularly BBB penetration and DILI risk. However, Ligand A possesses a much stronger binding affinity. For a GPCR target in the CNS, strong affinity is paramount. While Ligand A's DILI risk is concerning, and its TPSA is a bit high, the substantial affinity advantage (-9.9 vs -6.4 kcal/mol) makes it the more promising candidate. The lower clearance and P-gp efflux also contribute positively. The unusual negative half-life for Ligand A is a red flag that would need further investigation, but the binding affinity is a strong driver.

Output:
1
2025-04-17 04:31:21,697 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (365.5 & 361.5 Da) fall comfortably within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (91.32) is slightly above the preferred <90 for CNS targets, but still reasonable. Ligand B (43.43) is excellent, well below 90.

**3. logP:** Both ligands have good logP values (2.156 & 3.712), falling within the optimal 1-3 range. Ligand B is slightly higher, which could be beneficial for membrane permeability.

**4. H-Bond Donors:** Ligand A has 3 HBD, acceptable. Ligand B has 0, also acceptable.

**5. H-Bond Acceptors:** Ligand A has 5 HBA, acceptable. Ligand B has 6 HBA, also acceptable.

**6. QED:** Both ligands have good QED scores (0.658 & 0.717), indicating good drug-like properties.

**7. DILI:** Ligand A (42.1%) has a slightly higher DILI risk than Ligand B (20.9%), but both are below the concerning threshold of 60%.

**8. BBB:** This is a critical parameter for a CNS target like DRD2. Ligand A has a BBB percentile of 42.575%, which is below the desirable >70%. Ligand B shines here with 84.529%, indicating excellent potential for brain penetration.

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.018 & -5.047), which is unusual and suggests poor intestinal absorption. This is a significant drawback for both.

**10. Aqueous Solubility:** Both ligands have negative solubility values (-2.469 & -3.836), indicating poor aqueous solubility. This could pose formulation challenges.

**11. hERG Inhibition:** Ligand A (0.083) has a very low hERG risk, excellent. Ligand B (0.839) has a slightly higher, but still relatively low, hERG risk.

**12. Microsomal Clearance:** Ligand A (18.778) has lower microsomal clearance than Ligand B (94.551), suggesting better metabolic stability.

**13. In vitro Half-Life:** Ligand B (30.15 hours) has a significantly longer half-life than Ligand A (10.194 hours), which is a major advantage for dosing convenience.

**14. P-gp Efflux:** Ligand A (0.11) has lower P-gp efflux than Ligand B (0.386), which is favorable for CNS exposure.

**15. Binding Affinity:** Ligand B (-7.2 kcal/mol) has a slightly better binding affinity than Ligand A (-8.0 kcal/mol). While A is slightly better, the difference is not substantial enough to outweigh other factors.

**Overall Assessment:**

While Ligand A has slightly better affinity and lower P-gp efflux, Ligand B is significantly superior in terms of BBB penetration (84.5% vs 42.6%), in vitro half-life (30.2h vs 10.2h), and has a lower DILI risk. The poor Caco-2 and solubility are concerning for both, but can potentially be addressed with formulation strategies. For a CNS target, BBB penetration is paramount, and Ligand B clearly excels in this area.

Output:
1
2025-04-17 04:31:21,697 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B based on the provided guidelines, prioritizing GPCR-specific properties (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (351.447 Da) is slightly lower, which could be beneficial for permeability. Ligand B (374.503 Da) is also good.

**TPSA:** Ligand A (80.23) is excellent for CNS penetration, well below the 90 A^2 threshold. Ligand B (104.73) is still reasonable, but less optimal, being above 90 A^2.

**logP:** Ligand A (1.464) is within the optimal range (1-3). Ligand B (0.086) is quite low, potentially hindering membrane permeability and CNS entry.

**H-Bond Donors/Acceptors:** Ligand A (HBD=1, HBA=5) is favorable. Ligand B (HBD=3, HBA=5) is acceptable, but the higher HBD count could slightly reduce permeability.

**QED:** Ligand A (0.835) has a very good drug-likeness score. Ligand B (0.586) is acceptable but lower.

**DILI:** Both ligands have low DILI risk (Ligand A: 41.605, Ligand B: 32.61), which is positive.

**BBB:** Ligand A (67.468) has a good BBB percentile, but could be better. Ligand B (26.212) has a poor BBB percentile, a significant drawback for a CNS target.

**Caco-2 Permeability:** Ligand A (-4.657) has poor Caco-2 permeability. Ligand B (-5.327) also has poor Caco-2 permeability.

**Aqueous Solubility:** Both have poor aqueous solubility (-1.95 and -1.247 respectively).

**hERG:** Both ligands have very low hERG risk (0.119 and 0.098 respectively).

**Microsomal Clearance:** Ligand A (26.271) has higher clearance than Ligand B (12.099), suggesting lower metabolic stability.

**In vitro Half-Life:** Ligand B (22.096) has a longer half-life than Ligand A (17.653).

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.066 and 0.043 respectively).

**Binding Affinity:** Ligand B (-7.4 kcal/mol) has significantly better binding affinity than Ligand A (-0.0 kcal/mol). This is a substantial advantage.

**Overall Assessment:**

Ligand B has a much stronger binding affinity, which is the most important factor. However, it suffers from a very low logP and a poor BBB percentile. Ligand A has better TPSA, logP, and BBB penetration, but its binding affinity is extremely weak.

Considering the GPCR-specific priorities, the strong affinity of Ligand B is a major advantage that could potentially be overcome with further optimization to improve its logP and BBB penetration. The extremely weak affinity of Ligand A makes it a less promising starting point, even with its better ADME properties.

Output:
1
2025-04-17 04:31:21,697 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (364.511 and 349.406 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (58.64) is significantly better than Ligand B (71.53). For CNS targets, we want TPSA <= 90, and ideally closer to 60. Ligand A is much closer to the ideal range.

**3. logP:** Both ligands have good logP values (2.138 and 1.349), falling within the optimal 1-3 range. Ligand B is slightly lower, which could potentially affect permeability, but both are acceptable.

**4. H-Bond Donors:** Both have 1 HBD, which is within the acceptable limit of <= 5.

**5. H-Bond Acceptors:** Both have 4 HBA, also within the acceptable limit of <= 10.

**6. QED:** Both ligands have good QED scores (0.777 and 0.807), indicating good drug-like properties.

**7. DILI:** Both ligands have relatively low DILI risk (21.598 and 25.165 percentiles), below the 40 cutoff.

**8. BBB:** Ligand B (87.515) has a significantly higher BBB penetration percentile than Ligand A (61.807). This is a *major* advantage for a CNS target like DRD2.

**9. Caco-2 Permeability:** Ligand A (-4.923) has slightly better Caco-2 permeability than Ligand B (-4.499), but both are negative values, indicating poor permeability.

**10. Aqueous Solubility:** Ligand A (-3.281) has slightly better aqueous solubility than Ligand B (-2.384), but both are negative values, indicating poor solubility.

**11. hERG Inhibition:** Both ligands have low hERG inhibition risk (0.194 and 0.419), which is good.

**12. Microsomal Clearance:** Ligand B (15.966) has significantly lower microsomal clearance than Ligand A (29.181), suggesting better metabolic stability.

**13. In vitro Half-Life:** Ligand A (0.429) has a shorter in vitro half-life than Ligand B (-4.37), indicating faster metabolism.

**14. P-gp Efflux:** Both ligands have low P-gp efflux liability (0.06 and 0.084), which is favorable.

**15. Binding Affinity:** Ligand B (-7.7 kcal/mol) has a slightly better binding affinity than Ligand A (-7.3 kcal/mol). While the difference is not huge, it is over the 1.5 kcal/mol threshold that can outweigh other drawbacks.

**Overall Assessment:**

Ligand B is the stronger candidate. While Ligand A has better TPSA and Caco-2 permeability, Ligand B excels in the most critical areas for a CNS GPCR target: **BBB penetration** and **metabolic stability** (lower Cl_mic, longer t1/2). The slightly better binding affinity of Ligand B further strengthens its position. The differences in solubility and permeability are less critical given the importance of CNS penetration for DRD2.

Output:
1
2025-04-17 04:31:21,697 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (382.873 and 351.451 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Both ligands (95.16 and 97.6) are slightly above the optimal <90 for CNS targets, but not drastically so. This is a minor concern.

**3. logP:** Ligand A (2.042) is within the optimal 1-3 range. Ligand B (0.368) is quite low, potentially hindering permeability. This is a significant drawback for Ligand B.

**4. H-Bond Donors:** Both have 2 HBD, which is acceptable.

**5. H-Bond Acceptors:** Ligand A has 5 HBA, and Ligand B has 6. Both are within the acceptable limit of 10.

**6. QED:** Both ligands have QED values above 0.5 (0.766 and 0.692), indicating good drug-like properties.

**7. DILI:** Ligand A has a DILI risk of 64.288, which is approaching the higher risk threshold (>60). Ligand B has a very low DILI risk of 8.414, which is excellent.

**8. BBB:** Both ligands have similar BBB penetration (27.724 and 27.84), which is quite low and a major concern for a CNS target like DRD2. Neither is above the desirable 70.

**9. Caco-2 Permeability:** Both have negative Caco-2 values (-5.579 and -5.44), which is unusual and suggests poor permeability.

**10. Aqueous Solubility:** Both have negative solubility values (-3.286 and -0.339), which is also unusual and suggests poor solubility.

**11. hERG Inhibition:** Ligand A (0.358) has a slightly higher hERG risk than Ligand B (0.066), but both are relatively low.

**12. Microsomal Clearance:** Ligand A (23.169) has a higher clearance than Ligand B (-18.876, a negative value suggesting very high metabolic stability). This suggests Ligand B is more metabolically stable.

**13. In vitro Half-Life:** Ligand A (26.461) has a longer half-life than Ligand B (-2.398).

**14. P-gp Efflux:** Ligand A (0.11) has lower P-gp efflux than Ligand B (0.002), which is favorable for CNS penetration.

**15. Binding Affinity:** Ligand A (-9.2 kcal/mol) has significantly stronger binding affinity than Ligand B (-7.7 kcal/mol). This is a >1.5 kcal/mol difference, which is a substantial advantage.

**Overall Assessment:**

While both ligands have issues with BBB penetration and solubility/permeability, Ligand A is the more promising candidate. Its significantly stronger binding affinity (-9.2 vs -7.7 kcal/mol) is a major advantage that can potentially outweigh the slightly higher DILI risk and lower P-gp values. The lower logP of Ligand B is a significant concern, likely impacting its ability to cross cell membranes. The higher metabolic stability of Ligand B is a plus, but the affinity difference is more critical for a GPCR target.

Output:
1
2025-04-17 04:31:21,698 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (350.463 and 361.515 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (89.27) is better than Ligand B (54.26) as it is closer to the ideal <90 for CNS targets. Ligand B is excellent.

**logP:** Both ligands have good logP values (1.766 and 2.493), falling within the optimal 1-3 range.

**H-Bond Donors:** Ligand A has 2 HBD, which is acceptable. Ligand B has 0, which is also acceptable.

**H-Bond Acceptors:** Both ligands have 6 HBA, which is within the acceptable limit of <=10.

**QED:** Both ligands have acceptable QED scores (0.816 and 0.76), indicating good drug-like properties.

**DILI:** Ligand A (36.293) has a slightly higher DILI risk than Ligand B (27.414), but both are below the concerning threshold of 60.

**BBB:** Both ligands have good BBB penetration (64.87% and 65.917%), which is important for a CNS target like DRD2. However, ideally, we'd like to see >70%.

**Caco-2 Permeability:** Ligand A (-4.741) is significantly worse than Ligand B (-5.222). Lower values indicate lower permeability.

**Aqueous Solubility:** Ligand A (-3.307) is better than Ligand B (-0.742), indicating better solubility.

**hERG Inhibition:** Ligand A (0.247) has a lower hERG inhibition liability than Ligand B (0.602), which is favorable.

**Microsomal Clearance:** Ligand A (38.889) has a higher microsomal clearance than Ligand B (16.038), suggesting lower metabolic stability.

**In vitro Half-Life:** Ligand A (25.256) has a longer half-life than Ligand B (12.974), which is desirable.

**P-gp Efflux:** Ligand A (0.103) has slightly lower P-gp efflux liability than Ligand B (0.105), which is favorable for CNS penetration.

**Binding Affinity:** Ligand A (-8.4 kcal/mol) has a significantly stronger binding affinity than Ligand B (-7.0 kcal/mol). This is a substantial advantage.

**Overall Assessment:**

Ligand A has a significantly better binding affinity, a longer half-life, better solubility, and lower hERG risk. However, it has worse Caco-2 permeability and higher microsomal clearance. Ligand B has better permeability and metabolic stability but weaker binding affinity.

Given the GPCR-specific priorities, binding affinity is paramount. The 1.4 kcal/mol difference in binding affinity is substantial and likely outweighs the drawbacks of Ligand A's slightly lower permeability and metabolic stability. The BBB values are similar for both, and both are within an acceptable range.

Output:
1
2025-04-17 04:31:21,698 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (341.451 and 344.415 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (62.47) is excellent, well below the 90 A^2 threshold for CNS targets. Ligand B (98.32) is higher, but still potentially acceptable, though less ideal.

**logP:** Ligand A (4.833) is at the upper end of the optimal range (1-3) and could potentially cause solubility issues or off-target interactions. Ligand B (0.671) is quite low, which could hinder membrane permeability and CNS penetration.

**H-Bond Donors/Acceptors:** Ligand A (HBD=2, HBA=3) and Ligand B (HBD=3, HBA=4) both have reasonable numbers of H-bond donors and acceptors, within the guidelines.

**QED:** Both ligands have similar QED values (0.786 and 0.699), indicating good drug-like properties.

**DILI:** Ligand A (59.287) has a higher DILI risk than Ligand B (44.513), but both are below the concerning threshold of 60.

**BBB:** This is a critical parameter for a CNS target like DRD2. Ligand A (73.362) has a good BBB percentile, while Ligand B (22.295) is very poor.

**Caco-2 Permeability:** Ligand A (-4.361) and Ligand B (-5.029) both have negative Caco-2 values, which is unusual and suggests poor permeability. However, the scale is not specified, so these values are hard to interpret.

**Aqueous Solubility:** Both ligands have very poor aqueous solubility (-4.917 and -2.786). This is a significant concern, especially given Ligand A's already high logP.

**hERG Inhibition:** Ligand A (0.661) has a slightly higher hERG risk than Ligand B (0.105), but both are relatively low.

**Microsomal Clearance:** Ligand A (34.729) has moderate clearance, while Ligand B (-28.048) has negative clearance, which is not physically possible and likely an error in the data. This is a major red flag for Ligand B.

**In vitro Half-Life:** Ligand A (85.604) has a good in vitro half-life. Ligand B (-11.947) has a negative half-life, which is impossible and indicates a data error.

**P-gp Efflux:** Both ligands have very low P-gp efflux (0.676 and 0.005), which is favorable for CNS penetration.

**Binding Affinity:** Ligand B (-8.6 kcal/mol) has significantly stronger binding affinity than Ligand A (0.0 kcal/mol). This is a substantial advantage.

**Overall Assessment:**

Ligand B has a much stronger binding affinity, which is a major plus. However, it suffers from extremely poor BBB penetration, impossible values for clearance and half-life, and a low logP. Ligand A has a reasonable BBB, acceptable TPSA, and a good half-life, but its high logP and poor solubility are concerning. The negative values for clearance and half-life for Ligand B are highly suspect and likely indicate data errors.

Given the importance of BBB penetration for a CNS target, and the questionable ADME properties of Ligand B, Ligand A is the more viable candidate, despite its drawbacks. The poor solubility of Ligand A could potentially be addressed through formulation strategies.

Output:
0
2025-04-17 04:31:21,698 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (338.371 and 354.422 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (99.93) is slightly higher than Ligand B (89.87). Both are below the 140 A^2 threshold for oral absorption, and closer to the desirable <90 A^2 for CNS targets. Ligand B is preferable here.

**3. logP:** Ligand A (1.287) is within the optimal 1-3 range. Ligand B (0.218) is slightly low, which *could* indicate permeability issues, but is not a dealbreaker. Ligand A is preferable.

**4. H-Bond Donors:** Ligand A (2) and Ligand B (3) are both acceptable, being less than 5.

**5. H-Bond Acceptors:** Ligand A (6) and Ligand B (4) are both acceptable, being less than 10.

**6. QED:** Both ligands have similar QED values (0.705 and 0.676), indicating good drug-like properties.

**7. DILI:** Ligand A (82.396) has a higher DILI risk than Ligand B (25.591). This is a significant advantage for Ligand B.

**8. BBB:** Ligand B (71.501) has a substantially better BBB penetration percentile than Ligand A (26.638). This is *critical* for a CNS target like DRD2, making Ligand B much more promising.

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.471 and -5.419). This is unusual and suggests poor permeability. However, these values are on a scale where negative values are possible, and direct comparison is difficult without knowing the scale's specifics.

**10. Aqueous Solubility:** Both ligands have negative solubility values (-3.23 and -2.095), indicating poor solubility. Similar to Caco-2, the scale is unclear, making direct comparison difficult.

**11. hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.242 and 0.292).

**12. Microsomal Clearance:** Ligand A (-3.52) has a lower (better) microsomal clearance than Ligand B (-2.021), indicating greater metabolic stability.

**13. In vitro Half-Life:** Ligand A (2.39) has a slightly longer half-life than Ligand B (1.095).

**14. P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.028 and 0.03).

**15. Binding Affinity:** Both ligands have excellent binding affinities (-8.2 and -8.4 kcal/mol). Ligand B has a slightly better affinity.

**Overall Assessment:**

While Ligand A has a slightly better logP and metabolic stability, Ligand B is significantly superior due to its much better BBB penetration (71.501 vs 26.638) and lower DILI risk (25.591 vs 82.396). For a CNS target like DRD2, BBB penetration is paramount. The slight advantage in affinity for Ligand B further solidifies its position. The negative Caco-2 and solubility values are concerning for both, but the strong affinity and favorable CNS properties of Ligand B outweigh these concerns.

Output:
1
2025-04-17 04:31:21,698 - INFO - Reasoning:

Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (351.535 and 370.465 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (52.65) is better than Ligand B (50.27). Both are below the 90 A^2 threshold for CNS targets, which is excellent.

**3. logP:** Ligand A (2.652) is within the optimal 1-3 range. Ligand B (4.057) is slightly higher, potentially leading to solubility issues or off-target interactions, but still acceptable.

**4. H-Bond Donors:** Ligand A (1) is preferable to Ligand B (0). While both are low, a single donor can sometimes aid solubility.

**5. H-Bond Acceptors:** Ligand A (3) is preferable to Ligand B (4). Both are within the acceptable range of <=10.

**6. QED:** Both ligands have similar QED values (0.616 and 0.693), indicating good drug-like properties.

**7. DILI:** Ligand B (32.454) has a significantly lower DILI risk than Ligand A (4.731), making it safer from a liver toxicity perspective.

**8. BBB:** Ligand B (92.516) has a substantially higher BBB penetration percentile than Ligand A (83.637). This is *critical* for a CNS target like DRD2.

**9. Caco-2 Permeability:** Ligand A (-4.729) is better than Ligand B (-4.454). Higher values indicate better intestinal absorption, but these are both negative values.

**10. Aqueous Solubility:** Ligand A (-1.673) is better than Ligand B (-3.647). Higher values indicate better solubility.

**11. hERG Inhibition:** Ligand A (0.709) has a slightly lower hERG inhibition risk than Ligand B (0.345), which is favorable.

**12. Microsomal Clearance:** Ligand B (44.113) has lower microsomal clearance than Ligand A (56.538), suggesting better metabolic stability.

**13. In vitro Half-Life:** Ligand A (-2.695) has a longer half-life than Ligand B (-4.31), which is desirable.

**14. P-gp Efflux:** Ligand A (0.023) has lower P-gp efflux liability than Ligand B (0.328), meaning it's less likely to be pumped out of the brain, improving CNS exposure.

**15. Binding Affinity:** Ligand B (-7.1) has a slightly better binding affinity than Ligand A (-7.4), although the difference is small.

**Overall Assessment:**

While Ligand A has some advantages (slightly better Caco-2, solubility, half-life, and P-gp efflux), Ligand B is clearly superior due to its significantly better BBB penetration (92.516 vs 83.637), lower DILI risk (32.454 vs 4.731), and better metabolic stability (lower Cl_mic). For a CNS target like DRD2, BBB penetration is paramount. The small affinity difference is outweighed by these critical ADME properties.

Output:
1
2025-04-17 04:31:21,698 - INFO - Reasoning:

Let's analyze Ligand A and Ligand B against the provided guidelines, prioritizing GPCR-specific properties (BBB, logP, Pgp, TPSA, and affinity) for DRD2.

**Molecular Weight:** Both ligands (351.535 and 354.402 Da) fall within the ideal 200-500 Da range.

**TPSA:** Both ligands have TPSA values (43.86 and 43.37) below the 90 A^2 threshold desirable for CNS targets, which is excellent.

**logP:** Ligand A (2.77) is optimal (1-3). Ligand B (4.9) is slightly higher, potentially leading to solubility issues or off-target interactions, but still within a tolerable range.

**H-Bond Donors/Acceptors:** Both ligands have reasonable HBD (0) and HBA (3 & 4) counts, well within the guidelines.

**QED:** Ligand A (0.569) has a better QED score than Ligand B (0.372), indicating a more drug-like profile.

**DILI:** Ligand A (11.632) has a significantly lower DILI risk than Ligand B (88.057). This is a major advantage for Ligand A.

**BBB:** Ligand A (75.727) has a better BBB percentile than Ligand B (65.839), although both are reasonably good for a CNS target. Ligand A is closer to the >70 desirable threshold.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.607 and -4.147), which is unusual and suggests poor intestinal absorption. This is a concern for both.

**Aqueous Solubility:** Ligand A (-1.397) is better than Ligand B (-6.569) in terms of solubility, which is important for formulation and bioavailability.

**hERG Inhibition:** Both ligands have low hERG inhibition liability (0.765 and 0.287), which is favorable.

**Microsomal Clearance:** Ligand A (48.438) has a lower microsomal clearance than Ligand B (129.822), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand B (30.877) has a longer in vitro half-life than Ligand A (20.593), which is generally desirable.

**P-gp Efflux:** Ligand A (0.274) has lower P-gp efflux liability than Ligand B (0.476), which is important for CNS exposure.

**Binding Affinity:** Ligand B (-9.1 kcal/mol) has a significantly stronger binding affinity than Ligand A (-6.8 kcal/mol). This is a substantial advantage for Ligand B, potentially outweighing some of its ADME drawbacks. A difference of 2.3 kcal/mol is significant.

**Overall Assessment:**

While Ligand A excels in ADME properties (DILI, BBB, solubility, metabolic stability, P-gp efflux), Ligand B boasts a considerably stronger binding affinity. For a GPCR target like DRD2, a strong binding affinity is paramount. The improved ADME profile of Ligand A is attractive, but the 2.3 kcal/mol difference in binding affinity is likely to be the dominant factor in determining in vivo efficacy. The slightly higher logP of Ligand B is a manageable concern.

Output:
1
2025-04-17 04:31:21,699 - INFO - Batch 120 complete. Total preferences: 1920
2025-04-17 04:31:21,699 - INFO - Processing batch 121/512...
2025-04-17 04:32:06,303 - INFO - Okay, let's analyze these two ligands for their potential as DRD2 drug candidates. DRD2 is a GPCR in the CNS, so BBB penetration, logP, Pgp efflux, TPSA, and binding affinity are key.

**Ligand A:** [347.459, 83.22, 1.788, 3, 3, 0.596, 38.813, 47.421, -4.719, -3.071, 0.5, 26.833, -15.975, 0.193, -7.9]
**Ligand B:** [348.531, 58.2, 3.794, 2, 2, 0.631, 15.2, 71.772, -4.843, -3.97, 0.645, 55.997, -0.425, 0.2, -8.1]

**Step-by-step comparison:**

1. **MW:** Both are within the ideal range (200-500 Da).  A: 347.459, B: 348.531 - No significant difference.
2. **TPSA:** Ligand A (83.22) is higher than the ideal <90 for CNS targets, but still reasonably close. Ligand B (58.2) is excellent, well below 90.  **Advantage: B**
3. **logP:** Ligand A (1.788) is within the optimal range. Ligand B (3.794) is approaching the upper limit, but still acceptable. **Advantage: A** (slightly)
4. **HBD:** Both are acceptable (A: 3, B: 2). **No significant difference.**
5. **HBA:** Both are acceptable (A: 3, B: 2). **No significant difference.**
6. **QED:** Both are good (A: 0.596, B: 0.631). **No significant difference.**
7. **DILI:** Ligand A (38.813) is better than Ligand B (15.2), indicating lower liver injury risk. **Advantage: A**
8. **BBB:** Ligand B (71.772) is significantly better than Ligand A (47.421).  >70 is desirable for CNS targets. **Advantage: B** (major)
9. **Caco-2:** Both are negative, indicating poor permeability. **No significant difference.**
10. **Solubility:** Both are negative, indicating poor solubility. **No significant difference.**
11. **hERG:** Both are low risk (A: 0.5, B: 0.645). **No significant difference.**
12. **Cl_mic:** Ligand A (26.833) has lower clearance, suggesting better metabolic stability than Ligand B (55.997). **Advantage: A**
13. **t1/2:** Ligand A (-15.975) has a longer half-life than Ligand B (-0.425). **Advantage: A**
14. **Pgp:** Both are low efflux risk (A: 0.193, B: 0.2). **No significant difference.**
15. **Binding Affinity:** Ligand B (-8.1) has a slightly better binding affinity than Ligand A (-7.9). While the difference is small, it's still a positive for B. **Advantage: B** (slight)

**Overall Assessment:**

Ligand B is clearly superior regarding CNS penetration (BBB) and has a slightly better binding affinity. These are critical for a DRD2 target. While Ligand A has advantages in DILI, metabolic stability (Cl_mic, t1/2), and logP, the BBB penetration of Ligand B is the most important factor for a CNS-active drug. The TPSA is also significantly better for Ligand B. The small affinity difference can be optimized later.

Output:
1
2025-04-17 04:32:06,303 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (342.443 and 350.467 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (75.19) is significantly better than Ligand B (83.36). For CNS targets, we want TPSA <= 90, and A is closer to the optimal <= 60 range. B is approaching the upper limit.

**logP:** Ligand A (1.886) is within the optimal 1-3 range. Ligand B (0.29) is quite low, potentially hindering membrane permeability.

**H-Bond Donors/Acceptors:** Both have 1 HBD, which is good. Ligand A has 4 HBA, and Ligand B has 6. Both are acceptable (<=10), but A is slightly preferred.

**QED:** Both ligands have good QED scores (0.578 and 0.692), indicating good drug-like properties.

**DILI:** Ligand A (35.091) has a slightly higher DILI risk than Ligand B (19.038), but both are below the concerning threshold of 60.

**BBB:** Ligand A (60.838) has a moderate BBB penetration, while Ligand B (48.74) is lower. For a CNS target like DRD2, we ideally want >70, so both are suboptimal, but A is better.

**Caco-2:** Ligand A (-4.834) and Ligand B (-5.399) both have negative Caco-2 values, which is unusual and suggests very poor permeability. This is a significant concern for both.

**Solubility:** Ligand A (-2.353) is slightly better than Ligand B (0.001), but both are very poor. This is a major drawback.

**hERG:** Ligand A (0.382) has a lower hERG risk than Ligand B (0.087), which is preferable.

**Microsomal Clearance:** Ligand A (33.091) has a higher microsomal clearance than Ligand B (-12.52). This means Ligand B is more metabolically stable, which is a positive.

**In vitro Half-Life:** Ligand A (-10.044) has a negative half-life, which is impossible. This is a red flag. Ligand B (1.563) has a short half-life, but at least it's a plausible value.

**P-gp Efflux:** Ligand A (0.06) has lower P-gp efflux than Ligand B (0.012), which is favorable for CNS penetration.

**Binding Affinity:** Ligand B (-7.5) has a slightly better binding affinity than Ligand A (-7.3), but the difference is small (0.2 kcal/mol).

**Overall Assessment:**

Ligand A has better TPSA, logP, hERG, and P-gp efflux. However, its in vitro half-life is nonsensical, and its BBB penetration is only moderately good. Ligand B has better metabolic stability and a slightly better binding affinity, but suffers from very low logP, poor solubility, and lower BBB penetration. The negative half-life for Ligand A is a dealbreaker. While both have significant issues, Ligand B is slightly more promising due to the more realistic ADME profile, despite its lower logP.

Output:
1
2025-04-17 04:32:06,303 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (389.859 and 366.506 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (58.45) is slightly higher than Ligand B (54.18), but both are below the 90 A^2 threshold desirable for CNS targets.

**logP:** Both ligands have a logP around 3.3, which is optimal.

**H-Bond Donors/Acceptors:** Both have 1 HBD and 6 HBA, which are within acceptable limits.

**QED:** Ligand B (0.779) has a better QED score than Ligand A (0.57), indicating a more drug-like profile.

**DILI:** Ligand B (36.603) has a significantly lower DILI risk than Ligand A (69.794), making it safer.

**BBB:** Ligand B (82.862) has a substantially higher BBB penetration percentile than Ligand A (73.943). This is a *critical* advantage for a CNS target like DRD2.

**Caco-2 Permeability:** Ligand A (-5.311) and Ligand B (-4.697) both have negative values, which is unusual and suggests poor permeability. However, the scale is not specified, so it's hard to interpret.

**Aqueous Solubility:** Both ligands have very poor aqueous solubility (-3.299 and -3.451). This is a concern for formulation and bioavailability.

**hERG:** Both ligands have low hERG inhibition risk (0.953 and 0.607).

**Microsomal Clearance:** Ligand A (33.208) has a lower microsomal clearance than Ligand B (59.245), indicating better metabolic stability.

**In vitro Half-Life:** Ligand B (-7.103) has a negative half-life, which is impossible. This is a major red flag and suggests an error in the data or a very rapidly metabolized compound. Ligand A (30.842) has a reasonable half-life.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.583 and 0.57).

**Binding Affinity:** Ligand B (-7.0 kcal/mol) has a slightly better binding affinity than Ligand A (-6.5 kcal/mol). While the difference is not huge, it's a positive factor.

**Overall Assessment:**

Ligand B is clearly superior due to its significantly better BBB penetration, lower DILI risk, and slightly improved binding affinity. The QED score is also better. The negative half-life for Ligand B is a serious issue, but if this is a data error, it would become the clear frontrunner. Ligand A has better metabolic stability, but the BBB and safety profiles of Ligand B are more important for a CNS-targeting drug. The solubility issues are a concern for both, but can potentially be addressed with formulation strategies.

Output:
1
2025-04-17 04:32:06,304 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (341.346 Da) is slightly lower, which could be advantageous for permeability, but both are acceptable.

**TPSA:** Ligand A (92.93) is better than Ligand B (58.64) for CNS penetration, falling comfortably below the 90 A^2 threshold. Ligand B is also good, but A is preferable.

**logP:** Both ligands have good logP values (A: 1.927, B: 2.442), falling within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A has 2 HBD and 6 HBA, while Ligand B has 1 HBD and 4 HBA. Both are within acceptable limits (<=5 HBD, <=10 HBA).

**QED:** Both ligands have similar and good QED values (A: 0.74, B: 0.782), indicating good drug-like properties.

**DILI:** Ligand A (74.254) has a significantly higher DILI risk than Ligand B (31.601). This is a major concern for Ligand A.

**BBB:** Ligand B (83.831) has a much better BBB penetration percentile than Ligand A (47.809). This is crucial for a CNS target like DRD2.

**Caco-2 Permeability:** Ligand A (-5.169) has poor Caco-2 permeability, while Ligand B (-4.999) is slightly better, but still poor.

**Aqueous Solubility:** Both ligands have poor aqueous solubility (-2.851 and -3.357 respectively). This is not ideal, but can be addressed with formulation strategies.

**hERG Inhibition:** Both ligands show very low hERG inhibition risk (A: 0.075, B: 0.476).

**Microsomal Clearance:** Ligand A (75.585) has higher microsomal clearance than Ligand B (46.03), indicating lower metabolic stability.

**In vitro Half-Life:** Ligand B (4.573) has a longer in vitro half-life than Ligand A (-35.05), which is a significant advantage.

**P-gp Efflux:** Both ligands show low P-gp efflux liability (A: 0.187, B: 0.191).

**Binding Affinity:** Ligand B (-7.8 kcal/mol) has a significantly stronger binding affinity than Ligand A (-9.8 kcal/mol). This is a substantial advantage.

**Overall Assessment:**

Ligand B is clearly the superior candidate. While both have poor solubility and Caco-2 permeability, Ligand B excels in the most critical areas for a CNS GPCR target: BBB penetration, binding affinity, and metabolic stability (lower Cl_mic, longer t1/2). Ligand A's high DILI risk is a major red flag. The 1.5 kcal/mol difference in binding affinity, combined with the improved ADME properties, outweighs any minor drawbacks of Ligand B.

Output:
1
2025-04-17 04:32:06,304 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 drug candidates, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (402.288 Da) is slightly higher than Ligand B (352.385 Da), but both are acceptable.

**2. TPSA:** Ligand A (55.4) is significantly better than Ligand B (67.23). For CNS targets, we want TPSA <= 90, and ideally closer to 60. Ligand A is much closer to the ideal range.

**3. logP:** Ligand A (3.513) is optimal (1-3). Ligand B (1.198) is on the lower side, potentially hindering permeation.

**4. H-Bond Donors:** Both ligands have 1 HBD, which is within the acceptable limit of <= 5.

**5. H-Bond Acceptors:** Ligand A has 3 HBAs, and Ligand B has 4. Both are within the acceptable limit of <= 10.

**6. QED:** Both ligands have good QED values (A: 0.779, B: 0.81), indicating good drug-like properties.

**7. DILI:** Ligand A (61.303) has a higher DILI risk than Ligand B (52.346), but both are still reasonably low.

**8. BBB:** Ligand B (83.986) has a significantly better BBB penetration percentile than Ligand A (70.88). While A is still above the 70% threshold, B is more favorable for a CNS target.

**9. Caco-2 Permeability:** Ligand A (-4.722) has better Caco-2 permeability than Ligand B (-4.829), indicating better intestinal absorption.

**10. Aqueous Solubility:** Ligand A (-4.236) has better aqueous solubility than Ligand B (-2.045).

**11. hERG Inhibition:** Both ligands have very low hERG inhibition risk (A: 0.492, B: 0.209).

**12. Microsomal Clearance:** Ligand A (99.114) has very high microsomal clearance, indicating poor metabolic stability. Ligand B (17.902) has much lower clearance, suggesting better metabolic stability.

**13. In vitro Half-Life:** Ligand B (-24.442) has a much longer in vitro half-life than Ligand A (58.638).

**14. P-gp Efflux:** Ligand A (0.358) has lower P-gp efflux liability than Ligand B (0.034), which is favorable for CNS exposure.

**15. Binding Affinity:** Ligand A (-8.6 kcal/mol) has a slightly better binding affinity than Ligand B (-8.1 kcal/mol). The difference is 0.5 kcal/mol, which is significant.

**Overall Assessment:**

Ligand A has a better logP, Caco-2 permeability, solubility, and P-gp efflux, and slightly better affinity. However, Ligand B excels in BBB penetration, metabolic stability (lower Cl_mic and longer t1/2), and has a lower DILI risk.

Considering the GPCR-specific priorities for a CNS target like DRD2, BBB penetration and metabolic stability are crucial. While Ligand A's affinity is slightly better, the superior BBB penetration and metabolic stability of Ligand B outweigh this advantage. The lower logP of Ligand B is a concern, but the other benefits are more impactful.

Output:
1
2025-04-17 04:32:06,304 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (350.277 and 346.475 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (72.22) is excellent, well below the 90 A^2 threshold for CNS targets. Ligand B (76.02) is still reasonable, but slightly less favorable.

**logP:** Both ligands have logP values (2.566 and 2.919) within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A (0 HBD, 5 HBA) is slightly better than Ligand B (2 HBD, 4 HBA) in terms of balancing solubility and permeability.

**QED:** Ligand A (0.793) has a better QED score than Ligand B (0.533), indicating a more drug-like profile.

**DILI:** Ligand A (87.282) has a higher DILI risk than Ligand B (51.532). This is a significant drawback for Ligand A.

**BBB:** Ligand A (94.184) has a *much* better BBB penetration score than Ligand B (47.46). This is a critical advantage given DRD2 is a CNS target.

**Caco-2 Permeability:** Ligand A (-4.229) shows poor Caco-2 permeability, while Ligand B (-4.966) is even worse. Both are unfavorable, but A is slightly better.

**Aqueous Solubility:** Both ligands have very poor aqueous solubility (-4.842 and -3.172 respectively). This is a concern for both.

**hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.344 and 0.232).

**Microsomal Clearance:** Ligand A (31.996) has a lower microsomal clearance than Ligand B (61.287), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (31.971) has a longer in vitro half-life than Ligand B (17.672).

**P-gp Efflux:** Both ligands show low P-gp efflux liability (0.194 and 0.125).

**Binding Affinity:** Ligand A (-9.8 kcal/mol) has a significantly stronger binding affinity than Ligand B (-7.4 kcal/mol). This is a substantial advantage. The difference of 2.4 kcal/mol is quite large and can outweigh other concerns.

**Overall Assessment:**

Ligand A excels in BBB penetration and binding affinity, which are paramount for a CNS GPCR target like DRD2. It also has better QED, metabolic stability, and half-life. However, its DILI risk is higher and Caco-2 permeability is poor. Ligand B has a lower DILI risk, but suffers from significantly poorer BBB penetration and a weaker binding affinity.

The strong binding affinity and excellent BBB score of Ligand A are compelling. While the DILI risk is a concern, it might be mitigated through structural modifications during lead optimization. The poor solubility and permeability could also be addressed. The substantial affinity advantage of Ligand A is likely to outweigh its drawbacks, especially given the importance of potency for GPCR ligands.

Output:
1
2025-04-17 04:32:06,304 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (344.503 Da) is slightly lower, which is generally favorable for permeability.

**TPSA:** Ligand A (38.82) is excellent for CNS penetration, well below the 90 A^2 threshold. Ligand B (100.44) is higher, but still potentially acceptable, though less ideal.

**logP:** Both ligands have good logP values (A: 2.641, B: 1.392), falling within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A (HBD=1, HBA=4) and Ligand B (HBD=3, HBA=4) both have reasonable numbers of H-bond donors and acceptors, within the suggested limits.

**QED:** Both ligands have acceptable QED values (A: 0.861, B: 0.702), indicating good drug-like properties.

**DILI:** Ligand A (19.193) has a significantly lower DILI risk than Ligand B (64.288), which is a major advantage.

**BBB:** Ligand A (84.413) has a much higher BBB penetration percentile than Ligand B (46.801). This is *critical* for a CNS target like DRD2.

**Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual. However, the scale is not specified, so it's difficult to interpret.

**Aqueous Solubility:** Both have negative solubility values, again, difficult to interpret without knowing the scale.

**hERG:** Both ligands have low hERG inhibition risk (A: 0.886, B: 0.091).

**Microsomal Clearance:** Ligand A (-12.061) has a *much* lower (better) microsomal clearance than Ligand B (-29.248), indicating greater metabolic stability.

**In vitro Half-Life:** Ligand B (19.751) has a slightly longer in vitro half-life than Ligand A (16.185), but the difference isn't substantial.

**P-gp Efflux:** Ligand A (0.045) has a lower P-gp efflux liability than Ligand B (0.071), which is favorable for CNS exposure.

**Binding Affinity:** Ligand A (-8.2 kcal/mol) has a significantly stronger binding affinity than Ligand B (-0.0 kcal/mol). This is a decisive factor.

**Overall Assessment:**

Ligand A is clearly superior. It excels in the most important parameters for a CNS-targeting GPCR ligand: BBB penetration, binding affinity, metabolic stability (low Cl_mic), and DILI risk. While Ligand B has a slightly longer half-life, the substantial advantages of Ligand A in other key areas outweigh this minor difference. The negative solubility and Caco-2 values are concerning, but the strong affinity and excellent BBB penetration of Ligand A make it a much more promising candidate.

Output:
1
2025-04-17 04:32:06,304 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (348.447 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (82.7) is better than Ligand B (87.32). Both are below the 90 A^2 threshold desirable for CNS targets, but A is closer to the ideal.

**logP:** Ligand B (1.902) is better than Ligand A (0.713). A logP of 0.713 is quite low and may hinder membrane permeability. Ligand B is within the optimal 1-3 range.

**H-Bond Donors:** Ligand A (3) is slightly higher than Ligand B (2), but both are acceptable (<=5).

**H-Bond Acceptors:** Both ligands have 4 H-bond acceptors, which is within the acceptable range (<=10).

**QED:** Ligand A (0.614) is slightly better than Ligand B (0.555), both are above the 0.5 threshold.

**DILI:** Ligand A (12.02) has a significantly better DILI score than Ligand B (35.789). This is a major advantage for Ligand A.

**BBB:** Ligand A (71.733) has a significantly better BBB score than Ligand B (55.021).  For a CNS target like DRD2, a BBB > 70 is desirable, and A is closer to this threshold.

**Caco-2 Permeability:** Ligand A (-5.185) is better than Ligand B (-5.647), indicating better intestinal absorption.

**Aqueous Solubility:** Ligand A (-1) is better than Ligand B (-2.144). Higher solubility is generally preferred.

**hERG:** Both ligands have low hERG inhibition liability (0.385 and 0.253 respectively), which is good.

**Microsomal Clearance:** Ligand A (-8.816) is significantly better than Ligand B (-18.116). Lower clearance indicates better metabolic stability.

**In vitro Half-Life:** Ligand A (-1.508) is better than Ligand B (-7.164). Longer half-life is preferred.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.004 and 0.037 respectively), which is good.

**Binding Affinity:** Ligand B (-8.7 kcal/mol) has a slightly better binding affinity than Ligand A (-8.2 kcal/mol). While a 0.5 kcal/mol difference is not huge, it's a positive for Ligand B.

**Overall Assessment:**

Ligand A excels in ADME properties (DILI, BBB, clearance, half-life, solubility, Caco-2) and has a reasonable binding affinity. Ligand B has a slightly better binding affinity and logP, but suffers from significantly worse ADME properties, particularly DILI and BBB penetration. Given the CNS target, the superior BBB and ADME profile of Ligand A outweigh the slightly weaker binding affinity.

Output:
0
2025-04-17 04:32:06,305 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B based on the provided guidelines, prioritizing GPCR-specific properties (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (350.419 and 358.479 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (102.44) is higher than Ligand B (79.31). For CNS targets, TPSA should be <=90, so Ligand B is preferable.

**logP:** Ligand A (0.348) is quite low, potentially hindering permeation. Ligand B (0.752) is better, but still on the lower side of the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A has 2 HBD and 6 HBA, while Ligand B has 1 HBD and 5 HBA. Both are within acceptable limits.

**QED:** Both ligands have reasonable QED scores (0.701 and 0.623), indicating good drug-like properties.

**DILI:** Ligand A (49.632) has a higher DILI risk than Ligand B (15.355), which is a significant advantage for Ligand B.

**BBB:** Both ligands have similar BBB penetration (58.821 and 50.446), both are below the desirable >70 for CNS targets, but not drastically so.

**Caco-2 Permeability:** Ligand A (-5.302) has very poor Caco-2 permeability, suggesting poor absorption. Ligand B (-4.319) is slightly better, but still low.

**Aqueous Solubility:** Both ligands have very poor aqueous solubility (-0.901 and -0.661). This could pose formulation challenges.

**hERG Inhibition:** Both ligands show very low hERG inhibition risk (0.053 and 0.252).

**Microsomal Clearance:** Ligand A (8.152) has lower microsomal clearance than Ligand B (53.051), indicating better metabolic stability.

**In vitro Half-Life:** Ligand A (10.519 hours) has a longer half-life than Ligand B (3.78 hours), which is desirable.

**P-gp Efflux:** Both ligands exhibit very low P-gp efflux liability (0.004 and 0.051), which is favorable for CNS penetration.

**Binding Affinity:** Ligand A (-8.1 kcal/mol) has a significantly stronger binding affinity than Ligand B (-6.0 kcal/mol). This is a substantial advantage, potentially outweighing some of the ADME drawbacks.

**Overall Assessment:**

Ligand A has a much better binding affinity and metabolic stability, and longer half-life. However, its low logP and poor Caco-2 permeability are concerning. Ligand B has a better TPSA and significantly lower DILI risk, but weaker affinity. Given the GPCR target and the importance of CNS penetration, the stronger binding affinity of Ligand A is a critical factor. While the low logP and Caco-2 are drawbacks, these might be addressable through further optimization without drastically impacting the binding affinity. The lower DILI risk of Ligand B is attractive, but the substantial affinity difference favors Ligand A.

Output:
1
2025-04-17 04:32:06,305 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (351.451 and 341.411 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (89.35) is better than Ligand B (54.78). Both are below the 90 A^2 threshold for CNS targets, which is excellent.

**logP:** Ligand A (0.694) is slightly below the optimal 1-3 range, potentially hindering permeation. Ligand B (0.853) is also a bit low, but marginally better.

**H-Bond Donors/Acceptors:** Ligand A has 1 HBD and 6 HBA, while Ligand B has 0 HBD and 4 HBA. Both are within acceptable limits.

**QED:** Both ligands have reasonable QED scores (0.696 and 0.589), indicating good drug-like properties.

**DILI:** Ligand A (57.619) has a slightly higher DILI risk than Ligand B (38.813), but both are below the concerning threshold of 60.

**BBB:** Ligand A (58.86) and Ligand B (56.805) are both below the desirable >70 percentile for CNS targets. This is a significant drawback for both, but not a dealbreaker if other properties are strong.

**Caco-2 Permeability:** Ligand A (-5.024) has poor Caco-2 permeability, suggesting poor intestinal absorption. Ligand B (-4.293) is also poor, but slightly better.

**Aqueous Solubility:** Both ligands have very poor aqueous solubility (-1.087 and -1.896), which could pose formulation challenges.

**hERG Inhibition:** Both ligands show very low hERG inhibition risk (0.248 and 0.232).

**Microsomal Clearance:** Ligand A (38.167) has a higher microsomal clearance than Ligand B (9.406), indicating lower metabolic stability. This is a significant negative for Ligand A.

**In vitro Half-Life:** Ligand A (-19.372) has a very short in vitro half-life, while Ligand B (3.666) is slightly better.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.05 and 0.062), which is favorable for CNS penetration.

**Binding Affinity:** Ligand B (-7.5 kcal/mol) has a slightly better binding affinity than Ligand A (-7.2 kcal/mol). While the difference is less than the 1.5 kcal/mol threshold, it's still a positive for Ligand B.

**Overall Assessment:**

Considering the GPCR-specific priorities, Ligand B is the more promising candidate. While both have suboptimal BBB penetration and solubility, Ligand B has significantly better metabolic stability (lower Cl_mic, longer t1/2), slightly better Caco-2 permeability, and a marginally stronger binding affinity. Ligand A's high clearance and short half-life are major concerns. The slightly better TPSA of Ligand A is outweighed by its other weaknesses.



Output:
1
2025-04-17 04:32:06,305 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (356.344 and 355.435 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (49.85) is significantly better than Ligand B (96.97). For CNS targets, we want TPSA <= 90, so Ligand A is much more favorable.

**3. logP:** Ligand A (2.687) is optimal (1-3), while Ligand B (0.512) is a bit low, potentially hindering permeation.

**4. H-Bond Donors:** Ligand A (0) is preferable to Ligand B (2). Fewer HBDs generally improve permeability.

**5. H-Bond Acceptors:** Ligand A (3) is better than Ligand B (5). Lower HBA is generally preferred for CNS penetration.

**6. QED:** Ligand A (0.783) is better than Ligand B (0.588), indicating a more drug-like profile.

**7. DILI:** Ligand B (34.587) has a significantly lower DILI risk than Ligand A (68.437). This is a substantial advantage for Ligand B.

**8. BBB:** Ligand A (93.563) has a much higher BBB penetration percentile than Ligand B (78.79). This is a critical factor for a CNS target like DRD2.

**9. Caco-2:** Ligand A (-4.126) and Ligand B (-4.887) both have negative values, which is unusual and requires careful interpretation. Lower values suggest poor permeability.

**10. Solubility:** Ligand A (-3.007) and Ligand B (-1.499) both have negative solubility values, indicating poor aqueous solubility.

**11. hERG:** Ligand A (0.491) and Ligand B (0.168) both show low hERG inhibition risk, which is good.

**12. Cl_mic:** Ligand B (4.418) has much lower microsomal clearance than Ligand A (56.311), suggesting better metabolic stability.

**13. t1/2:** Ligand B (-6.406) has a longer in vitro half-life than Ligand A (-4.049).

**14. Pgp:** Ligand A (0.257) has lower P-gp efflux liability than Ligand B (0.018), which is favorable for CNS exposure.

**15. Binding Affinity:** Ligand A (-8.9 kcal/mol) has a significantly stronger binding affinity than Ligand B (-7.4 kcal/mol). This is a substantial advantage, potentially outweighing some ADME drawbacks.

**Overall Assessment:**

Ligand A excels in BBB penetration and binding affinity, which are crucial for a CNS GPCR target. However, it suffers from higher DILI risk, higher TPSA, and higher microsomal clearance. Ligand B has a better safety profile (lower DILI) and metabolic stability (lower Cl_mic, longer t1/2), but its TPSA is high, logP is low, and its binding affinity is weaker.

The difference in binding affinity (-8.9 vs -7.4 kcal/mol) is considerable (1.5 kcal/mol), and given the importance of potency for GPCRs, this difference is likely to be decisive. The superior BBB penetration of Ligand A further strengthens its position. While the higher DILI risk is a concern, it might be mitigated through further structural modifications.

Output:
1
2025-04-17 04:32:06,305 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (341.386 and 346.435 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (62.3) is significantly better than Ligand B (93.84). For CNS targets, we want TPSA <= 90, so Ligand A is preferable.

**logP:** Both ligands have acceptable logP values (2.62 and 1.331, respectively), falling within the 1-3 range. Ligand A is slightly better.

**H-Bond Donors/Acceptors:** Ligand A (HBD=1, HBA=3) is better than Ligand B (HBD=2, HBA=6) regarding the number of hydrogen bond donors and acceptors.

**QED:** Ligand A (0.93) has a much higher QED score than Ligand B (0.705), indicating better overall drug-likeness.

**DILI:** Ligand A (53.354) has a higher DILI risk than Ligand B (38.852), but both are below the concerning threshold of 60.

**BBB:** Ligand A (81.698) has a significantly higher BBB penetration percentile than Ligand B (62.854). This is a critical advantage for a CNS target like DRD2.

**Caco-2 Permeability:** Ligand A (-4.767) has worse Caco-2 permeability than Ligand B (-5.396). Lower values are worse.

**Aqueous Solubility:** Ligand A (-3.263) has worse aqueous solubility than Ligand B (-1.352). Lower values are worse.

**hERG:** Both ligands have very low hERG inhibition liability (0.334 and 0.25, respectively), which is excellent.

**Microsomal Clearance:** Ligand A (20.587) has lower microsomal clearance than Ligand B (17.551), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand B (31.889) has a significantly longer in vitro half-life than Ligand A (-7.17). This is a clear advantage for Ligand B.

**P-gp Efflux:** Ligand A (0.137) has much lower P-gp efflux liability than Ligand B (0.016), which is a significant advantage for CNS penetration.

**Binding Affinity:** Ligand A (-10.3 kcal/mol) has a substantially stronger binding affinity than Ligand B (-8.1 kcal/mol). This is a major advantage, potentially outweighing some ADME drawbacks. The difference is >1.5 kcal/mol.

**Overall Assessment:**

Ligand A excels in key areas for a CNS GPCR target: TPSA, BBB, P-gp efflux, and, most importantly, binding affinity. While Ligand B has a better half-life and solubility, the superior affinity and CNS penetration potential of Ligand A are more critical. The slightly higher DILI risk for Ligand A is acceptable given the strong binding affinity.

Output:
1
2025-04-17 04:32:06,306 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (346.471) is slightly lower, which is generally favorable for permeability.

**2. TPSA:** Ligand A (60.85) is significantly better than Ligand B (80.32). For CNS targets, TPSA < 90 is preferred, and A is closer to the optimal <60 range.

**3. logP:** Both ligands have good logP values (A: 2.463, B: 2.65), falling within the optimal 1-3 range.

**4. H-Bond Donors:** Ligand A (1) is preferable to Ligand B (2). Lower HBD generally improves permeability.

**5. H-Bond Acceptors:** Ligand A (3) is preferable to Ligand B (5) for similar reasons as HBD.

**6. QED:** Ligand A (0.891) has a much better QED score than Ligand B (0.674), indicating a more drug-like profile.

**7. DILI:** Ligand A (31.02) has a significantly lower DILI risk than Ligand B (65.568). This is a major advantage for A.

**8. BBB:** Ligand A (57.968) has a better BBB percentile than Ligand B (50.679), though both are below the desirable >70 for CNS targets.

**9. Caco-2 Permeability:** Ligand A (-4.385) has a worse Caco-2 permeability than Ligand B (-5.203) - lower values are less favorable.

**10. Aqueous Solubility:** Ligand A (-1.924) has better aqueous solubility than Ligand B (-3.702).

**11. hERG Inhibition:** Both ligands have low hERG inhibition risk (A: 0.566, B: 0.316).

**12. Microsomal Clearance:** Ligand B (37.898) has lower microsomal clearance than Ligand A (41.763), suggesting better metabolic stability.

**13. In vitro Half-Life:** Ligand B (39.647) has a much longer in vitro half-life than Ligand A (-2.544). This is a significant advantage for B.

**14. P-gp Efflux:** Ligand A (0.684) has a lower P-gp efflux liability than Ligand B (0.232), which is favorable for CNS penetration.

**15. Binding Affinity:** Both ligands have very similar and excellent binding affinities (A: -8.4 kcal/mol, B: -8.2 kcal/mol). The difference is not substantial enough to outweigh other factors.

**Overall Assessment:**

Considering the GPCR-specific priorities, Ligand A is the better candidate. While Ligand B has better metabolic stability (lower Cl_mic, longer t1/2) and slightly better Caco-2 permeability, Ligand A excels in critical areas for CNS penetration: lower TPSA, better QED, significantly lower DILI risk, and lower P-gp efflux. The BBB values are both suboptimal, but A is better. The similar binding affinities make the ADME properties the deciding factor.

Output:
0
2025-04-17 04:32:06,306 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (352.479 and 373.465 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (76.46) is better than Ligand B (49.77), both are below the 90 A^2 threshold for CNS targets.

**3. logP:** Ligand A (1.471) is within the optimal range (1-3), while Ligand B (3.429) is approaching the upper limit.

**4. H-Bond Donors:** Both have 1 HBD, which is acceptable.

**5. H-Bond Acceptors:** Ligand A has 5 HBA, and Ligand B has 4, both are within the acceptable range of <=10.

**6. QED:** Both ligands have good QED scores (0.692 and 0.797, respectively), indicating drug-like properties.

**7. DILI:** Both have low DILI risk (22.838 and 20.9, respectively).

**8. BBB:** Ligand B (86.545) significantly outperforms Ligand A (50.019) in BBB penetration, which is *critical* for a CNS target like DRD2.

**9. Caco-2 Permeability:** Ligand A (-4.816) is worse than Ligand B (-4.492), indicating lower intestinal absorption.

**10. Aqueous Solubility:** Ligand A (-0.849) is better than Ligand B (-3.433).

**11. hERG Inhibition:** Ligand A (0.1) has a much lower hERG risk than Ligand B (0.711).

**12. Microsomal Clearance:** Both have similar microsomal clearance (48.512 and 47.509).

**13. In vitro Half-Life:** Ligand A (31.649) has a longer half-life than Ligand B (22.871).

**14. P-gp Efflux:** Ligand A (0.016) has much lower P-gp efflux than Ligand B (0.544), which is favorable for CNS penetration.

**15. Binding Affinity:** Ligand A (-7.5) has a slightly better binding affinity than Ligand B (-6.9). However, the difference is less than 1.5 kcal/mol.

**Overall Assessment:**

While Ligand A has slightly better affinity and lower hERG risk, Ligand B excels in BBB penetration (86.545 vs 50.019) and has lower P-gp efflux. For a CNS target like DRD2, BBB penetration is paramount. The improved BBB and lower P-gp efflux of Ligand B are more significant advantages than the slightly better affinity of Ligand A, especially considering the affinity difference is not substantial.

Output:
1
2025-04-17 04:32:06,306 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (354.431) is slightly higher than Ligand B (337.423), but both are acceptable.

**TPSA:** Ligand A (55.57) is better than Ligand B (62.3). For CNS targets, we want TPSA <= 90, and ideally lower. Both are within this range, but A is closer to the optimal value.

**logP:** Ligand A (3.887) is slightly higher than Ligand B (2.754). Both are within the optimal 1-3 range, but A is approaching the upper limit.

**H-Bond Donors/Acceptors:** Ligand A (0 HBD, 5 HBA) and Ligand B (1 HBD, 3 HBA) both have reasonable numbers of H-bond donors and acceptors, well within the guidelines.

**QED:** Both ligands have good QED scores (A: 0.63, B: 0.933), indicating good drug-like properties. Ligand B is significantly better.

**DILI:** Ligand A (69.639) has a higher DILI risk than Ligand B (49.477). Both are acceptable (<60 is good), but B is preferable.

**BBB:** Ligand B (78.519) has a significantly better BBB penetration score than Ligand A (63.784). This is a *critical* factor for a CNS target like DRD2.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.131 and -4.889), which is unusual and suggests poor permeability. This is a significant drawback for both.

**Aqueous Solubility:** Both ligands have negative solubility values (-4.072 and -3.259), indicating very poor aqueous solubility. This is a major formulation challenge for both.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (A: 0.643, B: 0.555), which is good.

**Microsomal Clearance:** Ligand A (95.101) has a much higher microsomal clearance than Ligand B (18.337). This means A is likely to be metabolized more quickly, leading to a shorter duration of action.

**In vitro Half-Life:** Ligand B (-10.516) has a negative half-life, which is not physically possible and indicates a potential issue with the data or the molecule's stability. Ligand A (29.017) has a reasonable half-life.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (A: 0.829, B: 0.175). Ligand B is significantly better, which is beneficial for CNS penetration.

**Binding Affinity:** Both ligands have similar and excellent binding affinities (A: -9.0 kcal/mol, B: -8.9 kcal/mol). The difference is negligible.

**Overall Assessment:**

While Ligand A has a better half-life, Ligand B is superior in almost every other critical parameter for a CNS-targeting GPCR ligand. Specifically, its significantly better BBB penetration, lower DILI risk, lower P-gp efflux, and better QED outweigh the slightly higher TPSA and logP. The negative Caco-2 and solubility values are concerning for both, but can potentially be addressed with formulation strategies. The negative half-life for Ligand B is a red flag, but assuming this is a data error, it would be the preferred candidate.

Output:
1
2025-04-17 04:32:06,306 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (362.543 and 361.486 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (61.02) is higher than Ligand B (38.25). For a CNS target like DRD2, we ideally want TPSA <= 90, so both are acceptable, but B is significantly better.

**3. logP:** Both ligands have similar logP values (4.433 and 4.426), which are slightly above the optimal range of 1-3, but not drastically so. This could potentially lead to some off-target effects or solubility issues, but isn't a major concern at this stage.

**4. H-Bond Donors:** Ligand A has 2 HBD, and Ligand B has 0. Both are within the acceptable limit of <=5.

**5. H-Bond Acceptors:** Ligand A has 3 HBA, and Ligand B has 5. Both are within the acceptable limit of <=10.

**6. QED:** Both ligands have similar QED values (0.73 and 0.697), indicating good drug-like properties.

**7. DILI:** Ligand A has a DILI risk of 51.725, while Ligand B has 31.408. Both are good (below 40 is preferred, and both are below 60), but B is better.

**8. BBB:** Ligand A has a BBB penetration of 70.958, and Ligand B has 83.831. Both are good (>70), but B is significantly better, which is crucial for a CNS target.

**9. Caco-2 Permeability:** Ligand A (-5.079) and Ligand B (-4.665) both have negative values, which is unusual and suggests poor permeability. However, the scale isn't specified, so it's hard to interpret.

**10. Aqueous Solubility:** Both ligands have very poor aqueous solubility (-4.183 and -5.161). This is a concern, but can sometimes be overcome with formulation strategies.

**11. hERG Inhibition:** Both ligands have low hERG inhibition risk (0.9 and 0.801), which is good.

**12. Microsomal Clearance:** Ligand A (80.682) and Ligand B (77.316) have similar microsomal clearance values. Lower is better, indicating greater metabolic stability.

**13. In vitro Half-Life:** Ligand A (69.005) has a good in vitro half-life, while Ligand B (-27.017) has a negative value, which is concerning and suggests very rapid metabolism.

**14. P-gp Efflux:** Ligand A (0.366) and Ligand B (0.635) have low P-gp efflux liability, which is good for CNS penetration.

**15. Binding Affinity:** Ligand B (-8.1 kcal/mol) has a slightly better binding affinity than Ligand A (-7.7 kcal/mol). While both are good, the 0.4 kcal/mol difference is notable.

**Overall Assessment:**

Ligand B is the more promising candidate. It has a significantly better BBB score, lower DILI risk, and slightly better binding affinity. While both have poor solubility, the superior BBB penetration and lower toxicity profile of Ligand B outweigh the slightly better half-life of Ligand A. The negative half-life of Ligand B is a major red flag.

Output:
1
2025-04-17 04:32:06,306 - INFO - Batch 121 complete. Total preferences: 1936
2025-04-17 04:32:06,306 - INFO - Processing batch 122/512...
2025-04-17 04:32:47,522 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (350.415 and 364.452 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (91.26) is better than Ligand B (49.41). For CNS targets, we want TPSA <= 90, so Ligand A is marginally above this, while Ligand B is well within the desired range.

**logP:** Ligand A (0.836) is suboptimal, being slightly below the 1-3 range. Ligand B (4.041) is high, potentially leading to solubility issues and off-target effects.

**H-Bond Donors/Acceptors:** Ligand A has 3 HBD and 5 HBA, which are acceptable. Ligand B has 1 HBD and 2 HBA, also acceptable.

**QED:** Both ligands have reasonable QED values (0.751 and 0.693), indicating good drug-like properties.

**DILI:** Both ligands have low DILI risk (37.611 and 35.75), which is positive.

**BBB:** Ligand B (89.841) is significantly better than Ligand A (41.373) in terms of BBB penetration, a critical factor for CNS targets like DRD2. A value >70 is desirable, and Ligand B is approaching that, while Ligand A is considerably lower.

**Caco-2 Permeability:** Both have negative Caco-2 values (-4.855 and -4.324) which is unusual and suggests poor permeability. This is a significant drawback for both.

**Aqueous Solubility:** Both have negative solubility values (-1.321 and -4.716), indicating very poor aqueous solubility. This is a major concern for both compounds.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.382 and 0.5), which is good.

**Microsomal Clearance:** Ligand A (21.27 mL/min/kg) has much lower clearance than Ligand B (67.516 mL/min/kg), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (20.136 hours) has a longer half-life than Ligand B (15.77 hours), which is preferable.

**P-gp Efflux:** Both ligands show no P-gp efflux liability (0.104 and 0.203), which is favorable for CNS penetration.

**Binding Affinity:** Both ligands have similar binding affinities (0 kcal/mol).

**Overall Assessment:**

Ligand B excels in BBB penetration, a crucial property for a DRD2 ligand. However, it suffers from a high logP, which could lead to solubility and off-target issues. Ligand A has a better TPSA and metabolic stability (lower Cl_mic, longer t1/2), but its BBB penetration is significantly worse. Both compounds have poor solubility and permeability.

Considering the GPCR-specific priorities, BBB is paramount for CNS targets. While Ligand A has better ADME properties overall, the substantial difference in BBB penetration makes Ligand B the more promising candidate, *assuming* the high logP can be addressed through structural modifications. The poor solubility and permeability of both compounds are serious concerns that would need to be tackled in subsequent optimization.

Output:
1
2025-04-17 04:32:47,525 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (371.487 and 370.4 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (64.11) is significantly better than Ligand B (80.04). For CNS targets, we want TPSA <= 90, and A is closer to the optimal <=60 range. B is pushing the upper limit.

**3. logP:** Both ligands have a logP around 4.1, which is slightly high. While not ideal, it's acceptable, and similar for both.

**4. H-Bond Donors:** Ligand A (1) is preferable to Ligand B (3). Fewer HBDs generally improve permeability.

**5. H-Bond Acceptors:** Ligand A (6) is preferable to Ligand B (4). Fewer HBAs generally improve permeability.

**6. QED:** Both ligands have similar QED values (0.661 and 0.692), indicating good drug-likeness.

**7. DILI:** Ligand A (88.212) has a higher DILI risk than Ligand B (68.05). This is a negative for A, but not a dealbreaker.

**8. BBB:** Ligand B (76.425) has a significantly better BBB penetration percentile than Ligand A (46.646). This is *critical* for a CNS target like DRD2.

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.001 and -5.007), which is unusual and suggests poor permeability. This is concerning for both.

**10. Aqueous Solubility:** Both ligands have very poor aqueous solubility (-4.631 and -4.914). This is a significant drawback for both.

**11. hERG Inhibition:** Both ligands have similar, low hERG inhibition risk (0.551 and 0.561).

**12. Microsomal Clearance:** Ligand B (53.211) has lower microsomal clearance than Ligand A (75.952), indicating better metabolic stability.

**13. In vitro Half-Life:** Ligand B (18.365) has a much longer in vitro half-life than Ligand A (3.357). This is a significant advantage for B.

**14. P-gp Efflux:** Both ligands have low P-gp efflux liability (0.365 and 0.24).

**15. Binding Affinity:** Ligand B (-9.1 kcal/mol) has a significantly stronger binding affinity than Ligand A (-8.3 kcal/mol). This is a substantial advantage, potentially outweighing some of the ADME concerns.

**Overall Assessment:**

While Ligand A has better TPSA, HBD, and HBA values, Ligand B excels in the most critical areas for a CNS GPCR target: **BBB penetration and binding affinity**. The significantly stronger binding affinity of Ligand B (-9.1 vs -8.3) is a major advantage. The longer half-life and lower clearance also contribute to its favorability. The slightly higher DILI risk for A is a concern, but the much lower BBB penetration is a bigger issue. The poor solubility and Caco-2 permeability are drawbacks for both, but can potentially be addressed with formulation strategies.

Output:
1
2025-04-17 04:32:47,525 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B based on the provided guidelines, prioritizing GPCR-specific properties (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (364.515 and 375.519 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (65.54) is better than Ligand B (58.22). Both are below the 90 A^2 threshold for CNS targets, but A is closer to the ideal.

**logP:** Ligand A (1.823) is optimal (1-3), while Ligand B (4.391) is pushing the upper limit and could lead to solubility issues.

**H-Bond Donors/Acceptors:** Both have 1 HBD and 5 HBA, which are within acceptable ranges.

**QED:** Ligand A (0.866) has a significantly better QED score than Ligand B (0.666), indicating better overall drug-likeness.

**DILI:** Ligand A (21.636) has a much lower DILI risk than Ligand B (75.998), a significant advantage.

**BBB:** Ligand A (65.297) has a better BBB percentile than Ligand B (44.785). While both are not ideal (>70), A is substantially better for a CNS target like DRD2.

**Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and suggests poor permeability. However, the absolute value is smaller for Ligand A (-5.011 vs -5.309), suggesting marginally better permeability.

**Aqueous Solubility:** Ligand A (-1.25) is better than Ligand B (-4.482), indicating higher solubility.

**hERG:** Both ligands have low hERG inhibition liability (0.485 and 0.568), which is good.

**Microsomal Clearance:** Ligand A (4.299) has significantly lower microsomal clearance than Ligand B (113.255), indicating better metabolic stability.

**In vitro Half-Life:** Ligand A (33.644) has a much longer in vitro half-life than Ligand B (-15.561), which is a substantial advantage.

**P-gp Efflux:** Ligand A (0.055) has much lower P-gp efflux liability than Ligand B (0.488), which is crucial for CNS penetration.

**Binding Affinity:** Ligand A (-8.2 kcal/mol) has a slightly better binding affinity than Ligand B (-7.7 kcal/mol). While the difference is not huge, it contributes to the overall preference for A.

**Overall:** Considering all parameters, and especially prioritizing the GPCR-specific properties (BBB, logP, Pgp, TPSA, affinity), Ligand A is a significantly more promising drug candidate. It has better BBB penetration, a more favorable logP, lower P-gp efflux, better metabolic stability, longer half-life, lower DILI risk, and a slightly better binding affinity.

Output:
0
2025-04-17 04:32:47,526 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (345.447 and 358.389 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (70.81) is significantly better than Ligand B (87.32). For CNS targets, we want TPSA <= 90, and A is comfortably within that range, while B is approaching the upper limit.

**3. logP:** Both ligands have acceptable logP values (1.942 and 0.897), falling within the 1-3 range. Ligand A is slightly better.

**4. H-Bond Donors:** Ligand A (0) is preferable to Ligand B (2). Fewer HBDs generally improve membrane permeability.

**5. H-Bond Acceptors:** Ligand A (5) is better than Ligand B (4). Both are within the acceptable limit of <=10.

**6. QED:** Both ligands have similar QED values (0.769 and 0.723), indicating good drug-likeness.

**7. DILI:** Both ligands have low DILI risk (39.356 and 36.254), both well below the 40 threshold.

**8. BBB:** Ligand A (72.237) has a significantly better BBB percentile than Ligand B (62.97).  For CNS targets, >70 is desirable, and A is closer to this target.

**9. Caco-2 Permeability:** Ligand A (-4.686) is better than Ligand B (-4.853). Higher values indicate better intestinal absorption.

**10. Aqueous Solubility:** Both ligands have poor aqueous solubility (-1.488 and -1.741). This could pose formulation challenges, but is less critical than BBB for a CNS target.

**11. hERG Inhibition:** Both ligands have low hERG inhibition risk (0.534 and 0.585).

**12. Microsomal Clearance:** Ligand B (-16.997) has a *much* lower (better) microsomal clearance than Ligand A (56.097). This suggests significantly improved metabolic stability for Ligand B.

**13. In vitro Half-Life:** Ligand B (-15.714) has a much longer in vitro half-life than Ligand A (21.147). This is a significant advantage.

**14. P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.183 and 0.024).

**15. Binding Affinity:** Ligand B (-7.7) has a slightly better binding affinity than Ligand A (-8.0). While both are excellent, the difference isn't substantial enough to outweigh other factors.

**Overall Assessment:**

Ligand A excels in TPSA, logP, and crucially, BBB penetration. However, Ligand B demonstrates superior metabolic stability (lower Cl_mic) and a longer half-life, both critical for *in vivo* efficacy. Given the GPCR-specific priority of BBB penetration, and the fact that Ligand A is already at a respectable 72.237, the substantial improvements in metabolic stability and half-life offered by Ligand B are more compelling. While solubility is a concern for both, it can be addressed with formulation strategies. The slightly better affinity of Ligand B is a bonus.

Output:
1
2025-04-17 04:32:47,526 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the acceptable range (200-500 Da). Ligand A (346.515 Da) is slightly preferred as it's closer to the ideal range.

**TPSA:** Ligand A (41.57) is excellent for CNS penetration, well below 90. Ligand B (75.19) is still reasonable, but less optimal.

**logP:** Ligand A (4.158) is slightly high, potentially leading to solubility issues or off-target effects, but still within a tolerable range. Ligand B (2.625) is excellent.

**H-Bond Donors/Acceptors:** Both ligands have acceptable HBD (1) and HBA (A: 3, B: 5) counts.

**QED:** Both ligands have acceptable QED scores (A: 0.87, B: 0.771), indicating good drug-like properties.

**DILI:** Ligand A (13.3) has a significantly lower DILI risk than Ligand B (72.005), a major advantage.

**BBB:** Ligand A (93.874) has excellent BBB penetration, exceeding the 70% threshold. Ligand B (68.127) is lower, which is a concern for a CNS target.

**Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and suggests a potential issue with the data or modeling. However, the magnitude of the negative value for Ligand A (-4.492) is less extreme than for Ligand B (-5.1).

**Aqueous Solubility:** Both have negative solubility values, indicating poor solubility, but again, A (-3.583) is slightly better than B (-3.092).

**hERG Inhibition:** Both ligands show low hERG inhibition risk (A: 0.934, B: 0.151), which is good.

**Microsomal Clearance:** Ligand A (30.693) has a lower microsomal clearance than Ligand B (63.88), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (6.963) has a slightly longer half-life than Ligand B (17.734).

**P-gp Efflux:** Ligand A (0.418) has lower P-gp efflux than Ligand B (0.201), which is favorable for CNS exposure.

**Binding Affinity:** Ligand B (-9.1 kcal/mol) has a slightly better binding affinity than Ligand A (-8.7 kcal/mol). However, the difference is not substantial enough to outweigh the significant advantages of Ligand A in other critical parameters.

**Overall:**

Ligand A is the superior candidate. It excels in BBB penetration, DILI risk, metabolic stability, and P-gp efflux. While its logP is slightly higher, and its affinity slightly lower than Ligand B, the combination of favorable ADME properties, especially for a CNS target, makes it the more promising drug candidate. The negative Caco-2 and solubility values are concerning for both, but less so for Ligand A.

Output:
1
2025-04-17 04:32:47,526 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (371.216 Da) is slightly higher than Ligand B (346.475 Da), but both are acceptable.

**TPSA:**  Both ligands have TPSA values below the 90 A^2 threshold desirable for CNS targets. Ligand A (71.84 A^2) is slightly higher than Ligand B (66.4 A^2), but both are good.

**logP:** Both ligands have logP values within the optimal range (1-3). Ligand A (3.971) is at the higher end, while Ligand B (2.532) is more centrally located. This is a slight advantage for B, as very high logP can sometimes lead to off-target effects.

**H-Bond Donors/Acceptors:** Ligand A has 2 HBD and 4 HBA, while Ligand B has 0 HBD and 4 HBA. Both are within acceptable limits (<=5 HBD and <=10 HBA).

**QED:** Both ligands have similar QED values (0.799 and 0.794), indicating good drug-likeness.

**DILI:** Ligand A has a significantly higher DILI risk (81.427%) compared to Ligand B (34.277%). This is a major concern for Ligand A.

**BBB:** Ligand B has a much better BBB penetration percentile (90.578%) than Ligand A (69.95%). This is crucial for a CNS target like DRD2, giving a significant advantage to Ligand B.

**Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and suggests poor permeability. However, the scale is not specified, making direct comparison difficult.

**Aqueous Solubility:** Both have negative solubility values, which is also unusual. Again, the scale is not specified.

**hERG:** Both ligands have low hERG inhibition liability (0.416 and 0.612), which is good.

**Microsomal Clearance:** Ligand B has a higher microsomal clearance (61.623) than Ligand A (19.796), suggesting lower metabolic stability. This favors Ligand A.

**In vitro Half-Life:** Ligand A has a longer in vitro half-life (57.82 hours) than Ligand B (-14.177 hours). The negative value for B is concerning and suggests rapid degradation. This is a strong advantage for Ligand A.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.06 and 0.316), which is good for CNS penetration.

**Binding Affinity:** Ligand A has a slightly better binding affinity (-9.7 kcal/mol) than Ligand B (-8.4 kcal/mol). This 1.3 kcal/mol difference is substantial and could outweigh some of the ADME drawbacks of Ligand A.

**Overall Assessment:**

Despite the better binding affinity of Ligand A, the significantly higher DILI risk and lower BBB penetration are major drawbacks. Ligand B, while having slightly weaker affinity, has a much better safety profile (lower DILI) and significantly better BBB penetration, which is critical for a CNS drug. The negative half-life for Ligand B is a concern, but the other factors strongly favor it.

Output:
1
2025-04-17 04:32:47,526 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 drug candidates, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (408.34) is slightly higher than Ligand B (357.439), but both are acceptable.

**2. TPSA:** Ligand A (58.22) is excellent, well below the 90 Angstroms threshold for CNS targets. Ligand B (91.02) is slightly above the optimal threshold, potentially hindering BBB penetration, but not a complete dealbreaker.

**3. logP:** Ligand A (4.125) is a bit high, potentially leading to solubility issues or off-target interactions. Ligand B (1.859) is within the optimal range (1-3).

**4. H-Bond Donors:** Both ligands have 1 HBD, which is within the acceptable limit of 5.

**5. H-Bond Acceptors:** Ligand A has 4 HBAs, and Ligand B has 6. Both are acceptable (<=10).

**6. QED:** Both ligands have similar QED values (0.777 and 0.766), indicating good drug-likeness.

**7. DILI:** Ligand A (26.018) has a significantly lower DILI risk than Ligand B (65.452), which is a strong advantage.

**8. BBB:** Ligand A (74.292) has a much better BBB penetration percentile than Ligand B (40.093). This is crucial for a CNS target like DRD2.

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.973 and -4.965). These values are difficult to interpret without knowing the scale, but the similarity suggests similar absorption challenges.

**10. Aqueous Solubility:** Both ligands have negative solubility values (-4.04 and -3.055). Similar to Caco-2, the scale is unknown, but suggests potential formulation challenges.

**11. hERG Inhibition:** Ligand A (0.894) has a slightly higher hERG risk than Ligand B (0.165), but both are relatively low.

**12. Microsomal Clearance:** Ligand A (67.49) has a higher microsomal clearance than Ligand B (34.418), indicating lower metabolic stability.

**13. In vitro Half-Life:** Ligand B (55.809) has a longer in vitro half-life than Ligand A (-5.127), which is desirable.

**14. P-gp Efflux:** Ligand A (0.373) has lower P-gp efflux liability than Ligand B (0.081), which is favorable for CNS penetration.

**15. Binding Affinity:** Ligand A (-7.9 kcal/mol) has a significantly stronger binding affinity than Ligand B (-6.6 kcal/mol). This 1.3 kcal/mol difference is substantial and can outweigh some ADME drawbacks.

**Overall Assessment:**

Ligand A excels in binding affinity and BBB penetration, and has a much lower DILI risk and lower P-gp efflux. While its logP is slightly high and its metabolic stability is lower, the strong affinity and favorable CNS properties are critical for a DRD2 targeting drug. Ligand B has better metabolic stability and a more optimal logP, but its significantly weaker affinity and poor BBB penetration make it a less attractive candidate.

Output:
1
2025-04-17 04:32:47,527 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (355.395 Da) and Ligand B (350.503 Da) are comparable.

**TPSA:** Ligand A (133.7) is closer to the desirable threshold of 90 for CNS targets than Ligand B (67.43). This is a significant advantage for Ligand A regarding brain penetration.

**logP:** Ligand A (0.618) is slightly below the optimal range (1-3) but not drastically. Ligand B (2.64) is well within the optimal range.

**H-Bond Donors/Acceptors:** Ligand A (HBD=1, HBA=6) and Ligand B (HBD=2, HBA=3) both have acceptable numbers of H-bond donors and acceptors.

**QED:** Both ligands have reasonable QED values (Ligand A: 0.224, Ligand B: 0.672). Ligand B's QED is significantly better, suggesting a more drug-like profile.

**DILI:** Both ligands have low DILI risk (Ligand A: 33.346, Ligand B: 26.095), which is favorable. Ligand B has a slightly lower risk.

**BBB:** This is critical for a CNS target. Ligand A (41.993) has a poor BBB percentile, while Ligand B (70.88) is excellent, exceeding the desirable >70 threshold. This is a major advantage for Ligand B.

**Caco-2 Permeability:** Both have negative values, indicating poor permeability. Ligand A (-4.944) is worse than Ligand B (-5.104).

**Aqueous Solubility:** Both have negative values, indicating poor solubility. Ligand A (-0.914) is slightly better than Ligand B (-3.171).

**hERG Inhibition:** Both ligands have low hERG inhibition risk (Ligand A: 0.107, Ligand B: 0.496).

**Microsomal Clearance:** Ligand B (61.804) has a higher microsomal clearance than Ligand A (39.263), meaning Ligand A is more metabolically stable.

**In vitro Half-Life:** Ligand A (-18.39) has a negative half-life, which is not possible, and is a red flag. Ligand B (-0.382) is also negative, but less so.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (Ligand A: 0.009, Ligand B: 0.306).

**Binding Affinity:** Ligand B (-8.9 kcal/mol) has a significantly stronger binding affinity than Ligand A (-7.1 kcal/mol). This difference of 1.8 kcal/mol is substantial and can outweigh some ADME drawbacks.

**Overall Assessment:**

Ligand B is superior due to its significantly better BBB penetration, stronger binding affinity, and better QED score. While Ligand A has slightly better metabolic stability and solubility, the poor BBB penetration is a major drawback for a CNS-targeting drug. The negative half-life values for both are concerning and would require further investigation, but the magnitude of the difference in affinity and BBB makes Ligand B the more promising candidate.

Output:
1
2025-04-17 04:32:47,527 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B based on the provided guidelines, prioritizing GPCR-specific properties (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (350.48 and 359.50 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (49.41) is significantly better than Ligand B (101.64). For CNS targets, TPSA should be <= 90, and A is comfortably within this range, while B exceeds it. This is a substantial advantage for A.

**logP:** Both ligands have acceptable logP values (3.06 and 3.75), falling within the optimal 1-3 range. B is slightly higher, which *could* indicate potential off-target effects, but isn't a major concern.

**H-Bond Donors/Acceptors:** Ligand A (HBD=1, HBA=2) is preferable to Ligand B (HBD=3, HBA=8). Lower HBD/HBA generally improves permeability.

**QED:** Ligand A (0.775) has a much better QED score than Ligand B (0.463), indicating a more drug-like profile.

**DILI:** Ligand A (25.44) has a significantly lower DILI risk than Ligand B (69.14). This is a major advantage for A.

**BBB:** Ligand A (85.42) has a much higher BBB penetration percentile than Ligand B (60.45). This is *critical* for a CNS target like DRD2, making A far more promising.

**Caco-2 Permeability:** Ligand A (-4.301) is better than Ligand B (-5.314), indicating better intestinal absorption.

**Aqueous Solubility:** Ligand A (-3.343) is better than Ligand B (-4.017).

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.766 and 0.556).

**Microsomal Clearance:** Ligand A (41.34) has lower clearance than Ligand B (75.80), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (-19.73) has a longer half-life than Ligand B (18.06).

**P-gp Efflux:** Ligand A (0.26) has lower P-gp efflux than Ligand B (0.137), which is favorable for CNS penetration.

**Binding Affinity:** Ligand B (-8.0) has a slightly better binding affinity than Ligand A (-7.2). However, the difference (0.8 kcal/mol) is not substantial enough to outweigh the significant ADME advantages of Ligand A.

**Overall:** Ligand A is significantly better across most crucial ADME properties (TPSA, BBB, DILI, QED, Clearance, Half-life, P-gp efflux, Solubility) and has acceptable binding affinity. Ligand B's slightly better affinity is overshadowed by its poorer ADME profile, particularly its lower BBB penetration and higher DILI risk.

Output:
0
2025-04-17 04:32:47,527 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 drug candidates, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (357.451 and 362.417 Da) fall within the ideal range of 200-500 Da.

**TPSA:** Ligand A (107.97) is better than Ligand B (67.87). Both are below the 140 A^2 threshold for oral absorption, and Ligand B is particularly good at 67.87, being well below the 90 A^2 target for CNS penetration.

**logP:** Ligand B (1.296) is within the optimal range (1-3), while Ligand A (-0.348) is slightly below, potentially hindering permeation.

**H-Bond Donors/Acceptors:** Ligand A has 3 HBD and 5 HBA, while Ligand B has 1 HBD and 4 HBA. Both are within acceptable limits.

**QED:** Both ligands have good QED scores (0.495 and 0.595, respectively), indicating drug-like properties. Ligand B is slightly better.

**DILI:** Ligand A (15.626) has a lower DILI risk than Ligand B (20.047), which is preferable.

**BBB:** Ligand B (94.455) significantly outperforms Ligand A (25.979) in BBB penetration, a crucial factor for CNS targets like DRD2.

**Caco-2 Permeability:** Ligand A (-5.166) and Ligand B (-4.712) both have negative Caco-2 permeability values, which is unusual and suggests poor intestinal absorption.

**Aqueous Solubility:** Both ligands have poor aqueous solubility (-1.072 and -1.271).

**hERG Inhibition:** Ligand A (0.105) has a slightly lower hERG inhibition liability than Ligand B (0.435), which is better.

**Microsomal Clearance:** Ligand B (16.449) has a slightly higher microsomal clearance than Ligand A (15.552), indicating potentially lower metabolic stability.

**In vitro Half-Life:** Ligand B (14.892 hours) has a significantly longer half-life than Ligand A (0.047 hours), which is a major advantage.

**P-gp Efflux:** Ligand A (0.009) has a much lower P-gp efflux liability than Ligand B (0.036), which is favorable for CNS exposure.

**Binding Affinity:** Both ligands have excellent binding affinities (-7.7 and -7.8 kcal/mol), with Ligand B being slightly better. The affinity difference is minimal.

**Overall Assessment:**

While Ligand A has a lower DILI risk and P-gp efflux, Ligand B excels in critical areas for CNS GPCR targets: significantly better BBB penetration (94.455 vs 25.979), a more optimal logP (1.296 vs -0.348), and a much longer in vitro half-life (14.892 vs 0.047). The slightly better affinity of Ligand B is a bonus. The negative Caco-2 values for both are concerning, but the importance of BBB penetration for a CNS target outweighs this concern.

Output:
1
2025-04-17 04:32:47,527 - INFO - Reasoning:

Let's analyze Ligand A and Ligand B based on the provided guidelines, prioritizing GPCR-specific properties (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (354.422 Da) is slightly lower, which could be advantageous for permeability.

**TPSA:** Ligand A (70.08) is excellent for CNS penetration, well below the 90 A^2 threshold. Ligand B (87.3) is still reasonable, but less optimal.

**logP:** Both ligands have acceptable logP values (A: 1.239, B: 1.836), falling within the 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A (HBD=1, HBA=4) is better than Ligand B (HBD=3, HBA=3) regarding the number of hydrogen bond donors and acceptors, potentially leading to improved permeability.

**QED:** Both ligands have similar QED values (A: 0.699, B: 0.61), indicating good drug-likeness.

**DILI:** Ligand A (32.028) has a significantly lower DILI risk than Ligand B (21.946), which is a major advantage.

**BBB:** Ligand A (86.739) has a much higher BBB percentile than Ligand B (59.093). This is *critical* for a CNS target like DRD2.

**Caco-2 Permeability:** Ligand A (-4.156) has a more negative Caco-2 value, indicating lower permeability. Ligand B (-5.07) is even worse. This is a concern for both, but less critical than BBB for a CNS target.

**Aqueous Solubility:** Ligand A (-1.233) has better solubility than Ligand B (-3.088).

**hERG Inhibition:** Both ligands have very low hERG inhibition risk (A: 0.381, B: 0.1).

**Microsomal Clearance:** Ligand A (19.922) has significantly lower microsomal clearance than Ligand B (47.774), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (-10.831) has a more negative in vitro half-life, indicating a shorter half-life. Ligand B (17.609) is better.

**P-gp Efflux:** Ligand A (0.097) has lower P-gp efflux liability than Ligand B (0.017), which is favorable for CNS exposure.

**Binding Affinity:** Both ligands have very similar and strong binding affinities (A: -8.0 kcal/mol, B: -7.9 kcal/mol). The difference is negligible.

**Overall Assessment:**

Ligand A is significantly better overall, primarily due to its superior BBB penetration (86.7% vs 59.1%), lower DILI risk, lower microsomal clearance, and lower P-gp efflux. While its Caco-2 permeability is slightly worse, this is less critical for a CNS target. The binding affinities are nearly identical, so the ADME properties are the deciding factors.

Output:
1
2025-04-17 04:32:47,528 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (362.455 Da and 374.472 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (83.56) is better than Ligand B (33.2). For CNS targets, TPSA < 90 is preferred, both meet this.

**logP:** Ligand A (2.432) is within the optimal 1-3 range. Ligand B (4.214) is slightly higher, potentially leading to solubility issues or off-target interactions, though not drastically so.

**H-Bond Donors/Acceptors:** Ligand A has 2 HBD and 6 HBA, while Ligand B has 0 HBD and 3 HBA. Both are within acceptable limits (<=5 HBD and <=10 HBA).

**QED:** Both ligands have similar QED values (0.753 and 0.683), indicating good drug-likeness.

**DILI:** Ligand A (58.86) has a higher DILI risk than Ligand B (27.181). This is a significant advantage for Ligand B.

**BBB:** Ligand B (94.261) has a *much* higher BBB penetration percentile than Ligand A (55.991). This is a critical factor for a CNS target like DRD2.

**Caco-2 Permeability:** Ligand A (-5.21) has a more negative Caco-2 value, suggesting lower intestinal permeability than Ligand B (-4.51).

**Aqueous Solubility:** Ligand A (-2.191) has slightly better solubility than Ligand B (-4.69). However, solubility is less critical than BBB for CNS targets.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.524 and 0.665).

**Microsomal Clearance:** Ligand A (-4.767) has a lower (better) microsomal clearance than Ligand B (67.82). This suggests better metabolic stability for Ligand A.

**In vitro Half-Life:** Ligand A (38.938) has a longer in vitro half-life than Ligand B (-1.562). This is a positive for Ligand A.

**P-gp Efflux:** Ligand A (0.058) has lower P-gp efflux than Ligand B (0.225), which is favorable for CNS penetration.

**Binding Affinity:** Both ligands have very similar binding affinities (-7.4 kcal/mol and -7.3 kcal/mol). The difference is negligible.

**Conclusion:**

While Ligand A has better metabolic stability (lower Cl_mic, longer t1/2) and slightly better solubility, Ligand B *significantly* outperforms it in BBB penetration (94.261 vs 55.991) and has a much lower DILI risk. For a CNS target like DRD2, BBB penetration is paramount. The slight drawbacks of Ligand B in metabolic stability are likely outweighed by its superior brain exposure.

Output:
1
2025-04-17 04:32:47,528 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 drug candidates, considering the provided guidelines and GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (343.446 and 349.475 Da) fall within the ideal range of 200-500 Da.

**TPSA:** Ligand A (41.29) is significantly better than Ligand B (61.88). For CNS targets, TPSA should be <= 90, both are within this range, but A is much closer to the optimal range for brain penetration.

**logP:** Ligand A (3.365) is optimal (1-3), while Ligand B (1.171) is on the lower side, potentially hindering permeation.

**H-Bond Donors/Acceptors:** Both have 1 HBD and 4 HBA, which are acceptable.

**QED:** Both ligands have good QED scores (0.929 and 0.809), indicating drug-like properties.

**DILI:** Ligand A (12.679) has a much lower DILI risk than Ligand B (15.355), which is preferable.

**BBB:** Ligand A (86.584) has a significantly better BBB penetration percentile than Ligand B (73.517). This is a crucial factor for a CNS target like DRD2.

**Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and indicates poor permeability. However, the absolute value is smaller for Ligand A (-4.749 vs -4.645), suggesting slightly better permeability.

**Aqueous Solubility:** Both have very poor aqueous solubility (-1.718 and -1.837). This is a concern for both, but not a deciding factor given other differences.

**hERG:** Ligand A (0.934) has a lower hERG inhibition liability than Ligand B (0.238), indicating a lower risk of cardiotoxicity.

**Microsomal Clearance:** Ligand A (-7.601) has a much lower (better) microsomal clearance than Ligand B (29.51), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (13.408 hours) has a significantly longer half-life than Ligand B (7.716 hours).

**P-gp Efflux:** Ligand A (0.564) has lower P-gp efflux liability than Ligand B (0.012), which is favorable for CNS exposure.

**Binding Affinity:** Ligand B (-7.8 kcal/mol) has slightly better binding affinity than Ligand A (-9.9 kcal/mol). While affinity is important, the difference of 2.1 kcal/mol is not substantial enough to outweigh the significant ADME advantages of Ligand A.

**Conclusion:**

Considering the GPCR-specific priorities and the overall profile, **Ligand A is the more promising drug candidate.** It exhibits superior BBB penetration, lower DILI risk, better metabolic stability (lower Cl_mic and longer t1/2), lower P-gp efflux, and lower hERG liability, all critical for a CNS-targeting drug. While Ligand B has slightly better binding affinity, Ligand A's improved ADME properties, particularly its BBB penetration, make it the more viable option.

Output:
0
2025-04-17 04:32:47,528 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (335.363 and 350.503 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (65.38) is better than Ligand B (69.64). Both are below the 90 A^2 threshold for CNS targets, but A is closer to the ideal.

**3. logP:** Both ligands have good logP values (3.204 and 2.328), falling within the optimal 1-3 range. Ligand A is slightly higher, which *could* be beneficial for membrane permeability, but also increases the risk of off-target interactions.

**4. H-Bond Donors:** Ligand A (1) is preferable to Ligand B (2). Lower HBD generally improves permeability.

**5. H-Bond Acceptors:** Ligand A (5) is preferable to Ligand B (3). Lower HBA generally improves permeability.

**6. QED:** Ligand A (0.798) has a significantly better QED score than Ligand B (0.67), indicating a more drug-like profile.

**7. DILI:** Ligand B (6.941) has a much lower DILI risk than Ligand A (96.937). This is a *major* advantage for Ligand B.

**8. BBB:** Ligand A (72.082) has a better BBB percentile than Ligand B (64.017), which is crucial for a CNS target like DRD2.

**9. Caco-2:** Both have negative Caco-2 values, which is unusual and difficult to interpret. We'll proceed cautiously, assuming these indicate poor permeability.

**10. Solubility:** Ligand B (-2.038) has better solubility than Ligand A (-4.962).

**11. hERG:** Ligand A (0.765) has a slightly better hERG profile than Ligand B (0.461), indicating lower cardiotoxicity risk.

**12. Cl_mic:** Ligand B (27.923) has significantly lower microsomal clearance than Ligand A (64.237), suggesting better metabolic stability.

**13. t1/2:** Ligand A (23.549) has a longer in vitro half-life than Ligand B (0.46). This is a positive for Ligand A.

**14. Pgp:** Ligand A (0.534) has lower P-gp efflux liability than Ligand B (0.115), which is favorable for CNS penetration.

**15. Binding Affinity:** Ligand A (-9.7 kcal/mol) has a significantly stronger binding affinity than Ligand B (-8.0 kcal/mol). This is a substantial advantage for Ligand A, potentially outweighing some of its ADME drawbacks.

**Overall Assessment:**

Ligand A has a superior binding affinity and better BBB penetration and Pgp efflux, which are critical for a CNS GPCR target. It also has a better QED and in vitro half-life. However, Ligand B has a *much* better safety profile (DILI) and metabolic stability (Cl_mic) and better solubility. The large difference in DILI risk is a significant concern for Ligand A. The binding affinity difference is substantial (>1.5 kcal/mol), which is a strong argument in favor of A. Considering the balance, the stronger binding affinity and better CNS penetration of Ligand A are likely to be more important for DRD2 targeting than the slightly worse ADME profile, *provided* the DILI risk can be mitigated through further optimization.

Output:
1
2025-04-17 04:32:47,528 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (388.6) is slightly higher than Ligand B (349.4).

**TPSA:** Ligand A (58.64) is excellent for CNS penetration, well below 90. Ligand B (120.54) is higher, but still potentially acceptable, though less optimal.

**logP:** Both ligands have good logP values (A: 2.251, B: 1.643), falling within the 1-3 range.

**H-Bond Donors/Acceptors:** Both have 1 HBD and 5 HBA, which are within acceptable limits.

**QED:** Ligand A (0.622) has a better QED score than Ligand B (0.435), indicating better overall drug-likeness.

**DILI:** Both ligands have low DILI risk (A: 29.47, B: 30.52), both below the 40 threshold.

**BBB:** This is a critical parameter for a CNS target. Ligand A has a significantly higher BBB penetration percentile (71.97) compared to Ligand B (43.82).

**Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and suggests poor permeability. However, the scale is not defined, so it's difficult to interpret.

**Aqueous Solubility:** Both have negative solubility values, which is also unusual. Again, the scale is undefined.

**hERG Inhibition:** Both ligands show low hERG inhibition risk (A: 0.432, B: 0.109).

**Microsomal Clearance:** Ligand A (67.35) has a higher microsomal clearance than Ligand B (11.34), suggesting lower metabolic stability.

**In vitro Half-Life:** Ligand B (9.34 hours) has a longer half-life than Ligand A (-5.771 hours). The negative value for A is concerning.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (A: 0.16, B: 0.017), which is favorable for CNS penetration.

**Binding Affinity:** Ligand B (-7.5 kcal/mol) has a significantly better binding affinity than Ligand A (-6.3 kcal/mol). This is a substantial advantage (>1.5 kcal/mol difference).

**Overall Assessment:**

Ligand B has a superior binding affinity, a longer half-life, and lower P-gp efflux. However, Ligand A has a significantly better BBB penetration, a higher QED score, and lower microsomal clearance. The TPSA of Ligand A is also more favorable for CNS penetration. The negative Caco-2 and solubility values are concerning for both, but the difference in binding affinity is substantial. Given the importance of affinity for GPCRs, and the fact that Ligand B's affinity is significantly better, it outweighs the other drawbacks. The better BBB of Ligand A is important, but the affinity difference is larger.

Output:
1
2025-04-17 04:32:47,528 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 drug candidates, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (407.312 Da) is higher, but still acceptable. Ligand B (345.399 Da) is slightly lower, potentially favoring permeability.

**TPSA:** Ligand A (68.18) is excellent for CNS penetration, well below the 90 A^2 threshold. Ligand B (102.66) is higher, but still potentially acceptable, though less ideal for CNS targets.

**logP:** Ligand A (3.569) is within the optimal range (1-3). Ligand B (0.532) is quite low, potentially hindering membrane permeability and CNS penetration.

**H-Bond Donors/Acceptors:** Both ligands have reasonable HBD (2) and HBA (4/5) counts, falling within the guidelines.

**QED:** Both ligands have good QED scores (0.815 and 0.783), indicating good drug-like properties.

**DILI:** Ligand A (61.962) has a higher DILI risk than Ligand B (35.44), but both are below the concerning threshold of 60.

**BBB:** Ligand A (80.419) has a significantly better BBB percentile than Ligand B (28.887). This is a crucial advantage for a CNS target like DRD2.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values which is unusual and suggests a problem with the prediction method. However, the values are similar.

**Aqueous Solubility:** Both ligands have negative solubility values, which is also unusual. Again, the values are similar.

**hERG:** Both ligands have low hERG inhibition liability (0.737 and 0.435), indicating a low risk of cardiotoxicity.

**Microsomal Clearance:** Ligand A (70.855) has higher microsomal clearance than Ligand B (-8.019), suggesting lower metabolic stability. Ligand B's negative value is unusual and suggests high stability.

**In vitro Half-Life:** Ligand A (59.559) has a longer half-life than Ligand B (1.73), which is generally desirable.

**P-gp Efflux:** Ligand A (0.614) has lower P-gp efflux liability than Ligand B (0.039), which is beneficial for CNS exposure.

**Binding Affinity:** Both ligands have very strong binding affinities (-9.0 and -8.8 kcal/mol). The difference (0.2 kcal/mol) is not substantial enough to override other significant differences.

**Overall Assessment:**

Ligand A is the stronger candidate. While it has a slightly higher DILI risk and clearance, its superior BBB penetration, more favorable logP, and lower P-gp efflux are critical for a CNS-targeting GPCR like DRD2. Ligand B's low logP is a major drawback, likely hindering its ability to cross the blood-brain barrier effectively. The unusually negative Caco-2 and solubility values for both compounds are concerning, but the relative differences in other parameters are more decisive.

Output:
1
2025-04-17 04:32:47,529 - INFO - Batch 122 complete. Total preferences: 1952
2025-04-17 04:32:47,529 - INFO - Processing batch 123/512...
2025-04-17 04:33:28,521 - INFO - Reasoning:

Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (374.241 and 349.387 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (87.58) is excellent, falling well below the 90 A^2 threshold for CNS targets. Ligand B (107.11) is still reasonable but less optimal, being above 90 A^2.

**3. logP:** Ligand A (1.587) is within the optimal 1-3 range. Ligand B (-0.03) is slightly below 1, which *could* indicate permeability issues, although it's not drastically low.

**4. H-Bond Donors:** Both ligands have 2 HBD, which is acceptable (<=5).

**5. H-Bond Acceptors:** Ligand A has 5 HBA, and Ligand B has 6 HBA, both within the acceptable limit of <=10.

**6. QED:** Both ligands have very similar QED values (0.768 and 0.773), indicating good drug-like properties.

**7. DILI:** Ligand A (69.523) has a higher DILI risk than Ligand B (41.76). This is a significant negative for Ligand A.

**8. BBB:** Ligand A (70.609) has a better BBB penetration percentile than Ligand B (55.603). This is crucial for a CNS target like DRD2.

**9. Caco-2 Permeability:** Both ligands have the same Caco-2 permeability (-4.8), which is not ideal, but not a major discriminator.

**10. Aqueous Solubility:** Ligand A (-2.808) has slightly worse solubility than Ligand B (-1.496), but both are poor.

**11. hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.155 and 0.102).

**12. Microsomal Clearance:** Ligand A (8.165) has lower microsomal clearance than Ligand B (10.649), suggesting better metabolic stability.

**13. In vitro Half-Life:** Ligand A (-44.222) has a much longer in vitro half-life than Ligand B (-12.186). This is a significant advantage.

**14. P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.008 and 0.012).

**15. Binding Affinity:** Ligand A (-8.1 kcal/mol) has a significantly stronger binding affinity than Ligand B (-7.6 kcal/mol). This 0.5 kcal/mol difference is substantial and can outweigh some ADME drawbacks.

**Overall Assessment:**

Ligand A is superior despite the higher DILI risk. The stronger binding affinity (-8.1 vs -7.6 kcal/mol) is a major advantage for a GPCR target. It also has better BBB penetration and a significantly longer half-life. While the DILI risk is a concern, it might be mitigated through structural modifications during lead optimization. Ligand B's lower logP and BBB penetration are less desirable for a CNS target.

Output:
1
2025-04-17 04:33:28,522 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (343.427 and 361.467 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (77.59) is better than Ligand B (67.6). Both are below the 90 A^2 threshold for CNS targets, which is excellent.

**3. logP:** Both ligands have good logP values (2.683 and 2.478), falling within the optimal 1-3 range.

**4. H-Bond Donors:** Ligand A (3) is slightly higher than Ligand B (1), but both are within the acceptable limit of <=5.

**5. H-Bond Acceptors:** Ligand A (5) and Ligand B (6) are both within the acceptable limit of <=10.

**6. QED:** Both ligands have good QED values (0.728 and 0.817), indicating good drug-like properties.

**7. DILI:** Both ligands have similar DILI risk (52.772 and 52.423), and are both below the 60 threshold, indicating low risk.

**8. BBB:** Ligand A (66.188) has a better BBB percentile than Ligand B (49.942). This is a critical factor for a CNS target like DRD2. While >70 is desirable, Ligand A is significantly better.

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.957 and -5.096), which is unusual and likely indicates poor permeability. This is a significant drawback for both.

**10. Aqueous Solubility:** Both ligands have negative solubility values (-3.758 and -4.151), which is also unusual and indicates poor solubility.

**11. hERG Inhibition:** Both ligands have low hERG inhibition risk (0.81 and 0.42).

**12. Microsomal Clearance:** Ligand A (50.112) has lower microsomal clearance than Ligand B (61.544), indicating better metabolic stability.

**13. In vitro Half-Life:** Ligand B (9.163) has a significantly longer half-life than Ligand A (0.312). This is a major advantage for Ligand B.

**14. P-gp Efflux:** Ligand A (0.244) has lower P-gp efflux than Ligand B (0.192), which is favorable for CNS penetration.

**15. Binding Affinity:** Ligand A (-8.5 kcal/mol) has a slightly better binding affinity than Ligand B (-8.1 kcal/mol). This difference, while not huge, is meaningful.

**Overall Assessment:**

Despite both ligands having issues with Caco-2 permeability and aqueous solubility, Ligand A is slightly favored. Its better BBB penetration, lower P-gp efflux, and slightly improved binding affinity outweigh the longer half-life of Ligand B. The BBB is a critical factor for CNS targets, and Ligand A performs better in this regard. The affinity difference is also a plus.

Output:
0
2025-04-17 04:33:28,523 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (344.46 and 345.40 Da) fall comfortably within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (75.19) is slightly higher than Ligand B (71.97). Both are below the 90 A^2 threshold for CNS targets, which is good.

**3. logP:** Ligand A (2.329) is within the optimal 1-3 range. Ligand B (0.942) is slightly below, which *could* indicate permeability issues, but isn't a severe concern.

**4. H-Bond Donors:** Ligand A has 1 HBD, and Ligand B has 0. Both are within the acceptable limit of <=5.

**5. H-Bond Acceptors:** Ligand A has 4 HBA, and Ligand B has 5. Both are within the acceptable limit of <=10.

**6. QED:** Both ligands have similar QED values (0.824 and 0.815), indicating good drug-like properties.

**7. DILI:** Ligand A (31.563) has a significantly lower DILI risk than Ligand B (65.064). This is a major advantage for Ligand A.

**8. BBB:** Both ligands have excellent BBB penetration (74.292 and 73.129), exceeding the desirable >70 threshold for CNS targets.

**9. Caco-2 Permeability:** Ligand A (-5.029) has worse Caco-2 permeability compared to Ligand B (-4.32).

**10. Aqueous Solubility:** Ligand A (-2.139) has worse aqueous solubility compared to Ligand B (-1.997).

**11. hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.146 and 0.268).

**12. Microsomal Clearance:** Ligand A (31.69) has lower microsomal clearance than Ligand B (54.536), suggesting better metabolic stability.

**13. In vitro Half-Life:** Ligand A (-9.413) has a significantly longer in vitro half-life than Ligand B (-32.588). This is a substantial advantage.

**14. P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.019 and 0.068).

**15. Binding Affinity:** Ligand A (-8.5 kcal/mol) has a slightly better binding affinity than Ligand B (-7.4 kcal/mol). This 1.1 kcal/mol difference is significant and can outweigh minor ADME drawbacks.

**Overall Assessment:**

Ligand A is the stronger candidate. While Ligand B has slightly better Caco-2 permeability and solubility, Ligand A excels in crucial areas: significantly lower DILI risk, better metabolic stability (lower Cl_mic, longer t1/2), and superior binding affinity. The excellent BBB penetration is comparable for both. Given the GPCR target and the importance of CNS penetration, the combination of strong affinity, low toxicity (DILI), and good metabolic stability makes Ligand A the more promising drug candidate.

Output:
1
2025-04-17 04:33:28,523 - INFO - Reasoning:

Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (340.43 and 346.43 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (78.09) is slightly higher than Ligand B (75.63). Both are below the 90 A^2 threshold desirable for CNS targets, which is good.

**3. logP:** Both ligands have good logP values (1.259 and 1.441), falling within the optimal 1-3 range.

**4. H-Bond Donors:** Ligand A has 2 HBD, and Ligand B has 0. Both are within the acceptable limit of <=5.

**5. H-Bond Acceptors:** Ligand A has 3 HBA, and Ligand B has 5. Both are within the acceptable limit of <=10.

**6. QED:** Ligand A (0.81) has a significantly better QED score than Ligand B (0.575), indicating better overall drug-likeness.

**7. DILI:** Ligand A (30.83) has a lower DILI risk than Ligand B (38.74), suggesting a safer profile. Both are below the 40 threshold.

**8. BBB:** This is a crucial parameter for CNS targets like DRD2. Ligand B (83.29%) has a substantially higher BBB penetration percentile than Ligand A (61.50%). This is a major advantage for Ligand B.

**9. Caco-2 Permeability:** Ligand A (-5.197) has a more negative Caco-2 permeability value than Ligand B (-4.605). Lower values indicate lower permeability, which is a negative.

**10. Aqueous Solubility:** Ligand A (-2.09) has slightly better solubility than Ligand B (-1.237).

**11. hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.228 and 0.184).

**12. Microsomal Clearance:** Ligand B (32.789) has higher microsomal clearance than Ligand A (17.872), meaning it's metabolized faster. Lower clearance is preferred.

**13. In Vitro Half-Life:** Ligand A (-31.794) has a much longer in vitro half-life than Ligand B (-5.371). This is a significant advantage for Ligand A.

**14. P-gp Efflux:** Both ligands have low P-gp efflux liability (0.08 and 0.089).

**15. Binding Affinity:** Ligand A (-8.9 kcal/mol) has a significantly stronger binding affinity than Ligand B (-7.7 kcal/mol). This is a substantial advantage, potentially outweighing some ADME drawbacks.

**Overall Assessment:**

While Ligand B excels in BBB penetration, Ligand A demonstrates superior drug-likeness (QED), lower DILI risk, better metabolic stability (lower Cl_mic, longer t1/2), and significantly stronger binding affinity. The difference in binding affinity (-8.9 vs -7.7 kcal/mol) is substantial. Given the GPCR-specific prioritization, the strong affinity of Ligand A is a critical factor. The slightly lower BBB score of Ligand A is a concern, but the strong binding and improved ADME properties are likely to be more impactful for overall drug development success.

Output:
1
2025-04-17 04:33:28,523 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (370.861 and 377.417 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (46.34) is excellent, well below the 90 A^2 threshold for CNS targets. Ligand B (107.4) is higher, but still potentially acceptable, though less ideal.

**logP:** Ligand A (4.478) is a bit high, potentially leading to solubility issues and off-target effects. Ligand B (1.929) is within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A (0 HBD, 4 HBA) is favorable. Ligand B (1 HBD, 5 HBA) is also acceptable.

**QED:** Ligand A (0.667) has a good drug-likeness score. Ligand B (0.206) is significantly lower, indicating a less drug-like profile.

**DILI:** Ligand A (88.057) has a higher DILI risk, while Ligand B (47.77) is much lower and preferable.

**BBB:** Both ligands have good BBB penetration (Ligand A: 73.672, Ligand B: 71.733), exceeding the >70% threshold for CNS targets.

**Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and suggests a potential issue with the data or modeling. However, we'll proceed assuming these represent low permeability.

**Aqueous Solubility:** Both have negative solubility values, again suggesting a potential issue with the data.

**hERG Inhibition:** Ligand A (0.613) has a slightly higher hERG risk than Ligand B (0.384), but both are relatively low.

**Microsomal Clearance:** Ligand A (89.001) has higher clearance, suggesting lower metabolic stability. Ligand B (18.173) has much lower clearance, indicating better metabolic stability.

**In vitro Half-Life:** Ligand A (9.255) has a moderate half-life. Ligand B (-13.132) has a negative half-life, which is not physically possible and indicates a data issue.

**P-gp Efflux:** Ligand A (0.673) has moderate P-gp efflux. Ligand B (0.051) has very low P-gp efflux, which is highly desirable for CNS penetration.

**Binding Affinity:** Ligand A (-10.6 kcal/mol) has significantly stronger binding affinity than Ligand B (-6.5 kcal/mol). This is a substantial advantage.

**Overall Assessment:**

Despite Ligand A's superior binding affinity, several factors favor Ligand B. Ligand B has a better logP, significantly lower DILI risk, much better metabolic stability (lower Cl_mic), and lower P-gp efflux. The negative values for Caco-2 and solubility are concerning for both, but the other advantages of Ligand B are more compelling, especially considering the GPCR-specific focus on BBB penetration and minimizing efflux. The large difference in affinity *could* overcome the other issues with Ligand A, but the DILI risk and metabolic instability are significant concerns. The questionable solubility and permeability data also raise red flags.

Output:
1
2025-04-17 04:33:28,523 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (344.415 and 345.411 Da) fall within the ideal range of 200-500 Da.

**TPSA:** Ligand A (84.42) is excellent, well below the 90 A^2 threshold for CNS targets. Ligand B (126.88) is higher, but still potentially acceptable, though less ideal.

**logP:** Ligand A (1.239) is within the optimal range of 1-3. Ligand B (-0.373) is slightly below 1, which could hinder permeation, though not drastically.

**H-Bond Donors/Acceptors:** Ligand A (1 HBD, 5 HBA) is favorable. Ligand B (3 HBD, 10 HBA) is at the upper limit for HBA, and a bit high for HBD, potentially impacting permeability.

**QED:** Ligand A (0.834) has a very strong drug-like profile. Ligand B (0.615) is still acceptable, but less optimal.

**DILI:** Both ligands have similar, moderate DILI risk (65.103 and 62.66 percentile).

**BBB:** Ligand A (63.086) has a moderate BBB penetration. Ligand B (51.842) is significantly lower, which is a major concern for a CNS target like DRD2.

**Caco-2 Permeability:** Ligand A (-4.795) is poor. Ligand B (-5.682) is also poor.

**Aqueous Solubility:** Both ligands have poor aqueous solubility (-1.683 and -2.338).

**hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.134 and 0.577).

**Microsomal Clearance:** Ligand A (22.08) has moderate clearance. Ligand B (5.686) has very low clearance, suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (0.917) has a very short half-life. Ligand B (-6.088) has a long half-life, which is a significant advantage.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.016 and 0.004).

**Binding Affinity:** Ligand B (-8.2 kcal/mol) has a significantly stronger binding affinity than Ligand A (-7.8 kcal/mol). This 0.4 kcal/mol difference is substantial, and can outweigh some ADME concerns.

**Overall Assessment:**

Ligand B is the more promising candidate despite its slightly higher TPSA and lower logP. The significantly improved binding affinity (-8.2 vs -7.8 kcal/mol) and substantially better metabolic stability (lower Cl_mic, longer t1/2) are crucial advantages. The biggest drawback for Ligand B is its lower BBB penetration, but the strong binding affinity might compensate for that, potentially allowing for a lower dose to achieve therapeutic effect. Ligand A's poor Caco-2 permeability and very short half-life are significant liabilities.

Output:
1
2025-04-17 04:33:28,523 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (341.411 and 354.466 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (93.45) is slightly higher than Ligand B (78.43). Both are below the 90 A^2 threshold desirable for CNS targets, but B is better.

**logP:** Both ligands have good logP values (1.77 and 2.077), falling within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Both have 3 HBDs and 3 HBAs, which is acceptable.

**QED:** Both ligands have similar QED values (0.683 and 0.655), indicating good drug-likeness.

**DILI:** Ligand B (22.761) has a significantly lower DILI risk than Ligand A (42.458), which is a substantial advantage.

**BBB:** Both ligands have excellent BBB penetration (77.2% and 77.821%), exceeding the 70% threshold for CNS targets.

**Caco-2 Permeability:** Both have negative Caco-2 values which is unusual and suggests poor permeability. However, the values are similar (-5.094 and -4.789).

**Aqueous Solubility:** Both have negative solubility values which is also unusual and suggests poor solubility. The values are similar (-2.965 and -2.699).

**hERG Inhibition:** Both ligands have low hERG inhibition liability (0.339 and 0.521).

**Microsomal Clearance:** Both have similar microsomal clearance (25.217 and 24.959 mL/min/kg).

**In vitro Half-Life:** Ligand B (26.055 hours) has a slightly longer half-life than Ligand A (24.111 hours).

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.036 and 0.078), which is excellent for CNS penetration.

**Binding Affinity:** Ligand A (-8.3 kcal/mol) has a slightly better binding affinity than Ligand B (-8.0 kcal/mol), but the difference is small.

**Overall Assessment:**

While Ligand A has a marginally better binding affinity, Ligand B demonstrates a significantly lower DILI risk. Given the importance of safety profiles in drug development, and the fact that both ligands meet the key criteria for CNS penetration (BBB, logP, Pgp, TPSA), the lower DILI risk of Ligand B makes it the more promising candidate. The small difference in binding affinity is unlikely to outweigh the safety advantage.

Output:
1
2025-04-17 04:33:28,524 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (425.348 Da) is slightly higher, but acceptable. Ligand B (346.431 Da) is also good.

**TPSA:** Ligand A (66.48) is better than Ligand B (76.46). For CNS targets, we want TPSA <= 90, both are within this range, but A is closer to the optimal value.

**logP:** Ligand A (3.233) is optimal (1-3). Ligand B (1.528) is on the lower end, which *could* hinder permeability.

**H-Bond Donors/Acceptors:** Both ligands have 1 HBD, which is good. Ligand A has 3 HBA, and Ligand B has 5 HBA, both are acceptable (<=10).

**QED:** Both ligands have similar QED values (0.773 and 0.793), indicating good drug-like properties.

**DILI:** Ligand A (72.47) has a higher DILI risk than Ligand B (40.054). This is a significant drawback for Ligand A.

**BBB:** Ligand A (50.989) and Ligand B (58.976) are both below the desirable threshold of >70 for CNS targets. However, Ligand B is closer.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values, which is unusual and suggests poor permeability. Ligand A (-4.949) is slightly worse than Ligand B (-4.51).

**Aqueous Solubility:** Both ligands have negative solubility values, indicating poor solubility. Ligand A (-4.714) is slightly worse than Ligand B (-2.693).

**hERG Inhibition:** Ligand A (0.757) has a slightly higher hERG risk than Ligand B (0.115).

**Microsomal Clearance:** Ligand B (61.676) has a lower microsomal clearance than Ligand A (72.89), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand B (-22.942) has a significantly longer in vitro half-life than Ligand A (-1.724).

**P-gp Efflux:** Ligand A (0.312) has lower P-gp efflux than Ligand B (0.053), which is favorable for CNS penetration.

**Binding Affinity:** Ligand A (-9.3 kcal/mol) has a significantly stronger binding affinity than Ligand B (-7.6 kcal/mol). This is a substantial advantage.

**Overall Assessment:**

Ligand A has a much stronger binding affinity, but suffers from higher DILI risk, poorer solubility, and a shorter half-life. Ligand B has better ADME properties (lower DILI, better metabolic stability, longer half-life, lower P-gp efflux), but its binding affinity is weaker and logP is lower.

Given the GPCR-specific priorities, and the substantial affinity difference, I would lean towards **Ligand A** despite its ADME liabilities. The strong binding affinity (-9.3 kcal/mol) could potentially outweigh the ADME concerns, especially if further optimization can address the DILI risk and solubility. The P-gp efflux is also favorable. While BBB penetration isn't ideal for either, the stronger binding of A increases the chance of efficacy even with less efficient brain penetration.

Output:
1
2025-04-17 04:33:28,524 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (366.491 and 350.415 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (76.26) is better than Ligand B (79.31), both are below the 90 A^2 threshold desirable for CNS targets.

**logP:** Ligand A (0.548) is slightly lower than optimal (1-3), but still acceptable. Ligand B (-0.374) is quite low, potentially hindering membrane permeability.

**H-Bond Donors/Acceptors:** Ligand A (0 HBD, 7 HBA) is preferable to Ligand B (1 HBD, 5 HBA) as it has fewer potential issues with permeability. Both are within acceptable ranges.

**QED:** Both ligands have similar QED values (0.772 and 0.661), indicating good drug-likeness.

**DILI:** Ligand A (43.389) has a significantly lower DILI risk than Ligand B (15.51). This is a major advantage for Ligand A.

**BBB:** Ligand A (71.035) has a better BBB penetration percentile than Ligand B (46.724). This is crucial for a CNS target like DRD2.

**Caco-2 Permeability:** Ligand A (-4.944) has a worse Caco-2 permeability than Ligand B (-4.73). However, this is less critical than BBB for CNS targets.

**Aqueous Solubility:** Ligand A (-2.165) has a slightly worse aqueous solubility than Ligand B (-1.063).

**hERG Inhibition:** Ligand A (0.721) has a slightly higher hERG inhibition liability than Ligand B (0.125).

**Microsomal Clearance:** Ligand A (39.795) has a higher microsomal clearance than Ligand B (-6.165), meaning Ligand B is more metabolically stable.

**In vitro Half-Life:** Ligand A (-40.324) has a significantly shorter in vitro half-life than Ligand B (18.433). This is a disadvantage for Ligand A.

**P-gp Efflux:** Ligand A (0.196) has a lower P-gp efflux liability than Ligand B (0.031). This is a positive for Ligand A, improving CNS exposure.

**Binding Affinity:** Ligand B (-7.1 kcal/mol) has a slightly better binding affinity than Ligand A (-7.8 kcal/mol). While the difference is small, it's still a factor.

**Overall Assessment:**

Considering the GPCR-specific priorities, Ligand A is the more promising candidate. Its significantly better BBB penetration, lower DILI risk, and lower P-gp efflux outweigh the slightly lower affinity, solubility, and shorter half-life. The logP of Ligand B is a concern, potentially limiting its ability to cross cell membranes. The improved metabolic stability of Ligand B is a plus, but can be addressed through structural modifications.

Output:
1
2025-04-17 04:33:28,524 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 drug candidates, considering the provided guidelines and GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (357.451 and 356.463 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (102.34) is better than Ligand B (107.89). Both are reasonably good, but closer to the upper limit for CNS penetration. Ligand A is preferable.

**3. logP:** Ligand A (-1.055) is lower than optimal (1-3), potentially hindering permeability. Ligand B (0.334) is also low, but slightly better than A.

**4. H-Bond Donors:** Ligand A (3) is within the acceptable limit (<=5). Ligand B (4) is also acceptable.

**5. H-Bond Acceptors:** Ligand A (6) is within the acceptable limit (<=10). Ligand B (5) is also acceptable.

**6. QED:** Both ligands have similar QED values (0.58 and 0.549), indicating good drug-likeness.

**7. DILI:** Ligand A (15.51) has a slightly higher DILI risk than Ligand B (12.641), but both are below the concerning threshold of 40.

**8. BBB:** Both ligands have very low BBB penetration (27.918 and 27.259). This is a significant drawback for a CNS target like DRD2.

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 permeability values (-5.37 and -5.09), which is unusual and suggests poor intestinal absorption.

**10. Aqueous Solubility:** Both ligands have very low aqueous solubility (0.023 and -0.86). This is a major concern for bioavailability.

**11. hERG Inhibition:** Both ligands show very low hERG inhibition risk (0.038 and 0.063).

**12. Microsomal Clearance:** Ligand A (2.049) has a lower (better) microsomal clearance than Ligand B (-1.854). This suggests better metabolic stability for Ligand A.

**13. In vitro Half-Life:** Ligand A (6.838) has a longer half-life than Ligand B (5.687).

**14. P-gp Efflux:** Ligand A (0.003) has significantly lower P-gp efflux than Ligand B (0.01). This is crucial for CNS penetration.

**15. Binding Affinity:** Ligand B (-8) has a substantially better binding affinity than Ligand A (0). This is a major advantage, potentially outweighing some ADME drawbacks.

**Overall Assessment:**

Despite both ligands having significant ADME liabilities (poor BBB, solubility, and Caco-2 permeability), the vastly superior binding affinity of Ligand B (-8 kcal/mol vs. 0 kcal/mol) is a decisive factor. While the low BBB is a concern, the strong binding could potentially allow for efficacy at lower doses, mitigating the need for high brain exposure. Ligand A has slightly better metabolic stability and P-gp efflux, but the difference in affinity is too large to ignore.

Output:
1
2025-04-17 04:33:28,524 - INFO - Reasoning:

Let's analyze Ligand A and Ligand B based on the provided guidelines, prioritizing GPCR-specific properties (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (348.305 and 346.515 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (91.58) is slightly above the ideal <90 for CNS targets, but still reasonable. Ligand B (49.41) is excellent, well below 90.

**logP:** Both ligands have good logP values (2.804 and 3.832), falling within the optimal 1-3 range. Ligand B is slightly higher, which could be a minor concern for solubility, but is not a major drawback.

**H-Bond Donors/Acceptors:** Ligand A has 2 HBD and 5 HBA, which is acceptable. Ligand B has 1 HBD and 2 HBA, also acceptable.

**QED:** Ligand A (0.838) has a better QED score than Ligand B (0.621), indicating a more drug-like profile.

**DILI:** Ligand A (64.211) has a higher DILI risk than Ligand B (25.436). This is a significant negative for Ligand A.

**BBB:** Ligand B (77.472) has a much better BBB penetration percentile than Ligand A (57.619). This is a critical advantage for a CNS target like DRD2.

**Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and suggests a potential issue with the data or modeling. However, we'll proceed assuming these represent low permeability.

**Aqueous Solubility:** Both ligands have negative solubility values, again suggesting a potential issue with the data.

**hERG:** Both ligands have low hERG inhibition liability (0.768 and 0.472), which is good.

**Microsomal Clearance:** Ligand A (46.259) has lower microsomal clearance than Ligand B (54.541), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand B (-19.911) has a significantly longer in vitro half-life than Ligand A (-1.416). This is a major advantage.

**P-gp Efflux:** Ligand A (0.344) has lower P-gp efflux than Ligand B (0.198), which is desirable for CNS penetration.

**Binding Affinity:** Ligand B (-9.2 kcal/mol) has a slightly better binding affinity than Ligand A (-8.3 kcal/mol). While the difference is not huge, it's enough to be considered.

**Overall Assessment:**

Ligand B is the stronger candidate. It has a significantly better BBB score, a lower DILI risk, and a longer half-life. While Ligand A has a slightly better QED and lower P-gp efflux, the advantages of Ligand B in BBB, DILI, and half-life outweigh these factors, especially for a CNS target. The slightly better affinity of Ligand B further supports this conclusion. The negative solubility and Caco-2 values are concerning for both, but the other ADME properties of Ligand B are more favorable.



Output:
1
2025-04-17 04:33:28,524 - INFO - Reasoning:

Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (353.348 and 343.427 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (77.04) is significantly better than Ligand B (84.23). For CNS targets, we want TPSA <= 90, and A is closer to the ideal <60 range.

**3. logP:** Both ligands have good logP values (2.009 and 2.354), falling within the optimal 1-3 range.

**4. H-Bond Donors:** Ligand A (1) is preferable to Ligand B (2). Lower HBD generally improves permeability.

**5. H-Bond Acceptors:** Ligand A (5) is preferable to Ligand B (4). Lower HBA generally improves permeability.

**6. QED:** Ligand A (0.916) has a substantially better QED score than Ligand B (0.777), indicating a more drug-like profile.

**7. DILI:** Ligand A (56.572) has a slightly higher DILI risk than Ligand B (43.234), but both are acceptable (<60).

**8. BBB:** Ligand A (87.088) has a significantly better BBB penetration percentile than Ligand B (75.223). This is *critical* for a CNS target like DRD2.

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.888 and -4.881). These values are unusual and likely represent a scaling issue or error in the data. We cannot reliably compare based on this metric.

**10. Aqueous Solubility:** Both ligands have negative solubility values (-2.695 and -3.525). Similar to Caco-2, these are problematic and make comparison unreliable.

**11. hERG Inhibition:** Ligand A (0.638) has a lower hERG inhibition liability than Ligand B (0.254), which is favorable.

**12. Microsomal Clearance:** Ligand A (-33.474) has a *much* lower (better) microsomal clearance than Ligand B (47.883). This suggests better metabolic stability for Ligand A.

**13. In vitro Half-Life:** Ligand A (2.713) has a lower in vitro half-life than Ligand B (7.839). This is a slight drawback for Ligand A.

**14. P-gp Efflux:** Ligand A (0.093) has a significantly lower P-gp efflux liability than Ligand B (0.33). Lower P-gp efflux is highly desirable for CNS penetration.

**15. Binding Affinity:** Ligand B (-8.6) has a slightly better binding affinity than Ligand A (-9.0). While affinity is important, the difference of 0.4 kcal/mol is not substantial enough to outweigh the significant advantages of Ligand A in other critical ADME properties.

**Overall Assessment:**

Ligand A is the superior candidate. It excels in key properties for a CNS-targeting GPCR ligand: TPSA, BBB, P-gp efflux, microsomal clearance, QED, and hERG. While Ligand B has slightly better binding affinity and in vitro half-life, the differences are not large enough to overcome Ligand A's superior ADME profile, particularly its much better BBB penetration and metabolic stability. The problematic solubility and Caco-2 values for both compounds are a concern, but the overall profile of A is more promising.

Output:
1
2025-04-17 04:33:28,525 - INFO - Reasoning:

Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (367.318 and 367.421 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (84.22) is better than Ligand B (55.3). Both are below the 90 A^2 threshold desirable for CNS targets, but A is closer to the ideal.

**3. logP:** Ligand A (3.665) is within the optimal range (1-3), while Ligand B (4.391) is slightly higher. While still acceptable, the higher logP of B could potentially lead to off-target interactions or solubility issues.

**4. H-Bond Donors:** Ligand A (3) is acceptable, while Ligand B (0) is also good.

**5. H-Bond Acceptors:** Ligand A (2) is good, while Ligand B (6) is acceptable, but higher.

**6. QED:** Both ligands have similar QED values (0.671 and 0.588), both above the 0.5 threshold, indicating good drug-like properties.

**7. DILI:** Ligand A (56.65) has a lower DILI risk than Ligand B (67.39), which is preferable. Both are below the 60 threshold, but A is better.

**8. BBB:** Ligand B (96.006) significantly outperforms Ligand A (83.443) in terms of predicted BBB penetration. This is *critical* for a CNS target like DRD2.

**9. Caco-2 Permeability:** Both have negative values, indicating poor permeability. Ligand A (-5.068) is slightly better than Ligand B (-4.996).

**10. Aqueous Solubility:** Both have negative values, indicating poor solubility. Ligand A (-4.651) is slightly better than Ligand B (-4.444).

**11. hERG Inhibition:** Ligand A (0.712) has a lower hERG risk than Ligand B (0.932), which is preferable.

**12. Microsomal Clearance:** Ligand A (28.226) has significantly lower microsomal clearance than Ligand B (108.644), suggesting better metabolic stability.

**13. In vitro Half-Life:** Ligand B (47.726) has a longer in vitro half-life than Ligand A (30.768), which is desirable.

**14. P-gp Efflux:** Ligand A (0.087) has lower P-gp efflux liability than Ligand B (0.711), which is beneficial for CNS exposure.

**15. Binding Affinity:** Ligand B (-7.6 kcal/mol) has a significantly stronger binding affinity than Ligand A (-8.1 kcal/mol). This is a substantial advantage, potentially outweighing some of the ADME drawbacks.

**Overall Assessment:**

While Ligand A has better ADME properties (lower DILI, better metabolic stability, lower P-gp efflux, slightly better solubility and permeability, lower hERG), Ligand B's *significantly* higher BBB penetration and substantially stronger binding affinity are decisive. For a CNS GPCR target, BBB penetration is paramount, and the 1.5 kcal/mol affinity difference is substantial. The slightly worse ADME profile of B can be addressed with further optimization, but a poor BBB profile is much harder to fix.

Output:
1
2025-04-17 04:33:28,525 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (356.419 and 358.498 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (96.38) is slightly above the optimal <90 for CNS targets, but still reasonable. Ligand B (58.64) is excellent, well below 90. This favors Ligand B.

**3. logP:** Ligand A (-0.069) is a bit low, potentially hindering permeability. Ligand B (2.931) is within the optimal 1-3 range. This strongly favors Ligand B.

**4. H-Bond Donors:** Both ligands have 1 HBD, which is acceptable.

**5. H-Bond Acceptors:** Ligand A has 6 HBA, acceptable. Ligand B has 3 HBA, also acceptable.

**6. QED:** Both ligands have similar QED values (0.693 and 0.653), indicating good drug-likeness.

**7. DILI:** Ligand A (20.822) has a much lower DILI risk than Ligand B (36.758). This favors Ligand A.

**8. BBB:** Ligand B (89.066) has a significantly better BBB penetration percentile than Ligand A (66.809). This is a crucial advantage for a CNS target like DRD2 and strongly favors Ligand B.

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.626 and -4.455), which is unusual and suggests poor permeability. However, these values are on a scale where negative values are possible, and direct comparison is difficult without knowing the scale's specifics.

**10. Aqueous Solubility:** Both ligands have negative solubility values (-0.51 and -2.255). Again, interpreting these requires knowing the scale, but Ligand B appears to have poorer solubility.

**11. hERG Inhibition:** Ligand A (0.065) has a slightly lower hERG risk than Ligand B (0.602), which is preferable. This favors Ligand A.

**12. Microsomal Clearance:** Ligand B (45.516) has a higher microsomal clearance than Ligand A (24.004), indicating lower metabolic stability. This favors Ligand A.

**13. In vitro Half-Life:** Ligand B (39.039) has a significantly longer in vitro half-life than Ligand A (-10.427). This is a substantial advantage for Ligand B.

**14. P-gp Efflux:** Ligand A (0.019) has much lower P-gp efflux liability than Ligand B (0.21). This is a significant advantage for CNS exposure and favors Ligand A.

**15. Binding Affinity:** Ligand B (-7.2) has slightly better binding affinity than Ligand A (-7.1), but the difference is small (0.1 kcal/mol).

**Overall Assessment:**

While Ligand A has advantages in DILI, hERG, P-gp efflux, and microsomal clearance, Ligand B shines in crucial GPCR-specific properties: **BBB penetration, logP, and in vitro half-life**. The better BBB penetration and logP are particularly important for CNS targets. The slightly better affinity of Ligand B also contributes. The negative Caco-2 and solubility values are concerning for both, but the other advantages of Ligand B outweigh these concerns.

Output:
1
2025-04-17 04:33:28,525 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (361.47 and 374.85 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (72.48) is significantly better than Ligand B (77.0). Both are below the 90 A^2 threshold for CNS targets, but A is closer to the ideal.

**logP:** Both ligands have good logP values (3.818 and 3.753), falling within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A (2 HBD, 5 HBA) is slightly better than Ligand B (1 HBD, 6 HBA) in terms of balancing solubility and permeability. Both are within acceptable limits.

**QED:** Both ligands have reasonable QED scores (0.786 and 0.688), indicating good drug-like properties.

**DILI:** Ligand A (76.97) has a lower DILI risk than Ligand B (89.80), which is a significant advantage.

**BBB:** This is a critical parameter for a CNS target like DRD2. Ligand A (79.68) has a much higher BBB percentile than Ligand B (32.57). This is a major point in favor of Ligand A.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values, which is unusual and suggests poor permeability. However, the magnitude is similar (-4.539 vs -4.969).

**Aqueous Solubility:** Both ligands have negative solubility values, which is also unusual and suggests poor solubility. Again, the magnitude is similar (-4.506 vs -4.023).

**hERG Inhibition:** Both ligands have low hERG inhibition liability (0.523 and 0.32), which is good.

**Microsomal Clearance:** Ligand A (76.38) has a higher microsomal clearance than Ligand B (41.91), indicating lower metabolic stability. This is a drawback for Ligand A.

**In vitro Half-Life:** Ligand B (-0.741) has a slightly longer in vitro half-life than Ligand A (20.468), which is a minor advantage.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.439 and 0.258), which is desirable for CNS penetration.

**Binding Affinity:** Ligand B (-8.8 kcal/mol) has a slightly better binding affinity than Ligand A (-8.0 kcal/mol), but the difference is not huge (0.8 kcal/mol).

**Overall Assessment:**

Ligand A is significantly better due to its superior BBB penetration (79.68 vs 32.57) and lower DILI risk (76.97 vs 89.80). While Ligand A has higher microsomal clearance and a slightly weaker binding affinity, the BBB and DILI advantages are more crucial for a CNS-targeting GPCR like DRD2. The slight difference in binding affinity is unlikely to outweigh the substantial improvement in predicted CNS exposure and safety.

Output:
1
2025-04-17 04:33:28,525 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (351.407 and 346.435 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (122.31) is slightly above the optimal <90 for CNS targets, but still reasonable. Ligand B (107.72) is better, falling comfortably below 90.

**logP:** Both ligands have acceptable logP values (1.308 and 2.175), within the 1-3 range.

**H-Bond Donors/Acceptors:** Both have 3/6 HBD/HBA, which is acceptable, balancing solubility and permeability.

**QED:** Ligand A (0.706) has a better QED score than Ligand B (0.518), indicating a more drug-like profile.

**DILI:** Ligand A (72.47) has a higher DILI risk than Ligand B (37.456), which is a significant negative.

**BBB:** Both ligands have reasonable BBB penetration (55.215 and 56.34), but neither is exceptionally high (>70).

**Caco-2:** Ligand A (-4.597) and Ligand B (-5.269) both have negative Caco-2 values, which is unusual and suggests poor permeability. This is a concern for both.

**Aqueous Solubility:** Both ligands have poor aqueous solubility (-2.982 and -3.123).

**hERG:** Ligand A (0.052) has a slightly better hERG profile than Ligand B (0.649), indicating lower cardiotoxicity risk.

**Microsomal Clearance:** Ligand B (25.53) has lower microsomal clearance than Ligand A (37.987), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand B (-3.435) has a longer in vitro half-life than Ligand A (-0.61), which is favorable.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.005 and 0.101), which is excellent for CNS penetration.

**Binding Affinity:** Ligand B (-8.8 kcal/mol) has a stronger binding affinity than Ligand A (-8.2 kcal/mol). This 0.6 kcal/mol difference is substantial and could outweigh some of the ADME drawbacks.

**Overall Assessment:**

Ligand B is the better candidate. While both have poor solubility and Caco-2 permeability, Ligand B has a significantly stronger binding affinity, better metabolic stability (lower Cl_mic), longer half-life, and a much lower DILI risk. The slightly better TPSA and the stronger binding affinity of Ligand B are crucial for a GPCR target like DRD2. Although the BBB values aren't ideal for either, the lower P-gp efflux for both helps mitigate this. The DILI risk associated with Ligand A is a major concern.

Output:
1
2025-04-17 04:33:28,526 - INFO - Batch 123 complete. Total preferences: 1968
2025-04-17 04:33:28,526 - INFO - Processing batch 124/512...
2025-04-17 04:34:07,628 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (374.849 and 384.531 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (51.54) is significantly better than Ligand B (96.17). For CNS targets, we want TPSA <= 90, so Ligand A is much more favorable.

**logP:** Ligand A (3.531) is optimal (1-3), while Ligand B (1.391) is on the lower end. Lower logP can hinder permeation, making Ligand A preferable.

**H-Bond Donors/Acceptors:** Ligand A (0 HBD, 5 HBA) is better than Ligand B (2 HBD, 9 HBA). Both are within acceptable limits, but fewer H-bonds generally improve permeability.

**QED:** Both ligands have good QED scores (0.689 and 0.752), indicating good drug-like properties.

**DILI:** Ligand A (84.102) has a higher DILI risk than Ligand B (69.135), but both are reasonably acceptable.

**BBB:** Both ligands have excellent BBB penetration (73.866 and 71.888), exceeding the desirable >70 threshold for CNS targets.

**Caco-2 Permeability:** Ligand A (-4.398) has poor Caco-2 permeability, while Ligand B (-5.761) is also poor. This is a concern for both, but Ligand A is slightly better.

**Aqueous Solubility:** Ligand A (-5.085) has poor solubility, while Ligand B (-2.7) is also poor. This is a concern for both, but Ligand B is slightly better.

**hERG Inhibition:** Ligand A (0.435) has a lower hERG risk than Ligand B (0.056), which is preferable.

**Microsomal Clearance:** Ligand A (67.927) has higher microsomal clearance than Ligand B (23.011), indicating lower metabolic stability. Ligand B is significantly better here.

**In vitro Half-Life:** Ligand A (28.887) has a shorter half-life than Ligand B (6.626), indicating lower stability. Ligand B is significantly better here.

**P-gp Efflux:** Ligand A (0.755) has higher P-gp efflux than Ligand B (0.091), which is less desirable for CNS exposure. Ligand B is significantly better here.

**Binding Affinity:** Ligand B (-7.2 kcal/mol) has a significantly stronger binding affinity than Ligand A (-8.5 kcal/mol). This is a substantial advantage, and can often outweigh minor ADME drawbacks.

**Overall Assessment:**

While Ligand A has a better TPSA and logP, Ligand B excels in several critical areas for a CNS-targeting GPCR ligand: significantly better binding affinity, lower P-gp efflux, better metabolic stability (lower Cl_mic and longer t1/2), and lower hERG risk. The slightly higher DILI risk for Ligand A is less concerning than the ADME liabilities of Ligand A. The affinity difference is substantial.

Output:
1
2025-04-17 04:34:07,629 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (355.463 and 363.527 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (63.13) is significantly better than Ligand B (71.09). For CNS targets, we want TPSA <= 90, both are within this range, but A is closer to the ideal.

**3. logP:** Both ligands have good logP values (3.465 and 3.374), falling within the optimal 1-3 range.

**4. H-Bond Donors:** Both have 2 HBD, which is acceptable.

**5. H-Bond Acceptors:** Both have 4 HBA, which is acceptable.

**6. QED:** Both ligands have good QED scores (0.544 and 0.814), indicating good drug-like properties. Ligand B is slightly better here.

**7. DILI:** Ligand A (73.556) has a higher DILI risk than Ligand B (47.732). This is a significant drawback for Ligand A.

**8. BBB:** Both ligands have good BBB penetration (81.97% and 74.952%), exceeding the 70% threshold for CNS targets. Ligand A is slightly better.

**9. Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and suggests poor permeability. However, the scale is not specified, so it's hard to interpret.

**10. Aqueous Solubility:** Both have negative solubility values, also unusual and suggesting poor solubility. Again, the scale is not specified, making interpretation difficult.

**11. hERG Inhibition:** Ligand A (0.761) has a slightly higher hERG risk than Ligand B (0.356), but both are relatively low.

**12. Microsomal Clearance:** Ligand A (78.99) has higher microsomal clearance than Ligand B (73.655), indicating lower metabolic stability.

**13. In vitro Half-Life:** Ligand B (9.873) has a significantly longer in vitro half-life than Ligand A (58.241). This is a major advantage for Ligand B.

**14. P-gp Efflux:** Ligand A (0.735) has higher P-gp efflux than Ligand B (0.155), suggesting lower CNS exposure. This is a significant drawback for Ligand A.

**15. Binding Affinity:** Ligand A (-9.4 kcal/mol) has a slightly better binding affinity than Ligand B (-8.5 kcal/mol). This 1.9 kcal/mol difference is substantial and could potentially outweigh some of the ADME drawbacks.

**Overall Assessment:**

While Ligand A has a better binding affinity and slightly better BBB penetration, Ligand B is significantly better in terms of safety (lower DILI), metabolic stability (lower Cl_mic, longer t1/2), and P-gp efflux (lower efflux). The P-gp efflux difference is particularly important for a CNS target like DRD2. The solubility and Caco-2 values are concerning for both, but the other factors strongly favor Ligand B. The affinity difference, while notable, is likely less critical than the improved ADME profile of Ligand B.

Output:
1
2025-04-17 04:34:07,629 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (344.415 and 347.419 Da) fall comfortably within the ideal 200-500 Da range.

**TPSA:** Ligand A (67.79) is excellent, well below the 90 A^2 threshold for CNS targets. Ligand B (96.45) is higher, but still acceptable, though less optimal.

**logP:** Ligand A (1.096) is right in the sweet spot (1-3). Ligand B (-0.124) is a bit low, potentially hindering membrane permeability.

**H-Bond Donors/Acceptors:** Ligand A (0 HBD, 7 HBA) is favorable. Ligand B (2 HBD, 6 HBA) is also acceptable.

**QED:** Both ligands have good QED scores (0.585 and 0.68), indicating drug-like properties.

**DILI:** Ligand A (41.062) has a slightly higher DILI risk than Ligand B (31.33), but both are below the concerning threshold of 60.

**BBB:** This is crucial for a CNS target. Ligand A excels with 88.29%, while Ligand B is significantly lower at 49.515%.

**Caco-2 Permeability:** Ligand A (-4.493) has poor Caco-2 permeability, which is concerning. Ligand B (-5.691) is also poor, but slightly worse.

**Aqueous Solubility:** Ligand A (-2.61) and Ligand B (-0.538) both have poor solubility.

**hERG Inhibition:** Both ligands show very low hERG inhibition liability (0.413 and 0.037), which is excellent.

**Microsomal Clearance:** Ligand A (61.003) has moderate clearance, while Ligand B (-7.926) has negative clearance, which is excellent and indicates high metabolic stability.

**In vitro Half-Life:** Ligand A (-8.022) has a negative half-life, which is excellent. Ligand B (9.248) has a good half-life.

**P-gp Efflux:** Both ligands show very low P-gp efflux (0.047 and 0.001), which is favorable for CNS penetration.

**Binding Affinity:** Ligand B (-7.8 kcal/mol) has a significantly stronger binding affinity than Ligand A (-0.0 kcal/mol). This is a major advantage, potentially outweighing some ADME drawbacks.

**Overall Assessment:**

Ligand B is the stronger candidate. Despite its slightly higher TPSA and lower logP, its *significantly* improved binding affinity (-7.8 vs -0.0 kcal/mol) and superior metabolic stability (negative Cl_mic) are decisive. The better BBB score also favors Ligand B for a CNS target. While both have poor solubility and Caco-2 permeability, these can potentially be addressed through formulation strategies. The affinity difference is so large that it is likely to drive better *in vivo* efficacy.

Output:
1
2025-04-17 04:34:07,629 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 drug candidates, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (349.431 and 357.376 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (93.46) is slightly above the optimal <90 for CNS targets, but still reasonable. Ligand B (69.12) is well within the desired range. This favors Ligand B.

**3. logP:** Ligand A (1.739) is within the optimal 1-3 range. Ligand B (3.167) is at the higher end, but still acceptable.

**4. H-Bond Donors:** Ligand A (2) and Ligand B (1) are both within the acceptable limit of <=5.

**5. H-Bond Acceptors:** Ligand A (5) and Ligand B (3) are both within the acceptable limit of <=10.

**6. QED:** Both ligands have good QED scores (0.782 and 0.815), indicating good drug-like properties.

**7. DILI:** Both ligands have acceptable DILI risk (51.338 and 43.66), both below the 60 threshold.

**8. BBB:** Both ligands demonstrate good BBB penetration (70.105 and 76.696), exceeding the 70% threshold for CNS targets. Ligand B is slightly better.

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.857 and -4.67), which is unusual and suggests poor permeability. This is a significant concern for both.

**10. Aqueous Solubility:** Both ligands have negative solubility values (-3.149 and -3.982), indicating very poor aqueous solubility. This is a major drawback for both.

**11. hERG Inhibition:** Both ligands have low hERG inhibition risk (0.289 and 0.859).

**12. Microsomal Clearance:** Ligand A (42.167) has higher microsomal clearance than Ligand B (32.724), suggesting lower metabolic stability. This favors Ligand B.

**13. In vitro Half-Life:** Ligand B (-3.435) has a significantly longer in vitro half-life than Ligand A (7.814). This is a substantial advantage for Ligand B.

**14. P-gp Efflux:** Ligand A (0.051) has lower P-gp efflux liability than Ligand B (0.15), which is favorable for CNS penetration.

**15. Binding Affinity:** Ligand A (-8.4 kcal/mol) has a stronger binding affinity than Ligand B (-6.9 kcal/mol). This is a significant advantage for Ligand A (a difference of 1.5 kcal/mol).

**Overall Assessment:**

Despite the poor Caco-2 and solubility values for both compounds, the stronger binding affinity of Ligand A (-8.4 kcal/mol vs -6.9 kcal/mol) is a major advantage that outweighs the slightly better BBB and metabolic stability of Ligand B. The P-gp efflux is also better for Ligand A. While both have issues, the potency difference is substantial.

Output:
0
2025-04-17 04:34:07,629 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (360.443 and 363.531 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (95.08) is higher than Ligand B (63.91). For CNS targets, we prefer TPSA <= 90, so Ligand B is significantly better here.

**3. logP:** Ligand A (1.054) is within the optimal range (1-3), while Ligand B (3.829) is approaching the upper limit. Both are acceptable, but A is slightly preferred.

**4. H-Bond Donors:** Ligand A (1) is better than Ligand B (0). While both are acceptable, fewer HBDs generally improve permeability.

**5. H-Bond Acceptors:** Both ligands have 6 HBA, which is within the acceptable limit of <=10.

**6. QED:** Ligand A (0.879) has a significantly better QED score than Ligand B (0.635), indicating a more drug-like profile.

**7. DILI:** Ligand B (53.276) has a lower DILI risk than Ligand A (74.641), making it safer.

**8. BBB:** Ligand B (83.017) has a much higher BBB penetration percentile than Ligand A (52.074). This is *critical* for a CNS target like DRD2.

**9. Caco-2 Permeability:** Both have negative values, indicating poor permeability. However, the scale is not defined, so it's hard to interpret.

**10. Aqueous Solubility:** Both have negative values, indicating poor solubility. Again, the scale is undefined.

**11. hERG Inhibition:** Ligand A (0.066) has a lower hERG inhibition liability than Ligand B (0.43), which is preferable.

**12. Microsomal Clearance:** Ligand B (81.055) has a much higher microsomal clearance than Ligand A (18.129), meaning it's metabolized more quickly and has lower metabolic stability.

**13. In vitro Half-Life:** Ligand B (33.868) has a longer half-life than Ligand A (0.282), which is generally desirable.

**14. P-gp Efflux:** Ligand A (0.162) has lower P-gp efflux liability than Ligand B (0.833), which is better for CNS exposure.

**15. Binding Affinity:** Ligand A (-8.6 kcal/mol) has a slightly better binding affinity than Ligand B (-6.9 kcal/mol). This is a significant advantage.

**Overall Assessment:**

While Ligand A has better affinity, QED, hERG, and clearance, Ligand B *strongly* excels in BBB penetration (83.017 vs 52.074) and has a lower DILI risk. For a CNS target like DRD2, BBB penetration is paramount. The difference in affinity, while notable, can potentially be overcome with further optimization, but poor BBB penetration is a much more difficult hurdle. The longer half-life of Ligand B is also a plus. The lower TPSA of Ligand B also supports better CNS penetration.

Output:
1
2025-04-17 04:34:07,630 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (365.411 and 366.849 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (104.81) is higher than Ligand B (78.67). For CNS targets, TPSA should be <= 90. Both are acceptable, but Ligand B is better.

**logP:** Ligand A (0.108) is quite low, potentially hindering permeability. Ligand B (0.766) is better, falling within the optimal 1-3 range. This is a significant advantage for Ligand B.

**H-Bond Donors/Acceptors:** Ligand A has 2 HBD and 5 HBA, while Ligand B has 1 HBD and 5 HBA. Both are within acceptable limits (<=5 HBD and <=10 HBA).

**QED:** Both ligands have good QED scores (0.74 and 0.853, respectively), indicating good drug-like properties.

**DILI:** Ligand A (64.831) has a higher DILI risk than Ligand B (39.511). Lower is better, so Ligand B is preferable.

**BBB:** Ligand B (71.19) has a significantly better BBB penetration percentile than Ligand A (57.425). This is crucial for a CNS target like DRD2, making Ligand B more promising.

**Caco-2 Permeability:** Both have negative Caco-2 values (-4.865 and -4.862). These values are unusual and difficult to interpret without further context, but suggest poor permeability.

**Aqueous Solubility:** Both have negative solubility values (-2.429 and -1.812). Similar to Caco-2, these are unusual and suggest poor solubility.

**hERG Inhibition:** Ligand A (0.179) has a slightly lower hERG inhibition risk than Ligand B (0.272), which is favorable.

**Microsomal Clearance:** Ligand A (-0.083) has a lower (better) microsomal clearance than Ligand B (19.758). This suggests better metabolic stability for Ligand A.

**In vitro Half-Life:** Ligand A (0.887) has a shorter in vitro half-life than Ligand B (-2.78). A negative half-life is not possible, so this value is suspect. Assuming it's a percentile, Ligand B is better.

**P-gp Efflux:** Ligand A (0.02) has a lower P-gp efflux liability than Ligand B (0.148), which is better for CNS exposure.

**Binding Affinity:** Both ligands have excellent binding affinities (-8.3 and -8.0 kcal/mol). The difference of 0.3 kcal/mol is not substantial enough to outweigh other factors.

**Overall Assessment:**

Ligand B is the stronger candidate. While Ligand A has slightly better metabolic stability and lower P-gp efflux, Ligand B excels in key areas for a CNS GPCR target: significantly better BBB penetration, a more favorable logP, and lower DILI risk. The negative solubility and Caco-2 values are concerning for both, but the other advantages of Ligand B make it the more promising drug candidate.

Output:
1
2025-04-17 04:34:07,630 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (350.459 and 353.419 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (59.08) is significantly better than Ligand B (93.9). For CNS targets, we want TPSA <= 90, so Ligand A is much more favorable.

**3. logP:** Both ligands have good logP values (1.598 and 1.005), falling within the optimal 1-3 range.

**4. H-Bond Donors:** Both are acceptable (0 and 1, respectively), well below the threshold of 5.

**5. H-Bond Acceptors:** Ligand A (4) is better than Ligand B (6), but both are within the acceptable limit of 10.

**6. QED:** Both ligands have reasonable QED scores (0.707 and 0.666), indicating good drug-like properties.

**7. DILI:** Ligand A (15.936) has a much lower DILI risk than Ligand B (25.165). Both are below the 40 threshold, but A is preferable.

**8. BBB:** Ligand A (93.563) has a significantly higher BBB penetration percentile than Ligand B (83.133).  For a CNS target like DRD2, >70 is desirable, and A is closer to this mark.

**9. Caco-2 Permeability:** Ligand A (-4.179) is slightly better than Ligand B (-4.786). Higher values are better, but both are negative, indicating poor permeability.

**10. Aqueous Solubility:** Ligand A (-1.867) is slightly better than Ligand B (-1.262). Higher values are better, but both are negative, indicating poor solubility.

**11. hERG Inhibition:** Both ligands have low hERG inhibition risk (0.364 and 0.467).

**12. Microsomal Clearance:** Ligand A (57.078) has a higher (worse) microsomal clearance than Ligand B (1.425). Lower clearance is preferred.

**13. In vitro Half-Life:** Ligand A (25.021) has a longer half-life than Ligand B (1.992). This is favorable.

**14. P-gp Efflux:** Ligand A (0.044) has a much lower P-gp efflux liability than Ligand B (0.082). Lower is better, especially for CNS targets.

**15. Binding Affinity:** Ligand B (-7.5) has a slightly better binding affinity than Ligand A (-7.4). However, the difference is small (0.1 kcal/mol), and other factors are more important.

**Overall Assessment:**

Ligand A is significantly better overall. While Ligand B has slightly better binding affinity, Ligand A excels in crucial properties for a CNS-targeting GPCR ligand: TPSA, BBB penetration, DILI risk, and P-gp efflux. The improved TPSA and BBB are particularly important for brain exposure. While Ligand A has a higher microsomal clearance, the longer half-life partially mitigates this.



Output:
0
2025-04-17 04:34:07,630 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (346.383) is slightly lower, which is generally favorable for permeability. Ligand B (370.446) is also acceptable.

**TPSA:** Both ligands have TPSA values (A: 80.86, B: 83.55) below the 90 A^2 threshold for CNS targets, which is excellent.

**logP:** Both ligands exhibit good logP values (A: 2.21, B: 1.312) within the optimal range of 1-3. Ligand A is slightly higher, potentially offering better membrane permeability.

**H-Bond Donors/Acceptors:** Both ligands have acceptable HBD (1) and HBA (A: 5, B: 4) counts, balancing solubility and permeability.

**QED:** Both ligands have QED values above 0.5 (A: 0.859, B: 0.748), indicating good drug-like properties. Ligand A has a slightly better QED.

**DILI:** Ligand A (73.245) has a higher DILI risk than Ligand B (55.138). This is a concern for Ligand A.

**BBB:** Both ligands have excellent BBB penetration (A: 74.758, B: 74.176), exceeding the desirable >70 percentile for CNS targets.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values, which is unusual and indicates poor permeability. However, the scale is not specified, so it's difficult to interpret.

**Aqueous Solubility:** Both ligands have negative solubility values, which is also unusual and suggests poor solubility. Again, the scale is unclear.

**hERG Inhibition:** Both ligands have low hERG inhibition liability (A: 0.69, B: 0.335), which is favorable. Ligand B is slightly better.

**Microsomal Clearance:** Ligand A (35.665) has a higher microsomal clearance than Ligand B (-0.375), indicating lower metabolic stability. Ligand B is significantly better in this regard.

**In vitro Half-Life:** Ligand A (-14.164) has a negative half-life, which is not possible. Ligand B (19.741) has a reasonable half-life. This is a major issue for Ligand A.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (A: 0.151, B: 0.081), which is good for CNS exposure. Ligand B is slightly better.

**Binding Affinity:** Both ligands have very similar and strong binding affinities (A: -8.3, B: -8.2 kcal/mol). The difference is negligible.

**Overall Assessment:**

Ligand B is the superior candidate. While both ligands have good TPSA, logP, BBB, and binding affinity, Ligand B demonstrates significantly better ADME properties. Specifically, it has a lower DILI risk, a more reasonable in vitro half-life, and lower microsomal clearance. Ligand A has a concerning negative half-life and higher DILI risk, making it less likely to succeed as a drug candidate. The Caco-2 and solubility values are problematic for both, but the other ADME properties of B are much more favorable.

Output:
1
2025-04-17 04:34:07,630 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (346.431 and 354.411 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (85.25) is significantly better than Ligand B (136.87). For CNS targets, we want TPSA <= 90, and A is comfortably within that, while B is pushing the limit.

**logP:** Ligand A (0.855) is a bit low, potentially hindering permeability, but not drastically. Ligand B (-2.563) is quite low and a significant concern for CNS penetration.

**H-Bond Donors/Acceptors:** Ligand A (2 HBD, 5 HBA) and Ligand B (4 HBD, 5 HBA) are both acceptable.

**QED:** Ligand A (0.684) is good, indicating drug-likeness. Ligand B (0.43) is lower, suggesting a less favorable drug-like profile.

**DILI:** Ligand A (39.201) has a lower DILI risk than Ligand B (22.722), which is preferable.

**BBB:** Ligand A (42.187) is lower than desired (>70), but not terrible. Ligand B (53.548) is better, but still not optimal.

**Caco-2 Permeability:** Ligand A (-4.899) is poor. Ligand B (-5.934) is also poor.

**Aqueous Solubility:** Both ligands have poor aqueous solubility (-1.849 and -1.36 respectively).

**hERG:** Both ligands have very low hERG risk (0.049 and 0.027).

**Microsomal Clearance:** Ligand A (1.285) has much lower clearance than Ligand B (-33.85), indicating better metabolic stability.

**In vitro Half-Life:** Ligand A (-3.993) has a shorter half-life than Ligand B (-11.673).

**P-gp Efflux:** Both ligands have very low P-gp efflux (0.028 and 0.0).

**Binding Affinity:** Ligand B (-8.1) has a slightly better binding affinity than Ligand A (-7.2), a 0.9 kcal/mol difference.

**Overall Assessment:**

Considering the GPCR-specific priorities, Ligand A is the more promising candidate. While its BBB is not ideal, its significantly better TPSA, logP, DILI, and metabolic stability (Cl_mic) outweigh the slightly weaker binding affinity compared to Ligand B. Ligand B's very low logP is a major concern for CNS penetration, and its higher DILI risk is also unfavorable. The affinity difference, while present, is unlikely to overcome these significant ADME deficiencies.

Output:
0
2025-04-17 04:34:07,631 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (392.815 Da) is slightly higher than Ligand B (344.411 Da), but both are acceptable.

**TPSA:** Both ligands have TPSA values below the 90 A^2 threshold desirable for CNS targets. Ligand A (88.33 A^2) is closer to the ideal range than Ligand B (75.71 A^2).

**logP:** Both ligands have logP values within the optimal range (1-3). Ligand A (3.004) is at the upper end, while Ligand B (1.835) is at the lower end.

**H-Bond Donors/Acceptors:** Both ligands have acceptable HBD (1) and HBA (6/4) counts, falling within the guidelines.

**QED:** Ligand A (0.697) has a significantly better QED score than Ligand B (0.354), indicating a more drug-like profile.

**DILI:** Both ligands have DILI risk below 60, indicating a relatively low risk of liver injury. Ligand A (77.2) is slightly higher than Ligand B (63.048), but both are acceptable.

**BBB:** Ligand A (81.078) has a much higher BBB penetration percentile than Ligand B (44.785). This is a *critical* advantage for a CNS target like DRD2.

**Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and suggests poor permeability. However, the scale is not specified, so it's hard to interpret.

**Aqueous Solubility:** Both have negative solubility values, which is also unusual and suggests poor solubility.

**hERG:** Both ligands have very low hERG inhibition liability (0.595 and 0.158), which is excellent.

**Microsomal Clearance:** Ligand A (59.301) has a lower microsomal clearance than Ligand B (61.898), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (23.512 hours) has a significantly longer half-life than Ligand B (-36.595 hours). The negative value for Ligand B is concerning and likely indicates very rapid degradation.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.369 and 0.174), which is good.

**Binding Affinity:** Ligand B (-8.9 kcal/mol) has a slightly better binding affinity than Ligand A (-8.0 kcal/mol). However, the difference is less than 1.5 kcal/mol, and can be outweighed by other factors.

**Overall Assessment:**

Ligand A is the superior candidate. While Ligand B has slightly better binding affinity, Ligand A excels in crucial areas for CNS drug development: significantly better BBB penetration, a much higher QED score, and a longer in vitro half-life. The slightly higher logP of Ligand A is less concerning than the poor BBB penetration and low QED of Ligand B. The negative solubility and Caco-2 values are a concern for both, but the other advantages of Ligand A make it the more promising candidate.

Output:
1
2025-04-17 04:34:07,631 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (354.48 and 350.38 Da) fall comfortably within the ideal 200-500 Da range.

**TPSA:** Ligand A (58.12) is excellent, well below the 90 A^2 threshold for CNS targets. Ligand B (137.48) is higher, but still potentially acceptable, though less ideal.

**logP:** Ligand A (3.856) is at the upper end of the optimal range (1-3), but still reasonable. Ligand B (0.663) is quite low, potentially hindering membrane permeability and CNS penetration.

**H-Bond Donors/Acceptors:** Ligand A (1 HBD, 4 HBA) is good. Ligand B (3 HBD, 7 HBA) is also acceptable, but slightly higher counts could impact permeability.

**QED:** Ligand A (0.656) is good, indicating good drug-like properties. Ligand B (0.462) is lower, suggesting a less favorable overall drug-like profile.

**DILI:** Ligand A (62.16) is moderately risky. Ligand B (54.32) is better, indicating lower potential for liver injury.

**BBB:** Ligand A (74.18) is very good, exceeding the 70% threshold for CNS targets. Ligand B (45.25) is significantly lower, raising concerns about brain penetration.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.167 and -5.273), which is unusual and indicates very poor permeability. This is a major red flag for both.

**Aqueous Solubility:** Both ligands have negative solubility values (-2.743 and -1.942), indicating very poor aqueous solubility. This is also a significant concern.

**hERG Inhibition:** Ligand A (0.775) has a low risk of hERG inhibition. Ligand B (0.186) also shows low risk.

**Microsomal Clearance:** Ligand A (77.39) has a relatively high clearance, suggesting faster metabolism. Ligand B (-0.86) is extremely low, suggesting very high metabolic stability.

**In vitro Half-Life:** Ligand A (36.40 hours) is reasonable. Ligand B (-9.66 hours) is problematic, suggesting very rapid degradation.

**P-gp Efflux:** Ligand A (0.377) has low P-gp efflux, which is favorable for CNS penetration. Ligand B (0.015) also has very low P-gp efflux.

**Binding Affinity:** Ligand A (-8.7 kcal/mol) has a significantly stronger binding affinity than Ligand B (-7.4 kcal/mol). This 1.3 kcal/mol difference is substantial and could outweigh some of the ADME drawbacks.

**Overall Assessment:**

Despite the poor Caco-2 and solubility scores for both, Ligand A is the more promising candidate. Its superior BBB penetration, better QED, and significantly stronger binding affinity outweigh its higher DILI risk and clearance. Ligand B's low logP and poor BBB penetration are major drawbacks for a CNS-targeting drug. The extremely low (negative) half-life is also a serious concern. While Ligand B has better metabolic stability and lower DILI, the binding affinity is not strong enough to compensate for its other weaknesses.

Output:
0
2025-04-17 04:34:07,631 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (344.39 and 349.519 Da) fall comfortably within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (85.23) is better than Ligand B (52.65). For a CNS target like DRD2, a TPSA <= 90 is preferred, and both meet this criterion. Ligand A is slightly higher, but still acceptable.

**3. logP:** Both ligands have good logP values (1.769 and 2.262), falling within the optimal 1-3 range.

**4. H-Bond Donors:** Ligand A (2) and Ligand B (1) both have acceptable HBD counts, well below the threshold of 5.

**5. H-Bond Acceptors:** Ligand A (4) and Ligand B (3) are both within the acceptable range of <= 10.

**6. QED:** Both ligands have similar and good QED values (0.819 and 0.767), indicating good drug-like properties.

**7. DILI:** Ligand A (32.765) has a significantly lower DILI risk than Ligand B (4.808). This is a major advantage for Ligand A.

**8. BBB:** Both ligands have excellent BBB penetration (78.907 and 79.488), exceeding the desirable >70 threshold for CNS targets.

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.968 and -4.942). This is unusual and suggests poor permeability. However, these values are on a log scale and can be interpreted as very low permeability.

**10. Aqueous Solubility:** Both ligands have negative solubility values (-3.281 and -1.57). Again, these are log scale values and indicate very poor aqueous solubility.

**11. hERG Inhibition:** Both ligands have low hERG inhibition risk (0.758 and 0.58).

**12. Microsomal Clearance:** Ligand A (-22.156) has a much lower (better) microsomal clearance than Ligand B (5.937), indicating greater metabolic stability.

**13. In vitro Half-Life:** Ligand A (19.898) has a significantly longer half-life than Ligand B (3.843).

**14. P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.028).

**15. Binding Affinity:** Ligand B (-7.2 kcal/mol) has a slightly better binding affinity than Ligand A (-9.5 kcal/mol). While a 1.5 kcal/mol advantage is usually significant, the other factors are more important here.

**Overall Assessment:**

Ligand A is the superior candidate. While Ligand B has slightly better binding affinity, Ligand A demonstrates significantly better ADMET properties: lower DILI risk, much lower microsomal clearance, and a longer half-life. The poor Caco-2 and solubility for both compounds are concerning, but can potentially be addressed with formulation strategies. Given the CNS target, the excellent BBB penetration of both is a positive, but the superior ADME profile of Ligand A makes it the more promising drug candidate.

Output:
1
2025-04-17 04:34:07,631 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (366.38 and 350.503 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (78.87) is better than Ligand B (49.85). For CNS targets, we want TPSA <= 90, both are within this range, but A is closer to the upper limit.

**3. logP:** Both ligands have good logP values (1.941 and 2.543), falling within the optimal 1-3 range.

**4. H-Bond Donors:** Ligand A (2) is reasonable, while Ligand B (0) is also acceptable.

**5. H-Bond Acceptors:** Ligand A (4) is reasonable, while Ligand B (3) is also acceptable.

**6. QED:** Both ligands have acceptable QED values (0.391 and 0.709), with Ligand B being significantly better.

**7. DILI:** Ligand A (21.869) has a much lower DILI risk than Ligand B (11.632), indicating a safer profile.

**8. BBB:** Ligand B (88.329) has a significantly higher BBB penetration percentile than Ligand A (77.317). This is a critical factor for CNS targets like DRD2.

**9. Caco-2 Permeability:** Ligand A (-5.008) has a worse Caco-2 permeability than Ligand B (-4.311).

**10. Aqueous Solubility:** Ligand A (-2.003) has a worse aqueous solubility than Ligand B (-2.609).

**11. hERG Inhibition:** Both ligands have low hERG inhibition risk (0.513 and 0.367).

**12. Microsomal Clearance:** Ligand B (66.738) has a lower microsomal clearance than Ligand A (7.062), suggesting better metabolic stability.

**13. In vitro Half-Life:** Ligand A (-27.609) has a much longer in vitro half-life than Ligand B (0.062).

**14. P-gp Efflux:** Ligand A (0.08) has lower P-gp efflux liability than Ligand B (0.113), which is favorable for CNS penetration.

**15. Binding Affinity:** Ligand A (-8.1 kcal/mol) has a significantly stronger binding affinity than Ligand B (-7.0 kcal/mol). This is a substantial advantage.

**Overall Assessment:**

While Ligand B has better BBB penetration and metabolic stability, the significantly stronger binding affinity of Ligand A (-8.1 vs -7.0 kcal/mol) is a major advantage, especially for a GPCR target. The difference in affinity is likely to outweigh the slightly lower BBB and higher clearance of Ligand A. The lower DILI risk for Ligand A is also a positive factor. Although Ligand B has a better QED score, the binding affinity is the most important parameter.

Output:
1
2025-04-17 04:34:07,632 - INFO - Reasoning:

Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (350.419 and 362.455 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (107.55) is slightly above the preferred <90 for CNS targets, but acceptable. Ligand B (89.16) is excellent, well below 90.

**logP:** Ligand A (0.569) is quite low, potentially hindering membrane permeability. Ligand B (1.911) is much better, falling within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A has 3 HBD and 5 HBA, which are reasonable. Ligand B has 2 HBD and 6 HBA, also acceptable.

**QED:** Both ligands have good QED scores (0.695 and 0.735), indicating good drug-like properties.

**DILI:** Both have elevated DILI risk (58.395 and 61.07), but are still below the concerning 60 threshold.

**BBB:** Ligand A (32.299) has a poor BBB percentile, which is a significant drawback for a CNS target. Ligand B (40.791) is better, but still not ideal (aim for >70).

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.248 and -5.675), which is unusual and suggests poor permeability. This is a concern for both.

**Aqueous Solubility:** Both ligands have negative solubility values (-2.604 and -2.057) which is also unusual and suggests poor solubility.

**hERG:** Both ligands have low hERG risk (0.272 and 0.477).

**Microsomal Clearance:** Ligand A (20.258) has higher clearance than Ligand B (2.63), indicating lower metabolic stability.

**In vitro Half-Life:** Ligand A (11.756) has a slightly longer half-life than Ligand B (3.942).

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.038 and 0.083), which is favorable for CNS penetration.

**Binding Affinity:** Both ligands have very similar and strong binding affinities (-8.6 and -8.4 kcal/mol). The difference is less than the 1.5 kcal/mol threshold.

**Conclusion:**

Considering the GPCR-specific priorities, Ligand B is the more promising candidate. While both have issues with Caco-2 and Solubility, Ligand B's significantly better logP and moderately better BBB penetration outweigh the slightly longer half-life of Ligand A. The similar binding affinity makes these secondary factors decisive. Ligand A's low logP and poor BBB are major liabilities for a CNS-targeting drug.

Output:
1
2025-04-17 04:34:07,632 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (351.447 and 363.527 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (107.53) is slightly above the optimal <90 for CNS targets, but still reasonable. Ligand B (71.09) is excellent, well below 90.

**3. logP:** Ligand A (0.383) is quite low, potentially hindering permeability. Ligand B (3.142) is optimal.

**4. H-Bond Donors:** Ligand A (4) is acceptable. Ligand B (2) is also good.

**5. H-Bond Acceptors:** Both ligands (A: 4, B: 4) are within the acceptable limit of 10.

**6. QED:** Ligand A (0.498) is marginally above the 0.5 threshold, while Ligand B (0.697) is comfortably above.

**7. DILI:** Ligand A (28.693) has a lower DILI risk than Ligand B (40.52), both are acceptable.

**8. BBB:** Ligand A (29.12) has poor BBB penetration, a significant drawback for a CNS target. Ligand B (54.672) has moderate BBB penetration, which is better, but still not ideal (aim for >70).

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.488 and -5.016), which is unusual and suggests poor permeability. This is concerning for both.

**10. Aqueous Solubility:** Both ligands have negative solubility values (-2.181 and -3.193), which is also unusual and suggests poor solubility.

**11. hERG Inhibition:** Both ligands have low hERG inhibition risk (0.062 and 0.111).

**12. Microsomal Clearance:** Ligand A (27.274) has lower clearance, indicating better metabolic stability than Ligand B (52.846).

**13. In vitro Half-Life:** Ligand A (-0.566) has a negative half-life, which is not possible. Ligand B (13.732) has a reasonable half-life.

**14. P-gp Efflux:** Both ligands have low P-gp efflux liability (0.036 and 0.25).

**15. Binding Affinity:** Both ligands have similar strong binding affinities (-8.6 and -8.1 kcal/mol). The difference of 0.5 kcal/mol is not significant enough to override other ADME concerns.

**Overall Assessment:**

Ligand B is the better candidate despite the negative Caco-2 and solubility values. Its logP is optimal, TPSA is excellent, QED is good, and it has better BBB penetration than Ligand A. Ligand A's very low logP and poor BBB penetration are major liabilities for a CNS-targeting drug. While Ligand A has better metabolic stability, the other factors weigh more heavily in favor of Ligand B, especially considering the GPCR-specific priorities. The negative Caco-2 and solubility values for both are concerning and would require further investigation (e.g., experimental validation, salt screening, formulation studies).

Output:
1
2025-04-17 04:34:07,632 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (367.793 and 345.491 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (127.63) is borderline for CNS penetration, slightly above the preferred <90, while Ligand B (73.31) is excellent, well below 90.

**logP:** Both ligands have acceptable logP values (0.968 and 2.334), falling within the 1-3 range. Ligand B is slightly better positioned.

**H-Bond Donors/Acceptors:** Ligand A (2 HBD, 5 HBA) and Ligand B (3 HBD, 6 HBA) both fall within acceptable limits (<=5 HBD and <=10 HBA).

**QED:** Ligand B (0.735) has a significantly better QED score than Ligand A (0.441), indicating a more drug-like profile.

**DILI:** Ligand A (61.07) has a higher DILI risk than Ligand B (29.857), though both are reasonably acceptable.

**BBB:** Ligand B (70.143) is much better for CNS penetration than Ligand A (31.912). This is a critical factor for a DRD2 ligand.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.012 and -5.222), which is unusual and suggests poor permeability. However, these values are on a scale where negative values are possible and don't necessarily disqualify a compound outright.

**Aqueous Solubility:** Both ligands have negative solubility values (-1.997 and -2.228), indicating poor aqueous solubility. This is a concern for bioavailability.

**hERG:** Ligand A (0.129) has a slightly lower hERG risk than Ligand B (0.784), which is preferable.

**Microsomal Clearance:** Ligand A (-15.596) exhibits significantly lower microsomal clearance than Ligand B (-4.071), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand B (65.85) has a much longer in vitro half-life than Ligand A (10.232), which is a significant advantage.

**P-gp Efflux:** Ligand A (0.034) shows lower P-gp efflux liability than Ligand B (0.022), which is favorable for CNS exposure.

**Binding Affinity:** Ligand B (-8.3 kcal/mol) has a stronger binding affinity than Ligand A (-7.5 kcal/mol). The difference of 0.8 kcal/mol is substantial and can outweigh some of the ADME drawbacks of Ligand B.

**Overall Assessment:**

Ligand B is the stronger candidate. While it has slightly higher hERG risk and P-gp efflux, its superior BBB penetration, QED, binding affinity, and in vitro half-life are crucial advantages for a DRD2 ligand targeting CNS disorders. The lower TPSA of Ligand B is also highly beneficial. The negative Caco-2 and solubility values are concerns for both, but the significantly better binding affinity of Ligand B makes it more likely to be optimized to overcome these issues.



Output:
1
2025-04-17 04:34:07,632 - INFO - Batch 124 complete. Total preferences: 1984
2025-04-17 04:34:07,633 - INFO - Processing batch 125/512...
2025-04-17 04:34:50,224 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (379.81 Da) is slightly higher than Ligand B (357.495 Da), but both are acceptable.

**TPSA:** Both ligands have TPSA values around 90, which is acceptable for CNS penetration, though ideally below 90. Ligand A (90.37) is slightly higher than Ligand B (90.9), but the difference is negligible.

**logP:** Ligand A (2.23) is within the optimal range (1-3), while Ligand B (0.515) is below 1. This is a significant drawback for Ligand B, as lower logP can hinder membrane permeability and CNS penetration.

**H-Bond Donors/Acceptors:** Both ligands have reasonable HBD (3) and HBA (4/5) counts, falling within the acceptable limits.

**QED:** Ligand A (0.731) has a better QED score than Ligand B (0.496), indicating a more drug-like profile.

**DILI:** Ligand A (25.591) has a much lower DILI risk than Ligand B (4.188), which is a substantial advantage.

**BBB:** Ligand A (77.317) has a significantly higher BBB percentile than Ligand B (36.371). This is *critical* for a CNS target like DRD2.

**Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and suggests poor permeability. However, the scale is not specified, so it's hard to interpret.

**Aqueous Solubility:** Both have negative solubility values, which is also unusual and suggests poor solubility. Again, the scale is not specified.

**hERG:** Ligand A (0.659) has a slightly higher hERG risk than Ligand B (0.258), but both are relatively low.

**Microsomal Clearance:** Ligand A (-8.242) exhibits significantly lower (better) microsomal clearance than Ligand B (-0.81). This indicates greater metabolic stability for Ligand A.

**In vitro Half-Life:** Ligand A (18.712 hours) has a longer half-life than Ligand B (10.859 hours), which is desirable.

**P-gp Efflux:** Ligand A (0.118) has lower P-gp efflux liability than Ligand B (0.016), meaning it is less likely to be pumped out of the brain, improving CNS exposure.

**Binding Affinity:** Ligand A (-8.9 kcal/mol) has a significantly stronger binding affinity than Ligand B (-7.4 kcal/mol). This 1.5 kcal/mol difference is substantial and can outweigh some ADME drawbacks.

**Conclusion:**

Considering all factors, especially the GPCR-specific priorities, **Ligand A is the far more promising drug candidate.** It has superior BBB penetration, better metabolic stability, a longer half-life, lower DILI risk, a higher QED score, and a significantly stronger binding affinity. While both have issues with Caco-2 and solubility, the other advantages of Ligand A are decisive. Ligand B's low logP is a major concern for CNS penetration, making it less likely to be successful.

Output:
1
2025-04-17 04:34:50,225 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 drug candidates, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (350.344 and 352.431 Da) fall comfortably within the ideal 200-500 Da range.

**TPSA:** Ligand A (49.33) is excellent, well below the 90 A^2 threshold for CNS targets. Ligand B (84.94) is higher, but still potentially acceptable, though less ideal.

**logP:** Ligand A (2.511) is optimal. Ligand B (1.004) is a bit low, potentially hindering membrane permeability.

**H-Bond Donors/Acceptors:** Ligand A (0 HBD, 4 HBA) is favorable. Ligand B (1 HBD, 5 HBA) is also acceptable.

**QED:** Ligand A (0.85) is very good, indicating high drug-likeness. Ligand B (0.691) is still respectable, but lower.

**DILI:** Ligand A (45.677) has a moderate DILI risk, but is still acceptable. Ligand B (21.791) has a very low DILI risk, which is a significant advantage.

**BBB:** Ligand A (96.045) has excellent predicted BBB penetration. Ligand B (55.099) is considerably lower, which is a major drawback for a CNS target like DRD2.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.503 and -4.858), which is unusual and suggests poor permeability. However, these values are on a log scale and may not be directly comparable.

**Aqueous Solubility:** Both ligands have negative solubility values (-2.479 and -1.304), indicating poor aqueous solubility. This could pose formulation challenges.

**hERG:** Ligand A (0.907) has a slightly elevated hERG risk, but still within a manageable range. Ligand B (0.104) has very low hERG risk, a strong positive.

**Microsomal Clearance:** Ligand A (23.712) has moderate clearance, suggesting moderate metabolic stability. Ligand B (16.913) has lower clearance, indicating better metabolic stability.

**In vitro Half-Life:** Ligand A (-19.361) has a negative half-life, which is not physically possible and indicates a problem with the prediction. Ligand B (4.68) has a short half-life, which is less desirable.

**P-gp Efflux:** Ligand A (0.277) has low P-gp efflux, which is good for CNS penetration. Ligand B (0.031) has very low P-gp efflux, a significant advantage.

**Binding Affinity:** Ligand A (-8.6 kcal/mol) has a significantly stronger binding affinity than Ligand B (-7.7 kcal/mol). This 1.5 kcal/mol difference is substantial and can outweigh some ADME drawbacks.

**Overall Assessment:**

Ligand A excels in BBB penetration and binding affinity, crucial for a CNS GPCR target. However, its hERG risk is slightly elevated, and its in vitro half-life prediction is problematic. Ligand B has better metabolic stability, lower DILI and hERG risk, and very low P-gp efflux. However, its BBB penetration is significantly lower, and its binding affinity is weaker.

Given the importance of CNS penetration for DRD2, and the substantial difference in binding affinity, **Ligand A is the more promising candidate**, despite its slightly higher hERG risk and questionable half-life prediction. The strong affinity and excellent BBB penetration are likely to be more impactful for efficacy than the other drawbacks, which can potentially be addressed through further optimization.

Output:
0
2025-04-17 04:34:50,225 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (376.737 Da) is slightly higher than Ligand B (346.515 Da), but both are acceptable.

**TPSA:** Ligand A (51.22) is higher than Ligand B (40.62). For CNS targets, we want TPSA <= 90, so both are within range, but Ligand B is preferable.

**logP:** Ligand A (4.306) is slightly higher than the optimal range (1-3), potentially causing solubility issues. Ligand B (3.452) is within the optimal range. This favors Ligand B.

**H-Bond Donors/Acceptors:** Ligand A has 1 HBD and 3 HBA, while Ligand B has 0 HBD and 2 HBA. Both are within acceptable limits (<=5 HBD, <=10 HBA).

**QED:** Both ligands have similar QED values (0.791 and 0.782), indicating good drug-likeness.

**DILI:** Ligand A (67.739) has a higher DILI risk than Ligand B (15.277). This is a significant advantage for Ligand B.

**BBB:** Ligand B (87.476) has a much higher BBB penetration percentile than Ligand A (68.864). This is *critical* for a CNS target like DRD2, strongly favoring Ligand B.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.65 and -4.742). This is unusual and suggests poor permeability. However, the values are very similar.

**Aqueous Solubility:** Both ligands have negative solubility values (-4.404 and -3.38). This is also concerning, but again, the values are comparable.

**hERG:** Both ligands have low hERG inhibition liability (0.498 and 0.624), which is good.

**Microsomal Clearance:** Ligand B (78.891) has a higher microsomal clearance than Ligand A (39.254), indicating lower metabolic stability. This favors Ligand A.

**In vitro Half-Life:** Ligand A (23.814 hours) has a longer half-life than Ligand B (-4.132 hours). This is a significant advantage for Ligand A.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.321 and 0.341), which is good.

**Binding Affinity:** Both ligands have very similar and strong binding affinities (-9.2 and -9.4 kcal/mol). The difference is negligible.

**Overall Assessment:**

Ligand B is clearly superior due to its significantly better BBB penetration (87.476 vs 68.864) and lower DILI risk (15.277 vs 67.739). While Ligand A has better metabolic stability and half-life, the CNS penetration and safety profile are more critical for a DRD2 ligand. The slight disadvantage in metabolic stability can potentially be addressed through further optimization. The similar affinities make the ADME properties the deciding factor.

Output:
1
2025-04-17 04:34:50,225 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (356.463 and 349.435 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (84.94) is excellent, well below the 90 A^2 threshold for CNS targets. Ligand B (120) is higher, but still potentially acceptable, though less optimal.

**logP:** Ligand A (2.48) is within the optimal 1-3 range. Ligand B (0.829) is slightly below 1, which *could* indicate permeability issues, but isn't a hard disqualifier.

**H-Bond Donors/Acceptors:** Ligand A (1 HBD, 5 HBA) is good. Ligand B (4 HBD, 5 HBA) is also acceptable, though the higher HBD count could slightly impact permeability.

**QED:** Ligand A (0.708) has a better QED score than Ligand B (0.587), indicating a more drug-like profile.

**DILI:** Ligand A (46.956) has a significantly lower DILI risk than Ligand B (60.799), which is approaching a higher risk category.

**BBB:** This is critical for a CNS target. Ligand A (78.054) has a good BBB percentile, while Ligand B (27.142) is very poor, suggesting limited brain penetration.

**Caco-2 Permeability:** Ligand A (-4.317) is better than Ligand B (-5.467), indicating better intestinal absorption.

**Aqueous Solubility:** Both ligands have very poor aqueous solubility (-2.391 and -2.737 respectively). This is a concern for both, but could be mitigated with formulation strategies.

**hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.299 and 0.05 respectively).

**Microsomal Clearance:** Ligand A (43.844) has a higher, less desirable, microsomal clearance than Ligand B (14.217), indicating faster metabolism.

**In vitro Half-Life:** Both ligands have negative half-lives (-4.142 and -4.477), which is unusual and suggests rapid degradation *in vitro*. This is a concern for both.

**P-gp Efflux:** Ligand A (0.077) has lower P-gp efflux than Ligand B (0.099), suggesting better CNS exposure.

**Binding Affinity:** Ligand A (-7.6 kcal/mol) has a significantly stronger binding affinity than Ligand B (0.0 kcal/mol). This is a major advantage.

**Overall Assessment:**

Ligand A is clearly superior. Its significantly better binding affinity, favorable BBB penetration, lower DILI risk, better Caco-2 permeability, and lower P-gp efflux outweigh its slightly higher microsomal clearance and poor solubility. Ligand B's extremely poor BBB penetration is a deal-breaker for a CNS-targeting drug, and its binding affinity is essentially non-existent. While both have solubility and half-life concerns, these are addressable through formulation or structural modifications.

Output:
1
2025-04-17 04:34:50,225 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (349.39 and 369.45 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Both ligands (104.81 and 103.87) are slightly above the optimal <90 for CNS targets, but still reasonably acceptable.

**3. logP:** Ligand A (-0.671) is quite low, potentially hindering membrane permeability. Ligand B (0.029) is better, falling within the 1-3 range, though on the lower end.

**4. H-Bond Donors:** Both have 2 HBD, which is within the acceptable limit of <=5.

**5. H-Bond Acceptors:** Ligand A has 5 HBA, and Ligand B has 6. Both are within the acceptable limit of <=10.

**6. QED:** Ligand B (0.706) has a significantly better QED score than Ligand A (0.389), indicating a more drug-like profile.

**7. DILI:** Ligand A (42.924) has a much lower DILI risk than Ligand B (65.103), which is a significant advantage.

**8. BBB:** Ligand B (52.191) has a substantially better BBB penetration percentile than Ligand A (20.512). This is *critical* for a CNS target like DRD2.

**9. Caco-2 Permeability:** Both ligands have similar, very poor Caco-2 permeability (-5.124 and -5.142).

**10. Aqueous Solubility:** Both ligands have poor aqueous solubility (-2.293 and -1.983).

**11. hERG Inhibition:** Both ligands show very low hERG inhibition risk (0.022 and 0.05).

**12. Microsomal Clearance:** Ligand A (-8.94) has a much lower (better) microsomal clearance than Ligand B (29.569), suggesting better metabolic stability.

**13. In vitro Half-Life:** Ligand A (-15.997) has a much longer in vitro half-life than Ligand B (-2.355), which is a considerable advantage.

**14. P-gp Efflux:** Both ligands show very low P-gp efflux liability (0.024 and 0.008).

**15. Binding Affinity:** Ligand B (-7.6) has a significantly stronger binding affinity than Ligand A (0). This is a major advantage, potentially outweighing some of its ADME drawbacks.

**Overall Assessment:**

While Ligand A has better DILI, metabolic stability, and half-life, Ligand B's significantly stronger binding affinity (-7.6 kcal/mol vs 0 kcal/mol) and considerably better BBB penetration (52.191 vs 20.512) are decisive for a CNS GPCR target. The improved QED score also favors Ligand B. The lower logP of Ligand A is a concern for permeability. The poor Caco-2 and solubility are drawbacks for both, but can be addressed with formulation strategies.

Output:
1
2025-04-17 04:34:50,225 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (355.36 and 346.475 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (62.3) is excellent, well below the 90 A^2 threshold for CNS targets. Ligand B (78.09) is still reasonable but less optimal.

**3. logP:** Both ligands (2.022 and 2.133) are within the optimal 1-3 range.

**4. H-Bond Donors:** Ligand A (1) and Ligand B (2) both meet the <=5 criteria.

**5. H-Bond Acceptors:** Both ligands (3) are well below the 10 HBA threshold.

**6. QED:** Both ligands have good QED scores (0.794 and 0.828), indicating drug-like properties.

**7. DILI:** Ligand A (42.458) has a slightly higher DILI risk than Ligand B (14.308), but both are below the concerning 60 threshold.

**8. BBB:** This is crucial for a CNS target like DRD2. Ligand A (75.921) has a significantly better BBB percentile than Ligand B (61.07). While 70 is desirable, A is closer.

**9. Caco-2 Permeability:** Ligand A (-4.626) has poor Caco-2 permeability. Ligand B (-5.211) is also poor.

**10. Aqueous Solubility:** Ligand A (-2.306) and Ligand B (-1.483) both have poor aqueous solubility.

**11. hERG Inhibition:** Ligand A (0.309) has a lower hERG risk than Ligand B (0.543), which is preferable.

**12. Microsomal Clearance:** Ligand A (30.379) has a higher microsomal clearance than Ligand B (0.462), which suggests lower metabolic stability.

**13. In vitro Half-Life:** Ligand A (-25.935) has a shorter in vitro half-life than Ligand B (-24.95). Both are negative values, which is a bit unusual and suggests a very rapid clearance.

**14. P-gp Efflux:** Ligand A (0.029) has a much lower P-gp efflux liability than Ligand B (0.04). Lower is better for CNS penetration.

**15. Binding Affinity:** Ligand A (-9.6 kcal/mol) has a significantly stronger binding affinity than Ligand B (-0.0 kcal/mol). This is a major advantage, potentially outweighing some of the ADME drawbacks.

**Overall Assessment:**

Ligand A is the stronger candidate. Its significantly better binding affinity (-9.6 vs -0.0 kcal/mol) is the most important factor. It also has a better BBB score (75.921 vs 61.07) and lower P-gp efflux (0.029 vs 0.04), both critical for CNS penetration. While Ligand A has a higher DILI risk and poorer Caco-2 permeability and solubility, the substantial affinity advantage and improved CNS-related properties make it the more promising drug candidate.

Output:
1
2025-04-17 04:34:50,226 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (347.379 and 347.419 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (137.82) is slightly above the optimal <90 for CNS targets, but still reasonable. Ligand B (87.54) is excellent, well below 90.

**logP:** Ligand A (-0.621) is quite low, potentially hindering permeability. Ligand B (0.102) is better, falling within the 1-3 range, but still on the lower side.

**H-Bond Donors/Acceptors:** Ligand A has 4 HBD and 7 HBA, acceptable. Ligand B has 1 HBD and 5 HBA, also acceptable.

**QED:** Both ligands have good QED scores (0.527 and 0.766), indicating drug-like properties.

**DILI:** Ligand A (60.644) has a higher DILI risk than Ligand B (39.667), which is preferable.

**BBB:** This is crucial for a CNS target. Ligand A has a BBB percentile of 13.222, which is very poor. Ligand B has a much better BBB percentile of 55.099, though still not ideal (aim for >70).

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.844 and -5.038), which is unusual and suggests poor permeability. This is a significant concern for both.

**Aqueous Solubility:** Both ligands have negative solubility values (-1.907 and -1.965), indicating very poor aqueous solubility. This is a major drawback.

**hERG Inhibition:** Ligand A (0.031) has a very low hERG risk, excellent. Ligand B (0.166) is slightly higher, but still relatively low.

**Microsomal Clearance:** Ligand A (-29.997) has very low (and negative) microsomal clearance, suggesting high metabolic stability. Ligand B (9.963) has a moderate clearance.

**In vitro Half-Life:** Ligand A (4.362) has a short half-life. Ligand B (17.975) has a significantly longer half-life, which is more desirable.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.005 and 0.011), which is good for CNS penetration.

**Binding Affinity:** Ligand A (-9.0) has a significantly stronger binding affinity than Ligand B (-7.9). This is a substantial advantage.

**Overall Assessment:**

Ligand A has a much better binding affinity and lower DILI risk, and excellent hERG profile. However, its extremely low logP and poor BBB penetration are major concerns. The negative Caco-2 and solubility values are also problematic.

Ligand B has a better BBB penetration, longer half-life, and lower DILI risk. However, its binding affinity is weaker, and its logP is still low. The negative Caco-2 and solubility values are also problematic.

Despite the superior affinity of Ligand A, the poor BBB penetration is a critical drawback for a CNS target like DRD2. While the affinity difference is substantial (>1 kcal/mol), the lack of brain exposure severely limits its potential. Ligand B, while weaker in binding, has a significantly better chance of reaching the target in the brain.

Output:
1
2025-04-17 04:34:50,226 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (358.36 and 350.409 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Both ligands (59.5 and 58.2) are below the 90 Angstroms threshold desirable for CNS targets, which is excellent.

**3. logP:** Both ligands (3.089 and 3.334) are within the optimal 1-3 range.

**4. H-Bond Donors:** Ligand A has 0 HBD, while Ligand B has 2. Both are acceptable, staying below the 5 threshold.

**5. H-Bond Acceptors:** Ligand A has 4 HBA, and Ligand B has 2. Both are below the 10 threshold.

**6. QED:** Ligand A (0.759) has a significantly better QED score than Ligand B (0.558), indicating better overall drug-likeness.

**7. DILI:** Ligand A (47.693) has a slightly higher DILI risk than Ligand B (39.822), but both are below the concerning 60 threshold.

**8. BBB:** Ligand A (92.943) has a substantially better BBB penetration percentile than Ligand B (81.233). This is *critical* for a CNS target like DRD2.

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.001 and -4.483), which is unusual and suggests poor permeability. However, these values are on a log scale and can be difficult to interpret without further context.

**10. Aqueous Solubility:** Both ligands have very poor aqueous solubility (-3.481 and -3.494). This is a significant drawback.

**11. hERG Inhibition:** Ligand A (0.271) shows a lower hERG inhibition liability than Ligand B (0.539), which is preferable.

**12. Microsomal Clearance:** Ligand A (77.208) has a higher microsomal clearance than Ligand B (29.673), meaning it's metabolized faster. This is a negative for Ligand A.

**13. In vitro Half-Life:** Ligand B (18.267) has a much longer in vitro half-life than Ligand A (4.14). This is a significant advantage for Ligand B.

**14. P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.099 and 0.201), which is excellent for CNS penetration.

**15. Binding Affinity:** Ligand B (-9) has a slightly better binding affinity than Ligand A (-8). While both are excellent, the 1 kcal/mol difference is notable.

**Overall Assessment:**

Ligand A excels in BBB penetration, QED, and hERG inhibition. However, it suffers from higher microsomal clearance and a shorter half-life. Ligand B has a slightly better binding affinity and significantly better metabolic stability (lower Cl_mic and higher t1/2). Both have poor solubility and permeability. Given the importance of BBB penetration and metabolic stability for a CNS GPCR target, and the relatively small difference in binding affinity, Ligand B is the more promising candidate. The longer half-life of Ligand B is a major advantage.

Output:
1
2025-04-17 04:34:50,226 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (347.463 Da) is slightly lower, which could be beneficial for permeability, but both are acceptable.

**TPSA:** Ligand A (74.35) is better than Ligand B (61.44) as it is closer to the ideal range for CNS targets (<=90).

**logP:** Both ligands have good logP values (A: 1.398, B: 1.872), falling within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A (HBD=1, HBA=5) is slightly better than Ligand B (HBD=2, HBA=4) in terms of maintaining a balance between solubility and permeability.

**QED:** Both ligands have acceptable QED scores (A: 0.895, B: 0.779), indicating good drug-like properties.

**DILI:** Ligand A (25.824) has a significantly lower DILI risk than Ligand B (6.204), which is a major advantage.

**BBB:** Ligand B (66.344) has a better BBB penetration percentile than Ligand A (55.06), which is crucial for a CNS target like DRD2.

**Caco-2 Permeability:** Ligand A (-5.223) has a worse Caco-2 permeability than Ligand B (-5.557).

**Aqueous Solubility:** Ligand A (-0.851) has a slightly better aqueous solubility than Ligand B (-1.865).

**hERG Inhibition:** Both ligands have low hERG inhibition liability (A: 0.447, B: 0.385), which is good.

**Microsomal Clearance:** Ligand A (-17.107) has a lower (better) microsomal clearance than Ligand B (-7.97), suggesting greater metabolic stability.

**In vitro Half-Life:** Ligand B (3.475) has a longer in vitro half-life than Ligand A (-5.519), which is generally desirable.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (A: 0.017, B: 0.011).

**Binding Affinity:** Ligand B (-9.5 kcal/mol) has a significantly stronger binding affinity than Ligand A (-7.8 kcal/mol). This is a substantial advantage, potentially outweighing some of the ADME drawbacks.

**Overall Assessment:**

The key trade-offs are between Ligand B's superior binding affinity and BBB penetration versus Ligand A's lower DILI risk and better metabolic stability. Given that DRD2 is a CNS target, BBB penetration is paramount. The significantly stronger binding affinity of Ligand B is also a major factor. While Ligand A has a better safety profile regarding DILI, the difference in binding affinity is substantial (>1.5 kcal/mol), and the BBB penetration of Ligand B is acceptable.

Output:
1
2025-04-17 04:34:50,226 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight (MW):** Both ligands are within the ideal range (200-500 Da). Ligand A (356.438 Da) is slightly lower, which is generally favorable for permeability. Ligand B (370.802 Da) is also good.

**2. TPSA:** Ligand A (59.08) is excellent, well below the 90 A^2 threshold for CNS targets. Ligand B (33.2) is even better, further enhancing the probability of BBB penetration.

**3. logP:** Ligand A (1.096) is within the optimal range (1-3), but on the lower side. Ligand B (4.446) is above the optimal range, potentially leading to solubility issues and off-target interactions.

**4. H-Bond Donors (HBD):** Both ligands have 0 HBD, which is acceptable.

**5. H-Bond Acceptors (HBA):** Ligand A has 4 HBA, and Ligand B has 2 HBA, both are within the acceptable limit of <=10.

**6. QED:** Both ligands have good QED scores (A: 0.669, B: 0.752), indicating a generally drug-like profile.

**7. DILI:** Ligand A (20.938) has a significantly lower DILI risk than Ligand B (50.097), which is a major advantage.

**8. BBB:** Ligand A (88.678) has a very good BBB percentile, exceeding the 70% threshold. Ligand B (71.966) is still reasonable, but lower than Ligand A.

**9. Caco-2:** Both have negative values, which is unusual. Assuming these represent logP-like scales, lower values indicate poorer permeability.

**10. Solubility:** Ligand A (-1.324) has poor solubility, while Ligand B (-4.962) is even worse. This is a concern, but can sometimes be mitigated with formulation strategies.

**11. hERG:** Ligand A (0.586) has a low hERG risk, while Ligand B (0.799) is slightly higher but still acceptable.

**12. Cl_mic:** Ligand B (88.868) has a much higher microsomal clearance than Ligand A (19.209), suggesting lower metabolic stability.

**13. t1/2:** Ligand B (21.727) has a significantly longer in vitro half-life than Ligand A (1.496), which is a positive attribute.

**14. Pgp:** Ligand A (0.105) has lower P-gp efflux liability than Ligand B (0.257), which is favorable for CNS penetration.

**15. Binding Affinity:** Ligand B (-9.7 kcal/mol) has a significantly stronger binding affinity than Ligand A (0.0 kcal/mol). This is a substantial advantage and could potentially outweigh some of the ADME drawbacks.

**Overall Assessment:**

Ligand B has a much stronger binding affinity, and a longer half-life, which are very important for a GPCR target. However, it has a higher logP, higher DILI risk, and higher P-gp efflux. Ligand A has better solubility, lower DILI, better BBB penetration, and lower P-gp efflux.

Considering the GPCR-specific priorities, BBB penetration and affinity are paramount. While Ligand B's logP is a concern, its *significantly* stronger binding affinity (-9.7 kcal/mol vs 0.0 kcal/mol) is a major driver. The difference in affinity is so large that it likely outweighs the other drawbacks, especially if formulation strategies can address the solubility issue.

Output:
1
2025-04-17 04:34:50,226 - INFO - Reasoning:

Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (348.349 and 365.455 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (60.45) is significantly better than Ligand B (91.5). For CNS targets, we want TPSA <= 90, so Ligand A is much more favorable.

**3. logP:** Both ligands have good logP values (2.595 and 1.777), falling within the optimal 1-3 range.

**4. H-Bond Donors:** Both have acceptable HBD counts (1 and 2, respectively), well below the threshold of 5.

**5. H-Bond Acceptors:** Both ligands have 4 HBA, which is acceptable (<=10).

**6. QED:** Both ligands have reasonable QED scores (0.836 and 0.764), indicating good drug-like properties.

**7. DILI:** Both ligands have DILI risk around the 60 percentile, indicating moderate risk. Ligand A (59.946) is slightly better than Ligand B (64.288).

**8. BBB:** This is a critical parameter for a CNS target like DRD2. Ligand A has a much higher BBB penetration (92.129%) compared to Ligand B (77.317%).  A value >70 is desirable, and Ligand A is significantly closer to optimal.

**9. Caco-2 Permeability:** Ligand A (-3.968) and Ligand B (-4.972) both have negative values, which is unusual. Lower values indicate poor permeability. However, the scale isn't fully defined, so it's hard to interpret the absolute difference.

**10. Aqueous Solubility:** Both have poor aqueous solubility (-4.041 and -3.959). This could pose formulation challenges, but is less critical than BBB for CNS targets.

**11. hERG Inhibition:** Both ligands have low hERG inhibition risk (0.456 and 0.793).

**12. Microsomal Clearance:** Ligand B (43.634) has significantly lower microsomal clearance than Ligand A (80.726), suggesting better metabolic stability.

**13. In vitro Half-Life:** Ligand B (6.639 hours) has a better in vitro half-life than Ligand A (-32.209 hours). The negative value for Ligand A is concerning and likely an error or indicates very rapid degradation.

**14. P-gp Efflux:** Both ligands have low P-gp efflux liability (0.108 and 0.127).

**15. Binding Affinity:** Both ligands have excellent binding affinity (-8.9 and -9.0 kcal/mol). The difference is negligible.

**Overall Assessment:**

Ligand A excels in TPSA and BBB penetration, both crucial for CNS GPCR targets. While Ligand B has better metabolic stability (lower Cl_mic) and half-life, the significantly lower BBB penetration and higher TPSA are major drawbacks. The negative in vitro half-life for Ligand A is a red flag, but the superior BBB and TPSA make it the more promising candidate *despite* this issue, as it could potentially be addressed through structural modifications. The binding affinity is comparable.

Output:
1
2025-04-17 04:34:50,226 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (352.479 and 374.459 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (87.46) is excellent, falling well below the 90 A^2 threshold for CNS targets. Ligand B (109.08) is still reasonable but less optimal.

**logP:** Ligand A (1.031) is within the optimal 1-3 range. Ligand B (0.334) is a bit low, potentially hindering permeability.

**H-Bond Donors/Acceptors:** Both ligands have 2 HBD and reasonable HBA counts (5 and 7 respectively), satisfying the <5 HBD and <10 HBA guidelines.

**QED:** Both ligands have acceptable QED scores (0.767 and 0.631), indicating good drug-like properties.

**DILI:** Both ligands have low DILI risk (21.908 and 32.261), which is positive.

**BBB:** Ligand B (54.246) has a significantly better BBB percentile than Ligand A (30.167). This is a critical advantage for a CNS target like DRD2.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.14 and -5.132) which is unusual and suggests poor permeability.

**Aqueous Solubility:** Both ligands have negative solubility values (-0.753 and -1.21), indicating very poor aqueous solubility.

**hERG:** Both ligands have very low hERG inhibition risk (0.155 and 0.344).

**Microsomal Clearance:** Ligand B (4.252) has significantly lower microsomal clearance than Ligand A (31.822), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand B (30.666) has a longer in vitro half-life than Ligand A (12.875).

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.043 and 0.033).

**Binding Affinity:** Ligand A (-7.9 kcal/mol) has a slightly better binding affinity than Ligand B (-6.9 kcal/mol), a difference of 1.0 kcal/mol.

**Overall Assessment:**

While Ligand A has a slightly better binding affinity, Ligand B is superior overall, particularly for a CNS target. The significantly improved BBB penetration (54.246 vs 30.167), lower microsomal clearance, and longer half-life outweigh the minor affinity difference. Both have poor solubility and permeability, which would need to be addressed during optimization, but the ADME profile of Ligand B is more promising.

Output:
1
2025-04-17 04:34:50,226 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (352.475 and 350.503 Da) fall comfortably within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (76.66) is higher than Ligand B (58.64). For a CNS target like DRD2, we prefer TPSA <= 90, so both are acceptable, but B is better.

**3. logP:** Both ligands have good logP values (1.631 and 2.759), falling within the optimal 1-3 range. Ligand B is slightly better.

**4. H-Bond Donors:** Ligand A has 2 HBD, and Ligand B has 1. Both are within the acceptable limit of <=5.

**5. H-Bond Acceptors:** Ligand A has 4 HBA, and Ligand B has 3. Both are within the acceptable limit of <=10.

**6. QED:** Both ligands have similar QED values (0.762 and 0.718), indicating good drug-likeness.

**7. DILI:** Both ligands have low DILI risk (24.893 and 21.985 percentiles), which is excellent.

**8. BBB:** This is a crucial parameter for CNS targets. Ligand B (67.119%) is significantly better than Ligand A (58.007%). A value >70 is desirable, but >60 is a good start.

**9. Caco-2 Permeability:** Ligand A (-5.042) has worse Caco-2 permeability than Ligand B (-4.577). Lower values are less favorable.

**10. Aqueous Solubility:** Ligand A (-1.752) has worse aqueous solubility than Ligand B (-3.011). Lower values are less favorable.

**11. hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.249 and 0.511), which is excellent.

**12. Microsomal Clearance:** Ligand A (23.269) has lower microsomal clearance than Ligand B (49.45), indicating better metabolic stability.

**13. In vitro Half-Life:** Ligand A (9.616) has a slightly longer in vitro half-life than Ligand B (8.515).

**14. P-gp Efflux:** Ligand A (0.05) has much lower P-gp efflux liability than Ligand B (0.18), which is favorable for CNS penetration.

**15. Binding Affinity:** Ligand B (-8 kcal/mol) has a significantly stronger binding affinity than Ligand A (0 kcal/mol). This is a major advantage, potentially outweighing some of the ADME drawbacks of Ligand B.

**Overall Assessment:**

Ligand B is the better candidate. While Ligand A has slightly better metabolic stability and P-gp efflux, Ligand B excels in the most critical areas for a CNS GPCR target: BBB penetration and, most importantly, binding affinity. The substantial difference in binding affinity (-8 vs 0 kcal/mol) is a decisive factor. The slightly higher P-gp efflux and microsomal clearance of Ligand B are less concerning given its superior affinity and BBB penetration.

Output:
1
2025-04-17 04:34:50,226 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (357.435 and 349.435 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (80.32) is excellent, well below the 90 A^2 threshold for CNS targets. Ligand B (96.45) is still reasonable but closer to the 90 A^2 limit.

**logP:** Ligand A (2.615) is optimal (1-3). Ligand B (0.308) is quite low, potentially hindering membrane permeability and CNS penetration.

**H-Bond Donors/Acceptors:** Both ligands have 2 HBD and 5-6 HBA, which are within acceptable limits.

**QED:** Both ligands have good QED scores (0.637 and 0.666), indicating good drug-like properties.

**DILI:** Ligand A (90.694) has a higher DILI risk than Ligand B (38.736). This is a concern for Ligand A.

**BBB:** Both ligands have reasonably good BBB penetration (60.876 and 62.97), but neither exceeds the desirable >70% threshold.

**Caco-2 Permeability:** Ligand A (-5.005) has poor Caco-2 permeability, which is a significant negative. Ligand B (-4.629) is also poor, but slightly better than A.

**Aqueous Solubility:** Both ligands have poor aqueous solubility (-3.725 and -1.627).

**hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.334 and 0.075).

**Microsomal Clearance:** Ligand A (29.624) has higher microsomal clearance than Ligand B (19.696), suggesting lower metabolic stability.

**In vitro Half-Life:** Ligand B (-28.555) has a negative half-life, which is not possible and indicates a very rapid degradation. Ligand A (22.109) is more reasonable.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.3 and 0.004).

**Binding Affinity:** Ligand A (-9.2 kcal/mol) has significantly stronger binding affinity than Ligand B (-7.3 kcal/mol). The difference of 1.9 kcal/mol is substantial and can outweigh some ADME drawbacks.

**Overall Assessment:**

Ligand A has a much stronger binding affinity, a better TPSA, and a more reasonable half-life. However, it has a higher DILI risk and significantly poorer Caco-2 permeability. Ligand B has a better DILI profile, but its low logP, extremely short half-life, and weaker affinity are major drawbacks.

Given the GPCR-specific priorities, the strong binding affinity of Ligand A is a critical advantage. While the Caco-2 permeability is a concern, it might be addressable through formulation strategies. The DILI risk is also a concern, but could be mitigated with further structural modifications. The extremely poor half-life of Ligand B is a dealbreaker.

Output:
1
2025-04-17 04:34:50,226 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (412.292 Da) is slightly higher, but still acceptable. Ligand B (352.406 Da) is a bit lower, which could be advantageous for permeability.

**TPSA:** Ligand A (117.71) is borderline for CNS penetration, being above the preferred <90 threshold. Ligand B (70.08) is excellent, well below the threshold, suggesting better CNS penetration.

**logP:** Ligand A (2.211) is within the optimal range (1-3). Ligand B (0.054) is quite low, potentially hindering membrane permeability and reducing brain exposure.

**H-Bond Donors/Acceptors:** Ligand A has 3 HBD and 6 HBA, both acceptable. Ligand B has 1 HBD and 4 HBA, also acceptable.

**QED:** Both ligands have similar and good QED values (0.642 and 0.686, respectively), indicating good drug-like properties.

**DILI:** Ligand A has a higher DILI risk (78.131) than Ligand B (16.13), which is a significant concern.

**BBB:** Ligand B (74.06) has a much better BBB percentile than Ligand A (35.207). This is crucial for a CNS target like DRD2.

**Caco-2 Permeability:** Ligand A (-5.319) has poor Caco-2 permeability, indicating poor absorption. Ligand B (-4.467) also has poor Caco-2 permeability, but is slightly better than Ligand A.

**Aqueous Solubility:** Both ligands have very poor aqueous solubility (-2.927 and -2.332). This could pose formulation challenges.

**hERG Inhibition:** Ligand A (0.085) has a very low hERG risk, which is excellent. Ligand B (0.255) also has a low hERG risk, but slightly higher than Ligand A.

**Microsomal Clearance:** Ligand A (22.376) has a higher microsomal clearance than Ligand B (6.713), suggesting lower metabolic stability.

**In vitro Half-Life:** Ligand B (3.783) has a slightly longer in vitro half-life than Ligand A (-11.29), which is preferable.

**P-gp Efflux:** Ligand A (0.024) has very low P-gp efflux, which is excellent. Ligand B (0.044) also has low P-gp efflux, but slightly higher than Ligand A.

**Binding Affinity:** Ligand A (-8.8 kcal/mol) has a significantly stronger binding affinity than Ligand B (-7.8 kcal/mol). This is a substantial advantage, potentially outweighing some of the ADME drawbacks.

**Overall Assessment:**

While Ligand A has a superior binding affinity, its significantly higher DILI risk, poorer BBB penetration, and lower metabolic stability are major concerns. Ligand B, despite having a weaker affinity, exhibits a much more favorable ADME profile, particularly with its excellent BBB penetration and lower DILI risk. Given the CNS target and the importance of brain exposure, Ligand B is the more promising candidate. The 1.0 kcal/mol difference in binding affinity, while noticeable, is less critical than the ADME advantages of Ligand B, especially considering optimization potential.

Output:
1
2025-04-17 04:34:50,227 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight (MW):** Both ligands (362.495 and 373.538 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (58.64) is slightly higher than Ligand B (52.65). Both are below the 90 A^2 threshold for CNS targets, which is good.

**3. logP:** Ligand A (2.661) and Ligand B (1.917) are both within the optimal 1-3 range.

**4. H-Bond Donors (HBD):** Both ligands have 1 HBD, which is acceptable.

**5. H-Bond Acceptors (HBA):** Both ligands have 4 HBA, which is acceptable.

**6. QED:** Ligand A (0.876) has a higher QED than Ligand B (0.706), indicating a more drug-like profile.

**7. DILI:** Ligand A (35.052) has a significantly lower DILI risk than Ligand B (11.943). This is a major advantage for Ligand A.

**8. BBB:** Both ligands have good BBB penetration (Ligand A: 78.558, Ligand B: 70.764), exceeding the >70% threshold for CNS targets. Ligand A is slightly better.

**9. Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and suggests poor permeability. However, the scale is not defined, so it's hard to interpret.

**10. Aqueous Solubility:** Both have negative solubility values, again unusual.

**11. hERG Inhibition:** Both ligands show low hERG inhibition liability (Ligand A: 0.497, Ligand B: 0.6).

**12. Microsomal Clearance (Cl_mic):** Ligand B (24.389) has lower microsomal clearance than Ligand A (32.552), indicating better metabolic stability.

**13. In vitro Half-Life (t1/2):** Ligand B (3.804) has a longer half-life than Ligand A (2.585).

**14. P-gp Efflux:** Both ligands have low P-gp efflux liability (Ligand A: 0.198, Ligand B: 0.056). Ligand B is slightly better.

**15. Binding Affinity:** Ligand A (-8.5 kcal/mol) has a significantly stronger binding affinity than Ligand B (-7.1 kcal/mol). This is a substantial advantage, exceeding the 1.5 kcal/mol difference threshold.

**Overall Assessment:**

Ligand A is the stronger candidate. While Ligand B has slightly better metabolic stability and P-gp efflux, Ligand A's significantly superior binding affinity (-8.5 vs -7.1 kcal/mol) and much lower DILI risk outweigh these minor advantages. Both have acceptable BBB penetration and logP values. The unusual negative values for Caco-2 and solubility are concerning and would require further investigation, but the binding affinity and safety profile of Ligand A make it the more promising candidate.

Output:
1
2025-04-17 04:34:50,227 - INFO - Batch 125 complete. Total preferences: 2000
2025-04-17 04:34:50,227 - INFO - Processing batch 126/512...
2025-04-17 04:35:36,105 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (412.324 Da) is slightly higher than Ligand B (347.411 Da), but both are acceptable.

**2. TPSA:** Both ligands have TPSA values around 65, which is slightly above the optimal <90 for CNS targets, but still reasonable.

**3. logP:** Ligand A (3.628) is good, within the optimal 1-3 range. Ligand B (1.871) is at the lower end of the optimal range, potentially impacting permeability.

**4. H-Bond Donors:** Ligand A has 1 HBD, which is good. Ligand B has 0, also good.

**5. H-Bond Acceptors:** Ligand A has 4 HBA, acceptable. Ligand B has 5, also acceptable.

**6. QED:** Both ligands have similar QED values (0.695 and 0.601), indicating good drug-like properties.

**7. DILI:** Ligand A (37.03) has a much lower DILI risk than Ligand B (65.374). This is a significant advantage for Ligand A.

**8. BBB:** Ligand A (73.672) has a significantly better BBB penetration percentile than Ligand B (67.313). This is crucial for a CNS target like DRD2.

**9. Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and suggests poor permeability. However, the scale is not defined, so it's hard to interpret.

**10. Aqueous Solubility:** Both have negative solubility values, again, hard to interpret without knowing the scale.

**11. hERG Inhibition:** Both ligands have low hERG inhibition risk (0.387 and 0.243).

**12. Microsomal Clearance:** Ligand A (110.867) has higher microsomal clearance than Ligand B (80.909), meaning Ligand B is more metabolically stable.

**13. In vitro Half-Life:** Ligand B (-13.658) has a negative half-life, which is not possible and indicates a problem with the data. Ligand A (6.949) has a reasonable half-life.

**14. P-gp Efflux:** Both ligands have low P-gp efflux liability (0.39 and 0.125), which is favorable for CNS penetration.

**15. Binding Affinity:** Ligand A (-8.0 kcal/mol) has a significantly stronger binding affinity than Ligand B (-6.5 kcal/mol). This 1.5 kcal/mol difference is substantial and can outweigh minor ADME drawbacks.

**Overall Assessment:**

Ligand A is the stronger candidate. It has a significantly better binding affinity, a lower DILI risk, and a better BBB penetration percentile. While Ligand B has better metabolic stability, the superior affinity and CNS penetration potential of Ligand A are more critical for a DRD2 ligand. The negative values for Caco-2 and solubility are concerning for both, but the large affinity difference and better safety profile of A make it the better choice. The negative half-life for ligand B is a significant red flag.

Output:
1
2025-04-17 04:35:36,105 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (356.491 and 347.503 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (49.74) is slightly higher than Ligand B (43.86), but both are below the 90 A^2 threshold desirable for CNS targets.

**logP:** Ligand A (3.886) is at the upper end of the optimal range (1-3), while Ligand B (2.3) is closer to the lower end. While both are acceptable, a higher logP can sometimes improve BBB penetration, a key factor for DRD2.

**H-Bond Donors/Acceptors:** Both ligands have 0 HBD and 3 HBA, which are within acceptable limits.

**QED:** Ligand A (0.816) has a higher QED score than Ligand B (0.524), indicating a more drug-like profile.

**DILI:** Ligand A (44.009) has a slightly higher DILI risk than Ligand B (14.23), but both are below the concerning threshold of 60.

**BBB:** Both ligands have good BBB penetration (Ligand A: 78.209, Ligand B: 71.888), exceeding the 70% threshold.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values, which is unusual and suggests poor permeability. However, these values are on a log scale, so even negative values can be meaningful.

**Aqueous Solubility:** Both ligands have negative solubility values, indicating poor aqueous solubility. This is a concern for bioavailability.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (Ligand A: 0.663, Ligand B: 0.542).

**Microsomal Clearance:** Ligand A (71.399) has a higher microsomal clearance than Ligand B (37.22), suggesting lower metabolic stability.

**In vitro Half-Life:** Ligand B (-10.607) has a negative half-life, which is nonsensical. Ligand A (13.795) has a reasonable half-life.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (Ligand A: 0.411, Ligand B: 0.103).

**Binding Affinity:** Ligand A (-8.4 kcal/mol) has a significantly stronger binding affinity than Ligand B (-7.5 kcal/mol). This 0.9 kcal/mol difference is substantial and can outweigh some ADME drawbacks.

**Overall Assessment:**

Ligand A is the more promising candidate. While it has a slightly higher DILI risk and lower metabolic stability, its significantly stronger binding affinity (-8.4 vs -7.5 kcal/mol) and higher QED score are major advantages. Both ligands have poor solubility and Caco-2 permeability, which would need to be addressed in further optimization. The negative half-life for Ligand B is a critical flaw. The slightly better BBB and P-gp properties of Ligand B are not enough to overcome the affinity difference and the half-life issue.



Output:
1
2025-04-17 04:35:36,105 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (347.419 and 343.431 Da) fall comfortably within the ideal 200-500 Da range.

**TPSA:** Ligand A (120.04) is slightly above the optimal <90 for CNS targets, but not drastically. Ligand B (78.43) is excellent, well below 90.

**logP:** Ligand A (0.121) is quite low, potentially hindering membrane permeability. Ligand B (0.538) is also on the low side, but better than A. Both are below the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A has 3 HBD and 6 HBA, acceptable values. Ligand B has 1 HBD and 5 HBA, also acceptable and slightly more favorable.

**QED:** Both ligands have good QED scores (0.675 and 0.863), indicating good drug-like properties.

**DILI:** Both ligands have low DILI risk (29.236 and 23.11), which is positive.

**BBB:** This is a crucial parameter for a CNS target like DRD2. Ligand A has a BBB percentile of 15.083, which is very poor. Ligand B has a significantly better BBB percentile of 79.992, exceeding the desirable >70 threshold.

**Caco-2 Permeability:** Both have negative Caco-2 values (-5.601 and -5.054), which is unusual and suggests poor permeability. However, these values are on a scale where negative values are possible and don't necessarily preclude development.

**Aqueous Solubility:** Both ligands have poor aqueous solubility (-1.274 and -1.353). This could pose formulation challenges.

**hERG Inhibition:** Both ligands show very low hERG inhibition risk (0.197 and 0.417), which is excellent.

**Microsomal Clearance:** Ligand A has a moderate Cl_mic (6.256), while Ligand B has a very low Cl_mic (1.871), indicating better metabolic stability.

**In vitro Half-Life:** Ligand B has a significantly longer half-life (-11.898) compared to Ligand A (9.12), which is a major advantage.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.013 and 0.006), which is favorable for CNS penetration.

**Binding Affinity:** Both ligands have excellent binding affinities (-8 and -8.9 kcal/mol). Ligand B is slightly better, but the difference is not huge.

**Conclusion:**

Despite both ligands having good binding affinity and low hERG/P-gp liabilities, Ligand B is the far superior candidate. Its significantly better BBB penetration (79.992 vs 15.083), lower microsomal clearance, and longer half-life outweigh the slightly lower logP and solubility. The TPSA is also more favorable for Ligand B. The poor Caco-2 values are a concern for both, but the superior CNS penetration profile of Ligand B makes it the more promising drug candidate for a CNS target like DRD2.

Output:
1
2025-04-17 04:35:36,105 - INFO - Reasoning:

Let's analyze Ligand A and Ligand B against the provided guidelines, prioritizing GPCR-specific properties (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands fall within the ideal range (200-500 Da). Ligand A (362.499 Da) is slightly lower, which could be beneficial for permeability. Ligand B (422.241 Da) is still acceptable.

**TPSA:** Ligand A (76.88) is better than Ligand B (46.61) for CNS penetration, being closer to the ideal <90 A^2. Ligand B is quite low, which *could* indicate poor interactions.

**logP:** Both ligands have good logP values (A: 3.471, B: 3.681), falling within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A has 1 HBD and 5 HBA, while Ligand B has 0 HBD and 3 HBA. Both are within acceptable limits.

**QED:** Both ligands have reasonable QED scores (A: 0.853, B: 0.681), indicating good drug-like properties. Ligand A is slightly better.

**DILI:** Ligand A (72.819) has a higher DILI risk than Ligand B (35.867). This is a significant drawback for Ligand A.

**BBB:** Ligand B (89.492) has a significantly better BBB percentile than Ligand A (78.209). This is a crucial advantage for a CNS target like DRD2.

**Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual. However, the values are close enough to not be a major differentiator.

**Aqueous Solubility:** Both ligands have negative solubility values, also unusual. Again, they are close enough to not be a major differentiator.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (A: 0.569, B: 0.768).

**Microsomal Clearance:** Ligand A (46.728) has lower microsomal clearance than Ligand B (75.373), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand B (-11.113) has a longer in vitro half-life than Ligand A (-9.986).

**P-gp Efflux:** Both ligands have low P-gp efflux liability (A: 0.252, B: 0.274).

**Binding Affinity:** Ligand A (-8.1 kcal/mol) has a slightly better binding affinity than Ligand B (-7.7 kcal/mol). However, the difference is less than 1.5 kcal/mol, so it's not a decisive factor.

**Overall Assessment:**

Ligand B is the more promising candidate. While Ligand A has slightly better metabolic stability and binding affinity, Ligand B's significantly better BBB penetration and lower DILI risk are critical advantages for a CNS-targeting drug. The TPSA is also more favorable for CNS penetration. The slight difference in binding affinity is outweighed by the superior ADME properties of Ligand B.

Output:
1
2025-04-17 04:35:36,105 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (346.471 and 348.451 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (69.64) is significantly better than Ligand B (93.01). For CNS targets, we want TPSA <= 90, and A is comfortably within this range, while B is slightly above.

**3. logP:** Both ligands have acceptable logP values (1.86 and 0.851), falling within the 1-3 range.

**4. H-Bond Donors:** Both ligands have reasonable HBD counts (2 and 1, respectively), well below the threshold of 5.

**5. H-Bond Acceptors:** Ligand B (6) is slightly higher than Ligand A (3), but both are below the 10 threshold.

**6. QED:** Both ligands have good QED scores (0.747 and 0.823), indicating good drug-like properties.

**7. DILI:** Ligand B (49.128) has a lower DILI risk than Ligand A (16.906), which is a positive attribute.

**8. BBB:** Both ligands have similar BBB penetration (55.603 and 55.642). These are not ideal for a CNS target (desirable > 70), but are comparable.

**9. Caco-2:** Both ligands have negative Caco-2 values (-4.624 and -5.238). These values are unusual and likely represent a scaling issue or error in the data. We cannot reliably compare intestinal absorption from these values.

**10. Solubility:** Both ligands have negative solubility values (-2.592 and -1.443), which is also unusual and problematic. Again, we cannot reliably compare solubility.

**11. hERG:** Both ligands have very low hERG inhibition risk (0.246 and 0.026), which is excellent.

**12. Cl_mic:** Ligand B (8.267) has a lower microsomal clearance than Ligand A (11.367), suggesting better metabolic stability.

**13. t1/2:** Ligand A (-19.289) has a much longer in vitro half-life than Ligand B (6.475). This is a significant advantage.

**14. Pgp:** Both ligands have very low P-gp efflux liability (0.103 and 0.05), which is favorable for CNS penetration.

**15. Binding Affinity:** Ligand B (-8.5) has a slightly better binding affinity than Ligand A (-8.2), although the difference is relatively small.

**Overall Assessment:**

Considering the GPCR-specific priorities, Ligand A is slightly favored. While Ligand B has a lower DILI risk and better metabolic stability, Ligand A has a significantly better TPSA value, a longer half-life, and comparable binding affinity and BBB penetration. The negative solubility and Caco-2 values are concerning for both, but since we cannot reliably compare them, they don't factor into the decision. The slightly better affinity of Ligand B is unlikely to overcome the TPSA advantage of Ligand A for a CNS target.

Output:
1
2025-04-17 04:35:36,105 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (347.415 and 353.419 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (84.71) is excellent, well below the 90 A^2 threshold for CNS targets. Ligand B (105.76) is still reasonable but less optimal.

**logP:** Ligand A (3.004) is within the optimal 1-3 range. Ligand B (-0.647) is significantly lower, which could hinder membrane permeability and CNS penetration.

**H-Bond Donors/Acceptors:** Ligand A (HBD=1, HBA=4) and Ligand B (HBD=3, HBA=5) both have acceptable numbers of H-bond donors and acceptors.

**QED:** Ligand A (0.673) has a better QED score than Ligand B (0.478), indicating a more drug-like profile.

**DILI:** Ligand A (42.032) has a lower DILI risk than Ligand B (26.173), suggesting better hepatotoxicity potential.

**BBB:** Ligand A (82.823) has a significantly higher BBB percentile than Ligand B (60.644). This is a critical advantage for a CNS target like DRD2.

**Caco-2 Permeability:** Ligand A (-4.577) and Ligand B (-5.368) have negative Caco-2 values, which is unusual and indicates poor permeability. It's important to note the scale of this parameter.

**Aqueous Solubility:** Ligand A (-3.577) and Ligand B (-1.297) have negative solubility values, which is also unusual.

**hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.571 and 0.06, respectively).

**Microsomal Clearance:** Ligand A (24.15) has a slightly higher microsomal clearance than Ligand B (20.886), suggesting potentially lower metabolic stability.

**In vitro Half-Life:** Ligand A (6.599) has a longer in vitro half-life than Ligand B (1.426).

**P-gp Efflux:** Ligand A (0.106) has lower P-gp efflux liability than Ligand B (0.003), which is favorable for CNS penetration.

**Binding Affinity:** Ligand A (-9.6 kcal/mol) has a significantly stronger binding affinity than Ligand B (-7.4 kcal/mol). This is a substantial difference and a major factor in favor of Ligand A.

**Overall Assessment:**

Ligand A is clearly superior. It has a better BBB score, a more optimal logP, a higher QED, lower DILI risk, lower P-gp efflux, and, most importantly, a significantly stronger binding affinity. While both ligands have issues with Caco-2 and solubility, the superior CNS penetration properties and binding affinity of Ligand A outweigh these concerns, especially for a CNS-targeted GPCR like DRD2.

Output:
1
2025-04-17 04:35:36,106 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B based on the provided guidelines, prioritizing GPCR-specific properties (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (362.352 and 368.463 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (88.41) is excellent for CNS penetration, being well below 90. Ligand B (112.12) is still reasonable but less optimal.

**logP:** Ligand A (1.581) is within the optimal 1-3 range. Ligand B (-1.226) is below 1, which could hinder permeation.

**H-Bond Donors/Acceptors:** Both have 3 HBD and are within the acceptable limit of 5. Ligand A has 6 HBA, and Ligand B has 7, both are below the limit of 10.

**QED:** Both ligands have QED values (0.669 and 0.556) above 0.5, indicating good drug-like properties.

**DILI:** Ligand A (54.323) has a slightly higher DILI risk than Ligand B (36.099), but both are below the concerning threshold of 60.

**BBB:** This is a critical parameter for a CNS target like DRD2. Ligand A has a BBB percentile of 70.648, which is excellent. Ligand B has a significantly lower BBB percentile of 20.628, making CNS penetration less likely.

**Caco-2 Permeability:** Ligand A (-4.849) and Ligand B (-6.116) both have negative values, which is unusual. It's hard to interpret without knowing the scale, but lower values generally indicate poorer permeability.

**Aqueous Solubility:** Both ligands have very poor aqueous solubility (-2.396 and -2.017). This could pose formulation challenges.

**hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.501 and 0.049).

**Microsomal Clearance:** Ligand A (49.17) has a moderate clearance, while Ligand B (-14.61) has a negative clearance, which is not physically possible and likely indicates an error or an extremely stable compound.

**In vitro Half-Life:** Ligand A (10.56 hours) has a reasonable half-life. Ligand B (-7.069 hours) is also not physically possible.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.09 and 0.002), which is favorable for CNS exposure.

**Binding Affinity:** Both ligands have excellent binding affinities (-8.3 and -7.0 kcal/mol). Ligand A is slightly better (-8.3 kcal/mol).

**Conclusion:**

Considering the GPCR-specific priorities, Ligand A is the more promising candidate. Its superior BBB penetration (70.648 vs 20.628), acceptable logP, and slightly better binding affinity outweigh the slightly higher DILI risk and poor solubility. The negative values for clearance and half-life of Ligand B are concerning and likely indicate data errors.

Output:
1
2025-04-17 04:35:36,106 - INFO - Reasoning:

Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (337.463 Da) is slightly lower, which could be beneficial for permeability.

**2. TPSA:** Ligand A (38.33) is excellent for CNS penetration, well below the 90 A^2 threshold. Ligand B (124.47) is higher, potentially hindering BBB penetration, although still within a reasonable range.

**3. logP:** Ligand A (3.864) is at the upper end of the optimal range (1-3), but still acceptable. Ligand B (1.094) is quite low, potentially leading to poor membrane permeability.

**4. H-Bond Donors:** Both ligands have 1 HBD, which is within the acceptable limit of <=5.

**5. H-Bond Acceptors:** Ligand A has 2 HBAs, and Ligand B has 5 HBAs, both are within the acceptable limit of <=10.

**6. QED:** Ligand A (0.869) has a very good drug-likeness score. Ligand B (0.217) is poor, indicating potential issues with its overall drug-like properties.

**7. DILI:** Both ligands have acceptable DILI risk (Ligand A: 32.726, Ligand B: 35.091), both under the 40 threshold.

**8. BBB:** Both ligands have good BBB penetration (Ligand A: 73.129, Ligand B: 78.054), exceeding the 70% threshold for CNS targets.

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.742 and -4.714), which is unusual and difficult to interpret without further context. However, it suggests potentially poor intestinal absorption.

**10. Aqueous Solubility:** Both ligands have negative solubility values (-4.43 and -1.052), also unusual and suggesting poor aqueous solubility.

**11. hERG Inhibition:** Ligand A (0.904) has a slightly higher hERG risk than Ligand B (0.237), but both are relatively low.

**12. Microsomal Clearance:** Ligand A (93.296) has a high microsomal clearance, suggesting rapid metabolism. Ligand B (46.917) has lower clearance, indicating better metabolic stability.

**13. In vitro Half-Life:** Ligand A (8.496) has a shorter half-life than Ligand B (-28.417). The negative value for Ligand B is concerning and likely indicates an issue with the experimental setup or data quality.

**14. P-gp Efflux:** Ligand A (0.769) has moderate P-gp efflux, while Ligand B (0.023) has very low P-gp efflux, which is favorable for CNS penetration.

**15. Binding Affinity:** Ligand A (-9.5 kcal/mol) has significantly stronger binding affinity than Ligand B (-6.9 kcal/mol). This is a substantial difference (2.6 kcal/mol) and a major advantage.

**Overall Assessment:**

Despite Ligand A's higher metabolic clearance and slightly higher hERG risk, its significantly superior binding affinity (-9.5 vs -6.9 kcal/mol) and better QED score outweigh these drawbacks. The lower logP of Ligand B is a significant concern for CNS penetration, and its poor QED score raises red flags about its overall drug-likeness. While both have unusual solubility and Caco-2 values, the affinity difference is the most critical factor for a GPCR target.

Output:
1
2025-04-17 04:35:36,106 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (353.482 and 351.491 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (43.86) is significantly better than Ligand B (69.72). For CNS targets, we want TPSA <= 90, and ideally closer to 60. Ligand A is much closer to this ideal.

**3. logP:** Both ligands have good logP values (2.058 and 1.788), falling within the optimal 1-3 range.

**4. H-Bond Donors:** Both have a low number of HBDs (0 for A, 1 for B), which is favorable.

**5. H-Bond Acceptors:** Both have 3 HBAs, which is acceptable.

**6. QED:** Both ligands have similar, good QED values (0.671 and 0.711), indicating drug-likeness.

**7. DILI:** Ligand A (8.996) has a much lower DILI risk than Ligand B (10.973), which is a significant advantage.

**8. BBB:** Ligand A (96.123) has a substantially higher BBB penetration percentile than Ligand B (79.527). This is *critical* for a CNS target like DRD2.

**9. Caco-2:** Both have negative Caco-2 values (-4.492 and -4.363). This is unusual and suggests poor permeability. However, the negative values are similar, so it doesn't differentiate the two.

**10. Solubility:** Both have negative solubility values (-2.169 and -2.304), indicating poor aqueous solubility. Again, similar for both.

**11. hERG:** Both ligands have low hERG inhibition liability (0.655 and 0.226), which is good.

**12. Cl_mic:** Both have similar microsomal clearance values (39.221 and 39.422), indicating similar metabolic stability.

**13. t1/2:** Ligand B (-6.876) has a more negative in vitro half-life than Ligand A (-0.332). This suggests faster metabolism and a shorter half-life for Ligand B, which is less desirable.

**14. Pgp:** Both have very low Pgp efflux liability (0.023 and 0.02), which is excellent.

**15. Binding Affinity:** Ligand B (-7.0) has a slightly better binding affinity than Ligand A (-6.7), but the difference is only 0.3 kcal/mol. While affinity is important, the other ADME properties are more heavily weighted in this case, especially for a CNS target.

**Conclusion:**

Ligand A is the superior candidate. Its significantly better BBB penetration (96.123 vs 79.527), lower DILI risk (8.996 vs 10.973), and more favorable TPSA (43.86 vs 69.72) outweigh the slightly weaker binding affinity. The similar, problematic Caco-2 and solubility values don't differentiate the two. Given the GPCR target and the need for CNS penetration, Ligand A is the more promising drug candidate.

Output:
0
2025-04-17 04:35:36,106 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 drug candidates, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight (MW):** Both ligands are within the ideal range (200-500 Da). Ligand A (398.937 Da) is slightly higher than Ligand B (372.462 Da), but both are acceptable.

**2. TPSA:** Ligand A (76.13) is better than Ligand B (83.55). For CNS targets, we want TPSA <= 90, and both are under this threshold, but A is closer to the optimal range.

**3. logP:** Ligand A (3.407) is within the optimal range (1-3), but on the higher end. Ligand B (1.119) is also within range, but closer to the lower limit. While higher logP can sometimes be problematic, it's less concerning than a very low logP for CNS penetration.

**4. H-Bond Donors (HBD):** Both ligands have 1 HBD, which is within the acceptable limit of <=5.

**5. H-Bond Acceptors (HBA):** Ligand A has 5 HBA, and Ligand B has 4. Both are within the acceptable limit of <=10.

**6. QED:** Ligand A (0.856) has a better QED score than Ligand B (0.75), indicating a more drug-like profile.

**7. DILI:** Ligand B (52.074) has a significantly lower DILI risk than Ligand A (88.251). This is a substantial advantage for Ligand B.

**8. BBB:** Ligand B (78.868) has a better BBB percentile than Ligand A (68.748). Both are reasonably good, but >70 is desirable for CNS targets, and B is closer.

**9. Caco-2 Permeability:** Ligand A (-4.95) has better Caco-2 permeability than Ligand B (-5.205). However, both are negative values, indicating poor permeability.

**10. Aqueous Solubility:** Ligand A (-4.485) has better aqueous solubility than Ligand B (-2.275). Both are poor, but A is slightly better.

**11. hERG Inhibition:** Ligand A (0.547) has a slightly higher hERG inhibition risk than Ligand B (0.167). Lower is better.

**12. Microsomal Clearance (Cl_mic):** Ligand B (-8.32) has a significantly lower (better) microsomal clearance than Ligand A (15.003). This suggests better metabolic stability for Ligand B.

**13. In vitro Half-Life:** Ligand B (21.39) has a longer half-life than Ligand A (15.752). This is a positive attribute for Ligand B.

**14. P-gp Efflux:** Ligand A (0.462) has lower P-gp efflux than Ligand B (0.13). Lower efflux is better, especially for CNS targets.

**15. Binding Affinity:** Both ligands have very similar and strong binding affinities (-9.2 and -9.3 kcal/mol). The difference is negligible.

**Overall Assessment:**

While Ligand A has slightly better Caco-2 permeability and solubility, Ligand B demonstrates superior ADME properties, particularly regarding DILI risk, BBB penetration, metabolic stability (Cl_mic), and half-life. The similar binding affinities make the ADME profile the deciding factor. For a CNS target like DRD2, BBB penetration and minimizing toxicity (DILI) are critical. Ligand B excels in these areas. The lower P-gp efflux of ligand A is a minor advantage, but outweighed by the other benefits of ligand B.

Output:
1
2025-04-17 04:35:36,106 - INFO - Okay, let's analyze these two ligands for their potential as DRD2 drug candidates. DRD2 is a GPCR in the CNS, so BBB penetration, logP, Pgp efflux, TPSA, and binding affinity are paramount.

**Ligand A:** [350.459, 59.08, 1.148, 0, 4, 0.646, 19.193, 79.721, -4.423, -2.168, 0.2, 23.362, 6.05, 0.176, -8.1]
**Ligand B:** [385.873, 109.57, 0.656, 2, 4, 0.775, 66.964, 57.193, -5.458, -2.829, 0.122, 9.879, -12.74, 0.047, -7.8]

**Step-by-Step Comparison:**

1. **MW:** Both are within the ideal range (200-500 Da). A (350.459) is slightly preferred as it's closer to the lower end, potentially aiding permeability.
2. **TPSA:** A (59.08) is excellent, well below the 90 A<sup>2</sup> threshold for CNS targets. B (109.57) is higher, but still potentially acceptable, though less optimal.
3. **logP:** Both are good (1-3), A (1.148) is slightly better than B (0.656) as it's closer to the optimal range.
4. **HBD:** A (0) is ideal. B (2) is acceptable, but more donors can sometimes lead to issues.
5. **HBA:** Both have 4, which is within the acceptable limit of 10.
6. **QED:** Both are good (>=0.5), with B (0.775) being slightly better than A (0.646).
7. **DILI:** A (19.193) is significantly better than B (66.964), indicating a much lower risk of liver injury. This is a major advantage for A.
8. **BBB:** A (79.721) is excellent, exceeding the 70% threshold for CNS targets. B (57.193) is lower, which is a significant drawback for a CNS target.
9. **Caco-2:** A (-4.423) and B (-5.458) are both negative, which is unusual and suggests very poor permeability. This is a concern for both, but the negative values make direct comparison difficult.
10. **Solubility:** Both are very poor (-2.168 and -2.829). This is a significant issue for both compounds.
11. **hERG:** Both are very low (0.2 and 0.122), indicating very low cardiotoxicity risk.
12. **Cl_mic:** A (23.362) is higher than B (9.879), indicating faster metabolic clearance and potentially lower *in vivo* exposure. B is preferred here.
13. **t1/2:** A (6.05) is a relatively short half-life. B (-12.74) is extremely short, and likely indicates rapid metabolism or instability. A is preferred.
14. **Pgp:** Both are very low (0.176 and 0.047), suggesting minimal P-glycoprotein efflux. This is good for both.
15. **Affinity:** A (-8.1) is significantly better than B (-7.8), indicating a stronger binding affinity. A 0.3 kcal/mol difference is meaningful.

**Overall Assessment:**

Ligand A is the more promising candidate. While both compounds have poor solubility and Caco-2 permeability, A has a significantly better BBB score, lower DILI risk, and a stronger binding affinity. The faster metabolic clearance of A is a concern, but the superior binding affinity and CNS penetration potential outweigh this drawback. Ligand B's higher DILI risk and lower BBB penetration are significant liabilities for a CNS drug.

Output:
0
2025-04-17 04:35:36,106 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (343.43 and 349.40 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (75.44) is excellent, well below the 90 A^2 threshold for CNS targets. Ligand B (125.79) is higher, but still potentially acceptable, though less ideal.

**logP:** Ligand A (2.45) is within the optimal range of 1-3. Ligand B (-0.84) is below 1, which could hinder permeation.

**H-Bond Donors/Acceptors:** Both have 1 HBD, which is good. Ligand A has 4 HBA, which is acceptable. Ligand B has 8 HBA, which is approaching the upper limit and could impact permeability.

**QED:** Ligand A (0.85) has a very good drug-likeness score. Ligand B (0.63) is still acceptable, but lower.

**DILI:** Ligand A (41.1%) and Ligand B (53.0%) both have acceptable DILI risk, below the 60% threshold.

**BBB:** This is crucial for a CNS target. Ligand A (87.6%) is excellent, exceeding the 70% desirable threshold. Ligand B (57.7%) is significantly lower and a major concern.

**Caco-2 Permeability:** Ligand A (-4.89) is quite poor, indicating low intestinal absorption. Ligand B (-6.07) is even worse.

**Aqueous Solubility:** Ligand A (-3.63) is poor. Ligand B (0.02) is slightly better, but still very low.

**hERG Inhibition:** Ligand A (0.43) has very low hERG risk. Ligand B (0.03) is also very low.

**Microsomal Clearance:** Ligand A (70.5) is relatively high, suggesting faster metabolism. Ligand B (17.3) is much lower, indicating better metabolic stability.

**In vitro Half-Life:** Ligand A (1.86 hours) is short. Ligand B (9.23 hours) is considerably longer, a significant advantage.

**P-gp Efflux:** Ligand A (0.25) has low P-gp efflux, which is good for CNS penetration. Ligand B (0.03) has even lower efflux, which is excellent.

**Binding Affinity:** Ligand B (-7.2 kcal/mol) has a 0.5 kcal/mol advantage in binding affinity over Ligand A (-9.7 kcal/mol). This is a substantial difference.

**Overall Assessment:**

Ligand B has a significantly better binding affinity and metabolic stability (lower Cl_mic, longer t1/2) and P-gp efflux. However, its logP is poor, its TPSA is higher, and its BBB penetration is substantially lower than Ligand A. The poor BBB penetration of Ligand B is a critical drawback for a CNS target like DRD2, despite its superior affinity. Ligand A's excellent BBB penetration and acceptable TPSA outweigh its slightly weaker binding affinity and poorer metabolic properties. The poor Caco-2 and solubility of both are concerning, but can be addressed with formulation strategies.

Output:
1
2025-04-17 04:35:36,106 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (371.361 and 340.423 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (92.7) is slightly above the optimal <90 for CNS targets, but still reasonable. Ligand B (69.64) is well within the desired range.

**logP:** Both ligands (2.578 and 2.274) are within the optimal 1-3 range.

**H-Bond Donors:** Both have 2 HBD, which is acceptable (<=5).

**H-Bond Acceptors:** Ligand A has 5 HBA, and Ligand B has 3. Both are within the acceptable limit of <=10.

**QED:** Both ligands have good QED scores (0.762 and 0.826), indicating good drug-like properties.

**DILI:** Ligand A (69.678) has a higher DILI risk than Ligand B (17.449). This is a significant negative for Ligand A.

**BBB:** Ligand B (71.074) has a significantly better BBB penetration score than Ligand A (33.734). This is a crucial advantage for a CNS target like DRD2.

**Caco-2 Permeability:** Ligand A (-5.359) has poor Caco-2 permeability, while Ligand B (-4.992) is slightly better, but still not great.

**Aqueous Solubility:** Both ligands have poor aqueous solubility (-3.62 and -3.895). This could pose formulation challenges, but is less critical than BBB for CNS drugs.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.658 and 0.269).

**Microsomal Clearance:** Ligand A (17.297) has lower microsomal clearance than Ligand B (55.477), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand B (-12.106) has a negative half-life, which is concerning and likely an error or indicates very rapid degradation. Ligand A (33.149) has a reasonable in vitro half-life.

**P-gp Efflux:** Ligand A (0.136) has lower P-gp efflux than Ligand B (0.063), which is favorable for CNS penetration.

**Binding Affinity:** Ligand B (-9.0) has a slightly better binding affinity than Ligand A (-8.8), but the difference is relatively small (0.2 kcal/mol).

**Overall Assessment:**

Ligand B has a significantly better BBB score and a much lower DILI risk, which are critical for a CNS-targeting drug. While Ligand A has better metabolic stability and slightly lower P-gp efflux, the advantages are outweighed by the poor BBB penetration and higher DILI risk. The negative half-life for Ligand B is a major concern, but the other advantages are substantial enough to warrant further investigation into that result.

Output:
1
2025-04-17 04:35:36,106 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 drug candidates, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (361.431 and 366.487 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (116.76) is higher than the preferred <90 for CNS targets, but not drastically so. Ligand B (76.46) is well within the desired range. This favors Ligand B.

**3. logP:** Ligand A (0.318) is quite low, potentially hindering permeability. Ligand B (0.971) is better, but still on the lower side of the optimal 1-3 range.

**4. H-Bond Donors:** Ligand A (2) and Ligand B (1) are both acceptable, being less than 5.

**5. H-Bond Acceptors:** Ligand A (7) and Ligand B (6) are both acceptable, being less than 10.

**6. QED:** Both ligands (0.792 and 0.76) have good drug-likeness scores (>0.5).

**7. DILI:** Ligand A (68.088) has a higher DILI risk than Ligand B (35.634), which is preferable.

**8. BBB:** Ligand A (54.634) and Ligand B (52.966) are both below the desirable >70 for CNS targets. This is a significant concern for both, but they are relatively close.

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.743 and -5.31), which is unusual and suggests very poor permeability. This is a major red flag for both.

**10. Aqueous Solubility:** Both ligands have negative solubility values (-3.064 and -1.824), also unusual and suggesting poor solubility.

**11. hERG Inhibition:** Ligand A (0.046) has a very low hERG risk, while Ligand B (0.501) is slightly higher, but still relatively low. This favors Ligand A.

**12. Microsomal Clearance:** Ligand A (21.428) and Ligand B (24.038) have similar, moderate clearance values.

**13. In vitro Half-Life:** Ligand A (7.412) has a longer half-life than Ligand B (3.519), which is desirable.

**14. P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.043 and 0.048), which is good for CNS penetration.

**15. Binding Affinity:** Ligand B (-7.6 kcal/mol) has a significantly stronger binding affinity than Ligand A (-8.0 kcal/mol). A 0.6 kcal/mol difference in binding affinity is substantial and can often outweigh minor ADME deficiencies.

**Overall Assessment:**

Despite both ligands having issues with Caco-2 permeability, solubility, and BBB penetration, Ligand B is more promising. Its superior binding affinity (-7.6 vs -8.0 kcal/mol) is a significant advantage for a GPCR target. It also has a lower DILI risk and a slightly better logP value. While the TPSA is lower for Ligand B, both are still suboptimal. The longer half-life of Ligand A is a plus, but the stronger affinity of Ligand B is more critical for a CNS target.

Output:
1
2025-04-17 04:35:36,107 - INFO - Reasoning:

Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (364.555 Da) is slightly higher than Ligand B (346.347 Da), but both are acceptable.

**TPSA:** Ligand A (49.41) is excellent for CNS penetration, well below the 90 A^2 threshold. Ligand B (126.38) is higher, but still potentially acceptable, though less ideal for CNS targets.

**logP:** Ligand A (3.561) is within the optimal range (1-3). Ligand B (-0.474) is significantly lower, which could hinder membrane permeability and CNS penetration.

**H-Bond Donors/Acceptors:** Ligand A (1 HBD, 3 HBA) is favorable. Ligand B (2 HBD, 8 HBA) is slightly higher in both counts, potentially impacting permeability.

**QED:** Both ligands have acceptable QED values, with Ligand B (0.749) being slightly better than Ligand A (0.476).

**DILI:** Ligand A (36.758) has a lower DILI risk than Ligand B (56.301), which is preferable.

**BBB:** Ligand A (73.672) has a significantly better BBB percentile than Ligand B (37.263). This is a crucial factor for a CNS target like DRD2.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.03 and -5.06), which is unusual and suggests poor permeability. However, these values are on a log scale and could be interpreted as very low permeability.

**Aqueous Solubility:** Both ligands have negative solubility values (-3.932 and -2.442), indicating poor aqueous solubility. This could pose formulation challenges.

**hERG Inhibition:** Ligand A (0.463) has a lower hERG risk than Ligand B (0.066), which is a positive attribute.

**Microsomal Clearance:** Ligand A (86.613) has higher microsomal clearance than Ligand B (11.093), indicating faster metabolism and potentially lower *in vivo* exposure.

**In vitro Half-Life:** Ligand B (-4.722) has a negative half-life, which is not physically meaningful. Ligand A (4.179) has a more reasonable half-life.

**P-gp Efflux:** Ligand A (0.305) has lower P-gp efflux liability than Ligand B (0.028), which is beneficial for CNS penetration.

**Binding Affinity:** Ligand B (-8.9 kcal/mol) has a significantly stronger binding affinity than Ligand A (-6.5 kcal/mol). This is a substantial advantage.

**Overall Assessment:**

While Ligand B has a superior binding affinity, Ligand A is the more promising drug candidate overall. The key factors driving this decision are:

*   **BBB:** Ligand A's much higher BBB percentile (73.672 vs. 37.263) is critical for a CNS-targeting drug.
*   **logP:** Ligand A's logP (3.561) is within the optimal range, while Ligand B's (-0.474) is too low.
*   **P-gp Efflux:** Ligand A has lower P-gp efflux.
*   **DILI:** Ligand A has a lower DILI risk.
*   **Metabolic Stability:** Ligand B has a very low (and potentially problematic) half-life and low clearance, while Ligand A has a more reasonable half-life.

The affinity difference (-8.9 vs -6.5) is significant, but can potentially be addressed through further optimization of Ligand A. The ADME properties of Ligand A are much more favorable for CNS penetration and overall drug-likeness.



Output:
0
2025-04-17 04:35:36,107 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (381.841 and 349.475 Da) fall within the ideal range of 200-500 Da.

**TPSA:** Ligand A (89.55) is better than Ligand B (72.88) as it is closer to the <90 target for CNS penetration, although both are acceptable.

**logP:** Ligand A (1.541) and Ligand B (0.908) are both within the optimal range of 1-3. Ligand A is slightly preferred.

**H-Bond Donors:** Both ligands have 2 HBD, which is within the acceptable limit of <=5.

**H-Bond Acceptors:** Ligand A has 6 HBA, and Ligand B has 4. Both are below the limit of <=10.

**QED:** Both ligands have similar QED values (0.784 and 0.74), indicating good drug-likeness.

**DILI:** Ligand A (88.329) has a significantly higher DILI risk than Ligand B (5.235). This is a major drawback for Ligand A.

**BBB:** Ligand B (57.425) has a much better BBB percentile than Ligand A (39.822). For a CNS target like DRD2, this is a critical advantage.

**Caco-2 Permeability:** Ligand A (-5.006) has worse Caco-2 permeability than Ligand B (-4.957), though both are poor.

**Aqueous Solubility:** Ligand A (-3.776) has slightly worse solubility than Ligand B (-1.367), but both are poor.

**hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.163 and 0.155).

**Microsomal Clearance:** Ligand B (-6.515) has a significantly lower (better) microsomal clearance than Ligand A (34.179), indicating better metabolic stability.

**In vitro Half-Life:** Ligand B (-12.002) has a much longer in vitro half-life than Ligand A (9.108), which is a significant advantage.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.199 and 0.008). Ligand B is slightly better.

**Binding Affinity:** Both ligands have the same binding affinity (-8.4 kcal/mol), which is excellent.

**Overall Assessment:**

While both ligands have excellent binding affinity, Ligand B is significantly better overall due to its superior BBB penetration, lower DILI risk, improved metabolic stability (lower Cl_mic and longer t1/2), and slightly better P-gp efflux. Ligand A's high DILI risk and poor BBB penetration are major concerns for a CNS drug candidate. The slight advantages of Ligand A in TPSA and logP are outweighed by these significant drawbacks.

Output:
1
2025-04-17 04:35:36,107 - INFO - Batch 126 complete. Total preferences: 2016
2025-04-17 04:35:36,107 - INFO - Processing batch 127/512...
2025-04-17 04:36:16,860 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (414.158 Da) is higher, but still acceptable. Ligand B (337.471 Da) is slightly preferred.

**2. TPSA:**  For CNS targets, we want TPSA <= 90. Ligand A (84.86) is excellent. Ligand B (57.74) is also very good. Both meet the criteria.

**3. logP:** Optimal is 1-3. Ligand A (3.335) is slightly above the optimal range but still acceptable. Ligand B (4.238) is pushing the upper limit and could potentially cause solubility issues or off-target interactions.

**4. H-Bond Donors:**  <= 5 is preferred. Ligand A (2) and Ligand B (0) both meet this criterion.

**5. H-Bond Acceptors:** <= 10 is preferred. Ligand A (4) and Ligand B (5) both meet this criterion.

**6. QED:** >= 0.5 is desired. Both Ligand A (0.75) and Ligand B (0.791) are good.

**7. DILI:** Lower is better. Ligand A (96.549) has a significantly higher DILI risk than Ligand B (32.183). This is a major concern for Ligand A.

**8. BBB:**  >70 is desirable for CNS targets. Ligand A (47.344) is below this threshold, while Ligand B (74.292) is good. This is a significant advantage for Ligand B.

**9. Caco-2 Permeability:** Higher is better. Both are negative (-4.84 and -4.874), indicating poor permeability. This is a concern for both.

**10. Aqueous Solubility:** Higher is better. Both are negative (-4.394 and -4.917), indicating poor solubility. This is a concern for both.

**11. hERG Inhibition:** Lower is better. Ligand A (0.243) has a slightly lower hERG risk than Ligand B (0.695).

**12. Microsomal Clearance:** Lower is better. Ligand A (21.52) has a significantly lower clearance than Ligand B (56.796), suggesting better metabolic stability.

**13. In vitro Half-Life:** Longer is better. Ligand A (14.809) has a longer half-life than Ligand B (-2.915).

**14. P-gp Efflux:** Lower is better. Ligand A (0.108) has much lower P-gp efflux than Ligand B (0.335), which is a significant advantage for CNS penetration.

**15. Binding Affinity:** More negative is better. Ligand A (-8.8 kcal/mol) has a slightly better binding affinity than Ligand B (-7.9 kcal/mol). This is a positive for Ligand A, but the difference is not huge.

**Overall Assessment:**

While Ligand A has better affinity, lower P-gp efflux, and better metabolic stability, its high DILI risk and poor BBB penetration are major drawbacks for a CNS-targeting drug. Ligand B, despite slightly weaker affinity, has a much better safety profile (lower DILI), significantly better BBB penetration, and acceptable P-gp efflux. Given the GPCR-specific priorities, especially BBB and safety, Ligand B is the more promising candidate.

Output:
1
2025-04-17 04:36:16,860 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (355.479 and 366.527 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (82.11) is better than Ligand B (67.43). Both are below the 90 A^2 threshold desirable for CNS targets, but A is slightly higher and could be a minor drawback.

**logP:** Ligand B (2.098) is optimal (1-3), while Ligand A (0.221) is quite low, potentially hindering membrane permeability. This is a significant negative for Ligand A.

**H-Bond Donors/Acceptors:** Both ligands have 2 HBD and 4-5 HBA, which are within acceptable limits.

**QED:** Both ligands have similar QED values (0.712 and 0.724), indicating good drug-likeness.

**DILI:** Ligand A (15.006) has a much lower DILI risk than Ligand B (37.146), a substantial advantage.

**BBB:** Ligand B (45.134) has a significantly better BBB penetration percentile than Ligand A (25.708). This is a critical factor for a CNS target like DRD2, favoring Ligand B.

**Caco-2 Permeability:** Ligand A (-4.916) has a very poor Caco-2 permeability, while Ligand B (-5.486) is also poor, but slightly better.

**Aqueous Solubility:** Ligand A (-0.567) has slightly better aqueous solubility than Ligand B (-3.012), but both are quite poor.

**hERG:** Both ligands have low hERG inhibition risk (0.179 and 0.283).

**Microsomal Clearance:** Ligand A (-8.449) exhibits much lower microsomal clearance (better metabolic stability) than Ligand B (28.049). This is a significant advantage for Ligand A.

**In vitro Half-Life:** Ligand A (16.05) has a slightly longer in vitro half-life than Ligand B (15.368).

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.015 and 0.085).

**Binding Affinity:** Both ligands have the same binding affinity (-7 kcal/mol), so this parameter doesn't differentiate them.

**Overall Assessment:**

Ligand B excels in BBB penetration, a crucial factor for CNS targets. However, it suffers from a higher DILI risk and significantly higher microsomal clearance. Ligand A has a better safety profile (lower DILI) and metabolic stability (lower Cl_mic) but struggles with low logP and poor Caco-2 permeability, and a lower BBB score.

Considering the GPCR-specific priorities, the BBB is paramount for CNS targets. While Ligand A's low logP is a concern, the significantly better metabolic stability and lower DILI risk, coupled with the similar binding affinity, make it a slightly more promising candidate. The poor permeability could potentially be addressed through prodrug strategies or formulation approaches. The low logP is a bigger issue than the lower BBB, as it directly impacts the ability of the molecule to reach the target.

Output:
0
2025-04-17 04:36:16,860 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B based on the provided guidelines, prioritizing GPCR-specific properties (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (378.219 and 349.435 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (92.41) is better than Ligand B (102.06). Both are below the 140 A^2 threshold for oral absorption, and reasonably close to the 90 A^2 target for CNS penetration, but A is preferable.

**logP:** Ligand A (2.813) is optimal, while Ligand B (1.243) is a bit low, potentially hindering permeation.

**H-Bond Donors & Acceptors:** Ligand A (HBD=2, HBA=6) and Ligand B (HBD=1, HBA=7) both meet the criteria of <=5 HBD and <=10 HBA.

**QED:** Both ligands have similar QED values (0.731 and 0.72), indicating good drug-likeness.

**DILI:** Ligand A (94.106) has a higher DILI risk than Ligand B (47.77). This is a significant drawback for Ligand A.

**BBB:** Ligand B (62.04) has a substantially better BBB penetration percentile than Ligand A (33.036). This is crucial for a CNS target like DRD2.

**Caco-2 Permeability:** Both have negative Caco-2 values (-5.18 and -5.073), which is unusual and suggests poor permeability. However, these values are on a scale where negative values are possible and don't necessarily disqualify a compound.

**Aqueous Solubility:** Both have negative solubility values (-4.492 and -2.071), which is also unusual, but doesn't necessarily disqualify a compound.

**hERG:** Both ligands have very low hERG inhibition liability (0.291 and 0.211).

**Microsomal Clearance:** Ligand A (26.973) has a lower microsomal clearance than Ligand B (39.27), indicating better metabolic stability.

**In vitro Half-Life:** Ligand A (12.893) has a longer half-life than Ligand B (6.698).

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.106 and 0.08).

**Binding Affinity:** Ligand B (-7.2 kcal/mol) has a significantly stronger binding affinity than Ligand A (-10.1 kcal/mol). This is a major advantage for Ligand B.

**Overall Assessment:**

While Ligand A has better metabolic stability (lower Cl_mic, longer t1/2) and slightly better TPSA, Ligand B is superior due to its significantly better BBB penetration, and substantially stronger binding affinity. The higher DILI risk for Ligand A is also a concern. The affinity difference is large enough to outweigh the metabolic advantages of Ligand A, especially given that both compounds have acceptable (though unusual) permeability and solubility profiles.



Output:
1
2025-04-17 04:36:16,860 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (348.418 and 352.381 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (67.43) is slightly above the optimal <90 for CNS targets, but still reasonable. Ligand B (58.64) is well within the desired range.

**3. logP:** Ligand A (4.259) is at the higher end of the optimal range (1-3) and could potentially cause solubility issues. Ligand B (2.288) is well within the optimal range.

**4. H-Bond Donors:** Ligand A (2) and Ligand B (1) are both acceptable, being less than 5.

**5. H-Bond Acceptors:** Both ligands (A: 3, B: 3) are within the acceptable limit of 10.

**6. QED:** Both ligands have good QED values (A: 0.799, B: 0.849), indicating drug-like properties.

**7. DILI:** Ligand A (56.223) has a slightly higher DILI risk than Ligand B (47.421), but both are below the concerning threshold of 60.

**8. BBB:** This is crucial for a CNS target. Ligand B (95.192) has a significantly higher BBB penetration percentile than Ligand A (83.249). This is a major advantage for Ligand B.

**9. Caco-2 Permeability:** Both have negative values, which is unusual. Assuming these are logP values, they indicate poor permeability.

**10. Aqueous Solubility:** Both ligands have very poor aqueous solubility (-5.005 and -3.246). This is a significant drawback for both, but potentially more problematic for Ligand A due to its higher logP.

**11. hERG Inhibition:** Both ligands show low hERG inhibition risk (A: 0.704, B: 0.588).

**12. Microsomal Clearance:** Ligand B (34.726) has a much lower microsomal clearance than Ligand A (87.66), indicating better metabolic stability.

**13. In vitro Half-Life:** Ligand B (-15.825) has a negative half-life, which is not possible. This is likely an error in the data and raises concerns about the reliability of the data for Ligand B. Ligand A (22.463) has a reasonable half-life.

**14. P-gp Efflux:** Both ligands have low P-gp efflux liability (A: 0.366, B: 0.332).

**15. Binding Affinity:** Both ligands have excellent binding affinities (A: -9.5 kcal/mol, B: -8.6 kcal/mol). Ligand A has a slightly better affinity, but the difference (0.9 kcal/mol) is not substantial enough to outweigh other factors.

**Overall Assessment:**

While Ligand A has slightly better binding affinity and a plausible half-life, Ligand B is significantly better overall. Its superior BBB penetration, lower microsomal clearance (better metabolic stability), and more favorable logP profile make it a more promising drug candidate for a CNS target like DRD2. The negative half-life for Ligand B is a red flag that needs to be investigated, but assuming it is a data error, the other properties strongly favor Ligand B.

Output:
1
2025-04-17 04:36:16,861 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (373.475 Da) is slightly higher than Ligand B (347.415 Da), but both are acceptable.

**TPSA:** Both ligands have TPSA values below the 90 A^2 threshold desirable for CNS targets. Ligand B (82.86 A^2) is better than Ligand A (96.97 A^2).

**logP:** Both ligands have logP values within the optimal range (1-3). Ligand B (1.177) is slightly lower, which could be a minor drawback, while Ligand A (1.883) is closer to the ideal.

**H-Bond Donors/Acceptors:** Ligand A has 2 HBD and 5 HBA, while Ligand B has 1 HBD and 4 HBA. Both are within acceptable limits (<=5 HBD and <=10 HBA).

**QED:** Both ligands have good QED scores (Ligand A: 0.611, Ligand B: 0.871). Ligand B is better here.

**DILI:** Ligand A has a DILI risk of 63.164%, which is concerning (high risk). Ligand B has a much lower DILI risk of 39.977% (good). This is a significant advantage for Ligand B.

**BBB:** Both ligands have good BBB penetration (Ligand A: 74.486%, Ligand B: 62.233%). Ligand A is better, but both are reasonably good for a CNS target.

**Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and suggests poor permeability. However, the scale is not specified, so it's difficult to interpret.

**Aqueous Solubility:** Both have negative solubility values, also unusual. Again, the scale is unspecified.

**hERG Inhibition:** Both ligands show low hERG inhibition liability (Ligand A: 0.578, Ligand B: 0.185). Ligand B is better.

**Microsomal Clearance:** Ligand A has a higher microsomal clearance (20.782 mL/min/kg) than Ligand B (-2.274 mL/min/kg). This suggests Ligand B is more metabolically stable.

**In vitro Half-Life:** Ligand B has a longer in vitro half-life (21.726 hours) than Ligand A (-25.346 hours). This is a significant advantage for Ligand B.

**P-gp Efflux:** Ligand A has a P-gp efflux liability of 0.062, while Ligand B has a very low value of 0.053. Both are good.

**Binding Affinity:** Ligand A has a significantly better binding affinity (-6.9 kcal/mol) than Ligand B (-0.0 kcal/mol). This is a *major* advantage for Ligand A. A difference of 6.9 kcal/mol is substantial and can often outweigh other ADME concerns.

**Overall Assessment:**

While Ligand B has better ADME properties (lower DILI, better metabolic stability, longer half-life, slightly better TPSA), Ligand A's *much* stronger binding affinity (-6.9 vs -0.0 kcal/mol) is a decisive factor. For a GPCR target, potency is paramount. The ADME issues with Ligand A, while not ideal, might be addressable through further optimization, but the affinity of Ligand B is simply too low to be competitive.

Output:
1
2025-04-17 04:36:16,861 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (359.367 and 364.446 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (39.5) is excellent, well below the 90 A^2 threshold for CNS targets. Ligand B (81.34) is higher, but still potentially acceptable, though less ideal.

**3. logP:** Both ligands have a logP around 2.9, which is optimal (1-3).

**4. H-Bond Donors:** Ligand A (0) is preferable to Ligand B (1). Fewer HBDs generally improve permeability.

**5. H-Bond Acceptors:** Ligand A (4) is better than Ligand B (6). Lower HBA counts are generally preferred for CNS penetration.

**6. QED:** Both ligands have good QED scores (0.702 and 0.817), indicating good drug-like properties.

**7. DILI:** Ligand A (15.898) has a significantly lower DILI risk than Ligand B (56.689). This is a major advantage.

**8. BBB:** Ligand A (93.292) has a much higher BBB penetration percentile than Ligand B (85.459). This is critical for a CNS target like DRD2.

**9. Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and suggests a potential issue with the data or modeling. However, the values are similar (-4.287 vs -4.598).

**10. Aqueous Solubility:** Both have negative solubility values, which is also concerning. Ligand B is slightly worse (-4.165 vs -2.37).

**11. hERG Inhibition:** Ligand A (0.981) shows a slightly higher risk of hERG inhibition than Ligand B (0.691), but both are reasonably low.

**12. Microsomal Clearance:** Ligand A (12.756) has a lower microsomal clearance, suggesting better metabolic stability than Ligand B (51.558).

**13. In vitro Half-Life:** Ligand A (-10.696) has a longer in vitro half-life than Ligand B (-18.276), which is a positive attribute.

**14. P-gp Efflux:** Ligand A (0.247) has lower P-gp efflux liability than Ligand B (0.142), meaning it's less likely to be pumped out of the brain.

**15. Binding Affinity:** Ligand A (-7.3 kcal/mol) has slightly better binding affinity than Ligand B (-6.8 kcal/mol). While the difference isn't huge, it's enough to be considered.

**Overall Assessment:**

Ligand A is significantly better than Ligand B. It excels in crucial areas for a CNS-targeting GPCR ligand: BBB penetration, DILI risk, metabolic stability (lower Cl_mic and longer t1/2), and P-gp efflux. While both have issues with predicted solubility and Caco-2 permeability, Ligand A's superior ADME properties and slightly better affinity make it the more promising candidate.

Output:
1
2025-04-17 04:36:16,861 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (361.833 and 360.369 Da) are within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (79.6) is better than Ligand B (58.2). For CNS targets, we want TPSA <= 90, and both meet this criterion, but A is closer to the upper limit.

**3. logP:** Ligand A (2.278) is optimal (1-3). Ligand B (4.46) is higher, potentially leading to solubility issues and off-target effects.

**4. H-Bond Donors:** Ligand A (1) and Ligand B (2) are both acceptable (<=5).

**5. H-Bond Acceptors:** Ligand A (5) and Ligand B (2) are both acceptable (<=10).

**6. QED:** Ligand A (0.909) is excellent, indicating high drug-likeness. Ligand B (0.747) is still good, but not as strong.

**7. DILI:** Both ligands have similar DILI risk (60.372 and 61.07), placing them in a moderate risk category. This isn't a major differentiator.

**8. BBB:** Ligand A (86.817) has significantly better BBB penetration than Ligand B (67.701). This is *crucial* for a CNS target like DRD2.

**9. Caco-2 Permeability:** Ligand A (-5.005) and Ligand B (-4.794) are both poor, indicating low intestinal absorption. This is less critical for a CNS drug, as BBB penetration is more important.

**10. Aqueous Solubility:** Ligand A (-2.97) and Ligand B (-4.286) are both poor, but Ligand B is worse.

**11. hERG Inhibition:** Ligand A (0.511) has a lower hERG risk than Ligand B (0.766), which is preferable.

**12. Microsomal Clearance:** Ligand A (22.756) has lower clearance than Ligand B (42.777), suggesting better metabolic stability.

**13. In vitro Half-Life:** Ligand A (-5.088) has a shorter half-life than Ligand B (48.448). This is a drawback for Ligand A.

**14. P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.155 and 0.248), which is good for CNS penetration.

**15. Binding Affinity:** Ligand B (-9.8) has a slightly better binding affinity than Ligand A (-9.0). However, the difference is not substantial enough to overcome the other significant advantages of Ligand A.

**Overall Assessment:**

Ligand A is the more promising candidate. While Ligand B has slightly better affinity and half-life, Ligand A excels in critical areas for a CNS-targeting GPCR: significantly better BBB penetration, a more optimal logP, better solubility, lower hERG risk, and better metabolic stability. The QED score is also superior for Ligand A. The lower half-life of Ligand A could potentially be addressed through structural modifications.

Output:
1
2025-04-17 04:36:16,861 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (362.411 and 362.392 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (106.39) is higher than the preferred <90 for CNS targets, while Ligand B (49.85) is well within the range. This is a significant advantage for Ligand B.

**3. logP:** Ligand A (4.362) is slightly high, potentially leading to solubility issues or off-target effects. Ligand B (2.062) is optimal.

**4. H-Bond Donors:** Ligand A (2) is acceptable, while Ligand B (0) is also good.

**5. H-Bond Acceptors:** Ligand A (6) is acceptable, and Ligand B (3) is also good.

**6. QED:** Both ligands have good QED scores (0.586 and 0.772), indicating drug-like properties. Ligand B is slightly better.

**7. DILI:** Ligand A (94.804) has a high DILI risk, which is concerning. Ligand B (20.473) has a very low DILI risk, a major advantage.

**8. BBB:** Ligand A (63.746) has a moderate BBB penetration, while Ligand B (88.872) has excellent BBB penetration, crucial for a CNS target like DRD2.

**9. Caco-2:** Both have negative Caco-2 values, which is unusual and requires further investigation. However, the magnitude is similar, so this isn't a major differentiator.

**10. Solubility:** Both have negative solubility values, also unusual. Again, the magnitude is similar.

**11. hERG:** Ligand A (0.247) has a slightly higher hERG risk than Ligand B (0.581), although both are relatively low.

**12. Cl_mic:** Ligand A (77.721) has a higher microsomal clearance, indicating lower metabolic stability, compared to Ligand B (22.039).

**13. t1/2:** Ligand A (19.794) has a shorter in vitro half-life than Ligand B (-16.858 - note the negative value suggests a very rapid clearance or an issue with the assay).

**14. Pgp:** Ligand A (0.289) has lower P-gp efflux, which is favorable for CNS penetration, compared to Ligand B (0.073), which is even better.

**15. Binding Affinity:** Ligand A (-9.3 kcal/mol) has a significantly stronger binding affinity than Ligand B (-7.9 kcal/mol). This is a substantial advantage for Ligand A.

**Overall Assessment:**

While Ligand A boasts a superior binding affinity, its high DILI risk, higher logP, moderate BBB penetration, and lower metabolic stability are significant drawbacks. Ligand B, despite a slightly weaker affinity, presents a much more favorable ADME-Tox profile, particularly its excellent BBB penetration, low DILI risk, and better metabolic stability. For a CNS GPCR target like DRD2, a good ADME profile and CNS penetration are paramount. The 1.4 kcal/mol difference in binding affinity, while noticeable, can potentially be overcome with further optimization of Ligand B.

Output:
1
2025-04-17 04:36:16,862 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (348.403 and 368.371 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (113.44) is slightly above the optimal <90 for CNS targets, but still reasonable. Ligand B (58.64) is excellent, well below 90.

**logP:** Ligand A (-0.05) is a bit low, potentially hindering permeability. Ligand B (2.201) is within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A has 3 HBD and 6 HBA, acceptable values. Ligand B has 1 HBD and 3 HBA, also good.

**QED:** Both ligands have good QED scores (0.664 and 0.732), indicating drug-like properties.

**DILI:** Ligand A (42.652) has a slightly higher DILI risk than Ligand B (29.779), but both are below the concerning threshold of 60.

**BBB:** This is crucial for a CNS target. Ligand A (45.599) has a moderate BBB penetration, while Ligand B (91.508) is excellent, exceeding the desirable >70 threshold.

**Caco-2 Permeability:** Ligand A (-5.031) shows poor permeability. Ligand B (-4.48) is also poor, but slightly better than Ligand A.

**Aqueous Solubility:** Both ligands have negative solubility values (-1.762 and -2.481), indicating very poor aqueous solubility, which is a significant drawback.

**hERG Inhibition:** Ligand A (0.082) has very low hERG risk, a positive attribute. Ligand B (0.557) has a slightly higher, but still acceptable, hERG risk.

**Microsomal Clearance:** Ligand A (6.126) has lower clearance, suggesting better metabolic stability than Ligand B (21.361).

**In vitro Half-Life:** Ligand A (21.246) has a reasonable half-life. Ligand B (-21.391) has a negative half-life, which is not possible and likely represents an outlier or error in the data.

**P-gp Efflux:** Ligand A (0.008) has very low P-gp efflux, which is favorable for CNS penetration. Ligand B (0.057) also has low P-gp efflux.

**Binding Affinity:** Both ligands have strong binding affinities (-8.3 and -9.0 kcal/mol). Ligand B is slightly better (-9.0 kcal/mol).

**Overall Assessment:**

Ligand B clearly stands out due to its excellent BBB penetration (91.508), optimal logP (2.201), and slightly better binding affinity (-9.0 kcal/mol). While its solubility and Caco-2 permeability are poor, the strong BBB penetration can partially compensate for these issues for a CNS target. The negative half-life for Ligand B is a major concern and suggests a data error. However, even ignoring that, Ligand A's low logP and poor Caco-2 permeability are significant weaknesses. The slightly better metabolic stability of Ligand A is outweighed by the superior CNS penetration of Ligand B.

Output:
1
2025-04-17 04:36:16,862 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (354.491 and 349.475 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Both ligands have TPSA values (87.66 and 82.53) below the 140 A^2 threshold for good oral absorption, and reasonably close to the 90 A^2 target for CNS penetration. Ligand B is slightly better here.

**3. logP:** Both ligands have logP values (1.611 and 2.223) within the optimal 1-3 range.

**4. H-Bond Donors:** Ligand A has 3 HBD, and Ligand B has 2. Both are acceptable (<=5).

**5. H-Bond Acceptors:** Both ligands have 4 HBA, well within the acceptable limit of <=10.

**6. QED:** Both ligands have QED values (0.618 and 0.716) above 0.5, indicating good drug-likeness. Ligand B is slightly better.

**7. DILI:** Ligand A has a DILI risk of 8.026%, while Ligand B has 23.187%. Ligand A is significantly better regarding liver toxicity risk.

**8. BBB:** This is a crucial parameter for a CNS target like DRD2. Ligand A has a BBB penetration percentile of 61.535%, while Ligand B is at 40.364%. Ligand A is considerably better at predicted BBB penetration.

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.638 and -4.73), which is unusual and suggests poor permeability. This is a concern for both.

**10. Aqueous Solubility:** Both ligands have negative solubility values (-1.76 and -1.809), indicating very poor aqueous solubility. This is a significant drawback for both.

**11. hERG Inhibition:** Both ligands have low hERG inhibition liability (0.285 and 0.415), which is good.

**12. Microsomal Clearance:** Ligand A (40.814 mL/min/kg) has higher clearance than Ligand B (29.634 mL/min/kg), indicating lower metabolic stability. Ligand B is better here.

**13. In vitro Half-Life:** Ligand B has a significantly longer in vitro half-life (25.555 hours) compared to Ligand A (-0.182 hours). This is a major advantage for Ligand B.

**14. P-gp Efflux:** Both ligands show very low P-gp efflux liability (0.027 and 0.062). This is favorable for CNS exposure.

**15. Binding Affinity:** Both ligands have the same binding affinity (-7.4 kcal/mol), which is excellent.

**Overall Assessment:**

While both ligands have good binding affinity, Ligand A is superior due to its significantly better predicted BBB penetration (61.535% vs 40.364%) and lower DILI risk (8.026% vs 23.187%). The lower metabolic stability and half-life of Ligand A are concerns, but the BBB penetration is paramount for a CNS target. The poor solubility and Caco-2 permeability are drawbacks for both, but these can potentially be addressed with formulation strategies.

Output:
0
2025-04-17 04:36:16,862 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the acceptable range (200-500 Da). Ligand A (340.39) is slightly preferred as it's closer to the ideal range.

**TPSA:** Ligand A (98.73) is better than Ligand B (66.91). Both are below the 140 A^2 threshold for oral absorption and reasonably good for CNS penetration, but Ligand A is slightly higher and may present a minor disadvantage for CNS entry.

**logP:** Ligand A (2.322) is optimal (1-3), while Ligand B (4.436) is higher.  A logP > 4 can lead to solubility issues and off-target effects, making Ligand A more favorable.

**H-Bond Donors/Acceptors:** Ligand A (HBD=1, HBA=7) and Ligand B (HBD=2, HBA=5) both fall within acceptable limits.

**QED:** Ligand A (0.782) has a better QED score than Ligand B (0.621), indicating a more drug-like profile.

**DILI:** Both ligands have acceptable DILI risk (Ligand A: 72.12, Ligand B: 65.49), below the concerning threshold of 60.

**BBB:** Ligand B (76.27) has a significantly better BBB penetration percentile than Ligand A (41.22). This is a *critical* advantage for a CNS target like DRD2.

**Caco-2 Permeability:** Both have negative values, which is unusual and likely indicates a scaling issue in the data. It's hard to interpret these values directly.

**Aqueous Solubility:** Both have negative values, indicating poor solubility. This is a concern for both, but could be mitigated with formulation strategies.

**hERG Inhibition:** Ligand A (0.258) has a lower hERG inhibition risk than Ligand B (0.548), which is preferable.

**Microsomal Clearance:** Ligand A (39.90) has a lower microsomal clearance than Ligand B (48.75), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand B (49.43) has a significantly longer in vitro half-life than Ligand A (-5.85). This is a substantial advantage.

**P-gp Efflux:** Ligand A (0.034) has much lower P-gp efflux liability than Ligand B (0.29), which is crucial for CNS exposure.

**Binding Affinity:** Ligand B (-9.4 kcal/mol) has a significantly stronger binding affinity than Ligand A (-8.0 kcal/mol). This is a major advantage, potentially outweighing some of the ADME drawbacks.  The difference of >1.5 kcal/mol is substantial.

**Overall Assessment:**

Ligand B excels in BBB penetration and binding affinity, two of the most important factors for a CNS GPCR target. Its longer half-life is also a significant benefit. While it has a higher logP and P-gp efflux, the strong binding affinity and favorable BBB penetration are likely to compensate. Ligand A has better solubility and lower hERG risk, but its weaker affinity and poor BBB penetration are significant drawbacks.

Output:
1
2025-04-17 04:36:16,862 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (389.323 and 346.515 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (58.64) is slightly above the optimal <90 for CNS targets, but still reasonable. Ligand B (40.62) is excellent, well below 90.

**3. logP:** Both ligands have good logP values (3.149 and 3.907), falling within the 1-3 range.

**4. H-Bond Donors:** Ligand A has 1 HBD, while Ligand B has 0. Both are acceptable (<=5).

**5. H-Bond Acceptors:** Ligand A has 3 HBA, and Ligand B has 2. Both are within the acceptable range (<=10).

**6. QED:** Both ligands have acceptable QED scores (0.759 and 0.684), indicating good drug-like properties.

**7. DILI:** Both ligands have low DILI risk (27.336 and 20.396 percentiles), which is favorable.

**8. BBB:** Both ligands have excellent BBB penetration (78.286 and 81.233 percentiles), crucial for a CNS target like DRD2. Ligand B is slightly better.

**9. Caco-2 Permeability:** Both have negative Caco-2 values (-4.952 and -4.737), which is unusual and suggests poor permeability. This is a significant concern for both.

**10. Aqueous Solubility:** Both have negative solubility values (-3.393 and -3.158), indicating very poor aqueous solubility. This is a major drawback for both compounds.

**11. hERG Inhibition:** Both ligands have low hERG inhibition risk (0.405 and 0.481 percentiles).

**12. Microsomal Clearance:** Ligand A (27.746) has lower microsomal clearance than Ligand B (62.082), suggesting better metabolic stability.

**13. In vitro Half-Life:** Ligand A (19.319 hours) has a longer half-life than Ligand B (-8.13 hours). The negative value for Ligand B is concerning and likely an error, suggesting very rapid degradation.

**14. P-gp Efflux:** Both ligands have low P-gp efflux liability (0.211 and 0.504 percentiles), which is good for CNS exposure.

**15. Binding Affinity:** Both ligands have strong binding affinities (-8.0 and -7.7 kcal/mol). Ligand A has a slightly better affinity.

**Overall Assessment:**

Both compounds have significant issues with solubility and Caco-2 permeability. However, considering the GPCR-specific priorities, Ligand A is slightly more favorable. It has a better binding affinity, lower microsomal clearance, and longer half-life. While both have poor solubility and permeability, the slightly better ADME profile of Ligand A, combined with its superior binding, makes it a marginally better candidate. The negative half-life for Ligand B is a major red flag.

Output:
1
2025-04-17 04:36:16,862 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (344.459 Da and 334.463 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (68.18) is better than Ligand B (41.13), both are below the 90 A^2 threshold for CNS targets.

**logP:** Ligand A (3.469) is within the optimal 1-3 range, while Ligand B (4.799) is slightly higher. While still potentially acceptable, higher logP can lead to off-target effects and solubility issues.

**H-Bond Donors/Acceptors:** Both have 2 HBD, which is good. Ligand A has 4 HBA, and Ligand B has 1 HBA. Both are within acceptable limits (<=10).

**QED:** Both ligands have similar QED values (0.879 and 0.828), indicating good drug-likeness.

**DILI:** Both have relatively low DILI risk (45.25 and 43.932), which is favorable.

**BBB:** Ligand B (90.035) has a significantly better BBB penetration percentile than Ligand A (76.192). This is a critical advantage for a CNS target like DRD2.

**Caco-2 Permeability:** Ligand A (-4.877) and Ligand B (-4.492) are both negative, indicating low permeability. However, the scale is not clearly defined, so it is hard to interpret.

**Aqueous Solubility:** Ligand A (-4.488) and Ligand B (-5.839) are both negative, indicating low solubility.

**hERG Inhibition:** Ligand A (0.576) has a slightly lower hERG inhibition risk than Ligand B (0.851), which is preferable.

**Microsomal Clearance:** Ligand B (54.98) has a lower microsomal clearance than Ligand A (49.873), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand B (43.539) has a longer in vitro half-life than Ligand A (38.205), which is a positive attribute.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.121 and 0.377), which is excellent for CNS penetration.

**Binding Affinity:** Ligand B (-10.1 kcal/mol) has a significantly stronger binding affinity than Ligand A (-9.0 kcal/mol). This is a substantial advantage, potentially outweighing some of the minor ADME drawbacks of Ligand B.

**Overall Assessment:**

Ligand B is the more promising candidate. While Ligand A has a slightly better TPSA and hERG profile, Ligand B excels in the most crucial areas for a CNS-targeting GPCR ligand: BBB penetration and binding affinity. The stronger binding affinity of Ligand B (-10.1 kcal/mol vs -9.0 kcal/mol) is a significant advantage. The slightly higher logP of Ligand B is a minor concern, but the improved BBB and affinity are more important for this target.

Output:
1
2025-04-17 04:36:16,863 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (411.246 Da) is slightly higher than Ligand B (356.394 Da), but both are acceptable.

**TPSA:** Ligand A (52.57) is excellent for CNS penetration, well below the 90 A^2 threshold. Ligand B (92.01) is higher, but still potentially acceptable, though less ideal.

**logP:** Ligand A (3.809) is within the optimal range (1-3). Ligand B (0.665) is quite low, potentially hindering membrane permeability and CNS entry.

**H-Bond Donors/Acceptors:** Both have 2 HBDs, which is good. Ligand A has 3 HBAs, and Ligand B has 5. Both are within the acceptable limit of 10.

**QED:** Both ligands have similar QED values (0.805 and 0.749), indicating good drug-likeness.

**DILI:** Ligand A (69.794) has a higher DILI risk than Ligand B (35.595). This is a negative for Ligand A.

**BBB:** Ligand A (69.717) has a better BBB percentile than Ligand B (64.831), but both are reasonably good, though ideally >70 for a CNS target.

**Caco-2 Permeability:** Both have negative Caco-2 values (-4.884 and -4.895), which is unusual and suggests poor permeability. This is concerning for both.

**Aqueous Solubility:** Both have negative solubility values (-4.445 and -1.384), indicating poor aqueous solubility. This is a significant drawback for both compounds.

**hERG Inhibition:** Ligand A (0.887) has a slightly higher hERG risk than Ligand B (0.24).

**Microsomal Clearance:** Ligand B (5.048) has a lower microsomal clearance than Ligand A (25.223), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (4.563) has a longer half-life than Ligand B (2.1).

**P-gp Efflux:** Ligand A (0.583) has lower P-gp efflux than Ligand B (0.027), which is favorable for CNS penetration.

**Binding Affinity:** Ligand A (-9.8 kcal/mol) has a significantly stronger binding affinity than Ligand B (-7.2 kcal/mol). This is a substantial advantage for Ligand A, potentially outweighing some of its ADME drawbacks.

**Overall Assessment:**

Despite Ligand A's higher DILI risk, its superior binding affinity (-9.8 vs -7.2 kcal/mol), better BBB penetration, lower P-gp efflux, and longer half-life make it the more promising candidate. The difference in binding affinity is substantial (>1.5 kcal/mol). While both have poor solubility and permeability, the stronger binding of Ligand A suggests it might still achieve sufficient target engagement *in vivo*. The lower logP of Ligand B is a significant concern for CNS penetration.

Output:
1
2025-04-17 04:36:16,863 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (346.431 and 344.415 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (95.32) is better than Ligand B (98.22). Both are below the 140 A^2 threshold for oral absorption and reasonably close to the 90 A^2 target for CNS penetration, but A is preferable.

**logP:** Both ligands have good logP values (1.771 and 1.444), falling within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A (HBD=1, HBA=5) is slightly better than Ligand B (HBD=2, HBA=4) in terms of balancing solubility and permeability.

**QED:** Both ligands have acceptable QED values (0.812 and 0.763), indicating good drug-likeness.

**DILI:** Both ligands have the same DILI risk (43.66 percentile), which is good (low risk).

**BBB:** Ligand B (56.029) has a significantly better BBB penetration percentile than Ligand A (36.448). This is a *critical* advantage for a CNS target like DRD2.

**Caco-2 Permeability:** Ligand A (-4.542) has better Caco-2 permeability than Ligand B (-4.781), suggesting better intestinal absorption.

**Aqueous Solubility:** Ligand A (-2.172) has better aqueous solubility than Ligand B (-3.907).

**hERG Inhibition:** Both ligands have low hERG inhibition liability (0.402 and 0.333).

**Microsomal Clearance:** Ligand B (-11.523) has significantly lower microsomal clearance than Ligand A (49.368), indicating better metabolic stability. This is a substantial advantage.

**In vitro Half-Life:** Ligand B (12.912 hours) has a much longer in vitro half-life than Ligand A (-3.048 hours). This is a major advantage, potentially leading to less frequent dosing.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.034 and 0.102).

**Binding Affinity:** Ligand B (-7.9 kcal/mol) has a slightly better binding affinity than Ligand A (-7.6 kcal/mol). While the difference is not huge, it's still a positive factor.

**Overall Assessment:**

Ligand B is the stronger candidate. While Ligand A has slightly better TPSA, Caco-2 permeability, and solubility, Ligand B excels in the most important areas for a CNS GPCR target: BBB penetration, metabolic stability (lower Cl_mic, longer t1/2), and binding affinity. The improved BBB penetration and metabolic stability are particularly crucial for CNS drug development. The slightly better affinity further supports this conclusion.

Output:
1
2025-04-17 04:36:16,863 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (354.475 Da) is slightly lower, which could be favorable for permeability.

**TPSA:** Ligand A (51.96) is better than Ligand B (58.64). Both are reasonably good for CNS penetration, but A is closer to the preferred <90 cutoff for CNS targets.

**logP:** Ligand A (4.08) is slightly higher than the optimal range (1-3), but still acceptable. Ligand B (2.976) is within the optimal range. Higher logP can sometimes lead to off-target effects, but is less concerning than poor solubility.

**H-Bond Donors/Acceptors:** Ligand A (0 HBD, 4 HBA) and Ligand B (1 HBD, 4 HBA) both have acceptable counts, well within the guidelines.

**QED:** Both ligands have reasonable QED scores (A: 0.709, B: 0.634), indicating good drug-like properties.

**DILI:** Ligand A (80.923) has a higher DILI risk than Ligand B (26.173). This is a significant drawback for Ligand A.

**BBB:** Ligand B (77.705) has a significantly better BBB penetration score than Ligand A (60.566). This is crucial for a CNS target like DRD2.

**Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and suggests a potential issue with the prediction method, or a very poor permeability. However, the negative values are very close, so this isn't a major differentiator.

**Aqueous Solubility:** Both ligands have negative solubility values, again suggesting issues with the prediction method.

**hERG:** Both ligands have low hERG inhibition liability (A: 0.479, B: 0.581), which is good.

**Microsomal Clearance:** Ligand B (79.271) has a higher microsomal clearance than Ligand A (27.207), indicating faster metabolism and potentially lower *in vivo* exposure.

**In vitro Half-Life:** Ligand A (59.679) has a much longer half-life than Ligand B (-9.497). This is a significant advantage for Ligand A.

**P-gp Efflux:** Ligand A (0.59) has lower P-gp efflux liability than Ligand B (0.301), which is favorable for CNS penetration.

**Binding Affinity:** Ligand B (-7.0 kcal/mol) has a slightly better binding affinity than Ligand A (-10.2 kcal/mol). However, the difference is not substantial enough to outweigh other factors.

**Overall Assessment:**

Ligand B is the stronger candidate. While Ligand A has a longer half-life and lower P-gp efflux, Ligand B's significantly better BBB penetration and much lower DILI risk are critical advantages for a CNS-targeting drug. The slightly better affinity of Ligand B is also a plus. The negative solubility and Caco-2 values are concerning for both, but the other factors heavily favor Ligand B.

Output:
1
2025-04-17 04:36:16,863 - INFO - Batch 127 complete. Total preferences: 2032
2025-04-17 04:36:16,863 - INFO - Processing batch 128/512...
2025-04-17 04:36:58,285 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (381.837 Da) is slightly higher than Ligand B (354.401 Da), but both are acceptable.

**TPSA:** Both ligands have TPSA values below the 90 A^2 threshold desirable for CNS targets. Ligand A (81.7 A^2) is slightly higher than Ligand B (76.02 A^2), but both are good.

**logP:** Both ligands have logP values within the optimal range (1-3). Ligand A (3.311) is at the higher end, while Ligand B (2.649) is closer to the middle. This is a slight advantage for B.

**H-Bond Donors/Acceptors:** Ligand A has 1 HBD and 5 HBA, while Ligand B has 2 HBD and 4 HBA. Both are within acceptable limits (<=5 HBD and <=10 HBA).

**QED:** Both ligands have QED values above 0.5, indicating good drug-like properties (A: 0.803, B: 0.705).

**DILI:** Ligand A has a higher DILI risk (85.925%) than Ligand B (52.85%). This is a significant negative for Ligand A.

**BBB:** Ligand B has a significantly better BBB penetration score (85.498%) than Ligand A (53.587%). This is a crucial advantage for a CNS target like DRD2.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values, which is unusual and suggests poor permeability. However, the scale isn't specified, so it's difficult to interpret.

**Aqueous Solubility:** Both ligands have negative solubility values, suggesting poor solubility. Again, the scale is unspecified.

**hERG:** Both ligands have low hERG inhibition liability (A: 0.272, B: 0.241), which is positive.

**Microsomal Clearance:** Ligand B has a slightly lower microsomal clearance (35.514 mL/min/kg) than Ligand A (29.837 mL/min/kg), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand B has a negative half-life (-1.328 hours), which is problematic. Ligand A has a half-life of 8.068 hours, which is much better.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (A: 0.472, B: 0.145), which is favorable for CNS penetration. Ligand B is better.

**Binding Affinity:** Ligand B has a significantly stronger binding affinity (-8.4 kcal/mol) than Ligand A (-10.0 kcal/mol). This is a major advantage for Ligand B.

**Overall Assessment:**

Ligand B is clearly the better candidate. While its in vitro half-life is concerning, its superior BBB penetration, lower DILI risk, and significantly stronger binding affinity outweigh the drawbacks. The better logP and P-gp efflux also contribute to its favorability for CNS targeting. Ligand A's high DILI risk and lower BBB penetration are significant concerns.

Output:
1
2025-04-17 04:36:58,286 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (359.37 & 350.50 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (39.5) is significantly better than Ligand B (69.64). For CNS targets, we want TPSA <= 90, and ideally closer to 60. Ligand A is much closer to this ideal.

**3. logP:** Both ligands have good logP values (2.89 & 2.33), falling within the optimal 1-3 range.

**4. H-Bond Donors:** Ligand A (0) is preferable to Ligand B (2). Fewer HBDs generally improve permeability.

**5. H-Bond Acceptors:** Ligand A (4) is slightly better than Ligand B (3), both are acceptable.

**6. QED:** Both ligands have similar and good QED values (0.70 & 0.74), indicating good drug-like properties.

**7. DILI:** Ligand A (15.9%) has a much lower DILI risk than Ligand B (6.6%). Both are good, but A is better.

**8. BBB:** This is critical for a CNS target like DRD2. Ligand A (93.3%) is excellent, exceeding the desirable >70% threshold. Ligand B (62.2%) is significantly lower and less promising for CNS penetration.

**9. Caco-2 Permeability:** Both have negative values, which is unusual and suggests an issue with the data or model. However, the magnitude is similar.

**10. Aqueous Solubility:** Both have negative values, again suggesting a data/model issue. Similar magnitudes.

**11. hERG Inhibition:** Ligand A (0.98) is better than Ligand B (0.36), indicating lower cardiotoxicity risk.

**12. Microsomal Clearance:** Ligand A (12.76) is much better than Ligand B (45.98). Lower clearance indicates better metabolic stability.

**13. In vitro Half-Life:** Ligand A (-10.70) is better than Ligand B (-5.67). A more negative value indicates a longer half-life.

**14. P-gp Efflux:** Ligand A (0.25) is significantly better than Ligand B (0.06). Lower P-gp efflux is crucial for CNS exposure.

**15. Binding Affinity:** Ligand B (-8.4 kcal/mol) has a slightly better binding affinity than Ligand A (-7.3 kcal/mol). While affinity is important, the difference of 1.1 kcal/mol is not substantial enough to outweigh the significant advantages of Ligand A in ADME properties, especially BBB penetration.

**Overall Assessment:**

Ligand A is the superior candidate. It excels in critical GPCR-specific properties like BBB penetration, P-gp efflux, and metabolic stability. While Ligand B has slightly better binding affinity, Ligand A's superior ADME profile, particularly its high BBB value, makes it far more likely to be a viable drug candidate for a CNS target like DRD2.

Output:
1
2025-04-17 04:36:58,286 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (352.435 and 345.487 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (109.74) is better than Ligand B (73.99). For CNS targets, TPSA < 90 is preferred. Ligand B is well within this range, while Ligand A is slightly above, but not critically so.

**3. logP:** Ligand A (1.202) is optimal (1-3), while Ligand B (3.687) is pushing the upper limit. Higher logP can lead to off-target effects and solubility issues.

**4. H-Bond Donors:** Ligand A (1) is better than Ligand B (3). Fewer HBDs generally improve permeability.

**5. H-Bond Acceptors:** Ligand A (5) is better than Ligand B (2). Fewer HBAs generally improve permeability.

**6. QED:** Ligand A (0.718) is better than Ligand B (0.597), indicating a more drug-like profile.

**7. DILI:** Ligand A (27.879) has a significantly lower DILI risk than Ligand B (41.76). Both are below the 60% threshold, but A is preferable.

**8. BBB:** Ligand A (72.896) has a better BBB penetration percentile than Ligand B (63.862). Both are reasonably good, but for a CNS target like DRD2, higher is better.

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.16 and -5.069), which is unusual and suggests poor permeability. This is a significant concern for both.

**10. Aqueous Solubility:** Both ligands have negative solubility values (-1.444 and -4.226), indicating very poor aqueous solubility. This is a major drawback for both.

**11. hERG Inhibition:** Ligand A (0.172) has a much lower hERG inhibition risk than Ligand B (0.722). This is a critical advantage for Ligand A.

**12. Microsomal Clearance:** Ligand A (36.075) has lower microsomal clearance than Ligand B (62.427), suggesting better metabolic stability.

**13. In vitro Half-Life:** Ligand B (9.41) has a slightly longer half-life than Ligand A (8.46), but the difference is not substantial.

**14. P-gp Efflux:** Ligand A (0.052) has significantly lower P-gp efflux liability than Ligand B (0.507), which is crucial for CNS penetration.

**15. Binding Affinity:** Ligand B (-8.7 kcal/mol) has a stronger binding affinity than Ligand A (-7.0 kcal/mol). This is a substantial advantage for Ligand B.

**Overall Assessment:**

Despite the stronger binding affinity of Ligand B, Ligand A is the more promising candidate. The key advantages of Ligand A are its significantly better ADME properties: lower DILI risk, better BBB penetration, lower hERG inhibition, lower P-gp efflux, and better metabolic stability. While both have poor Caco-2 permeability and solubility, the ADME profile of Ligand A is far superior, making it more likely to succeed as a drug candidate. The 1.7 kcal/mol difference in binding affinity, while significant, can potentially be overcome with further optimization, whereas fixing the severe ADME liabilities of Ligand B would be much more challenging.

Output:
0
2025-04-17 04:36:58,286 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (364.467 Da) is slightly better than Ligand B (403.555 Da) as it's closer to the lower end, potentially aiding permeability.

**TPSA:** Both ligands have TPSA values (82.63 and 87.54 respectively) that are acceptable for oral absorption (<140), but higher than ideal for CNS penetration (<90). This is a potential concern for both, but not a dealbreaker.

**logP:** Ligand A (3.065) is within the optimal range (1-3). Ligand B (-0.375) is significantly below this, which is a major drawback. Low logP can severely hinder membrane permeability and CNS penetration.

**H-Bond Donors/Acceptors:** Ligand A (2 HBD, 5 HBA) and Ligand B (1 HBD, 8 HBA) both fall within acceptable ranges.

**QED:** Both ligands have similar QED values (0.74 and 0.736), indicating good drug-like properties.

**DILI:** Ligand B (74.68) has a higher DILI risk than Ligand A (56.146). While both are above the preferred <40, Ligand A is considerably better.

**BBB:** Both ligands have low BBB penetration (30.283 and 31.756 respectively). This is a significant issue for a CNS target like DRD2, but not insurmountable if other properties are strong.

**Caco-2 Permeability:** Both ligands show poor Caco-2 permeability (-5.072 and -5.529). This suggests poor intestinal absorption, which could limit oral bioavailability.

**Aqueous Solubility:** Both ligands have very poor aqueous solubility (-2.762 and -3.191). This is a formulation challenge.

**hERG Inhibition:** Ligand A (0.48) has a slightly better hERG profile than Ligand B (0.079), indicating lower cardiotoxicity risk.

**Microsomal Clearance:** Ligand A (68.171) has higher microsomal clearance than Ligand B (42.913), suggesting lower metabolic stability.

**In vitro Half-Life:** Ligand B (1.05 hours) has a very short half-life, while Ligand A (-10.328 hours) is better, although still not ideal.

**P-gp Efflux:** Ligand A (0.226) has lower P-gp efflux than Ligand B (0.03), which is favorable for CNS exposure.

**Binding Affinity:** Ligand A (-8.0 kcal/mol) has a significantly stronger binding affinity than Ligand B (-6.9 kcal/mol). This 1.1 kcal/mol difference is substantial and can outweigh some ADME drawbacks.

**Overall Assessment:**

Ligand A is the superior candidate. While both have issues with BBB penetration and solubility, Ligand A's significantly better logP, binding affinity, DILI risk, P-gp efflux, and in vitro half-life outweigh its slightly higher clearance. Ligand B's very low logP is a critical flaw, severely impacting its potential for CNS penetration and overall bioavailability. The stronger binding affinity of Ligand A also provides a significant advantage.

Output:
1
2025-04-17 04:36:58,286 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (347.419 and 346.479 Da) fall comfortably within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (89.35) is slightly higher than Ligand B (83.99), but both are below the 90 A^2 threshold desirable for CNS targets.

**3. logP:** Ligand A (0.71) is a bit low, potentially hindering permeability. Ligand B (2.885) is within the optimal 1-3 range. This is a significant advantage for Ligand B.

**4. H-Bond Donors:** Ligand A (1) is better than Ligand B (3), as fewer HBDs generally improve permeability.

**5. H-Bond Acceptors:** Ligand A (6) is better than Ligand B (7).

**6. QED:** Both ligands have reasonable QED values (0.866 and 0.7), indicating good drug-like properties.

**7. DILI:** Ligand A (47.926) has a lower DILI risk than Ligand B (55.525), which is preferable.

**8. BBB:** Both ligands have good BBB penetration (73.517 and 78.674), exceeding the 70% threshold for CNS targets. Ligand B is slightly better.

**9. Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual. It's difficult to interpret without knowing the scale, but it suggests poor permeability.

**10. Aqueous Solubility:** Both have negative solubility values, also unusual. Again, difficult to interpret without knowing the scale, but suggests poor solubility.

**11. hERG Inhibition:** Ligand A (0.099) shows a much lower hERG inhibition liability than Ligand B (0.671). This is a critical advantage for Ligand A.

**12. Microsomal Clearance:** Ligand A (30.776) has a lower microsomal clearance than Ligand B (66.062), indicating better metabolic stability.

**13. In vitro Half-Life:** Ligand B (32.535) has a significantly longer in vitro half-life than Ligand A (5.379). This is a positive for Ligand B.

**14. P-gp Efflux:** Ligand A (0.032) has much lower P-gp efflux liability than Ligand B (0.046), which is crucial for CNS penetration.

**15. Binding Affinity:** Both ligands have very similar and excellent binding affinities (-8.6 and -8.5 kcal/mol). The difference is negligible.

**Overall Assessment:**

While Ligand B has a better logP and half-life, Ligand A excels in several critical areas: lower hERG inhibition, lower P-gp efflux, lower DILI risk, and lower microsomal clearance. The slightly better logP of Ligand B is outweighed by the safety and pharmacokinetic advantages of Ligand A, especially given that both have comparable affinity and acceptable BBB penetration. The negative Caco-2 and solubility values are concerning for both, but the other factors favor Ligand A.

Output:
0
2025-04-17 04:36:58,286 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (349.519 and 349.431 Da) fall comfortably within the ideal 200-500 Da range.

**TPSA:** Ligand A (44.81) is significantly better than Ligand B (93.46). For CNS targets, we want TPSA <= 90, and ideally <= 60. Ligand A is within a reasonable range, while Ligand B is quite high, potentially hindering BBB penetration.

**logP:** Both ligands have acceptable logP values (2.853 and 1.294), falling within the 1-3 optimal range. Ligand A is slightly better.

**H-Bond Donors/Acceptors:** Ligand A (HBD=1, HBA=3) is preferable to Ligand B (HBD=2, HBA=5) as it has fewer H-bonds, which generally improves permeability. Both are within acceptable limits.

**QED:** Ligand A (0.849) has a much better QED score than Ligand B (0.621), indicating a more drug-like profile.

**DILI:** Ligand A (5.118) has a significantly lower DILI risk than Ligand B (14.541). This is a major advantage for Ligand A.

**BBB:** Ligand A (82.047) has a much higher BBB percentile than Ligand B (51.609). Given that DRD2 is a CNS target, this is a critical advantage for Ligand A. A value >70 is desirable, and Ligand A is approaching that.

**Caco-2 Permeability:** Both have negative Caco-2 values (-4.646 and -4.796). These values are unusual and difficult to interpret without further context, but suggest poor permeability.

**Aqueous Solubility:** Both ligands have negative solubility values (-1.756 and -1.983), also unusual and suggesting poor solubility.

**hERG:** Both ligands have very low hERG inhibition liability (0.779 and 0.071), which is excellent.

**Microsomal Clearance:** Ligand A (-5.072) has a much lower (better) microsomal clearance than Ligand B (27.208), suggesting greater metabolic stability.

**In vitro Half-Life:** Ligand A (12.184) has a longer in vitro half-life than Ligand B (-3.052), which is desirable.

**P-gp Efflux:** Ligand A (0.043) has a much lower P-gp efflux liability than Ligand B (0.007), indicating better potential for CNS exposure.

**Binding Affinity:** Ligand A (-10.2 kcal/mol) has a significantly stronger binding affinity than Ligand B (-7.3 kcal/mol). This is a substantial advantage, exceeding the 1.5 kcal/mol difference threshold.

**Overall Assessment:**

Ligand A is superior to Ligand B across almost all key parameters. It has better TPSA, QED, DILI, BBB, metabolic stability, half-life, P-gp efflux, and *significantly* better binding affinity. While both have poor Caco-2 and solubility values, the superior binding affinity and CNS penetration profile of Ligand A outweigh these concerns. The substantial difference in binding affinity (-10.2 vs -7.3 kcal/mol) is a key driver in this decision.

Output:
1
2025-04-17 04:36:58,287 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 drug candidates, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (376.873 Da) is slightly higher than Ligand B (344.419 Da), but both are acceptable.

**TPSA:** Both ligands have TPSA values below 90 (Ligand A: 88.49, Ligand B: 85.17), which is favorable for CNS penetration.

**logP:** Ligand A (2.787) is within the optimal range (1-3), while Ligand B (0.735) is slightly below, potentially hindering permeation.

**H-Bond Donors/Acceptors:** Ligand A (HBD=2, HBA=6) and Ligand B (HBD=1, HBA=7) both have reasonable H-bond properties, falling within acceptable limits.

**QED:** Both ligands have good QED scores (Ligand A: 0.646, Ligand B: 0.88), indicating drug-like properties. Ligand B is slightly better here.

**DILI:** Ligand A (78.247) has a higher DILI risk than Ligand B (61.419), but both are below the concerning threshold of 60, indicating acceptable liver safety.

**BBB:** This is a critical parameter for CNS targets. Ligand B (68.786) has a significantly better BBB percentile than Ligand A (30.05). This is a major advantage for Ligand B.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.504 and -5.139), which is unusual and suggests poor permeability. However, these values are on a scale where negative values are possible, and direct comparison is difficult without knowing the scale's specifics.

**Aqueous Solubility:** Both ligands have negative solubility values (-3.433 and -1.458). Similar to Caco-2, interpretation is difficult without knowing the scale.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (Ligand A: 0.265, Ligand B: 0.547).

**Microsomal Clearance:** Ligand B (-12.174) has a much lower (better) microsomal clearance than Ligand A (42.872), indicating better metabolic stability.

**In vitro Half-Life:** Ligand B (33.177) has a significantly longer in vitro half-life than Ligand A (-6.957), which is desirable.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (Ligand A: 0.268, Ligand B: 0.058). Ligand B is slightly better.

**Binding Affinity:** Ligand A (-8.4 kcal/mol) has a slightly better binding affinity than Ligand B (-7.7 kcal/mol). This is a 0.7 kcal/mol difference, which is significant, but not overwhelming.

**Overall Assessment:**

While Ligand A has a slightly better binding affinity, Ligand B demonstrates superior ADME properties crucial for CNS drug development. Specifically, its significantly higher BBB penetration, lower microsomal clearance, and longer half-life are highly advantageous. The slightly lower logP of Ligand B is a minor concern, but the substantial improvements in other key parameters outweigh this drawback. Given the GPCR-specific priorities, Ligand B is the more promising candidate.

Output:
1
2025-04-17 04:36:58,287 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (346.475 and 359.455 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (83.98) is better than Ligand B (87.22). Both are below the 90 A^2 threshold for CNS targets, but A is closer to the optimal range.

**3. logP:** Ligand A (2.544) is slightly better than Ligand B (1.46). Both are within the optimal 1-3 range, but B is closer to the lower limit, potentially impacting permeability.

**4. H-Bond Donors:** Both ligands have 2 HBD, which is within the acceptable limit of <=5.

**5. H-Bond Acceptors:** Ligand A has 4 HBA, while Ligand B has 6. Both are below the 10 limit, but A is preferable.

**6. QED:** Both ligands have similar QED values (0.795 and 0.774), indicating good drug-likeness.

**7. DILI:** Ligand A (39.977) has a lower DILI risk than Ligand B (71.539). This is a significant advantage for A.

**8. BBB:** Ligand A (76.231) has a slightly better BBB percentile than Ligand B (70.143). Both are above 70, which is desirable for CNS targets.

**9. Caco-2 Permeability:** Ligand A (-4.708) has a worse Caco-2 permeability than Ligand B (-5.414). Lower values indicate lower permeability.

**10. Aqueous Solubility:** Ligand A (-4.046) has better aqueous solubility than Ligand B (-3.408).

**11. hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.196 and 0.168).

**12. Microsomal Clearance:** Ligand B (39.709) has lower microsomal clearance than Ligand A (51.162), suggesting better metabolic stability.

**13. In vitro Half-Life:** Ligand B (8.198) has a significantly longer in vitro half-life than Ligand A (1). This is a major advantage for B.

**14. P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.044 and 0.04).

**15. Binding Affinity:** Ligand B (-8.7) has a slightly better binding affinity than Ligand A (-8.5). While the difference is small, it's still a positive for B.

**Overall Assessment:**

Ligand A excels in TPSA, DILI risk, solubility, and has a good BBB score. However, it suffers from higher microsomal clearance and a shorter half-life, and lower Caco-2 permeability. Ligand B, while slightly worse in TPSA and DILI, has a significantly longer half-life, better metabolic stability (lower Cl_mic), and a slightly better binding affinity. For a CNS target like DRD2, metabolic stability and half-life are critical. The small advantage in binding affinity for B, combined with its superior metabolic profile, outweighs the slightly higher DILI risk and worse TPSA.

Output:
1
2025-04-17 04:36:58,287 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (355.479 and 365.459 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (101.9) is better than Ligand B (110.16). For CNS targets, we want TPSA <= 90, so both are slightly above the optimal range, but A is closer.

**3. logP:** Ligand B (0.963) is within the optimal 1-3 range, while Ligand A (-0.14) is below 1, potentially hindering permeation. This is a significant advantage for B.

**4. H-Bond Donors:** Ligand A (4) is higher than Ligand B (1), but both are within the acceptable limit of <=5.

**5. H-Bond Acceptors:** Both ligands have 5 HBA, which is within the acceptable limit of <=10.

**6. QED:** Ligand B (0.854) has a higher QED than Ligand A (0.509), indicating a more drug-like profile.

**7. DILI:** Ligand A (6.359%) has a much lower DILI risk than Ligand B (50.136%). This is a substantial advantage for A.

**8. BBB:** Ligand B (49.942%) is better than Ligand A (25.126%), but both are below the desirable >70% threshold for CNS targets. However, B is significantly better.

**9. Caco-2:** Both have negative Caco-2 values (-5.582 and -5.067), which is unusual and suggests poor permeability. This is a concern for both.

**10. Solubility:** Ligand A (-0.994) has slightly better solubility than Ligand B (-3.5).

**11. hERG:** Ligand A (0.098) has a lower hERG risk than Ligand B (0.335).

**12. Cl_mic:** Ligand A (-21.673) has a much lower (better) microsomal clearance than Ligand B (21.192). This suggests better metabolic stability for A.

**13. t1/2:** Ligand B (-45.489) has a much longer in vitro half-life than Ligand A (-1.16). This is a significant advantage for B.

**14. Pgp:** Ligand A (0.003) has a much lower P-gp efflux liability than Ligand B (0.026). This is crucial for CNS penetration and favors A.

**15. Binding Affinity:** Ligand A (-7.4) has a slightly better binding affinity than Ligand B (-0.0). This is a significant advantage for A.

**Overall Assessment:**

While Ligand B has advantages in BBB penetration and in vitro half-life, Ligand A is superior in most critical ADME properties, including DILI risk, metabolic stability (Cl_mic), P-gp efflux, and, crucially, binding affinity. The low logP of Ligand A is a concern, but the strong binding affinity (-7.4 kcal/mol) can potentially compensate for this. The significantly better safety profile (DILI) and metabolic stability of A are also important considerations. Given the GPCR-specific priorities, the strong affinity and lower efflux of A outweigh the slightly higher TPSA and lower logP.

Output:
0
2025-04-17 04:36:58,287 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (353.3 and 355.4) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (88.15) is excellent for CNS penetration, being well below 90. Ligand B (35.58) is also very good, but significantly higher than A.

**logP:** Both ligands (2.91 and 2.251) are within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Both have 1 HBD, which is good. Ligand A has 5 HBA, while Ligand B has 3. Both are acceptable (<=10).

**QED:** Both ligands have high QED scores (0.863 and 0.842), indicating good drug-likeness.

**DILI:** Ligand A has a DILI risk of 78.558, which is concerning (high risk). Ligand B has a much lower DILI risk of 23.653, which is excellent.

**BBB:** Ligand A has a BBB penetration percentile of 76.115, which is good but Ligand B is superior at 90.074, exceeding the >70 desirable threshold for CNS targets.

**Caco-2 Permeability:** Both have negative Caco-2 values (-4.409 and -4.418), which is unusual and suggests poor permeability. This is a significant drawback for both.

**Aqueous Solubility:** Both have negative solubility values (-4.351 and -1.647), indicating poor aqueous solubility. Ligand B is slightly better than A.

**hERG Inhibition:** Ligand A (0.686) has a slightly lower hERG risk than Ligand B (0.943), which is preferable.

**Microsomal Clearance:** Ligand A (40.403) has a better (lower) microsomal clearance than Ligand B (-31.537), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (-17.257) has a longer in vitro half-life than Ligand B (-4.895).

**P-gp Efflux:** Ligand A (0.284) has lower P-gp efflux liability than Ligand B (0.173), which is beneficial for CNS exposure.

**Binding Affinity:** Ligand B (-9.6 kcal/mol) has a significantly stronger binding affinity than Ligand A (-7.1 kcal/mol). This difference of 2.5 kcal/mol is substantial and can outweigh some of the ADME drawbacks.

**Overall Assessment:**

Ligand B is the stronger candidate. While both have poor Caco-2 and solubility, Ligand B's significantly improved BBB penetration and substantially better binding affinity are crucial for a CNS-targeting GPCR like DRD2. The lower DILI risk is also a major advantage. Although Ligand A has better metabolic stability and slightly lower hERG risk, the affinity difference and BBB penetration of Ligand B are more important in this context.

Output:
1
2025-04-17 04:36:58,287 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (353.388 and 360.845 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (30.29) is excellent, well below the 90 A^2 threshold for CNS targets. Ligand B (67.23) is higher, but still potentially acceptable, though less ideal.

**logP:** Ligand A (3.953) is at the upper end of the optimal range (1-3), but still acceptable. Ligand B (2.498) is good, falling comfortably within the optimal range.

**H-Bond Donors/Acceptors:** Ligand A (0 HBD, 4 HBA) and Ligand B (1 HBD, 4 HBA) both have reasonable numbers of H-bond donors and acceptors, well within the guidelines.

**QED:** Both ligands have good QED scores (0.815 and 0.91), indicating good drug-like properties.

**DILI:** Ligand A (35.479) has a lower DILI risk than Ligand B (59.287), which is approaching a concerning level.

**BBB:** This is critical for a CNS target like DRD2. Ligand A (96.084) has a very high BBB penetration percentile, which is excellent. Ligand B (68.166) is considerably lower, and while not terrible, is less desirable.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.488 and -4.954), which is unusual and suggests poor permeability. This is a significant concern for both.

**Aqueous Solubility:** Both ligands have negative solubility values (-4.213 and -3.494), which is also concerning. Poor solubility can hinder bioavailability.

**hERG Inhibition:** Ligand A (0.936) has a slightly higher hERG risk than Ligand B (0.329), but both are relatively low.

**Microsomal Clearance:** Ligand A (67.589) has a higher microsomal clearance than Ligand B (14.556), suggesting faster metabolism and potentially lower *in vivo* exposure.

**In vitro Half-Life:** Ligand B (24.538 hours) has a significantly longer half-life than Ligand A (1.019 hours), which is a major advantage.

**P-gp Efflux:** Ligand A (0.882) has slightly higher P-gp efflux liability than Ligand B (0.179), which is less favorable for CNS penetration.

**Binding Affinity:** Both ligands have excellent binding affinities (-9.6 and -8.7 kcal/mol). Ligand A is slightly better, but the difference is not huge.

**Overall Assessment:**

Ligand A excels in BBB penetration and has slightly better binding affinity. However, it has concerningly high microsomal clearance, moderate P-gp efflux, and a slightly higher DILI risk. Ligand B has a much better half-life and lower P-gp efflux, and a lower DILI risk, but its BBB penetration is significantly lower. The poor Caco-2 and solubility for both are concerning.

Given the importance of BBB penetration for a CNS target like DRD2, and the substantial difference in this parameter, Ligand A is the more promising candidate *despite* its other drawbacks. The slightly better affinity and excellent BBB penetration outweigh the concerns about clearance and P-gp efflux, especially if formulation strategies can address the solubility issues.

Output:
0
2025-04-17 04:36:58,288 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (355.435 Da) is slightly higher than Ligand B (337.423 Da), but both are acceptable.

**TPSA:** Ligand A (107.97) is borderline for CNS penetration, being above the preferred <90. Ligand B (62.61) is excellent, well below 90, suggesting better CNS penetration potential.

**logP:** Ligand A (-0.593) is a bit low, potentially hindering membrane permeability. Ligand B (2.366) is within the optimal range (1-3).

**H-Bond Donors/Acceptors:** Ligand A has 3 HBD and 5 HBA, which are acceptable. Ligand B has 2 HBD and 3 HBA, also acceptable.

**QED:** Both ligands have good QED scores (A: 0.566, B: 0.845), indicating drug-like properties. Ligand B is better.

**DILI:** Ligand A (11.322) has a very low DILI risk, significantly better than Ligand B (58.55), which is moderately high.

**BBB:** Ligand A (36.06) has poor predicted BBB penetration. Ligand B (64.211) is better, but still not ideal (aim for >70).

**Caco-2 Permeability:** Both have negative values, which is unusual. Assuming these are percentile scores, Ligand A (-5.256) is very poor, and Ligand B (-4.545) is also poor, but slightly better.

**Aqueous Solubility:** Both have negative values, which is unusual. Assuming these are percentile scores, both have very poor solubility.

**hERG Inhibition:** Ligand A (0.053) has very low hERG risk, excellent. Ligand B (0.316) has a slightly elevated, but still relatively low, hERG risk.

**Microsomal Clearance:** Ligand A (-18.662) has very low clearance, suggesting high metabolic stability. Ligand B (4.724) has moderate clearance.

**In vitro Half-Life:** Ligand A (15.872) has a moderate half-life. Ligand B (33.974) has a longer half-life, which is preferable.

**P-gp Efflux:** Ligand A (0.002) has very low P-gp efflux, excellent. Ligand B (0.101) has low P-gp efflux, but higher than Ligand A.

**Binding Affinity:** Ligand B (-8.5 kcal/mol) has a significantly stronger binding affinity than Ligand A (-7.3 kcal/mol). This >1.5 kcal/mol difference is substantial and can outweigh some ADME drawbacks.

**Overall Assessment:**

Ligand B is the stronger candidate despite some ADME liabilities. The significantly improved binding affinity (-8.5 vs -7.3 kcal/mol) is a major advantage, especially for a GPCR target. While its DILI risk is higher and BBB penetration is not ideal, the superior affinity, better logP, and longer half-life make it more promising. Ligand A has excellent safety profiles (DILI, hERG, Pgp), but its poor logP, TPSA, and weaker affinity are significant drawbacks, especially for a CNS target.

Output:
1
2025-04-17 04:36:58,288 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (350.39 Da) is slightly lower, which could be advantageous for permeability, but both are acceptable.

**TPSA:** Both ligands have TPSA values below 90 (A: 89.31, B: 86.29), which is excellent for CNS penetration.

**logP:** Both ligands have logP values between 3 and 4 (A: 3.553, B: 3.653), falling within the optimal range.

**H-Bond Donors/Acceptors:** Ligand A (HBD=1, HBA=4) and Ligand B (HBD=2, HBA=4) both have reasonable H-bond donor and acceptor counts, well within the guidelines.

**QED:** Both ligands have QED values above 0.5 (A: 0.601, B: 0.596), indicating good drug-likeness.

**DILI:** Ligand A (53.819) has a slightly higher DILI risk than Ligand B (36.797), but both are below the concerning threshold of 60.

**BBB:** This is a crucial parameter for a CNS target. Ligand A has a significantly higher BBB percentile (81.737) compared to Ligand B (32.416). This is a major advantage for Ligand A.

**Caco-2 Permeability:** Ligand A (-4.436) shows poor Caco-2 permeability, while Ligand B (-5.127) is also poor, but slightly worse.

**Aqueous Solubility:** Ligand A (-4.227) has poor solubility, while Ligand B (-2.882) is slightly better, but still poor.

**hERG Inhibition:** Ligand A (0.227) has a lower hERG inhibition liability than Ligand B (0.567), which is favorable.

**Microsomal Clearance:** Ligand B (50.117) has a higher microsomal clearance than Ligand A (38.126), indicating faster metabolism and potentially lower *in vivo* exposure.

**In vitro Half-Life:** Ligand B (26.165 hours) has a significantly longer half-life than Ligand A (-0.158 hours). This is a substantial advantage for Ligand B.

**P-gp Efflux:** Ligand A (0.268) has lower P-gp efflux liability than Ligand B (0.382), which is beneficial for CNS exposure.

**Binding Affinity:** Ligand A (-9.1 kcal/mol) has a significantly stronger binding affinity than Ligand B (-6.7 kcal/mol). This difference of 2.4 kcal/mol is substantial and can outweigh some ADME drawbacks.

**Overall Assessment:**

Ligand A excels in binding affinity and BBB penetration, and has lower hERG and P-gp efflux. However, it has poor Caco-2 permeability and aqueous solubility, and a very short half-life. Ligand B has a longer half-life and slightly better solubility, but significantly weaker binding affinity and poor BBB penetration.

Given the importance of CNS penetration for DRD2 and the substantial difference in binding affinity, Ligand A is the more promising candidate despite its ADME liabilities. The strong binding affinity could potentially be optimized through structural modifications to improve solubility and metabolic stability. The poor BBB of ligand B is a major drawback for a CNS target.

Output:
0
2025-04-17 04:36:58,288 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (349.406 and 367.852 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (80.32) is better than Ligand B (59.23). Both are below the 90 A^2 threshold for CNS targets, but A is closer to the ideal.

**3. logP:** Ligand A (1.518) is optimal, while Ligand B (4.483) is high. High logP can lead to solubility issues and off-target interactions.

**4. H-Bond Donors:** Ligand A (2) is acceptable, and Ligand B (0) is also good.

**5. H-Bond Acceptors:** Both ligands have 4 HBA, which is within the acceptable range.

**6. QED:** Ligand A (0.816) is better than Ligand B (0.723), indicating a more drug-like profile.

**7. DILI:** Ligand A (44.397) has a lower DILI risk than Ligand B (52.772), both are acceptable.

**8. BBB:** Both ligands have excellent BBB penetration (Ligand A: 87.553, Ligand B: 83.249).

**9. Caco-2 Permeability:** Ligand A (-4.779) has worse Caco-2 permeability than Ligand B (-4.589).

**10. Aqueous Solubility:** Ligand A (-2.113) has better aqueous solubility than Ligand B (-5.042).

**11. hERG Inhibition:** Both ligands have very low hERG inhibition risk (Ligand A: 0.341, Ligand B: 0.58).

**12. Microsomal Clearance:** Ligand A (16.96) has significantly lower microsomal clearance than Ligand B (81.313), suggesting better metabolic stability.

**13. In vitro Half-Life:** Ligand A (-1.93) has a worse in vitro half-life than Ligand B (31.713).

**14. P-gp Efflux:** Both ligands have low P-gp efflux (Ligand A: 0.044, Ligand B: 0.645).

**15. Binding Affinity:** Ligand B (-8.1) has a significantly stronger binding affinity than Ligand A (-9.0). This is a substantial advantage.

**Overall Assessment:**

Ligand B has a much stronger binding affinity, which is the most important factor. While its logP is higher, the excellent BBB penetration and acceptable other properties, combined with the significant affinity advantage, make it the more promising candidate. Ligand A has better solubility and metabolic stability, but the difference in binding affinity is too large to ignore.

Output:
1
2025-04-17 04:36:58,288 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (357.523 and 354.447 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (68.01) is excellent, well below the 90 A^2 threshold for CNS targets. Ligand B (79.31) is still reasonable but less optimal, approaching the 90 A^2 limit.

**3. logP:** Ligand A (4.465) is slightly high, potentially leading to solubility issues or off-target interactions. Ligand B (0.117) is very low, which is concerning for membrane permeability and CNS penetration despite being a GPCR.

**4. H-Bond Donors:** Ligand A (2) and Ligand B (1) both meet the HBD <= 5 criteria.

**5. H-Bond Acceptors:** Ligand A (4) and Ligand B (5) both meet the HBA <= 10 criteria.

**6. QED:** Both ligands have good QED values (0.802 and 0.759), indicating drug-like properties.

**7. DILI:** Ligand A (55.68) has a moderate DILI risk, while Ligand B (13.843) has a very low DILI risk.

**8. BBB:** Both ligands have good BBB penetration (80.962 and 55.874), but Ligand A is significantly better, exceeding the desirable >70% threshold.

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.992 and -4.47). This is unusual and suggests poor permeability.

**10. Aqueous Solubility:** Both ligands have negative solubility values (-4.003 and -1.513), indicating poor aqueous solubility.

**11. hERG Inhibition:** Ligand A (0.786) has a slightly elevated hERG risk, while Ligand B (0.304) has a very low hERG risk.

**12. Microsomal Clearance:** Ligand A (35.825) and Ligand B (25.634) have moderate clearance values. Lower is better.

**13. In vitro Half-Life:** Ligand A (31.825) has a better half-life than Ligand B (2.697).

**14. P-gp Efflux:** Ligand A (0.707) has a lower P-gp efflux liability than Ligand B (0.028), which is favorable for CNS penetration.

**15. Binding Affinity:** Ligand B (-7.1 kcal/mol) has a significantly stronger binding affinity than Ligand A (-9.4 kcal/mol). This is a substantial advantage.

**Overall Assessment:**

Ligand B has a much stronger binding affinity, a lower DILI risk, and a lower hERG risk. However, its very low logP is a major concern, suggesting poor permeability and potentially very limited CNS exposure despite the BBB percentile. Ligand A has a better logP and BBB penetration, but its affinity is weaker, and it has a higher DILI and hERG risk. The negative Caco-2 and solubility values for both are concerning and need further investigation.

Given the GPCR-specific priorities, BBB penetration and logP are crucial. While Ligand B's affinity is excellent, its extremely low logP is a significant drawback that likely outweighs its benefits. Ligand A, despite its weaker affinity, has a more reasonable logP and better BBB penetration.

Output:
1
2025-04-17 04:36:58,289 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (345.418 and 374.35 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (56.15) and Ligand B (58.64) are both below the 90 A^2 threshold for CNS targets, which is excellent.

**3. logP:** Both ligands have good logP values (3.131 and 2.846), falling within the optimal 1-3 range.

**4. H-Bond Donors:** Both have 1 HBD, which is acceptable.

**5. H-Bond Acceptors:** Ligand A has 4 HBA, and Ligand B has 3. Both are below the 10 threshold.

**6. QED:** Ligand A (0.906) has a superior QED score compared to Ligand B (0.525), indicating better overall drug-likeness.

**7. DILI:** Ligand A (67.546) has a higher DILI risk than Ligand B (35.285). This is a significant drawback for Ligand A.

**8. BBB:** Both ligands have excellent BBB penetration (89.492 and 90.772), exceeding the desirable >70 threshold for CNS targets.

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.588 and -4.569). These values are unusual and suggest poor permeability. However, these are likely reported as logP values, and negative values indicate very low permeability.

**10. Aqueous Solubility:** Both ligands have negative solubility values (-4.07 and -2.778), indicating very poor aqueous solubility.

**11. hERG Inhibition:** Both ligands have low hERG inhibition risk (0.643 and 0.756).

**12. Microsomal Clearance:** Ligand A (66.844) has a significantly higher microsomal clearance than Ligand B (23.579), suggesting lower metabolic stability.

**13. In vitro Half-Life:** Ligand A (9.456) has a slightly longer half-life than Ligand B (6.166).

**14. P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.237 and 0.295), which is favorable for CNS penetration.

**15. Binding Affinity:** Ligand B (-8.6 kcal/mol) has a slightly better binding affinity than Ligand A (-9.0 kcal/mol). Although the difference is small, it is still a factor.

**Overall Assessment:**

Despite the similar affinities, Ligand B is the more promising candidate. Ligand A has a significantly higher DILI risk and higher microsomal clearance, indicating poorer metabolic stability. While Ligand A has a slightly longer half-life and better QED, the DILI and clearance concerns outweigh these benefits. Both ligands have poor solubility and permeability, which is a concern, but can be addressed with formulation strategies.

Output:
1
2025-04-17 04:36:58,289 - INFO - Batch 128 complete. Total preferences: 2048
2025-04-17 04:36:58,289 - INFO - Processing batch 129/512...
2025-04-17 04:37:39,937 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight (MW):** Both ligands (359.348 and 345.443 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Both ligands have a TPSA of 78.51, which is acceptable for oral absorption but slightly high for optimal CNS penetration (ideally <90, but closer to <70 is better).

**3. logP:** Both ligands have similar logP values (1.025 and 0.976), falling within the optimal 1-3 range.

**4. H-Bond Donors (HBD):** Both have 2 HBD, well within the acceptable limit of <=5.

**5. H-Bond Acceptors (HBA):** Both have 3 HBA, also within the acceptable limit of <=10.

**6. QED:** Ligand A (0.736) has a better QED score than Ligand B (0.591), indicating a more drug-like profile.

**7. DILI:** Ligand A (37.611) has a slightly higher DILI risk than Ligand B (15.394), but both are below the concerning threshold of 60.

**8. BBB:** This is a critical parameter for a CNS target like DRD2. Ligand A has a significantly higher BBB penetration percentile (79.721) compared to Ligand B (52.695). This is a major advantage for Ligand A.

**9. Caco-2 Permeability:** Ligand A (-4.951) and Ligand B (-5.263) both have negative Caco-2 values, which is unusual and suggests poor permeability. However, the scale is not defined, so it's difficult to interpret the absolute difference.

**10. Aqueous Solubility:** Both ligands have very poor aqueous solubility (-2.522 and -2.295). This could pose formulation challenges.

**11. hERG Inhibition:** Both ligands show very low hERG inhibition risk (0.069 and 0.078).

**12. Microsomal Clearance (Cl_mic):** Ligand B (-9.196) has a more negative Cl_mic value than Ligand A (-1.499), suggesting slower clearance and better metabolic stability. This is a positive for Ligand B.

**13. In vitro Half-Life:** Ligand B (11.301) has a longer in vitro half-life than Ligand A (-29.36). This is a significant advantage for Ligand B.

**14. P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.012 and 0.011).

**15. Binding Affinity:** Both ligands have the same binding affinity (-8.0 kcal/mol), which is excellent.

**Overall Assessment:**

While Ligand B has better metabolic stability (lower Cl_mic) and a longer half-life, the significantly superior BBB penetration of Ligand A (79.721 vs 52.695) is the deciding factor for a CNS-targeting drug. The slightly better QED score of Ligand A also contributes. The poor solubility of both compounds is a concern, but can potentially be addressed with formulation strategies. Given the importance of CNS penetration for DRD2, Ligand A is the more promising candidate.

Output:
1
2025-04-17 04:37:39,937 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (365.543 and 361.389 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (61.44) is significantly better than Ligand B (71.11). For CNS targets, we want TPSA <= 90, and ideally closer to 60. Ligand A is much closer to the ideal range.

**3. logP:** Ligand A (1.793) is within the optimal range (1-3). Ligand B (0.259) is quite low, potentially hindering membrane permeability.

**4. H-Bond Donors:** Ligand A (2) and Ligand B (1) are both acceptable.

**5. H-Bond Acceptors:** Ligand A (4) and Ligand B (5) are both acceptable.

**6. QED:** Both ligands have similar QED values (0.722 and 0.659), indicating good drug-likeness.

**7. DILI:** Ligand A (16.44) has a lower DILI risk than Ligand B (18.728), which is preferable.

**8. BBB:** Ligand B (86.545) has a significantly higher BBB penetration percentile than Ligand A (70.415). This is a crucial factor for CNS targets like DRD2.

**9. Caco-2 Permeability:** Both have negative values which is unusual. However, the magnitude of the negative value for Ligand A (-5.235) is more negative than Ligand B (-5.177), suggesting potentially lower permeability for Ligand A.

**10. Aqueous Solubility:** Both have negative values, which is unusual. Ligand B (-1.403) is slightly better (less negative) than Ligand A (-2.939).

**11. hERG Inhibition:** Both ligands show low hERG inhibition liability (0.348 and 0.448), which is good.

**12. Microsomal Clearance:** Ligand A (74.94) has a higher microsomal clearance than Ligand B (-30.546). A negative value for Ligand B suggests very high metabolic stability, which is a major advantage.

**13. In vitro Half-Life:** Ligand B (-14.558) has a much longer in vitro half-life than Ligand A (24.657). Again, the negative value for Ligand B suggests an extremely long half-life.

**14. P-gp Efflux:** Both ligands have low P-gp efflux liability (0.1 and 0.007), which is favorable.

**15. Binding Affinity:** Ligand A (-8.9 kcal/mol) has a slightly better binding affinity than Ligand B (-8.7 kcal/mol). While the difference is small, it's still a positive factor.

**Overall Assessment:**

Ligand B excels in BBB penetration, metabolic stability (low Cl_mic, long t1/2), and P-gp efflux. Ligand A has a better TPSA and slightly better binding affinity. The low logP of Ligand B is a concern, but its superior BBB penetration and metabolic stability are highly valuable for a CNS target like DRD2. The slightly better affinity of Ligand A is not enough to overcome the significant advantages of Ligand B in ADME properties crucial for CNS drug development.

Output:
1
2025-04-17 04:37:39,937 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (352.356 and 349.475 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (51.22) is excellent, well below the 90 A^2 threshold for CNS targets. Ligand B (101.29) is higher, but still potentially acceptable, though less ideal.

**logP:** Ligand A (4.892) is slightly high, potentially leading to solubility issues or off-target interactions. Ligand B (1.478) is good, within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A (1 HBD, 4 HBA) is favorable. Ligand B (3 HBD, 3 HBA) is also acceptable.

**QED:** Both ligands have reasonable QED scores (0.778 and 0.677), indicating good drug-like properties.

**DILI:** Ligand A (64.793) has a higher DILI risk than Ligand B (19.038), which is a significant concern.

**BBB:** Ligand A (71.229) has a better BBB penetration percentile than Ligand B (62.427), which is important for a CNS target like DRD2.

**Caco-2 Permeability:** Ligand A (-4.693) has poor Caco-2 permeability, while Ligand B (-5.296) is also poor.

**Aqueous Solubility:** Ligand A (-6.165) has very poor aqueous solubility. Ligand B (-3.226) is also poor, but better than Ligand A.

**hERG:** Ligand A (0.769) has a slightly higher hERG risk than Ligand B (0.13), which is preferable.

**Microsomal Clearance:** Ligand A (111.543) has higher microsomal clearance, indicating faster metabolism, than Ligand B (17.222), which is better.

**In vitro Half-Life:** Ligand A (14.139) has a longer half-life than Ligand B (4.188).

**P-gp Efflux:** Ligand A (0.581) has lower P-gp efflux than Ligand B (0.029), which is favorable for CNS penetration.

**Binding Affinity:** Both ligands have the same binding affinity (-8.9 kcal/mol), which is excellent.

**Overall Assessment:**

While both ligands have excellent binding affinity, Ligand B is the more promising candidate. Ligand A's high DILI risk, poor aqueous solubility, and high microsomal clearance are significant drawbacks. Ligand B has a much lower DILI risk, better solubility, and lower clearance. Although Ligand A has slightly better BBB penetration and lower P-gp efflux, the ADME-Tox profile of Ligand B is substantially better. The slightly higher logP of Ligand A is also a concern. Given the GPCR-specific priorities, the improved safety profile of Ligand B outweighs the minor differences in BBB and P-gp.

Output:
1
2025-04-17 04:37:39,937 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (347.503 and 367.53 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (43.86) is significantly better than Ligand B (29.54). For CNS targets, we want TPSA <= 90, and ideally lower. Ligand A is still a bit high, but much closer to the ideal than B.

**3. logP:** Ligand A (2.112) is within the optimal 1-3 range. Ligand B (4.564) is higher, potentially leading to solubility issues and off-target interactions.

**4. H-Bond Donors:** Both have 0 HBD, which is acceptable.

**5. H-Bond Acceptors:** Both have 3 HBA, which is acceptable.

**6. QED:** Ligand A (0.782) has a better QED score than Ligand B (0.641), indicating a more drug-like profile.

**7. DILI:** Ligand A (6.747) has a much lower DILI risk than Ligand B (12.485). This is a significant advantage.

**8. BBB:** Ligand A (86.002) has a good BBB penetration percentile, though not exceptional. Ligand B (94.998) is excellent. This is a key factor for CNS targets.

**9. Caco-2 Permeability:** Ligand A (-4.787) is worse than Ligand B (-4.329), indicating lower intestinal absorption.

**10. Aqueous Solubility:** Ligand A (-0.924) is better than Ligand B (-4.74), suggesting better formulation potential.

**11. hERG Inhibition:** Ligand A (0.653) has a lower hERG inhibition risk than Ligand B (0.916).

**12. Microsomal Clearance:** Ligand A (13.206) has lower microsomal clearance than Ligand B (119.008), indicating better metabolic stability.

**13. In vitro Half-Life:** Ligand A (-11.053) has a much longer in vitro half-life than Ligand B (25.2).

**14. P-gp Efflux:** Ligand A (0.043) has much lower P-gp efflux liability than Ligand B (0.467), which is crucial for CNS penetration.

**15. Binding Affinity:** Ligand A (-8.8 kcal/mol) has a slightly better binding affinity than Ligand B (-6.8 kcal/mol). The difference is >1.5 kcal/mol, making it a significant advantage.

**Overall Assessment:**

Ligand A has several advantages: better DILI risk, better metabolic stability (lower Cl_mic, longer t1/2), lower P-gp efflux, better solubility, lower hERG risk, and a slightly better binding affinity. While Ligand B has a better BBB score and Caco-2 permeability, the other ADME/Tox properties of Ligand A are far more favorable, especially considering the CNS target. The superior binding affinity of Ligand A further strengthens its candidacy. The TPSA is a slight concern for both, but Ligand A is closer to the ideal range.

Output:
1
2025-04-17 04:37:39,937 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (374.884 and 344.455 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (67.43) is slightly above the optimal <90 for CNS targets, but acceptable. Ligand B (53.76) is well within the desired range.

**3. logP:** Both ligands have good logP values (2.372 and 3.016), falling within the 1-3 range.

**4. H-Bond Donors:** Ligand A has 2 HBD, and Ligand B has 0. Both are acceptable (<=5).

**5. H-Bond Acceptors:** Both ligands have 3 HBA, which is within the acceptable limit of <=10.

**6. QED:** Both ligands have similar and good QED scores (0.701 and 0.715), indicating good drug-like properties.

**7. DILI:** Ligand A (32.765) has a slightly higher DILI risk than Ligand B (23.885), but both are below the 40 threshold and considered low risk.

**8. BBB:** This is a critical parameter for CNS targets like DRD2. Ligand A has a BBB percentile of 84.955, which is excellent (>70). Ligand B has a BBB percentile of 67.778, which is acceptable but less favorable.

**9. Caco-2 Permeability:** Both have negative values, which is unusual. Assuming these are logP values, both are very poor.

**10. Aqueous Solubility:** Both have negative values, which is unusual.

**11. hERG Inhibition:** Both ligands have low hERG inhibition risk (0.516 and 0.466).

**12. Microsomal Clearance:** Ligand A (45.353) has lower microsomal clearance than Ligand B (64.199), indicating better metabolic stability.

**13. In vitro Half-Life:** Ligand A (26.64) has a slightly longer half-life than Ligand B (21.462).

**14. P-gp Efflux:** Both ligands have low P-gp efflux liability (0.217 and 0.371), which is favorable for CNS penetration.

**15. Binding Affinity:** Ligand B (-7.9 kcal/mol) has a slightly better binding affinity than Ligand A (-7.6 kcal/mol), although the difference is small (0.3 kcal/mol).

**Overall Assessment:**

Ligand A is slightly better overall. While Ligand B has a slightly better binding affinity, Ligand A's significantly better BBB penetration (84.955 vs 67.778) and lower microsomal clearance are crucial advantages for a CNS-targeting drug. The small difference in binding affinity is unlikely to outweigh the benefits of improved CNS exposure and metabolic stability.

Output:
1
2025-04-17 04:37:39,937 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (364.408 and 345.363 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (69.64) is excellent, well below the 90 A^2 threshold for CNS targets. Ligand B (128.2) is higher, but still potentially acceptable, though less ideal.

**logP:** Ligand A (2.091) is optimal (1-3). Ligand B (-0.014) is slightly below 1, which could hinder permeation.

**H-Bond Donors/Acceptors:** Both ligands have 2 HBDs, which is good. Ligand A has 3 HBAs, and Ligand B has 7 HBAs. Both are within the acceptable limits (<=10), but Ligand B's higher HBA count could slightly impact permeability.

**QED:** Both ligands have good QED scores (0.758 and 0.8), indicating good drug-like properties.

**DILI:** Ligand A (18.418) has a much lower DILI risk than Ligand B (61.691), which is a significant advantage.

**BBB:** Ligand A (74.486) has a good BBB percentile, exceeding the 70% threshold for CNS targets. Ligand B (33.579) is considerably lower, raising concerns about CNS penetration.

**Caco-2 Permeability:** Ligand A (-4.722) and Ligand B (-5.376) both have negative Caco-2 values, which is unusual and suggests poor permeability. However, these values are on a scale where negative values are possible, and direct comparison is difficult without knowing the scale's specifics.

**Aqueous Solubility:** Both ligands have very low solubility scores (-2.823 and -2.753), which could pose formulation challenges.

**hERG:** Both ligands have low hERG inhibition liability (0.541 and 0.117), which is favorable.

**Microsomal Clearance:** Ligand A (25.451) has higher microsomal clearance than Ligand B (-15.184), suggesting lower metabolic stability.

**In vitro Half-Life:** Ligand B (-12.163) has a longer in vitro half-life than Ligand A (-18.313), which is a positive.

**P-gp Efflux:** Ligand A (0.147) has lower P-gp efflux liability than Ligand B (0.012), which is beneficial for CNS exposure.

**Binding Affinity:** Ligand A (-8.6 kcal/mol) has a slightly better binding affinity than Ligand B (-7.6 kcal/mol). While both are good, the 1 kcal/mol difference is significant.

**Overall Assessment:**

Ligand A is the stronger candidate. It excels in crucial areas for a CNS-targeting GPCR ligand: TPSA, logP, BBB penetration, and binding affinity. Its DILI risk is also significantly lower. While its solubility and microsomal clearance are concerns, the superior BBB and affinity outweigh these drawbacks. Ligand B's low logP and poor BBB penetration are major liabilities.

Output:
0
2025-04-17 04:37:39,938 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B based on the provided guidelines, prioritizing GPCR-specific properties (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (344.419 and 348.403 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (103.91) is better than Ligand B (113.44). Both are below the 140 A^2 threshold for oral absorption, but Ligand A is closer to the desirable <90 A^2 for CNS targets.

**logP:** Ligand A (0.779) is within the optimal 1-3 range, but on the lower end. Ligand B (-0.111) is below 1, which could hinder permeation. This is a significant advantage for Ligand A.

**H-Bond Donors/Acceptors:** Ligand A (HBD=1, HBA=6) is preferable to Ligand B (HBD=3, HBA=6). Lower HBD is generally better for CNS penetration.

**QED:** Ligand A (0.869) has a higher QED score than Ligand B (0.684), indicating a more drug-like profile.

**DILI:** Ligand B (63.397) has a slightly higher DILI risk than Ligand A (48.895), but both are acceptable (<60 is good).

**BBB:** This is a crucial parameter for DRD2. Ligand A (60.644) is significantly better than Ligand B (27.142). A value >70 is desirable, and Ligand A is closer to that threshold.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.009 and -5.399), which is unusual and suggests poor permeability. This is a concern for both.

**Aqueous Solubility:** Both ligands have negative solubility values (-3.197 and -2.096), indicating very poor aqueous solubility. This is a major drawback for both.

**hERG:** Both ligands have very low hERG inhibition liability (0.031 and 0.09), which is excellent.

**Microsomal Clearance:** Ligand A (9.796) has a lower (better) microsomal clearance than Ligand B (-5.592).

**In vitro Half-Life:** Ligand A (-6.813) has a longer (better) in vitro half-life than Ligand B (18.004).

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.015 and 0.016), which is favorable.

**Binding Affinity:** Ligand B (-7.5 kcal/mol) has a slightly better binding affinity than Ligand A (-7.2 kcal/mol), but the difference is relatively small (0.3 kcal/mol).

**Overall Assessment:**

Considering the GPCR-specific priorities, Ligand A is the more promising candidate. While Ligand B has slightly better binding affinity, Ligand A excels in crucial areas for CNS penetration: significantly better BBB (60.644 vs 27.142), a more favorable logP (0.779 vs -0.111), and a better QED score. The better metabolic stability (lower Cl_mic) and longer half-life of Ligand A are also advantageous. The poor solubility and Caco-2 permeability are concerns for both, but the CNS-focused properties of Ligand A make it the better choice.

Output:
0
2025-04-17 04:37:39,938 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (374.463 and 351.372 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (130.13) is borderline for CNS penetration, slightly above the preferred <90, while Ligand B (67.89) is well within the optimal range. This is a significant advantage for Ligand B.

**logP:** Ligand A (-0.315) is quite low, potentially hindering membrane permeability. Ligand B (3.943) is close to the upper limit of the optimal range but still acceptable.

**H-Bond Donors/Acceptors:** Ligand A has 3 HBD and 6 HBA, which are reasonable. Ligand B has 0 HBD and 3 HBA, also acceptable.

**QED:** Both ligands have good QED scores (0.51 and 0.807), indicating drug-like properties. Ligand B is slightly better.

**DILI:** Ligand A (60.295) has a moderate DILI risk, while Ligand B (26.793) has a low DILI risk. This favors Ligand B.

**BBB:** Ligand A (47.809) has a poor BBB penetration percentile, which is a major drawback for a CNS target like DRD2. Ligand B (74.37) has a good BBB penetration percentile, a significant advantage.

**Caco-2 Permeability:** Ligand A (-5.47) has very poor Caco-2 permeability, suggesting poor absorption. Ligand B (-4.24) is also poor, but slightly better than A.

**Aqueous Solubility:** Both ligands have negative solubility values (-2.219 and -3.932), indicating poor aqueous solubility. This could pose formulation challenges.

**hERG Inhibition:** Ligand A (0.25) has a low hERG risk, while Ligand B (0.802) has a slightly elevated risk.

**Microsomal Clearance:** Ligand A (-8.541) has a very low (good) microsomal clearance, indicating high metabolic stability. Ligand B (59.264) has a high microsomal clearance, suggesting rapid metabolism.

**In vitro Half-Life:** Ligand A (32.565) has a moderate in vitro half-life. Ligand B (-9.547) has a very short half-life, which is undesirable.

**P-gp Efflux:** Ligand A (0.169) has low P-gp efflux, which is good for CNS penetration. Ligand B (0.175) is similar.

**Binding Affinity:** Ligand A (-8.0) has a slightly better binding affinity than Ligand B (-7.2). However, the difference is less than 1.5 kcal/mol, and can be overcome by other factors.

**Overall Assessment:**

Ligand B is significantly more promising due to its superior BBB penetration, lower DILI risk, and better TPSA. While Ligand A has slightly better binding affinity and metabolic stability, the poor BBB penetration and low logP are critical drawbacks for a CNS-targeted GPCR. The poor solubility of both compounds is a concern, but can potentially be addressed through formulation strategies. The faster clearance and shorter half-life of Ligand B are also concerns, but could be improved through structural modifications.

Output:
1
2025-04-17 04:37:39,938 - INFO - Reasoning:

Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (386.5) is slightly higher than Ligand B (354.4), but both are acceptable.

**2. TPSA:** Ligand A (100.62) is borderline for CNS targets (ideally <90), while Ligand B (36.69) is excellent. This is a significant advantage for Ligand B.

**3. logP:** Ligand A (0.667) is a bit low, potentially hindering membrane permeability. Ligand B (3.788) is within the optimal range (1-3).

**4. H-Bond Donors:** Ligand A (1) and Ligand B (0) are both acceptable.

**5. H-Bond Acceptors:** Ligand A (5) and Ligand B (3) are both acceptable.

**6. QED:** Both ligands have good QED scores (A: 0.742, B: 0.829), indicating drug-likeness.

**7. DILI:** Ligand A (54.56) has a moderate DILI risk, while Ligand B (15.82) has a very low risk. This favors Ligand B.

**8. BBB:** Ligand A (82.09) has good BBB penetration, but Ligand B (91.04) is even better. This is crucial for a CNS target like DRD2, and favors Ligand B.

**9. Caco-2:** Both ligands have negative Caco-2 values, which is unusual and suggests a potential issue with permeability prediction. However, the magnitude is similar.

**10. Solubility:** Both ligands have negative solubility values, which is also unusual. Again, the magnitude is similar.

**11. hERG:** Ligand A (0.271) has a very low hERG risk, while Ligand B (0.943) has a slightly higher, but still acceptable, risk.

**12. Cl_mic:** Ligand A (49.94) has a moderate clearance, while Ligand B (-6.33) has a negative clearance, indicating very high metabolic stability. This is a major advantage for Ligand B.

**13. t1/2:** Ligand A (-21.3) has a negative half-life, which is unrealistic. Ligand B (59.85) has a good half-life.

**14. Pgp:** Ligand A (0.121) has low P-gp efflux, while Ligand B (0.499) has a slightly higher efflux. Ligand A is better here.

**15. Binding Affinity:** Both ligands have excellent binding affinities (A: -9.5 kcal/mol, B: -8.7 kcal/mol). Ligand A is slightly stronger, but the difference is likely not enough to overcome its other weaknesses.

**Overall Assessment:**

Ligand B consistently outperforms Ligand A in key properties for a CNS-targeting GPCR ligand. It has a significantly better TPSA, logP, DILI risk, BBB penetration, and metabolic stability. While Ligand A has a slightly better binding affinity and Pgp efflux, the other advantages of Ligand B, especially its favorable ADME profile and CNS penetration, make it the more promising drug candidate. The unrealistic half-life for Ligand A is also a major red flag.

Output:
1
2025-04-17 04:37:39,938 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 drug candidates, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (346.402 and 337.375 Da) fall within the ideal range of 200-500 Da.

**TPSA:** Ligand A (58.64) is better than Ligand B (60.7), both are below the 90 A^2 threshold for CNS targets, which is good.

**logP:** Both ligands have good logP values (2.483 and 3.588), falling within the optimal 1-3 range. Ligand B is slightly higher, which could be a minor concern for solubility, but not a dealbreaker.

**H-Bond Donors/Acceptors:** Both ligands have acceptable HBD (1) and HBA (3 & 4) counts, well within the limits of 5 and 10 respectively.

**QED:** Both ligands have good QED scores (0.673 and 0.79), indicating good drug-like properties.

**DILI:** Ligand A (40.287) has a lower DILI risk than Ligand B (68.941). This is a significant advantage for Ligand A.

**BBB:** Both ligands have excellent BBB penetration (75.921 and 72.625), exceeding the desirable threshold of 70% for CNS targets.

**Caco-2 Permeability:** Both ligands have negative Caco-2 permeability values (-4.457 and -4.956), which is unusual and suggests poor intestinal absorption. This is a significant drawback for both. However, for a CNS target, oral bioavailability is less critical than BBB penetration.

**Aqueous Solubility:** Both ligands have very poor aqueous solubility (-3.717 and -4.373). This could pose formulation challenges.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.449 and 0.876).

**Microsomal Clearance:** Ligand A (53.748) has lower microsomal clearance than Ligand B (65.034), indicating better metabolic stability.

**In vitro Half-Life:** Ligand B (94.48) has a significantly longer in vitro half-life than Ligand A (8.364). This is a major advantage for Ligand B, potentially allowing for less frequent dosing.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.211 and 0.873), which is favorable for CNS exposure.

**Binding Affinity:** Ligand B (-10.4 kcal/mol) has a substantially stronger binding affinity than Ligand A (-8.5 kcal/mol). This difference of 1.9 kcal/mol is very significant and can outweigh some of the ADME drawbacks.

**Overall Assessment:**

While Ligand A has advantages in DILI and metabolic stability, the significantly stronger binding affinity of Ligand B (-10.4 vs -8.5 kcal/mol) is the most crucial factor for a GPCR target. The longer half-life of Ligand B is also a significant benefit. The poor Caco-2 permeability and solubility are concerns, but less critical for a CNS-focused drug. The slightly higher logP and DILI risk of Ligand B are manageable given the substantial improvement in binding affinity.

Output:
1
2025-04-17 04:37:39,938 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (366.53 & 358.51 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (67.43) is higher than Ligand B (54.18). For CNS targets, TPSA < 90 is preferred. Both are acceptable, but B is better.

**logP:** Both ligands have good logP values (3.14 & 2.94), falling within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A has 2 HBD and 4 HBA, while Ligand B has 1 HBD and 6 HBA. Both are within acceptable limits (<=5 HBD and <=10 HBA).

**QED:** Both ligands have good QED scores (0.66 & 0.74), indicating good drug-like properties.

**DILI:** Ligand A (49.01) has a slightly higher DILI risk than Ligand B (8.53). Lower is better, so B is preferable.

**BBB:** This is a critical parameter for CNS targets. Ligand B (71.93) has a significantly better BBB penetration percentile than Ligand A (61.38).  >70 is desirable, and B is closer to this threshold.

**Caco-2 Permeability:** Both have negative Caco-2 values (-5.284 & -5.176), which is unusual and suggests poor permeability. This is a significant concern for both.

**Aqueous Solubility:** Both have negative solubility values (-2.958 & -2.305), indicating poor aqueous solubility. This is also a concern.

**hERG Inhibition:** Both ligands show low hERG inhibition liability (0.699 & 0.835), which is good.

**Microsomal Clearance:** Ligand A (47.34) and Ligand B (50.32) have similar microsomal clearance values. Lower is better, so neither has a significant advantage here.

**In vitro Half-Life:** Ligand B (7.05) has a significantly longer half-life than Ligand A (39.97). Longer half-life is generally preferred.

**P-gp Efflux:** Ligand A (0.495) has lower P-gp efflux liability than Ligand B (0.367). Lower is better, so A is preferable.

**Binding Affinity:** Both ligands have excellent binding affinities (-7.6 & -7.5 kcal/mol). The difference of 0.1 kcal/mol is not substantial enough to outweigh other factors.

**Overall Assessment:**

Ligand B is the more promising candidate. While both have issues with Caco-2 permeability and solubility, Ligand B excels in BBB penetration (71.93 vs 61.38) and has a longer half-life (7.05 vs 39.97) and a much lower DILI risk (8.53 vs 49.01). These factors are particularly important for a CNS-targeting GPCR like DRD2. The slightly better P-gp efflux for Ligand A is not enough to offset the advantages of Ligand B.

Output:
1
2025-04-17 04:37:39,938 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (354.439 and 344.419 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (96.45) is better than Ligand B (111.06). For CNS targets, we want TPSA <= 90, so Ligand A is closer to this threshold.

**3. logP:** Both ligands have good logP values (2.368 and 2.066), falling within the optimal 1-3 range.

**4. H-Bond Donors:** Ligand A (2) is slightly higher than Ligand B (1), but both are acceptable (<=5).

**5. H-Bond Acceptors:** Ligand A (6) is higher than Ligand B (4), but both are within the acceptable range (<=10).

**6. QED:** Ligand A (0.75) has a significantly better QED score than Ligand B (0.484), indicating a more drug-like profile.

**7. DILI:** Ligand A (80.535) has a higher DILI risk than Ligand B (30.593). This is a significant drawback for Ligand A.

**8. BBB:** Ligand B (52.966) has a better BBB penetration percentile than Ligand A (49.205), although both are below the desirable >70 for CNS targets.

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.697 and -5.113), which is unusual and suggests poor permeability. However, these values are on a different scale and hard to interpret directly.

**10. Aqueous Solubility:** Both ligands have negative solubility values (-2.51 and -1.971), also unusual and suggesting poor solubility.

**11. hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.123 and 0.134).

**12. Microsomal Clearance:** Ligand B (5.658) has significantly lower microsomal clearance than Ligand A (24.718), indicating better metabolic stability.

**13. In vitro Half-Life:** Ligand B (-14.075) has a longer in vitro half-life than Ligand A (-11.611).

**14. P-gp Efflux:** Both ligands have low P-gp efflux liability (0.309 and 0.01). Ligand B is better.

**15. Binding Affinity:** Ligand A (-9.5 kcal/mol) has a significantly stronger binding affinity than Ligand B (-6.9 kcal/mol). This is a substantial advantage.

**Overall Assessment:**

Ligand A has a much stronger binding affinity, which is a major plus for GPCRs. However, it suffers from higher DILI risk, lower BBB penetration, and higher metabolic clearance. Ligand B, while having weaker affinity, exhibits a better safety profile (lower DILI), better BBB penetration, better metabolic stability, and a longer half-life.

Given the GPCR-specific priorities, and the fact that the affinity difference is quite large (2.6 kcal/mol), the stronger binding of Ligand A likely outweighs its ADME drawbacks, *provided* the DILI risk can be mitigated through structural modifications. The difference in affinity is substantial enough to potentially overcome the other issues.

Output:
1
2025-04-17 04:37:39,938 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (349.431 and 378.46 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (95.71) is better than Ligand B (42.43). For CNS targets, TPSA should be <=90, so Ligand A is closer to the threshold, while Ligand B is well within.

**logP:** Ligand A (2.256) is optimal (1-3), while Ligand B (4.364) is slightly high, potentially leading to solubility issues and off-target effects.

**H-Bond Donors/Acceptors:** Ligand A has 2 HBD and 5 HBA, both acceptable. Ligand B has 0 HBD and 4 HBA, also acceptable.

**QED:** Both ligands have good QED scores (0.554 and 0.738 respectively), indicating good drug-like properties.

**DILI:** Ligand A (27.414) has a much lower DILI risk than Ligand B (44.552), which is a significant advantage. Both are below the 60 threshold, but A is preferable.

**BBB:** Ligand B (83.637) has a significantly higher BBB penetration percentile than Ligand A (54.478). This is a crucial factor for a CNS target like DRD2.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.844 and -4.535), which is unusual and suggests poor permeability. This is a concern for both.

**Aqueous Solubility:** Both have negative solubility values (-2.747 and -3.934), also concerning.

**hERG Inhibition:** Both ligands show low hERG inhibition liability (0.653 and 0.48), which is good.

**Microsomal Clearance:** Ligand A (23.562) has lower microsomal clearance than Ligand B (53.575), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand B (15.101) has a longer in vitro half-life than Ligand A (10.082), which is preferable.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.169 and 0.364), which is good for CNS penetration.

**Binding Affinity:** Ligand B (-7.7 kcal/mol) has a slightly better binding affinity than Ligand A (-7.0 kcal/mol). This 0.7 kcal/mol difference is significant.

**Overall Assessment:**

Ligand B excels in BBB penetration and binding affinity, which are critical for a CNS GPCR target. However, it has a higher logP and DILI risk. Ligand A has better TPSA, DILI, and metabolic stability. The difference in binding affinity (0.7 kcal/mol) is substantial enough to outweigh the slightly higher logP and DILI of Ligand B, especially considering the importance of strong binding for GPCR ligands. The poor Caco-2 and solubility values are concerning for both, but can be addressed with formulation strategies.

Output:
1
2025-04-17 04:37:39,938 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (377.725 Da) is slightly higher than Ligand B (345.487 Da), but both are acceptable.

**TPSA:** Both ligands have TPSA values below the 90 A^2 threshold desirable for CNS targets. Ligand A (88.24 A^2) is closer to the threshold than Ligand B (73.2 A^2), which is excellent.

**logP:** Both ligands have logP values within the optimal range (1-3). Ligand A (2.939) and Ligand B (3.006) are very similar and both are good.

**H-Bond Donors/Acceptors:** Ligand A has 3 HBD and 4 HBA, while Ligand B has 1 HBD and 3 HBA. Both are within acceptable limits (<=5 HBD and <=10 HBA).

**QED:** Both ligands have similar QED values (0.715 and 0.721), indicating good drug-like properties.

**DILI:** Ligand A has a DILI risk of 69.484, which is approaching the higher risk threshold (>60). Ligand B has a much lower DILI risk of 14.385, which is excellent. This is a significant advantage for Ligand B.

**BBB:** Ligand A has a BBB penetration of 61.962%, which is below the desirable >70% for CNS targets. Ligand B has a BBB penetration of 58.123%, also below the desired threshold. Both are suboptimal, but neither is drastically low.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.08 and -4.668), which is unusual and suggests poor permeability. This is a concern for both.

**Aqueous Solubility:** Both ligands have negative solubility values (-3.968 and -2.598), indicating very poor aqueous solubility. This is a significant drawback for both.

**hERG Inhibition:** Both ligands have low hERG inhibition liability (0.652 and 0.478), which is good.

**Microsomal Clearance:** Ligand A has a lower microsomal clearance (11.891 mL/min/kg) than Ligand B (14.021 mL/min/kg), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A has a longer in vitro half-life (42.225 hours) than Ligand B (-4.684 hours). The negative value for Ligand B is concerning and likely an error or indicates very rapid degradation.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.222 and 0.042), which is favorable for CNS penetration.

**Binding Affinity:** Ligand A has a significantly stronger binding affinity (-8.9 kcal/mol) than Ligand B (-7.3 kcal/mol). This is a substantial advantage for Ligand A, exceeding the 1.5 kcal/mol difference that can outweigh other drawbacks.

**Overall Assessment:**

Ligand A's primary advantage is its significantly better binding affinity. However, Ligand B has a much better safety profile (lower DILI) and slightly better metabolic stability. The negative half-life for Ligand B is a major red flag. Both have poor solubility and permeability. Given the importance of binding affinity for GPCRs, and the relatively modest difference in BBB penetration, Ligand A is the more promising candidate *despite* the higher DILI risk, as this can be addressed with further optimization. The negative half-life of Ligand B is a showstopper.

Output:
0
2025-04-17 04:37:39,939 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, considering the provided guidelines and GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (354.397 and 355.435 Da) fall comfortably within the ideal 200-500 Da range.

**TPSA:** Ligand A (50.8) is significantly better than Ligand B (130.75). For CNS targets, TPSA should be <= 90, and A is well within this range, while B is considerably above.

**logP:** Ligand A (2.411) is optimal (1-3), while Ligand B (-0.392) is below 1, potentially hindering permeation.

**H-Bond Donors/Acceptors:** Ligand A (HBD=1, HBA=4) is favorable. Ligand B (HBD=4, HBA=5) is acceptable but less ideal, with a higher number of HBDs.

**QED:** Ligand A (0.882) has a very strong drug-like profile, while Ligand B (0.418) is below the desirable threshold of 0.5.

**DILI:** Ligand A (36.72) has a low DILI risk, while Ligand B (14.889) also has a low DILI risk.

**BBB:** Ligand A (73.362) has a good BBB penetration percentile, exceeding the 70% threshold for CNS targets. Ligand B (38.232) is significantly lower and less likely to achieve sufficient CNS exposure.

**Caco-2 Permeability:** Ligand A (-4.505) and Ligand B (-5.86) both have negative values, which is unusual and may indicate issues with the data or the scale used. However, the more negative value for B suggests poorer permeability.

**Aqueous Solubility:** Ligand A (-2.083) and Ligand B (-1.886) both have negative values, which is also unusual.

**hERG Inhibition:** Ligand A (0.835) has a low hERG risk, while Ligand B (0.055) also has a low hERG risk.

**Microsomal Clearance:** Ligand A (-7.731) has a very low (and favorable) microsomal clearance, indicating high metabolic stability. Ligand B (27.014) has a much higher clearance, suggesting faster metabolism.

**In vitro Half-Life:** Ligand A (-7.026) has a very long in vitro half-life, while Ligand B (-7.24) also has a long in vitro half-life.

**P-gp Efflux:** Ligand A (0.15) has low P-gp efflux, which is beneficial for CNS penetration. Ligand B (0.005) also has low P-gp efflux.

**Binding Affinity:** Ligand A (-0.0) has a slightly weaker binding affinity than Ligand B (-7.6). However, the difference is substantial enough to potentially outweigh some of the ADME drawbacks of Ligand B.

**Overall Assessment:**

Ligand A is superior due to its favorable TPSA, logP, QED, BBB, and microsomal clearance. While Ligand B has a better binding affinity, the significantly poorer TPSA, logP, and BBB penetration make it less likely to be a viable CNS drug candidate. The combination of good potency and ADME properties makes Ligand A the better choice.

Output:
0
2025-04-17 04:37:39,939 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (339.395 and 346.387 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (81.01) is significantly better than Ligand B (102.32). For CNS targets, we want TPSA <= 90, and A is comfortably within this range, while B is slightly above.

**3. logP:** Ligand A (3.607) is optimal (1-3), while Ligand B (0.543) is quite low, potentially hindering permeation.

**4. H-Bond Donors:** Ligand A (1) and Ligand B (2) are both acceptable (<=5).

**5. H-Bond Acceptors:** Ligand A (5) and Ligand B (6) are both acceptable (<=10).

**6. QED:** Ligand A (0.768) is better than Ligand B (0.528), indicating a more drug-like profile.

**7. DILI:** Ligand B (66.15) has a slightly better DILI risk profile than Ligand A (78.17), but both are reasonably acceptable (< 80).

**8. BBB:** Ligand B (44.591) is significantly better than Ligand A (30.71). For a CNS target like DRD2, a BBB percentile > 70 is desirable. While neither is ideal, B is closer.

**9. Caco-2:** Both ligands have negative Caco-2 values (-4.741 and -4.762), which is unusual and suggests poor permeability. This is a significant concern for both.

**10. Solubility:** Both ligands have negative solubility values (-5.556 and -2.627), which is also concerning.

**11. hERG:** Ligand A (0.656) has a slightly better hERG profile than Ligand B (0.026). Lower is better.

**12. Cl_mic:** Ligand A (37.905) has lower microsomal clearance than Ligand B (45.404), suggesting better metabolic stability.

**13. t1/2:** Ligand A (-20.265) has a longer in vitro half-life than Ligand B (-2.219).

**14. Pgp:** Ligand A (0.441) has lower P-gp efflux liability than Ligand B (0.011), which is favorable for CNS penetration.

**15. Binding Affinity:** Ligand A (-9.4 kcal/mol) has a significantly stronger binding affinity than Ligand B (-7.3 kcal/mol). This is a substantial advantage (2.1 kcal/mol difference).

**Overall Assessment:**

Despite Ligand B having a better BBB score, Ligand A is the stronger candidate. The significantly better binding affinity (-9.4 vs -7.3 kcal/mol) outweighs the lower BBB. Furthermore, Ligand A has better TPSA, logP, QED, metabolic stability (Cl_mic and t1/2), and P-gp efflux liability. While both have poor Caco-2 and solubility, the superior potency and ADME properties of Ligand A make it more likely to succeed as a DRD2 drug candidate.

Output:
1
2025-04-17 04:37:39,939 - INFO - Batch 129 complete. Total preferences: 2064
2025-04-17 04:37:39,939 - INFO - Processing batch 130/512...
2025-04-17 04:38:23,574 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (358.454 and 347.419 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (67.87) is excellent, well below the 90 A^2 threshold for CNS targets. Ligand B (106.82) is higher, but still potentially acceptable, though less ideal.

**logP:** Ligand A (1.531) is within the optimal 1-3 range. Ligand B (0.008) is very low, potentially hindering membrane permeability and CNS penetration.

**H-Bond Donors/Acceptors:** Ligand A (HBD=1, HBA=4) is favorable. Ligand B (HBD=2, HBA=6) is also reasonable, but slightly higher.

**QED:** Ligand A (0.643) is good, indicating a drug-like profile. Ligand B (0.365) is below the 0.5 threshold, suggesting a less favorable drug-like profile.

**DILI:** Ligand A (26.444) has a very low DILI risk. Ligand B (13.416) also has a low DILI risk, but is slightly higher than A.

**BBB:** Ligand A (97.325) has excellent predicted BBB penetration. Ligand B (64.676) is significantly lower, raising concerns about CNS exposure. This is a critical factor for a DRD2 ligand.

**Caco-2 Permeability:** Ligand A (-4.543) has poor Caco-2 permeability. Ligand B (-5.401) is even worse. Both are unfavorable.

**Aqueous Solubility:** Ligand A (-2.456) has poor aqueous solubility. Ligand B (-1.748) is slightly better, but still poor.

**hERG Inhibition:** Both ligands (0.69 and 0.678) show low hERG inhibition risk.

**Microsomal Clearance:** Ligand A (52.333) has moderate clearance. Ligand B (-21.161) has negative clearance, which is not physically possible and likely indicates an error or outlier in the prediction. However, even interpreting it as very low clearance, it's still favorable.

**In vitro Half-Life:** Ligand A (11.259 hours) is reasonable. Ligand B (13.903 hours) is slightly better.

**P-gp Efflux:** Both ligands (0.087 and 0.013) have low P-gp efflux, which is good for CNS penetration.

**Binding Affinity:** Ligand B (-7.5 kcal/mol) has a slightly better binding affinity than Ligand A (-7.2 kcal/mol), but the difference is relatively small (0.3 kcal/mol).

**Overall Assessment:**

Ligand A excels in TPSA, BBB, and DILI. Its logP is good, and its affinity is strong. The main drawbacks are its poor Caco-2 permeability and solubility.

Ligand B has a slightly better affinity and half-life, but suffers from a very low logP, significantly lower BBB penetration, and a poor QED score. The negative microsomal clearance is a red flag.

Given the GPCR-specific priorities, especially BBB penetration for a CNS target like DRD2, **Ligand A is the more promising candidate**. The slightly better affinity of Ligand B is unlikely to outweigh the significant concerns regarding its CNS exposure and drug-like properties. The poor solubility and permeability of Ligand A could be addressed with formulation strategies.

Output:
0
2025-04-17 04:38:23,575 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (355.454) is slightly higher than Ligand B (340.467), but both are acceptable.

**TPSA:** Ligand A (64.09) is better than Ligand B (49.41). For CNS targets, we want TPSA <= 90, and ideally lower. Both are well within this range, but Ligand B is closer to the ideal.

**logP:** Ligand B (3.188) is optimal (1-3), while Ligand A (0.498) is quite low. Low logP can hinder membrane permeability. This is a significant advantage for Ligand B.

**H-Bond Donors & Acceptors:** Both ligands have 1 HBD, which is good. Ligand A has 4 HBA, and Ligand B has 2 HBA. Both are within the acceptable limit of <=10, with Ligand B being slightly more favorable.

**QED:** Both ligands have a QED > 0.5 (0.801 and 0.829 respectively), indicating good drug-like properties.

**DILI:** Ligand B (25.785) has a much lower DILI risk than Ligand A (8.414). This is a significant advantage for Ligand B.

**BBB:** Ligand B (77.2) has a significantly better BBB penetration percentile than Ligand A (57.464).  For a CNS target like DRD2, >70 is desirable, and Ligand B is closer to this threshold.

**Caco-2 Permeability:** Both have negative values, which is unusual. However, the magnitude is similar, so this isn't a major differentiator.

**Aqueous Solubility:** Both have negative values, indicating poor solubility. Ligand A (-0.642) is slightly better than Ligand B (-3.675), but both are problematic.

**hERG Inhibition:** Both ligands have relatively low hERG risk (0.505 and 0.737), which is good.

**Microsomal Clearance:** Ligand A (-40.341) has a much lower (better) microsomal clearance than Ligand B (59.471), suggesting greater metabolic stability.

**In vitro Half-Life:** Ligand B (-4.505) has a slightly longer half-life than Ligand A (5.624).

**P-gp Efflux:** Ligand A (0.018) has a much lower P-gp efflux liability than Ligand B (0.417), which is beneficial for CNS penetration.

**Binding Affinity:** Ligand B (-9.7 kcal/mol) has a significantly stronger binding affinity than Ligand A (-8.5 kcal/mol). This is a substantial advantage, and can often outweigh minor ADME drawbacks.

**Overall Assessment:**

Ligand B is clearly superior. It has better logP, DILI, BBB penetration, and binding affinity. While Ligand A has better metabolic stability (lower Cl_mic) and lower P-gp efflux, the substantial advantages of Ligand B in terms of CNS penetration (BBB), safety (DILI), and potency (affinity) outweigh these drawbacks. The low logP of Ligand A is a major concern for brain penetration.



Output:
1
2025-04-17 04:38:23,575 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B based on the provided guidelines, prioritizing GPCR-specific properties (BBB, logP, Pgp, TPSA, and affinity) for DRD2.

**Molecular Weight:** Both ligands (345.443 and 343.362 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (78.51) is significantly better than Ligand B (95.04). For CNS targets, we want TPSA <= 90, and A is comfortably within that range, while B is slightly above.

**logP:** Both ligands have acceptable logP values (1.712 and 2.373, respectively), falling within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A (HBD=2, HBA=3) is slightly more favorable than Ligand B (HBD=1, HBA=6), but both are within acceptable limits.

**QED:** Both have reasonable QED scores (0.753 and 0.642), suggesting good drug-like properties.

**DILI:** Ligand A (42.497) has a considerably lower DILI risk than Ligand B (68.825). Lower is better, and A is well below the 60 threshold, while B is approaching it.

**BBB:** This is a critical parameter for a CNS target like DRD2. Ligand A (59.946) is lower than Ligand B (84.374). While ideally >70, B is significantly better at predicting BBB penetration.

**Caco-2 Permeability:** Both have negative Caco-2 values (-5.003 and -4.746), which is unusual and suggests poor permeability. However, the scale isn't defined, so it's hard to interpret.

**Aqueous Solubility:** Both ligands have negative solubility values (-2.602 and -4.095), again unusual and suggesting poor solubility.

**hERG Inhibition:** Both have low hERG inhibition risk (0.207 and 0.398).

**Microsomal Clearance:** Ligand A (-4.434) has a much lower (better) microsomal clearance than Ligand B (15.184). This indicates better metabolic stability for Ligand A.

**In vitro Half-Life:** Ligand A (7.588) has a slightly better half-life than Ligand B (-4.503).

**P-gp Efflux:** Ligand A (0.038) has significantly lower P-gp efflux liability than Ligand B (0.216). Lower is better, especially for CNS targets.

**Binding Affinity:** Ligand B (-9.0) has a significantly stronger binding affinity than Ligand A (-7.7). This is a substantial advantage (1.3 kcal/mol difference).

**Overall Assessment:**

Ligand B has a much better binding affinity and BBB penetration, which are crucial for a CNS GPCR target. However, it has higher DILI risk, P-gp efflux, and microsomal clearance. Ligand A has better TPSA, DILI, metabolic stability, and P-gp efflux, but its affinity and BBB penetration are weaker.

The affinity difference is substantial. While Ligand A has better ADME properties overall, the improved binding of Ligand B is likely to outweigh these drawbacks, especially given the potential for further optimization of ADME properties.

Output:
1
2025-04-17 04:38:23,575 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (348.49 and 344.37 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (58.64) is significantly better than Ligand B (89.6). For CNS targets, we want TPSA <= 90, and A is comfortably within this range, while B is approaching the upper limit.

**3. logP:** Ligand A (2.511) is optimal (1-3). Ligand B (0.692) is a bit low, potentially hindering membrane permeability.

**4. H-Bond Donors:** Both ligands have 1 HBD, which is within the acceptable limit of <=5.

**5. H-Bond Acceptors:** Ligand A has 3 HBAs, and Ligand B has 6. Both are within the acceptable limit of <=10, but A is preferable.

**6. QED:** Both ligands have good QED scores (0.751 and 0.881), indicating good drug-like properties.

**7. DILI:** Ligand A (24.74) has a much lower DILI risk than Ligand B (68.24). This is a significant advantage for A.

**8. BBB:** Ligand A (76.08) has a significantly better BBB penetration percentile than Ligand B (56.38). This is *critical* for a CNS target like DRD2.

**9. Caco-2 Permeability:** Ligand A (-4.667) is better than Ligand B (-5.045), indicating better intestinal absorption.

**10. Aqueous Solubility:** Ligand A (-3.159) is better than Ligand B (-2.764), indicating better solubility.

**11. hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.216 and 0.208).

**12. Microsomal Clearance:** Ligand A (53.37) has higher microsomal clearance than Ligand B (5.27), meaning B is more metabolically stable.

**13. In vitro Half-Life:** Ligand B (45.08) has a longer in vitro half-life than Ligand A (4.57). This is a slight advantage for B.

**14. P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.078 and 0.105).

**15. Binding Affinity:** Ligand B (-7.9) has a slightly better binding affinity than Ligand A (-8.7). While a 1.5 kcal/mol advantage is usually significant, the other ADME properties of A are much more favorable.

**Overall Assessment:**

Ligand A is the superior candidate. While Ligand B has slightly better binding affinity and metabolic stability, Ligand A excels in crucial properties for a CNS-targeting GPCR ligand: TPSA, logP, BBB penetration, and DILI risk. The significantly better BBB score for A outweighs the small affinity difference. The lower TPSA and better logP will also contribute to better CNS exposure.

Output:
1
2025-04-17 04:38:23,575 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands fall within the ideal range (200-500 Da). Ligand A (438.631 Da) is slightly higher than Ligand B (367.563 Da), but both are acceptable.

**TPSA:** Ligand A (46.5) is excellent for CNS penetration, well below the 90 A^2 threshold. Ligand B (54.26) is still reasonable but less optimal.

**logP:** Ligand A (4.85) is a bit high, potentially leading to solubility issues or off-target interactions. Ligand B (2.277) is within the optimal range (1-3).

**H-Bond Donors/Acceptors:** Ligand A (1 HBD, 3 HBA) and Ligand B (0 HBD, 6 HBA) both have acceptable numbers of H-bonds.

**QED:** Both ligands have good QED values (A: 0.729, B: 0.772), indicating drug-like properties.

**DILI:** Ligand A (78.945) has a higher DILI risk than Ligand B (33.463). This is a significant concern.

**BBB:** Ligand A (79.139) has excellent BBB penetration, exceeding the desirable 70% threshold. Ligand B (56.146) is lower, potentially limiting CNS exposure.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.653 and -4.895), which is unusual and suggests poor permeability. This is a red flag for both.

**Aqueous Solubility:** Both ligands have very poor aqueous solubility (-5.723 and -2.416). This is a major issue for formulation and bioavailability.

**hERG Inhibition:** Ligand A (0.545) has a slightly higher hERG risk than Ligand B (0.295), but both are relatively low.

**Microsomal Clearance:** Both ligands have similar microsomal clearance rates (A: 58.923, B: 57.355), indicating moderate metabolic stability.

**In vitro Half-Life:** Ligand A (24.751 hours) has a significantly longer half-life than Ligand B (4.875 hours).

**P-gp Efflux:** Ligand A (0.595) has lower P-gp efflux liability than Ligand B (0.071), which is favorable for CNS penetration.

**Binding Affinity:** Ligand A (-9 kcal/mol) has a significantly stronger binding affinity than Ligand B (-7 kcal/mol). This is a crucial advantage.

**Overall Assessment:**

Ligand A has a superior binding affinity and better BBB penetration and P-gp efflux, which are critical for a CNS-targeting GPCR. However, it suffers from a higher DILI risk and a higher logP. Ligand B has a better logP and lower DILI risk, but its weaker affinity and lower BBB penetration are significant drawbacks. The substantial difference in binding affinity (-9 vs -7 kcal/mol) is likely to outweigh the other concerns, especially considering the importance of potency for GPCR ligands. The poor solubility and Caco-2 permeability are concerning for both, but these could potentially be addressed through formulation strategies.

Output:
1
2025-04-17 04:38:23,576 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (358.869 and 361.511 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (51.22) is better than Ligand B (53.51). Both are reasonably close to the <90 target for CNS drugs, but A is preferable.

**3. logP:** Both ligands have good logP values (3.914 and 3.095), falling within the optimal 1-3 range.

**4. H-Bond Donors:** Ligand A (1) is better than Ligand B (0). While both are acceptable, having at least one HBD can improve solubility.

**5. H-Bond Acceptors:** Ligand B (4) is slightly better than Ligand A (3), but both are within the acceptable limit of <=10.

**6. QED:** Both ligands have similar and good QED values (0.816 and 0.813), indicating good drug-like properties.

**7. DILI:** Ligand A (29.391) has a significantly lower DILI risk than Ligand B (45.56). This is a substantial advantage for Ligand A.

**8. BBB:** Both ligands have excellent BBB penetration (73.827 and 77.743), exceeding the desirable >70 threshold for CNS targets. Ligand B is slightly better.

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.737 and -4.719). This is unusual and suggests poor permeability. However, the values are very close.

**10. Aqueous Solubility:** Both ligands have negative solubility values (-4.58 and -3.086), indicating poor aqueous solubility. Ligand B is slightly better.

**11. hERG Inhibition:** Both ligands have low hERG inhibition liability (0.54 and 0.525), which is good.

**12. Microsomal Clearance:** Ligand A (95.384) has a higher microsomal clearance than Ligand B (66.378), indicating lower metabolic stability. This is a disadvantage for Ligand A.

**13. In vitro Half-Life:** Ligand B (-12.121) has a significantly longer in vitro half-life than Ligand A (0.378), suggesting better metabolic stability. This is a major advantage for Ligand B.

**14. P-gp Efflux:** Both ligands have low P-gp efflux liability (0.246 and 0.308), which is favorable for CNS penetration.

**15. Binding Affinity:** Ligand A (-9.5 kcal/mol) has a significantly stronger binding affinity than Ligand B (-7.8 kcal/mol). This is a substantial advantage for Ligand A, potentially outweighing some of its ADME drawbacks. The difference is >1.5 kcal/mol.

**Overall Assessment:**

Ligand A has a significantly better binding affinity and lower DILI risk. However, Ligand B has better metabolic stability (lower Cl_mic, longer t1/2) and slightly better BBB penetration. The strong binding affinity of Ligand A is a major driver, and the difference in affinity is substantial. While the negative Caco-2 and solubility values are concerning for both, the strong binding of A could potentially overcome these issues with appropriate formulation strategies.

Output:
1
2025-04-17 04:38:23,576 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (347.277 Da) is slightly better, being closer to the lower end which can aid permeability.

**TPSA:** Ligand B (62.3) is significantly better than Ligand A (104.31). For CNS targets, we want TPSA <= 90, and Ligand B comfortably meets this, while Ligand A is pushing the limit.

**logP:** Both ligands have good logP values (A: 2.586, B: 3.193), falling within the optimal 1-3 range. Ligand B is slightly higher, which could potentially lead to solubility issues, but isn't a major concern.

**H-Bond Donors/Acceptors:** Ligand A has 3 HBD and 5 HBA, while Ligand B has 1 HBD and 5 HBA. Both are acceptable, within the recommended limits.

**QED:** Both ligands have good QED scores (A: 0.632, B: 0.825), indicating good drug-like properties. Ligand B is slightly better.

**DILI:** Ligand A has a very high DILI risk (99.108), which is a significant red flag. Ligand B has a much lower, and acceptable, DILI risk (56.689).

**BBB:** Ligand B has a substantially better BBB penetration score (61.264) compared to Ligand A (31.64). For a CNS target like DRD2, BBB penetration is crucial, making Ligand B far superior in this regard.

**Caco-2 Permeability:** Ligand A (-4.913) has better Caco-2 permeability than Ligand B (-5.324), but both are negative values, which is unusual and requires further investigation.

**Aqueous Solubility:** Ligand A (-4.975) has better aqueous solubility than Ligand B (-4.5), but both are negative values, which is unusual and requires further investigation.

**hERG Inhibition:** Both ligands have low hERG inhibition liability (A: 0.714, B: 0.41), which is good.

**Microsomal Clearance:** Ligand B (32.039) has lower microsomal clearance than Ligand A (61.199), indicating better metabolic stability.

**In vitro Half-Life:** Ligand A (-9.025) has a longer in vitro half-life than Ligand B (0.033).

**P-gp Efflux:** Ligand A (0.328) has lower P-gp efflux than Ligand B (0.271), which is desirable for CNS exposure.

**Binding Affinity:** Ligand A (-9.7 kcal/mol) has a significantly stronger binding affinity than Ligand B (-8.4 kcal/mol). This is a substantial advantage.

**Overall Assessment:**

While Ligand A boasts a superior binding affinity, its extremely high DILI risk and poor BBB penetration are major drawbacks. Ligand B, despite slightly weaker affinity, presents a much more favorable ADME-Tox profile, particularly its significantly lower DILI risk and substantially improved BBB penetration, which are critical for a CNS-targeting drug. The lower clearance and better QED of Ligand B also contribute to its improved profile. The affinity difference, while notable, might be overcome with further optimization of Ligand B.

Output:
1
2025-04-17 04:38:23,576 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (354.491 and 352.475 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (78.87) is slightly higher than Ligand B (70.08). Both are below the 90 A^2 threshold for CNS targets, which is good.

**3. logP:** Both ligands have similar logP values (1.563 and 1.578), falling within the optimal 1-3 range.

**4. H-Bond Donors:** Ligand A has 2 HBD, and Ligand B has 1. Both are within the acceptable limit of <=5.

**5. H-Bond Acceptors:** Both ligands have 4 HBA, which is within the acceptable limit of <=10.

**6. QED:** Ligand A (0.759) has a higher QED than Ligand B (0.532), indicating a more drug-like profile.

**7. DILI:** Ligand A (19.038) has a significantly lower DILI risk than Ligand B (14.23). This is a substantial advantage.

**8. BBB:** Ligand B (64.482) has a considerably higher BBB penetration percentile than Ligand A (44.281). This is a critical factor for a CNS target like DRD2.

**9. Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and suggests poor permeability. However, the values are similar (-4.656 vs -4.597).

**10. Aqueous Solubility:** Both have negative solubility values, indicating poor solubility. Ligand B (-1.358) is slightly better than Ligand A (-2.304).

**11. hERG Inhibition:** Both ligands have low hERG inhibition risk (0.333 and 0.467).

**12. Microsomal Clearance:** Both have similar microsomal clearance values (37.641 and 36.705), indicating similar metabolic stability.

**13. In vitro Half-Life:** Ligand B (0.295 hours) has a much shorter half-life than Ligand A (14.263 hours). This is a significant drawback for Ligand B.

**14. P-gp Efflux:** Both ligands have low P-gp efflux liability (0.098 and 0.184).

**15. Binding Affinity:** Ligand B (-7.6 kcal/mol) has a significantly stronger binding affinity than Ligand A (-6.6 kcal/mol). This is a 1.0 kcal/mol difference, which is substantial and can often outweigh other ADME concerns.

**Overall Assessment:**

While Ligand A has better QED, DILI, and *much* better in vitro half-life, Ligand B's superior BBB penetration and significantly stronger binding affinity are crucial for a CNS GPCR target like DRD2. The 1.0 kcal/mol difference in binding affinity is a major advantage. The poor solubility and Caco-2 permeability are concerns for both, but can potentially be addressed through formulation strategies. The shorter half-life of Ligand B is a concern, but could be improved through structural modifications.

Output:
1
2025-04-17 04:38:23,576 - INFO - Reasoning:

Let's analyze Ligand A and Ligand B for their potential as DRD2 drug candidates, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (382.247 and 344.459 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (84.22) is better than Ligand B (78.09) as both are below the 90 A^2 threshold for CNS targets.

**3. logP:** Both ligands have excellent logP values (3.009 and 2.839) within the optimal 1-3 range.

**4. H-Bond Donors:** Both have 2 HBD, which is acceptable.

**5. H-Bond Acceptors:** Ligand A has 4 HBA, and Ligand B has 3. Both are within the acceptable limit of 10.

**6. QED:** Ligand A (0.833) has a significantly better QED score than Ligand B (0.641), indicating a more drug-like profile.

**7. DILI:** Ligand A (76.115) has a higher DILI risk than Ligand B (54.983), which is a negative for Ligand A.

**8. BBB:** Ligand B (58.86) has a better BBB penetration percentile than Ligand A (49.244), but both are below the desirable >70 for CNS targets.

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 values, which is unusual and suggests poor permeability. Ligand A (-5.13) is slightly better than Ligand B (-5.361).

**10. Aqueous Solubility:** Both ligands have negative solubility values, indicating poor aqueous solubility. Ligand A (-3.646) is slightly better than Ligand B (-3.313).

**11. hERG Inhibition:** Ligand A (0.01) has a much lower hERG inhibition risk than Ligand B (0.242), which is a significant advantage.

**12. Microsomal Clearance:** Ligand B (48.488) has a lower microsomal clearance than Ligand A (6.807), suggesting better metabolic stability.

**13. In vitro Half-Life:** Ligand B (8.935) has a significantly longer in vitro half-life than Ligand A (-22.531), which is a major advantage.

**14. P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.011 and 0.177), which is good.

**15. Binding Affinity:** Ligand A (-8.6 kcal/mol) has a significantly stronger binding affinity than Ligand B (-7.5 kcal/mol). This >1.5 kcal/mol difference is substantial and can outweigh some ADME drawbacks.

**Overall Assessment:**

Ligand A has a superior binding affinity and a better QED score, and lower hERG risk. However, Ligand B has a better BBB, lower DILI risk, better metabolic stability (lower Cl_mic), and a longer half-life. The strong affinity of Ligand A is a significant advantage for a GPCR target. While both have poor solubility and permeability, the affinity difference is large enough to make Ligand A the more promising candidate, assuming formulation strategies can address the solubility/permeability issues.

Output:
1
2025-04-17 04:38:23,576 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (344.455 and 339.439 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Both ligands (59.5 and 58.37) are well below the 90 A^2 threshold for CNS targets, which is excellent.

**3. logP:** Both ligands have logP values (3.154 and 3.877) within the optimal 1-3 range. Ligand B is slightly higher, which could potentially lead to some off-target effects, but is still acceptable.

**4. H-Bond Donors:** Ligand A has 0 HBD, and Ligand B has 1 HBD. Both are within the acceptable limit of <=5.

**5. H-Bond Acceptors:** Both ligands have 4 HBA, well below the limit of <=10.

**6. QED:** Both ligands have good QED scores (0.79 and 0.84), indicating drug-like properties.

**7. DILI:** Ligand A (30.826) has a significantly lower DILI risk than Ligand B (57.154). This is a substantial advantage for Ligand A.

**8. BBB:** Both ligands have high BBB penetration (91.857 and 85.421), which is crucial for CNS targets like DRD2. Ligand A is slightly better.

**9. Caco-2:** Both have negative Caco-2 values (-4.347 and -4.902), which is unusual and suggests poor permeability. This is a significant drawback for both.

**10. Solubility:** Both have negative solubility values (-3.683 and -4.115), indicating very poor aqueous solubility. This is a major concern for both compounds.

**11. hERG:** Both ligands have low hERG inhibition risk (0.723 and 0.773).

**12. Cl_mic:** Ligand A has a lower microsomal clearance (83.967) than Ligand B (108.369), suggesting better metabolic stability.

**13. t1/2:** Ligand A has a longer in vitro half-life (-7.449) than Ligand B (-6.997).

**14. Pgp:** Both ligands have low P-gp efflux liability (0.454 and 0.704).

**15. Binding Affinity:** Ligand A (-8.2 kcal/mol) has a slightly better binding affinity than Ligand B (-8.6 kcal/mol). While the difference is small, it's still a positive for Ligand A.

**Overall Assessment:**

Despite the poor Caco-2 and solubility for both compounds, Ligand A is the more promising candidate. It has a significantly lower DILI risk, better metabolic stability (lower Cl_mic, longer t1/2), slightly better BBB penetration, and a slightly stronger binding affinity. The negative Caco-2 and solubility values are concerning and would require significant medicinal chemistry efforts to address, but the other favorable properties of Ligand A make it a better starting point.

Output:
0
2025-04-17 04:38:23,577 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (346.431 Da) is slightly lower, which is generally favorable for permeability. Ligand B (364.511 Da) is also good.

**TPSA:** Ligand A (87.46) is better than Ligand B (57.69). For CNS targets, we want TPSA <= 90, both are within this range, but A is closer to the upper limit.

**logP:** Both ligands have acceptable logP values (A: 0.939, B: 1.25), falling within the optimal 1-3 range. Ligand B is slightly better.

**H-Bond Donors/Acceptors:** Ligand A has 2 HBD and 5 HBA, while Ligand B has 0 HBD and 3 HBA. Both are within the acceptable limits (<=5 HBD and <=10 HBA).

**QED:** Both ligands have similar QED values (A: 0.751, B: 0.757), indicating good drug-like properties.

**DILI:** Both ligands have low DILI risk (A: 39.511, B: 35.634), which is good.

**BBB:** This is a critical parameter for CNS targets. Ligand B (57.736) has a significantly higher BBB percentile than Ligand A (29.275). This is a major advantage for Ligand B.

**Caco-2 Permeability:** Ligand A (-4.993) and Ligand B (-4.648) both exhibit poor Caco-2 permeability.

**Aqueous Solubility:** Both ligands have poor aqueous solubility (A: -1.956, B: -2.541).

**hERG Inhibition:** Both ligands have very low hERG inhibition risk (A: 0.079, B: 0.217).

**Microsomal Clearance:** Ligand A (37.036) has lower microsomal clearance than Ligand B (49.571), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (-8.864) has a longer in vitro half-life than Ligand B (-2.587).

**P-gp Efflux:** Both ligands have low P-gp efflux liability (A: 0.099, B: 0.193).

**Binding Affinity:** Ligand B (-7.6 kcal/mol) has a slightly better binding affinity than Ligand A (-7.1 kcal/mol). Although the difference is less than the 1.5 kcal/mol threshold, it's still a positive factor.

**Overall Assessment:**

Ligand B is the more promising candidate. The significantly higher BBB penetration (57.736 vs. 29.275) is the most crucial factor for a CNS-targeting drug. While Ligand A has better metabolic stability and half-life, the BBB advantage of Ligand B outweighs these benefits. Both have similar drug-like properties and low toxicity risks. The slightly better binding affinity of Ligand B further supports its selection.

Output:
1
2025-04-17 04:38:23,577 - INFO - Reasoning:

Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (349.435 and 357.42 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (110.93) is slightly above the preferred <90 for CNS targets, but not drastically. Ligand B (38.13) is excellent, well below 90. This favors Ligand B.

**3. logP:** Ligand A (0.952) is a bit low, potentially impacting permeability. Ligand B (3.89) is excellent, falling within the optimal 1-3 range. This strongly favors Ligand B.

**4. H-Bond Donors:** Ligand A (4) is acceptable. Ligand B (0) is also good, potentially improving permeability.

**5. H-Bond Acceptors:** Ligand A (4) is acceptable. Ligand B (3) is also good.

**6. QED:** Both ligands (0.634 and 0.695) have good drug-likeness scores, exceeding the 0.5 threshold.

**7. DILI:** Ligand A (16.867) has a much lower DILI risk than Ligand B (30.748). This favors Ligand A.

**8. BBB:** Ligand B (94.61) has a significantly higher BBB penetration score than Ligand A (63.862). This is a critical advantage for a CNS target like DRD2 and strongly favors Ligand B.

**9. Caco-2 Permeability:** Ligand A (-5.662) has poor Caco-2 permeability. Ligand B (-4.202) is also poor, but slightly better.

**10. Aqueous Solubility:** Ligand A (-1.084) has poor aqueous solubility. Ligand B (-3.763) is even worse. Both are problematic, but the lower logP of A might help slightly.

**11. hERG Inhibition:** Ligand A (0.363) has a very low hERG risk. Ligand B (0.626) is slightly higher, but still relatively low. This favors Ligand A.

**12. Microsomal Clearance:** Ligand A (-4.654) has a negative clearance, indicating very high metabolic stability. Ligand B (60.136) has high clearance, suggesting rapid metabolism. This strongly favors Ligand A.

**13. In vitro Half-Life:** Ligand A (9.209) has a moderate half-life. Ligand B (-10.97) has a negative half-life, which is not physically meaningful and suggests instability or a problem with the assay. This dramatically favors Ligand A.

**14. P-gp Efflux:** Ligand A (0.017) has very low P-gp efflux, which is excellent for CNS penetration. Ligand B (0.34) has moderate P-gp efflux. This favors Ligand A.

**15. Binding Affinity:** Ligand B (-7.1) has a slightly better binding affinity than Ligand A (-8.2). While affinity is important, the difference of 1.1 kcal/mol is not substantial enough to overcome the significant ADME deficiencies of Ligand B.

**Overall Assessment:**

Ligand B excels in BBB penetration and logP, which are crucial for CNS GPCR targets. However, it suffers from poor metabolic stability (high Cl_mic), a questionable half-life, and poor solubility. Ligand A, while having a slightly lower BBB score and logP, demonstrates significantly better metabolic stability, P-gp efflux, and a more reasonable half-life. The DILI and hERG risks are also lower for Ligand A. Considering the balance of properties and the importance of metabolic stability and CNS penetration for a DRD2 ligand, Ligand A is the more promising candidate.

Output:
0
2025-04-17 04:38:23,577 - INFO - Okay, let's analyze these two ligands for their potential as DRD2 drug candidates.

**Step-by-step comparison:**

1. **MW:** Both ligands (A: 336.395 Da, B: 339.435 Da) fall within the ideal 200-500 Da range. No significant difference here.

2. **TPSA:** Ligand A (71.11) is significantly better than Ligand B (38.77). For a CNS target like DRD2, we want TPSA as low as possible, ideally under 90, and A is closer to this target.

3. **logP:** Ligand A (2.868) is within the optimal 1-3 range. Ligand B (4.37) is a bit high, potentially leading to solubility issues and off-target interactions.

4. **HBD:** Ligand A (1) is preferable to Ligand B (0). While both are low, a single H-bond donor can aid solubility without significantly impacting permeability.

5. **HBA:** Ligand A (4) is better than Ligand B (3). Both are acceptable, but fewer HBA generally improves permeability.

6. **QED:** Ligand A (0.798) has a much better QED score than Ligand B (0.476). This indicates a more drug-like profile for Ligand A.

7. **DILI:** Ligand A (72.043) has a slightly higher DILI risk than Ligand B (42.536), but both are below the concerning threshold of 60.

8. **BBB:** Ligand B (56.65) has a significantly better BBB penetration percentile than Ligand A (43.505). This is a *critical* factor for a CNS target like DRD2.

9. **Caco-2:** Ligand A (-5.018) has a more negative Caco-2 value, which is unusual and suggests very poor permeability. Ligand B (-4.584) is also poor, but less so.

10. **Solubility:** Ligand A (-3.573) and Ligand B (-4.625) both have poor aqueous solubility.

11. **hERG:** Both ligands have low hERG risk (A: 0.632, B: 0.787).

12. **Cl_mic:** Ligand A (26.806) has a lower microsomal clearance than Ligand B (96.049), suggesting better metabolic stability.

13. **t1/2:** Ligand A (-4.849) has a more negative in vitro half-life, which is unusual and suggests a very short half-life. Ligand B (-0.467) is better.

14. **Pgp:** Ligand A (0.205) has a lower P-gp efflux liability than Ligand B (0.548), which is favorable for CNS penetration.

15. **Binding Affinity:** Ligand A (-8.9 kcal/mol) has a significantly stronger binding affinity than Ligand B (-7.8 kcal/mol). This is a substantial advantage.

**GPCR-Specific Priorities:**

For DRD2 (a CNS GPCR), we prioritize BBB, logP, TPSA, Pgp, and affinity. Ligand B excels in BBB penetration. Ligand A has better TPSA, Pgp, and a *much* stronger binding affinity. The logP of Ligand A is better.

**Overall Assessment:**

Despite Ligand B's better BBB score, the significantly stronger binding affinity of Ligand A (-8.9 vs -7.8 kcal/mol) is a major advantage. A 1.1 kcal/mol difference is substantial and can often outweigh minor ADME drawbacks. The better TPSA and Pgp values for Ligand A also contribute to its favorability. While the Caco-2 and t1/2 values for Ligand A are concerning, these can potentially be addressed through structural modifications. The solubility is also poor for both, but can be improved.

Therefore, I predict Ligand A is the more viable drug candidate.

Output:
1
2025-04-17 04:38:23,577 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (364.471 and 348.491 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (83.89) is better than Ligand B (70.39). Both are below the 90 A^2 threshold desirable for CNS targets, but Ligand A is slightly higher and could pose a minor permeability issue.

**logP:** Both ligands have good logP values (1.514 and 1.921), falling within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A (HBD=1, HBA=6) is slightly better than Ligand B (HBD=2, HBA=5) in terms of balancing solubility and permeability.

**QED:** Both ligands have strong drug-like profiles (0.858 and 0.872).

**DILI:** Ligand A (35.401) has a significantly lower DILI risk than Ligand B (8.957), which is a major advantage.

**BBB:** Ligand B (75.107) has a much better BBB penetration score than Ligand A (47.111). This is *critical* for a CNS target like DRD2.

**Caco-2 Permeability:** Ligand A (-5.19) has a worse Caco-2 permeability than Ligand B (-4.757), suggesting lower intestinal absorption.

**Aqueous Solubility:** Both have poor aqueous solubility (-1.303 and -2.058).

**hERG Inhibition:** Ligand A (0.118) shows lower hERG inhibition liability than Ligand B (0.336), which is favorable.

**Microsomal Clearance:** Ligand A (-0.379) has a lower (better) microsomal clearance than Ligand B (14.262), indicating greater metabolic stability.

**In vitro Half-Life:** Ligand A (8.29) has a longer half-life than Ligand B (-1.647), which is desirable.

**P-gp Efflux:** Ligand A (0.029) has much lower P-gp efflux liability than Ligand B (0.04), which is beneficial for CNS exposure.

**Binding Affinity:** Ligand A (-8.1 kcal/mol) has a slightly better binding affinity than Ligand B (-7.1 kcal/mol). The difference is 1 kcal/mol, which is significant.

**Overall Assessment:**

Ligand A excels in metabolic stability (Cl_mic, t1/2), DILI risk, P-gp efflux, and binding affinity. While its BBB penetration is lower, its superior affinity and safety profile are compelling. Ligand B's main advantage is its BBB penetration, but it is offset by higher DILI risk, worse metabolic stability, and lower affinity. Given the importance of affinity for GPCRs and the relatively modest difference in BBB penetration, the better overall profile of Ligand A makes it the more promising candidate.

Output:
1
2025-04-17 04:38:23,578 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (369.511 Da) is slightly higher than Ligand B (350.419 Da), but both are acceptable.

**TPSA:** Ligand A (46.17) is excellent for CNS penetration, well below the 90 A^2 threshold. Ligand B (115.97) is higher, but still potentially acceptable, though less ideal.

**logP:** Ligand A (4.159) is slightly high, potentially leading to solubility issues or off-target effects. Ligand B (-0.731) is too low, which could hinder membrane permeability and CNS penetration.

**H-Bond Donors/Acceptors:** Ligand A (HBD=1, HBA=4) is within acceptable limits. Ligand B (HBD=3, HBA=4) is also acceptable.

**QED:** Both ligands have reasonable QED scores (A: 0.823, B: 0.567), indicating good drug-like properties.

**DILI:** Ligand A (70.686) has a higher DILI risk than Ligand B (18.883), which is a significant concern.

**BBB:** Ligand A (87.088) has excellent BBB penetration, exceeding the 70% threshold. Ligand B (43.001) has poor BBB penetration, a major drawback for a CNS target.

**Caco-2 Permeability:** Ligand A (-4.982) has poor Caco-2 permeability. Ligand B (-5.287) also has poor Caco-2 permeability.

**Aqueous Solubility:** Both ligands have poor aqueous solubility (A: -5.304, B: -1.076).

**hERG Inhibition:** Ligand A (0.589) has a low hERG inhibition risk. Ligand B (0.138) also has a low hERG inhibition risk.

**Microsomal Clearance:** Ligand A (68.438) has moderate clearance, while Ligand B (-47.926) has negative clearance, which is not possible and likely indicates an error in the data or a very stable compound.

**In vitro Half-Life:** Ligand A (61.485) has a reasonable half-life. Ligand B (2.979) has a very short half-life.

**P-gp Efflux:** Ligand A (0.828) has moderate P-gp efflux. Ligand B (0.003) has very low P-gp efflux, which is favorable for CNS penetration.

**Binding Affinity:** Ligand A (-9.3 kcal/mol) has significantly stronger binding affinity than Ligand B (-8.4 kcal/mol). The difference of 0.9 kcal/mol is substantial and could outweigh some ADME drawbacks.

**Overall Assessment:**

Ligand A excels in binding affinity and BBB penetration, crucial for a CNS GPCR target. However, its higher DILI risk and poor Caco-2 permeability are significant concerns. Ligand B has a lower DILI risk and P-gp efflux, but suffers from poor BBB penetration, low logP, and a very short half-life. The strong affinity of Ligand A is a major advantage, and while the DILI risk is concerning, it might be mitigated through structural modifications. The poor BBB penetration of Ligand B is a more difficult issue to address.

Output:
1
2025-04-17 04:38:23,578 - INFO - Reasoning:

Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the acceptable range (200-500 Da). Ligand A (335.403 Da) is slightly preferred due to being lower in weight.

**TPSA:** Both ligands have TPSA values below 90, which is good for CNS penetration. Ligand A (59.32) is better than Ligand B (50.16) in this regard.

**logP:** Both ligands have logP values around 4.1, which is slightly high but acceptable. This could potentially lead to some off-target effects or solubility issues, but is not a major concern.

**H-Bond Donors/Acceptors:** Ligand A (0 HBD, 4 HBA) is better than Ligand B (1 HBD, 3 HBA) regarding these parameters. Lower counts are generally preferred for better permeability.

**QED:** Both ligands have good QED scores (A: 0.537, B: 0.776), indicating drug-like properties. Ligand B is slightly better.

**DILI:** Both ligands have DILI risk around the 50-60 percentile, which is acceptable, but not ideal. Ligand B is slightly better.

**BBB:** This is a crucial parameter for CNS targets. Ligand B (86.739%) significantly outperforms Ligand A (55.254%). This is a major advantage for Ligand B.

**Caco-2 Permeability:** Both have negative values, which is unusual. However, the magnitude is similar.

**Aqueous Solubility:** Both have negative values, which is also unusual. The values are similar.

**hERG Inhibition:** Both ligands show low hERG inhibition liability (A: 0.851, B: 0.746), which is good.

**Microsomal Clearance:** Ligand A (115.544) has higher clearance than Ligand B (62.741), meaning Ligand B is more metabolically stable.

**In vitro Half-Life:** Ligand B (30.577 hours) has a significantly longer half-life than Ligand A (-17.357 hours). This is a substantial advantage for Ligand B.

**P-gp Efflux:** Both ligands have similar P-gp efflux liability (A: 0.609, B: 0.662).

**Binding Affinity:** Both ligands have very similar binding affinities (-8.5 kcal/mol). This difference is negligible.

**Overall Assessment:**

While Ligand A has slightly better TPSA and H-bonding properties, Ligand B excels in the critical areas for CNS GPCR targets: BBB penetration and metabolic stability (lower Cl_mic and longer t1/2). The higher QED and slightly lower DILI risk for Ligand B are also beneficial. The similar binding affinity makes the ADME properties the deciding factor.

Output:
1
2025-04-17 04:38:23,578 - INFO - Batch 130 complete. Total preferences: 2080
2025-04-17 04:38:23,578 - INFO - Processing batch 131/512...
2025-04-17 04:39:03,791 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B based on the provided guidelines, prioritizing GPCR-specific properties (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (349.475 and 350.522 Da) fall within the ideal range of 200-500 Da.

**TPSA:** Ligand A (61.88) is higher than the preferred <90 for CNS targets, but not drastically so. Ligand B (23.55) is excellent, well below the threshold.

**logP:** Ligand A (1.338) is within the optimal 1-3 range. Ligand B (4.186) is slightly above, potentially leading to solubility issues and off-target interactions, but still within a reasonable range.

**H-Bond Donors/Acceptors:** Ligand A (1 HBD, 4 HBA) is good. Ligand B (0 HBD, 2 HBA) is also favorable.

**QED:** Both ligands have good QED scores (0.531 and 0.643, respectively), indicating drug-like properties.

**DILI:** Both ligands have low DILI risk (6.863 and 5.584 percentiles), which is positive.

**BBB:** This is a crucial parameter for a CNS target like DRD2. Ligand A has a BBB percentile of 62.117, which is okay but not ideal. Ligand B shines here with a BBB percentile of 97.247, indicating excellent brain penetration potential.

**Caco-2 Permeability:** Both have negative values, which is unusual. Assuming these are logP-like scales, lower values suggest poorer permeability.

**Aqueous Solubility:** Both have negative values, which is unusual. Assuming these are logS-like scales, lower values suggest poorer solubility.

**hERG:** Both ligands show low hERG inhibition liability (0.311 and 0.899), minimizing cardiotoxicity risk.

**Microsomal Clearance:** Ligand A (34.798 mL/min/kg) is slightly higher than Ligand B (26.694 mL/min/kg), suggesting potentially lower metabolic stability for Ligand A.

**In vitro Half-Life:** Ligand B has a significantly longer in vitro half-life ( -22.388 hours) compared to Ligand A (7.032 hours), which is a major advantage.

**P-gp Efflux:** Ligand A (0.011) shows very low P-gp efflux, which is excellent. Ligand B (0.332) is slightly higher, indicating some potential for efflux, but still reasonable.

**Binding Affinity:** Ligand A (-8.2 kcal/mol) has a slightly better binding affinity than Ligand B (-7.3 kcal/mol). However, the difference is less than 1.5 kcal/mol, so it doesn't overwhelmingly outweigh other factors.

**Conclusion:**

Considering the GPCR-specific priorities, Ligand B is the more promising candidate. Its exceptionally high BBB penetration (97.247%) is a significant advantage for a CNS target. While Ligand A has slightly better binding affinity, Ligand B compensates with superior BBB, longer half-life, and comparable ADME properties. The slightly higher logP of Ligand B is a minor concern, but the benefits outweigh this potential drawback.

Output:
1
2025-04-17 04:39:03,791 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (363.439 and 373.341 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (84.67) is excellent, falling well below the 90 A^2 threshold for CNS targets. Ligand B (116.64) is higher, but still reasonable, though less optimal.

**logP:** Ligand A (2.15) is within the optimal 1-3 range. Ligand B (-0.765) is below 1, which could hinder permeation.

**H-Bond Donors/Acceptors:** Both ligands have acceptable HBD (1 & 2) and HBA (6 & 6) counts, well within the guidelines.

**QED:** Both ligands have QED values above 0.7, indicating good drug-likeness.

**DILI:** Both ligands have DILI risk around 66-72, which is acceptable, though not ideal.

**BBB:** Both ligands exhibit good BBB penetration (76.309% and 71.268%), crucial for a CNS target like DRD2.

**Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and suggests a potential issue with the data or modeling. However, we'll proceed assuming this represents low permeability.

**Aqueous Solubility:** Both ligands have very poor aqueous solubility (-3.46 and -3.542). This could pose formulation challenges.

**hERG Inhibition:** Both ligands show low hERG inhibition risk (0.3 and 0.416).

**Microsomal Clearance:** Ligand A (33.549) has moderate clearance, while Ligand B (-30.121) has negative clearance, which is not physically possible and indicates a data issue.

**In vitro Half-Life:** Ligand A (13.83 hours) has a reasonable half-life. Ligand B (-40.687 hours) has a negative half-life, which is not physically possible and indicates a data issue.

**P-gp Efflux:** Both ligands show low P-gp efflux liability (0.116 and 0.013), which is favorable for CNS penetration.

**Binding Affinity:** Ligand B (-9.2 kcal/mol) has a significantly stronger binding affinity than Ligand A (-7.5 kcal/mol). This >1.5 kcal/mol difference is a major advantage.

**Overall Assessment:**

Despite the issues with Caco-2, solubility, and the physically impossible values for clearance and half-life for Ligand B, its substantially superior binding affinity (-9.2 vs -7.5 kcal/mol) is the deciding factor. The strong binding is likely to outweigh the ADME concerns, especially given the acceptable BBB penetration and low P-gp efflux. Ligand A's ADME profile is slightly better, but the difference in affinity is too significant to ignore for a GPCR target. The negative values for clearance and half-life of Ligand B are concerning and would require further investigation, but the initial binding affinity makes it the more promising candidate.

Output:
1
2025-04-17 04:39:03,791 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 drug candidates, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (350.407 and 342.439 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (103.59) is higher than the preferred <90 for CNS targets, but still potentially acceptable. Ligand B (58.64) is excellent, well below the threshold. This favors Ligand B.

**3. logP:** Both ligands (2.512 and 2.206) are within the optimal 1-3 range.

**4. H-Bond Donors:** Ligand A (2) and Ligand B (1) are both within the acceptable limit of <=5.

**5. H-Bond Acceptors:** Ligand A (7) and Ligand B (3) are both within the acceptable limit of <=10.

**6. QED:** Both ligands have good QED scores (0.704 and 0.892), indicating drug-like properties.

**7. DILI:** Ligand A (97.674) has a very high DILI risk, which is a significant concern. Ligand B (35.634) has a low DILI risk, which is highly favorable.

**8. BBB:** Ligand A (48.391) has a low BBB penetration percentile, which is problematic for a CNS target. Ligand B (93.874) has excellent BBB penetration, a major advantage.

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.135 and -4.627) which is unusual and suggests poor permeability. This is a concern for both.

**10. Aqueous Solubility:** Both ligands have negative solubility values (-5.176 and -3.054) which is also unusual and suggests poor solubility. This is a concern for both.

**11. hERG:** Both ligands have low hERG inhibition risk (0.565 and 0.571).

**12. Microsomal Clearance:** Ligand A (21.195) has lower clearance than Ligand B (71.346), suggesting better metabolic stability.

**13. In vitro Half-Life:** Ligand A (57.902) has a longer half-life than Ligand B (22.454).

**14. P-gp Efflux:** Both ligands have low P-gp efflux liability (0.187 and 0.349).

**15. Binding Affinity:** Ligand A (-9.2 kcal/mol) has a slightly better binding affinity than Ligand B (-8.3 kcal/mol), but the difference is not substantial enough to overcome the other significant drawbacks.

**Overall Assessment:**

Ligand B is significantly more promising. While both ligands have issues with Caco-2 and solubility, Ligand B excels in crucial areas for a CNS GPCR target: excellent BBB penetration, low DILI risk, and a good QED score. Ligand A's high DILI risk and poor BBB penetration are major red flags. Although Ligand A has slightly better affinity and metabolic stability, these advantages are outweighed by the serious safety and pharmacokinetic concerns.

Output:
1
2025-04-17 04:39:03,791 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (374.547 and 349.479 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (83.55) is better than Ligand B (74.49) as both are below the 90 A^2 threshold for CNS targets.

**logP:** Ligand A (1.989) is within the optimal 1-3 range, while Ligand B (0.783) is slightly below 1, potentially hindering permeation.

**H-Bond Donors:** Both ligands have 1 HBD, which is acceptable.

**H-Bond Acceptors:** Ligand A has 4 HBA, and Ligand B has 6. Both are within the acceptable limit of 10.

**QED:** Both ligands have similar QED values (0.704 and 0.751), indicating good drug-likeness.

**DILI:** Ligand A (27.142) has a significantly lower DILI risk than Ligand B (8.569), suggesting better hepatotoxicity profile.

**BBB:** Ligand A (68.941) has a better BBB penetration percentile than Ligand B (53.238), which is crucial for a CNS target like DRD2. While >70 is desirable, 68.941 is still reasonably good.

**Caco-2 Permeability:** Ligand A (-5.037) has a worse Caco-2 permeability than Ligand B (-4.862), but both are negative values, indicating poor permeability.

**Aqueous Solubility:** Ligand A (-2.69) has better aqueous solubility than Ligand B (-0.174).

**hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.34 and 0.141).

**Microsomal Clearance:** Ligand A (16.49) has a higher microsomal clearance than Ligand B (5.321), indicating lower metabolic stability.

**In vitro Half-Life:** Ligand B (17.33) has a significantly longer in vitro half-life than Ligand A (4.65).

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.133 and 0.037).

**Binding Affinity:** Both ligands have excellent binding affinity (-7.3 and -7.0 kcal/mol), with Ligand A being slightly better. The difference is less than 1.5 kcal/mol, so this is not a deciding factor.

**Overall Assessment:**

Considering the GPCR-specific priorities, Ligand A is more promising. It has a better BBB score, lower DILI risk, and slightly better binding affinity. Although Ligand B has a longer half-life and better Caco-2 permeability, the CNS target necessitates prioritizing BBB penetration and minimizing toxicity. The slightly lower metabolic stability of Ligand A can be addressed through structural modifications during lead optimization. Ligand B's lower logP is also a concern for CNS penetration.

Output:
1
2025-04-17 04:39:03,792 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (350.503 and 355.454 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (49.85) is significantly better than Ligand B (78.51). For CNS targets, we want TPSA <= 90, and A is comfortably within that range, while B is approaching the upper limit.

**3. logP:** Ligand A (3.143) is optimal (1-3), while Ligand B (1.538) is at the lower end, potentially hindering permeability.

**4. H-Bond Donors:** Ligand A (0) is preferable to Ligand B (2). Fewer HBDs generally improve permeability.

**5. H-Bond Acceptors:** Both ligands have 3 HBAs, which is acceptable.

**6. QED:** Both ligands have good QED scores (0.632 and 0.759), indicating drug-like properties.

**7. DILI:** Ligand A (16.906) has a slightly higher DILI risk than Ligand B (20.279), but both are relatively low and acceptable.

**8. BBB:** Both ligands have excellent BBB penetration (90.461 and 88.639), exceeding the desirable >70 threshold for CNS targets.

**9. Caco-2 Permeability:** Ligand A (-4.481) is worse than Ligand B (-4.848), but both are negative values, indicating poor permeability.

**10. Aqueous Solubility:** Both ligands have poor aqueous solubility (-2.092 and -2.378). This could be a formulation challenge, but not a deal-breaker if other properties are strong.

**11. hERG Inhibition:** Ligand A (0.635) has a slightly better hERG profile than Ligand B (0.413), indicating lower cardiotoxicity risk.

**12. Microsomal Clearance:** Ligand A (75.58) has higher clearance than Ligand B (-4.11), suggesting lower metabolic stability. This is a significant drawback for A.

**13. In vitro Half-Life:** Ligand B (-24.32) has a much longer half-life than Ligand A (-4.897), which is a major advantage.

**14. P-gp Efflux:** Ligand A (0.389) has lower P-gp efflux than Ligand B (0.054), which is desirable for CNS exposure.

**15. Binding Affinity:** Ligand B (-8.3) has a significantly stronger binding affinity than Ligand A (0), by over 8 kcal/mol. This is a substantial difference and can outweigh many other ADME concerns.

**Overall Assessment:**

While Ligand A has a better TPSA and P-gp efflux profile, Ligand B's significantly stronger binding affinity (-8.3 kcal/mol vs 0 kcal/mol) and longer half-life are crucial advantages, especially for a GPCR target like DRD2. The slightly lower logP of Ligand B is a minor concern, but the strong affinity is likely to compensate. The higher clearance of Ligand A is a significant negative.

Output:
1
2025-04-17 04:39:03,792 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (349.431 Da) is slightly lower, which could be beneficial for permeability.

**2. TPSA:** Ligand A (98.74) is better than Ligand B (113.32). For CNS targets, we want TPSA <= 90, so both are a bit high, but A is closer.

**3. logP:** Ligand A (-0.055) is lower than the optimal 1-3 range, potentially hindering permeation. Ligand B (0.974) is closer to the ideal range.

**4. H-Bond Donors:** Both have 4 HBD, which is acceptable (<=5).

**5. H-Bond Acceptors:** Both have 4 HBA, which is acceptable (<=10).

**6. QED:** Both have reasonable QED scores (A: 0.606, B: 0.51), indicating good drug-like properties.

**7. DILI:** Ligand A (19.232) has a significantly lower DILI risk than Ligand B (28.499). This is a major advantage for A.

**8. BBB:** Ligand A (46.336) has a lower BBB penetration percentile than Ligand B (55.138). While both are not ideal (>70), B is better.

**9. Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and suggests poor permeability. However, the scale is not specified, so it's hard to interpret.

**10. Aqueous Solubility:** Both have negative solubility values, again, making interpretation difficult without knowing the scale.

**11. hERG Inhibition:** Ligand A (0.039) has a lower hERG inhibition risk than Ligand B (0.137). This is a positive for A.

**12. Microsomal Clearance:** Ligand A (-6.348) has a lower (better) microsomal clearance than Ligand B (10.869). This suggests better metabolic stability for A.

**13. In vitro Half-Life:** Ligand A (11.551) has a longer half-life than Ligand B (9.439).

**14. P-gp Efflux:** Ligand A (0.008) has a much lower P-gp efflux liability than Ligand B (0.016). This is crucial for CNS penetration and is a significant advantage for A.

**15. Binding Affinity:** Ligand B (-7.3 kcal/mol) has a better binding affinity than Ligand A (-8.1 kcal/mol). This is a substantial difference and a strong point in favor of B.

**Overall Assessment:**

While Ligand B has a better binding affinity and slightly better BBB penetration, Ligand A demonstrates a significantly better safety profile (lower DILI, hERG), better metabolic stability (lower Cl_mic, longer t1/2), and lower P-gp efflux. Considering DRD2 is a CNS target, minimizing efflux and maximizing CNS exposure are critical. The affinity difference, while notable, might be overcome with further optimization of Ligand A. The poor solubility and permeability for both are concerning, but the other advantages of Ligand A make it the more promising starting point.

Output:
0
2025-04-17 04:39:03,792 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (335.363 and 335.367 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (83.37) is significantly better than Ligand B (98.81). For CNS targets, we want TPSA <= 90, and A is comfortably within that range, while B is close to the upper limit.

**3. logP:** Ligand A (3.559) is slightly higher than Ligand B (2.751), both are within the optimal 1-3 range.

**4. H-Bond Donors:** Ligand A (3) is higher than Ligand B (1). While both are acceptable (<=5), lower is generally preferred for BBB penetration.

**5. H-Bond Acceptors:** Ligand A (3) and Ligand B (5) are both acceptable (<=10).

**6. QED:** Both ligands have good QED values (0.684 and 0.776, respectively), indicating good drug-like properties.

**7. DILI:** Both ligands have acceptable DILI risk (89.066 and 82.513 percentiles), indicating low potential for liver injury.

**8. BBB:** Ligand A (72.082) has a better BBB percentile than Ligand B (64.754). A value >70 is desirable for CNS targets, and A is closer to that threshold.

**9. Caco-2 Permeability:** Ligand A (-4.971) has worse Caco-2 permeability than Ligand B (-5.148). Lower values indicate lower permeability.

**10. Aqueous Solubility:** Ligand A (-5.101) has worse solubility than Ligand B (-3.824). Higher values are better.

**11. hERG Inhibition:** Both ligands have low hERG inhibition risk (0.604 and 0.453, respectively).

**12. Microsomal Clearance:** Ligand A (30.913) has higher microsomal clearance than Ligand B (25.01). Lower clearance is preferred for metabolic stability.

**13. In vitro Half-Life:** Ligand A (133.22) has a much longer half-life than Ligand B (6.391). This is a significant advantage.

**14. P-gp Efflux:** Ligand A (0.204) has lower P-gp efflux than Ligand B (0.189), meaning it's less likely to be pumped out of the brain, which is beneficial for CNS targets.

**15. Binding Affinity:** Ligand B (-7.6 kcal/mol) has a significantly stronger binding affinity than Ligand A (-10.2 kcal/mol). This is a substantial advantage, potentially outweighing some ADME drawbacks.

**Overall Assessment:**

Ligand B has a much better binding affinity, which is the most important factor. While Ligand A has better BBB penetration and a longer half-life, the difference in binding affinity is substantial (1.5 kcal/mol difference). The slightly higher TPSA of Ligand B is manageable, and its other ADME properties are reasonable. The improved binding affinity will likely translate to greater efficacy, making it the more promising candidate.

Output:
1
2025-04-17 04:39:03,792 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (350.463 and 351.407 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (98.32) is significantly better than Ligand B (135.95). For CNS targets, we want TPSA <= 90, so Ligand A is closer to this threshold. Ligand B is above the preferred range.

**logP:** Ligand A (1.683) is within the optimal 1-3 range. Ligand B (-0.827) is slightly below 1, which *could* indicate permeability issues, although not drastically.

**H-Bond Donors/Acceptors:** Ligand A has 3 HBD and 4 HBA, while Ligand B has 5 HBD and 4 HBA. Both are acceptable, though Ligand A is slightly more favorable.

**QED:** Ligand A (0.697) has a better QED score than Ligand B (0.391), indicating higher drug-likeness.

**DILI:** Ligand A (21.908) has a much lower DILI risk than Ligand B (33.579). This is a significant advantage for Ligand A.

**BBB:** Ligand A (25.204) has a lower BBB penetration percentile than Ligand B (38.232). While both are not ideal (>70 is desirable), Ligand B is better in this regard.

**Caco-2 Permeability:** Both have negative values (-5.259 and -5.617), which is unusual and difficult to interpret without knowing the scale. However, they are similar.

**Aqueous Solubility:** Both have negative values (-1.292 and -1.987), again, difficult to interpret without the scale. They are also similar.

**hERG Inhibition:** Both ligands show very low hERG inhibition risk (0.129 and 0.064).

**Microsomal Clearance:** Ligand A (-1.45) has a more negative value, suggesting *lower* clearance and better metabolic stability than Ligand B (-9.939).

**In vitro Half-Life:** Ligand A (-29.962) has a much more negative value, indicating a longer in vitro half-life than Ligand B (-8.991).

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.019 and 0.012).

**Binding Affinity:** Ligand A (-7.6 kcal/mol) has slightly better binding affinity than Ligand B (-8.2 kcal/mol). While the difference is small, it's still a positive for Ligand A.

**Overall Assessment:**

Considering the GPCR-specific priorities, Ligand A is the better candidate. It has a significantly better TPSA, DILI, metabolic stability (Cl_mic and t1/2), and QED score. While Ligand B has slightly better BBB penetration, the other advantages of Ligand A outweigh this. The binding affinity difference is minor, but still favors Ligand A. The negative Caco-2 and solubility values are concerning for both, but similar.

Output:
0
2025-04-17 04:39:03,792 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (352.479 and 351.451 Da) fall comfortably within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (96.25) is better than Ligand B (100.35). Both are below the 140 A^2 threshold for oral absorption, and reasonably close to the 90 A^2 target for CNS penetration.

**3. logP:** Ligand A (1.418) is better than Ligand B (0.574). Both are within the optimal 1-3 range, but Ligand B is closer to the lower limit which could potentially hinder permeation.

**4. H-Bond Donors:** Ligand A (3) is slightly higher than Ligand B (2), but both are acceptable (<=5).

**5. H-Bond Acceptors:** Ligand A (5) is slightly lower than Ligand B (6), but both are acceptable (<=10).

**6. QED:** Both ligands have good QED scores (0.626 and 0.713, respectively), indicating good drug-like properties.

**7. DILI:** Ligand A (15.238%) has a significantly lower DILI risk than Ligand B (33.889%). This is a substantial advantage for Ligand A.

**8. BBB:** Ligand B (30.942%) is slightly better than Ligand A (23.071%), but both are relatively low. For a CNS target like DRD2, >70% is desirable.

**9. Caco-2:** Both ligands have negative Caco-2 values (-5.307 and -5.275), which is unusual and suggests poor permeability. This is a significant drawback for both.

**10. Solubility:** Both ligands have negative solubility values (-1.197 and -1.195), indicating very poor aqueous solubility. This is a major concern for bioavailability.

**11. hERG:** Both ligands have very low hERG inhibition risk (0.164 and 0.07, respectively).

**12. Cl_mic:** Ligand B (-14.684) has a much lower (better) microsomal clearance than Ligand A (21.522), suggesting greater metabolic stability.

**13. t1/2:** Ligand B (5.383) has a positive in vitro half-life, while Ligand A (-9.858) has a negative one. This suggests Ligand B is more stable.

**14. Pgp:** Both ligands have very low P-gp efflux liability (0.025 and 0.017, respectively).

**15. Binding Affinity:** Ligand A (-7.8 kcal/mol) has a slightly better binding affinity than Ligand B (-7.4 kcal/mol). While the difference is not huge, it is above the 1.5 kcal/mol threshold where it can outweigh other drawbacks.

**Overall Assessment:**

Ligand A is preferable despite the lower BBB and higher Cl_mic. The significantly lower DILI risk, slightly better affinity, and better logP are crucial advantages. The poor Caco-2 and solubility are concerning for both, but can potentially be addressed with formulation strategies. The slightly better affinity of Ligand A, combined with the lower DILI risk, makes it the more promising candidate.

Output:
0
2025-04-17 04:39:03,793 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (375.45 Da) is slightly higher than Ligand B (346.387 Da), but both are acceptable.

**TPSA:** Ligand A (96.53) is better than Ligand B (106.34) as it is closer to the desired value of <90 for CNS targets.

**logP:** Ligand A (2.151) is optimal (1-3). Ligand B (-0.219) is significantly lower, which could hinder permeation.

**H-Bond Donors/Acceptors:** Ligand A (HBD=3, HBA=5) and Ligand B (HBD=2, HBA=4) both fall within acceptable limits (<=5 HBD, <=10 HBA).

**QED:** Ligand B (0.772) has a better QED score than Ligand A (0.446), indicating a more drug-like profile.

**DILI:** Ligand A (19.193) has a much lower DILI risk than Ligand B (49.864). This is a significant advantage for Ligand A.

**BBB:** Ligand A (69.988) has a better BBB penetration score than Ligand B (50.679), which is crucial for a CNS target like DRD2. While both are not >70, A is closer.

**Caco-2 Permeability:** Both have negative values, which is unusual and suggests poor permeability. Ligand A (-5.082) is slightly better than Ligand B (-4.944).

**Aqueous Solubility:** Both have negative values, indicating very poor solubility. Ligand A (-1.149) is slightly better than Ligand B (-2.999).

**hERG Inhibition:** Both ligands show low hERG inhibition liability (0.292 and 0.122 respectively), which is good.

**Microsomal Clearance:** Ligand B (-15.014) has a significantly lower (better) microsomal clearance than Ligand A (39.765), indicating better metabolic stability.

**In vitro Half-Life:** Ligand B (-3.417) has a slightly better in vitro half-life than Ligand A (-8.26).

**P-gp Efflux:** Both ligands show minimal P-gp efflux liability (0.014 and 0.008 respectively).

**Binding Affinity:** Ligand B (-9.0 kcal/mol) has a significantly stronger binding affinity than Ligand A (-6.0 kcal/mol). This is a substantial advantage.

**Overall Assessment:**

Ligand B has a significantly better binding affinity and metabolic stability. However, its poor logP, higher DILI risk, and lower BBB penetration are major drawbacks for a CNS-targeted GPCR. Ligand A, while having a weaker affinity, has a better logP, lower DILI, and better BBB penetration, making it more likely to reach the target in the brain. The affinity difference is significant (~3 kcal/mol), but the ADME properties of Ligand A are more favorable for CNS penetration and reduced toxicity. Given the GPCR-specific priorities, the balance tips towards Ligand A.

Output:
0
2025-04-17 04:39:03,793 - INFO - Reasoning:

Let's analyze Ligand A and Ligand B based on the provided guidelines, prioritizing GPCR-specific properties (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (354.5 & 358.5 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (58.64) is significantly better than Ligand B (76.66). For CNS targets, TPSA should be <= 90, both are within this range, but A is closer to the optimal <60 range.

**logP:** Both ligands have good logP values (3.23 & 2.27), falling within the 1-3 range. Ligand A is slightly better.

**H-Bond Donors/Acceptors:** Ligand A (HBD=1, HBA=3) is preferable to Ligand B (HBD=2, HBA=4) as lower values generally improve permeability.

**QED:** Ligand A (0.613) has a better QED score than Ligand B (0.464), indicating better overall drug-likeness.

**DILI:** Ligand A (7.79) has a much lower DILI risk than Ligand B (31.60), making it safer.

**BBB:** Both ligands have excellent BBB penetration (A: 81.04%, B: 84.53%), exceeding the desirable >70% threshold for CNS targets. B is slightly better.

**Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual. Assuming these are logP values, they are very poor.

**Aqueous Solubility:** Both have negative solubility values, which is also unusual.

**hERG:** Both ligands have low hERG inhibition liability (A: 0.64, B: 0.51), indicating low cardiotoxicity risk.

**Microsomal Clearance:** Ligand A (65.44) has a higher microsomal clearance than Ligand B (37.02), suggesting lower metabolic stability. This is a drawback for Ligand A.

**In vitro Half-Life:** Ligand B (-10.86) has a significantly longer in vitro half-life than Ligand A (5.35), which is a major advantage.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (A: 0.21, B: 0.15), which is good for CNS penetration.

**Binding Affinity:** Ligand B (-7.9 kcal/mol) has a slightly better binding affinity than Ligand A (-7.4 kcal/mol). While the difference is less than the 1.5 kcal/mol threshold, it's still a factor.

**Overall Assessment:**

Ligand A excels in TPSA, logP, QED, and DILI risk. However, it suffers from higher microsomal clearance and a shorter half-life. Ligand B has a slightly better affinity, BBB penetration, and a significantly longer half-life, which are crucial for CNS drug development. The lower DILI risk of A is attractive, but the improved metabolic stability of B is more important for a GPCR target. The negative Caco-2 and solubility values are concerning for both, but the other parameters are more important for a CNS target.

Output:
1
2025-04-17 04:39:03,793 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (348.422 and 347.419 Da) fall comfortably within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (77.23) is significantly better than Ligand B (106.82). For CNS targets, we want TPSA <= 90, so Ligand A is preferable.

**3. logP:** Ligand A (1.263) is within the optimal 1-3 range. Ligand B (0.008) is quite low, potentially hindering membrane permeability.

**4. H-Bond Donors:** Ligand A (3) and Ligand B (2) are both acceptable, being <= 5.

**5. H-Bond Acceptors:** Ligand A (3) and Ligand B (6) are both acceptable, being <= 10.

**6. QED:** Ligand A (0.724) is much better than Ligand B (0.365). A QED > 0.5 is desirable, and Ligand A easily meets this criterion.

**7. DILI:** Ligand A (34.626) has a much lower DILI risk than Ligand B (13.416). Both are below 40, indicating low risk, but A is better.

**8. BBB:** Ligand A (76.735) has a significantly higher BBB penetration percentile than Ligand B (64.676).  For a CNS target like DRD2, >70 is desirable, and A is closer to this threshold.

**9. Caco-2 Permeability:** Both are negative, indicating poor permeability. However, the scale is not provided, so it's hard to interpret the absolute values.

**10. Aqueous Solubility:** Both are negative, indicating poor solubility. Again, the scale is not provided, making interpretation difficult.

**11. hERG Inhibition:** Both ligands have low hERG inhibition risk (0.603 and 0.678).

**12. Microsomal Clearance:** Ligand B (-21.161) has a much lower (better) microsomal clearance than Ligand A (-10.32). This suggests greater metabolic stability for Ligand B.

**13. In vitro Half-Life:** Ligand B (13.903) has a slightly longer half-life than Ligand A (16.819).

**14. P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.029 and 0.013).

**15. Binding Affinity:** Ligand A (-8.7 kcal/mol) has a significantly stronger binding affinity than Ligand B (-7.5 kcal/mol). This >1.5 kcal/mol difference is substantial and can outweigh minor ADME drawbacks.

**Overall Assessment:**

Ligand A is the stronger candidate. While Ligand B has better metabolic stability (lower Cl_mic) and a slightly longer half-life, Ligand A excels in crucial areas for a CNS-targeting GPCR ligand: TPSA, logP, QED, BBB penetration, and, most importantly, binding affinity. The significantly stronger binding affinity of Ligand A (-8.7 vs -7.5 kcal/mol) is a major advantage. The better TPSA and logP values also suggest better permeability.

Output:
1
2025-04-17 04:39:03,793 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (352.429 and 352.431 Da) fall comfortably within the ideal 200-500 Da range.

**TPSA:** Ligand A (50.16) is excellent, well below the 90 A^2 threshold for CNS targets. Ligand B (99.1) is higher, but still potentially acceptable, though less ideal.

**logP:** Ligand A (3.129) is optimal. Ligand B (-0.205) is significantly low, potentially hindering membrane permeability and CNS penetration.

**H-Bond Donors/Acceptors:** Ligand A (HBD=1, HBA=3) is favorable. Ligand B (HBD=3, HBA=5) is also acceptable, but slightly higher.

**QED:** Ligand A (0.909) is excellent, indicating high drug-likeness. Ligand B (0.65) is still reasonable, above the 0.5 threshold.

**DILI:** Ligand A (25.94) has a very low DILI risk. Ligand B (21.869) also shows low DILI risk.

**BBB:** Ligand A (92.012) has excellent BBB penetration potential. Ligand B (32.144) has poor BBB penetration, a critical drawback for a CNS target like DRD2.

**Caco-2 Permeability:** Ligand A (-4.495) is concerningly low. Ligand B (-4.961) is also low.

**Aqueous Solubility:** Ligand A (-2.984) and Ligand B (-1.084) both have poor aqueous solubility.

**hERG Inhibition:** Ligand A (0.872) and Ligand B (0.108) both show low hERG inhibition risk.

**Microsomal Clearance:** Ligand A (-2.479) indicates good metabolic stability (negative value). Ligand B (-7.273) shows even better metabolic stability.

**In vitro Half-Life:** Ligand A (10.418 hours) is reasonable. Ligand B (37.83 hours) is excellent.

**P-gp Efflux:** Ligand A (0.197) shows low P-gp efflux, which is favorable for CNS penetration. Ligand B (0.005) shows very low P-gp efflux, even more favorable.

**Binding Affinity:** Ligand A (0.0) is significantly weaker than Ligand B (-7.7). The 1.5 kcal/mol advantage is far exceeded here.

**Overall Assessment:**

Despite Ligand A's excellent BBB penetration and low DILI risk, its significantly weaker binding affinity (-7.7 kcal/mol for B vs 0.0 kcal/mol for A) and low Caco-2 permeability are major drawbacks. Ligand B's strong binding affinity is a huge advantage that outweighs its less optimal logP, TPSA, and Caco-2 permeability. The poor logP of Ligand B could be addressed through structural modifications. The strong binding affinity is more difficult to achieve.

Output:
1
2025-04-17 04:39:03,794 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (333.391 and 349.431 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (55.32) is significantly better than Ligand B (80.23). For CNS targets, we want TPSA <= 90, and A is comfortably within this range, while B is approaching the upper limit.

**logP:** Ligand A (3.819) is good, within the optimal 1-3 range. Ligand B (1.099) is a bit low, potentially hindering membrane permeability.

**H-Bond Donors/Acceptors:** Ligand A (0 HBD, 4 HBA) is preferable to Ligand B (1 HBD, 5 HBA). Both are within acceptable limits, but fewer H-bonds generally improve permeability.

**QED:** Both ligands have similar and acceptable QED values (0.712 and 0.754, respectively).

**DILI:** Ligand A (88.096) has a higher DILI risk than Ligand B (19.736). This is a significant drawback for Ligand A.

**BBB:** Ligand A (74.176) has a much better BBB penetration percentile than Ligand B (55.487). This is *critical* for a CNS target like DRD2.

**Caco-2 Permeability:** Both have negative Caco-2 values (-4.489 and -4.827), which is unusual and suggests poor permeability. However, these values are on a scale where negative values are possible and don't necessarily preclude development, especially if other properties are favorable.

**Aqueous Solubility:** Both have very poor aqueous solubility (-4.822 and -1.54). This could pose formulation challenges.

**hERG Inhibition:** Ligand A (0.593) has a slightly higher hERG risk than Ligand B (0.109). Lower is better here.

**Microsomal Clearance:** Ligand A (101.078) has higher microsomal clearance than Ligand B (-9.208), indicating faster metabolism and potentially lower *in vivo* exposure.

**In vitro Half-Life:** Ligand B (-0.864) has a slightly longer half-life than Ligand A (-9.222).

**P-gp Efflux:** Ligand A (0.508) has better P-gp efflux properties than Ligand B (0.009). Lower P-gp efflux is desirable for CNS penetration.

**Binding Affinity:** Ligand B (-8.7 kcal/mol) has a slightly better binding affinity than Ligand A (-9.5 kcal/mol). While both are excellent, the difference is not substantial enough to overcome other weaknesses.

**Overall Assessment:**

Ligand A excels in BBB penetration, TPSA, and P-gp efflux, all crucial for CNS GPCR targets. However, it suffers from higher DILI risk and faster metabolic clearance. Ligand B has a better safety profile (lower DILI, lower hERG), better metabolic stability, and slightly better affinity, but its BBB penetration is significantly lower, and its logP is suboptimal.

Considering the importance of CNS penetration for a DRD2 ligand, and the relatively small difference in binding affinity, **Ligand A is the more promising candidate despite its higher DILI risk.** The DILI risk can potentially be mitigated through structural modifications during lead optimization. The poor BBB penetration of Ligand B is a more difficult property to improve.

Output:
0
2025-04-17 04:39:03,794 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 drug candidates, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (353.463 and 343.427 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (87.74) is better than Ligand B (91.32) as it is closer to the <90 threshold for CNS targets.

**3. logP:** Ligand B (2.119) is better than Ligand A (0.705). A logP between 1-3 is optimal, and Ligand A is slightly below this range, potentially hindering permeation.

**4. H-Bond Donors:** Ligand A (2) is preferable to Ligand B (3) as lower HBDs generally improve permeability.

**5. H-Bond Acceptors:** Both ligands have 4 HBA, which is acceptable (<=10).

**6. QED:** Both ligands have acceptable QED values (0.598 and 0.661, both >= 0.5).

**7. DILI:** Ligand A (18.651) is significantly better than Ligand B (39.899) regarding DILI risk. Lower is better, and Ligand A is well below the 40% threshold, while Ligand B is approaching a moderate risk.

**8. BBB:** Ligand A (60.45) has a better BBB percentile than Ligand B (45.754), though both are below the desirable >70% for CNS targets. However, for a GPCR, BBB is a high priority.

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.013 and -5.075), which is unusual and suggests poor permeability. This is a significant drawback for both.

**10. Aqueous Solubility:** Both have negative solubility values (-0.739 and -2.593), indicating poor solubility.

**11. hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.197 and 0.065).

**12. Microsomal Clearance:** Ligand B (-2.621) has a negative clearance, which is not physically possible and likely indicates an error or a very stable compound. Ligand A (31.228) has a higher, but still reasonable, clearance.

**13. In vitro Half-Life:** Ligand B (14.724) has a longer half-life than Ligand A (-0.635).

**14. P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.018 and 0.024).

**15. Binding Affinity:** Ligand B (-8.6 kcal/mol) has a significantly stronger binding affinity than Ligand A (-7.0 kcal/mol). A difference of >1.5 kcal/mol is a strong advantage.

**Overall Assessment:**

Despite Ligand B's superior binding affinity, the concerning negative clearance value and higher DILI risk are major red flags. The negative Caco-2 and solubility values are also problematic for both. Ligand A, while having a weaker affinity, presents a more balanced profile with a lower DILI risk, better BBB penetration, and a plausible (though not ideal) clearance value. The slightly lower logP of Ligand A is a concern, but could potentially be addressed through further optimization.

Given the GPCR-specific priorities, and the significant issues with Ligand B, I would choose Ligand A as the more viable starting point for further development.

Output:
0
2025-04-17 04:39:03,794 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (341.375 Da) is slightly lower, which could be beneficial for permeability.

**2. TPSA:** Ligand A (101.7) is better than Ligand B (78.87). For CNS targets, we want TPSA <= 90, so Ligand B is preferable.

**3. logP:** Ligand B (1.555) is better than Ligand A (0.192). The optimal range is 1-3, and Ligand A is quite low, potentially hindering permeation.

**4. H-Bond Donors:** Ligand A (1) is better than Ligand B (2). Lower is generally preferred.

**5. H-Bond Acceptors:** Ligand A (7) is better than Ligand B (4). Lower is generally preferred.

**6. QED:** Both ligands have similar, good QED values (0.733 and 0.743).

**7. DILI:** Ligand B (33.424) is significantly better than Ligand A (70.105). Lower DILI is crucial.

**8. BBB:** Ligand B (58.24) is better than Ligand A (53.974), although both are below the desirable >70 for CNS targets.

**9. Caco-2 Permeability:** Ligand A (-5.349) is better than Ligand B (-4.917). Higher is better.

**10. Aqueous Solubility:** Ligand A (-2.706) is better than Ligand B (-2.548). Higher is better.

**11. hERG Inhibition:** Both ligands have very low hERG risk (0.292 and 0.299).

**12. Microsomal Clearance:** Ligand A (4.69) is significantly better than Ligand B (18.762). Lower clearance indicates better metabolic stability.

**13. In vitro Half-Life:** Ligand A (6.929) is better than Ligand B (35.571). Longer half-life is preferred.

**14. P-gp Efflux:** Both ligands have similar, low P-gp efflux liability (0.082 and 0.08).

**15. Binding Affinity:** Both ligands have excellent binding affinity (-7.9 and -7.8 kcal/mol). The difference is minimal.

**Overall Assessment:**

Ligand B excels in TPSA, logP, and DILI. Ligand A has better Caco-2 permeability, solubility, clearance, and half-life. Considering the GPCR-specific priorities, logP and TPSA are crucial for CNS penetration. Ligand B's logP is within the optimal range, while Ligand A's is too low. The DILI risk for Ligand B is also considerably lower. While Ligand A has better metabolic stability, the improved CNS penetration potential and lower toxicity risk of Ligand B outweigh this advantage.

Output:
1
2025-04-17 04:39:03,794 - INFO - Batch 131 complete. Total preferences: 2096
2025-04-17 04:39:03,794 - INFO - Processing batch 132/512...
2025-04-17 04:39:44,555 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands fall within the ideal 200-500 Da range (A: 426.738, B: 383.901).

**TPSA:** Ligand A (30.93) is excellent for CNS penetration, well below the 90 A^2 threshold. Ligand B (82.53) is higher, but still potentially acceptable, though less ideal.

**logP:** Ligand A (4.477) is slightly high, potentially leading to solubility issues or off-target effects. Ligand B (1.923) is within the optimal range.

**H-Bond Donors/Acceptors:** Ligand A (0 HBD, 4 HBA) and Ligand B (2 HBD, 5 HBA) both have reasonable numbers of H-bond donors and acceptors.

**QED:** Both ligands have good QED scores (A: 0.681, B: 0.813), suggesting good drug-like properties.

**DILI:** Both ligands have acceptable DILI risk (A: 37.611, B: 51.338), below the 60 threshold.

**BBB:** This is critical for a CNS target. Ligand A has a very good BBB percentile (78.48), while Ligand B's is significantly lower (33.656).

**Caco-2 Permeability:** Both have negative Caco-2 values (-4.826 and -4.924) which is unusual and suggests poor permeability.

**Aqueous Solubility:** Both have negative solubility values (-5.452 and -3.415), also unusual and suggests poor solubility.

**hERG Inhibition:** Both ligands have low hERG inhibition liability (A: 0.957, B: 0.159), which is positive.

**Microsomal Clearance:** Ligand A (49.977) has moderate clearance, while Ligand B (-1.814) has *very* low clearance, suggesting high metabolic stability.

**In vitro Half-Life:** Ligand B has a longer half-life (40.18 hours) than Ligand A (7.692 hours).

**P-gp Efflux:** Ligand A (0.763) has moderate P-gp efflux, while Ligand B (0.125) has very low efflux, which is favorable for CNS penetration.

**Binding Affinity:** Ligand B (-8.5 kcal/mol) has a slightly better binding affinity than Ligand A (-7.9 kcal/mol), although both are strong binders.

**Overall Assessment:**

Ligand B has several advantages: better logP, significantly lower P-gp efflux, much better metabolic stability (lower Cl_mic, longer t1/2), and slightly better binding affinity. The biggest advantage of Ligand A is its superior BBB penetration. However, the low P-gp efflux of Ligand B, coupled with its metabolic stability, likely outweighs the slightly better BBB score of Ligand A, especially considering the unusual negative solubility and Caco-2 values for both. The negative solubility and Caco-2 values are concerning for both, but the other properties of Ligand B are more favorable overall.

Output:
1
2025-04-17 04:39:44,556 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (344.365 Da) is slightly better, being closer to the lower end which can aid permeability.

**TPSA:** Ligand A (51.85) is significantly better than Ligand B (98.32). For CNS targets, we want TPSA <= 90, and Ligand A comfortably meets this, while Ligand B is close to exceeding it.

**logP:** Both ligands have good logP values (A: 2.926, B: 1.865) within the optimal range of 1-3. Ligand A is slightly higher, which could be beneficial for membrane permeability.

**H-Bond Donors/Acceptors:** Ligand A (HBD=1, HBA=4) is preferable to Ligand B (HBD=3, HBA=5) as it has fewer potential issues with permeability. Both are within acceptable limits.

**QED:** Both ligands have similar QED values (A: 0.774, B: 0.735), indicating good drug-like properties.

**DILI:** Both ligands have acceptable DILI risk (A: 70.841, B: 67.507), below the concerning threshold of 60.

**BBB:** This is a crucial parameter for CNS targets. Ligand A has a significantly higher BBB percentile (85.459) than Ligand B (19.504). This is a major advantage for Ligand A.

**Caco-2 Permeability:** Ligand A (-4.712) has a more favorable Caco-2 permeability compared to Ligand B (-5.228), suggesting better intestinal absorption.

**Aqueous Solubility:** Both ligands have very poor aqueous solubility (-3.545 and -3.797 respectively). This is a concern for both, but not a deciding factor between the two.

**hERG Inhibition:** Both ligands have low hERG inhibition liability (A: 0.654, B: 0.347), which is good.

**Microsomal Clearance:** Ligand A (6.43) has a considerably lower microsomal clearance than Ligand B (18.975), indicating better metabolic stability.

**In vitro Half-Life:** Ligand A (11.4) has a longer in vitro half-life than Ligand B (-15.265), which is desirable.

**P-gp Efflux:** Ligand A (0.275) has lower P-gp efflux liability than Ligand B (0.174), which is beneficial for CNS exposure.

**Binding Affinity:** Ligand A (-10.1 kcal/mol) has a significantly stronger binding affinity than Ligand B (-8.7 kcal/mol). This difference in affinity is substantial (>1.5 kcal/mol), and can outweigh minor ADME drawbacks.

**Overall:** Considering all parameters, Ligand A is the superior candidate. It excels in key GPCR-relevant properties like BBB penetration, TPSA, metabolic stability (Cl_mic), and most importantly, binding affinity. While both have solubility concerns, Ligand A's superior profile in other critical areas makes it the more promising drug candidate.

Output:
1
2025-04-17 04:39:44,556 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (373.806 and 356.495 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (35.58) is excellent, well below the 90 A^2 threshold for CNS targets. Ligand B (54.18) is higher, but still reasonably acceptable, though less ideal.

**3. logP:** Both ligands have good logP values (3.044 and 3.618), falling within the optimal 1-3 range.

**4. H-Bond Donors:** Both have 1 HBD, which is within the acceptable limit of <=5.

**5. H-Bond Acceptors:** Ligand A has 2 HBA, and Ligand B has 6 HBA. Both are within the acceptable limit of <=10, but Ligand A is preferable.

**6. QED:** Ligand A (0.821) has a much better QED score than Ligand B (0.67), indicating better overall drug-likeness.

**7. DILI:** Ligand A (27.181) has a significantly lower DILI risk than Ligand B (44.242).

**8. BBB:** This is critical for a CNS target. Ligand A has a very high BBB penetration percentile (92.555), while Ligand B is considerably lower (55.603).

**9. Caco-2 Permeability:** Ligand A (-4.864) shows poor Caco-2 permeability. Ligand B (-5.47) is slightly worse.

**10. Aqueous Solubility:** Both have negative values, indicating poor aqueous solubility. Ligand A (-3.953) is slightly better than Ligand B (-3.184).

**11. hERG Inhibition:** Both ligands have low hERG inhibition risk (0.882 and 0.75).

**12. Microsomal Clearance:** Ligand A (17.023) has a lower microsomal clearance than Ligand B (74.286), suggesting better metabolic stability.

**13. In vitro Half-Life:** Ligand A (11.198) has a longer in vitro half-life than Ligand B (-4.583).

**14. P-gp Efflux:** Both ligands have low P-gp efflux liability (0.235 and 0.205).

**15. Binding Affinity:** Ligand A (-8.7 kcal/mol) has a slightly better binding affinity than Ligand B (-7.5 kcal/mol). While both are good, the 1.2 kcal/mol difference is significant.

**Overall Assessment:**

Ligand A is significantly better overall. It excels in crucial areas for a CNS-targeting GPCR ligand: high BBB penetration, low DILI risk, better QED, better metabolic stability (lower Cl_mic, longer t1/2), and slightly better binding affinity. While both have poor Caco-2 permeability and solubility, the strong CNS properties of Ligand A outweigh these drawbacks. Ligand B's lower BBB penetration and higher DILI risk are major concerns.

Output:
1
2025-04-17 04:39:44,556 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (360.479 and 348.403 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (66.48) is excellent, well below the 90 A^2 threshold for CNS targets. Ligand B (95.75) is higher, but still potentially acceptable, though less ideal.

**logP:** Ligand A (3.079) is optimal (1-3). Ligand B (0.572) is quite low, potentially hindering membrane permeability and CNS penetration.

**H-Bond Donors/Acceptors:** Both ligands have acceptable HBD (1) and HBA (3 for A, 5 for B) counts, well within the guidelines.

**QED:** Both ligands have good QED scores (0.824 and 0.839), indicating good drug-like properties.

**DILI:** Ligand A (55.913) has a moderate DILI risk. Ligand B (35.014) has a lower, more favorable DILI risk.

**BBB:** Ligand A (72.237) has a good BBB percentile, exceeding the 70% threshold for CNS targets. Ligand B (48.158) is significantly lower, raising concerns about CNS penetration.

**Caco-2 Permeability:** Ligand A (-4.762) and Ligand B (-5.016) both have negative Caco-2 values. This is unusual and requires further investigation, but suggests poor permeability.

**Aqueous Solubility:** Ligand A (-4.935) and Ligand B (-1.719) both have negative solubility values, suggesting poor solubility.

**hERG Inhibition:** Both ligands have low hERG inhibition liability (0.632 and 0.116), which is positive.

**Microsomal Clearance:** Ligand A (50.463) has moderate clearance. Ligand B (9.51) has very low clearance, suggesting good metabolic stability.

**In vitro Half-Life:** Ligand B (12.427) has a longer half-life than Ligand A (5.204), which is desirable.

**P-gp Efflux:** Ligand A (0.171) has low P-gp efflux, which is good for CNS exposure. Ligand B (0.01) has even lower P-gp efflux, which is excellent.

**Binding Affinity:** Ligand A (-11.2 kcal/mol) has significantly stronger binding affinity than Ligand B (-7.5 kcal/mol). This is a substantial advantage.

**Overall Assessment:**

Despite the poor Caco-2 and solubility values for both, Ligand A is the more promising candidate. Its superior binding affinity (-11.2 vs -7.5 kcal/mol) is a major advantage, and the difference is large enough to potentially overcome the moderate DILI risk and slightly lower BBB penetration compared to Ligand B. Ligand B's low logP is a significant drawback for a CNS target, and while it has better metabolic stability and lower P-gp efflux, the weaker binding affinity is a critical issue. The strong binding of Ligand A suggests it's more likely to be effective at lower doses, potentially mitigating some of the DILI concerns.

Output:
1
2025-04-17 04:39:44,556 - INFO - Reasoning:

Let's analyze Ligand A and Ligand B based on the provided guidelines, prioritizing GPCR-specific properties (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (359.897 and 348.418 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (38.33) is excellent for CNS penetration, well below the 90 A^2 threshold. Ligand B (58.64) is still reasonable, but less optimal.

**logP:** Ligand A (4.981) is slightly high, potentially leading to solubility issues or off-target interactions. Ligand B (1.761) is good, within the 1-3 range.

**H-Bond Donors/Acceptors:** Both ligands have acceptable HBD (1) and HBA (2 & 3) counts.

**QED:** Both ligands have good QED scores (0.685 and 0.729), indicating drug-likeness.

**DILI:** Ligand A (39.667) has a slightly higher DILI risk than Ligand B (28.189), but both are below the concerning 60 threshold.

**BBB:** This is a critical parameter for a CNS target like DRD2. Ligand B (78.519) has a significantly better BBB percentile than Ligand A (40.403).

**Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and suggests a potential issue with the data or modeling. However, we can still compare the relative values. Ligand A (-4.938) is worse than Ligand B (-4.43).

**Aqueous Solubility:** Both have negative solubility values, which is also unusual. Ligand A (-5.199) is worse than Ligand B (-2.863).

**hERG:** Both ligands have low hERG inhibition liability (0.795 and 0.698).

**Microsomal Clearance:** Ligand B (64.865) has lower microsomal clearance than Ligand A (94.692), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand B (-7.443) has a negative half-life, which is impossible. Ligand A (41.022) has a reasonable half-life. This is a significant red flag for Ligand B.

**P-gp Efflux:** Ligand A (0.692) has lower P-gp efflux than Ligand B (0.113), which is favorable for CNS penetration.

**Binding Affinity:** Ligand A (-9.5 kcal/mol) has a significantly stronger binding affinity than Ligand B (-7.6 kcal/mol). The difference of 1.9 kcal/mol is substantial and could outweigh some of the ADME drawbacks of Ligand A.

**Overall Assessment:**

Ligand A has a superior binding affinity, which is paramount for GPCR targets. However, its higher logP and lower BBB penetration are concerns. Ligand B has better ADME properties (BBB, logP, clearance), but its significantly weaker binding affinity is a major drawback. The negative half-life for Ligand B is a showstopper. Considering the importance of CNS penetration for DRD2 and the substantial affinity difference, Ligand A is the more promising candidate, *despite* its less ideal logP and BBB. Further optimization could address these issues while maintaining the strong binding affinity.

Output:
1
2025-04-17 04:39:44,556 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B based on the provided guidelines, prioritizing GPCR-specific properties (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (347.459 Da) is slightly lower, which could be beneficial for permeability.

**TPSA:** Ligand A (64.09) is excellent for CNS penetration, well below the 90 A^2 threshold. Ligand B (97.11) is higher, but still potentially acceptable, though less ideal.

**logP:** Ligand A (0.018) is very low, which is a significant concern for membrane permeability and CNS penetration. Ligand B (2.03) is within the optimal range (1-3).

**H-Bond Donors/Acceptors:** Ligand A (HBD=1, HBA=4) and Ligand B (HBD=3, HBA=5) both have reasonable H-bond characteristics.

**QED:** Both ligands have good QED scores (A: 0.688, B: 0.709), indicating generally drug-like properties.

**DILI:** Ligand A (5.196) has a very favorable DILI score. Ligand B (66.886) has a significantly higher DILI risk, which is a major concern.

**BBB:** Ligand A (31.601) has a low BBB percentile, indicating poor brain penetration. Ligand B (75.843) has a good BBB percentile, crucial for a DRD2 targeting drug.

**Caco-2 Permeability:** Ligand A (-4.716) has very poor Caco-2 permeability, consistent with its low logP. Ligand B (-5.219) also has poor Caco-2 permeability, but is slightly better than A.

**Aqueous Solubility:** Ligand A (-0.246) has poor solubility, while Ligand B (-3.142) has even worse solubility.

**hERG Inhibition:** Ligand A (0.153) has a low hERG risk, which is positive. Ligand B (0.535) has a slightly higher, but still acceptable, hERG risk.

**Microsomal Clearance:** Ligand A (-11.773) has very low microsomal clearance, suggesting high metabolic stability. Ligand B (9.203) has faster clearance.

**In vitro Half-Life:** Ligand A (1.51) has a short half-life. Ligand B (29.477) has a much longer half-life, which is desirable.

**P-gp Efflux:** Ligand A (0.03) has very low P-gp efflux, which is good for CNS exposure. Ligand B (0.12) has slightly higher P-gp efflux.

**Binding Affinity:** Ligand B (-9.6 kcal/mol) has significantly better binding affinity than Ligand A (-7.7 kcal/mol). This >1.5 kcal/mol difference is substantial and can outweigh some ADME drawbacks.

**Overall Assessment:**

Ligand A has a better safety profile (DILI, hERG) and metabolic stability, but its extremely low logP and resulting poor BBB penetration and Caco-2 permeability are major liabilities for a CNS target like DRD2. Ligand B, despite a higher DILI risk and faster clearance, possesses a much better logP, significantly better BBB penetration, and a substantially stronger binding affinity. For a CNS GPCR target, the combination of good affinity and BBB penetration is paramount. While the DILI risk of Ligand B is concerning, it might be mitigated through structural modifications in subsequent optimization. The poor permeability of Ligand A is a more fundamental issue that would be very difficult to overcome.

Output:
1
2025-04-17 04:39:44,556 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (347.371 and 365.499 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (112.78) is slightly above the optimal <90 for CNS targets, but still reasonable. Ligand B (71.53) is excellent, well below 90.

**logP:** Ligand A (0.944) is a bit low, potentially impacting permeability. Ligand B (1.916) is better, falling within the 1-3 optimal range.

**H-Bond Donors/Acceptors:** Ligand A has 2 HBD and 5 HBA, which are acceptable. Ligand B has 1 HBD and 5 HBA, also acceptable.

**QED:** Both ligands have good QED scores (0.587 and 0.679), indicating good drug-like properties.

**DILI:** Ligand A (41.024) has a slightly higher DILI risk than Ligand B (27.259), but both are below the concerning threshold of 60.

**BBB:** This is crucial for a CNS target. Ligand B (80.264) shows significantly better BBB penetration potential than Ligand A (62.233). This is a major advantage for Ligand B.

**Caco-2 Permeability:** Both have negative Caco-2 values (-4.937 and -4.912), which is unusual and suggests poor permeability. This is a concern for both, but the values are similar.

**Aqueous Solubility:** Both have negative solubility values (-2.64 and -2.245), which is also unusual and suggests poor solubility. This is a concern for both, but the values are similar.

**hERG:** Both ligands have low hERG inhibition liability (0.327 and 0.431), which is positive.

**Microsomal Clearance:** Ligand A (-7.118) has a much lower (better) microsomal clearance than Ligand B (44.006), indicating better metabolic stability.

**In vitro Half-Life:** Ligand A (4.977) has a shorter half-life than Ligand B (10.355).

**P-gp Efflux:** Ligand A (0.104) has significantly lower P-gp efflux liability than Ligand B (0.058), which is beneficial for CNS exposure.

**Binding Affinity:** Ligand A (-9.6 kcal/mol) has a substantially stronger binding affinity than Ligand B (-6.9 kcal/mol). This is a significant advantage, potentially outweighing some of the ADME drawbacks.

**Overall Assessment:**

Ligand A has a much better binding affinity and lower P-gp efflux, and better metabolic stability. However, Ligand B has a significantly better BBB penetration and a slightly lower DILI risk. The affinity difference is substantial (>2.7 kcal/mol), and for a GPCR, strong binding is paramount. While the low Caco-2 and solubility are concerning for both, the superior affinity of Ligand A, coupled with acceptable (though not ideal) BBB and DILI, makes it the more promising candidate.

Output:
1
2025-04-17 04:39:44,556 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 drug candidates, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (368.459 Da and 353.507 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (113.44) is borderline for CNS penetration, being above the preferred <90. Ligand B (70.67) is excellent, well below 90.

**logP:** Ligand A (0.368) is quite low, potentially hindering membrane permeability. Ligand B (1.687) is within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A has 3 HBD and 7 HBA, acceptable values. Ligand B has 2 HBD and 4 HBA, also acceptable.

**QED:** Both ligands have good QED scores (0.607 and 0.731), indicating drug-like properties.

**DILI:** Ligand A has a DILI risk of 68.903, which is moderately high. Ligand B has a much lower DILI risk of 10.198, which is excellent.

**BBB:** Ligand A's BBB penetration (23.42) is very poor, a significant drawback for a CNS target. Ligand B's BBB penetration (41.218) is better, though still not ideal (aim for >70).

**Caco-2 Permeability:** Both have negative Caco-2 values (-5.49 and -5.076). This is unusual and suggests poor permeability. However, these values are on a log scale and negative values are not uncommon for compounds with limited permeability.

**Aqueous Solubility:** Both have negative solubility values (-2.251 and -1.582). This is also unusual, and suggests poor aqueous solubility.

**hERG:** Both ligands have low hERG inhibition liability (0.078 and 0.257), which is good.

**Microsomal Clearance:** Ligand A has a higher Cl_mic (15.769) than Ligand B (3.827), indicating faster metabolism and lower metabolic stability.

**In vitro Half-Life:** Ligand A has a negative half-life (-13.09), which is problematic and likely indicates rapid degradation. Ligand B has a half-life of 16.585, which is reasonable.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.006 and 0.017), which is favorable for CNS penetration.

**Binding Affinity:** Ligand B (-8.0 kcal/mol) has a significantly stronger binding affinity than Ligand A (-7.6 kcal/mol). While both are good, the 0.4 kcal/mol difference is noteworthy.

**Overall Assessment:**

Ligand B is clearly the more promising candidate. While its BBB penetration isn't ideal, it's significantly better than Ligand A's. Critically, Ligand B has a much better logP, lower DILI risk, better metabolic stability (lower Cl_mic, higher t1/2), and a stronger binding affinity. Ligand A's poor BBB, low logP, and high DILI risk are major concerns. The negative solubility and Caco-2 values for both are concerning, but the other factors strongly favor Ligand B.

Output:
1
2025-04-17 04:39:44,556 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (353.463 and 347.39 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (81.16) is slightly above the optimal <90 for CNS targets, but still reasonable. Ligand B (71.53) is excellent, well below 90.

**logP:** Ligand A (0.321) is quite low, potentially hindering membrane permeability. Ligand B (1.944) is much better, falling within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Both ligands have 1 HBD and 4 HBA, which are within acceptable limits.

**QED:** Both ligands have good QED scores (0.772 and 0.907), indicating drug-like properties.

**DILI:** Ligand A (25.514) has a much lower DILI risk than Ligand B (53.625), which is a significant advantage.

**BBB:** Ligand B (66.886) has a substantially better BBB penetration score than Ligand A (46.607). This is crucial for a CNS target like DRD2.

**Caco-2 Permeability:** Both have very poor Caco-2 permeability (-4.508 and -4.501). This is a concern for oral bioavailability, but less critical for a CNS target where direct delivery or other routes might be considered.

**Aqueous Solubility:** Both have poor aqueous solubility (-0.438 and -2.277). This could pose formulation challenges.

**hERG:** Both ligands show low hERG inhibition risk (0.11 and 0.264).

**Microsomal Clearance:** Ligand A (27.523) has a lower microsomal clearance than Ligand B (29.178), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand B (-18.57) has a significantly longer in vitro half-life than Ligand A (-5.097). This is a major advantage.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.022 and 0.076).

**Binding Affinity:** Ligand B (-8.7 kcal/mol) has a significantly stronger binding affinity than Ligand A (-7.3 kcal/mol). This 1.4 kcal/mol difference is substantial and can outweigh some of the ADME drawbacks.

**Overall Assessment:**

Ligand B is the stronger candidate. While Ligand A has a better DILI profile, Ligand B excels in the key GPCR properties: significantly better BBB penetration, a substantially stronger binding affinity, and a longer half-life. The logP value for Ligand B is also much more favorable. The poor Caco-2 and solubility are drawbacks for both, but less critical given the CNS target. The improved affinity and BBB penetration of Ligand B are likely to translate to better in vivo efficacy.

Output:
1
2025-04-17 04:39:44,556 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B based on the provided guidelines, prioritizing GPCR-specific properties (BBB, logP, Pgp, TPSA, and affinity) for DRD2.

**Molecular Weight:** Both ligands (369.443 and 357.336 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (107.97) is higher than Ligand B (83.88). For CNS targets, TPSA should be <=90. Ligand B is preferable here.

**logP:** Ligand A (-0.018) is quite low, potentially hindering permeation. Ligand B (1.622) is within the optimal 1-3 range. Ligand B is significantly better.

**H-Bond Donors:** Ligand A (3) is acceptable, while Ligand B (1) is even better, contributing to improved permeability.

**H-Bond Acceptors:** Ligand A (6) and Ligand B (5) are both within the acceptable limit of <=10.

**QED:** Both ligands have good QED values (0.511 and 0.816), indicating good drug-like properties. Ligand B is slightly better.

**DILI:** Both ligands have similar DILI risk (53.432 and 55.099), both falling within the acceptable range (<60).

**BBB:** Ligand B (56.107) has a considerably better BBB percentile than Ligand A (33.385). This is a critical factor for a CNS target like DRD2.

**Caco-2 Permeability:** Both have negative values, which is unusual. Assuming these are logP-like scales, lower values indicate poorer permeability. They are comparable, but neither is ideal.

**Aqueous Solubility:** Both ligands have negative solubility values, which is unusual. Assuming these are logS-like scales, lower values indicate poorer solubility. They are comparable, but neither is ideal.

**hERG Inhibition:** Ligand A (0.172) has a slightly lower hERG risk than Ligand B (0.664), which is preferable.

**Microsomal Clearance:** Ligand A (-24.539) has a much lower (better) microsomal clearance than Ligand B (11.52). This suggests better metabolic stability for Ligand A.

**In vitro Half-Life:** Ligand A (-0.863) has a negative half-life, which is unusual. Ligand B (-21.108) also has a negative half-life, indicating very rapid metabolism. Both are poor.

**P-gp Efflux:** Ligand A (0.024) has a much lower P-gp efflux liability than Ligand B (0.079), which is crucial for CNS penetration.

**Binding Affinity:** Both ligands have excellent binding affinity (-7.1 and -7.0 kcal/mol), with Ligand A being slightly better. The affinity difference isn't substantial enough to outweigh other significant ADME differences.

**Overall Assessment:**

Ligand B is superior due to its significantly better logP, TPSA, and BBB penetration. While Ligand A has slightly better affinity and lower P-gp efflux and microsomal clearance, the poor logP and higher TPSA of Ligand A are major drawbacks for a CNS-targeting GPCR. The better BBB penetration of Ligand B is a critical advantage.

Output:
1
2025-04-17 04:39:44,557 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (363.384 and 379.917 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (83.29) is better than Ligand B (70.84). Both are below the 90 A^2 threshold for CNS targets, which is excellent.

**logP:** Ligand A (2.05) is optimal (1-3), while Ligand B (4.135) is pushing the upper limit and could present solubility issues.

**H-Bond Donors/Acceptors:** Ligand A (2 HBD, 5 HBA) and Ligand B (1 HBD, 6 HBA) both have acceptable numbers of H-bond donors and acceptors.

**QED:** Ligand A (0.775) has a significantly better QED score than Ligand B (0.421), indicating a more drug-like profile.

**DILI:** Ligand A (27.22) has a much lower DILI risk than Ligand B (69.833), which is a significant advantage.

**BBB:** Ligand A (82.435) has a substantially better BBB penetration score than Ligand B (60.644). This is *critical* for a CNS target like DRD2.

**Caco-2 Permeability:** Ligand A (-4.947) and Ligand B (-5.961) both have negative values, indicating poor permeability.

**Aqueous Solubility:** Ligand A (-2.498) and Ligand B (-3.443) both have poor aqueous solubility.

**hERG:** Ligand A (0.296) has a lower hERG inhibition liability than Ligand B (0.88), making it safer from a cardiotoxicity perspective.

**Microsomal Clearance:** Ligand A (28.443) has a lower microsomal clearance than Ligand B (65.612), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (-9.361) has a worse in vitro half-life than Ligand B (135.866).

**P-gp Efflux:** Ligand A (0.016) has a much lower P-gp efflux liability than Ligand B (0.602), which is crucial for CNS penetration.

**Binding Affinity:** Ligand B (-7.2 kcal/mol) has a slightly better binding affinity than Ligand A (-8.8 kcal/mol). However, the difference is less than 1.5 kcal/mol, and can be outweighed by other factors.

**Overall Assessment:**

Ligand A is significantly better overall. While Ligand B has slightly better binding affinity, Ligand A excels in almost all other crucial parameters, especially those prioritized for GPCRs targeting the CNS: BBB penetration, P-gp efflux, DILI risk, and QED. The lower logP and better metabolic stability of Ligand A are also favorable. The poor Caco-2 and solubility are concerns for both, but can be addressed with formulation strategies. The difference in half-life is not enough to overcome the other advantages of Ligand A.

Output:
0
2025-04-17 04:39:44,557 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 drug candidates, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (348.443 Da) is slightly lower, which is generally favorable for permeability. Ligand B (370.827 Da) is also good.

**TPSA:** Ligand A (98.66) is better than Ligand B (49.41). For CNS targets, we want TPSA <= 90, so Ligand A is closer to this threshold, suggesting better CNS penetration potential.

**logP:** Both ligands have good logP values (Ligand A: 1.873, Ligand B: 2.178), falling within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A has 4 HBD and 4 HBA, while Ligand B has 1 HBD and 2 HBA. Both are within acceptable limits (<=5 HBD and <=10 HBA).

**QED:** Both ligands have similar QED values (Ligand A: 0.631, Ligand B: 0.609), indicating good drug-like properties.

**DILI:** Both ligands have low DILI risk (Ligand A: 37.03, Ligand B: 35.75), below the 40 threshold.

**BBB:** This is a crucial parameter for CNS targets. Ligand B (83.56) has a significantly higher BBB percentile than Ligand A (51.493). A value >70 is desirable, and Ligand B is much closer to that.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values, which is unusual and suggests poor permeability. However, the scale isn't specified, so it's hard to interpret.

**Aqueous Solubility:** Both ligands have negative solubility values, again, making interpretation difficult without knowing the scale.

**hERG:** Both ligands show low hERG inhibition liability (Ligand A: 0.359, Ligand B: 0.381), which is good.

**Microsomal Clearance:** Ligand A (26.019) has a higher microsomal clearance than Ligand B (10.833), indicating lower metabolic stability. Lower clearance is preferred.

**In vitro Half-Life:** Ligand B (1.883) has a slightly longer half-life than Ligand A (15.379).

**P-gp Efflux:** Both ligands have low P-gp efflux liability (Ligand A: 0.096, Ligand B: 0.056), which is favorable for CNS penetration.

**Binding Affinity:** Both ligands have very similar and strong binding affinities (Ligand A: -8.8 kcal/mol, Ligand B: -8.5 kcal/mol). The difference of 0.3 kcal/mol is unlikely to be decisive.

**Overall Assessment:**

Ligand B is superior due to its significantly better BBB penetration (83.56 vs 51.493), lower microsomal clearance (10.833 vs 26.019), and slightly longer half-life. While Ligand A has a slightly better TPSA, the BBB advantage of Ligand B is more critical for a CNS target like DRD2. The similar affinities make the ADME properties the deciding factor.

Output:
1
2025-04-17 04:39:44,557 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (363.46 & 348.42 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (71.09) is higher than Ligand B (58.64). For CNS targets, we prefer TPSA <= 90, so both are acceptable, but B is better.

**3. logP:** Both ligands have good logP values (3.31 & 2.39), falling within the optimal 1-3 range.

**4. H-Bond Donors:** Ligand A (2) and Ligand B (1) are both within the acceptable limit of <=5. B is slightly better.

**5. H-Bond Acceptors:** Ligand A (4) and Ligand B (3) are both within the acceptable limit of <=10. B is slightly better.

**6. QED:** Both ligands have similar and good QED values (0.707 & 0.734), indicating good drug-like properties.

**7. DILI:** Ligand A (64.83) has a slightly higher DILI risk than Ligand B (51.34), but both are reasonably low.

**8. BBB:** This is crucial for a CNS target like DRD2. Ligand B (88.29) has a significantly better BBB penetration percentile than Ligand A (64.83). This is a major advantage for B.

**9. Caco-2 Permeability:** Both have negative values, which is unusual. I will assume these are percentile scores and higher is better. Ligand A (-4.995) is worse than Ligand B (-4.585).

**10. Aqueous Solubility:** Both have negative solubility values, which is also unusual. I will assume these are percentile scores and higher is better. Ligand A (-3.457) is worse than Ligand B (-2.122).

**11. hERG:** Both ligands have low hERG inhibition liability (0.691 & 0.543), which is good.

**12. Microsomal Clearance:** Ligand B (37.37) has lower microsomal clearance than Ligand A (44.32), suggesting better metabolic stability.

**13. In vitro Half-Life:** Ligand B (42.17) has a slightly longer in vitro half-life than Ligand A (40.45).

**14. P-gp Efflux:** Ligand A (0.583) has higher P-gp efflux liability than Ligand B (0.142). Lower P-gp efflux is preferred for CNS penetration, giving B another advantage.

**15. Binding Affinity:** Both ligands have very similar and excellent binding affinities (-8.8 & -8.6 kcal/mol). The difference is negligible.

**Overall Assessment:**

Ligand B is superior to Ligand A. While both have good potency and drug-like properties, Ligand B exhibits significantly better BBB penetration, lower P-gp efflux, and better metabolic stability (lower Cl_mic and longer t1/2). These factors are particularly important for a CNS-targeting GPCR like DRD2. The slightly better TPSA, HBD, HBA, solubility, and Caco-2 permeability also contribute to its advantage.



Output:
1
2025-04-17 04:39:44,557 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (363.429 and 362.495 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (38.33) is excellent, well below the 90 A^2 threshold for CNS targets. Ligand B (69.64) is higher, but still potentially acceptable, though less ideal.

**3. logP:** Ligand A (4.863) is slightly high, potentially leading to solubility issues or off-target interactions. Ligand B (2.613) is within the optimal 1-3 range.

**4. H-Bond Donors:** Ligand A (1) and Ligand B (2) are both within the acceptable limit of <=5.

**5. H-Bond Acceptors:** Ligand A (3) and Ligand B (4) are both within the acceptable limit of <=10.

**6. QED:** Both ligands have good QED values (0.714 and 0.865), indicating drug-like properties.

**7. DILI:** Ligand A (63.746) has a higher DILI risk than Ligand B (42.885). This is a negative for Ligand A.

**8. BBB:** Ligand A (84.141) has a significantly better BBB penetration percentile than Ligand B (67.584). This is a crucial advantage for a CNS target like DRD2.

**9. Caco-2 Permeability:** Ligand A (-4.652) has poor Caco-2 permeability. Ligand B (-5.077) is similarly poor.

**10. Aqueous Solubility:** Ligand A (-5.795) has poor aqueous solubility, likely due to its high logP. Ligand B (-2.503) is better, but still not great.

**11. hERG Inhibition:** Both ligands have low hERG inhibition risk (0.577 and 0.311).

**12. Microsomal Clearance:** Ligand A (89.412) has higher microsomal clearance, indicating lower metabolic stability, compared to Ligand B (15.889).

**13. In vitro Half-Life:** Ligand A (13.109) has a shorter in vitro half-life than Ligand B (16.09).

**14. P-gp Efflux:** Both ligands have low P-gp efflux liability (0.236 and 0.18).

**15. Binding Affinity:** Both ligands have excellent binding affinities (-9.2 and -8.9 kcal/mol). The difference of 0.3 kcal/mol is not substantial enough to override other ADME concerns.

**Overall Assessment:**

Ligand A has a significant advantage in BBB penetration, which is paramount for a CNS target. However, it suffers from poor solubility, higher DILI risk, and lower metabolic stability. Ligand B has better solubility, lower DILI, and better metabolic stability, but its BBB penetration is considerably lower. Given the importance of CNS penetration for DRD2, and the relatively small difference in binding affinity, Ligand A is the more promising candidate, *provided* solubility can be improved through formulation strategies. The higher DILI risk is a concern, but potentially manageable.

Output:
1
2025-04-17 04:39:44,557 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (372.377 and 364.408 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (84.5) is better than Ligand B (58.64). Both are below the 90 A^2 threshold desirable for CNS targets.

**logP:** Both ligands have good logP values (2.607 and 2.089), falling within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A has 2 HBD and 4 HBA, while Ligand B has 1 HBD and 3 HBA. Both are within acceptable limits (<=5 HBD and <=10 HBA).

**QED:** Both ligands have similar QED values (0.653 and 0.604), indicating good drug-likeness.

**DILI:** Ligand A (36.836) has a slightly higher DILI risk than Ligand B (28.383), but both are below the 40 threshold, indicating low risk.

**BBB:** This is a critical parameter for CNS targets. Ligand B (93.563) has a significantly higher BBB penetration percentile than Ligand A (71.966). This is a major advantage for Ligand B.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.826 and -4.598). These values are unusual and suggest poor permeability. However, the scale is not specified, so it's difficult to interpret.

**Aqueous Solubility:** Both ligands have negative solubility values (-2.111 and -2.303), which is also unusual. Again, the scale is not specified, making interpretation difficult.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.519 and 0.651).

**Microsomal Clearance:** Ligand A (43.012) has a higher microsomal clearance than Ligand B (35.77), indicating lower metabolic stability.

**In vitro Half-Life:** Ligand B (-4.503) has a negative half-life, which is not possible. This is likely an error in the data. Ligand A (39.258) has a reasonable half-life.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.138 and 0.205), which is favorable for CNS penetration.

**Binding Affinity:** Both ligands have the same binding affinity (-7.8 kcal/mol), which is excellent.

**Conclusion:**

While Ligand A has a slightly better TPSA and in vitro half-life, Ligand B is superior due to its significantly higher BBB penetration (93.563 vs 71.966). Given that DRD2 is a CNS target, BBB penetration is paramount. The slightly lower DILI risk for Ligand B is also a plus. The unusual negative values for Caco-2 and solubility are concerning for both, but the strong affinity and favorable P-gp efflux mitigate these concerns somewhat. The negative half-life for Ligand B is a data error that would need to be investigated.

Output:
1
2025-04-17 04:39:44,557 - INFO - Reasoning:

Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (342.4 and 348.4 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (76.58) is significantly better than Ligand B (85.69). For CNS targets, we want TPSA <= 90, and A is closer to the optimal <=60.

**3. logP:** Ligand A (2.349) is within the optimal 1-3 range. Ligand B (-0.012) is slightly below 1, which *could* hinder permeation, though not drastically.

**4. H-Bond Donors:** Both ligands have 1 HBD, which is acceptable (<=5).

**5. H-Bond Acceptors:** Ligand A has 5 HBAs, and Ligand B has 6. Both are within the acceptable limit of <=10.

**6. QED:** Ligand A (0.836) is better than Ligand B (0.76), indicating a more drug-like profile.

**7. DILI:** Both ligands have similar DILI risk (64.6% and 63.1%), both being acceptable (<60 is good, but these are not high risk).

**8. BBB:** Both ligands have good BBB penetration (73.4% and 71.6%), exceeding the desirable threshold of >70 for CNS targets.

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.586 and -4.779). These values are unusual and difficult to interpret without further context. However, they suggest poor permeability.

**10. Aqueous Solubility:** Both ligands have negative solubility values (-2.135 and -1.83). These values are also unusual and suggest poor solubility.

**11. hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.337% and 0.043%).

**12. Microsomal Clearance:** Ligand B (30.019) has significantly lower microsomal clearance than Ligand A (75.343), indicating better metabolic stability.

**13. In vitro Half-Life:** Ligand B (23.747 hours) has a much longer half-life than Ligand A (-12.077 hours). The negative value for A is concerning and likely an error.

**14. P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.023% and 0.021%).

**15. Binding Affinity:** Ligand B (-9.3 kcal/mol) has a significantly stronger binding affinity than Ligand A (-8.1 kcal/mol). This is a >1.2 kcal/mol advantage, which is substantial and can outweigh some ADME drawbacks.

**Overall Assessment:**

While Ligand A has a better TPSA and QED, Ligand B excels in crucial areas for a CNS GPCR target: significantly stronger binding affinity, better metabolic stability (lower Cl_mic), and a longer half-life. The slightly lower logP of Ligand B is a minor concern, but the strong affinity likely compensates. The negative Caco-2 and solubility values are concerning for both, but the affinity difference is significant.

Output:
1
2025-04-17 04:39:44,558 - INFO - Batch 132 complete. Total preferences: 2112
2025-04-17 04:39:44,558 - INFO - Processing batch 133/512...
2025-04-17 04:40:24,398 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (352.435 and 365.499 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (104.39) is slightly above the preferred <90 for CNS targets, while Ligand B (82.53) is well within the range. This gives a slight edge to Ligand B.

**3. logP:** Both ligands (1.557 and 1.682) are within the optimal 1-3 range.

**4. H-Bond Donors:** Both have 2 HBD, which is acceptable.

**5. H-Bond Acceptors:** Both have 5 HBA, which is acceptable.

**6. QED:** Ligand B (0.732) has a better QED score than Ligand A (0.491), indicating a more drug-like profile.

**7. DILI:** Both ligands have acceptable DILI risk (27.142 and 35.673), below the 40 threshold.

**8. BBB:** Ligand B (40.558) has a slightly better BBB percentile than Ligand A (36.526), but both are below the desirable >70 for CNS targets. This is a critical factor, and both are suboptimal.

**9. Caco-2 Permeability:** Both have negative Caco-2 values (-5.467 and -5.074), which is unusual and suggests poor permeability. This is a significant concern for both.

**10. Aqueous Solubility:** Both have negative solubility values (-0.505 and -2.64), indicating very poor aqueous solubility. This is a major drawback for both.

**11. hERG Inhibition:** Both ligands show very low hERG inhibition risk (0.333 and 0.151).

**12. Microsomal Clearance:** Ligand A (37.186) has higher microsomal clearance than Ligand B (28.589), suggesting lower metabolic stability. Ligand B is preferable here.

**13. In vitro Half-Life:** Ligand B (32.385) has a longer in vitro half-life than Ligand A (-36.45), indicating better stability.

**14. P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.028 and 0.046).

**15. Binding Affinity:** Ligand B (-7.7 kcal/mol) has a slightly better binding affinity than Ligand A (-7.2 kcal/mol). While the difference is not huge, it's enough to be considered.

**Overall Assessment:**

While both ligands have significant drawbacks (poor solubility and permeability), Ligand B is more promising. It has a better QED score, lower microsomal clearance, longer half-life, and slightly better binding affinity. The TPSA is also more favorable. The BBB values are both poor, but Ligand B is marginally better. Given the GPCR-specific priorities, the slight improvements in key ADME properties and affinity make Ligand B the more viable candidate.

Output:
1
2025-04-17 04:40:24,398 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (364.383 and 340.383 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (41.57) is significantly better than Ligand B (92.35). For CNS targets, TPSA should be <=90, so Ligand A is much more favorable.

**logP:** Ligand A (4.372) is slightly higher than the optimal range (1-3), but still potentially acceptable. Ligand B (2.49) is within the optimal range. However, for a GPCR, a slightly higher logP can be tolerated if other properties are good.

**H-Bond Donors/Acceptors:** Ligand A (HBD=1, HBA=3) is better than Ligand B (HBD=3, HBA=5) in terms of maintaining a balance between solubility and permeability.

**QED:** Both ligands have similar QED values (0.627 and 0.587), indicating reasonable drug-likeness.

**DILI:** Ligand A (31.02) has a much lower DILI risk than Ligand B (77.394). This is a significant advantage.

**BBB:** Ligand A (87.088) has a substantially higher BBB penetration percentile than Ligand B (66.421). This is *critical* for a CNS target like DRD2.

**Caco-2 Permeability:** Both have negative Caco-2 values (-4.673 and -4.87), which is unusual and suggests poor permeability. However, these values are on a scale where negative values are possible and don't necessarily disqualify a compound.

**Aqueous Solubility:** Both ligands have negative solubility values (-3.752 and -4.048), indicating poor aqueous solubility. This is a concern, but can sometimes be overcome with formulation strategies.

**hERG Inhibition:** Ligand A (0.933) has a slightly higher hERG inhibition risk than Ligand B (0.319), but both are relatively low.

**Microsomal Clearance:** Both ligands have similar microsomal clearance values (55.391 and 55.478), suggesting similar metabolic stability.

**In vitro Half-Life:** Both ligands have similar in vitro half-lives (27.854 and 26.721 hours).

**P-gp Efflux:** Ligand A (0.279) has significantly lower P-gp efflux liability than Ligand B (0.087). Lower P-gp efflux is desirable for CNS penetration.

**Binding Affinity:** Ligand B (-9.5 kcal/mol) has a slightly better binding affinity than Ligand A (-8.5 kcal/mol). However, the difference (1 kcal/mol) is not substantial enough to outweigh the significant advantages of Ligand A in other key properties.

**Overall Assessment:**

Ligand A is significantly better suited as a drug candidate for DRD2. Its superior BBB penetration, lower DILI risk, lower P-gp efflux, and more favorable TPSA outweigh the slightly weaker binding affinity and higher logP. The negative Caco-2 and solubility values are concerns for both, but are less critical given the CNS target.



Output:
1
2025-04-17 04:40:24,398 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (346.391 and 343.45 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (124.2) is slightly above the optimal <90 for CNS targets, but still reasonable. Ligand B (55.63) is excellent, well below the threshold.

**logP:** Ligand A (2.384) is within the optimal 1-3 range. Ligand B (4.219) is slightly high, potentially leading to solubility issues or off-target interactions, but not drastically so.

**H-Bond Donors/Acceptors:** Both ligands have 1 HBD and 5 HBA, which are within acceptable limits.

**QED:** Ligand B (0.903) has a significantly better QED score than Ligand A (0.352), indicating a more drug-like profile.

**DILI:** Ligand A (60.217) and Ligand B (49.283) both have acceptable DILI risk, but Ligand B is preferable.

**BBB:** This is a crucial parameter for CNS targets. Ligand B (88.174) has a very good BBB percentile, exceeding the desirable >70 threshold. Ligand A (61.807) is lower, suggesting poorer brain penetration.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values, which is unusual and suggests a potential issue with the data or modeling. However, we'll proceed assuming these represent low permeability.

**Aqueous Solubility:** Both ligands have negative solubility values, which is also unusual. This suggests poor aqueous solubility, a potential formulation challenge.

**hERG Inhibition:** Both ligands have low hERG inhibition liability, which is good.

**Microsomal Clearance:** Ligand A (54.53) and Ligand B (46.825) have similar microsomal clearance values. Lower is better, so Ligand B is slightly preferable.

**In vitro Half-Life:** Ligand B (34.267) has a significantly longer in vitro half-life than Ligand A (-3.65), which is a major advantage.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability, which is good.

**Binding Affinity:** Ligand B (-8.2 kcal/mol) has a slightly better binding affinity than Ligand A (-8.0 kcal/mol), although the difference is small.

**Overall Assessment:**

Ligand B is the stronger candidate. While both ligands have acceptable MW, HBD/HBA, and hERG profiles, Ligand B excels in crucial areas for CNS GPCRs: BBB penetration (88.174 vs 61.807), QED (0.903 vs 0.352), and in vitro half-life (34.267 vs -3.65). The slightly higher logP of Ligand B is a minor concern compared to the significant advantages in CNS penetration and drug-likeness. The similar affinities make these factors the deciding criteria.

Output:
1
2025-04-17 04:40:24,398 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (338.426 Da) is slightly better, being closer to the lower end which can aid permeability.

**2. TPSA:** Ligand A (46.33) is excellent, well below the 90 A^2 threshold for CNS targets. Ligand B (67.43) is still reasonable, but less optimal.

**3. logP:** Both ligands have good logP values (A: 3.752, B: 2.87), falling within the 1-3 range. Ligand A is slightly higher, which could be beneficial for membrane permeability, but needs to be balanced against solubility.

**4. H-Bond Donors:** Both have acceptable HBD counts (A: 1, B: 2), well below the 5 limit.

**5. H-Bond Acceptors:** Both have acceptable HBA counts (A: 2, B: 5), within the 10 limit.

**6. QED:** Both have good QED scores (A: 0.923, B: 0.609), indicating drug-like properties. Ligand A is significantly better.

**7. DILI:** Ligand A (23.187) has a much lower DILI risk than Ligand B (57.697), making it safer.

**8. BBB:** This is a critical parameter for a CNS target like DRD2. Ligand A (88.833) has a very good BBB penetration percentile, exceeding the desirable >70 threshold. Ligand B (64.637) is significantly lower and less promising for CNS exposure.

**9. Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and suggests a potential issue with the data or modeling. However, we can interpret this as very low permeability.

**10. Aqueous Solubility:** Both have negative solubility values, again suggesting a potential data issue.

**11. hERG Inhibition:** Both ligands have low hERG inhibition risk (A: 0.89, B: 0.552).

**12. Microsomal Clearance:** Ligand A (5.915) has a lower microsomal clearance than Ligand B (65.601), indicating better metabolic stability.

**13. In vitro Half-Life:** Ligand A (-14.089) has a negative half-life, which is not physically possible and indicates a data issue. Ligand B (20.488) is reasonable.

**14. P-gp Efflux:** Ligand A (0.405) has lower P-gp efflux liability than Ligand B (0.608), which is favorable for CNS penetration.

**15. Binding Affinity:** Ligand A (-9.9 kcal/mol) has a significantly stronger binding affinity than Ligand B (-7.0 kcal/mol). This is a substantial advantage, potentially outweighing some of the ADME concerns.

**Overall Assessment:**

Despite some data anomalies (negative Caco-2 and solubility, negative half-life), Ligand A is clearly the superior candidate. It excels in critical GPCR parameters like BBB penetration, binding affinity, and DILI risk. Its lower P-gp efflux and better metabolic stability further support its potential. While the negative values are concerning and would require investigation, the strong affinity and favorable CNS properties make Ligand A the more promising drug candidate. Ligand B's lower BBB penetration and higher DILI risk are significant drawbacks.

Output:
1
2025-04-17 04:40:24,399 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 drug candidates, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (337.383 and 354.447 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (85.84) is better than Ligand B (87.15). Both are below the 90 A^2 threshold desirable for CNS targets, but lower is better.

**3. logP:** Ligand A (2.504) is optimal (1-3), while Ligand B (0.593) is slightly low, potentially hindering permeation.

**4. H-Bond Donors:** Both ligands have 1 HBD, which is within the acceptable limit of <=5.

**5. H-Bond Acceptors:** Ligand A has 6 HBA, and Ligand B has 5. Both are below the acceptable limit of <=10.

**6. QED:** Both ligands have acceptable QED values (0.747 and 0.689, both >= 0.5).

**7. DILI:** Ligand A (69.058) has a higher DILI risk than Ligand B (24.544). This is a significant drawback for Ligand A.

**8. BBB:** Ligand A (74.641) has a significantly better BBB penetration percentile than Ligand B (55.215). This is a crucial factor for a CNS target like DRD2.

**9. Caco-2 Permeability:** Ligand A (-5.16) has worse Caco-2 permeability than Ligand B (-4.639). Lower values indicate poorer permeability.

**10. Aqueous Solubility:** Ligand A (-3.244) has worse aqueous solubility than Ligand B (-0.95).

**11. hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.116 and 0.141).

**12. Microsomal Clearance:** Both ligands have similar microsomal clearance (19.501 and 19.898 mL/min/kg).

**13. In vitro Half-Life:** Ligand A (6.018) has a slightly longer half-life than Ligand B (2.407).

**14. P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.078 and 0.058).

**15. Binding Affinity:** Ligand A (-7.8 kcal/mol) has a slightly better binding affinity than Ligand B (-7.6 kcal/mol). While the difference is small (0.2 kcal/mol), it's still a positive for Ligand A.

**Overall Assessment:**

Ligand A excels in BBB penetration and binding affinity, which are critical for a CNS GPCR target. However, its higher DILI risk and poorer solubility/permeability are concerning. Ligand B has a much better safety profile (lower DILI) and better solubility/permeability, but its BBB penetration is significantly lower, which is a major disadvantage for a CNS drug.

Considering the GPCR-specific priorities, the improved BBB penetration of Ligand A is a strong advantage that outweighs its slightly higher DILI risk and lower solubility/permeability. The small affinity difference isn't decisive.

Output:
1
2025-04-17 04:40:24,399 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (344.415 and 350.419 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (96.11) is slightly higher than Ligand B (93.53), but both are below the 90-140 threshold for oral absorption and acceptable for CNS penetration.

**logP:** Ligand A (1.614) and Ligand B (0.965) are both within the optimal 1-3 range. Ligand B is slightly lower, which could potentially impact permeability, but it's not a major concern.

**H-Bond Donors/Acceptors:** Ligand A has 3 HBD and 4 HBA, while Ligand B has 1 HBD and 6 HBA. Both are within acceptable limits (<=5 HBD and <=10 HBA).

**QED:** Both ligands have similar QED values (0.711 and 0.67), indicating good drug-like properties.

**DILI:** Ligand A (56.805) has a lower DILI risk than Ligand B (41.179), which is favorable.

**BBB:** This is a critical parameter for a CNS target like DRD2. Ligand B (72.78) has a significantly higher BBB percentile than Ligand A (51.415). This is a major advantage for Ligand B.

**Caco-2 Permeability:** Ligand A (-5.367) shows poor Caco-2 permeability, while Ligand B (-4.527) is better, but still not great.

**Aqueous Solubility:** Ligand A (-2.687) has slightly better solubility than Ligand B (-1.817).

**hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.459 and 0.125).

**Microsomal Clearance:** Ligand A (1.758) has significantly lower microsomal clearance than Ligand B (85.15), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (14.813 hours) has a much longer half-life than Ligand B (-22.437 hours - this is a negative value, indicating a very short half-life or instability).

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.04 and 0.046), which is good.

**Binding Affinity:** Ligand A (-8.7 kcal/mol) has a slightly better binding affinity than Ligand B (-6.9 kcal/mol). This is a 1.8 kcal/mol difference, which is substantial and could outweigh some ADME drawbacks.

**Overall Assessment:**

While Ligand A has better metabolic stability (lower Cl_mic, longer t1/2) and slightly better binding affinity, Ligand B has a significantly higher BBB penetration (72.78 vs 51.415) and a lower DILI risk. For a CNS target like DRD2, BBB penetration is paramount. The 1.8 kcal/mol difference in binding affinity is significant, but the improved CNS exposure potential of Ligand B is more crucial. The poor Caco-2 permeability of Ligand A is also a concern.

Output:
1
2025-04-17 04:40:24,399 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (338.367 and 341.503 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (94.05) is slightly above the optimal <90 for CNS targets, but still reasonable. Ligand B (36.33) is excellent, well below the threshold.

**logP:** Ligand A (3.232) is within the optimal 1-3 range. Ligand B (2.203) is also good, slightly lower but still acceptable.

**H-Bond Donors/Acceptors:** Both ligands have 1 HBD and 5-6 HBA, which are within acceptable limits.

**QED:** Both ligands have similar QED scores (0.785 and 0.784), indicating good drug-likeness.

**DILI:** Ligand A (82.784) has a significantly higher DILI risk than Ligand B (11.749). This is a major concern for Ligand A.

**BBB:** Ligand B (75.533) has a much better BBB penetration score than Ligand A (58.782). This is crucial for a CNS target like DRD2.

**Caco-2 Permeability:** Ligand A (-4.868) has poor Caco-2 permeability, suggesting poor intestinal absorption. Ligand B (-5.14) is also poor, but slightly better.

**Aqueous Solubility:** Ligand A (-3.926) has poor aqueous solubility. Ligand B (-0.507) is also poor, but better than Ligand A.

**hERG:** Ligand A (0.164) has a slightly higher hERG risk than Ligand B (0.971), but both are relatively low.

**Microsomal Clearance:** Ligand B (-7.695) has significantly lower (better) microsomal clearance than Ligand A (47.738), indicating improved metabolic stability.

**In vitro Half-Life:** Ligand B (-6.633) has a longer in vitro half-life than Ligand A (-33.726), which is desirable.

**P-gp Efflux:** Ligand A (0.128) has lower P-gp efflux than Ligand B (0.106), which is slightly better for CNS penetration.

**Binding Affinity:** Both ligands have excellent binding affinities (-9.0 and -8.8 kcal/mol), with Ligand A being slightly stronger. However, the difference is small and likely not enough to overcome other significant drawbacks.

**Overall Assessment:**

Ligand B is the superior candidate. While both have good binding affinity, Ligand B significantly outperforms Ligand A in critical ADME properties for a CNS-targeting GPCR: lower DILI risk, much better BBB penetration, improved metabolic stability (lower Cl_mic, longer t1/2), and slightly better P-gp efflux. Ligand A's high DILI risk and poor BBB penetration are major red flags. The slightly better affinity of Ligand A is unlikely to compensate for these deficiencies.

Output:
1
2025-04-17 04:40:24,399 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (360.351 and 343.383 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (49.41) is excellent, well below the 90 A^2 threshold for CNS targets. Ligand B (97.37) is higher, but still potentially acceptable, though less ideal.

**3. logP:** Both ligands have good logP values (2.821 and 2.213), falling within the optimal 1-3 range.

**4. H-Bond Donors:** Ligand A (1) and Ligand B (2) are both within the acceptable limit of <=5.

**5. H-Bond Acceptors:** Ligand A (2) and Ligand B (5) are both within the acceptable limit of <=10.

**6. QED:** Both ligands have similar QED values (0.821 and 0.716), indicating good drug-like properties.

**7. DILI:** Ligand A (35.983) has a significantly lower DILI risk than Ligand B (61.303). This is a substantial advantage.

**8. BBB:** Ligand A (79.333) has a much better BBB penetration percentile than Ligand B (55.642). This is *critical* for a CNS target like DRD2.

**9. Caco-2 Permeability:** Ligand A (-4.408) has a better (less negative) Caco-2 value than Ligand B (-5.431), suggesting better intestinal absorption.

**10. Aqueous Solubility:** Ligand A (-3.032) has a better (less negative) solubility value than Ligand B (-2.056).

**11. hERG Inhibition:** Both ligands have low hERG inhibition risk (0.714 and 0.253).

**12. Microsomal Clearance:** Ligand A (8.716) has a lower microsomal clearance than Ligand B (32.495), indicating better metabolic stability.

**13. In vitro Half-Life:** Ligand B (22.421) has a longer in vitro half-life than Ligand A (5.223). This is a slight advantage for Ligand B.

**14. P-gp Efflux:** Ligand A (0.027) has a much lower P-gp efflux liability than Ligand B (0.2). This is important for CNS exposure.

**15. Binding Affinity:** Both ligands have very similar and excellent binding affinities (-9.4 and -9.3 kcal/mol). The difference is negligible.

**Overall Assessment:**

Ligand A is significantly better overall. While Ligand B has a slightly longer half-life, Ligand A excels in crucial areas for a CNS-targeting GPCR ligand: BBB penetration, lower DILI risk, lower P-gp efflux, better solubility, and better metabolic stability. The TPSA is also much more favorable for CNS penetration. The binding affinity is comparable, so the superior ADME properties of Ligand A make it the more promising candidate.

Output:
1
2025-04-17 04:40:24,399 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (335.411 and 347.371 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (73.95) is significantly better than Ligand B (101.74). For CNS targets, we want TPSA <= 90, and A is comfortably within that, while B is pushing the limit.

**logP:** Both ligands have acceptable logP values (1.878 and 0.825), falling within the 1-3 range.

**H-Bond Donors/Acceptors:** Both have 1 HBD, which is good. Ligand A has 5 HBA, while Ligand B has 6. Both are acceptable (<=10).

**QED:** Both ligands have good QED scores (0.909 and 0.765), indicating drug-like properties.

**DILI:** Both have similar, acceptable DILI risk (46.762 and 46.297, both <60).

**BBB:** Ligand B (75.805) has a significantly better BBB percentile than Ligand A (64.327). This is a crucial factor for a CNS target like DRD2.

**Caco-2 Permeability:** Ligand A (-5.102) has worse Caco-2 permeability than Ligand B (-4.523), but both are negative values which is not ideal.

**Aqueous Solubility:** Both have poor aqueous solubility (-2.366 and -2.094). This could pose formulation challenges, but is less critical than BBB for CNS drugs.

**hERG:** Both ligands have low hERG inhibition liability (0.586 and 0.14).

**Microsomal Clearance:** Ligand A (-14.051) has much better microsomal clearance (lower clearance = better metabolic stability) than Ligand B (68.255).

**In vitro Half-Life:** Ligand A (38.232) has a better in vitro half-life than Ligand B (-29.736).

**P-gp Efflux:** Both have low P-gp efflux liability (0.103 and 0.04).

**Binding Affinity:** Ligand B (-8.5 kcal/mol) has a slightly better binding affinity than Ligand A (-9.0 kcal/mol). While A has a better affinity, the difference is not substantial enough to overcome the other deficiencies.

**Overall Assessment:**

Ligand A excels in TPSA, metabolic stability (Cl_mic, t1/2) and has slightly better binding affinity. However, Ligand B has a significantly better BBB penetration, which is paramount for a CNS target. While Ligand A has better metabolic stability, the improved CNS penetration of Ligand B is more critical. The slightly weaker binding affinity of Ligand B can potentially be optimized in subsequent iterations.

Output:
1
2025-04-17 04:40:24,399 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (341.455 and 354.422 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (71.09) is excellent, well below the 90 A^2 threshold for CNS targets. Ligand B (78.87) is still acceptable, but less optimal.

**logP:** Ligand A (2.686) is within the optimal 1-3 range. Ligand B (1.633) is slightly lower, but still reasonable.

**H-Bond Donors/Acceptors:** Both ligands have 2 HBD and 3-4 HBA, which are within acceptable limits.

**QED:** Both ligands have similar QED values (0.782 and 0.711), indicating good drug-likeness.

**DILI:** Both ligands have low DILI risk (43.66 and 45.095 percentile), which is favorable.

**BBB:** Ligand B (85.653) has a significantly higher BBB penetration percentile than Ligand A (70.415). This is a crucial advantage for a CNS target like DRD2.

**Caco-2 Permeability:** Ligand A (-4.762) has a worse Caco-2 permeability than Ligand B (-5.064), indicating lower intestinal absorption.

**Aqueous Solubility:** Ligand A (-3.558) has slightly better aqueous solubility than Ligand B (-2.857).

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.183 and 0.425).

**Microsomal Clearance:** Ligand B (-2.837) has a significantly *lower* (better) microsomal clearance than Ligand A (51.604), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand B (3.094) has a longer in vitro half-life than Ligand A (-19.828).

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.118 and 0.12).

**Binding Affinity:** Ligand B (-8.3 kcal/mol) has a slightly better binding affinity than Ligand A (-9.0 kcal/mol). While A is better, the difference isn't massive.

**Overall Assessment:**

Ligand B is the stronger candidate. While Ligand A has slightly better binding affinity, Ligand B excels in crucial areas for a CNS-targeting GPCR: significantly higher BBB penetration, better metabolic stability (lower Cl_mic and longer t1/2), and acceptable TPSA and logP values. The Caco-2 permeability is slightly worse for B, but this is less critical for a CNS drug. The small difference in binding affinity is outweighed by the superior ADME properties of Ligand B.

Output:
1
2025-04-17 04:40:24,399 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 drug candidates, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (361.31 Da) is slightly higher than Ligand B (350.438 Da), but both are acceptable.

**TPSA:** Ligand A (29.54) is excellent for CNS penetration, well below the 90 A^2 threshold. Ligand B (76.02) is higher, but still reasonable, although less favorable for CNS targets.

**logP:** Ligand A (3.919) is at the upper end of the optimal range (1-3), potentially raising concerns about solubility and off-target effects. Ligand B (1.91) is well within the optimal range.

**H-Bond Donors/Acceptors:** Ligand A (0 HBD, 2 HBA) is favorable. Ligand B (2 HBD, 4 HBA) is also acceptable.

**QED:** Both ligands have similar and good QED values (0.748 and 0.752, respectively), indicating good drug-like properties.

**DILI:** Ligand A (48.313) has a slightly higher DILI risk than Ligand B (28.538), but both are below the 60 threshold and considered relatively safe.

**BBB:** This is a critical parameter for a CNS target like DRD2. Ligand A has a very high BBB penetration percentile (98.022), significantly better than Ligand B (75.378).

**Caco-2 Permeability:** Ligand A (-4.306) shows poor Caco-2 permeability, which is concerning. Ligand B (-5.122) is also poor, but slightly better.

**Aqueous Solubility:** Ligand A (-4.708) has very poor aqueous solubility, a significant drawback. Ligand B (-2.182) is also poor, but better than Ligand A.

**hERG Inhibition:** Both ligands have low hERG inhibition liability (0.821 and 0.393, respectively), which is good.

**Microsomal Clearance:** Ligand A (38.317) has higher microsomal clearance than Ligand B (11.48), suggesting lower metabolic stability.

**In vitro Half-Life:** Ligand B (1.548 hours) has a longer half-life than Ligand A (0.565 hours).

**P-gp Efflux:** Ligand A (0.329) has lower P-gp efflux than Ligand B (0.157), which is favorable for CNS exposure.

**Binding Affinity:** Both ligands have excellent binding affinity (-8.4 and -8.6 kcal/mol), with Ligand B being slightly better. The difference is small enough that it's unlikely to overcome significant ADME deficiencies.

**Overall Assessment:**

Ligand A excels in BBB penetration and P-gp efflux, but suffers from poor Caco-2 permeability and aqueous solubility, and has higher microsomal clearance. Ligand B has better solubility, permeability, and metabolic stability, but lower BBB penetration. Given the importance of BBB penetration for a CNS target like DRD2, and the relatively small difference in binding affinity, Ligand A is the more promising candidate *despite* its ADME liabilities. These liabilities could potentially be addressed through formulation strategies or further chemical modifications. The high BBB score is a significant advantage.

Output:
0
2025-04-17 04:40:24,400 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (361.471 and 348.487 Da) fall within the ideal range of 200-500 Da.

**TPSA:** Ligand A (99.77) is higher than Ligand B (67.43). For CNS targets, TPSA should be <= 90. Ligand B is preferable here.

**logP:** Both ligands (2.341 and 2.537) are within the optimal range of 1-3.

**H-Bond Donors:** Ligand A (3) and Ligand B (2) are both acceptable, being <= 5.

**H-Bond Acceptors:** Ligand A (5) and Ligand B (3) are both acceptable, being <= 10.

**QED:** Both ligands have good QED scores (0.705 and 0.82), indicating good drug-like properties.

**DILI:** Ligand A (59.403) has a higher DILI risk than Ligand B (23.071). Lower is better, so Ligand B is preferable.

**BBB:** Ligand B (52.036) has a significantly better BBB penetration score than Ligand A (37.379). This is *critical* for a CNS target like DRD2.

**Caco-2 Permeability:** Ligand A (-5.671) and Ligand B (-4.966) both have negative values, which is unusual and suggests poor permeability. However, the scale isn't specified, so it's difficult to interpret.

**Aqueous Solubility:** Both ligands (-2.8 and -2.691) have poor solubility.

**hERG Inhibition:** Both ligands (0.123 and 0.193) have low hERG inhibition risk, which is good.

**Microsomal Clearance:** Ligand A (-4.148) has a lower (better) microsomal clearance than Ligand B (24.804). This suggests better metabolic stability for Ligand A.

**In vitro Half-Life:** Ligand A (6.01) has a slightly better half-life than Ligand B (-0.213).

**P-gp Efflux:** Both ligands (0.088 and 0.091) have low P-gp efflux, which is good for CNS penetration.

**Binding Affinity:** Ligand B (-9.3 kcal/mol) has a slightly better binding affinity than Ligand A (-8.6 kcal/mol). While both are good, the difference is significant.

**Overall Assessment:**

Ligand B is the stronger candidate. Its superior BBB penetration (52.036 vs 37.379) is a major advantage for a CNS target. It also has a significantly lower DILI risk. While Ligand A has better metabolic stability and half-life, the BBB and DILI advantages of Ligand B outweigh these factors. The slightly better affinity of Ligand B further supports this conclusion.

Output:
1
2025-04-17 04:40:24,400 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (360.5 & 363.5 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (23.55) is excellent, well below the 90 A^2 threshold for CNS targets. Ligand B (62.74) is higher, but still potentially acceptable, though less ideal.

**3. logP:** Ligand A (4.454) is slightly high, potentially leading to solubility issues or off-target interactions. Ligand B (1.948) is within the optimal 1-3 range.

**4. H-Bond Donors:** Both ligands have 0 HBD, which is acceptable.

**5. H-Bond Acceptors:** Ligand A has 3 HBA, and Ligand B has 5 HBA. Both are below the 10 threshold.

**6. QED:** Both ligands have good QED scores (0.786 and 0.823), indicating drug-like properties.

**7. DILI:** Ligand A (26.018) has a much lower DILI risk than Ligand B (62.854), which is a significant advantage.

**8. BBB:** Ligand A (97.325) has excellent BBB penetration, exceeding the desirable >70% threshold for CNS targets. Ligand B (55.138) is considerably lower, raising concerns about CNS exposure.

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.85 and -4.756). This is unusual and suggests poor permeability. However, these values are on a log scale and a negative value doesn't necessarily disqualify a compound.

**10. Aqueous Solubility:** Both ligands have negative solubility values (-3.466 and -1.857). This is a concern, but can sometimes be overcome with formulation strategies.

**11. hERG Inhibition:** Ligand A (0.983) has a slightly higher hERG risk than Ligand B (0.376), but both are relatively low.

**12. Microsomal Clearance:** Ligand A (51.789) has higher microsomal clearance than Ligand B (42.724), indicating lower metabolic stability.

**13. In vitro Half-Life:** Both ligands have similar in vitro half-lives (16.706 and 17.17 hours).

**14. P-gp Efflux:** Ligand A (0.859) has higher P-gp efflux than Ligand B (0.281), which is unfavorable for CNS penetration.

**15. Binding Affinity:** Ligand A (-9.2 kcal/mol) has significantly stronger binding affinity than Ligand B (-0.0 kcal/mol). This is a substantial advantage, potentially outweighing some of its ADME drawbacks.

**Overall Assessment:**

Ligand A is the stronger candidate despite some ADME concerns. Its *exceptional* binding affinity (-9.2 kcal/mol) and excellent BBB penetration (97.325) are critical for a CNS-targeting GPCR like DRD2. The lower DILI risk is also a major plus. While the higher logP and P-gp efflux are drawbacks, the strong affinity suggests a higher probability of achieving sufficient target engagement *in vivo*. Ligand B's lower affinity and poor BBB penetration make it a less attractive candidate, even with its better logP and P-gp efflux.

Output:
1
2025-04-17 04:40:24,400 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (341.37 & 354.37 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (80.76) is significantly better than Ligand B (49.41), being closer to the desirable <90 for CNS targets. Ligand B is excellent.

**logP:** Both ligands have good logP values (2.536 and 3.743), falling within the optimal 1-3 range. Ligand B is slightly higher, potentially raising solubility concerns, but still acceptable.

**H-Bond Donors/Acceptors:** Both have 1 HBD, which is good. Ligand A has 5 HBA, while Ligand B has 2. Both are within acceptable limits (<=10).

**QED:** Both ligands have high QED scores (0.904 and 0.823), indicating good drug-like properties.

**DILI:** Ligand A (90.694) has a considerably higher DILI risk than Ligand B (37.922). This is a significant negative for Ligand A.

**BBB:** Ligand B (91.508) has a much better BBB penetration score than Ligand A (55.293). This is crucial for a CNS target like DRD2.

**Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and suggests a potential issue with the data or modeling. However, the values are similar (-4.549 vs -4.232).

**Aqueous Solubility:** Both have negative solubility values, which is also unusual. Ligand A (-3.799) is slightly better than Ligand B (-4.84).

**hERG:** Both ligands have low hERG inhibition liability (0.209 and 0.645), which is good.

**Microsomal Clearance:** Ligand B (51.296) has higher microsomal clearance than Ligand A (19.096), suggesting faster metabolism and potentially lower *in vivo* exposure.

**In vitro Half-Life:** Ligand A (-31.567) has a negative half-life, which is not physically possible and indicates a data issue. Ligand B (33.613) has a reasonable half-life.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.107 and 0.361), which is favorable for CNS penetration.

**Binding Affinity:** Both ligands have the same binding affinity (-9.6 kcal/mol), which is excellent.

**Overall Assessment:**

Ligand B is clearly superior. While both have excellent binding affinity, Ligand B demonstrates significantly better ADME properties: a much lower DILI risk, substantially improved BBB penetration, and a more reasonable *in vitro* half-life. Ligand A's high DILI risk and questionable half-life are major concerns. The TPSA of Ligand B is also excellent. The slightly higher logP of Ligand B is a minor concern compared to the advantages it offers.

Output:
1
2025-04-17 04:40:24,400 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (370.425 and 359.442 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (86.88) is excellent, falling well below the 90 A^2 threshold for CNS targets. Ligand B (107.53) is still reasonable but less optimal, being closer to the 140 A^2 limit for oral absorption.

**3. logP:** Ligand A (2.932) is within the optimal 1-3 range. Ligand B (0.27) is quite low, potentially hindering membrane permeability and CNS penetration.

**4. H-Bond Donors:** Both ligands have 3-4 HBD, which is acceptable.

**5. H-Bond Acceptors:** Both ligands have 4 HBA, which is acceptable.

**6. QED:** Ligand A (0.668) has a better QED score than Ligand B (0.449), indicating a more drug-like profile.

**7. DILI:** Ligand A (67.817) has a higher DILI risk than Ligand B (13.106). This is a concern for Ligand A, but not a deal-breaker at this stage.

**8. BBB:** Ligand A (61.923) has a better BBB percentile than Ligand B (58.55). While both are below the desirable >70% for CNS targets, Ligand A is closer.

**9. Caco-2:** Both ligands have negative Caco-2 values, which is unusual and suggests poor permeability. However, the scale is not specified, so it's difficult to interpret.

**10. Solubility:** Both ligands have negative solubility values, again making interpretation difficult.

**11. hERG:** Both ligands have very low hERG inhibition liability (0.152 and 0.157), which is excellent.

**12. Cl_mic:** Ligand B (25.899) has lower microsomal clearance than Ligand A (36.755), suggesting better metabolic stability.

**13. t1/2:** Ligand B (-11.056) has a significantly longer *in vitro* half-life than Ligand A (-3.662). This is a major advantage for Ligand B.

**14. Pgp:** Both ligands have very low Pgp efflux liability (0.008 and 0.153), which is good.

**15. Binding Affinity:** Both ligands have similar, strong binding affinities (-8.8 and -8.0 kcal/mol). The difference is less than the 1.5 kcal/mol threshold.

**Overall Assessment:**

Considering the GPCR-specific priorities, Ligand A has a better TPSA and slightly better BBB penetration. However, Ligand B has a significantly better *in vitro* half-life, lower DILI risk, and better metabolic stability (lower Cl_mic). The lower logP of Ligand B is a concern, but the strong binding affinity might compensate. Given the importance of CNS penetration for a DRD2 ligand, and the better ADME profile of Ligand B, it is the more promising candidate.

Output:
1
2025-04-17 04:40:24,400 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (350.503 and 369.527 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (67.43) is significantly better than Ligand B (73.91). For CNS targets, we want TPSA <= 90, and A is closer to the ideal <=60.

**3. logP:** Both ligands (2.662 and 2.62) are within the optimal 1-3 range.

**4. H-Bond Donors:** Both have 2 HBD, which is acceptable.

**5. H-Bond Acceptors:** Ligand A has 3 HBA, while Ligand B has 5. Both are within the acceptable limit of <=10, but A is preferable.

**6. QED:** Both ligands have good QED scores (0.628 and 0.663), indicating good drug-like properties.

**7. DILI:** Ligand A (9.461) has a much lower DILI risk than Ligand B (25.087). This is a significant advantage for A.

**8. BBB:** This is crucial for a CNS target like DRD2. Ligand A (78.286) has a significantly higher BBB penetration percentile than Ligand B (54.711). A score >70 is desirable, and A is much closer.

**9. Caco-2 Permeability:** Ligand A (-4.466) has a worse Caco-2 permeability than Ligand B (-5.047). Lower values are less favorable.

**10. Aqueous Solubility:** Ligand A (-3.311) has a worse solubility than Ligand B (-2.817). Higher values are better.

**11. hERG Inhibition:** Ligand A (0.313) has a lower hERG inhibition risk than Ligand B (0.809), which is preferable.

**12. Microsomal Clearance:** Ligand A (80.146) has a higher microsomal clearance than Ligand B (53.099), indicating lower metabolic stability. This favors B.

**13. In vitro Half-Life:** Ligand B (93.106) has a significantly longer in vitro half-life than Ligand A (13.646). This is a strong advantage for B.

**14. P-gp Efflux:** Ligand A (0.036) has much lower P-gp efflux liability than Ligand B (0.799). Lower efflux is better, especially for CNS penetration, and this is a major advantage for A.

**15. Binding Affinity:** Ligand A (-7.7) has a slightly better binding affinity than Ligand B (-6.8). While both are good, the 0.9 kcal/mol difference is noteworthy.

**Overall Assessment:**

Ligand A excels in key areas for a CNS-targeting GPCR ligand: TPSA, DILI risk, BBB penetration, hERG inhibition, and P-gp efflux. Its binding affinity is also slightly better. While it has poorer Caco-2 permeability, solubility, and metabolic stability (higher Cl_mic, shorter t1/2) compared to Ligand B, the CNS-specific properties are paramount. The significantly better BBB and lower P-gp efflux of Ligand A are likely to translate to higher brain exposure, outweighing the ADME drawbacks.

Output:
1
2025-04-17 04:40:24,401 - INFO - Batch 133 complete. Total preferences: 2128
2025-04-17 04:40:24,401 - INFO - Processing batch 134/512...
2025-04-17 04:41:05,041 - INFO - Reasoning:

Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (359.373 and 362.348 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (111.55) is slightly above the optimal <90 for CNS targets, while Ligand B (89.87) is well within the desired range. This favors Ligand B.

**logP:** Ligand A (0.174) is quite low, potentially hindering permeation. Ligand B (0.039) is even lower, posing a similar concern. Both are below the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A has 4 HBD and 5 HBA, acceptable values. Ligand B has 3 HBD and 4 HBA, also acceptable.

**QED:** Both ligands have good QED scores (0.529 and 0.619), indicating drug-like properties.

**DILI:** Both ligands have low DILI risk (31.834 and 29.624), which is positive.

**BBB:** Ligand B (69.523) has a better BBB percentile than Ligand A (56.495), although both are below the desirable >70 for CNS targets. This is a significant advantage for Ligand B.

**Caco-2 Permeability:** Ligand A (-5.167) and Ligand B (-4.794) both have negative values, suggesting poor permeability.

**Aqueous Solubility:** Both ligands have very poor aqueous solubility (-2.088 and -1.461). This is a major drawback for both.

**hERG Inhibition:** Both ligands show low hERG inhibition risk (0.169 and 0.366).

**Microsomal Clearance:** Ligand B (-15.762) has significantly lower (better) microsomal clearance than Ligand A (35.554), indicating greater metabolic stability.

**In vitro Half-Life:** Ligand B (-41.96) has a much longer in vitro half-life than Ligand A (-7.445).

**P-gp Efflux:** Both ligands show very low P-gp efflux liability (0.018 and 0.039), which is favorable for CNS penetration.

**Binding Affinity:** Ligand B (-8.3 kcal/mol) has a stronger binding affinity than Ligand A (-7.4 kcal/mol). This 0.9 kcal/mol difference is substantial and can outweigh some ADME drawbacks.

**Overall Assessment:**

Ligand B is the stronger candidate. While both have poor solubility and permeability, Ligand B excels in several key areas for a CNS-targeting GPCR ligand: better BBB penetration, significantly improved metabolic stability (lower Cl_mic and longer t1/2), and a substantially higher binding affinity. The lower TPSA of Ligand B is also beneficial. The slightly lower logP is a concern, but the superior binding affinity and pharmacokinetic properties likely compensate for this.

Output:
1
2025-04-17 04:41:05,042 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (342.399 Da) is slightly better, being closer to the lower end which can aid permeability.

**TPSA:** Ligand A (78.67) is significantly better than Ligand B (112.57). For CNS targets, TPSA should be <= 90. Ligand A comfortably meets this, while Ligand B is approaching a less desirable range.

**logP:** Ligand A (-0.36) is a bit low, potentially hindering permeation. Ligand B (1.579) is within the optimal range (1-3). This is a clear advantage for Ligand B.

**H-Bond Donors/Acceptors:** Ligand A (1 HBD, 5 HBA) is preferable to Ligand B (3 HBD, 5 HBA). Fewer H-bonds generally improve membrane permeability.

**QED:** Both ligands have acceptable QED values (A: 0.761, B: 0.607), indicating good drug-like properties.

**DILI:** Ligand A (20.202) has a much lower DILI risk than Ligand B (47.77), which is a significant advantage.

**BBB:** Ligand A (43.932) has a lower BBB penetration percentile than Ligand B (50.407). While both are not ideal (aim for >70), Ligand B is slightly better.

**Caco-2 Permeability:** Ligand A (-4.801) has poor Caco-2 permeability, while Ligand B (-5.689) is also poor. This is a concern for both, but similar.

**Aqueous Solubility:** Ligand A (-0.947) has slightly better solubility than Ligand B (-2.541).

**hERG Inhibition:** Both ligands have low hERG inhibition risk (A: 0.137, B: 0.417).

**Microsomal Clearance:** Ligand A (-19.125) has a much lower (better) microsomal clearance than Ligand B (19.023), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (-14.801) has a longer in vitro half-life than Ligand B (10.792), which is desirable.

**P-gp Efflux:** Ligand A (0.017) has significantly lower P-gp efflux liability than Ligand B (0.093), which is crucial for CNS penetration.

**Binding Affinity:** Ligand B (-7.8) has a slightly better binding affinity than Ligand A (-8.4). However, the difference is less than 1.5 kcal/mol and can be outweighed by other factors.

**Overall Assessment:**

Ligand A excels in TPSA, DILI, metabolic stability (Cl_mic & t1/2), and P-gp efflux. While its logP is suboptimal, the other advantages, particularly the lower DILI and P-gp efflux, are highly valuable for a CNS-targeting drug. Ligand B has a better logP and slightly better BBB penetration, but suffers from higher DILI, higher P-gp efflux, and poorer metabolic stability. Considering the GPCR-specific priorities, especially BBB, logP, Pgp, TPSA, and affinity, Ligand A is the more promising candidate. The slightly weaker affinity of Ligand A can likely be optimized in further iterations, while addressing the issues with Ligand B (DILI, P-gp) would be more challenging.

Output:
0
2025-04-17 04:41:05,042 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (353.4 and 345.5 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (89.35) is better than Ligand B (54.34). Both are below the 90 A^2 threshold desirable for CNS targets, but A is closer to the upper limit.

**3. logP:** Ligand B (2.973) is optimal (1-3), while Ligand A (0.84) is slightly low, potentially impacting permeability.

**4. H-Bond Donors:** Both ligands have 1 HBD, which is within the acceptable limit of <=5.

**5. H-Bond Acceptors:** Ligand A has 6 HBAs, and Ligand B has 3. Both are within the acceptable limit of <=10.

**6. QED:** Both ligands have good QED scores (0.81 and 0.892), indicating drug-like properties.

**7. DILI:** Ligand B (21.52) has a significantly lower DILI risk than Ligand A (55.913), making it safer from a liver toxicity perspective.

**8. BBB:** Ligand A (84.141) has a better BBB penetration percentile than Ligand B (77.821), which is crucial for a CNS target like DRD2.

**9. Caco-2 Permeability:** Ligand A (-4.869) has better Caco-2 permeability than Ligand B (-4.53).

**10. Aqueous Solubility:** Ligand A (-1.511) has better aqueous solubility than Ligand B (-2.773).

**11. hERG Inhibition:** Ligand A (0.096) has a lower hERG inhibition liability than Ligand B (0.373), reducing the risk of cardiotoxicity.

**12. Microsomal Clearance:** Both ligands have similar microsomal clearance (35.394 and 36.805), suggesting comparable metabolic stability.

**13. In vitro Half-Life:** Ligand B (12.945) has a significantly longer in vitro half-life than Ligand A (5.138), indicating potentially less frequent dosing.

**14. P-gp Efflux:** Both ligands have low P-gp efflux liability (0.103 and 0.11).

**15. Binding Affinity:** Ligand A (-9.0) has a significantly stronger binding affinity than Ligand B (-7.0). This is a substantial advantage, potentially outweighing some of the ADME drawbacks.

**Overall Assessment:**

While Ligand B has better safety (DILI) and PK (half-life), Ligand A's significantly stronger binding affinity (-9.0 vs -7.0 kcal/mol) is a major advantage for a GPCR target. The difference in affinity is large enough to compensate for the slightly lower logP and BBB. Ligand A also has better Caco-2 permeability and solubility. Given the importance of potency for GPCRs, and the acceptable BBB penetration of Ligand A, it is the more promising candidate.

Output:
1
2025-04-17 04:41:05,042 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (346.435 and 359.436 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (104.7) is better than Ligand B (46.09). For CNS targets, TPSA should be <= 90, and both meet this criterion, but A is closer to the upper limit.

**logP:** Ligand A (0.888) is suboptimal, being slightly below the preferred 1-3 range. Ligand B (4.642) is too high, potentially leading to solubility issues and off-target interactions.

**H-Bond Donors:** Ligand A (3) is acceptable, while Ligand B (0) is also good.

**H-Bond Acceptors:** Ligand A (5) is acceptable, and Ligand B (3) is also good.

**QED:** Both ligands have good QED scores (0.594 and 0.645), indicating drug-likeness.

**DILI:** Both have similar and acceptable DILI risk (38.193 and 37.069).

**BBB:** This is a crucial parameter for a CNS target like DRD2. Ligand B (92.943) significantly outperforms Ligand A (32.493). This is a major advantage for Ligand B.

**Caco-2 Permeability:** Ligand A (-5.775) is poor, while Ligand B (-4.575) is also poor, but slightly better.

**Aqueous Solubility:** Ligand A (-1.583) is poor, while Ligand B (-4.6) is even worse.

**hERG Inhibition:** Ligand A (0.547) has a slightly better hERG profile than Ligand B (0.843), but both are relatively low risk.

**Microsomal Clearance:** Ligand A (15.189) has a much lower (better) microsomal clearance than Ligand B (56.211), indicating better metabolic stability.

**In vitro Half-Life:** Ligand B (23.51) has a significantly longer half-life than Ligand A (2.131), which is a positive attribute.

**P-gp Efflux:** Ligand A (0.01) shows very low P-gp efflux, which is excellent for CNS penetration. Ligand B (0.681) has moderate P-gp efflux.

**Binding Affinity:** Both ligands have the same excellent binding affinity (-7.4 kcal/mol).

**Overall Assessment:**

Ligand B excels in BBB penetration and in vitro half-life, which are critical for CNS drug development. However, it suffers from a high logP and poor solubility. Ligand A has better metabolic stability (lower Cl_mic) and lower P-gp efflux, but its BBB penetration is very poor and logP is suboptimal.

Given the importance of BBB penetration for a CNS target like DRD2, and the equal binding affinity, Ligand B is the more promising candidate *despite* its drawbacks. The high logP and poor solubility might be addressable through formulation strategies or further chemical modifications, but poor BBB penetration is much harder to overcome. The lower P-gp efflux of Ligand A is beneficial, but the large difference in BBB makes Ligand B the better choice.

Output:
1
2025-04-17 04:41:05,042 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (398.26 Da) is slightly higher than Ligand B (361.829 Da), but both are acceptable.

**TPSA:** Both ligands have TPSA values around 80, which is a bit high for optimal CNS penetration (ideally <90). Ligand A (78.92) is slightly better than Ligand B (80.32).

**logP:** Ligand A (4.019) is at the upper end of the optimal range (1-3), while Ligand B (2.212) is well within the range. High logP can sometimes lead to off-target effects, but is less concerning than low logP for CNS targets.

**H-Bond Donors/Acceptors:** Ligand A has 1 HBD and 4 HBA, while Ligand B has 2 HBD and 4 HBA. Both are within acceptable limits.

**QED:** Ligand A (0.704) has a significantly better QED score than Ligand B (0.45), indicating a more drug-like profile.

**DILI:** Both ligands have relatively high DILI risk, with Ligand A at 73.245 and Ligand B at 76.464. This is a concern for both, but not a deciding factor at this stage.

**BBB:** Ligand A (49.593) has a lower BBB percentile than Ligand B (62.117). This is a significant drawback for a CNS target like DRD2, as BBB penetration is crucial.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.193 and -4.918), which is unusual and suggests poor intestinal absorption. This is a negative for both.

**Aqueous Solubility:** Both ligands have very poor aqueous solubility (-4.824 and -3.168). This is a major concern for formulation and bioavailability.

**hERG Inhibition:** Both ligands show low hERG inhibition risk (0.795 and 0.173), which is positive.

**Microsomal Clearance:** Both have similar microsomal clearance rates (64.194 and 65.64 mL/min/kg), indicating moderate metabolic stability.

**In vitro Half-Life:** Ligand A (124.993) has a significantly longer in vitro half-life than Ligand B (68.784). This is a positive for Ligand A.

**P-gp Efflux:** Ligand A (0.453) has lower P-gp efflux than Ligand B (0.094), which is favorable for CNS exposure.

**Binding Affinity:** Both ligands have excellent binding affinity (-9.8 and -9.1 kcal/mol). Ligand A has a 0.7 kcal/mol advantage, which is substantial.

**Overall Assessment:**

Ligand A has a better QED, longer half-life, and lower P-gp efflux, and a slightly better affinity. However, its BBB penetration is significantly worse than Ligand B. Ligand B has a better logP and BBB, but a lower QED, shorter half-life, and higher P-gp efflux. Given the importance of BBB penetration for a CNS target like DRD2, and the relatively small difference in affinity, Ligand B is the more promising candidate. The poor solubility and Caco-2 permeability are concerns for both, but these can potentially be addressed through formulation strategies.

Output:
1
2025-04-17 04:41:05,042 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (346.475) is slightly better positioned.

**TPSA:** Ligand A (78.09) is significantly better than Ligand B (104.45). For CNS targets, we want TPSA <= 90, and Ligand A is comfortably within that range, while Ligand B is close to the upper limit and less desirable.

**logP:** Ligand A (2.375) is optimal (1-3), while Ligand B (-0.207) is below 1, which could hinder permeation. This is a significant advantage for Ligand A.

**H-Bond Donors/Acceptors:** Ligand A (HBD=2, HBA=3) and Ligand B (HBD=1, HBA=8) both fall within acceptable ranges.

**QED:** Both ligands have good QED values (A: 0.639, B: 0.787), indicating drug-like properties.

**DILI:** Ligand B (47.421) has a lower DILI risk than Ligand A (16.208), which is a positive for Ligand B.

**BBB:** Ligand A (60.644) has a better BBB percentile than Ligand B (32.92). While >70 is desirable, 60.644 is still reasonably good, and a substantial improvement over Ligand B's value. This is a critical factor for a CNS target like DRD2.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.031 and -5.023), which is unusual and suggests poor permeability. This is a concern for both, but doesn't differentiate them.

**Aqueous Solubility:** Both ligands have negative solubility values (-2.585 and -1.769), indicating poor solubility. This is a concern for both, but doesn't differentiate them.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (A: 0.381, B: 0.103).

**Microsomal Clearance:** Ligand B (9.46) has significantly lower microsomal clearance than Ligand A (40.282), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand B (20.927) has a longer in vitro half-life than Ligand A (-17.97), which is a positive.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (A: 0.178, B: 0.152).

**Binding Affinity:** Ligand B (-7.8) has a slightly better binding affinity than Ligand A (-7.6), but the difference is small (0.2 kcal/mol).

**Overall Assessment:**

Ligand A excels in TPSA, logP, and BBB penetration, all critical for CNS GPCR targets. While Ligand B has better DILI, metabolic stability (Cl_mic), and half-life, its poor logP and BBB penetration are significant drawbacks for a CNS drug. The slight affinity difference isn't enough to overcome these ADME deficiencies. The negative Caco-2 and solubility values are concerning for both, but can potentially be addressed with formulation strategies.

Output:
0
2025-04-17 04:41:05,042 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (385.873 Da) is slightly higher than Ligand B (347.423 Da), but both are acceptable.

**TPSA:** Ligand A (81.62) is better than Ligand B (93.7). For CNS targets, we want TPSA <= 90, so Ligand A is preferable.

**logP:** Ligand A (2.577) is optimal (1-3). Ligand B (-0.109) is quite low, potentially hindering permeation. This is a significant disadvantage for Ligand B.

**H-Bond Donors/Acceptors:** Ligand A (0 HBD, 7 HBA) is better than Ligand B (2 HBD, 6 HBA). Both are within acceptable limits, but fewer H-bonds generally improve permeability.

**QED:** Both ligands have good QED scores (Ligand A: 0.535, Ligand B: 0.772). Ligand B is slightly better here.

**DILI:** Ligand A (83.133) has a higher DILI risk than Ligand B (56.65). This favors Ligand B.

**BBB:** Ligand A (76.386) has a better BBB penetration score than Ligand B (55.37). This is a crucial factor for a CNS target like DRD2, strongly favoring Ligand A.

**Caco-2 Permeability:** Ligand A (-4.616) and Ligand B (-5.088) both have negative values, which is unusual and suggests poor permeability. However, the scale isn't specified, so it's hard to interpret.

**Aqueous Solubility:** Ligand A (-3.395) and Ligand B (-1.908) both have negative values, indicating poor solubility.

**hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.288).

**Microsomal Clearance:** Ligand A (57.17) has a higher clearance than Ligand B (17.661). This suggests Ligand B is more metabolically stable, which is favorable.

**In vitro Half-Life:** Ligand B (9.418) has a longer half-life than Ligand A (1.713), which is a significant advantage.

**P-gp Efflux:** Both ligands have similar P-gp efflux liability (0.226 and 0.004).

**Binding Affinity:** Ligand B (-8.4 kcal/mol) has a significantly stronger binding affinity than Ligand A (-7.7 kcal/mol). This is a substantial advantage for Ligand B, potentially outweighing some of its ADME drawbacks.

**Overall Assessment:**

Ligand A excels in BBB penetration and TPSA, crucial for CNS GPCR targets. However, Ligand B boasts a much stronger binding affinity and better metabolic stability (lower Cl_mic, longer t1/2). The low logP of Ligand B is a concern, but the significantly improved affinity (-8.4 vs -7.7 kcal/mol) is a large advantage. Considering the importance of potency for GPCR ligands, and the relatively good (though not ideal) ADME properties of Ligand B, it appears to be the more promising candidate.

Output:
1
2025-04-17 04:41:05,042 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B based on the provided guidelines, prioritizing GPCR-specific properties (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (351.535 and 358.345 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (52.65) is significantly better than Ligand B (93.65). For CNS targets, we want TPSA <= 90, and A is comfortably within this range, while B is close to the upper limit and less desirable.

**logP:** Ligand A (2.653) is optimal (1-3), while Ligand B (0.163) is quite low, potentially hindering permeation.

**H-Bond Donors/Acceptors:** Both have acceptable HBD (1) and Ligand A has acceptable HBA (3), while Ligand B has a higher HBA count (7), which could slightly impact permeability.

**QED:** Ligand A (0.749) has a better QED score than Ligand B (0.548), indicating a more drug-like profile.

**DILI:** Ligand A (8.298) has a much lower DILI risk than Ligand B (64.521), a significant advantage.

**BBB:** Both ligands have good BBB penetration (A: 70.531, B: 73.866), exceeding the 70% threshold for CNS targets. B is slightly better, but A is still acceptable.

**Caco-2 Permeability:** Both have negative Caco-2 values (-4.926 and -4.796). This is unusual and suggests poor permeability *in vitro*. However, we must consider this in context with other properties.

**Aqueous Solubility:** Both have negative solubility values (-1.079 and -1.567). This is also unusual and suggests poor solubility.

**hERG:** Ligand A (0.704) has a lower hERG risk than Ligand B (0.206), which is preferable.

**Microsomal Clearance:** Ligand A (18.932) has a lower microsomal clearance than Ligand B (33.384), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (-3.661) has a more favorable (less negative) in vitro half-life than Ligand B (-15.299).

**P-gp Efflux:** Both have very low P-gp efflux liability (A: 0.103, B: 0.012), which is good for CNS exposure.

**Binding Affinity:** Ligand B (-6.2 kcal/mol) has a significantly better binding affinity than Ligand A (0.0 kcal/mol). This is a substantial advantage, potentially outweighing some of the ADME drawbacks.

**Overall Assessment:**

Ligand B has a much stronger binding affinity, which is crucial for GPCR targets. However, it suffers from a low logP, higher TPSA, higher DILI risk, and poorer metabolic stability. Ligand A has a better ADME profile overall (better TPSA, logP, DILI, clearance, half-life, and hERG), but its binding affinity is very weak.

Given the strong emphasis on affinity for GPCRs, and the >1.5 kcal/mol advantage of Ligand B, I would prioritize Ligand B despite its ADME liabilities. Further optimization could focus on improving its logP and metabolic stability while retaining the strong binding affinity. The poor solubility and permeability would also need to be addressed.

Output:
1
2025-04-17 04:41:05,042 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (360.426 and 349.479 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (77.1) is slightly higher than Ligand B (74.49). Both are below the 90 A^2 threshold for CNS targets, which is good.

**3. logP:** Both ligands have acceptable logP values (0.686 and 0.783), falling within the 1-3 range.

**4. H-Bond Donors:** Both have 1 HBD, which is within the acceptable limit of <=5.

**5. H-Bond Acceptors:** Ligand A has 5 HBAs, and Ligand B has 6. Both are below the 10 limit.

**6. QED:** Ligand B (0.751) has a significantly better QED score than Ligand A (0.458), indicating a more drug-like profile.

**7. DILI:** Ligand A (18.302) has a higher DILI risk than Ligand B (8.569). Lower is better, so Ligand B is preferable.

**8. BBB:** This is a critical parameter for a CNS target like DRD2. Ligand A has a BBB percentile of 80.884, while Ligand B has 53.238. Ligand A is significantly better here.

**9. Caco-2 Permeability:** Both have negative values (-4.734 and -4.862). This is unusual and suggests poor permeability. However, the values are similar.

**10. Aqueous Solubility:** Both have negative values (-1.33 and -0.174). This suggests poor solubility, but again, the values are similar.

**11. hERG Inhibition:** Both ligands have low hERG inhibition liability (0.318 and 0.141), which is good.

**12. Microsomal Clearance:** Ligand A (13.881) has higher microsomal clearance than Ligand B (5.321), suggesting lower metabolic stability. Ligand B is preferable.

**13. In vitro Half-Life:** Ligand B (17.33) has a longer in vitro half-life than Ligand A (-11.715). A positive half-life is good, and Ligand B is significantly better.

**14. P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.038 and 0.037).

**15. Binding Affinity:** Ligand B (-7.0 kcal/mol) has a slightly better binding affinity than Ligand A (-6.6 kcal/mol). While both are good, the difference is notable.

**Overall Assessment:**

Ligand A excels in BBB penetration, a crucial factor for CNS targets. However, Ligand B demonstrates superior drug-likeness (QED), lower DILI risk, better metabolic stability (lower Cl_mic, longer t1/2), and slightly better binding affinity. The difference in BBB is significant, but the other advantages of Ligand B, particularly its better ADME profile, make it the more promising candidate. The negative Caco-2 and solubility values are concerning for both, but can be addressed with formulation strategies.

Output:
1
2025-04-17 04:41:05,043 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (366.37 and 352.341 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (102.43) is higher than Ligand B (86.94). For CNS targets, TPSA should be <=90. Ligand B is better here.

**3. logP:** Both ligands have acceptable logP values (0.69 and 0.54), falling within the 1-3 range.

**4. H-Bond Donors:** Ligand A has 1 HBD, while Ligand B has 2. Both are within the acceptable limit of <=5.

**5. H-Bond Acceptors:** Ligand A has 6 HBA, and Ligand B has 5. Both are within the acceptable limit of <=10.

**6. QED:** Both ligands have good QED scores (0.799 and 0.822), indicating good drug-like properties.

**7. DILI:** Ligand A has a high DILI risk (98.449%), while Ligand B has a moderate risk (55.991%). This is a significant advantage for Ligand B.

**8. BBB:** Ligand A has a good BBB penetration percentile (81.737%), while Ligand B is lower (42.807%). This is a crucial factor for CNS targets, favoring Ligand A.

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.56 and -4.896), which is unusual and suggests poor permeability. This is a concern for both.

**10. Aqueous Solubility:** Both ligands have very poor aqueous solubility (-3.613 and -1.961). This could pose formulation challenges.

**11. hERG Inhibition:** Both ligands have low hERG inhibition risk (0.275 and 0.657).

**12. Microsomal Clearance:** Ligand A has a moderate clearance (49.002), while Ligand B has a very low clearance (-22.819). Lower clearance is better for metabolic stability, strongly favoring Ligand B.

**13. In vitro Half-Life:** Ligand A has a moderate half-life (31.722), while Ligand B has a very short half-life (11.33). Ligand A is better here.

**14. P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.133 and 0.012), which is good.

**15. Binding Affinity:** Both ligands have excellent binding affinities (-9.0 and -9.1 kcal/mol), with a very slight edge to Ligand B.

**Overall Assessment:**

Ligand B has several key advantages: significantly lower DILI risk and much better metabolic stability (lower Cl_mic). While Ligand A has better BBB penetration and in vitro half-life, the DILI and metabolic stability concerns with Ligand A are substantial. The slight advantage in affinity for Ligand B, coupled with the lower DILI and better metabolic stability, outweighs the BBB difference. The poor Caco-2 and solubility are concerns for both, but can potentially be addressed with formulation strategies.

Output:
1
2025-04-17 04:41:05,043 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (386.5) is slightly higher than Ligand B (354.4), but both are acceptable.

**TPSA:** Ligand A (100.62) is borderline for CNS penetration, being slightly above the preferred <90 threshold. Ligand B (38.82) is excellent, well below 90, suggesting better CNS penetration potential.

**logP:** Ligand A (0.667) is a bit low, potentially hindering membrane permeability. Ligand B (1.785) is better, falling within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Both ligands have a reasonable number of HBD (1) and HBA (Ligand A: 5, Ligand B: 3), generally favorable for drug-likeness.

**QED:** Both ligands have good QED scores (A: 0.742, B: 0.847), indicating good overall drug-like properties.

**DILI:** Ligand A (54.56) has a moderate DILI risk, while Ligand B (19.19) has a very low risk, which is a significant advantage.

**BBB:** Both ligands show good BBB penetration (A: 82.09, B: 87.32), but Ligand B is slightly better.

**Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and likely indicates an issue with the prediction model or the compounds themselves. This is difficult to interpret without further information.

**Aqueous Solubility:** Both have negative solubility values, which is also unusual. This suggests poor aqueous solubility.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (A: 0.271, B: 0.894).

**Microsomal Clearance:** Ligand A (49.94) has a moderate clearance, while Ligand B (-10.27) has a negative clearance, which is not physically meaningful and suggests a problem with the prediction.

**In vitro Half-Life:** Ligand A (-21.3) has a negative half-life, which is not physically meaningful. Ligand B (-5.21) also has a negative half-life.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (A: 0.121, B: 0.039), which is favorable for CNS penetration.

**Binding Affinity:** Both ligands have strong binding affinities (A: -9.5 kcal/mol, B: -8.4 kcal/mol). Ligand A has a 1.1 kcal/mol advantage, which is substantial.

**Overall Assessment:**

Ligand A has a better binding affinity, which is a key factor for GPCRs. However, its lower logP and higher DILI risk are concerning. The negative values for Caco-2, solubility, and half-life are problematic and suggest issues with the prediction model or the compounds themselves.

Ligand B has a more favorable ADME profile overall, with better logP, lower DILI risk, and better BBB penetration. While its binding affinity is slightly weaker, the improved ADME properties, particularly the lower DILI risk, make it a more promising candidate. The negative values for Caco-2, solubility, and half-life are also problematic, but less so given the other advantages.

Considering the GPCR-specific priorities and the overall balance of properties, Ligand B is the more viable drug candidate.

Output:
1
2025-04-17 04:41:05,043 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (352.431 and 361.442 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (84.94) is better than Ligand B (62.39) as it is closer to the optimal range for CNS targets (<=90).

**3. logP:** Ligand B (3.357) is slightly higher than Ligand A (0.743). While both are within the 1-3 range, Ligand B is closer to the upper limit. Ligand A's lower logP might hinder permeation.

**4. H-Bond Donors:** Both have 1 HBD, which is acceptable.

**5. H-Bond Acceptors:** Ligand A has 5, and Ligand B has 6. Both are within the acceptable limit of <=10.

**6. QED:** Both ligands have good QED scores (0.54 and 0.667, respectively), indicating good drug-like properties.

**7. DILI:** Ligand A (20.512) has a significantly lower DILI risk than Ligand B (47.15). This is a major advantage for Ligand A.

**8. BBB:** Ligand A (65.839) has a better BBB penetration percentile than Ligand B (51.415). While neither is >70, Ligand A is closer. This is crucial for a CNS target like DRD2.

**9. Caco-2 Permeability:** Ligand A (-4.554) has a more negative Caco-2 value, suggesting lower permeability than Ligand B (-5.216).

**10. Aqueous Solubility:** Ligand A (-1.609) has a slightly better solubility than Ligand B (-2.881).

**11. hERG Inhibition:** Ligand A (0.121) has a lower hERG inhibition risk than Ligand B (0.833), which is a significant safety advantage.

**12. Microsomal Clearance:** Ligand A (60.864) has a higher microsomal clearance than Ligand B (45.105), meaning it is less metabolically stable.

**13. In vitro Half-Life:** Ligand B (32.751) has a longer in vitro half-life than Ligand A (-16.323), indicating better metabolic stability.

**14. P-gp Efflux:** Ligand A (0.005) has a much lower P-gp efflux liability than Ligand B (0.625). This is very important for CNS penetration.

**15. Binding Affinity:** Both ligands have very similar binding affinities (-7.7 and -7.8 kcal/mol). The difference is negligible.

**Overall Assessment:**

Ligand A is the better candidate. While Ligand B has a slightly better logP and in vitro half-life, Ligand A excels in critical areas for a CNS-targeting GPCR ligand: lower DILI risk, better BBB penetration, lower hERG inhibition, and significantly lower P-gp efflux. The slightly lower Caco-2 permeability of Ligand A is less concerning than the higher DILI and P-gp efflux of Ligand B. The similar binding affinities make these ADME properties the deciding factors.

Output:
0
2025-04-17 04:41:05,043 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (364.515 and 351.393 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (58.44) is better than Ligand B (55.4). Both are below the 90 A^2 threshold desirable for CNS targets, which is excellent.

**3. logP:** Ligand A (2.015) is within the optimal 1-3 range. Ligand B (3.203) is slightly higher, still acceptable but edging towards potential solubility issues.

**4. H-Bond Donors:** Ligand A (0) is preferable to Ligand B (1). Fewer HBDs generally improve permeability.

**5. H-Bond Acceptors:** Ligand A (5) is better than Ligand B (3). Both are below the 10 threshold.

**6. QED:** Both ligands have similar QED values (0.802 and 0.801), indicating good drug-likeness.

**7. DILI:** Ligand A (52.772) has a higher DILI risk than Ligand B (25.979). This is a significant advantage for Ligand B.

**8. BBB:** Ligand B (97.286) has a substantially higher BBB penetration percentile than Ligand A (77.2). This is *critical* for a CNS target like DRD2 and heavily favors Ligand B.

**9. Caco-2 Permeability:** Ligand A (-4.87) is better than Ligand B (-4.656). Higher values indicate better intestinal absorption.

**10. Aqueous Solubility:** Ligand A (-2.35) is better than Ligand B (-3.661). Higher values indicate better aqueous solubility.

**11. hERG Inhibition:** Ligand A (0.259) has a lower hERG inhibition risk than Ligand B (0.622). This is a positive for Ligand A.

**12. Microsomal Clearance:** Ligand A (77.656) has a higher microsomal clearance than Ligand B (42.481), indicating lower metabolic stability. Ligand B is preferable here.

**13. In vitro Half-Life:** Ligand A (-7.177) has a significantly longer in vitro half-life than Ligand B (-1.722). This is a strong advantage for Ligand A.

**14. P-gp Efflux:** Ligand A (0.234) has lower P-gp efflux liability than Ligand B (0.135), meaning it's less likely to be pumped out of the brain, which is good.

**15. Binding Affinity:** Ligand B (-9) has a significantly stronger binding affinity than Ligand A (-7). A 2 kcal/mol difference is substantial and can often outweigh minor ADME drawbacks.

**Overall Assessment:**

While Ligand A has advantages in half-life, solubility, and P-gp efflux, Ligand B excels in the most critical areas for a CNS-targeting GPCR: **BBB penetration and binding affinity**. The significantly lower DILI risk for Ligand B is also a major benefit. The slightly higher logP of Ligand B is a minor concern, but the strong affinity and excellent BBB penetration outweigh this.

Output:
1
2025-04-17 04:41:05,044 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (341.455 and 351.447 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (56.15) is significantly better than Ligand B (93.46). For CNS targets, TPSA should be <=90, and A is comfortably within that range, while B is nearing the upper limit.

**logP:** Both ligands have acceptable logP values (3.12 and 2.286, respectively), falling within the 1-3 optimal range.

**H-Bond Donors/Acceptors:** Ligand A (HBD=1, HBA=4) and Ligand B (HBD=2, HBA=5) both have reasonable numbers of H-bond donors and acceptors, well within the suggested limits.

**QED:** Ligand A (0.751) has a better QED score than Ligand B (0.631), indicating a more drug-like profile.

**DILI:** Ligand A (20.861) has a much lower DILI risk than Ligand B (53.819). This is a significant advantage for A.

**BBB:** Both ligands have good BBB penetration (Ligand A: 71.656, Ligand B: 78.286), exceeding the >70% threshold for CNS targets. B is slightly better, but A is still acceptable.

**Caco-2 Permeability:** Both have negative Caco-2 values (-5.112 and -4.9), which is unusual and suggests poor permeability. However, these values are on a scale where negative values are possible, and direct comparison is difficult without knowing the scale's specifics.

**Aqueous Solubility:** Both have negative solubility values (-1.736 and -2.436), indicating poor aqueous solubility. Similar to Caco-2, the scale is unclear.

**hERG Inhibition:** Ligand A (0.834) has a lower hERG inhibition risk than Ligand B (0.415), which is preferable.

**Microsomal Clearance:** Ligand A (38.765) has significantly lower microsomal clearance than Ligand B (63.919), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (6.394) has a better in vitro half-life than Ligand B (-18.212). A negative half-life is concerning and indicates rapid degradation for Ligand B.

**P-gp Efflux:** Ligand A (0.675) has lower P-gp efflux than Ligand B (0.449), which is favorable for CNS exposure.

**Binding Affinity:** Ligand A (-8.5 kcal/mol) has a slightly better binding affinity than Ligand B (-7.8 kcal/mol). While both are good, the 0.7 kcal/mol difference is noticeable.

**Overall Assessment:**

Ligand A consistently outperforms Ligand B across most crucial ADME-Tox properties, including DILI, metabolic stability (Cl_mic, t1/2), P-gp efflux, and hERG inhibition. It also has a better QED score and slightly better binding affinity. While both have issues with Caco-2 permeability and solubility, Ligand A's superior profile in other key areas makes it the more promising candidate, especially considering the CNS target.

Output:
0
2025-04-17 04:41:05,044 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (348.491 and 346.471 Da) fall comfortably within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (58.44) is better than Ligand B (62.55). Both are below the 90 A^2 threshold for CNS targets, which is good.

**3. logP:** Ligand A (2.36) is within the optimal 1-3 range. Ligand B (3.586) is slightly higher, but still acceptable.

**4. H-Bond Donors:** Ligand A (0) is preferable to Ligand B (1). Fewer HBDs generally improve permeability.

**5. H-Bond Acceptors:** Ligand A (4) is preferable to Ligand B (3).

**6. QED:** Both ligands have good QED scores (0.76 and 0.856), indicating drug-like properties.

**7. DILI:** Both ligands have low DILI risk (25.669 and 27.608), which is excellent.

**8. BBB:** Ligand B (86.623) has a significantly better BBB penetration percentile than Ligand A (79.139). This is a crucial factor for a CNS target like DRD2.

**9. Caco-2 Permeability:** Ligand A (-4.682) is better than Ligand B (-4.564). Higher values are better.

**10. Aqueous Solubility:** Ligand A (-1.6) is better than Ligand B (-3.373). Higher values are better.

**11. hERG Inhibition:** Both ligands show low hERG inhibition liability (0.268 and 0.594), which is favorable.

**12. Microsomal Clearance:** Ligand A (48.252) has lower microsomal clearance than Ligand B (57.002), suggesting better metabolic stability.

**13. In vitro Half-Life:** Ligand B (47.016) has a significantly longer in vitro half-life than Ligand A (8.329).

**14. P-gp Efflux:** Ligand A (0.149) has lower P-gp efflux than Ligand B (0.481), which is beneficial for CNS exposure.

**15. Binding Affinity:** Ligand B (-8.9 kcal/mol) has a significantly stronger binding affinity than Ligand A (-7.2 kcal/mol). This is a substantial advantage (>1.5 kcal/mol difference).

**Overall Assessment:**

While Ligand A has some advantages in terms of TPSA, solubility, P-gp efflux and metabolic stability, Ligand B's superior BBB penetration and *much* stronger binding affinity are decisive. The difference in binding affinity is substantial enough to outweigh the minor drawbacks in P-gp efflux and metabolic stability. The longer half-life of Ligand B is also a positive attribute. For a CNS target like DRD2, maximizing brain exposure (BBB) and target engagement (affinity) are paramount.

Output:
1
2025-04-17 04:41:05,044 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (353.419 and 338.371 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (104.81) is better than Ligand B (111.06) as it is closer to the <90 A^2 threshold for CNS targets. Ligand B is still acceptable, but A is preferable.

**3. logP:** Ligand B (1.649) is within the optimal 1-3 range, while Ligand A (-0.038) is slightly below 1, which could potentially hinder permeation. This is a significant drawback for Ligand A.

**4. H-Bond Donors:** Ligand A (2) is slightly higher than Ligand B (1), but both are within the acceptable limit of <=5.

**5. H-Bond Acceptors:** Ligand A (5) is slightly higher than Ligand B (4), but both are within the acceptable limit of <=10.

**6. QED:** Ligand A (0.675) has a significantly better QED score than Ligand B (0.29), indicating a more drug-like profile.

**7. DILI:** Ligand B (62.893) has a higher DILI risk than Ligand A (24.312). This favors Ligand A.

**8. BBB:** Ligand A (48.119) has a better BBB percentile than Ligand B (32.416), which is crucial for a CNS target like DRD2. While both are below the ideal >70, A is significantly better.

**9. Caco-2:** Both ligands have negative Caco-2 values (-5.127 and -4.786), which is unusual and suggests poor permeability. This is a concern for both.

**10. Solubility:** Both ligands have negative solubility values (-1.798 and -2.571), which is also unusual and suggests poor solubility. This is a concern for both.

**11. hERG:** Both ligands have very low hERG inhibition risk (0.086 and 0.114).

**12. Cl_mic:** Ligand B (3.149) has a lower microsomal clearance than Ligand A (8.014), indicating better metabolic stability.

**13. t1/2:** Ligand B (-20.631) has a more negative in vitro half-life, which is unusual and suggests a very short half-life. Ligand A (-13.828) is also negative, but less so.

**14. Pgp:** Both ligands have very low P-gp efflux liability (0.011 and 0.021).

**15. Binding Affinity:** Ligand B (-7.3 kcal/mol) has a slightly better binding affinity than Ligand A (-6.6 kcal/mol). This is a 0.7 kcal/mol difference, which is significant but not overwhelming.

**Overall Assessment:**

Despite Ligand B having slightly better binding affinity and metabolic stability, Ligand A is the more promising candidate. Its superior BBB penetration, lower DILI risk, better QED score, and more favorable TPSA outweigh the slightly weaker affinity and higher clearance. The negative Caco-2 and solubility values are concerning for both, but can be addressed with formulation strategies. The logP of Ligand A is a concern, but the other factors make it the better choice.

Output:
0
2025-04-17 04:41:05,044 - INFO - Batch 134 complete. Total preferences: 2144
2025-04-17 04:41:05,044 - INFO - Processing batch 135/512...
2025-04-17 04:41:45,731 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the acceptable range (200-500 Da). Ligand A (331.419 Da) is slightly preferred as it's closer to the lower end, potentially aiding permeability.

**TPSA:** Ligand A (54.02) is significantly better than Ligand B (91.76). For CNS targets, TPSA < 90 is desirable, and A is comfortably within this range, while B is close to the upper limit. This is a significant advantage for A.

**logP:** Ligand A (3.761) is optimal, while Ligand B (1.798) is on the lower side. While not terrible, lower logP can hinder membrane permeability.

**H-Bond Donors/Acceptors:** Both have acceptable HBD counts (2). Ligand B has a higher HBA count (6 vs 3), which could slightly impact permeability, but isn't a major concern.

**QED:** Both ligands have reasonable QED values (A: 0.748, B: 0.593), indicating good drug-like properties. A is slightly better.

**DILI:** Ligand A (62.233) has a higher DILI risk than Ligand B (43.273). This is a negative for A, but not a dealbreaker.

**BBB:** Ligand A (76.929) has a significantly better BBB penetration percentile than Ligand B (28.655). This is *crucial* for a CNS target like DRD2.

**Caco-2 Permeability:** Both have negative Caco-2 values (-4.938 and -4.807), which is unusual and suggests poor permeability. However, these values are on a scale where negative values are possible and don't necessarily preclude development.

**Aqueous Solubility:** Both have negative solubility values (-3.912 and -1.591). Similar to Caco-2, these values are on a scale where negative values are possible.

**hERG Inhibition:** Both ligands have low hERG inhibition liability (A: 0.714, B: 0.342), which is good.

**Microsomal Clearance:** Ligand B (32.597) has a lower microsomal clearance than Ligand A (61.594), indicating better metabolic stability. This is a positive for B.

**In vitro Half-Life:** Both have similar in vitro half-lives (A: 42.346, B: 44.66).

**P-gp Efflux:** Ligand A (0.387) has lower P-gp efflux liability than Ligand B (0.25), which is favorable for CNS penetration.

**Binding Affinity:** Ligand B (-6.7 kcal/mol) has a significantly better binding affinity than Ligand A (-10.0 kcal/mol). This is a substantial advantage for B, potentially outweighing some of its ADME drawbacks.

**Overall Assessment:**

While Ligand A has better TPSA, logP, BBB, and P-gp properties, the significantly stronger binding affinity of Ligand B (-6.7 vs -10.0 kcal/mol) is a decisive factor. The affinity difference is large enough to potentially overcome the less favorable BBB and TPSA values. The lower DILI risk for B is also a plus.

Output:
1
2025-04-17 04:41:45,731 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (350.463 and 366.487 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (87.32) is excellent, falling well below the 90 A^2 threshold for CNS targets. Ligand B (100.28) is still reasonable but less optimal.

**logP:** Both ligands have logP values within the optimal range (1.748 and 2.621).

**H-Bond Donors/Acceptors:** Ligand A (2 HBD, 4 HBA) is slightly better than Ligand B (3 HBD, 7 HBA) in terms of maintaining a balance between solubility and permeability. Both are within acceptable limits.

**QED:** Ligand A (0.784) has a better QED score than Ligand B (0.559), indicating a more drug-like profile.

**DILI:** Ligand B (60.915) has a higher DILI risk than Ligand A (40.636), making Ligand A preferable.

**BBB:** Ligand A (61.38) has a significantly better BBB penetration percentile than Ligand B (46.724). This is a crucial factor for a CNS target like DRD2.

**Caco-2 Permeability:** Ligand A (-4.854) has a worse Caco-2 permeability than Ligand B (-5.244), but both are negative values, indicating poor permeability.

**Aqueous Solubility:** Ligand A (-2.854) has better solubility than Ligand B (-2.328), though both are poor.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.474 and 0.692).

**Microsomal Clearance:** Ligand B (60.968) has a significantly higher microsomal clearance than Ligand A (20.856), suggesting lower metabolic stability.

**In vitro Half-Life:** Ligand A (-8.771) has a longer in vitro half-life than Ligand B (24.009). Note that negative values for half-life are unusual and likely represent a scale issue. Assuming lower values are better, Ligand A is still preferable.

**P-gp Efflux:** Ligand A (0.089) has lower P-gp efflux liability than Ligand B (0.567), which is desirable for CNS penetration.

**Binding Affinity:** Ligand B (-6.9 kcal/mol) has a slightly better binding affinity than Ligand A (-8.0 kcal/mol). However, the difference is not substantial enough to outweigh the numerous advantages of Ligand A.

**Overall:** Ligand A demonstrates a superior profile for CNS drug development, particularly due to its better BBB penetration, lower DILI risk, lower P-gp efflux, and better metabolic stability. While Ligand B has slightly better binding affinity, the other ADME/Tox properties of Ligand A are more favorable for a DRD2-targeting drug.

Output:
1
2025-04-17 04:41:45,731 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (360.454 and 357.451 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (49.41) is excellent, well below the 90 A^2 threshold for CNS targets. Ligand B (107.97) is higher, but still potentially acceptable, though less desirable.

**logP:** Ligand A (3.62) is optimal (1-3). Ligand B (-0.323) is significantly below this range, which could hinder membrane permeability and brain penetration.

**H-Bond Donors/Acceptors:** Ligand A (HBD=1, HBA=3) is favorable. Ligand B (HBD=3, HBA=6) is also acceptable, but slightly higher counts could impact permeability.

**QED:** Ligand A (0.909) is excellent, indicating a highly drug-like profile. Ligand B (0.365) is poor, suggesting potential issues with developability.

**DILI:** Ligand A (51.26) has a moderate DILI risk, but is still acceptable. Ligand B (13.61) has a very low DILI risk, which is positive.

**BBB:** Ligand A (87.825) has excellent BBB penetration potential, exceeding the 70% threshold. Ligand B (30.71) has very poor BBB penetration, a major drawback for a CNS target.

**Caco-2 Permeability:** Ligand A (-4.769) is negative, which is unusual and suggests low permeability. Ligand B (-5.158) is also negative, indicating low permeability.

**Aqueous Solubility:** Ligand A (-3.924) is low, which could pose formulation challenges. Ligand B (-0.51) is also low, but slightly better than Ligand A.

**hERG Inhibition:** Ligand A (0.817) has a low risk of hERG inhibition. Ligand B (0.136) also has a low risk.

**Microsomal Clearance:** Ligand A (38.673) has moderate clearance, suggesting reasonable metabolic stability. Ligand B (50.879) has higher clearance, indicating faster metabolism.

**In vitro Half-Life:** Ligand A (19.927 hours) has a good half-life. Ligand B (-17.887 hours) has a negative half-life, which is not possible and indicates a significant issue.

**P-gp Efflux:** Ligand A (0.597) has moderate P-gp efflux. Ligand B (0.005) has very low P-gp efflux, which is favorable for CNS penetration.

**Binding Affinity:** Ligand A (-8.1 kcal/mol) has significantly stronger binding affinity than Ligand B (-6.8 kcal/mol). The difference of 1.3 kcal/mol is substantial and can outweigh some ADME drawbacks.

**Overall Assessment:**

Ligand A excels in key areas for a CNS GPCR target: TPSA, BBB, and, most importantly, binding affinity. While its solubility and Caco-2 permeability are concerns, its strong affinity and good BBB penetration are highly advantageous. Ligand B suffers from poor logP, very low BBB penetration, a negative in vitro half-life, and significantly weaker binding affinity. The QED score is also very low.

Output:
1
2025-04-17 04:41:45,731 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (368.949 and 364.475 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (49.41) is excellent, well below the 90 A^2 threshold for CNS targets. Ligand B (85.91) is higher, but still potentially acceptable, though less ideal.

**logP:** Ligand A (4.233) is slightly high, potentially leading to solubility issues or off-target effects. Ligand B (0.666) is quite low, which could hinder membrane permeability and CNS penetration.

**H-Bond Donors/Acceptors:** Ligand A (1 HBD, 2 HBA) is good. Ligand B (0 HBD, 8 HBA) is also reasonable, though the higher HBA count might slightly impact permeability.

**QED:** Both ligands have similar QED values (0.762 and 0.718), indicating good drug-like properties.

**DILI:** Ligand A (15.626) has a much lower DILI risk than Ligand B (62.893), which is a significant advantage.

**BBB:** Ligand A (72.78) has a better BBB percentile than Ligand B (66.382), although both are reasonably good.

**Caco-2:** Ligand A (-4.389) has a worse Caco-2 permeability than Ligand B (-5.057), suggesting lower intestinal absorption.

**Solubility:** Ligand A (-4.469) has a worse solubility than Ligand B (-1.553).

**hERG:** Ligand A (0.587) has a better hERG profile than Ligand B (0.152).

**Microsomal Clearance:** Ligand A (89.884) has a higher microsomal clearance than Ligand B (33.608), indicating lower metabolic stability.

**In vitro Half-Life:** Ligand A (39.349) has a longer half-life than Ligand B (22.617).

**P-gp Efflux:** Ligand A (0.261) has lower P-gp efflux liability than Ligand B (0.158), which is favorable for CNS penetration.

**Binding Affinity:** Ligand A (-7.9 kcal/mol) has a slightly stronger binding affinity than Ligand B (-7.7 kcal/mol). While the difference is small, it's still a positive for Ligand A.

**Overall Assessment:**

Considering the GPCR-specific priorities, Ligand A is the better candidate. Its superior BBB penetration, lower DILI risk, better hERG profile, and slightly better binding affinity outweigh its slightly higher logP and lower Caco-2/solubility. Ligand B's low logP is a significant concern for CNS penetration, and its higher DILI risk is undesirable. The difference in affinity is small enough that the other ADME properties are more important in this case.

Output:
0
2025-04-17 04:41:45,731 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (358.511 and 342.414 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (57.26) is slightly above the optimal <90 for CNS targets, but still reasonable. Ligand B (43.78) is well within the desired range.

**logP:** Both ligands have logP values around 2.9-3.0, which is optimal.

**H-Bond Donors/Acceptors:** Ligand A has 2 HBD and 5 HBA, while Ligand B has 1 HBD and 3 HBA. Both are within acceptable limits.

**QED:** Both ligands have good QED scores (0.882 and 0.933), indicating good drug-likeness.

**DILI:** Ligand A (71.152) has a higher DILI risk than Ligand B (47.654). This is a significant negative for Ligand A.

**BBB:** Both ligands show good BBB penetration (66.576 and 71.462), but Ligand B is slightly better. Both are above the 70% threshold for CNS targets.

**Caco-2 Permeability:** Ligand A (-5.011) has poor Caco-2 permeability, which is a concern for oral absorption. Ligand B (-4.381) is also poor, but slightly better than A.

**Aqueous Solubility:** Both ligands have very poor aqueous solubility (-3.385 and -1.726). This is a significant drawback for both.

**hERG:** Both ligands have similar, low hERG inhibition risk (0.79 and 0.897).

**Microsomal Clearance:** Ligand A (30.221) has a higher microsomal clearance than Ligand B (-12.725), indicating lower metabolic stability. This is a negative for Ligand A.

**In vitro Half-Life:** Ligand B (11.247) has a shorter in vitro half-life than Ligand A (36.654). This favors Ligand A.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.498 and 0.454), which is good for CNS penetration.

**Binding Affinity:** Ligand B (-9.8 kcal/mol) has a significantly stronger binding affinity than Ligand A (-7.8 kcal/mol). This is a crucial advantage for Ligand B, exceeding the 1.5 kcal/mol difference threshold.

**Overall Assessment:**

Ligand B is the stronger candidate. While both have poor solubility, Ligand B's significantly improved binding affinity (-9.8 vs -7.8 kcal/mol) outweighs the slightly shorter half-life. It also has a lower DILI risk and slightly better BBB penetration and Caco-2 permeability. Ligand A's higher DILI risk and poorer metabolic stability are significant drawbacks. The affinity difference is substantial enough to overcome the solubility concerns, assuming formulation strategies can be employed.

Output:
1
2025-04-17 04:41:45,731 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (348.38 and 360.40 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (95.25) is slightly higher than Ligand B (88.12), but both are below the 90 A^2 threshold desirable for CNS targets.

**logP:** Both ligands have good logP values (1.749 and 1.135), falling within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A has 4 HBD and 3 HBA, while Ligand B has 0 HBD and 9 HBA. Both are within acceptable limits (<=5 HBD and <=10 HBA).

**QED:** Both ligands have similar QED values (0.49 and 0.514), indicating reasonable drug-likeness.

**DILI:** Both ligands have relatively high DILI risk (83.17 and 87.09), which is a concern, but not immediately disqualifying.

**BBB:** Ligand A has a significantly better BBB penetration percentile (81.78%) compared to Ligand B (69.76%). This is a crucial advantage for a CNS target like DRD2.

**Caco-2 Permeability:** Ligand A (-5.138) has worse Caco-2 permeability than Ligand B (-4.505), indicating potentially lower intestinal absorption.

**Aqueous Solubility:** Both ligands have poor aqueous solubility (-3.553 and -3.334). This could pose formulation challenges.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.48 and 0.542), which is good.

**Microsomal Clearance:** Ligand A has a lower (better) microsomal clearance (-0.393) than Ligand B (64.886), suggesting greater metabolic stability.

**In vitro Half-Life:** Ligand A has a shorter half-life (28.192 hours) than Ligand B (12.715 hours).

**P-gp Efflux:** Ligand A has lower P-gp efflux liability (0.119) than Ligand B (0.691), which is favorable for CNS penetration.

**Binding Affinity:** Ligand B has a significantly better binding affinity (-7.1 kcal/mol) than Ligand A (-9.8 kcal/mol). This is a substantial advantage.

**Overall Assessment:**

Ligand B has a significantly better binding affinity, which is the most important factor. However, Ligand A has superior BBB penetration and P-gp efflux properties, and better metabolic stability. The difference in binding affinity (-7.1 vs -9.8) is substantial (2.7 kcal/mol), likely outweighing the advantages of Ligand A in terms of BBB and metabolic stability. The DILI risk is high for both, but can be addressed during optimization.

Output:
1
2025-04-17 04:41:45,732 - INFO - Reasoning:

Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (349.431 and 348.399 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Both ligands (95.67 and 93.73) are reasonably close to the 90 A^2 threshold for CNS targets, but slightly above. This isn't a major concern, but it's a point to consider.

**3. logP:** Both ligands have logP values (1.705 and 1.619) within the optimal range of 1-3.

**4. H-Bond Donors:** Both have 2 HBD, which is within the acceptable limit of <=5.

**5. H-Bond Acceptors:** Both have 5 HBA, also within the acceptable limit of <=10.

**6. QED:** Both ligands have QED values above 0.5 (0.523 and 0.577), indicating good drug-likeness.

**7. DILI:** Ligand A (30.865) has a significantly lower DILI risk than Ligand B (62.35). This is a substantial advantage for Ligand A.

**8. BBB:** Both ligands have similar BBB penetration percentiles (46.336 and 48.391). These are acceptable, but not ideal for a CNS target (ideally >70).

**9. Caco-2 Permeability:** Both have negative Caco-2 values (-4.888 and -4.937). This is unusual and suggests poor permeability. However, these values are on a log scale and are likely representing very low permeability.

**10. Aqueous Solubility:** Both have negative solubility values (-1.529 and -2.682), indicating poor aqueous solubility. This is a potential issue for formulation.

**11. hERG Inhibition:** Both ligands show very low hERG inhibition liability (0.308 and 0.193), which is excellent.

**12. Microsomal Clearance:** Ligand A (27.453) has a higher microsomal clearance than Ligand B (-5.24).  A negative value for Ligand B suggests very high metabolic stability, which is a significant advantage.

**13. In vitro Half-Life:** Ligand A (-17.207) has a negative in vitro half-life, which is unusual and suggests very rapid metabolism. Ligand B (7.735) has a more reasonable half-life.

**14. P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.074 and 0.037), which is beneficial for CNS penetration.

**15. Binding Affinity:** Both ligands have identical binding affinities (-8.2 kcal/mol). This eliminates affinity as a differentiating factor.

**Overall Assessment:**

While both ligands have similar binding affinities and acceptable logP/TPSA values, Ligand B is superior due to its significantly better metabolic stability (negative Cl_mic) and more reasonable in vitro half-life. Ligand A's higher DILI risk and very rapid metabolism are major drawbacks. The similar BBB values are not enough to overcome these issues. The poor Caco-2 and solubility are concerning for both, but can potentially be addressed with formulation strategies.

Output:
1
2025-04-17 04:41:45,732 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (354.416 and 345.426 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (55.12) is excellent, well below the 90 A^2 threshold for CNS targets. Ligand B (73.45) is still reasonable but less optimal.

**logP:** Ligand A (4.558) is slightly high, potentially leading to solubility issues or off-target interactions. Ligand B (1.777) is good, falling within the 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A (2 HBD, 2 HBA) is favorable. Ligand B (1 HBD, 7 HBA) is acceptable, but the higher HBA count could slightly impact permeability.

**QED:** Both ligands have similar QED values (0.818 and 0.701), indicating good drug-likeness.

**DILI:** Ligand A (27.879) has a lower DILI risk than Ligand B (37.999), which is preferable.

**BBB:** Both ligands have excellent BBB penetration (85.847 and 85.731), exceeding the 70% threshold for CNS targets.

**Caco-2 Permeability:** Ligand A (-4.629) has poor Caco-2 permeability, while Ligand B (-5.282) is also poor, but slightly worse.

**Aqueous Solubility:** Ligand A (-4.028) has poor solubility, while Ligand B (-2.116) is also poor, but slightly better.

**hERG Inhibition:** Ligand A (0.803) has a slightly higher hERG risk than Ligand B (0.263), which is preferable.

**Microsomal Clearance:** Ligand A (3.428) has lower microsomal clearance, indicating better metabolic stability than Ligand B (11.869).

**In vitro Half-Life:** Ligand A (24.161) has a longer half-life than Ligand B (-6.563), which is desirable.

**P-gp Efflux:** Ligand A (0.218) has lower P-gp efflux, suggesting better CNS exposure than Ligand B (0.178).

**Binding Affinity:** Ligand A (-9.6 kcal/mol) has a significantly stronger binding affinity than Ligand B (-7.2 kcal/mol). This 1.5+ kcal/mol difference is substantial and can outweigh some ADME drawbacks.

**Overall Assessment:**

Ligand A has a superior binding affinity and better metabolic stability (lower Cl_mic, longer t1/2), lower DILI risk, and lower P-gp efflux. While its logP is a bit high and Caco-2 permeability/solubility are poor, the strong binding affinity and favorable CNS penetration properties are critical for a DRD2 ligand. Ligand B has a better logP and slightly better solubility/permeability, but its weaker affinity and higher metabolic clearance are significant drawbacks. The strong affinity of Ligand A is the deciding factor.

Output:
1
2025-04-17 04:41:45,732 - INFO - Reasoning:

Let's analyze Ligand A and Ligand B for their potential as DRD2 drug candidates, considering the provided guidelines and GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight (MW):** Both ligands (356.463 and 348.531 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (99.1) is higher than the preferred <90 for CNS targets, while Ligand B (41.57) is well within the range. This is a significant advantage for Ligand B.

**3. logP:** Ligand A (0.146) is quite low, potentially hindering permeability. Ligand B (3.493) is optimal.

**4. H-Bond Donors (HBD):** Ligand A (3) is acceptable. Ligand B (1) is also good.

**5. H-Bond Acceptors (HBA):** Ligand A (5) is acceptable. Ligand B (3) is also good.

**6. QED:** Both ligands have good QED scores (0.629 and 0.799), indicating drug-like properties.

**7. DILI:** Ligand A (15.898) has a lower DILI risk than Ligand B (12.136), which is favorable.

**8. BBB:** Ligand B (86.041) shows significantly better BBB penetration potential than Ligand A (23.536). This is *critical* for a CNS target like DRD2.

**9. Caco-2 Permeability:** Ligand A (-5.003) has poor Caco-2 permeability. Ligand B (-4.718) also has poor Caco-2 permeability.

**10. Aqueous Solubility:** Ligand A (-1.54) has poor aqueous solubility. Ligand B (-3.998) also has poor aqueous solubility.

**11. hERG Inhibition:** Ligand A (0.128) has a very low hERG risk, better than Ligand B (0.716).

**12. Microsomal Clearance (Cl_mic):** Ligand A (18.111) has a lower clearance, indicating better metabolic stability, than Ligand B (61.409).

**13. In vitro Half-Life:** Ligand B (11.318) has a slightly longer half-life than Ligand A (9.418).

**14. P-gp Efflux:** Ligand A (0.028) shows very low P-gp efflux, which is highly desirable for CNS penetration. Ligand B (0.264) shows slightly higher P-gp efflux.

**15. Binding Affinity:** Both ligands have very similar and strong binding affinities (-7.3 and -7.2 kcal/mol). The difference is negligible.

**Overall Assessment:**

While Ligand A has a slightly better DILI and P-gp efflux profile, and better metabolic stability, Ligand B is significantly superior regarding key GPCR-specific properties. The much higher BBB penetration (86.041 vs. 23.536) and optimal logP (3.493 vs. 0.146) of Ligand B are crucial for CNS drug development. The lower TPSA of Ligand B is also a significant advantage. The slight differences in other ADME properties are less critical given the strong affinity of both compounds.

Output:
1
2025-04-17 04:41:45,732 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (338.367 and 346.475 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (97.23) is slightly above the optimal <90 for CNS targets, but still reasonable. Ligand B (76.02) is well within the desired range. This favors Ligand B.

**3. logP:** Both ligands have good logP values (2.448 and 1.861), falling within the 1-3 range.

**4. H-Bond Donors:** Both have 2 HBD, which is acceptable.

**5. H-Bond Acceptors:** Ligand A has 6 HBA, and Ligand B has 4 HBA, both within the acceptable limit of <=10.

**6. QED:** Both ligands have good QED scores (0.741 and 0.854), indicating good drug-like properties.

**7. DILI:** Ligand A (75.378) has a higher DILI risk than Ligand B (30.593). This is a significant advantage for Ligand B.

**8. BBB:** Ligand B (61.962) has a substantially better BBB penetration score than Ligand A (27.957). This is *critical* for a CNS target like DRD2 and strongly favors Ligand B.

**9. Caco-2 Permeability:** Both have negative Caco-2 values (-4.953 and -4.985), which is unusual and suggests poor permeability. This is a concern for both, but doesn't differentiate them.

**10. Aqueous Solubility:** Both have negative solubility values (-3.343 and -2.31), indicating poor solubility. This is a concern for both, but doesn't differentiate them.

**11. hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.279 and 0.088).

**12. Microsomal Clearance:** Ligand A (61.574) has higher microsomal clearance than Ligand B (15.242), meaning it's less metabolically stable. Ligand B is favored here.

**13. In vitro Half-Life:** Ligand B (10.825) has a longer in vitro half-life than Ligand A (-14.422). This is a significant advantage for Ligand B.

**14. P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.021 and 0.036).

**15. Binding Affinity:** Both ligands have comparable binding affinities (-8.7 and -8.5 kcal/mol), which are both excellent. The difference is not substantial enough to outweigh other factors.

**Overall Assessment:**

Ligand B is significantly better due to its superior BBB penetration, lower DILI risk, lower microsomal clearance (better metabolic stability), and longer in vitro half-life. While both have issues with Caco-2 permeability and solubility, the CNS target prioritization makes BBB and metabolic stability paramount. The slight advantage in these key ADME properties of Ligand B outweighs the comparable binding affinities.

Output:
1
2025-04-17 04:41:45,732 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (349.431 and 346.431 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (80.76) is significantly better than Ligand B (98.32). For CNS targets, we want TPSA <= 90, so Ligand A is preferable.

**3. logP:** Both ligands have good logP values (2.063 and 1.239), falling within the optimal 1-3 range.

**4. H-Bond Donors:** Ligand A (1) is better than Ligand B (3). Lower HBD generally improves permeability.

**5. H-Bond Acceptors:** Ligand A (5) is better than Ligand B (4). Lower HBA generally improves permeability.

**6. QED:** Ligand A (0.903) is significantly better than Ligand B (0.714), indicating a more drug-like profile.

**7. DILI:** Both ligands have acceptable DILI risk (45.715 and 42.807, both < 60).

**8. BBB:** Ligand A (77.123) is much better than Ligand B (43.893).  A BBB percentile > 70 is desirable for CNS targets, and Ligand A is closer to this threshold.

**9. Caco-2 Permeability:** Ligand A (-4.194) is better than Ligand B (-5.315) - less negative values are better.

**10. Aqueous Solubility:** Ligand A (-2.029) is better than Ligand B (-1.874) - less negative values are better.

**11. hERG Inhibition:** Both ligands have low hERG inhibition risk (0.342 and 0.468).

**12. Microsomal Clearance:** Ligand B (-18.543) has a lower (better) microsomal clearance than Ligand A (26.539), suggesting greater metabolic stability.

**13. In vitro Half-Life:** Ligand B (-27.17) has a longer (better) in vitro half-life than Ligand A (-9.973).

**14. P-gp Efflux:** Ligand A (0.029) is significantly better than Ligand B (0.074). Lower P-gp efflux is crucial for CNS penetration.

**15. Binding Affinity:** Ligand B (-8.8 kcal/mol) has a slightly better binding affinity than Ligand A (-7.5 kcal/mol). This is a 1.3 kcal/mol difference, which is significant.

**Overall Assessment:**

While Ligand B has a slightly better binding affinity and improved metabolic stability and half-life, Ligand A is superior in almost all other critical ADME properties, especially those prioritized for CNS GPCR targets. Ligand A's significantly better TPSA, BBB penetration, P-gp efflux, QED, and solubility outweigh the modest affinity difference. The better BBB and lower P-gp efflux of Ligand A are particularly important for CNS drug development.

Output:
0
2025-04-17 04:41:45,732 - INFO - Reasoning:

Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (348.403 and 348.487 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (117.52) is higher than Ligand B (78.43). For CNS targets, TPSA < 90 is preferred. Ligand B is significantly better here.

**3. logP:** Ligand A (-0.128) is quite low, potentially hindering membrane permeability. Ligand B (1.983) is within the optimal 1-3 range. This is a significant advantage for Ligand B.

**4. H-Bond Donors:** Both ligands have 3 HBD, which is acceptable (<=5).

**5. H-Bond Acceptors:** Ligand A has 4 HBA, and Ligand B has 3. Both are within the acceptable range (<=10).

**6. QED:** Both ligands have good QED scores (0.664 and 0.711), indicating drug-like properties.

**7. DILI:** Ligand A (44.552) has a higher DILI risk than Ligand B (16.247). Lower is better, and Ligand B is clearly preferable.

**8. BBB:** Ligand A (53.625) and Ligand B (62.156) both have reasonable BBB penetration, but Ligand B is better. A value >70 is desirable for CNS targets, and both are below this, but B is closer.

**9. Caco-2:** Both have negative Caco-2 values, which is unusual and suggests poor permeability. However, the scale is not specified, so it's hard to interpret.

**10. Solubility:** Both ligands have negative solubility values, which is also unusual. Again, the scale is not specified, so it's hard to interpret.

**11. hERG:** Both ligands have very low hERG inhibition risk (0.116 and 0.135).

**12. Cl_mic:** Ligand A (-6.56) has a negative microsomal clearance, which is not physically possible. This is likely an error in the data. Ligand B (20.138) has a higher clearance, indicating faster metabolism. Lower is better, so Ligand A *would* be preferred if the value were valid.

**13. t1/2:** Ligand A (-0.715) has a negative half-life, which is not physically possible, likely an error in the data. Ligand B (3.138) has a short half-life, but it's a valid value.

**14. Pgp:** Both ligands have very low Pgp efflux liability (0.004 and 0.03).

**15. Binding Affinity:** Ligand B (-8.6 kcal/mol) has a slightly better binding affinity than Ligand A (-8.1 kcal/mol). While the difference is not huge, it is within the range where it can outweigh minor ADME drawbacks.

**Overall Assessment:**

Despite the questionable solubility, Caco-2, Cl_mic, and t1/2 values, Ligand B is the more promising candidate. It has a better logP, TPSA, DILI risk, and slightly better BBB penetration and affinity. The negative values for clearance and half-life of Ligand A are concerning data errors. The lower TPSA and more favorable logP of Ligand B are particularly important for a CNS-targeting GPCR like DRD2.

Output:
1
2025-04-17 04:41:45,732 - INFO - Reasoning:

Let's analyze Ligand A and Ligand B against the provided guidelines, prioritizing GPCR-specific properties (BBB, logP, Pgp, TPSA, and affinity) for DRD2.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (438.591 Da) is higher, but acceptable. Ligand B (355.563 Da) is also good.

**TPSA:** Ligand A (96.01) is slightly above the optimal <90 for CNS targets, but still reasonable. Ligand B (49.77) is excellent, well below the threshold.

**logP:** Ligand A (2.993) is within the optimal 1-3 range. Ligand B (4.111) is slightly above, potentially raising concerns about solubility and off-target effects, but not drastically.

**H-Bond Donors/Acceptors:** Ligand A (3 HBD, 5 HBA) is good. Ligand B (1 HBD, 3 HBA) is also excellent.

**QED:** Ligand A (0.389) is below the desirable 0.5 threshold, indicating a less drug-like profile. Ligand B (0.677) is above 0.5, suggesting better drug-likeness.

**DILI:** Ligand A (96.045) has a high DILI risk (above 60). Ligand B (2.559) has very low DILI risk, a significant advantage.

**BBB:** Ligand A (54.246) has moderate BBB penetration, below the >70 desirable for CNS targets. Ligand B (84.684) has excellent BBB penetration, a major positive for DRD2 targeting.

**Caco-2 Permeability:** Ligand A (-5.124) has poor Caco-2 permeability. Ligand B (-3.975) also has poor Caco-2 permeability.

**Aqueous Solubility:** Both ligands have very poor aqueous solubility (-5 and -3.723 respectively). This is a concern for both.

**hERG Inhibition:** Ligand A (0.165) has a low hERG risk. Ligand B (0.885) has a slightly higher, but still acceptable, hERG risk.

**Microsomal Clearance:** Ligand A (28.532) has moderate clearance. Ligand B (101.675) has high clearance, suggesting poorer metabolic stability.

**In vitro Half-Life:** Ligand A (44.85) has a moderate half-life. Ligand B (11.425) has a short half-life, potentially requiring more frequent dosing.

**P-gp Efflux:** Ligand A (0.124) has low P-gp efflux, which is good for CNS penetration. Ligand B (0.609) has moderate P-gp efflux, which is less desirable.

**Binding Affinity:** Ligand A (-9.8 kcal/mol) has significantly stronger binding affinity than Ligand B (-6.4 kcal/mol). This is a substantial advantage, potentially outweighing some of its other drawbacks.

**Overall Assessment:**

While Ligand A boasts a much stronger binding affinity, its high DILI risk, moderate BBB penetration, poor Caco-2 permeability, and lower QED are significant concerns. Ligand B, despite weaker affinity, presents a much more favorable ADME-Tox profile, particularly its excellent BBB penetration, low DILI risk, and lower P-gp efflux. For a CNS target like DRD2, good brain penetration and safety (low DILI) are paramount. The affinity difference, while substantial, might be overcome with further optimization of Ligand B, whereas mitigating the safety concerns of Ligand A would be far more challenging.

Output:
1
2025-04-17 04:41:45,733 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (364.408 and 361.877 Da) fall within the ideal 200-500 Da range. No significant difference here.

**2. TPSA:** Ligand A (60.85) is slightly higher than Ligand B (52.57). Both are below the 90 A^2 threshold desirable for CNS targets, but Ligand B is closer to the optimal range.

**3. logP:** Both ligands have good logP values (1.899 and 1.509), falling within the 1-3 range. No major difference.

**4. H-Bond Donors:** Ligand A has 1 HBD, while Ligand B has 0. Both are acceptable (<=5).

**5. H-Bond Acceptors:** Ligand A has 3 HBA, and Ligand B has 5. Both are within the acceptable range (<=10).

**6. QED:** Both ligands have good QED scores (0.783 and 0.816), indicating good drug-like properties.

**7. DILI:** Ligand A (23.846) has a lower DILI risk than Ligand B (38.387). This is a significant advantage for Ligand A.

**8. BBB:** Both ligands exhibit excellent BBB penetration (91.47% and 93.253%), exceeding the desirable >70% threshold for CNS targets. Ligand B is slightly better.

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.496 and -4.911). This is unusual and suggests poor permeability, but the scale is not defined. It's difficult to interpret without knowing the scale.

**10. Aqueous Solubility:** Both ligands have negative solubility values (-2.878 and -2.433). Similar to Caco-2, the scale is unknown, making interpretation difficult.

**11. hERG Inhibition:** Both ligands show low hERG inhibition risk (0.584 and 0.803).

**12. Microsomal Clearance:** Ligand A (45.83) has a slightly higher microsomal clearance than Ligand B (43.492), indicating potentially lower metabolic stability.

**13. In vitro Half-Life:** Ligand B (-1.076) has a longer in vitro half-life than Ligand A (-8.299). This is a significant advantage for Ligand B.

**14. P-gp Efflux:** Both ligands have low P-gp efflux liability (0.21 and 0.069), which is favorable for CNS penetration. Ligand B is better.

**15. Binding Affinity:** Both ligands have the same binding affinity (-7.3 kcal/mol), which is excellent.

**Overall Assessment:**

While both ligands have excellent binding affinity and BBB penetration, Ligand B has several advantages: slightly better TPSA, longer half-life, lower P-gp efflux, and a slightly better BBB score. Ligand A has a lower DILI risk, which is important. However, the longer half-life and lower P-gp efflux of Ligand B are more critical for CNS drug development, especially given the similar affinity. The negative values for Caco-2 and solubility are concerning for both, but without knowing the scale, it's hard to weigh their importance.

Output:
1
2025-04-17 04:41:45,733 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B based on the provided guidelines, prioritizing GPCR-specific properties (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (346.471 and 348.462 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (60.85) is slightly higher than Ligand B (49.41). Both are below the 90 A^2 threshold for CNS targets, but B is better.

**logP:** Ligand A (1.816) is within the optimal 1-3 range. Ligand B (2.668) is also within range, but slightly higher.

**H-Bond Donors/Acceptors:** Both ligands have 1 HBD, which is good. Ligand A has 3 HBA, and Ligand B has 2. Both are acceptable (<=10).

**QED:** Ligand B (0.83) has a significantly better QED score than Ligand A (0.565), indicating a more drug-like profile.

**DILI:** Ligand A (6.01) has a much lower DILI risk than Ligand B (19.193). This is a significant advantage for Ligand A.

**BBB:** Ligand B (79.062) has a substantially better BBB penetration percentile than Ligand A (65.374). This is *critical* for a CNS target like DRD2.

**Caco-2 Permeability:** Ligand A (-4.398) has a better Caco-2 permeability than Ligand B (-4.825).

**Aqueous Solubility:** Ligand A (-1.747) has better aqueous solubility than Ligand B (-3.861).

**hERG Inhibition:** Ligand A (0.205) has a lower hERG inhibition liability than Ligand B (0.517), which is preferable.

**Microsomal Clearance:** Ligand B (34.362) has a higher microsomal clearance than Ligand A (24.052), meaning Ligand A is more metabolically stable.

**In vitro Half-Life:** Ligand B (-10.501) has a longer in vitro half-life than Ligand A (-4.71), which is generally desirable.

**P-gp Efflux:** Ligand A (0.031) has a much lower P-gp efflux liability than Ligand B (0.205). Lower P-gp efflux is crucial for CNS penetration.

**Binding Affinity:** Both ligands have very similar binding affinities (-7.9 and -7.8 kcal/mol), which are both excellent. The difference is negligible.

**Overall Assessment:**

Ligand B excels in BBB penetration and in vitro half-life, which are important for CNS drug development. However, it suffers from higher DILI risk, higher P-gp efflux, and lower aqueous solubility. Ligand A has a better safety profile (lower DILI & hERG), better solubility, and lower P-gp efflux, which are all crucial for CNS penetration and overall drug development. While Ligand B's BBB is better, the combination of Ligand A's superior ADME properties, especially the lower P-gp efflux and DILI, makes it a more promising candidate. The slight difference in binding affinity is not significant enough to outweigh these ADME advantages.

Output:
0
2025-04-17 04:41:45,733 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (353.853 and 347.419 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (46.92) is excellent, well below the 90 A^2 threshold for CNS targets. Ligand B (87.54) is higher, but still potentially acceptable, though less ideal.

**logP:** Ligand A (4.651) is slightly high, potentially leading to solubility issues or off-target interactions. Ligand B (0.246) is very low, which could hinder membrane permeability and target engagement.

**H-Bond Donors/Acceptors:** Both have acceptable HBD counts (1). Ligand A has 3 HBA, while Ligand B has 5. Both are within the acceptable range of <=10.

**QED:** Both ligands have good QED scores (0.725 and 0.827), indicating good drug-like properties.

**DILI:** Ligand A (74.99) has a higher DILI risk than Ligand B (58.085), but both are reasonably acceptable.

**BBB:** Ligand A (64.444) has a better BBB percentile than Ligand B (53.974). While neither is >70, A is closer. This is crucial for a CNS target like DRD2.

**Caco-2 Permeability:** Both have negative Caco-2 values (-4.796 and -4.937), which is unusual and suggests poor permeability. This is a significant concern for both.

**Aqueous Solubility:** Both have very poor aqueous solubility (-5.032 and -1.553). This is a major drawback, especially given Ligand A's already borderline logP.

**hERG Inhibition:** Ligand A (0.731) has a slightly higher hERG risk than Ligand B (0.136). Lower is better here.

**Microsomal Clearance:** Ligand A (90.588) has a much higher microsomal clearance than Ligand B (21.205), indicating faster metabolism and potentially lower *in vivo* exposure.

**In vitro Half-Life:** Ligand A (57.77) has a longer half-life than Ligand B (19.176).

**P-gp Efflux:** Ligand A (0.603) has lower P-gp efflux than Ligand B (0.014), which is favorable for CNS penetration.

**Binding Affinity:** Ligand B (-7.8 kcal/mol) has significantly stronger binding affinity than Ligand A (-9.1 kcal/mol). This is a substantial advantage.

**Overall Assessment:**

Ligand B's significantly stronger binding affinity (-7.8 vs -9.1 kcal/mol) is a major advantage that could potentially overcome some of its other weaknesses. However, its very low logP and poor Caco-2 permeability are serious concerns. Ligand A has better BBB penetration and lower P-gp efflux, but its high logP, poor solubility, and high metabolic clearance are problematic.

Considering the GPCR-specific priorities, BBB and affinity are paramount. While neither ligand excels in all areas, Ligand B's superior affinity is likely to be more impactful, *if* the permeability issues can be addressed through formulation or further structural modifications. Ligand A's issues are more numerous and potentially harder to resolve.

Output:
1
2025-04-17 04:41:45,733 - INFO - Batch 135 complete. Total preferences: 2160
2025-04-17 04:41:45,733 - INFO - Processing batch 136/512...
2025-04-17 04:42:36,653 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (348.367 Da) is slightly lower, which is generally favorable for permeability.

**TPSA:** Ligand A (122.28) is better than Ligand B (64.43). For CNS targets, TPSA should be <=90. Ligand B is well within this range, while Ligand A is slightly above, but still acceptable.

**logP:** Ligand B (3.06) is optimal (1-3), while Ligand A (-1.376) is quite low. Low logP can hinder membrane permeability. This is a significant drawback for Ligand A.

**H-Bond Donors/Acceptors:** Ligand A has 1 HBD and 9 HBA, while Ligand B has 0 HBD and 5 HBA. Both are within acceptable limits (<=5 HBD and <=10 HBA).

**QED:** Both ligands have similar QED values (0.678 and 0.595), indicating reasonable drug-likeness.

**DILI:** Ligand B (19.698) has a much lower DILI risk than Ligand A (58.434). This is a considerable advantage for Ligand B.

**BBB:** Ligand B (78.054) has a significantly higher BBB penetration percentile than Ligand A (40.791). For a CNS target like DRD2, this is a crucial factor, making Ligand B much more promising.

**Caco-2 Permeability:** Ligand A (-5.517) has a negative Caco-2 value, which is unusual and suggests very poor permeability. Ligand B (-4.542) is also low, but better than A.

**Aqueous Solubility:** Ligand A (-0.828) has poor solubility, while Ligand B (-2.025) is also poor. Solubility is not a primary concern if permeability and BBB penetration are good.

**hERG Inhibition:** Ligand A (0.096) has a slightly lower hERG risk than Ligand B (0.393), but both are relatively low.

**Microsomal Clearance:** Ligand B (63.482) has a higher microsomal clearance than Ligand A (20.458), meaning it's metabolized faster. This is a negative for Ligand B, but not a dealbreaker.

**In vitro Half-Life:** Ligand B (21.582) has a longer half-life than Ligand A (-3.664). This is a significant advantage for Ligand B.

**P-gp Efflux:** Ligand A (0.011) has a very low P-gp efflux liability, which is excellent. Ligand B (0.293) is higher, but still reasonable.

**Binding Affinity:** Ligand A (-7.5 kcal/mol) has a slightly better binding affinity than Ligand B (-6.8 kcal/mol). However, the difference is less than 1.5 kcal/mol, and can be overcome by superior ADME properties.

**Overall Assessment:**

Ligand B is the stronger candidate. While its binding affinity is slightly lower, it significantly outperforms Ligand A in critical areas for a CNS GPCR target: BBB penetration, DILI risk, and in vitro half-life. Ligand A's low logP and poor Caco-2 permeability are major concerns. The lower P-gp efflux for Ligand A is a minor advantage that doesn't outweigh the other significant drawbacks.

Output:
1
2025-04-17 04:42:36,654 - INFO - Reasoning:

Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (361.881 and 363.523 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (71.76) is significantly better than Ligand B (41.93). For CNS targets, TPSA should be <= 90, and lower is preferable. Ligand A is still acceptable, while Ligand B is excellent.

**3. logP:** Ligand A (2.887) is within the optimal 1-3 range. Ligand B (4.588) is slightly higher, potentially leading to solubility issues and off-target interactions, though not drastically.

**4. H-Bond Donors:** Both ligands have 1 HBD, which is within the acceptable limit of <= 5.

**5. H-Bond Acceptors:** Ligand A has 7 HBAs, and Ligand B has 5. Both are within the acceptable limit of <= 10.

**6. QED:** Ligand A (0.882) has a better QED score than Ligand B (0.708), indicating a more drug-like profile.

**7. DILI:** Ligand A (69.872) has a higher DILI risk than Ligand B (12.059). This is a significant negative for Ligand A.

**8. BBB:** Both ligands have good BBB penetration (Ligand A: 77.472, Ligand B: 74.37). Both are above the desirable 70% threshold for CNS targets.

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.184 and -5.103). This is unusual and suggests poor permeability. However, these values are on a scale where negative values are possible, and direct comparison is difficult without knowing the scale's specifics.

**10. Aqueous Solubility:** Both ligands have negative solubility values (-3.963 and -4.314). Similar to Caco-2, these values are on a scale where negative values are possible, and direct comparison is difficult without knowing the scale's specifics.

**11. hERG Inhibition:** Ligand A (0.495) has a lower hERG risk than Ligand B (0.947), which is preferable.

**12. Microsomal Clearance:** Ligand A (86.306) has lower microsomal clearance than Ligand B (118.825), indicating better metabolic stability.

**13. In vitro Half-Life:** Ligand B (31.267) has a significantly longer in vitro half-life than Ligand A (11.362). This is a major advantage for Ligand B.

**14. P-gp Efflux:** Ligand A (0.126) has lower P-gp efflux than Ligand B (0.578), which is favorable for CNS penetration.

**15. Binding Affinity:** Ligand B (-7.1 kcal/mol) has a stronger binding affinity than Ligand A (-9.3 kcal/mol). A difference of 1.5 kcal/mol or greater is considered significant, and this difference favors Ligand B.

**Overall Assessment:**

While Ligand A has a better QED, lower P-gp efflux, and lower hERG risk, Ligand B is superior overall. The most crucial factors are:

*   **Binding Affinity:** Ligand B has a significantly stronger binding affinity.
*   **DILI Risk:** Ligand B has a much lower DILI risk.
*   **Metabolic Stability:** Ligand B has a longer half-life, indicating better metabolic stability.
*   **TPSA:** Ligand B has a lower TPSA, which is beneficial for CNS penetration.

The slightly higher logP of Ligand B is a minor concern, but the benefits outweigh this drawback.

Output:
1
2025-04-17 04:42:36,654 - INFO - Reasoning:

Let's analyze Ligand A and Ligand B based on the provided guidelines, prioritizing GPCR-specific properties (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Ligand A (453.2 Da) is within the ideal range, while Ligand B (362.434 Da) is also acceptable, though on the lower side.

**TPSA:** Ligand A (127.68) is slightly above the optimal 90 for CNS targets, but still reasonable. Ligand B (77.75) is excellent for CNS penetration.

**logP:** Both ligands have good logP values (A: 1.419, B: 1.669), falling within the 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A (HBD=2, HBA=8) and Ligand B (HBD=1, HBA=8) both have acceptable numbers of hydrogen bond donors and acceptors.

**QED:** Both ligands have reasonable QED scores (A: 0.442, B: 0.593), with Ligand B being slightly more drug-like.

**DILI:** Ligand A (98.953) shows a high DILI risk, which is a significant concern. Ligand B (77.549) has a lower, more acceptable DILI risk.

**BBB:** Ligand A (45.134) has a poor BBB penetration score, making it less suitable for a CNS target. Ligand B (67.623) has a better, though not ideal, BBB score.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.282 and -4.953), which is unusual and suggests poor permeability. However, these values are on a scale where negative values are possible, and the magnitude matters.

**Aqueous Solubility:** Both ligands have negative solubility values (-4.079 and -3.363), indicating poor aqueous solubility.

**hERG:** Both ligands have low hERG inhibition liability (A: 0.3, B: 0.21), which is positive.

**Microsomal Clearance:** Ligand A (47.383) has a higher microsomal clearance than Ligand B (35.712), suggesting lower metabolic stability.

**In vitro Half-Life:** Ligand A (21.234) has a longer half-life than Ligand B (11.017).

**P-gp Efflux:** Both ligands have low P-gp efflux liability (A: 0.171, B: 0.124), which is favorable for CNS penetration.

**Binding Affinity:** Ligand A (-7.9 kcal/mol) has a significantly stronger binding affinity than Ligand B (-6.7 kcal/mol). This 1.2 kcal/mol difference is substantial and could outweigh some ADME drawbacks.

**Overall Assessment:**

Despite the stronger binding affinity of Ligand A, its high DILI risk and poor BBB penetration are major drawbacks for a CNS-targeted drug. The poor solubility and permeability of both compounds are also concerning. Ligand B, while having a weaker affinity, exhibits a much better safety profile (lower DILI) and a better (though still not ideal) BBB score. The slightly better QED, lower clearance, and lower P-gp efflux also favor Ligand B. Given the GPCR-specific priorities, particularly BBB and safety, and the substantial difference in DILI risk, Ligand B is the more promising candidate.

Output:
1
2025-04-17 04:42:36,654 - INFO - Okay, let's analyze these two ligands for their potential as DRD2 drug candidates.

**Ligand A:** [351.447, 79.9, 0.04, 2, 5, 0.677, 15.045, 48.391, -5.164, -1.107, 0.1, -8.943, 15.155, 0.01, -7.4]
**Ligand B:** [341.503, 55.63, 3.601, 1, 5, 0.734, 25.204, 83.56, -5.26, -3.763, 0.33, 36.806, -6.632, 0.341, -7.3]

Here's a breakdown comparing each property, with a focus on GPCR (and specifically CNS) priorities:

1. **MW:** Both are within the ideal 200-500 Da range. Ligand A (351.447) is slightly higher, but both are acceptable.
2. **TPSA:** Ligand A (79.9) is higher than Ligand B (55.63). For CNS targets, we want TPSA <= 90, so both pass, but Ligand B is significantly better.
3. **logP:** Ligand A (0.04) is very low, potentially hindering membrane permeability. Ligand B (3.601) is within the optimal 1-3 range. This is a significant advantage for Ligand B.
4. **HBD:** Ligand A (2) and Ligand B (1) are both good, below the 5 threshold.
5. **HBA:** Both ligands have 5 HBA, which is acceptable (<=10).
6. **QED:** Both have good QED scores (A: 0.677, B: 0.734), indicating drug-like properties.
7. **DILI:** Ligand A (15.045) has a much lower DILI risk than Ligand B (25.204). This is a positive for Ligand A.
8. **BBB:** Ligand B (83.56) has a much higher BBB penetration percentile than Ligand A (48.391).  This is *critical* for a CNS target like DRD2, making Ligand B strongly favored.
9. **Caco-2:** Both have negative Caco-2 values, suggesting poor permeability. This is a concern for both, but the scale is not clear.
10. **Solubility:** Both have negative solubility values, suggesting poor solubility. This is a concern for both, but the scale is not clear.
11. **hERG:** Both have low hERG inhibition liability (A: 0.1, B: 0.33), which is good.
12. **Cl_mic:** Ligand A (-8.943) has a *much* lower (better) microsomal clearance than Ligand B (36.806), indicating better metabolic stability.
13. **t1/2:** Ligand A (15.155) has a longer in vitro half-life than Ligand B (-6.632). This is a positive for Ligand A.
14. **Pgp:** Ligand A (0.01) has significantly lower P-gp efflux liability than Ligand B (0.341), which is favorable for CNS penetration.
15. **Affinity:** Both have very similar and strong binding affinities (A: -7.4, B: -7.3). The difference is negligible.

**Overall Assessment:**

Ligand B excels in BBB penetration and has a more favorable logP. These are the most important factors for a CNS GPCR target. While Ligand A has better metabolic stability (Cl_mic, t1/2), lower DILI risk, and lower P-gp efflux, the poor logP and lower BBB penetration are significant drawbacks. The small difference in binding affinity is not enough to overcome these issues.

Therefore, I predict Ligand B is the more viable drug candidate.

1
2025-04-17 04:42:36,654 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (337.375 and 353.857 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (64.63) is better than Ligand B (56.84) as it is closer to the <90 A^2 threshold for CNS targets.

**3. logP:** Both ligands have good logP values (2.831 and 3.927) within the optimal 1-3 range, though Ligand B is slightly higher.

**4. H-Bond Donors:** Ligand A (1) is preferable to Ligand B (2) as lower HBDs generally improve permeability.

**5. H-Bond Acceptors:** Both ligands have the same number of HBA (4), which is within the acceptable limit of <=10.

**6. QED:** Ligand A (0.852) has a better QED score than Ligand B (0.746), indicating a more drug-like profile.

**7. DILI:** Ligand A (55.409) has a lower DILI risk than Ligand B (71.074), making it safer.

**8. BBB:** Ligand B (91.392) significantly outperforms Ligand A (66.615) in BBB penetration, a critical factor for CNS targets like DRD2. This is a major advantage for Ligand B.

**9. Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and suggests poor permeability. However, the scale is not defined, so this is difficult to interpret.

**10. Aqueous Solubility:** Both have negative solubility values, which is also unusual.

**11. hERG Inhibition:** Ligand A (0.415) has a lower hERG inhibition liability than Ligand B (0.901), reducing cardiotoxicity risk.

**12. Microsomal Clearance:** Ligand B (33.673) has lower microsomal clearance than Ligand A (44.343), indicating better metabolic stability.

**13. In vitro Half-Life:** Ligand B (-4.86) has a longer half-life than Ligand A (-15.39), which is desirable.

**14. P-gp Efflux:** Both ligands show P-gp efflux liability (-10.5 and -9.2), but they are similar.

**15. Binding Affinity:** Both ligands have very similar binding affinities (-9.2 and -10.5 kcal/mol).

**Overall Assessment:**

Ligand B excels in BBB penetration and metabolic stability (lower Cl_mic, longer t1/2), which are crucial for a CNS-targeting GPCR. While Ligand A has a better QED, lower DILI, and lower hERG risk, the substantial advantage of Ligand B in BBB penetration outweighs these benefits. The similar binding affinities mean potency isn't a differentiating factor. The negative values for Caco-2 and solubility are concerning for both, but the BBB is the most important factor for a CNS target.

Output:
1
2025-04-17 04:42:36,654 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (351.407 and 356.491 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (116.68) is better than Ligand B (42.43). For CNS targets, TPSA should be <=90. Ligand A is close to the upper limit, while Ligand B is well within the desired range.

**logP:** Ligand A (-0.966) is suboptimal, being below the preferred 1-3 range. Ligand B (3.592) is excellent, falling squarely within the optimal range. This is a significant advantage for Ligand B.

**H-Bond Donors/Acceptors:** Ligand A has 3 HBD and 7 HBA, which are acceptable. Ligand B has 0 HBD and 4 HBA, also acceptable.

**QED:** Both ligands have good QED scores (0.524 and 0.731, respectively), indicating drug-like properties.

**DILI:** Both ligands have similar, low DILI risk (31.097 and 31.834 percentile).

**BBB:** Ligand B (77.007) is significantly better than Ligand A (50.523) in terms of BBB penetration, which is crucial for a CNS target like DRD2. A value >70 is desirable, and Ligand B is approaching that threshold.

**Caco-2 Permeability:** Ligand A (-5.139) has poor Caco-2 permeability, while Ligand B (-4.685) is slightly better, but still not ideal.

**Aqueous Solubility:** Ligand A (-1.162) has poor aqueous solubility, while Ligand B (-4.38) is also poor.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.124 and 0.485 percentile).

**Microsomal Clearance:** Ligand A (-6.469) has lower (better) microsomal clearance than Ligand B (117.506), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (-15.256) has a very short half-life, while Ligand B (-40.312) is also short, but less so than Ligand A.

**P-gp Efflux:** Ligand A (0.002) has very low P-gp efflux, which is excellent. Ligand B (0.276) has slightly higher P-gp efflux, but still relatively low.

**Binding Affinity:** Ligand B (-7.4 kcal/mol) has slightly better binding affinity than Ligand A (-7.1 kcal/mol), although the difference is small.

**Overall Assessment:**

Ligand B is the stronger candidate. While Ligand A has better metabolic stability (lower Cl_mic) and P-gp efflux, Ligand B excels in the critical areas for a CNS-targeting GPCR: logP, BBB penetration, and has slightly better binding affinity. The poor solubility and Caco-2 permeability of both compounds are concerns, but can potentially be addressed through formulation strategies. The significantly better BBB penetration of Ligand B outweighs the advantages of Ligand A.

Output:
1
2025-04-17 04:42:36,655 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B based on the provided guidelines, prioritizing GPCR-specific properties (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (371.503 Da) is slightly higher than Ligand B (284.428 Da), but both are acceptable.

**TPSA:** Ligand A (98.74) is borderline for CNS targets (ideally <90), while Ligand B (6.48) is excellent, well below the threshold. This is a significant advantage for Ligand B.

**logP:** Ligand A (0.124) is quite low, potentially hindering permeation. Ligand B (4.241) is slightly high, potentially causing solubility/off-target issues, but still within a reasonable range.

**H-Bond Donors/Acceptors:** Ligand A has 3 HBD and 5 HBA, which are acceptable. Ligand B has 0 HBD and 3 HBA, also acceptable.

**QED:** Both ligands have good QED scores (A: 0.591, B: 0.829), indicating good drug-like properties. Ligand B is slightly better.

**DILI:** Ligand A (29.779) has a much lower DILI risk than Ligand B (49.166), which is a significant advantage.

**BBB:** Ligand A (20.008) has poor BBB penetration, a major drawback for a CNS target like DRD2. Ligand B (98.914) has excellent BBB penetration, a critical advantage.

**Caco-2 Permeability:** Ligand A (-5.605) has very poor Caco-2 permeability, while Ligand B (-4.233) is also poor, but slightly better.

**Aqueous Solubility:** Both ligands have poor aqueous solubility (A: -1.949, B: -4.438).

**hERG Inhibition:** Ligand A (0.104) has very low hERG inhibition risk, a significant advantage. Ligand B (0.968) has moderate hERG risk.

**Microsomal Clearance:** Ligand A (24.119) and Ligand B (20.903) have similar, relatively low, microsomal clearance, suggesting reasonable metabolic stability.

**In vitro Half-Life:** Ligand A (16.474) has a longer half-life than Ligand B (2.008), which is desirable.

**P-gp Efflux:** Ligand A (0.012) has very low P-gp efflux, a major advantage for CNS penetration. Ligand B (0.512) has moderate P-gp efflux.

**Binding Affinity:** Ligand B (-7.5 kcal/mol) has a significantly stronger binding affinity than Ligand A (-6.9 kcal/mol). This 1.5 kcal/mol difference is substantial and can outweigh some ADME drawbacks.

**Overall Assessment:**

Ligand B excels in binding affinity and BBB penetration, both crucial for a DRD2 ligand. While its logP is slightly high and solubility is poor, the strong affinity and excellent BBB penetration are compelling. Ligand A has better DILI and hERG profiles, lower P-gp efflux, and longer half-life, but its very poor BBB penetration and low logP are major liabilities for a CNS target. The TPSA of Ligand B is also significantly better.

Output:
1
2025-04-17 04:42:36,655 - INFO - Okay, let's analyze these two ligands for their potential as DRD2 drug candidates.

**Ligand A: [381.929, 71.09, 3.392, 2, 4, 0.821, 49.942, 56.495, -5.076, -4.253, 0.337, 36.87, 25.43, 0.362, -9.2]**
**Ligand B: [368.551, 83.37, 2.582, 1, 7, 0.804, 43.117, 93.408, -4.9, -3.399, 0.801, 69.847, -3.028, 0.205, -7.7]**

**Step-by-step comparison:**

1. **MW:** Both ligands are within the ideal range (200-500 Da). A (381.929) is slightly higher than B (368.551), but both are acceptable.
2. **TPSA:** A (71.09) is significantly better than B (83.37). For a CNS target like DRD2, we want TPSA < 90, and A is closer to the ideal <60. B is pushing the upper limit.
3. **logP:** Both are within the optimal range (1-3), with A (3.392) being slightly higher than B (2.582). This isn't a major concern for either.
4. **HBD:** A (2) is preferable to B (1). While both are low, lower HBD can sometimes improve BBB penetration.
5. **HBA:** A (4) is better than B (7). Lower HBA is generally preferred for CNS penetration.
6. **QED:** Both are very similar and good (A: 0.821, B: 0.804), indicating good drug-like properties.
7. **DILI:** Both have acceptable DILI risk (A: 49.942, B: 43.117), below the 60% threshold. B is slightly better.
8. **BBB:** This is *critical* for a CNS target. B (93.408) is excellent, significantly better than A (56.495). This is a major advantage for B.
9. **Caco-2:** Both have negative values, which is unusual. Assuming these are logP-scaled permeability values, lower (more negative) values indicate poorer permeability. A (-5.076) is worse than B (-4.9).
10. **Solubility:** Both have negative values, indicating poor solubility. A (-4.253) is worse than B (-3.399). Solubility is a concern for both, but less so than BBB for CNS targets.
11. **hERG:** Both have very low hERG risk (A: 0.337, B: 0.801), which is excellent.
12. **Cl_mic:** A (36.87) has lower clearance than B (69.847), suggesting better metabolic stability. This is a positive for A.
13. **t1/2:** A (25.43) has a longer half-life than B (-3.028). This is a significant advantage for A. Note the negative value for B is concerning.
14. **Pgp:** A (0.362) has lower P-gp efflux than B (0.205), suggesting better CNS exposure.
15. **Binding Affinity:** A (-9.2) has a significantly stronger binding affinity than B (-7.7). This is a substantial advantage for A (1.5 kcal/mol difference).

**GPCR-Specific Priorities:**

For DRD2 (a CNS GPCR), we prioritize BBB, logP, TPSA, Pgp, and affinity.

*   **BBB:** B is significantly better.
*   **logP:** Both are good, A slightly better.
*   **TPSA:** A is much better.
*   **Pgp:** A is better.
*   **Affinity:** A is *much* better.

**Conclusion:**

While Ligand B has a superior BBB score, Ligand A has a significantly stronger binding affinity (-9.2 vs -7.7 kcal/mol) and better TPSA, Pgp, and metabolic stability. The difference in affinity is substantial and likely outweighs the advantage of B's BBB score, especially considering A's acceptable (though not ideal) BBB penetration. The longer half-life of A is also a significant benefit.

Therefore, I predict **Ligand A** is the more viable drug candidate.

1
2025-04-17 04:42:36,655 - INFO - Reasoning:

Let's analyze Ligand A and Ligand B for their potential as DRD2 drug candidates, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (450.244 Da) is higher, but still acceptable. Ligand B (362.415 Da) is slightly better.

**2. TPSA:**  For CNS targets, we want TPSA <= 90. Ligand A (104.62) is slightly above this, while Ligand B (117) is further above. This is a negative for both, but more so for Ligand B.

**3. logP:** Both ligands have good logP values (A: 1.639, B: 1.313), falling within the optimal 1-3 range.

**4. H-Bond Donors:** Both have 2 HBD, which is within the acceptable limit of <= 5.

**5. H-Bond Acceptors:** Ligand A has 6 HBA, and Ligand B has 8. Both are acceptable (<=10), but Ligand A is slightly better.

**6. QED:** Both have good QED scores (A: 0.591, B: 0.703), indicating good drug-like properties. Ligand B is slightly better.

**7. DILI:** Both have high DILI risk (A: 84.994, B: 89.57). This is a concern for both, but Ligand B is slightly worse.

**8. BBB:** This is *critical* for a CNS target like DRD2. Ligand A has a BBB percentile of 43.117, which is okay, but not great. Ligand B has a very low BBB percentile of 14.812, which is a significant drawback.

**9. Caco-2:** Both have negative Caco-2 values (-5.529 and -5.95), which is unusual and suggests poor permeability.

**10. Solubility:** Both have negative solubility values (-3.874 and -1.976), indicating poor aqueous solubility.

**11. hERG:** Both have very low hERG inhibition liability (A: 0.347, B: 0.05). This is positive for both.

**12. Cl_mic:** Ligand B has a lower (better) microsomal clearance (-23.368) than Ligand A (31.978), indicating better metabolic stability.

**13. t1/2:** Ligand B has a much longer in vitro half-life (29.299 hours) than Ligand A (-1.787 hours). This is a significant advantage for Ligand B.

**14. Pgp:** Both have very low Pgp efflux liability (A: 0.037, B: 0.012). This is positive for both.

**15. Binding Affinity:** Both have excellent binding affinities (A: -9.5 kcal/mol, B: -8.0 kcal/mol). Ligand A is significantly more potent.

**Overall Assessment:**

While Ligand B has better metabolic stability (Cl_mic, t1/2) and a slightly better QED, Ligand A's significantly superior binding affinity (-9.5 vs -8.0 kcal/mol) and moderately better BBB penetration (43.1 vs 14.8) are decisive. The affinity difference is substantial enough to potentially overcome the slightly higher TPSA and DILI risk. The poor Caco-2 and solubility are concerns for both, but can be addressed with formulation strategies. Given the GPCR-specific priorities, the binding affinity and BBB are the most important factors here.

Output:
0
2025-04-17 04:42:36,655 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (365.455 and 337.379 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Both ligands have a TPSA of approximately 99.5, which is slightly above the optimal <90 for CNS targets, but still potentially acceptable.

**3. logP:** Both ligands have logP values around 1.5, which is within the optimal 1-3 range.

**4. H-Bond Donors:** Ligand A (1 HBD) is better than Ligand B (2 HBDs) regarding this parameter.

**5. H-Bond Acceptors:** Both ligands have 5 HBAs, which is within the acceptable limit of <=10.

**6. QED:** Both ligands have good QED scores (0.824 and 0.86), indicating drug-like properties.

**7. DILI:** Ligand A (53.858 percentile) has a slightly higher DILI risk than Ligand B (41.024 percentile), but both are below the concerning threshold of 60.

**8. BBB:** This is a critical parameter for a CNS target like DRD2. Ligand A has a BBB penetration of 75.301%, which is good (>70). Ligand B has a significantly lower BBB penetration of 24.661%, making it less desirable.

**9. Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and suggests poor permeability. However, these values are on a log scale and the negative values may represent very low permeability.

**10. Aqueous Solubility:** Both ligands have negative solubility values, indicating poor aqueous solubility.

**11. hERG Inhibition:** Ligand A (0.559) has a slightly lower hERG inhibition risk than Ligand B (0.773), which is preferable.

**12. Microsomal Clearance:** Ligand B (-35.893) has a much lower (better) microsomal clearance than Ligand A (-5.85). This suggests better metabolic stability for Ligand B.

**13. In vitro Half-Life:** Ligand B (28.891) has a longer in vitro half-life than Ligand A (23.046), which is a positive attribute.

**14. P-gp Efflux:** Ligand A (0.106) has a lower P-gp efflux liability than Ligand B (0.144), which is favorable for CNS penetration.

**15. Binding Affinity:** Ligand B (-9.3 kcal/mol) has a significantly stronger binding affinity than Ligand A (-8.5 kcal/mol). This is a substantial advantage, potentially outweighing some of the ADME drawbacks.

**Overall Assessment:**

While Ligand B has better metabolic stability (lower Cl_mic) and a longer half-life, the significantly better binding affinity (-9.3 vs -8.5 kcal/mol) and acceptable DILI risk are major advantages. The biggest drawback for Ligand B is its poor BBB penetration (24.661%). However, the strong binding affinity might compensate for reduced BBB penetration to some extent, especially if the compound exhibits sufficient residence time at the receptor. Ligand A has better BBB penetration and P-gp efflux, but its weaker binding affinity is a significant disadvantage. Considering the GPCR-specific priorities, the binding affinity is paramount.

Output:
1
2025-04-17 04:42:36,656 - INFO - Reasoning:

Let's analyze Ligand A and Ligand B based on the provided guidelines, prioritizing GPCR-specific properties (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (367.471 Da) is slightly higher than Ligand B (356.463 Da), but both are acceptable.

**TPSA:** Ligand A (71.97) is significantly better than Ligand B (99.1). For CNS targets, we want TPSA <= 90, so Ligand A is much closer to this threshold, indicating better potential for brain penetration.

**logP:** Ligand A (2.025) is optimal (1-3), while Ligand B (0.431) is a bit low, potentially hindering permeation.

**H-Bond Donors/Acceptors:** Ligand A (0 HBD, 6 HBA) is preferable to Ligand B (3 HBD, 5 HBA). Lower HBD/HBA generally improves permeability.

**QED:** Both ligands have reasonable QED scores (A: 0.814, B: 0.586), indicating good drug-like properties.

**DILI:** Ligand A (57.697) has a higher DILI risk than Ligand B (15.898), but both are below the concerning threshold of 60.

**BBB:** Ligand A (71.501) has a significantly better BBB percentile than Ligand B (33.385). This is a critical factor for a CNS target like DRD2, and favors Ligand A.

**Caco-2 Permeability:** Both are negative, indicating poor permeability. However, the scale is not defined, so it's hard to interpret.

**Aqueous Solubility:** Both are negative, indicating poor solubility. Again, the scale is not defined.

**hERG:** Both ligands have very low hERG inhibition liability (A: 0.401, B: 0.136), which is excellent.

**Microsomal Clearance:** Ligand A (36.683) has a higher microsomal clearance than Ligand B (16.664), suggesting lower metabolic stability.

**In vitro Half-Life:** Ligand B (9.937) has a longer in vitro half-life than Ligand A (-5.036), which is a positive.

**P-gp Efflux:** Ligand A (0.326) has lower P-gp efflux liability than Ligand B (0.026), which is favorable for CNS penetration.

**Binding Affinity:** Both ligands have very similar binding affinities (-7.3 kcal/mol and -7.2 kcal/mol). The difference is negligible.

**Overall Assessment:**

Considering the GPCR-specific priorities, Ligand A is the more promising candidate. It has a significantly better TPSA and BBB percentile, a more optimal logP, and lower P-gp efflux. While its DILI risk and microsomal clearance are slightly higher, the advantages in CNS penetration properties outweigh these drawbacks, especially given the similar binding affinities. Ligand B's lower logP and significantly worse BBB are major concerns for a CNS-targeting drug.

Output:
1
2025-04-17 04:42:36,656 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (367.471 and 372.491 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (97.39) is slightly higher than Ligand B (93.53), but both are below the 140 threshold for oral absorption and reasonably close to the 90 threshold desirable for CNS targets.

**3. logP:** Ligand A (2.044) is optimal, while Ligand B (0.701) is slightly low, potentially hindering permeation.

**4. H-Bond Donors:** Ligand A (2) and Ligand B (1) are both within the acceptable limit of <=5.

**5. H-Bond Acceptors:** Ligand A (5) and Ligand B (6) are both within the acceptable limit of <=10.

**6. QED:** Ligand A (0.849) has a better QED score than Ligand B (0.689), suggesting a more drug-like profile.

**7. DILI:** Ligand A (56.921) has a higher DILI risk than Ligand B (40.287), but both are reasonably acceptable.

**8. BBB:** Ligand A (71.035) exhibits significantly better BBB penetration potential than Ligand B (64.831). This is a crucial factor for a CNS target like DRD2.

**9. Caco-2 Permeability:** Both ligands have very poor Caco-2 permeability (-4.817 and -4.816). This is a concern for oral bioavailability.

**10. Aqueous Solubility:** Both ligands have poor aqueous solubility (-2.943 and -2.078).

**11. hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.216 and 0.142).

**12. Microsomal Clearance:** Ligand A (54.041) has higher microsomal clearance than Ligand B (49.464), indicating lower metabolic stability.

**13. In vitro Half-Life:** Ligand B (-25.907) has a better in vitro half-life than Ligand A (-39.207).

**14. P-gp Efflux:** Ligand A (0.043) has lower P-gp efflux than Ligand B (0.038), which is favorable for CNS exposure.

**15. Binding Affinity:** Ligand A (-8.4 kcal/mol) has a significantly stronger binding affinity than Ligand B (-7.4 kcal/mol). This 1.0 kcal/mol difference is substantial and can outweigh some of the ADME drawbacks.

**Overall Assessment:**

While both ligands have issues with Caco-2 permeability and aqueous solubility, Ligand A is the more promising candidate. Its superior BBB penetration (71.035 vs. 64.831), better QED score (0.849 vs. 0.689), lower P-gp efflux (0.043 vs 0.038) and *significantly* stronger binding affinity (-8.4 vs -7.4 kcal/mol) outweigh its slightly higher DILI risk and microsomal clearance. The strong binding affinity is a key advantage for GPCR targets, and the improved BBB penetration is critical for CNS activity.

Output:
1
2025-04-17 04:42:36,656 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (385.869 Da) is slightly higher than Ligand B (357.384 Da), but both are acceptable.

**TPSA:** Ligand A (77.88) is better than Ligand B (84.31). For CNS targets, we want TPSA <= 90, so both are acceptable, but A is preferred.

**logP:** Ligand A (3.38) is optimal, while Ligand B (2.153) is slightly lower but still within the acceptable range (1-3). A is slightly preferred.

**H-Bond Donors:** Ligand A (1) is better than Ligand B (2). Lower is generally preferred for BBB penetration.

**H-Bond Acceptors:** Ligand A (7) is better than Ligand B (6). Both are within the acceptable range (<=10).

**QED:** Ligand B (0.793) has a higher QED score than Ligand A (0.526), indicating a more drug-like profile. This is a point in favor of B.

**DILI:** Ligand B (51.842) has a significantly lower DILI risk than Ligand A (71.423). This is a substantial advantage for B.

**BBB:** Ligand B (72.741) has a significantly better BBB penetration percentile than Ligand A (46.375). This is *critical* for a CNS target like DRD2, making B highly favored.

**Caco-2 Permeability:** Ligand A (-4.7) has better Caco-2 permeability than Ligand B (-5.226). However, both are negative values which are difficult to interpret without knowing the scale.

**Aqueous Solubility:** Ligand A (-3.962) has better aqueous solubility than Ligand B (-3.033). Both are negative values, which is concerning, but A is slightly better.

**hERG:** Ligand A (0.307) has a slightly better hERG profile than Ligand B (0.185), meaning lower risk of cardiotoxicity.

**Microsomal Clearance:** Ligand B (-10.638) has much lower microsomal clearance than Ligand A (65.629), suggesting better metabolic stability. This is a significant advantage for B.

**In vitro Half-Life:** Ligand B (-16.209) has a much longer in vitro half-life than Ligand A (50.75). This is a major advantage for B, potentially allowing for less frequent dosing.

**P-gp Efflux:** Ligand A (0.579) has higher P-gp efflux than Ligand B (0.106). Lower P-gp efflux is preferred, especially for CNS targets, so B is favored.

**Binding Affinity:** Ligand B (-8.2 kcal/mol) has a slightly better binding affinity than Ligand A (-7.8 kcal/mol). While both are good, the difference is significant enough to be a factor.

**Overall Assessment:**

Ligand B consistently outperforms Ligand A in the most critical parameters for a CNS-targeting GPCR ligand: BBB penetration, DILI risk, metabolic stability (Cl_mic and t1/2), and P-gp efflux. While Ligand A has slightly better solubility and Caco-2 permeability, these are outweighed by the substantial advantages of Ligand B in CNS penetration and safety. The slightly better binding affinity of B further solidifies its position as the superior candidate.

Output:
1
2025-04-17 04:42:36,656 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (367.471 and 356.463 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (75.88) is better than Ligand B (79.31). Both are below the 90 A^2 threshold desirable for CNS targets, but A is closer to the ideal.

**3. logP:** Ligand A (1.7) is better than Ligand B (0.504). Both are within the optimal 1-3 range, but B is quite low and may have permeability issues.

**4. H-Bond Donors:** Ligand A (0) is better than Ligand B (1). Lower is generally preferred.

**5. H-Bond Acceptors:** Ligand A (6) is better than Ligand B (5). Both are acceptable.

**6. QED:** Ligand A (0.774) is better than Ligand B (0.685). Both are above the 0.5 threshold, indicating good drug-likeness.

**7. DILI:** Ligand A (50.485) is significantly better than Ligand B (23.924). Lower DILI risk is crucial.

**8. BBB:** Ligand A (88.135) is *much* better than Ligand B (38.852). For a CNS target like DRD2, high BBB penetration is critical. This is a major advantage for Ligand A.

**9. Caco-2 Permeability:** Ligand A (-4.776) is better than Ligand B (-4.379). Both are negative, indicating poor permeability, but A is slightly better.

**10. Aqueous Solubility:** Ligand A (-3.146) is better than Ligand B (-0.664). Both are negative, indicating poor solubility, but A is slightly better.

**11. hERG Inhibition:** Ligand A (0.823) is better than Ligand B (0.408). Lower hERG inhibition is preferred.

**12. Microsomal Clearance:** Ligand A (65.98) is worse than Ligand B (31.649). Lower clearance is better for metabolic stability, favoring Ligand B.

**13. In vitro Half-Life:** Ligand A (6.317) is better than Ligand B (5.361). Longer half-life is generally desirable.

**14. P-gp Efflux:** Ligand A (0.202) is better than Ligand B (0.162). Lower P-gp efflux is better, especially for CNS targets.

**15. Binding Affinity:** Ligand B (-7.8) is slightly better than Ligand A (-7.5). While both are excellent, B has a 0.3 kcal/mol advantage.

**Overall Assessment:**

While Ligand B has a slightly better binding affinity and lower microsomal clearance, Ligand A is significantly superior in almost all other critical ADME properties, *especially* BBB penetration (88.135 vs. 38.852). Given that DRD2 is a CNS target, the ability to cross the blood-brain barrier is paramount. Ligand A also has a much lower DILI risk. The small affinity difference is likely outweighed by the substantial improvement in ADME properties, particularly BBB.

Output:
1
2025-04-17 04:42:36,656 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (348.447 and 356.413 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (85.25) is better than Ligand B (60.85) as it is closer to the ideal range for CNS targets (<90).

**3. logP:** Both ligands (1.425 and 1.5) are within the optimal 1-3 range.

**4. H-Bond Donors:** Ligand A (2) is slightly better than Ligand B (1) as it is still within the acceptable range of <=5.

**5. H-Bond Acceptors:** Ligand A (6) is slightly worse than Ligand B (3). Both are within the acceptable range of <=10.

**6. QED:** Both ligands have good QED scores (0.76 and 0.812), indicating good drug-like properties.

**7. DILI:** Ligand A (34.626) has a significantly lower DILI risk than Ligand B (13.61). Both are below the 40 threshold, but A is preferable.

**8. BBB:** Ligand B (87.553) has a substantially better BBB penetration score than Ligand A (68.786). This is a *critical* factor for a CNS target like DRD2.

**9. Caco-2 Permeability:** Ligand A (-4.835) has better Caco-2 permeability than Ligand B (-4.507).

**10. Aqueous Solubility:** Ligand A (-1.623) has better aqueous solubility than Ligand B (-2.025).

**11. hERG Inhibition:** Ligand A (0.114) has a lower hERG inhibition liability than Ligand B (0.529), which is preferable.

**12. Microsomal Clearance:** Ligand B (6.455) has significantly lower microsomal clearance than Ligand A (65.299), indicating better metabolic stability.

**13. In vitro Half-Life:** Ligand B (17.618) has a longer in vitro half-life than Ligand A (11.863).

**14. P-gp Efflux:** Ligand A (0.031) has lower P-gp efflux liability than Ligand B (0.048), which is preferable for CNS penetration.

**15. Binding Affinity:** Ligand A (-7.9) has a slightly better binding affinity than Ligand B (-7.4). While both are excellent, the 0.5 kcal/mol difference is noteworthy.

**Overall Assessment:**

Ligand B excels in BBB penetration and metabolic stability (lower Cl_mic and longer t1/2), which are crucial for CNS GPCR targets. While Ligand A has slightly better affinity, solubility, and lower DILI/hERG risk, the superior BBB score of Ligand B outweighs these advantages. The difference in affinity is not large enough to overcome the substantial advantage in CNS penetration.

Output:
1
2025-04-17 04:42:36,657 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, considering the provided guidelines and GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (342.399 and 357.426 Da) fall within the ideal 200-500 Da range.

**TPSA:** Both ligands (86.11 and 87.74) are below the 90 A^2 threshold desirable for CNS targets, which is good.

**logP:** Ligand A (2.263) is within the optimal 1-3 range. Ligand B (0.383) is below 1, which is a concern for permeability.

**H-Bond Donors/Acceptors:** Ligand A has 1 HBD and 6 HBA, well within acceptable limits. Ligand B has 2 HBD and 4 HBA, also acceptable.

**QED:** Both ligands have similar QED values (0.68 and 0.69), indicating good drug-likeness.

**DILI:** Ligand A (85.576) has a higher DILI risk than Ligand B (28.189). This is a significant drawback for Ligand A.

**BBB:** Ligand B (75.572) has a significantly better BBB penetration percentile than Ligand A (48.507). This is crucial for a CNS target like DRD2.

**Caco-2 Permeability:** Both have negative Caco-2 values, suggesting poor permeability. However, the scale is not defined, so it's hard to interpret.

**Aqueous Solubility:** Both have negative solubility values, suggesting poor solubility. Again, the scale is not defined.

**hERG:** Both ligands have low hERG inhibition liability (0.126 and 0.285), which is positive.

**Microsomal Clearance:** Ligand A (61.549) has a higher microsomal clearance than Ligand B (-1.121), suggesting lower metabolic stability.

**In vitro Half-Life:** Ligand B (6.945) has a longer in vitro half-life than Ligand A (-3.776), which is desirable.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.117 and 0.015), which is excellent for CNS penetration.

**Binding Affinity:** Ligand B (-8.4 kcal/mol) has a significantly stronger binding affinity than Ligand A (-0.0 kcal/mol). This is a major advantage.

**Overall Assessment:**

Ligand B is clearly superior. It has a significantly better binding affinity, a much better BBB percentile, lower DILI risk, and a longer half-life. While its logP is slightly low, the strong affinity and excellent CNS penetration potential outweigh this drawback. Ligand A's high DILI risk and poor affinity are significant concerns.

Output:
1
2025-04-17 04:42:36,657 - INFO - Batch 136 complete. Total preferences: 2176
2025-04-17 04:42:36,657 - INFO - Processing batch 137/512...
2025-04-17 04:43:24,388 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (345.403 and 351.491 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (129.18) is slightly above the ideal <90 for CNS targets, but still reasonable. Ligand B (78.51) is excellent, well below 90.

**logP:** Ligand A (0.492) is quite low, potentially hindering membrane permeability. Ligand B (1.714) is better, falling within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Both have 2 HBD and are within the acceptable limits. Ligand A has 5 HBA, while Ligand B has 3. Both are acceptable, but lower is generally preferred.

**QED:** Both ligands have acceptable QED scores (0.743 and 0.686, both >0.5).

**DILI:** Ligand A (53.858) has a moderate DILI risk, while Ligand B (20.434) has a very low risk. This favors Ligand B.

**BBB:** Ligand B (59.946) shows better BBB penetration than Ligand A (40.52). While neither is >70, Ligand B is significantly better, which is crucial for a CNS target like DRD2.

**Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and suggests poor permeability. However, the scale is not specified, so it's hard to interpret.

**Aqueous Solubility:** Both have negative solubility values, which is also unusual.

**hERG:** Both ligands show low hERG inhibition liability (0.208 and 0.088), which is good.

**Microsomal Clearance:** Ligand A (21.82) has higher clearance than Ligand B (11.905), indicating lower metabolic stability.

**In vitro Half-Life:** Ligand B (-0.656) has a slightly longer half-life than Ligand A (20.371).

**P-gp Efflux:** Ligand A (0.037) shows lower P-gp efflux than Ligand B (0.013), which is favorable for CNS penetration.

**Binding Affinity:** Ligand A (-7.6 kcal/mol) has a significantly stronger binding affinity than Ligand B (-6.9 kcal/mol). This is a substantial advantage.

**Overall Assessment:**

Ligand A has a significantly better binding affinity, which is a major plus. However, its low logP, moderate DILI risk, and lower BBB penetration are concerning. Ligand B, while having a slightly weaker affinity, has a much better logP, lower DILI risk, better BBB penetration, and better metabolic stability.

Considering the GPCR-specific priorities, BBB penetration and logP are particularly important for CNS targets. The affinity difference (0.7 kcal/mol) is notable, but the ADME improvements of Ligand B are likely to outweigh this difference, especially given the potential for further optimization of Ligand B's affinity.

Output:
1
2025-04-17 04:43:24,388 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (349.381 and 353.463 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (64.6) is significantly better than Ligand B (107.53). For CNS targets, we want TPSA <= 90, so Ligand A is much more favorable.

**3. logP:** Ligand A (3.091) is within the optimal range (1-3). Ligand B (0.75) is below 1, which could hinder permeation.

**4. H-Bond Donors:** Both have 3 HBD, which is acceptable (<=5).

**5. H-Bond Acceptors:** Both have 4 HBA, which is acceptable (<=10).

**6. QED:** Ligand A (0.75) is better than Ligand B (0.516), indicating a more drug-like profile.

**7. DILI:** Ligand A (46.297) has a slightly higher DILI risk than Ligand B (15.898), but both are below the concerning threshold of 60.

**8. BBB:** Ligand A (52.966) and Ligand B (46.568) are both below the desirable threshold of 70 for CNS targets. However, this is less critical if other properties are strong.

**9. Caco-2:** Both have negative Caco-2 values (-5.128 and -5.325), which is unusual and suggests poor permeability. This is a significant drawback for both.

**10. Solubility:** Both have negative solubility values (-3.052 and -1.396), indicating poor aqueous solubility. This is also a significant drawback.

**11. hERG:** Ligand A (0.773) has a slightly higher hERG risk than Ligand B (0.047), but both are relatively low.

**12. Cl_mic:** Ligand A (46.613) has better metabolic stability (lower clearance) than Ligand B (16.955).

**13. t1/2:** Ligand A (-7.187) has a much longer in vitro half-life than Ligand B (-2.495).

**14. Pgp:** Ligand A (0.159) shows lower P-gp efflux than Ligand B (0.006), which is favorable for CNS penetration.

**15. Affinity:** Ligand B (-7.4) has a slightly better binding affinity than Ligand A (-9.3). However, the difference is not substantial enough to overcome the other significant drawbacks of Ligand B.

**Overall Assessment:**

Despite the slightly better affinity of Ligand B, Ligand A is the more promising candidate. Ligand A has a much better TPSA, logP, QED, metabolic stability, half-life, and Pgp efflux profile. While both have poor Caco-2 and solubility, the superior CNS-relevant properties of Ligand A (lower TPSA, better logP, lower Pgp) make it more likely to achieve adequate brain exposure. The slightly higher DILI risk for Ligand A is less concerning than the poor permeability and solubility of Ligand B.

Output:
1
2025-04-17 04:43:24,389 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (362.308 and 372.491 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (84.43) is excellent, well below the 90 A^2 threshold for CNS targets. Ligand B (90.98) is slightly higher but still acceptable.

**logP:** Ligand A (2.001) is optimal. Ligand B (-0.113) is significantly lower than the ideal 1-3 range, which could hinder permeability.

**H-Bond Donors/Acceptors:** Ligand A (0 HBD, 8 HBA) is favorable. Ligand B (2 HBD, 5 HBA) is also acceptable.

**QED:** Both ligands have reasonable QED scores (0.777 and 0.679), indicating good drug-like properties.

**DILI:** Ligand A (70.88) has a higher DILI risk than Ligand B (40.287), but both are reasonably acceptable.

**BBB:** Ligand A (87.786) has a significantly better BBB penetration percentile than Ligand B (63.203). This is a critical advantage for a CNS target like DRD2.

**Caco-2 Permeability:** Ligand A (-4.779) has poor Caco-2 permeability, while Ligand B (-5.276) is also poor.

**Aqueous Solubility:** Ligand A (-3.305) has poor aqueous solubility, while Ligand B (-1.377) is also poor.

**hERG:** Both ligands have very low hERG inhibition risk (0.121 and 0.14).

**Microsomal Clearance:** Ligand A (25.877) has a higher microsomal clearance than Ligand B (-6.987), suggesting lower metabolic stability.

**In vitro Half-Life:** Ligand B (-21.135) has a significantly longer in vitro half-life than Ligand A (-12.813).

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.113 and 0.004).

**Binding Affinity:** Ligand A (-8.8 kcal/mol) has a slightly better binding affinity than Ligand B (-7.6 kcal/mol), but the difference is not substantial.

**Overall Assessment:**

Ligand A excels in TPSA, logP, and BBB penetration, which are crucial for CNS GPCR targets. While its Caco-2 permeability and aqueous solubility are poor, its strong binding affinity and good BBB penetration outweigh these drawbacks. Ligand B has a better half-life and lower DILI risk, but its poor logP and significantly lower BBB penetration are major concerns for a CNS drug.

Output:
1
2025-04-17 04:43:24,389 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (345.403 Da) is slightly lower, which could be beneficial for permeability, while Ligand B (380.941 Da) is still well within the range.

**TPSA:** Ligand A (102.16) is better than Ligand B (49.41) as it is closer to the <90 A^2 threshold for CNS targets. Ligand B is quite low, which could be a concern for selectivity.

**logP:** Ligand A (1.272) is within the optimal range (1-3). Ligand B (3.949) is at the higher end of the optimal range, potentially increasing off-target interactions or solubility issues.

**H-Bond Donors/Acceptors:** Ligand A has 2 HBD and 8 HBA, while Ligand B has 1 HBD and 3 HBA. Both are within acceptable limits.

**QED:** Both ligands have good QED scores (A: 0.787, B: 0.84), indicating good drug-like properties.

**DILI:** Both ligands have similar DILI risk (A: 56.572, B: 54.556), and are both acceptable.

**BBB:** Ligand B (77.007) has a significantly better BBB percentile than Ligand A (48.352). This is a crucial advantage for a CNS target like DRD2.

**Caco-2 Permeability:** Ligand A (-4.894) has a worse Caco-2 permeability than Ligand B (-5.004), indicating lower intestinal absorption.

**Aqueous Solubility:** Ligand A (-2.094) has better aqueous solubility than Ligand B (-4.831).

**hERG Inhibition:** Ligand A (0.092) has a lower hERG inhibition risk than Ligand B (0.526), which is preferable.

**Microsomal Clearance:** Ligand B (57.208) has higher microsomal clearance than Ligand A (6.877), suggesting lower metabolic stability.

**In vitro Half-Life:** Ligand A (-1.589) has a longer in vitro half-life than Ligand B (-2.334).

**P-gp Efflux:** Ligand A (0.019) has lower P-gp efflux liability than Ligand B (0.583), which is beneficial for CNS exposure.

**Binding Affinity:** Both ligands have excellent binding affinities (A: -9.2 kcal/mol, B: -8.0 kcal/mol). Ligand A has a 1.2 kcal/mol advantage, which is significant and can outweigh some ADME drawbacks.

**Overall Assessment:**

Ligand A has a superior binding affinity, better TPSA, lower hERG risk, lower P-gp efflux, and better metabolic stability. However, Ligand B has a significantly higher BBB penetration. Given that DRD2 is a CNS target, BBB penetration is paramount. While Ligand A's affinity is better, the substantial difference in BBB (48.352 vs 77.007) makes Ligand B more likely to reach the target in the brain. The slightly higher logP and P-gp efflux of Ligand B are less concerning than the poor BBB of Ligand A.

Output:
1
2025-04-17 04:43:24,389 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B based on the provided guidelines, prioritizing GPCR-specific properties (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (364.873) is slightly lower, which could be beneficial for permeability.

**TPSA:** Ligand A (58.64) is significantly better than Ligand B (67.43). For a CNS target like DRD2, TPSA should be <= 90, and lower is preferred. Ligand A is well within this range, while Ligand B is approaching the upper limit.

**logP:** Both ligands have good logP values (A: 3.428, B: 2.694) within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A (HBD=1, HBA=3) is slightly better than Ligand B (HBD=2, HBA=3) in terms of maintaining a balance between solubility and permeability.

**QED:** Ligand A (0.814) has a much higher QED score than Ligand B (0.262), indicating a significantly more drug-like profile.

**DILI:** Both ligands have low DILI risk (A: 33.075, B: 31.718), which is good.

**BBB:** Ligand A (90.151) has a significantly better BBB percentile than Ligand B (68.127). A BBB > 70 is desirable for CNS targets, and Ligand A is very close, while Ligand B is considerably lower. This is a crucial factor for DRD2.

**Caco-2 Permeability:** Ligand A (-4.396) and Ligand B (-4.787) both have negative values, which is unusual and suggests very low permeability. However, the scale isn't explicitly defined, so we can't draw strong conclusions.

**Aqueous Solubility:** Ligand A (-4.569) and Ligand B (-3.297) both have negative values, indicating low solubility.

**hERG:** Both ligands have low hERG risk (A: 0.622, B: 0.334).

**Microsomal Clearance:** Ligand A (68.607) has higher microsomal clearance than Ligand B (44.594), suggesting lower metabolic stability.

**In vitro Half-Life:** Ligand B (13.436) has a significantly longer in vitro half-life than Ligand A (-4.342), which is a positive attribute.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (A: 0.21, B: 0.196), which is good for CNS penetration.

**Binding Affinity:** Ligand B (-7.0) has a slightly better binding affinity than Ligand A (-9.0). However, the difference is not substantial enough to outweigh the other significant advantages of Ligand A.

**Overall Assessment:**

Ligand A is the better candidate. While Ligand B has a slightly better binding affinity and longer half-life, Ligand A excels in critical areas for a CNS-targeting GPCR: TPSA, BBB, and QED. The significantly higher BBB percentile and better TPSA of Ligand A are crucial for brain penetration. The higher QED score suggests a more generally drug-like molecule. The lower metabolic stability of Ligand A could be addressed through structural modifications, but the CNS penetration advantages of Ligand A are harder to achieve *post hoc*.

Output:
1
2025-04-17 04:43:24,389 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (373.322 and 346.387 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (81.67) is significantly better than Ligand B (122.55). For CNS targets, we want TPSA <= 90, so Ligand A is preferable.

**3. logP:** Both ligands have acceptable logP values (1.123 and 0.454), falling within the 1-3 range. Ligand A is slightly better.

**4. H-Bond Donors:** Both have 4 HBD, which is acceptable (<=5).

**5. H-Bond Acceptors:** Ligand A has 4 HBA, and Ligand B has 5. Both are within the acceptable limit of <=10.

**6. QED:** Both ligands have reasonable QED values (0.462 and 0.577), indicating drug-like properties. Ligand B is slightly better.

**7. DILI:** Ligand A (48.468) has a much lower DILI risk than Ligand B (67.119). This is a significant advantage for Ligand A.

**8. BBB:** Ligand A (50.523) has a lower BBB penetration percentile than Ligand B (62.544). While both are not ideal (>70 is desired), Ligand B is better in this regard.

**9. Caco-2 Permeability:** Both have negative Caco-2 values (-5.264 and -5.478). This is unusual and suggests poor permeability, but the values are close enough to not be a major differentiator.

**10. Aqueous Solubility:** Both have negative solubility values (-2.196 and -3.053). This is also unusual and suggests poor solubility. Again, the values are close.

**11. hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.413 and 0.197).

**12. Microsomal Clearance:** Ligand B (-4.178) has lower (better) microsomal clearance than Ligand A (5.289). This suggests greater metabolic stability for Ligand B.

**13. In vitro Half-Life:** Ligand B (-15.896) has a longer in vitro half-life than Ligand A (-13.428).

**14. P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.016 and 0.008).

**15. Binding Affinity:** Both ligands have very strong binding affinity (-9.0 and -9.1 kcal/mol). The difference is negligible.

**Overall Assessment:**

Considering the GPCR-specific priorities, Ligand A is better due to its significantly lower DILI risk and lower TPSA. While Ligand B has slightly better BBB penetration and metabolic stability, the DILI risk associated with Ligand B is concerning. For a CNS target, a lower TPSA is also beneficial for brain penetration. The binding affinity is comparable for both. Therefore, Ligand A is the more promising candidate.

Output:
1
2025-04-17 04:43:24,390 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (346.431 Da) is slightly lower, which could be beneficial for permeability, but both are acceptable.

**TPSA:** Ligand A (83.56) is better than Ligand B (69.64) as it is closer to the ideal range for CNS targets (<=90).

**logP:** Both ligands have good logP values (A: 1.692, B: 2.568), falling within the optimal range of 1-3.

**H-Bond Donors/Acceptors:** Both ligands have 2 HBD and 4 HBA, which is within acceptable limits.

**QED:** Ligand A (0.872) has a significantly better QED score than Ligand B (0.644), indicating a more drug-like profile.

**DILI:** Ligand B (33.307) has a lower DILI risk than Ligand A (46.297), which is a positive attribute.

**BBB:** Ligand B (71.074) has a substantially better BBB penetration score than Ligand A (56.456). This is *critical* for a CNS target like DRD2.

**Caco-2 Permeability:** Ligand A (-4.99) has a much worse Caco-2 permeability than Ligand B (-5.135). Both are negative, suggesting poor permeability, but A is slightly better.

**Aqueous Solubility:** Ligand A (-1.482) has better solubility than Ligand B (-3.027).

**hERG Inhibition:** Ligand A (0.095) has a lower hERG inhibition liability than Ligand B (0.588), which is favorable.

**Microsomal Clearance:** Ligand A (-13.028) has a much lower (better) microsomal clearance than Ligand B (50.796), suggesting greater metabolic stability.

**In vitro Half-Life:** Ligand A (3.238) has a shorter half-life than Ligand B (-2.871).

**P-gp Efflux:** Ligand A (0.01) has a much lower P-gp efflux liability than Ligand B (0.397), which is highly desirable for CNS penetration.

**Binding Affinity:** Ligand B (-7.5 kcal/mol) has a significantly better binding affinity than Ligand A (0.0 kcal/mol). This is a major advantage, potentially outweighing some of the ADME drawbacks.

**Overall Assessment:**

While Ligand A has better QED, metabolic stability, and lower hERG risk, Ligand B excels in the most critical areas for a CNS-targeting GPCR: **BBB penetration and binding affinity**. The significantly stronger binding affinity of Ligand B (-7.5 kcal/mol vs 0 kcal/mol) is a decisive factor. The better BBB score (71.074 vs 56.456) further strengthens its position. Although Ligand B has a higher DILI risk and P-gp efflux, the strong binding and BBB penetration are likely to be more impactful for *in vivo* efficacy.

Output:
1
2025-04-17 04:43:24,390 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (336.315 and 345.487 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (134.36) is better than Ligand B (43.86). For CNS targets, we want TPSA <= 90, and Ligand A is closer to this threshold. Ligand B is excellent.

**logP:** Both ligands have good logP values (1.399 and 1.908), falling within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A has 3 HBD and 7 HBA, which is acceptable. Ligand B has 0 HBD and 3 HBA, also acceptable.

**QED:** Both ligands have good QED scores (0.512 and 0.691), indicating drug-like properties.

**DILI:** Ligand A has a high DILI risk (98.449 percentile), which is a significant concern. Ligand B has a very low DILI risk (13.571 percentile), a major advantage.

**BBB:** Ligand B has a much higher BBB penetration (71.229 percentile) than Ligand A (29.12 percentile). This is critical for a CNS target like DRD2.

**Caco-2 Permeability:** Ligand A has a negative Caco-2 value (-5.435), which is unusual and concerning. Ligand B has a negative value as well (-4.69), but is slightly better.

**Aqueous Solubility:** Ligand A has a negative solubility (-4.119), which is a significant drawback. Ligand B also has a negative solubility (-2.127), but is slightly better.

**hERG:** Both ligands have low hERG inhibition liability (0.498 and 0.462), which is good.

**Microsomal Clearance:** Ligand A has a lower Cl_mic (9.925) than Ligand B (51.776), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A has a longer half-life (10.995 hours) than Ligand B (2.08 hours), which is desirable.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.143 and 0.096), which is good.

**Binding Affinity:** Ligand A has a significantly stronger binding affinity (-9.5 kcal/mol) than Ligand B (-6.9 kcal/mol). This is a substantial advantage, potentially outweighing some of the ADME concerns.

**Overall Assessment:**

Ligand A has a much better binding affinity and metabolic stability, but suffers from very poor solubility, questionable permeability, and a high DILI risk. Ligand B has a significantly better safety profile (low DILI, good BBB penetration) and better solubility, but weaker binding affinity.

Given the GPCR-specific priorities, BBB penetration is crucial for CNS targets. While the affinity of Ligand A is very attractive, the high DILI risk and poor solubility are major liabilities. Ligand B's superior safety and CNS penetration, combined with a still-reasonable affinity, make it the more promising candidate. The difference in affinity (2.6 kcal/mol) is substantial, but not insurmountable during lead optimization.

Output:
1
2025-04-17 04:43:24,390 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (330.475 and 352.435 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (27.82) is excellent, well below the 90 A^2 threshold for CNS targets. Ligand B (96.55) is higher, but still potentially acceptable, although less ideal.

**logP:** Ligand A (4.882) is slightly high, potentially leading to solubility issues or off-target interactions. Ligand B (0.881) is quite low, which could hinder membrane permeability and CNS penetration.

**H-Bond Donors/Acceptors:** Both ligands have 2 HBDs, which is good. Ligand A has 1 HBA, and Ligand B has 5 HBAs. Both are within acceptable limits (<=10).

**QED:** Both ligands have good QED values (0.662 and 0.759, respectively), indicating generally drug-like properties.

**DILI:** Ligand A (32.571) has a lower DILI risk than Ligand B (52.695), which is preferable.

**BBB:** This is critical for a CNS target. Ligand A (83.56) has a significantly higher BBB percentile than Ligand B (45.56). This is a major advantage for Ligand A.

**Caco-2 Permeability:** Both have negative values, which is unusual and suggests a potential issue with the data. However, the magnitude of negativity for Ligand A (-5.236) is greater than Ligand B (-5.033), which could indicate lower permeability.

**Aqueous Solubility:** Both have negative values, which is also unusual. Again, the magnitude of negativity for Ligand A (-4.546) is greater than Ligand B (-1.554), suggesting lower solubility for Ligand A.

**hERG Inhibition:** Ligand A (0.948) has a lower hERG risk than Ligand B (0.226), which is better.

**Microsomal Clearance:** Ligand A (-9.21) has a more negative value, indicating lower clearance and better metabolic stability than Ligand B (3.612).

**In vitro Half-Life:** Ligand A (16.351) has a longer half-life than Ligand B (-14.673), which is desirable.

**P-gp Efflux:** Ligand A (0.648) has lower P-gp efflux liability than Ligand B (0.012), which is beneficial for CNS penetration.

**Binding Affinity:** Ligand A (-9.4 kcal/mol) has a significantly stronger binding affinity than Ligand B (-8.1 kcal/mol). The 1.3 kcal/mol difference is substantial and can outweigh some ADME drawbacks.

**Overall Assessment:**

Ligand A is the stronger candidate. While its logP is slightly elevated and solubility is low (both potentially addressable with further optimization), its superior BBB penetration, significantly stronger binding affinity, lower DILI risk, better metabolic stability, longer half-life, and lower P-gp efflux outweigh these concerns. Ligand B's low logP is a major drawback for CNS penetration, and its weaker binding affinity is also a significant disadvantage.

Output:
0
2025-04-17 04:43:24,390 - INFO - Okay, let's analyze these two ligands for their potential as DRD2 drug candidates. DRD2 is a GPCR in the CNS, so BBB penetration, logP, Pgp efflux, TPSA, and binding affinity are paramount.

**Ligand A:** [350.463, 107.11 ,   1.297,   4.   ,   4.   ,   0.477,  28.887,  13.61 , -5.708,  -1.726,   0.111,   4.289, -15.202,   0.035,  -7.8  ]
**Ligand B:** [358.877,  68.52 ,   2.937,   1.   ,   6.   ,   0.824,  48.662,  75.805, -5.376,  -3.167,   0.219,  31.531,  10.946,   0.272,  -7.8  ]

**1. Molecular Weight:** Both ligands are within the ideal range (200-500 Da).

**2. TPSA:** Ligand A (107.11) is higher than ideal for CNS penetration (<90), but still potentially acceptable. Ligand B (68.52) is excellent, well below the 90 threshold.

**3. logP:** Ligand A (1.297) is good, within the optimal range. Ligand B (2.937) is also good, leaning towards the higher end of optimal.

**4. H-Bond Donors:** Ligand A (4) is acceptable. Ligand B (1) is also good, potentially improving permeability.

**5. H-Bond Acceptors:** Ligand A (4) is acceptable. Ligand B (6) is also acceptable.

**6. QED:** Ligand A (0.477) is below the desirable threshold of 0.5. Ligand B (0.824) is excellent, indicating a strong drug-like profile.

**7. DILI:** Ligand A (28.887) has a low DILI risk, which is excellent. Ligand B (48.662) is slightly higher, but still within an acceptable range.

**8. BBB:** Ligand A (13.61) has very poor predicted BBB penetration. Ligand B (75.805) is excellent, exceeding the 70% threshold for CNS targets. This is a *major* advantage for Ligand B.

**9. Caco-2 Permeability:** Both have negative values, which is unusual and suggests an issue with the prediction method. However, the magnitude of the negative value for Ligand A (-5.708) is larger, suggesting potentially worse permeability.

**10. Aqueous Solubility:** Both have negative values, again suggesting an issue with the prediction method.

**11. hERG Inhibition:** Both have very low hERG risk.

**12. Microsomal Clearance:** Ligand A (4.289) has lower clearance, indicating better metabolic stability. Ligand B (31.531) has significantly higher clearance.

**13. In vitro Half-Life:** Ligand A (-15.202) has a negative half-life, which is nonsensical. Ligand B (10.946) has a reasonable half-life.

**14. P-gp Efflux:** Ligand A (0.035) has very low P-gp efflux, which is good. Ligand B (0.272) also has low P-gp efflux.

**15. Binding Affinity:** Both ligands have the same binding affinity (-7.8 kcal/mol), which is excellent.

**Overall Assessment:**

Despite Ligand A having better metabolic stability (lower Cl_mic) and lower P-gp efflux, the critical factor is BBB penetration. Ligand B's excellent BBB penetration (75.8%) compared to Ligand A's very poor penetration (13.61%) is decisive for a CNS target like DRD2. The better QED score and more reasonable half-life of Ligand B also contribute to its favorability. The issues with solubility and Caco-2 permeability are concerning but might be addressable with formulation strategies. The nonsensical half-life prediction for Ligand A is a red flag.

Therefore, Ligand B is the more promising drug candidate.

1
2025-04-17 04:43:24,390 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (354.491 Da) is slightly higher than Ligand B (284.428 Da), but both are acceptable.

**TPSA:** Ligand A (89.87) is excellent for CNS penetration, falling well below the 90 A^2 threshold. Ligand B (6.48) is *extremely* low, which is generally favorable for BBB penetration but could potentially indicate a lack of necessary interactions.

**logP:** Ligand A (1.44) is optimal. Ligand B (4.241) is a bit high, potentially leading to solubility issues and off-target effects.

**H-Bond Donors/Acceptors:** Ligand A has 3 HBD and 4 HBA, which are within acceptable limits. Ligand B has 0 HBD and 3 HBA, also acceptable.

**QED:** Both ligands have good QED scores (A: 0.697, B: 0.829), indicating good drug-like properties.

**DILI:** Ligand A (16.092) has a very low DILI risk, which is excellent. Ligand B (49.166) is moderately higher, but still within an acceptable range.

**BBB:** Ligand A (60.76) has moderate BBB penetration, which is a concern for a CNS target. Ligand B (98.914) has *excellent* BBB penetration, a significant advantage.

**Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and suggests poor permeability. However, the scale is not specified, so it's difficult to interpret.

**Aqueous Solubility:** Both have negative solubility values, which is also unusual and indicates poor solubility.

**hERG:** Ligand A (0.18) has a very low hERG risk. Ligand B (0.968) has a slightly elevated hERG risk, but still relatively low.

**Microsomal Clearance:** Ligand A (19.154) has moderate clearance, while Ligand B (20.903) is also moderate.

**In vitro Half-Life:** Ligand A (-8.445) has a very short half-life, a significant drawback. Ligand B (2.008) has a short half-life, but is better than Ligand A.

**P-gp Efflux:** Ligand A (0.05) has very low P-gp efflux, which is excellent for CNS exposure. Ligand B (0.512) has moderate P-gp efflux.

**Binding Affinity:** Ligand B (-7.5 kcal/mol) has a 0.5 kcal/mol stronger binding affinity than Ligand A (-8.0 kcal/mol). While both are good, the difference is not huge.

**Overall Assessment:**

Ligand B is the more promising candidate. Its exceptionally high BBB penetration is a major advantage for a CNS target like DRD2. While its logP is slightly high, the superior BBB penetration and better (though still short) half-life outweigh this concern. Ligand A's poor BBB penetration and very short half-life are significant liabilities. The slightly better affinity of Ligand A is not enough to compensate for these ADME deficiencies.

Output:
1
2025-04-17 04:43:24,391 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (346.431 and 353.419 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (87.46) is better than Ligand B (100.89). Both are below the 140 A^2 threshold for oral absorption, and Ligand A is closer to the preferred <90 A^2 for CNS targets.

**3. logP:** Ligand A (0.683) is slightly better than Ligand B (0.075), both are a bit low, but Ligand A is closer to the optimal 1-3 range. Low logP can hinder permeation.

**4. H-Bond Donors:** Ligand A (2) is slightly higher than Ligand B (1), but both are within the acceptable limit of <=5.

**5. H-Bond Acceptors:** Ligand A (5) is higher than Ligand B (6), but both are within the acceptable limit of <=10.

**6. QED:** Both ligands have similar QED values (0.742 and 0.725), indicating good drug-like properties.

**7. DILI:** Ligand A (31.718) has a lower DILI risk than Ligand B (36.758), both are good (<40).

**8. BBB:** Ligand A (51.183) has a slightly lower BBB penetration than Ligand B (55.797). While both are not ideal (>70), Ligand B is better.

**9. Caco-2 Permeability:** Ligand A (-4.993) is slightly better than Ligand B (-4.947). Both are negative, suggesting poor permeability.

**10. Aqueous Solubility:** Ligand A (-1.745) is slightly better than Ligand B (-1.24). Both are negative, suggesting poor solubility.

**11. hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.184 and 0.139).

**12. Microsomal Clearance:** Ligand A (-10.675) has significantly lower (better) microsomal clearance than Ligand B (-8.214), indicating better metabolic stability.

**13. In vitro Half-Life:** Ligand A (-11.9) has a significantly longer half-life than Ligand B (20.411), which is a major advantage.

**14. P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.065 and 0.01).

**15. Binding Affinity:** Both ligands have the same binding affinity (-7.6 kcal/mol), which is excellent.

**Overall Assessment:**

While Ligand B has a slightly better BBB score, Ligand A is superior in most other critical ADME properties. Specifically, Ligand A has better TPSA, logP, DILI risk, microsomal clearance, and *significantly* better in vitro half-life. Given the GPCR-specific focus on BBB, logP, Pgp, TPSA, and affinity, Ligand A's superior ADME profile, despite the slightly lower BBB, makes it the more promising candidate. The improved metabolic stability and longer half-life are particularly valuable.

Output:
0
2025-04-17 04:43:24,391 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (371.325 Da) is slightly higher than Ligand B (347.419 Da), but both are acceptable.

**TPSA:** Ligand A (44.37) is excellent, well below the 90 A^2 threshold for CNS targets. Ligand B (96.45) is higher, but still potentially acceptable, though less ideal for brain penetration.

**logP:** Ligand A (4.221) is at the upper end of the optimal range (1-3) and could potentially lead to solubility issues or off-target interactions. Ligand B (-0.124) is significantly below the optimal range, suggesting poor membrane permeability.

**H-Bond Donors/Acceptors:** Both ligands have 2 HBD, which is good. Ligand A has 2 HBA, also good. Ligand B has 6 HBA, which is higher and could potentially affect permeability.

**QED:** Both ligands have similar QED values (0.705 and 0.68), indicating good drug-like properties.

**DILI:** Ligand A (58.938) has a moderate DILI risk, while Ligand B (31.33) has a very low DILI risk, which is a significant advantage.

**BBB:** Ligand A (77.007) has a good BBB percentile, desirable for a CNS target. Ligand B (49.515) has a lower BBB percentile, which is a concern.

**Caco-2 Permeability:** Ligand A (-4.502) has poor Caco-2 permeability, which is concerning. Ligand B (-5.691) is also poor, but slightly worse.

**Aqueous Solubility:** Ligand A (-4.716) has poor aqueous solubility, consistent with its high logP. Ligand B (-0.538) has slightly better solubility, but still not ideal.

**hERG Inhibition:** Ligand A (0.836) has a low hERG risk. Ligand B (0.037) has a very low hERG risk, which is a positive.

**Microsomal Clearance:** Ligand A (59.468) has moderate microsomal clearance. Ligand B (-7.926) has negative clearance, which is unusual and likely indicates very high metabolic stability.

**In vitro Half-Life:** Ligand A (49.525) has a moderate in vitro half-life. Ligand B (9.248) has a very short half-life.

**P-gp Efflux:** Ligand A (0.162) has low P-gp efflux, which is good for CNS penetration. Ligand B (0.001) has very low P-gp efflux, even better.

**Binding Affinity:** Ligand A (-8.5 kcal/mol) has a significantly stronger binding affinity than Ligand B (-7.8 kcal/mol). This 1.7 kcal/mol difference is substantial and can outweigh some ADME drawbacks.

**Overall Assessment:**

Ligand A has a stronger binding affinity and better BBB penetration, which are crucial for a CNS GPCR target. However, it suffers from poor solubility, poor Caco-2 permeability, and moderate DILI risk. Ligand B has a better safety profile (lower DILI, hERG) and excellent P-gp efflux properties, but its low logP and weaker binding affinity are significant drawbacks.

Given the importance of affinity for GPCRs, and the relatively good BBB value for Ligand A, I believe **Ligand A** is the more promising candidate, despite its ADME liabilities. The stronger binding could potentially be optimized through further structural modifications to improve solubility and permeability, while maintaining the desired CNS penetration.

Output:
0
2025-04-17 04:43:24,391 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (346.431 and 346.387 Da) fall comfortably within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (86.63) is excellent, well below the 90 A^2 threshold for CNS targets. Ligand B (108.46) is still reasonable, but less optimal, being above 90 A^2.

**3. logP:** Ligand A (0.868) is slightly below the optimal 1-3 range, potentially impacting permeability. Ligand B (0.588) is even lower, raising more concerns about permeability.

**4. H-Bond Donors:** Ligand A (1) is good. Ligand B (2) is acceptable.

**5. H-Bond Acceptors:** Ligand A (5) is good. Ligand B (6) is acceptable.

**6. QED:** Ligand A (0.855) is excellent, indicating high drug-likeness. Ligand B (0.36) is poor, suggesting potential issues.

**7. DILI:** Both ligands have relatively low DILI risk (30.399 and 35.285), which is positive.

**8. BBB:** Ligand A (58.511) is suboptimal for a CNS target, falling below the desirable >70 percentile. Ligand B (64.482) is also suboptimal. However, the other properties of A are more favorable.

**9. Caco-2:** Ligand A (-4.851) and Ligand B (-5.381) both have negative values, which is unusual and suggests very poor permeability. This is a significant concern for both.

**10. Solubility:** Ligand A (-0.653) and Ligand B (-2.749) both have negative solubility values, indicating poor aqueous solubility. Ligand B is worse.

**11. hERG:** Both ligands have low hERG risk (0.361 and 0.556), which is good.

**12. Cl_mic:** Ligand A (8.284) has a lower microsomal clearance, indicating better metabolic stability than Ligand B (-4.218).

**13. t1/2:** Ligand A (4.697) has a better in vitro half-life than Ligand B (-21.26).

**14. Pgp:** Both ligands have very low Pgp efflux liability (0.044 and 0.026), which is excellent for CNS penetration.

**15. Binding Affinity:** Both ligands have excellent binding affinity (-8.4 and -8.5 kcal/mol). The difference is negligible.

**Overall Assessment:**

Despite both ligands having excellent binding affinity, Ligand A is the better candidate. It has a significantly better QED score, lower DILI, better metabolic stability (lower Cl_mic, longer t1/2), and a slightly better TPSA. While both have poor Caco-2 and solubility, Ligand A's other properties are more favorable for a CNS-targeting drug. The slightly lower logP of Ligand A is a concern, but less problematic than the poor QED and solubility of Ligand B. The BBB values for both are suboptimal, but can be addressed with further optimization.

Output:
0
2025-04-17 04:43:24,391 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (348.363 Da) is slightly lower, which could be beneficial for permeability. Ligand B (379.36 Da) is also good.

**TPSA:** Ligand A (137.24) is slightly above the preferred <90 for CNS targets, but still reasonable. Ligand B (102.76) is better, falling comfortably below 90, suggesting better CNS penetration potential.

**logP:** Ligand A (-1.178) is a bit low, potentially hindering membrane permeability. Ligand B (0.431) is closer to the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Both have 3 HBD and are within acceptable limits. Ligand A has 7 HBA, while Ligand B has 6. Both are acceptable, but lower is generally preferred.

**QED:** Both ligands have good QED scores (A: 0.597, B: 0.663), indicating good drug-like properties.

**DILI:** Both ligands have similar, moderately high DILI risk (A: 60.799, B: 61.07). This is a concern, but not a deal-breaker at this stage.

**BBB:** This is crucial for a CNS target. Ligand A has a BBB percentile of 13.61, which is very low and a significant drawback. Ligand B has a much better BBB percentile of 41.838, making it substantially more likely to reach the brain.

**Caco-2 Permeability:** Ligand A (-6.187) has poor Caco-2 permeability, consistent with its low logP. Ligand B (-5.325) is also poor, but slightly better than A.

**Aqueous Solubility:** Both have very poor aqueous solubility (A: -0.976, B: -2.662). This could pose formulation challenges.

**hERG:** Both ligands show very low hERG inhibition liability (A: 0.029, B: 0.138), which is excellent.

**Microsomal Clearance:** Ligand A (-22.888) has lower (better) microsomal clearance than Ligand B (-19.571), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand B (-26.208) has a significantly longer in vitro half-life than Ligand A (-1.81), which is a major advantage.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (A: 0.006, B: 0.015), which is favorable for CNS penetration.

**Binding Affinity:** Both ligands have the same binding affinity (-8.5 kcal/mol), which is excellent and strong.

**Conclusion:**

While both ligands have good binding affinity and low hERG risk, Ligand B is significantly better overall for DRD2 targeting. Its superior BBB penetration (41.838 vs 13.61), better logP, and longer half-life outweigh the slightly higher microsomal clearance and poorer solubility compared to Ligand A. The poor solubility is a concern for both, but can be addressed with formulation strategies. Ligand A's extremely low BBB penetration makes it a much less viable candidate.

Output:
1
2025-04-17 04:43:24,391 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (388.291 Da) is slightly higher than Ligand B (335.363 Da), but both are acceptable.

**TPSA:** Ligand A (64.63) is significantly better than Ligand B (84.08). For CNS targets, we want TPSA <= 90, and ideally lower. Ligand A is much closer to the ideal range.

**logP:** Both ligands have good logP values (A: 3.783, B: 2.679) falling within the optimal 1-3 range. Ligand A is slightly higher, which could potentially lead to off-target effects, but is still within an acceptable range.

**H-Bond Donors/Acceptors:** Ligand A (HBD=1, HBA=4) and Ligand B (HBD=2, HBA=4) both have reasonable H-bond properties, well within the guidelines.

**QED:** Ligand A (0.754) has a better QED score than Ligand B (0.555), indicating a more drug-like profile.

**DILI:** Ligand B (90.112) has a significantly higher DILI risk than Ligand A (51.687). This is a major concern for Ligand B.

**BBB:** Ligand A (64.366) has a much better BBB penetration percentile than Ligand B (54.246). For a CNS target like DRD2, >70% is desirable, and Ligand A is closer to this threshold.

**Caco-2 Permeability:** Ligand A (-4.313) and Ligand B (-5.168) both have negative values, indicating poor permeability. This is a concern for both, but the scale is not clearly defined.

**Aqueous Solubility:** Both ligands have very poor aqueous solubility (-4.858 and -4.833 respectively). This is a significant drawback for both, potentially hindering formulation and bioavailability.

**hERG Inhibition:** Ligand A (0.253) has a lower hERG inhibition liability than Ligand B (0.572), which is preferable.

**Microsomal Clearance:** Ligand A (96.681) has higher microsomal clearance than Ligand B (88.599), meaning it's metabolized faster. This is a negative for Ligand A.

**In vitro Half-Life:** Ligand B (-12.756) has a negative half-life, which is not possible. This is likely an error in the data, and makes it difficult to assess its metabolic stability. Ligand A (8.974) has a reasonable half-life.

**P-gp Efflux:** Ligand A (0.109) has much lower P-gp efflux liability than Ligand B (0.241), which is beneficial for CNS penetration.

**Binding Affinity:** Ligand B (-9.7 kcal/mol) has a significantly stronger binding affinity than Ligand A (-7.6 kcal/mol). This is a substantial advantage for Ligand B, potentially outweighing some of its ADME drawbacks. A difference of >1.5 kcal/mol is considered significant.

**Overall Assessment:**

While Ligand B boasts a superior binding affinity, its significantly higher DILI risk, lower BBB penetration, and questionable half-life are major concerns. Ligand A, despite its weaker affinity, presents a much more favorable ADME profile, particularly regarding CNS penetration (BBB, Pgp), and safety (DILI, hERG). Given the GPCR-specific priorities for DRD2, the better ADME properties of Ligand A, especially the improved BBB and lower toxicity, make it the more promising candidate. The affinity difference, while substantial, might be addressable through further optimization of Ligand A.

Output:
0
2025-04-17 04:43:24,392 - INFO - Batch 137 complete. Total preferences: 2192
2025-04-17 04:43:24,392 - INFO - Processing batch 138/512...
2025-04-17 04:44:05,518 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 drug candidates, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (353.438 Da and 351.437 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (64.09) is higher than Ligand B (29.54). For CNS targets, TPSA should be <= 90, so both are acceptable, but B is significantly better.

**3. logP:** Ligand A (0.249) is quite low, potentially hindering membrane permeability. Ligand B (4.179) is higher, approaching the upper limit but still within the acceptable range of 1-3. This favors B.

**4. H-Bond Donors:** Ligand A (1) is good. Ligand B (0) is also good.

**5. H-Bond Acceptors:** Ligand A (4) is good. Ligand B (2) is also good.

**6. QED:** Both ligands have similar QED values (0.787 and 0.796), indicating good drug-likeness.

**7. DILI:** Ligand A (8.143) has a very low DILI risk. Ligand B (21.442) is higher, but still relatively low and acceptable.

**8. BBB:** This is a critical parameter for CNS targets. Ligand A (68.36) is below the desirable threshold of >70. Ligand B (96.743) is excellent, indicating high potential for brain penetration. This is a major advantage for B.

**9. Caco-2 Permeability:** Both have negative values, which is unusual. Assuming these are percentile scores, Ligand A (-4.819) is worse than Ligand B (-4.214).

**10. Aqueous Solubility:** Both have negative values, which is unusual. Assuming these are percentile scores, Ligand A (-0.823) is worse than Ligand B (-5.125).

**11. hERG Inhibition:** Ligand A (0.521) has a lower hERG risk than Ligand B (0.873), which is preferable.

**12. Microsomal Clearance:** Ligand A (7.647) has lower clearance, suggesting better metabolic stability than Ligand B (73.39).

**13. In vitro Half-Life:** Ligand B (19.794) has a significantly longer half-life than Ligand A (3.542), which is desirable.

**14. P-gp Efflux:** Ligand A (0.031) has very low P-gp efflux, which is excellent. Ligand B (0.541) is higher, but still relatively low.

**15. Binding Affinity:** Ligand B (-8.8 kcal/mol) has a stronger binding affinity than Ligand A (-7.8 kcal/mol). The difference is 1 kcal/mol, which is significant.

**Overall Assessment:**

Ligand B is the stronger candidate. While Ligand A has better hERG and P-gp profiles, Ligand B excels in the most critical areas for a CNS-targeting GPCR: BBB penetration and binding affinity. The higher logP and longer half-life of B also contribute to its favorability. The slightly higher DILI risk and P-gp efflux are less concerning given the substantial advantages in BBB and affinity.

Output:
1
2025-04-17 04:44:05,519 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (372.734 and 342.399 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (83.81) is better than Ligand B (87.32). Both are below the 90 A^2 threshold for CNS targets, which is good.

**3. logP:** Ligand A (4.023) is slightly higher than the optimal 1-3 range, but still potentially acceptable. Ligand B (1.512) is on the low side, potentially hindering permeability.

**4. H-Bond Donors:** Both ligands have 2 HBD, which is within the acceptable limit of <=5.

**5. H-Bond Acceptors:** Both ligands have 4 HBA, which is within the acceptable limit of <=10.

**6. QED:** Both ligands have good QED scores (0.727 and 0.833), indicating good drug-like properties.

**7. DILI:** Ligand A (98.255) has a very high DILI risk, which is a significant concern. Ligand B (63.978) has a moderate DILI risk, which is much better.

**8. BBB:** Ligand A (70.997) has a good BBB penetration percentile, desirable for a CNS target. Ligand B (43.273) has a poor BBB penetration percentile, which is a major drawback.

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 values, which is unusual and suggests poor permeability. However, these values are on a different scale and are difficult to interpret without further information.

**10. Aqueous Solubility:** Both ligands have negative solubility values, which is also unusual and suggests poor solubility.

**11. hERG Inhibition:** Both ligands have low hERG inhibition risk (0.353 and 0.236).

**12. Microsomal Clearance:** Ligand A (51.721) has higher microsomal clearance than Ligand B (25.148), indicating lower metabolic stability.

**13. In vitro Half-Life:** Ligand B (-24.151) has a negative half-life, which is not physically possible and suggests an issue with the data. Ligand A (20.539) has a reasonable half-life.

**14. P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.197 and 0.094), which is favorable for CNS penetration.

**15. Binding Affinity:** Both ligands have excellent binding affinities (-9.2 and -8.5 kcal/mol). Ligand A is slightly better (-9.2 kcal/mol).

**Overall Assessment:**

Ligand A has a better binding affinity and BBB penetration, but suffers from a very high DILI risk and higher metabolic clearance. Ligand B has a better safety profile (lower DILI) and metabolic stability, but has poor BBB penetration and a questionable half-life value.

Given the GPCR-specific priorities, BBB penetration is crucial for CNS targets like DRD2. However, the extremely high DILI risk associated with Ligand A is a major red flag. While a strong affinity is important, a high risk of liver injury is likely to derail development. The negative half-life for Ligand B is also concerning, suggesting a data quality issue.

Despite the questionable half-life, Ligand B is the more promising candidate due to its significantly lower DILI risk. Further investigation is needed to clarify the half-life data, but the lower toxicity profile makes it a better starting point for optimization.

Output:
1
2025-04-17 04:44:05,519 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 drug candidates, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (362.455 Da) is slightly higher than Ligand B (344.499 Da), but both are acceptable.

**TPSA:** Ligand A (97.12) is borderline for CNS penetration, being above the preferred <90 threshold, while Ligand B (49.41) is excellent, well below 90. This is a significant advantage for Ligand B.

**logP:** Both ligands have acceptable logP values (Ligand A: 1.93, Ligand B: 3.276), falling within the optimal 1-3 range. Ligand B is closer to the upper limit, which *could* raise solubility concerns, but is still acceptable.

**H-Bond Donors/Acceptors:** Ligand A has 2 HBD and 6 HBA, while Ligand B has 1 HBD and 2 HBA. Both are within the desirable limits (HBD <= 5, HBA <= 10).

**QED:** Both ligands have reasonable QED scores (Ligand A: 0.784, Ligand B: 0.687), indicating good drug-like properties.

**DILI:** Ligand A has a higher DILI risk (69.135%) than Ligand B (14.889%). This is a substantial difference, favoring Ligand B.

**BBB:** Ligand B has a significantly higher BBB penetration percentile (73.401%) than Ligand A (52.191%). This is crucial for a CNS target like DRD2 and strongly favors Ligand B.

**Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and likely indicates a problem with the prediction method. We'll proceed cautiously with this metric.

**Aqueous Solubility:** Both ligands have negative solubility values, also likely an artifact of the prediction.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (Ligand A: 0.102, Ligand B: 0.46).

**Microsomal Clearance:** Ligand B has a higher microsomal clearance (69.006) than Ligand A (36.2), suggesting lower metabolic stability. This is a negative for Ligand B.

**In vitro Half-Life:** Ligand A has a significantly longer in vitro half-life (-12.789 hours) than Ligand B (0.883 hours). This is a strong advantage for Ligand A.

**P-gp Efflux:** Ligand A has lower P-gp efflux liability (0.16) than Ligand B (0.318), which is preferable for CNS penetration.

**Binding Affinity:** Both ligands have very similar binding affinities (-8.1 kcal/mol and -8.2 kcal/mol). The difference is negligible.

**Overall Assessment:**

Ligand B excels in key properties for a CNS-targeting GPCR: TPSA, BBB penetration, and DILI risk. While its microsomal clearance is higher (less desirable), the substantial advantage in BBB penetration and lower toxicity risk outweigh this drawback. Ligand A has better metabolic stability and P-gp efflux, but its higher TPSA and lower BBB penetration are significant liabilities. Given the importance of CNS penetration for DRD2, Ligand B is the more promising candidate.

Output:
1
2025-04-17 04:44:05,519 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (348.487) is slightly better positioned.

**TPSA:** Ligand A (67.43) is excellent for CNS penetration, well below the 90 A^2 threshold. Ligand B (98.66) is higher, but still potentially acceptable, though less ideal.

**logP:** Ligand A (3.59) is optimal. Ligand B (0.59) is quite low, potentially hindering membrane permeability and CNS entry.

**H-Bond Donors & Acceptors:** Both have acceptable HBD counts (2). Ligand B has a higher HBA count (7) compared to Ligand A (3), but both are within the acceptable limit of 10.

**QED:** Both ligands have good QED scores (A: 0.717, B: 0.661), indicating generally drug-like properties.

**DILI:** Ligand A (36.099) has a lower DILI risk than Ligand B (46.103), which is preferable.

**BBB:** Ligand A (73.827) has a significantly better BBB percentile than Ligand B (50.756). This is a critical advantage for a CNS target like DRD2.

**Caco-2 Permeability:** Ligand A (-4.627) shows poor Caco-2 permeability, which is a concern. Ligand B (-5.358) is also poor, but slightly worse.

**Aqueous Solubility:** Ligand A (-3.356) has slightly better solubility than Ligand B (-1.108), although both are quite poor.

**hERG Inhibition:** Ligand A (0.736) has a slightly better hERG profile than Ligand B (0.274), indicating lower cardiotoxicity risk.

**Microsomal Clearance:** Ligand A (57.942) has a moderate clearance, while Ligand B (8.742) has very low clearance, suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (25.831) has a moderate half-life, while Ligand B (9.341) has a shorter half-life.

**P-gp Efflux:** Ligand A (0.228) shows lower P-gp efflux, which is favorable for CNS penetration. Ligand B (0.064) has even lower P-gp efflux, which is excellent.

**Binding Affinity:** Ligand A (-8.8 kcal/mol) has a significantly stronger binding affinity than Ligand B (-7.7 kcal/mol). This difference of 1.1 kcal/mol is substantial and can outweigh some ADME drawbacks.

**Overall Assessment:**

Ligand A excels in key areas for a CNS-targeting GPCR ligand: TPSA, BBB, and especially binding affinity. While its Caco-2 permeability and solubility are poor, the strong binding and good BBB penetration are major advantages. Ligand B has better metabolic stability and P-gp efflux, but suffers from a low logP and significantly weaker binding affinity. The affinity difference is the deciding factor. The stronger binding of Ligand A is likely to translate to greater efficacy, and the better BBB penetration will ensure sufficient brain exposure.

Output:
1
2025-04-17 04:44:05,519 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 drug candidates, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight (MW):** Both ligands are within the ideal range (200-500 Da). Ligand A (384.908 Da) is slightly higher than Ligand B (351.535 Da), but both are acceptable.

**2. TPSA:** Ligand A (47.61) is better than Ligand B (52.65). Both are below the 90 A^2 threshold for CNS targets, which is good.

**3. logP:** Both ligands have good logP values (Ligand A: 1.921, Ligand B: 2.815), falling within the optimal 1-3 range.

**4. H-Bond Donors (HBD):** Both ligands have acceptable HBD counts (Ligand A: 2, Ligand B: 1), well below the 5 limit.

**5. H-Bond Acceptors (HBA):** Both ligands have acceptable HBA counts (Ligand A: 3, Ligand B: 3), below the 10 limit.

**6. QED:** Ligand A (0.763) has a better QED score than Ligand B (0.486), indicating a more drug-like profile.

**7. DILI:** Ligand A (35.556) has a significantly lower DILI risk than Ligand B (14.618), which is a major advantage.

**8. BBB:** Ligand A (75.107) has a better BBB percentile than Ligand B (69.678). Both are reasonably good for a CNS target, but Ligand A is preferable.

**9. Caco-2 Permeability:** Both have negative values which is unusual. Assuming these are log scale values, Ligand A (-4.965) is better than Ligand B (-4.704).

**10. Aqueous Solubility:** Both have negative values which is unusual. Assuming these are log scale values, Ligand A (-3.646) is better than Ligand B (-2.748).

**11. hERG Inhibition:** Both ligands have low hERG inhibition risk (Ligand A: 0.593, Ligand B: 0.438).

**12. Microsomal Clearance (Cl_mic):** Ligand A (-23.414) has a much lower (better) microsomal clearance than Ligand B (46.091), indicating greater metabolic stability.

**13. In vitro Half-Life:** Ligand A (-0.537) has a shorter half-life than Ligand B (10.313). This is a drawback for Ligand A.

**14. P-gp Efflux:** Ligand A (0.183) has lower P-gp efflux than Ligand B (0.108), which is beneficial for CNS penetration.

**15. Binding Affinity:** Ligand A (-7.8 kcal/mol) has a better binding affinity than Ligand B (-6.6 kcal/mol). The difference of 1.2 kcal/mol is significant and can outweigh some of the ADME drawbacks.

**Overall Assessment:**

Ligand A is the superior candidate. It demonstrates a significantly lower DILI risk, better BBB penetration, lower microsomal clearance (better metabolic stability), and a stronger binding affinity. While Ligand A has a shorter in vitro half-life, its other advantages, particularly the superior affinity and safety profile, make it the more promising drug candidate for a CNS target like DRD2.

Output:
1
2025-04-17 04:44:05,520 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (342.439 Da) is slightly better positioned.

**TPSA:** Ligand A (78.43) is excellent for CNS penetration, well below the 90 A^2 threshold. Ligand B (134.67) is higher, potentially hindering BBB penetration, though still within an acceptable range for some CNS drugs.

**logP:** Ligand A (2.358) is optimal. Ligand B (0.921) is a bit low, potentially impacting membrane permeability.

**H-Bond Donors/Acceptors:** Both have 3 HBD, which is good. Ligand A has 3 HBA, while Ligand B has 7. Higher HBA can sometimes reduce permeability.

**QED:** Both ligands have similar and acceptable QED values (A: 0.603, B: 0.646).

**DILI:** Ligand A (19.969) has a much lower DILI risk than Ligand B (81.427), a significant advantage.

**BBB:** Ligand A (42.497) has a better BBB percentile than Ligand B (37.418), though both are below the desirable >70% for CNS targets.

**Caco-2 Permeability:** Ligand A (-5.135) has a more negative Caco-2 value, suggesting lower permeability. Ligand B (-5.343) is similar, indicating poor intestinal absorption for both.

**Aqueous Solubility:** Both have very poor aqueous solubility (-2.689 and -3.142 respectively). This is a concern for both compounds.

**hERG:** Both ligands have very low hERG risk (0.307 and 0.083 respectively).

**Microsomal Clearance:** Ligand B (18.17) has lower microsomal clearance than Ligand A (43.417), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (19.728) has a longer half-life than Ligand B (6.51), which is favorable.

**P-gp Efflux:** Ligand A (0.198) has lower P-gp efflux than Ligand B (0.071), which is better for CNS exposure.

**Binding Affinity:** Both ligands have very similar and excellent binding affinities (-8.7 and -8.6 kcal/mol). The difference is negligible.

**Overall Assessment:**

Considering the GPCR-specific priorities, Ligand A is the better candidate. Its superior TPSA, logP, lower DILI risk, and better BBB penetration (even if still suboptimal) outweigh the slightly lower Caco-2 permeability and higher clearance. The binding affinity is essentially the same for both. The lower P-gp efflux for Ligand A is also a plus for CNS penetration. While solubility is poor for both, this can be addressed with formulation strategies.

Output:
0
2025-04-17 04:44:05,520 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (347.419 Da) is slightly lower, which could be beneficial for permeability, but both are acceptable.

**TPSA:** Ligand A (100.21) is slightly above the optimal <90 for CNS targets, but still reasonable. Ligand B (76.66) is excellent, falling well within the desired range. This favors Ligand B.

**logP:** Ligand A (0.074) is quite low, potentially hindering membrane permeability and CNS penetration. Ligand B (1.335) is much better, falling within the optimal 1-3 range. This is a significant advantage for Ligand B.

**H-Bond Donors/Acceptors:** Both ligands have 2 HBD and 5 HBA, which are within acceptable limits.

**QED:** Both ligands have similar QED values (0.649 and 0.661), indicating good drug-likeness.

**DILI:** Ligand A (57.387) has a higher DILI risk than Ligand B (33.656). Lower is better, so Ligand B is preferred.

**BBB:** Both ligands have reasonably good BBB penetration (Ligand A: 65.839, Ligand B: 62.544). However, a value >70 is desirable for CNS targets, and neither quite reaches this.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.445 and -5.493), which is unusual and suggests poor permeability. This is a concern for both.

**Aqueous Solubility:** Both ligands have very poor aqueous solubility (-1.748 and -1.878). This could pose formulation challenges.

**hERG Inhibition:** Both ligands show low hERG inhibition risk (0.07 and 0.276), which is positive.

**Microsomal Clearance:** Ligand A (7.459) has significantly lower microsomal clearance than Ligand B (24.113), indicating better metabolic stability. This favors Ligand A.

**In vitro Half-Life:** Ligand B (13.845) has a longer in vitro half-life than Ligand A (-7.994), which is generally desirable. This favors Ligand B.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.023 and 0.055), which is excellent for CNS penetration.

**Binding Affinity:** Ligand B (-8.1 kcal/mol) has a slightly better binding affinity than Ligand A (-7.1 kcal/mol). While both are good, the 1.0 kcal/mol difference is significant and can outweigh some ADME drawbacks.

**Overall Assessment:**

Ligand B is the stronger candidate. While both have poor solubility and Caco-2 permeability, Ligand B excels in key GPCR-relevant properties: a more optimal logP, lower DILI risk, and a better binding affinity. The longer half-life is also a plus. Ligand A's lower clearance is attractive, but the significantly lower logP and weaker binding are more concerning for a CNS-targeting drug.

Output:
1
2025-04-17 04:44:05,520 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (345.443 Da) is slightly lower, which could be beneficial for permeability, but both are acceptable.

**TPSA:** Both ligands have TPSA values (75.44 and 76.14) that are above the optimal <90 for CNS targets, but still reasonable.

**logP:** Both ligands have logP values (2.847 and 3.011) within the optimal range of 1-3.

**H-Bond Donors/Acceptors:** Ligand A (HBD=1, HBA=4) is better than Ligand B (HBD=2, HBA=6) in terms of H-bonding potential, being closer to the ideal ranges.

**QED:** Ligand A (0.852) has a significantly higher QED score than Ligand B (0.65), indicating a more drug-like profile.

**DILI:** Both ligands have DILI risk around the 60 percentile, suggesting moderate risk. Ligand A (60.295) is slightly better.

**BBB:** Ligand B (85.692) has a significantly higher BBB penetration percentile than Ligand A (74.254). This is a crucial advantage for a CNS target like DRD2.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values, which is unusual and potentially problematic. It suggests poor permeability. However, the scale is not specified, so we cannot definitively assess this.

**Aqueous Solubility:** Both ligands have negative solubility values, which is also unusual and potentially problematic.

**hERG Inhibition:** Both ligands show low hERG inhibition liability (0.154 and 0.279), which is favorable.

**Microsomal Clearance:** Both ligands have similar microsomal clearance values (64.782 and 62.192), suggesting moderate metabolic stability.

**In vitro Half-Life:** Ligand B (-7.152 hours) has a much longer in vitro half-life than Ligand A (-27.179 hours). This is a significant advantage.

**P-gp Efflux:** Both ligands show low P-gp efflux liability (0.367 and 0.168), which is good. Ligand B is slightly better.

**Binding Affinity:** Ligand B (-8.1 kcal/mol) has a significantly stronger binding affinity than Ligand A (-0.0 kcal/mol). This is a major advantage, potentially outweighing some of the ADME drawbacks.

**Overall Assessment:**

Ligand B is the stronger candidate. While Ligand A has better QED and slightly lower DILI, Ligand B's significantly higher BBB penetration and *much* stronger binding affinity are critical for a CNS GPCR target. The longer half-life of Ligand B is also a significant benefit. The negative values for Caco-2 and solubility are concerning for both, but the superior binding and BBB penetration of Ligand B make it the more promising candidate.

Output:
1
2025-04-17 04:44:05,520 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B based on the provided guidelines, prioritizing GPCR-specific properties (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (410.316 Da) is slightly higher than Ligand B (341.371 Da), but both are acceptable.

**TPSA:** Ligand A (67.4) is better than Ligand B (79.51). For CNS targets, we want TPSA <= 90, and ideally closer to 60. Ligand A is closer to the ideal range.

**logP:** Ligand A (2.319) is optimal (1-3), while Ligand B (0.783) is a bit low, potentially hindering permeability.

**H-Bond Donors/Acceptors:** Both ligands have 0 HBD and 6 HBA, which are within acceptable limits.

**QED:** Both ligands have acceptable QED values (A: 0.731, B: 0.61), indicating good drug-like properties.

**DILI:** Ligand A (21.171) has a significantly lower DILI risk than Ligand B (62.737), making it safer from a liver toxicity perspective.

**BBB:** Ligand A (72.431) has a better BBB penetration percentile than Ligand B (63.552). Both are reasonably good, but A is preferable for a CNS target like DRD2.

**Caco-2 Permeability:** Ligand A (-5.342) and Ligand B (-4.843) both have negative values, indicating poor permeability. This is a concern for both.

**Aqueous Solubility:** Both ligands have very poor aqueous solubility (-1.59 and -1.574, respectively). This could pose formulation challenges.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.376 and 0.351, respectively).

**Microsomal Clearance:** Ligand A (7.121) has a lower microsomal clearance than Ligand B (26.659), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (34.77) has a longer half-life than Ligand B (-13.104), which is desirable.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.064 and 0.06, respectively), which is good for CNS penetration.

**Binding Affinity:** Ligand B (-8.1) has a slightly better binding affinity than Ligand A (-7.9), but the difference is only 0.2 kcal/mol. Given the other ADME properties, this difference is unlikely to be decisive.

**Overall Assessment:**

Ligand A is superior due to its better BBB penetration, lower DILI risk, better metabolic stability (lower Cl_mic and longer t1/2), and optimal logP. While both have poor Caco-2 permeability and solubility, the other advantages of Ligand A outweigh the slightly better affinity of Ligand B. The improved ADME profile of Ligand A makes it a more promising drug candidate for a CNS target like DRD2.

Output:
1
2025-04-17 04:44:05,521 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (350.423 and 344.415 Da) fall within the ideal range of 200-500 Da.

**TPSA:** Ligand A (128.01) is slightly above the optimal <90 for CNS targets, but still reasonable. Ligand B (87.46) is excellent, well below the 90 threshold.

**logP:** Ligand A (0.355) is quite low, potentially hindering permeability. Ligand B (0.982) is better, approaching the optimal range of 1-3.

**H-Bond Donors/Acceptors:** Ligand A (5 HBD, 4 HBA) is acceptable. Ligand B (2 HBD, 5 HBA) is also good.

**QED:** Both ligands have reasonable QED scores (0.455 and 0.784 respectively), with Ligand B being significantly better.

**DILI:** Both ligands have acceptable DILI risk (39.473 and 41.877), below the 40 threshold.

**BBB:** Ligand A (39.899) has a poor BBB percentile, which is a major concern for a CNS target like DRD2. Ligand B (33.075) is also low, but slightly better.

**Caco-2 Permeability:** Ligand A (-5.801) has very poor Caco-2 permeability. Ligand B (-4.871) is also poor, but slightly better.

**Aqueous Solubility:** Both ligands have very poor aqueous solubility (-1.469 and -1.473).

**hERG:** Both ligands have very low hERG inhibition risk (0.068 and 0.336).

**Microsomal Clearance:** Ligand A (-12.607) has excellent metabolic stability (low clearance). Ligand B (11.022) has moderate clearance, which is less desirable.

**In vitro Half-Life:** Ligand A (-3.006) has a very short half-life. Ligand B (20.857) has a much longer, and more favorable, half-life.

**P-gp Efflux:** Both ligands have very low P-gp efflux (0.006 and 0.065), which is good for CNS penetration.

**Binding Affinity:** Ligand B (-8.3 kcal/mol) has a slightly better binding affinity than Ligand A (-7.7 kcal/mol), although both are good.

**Overall Assessment:**

Ligand A suffers from very poor BBB penetration, poor Caco-2 permeability, and a short half-life, despite having good metabolic stability and acceptable DILI/hERG. The low logP is also a significant drawback.

Ligand B, while also having poor Caco-2 permeability and BBB penetration, has a better logP, a significantly better QED score, and a much longer half-life. The slightly stronger binding affinity is a bonus.

Given the GPCR-specific priorities, BBB penetration is crucial for a CNS target. While both are low, Ligand B's other properties are more favorable, making it a slightly better candidate. The longer half-life and better QED are significant advantages.

Output:
1
2025-04-17 04:44:05,521 - INFO - Reasoning:

Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (349.387 Da) is slightly lower, which could be beneficial for permeability. Ligand B (368.631 Da) is also good.

**2. TPSA:** Ligand A (92.95) is borderline for CNS targets (ideally <90), but acceptable. Ligand B (23.55) is excellent, well below the 90 threshold, suggesting better CNS penetration potential.

**3. logP:** Ligand A (0.742) is a bit low, potentially hindering membrane permeability. Ligand B (4.538) is high, potentially causing solubility issues and off-target effects.

**4. H-Bond Donors:** Both ligands have 0 HBD, which is good.

**5. H-Bond Acceptors:** Ligand A has 6 HBA, acceptable. Ligand B has 3 HBA, also acceptable.

**6. QED:** Ligand A (0.703) has a better QED score than Ligand B (0.529), indicating a more drug-like profile.

**7. DILI:** Ligand A (38.62) has a slightly higher DILI risk than Ligand B (10.237), but both are below the concerning threshold of 60.

**8. BBB:** Both ligands have good BBB penetration (Ligand A: 76.813, Ligand B: 73.75), but Ligand A is slightly better.

**9. Caco-2 Permeability:** Both have negative values, which is unusual. Assuming these are percentile scores, both are very poor.

**10. Aqueous Solubility:** Both have negative values, which is also unusual. Assuming these are percentile scores, both are very poor.

**11. hERG Inhibition:** Both ligands have very low hERG inhibition risk (Ligand A: 0.028, Ligand B: 0.854).

**12. Microsomal Clearance:** Ligand A (66.044) has lower clearance than Ligand B (85.615), suggesting better metabolic stability.

**13. In vitro Half-Life:** Ligand A (-17.227) has a negative half-life, which is impossible. Ligand B (20.431) has a reasonable half-life.

**14. P-gp Efflux:** Both ligands have low P-gp efflux liability (Ligand A: 0.023, Ligand B: 0.463).

**15. Binding Affinity:** Both ligands have similar binding affinities (Ligand A: -6.5 kcal/mol, Ligand B: -6.3 kcal/mol). The difference is not substantial enough to be decisive.

**Overall Assessment:**

Ligand B has a significantly better TPSA and a more favorable logP, which are crucial for CNS GPCR targets. However, its QED is lower, and its microsomal clearance is higher. The negative values for Caco-2 and solubility are concerning for both. The negative half-life for Ligand A is a showstopper.

Considering the GPCR-specific priorities and the overall profile, Ligand B is slightly more promising despite its higher logP, due to its superior TPSA and reasonable BBB penetration. The negative half-life of Ligand A makes it an unlikely candidate.

Output:
1
2025-04-17 04:44:05,521 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (359.348 and 345.418 Da) are within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (68.46) is better than Ligand B (61.44). Both are below the 90 A^2 threshold desirable for CNS targets, which is excellent.

**3. logP:** Both ligands have good logP values (2.439 and 2.147), falling within the optimal 1-3 range.

**4. H-Bond Donors:** Ligand A (0) is preferable to Ligand B (2). Fewer HBDs generally improve permeability.

**5. H-Bond Acceptors:** Ligand A (5) is preferable to Ligand B (3). Both are below the 10 threshold.

**6. QED:** Ligand A (0.826) has a significantly better QED score than Ligand B (0.588), indicating a more drug-like profile.

**7. DILI:** Both ligands have low DILI risk (41.411 and 39.434), which is good.

**8. BBB:** Ligand A (99.186) has a *much* higher BBB penetration score than Ligand B (70.105). This is a critical advantage for a CNS target like DRD2.

**9. Caco-2 Permeability:** Ligand A (-4.426) is slightly better than Ligand B (-4.777), but both are negative, indicating poor permeability.

**10. Aqueous Solubility:** Both ligands have poor aqueous solubility (-3.371 and -3.139). This could be a formulation challenge, but is less critical than BBB penetration for a CNS target.

**11. hERG Inhibition:** Ligand A (0.298) has a lower hERG inhibition liability than Ligand B (0.747), making it safer from a cardiotoxicity perspective.

**12. Microsomal Clearance:** Ligand B (18.237) has a significantly higher microsomal clearance than Ligand A (6.165). This means Ligand A is more metabolically stable.

**13. In vitro Half-Life:** Ligand A (1.262) has a shorter half-life than Ligand B (-3.77), which is a negative.

**14. P-gp Efflux:** Ligand A (0.115) has lower P-gp efflux liability than Ligand B (0.133), which is favorable for CNS exposure.

**15. Binding Affinity:** Ligand A (-8.0) has a slightly better binding affinity than Ligand B (-6.9). While both are good, the 1.1 kcal/mol difference is significant.

**Overall Assessment:**

Ligand A is the stronger candidate. Its superior BBB penetration, lower P-gp efflux, better QED, lower hERG risk, and better metabolic stability outweigh the slightly shorter half-life. The significantly better binding affinity further solidifies its advantage. While both have poor solubility and Caco-2 permeability, these are less crucial for a CNS-targeted GPCR where BBB penetration is paramount.

Output:
1
2025-04-17 04:44:05,521 - INFO - Reasoning:

Let's analyze Ligand A and Ligand B against the provided guidelines, prioritizing GPCR-specific properties (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (352.387 and 341.411 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (102.96) is slightly above the optimal <90 for CNS targets, while Ligand B (85.43) is comfortably within the range. This favors Ligand B.

**logP:** Ligand A (0.224) is quite low, potentially hindering permeation. Ligand B (1.517) is within the optimal 1-3 range. This is a significant advantage for Ligand B.

**H-Bond Donors/Acceptors:** Ligand A has 2 HBD and 6 HBA, while Ligand B has 3 HBD and 3 HBA. Both are acceptable within the guidelines.

**QED:** Ligand B (0.788) has a considerably higher QED score than Ligand A (0.368), indicating better overall drug-likeness.

**DILI:** Both ligands have acceptable DILI risk (Ligand A: 51.338, Ligand B: 45.522), below the 60 threshold.

**BBB:** Ligand A (60.45) is borderline for CNS penetration, while Ligand B (43.001) is lower. While both are not ideal, the other properties of Ligand B are more favorable.

**Caco-2 Permeability:** Both have negative Caco-2 values (-5.494 and -5.035), which is unusual and difficult to interpret without further context. It suggests poor permeability, but the scale isn't clearly defined.

**Aqueous Solubility:** Both have negative solubility values (-1.878 and -3.421), also unusual. Again, the scale is unclear, but suggests poor solubility.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (Ligand A: 0.098, Ligand B: 0.404).

**Microsomal Clearance:** Ligand A (20.695) has a higher microsomal clearance than Ligand B (10.532), suggesting lower metabolic stability.

**In vitro Half-Life:** Ligand B (-10.259) has a longer in vitro half-life than Ligand A (-17.196), which is favorable.

**P-gp Efflux:** Ligand A (0.044) has lower P-gp efflux liability than Ligand B (0.061), which is beneficial for CNS exposure.

**Binding Affinity:** Ligand B (-8.5 kcal/mol) has a slightly better binding affinity than Ligand A (-7.8 kcal/mol). While the difference is less than the 1.5 kcal/mol threshold, it contributes to the overall preference for Ligand B.

**Overall Assessment:**

Ligand B is significantly more promising. It has a better logP, QED, and in vitro half-life, and a slightly better binding affinity. While its BBB is not ideal, the combination of improved physicochemical properties and drug-likeness outweighs the slightly lower BBB score. Ligand A's very low logP is a major concern, likely leading to poor permeability. The negative Caco-2 and solubility values are concerning for both, but less critical than the logP and QED differences.

Output:
1
2025-04-17 04:44:05,521 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B based on the provided guidelines, prioritizing GPCR-specific properties (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (347.423 and 347.415 Da) fall within the ideal range of 200-500 Da.

**TPSA:** Ligand A (101.53) is slightly above the preferred <90 for CNS targets, while Ligand B (83.76) is well within the range. This favors Ligand B.

**logP:** Ligand A (0.823) is a bit low, potentially hindering permeability. Ligand B (2.722) is within the optimal 1-3 range. This favors Ligand B.

**H-Bond Donors/Acceptors:** Ligand A has 1 HBD and 7 HBA, which are acceptable. Ligand B has 0 HBD and 4 HBA, also acceptable.

**QED:** Ligand A (0.864) has a better QED score than Ligand B (0.561), indicating a more drug-like profile. This favors Ligand A.

**DILI:** Ligand A (24.622) has a significantly lower DILI risk than Ligand B (50.213). This strongly favors Ligand A.

**BBB:** Ligand A (75.223) and Ligand B (82.28) both have good BBB penetration, but Ligand B is slightly better. For a CNS target like DRD2, this is important, favoring Ligand B.

**Caco-2 Permeability:** Ligand A (-4.865) has poor Caco-2 permeability, while Ligand B (-4.495) is slightly better, but both are unfavorable.

**Aqueous Solubility:** Both ligands have poor aqueous solubility (-1.966 and -3.035 respectively).

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.78 and 0.682 respectively).

**Microsomal Clearance:** Ligand A (-25.612) has much lower microsomal clearance (better metabolic stability) than Ligand B (89.815). This strongly favors Ligand A.

**In vitro Half-Life:** Ligand A (15.487 hours) has a significantly longer half-life than Ligand B (0.26 hours). This favors Ligand A.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.006 and 0.246 respectively).

**Binding Affinity:** Both ligands have excellent binding affinity (-7.8 and -7.9 kcal/mol), with Ligand B being slightly better. This is a critical factor.

**Overall Assessment:**

While Ligand B has better TPSA, logP, and BBB penetration, Ligand A excels in crucial ADMET properties like DILI risk, microsomal clearance, and in vitro half-life. The slightly better binding affinity of Ligand B is not enough to overcome the significant metabolic liabilities of Ligand B. Considering the GPCR-specific priorities, the improved ADMET profile of Ligand A, particularly its lower DILI and better metabolic stability, makes it the more promising drug candidate.

Output:
0
2025-04-17 04:44:05,522 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, considering the provided guidelines and GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (348.403 and 355.37 Da) fall comfortably within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (124.34) is slightly above the preferred <90 for CNS targets, but still reasonable. Ligand B (113.53) is better, falling comfortably below 90.

**3. logP:** Ligand A (0.835) is a bit low, potentially hindering permeation. Ligand B (0.698) is also low, with similar concerns. Both are below the optimal 1-3 range.

**4. H-Bond Donors:** Ligand A (3) is acceptable. Ligand B (2) is also acceptable.

**5. H-Bond Acceptors:** Ligand A (6) is acceptable. Ligand B (7) is also acceptable.

**6. QED:** Ligand A (0.654) is good, indicating drug-like properties. Ligand B (0.55) is acceptable, but less ideal than A.

**7. DILI:** Ligand A (54.827) has a lower DILI risk than Ligand B (59.984), both are acceptable.

**8. BBB:** This is a critical parameter for CNS targets. Ligand A (20.861) has a very poor BBB penetration percentile. Ligand B (72.276) is much better, exceeding the desirable >70 threshold.

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.263 and -5.127), which is unusual and suggests poor permeability. This is a significant concern for both.

**10. Aqueous Solubility:** Both ligands have negative solubility values (-3.014 and -2.995), which is also unusual and suggests poor solubility. This is a significant concern for both.

**11. hERG Inhibition:** Both ligands have low hERG inhibition risk (0.266 and 0.327).

**12. Microsomal Clearance:** Ligand A (2.313) has a lower clearance, indicating better metabolic stability than Ligand B (11.297).

**13. In vitro Half-Life:** Ligand A (7.855) has a better in vitro half-life than Ligand B (-12.705).

**14. P-gp Efflux:** Both ligands have low P-gp efflux liability (0.067 and 0.064).

**15. Binding Affinity:** Ligand A (-7.7 kcal/mol) has a significantly stronger binding affinity than Ligand B (-6.8 kcal/mol). This >1.5 kcal/mol difference is substantial.

**Overall Assessment:**

Despite the unusual negative values for Caco-2 and solubility, the primary differentiating factor is the BBB penetration. Ligand B's significantly higher BBB percentile (72.276) compared to Ligand A (20.861) is crucial for a CNS target like DRD2. While Ligand A has better metabolic stability and a stronger binding affinity, the poor BBB penetration makes it less likely to reach the target in the brain. The substantial affinity difference of Ligand A is tempting, but cannot overcome the critical lack of brain exposure.

Output:
1
2025-04-17 04:44:05,522 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (342.399 and 371.503 Da) fall within the ideal 200-500 Da range.

**TPSA:** Both ligands have a TPSA of approximately 78-79 A<sup>2</sup>, which is excellent for CNS penetration, being well below the 90 A<sup>2</sup> threshold.

**logP:** Ligand A (1.968) is optimal, while Ligand B (0.109) is quite low. A logP below 1 can hinder permeation. This is a significant disadvantage for Ligand B.

**H-Bond Donors/Acceptors:** Ligand A has 1 HBD and 4 HBA, well within acceptable limits. Ligand B has 0 HBD and 5 HBA, also acceptable.

**QED:** Ligand A (0.925) has a very strong drug-like profile. Ligand B (0.662) is still reasonable, but less favorable.

**DILI:** Ligand A (68.244) has a moderate DILI risk, while Ligand B (21.753) has a very low DILI risk. This favors Ligand B.

**BBB:** Ligand A (67.08) has a good BBB penetration percentile, but Ligand B (52.811) is lower. For a CNS target like DRD2, a higher BBB value is preferred. Ligand A is better here.

**Caco-2 Permeability:** Both have negative Caco-2 values, indicating poor permeability. This is concerning for both, but the values are close.

**Aqueous Solubility:** Both ligands have negative solubility values, indicating poor solubility. This is a concern for both.

**hERG Inhibition:** Both ligands have very low hERG inhibition liability (0.343 and 0.116), which is excellent.

**Microsomal Clearance:** Ligand A (12.476 mL/min/kg) has a moderate clearance, while Ligand B (-8.189 mL/min/kg) has a negative clearance, which is unusual and suggests very high metabolic stability. This is a strong advantage for Ligand B.

**In vitro Half-Life:** Ligand A (-30.338 hours) has a negative half-life, which is also unusual and suggests very high stability. Ligand B (28.657 hours) is reasonable.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.018 and 0.019), which is good for CNS exposure.

**Binding Affinity:** Ligand A (-9.2 kcal/mol) has a significantly stronger binding affinity than Ligand B (-7.5 kcal/mol). This is a substantial advantage, potentially outweighing some ADME drawbacks. The difference of 1.7 kcal/mol is significant.

**Overall Assessment:**

Ligand A excels in binding affinity and has a good BBB score, but suffers from poor Caco-2 and solubility. Ligand B has a better safety profile (lower DILI, better metabolic stability) but significantly weaker binding affinity and a lower BBB score. Given the importance of affinity for GPCRs, and the substantial difference in binding energy (-9.2 vs -7.5 kcal/mol), Ligand A is the more promising candidate *despite* its ADME liabilities. The strong binding could potentially be optimized with further medicinal chemistry efforts to improve solubility and permeability.

Output:
0
2025-04-17 04:44:05,522 - INFO - Batch 138 complete. Total preferences: 2208
2025-04-17 04:44:05,522 - INFO - Processing batch 139/512...
2025-04-17 04:44:47,054 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (344.46 and 363.40 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (76.02) is significantly better than Ligand B (123.17). For CNS targets, we want TPSA <= 90, and A is comfortably within that, while B is pushing the limit.

**logP:** Ligand A (2.506) is optimal (1-3), while Ligand B (0.038) is quite low, potentially hindering membrane permeability.

**H-Bond Donors/Acceptors:** Both have 2 HBDs, which is good. Ligand A has 4 HBAs, while Ligand B has 7. Both are acceptable (<=10), but A is preferable.

**QED:** Both ligands have similar QED values (0.779 and 0.742), indicating good drug-likeness.

**DILI:** Ligand A (51.65) has a much lower DILI risk than Ligand B (89.996). This is a significant advantage for A.

**BBB:** Ligand A (58.51) is better than Ligand B (44.67), although both are below the desirable >70 for CNS targets. However, given the other properties, a better BBB score is valuable.

**Caco-2 Permeability:** Both have negative values (-4.8 and -4.915), which is unusual and requires further investigation. It's difficult to interpret without knowing the scale.

**Aqueous Solubility:** Both have negative values (-3.33 and -3.359), which is also unusual and requires further investigation.

**hERG Inhibition:** Both ligands show very low hERG inhibition liability (0.137 and 0.053), which is excellent.

**Microsomal Clearance:** Both have similar microsomal clearance (26.85 and 27.74), suggesting comparable metabolic stability.

**In vitro Half-Life:** Ligand A (11.09) has a positive half-life, while Ligand B (-45.58) has a negative half-life, which is concerning.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.075 and 0.009), which is favorable for CNS penetration.

**Binding Affinity:** Ligand A (-8.7 kcal/mol) has a slightly better binding affinity than Ligand B (-8.3 kcal/mol). While the difference isn't huge, it's still a positive factor.

**Overall Assessment:**

Ligand A is significantly better than Ligand B. It has a more favorable TPSA, logP, DILI score, and in vitro half-life. While both have low hERG and P-gp efflux, the combination of better ADME properties and slightly improved binding affinity makes Ligand A the more promising candidate. The negative Caco-2 and solubility values are concerning for both, but the other advantages of A outweigh this.

Output:
1
2025-04-17 04:44:47,054 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (351.447 and 364.555 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (78.95) is significantly better than Ligand B (49.41), falling well below the 90 A^2 threshold for CNS targets. Ligand B is also good, but A is preferable.

**logP:** Ligand A (0.104) is quite low, potentially hindering permeation. Ligand B (3.392) is within the optimal 1-3 range. This is a significant advantage for Ligand B.

**H-Bond Donors/Acceptors:** Both have 1 HBD, which is good. Ligand A has 4 HBA, while Ligand B has 3. Both are acceptable, below the 10 threshold.

**QED:** Both ligands have good QED scores (0.629 and 0.705), indicating good drug-like properties.

**DILI:** Ligand A (20.396) has a much lower DILI risk than Ligand B (33.307), which is a positive for A. Both are below the 40 threshold.

**BBB:** Ligand A (46.995) has a poor BBB percentile, a major drawback for a CNS target. Ligand B (58.24) is better, but still not ideal (aim for >70).

**Caco-2 Permeability:** Ligand A (-4.879) has very poor Caco-2 permeability. Ligand B (-4.98) is also poor, but slightly better.

**Aqueous Solubility:** Both ligands have very poor aqueous solubility (-0.892 and -4.112). This could pose formulation challenges.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.127 and 0.32), which is good.

**Microsomal Clearance:** Ligand A (16.964) has lower microsomal clearance than Ligand B (75.586), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (-6.875) has a negative half-life, which is unusual and concerning. Ligand B (6.893) has a reasonable half-life.

**P-gp Efflux:** Ligand A (0.009) has very low P-gp efflux, which is excellent for CNS penetration. Ligand B (0.278) is higher, but still reasonable.

**Binding Affinity:** Ligand B (-8.0) has a significantly stronger binding affinity than Ligand A (-6.5), a difference of 1.5 kcal/mol. This is a substantial advantage that can outweigh some ADME drawbacks.

**Overall Assessment:**

Ligand A has advantages in DILI, P-gp efflux, and microsomal clearance. However, its extremely poor BBB penetration, very low Caco-2 permeability, and unusual negative in vitro half-life are major concerns. The low logP is also problematic.

Ligand B, while having a higher DILI risk and P-gp efflux, boasts a significantly stronger binding affinity and a much better logP value. Its BBB penetration is still not ideal, but better than Ligand A. The reasonable half-life is also a plus.

Given the GPCR-specific priorities, the stronger binding affinity of Ligand B, combined with its more favorable logP, outweighs the slightly higher DILI and P-gp efflux. The poor BBB of both is a concern that would need to be addressed in further optimization, but the stronger starting point of Ligand B makes it the more promising candidate.

Output:
1
2025-04-17 04:44:47,054 - INFO - Reasoning:

Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (364.339 and 346.471 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (58.64) is excellent, well below the 90 A^2 threshold for CNS targets. Ligand B (78.43) is still reasonable but less optimal.

**3. logP:** Both ligands have good logP values (1.826 and 2.093), falling within the 1-3 range.

**4. H-Bond Donors:** Ligand A (1) is preferable to Ligand B (3). Fewer HBDs generally improve permeability.

**5. H-Bond Acceptors:** Both ligands have 3 HBA, which is acceptable.

**6. QED:** Ligand A (0.775) has a better QED score than Ligand B (0.53), indicating a more drug-like profile.

**7. DILI:** Ligand A (41.179) has a significantly lower DILI risk than Ligand B (14.579), which is a major advantage.

**8. BBB:** Ligand A (87.476) has a much higher BBB penetration percentile than Ligand B (43.156). This is *critical* for a CNS target like DRD2.

**9. Caco-2 Permeability:** Ligand A (-4.649) and Ligand B (-4.895) have similar, and poor Caco-2 permeability.

**10. Aqueous Solubility:** Ligand A (-3.749) and Ligand B (-2.256) have similar, and poor aqueous solubility.

**11. hERG:** Both ligands have very low hERG inhibition risk (0.42 and 0.11).

**12. Microsomal Clearance:** Ligand A (35.102) has a higher microsomal clearance than Ligand B (20.899), indicating lower metabolic stability.

**13. In vitro Half-Life:** Ligand B (-6.009) has a better (longer) in vitro half-life than Ligand A (-10.01).

**14. P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.12 and 0.062).

**15. Binding Affinity:** Ligand B (-8.6 kcal/mol) has a slightly better binding affinity than Ligand A (-7.9 kcal/mol). While a 0.7 kcal/mol difference is noticeable, it's not a huge gap and can be overcome with optimization.

**Overall Assessment:**

Ligand A is the superior candidate. The significantly better BBB penetration (87.476 vs 43.156) and lower DILI risk (41.179 vs 14.579) outweigh the slightly weaker affinity and higher clearance. For a CNS target, BBB penetration is paramount. The better QED score also supports Ligand A's drug-like properties. While both have poor Caco-2 and solubility, these can be addressed during lead optimization.

Output:
1
2025-04-17 04:44:47,054 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (342.418 and 345.443 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (62.46) is significantly better than Ligand B (84.23). For CNS targets, we want TPSA <= 90, and A is comfortably within this range, while B is approaching the upper limit.

**logP:** Both ligands have acceptable logP values (1.482 and 2.662, respectively), falling within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A has 1 HBD and 5 HBA, while Ligand B has 2 HBD and 4 HBA. Both are within acceptable limits (<=5 HBD and <=10 HBA).

**QED:** Ligand A (0.806) has a significantly better QED score than Ligand B (0.504). A higher QED suggests better drug-like properties.

**DILI:** Both ligands have low DILI risk (44.242 and 42.148, respectively), both below the 60 threshold.

**BBB:** Ligand A (84.374) has a much better BBB percentile than Ligand B (68.554). For a CNS target like DRD2, a BBB > 70 is highly desirable, and A is closer to this mark.

**Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and suggests poor permeability. However, the scale is not clearly defined, so it's hard to interpret.

**Aqueous Solubility:** Both have negative solubility values, which is also unusual. Again, the scale is unclear, but it suggests poor solubility.

**hERG:** Both ligands have very low hERG inhibition liability (0.93 and 0.07, respectively), indicating a low risk of cardiotoxicity.

**Microsomal Clearance:** Ligand A (38.188) has a lower microsomal clearance than Ligand B (64.825), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (-34.951) has a more negative (longer) in vitro half-life than Ligand B (-28.822).

**P-gp Efflux:** Ligand A (0.53) has a lower P-gp efflux liability than Ligand B (0.181), which is favorable for CNS penetration.

**Binding Affinity:** Ligand A (-9.4 kcal/mol) has a significantly stronger binding affinity than Ligand B (-7.7 kcal/mol). This is a crucial factor, and the 1.7 kcal/mol difference is substantial.

**Conclusion:**

Considering all factors, especially the GPCR-specific priorities for a CNS target, **Ligand A is the superior candidate**. It has better TPSA, BBB penetration, QED, metabolic stability (lower Cl_mic, longer t1/2), lower P-gp efflux, and significantly stronger binding affinity. While both have issues with Caco-2 and solubility, the superior CNS penetration and binding affinity of Ligand A outweigh these concerns.

Output:
1
2025-04-17 04:44:47,054 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 drug candidates, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (342.37 Da) is slightly lower, which can be advantageous for permeability.

**TPSA:** Ligand A (63.45) is better than Ligand B (49.77) as it is closer to the ideal range for CNS targets (<=90).

**logP:** Both ligands have good logP values (A: 3.989, B: 3.072), falling within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A (HBD=0, HBA=3) is preferable to Ligand B (HBD=1, HBA=4) as lower numbers generally improve CNS penetration.

**QED:** Both ligands have good QED scores (A: 0.623, B: 0.817), indicating good drug-like properties.

**DILI:** Ligand A (70.841) has a higher DILI risk than Ligand B (13.067). This is a significant drawback for Ligand A.

**BBB:** Ligand A (83.249) has a better BBB penetration percentile than Ligand B (76.735), which is crucial for a CNS target like DRD2.

**Caco-2 Permeability:** Ligand A (-4.541) has a worse Caco-2 permeability than Ligand B (-4.73).

**Aqueous Solubility:** Ligand A (-5.313) has worse aqueous solubility than Ligand B (-3.682).

**hERG:** Both ligands have similar hERG inhibition liability (A: 0.812, B: 0.862).

**Microsomal Clearance:** Ligand A (83.779) has a higher microsomal clearance than Ligand B (19.685), indicating lower metabolic stability.

**In vitro Half-Life:** Ligand B (34.006) has a longer in vitro half-life than Ligand A (21.38), which is desirable.

**P-gp Efflux:** Ligand A (0.52) has lower P-gp efflux liability than Ligand B (0.832), which is favorable for CNS penetration.

**Binding Affinity:** Both ligands have excellent binding affinities (A: -9.5 kcal/mol, B: -8.5 kcal/mol). Ligand A is 1 kcal/mol better, which is a substantial advantage.

**Overall Assessment:**

Ligand A excels in binding affinity, BBB penetration, and P-gp efflux. However, it suffers from higher DILI risk, worse solubility, and faster clearance. Ligand B has a better safety profile (lower DILI), better metabolic stability (lower Cl_mic, longer t1/2), and better solubility, but its affinity and BBB penetration are slightly lower.

Considering the GPCR-specific priorities, the strong binding affinity and good BBB penetration of Ligand A are very attractive. While the DILI risk is concerning, it might be mitigated through structural modifications. The difference in binding affinity (1 kcal/mol) is significant enough to potentially outweigh the ADME drawbacks, especially given the importance of potency for CNS targets.

Output:
1
2025-04-17 04:44:47,054 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B based on the provided guidelines, prioritizing GPCR-specific properties (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (346.515 and 351.382 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (40.62) is significantly better than Ligand B (109.14). For CNS targets, TPSA should be <= 90, and A is well within this, while B exceeds it. This is a substantial advantage for A.

**logP:** Ligand A (3.452) is optimal (1-3), while Ligand B (-0.456) is below 1, which may impede permeation. This is a significant advantage for A.

**H-Bond Donors/Acceptors:** Ligand A (0 HBD, 2 HBA) is preferable to Ligand B (3 HBD, 6 HBA) as it has fewer potential issues with permeability.

**QED:** Both ligands have reasonable QED scores (A: 0.782, B: 0.576), indicating drug-like properties.

**DILI:** Ligand A (15.277) has a much lower DILI risk than Ligand B (68.166). This is a significant advantage for A.

**BBB:** Ligand A (87.476) has excellent BBB penetration, exceeding the desirable >70% threshold. Ligand B (42.148) is considerably lower, raising concerns about CNS exposure. This is a critical advantage for A, given the target is DRD2.

**Caco-2 Permeability:** Ligand A (-4.742) and Ligand B (-5.314) both have negative values, which is unusual. However, the magnitude is similar, so this isn't a major differentiator.

**Aqueous Solubility:** Ligand A (-3.38) and Ligand B (-1.917) both have negative values, indicating poor solubility. This is a drawback for both, but less concerning for CNS drugs where BBB penetration is paramount.

**hERG Inhibition:** Ligand A (0.624) has a lower hERG risk than Ligand B (0.075). This is a slight advantage for A.

**Microsomal Clearance:** Ligand A (78.891) has higher clearance than Ligand B (-14.032). This suggests lower metabolic stability for A, a disadvantage.

**In vitro Half-Life:** Ligand A (-4.132) has a shorter half-life than Ligand B (-18.991). This is a disadvantage for A.

**P-gp Efflux:** Ligand A (0.341) has lower P-gp efflux than Ligand B (0.017), which is favorable for CNS penetration. This is an advantage for A.

**Binding Affinity:** Ligand A (-9.4 kcal/mol) has a significantly stronger binding affinity than Ligand B (-7.5 kcal/mol). This is a substantial advantage for A, and can outweigh some of the ADME drawbacks.

**Overall Assessment:**

Ligand A is clearly superior. It excels in key GPCR-specific properties (BBB, TPSA, logP, Pgp) and has a much stronger binding affinity. While it has some ADME liabilities (clearance, half-life), these are less critical for a CNS target, especially given the strong affinity. Ligand B's poor logP and BBB penetration are major drawbacks that significantly reduce its potential as a CNS drug candidate.

Output:
1
2025-04-17 04:44:47,055 - INFO - Reasoning:

Let's analyze Ligand A and Ligand B based on the provided guidelines, prioritizing GPCR-specific properties (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (366.53 and 342.40 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (67.43) is significantly better than Ligand B (100.97). For CNS targets, we want TPSA <= 90, so Ligand A is preferable.

**logP:** Ligand A (3.345) is optimal (1-3), while Ligand B (1.084) is on the lower side, potentially hindering permeability.

**H-Bond Donors/Acceptors:** Ligand A (HBD=2, HBA=4) and Ligand B (HBD=1, HBA=6) both fall within acceptable ranges.

**QED:** Both ligands have good QED scores (0.693 and 0.843), indicating drug-likeness.

**DILI:** Ligand A (31.563) has a much lower DILI risk than Ligand B (57.193), suggesting better safety.

**BBB:** Ligand A (74.952) has a significantly better BBB penetration score than Ligand B (64.056). This is *critical* for a CNS target like DRD2.

**Caco-2 Permeability:** Ligand A (-4.811) and Ligand B (-5.1) are both very poor. This is a concern for oral bioavailability, but less critical for a CNS target where direct delivery or other routes might be considered.

**Aqueous Solubility:** Ligand A (-3.371) and Ligand B (-1.194) are both poor. Solubility is a concern, but can be addressed with formulation strategies.

**hERG Inhibition:** Ligand A (0.591) has a lower hERG risk than Ligand B (0.062), which is a positive.

**Microsomal Clearance:** Ligand A (67.789) has higher clearance than Ligand B (13.114), indicating faster metabolism and potentially lower exposure.

**In vitro Half-Life:** Ligand A (30.197) has a slightly longer half-life than Ligand B (27.173).

**P-gp Efflux:** Ligand A (0.202) has lower P-gp efflux than Ligand B (0.006), which is favorable for CNS penetration.

**Binding Affinity:** Ligand B (-8.3) has a slightly better binding affinity than Ligand A (-8.1), but the difference is small (0.2 kcal/mol). Given the other significant advantages of Ligand A, this difference is unlikely to be decisive.

**Conclusion:**

Considering the GPCR-specific priorities, Ligand A is the more promising candidate. It has a significantly better TPSA, logP, BBB penetration, and DILI risk profile. While its Caco-2 permeability and aqueous solubility are poor, these can be addressed with formulation. The slightly weaker binding affinity is outweighed by the superior ADME properties, particularly the improved BBB penetration crucial for a CNS target.

Output:
1
2025-04-17 04:44:47,055 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (359.411 and 363.462 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (90.09) is slightly above the preferred <90 for CNS targets, but still reasonable. Ligand B (85) is excellent.

**logP:** Ligand A (0.643) is a bit low, potentially hindering permeability. Ligand B (2.858) is optimal.

**H-Bond Donors/Acceptors:** Ligand A has 0 HBD and 7 HBA, which is good. Ligand B has 1 HBD and 6 HBA, also good. Both are within acceptable limits.

**QED:** Both ligands have good QED scores (0.67 and 0.853), indicating drug-like properties.

**DILI:** Ligand A (85.149) has a higher DILI risk than Ligand B (61.574), though both are acceptable.

**BBB:** Ligand B (85.459) has a significantly better BBB penetration score than Ligand A (69.678). This is a critical advantage for a CNS target like DRD2.

**Caco-2 Permeability:** Ligand A (-5.026) shows poor Caco-2 permeability, suggesting poor absorption. Ligand B (-4.885) is also poor, but slightly better.

**Aqueous Solubility:** Both ligands have very poor aqueous solubility (-3.513 and -3.93). This could pose formulation challenges.

**hERG:** Both ligands have low hERG inhibition risk (0.208 and 0.454).

**Microsomal Clearance:** Ligand A (67.096) has higher microsomal clearance than Ligand B (34.842), indicating lower metabolic stability.

**In vitro Half-Life:** Ligand B (8.19 hours) has a significantly longer half-life than Ligand A (-26.307 hours - which is likely an error and should be interpreted as very short).

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.207 and 0.137), which is favorable for CNS penetration.

**Binding Affinity:** Ligand B (-7.4 kcal/mol) has a stronger binding affinity than Ligand A (-8.8 kcal/mol). While A is stronger, the difference isn't massive.

**Overall Assessment:**

Ligand B is the superior candidate. It excels in key areas for a CNS-targeting GPCR ligand: BBB penetration, logP, metabolic stability (lower Cl_mic, longer t1/2), and binding affinity. While both have poor solubility and Caco-2 permeability, the improved CNS properties of Ligand B outweigh these drawbacks. Ligand A's poor BBB and shorter half-life are significant liabilities.

Output:
1
2025-04-17 04:44:47,055 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (348.359 Da) is slightly lower, which could be beneficial for permeability.

**TPSA:** Ligand B (75.19) is significantly better than Ligand A (105.02). For CNS targets, we want TPSA <= 90, so Ligand B is closer to this threshold.

**logP:** Ligand B (2.126) is optimal (1-3), while Ligand A (0.466) is quite low, potentially hindering membrane permeability.

**H-Bond Donors:** Both have 1 HBD, which is good.

**H-Bond Acceptors:** Ligand A has 7 HBA, and Ligand B has 6. Both are acceptable (<=10).

**QED:** Ligand B (0.867) has a much better QED score than Ligand A (0.468), indicating a more drug-like profile.

**DILI:** Both ligands have acceptable DILI risk (Ligand A: 61.148, Ligand B: 55.293), though Ligand B is slightly better.

**BBB:** Ligand B (63.862) has a better BBB percentile than Ligand A (53.897), but both are below the desirable >70 for CNS targets.

**Caco-2 Permeability:** Ligand A (-4.915) and Ligand B (-5.277) both have negative values, which is unusual and suggests very poor permeability. This is a significant concern for both.

**Aqueous Solubility:** Both have very poor aqueous solubility (-2.679 and -2.755).

**hERG Inhibition:** Ligand A (0.432) has a slightly higher hERG risk than Ligand B (0.274), but both are relatively low.

**Microsomal Clearance:** Ligand A (12.395) has a much lower (better) microsomal clearance than Ligand B (31.413), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (-8.761) has a longer (better) in vitro half-life than Ligand B (-5.546).

**P-gp Efflux:** Ligand A (0.035) shows significantly lower P-gp efflux than Ligand B (0.094), which is crucial for CNS penetration.

**Binding Affinity:** Both ligands have the same binding affinity (-8.1 kcal/mol), which is excellent.

**Overall Assessment:**

While both ligands have excellent binding affinity, Ligand B is superior in most ADME properties critical for a CNS-targeting GPCR. Its TPSA and logP are much better, and it has a higher QED and BBB percentile. However, the poor Caco-2 permeability and solubility are major drawbacks for both. Ligand A has better metabolic stability (lower Cl_mic, longer t1/2) and lower P-gp efflux, which are important for CNS exposure. Given the importance of BBB penetration and logP for CNS GPCRs, and the better values of these parameters for Ligand B, it is the more promising candidate despite the slightly higher P-gp efflux and worse metabolic stability. The poor solubility and permeability would need to be addressed through formulation or further structural modifications.

Output:
1
2025-04-17 04:44:47,055 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (346.471 Da) is slightly lower, which could be beneficial for permeability.

**2. TPSA:** Ligand A (57.69) is significantly better than Ligand B (92.93). For CNS targets, we want TPSA <= 90, so Ligand A is much more favorable.

**3. logP:** Both ligands have good logP values (A: 2.55, B: 2.669), falling within the optimal 1-3 range.

**4. H-Bond Donors:** Ligand A (0) is better than Ligand B (2). Fewer H-bond donors generally improve permeability.

**5. H-Bond Acceptors:** Ligand A (3) is better than Ligand B (5). Fewer H-bond acceptors also generally improve permeability.

**6. QED:** Both ligands have similar QED values (A: 0.695, B: 0.691), indicating good drug-likeness.

**7. DILI:** Ligand A (31.679) has a significantly lower DILI risk than Ligand B (53.432). Both are acceptable, but A is preferred.

**8. BBB:** This is a critical parameter for CNS targets. Ligand A (85.421) has a much higher BBB percentile than Ligand B (34.858). This is a major advantage for Ligand A.

**9. Caco-2 Permeability:** Ligand A (-4.736) and Ligand B (-5.146) both have negative values, which is unusual. It's difficult to interpret without knowing the scale, but assuming lower values are worse, they are both poor.

**10. Aqueous Solubility:** Both ligands have poor aqueous solubility (-2.756 and -2.954). This could pose formulation challenges, but is less critical than BBB for CNS drugs.

**11. hERG Inhibition:** Both ligands have very low hERG inhibition risk (A: 0.29, B: 0.156).

**12. Microsomal Clearance:** Ligand A (49.802) has a moderate clearance, while Ligand B (9.286) has a very low clearance. This suggests Ligand B is more metabolically stable.

**13. In vitro Half-Life:** Ligand A (-9.806) has a negative half-life, which is not possible. This is a data error and is a significant concern. Ligand B (63.389) has a good half-life.

**14. P-gp Efflux:** Both ligands have low P-gp efflux liability (A: 0.41, B: 0.195).

**15. Binding Affinity:** Ligand B (-8.0) has a slightly better binding affinity than Ligand A (-7.8). However, the difference is relatively small (0.2 kcal/mol).

**Overall Assessment:**

Despite the slightly better affinity of Ligand B, Ligand A is the more promising candidate. The significantly better TPSA, BBB penetration, lower DILI risk, and fewer H-bonds outweigh the small difference in affinity. The negative half-life for Ligand A is a major red flag and suggests a data error. If the half-life data for Ligand A were corrected, it would be the clear choice. However, even with the erroneous half-life, the other properties strongly favor Ligand A.

Output:
1
2025-04-17 04:44:47,055 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B based on the provided guidelines, prioritizing GPCR-specific properties (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (360.445 and 386.361 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (67.43) is better than Ligand B (41.13). For CNS targets, we want TPSA <= 90, both are well within this range, but lower is generally preferred for BBB penetration.

**logP:** Ligand B (4.416) is slightly higher than Ligand A (3.622). While both are above the optimal 1-3 range, Ligand B is pushing the upper limit and may have solubility issues.

**H-Bond Donors/Acceptors:** Both have 2 HBDs, which is good. Ligand A has 3 HBAs, and Ligand B has 2 HBAs. Both are within acceptable limits.

**QED:** Both ligands have similar QED values (0.787 and 0.753), indicating good drug-likeness.

**DILI:** Ligand A (33.656) has a significantly lower DILI risk than Ligand B (53.625). This is a substantial advantage for Ligand A.

**BBB:** Ligand A (89.453) has a better BBB percentile than Ligand B (80.264). Both are good, but Ligand A is closer to the desirable >70 threshold for CNS targets.

**Caco-2 Permeability:** Ligand A (-4.222) has better Caco-2 permeability than Ligand B (-5.148). Higher values indicate better intestinal absorption.

**Aqueous Solubility:** Ligand A (-4.059) has better aqueous solubility than Ligand B (-4.495).

**hERG:** Both ligands have similar hERG values (0.614 and 0.692), indicating low risk of cardiotoxicity.

**Microsomal Clearance:** Ligand B (23.535) has significantly lower microsomal clearance than Ligand A (61.17). Lower clearance indicates better metabolic stability, a significant advantage for Ligand B.

**In vitro Half-Life:** Ligand B (2.367) has a longer in vitro half-life than Ligand A (-11.102). This is a substantial advantage for Ligand B.

**P-gp Efflux:** Ligand A (0.055) has lower P-gp efflux than Ligand B (0.229). Lower efflux is preferred for CNS exposure.

**Binding Affinity:** Ligand B (-8.3) has a slightly better binding affinity than Ligand A (-7.9). This difference of 0.4 kcal/mol is significant, and can potentially outweigh some ADME drawbacks.

**Overall Assessment:**

Ligand B has a superior binding affinity and better metabolic stability (lower Cl_mic and longer t1/2). However, Ligand A has a significantly lower DILI risk, better BBB penetration, better Caco-2 permeability, better solubility, and lower P-gp efflux. Given the CNS target and the importance of BBB penetration and minimizing toxicity, the lower DILI risk and better BBB of Ligand A are crucial. The affinity difference, while notable, is not large enough to overcome the ADME advantages of Ligand A.

Output:
0
2025-04-17 04:44:47,055 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (358.429 Da) is slightly lower, which is generally favorable for permeability.

**TPSA:** Ligand A (49.85) is significantly better than Ligand B (80.32). For CNS targets, a TPSA <= 90 is preferred, and Ligand A is comfortably within this range, while Ligand B is approaching the upper limit.

**logP:** Both ligands have similar logP values (A: 2.091, B: 2.131), falling within the optimal range of 1-3.

**H-Bond Donors/Acceptors:** Ligand A (HBD=0, HBA=3) has fewer H-bonds than Ligand B (HBD=2, HBA=6). This is generally favorable for CNS penetration.

**QED:** Both ligands have good QED scores (A: 0.7, B: 0.814), indicating good drug-like properties.

**DILI:** Ligand A (13.339) has a much lower DILI risk than Ligand B (65.258). This is a significant advantage for Ligand A.

**BBB:** Ligand A (93.718) has a substantially better BBB penetration percentile than Ligand B (66.382). This is *critical* for a CNS target like DRD2.

**Caco-2 Permeability:** Ligand A (-4.543) has a worse Caco-2 permeability than Ligand B (-5.332), but both are negative values, indicating poor permeability.

**Aqueous Solubility:** Ligand A (-2.415) has slightly better solubility than Ligand B (-3.442), but both are poor.

**hERG:** Both ligands have low hERG inhibition liability (A: 0.578, B: 0.263), which is good.

**Microsomal Clearance:** Ligand A (38.471) has higher microsomal clearance than Ligand B (32.137), indicating lower metabolic stability.

**In vitro Half-Life:** Ligand B (23.589) has a significantly longer in vitro half-life than Ligand A (1.517).

**P-gp Efflux:** Ligand A (0.148) has much lower P-gp efflux liability than Ligand B (0.21), which is favorable for CNS exposure.

**Binding Affinity:** Ligand B (-8.5) has a slightly better binding affinity than Ligand A (-8.1), but the difference is relatively small (0.4 kcal/mol).

**Overall Assessment:**

Despite Ligand B having a slightly better binding affinity and longer half-life, Ligand A is the more promising candidate. The significantly better BBB penetration (93.718 vs 66.382), lower DILI risk (13.339 vs 65.258), lower P-gp efflux (0.148 vs 0.21), and lower TPSA (49.85 vs 80.32) outweigh the small difference in affinity and the slightly worse metabolic stability. For a CNS target like DRD2, BBB penetration and minimizing off-target effects (DILI) are paramount.

Output:
0
2025-04-17 04:44:47,055 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (359.853 and 347.459 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (46.61) is significantly better than Ligand B (69.72). For CNS targets, TPSA should be <= 90, and ideally lower. Ligand A is well within this range, while Ligand B is approaching the upper limit and less favorable.

**3. logP:** Ligand A (4.82) is higher than the optimal 1-3 range, potentially causing solubility issues and off-target interactions. Ligand B (1.174) is slightly below the optimal range, which *could* hinder permeation. However, given the CNS target, a slightly lower logP is less concerning than a very high one.

**4. H-Bond Donors:** Both have acceptable HBD counts (0 for A, 1 for B), well below the threshold of 5.

**5. H-Bond Acceptors:** Both have acceptable HBA counts (3 for both), well below the threshold of 10.

**6. QED:** Both ligands have good QED scores (0.735 and 0.779), indicating good drug-like properties.

**7. DILI:** Ligand A (61.225) has a higher DILI risk than Ligand B (21.442). This is a significant drawback for Ligand A.

**8. BBB:** Ligand A (73.633) has a better BBB penetration percentile than Ligand B (63.629). This is crucial for a CNS target like DRD2.

**9. Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and suggests poor permeability. However, the values are close enough that this isn't a major differentiator.

**10. Aqueous Solubility:** Both have negative solubility values, which is also unusual. Again, the values are close enough that this isn't a major differentiator.

**11. hERG Inhibition:** Ligand A (0.79) shows a slightly higher hERG inhibition risk than Ligand B (0.1). Lower is better, so Ligand B is preferable.

**12. Microsomal Clearance:** Ligand A (120.418) has a higher microsomal clearance than Ligand B (33.043), meaning it's less metabolically stable. Lower clearance is preferred.

**13. In vitro Half-Life:** Ligand A (31.1) has a longer half-life than Ligand B (7.678). This is a positive for Ligand A.

**14. P-gp Efflux:** Ligand A (0.306) has lower P-gp efflux than Ligand B (0.039), which is favorable for CNS penetration.

**15. Binding Affinity:** Ligand A (-8.3 kcal/mol) has a significantly stronger binding affinity than Ligand B (-0.0 kcal/mol). This is a *major* advantage for Ligand A, potentially outweighing some of its ADME drawbacks.

**Overall Assessment:**

While Ligand A has some concerning ADME properties (higher logP, higher DILI, higher hERG, higher Cl_mic), its *significantly* stronger binding affinity (-8.3 vs -0.0 kcal/mol) and better BBB penetration are compelling. The affinity difference is substantial. Ligand B has better ADME properties overall, but its extremely weak binding affinity makes it unlikely to be a viable drug candidate. For a GPCR, strong affinity is paramount, and optimization can be performed to address the ADME liabilities of Ligand A.

Output:
1
2025-04-17 04:44:47,056 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (373.806 and 346.391 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (35.58) is excellent, well below the 90 A^2 target for CNS drugs. Ligand B (123.21) is higher, but still within an acceptable range, though less favorable.

**logP:** Ligand A (3.044) is optimal. Ligand B (-1.105) is significantly lower, potentially hindering membrane permeability and CNS penetration.

**H-Bond Donors/Acceptors:** Ligand A (HBD=1, HBA=2) is good. Ligand B (HBD=2, HBA=6) is acceptable, but the higher HBA count could affect permeability.

**QED:** Ligand A (0.821) is excellent, indicating high drug-likeness. Ligand B (0.648) is still reasonable, but lower.

**DILI:** Both ligands have low DILI risk (Ligand A: 27.181, Ligand B: 30.826), below the 40 threshold.

**BBB:** Ligand A (92.555) has excellent predicted BBB penetration, exceeding the 70% threshold. Ligand B (54.711) is significantly lower, a major drawback for a CNS target.

**Caco-2 Permeability:** Ligand A (-4.864) is negative, which is unusual and requires further investigation, but could indicate poor permeability. Ligand B (-5.908) is also negative and similarly concerning.

**Aqueous Solubility:** Ligand A (-3.953) and Ligand B (-1.373) both have negative solubility values, suggesting poor aqueous solubility.

**hERG Inhibition:** Ligand A (0.882) has a low hERG risk. Ligand B (0.041) also has a very low hERG risk.

**Microsomal Clearance:** Ligand A (17.023) has moderate clearance. Ligand B (-20.794) has negative clearance, which is not physically possible and indicates an issue with the data or prediction method.

**In vitro Half-Life:** Ligand A (11.198 hours) is reasonable. Ligand B (-2.619 hours) is negative and unrealistic.

**P-gp Efflux:** Ligand A (0.235) has low P-gp efflux, which is favorable. Ligand B (0.006) also has very low P-gp efflux.

**Binding Affinity:** Both ligands have comparable and strong binding affinities (Ligand A: -8.7 kcal/mol, Ligand B: -8.2 kcal/mol). The difference of 0.5 kcal/mol, while present, is unlikely to outweigh the significant ADME differences.

**Conclusion:**

Ligand A is the superior candidate. While both ligands bind well, Ligand A has significantly better predicted BBB penetration, a more optimal logP, and a higher QED score. The negative Caco-2 and solubility values are concerning for both, but the other advantages of Ligand A, particularly its BBB score, make it the more promising candidate for a CNS-targeting drug like a DRD2 ligand. The negative clearance and half-life values for Ligand B are also red flags, indicating potential data quality issues.

Output:
1
2025-04-17 04:44:47,056 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (374.413 and 349.431 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (93.21) is slightly above the ideal <90 for CNS targets, but still acceptable. Ligand B (78.95) is well within the desired range.

**3. logP:** Ligand A (1.08) is at the lower end of optimal, but acceptable. Ligand B (0.141) is quite low and could indicate poor membrane permeability.

**4. H-Bond Donors:** Ligand A (2) and Ligand B (1) are both within the acceptable limit of <=5.

**5. H-Bond Acceptors:** Ligand A (6) and Ligand B (4) are both within the acceptable limit of <=10.

**6. QED:** Both ligands have good QED scores (0.664 and 0.769, respectively), indicating drug-like properties.

**7. DILI:** Ligand A (55.448) has a moderate DILI risk, while Ligand B (32.067) has a lower, more favorable DILI risk.

**8. BBB:** This is crucial for a CNS target. Ligand A has a good BBB percentile (83.443), exceeding the desirable >70 threshold. Ligand B (64.87) is below this threshold, which is a significant drawback.

**9. Caco-2 Permeability:** Ligand A (-5.041) and Ligand B (-4.842) have negative values, which is unusual and suggests poor permeability. However, the scale isn't specified, so it's hard to interpret.

**10. Aqueous Solubility:** Both ligands have negative solubility values (-2.853 and -1.173), suggesting poor aqueous solubility. This is a concern for formulation.

**11. hERG Inhibition:** Both ligands have low hERG inhibition risk (0.418 and 0.158), which is positive.

**12. Microsomal Clearance:** Ligand A (6.575) has a moderate clearance, while Ligand B (-1.79) has a negative clearance, which is not physically possible and likely indicates an error or different scale. Assuming this is a percentile, it suggests very high metabolic stability.

**13. In vitro Half-Life:** Ligand A (8.848) has a reasonable half-life. Ligand B (5.851) has a shorter half-life.

**14. P-gp Efflux:** Ligand A (0.109) has low P-gp efflux, which is favorable for CNS penetration. Ligand B (0.021) also has very low P-gp efflux.

**15. Binding Affinity:** Ligand B (-7.9 kcal/mol) has a slightly better binding affinity than Ligand A (-8.4 kcal/mol). However, the difference is small.

**Overall Assessment:**

Ligand A is preferable due to its significantly better BBB penetration (83.443 vs 64.87). While Ligand B has slightly better affinity and lower DILI, the BBB is a critical factor for CNS targets like DRD2. The low logP of Ligand B is also concerning for permeability. The negative clearance value for Ligand B is also a red flag.

Output:
1
2025-04-17 04:44:47,056 - INFO - Reasoning:

Let's analyze Ligand A and Ligand B based on the provided guidelines, prioritizing GPCR-specific properties (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (387.908 Da) is slightly higher than Ligand B (358.423 Da), but both are acceptable.

**TPSA:** Ligand A (62.3) is significantly better than Ligand B (93.84). For CNS targets, TPSA should be <=90, and A is comfortably within this range, while B is close to the upper limit. This is a significant advantage for A.

**logP:** Both ligands have good logP values (A: 2.984, B: 2.092), falling within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Both have acceptable HBD (1) and HBA (A: 4, B: 6) counts.

**QED:** Both have reasonable QED scores (A: 0.815, B: 0.683), indicating good drug-like properties. A is slightly better.

**DILI:** Both have acceptable DILI risk (A: 41.411, B: 51.377), below the concerning threshold of 60.

**BBB:** Ligand A (69.523) is better than Ligand B (60.101). While both are not exceptional, A is closer to the desirable >70 for CNS targets.

**Caco-2 Permeability:** Ligand A (-4.586) is better than Ligand B (-5.311), indicating better intestinal absorption.

**Aqueous Solubility:** Ligand A (-3.727) is better than Ligand B (-2.509).

**hERG Inhibition:** Both ligands have very low hERG inhibition risk (A: 0.428, B: 0.16), which is excellent.

**Microsomal Clearance:** Both have similar microsomal clearance rates (A: 35.123, B: 37.702).

**In vitro Half-Life:** Ligand B (-9.099) has a slightly better (longer) in vitro half-life than Ligand A (-7.5).

**P-gp Efflux:** Ligand A (0.193) is better than Ligand B (0.09), indicating lower P-gp efflux and potentially better CNS exposure.

**Binding Affinity:** Ligand B (-7.2) has a slightly better binding affinity than Ligand A (-8.0). However, the difference is relatively small.

**Overall Assessment:**

Considering the GPCR-specific priorities, Ligand A is the better candidate. Its significantly lower TPSA, better BBB penetration, and lower P-gp efflux are crucial for CNS drug development. While Ligand B has a slightly better binding affinity and half-life, the advantages of A in terms of permeability and CNS penetration outweigh these minor differences. The affinity difference is not large enough to overcome the ADME advantages of A.

Output:
1
2025-04-17 04:44:47,056 - INFO - Batch 139 complete. Total preferences: 2224
2025-04-17 04:44:47,056 - INFO - Processing batch 140/512...
2025-04-17 04:45:29,741 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (362.455 and 359.495 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (79.54) is slightly higher than Ligand B (66.32). Both are below the 90 A^2 threshold desirable for CNS targets, but Ligand B is preferable.

**logP:** Ligand A (2.217) is within the optimal 1-3 range. Ligand B (3.348) is slightly higher, but still acceptable.

**H-Bond Donors/Acceptors:** Ligand A has 0 HBD and 6 HBA, while Ligand B has 1 HBD and 5 HBA. Both are within acceptable limits (<=5 HBD and <=10 HBA).

**QED:** Both ligands have good QED scores (0.787 and 0.889, respectively), indicating good drug-like properties. Ligand B is slightly better.

**DILI:** Ligand A (52.191) has a slightly higher DILI risk than Ligand B (36.254). Ligand B is significantly better here.

**BBB:** Both ligands have excellent BBB penetration (76.464 and 75.572), exceeding the desirable >70% threshold for CNS targets.

**Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and suggests a potential issue with the data or modeling. However, we'll proceed assuming these represent low permeability.

**Aqueous Solubility:** Both have negative solubility values, which is also unusual. Again, we'll assume this indicates poor solubility.

**hERG Inhibition:** Both ligands show very low hERG inhibition risk (0.282 and 0.424), which is excellent.

**Microsomal Clearance:** Ligand A (25.908) has a lower microsomal clearance than Ligand B (54.377), indicating better metabolic stability.

**In vitro Half-Life:** Ligand A (11.935) has a longer half-life than Ligand B (-4.833). The negative value for Ligand B is concerning and suggests rapid degradation.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.121 and 0.364), which is favorable for CNS penetration.

**Binding Affinity:** Ligand B (-7.6 kcal/mol) has a slightly better binding affinity than Ligand A (-8.0 kcal/mol). While the difference is small, it's still a factor.

**Overall Assessment:**

Ligand B is slightly better overall. It has a lower DILI risk, a slightly better QED score, and a better binding affinity. The main drawback for Ligand B is the negative in vitro half-life, which is a significant concern. However, Ligand A has a higher TPSA and a higher DILI risk, and a shorter half-life. Given the importance of metabolic stability and a longer half-life for CNS drugs, Ligand A is the better candidate.

Output:
0
2025-04-17 04:45:29,741 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (374.809 Da) is slightly higher than Ligand B (350.419 Da), but both are acceptable.

**TPSA:** Ligand A (105.07) is better than Ligand B (111.53) for CNS penetration, being closer to the <90 target for CNS targets.

**logP:** Ligand A (2.882) is optimal (1-3). Ligand B (-0.061) is quite low, potentially hindering permeation. This is a significant drawback.

**H-Bond Donors/Acceptors:** Both ligands have acceptable HBD (2) and HBA (6/5) counts.

**QED:** Both ligands have good QED scores (0.711 and 0.668), indicating drug-likeness.

**DILI:** Ligand A (99.341) has a very high DILI risk, which is a major concern. Ligand B (21.908) has a low DILI risk, a significant advantage.

**BBB:** Ligand A (12.99) has extremely poor BBB penetration, making it unlikely to be effective for a CNS target like DRD2. Ligand B (58.278) is better, but still not ideal (below 70).

**Caco-2 Permeability:** Ligand A (-5.338) shows poor permeability. Ligand B (-4.971) is also poor, but slightly better.

**Aqueous Solubility:** Ligand A (-3.297) and Ligand B (-1.362) both have poor aqueous solubility.

**hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.026 and 0.073).

**Microsomal Clearance:** Ligand A (-5.856) has lower (better) microsomal clearance than Ligand B (-6.492).

**In vitro Half-Life:** Ligand B (17.3 hours) has a much longer half-life than Ligand A (-5.264 hours).

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.034 and 0.009).

**Binding Affinity:** Ligand B (-7.1 kcal/mol) has a slightly better binding affinity than Ligand A (-9.4 kcal/mol). While Ligand A has a stronger binding affinity, the difference is not substantial enough to overcome its other significant liabilities.

**Overall Assessment:**

Ligand A suffers from extremely poor BBB penetration and a very high DILI risk, making it a poor candidate despite its slightly better binding affinity. Ligand B, while not perfect, has a much more favorable profile. Its lower logP and BBB penetration are concerns, but its significantly lower DILI risk, longer half-life, and acceptable binding affinity make it the more promising candidate. The GPCR-specific priorities heavily favor Ligand B.

Output:
1
2025-04-17 04:45:29,741 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (345.418 and 342.403 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (53.51) is excellent, well below the 90 A^2 threshold for CNS targets. Ligand B (103.01) is higher, but still potentially acceptable, though less ideal.

**logP:** Ligand A (2.472) is optimal (1-3). Ligand B (1.028) is on the lower side, potentially hindering permeability.

**H-Bond Donors/Acceptors:** Ligand A (0 HBD, 3 HBA) is favorable. Ligand B (3 HBD, 5 HBA) is also acceptable, but slightly higher counts could affect permeability.

**QED:** Both ligands have similar QED values (0.796 and 0.697), indicating good drug-like properties.

**DILI:** Ligand A (26.134) has a much lower DILI risk than Ligand B (55.176), which is a significant advantage.

**BBB:** Ligand A (90.074) has excellent BBB penetration potential, exceeding the desirable >70% threshold. Ligand B (30.399) is considerably lower, raising concerns about CNS exposure. This is a critical factor for a DRD2 ligand.

**Caco-2 Permeability:** Ligand A (-4.221) has poor Caco-2 permeability. Ligand B (-5.633) is even worse.

**Aqueous Solubility:** Both ligands have very poor aqueous solubility (-2.805 and -2.387 respectively). This could pose formulation challenges.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.305 and 0.607).

**Microsomal Clearance:** Ligand A (37.583) has a moderate clearance, while Ligand B (-28.31) has a negative clearance, which is not physically possible and likely an error in the data. This suggests Ligand B is significantly more metabolically stable.

**In vitro Half-Life:** Ligand A (14.556 hours) has a reasonable half-life. Ligand B (-6.484 hours) is also likely an error in the data.

**P-gp Efflux:** Both ligands show very low P-gp efflux liability (0.043 and 0.013).

**Binding Affinity:** Both ligands have excellent binding affinities (-8.0 and -8.5 kcal/mol), with Ligand B being slightly stronger. However, the affinity difference is not substantial enough to overcome the other significant drawbacks of Ligand B.

**Overall Assessment:**

Ligand A is the stronger candidate. While its Caco-2 permeability and aqueous solubility are poor, its excellent BBB penetration, low DILI risk, and good overall drug-like properties outweigh these concerns. Ligand B has a better binding affinity, but its significantly lower BBB penetration, higher DILI risk, and questionable clearance/half-life data make it a less viable candidate. The negative values for clearance and half-life are particularly concerning and likely indicate data errors.

Output:
1
2025-04-17 04:45:29,742 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (347.371 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (108.81) is slightly above the optimal <90 for CNS targets, but still reasonable. Ligand B (97.81) is better, falling comfortably under 90.

**3. logP:** Both ligands have good logP values (A: 0.971, B: 1.464), within the 1-3 range.

**4. H-Bond Donors:** Ligand A (2) and Ligand B (1) are both acceptable, below the threshold of 5. Ligand B is slightly better.

**5. H-Bond Acceptors:** Both ligands have 6 H-bond acceptors, which is acceptable (<=10).

**6. QED:** Both ligands have high QED scores (A: 0.806, B: 0.899), indicating good drug-like properties. Ligand B is slightly better.

**7. DILI:** Ligand A (53.005) has a lower DILI risk than Ligand B (74.99), which is a significant advantage.

**8. BBB:** This is crucial for a CNS target. Ligand B (62.931) has a substantially better BBB penetration percentile than Ligand A (27.646). This is a major point in favor of Ligand B.

**9. Caco-2 Permeability:** Both have negative values (-5.078 and -4.584). This is unusual and suggests poor permeability. However, these values are on a scale where negative values are possible, and direct comparison is difficult without knowing the scale's specifics.

**10. Aqueous Solubility:** Both have negative values (-1.993 and -2.367), suggesting poor solubility. Similar to Caco-2, interpretation is limited without knowing the scale.

**11. hERG:** Both ligands have very low hERG inhibition risk (A: 0.152, B: 0.18).

**12. Microsomal Clearance:** Ligand A (19.564) has lower microsomal clearance than Ligand B (23.809), suggesting better metabolic stability.

**13. In vitro Half-Life:** Ligand B (-8.901) has a longer in vitro half-life than Ligand A (-2.816).

**14. P-gp Efflux:** Both have very low P-gp efflux liability (A: 0.034, B: 0.08).

**15. Binding Affinity:** Ligand B (-7.4 kcal/mol) has a slightly better binding affinity than Ligand A (-8.1 kcal/mol). While A is stronger, the difference is less than the 1.5 kcal/mol threshold.

**Overall Assessment:**

Ligand B is the more promising candidate. Its significantly improved BBB penetration (62.931 vs 27.646) is the most important factor, given the CNS target. It also has a slightly better QED score, longer half-life, and better binding affinity. While Ligand A has a lower DILI risk and better metabolic stability, the BBB advantage of Ligand B outweighs these benefits for a CNS-targeting drug. The poor Caco-2 and solubility values are concerning for both, but can be addressed with formulation strategies.



Output:
1
2025-04-17 04:45:29,742 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (364.364 Da) is slightly higher than Ligand B (345.487 Da), but both are acceptable.

**TPSA:** Both ligands have TPSA values below the 90 A^2 threshold desirable for CNS targets. Ligand A (87.66 A^2) is slightly higher than Ligand B (81.99 A^2), but both are good.

**logP:** Both ligands have logP values within the optimal range (1-3). Ligand A (1.046) is closer to the lower end, while Ligand B (3.053) is at the upper end. This is a slight advantage for B, as it may have better membrane permeability.

**H-Bond Donors/Acceptors:** Ligand A has 3 HBD and 4 HBA, while Ligand B has 2 HBD and 3 HBA. Both are within acceptable limits (<=5 HBD and <=10 HBA).

**QED:** Both ligands have QED values above 0.5 (Ligand A: 0.637, Ligand B: 0.696), indicating good drug-like properties. Ligand B is slightly better.

**DILI:** Ligand A has a DILI risk of 38.736%, while Ligand B has 21.753%. Ligand B is significantly better in terms of potential liver toxicity.

**BBB:** Ligand A has a BBB penetration of 80.419%, which is good for a CNS target. Ligand B has a BBB penetration of 66.886%, which is lower, but still potentially acceptable. Ligand A is significantly better here.

**Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and suggests poor permeability. Ligand A (-5.065) is slightly better than Ligand B (-4.885).

**Aqueous Solubility:** Both ligands have very poor aqueous solubility (-1.771 and -3.723 respectively). This is a significant drawback for both.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.334 and 0.648 respectively).

**Microsomal Clearance:** Ligand A has zero microsomal clearance, which is excellent. Ligand B has a clearance of 54.508 mL/min/kg, which is moderate. Ligand A is much better here.

**In vitro Half-Life:** Ligand A has a very long in vitro half-life (-18.091 hours), which is highly desirable. Ligand B has a short half-life (3.4 hours).

**P-gp Efflux:** Ligand A has very low P-gp efflux (0.031), which is excellent for CNS penetration. Ligand B has moderate P-gp efflux (0.123).

**Binding Affinity:** Both ligands have similar binding affinities (-9.2 kcal/mol and -8.8 kcal/mol). Ligand A is slightly better, but the difference is not huge.

**Overall Assessment:**

Ligand A excels in BBB penetration, microsomal clearance, in vitro half-life, and P-gp efflux. It also has a slightly better binding affinity. While its solubility is poor, its other ADME properties are significantly better, making it a more promising candidate for a CNS-targeting drug like a DRD2 ligand. Ligand B has a better DILI score and logP, but its poorer BBB, clearance, and half-life are major drawbacks.

Output:
0
2025-04-17 04:45:29,742 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B based on the provided guidelines, prioritizing GPCR-specific properties (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Ligand A (453.28 Da) is within the ideal range, while Ligand B (346.431 Da) is towards the lower end but still acceptable.

**TPSA:** Ligand A (79.46) is better suited for CNS penetration than Ligand B (98.32), being closer to the <90 target for CNS targets.

**logP:** Ligand A (4.084) is slightly high, potentially leading to solubility issues or off-target effects. Ligand B (1.297) is a bit low, potentially hindering permeation.

**H-Bond Donors/Acceptors:** Both ligands have 3 HBD and a reasonable number of HBA (3 and 4 respectively), falling within acceptable limits.

**QED:** Both ligands have good QED scores (0.577 and 0.648), indicating drug-like properties.

**DILI:** Ligand A (85.77) has a significantly higher DILI risk than Ligand B (29.818). This is a major concern.

**BBB:** Ligand A (60.954) has a moderate BBB penetration, while Ligand B (43.001) is lower. Both are below the desirable >70 for CNS targets, but A is better.

**Caco-2 Permeability:** Ligand A (-4.995) and Ligand B (-5.17) both show poor Caco-2 permeability.

**Aqueous Solubility:** Ligand A (-5.416) and Ligand B (-1.944) both have poor aqueous solubility.

**hERG Inhibition:** Ligand A (0.811) has a slightly higher hERG risk than Ligand B (0.085).

**Microsomal Clearance:** Ligand A (47.951) has a higher microsomal clearance than Ligand B (0.885), suggesting lower metabolic stability.

**In vitro Half-Life:** Ligand A (53.587) has a longer half-life than Ligand B (-3.916).

**P-gp Efflux:** Ligand A (0.378) has lower P-gp efflux liability than Ligand B (0.021), which is favorable for CNS penetration.

**Binding Affinity:** Ligand A (-8.2 kcal/mol) has a slightly better binding affinity than Ligand B (-7.9 kcal/mol). While the difference is small, it's a positive factor.

**Overall Assessment:**

Ligand A has a better binding affinity, TPSA, BBB, P-gp efflux, and half-life. However, its significantly higher DILI risk, higher logP, and higher microsomal clearance are major drawbacks. Ligand B has a much better safety profile (DILI, hERG) and better metabolic stability, but suffers from lower BBB penetration and a slightly weaker binding affinity.

Given the CNS target and the importance of safety, the lower DILI risk of Ligand B is a critical advantage. While its affinity is slightly lower, the difference is not substantial enough to outweigh the safety concerns associated with Ligand A. The poor Caco-2 and solubility are concerns for both, but can be addressed with formulation strategies.

Output:
1
2025-04-17 04:45:29,742 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B against the provided guidelines, with a focus on GPCR (DRD2) properties.

**1. Molecular Weight:** Both ligands (348.443 and 345.487 Da) fall comfortably within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (98.66) is higher than Ligand B (54.34). For CNS targets, TPSA should be <= 90. Ligand A is slightly above this, while Ligand B is well within the range. This favors Ligand B.

**3. logP:** Both ligands have good logP values (1.873 and 2.647), falling within the optimal 1-3 range.

**4. H-Bond Donors:** Ligand A has 4 HBD, while Ligand B has 1. Both are acceptable (<=5).

**5. H-Bond Acceptors:** Ligand A has 4 HBA, and Ligand B has 3. Both are acceptable (<=10).

**6. QED:** Both ligands have good QED scores (0.631 and 0.912), indicating good drug-like properties. Ligand B is slightly better.

**7. DILI:** Ligand A (37.03) has a slightly higher DILI risk than Ligand B (18.728). Both are below 40, indicating low risk, but B is preferable.

**8. BBB:** This is a crucial parameter for CNS targets. Ligand B (78.868) has a significantly higher BBB percentile than Ligand A (51.493). This is a strong advantage for Ligand B.

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.707 and -4.939). This is unusual and suggests poor permeability, but the values are close enough to not be a major differentiator.

**10. Aqueous Solubility:** Both ligands have negative solubility values (-2.767 and -2.08). This is also unusual and suggests poor solubility, but again, the values are close.

**11. hERG Inhibition:** Both ligands have low hERG inhibition liability (0.359 and 0.412), which is good.

**12. Microsomal Clearance:** Ligand A (26.019) has higher microsomal clearance than Ligand B (14.576), indicating lower metabolic stability. This favors Ligand B.

**13. In vitro Half-Life:** Ligand B (1.593) has a slightly longer half-life than Ligand A (15.379).

**14. P-gp Efflux:** Ligand A (0.096) has lower P-gp efflux than Ligand B (0.242), which is favorable for CNS penetration.

**15. Binding Affinity:** Both ligands have very similar and strong binding affinities (-8.8 and -8.7 kcal/mol). The difference is negligible.

**Overall Assessment:**

Ligand B is the stronger candidate. While both ligands have good binding affinity and acceptable physicochemical properties, Ligand B excels in key areas for a CNS-targeting GPCR: significantly better BBB penetration (78.9% vs 51.5%), lower DILI risk, better metabolic stability (lower Cl_mic), and a slightly longer half-life. The lower TPSA of Ligand B is also advantageous. The slightly better P-gp efflux of Ligand A is a minor advantage that is outweighed by the other benefits of Ligand B.

Output:
1
2025-04-17 04:45:29,742 - INFO - Reasoning:

Let's analyze Ligand A and Ligand B for their potential as DRD2 drug candidates, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (357.303 and 352.479 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (38.77) is excellent, well below the 90 A^2 threshold for CNS targets. Ligand B (83.03) is higher, but still potentially acceptable, though less ideal.

**3. logP:** Ligand A (3.419) is optimal (1-3). Ligand B (1.286) is on the lower side, potentially hindering permeability.

**4. H-Bond Donors:** Ligand A (0) is good. Ligand B (2) is acceptable.

**5. H-Bond Acceptors:** Ligand A (3) is good. Ligand B (5) is acceptable.

**6. QED:** Both ligands have similar QED values (0.563 and 0.509), indicating good drug-like properties.

**7. DILI:** Ligand A (63.629) has a moderate DILI risk. Ligand B (12.098) has a very low DILI risk, a significant advantage.

**8. BBB:** Ligand A (80.458) has excellent BBB penetration. Ligand B (65.801) is also good, but not as high as Ligand A.

**9. Caco-2 Permeability:** Ligand A (-4.058) has poor Caco-2 permeability. Ligand B (-5.186) also has poor Caco-2 permeability.

**10. Aqueous Solubility:** Ligand A (-4.102) has poor aqueous solubility. Ligand B (-1.864) has slightly better aqueous solubility, but still poor.

**11. hERG Inhibition:** Both ligands have low hERG inhibition risk (0.807 and 0.454).

**12. Microsomal Clearance:** Ligand A (62.196) has moderate clearance. Ligand B (-0.409) has very low clearance, indicating good metabolic stability.

**13. In vitro Half-Life:** Ligand A (7.609) has a moderate half-life. Ligand B (10.112) has a longer half-life, which is desirable.

**14. P-gp Efflux:** Ligand A (0.32) has low P-gp efflux, which is good. Ligand B (0.03) has very low P-gp efflux, even better.

**15. Binding Affinity:** Both ligands have very similar and excellent binding affinities (-8.7 and -8.0 kcal/mol). The difference is less than 1.5 kcal/mol, so it's not a deciding factor.

**Overall Assessment:**

Ligand A excels in BBB penetration and has a good logP. However, it suffers from poor Caco-2 permeability and aqueous solubility, and moderate DILI risk and clearance. Ligand B has a significantly lower DILI risk, better metabolic stability (lower clearance, longer half-life), and lower P-gp efflux. While its logP is lower and TPSA is higher, the advantages in safety (DILI) and pharmacokinetics (clearance, half-life, P-gp) outweigh these drawbacks, especially considering the similar binding affinities.

Output:
1
2025-04-17 04:45:29,743 - INFO - Reasoning:

Let's analyze Ligand A and Ligand B based on the provided guidelines, prioritizing GPCR-specific properties (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (350.434 and 348.451 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (62.55) is excellent, well below the 90 A^2 threshold for CNS targets. Ligand B (93.36) is higher, but still potentially acceptable, though less ideal.

**logP:** Ligand A (2.941) is optimal (1-3). Ligand B (-0.727) is significantly outside the optimal range and is quite low, potentially hindering permeation.

**H-Bond Donors/Acceptors:** Ligand A (HBD=1, HBA=3) is favorable. Ligand B (HBD=3, HBA=5) is also acceptable, but slightly higher.

**QED:** Ligand A (0.888) is excellent, indicating high drug-likeness. Ligand B (0.604) is still good, exceeding the 0.5 threshold.

**DILI:** Ligand A (31.679) has a very low DILI risk. Ligand B (11.283) also has a low DILI risk.

**BBB:** Ligand A (81.892) has a good BBB percentile, exceeding the 70% threshold for CNS targets. Ligand B (38.232) is significantly lower and less likely to cross the BBB effectively. This is a major drawback for a DRD2 ligand.

**Caco-2 Permeability:** Ligand A (-4.597) is negative, which is unusual and requires further investigation, but doesn't immediately disqualify it. Ligand B (-5.81) is also negative.

**Aqueous Solubility:** Ligand A (-3.127) is negative, and Ligand B (-0.494) is also negative. Both are poor, but this is less critical for CNS drugs if BBB penetration is good.

**hERG Inhibition:** Ligand A (0.706) has a low hERG risk. Ligand B (0.141) also has a very low hERG risk.

**Microsomal Clearance:** Ligand A (30.482) has moderate clearance. Ligand B (-11.714) has negative clearance, which is not physically possible and indicates an error or unusual in vitro behavior.

**In vitro Half-Life:** Ligand A (12.447 hours) is reasonable. Ligand B (-12.198 hours) is negative, which is not physically possible.

**P-gp Efflux:** Ligand A (0.29) has low P-gp efflux, which is favorable for CNS penetration. Ligand B (0.001) has extremely low P-gp efflux, which is also favorable.

**Binding Affinity:** Both ligands have similar and strong binding affinities (-8.9 and -8.3 kcal/mol). The difference of 0.6 kcal/mol is not substantial enough to outweigh other significant differences.

**Conclusion:**

Ligand A is significantly better due to its superior logP, BBB penetration, and reasonable metabolic stability. Ligand B has a poor logP and a non-sensical negative clearance/half-life, making it a less viable candidate. While both have good affinity, the ADME properties of Ligand A are far more favorable for a CNS-targeting drug.

Output:
1
2025-04-17 04:45:29,743 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (348.403 and 360.445 Da) fall within the ideal range of 200-500 Da.

**TPSA:** Ligand A (96.69) is slightly above the optimal <90 for CNS targets, but still reasonable. Ligand B (60.85) is excellent, well below 90.

**logP:** Ligand A (0.216) is quite low, potentially hindering permeability. Ligand B (2.134) is within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A has 2 HBD and 6 HBA, which are acceptable. Ligand B has 1 HBD and 3 HBA, also acceptable.

**QED:** Both ligands have similar QED values (0.793 and 0.721), indicating good drug-likeness.

**DILI:** Ligand A (58.24) has a moderate DILI risk, while Ligand B (25.087) has a very low DILI risk, which is a significant advantage.

**BBB:** Ligand A (13.222) has very poor predicted BBB penetration, a critical drawback for a CNS target. Ligand B (82.047) has excellent predicted BBB penetration.

**Caco-2 Permeability:** Ligand A (-5.169) has very poor Caco-2 permeability, consistent with its low logP. Ligand B (-4.384) also has poor permeability but is better than Ligand A.

**Aqueous Solubility:** Both ligands have poor aqueous solubility (-1.328 and -2.271). This could pose formulation challenges, but isn't a dealbreaker if other properties are favorable.

**hERG Inhibition:** Ligand A (0.068) has very low hERG inhibition risk. Ligand B (0.541) has a slightly higher, but still acceptable, risk.

**Microsomal Clearance:** Ligand A (11.525) has lower clearance than Ligand B (38.896), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (8.421) has a shorter half-life than Ligand B (-18.744), which is unfavorable.

**P-gp Efflux:** Ligand A (0.019) has very low P-gp efflux, which is good. Ligand B (0.13) has slightly higher efflux, but still relatively low.

**Binding Affinity:** Ligand B (-7.1 kcal/mol) has a slightly better binding affinity than Ligand A (-8.4 kcal/mol). While Ligand A has a slightly better affinity, the difference is not substantial enough to overcome its significant ADME deficiencies.

**Overall Assessment:**

Ligand B is the far superior candidate. Its excellent BBB penetration, low DILI risk, and acceptable logP outweigh its slightly lower affinity and solubility concerns. Ligand A's extremely poor BBB penetration and low logP are major liabilities for a CNS-targeting drug, despite its slightly better binding affinity. The GPCR-specific priorities heavily favor Ligand B.

Output:
1
2025-04-17 04:45:29,743 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (375.491 and 385.917 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (118.8) is better than Ligand B (69.72). For CNS targets, TPSA should be <=90, and both meet this criterion, but A is closer to the upper limit.

**logP:** Ligand B (2.085) is optimal (1-3), while Ligand A (-0.024) is slightly below 1, potentially hindering permeation. This is a significant drawback for A.

**H-Bond Donors/Acceptors:** Ligand A has 2 HBD and 5 HBA, while Ligand B has 1 HBD and 4 HBA. Both are within acceptable limits (<=5 HBD and <=10 HBA).

**QED:** Both ligands have good QED scores (0.618 and 0.78), indicating good drug-like properties.

**DILI:** Ligand A (30.748) has a lower DILI risk than Ligand B (50.33), which is preferable.

**BBB:** Ligand B (71.074) has a better BBB penetration percentile than Ligand A (64.87). Both are above the desirable 70% threshold for CNS targets, but B is slightly better.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values, which is unusual and suggests a potential issue with the data or the model. However, we can still compare their relative values. Ligand A (-5.195) is slightly better than Ligand B (-4.788).

**Aqueous Solubility:** Both ligands have negative solubility values, again suggesting a potential issue with the data. Ligand B (-3.02) is slightly better than Ligand A (-1.667).

**hERG Inhibition:** Both ligands have low hERG inhibition liability (0.091 and 0.242), which is good.

**Microsomal Clearance:** Both have similar microsomal clearance values (31.241 and 31.95 mL/min/kg).

**In vitro Half-Life:** Ligand B (19.471) has a longer in vitro half-life than Ligand A (-27.547). A negative half-life is not physically possible and indicates a data issue.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.019 and 0.091), which is excellent for CNS penetration.

**Binding Affinity:** Ligand B (-8.2 kcal/mol) has a significantly stronger binding affinity than Ligand A (-7.4 kcal/mol). This >1.5 kcal/mol difference is substantial and can outweigh minor ADME drawbacks.

**Overall Assessment:**

Ligand B is the stronger candidate. While Ligand A has a slightly lower DILI risk, Ligand B excels in crucial areas for a CNS-targeting GPCR ligand: better logP, better BBB penetration, significantly stronger binding affinity, and a more reasonable in vitro half-life. The negative solubility and Caco-2 values are concerning for both, but the superior affinity and CNS penetration of Ligand B make it the more promising candidate.

Output:
1
2025-04-17 04:45:29,743 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (338.407 and 346.427 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (58.64) is significantly better than Ligand B (91.57). For CNS targets, we want TPSA <= 90, and A is comfortably within that range, while B is close to the upper limit. This favors A.

**3. logP:** Both ligands have acceptable logP values (2.924 and 1.694), falling within the 1-3 range. B is slightly lower, which *could* indicate slightly poorer membrane permeability, but it's not a major concern.

**4. H-Bond Donors:** Ligand A (1) is preferable to Ligand B (3). Fewer HBDs generally improve permeability.

**5. H-Bond Acceptors:** Ligand A (3) is preferable to Ligand B (4), for similar reasons as HBDs.

**6. QED:** Ligand A (0.881) has a better QED score than Ligand B (0.668), indicating a more drug-like profile.

**7. DILI:** Ligand B (31.369) has a much lower DILI risk than Ligand A (74.796). This is a significant advantage for B.

**8. BBB:** Ligand A (74.719) has a better BBB percentile than Ligand B (33.54). This is *crucial* for a CNS target like DRD2, and strongly favors A.

**9. Caco-2 Permeability:** Ligand A (-4.548) has a worse Caco-2 permeability than Ligand B (-5.081). Lower values are less desirable.

**10. Aqueous Solubility:** Ligand A (-4.428) has a worse aqueous solubility than Ligand B (-2.442). Lower values are less desirable.

**11. hERG Inhibition:** Ligand A (0.723) has a higher hERG inhibition risk than Ligand B (0.1). This is a significant advantage for B.

**12. Microsomal Clearance:** Ligand B (23.961) has a lower microsomal clearance than Ligand A (64.982), indicating better metabolic stability. This favors B.

**13. In vitro Half-Life:** Ligand A (39.074) has a longer half-life than Ligand B (32.812). This is a slight advantage for A.

**14. P-gp Efflux:** Ligand A (0.43) has lower P-gp efflux than Ligand B (0.098). Lower efflux is better for CNS exposure, favoring A.

**15. Binding Affinity:** Ligand A (-9.6 kcal/mol) has a significantly stronger binding affinity than Ligand B (-8.1 kcal/mol). This is a substantial advantage for A, potentially outweighing some of the ADME drawbacks. The difference is >1.5 kcal/mol.

**Overall Assessment:**

The key trade-offs are:

*   **Ligand A:** Excellent affinity and BBB penetration, but higher DILI risk, hERG inhibition, and worse solubility/permeability.
*   **Ligand B:** Lower DILI and hERG risk, better metabolic stability, solubility, and permeability, but significantly weaker affinity and poor BBB.

Given the importance of CNS penetration for a DRD2 ligand, and the substantial affinity advantage of Ligand A, I believe **Ligand A** is the more promising candidate. The strong binding affinity could potentially be optimized to mitigate some of the ADME liabilities through further structural modifications. The poor BBB of Ligand B is a major drawback for a CNS target.

Output:
1
2025-04-17 04:45:29,744 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (365.817 and 368.39 Da) fall within the ideal range of 200-500 Da.

**TPSA:** Ligand A (82.71) is excellent for CNS penetration, being well below 90. Ligand B (127.31) is higher, but still potentially acceptable, though less ideal.

**logP:** Ligand A (1.454) is within the optimal range of 1-3. Ligand B (-0.085) is slightly below 1, which *could* indicate permeability issues, but isn't a hard disqualifier.

**H-Bond Donors/Acceptors:** Ligand A (HBD=1, HBA=4) is favorable. Ligand B (HBD=3, HBA=7) is also acceptable, though slightly higher.

**QED:** Both ligands have reasonable QED values (0.785 and 0.677), indicating good drug-like properties.

**DILI:** Both ligands have relatively high DILI risk (74.292 and 79.682), which is a concern. However, this can sometimes be mitigated with structural modifications.

**BBB:** This is a critical parameter for a CNS target like DRD2. Ligand A has a significantly better BBB percentile (64.754) than Ligand B (38.038). This is a major advantage for Ligand A.

**Caco-2 Permeability:** Ligand A (-4.759) and Ligand B (-5.354) both have negative Caco-2 values, which is unusual and suggests poor permeability. This is a significant drawback for both.

**Aqueous Solubility:** Both ligands have poor aqueous solubility (-2.357 and -1.785). This could present formulation challenges.

**hERG:** Both ligands have very low hERG inhibition liability (0.138 and 0.092), which is excellent.

**Microsomal Clearance:** Ligand A (67.891) has a moderate clearance, while Ligand B (-27.756) has a *negative* clearance, which is not physically possible. This suggests an error in the data or a highly unusual metabolic profile for Ligand B. This is a major red flag.

**In vitro Half-Life:** Ligand A (-6.935) has a negative half-life, which is also not physically possible, suggesting data issues. Ligand B (5.935) has a reasonable half-life.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.098 and 0.028), which is favorable for CNS penetration.

**Binding Affinity:** Ligand B (-8.9 kcal/mol) has a significantly stronger binding affinity than Ligand A (-7.8 kcal/mol). This is a substantial advantage for Ligand B, potentially outweighing some of its other drawbacks.

**Overall Assessment:**

Despite Ligand B's superior binding affinity, the negative values for microsomal clearance and half-life are highly problematic and suggest data errors or a fundamentally flawed molecule. Ligand A also has issues with negative Caco-2 and half-life values, but these are less concerning than the impossible values for Ligand B. The significantly better BBB penetration of Ligand A, combined with acceptable (though not ideal) ADME properties, makes it the more promising candidate, *assuming the negative values are corrected or explained*.

Output:
0
2025-04-17 04:45:29,744 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (346.431 Da) is slightly better, being closer to the lower end which can aid permeability.

**TPSA:** Ligand A (68.62) is excellent, well below the 90 A^2 threshold for CNS targets. Ligand B (137.4) is higher, approaching the upper limit for good oral absorption (140 A^2) and less ideal for CNS penetration.

**logP:** Both ligands have good logP values (A: 2.396, B: 2.001) falling within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A (HBD=1, HBA=5) is better than Ligand B (HBD=5, HBA=7) in terms of balancing solubility and permeability. Fewer H-bonds generally improve permeability.

**QED:** Ligand A (0.872) has a significantly better QED score than Ligand B (0.44), indicating a more drug-like profile.

**DILI:** Ligand A (52.966) has a lower DILI risk than Ligand B (81.776), suggesting better hepatotoxicity potential.

**BBB:** This is a critical parameter for a CNS target like DRD2. Ligand A (73.905) has a good BBB percentile, exceeding the 70% threshold. Ligand B (47.421) is significantly lower, indicating poor predicted brain penetration.

**Caco-2 Permeability:** Ligand A (-4.437) has a negative Caco-2 value, which is unusual and may indicate issues with the prediction method or a very low permeability. Ligand B (-5.519) is also negative and similarly concerning.

**Aqueous Solubility:** Both ligands have negative solubility values, which is also unusual. This suggests the prediction method is struggling with these compounds.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (A: 0.448, B: 0.617).

**Microsomal Clearance:** Ligand A (69.68) has a lower microsomal clearance than Ligand B (12.474), indicating better metabolic stability.

**In vitro Half-Life:** Ligand A (-6.473) has a negative half-life, which is not physically possible and indicates a problem with the prediction. Ligand B (30.807) is more reasonable.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (A: 0.04, B: 0.05).

**Binding Affinity:** Ligand B (-9.3 kcal/mol) has a significantly stronger binding affinity than Ligand A (-7.5 kcal/mol). This is a substantial advantage (1.8 kcal/mol difference).

**Overall Assessment:**

Despite the concerning negative values for Caco-2 and solubility, and the negative half-life for Ligand A, Ligand A is the more promising candidate. Its superior TPSA, QED, DILI, BBB, and metabolic stability (lower Cl_mic) are crucial for a CNS-targeting GPCR ligand. The stronger binding affinity of Ligand B is attractive, but the poor BBB penetration and higher DILI risk are significant drawbacks. The negative predictions for solubility and permeability for both compounds are concerning and would require experimental validation, but the overall profile of Ligand A is more favorable for development as a CNS drug.

Output:
0
2025-04-17 04:45:29,744 - INFO - Reasoning:

Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (343.354 Da) is slightly lower, which could be beneficial for permeability. Ligand B (361.389 Da) is also good.

**TPSA:** Ligand A (66.84) is excellent, well below the 90 A^2 threshold for CNS targets. Ligand B (112.73) is higher, but still potentially acceptable, though less ideal for CNS penetration.

**logP:** Ligand A (2.874) is optimal. Ligand B (0.177) is quite low, potentially hindering membrane permeability and CNS penetration.

**H-Bond Donors/Acceptors:** Ligand A (1 HBD, 4 HBA) is favorable. Ligand B (3 HBD, 4 HBA) is also reasonable.

**QED:** Both ligands have acceptable QED values (Ligand A: 0.848, Ligand B: 0.535), indicating good drug-like properties.

**DILI:** Ligand A (53.625) has a moderate DILI risk, while Ligand B (34.82) has a lower, more favorable DILI risk.

**BBB:** Ligand A (77.084) has a good BBB percentile, exceeding the 70% threshold. Ligand B (57.076) is lower, suggesting reduced CNS penetration. This is a critical factor for DRD2.

**Caco-2 Permeability:** Ligand A (-4.298) has poor Caco-2 permeability. Ligand B (-5.228) also has poor Caco-2 permeability.

**Aqueous Solubility:** Ligand A (-4.422) has poor solubility. Ligand B (-2.163) has slightly better solubility.

**hERG:** Both ligands have low hERG risk (Ligand A: 0.49, Ligand B: 0.31).

**Microsomal Clearance:** Ligand A (87.235) has higher microsomal clearance, indicating faster metabolism. Ligand B (17.033) has much lower clearance, suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (-6.679) has a short half-life. Ligand B (-17.592) has a very short half-life.

**P-gp Efflux:** Both ligands have low P-gp efflux (Ligand A: 0.119, Ligand B: 0.042), which is good for CNS exposure.

**Binding Affinity:** Both ligands have comparable binding affinities (-7.7 kcal/mol and -7.6 kcal/mol), which are excellent. The difference is negligible.

**Overall Assessment:**

Ligand A is superior due to its significantly better BBB penetration (77.084 vs 57.076) and optimal logP (2.874 vs 0.177). While Ligand B has a slightly lower DILI risk and better metabolic stability, the CNS target necessitates prioritizing BBB and logP. The comparable binding affinities make these factors the deciding ones. The poor Caco-2 and solubility for both are concerning, but can be addressed with formulation strategies.

Output:
1
2025-04-17 04:45:29,744 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (338.371 and 342.41 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (93.96) is better than Ligand B (43.37). For CNS targets, TPSA should be <=90, so Ligand A is closer to the ideal range.

**logP:** Ligand A (2.549) is optimal (1-3). Ligand B (4.607) is slightly higher, potentially leading to solubility issues or off-target interactions, but still within a tolerable range.

**H-Bond Donors/Acceptors:** Ligand A has 2 HBD and 7 HBA, while Ligand B has 0 HBD and 3 HBA. Both are within acceptable limits (<=5 HBD and <=10 HBA).

**QED:** Both ligands have acceptable QED values (0.687 and 0.569, both >= 0.5).

**DILI:** Ligand A (84.606) has a higher DILI risk than Ligand B (65.413). This is a negative for Ligand A.

**BBB:** Both ligands have good BBB penetration (72.237 and 71.229, both >70), which is crucial for CNS targets like DRD2.

**Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and suggests poor permeability. However, these values are on a different scale and difficult to interpret directly without knowing the scale's specifics.

**Aqueous Solubility:** Both have negative solubility values, which is also unusual. Again, the scale is unknown, making direct comparison difficult.

**hERG Inhibition:** Both ligands show very low hERG inhibition risk (0.198 and 0.409).

**Microsomal Clearance:** Ligand A (35.897) has significantly lower microsomal clearance than Ligand B (123.748), indicating better metabolic stability.

**In vitro Half-Life:** Ligand A (9.603) has a shorter half-life than Ligand B (25.382).

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.368 and 0.647).

**Binding Affinity:** Ligand A (-9.4 kcal/mol) has a significantly stronger binding affinity than Ligand B (-8.8 kcal/mol). This 0.6 kcal/mol difference is substantial and can outweigh some ADME drawbacks.

**Overall Assessment:**

Ligand A is superior due to its significantly higher binding affinity, lower microsomal clearance (better metabolic stability), and more favorable TPSA. While Ligand A has a higher DILI risk, the strong binding affinity is a major advantage for a GPCR target. The negative solubility and Caco-2 values are concerning for both, but the potency difference is likely to be more impactful in early stages of development.

Output:
1
2025-04-17 04:45:29,744 - INFO - Batch 140 complete. Total preferences: 2240
2025-04-17 04:45:29,745 - INFO - Processing batch 141/512...
2025-04-17 04:46:13,470 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight (MW):** Both ligands (376.513 and 360.483 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (49.41) is significantly better than Ligand B (60.23).  For CNS targets, we want TPSA <= 90, and ideally closer to 60. Ligand A is much closer to this ideal.

**3. logP:** Both ligands have good logP values (3.31 and 3.666), falling within the optimal 1-3 range.

**4. H-Bond Donors (HBD):** Both ligands are acceptable (1 and 0 respectively), well below the threshold of 5.

**5. H-Bond Acceptors (HBA):** Both ligands are acceptable (3 and 7 respectively), below the threshold of 10.

**6. QED:** Both ligands have similar, acceptable QED values (0.595 and 0.543), indicating good drug-like properties.

**7. DILI:** Ligand A (15.743) has a much lower DILI risk than Ligand B (35.13). This is a significant advantage.

**8. BBB:** This is a critical parameter for CNS targets. Ligand A (94.184) has excellent BBB penetration, exceeding the desirable >70 threshold. Ligand B (51.687) is considerably lower and less promising for CNS activity.

**9. Caco-2 Permeability:** Ligand A (-4.981) and Ligand B (-5.526) both have negative values, indicating poor permeability. This is concerning but not a dealbreaker if other properties are strong.

**10. Aqueous Solubility:** Both ligands have very poor aqueous solubility (-2.94 and -2.936). This could pose formulation challenges.

**11. hERG Inhibition:** Both ligands have similar, low hERG inhibition risk (0.8 and 0.855).

**12. Microsomal Clearance (Cl_mic):** Ligand A (34.036) has lower clearance than Ligand B (76.429), suggesting better metabolic stability.

**13. In vitro Half-Life (t1/2):** Ligand B (42.96) has a significantly longer half-life than Ligand A (-2.011). This is a positive for Ligand B, but can be overcome with formulation strategies.

**14. P-gp Efflux:** Both ligands have similar P-gp efflux liability (0.17 and 0.6).

**15. Binding Affinity:** Ligand B (-7.3) has a slightly better binding affinity than Ligand A (-7.1), but the difference is small (0.2 kcal/mol). This difference is unlikely to outweigh the substantial advantages of Ligand A in other key ADME properties.

**Overall Assessment:**

Ligand A is the superior candidate. While Ligand B has slightly better affinity and half-life, Ligand A excels in critical areas for a CNS-targeting GPCR ligand: TPSA, BBB penetration, and DILI risk. The lower metabolic clearance of Ligand A is also a benefit. The poor solubility and Caco-2 permeability are concerns for both, but can potentially be addressed through formulation strategies. The significantly better BBB penetration of Ligand A is the deciding factor.

Output:
1
2025-04-17 04:46:13,470 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (354.491 and 360.443 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (84.5) is excellent, well below the 90 threshold for CNS targets. Ligand B (96.17) is still reasonable but less optimal.

**logP:** Ligand A (2.7) is within the optimal 1-3 range. Ligand B (0.639) is quite low, potentially hindering membrane permeability and CNS penetration despite a good TPSA.

**H-Bond Donors/Acceptors:** Both have 2 HBDs, which is good. Ligand A has 4 HBAs, and Ligand B has 8 HBAs. Both are acceptable, but Ligand A is slightly better.

**QED:** Both ligands have similar QED values (0.624 and 0.61), indicating good drug-likeness.

**DILI:** Ligand A (22.373) has a significantly lower DILI risk than Ligand B (79.953), which is a substantial advantage.

**BBB:** Ligand A (69.756) has a good BBB percentile, although ideally >70. Ligand B (38.891) is considerably lower, raising concerns about CNS exposure. This is a critical factor for a DRD2 ligand.

**Caco-2 Permeability:** Ligand A (-4.66) is poor, while Ligand B (-5.459) is even worse. Both are problematic, but the lower logP of B likely contributes to this.

**Aqueous Solubility:** Both are very poor (-2.889 and -2.713). This could pose formulation challenges, but might be mitigated by formulation strategies.

**hERG:** Both ligands have very low hERG risk (0.254 and 0.212).

**Microsomal Clearance:** Ligand B (33.434) has a lower microsomal clearance than Ligand A (69.369), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (-7.328) has a significantly longer half-life than Ligand B (-1.826).

**P-gp Efflux:** Both have low P-gp efflux liability (0.097 and 0.075).

**Binding Affinity:** Ligand B (-8.5 kcal/mol) has a stronger binding affinity than Ligand A (-7.7 kcal/mol). This is a 0.8 kcal/mol difference, which is significant.

**Overall Assessment:**

While Ligand B boasts a better binding affinity and metabolic stability, Ligand A is the more promising candidate. The significantly lower DILI risk, better BBB penetration, and longer half-life of Ligand A outweigh the affinity advantage of Ligand B, especially considering the target is a CNS GPCR. The poor Caco-2 permeability is a concern for both, but can be addressed through formulation. The low logP of Ligand B is a major drawback for CNS penetration.

Output:
1
2025-04-17 04:46:13,470 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (380.725 and 358.844 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (65.22) is higher than Ligand B (44.1). For CNS targets, we prefer TPSA <= 90, so both are acceptable, but B is better.

**3. logP:** Both ligands have good logP values (4.463 and 4.797), falling within the optimal 1-3 range, although slightly high.

**4. H-Bond Donors:** Both have 0 HBD, which is good.

**5. H-Bond Acceptors:** Ligand A has 5 HBA, and Ligand B has 2. Both are acceptable (<=10), with B being preferable.

**6. QED:** Both ligands have good QED scores (0.578 and 0.713), indicating good drug-like properties.

**7. DILI:** Ligand A (77.627) has a higher DILI risk than Ligand B (45.173). B is significantly better here.

**8. BBB:** Ligand A (68.67) and Ligand B (75.921) both have reasonably good BBB penetration, but B is better, exceeding 70%. This is crucial for a CNS target like DRD2.

**9. Caco-2 Permeability:** Both have negative Caco-2 values (-4.414 and -4.537), which is unusual and suggests poor permeability. This is a significant drawback for both.

**10. Aqueous Solubility:** Both have very poor aqueous solubility (-5.47 and -5.431). This is a concern for formulation and bioavailability.

**11. hERG Inhibition:** Ligand A (0.221) has slightly lower hERG inhibition risk than Ligand B (0.927), which is preferable.

**12. Microsomal Clearance:** Ligand A (79.997) has higher microsomal clearance than Ligand B (69.862), indicating lower metabolic stability. B is better.

**13. In vitro Half-Life:** Ligand B (0.892) has a very short half-life, while Ligand A (7.522) is better.

**14. P-gp Efflux:** Ligand A (0.263) has lower P-gp efflux than Ligand B (0.458), which is preferable for CNS exposure.

**15. Binding Affinity:** Ligand A (-9.1 kcal/mol) has a slightly better binding affinity than Ligand B (-8.5 kcal/mol). This is a significant advantage.

**Overall Assessment:**

While Ligand A has a better binding affinity and P-gp efflux, Ligand B demonstrates superior ADME properties, particularly regarding DILI risk, BBB penetration, and microsomal clearance. The Caco-2 and solubility are poor for both, but the better overall profile of Ligand B, especially for a CNS target, makes it the more promising candidate. The 0.6 kcal/mol difference in binding affinity can potentially be overcome with further optimization, while addressing the solubility and permeability issues is more challenging.

Output:
1
2025-04-17 04:46:13,470 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (348.491 and 354.47 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Both ligands have a TPSA of 47.1, which is acceptable but on the higher side for CNS penetration. Ideally, we'd like to see values below 90, and these are right at the limit.

**3. logP:** Ligand A (0.506) is slightly lower than optimal (1-3), potentially hindering membrane permeability. Ligand B (0.431) is even lower, raising more concern about permeability.

**4. H-Bond Donors:** Both ligands have 0 HBD, which is good.

**5. H-Bond Acceptors:** Both ligands have 4 HBA, which is acceptable.

**6. QED:** Ligand B (0.738) has a better QED score than Ligand A (0.497), indicating a more drug-like profile.

**7. DILI:** Ligand A (13.3) has a significantly lower DILI risk than Ligand B (8.841), which is a major advantage.

**8. BBB:** Ligand B (76.541) has a substantially better BBB penetration percentile than Ligand A (54.517). This is a critical factor for a CNS target like DRD2.

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.627 and -4.747), which is unusual and suggests poor intestinal absorption. This is not a primary concern for a CNS target where direct delivery or high brain exposure is prioritized.

**10. Aqueous Solubility:** Both ligands have negative solubility values (-0.357 and -1.12), indicating poor aqueous solubility. This could pose formulation challenges.

**11. hERG Inhibition:** Both ligands have low hERG inhibition risk (0.255 and 0.477).

**12. Microsomal Clearance:** Ligand B (-22.906) has a much lower (better) microsomal clearance than Ligand A (7.489), suggesting greater metabolic stability.

**13. In vitro Half-Life:** Ligand B (-23.267) has a much longer in vitro half-life than Ligand A (-11.855), which is highly desirable.

**14. P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.01 and 0.008).

**15. Binding Affinity:** Both ligands have similar binding affinities (-6.4 and -6.9 kcal/mol). Ligand B is slightly better, but the difference is not substantial enough to outweigh other factors.

**Overall Assessment:**

Ligand B is superior due to its significantly better BBB penetration (76.541 vs 54.517), lower microsomal clearance, and longer half-life. While its logP is low, the strong BBB penetration suggests it can still reach the target in the CNS. The better QED score is also a positive. Ligand A has a lower DILI risk, but the BBB issue is more critical for a CNS drug.

Output:
1
2025-04-17 04:46:13,470 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (347.331 and 344.419 Da) fall within the ideal range of 200-500 Da.

**TPSA:** Ligand A (123.47) is slightly above the optimal <90 for CNS targets, but still reasonable. Ligand B (103.01) is better, falling comfortably below 90.

**logP:** Ligand A (-0.684) is a bit low, potentially hindering permeability. Ligand B (1.046) is within the optimal 1-3 range. This is a significant advantage for Ligand B.

**H-Bond Donors/Acceptors:** Ligand A (1 HBD, 8 HBA) is better than Ligand B (3 HBD, 6 HBA) in terms of balancing solubility and permeability.

**QED:** Both ligands have good QED scores (0.658 and 0.694), indicating drug-like properties.

**DILI:** Ligand A (69.019) has a higher DILI risk than Ligand B (57.387), though both are acceptable.

**BBB:** Ligand A (48.003) has a low BBB penetration percentile, which is a major drawback for a CNS target. Ligand B (36.642) is also low, but slightly better. Both are far from the desirable >70.

**Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and suggests poor permeability.

**Aqueous Solubility:** Both have negative solubility values, which is also unusual and suggests poor solubility.

**hERG:** Ligand A (0.032) has a very low hERG risk, which is excellent. Ligand B (0.441) has a slightly higher, but still acceptable, hERG risk.

**Microsomal Clearance:** Ligand A (28.832) has lower microsomal clearance than Ligand B (38.367), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (-28.733) has a negative half-life, which is not possible. Ligand B (19.976) has a reasonable half-life.

**P-gp Efflux:** Ligand A (0.053) has lower P-gp efflux, which is beneficial for CNS penetration. Ligand B (0.011) has even lower P-gp efflux, which is even better.

**Binding Affinity:** Ligand B (-8.8 kcal/mol) has a significantly stronger binding affinity than Ligand A (-7.4 kcal/mol). This >1.5 kcal/mol difference is a substantial advantage.

**Overall Assessment:**

Ligand B is the superior candidate. While both have issues with Caco-2 and solubility, Ligand B's stronger binding affinity, better logP, and lower P-gp efflux outweigh Ligand A's slightly better H-bonding profile and lower DILI. The biggest concern for both is the low BBB penetration, but the stronger affinity of Ligand B makes it more likely to achieve sufficient target engagement even with limited brain exposure. The negative half-life for Ligand A is a critical flaw.

Output:
1
2025-04-17 04:46:13,471 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (366.37 and 362.86 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (89.9) is better than Ligand B (67.23). Both are below the 90 A^2 threshold for CNS targets, which is excellent.

**logP:** Both ligands have good logP values (2.442 and 1.986), falling within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Both have 1 HBD, which is good. Ligand A has 7 HBA, while Ligand B has 4. Both are acceptable, being under the 10 HBA limit.

**QED:** Both ligands have good QED scores (0.624 and 0.814), indicating good drug-like properties.

**DILI:** Ligand A (85.27%) has a significantly higher DILI risk than Ligand B (49.59%). This is a major concern for Ligand A.

**BBB:** Ligand B (74.45%) has a better BBB penetration score than Ligand A (68.40%). Both are above 70%, which is desirable for CNS targets, but B is preferable.

**Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and suggests poor permeability. However, the scale is not specified, so it's hard to interpret.

**Aqueous Solubility:** Both have negative solubility values, indicating poor solubility. Again, the scale is unspecified.

**hERG:** Both ligands have very low hERG inhibition liability (0.251 and 0.178), which is excellent.

**Microsomal Clearance:** Ligand B (1.325) has much lower microsomal clearance than Ligand A (92.721), indicating better metabolic stability.

**In vitro Half-Life:** Ligand B (3.09 hours) has a slightly longer half-life than Ligand A (41.904 hours), though the units are inconsistent.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.646 and 0.232), which is good for CNS penetration.

**Binding Affinity:** Ligand B (-8.9 kcal/mol) has a slightly better binding affinity than Ligand A (-8.3 kcal/mol). While the difference is not huge, it's still a factor.

**Overall Assessment:**

Ligand B is significantly better overall. It has a much lower DILI risk, better metabolic stability (lower Cl_mic), a slightly better BBB score, and a slightly better binding affinity. While both have issues with Caco-2 and solubility, the DILI and metabolic stability advantages of Ligand B are crucial. The slightly better affinity further supports choosing Ligand B.

Output:
1
2025-04-17 04:46:13,471 - INFO - Reasoning:

Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (397.276) is slightly higher than Ligand B (361.511), but both are acceptable.

**2. TPSA:** Ligand A (47.09) is better than Ligand B (52.65). For CNS targets, we want TPSA <= 90, and ideally lower. Both are well within this range, but A is preferable.

**3. logP:** Ligand A (4.782) is higher than Ligand B (1.836). While 4.782 is approaching the upper limit of optimal (1-3), it's not drastically outside. Ligand B's logP is quite low, potentially hindering permeation. This favors Ligand A.

**4. H-Bond Donors:** Ligand A (0) is better than Ligand B (1). Fewer H-bond donors generally improve permeability.

**5. H-Bond Acceptors:** Ligand A (5) is better than Ligand B (4). Both are within the acceptable range of <=10.

**6. QED:** Ligand B (0.814) is better than Ligand A (0.488). A higher QED generally indicates better drug-likeness. This slightly favors Ligand B.

**7. DILI:** Ligand B (32.067) is significantly better than Ligand A (67.623). Lower DILI risk is crucial. This is a strong advantage for Ligand B.

**8. BBB:** Ligand A (81.698) is better than Ligand B (65.413). For a CNS target like DRD2, high BBB penetration is critical. Ligand A is desirable (>70), while Ligand B is below this threshold.

**9. Caco-2:** Ligand A (-5.022) is better than Ligand B (-4.799). Higher Caco-2 permeability is preferred.

**10. Solubility:** Ligand A (-3.68) is better than Ligand B (-1.731). Higher solubility is generally preferred.

**11. hERG:** Ligand A (0.923) is better than Ligand B (0.669). Lower hERG inhibition is crucial for avoiding cardiotoxicity.

**12. Cl_mic:** Ligand B (7.983) is better than Ligand A (46.364). Lower microsomal clearance indicates greater metabolic stability, which is highly desirable.

**13. t1/2:** Ligand A (70.822) is better than Ligand B (6.363). A longer half-life is generally preferred.

**14. Pgp:** Ligand A (0.848) is better than Ligand B (0.227). Lower P-gp efflux is preferred for CNS exposure.

**15. Binding Affinity:** Ligand A (-9.5) is significantly better than Ligand B (-8). A difference of >1.5 kcal/mol is substantial and can outweigh minor ADME drawbacks.

**Overall Assessment:**

Ligand A excels in binding affinity, BBB penetration, solubility, hERG, Pgp efflux, and in vitro half-life. Ligand B has a better QED, DILI score, and microsomal clearance. However, the significantly stronger binding affinity of Ligand A (-9.5 vs -8 kcal/mol) and its superior BBB penetration are critical for a CNS target like DRD2. While Ligand B's lower DILI is attractive, the potency and CNS penetration advantages of Ligand A are more important in this context. The slightly higher logP of Ligand A is manageable.

Output:
1
2025-04-17 04:46:13,471 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (365.415 and 350.463 Da) are within the ideal 200-500 Da range.

**TPSA:** Ligand A (108.49) is higher than Ligand B (84.42). For CNS targets, we prefer TPSA <= 90, so Ligand B is better here.

**logP:** Ligand A (0.469) is quite low, potentially hindering permeability. Ligand B (1.952) is within the optimal 1-3 range. This is a significant advantage for Ligand B.

**H-Bond Donors:** Both have 1 HBD, which is acceptable.

**H-Bond Acceptors:** Ligand A has 7 HBA, and Ligand B has 6. Both are within the acceptable limit of <=10.

**QED:** Both ligands have reasonable QED values (0.764 and 0.685), indicating good drug-like properties.

**DILI:** Ligand A (73.245) has a higher DILI risk than Ligand B (52.191). Both are acceptable (<60 is good), but B is preferable.

**BBB:** Ligand A (32.222) has a very low BBB penetration percentile, making it unlikely to effectively reach the target in the CNS. Ligand B (44.281) is better, but still not ideal (we want >70 for CNS targets).

**Caco-2 Permeability:** Ligand A (-5.047) shows poor permeability. Ligand B (-4.735) is slightly better, but both are quite poor.

**Aqueous Solubility:** Both ligands have very poor aqueous solubility (-1.912 and -2.047). This could pose formulation challenges.

**hERG Inhibition:** Both ligands show low hERG inhibition liability (0.279 and 0.104), which is good.

**Microsomal Clearance:** Ligand A (24.853) has lower microsomal clearance than Ligand B (77.883), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (-25.328) has a negative half-life, which is not possible. This is likely an error in the data. Ligand B (4.482) has a short half-life, but it's a realistic value.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.03), which is favorable for CNS penetration.

**Binding Affinity:** Ligand A (-7.1 kcal/mol) has a slightly better binding affinity than Ligand B (-6.9 kcal/mol). However, the difference is less than 1.5 kcal/mol.

**Overall Assessment:**

Considering the GPCR-specific priorities, Ligand B is the more promising candidate. While its binding affinity is slightly lower, its significantly better logP, TPSA, and BBB penetration outweigh this difference. Ligand A's very low BBB penetration and poor permeability are major drawbacks for a CNS target. The negative half-life reported for Ligand A is also a red flag.

Output:
1
2025-04-17 04:46:13,471 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight (MW):** Both ligands (351.353 and 348.487 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (73.64) is better than Ligand B (69.64) in terms of TPSA, both are below the 90 A^2 threshold for CNS targets.

**3. logP:** Both ligands have good logP values (1.777 and 2.082) falling within the optimal 1-3 range.

**4. H-Bond Donors (HBD):** Both ligands are acceptable (0 and 2, respectively), well below the limit of 5.

**5. H-Bond Acceptors (HBA):** Both ligands are acceptable (4 and 3, respectively), well below the limit of 10.

**6. QED:** Both ligands have similar, good QED values (0.81 and 0.799), indicating good drug-like properties.

**7. DILI:** Ligand A (48.275) has a slightly higher DILI risk than Ligand B (9.19), but both are below the concerning threshold of 60.

**8. BBB:** Ligand A (85.731) has a significantly better BBB penetration percentile than Ligand B (64.793). This is a critical advantage for a CNS target like DRD2.

**9. Caco-2 Permeability:** Ligand A (-4.159) has a higher Caco-2 permeability than Ligand B (-4.907).

**10. Aqueous Solubility:** Both ligands have similar, poor aqueous solubility (-2.409 and -2.162). This is a potential concern for both, but not a deciding factor.

**11. hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.536 and 0.435).

**12. Microsomal Clearance (Cl_mic):** Ligand A (15.972) has a lower microsomal clearance than Ligand B (22.749), suggesting better metabolic stability.

**13. In vitro Half-Life:** Ligand A (-12.621) has a longer in vitro half-life than Ligand B (9.818).

**14. P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.136 and 0.125).

**15. Binding Affinity:** Ligand B (-9.1) has a slightly better binding affinity than Ligand A (-8.0). However, the difference is less than 1.5 kcal/mol.

**Overall Assessment:**

Considering the GPCR-specific priorities, Ligand A is the more promising candidate. Its significantly better BBB penetration (85.731 vs 64.793) is a major advantage for a CNS target. It also exhibits better metabolic stability (lower Cl_mic and longer half-life) and Caco-2 permeability. While Ligand B has slightly better binding affinity, the difference is not substantial enough to outweigh the advantages of Ligand A regarding CNS penetration and metabolic properties.

Output:
1
2025-04-17 04:46:13,471 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (370.515 and 347.503 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (78.87) is higher than Ligand B (61.44). For CNS targets, we prefer TPSA <= 90, so both are acceptable, but B is better.

**3. logP:** Both ligands have good logP values (1.189 and 2.086), falling within the optimal 1-3 range.

**4. H-Bond Donors:** Both have 2 HBD, which is within the acceptable limit of <=5.

**5. H-Bond Acceptors:** Ligand A has 5 HBA, and Ligand B has 3. Both are below the limit of <=10.

**6. QED:** Both ligands have good QED scores (0.658 and 0.693), indicating good drug-like properties.

**7. DILI:** Ligand A (22.489) has a slightly higher DILI risk than Ligand B (4.343), but both are well below the concerning threshold of 60.

**8. BBB:** This is a crucial parameter for CNS targets. Ligand B (70.531) has a significantly better BBB penetration percentile than Ligand A (25.824). This is a major advantage for B.

**9. Caco-2 Permeability:** Both have negative values, which is unusual and suggests poor permeability. However, the scale isn't specified, so it's hard to interpret.

**10. Aqueous Solubility:** Both have negative values, which is also unusual. Again, the scale is unclear, making interpretation difficult.

**11. hERG Inhibition:** Both ligands show low hERG inhibition liability (0.133 and 0.363), which is favorable.

**12. Microsomal Clearance:** Ligand B (-21.433) has a much lower (better) microsomal clearance than Ligand A (28.613), indicating greater metabolic stability.

**13. In vitro Half-Life:** Ligand B (-5.91) has a longer in vitro half-life than Ligand A (-3.959), which is desirable.

**14. P-gp Efflux:** Both ligands show low P-gp efflux liability (0.039 and 0.032), which is good.

**15. Binding Affinity:** Ligand B (-9.1 kcal/mol) has a significantly stronger binding affinity than Ligand A (-6.9 kcal/mol). This difference of 2.2 kcal/mol is substantial and can outweigh minor drawbacks in other properties.

**Overall Assessment:**

Ligand B is clearly the superior candidate. It has a significantly better BBB penetration, a much stronger binding affinity, better metabolic stability (lower Cl_mic and longer t1/2), and a lower DILI risk. While both have unusual solubility and Caco-2 permeability values, the other advantages of Ligand B, particularly its strong affinity and BBB penetration, make it the more promising drug candidate for a CNS target like DRD2.

Output:
1
2025-04-17 04:46:13,471 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (361.27 and 351.447 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (64.11) is excellent, well below the 90 A^2 threshold for CNS targets. Ligand B (78.95) is still reasonable but less optimal.

**logP:** Ligand A (3.396) is within the optimal 1-3 range. Ligand B (0.53) is quite low, potentially hindering membrane permeability and CNS penetration despite a good BBB score.

**H-Bond Donors/Acceptors:** Both have 1 HBD and 4 HBA, which are acceptable values.

**QED:** Both ligands have good QED scores (0.655 and 0.801), indicating drug-like properties.

**DILI:** Ligand A (68.166) has a higher DILI risk than Ligand B (16.247). This is a significant negative for Ligand A.

**BBB:** Both ligands have good BBB penetration (77.821 and 74.486), which is crucial for a CNS target like DRD2.

**Caco-2 Permeability:** Ligand A (-4.834) has poor Caco-2 permeability, while Ligand B (-4.522) is also poor, but slightly better.

**Aqueous Solubility:** Both ligands have very poor aqueous solubility (-3.165 and -1.389). This could pose formulation challenges.

**hERG Inhibition:** Both ligands show low hERG inhibition risk (0.405 and 0.136).

**Microsomal Clearance:** Ligand A (19.684) has higher microsomal clearance than Ligand B (-0.838), suggesting lower metabolic stability.

**In vitro Half-Life:** Ligand B (-12.294) has a significantly longer in vitro half-life than Ligand A (7.641).

**P-gp Efflux:** Ligand A (0.119) shows lower P-gp efflux liability than Ligand B (0.016), which is favorable for CNS penetration.

**Binding Affinity:** Ligand A (-9.6 kcal/mol) has a significantly stronger binding affinity than Ligand B (-7.8 kcal/mol). The 1.8 kcal/mol difference is substantial and could outweigh some of the ADME drawbacks of Ligand A.

**Overall Assessment:**

Ligand A has a much stronger binding affinity, a better TPSA, and lower P-gp efflux. However, it suffers from higher DILI risk, higher microsomal clearance, poor Caco-2 permeability, and lower in vitro half-life. Ligand B has better ADME properties (lower DILI, better metabolic stability, slightly better Caco-2, longer half-life) but significantly weaker binding affinity and a concerningly low logP.

Given the importance of binding affinity for GPCRs, and the fact that both ligands have acceptable BBB penetration, the stronger affinity of Ligand A is the deciding factor. While its ADME properties are less ideal, optimization efforts could focus on improving those aspects without sacrificing potency. The low logP of Ligand B is a major concern that would be difficult to overcome.

Output:
1
2025-04-17 04:46:13,471 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B based on the provided guidelines, prioritizing GPCR-specific properties (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (348.403 and 366.571 Da) fall within the ideal range of 200-500 Da.

**TPSA:** Ligand A (109.42) is higher than the preferred <90 for CNS targets, while Ligand B (42.43) is excellent. This is a significant advantage for Ligand B.

**logP:** Ligand A (0.767) is a bit low, potentially hindering permeation. Ligand B (4.893) is high, potentially causing solubility or off-target issues, but within an acceptable range.

**H-Bond Donors/Acceptors:** Ligand A has 3 HBD and 5 HBA, which are reasonable. Ligand B has 0 HBD and 4 HBA, also acceptable.

**QED:** Both ligands have similar QED values (0.703 and 0.657), indicating good drug-likeness.

**DILI:** Ligand A (44.591) has a slightly higher DILI risk than Ligand B (14.773), though both are below the concerning threshold of 60.

**BBB:** Ligand B (91.508) has a significantly higher BBB penetration percentile than Ligand A (67.701). This is a crucial advantage for a CNS target like DRD2.

**Caco-2 Permeability:** Both have negative values, indicating permeability issues. However, the scale is not defined, so it's hard to interpret.

**Aqueous Solubility:** Both have negative values, indicating poor solubility. Again, the scale is not defined.

**hERG Inhibition:** Ligand A (0.064) has a slightly lower hERG inhibition risk than Ligand B (0.685), which is preferable.

**Microsomal Clearance:** Ligand B (110.014) has a much higher microsomal clearance than Ligand A (18.909), suggesting lower metabolic stability.

**In vitro Half-Life:** Ligand A (-11.96) has a negative half-life, which is problematic. Ligand B (11.467) has a reasonable half-life.

**P-gp Efflux:** Ligand A (0.013) has very low P-gp efflux, which is excellent for CNS penetration. Ligand B (0.633) has moderate P-gp efflux.

**Binding Affinity:** Ligand A (-8.3 kcal/mol) has a significantly stronger binding affinity than Ligand B (-6.8 kcal/mol). This is a substantial advantage for Ligand A, potentially outweighing some of its ADME drawbacks.

**Overall Assessment:**

Ligand B excels in TPSA and BBB penetration, which are critical for CNS GPCR targets. However, it suffers from higher logP and significantly higher microsomal clearance. Ligand A has a much better binding affinity and lower P-gp efflux, but its TPSA is higher and logP is lower. The superior binding affinity of Ligand A (-8.3 vs -6.8 kcal/mol) is a substantial advantage, and the low P-gp efflux is also favorable for CNS penetration. While Ligand A's TPSA is not ideal, the strong binding could compensate. The negative half-life of Ligand A is a major concern, though.

Considering the balance, the stronger binding affinity and lower P-gp efflux of Ligand A, despite its TPSA and half-life concerns, make it a more promising starting point for optimization. The half-life could be addressed through structural modifications.

Output:
0
2025-04-17 04:46:13,471 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (367.471 and 348.491 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (102.76) is higher than the preferred <90 for CNS targets, while Ligand B (55.89) is well within the range. This is a significant advantage for Ligand B.

**logP:** Ligand A (0.583) is a bit low, potentially hindering permeability. Ligand B (0.851) is also on the lower side, but slightly better. Both could benefit from increased lipophilicity, but aren't drastically outside the acceptable range.

**H-Bond Donors/Acceptors:** Ligand A has 3 HBD and 6 HBA, which are acceptable. Ligand B has 1 HBD and 4 HBA, also acceptable.

**QED:** Both ligands have good QED scores (0.612 and 0.723), indicating good drug-like properties.

**DILI:** Ligand A (34.858) has a slightly higher DILI risk than Ligand B (8.375), but both are below the concerning threshold of 60.

**BBB:** Ligand B (61.729) has a significantly better BBB percentile than Ligand A (33.23). This is a crucial advantage for a CNS target like DRD2.

**Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and suggests a potential issue with the data or the model used to predict it. However, the values are comparable.

**Aqueous Solubility:** Both ligands have negative solubility values, which is also unusual and potentially problematic. Again, values are comparable.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.171 and 0.202).

**Microsomal Clearance:** Ligand A (4.678) has slightly better metabolic stability (lower clearance) than Ligand B (3.023).

**In vitro Half-Life:** Ligand B (-14.1) has a much longer half-life than Ligand A (-7.908). This is a significant advantage.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.03 and 0.005), which is favorable for CNS penetration.

**Binding Affinity:** Ligand B (-7.7 kcal/mol) has a slightly better binding affinity than Ligand A (-7.2 kcal/mol), although the difference is not huge.

**Overall Assessment:**

Ligand B is the stronger candidate. It excels in key areas for a CNS-targeting GPCR ligand: significantly better BBB penetration, a longer half-life, and a slightly improved binding affinity. While Ligand A has slightly better metabolic stability, the benefits of Ligand B's improved CNS properties outweigh this. The TPSA of Ligand B is also much more favorable. The unusual negative values for Caco-2 and solubility are a concern for both, but don't dramatically shift the overall assessment.

Output:
1
2025-04-17 04:46:13,471 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (385.247 Da) is slightly higher than Ligand B (350.423 Da), but both are acceptable.

**2. TPSA:** Ligand A (80.68) is significantly better than Ligand B (113.24). For CNS targets, we want TPSA <= 90, and Ligand A is comfortably within this range, while Ligand B is above. This is a significant advantage for Ligand A.

**3. logP:** Ligand A (3.907) is optimal, while Ligand B (-0.278) is quite low. A logP below 1 can hinder permeation. This is a major advantage for Ligand A.

**4. H-Bond Donors:** Both ligands have 2 HBD, which is within the acceptable limit of <=5.

**5. H-Bond Acceptors:** Ligand A has 5 HBA, and Ligand B has 7. Both are within the limit of <=10, but Ligand A is slightly better.

**6. QED:** Both ligands have similar QED values (0.756 and 0.73), indicating good drug-like properties.

**7. DILI:** Ligand A (77.627) has a higher DILI risk than Ligand B (48.197). While both are below the concerning threshold of 60, Ligand B is preferable here.

**8. BBB:** Ligand A (57.154) has a significantly better BBB penetration percentile than Ligand B (27.336). For a CNS target like DRD2, this is a critical factor, and Ligand A is much more promising.

**9. Caco-2 Permeability:** Ligand A (-4.68) and Ligand B (-5.484) both have negative values, which is unusual and suggests poor permeability. However, the scale isn't specified, so it's difficult to interpret.

**10. Aqueous Solubility:** Ligand A (-4.984) and Ligand B (-1.486) both have negative values, suggesting poor solubility. Again, the scale is unclear.

**11. hERG Inhibition:** Ligand A (0.471) has a slightly higher hERG risk than Ligand B (0.021). Ligand B is much preferable here.

**12. Microsomal Clearance:** Ligand A (51.987) has higher clearance than Ligand B (-2.722). Lower clearance is preferred for metabolic stability, so Ligand B is better.

**13. In vitro Half-Life:** Ligand A (44.646) has a longer half-life than Ligand B (5.146). This is an advantage for Ligand A.

**14. P-gp Efflux:** Ligand A (0.332) has lower P-gp efflux than Ligand B (0.021). Lower efflux is preferred for CNS exposure, so Ligand A is better.

**15. Binding Affinity:** Ligand B (-9.1 kcal/mol) has a significantly stronger binding affinity than Ligand A (-8.2 kcal/mol). This is a substantial advantage for Ligand B. A difference of 0.9 kcal/mol is meaningful.

**Overall Assessment:**

While Ligand B has a superior binding affinity and lower DILI/hERG risk, Ligand A excels in crucial properties for CNS penetration: TPSA, logP, and BBB. The significantly better BBB penetration of Ligand A, coupled with its acceptable logP and TPSA, outweighs the affinity advantage of Ligand B. The poor solubility and permeability of both compounds are concerns, but can potentially be addressed with formulation strategies. Given the GPCR-specific priorities, and the importance of CNS penetration for DRD2, Ligand A is the more promising candidate.

Output:
1
2025-04-17 04:46:13,472 - INFO - Reasoning:

Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (373.869 Da) is slightly higher than Ligand B (340.383 Da), but both are acceptable.

**2. TPSA:** Ligand A (63.05) is significantly better than Ligand B (95.42). For CNS targets, we want TPSA <= 90, and Ligand A is comfortably within that range, while Ligand B is close to the upper limit and less favorable.

**3. logP:** Ligand A (3.345) is optimal (1-3), while Ligand B (1.412) is on the lower side. Lower logP can hinder permeation, making Ligand A preferable.

**4. H-Bond Donors:** Ligand A (1) and Ligand B (2) are both acceptable (<=5).

**5. H-Bond Acceptors:** Ligand A (6) and Ligand B (5) are both acceptable (<=10).

**6. QED:** Both ligands have good QED scores (Ligand A: 0.764, Ligand B: 0.877), indicating good drug-like properties.

**7. DILI:** Ligand A (79.411) has a higher DILI risk than Ligand B (63.746). While both are below the concerning threshold of 60, Ligand B is better.

**8. BBB:** This is crucial for a CNS target. Ligand A (73.401) has a good BBB percentile, while Ligand B (23.924) is very poor. This is a major advantage for Ligand A.

**9. Caco-2 Permeability:** Both are negative (-5.16 and -5.145), which isn't directly interpretable without knowing the scale. However, it's not a primary concern given the other data.

**10. Aqueous Solubility:** Both are negative (-4.116 and -2.954), again scale is unknown.

**11. hERG Inhibition:** Ligand A (0.593) has a slightly higher hERG risk than Ligand B (0.093), but both are relatively low.

**12. Microsomal Clearance:** Ligand A (72.152) has higher clearance than Ligand B (2.699), meaning it's less metabolically stable. Ligand B is significantly better here.

**13. In vitro Half-Life:** Ligand A (46.79) has a longer half-life than Ligand B (-23.929). This is a positive for Ligand A.

**14. P-gp Efflux:** Ligand A (0.675) has lower P-gp efflux than Ligand B (0.01), which is favorable for CNS penetration.

**15. Binding Affinity:** Ligand A (-10.1 kcal/mol) has a significantly stronger binding affinity than Ligand B (-8.6 kcal/mol). This is a substantial advantage for Ligand A, and can outweigh some of its ADME drawbacks.

**Overall Assessment:**

Ligand A is the stronger candidate. While it has a slightly higher DILI risk and clearance, its superior BBB penetration, optimal logP, excellent binding affinity, and lower P-gp efflux outweigh these concerns. Ligand B's poor BBB penetration is a significant drawback for a CNS-targeting drug, despite its better metabolic stability and lower DILI. The affinity difference is also substantial.

Output:
1
2025-04-17 04:46:13,472 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight (MW):** Both ligands (343.431 and 346.515 Da) fall comfortably within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (69.64) is better than Ligand B (40.62). Both are below the 90 A^2 threshold for CNS targets, but Ligand A is closer to the upper limit, potentially impacting BBB penetration slightly more than Ligand B.

**3. logP:** Ligand A (1.348) is within the optimal 1-3 range, while Ligand B (3.64) is at the higher end. While still acceptable, the higher logP of Ligand B could lead to solubility issues or off-target interactions.

**4. H-Bond Donors (HBD):** Both ligands have 0 HBD, which is acceptable.

**5. H-Bond Acceptors (HBA):** Ligand A has 5 HBA, while Ligand B has 2. Both are within the acceptable range of <=10.

**6. QED:** Ligand A (0.828) has a significantly better QED score than Ligand B (0.66), indicating a more drug-like profile.

**7. DILI:** Ligand A (51.26) has a moderate DILI risk, while Ligand B (16.053) has a very low DILI risk. This is a significant advantage for Ligand B.

**8. BBB:** Ligand A (87.631) and Ligand B (92.982) both have excellent BBB penetration potential, exceeding the desirable >70 percentile. Ligand B is slightly better.

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 values, which is unusual and potentially problematic. However, these values are on a different scale and hard to interpret without further context.

**10. Aqueous Solubility:** Both ligands have negative solubility values, indicating poor aqueous solubility. This is a concern for both, but potentially more so for Ligand B due to its higher logP.

**11. hERG Inhibition:** Both ligands have low hERG inhibition risk (0.278 and 0.389, respectively).

**12. Microsomal Clearance:** Ligand A (29.376) has lower microsomal clearance than Ligand B (71.405), suggesting better metabolic stability.

**13. In vitro Half-Life:** Ligand A (-6.895) has a much longer in vitro half-life than Ligand B (-20.052). This is a significant advantage for Ligand A.

**14. P-gp Efflux:** Both ligands have low P-gp efflux liability (0.166 and 0.334, respectively).

**15. Binding Affinity:** Both ligands have very similar and excellent binding affinities (-7.6 and -7.7 kcal/mol). The difference is negligible.

**Overall Assessment:**

Ligand B excels in BBB penetration and DILI risk. However, Ligand A demonstrates superior drug-likeness (QED), metabolic stability (lower Cl_mic), and a longer in vitro half-life. While both have poor solubility, the other advantages of Ligand A, particularly its better metabolic stability and half-life, make it a more promising candidate, especially considering the importance of CNS penetration and duration of action for DRD2 targets. The slightly higher TPSA of Ligand A is a minor concern compared to the other benefits.

Output:
1
2025-04-17 04:46:13,472 - INFO - Batch 141 complete. Total preferences: 2256
2025-04-17 04:46:13,472 - INFO - Processing batch 142/512...
2025-04-17 04:46:54,875 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 drug candidates, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (354.801 and 361.486 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (85.59) is better than Ligand B (37.27). For CNS targets, we want TPSA <= 90, both are within this range, but A is closer to the upper limit.

**logP:** Both ligands have good logP values (2.842 and 3.174), falling within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Both have 1 HBD, which is good. Ligand A has 6 HBA, while Ligand B has 4. Both are within the acceptable limit of <=10.

**QED:** Both ligands have good QED scores (0.731 and 0.889), indicating good drug-like properties.

**DILI:** Ligand A (95.502) has a significantly higher DILI risk than Ligand B (54.75). This is a major concern for Ligand A.

**BBB:** Ligand B (85.925) has a better BBB penetration percentile than Ligand A (77.007). Both are reasonably good, but B is better.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.898 and -4.987), which is unusual and suggests poor permeability. This is a significant drawback for both.

**Aqueous Solubility:** Both ligands have negative solubility values (-3.974 and -3.48), which is also concerning. Poor solubility can hinder bioavailability.

**hERG:** Ligand A (0.304) has a lower hERG inhibition liability than Ligand B (0.962), which is favorable.

**Microsomal Clearance:** Ligand B (42.283) has lower microsomal clearance than Ligand A (64.697), indicating better metabolic stability.

**In vitro Half-Life:** Ligand B (23.637) has a longer in vitro half-life than Ligand A (31.676), which is preferable.

**P-gp Efflux:** Ligand A (0.341) has lower P-gp efflux liability than Ligand B (0.546), which is better for CNS exposure.

**Binding Affinity:** Ligand A (-10.3 kcal/mol) has a significantly stronger binding affinity than Ligand B (-8.0 kcal/mol). This is a substantial advantage for Ligand A.

**Overall Assessment:**

Ligand A has a much stronger binding affinity, lower P-gp efflux, and lower hERG risk. However, it has a significantly higher DILI risk and slightly lower BBB penetration. Ligand B has better metabolic stability, longer half-life, lower DILI, and better BBB, but its binding affinity is considerably weaker.

Given the GPCR-specific priorities, BBB penetration is crucial for CNS targets like DRD2. However, the substantial difference in binding affinity (-10.3 vs -8.0 kcal/mol) is a major factor. A 2.3 kcal/mol difference is significant and can often outweigh minor ADME drawbacks. The DILI risk for Ligand A is concerning, but could potentially be mitigated through structural modifications. The poor Caco-2 and solubility for both are concerning and would need to be addressed.

Considering the balance, the stronger binding affinity of Ligand A is a decisive advantage, particularly for a GPCR target where achieving sufficient receptor occupancy is critical.

Output:
0
2025-04-17 04:46:54,876 - INFO - Reasoning:

Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (355.485 and 391.896 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (66.91) is significantly better than Ligand B (93.36). For CNS targets, we want TPSA <= 90, so Ligand A is preferable.

**3. logP:** Both ligands have good logP values (3.352 and 2.46), falling within the optimal 1-3 range.

**4. H-Bond Donors:** Ligand A (2) is slightly higher than Ligand B (1), but both are acceptable (<=5).

**5. H-Bond Acceptors:** Ligand A (5) is slightly higher than Ligand B (4), but both are acceptable (<=10).

**6. QED:** Both ligands have similar and good QED values (0.636 and 0.689), indicating good drug-like properties.

**7. DILI:** Ligand A (62.582) has a higher DILI risk than Ligand B (44.591). This favors Ligand B.

**8. BBB:** Both ligands have excellent BBB penetration (78.519 and 82.047), exceeding the desirable >70 threshold for CNS targets.

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 values, which is unusual and suggests potential issues with the data or modeling. However, the values are similar (-5.321 and -4.741).

**10. Aqueous Solubility:** Both ligands have negative solubility values, which is also unusual. Again, the values are similar (-4.272 and -3.617).

**11. hERG Inhibition:** Both ligands show low hERG inhibition liability (0.506 and 0.383), which is good.

**12. Microsomal Clearance:** Ligand B (35.288) has a lower microsomal clearance than Ligand A (40.416), indicating better metabolic stability.

**13. In vitro Half-Life:** Ligand B (-1.102) has a negative half-life, which is concerning and likely an artifact of the modeling. Ligand A (26.795) has a reasonable half-life.

**14. P-gp Efflux:** Both ligands have low P-gp efflux liability (0.241 and 0.143), which is favorable for CNS penetration.

**15. Binding Affinity:** Ligand A (-9.6 kcal/mol) has a significantly stronger binding affinity than Ligand B (-6.6 kcal/mol). This is a substantial advantage (>1.5 kcal/mol difference).

**Overall Assessment:**

While Ligand B has a slightly better DILI profile and metabolic stability, the significantly stronger binding affinity of Ligand A (-9.6 vs -6.6 kcal/mol) is a major advantage, especially for a GPCR target. The TPSA of Ligand A is also more favorable for CNS penetration. The unusual negative values for Caco-2 and Solubility are concerning for both, but the affinity difference is the deciding factor.

Output:
1
2025-04-17 04:46:54,876 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (347.415 and 367.471 Da) fall within the ideal 200-500 Da range.

**TPSA:** Both ligands (93.71 and 91.76) are below the 140 A^2 threshold for good oral absorption, and reasonably close to the 90 A^2 target for CNS penetration. Ligand B is slightly better.

**logP:** Ligand A (0.456) is a bit low, potentially hindering permeation. Ligand B (1.041) is better, falling within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Both have 2 HBDs, which is good. Ligand A has 4 HBAs, and Ligand B has 6. Both are acceptable, but Ligand B is slightly higher.

**QED:** Both ligands have good QED scores (0.809 and 0.751), indicating drug-like properties.

**DILI:** Ligand A (27.414) has a much lower DILI risk than Ligand B (42.187), which is a significant advantage.

**BBB:** Both ligands have relatively low BBB penetration (31.408 and 39.511). This is a concern for a CNS target like DRD2, but we'll consider it alongside other factors.

**Caco-2 Permeability:** Both have negative Caco-2 values (-4.821 and -4.88), which is unusual and suggests poor permeability.

**Aqueous Solubility:** Both have poor aqueous solubility (-1.5 and -1.153).

**hERG Inhibition:** Both have very low hERG inhibition risk (0.117 and 0.245).

**Microsomal Clearance:** Ligand A (-15.331) has significantly lower (better) microsomal clearance than Ligand B (-0.578), indicating greater metabolic stability.

**In vitro Half-Life:** Ligand A (-21.148) has a much longer in vitro half-life than Ligand B (6.235), which is a major advantage.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.016 and 0.029), which is good for CNS penetration.

**Binding Affinity:** Ligand A (-8.1 kcal/mol) has a significantly stronger binding affinity than Ligand B (-6.9 kcal/mol). This is a substantial difference and a key factor.

**Overall Assessment:**

Ligand A is the stronger candidate despite its lower logP and BBB. The significantly better binding affinity (-8.1 vs -6.9 kcal/mol), lower DILI risk, lower microsomal clearance, and longer half-life outweigh the slightly lower logP and BBB. While both have poor solubility and Caco-2 permeability, the affinity difference is substantial enough to prioritize Ligand A for further optimization. The better metabolic stability and reduced toxicity profile also contribute to its favorability.

Output:
1
2025-04-17 04:46:54,876 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (370.877 and 349.406 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (78.87) is higher than Ligand B (57). For CNS targets, TPSA should be <= 90, so both are acceptable, but B is better.

**3. logP:** Both ligands have good logP values (1.555 and 1.386), falling within the optimal 1-3 range.

**4. H-Bond Donors:** Ligand A (2) is acceptable, while Ligand B (0) is also good.

**5. H-Bond Acceptors:** Both ligands have 4 H-bond acceptors, which is within the acceptable limit of <=10.

**6. QED:** Both ligands have good QED scores (0.743 and 0.81), indicating good drug-like properties.

**7. DILI:** Ligand A (33.424) has a lower DILI risk than Ligand B (15.51), which is preferable.

**8. BBB:** This is a critical parameter for CNS targets. Ligand B (93.37) has a significantly higher BBB penetration percentile than Ligand A (58.24). This is a major advantage for Ligand B.

**9. Caco-2 Permeability:** Ligand A (-4.917) and Ligand B (-4.558) both have negative values, indicating poor permeability.

**10. Aqueous Solubility:** Both ligands have poor aqueous solubility (-2.548 and -2.017 respectively).

**11. hERG Inhibition:** Both ligands have low hERG inhibition risk (0.299 and 0.488).

**12. Microsomal Clearance:** Ligand B (4.371) has significantly lower microsomal clearance than Ligand A (18.762), suggesting better metabolic stability.

**13. In vitro Half-Life:** Ligand B (7.716) has a slightly longer half-life than Ligand A (35.571).

**14. P-gp Efflux:** Both ligands have low P-gp efflux liability (0.08 and 0.062).

**15. Binding Affinity:** Ligand B (-9.7 kcal/mol) has a significantly stronger binding affinity than Ligand A (-7.8 kcal/mol). This is a substantial advantage, exceeding the 1.5 kcal/mol threshold.

**Overall Assessment:**

While Ligand A has a slightly better DILI score, Ligand B excels in the most critical areas for a CNS-targeting GPCR ligand: BBB penetration and binding affinity. The significantly higher BBB value and the stronger binding affinity of Ligand B outweigh the slightly higher DILI risk and lower BBB of Ligand A. The lower clearance and longer half-life of Ligand B are also beneficial.

Output:
1
2025-04-17 04:46:54,877 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B against the provided guidelines, prioritizing GPCR-specific properties (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (356.5 and 350.5 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (57.26) is significantly better than Ligand B (87.46). For CNS targets, TPSA should be <=90, and A is comfortably within this range, while B is approaching the upper limit.

**logP:** Ligand A (3.39) is optimal (1-3), while Ligand B (1.483) is on the lower side. Lower logP can hinder permeation, especially across the BBB.

**H-Bond Donors/Acceptors:** Both have 2 HBD and 5 HBA, which are acceptable.

**QED:** Ligand A (0.882) has a higher QED score than Ligand B (0.743), indicating better overall drug-likeness.

**DILI:** Ligand B (35.285) has a much lower DILI risk than Ligand A (59.829), which is a significant advantage.

**BBB:** Ligand A (94.184) has a substantially higher BBB penetration percentile than Ligand B (66.227). This is *critical* for a CNS target like DRD2.

**Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and suggests potential issues with the modeling or data. However, the magnitude of the negative value is similar.

**Aqueous Solubility:** Both have negative solubility values, indicating poor aqueous solubility. This is a concern for both, but may be less critical if BBB penetration is high.

**hERG:** Ligand A (0.867) has a slightly higher hERG risk than Ligand B (0.259), making B safer from a cardiotoxicity perspective.

**Microsomal Clearance:** Ligand B (23.124) has a much higher microsomal clearance than Ligand A (4.602), indicating faster metabolism and potentially lower *in vivo* exposure.

**In vitro Half-Life:** Ligand A (40.18) has a longer half-life than Ligand B (-5.478), which is a positive attribute.

**P-gp Efflux:** Ligand A (0.421) has lower P-gp efflux liability than Ligand B (0.068), meaning A is less likely to be pumped out of the brain.

**Binding Affinity:** Ligand A (-8.4 kcal/mol) has a slightly better binding affinity than Ligand B (-7.8 kcal/mol). While both are good, the 1.5 kcal/mol difference is worth considering.

**Overall Assessment:**

Ligand A excels in BBB penetration, binding affinity, P-gp efflux, and metabolic stability (lower Cl_mic, longer t1/2). Ligand B has a lower DILI risk and hERG inhibition liability. However, for a CNS target, the superior BBB penetration of Ligand A is paramount. The slightly better affinity and lower P-gp efflux further strengthen its profile. While the DILI risk is higher for A, it's not excessively high, and the benefits outweigh this drawback. The solubility issues are a concern for both, but can be addressed with formulation strategies.

Output:
1
2025-04-17 04:46:54,877 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (359.5 & 357.5 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (54.46) is significantly better than Ligand B (102.34). For CNS targets, TPSA should be <=90, so Ligand A is much more favorable.

**logP:** Ligand A (2.825) is optimal (1-3). Ligand B (-1.055) is too low, potentially hindering membrane permeability.

**H-Bond Donors/Acceptors:** Ligand A (1 HBD, 5 HBA) is better balanced. Ligand B (3 HBD, 6 HBA) is acceptable but less ideal.

**QED:** Ligand A (0.862) is excellent, indicating strong drug-likeness. Ligand B (0.512) is acceptable, but lower.

**DILI:** Ligand A (68.05) is better than Ligand B (10.90), both are acceptable, but lower is better.

**BBB:** Ligand A (67.003) is good, exceeding the 70% threshold for CNS targets. Ligand B (28.693) is poor, suggesting limited brain penetration. This is a major drawback for a DRD2 ligand.

**Caco-2 Permeability:** Ligand A (-4.986) and Ligand B (-5.108) are both negative, meaning they are percentile scores. Both are similar, and not particularly high, but not a dealbreaker.

**Aqueous Solubility:** Ligand A (-2.971) and Ligand B (-0.298) are both negative, meaning they are percentile scores. Ligand B has slightly better solubility.

**hERG:** Ligand A (0.865) is better than Ligand B (0.066), indicating a lower risk of cardiotoxicity.

**Microsomal Clearance:** Ligand A (54.586) is better than Ligand B (9.853), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (54.609) is better than Ligand B (-8.588), suggesting a longer half-life.

**P-gp Efflux:** Ligand A (0.653) is better than Ligand B (0.007), indicating lower P-gp efflux and better CNS exposure.

**Binding Affinity:** Ligand B (-7.0 kcal/mol) has a significantly better binding affinity than Ligand A (-0.0 kcal/mol). This is a substantial advantage.

**Overall Assessment:**

Despite Ligand B's superior binding affinity, Ligand A is the more promising candidate. The critical factors for a CNS-targeting GPCR like DRD2 are BBB penetration, TPSA, and logP. Ligand A excels in these areas, while Ligand B fails to meet the TPSA and BBB thresholds and has a suboptimal logP. The significant difference in binding affinity *could* potentially overcome these ADME issues, but the poor predicted CNS exposure makes Ligand B a less viable candidate.

Output:
0
2025-04-17 04:46:54,877 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (338.459 and 318.873 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (60.56) is better than Ligand B (6.48). For CNS targets, a TPSA <= 90 is desirable, both meet this. However, lower is generally better for brain penetration, so A is favored.

**3. logP:** Ligand A (2.815) is within the optimal 1-3 range. Ligand B (4.894) is slightly above, potentially leading to solubility issues and off-target interactions.

**4. H-Bond Donors:** Ligand A (1) is good. Ligand B (0) is also acceptable.

**5. H-Bond Acceptors:** Ligand A (6) is good. Ligand B (3) is also good.

**6. QED:** Both ligands have similar QED values (0.72 and 0.792), indicating good drug-like properties.

**7. DILI:** Ligand A (41.024) has a lower DILI risk than Ligand B (53.625), which is preferable.

**8. BBB:** This is a critical parameter for a CNS target like DRD2. Ligand B (99.147) has *excellent* BBB penetration, significantly better than Ligand A (61.303). This is a major advantage for Ligand B.

**9. Caco-2 Permeability:** Ligand A (-5.465) and Ligand B (-4.228) both have negative values, which is unusual and suggests poor permeability. However, the scale is not specified, so it's hard to interpret.

**10. Aqueous Solubility:** Ligand A (-2.324) and Ligand B (-5.464) both have negative values, suggesting poor solubility.

**11. hERG Inhibition:** Ligand A (0.637) has a lower hERG risk than Ligand B (0.969), which is preferable.

**12. Microsomal Clearance:** Ligand A (22.341) and Ligand B (26.179) have similar microsomal clearance values.

**13. In vitro Half-Life:** Ligand B (47.055) has a much longer in vitro half-life than Ligand A (-17.77), which is a significant advantage.

**14. P-gp Efflux:** Ligand A (0.344) has lower P-gp efflux than Ligand B (0.725), which is preferable for CNS exposure.

**15. Binding Affinity:** Ligand B (-7.1) has a significantly stronger binding affinity than Ligand A (-8.9). A >1.5 kcal/mol advantage in binding is considered substantial and can outweigh minor ADME drawbacks.

**Overall Assessment:**

Ligand B excels in BBB penetration and binding affinity, two critical factors for a CNS GPCR target. While its logP is slightly higher and P-gp efflux is higher than Ligand A, the significantly improved BBB and binding affinity outweigh these concerns. Ligand B also has a much better in vitro half-life. Ligand A has a slightly better DILI and hERG profile, and lower P-gp efflux, but these differences are less impactful than the gains in BBB and affinity offered by Ligand B.

Output:
1
2025-04-17 04:46:54,877 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (346.475 and 364.515 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (87.46) is better than Ligand B (83.12), both are below the 90 A^2 threshold for CNS targets.

**3. logP:** Ligand A (1.503) is within the optimal 1-3 range, while Ligand B (2.28) is also acceptable.

**4. H-Bond Donors:** Both ligands have 3 HBD, which is within the acceptable limit of <=5.

**5. H-Bond Acceptors:** Ligand A has 3 HBA, while Ligand B has 5. Both are within the acceptable limit of <=10.

**6. QED:** Both ligands have similar QED values (0.699 and 0.659), both above the 0.5 threshold, indicating good drug-likeness.

**7. DILI:** Ligand A (12.02) has a significantly lower DILI risk than Ligand B (46.375). This is a major advantage for Ligand A.

**8. BBB:** Ligand A (76.464) has a better BBB penetration percentile than Ligand B (63.629). While both are not ideal (>70), Ligand A is closer to the desired range for a CNS target.

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.376 and -5.347), which is unusual and suggests poor permeability. This is a significant drawback for both.

**10. Aqueous Solubility:** Both ligands have negative solubility values (-1.64 and -3.245), indicating poor aqueous solubility. This is a concern for both.

**11. hERG Inhibition:** Both ligands have low hERG inhibition risk (0.366 and 0.449).

**12. Microsomal Clearance:** Ligand A (-6.933) has significantly lower microsomal clearance than Ligand B (33.69), indicating better metabolic stability.

**13. In vitro Half-Life:** Ligand A (3.662) has a shorter half-life than Ligand B (30.923). This is a disadvantage for Ligand A.

**14. P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.017 and 0.047).

**15. Binding Affinity:** Ligand B (-7.6) has a slightly better binding affinity than Ligand A (-7.1). However, the difference is only 0.5 kcal/mol, which might not be enough to overcome other drawbacks.

**Overall Assessment:**

Ligand A is the more promising candidate. Despite a slightly weaker binding affinity, it demonstrates significantly better predicted safety (lower DILI), better BBB penetration, and improved metabolic stability (lower Cl_mic). The poor Caco-2 and solubility are concerns for both, but the other advantages of Ligand A outweigh the small affinity difference. Given the GPCR target and the importance of CNS penetration, the better BBB and lower DILI risk of Ligand A are crucial.

Output:
1
2025-04-17 04:46:54,877 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 drug candidates, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (357.479 and 347.503 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (75.11) is higher than Ligand B (61.44). For CNS targets, we prefer TPSA <= 90, so both are acceptable, but B is better.

**3. logP:** Ligand A (4.283) is higher than Ligand B (2.374). While both are above 1, A is pushing the upper limit and could present solubility issues. B is closer to the optimal 1-3 range.

**4. H-Bond Donors:** Both ligands have 2 HBD, which is within the acceptable limit of <= 5.

**5. H-Bond Acceptors:** Ligand A has 5 HBA, and Ligand B has 3. Both are within the acceptable limit of <= 10.

**6. QED:** Both ligands have good QED scores (0.593 and 0.695, respectively), indicating good drug-like properties.

**7. DILI:** Ligand A (80.651) has a significantly higher DILI risk than Ligand B (8.181). This is a major concern for Ligand A.

**8. BBB:** Ligand B (77.433) has a much better BBB penetration score than Ligand A (49.011). Given that DRD2 is a CNS target, this is a critical advantage for Ligand B.

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.183 and -5.402). This is unusual and suggests poor permeability. However, these values are on a strange scale and may not be directly comparable.

**10. Aqueous Solubility:** Both ligands have negative solubility values (-5.167 and -1.401). This is also unusual and suggests poor solubility.

**11. hERG Inhibition:** Both ligands have low hERG inhibition risk (0.082 and 0.58).

**12. Microsomal Clearance:** Ligand A (61.272) has a higher microsomal clearance than Ligand B (15.374), indicating lower metabolic stability.

**13. In vitro Half-Life:** Ligand B (17.114) has a significantly longer in vitro half-life than Ligand A (-3.21).

**14. P-gp Efflux:** Ligand A (0.122) has slightly lower P-gp efflux than Ligand B (0.053), which is a slight advantage.

**15. Binding Affinity:** Ligand B (-8.6) has a slightly better binding affinity than Ligand A (-8.3). While the difference is small, it's still a positive for B.

**Overall Assessment:**

Ligand B is significantly better. It has a much lower DILI risk, substantially better BBB penetration, improved metabolic stability (lower Cl_mic, longer t1/2), and slightly better binding affinity. While both have issues with Caco-2 and solubility, the CNS target profile heavily favors Ligand B due to its superior BBB score. Ligand A's high DILI risk is a major red flag.



Output:
1
2025-04-17 04:46:54,878 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (354.491 and 356.491 Da) fall comfortably within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (67.87) is slightly higher than Ligand B (53.43). For a CNS target like DRD2, TPSA < 90 is preferred, and both are within this range, but B is better.

**3. logP:** Ligand A (1.971) is within the optimal 1-3 range. Ligand B (3.733) is at the higher end of the optimal range, potentially raising concerns about solubility and off-target effects, but still acceptable.

**4. H-Bond Donors:** Both ligands have 1 HBD, which is within the acceptable limit of <=5.

**5. H-Bond Acceptors:** Both ligands have 4 HBA, which is within the acceptable limit of <=10.

**6. QED:** Both ligands have similar QED values (0.759 and 0.769), indicating good drug-likeness.

**7. DILI:** Ligand A (16.402) has a significantly lower DILI risk than Ligand B (36.952). This is a substantial advantage for Ligand A.

**8. BBB:** Ligand A (68.437) is slightly below the desirable >70 percentile for CNS targets, but still reasonably good. Ligand B (70.027) is slightly better, exceeding the 70% threshold.

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.461 and -4.881), which is unusual and suggests poor permeability. This is a significant drawback for both.

**10. Aqueous Solubility:** Both ligands have negative solubility values (-2.296 and -3.394), indicating very poor aqueous solubility. This is a major concern for both.

**11. hERG Inhibition:** Ligand A (0.331) has a lower hERG inhibition liability than Ligand B (0.68), which is preferable.

**12. Microsomal Clearance:** Ligand A (46.098) has lower microsomal clearance than Ligand B (75.864), indicating better metabolic stability.

**13. In vitro Half-Life:** Ligand B (42.988) has a significantly longer in vitro half-life than Ligand A (6.106). This is a major advantage for Ligand B.

**14. P-gp Efflux:** Ligand A (0.049) has much lower P-gp efflux liability than Ligand B (0.719), which is crucial for CNS penetration.

**15. Binding Affinity:** Both ligands have very similar and excellent binding affinities (-7.6 and -7.5 kcal/mol). The difference is negligible.

**Overall Assessment:**

While both ligands have excellent binding affinity, Ligand A is the more promising candidate. Its lower DILI risk, lower hERG inhibition, lower P-gp efflux, and better metabolic stability are significant advantages. Although its BBB penetration is slightly lower and half-life shorter than Ligand B, the ADME-Tox profile of Ligand A is considerably more favorable. The poor Caco-2 and solubility are concerning for both, but can be addressed with formulation strategies. The lower P-gp efflux of Ligand A is particularly important for CNS targets.

Output:
0
2025-04-17 04:46:54,878 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (349.402 and 347.415 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (64.63) is excellent, well below the 90 A^2 threshold for CNS targets. Ligand B (111.55) is higher, but still potentially acceptable, though less ideal.

**3. logP:** Ligand A (2.49) is optimal (1-3). Ligand B (-0.013) is quite low, potentially hindering membrane permeability and CNS penetration.

**4. H-Bond Donors:** Ligand A (1) is good. Ligand B (4) is higher, but still within the acceptable limit of 5.

**5. H-Bond Acceptors:** Ligand A (4) is good. Ligand B (5) is also acceptable.

**6. QED:** Ligand A (0.83) is excellent, indicating strong drug-likeness. Ligand B (0.469) is lower, suggesting a less favorable drug-like profile.

**7. DILI:** Ligand A (46.956) has a moderate DILI risk, but is acceptable. Ligand B (31.059) has a lower DILI risk, which is favorable.

**8. BBB:** This is crucial for a CNS target like DRD2. Ligand A (95.153) shows excellent BBB penetration. Ligand B (18.147) is very poor, a significant drawback.

**9. Caco-2 Permeability:** Ligand A (-4.737) is poor. Ligand B (-5.035) is also poor. This is less critical given the focus on BBB for CNS targets.

**10. Aqueous Solubility:** Ligand A (-3.497) is poor. Ligand B (-1.848) is also poor, but slightly better than A.

**11. hERG Inhibition:** Both ligands (0.699 and 0.205) have low hERG inhibition risk, which is good.

**12. Microsomal Clearance:** Ligand A (46.235) has moderate clearance. Ligand B (4.134) has very low clearance, suggesting better metabolic stability.

**13. In vitro Half-Life:** Ligand A (16.611) has a moderate half-life. Ligand B (-14.3) is a negative half-life, which is not realistic and likely an error, but indicates very rapid metabolism.

**14. P-gp Efflux:** Ligand A (0.319) has low P-gp efflux, which is favorable for CNS penetration. Ligand B (0.029) also has very low P-gp efflux.

**15. Binding Affinity:** Both ligands have very good binding affinity (-8.9 and -8.1 kcal/mol). The difference (0.8 kcal/mol) is not large enough to overcome the significant ADME differences.

**Conclusion:**

Ligand A is the better candidate despite the slightly higher DILI risk and poor Caco-2/Solubility. Its excellent BBB penetration (95.153), optimal logP (2.49), good QED (0.83), and strong binding affinity (-8.9 kcal/mol) make it far more likely to reach the DRD2 receptor in the brain and exert a therapeutic effect. Ligand B's extremely poor BBB penetration (18.147) and low logP are major liabilities that cannot be easily overcome, even with its slightly better metabolic stability.

Output:
1
2025-04-17 04:46:54,878 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal 200-500 Da range (A: 371.531, B: 345.447).

**TPSA:** Ligand A (54.02) is excellent for CNS penetration, well below the 90 A^2 threshold. Ligand B (110) is higher, but still potentially acceptable, though less ideal.

**logP:** Ligand A (4.935) is at the upper end of the optimal range, potentially leading to solubility issues. Ligand B (1.533) is a bit low, which could hinder membrane permeability.

**H-Bond Donors/Acceptors:** Ligand A (HBD=2, HBA=4) is well within acceptable limits. Ligand B (HBD=3, HBA=5) is also acceptable.

**QED:** Both ligands have reasonable QED values (A: 0.683, B: 0.588), indicating good drug-like properties.

**DILI:** Ligand A (67.856) has a higher DILI risk than Ligand B (46.258), which is preferable.

**BBB:** Both ligands have very good BBB penetration (A: 76.658, B: 76.347), exceeding the 70% threshold.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values which is unusual and suggests a potential issue with the data or modeling. However, we'll proceed assuming this is a relative comparison.

**Aqueous Solubility:** Both ligands have negative solubility values, which is also unusual.

**hERG:** Both ligands have low hERG inhibition liability (A: 0.482, B: 0.325), which is good.

**Microsomal Clearance:** Ligand A (65.66) has a higher clearance than Ligand B (34.85), indicating lower metabolic stability.

**In vitro Half-Life:** Ligand B (-27.489) has a significantly *longer* in vitro half-life than Ligand A (61.623), which is a major advantage.

**P-gp Efflux:** Ligand A (0.432) has slightly higher P-gp efflux liability than Ligand B (0.041), meaning B is likely to have better CNS exposure.

**Binding Affinity:** Both ligands have excellent binding affinity (A: -8.7 kcal/mol, B: -8.3 kcal/mol). Ligand A is slightly better (-8.7 vs -8.3), but the difference is less than the 1.5 kcal/mol threshold that would decisively favor it.

**Overall Assessment:**

Ligand B is the more promising candidate. While Ligand A has slightly better binding affinity, Ligand B has a significantly better metabolic profile (lower Cl_mic, much longer t1/2), lower P-gp efflux, and lower DILI risk. The slightly lower logP of Ligand B is a minor concern, but is outweighed by these other advantages, especially for a CNS target where good BBB penetration is crucial. The unusual negative values for Caco-2 and solubility are concerning, but we are comparing the two ligands and assuming the values are relatively accurate.

Output:
1
2025-04-17 04:46:54,878 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B based on the provided guidelines, prioritizing GPCR-specific properties (BBB, logP, Pgp, TPSA, and affinity) for DRD2.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (348.359 Da) is slightly lower, which could be beneficial for permeability, but both are acceptable.

**TPSA:** Ligand A (109.83) is higher than the optimal <90 for CNS targets, while Ligand B (62.3) is well within the desired range. This is a significant advantage for Ligand B regarding brain penetration.

**logP:** Ligand A (0.601) is quite low, potentially hindering membrane permeability. Ligand B (2.832) is within the optimal 1-3 range. This favors Ligand B.

**H-Bond Donors/Acceptors:** Ligand A has 2 HBD and 7 HBA, which are acceptable. Ligand B has 1 HBD and 4 HBA, also acceptable.

**QED:** Both ligands have good QED scores (A: 0.786, B: 0.858), indicating drug-like properties.

**DILI:** Ligand A (72.703) has a higher DILI risk than Ligand B (38.193), though both are below the concerning threshold of 60.

**BBB:** Ligand B (81.621) has a significantly higher BBB percentile than Ligand A (34.626). This is a crucial advantage for a CNS target like DRD2.

**Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and suggests poor permeability. However, the scale is not specified, so it's hard to interpret.

**Aqueous Solubility:** Both ligands have negative solubility values, which is also unusual. Again, the scale is unknown.

**hERG:** Both ligands have low hERG inhibition liability (A: 0.221, B: 0.321), which is positive.

**Microsomal Clearance:** Ligand A (5.878) has lower microsomal clearance than Ligand B (8.323), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (23.017 hours) has a longer half-life than Ligand B (-31.17 hours). The negative value for Ligand B is concerning and likely an error.

**P-gp Efflux:** Ligand A (0.051) has very low P-gp efflux, which is excellent for CNS penetration. Ligand B (0.127) is also low, but higher than A.

**Binding Affinity:** Ligand B (-8.2 kcal/mol) has a significantly stronger binding affinity than Ligand A (0.0 kcal/mol). This is a major advantage, potentially outweighing some of the ADME drawbacks of Ligand A.

**Overall Assessment:**

Ligand B is the stronger candidate. Its superior BBB penetration, optimal logP, and significantly higher binding affinity are critical for a CNS-targeting GPCR like DRD2. While Ligand A has better P-gp efflux and metabolic stability, the substantial advantage in affinity and BBB penetration of Ligand B outweighs these factors. The negative values for Caco-2 and solubility are concerning for both, but the affinity difference is paramount.

Output:
1
2025-04-17 04:46:54,879 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (367.515 Da and 362.459 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (71.0) is significantly better than Ligand B (85.17). For CNS targets, we want TPSA <= 90, and A is closer to the ideal <= 60-70 range. B is pushing the upper limit.

**3. logP:** Both ligands have good logP values (2.18 and 1.3), falling within the optimal 1-3 range.

**4. H-Bond Donors:** Both have 1 HBD, which is acceptable.

**5. H-Bond Acceptors:** Ligand A has 5 HBA, while Ligand B has 8. Both are within the acceptable limit of <=10, but A is preferable.

**6. QED:** Both have similar QED values (0.781 and 0.713), indicating good drug-likeness.

**7. DILI:** Ligand A (33.618) has a significantly lower DILI risk than Ligand B (52.307). Both are below the 60 threshold, but A is much safer.

**8. BBB:** Ligand B (77.627) has a substantially better BBB penetration percentile than Ligand A (61.38). This is a critical factor for a CNS target like DRD2, and initially favors B.

**9. Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and suggests poor permeability. However, the absolute value is more important. Ligand A (-5.057) is slightly better than Ligand B (-5.407), indicating marginally better permeability.

**10. Aqueous Solubility:** Both have negative solubility values, which is also unusual. Ligand A (-3.142) is slightly better than Ligand B (-2.167).

**11. hERG Inhibition:** Ligand A (0.189) has a lower hERG inhibition liability than Ligand B (0.405), making it safer from a cardiotoxicity perspective.

**12. Microsomal Clearance:** Ligand B (46.53) has a lower microsomal clearance than Ligand A (31.571), suggesting better metabolic stability.

**13. In vitro Half-Life:** Ligand B (10.96) has a longer in vitro half-life than Ligand A (2.124). This is a significant advantage.

**14. P-gp Efflux:** Ligand A (0.062) has lower P-gp efflux liability than Ligand B (0.06). This is a slight advantage for A.

**15. Binding Affinity:** Ligand A (-7.7 kcal/mol) has a slightly better binding affinity than Ligand B (-7.3 kcal/mol). While both are good, the 0.4 kcal/mol difference is noticeable.

**Overall Assessment:**

Ligand A excels in TPSA, DILI, hERG, and binding affinity, while Ligand B shines in BBB penetration and in vitro half-life. Given the GPCR-specific priorities, BBB is crucial for CNS targets. However, the significantly better safety profile (DILI, hERG) and slightly better affinity of Ligand A, combined with its superior TPSA, outweigh the BBB advantage of Ligand B. The slightly better permeability and lower P-gp efflux also contribute to A's favorability. The difference in half-life is notable, but can potentially be addressed through structural modifications.

Output:
0
2025-04-17 04:46:54,879 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (408.296 Da) is slightly higher than Ligand B (364.471 Da), but both are acceptable.

**TPSA:** Ligand A (76.39) is better than Ligand B (85.37). For CNS targets, we want TPSA <= 90, and both are below this threshold, but A is closer to the optimal range.

**logP:** Both ligands have good logP values (A: 3.293, B: 2.617), falling within the 1-3 range.

**H-Bond Donors/Acceptors:** Both have 2 HBD, which is good. Ligand A has 4 HBA, and Ligand B has 6 HBA. Both are acceptable (<=10), but A is preferable.

**QED:** Both ligands have similar QED values (A: 0.796, B: 0.752), indicating good drug-like properties.

**DILI:** Ligand A (50.291) has a lower DILI risk than Ligand B (58.123), which is preferable. Both are below the concerning threshold of 60.

**BBB:** This is a critical parameter for CNS targets. Ligand A (78.868) has a significantly better BBB percentile than Ligand B (49.205). This is a major advantage for Ligand A.

**Caco-2 Permeability:** Ligand A (-5.203) and Ligand B (-4.761) both have negative values, indicating poor permeability. This is a concern for both, but the values are similar.

**Aqueous Solubility:** Both have poor solubility values (A: -3.538, B: -2.006). This could pose formulation challenges, but is less critical than BBB for a CNS target.

**hERG Inhibition:** Both ligands show low hERG inhibition risk (A: 0.497, B: 0.227), which is good.

**Microsomal Clearance:** Ligand B (24.034) has a lower microsomal clearance than Ligand A (51.695), suggesting better metabolic stability. This is a point in favor of Ligand B.

**In vitro Half-Life:** Both ligands have similar in vitro half-lives (A: 30.283, B: 31.757).

**P-gp Efflux:** Ligand A (0.376) has lower P-gp efflux than Ligand B (0.026), which is favorable for CNS penetration.

**Binding Affinity:** Ligand A (-9.6 kcal/mol) has a significantly stronger binding affinity than Ligand B (-7.6 kcal/mol). This is a substantial advantage, potentially outweighing some of the ADME drawbacks. The difference is >1.5 kcal/mol.

**Overall Assessment:**

Ligand A is the stronger candidate. While Ligand B has better metabolic stability (lower Cl_mic), Ligand A excels in the most crucial areas for a CNS-targeting GPCR ligand: significantly higher binding affinity, better BBB penetration, and lower P-gp efflux. The slightly higher TPSA and lower solubility of Ligand A are less concerning given the strong affinity and improved CNS exposure.



Output:
1
2025-04-17 04:46:54,879 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B against the provided guidelines, prioritizing GPCR-specific properties (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (350.419 and 364.408 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (85.69) is better than Ligand B (58.64), both are below the 90 A^2 threshold for CNS targets.

**logP:** Ligand B (2.294) is optimal (1-3), while Ligand A (0.577) is a bit low, potentially hindering permeation.

**H-Bond Donors:** Both have 1 HBD, which is good.

**H-Bond Acceptors:** Ligand A has 6 HBA, and Ligand B has 3 HBA. Both are within the acceptable range of <=10.

**QED:** Ligand A (0.789) is slightly better than Ligand B (0.673), both are above the 0.5 threshold.

**DILI:** Ligand B (14.889) is significantly better than Ligand A (51.183), indicating a much lower risk of drug-induced liver injury.

**BBB:** Ligand B (98.022) is excellent, exceeding the desirable >70% threshold for CNS targets. Ligand A (72.237) is good, but not as high. This is a major advantage for Ligand B.

**Caco-2 Permeability:** Both have negative values (-4.715 and -4.355). This is unusual and suggests poor permeability. However, the scale isn't fully defined, so we can't definitively say which is worse.

**Aqueous Solubility:** Both have negative values (-1.771 and -2.071), indicating poor solubility. Similar to Caco-2, the scale is unclear.

**hERG Inhibition:** Ligand A (0.21) is much better than Ligand B (0.665), indicating a lower risk of cardiotoxicity.

**Microsomal Clearance:** Ligand B (5.141) has significantly lower clearance than Ligand A (21.483), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand B (-13.7) has a negative half-life, which is impossible. This is a major red flag and suggests an issue with the data or the compound itself. Ligand A (36.025) is reasonable.

**P-gp Efflux:** Ligand A (0.018) is much better than Ligand B (0.032), indicating lower P-gp efflux and potentially better CNS exposure.

**Binding Affinity:** Ligand B (-8.1 kcal/mol) has significantly stronger binding affinity than Ligand A (0.0 kcal/mol). This is a substantial advantage, potentially outweighing some ADME concerns.

**Overall Assessment:**

Ligand B excels in BBB penetration and binding affinity, which are critical for a CNS-targeting GPCR. Its lower DILI risk and better metabolic stability are also significant advantages. The negative half-life is a serious concern, however. Ligand A has better hERG and P-gp profiles, but its lower logP and weaker binding affinity are drawbacks. Given the importance of BBB penetration and affinity for CNS GPCRs, and the substantial difference in binding affinity, Ligand B is more promising *despite* the implausible half-life value. The negative half-life needs investigation, but the other properties suggest it's worth pursuing.

Output:
1
2025-04-17 04:46:54,879 - INFO - Batch 142 complete. Total preferences: 2272
2025-04-17 04:46:54,879 - INFO - Processing batch 143/512...
2025-04-17 04:47:37,127 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (346.431 and 354.495 Da) fall within the ideal range of 200-500 Da.

**TPSA:** Ligand A (85.25) is better than Ligand B (104.53). For CNS targets, we want TPSA <= 90, so Ligand A is preferable.

**logP:** Both ligands have acceptable logP values (1.442 and 1.757), falling within the optimal range of 1-3.

**H-Bond Donors/Acceptors:** Ligand A (HBD=2, HBA=5) is slightly better than Ligand B (HBD=3, HBA=3) in terms of balancing solubility and permeability. Both are within acceptable limits.

**QED:** Ligand A (0.708) has a significantly better QED score than Ligand B (0.521), indicating a more drug-like profile.

**DILI:** Both ligands have low DILI risk (23.614 and 22.489 percentile), which is good.

**BBB:** Ligand B (78.674) has a much better BBB penetration percentile than Ligand A (54.013). This is a *critical* factor for a CNS target like DRD2.

**Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and suggests poor permeability. However, the scale isn't specified, so it's hard to interpret.

**Aqueous Solubility:** Both have negative solubility values, which is also unusual and suggests poor solubility. Again, the scale is unknown.

**hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.077 and 0.367), which is excellent.

**Microsomal Clearance:** Ligand A (10.191) has significantly lower microsomal clearance than Ligand B (33.501), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (12.638 hours) has a positive half-life, while Ligand B (-10.859 hours) has a negative half-life, which is not physically possible and indicates a potential issue with the data or the model.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.023 and 0.056), which is favorable for CNS penetration.

**Binding Affinity:** Ligand A (-7.8 kcal/mol) has a slightly better binding affinity than Ligand B (-7.2 kcal/mol). While both are good, the 0.6 kcal/mol difference is potentially significant.

**Overall Assessment:**

Ligand A has advantages in TPSA, QED, metabolic stability (Cl_mic), and binding affinity. However, Ligand B has a substantially better BBB penetration score, which is paramount for a CNS drug targeting DRD2. The negative half-life for Ligand B is a major red flag. While the Caco-2 and solubility values are concerning for both, the BBB score for Ligand B is the most important factor. Given the importance of CNS penetration for DRD2, and the questionable half-life of Ligand B, Ligand A is the more promising candidate.

Output:
0
2025-04-17 04:47:37,128 - INFO - Reasoning:

Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (336.435 Da) is slightly lower, which could be advantageous for permeability, but both are acceptable.

**TPSA:** Ligand A (45.33) is excellent for CNS penetration, well below the 90 A^2 threshold. Ligand B (81.91) is higher, but still potentially acceptable, though less ideal.

**logP:** Ligand A (3.692) is optimal. Ligand B (2.463) is also within the optimal range, but closer to the lower bound.

**H-Bond Donors/Acceptors:** Both ligands have a reasonable number of HBD (1) and HBA (Ligand A: 3, Ligand B: 6), staying within the guidelines.

**QED:** Both ligands have good QED scores (A: 0.698, B: 0.716), indicating drug-like properties.

**DILI:** Ligand A (48.352) has a slightly higher DILI risk than Ligand B (38.154), but both are below the concerning threshold of 60.

**BBB:** Both ligands exhibit good BBB penetration (Ligand A: 76.347, Ligand B: 88.794). Ligand B is better, exceeding 80%, which is highly desirable for a CNS target.

**Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and suggests a potential issue with the experimental setup or data quality. However, we'll proceed assuming these represent low permeability.

**Aqueous Solubility:** Both ligands have very poor aqueous solubility (Ligand A: -5.197, Ligand B: -2.529). This is a significant concern for bioavailability.

**hERG:** Both ligands have low hERG inhibition risk (A: 0.882, B: 0.864).

**Microsomal Clearance:** Ligand A (92.3) has higher microsomal clearance than Ligand B (69.526), suggesting lower metabolic stability.

**In vitro Half-Life:** Ligand B (-0.195) has a very short half-life, which is a major drawback. Ligand A (28.034) has a much better half-life.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (A: 0.649, B: 0.296), which is good for CNS exposure. Ligand B is slightly better.

**Binding Affinity:** Ligand B (-7.6 kcal/mol) has a significantly stronger binding affinity than Ligand A (-9.5 kcal/mol). This is a substantial advantage, potentially outweighing some of the ADME concerns.

**Overall Assessment:**

While Ligand B has a superior binding affinity and better BBB penetration and P-gp efflux, its extremely short in vitro half-life is a critical flaw. The poor solubility of both compounds is a concern, but can potentially be addressed with formulation strategies. Ligand A, despite its weaker affinity, has a much more reasonable half-life and acceptable metabolic stability. Given the importance of metabolic stability and reasonable half-life for *in vivo* efficacy, and the fact that the affinity difference, while significant, isn't enormous, Ligand A is the more promising candidate.

Output:
0
2025-04-17 04:47:37,128 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (334.419 Da) is slightly lower, which is generally favorable for permeability.

**TPSA:** Ligand A (45.33) is significantly better than Ligand B (69.04). For CNS targets, TPSA should be <= 90, and lower is preferable. Ligand A is much closer to the optimal range for CNS penetration.

**logP:** Both ligands have acceptable logP values (A: 4.371, B: 2.971), falling within the 1-3 range. Ligand B is slightly better here, being closer to the optimal range. However, Ligand A's value is still acceptable.

**H-Bond Donors/Acceptors:** Both ligands have a reasonable number of HBD (1) and HBA (A: 2, B: 5), generally within acceptable limits.

**QED:** Both ligands have good QED values (A: 0.77, B: 0.839), indicating good drug-like properties.

**DILI:** Both ligands have relatively high DILI risk (A: 75.107, B: 78.402), but are still within a range that isn't immediately disqualifying.

**BBB:** Both ligands show good BBB penetration (A: 69.407, B: 74.176). Ligand B is slightly better, but both are below the desirable >70 threshold.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.845 and -4.675). This is unusual and suggests poor permeability. However, these values are on a log scale, so the negative values indicate very low permeability.

**Aqueous Solubility:** Both ligands have very poor aqueous solubility (-6.165 and -4.082). This is a significant concern for bioavailability.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (A: 0.796, B: 0.207). Ligand B is better here.

**Microsomal Clearance:** Ligand A (57.796) has a higher microsomal clearance than Ligand B (45.061), suggesting lower metabolic stability.

**In vitro Half-Life:** Ligand B (-1.932) has a negative in vitro half-life, which is not possible and indicates a problem with the data. Ligand A (23.464) has a reasonable half-life.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (A: 0.695, B: 0.107). Ligand B is better here.

**Binding Affinity:** Both ligands have very similar and excellent binding affinities (A: -9.5 kcal/mol, B: -9.3 kcal/mol). The difference is less than 1.5 kcal/mol, so it's not a major deciding factor.

**Overall Assessment:**

Considering the GPCR-specific priorities, Ligand A is slightly more favorable. While Ligand B has better logP and P-gp efflux, Ligand A has a significantly lower TPSA, a more reasonable in vitro half-life, and comparable binding affinity. The poor Caco-2 and solubility for both are concerning, but the lower TPSA of Ligand A is crucial for CNS penetration. The negative half-life for Ligand B is a red flag.

Output:
0
2025-04-17 04:47:37,128 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (354.451 and 349.431 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (99.77) is slightly higher than Ligand B (91.76). Both are below the 140 A^2 threshold for oral absorption, and reasonably close to the 90 A^2 target for CNS penetration, but Ligand B is preferable.

**3. logP:** Ligand A (0.229) is quite low, potentially hindering permeability. Ligand B (0.724) is better, approaching the optimal 1-3 range. This is a significant advantage for Ligand B.

**4. H-Bond Donors:** Ligand A (3) is acceptable. Ligand B (2) is even better, potentially improving permeability.

**5. H-Bond Acceptors:** Ligand A (4) is acceptable. Ligand B (5) is also acceptable.

**6. QED:** Both ligands have good QED scores (0.57 and 0.722), indicating good drug-like properties. Ligand B is slightly better.

**7. DILI:** Both ligands have low DILI risk (29.624 and 24.893), which is positive. Ligand B is slightly better.

**8. BBB:** Ligand A (73.672) has a good BBB percentile, exceeding the 70% threshold for CNS targets. Ligand B (61.264) is below this threshold, which is a significant drawback.

**9. Caco-2:** Both have negative Caco-2 values, which is unusual and suggests poor permeability. This is a concern for both, but the values are difficult to interpret without knowing the scale.

**10. Solubility:** Both have negative solubility values, which is also unusual and suggests poor solubility. This is a concern for both, but the values are difficult to interpret without knowing the scale.

**11. hERG:** Both ligands show very low hERG inhibition risk (0.269 and 0.238), which is excellent.

**12. Cl_mic:** Ligand A (-11.81) has a negative clearance, which is impossible. This is a data error. Ligand B (28.85) has a high clearance, indicating poor metabolic stability.

**13. t1/2:** Ligand A (3.144) has a short half-life. Ligand B (-2.548) has a negative half-life, which is impossible. This is a data error.

**14. Pgp:** Both have very low Pgp efflux liability (0.008 and 0.04), which is excellent for CNS penetration.

**15. Binding Affinity:** Ligand B (-7.4 kcal/mol) has a slightly better binding affinity than Ligand A (-7.2 kcal/mol). While the difference is small, it's within the range where it could outweigh minor ADME drawbacks.

**Overall Assessment:**

Despite the unusual negative values for Caco-2 and solubility, and the data errors for Cl_mic and t1/2, Ligand B appears to be the better candidate. It has a more favorable logP, slightly better QED and DILI, and slightly better binding affinity. The biggest drawback for Ligand B is its lower BBB penetration compared to Ligand A. However, the low logP of Ligand A is a significant concern for permeability, and the data errors for Ligand A are concerning. Considering the GPCR-specific priorities, the slightly better affinity and logP of Ligand B, combined with its acceptable Pgp efflux, make it the more promising candidate, *assuming the negative values are corrected or clarified*.

Output:
1
2025-04-17 04:47:37,129 - INFO - Reasoning:

Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (346.471 and 342.418 Da) fall comfortably within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (58.64) is better than Ligand B (61.02) as it's closer to the <90 A^2 threshold for CNS targets.

**3. logP:** Both ligands (2.732 and 2.666) are within the optimal 1-3 range.

**4. H-Bond Donors:** Ligand A (1) is preferable to Ligand B (2) as fewer HBDs generally improve permeability.

**5. H-Bond Acceptors:** Both ligands have 3 HBAs, which is acceptable.

**6. QED:** Both ligands have good QED scores (0.787 and 0.878), indicating good drug-like properties.

**7. DILI:** Ligand A (29.081) has a lower DILI risk than Ligand B (32.261), which is favorable.

**8. BBB:** Ligand B (81.698) has a significantly better BBB penetration percentile than Ligand A (75.727). This is a critical advantage for a CNS target like DRD2.

**9. Caco-2 Permeability:** Ligand A (-4.671) has a worse Caco-2 permeability than Ligand B (-5.23).

**10. Aqueous Solubility:** Ligand A (-2.771) has better aqueous solubility than Ligand B (-3.118).

**11. hERG Inhibition:** Both ligands have low hERG inhibition risk (0.714 and 0.681).

**12. Microsomal Clearance:** Ligand B (19.316) has a lower microsomal clearance than Ligand A (70.533), suggesting better metabolic stability.

**13. In vitro Half-Life:** Ligand A (19.253) has a better in vitro half-life than Ligand B (-26.211).

**14. P-gp Efflux:** Ligand A (0.206) has lower P-gp efflux liability than Ligand B (0.171), which is beneficial for CNS exposure.

**15. Binding Affinity:** Ligand B (-7.8 kcal/mol) has a stronger binding affinity than Ligand A (-8.2 kcal/mol). While both are excellent, the difference is significant.

**Overall Assessment:**

While Ligand A has some advantages in solubility, DILI, and P-gp efflux, Ligand B is superior due to its significantly better BBB penetration (81.7% vs 75.7%), stronger binding affinity (-7.8 vs -8.2 kcal/mol), and lower microsomal clearance. The improved BBB penetration and affinity are particularly important for a CNS GPCR target like DRD2, outweighing the minor drawbacks in other parameters.

Output:
1
2025-04-17 04:47:37,129 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (346.43 and 370.84 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (80.57) is excellent, well below the 90 Angstroms threshold for CNS targets. Ligand B (93.65) is still reasonable but less optimal, approaching the upper limit.

**3. logP:** Both ligands have good logP values (2.26 and 1.43), falling within the 1-3 range. Ligand A is slightly better.

**4. H-Bond Donors:** Both ligands have acceptable HBD counts (2 and 1, respectively), well below the 5 threshold.

**5. H-Bond Acceptors:** Ligand A (4) is good, while Ligand B (7) is higher but still within the acceptable limit of 10.

**6. QED:** Both ligands have similar and good QED values (0.708 and 0.757), indicating good drug-like properties.

**7. DILI:** Ligand A (39.98%) has a significantly lower DILI risk than Ligand B (73.98%). This is a major advantage for Ligand A.

**8. BBB:** Ligand B (83.33%) has a substantially better BBB penetration score than Ligand A (65.57%). This is a critical factor for a CNS target like DRD2.

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.706 and -4.777), which is unusual and suggests poor permeability. This is a concern for both.

**10. Aqueous Solubility:** Both ligands have negative solubility values (-2.87 and -3.131), which is also concerning. Poor solubility can hinder bioavailability.

**11. hERG Inhibition:** Both ligands show very low hERG inhibition risk (0.185 and 0.174).

**12. Microsomal Clearance:** Ligand A (40.18 mL/min/kg) has a higher microsomal clearance than Ligand B (59.96 mL/min/kg), suggesting lower metabolic stability.

**13. In vitro Half-Life:** Ligand B (13.53 hours) has a significantly longer in vitro half-life than Ligand A (39.41 hours). This is a positive for Ligand B.

**14. P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.129 and 0.048).

**15. Binding Affinity:** Ligand B (-7.5 kcal/mol) has a stronger binding affinity than Ligand A (-6.9 kcal/mol). This difference of 0.6 kcal/mol is substantial and could outweigh some ADME drawbacks.

**Overall Assessment:**

Ligand B has a significantly better BBB score and binding affinity, which are crucial for a CNS GPCR target. However, it has a higher DILI risk and a shorter half-life. Ligand A has a lower DILI risk and better TPSA, but its BBB penetration is considerably worse, and its binding affinity is weaker. The poor Caco-2 and solubility for both are concerning, but can potentially be addressed through formulation strategies.

Given the importance of CNS penetration and potency for DRD2, the stronger binding affinity and better BBB score of Ligand B are more compelling, despite the higher DILI risk. The DILI risk is manageable with further optimization, while improving BBB and affinity are typically more challenging.

Output:
1
2025-04-17 04:47:37,129 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (352.341 and 368.302 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (85.26) is better than Ligand B (72.8). Both are below the 90 A^2 threshold desirable for CNS targets.

**3. logP:** Both ligands have excellent logP values (2.741 and 2.69), falling within the optimal 1-3 range.

**4. H-Bond Donors:** Ligand A (0) is preferable to Ligand B (3). Lower HBD generally improves permeability.

**5. H-Bond Acceptors:** Ligand A (6) is better than Ligand B (3). Both are below the 10 threshold.

**6. QED:** Ligand A (0.841) is significantly better than Ligand B (0.716), indicating a more drug-like profile.

**7. DILI:** Ligand A (68.011) has a higher DILI risk than Ligand B (47.421), but both are acceptable (<60).

**8. BBB:** Ligand A (94.649) is *much* better than Ligand B (64.211). This is a critical factor for a CNS target like DRD2.

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.555 and -4.889). This is unusual and suggests poor permeability. However, these values are on a scale where negative values are possible, and the absolute magnitude isn't directly comparable to positive values.

**10. Aqueous Solubility:** Both ligands have negative solubility values (-3.478 and -3.19). Similar to Caco-2, this suggests poor solubility.

**11. hERG Inhibition:** Ligand A (0.2) has a lower hERG risk than Ligand B (0.577), which is preferable.

**12. Microsomal Clearance:** Ligand B (-6.423) has a *much* lower (better) microsomal clearance than Ligand A (32.069), indicating greater metabolic stability.

**13. In vitro Half-Life:** Ligand B (21.432) has a significantly longer half-life than Ligand A (0.249), which is a major advantage.

**14. P-gp Efflux:** Ligand A (0.122) has lower P-gp efflux than Ligand B (0.102), which is preferable for CNS penetration.

**15. Binding Affinity:** Ligand B (-8.9 kcal/mol) has a slightly better binding affinity than Ligand A (-8.5 kcal/mol), although the difference is relatively small.

**Overall Assessment:**

While Ligand B has better metabolic stability (lower Cl_mic, longer t1/2) and slightly better affinity, Ligand A is superior due to its significantly better BBB penetration (94.649 vs. 64.211), higher QED, lower HBD/HBA, and lower hERG risk. For a CNS target like DRD2, BBB penetration is paramount. The slightly better affinity of Ligand B is unlikely to overcome the substantial difference in predicted brain exposure.

Output:
0
2025-04-17 04:47:37,129 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight (MW):** Both ligands (355.435 and 344.415 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (107.97) is slightly above the optimal <90 for CNS targets, but still reasonable. Ligand B (84.42) is well within the desired range.

**3. logP:** Ligand A (-0.593) is a bit low, potentially hindering membrane permeability. Ligand B (1.706) is within the optimal 1-3 range. This is a significant advantage for Ligand B.

**4. H-Bond Donors (HBD):** Ligand A (3) and Ligand B (1) are both acceptable, being less than or equal to 5.

**5. H-Bond Acceptors (HBA):** Both ligands (A: 5, B: 5) are within the acceptable limit of <=10.

**6. QED:** Both ligands have good QED scores (A: 0.566, B: 0.899), indicating drug-like properties. Ligand B is better here.

**7. DILI:** Ligand A (11.322) has a much lower DILI risk than Ligand B (63.125). This is a positive for Ligand A.

**8. BBB:** Ligand B (67.895) has a better BBB percentile than Ligand A (36.06). This is a crucial advantage for a CNS target like DRD2.

**9. Caco-2 Permeability:** Both have negative values, which is unusual. Assuming these are percentile scores, Ligand A (-5.256) is worse than Ligand B (-4.692).

**10. Aqueous Solubility:** Both have negative values, which is unusual. Assuming these are percentile scores, Ligand A (-0.574) is worse than Ligand B (-3.116).

**11. hERG Inhibition:** Both ligands have very low hERG risk (A: 0.053, B: 0.196).

**12. Microsomal Clearance:** Ligand A (-18.662) has significantly lower (better) microsomal clearance than Ligand B (32.254), suggesting better metabolic stability.

**13. In vitro Half-Life:** Ligand A (15.872) has a shorter half-life than Ligand B (-19.331). Assuming negative values indicate longer half-life, Ligand B is better.

**14. P-gp Efflux:** Both ligands have very low P-gp efflux liability (A: 0.002, B: 0.13).

**15. Binding Affinity:** Ligand B (-9.0 kcal/mol) has a significantly stronger binding affinity than Ligand A (-7.3 kcal/mol). This >1.5 kcal/mol difference is substantial and can outweigh some ADME drawbacks.

**Overall Assessment:**

Ligand B is superior due to its better logP, BBB penetration, binding affinity, QED, and in vitro half-life. While Ligand A has a lower DILI risk and better metabolic stability, the importance of BBB penetration and strong binding for a CNS GPCR target like DRD2 outweighs these advantages. The slightly lower TPSA of Ligand B is also favorable.

Output:
1
2025-04-17 04:47:37,130 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (352.479 and 344.459 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (96.25) is slightly higher than Ligand B (86.88). Both are below the 90 A^2 threshold desirable for CNS targets, but Ligand B is preferable.

**3. logP:** Ligand A (1.418) and Ligand B (2.157) are both within the optimal range of 1-3. Ligand B is slightly better.

**4. H-Bond Donors:** Both ligands have 3 HBD, which is acceptable (<=5).

**5. H-Bond Acceptors:** Ligand A has 5 HBA, and Ligand B has 3 HBA. Both are within the acceptable range (<=10), with Ligand B being slightly more favorable.

**6. QED:** Both ligands have similar QED values (0.626 and 0.663), indicating good drug-likeness.

**7. DILI:** Ligand A (15.238%) has a significantly lower DILI risk than Ligand B (35.556%). This is a major advantage for Ligand A.

**8. BBB:** Ligand B (60.682%) has a much better BBB penetration percentile than Ligand A (23.071%). This is a critical factor for a CNS target like DRD2, making Ligand B initially more appealing.

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.307 and -5.303), which is unusual and suggests poor permeability. This is a concern for both.

**10. Aqueous Solubility:** Both ligands have negative solubility values (-1.197 and -2.305), indicating poor aqueous solubility. This is a significant drawback for both.

**11. hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.164 and 0.135).

**12. Microsomal Clearance:** Ligand B (34.289) has a higher microsomal clearance than Ligand A (21.522), suggesting faster metabolism and lower metabolic stability. Ligand A is preferable.

**13. In vitro Half-Life:** Both have negative half-life values (-9.858 and -9.948), which is not physically meaningful and likely indicates a problem with the data or model.

**14. P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.025 and 0.094).

**15. Binding Affinity:** Ligand B (-9.2 kcal/mol) has a significantly stronger binding affinity than Ligand A (-7.8 kcal/mol). This is a substantial advantage for Ligand B, potentially outweighing some of the ADME concerns.

**Overall Assessment:**

Ligand B has a much better BBB penetration and significantly stronger binding affinity, which are crucial for a CNS GPCR target. However, it has a higher DILI risk and faster metabolic clearance. Ligand A has a lower DILI risk and slower metabolic clearance, but its BBB penetration and binding affinity are considerably weaker.

The strong affinity of Ligand B is a significant advantage. While the BBB penetration isn't ideal (>70 is preferred), it's still reasonably good (60.682%). The DILI risk is moderate but not alarming. The poor solubility and permeability are concerning for both, but can potentially be addressed through formulation strategies. Given the importance of affinity for GPCRs, and the fact that the difference in affinity is >1.5 kcal/mol, I would prioritize Ligand B.

Output:
1
2025-04-17 04:47:37,130 - INFO - Reasoning:

Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (352.475 and 368.459 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (70.08) is excellent, well below the 90 A^2 threshold for CNS targets. Ligand B (115.39) is higher, but still potentially acceptable, though less ideal.

**3. logP:** Ligand A (1.273) is within the optimal 1-3 range. Ligand B (-0.709) is slightly below 1, which could indicate permeability issues.

**4. H-Bond Donors:** Ligand A (1) is good. Ligand B (3) is also acceptable, but edging towards the higher end of the preferred range.

**5. H-Bond Acceptors:** Ligand A (4) is good. Ligand B (5) is also acceptable.

**6. QED:** Both ligands have reasonable QED values (0.635 and 0.588), indicating good drug-like properties.

**7. DILI:** Ligand A (18.651) has a significantly lower DILI risk than Ligand B (35.595). This is a substantial advantage.

**8. BBB:** Ligand A (48.003) has a moderate BBB penetration, while Ligand B (16.324) has very poor predicted BBB penetration. This is a critical difference for a CNS target like DRD2.

**9. Caco-2 Permeability:** Ligand A (-4.179) has poor Caco-2 permeability. Ligand B (-5.394) is even worse.

**10. Aqueous Solubility:** Ligand A (-1.836) has poor solubility. Ligand B (-2.462) is even worse.

**11. hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.464 and 0.11).

**12. Microsomal Clearance:** Ligand A (28.327) has a higher microsomal clearance than Ligand B (4.302), suggesting lower metabolic stability.

**13. In vitro Half-Life:** Ligand B (-12.806) has a much longer in vitro half-life than Ligand A (-1.486).

**14. P-gp Efflux:** Ligand A (0.164) has lower P-gp efflux than Ligand B (0.007), which is favorable for CNS penetration.

**15. Binding Affinity:** Ligand B (-8.2) has a significantly stronger binding affinity than Ligand A (-5.9), a difference of 2.3 kcal/mol. This is a major advantage.

**Overall Assessment:**

While Ligand B boasts a substantially better binding affinity and longer half-life, its poor BBB penetration is a major drawback for a CNS target. Ligand A has a better BBB score, lower DILI risk, and better P-gp efflux, but suffers from weaker binding affinity, poor Caco-2 permeability, and poor solubility.

Given the GPCR-specific priorities, especially BBB penetration for CNS targets, and the substantial affinity difference, the stronger binding affinity of Ligand B is likely to outweigh its other deficiencies. Optimization efforts could focus on improving its BBB penetration.

Output:
1
2025-04-17 04:47:37,130 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (343.387 and 343.431 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (101.22) is higher than Ligand B (74.09). For CNS targets, TPSA < 90 is preferred. Ligand B is significantly better in this regard.

**3. logP:** Both ligands have good logP values (1.364 and 1.725), falling within the optimal 1-3 range. Ligand B is slightly better.

**4. H-Bond Donors:** Both have 1 HBD, which is acceptable (<=5).

**5. H-Bond Acceptors:** Ligand A has 6 HBA, and Ligand B has 7. Both are within the acceptable range (<=10).

**6. QED:** Both ligands have similar QED values (0.814 and 0.805), indicating good drug-likeness.

**7. DILI:** Ligand A (60.605) has a slightly higher DILI risk than Ligand B (44.397). Both are acceptable (<60 is good), but B is preferable.

**8. BBB:** Both ligands exhibit excellent BBB penetration (74.37% and 76.154%), exceeding the desirable threshold of >70%. Ligand B is marginally better.

**9. Caco-2 Permeability:** Ligand A (-4.78) and Ligand B (-5.422) have negative values, which is unusual and suggests poor permeability. Lower values are worse. Ligand B is slightly worse.

**10. Aqueous Solubility:** Both ligands have very poor aqueous solubility (-2.047 and -1.956). This is a significant concern for bioavailability.

**11. hERG Inhibition:** Both ligands have low hERG inhibition risk (0.258 and 0.304).

**12. Microsomal Clearance:** Ligand B (39.06) has lower microsomal clearance than Ligand A (56.445), suggesting better metabolic stability.

**13. In vitro Half-Life:** Ligand B (-9.142) has a longer in vitro half-life than Ligand A (-21.792), which is desirable.

**14. P-gp Efflux:** Both ligands have low P-gp efflux liability (0.053 and 0.274), which is good for CNS exposure. Ligand A is slightly better.

**15. Binding Affinity:** Ligand B (-8.8 kcal/mol) has slightly better binding affinity than Ligand A (-7.9 kcal/mol). While both are strong binders, the difference is significant.

**Overall Assessment:**

While both compounds have good overall profiles, Ligand B is more favorable. It has a lower TPSA, lower DILI risk, better metabolic stability (lower Cl_mic), a longer half-life, and slightly better binding affinity. The solubility is a concern for both, but the other advantages of Ligand B outweigh this drawback, especially considering the GPCR target and the need for good CNS penetration.

Output:
1
2025-04-17 04:47:37,130 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (354.353 and 345.407 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (76.66) is excellent, well below the 90 A^2 threshold for CNS targets. Ligand B (97.94) is higher, but still potentially acceptable, though less ideal.

**logP:** Ligand A (2.161) is optimal (1-3). Ligand B (0.089) is quite low, which could hinder membrane permeability and CNS penetration.

**H-Bond Donors/Acceptors:** Ligand A (2 HBD, 4 HBA) is within the preferred limits. Ligand B (1 HBD, 7 HBA) is also acceptable.

**QED:** Ligand B (0.767) has a better QED score than Ligand A (0.405), indicating a more drug-like profile overall.

**DILI:** Both ligands have acceptable DILI risk (Ligand A: 58.046, Ligand B: 53.47).

**BBB:** Ligand A (82.513) has a significantly better BBB percentile than Ligand B (43.583). This is a crucial factor for a CNS target like DRD2.

**Caco-2 Permeability:** Ligand A (-4.719) has a negative value, indicating poor permeability. Ligand B (-5.485) is also poor, but slightly worse.

**Aqueous Solubility:** Ligand A (-3.886) has poor solubility, while Ligand B (-1.006) is also poor, but better than A.

**hERG:** Both ligands have very low hERG risk (Ligand A: 0.56, Ligand B: 0.03).

**Microsomal Clearance:** Ligand B (-11.556) has a much lower (better) microsomal clearance than Ligand A (67.29), suggesting greater metabolic stability.

**In vitro Half-Life:** Ligand B (26.275) has a better in vitro half-life than Ligand A (-9.806).

**P-gp Efflux:** Both ligands have low P-gp efflux liability (Ligand A: 0.25, Ligand B: 0.007), which is favorable for CNS penetration.

**Binding Affinity:** Both ligands have excellent binding affinity (Ligand A: -8 kcal/mol, Ligand B: -7.8 kcal/mol). Ligand A has a slight advantage in affinity, but it's not substantial enough to overcome its other weaknesses.

**Overall Assessment:**

Ligand A excels in binding affinity and BBB penetration, but suffers from poor Caco-2 permeability and aqueous solubility. Ligand B has better QED, metabolic stability (lower Cl_mic), and half-life, but its logP is very low and its BBB penetration is significantly worse.

Given the GPCR-specific priorities, particularly BBB for a CNS target, and the relatively small difference in binding affinity, **Ligand A is the more promising candidate**. The poor solubility and permeability of Ligand A could potentially be addressed through formulation strategies. The low logP of Ligand B is a more fundamental issue that would be harder to overcome.

Output:
1
2025-04-17 04:47:37,131 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 drug candidates, considering the provided guidelines and GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (438.591 Da) is closer to the upper limit, while Ligand B (362.539 Da) is more central.

**TPSA:** Ligand A (96.01) is slightly above the optimal <90 for CNS targets, but still potentially acceptable. Ligand B (45.47) is well within the desired range.

**logP:** Both ligands have good logP values (A: 2.993, B: 3.975), falling within the 1-3 optimal range. Ligand B is slightly higher, which could potentially lead to some off-target interactions, but is not a major concern.

**H-Bond Donors/Acceptors:** Ligand A has 3 HBD and 5 HBA, which are acceptable. Ligand B has 1 HBD and 4 HBA, also acceptable.

**QED:** Ligand B (0.772) has a significantly better QED score than Ligand A (0.389), indicating a more drug-like profile.

**DILI:** Ligand B (29.391) has a much lower DILI risk than Ligand A (96.045), which is a significant advantage.

**BBB:** Ligand B (63.086) has a better BBB penetration percentile than Ligand A (54.246), although both are not ideal (>70 is preferred). This is a critical factor for a CNS target like DRD2.

**Caco-2 Permeability:** Ligand A (-5.124) has poor Caco-2 permeability, suggesting poor intestinal absorption. Ligand B (-4.797) is also low, but slightly better.

**Aqueous Solubility:** Both ligands have very poor aqueous solubility (-5 for A, -3.889 for B). This could pose formulation challenges.

**hERG Inhibition:** Ligand A (0.165) has a slightly better hERG profile than Ligand B (0.737), indicating lower cardiotoxicity risk.

**Microsomal Clearance:** Ligand B (78.019) has a higher microsomal clearance than Ligand A (28.532), suggesting faster metabolism and potentially lower in vivo exposure.

**In vitro Half-Life:** Ligand A (44.85) has a longer in vitro half-life than Ligand B (38.111), which is favorable.

**P-gp Efflux:** Ligand A (0.124) has lower P-gp efflux liability than Ligand B (0.733), suggesting better CNS exposure.

**Binding Affinity:** Ligand A (-9.8 kcal/mol) has a significantly stronger binding affinity than Ligand B (-6.4 kcal/mol). This is a substantial advantage, potentially outweighing some of the ADME drawbacks. The difference of 3.4 kcal/mol is very significant.

**Overall Assessment:**

While Ligand B has better ADME properties (QED, DILI, BBB, P-gp efflux) and a slightly better hERG profile, the significantly stronger binding affinity of Ligand A (-9.8 kcal/mol vs -6.4 kcal/mol) is a decisive factor. The affinity difference is large enough to potentially overcome the poorer ADME profile, especially considering that some ADME issues (solubility, Caco-2) can be addressed through formulation strategies. The improved P-gp efflux for Ligand A also helps with CNS penetration.

Output:
1
2025-04-17 04:47:37,131 - INFO - Reasoning:

Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (383.231 and 367.515 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (76.66) is slightly higher than Ligand B (69.72). Both are below the 90 A^2 threshold desirable for CNS targets, but Ligand B is preferable.

**3. logP:** Ligand A (3.978) is at the upper end of the optimal range (1-3), while Ligand B (1.245) is at the lower end. While Ligand A's logP isn't *bad*, Ligand B's is quite low, potentially hindering membrane permeability.

**4. H-Bond Donors:** Ligand A (2) and Ligand B (1) both meet the <=5 criteria.

**5. H-Bond Acceptors:** Both ligands (A: 4, B: 4) are well within the <=10 limit.

**6. QED:** Both ligands have similar QED values (A: 0.791, B: 0.743), indicating good drug-like properties.

**7. DILI:** Ligand A (86.972) has a significantly higher DILI risk than Ligand B (55.448). This is a substantial negative for Ligand A.

**8. BBB:** Ligand A (57.193) has a better BBB penetration percentile than Ligand B (52.811), but both are below the desirable >70 for CNS targets.

**9. Caco-2:** Both have negative Caco-2 values (-4.711 and -4.833), which is unusual and suggests poor permeability.

**10. Solubility:** Both have negative solubility values (-5.186 and -2.877), also unusual and suggesting poor solubility.

**11. hERG:** Ligand A (0.51) has a slightly higher hERG risk than Ligand B (0.148), but both are relatively low.

**12. Cl_mic:** Ligand A (33.826) has a lower microsomal clearance than Ligand B (48.712), indicating better metabolic stability.

**13. t1/2:** Ligand B (-20.441) has a *negative* in vitro half-life, which is impossible and indicates a significant problem. Ligand A (10.103) is reasonable.

**14. Pgp:** Ligand A (0.314) has lower P-gp efflux liability than Ligand B (0.056), which is favorable for CNS penetration.

**15. Binding Affinity:** Ligand A (-8.6 kcal/mol) has a significantly stronger binding affinity than Ligand B (-7.4 kcal/mol). This is a >1.2 kcal/mol difference, which is substantial.

**Overall Assessment:**

Despite Ligand A's higher logP and DILI risk, the significantly stronger binding affinity (-8.6 vs -7.4 kcal/mol) and the problematic negative half-life of Ligand B make Ligand A the more promising candidate. The difference in affinity is large enough to potentially overcome the slightly higher DILI risk, especially given that DILI prediction is not always accurate. The negative half-life of Ligand B is a showstopper.

Output:
1
2025-04-17 04:47:37,131 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (357.38 and 362.50 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (65.46) is slightly higher than Ligand B (62.55), but both are below the 90 A^2 threshold desirable for CNS targets.

**logP:** Both ligands have good logP values (2.79 and 2.52), falling within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A has 2 HBD and 3 HBA, while Ligand B has 1 HBD and 4 HBA. Both are within acceptable limits (<=5 HBD and <=10 HBA).

**QED:** Both ligands have similar QED values (0.87 and 0.85), indicating good drug-like properties.

**DILI:** Ligand A (15.9%) has a significantly lower DILI risk than Ligand B (23.2%). This is a substantial advantage.

**BBB:** Ligand A (82.0%) has a considerably higher BBB penetration percentile than Ligand B (64.5%). This is *critical* for a CNS target like DRD2.

**Caco-2 Permeability:** Ligand A (-4.614) has a worse Caco-2 permeability than Ligand B (-5.307). Lower values indicate lower permeability.

**Aqueous Solubility:** Both ligands have very poor aqueous solubility (-2.815 and -2.875). This is a concern for both, but not a deciding factor given the other properties.

**hERG Inhibition:** Both ligands show low hERG inhibition liability (0.49 and 0.25), which is good.

**Microsomal Clearance:** Ligand A (5.09) has a much lower microsomal clearance than Ligand B (32.20). Lower clearance means better metabolic stability.

**In vitro Half-Life:** Ligand B (31.31) has a significantly longer in vitro half-life than Ligand A (-0.95). This is a positive for Ligand B.

**P-gp Efflux:** Ligand A (0.11) has lower P-gp efflux liability than Ligand B (0.15). Lower efflux is preferable for CNS penetration.

**Binding Affinity:** Ligand B (-7.8 kcal/mol) has a better binding affinity than Ligand A (-9.3 kcal/mol). This is a significant advantage, exceeding the 1.5 kcal/mol threshold.

**Overall Assessment:**

While Ligand B has a better binding affinity and in vitro half-life, Ligand A demonstrates superior ADME properties crucial for CNS drug development. Specifically, the significantly higher BBB penetration (82% vs 64.5%), lower DILI risk (15.9% vs 23.2%), and lower microsomal clearance (5.09 vs 32.20) of Ligand A are compelling advantages. The slightly worse Caco-2 permeability of Ligand A is less concerning given the primary focus on CNS penetration. The affinity difference, while present, might be overcome with further optimization of Ligand A, while improving the ADME profile of Ligand B would be more challenging.

Output:
0
2025-04-17 04:47:37,131 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B against the provided guidelines, prioritizing GPCR-specific properties (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (369.487 and 351.531 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (92.51) is better than Ligand B (38.77). For CNS targets, TPSA should be <= 90, so Ligand A is closer to the ideal.

**logP:** Ligand A (2.081) is optimal (1-3), while Ligand B (4.397) is slightly high, potentially leading to solubility issues or off-target effects.

**H-Bond Donors/Acceptors:** Ligand A (HBD=1, HBA=5) and Ligand B (HBD=0, HBA=3) both have acceptable numbers of H-bond donors and acceptors.

**QED:** Ligand A (0.88) is significantly better than Ligand B (0.682), indicating a more drug-like profile.

**DILI:** Ligand A (37.805) has a lower DILI risk than Ligand B (17.642), both are good.

**BBB:** Ligand B (91.392) has a significantly higher BBB penetration percentile than Ligand A (80.264). This is a crucial factor for a CNS target like DRD2.

**Caco-2 Permeability:** Ligand A (-4.617) and Ligand B (-4.23) are both negative, indicating poor permeability.

**Aqueous Solubility:** Ligand A (-2.65) and Ligand B (-4.843) are both negative, indicating poor solubility.

**hERG Inhibition:** Ligand A (0.129) has a lower hERG inhibition liability than Ligand B (0.828), which is preferable.

**Microsomal Clearance:** Ligand B (128.637) has a much higher microsomal clearance than Ligand A (16.343), suggesting poorer metabolic stability.

**In vitro Half-Life:** Ligand A (12.158) has a longer in vitro half-life than Ligand B (0.154).

**P-gp Efflux:** Ligand A (0.038) has a much lower P-gp efflux liability than Ligand B (0.806), which is beneficial for CNS exposure.

**Binding Affinity:** Ligand A (-8.5 kcal/mol) has a significantly stronger binding affinity than Ligand B (-6.5 kcal/mol). This is a substantial advantage, potentially outweighing some ADME drawbacks.

**Overall Assessment:**

While Ligand B has superior BBB penetration, Ligand A excels in most other critical parameters, especially binding affinity, metabolic stability (lower Cl_mic, longer t1/2), P-gp efflux, and QED. The significantly stronger binding affinity of Ligand A (-8.5 vs -6.5 kcal/mol) is a major advantage for a GPCR target. The slightly lower BBB of Ligand A is a concern, but the other benefits are substantial. Given the importance of potency and ADME properties for GPCRs, and the significant difference in binding affinity, Ligand A is the more promising candidate.

Output:
1
2025-04-17 04:47:37,132 - INFO - Batch 143 complete. Total preferences: 2288
2025-04-17 04:47:37,132 - INFO - Processing batch 144/512...
2025-04-17 04:48:19,343 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (355.312 and 338.411 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (68.65) is better than Ligand B (74.33). Both are below the 90 A^2 threshold desirable for CNS targets, but A is closer to the ideal.

**logP:** Both ligands have good logP values (2.875 and 1.725), falling within the optimal 1-3 range. Ligand A is slightly better.

**H-Bond Donors/Acceptors:** Ligand A (HBD=1, HBA=5) is slightly better than Ligand B (HBD=2, HBA=4) in terms of balancing solubility and permeability.

**QED:** Both ligands have good QED scores (0.774 and 0.871), indicating good drug-like properties. Ligand B is slightly better.

**DILI:** Both ligands have similar DILI risk (53.47 and 58.938), both are acceptable (below 60).

**BBB:** Ligand A (64.482) has a significantly better BBB penetration percentile than Ligand B (54.052). This is a crucial factor for a CNS target like DRD2.

**Caco-2 Permeability:** Ligand A (-4.575) has better Caco-2 permeability than Ligand B (-5.314).

**Aqueous Solubility:** Ligand A (-4.26) has better aqueous solubility than Ligand B (-2.501).

**hERG:** Both ligands have very low hERG risk (0.513 and 0.544).

**Microsomal Clearance:** Ligand B (-15.436) has significantly lower microsomal clearance than Ligand A (45.867), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand B (33.958) has a longer in vitro half-life than Ligand A (-7.109).

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.288 and 0.028).

**Binding Affinity:** Ligand A (-9.0 kcal/mol) has a slightly better binding affinity than Ligand B (-9.2 kcal/mol). While the difference is small, it's still a positive for Ligand A.

**Overall Assessment:**

Ligand A excels in BBB penetration, Caco-2 permeability, solubility, and has a slightly better affinity. Ligand B has a better QED, lower clearance, and longer half-life. However, for a CNS target like DRD2, BBB penetration is paramount. Ligand A's superior BBB score (64.482 vs 54.052) outweighs the benefits of Ligand B's improved metabolic stability. The small difference in binding affinity also favors Ligand A.

Output:
1
2025-04-17 04:48:19,344 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 drug candidates, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (423.376 Da) is slightly higher, but acceptable. Ligand B (346.427 Da) is also good.

**TPSA:** Ligand A (63.4) is better than Ligand B (80.57). For CNS targets, we want TPSA <= 90, both are within this range, but A is closer to the optimal <60 for good CNS penetration.

**logP:** Ligand A (3.881) is optimal, while Ligand B (2.287) is a bit low, potentially hindering membrane permeability.

**H-Bond Donors/Acceptors:** Ligand A (HBD=1, HBA=3) is better than Ligand B (HBD=2, HBA=4). Both are within acceptable limits, but lower is generally preferred for better permeability.

**QED:** Ligand A (0.794) is significantly better than Ligand B (0.408), indicating a more drug-like profile.

**DILI:** Ligand B (33.695) has a much lower DILI risk than Ligand A (63.823). This is a significant advantage for Ligand B.

**BBB:** Ligand A (78.674) has a better BBB percentile than Ligand B (56.805). This is crucial for a CNS target like DRD2, making A more promising.

**Caco-2 Permeability:** Ligand A (-4.75) is significantly better than Ligand B (-5.011). Higher values indicate better intestinal absorption.

**Aqueous Solubility:** Ligand B (-1.986) is better than Ligand A (-4.534). Better solubility is generally desirable.

**hERG Inhibition:** Ligand A (0.687) has a slightly higher hERG risk than Ligand B (0.288), which is preferable.

**Microsomal Clearance:** Ligand B (32.158) has lower microsomal clearance than Ligand A (61.858), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (18.036) has a longer half-life than Ligand B (14.152).

**P-gp Efflux:** Ligand A (0.38) has lower P-gp efflux than Ligand B (0.159), which is better for CNS exposure.

**Binding Affinity:** Ligand A (-9.2 kcal/mol) has a significantly stronger binding affinity than Ligand B (-8.2 kcal/mol). This is a substantial advantage, potentially outweighing some of the ADME drawbacks of Ligand A.

**Overall Assessment:**

Ligand A excels in binding affinity and BBB penetration, crucial for a CNS GPCR target. It also has better Caco-2 permeability, in vitro half-life, and P-gp efflux. However, it has higher DILI risk and a slightly higher hERG risk.

Ligand B has a much better safety profile (lower DILI, lower hERG), better solubility, and metabolic stability. However, its lower binding affinity, lower BBB penetration, and lower logP are significant drawbacks.

The difference in binding affinity (-9.2 vs -8.2 kcal/mol) is substantial (1 kcal/mol difference). Given the importance of potency for GPCRs, and the fact that we can potentially mitigate some of the ADME issues with further optimization, the stronger affinity of Ligand A makes it the more promising candidate.

Output:
1
2025-04-17 04:48:19,344 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B based on the provided guidelines, prioritizing GPCR-specific properties (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (349.341 and 350.459 Da) fall within the ideal 200-500 Da range.

**TPSA:** Both ligands (79.26 and 78.87) are below the 90 A^2 threshold desirable for CNS targets, which is excellent.

**logP:** Ligand A (1.337) is within the optimal 1-3 range. Ligand B (0.951) is slightly below 1, potentially impacting permeability.

**H-Bond Donors/Acceptors:** Both ligands have 2 HBD and 5/4 HBA, respectively, which are within acceptable limits.

**QED:** Ligand A (0.854) has a better QED score than Ligand B (0.699), indicating a more drug-like profile.

**DILI:** Ligand A (84.374) has a higher DILI risk than Ligand B (9.965). This is a significant drawback for Ligand A.

**BBB:** Ligand A (64.017) has a moderate BBB penetration, while Ligand B (46.336) has a lower BBB penetration. Both are below the desirable >70 for CNS targets, but A is better.

**Caco-2 Permeability:** Ligand A (-5.056) has a negative Caco-2 value, suggesting poor permeability. Ligand B (-4.771) is also negative, but slightly less so.

**Aqueous Solubility:** Both ligands have negative solubility values (-3.594 and -1.279), indicating poor aqueous solubility, which could pose formulation challenges. Ligand B is better here.

**hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.469 and 0.147).

**Microsomal Clearance:** Ligand A (3.827) has significantly lower microsomal clearance than Ligand B (15.408), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (-9.079) has a much longer in vitro half-life than Ligand B (2.179), which is a major advantage.

**P-gp Efflux:** Ligand A (0.112) has lower P-gp efflux than Ligand B (0.049), which is beneficial for CNS exposure.

**Binding Affinity:** Ligand A (-9.1 kcal/mol) has a stronger binding affinity than Ligand B (-8.1 kcal/mol). The difference of 1 kcal/mol is substantial and can outweigh some ADME concerns.

**Overall Assessment:**

Ligand A has a significantly better binding affinity and metabolic stability (lower Cl_mic, longer t1/2) and lower P-gp efflux. However, it has a much higher DILI risk and poor Caco-2 permeability. Ligand B has a lower DILI risk and slightly better solubility, but weaker affinity, higher clearance, and higher P-gp efflux.

Given the target is a CNS GPCR (DRD2), strong binding affinity and BBB penetration are crucial. While Ligand A's BBB is not ideal, its significantly superior affinity and metabolic stability, coupled with lower P-gp efflux, make it the more promising candidate, *despite* the higher DILI risk and poor Caco-2. The DILI risk might be mitigated with structural modifications during lead optimization. The poor Caco-2 permeability is less critical for a CNS target.

Output:
1
2025-04-17 04:48:19,344 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (355.331 and 369.487 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (38.33) is excellent, well below the 90 A^2 threshold for CNS targets. Ligand B (87.74) is higher, but still potentially acceptable, though less ideal.

**logP:** Ligand A (4.318) is slightly high, potentially leading to solubility issues or off-target interactions. Ligand B (0.499) is quite low, which could hinder membrane permeability and CNS penetration.

**H-Bond Donors/Acceptors:** Ligand A (HBD=1, HBA=2) and Ligand B (HBD=2, HBA=5) both have reasonable numbers of H-bond donors and acceptors.

**QED:** Both ligands have acceptable QED values (0.812 and 0.684, respectively), indicating good drug-like properties.

**DILI:** Ligand A (52.191) has a slightly higher DILI risk than Ligand B (45.366), but both are below the concerning 60 percentile.

**BBB:** This is a critical parameter for a CNS target. Ligand A has a significantly better BBB penetration score (74.758%) compared to Ligand B (40.403%). This is a major advantage for Ligand A.

**Caco-2 Permeability:** Ligand A (-4.324) and Ligand B (-5.255) both have negative Caco-2 values, which is unusual and suggests poor permeability. However, the scale isn't specified, so we can't interpret these values definitively.

**Aqueous Solubility:** Ligand A (-5.047) and Ligand B (-1.776) both have negative solubility values, which is also unusual and suggests poor solubility.

**hERG Inhibition:** Ligand A (0.768) has a slightly higher hERG risk than Ligand B (0.313), but both are relatively low.

**Microsomal Clearance:** Ligand B (24.407) has a lower microsomal clearance than Ligand A (65.678), indicating better metabolic stability.

**In vitro Half-Life:** Ligand B (-21.61) has a much longer in vitro half-life than Ligand A (-5.886), which is a significant advantage.

**P-gp Efflux:** Ligand A (0.208) has a lower P-gp efflux liability than Ligand B (0.033), suggesting better CNS exposure.

**Binding Affinity:** Both ligands have excellent binding affinities (-9.4 and -8.4 kcal/mol). Ligand A has a 1 kcal/mol advantage.

**Overall Assessment:**

While Ligand B has better metabolic stability (lower Cl_mic, longer t1/2) and slightly lower DILI/hERG risk, Ligand A is significantly better regarding BBB penetration and has a slightly better binding affinity. Given that this is a CNS target (DRD2), BBB penetration is paramount. The higher logP of Ligand A is a concern, but the strong affinity and excellent BBB penetration outweigh this drawback. The poor solubility and permeability values for both ligands are concerning, but could potentially be addressed through formulation strategies.

Output:
1
2025-04-17 04:48:19,345 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (365.419 Da and 377.463 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (126.13) is slightly above the optimal <90 for CNS targets, but still reasonable. Ligand B (105.25) is better, falling comfortably below 90.

**logP:** Ligand A (-0.698) is a bit low, potentially hindering permeation. Ligand B (-1.208) is also low, but slightly lower than A. Both are below the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A has 2 HBD and 9 HBA, which are acceptable. Ligand B has 1 HBD and 7 HBA, also acceptable.

**QED:** Both ligands have QED values (0.693 and 0.594) above the 0.5 threshold, indicating good drug-like properties.

**DILI:** Ligand A (76.425) has a higher DILI risk than Ligand B (43.622). This is a significant negative for Ligand A.

**BBB:** Ligand B (56.301) has a substantially better BBB penetration percentile than Ligand A (23.071). This is a crucial advantage for a CNS target like DRD2.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.755 and -5.299), which is unusual and suggests poor permeability. This is a concern for both.

**Aqueous Solubility:** Both ligands have negative solubility values (-1.461 and -0.936), indicating poor solubility. This is also a concern for both.

**hERG:** Both ligands have low hERG inhibition liability (0.049 and 0.133), which is positive.

**Microsomal Clearance:** Ligand A (3.67) has a higher microsomal clearance than Ligand B (-2.593), meaning Ligand B is likely more metabolically stable.

**In vitro Half-Life:** Ligand A (1.046) has a shorter half-life than Ligand B (0.506).

**P-gp Efflux:** Ligand A (0.034) has lower P-gp efflux liability than Ligand B (0.008), which is better for CNS penetration.

**Binding Affinity:** Both ligands have very similar binding affinities (-7.4 and -7.3 kcal/mol), which are both excellent. The difference is negligible.

**Conclusion:**

Considering all factors, **Ligand B is the more promising drug candidate.** While both have issues with Caco-2 permeability and solubility, Ligand B's significantly better BBB penetration (56.301 vs 23.071), lower DILI risk (43.622 vs 76.425), and improved metabolic stability (-2.593 vs 3.67) outweigh the slight advantage of Ligand A in P-gp efflux. The binding affinities are essentially the same, so the ADME properties become the deciding factor for a CNS-targeting GPCR.

Output:
1
2025-04-17 04:48:19,345 - INFO - Reasoning:

Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (376.425 and 347.419 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (82.78) is better than Ligand B (95.5). For CNS targets, we want TPSA <= 90, so Ligand A is preferable.

**3. logP:** Ligand A (2.086) is optimal (1-3), while Ligand B (0.232) is quite low, potentially hindering permeation. This is a significant advantage for Ligand A.

**4. H-Bond Donors:** Both have acceptable HBD counts (2 and 1 respectively, both <=5).

**5. H-Bond Acceptors:** Both have acceptable HBA counts (5 each, both <=10).

**6. QED:** Both ligands have good QED values (0.761 and 0.787, both >=0.5).

**7. DILI:** Ligand A (32.067) has a lower DILI risk than Ligand B (45.173), both are acceptable (<40 is good, <60 is preferred).

**8. BBB:** Ligand A (59.093) has a better BBB percentile than Ligand B (54.556), although both are below the desirable >70 for CNS targets.

**9. Caco-2 Permeability:** Ligand A (-5.204) has a worse Caco-2 permeability than Ligand B (-4.669), but both are negative values, indicating poor permeability.

**10. Aqueous Solubility:** Ligand A (-3.399) has better solubility than Ligand B (-1.089), both are negative values indicating poor solubility.

**11. hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.464 and 0.098, both low).

**12. Microsomal Clearance:** Ligand A (-1.435) has a lower (better) microsomal clearance than Ligand B (8.655), indicating better metabolic stability.

**13. In vitro Half-Life:** Ligand A (15.516) has a longer half-life than Ligand B (13.707).

**14. P-gp Efflux:** Ligand A (0.074) has lower P-gp efflux than Ligand B (0.035), which is better for CNS exposure.

**15. Binding Affinity:** Ligand A (-7.9) has a slightly better binding affinity than Ligand B (-7.5). While both are excellent, the 0.4 kcal/mol difference is noticeable.

**Overall Assessment:**

Ligand A is significantly better. It has a more optimal logP, lower TPSA, better BBB penetration, lower DILI risk, better metabolic stability (lower Cl_mic), longer half-life, lower P-gp efflux, and slightly better binding affinity. While both have poor Caco-2 permeability and solubility, the other advantages of Ligand A, particularly its logP and TPSA, make it a more promising candidate for a CNS-targeting drug like a DRD2 ligand.

Output:
1
2025-04-17 04:48:19,345 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (363.82) is slightly higher than Ligand B (349.391), but both are acceptable.

**TPSA:** Ligand A (74.15) is excellent for CNS penetration, well below the 90 A^2 threshold. Ligand B (129.37) is higher, but still potentially acceptable, though less ideal.

**logP:** Ligand A (3.989) is optimal. Ligand B (-1.432) is significantly low, potentially hindering membrane permeability and CNS entry.

**H-Bond Donors/Acceptors:** Ligand A (HBD=2, HBA=3) is well within the acceptable ranges. Ligand B (HBD=4, HBA=7) is also acceptable, but closer to the upper limits.

**QED:** Ligand A (0.794) has a strong drug-like profile. Ligand B (0.405) is lower, indicating a less favorable overall drug-likeness.

**DILI:** Both ligands have similar DILI risk (Ligand A: 53.315, Ligand B: 55.797), and are both reasonably low risk.

**BBB:** Ligand A (80.613) has excellent predicted BBB penetration. Ligand B (27.026) is very poor, a major concern for a CNS target like DRD2.

**Caco-2 Permeability:** Ligand A (-4.47) is negative, which is unusual and requires further investigation, but doesn't immediately disqualify it. Ligand B (-5.712) is also negative and similarly problematic.

**Aqueous Solubility:** Both ligands have poor predicted aqueous solubility (Ligand A: -5.637, Ligand B: -1.427). This could pose formulation challenges.

**hERG Inhibition:** Ligand A (0.735) has a low risk of hERG inhibition. Ligand B (0.034) also has a very low risk.

**Microsomal Clearance:** Ligand A (43.019) has moderate clearance. Ligand B (-20.448) has negative clearance, which is not physically possible and indicates a data error or modeling artifact.

**In vitro Half-Life:** Ligand A (58.717) has a reasonable half-life. Ligand B (-2.712) has a negative half-life, which is impossible and indicative of a data issue.

**P-gp Efflux:** Ligand A (0.247) has low P-gp efflux, which is favorable. Ligand B (0.006) also has very low P-gp efflux.

**Binding Affinity:** Ligand A (-9.6 kcal/mol) has significantly stronger binding affinity than Ligand B (-7.2 kcal/mol). This is a substantial advantage.

**Overall Assessment:**

Ligand A is significantly more promising. It has a better logP, a much higher predicted BBB penetration, a stronger binding affinity, and a more favorable QED score. While both have poor solubility and Caco-2 permeability, the superior CNS penetration and affinity of Ligand A outweigh these concerns. Ligand B has a very poor logP and critically, its negative clearance and half-life values are red flags, suggesting data quality issues or a fundamentally problematic structure. The large difference in binding affinity (-9.6 vs -7.2) is also a major factor.

Output:
1
2025-04-17 04:48:19,345 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (351.535 and 349.519 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (61.44) is slightly above the optimal <90 for CNS targets, but still reasonable. Ligand B (52.65) is excellent, well below 90.

**3. logP:** Both ligands have good logP values (3.539 and 2.263), falling within the 1-3 range.

**4. H-Bond Donors:** Ligand A (2) and Ligand B (1) both meet the HBD <=5 criteria.

**5. H-Bond Acceptors:** Ligand A (2) and Ligand B (3) both meet the HBA <=10 criteria.

**6. QED:** Both ligands have good QED scores (0.796 and 0.828), indicating drug-like properties.

**7. DILI:** Ligand A (16.557) has a better DILI score than Ligand B (9.267), indicating lower liver injury risk. Both are below the 40 threshold.

**8. BBB:** This is crucial for a CNS target. Ligand A (91.508) has a significantly better BBB percentile than Ligand B (69.678).  Ligand A is >70, making it highly desirable.

**9. Caco-2:** Both ligands have negative Caco-2 values, which is unusual and suggests poor permeability. This is a concern for both.

**10. Solubility:** Both ligands have negative solubility values, which is also unusual and suggests poor solubility. This is a concern for both.

**11. hERG:** Both ligands have low hERG inhibition liability (0.523 and 0.484), which is good.

**12. Cl_mic:** Ligand B (25.098) has a lower microsomal clearance than Ligand A (37.279), suggesting better metabolic stability.

**13. t1/2:** Ligand B (-4.781) has a longer in vitro half-life than Ligand A (-8.332).

**14. Pgp:** Ligand B (0.062) has significantly lower P-gp efflux liability than Ligand A (0.152), which is highly desirable for CNS penetration.

**15. Binding Affinity:** Ligand A (-8.5) has a significantly stronger binding affinity than Ligand B (-0.0). This is a major advantage. A difference of >1.5 kcal/mol can outweigh other drawbacks.

**Overall Assessment:**

While Ligand B has advantages in metabolic stability (Cl_mic, t1/2) and P-gp efflux, Ligand A's superior binding affinity (-8.5 vs -0.0 kcal/mol) and significantly better BBB penetration (91.5 vs 69.7) are decisive. The strong binding affinity suggests a higher probability of achieving efficacy, and the BBB score is critical for a CNS target like DRD2. The Caco-2 and solubility issues are concerning for both, but can potentially be addressed through formulation strategies. The slightly higher DILI risk for Ligand B is also a minor concern.

Output:
1
2025-04-17 04:48:19,345 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (342.487 and 371.497 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (50.16) is slightly above the optimal <90 for CNS targets, but still reasonable. Ligand B (45.23) is excellent, well below 90.

**3. logP:** Both ligands have good logP values (3.54 and 3.486), falling within the 1-3 range.

**4. H-Bond Donors:** Both have 1 HBD, which is acceptable.

**5. H-Bond Acceptors:** Ligand A has 3 HBA, and Ligand B has 4. Both are within the acceptable limit of <=10.

**6. QED:** Both ligands have good QED scores (0.837 and 0.798), indicating good drug-like properties.

**7. DILI:** Ligand A (37.224) has a slightly higher DILI risk than Ligand B (26.91), but both are below the concerning threshold of 60.

**8. BBB:** This is a critical parameter for a CNS target. Ligand A has 81.078% BBB penetration, which is good, but Ligand B is significantly better at 90.229%.

**9. Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and suggests poor permeability. However, these values are on a scale where negative values are possible.

**10. Aqueous Solubility:** Both ligands have poor aqueous solubility (-3.98 and -3.36). This could be a formulation challenge.

**11. hERG Inhibition:** Both ligands have low hERG inhibition risk (0.734 and 0.764).

**12. Microsomal Clearance:** Ligand A (76.678) has higher microsomal clearance than Ligand B (8.131), suggesting lower metabolic stability.

**13. In vitro Half-Life:** Ligand A (48.369) has a longer half-life than Ligand B (-0.08), which is a positive.

**14. P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.337 and 0.234), which is excellent for CNS penetration.

**15. Binding Affinity:** Both ligands have very similar and excellent binding affinities (-9.0 and -8.9 kcal/mol). The difference is negligible.

**Overall Assessment:**

Ligand B is slightly favored due to its superior BBB penetration (90.229% vs 81.078%), lower DILI risk (26.91 vs 37.224), and significantly better metabolic stability (lower Cl_mic and a positive half-life value). While Ligand A has a slightly longer half-life, the other advantages of Ligand B outweigh this. The similar binding affinities mean that the ADME properties become the deciding factors.

Output:
1
2025-04-17 04:48:19,346 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (363.435 and 339.403 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (85.61) is excellent, being well below the 90 A^2 threshold for CNS targets. Ligand B (101.38) is still reasonable, but less optimal.

**3. logP:** Both ligands have good logP values (2.964 and 2.039), falling within the optimal 1-3 range.

**4. H-Bond Donors:** Ligand A (1) and Ligand B (2) are both acceptable, being less than 5.

**5. H-Bond Acceptors:** Ligand A (5) and Ligand B (6) are both acceptable, being less than 10.

**6. QED:** Ligand A (0.883) has a significantly better QED score than Ligand B (0.686), indicating a more drug-like profile.

**7. DILI:** Both ligands have similar DILI risk (80.031 and 80.923), indicating a moderate risk. This isn't a major differentiator.

**8. BBB:** This is critical for a CNS target like DRD2. Ligand A has a very good BBB penetration percentile (81.078), exceeding the desirable >70 threshold. Ligand B's BBB penetration (37.767) is poor and a significant drawback.

**9. Caco-2 Permeability:** Ligand A (-4.492) and Ligand B (-5.621) both have negative values, indicating poor permeability. This is not ideal, but not a primary concern given the focus on CNS penetration.

**10. Aqueous Solubility:** Both ligands have poor aqueous solubility (-3.667 and -3.152). This could pose formulation challenges but is less critical than BBB penetration for a CNS drug.

**11. hERG Inhibition:** Ligand A (0.787) has a slightly higher hERG risk than Ligand B (0.284), but both are relatively low.

**12. Microsomal Clearance:** Ligand A (36.076) has a higher microsomal clearance than Ligand B (5.575), suggesting lower metabolic stability.

**13. In vitro Half-Life:** Ligand A (92.965) has a much longer in vitro half-life than Ligand B (2.472), which is a significant advantage.

**14. P-gp Efflux:** Ligand A (0.671) has a lower P-gp efflux liability than Ligand B (0.187), meaning it's less likely to be pumped out of the brain.

**15. Binding Affinity:** Ligand B (-8.6 kcal/mol) has a slightly better binding affinity than Ligand A (-9.3 kcal/mol). While a difference of 0.7 kcal/mol is noticeable, the other ADME properties are more decisive.

**Overall Assessment:**

Ligand A is the stronger candidate. Its superior BBB penetration, better QED score, longer half-life, and lower P-gp efflux outweigh the slightly weaker binding affinity and higher microsomal clearance. The poor solubility and Caco-2 permeability are concerns, but less critical for a CNS-targeting drug where BBB penetration is paramount. Ligand B's poor BBB penetration is a deal-breaker.

Output:
1
2025-04-17 04:48:19,346 - INFO - Reasoning:

Let's analyze Ligand A and Ligand B based on the provided guidelines, prioritizing GPCR-specific properties (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (354.366 and 343.471 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (86.88) is better than Ligand B (62.3). Both are below the 90 A^2 threshold desirable for CNS targets, but Ligand B is significantly lower, which is positive.

**logP:** Both ligands have good logP values (2.992 and 2.702), falling within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A has 3 HBD and 4 HBA, while Ligand B has 1 HBD and 3 HBA. Both are within acceptable limits (<=5 HBD and <=10 HBA).

**QED:** Ligand B (0.789) has a better QED score than Ligand A (0.484), indicating a more drug-like profile.

**DILI:** Ligand A has a very high DILI risk (99.341 percentile), which is a major concern. Ligand B has a much lower DILI risk (20.396 percentile), making it significantly safer.

**BBB:** Ligand B (76.037 percentile) has a much better BBB penetration score than Ligand A (56.068 percentile). This is crucial for a CNS target like DRD2.

**Caco-2 Permeability:** Ligand A (-5.122) has a negative Caco-2 value, which is unusual and suggests poor permeability. Ligand B (-4.743) is also negative, but slightly less so.

**Aqueous Solubility:** Ligand A (-4.459) and Ligand B (-2.446) both have poor aqueous solubility.

**hERG Inhibition:** Both ligands have low hERG inhibition liability (0.512 and 0.411, respectively).

**Microsomal Clearance:** Ligand A (2.539 mL/min/kg) has a lower microsomal clearance than Ligand B (61.541 mL/min/kg), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (52.569 hours) has a significantly longer in vitro half-life than Ligand B (-12.952 hours).

**P-gp Efflux:** Ligand A (0.348) has lower P-gp efflux liability than Ligand B (0.197), which is favorable for CNS penetration.

**Binding Affinity:** Ligand A (-10.1 kcal/mol) has a significantly stronger binding affinity than Ligand B (-8.5 kcal/mol). This is a substantial advantage.

**Overall Assessment:**

While Ligand A boasts a significantly better binding affinity and metabolic stability, its extremely high DILI risk and poor BBB penetration are major drawbacks. Ligand B, despite a weaker affinity, presents a much more favorable safety profile (low DILI), better BBB penetration, and a better QED score. Given the CNS target, BBB penetration and safety are paramount. The 1.6 kcal/mol difference in binding affinity, while significant, can potentially be overcome with further optimization of Ligand B. The poor solubility and Caco-2 values of both molecules would need to be addressed, but these are generally easier to improve than fundamental issues like high DILI risk.

Output:
1
2025-04-17 04:48:19,346 - INFO - Reasoning:

Let's analyze Ligand A and Ligand B based on the provided guidelines, prioritizing GPCR-specific properties (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (338.407) is slightly lower, which could be beneficial for permeability.

**TPSA:** Ligand A (53.76) is excellent for CNS penetration, well below the 90 A^2 threshold. Ligand B (95.57) is higher, potentially hindering BBB penetration, but still within a reasonable range.

**logP:** Both ligands have good logP values (A: 2.27, B: 2.218), falling within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A (HBD=0, HBA=3) is preferable to Ligand B (HBD=1, HBA=10) as it has fewer hydrogen bond acceptors, which can improve membrane permeability.

**QED:** Both ligands have acceptable QED scores (A: 0.792, B: 0.688), indicating reasonable drug-likeness.

**DILI:** Ligand A (31.252) has a significantly lower DILI risk than Ligand B (70.803), which is a major advantage.

**BBB:** Ligand A (85.498) has a much higher BBB percentile than Ligand B (35.75), crucial for a CNS target like DRD2.

**Caco-2 Permeability:** Ligand A (-4.38) has a worse Caco-2 value than Ligand B (-5.169), but both are quite poor.

**Aqueous Solubility:** Ligand A (-3.939) has a slightly better solubility than Ligand B (-2.714), but both are very poor.

**hERG:** Both ligands have low hERG risk (A: 0.313, B: 0.234).

**Microsomal Clearance:** Ligand B (58.643) has a higher microsomal clearance than Ligand A (13.299), suggesting lower metabolic stability.

**In vitro Half-Life:** Ligand A (14.306) has a longer in vitro half-life than Ligand B (-12.334), which is favorable.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (A: 0.092, B: 0.174).

**Binding Affinity:** Ligand A (-7.8 kcal/mol) has a significantly stronger binding affinity than Ligand B (-5.9 kcal/mol). This 1.9 kcal/mol difference is substantial and can outweigh some ADME drawbacks.

**Overall Assessment:**

Ligand A is clearly superior. It has a significantly better safety profile (lower DILI), much better BBB penetration, stronger binding affinity, and improved metabolic stability (lower Cl_mic, longer t1/2). While its Caco-2 and solubility are poor, the strong affinity and CNS-favorable properties outweigh these concerns, especially for a CNS-targeted GPCR like DRD2. Ligand B's higher DILI risk and poor BBB penetration are significant drawbacks.

Output:
1
2025-04-17 04:48:19,346 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (356.394 and 346.471 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (92.01) is slightly above the optimal <90 for CNS targets, but still reasonable. Ligand B (69.64) is excellent, well below 90, favoring CNS penetration.

**logP:** Ligand A (0.665) is a bit low, potentially hindering permeability. Ligand B (3.704) is near the upper limit of the optimal range (1-3), but still acceptable.

**H-Bond Donors/Acceptors:** Both ligands have 2 HBD and 5/3 HBA, respectively, which are within acceptable limits.

**QED:** Both ligands have good QED scores (0.749 and 0.825), indicating good drug-like properties.

**DILI:** Ligand A (35.595) has a slightly higher DILI risk than Ligand B (19.504). Both are below the concerning threshold of 60, but lower is preferred.

**BBB:** Ligand B (76.658) has a significantly better BBB percentile than Ligand A (64.831). This is a crucial factor for a CNS target like DRD2.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.895 and -4.783), which is unusual and suggests poor permeability. This is a significant concern for both.

**Aqueous Solubility:** Both ligands have negative solubility values (-1.384 and -4.418), indicating very poor aqueous solubility. This is a major drawback for both.

**hERG Inhibition:** Ligand A (0.24) has a lower hERG inhibition risk than Ligand B (0.654), which is favorable.

**Microsomal Clearance:** Ligand B (92.127) has a much higher microsomal clearance than Ligand A (5.048), indicating faster metabolism and potentially lower *in vivo* exposure.

**In vitro Half-Life:** Ligand B (2.485) has a slightly shorter half-life than Ligand A (2.1), but both are relatively short.

**P-gp Efflux:** Ligand A (0.027) has much lower P-gp efflux liability than Ligand B (0.15), which is beneficial for CNS penetration.

**Binding Affinity:** Ligand B (-8.3 kcal/mol) has a significantly stronger binding affinity than Ligand A (-7.2 kcal/mol). This 1.1 kcal/mol difference is substantial and can outweigh some ADME deficiencies.

**Overall Assessment:**

Despite the poor Caco-2 and solubility for both compounds, Ligand B is the more promising candidate. The significantly stronger binding affinity (-8.3 vs -7.2 kcal/mol) and better BBB penetration (76.66% vs 64.83%) outweigh the slightly higher DILI and hERG risk, and faster metabolism. The lower P-gp efflux for Ligand A is a positive, but the affinity and BBB are more critical for a CNS GPCR target. The poor solubility and permeability would need to be addressed through formulation strategies, but the improved potency and CNS exposure potential of Ligand B make it the better starting point.

Output:
1
2025-04-17 04:48:19,347 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (349.391 Da) is slightly lower, which is generally favorable for permeability. Ligand B (367.865 Da) is also good.

**TPSA:** Ligand A (127.32) is borderline for CNS penetration, being slightly above the preferred <90. Ligand B (56.49) is excellent, well below 90, indicating good potential for CNS penetration.

**logP:** Ligand A (-0.464) is quite low, potentially hindering membrane permeability and CNS entry. Ligand B (4.36) is high, potentially leading to solubility issues and off-target interactions, but for a GPCR, a higher logP can be tolerated if other properties are favorable.

**H-Bond Donors/Acceptors:** Ligand A has 3 HBD and 5 HBA, which are acceptable. Ligand B has 0 HBD and 6 HBA, also acceptable.

**QED:** Both ligands have similar QED values (0.52 and 0.526), indicating good drug-like properties.

**DILI:** Ligand A (41.024) has a lower DILI risk than Ligand B (85.692), which is a significant advantage.

**BBB:** Ligand A (31.834) has poor predicted BBB penetration. Ligand B (48.391) is better, but still not ideal (aim for >70).

**Caco-2 Permeability:** Both have negative Caco-2 values (-5.449 and -5.111), which is unusual and suggests poor permeability. This is concerning for both.

**Aqueous Solubility:** Both have negative solubility values (-1.625 and -4.415), indicating very poor aqueous solubility. This could pose formulation challenges.

**hERG Inhibition:** Ligand A (0.351) has a lower hERG risk than Ligand B (0.539), which is preferable.

**Microsomal Clearance:** Ligand A (0.735) has a much lower microsomal clearance than Ligand B (34.16), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (-5.889) has a very short predicted half-life, while Ligand B (-7.941) is even shorter. Both are poor.

**P-gp Efflux:** Ligand A (0.018) has very low P-gp efflux liability, which is excellent for CNS penetration. Ligand B (0.579) has moderate P-gp efflux, which is less desirable.

**Binding Affinity:** Ligand B (-9.9 kcal/mol) has a significantly stronger binding affinity than Ligand A (-7.3 kcal/mol). This is a substantial advantage, potentially outweighing some of its ADME drawbacks. The difference is >1.5 kcal/mol.

**Overall Assessment:**

Ligand B has a much stronger binding affinity, which is the most critical factor for GPCRs. While its logP is high and DILI risk is elevated, the substantial affinity advantage is likely to be decisive. Ligand A has better ADME properties (lower DILI, better P-gp efflux, lower clearance) but its significantly weaker binding affinity makes it less promising. The poor Caco-2 and solubility for both are concerning, but can potentially be addressed with formulation strategies. Given the CNS target, the slightly better TPSA of Ligand B is also a plus.

Output:
1
2025-04-17 04:48:19,347 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (351.4 & 349.5 Da) fall comfortably within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (75.43) is slightly higher than Ligand B (69.72). Both are below the 90 A^2 threshold desirable for CNS targets, but B is closer to optimal.

**3. logP:** Ligand A (2.944) is within the optimal 1-3 range. Ligand B (1.566) is on the lower end, potentially impacting permeability.

**4. H-Bond Donors:** Ligand A has 2 HBD, and Ligand B has 1. Both are within the acceptable limit of <=5.

**5. H-Bond Acceptors:** Both ligands have 3 HBA, well within the <=10 limit.

**6. QED:** Both ligands have QED values above 0.5 (0.603 and 0.56), indicating good drug-like properties.

**7. DILI:** Ligand A (47.15) has a moderate DILI risk, while Ligand B (14.62) has a very low DILI risk, which is a significant advantage.

**8. BBB:** Ligand A (86.002) has a good BBB penetration percentile, exceeding the 70% threshold for CNS targets. Ligand B (71.229) is also acceptable but lower. This is a critical factor for DRD2.

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.828 and -4.874). These values are unusual and likely represent logPapp values (permeability coefficient). Lower (more negative) values indicate lower permeability. They are similar and suggest moderate permeability.

**10. Aqueous Solubility:** Both ligands have negative solubility values (-3.632 and -1.838), likely logS values. Lower values indicate lower solubility. Ligand B is slightly better in this regard.

**11. hERG Inhibition:** Both ligands have low hERG inhibition risk (0.706 and 0.27).

**12. Microsomal Clearance:** Ligand A (15.912) has lower microsomal clearance than Ligand B (56.43), suggesting better metabolic stability.

**13. In vitro Half-Life:** Ligand A (-27.696) has a significantly longer in vitro half-life than Ligand B (-14.682).

**14. P-gp Efflux:** Both ligands have low P-gp efflux liability (0.077 and 0.091).

**15. Binding Affinity:** Ligand A (-10.2 kcal/mol) has a significantly stronger binding affinity than Ligand B (-8.9 kcal/mol). This >1.5 kcal/mol difference is substantial and can outweigh some ADME drawbacks.

**Overall Assessment:**

Ligand A excels in binding affinity and has a good BBB penetration, a long half-life, and acceptable DILI risk. While its TPSA is slightly higher and logP is at the upper end of optimal, the strong binding affinity and good CNS penetration are crucial for a DRD2 ligand. Ligand B has a lower DILI risk and slightly better TPSA/solubility, but its significantly weaker binding affinity and lower BBB penetration are major drawbacks. The affinity difference is substantial enough to favor Ligand A.

Output:
1
2025-04-17 04:48:19,347 - INFO - Okay, let's analyze these two ligands for their potential as DRD2 drug candidates.

**Step-by-step comparison:**

1. **MW:** Both ligands (A: 370.739 Da, B: 347.419 Da) fall within the ideal 200-500 Da range. No clear advantage here.

2. **TPSA:** Ligand A (76.66) is significantly better than Ligand B (86.28). For a CNS target like DRD2, we want TPSA as close to 90 as possible, and A is closer.

3. **logP:** Both ligands have good logP values (A: 2.71, B: 2.889), falling within the optimal 1-3 range. No significant difference.

4. **HBD:** Ligand A (2) is slightly better than Ligand B (0). While both are acceptable, a small number of HBDs can improve permeability.

5. **HBA:** Ligand A (4) is lower than Ligand B (7). Lower HBA is generally preferred for better permeability.

6. **QED:** Both ligands have good QED scores (A: 0.811, B: 0.845), indicating good drug-like properties. B is slightly better.

7. **DILI:** Ligand A (98.216) has a *very* high DILI risk, which is a major concern. Ligand B (60.682) is still elevated, but significantly lower and within a potentially manageable range with further optimization.

8. **BBB:** Ligand B (92.4) has a much better BBB penetration score than Ligand A (52.423). This is *critical* for a CNS target like DRD2.

9. **Caco-2:** Both have negative Caco-2 values which is unusual and suggests a potential issue with the data. However, the values are similar.

10. **Solubility:** Both ligands have negative solubility values, which is also unusual. The values are similar.

11. **hERG:** Both ligands have low hERG inhibition liability (A: 0.382, B: 0.174). B is slightly better.

12. **Cl_mic:** Ligand A (26.662) has a lower microsomal clearance than Ligand B (57.951), suggesting better metabolic stability.

13. **t1/2:** Ligand B (-21.214) has a negative half-life, which is not possible. This is a data issue. Ligand A (12.434) has a reasonable in vitro half-life.

14. **Pgp:** Both ligands have very low Pgp efflux liability (A: 0.237, B: 0.179). B is slightly better.

15. **Binding Affinity:** Both ligands have excellent binding affinities (A: -9.3 kcal/mol, B: -8.0 kcal/mol). Ligand A is significantly more potent.

**GPCR-Specific Priorities & Overall Assessment:**

For a GPCR like DRD2, BBB penetration, logP, Pgp efflux, TPSA, and affinity are key. While Ligand A has a superior binding affinity, its extremely high DILI risk and poor BBB penetration are major drawbacks. Ligand B, despite being slightly less potent, has a much better safety profile (lower DILI) and significantly better BBB penetration. The issues with the Caco-2 and solubility data are concerning for both, but the DILI and BBB issues for Ligand A are more critical for a CNS drug. The negative half-life for Ligand B is a data quality issue.

**Conclusion:**

Considering all factors, especially the GPCR-specific priorities and the critical importance of BBB penetration for a CNS target, **Ligand B** is the more viable drug candidate. The superior binding affinity of Ligand A is outweighed by its unacceptable DILI risk and poor CNS exposure.

Output:
1
2025-04-17 04:48:19,347 - INFO - Batch 144 complete. Total preferences: 2304
2025-04-17 04:48:19,347 - INFO - Processing batch 145/512...
2025-04-17 04:49:02,230 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, considering the provided guidelines and GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (347.434 and 346.431 Da) fall comfortably within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (44.81) is significantly better than Ligand B (82.18). For a CNS target like DRD2, TPSA should be <= 90, and ideally lower. Ligand A is well within this range, while Ligand B is approaching the upper limit and less favorable.

**3. logP:** Both ligands have acceptable logP values (2.473 and 3.483), falling within the optimal 1-3 range. Ligand B is slightly higher, which could potentially lead to solubility issues, but it's not a major concern.

**4. H-Bond Donors:** Both have 1 HBD, which is within the acceptable limit of <=5.

**5. H-Bond Acceptors:** Ligand A has 3 HBAs, and Ligand B has 7. Both are within the limit of <=10, but Ligand A is preferable.

**6. QED:** Both ligands have similar QED values (0.89 and 0.806), indicating good drug-likeness.

**7. DILI:** Ligand A (10.741) has a much lower DILI risk than Ligand B (54.634). This is a significant advantage for Ligand A.

**8. BBB:** Both ligands have excellent BBB penetration (86.196% and 81.97%), exceeding the desirable threshold of >70%. This is crucial for a CNS target.

**9. Caco-2 Permeability:** Both have negative Caco-2 values (-4.542 and -4.654). This is unusual and suggests poor permeability. However, the values are similar, so it doesn't strongly differentiate the two.

**10. Aqueous Solubility:** Ligand A (-1.606) has better aqueous solubility than Ligand B (-4.964).

**11. hERG Inhibition:** Ligand A (0.864) has a lower hERG inhibition risk than Ligand B (0.177). This is a significant advantage for Ligand A.

**12. Microsomal Clearance:** Ligand A (-1.244) has a lower (better) microsomal clearance than Ligand B (97.828). This suggests better metabolic stability for Ligand A.

**13. In vitro Half-Life:** Ligand A (8.602) has a longer in vitro half-life than Ligand B (12.842).

**14. P-gp Efflux:** Ligand A (0.068) has a lower P-gp efflux liability than Ligand B (0.286), which is favorable for CNS penetration.

**15. Binding Affinity:** Ligand A (-9.7 kcal/mol) has a slightly better binding affinity than Ligand B (-8.4 kcal/mol). While both are good, the 1.3 kcal/mol difference is substantial and can outweigh minor ADME drawbacks.

**Overall Assessment:**

Ligand A consistently outperforms Ligand B across most critical parameters. It has a lower TPSA, lower DILI risk, better solubility, lower hERG inhibition, better metabolic stability, lower P-gp efflux, and a slightly stronger binding affinity. While both have good BBB penetration, the overall profile of Ligand A is significantly more favorable for development as a DRD2-targeting drug.

Output:
1
2025-04-17 04:49:02,230 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 drug candidates, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (346.471 Da) is slightly lower, which could be beneficial for permeability. Ligand B (406.28 Da) is also acceptable.

**2. TPSA:** Ligand A (60.85) is better than Ligand B (68.46). Both are below the 90 A^2 threshold desirable for CNS targets, but A is closer to the optimal range.

**3. logP:** Both ligands have good logP values (A: 2.094, B: 3.112), falling within the 1-3 range. Ligand B is slightly higher, which might raise concerns about solubility, but isn't a major issue.

**4. H-Bond Donors:** Ligand A (1) is preferable to Ligand B (0). A single HBD can contribute to solubility without significantly hindering permeability.

**5. H-Bond Acceptors:** Ligand A (3) is preferable to Ligand B (5). Lower HBA is generally better for CNS penetration.

**6. QED:** Both ligands have acceptable QED values (A: 0.796, B: 0.69), indicating good drug-like properties.

**7. DILI:** Ligand A (13.843) has a significantly lower DILI risk than Ligand B (44.824). This is a substantial advantage for Ligand A.

**8. BBB:** Ligand A (69.058) is lower than Ligand B (83.831). While both are reasonably good, Ligand B has a considerably better predicted BBB penetration, which is crucial for a CNS target like DRD2.

**9. Caco-2 Permeability:** Ligand A (-4.898) has a worse Caco-2 permeability than Ligand B (-4.453).

**10. Aqueous Solubility:** Ligand A (-1.981) has a worse aqueous solubility than Ligand B (-4.189).

**11. hERG Inhibition:** Ligand A (0.235) has a lower hERG inhibition liability than Ligand B (0.78). This is a significant safety advantage for Ligand A.

**12. Microsomal Clearance:** Ligand A (21.234) has a lower microsomal clearance than Ligand B (77.297), suggesting better metabolic stability.

**13. In vitro Half-Life:** Ligand A (9.322) has a shorter half-life than Ligand B (26.264). This is a drawback for Ligand A.

**14. P-gp Efflux:** Ligand A (0.093) has lower P-gp efflux liability than Ligand B (0.426). This is a significant advantage for CNS exposure.

**15. Binding Affinity:** Ligand B (-7.2 kcal/mol) has a slightly better binding affinity than Ligand A (-8.5 kcal/mol). While A has a better affinity, the difference is not substantial enough to outweigh the other factors.

**Overall Assessment:**

Ligand A demonstrates a superior ADMET profile, with lower DILI risk, lower hERG inhibition, lower P-gp efflux, and better metabolic stability. While Ligand B has a slightly better BBB penetration and binding affinity, the safety and pharmacokinetic advantages of Ligand A are more compelling for a CNS drug candidate. The slightly lower BBB of Ligand A is less concerning given its other favorable properties.

Output:
0
2025-04-17 04:49:02,231 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (347.371 and 357.407 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Both ligands have TPSA values (121.96 and 119.41) below the 140 threshold for oral absorption, but above the preferred <90 for CNS targets. This is a moderate concern for both, but not disqualifying.

**3. logP:** Ligand A (0.457) is quite low, potentially hindering membrane permeability. Ligand B (-2.058) is also low, but less so than A. Both are below the optimal 1-3 range.

**4. H-Bond Donors:** Both ligands have 3 HBD, which is within the acceptable limit of <=5.

**5. H-Bond Acceptors:** Ligand A has 5 HBA, and Ligand B has 6 HBA, both within the acceptable limit of <=10.

**6. QED:** Ligand A (0.668) has a better QED score than Ligand B (0.46), indicating better overall drug-likeness.

**7. DILI:** Ligand A (34.781) has a significantly lower DILI risk than Ligand B (16.44), which is a major advantage.

**8. BBB:** Ligand A (62.699) has a higher BBB percentile than Ligand B (17.138). This is *critical* for a CNS target like DRD2.

**9. Caco-2 Permeability:** Both have negative Caco-2 values (-5.46 and -5.411), which is unusual and suggests poor permeability. This is a concern for both.

**10. Aqueous Solubility:** Both have negative solubility values (-3.829 and -0.962), which is also unusual and suggests poor solubility. This is a concern for both.

**11. hERG Inhibition:** Both have very low hERG inhibition risk (0.187 and 0.026).

**12. Microsomal Clearance:** Both have negative Cl_mic values (-2.781 and -2.72), which is unusual and suggests very slow clearance.

**13. In vitro Half-Life:** Both have negative half-life values (-10.417 and 12.294), which is unusual.

**14. P-gp Efflux:** Both have very low P-gp efflux liability (0.006 and 0.002). This is good, as it suggests better CNS exposure.

**15. Binding Affinity:** Ligand A (-7.8 kcal/mol) has a slightly better binding affinity than Ligand B (-7.2 kcal/mol), although both are good.

**Overall Assessment:**

While both ligands have some concerning ADME properties (low logP, unusual solubility and permeability values), Ligand A is significantly better due to its much higher BBB penetration (62.7% vs 17.1%), lower DILI risk (34.8% vs 16.4%), and slightly better binding affinity (-7.8 vs -7.2 kcal/mol). The improved BBB penetration is particularly important for a CNS target like DRD2. The QED score is also better for Ligand A. The unusual negative values for Caco-2, solubility, Cl_mic and t1/2 are concerning for both, and would require further investigation, but the overall profile of Ligand A is more promising.

Output:
0
2025-04-17 04:49:02,231 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (340.299 and 349.391 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (132.39) is slightly above the optimal <90 for CNS targets, but still reasonable. Ligand B (116.56) is well within the desired range.

**logP:** Ligand A (1.634) is within the optimal 1-3 range. Ligand B (-1.279) is below 1, which could hinder permeation.

**H-Bond Donors/Acceptors:** Ligand A (1 HBD, 8 HBA) is favorable. Ligand B (3 HBD, 6 HBA) is also acceptable, though slightly higher in HBD count.

**QED:** Both ligands have reasonable QED scores (0.409 and 0.612), with Ligand B being slightly more drug-like.

**DILI:** Ligand A (97.984) has a high DILI risk, which is a significant concern. Ligand B (32.571) has a much lower, acceptable DILI risk.

**BBB:** Ligand A (68.282) has a moderate BBB penetration, which is borderline for a CNS target. Ligand B (13.92) has very poor predicted BBB penetration, making it less suitable for a CNS target like DRD2.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.163 and -5.578), which is unusual and suggests poor permeability. However, these values are on a scale where negative values are possible, and direct comparison is difficult without knowing the scale's specifics.

**Aqueous Solubility:** Both ligands have negative solubility values (-3.968 and -1.289), indicating poor solubility.

**hERG:** Both ligands have very low hERG risk (0.132 and 0.016).

**Microsomal Clearance:** Ligand A (51.473) has moderate clearance, while Ligand B (-1.272) has a negative clearance, which is not physically realistic and suggests a potential issue with the prediction method or the molecule's structure.

**In vitro Half-Life:** Ligand A (29.071) has a reasonable half-life. Ligand B (-5.281) has a negative half-life, which is not possible and indicates a problem with the prediction.

**P-gp Efflux:** Both ligands show very low P-gp efflux (0.128 and 0.002), which is favorable for CNS penetration.

**Binding Affinity:** Both ligands have the same excellent binding affinity (-9.4 kcal/mol).

**Overall Assessment:**

While both ligands exhibit excellent binding affinity, Ligand A is significantly hampered by its high DILI risk and borderline BBB penetration. Ligand B suffers from extremely poor predicted BBB penetration, solubility, and unrealistic clearance/half-life values. The negative values for Caco-2, solubility, clearance, and half-life for Ligand B raise serious concerns about the reliability of its predictions. Although Ligand A has a higher DILI risk, it is the more viable candidate due to the more reasonable ADME predictions.

Output:
0
2025-04-17 04:49:02,231 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (345.414 and 342.399 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (47.56) is significantly better than Ligand B (79.54). For CNS targets, TPSA should be <= 90, and lower is preferred. Ligand A is well within this range, while Ligand B is approaching the upper limit.

**3. logP:** Ligand A (4.121) is slightly higher than the optimal 1-3 range, but still potentially acceptable. Ligand B (2.063) is within the optimal range. However, for a GPCR, a slightly higher logP can be tolerated if other properties are favorable.

**4. H-Bond Donors:** Ligand A (1) is good. Ligand B (0) is also acceptable.

**5. H-Bond Acceptors:** Ligand A (3) is good. Ligand B (5) is acceptable, but higher.

**6. QED:** Both ligands have similar QED values (0.857 and 0.853), indicating good drug-likeness.

**7. DILI:** Both ligands have similar DILI risk (62.001 and 64.56), indicating moderate risk. This isn't a major differentiating factor.

**8. BBB:** Ligand A (65.258) and Ligand B (63.125) are both reasonably good, but below the desirable >70 for CNS targets. However, this is not a huge difference.

**9. Caco-2:** Both ligands have negative Caco-2 values (-4.275 and -4.737). This is unusual and suggests poor permeability. This is a significant drawback for both.

**10. Solubility:** Both ligands have negative solubility values (-4.894 and -1.838). This is also concerning, indicating poor aqueous solubility.

**11. hERG:** Ligand A (0.779) has a slightly higher hERG risk than Ligand B (0.249), but both are relatively low.

**12. Cl_mic:** Ligand A (70.126) has a higher microsomal clearance than Ligand B (40.476), indicating lower metabolic stability. This is a disadvantage for Ligand A.

**13. t1/2:** Ligand A (12.71) has a longer half-life than Ligand B (5.091). This is a positive for Ligand A.

**14. Pgp:** Ligand A (0.352) has lower P-gp efflux liability than Ligand B (0.109), which is favorable for CNS penetration.

**15. Binding Affinity:** Ligand A (-8.3 kcal/mol) has significantly stronger binding affinity than Ligand B (-7.1 kcal/mol). This is a substantial advantage, exceeding the 1.5 kcal/mol threshold.

**Overall Assessment:**

Despite both ligands having issues with Caco-2 and Solubility, Ligand A is the better candidate. The much stronger binding affinity (-8.3 vs -7.1 kcal/mol) is a critical advantage, especially for a GPCR target. Ligand A also has better Pgp efflux liability and a longer half-life, outweighing its slightly higher logP and microsomal clearance. The TPSA is also significantly better for Ligand A.



Output:
0
2025-04-17 04:49:02,231 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (349.519 and 356.455 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (43.86) is significantly better than Ligand B (95.59). For CNS targets, we want TPSA <= 90, and ideally lower. Ligand A is well within this range, while Ligand B is pushing the upper limit and could face permeability issues.

**logP:** Both ligands have acceptable logP values (2.524 and 2.907), falling within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A (0 HBD, 3 HBA) is preferable to Ligand B (3 HBD, 7 HBA). Lower HBD/HBA generally improves permeability.

**QED:** Both ligands have similar QED values (0.633 and 0.628), indicating good drug-likeness.

**DILI:** Ligand A (6.979) has a much lower DILI risk than Ligand B (77.549). This is a significant advantage for Ligand A.

**BBB:** Ligand A (83.831) has a substantially higher BBB penetration percentile than Ligand B (57.115). This is *critical* for a CNS target like DRD2. A value >70 is desirable, and Ligand A is close, while Ligand B is considerably lower.

**Caco-2 Permeability:** Ligand A (-4.903) is better than Ligand B (-5.294), indicating better intestinal absorption.

**Aqueous Solubility:** Ligand A (-1.377) is better than Ligand B (-3.74), suggesting better solubility.

**hERG:** Both ligands have similar, low hERG inhibition liability (0.735 and 0.69).

**Microsomal Clearance:** Ligand A (45.185) has higher clearance than Ligand B (35.401), meaning Ligand B is more metabolically stable.

**In vitro Half-Life:** Ligand B (26.041) has a significantly longer half-life than Ligand A (-1.891). This is a positive for Ligand B.

**P-gp Efflux:** Ligand A (0.105) has lower P-gp efflux liability than Ligand B (0.209), which is favorable for CNS penetration.

**Binding Affinity:** Ligand B (-8.4) has a stronger binding affinity than Ligand A (-7.0). This is a 1.4 kcal/mol difference, which is substantial and could potentially outweigh some of the ADME drawbacks.

**Overall Assessment:**

While Ligand B has a better binding affinity and metabolic stability, Ligand A is significantly better in terms of BBB penetration, TPSA, DILI risk, solubility, and P-gp efflux.  For a CNS target like DRD2, BBB penetration is paramount. The lower TPSA and reduced efflux of Ligand A also contribute to better CNS exposure. The improved safety profile (lower DILI) is also a major benefit. The 1.4 kcal/mol difference in binding affinity, while significant, can potentially be optimized in subsequent rounds of medicinal chemistry.

Output:
0
2025-04-17 04:49:02,231 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (332.447 Da) is slightly lower, which could be beneficial for permeability, while Ligand B (348.403 Da) is also good.

**TPSA:** Ligand A (25.36) is excellent, well below the 90 A^2 threshold for CNS targets. Ligand B (104.54) is higher, but still potentially acceptable, though less ideal.

**logP:** Ligand A (3.896) is optimal, within the 1-3 range. Ligand B (0.303) is quite low, which raises concerns about permeability and potentially binding.

**H-Bond Donors/Acceptors:** Ligand A (0 HBD, 3 HBA) is favorable. Ligand B (2 HBD, 5 HBA) is also acceptable, but slightly higher.

**QED:** Both ligands have similar QED values (0.777 and 0.769), indicating good drug-likeness.

**DILI:** Ligand A (12.369) has a significantly lower DILI risk than Ligand B (37.611), making it safer from a liver toxicity perspective.

**BBB:** Ligand A (71.927) has a good BBB penetration percentile, exceeding the 70% threshold for CNS targets. Ligand B (56.65) is lower, which is a significant drawback for a CNS target like DRD2.

**Caco-2 Permeability:** Ligand A (-4.825) has a negative value, which is unusual and suggests very poor permeability. Ligand B (-5.304) is similarly poor.

**Aqueous Solubility:** Ligand A (-4.333) and Ligand B (-1.468) both have negative solubility values, indicating poor solubility.

**hERG Inhibition:** Ligand A (0.847) has a lower hERG inhibition liability than Ligand B (0.069), which is preferable.

**Microsomal Clearance:** Ligand A (29.658) has a higher microsomal clearance than Ligand B (12.029), suggesting lower metabolic stability.

**In vitro Half-Life:** Ligand A (-21.647) has a negative half-life, which is not physically possible and indicates a problem with the data. Ligand B (9.683) is reasonable.

**P-gp Efflux:** Ligand A (0.407) has lower P-gp efflux liability than Ligand B (0.023), which is favorable for CNS penetration.

**Binding Affinity:** Ligand A (-9.4 kcal/mol) has a significantly stronger binding affinity than Ligand B (-8.2 kcal/mol). This >1.5 kcal/mol difference is substantial and can outweigh some ADME drawbacks.

**Overall Assessment:**

Despite the negative Caco-2 and solubility values for both compounds, Ligand A is the stronger candidate. Its superior BBB penetration, significantly lower DILI risk, lower P-gp efflux, and *much* stronger binding affinity outweigh its higher clearance and the problematic half-life value. Ligand B's low logP and lower BBB penetration are major concerns for a CNS target. The negative half-life for Ligand A is a data quality issue that would need to be investigated, but the other factors strongly favor it.

Output:
1
2025-04-17 04:49:02,231 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the acceptable range (200-500 Da). Ligand A (365.47 Da) is slightly lower, which could be advantageous for permeability.

**TPSA:** Ligand A (46.61) is excellent for CNS penetration, well below the 90 A^2 threshold. Ligand B (97.39) is higher, potentially hindering BBB penetration.

**logP:** Ligand A (4.039) is at the upper end of the optimal range (1-3), potentially leading to solubility issues or off-target interactions. Ligand B (1.689) is good, falling comfortably within the optimal range.

**H-Bond Donors/Acceptors:** Ligand A (0 HBD, 3 HBA) is favorable. Ligand B (2 HBD, 6 HBA) is also acceptable, though slightly higher.

**QED:** Ligand A (0.709) has a better QED score than Ligand B (0.569), indicating a more drug-like profile.

**DILI:** Ligand A (63.397) has a moderate DILI risk, while Ligand B (99.031) has a very high DILI risk, which is a significant concern.

**BBB:** Ligand A (59.325) has a moderate BBB penetration, while Ligand B (46.879) has a poor BBB penetration. This is a critical factor for a CNS target like DRD2.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values, which is unusual and suggests poor permeability. However, the scale is not specified, so it's hard to interpret.

**Aqueous Solubility:** Both ligands have negative solubility values, indicating poor aqueous solubility.

**hERG:** Ligand A (0.775) has a lower hERG risk than Ligand B (0.181), which is preferable.

**Microsomal Clearance:** Ligand A (118.214) has a higher microsomal clearance than Ligand B (7.806), suggesting lower metabolic stability.

**In vitro Half-Life:** Ligand B (-24.644) has a very short half-life, which is a major drawback. Ligand A (3.684) has a short half-life, but is better than Ligand B.

**P-gp Efflux:** Ligand A (0.524) has a lower P-gp efflux liability than Ligand B (0.131), which is favorable for CNS exposure.

**Binding Affinity:** Both ligands have excellent binding affinities (-8.9 kcal/mol and -9.4 kcal/mol). Ligand B is slightly more potent.

**Overall Assessment:**

Despite Ligand B having a slightly better binding affinity, Ligand A is the more promising candidate. The primary reasons are its significantly better BBB penetration, lower DILI risk, and lower P-gp efflux. While Ligand A's logP is slightly high and its metabolic stability is a concern, these issues are less critical than the poor CNS penetration and high DILI risk of Ligand B. The negative solubility and Caco-2 values are concerning for both, but can be addressed with formulation strategies.

Output:
0
2025-04-17 04:49:02,231 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (359.369 and 355.391 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (68.23) is excellent, well below the 90 A^2 threshold for CNS targets. Ligand B (111.4) is higher, but still potentially acceptable, though less optimal.

**3. logP:** Ligand A (1.759) is within the optimal 1-3 range. Ligand B (-1.647) is below 1, which could hinder permeation.

**4. H-Bond Donors:** Both ligands have 1 HBD, which is good.

**5. H-Bond Acceptors:** Ligand A has 5 HBA, and Ligand B has 6 HBA, both are within the acceptable limit of 10.

**6. QED:** Ligand A (0.804) has a very strong drug-like profile. Ligand B (0.611) is still acceptable, but less favorable.

**7. DILI:** Both ligands have low DILI risk (39.434 and 34.742 percentile), which is good.

**8. BBB:** Ligand A excels with a BBB penetration of 83.172%, highly desirable for a CNS target like DRD2. Ligand B is significantly lower at 62.195%, which is concerning for CNS exposure.

**9. Caco-2:** Ligand A (-4.316) and Ligand B (-5.28) both have negative values, suggesting poor Caco-2 permeability. This is a weakness for both, but less critical for a CNS target where direct absorption isn't as vital.

**10. Solubility:** Both ligands have poor aqueous solubility (-1.918 and -1.627). This could pose formulation challenges, but can be addressed.

**11. hERG:** Both ligands have very low hERG inhibition risk (0.455 and 0.067).

**12. Cl_mic:** Ligand A (6.469) has a lower microsomal clearance than Ligand B (-12.873), indicating better metabolic stability.

**13. t1/2:** Ligand A (-11.86) has a negative in vitro half-life, which is unusual and suggests rapid metabolism. Ligand B (-0.625) is also short, but less so.

**14. Pgp:** Ligand A (0.173) has lower P-gp efflux liability than Ligand B (0.006), which is favorable for CNS penetration.

**15. Binding Affinity:** Ligand A (-8.1 kcal/mol) has a significantly stronger binding affinity than Ligand B (-7.5 kcal/mol). This 0.6 kcal/mol difference is substantial and can outweigh some of the ADME drawbacks.

**Overall Assessment:**

Ligand A is the stronger candidate. Its superior BBB penetration, better metabolic stability (lower Cl_mic), lower Pgp efflux, and significantly stronger binding affinity outweigh its slightly lower QED and solubility concerns. While both have poor Caco-2 permeability and solubility, the CNS target profile prioritizes BBB penetration and affinity, where Ligand A clearly wins. Ligand B's negative logP and lower BBB are significant drawbacks.

Output:
1
2025-04-17 04:49:02,231 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (377.535 Da) is slightly higher than Ligand B (338.411 Da), but both are acceptable.

**TPSA:** Ligand A (53.51) is significantly better than Ligand B (94.88). For CNS targets, we want TPSA <= 90, so Ligand A is much more favorable.

**logP:** Ligand A (3.331) is within the optimal range (1-3), while Ligand B (1.995) is at the lower end. While still acceptable, lower logP can sometimes hinder permeability.

**H-Bond Donors/Acceptors:** Ligand A (0 HBD, 5 HBA) and Ligand B (2 HBD, 4 HBA) both have reasonable numbers of H-bond donors and acceptors, well within the guidelines.

**QED:** Both ligands have good QED scores (Ligand A: 0.776, Ligand B: 0.821), indicating a generally drug-like profile.

**DILI:** Both ligands have similar DILI risk (Ligand A: 48.081, Ligand B: 59.519), and are both below the concerning threshold of 60.

**BBB:** This is a critical parameter for a CNS target like DRD2. Ligand A has a much higher BBB penetration percentile (77.084) compared to Ligand B (35.324). This is a major advantage for Ligand A.

**Caco-2 Permeability:** Both are negative, indicating poor permeability. However, the scale is not specified, so it's difficult to interpret the absolute values.

**Aqueous Solubility:** Both ligands have negative solubility values, indicating poor aqueous solubility. This is a potential issue for both, but can be mitigated with formulation strategies.

**hERG Inhibition:** Both ligands have very low hERG inhibition risk (Ligand A: 0.274, Ligand B: 0.295).

**Microsomal Clearance:** Ligand B (19.099) has a significantly lower microsomal clearance than Ligand A (60.298), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand B (-13.631) has a negative half-life, which is unusual and problematic. Ligand A (20.366) has a reasonable half-life.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (Ligand A: 0.209, Ligand B: 0.041).

**Binding Affinity:** Ligand B (-8.0 kcal/mol) has a slightly better binding affinity than Ligand A (-7.0 kcal/mol). However, the difference is only 1 kcal/mol, which may not be enough to overcome the other significant differences.

**Overall Assessment:**

Ligand A is significantly better due to its superior TPSA and BBB penetration, both crucial for CNS drug development. While Ligand B has slightly better affinity and metabolic stability, the poor BBB penetration and problematic half-life are major drawbacks. The difference in affinity is unlikely to outweigh the advantages of Ligand A.

Output:
1
2025-04-17 04:49:02,232 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (343.43 and 353.42 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (91.32) is better than Ligand B (100.46). Both are below the 140 A^2 threshold for oral absorption, and Ligand A is closer to the preferred <90 A^2 for CNS targets.

**logP:** Ligand A (2.361) is within the optimal 1-3 range. Ligand B (-0.098) is slightly negative, which could hinder permeation.

**H-Bond Donors/Acceptors:** Ligand A has 3 HBD and 4 HBA, while Ligand B has 2 HBD and 6 HBA. Both are within acceptable limits.

**QED:** Both ligands have reasonable QED values (0.692 and 0.531), indicating good drug-like properties.

**DILI:** Both ligands have low DILI risk (23.07 and 21.95), which is favorable.

**BBB:** Both ligands have similar BBB penetration (35.98 and 37.38). While not ideal (>70), they are comparable.

**Caco-2 Permeability:** Ligand A (-5.168) has worse Caco-2 permeability than Ligand B (-4.81).

**Aqueous Solubility:** Ligand A (-2.544) has worse aqueous solubility than Ligand B (-1.252).

**hERG:** Both ligands have very low hERG risk (0.057 and 0.237).

**Microsomal Clearance:** Ligand A (20.09) has higher microsomal clearance than Ligand B (-0.662), suggesting lower metabolic stability.

**In vitro Half-Life:** Ligand A (-12.685) has a shorter in vitro half-life than Ligand B (11.472).

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.028 and 0.023).

**Binding Affinity:** Ligand B (-7.2 kcal/mol) has a significantly stronger binding affinity than Ligand A (-9.1 kcal/mol). This is a substantial advantage.

**Overall Assessment:**

Ligand B is the better candidate. While Ligand A has a slightly better TPSA, Ligand B excels in crucial areas for a CNS-targeting GPCR ligand. Specifically, its significantly stronger binding affinity (-7.2 vs -9.1 kcal/mol) is a major advantage that can compensate for the slightly less favorable logP and TPSA. The better Caco-2 permeability, aqueous solubility, and metabolic stability (lower Cl_mic and longer t1/2) also contribute to its superior profile. The BBB values are similar, so this isn't a differentiating factor.



Output:
1
2025-04-17 04:49:02,232 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (384.542) is slightly higher than Ligand B (346.431), but both are acceptable.

**TPSA:** Ligand A (49.41) is excellent for CNS penetration, well below the 90 A^2 threshold. Ligand B (89.53) is higher, but still potentially acceptable, though less ideal.

**logP:** Ligand A (3.672) is within the optimal range (1-3). Ligand B (1.053) is at the lower end, potentially hindering permeability.

**H-Bond Donors/Acceptors:** Ligand A has 1 HBD and 4 HBA, which are reasonable. Ligand B has 2 HBD and 4 HBA, also acceptable.

**QED:** Both ligands have good QED values (A: 0.787, B: 0.834), indicating drug-like properties.

**DILI:** Ligand A (51.609) has a moderate DILI risk, while Ligand B (24.661) has a very low risk. This favors Ligand B.

**BBB:** Ligand A (82.784) has a good BBB penetration percentile, exceeding the 70% threshold for CNS targets. Ligand B (54.983) is lower, suggesting reduced CNS exposure. This is a significant advantage for Ligand A.

**Caco-2 Permeability:** Ligand A (-4.835) and Ligand B (-5.02) both have very poor Caco-2 permeability. This is a concern for oral bioavailability for both, but less critical for a CNS target where direct delivery or other routes are possible.

**Aqueous Solubility:** Ligand A (-4.468) and Ligand B (-1.785) both have poor aqueous solubility.

**hERG Inhibition:** Ligand A (0.694) has a low hERG risk, while Ligand B (0.176) has a very low risk. Both are favorable.

**Microsomal Clearance:** Ligand A (44.765) has moderate clearance, while Ligand B (-10.068) has negative clearance, which is not possible and likely an error in the data. This is a major red flag for Ligand B.

**In vitro Half-Life:** Ligand A (10.916) has a reasonable half-life. Ligand B (-12.808) has a negative half-life, which is impossible and indicates a data error.

**P-gp Efflux:** Ligand A (0.427) has low P-gp efflux, which is good for CNS penetration. Ligand B (0.01) has very low P-gp efflux, which is even better.

**Binding Affinity:** Ligand A (-8.2 kcal/mol) has a significantly stronger binding affinity than Ligand B (-7.2 kcal/mol). This 1 kcal/mol difference is substantial and can outweigh some ADME drawbacks.

**Overall Assessment:**

Ligand A excels in binding affinity and BBB penetration, crucial for a CNS-targeting GPCR. While its DILI risk is moderate, the strong affinity and good BBB outweigh this concern. Ligand B has a lower DILI risk and P-gp efflux, but its significantly lower BBB penetration, and *impossible* values for clearance and half-life make it a poor candidate. The negative values for clearance and half-life are highly suspect and indicative of a data issue.

Output:
1
2025-04-17 04:49:02,232 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (358.385 and 342.363 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (75.71) is significantly better than Ligand B (114.33). For CNS targets, we want TPSA <= 90, and A is comfortably within this range, while B is above.

**3. logP:** Both ligands have good logP values (1.503 and 1.022), falling within the optimal 1-3 range.

**4. H-Bond Donors:** Both have 1 HBD, which is acceptable.

**5. H-Bond Acceptors:** Ligand A has 4 HBAs, while Ligand B has 9.  While both are under the 10 threshold, A is preferable.

**6. QED:** Ligand A (0.577) has a better QED score than Ligand B (0.404), indicating better overall drug-likeness.

**7. DILI:** Ligand A (33.346) has a much lower DILI risk than Ligand B (87.747). This is a significant advantage for A.

**8. BBB:** Ligand A (83.094) has a significantly higher BBB penetration percentile than Ligand B (57.736). This is *critical* for a CNS target like DRD2.

**9. Caco-2 Permeability:** Ligand A (-4.556) is better than Ligand B (-5.169), indicating better intestinal absorption.

**10. Aqueous Solubility:** Ligand A (-2.201) is better than Ligand B (-3.036), suggesting better solubility.

**11. hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.265 and 0.121).

**12. Microsomal Clearance:** Ligand A (32.322) has lower microsomal clearance than Ligand B (55.856), indicating better metabolic stability.

**13. In vitro Half-Life:** Ligand A (-29.766) has a much longer in vitro half-life than Ligand B (6.057).

**14. P-gp Efflux:** Ligand A (0.034) has lower P-gp efflux than Ligand B (0.1), which is favorable for CNS penetration.

**15. Binding Affinity:** Ligand B (-8.6) has a slightly better binding affinity than Ligand A (-8.3), but the difference is only 0.3 kcal/mol. Given the substantial advantages of Ligand A in other key ADME properties, this small difference in affinity is unlikely to be decisive.

**Overall:** Ligand A is significantly better across nearly all crucial ADME properties, especially BBB penetration, DILI risk, metabolic stability, and QED. While Ligand B has slightly better binding affinity, the other advantages of Ligand A, particularly for a CNS target, outweigh this minor difference.

Output:
1
2025-04-17 04:49:02,232 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (346.391 Da) is slightly lower, which *could* be beneficial for permeability, but both are acceptable.

**TPSA:** Ligand A (115.35) is borderline for CNS penetration, being above the ideal <90, but not drastically so. Ligand B (93.21) is much better, falling comfortably within the desired range. This is a significant advantage for Ligand B.

**logP:** Ligand A (-0.478) is quite low, potentially hindering membrane permeability and brain penetration. Ligand B (1.51) is within the optimal range (1-3). This is a major advantage for Ligand B.

**H-Bond Donors/Acceptors:** Ligand A (HBD=1, HBA=7) and Ligand B (HBD=2, HBA=6) both have reasonable numbers of H-bond donors and acceptors, unlikely to cause major issues.

**QED:** Both ligands have similar and good QED values (A: 0.77, B: 0.798), indicating good drug-like properties.

**DILI:** Ligand A (39.434) has a lower DILI risk than Ligand B (66.344), which is a positive. However, both are below the concerning threshold of 60.

**BBB:** Ligand A (17.1) has a very low BBB penetration percentile, making it unlikely to effectively reach the target in the CNS. Ligand B (61.342) has a much better BBB percentile, although still not ideal (>70). This is a critical advantage for Ligand B.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.102 and -5.434), which is unusual and suggests poor permeability. This is a concern for both, but doesn't necessarily disqualify either.

**Aqueous Solubility:** Both ligands have negative solubility values (-1.998 and -3.106), indicating poor aqueous solubility. This could pose formulation challenges.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (A: 0.075, B: 0.163).

**Microsomal Clearance:** Ligand A (5.276) has a lower microsomal clearance, suggesting better metabolic stability than Ligand B (17.735).

**In vitro Half-Life:** Ligand B (19.241 hours) has a significantly longer in vitro half-life than Ligand A (-0.835 hours). This is a substantial advantage for Ligand B.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (A: 0.009, B: 0.099).

**Binding Affinity:** Ligand B (-9.3 kcal/mol) has a significantly stronger binding affinity than Ligand A (-7.3 kcal/mol). This difference of 2 kcal/mol is substantial and can outweigh many ADME drawbacks.

**Overall Assessment:**

Ligand B is the superior candidate. While Ligand A has a slightly lower DILI risk and better metabolic stability, Ligand B excels in the critical GPCR-relevant properties: TPSA, logP, BBB penetration, and, most importantly, binding affinity. The significantly stronger binding affinity of Ligand B (-9.3 vs -7.3 kcal/mol) is a major advantage, and its better BBB penetration (61.342 vs 17.1) makes it far more likely to reach the DRD2 receptor in the CNS. The longer half-life is also a significant benefit. The solubility and Caco-2 issues are concerns for both, but the potency and CNS penetration advantages of Ligand B are more crucial for a DRD2-targeted drug.

Output:
1
2025-04-17 04:49:02,232 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (356.813 and 364.511 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Both ligands have TPSA values (68.21 and 67.43) below the 90 A^2 threshold desirable for CNS targets, which is excellent.

**3. logP:** Both ligands have logP values (3.491 and 3.668) within the optimal 1-3 range.

**4. H-Bond Donors:** Ligand A (0 HBD) is preferable to Ligand B (2 HBD) as fewer HBDs generally correlate with better membrane permeability.

**5. H-Bond Acceptors:** Ligand A (6 HBA) is slightly higher than Ligand B (4 HBA), but both are within the acceptable limit of 10.

**6. QED:** Both ligands have acceptable QED scores (0.515 and 0.42), indicating reasonable drug-likeness.

**7. DILI:** Ligand A (82.319) has a higher DILI risk than Ligand B (48.042). This is a significant drawback for Ligand A.

**8. BBB:** Both ligands have good BBB penetration (65.297 and 64.211), but neither exceeds the desirable 70% threshold.

**9. Caco-2 Permeability:** Ligand A (-4.543) has a worse Caco-2 permeability than Ligand B (-5.214), indicating lower intestinal absorption.

**10. Aqueous Solubility:** Ligand A (-4.02) has better aqueous solubility than Ligand B (-3.029).

**11. hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.445 and 0.416).

**12. Microsomal Clearance:** Ligand A (119.652) has higher microsomal clearance than Ligand B (41.412), indicating lower metabolic stability.

**13. In vitro Half-Life:** Ligand A (72.011) has a longer in vitro half-life than Ligand B (16.284).

**14. P-gp Efflux:** Ligand A (0.106) has lower P-gp efflux than Ligand B (0.307), which is favorable for CNS exposure.

**15. Binding Affinity:** Ligand B (-8.5 kcal/mol) has a significantly better binding affinity than Ligand A (-7.6 kcal/mol). This 0.9 kcal/mol difference is substantial and can outweigh some ADME drawbacks.

**Overall Assessment:**

While Ligand A has advantages in P-gp efflux and in vitro half-life, Ligand B is significantly better in terms of binding affinity and has a much lower DILI risk. The improved affinity of Ligand B is a critical factor for GPCR targets, and the lower DILI risk is a major safety advantage. The slightly lower BBB penetration and higher P-gp efflux of Ligand B are less concerning given the strong binding affinity.

Output:
1
2025-04-17 04:49:02,232 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (354.535 and 345.443 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Both ligands have TPSA values (78.43 and 75.44) below the 90 A^2 threshold desirable for CNS targets, which is good.

**3. logP:** Both ligands have logP values (2.724 and 2.698) within the optimal range of 1-3.

**4. H-Bond Donors:** Ligand A has 3 HBD, and Ligand B has 1. Both are within the acceptable limit of <=5.

**5. H-Bond Acceptors:** Ligand A has 3 HBA, and Ligand B has 4. Both are within the acceptable limit of <=10.

**6. QED:** Ligand B (0.851) has a significantly better QED score than Ligand A (0.564), suggesting a more drug-like profile.

**7. DILI:** Ligand A (8.375 percentile) has a much lower DILI risk than Ligand B (34.277 percentile). This is a significant advantage for Ligand A.

**8. BBB:** Both ligands have good BBB penetration (72.625% and 76.658%), exceeding the 70% threshold for CNS targets. Ligand B is slightly better.

**9. Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and suggests poor permeability. However, these values are on a scale where negative values are possible.

**10. Aqueous Solubility:** Both ligands have negative solubility values, indicating poor aqueous solubility.

**11. hERG Inhibition:** Both ligands have low hERG inhibition risk (0.464 and 0.431).

**12. Microsomal Clearance:** Ligand A (53.685 mL/min/kg) has a lower microsomal clearance than Ligand B (58.362 mL/min/kg), indicating better metabolic stability.

**13. In vitro Half-Life:** Ligand A (8.771 hours) has a shorter half-life than Ligand B (-15.693 hours). The negative value for ligand B is concerning and likely an error.

**14. P-gp Efflux:** Both ligands have low P-gp efflux liability (0.086 and 0.159).

**15. Binding Affinity:** Ligand B (-9.2 kcal/mol) has a significantly stronger binding affinity than Ligand A (-8.0 kcal/mol). This is a substantial advantage, exceeding the 1.5 kcal/mol difference threshold.

**Overall Assessment:**

While Ligand A has advantages in DILI risk and metabolic stability, the significantly stronger binding affinity of Ligand B (-9.2 vs -8.0 kcal/mol) is the most critical factor for a GPCR target. The slightly better BBB and QED of Ligand B also contribute to its favorability. The negative half-life value for Ligand B is a red flag, but the affinity difference is so large that it likely outweighs this concern.

Output:
1
2025-04-17 04:49:02,232 - INFO - Batch 145 complete. Total preferences: 2320
2025-04-17 04:49:02,232 - INFO - Processing batch 146/512...
2025-04-17 04:49:45,385 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (348.403 and 352.435 Da) fall within the ideal 200-500 Da range.

**TPSA:** Both ligands (91.93 and 90.98) are close to the 90 A^2 threshold for CNS targets, which is good.

**logP:** Ligand A (1.316) is slightly better than Ligand B (0.51) as it's closer to the optimal 1-3 range. Ligand B is a bit low, potentially hindering permeation.

**H-Bond Donors & Acceptors:** Both have similar HBD (3 & 2) and HBA (4 & 4) counts, both within acceptable limits.

**QED:** Ligand A (0.765) has a better QED score than Ligand B (0.538), indicating a more drug-like profile.

**DILI:** Ligand B (46.762) has a significantly lower DILI risk than Ligand A (60.682), which is a substantial advantage.

**BBB:** Both ligands have good BBB penetration (Ligand A: 76.309, Ligand B: 70.88), but Ligand A is better. Both are above the 70% threshold desirable for CNS targets.

**Caco-2 Permeability:** Both have negative Caco-2 values (-5.135 and -5.035) which is unusual and suggests poor permeability. This is a significant concern for both.

**Aqueous Solubility:** Both have negative solubility values (-2.392 and -1.657) which is also concerning.

**hERG:** Both ligands have very low hERG inhibition liability (0.368 and 0.476), which is excellent.

**Microsomal Clearance:** Ligand B (-12.633) has much lower (better) microsomal clearance than Ligand A (3.538), suggesting greater metabolic stability.

**In vitro Half-Life:** Ligand B (5.208) has a slightly longer half-life than Ligand A (43.365). This is a positive for Ligand B.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.015 and 0.01), which is favorable for CNS penetration.

**Binding Affinity:** Both ligands have the same binding affinity (-8.8 kcal/mol), which is excellent and strongly favors both.

**Overall Assessment:**

The binding affinity is identical, so that doesn't differentiate them. Ligand B has a significantly better DILI score and a much more favorable microsomal clearance, indicating better safety and metabolic stability. However, Ligand A has a slightly better BBB and QED score. The negative Caco-2 and solubility values are concerning for both. Given the GPCR-specific priorities, the lower DILI and improved metabolic stability of Ligand B are more critical, especially considering the CNS target.

Output:
1
2025-04-17 04:49:45,385 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (348.491 Da) is slightly lower, which could be advantageous for permeability.

**2. TPSA:** Ligand A (47.1) is excellent, well below the 90 Angstrom threshold for CNS targets. Ligand B (67.07) is still reasonable but less optimal.

**3. logP:** Ligand A (0.482) is a bit low, potentially hindering membrane permeability. Ligand B (3.025) is within the optimal range (1-3).

**4. H-Bond Donors:** Both ligands have acceptable HBD counts (0 for A, 1 for B), well under the 5 limit.

**5. H-Bond Acceptors:** Ligand A (4) and Ligand B (6) are both within the acceptable limit of 10.

**6. QED:** Both ligands have good QED scores (0.64 and 0.691), indicating good drug-like properties.

**7. DILI:** Ligand A (3.296) has a very favorable DILI score, indicating low liver injury risk. Ligand B (37.728) is also acceptable, but higher.

**8. BBB:** This is critical for a CNS target. Ligand A scores very well (90.074%), suggesting excellent brain penetration. Ligand B (53.974%) is significantly lower and a major concern.

**9. Caco-2 Permeability:** Ligand A (-4.912) and Ligand B (-5.337) both have negative values, which is unusual and indicates very poor permeability. This is a significant drawback for both.

**10. Aqueous Solubility:** Both ligands have very poor solubility (-0.576 and -2.456). This is a significant issue for both compounds.

**11. hERG Inhibition:** Both ligands show low hERG inhibition risk (0.621 and 0.646).

**12. Microsomal Clearance:** Ligand A (21.551) has lower clearance than Ligand B (26.555), suggesting better metabolic stability.

**13. In vitro Half-Life:** Ligand A (-11.213) has a negative half-life, which is not possible and likely indicates an issue with the data. Ligand B (40.944) has a reasonable half-life.

**14. P-gp Efflux:** Both ligands have low P-gp efflux liability (0.01 and 0.289), which is positive for CNS penetration.

**15. Binding Affinity:** Ligand A (-7.9 kcal/mol) has a slightly better binding affinity than Ligand B (-6.9 kcal/mol). The 1 kcal/mol difference is significant and could outweigh some of the ADME drawbacks.

**Overall Assessment:**

While both compounds have solubility and permeability issues, Ligand A is significantly better due to its superior BBB penetration (90% vs 54%), lower DILI risk, and slightly better binding affinity. The negative half-life for Ligand A is a data quality concern, but the other factors strongly favor it. Ligand B's lower BBB penetration is a major drawback for a CNS-targeted drug.



Output:
0
2025-04-17 04:49:45,386 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (347.46 and 358.79 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (70.67) is significantly better than Ligand B (105.83). For CNS targets, we want TPSA <= 90, so Ligand A is preferable.

**logP:** Ligand A (0.664) is a bit low, potentially hindering permeation. Ligand B (2.288) is better, falling within the optimal 1-3 range.

**H-Bond Donors:** Both have 2 HBD, which is acceptable.

**H-Bond Acceptors:** Ligand A has 4 HBA, while Ligand B has 7. Both are within the acceptable limit of <=10, but Ligand A is better.

**QED:** Both have similar QED values (0.664 and 0.696), indicating good drug-likeness.

**DILI:** Ligand A (18.73) has a much lower DILI risk than Ligand B (85.50). This is a significant advantage for Ligand A.

**BBB:** Ligand B (68.75) has a better BBB penetration percentile than Ligand A (54.87), but both are below the desirable >70 for CNS targets.

**Caco-2:** Both have negative Caco-2 values, which is unusual and suggests poor permeability. However, the scale is not specified, so it's hard to interpret.

**Solubility:** Both have negative solubility values, which is also unusual and suggests poor solubility. Again, the scale is not specified.

**hERG:** Ligand A (0.208) has a much lower hERG inhibition liability than Ligand B (0.566), indicating a lower risk of cardiotoxicity.

**Microsomal Clearance:** Ligand A (1.85) has significantly lower microsomal clearance than Ligand B (53.70), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand B (26.42) has a longer half-life than Ligand A (6.45), which is generally desirable.

**P-gp Efflux:** Ligand A (0.014) has a much lower P-gp efflux liability than Ligand B (0.018), meaning it is less likely to be pumped out of the brain, improving CNS exposure.

**Binding Affinity:** Ligand B (-8.9 kcal/mol) has a significantly stronger binding affinity than Ligand A (-6.6 kcal/mol). This is a substantial advantage for Ligand B, potentially outweighing some of its ADME drawbacks. A difference of >1.5 kcal/mol is considered significant.

**Overall Assessment:**

Ligand B has a much better binding affinity and a longer half-life. However, it suffers from higher TPSA, significantly higher DILI risk, higher hERG risk, and higher P-gp efflux, and worse metabolic stability. Ligand A excels in TPSA, DILI, hERG, P-gp efflux, and metabolic stability. The affinity difference is significant, but the ADME profile of Ligand B is concerning, especially the high DILI and P-gp efflux. For a CNS target like DRD2, a good BBB is crucial, and while Ligand B is better than A, both are suboptimal. Given the importance of ADME properties for CNS drugs, and the substantial improvements Ligand A offers in those areas, I would prioritize Ligand A as the more viable starting point for optimization, despite its weaker binding affinity. Further optimization of Ligand A could potentially improve its affinity while maintaining its favorable ADME properties.

Output:
0
2025-04-17 04:49:45,386 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (342.53 & 343.51 Da) fall comfortably within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (23.55) is significantly better than Ligand B (38.33). For CNS targets, we want TPSA <= 90, and ideally much lower. Ligand A is excellent, while Ligand B is approaching the upper limit and less favorable.

**3. logP:** Both ligands have logP values around 4.18 and 4.86, which is slightly high. While acceptable, it could potentially lead to solubility issues or off-target interactions. Ligand B is a bit more concerning due to the higher logP.

**4. H-Bond Donors/Acceptors:** Ligand A (0 HBD, 2 HBA) is better than Ligand B (1 HBD, 3 HBA). Lower counts are generally preferred for better permeability.

**5. QED:** Both ligands have similar QED values (0.742 and 0.75), indicating good drug-like properties.

**6. DILI:** Ligand A (5.12) has a much lower DILI risk than Ligand B (13.84). This is a significant advantage for Ligand A.

**7. BBB:** Ligand A (92.56) has a substantially higher BBB penetration percentile than Ligand B (71.66). This is *critical* for a CNS target like DRD2.

**8. Caco-2 Permeability:** Both have negative values (-4.7 and -4.61), which is unusual and suggests a potential issue with the data or a very poor permeability. However, the negative values are very close, so this isn't a major differentiator.

**9. Aqueous Solubility:** Ligand A (-3.622) is better than Ligand B (-5.217), meaning it has better solubility.

**10. hERG Inhibition:** Both ligands show low hERG inhibition risk (0.938 and 0.754), which is good.

**11. Microsomal Clearance:** Ligand A (79.49) has lower microsomal clearance than Ligand B (100.74), indicating better metabolic stability.

**12. In vitro Half-Life:** Ligand A (-7.321) has a significantly longer in vitro half-life than Ligand B (5.629). This is a major advantage.

**13. P-gp Efflux:** Ligand A (0.448) has lower P-gp efflux than Ligand B (0.671), which is favorable for CNS penetration.

**14. Binding Affinity:** Ligand B (-8.1) has a slightly better binding affinity than Ligand A (-7.8). While a 0.3 kcal/mol difference is noticeable, the other ADME properties of Ligand A are far superior.

**Overall Assessment:**

Ligand A is the clear winner. While Ligand B has slightly better binding affinity, Ligand A excels in almost all other crucial parameters, especially those prioritized for GPCRs targeting the CNS: TPSA, BBB, DILI, metabolic stability (Cl_mic & t1/2), solubility, and P-gp efflux. The superior BBB penetration and lower toxicity profile of Ligand A are particularly important for a CNS drug candidate.

Output:
0
2025-04-17 04:49:45,386 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (346.471 and 356.413 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (58.64) is significantly better than Ligand B (66.48). For CNS targets, we want TPSA <= 90, and ideally closer to 60. Ligand A is closer to this ideal.

**3. logP:** Both ligands (2.243 and 2.168) are within the optimal 1-3 range.

**4. H-Bond Donors:** Both have 1 HBD, which is acceptable.

**5. H-Bond Acceptors:** Both have 3 HBA, which is acceptable.

**6. QED:** Ligand A (0.849) has a substantially better QED score than Ligand B (0.562), indicating a more drug-like profile.

**7. DILI:** Ligand A (14.618) has a much lower DILI risk than Ligand B (31.136), a significant advantage.

**8. BBB:** Ligand B (95.618) has a superior BBB penetration percentile than Ligand A (78.558). This is a critical factor for CNS targets like DRD2.

**9. Caco-2 Permeability:** Both have negative values (-4.725 and -4.613), which is unusual and requires further investigation. However, the values are similar.

**10. Aqueous Solubility:** Both have negative values (-2.803 and -2.628), indicating poor aqueous solubility. This is a concern for both, but not a deciding factor.

**11. hERG Inhibition:** Both ligands show low hERG inhibition risk (0.404 and 0.374).

**12. Microsomal Clearance:** Ligand B (14.668) has a lower (better) microsomal clearance than Ligand A (24.557), suggesting better metabolic stability.

**13. In vitro Half-Life:** Ligand A (2.702) has a better in vitro half-life than Ligand B (-44.493). A negative value for half-life is concerning for Ligand B.

**14. P-gp Efflux:** Both ligands show low P-gp efflux liability (0.093 and 0.047).

**15. Binding Affinity:** Ligand B (-7.6 kcal/mol) has a slightly better binding affinity than Ligand A (-8.5 kcal/mol). While a 0.9 kcal/mol difference is noticeable, it's not a massive advantage, especially considering the other factors.

**Overall Assessment:**

Ligand A has a more favorable overall profile. It has better QED, significantly lower DILI risk, and a better in vitro half-life. While Ligand B has better BBB penetration and slightly better binding affinity, the other drawbacks (higher DILI, worse QED, and negative half-life) are more concerning. Given the GPCR-specific priorities, the improved safety profile and drug-likeness of Ligand A outweigh the slightly better BBB and affinity of Ligand B.

Output:
1
2025-04-17 04:49:45,386 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (343.402 and 342.399 Da) fall within the ideal range of 200-500 Da.

**TPSA:** Ligand A (63.25) is excellent, well below the 90 A^2 threshold for CNS targets. Ligand B (78.67) is still reasonable, but less optimal.

**logP:** Ligand A (3.015) is within the optimal range of 1-3. Ligand B (1.622) is at the lower end, potentially impacting permeability.

**H-Bond Donors/Acceptors:** Ligand A has 2 HBD and 3 HBA, both acceptable. Ligand B has 1 HBD and 5 HBA, also acceptable.

**QED:** Both ligands have good QED scores (0.812 and 0.893), indicating good drug-like properties.

**DILI:** Ligand A (40.403) has a lower DILI risk than Ligand B (67.429), which is a significant advantage.

**BBB:** Ligand A (83.831) has a much better BBB penetration score than Ligand B (53.587). This is *critical* for a CNS target like DRD2.

**Caco-2 Permeability:** Ligand A (-4.427) has a lower (worse) Caco-2 permeability than Ligand B (-5.093).

**Aqueous Solubility:** Ligand A (-3.698) has a lower (worse) aqueous solubility than Ligand B (-1.68).

**hERG:** Both ligands have very low hERG inhibition risk (0.441 and 0.115).

**Microsomal Clearance:** Ligand B (30.927) has a lower microsomal clearance, suggesting better metabolic stability than Ligand A (38.004).

**In vitro Half-Life:** Ligand A (26.433) has a longer in vitro half-life than Ligand B (-0.988).

**P-gp Efflux:** Ligand A (0.085) has lower P-gp efflux, which is favorable for CNS penetration, compared to Ligand B (0.104).

**Binding Affinity:** Ligand A (-9.6 kcal/mol) has a significantly stronger binding affinity than Ligand B (-8.5 kcal/mol). This 1.1 kcal/mol difference is substantial and can outweigh some ADME drawbacks.

**Overall Assessment:**

Ligand A is the stronger candidate. The superior binding affinity, excellent TPSA, good logP, significantly better BBB penetration, and lower DILI risk are compelling. While Ligand B has slightly better metabolic stability and Caco-2 permeability, the CNS target requires high BBB penetration, which Ligand A delivers. The affinity difference is also substantial.

Output:
1
2025-04-17 04:49:45,386 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (339.418 and 348.403 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (47.67) is excellent, well below the 90 A^2 threshold for CNS targets. Ligand B (104.39) is higher, but still reasonable, though less favorable for CNS penetration.

**3. logP:** Ligand A (3.36) is optimal (1-3). Ligand B (0.572) is quite low, potentially hindering permeability and CNS penetration.

**4. H-Bond Donors:** Ligand A (1) is good. Ligand B (2) is acceptable.

**5. H-Bond Acceptors:** Both ligands (A: 5, B: 5) are within the acceptable limit of 10.

**6. QED:** Both ligands have similar, good QED values (A: 0.749, B: 0.757), indicating good drug-like properties.

**7. DILI:** Ligand A (30.399) has a much lower DILI risk than Ligand B (60.489), which is approaching a concerning level.

**8. BBB:** Ligand A (69.407) has a significantly better BBB percentile than Ligand B (38.426). This is a crucial factor for a CNS target like DRD2.

**9. Caco-2:** Both have negative values (-5.205 and -5.275), which is unusual and hard to interpret without knowing the scale. Assuming these are logP-like scales, lower values suggest poorer permeability.

**10. Solubility:** Both ligands have negative solubility values (-2.863 and -2.676), suggesting poor aqueous solubility. This could be a formulation challenge.

**11. hERG:** Both ligands have low hERG inhibition risk (A: 0.781, B: 0.201).

**12. Cl_mic:** Ligand A (12.596) has a more favorable (lower) microsomal clearance than Ligand B (-0.434, which is likely an error or indicates very rapid clearance).

**13. t1/2:** Ligand A (11.328) has a better in vitro half-life than Ligand B (-24.367, which is likely an error or indicates very rapid metabolism).

**14. Pgp:** Ligand A (0.335) has a lower P-gp efflux liability than Ligand B (0.008), meaning it's less likely to be pumped out of the brain.

**15. Binding Affinity:** Ligand B (-8.8 kcal/mol) has a slightly better binding affinity than Ligand A (-7.9 kcal/mol). However, the difference is less than the 1.5 kcal/mol threshold where affinity alone outweighs other drawbacks.

**Overall Assessment:**

Ligand A is significantly better overall. While Ligand B has slightly better binding affinity, Ligand A excels in crucial ADME properties for a CNS-targeting GPCR: TPSA, logP, BBB penetration, DILI risk, metabolic stability (Cl_mic and t1/2), and P-gp efflux. Ligand B's low logP and poor BBB penetration are major concerns. The negative values for Caco-2 and solubility are concerning for both, but the other advantages of Ligand A make it the more promising candidate.

Output:
1
2025-04-17 04:49:45,387 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (350.503 and 367.559 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (58.64) is better than Ligand B (47.36) as it's closer to the <90 A^2 threshold for CNS targets.

**logP:** Both ligands have good logP values (2.45 and 3.479), falling within the optimal 1-3 range. Ligand B is slightly higher, which *could* be a minor concern for solubility, but isn't a dealbreaker.

**H-Bond Donors/Acceptors:** Ligand A has 1 HBD and 3 HBA, while Ligand B has 0 HBD and 5 HBA. Both are within acceptable limits (<=5 HBD and <=10 HBA).

**QED:** Both ligands have similar QED values (0.684 and 0.67), indicating good drug-likeness.

**DILI:** Ligand A (15.665) has a significantly lower DILI risk than Ligand B (19.426), which is a substantial advantage.

**BBB:** Ligand B (74.835) has a much better BBB penetration percentile than Ligand A (54.634). This is a *critical* factor for a CNS target like DRD2.

**Caco-2 Permeability:** Ligand A (-4.332) has better Caco-2 permeability than Ligand B (-4.858), indicating better intestinal absorption.

**Aqueous Solubility:** Ligand A (-2.884) has better aqueous solubility than Ligand B (-3.379).

**hERG Inhibition:** Both ligands have similar, low hERG inhibition risk (0.439 and 0.636).

**Microsomal Clearance:** Ligand B (97.085) has significantly higher microsomal clearance than Ligand A (43.85), suggesting lower metabolic stability.

**In vitro Half-Life:** Ligand B (5.162) has a longer in vitro half-life than Ligand A (1.087), which is generally desirable.

**P-gp Efflux:** Ligand A (0.088) has much lower P-gp efflux liability than Ligand B (0.351), which is crucial for CNS penetration.

**Binding Affinity:** Ligand A (-6.9 kcal/mol) has a slightly better binding affinity than Ligand B (-6.7 kcal/mol), although the difference is small.

**Overall Assessment:**

Ligand B excels in BBB penetration and in vitro half-life, which are important. However, its higher DILI risk, higher P-gp efflux, and higher microsomal clearance are significant drawbacks. Ligand A has a better safety profile (lower DILI), better permeability (Caco-2 and P-gp), better solubility, and comparable affinity, despite a slightly lower BBB score. Given the importance of minimizing off-target effects and maximizing CNS exposure for a DRD2 ligand, Ligand A is the more promising candidate. The small difference in binding affinity is outweighed by the more favorable ADME-Tox properties of Ligand A.

Output:
0
2025-04-17 04:49:45,387 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (402.248 Da) is slightly higher than Ligand B (350.503 Da), but both are acceptable.

**2. TPSA:** Ligand A (84.08) is better than Ligand B (60.85). For CNS targets, we want TPSA <= 90, and both are within this limit. Lower TPSA generally favors BBB penetration.

**3. logP:** Both ligands have good logP values (A: 2.667, B: 2.47), falling within the optimal 1-3 range.

**4. H-Bond Donors:** Ligand A (2) and Ligand B (1) are both acceptable, being less than 5.

**5. H-Bond Acceptors:** Ligand A (4) and Ligand B (3) are both acceptable, being less than 10.

**6. QED:** Both ligands have similar QED values (A: 0.688, B: 0.616), both above the 0.5 threshold, indicating good drug-like properties.

**7. DILI:** Ligand A (83.598) has a significantly higher DILI risk than Ligand B (7.794). This is a major concern for Ligand A.

**8. BBB:** Ligand B (60.954) has a better BBB percentile than Ligand A (51.532). While neither is >70, Ligand B is closer and more desirable for a CNS target.

**9. Caco-2 Permeability:** Ligand A (-5.162) has worse Caco-2 permeability than Ligand B (-4.449). Lower (more negative) values indicate poorer permeability.

**10. Aqueous Solubility:** Ligand A (-5.091) has worse aqueous solubility than Ligand B (-1.844). Lower (more negative) values indicate poorer solubility.

**11. hERG Inhibition:** Both ligands have low hERG inhibition risk (A: 0.775, B: 0.486), which is good.

**12. Microsomal Clearance:** Ligand B (63.201) has higher microsomal clearance than Ligand A (42.481), meaning it's metabolized faster. Lower clearance is preferred.

**13. In vitro Half-Life:** Ligand A (10.595) has a longer in vitro half-life than Ligand B (5.12). This is a positive for Ligand A.

**14. P-gp Efflux:** Ligand A (0.478) has lower P-gp efflux than Ligand B (0.111). Lower P-gp efflux is preferred for CNS exposure.

**15. Binding Affinity:** Ligand A (-9.0) has significantly better binding affinity than Ligand B (-6.7). This is a substantial advantage. A difference of >1.5 kcal/mol can often outweigh other drawbacks.

**Overall Assessment:**

Ligand A has a much stronger binding affinity, a longer half-life, and lower P-gp efflux. However, it has a significantly higher DILI risk, worse BBB penetration, lower Caco-2 permeability, and lower aqueous solubility. Ligand B has a better safety profile (lower DILI), better BBB penetration, and better solubility/permeability, but weaker binding affinity.

Given the GPCR-specific priorities, and the substantial affinity difference, the stronger binding of Ligand A is a major advantage. The higher DILI risk is concerning, but could potentially be mitigated through structural modifications. The lower BBB penetration is also a concern, but the affinity advantage is significant. The solubility/permeability issues are less critical than the DILI and BBB, as these can be addressed with formulation strategies.

Output:
1
2025-04-17 04:49:45,387 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 drug candidates, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (342.418 and 350.419 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (62.46) is excellent, well below the 90 A^2 threshold for CNS targets. Ligand B (96.69) is higher but still acceptable, though less ideal.

**3. logP:** Ligand A (1.482) is within the optimal 1-3 range. Ligand B (0.499) is slightly low, potentially hindering permeation.

**4. H-Bond Donors:** Ligand A (1) and Ligand B (2) are both within the acceptable limit of <=5.

**5. H-Bond Acceptors:** Ligand A (5) and Ligand B (6) are both within the acceptable limit of <=10.

**6. QED:** Both ligands have good QED values (0.806 and 0.754), indicating drug-like properties.

**7. DILI:** Ligand A (44.242) has a lower DILI risk than Ligand B (51.493), which is preferable. Both are below the concerning 60 threshold.

**8. BBB:** This is a critical parameter for a CNS target like DRD2. Ligand A (84.374) has a significantly higher BBB percentile than Ligand B (36.448). This is a major advantage for Ligand A.

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.006 and -5.249), which is unusual and suggests poor permeability. However, these values are on a scale where negative values are possible, and direct comparison is difficult without knowing the scale's specifics.

**10. Aqueous Solubility:** Both ligands have negative solubility values (-2.358 and -1.978), which is also unusual. Again, the scale is unknown, but it suggests poor solubility.

**11. hERG Inhibition:** Ligand A (0.93) has a slightly higher hERG risk than Ligand B (0.126), but both are relatively low.

**12. Microsomal Clearance:** Ligand A (38.188) has a higher microsomal clearance than Ligand B (-5.033). This suggests Ligand B is more metabolically stable, which is desirable.

**13. In vitro Half-Life:** Ligand A (-34.951) has a negative half-life, which is not physically possible and indicates a problem with the data or scale. Ligand B (17.241) has a reasonable half-life.

**14. P-gp Efflux:** Ligand A (0.53) has lower P-gp efflux than Ligand B (0.013), which is favorable for CNS penetration.

**15. Binding Affinity:** Ligand A (-9.4 kcal/mol) has a significantly stronger binding affinity than Ligand B (-7.8 kcal/mol). This is a substantial advantage that can outweigh some of the ADME drawbacks.

**Overall Assessment:**

Ligand A is the stronger candidate despite some concerning values (negative half-life and solubility). The significantly better BBB penetration, much stronger binding affinity, and lower P-gp efflux outweigh the slightly higher DILI and hERG risk. The negative half-life is a major red flag, but could be an artifact of the data. Ligand B's low logP and poor BBB penetration are significant drawbacks for a CNS-targeting drug.

Output:
1
2025-04-17 04:49:45,387 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (377.413 and 359.352 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (91.76) is better than Ligand B (97.64). Both are below the 140 A^2 threshold for oral absorption, and reasonably close to the 90 A^2 target for CNS penetration, but A is preferable.

**3. logP:** Ligand B (2.534) is better than Ligand A (0.672). A logP between 1-3 is optimal, and B falls within this range, while A is slightly low, potentially hindering permeation.

**4. H-Bond Donors:** Ligand A (2) is better than Ligand B (3). Lower HBD is generally preferred.

**5. H-Bond Acceptors:** Ligand A (6) is better than Ligand B (3). Lower HBA is generally preferred.

**6. QED:** Both ligands have good QED scores (0.618 and 0.708, respectively), indicating drug-like properties. Ligand B is slightly better.

**7. DILI:** Both ligands have similar DILI risk (46.724 and 48.468), both are acceptable.

**8. BBB:** Ligand A (74.254) is significantly better than Ligand B (53.393). This is a *critical* factor for a CNS target like DRD2. A value >70 is desirable, and A is closer to this threshold.

**9. Caco-2 Permeability:** Both have negative values (-5.04 and -5.124). This is unusual and suggests very poor permeability.

**10. Aqueous Solubility:** Both have negative values (-1.629 and -2.944). This suggests very poor solubility.

**11. hERG Inhibition:** Both ligands have low hERG inhibition risk (0.552 and 0.579).

**12. Microsomal Clearance:** Ligand A (-2.322) is better than Ligand B (-3.59). Lower clearance indicates better metabolic stability.

**13. In vitro Half-Life:** Ligand A (6.062) is better than Ligand B (-20.121). A longer half-life is generally preferred.

**14. P-gp Efflux:** Both ligands have very low P-gp efflux (0.079 and 0.128), which is good for CNS penetration.

**15. Binding Affinity:** Ligand A (-7.6 kcal/mol) is slightly better than Ligand B (-7.4 kcal/mol). While both are good, the 0.2 kcal/mol difference could be significant.

**Overall Assessment:**

Despite Ligand B having a more optimal logP, Ligand A is the stronger candidate. The significantly higher BBB penetration (74.254 vs 53.393) is crucial for a CNS target. Additionally, Ligand A has better metabolic stability (Cl_mic) and half-life. The slight advantage in binding affinity further supports this conclusion. The poor Caco-2 and solubility values are concerning for both, but can be addressed with formulation strategies.

Output:
0
2025-04-17 04:49:45,388 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B based on the provided guidelines, prioritizing GPCR-specific properties (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (363.845 and 354.401 Da) fall within the ideal range of 200-500 Da.

**TPSA:** Ligand A (87.3) is slightly above the optimal <90 for CNS targets, but still reasonable. Ligand B (76.02) is well within the desired range.

**logP:** Both ligands have good logP values (1.345 and 2.33), falling within the 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A has 3 HBD and 3 HBA, while Ligand B has 2 HBD and 4 HBA. Both are within acceptable limits (<=5 HBD, <=10 HBA).

**QED:** Both ligands have good QED scores (0.526 and 0.738), indicating good drug-like properties.

**DILI:** Ligand A (41.528) has a slightly higher DILI risk than Ligand B (52.423), but both are below the concerning threshold of 60.

**BBB:** This is a crucial parameter for CNS targets. Ligand B (73.943) has a significantly better BBB percentile than Ligand A (61.535). This is a major advantage for Ligand B.

**Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and suggests poor permeability. However, the scale is not specified, so it's difficult to interpret.

**Aqueous Solubility:** Both ligands have negative solubility values, indicating poor solubility. This is a concern for both.

**hERG:** Both ligands have very low hERG inhibition liability (0.186 and 0.183), which is excellent.

**Microsomal Clearance:** Ligand A (5.783) has a lower microsomal clearance than Ligand B (15.806), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (12.097 hours) has a positive half-life, while Ligand B (-12.755 hours) has a negative half-life, which is unusual. This suggests Ligand A is more stable.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.057 and 0.063), which is favorable for CNS penetration.

**Binding Affinity:** Ligand B (-7.3 kcal/mol) has a slightly better binding affinity than Ligand A (-9.0 kcal/mol). While A is stronger, the difference is not substantial enough to outweigh other factors.

**Overall Assessment:**

Ligand B is the more promising candidate. The significantly higher BBB percentile (73.943 vs 61.535) is a critical advantage for a CNS-targeting drug. While Ligand A has better metabolic stability (lower Cl_mic and positive half-life), the improved brain penetration potential of Ligand B is more important for a DRD2 ligand. The slight difference in binding affinity is not enough to overcome the BBB advantage.

Output:
1
2025-04-17 04:49:45,388 - INFO - Reasoning:

Let's analyze Ligand A and Ligand B against the provided guidelines, prioritizing GPCR properties (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (372.809 and 358.435 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (113.76) is slightly above the optimal <90 for CNS targets, but still reasonable. Ligand B (105.17) is better, falling closer to the desired range.

**logP:** Ligand A (-0.434) is quite low, potentially hindering permeation. Ligand B (0.082) is better, within the optimal 1-3 range, though on the lower end.

**H-Bond Donors/Acceptors:** Both have 2 HBD and are within acceptable limits. Ligand A has 7 HBA, while Ligand B has 6. Both are acceptable (<10).

**QED:** Both ligands have acceptable QED scores (0.628 and 0.566, both >0.5).

**DILI:** Ligand A (60.566) has a moderate DILI risk, while Ligand B (12.136) has a very low risk. This is a significant advantage for Ligand B.

**BBB:** Ligand A (20.822) has poor BBB penetration, a critical drawback for a CNS target like DRD2. Ligand B (54.634) shows significantly better BBB penetration, although still not ideal (>70).

**Caco-2 Permeability:** Both have negative Caco-2 values, indicating poor permeability. This is concerning, but less critical than BBB for a CNS target.

**Aqueous Solubility:** Both have negative solubility values, indicating poor solubility. This could pose formulation challenges.

**hERG:** Both ligands have very low hERG inhibition risk (0.023 and 0.212).

**Microsomal Clearance:** Ligand A (15.553) has lower clearance than Ligand B (25.637), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (9.796) has a positive half-life, while Ligand B (-17.857) has a negative half-life. This is a major red flag for Ligand B.

**P-gp Efflux:** Both have very low P-gp efflux liability (0.02).

**Binding Affinity:** Ligand A (-7.4 kcal/mol) has a stronger binding affinity than Ligand B (-6.6 kcal/mol), a difference of 0.8 kcal/mol. This is a substantial advantage.

**Overall Assessment:**

Despite Ligand A's better binding affinity and metabolic stability, its extremely poor BBB penetration is a deal-breaker for a CNS drug targeting DRD2. Ligand B, while having a weaker affinity and a concerning negative half-life, possesses significantly better BBB penetration and a much lower DILI risk. The improved BBB penetration is crucial for CNS exposure. The negative half-life of Ligand B is a serious issue that would require significant medicinal chemistry effort to address, but the starting point is better.

Output:
1
2025-04-17 04:49:45,388 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (339.4 and 344.5 Da) fall comfortably within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (79.26) is higher than Ligand B (52.61). For a CNS target like DRD2, TPSA < 90 is preferred, so both are acceptable, but B is better.

**3. logP:** Ligand A (2.388) and Ligand B (4.299) are both within the optimal 1-3 range, but B is pushing the upper limit.

**4. H-Bond Donors:** Ligand A (2) and Ligand B (1) are both acceptable (<=5).

**5. H-Bond Acceptors:** Ligand A (4) and Ligand B (5) are both acceptable (<=10).

**6. QED:** Both ligands have reasonable QED values (0.898 and 0.735), indicating good drug-like properties.

**7. DILI:** Ligand A (77.3%) has a higher DILI risk than Ligand B (41.8%). This is a significant advantage for B.

**8. BBB:** Ligand A (79.3%) has a better BBB penetration score than Ligand B (52.9%). This is a crucial factor for CNS targets, favoring A.

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.93 and -4.78), which is unusual and suggests poor permeability. This is a concern for both.

**10. Aqueous Solubility:** Both ligands have negative solubility values (-3.81 and -4.13), indicating very poor aqueous solubility. This is a major drawback for both.

**11. hERG Inhibition:** Ligand A (0.375) has a lower hERG inhibition liability than Ligand B (0.7), which is preferable.

**12. Microsomal Clearance:** Ligand A (5.04) has a lower microsomal clearance than Ligand B (79.92), indicating better metabolic stability. This is a significant advantage for A.

**13. In vitro Half-Life:** Ligand A (35.07) has a longer in vitro half-life than Ligand B (0.47), which is desirable.

**14. P-gp Efflux:** Ligand A (0.082) has lower P-gp efflux liability than Ligand B (0.252), which is beneficial for CNS exposure.

**15. Binding Affinity:** Ligand B (-7.9 kcal/mol) has a significantly stronger binding affinity than Ligand A (-10.2 kcal/mol). This is a substantial advantage for B, potentially outweighing some of its ADME drawbacks.

**Overall Assessment:**

Ligand B has a significantly better binding affinity, lower DILI risk, and a more favorable TPSA. However, Ligand A has better BBB penetration, metabolic stability, longer half-life, lower P-gp efflux, and lower hERG inhibition. The poor Caco-2 and solubility for both are concerning. Given the importance of binding affinity for GPCR ligands, and the fact that the difference in affinity is substantial (over 2 kcal/mol), Ligand B is the more promising candidate despite its slightly worse BBB and higher P-gp efflux. The lower DILI risk is also a significant benefit.

Output:
1
2025-04-17 04:49:45,388 - INFO - Reasoning:

Let's analyze Ligand A and Ligand B based on the provided guidelines, prioritizing GPCR properties (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (371.825 and 375.607 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (119.28) is excellent for CNS penetration, being below the 90 A^2 threshold. Ligand B (21.06) is also very good, significantly below the threshold.

**logP:** Ligand A (3.286) is within the optimal 1-3 range. Ligand B (4.987) is slightly above, potentially raising concerns about solubility and off-target effects, but not drastically.

**H-Bond Donors/Acceptors:** Ligand A has 2 HBD and 7 HBA, both acceptable. Ligand B has 0 HBD and 5 HBA, also acceptable.

**QED:** Both ligands have reasonable QED values (0.473 and 0.649), indicating moderate drug-likeness. Ligand B is better here.

**DILI:** Ligand A has a DILI risk of 75.456, which is concerning (high risk). Ligand B has a much lower DILI risk of 26.173, which is good.

**BBB:** Ligand A has a BBB penetration of 67.041, which is acceptable but not ideal for a CNS target. Ligand B exhibits excellent BBB penetration at 84.141, exceeding the 70% threshold. This is a significant advantage.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.803 and -5.583), which is unusual and suggests poor permeability. However, these values are on a log scale and negative values indicate very low permeability.

**Aqueous Solubility:** Both ligands have negative solubility values (-4.648 and -3.891), indicating very poor aqueous solubility. This is a major drawback for both.

**hERG Inhibition:** Ligand A (0.091) has a very low hERG risk, which is excellent. Ligand B (0.893) has a slightly elevated hERG risk, but still relatively low.

**Microsomal Clearance:** Ligand A (53.631) and Ligand B (64.445) both have moderate microsomal clearance. Lower is better, so Ligand A is slightly preferable.

**In vitro Half-Life:** Ligand A (-2.483) has a negative half-life, which is not possible and likely indicates a very rapid degradation. Ligand B (-14.241) also has a negative half-life, indicating very rapid degradation.

**P-gp Efflux:** Ligand A (0.057) has very low P-gp efflux, which is excellent for CNS penetration. Ligand B (0.729) has a higher, but still moderate, P-gp efflux.

**Binding Affinity:** Ligand B (-7.2 kcal/mol) has a significantly stronger binding affinity than Ligand A (-8.2 kcal/mol). A difference of 1 kcal/mol is substantial.

**Overall Assessment:**

Ligand B is the stronger candidate. While both have poor solubility and permeability, Ligand B's superior BBB penetration, significantly stronger binding affinity, and much lower DILI risk outweigh the slightly higher logP and P-gp efflux. The negative half-life values are concerning for both, but can be addressed through structural modifications. Ligand A's high DILI risk and poor half-life are major drawbacks.

Output:
1
2025-04-17 04:49:45,388 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (362.407 Da) is slightly higher than Ligand B (345.443 Da), but both are acceptable.

**TPSA:** Ligand A (93.73) is borderline for CNS targets (<=90), while Ligand B (60.93) is well within the desired range. This favors Ligand B.

**logP:** Both ligands have good logP values (Ligand A: 1.403, Ligand B: 1.19), falling within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A has 2 HBD and 6 HBA, while Ligand B has 0 HBD and 3 HBA. Both are within acceptable limits (<=5 HBD and <=10 HBA).

**QED:** Both ligands have reasonable QED values (Ligand A: 0.421, Ligand B: 0.722). Ligand B's higher QED suggests a more drug-like profile.

**DILI:** Ligand A (83.249) has a higher DILI risk than Ligand B (47.693). This favors Ligand B.

**BBB:** This is a crucial parameter for CNS targets. Ligand B (71.462) has a significantly better BBB percentile than Ligand A (54.634). This is a major advantage for Ligand B.

**Caco-2 Permeability:** Ligand A (-5.036) and Ligand B (-4.567) both have negative values, which is unusual. However, the scale is not specified, so it's hard to interpret.

**Aqueous Solubility:** Ligand A (-3.254) and Ligand B (-1.666) both have negative values, suggesting poor solubility.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (Ligand A: 0.323, Ligand B: 0.39).

**Microsomal Clearance:** Ligand A (20.899) has lower microsomal clearance than Ligand B (43.402), indicating better metabolic stability. This favors Ligand A.

**In vitro Half-Life:** Ligand A (31.613) has a longer in vitro half-life than Ligand B (-8.919). This is a significant advantage for Ligand A.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (Ligand A: 0.243, Ligand B: 0.128).

**Binding Affinity:** Ligand B (-8.9 kcal/mol) has a slightly better binding affinity than Ligand A (-7.6 kcal/mol). This is a significant advantage for Ligand B, potentially outweighing some of the ADME drawbacks of Ligand A.

**Overall Assessment:**

Ligand B is the more promising candidate. While Ligand A has better metabolic stability and half-life, Ligand B excels in critical areas for a CNS-targeting GPCR ligand: significantly better BBB penetration, a higher QED score, lower DILI risk, and slightly better binding affinity. The lower TPSA of Ligand B is also favorable. The solubility issues are a concern for both, but can potentially be addressed through formulation strategies.



Output:
1
2025-04-17 04:49:45,389 - INFO - Batch 146 complete. Total preferences: 2336
2025-04-17 04:49:45,389 - INFO - Processing batch 147/512...
2025-04-17 04:50:25,892 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (348.443 and 340.383 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (59.08) is significantly better than Ligand B (79.54). For CNS targets, we want TPSA <= 90, and A is comfortably within this range, while B is approaching the upper limit.

**3. logP:** Both ligands have good logP values (1.557 and 1.753), falling within the optimal 1-3 range.

**4. H-Bond Donors:** Both have 0 HBD, which is acceptable.

**5. H-Bond Acceptors:** Ligand A has 4 HBA, and Ligand B has 5. Both are within the acceptable limit of <=10.

**6. QED:** Both ligands have good QED scores (0.774 and 0.832), indicating good drug-like properties.

**7. DILI:** Both ligands have acceptable DILI risk (21.171 and 63.668). Ligand A is preferable here, being significantly lower.

**8. BBB:** This is a crucial parameter for a CNS target like DRD2. Ligand A has a BBB percentile of 64.715, while Ligand B is much lower at 44.591.  A value >70 is desirable, but A is better than B.

**9. Caco-2 Permeability:** Both have negative values (-4.392 and -4.879), which is unusual and suggests poor permeability. However, these are likely scales and not absolute values, so we can't directly compare.

**10. Aqueous Solubility:** Both have negative values (-2.069 and -2.306), suggesting poor solubility. Similar to Caco-2, these are likely scales.

**11. hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.268 and 0.242).

**12. Microsomal Clearance:** Ligand A (57.924) has a higher clearance than Ligand B (25.622), indicating lower metabolic stability. This favors Ligand B.

**13. In vitro Half-Life:** Ligand B (29.064) has a significantly longer half-life than Ligand A (8.58). This is a strong advantage for Ligand B.

**14. P-gp Efflux:** Both have low P-gp efflux liability (0.037 and 0.146).

**15. Binding Affinity:** Ligand B (-9.1 kcal/mol) has a significantly stronger binding affinity than Ligand A (-7.3 kcal/mol). This is a substantial advantage, potentially outweighing some ADME drawbacks. The difference is >1.5 kcal/mol.

**Overall Assessment:**

While Ligand A has better TPSA, DILI, and BBB, Ligand B has a significantly stronger binding affinity (-9.1 vs -7.3 kcal/mol) and a much longer half-life. The improved affinity is a major advantage for a GPCR ligand, and the longer half-life is desirable. The slightly higher TPSA and DILI of Ligand B are less concerning given the substantial improvement in binding and metabolic stability.

Output:
1
2025-04-17 04:50:25,892 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (360.479 and 352.479 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (78.43) is significantly better than Ligand B (96.25). For CNS targets, we want TPSA <= 90, so Ligand A is preferable.

**3. logP:** Both ligands have acceptable logP values (2.844 and 1.538), falling within the 1-3 range. Ligand A is slightly better.

**4. H-Bond Donors:** Both have 3 HBD, which is within the acceptable limit of <=5.

**5. H-Bond Acceptors:** Ligand A has 4 HBA, and Ligand B has 5. Both are acceptable (<=10), but Ligand A is slightly better.

**6. QED:** Both ligands have reasonable QED scores (0.677 and 0.595), indicating good drug-like properties.

**7. DILI:** Both have low DILI risk (33.307 and 27.491), well below the 40% threshold.

**8. BBB:** Ligand B (50.679) has a much better BBB percentile than Ligand A (28.189). For a CNS target like DRD2, BBB penetration is crucial, and >70 is desirable. Ligand B is significantly better here.

**9. Caco-2 Permeability:** Both have negative Caco-2 values (-5.436 and -5.2), which is unusual and suggests poor permeability. This is a concern for both.

**10. Aqueous Solubility:** Both have negative solubility values (-2.976 and -1.958), indicating very poor solubility. This is a significant drawback for both compounds.

**11. hERG Inhibition:** Both have low hERG inhibition liability (0.339 and 0.173), which is good.

**12. Microsomal Clearance:** Both have similar microsomal clearance values (47.544 and 46.659), suggesting similar metabolic stability.

**13. In vitro Half-Life:** Ligand B (21.257) has a much longer in vitro half-life than Ligand A (-5.437). This is a significant advantage for Ligand B.

**14. P-gp Efflux:** Both have low P-gp efflux liability (0.101 and 0.075), which is favorable for CNS penetration.

**15. Binding Affinity:** Ligand A (-8.7 kcal/mol) has a significantly stronger binding affinity than Ligand B (-7.3 kcal/mol). This is a substantial advantage, potentially outweighing some ADME drawbacks.

**Overall Assessment:**

While Ligand B has a much better BBB penetration and longer half-life, Ligand A's significantly stronger binding affinity (-8.7 vs -7.3 kcal/mol) is a major advantage. The difference of 1.4 kcal/mol is substantial and can often compensate for less-than-ideal ADME properties, especially given that both compounds have significant solubility and permeability issues. The lower TPSA of Ligand A is also beneficial. Given the importance of affinity for GPCRs, and the fact that both have acceptable (though not ideal) safety profiles, Ligand A is the more promising candidate.

Output:
1
2025-04-17 04:50:25,892 - INFO - Reasoning:

Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (366.799 and 376.475 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (50.16) is excellent, well below the 90 A^2 threshold for CNS targets. Ligand B (110.8) is higher, but still potentially acceptable, though less ideal.

**3. logP:** Ligand A (3.961) is optimal. Ligand B (-0.374) is significantly low, potentially hindering membrane permeability and CNS penetration.

**4. H-Bond Donors:** Ligand A (1) and Ligand B (2) are both within the acceptable limit of <=5.

**5. H-Bond Acceptors:** Ligand A (3) and Ligand B (6) are both within the acceptable limit of <=10.

**6. QED:** Both ligands have good QED scores (0.893 and 0.568), indicating drug-like properties.

**7. DILI:** Ligand A (66.072) has a higher DILI risk than Ligand B (39.046), but both are below the concerning 60 threshold.

**8. BBB:** Ligand A (89.957) has a significantly better BBB penetration prediction than Ligand B (63.784). This is crucial for a CNS target like DRD2.

**9. Caco-2 Permeability:** Ligand A (-4.407) has poor predicted Caco-2 permeability. Ligand B (-5.563) is also poor, but slightly worse.

**10. Aqueous Solubility:** Ligand A (-5.509) has poor predicted solubility. Ligand B (-1.497) is also poor, but slightly better.

**11. hERG Inhibition:** Both ligands have very low predicted hERG inhibition risk (0.562 and 0.134).

**12. Microsomal Clearance:** Ligand A (27.864) has a moderate clearance. Ligand B (-1.488) is predicted to have very low clearance, indicating good metabolic stability.

**13. In vitro Half-Life:** Ligand A (-19.279) has a negative half-life, which is not physically meaningful and suggests a potential issue with the prediction. Ligand B (17.689) has a reasonable half-life.

**14. P-gp Efflux:** Ligand A (0.087) has low P-gp efflux, which is favorable for CNS penetration. Ligand B (0.013) also has very low P-gp efflux.

**15. Binding Affinity:** Ligand A (-8.8 kcal/mol) has a significantly stronger binding affinity than Ligand B (-7.2 kcal/mol). This is a substantial difference and a major advantage.

**Overall Assessment:**

Despite Ligand A's stronger binding affinity, its poor Caco-2 permeability, poor solubility, and questionable half-life prediction are major drawbacks. Ligand B, while having a weaker affinity, has a better logP, better metabolic stability (lower Cl_mic, better t1/2), and a more reasonable BBB prediction. The significantly better affinity of Ligand A might overcome some of these issues, but the poor ADME properties are concerning. Given the GPCR-specific priorities, and the importance of BBB penetration for a CNS target, Ligand A is the better candidate due to its superior binding affinity.

Output:
0
2025-04-17 04:50:25,892 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (362.539 Da) and Ligand B (350.423 Da) are comparable.

**TPSA:** Ligand A (43.78) is significantly better than Ligand B (110.08). For CNS targets, TPSA should be <= 90, so Ligand A is much more favorable.

**logP:** Ligand A (4.412) is higher than optimal (1-3) but not drastically so. Ligand B (0.177) is very low, potentially hindering permeation. This is a significant advantage for Ligand A.

**H-Bond Donors/Acceptors:** Both have acceptable HBD counts (1). Ligand B has a higher HBA count (7) compared to Ligand A (3), but both are within the acceptable limit of 10.

**QED:** Ligand A (0.865) has a better QED score than Ligand B (0.636), indicating a more drug-like profile.

**DILI:** Ligand A (10.585) has a much lower DILI risk than Ligand B (43.234).

**BBB:** Ligand A (85.731) has a significantly higher BBB penetration percentile than Ligand B (63.862). This is crucial for a CNS target like DRD2, making Ligand A highly preferable.

**Caco-2 Permeability:** Ligand A (-4.703) and Ligand B (-5.32) both have negative values, indicating poor permeability. However, the scale isn't explicitly defined, so it's hard to interpret the absolute difference.

**Aqueous Solubility:** Ligand A (-3.335) and Ligand B (-0.711) both have negative values, suggesting poor solubility. Ligand B is slightly better.

**hERG Inhibition:** Ligand A (0.743) has a slightly higher hERG risk than Ligand B (0.022), but both are relatively low.

**Microsomal Clearance:** Both ligands have similar microsomal clearance values (Ligand A: 35.014, Ligand B: 35.373).

**In vitro Half-Life:** Ligand A (8.514) has a better in vitro half-life than Ligand B (-16.449).

**P-gp Efflux:** Ligand A (0.471) has a lower P-gp efflux liability than Ligand B (0.05), which is favorable for CNS penetration.

**Binding Affinity:** Ligand A (-9 kcal/mol) has a significantly stronger binding affinity than Ligand B (-7.7 kcal/mol). This is a substantial advantage.

**Overall Assessment:**

Ligand A is clearly superior. It excels in critical areas for a CNS-targeting GPCR ligand: TPSA, BBB penetration, binding affinity, DILI risk, QED, and P-gp efflux. While Ligand A's logP is slightly high, the benefits outweigh this drawback. Ligand B's low logP and poor BBB penetration are major liabilities.

Output:
1
2025-04-17 04:50:25,893 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (347.459 and 346.519 Da) fall comfortably within the ideal 200-500 Da range.

**TPSA:** Ligand A (82.53) is better than Ligand B (61.02). Both are below the 90 A^2 threshold desirable for CNS targets, but Ligand B is closer to the optimal range.

**logP:** Ligand A (1.684) is within the optimal 1-3 range, while Ligand B (3.395) is at the higher end. While still acceptable, higher logP can sometimes lead to off-target effects.

**H-Bond Donors/Acceptors:** Both have 2 HBD and a reasonable number of HBA (4 for A, 3 for B), satisfying the <5 HBD and <10 HBA guidelines.

**QED:** Ligand A (0.868) has a significantly better QED score than Ligand B (0.709), indicating a more drug-like profile.

**DILI:** Ligand A (28.306) has a much lower DILI risk than Ligand B (19.426), which is a significant advantage.

**BBB:** Ligand B (70.997) has a better BBB penetration percentile than Ligand A (59.364). This is a critical factor for CNS targets like DRD2.

**Caco-2 Permeability:** Ligand A (-4.631) has a worse Caco-2 permeability than Ligand B (-5.163). Lower values indicate worse permeability.

**Aqueous Solubility:** Ligand A (-2.215) has better aqueous solubility than Ligand B (-3.135).

**hERG Inhibition:** Both ligands have relatively low hERG inhibition risk (0.352 and 0.661, respectively).

**Microsomal Clearance:** Ligand A (20.835) has a lower microsomal clearance than Ligand B (53.526), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand B (-8.23) has a longer in vitro half-life than Ligand A (-0.025). This is a positive attribute.

**P-gp Efflux:** Ligand A (0.102) has lower P-gp efflux liability than Ligand B (0.277), which is favorable for CNS penetration.

**Binding Affinity:** Both ligands have the same binding affinity (-8.7 kcal/mol), which is excellent.

**Overall Assessment:**

Ligand B excels in BBB penetration and in vitro half-life, which are important for a CNS target. However, Ligand A demonstrates superior scores in QED, DILI risk, solubility, metabolic stability (lower Cl_mic), and P-gp efflux. The binding affinity is identical. Considering the GPCR-specific priorities, the better BBB of Ligand B is a strong point. However, the significantly lower DILI risk and better overall drug-likeness (QED) of Ligand A, combined with its lower P-gp efflux, make it a more promising candidate. The slightly worse Caco-2 permeability of Ligand A is less concerning given the CNS target.

Output:
0
2025-04-17 04:50:25,893 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (352.475 and 350.459 Da) fall comfortably within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (86.71) and Ligand B (84.5) are both below the 90 A^2 threshold for CNS targets, which is excellent.

**3. logP:** Ligand A (1.365) and Ligand B (2.085) are both within the optimal 1-3 range.

**4. H-Bond Donors:** Both ligands have 2 HBD, which is acceptable.

**5. H-Bond Acceptors:** Both ligands have 4 HBA, which is also acceptable.

**6. QED:** Ligand A (0.656) has a slightly better QED score than Ligand B (0.587), indicating a more drug-like profile. Both are above the 0.5 threshold.

**7. DILI:** Ligand A (9.655) has a significantly lower DILI risk than Ligand B (35.634). This is a major advantage for Ligand A.

**8. BBB:** Ligand A (53.16) has a slightly better BBB percentile than Ligand B (48.197). While neither are above the desirable >70% for CNS targets, A is closer.

**9. Caco-2 Permeability:** Ligand A (-4.942) and Ligand B (-4.657) both have negative values, indicating poor permeability.

**10. Aqueous Solubility:** Ligand A (-0.991) has slightly better solubility than Ligand B (-2.347).

**11. hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.181 and 0.133 respectively).

**12. Microsomal Clearance:** Ligand A (10.231) has significantly lower microsomal clearance than Ligand B (57.556), suggesting better metabolic stability.

**13. In vitro Half-Life:** Ligand A (-10.89) has a longer in vitro half-life than Ligand B (-13.928).

**14. P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.025 and 0.084 respectively).

**15. Binding Affinity:** Ligand B (-8.5 kcal/mol) has a slightly better binding affinity than Ligand A (-7.6 kcal/mol). This is a 0.9 kcal/mol difference, which is notable but not overwhelming.

**Overall Assessment:**

While Ligand B has a slightly better binding affinity, Ligand A is significantly better across multiple crucial ADME-Tox properties. Specifically, the much lower DILI risk and improved metabolic stability (lower Cl_mic and longer t1/2) of Ligand A are highly favorable. The slightly better BBB penetration and solubility also contribute to its advantage. Given the GPCR-specific priorities, the improved safety profile and pharmacokinetic properties of Ligand A outweigh the small difference in binding affinity.

Output:
1
2025-04-17 04:50:25,893 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (367.921 and 358.389 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (44.81) is excellent, well below the 90 A^2 threshold for CNS targets. Ligand B (96.25) is higher, but still potentially acceptable, though less ideal.

**logP:** Ligand A (3.086) is optimal (1-3). Ligand B (1.7) is at the lower end, potentially impacting permeability.

**H-Bond Donors/Acceptors:** Ligand A (HBD=1, HBA=3) is good. Ligand B (HBD=3, HBA=5) is also acceptable, though slightly higher.

**QED:** Ligand A (0.729) is strong, indicating good drug-likeness. Ligand B (0.586) is acceptable, but lower.

**DILI:** Ligand A (11.594) has a very low DILI risk. Ligand B (59.131) is higher, indicating a moderate risk.

**BBB:** Ligand A (91.857) has excellent BBB penetration potential. Ligand B (52.811) is significantly lower, a major concern for a CNS target.

**Caco-2 Permeability:** Ligand A (-4.214) is poor, suggesting low intestinal absorption. Ligand B (-5.124) is even worse.

**Aqueous Solubility:** Both ligands have poor aqueous solubility (-2.413 and -2.127 respectively). This could pose formulation challenges.

**hERG Inhibition:** Ligand A (0.802) has a low hERG risk. Ligand B (0.3) is even lower, indicating very low cardiotoxicity potential.

**Microsomal Clearance:** Both ligands have similar microsomal clearance (42.81 and 46.174 mL/min/kg).

**In vitro Half-Life:** Ligand A (46.846 hours) has a good in vitro half-life. Ligand B (-5.666 hours) has a negative half-life, which is not possible and likely indicates a data error or a very rapid degradation.

**P-gp Efflux:** Ligand A (0.084) has low P-gp efflux, which is favorable for CNS penetration. Ligand B (0.107) is slightly higher, but still relatively low.

**Binding Affinity:** Both ligands have the same excellent binding affinity (-7.8 kcal/mol).

**Overall Assessment:**

Ligand A is significantly better due to its superior BBB penetration (91.857 vs 52.811), lower DILI risk (11.594 vs 59.131), and better in vitro half-life (46.846 vs -5.666). While both have poor Caco-2 permeability and solubility, these are less critical for a CNS target. The slightly better logP and QED of Ligand A also contribute to its favorability. The negative half-life for Ligand B is a showstopper.

Output:
0
2025-04-17 04:50:25,893 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (342.443 Da) is slightly lower, which could be advantageous for permeability.

**2. TPSA:** Both ligands have TPSA values below the 90 A^2 threshold for CNS targets, but Ligand B (61.92 A^2) is better than Ligand A (66.71 A^2). Lower TPSA generally favors BBB penetration.

**3. logP:** Both ligands have logP values within the optimal range (1-3). Ligand A (2.491) is slightly better than Ligand B (3.471) as it is closer to the lower end of the range.

**4. H-Bond Donors:** Ligand A has 1 HBD, and Ligand B has 0. Both are acceptable, being less than 5.

**5. H-Bond Acceptors:** Both ligands have 4 HBAs, which is within the acceptable limit of 10.

**6. QED:** Both ligands have QED values above 0.5, indicating good drug-like properties. Ligand A (0.877) is slightly better than Ligand B (0.699).

**7. DILI:** Ligand A (32.571) has a significantly lower DILI risk than Ligand B (55.797). This is a major advantage for Ligand A.

**8. BBB:** Ligand A (69.407) has a better BBB percentile than Ligand B (54.595). While both are below the ideal >70, Ligand A is closer. This is crucial for a CNS target like DRD2.

**9. Caco-2 Permeability:** Both have negative values, which is unusual and suggests poor permeability. However, the scale is not defined, so we can't interpret these values directly.

**10. Aqueous Solubility:** Both have negative values, indicating poor solubility. Again, the scale is not defined.

**11. hERG Inhibition:** Both ligands have low hERG inhibition risk (Ligand A: 0.602, Ligand B: 0.909).

**12. Microsomal Clearance:** Ligand A (35.443) has a lower microsomal clearance than Ligand B (73.793), suggesting better metabolic stability.

**13. In vitro Half-Life:** Both ligands have similar in vitro half-lives (Ligand A: 10.925, Ligand B: 10.987).

**14. P-gp Efflux:** Ligand A (0.109) has significantly lower P-gp efflux liability than Ligand B (0.551). Lower P-gp efflux is highly desirable for CNS penetration.

**15. Binding Affinity:** Ligand A (-8.6 kcal/mol) has a significantly stronger binding affinity than Ligand B (-7.0 kcal/mol). This is a substantial advantage, potentially outweighing minor ADME drawbacks.

**Overall Assessment:**

Ligand A is the superior candidate. It has a better binding affinity, lower DILI risk, better BBB penetration, lower P-gp efflux, and better metabolic stability. While both have issues with Caco-2 and solubility, the affinity and safety profile of Ligand A make it more promising. The 1.6 kcal/mol difference in binding affinity is significant.

Output:
0
2025-04-17 04:50:25,893 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B based on the provided guidelines, prioritizing GPCR-specific properties (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (377.824 Da) is slightly higher than Ligand B (346.383 Da), but both are acceptable.

**TPSA:** Ligand A (59.42) is significantly better than Ligand B (104.73). For CNS targets, TPSA should be <=90. Ligand A is well within this range, while Ligand B is pushing the limit and could have reduced brain penetration.

**logP:** Ligand A (4.682) is higher than the optimal range (1-3), potentially leading to solubility issues or off-target effects. Ligand B (1.194) is at the lower end of the optimal range, which is acceptable but could potentially limit permeability.

**H-Bond Donors/Acceptors:** Ligand A (HBD=1, HBA=5) is preferable to Ligand B (HBD=3, HBA=5) as lower HBD generally improves permeability. Both are within acceptable limits.

**QED:** Ligand B (0.671) has a better QED score than Ligand A (0.397), indicating a more drug-like profile.

**DILI:** Ligand B (54.556) has a significantly lower DILI risk than Ligand A (80.031). This is a major advantage for Ligand B.

**BBB:** Ligand B (68.592) has a substantially better BBB percentile than Ligand A (33.385). This is crucial for a CNS target like DRD2.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.851 and -4.948), which is unusual and suggests poor permeability. However, these values are on a scale where negative values are possible, and direct comparison is difficult without knowing the scale's specifics.

**Aqueous Solubility:** Both ligands have negative solubility values (-5.549 and -2.961), again suggesting poor aqueous solubility. Similar to Caco-2, the scale is unknown.

**hERG Inhibition:** Both ligands show low hERG inhibition risk (0.457 and 0.281).

**Microsomal Clearance:** Ligand B (35.717) has significantly lower microsomal clearance than Ligand A (138.992), indicating better metabolic stability.

**In vitro Half-Life:** Ligand B (-6.364) has a longer in vitro half-life than Ligand A (-1.523), which is desirable.

**P-gp Efflux:** Ligand B (0.199) has lower P-gp efflux liability than Ligand A (0.423), which is beneficial for CNS penetration.

**Binding Affinity:** Both ligands have excellent binding affinities (-9.5 kcal/mol and -8.9 kcal/mol). Ligand A has a slightly better affinity, but the difference is likely not enough to overcome its other drawbacks.

**Overall Assessment:**

Ligand B is the superior candidate. Despite a slightly lower binding affinity, it excels in critical areas for a CNS-targeting GPCR: significantly better BBB penetration, lower DILI risk, better metabolic stability (lower Cl_mic, longer t1/2), lower P-gp efflux, and a better QED score. Ligand A's high logP and poor BBB penetration are significant concerns. While TPSA is better for Ligand A, the other ADME properties of Ligand B are far more favorable for CNS drug development.

Output:
1
2025-04-17 04:50:25,893 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (384.219 Da) is slightly higher than Ligand B (351.447 Da), but both are acceptable.

**TPSA:** Ligand A (107.49) is higher than Ligand B (87.74). For CNS targets, we prefer TPSA <= 90. Ligand B is better in this regard.

**logP:** Ligand A (4.191) is higher than Ligand B (0.435). While 4.191 is at the upper end of the optimal range (1-3), it's still acceptable. Ligand B's logP is quite low, potentially hindering permeation.

**H-Bond Donors/Acceptors:** Both have 2 HBDs, which is good. Ligand A has 6 HBAs, while Ligand B has 4. Both are within the acceptable limit of <=10.

**QED:** Ligand B (0.68) has a better QED score than Ligand A (0.346), indicating a more drug-like profile.

**DILI:** Ligand A (90.423) has a significantly higher DILI risk than Ligand B (20.977). This is a major concern for Ligand A.

**BBB:** Ligand A (54.478) and Ligand B (59.752) are both below the desirable threshold of >70 for CNS targets. However, Ligand B is slightly better.

**Caco-2 Permeability:** Ligand A (-4.853) and Ligand B (-5.102) both have negative Caco-2 values, which is not ideal.

**Aqueous Solubility:** Ligand A (-6.481) and Ligand B (-1.32) both have negative solubility values, indicating poor aqueous solubility. Ligand B is better than Ligand A.

**hERG Inhibition:** Ligand A (0.647) has a slightly higher hERG inhibition liability than Ligand B (0.117), but both are relatively low risk.

**Microsomal Clearance:** Ligand B (-9.038) has a negative clearance, which is excellent, indicating very high metabolic stability. Ligand A (80.792) has a moderate clearance.

**In vitro Half-Life:** Ligand B (7.285) has a slightly longer half-life than Ligand A (30.5).

**P-gp Efflux:** Ligand A (0.26) has a lower P-gp efflux liability than Ligand B (0.007), which is preferable for CNS penetration.

**Binding Affinity:** Ligand A (-8.4 kcal/mol) has a significantly better binding affinity than Ligand B (-7.7 kcal/mol). This is a substantial advantage.

**Overall Assessment:**

Ligand A has a much stronger binding affinity, which is a key factor for GPCRs. However, its high DILI risk is a major drawback. Ligand B has a better safety profile (lower DILI, better QED, better metabolic stability), but its lower logP and weaker binding affinity are concerns. Considering the importance of CNS penetration for DRD2, the slightly better BBB and P-gp efflux of Ligand A are also beneficial. The difference in binding affinity (-0.7 kcal/mol) is significant enough to potentially overcome some of Ligand A's ADME liabilities, especially if further optimization can mitigate the DILI risk.

Output:
1
2025-04-17 04:50:25,893 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (353.423 and 353.413 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (125.35) is higher than the preferred <90 for CNS targets, while Ligand B (62.3) is well within the range. This is a significant advantage for Ligand B.

**3. logP:** Ligand A (-0.902) is below the optimal 1-3 range and could indicate poor membrane permeability. Ligand B (2.855) is within the optimal range.

**4. H-Bond Donors:** Ligand A (4) is acceptable, while Ligand B (1) is even better, potentially improving permeability.

**5. H-Bond Acceptors:** Ligand A (6) is acceptable, while Ligand B (3) is also good.

**6. QED:** Both ligands have reasonable QED values (0.458 and 0.885), with Ligand B being significantly better, suggesting a more drug-like profile.

**7. DILI:** Both ligands have low DILI risk (37.224 and 32.571), which is positive.

**8. BBB:** This is crucial for a CNS target like DRD2. Ligand A has a BBB percentile of 20.822, which is quite low and concerning. Ligand B has a much higher BBB percentile of 91.431, making it far more likely to reach the target in the brain.

**9. Caco-2 Permeability:** Both have negative values, which is unusual. However, the magnitude is similar.

**10. Aqueous Solubility:** Both have negative values, which is also unusual. The magnitude is similar.

**11. hERG Inhibition:** Both ligands show low hERG inhibition risk (0.107 and 0.512).

**12. Microsomal Clearance:** Ligand A (12.115) has higher clearance than Ligand B (7.441), indicating lower metabolic stability.

**13. In vitro Half-Life:** Ligand B (-19.35) has a negative half-life, which is not possible. Ligand A (23.39) is reasonable. This is a data error for Ligand B.

**14. P-gp Efflux:** Ligand A (0.01) has very low P-gp efflux, which is excellent. Ligand B (0.093) is also low, but slightly higher.

**15. Binding Affinity:** Ligand B (-9.0 kcal/mol) has a significantly stronger binding affinity than Ligand A (-7.7 kcal/mol). This difference of 1.3 kcal/mol is substantial and can outweigh some ADME drawbacks.

**Overall Assessment:**

Ligand B is significantly better suited as a drug candidate for DRD2. It has a much more favorable TPSA, logP, and, critically, BBB penetration. While Ligand A has lower P-gp efflux, the superior BBB, logP, affinity, and QED of Ligand B outweigh this advantage. The negative half-life value for Ligand B is a data error, but even ignoring that, the other properties strongly favor Ligand B.

Output:
1
2025-04-17 04:50:25,893 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (342.37 and 345.447 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (49.85) is excellent, well below the 90 Angstroms threshold for CNS targets. Ligand B (70.47) is still reasonable but less optimal, approaching the 90 Angstroms limit.

**3. logP:** Ligand A (2.922) is within the optimal 1-3 range. Ligand B (0.403) is significantly lower, potentially hindering membrane permeability and CNS penetration.

**4. H-Bond Donors:** Ligand A (0) is good. Ligand B (1) is acceptable.

**5. H-Bond Acceptors:** Ligand A (3) is good. Ligand B (5) is acceptable.

**6. QED:** Both ligands have similar and good QED values (0.858 and 0.785, respectively), indicating good drug-like properties.

**7. DILI:** Ligand A (77.123) has a higher DILI risk than Ligand B (16.208). This is a concern for Ligand A.

**8. BBB:** Ligand A (89.492) has a very good BBB penetration percentile, exceeding the desirable >70% threshold for CNS targets. Ligand B (39.511) is significantly lower, raising concerns about reaching the target in the brain.

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 values which is unusual and suggests a potential issue with the data or the model used to predict this value. However, we can still compare them relatively. Ligand A (-4.13) is slightly better than Ligand B (-4.911).

**10. Aqueous Solubility:** Both ligands have negative solubility values, which is also unusual. Ligand B (-0.708) is slightly better than Ligand A (-2.945).

**11. hERG Inhibition:** Ligand A (0.708) has a slightly higher hERG risk than Ligand B (0.227), but both are relatively low.

**12. Microsomal Clearance:** Ligand B (-18.796) has a lower (better) microsomal clearance than Ligand A (33.385), indicating greater metabolic stability.

**13. In vitro Half-Life:** Ligand B (-3.305) has a longer half-life than Ligand A (-23.973).

**14. P-gp Efflux:** Ligand A (0.369) has lower P-gp efflux than Ligand B (0.016), which is favorable for CNS penetration.

**15. Binding Affinity:** Ligand A (-8.8 kcal/mol) has a significantly stronger binding affinity than Ligand B (-7.4 kcal/mol). This is a substantial advantage, exceeding the 1.5 kcal/mol difference threshold.

**Overall Assessment:**

Despite the higher DILI risk, Ligand A is the more promising candidate. Its superior BBB penetration, favorable logP, and significantly stronger binding affinity outweigh the DILI concern, especially given the potency advantage. The lower P-gp efflux also contributes to better CNS exposure. Ligand B's low logP and poor BBB penetration are major drawbacks for a CNS-targeted GPCR ligand. The unusual negative values for Caco-2 and solubility are concerning, but the relative comparison still favors Ligand A.

Output:
1
2025-04-17 04:50:25,893 - INFO - Reasoning:

Let's analyze Ligand A and Ligand B based on the provided guidelines, prioritizing GPCR-specific properties (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (342.395 and 348.422 Da) fall comfortably within the ideal 200-500 Da range.

**TPSA:** Ligand A (79.62) is slightly higher than Ligand B (67.23), but both are below the 90 A^2 threshold desirable for CNS targets. Ligand B is preferable here.

**logP:** Both ligands have good logP values (1.717 and 1.834), falling within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Both have 1 HBD and 4 HBA, which are acceptable.

**QED:** Both ligands have high QED scores (0.907 and 0.903), indicating good drug-like properties.

**DILI:** Ligand A (60.566) has a higher DILI risk than Ligand B (18.108). This is a significant advantage for Ligand B.

**BBB:** Ligand B (85.459) has a considerably higher BBB penetration percentile than Ligand A (75.339). This is *critical* for a CNS target like DRD2, making Ligand B strongly favored.

**Caco-2 Permeability:** Ligand A (-4.617) has worse Caco-2 permeability than Ligand B (-5.071). Both are negative, but B is slightly better.

**Aqueous Solubility:** Ligand A (-3.349) has worse aqueous solubility than Ligand B (-2.137).

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.238 and 0.322).

**Microsomal Clearance:** Ligand B (5.79) has significantly lower microsomal clearance than Ligand A (36.95), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand B (-14.004) has a longer in vitro half-life than Ligand A (-21.059).

**P-gp Efflux:** Ligand A (0.263) has slightly lower P-gp efflux liability than Ligand B (0.012), which is preferable.

**Binding Affinity:** Both ligands have excellent binding affinities (-9.7 and -8.3 kcal/mol). Ligand A is slightly better (-9.7 kcal/mol), but the difference is less than the 1.5 kcal/mol threshold to outweigh other factors.

**Overall Assessment:**

Ligand B is the superior candidate. While Ligand A has a slightly better binding affinity, Ligand B excels in crucial ADME properties for a CNS-targeting GPCR: significantly better BBB penetration, lower DILI risk, lower microsomal clearance, and longer half-life. The small advantage in binding affinity of Ligand A does not compensate for these substantial improvements in drug-like properties.

Output:
1
2025-04-17 04:50:25,893 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight (MW):** Both ligands (361.873 and 360.527 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (53.51) is significantly better than Ligand B (61.92). For a CNS target like DRD2, we want TPSA <= 90, and A is closer to this threshold.

**3. logP:** Both ligands have good logP values (2.383 and 3.139), falling within the optimal 1-3 range. Ligand B is slightly higher, which could potentially lead to off-target effects but isn't a major concern.

**4. H-Bond Donors (HBD):** Both ligands have 0 HBD, which is acceptable.

**5. H-Bond Acceptors (HBA):** Ligand A has 3 HBA, and Ligand B has 5. Both are within the acceptable limit of <= 10.

**6. QED:** Both ligands have reasonable QED values (0.827 and 0.714), indicating good drug-like properties.

**7. DILI:** Ligand A (35.479) has a slightly higher DILI risk than Ligand B (17.216), but both are below the concerning threshold of 60.

**8. BBB:** Both ligands have excellent BBB penetration (75.611 and 79.139), exceeding the desirable >70 threshold for CNS targets. Ligand B is marginally better.

**9. Caco-2:** Both have negative Caco-2 values which is unusual and likely indicates a problem with the data.

**10. Solubility:** Both have negative solubility values which is unusual and likely indicates a problem with the data.

**11. hERG:** Both ligands show low hERG inhibition liability (0.317 and 0.641), which is favorable.

**12. Cl_mic:** Ligand A (36.047) has a lower microsomal clearance than Ligand B (76.566), suggesting better metabolic stability. This is a significant advantage.

**13. t1/2:** Ligand A (-30.379) has a negative in vitro half-life, which is not possible. Ligand B (-14.874) also has a negative in vitro half-life, which is not possible. This suggests a problem with the data.

**14. Pgp:** Both ligands have low P-gp efflux liability (0.208 and 0.432), which is good for CNS penetration.

**15. Binding Affinity:** Ligand A (-8.4 kcal/mol) has a significantly stronger binding affinity than Ligand B (-6.7 kcal/mol). This is a substantial advantage (>1.5 kcal/mol difference).

**Overall Assessment:**

Considering the GPCR-specific priorities, Ligand A is the better candidate. While Ligand B has slightly better BBB penetration, Ligand A's superior binding affinity, lower microsomal clearance, and lower TPSA outweigh this minor difference. The negative values for Caco-2 and t1/2 are concerning and suggest potential data quality issues, but the large difference in binding affinity is a key factor.

Output:
1
2025-04-17 04:50:25,894 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 drug candidates, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (341.43 and 353.48 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (29.54) is excellent, well below the 90 A^2 threshold for CNS targets. Ligand B (43.86) is still reasonable, but higher, potentially impacting BBB penetration slightly.

**logP:** Ligand A (4.438) is at the upper end of the optimal range (1-3), potentially leading to solubility issues. Ligand B (1.917) is good, within the optimal range.

**H-Bond Donors/Acceptors:** Both ligands have low HBD (0) and acceptable HBA (2 and 3 respectively), which is favorable for permeability.

**QED:** Both ligands have QED values above 0.7, indicating good drug-likeness.

**DILI:** Ligand A (50.33) has a moderate DILI risk, while Ligand B (6.01) has a very low DILI risk, a significant advantage.

**BBB:** Ligand A (89.07) has good BBB penetration, but Ligand B (95.66) is even better, exceeding 90%, which is highly desirable for a CNS target like DRD2.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values, which is unusual and could indicate issues with the prediction method or the compounds themselves. However, we'll proceed assuming they represent low permeability.

**Aqueous Solubility:** Both ligands have negative solubility values, which is also unusual. This suggests poor aqueous solubility, which could be a formulation challenge.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.87 and 0.702 respectively).

**Microsomal Clearance:** Ligand A (59.92) has a higher clearance than Ligand B (0.082), indicating lower metabolic stability.

**In vitro Half-Life:** Ligand A (27.65) has a longer half-life than Ligand B (1.19), which is preferable.

**P-gp Efflux:** Ligand A (0.594) has lower P-gp efflux liability than Ligand B (0.042), which is beneficial for CNS exposure.

**Binding Affinity:** Ligand B (-7.9 kcal/mol) has a significantly stronger binding affinity than Ligand A (-9.2 kcal/mol). This 1.7 kcal/mol difference is substantial and can outweigh some ADME drawbacks.

**Overall Assessment:**

While Ligand A has a better half-life and P-gp efflux profile, Ligand B is superior overall. The most critical factors for a CNS-targeting GPCR like DRD2 are BBB penetration and binding affinity. Ligand B excels in both of these areas, with a very high BBB percentile and a significantly stronger binding affinity. Furthermore, Ligand B has a much lower DILI risk. The slightly higher TPSA and lower half-life of Ligand B are less concerning given the substantial advantage in binding affinity and BBB penetration. The negative solubility and Caco-2 values are concerning for both, but can be addressed with formulation strategies.

Output:
1
2025-04-17 04:50:25,894 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (352.45 and 349.475 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (49.85) is significantly better than Ligand B (74.43). For CNS targets, we want TPSA <= 90, and ideally closer to 60. Ligand A is much closer to this ideal.

**3. logP:** Both ligands have good logP values (2.023 and 2.353), falling within the optimal 1-3 range.

**4. H-Bond Donors:** Ligand A (0) is preferable to Ligand B (2). Fewer H-bond donors generally improve permeability.

**5. H-Bond Acceptors:** Both ligands have 3 H-bond acceptors, which is acceptable (<=10).

**6. QED:** Both ligands have similar and good QED values (0.712 and 0.793), indicating good drug-like properties.

**7. DILI:** Both ligands have low DILI risk (28.306 and 25.359), which is positive.

**8. BBB:** This is a critical parameter for a CNS target like DRD2. Ligand A has a significantly higher BBB percentile (93.408) compared to Ligand B (64.637). This is a major advantage for Ligand A.

**9. Caco-2 Permeability:** Ligand A (-4.049) is better than Ligand B (-4.769), indicating slightly better intestinal absorption.

**10. Aqueous Solubility:** Both ligands have similar and poor aqueous solubility (-2.671 and -2.551). This could pose formulation challenges, but is less critical than BBB for CNS targets.

**11. hERG Inhibition:** Both ligands have low hERG inhibition liability (0.679 and 0.579), which is good.

**12. Microsomal Clearance:** Ligand B (12.067) has a lower microsomal clearance than Ligand A (30.459), suggesting better metabolic stability. However, the difference isn't massive.

**13. In vitro Half-Life:** Ligand B (-9.45) has a longer in vitro half-life than Ligand A (-15.666). This is a positive for Ligand B.

**14. P-gp Efflux:** Ligand A (0.189) has lower P-gp efflux than Ligand B (0.138), which is favorable for CNS penetration.

**15. Binding Affinity:** Ligand B (-7.9) has a slightly better binding affinity than Ligand A (-6.9). This is a 1.0 kcal/mol difference, which is significant, but needs to be weighed against other factors.

**Overall Assessment:**

Ligand A is the stronger candidate. While Ligand B has slightly better affinity and metabolic stability, Ligand A's significantly superior BBB penetration (93.4 vs 64.6) and lower TPSA (49.85 vs 74.43) are crucial for a CNS-targeting drug. The lower P-gp efflux also helps. The 1.0 kcal/mol difference in binding affinity can potentially be optimized in subsequent iterations of drug design, whereas improving BBB penetration is often more challenging.

Output:
1
2025-04-17 04:50:25,894 - INFO - Batch 147 complete. Total preferences: 2352
2025-04-17 04:50:25,894 - INFO - Processing batch 148/512...
2025-04-17 04:51:09,122 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (353.467 Da) is slightly lower, which could be advantageous for permeability, while Ligand B (379.404 Da) is still well within the range.

**TPSA:** Ligand A (93.78) is closer to the upper limit for CNS targets (<=90), but still acceptable. Ligand B (71.53) is excellent, well below the 90 threshold, suggesting better CNS penetration potential.

**logP:** Ligand A (-0.101) is quite low, potentially hindering membrane permeability and reducing brain exposure. Ligand B (2.605) is within the optimal range (1-3), indicating good lipophilicity.

**H-Bond Donors/Acceptors:** Ligand A has 3 HBD and 4 HBA, which are reasonable. Ligand B has 1 HBD and 5 HBA, also acceptable.

**QED:** Both ligands have good QED scores (Ligand A: 0.478, Ligand B: 0.825), indicating drug-like properties. Ligand B is significantly better.

**DILI:** Both have acceptable DILI risk (Ligand A: 12.175, Ligand B: 62.389), though Ligand B is higher, it is still below the concerning threshold of 60.

**BBB:** Ligand A (63.784) is below the desirable threshold of 70 for CNS targets. Ligand B (82.125) is excellent, exceeding the 70% threshold, suggesting better brain penetration.

**Caco-2 Permeability:** Both have negative values (-5.37 and -4.655), which is unusual and suggests poor permeability. However, these values are on a scale where negative values are possible and don't necessarily indicate a complete lack of permeability.

**Aqueous Solubility:** Both have negative values (-0.615 and -3.503), indicating poor solubility. This could be a formulation challenge.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (Ligand A: 0.243, Ligand B: 0.485).

**Microsomal Clearance:** Ligand A (-9.376) has a negative clearance, which is not physically possible and likely indicates an error or an extremely stable compound. Ligand B (23.722) is moderate, suggesting reasonable metabolic stability.

**In vitro Half-Life:** Ligand A (-1.109) has a negative half-life, which is not physically possible and likely indicates an error. Ligand B (-23.455) is also negative, indicating an issue with the data.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (Ligand A: 0.001, Ligand B: 0.124), which is favorable for CNS penetration.

**Binding Affinity:** Both ligands have comparable binding affinities (Ligand A: -7.4 kcal/mol, Ligand B: -7.6 kcal/mol). The difference is minimal.

**Overall Assessment:**

Ligand B is significantly more promising. It has a better logP, a much better BBB score, a higher QED, and a more reasonable (though still moderate) microsomal clearance. The negative values for Caco-2 and half-life for both compounds are concerning and require further investigation, but the other properties strongly favor Ligand B. Ligand A's low logP and negative clearance/half-life values are major red flags.

Output:
1
2025-04-17 04:51:09,123 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (366.418 and 344.419 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (85.25) is better than Ligand B (103.01). Both are below 140, but for a CNS target, <90 is preferred. Ligand A is closer to this target.

**3. logP:** Both ligands have good logP values (1.244 and 1.046), falling within the optimal 1-3 range.

**4. H-Bond Donors:** Ligand A (2) is preferable to Ligand B (3). Lower HBD generally improves permeability.

**5. H-Bond Acceptors:** Both ligands have the same number of HBA (6), which is acceptable (<=10).

**6. QED:** Ligand A (0.806) has a significantly better QED score than Ligand B (0.694), indicating a more drug-like profile.

**7. DILI:** Ligand B (57.387) has a lower DILI risk than Ligand A (76.464), which is a positive attribute.

**8. BBB:** Ligand A (66.576) has a substantially better BBB penetration percentile than Ligand B (36.642). This is *critical* for a CNS target like DRD2.

**9. Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and suggests poor permeability. Ligand A (-5.057) is slightly better than Ligand B (-5.314).

**10. Aqueous Solubility:** Both have negative solubility values, indicating poor solubility. Ligand A (-2.442) is slightly better than Ligand B (-2.735).

**11. hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.183 and 0.441).

**12. Microsomal Clearance:** Ligand A (16.832) has a lower microsomal clearance than Ligand B (38.367), implying better metabolic stability.

**13. In vitro Half-Life:** Ligand A (45.104) has a longer in vitro half-life than Ligand B (19.976), which is desirable.

**14. P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.037 and 0.011), which is favorable for CNS penetration.

**15. Binding Affinity:** Ligand B (-8.8 kcal/mol) has a significantly stronger binding affinity than Ligand A (-7.2 kcal/mol). This is a substantial advantage (>1.5 kcal/mol difference).

**Overall Assessment:**

While Ligand B boasts a superior binding affinity, Ligand A has a much better BBB score, QED, metabolic stability (lower Cl_mic, longer t1/2), and is closer to the ideal TPSA range. The difference in binding affinity is significant, but the poor BBB penetration of Ligand B is a major concern for a CNS target. The better ADME properties of Ligand A, particularly the BBB score, outweigh the affinity difference.

Output:
0
2025-04-17 04:51:09,123 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (348.4 and 346.5 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (95.94) is slightly above the optimal <90 for CNS targets, but still reasonable. Ligand B (49.41) is excellent, well below 90.

**logP:** Ligand A (-0.53) is a bit low, potentially hindering permeability. Ligand B (3.524) is within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A (2 HBD, 5 HBA) is good. Ligand B (1 HBD, 2 HBA) is also good. Both are within acceptable limits.

**QED:** Both ligands have acceptable QED values (0.629 and 0.513, respectively), indicating good drug-like properties.

**DILI:** Ligand A (41.411) has a slightly higher DILI risk than Ligand B (6.824), but both are below the concerning threshold of 60.

**BBB:** This is critical for a CNS target. Ligand A (26.483) has a poor BBB percentile, while Ligand B (79.139) is excellent, exceeding the desirable >70 threshold.

**Caco-2 Permeability:** Ligand A (-5.064) shows poor permeability. Ligand B (-4.761) is also poor, but slightly better than A.

**Aqueous Solubility:** Both ligands have very poor aqueous solubility (-2.424 and -3.515 respectively). This is a concern for both, but might be mitigated by formulation strategies.

**hERG Inhibition:** Ligand A (0.044) has a very low hERG risk, which is excellent. Ligand B (0.594) is slightly higher, but still relatively low.

**Microsomal Clearance:** Ligand A (-2.291) suggests good metabolic stability (negative value indicates slower clearance). Ligand B (77.552) indicates rapid clearance, a significant drawback.

**In vitro Half-Life:** Ligand A (-11.015) suggests a long half-life, which is favorable. Ligand B (-5.838) suggests a shorter half-life.

**P-gp Efflux:** Ligand A (0.088) has low P-gp efflux, which is good for CNS penetration. Ligand B (0.106) also has low P-gp efflux.

**Binding Affinity:** Ligand B (-8.8 kcal/mol) has a significantly stronger binding affinity than Ligand A (-7.6 kcal/mol). This >1.5 kcal/mol difference is substantial and can outweigh some ADME concerns.

**Overall Assessment:**

Ligand B is the stronger candidate. While both have poor solubility and Caco-2 permeability, Ligand B excels in the most critical areas for a CNS GPCR target: high BBB penetration, significantly better binding affinity, and acceptable DILI and hERG risks. The faster clearance and shorter half-life of Ligand B are drawbacks, but potentially addressable through structural modifications. Ligand A's poor BBB penetration is a major hurdle that is less likely to be overcome.

Output:
1
2025-04-17 04:51:09,123 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (358.427 Da and 363.571 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (104.03) is higher than the preferred <90 for CNS targets, while Ligand B (48.99) is well within the range. This is a significant advantage for Ligand B.

**logP:** Ligand A (1.077) is within the optimal 1-3 range. Ligand B (4.584) is slightly high, potentially leading to solubility issues and off-target interactions, though not drastically so.

**H-Bond Donors/Acceptors:** Ligand A has 1 HBD and 8 HBA, both acceptable. Ligand B has 1 HBD and 3 HBA, also acceptable.

**QED:** Ligand A (0.872) has a better QED score than Ligand B (0.698), indicating a more drug-like profile.

**DILI:** Ligand A (81.776) has a higher DILI risk than Ligand B (21.636). This is a significant concern for Ligand A.

**BBB:** Ligand B (78.635) has a much better BBB penetration percentile than Ligand A (53.083). This is crucial for a CNS target like DRD2.

**Caco-2 Permeability:** Both have negative values (-5.221 and -5.13), indicating poor permeability. This is a concern for both, but less critical for CNS targets where BBB penetration is prioritized.

**Aqueous Solubility:** Both have negative values (-3.318 and -4.541) indicating poor solubility.

**hERG:** Both ligands have low hERG inhibition risk (0.364 and 0.563).

**Microsomal Clearance:** Ligand A (24.362) has lower microsomal clearance than Ligand B (88.683), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (9.499) has a longer half-life than Ligand B (-5.073). This is a positive for Ligand A.

**P-gp Efflux:** Both have very low P-gp efflux liability (0.121 and 0.332).

**Binding Affinity:** Ligand B (-7.8 kcal/mol) has a significantly stronger binding affinity than Ligand A (0.0 kcal/mol). This is a major advantage for Ligand B, potentially outweighing some of its ADME drawbacks.

**Overall Assessment:**

Ligand B is the more promising candidate. While its logP is slightly elevated, its superior BBB penetration, significantly stronger binding affinity, and much lower DILI risk are critical advantages for a CNS-targeting GPCR like DRD2. Ligand A has better QED and metabolic stability, but the poor BBB penetration and high DILI risk are major drawbacks. The substantial difference in binding affinity (-7.8 vs 0.0 kcal/mol) is a decisive factor.

Output:
1
2025-04-17 04:51:09,123 - INFO - Reasoning:

Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (360.5) is slightly better, being closer to the lower end which can aid permeability.

**2. TPSA:** Ligand A (23.55) is significantly better than Ligand B (41.05). For CNS targets, we want TPSA <= 90, and ideally much lower. Ligand A is excellent, while Ligand B is approaching a less desirable range.

**3. logP:** Both ligands have logP values around 4.1-4.6, which is slightly high. While not disqualifying, it could potentially lead to solubility issues or off-target interactions.

**4. H-Bond Donors:** Both are low (0 and 1), which is good for permeability.

**5. H-Bond Acceptors:** Ligand A (3) is better than Ligand B (6). Lower HBA is generally preferred for CNS penetration.

**6. QED:** Both ligands have similar QED values (0.706 and 0.697), indicating good drug-likeness.

**7. DILI:** Ligand B (89.7) has a higher DILI risk than Ligand A (57.3). Lower DILI is preferred.

**8. BBB:** Both ligands have excellent BBB penetration (>80%). Ligand A (81.7) is slightly better. This is a critical factor for a CNS target like DRD2.

**9. Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and suggests poor permeability. However, the scale is not specified, so it's hard to interpret.

**10. Aqueous Solubility:** Both have negative solubility values, indicating poor aqueous solubility. This is a concern, but can be addressed with formulation strategies.

**11. hERG Inhibition:** Both ligands have low hERG inhibition risk (0.95 and 0.84).

**12. Microsomal Clearance:** Ligand A (121.4) has a higher microsomal clearance than Ligand B (101.0). Lower clearance is better for metabolic stability.

**13. In vitro Half-Life:** Ligand B (27.6) has a shorter half-life than Ligand A (33.9). Longer half-life is generally preferred.

**14. P-gp Efflux:** Both ligands have low P-gp efflux liability (0.728 and 0.695).

**15. Binding Affinity:** Both ligands have very similar and excellent binding affinities (-8.2 and -8.3 kcal/mol). The difference is negligible.

**Overall Assessment:**

Ligand A is superior due to its lower TPSA, lower DILI risk, slightly better BBB penetration, and longer half-life. While both have issues with solubility and Caco-2 permeability, the other factors favor Ligand A. The slightly higher clearance of Ligand A is a minor drawback compared to the benefits. Given the importance of BBB penetration for a CNS target, Ligand A is the more promising candidate.

Output:
0
2025-04-17 04:51:09,123 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (357.475 and 346.471 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (46.61) is significantly better than Ligand B (66.48). For CNS targets, we want TPSA <= 90, and A is much closer to the optimal range.

**logP:** Ligand A (4.229) is slightly higher than the optimal 1-3 range, but still potentially acceptable. Ligand B (2.576) is well within the optimal range. However, for a GPCR, some lipophilicity is beneficial for membrane penetration.

**H-Bond Donors/Acceptors:** Both have a reasonable number of HBD/HBA (A: 0/3, B: 1/3), well within the guidelines.

**QED:** Both ligands have similar QED values (A: 0.777, B: 0.752), indicating good drug-like properties.

**DILI:** Ligand A (75.611) has a higher DILI risk than Ligand B (27.608). This is a significant drawback for Ligand A.

**BBB:** Both ligands have good BBB penetration (A: 63.94, B: 73.827), but Ligand B is slightly better. A value >70 is desirable for CNS targets, and B is closer.

**Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual. However, the magnitude is similar (-4.281 for A and -4.892 for B).

**Aqueous Solubility:** Both have negative solubility values, which is also unusual. The magnitude is similar (-5.824 for A and -2.954 for B).

**hERG Inhibition:** Both ligands show low hERG inhibition risk (A: 0.79, B: 0.168), with Ligand B being significantly lower.

**Microsomal Clearance:** Ligand A (87.877) has a higher microsomal clearance than Ligand B (14.508), indicating lower metabolic stability.

**In vitro Half-Life:** Both have negative half-life values (-19.732 for A and -20.818 for B), which is unusual.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (A: 0.601, B: 0.114), with Ligand B being significantly lower. Lower P-gp efflux is crucial for CNS penetration.

**Binding Affinity:** Both ligands have excellent binding affinity (A: -9.4 kcal/mol, B: -8.6 kcal/mol). Ligand A has a 0.8 kcal/mol advantage, which is substantial.

**Overall Assessment:**

Ligand A has a better binding affinity, but suffers from higher DILI risk, higher microsomal clearance (lower metabolic stability), and a higher TPSA. Ligand B has better ADME properties overall (lower DILI, lower clearance, better P-gp efflux, better hERG), and a good BBB score. The 0.8 kcal/mol difference in binding affinity, while significant, is likely outweighed by the superior ADME profile of Ligand B, particularly the lower DILI and better metabolic stability. For a CNS target like DRD2, good BBB penetration and minimal efflux are critical, and Ligand B excels in these areas.

Output:
1
2025-04-17 04:51:09,124 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (360.483 and 363.527 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (85.23) is slightly higher than Ligand B (71.09). Both are below the 90 A^2 threshold desirable for CNS targets, but Ligand B is preferable.

**3. logP:** Ligand A (2.23) is within the optimal range (1-3). Ligand B (3.142) is at the higher end of optimal, but still acceptable.

**4. H-Bond Donors:** Both ligands have 2 HBD, which is within the acceptable limit of <=5.

**5. H-Bond Acceptors:** Ligand A has 5 HBA, and Ligand B has 4. Both are below the acceptable limit of <=10.

**6. QED:** Both ligands have good QED scores (0.635 and 0.697 respectively), indicating drug-like properties.

**7. DILI:** Ligand A (53.276) has a slightly higher DILI risk than Ligand B (40.52). Ligand B is preferable here.

**8. BBB:** Both ligands have similar BBB penetration (56.34 and 54.672 percentile). Neither is outstanding (>70), but both are reasonable for a starting point.

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.094 and -5.016), which is unusual and suggests poor permeability. This is a significant concern for both.

**10. Aqueous Solubility:** Both ligands have negative solubility values (-2.637 and -3.193), indicating very poor aqueous solubility. This is a major drawback for both.

**11. hERG Inhibition:** Ligand A (0.558) has a slightly higher hERG risk than Ligand B (0.111). Ligand B is preferable.

**12. Microsomal Clearance:** Ligand B (52.846) has a higher microsomal clearance than Ligand A (5.367), indicating faster metabolism and lower metabolic stability. Ligand A is preferable.

**13. In vitro Half-Life:** Ligand A (17.912) has a longer half-life than Ligand B (13.732). Ligand A is preferable.

**14. P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.112 and 0.25). This is good for CNS exposure.

**15. Binding Affinity:** Ligand B (-8.1 kcal/mol) has a significantly stronger binding affinity than Ligand A (-0.0 kcal/mol). This is a substantial advantage, potentially outweighing some of the ADME concerns.

**Overall Assessment:**

Ligand B has a much better binding affinity, a slightly better TPSA, lower DILI risk, and lower hERG risk. While both have poor Caco-2 permeability and solubility, the strong binding affinity of Ligand B is a critical advantage for a GPCR target like DRD2. The better affinity could potentially be optimized with further structural modifications to address the solubility and permeability issues. Ligand A has better metabolic stability and half-life, but the negligible binding affinity makes it a poor candidate.

Output:
1
2025-04-17 04:51:09,124 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (345.487 and 348.443 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (54.46) is significantly better than Ligand B (67.87). For CNS targets, we want TPSA <= 90, and ideally closer to 60. Ligand A is much closer to this ideal.

**3. logP:** Ligand A (4.319) is slightly higher than optimal (1-3), but still potentially acceptable. Ligand B (2.288) is within the optimal range. However, for a GPCR, a slightly higher logP can sometimes be tolerated if other properties are favorable.

**4. H-Bond Donors:** Both have 1 HBD, which is good.

**5. H-Bond Acceptors:** Ligand A has 3 HBAs, Ligand B has 4. Both are acceptable (<=10).

**6. QED:** Ligand A (0.809) has a better QED score than Ligand B (0.549), indicating a more drug-like profile.

**7. DILI:** Ligand A (23.342) has a much lower DILI risk than Ligand B (35.595). Both are below the 40% threshold, but A is preferable.

**8. BBB:** Ligand A (85.033) has a significantly better BBB penetration percentile than Ligand B (74.254). For a CNS target like DRD2, >70% is highly desirable, and A is closer to this.

**9. Caco-2:** Ligand A (-4.182) and Ligand B (-5.176) both have negative values, which is unusual and suggests poor permeability. However, the scale isn't specified, so it's hard to interpret.

**10. Solubility:** Ligand A (-3.674) and Ligand B (-2.205) both have negative solubility values, indicating poor aqueous solubility. This is a concern, but can sometimes be overcome with formulation strategies.

**11. hERG:** Both ligands have relatively low hERG inhibition risk (0.459 and 0.669).

**12. Cl_mic:** Ligand B (32.428) has a lower microsomal clearance than Ligand A (88.028), suggesting better metabolic stability.

**13. t1/2:** Ligand B (-15.413) has a much longer in vitro half-life than Ligand A (-2.209). This is a significant advantage.

**14. Pgp:** Ligand A (0.066) has a much lower P-gp efflux liability than Ligand B (0.189), which is crucial for CNS penetration.

**15. Binding Affinity:** Both ligands have excellent binding affinities (-8.5 and -8.1 kcal/mol). The difference of 0.4 kcal/mol is not substantial enough to outweigh other significant differences.

**Overall Assessment:**

Ligand A is superior due to its significantly better TPSA, BBB penetration, lower DILI risk, and lower P-gp efflux. While Ligand B has better metabolic stability (lower Cl_mic and longer t1/2), the CNS-specific properties of Ligand A are more critical for a DRD2 ligand. The slightly higher logP of Ligand A is acceptable given its other favorable properties.

Output:
0
2025-04-17 04:51:09,124 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (345.487 Da) is slightly lower, which *could* be beneficial for permeability, but both are acceptable.

**2. TPSA:** Ligand A (43.86) is significantly better than Ligand B (62.15). For CNS targets, we want TPSA <= 90, and ideally closer to 60. Ligand A is much closer to the ideal range, suggesting better CNS penetration potential.

**3. logP:** Both ligands have acceptable logP values (Ligand A: 1.432, Ligand B: 3.382), falling within the 1-3 range. Ligand B is closer to the upper limit, which *could* raise concerns about solubility or off-target effects, but isn't a dealbreaker.

**4. H-Bond Donors:** Both have 0 HBD, which is good.

**5. H-Bond Acceptors:** Ligand A has 3 HBA, while Ligand B has 6. Both are within the acceptable limit of <=10, but Ligand A is preferable.

**6. QED:** Both ligands have reasonable QED values (Ligand A: 0.774, Ligand B: 0.609), indicating good drug-like properties. Ligand A is slightly better.

**7. DILI:** Ligand A (9.655) has a much lower DILI risk than Ligand B (41.915). This is a significant advantage for Ligand A.

**8. BBB:** Both ligands have good BBB penetration (Ligand A: 73.905, Ligand B: 71.268), exceeding the 70% threshold for CNS targets. Ligand A is slightly better.

**9. Caco-2 Permeability:** Ligand A (-4.838) has worse Caco-2 permeability than Ligand B (-5.279). Lower (more negative) values are less favorable.

**10. Aqueous Solubility:** Ligand A (-1.959) has worse aqueous solubility than Ligand B (-2.685). Lower (more negative) values are less favorable.

**11. hERG Inhibition:** Both ligands have low hERG inhibition risk (Ligand A: 0.443, Ligand B: 0.882). Ligand A is better.

**12. Microsomal Clearance:** Ligand A (10.665) has lower microsomal clearance than Ligand B (55.847), indicating better metabolic stability. This is a significant advantage for Ligand A.

**13. In vitro Half-Life:** Ligand A (9.378) has a lower in vitro half-life than Ligand B (50.898). Ligand B is preferable.

**14. P-gp Efflux:** Ligand A (0.066) has much lower P-gp efflux than Ligand B (0.42). This is a major advantage for Ligand A, as it will lead to better CNS exposure.

**15. Binding Affinity:** Ligand A (-7.6) has slightly better binding affinity than Ligand B (-7.4). While the difference is small, it's still a positive for Ligand A.

**Overall Assessment:**

Considering all parameters, and prioritizing GPCR-specific properties, **Ligand A is the more promising drug candidate.** It excels in TPSA, DILI risk, metabolic stability (Cl_mic), P-gp efflux, and has slightly better affinity and BBB penetration. While Ligand B has better Caco-2 permeability and in vitro half-life, the advantages of Ligand A in key areas like CNS penetration (TPSA, P-gp, BBB) and safety (DILI) are more critical for a DRD2 target.



Output:
0
2025-04-17 04:51:09,124 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 drug candidates, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (337.379 Da) is slightly lower, which *could* be advantageous for permeability, but both are acceptable.

**2. TPSA:** Both ligands have TPSA values below 100, which is good for CNS penetration. Ligand A (99.58) is slightly higher, but still within a reasonable range.

**3. logP:** Both ligands have logP values within the optimal range (1-3). Ligand B (2.604) is a bit higher than Ligand A (1.454), potentially raising concerns about solubility and off-target effects, but it's not extreme.

**4. H-Bond Donors:** Both ligands have 2 HBD, which is acceptable.

**5. H-Bond Acceptors:** Ligand A has 5 HBA, and Ligand B has 7. Both are within the acceptable limit of 10.

**6. QED:** Ligand A (0.86) has a significantly better QED score than Ligand B (0.673), indicating a more drug-like profile.

**7. DILI:** Ligand A (41.024%) has a much lower DILI risk than Ligand B (77.627%). This is a significant advantage for Ligand A.

**8. BBB:** Ligand B (34.277%) has a better BBB penetration score than Ligand A (24.661%), which is crucial for a CNS target like DRD2. This is a major advantage for Ligand B.

**9. Caco-2 Permeability:** Ligand A (-4.808) has a more negative Caco-2 value, suggesting *lower* permeability than Ligand B (-5.649). Both are poor, but B is slightly better.

**10. Aqueous Solubility:** Both ligands have very poor aqueous solubility (-2.682). This could pose formulation challenges.

**11. hERG Inhibition:** Ligand A (0.773) has a slightly higher hERG inhibition risk than Ligand B (0.13). This is a positive for Ligand B.

**12. Microsomal Clearance:** Ligand A (-35.893) has a much lower (better) microsomal clearance than Ligand B (21.853), indicating greater metabolic stability.

**13. In vitro Half-Life:** Ligand B (47.454) has a significantly longer in vitro half-life than Ligand A (28.891). This is a positive for Ligand B.

**14. P-gp Efflux:** Ligand A (0.144) has a lower P-gp efflux liability than Ligand B (0.357), which is favorable for CNS exposure.

**15. Binding Affinity:** Ligand B (-7.7 kcal/mol) has a significantly stronger binding affinity than Ligand A (-9.3 kcal/mol). This is a substantial advantage for Ligand B, and can often outweigh other drawbacks.

**Overall Assessment:**

Ligand B has a stronger binding affinity and better BBB penetration, a longer half-life, and lower hERG risk. These are key advantages for a CNS GPCR target. While Ligand B has a higher DILI risk and slightly worse QED, the substantial affinity advantage and reasonable BBB are compelling. Ligand A has better metabolic stability and lower DILI, but its weaker affinity and lower BBB penetration are significant drawbacks.

Output:
1
2025-04-17 04:51:09,124 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (368.503 and 350.503 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (83.56) is better than Ligand B (67.43). Both are below the 90 A^2 threshold for CNS targets, which is excellent.

**logP:** Both ligands have good logP values (2.111 and 2.949), falling within the optimal 1-3 range. Ligand B is slightly higher, potentially aiding membrane permeability.

**H-Bond Donors/Acceptors:** Both have 2 HBDs, which is good. Ligand A has 6 HBAs, and Ligand B has 3 HBAs. Both are within acceptable limits (<=10).

**QED:** Ligand A (0.687) has a better QED score than Ligand B (0.496), indicating a more drug-like profile.

**DILI:** Ligand A (52.889) has a higher DILI risk than Ligand B (13.843). This is a significant advantage for Ligand B.

**BBB:** Ligand A (76.309) has a better BBB penetration percentile than Ligand B (69.058). Both are reasonably good, but A is closer to the desirable >70 threshold for CNS targets.

**Caco-2 Permeability:** Ligand A (-5.084) has worse Caco-2 permeability than Ligand B (-4.522), indicating lower intestinal absorption.

**Aqueous Solubility:** Ligand A (-2.614) has worse aqueous solubility than Ligand B (-3.073).

**hERG Inhibition:** Both ligands show low hERG inhibition liability (0.6 and 0.421), which is good.

**Microsomal Clearance:** Ligand A (18.168) has lower microsomal clearance than Ligand B (66.755), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (25.16) has a shorter half-life than Ligand B (-7.171). The negative value for Ligand B is unusual and suggests a very long half-life, which is highly desirable.

**P-gp Efflux:** Ligand A (0.158) has lower P-gp efflux than Ligand B (0.295), which is favorable for CNS exposure.

**Binding Affinity:** Ligand B (-8.6 kcal/mol) has a significantly stronger binding affinity than Ligand A (-6.6 kcal/mol). This >1.5 kcal/mol difference is a major advantage.

**Overall Assessment:**

Ligand B clearly wins out due to its significantly superior binding affinity (-8.6 vs -6.6 kcal/mol) and much lower DILI risk. While Ligand A has a slightly better BBB score and lower P-gp efflux, the substantial affinity difference and reduced toxicity risk of Ligand B outweigh these minor advantages. The very long in vitro half-life of Ligand B is also a significant positive. The slightly lower BBB score of Ligand B is still acceptable, and can potentially be improved with further optimization.

Output:
1
2025-04-17 04:51:09,125 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (374.409 Da and 352.494 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (85.36) is better than Ligand B (49.41). For CNS targets, we want TPSA <= 90. Both are within this range, but A is closer to the upper limit.

**logP:** Both ligands have good logP values (2.575 and 3.614), falling within the optimal 1-3 range. Ligand B is slightly higher, which could potentially lead to some off-target effects, but is still acceptable.

**H-Bond Donors/Acceptors:** Both ligands have 1 HBD, which is good. Ligand A has 6 HBA, while Ligand B has 2. Both are within the acceptable limit of <=10, and B is preferable here.

**QED:** Ligand A (0.816) has a significantly better QED score than Ligand B (0.611), indicating better overall drug-likeness.

**DILI:** Ligand A (70.182) has a higher DILI risk than Ligand B (12.214). This is a significant drawback for Ligand A.

**BBB:** Both ligands have excellent BBB penetration (83.366% and 85.964%), exceeding the desirable >70% threshold for CNS targets. Ligand B is slightly better.

**Caco-2 Permeability:** Both have negative Caco-2 values which is unusual and indicates poor permeability.

**Aqueous Solubility:** Both ligands have very poor aqueous solubility (-3.998 and -3.218). This is a major concern for both, potentially impacting bioavailability.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.514 and 0.593).

**Microsomal Clearance:** Ligand B (36.792) has a higher microsomal clearance than Ligand A (18.599), indicating lower metabolic stability. Ligand A is preferable here.

**In vitro Half-Life:** Ligand A (33.346 hours) has a much longer half-life than Ligand B (3.242 hours). This is a significant advantage for Ligand A.

**P-gp Efflux:** Both ligands have very low P-gp efflux (0.157 and 0.181), which is good for CNS exposure.

**Binding Affinity:** Both ligands have excellent binding affinity (-8.3 kcal/mol and -8.0 kcal/mol). The difference is relatively small.

**Overall Assessment:**

Ligand A has a better QED, longer half-life, and lower microsomal clearance. However, it has a significantly higher DILI risk and slightly worse TPSA. Ligand B has a lower DILI risk, better TPSA, and slightly better BBB penetration, but a much shorter half-life and higher microsomal clearance.

Considering the GPCR-specific priorities, BBB is critical. Both are good. Affinity is also crucial, and they are very similar. The biggest differentiating factor is the DILI risk. A high DILI risk is a major red flag in drug development. While a longer half-life is desirable, the potential for liver toxicity with Ligand A outweighs this benefit.

Output:
1
2025-04-17 04:51:09,125 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B based on the provided guidelines, prioritizing GPCR-specific properties (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (345.374) is slightly lower, which could be advantageous for permeability.

**TPSA:** Ligand A (91.32) is better than Ligand B (107.4), falling closer to the preferred <90 for CNS targets.

**logP:** Both ligands have acceptable logP values (A: 2.231, B: 2.668), within the 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A (HBD=3, HBA=4) is slightly better than Ligand B (HBD=1, HBA=4) in terms of HBD count, but both are within acceptable limits.

**QED:** Ligand A (0.572) has a significantly better QED score than Ligand B (0.376), indicating a more drug-like profile.

**DILI:** Both ligands have moderate DILI risk (A: 54.556, B: 59.131), but A is slightly better.

**BBB:** Ligand B (77.898) has a substantially better BBB penetration score than Ligand A (53.432). This is a critical factor for a CNS target like DRD2.

**Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and suggests poor permeability. However, the scale is not defined, so it's hard to interpret.

**Aqueous Solubility:** Both have negative solubility values, indicating poor solubility. This is a concern for bioavailability.

**hERG:** Both ligands have low hERG inhibition liability (A: 0.403, B: 0.353), which is good.

**Microsomal Clearance:** Ligand B (1.792) has significantly lower microsomal clearance than Ligand A (62.646), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand B (7.068) has a much longer in vitro half-life than Ligand A (-39.274). This is a significant advantage.

**P-gp Efflux:** Ligand A (0.133) has lower P-gp efflux liability than Ligand B (0.1), which is favorable for CNS penetration.

**Binding Affinity:** Ligand B (-7.7 kcal/mol) has a significantly stronger binding affinity than Ligand A (-9.7 kcal/mol). This is a crucial advantage, potentially outweighing some ADME drawbacks.

**Overall Assessment:**

While Ligand A has better QED, TPSA, and slightly better DILI, Ligand B excels in the most critical areas for a CNS-targeting GPCR: BBB penetration, metabolic stability (low Cl_mic, long t1/2), and, most importantly, binding affinity. The substantial difference in binding affinity (-7.7 vs -9.7 kcal/mol) is a major factor. Although solubility and Caco-2 are poor for both, the superior CNS penetration and metabolic profile of Ligand B, combined with its strong binding, make it the more promising candidate.

Output:
1
2025-04-17 04:51:09,125 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight (MW):** Both ligands (361.793 and 348.407 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Both ligands (108.06 and 109.3) are slightly above the optimal <90 for CNS targets, but still reasonably acceptable.

**3. logP:** Ligand A (2.725) is within the optimal 1-3 range. Ligand B (-0.393) is significantly below this, which is a concern for permeability.

**4. H-Bond Donors (HBD):** Both ligands (3 and 2) are within the acceptable limit of <=5.

**5. H-Bond Acceptors (HBA):** Ligand A (6) is within the acceptable limit of <=10. Ligand B (8) is also within the limit.

**6. QED:** Both ligands (0.659 and 0.761) have good drug-likeness scores, exceeding the 0.5 threshold.

**7. DILI:** Ligand A (98.953) has a high DILI risk, which is a significant drawback. Ligand B (57.154) has a moderate DILI risk, better than A but still not ideal.

**8. BBB:** Ligand A (51.725) has a moderate BBB penetration, which is acceptable but not great for a CNS target. Ligand B (23.187) has very poor predicted BBB penetration, a major concern.

**9. Caco-2:** Both ligands have negative Caco-2 values (-5.006 and -5.201), which is unusual and suggests potential issues with intestinal absorption. This is likely an artifact of the prediction method.

**10. Solubility:** Both ligands have negative solubility values (-5.073 and -0.929), also likely an artifact.

**11. hERG:** Both ligands have low hERG inhibition liability (0.472 and 0.098), which is positive.

**12. Cl_mic:** Ligand A (48.258) has a moderate clearance. Ligand B (-6.823) has a *negative* clearance, which is impossible and indicates a prediction error.

**13. t1/2:** Ligand A (49.414) has a reasonable in vitro half-life. Ligand B (5.592) has a very short half-life, which is undesirable.

**14. Pgp:** Both ligands have very low Pgp efflux liability (0.056 and 0.019), which is favorable for CNS penetration.

**15. Binding Affinity:** Both ligands have strong binding affinities (-8.7 and -8.1 kcal/mol), with Ligand A being slightly better. The 0.6 kcal/mol difference is significant.

**Overall Assessment:**

Ligand A has a better binding affinity and a more reasonable logP, but suffers from a very high DILI risk and moderate BBB penetration. Ligand B has a lower DILI risk, but its logP is very low, and its predicted BBB penetration is extremely poor, and its clearance is nonsensical. The negative values for Caco-2 and solubility are concerning for both, but likely prediction artifacts.

Given the GPCR-specific priorities, BBB penetration is crucial for a CNS target like DRD2. While Ligand A's BBB is not ideal, it is significantly better than Ligand B's. The stronger binding affinity of Ligand A also outweighs the DILI risk to some extent, as optimization could potentially address the DILI liability. The negative clearance for Ligand B is a showstopper.

Output:
0
2025-04-17 04:51:09,125 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B based on the provided guidelines, prioritizing GPCR-specific properties (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (342.395 Da) is slightly lower, which can be beneficial for permeability.

**TPSA:** Ligand A (74.45) is better than Ligand B (50.8). For CNS targets, we want TPSA <= 90, both are within this range, but A is closer to the ideal.

**logP:** Both ligands have good logP values (A: 3.367, B: 3.959), falling within the optimal 1-3 range. B is slightly higher, potentially increasing off-target interactions, but not drastically.

**H-Bond Donors/Acceptors:** Ligand A (HBD=0, HBA=6) is preferable to Ligand B (HBD=1, HBA=3). Lower HBD/HBA generally improves permeability.

**QED:** Both ligands have good QED values (A: 0.567, B: 0.851), indicating good drug-like properties. B is better here.

**DILI:** Ligand A (73.09) has a higher DILI risk than Ligand B (47.421). This is a significant advantage for Ligand B.

**BBB:** Ligand B (92.904) has a significantly better BBB penetration percentile than Ligand A (81.776). This is *critical* for a CNS target like DRD2.

**Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and suggests a potential issue with the data or modeling. However, the values are similar (-4.784 vs -4.451).

**Aqueous Solubility:** Both have negative solubility values, again unusual. The values are similar (-4.029 vs -4.484).

**hERG:** Ligand A (0.141) has a slightly lower hERG risk than Ligand B (0.732), which is favorable.

**Microsomal Clearance:** Ligand A (68.982) has a lower microsomal clearance than Ligand B (49.782), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand B (18.471) has a significantly longer in vitro half-life than Ligand A (-1.216). This is a major advantage for B.

**P-gp Efflux:** Ligand A (0.315) has lower P-gp efflux liability than Ligand B (0.412), which is favorable for CNS exposure.

**Binding Affinity:** Ligand B (-9.0) has a slightly better binding affinity than Ligand A (-8.9). While the difference is small, it's still a positive for B.

**Overall Assessment:**

Ligand B is the stronger candidate. While Ligand A has some advantages (lower TPSA, lower Pgp efflux, lower hERG), Ligand B excels in the most crucial areas for a CNS-targeting GPCR: **BBB penetration** and **in vitro half-life**. The lower DILI risk and slightly better affinity also contribute to its favorability. The similar solubility and Caco-2 values are less concerning given the primary focus on CNS penetration.




Output:
1
2025-04-17 04:51:09,126 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (349.37 and 359.51 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (127.82) is higher than the preferred <90 for CNS targets, while Ligand B (20.31) is excellent. This is a significant advantage for Ligand B.

**logP:** Ligand A (0.262) is quite low, potentially hindering membrane permeability. Ligand B (4.866) is slightly high, but still within an acceptable range, though it could raise solubility concerns.

**H-Bond Donors/Acceptors:** Ligand A has 3 HBD and 7 HBA, which are reasonable. Ligand B has 0 HBD and 2 HBA, which is also acceptable, potentially favoring permeability due to fewer hydrogen bonds.

**QED:** Both ligands have good QED scores (0.463 and 0.585), indicating reasonable drug-likeness.

**DILI:** Ligand A (73.052) has a higher DILI risk than Ligand B (32.648), which is preferable.

**BBB:** Ligand B (96.2) has a very high BBB penetration score, which is crucial for a CNS target like DRD2. Ligand A (55.603) is significantly lower and less desirable.

**Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and suggests potential issues with the calculation or experimental data. However, the magnitude is similar.

**Aqueous Solubility:** Both have negative solubility values, again unusual. Ligand A (-2.719) is slightly better than Ligand B (-4.58).

**hERG Inhibition:** Both ligands show low hERG inhibition risk (0.651 and 0.936).

**Microsomal Clearance:** Ligand B (90.527) has a much higher microsomal clearance than Ligand A (19.134), indicating faster metabolism and potentially lower *in vivo* exposure.

**In vitro Half-Life:** Ligand B (33.831) has a longer half-life than Ligand A (16.018), which is generally desirable.

**P-gp Efflux:** Ligand A (0.073) has a lower P-gp efflux liability than Ligand B (0.927), which is beneficial for CNS penetration.

**Binding Affinity:** Ligand B (-7.7 kcal/mol) has a slightly better binding affinity than Ligand A (-8.2 kcal/mol). While the difference is small, it's still a positive for Ligand B.

**Overall Assessment:**

Ligand B is the stronger candidate. Its excellent BBB penetration, favorable TPSA, acceptable logP, lower DILI risk, and slightly better binding affinity outweigh its higher P-gp efflux and microsomal clearance. Ligand A's low logP and poor BBB penetration are significant drawbacks for a CNS-targeting drug. The unusual negative solubility and Caco-2 values for both compounds warrant further investigation, but do not fundamentally change the overall ranking.

Output:
1
2025-04-17 04:51:09,126 - INFO - Batch 148 complete. Total preferences: 2368
2025-04-17 04:51:09,126 - INFO - Processing batch 149/512...
2025-04-17 04:51:49,898 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight (MW):** Both ligands (360.483 and 356.423 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (85.23) is significantly better than Ligand B (117.79). For CNS targets, we want TPSA <= 90, and A is comfortably within this range, while B is above.

**3. logP:** Both ligands have good logP values (2.23 and 1.11), falling within the optimal 1-3 range. Ligand A is slightly better.

**4. H-Bond Donors (HBD):** Both have 2 HBD, which is acceptable (<=5).

**5. H-Bond Acceptors (HBA):** Ligand A has 5 HBA, and Ligand B has 7. Both are within the acceptable range (<=10), but A is preferable.

**6. QED:** Both have similar QED values (0.635 and 0.603), indicating good drug-likeness.

**7. DILI:** Ligand A (53.276) has a slightly higher DILI risk than Ligand B (49.864), but both are below the concerning threshold of 60.

**8. BBB:** Both have similar BBB penetration (56.34 and 58.278). Neither are above the desirable 70, but this is not a dealbreaker as potency can compensate.

**9. Caco-2 Permeability:** Both have negative Caco-2 values (-5.094 and -5.058), which is unusual and suggests poor permeability. This is a significant concern for both.

**10. Aqueous Solubility:** Both have negative solubility values (-2.637 and -1.721), indicating very poor aqueous solubility. This is a major drawback for both.

**11. hERG Inhibition:** Ligand A (0.558) has a slightly higher hERG inhibition risk than Ligand B (0.089). This is a significant advantage for B.

**12. Microsomal Clearance:** Ligand B (45.559) has a much lower microsomal clearance than Ligand A (5.367), indicating better metabolic stability. This is a strong advantage for B.

**13. In vitro Half-Life:** Ligand B (-7.989) has a significantly longer in vitro half-life than Ligand A (17.912). This is a major advantage for B.

**14. P-gp Efflux:** Ligand A (0.112) has slightly higher P-gp efflux liability than Ligand B (0.069). This is a slight advantage for B.

**15. Binding Affinity:** Ligand B (-7.0) has a significantly stronger binding affinity than Ligand A (0.0). This is a *major* advantage for B, easily outweighing minor ADME drawbacks.

**Overall Assessment:**

While both ligands have significant ADME issues (poor solubility and permeability), Ligand B is clearly superior. Its substantially stronger binding affinity (-7.0 kcal/mol vs 0.0 kcal/mol) is the most important factor. Additionally, it has better metabolic stability (lower Cl_mic), longer half-life, lower hERG risk, and slightly better P-gp efflux. The lower TPSA of Ligand A is a positive, but the affinity difference is too large to ignore.

Output:
1
2025-04-17 04:51:49,899 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (363.355 and 350.459 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (131.36) is borderline for CNS penetration, being slightly above the preferred <90, but still reasonable. Ligand B (67.87) is excellent, well below 90, indicating good potential for CNS penetration.

**logP:** Ligand A (0.917) is a bit low, potentially hindering membrane permeability. Ligand B (1.622) is better, falling within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A (0 HBD, 8 HBA) is good. Ligand B (1 HBD, 4 HBA) is also good, both within acceptable limits.

**QED:** Both ligands have good QED scores (0.57 and 0.739), suggesting generally drug-like properties.

**DILI:** Ligand A (88.251) has a higher DILI risk than Ligand B (12.136), which is a significant concern.

**BBB:** Ligand B (75.107) has a significantly better BBB percentile than Ligand A (55.603). This is crucial for a CNS target like DRD2.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.61 and -4.722), which is unusual and suggests poor permeability. However, these values are on a log scale and the negative values could indicate very low permeability.

**Aqueous Solubility:** Both ligands have negative solubility values (-5.026 and -2.046), which is also unusual and suggests poor solubility.

**hERG:** Both ligands have low hERG risk (0.304 and 0.292).

**Microsomal Clearance:** Ligand B (32.467) has lower microsomal clearance than Ligand A (42.482), indicating better metabolic stability.

**In vitro Half-Life:** Ligand B (13.775) has a much better in vitro half-life than Ligand A (-38.412).

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.238 and 0.034), which is favorable for CNS penetration.

**Binding Affinity:** Ligand A (-7.7 kcal/mol) has a slightly better binding affinity than Ligand B (-7.3 kcal/mol), but the difference is relatively small (0.4 kcal/mol).

**Overall Assessment:**

Ligand B is the more promising candidate. While Ligand A has slightly better binding affinity, Ligand B excels in critical ADME properties for a CNS-targeting GPCR. Specifically, its significantly better BBB penetration, lower DILI risk, improved metabolic stability (lower Cl_mic, longer t1/2), and better logP outweigh the minor affinity difference. The negative Caco-2 and solubility values are concerning for both, but the other advantages of Ligand B make it the preferred choice.

Output:
1
2025-04-17 04:51:49,899 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (361.511 and 350.478 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (75.43) is higher than Ligand B (49.41). For a CNS target like DRD2, TPSA should be <= 90, so both are acceptable, but B is significantly better.

**logP:** Both ligands have good logP values (2.621 and 2.912), falling within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A has 2 HBD and 4 HBA, while Ligand B has 1 HBD and 2 HBA. Both are within acceptable limits (<=5 HBD and <=10 HBA).

**QED:** Both ligands have good QED scores (0.817 and 0.847), indicating good drug-like properties.

**DILI:** Ligand A (22.063) has a slightly higher DILI risk than Ligand B (17.449), but both are well below the concerning threshold of 60.

**BBB:** Ligand B (93.253) has a significantly higher BBB penetration percentile than Ligand A (89.686). This is a crucial advantage for a CNS target.

**Caco-2 Permeability:** Ligand A (-5.455) and Ligand B (-4.915) have negative values, indicating low permeability. This is a potential concern for both.

**Aqueous Solubility:** Both ligands have very poor aqueous solubility (-3.774 and -4.042). This could pose formulation challenges.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.495 and 0.655).

**Microsomal Clearance:** Ligand B (25.1) has a higher microsomal clearance than Ligand A (12.905), suggesting lower metabolic stability.

**In vitro Half-Life:** Ligand A (-5.629) has a longer in vitro half-life than Ligand B (8.432), which is favorable.

**P-gp Efflux:** Ligand A (0.115) has lower P-gp efflux liability than Ligand B (0.098), which is desirable for CNS penetration.

**Binding Affinity:** Ligand B (-10.0) has a significantly stronger binding affinity than Ligand A (-8.8). This is a substantial advantage, potentially outweighing some of the ADME drawbacks. A difference of >1.5 kcal/mol is considered significant.

**Overall Assessment:**

Ligand B is the stronger candidate. While both have poor solubility and Caco-2 permeability, Ligand B's superior BBB penetration and significantly improved binding affinity are critical advantages for a DRD2 ligand targeting CNS disorders. The slightly higher metabolic clearance of Ligand B is a concern, but the potency difference is substantial enough to prioritize it.



Output:
1
2025-04-17 04:51:49,899 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (344.474 and 350.463 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (55.12) is significantly better than Ligand B (85.25). For CNS targets, we want TPSA <= 90, and A is comfortably within that range, while B is approaching the upper limit.

**3. logP:** Both ligands have good logP values (3.437 and 2.332), falling within the optimal 1-3 range.

**4. H-Bond Donors:** Both have 2 HBD, which is acceptable.

**5. H-Bond Acceptors:** Ligand A has 2 HBA, while Ligand B has 5.  Lower is generally preferred, and A is better here.

**6. QED:** Ligand A (0.86) has a higher QED than Ligand B (0.678), indicating a more drug-like profile.

**7. DILI:** Ligand B (42.148) has a lower DILI risk than Ligand A (11.439), which is a positive for B.

**8. BBB:** Ligand A (89.802) has a substantially better BBB penetration percentile than Ligand B (79.333). This is *critical* for a CNS target like DRD2.

**9. Caco-2 Permeability:** Both have negative values (-4.857 and -4.528). This is unusual and requires further investigation, but the values are similar.

**10. Aqueous Solubility:** Both have negative values (-3.421 and -3.75). This is also unusual and requires further investigation, but the values are similar.

**11. hERG:** Ligand A (0.882) has a slightly higher hERG risk than Ligand B (0.266), which is a positive for B.

**12. Microsomal Clearance:** Ligand B (58.916) has a higher microsomal clearance than Ligand A (47.953), meaning A is more metabolically stable.

**13. In vitro Half-Life:** Ligand A (4.917) has a shorter half-life than Ligand B (12.295).

**14. P-gp Efflux:** Ligand A (0.341) has lower P-gp efflux than Ligand B (0.069), which is favorable for CNS penetration.

**15. Binding Affinity:** Ligand B (-7.3 kcal/mol) has a significantly better binding affinity than Ligand A (-9.3 kcal/mol). This is a substantial advantage.

**Overall Assessment:**

While Ligand A has better BBB penetration and P-gp efflux, Ligand B's significantly stronger binding affinity (-7.3 vs -9.3 kcal/mol) is a major advantage that can outweigh some of the ADME drawbacks. The lower DILI and hERG risk for Ligand B are also positive. The TPSA of Ligand B is a bit higher, but still within an acceptable range. The slightly higher metabolic clearance and shorter half-life of Ligand B are concerns, but can potentially be addressed through structural modifications. Given the importance of affinity for GPCR ligands, and the CNS target, Ligand B is the more promising candidate.

Output:
1
2025-04-17 04:51:49,899 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (345.443 and 346.475 Da) fall comfortably within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (84.23) is better than Ligand B (59.51), both are below the 90 A^2 threshold for CNS targets.

**3. logP:** Both ligands have good logP values (2.3 and 2.828), falling within the optimal 1-3 range. Ligand B is slightly higher, which could be beneficial for membrane permeability.

**4. H-Bond Donors:** Ligand A (2) is slightly higher than Ligand B (1), but both are within the acceptable limit of 5.

**5. H-Bond Acceptors:** Ligand A (4) is lower than Ligand B (6), both are within the acceptable limit of 10.

**6. QED:** Both ligands have good QED scores (0.673 and 0.731), indicating good drug-like properties.

**7. DILI:** Both ligands have acceptable DILI risk (49.011 and 39.667), below the 60 threshold. Ligand B has a slightly lower risk.

**8. BBB:** This is a critical parameter for a CNS target like DRD2. Ligand B (97.286) significantly outperforms Ligand A (56.65), exceeding the desirable >70 threshold.

**9. Caco-2 Permeability:** Ligand A (-4.633) and Ligand B (-4.896) both have negative values, indicating poor permeability.

**10. Aqueous Solubility:** Ligand A (-4.443) and Ligand B (-3.169) both have negative values, indicating poor solubility.

**11. hERG Inhibition:** Ligand A (0.131) has a lower hERG risk than Ligand B (0.869).

**12. Microsomal Clearance:** Ligand A (43.062) has a lower clearance than Ligand B (73.185), suggesting better metabolic stability.

**13. In vitro Half-Life:** Ligand B (33.963) has a significantly longer half-life than Ligand A (2.51).

**14. P-gp Efflux:** Ligand A (0.24) has lower P-gp efflux than Ligand B (0.174), which is better for CNS exposure.

**15. Binding Affinity:** Ligand B (-7.6 kcal/mol) has a slightly better binding affinity than Ligand A (-7.2 kcal/mol). While the difference is not huge, it's enough to potentially overcome some ADME drawbacks.

**Overall Assessment:**

Ligand B is the stronger candidate. The significantly higher BBB penetration (97.286 vs 56.65) is a major advantage for a CNS-targeting drug. While Ligand A has better hERG and clearance, the improved CNS exposure potential of Ligand B, coupled with its slightly better affinity and half-life, outweighs these factors. Both ligands have poor solubility and permeability, which would need to be addressed in further optimization, but the BBB score is the deciding factor here.

Output:
1
2025-04-17 04:51:49,900 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 drug candidates, considering the provided guidelines and GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (356.482 and 356.413 Da) fall comfortably within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (78.43) is slightly higher than Ligand B (66.57). Both are below the 90 A^2 threshold desirable for CNS targets, but Ligand B is preferable.

**3. logP:** Ligand A (2.348) and Ligand B (3.477) are both within the optimal 1-3 range. Ligand B is slightly higher, which could be beneficial for membrane permeability, but needs to be balanced against solubility.

**4. H-Bond Donors:** Ligand A (3) is higher than Ligand B (1). Lower HBD is generally preferred for BBB penetration. Ligand B is better here.

**5. H-Bond Acceptors:** Ligand A (3) and Ligand B (4) are both acceptable, below the 10 threshold.

**6. QED:** Ligand B (0.774) has a significantly better QED score than Ligand A (0.526), indicating a more drug-like profile.

**7. DILI:** Ligand A (8.53) has a much lower DILI risk than Ligand B (19.504). This is a significant advantage for Ligand A.

**8. BBB:** Ligand B (89.608) has a substantially higher BBB penetration percentile than Ligand A (76.464). This is *critical* for a CNS target like DRD2, making Ligand B strongly favored.

**9. Caco-2 Permeability:** Ligand A (-4.697) and Ligand B (-4.416) both have negative values, which is unusual and suggests poor permeability. The values are very close, so this isn't a major differentiator.

**10. Aqueous Solubility:** Ligand A (-2.765) and Ligand B (-3.735) both have negative solubility values, indicating poor aqueous solubility. Ligand B is slightly worse.

**11. hERG Inhibition:** Both ligands have low hERG inhibition risk (0.465 and 0.642 respectively), which is good.

**12. Microsomal Clearance:** Ligand A (36.064) has higher microsomal clearance than Ligand B (27.408), meaning Ligand B is more metabolically stable.

**13. In vitro Half-Life:** Ligand B (5.738) has a much longer in vitro half-life than Ligand A (-11.024). This is a significant advantage for Ligand B.

**14. P-gp Efflux:** Both ligands have low P-gp efflux liability (0.105 and 0.231 respectively).

**15. Binding Affinity:** Ligand B (-8.1 kcal/mol) has a significantly stronger binding affinity than Ligand A (-7.4 kcal/mol). This >1.5 kcal/mol difference is a major advantage for Ligand B, potentially outweighing some of its ADME drawbacks.

**Overall Assessment:**

While Ligand A has a better DILI profile, Ligand B is superior overall, especially considering the GPCR-specific priorities. Ligand B has significantly better BBB penetration, a longer half-life, stronger binding affinity, and a better QED score. The slightly higher logP and DILI risk are acceptable trade-offs for these advantages, particularly the strong affinity and BBB penetration.

Output:
1
2025-04-17 04:51:49,900 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (350.369 and 348.487 Da) fall comfortably within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (68.18) is higher than Ligand B (49.85). For a CNS target like DRD2, a TPSA below 90 is preferred, and ideally below 60. Ligand B is significantly better in this regard.

**3. logP:** Both ligands have good logP values (2.877 and 2.299), falling within the optimal 1-3 range.

**4. H-Bond Donors:** Ligand A has 2 HBD, and Ligand B has 0. Both are acceptable (<=5).

**5. H-Bond Acceptors:** Ligand A has 4 HBA, and Ligand B has 3. Both are acceptable (<=10).

**6. QED:** Ligand A (0.871) has a higher QED than Ligand B (0.663), indicating a more drug-like profile overall.

**7. DILI:** Ligand A (73.982) has a higher DILI risk than Ligand B (17.759). This is a significant advantage for Ligand B.

**8. BBB:** Both ligands have excellent BBB penetration (Ligand A: 90.617, Ligand B: 81.698), exceeding the >70% threshold for CNS targets. Ligand A is slightly better.

**9. Caco-2:** Both have negative Caco-2 values which is unusual and suggests poor permeability.

**10. Solubility:** Both ligands have negative solubility values, which is also unusual and suggests poor solubility.

**11. hERG:** Both ligands have low hERG inhibition risk (0.451 and 0.409).

**12. Cl_mic:** Ligand A (19.135) has a lower microsomal clearance than Ligand B (49.895), suggesting better metabolic stability.

**13. t1/2:** Ligand A (52.866) has a longer in vitro half-life than Ligand B (5.993). This is a significant advantage for Ligand A.

**14. Pgp:** Ligand A (0.166) has lower P-gp efflux liability than Ligand B (0.082), suggesting better CNS exposure.

**15. Binding Affinity:** Ligand A (-9.7 kcal/mol) has a significantly stronger binding affinity than Ligand B (-6.5 kcal/mol). This is a crucial advantage, as a >1.5 kcal/mol difference can outweigh other drawbacks.

**Overall Assessment:**

While Ligand A has a better half-life, Pgp efflux, and most importantly, *much* stronger binding affinity, Ligand B has a significantly lower DILI risk and a lower TPSA. Given the GPCR-specific priorities, the strong binding affinity of Ligand A is the most important factor. The slightly higher TPSA of Ligand A is less concerning than the higher DILI risk of Ligand A. The negative Caco-2 and solubility values are concerning for both, but can be addressed through formulation strategies.

Output:
1
2025-04-17 04:51:49,900 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (374.35 and 397.917 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (58.64) is significantly better than Ligand B (102.82). For CNS targets, we want TPSA <= 90, and A is comfortably within this range, while B exceeds it.

**logP:** Both ligands (2.352 and 2.85) are within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Both have acceptable HBD counts (1). Ligand B has a higher HBA count (9) compared to Ligand A (3), but both are still within the acceptable limit of <=10.

**QED:** Both ligands have similar QED values (0.696 and 0.685), indicating good drug-likeness.

**DILI:** Ligand A (31.02) has a much lower DILI risk than Ligand B (84.839). This is a significant advantage for A.

**BBB:** Ligand A (76.774) has a significantly higher BBB penetration percentile than Ligand B (65.723).  Given this is a CNS target, this is a crucial advantage. A value >70 is desirable, and A is closer to that threshold.

**Caco-2 Permeability:** Ligand A (-4.528) has a better (less negative) Caco-2 permeability than Ligand B (-5.302), indicating better intestinal absorption.

**Aqueous Solubility:** Ligand A (-2.104) has better aqueous solubility than Ligand B (-3.53).

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.488 and 0.292).

**Microsomal Clearance:** Ligand A (23.818) has a lower microsomal clearance than Ligand B (52.891), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (-22.934) has a much longer in vitro half-life than Ligand B (6.925).

**P-gp Efflux:** Ligand A (0.035) has lower P-gp efflux liability than Ligand B (0.258), which is favorable for CNS penetration.

**Binding Affinity:** Ligand B (-7.1) has a slightly better binding affinity than Ligand A (-7.8). However, the difference is only 0.7 kcal/mol, and the other advantages of Ligand A likely outweigh this.

**Overall:** Ligand A is significantly better across most ADMET properties, especially BBB penetration, DILI risk, metabolic stability, and P-gp efflux. While Ligand B has slightly better binding affinity, the substantial improvements in other crucial parameters for a CNS-targeting GPCR make Ligand A the more promising drug candidate.

Output:
1
2025-04-17 04:51:49,900 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (349.391 and 364.833 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (107.77) is slightly above the preferred <90 for CNS targets, while Ligand B (80.37) is well within the range. This favors Ligand B.

**logP:** Ligand A (-1.264) is quite low, potentially hindering membrane permeability. Ligand B (2.264) is within the optimal 1-3 range. This is a significant advantage for Ligand B.

**H-Bond Donors/Acceptors:** Ligand A has 2 HBD and 6 HBA, both acceptable. Ligand B has 1 HBD and 5 HBA, also acceptable.

**QED:** Both ligands have good QED scores (0.69 and 0.882), indicating drug-like properties.

**DILI:** Ligand A (25.553) has a much lower DILI risk than Ligand B (61.846). This is a strong positive for Ligand A.

**BBB:** Ligand A (49.011) and Ligand B (46.142) both have low BBB penetration, which is concerning for a CNS target like DRD2. Neither is above the desirable >70 percentile.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.197 and -5.086), which is unusual and suggests poor permeability.

**Aqueous Solubility:** Both ligands have negative solubility values (-0.795 and -3.094), indicating very poor aqueous solubility.

**hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.204 and 0.166).

**Microsomal Clearance:** Ligand A (-8.111) has a much lower (better) microsomal clearance than Ligand B (18.162), indicating greater metabolic stability.

**In vitro Half-Life:** Ligand A (-3.856) has a negative half-life, which is not physically possible. This is a major red flag. Ligand B (34.735) has a reasonable half-life.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.013 and 0.085), which is favorable for CNS penetration.

**Binding Affinity:** Ligand A (-8.5 kcal/mol) has a slightly better binding affinity than Ligand B (-7.7 kcal/mol). However, the difference is less than the 1.5 kcal/mol threshold where affinity strongly outweighs other factors.

**Overall Assessment:**

Despite Ligand A's slightly better affinity and lower DILI risk, its extremely poor (and impossible) in vitro half-life and low logP are major drawbacks. The negative solubility and Caco-2 values are also concerning. Ligand B, while having a higher DILI risk, has a more reasonable logP, a positive half-life, and acceptable H-bond characteristics. While both have poor BBB penetration, Ligand B's overall profile is more promising for further optimization. The negative values for solubility and Caco-2 for both ligands suggest experimental issues or significant limitations.

Output:
1
2025-04-17 04:51:49,900 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (395.204 Da) is slightly higher than Ligand B (349.391 Da), but both are acceptable.

**TPSA:** Ligand A (49.69) is excellent for CNS penetration, well below the 90 A^2 threshold. Ligand B (115.47) is higher, but still potentially acceptable, though less ideal.

**logP:** Ligand A (4.487) is a bit high, potentially leading to solubility issues or off-target interactions. Ligand B (-0.688) is quite low, which could hinder membrane permeability and CNS penetration.

**H-Bond Donors/Acceptors:** Both ligands have 2 HBD and 3/5 HBA, which are within acceptable limits.

**QED:** Both ligands have QED values above 0.6, indicating good drug-likeness.

**DILI:** Both ligands have acceptable DILI risk (Ligand A: 40.054, Ligand B: 45.56), below the 60 threshold.

**BBB:** Both ligands have reasonable BBB penetration (Ligand A: 50.019, Ligand B: 53.742). While not exceeding the desirable >70, they are not disqualifying.

**Caco-2 Permeability:** Ligand A (-4.679) shows poor Caco-2 permeability, which is concerning. Ligand B (-5.602) is also poor, but slightly worse.

**Aqueous Solubility:** Both ligands have poor aqueous solubility (Ligand A: -4.854, Ligand B: -2.172). This is a potential issue, especially given Ligand A's higher logP.

**hERG Inhibition:** Both ligands show very low hERG inhibition risk (Ligand A: 0.861, Ligand B: 0.022).

**Microsomal Clearance:** Ligand A (29.197) has moderate clearance, while Ligand B (-18.727) has negative clearance, suggesting high metabolic stability. This is a significant advantage for Ligand B.

**In vitro Half-Life:** Ligand B (-19.745) has a very long in vitro half-life, while Ligand A (33.867) is moderate. This further supports Ligand B's favorable metabolic profile.

**P-gp Efflux:** Both ligands show low P-gp efflux (Ligand A: 0.819, Ligand B: 0.004), which is good for CNS exposure.

**Binding Affinity:** Both ligands have comparable binding affinities (Ligand A: -8.8 kcal/mol, Ligand B: -8.0 kcal/mol). Ligand A is slightly better, but the difference is less than 1.5 kcal/mol.

**Overall Assessment:**

Ligand A has a slightly better binding affinity, but suffers from poor Caco-2 permeability and a higher logP. Ligand B, while having slightly weaker affinity, exhibits significantly better metabolic stability (lower Cl_mic, longer t1/2), lower P-gp efflux, and a more reasonable TPSA. Considering the GPCR-specific priorities for CNS targets, metabolic stability and BBB penetration are crucial. While both have similar BBB values, the improved metabolic profile of Ligand B makes it a more promising candidate. The lower logP of Ligand B, despite being negative, is less concerning than the high logP of Ligand A, given the importance of metabolic stability for CNS drugs.

Output:
1
2025-04-17 04:51:49,901 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (407.268 Da) is slightly higher, but acceptable. Ligand B (356.375 Da) is also good.

**TPSA:** Ligand A (96.11) is excellent for CNS penetration, being below the 90 A^2 threshold. Ligand B (120.03) is higher, but still potentially acceptable, though less ideal.

**logP:** Ligand A (2.836) is within the optimal range (1-3). Ligand B (-0.922) is below 1, which is a concern for permeability.

**H-Bond Donors/Acceptors:** Ligand A (HBD=3, HBA=4) is good. Ligand B (HBD=2, HBA=7) is also acceptable, though the higher HBA count could slightly impact permeability.

**QED:** Both ligands have reasonable QED scores (A: 0.665, B: 0.54), indicating decent drug-likeness.

**DILI:** Both ligands have acceptable DILI risk (A: 70.182, B: 47.499), below the concerning threshold of 60.

**BBB:** Ligand A (64.172) has a better BBB percentile than Ligand B (56.611), which is crucial for a CNS target like DRD2. While both are not >70, A is closer.

**Caco-2 Permeability:** Both have negative Caco-2 values (-5.112 and -5.381). This is unusual and suggests poor permeability, but the scale is not clearly defined. We'll consider this a neutral point for now.

**Aqueous Solubility:** Both have negative solubility values (-3.629 and -1.046). Similar to Caco-2, this is concerning, but the scale is unclear.

**hERG Inhibition:** Both ligands have very low hERG inhibition risk (A: 0.474, B: 0.022), which is excellent.

**Microsomal Clearance:** Ligand A (47.591) has higher clearance than Ligand B (19.686), suggesting lower metabolic stability.

**In vitro Half-Life:** Ligand B (-8.827) has a negative half-life, which is not physically possible and likely an error in the data. Ligand A (9.417) is reasonable.

**P-gp Efflux:** Ligand A (0.223) has lower P-gp efflux than Ligand B (0.016), which is favorable for CNS penetration.

**Binding Affinity:** Ligand A (-8.7 kcal/mol) has significantly stronger binding affinity than Ligand B (-7.1 kcal/mol). This is a substantial advantage (1.6 kcal/mol difference).

**Overall Assessment:**

Ligand A is the stronger candidate. It has better BBB penetration, significantly better binding affinity, lower P-gp efflux, and a reasonable half-life. While its TPSA is slightly higher and clearance is higher than Ligand B, the superior affinity and CNS penetration properties outweigh these drawbacks. Ligand B's negative logP and half-life are major concerns. The negative solubility and Caco-2 values for both are concerning but hard to interpret without knowing the scale.



Output:
1
2025-04-17 04:51:49,901 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B based on the provided guidelines, prioritizing GPCR-specific properties (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (382.917 Da) is slightly higher than Ligand B (350.423 Da), but both are acceptable.

**TPSA:** Ligand A (67.23) is significantly better than Ligand B (94.8). For CNS targets, we want TPSA <= 90, so Ligand A is much more favorable.

**logP:** Ligand A (1.96) is within the optimal range (1-3). Ligand B (-1.199) is below 1, which could hinder permeation. This is a significant negative for Ligand B.

**H-Bond Donors/Acceptors:** Both ligands have acceptable HBD (1) and HBA (5 for A, 7 for B) values, falling within the guidelines.

**QED:** Both ligands have good QED values (0.808 and 0.717), indicating good drug-like properties.

**DILI:** Ligand A (59.984) has a higher DILI risk than Ligand B (29.857). While both are below the concerning threshold of 60, Ligand B is preferable here.

**BBB:** Ligand A (51.842) and Ligand B (58.938) are both below the desirable threshold of 70 for CNS targets, but Ligand B is slightly better.

**Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and suggests poor permeability. However, the magnitude of negativity is important. Ligand A (-5.063) is worse than Ligand B (-4.917).

**Aqueous Solubility:** Both have negative solubility values, which is also unusual. Ligand A (-3.614) is slightly worse than Ligand B (-0.357).

**hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.367 and 0.137).

**Microsomal Clearance:** Ligand A (37.172) has higher clearance than Ligand B (3.008), indicating lower metabolic stability. Ligand B is significantly better.

**In vitro Half-Life:** Ligand A (-26.36) has a negative half-life, which is problematic. Ligand B (6.133) is positive and reasonable.

**P-gp Efflux:** Ligand A (0.207) has lower P-gp efflux than Ligand B (0.026), which is favorable for CNS penetration.

**Binding Affinity:** Ligand A (-8.1 kcal/mol) has a significantly stronger binding affinity than Ligand B (-6.7 kcal/mol). This is a substantial advantage, potentially outweighing some ADME drawbacks.

**Overall Assessment:**

Ligand A has a much better binding affinity and a more favorable TPSA. However, it suffers from worse Caco-2 permeability, solubility, and metabolic stability (higher Cl_mic, negative half-life). Ligand B has better DILI risk and metabolic stability, but its logP is concerningly low and its binding affinity is weaker.

Given the GPCR target and the importance of CNS penetration, the strong binding affinity of Ligand A is a major advantage. While its ADME properties are not ideal, the difference in binding affinity (-8.1 vs -6.7 kcal/mol) is substantial (1.4 kcal/mol difference), and could be optimized through further medicinal chemistry. The lower TPSA of Ligand A also supports better CNS penetration.

Output:
1
2025-04-17 04:51:49,901 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (369.462 and 357.47 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (62.74) is excellent, well below the 90 A^2 threshold for CNS targets. Ligand B (72.88) is still reasonable, but less optimal.

**logP:** Ligand A (3.525) is at the upper end of the optimal range (1-3), potentially raising solubility concerns, but still acceptable. Ligand B (0.792) is low, which could hinder membrane permeability and CNS penetration.

**H-Bond Donors/Acceptors:** Ligand A (0 HBD, 5 HBA) is favorable. Ligand B (2 HBD, 4 HBA) is also acceptable.

**QED:** Both ligands have QED values (0.815 and 0.707) above 0.5, indicating good drug-like properties.

**DILI:** Both ligands have low DILI risk (50.174 and 5.584 percentiles), which is positive.

**BBB:** Ligand A (83.443) has a very good BBB penetration score, exceeding the 70% threshold. Ligand B (71.966) is close but slightly below the desirable threshold.

**Caco-2:** Both ligands have negative Caco-2 values (-4.273 and -4.955), which is unusual and difficult to interpret without further context. However, negative values typically indicate poor permeability.

**Solubility:** Both ligands have negative solubility values (-3.979 and -0.957), which is also concerning.

**hERG:** Both ligands have low hERG inhibition liability (0.424 and 0.419), which is good.

**Microsomal Clearance:** Ligand A (85.547) has high microsomal clearance, suggesting rapid metabolism. Ligand B (-10.63) has negative clearance, which is not possible and likely an error.

**In vitro Half-Life:** Ligand A (-4.79) has a negative half-life, which is not possible. Ligand B (-2.698) also has a negative half-life.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.322 and 0.013), which is favorable for CNS penetration.

**Binding Affinity:** Ligand A (-8.1 kcal/mol) has a significantly stronger binding affinity than Ligand B (-7.4 kcal/mol). This 0.7 kcal/mol difference is substantial and could outweigh some of the ADME drawbacks.

**Overall Assessment:**

Despite the unusual negative values for Caco-2, solubility, and half-life, Ligand A appears to be the more promising candidate. Its superior BBB penetration, stronger binding affinity, and acceptable logP and TPSA values are key advantages for a CNS-targeting GPCR. The high microsomal clearance is a concern, but the strong binding affinity might compensate for it. Ligand B's low logP is a significant drawback, and its BBB score is borderline. The negative values for clearance and half-life are also problematic.

Output:
1
2025-04-17 04:51:49,901 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (333.435 Da) is slightly lower, which is generally favorable for permeability. Ligand B (360.479 Da) is also good.

**TPSA:** Ligand A (48.13) is excellent, well below the 90 A^2 threshold for CNS targets. Ligand B (73.66) is still reasonable, but less optimal.

**logP:** Both ligands have a logP around 3.3, which is within the optimal range of 1-3.

**H-Bond Donors/Acceptors:** Both have 2 HBDs, which is good. Ligand A has 2 HBAs, and Ligand B has 5 HBAs. Both are within the acceptable limit of 10, but Ligand A is preferable.

**QED:** Both ligands have good QED scores (A: 0.772, B: 0.857), indicating drug-like properties.

**DILI:** Ligand A (59.519) has a moderate DILI risk, while Ligand B (23.846) has a very low DILI risk. This is a significant advantage for Ligand B.

**BBB:** Ligand A (87.088) has excellent BBB penetration, exceeding the 70% threshold. Ligand B (40.946) is significantly lower, which is a major drawback for a CNS target.

**Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and suggests poor permeability. However, the scale is not defined, so it's hard to interpret.

**Aqueous Solubility:** Both have negative solubility values, indicating poor solubility. This is a concern for both.

**hERG:** Both have low hERG inhibition liability (A: 0.938, B: 0.47), which is good.

**Microsomal Clearance:** Ligand A (5.185) has lower microsomal clearance than Ligand B (80.623), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (20.613 hours) has a much longer half-life than Ligand B (-33.532 hours). The negative value for B is concerning and suggests rapid degradation.

**P-gp Efflux:** Ligand A (0.538) has lower P-gp efflux than Ligand B (0.279), which is favorable for CNS exposure.

**Binding Affinity:** Ligand A (-10.7 kcal/mol) has significantly stronger binding affinity than Ligand B (-7.7 kcal/mol). This is a substantial advantage, potentially outweighing some ADME concerns.

**Overall Assessment:**

Ligand A excels in key areas for a CNS GPCR target: TPSA, BBB penetration, metabolic stability, half-life, P-gp efflux, and, crucially, binding affinity. While its DILI risk is moderate and solubility is poor, the strong binding affinity and favorable CNS penetration properties are highly desirable. Ligand B has a better DILI profile, but its significantly lower BBB penetration, poor half-life, and weaker binding affinity make it a less promising candidate.

Output:
1
2025-04-17 04:51:49,902 - INFO - Reasoning:

Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (345.403 and 349.475 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (107.19) is higher than the preferred <90 for CNS targets, while Ligand B (71) is well within the range. This is a significant advantage for Ligand B.

**3. logP:** Ligand A (0.308) is quite low, potentially hindering membrane permeability. Ligand B (2.354) is within the optimal 1-3 range. This favors Ligand B.

**4. H-Bond Donors:** Ligand A (3) is acceptable, while Ligand B (1) is even better, suggesting potentially improved permeability.

**5. H-Bond Acceptors:** Both ligands (A: 5, B: 4) are within the acceptable limit of 10.

**6. QED:** Both ligands have similar, good QED values (A: 0.712, B: 0.717).

**7. DILI:** Ligand A (51.609) has a moderate DILI risk, while Ligand B (18.302) has a very low risk. This is a strong advantage for Ligand B.

**8. BBB:** Ligand A (25.94) has a very poor BBB penetration prediction, making it unlikely to reach the target in the CNS. Ligand B (73.943) has excellent predicted BBB penetration. This is a critical advantage for Ligand B, given DRD2 is a CNS target.

**9. Caco-2 Permeability:** Ligand A (-5.668) shows poor permeability, consistent with its low logP. Ligand B (-4.685) is slightly better, but still not ideal.

**10. Aqueous Solubility:** Both ligands have very poor aqueous solubility (-2.023 and -2.404 respectively). This could pose formulation challenges, but is less critical than BBB penetration for a CNS target.

**11. hERG Inhibition:** Both ligands have low hERG inhibition risk (A: 0.069, B: 0.322).

**12. Microsomal Clearance:** Ligand A (-12.383) has lower (better) microsomal clearance than Ligand B (45.655), suggesting greater metabolic stability.

**13. In vitro Half-Life:** Ligand A (-31.369) has a very short predicted half-life, while Ligand B (1.811) is slightly better, but still short.

**14. P-gp Efflux:** Both ligands show minimal P-gp efflux liability (A: 0.01, B: 0.076).

**15. Binding Affinity:** Ligand B (-8.8 kcal/mol) has a slightly better binding affinity than Ligand A (-8.0 kcal/mol). While the difference isn't huge, it contributes to the overall favorability of Ligand B.

**Overall Assessment:**

Ligand B is significantly more promising. Its superior BBB penetration, lower DILI risk, better logP, and lower TPSA outweigh the slightly worse metabolic stability and half-life compared to Ligand A. The affinity difference, while small, further supports choosing Ligand B. Given the CNS target (DRD2), BBB penetration is paramount, and Ligand B excels in this area.

Output:
1
2025-04-17 04:51:49,902 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (346.475 and 350.547 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (67.23) is slightly higher than the ideal <90 for CNS targets, but still reasonable. Ligand B (49.41) is excellent, well below the threshold.

**logP:** Ligand A (2.256) is within the optimal 1-3 range. Ligand B (4.28) is a bit high, potentially leading to solubility issues and off-target interactions, although not drastically so.

**H-Bond Donors/Acceptors:** Both ligands have acceptable HBD (1) and HBA (A: 4, B: 2) counts, well within the guidelines.

**QED:** Both ligands have reasonable QED scores (A: 0.823, B: 0.745), indicating good drug-like properties.

**DILI:** Ligand A (16.014) has a significantly lower DILI risk than Ligand B (21.791), which is a major advantage.

**BBB:** Ligand B (83.288) has a substantially better BBB penetration percentile than Ligand A (71.113). This is a critical factor for a CNS target like DRD2.

**Caco-2 Permeability:** Both have negative values, indicating poor permeability. This is unusual and needs further investigation, but we'll proceed with relative comparison.

**Aqueous Solubility:** Both have negative values, indicating poor solubility. This is also unusual and needs further investigation, but we'll proceed with relative comparison.

**hERG Inhibition:** Both ligands show low hERG inhibition risk (A: 0.32, B: 0.62).

**Microsomal Clearance:** Ligand B (75.869) has higher microsomal clearance than Ligand A (57.194), suggesting lower metabolic stability.

**In vitro Half-Life:** Ligand A (-7.706) has a longer in vitro half-life than Ligand B (-4.847).

**P-gp Efflux:** Both ligands have low P-gp efflux liability (A: 0.172, B: 0.444).

**Binding Affinity:** Ligand B (-8.3 kcal/mol) has a significantly stronger binding affinity than Ligand A (-7.7 kcal/mol). This is a substantial advantage, exceeding the 1.5 kcal/mol threshold.

**Overall Assessment:**

Ligand B excels in BBB penetration and binding affinity, two crucial factors for a DRD2 ligand. However, it suffers from higher logP, higher DILI risk, and faster metabolic clearance. Ligand A has a better safety profile (lower DILI) and better metabolic stability, but its BBB penetration and binding affinity are weaker.

The difference in binding affinity (-8.3 vs -7.7) is significant enough to outweigh the slightly higher logP and DILI risk of Ligand B, *especially* given the importance of potency for GPCR targets. The superior BBB penetration further solidifies Ligand B's potential.

Output:
1
2025-04-17 04:51:49,902 - INFO - Batch 149 complete. Total preferences: 2384
2025-04-17 04:51:49,902 - INFO - Processing batch 150/512...
2025-04-17 04:52:30,948 - INFO - Reasoning:

Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (346.39 and 350.46 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (104.54) is slightly above the optimal <90 for CNS targets, while Ligand B (96.11) is closer to the desired range.

**3. logP:** Ligand A (0.221) is quite low, potentially hindering membrane permeability. Ligand B (2.02) is within the optimal 1-3 range. This is a significant advantage for Ligand B.

**4. H-Bond Donors:** Ligand A (2) and Ligand B (3) are both acceptable, being less than 5.

**5. H-Bond Acceptors:** Ligand A (5) and Ligand B (4) are both acceptable, being less than 10.

**6. QED:** Both ligands have good QED scores (0.655 and 0.668), indicating drug-like properties.

**7. DILI:** Both have relatively low DILI risk (38.97 and 31.49 percentiles), which is good.

**8. BBB:** Ligand B (72.74%) is significantly better than Ligand A (48.35%) in terms of predicted BBB penetration, a crucial factor for CNS targets like DRD2.

**9. Caco-2 Permeability:** Both have negative Caco-2 values (-4.787 and -4.711). This is unusual and suggests a potential issue with the prediction method, or a very poor permeability.

**10. Aqueous Solubility:** Both have negative solubility values (-1.699 and -2.526) which is also unusual and suggests a potential issue with the prediction method, or a very poor solubility.

**11. hERG Inhibition:** Ligand A (0.028) has a very low hERG risk, while Ligand B (0.479) is slightly higher, but still relatively low.

**12. Microsomal Clearance:** Ligand A (27.34) has higher predicted clearance than Ligand B (21.46), suggesting lower metabolic stability.

**13. In vitro Half-Life:** Ligand B (-17.42) has a better (less negative) in vitro half-life than Ligand A (-43.04), indicating better stability.

**14. P-gp Efflux:** Ligand A (0.006) has very low P-gp efflux liability, which is good. Ligand B (0.112) is slightly higher, but still relatively low.

**15. Binding Affinity:** Both ligands have very similar and strong binding affinities (-7.8 and -7.7 kcal/mol). The difference is negligible.

**Overall Assessment:**

While both ligands have good binding affinity and acceptable DILI risks, Ligand B is significantly better overall. Its logP is optimal, its BBB penetration is much higher, and it has better metabolic stability (lower Cl_mic, better t1/2). Ligand A's low logP is a major concern for CNS penetration, despite its slightly lower P-gp efflux. The negative Caco-2 and solubility values are concerning for both, but the other ADME properties of Ligand B are superior. Given the GPCR-specific priorities, especially BBB penetration, Ligand B is the more promising candidate.

Output:
1
2025-04-17 04:52:30,949 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (343.471 Da) is slightly lower, which is generally favorable for permeability.

**2. TPSA:** Ligand A (62.3) is significantly better than Ligand B (104.81). For CNS targets, TPSA < 90 is preferred, and Ligand A is well within this range, while Ligand B is approaching the upper limit.

**3. logP:** Ligand A (2.702) is optimal (1-3), while Ligand B (-0.542) is quite low. A low logP can hinder membrane permeability and CNS penetration.

**4. H-Bond Donors:** Both ligands have acceptable HBD counts (Ligand A: 1, Ligand B: 2), well below the threshold of 5.

**5. H-Bond Acceptors:** Both ligands have acceptable HBA counts (Ligand A: 3, Ligand B: 5), below the threshold of 10.

**6. QED:** Both ligands have reasonable QED values (Ligand A: 0.789, Ligand B: 0.594), indicating good drug-like properties.

**7. DILI:** Ligand A (20.396) has a much lower DILI risk than Ligand B (30.593), which is a significant advantage.

**8. BBB:** Ligand A (76.037) has a better BBB percentile than Ligand B (67.468). Both are reasonably good, but >70 is desirable for CNS targets, and Ligand A is closer.

**9. Caco-2:** Ligand A (-4.743) and Ligand B (-5.15) both have negative Caco-2 values, which is unusual and suggests poor permeability. However, the scale isn't specified, so it's difficult to interpret.

**10. Solubility:** Ligand A (-2.446) and Ligand B (-1.886) both have negative solubility values, which is also unusual.

**11. hERG:** Both ligands have low hERG inhibition liability (Ligand A: 0.411, Ligand B: 0.163), which is good.

**12. Cl_mic:** Ligand A (61.541) has a higher microsomal clearance than Ligand B (22.438), indicating lower metabolic stability. This is a drawback for Ligand A.

**13. t1/2:** Ligand B (-18.849) has a longer in vitro half-life than Ligand A (-12.952), which is a positive for Ligand B.

**14. Pgp:** Ligand A (0.197) has lower P-gp efflux liability than Ligand B (0.011), which is beneficial for CNS penetration.

**15. Binding Affinity:** Ligand A (-8.5 kcal/mol) has a significantly stronger binding affinity than Ligand B (-7.7 kcal/mol). This is a substantial advantage, potentially outweighing some of the ADME drawbacks.

**Overall Assessment:**

Ligand A is the stronger candidate. While it has higher microsomal clearance, its superior TPSA, logP, BBB penetration, lower DILI risk, and significantly better binding affinity outweigh this disadvantage. The lower logP and solubility of Ligand B are concerning for CNS penetration and bioavailability. The substantial affinity difference (-0.8 kcal/mol) is a significant factor favoring Ligand A.

Output:
0
2025-04-17 04:52:30,949 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (350.463 and 356.388 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (76.46) is better than Ligand B (58.2). Both are below the 90 A^2 threshold for CNS targets, but Ligand B is closer to optimal.

**3. logP:** Ligand A (1.376) is within the optimal 1-3 range. Ligand B (3.005) is at the higher end of optimal, but still acceptable.

**4. H-Bond Donors:** Ligand A (1) is preferable to Ligand B (2). Fewer HBDs generally improve permeability.

**5. H-Bond Acceptors:** Ligand A (5) is preferable to Ligand B (2). Fewer HBAs generally improve permeability.

**6. QED:** Both ligands have similar QED values (0.806 and 0.789), indicating good drug-likeness.

**7. DILI:** Both ligands have low DILI risk (32.842 and 30.05), which is excellent.

**8. BBB:** Ligand B (85.964) has a significantly better BBB penetration percentile than Ligand A (75.107). This is a crucial advantage for a CNS target like DRD2.

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.524 and -4.58). This is unusual and suggests poor permeability. However, negative values are sometimes artifacts of the prediction method.

**10. Aqueous Solubility:** Both ligands have negative solubility values (-1.921 and -3.831). Similar to Caco-2, these are concerning and suggest poor solubility.

**11. hERG Inhibition:** Both ligands have low hERG inhibition risk (0.343 and 0.544).

**12. Microsomal Clearance:** Ligand A (37.385) has lower microsomal clearance than Ligand B (43.405), suggesting better metabolic stability.

**13. In vitro Half-Life:** Ligand A (9.197) has a positive half-life, while Ligand B (-9.266) has a negative half-life. This is a major red flag for Ligand B.

**14. P-gp Efflux:** Both ligands have low P-gp efflux liability (0.048 and 0.07).

**15. Binding Affinity:** Ligand B (-8.9 kcal/mol) has a significantly stronger binding affinity than Ligand A (-7.1 kcal/mol). This is a substantial advantage (1.8 kcal/mol difference).

**Overall Assessment:**

While Ligand A has better physicochemical properties (TPSA, HBD, HBA, Cl_mic, t1/2), Ligand B's significantly stronger binding affinity (-8.9 vs -7.1 kcal/mol) and superior BBB penetration (85.964 vs 75.107) are critical for a CNS GPCR target. The negative Caco-2 and solubility values are concerning for both, but the potency and BBB advantage of Ligand B outweigh these drawbacks. The negative half-life for Ligand B is a significant concern, but could potentially be addressed through structural modification.

Output:
1
2025-04-17 04:52:30,949 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (360.394 and 355.463 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (67.43) is slightly higher than Ligand B (63.13). Both are below the 90 A^2 threshold desirable for CNS targets, but B is better.

**3. logP:** Both ligands have good logP values (3.832 and 3.465), falling within the optimal 1-3 range.

**4. H-Bond Donors:** Both have 2 HBD, which is acceptable.

**5. H-Bond Acceptors:** Ligand A has 3 HBA, and Ligand B has 4. Both are below the 10 threshold.

**6. QED:** Ligand A (0.77) has a better QED score than Ligand B (0.544), indicating a more drug-like profile.

**7. DILI:** Ligand B (73.556) has a higher DILI risk than Ligand A (67.158), though both are reasonably acceptable.

**8. BBB:** Ligand B (81.97) has a significantly better BBB penetration percentile than Ligand A (56.766). This is a crucial advantage for a CNS target like DRD2.

**9. Caco-2 Permeability:** Ligand A (-4.753) has worse Caco-2 permeability than Ligand B (-5.044). Lower values are less desirable.

**10. Aqueous Solubility:** Ligand A (-3.848) has slightly better aqueous solubility than Ligand B (-4.114).

**11. hERG Inhibition:** Both ligands have low hERG inhibition risk (0.677 and 0.761).

**12. Microsomal Clearance:** Ligand B (78.99) has a slightly lower microsomal clearance than Ligand A (83.364), suggesting better metabolic stability.

**13. In vitro Half-Life:** Ligand B (58.241) has a significantly longer in vitro half-life than Ligand A (15.29).

**14. P-gp Efflux:** Both ligands have low P-gp efflux liability (0.451 and 0.735).

**15. Binding Affinity:** Both ligands have excellent binding affinity (-9.2 and -9.4 kcal/mol). The difference is minimal.

**Overall Assessment:**

While Ligand A has a better QED and slightly better solubility, Ligand B is superior due to its significantly better BBB penetration (81.97 vs 56.766), longer half-life (58.241 vs 15.29), and slightly improved metabolic stability (lower Cl_mic). For a CNS GPCR target like DRD2, BBB penetration is paramount. The small differences in other parameters are outweighed by this critical advantage.

Output:
1
2025-04-17 04:52:30,950 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (340.43 and 348.45 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (67.23) is significantly better than Ligand B (97.35). For CNS targets, we want TPSA <= 90, so Ligand A is preferable.

**logP:** Ligand A (1.83) is within the optimal 1-3 range, while Ligand B (0.75) is slightly below 1, potentially hindering permeation.

**H-Bond Donors/Acceptors:** Both have 1 HBD, which is good. Ligand A has 5 HBA, and Ligand B has 6. Both are acceptable (<=10).

**QED:** Both ligands have good QED scores (0.90 and 0.85), suggesting good drug-like properties.

**DILI:** Ligand A (61.07) has a higher DILI risk than Ligand B (35.60), but both are below the concerning threshold of 60.

**BBB:** Both ligands have excellent BBB penetration (75.11 and 71.73), which is crucial for a CNS target like DRD2.

**Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and difficult to interpret without knowing the scale. However, the magnitude of the negative value for Ligand A (-4.98) is less than that for Ligand B (-5.13), suggesting slightly better permeability.

**Aqueous Solubility:** Both ligands have negative solubility values, which is also unusual. Ligand B (-1.34) is slightly better than Ligand A (-3.46).

**hERG:** Both ligands have very low hERG inhibition risk (0.59 and 0.09).

**Microsomal Clearance:** Ligand A (48.18) has a significantly higher microsomal clearance than Ligand B (16.54), indicating lower metabolic stability.

**In vitro Half-Life:** Ligand B (-13.35) has a much longer in vitro half-life than Ligand A (-6.87).

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.21 and 0.04).

**Binding Affinity:** Ligand A (-8.7 kcal/mol) has a slightly better binding affinity than Ligand B (-7.9 kcal/mol). The difference is 0.8 kcal/mol, which is significant.

**Overall Assessment:**

Ligand A excels in TPSA, logP, and binding affinity. However, it suffers from higher DILI risk, higher microsomal clearance, and shorter half-life. Ligand B has better metabolic stability (lower Cl_mic, longer t1/2) and a lower DILI risk, but its logP is suboptimal and its TPSA is higher.

Given the GPCR-specific priorities, the slightly better affinity of Ligand A, combined with its superior TPSA and logP, outweighs its slightly worse metabolic properties. The BBB penetration is excellent for both. The 0.8 kcal/mol affinity difference is also a substantial advantage.

Output:
1
2025-04-17 04:52:30,950 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (352.519 and 348.487 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (69.64) is slightly higher than Ligand B (58.64), but both are below the 90 A^2 threshold desirable for CNS targets. Ligand B is preferable here.

**3. logP:** Both ligands have good logP values (2.861 and 2.368), falling within the optimal 1-3 range.

**4. H-Bond Donors:** Ligand A has 2 HBD, and Ligand B has 1. Both are within the acceptable limit of <=5.

**5. H-Bond Acceptors:** Both ligands have 3 HBA, well within the acceptable limit of <=10.

**6. QED:** Both ligands have similar QED values (0.706 and 0.719), indicating good drug-likeness.

**7. DILI:** Ligand A (7.949) has a significantly lower DILI risk than Ligand B (13.61). This is a substantial advantage for Ligand A.

**8. BBB:** Ligand B (83.598) has a notably higher BBB penetration percentile than Ligand A (74.37). This is a crucial factor for a CNS target like DRD2, making Ligand B more attractive.

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.649 and -4.648), which is unusual and suggests poor permeability. This is a concern for both.

**10. Aqueous Solubility:** Both ligands have negative solubility values (-2.498 and -3.343), indicating poor aqueous solubility. This is a significant drawback for both.

**11. hERG Inhibition:** Both ligands have low hERG inhibition risk (0.454 and 0.606).

**12. Microsomal Clearance:** Ligand A (37.674) has lower microsomal clearance than Ligand B (66.787), suggesting better metabolic stability.

**13. In vitro Half-Life:** Ligand B (-11.882) has a significantly longer in vitro half-life than Ligand A (-5.031). This is a positive for Ligand B.

**14. P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.184 and 0.245).

**15. Binding Affinity:** Both ligands have excellent binding affinities (-8.0 and -7.4 kcal/mol). Ligand A has a 0.6 kcal/mol advantage, which is significant.

**Overall Assessment:**

While both compounds have good affinity, the decision hinges on balancing CNS penetration (BBB) with safety (DILI) and metabolic stability. Ligand B excels in BBB penetration and has a longer half-life, which are critical for CNS drug development. However, Ligand A has a much lower DILI risk and better metabolic stability. The affinity difference (0.6 kcal/mol) is substantial enough to potentially overcome the slightly lower BBB and higher DILI of Ligand A, especially considering the poor solubility and permeability of both. Given the importance of minimizing liver toxicity, and the relatively small difference in binding affinity, I favor Ligand A.

Output:
0
2025-04-17 04:52:30,950 - INFO - Reasoning:

Let's analyze Ligand A and Ligand B for their potential as DRD2 drug candidates, considering the provided guidelines and GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight (MW):** Both ligands (344.415 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (99.24) is slightly higher than Ligand B (93.21). Both are below the 140 threshold for oral absorption and reasonably close to the 90 threshold for CNS targets, but Ligand B is preferable.

**3. logP:** Both ligands have good logP values (1.225 and 1.322, respectively), falling within the optimal 1-3 range.

**4. H-Bond Donors (HBD):** Both ligands have 2 HBD, which is within the acceptable limit of <=5.

**5. H-Bond Acceptors (HBA):** Ligand A has 6 HBA, and Ligand B has 5. Both are within the acceptable limit of <=10.

**6. QED:** Both ligands have good QED scores (0.702 and 0.759, respectively), indicating good drug-like properties.

**7. DILI:** Ligand A (43.04) has a lower DILI risk than Ligand B (63.04), which is preferable.

**8. BBB:** Ligand A (77.821) has a significantly better BBB penetration percentile than Ligand B (68.282). This is a *critical* factor for a CNS target like DRD2.

**9. Caco-2 Permeability:** Ligand A (-5.262) has worse Caco-2 permeability than Ligand B (-4.645).

**10. Aqueous Solubility:** Ligand A (-2.69) has worse aqueous solubility than Ligand B (-3.28).

**11. hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.453 and 0.125, respectively). Ligand B is slightly better.

**12. Microsomal Clearance (Cl_mic):** Ligand A (46.033) has lower microsomal clearance than Ligand B (53.498), indicating better metabolic stability.

**13. In vitro Half-Life:** Ligand A (-9.658) has a significantly longer in vitro half-life than Ligand B (-20.316). This is a significant advantage.

**14. P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.091 and 0.057, respectively). Ligand B is slightly better.

**15. Binding Affinity:** Both ligands have very similar and good binding affinities (-8.0 and -7.9 kcal/mol, respectively). The difference is negligible.

**Overall Assessment:**

While Ligand B has slightly better Caco-2 permeability, solubility, hERG, and P-gp efflux, Ligand A *significantly* outperforms it in BBB penetration and in vitro half-life. Given that DRD2 is a CNS target, BBB penetration is paramount. The longer half-life of Ligand A is also a substantial benefit. The lower DILI risk for Ligand A is also a positive. The small advantage in binding affinity for Ligand B is outweighed by the superior CNS properties of Ligand A.

Output:
1
2025-04-17 04:52:30,950 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B based on the provided guidelines, prioritizing GPCR-specific properties (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (357.451 and 348.462 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (91.34) is slightly above the optimal <90 for CNS targets, while Ligand B (40.62) is well within the desired range. This is a significant advantage for Ligand B.

**logP:** Ligand A (-0.79) is below the optimal 1-3 range, potentially hindering permeability. Ligand B (2.338) is within the optimal range. This favors Ligand B.

**H-Bond Donors/Acceptors:** Ligand A has 2 HBD and 6 HBA, both acceptable. Ligand B has 0 HBD and 2 HBA, also acceptable.

**QED:** Both ligands have good QED scores (0.621 and 0.663), indicating drug-like properties.

**DILI:** Ligand A (21.171) has a lower DILI risk than Ligand B (10.702), which is a positive attribute.

**BBB:** This is a critical parameter for CNS targets. Ligand A (24.506) has a very low BBB penetration, making it unlikely to reach the target in the brain. Ligand B (86.817) has excellent BBB penetration, a major advantage.

**Caco-2 Permeability:** Ligand A (-5.151) shows poor permeability, while Ligand B (-4.478) is slightly better, but still not great.

**Aqueous Solubility:** Ligand A (-0.007) and Ligand B (-3.054) both have poor solubility.

**hERG:** Ligand A (0.102) has a very low hERG risk, while Ligand B (0.672) has a slightly elevated risk, but still relatively low.

**Microsomal Clearance:** Ligand A (-17.901) has a negative clearance, which is unusual and suggests very high metabolic stability. Ligand B (39.815) has a moderate clearance.

**In vitro Half-Life:** Ligand A (9.682) has a moderate half-life, while Ligand B (-14.003) has a negative half-life, also unusual and suggesting very high stability.

**P-gp Efflux:** Ligand A (0.019) has very low P-gp efflux, which is favorable for CNS penetration. Ligand B (0.121) has slightly higher efflux.

**Binding Affinity:** Ligand B (-8.0) has a significantly stronger binding affinity than Ligand A (-7.2), exceeding the 1.5 kcal/mol advantage threshold.

**Overall Assessment:**

Ligand B is the superior candidate. While Ligand A has a lower DILI risk and very low P-gp efflux, its poor logP, TPSA, and *extremely* low BBB penetration are major drawbacks for a CNS target. Ligand B excels in the critical areas of BBB penetration, logP, and binding affinity. The stronger binding affinity of Ligand B can potentially compensate for its slightly higher P-gp efflux and moderate DILI risk. The unusual negative values for clearance and half-life for Ligand B warrant further investigation, but are initially positive signs of high stability.

Output:
1
2025-04-17 04:52:30,950 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (356.394 and 350.419 Da) fall comfortably within the ideal 200-500 Da range.

**TPSA:** Ligand A (99.1) is slightly higher than Ligand B (87.9). Both are below the 140 threshold for oral absorption, and closer to the desirable <90 for CNS targets, but Ligand B is preferable.

**logP:** Ligand A (-0.933) is a bit low, potentially hindering permeation. Ligand B (0.176) is better, falling within the optimal 1-3 range, though still on the lower side.

**H-Bond Donors/Acceptors:** Ligand A has 3 HBD and 5 HBA, while Ligand B has 1 HBD and 6 HBA. Both are within acceptable limits, but Ligand B has a more favorable HBD count.

**QED:** Both ligands have good QED scores (0.591 and 0.765), indicating good drug-like properties. Ligand B is slightly better.

**DILI:** Ligand A (14.618) has a significantly lower DILI risk than Ligand B (48.197), which is a substantial advantage.

**BBB:** Ligand A (46.336) has a lower BBB penetration percentile than Ligand B (56.572). While neither is above the highly desirable >70, Ligand B is better.

**Caco-2 Permeability:** Both have negative values (-5.23 and -4.529), indicating poor permeability. This is a concern for both.

**Aqueous Solubility:** Both have negative values (-1.088 and -1.056), indicating poor solubility. This is a concern for both.

**hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.282 and 0.137).

**Microsomal Clearance:** Ligand A (-9.604) has a much lower (better) microsomal clearance than Ligand B (24.381), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (7.215 hours) has a shorter half-life than Ligand B (10.641 hours).

**P-gp Efflux:** Ligand A (0.008) has a very low P-gp efflux liability, which is excellent for CNS penetration. Ligand B (0.153) is higher, but still relatively low.

**Binding Affinity:** Ligand B (-7.4 kcal/mol) has a slightly better binding affinity than Ligand A (-8.1 kcal/mol). While the difference is not huge, it's enough to consider.

**Overall Assessment:**

Ligand A excels in DILI risk and P-gp efflux, and has better metabolic stability (lower Cl_mic). However, its logP is suboptimal, and its BBB penetration is lower. Ligand B has a slightly better affinity, BBB, and QED, but a significantly higher DILI risk and poorer metabolic stability.

Given the GPCR-specific priorities, and the importance of minimizing off-target effects (DILI) and maximizing CNS exposure (P-gp, BBB), Ligand A is the more promising candidate despite its slightly lower affinity and BBB. The lower DILI risk and exceptionally low P-gp efflux are significant advantages for a CNS-targeting drug. The slightly lower logP can be addressed through further optimization.

Output:
0
2025-04-17 04:52:30,951 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (380.861 Da) is slightly higher than Ligand B (351.535 Da), but both are acceptable.

**TPSA:** Ligand A (111.06) is borderline for CNS penetration, being above the ideal <90. Ligand B (52.65) is excellent for CNS penetration. This is a significant advantage for Ligand B.

**logP:** Both ligands have good logP values (A: 2.466, B: 2.818), falling within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Both ligands have acceptable HBD (1) and HBA (A: 5, B: 3) counts.

**QED:** Both ligands have reasonable QED scores (A: 0.376, B: 0.718). Ligand B's QED is considerably better, indicating a more drug-like profile.

**DILI:** Both ligands have low DILI risk (A: 75.301, B: 6.437). Ligand B is significantly better here, suggesting lower potential for liver toxicity.

**BBB:** Ligand B (79.256) has a much better BBB percentile than Ligand A (41.722). This is a critical advantage for a CNS target like DRD2.

**Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual. It's difficult to interpret without knowing the scale, but it suggests poor permeability.

**Aqueous Solubility:** Both have negative solubility values, which is also unusual and suggests poor solubility.

**hERG:** Both ligands have low hERG inhibition liability (A: 0.261, B: 0.614), which is good.

**Microsomal Clearance:** Ligand A (6.711) has significantly lower microsomal clearance than Ligand B (23.924), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (-14.786) has a negative half-life, which is not physically possible and indicates an issue with the data. Ligand B (-10.998) also has a negative half-life.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (A: 0.26, B: 0.034). Ligand B is slightly better.

**Binding Affinity:** Both ligands have very similar and excellent binding affinities (A: -7.3 kcal/mol, B: -7.2 kcal/mol). The difference is negligible.

**Overall Assessment:**

While Ligand A has better metabolic stability (lower Cl_mic), Ligand B excels in crucial areas for a CNS-targeting GPCR ligand: TPSA, BBB, QED, and DILI. The negative half-life values are concerning for both, but the other advantages of Ligand B, particularly its superior BBB penetration and lower DILI risk, outweigh the slightly better metabolic stability of Ligand A. The similar binding affinities make the ADME properties the deciding factor.

Output:
1
2025-04-17 04:52:30,951 - INFO - Reasoning:

Let's analyze Ligand A and Ligand B for their potential as DRD2 drug candidates, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight (MW):** Both ligands (342.355 and 337.398 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (93.53) is slightly above the optimal <90 for CNS targets, but still reasonable. Ligand B (48.99) is excellent, well below 90.

**3. logP:** Ligand A (0.234) is quite low, potentially hindering membrane permeability. Ligand B (4.289) is a bit high, potentially causing solubility issues or off-target interactions, but closer to the optimal range of 1-3.

**4. H-Bond Donors (HBD):** Both ligands have 1 HBD, which is within the acceptable limit of <=5.

**5. H-Bond Acceptors (HBA):** Ligand A has 6 HBA, and Ligand B has 3 HBA, both within the acceptable limit of <=10.

**6. QED:** Both ligands have similar QED values (0.786 and 0.725), indicating good drug-like properties.

**7. DILI:** Both ligands have similar DILI risk (67.429 and 67.817), indicating moderate risk, but not alarmingly high.

**8. BBB:** This is a critical parameter for CNS targets. Ligand A has a BBB percentile of 64.482, which is below the desirable >70. Ligand B has a significantly higher BBB percentile of 91.663, making it much more promising for CNS penetration.

**9. Caco-2 Permeability:** Ligand A (-4.633) and Ligand B (-5.144) both have negative values, indicating poor permeability. This is concerning, but could be offset by other factors.

**10. Aqueous Solubility:** Both ligands have poor aqueous solubility (-2.226 and -3.586).

**11. hERG Inhibition:** Both ligands have low hERG inhibition risk (0.321 and 0.919).

**12. Microsomal Clearance:** Ligand A (29.542) has lower clearance than Ligand B (53.544), suggesting better metabolic stability.

**13. In vitro Half-Life:** Ligand A (-19.936) has a negative half-life, which is unusual and likely indicates rapid degradation. Ligand B (20.506) has a reasonable half-life.

**14. P-gp Efflux:** Ligand A (0.047) has very low P-gp efflux liability, which is excellent for CNS exposure. Ligand B (0.815) has moderate P-gp efflux liability.

**15. Binding Affinity:** Ligand B (-9.8 kcal/mol) has a significantly stronger binding affinity than Ligand A (-8.1 kcal/mol). This >1.5 kcal/mol difference is substantial and can outweigh some ADME drawbacks.

**Overall Assessment:**

While Ligand A has better metabolic stability and lower P-gp efflux, Ligand B is the superior candidate. The significantly higher BBB penetration (91.663 vs 64.482) and much stronger binding affinity (-9.8 vs -8.1 kcal/mol) are critical advantages for a DRD2 targeting drug. The slightly higher logP of Ligand B is a concern, but manageable. The poor solubility and Caco-2 permeability are drawbacks for both, but the improved CNS exposure potential of Ligand B is paramount.

Output:
1
2025-04-17 04:52:30,951 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 drug candidates, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (362.495 and 348.403 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (62.55) is significantly better than Ligand B (96.69).  For CNS targets, we want TPSA <= 90, and A is comfortably within that, while B is pushing the limit.

**3. logP:** Ligand A (2.523) is optimal (1-3), while Ligand B (0.216) is quite low, potentially hindering membrane permeability.

**4. H-Bond Donors:** Both have acceptable HBD counts (1 and 2, respectively), well below the threshold of 5.

**5. H-Bond Acceptors:** Both ligands have acceptable HBA counts (4 and 6, respectively), below the threshold of 10.

**6. QED:** Both ligands have good QED scores (0.845 and 0.793), indicating good drug-like properties.

**7. DILI:** Ligand A (23.226) has a much lower DILI risk than Ligand B (58.24).  A is well below the 40% threshold, while B is approaching a concerning level.

**8. BBB:** This is critical for a CNS target like DRD2. Ligand A (64.482) is reasonably good, while Ligand B (13.222) is very poor, suggesting limited brain penetration.

**9. Caco-2 Permeability:** Both have negative values, indicating poor permeability. However, the scale is not specified, so it's difficult to interpret the absolute impact.

**10. Aqueous Solubility:** Both have negative values, indicating poor solubility. Again, the scale is not specified.

**11. hERG Inhibition:** Both ligands show very low hERG inhibition risk (0.254 and 0.068, respectively).

**12. Microsomal Clearance:** Ligand A (32.204) has a higher clearance than Ligand B (11.525), suggesting potentially lower metabolic stability.

**13. In vitro Half-Life:** Ligand A (31.308) has a longer half-life than Ligand B (8.421).

**14. P-gp Efflux:** Ligand A (0.149) has lower P-gp efflux than Ligand B (0.019), which is favorable for CNS penetration.

**15. Binding Affinity:** Ligand B (-8.4 kcal/mol) has a slightly better binding affinity than Ligand A (-7.8 kcal/mol). The difference of 0.6 kcal/mol is not substantial enough to outweigh the significant ADME deficiencies of Ligand B.

**Overall Assessment:**

Ligand A is significantly better overall. While its clearance is higher, its superior TPSA, logP, BBB penetration, lower DILI risk, and lower P-gp efflux make it a much more promising candidate for a CNS-targeting drug like a DRD2 modulator. Ligand B's poor logP and extremely low BBB penetration are major drawbacks that are unlikely to be overcome. The slight affinity advantage of Ligand B is not enough to compensate for these issues.

Output:
1
2025-04-17 04:52:30,951 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (333.439 and 359.499 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (62.73) is significantly better than Ligand B (70.15). For CNS targets, we want TPSA <= 90, and A is closer to the ideal <=60 range.

**3. logP:** Ligand A (4.323) is slightly higher than the optimal 1-3 range, but still potentially acceptable. Ligand B (2.478) is well within the optimal range.

**4. H-Bond Donors:** Both ligands have 2 HBD, which is within the acceptable limit of <=5.

**5. H-Bond Acceptors:** Ligand A has 5 HBA, and Ligand B has 6. Both are within the acceptable limit of <=10.

**6. QED:** Both ligands have good QED values (0.63 and 0.855), indicating drug-like properties.

**7. DILI:** Ligand A (76.464) has a higher DILI risk than Ligand B (54.75). This is a negative for Ligand A.

**8. BBB:** Both ligands have very similar BBB penetration (68.166 and 68.437). While not exceeding the desirable >70, they are both reasonable.

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.117 and -5.135). This is unusual and suggests poor permeability.

**10. Aqueous Solubility:** Both ligands have negative solubility values (-4.334 and -3.422), indicating very poor aqueous solubility. This is a significant drawback for both.

**11. hERG Inhibition:** Both ligands have low hERG inhibition risk (0.861 and 0.8), which is good.

**12. Microsomal Clearance:** Ligand A (88.532) has higher microsomal clearance than Ligand B (48.046), indicating lower metabolic stability.

**13. In vitro Half-Life:** Ligand B (32.235) has a significantly longer in vitro half-life than Ligand A (62.641).

**14. P-gp Efflux:** Ligand A (0.753) has a slightly higher P-gp efflux liability than Ligand B (0.177). Lower is better for CNS penetration.

**15. Binding Affinity:** Ligand A (-8.0) has a significantly stronger binding affinity than Ligand B (-0.0). This is a major advantage for Ligand A.

**Overall Assessment:**

Despite the poor solubility and permeability indicated by the negative Caco-2 and solubility values, the significantly stronger binding affinity of Ligand A (-8.0 kcal/mol vs -0.0 kcal/mol) is a decisive factor. A binding affinity difference of 8 kcal/mol is substantial and can often outweigh ADME drawbacks, especially if optimization can improve solubility/permeability. Ligand B's better ADME profile is overshadowed by its extremely weak binding. The slightly higher DILI risk and P-gp efflux for Ligand A are less concerning than the lack of potency in Ligand B.

Output:
1
2025-04-17 04:52:30,951 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B based on the provided guidelines, prioritizing GPCR-specific properties (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (352.513 and 368.415 Da) fall within the ideal range of 200-500 Da.

**TPSA:** Ligand A (15.27) is significantly better than Ligand B (49.41). For CNS targets, TPSA should be <= 90, and ideally lower. Ligand A is excellent, while Ligand B is approaching the upper limit and could hinder BBB penetration.

**logP:** Ligand A (4.776) is slightly higher than the optimal range (1-3), but still acceptable. Ligand B (3.599) is within the optimal range. However, given the importance of BBB penetration, a slightly higher logP isn't as detrimental if other factors are favorable.

**H-Bond Donors/Acceptors:** Both ligands have 1 HBD and 2 HBA, which are within acceptable limits.

**QED:** Both ligands have reasonable QED scores (0.724 and 0.666), indicating good drug-like properties.

**DILI:** Ligand A (6.592) has a slightly higher DILI risk than Ligand B (24.893), but both are below the concerning threshold of 40.

**BBB:** Both ligands exhibit excellent BBB penetration (Ligand A: 95.269, Ligand B: 93.874). This is a critical factor for CNS targets like DRD2.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.672 and -4.415), which is unusual and suggests poor permeability. However, these values are on a log scale, and the absolute difference isn't huge.

**Aqueous Solubility:** Both ligands have very poor aqueous solubility (-3.319 and -3.654). This is a significant drawback, but can sometimes be overcome with formulation strategies.

**hERG Inhibition:** Both ligands show low hERG inhibition risk (0.99 and 0.594), which is favorable.

**Microsomal Clearance:** Ligand A (5.083) has a lower microsomal clearance than Ligand B (46.486), indicating better metabolic stability. This is a significant advantage.

**In vitro Half-Life:** Ligand A (33.901) has a longer in vitro half-life than Ligand B (-5.476), which is desirable.

**P-gp Efflux:** Ligand A (0.552) has lower P-gp efflux than Ligand B (0.09), which is better for CNS exposure.

**Binding Affinity:** Ligand A (-8.6 kcal/mol) has a significantly stronger binding affinity than Ligand B (-7.6 kcal/mol). This 1 kcal/mol difference is substantial and can outweigh some of the ADME drawbacks.

**Overall Assessment:**

Ligand A is the stronger candidate. While it has a slightly higher logP and DILI risk, its significantly superior binding affinity, lower microsomal clearance, longer half-life, lower P-gp efflux, and *much* lower TPSA make it a more promising drug candidate for DRD2. The lower TPSA is particularly important for CNS penetration, and the strong binding affinity provides a greater margin for overcoming potential ADME challenges.



Output:
1
2025-04-17 04:52:30,952 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (360.439 Da) is slightly lower, which could be beneficial for permeability, but both are acceptable.

**TPSA:** Ligand A (85.28) is excellent for CNS penetration, well below the 90 A^2 threshold. Ligand B (130.39) is higher, but still potentially acceptable, though less ideal.

**logP:** Ligand A (1.8) is within the optimal range (1-3). Ligand B (0.218) is quite low, potentially hindering membrane permeability and CNS entry. This is a significant drawback.

**H-Bond Donors/Acceptors:** Ligand A (0 HBD, 7 HBA) and Ligand B (3 HBD, 7 HBA) both have reasonable numbers of H-bond donors and acceptors, falling within acceptable limits.

**QED:** Both ligands have reasonable QED values (A: 0.73, B: 0.595), indicating good drug-like properties.

**DILI:** Ligand A (74.021) has a lower DILI risk than Ligand B (80.109), which is preferable.

**BBB:** This is crucial for a CNS target. Ligand A (70.764) has a good BBB percentile, exceeding the 70% threshold. Ligand B (11.865) is very poor, indicating limited brain penetration. This is a major disadvantage.

**Caco-2 Permeability:** Ligand A (-4.665) has poor Caco-2 permeability. Ligand B (-6.084) is even worse. Both are concerning, but the lower logP of B likely contributes to this.

**Aqueous Solubility:** Both ligands have similar, very poor aqueous solubility (-1.815 and -1.85). This will require formulation work.

**hERG Inhibition:** Both ligands show very low hERG inhibition risk (0.14 and 0.011).

**Microsomal Clearance:** Ligand A (67.495) has higher microsomal clearance than Ligand B (6.168), suggesting Ligand B is more metabolically stable.

**In vitro Half-Life:** Ligand A (-33.358) has a negative half-life (likely an error in the data), which is not useful. Ligand B (9.152) has a short half-life, but it's a positive value.

**P-gp Efflux:** Both ligands show low P-gp efflux liability (0.101 and 0.016), which is good.

**Binding Affinity:** Ligand B (-7.7 kcal/mol) has a significantly stronger binding affinity than Ligand A (-8.3 kcal/mol). This is a substantial advantage.

**Overall Assessment:**

Despite the superior binding affinity of Ligand B, its extremely poor BBB penetration (11.865%) and low logP (0.218) are major drawbacks for a CNS target like DRD2. The poor Caco-2 permeability also adds to the concern. Ligand A, while having a slightly weaker affinity, possesses a much more favorable BBB profile (70.764%) and a better logP (1.8). Although its Caco-2 permeability is also poor and solubility is low, the ability to cross the blood-brain barrier is paramount for CNS drug development. The negative half-life for Ligand A is suspect and would need further investigation.

Output:
1
2025-04-17 04:52:30,952 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 drug candidates, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (349.475 Da) is slightly lower, which could be advantageous for permeability, but both are acceptable.

**TPSA:** Ligand A (65.79) is significantly better than Ligand B (97.27). For CNS targets, we want TPSA <= 90, so Ligand A is much closer to this threshold.

**logP:** Both ligands have good logP values (A: 2.203, B: 1.023) falling within the optimal range of 1-3.

**H-Bond Donors/Acceptors:** Ligand A (HBD=1, HBA=4) is better than Ligand B (HBD=2, HBA=5). Both are within acceptable limits, but fewer H-bonds generally improve permeability.

**QED:** Both ligands have acceptable QED values (A: 0.855, B: 0.703), indicating good drug-like properties.

**DILI:** Ligand A (21.093) has a much lower DILI risk than Ligand B (36.603), which is a significant advantage. Both are below the 40% threshold, but A is preferable.

**BBB:** This is a critical parameter for CNS targets. Ligand A (63.94) is better than Ligand B (48.662), though ideally, we'd want >70. However, the difference is substantial.

**Caco-2 Permeability:** Ligand A (-4.866) and Ligand B (-5.167) both have negative values, which is unusual. It is difficult to interpret without knowing the scale.

**Aqueous Solubility:** Both ligands have negative solubility values (-1.347 and -1.633). This is concerning and would require further investigation.

**hERG Inhibition:** Ligand A (0.746) has a lower hERG risk than Ligand B (0.085), which is a positive.

**Microsomal Clearance:** Ligand A (0.305) has a much lower microsomal clearance than Ligand B (3.282), indicating better metabolic stability.

**In vitro Half-Life:** Ligand A (27.795) has a significantly longer half-life than Ligand B (14.046), which is desirable.

**P-gp Efflux:** Ligand A (0.194) has lower P-gp efflux than Ligand B (0.034), meaning better CNS exposure.

**Binding Affinity:** Both ligands have excellent binding affinity (-8.0 and -8.2 kcal/mol). The difference is minimal and doesn't outweigh the other significant differences.

**Overall:**

Ligand A consistently outperforms Ligand B across most critical ADME properties, especially BBB, DILI, metabolic stability (Cl_mic and t1/2), and P-gp efflux. While both have similar affinity, the superior ADME profile of Ligand A makes it a much more promising drug candidate for a CNS target like DRD2. The solubility is a concern for both, but manageable.

Output:
1
2025-04-17 04:52:30,952 - INFO - Batch 150 complete. Total preferences: 2400
2025-04-17 04:52:30,952 - INFO - Processing batch 151/512...
2025-04-17 04:53:11,725 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (361.4 and 368.8 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (91.32) is better than Ligand B (93.53), both are reasonably close to the <90 desired for CNS targets, but A is preferable.

**3. logP:** Ligand A (2.609) is optimal (1-3). Ligand B (0.748) is a bit low, potentially hindering permeation.

**4. H-Bond Donors:** Ligand A (3) is acceptable. Ligand B (1) is also good.

**5. H-Bond Acceptors:** Ligand A (5) is acceptable. Ligand B (6) is also acceptable.

**6. QED:** Both ligands have good QED scores (0.577 and 0.774), indicating good drug-like properties.

**7. DILI:** Ligand B (55.68) has a significantly lower DILI risk than Ligand A (75.456). This is a substantial advantage for Ligand B.

**8. BBB:** Ligand B (85.459) has a much better BBB penetration percentile than Ligand A (43.583). This is *critical* for a CNS target like DRD2.

**9. Caco-2 Permeability:** Ligand A (-5.399) is worse than Ligand B (-4.816), indicating lower intestinal absorption.

**10. Aqueous Solubility:** Ligand A (-4.116) is worse than Ligand B (-3.018), indicating lower solubility.

**11. hERG Inhibition:** Ligand A (0.435) is better than Ligand B (0.123), meaning lower risk of cardiotoxicity.

**12. Microsomal Clearance:** Ligand A (34.802) has lower clearance than Ligand B (37.045), suggesting better metabolic stability.

**13. In vitro Half-Life:** Ligand A (-7.14) has a longer half-life than Ligand B (4.808).

**14. P-gp Efflux:** Ligand A (0.149) has lower P-gp efflux than Ligand B (0.073), meaning better CNS exposure.

**15. Binding Affinity:** Ligand A (-9.8) has a significantly stronger binding affinity than Ligand B (-8.0). This is a major advantage for Ligand A.

**Overall Assessment:**

While Ligand A has a superior binding affinity and better metabolic stability, the significantly better BBB penetration (85.459 vs 43.583) and lower DILI risk of Ligand B are crucial for a CNS drug. The slightly lower logP of Ligand B is a concern, but the strong BBB penetration suggests it can still achieve adequate CNS exposure. The superior affinity of Ligand A is tempting, but the poor BBB penetration is a major drawback. For a GPCR in the CNS, getting the drug *to* the target is paramount.

Output:
1
2025-04-17 04:53:11,726 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (354.451 and 391.43 Da) fall within the ideal 200-500 Da range.

**TPSA:** Both ligands (113.76 and 117.62) are reasonably close to the 90 A^2 threshold for CNS targets, but slightly above. This isn't a dealbreaker, but it suggests potential permeability limitations.

**logP:** Ligand A (0.498) is a bit low, potentially hindering membrane permeability. Ligand B (0.792) is also on the lower side, but better than A. Ideally, we want 1-3.

**H-Bond Donors/Acceptors:** Both have 3 HBDs, which is good. Ligand A has 4 HBAs, and Ligand B has 7. While both are within the acceptable range, Ligand A is preferable.

**QED:** Ligand A (0.551) has a better QED score than Ligand B (0.421), indicating a more drug-like profile.

**DILI:** Ligand B (57.154) has a significantly higher DILI risk than Ligand A (20.279). This is a major concern for Ligand B.

**BBB:** Ligand A (73.788) has a much better BBB penetration percentile than Ligand B (32.028). This is *critical* for a CNS target like DRD2.

**Caco-2 Permeability:** Both have negative Caco-2 values (-5.484 and -5.746), which is unusual and suggests poor permeability. However, these values are on a scale where negative values are possible, and the absolute magnitude isn't directly comparable to percentile scores.

**Aqueous Solubility:** Both have negative solubility values (-1.853 and -1.793), indicating poor aqueous solubility. This could pose formulation challenges.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.329 and 0.272).

**Microsomal Clearance:** Ligand A (-14.215) has a much lower (better) microsomal clearance than Ligand B (13.304), suggesting greater metabolic stability.

**In vitro Half-Life:** Ligand B (17.492) has a significantly longer half-life than Ligand A (2.826). This is a positive for Ligand B.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.006 and 0.035). This is good, as it suggests better CNS exposure.

**Binding Affinity:** Both ligands have comparable binding affinities (-8.0 and -6.9 kcal/mol). Ligand A is significantly more potent. The 1.1 kcal/mol difference is substantial and can outweigh some ADME drawbacks.

**Overall Assessment:**

Ligand A is the stronger candidate. While both have issues with solubility and Caco-2 permeability, Ligand A's superior BBB penetration, lower DILI risk, better metabolic stability (lower Cl_mic), and significantly better binding affinity outweigh the longer half-life of Ligand B. The lower logP of Ligand A is a concern, but the strong binding affinity might compensate. For a CNS target, BBB penetration is paramount, and Ligand A excels in this area.

Output:
0
2025-04-17 04:53:11,726 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (354.4 and 347.3 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (50.8) is significantly better than Ligand B (105.64). For CNS targets, we want TPSA <= 90, and A is comfortably within that, while B exceeds it.

**3. logP:** Both ligands have acceptable logP values (3.04 and 0.767), falling within the 1-3 range, though B is on the lower end.

**4. H-Bond Donors:** Ligand A (1) and Ligand B (2) are both acceptable.

**5. H-Bond Acceptors:** Ligand A (3) and Ligand B (4) are both acceptable.

**6. QED:** Both ligands have good QED scores (0.908 and 0.785), indicating good drug-like properties.

**7. DILI:** Both ligands have acceptable DILI risk (56.7 and 49.0), below the 60 threshold.

**8. BBB:** Ligand A (85.1%) is significantly better than Ligand B (72.0%). For a CNS target like DRD2, >70% BBB penetration is desirable, and A is closer to this target.

**9. Caco-2 Permeability:** Ligand A (-4.15) and Ligand B (-5.241) are both negative, indicating poor permeability. However, the scale isn't specified, so it's hard to interpret.

**10. Aqueous Solubility:** Both ligands have poor aqueous solubility (-2.972 and -3.241). This could be a formulation challenge, but not a dealbreaker if other properties are strong.

**11. hERG Inhibition:** Both ligands have very low hERG risk (0.397 and 0.18).

**12. Microsomal Clearance:** Ligand A (42.48) is higher than Ligand B (0.169), indicating faster clearance and lower metabolic stability. This is a negative for A.

**13. In vitro Half-Life:** Ligand A (-8.007) is significantly better than Ligand B (32.731), indicating a longer half-life.

**14. P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.152 and 0.027).

**15. Binding Affinity:** Both ligands have excellent binding affinity (-9.3 kcal/mol). The difference is negligible.

**Overall Assessment:**

Ligand A is superior due to its significantly better TPSA and BBB penetration, both crucial for CNS GPCR targets. While Ligand A has a higher microsomal clearance, its longer half-life and comparable affinity outweigh this drawback. Ligand B's higher TPSA and lower BBB penetration are significant liabilities for a CNS-targeted drug.

Output:
1
2025-04-17 04:53:11,726 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (366.443 and 344.371 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (127.31) is slightly above the preferred <90 for CNS targets, while Ligand B (117.13) is closer, but still above. This is a minor drawback for both, but more significant for A.

**logP:** Ligand A (-0.205) is quite low, potentially hindering membrane permeability. Ligand B (1.628) is within the optimal 1-3 range. This is a significant advantage for B.

**H-Bond Donors/Acceptors:** Both have 3 HBDs, which is acceptable. Ligand A has 7 HBAs, while Ligand B has 4. Both are acceptable, but B is preferable.

**QED:** Ligand A (0.593) has a good drug-likeness score, while Ligand B (0.402) is below the 0.5 threshold, indicating a less favorable overall profile.

**DILI:** Ligand A (57.154) has a lower DILI risk than Ligand B (72.703), which is a positive for A.

**BBB:** Ligand B (57.464) has a significantly better BBB penetration percentile than Ligand A (24.855). This is *crucial* for a CNS target like DRD2 and heavily favors B.

**Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and suggests poor permeability. However, the scale is not specified, so it's difficult to interpret.

**Aqueous Solubility:** Both have negative solubility values, suggesting poor solubility. Again, the scale is not specified.

**hERG:** Ligand A (0.12) has a lower hERG risk than Ligand B (0.618), which is a positive for A.

**Microsomal Clearance:** Ligand A (-12.647) has a negative clearance, which is not possible and likely indicates an error in the data or a different unit. Ligand B (38.435) has a moderate clearance.

**In vitro Half-Life:** Ligand A (53.761) has a longer half-life than Ligand B (-8.622), but the negative value for B is problematic.

**P-gp Efflux:** Ligand A (0.074) has lower P-gp efflux liability than Ligand B (0.202), which is favorable for CNS penetration.

**Binding Affinity:** Ligand B (-9.3 kcal/mol) has a stronger binding affinity than Ligand A (-8.4 kcal/mol). This is a significant advantage for B, potentially outweighing some of its ADME drawbacks.

**Overall Assessment:**

Despite Ligand A's better QED, lower DILI, and lower P-gp efflux, Ligand B is the stronger candidate. The critical factors are:

*   **BBB:** Ligand B's significantly higher BBB penetration is paramount for a CNS target.
*   **logP:** Ligand B's logP is within the optimal range, while Ligand A's is too low.
*   **Affinity:** Ligand B has a substantially stronger binding affinity.
*   The negative values for clearance and half-life for Ligand B are concerning and should be investigated, but the affinity and BBB are strong enough to prioritize it.

Output:
1
2025-04-17 04:53:11,727 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (369.531 and 361.475 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (90.27) is excellent, falling below the 90 threshold for CNS targets. Ligand B (97.62) is still reasonable but less optimal, exceeding the preferred range.

**3. logP:** Both ligands have good logP values (2.417 and 1.418), falling within the 1-3 range.

**4. H-Bond Donors:** Ligand A (1) is preferable to Ligand B (2) as lower HBD generally improves permeability.

**5. H-Bond Acceptors:** Ligand B (8) is higher than Ligand A (4). Lower HBA is generally preferred.

**6. QED:** Both ligands have good QED scores (0.599 and 0.803), indicating good drug-like properties.

**7. DILI:** Ligand A (23.226) has a significantly lower DILI risk than Ligand B (62.621), which is a substantial advantage.

**8. BBB:** Ligand A (78.79) has a much better BBB percentile than Ligand B (57.736). This is *critical* for a CNS target like DRD2.

**9. Caco-2 Permeability:** Ligand A (-4.978) is better than Ligand B (-5.66), indicating slightly improved intestinal absorption.

**10. Aqueous Solubility:** Ligand A (-2.86) is better than Ligand B (-2.557), indicating better solubility.

**11. hERG Inhibition:** Ligand A (0.771) has a lower hERG inhibition liability than Ligand B (0.126), which is a positive.

**12. Microsomal Clearance:** Ligand A (34.707) has a higher (worse) microsomal clearance than Ligand B (2.816), suggesting lower metabolic stability.

**13. In vitro Half-Life:** Ligand A (-46.446) has a much longer in vitro half-life than Ligand B (15.632), which is a significant advantage.

**14. P-gp Efflux:** Ligand A (0.214) has a lower P-gp efflux liability than Ligand B (0.01), which is a positive.

**15. Binding Affinity:** Ligand B (-8.8 kcal/mol) has a stronger binding affinity than Ligand A (-7.1 kcal/mol). This is a 1.7 kcal/mol difference, which is substantial and could potentially outweigh some ADME drawbacks.

**Overall Assessment:**

While Ligand B has a better binding affinity, Ligand A is the superior candidate. The significantly better BBB penetration (78.79 vs 57.736), much lower DILI risk (23.226 vs 62.621), longer half-life, and better solubility/permeability properties of Ligand A outweigh the affinity difference. For a CNS target like DRD2, achieving sufficient brain exposure is paramount, and Ligand A is far more likely to achieve this. The lower DILI risk is also a crucial safety consideration.

Output:
0
2025-04-17 04:53:11,727 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (354.382 and 354.401 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (103.68) is higher than the preferred <90 for CNS targets, while Ligand B (79.53) is well within the range. This is a significant advantage for Ligand B.

**3. logP:** Ligand A (0.574) is quite low, potentially hindering membrane permeability. Ligand B (2.018) is much better, falling within the optimal 1-3 range.

**4. H-Bond Donors:** Ligand A (3) is acceptable, while Ligand B (1) is even better, potentially improving permeability.

**5. H-Bond Acceptors:** Both ligands have 4 HBA, which is within the acceptable limit of <=10.

**6. QED:** Both ligands have good QED scores (0.666 and 0.877), indicating good drug-like properties. Ligand B is slightly better.

**7. DILI:** Both ligands show low DILI risk (30.244 and 34.781), which is favorable.

**8. BBB:** Ligand A (59.364) has a moderate BBB penetration, while Ligand B (94.339) is excellent, exceeding the desirable >70 threshold for CNS targets. This is a major advantage for Ligand B.

**9. Caco-2 Permeability:** Ligand A (-5.235) has poor Caco-2 permeability, while Ligand B (-4.806) is slightly better, but still not great.

**10. Aqueous Solubility:** Both ligands have poor aqueous solubility (-1.708 and -2.002). This could pose formulation challenges, but is less critical than BBB penetration for a CNS target.

**11. hERG Inhibition:** Both ligands have low hERG inhibition risk (0.102 and 0.63).

**12. Microsomal Clearance:** Ligand A (-17.009) has a very low (good) microsomal clearance, indicating high metabolic stability. Ligand B (-9.971) is also good, but not as favorable as Ligand A.

**13. In vitro Half-Life:** Ligand A (16.784) has a good in vitro half-life, while Ligand B (-8.824) is poor.

**14. P-gp Efflux:** Ligand A (0.003) has very low P-gp efflux, which is excellent for CNS exposure. Ligand B (0.042) also has low P-gp efflux, but slightly higher than Ligand A.

**15. Binding Affinity:** Ligand A (-7.9) and Ligand B (-8.4) both have excellent binding affinities. Ligand B is slightly stronger, but the difference is relatively small.

**Overall Assessment:**

Ligand B is the superior candidate. While Ligand A has better metabolic stability and P-gp efflux, Ligand B excels in critical areas for a CNS-targeting GPCR ligand: TPSA, logP, and especially BBB penetration. The significantly higher BBB score for Ligand B outweighs the slight advantages of Ligand A in metabolic stability and P-gp efflux. The better logP of Ligand B also contributes to its improved predicted permeability.

Output:
1
2025-04-17 04:53:11,727 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (342.443 and 347.419 Da) fall comfortably within the ideal 200-500 Da range.

**TPSA:** Ligand A (85.23) is better than Ligand B (87.54), both are below the 90 A^2 threshold for CNS targets, which is good.

**logP:** Ligand A (2.494) is optimal (1-3), while Ligand B (0.019) is very low, potentially hindering permeation. This is a significant disadvantage for Ligand B.

**H-Bond Donors/Acceptors:** Ligand A (HBD=2, HBA=3) and Ligand B (HBD=1, HBA=5) both have reasonable numbers of H-bond donors and acceptors, well within the acceptable limits.

**QED:** Ligand A (0.881) has a higher QED than Ligand B (0.705), indicating a more drug-like profile.

**DILI:** Ligand A (32.105) has a lower DILI risk than Ligand B (44.126), both are acceptable, but A is preferable.

**BBB:** Ligand A (53.083) and Ligand B (58.821) are both below the desirable >70 percentile for CNS targets, but not drastically.

**Caco-2 Permeability:** Ligand A (-4.711) is better than Ligand B (-5.224), indicating better intestinal absorption.

**Aqueous Solubility:** Ligand A (-3.382) is better than Ligand B (-0.996), which is a significant advantage for formulation.

**hERG Inhibition:** Ligand A (0.407) has a lower hERG risk than Ligand B (0.049), which is a positive attribute.

**Microsomal Clearance:** Ligand A (0.022) has a much lower microsomal clearance than Ligand B (10.739), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (18.938) has a longer half-life than Ligand B (15.894).

**P-gp Efflux:** Ligand A (0.024) has lower P-gp efflux liability than Ligand B (0.019), which is beneficial for CNS exposure.

**Binding Affinity:** Ligand A (-8.7 kcal/mol) has a significantly stronger binding affinity than Ligand B (-7.4 kcal/mol). This 1.3 kcal/mol difference is substantial and can outweigh minor ADME drawbacks.

**Conclusion:**

Considering all factors, especially the GPCR-specific priorities, **Ligand A is the more promising drug candidate.** It has superior logP, QED, DILI, solubility, hERG risk, metabolic stability, half-life, P-gp efflux, and, most importantly, binding affinity. While both ligands have suboptimal BBB penetration, the significant advantages of Ligand A in other critical parameters make it the better choice.

Output:
1
2025-04-17 04:53:11,727 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (346.39 and 342.44 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (106.34) is higher than Ligand B (67.43). For CNS targets, we prefer TPSA <= 90, so Ligand B is significantly better here.

**logP:** Ligand A (-0.219) is quite low, potentially hindering permeation. Ligand B (2.364) is within the optimal 1-3 range. This favors Ligand B.

**H-Bond Donors/Acceptors:** Both have 2 HBDs, which is good. Ligand A has 4 HBAs, and Ligand B has 3. Both are acceptable (<=10).

**QED:** Both ligands have similar QED values (0.772 and 0.748), indicating good drug-likeness.

**DILI:** Ligand A (49.86) and Ligand B (56.84) both have acceptable DILI risk, below the 60 threshold.

**BBB:** Ligand B (67.62) has a better BBB percentile than Ligand A (50.68), though both are below the desirable >70 for CNS targets. However, Ligand B is closer.

**Caco-2 Permeability:** Both have negative Caco-2 values (-4.944 and -4.67), which is unusual and suggests poor permeability. This is a concern for both.

**Aqueous Solubility:** Both have negative solubility values (-2.999 and -3.036), also unusual and indicating poor solubility.

**hERG:** Both ligands have low hERG inhibition liability (0.122 and 0.317), which is good.

**Microsomal Clearance:** Ligand A (-15.014) has a much lower (better) microsomal clearance than Ligand B (57.6). This indicates better metabolic stability for Ligand A.

**In vitro Half-Life:** Ligand A (-3.417) has a negative half-life, which is not physically possible and suggests an issue with the data. Ligand B (-10.564) is also negative, indicating a data problem for both.

**P-gp Efflux:** Both have very low P-gp efflux liability (0.008 and 0.177), which is favorable for CNS penetration.

**Binding Affinity:** Ligand A (-9.0 kcal/mol) has a significantly stronger binding affinity than Ligand B (-8.8 kcal/mol). This is a substantial advantage.

**Overall Assessment:**

Despite the questionable solubility and permeability data for both, Ligand A is more promising. The significantly stronger binding affinity (-9.0 vs -8.8 kcal/mol) is a major advantage, and the lower microsomal clearance suggests better metabolic stability. While Ligand B has a better TPSA and logP, the affinity difference outweighs these benefits, especially for a GPCR target where potency is crucial. The BBB values are both suboptimal, but Ligand B is slightly better. The negative half-life and solubility values are concerning for both, and would require further investigation.

Output:
1
2025-04-17 04:53:11,727 - INFO - Reasoning:

Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (359.455 and 364.446 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (92.07) is slightly above the optimal <90 for CNS targets, but still reasonable. Ligand B (76.02) is excellent, well below 90.

**3. logP:** Both ligands have good logP values (1.872 and 1.759), falling within the 1-3 range.

**4. H-Bond Donors:** Ligand A (3) and Ligand B (2) are both acceptable, being less than 5.

**5. H-Bond Acceptors:** Ligand A (6) and Ligand B (5) are both acceptable, being less than 10.

**6. QED:** Both ligands have good QED scores (0.626 and 0.867), indicating drug-like properties. Ligand B is better.

**7. DILI:** Both ligands have similar DILI risk (64.986 and 65.568), placing them in a moderate risk category, but not alarming.

**8. BBB:** This is critical for a CNS target like DRD2. Ligand A has a BBB percentile of 48.74, which is below the desirable >70. Ligand B has a much better BBB percentile of 72.237, exceeding the threshold.

**9. Caco-2 Permeability:** Both have negative values, which is unusual. Assuming these are logP values, they indicate poor permeability.

**10. Aqueous Solubility:** Both ligands have negative solubility values, indicating poor solubility.

**11. hERG Inhibition:** Both ligands have low hERG inhibition liability (0.211 and 0.485), which is positive.

**12. Microsomal Clearance:** Ligand A (10.029) has a moderate clearance, while Ligand B (-14.448) has a *negative* clearance, which is highly unusual and suggests exceptional metabolic stability.

**13. In vitro Half-Life:** Ligand A (85.188) has a good half-life. Ligand B (6.028) has a very short half-life.

**14. P-gp Efflux:** Both ligands have low P-gp efflux liability (0.205 and 0.046), which is favorable for CNS penetration.

**15. Binding Affinity:** Both ligands have excellent binding affinities (-9.1 and -9.6 kcal/mol). Ligand B is slightly better (-9.6 vs -9.1).

**Overall Assessment:**

While both ligands have good binding affinity and acceptable physicochemical properties, Ligand B is significantly more promising due to its superior BBB penetration (72.237 vs 48.74), better QED, and exceptionally low (negative) microsomal clearance, indicating high metabolic stability. The shorter half-life of Ligand B is a drawback, but the metabolic stability might compensate for this. Ligand A's lower BBB penetration is a major concern for a CNS target.

Output:
1
2025-04-17 04:53:11,728 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (348.443) is slightly better positioned.

**TPSA:** Ligand B (64.09) is significantly better than Ligand A (87.66). For CNS targets, we want TPSA <= 90, and Ligand B is comfortably within this range, while A is approaching the upper limit.

**logP:** Both ligands have acceptable logP values (Ligand A: 2.314, Ligand B: 0.892). Ligand A is slightly better, falling within the optimal 1-3 range, while Ligand B is a bit low, potentially impacting permeability.

**H-Bond Donors/Acceptors:** Ligand A (HBD=3, HBA=4) is slightly better than Ligand B (HBD=1, HBA=5) in terms of balance.

**QED:** Both ligands have good QED scores (Ligand A: 0.736, Ligand B: 0.778), indicating good drug-like properties.

**DILI:** Ligand B (5.894) has a much lower DILI risk than Ligand A (33.773). This is a significant advantage for Ligand B.

**BBB:** Ligand A (77.821) has a better BBB percentile than Ligand B (62.233). This is a crucial factor for CNS targets like DRD2, and gives A a substantial edge.

**Caco-2 Permeability:** Ligand A (-4.276) shows better Caco-2 permeability than Ligand B (-4.9).

**Aqueous Solubility:** Ligand A (-3.097) has better aqueous solubility than Ligand B (-1.028).

**hERG:** Both ligands have low hERG inhibition liability (Ligand A: 0.236, Ligand B: 0.187).

**Microsomal Clearance:** Ligand B (10.415) has significantly lower microsomal clearance than Ligand A (47.131), indicating better metabolic stability.

**In vitro Half-Life:** Ligand B (-11.501) has a longer in vitro half-life than Ligand A (-32.653).

**P-gp Efflux:** Ligand A (0.04) has lower P-gp efflux than Ligand B (0.006), which is favorable for CNS penetration.

**Binding Affinity:** Ligand A (-8.5 kcal/mol) has a significantly stronger binding affinity than Ligand B (-6.1 kcal/mol). This is a major advantage for Ligand A, potentially outweighing some of its ADME drawbacks.

**Overall Assessment:**

The decision is close. Ligand A excels in binding affinity and BBB penetration, which are critical for a CNS GPCR target. It also has better Caco-2 permeability and solubility. However, Ligand B demonstrates a much better safety profile (lower DILI), improved metabolic stability (lower Cl_mic, longer t1/2), and a lower TPSA. The affinity difference is substantial (>2 kcal/mol), and for a GPCR, strong binding is paramount. While Ligand B's lower logP and BBB are concerns, the strong affinity of Ligand A makes it the more promising candidate.

Output:
1
2025-04-17 04:53:11,728 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B based on the provided guidelines, prioritizing GPCR-specific properties (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (340.423 Da) is slightly lower, which could be beneficial for permeability.

**TPSA:** Ligand A (67.43) is significantly better than Ligand B (122.76). For CNS targets, TPSA should be <=90, so Ligand A is much more favorable.

**logP:** Both ligands have acceptable logP values (Ligand A: 1.885, Ligand B: 1.085), falling within the 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A (HBD=2, HBA=3) is better than Ligand B (HBD=3, HBA=9) in terms of balancing solubility and permeability. Ligand B has a higher number of HBA, which could potentially hinder permeability.

**QED:** Both ligands have similar QED values (Ligand A: 0.614, Ligand B: 0.601), indicating good drug-likeness.

**DILI:** Ligand B (68.825) has a higher DILI risk than Ligand A (55.332), though both are reasonably acceptable.

**BBB:** Ligand B (61.535) has a slightly better BBB penetration than Ligand A (49.864), but both fall short of the desirable >70 for CNS targets.

**Caco-2 Permeability:** Ligand A (-4.66) has a better Caco-2 permeability than Ligand B (-5.478), indicating better intestinal absorption.

**Aqueous Solubility:** Ligand A (-3.109) has better aqueous solubility than Ligand B (-2.787).

**hERG Inhibition:** Both ligands have very low hERG inhibition risk (Ligand A: 0.171, Ligand B: 0.138).

**Microsomal Clearance:** Ligand B (18.132) has a higher microsomal clearance than Ligand A (13.432), suggesting lower metabolic stability.

**In vitro Half-Life:** Ligand A (-1.375) has a better in vitro half-life than Ligand B (-23.202).

**P-gp Efflux:** Ligand A (0.058) has lower P-gp efflux liability than Ligand B (0.012), which is favorable for CNS exposure.

**Binding Affinity:** Both ligands have very similar and strong binding affinities (Ligand A: -8.5 kcal/mol, Ligand B: -8.0 kcal/mol). The difference is less than 1.5 kcal/mol, so it's not a deciding factor.

**Overall Assessment:**

Ligand A is superior due to its significantly lower TPSA, better Caco-2 permeability, better solubility, better metabolic stability (lower Cl_mic, higher t1/2), and lower P-gp efflux. While Ligand B has a slightly better BBB score, the other advantages of Ligand A, particularly the TPSA, outweigh this difference for a CNS GPCR target like DRD2.

Output:
1
2025-04-17 04:53:11,728 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (349.479 and 342.483 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (79.26) is better than Ligand B (58.2). Both are below the 90 A^2 threshold desirable for CNS targets, but Ligand B is significantly lower, which is a plus.

**logP:** Ligand A (1.432) is within the optimal 1-3 range. Ligand B (3.901) is at the higher end of the optimal range, potentially raising concerns about solubility and off-target effects, but still acceptable.

**H-Bond Donors/Acceptors:** Both ligands have 2 HBDs and 5/2 HBAs, respectively, which are within acceptable limits.

**QED:** Both ligands have good QED scores (0.626 and 0.852), indicating good drug-like properties.

**DILI:** Ligand A (16.053) has a much lower DILI risk than Ligand B (39.667), which is a significant advantage.

**BBB:** Ligand B (83.288) has a substantially better BBB penetration percentile than Ligand A (57.736). This is a critical factor for a CNS target like DRD2.

**Caco-2 Permeability:** Ligand A (-5.083) has poor Caco-2 permeability, while Ligand B (-4.4) is also poor, but slightly better.

**Aqueous Solubility:** Ligand A (-1.499) has slightly better aqueous solubility than Ligand B (-5.056).

**hERG:** Both ligands have low hERG inhibition risk (0.285 and 0.598).

**Microsomal Clearance:** Ligand A (6.006) has lower microsomal clearance than Ligand B (64.117), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand B (34.83) has a significantly longer in vitro half-life than Ligand A (1.598).

**P-gp Efflux:** Ligand A (0.008) has very low P-gp efflux, which is excellent for CNS penetration. Ligand B (0.427) is higher, but still relatively low.

**Binding Affinity:** Ligand B (-9.1 kcal/mol) has a significantly stronger binding affinity than Ligand A (-7.6 kcal/mol). This is a substantial advantage, potentially outweighing some ADME drawbacks.

**Overall Assessment:**

Ligand B excels in BBB penetration and binding affinity, the two most critical factors for a CNS GPCR target. While its DILI risk is higher and Caco-2 permeability is poor, the strong affinity and good BBB penetration are likely to be more impactful for efficacy. Ligand A has better metabolic stability and lower DILI, but its significantly weaker binding affinity and poor BBB penetration make it less promising. The difference in binding affinity (>1.5 kcal/mol) is a major deciding factor.

Output:
1
2025-04-17 04:53:11,728 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 drug candidates, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (363.487 and 384.929 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (88.91) is better than Ligand B (67.43) as it is closer to the <90 A^2 threshold for CNS targets.

**3. logP:** Both ligands have good logP values (2.145 and 3.397), falling within the optimal 1-3 range. Ligand B is slightly higher, which *could* be a minor concern for solubility, but isn't a dealbreaker.

**4. H-Bond Donors:** Both have 2 HBD, which is within the acceptable limit of <=5.

**5. H-Bond Acceptors:** Ligand A has 6 HBA, and Ligand B has 4. Both are below the 10 threshold.

**6. QED:** Both ligands have reasonable QED values (0.823 and 0.708), indicating good drug-like properties.

**7. DILI:** Ligand A (49.593) has a significantly lower DILI risk than Ligand B (65.374). This is a substantial advantage.

**8. BBB:** Both ligands have similar BBB penetration (57.464 and 58.55), which is acceptable but not outstanding. Ideally, we'd want >70 for a CNS target.

**9. Caco-2:** Both have negative Caco-2 values (-5.234 and -5.214), which is unusual and suggests very poor permeability. This is a significant drawback for both compounds.

**10. Solubility:** Both have negative solubility values (-2.585 and -3.795), indicating very poor aqueous solubility. This is a major concern for both.

**11. hERG:** Both ligands have low hERG inhibition risk (0.571 and 0.329).

**12. Cl_mic:** Ligand B (36.411) has a lower microsomal clearance than Ligand A (46.608), suggesting better metabolic stability.

**13. t1/2:** Ligand B (24.816) has a longer in vitro half-life than Ligand A (21.112).

**14. Pgp:** Both ligands have very low P-gp efflux liability (0.071 and 0.403), which is excellent for CNS penetration.

**15. Binding Affinity:** Ligand B (-8.3 kcal/mol) has a significantly stronger binding affinity than Ligand A (-7.0 kcal/mol). This is a >1.3 kcal/mol advantage, which is substantial and can outweigh some ADME concerns.

**Overall Assessment:**

Ligand B has a significantly better binding affinity and slightly better metabolic stability and half-life. However, Ligand A has a much lower DILI risk and a slightly better TPSA. Both compounds have poor solubility and Caco-2 permeability, which are major drawbacks. Given the importance of binding affinity for GPCRs, and the substantial difference in affinity between the two ligands, Ligand B is the more promising candidate *despite* the higher DILI risk. The DILI risk could potentially be mitigated through structural modifications. The poor solubility and permeability are more challenging, but could also be addressed with prodrug strategies or formulation approaches.

Output:
1
2025-04-17 04:53:11,728 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (341.375 Da) is slightly better, being closer to the lower end which can aid permeability.

**2. TPSA:** Ligand A (101.7) is significantly better than Ligand B (133.91). For CNS targets, TPSA should be <=90, so Ligand A is closer to this threshold.

**3. logP:** Ligand A (0.192) is quite low, potentially hindering permeation. Ligand B (-2.206) is even lower, raising concerns about absorption. Both are suboptimal, but Ligand A is slightly better.

**4. H-Bond Donors:** Ligand A (1) is good. Ligand B (3) is acceptable but less ideal.

**5. H-Bond Acceptors:** Both ligands have 7 HBA, which is within the acceptable range.

**6. QED:** Ligand A (0.733) is significantly better than Ligand B (0.387), indicating a more drug-like profile.

**7. DILI:** Ligand A (70.105) is better than Ligand B (41.838), indicating a lower risk of drug-induced liver injury.

**8. BBB:** Ligand A (53.974) is better than Ligand B (35.401), although both are below the desirable >70 percentile for CNS targets. This is a critical factor for DRD2.

**9. Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and suggests poor permeability. Ligand A (-5.349) is slightly better than Ligand B (-5.507).

**10. Aqueous Solubility:** Both have negative solubility values, also unusual. Ligand A (-2.706) is slightly better than Ligand B (-1.347).

**11. hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.292 and 0.032, respectively), which is excellent.

**12. Microsomal Clearance:** Ligand A (4.69) has a much lower clearance than Ligand B (44.321), suggesting better metabolic stability.

**13. In vitro Half-Life:** Ligand A (6.929) has a better half-life than Ligand B (-51.506).

**14. P-gp Efflux:** Ligand A (0.082) has lower P-gp efflux than Ligand B (0.004), which is favorable for CNS penetration.

**15. Binding Affinity:** Ligand B (-7.2 kcal/mol) has a slightly better binding affinity than Ligand A (-7.9 kcal/mol). While a difference of 0.7 kcal/mol isn't huge, it's a positive for Ligand B.

**Overall Assessment:**

Despite Ligand B's slightly better affinity, Ligand A is the more promising candidate. Ligand A demonstrates superior drug-likeness (QED), lower DILI risk, better BBB penetration (though still suboptimal), significantly better metabolic stability (lower Cl_mic and higher t1/2), and lower P-gp efflux. While both have issues with logP and permeability, Ligand A's overall profile is more favorable for CNS drug development, especially considering the GPCR-specific priorities. The better ADME properties of Ligand A are likely to translate to better *in vivo* exposure at the target site, even with the slightly weaker binding affinity.



Output:
0
2025-04-17 04:53:11,729 - INFO - Reasoning:

Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (358.427 and 365.375 Da) fall comfortably within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (94.82) is higher than the preferred <90 for CNS targets, but not drastically so. Ligand B (56.07) is excellent, well below the threshold. This favors Ligand B.

**3. logP:** Both ligands (2.562 and 2.698) are within the optimal 1-3 range. No significant difference here.

**4. H-Bond Donors:** Ligand A has 1 HBD, which is good. Ligand B has 0, also good.

**5. H-Bond Acceptors:** Ligand A has 8 HBA, acceptable. Ligand B has 6 HBA, also acceptable.

**6. QED:** Both ligands have good QED scores (0.728 and 0.751), indicating good drug-like properties.

**7. DILI:** Ligand A (89.802) has a higher DILI risk than Ligand B (35.867). This is a significant advantage for Ligand B.

**8. BBB:** This is crucial for a CNS target like DRD2. Ligand B (95.308) has excellent BBB penetration, exceeding the desirable >70% threshold. Ligand A (45.134) is considerably lower, raising concerns about CNS exposure. This is a major advantage for Ligand B.

**9. Caco-2 Permeability:** Both have negative values, indicating poor permeability. However, the scale is not specified, making direct comparison difficult.

**10. Aqueous Solubility:** Both have negative values, indicating poor solubility. Again, the scale is not specified.

**11. hERG Inhibition:** Ligand A (0.334) has a slightly lower hERG risk than Ligand B (0.595), which is a minor benefit.

**12. Microsomal Clearance:** Ligand B (24.522) has significantly lower microsomal clearance than Ligand A (63.988), suggesting better metabolic stability. This favors Ligand B.

**13. In vitro Half-Life:** Ligand B (-4.014) has a longer half-life than Ligand A (-17.454), which is a significant advantage.

**14. P-gp Efflux:** Ligand A (0.161) has lower P-gp efflux than Ligand B (0.215), which is slightly better for CNS exposure.

**15. Binding Affinity:** Ligand A (-8.6 kcal/mol) has a slightly better binding affinity than Ligand B (-7.5 kcal/mol). This is a 1.1 kcal/mol difference, which is significant, but needs to be weighed against the ADME properties.

**Overall Assessment:**

While Ligand A has a slightly better binding affinity, Ligand B overwhelmingly wins on ADME properties critical for a CNS-targeting GPCR. Specifically, its superior BBB penetration, lower DILI risk, better metabolic stability (lower Cl_mic and longer t1/2), and acceptable TPSA make it a much more promising drug candidate. The 1.1 kcal/mol difference in binding affinity is unlikely to overcome the significant ADME advantages of Ligand B.

Output:
1
2025-04-17 04:53:11,729 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (352.475 and 350.419 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (66.92) is significantly better than Ligand B (104.65). For CNS targets, we want TPSA <= 90, and A is comfortably within that range, while B exceeds it.

**3. logP:** Ligand A (2.239) is optimal (1-3), while Ligand B (0.996) is slightly low, potentially hindering permeation.

**4. H-Bond Donors:** Ligand A (0) is preferable to Ligand B (2). Fewer HBDs generally improve permeability.

**5. H-Bond Acceptors:** Ligand A (4) is better than Ligand B (6). Lower HBA is generally preferred.

**6. QED:** Both ligands have good QED scores (A: 0.471, B: 0.688), indicating reasonable drug-likeness. B is slightly better here.

**7. DILI:** Ligand A (19.504) has a much lower DILI risk than Ligand B (37.146). This is a significant advantage for A.

**8. BBB:** Ligand A (75.107) has a substantially higher BBB penetration percentile than Ligand B (39.473). This is *critical* for a CNS target like DRD2.

**9. Caco-2:** Ligand A (-4.293) and Ligand B (-5.359) both have negative values, which is unusual. It's difficult to interpret without knowing the scale, but generally lower (more negative) values indicate poorer permeability.

**10. Solubility:** Both have negative solubility values (-1.982 and -1.658), again making interpretation difficult without knowing the scale.

**11. hERG:** Both ligands show very low hERG inhibition liability (A: 0.328, B: 0.07). This is good.

**12. Cl_mic:** Ligand A (85.586) has a higher microsomal clearance than Ligand B (19.993), suggesting faster metabolism and potentially lower *in vivo* exposure. This favors B.

**13. t1/2:** Ligand A (-15.672) has a negative half-life, which is not physically possible and suggests an issue with the data or model. Ligand B (0.397) has a very short half-life. Both are poor.

**14. Pgp:** Ligand A (0.063) shows lower P-gp efflux liability than Ligand B (0.016), which is beneficial for CNS penetration.

**15. Binding Affinity:** Ligand B (-7.4 kcal/mol) has a slightly better binding affinity than Ligand A (-6.9 kcal/mol). While a 1.5 kcal/mol difference is significant, the other ADME properties are more critical in this case.

**Overall Assessment:**

Despite Ligand B having slightly better binding affinity and QED, Ligand A is the superior candidate. The significantly better TPSA, logP, DILI risk, and *especially* BBB penetration make it much more likely to reach the target in the CNS. The problematic half-life for both is concerning, but can be addressed through structural modifications. Ligand B's higher TPSA and lower BBB are major drawbacks for a CNS-targeting drug.

Output:
1
2025-04-17 04:53:11,729 - INFO - Batch 151 complete. Total preferences: 2416
2025-04-17 04:53:11,729 - INFO - Processing batch 152/512...
2025-04-17 04:53:51,808 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (370.396 Da) and Ligand B (351.451 Da) are both acceptable.

**TPSA:** Ligand A (51.22) is significantly better than Ligand B (90.7). For CNS targets, TPSA should be <= 90, so Ligand A is much more favorable.

**logP:** Ligand A (4.127) is slightly high, potentially leading to solubility issues, but still within a reasonable range. Ligand B (0.347) is too low, potentially hindering membrane permeability and CNS penetration.

**H-Bond Donors/Acceptors:** Ligand A (HBD=1, HBA=4) is better than Ligand B (HBD=2, HBA=5). Both are within acceptable limits, but fewer H-bonds generally improve permeability.

**QED:** Both ligands have good QED scores (Ligand A: 0.588, Ligand B: 0.774).

**DILI:** Ligand A (68.786) has a higher DILI risk than Ligand B (18.108). This is a negative for Ligand A, but not a deal-breaker at this stage.

**BBB:** Ligand A (80.419) has a much better BBB percentile than Ligand B (46.762). This is *critical* for a CNS target like DRD2.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.991 and -4.842). These values are unusual and difficult to interpret without further information, but suggest poor permeability.

**Aqueous Solubility:** Both ligands have negative solubility values (-4.904 and -0.434), indicating very poor aqueous solubility. This is a concern for both.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (Ligand A: 0.681, Ligand B: 0.26).

**Microsomal Clearance:** Ligand A (55.039) has a higher microsomal clearance than Ligand B (5.76), suggesting lower metabolic stability.

**In vitro Half-Life:** Ligand A (9.639) has a longer half-life than Ligand B (-2.158).

**P-gp Efflux:** Ligand A (0.273) has lower P-gp efflux than Ligand B (0.007), which is favorable for CNS penetration.

**Binding Affinity:** Ligand A (-9.1 kcal/mol) has a significantly stronger binding affinity than Ligand B (-7.1 kcal/mol). This is a substantial advantage.

**Overall Assessment:**

Despite the higher DILI risk and clearance for Ligand A, its superior BBB penetration, TPSA, P-gp efflux, and *much* stronger binding affinity make it the more promising candidate. The low logP of Ligand B is a significant drawback for CNS penetration, and its weaker binding affinity is less desirable. The solubility issues are concerning for both, but can potentially be addressed with formulation strategies. The negative Caco-2 values are also concerning. However, the affinity and BBB are the most important factors here, and Ligand A clearly wins.

Output:
1
2025-04-17 04:53:51,808 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (349.475 and 344.455 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Both ligands have TPSA values (78.51 and 78.43) below the 90 A^2 threshold for CNS targets, which is excellent.

**3. logP:** Ligand A (1.59) is optimal, while Ligand B (2.925) is also within the acceptable range (1-3).

**4. H-Bond Donors:** Both ligands have 2-3 HBD, which is within the acceptable limit of <=5.

**5. H-Bond Acceptors:** Both ligands have 3 HBA, which is within the acceptable limit of <=10.

**6. QED:** Both ligands have QED values (0.685 and 0.603) above 0.5, indicating good drug-likeness.

**7. DILI:** Ligand A (15.083) has a much lower DILI risk than Ligand B (20.24), both being good (<40).

**8. BBB:** Ligand A (69.407) has a slightly lower BBB percentile than Ligand B (67.623), but both are below the desirable >70 for CNS targets.

**9. Caco-2 Permeability:** Ligand A (-5.023) has worse Caco-2 permeability than Ligand B (-4.647).

**10. Aqueous Solubility:** Ligand A (-1.96) has better aqueous solubility than Ligand B (-3.116).

**11. hERG Inhibition:** Both ligands have low hERG inhibition liability (0.262 and 0.526).

**12. Microsomal Clearance:** Ligand A (17.404) has significantly lower microsomal clearance than Ligand B (48.759), suggesting better metabolic stability.

**13. In vitro Half-Life:** Ligand A (-5.891) has a longer in vitro half-life than Ligand B (8.73).

**14. P-gp Efflux:** Ligand A (0.019) has much lower P-gp efflux liability than Ligand B (0.42), which is crucial for CNS penetration.

**15. Binding Affinity:** Ligand B (-8.4 kcal/mol) has a slightly better binding affinity than Ligand A (-7.5 kcal/mol). The difference is 0.9 kcal/mol, which is significant.

**Overall Assessment:**

While Ligand B has a slightly better binding affinity, Ligand A is superior in almost all other crucial ADME properties, particularly those important for CNS drugs. Ligand A exhibits lower DILI risk, better metabolic stability (lower Cl_mic, longer t1/2), significantly lower P-gp efflux, and better solubility. The difference in binding affinity (0.9 kcal/mol) is likely outweighed by the substantial improvements in ADME properties, especially P-gp efflux and metabolic stability, which will translate to better brain exposure.

Output:
0
2025-04-17 04:53:51,809 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (336.435 Da) is slightly lower, which could be beneficial for permeability.

**TPSA:** Ligand A (49.41) is excellent for CNS penetration, well below the 90 A^2 threshold. Ligand B (122.83) is higher, but still potentially acceptable, though less ideal.

**logP:** Ligand A (2.663) is optimal. Ligand B (-0.898) is quite low, potentially hindering membrane permeability and CNS entry.

**H-Bond Donors/Acceptors:** Ligand A (HBD=1, HBA=2) is favorable. Ligand B (HBD=3, HBA=6) is also acceptable, but slightly higher counts could impact permeability.

**QED:** Ligand A (0.679) is good, indicating drug-likeness. Ligand B (0.46) is lower, suggesting a less ideal drug-like profile.

**DILI:** Ligand A (42.264) has a low DILI risk. Ligand B (19.775) also has a low DILI risk.

**BBB:** Ligand A (63.203) has moderate BBB penetration. Ligand B (74.758) has better BBB penetration, exceeding the 70% threshold desirable for CNS targets.

**Caco-2 Permeability:** Ligand A (-4.603) indicates poor Caco-2 permeability. Ligand B (-5.737) is even worse.

**Aqueous Solubility:** Ligand A (-4.153) indicates poor solubility. Ligand B (-1.723) is better, but still not ideal.

**hERG Inhibition:** Both ligands have very low hERG inhibition risk (Ligand A: 0.223, Ligand B: 0.028).

**Microsomal Clearance:** Ligand A (16.808) has moderate clearance. Ligand B (-3.724) has negative clearance, which is not physically possible and likely indicates an issue with the prediction or data.

**In vitro Half-Life:** Ligand A (5.396 hours) is a reasonable half-life. Ligand B (-5.277 hours) is also not physically possible.

**P-gp Efflux:** Ligand A (0.109) has low P-gp efflux, which is good for CNS penetration. Ligand B (0.002) has very low P-gp efflux, even better.

**Binding Affinity:** Ligand A (-8.5 kcal/mol) has a significantly stronger binding affinity than Ligand B (-7.7 kcal/mol). This 0.8 kcal/mol difference is substantial and could outweigh some ADME drawbacks.

**Overall Assessment:**

Ligand A has a better overall profile, despite the lower BBB and Caco-2 permeability. Its superior binding affinity (-8.5 kcal/mol vs -7.7 kcal/mol) is a major advantage, especially for a GPCR target. The logP value is optimal, and the DILI risk is low. The TPSA is excellent for CNS penetration. While the Caco-2 and solubility are not ideal, the strong binding and favorable P-gp efflux could compensate. Ligand B has issues with negative values for clearance and half-life, which are not possible and indicate a significant problem with the prediction.

Output:
1
2025-04-17 04:53:51,809 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (361.389 and 352.435 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Both ligands have TPSA values (87.74 and 85.69) below the 90 A^2 threshold for CNS targets, which is good.

**3. logP:** Ligand A (1.416) is within the optimal range (1-3). Ligand B (0.121) is quite low, potentially hindering permeation.

**4. H-Bond Donors:** Both ligands have acceptable HBD counts (2 and 1, respectively), well below the 5 limit.

**5. H-Bond Acceptors:** Both ligands have acceptable HBA counts (4 and 6, respectively), below the 10 limit.

**6. QED:** Both ligands have QED values (0.775 and 0.682) above 0.5, indicating good drug-likeness.

**7. DILI:** Ligand A (38.581) has a slightly higher DILI risk than Ligand B (22.334), but both are below the concerning threshold of 60.

**8. BBB:** Ligand A (72.082) has a significantly better BBB percentile than Ligand B (51.997). This is a crucial factor for a CNS target like DRD2.

**9. Caco-2 Permeability:** Ligand A (-4.755) has a worse Caco-2 permeability than Ligand B (-5.34), but both are poor.

**10. Aqueous Solubility:** Ligand A (-2.338) has better aqueous solubility than Ligand B (0.326).

**11. hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.2 and 0.129, respectively).

**12. Microsomal Clearance:** Ligand A (-21.192) has a much lower (better) microsomal clearance than Ligand B (-1.539), indicating greater metabolic stability.

**13. In vitro Half-Life:** Ligand A (-33.322) has a much longer in vitro half-life than Ligand B (20.468).

**14. P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.031 and 0.008, respectively).

**15. Binding Affinity:** Both ligands have similar and strong binding affinities (-8.0 and -7.6 kcal/mol). The difference is less than 1.5 kcal/mol, so it doesn't significantly sway the decision.

**Overall Assessment:**

Ligand A is clearly the more promising candidate. While Ligand B has a slightly better DILI score, Ligand A excels in crucial areas for CNS drug development: significantly better BBB penetration, much improved metabolic stability (lower Cl_mic and longer t1/2), and better aqueous solubility. The logP value for Ligand A is also more favorable. The similar binding affinities make these ADME properties the deciding factors.

Output:
1
2025-04-17 04:53:51,809 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (340.39 Da) is slightly better, being closer to the lower end which can aid permeability.

**TPSA:** Ligand A (113.24) is significantly better than Ligand B (139.96). For CNS targets, TPSA should be <= 90, and Ligand A is closer to this threshold.

**logP:** Both ligands have similar logP values (0.443 and 0.389), which are a bit low. Ideally, logP should be between 1-3. This could indicate potential permeability issues for both, but isn't a major differentiator here.

**H-Bond Donors/Acceptors:** Both have 3 HBDs, which is acceptable. Ligand B has 8 HBAs compared to Ligand A's 5. While both are within the acceptable range of <=10, fewer HBAs are generally preferred for better membrane permeability.

**QED:** Both ligands have reasonable QED scores (0.684 and 0.594), indicating good drug-like properties.

**DILI:** Ligand B (86.39) has a significantly higher DILI risk than Ligand A (56.15). This is a major concern.

**BBB:** Ligand A (78.56) has a much better BBB penetration score than Ligand B (50.68). This is *critical* for a CNS target like DRD2.

**Caco-2 Permeability:** Both have negative Caco-2 values (-5.514 and -5.662), which is unusual and suggests poor permeability. However, these values are on a scale where negative values are possible, and direct comparison is difficult without knowing the scale's specifics.

**Aqueous Solubility:** Both have very poor aqueous solubility (-2.637 and -2.643). This could pose formulation challenges.

**hERG Inhibition:** Both ligands show low hERG inhibition liability (0.271 and 0.362), which is good.

**Microsomal Clearance:** Ligand A (32.814) has a higher microsomal clearance than Ligand B (8.095), meaning it's metabolized faster. This is a negative for Ligand A.

**In vitro Half-Life:** Ligand B (10.647) has a longer in vitro half-life than Ligand A (-17.418). This is a significant advantage for Ligand B.

**P-gp Efflux:** Both have very low P-gp efflux liability (0.006 and 0.129), which is favorable for CNS penetration.

**Binding Affinity:** Ligand A (-9.9 kcal/mol) has a significantly stronger binding affinity than Ligand B (-8.4 kcal/mol). This is a substantial advantage, potentially outweighing some of the ADME drawbacks.

**Overall Assessment:**

Ligand A is the stronger candidate. While it has a higher microsomal clearance and lower half-life, its significantly better BBB penetration, lower DILI risk, and *much* stronger binding affinity outweigh these drawbacks. The TPSA is also more favorable. The poor solubility and Caco-2 permeability are concerns for both, but the affinity difference is substantial. For a CNS target, BBB penetration is paramount, and Ligand A excels in this area.

Output:
0
2025-04-17 04:53:51,810 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (356.5 and 345.4 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (61.6) is significantly better than Ligand B (80.12). For CNS targets, we want TPSA <= 90, and A is much closer to the ideal <= 60 range. B is pushing the upper limit.

**logP:** Both ligands have good logP values (2.33 and 1.38), falling within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Both have acceptable HBD (2 and 1) and HBA (5 and 5) counts.

**QED:** Both ligands have reasonable QED scores (0.867 and 0.757), indicating good drug-like properties.

**DILI:** Ligand A (64.5) has a higher DILI risk than Ligand B (37.1), which is a negative for A.

**BBB:** Ligand A (84.8%) has a substantially better BBB penetration score than Ligand B (54.0%). This is *critical* for a CNS target like DRD2.

**Caco-2 Permeability:** Ligand A (-4.95) and Ligand B (-5.14) both have very poor Caco-2 permeability. This is a concern for oral bioavailability, but less critical for a CNS target where direct delivery or other routes may be considered.

**Aqueous Solubility:** Ligand A (-3.91) is slightly better than Ligand B (-1.56), but both are quite poor.

**hERG:** Ligand A (0.89) has a slightly higher hERG risk than Ligand B (0.06), which is a negative for A.

**Microsomal Clearance:** Ligand B (33.6) has lower microsomal clearance than Ligand A (48.4), indicating better metabolic stability.

**In vitro Half-Life:** Ligand B (3.66) has a shorter half-life than Ligand A (-9.11), which is a negative for B. Note that negative values here likely indicate a very long half-life.

**P-gp Efflux:** Ligand A (0.46) has lower P-gp efflux than Ligand B (0.02), which is favorable for CNS penetration.

**Binding Affinity:** Ligand B (-7.5 kcal/mol) has a significantly better binding affinity than Ligand A (-9.5 kcal/mol). This is a substantial advantage for B.

**Overall Assessment:**

While Ligand A has better BBB penetration and P-gp efflux, Ligand B has a significantly stronger binding affinity (-7.5 vs -9.5 kcal/mol). The affinity difference is large enough to potentially overcome some of the ADME drawbacks of Ligand B. The lower DILI risk and better metabolic stability of Ligand B are also favorable. The poor Caco-2 permeability is less of a concern given the CNS target. The TPSA of Ligand B is a concern, but not disqualifying.

Output:
1
2025-04-17 04:53:51,810 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (357.401 and 375.887 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (78.51) is better than Ligand B (40.54). For CNS targets, we want TPSA <= 90, both are well within this range, but A is closer to the upper limit.

**logP:** Ligand A (1.196) is within the optimal 1-3 range. Ligand B (3.819) is also within the range, but approaching the upper limit.

**H-Bond Donors/Acceptors:** Ligand A has 2 HBD and 3 HBA, while Ligand B has 1 HBD and 2 HBA. Both are acceptable, well under the limits of 5 and 10 respectively.

**QED:** Both ligands have similar QED values (0.75 and 0.742), indicating good drug-likeness.

**DILI:** Ligand A (27.608) has a slightly higher DILI risk than Ligand B (19.155), but both are below the 40 threshold and considered good.

**BBB:** Both ligands have excellent BBB penetration (Ligand A: 83.366, Ligand B: 89.957). Ligand B is slightly better, exceeding 85%. This is crucial for a CNS target like DRD2.

**Caco-2 Permeability:** Both have negative Caco-2 values (-4.863 and -4.458). This is unusual and suggests poor permeability. However, Caco-2 values can be unreliable and are less important than BBB for CNS targets.

**Aqueous Solubility:** Both ligands have very poor aqueous solubility (-2.23 and -4.254). This is a significant drawback, but can potentially be addressed through formulation strategies.

**hERG Inhibition:** Ligand A (0.154) has a lower hERG inhibition risk than Ligand B (0.831), which is preferable.

**Microsomal Clearance:** Ligand A (1.054) has much lower microsomal clearance than Ligand B (29.622), indicating better metabolic stability.

**In vitro Half-Life:** Ligand A (-1.634) has a negative half-life, which is not possible. Ligand B (44.804) has a good in vitro half-life. This is a major advantage for Ligand B.

**P-gp Efflux:** Ligand A (0.01) has very low P-gp efflux, which is highly desirable for CNS penetration. Ligand B (0.419) has moderate P-gp efflux.

**Binding Affinity:** Both ligands have excellent binding affinity (-8.2 and -8.5 kcal/mol). Ligand B is slightly better (-8.5 kcal/mol).

**Overall Assessment:**

Ligand B has a better BBB score, a longer half-life, and slightly better binding affinity. However, Ligand A has better metabolic stability (lower Cl_mic), lower hERG risk, and significantly lower P-gp efflux. The poor solubility of both is a concern, but the excellent BBB penetration somewhat mitigates the P-gp efflux issue. The negative half-life for Ligand A is a showstopper.

Considering the GPCR-specific priorities, the slightly better BBB penetration and affinity of Ligand B, combined with its reasonable metabolic stability, outweigh the slightly higher hERG and P-gp efflux.

Output:
1
2025-04-17 04:53:51,810 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (352.475 and 356.442 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (70.08) is significantly better than Ligand B (96.25). For CNS targets, we want TPSA <= 90, and A is comfortably within that range, while B is close to the upper limit. This favors A.

**3. logP:** Both ligands have acceptable logP values (1.127 and 1.335), falling within the optimal 1-3 range.

**4. H-Bond Donors:** Ligand A (1) is better than Ligand B (3). Lower HBD generally improves permeability.

**5. H-Bond Acceptors:** Ligand A (4) is better than Ligand B (5). Lower HBA generally improves permeability.

**6. QED:** Ligand A (0.827) has a significantly better QED score than Ligand B (0.655), indicating a more drug-like profile.

**7. DILI:** Ligand B (38.348) has a slightly better DILI score than Ligand A (20.706), but both are below the concerning threshold of 60.

**8. BBB:** Ligand A (81.698) has a much higher BBB percentile than Ligand B (64.831). This is a critical factor for a CNS target like DRD2, and strongly favors A.

**9. Caco-2 Permeability:** Ligand A (-4.145) is slightly better than Ligand B (-4.976) but both are negative, indicating poor permeability.

**10. Aqueous Solubility:** Both ligands have very poor aqueous solubility (-1.929 and -1.93). This is a concern for both, but not a deciding factor between them.

**11. hERG Inhibition:** Both ligands have low hERG inhibition risk (0.383 and 0.324).

**12. Microsomal Clearance:** Ligand B (33.686) has slightly lower microsomal clearance than Ligand A (35.958), suggesting slightly better metabolic stability.

**13. In vitro Half-Life:** Ligand A (-6.896) has a significantly longer in vitro half-life than Ligand B (-1.174).

**14. P-gp Efflux:** Both ligands have low P-gp efflux liability (0.111 and 0.046).

**15. Binding Affinity:** Ligand B (-8.0) has a slightly better binding affinity than Ligand A (-7.5), a difference of 0.5 kcal/mol. While affinity is crucial, the other ADME properties are also important.

**Overall Assessment:**

Ligand A is the superior candidate. While Ligand B has slightly better binding affinity and lower clearance, Ligand A excels in critical properties for CNS penetration and drug-likeness: significantly better TPSA, BBB, QED, HBD, HBA, and half-life. The 0.5 kcal/mol difference in binding affinity is unlikely to outweigh the substantial advantages of Ligand A in terms of ADME properties, especially for a CNS target like DRD2.

Output:
0
2025-04-17 04:53:51,810 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (343.475 and 346.523 Da) fall comfortably within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (54.26) is better than Ligand B (56.32). Both are below the 90 A^2 threshold desirable for CNS targets, but A is closer to optimal.

**3. logP:** Both ligands have good logP values (2.69 and 2.577), falling within the optimal 1-3 range.

**4. H-Bond Donors:** Ligand A (0) is preferable to Ligand B (2). Fewer HBDs generally improve permeability.

**5. H-Bond Acceptors:** Ligand A (5) is preferable to Ligand B (6).

**6. QED:** Both ligands have similar QED values (0.809 and 0.791), indicating good drug-likeness.

**7. DILI:** Ligand A (48.546) has a significantly lower DILI risk than Ligand B (14.114). This is a major advantage for Ligand A.

**8. BBB:** Both ligands have excellent BBB penetration (79.139 and 80.69), exceeding the >70% threshold for CNS targets.

**9. Caco-2 Permeability:** Ligand A (-4.723) is worse than Ligand B (-5.319). Lower values indicate lower permeability.

**10. Aqueous Solubility:** Ligand A (-2.83) is better than Ligand B (-1.642). Higher values indicate better solubility.

**11. hERG Inhibition:** Both ligands have low hERG inhibition risk (0.53 and 0.942).

**12. Microsomal Clearance:** Ligand A (87.403) has higher clearance than Ligand B (-4.579). This suggests Ligand B is more metabolically stable, which is desirable.

**13. In vitro Half-Life:** Ligand B (26.194) has a longer half-life than Ligand A (19.68).

**14. P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.344 and 0.023).

**15. Binding Affinity:** Both ligands have very similar and strong binding affinities (-8.5 and -8.8 kcal/mol). The difference is negligible.

**Overall Assessment:**

Ligand A excels in several key areas: lower DILI risk, better TPSA, fewer HBDs/HBAs, and better solubility. Ligand B has a slight advantage in metabolic stability (lower Cl_mic and longer half-life) and Caco-2 permeability, but these are outweighed by A's superior safety profile (DILI) and drug-like properties. Given the importance of minimizing toxicity for CNS drugs, and the similar binding affinities, Ligand A is the more promising candidate.

Output:
1
2025-04-17 04:53:51,810 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (363.889 Da and 386.945 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (84.22) is better than Ligand B (78.43). Both are below the 90 A^2 threshold desirable for CNS targets.

**3. logP:** Both ligands have good logP values (3.126 and 2.989), falling within the optimal 1-3 range.

**4. H-Bond Donors:** Both have 3 HBD, which is acceptable.

**5. H-Bond Acceptors:** Ligand A has 3 HBA, while Ligand B has 4. Both are within the acceptable limit of <=10.

**6. QED:** Both ligands have similar QED values (0.703 and 0.642), indicating good drug-likeness.

**7. DILI:** Ligand A (49.399) has a slightly higher DILI risk than Ligand B (44.63), but both are below the concerning 60 threshold.

**8. BBB:** This is a critical parameter for a CNS target like DRD2. Ligand A has a significantly better BBB penetration percentile (75.727) compared to Ligand B (54.478). This is a major advantage for Ligand A.

**9. Caco-2 Permeability:** Both have negative Caco-2 values which is unusual and suggests poor permeability. Ligand A (-5.007) is slightly worse than Ligand B (-4.916).

**10. Aqueous Solubility:** Both have negative solubility values, which is also unusual. Ligand A (-4.397) is slightly worse than Ligand B (-3.929).

**11. hERG Inhibition:** Both ligands show low hERG inhibition liability (0.611 and 0.471), which is favorable.

**12. Microsomal Clearance:** Ligand B (57.558) has significantly higher microsomal clearance than Ligand A (16.121), suggesting lower metabolic stability.

**13. In vitro Half-Life:** Ligand B (23.601) has a longer in vitro half-life than Ligand A (4.666), which is generally desirable.

**14. P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.067 and 0.564), which is good.

**15. Binding Affinity:** Ligand A (-9.0 kcal/mol) has a substantially stronger binding affinity than Ligand B (-8.3 kcal/mol). This difference of 0.7 kcal/mol is significant and can outweigh some ADME drawbacks.

**Overall Assessment:**

Ligand A is the more promising candidate. While both ligands have acceptable physicochemical properties, Ligand A excels in the most crucial areas for a CNS-targeting GPCR ligand: significantly better BBB penetration and a much stronger binding affinity. The slightly higher DILI risk and lower half-life of Ligand A are less concerning given its superior affinity and BBB penetration. The poor Caco-2 and solubility values are concerning for both, but can be addressed with formulation strategies.

Output:
1
2025-04-17 04:53:51,811 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (345.395 Da) is slightly lower, which is generally favorable for permeability. Ligand B (366.433 Da) is also good.

**TPSA:** Ligand A (72.91) is better than Ligand B (53.43) as it is closer to the optimal range for CNS targets (<=90).

**logP:** Ligand A (1.96) is within the optimal range (1-3). Ligand B (4.078) is slightly higher, potentially leading to solubility issues or off-target interactions, but not drastically so.

**H-Bond Donors/Acceptors:** Ligand A has 0 HBD and 5 HBA, which is excellent. Ligand B has 1 HBD and 4 HBA, also good. Both are within acceptable limits.

**QED:** Both ligands have good QED values (A: 0.763, B: 0.838), indicating drug-like properties.

**DILI:** Ligand A (39.783) has a slightly higher DILI risk than Ligand B (27.336), but both are below the 40 threshold and considered good.

**BBB:** Both ligands have excellent BBB penetration (A: 88.91, B: 86.972), exceeding the desirable >70 threshold for CNS targets.

**Caco-2 Permeability:** Both ligands exhibit negative Caco-2 permeability values, which is unusual and suggests potential issues with the experimental measurement or the compounds themselves. However, we will proceed assuming these are relative values and focus on the other parameters.

**Aqueous Solubility:** Both ligands have very poor aqueous solubility (-3.325 and -4.771). This is a significant concern.

**hERG Inhibition:** Both ligands show low hERG inhibition risk (A: 0.576, B: 0.711).

**Microsomal Clearance:** Ligand A (75.949) has a lower microsomal clearance than Ligand B (85.566), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (6.406 hours) has a shorter half-life than Ligand B (-13.734 hours). The negative value for Ligand B is concerning and likely an error.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (A: 0.298, B: 0.317), which is favorable for CNS exposure.

**Binding Affinity:** Ligand A (-8.8 kcal/mol) has a significantly stronger binding affinity than Ligand B (-7.1 kcal/mol). This is a >1.5 kcal/mol advantage, which can outweigh minor ADME drawbacks.

**Overall Assessment:**

Ligand A is superior due to its significantly better binding affinity (-8.8 vs -7.1 kcal/mol), lower microsomal clearance, and slightly better TPSA. While both have poor solubility, the stronger binding of Ligand A makes it more likely to achieve efficacy at lower concentrations, potentially mitigating the solubility issue. The negative half-life for Ligand B is a major red flag.

Output:
0
2025-04-17 04:53:51,811 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (349.519 and 367.515 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (61.44) is significantly better than Ligand B (82.53). For CNS targets, we want TPSA <= 90, and A is comfortably within this range, while B is approaching the upper limit.

**logP:** Both ligands (2.452 and 2.609) are within the optimal 1-3 range.

**H-Bond Donors:** Both have 2 HBD, which is acceptable.

**H-Bond Acceptors:** Ligand A has 3 HBA, and Ligand B has 5. Both are acceptable (<=10), but A is preferable.

**QED:** Both ligands have good QED scores (0.637 and 0.836), indicating good drug-like properties.

**DILI:** Ligand A (9.306) has a much lower DILI risk than Ligand B (63.513). This is a significant advantage for A.

**BBB:** Ligand A (69.407) has a better BBB penetration score than Ligand B (66.033), although both are reasonably good. For CNS targets, >70 is desirable, but these are still acceptable.

**Caco-2:** Both have negative Caco-2 permeability values (-4.922 and -5.018), which is unusual and suggests poor permeability. This is a concern for both, but doesn't differentiate them.

**Solubility:** Both have negative solubility values (-2.095 and -3.841), which is also concerning, indicating poor aqueous solubility. Again, this is a shared issue.

**hERG:** Ligand A (0.418) has a lower hERG inhibition liability than Ligand B (0.724), which is preferable.

**Microsomal Clearance:** Ligand A (38.046) has a higher microsomal clearance than Ligand B (24.072), indicating lower metabolic stability. This favors B.

**In vitro Half-Life:** Ligand B (3.194) has a longer half-life than Ligand A (9.358), which is a positive for B.

**P-gp Efflux:** Ligand A (0.054) has significantly lower P-gp efflux liability than Ligand B (0.281). Lower P-gp efflux is crucial for CNS penetration, giving A a substantial advantage.

**Binding Affinity:** Ligand A (-8.0) has a significantly stronger binding affinity than Ligand B (-0.0). This is the most important factor, and the >1.5 kcal/mol advantage of A outweighs many of its minor drawbacks.

**Overall:**

Ligand A is the stronger candidate. While both have issues with Caco-2 and solubility, Ligand A's superior binding affinity, lower DILI risk, lower P-gp efflux, and better TPSA outweigh its slightly higher clearance and shorter half-life. The strong binding affinity is particularly important for a GPCR target.

Output:
1
2025-04-17 04:53:51,811 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (354.422 and 345.443 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (87.66) is slightly higher than Ligand B (81.67), but both are below the 90 A^2 threshold desirable for CNS targets.

**3. logP:** Both ligands have acceptable logP values (0.94 and 1.316), falling within the 1-3 range. Ligand B is slightly better.

**4. H-Bond Donors:** Both have 3 HBD, which is within the acceptable limit of <=5.

**5. H-Bond Acceptors:** Both have 4 HBA, also within the acceptable limit of <=10.

**6. QED:** Ligand B (0.651) has a better QED score than Ligand A (0.469), indicating a more drug-like profile.

**7. DILI:** Ligand A (23.187) has a significantly lower DILI risk than Ligand B (46.219). This is a substantial advantage for Ligand A.

**8. BBB:** Ligand A (71.501) has a better BBB percentile than Ligand B (54.75). This is a critical advantage for a CNS target like DRD2.

**9. Caco-2 Permeability:** Ligand A (-5.264) has worse Caco-2 permeability than Ligand B (-4.922).

**10. Aqueous Solubility:** Ligand A (-2.557) has slightly worse solubility than Ligand B (-2.061).

**11. hERG Inhibition:** Both ligands have similar, low hERG inhibition liability (0.27 and 0.5).

**12. Microsomal Clearance:** Ligand A (-18.924) has significantly lower microsomal clearance than Ligand B (2.456), suggesting better metabolic stability.

**13. In vitro Half-Life:** Ligand B (18.538) has a significantly longer in vitro half-life than Ligand A (4.381).

**14. P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.062 and 0.064).

**15. Binding Affinity:** Both ligands have the same binding affinity (-8.7 kcal/mol), which is excellent.

**Overall Assessment:**

While Ligand B has a better QED and in vitro half-life, Ligand A demonstrates superior properties regarding safety (DILI) and CNS penetration (BBB). The significantly lower DILI risk and better BBB penetration of Ligand A are crucial for a CNS drug candidate. The lower clearance of Ligand A also suggests better metabolic stability. The slight disadvantages in Caco-2 permeability and solubility are less critical than the advantages in safety and CNS exposure. Given the GPCR-specific priorities, the improved BBB and lower DILI risk of Ligand A outweigh the benefits of Ligand B's slightly better QED and half-life.

Output:
0
2025-04-17 04:53:51,812 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B based on the provided guidelines, prioritizing GPCR-specific properties (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (340.442) is slightly lower, which could be beneficial for permeability.

**TPSA:** Ligand A (24.5) is excellent for CNS penetration, well below the 90 A^2 threshold. Ligand B (82.23) is higher, potentially hindering BBB penetration, but still within a reasonable range.

**logP:** Ligand A (3.475) is optimal. Ligand B (1.686) is a bit low, potentially impacting membrane permeability.

**H-Bond Donors/Acceptors:** Ligand A (1 HBD, 3 HBA) and Ligand B (0 HBD, 5 HBA) both fall within acceptable ranges.

**QED:** Both ligands have good QED scores (A: 0.922, B: 0.815), indicating drug-like properties.

**DILI:** Ligand A (32.105) has a lower DILI risk than Ligand B (48.662), which is preferable.

**BBB:** This is a critical parameter for a CNS target. Ligand A (96.084) has excellent BBB penetration, while Ligand B (74.758) is good but less favorable.

**Caco-2 Permeability:** Both have negative values, indicating poor permeability. This is unusual and requires further investigation, but the relative values suggest Ligand A (-4.706) is slightly better than Ligand B (-4.54).

**Aqueous Solubility:** Both have negative values, indicating poor solubility. Ligand A (-3.005) is slightly better than Ligand B (-3.258).

**hERG Inhibition:** Ligand A (0.967) has a slightly higher hERG risk than Ligand B (0.231), but both are relatively low.

**Microsomal Clearance:** Ligand A (10.083) has lower clearance, indicating better metabolic stability, compared to Ligand B (40.156).

**In vitro Half-Life:** Ligand A (37.007) has a longer half-life than Ligand B (15.693), which is desirable.

**P-gp Efflux:** Ligand A (0.496) has lower P-gp efflux, which is favorable for CNS exposure, compared to Ligand B (0.052).

**Binding Affinity:** Ligand A (-8.6 kcal/mol) has significantly stronger binding affinity than Ligand B (-6.6 kcal/mol). This is a substantial advantage, potentially outweighing some of the ADME drawbacks of Ligand B.

**Overall Assessment:**

Ligand A is the superior candidate. It excels in key GPCR-specific properties: BBB penetration, metabolic stability, half-life, and, most importantly, binding affinity. While Ligand B has a slightly lower hERG risk, the significantly stronger binding affinity of Ligand A, combined with its better BBB and metabolic properties, makes it the more promising drug candidate. The slightly lower logP of Ligand B is a concern, and the significantly weaker binding affinity is a major drawback.



Output:
1
2025-04-17 04:53:51,812 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (347.459 Da) is slightly lower, which could be beneficial for permeability.

**TPSA:** Ligand A (65.79) is higher than the ideal <90 for CNS targets, but still reasonable. Ligand B (29.54) is excellent, well below the threshold. This favors Ligand B.

**logP:** Ligand A (2.183) is within the optimal range (1-3). Ligand B (4.234) is slightly above, potentially leading to solubility issues and off-target interactions, but not dramatically so.

**H-Bond Donors/Acceptors:** Ligand A has 1 HBD and 4 HBA, which is acceptable. Ligand B has 0 HBD and 2 HBA, also acceptable.

**QED:** Both ligands have reasonable QED scores (A: 0.907, B: 0.703), indicating good drug-like properties. Ligand A is better here.

**DILI:** Ligand A (15.626) has a significantly lower DILI risk than Ligand B (26.134). This is a strong advantage for Ligand A.

**BBB:** Ligand A (69.407) is below the desirable >70 for CNS targets, but not terrible. Ligand B (96.123) is excellent, exceeding the threshold. This is a major advantage for Ligand B.

**Caco-2 Permeability:** Both have negative values, indicating poor permeability. Ligand A (-4.977) is worse than Ligand B (-4.136).

**Aqueous Solubility:** Both have negative values, indicating poor solubility. Ligand B (-5.232) is worse than Ligand A (-1.6).

**hERG Inhibition:** Ligand A (0.615) has a slightly higher hERG risk than Ligand B (0.834), but both are relatively low.

**Microsomal Clearance:** Ligand A (0.977) has much lower clearance than Ligand B (58.674), suggesting better metabolic stability. This is a significant advantage for Ligand A.

**In vitro Half-Life:** Ligand A (20.731) has a longer half-life than Ligand B (-9.777). This is a strong advantage for Ligand A.

**P-gp Efflux:** Ligand A (0.075) has much lower P-gp efflux than Ligand B (0.253), meaning better CNS exposure. This is a significant advantage for Ligand A.

**Binding Affinity:** Both ligands have good binding affinities (A: -8 kcal/mol, B: -7.7 kcal/mol), but Ligand A is slightly better. The 1.5 kcal/mol advantage of Ligand A is significant enough to outweigh some of the ADME drawbacks of Ligand B.

**Overall Assessment:**

Ligand B excels in BBB penetration and TPSA, crucial for CNS targets. However, Ligand A demonstrates superior metabolic stability (lower Cl_mic), longer half-life, lower P-gp efflux, lower DILI risk, and slightly better binding affinity. While Ligand B has a better BBB score, Ligand A's lower P-gp efflux will also contribute to better brain penetration. Considering the balance of properties, and prioritizing metabolic stability and safety (DILI) alongside CNS penetration, Ligand A is the more promising candidate.

Output:
0
2025-04-17 04:53:51,812 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (348.487 and 345.443 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (53.01) is significantly better than Ligand B (67.6). For CNS targets, TPSA < 90 is preferred, and A is much closer to the optimal <60 range. B is pushing the upper limit.

**3. logP:** Both ligands have acceptable logP values (2.528 and 3.927), falling within the 1-3 range. B is slightly higher, which *could* indicate potential off-target effects, but isn't a major concern.

**4. H-Bond Donors:** Both have 1 HBD, which is good.

**5. H-Bond Acceptors:** Both have 4 HBA, which is also good.

**6. QED:** Both ligands have similar QED values (0.858 and 0.826), indicating good drug-like properties.

**7. DILI:** Ligand A (8.181) has a much lower DILI risk than Ligand B (54.168). This is a significant advantage for A.

**8. BBB:** Ligand A (51.183) has a lower BBB penetration percentile than Ligand B (62.854). While both are not ideal (>70 is desirable), B is better.

**9. Caco-2 Permeability:** Ligand A (-4.718) has slightly better Caco-2 permeability than Ligand B (-4.529), though both are negative values which is unusual.

**10. Aqueous Solubility:** Ligand A (-2.309) has better aqueous solubility than Ligand B (-3.96).

**11. hERG Inhibition:** Ligand A (0.846) has a slightly higher hERG inhibition risk than Ligand B (0.318). B is preferable here.

**12. Microsomal Clearance:** Ligand A (63.453) has lower microsomal clearance than Ligand B (103.281), indicating better metabolic stability.

**13. In vitro Half-Life:** Ligand A (-9.164) has a much longer in vitro half-life than Ligand B (-2.724).

**14. P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.048 and 0.082).

**15. Binding Affinity:** Ligand B (-8.5) has a slightly better binding affinity than Ligand A (-8.0). However, the difference is only 0.5 kcal/mol, which is less critical than the ADME differences.

**Overall Assessment:**

Considering the GPCR-specific priorities, Ligand A is the more promising candidate. While Ligand B has slightly better BBB penetration and binding affinity, Ligand A excels in critical areas like TPSA, DILI risk, metabolic stability (Cl_mic and t1/2), and solubility. The lower DILI risk and improved metabolic stability are particularly important for a CNS-targeting drug. The TPSA value of A is also much more favorable for CNS penetration. The small difference in binding affinity (0.5 kcal/mol) is unlikely to outweigh the substantial ADME advantages of Ligand A.

Output:
0
2025-04-17 04:53:51,812 - INFO - Batch 152 complete. Total preferences: 2432
2025-04-17 04:53:51,813 - INFO - Processing batch 153/512...
2025-04-17 04:54:31,758 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (382.247 Da) is slightly higher than Ligand B (344.499 Da), but both are acceptable.

**TPSA:** Ligand A (84.22) is better than Ligand B (49.41) as it is closer to the ideal range for CNS targets (<=90). Ligand B is very low, which could potentially reduce binding affinity.

**logP:** Both ligands have good logP values (A: 3.035, B: 3.614), falling within the optimal range of 1-3.

**H-Bond Donors/Acceptors:** Ligand A has 2 HBD and 4 HBA, while Ligand B has 1 HBD and 2 HBA. Both are within acceptable limits (<=5 HBD and <=10 HBA).

**QED:** Both ligands have similar and good QED values (A: 0.721, B: 0.744), indicating good drug-like properties.

**DILI:** Ligand A has a higher DILI risk (87.786%) than Ligand B (11.4%). This is a significant drawback for Ligand A.

**BBB:** Ligand B has a substantially better BBB penetration percentile (82.28%) than Ligand A (36.022%). This is crucial for a CNS target like DRD2.

**Caco-2 Permeability:** Ligand A has a negative Caco-2 value (-5.542) which is concerning. Ligand B also has a negative value (-4.308) but is slightly better.

**Aqueous Solubility:** Both ligands have poor aqueous solubility (-3.058 and -3.867 respectively). This could pose formulation challenges.

**hERG Inhibition:** Ligand A (0.029) has a much lower hERG inhibition liability than Ligand B (0.723), which is a significant advantage.

**Microsomal Clearance:** Ligand B has a much higher microsomal clearance (86.669) than Ligand A (17.902), suggesting lower metabolic stability for Ligand B.

**In vitro Half-Life:** Ligand B has a longer in vitro half-life (9.229 hours) than Ligand A (-4.287 hours), which is preferable.

**P-gp Efflux:** Ligand A (0.052) has lower P-gp efflux liability than Ligand B (0.123), which is beneficial for CNS penetration.

**Binding Affinity:** Both ligands have strong binding affinities (A: -8.7 kcal/mol, B: -8.1 kcal/mol). Ligand A has a slightly better affinity.

**Overall Assessment:**

While Ligand A has a slightly better binding affinity and lower hERG risk and P-gp efflux, its significantly higher DILI risk and poor BBB penetration are major concerns. Ligand B, despite slightly lower affinity, exhibits a much better safety profile (lower DILI), significantly better BBB penetration, and a longer half-life. The improved BBB penetration is particularly important for a CNS target like DRD2. The negative Caco-2 values for both are concerning, but the other advantages of Ligand B outweigh this drawback.

Output:
1
2025-04-17 04:54:31,759 - INFO - Reasoning:

Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (356.304 and 344.499 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (100.27) is higher than the preferred <90 for CNS targets, but not drastically so. Ligand B (49.41) is excellent, well below the threshold.

**3. logP:** Ligand A (0.815) is a bit low, potentially hindering permeation. Ligand B (3.298) is optimal.

**4. H-Bond Donors:** Ligand A (3) is acceptable. Ligand B (1) is also good.

**5. H-Bond Acceptors:** Ligand A (6) is acceptable. Ligand B (2) is also good.

**6. QED:** Both ligands have reasonable QED scores (0.753 and 0.628), suggesting good drug-like properties.

**7. DILI:** Ligand A (67.468) has a moderate DILI risk, while Ligand B (29.236) has a very low risk.

**8. BBB:** Ligand A (59.442) is below the desirable >70 for CNS targets. Ligand B (73.672) is excellent, exceeding the threshold. This is a crucial difference given DRD2's role in CNS disorders.

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 values, which is unusual and suggests a potential issue with the data or modeling. However, we can still compare the relative values. Ligand A (-4.792) is slightly better than Ligand B (-4.821).

**10. Aqueous Solubility:** Both ligands have negative solubility values, which is also unusual. Ligand A (-2.5) is slightly better than Ligand B (-3.446).

**11. hERG Inhibition:** Both ligands have low hERG inhibition risk (0.234 and 0.245).

**12. Microsomal Clearance:** Ligand A (-4.335) has a lower (better) clearance than Ligand B (47.179), indicating greater metabolic stability.

**13. In vitro Half-Life:** Ligand A (-21.038) has a longer half-life than Ligand B (-11.256).

**14. P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.03 and 0.131).

**15. Binding Affinity:** Both ligands have very similar and strong binding affinities (-8.6 and -8.2 kcal/mol). The difference of 0.4 kcal/mol is not substantial enough to outweigh other factors.

**Overall Assessment:**

Ligand B is the more promising candidate. While Ligand A has better metabolic stability and half-life, Ligand B excels in crucial areas for a CNS-targeting GPCR ligand: significantly better BBB penetration (73.7% vs 59.4%), a more optimal logP (3.3 vs 0.8), and a lower DILI risk (29.2% vs 67.5%). The TPSA of Ligand B is also much more favorable. The slight advantage of Ligand A in clearance and half-life is less critical than the CNS penetration and safety profile of Ligand B.

Output:
1
2025-04-17 04:54:31,759 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (348.447 and 351.491 Da) fall comfortably within the ideal 200-500 Da range.

**TPSA:** Ligand A (68.62) is slightly higher than Ligand B (53.09). Both are below the 90 A^2 threshold desirable for CNS targets, but Ligand B is better.

**logP:** Both ligands have good logP values (1.945 and 1.718), falling within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A has 1 HBD and 5 HBA, while Ligand B has 0 HBD and 4 HBA. Both are within acceptable limits (<=5 HBD, <=10 HBA).

**QED:** Ligand A (0.883) has a higher QED score than Ligand B (0.731), suggesting better overall drug-likeness.

**DILI:** Ligand A (26.057) has a significantly lower DILI risk than Ligand B (12.214), indicating a safer profile.

**BBB:** Ligand A (94.61) has a much higher BBB penetration percentile than Ligand B (74.254). This is *critical* for a CNS target like DRD2.

**Caco-2 Permeability:** Both have negative Caco-2 values (-4.527 and -4.507), which is unusual and suggests poor permeability. This is a concern for both.

**Aqueous Solubility:** Both have negative solubility values (-2.036 and -0.722), which is also concerning.

**hERG:** Both ligands have low hERG inhibition liability (0.168 and 0.434), which is good.

**Microsomal Clearance:** Ligand B (17.86) has higher microsomal clearance than Ligand A (1.196), meaning Ligand A is more metabolically stable.

**In vitro Half-Life:** Ligand A (16.86 hours) has a longer in vitro half-life than Ligand B (-2.409 hours).

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.049 and 0.024), which is favorable for CNS penetration.

**Binding Affinity:** Ligand A (-9.1 kcal/mol) has a significantly stronger binding affinity than Ligand B (-6.1 kcal/mol). This is a substantial advantage, potentially outweighing some ADME concerns.

**Conclusion:**

While both ligands have issues with Caco-2 permeability and solubility, Ligand A is the superior candidate. Its significantly higher BBB penetration, lower DILI risk, better metabolic stability (lower Cl_mic, longer t1/2), and *much* stronger binding affinity make it a more promising drug candidate for DRD2, a CNS target. The affinity difference is particularly compelling.

Output:
1
2025-04-17 04:54:31,759 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (348.45 & 352.43 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (87.46) is better than Ligand B (42.43). For CNS targets, TPSA should be <= 90, both meet this criteria, but A is closer to the upper limit.

**logP:** Ligand A (0.737) is slightly below the optimal 1-3 range, potentially hindering permeability. Ligand B (3.659) is within the optimal range. This favors B.

**H-Bond Donors/Acceptors:** Ligand A has 2 HBD and 5 HBA, while Ligand B has 0 HBD and 3 HBA. Both are within acceptable limits (<=5 HBD, <=10 HBA).

**QED:** Both ligands have good QED scores (0.611 and 0.785, respectively), indicating drug-like properties.

**DILI:** Both ligands show low DILI risk (26.10 and 21.68, respectively).

**BBB:** This is crucial for a CNS target. Ligand B (93.25) is significantly better than Ligand A (53.70). This is a major advantage for B.

**Caco-2 Permeability:** Both have negative values (-4.81 and -4.55), indicating poor permeability. This is a concern for both, but not a deciding factor given the other data.

**Aqueous Solubility:** Both have negative solubility values (-1.383 and -3.055), indicating poor solubility. This is a concern for both, but not a deciding factor given the other data.

**hERG Inhibition:** Ligand A (0.1) has a lower hERG risk than Ligand B (0.715), which is preferable.

**Microsomal Clearance:** Ligand B (56.14) has a higher clearance than Ligand A (31.47), indicating lower metabolic stability. This favors A.

**In vitro Half-Life:** Both have negative half-lives (-4.577 and -4.683), which is not meaningful in this context.

**P-gp Efflux:** Ligand A (0.044) has significantly lower P-gp efflux liability than Ligand B (0.131), which is highly desirable for CNS penetration.

**Binding Affinity:** Both ligands have excellent binding affinities (-7.0 and -6.8 kcal/mol). The difference of 0.2 kcal/mol is not substantial enough to outweigh other factors.

**Overall Assessment:**

Ligand B excels in BBB penetration and has a good logP. However, it suffers from higher P-gp efflux and higher microsomal clearance. Ligand A has better P-gp efflux, lower clearance, and lower hERG risk, but its BBB penetration is significantly lower and logP is suboptimal. Given the importance of BBB penetration for a CNS target like DRD2, and the relatively small difference in binding affinity, **Ligand B is the more promising candidate.**

Output:
1
2025-04-17 04:54:31,759 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B based on the provided guidelines, prioritizing GPCR-specific properties (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (358.36 and 356.463 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (58.64) is significantly better than Ligand B (77.1).  For CNS targets, TPSA < 90 is preferred, and A is much closer to the <60 ideal. B is pushing the upper limit.

**logP:** Ligand A (4.273) is higher than the optimal 1-3 range, but still potentially manageable. Ligand B (0.962) is low, which could hinder permeation.

**H-Bond Donors/Acceptors:** Both have acceptable HBD (1) and HBA (A: 3, B: 5) counts.

**QED:** Ligand A (0.878) has a better QED score than Ligand B (0.666), indicating a more drug-like profile.

**DILI:** Ligand A (56.223) has a higher DILI risk than Ligand B (15.859). This is a significant drawback for A.

**BBB:** Ligand A (96.006) has excellent BBB penetration, while Ligand B (73.129) is good, but less favorable. This is a critical factor for a CNS target like DRD2.

**Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and suggests a potential issue with the data or modeling. However, the magnitude of the negative value is similar.

**Aqueous Solubility:** Both have negative solubility values, which is also unusual. Again, the magnitude is similar.

**hERG:** Ligand A (0.387) has a slightly higher hERG risk than Ligand B (0.204), but both are relatively low.

**Microsomal Clearance:** Ligand A (58.439) has significantly higher microsomal clearance than Ligand B (27.836), suggesting lower metabolic stability.

**In vitro Half-Life:** Ligand A (-10.058) has a very short predicted half-life, a major concern. Ligand B (-7.666) is also short, but better than A.

**P-gp Efflux:** Ligand A (0.115) has lower P-gp efflux than Ligand B (0.01), which is beneficial for CNS penetration.

**Binding Affinity:** Ligand A (-7.9 kcal/mol) has a stronger binding affinity than Ligand B (-6.9 kcal/mol). This is a substantial difference (1 kcal/mol) and could outweigh some of the ADME drawbacks.

**Overall Assessment:**

Ligand A has a significantly better binding affinity and BBB penetration, and lower P-gp efflux, which are crucial for a CNS GPCR target. However, it suffers from higher DILI risk, higher clearance, and a very short half-life. Ligand B has a lower DILI risk and better metabolic stability, but its lower affinity and BBB penetration are significant drawbacks.

The affinity difference of 1 kcal/mol is substantial, and the excellent BBB penetration of Ligand A are compelling. While the ADME properties of A are concerning, they might be addressable through further optimization. The lower affinity of B is harder to overcome.

Output:
1
2025-04-17 04:54:31,759 - INFO - Reasoning:

Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight (MW):** Both ligands (354.535 and 359.392 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (58.64) is significantly better than Ligand B (73.2). For CNS targets, we want TPSA <= 90, and ideally closer to 60. Ligand A is much closer to this ideal.

**3. logP:** Both ligands have good logP values (3.373 and 2.909), falling within the optimal 1-3 range.

**4. H-Bond Donors (HBD):** Both have 1 HBD, which is acceptable.

**5. H-Bond Acceptors (HBA):** Both have 3 HBA, which is acceptable.

**6. QED:** Both ligands have good QED scores (0.612 and 0.792), indicating good drug-like properties.

**7. DILI:** Ligand A (16.247) has a slightly higher DILI risk than Ligand B (14.696), but both are below the concerning threshold of 40.

**8. BBB:** Ligand B (93.874) has a significantly better BBB penetration score than Ligand A (74.641).  For a CNS target like DRD2, >70 is desirable, and Ligand B exceeds this, while Ligand A is close.

**9. Caco-2 Permeability:** Both have negative Caco-2 values (-4.501 and -4.602). This is unusual and suggests poor permeability. However, these values are on a scale where negative values are possible and don't necessarily disqualify a compound.

**10. Aqueous Solubility:** Both have negative solubility values (-3.116 and -3.013), indicating poor aqueous solubility. This is a concern, but can sometimes be overcome with formulation strategies.

**11. hERG Inhibition:** Both ligands have low hERG inhibition risk (0.797 and 0.531).

**12. Microsomal Clearance (Cl_mic):** Ligand B (-13.297) has significantly lower (better) microsomal clearance than Ligand A (74.255). This suggests better metabolic stability for Ligand B.

**13. In vitro Half-Life:** Ligand B (-23.747) has a much longer in vitro half-life than Ligand A (-8.803), indicating better stability.

**14. P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.568 and 0.045), which is excellent for CNS penetration.

**15. Binding Affinity:** Ligand B (-8.5 kcal/mol) has a significantly stronger binding affinity than Ligand A (-0.0 kcal/mol). This is a crucial difference. A difference of >1.5 kcal/mol is considered significant, and here it's a massive 8.5 kcal/mol difference.

**Overall Assessment:**

While Ligand A has a slightly better TPSA, Ligand B excels in almost every other critical parameter, especially BBB penetration, metabolic stability (Cl_mic and t1/2), and, most importantly, binding affinity. The substantial difference in binding affinity outweighs the minor TPSA advantage of Ligand A. Given the GPCR target and the need for CNS penetration, Ligand B is the far more promising candidate.

Output:
1
2025-04-17 04:54:31,760 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 drug candidates, considering the provided guidelines and GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (346.471 and 352.475 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (71.34) is excellent, well below the 90 A^2 threshold for CNS targets. Ligand B (98.66) is still reasonable but less optimal, approaching the 100 A^2 limit.

**logP:** Ligand A (3.21) is within the optimal 1-3 range. Ligand B (0.955) is slightly below 1, which *could* indicate permeability issues, though not severely.

**H-Bond Donors/Acceptors:** Ligand A has 2 HBD and 3 HBA, both well within acceptable limits. Ligand B has 4 HBD and 4 HBA, also acceptable, but slightly higher than Ligand A.

**QED:** Ligand A (0.796) has a better QED score than Ligand B (0.572), suggesting a more drug-like profile.

**DILI:** Ligand A (43.195) has a significantly lower DILI risk than Ligand B (14.424), which is a major advantage.

**BBB:** Ligand A (70.299) has a good BBB percentile, exceeding the 70% threshold for CNS targets. Ligand B (24.738) is significantly lower, indicating poor predicted brain penetration. This is a critical disadvantage for a DRD2 ligand.

**Caco-2 Permeability:** Ligand A (-4.538) and Ligand B (-5.172) both have negative values, which is unusual and suggests very poor permeability. However, the scale is not specified, so it is difficult to interpret these values.

**Aqueous Solubility:** Ligand A (-3.972) and Ligand B (-2.354) also have negative values, which is unusual and suggests very poor solubility. Again, the scale is not specified.

**hERG:** Both ligands have low hERG inhibition liability (0.312 and 0.185, respectively), which is positive.

**Microsomal Clearance:** Ligand A (49.323) has moderate clearance, while Ligand B (-6.533) has negative clearance, which is not possible and likely indicates an error in the data.

**In vitro Half-Life:** Ligand A (62.362) has a reasonable half-life. Ligand B (20.392) has a shorter half-life, which could necessitate more frequent dosing.

**P-gp Efflux:** Ligand A (0.311) has lower P-gp efflux liability than Ligand B (0.038), which is favorable for CNS exposure.

**Binding Affinity:** Both ligands have very similar and excellent binding affinities (-8.5 and -8.3 kcal/mol). The difference is less than the 1.5 kcal/mol threshold.

**Conclusion:**

Considering all factors, especially the GPCR-specific priorities, **Ligand A is the more promising drug candidate.** Its superior BBB penetration, lower DILI risk, better QED score, and lower P-gp efflux liability outweigh the slightly less optimal TPSA and solubility/permeability values (assuming the negative values are not errors). Ligand B's poor BBB penetration is a significant drawback for a CNS target like DRD2. The negative clearance value for Ligand B is also concerning and suggests data quality issues.

Output:
0
2025-04-17 04:54:31,760 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (338.455 and 346.515 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (58.95) is significantly better than Ligand B (40.62). Both are below the 90 A^2 threshold for CNS targets, but A is closer to the ideal.

**3. logP:** Ligand A (1.988) is within the optimal 1-3 range. Ligand B (3.916) is at the higher end but still acceptable.

**4. H-Bond Donors:** Ligand A (2) is reasonable. Ligand B (0) is also good.

**5. H-Bond Acceptors:** Ligand A (4) is good. Ligand B (2) is also good.

**6. QED:** Ligand A (0.847) is excellent, indicating high drug-likeness. Ligand B (0.444) is below the 0.5 threshold, suggesting a less favorable drug-like profile.

**7. DILI:** Ligand A (13.3) has a much lower DILI risk than Ligand B (16.983). Both are below 40, which is good.

**8. BBB:** Ligand B (90.074) has a significantly better BBB penetration score than Ligand A (77.007). This is a critical factor for a CNS target like DRD2.

**9. Caco-2 Permeability:** Ligand A (-5.533) has a negative value, indicating poor permeability. Ligand B (-4.721) is also poor, but slightly better than A.

**10. Aqueous Solubility:** Ligand A (-1.185) has poor solubility. Ligand B (-3.76) is even worse. This could pose formulation challenges.

**11. hERG Inhibition:** Both ligands (0.686 and 0.674) have similar, relatively low hERG inhibition risk.

**12. Microsomal Clearance:** Ligand A (3.597) has a lower (better) microsomal clearance than Ligand B (69.854), indicating greater metabolic stability.

**13. In vitro Half-Life:** Ligand A (-1.544) has a negative half-life, which is unusual and suggests rapid metabolism or instability. Ligand B (4.666) has a reasonable half-life.

**14. P-gp Efflux:** Both ligands (0.224 and 0.778) have relatively low P-gp efflux, which is good for CNS penetration.

**15. Binding Affinity:** Ligand B (-7.3 kcal/mol) has a significantly stronger binding affinity than Ligand A (-9.4 kcal/mol). This is a substantial advantage.

**Overall Assessment:**

Ligand B excels in BBB penetration and binding affinity, which are crucial for a CNS GPCR target. While its QED and solubility are weaker, the strong affinity could potentially compensate. Ligand A has better TPSA, DILI, and metabolic stability, but its poor BBB, solubility, and questionable half-life are significant drawbacks. The difference in binding affinity is also substantial.

Considering the GPCR-specific priorities, the superior binding affinity and BBB penetration of Ligand B outweigh its other weaknesses.

Output:
1
2025-04-17 04:54:31,760 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B against the provided guidelines, prioritizing GPCR-specific properties (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (345.443 and 362.499 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (61.88) is significantly better than Ligand B (75.19). For CNS targets, we want TPSA <= 90, and A is closer to the optimal <=60 range. B is pushing the upper limit.

**logP:** Both ligands have good logP values (2.666 and 1.956), falling within the 1-3 range.

**H-Bond Donors/Acceptors:** Both have 1 HBD, which is good. Ligand A has 4 HBA, and Ligand B has 5. Both are acceptable (<=10).

**QED:** Both ligands have good QED scores (0.834 and 0.886), indicating good drug-likeness.

**DILI:** Ligand A (38.891) has a much lower DILI risk than Ligand B (63.901). This is a significant advantage for A.

**BBB:** Ligand A (83.637) has a substantially better BBB penetration score than Ligand B (67.584).  For CNS targets, >70 is desirable, and A is closer.

**Caco-2 Permeability:** Both have negative Caco-2 values (-5.014 and -5.261), which is unusual and suggests poor permeability. However, these values are on a scale where negative values are possible, and direct comparison is difficult without knowing the scale's specifics.

**Aqueous Solubility:** Both have very poor aqueous solubility (-3.005 and -3.03). This is a concern for both, but might be mitigated by formulation strategies.

**hERG Inhibition:** Ligand A (0.74) has a slightly higher hERG risk than Ligand B (0.172), but both are relatively low.

**Microsomal Clearance:** Ligand A (-1.61) has much better metabolic stability (lower clearance) than Ligand B (41.613).

**In vitro Half-Life:** Ligand A (-1.395) has a longer in vitro half-life than Ligand B (0.912).

**P-gp Efflux:** Ligand A (0.047) has significantly lower P-gp efflux liability than Ligand B (0.073). Lower P-gp is crucial for CNS penetration.

**Binding Affinity:** Ligand A (-9.2 kcal/mol) has a significantly stronger binding affinity than Ligand B (-0.0 kcal/mol). This is the most important factor, and the difference is substantial (>1.5 kcal/mol advantage).

**Conclusion:**

Considering all factors, especially the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity), **Ligand A is the far superior candidate**. Its significantly better BBB penetration, lower DILI risk, lower P-gp efflux, better metabolic stability, longer half-life, and *much* stronger binding affinity outweigh its slightly higher hERG risk and poor solubility. The TPSA is also more favorable for CNS penetration. While both have poor Caco-2 permeability and solubility, the affinity difference is so large that it is likely to be the dominant factor in determining success.

Output:
1
2025-04-17 04:54:31,760 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (348.447) is slightly better as it's closer to the lower end, potentially aiding permeability.

**TPSA:** Ligand A (74.24) is significantly better than Ligand B (102.05). For CNS targets, TPSA should be <= 90, and Ligand A is comfortably within this range, while Ligand B is slightly above.

**logP:** Both ligands have acceptable logP values (A: 0.744, B: 1.565), falling within the optimal 1-3 range. Ligand B is slightly better, being closer to the middle of the range.

**H-Bond Donors/Acceptors:** Ligand A (HBD=1, HBA=5) and Ligand B (HBD=2, HBA=6) are both reasonable.

**QED:** Both ligands have similar and good QED values (A: 0.768, B: 0.737), indicating good drug-like properties.

**DILI:** Ligand A (19.969) has a much lower DILI risk than Ligand B (57.154). This is a significant advantage for Ligand A.

**BBB:** Ligand A (64.831) has a substantially better BBB penetration percentile than Ligand B (30.593). This is *critical* for a CNS target like DRD2.

**Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and suggests poor permeability. However, the absolute value for Ligand A (-5.029) is less negative than Ligand B (-5.466), indicating slightly better potential absorption.

**Aqueous Solubility:** Both ligands have very poor aqueous solubility (-1.215 and -1.546). This is a concern for both, but not a deciding factor.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (A: 0.463, B: 0.228). Ligand B is slightly better here.

**Microsomal Clearance:** Ligand A (9.405) has a lower microsomal clearance than Ligand B (25.32), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (4.888) has a slightly better in vitro half-life than Ligand B (-0.156).

**P-gp Efflux:** Both have very low P-gp efflux liability (A: 0.056, B: 0.059).

**Binding Affinity:** Ligand A (-9.4 kcal/mol) has a significantly stronger binding affinity than Ligand B (-8.1 kcal/mol). This is a substantial advantage, potentially outweighing some of the ADME drawbacks.

**Overall Assessment:**

Ligand A is the superior candidate. While both have solubility issues, Ligand A excels in the critical areas for a CNS GPCR target: BBB penetration, DILI risk, and, most importantly, binding affinity. Its TPSA is also better, and it has improved metabolic stability. The 1.3 kcal/mol difference in binding affinity is substantial and likely to be a key driver of efficacy.

Output:
1
2025-04-17 04:54:31,760 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (350.39 and 366.487 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (78.87) is better than Ligand B (69.48) in terms of TPSA. Both are below the 90 A^2 threshold for CNS targets, but A is closer to the ideal range.

**3. logP:** Both ligands have good logP values (2.77 and 2.997), falling within the optimal 1-3 range.

**4. H-Bond Donors:** Ligand A (2) is preferable to Ligand B (0) as having some HBD can improve solubility.

**5. H-Bond Acceptors:** Ligand B (7) is preferable to Ligand A (4) as having some HBA can improve solubility.

**6. QED:** Ligand A (0.819) has a significantly better QED score than Ligand B (0.682), indicating a more drug-like profile.

**7. DILI:** Ligand A (44.591) has a lower DILI risk than Ligand B (57.154), which is favorable.

**8. BBB:** Ligand A (76.735) has a substantially better BBB percentile than Ligand B (54.013). This is *critical* for a CNS target like DRD2.

**9. Caco-2:** Both ligands have negative Caco-2 values (-4.639 and -4.663) which is not ideal.

**10. Solubility:** Both ligands have negative solubility values (-3.568 and -2.256) which is not ideal.

**11. hERG:** Both ligands have low hERG inhibition liability (0.7 and 0.654), which is good.

**12. Cl_mic:** Ligand A (33.783) has a lower microsomal clearance than Ligand B (84.523), suggesting better metabolic stability.

**13. t1/2:** Ligand A (42.479) has a longer in vitro half-life than Ligand B (-16.513), which is desirable.

**14. Pgp:** Ligand A (0.138) has a lower P-gp efflux liability than Ligand B (0.28), suggesting better CNS exposure.

**15. Binding Affinity:** Ligand A (-8.1 kcal/mol) has a significantly stronger binding affinity than Ligand B (-6.3 kcal/mol). This is a substantial advantage, exceeding the 1.5 kcal/mol threshold.

**Overall Assessment:**

Ligand A is clearly superior. It excels in the most important parameters for a CNS-targeting GPCR ligand: BBB penetration, binding affinity, metabolic stability (Cl_mic and t1/2), and P-gp efflux. While both have issues with Caco-2 and Solubility, the strong affinity and favorable ADME properties of Ligand A outweigh these concerns. The QED and DILI scores are also better for Ligand A.

Output:
1
2025-04-17 04:54:31,761 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (343.446 and 347.415 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (37.39) is excellent, well below the 90 A^2 threshold for CNS targets. Ligand B (86.88) is higher, but still potentially acceptable, though less ideal.

**logP:** Ligand A (3.768) is at the upper end of the optimal range (1-3), while Ligand B (1.386) is at the lower end. While both are within range, a higher logP can aid in BBB penetration.

**H-Bond Donors & Acceptors:** Both ligands have 1 HBD, which is good. Ligand A has 4 HBA, and Ligand B has 5. Both are within the acceptable limit of 10.

**QED:** Both ligands have a QED of 0.83-0.84, indicating good drug-like properties.

**DILI:** Ligand A (34.665) has a lower DILI risk than Ligand B (50.136), which is a significant advantage.

**BBB:** Ligand A (84.451) has a much better BBB percentile than Ligand B (68.67). This is a critical factor for a CNS target like DRD2.

**Caco-2 Permeability:** Ligand A (-4.764) has a negative Caco-2 value, which is concerning. Ligand B (-4.589) is also negative, but slightly less so. Both suggest poor intestinal absorption.

**Aqueous Solubility:** Both ligands have poor aqueous solubility (-3.461 and -2.68 respectively). This could pose formulation challenges.

**hERG:** Ligand A (0.936) has a slightly higher hERG risk than Ligand B (0.166). Ligand B is much preferred here.

**Microsomal Clearance:** Ligand A (61.436) has a higher microsomal clearance than Ligand B (21.14), indicating lower metabolic stability.

**In vitro Half-Life:** Ligand A (21.082) has a longer half-life than Ligand B (13.029), which is preferable.

**P-gp Efflux:** Ligand A (0.499) has lower P-gp efflux than Ligand B (0.304), which is beneficial for CNS penetration.

**Binding Affinity:** Ligand A (-9.2 kcal/mol) has a significantly stronger binding affinity than Ligand B (-7.9 kcal/mol). This is a substantial advantage, potentially outweighing some of the ADME drawbacks.

**Overall Assessment:**

Despite Ligand A's poor Caco-2 permeability and higher microsomal clearance, its significantly superior binding affinity (-9.2 vs -7.9 kcal/mol) and excellent BBB penetration (84.451 vs 68.67) make it the more promising candidate. The strong binding affinity suggests it may be effective at lower doses, potentially mitigating some of the ADME concerns. Ligand B has a better hERG profile and lower DILI risk, but the weaker binding and lower BBB penetration are significant drawbacks for a CNS-targeted GPCR.

Output:
1
2025-04-17 04:54:31,761 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (349.4) is slightly better positioned.

**TPSA:** Ligand B (92.34) is significantly better than Ligand A (125.79). For CNS targets, we want TPSA <= 90, so Ligand B is closer to this threshold.

**logP:** Ligand B (1.356) is within the optimal range (1-3), while Ligand A (-0.842) is slightly below, which could hinder permeation.

**H-Bond Donors/Acceptors:** Ligand A (1 HBD, 8 HBA) and Ligand B (2 HBD, 5 HBA) both fall within acceptable limits.

**QED:** Both ligands have similar QED values (0.625 and 0.587), indicating good drug-likeness.

**DILI:** Ligand B (35.014) has a much lower DILI risk than Ligand A (52.966), making it safer.

**BBB:** Ligand B (65.413) has a significantly better BBB penetration percentile than Ligand A (57.736).  A value >70 is desirable for CNS targets, but 65.413 is preferable to 57.736.

**Caco-2 Permeability:** Ligand A (-6.065) has a worse Caco-2 permeability than Ligand B (-5.619), indicating poorer intestinal absorption.

**Aqueous Solubility:** Ligand A (0.021) has slightly better aqueous solubility than Ligand B (-2.651).

**hERG Inhibition:** Ligand B (0.205) has a much lower hERG inhibition liability than Ligand A (0.026), which is a significant safety advantage.

**Microsomal Clearance:** Ligand B (48.817) has a better microsomal clearance than Ligand A (17.276), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand B (21.005) has a longer in vitro half-life than Ligand A (9.225), which is desirable.

**P-gp Efflux:** Ligand A (0.029) has a slightly lower P-gp efflux liability than Ligand B (0.094), which could lead to better CNS exposure.

**Binding Affinity:** Both ligands have the same binding affinity (-7.2 kcal/mol), which is excellent.

**Overall Assessment:**

Ligand B is superior to Ligand A. While Ligand A has slightly better solubility and P-gp efflux, Ligand B excels in critical areas for a CNS-targeting GPCR ligand: TPSA, BBB penetration, DILI risk, hERG inhibition, metabolic stability (Cl_mic and t1/2), and Caco-2 permeability. The similar binding affinity removes that as a differentiating factor. The lower logP of Ligand A is a concern.



Output:
1
2025-04-17 04:54:31,761 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (343.362 and 357.445 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (80.12) is better than Ligand B (61.44), both are below the 90 A^2 threshold desirable for CNS targets.

**logP:** Ligand A (0.899) is a bit low, potentially hindering permeability. Ligand B (1.939) is better, falling within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A has 1 HBD and 5 HBA, while Ligand B has 2 HBD and 3 HBA. Both are within acceptable limits.

**QED:** Ligand A (0.837) has a better QED score than Ligand B (0.685), indicating a more drug-like profile.

**DILI:** Ligand B (24.661) has a significantly lower DILI risk than Ligand A (54.517), which is a major advantage.

**BBB:** Ligand B (83.249) has a much higher BBB penetration percentile than Ligand A (57.968). This is *critical* for a CNS target like DRD2.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.893 and -4.956), which is unusual and suggests poor permeability. However, these values are on a log scale and are likely representing very low permeability.

**Aqueous Solubility:** Both ligands have negative solubility values (-1.74 and -2.373), indicating poor aqueous solubility.

**hERG Inhibition:** Ligand A (0.209) has a lower hERG inhibition liability than Ligand B (0.539), which is preferable.

**Microsomal Clearance:** Ligand A (19.291) has a higher microsomal clearance than Ligand B (5.294), suggesting lower metabolic stability.

**In vitro Half-Life:** Ligand B (-13.165) has a longer in vitro half-life than Ligand A (-19.095).

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.033 and 0.038).

**Binding Affinity:** Both ligands have similar binding affinities (-8.9 and -8.3 kcal/mol), both being excellent. The difference of 0.6 kcal/mol is not substantial enough to override other factors.

**Overall Assessment:**

Ligand B is the stronger candidate. While Ligand A has a better QED and lower hERG risk, Ligand B's significantly better BBB penetration and lower DILI risk are paramount for a CNS-targeting drug. The slightly better logP and in vitro half-life also contribute to its favorability. The poor Caco-2 and solubility are concerns for both, but can be addressed with formulation strategies.

Output:
1
2025-04-17 04:54:31,761 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (344.346) is slightly better, being closer to the lower end which can aid permeability.

**TPSA:** Both ligands have TPSA values below 140, suggesting good oral absorption potential. Ligand A (89.01) is better than Ligand B (96.37) and importantly, is below the 90 threshold desirable for CNS targets.

**logP:** Both ligands have logP values between 1 and 3 (2.533 and 2.352 respectively), which is optimal.

**H-Bond Donors/Acceptors:** Ligand A (HBD=2, HBA=5) is preferable to Ligand B (HBD=3, HBA=6) as it has fewer H-bonds, potentially improving permeability. Both are within acceptable limits.

**QED:** Both ligands have similar QED values (0.712 and 0.681), indicating good drug-like properties.

**DILI:** Ligand B (72.586) has a slightly better DILI score than Ligand A (88.251), but both are acceptable (below 60 is ideal, both are below 90).

**BBB:** Ligand A (66.615) has a significantly better BBB percentile than Ligand B (53.432). This is a *critical* factor for a CNS target like DRD2.

**Caco-2 Permeability:** Ligand A (-4.846) has a better Caco-2 permeability than Ligand B (-5.351), suggesting better intestinal absorption.

**Aqueous Solubility:** Both ligands have very poor aqueous solubility (-4.106 and -4.199). This could be a formulation challenge, but is less critical than BBB for a CNS target.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.657 and 0.431), which is good.

**Microsomal Clearance:** Both ligands have similar microsomal clearance values (52.978 and 53.127), indicating similar metabolic stability.

**In vitro Half-Life:** Ligand A (15.902) has a significantly longer in vitro half-life than Ligand B (-0.042). This is a major advantage.

**P-gp Efflux:** Ligand A (0.351) has lower P-gp efflux liability than Ligand B (0.086), which is beneficial for CNS exposure.

**Binding Affinity:** Ligand B (-8.9 kcal/mol) has a slightly better binding affinity than Ligand A (-9.8 kcal/mol). While a difference of 0.9 kcal/mol is noticeable, the ADME advantages of Ligand A are substantial.

**Overall:** While Ligand B has slightly better binding affinity, Ligand A exhibits superior ADME properties, particularly its significantly better BBB penetration (66.615 vs 53.432), longer half-life, and lower P-gp efflux. For a CNS target like DRD2, these factors are paramount. The slightly weaker binding of Ligand A can potentially be optimized in subsequent iterations, while improving ADME properties is often more challenging.

Output:
0
2025-04-17 04:54:31,762 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (348.462 and 346.515 Da) fall comfortably within the ideal 200-500 Da range.

**2. TPSA:** Both ligands have a TPSA of 49.41, which is excellent for CNS penetration (well below the 90 A^2 threshold).

**3. logP:** Ligand A (2.845) is optimal, while Ligand B (3.666) is slightly higher but still acceptable.

**4. H-Bond Donors:** Both have 1 HBD, which is good.

**5. H-Bond Acceptors:** Both have 2 HBA, which is good.

**6. QED:** Both ligands have QED values above 0.5 (0.593 and 0.746), indicating good drug-likeness.

**7. DILI:** Ligand A (16.324) has a significantly lower DILI risk than Ligand B (6.592). This is a substantial advantage.

**8. BBB:** Both ligands have excellent BBB penetration (86.468 and 85.111), exceeding the desirable >70 threshold.

**9. Caco-2 Permeability:** Both have negative Caco-2 values (-4.823 and -4.852), which is unusual and suggests poor permeability. However, these values are on the same scale, so this isn't a differentiating factor.

**10. Aqueous Solubility:** Both have negative solubility values (-3.428 and -3.459), indicating poor aqueous solubility. Again, similar for both.

**11. hERG Inhibition:** Both ligands show low hERG inhibition liability (0.69 and 0.532), which is positive.

**12. Microsomal Clearance:** Ligand A (29.054) has lower microsomal clearance than Ligand B (36.358), suggesting better metabolic stability.

**13. In vitro Half-Life:** Ligand A (-3.018) has a significantly longer in vitro half-life than Ligand B (-14.278). This is a major advantage.

**14. P-gp Efflux:** Both have very low P-gp efflux liability (0.178 and 0.157), which is favorable for CNS penetration.

**15. Binding Affinity:** Ligand B (-8.9 kcal/mol) has a slightly better binding affinity than Ligand A (-8.2 kcal/mol). While a 0.7 kcal/mol difference is noticeable, it's not a huge gap, and can be overcome by superior ADME properties.

**Overall Assessment:**

Ligand A is the better candidate. While Ligand B has slightly better binding affinity, Ligand A demonstrates significantly better safety (lower DILI), metabolic stability (lower Cl_mic, longer t1/2), and comparable BBB penetration and logP. Given the GPCR-specific priorities, the improved ADME profile of Ligand A outweighs the small difference in binding affinity.

Output:
0
2025-04-17 04:54:31,762 - INFO - Batch 153 complete. Total preferences: 2448
2025-04-17 04:54:31,762 - INFO - Processing batch 154/512...
2025-04-17 04:55:12,236 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (347.419 and 351.491 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (109.14) is higher than the preferred <90 for CNS targets, while Ligand B (61.88) is well within the range. This is a significant advantage for Ligand B.

**3. logP:** Ligand A (0.15) is quite low, potentially hindering membrane permeability. Ligand B (1.251) is within the optimal 1-3 range. This favors Ligand B.

**4. H-Bond Donors:** Ligand A (3) is acceptable, while Ligand B (1) is even better, potentially improving permeability.

**5. H-Bond Acceptors:** Ligand A (6) is acceptable, and Ligand B (4) is also good.

**6. QED:** Both ligands have good QED scores (0.58 and 0.715), indicating drug-like properties.

**7. DILI:** Ligand A (45.25) has a moderate DILI risk, while Ligand B (5.933) has a very low risk. This is a clear advantage for Ligand B.

**8. BBB:** Ligand A (29.003) has a poor BBB percentile, making CNS penetration unlikely. Ligand B (70.88) has a very good BBB percentile, crucial for a DRD2 ligand. This is a major advantage for Ligand B.

**9. Caco-2 Permeability:** Ligand A (-5.662) has poor Caco-2 permeability, consistent with its low logP. Ligand B (-4.828) is also not great, but better than A.

**10. Aqueous Solubility:** Both have negative solubility values, indicating poor solubility. This is a concern for both, but might be less critical if permeability is good.

**11. hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.049 and 0.45).

**12. Microsomal Clearance:** Ligand A (-7.516) has a very low (negative) clearance, suggesting high metabolic stability. Ligand B (20.715) has a moderate clearance. This favors Ligand A, but the difference isn't huge.

**13. In vitro Half-Life:** Ligand A (6.949) has a moderate half-life, while Ligand B (10.327) has a longer half-life. This favors Ligand B.

**14. P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.011 and 0.007), which is good for CNS penetration.

**15. Binding Affinity:** Ligand A (-7.9) has slightly better binding affinity than Ligand B (-7.5). However, the difference is only 0.4 kcal/mol, which is not enough to overcome the significant ADME deficiencies of Ligand A.

**Overall Assessment:**

Ligand B is significantly more promising. While Ligand A has slightly better binding affinity, Ligand B excels in crucial ADME properties for a CNS-targeting GPCR ligand: TPSA, logP, BBB penetration, DILI risk, and half-life. The poor BBB and logP of Ligand A make it unlikely to reach the target in the brain, even with its slightly better affinity. Ligand B's profile suggests it has a much higher probability of becoming a viable drug candidate.

Output:
1
2025-04-17 04:55:12,237 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (371.507 and 347.507 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (87.54) is better than Ligand B (53.4). Both are below the 90 A^2 threshold desirable for CNS targets, but A is closer to the upper limit.

**logP:** Ligand A (0.955) is slightly lower than optimal (1-3), but still acceptable. Ligand B (2.215) is within the optimal range.

**H-Bond Donors/Acceptors:** Both ligands have 1 HBD and 4-5 HBA, which are within acceptable limits.

**QED:** Both ligands have good QED scores (0.755 and 0.912), indicating good drug-like properties.

**DILI:** Ligand A (35.052) has a significantly lower DILI risk than Ligand B (5.312), which is a major advantage.

**BBB:** Ligand A (75.107) and Ligand B (72.082) both have good BBB penetration, but A is slightly better. Both are above the 70 percentile threshold.

**Caco-2 Permeability:** Ligand A (-4.927) has slightly better Caco-2 permeability than Ligand B (-4.749), but both are negative values, suggesting poor permeability.

**Aqueous Solubility:** Ligand A (-1.686) has slightly better solubility than Ligand B (-0.695), but both are negative values, suggesting poor solubility.

**hERG:** Both ligands have low hERG inhibition liability (0.319 and 0.68), which is good.

**Microsomal Clearance:** Ligand A (19.037) has a higher microsomal clearance than Ligand B (-12.957). This means Ligand B is more metabolically stable, a significant advantage.

**In vitro Half-Life:** Ligand B (5.494) has a much longer in vitro half-life than Ligand A (-55.624), which is a substantial benefit.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.021 and 0.042), which is excellent for CNS penetration.

**Binding Affinity:** Both ligands have similar binding affinities (-8.3 and -8.5 kcal/mol), both of which are excellent.

**Overall Assessment:**

While Ligand A has a slightly better BBB and TPSA, Ligand B has a significantly better metabolic profile (lower Cl_mic, longer t1/2), lower DILI risk, and a slightly better logP. The similar binding affinities make the ADME properties the deciding factor. For a CNS target like DRD2, metabolic stability and minimizing off-target effects (DILI) are crucial.

Output:
1
2025-04-17 04:55:12,237 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (366.527 and 343.475 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (75.27) is slightly above the preferred <90 for CNS targets, while Ligand B (70.15) is well within the range. This gives a slight edge to Ligand B.

**3. logP:** Ligand A (4.1) is a bit high, potentially leading to solubility issues and off-target effects. Ligand B (2.666) is closer to the optimal 1-3 range. This is a significant advantage for Ligand B.

**4. H-Bond Donors:** Both have 2 HBD, which is acceptable.

**5. H-Bond Acceptors:** Ligand A has 3 HBA, and Ligand B has 5. Both are within the acceptable limit of <=10.

**6. QED:** Both ligands have similar QED values (0.824 and 0.831), indicating good drug-likeness.

**7. DILI:** Ligand A (43.117) has a slightly higher DILI risk than Ligand B (26.483), although both are below the concerning threshold of 60.

**8. BBB:** Ligand B (90.772) has a significantly better BBB penetration percentile than Ligand A (82.551). This is a crucial advantage for a CNS target like DRD2.

**9. Caco-2:** Ligand A (-4.42) and Ligand B (-5.114) both have negative Caco-2 values, which is unusual and suggests poor permeability. However, the scale is not defined, so it's difficult to interpret.

**10. Solubility:** Ligand A (-5.119) has worse solubility than Ligand B (-2.601). This is consistent with its higher logP.

**11. hERG:** Ligand A (0.492) has a slightly lower hERG risk than Ligand B (0.723), but both are relatively low.

**12. Cl_mic:** Ligand B (44.682) has a slightly higher microsomal clearance than Ligand A (39.62), suggesting potentially lower metabolic stability.

**13. t1/2:** Ligand A (38.62) has a longer in vitro half-life than Ligand B (25.737). This is a positive for Ligand A.

**14. Pgp:** Ligand A (0.174) has lower P-gp efflux liability than Ligand B (0.136), which is favorable for CNS penetration.

**15. Binding Affinity:** Ligand B (-9.2 kcal/mol) has a significantly stronger binding affinity than Ligand A (-8.6 kcal/mol). This is a substantial advantage that can outweigh minor ADME drawbacks.

**Overall Assessment:**

Ligand B is the more promising candidate. It has a better logP, significantly better BBB penetration, and a substantially stronger binding affinity. While Ligand A has a slightly longer half-life and lower Pgp efflux, the advantages of Ligand B in terms of CNS penetration and potency are more critical for a DRD2 ligand. The slightly higher Cl_mic for Ligand B is a minor concern that could be addressed through structural modifications.

Output:
1
2025-04-17 04:55:12,237 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (351.328 and 346.475 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (62.3) is excellent, well below the 90 A^2 threshold for CNS targets. Ligand B (78.09) is still reasonable but less optimal.

**3. logP:** Both ligands have good logP values (2.499 and 2.303), falling within the optimal 1-3 range.

**4. H-Bond Donors:** Ligand A (1) and Ligand B (2) both meet the HBD <=5 criteria.

**5. H-Bond Acceptors:** Both ligands (3) meet the HBA <=10 criteria.

**6. QED:** Ligand A (0.9) is excellent, indicating high drug-likeness. Ligand B (0.795) is still good, but less so.

**7. DILI:** Ligand A (67.313) has a moderate DILI risk, while Ligand B (13.687) has a very low DILI risk. This favors Ligand B.

**8. BBB:** Ligand A (78.79) has a good BBB percentile, exceeding the 70% threshold for CNS targets. Ligand B (55.332) is significantly lower and less desirable for CNS penetration. This is a major advantage for Ligand A.

**9. Caco-2:** Both have negative values, which is unusual. Assuming these represent logP-like scales, lower values indicate poorer permeability. Ligand A (-4.592) is worse than Ligand B (-5.056).

**10. Solubility:** Both have negative values, which is unusual. Assuming these represent logS-like scales, lower values indicate poorer solubility. Ligand A (-2.403) is better than Ligand B (-1.837).

**11. hERG:** Both ligands have very low hERG risk (0.341 and 0.37).

**12. Cl_mic:** Ligand A (33.527) has a moderate clearance, while Ligand B (18.241) has lower clearance, suggesting better metabolic stability. This favors Ligand B.

**13. t1/2:** Ligand A (-9.66) has a very long half-life, while Ligand B (-18.015) has an even longer half-life. This strongly favors Ligand B.

**14. Pgp:** Both ligands have very low Pgp efflux liability (0.082 and 0.031).

**15. Binding Affinity:** Ligand A (-9.8) has a significantly stronger binding affinity than Ligand B (-8.0). This is a substantial advantage for Ligand A.

**Overall Assessment:**

Ligand A excels in BBB penetration and, crucially, binding affinity. The strong binding affinity can potentially offset some of its less favorable ADME properties. Ligand B has better DILI and metabolic stability (lower Cl_mic) and a longer half-life, but its BBB penetration is significantly lower, which is critical for a CNS target like DRD2. The superior binding affinity of Ligand A is a significant advantage, and the acceptable BBB score makes it the more promising candidate.

Output:
0
2025-04-17 04:55:12,238 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (356.491 and 370.479 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (62.22) is excellent, well below the 90 A^2 threshold for CNS targets. Ligand B (103.45) is higher, but still reasonably acceptable, though less optimal.

**logP:** Ligand A (3.209) is within the optimal 1-3 range. Ligand B (-0.633) is significantly lower, which could hinder membrane permeability and CNS penetration.

**H-Bond Donors/Acceptors:** Both ligands have 2 HBDs, which is good. Ligand A has 4 HBAs, and Ligand B has 7 HBAs. Both are acceptable, but Ligand A is slightly better.

**QED:** Both ligands have reasonable QED scores (0.835 and 0.558), indicating drug-like properties. Ligand A's is better.

**DILI:** Both ligands have low DILI risk (49.632 and 47.15), which is favorable.

**BBB:** Ligand A (68.515) is better than Ligand B (48.623) for CNS penetration, although ideally we want >70%.

**Caco-2 Permeability:** Ligand A (-4.79) is unfavorable, indicating poor permeability. Ligand B (-5.653) is even worse.

**Aqueous Solubility:** Ligand A (-4.465) is unfavorable, suggesting poor solubility. Ligand B (-1.949) is also unfavorable, but slightly better than Ligand A.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.623 and 0.476), which is good.

**Microsomal Clearance:** Ligand A (55.283) has higher clearance than Ligand B (22.765), suggesting lower metabolic stability. Ligand B is better here.

**In vitro Half-Life:** Ligand A (9.422) has a better half-life than Ligand B (-15.773).

**P-gp Efflux:** Ligand A (0.678) has lower P-gp efflux than Ligand B (0.015), meaning it is less likely to be pumped out of the brain.

**Binding Affinity:** Ligand A (-9.1 kcal/mol) has a significantly stronger binding affinity than Ligand B (-7.0 kcal/mol). This is a substantial advantage.

**Overall Assessment:**

Ligand A is superior despite its poor Caco-2 permeability and solubility. The significantly stronger binding affinity (-9.1 vs -7.0 kcal/mol) is a major advantage, and can often compensate for some ADME liabilities. Additionally, Ligand A has better BBB penetration and lower P-gp efflux, both crucial for CNS targets. While Ligand B has better metabolic stability, the difference in binding affinity is too large to ignore. The lower logP of Ligand B is a significant concern for CNS penetration.

Output:
1
2025-04-17 04:55:12,238 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (344.5 and 341.4 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (40.62) is significantly better than Ligand B (71.09). For CNS targets, we want TPSA <= 90, and ideally closer to 60. Ligand A is much closer to this ideal.

**3. logP:** Both ligands have good logP values (3.94 and 2.44), falling within the 1-3 optimal range. Ligand A is slightly higher, which could be beneficial for membrane permeability, but isn't a major concern for either.

**4. H-Bond Donors:** Ligand A (0) is preferable to Ligand B (2). Fewer H-bond donors generally improve permeability.

**5. H-Bond Acceptors:** Ligand A (2) is preferable to Ligand B (3). Fewer H-bond acceptors generally improve permeability.

**6. QED:** Both ligands have good QED scores (0.703 and 0.848), indicating good drug-like properties.

**7. DILI:** Ligand A (23.9) has a much lower DILI risk than Ligand B (50.1). This is a significant advantage for Ligand A.

**8. BBB:** Ligand A (96.8) has a significantly higher BBB penetration percentile than Ligand B (83.2). This is *critical* for a CNS target like DRD2.

**9. Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and suggests a potential issue with the prediction method. However, the magnitude is similar.

**10. Aqueous Solubility:** Both have negative solubility values, again suggesting a potential issue with the prediction method. The magnitude is similar.

**11. hERG:** Both ligands have low hERG inhibition liability (0.878 and 0.257), which is good.

**12. Microsomal Clearance:** Ligand A (96.6) has a much higher microsomal clearance than Ligand B (37.2), indicating lower metabolic stability. This is a drawback for Ligand A.

**13. In vitro Half-Life:** Ligand B (-20.1) has a negative half-life, which is nonsensical. Ligand A (12.0) is reasonable.

**14. P-gp Efflux:** Both have very low P-gp efflux liability (0.674 and 0.108), which is good for CNS penetration.

**15. Binding Affinity:** Both ligands have excellent binding affinities (-9.0 and -9.4 kcal/mol). The difference is minimal.

**Overall Assessment:**

Ligand A is significantly better overall, despite the higher microsomal clearance. The superior BBB penetration (96.8 vs. 83.2), lower DILI risk (23.9 vs. 50.1), lower TPSA (40.6 vs 71.1), and fewer H-bonds make it a much more promising candidate for a CNS-targeting drug like a DRD2 ligand. The slightly higher logP is also favorable. The nonsensical half-life prediction for Ligand B is a major red flag. While Ligand A's clearance is higher, the other advantages outweigh this drawback, especially considering the importance of CNS penetration for this target.

Output:
1
2025-04-17 04:55:12,238 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (339.443 and 359.436 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (64.86) is better than Ligand B (46.09) as it is closer to the optimal range for CNS targets (<=90).

**logP:** Both ligands have logP values (3.244 and 4.642) within the optimal 1-3 range, but Ligand B is slightly higher, potentially increasing off-target effects.

**H-Bond Donors/Acceptors:** Ligand A has 1 HBD and 6 HBA, while Ligand B has 0 HBD and 3 HBA. Both are within acceptable limits.

**QED:** Ligand A (0.926) has a significantly better QED score than Ligand B (0.645), indicating a more drug-like profile.

**DILI:** Ligand A (48.313) has a slightly higher DILI risk than Ligand B (37.069), but both are below the concerning threshold of 60.

**BBB:** Ligand B (92.943) has a considerably higher BBB penetration percentile than Ligand A (82.513). This is a critical advantage for a CNS target like DRD2.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.851 and -4.575), which is unusual and suggests poor permeability. This is a significant concern for both.

**Aqueous Solubility:** Both ligands have negative solubility values (-4.233 and -4.6), indicating very poor aqueous solubility. This is a major drawback.

**hERG Inhibition:** Ligand A (0.361) shows a lower hERG inhibition liability than Ligand B (0.843), which is preferable.

**Microsomal Clearance:** Ligand B (56.211) has slightly higher microsomal clearance than Ligand A (52.256), suggesting lower metabolic stability.

**In vitro Half-Life:** Ligand A (-7.68) has a significantly longer in vitro half-life than Ligand B (23.51), which is a positive attribute.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (-9 and -7.4), which is good for CNS penetration.

**Binding Affinity:** Ligand B (-7.4) has a slightly better binding affinity than Ligand A (-9), although both are excellent. The 1.5 kcal/mol difference could be significant.

**Overall Assessment:**

While Ligand B has a better BBB score and slightly better affinity, Ligand A has a much better QED, lower hERG risk, and a significantly longer half-life. Both have poor solubility and permeability. Given the importance of BBB for CNS targets, Ligand B initially appears more promising. However, the significantly better drug-likeness (QED) and safety profile (hERG) of Ligand A, combined with its longer half-life, make it a more balanced candidate. The slightly weaker affinity can potentially be optimized in further iterations. The poor solubility and permeability are significant issues for both, but can be addressed with formulation strategies.

Output:
1
2025-04-17 04:55:12,238 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (361.32 and 345.443 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (87.74) is excellent, falling well below the 90 A^2 threshold for CNS targets. Ligand B (91.32) is slightly higher, but still acceptable.

**3. logP:** Ligand A (0.687) is a bit low, potentially hindering permeability. Ligand B (1.781) is better, falling within the optimal 1-3 range.

**4. H-Bond Donors:** Ligand A (2) and Ligand B (3) are both within the acceptable limit of <=5.

**5. H-Bond Acceptors:** Both ligands (A: 4, B: 4) are well below the 10 threshold.

**6. QED:** Ligand A (0.709) has a significantly better QED score than Ligand B (0.47), indicating a more drug-like profile.

**7. DILI:** Ligand A (56.805) has a lower DILI risk than Ligand B (46.452), suggesting better safety.

**8. BBB:** This is crucial for a CNS target. Ligand A (91.392) has a very high BBB penetration percentile, which is excellent. Ligand B (27.181) has a very low BBB percentile, making it less likely to reach the target in the brain.

**9. Caco-2:** Both ligands have negative Caco-2 values (-5.042 and -4.997), which is unusual and suggests poor permeability. This is a significant concern for both.

**10. Solubility:** Both ligands have very low solubility scores (-2.872 and -2.422). This is a major drawback for both compounds.

**11. hERG:** Both ligands have low hERG inhibition liability (0.139 and 0.379), which is good.

**12. Cl_mic:** Ligand A (5.569) has a lower microsomal clearance than Ligand B (24.49), indicating better metabolic stability.

**13. t1/2:** Ligand A (33.441) has a longer in vitro half-life than Ligand B (-28.577), which is desirable.

**14. Pgp:** Ligand A (0.011) has significantly lower P-gp efflux liability than Ligand B (0.068), meaning it's more likely to accumulate in the brain.

**15. Binding Affinity:** Ligand A (-8.7 kcal/mol) has a slightly better binding affinity than Ligand B (-7.8 kcal/mol), although both are good.

**Overall Assessment:**

Despite the poor Caco-2 and solubility values for both, Ligand A is the superior candidate. Its significantly better BBB penetration, lower Pgp efflux, better metabolic stability (lower Cl_mic, longer t1/2), lower DILI risk, and slightly better binding affinity outweigh the slightly lower logP. The high BBB value is particularly important for a CNS target like DRD2. While both have issues, Ligand A is more likely to reach the target and have a favorable safety profile.

Output:
0
2025-04-17 04:55:12,238 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (353.463 and 360.527 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (87.74) is better than Ligand B (41.37). Both are below the 90 A^2 threshold desirable for CNS targets.

**logP:** Ligand B (2.938) is optimal (1-3), while Ligand A (0.681) is a bit low, potentially hindering permeation.

**H-Bond Donors:** Ligand A (2) is preferable to Ligand B (0).

**H-Bond Acceptors:** Ligand A (4) is preferable to Ligand B (5).

**QED:** Both ligands have good QED scores (0.705 and 0.762, respectively), indicating drug-like properties.

**DILI:** Ligand A (15.2) has a significantly lower DILI risk than Ligand B (29.624), which is a major advantage.

**BBB:** Ligand B (77.549) has a much better BBB penetration score than Ligand A (50.019). This is a critical factor for a CNS target like DRD2.

**Caco-2 Permeability:** Both have negative values (-5.121 and -5.051), which is unusual and suggests poor permeability. However, these values are on a scale where negative values are possible, and direct comparison is difficult without knowing the scale's specifics.

**Aqueous Solubility:** Both have negative values (-0.862 and -2.331), which again suggests poor solubility.

**hERG Inhibition:** Ligand A (0.089) has a lower hERG inhibition liability than Ligand B (0.573), indicating a lower risk of cardiotoxicity.

**Microsomal Clearance:** Ligand A (8.858) has a lower microsomal clearance than Ligand B (58.315), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand B (18.661) has a longer in vitro half-life than Ligand A (10.292).

**P-gp Efflux:** Ligand A (0.009) has significantly lower P-gp efflux liability than Ligand B (0.346), which is crucial for CNS penetration.

**Binding Affinity:** Ligand A (-7.8 kcal/mol) has a slightly better binding affinity than Ligand B (-7.4 kcal/mol). While the difference is not huge, it's enough to potentially outweigh some ADME drawbacks.

**Overall Assessment:**

Ligand A excels in DILI risk, metabolic stability (Cl_mic), P-gp efflux, and binding affinity. Ligand B has a significantly better BBB score and a longer half-life. However, the lower DILI, P-gp, and better affinity of Ligand A are more critical for a CNS GPCR target. The slightly lower BBB of Ligand A is a concern, but the other advantages are substantial. The poor Caco-2 and solubility values are concerning for both, but can be addressed through formulation strategies.

Output:
0
2025-04-17 04:55:12,238 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (371.849 and 362.499 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (62.3) is excellent, well below the 90 threshold for CNS targets. Ligand B (97.11) is higher, but still potentially acceptable, though less ideal.

**logP:** Ligand A (4.327) is slightly high, potentially leading to solubility issues or off-target interactions. Ligand B (2.24) is within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A (1 HBD, 4 HBA) is favorable. Ligand B (3 HBD, 5 HBA) is also acceptable.

**QED:** Both ligands have good QED scores (0.692 and 0.718), indicating good drug-like properties.

**DILI:** Ligand A (85.886) has a higher DILI risk than Ligand B (62.466), which is preferable.

**BBB:** Both ligands have similar BBB penetration (69.213 and 61.923), but both are below the desirable >70 for CNS targets.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.595 and -4.989), which is unusual and suggests poor permeability. This is a significant concern.

**Aqueous Solubility:** Both ligands have very poor aqueous solubility (-5.362 and -3.786). This is a major drawback.

**hERG Inhibition:** Both ligands show low hERG inhibition risk (0.594 and 0.507).

**Microsomal Clearance:** Ligand A (64.459) has higher clearance than Ligand B (-0.848), indicating lower metabolic stability.

**In vitro Half-Life:** Ligand A (62.893) has a longer half-life than Ligand B (22.619).

**P-gp Efflux:** Ligand A (0.417) has lower P-gp efflux liability than Ligand B (0.078), which is favorable for CNS penetration.

**Binding Affinity:** Ligand A (-9.2 kcal/mol) has significantly stronger binding affinity than Ligand B (-7.3 kcal/mol). This is a substantial advantage, potentially outweighing some of its other drawbacks.

**Overall Assessment:**

Ligand A's primary advantage is its significantly higher binding affinity. However, it suffers from a higher logP, higher DILI risk, and higher microsomal clearance. Ligand B has better physicochemical properties (logP, DILI, Cl_mic) but weaker binding affinity. Both have poor solubility and Caco-2 permeability.

Given the GPCR-specific priorities, and the substantial affinity difference, Ligand A is the more promising candidate *despite* its drawbacks. The strong binding affinity could be optimized through further medicinal chemistry efforts to address the logP and metabolic stability issues. The poor solubility and permeability are concerning, but might be addressed with formulation strategies.

Output:
1
2025-04-17 04:55:12,238 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (381.78 and 358.55 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (64.63) is higher than Ligand B (33.2). For CNS targets, we prefer TPSA <= 90, so both are acceptable, but B is significantly better.

**3. logP:** Ligand A (3.137) is within the optimal 1-3 range. Ligand B (4.512) is slightly above, potentially raising concerns about solubility and off-target effects, but not drastically.

**4. H-Bond Donors:** Ligand A (1) and Ligand B (0) are both good, being <=5.

**5. H-Bond Acceptors:** Ligand A (4) and Ligand B (3) are both good, being <=10.

**6. QED:** Both ligands have similar QED values (0.769 and 0.726), indicating good drug-like properties.

**7. DILI:** Ligand A (53.974) has a higher DILI risk than Ligand B (17.371). This is a significant advantage for Ligand B.

**8. BBB:** Ligand B (74.641) has a substantially better BBB penetration percentile than Ligand A (49.748). This is *critical* for a CNS target like DRD2.

**9. Caco-2 Permeability:** Both have negative values which is unusual, but we can interpret this as very low permeability.

**10. Aqueous Solubility:** Both have negative values which is unusual, but we can interpret this as very low solubility.

**11. hERG:** Both ligands have low hERG inhibition liability (0.472 and 0.517), which is good.

**12. Microsomal Clearance:** Ligand A (81.806) has higher microsomal clearance than Ligand B (62.544), indicating lower metabolic stability.

**13. In vitro Half-Life:** Ligand B (17.811 hours) has a significantly longer half-life than Ligand A (0.47 hours). This is a major advantage.

**14. P-gp Efflux:** Ligand A (0.098) has lower P-gp efflux than Ligand B (0.605), which is a slight advantage for CNS exposure.

**15. Binding Affinity:** Ligand A (-8.1 kcal/mol) has a slightly better binding affinity than Ligand B (-7.8 kcal/mol). While a 0.3 kcal/mol difference is noticeable, it's not a huge gap and can be overcome by superior ADME properties.

**Overall Assessment:**

Ligand B is the more promising candidate. While Ligand A has slightly better binding affinity, Ligand B excels in key ADME properties crucial for CNS drug development: significantly better BBB penetration, lower DILI risk, and a much longer in vitro half-life. The slightly higher logP of Ligand B is a minor concern compared to the substantial benefits in BBB, DILI, and half-life. The lower P-gp efflux of Ligand A is a small advantage, but not enough to offset the other benefits of Ligand B.

Output:
1
2025-04-17 04:55:12,239 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (359.5 & 352.5 Da) fall comfortably within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (73.2) is better than Ligand B (76.7). Both are below the 90 A^2 threshold desirable for CNS targets, but A is closer to the optimal range.

**3. logP:** Ligand A (3.03) is within the optimal 1-3 range. Ligand B (1.63) is at the lower end, potentially hindering permeability.

**4. H-Bond Donors:** Ligand A (1) is preferable to Ligand B (2). Fewer HBDs generally improve permeability.

**5. H-Bond Acceptors:** Both ligands have 4 HBA, which is acceptable.

**6. QED:** Ligand A (0.90) has a significantly better QED score than Ligand B (0.66), indicating a more drug-like profile.

**7. DILI:** Ligand A (50.1) has a higher DILI risk than Ligand B (15.0). This is a negative for Ligand A.

**8. BBB:** Both ligands have acceptable BBB penetration (Ligand A: 60.7, Ligand B: 65.8). However, for a CNS target like DRD2, higher is better, giving a slight edge to Ligand B.

**9. Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and suggests poor permeability. This is a significant concern for both.

**10. Aqueous Solubility:** Both have negative solubility values, which is also unusual and suggests poor solubility. This is a significant concern for both.

**11. hERG Inhibition:** Both ligands show low hERG inhibition risk (Ligand A: 0.60, Ligand B: 0.37).

**12. Microsomal Clearance:** Ligand A (21.0) has lower microsomal clearance than Ligand B (53.4), indicating better metabolic stability.

**13. In vitro Half-Life:** Ligand A (1.51) has a shorter half-life than Ligand B (12.93). Longer half-life is generally preferred.

**14. P-gp Efflux:** Ligand A (0.297) has lower P-gp efflux than Ligand B (0.038), which is favorable for CNS penetration.

**15. Binding Affinity:** Ligand A (-8.8 kcal/mol) has a significantly stronger binding affinity than Ligand B (-7.3 kcal/mol). This is a crucial advantage, potentially outweighing some of the ADME drawbacks.

**Overall Assessment:**

Despite Ligand A's higher DILI risk, its superior binding affinity (-8.8 vs -7.3 kcal/mol), better QED, lower P-gp efflux, and lower microsomal clearance make it the more promising candidate. The affinity difference is substantial (>1.5 kcal/mol), and the lower P-gp efflux is particularly important for CNS targets. While both have concerning Caco-2 and solubility values, the stronger binding of Ligand A suggests it might be more effective *in vivo* even with these limitations.

Output:
1
2025-04-17 04:55:12,239 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (340.467 Da) is slightly lower, which is generally favorable for permeability.

**2. TPSA:** Ligand A (52.57) is significantly better than Ligand B (59.07). For CNS targets, we want TPSA <= 90, and lower is better. Ligand A is comfortably within this range, while Ligand B is approaching the upper limit.

**3. logP:** Both ligands have acceptable logP values (A: 2.705, B: 4.251). Ligand A is optimal (1-3), while Ligand B is slightly higher, potentially raising concerns about solubility and off-target effects, but still within a reasonable range.

**4. H-Bond Donors:** Both have 2 HBD, which is within the ideal range of <=5.

**5. H-Bond Acceptors:** Ligand A has 3 HBA, and Ligand B has 6. Both are within the acceptable limit of <=10, but Ligand A is preferable.

**6. QED:** Both ligands have good QED scores (A: 0.783, B: 0.813), indicating good drug-like properties.

**7. DILI:** Ligand A (12.718%) has a much lower DILI risk than Ligand B (75.649%). This is a significant advantage for Ligand A.

**8. BBB:** Ligand A (81.698%) has a better BBB penetration score than Ligand B (74.098%). Both are above the 70% threshold desirable for CNS targets, but A is better.

**9. Caco-2 Permeability:** Ligand A (-4.677) has worse Caco-2 permeability than Ligand B (-5.066). Lower values indicate lower permeability.

**10. Aqueous Solubility:** Ligand A (-2.924) has better aqueous solubility than Ligand B (-5.052).

**11. hERG Inhibition:** Both ligands have low hERG inhibition risk (A: 0.754, B: 0.643).

**12. Microsomal Clearance:** Ligand A (24.134) has a lower microsomal clearance than Ligand B (71.493), indicating better metabolic stability.

**13. In vitro Half-Life:** Ligand B (76.329) has a significantly longer in vitro half-life than Ligand A (9.818). This is a positive for Ligand B.

**14. P-gp Efflux:** Ligand A (0.217) has lower P-gp efflux than Ligand B (0.353), which is favorable for CNS exposure.

**15. Binding Affinity:** Both ligands have excellent binding affinity (A: -8.5 kcal/mol, B: -8.3 kcal/mol). Ligand A is slightly better, but the difference is small.

**Overall Assessment:**

Ligand A is the stronger candidate. While Ligand B has a longer half-life, Ligand A excels in critical areas for a CNS-targeting GPCR ligand: lower TPSA, significantly lower DILI risk, better BBB penetration, better solubility, lower P-gp efflux, and slightly better binding affinity. The slightly lower Caco-2 permeability of Ligand A is less concerning given the CNS target and the other favorable properties. The improved metabolic stability of Ligand A is also a significant advantage.

Output:
1
2025-04-17 04:55:12,239 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 drug candidates, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (348.49 and 351.49 Da) are within the ideal 200-500 Da range.

**TPSA:** Ligand A (69.64) is excellent, falling well below the 90 A^2 threshold for CNS targets. Ligand B (81.67) is still reasonable but less optimal.

**logP:** Ligand A (1.94) is within the optimal 1-3 range. Ligand B (0.892) is slightly below 1, which *could* indicate permeability issues, though not drastically.

**H-Bond Donors/Acceptors:** Ligand A (2 HBD, 3 HBA) and Ligand B (3 HBD, 4 HBA) both satisfy the <5 HBD and <10 HBA guidelines.

**QED:** Ligand A (0.771) has a better QED score than Ligand B (0.576), indicating a more drug-like profile.

**DILI:** Both ligands have low DILI risk (5.82 and 5.97, respectively), which is good.

**BBB:** This is a critical parameter for a CNS target like DRD2. Ligand A has a significantly better BBB penetration percentile (61.69) than Ligand B (50.76). While both are below the ideal >70, A is considerably closer.

**Caco-2 Permeability:** Ligand A (-4.715) shows better Caco-2 permeability than Ligand B (-5.268).

**Aqueous Solubility:** Both ligands have poor aqueous solubility (-2.617 and -2.181, respectively). This could pose formulation challenges.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.432 and 0.339, respectively).

**Microsomal Clearance:** Ligand A (40.997) has a higher microsomal clearance than Ligand B (20.588), suggesting lower metabolic stability.

**In vitro Half-Life:** Ligand B (15.063 hours) has a much longer in vitro half-life than Ligand A (-7.41 hours). This is a significant advantage for dosing frequency.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.065 and 0.035, respectively), which is favorable for CNS penetration.

**Binding Affinity:** Ligand B (-7.9 kcal/mol) has a slightly better binding affinity than Ligand A (-8.4 kcal/mol). However, the difference is relatively small.

**Overall Assessment:**

Ligand A excels in TPSA, logP, and BBB penetration, making it more suitable for a CNS target. However, its metabolic stability (higher Cl_mic, shorter half-life) is a concern. Ligand B has a better half-life and slightly improved binding affinity, but its lower logP and BBB penetration are less desirable. Considering the GPCR-specific priorities, the better BBB penetration of Ligand A is a significant advantage. The slightly weaker affinity can potentially be optimized in later stages of drug development.



Output:
1
2025-04-17 04:55:12,239 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands are within the acceptable range (200-500 Da). Ligand A (336.395 Da) is slightly preferred due to being lower in weight.

**2. TPSA:** Ligand A (92.24) is excellent for CNS penetration, being below the 90 threshold. Ligand B (47.56) is also very good.

**3. logP:** Ligand A (2.062) is optimal. Ligand B (4.654) is a bit high, potentially leading to solubility issues and off-target interactions, though still within a reasonable range.

**4. H-Bond Donors:** Both ligands have 1 HBD, which is acceptable.

**5. H-Bond Acceptors:** Ligand A has 5 HBA, and Ligand B has 4. Both are within the acceptable limit of 10.

**6. QED:** Ligand A (0.922) has a very strong drug-like profile. Ligand B (0.467) is considerably lower, indicating a less favorable overall drug-likeness.

**7. DILI:** Ligand A (58.627) has a moderate DILI risk. Ligand B (20.706) has a significantly lower DILI risk, which is a major advantage.

**8. BBB:** Ligand A (70.88) has good BBB penetration. Ligand B (89.027) has excellent BBB penetration, a critical factor for a CNS target like DRD2.

**9. Caco-2 permeability:** Both ligands have negative Caco-2 values, which is unusual and suggests poor permeability. However, these values are on a different scale and difficult to interpret without further context.

**10. Aqueous Solubility:** Both ligands have negative solubility values, indicating poor aqueous solubility.

**11. hERG inhibition:** Both ligands have low hERG inhibition liability, which is good.

**12. Microsomal Clearance:** Ligand A (58.29) has moderate clearance. Ligand B (84.629) has higher clearance, meaning faster metabolism and potentially lower exposure.

**13. In vitro Half-Life:** Ligand A (9.341 hours) has a reasonable half-life. Ligand B (46.179 hours) has a much longer half-life, which is a significant advantage.

**14. P-gp efflux:** Both ligands have low P-gp efflux liability, which is good for CNS penetration.

**15. Binding Affinity:** Ligand B (-7.8 kcal/mol) has a significantly stronger binding affinity than Ligand A (-9.5 kcal/mol). This is a substantial difference and could outweigh some of the other drawbacks.

**Overall Assessment:**

While Ligand A has better QED and a slightly lower MW, Ligand B presents a more compelling profile for a DRD2 ligand. The significantly stronger binding affinity (-7.8 vs -9.5 kcal/mol) is a major advantage. Furthermore, Ligand B has excellent BBB penetration (89.027), lower DILI risk (20.706), and a much longer in vitro half-life (46.179 hours). The higher logP and clearance are concerns, but the strong affinity and CNS properties of Ligand B are more critical for this target.

Output:
1
2025-04-17 04:55:12,239 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (335.407 Da) is slightly lower, which could be advantageous for permeability.

**TPSA:** Ligand A (68.02) is significantly better than Ligand B (74.3), falling well within the desirable range for CNS penetration (<90). Ligand B is approaching the upper limit.

**logP:** Both ligands have acceptable logP values (A: 3.31, B: 1.792), falling within the 1-3 range. Ligand A is slightly higher, which could potentially lead to off-target effects, but is still reasonable.

**H-Bond Donors/Acceptors:** Ligand A (HBD=1, HBA=4) is better than Ligand B (HBD=0, HBA=6) in terms of balancing solubility and permeability.

**QED:** Both ligands have similar, acceptable QED values (A: 0.75, B: 0.647), indicating good drug-like properties.

**DILI:** Both ligands have similar, moderately high DILI risk (A: 61.342, B: 65.374). This is a concern for both, but not a dealbreaker at this stage.

**BBB:** Ligand A (75.921) has a significantly better BBB percentile than Ligand B (65.374). This is a crucial advantage for a CNS target like DRD2.

**Caco-2 Permeability:** Ligand A (-5.206) has a more negative Caco-2 value, which is unusual and suggests *higher* permeability. Ligand B (-4.345) is also negative, but less so.

**Aqueous Solubility:** Both ligands have poor aqueous solubility (A: -2.732, B: -3.153). This could pose formulation challenges.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (A: 0.391, B: 0.476).

**Microsomal Clearance:** Ligand B (85.432) has a higher microsomal clearance than Ligand A (58.009), suggesting lower metabolic stability.

**In vitro Half-Life:** Ligand A (45.073) has a better in vitro half-life than Ligand B (-41.326).

**P-gp Efflux:** Both ligands have low P-gp efflux liability (A: 0.197, B: 0.261).

**Binding Affinity:** Ligand B (-7.0) has a significantly better binding affinity than Ligand A (-10.0). This is a substantial advantage.

**Overall Assessment:**

While Ligand B boasts a superior binding affinity, Ligand A has more favorable ADME properties, particularly regarding BBB penetration, TPSA, and metabolic stability. Given DRD2 is a CNS target, the enhanced BBB penetration and lower clearance of Ligand A are critical advantages. The significantly stronger binding affinity of Ligand B is tempting, but the lower BBB and higher clearance are substantial drawbacks. The solubility issues are a concern for both, but can potentially be addressed with formulation strategies.

Output:
1
2025-04-17 04:55:12,240 - INFO - Batch 154 complete. Total preferences: 2464
2025-04-17 04:55:12,240 - INFO - Processing batch 155/512...
2025-04-17 04:55:52,977 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (359.809 and 361.467 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (71.55) is significantly better than Ligand B (82.53). For CNS targets, we want TPSA <= 90, and A is closer to the optimal <=60 range. B is pushing the upper limit.

**3. logP:** Both ligands have good logP values (3.649 and 2.748), falling within the 1-3 optimal range.

**4. H-Bond Donors:** Both have 2 HBD, which is within the acceptable limit of <=5.

**5. H-Bond Acceptors:** Ligand A has 4 HBA, and Ligand B has 5. Both are acceptable (<=10).

**6. QED:** Both ligands have good QED scores (0.659 and 0.743), indicating good drug-like properties.

**7. DILI:** Ligand A (73.362) has a higher DILI risk than Ligand B (47.693). This is a negative for A.

**8. BBB:** Both ligands have similar BBB penetration (37.96% and 36.371%). Neither is ideal (>70%), but this is less critical if other properties are strong.

**9. Caco-2:** Both have negative Caco-2 values (-4.991 and -5.441). This is unusual and suggests poor permeability. However, these values are on a scale where negative values are possible and don't necessarily mean zero permeability.

**10. Solubility:** Ligand A (-5.14) has worse solubility than Ligand B (-3.491). Solubility is important, but can often be addressed with formulation.

**11. hERG:** Both ligands have low hERG inhibition risk (0.63 and 0.618).

**12. Cl_mic:** Ligand A (41.837) has a lower microsomal clearance than Ligand B (83.084), indicating better metabolic stability. This is a significant advantage for A.

**13. t1/2:** Ligand A (25.341) has a longer in vitro half-life than Ligand B (-19.987). This is a substantial advantage for A.

**14. Pgp:** Ligand A (0.575) has lower P-gp efflux liability than Ligand B (0.202). Lower Pgp is desirable for CNS penetration and bioavailability, making A more favorable.

**15. Binding Affinity:** Ligand A (-9.7 kcal/mol) has significantly stronger binding affinity than Ligand B (-8.5 kcal/mol). This >1.5 kcal/mol difference is a major advantage for A, potentially outweighing some of its ADME drawbacks.

**Overall Assessment:**

Ligand A is the stronger candidate. While its DILI risk is higher and solubility is lower, its significantly better TPSA, metabolic stability (Cl_mic, t1/2), Pgp efflux, and *much* stronger binding affinity outweigh these concerns. The affinity difference is particularly important for a GPCR target. Both have suboptimal BBB, but the improved ADME profile of A, particularly the lower Pgp and better metabolic stability, should translate to better CNS exposure despite the similar BBB values.

Output:
1
2025-04-17 04:55:52,978 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (367.471 and 356.507 Da) fall within the ideal range of 200-500 Da.

**TPSA:** Ligand A (100.55) is slightly above the optimal <90 for CNS targets, while Ligand B (70.08) is well within the desired range. This favors Ligand B.

**logP:** Ligand A (0.689) is a bit low, potentially hindering permeability. Ligand B (2.192) is within the optimal 1-3 range. This favors Ligand B.

**H-Bond Donors/Acceptors:** Ligand A has 3 HBD and 6 HBA, both acceptable. Ligand B has 1 HBD and 4 HBA, also acceptable. No clear advantage here.

**QED:** Both ligands have similar QED values (0.658 and 0.687), indicating good drug-likeness.

**DILI:** Ligand A (54.323) has a higher DILI risk than Ligand B (12.253). This favors Ligand B.

**BBB:** Ligand B (79.566) has a significantly better BBB penetration percentile than Ligand A (41.024). This is a *critical* advantage for a CNS target like DRD2.

**Caco-2 Permeability:** Ligand A (-5.36) has poor Caco-2 permeability, while Ligand B (-4.229) is slightly better, but still not great.

**Aqueous Solubility:** Both ligands have very poor aqueous solubility (-1.048 and -1.131). This is a concern for both, but can be addressed with formulation strategies.

**hERG Inhibition:** Ligand A (0.059) has a slightly lower hERG inhibition risk than Ligand B (0.243), which is a minor advantage.

**Microsomal Clearance:** Ligand B (74.952) has a much higher microsomal clearance than Ligand A (9.56), indicating lower metabolic stability. This favors Ligand A.

**In vitro Half-Life:** Ligand A (24.223) has a longer in vitro half-life than Ligand B (-4.874), which is a significant advantage.

**P-gp Efflux:** Ligand A (0.016) has much lower P-gp efflux liability than Ligand B (0.096), which is a substantial advantage for CNS penetration.

**Binding Affinity:** Ligand A (-7.5) has a slightly better binding affinity than Ligand B (-6.7), but the difference is less than 1.5 kcal/mol.

**Overall Assessment:**

Ligand B excels in BBB penetration and has a lower DILI risk, which are crucial for a CNS GPCR target. However, it suffers from higher P-gp efflux and higher microsomal clearance. Ligand A has better metabolic stability, lower P-gp efflux, and slightly better binding affinity, but its BBB penetration is significantly worse.

Considering the GPCR-specific priorities, the superior BBB penetration of Ligand B outweighs its drawbacks, especially given that solubility issues can be addressed with formulation. The slightly better affinity of Ligand A is not enough to compensate for its poor CNS penetration.

Output:
1
2025-04-17 04:55:52,978 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (346.402 and 341.455 Da) fall comfortably within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (58.64) is slightly higher than Ligand B (53.51), but both are below the 90 A^2 threshold desirable for CNS targets.

**3. logP:** Both ligands have good logP values (2.202 and 2.786), falling within the optimal 1-3 range. Ligand B is slightly higher, which could be beneficial for membrane permeability.

**4. H-Bond Donors:** Ligand A has 1 HBD, while Ligand B has 0. Both are within the acceptable limit of <=5.

**5. H-Bond Acceptors:** Both ligands have 3 HBAs, well below the limit of <=10.

**6. QED:** Both ligands have good QED scores (0.635 and 0.831), indicating good drug-like properties. Ligand B is slightly better.

**7. DILI:** Ligand A (37.96) has a slightly higher DILI risk than Ligand B (20.396), but both are below the concerning threshold of 60.

**8. BBB:** Both ligands have excellent BBB penetration (84.529% and 84.917%), exceeding the desirable >70% for CNS targets. This is a critical factor for DRD2.

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.646 and -4.728). This is unusual and suggests poor permeability. However, these values are on a log scale and a negative value doesn't necessarily preclude development, especially if other properties are favorable.

**10. Aqueous Solubility:** Both ligands have very poor aqueous solubility (-2.486 and -2.114). This is a significant drawback and could pose formulation challenges.

**11. hERG Inhibition:** Both ligands have low hERG inhibition risk (0.769 and 0.341), which is positive. Ligand B is slightly better.

**12. Microsomal Clearance:** Ligand A (31.456) has higher microsomal clearance than Ligand B (25.606), suggesting lower metabolic stability.

**13. In vitro Half-Life:** Ligand B (-14.813) has a significantly longer in vitro half-life than Ligand A (-0.624), which is a major advantage.

**14. P-gp Efflux:** Both ligands have low P-gp efflux liability (0.299 and 0.143), which is favorable for CNS exposure. Ligand B is slightly better.

**15. Binding Affinity:** Ligand A (-9.4 kcal/mol) has a slightly better binding affinity than Ligand B (-8.1 kcal/mol). This 1.3 kcal/mol difference is substantial and could outweigh some of the ADME drawbacks.

**Overall Assessment:**

While both ligands have good BBB penetration and acceptable logP values, Ligand B demonstrates superior ADME properties, particularly in terms of DILI risk, in vitro half-life, and P-gp efflux. The slightly better solubility and lower DILI of Ligand B are important. Although Ligand A has a slightly better binding affinity, the ADME profile of Ligand B is more promising for development as a CNS-active drug. The solubility issues for both compounds would need to be addressed through formulation strategies.

Output:
1
2025-04-17 04:55:52,978 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (351.491 Da) is slightly lower, which could be beneficial for permeability. Ligand B (382.511 Da) is also acceptable.

**TPSA:** Ligand A (64.09) is excellent, well below the 90 A^2 threshold for CNS targets. Ligand B (105.39) is higher but still reasonable, though less optimal for CNS penetration.

**logP:** Both ligands have logP values within the optimal range (1-3). Ligand A (1.083) is slightly lower, while Ligand B (1.526) is a bit higher. Both are acceptable.

**H-Bond Donors/Acceptors:** Ligand A (HBD=1, HBA=4) and Ligand B (HBD=2, HBA=6) both fall within acceptable limits.

**QED:** Both ligands have good QED scores (A: 0.805, B: 0.788), indicating drug-like properties.

**DILI:** Both ligands have low DILI risk (A: 3.218, B: 82.435). Ligand A is significantly better here.

**BBB:** This is a critical parameter for a CNS target like DRD2. Ligand A has a very high BBB penetration percentile (80.574), which is excellent. Ligand B's BBB penetration (39.822) is quite poor, a major drawback.

**Caco-2 Permeability:** Ligand A (-4.665) and Ligand B (-5.372) both have negative values, which is unusual. This suggests poor permeability.

**Aqueous Solubility:** Both ligands have poor aqueous solubility (-1.16 and -2.408 respectively).

**hERG Inhibition:** Both ligands show very low hERG inhibition risk (A: 0.551, B: 0.182).

**Microsomal Clearance:** Ligand A (17.293) has lower microsomal clearance than Ligand B (22.621), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (-7.665) has a longer in vitro half-life than Ligand B (28.394).

**P-gp Efflux:** Ligand A (0.019) has significantly lower P-gp efflux liability than Ligand B (0.163), which is favorable for CNS exposure.

**Binding Affinity:** Both ligands have excellent binding affinities (A: -7.4 kcal/mol, B: -7.7 kcal/mol). Ligand B is slightly better, but the difference is small and potentially outweighed by other factors.

**Overall Assessment:**

Ligand A is the superior candidate. While Ligand B has slightly better binding affinity, Ligand A excels in critical areas for CNS drug development: significantly better BBB penetration, lower DILI risk, lower P-gp efflux, and better metabolic stability. The poor Caco-2 and solubility scores are a concern for both, but can be addressed with formulation strategies. The substantial advantage in BBB penetration for Ligand A is decisive for a DRD2 targeting drug.

Output:
0
2025-04-17 04:55:52,978 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (341.455 Da) is slightly lower, which could be favorable for permeability, but both are acceptable.

**TPSA:** Ligand A (81.15) is better than Ligand B (58.64) for CNS penetration, falling well below the 90 A^2 threshold. Ligand B is also good, but A is preferable.

**logP:** Ligand A (4.276) is a bit high, potentially leading to solubility issues and off-target effects. Ligand B (2.294) is within the optimal range (1-3). This is a significant advantage for Ligand B.

**H-Bond Donors/Acceptors:** Ligand A (HBD=2, HBA=4) and Ligand B (HBD=1, HBA=3) both have reasonable numbers of H-bond donors and acceptors, well within the guidelines.

**QED:** Both ligands have acceptable QED values (A: 0.822, B: 0.681), indicating good drug-like properties.

**DILI:** Ligand A (43.234) has a higher DILI risk than Ligand B (14.424). This is a clear advantage for Ligand B.

**BBB:** Ligand A (79.527) and Ligand B (91.663) both show good BBB penetration, but Ligand B is significantly better, exceeding 90%. This is crucial for a CNS target like DRD2.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values, which is unusual and potentially indicates issues with the modeling or data. However, the values are similar, so it doesn't strongly favor either.

**Aqueous Solubility:** Both ligands have negative solubility values, which is also unusual. Again, the values are similar and don't provide a clear differentiator.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (A: 0.769, B: 0.666).

**Microsomal Clearance:** Both ligands have similar microsomal clearance rates (A: 44.166, B: 44.07), suggesting comparable metabolic stability.

**In vitro Half-Life:** Ligand A (5.571) has a longer half-life than Ligand B (3.929), which is generally desirable.

**P-gp Efflux:** Ligand A (0.711) has lower P-gp efflux than Ligand B (0.111), which is beneficial for CNS exposure.

**Binding Affinity:** Ligand A (-9.5 kcal/mol) has a significantly stronger binding affinity than Ligand B (-8.3 kcal/mol). This is a substantial advantage for Ligand A, potentially outweighing some of its ADME drawbacks. The difference is >1.5 kcal/mol.

**Overall Assessment:**

While Ligand B excels in ADME properties (lower logP, lower DILI, better BBB penetration, lower P-gp efflux), Ligand A boasts a considerably stronger binding affinity. For a GPCR target, especially in the CNS, a strong binding affinity is paramount. The slightly higher logP and DILI risk of Ligand A are potentially manageable through further optimization, especially given the significant affinity advantage. The better BBB penetration of Ligand B is a plus, but Ligand A's P-gp efflux is also favorable.

Output:
1
2025-04-17 04:55:52,978 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (347.459 and 354.447 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (75.44) is slightly above the optimal <90 for CNS targets, but still reasonable. Ligand B (68.31) is excellent, well below 90.

**3. logP:** Ligand A (2.952) is within the optimal 1-3 range. Ligand B (0.832) is a bit low, potentially hindering permeability.

**4. H-Bond Donors:** Ligand A (1) is good. Ligand B (0) is also good.

**5. H-Bond Acceptors:** Ligand A (4) is good. Ligand B (5) is also good.

**6. QED:** Ligand A (0.823) is excellent, indicating high drug-likeness. Ligand B (0.604) is still acceptable, above the 0.5 threshold.

**7. DILI:** Ligand A (33.501) has a low DILI risk. Ligand B (23.342) has an even lower DILI risk, which is favorable.

**8. BBB:** Ligand A (71.811) is good, exceeding the 70% threshold for CNS targets. Ligand B (83.56) is *excellent*, significantly better for CNS penetration.

**9. Caco-2:** Both ligands have negative Caco-2 values (-4.406 and -4.467), which is unusual and suggests poor permeability. This is a significant concern for both.

**10. Solubility:** Both ligands have negative solubility values (-2.93 and -1.223), which is also concerning. Poor solubility can hinder bioavailability.

**11. hERG:** Ligand A (0.428) has a low hERG risk. Ligand B (0.172) has an even lower hERG risk, which is preferable.

**12. Cl_mic:** Ligand A (76.278) has a higher microsomal clearance, suggesting lower metabolic stability. Ligand B (19.745) has much lower clearance, indicating better metabolic stability.

**13. t1/2:** Ligand A (13.078) has a moderate in vitro half-life. Ligand B (5.121) has a shorter half-life, which could necessitate more frequent dosing.

**14. Pgp:** Ligand A (0.148) has low P-gp efflux, which is good for CNS exposure. Ligand B (0.056) has even lower P-gp efflux, further enhancing CNS penetration potential.

**15. Binding Affinity:** Ligand A (-8.5 kcal/mol) has a significantly stronger binding affinity than Ligand B (-7.3 kcal/mol). This 1.2 kcal/mol difference is substantial and could outweigh some ADME drawbacks.

**Overall Assessment:**

While both ligands have concerning Caco-2 and solubility values, the superior binding affinity of Ligand A (-8.5 kcal/mol vs -7.3 kcal/mol) is a major advantage, particularly for a GPCR target. Ligand B has better BBB penetration and metabolic stability, but the affinity difference is critical. The lower Pgp efflux for Ligand B is also a plus, but the affinity difference is more important. The slightly higher TPSA of Ligand A is not a dealbreaker.

Output:
1
2025-04-17 04:55:52,979 - INFO - Reasoning:

Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (408.286 Da) is slightly higher than Ligand B (344.411 Da), but both are acceptable.

**2. TPSA:** Ligand A (20.31) is excellent, well below the 90 A^2 threshold for CNS targets. Ligand B (75.71) is higher, but still potentially acceptable, though less ideal for CNS penetration.

**3. logP:** Ligand A (4.997) is a bit high, potentially leading to solubility issues and off-target interactions. Ligand B (1.336) is within the optimal range (1-3).

**4. H-Bond Donors:** Both ligands have acceptable HBD counts (Ligand A: 0, Ligand B: 1), well below the 5 threshold.

**5. H-Bond Acceptors:** Both ligands have acceptable HBA counts (Ligand A: 1, Ligand B: 4), well below the 10 threshold.

**6. QED:** Ligand A (0.7) is better than Ligand B (0.464), indicating a more drug-like profile.

**7. DILI:** Ligand A (54.75) has a moderate DILI risk, while Ligand B (32.067) has a lower, more favorable risk.

**8. BBB:** This is crucial for a CNS target like DRD2. Ligand A (93.331) has excellent BBB penetration, exceeding the 70% threshold. Ligand B (46.026) has poor BBB penetration, a significant drawback.

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.644 and -4.678). This is unusual and suggests potential issues with intestinal absorption, but the values are very similar and don't differentiate the two.

**10. Aqueous Solubility:** Both ligands have negative solubility values (-6.424 and -2.588). This is also unusual and suggests poor aqueous solubility, but again, the values are similar.

**11. hERG Inhibition:** Ligand A (0.912) has a slightly higher hERG risk than Ligand B (0.074), but both are relatively low.

**12. Microsomal Clearance:** Ligand A (76.386) has higher clearance than Ligand B (33.169), implying lower metabolic stability.

**13. In vitro Half-Life:** Ligand A (38.567) has a longer half-life than Ligand B (3.571), which is desirable.

**14. P-gp Efflux:** Ligand A (0.711) has lower P-gp efflux than Ligand B (0.017), which is beneficial for CNS exposure.

**15. Binding Affinity:** Ligand B (-8.6 kcal/mol) has a slightly stronger binding affinity than Ligand A (-9.0 kcal/mol). While the difference is small, it's still a factor.

**Overall Assessment:**

Ligand A excels in BBB penetration, P-gp efflux, and in vitro half-life. While its logP is a bit high and clearance is higher, the excellent BBB penetration is a major advantage for a CNS target. Ligand B has better logP and DILI, but its poor BBB penetration is a critical flaw for DRD2. The slightly better affinity of Ligand B is unlikely to overcome the significant BBB issue.

Output:
1
2025-04-17 04:55:52,979 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (378.523 and 362.543 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (78.09) is better than Ligand B (50.28). Both are below the 90 A^2 threshold for CNS targets, but Ligand A is closer to the upper limit, which might slightly hinder BBB penetration compared to Ligand B.

**3. logP:** Ligand A (2.003) is within the optimal 1-3 range. Ligand B (3.754) is slightly higher, potentially increasing off-target effects and decreasing solubility, but still acceptable.

**4. H-Bond Donors:** Ligand A (2) and Ligand B (1) are both acceptable (<=5).

**5. H-Bond Acceptors:** Ligand A (5) and Ligand B (6) are both acceptable (<=10).

**6. QED:** Both ligands have similar QED values (0.834 and 0.805), indicating good drug-like properties.

**7. DILI:** Ligand A (65.917) has a slightly lower DILI risk than Ligand B (69.484), which is preferable. Both are still relatively high, indicating a potential concern.

**8. BBB:** Ligand B (82.086) significantly outperforms Ligand A (32.765) in BBB penetration, a critical factor for CNS targets like DRD2. This is a major advantage for Ligand B.

**9. Caco-2 Permeability:** Ligand A (-5.622) is significantly better than Ligand B (-4.754), indicating better intestinal absorption. However, for a CNS target, intestinal absorption is less critical than BBB penetration.

**10. Aqueous Solubility:** Ligand A (-3.196) is better than Ligand B (-4.824), which is a positive attribute.

**11. hERG Inhibition:** Ligand A (0.289) has a lower hERG inhibition risk than Ligand B (0.719), which is a significant advantage.

**12. Microsomal Clearance:** Ligand A (16.792) has a lower microsomal clearance than Ligand B (102.003), suggesting better metabolic stability.

**13. In vitro Half-Life:** Ligand A (-9.844) has a longer in vitro half-life than Ligand B (11.5), which is desirable.

**14. P-gp Efflux:** Ligand A (0.084) has significantly lower P-gp efflux than Ligand B (0.408), meaning it's less likely to be pumped out of the brain, improving CNS exposure.

**15. Binding Affinity:** Ligand A (-7.9) has a slightly better binding affinity than Ligand B (-7.4), but the difference is relatively small (0.5 kcal/mol).

**Overall Assessment:**

While Ligand A has advantages in several ADME properties (lower DILI, better solubility, lower hERG, lower Cl_mic, longer t1/2, lower Pgp efflux) and slightly better affinity, Ligand B's *significantly* superior BBB penetration (82.086 vs. 32.765) is the deciding factor for a CNS target like DRD2. The higher logP of Ligand B is a minor concern, but the substantial BBB advantage outweighs this.

Output:
1
2025-04-17 04:55:52,979 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (357.451 and 348.403 Da) fall within the ideal 200-500 Da range.

**TPSA:** Both ligands (88.18 and 85.69) are below the 90 A^2 threshold desirable for CNS targets, which is excellent.

**logP:** Ligand A (0.014) is quite low, potentially hindering permeability. Ligand B (0.243) is also low, but slightly better than A. Both are below the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Both have 1 HBD and are within acceptable ranges (<=5 HBD, <=10 HBA). Ligand B has 6 HBA, while Ligand A has 5.

**QED:** Both ligands have good QED scores (0.588 and 0.824), indicating good drug-like properties. Ligand B is better here.

**DILI:** Both have acceptable DILI risk (26.444 and 37.146), well below the 60 threshold.

**BBB:** Ligand B (83.327) has a significantly better BBB penetration percentile than Ligand A (55.138). This is a *critical* advantage for a CNS target like DRD2.

**Caco-2 Permeability:** Both have negative Caco-2 values (-4.94 and -4.743), which is unusual and suggests poor permeability. However, these values are on a log scale and can be difficult to interpret directly without knowing the base of the log.

**Aqueous Solubility:** Both have poor aqueous solubility (-0.213 and -1.251). This could be a formulation challenge.

**hERG Inhibition:** Both have low hERG inhibition risk (0.088 and 0.289).

**Microsomal Clearance:** Ligand A (16.653) has a higher microsomal clearance than Ligand B (7.377), indicating lower metabolic stability.

**In vitro Half-Life:** Ligand B (-3.182) has a better (longer) in vitro half-life than Ligand A (-30.305).

**P-gp Efflux:** Both have very low P-gp efflux liability (0.009 and 0.015), which is favorable for CNS penetration.

**Binding Affinity:** Ligand B (-8.5 kcal/mol) has a significantly stronger binding affinity than Ligand A (-7.0 kcal/mol). This is a substantial advantage, exceeding the 1.5 kcal/mol difference that can outweigh other drawbacks.

**Overall Assessment:**

Ligand B is the superior candidate. While both have issues with logP and solubility, Ligand B excels in the most critical areas for a CNS GPCR target: BBB penetration and binding affinity. The significantly better BBB score and stronger binding affinity outweigh the slightly lower logP and solubility compared to Ligand A. The improved metabolic stability (lower Cl_mic and better half-life) further strengthens the case for Ligand B.

Output:
1
2025-04-17 04:55:52,979 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (361.423 and 346.427 Da) fall within the ideal range of 200-500 Da.

**TPSA:** Ligand A (110.52) is higher than the preferred <90 for CNS targets, while Ligand B (56.1) is well within the range. This is a significant advantage for Ligand B.

**logP:** Both ligands have acceptable logP values (1.808 and 3.131), falling within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A has 3 HBD and 5 HBA, while Ligand B has 1 HBD and 6 HBA. Both are within acceptable limits (<=5 HBD and <=10 HBA).

**QED:** Both ligands have good QED scores (0.537 and 0.792), indicating good drug-like properties.

**DILI:** Ligand A (93.37) has a higher DILI risk than Ligand B (47.421). This is a concern for Ligand A.

**BBB:** Ligand B (73.594) has a significantly better BBB percentile than Ligand A (51.221). This is a crucial advantage for a CNS target like DRD2.

**Caco-2 Permeability:** Ligand A (-5.36) has poor Caco-2 permeability, which is a major drawback. Ligand B (-4.589) is also not great, but better than A.

**Aqueous Solubility:** Both ligands have poor aqueous solubility (-3.59 and -3.186). This could pose formulation challenges, but is less critical than BBB penetration for a CNS drug.

**hERG Inhibition:** Ligand A (0.317) has a slightly higher hERG inhibition risk than Ligand B (0.862), but both are relatively low.

**Microsomal Clearance:** Ligand A (20.165) has higher microsomal clearance than Ligand B (17.123), suggesting lower metabolic stability.

**In vitro Half-Life:** Ligand B (52.893) has a significantly longer in vitro half-life than Ligand A (-9.884). This is a major advantage for Ligand B.

**P-gp Efflux:** Ligand A (0.201) has lower P-gp efflux than Ligand B (0.194), which is slightly better.

**Binding Affinity:** Ligand A (-8.9 kcal/mol) has a slightly better binding affinity than Ligand B (-7.8 kcal/mol). However, the difference is less than 1.5 kcal/mol, and can be outweighed by other factors.

**Overall Assessment:**

Ligand B is the more promising candidate. While Ligand A has slightly better binding affinity, Ligand B excels in critical ADME properties for a CNS-targeting GPCR: significantly better BBB penetration, lower DILI risk, longer half-life, and a much more favorable TPSA. The poor Caco-2 permeability of both is a concern, but less critical for a CNS target where direct absorption into the brain is prioritized.



Output:
1
2025-04-17 04:55:52,980 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (388.471 Da) is slightly higher than Ligand B (347.35 Da), but both are acceptable.

**TPSA:** Ligand A (130.39) is borderline for CNS penetration, being slightly above the preferred <90 threshold. Ligand B (100.35) is well within the desirable range for CNS targets. This gives a slight edge to Ligand B.

**logP:** Ligand A (-0.115) is quite low, potentially hindering membrane permeability. Ligand B (0.558) is better, falling within the optimal 1-3 range. This is a significant advantage for Ligand B.

**H-Bond Donors/Acceptors:** Ligand A has 3 HBD and 7 HBA, while Ligand B has 2 HBD and 6 HBA. Both are within acceptable limits.

**QED:** Both ligands have good QED scores (A: 0.633, B: 0.79), indicating good drug-like properties. Ligand B is slightly better.

**DILI:** Both ligands have high DILI risk (A: 79.953, B: 78.441), which is a concern. This will need to be addressed in later optimization.

**BBB:** Ligand A (36.371%) has a poor BBB penetration percentile, while Ligand B (58.782%) is better, but still not ideal (>70 is desirable). This is a significant drawback for Ligand A, given the CNS target.

**Caco-2:** Both have negative Caco-2 values (-5.319 and -5.052), which is unusual and difficult to interpret without further context. However, it suggests poor intestinal absorption for both.

**Solubility:** Both have negative solubility values (-2.769 and -2.412), also unusual and suggesting poor aqueous solubility.

**hERG:** Both ligands have low hERG risk (A: 0.312, B: 0.153).

**Microsomal Clearance:** Ligand A (30.708) has higher clearance than Ligand B (-15.317), indicating lower metabolic stability. Ligand B is preferable here.

**In vitro Half-Life:** Ligand B (11.288 hours) has a longer half-life than Ligand A (-12.807 hours), which is desirable.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (A: 0.042, B: 0.003), which is good for CNS penetration.

**Binding Affinity:** Ligand A (-8.5 kcal/mol) has a slightly better binding affinity than Ligand B (-7.8 kcal/mol). This is a 0.7 kcal/mol difference, which is a reasonable advantage.

**Overall Assessment:**

Despite Ligand A's slightly better binding affinity, Ligand B is the more promising candidate. Ligand B has a significantly better logP, a more favorable TPSA, better BBB penetration, and improved metabolic stability (lower Cl_mic and longer t1/2). The lower logP and poor BBB of Ligand A are major drawbacks for a CNS-targeting GPCR. While both have concerning DILI scores, the ADME properties of Ligand B are generally more favorable.

Output:
1
2025-04-17 04:55:52,980 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (386.546 Da) is slightly higher than Ligand B (344.455 Da), but both are acceptable.

**TPSA:** Ligand A (98.54) is approaching the upper limit for CNS targets (<=90), while Ligand B (53.76) is well within the ideal range. This favors Ligand B.

**logP:** Both ligands have good logP values (A: 2.936, B: 3.29), falling within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A has 1 HBD and 5 HBA, while Ligand B has 0 HBD and 3 HBA. Both are within acceptable limits.

**QED:** Ligand B (0.845) has a significantly better QED score than Ligand A (0.421), indicating a more drug-like profile.

**DILI:** Ligand A (68.903) has a higher DILI risk than Ligand B (47.034), though both are reasonably acceptable.

**BBB:** Both ligands show good BBB penetration (A: 72.819%, B: 77.123%), exceeding the 70% threshold for CNS targets. Ligand B is slightly better.

**Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and suggests a problem with the data or the model used to predict it. It's hard to draw conclusions from this.

**Aqueous Solubility:** Both have negative solubility values, again suggesting a problem with the data.

**hERG Inhibition:** Both ligands have low hERG inhibition liability (A: 0.819, B: 0.661), which is good.

**Microsomal Clearance:** Ligand A (91.463) has a higher microsomal clearance than Ligand B (57.089), indicating lower metabolic stability. This favors Ligand B.

**In vitro Half-Life:** Ligand B (30.797 hours) has a significantly longer half-life than Ligand A (-11.448 hours). This is a major advantage for Ligand B.

**P-gp Efflux:** Ligand A (0.598) shows some P-gp efflux, while Ligand B (0.526) shows less. Both are relatively low, but lower is better for CNS penetration.

**Binding Affinity:** Ligand B (-8.9 kcal/mol) has a substantially stronger binding affinity than Ligand A (-0.0 kcal/mol). This is a critical advantage, potentially outweighing minor ADME drawbacks.

**Overall Assessment:**

Ligand B is clearly the superior candidate. It exhibits a better QED score, lower DILI risk, better metabolic stability (lower Cl_mic, longer t1/2), and, most importantly, a significantly stronger binding affinity for DRD2. While both have acceptable BBB penetration and logP values, Ligand B's superior profile across multiple parameters makes it the more promising drug candidate. The negative solubility and Caco-2 values are concerning and would need further investigation, but the other advantages of Ligand B are substantial.

Output:
1
2025-04-17 04:55:52,980 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (353.507 Da) is slightly lower, which is generally favorable for permeability. Ligand B (382.51 Da) is also acceptable.

**TPSA:** Ligand A (61.88) is better than Ligand B (49.41) as it is closer to the <90 A^2 threshold for CNS targets.

**logP:** Ligand A (1.497) is within the optimal range (1-3). Ligand B (4.509) is higher, potentially leading to solubility issues and off-target interactions.

**H-Bond Donors/Acceptors:** Both ligands have 1 HBD and 4 HBA, which are within acceptable limits.

**QED:** Both ligands have similar QED values (0.753 and 0.763), indicating good drug-likeness.

**DILI:** Ligand A (5.312) has a much lower DILI risk than Ligand B (20.396), which is a significant advantage.

**BBB:** Ligand B (86.623) has a significantly higher BBB penetration percentile than Ligand A (56.029). This is a crucial factor for a CNS target like DRD2.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.848 and -4.908), which is unusual and suggests poor permeability. However, these values are on a different scale and may not be directly comparable.

**Aqueous Solubility:** Both ligands have negative solubility values (-1.078 and -3.71), which is also unusual and suggests poor solubility.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.505 and 0.637).

**Microsomal Clearance:** Ligand A (0.907) has much lower microsomal clearance than Ligand B (55.76), indicating better metabolic stability.

**In vitro Half-Life:** Ligand A (6.805) has a longer in vitro half-life than Ligand B (17.095).

**P-gp Efflux:** Ligand A (0.012) has significantly lower P-gp efflux liability than Ligand B (0.375), which is beneficial for CNS exposure.

**Binding Affinity:** Ligand A (-8.0) has a stronger binding affinity than Ligand B (-6.8). This is a substantial difference (1.2 kcal/mol), and affinity is a primary driver of potency.

**Overall Assessment:**

While Ligand B has a superior BBB score, Ligand A excels in most other critical parameters. It has a better TPSA, logP, significantly lower DILI and P-gp efflux, better metabolic stability (lower Cl_mic and longer t1/2), and a much stronger binding affinity. The higher BBB of Ligand B is attractive, but the substantial advantages of Ligand A in other areas, particularly its binding affinity and safety profile (DILI), outweigh this benefit. The negative Caco-2 and solubility values are concerning for both, but can potentially be addressed through formulation strategies.

Output:
1
2025-04-17 04:55:52,980 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (360.523 and 347.419 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (40.62) is excellent, well below the 90 A^2 threshold for CNS targets. Ligand B (96.33) is higher, but still potentially acceptable, though less ideal.

**logP:** Ligand A (2.952) is optimal (1-3). Ligand B (0.296) is quite low, potentially hindering membrane permeability and CNS penetration.

**H-Bond Donors/Acceptors:** Ligand A (0 HBD, 3 HBA) is favorable. Ligand B (2 HBD, 5 HBA) is also acceptable, though slightly higher.

**QED:** Both ligands have similar, good QED values (0.783 and 0.766, both > 0.5).

**DILI:** Ligand A (39.201) has a lower DILI risk than Ligand B (49.554), both are acceptable, but A is preferred.

**BBB:** Both ligands have very similar, excellent BBB penetration (82.474% and 82.202%, both > 70%).

**Caco-2 Permeability:** Both have negative Caco-2 values (-4.953 and -4.742), which is unusual and suggests a potential issue with the data or modeling. However, given the other parameters, we'll proceed cautiously.

**Aqueous Solubility:** Both have negative solubility values (-3.825 and -2.495), also unusual. This suggests poor solubility, which could be a formulation challenge.

**hERG:** Both ligands have low hERG inhibition liability (0.75 and 0.145), which is good.

**Microsomal Clearance:** Ligand A (99.262) has significantly higher microsomal clearance than Ligand B (32.975), indicating lower metabolic stability.

**In vitro Half-Life:** Ligand B (19.981 hours) has a much longer in vitro half-life than Ligand A (1.847 hours).

**P-gp Efflux:** Ligand A (0.506) has lower P-gp efflux than Ligand B (0.011), which is favorable for CNS penetration.

**Binding Affinity:** Both ligands have the same excellent binding affinity (-8.2 kcal/mol).

**Overall Assessment:**

Ligand A has better logP, TPSA, DILI, and P-gp efflux. However, Ligand B has a substantially longer half-life and lower microsomal clearance, which are crucial for *in vivo* efficacy. The negative Caco-2 and solubility values are concerning for both, but the significantly better metabolic stability of Ligand B is a major advantage, especially for a CNS target where maintaining adequate brain exposure is critical. While Ligand A has a slight edge in some ADME properties, the longer half-life of Ligand B outweighs these differences.

Output:
1
2025-04-17 04:55:52,980 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (354.441 and 363.443 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (49.41) is excellent, well below the 90 A^2 threshold for CNS targets. Ligand B (96.78) is higher, but still potentially acceptable, though less ideal.

**logP:** Ligand A (2.967) is optimal (1-3). Ligand B (0.98) is a bit low, potentially hindering permeability.

**H-Bond Donors/Acceptors:** Both ligands have 1 HBD, which is good. Ligand A has 2 HBA, and Ligand B has 7 HBA. Both are within the acceptable range (<=10), but Ligand B's higher HBA count could slightly affect permeability.

**QED:** Both ligands have good QED values (0.825 and 0.863), indicating drug-like properties.

**DILI:** Ligand A (14.036) has a very low DILI risk. Ligand B (50.136) is higher, suggesting a moderate risk, but still not overly concerning.

**BBB:** Ligand A (89.608) has excellent BBB penetration potential. Ligand B (70.958) is acceptable, but less desirable for a CNS target.

**Caco-2 Permeability:** Both have negative values, indicating poor permeability. However, the scale is not specified, so it's hard to interpret.

**Aqueous Solubility:** Both have negative values, indicating poor solubility. Again, the scale is not specified.

**hERG:** Both ligands have low hERG inhibition liability (0.652 and 0.311), which is good.

**Microsomal Clearance:** Ligand A (24.723) has moderate clearance. Ligand B (3.917) has very low clearance, suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (-17.461) has a negative half-life, which is problematic. Ligand B (30.648) has a reasonable half-life.

**P-gp Efflux:** Ligand A (0.115) has low P-gp efflux, which is favorable for CNS penetration. Ligand B (0.261) also has low P-gp efflux.

**Binding Affinity:** Both ligands have strong binding affinities (-9.1 and -8.5 kcal/mol). Ligand A is slightly better (-9.1 kcal/mol).

**Overall Assessment:**

Ligand A excels in TPSA, BBB, P-gp efflux, and binding affinity. Its logP is optimal. However, its in vitro half-life is a major concern. Ligand B has better metabolic stability (lower Cl_mic, better t1/2) and a lower DILI risk, but its logP is suboptimal and BBB penetration is less favorable.

Given the importance of BBB penetration for a CNS target like DRD2, and the slightly better affinity of Ligand A, I would initially favor Ligand A *if* the negative half-life can be addressed through structural modifications. However, the negative half-life is a significant red flag. Ligand B is a more conservative choice with better ADME properties overall, but slightly weaker binding.

Output:
0
2025-04-17 04:55:52,981 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (350.39 and 345.359 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (86.71) is excellent, falling well below the 90 A^2 threshold for CNS targets. Ligand B (130.24) is higher, but still potentially acceptable, though less ideal.

**logP:** Ligand A (2.209) is optimal. Ligand B (0.074) is quite low, potentially hindering permeability and CNS penetration.

**H-Bond Donors/Acceptors:** Ligand A (HBD=2, HBA=3) is well within acceptable limits. Ligand B (HBD=3, HBA=7) is also acceptable, but the higher HBA count could slightly impact permeability.

**QED:** Ligand A (0.872) is excellent, indicating strong drug-likeness. Ligand B (0.675) is still reasonable, but lower than A.

**DILI:** Both ligands have similar DILI risk (61.807 and 61.303 percentile), indicating moderate risk. This isn't a major differentiator.

**BBB:** Ligand A (36.836%) is concerningly low for a CNS target. Ligand B (46.336%) is also low, but slightly better. Both would likely require structural modifications to improve brain penetration.

**Caco-2 Permeability:** Ligand A (-4.815) and Ligand B (-5.24) both show poor Caco-2 permeability. This is a significant concern for oral bioavailability.

**Aqueous Solubility:** Both ligands have very poor aqueous solubility (-2.234 and -2.106). This will pose formulation challenges.

**hERG Inhibition:** Both ligands show very low hERG inhibition risk (0.063 and 0.108 percentile), which is excellent.

**Microsomal Clearance:** Ligand A (-7.487) has a very low (good) microsomal clearance, suggesting good metabolic stability. Ligand B (-1.051) has a higher clearance, indicating faster metabolism.

**In vitro Half-Life:** Ligand A (-3.032) has a negative half-life, which is unusual and likely an error in the data. Ligand B (21.418) has a reasonable half-life.

**P-gp Efflux:** Both ligands show very low P-gp efflux liability (0.01 and 0.013), which is favorable for CNS penetration.

**Binding Affinity:** Both ligands have excellent binding affinity (-8.9 and -8.7 kcal/mol), with Ligand A being slightly better. The affinity difference is not large enough to overcome other significant drawbacks.

**Overall Assessment:**

Ligand A initially appears better due to its superior logP, QED, and microsomal clearance. However, its extremely low BBB penetration and negative half-life are major red flags. Ligand B has a lower logP and higher clearance, but its BBB penetration is slightly better, and its half-life is reasonable. The poor Caco-2 permeability and solubility are shared concerns for both.

Considering the GPCR-specific priorities, BBB is critical for a CNS target. While both are poor, Ligand B is marginally better. The better metabolic stability of Ligand A is appealing, but the negative half-life is a serious issue. Given the data, Ligand B is the slightly more promising starting point, despite its lower logP, because it has a more plausible pharmacokinetic profile.

Output:
1
2025-04-17 04:55:52,981 - INFO - Batch 155 complete. Total preferences: 2480
2025-04-17 04:55:52,981 - INFO - Processing batch 156/512...
2025-04-17 04:56:35,375 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (362.832 and 338.499 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (46.34) is better than Ligand B (42.22). Both are below the 90 A^2 threshold desirable for CNS targets, which is excellent.

**3. logP:** Both ligands have logP values around 4.7-4.9, slightly above the optimal 1-3 range. This could potentially lead to solubility issues or off-target interactions, but is not a dealbreaker.

**4. H-Bond Donors:** Ligand A (0) is preferable to Ligand B (1). Fewer HBDs generally improve membrane permeability.

**5. H-Bond Acceptors:** Ligand A (3) is preferable to Ligand B (4). Fewer HBAs generally improve membrane permeability.

**6. QED:** Ligand A (0.697) is better than Ligand B (0.546), indicating a more drug-like profile.

**7. DILI:** Both ligands have low DILI risk (42.497 and 39.628 percentiles), which is good.

**8. BBB:** Both ligands exhibit excellent BBB penetration (91.857 and 92.284 percentiles), crucial for a CNS target like DRD2.

**9. Caco-2 Permeability:** Ligand A (-4.718) is worse than Ligand B (-5.011). Lower values here indicate lower permeability.

**10. Aqueous Solubility:** Ligand A (-4.644) is slightly better than Ligand B (-4.173), but both are quite poor. This is a concern given the already high logP values.

**11. hERG Inhibition:** Both ligands have relatively low hERG inhibition risk (0.733 and 0.926 percentiles).

**12. Microsomal Clearance:** Ligand B (62.002) has a lower microsomal clearance than Ligand A (81.635), suggesting better metabolic stability.

**13. In vitro Half-Life:** Ligand B (35.002 hours) has a longer half-life than Ligand A (24.269 hours), which is desirable.

**14. P-gp Efflux:** Ligand A (0.727) shows lower P-gp efflux than Ligand B (0.966), which is favorable for CNS penetration.

**15. Binding Affinity:** Ligand B (-7.9 kcal/mol) has a significantly stronger binding affinity than Ligand A (-8.4 kcal/mol). A 0.5 kcal/mol difference is substantial and can often outweigh minor ADME drawbacks.

**Overall Assessment:**

While Ligand A has slightly better QED, TPSA, and P-gp efflux, Ligand B's superior binding affinity (-7.9 vs -8.4 kcal/mol) and better metabolic stability (lower Cl_mic, longer t1/2) are more critical for a GPCR target. The BBB penetration is excellent for both. The slightly higher logP is a concern for both, but the strong affinity of Ligand B makes it more likely to overcome potential solubility issues.

Output:
1
2025-04-17 04:56:35,376 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (355.5 & 381.9 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (52.65) is significantly better than Ligand B (71.53). For CNS targets, we want TPSA <= 90, and ideally closer to 60. Ligand A is much closer to this ideal.

**logP:** Both ligands have a logP around 2.2, which is optimal (1-3).

**H-Bond Donors/Acceptors:** Both have 1 HBD, which is good. Ligand A has 3 HBA, while Ligand B has 5. Both are acceptable (<=10), but Ligand A is slightly better.

**QED:** Both ligands have good QED scores (0.645 and 0.812), indicating good drug-like properties.

**DILI:** Ligand A (5.584) has a much lower DILI risk than Ligand B (61.031). This is a significant advantage for Ligand A.

**BBB:** Ligand A (92.943) has excellent BBB penetration, exceeding the desirable >70% threshold. Ligand B (79.604) is still reasonable, but lower.

**Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and suggests poor permeability. However, the scale is not defined, so it's hard to interpret.

**Aqueous Solubility:** Ligand A (-1.13) has better solubility than Ligand B (-3.473), which is important for formulation.

**hERG Inhibition:** Ligand A (0.802) has a lower hERG risk than Ligand B (0.335). Lower is better.

**Microsomal Clearance:** Ligand A (6.685) has significantly lower microsomal clearance than Ligand B (21.256), indicating better metabolic stability.

**In vitro Half-Life:** Ligand A (2.891) has a longer half-life than Ligand B (0.271).

**P-gp Efflux:** Ligand A (0.044) has much lower P-gp efflux liability than Ligand B (0.274), which is crucial for CNS penetration.

**Binding Affinity:** Ligand B (-8.3 kcal/mol) has a slightly better binding affinity than Ligand A (-7.5 kcal/mol). While a 1.5 kcal/mol difference is significant, the other ADME properties of Ligand A are far superior.

**Overall Assessment:**

Ligand A is significantly better overall. While Ligand B has slightly better binding affinity, Ligand A excels in almost every other crucial parameter, especially those prioritized for CNS GPCR targets: BBB penetration, DILI risk, metabolic stability (Cl_mic & t1/2), P-gp efflux, and TPSA. The lower hERG risk and better solubility also contribute to its superior profile. The negative Caco-2 values are concerning for both, but the other advantages of Ligand A outweigh this.

Output:
1
2025-04-17 04:56:35,376 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (346.391 Da) is slightly lower, which is generally favorable for permeability. Ligand B (391.88 Da) is still acceptable.

**TPSA:** Ligand A (102.12) is borderline for CNS penetration, being slightly above the preferred <90. Ligand B (86.29) is excellent, well below the threshold.

**logP:** Ligand A (0.177) is quite low, potentially hindering membrane permeability and CNS penetration. Ligand B (3.653) is within the optimal range (1-3). This is a significant advantage for Ligand B.

**H-Bond Donors/Acceptors:** Ligand A (HBD=1, HBA=7) and Ligand B (HBD=2, HBA=4) both have reasonable numbers of H-bond donors and acceptors, falling within the acceptable limits.

**QED:** Both ligands have acceptable QED scores (A: 0.804, B: 0.596), indicating good drug-like properties.

**DILI:** Ligand A (67.429) has a higher DILI risk than Ligand B (36.797). Lower is better, making Ligand B preferable.

**BBB:** Ligand A (70.919) has a good BBB percentile, while Ligand B (32.416) is quite low. This is a key advantage for Ligand A, given the CNS target.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values, which is unusual and suggests a potential issue with the data or modeling. However, the magnitude of negativity is important. Ligand A (-4.962) is more negative than Ligand B (-5.127), suggesting potentially worse permeability.

**Aqueous Solubility:** Both ligands have negative solubility values, which is also unusual. Again, the magnitude matters. Ligand A (-2.096) is slightly better than Ligand B (-2.882).

**hERG Inhibition:** Both ligands have low hERG inhibition risk (A: 0.207, B: 0.567), which is good.

**Microsomal Clearance:** Ligand A (29.632) has lower microsomal clearance than Ligand B (50.117), indicating better metabolic stability.

**In vitro Half-Life:** Ligand A (41.295) has a longer in vitro half-life than Ligand B (26.165), which is desirable.

**P-gp Efflux:** Ligand A (0.099) has a significantly lower P-gp efflux liability than Ligand B (0.382), which is crucial for CNS penetration.

**Binding Affinity:** Ligand A (-8.4 kcal/mol) has a substantially stronger binding affinity than Ligand B (-6.7 kcal/mol). This is a major advantage for Ligand A, potentially outweighing some of its ADME drawbacks.

**Overall Assessment:**

Ligand A excels in binding affinity, metabolic stability, P-gp efflux, and BBB penetration. However, its low logP is a concern. Ligand B has better TPSA and DILI, and a more optimal logP, but suffers from weaker binding affinity and poorer BBB penetration.

Given the GPCR-specific priorities for DRD2 (BBB, logP, Pgp, TPSA, and affinity), the stronger binding affinity and better BBB/Pgp properties of Ligand A are more critical, even with the lower logP. The difference in affinity (-8.4 vs -6.7 kcal/mol) is substantial. While the low logP is a concern, it might be addressable through further optimization without significantly impacting the strong binding.

Output:
0
2025-04-17 04:56:35,376 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (356.463 and 350.507 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (88.1) is better than Ligand B (55.89) as it is closer to the ideal range for CNS targets (<=90). Ligand B is excellent.

**3. logP:** Ligand B (0.943) is slightly better than Ligand A (0.41). Both are a bit low, potentially hindering permeation, but Ligand B is closer to the optimal 1-3 range.

**4. H-Bond Donors:** Ligand A (2) is slightly higher than Ligand B (1), but both are within the acceptable limit of <=5.

**5. H-Bond Acceptors:** Ligand A (5) is higher than Ligand B (4), but both are within the acceptable limit of <=10.

**6. QED:** Ligand A (0.625) is better than Ligand B (0.497), indicating a more drug-like profile.

**7. DILI:** Ligand B (4.382) has a significantly lower DILI risk than Ligand A (12.33), which is a major advantage.

**8. BBB:** Ligand B (62.233) has a better BBB penetration score than Ligand A (57.736), though both are not ideal (>70). This is a critical factor for a CNS target like DRD2.

**9. Caco-2 Permeability:** Ligand A (-4.685) has a much better Caco-2 permeability than Ligand B (-5.223).

**10. Aqueous Solubility:** Ligand B (0.103) has better solubility than Ligand A (-1.037).

**11. hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.183 and 0.452).

**12. Microsomal Clearance:** Ligand B (-19.859) has a significantly lower (better) microsomal clearance than Ligand A (21.068), suggesting better metabolic stability.

**13. In vitro Half-Life:** Ligand B (-5.788) has a much longer in vitro half-life than Ligand A (3.385).

**14. P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.011 and 0.009).

**15. Binding Affinity:** Ligand B (-7.3 kcal/mol) has slightly better binding affinity than Ligand A (-7.0 kcal/mol). While the difference is small, it's still a positive for Ligand B.

**Overall Assessment:**

While Ligand A has better Caco-2 permeability and QED, Ligand B is superior in almost all other critical parameters for a CNS-targeting GPCR ligand. Specifically, Ligand B demonstrates a significantly lower DILI risk, better BBB penetration, improved metabolic stability (lower Cl_mic, longer t1/2), and slightly better binding affinity. The slightly lower logP of Ligand B is a minor concern, but the substantial advantages in safety (DILI) and CNS penetration outweigh this.

Output:
1
2025-04-17 04:56:35,376 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B based on the provided guidelines, prioritizing GPCR-specific properties (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (361.433 and 355.507 Da) fall within the ideal range of 200-500 Da.

**TPSA:** Ligand A (64.09) is better than Ligand B (59.22) as it is closer to the <90 A^2 threshold for CNS targets.

**logP:** Ligand B (3.765) is higher than Ligand A (0.794). While both are within the acceptable range, Ligand B is approaching the upper limit where solubility issues might arise. Ligand A is quite low, potentially hindering permeation.

**H-Bond Donors/Acceptors:** Both have 1 HBD and 4 HBA, which are within acceptable limits.

**QED:** Both ligands have good QED scores (0.787 and 0.858, respectively), indicating drug-likeness.

**DILI:** Ligand A (10.857) has a significantly lower DILI risk than Ligand B (38.348), which is a major advantage.

**BBB:** Ligand B (92.555) has a much higher BBB penetration percentile than Ligand A (72.16). This is a critical factor for a CNS target like DRD2.

**Caco-2 Permeability:** Ligand A (-4.64) has a worse Caco-2 permeability than Ligand B (-5.009).

**Aqueous Solubility:** Ligand A (-0.384) has better aqueous solubility than Ligand B (-3.884).

**hERG Inhibition:** Ligand A (0.598) has a lower hERG inhibition liability than Ligand B (0.871), which is preferable.

**Microsomal Clearance:** Ligand B (76.594) has a much higher microsomal clearance than Ligand A (-7.139), indicating lower metabolic stability.

**In vitro Half-Life:** Ligand A (-20.961) has a much longer in vitro half-life than Ligand B (0.524).

**P-gp Efflux:** Ligand A (0.029) has much lower P-gp efflux liability than Ligand B (0.706), which is beneficial for CNS exposure.

**Binding Affinity:** Ligand B (-8.3 kcal/mol) has a stronger binding affinity than Ligand A (-7.1 kcal/mol). The difference of 1.2 kcal/mol is substantial and could outweigh some ADME drawbacks.

**Overall Assessment:**

Ligand B excels in BBB penetration and binding affinity, which are paramount for a CNS GPCR target. However, it suffers from higher DILI risk, higher P-gp efflux, and poorer metabolic stability. Ligand A has a better safety profile (lower DILI, hERG, P-gp), better metabolic stability (lower Cl_mic, longer t1/2), and better solubility, but its BBB penetration and binding affinity are weaker.

The affinity difference is significant (1.2 kcal/mol). Given the importance of potency for GPCRs, and the fact that we can potentially mitigate some of the ADME issues with Ligand B through formulation or structural modifications, I believe Ligand B is the more promising candidate.

Output:
1
2025-04-17 04:56:35,376 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight (MW):** Both ligands (351.491 and 343.519 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (78.51) is better than Ligand B (53.08). For CNS targets, we want TPSA <= 90, both are within this range, but A is closer to the upper limit.

**3. logP:** Ligand A (1.835) is optimal (1-3), while Ligand B (3.84) is pushing the upper limit. Higher logP can lead to off-target effects and solubility issues.

**4. H-Bond Donors (HBD):** Both ligands have 2 HBD, which is within the acceptable limit of <=5.

**5. H-Bond Acceptors (HBA):** Ligand A has 3 HBA, and Ligand B has 5 HBA, both are within the acceptable limit of <=10.

**6. QED:** Both ligands have good QED scores (0.63 and 0.703), indicating good drug-like properties.

**7. DILI:** Ligand A (15.2) has a much lower DILI risk than Ligand B (29.779). This is a significant advantage for A.

**8. BBB:** Ligand B (90.384) has a significantly higher BBB penetration percentile than Ligand A (67.158). This is a crucial factor for a CNS target like DRD2.

**9. Caco-2 Permeability:** Ligand A (-4.733) has a more negative Caco-2 value than Ligand B (-5.276), suggesting lower permeability.

**10. Aqueous Solubility:** Ligand A (-2.335) has a more negative solubility value than Ligand B (-2.957), suggesting lower solubility.

**11. hERG Inhibition:** Ligand A (0.191) has a lower hERG inhibition liability than Ligand B (0.945), which is preferable.

**12. Microsomal Clearance:** Ligand A (43.554) has higher microsomal clearance than Ligand B (28.448), meaning it's less metabolically stable.

**13. In vitro Half-Life:** Ligand B (18.626) has a significantly longer in vitro half-life than Ligand A (-1.432).

**14. P-gp Efflux:** Ligand A (0.018) has a much lower P-gp efflux liability than Ligand B (0.331), which is beneficial for CNS penetration.

**15. Binding Affinity:** Ligand B (-9.2 kcal/mol) has a significantly stronger binding affinity than Ligand A (-7.4 kcal/mol). This is a substantial advantage, potentially outweighing some ADME drawbacks.

**Overall Assessment:**

Ligand B excels in BBB penetration and binding affinity, both critical for a CNS GPCR target. While its logP is slightly higher and it has a higher P-gp efflux, the strong affinity and excellent BBB penetration are major positives. Ligand A has better DILI and hERG profiles, and lower P-gp efflux, but its weaker affinity, lower BBB, and poorer metabolic stability are significant drawbacks. The difference in binding affinity (1.8 kcal/mol) is large enough to overcome the slightly less favorable ADME profile of Ligand B.

Output:
1
2025-04-17 04:56:35,377 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (355.435 and 348.363 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (104.81) is significantly better than Ligand B (137.24). For CNS targets, we want TPSA <= 90, so Ligand A is closer to this threshold. Ligand B is above this preferred range.

**logP:** Ligand A (0.209) is quite low, potentially hindering membrane permeability. Ligand B (-1.178) is also low, but slightly better than A. Both are below the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A (HBD=2, HBA=5) is better than Ligand B (HBD=3, HBA=7) in terms of balancing solubility and permeability.

**QED:** Both ligands have good QED scores (A: 0.502, B: 0.597), indicating drug-like properties.

**DILI:** Ligand A (24.234) has a much lower DILI risk than Ligand B (60.799). This is a significant advantage for Ligand A.

**BBB:** Ligand A (66.499) has a substantially better BBB penetration score than Ligand B (13.61). This is *critical* for a CNS target like DRD2.

**Caco-2 Permeability:** Ligand A (-4.558) is worse than Ligand B (-6.187), indicating lower intestinal absorption. However, for a CNS target, intestinal absorption is less critical than BBB penetration.

**Aqueous Solubility:** Ligand A (-1.849) is better than Ligand B (-0.976), indicating better solubility.

**hERG:** Both ligands have very low hERG inhibition liability (A: 0.081, B: 0.029), which is excellent.

**Microsomal Clearance:** Ligand B (-22.888) has a lower (better) microsomal clearance than Ligand A (75.67), suggesting greater metabolic stability.

**In vitro Half-Life:** Ligand B (-1.81) has a slightly better in vitro half-life than Ligand A (-27.172).

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (A: 0.006, B: 0.006).

**Binding Affinity:** Ligand B (-8.5 kcal/mol) has a slightly better binding affinity than Ligand A (-7.6 kcal/mol). While a difference of 0.9 kcal/mol is noticeable, it's not a huge difference and can be overcome by superior ADME properties.

**Overall Assessment:**

Ligand A is significantly better overall, primarily due to its much improved BBB penetration (66.5% vs 13.6%) and lower DILI risk (24.2% vs 60.8%). While Ligand B has slightly better binding affinity and metabolic stability, the CNS target necessitates prioritizing BBB penetration. The lower TPSA of Ligand A is also beneficial. The slightly lower logP of Ligand A is a concern, but the strong BBB score and low DILI outweigh this.

Output:
1
2025-04-17 04:56:35,377 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B based on the provided guidelines, prioritizing GPCR-specific properties (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (348.447) is slightly lower, which could be beneficial for permeability.

**TPSA:** Ligand A (78.68) is excellent for CNS penetration, well below the 90 A^2 threshold. Ligand B (33.2) is also very good.

**logP:** Ligand A (1.224) is optimal. Ligand B (4.93) is high, potentially leading to solubility issues and off-target interactions.

**H-Bond Donors/Acceptors:** Ligand A (HBD=1, HBA=5) and Ligand B (HBD=0, HBA=3) both fall within acceptable ranges.

**QED:** Both ligands have reasonable QED scores (A: 0.836, B: 0.728), indicating good drug-like properties.

**DILI:** Both ligands have low DILI risk (A: 33.114, B: 22.722).

**BBB:** Both ligands exhibit excellent BBB penetration (A: 81.97, B: 87.127), exceeding the 70% threshold. Ligand B is slightly better.

**Caco-2 Permeability:** Ligand A (-4.77) has poor Caco-2 permeability, while Ligand B (-5.185) is also poor.

**Aqueous Solubility:** Ligand A (-1.667) has poor aqueous solubility, while Ligand B (-4.684) is even worse.

**hERG Inhibition:** Ligand A (0.387) shows low hERG inhibition risk, which is good. Ligand B (0.765) is slightly higher but still acceptable.

**Microsomal Clearance:** Ligand A (23.763) has lower clearance, suggesting better metabolic stability than Ligand B (88.877).

**In vitro Half-Life:** Ligand A (12.489) has a longer half-life than Ligand B (3.088).

**P-gp Efflux:** Ligand A (0.063) has very low P-gp efflux, which is favorable for CNS exposure. Ligand B (0.497) has a higher, but still reasonable, P-gp efflux.

**Binding Affinity:** Ligand B (-7.7 kcal/mol) has a significantly stronger binding affinity than Ligand A (-8.3 kcal/mol). This 1.5 kcal/mol difference is substantial and can outweigh some ADME drawbacks.

**Overall Assessment:**

While Ligand A has better solubility, metabolic stability, and P-gp efflux, Ligand B's significantly stronger binding affinity (-7.7 vs -8.3 kcal/mol) is a crucial advantage for a GPCR target. The higher logP of Ligand B is a concern, but the excellent BBB penetration mitigates some of the potential issues with solubility and off-target effects. The longer half-life of Ligand A is a plus, but the affinity difference is more important for initial potency.

Output:
1
2025-04-17 04:56:35,377 - INFO - Reasoning:

Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (346.274 and 354.495 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (123.46) is borderline but acceptable for CNS penetration, while Ligand B (56.33) is excellent, well below the 90 A^2 threshold. This favors Ligand B.

**logP:** Ligand A (1.354) is within the optimal 1-3 range. Ligand B (-0.036) is slightly below 1, which could potentially hinder permeation, but is not a major concern.

**H-Bond Donors/Acceptors:** Ligand A has 2 HBD and 7 HBA, which are reasonable. Ligand B has 0 HBD and 5 HBA, also acceptable.

**QED:** Both ligands have reasonable QED values (0.486 and 0.642), indicating drug-like properties. Ligand B is slightly better.

**DILI:** Ligand A has a very high DILI risk (99.147%), which is a significant red flag. Ligand B has a very low DILI risk (5.467%), a major advantage.

**BBB:** Both ligands have good BBB penetration (63.474% and 66.925%), but neither exceeds the desirable >70% threshold.

**Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and suggests a potential issue with the data or modeling. However, the magnitude of the negative value for Ligand A (-4.92) is larger, suggesting worse permeability.

**Aqueous Solubility:** Both have negative solubility values, again unusual. Ligand A (-4.093) is slightly worse than Ligand B (0.469).

**hERG Inhibition:** Ligand A (0.207) has a slightly higher hERG risk than Ligand B (0.354), but both are relatively low.

**Microsomal Clearance:** Ligand A (9.355) has a higher microsomal clearance than Ligand B (29.959), indicating lower metabolic stability.

**In vitro Half-Life:** Ligand A (32.58) has a longer half-life than Ligand B (-28.486), which is a positive. However, the negative value for Ligand B is concerning.

**P-gp Efflux:** Ligand A (0.149) has lower P-gp efflux liability than Ligand B (0.003), which is favorable for CNS exposure.

**Binding Affinity:** Ligand A (-10.3 kcal/mol) has significantly stronger binding affinity than Ligand B (-6.9 kcal/mol). This is a substantial advantage, potentially outweighing some of its ADME drawbacks.

**Overall Assessment:**

Despite Ligand A's superior binding affinity, its extremely high DILI risk is a deal-breaker. The negative Caco-2 and solubility values are also concerning. Ligand B, while having a weaker binding affinity, possesses a much more favorable safety profile (low DILI) and better TPSA. The slightly suboptimal logP is less concerning than the DILI risk. The negative half-life for Ligand B is a data quality issue that would need to be investigated.

Output:
1
2025-04-17 04:56:35,377 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (342.53 and 351.38 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (23.55) is excellent, well below the 90 A^2 threshold for CNS targets. Ligand B (95.5) is significantly higher, potentially hindering BBB penetration.

**logP:** Ligand A (4.149) is slightly above the optimal 1-3 range, but still potentially acceptable given the strong affinity. Ligand B (-0.447) is considerably low, which could limit permeability and CNS exposure.

**H-Bond Donors/Acceptors:** Ligand A (0 HBD, 2 HBA) is favorable. Ligand B (1 HBD, 5 HBA) is also reasonable, though slightly higher in HBA count.

**QED:** Both ligands have similar QED values (0.802 and 0.718), indicating good drug-likeness.

**DILI:** Ligand A (7.251) has a much lower DILI risk than Ligand B (61.07), which is a significant advantage.

**BBB:** Ligand A (93.292) has excellent BBB penetration potential, exceeding the desirable >70 percentile. Ligand B (73.827) is lower, but still in a reasonable range.

**Caco-2 Permeability:** Ligand A (-4.625) shows poor Caco-2 permeability. Ligand B (-5.096) is also poor.

**Aqueous Solubility:** Ligand A (-2.537) and Ligand B (-0.982) both have poor aqueous solubility.

**hERG:** Ligand A (0.827) has a lower hERG risk than Ligand B (0.067).

**Microsomal Clearance:** Ligand A (10.217) has a higher microsomal clearance than Ligand B (1.546), meaning Ligand B is more metabolically stable.

**In vitro Half-Life:** Ligand B (6.763) has a longer in vitro half-life than Ligand A (2.406), which is preferable.

**P-gp Efflux:** Ligand A (0.427) has lower P-gp efflux than Ligand B (0.008), which is beneficial for CNS exposure.

**Binding Affinity:** Ligand A (-8.9 kcal/mol) has a significantly stronger binding affinity than Ligand B (-7.6 kcal/mol). The 1.3 kcal/mol difference is substantial and can often outweigh minor ADME drawbacks.

**Overall Assessment:**

Despite the poor Caco-2 permeability and solubility for both compounds, Ligand A is the more promising candidate. Its superior BBB penetration, lower DILI risk, significantly stronger binding affinity, and lower P-gp efflux outweigh the slightly higher logP and faster clearance. Ligand B's low logP is a major concern for CNS penetration, and its higher DILI risk is also unfavorable. The affinity difference is substantial enough to prioritize Ligand A.

Output:
1
2025-04-17 04:56:35,378 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (347.38 and 347.39 Da) fall comfortably within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (137.82) is borderline for CNS penetration, slightly above the preferred <90, but acceptable. Ligand B (87.31) is excellent, well below 90, suggesting better CNS penetration potential.

**3. logP:** Ligand A (-0.621) is quite low, potentially hindering membrane permeability and bioavailability. Ligand B (2.255) is within the optimal 1-3 range.

**4. H-Bond Donors:** Ligand A (4) is acceptable. Ligand B (2) is also good.

**5. H-Bond Acceptors:** Both ligands (7) are within the acceptable limit of 10.

**6. QED:** Both ligands have good QED scores (0.527 and 0.829), indicating drug-like properties. Ligand B is superior.

**7. DILI:** Both ligands have similar DILI risk (60.644 and 59.403), indicating moderate risk. This isn't a major differentiating factor.

**8. BBB:** This is crucial for a CNS target. Ligand A has a BBB percentile of 13.222, which is very poor. Ligand B has a much better BBB percentile of 67.701, making it significantly more promising for CNS penetration.

**9. Caco-2 Permeability:** Both have negative values (-5.844 and -5.184), which is unusual and difficult to interpret without more context. However, the negative values suggest poor permeability.

**10. Aqueous Solubility:** Both have negative values (-1.907 and -3.455), also unusual. This suggests poor solubility.

**11. hERG Inhibition:** Ligand A (0.031) has a very low hERG risk, which is excellent. Ligand B (0.506) has a slightly higher, but still relatively low, hERG risk.

**12. Microsomal Clearance:** Ligand A (-29.997) has very low clearance, suggesting high metabolic stability. Ligand B (31.217) has moderate clearance, indicating less metabolic stability.

**13. In vitro Half-Life:** Ligand A (4.362) has a short half-life. Ligand B (36.388) has a much longer half-life, which is beneficial.

**14. P-gp Efflux:** Both ligands have similar P-gp efflux liability (-9 and -8.7), indicating moderate efflux.

**15. Binding Affinity:** Ligand A (-9.0) has a significantly stronger binding affinity than Ligand B (-8.7). This is a substantial advantage.

**Overall Assessment:**

While Ligand A boasts a superior binding affinity, its extremely poor BBB penetration and low logP are major drawbacks for a CNS target like DRD2. Ligand B, despite slightly weaker affinity, has a much better logP, significantly better BBB penetration, and a longer half-life. The combination of these factors makes Ligand B a more promising drug candidate. The better BBB and logP will likely translate to better brain exposure, even with slightly lower affinity.

Output:
1
2025-04-17 04:56:35,378 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, considering the provided guidelines and GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (346.43 and 344.46 Da) fall comfortably within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (78.87) is higher than Ligand B (49.85). For a CNS target like DRD2, TPSA should be <=90, so both are acceptable, but B is significantly better.

**3. logP:** Both ligands (1.60 and 1.83) are within the optimal 1-3 range.

**4. H-Bond Donors:** Ligand A has 2 HBD, and Ligand B has 0. Both are acceptable (<=5).

**5. H-Bond Acceptors:** Ligand A has 4 HBA, and Ligand B has 3. Both are acceptable (<=10).

**6. QED:** Both ligands have reasonable QED values (0.786 and 0.565), indicating good drug-like properties.

**7. DILI:** Ligand A (36.76%) has a slightly higher DILI risk than Ligand B (18.15%). Both are below the 40% threshold, indicating low risk.

**8. BBB:** This is a critical parameter for CNS targets. Ligand A has a BBB percentile of 40.52%, while Ligand B has 63.78%. Ligand B is significantly better at predicted BBB penetration, exceeding the desirable >70% threshold.

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.572 and -4.445). This is unusual and suggests poor permeability. However, the scale isn't defined, so it's hard to interpret.

**10. Aqueous Solubility:** Both ligands have negative solubility values (-2.007 and -2.246). This is also unusual and suggests poor solubility.

**11. hERG Inhibition:** Both ligands have low hERG inhibition risk (0.532 and 0.193).

**12. Microsomal Clearance:** Ligand A (37.60) has a higher microsomal clearance than Ligand B (34.56), indicating lower metabolic stability.

**13. In vitro Half-Life:** Ligand B (-7.799) has a significantly longer in vitro half-life than Ligand A (-22.865).

**14. P-gp Efflux:** Both ligands have low P-gp efflux liability (0.227 and 0.155).

**15. Binding Affinity:** Both ligands have very similar binding affinities (-8.6 and -8.2 kcal/mol). The difference is less than 1.5 kcal/mol, so it's not a deciding factor.

**Overall Assessment:**

Ligand B is the more promising candidate. While both ligands have similar binding affinities and acceptable physicochemical properties, Ligand B demonstrates a significantly better BBB penetration (63.78% vs 40.52%), a longer in vitro half-life, and lower DILI risk. These factors are particularly important for a CNS-targeting GPCR like DRD2. The negative Caco-2 and solubility values are concerning for both, but the superior CNS properties of Ligand B outweigh these drawbacks.

Output:
1
2025-04-17 04:56:35,378 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (360.426 and 346.439 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (88.1) is excellent, well below the 90 A^2 threshold for CNS targets. Ligand B (126.8) is still reasonable but higher, potentially impacting BBB penetration.

**3. logP:** Ligand A (0.254) is quite low, potentially hindering membrane permeability. Ligand B (0.723) is better, though still on the lower side of the optimal 1-3 range.

**4. H-Bond Donors:** Ligand A (2) is good. Ligand B (4) is acceptable, but approaching the upper limit.

**5. H-Bond Acceptors:** Ligand A (5) is good. Ligand B (9) is at the upper limit, potentially impacting permeability.

**6. QED:** Both ligands have acceptable QED values (0.709 and 0.578, respectively), indicating reasonable drug-likeness.

**7. DILI:** Ligand A (35.285) has a lower DILI risk than Ligand B (48.623), which is favorable.

**8. BBB:** Ligand A (60.876) has a better BBB percentile than Ligand B (54.634), though both are below the desirable >70% for CNS targets. This is a critical factor for DRD2.

**9. Caco-2 Permeability:** Ligand A (-4.799) has a very poor Caco-2 permeability, suggesting significant absorption issues. Ligand B (-5.589) is similarly poor.

**10. Aqueous Solubility:** Both ligands have very poor aqueous solubility (-0.739 and -2.103). This is a significant concern for formulation and bioavailability.

**11. hERG Inhibition:** Both ligands have low hERG inhibition risk (0.309 and 0.343).

**12. Microsomal Clearance:** Ligand A (-5.393) has significantly lower (better) microsomal clearance than Ligand B (14.482), indicating better metabolic stability.

**13. In vitro Half-Life:** Ligand A (-1.862) has a slightly better in vitro half-life than Ligand B (16.983).

**14. P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.031 and 0.011), which is good for CNS penetration.

**15. Binding Affinity:** Both ligands have excellent binding affinity (-8.1 and -8.4 kcal/mol). The difference is minimal.

**Overall Assessment:**

Despite both ligands having excellent binding affinity, Ligand A is the more promising candidate. While its logP is low, its superior TPSA, lower DILI risk, better BBB penetration (though still suboptimal), and significantly better metabolic stability (lower Cl_mic and better half-life) outweigh the slightly lower logP. The poor Caco-2 permeability and solubility are concerns for both, but can be addressed with formulation strategies. Given the GPCR-specific emphasis on BBB penetration and metabolic stability for CNS targets, Ligand A is the better choice.

Output:
0
2025-04-17 04:56:35,378 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (349.5 and 366.5 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (61.44) is significantly better than Ligand B (84.42). For CNS targets, TPSA should be <= 90, and A is comfortably within this range, while B is approaching the upper limit.

**logP:** Both ligands have good logP values (2.596 and 2.166), falling within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A has 2 HBD and 3 HBA, while Ligand B has 1 HBD and 7 HBA. Both are within acceptable limits (<=5 HBD, <=10 HBA).

**QED:** Both ligands have good QED scores (0.629 and 0.777), indicating good drug-like properties.

**DILI:** Ligand A (6.592) has a much lower DILI risk than Ligand B (47.344). This is a significant advantage.

**BBB:** Both ligands have acceptable BBB penetration (78.79% and 71.927%). However, Ligand A is slightly better.

**Caco-2 Permeability:** Ligand A (-5.116) has a worse Caco-2 permeability than Ligand B (-4.732). Higher values are better.

**Aqueous Solubility:** Ligand A (-2.037) has a worse aqueous solubility than Ligand B (-3.044). Higher values are better.

**hERG Inhibition:** Ligand A (0.658) has a slightly higher hERG inhibition risk than Ligand B (0.329), but both are relatively low.

**Microsomal Clearance:** Ligand A (-13.375) has a much lower (better) microsomal clearance than Ligand B (87.031), suggesting better metabolic stability.

**In vitro Half-Life:** Both ligands have similar in vitro half-lives (-2.366 and -2.314).

**P-gp Efflux:** Ligand A (0.061) has a much lower P-gp efflux liability than Ligand B (0.102), which is crucial for CNS penetration.

**Binding Affinity:** Both ligands have excellent binding affinities (-8.0 and -7.7 kcal/mol). The difference of 0.3 kcal/mol is not substantial enough to override other significant differences.

**Overall Assessment:**

Ligand A is superior due to its significantly better TPSA, DILI risk, microsomal clearance, and P-gp efflux. While Ligand B has slightly better Caco-2 permeability and aqueous solubility, these are less critical for a CNS target like DRD2. The slightly better BBB penetration of Ligand A further supports its selection. The binding affinity difference is minimal.

Output:
1
2025-04-17 04:56:35,379 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (344.411 Da) is slightly lower, which could be beneficial for permeability.

**TPSA:** Ligand A (75.8) is excellent for CNS penetration, well below the 90 A^2 threshold. Ligand B (106.1) is higher, but still potentially acceptable, though less ideal.

**logP:** Ligand A (3.109) is optimal. Ligand B (0.693) is quite low, potentially hindering membrane permeability and CNS entry.

**H-Bond Donors/Acceptors:** Ligand A (HBD=1, HBA=6) and Ligand B (HBD=2, HBA=7) both fall within acceptable ranges.

**QED:** Both ligands have similar and good QED values (A: 0.84, B: 0.812).

**DILI:** Both ligands have high DILI risk (A: 17.449, B: 83.404), but Ligand B is significantly higher.

**BBB:** Ligand A (83.172) has excellent BBB penetration potential, exceeding the 70% threshold. Ligand B (30.787) is poor, a major drawback for a CNS target.

**Caco-2 Permeability:** Ligand A (-4.992) is better than Ligand B (-5.479), indicating slightly better intestinal absorption.

**Aqueous Solubility:** Ligand A (-4.024) is better than Ligand B (-1.556), suggesting better formulation potential.

**hERG Inhibition:** Ligand A (0.812) has a slightly higher hERG risk than Ligand B (0.07), but both are relatively low.

**Microsomal Clearance:** Ligand A (91.086) has higher clearance, suggesting lower metabolic stability compared to Ligand B (-11.344).

**In vitro Half-Life:** Ligand B (21.157) has a longer half-life than Ligand A (-29.431), which is a positive attribute.

**P-gp Efflux:** Ligand A (0.499) has lower P-gp efflux, which is favorable for CNS penetration, while Ligand B (0.006) has very low efflux.

**Binding Affinity:** Ligand A (-8.8 kcal/mol) has a significantly stronger binding affinity than Ligand B (-7.8 kcal/mol). This 1.0 kcal/mol difference is substantial and can outweigh some ADME liabilities.

**Overall Assessment:**

Ligand A is the stronger candidate. While it has higher microsomal clearance, its superior BBB penetration, optimal logP, and significantly better binding affinity are crucial for a CNS-targeting GPCR like DRD2. Ligand B's low logP and poor BBB penetration are major liabilities that are difficult to overcome. The better half-life of Ligand B is less important than the other factors.

Output:
1
2025-04-17 04:56:35,379 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (366.571 and 354.535 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (58.2) is excellent, well below the 90 A^2 threshold for CNS targets. Ligand B (78.43) is still reasonable but less optimal.

**3. logP:** Both ligands have good logP values (3.503 and 2.724), falling within the 1-3 range.

**4. H-Bond Donors:** Both have acceptable HBD counts (2 and 3 respectively), below the threshold of 5.

**5. H-Bond Acceptors:** Both have acceptable HBA counts (3), below the threshold of 10.

**6. QED:** Both ligands have reasonable QED values (0.459 and 0.564), with Ligand B slightly better.

**7. DILI:** Ligand A (20.008) has a much lower DILI risk than Ligand B (8.375), indicating a safer profile.

**8. BBB:** Ligand B (72.625) has a significantly better BBB penetration percentile than Ligand A (55.719). This is a crucial factor for a CNS target like DRD2.

**9. Caco-2 Permeability:** Both have negative Caco-2 values (-4.905 and -4.608). These values are unusual and suggest poor permeability. However, the scale isn't specified, so it's difficult to interpret.

**10. Aqueous Solubility:** Both have negative solubility values (-4.204 and -2.972), again, difficult to interpret without knowing the scale.

**11. hERG Inhibition:** Both ligands show low hERG inhibition liability (0.391 and 0.464), which is good.

**12. Microsomal Clearance:** Ligand A (47.518) has lower microsomal clearance than Ligand B (53.685), suggesting better metabolic stability.

**13. In vitro Half-Life:** Ligand A (33.13) has a longer in vitro half-life than Ligand B (8.771), which is desirable.

**14. P-gp Efflux:** Both ligands have low P-gp efflux liability (0.28 and 0.086), which is favorable for CNS penetration.

**15. Binding Affinity:** Ligand B (-8.0 kcal/mol) has a slightly better binding affinity than Ligand A (-7.2 kcal/mol). This 0.8 kcal/mol difference is significant and could outweigh some ADME drawbacks.

**Overall Assessment:**

Ligand B excels in BBB penetration and binding affinity, two critical factors for a DRD2 ligand. However, Ligand A demonstrates a considerably better safety profile (lower DILI) and improved metabolic stability (lower Cl_mic, longer t1/2). The negative values for Caco-2 and solubility for both ligands are concerning and require further investigation.

Given the importance of CNS penetration for DRD2, and the significant affinity advantage of Ligand B, I would lean towards **Ligand B** as the more promising candidate, *assuming* the negative Caco-2 and solubility values are not indicative of a major issue. Further investigation into these properties is crucial.

Output:
1
2025-04-17 04:56:35,379 - INFO - Batch 156 complete. Total preferences: 2496
2025-04-17 04:56:35,379 - INFO - Processing batch 157/512...
2025-04-17 04:57:17,323 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (341.39 and 348.443 Da) fall comfortably within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (83.6) is better than Ligand B (62.99). Both are below the 90 A^2 threshold for CNS targets, but A is closer to the upper limit.

**3. logP:** Both ligands (2.38 and 2.33) are within the optimal 1-3 range.

**4. H-Bond Donors:** Ligand A has 1 HBD, while Ligand B has 0. Both are acceptable (<=5).

**5. H-Bond Acceptors:** Ligand A has 5 HBA, and Ligand B has 4. Both are within the acceptable range (<=10).

**6. QED:** Ligand A (0.874) has a significantly better QED score than Ligand B (0.791), indicating a more drug-like profile.

**7. DILI:** Ligand A (56.727) has a higher DILI risk than Ligand B (22.102). This is a significant drawback for Ligand A.

**8. BBB:** Both ligands have excellent BBB penetration (Ligand A: 81.039, Ligand B: 80.574), exceeding the desirable >70 percentile for CNS targets.

**9. Caco-2 Permeability:** Ligand A (-4.685) has poorer Caco-2 permeability than Ligand B (-4.276). Lower values are less favorable.

**10. Aqueous Solubility:** Ligand A (-4.121) has poorer aqueous solubility than Ligand B (-1.573). Lower values are less favorable.

**11. hERG Inhibition:** Both ligands have low hERG inhibition risk (Ligand A: 0.418, Ligand B: 0.286).

**12. Microsomal Clearance:** Ligand B (41.896) has a lower (better) microsomal clearance than Ligand A (22.004), suggesting better metabolic stability.

**13. In vitro Half-Life:** Ligand B (47.08) has a significantly longer in vitro half-life than Ligand A (0.014). This is a major advantage for Ligand B.

**14. P-gp Efflux:** Both ligands have low P-gp efflux (Ligand A: 0.222, Ligand B: 0.101). Ligand B is slightly better.

**15. Binding Affinity:** Ligand A (-9.3 kcal/mol) has a significantly stronger binding affinity than Ligand B (-7.4 kcal/mol). This is a substantial advantage for Ligand A.

**Overall Assessment:**

While Ligand A boasts superior binding affinity, its significantly higher DILI risk, poorer solubility, lower Caco-2 permeability, and much shorter half-life are major concerns. Ligand B, despite a slightly weaker binding affinity, presents a much more favorable ADME-Tox profile, with lower DILI risk, better solubility, better permeability, and a much longer half-life. Given the GPCR-specific priorities, and the importance of a balanced profile for CNS drug development, Ligand B is the more promising candidate. The 1.9 kcal/mol difference in binding affinity, while substantial, can potentially be optimized during lead optimization, whereas mitigating the severe ADME liabilities of Ligand A would be far more challenging.

Output:
1
2025-04-17 04:57:17,323 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (355.375 and 346.475 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (98.25) is slightly higher than Ligand B (86.88). Both are below the 140 A^2 threshold for oral absorption, but only Ligand B is approaching the more stringent <90 A^2 for CNS targets.

**3. logP:** Both ligands have similar logP values (2.388 and 2.346), falling within the optimal 1-3 range.

**4. H-Bond Donors:** Ligand A (1) is better than Ligand B (3), as fewer HBDs generally improve permeability.

**5. H-Bond Acceptors:** Ligand A (6) is better than Ligand B (3), as fewer HBAs generally improve permeability.

**6. QED:** Ligand A (0.754) has a significantly higher QED score than Ligand B (0.449), indicating a more drug-like profile.

**7. DILI:** Ligand A (98.992) has a much higher DILI risk than Ligand B (23.187). This is a significant drawback for Ligand A.

**8. BBB:** Ligand B (46.879) has a better BBB penetration percentile than Ligand A (39.007). While neither are above the desirable >70 for CNS targets, Ligand B is closer.

**9. Caco-2 Permeability:** Ligand A (-5.153) has a worse Caco-2 permeability than Ligand B (-5.434). Both are negative, indicating poor permeability.

**10. Aqueous Solubility:** Ligand A (-3.289) has slightly better aqueous solubility than Ligand B (-2.177).

**11. hERG Inhibition:** Ligand A (0.066) has a lower hERG inhibition risk than Ligand B (0.346), which is favorable.

**12. Microsomal Clearance:** Ligand A (-0.676) has a lower (better) microsomal clearance than Ligand B (25.137), suggesting better metabolic stability.

**13. In vitro Half-Life:** Ligand A (18.862) has a shorter in vitro half-life than Ligand B (-30.406). A negative value for Ligand B is unusual and likely indicates a very long half-life.

**14. P-gp Efflux:** Ligand A (0.061) has lower P-gp efflux liability than Ligand B (0.186), which is beneficial for CNS penetration.

**15. Binding Affinity:** Ligand A (-10.2 kcal/mol) has a significantly stronger binding affinity than Ligand B (-7.9 kcal/mol). This is a substantial advantage.

**Overall Assessment:**

Ligand A has a much stronger binding affinity and better metabolic stability (lower Cl_mic) and P-gp efflux. However, it has a significantly higher DILI risk and a lower BBB penetration. Ligand B has a lower DILI risk, better BBB, and a longer half-life, but its binding affinity is considerably weaker.

Given the GPCR-specific priorities, and the importance of CNS penetration for DRD2 (a CNS target), the stronger affinity of Ligand A is likely to outweigh its drawbacks, *provided* the DILI risk can be mitigated through structural modifications. The difference in affinity (-2.3 kcal/mol) is substantial and could be crucial for efficacy. The lower P-gp efflux of Ligand A also helps with CNS exposure.

Output:
1
2025-04-17 04:57:17,324 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B based on the provided guidelines, prioritizing GPCR-specific properties (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (346.515 and 349.391 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (49.41) is excellent, well below the 90 A^2 threshold for CNS targets. Ligand B (96.77) is higher, but still potentially acceptable, though less ideal.

**logP:** Ligand A (3.522) is optimal (1-3). Ligand B (-1.002) is significantly lower, which could hinder permeability and CNS penetration.

**H-Bond Donors/Acceptors:** Both ligands have 1 HBD, which is good. Ligand A has 2 HBA, while Ligand B has 6. Both are within the acceptable range (<=10), but Ligand B is closer to the upper limit.

**QED:** Both ligands have similar QED values (0.774 and 0.703), indicating good drug-like properties.

**DILI:** Ligand A (31.563) has a much lower DILI risk than Ligand B (57.076), making it safer. Both are below the concerning threshold of 60.

**BBB:** Ligand A (74.564) has a significantly better BBB percentile than Ligand B (53.432). This is a critical factor for a CNS target like DRD2.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.767 and -4.753), which is unusual and suggests poor permeability. However, these values are on a log scale and difficult to interpret without further context.

**Aqueous Solubility:** Both ligands have negative solubility values (-4.015 and -1.39), also unusual and suggesting poor solubility.

**hERG:** Ligand A (0.465) has a much lower hERG risk than Ligand B (0.042).

**Microsomal Clearance:** Ligand A (64.038) has higher clearance than Ligand B (-9.767), indicating lower metabolic stability. This is a drawback for Ligand A.

**In vitro Half-Life:** Ligand B (-3.92) has a slightly better in vitro half-life than Ligand A (-17.451).

**P-gp Efflux:** Ligand A (0.332) has a higher P-gp efflux liability than Ligand B (0.012), which is undesirable for CNS penetration.

**Binding Affinity:** Ligand B (-7.5 kcal/mol) has a significantly stronger binding affinity than Ligand A (0.0 kcal/mol). This is a substantial advantage that could outweigh some of its ADME drawbacks.

**Overall Assessment:**

Ligand B has a much stronger binding affinity, which is paramount for GPCR targeting. However, it suffers from a very low logP, potentially hindering permeability and BBB penetration. Ligand A has better ADME properties (BBB, logP, DILI, hERG) but significantly weaker binding affinity. Given the importance of affinity for GPCRs, and the substantial difference (-7.5 vs 0 kcal/mol), Ligand B is more likely to be a viable drug candidate *if* its permeability issues can be addressed through formulation or structural modifications. The poor logP is a significant concern, but the strong binding is a major advantage.

Output:
1
2025-04-17 04:57:17,324 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (351.422 and 350.459 Da) fall comfortably within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (62.74) is excellent, well below the 90 A^2 threshold for CNS targets. Ligand B (78.87) is still reasonable, but less optimal.

**3. logP:** Both ligands have logP values (1.45 and 1.751) within the optimal 1-3 range.

**4. H-Bond Donors:** Ligand A (0) is ideal, while Ligand B (2) is acceptable.

**5. H-Bond Acceptors:** Both ligands have 4 H-bond acceptors, which is within the acceptable limit of <=10.

**6. QED:** Both ligands have good QED scores (0.64 and 0.686), indicating drug-like properties.

**7. DILI:** Ligand A (23.226) has a significantly lower DILI risk than Ligand B (41.024). This is a substantial advantage.

**8. BBB:** This is a critical parameter for a CNS target like DRD2. Ligand A exhibits a very high BBB penetration percentile (87.941), while Ligand B is much lower (29.585). This is a major differentiating factor.

**9. Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and suggests a potential issue with permeability prediction. However, the absolute values are similar.

**10. Aqueous Solubility:** Both ligands have very poor predicted aqueous solubility (-0.469 and -1.588). This is a concern for both, but more so for Ligand B.

**11. hERG Inhibition:** Both ligands show low hERG inhibition risk (0.479 and 0.217).

**12. Microsomal Clearance:** Both have similar microsomal clearance values (22.46 and 23.233).

**13. In vitro Half-Life:** Ligand A (6.336) has a slightly better in vitro half-life than Ligand B (-7.256).

**14. P-gp Efflux:** Both have very low P-gp efflux liability (0.069 and 0.213).

**15. Binding Affinity:** Ligand B (-7.8 kcal/mol) has a slightly better binding affinity than Ligand A (-7.4 kcal/mol), but the difference is not substantial enough to overcome the other significant advantages of Ligand A.

**Overall Assessment:**

Ligand A is the superior candidate. Its significantly better BBB penetration, lower DILI risk, and favorable TPSA outweigh the slightly weaker binding affinity compared to Ligand B. The poor aqueous solubility is a concern for both, but can be addressed with formulation strategies. Given the CNS target, BBB penetration is paramount, and Ligand A excels in this area.

Output:
0
2025-04-17 04:57:17,324 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (342.443) is slightly lower, which could be beneficial for permeability, but both are acceptable.

**TPSA:** Ligand A (86.88) is excellent for CNS penetration, being well below 90. Ligand B (49.85) is even better. Both are favorable.

**logP:** Both ligands have good logP values (A: 2.045, B: 2.384), falling within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A has 3 HBD and 3 HBA, while Ligand B has 0 HBD and 4 HBA. Both are within acceptable limits (<=5 HBD, <=10 HBA).

**QED:** Both ligands have good QED scores (A: 0.663, B: 0.745), indicating drug-likeness.

**DILI:** Ligand A (57.619) has a slightly higher DILI risk than Ligand B (46.375), but both are below the concerning threshold of 60.

**BBB:** This is a critical parameter for a CNS target. Ligand B (91.819) has a significantly higher BBB percentile than Ligand A (64.25). This is a major advantage for Ligand B.

**Caco-2 Permeability:** Ligand A (-5.241) has a negative Caco-2 value, which is unusual and suggests poor permeability. Ligand B (-4.418) is also negative, but less so.

**Aqueous Solubility:** Both ligands have negative solubility values, indicating poor aqueous solubility. This is a potential issue for both, but can be mitigated with formulation strategies.

**hERG Inhibition:** Both ligands have low hERG inhibition liability (A: 0.359, B: 0.416), which is good.

**Microsomal Clearance:** Ligand A (30.026) has lower microsomal clearance than Ligand B (51.438), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand B (28.335) has a longer in vitro half-life than Ligand A (17.337), which is desirable.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (A: 0.323, B: 0.204), which is favorable for CNS penetration. Ligand B is slightly better.

**Binding Affinity:** Ligand B (-7.8 kcal/mol) has a significantly stronger binding affinity than Ligand A (-10.0 kcal/mol). This is a substantial advantage, and can often outweigh minor ADME concerns.

**Overall Assessment:**

Ligand B is the stronger candidate. While Ligand A has slightly better metabolic stability, Ligand B excels in the most critical areas for a CNS GPCR target: BBB penetration and binding affinity. The significantly higher BBB percentile and stronger binding affinity of Ligand B outweigh the slightly higher clearance and shorter half-life compared to Ligand A. The negative Caco-2 values for both are concerning, but the strong affinity of B suggests it may still be able to achieve sufficient target engagement *in vivo*.

Output:
1
2025-04-17 04:57:17,324 - INFO - Reasoning:

Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (349.475 and 364.364 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (70.67) is better than Ligand B (75.71). Both are below the 90 A^2 threshold for CNS targets, but A is closer to the optimal range.

**3. logP:** Both ligands have similar logP values (1.792 and 1.778), falling within the optimal 1-3 range.

**4. H-Bond Donors:** Ligand A has 2 HBD, while Ligand B has 1. Both are acceptable (<=5).

**5. H-Bond Acceptors:** Both ligands have 4 HBA, which is within the acceptable range (<=10).

**6. QED:** Both ligands have good QED scores (0.656 and 0.755), indicating drug-like properties.

**7. DILI:** Ligand A (14.23) has a significantly lower DILI risk than Ligand B (38.503). This is a major advantage for Ligand A.

**8. BBB:** Ligand B (98.022) has a much higher BBB penetration percentile than Ligand A (57.619). This is a critical advantage for a CNS target like DRD2.

**9. Caco-2 Permeability:** Ligand A (-5.469) has worse Caco-2 permeability than Ligand B (-4.572), suggesting lower intestinal absorption.

**10. Aqueous Solubility:** Ligand A (-1.694) has slightly better aqueous solubility than Ligand B (-3.078).

**11. hERG Inhibition:** Ligand A (0.124) has a lower hERG inhibition liability than Ligand B (0.433), indicating a lower risk of cardiotoxicity.

**12. Microsomal Clearance:** Ligand A (-8.264) has significantly lower microsomal clearance than Ligand B (24.445), suggesting better metabolic stability.

**13. In vitro Half-Life:** Ligand A (2.235) has a shorter in vitro half-life than Ligand B (-29.111), which is a disadvantage.

**14. P-gp Efflux:** Ligand A (0.013) has significantly lower P-gp efflux liability than Ligand B (0.076), which is crucial for CNS penetration.

**15. Binding Affinity:** Ligand A (-7.8) has a slightly better binding affinity than Ligand B (-7.3). While both are good, the 0.5 kcal/mol difference is notable.

**Overall Assessment:**

Ligand B excels in BBB penetration, which is paramount for a CNS target. However, it suffers from higher DILI risk, higher P-gp efflux, higher microsomal clearance, and lower metabolic stability. Ligand A has a better safety profile (lower DILI, hERG, P-gp), better metabolic stability, and slightly better affinity, but its BBB penetration is considerably lower.

Considering the GPCR-specific priorities, the superior BBB penetration of Ligand B is a significant advantage that outweighs its drawbacks, *especially* given the target is DRD2. While Ligand A's safety profile is attractive, achieving sufficient CNS exposure is critical for efficacy.

Output:
1
2025-04-17 04:57:17,324 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (348.487 Da) is slightly preferred as it's closer to the lower end, potentially aiding permeability.

**TPSA:** Ligand A (78.43) is significantly better than Ligand B (29.54). For CNS targets, TPSA < 90 is desirable, and Ligand B is excellent in this regard. Ligand A is still acceptable, but B is better.

**logP:** Ligand A (1.846) is optimal (1-3). Ligand B (4.803) is high and could lead to solubility issues and off-target interactions. This is a significant drawback for Ligand B.

**H-Bond Donors/Acceptors:** Ligand A has 3 HBD and 3 HBA, which is good. Ligand B has 0 HBD and 4 HBA, also acceptable.

**QED:** Both ligands have similar QED values (0.557 and 0.545), indicating good drug-likeness.

**DILI:** Ligand A (7.445) has a much lower DILI risk than Ligand B (19.581). This is a substantial advantage for Ligand A.

**BBB:** Ligand B (77.084) has a significantly higher BBB penetration percentile than Ligand A (49.981). This is a critical factor for a CNS target like DRD2, making Ligand B more promising.

**Caco-2 Permeability:** Ligand A (-4.648) has poor Caco-2 permeability. Ligand B (-5.008) is also poor, but slightly better.

**Aqueous Solubility:** Both ligands have very poor aqueous solubility (-3.111 and -4.819). This is a concern for both, but might be manageable with formulation strategies.

**hERG Inhibition:** Ligand A (0.144) has a very low hERG inhibition liability, a significant advantage. Ligand B (0.795) is higher, posing a potential cardiotoxicity risk.

**Microsomal Clearance:** Ligand A (36.446) has lower microsomal clearance than Ligand B (118.604), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (-5.097) has a negative half-life, which is unusual and suggests very rapid metabolism. Ligand B (21.65) has a reasonable half-life.

**P-gp Efflux:** Ligand A (0.023) has very low P-gp efflux, which is excellent for CNS penetration. Ligand B (0.774) has higher efflux, which is less desirable.

**Binding Affinity:** Ligand A (-7.6 kcal/mol) has a slightly better binding affinity than Ligand B (-6.4 kcal/mol). The 1.2 kcal/mol difference is substantial enough to consider, even with other drawbacks.

**Overall Assessment:**

Ligand B excels in BBB penetration and has a reasonable in vitro half-life. However, it suffers from high logP, higher DILI risk, and higher P-gp efflux. Ligand A has better metabolic stability (lower Cl_mic), lower DILI, lower hERG risk, and better P-gp efflux. While its BBB is lower and Caco-2 permeability is poor, its superior binding affinity and more favorable ADME properties (excluding solubility) make it the more promising candidate. The better binding affinity can potentially compensate for the lower BBB, and formulation strategies can be explored to improve solubility.

Output:
0
2025-04-17 04:57:17,325 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (382.255 and 370.871 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (107.71) is higher than the preferred <90 for CNS targets, while Ligand B (32.34) is excellent. This is a significant advantage for Ligand B.

**3. logP:** Both ligands (4.425 and 4.261) are slightly above the optimal 1-3 range, but not drastically so. The potential for off-target effects and solubility issues is moderate.

**4. H-Bond Donors:** Ligand A (2) and Ligand B (1) are both within the acceptable limit of <=5.

**5. H-Bond Acceptors:** Ligand A (4) and Ligand B (2) are both within the acceptable limit of <=10.

**6. QED:** Both ligands have reasonable QED values (0.42 and 0.759), with Ligand B being better.

**7. DILI:** Ligand A (72.043) has a higher DILI risk than Ligand B (17.449), which is a significant advantage for B.

**8. BBB:** Ligand B (93.098) has a much better BBB percentile than Ligand A (61.923). This is crucial for a CNS target like DRD2.

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.824 and -4.816), which is unusual and suggests poor permeability. This is a concern for both.

**10. Aqueous Solubility:** Both ligands have negative solubility values (-4.952 and -4.782), indicating very poor aqueous solubility. This is a major drawback for both compounds.

**11. hERG Inhibition:** Ligand A (0.652) has a slightly lower hERG inhibition risk than Ligand B (0.942), which is a minor advantage.

**12. Microsomal Clearance:** Ligand A (56.634) has a higher microsomal clearance than Ligand B (39.717), meaning B is more metabolically stable.

**13. In vitro Half-Life:** Ligand B (9.481) has a much shorter in vitro half-life than Ligand A (93.457). This is a significant advantage for A.

**14. P-gp Efflux:** Ligand A (0.242) has a lower P-gp efflux liability than Ligand B (0.569), which is beneficial for CNS penetration.

**15. Binding Affinity:** Both ligands have very similar and excellent binding affinities (-8.6 and -8.5 kcal/mol). The difference is negligible.

**Overall Assessment:**

Considering the GPCR-specific priorities, Ligand B is the more promising candidate. Its significantly better TPSA, DILI risk, and BBB penetration outweigh the drawbacks of slightly higher P-gp efflux and shorter half-life. While both have poor solubility and Caco-2 permeability, the CNS target makes BBB a critical factor. Ligand A's longer half-life is a plus, but the higher TPSA and DILI risk are concerning.

Output:
1
2025-04-17 04:57:17,325 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Ligand A (453.2 Da) is within the ideal range, while Ligand B (347.409 Da) is also acceptable, though closer to the lower limit.

**TPSA:** Ligand A (127.68) is above the preferred <90 for CNS targets, but not drastically so. Ligand B (45.23) is excellent for CNS penetration.

**logP:** Ligand A (1.419) is within the optimal range. Ligand B (3.278) is also within the optimal range, but approaching the upper limit.

**H-Bond Donors:** Ligand A (2) and Ligand B (1) are both acceptable.

**H-Bond Acceptors:** Ligand A (8) and Ligand B (3) are both acceptable.

**QED:** Ligand A (0.442) is below the desirable threshold of 0.5, indicating a less drug-like profile. Ligand B (0.923) is excellent.

**DILI:** Ligand A (98.953) has a very high DILI risk. Ligand B (54.789) has a moderate DILI risk, but is significantly better than Ligand A.

**BBB:** Ligand A (45.134) has poor BBB penetration, a critical drawback for a CNS target. Ligand B (89.957) has excellent BBB penetration.

**Caco-2 Permeability:** Ligand A (-5.282) has poor Caco-2 permeability. Ligand B (-4.466) has better, but still poor Caco-2 permeability.

**Aqueous Solubility:** Ligand A (-4.079) has poor aqueous solubility. Ligand B (-3.604) has slightly better aqueous solubility.

**hERG Inhibition:** Ligand A (0.3) has a low risk of hERG inhibition. Ligand B (0.817) has a slightly higher risk, but still acceptable.

**Microsomal Clearance:** Ligand A (47.383) has moderate clearance. Ligand B (32.669) has lower clearance, suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (21.234) has a moderate half-life. Ligand B (35.235) has a longer half-life.

**P-gp Efflux:** Ligand A (0.171) has low P-gp efflux, which is good. Ligand B (0.466) has slightly higher P-gp efflux, but still acceptable.

**Binding Affinity:** Ligand B (-8.7 kcal/mol) has a significantly stronger binding affinity than Ligand A (-7.9 kcal/mol) - a difference of 0.8 kcal/mol, which is substantial.

**Overall Assessment:**

Ligand B is clearly superior. While both ligands have acceptable MW and logP values, Ligand B excels in crucial areas for a CNS-targeting GPCR ligand: BBB penetration, QED, DILI risk, metabolic stability (lower Cl_mic, longer t1/2), and, most importantly, binding affinity. Ligand A's poor BBB penetration and high DILI risk are major red flags. The stronger binding affinity of Ligand B can potentially compensate for the slightly higher Pgp efflux and hERG risk.

Output:
1
2025-04-17 04:57:17,325 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 drug candidates, considering the provided guidelines and GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (358.429 and 337.423 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (67.43) is slightly higher than Ligand B (62.61). Both are below the 90 A^2 threshold desirable for CNS targets, but Ligand B is preferable.

**3. logP:** Both ligands have excellent logP values (2.417 and 2.366) falling within the optimal 1-3 range.

**4. H-Bond Donors:** Both have 2 HBD, well within the acceptable limit of 5.

**5. H-Bond Acceptors:** Both have 3 HBA, also within the acceptable limit of 10.

**6. QED:** Ligand B (0.845) has a significantly better QED score than Ligand A (0.622), indicating a more drug-like profile.

**7. DILI:** Ligand A (29.042) has a much lower DILI risk than Ligand B (58.55). This is a significant advantage for Ligand A.

**8. BBB:** Ligand A (89.066) has a substantially higher BBB penetration percentile than Ligand B (64.211). This is *critical* for a CNS target like DRD2, making Ligand A much more promising.

**9. Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and suggests poor permeability. Ligand A (-4.861) is slightly worse than Ligand B (-4.545).

**10. Aqueous Solubility:** Both have negative solubility values, which is also unusual and suggests poor solubility. Ligand A (-2.691) is slightly worse than Ligand B (-3.272).

**11. hERG Inhibition:** Both ligands have low hERG inhibition risk (0.419 and 0.316), which is good.

**12. Microsomal Clearance:** Ligand B (4.724) has significantly lower microsomal clearance than Ligand A (24.161), suggesting better metabolic stability.

**13. In vitro Half-Life:** Ligand B (33.974) has a much longer in vitro half-life than Ligand A (2.168), which is a significant advantage.

**14. P-gp Efflux:** Both have very low P-gp efflux liability (0.03 and 0.101), which is favorable for CNS penetration.

**15. Binding Affinity:** Ligand B (-8.5 kcal/mol) has a slightly better binding affinity than Ligand A (-7.8 kcal/mol). This 0.7 kcal/mol difference is notable.

**Overall Assessment:**

While Ligand B has better affinity and metabolic stability (lower Cl_mic, longer t1/2), Ligand A is significantly better regarding crucial CNS properties: BBB penetration and DILI risk. The substantial difference in BBB (89.066 vs 64.211) is a major factor favoring Ligand A. The lower DILI risk is also a significant benefit. The slightly worse Caco-2 and solubility for Ligand A are concerning, but potentially addressable with formulation strategies. The affinity difference, while present, is less than 1.5 kcal/mol and is outweighed by the superior CNS properties of Ligand A.

Output:
1
2025-04-17 04:57:17,325 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (352.341 and 337.335 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (85.26) is excellent, well below the 90 A^2 threshold for CNS targets. Ligand B (104.46) is still reasonable but less optimal, being above 90 A^2.

**3. logP:** Ligand A (2.741) is within the optimal 1-3 range. Ligand B (1.196) is a bit low, potentially hindering permeation.

**4. H-Bond Donors:** Ligand A (0) is ideal. Ligand B (3) is acceptable.

**5. H-Bond Acceptors:** Ligand A (6) is good. Ligand B (5) is also good.

**6. QED:** Both ligands have reasonable QED values (0.841 and 0.727), indicating good drug-like properties.

**7. DILI:** Both ligands have acceptable DILI risk (68.011 and 64.521), below the concerning threshold of 60.

**8. BBB:** This is critical for a CNS target. Ligand A scores very highly (94.649), indicating excellent predicted BBB penetration. Ligand B scores poorly (24.855), suggesting very limited CNS exposure.

**9. Caco-2 Permeability:** Ligand A (-4.555) is poor. Ligand B (-5.126) is also poor.

**10. Aqueous Solubility:** Both ligands have very poor solubility (-3.478 and -3.958). This is a significant drawback.

**11. hERG Inhibition:** Both ligands show very low hERG inhibition risk (0.2 and 0.144).

**12. Microsomal Clearance:** Ligand A (32.069) has moderate clearance. Ligand B (-28.535) has negative clearance, which is not possible and likely indicates an error in the data or a very stable compound.

**13. In vitro Half-Life:** Ligand A (0.249) has a very short half-life. Ligand B (28.545) has a very long half-life.

**14. P-gp Efflux:** Both ligands show very low P-gp efflux liability (0.122 and 0.024).

**15. Binding Affinity:** Both ligands have excellent binding affinities (-8.5 and -8.1 kcal/mol). The difference is 0.4 kcal/mol, which isn't substantial enough to overcome other significant differences.

**Overall Assessment:**

Ligand A is significantly better due to its superior BBB penetration (94.649 vs 24.855). While both have poor solubility and Caco-2 permeability, the ability to cross the blood-brain barrier is paramount for a DRD2 ligand targeting CNS disorders. Ligand B's extremely low BBB penetration makes it a poor candidate, despite its long half-life. The negative clearance for Ligand B is also a red flag.

Output:
1
2025-04-17 04:57:17,326 - INFO - Reasoning:

Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (353.423 and 357.391 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (107.78) is better than Ligand B (20.31). For CNS targets, we want TPSA <= 90, so Ligand A is closer to this threshold. Ligand B is exceptionally low, which *could* be beneficial for BBB penetration but might also indicate a lack of necessary interactions.

**logP:** Ligand A (-0.454) is suboptimal, being below the preferred 1-3 range. Ligand B (4.488) is too high, potentially leading to solubility issues and off-target effects.

**H-Bond Donors/Acceptors:** Ligand A has 2 HBD and 6 HBA, which are reasonable. Ligand B has 0 HBD and 1 HBA, which is quite low and could impact solubility and binding.

**QED:** Both ligands have similar QED values (0.655 and 0.687), indicating good drug-likeness.

**DILI:** Ligand A (31.989) has a slightly higher DILI risk than Ligand B (26.173), but both are below the concerning threshold of 60.

**BBB:** This is a critical parameter for a CNS target like DRD2. Ligand B (94.261) is excellent, exceeding the desirable >70 percentile. Ligand A (50.523) is moderate, falling short of the ideal range.

**Caco-2 Permeability:** Ligand A (-5.241) is poor, indicating low intestinal absorption. Ligand B (-4.259) is also poor, but slightly better than Ligand A.

**Aqueous Solubility:** Ligand A (-0.405) is poor, consistent with its low logP. Ligand B (-5.323) is even worse, likely due to its high logP.

**hERG Inhibition:** Ligand A (0.114) has a very low hERG risk, which is excellent. Ligand B (0.825) has a moderate hERG risk.

**Microsomal Clearance:** Ligand A (33.488) has a moderate clearance. Ligand B (58.752) has a higher clearance, suggesting lower metabolic stability.

**In vitro Half-Life:** Ligand A (-22.34) has a very short half-life. Ligand B (15.617) has a moderate half-life.

**P-gp Efflux:** Ligand A (0.005) has very low P-gp efflux, which is highly desirable for CNS penetration. Ligand B (0.616) has moderate P-gp efflux.

**Binding Affinity:** Ligand B (-8.5 kcal/mol) has a significantly stronger binding affinity than Ligand A (-7.5 kcal/mol). This >1.5 kcal/mol difference is substantial and can outweigh some ADME drawbacks.

**Overall Assessment:**

Ligand B excels in BBB penetration and binding affinity, the two most critical factors for a CNS-targeting GPCR ligand. While its logP is high and solubility is low, the strong affinity might compensate for these issues. Ligand A has better TPSA and hERG, but its poor BBB penetration, solubility, and half-life are significant drawbacks. The superior affinity of Ligand B is a decisive factor.

Output:
1
2025-04-17 04:57:17,326 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (360.445 and 348.403 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (58.64) is excellent, well below the 90 A^2 threshold for CNS targets. Ligand B (113.44) is higher, but still potentially acceptable, though less ideal.

**logP:** Ligand A (2.446) is optimal (1-3). Ligand B (-0.262) is significantly lower, which could hinder membrane permeability and CNS penetration.

**H-Bond Donors/Acceptors:** Ligand A (HBD=1, HBA=3) is within the preferred limits. Ligand B (HBD=3, HBA=6) is also acceptable, but higher.

**QED:** Ligand A (0.792) has a very good drug-likeness score. Ligand B (0.53) is still acceptable, but less favorable.

**DILI:** Ligand A (35.75) has a lower DILI risk than Ligand B (47.964), indicating a safer profile.

**BBB:** Ligand A (90.074) shows excellent BBB penetration potential, exceeding the desirable >70% threshold. Ligand B (63.707) is considerably lower, which is a major concern for a CNS target like DRD2.

**Caco-2 Permeability:** Ligand A (-4.292) is poor, while Ligand B (-5.333) is even worse. Both are problematic, but the negative values suggest low intestinal absorption.

**Aqueous Solubility:** Ligand A (-2.982) and Ligand B (-1.015) both have poor aqueous solubility.

**hERG Inhibition:** Ligand A (0.608) has a low hERG risk. Ligand B (0.028) has a very low hERG risk. Both are good.

**Microsomal Clearance:** Ligand A (37.257) has a higher clearance than Ligand B (15.482), suggesting lower metabolic stability.

**In vitro Half-Life:** Ligand A (-23.003) has a negative half-life, which is not possible. This is likely an error in the data. Ligand B (0.384) has a very short half-life. Both are problematic.

**P-gp Efflux:** Ligand A (0.108) shows low P-gp efflux, which is favorable for CNS penetration. Ligand B (0.006) shows very low P-gp efflux, which is even more favorable.

**Binding Affinity:** Both ligands have similar and strong binding affinities (-8.6 and -8.1 kcal/mol, respectively). The difference of 0.5 kcal/mol is not substantial enough to override other significant differences.

**Overall Assessment:**

Ligand A is superior due to its significantly better BBB penetration, optimal logP, and lower DILI risk, despite its higher microsomal clearance and questionable half-life value. Ligand B's poor logP and lower BBB penetration are major drawbacks for a CNS-targeted drug. While both have poor solubility and Caco-2 permeability, these can be addressed with formulation strategies. The affinity difference is not large enough to favor Ligand B.

Output:
0
2025-04-17 04:57:17,326 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (351.451 and 350.463 Da) are within the ideal range of 200-500 Da.

**TPSA:** Ligand A (109.61) is higher than Ligand B (87.46). For CNS targets, TPSA should be <= 90, so Ligand B is preferable.

**logP:** Ligand A (2.076) is within the optimal range (1-3). Ligand B (0.953) is slightly below, which *could* indicate permeability issues, but isn't a major concern.

**H-Bond Donors/Acceptors:** Ligand A (HBD=1, HBA=4) and Ligand B (HBD=2, HBA=5) both have acceptable numbers of H-bond donors and acceptors.

**QED:** Ligand B (0.694) has a better QED score than Ligand A (0.43), indicating a more drug-like profile.

**DILI:** Ligand B (12.408) has a significantly lower DILI risk than Ligand A (20.589), which is a major advantage.

**BBB:** Ligand B (45.638) has a much higher BBB penetration percentile than Ligand A (22.257). This is *critical* for a CNS target like DRD2.

**Caco-2 Permeability:** Ligand A (-4.858) and Ligand B (-5.063) both have negative Caco-2 values, which is unusual and suggests poor permeability. This is a concern for both, but doesn't strongly differentiate them.

**Aqueous Solubility:** Ligand A (-1.184) and Ligand B (-0.623) both have negative solubility values, indicating poor solubility.

**hERG:** Both ligands have very low hERG inhibition liability (0.178 and 0.17), which is excellent.

**Microsomal Clearance:** Both ligands have similar microsomal clearance (18.578 and 18.935 mL/min/kg), suggesting comparable metabolic stability.

**In vitro Half-Life:** Ligand B (-13.058) has a negative half-life, which is concerning and suggests rapid degradation. Ligand A (15.725) has a more reasonable half-life.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.039 and 0.053), which is good.

**Binding Affinity:** Ligand B (-7.6 kcal/mol) has a significantly stronger binding affinity than Ligand A (-6.3 kcal/mol). This 1.3 kcal/mol difference is substantial and can outweigh some ADME drawbacks.

**Overall Assessment:**

Ligand B is the stronger candidate. While its half-life is concerning, its significantly better BBB penetration, lower DILI risk, and substantially improved binding affinity are decisive advantages for a CNS GPCR target. The slightly lower logP is a minor concern, but the strong affinity and BBB penetration are more important. Ligand A's higher TPSA is also a drawback.

Output:
1
2025-04-17 04:57:17,326 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 drug candidates, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (360.483 and 346.343 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (69.56) is excellent, well below the 90 A^2 threshold for CNS targets. Ligand B (126.32) is higher, but still potentially acceptable, though less ideal.

**logP:** Ligand A (2.198) is optimal (1-3). Ligand B (0.128) is quite low, potentially hindering membrane permeability and CNS penetration.

**H-Bond Donors/Acceptors:** Ligand A (HBD=1, HBA=6) is within acceptable limits. Ligand B (HBD=3, HBA=6) is also acceptable.

**QED:** Both ligands have reasonable QED values (A: 0.889, B: 0.706), indicating good drug-like properties.

**DILI:** Ligand A (60.062) is borderline acceptable, while Ligand B (85.653) has a significantly higher DILI risk.

**BBB:** Ligand A (64.986) is decent, but ideally we'd want >70 for a CNS target. Ligand B (27.801) is very poor, suggesting limited brain penetration. This is a major concern for a DRD2 ligand.

**Caco-2 Permeability:** Ligand A (-4.889) is negative, suggesting poor permeability. Ligand B (-5.734) is also negative, and slightly worse.

**Aqueous Solubility:** Both ligands have negative solubility values (-2.621 and -2.978), which is unusual and suggests very poor solubility. This is a significant drawback for both.

**hERG Inhibition:** Ligand A (0.507) has a low risk of hERG inhibition. Ligand B (0.052) has a very low risk.

**Microsomal Clearance:** Ligand A (58.386) has moderate clearance, while Ligand B (-21.523) has negative clearance, which is not possible and indicates an issue with the data.

**In vitro Half-Life:** Ligand A (10.314 hours) is reasonable. Ligand B (29.641 hours) is better.

**P-gp Efflux:** Ligand A (0.333) has low P-gp efflux, which is good for CNS penetration. Ligand B (0.019) has very low P-gp efflux, which is excellent.

**Binding Affinity:** Ligand B (-8.3 kcal/mol) has a significantly stronger binding affinity than Ligand A (-7.6 kcal/mol). This is a substantial advantage.

**Overall Assessment:**

Ligand B has a much stronger binding affinity, better half-life, and lower P-gp efflux. However, it suffers from a very low logP, poor BBB penetration, and a high DILI risk. Ligand A has a better logP and acceptable P-gp efflux, but its binding affinity is weaker and Caco-2 permeability is poor. The low logP of Ligand B is a major concern for CNS penetration, and the high DILI risk is also problematic. While the affinity of Ligand B is attractive, the ADME properties of Ligand A are more favorable for a CNS-targeting GPCR. The negative clearance value for Ligand B is also a red flag.

Output:
1
2025-04-17 04:57:17,326 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 drug candidates, considering the provided guidelines and GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (363.527 Da) is slightly higher than Ligand B (339.395 Da), but both are acceptable.

**TPSA:** Ligand A (62.3) is significantly better than Ligand B (84.23). For CNS targets, we want TPSA <= 90, and ideally closer to 60. Ligand A is much closer to the ideal range.

**logP:** Both ligands have good logP values (A: 2.865, B: 3.388), falling within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Both have acceptable HBD (A: 1, B: 2) and HBA (both 4) counts.

**QED:** Both have good QED scores (A: 0.845, B: 0.79), indicating good drug-like properties.

**DILI:** Ligand A (26.057) has a much lower DILI risk than Ligand B (65.452). This is a significant advantage for Ligand A.

**BBB:** Ligand A (71.966) has a better BBB penetration score than Ligand B (55.874). While both are not extremely high, Ligand A exceeds the 70% threshold desirable for CNS targets.

**Caco-2 Permeability:** Ligand A (-4.792) and Ligand B (-5.085) both have negative Caco-2 values, which is unusual and suggests poor permeability. However, the scale is not explicitly defined, so it's difficult to interpret the absolute impact.

**Aqueous Solubility:** Both have poor aqueous solubility (A: -2.694, B: -3.47). This could pose formulation challenges.

**hERG Inhibition:** Both ligands have similar, low hERG inhibition risk (A: 0.307, B: 0.319).

**Microsomal Clearance:** Ligand A (59.09) has a higher microsomal clearance than Ligand B (29.486), indicating lower metabolic stability. This is a drawback for Ligand A.

**In vitro Half-Life:** Ligand A (18.822) has a shorter half-life than Ligand B (11.736), further supporting the lower metabolic stability of Ligand A.

**P-gp Efflux:** Both have similar P-gp efflux liability (A: 0.233, B: 0.294).

**Binding Affinity:** Ligand B (-9.1 kcal/mol) has a significantly stronger binding affinity than Ligand A (-7.9 kcal/mol). This is a substantial advantage for Ligand B, potentially outweighing some of its ADME drawbacks.

**Overall Assessment:**

Ligand A excels in TPSA, DILI risk, and BBB penetration, all critical for a CNS-targeting GPCR. However, it suffers from higher microsomal clearance and shorter half-life. Ligand B, while having a higher TPSA and DILI risk, boasts a significantly stronger binding affinity.

Given the importance of potency for GPCR ligands, and the 1.2 kcal/mol difference in binding affinity, Ligand B is the more promising candidate despite its slightly less favorable ADME profile. The stronger binding could allow for a lower dose, potentially mitigating some of the ADME concerns.

Output:
1
2025-04-17 04:57:17,327 - INFO - Batch 157 complete. Total preferences: 2512
2025-04-17 04:57:17,327 - INFO - Processing batch 158/512...
2025-04-17 04:57:59,436 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 drug candidates, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (359.495 and 362.459 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (73.2) is significantly better than Ligand B (117). For CNS targets, we want TPSA <= 90, so Ligand A is preferable.

**logP:** Ligand A (3.026) is optimal (1-3). Ligand B (1.21) is a bit low and might struggle with membrane permeability.

**H-Bond Donors:** Ligand A (1) is good. Ligand B (3) is acceptable but less ideal.

**H-Bond Acceptors:** Ligand A (4) is good. Ligand B (6) is acceptable.

**QED:** Both ligands have reasonable QED scores (0.901 and 0.756), indicating good drug-like properties.

**DILI:** Ligand A (50.136) has a lower DILI risk than Ligand B (65.529), which is preferable.

**BBB:** Ligand A (60.682) is better than Ligand B (48.391), but ideally, we want >70 for CNS targets. Ligand A is closer to this threshold.

**Caco-2 Permeability:** Ligand A (-4.989) and Ligand B (-5.545) both have negative values, which is unusual and suggests poor permeability. However, the scale isn't specified, so it's hard to interpret.

**Aqueous Solubility:** Ligand A (-3.464) and Ligand B (-2.643) both have negative values, which is also unusual and suggests poor solubility. Again, the scale is unspecified.

**hERG:** Both ligands have low hERG inhibition risk (0.604 and 0.575).

**Microsomal Clearance:** Ligand B (-24.182) has significantly lower (better) microsomal clearance than Ligand A (21.015), indicating better metabolic stability.

**In vitro Half-Life:** Ligand B (-26.19) has a much longer half-life than Ligand A (1.511), which is a significant advantage.

**P-gp Efflux:** Ligand A (0.297) has lower P-gp efflux than Ligand B (0.169), which is preferable for CNS penetration.

**Binding Affinity:** Ligand A (-8.8 kcal/mol) has slightly better binding affinity than Ligand B (-7.9 kcal/mol). While both are good, the 0.9 kcal/mol difference is notable.

**Overall Assessment:**

Considering the GPCR-specific priorities, Ligand A is more promising. It has a better TPSA, logP, BBB penetration, and binding affinity. While Ligand B has superior metabolic stability and half-life, the better CNS penetration properties of Ligand A are more critical for a DRD2 target. The small advantage in binding affinity also supports choosing Ligand A. The unusual negative values for Caco-2 and solubility are concerning for both, but the other properties favor Ligand A.

Output:
0
2025-04-17 04:57:59,436 - INFO - Reasoning:

Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (362.239 Da and 349.475 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (98.82) is slightly higher than Ligand B (83.71). For CNS targets, we prefer TPSA <= 90, so Ligand B is better here.

**3. logP:** Ligand B (1.838) is within the optimal 1-3 range. Ligand A (0.708) is a bit low, potentially hindering membrane permeability.

**4. H-Bond Donors:** Ligand A (2) and Ligand B (1) are both acceptable, being <= 5.

**5. H-Bond Acceptors:** Ligand A (5) and Ligand B (3) are both acceptable, being <= 10.

**6. QED:** Ligand B (0.712) has a significantly better QED score than Ligand A (0.356), indicating a more drug-like profile.

**7. DILI:** Ligand A (94.959) has a very high DILI risk, while Ligand B (19.969) has a low risk. This is a major concern for Ligand A.

**8. BBB:** Both ligands have good BBB penetration (Ligand A: 75.029, Ligand B: 78.092), exceeding the >70 threshold for CNS targets. Ligand B is slightly better.

**9. Caco-2:** Both have negative Caco-2 values, which is unusual and suggests poor permeability. This is a concern for both.

**10. Solubility:** Both have negative solubility values, which is also unusual and suggests poor solubility. This is a concern for both.

**11. hERG:** Ligand A (0.17) has a lower hERG inhibition risk than Ligand B (0.593), which is preferable.

**12. Cl_mic:** Ligand A (-6.873) has a more negative value, indicating lower clearance and better metabolic stability than Ligand B (22.944).

**13. t1/2:** Ligand A (22.047) has a longer in vitro half-life than Ligand B (-12.968), which is desirable.

**14. Pgp:** Ligand A (0.013) has a much lower Pgp efflux liability than Ligand B (0.095), which is highly beneficial for CNS penetration.

**15. Binding Affinity:** Ligand A (-9.1) has a significantly stronger binding affinity than Ligand B (-7.7). This is a substantial advantage, potentially outweighing some of its ADME drawbacks.

**Overall Assessment:**

Ligand A has a much stronger binding affinity and better metabolic stability (lower Cl_mic, longer t1/2) and lower Pgp efflux. However, it has a very high DILI risk, a lower QED score, and a lower logP. Ligand B has a better TPSA, QED, and DILI profile, but weaker binding affinity and worse metabolic stability.

Given the GPCR-specific priorities, and the substantial affinity difference, I believe Ligand A is the more promising candidate *despite* its DILI risk. The strong binding affinity could allow for a lower dose, potentially mitigating the DILI concern. Further optimization could focus on reducing the DILI risk while maintaining the strong affinity.

Output:
1
2025-04-17 04:57:59,436 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B based on the provided guidelines, prioritizing GPCR-specific properties (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (378.925 Da) is slightly higher than Ligand B (344.415 Da), but both are acceptable.

**TPSA:** Ligand A (41.57) is excellent for CNS penetration, well below the 90 A^2 threshold. Ligand B (84.42) is higher but still potentially acceptable, though less ideal.

**logP:** Ligand A (4.443) is a bit high, potentially leading to solubility issues and off-target effects. Ligand B (1.239) is quite low, which could hinder permeation.

**H-Bond Donors/Acceptors:** Both ligands have 1 HBD, which is good. Ligand A has 3 HBA, and Ligand B has 5 HBA. Both are within the acceptable limits of 10.

**QED:** Both ligands have good QED scores (A: 0.807, B: 0.834), indicating drug-likeness.

**DILI:** Ligand A (48.391) has a better DILI score than Ligand B (65.103), suggesting lower liver injury risk.

**BBB:** Ligand A (78.48) has a significantly better BBB percentile than Ligand B (63.086). This is a crucial factor for a CNS target like DRD2.

**Caco-2 Permeability:** Both have negative values (-4.805 and -4.795), which is unusual and requires further investigation. However, the values are very similar.

**Aqueous Solubility:** Both have negative values (-4.82 and -1.683), indicating poor aqueous solubility. Ligand B is slightly better in this regard.

**hERG Inhibition:** Ligand A (0.81) has a slightly higher hERG risk than Ligand B (0.134), but both are relatively low.

**Microsomal Clearance:** Ligand A (63.814) has higher microsomal clearance than Ligand B (22.08), meaning faster metabolism and potentially lower exposure.

**In vitro Half-Life:** Ligand A (18.794) has a shorter half-life than Ligand B (0.917).

**P-gp Efflux:** Ligand A (0.632) has a lower P-gp efflux liability than Ligand B (0.016), which is favorable for CNS penetration.

**Binding Affinity:** Ligand B (-7.8 kcal/mol) has a significantly stronger binding affinity than Ligand A (-9.4 kcal/mol). This is a substantial advantage.

**Overall Assessment:**

Ligand B has a significantly better binding affinity, which is a primary driver for potency. However, it suffers from a lower BBB penetration, higher P-gp efflux, and lower solubility. Ligand A has better BBB, lower P-gp, and lower DILI risk, but weaker binding and faster clearance.

Given the importance of CNS penetration for a DRD2 target, and the substantial affinity difference, the stronger binding of Ligand B is likely to outweigh its ADME liabilities, *assuming* formulation strategies can address the solubility and permeability issues. The difference in binding affinity (-7.8 vs -9.4) is significant.

Output:
1
2025-04-17 04:57:59,437 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (366.849 Da) is slightly higher than Ligand B (344.415 Da), but both are acceptable.

**TPSA:** Ligand A (76.46) is better than Ligand B (87.32). For CNS targets, we want TPSA <= 90, and both are under that threshold, but A is closer to the optimal range.

**logP:** Ligand A (3.421) is optimal (1-3), while Ligand B (1.566) is on the lower end. Lower logP can hinder permeation, making Ligand A preferable.

**H-Bond Donors/Acceptors:** Ligand A (HBD=1, HBA=5) and Ligand B (HBD=2, HBA=4) both have reasonable numbers of H-bond donors and acceptors, well within the guidelines.

**QED:** Both ligands have good QED values (A: 0.902, B: 0.862), indicating good drug-like properties.

**DILI:** Ligand A (71.656) has a higher DILI risk than Ligand B (52.695). This is a negative for Ligand A.

**BBB:** Ligand A (71.307) has a better BBB penetration percentile than Ligand B (52.889). This is a significant advantage for a CNS target like DRD2.

**Caco-2 Permeability:** Ligand A (-4.359) has worse Caco-2 permeability than Ligand B (-5.024), meaning B is better at intestinal absorption. However, for a CNS target, intestinal absorption is less critical than BBB penetration.

**Aqueous Solubility:** Ligand A (-3.877) has better aqueous solubility than Ligand B (-2.675).

**hERG Inhibition:** Both ligands have low hERG inhibition risk (A: 0.454, B: 0.512).

**Microsomal Clearance:** Ligand A (83.319) has higher microsomal clearance than Ligand B (7.541), suggesting lower metabolic stability. This is a negative for Ligand A.

**In vitro Half-Life:** Ligand A (66.29) has a longer half-life than Ligand B (10.442). This is a positive for Ligand A.

**P-gp Efflux:** Ligand A (0.288) has lower P-gp efflux than Ligand B (0.036), which is favorable for CNS exposure.

**Binding Affinity:** Ligand A (-8.3 kcal/mol) has a significantly stronger binding affinity than Ligand B (-7.3 kcal/mol). This is a major advantage for Ligand A, potentially outweighing some of its ADME drawbacks. The difference of 1 kcal/mol is substantial.

**Overall Assessment:**

Ligand A has a superior binding affinity and better BBB penetration, which are critical for a CNS GPCR target. While it has a higher DILI risk and lower metabolic stability (higher Cl_mic), the strong affinity and good BBB penetration are likely to be more important. Ligand B has better solubility and lower DILI, but its weaker affinity and lower BBB penetration are significant drawbacks. The difference in binding affinity is substantial enough to favor Ligand A.

Output:
1
2025-04-17 04:57:59,437 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (353.375 and 351.426 Da) fall within the ideal range of 200-500 Da.

**TPSA:** Ligand A (121.11) is borderline for CNS penetration, being slightly above the preferred <90 threshold. Ligand B (78.43) is well within the ideal range for CNS targets. This is a significant advantage for Ligand B.

**logP:** Ligand A (0.166) is quite low, potentially hindering membrane permeability. Ligand B (0.796) is better, but still on the lower side of the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A has 3 HBD and 6 HBA, which are acceptable. Ligand B has 1 HBD and 5 HBA, also acceptable.

**QED:** Both ligands have good QED scores (0.544 and 0.786), indicating drug-like properties.

**DILI:** Both ligands have acceptable DILI risk (47.732 and 42.458), below the 60 threshold.

**BBB:** This is a crucial parameter for a CNS target. Ligand A has a BBB percentile of 24.777, which is poor. Ligand B has a much better BBB percentile of 84.413, indicating good brain penetration potential.

**Caco-2 Permeability:** Ligand A (-5.43) shows poor permeability. Ligand B (-4.661) is also poor, but slightly better than Ligand A.

**Aqueous Solubility:** Both ligands have poor aqueous solubility (-0.886 and -0.876). This could pose formulation challenges.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.16 and 0.44).

**Microsomal Clearance:** Ligand A has a high microsomal clearance (-31.563), suggesting rapid metabolism and potentially low bioavailability. Ligand B has a lower clearance (20.786), indicating better metabolic stability.

**In vitro Half-Life:** Ligand A has a half-life of 13.725 hours, which is reasonable. Ligand B has a negative half-life (-20.411), which is not physically possible and likely indicates an issue with the data or model prediction.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.02 and 0.026), which is favorable for CNS penetration.

**Binding Affinity:** Ligand A has a binding affinity of -8.1 kcal/mol, which is excellent. Ligand B has a binding affinity of -7.5 kcal/mol, also very good, but 0.6 kcal/mol weaker than Ligand A.

**Overall Assessment:**

Ligand A has a superior binding affinity, which is a major plus. However, its poor BBB penetration, low logP, and high metabolic clearance are significant drawbacks for a CNS-targeting drug. Ligand B, despite slightly weaker affinity, has a much better BBB score, lower metabolic clearance, and a more favorable TPSA. The better BBB and metabolic stability are likely to translate into higher brain exposure *in vivo*, potentially compensating for the slightly weaker binding. The negative half-life for Ligand B is a major concern and suggests the data might be unreliable.

Considering the GPCR-specific priorities and the importance of CNS penetration for DRD2, Ligand B is the more promising candidate, assuming the half-life data is an error.

Output:
1
2025-04-17 04:57:59,437 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B based on the provided guidelines, prioritizing GPCR-specific properties (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (387.933) is slightly higher than Ligand B (343.387), but both are acceptable.

**TPSA:** Ligand A (71.53) is significantly better than Ligand B (93.26). For CNS targets, we want TPSA <= 90, so Ligand A is preferable.

**logP:** Both ligands have good logP values (A: 2.969, B: 1.439) within the optimal range of 1-3.

**H-Bond Donors/Acceptors:** Both have acceptable HBD (1) and HBA (A: 5, B: 6) counts.

**QED:** Both ligands have good QED scores (A: 0.626, B: 0.848), indicating good drug-like properties. Ligand B is slightly better here.

**DILI:** Ligand A (45.328) has a lower DILI risk than Ligand B (58.511), which is favorable.

**BBB:** Ligand A (77.549) has a significantly better BBB penetration score than Ligand B (68.941). This is a *critical* factor for a CNS target like DRD2, making Ligand A much more promising.

**Caco-2 Permeability:** Ligand A (-4.813) is better than Ligand B (-5.131), indicating better intestinal absorption.

**Aqueous Solubility:** Ligand A (-3.406) is better than Ligand B (-2.552).

**hERG:** Ligand A (0.64) has a slightly higher hERG risk than Ligand B (0.159), but both are relatively low.

**Microsomal Clearance:** Ligand B (30.541) has a lower microsomal clearance than Ligand A (46.224), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand B (-21.478) has a significantly longer in vitro half-life than Ligand A (43.782), which is a positive attribute.

**P-gp Efflux:** Ligand A (0.342) has lower P-gp efflux than Ligand B (0.054), which is desirable for CNS penetration.

**Binding Affinity:** Ligand B (-8.2) has a stronger binding affinity than Ligand A (-6.9) by 1.3 kcal/mol. This is a substantial difference and a significant advantage for Ligand B.

**Overall Assessment:**

While Ligand B has superior binding affinity and metabolic stability (lower Cl_mic, longer t1/2), Ligand A excels in crucial properties for CNS drug development: TPSA, BBB penetration, and P-gp efflux. The 1.3 kcal/mol difference in binding affinity is significant, but the substantial improvement in CNS penetration properties for Ligand A outweighs this difference, especially considering the DRD2 target. The lower DILI risk for Ligand A is also a positive factor.

Output:
1
2025-04-17 04:57:59,437 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (348.45 & 347.38 Da) fall comfortably within the ideal 200-500 Da range.

**TPSA:** Ligand A (74.77) is excellent, well below the 90 A^2 threshold for CNS targets. Ligand B (107.17) is higher, but still potentially acceptable, though less ideal.

**logP:** Ligand A (1.288) is within the optimal 1-3 range. Ligand B (-0.249) is slightly below 1, which *could* indicate permeability issues, though not drastically.

**H-Bond Donors/Acceptors:** Both ligands have 1 HBD, which is good. Ligand A has 5 HBA, acceptable. Ligand B has 8 HBA, which is higher, potentially impacting permeability.

**QED:** Both ligands have similar and good QED values (0.728 and 0.74), indicating good drug-like properties.

**DILI:** Ligand A (13.998) has a very low DILI risk, significantly better than Ligand B (73.982), which is considered high risk.

**BBB:** Ligand A (83.288) has a good BBB penetration percentile, exceeding the 70% threshold for CNS targets. Ligand B (70.997) is close, but slightly below this desirable level.

**Caco-2 Permeability:** Ligand A (-4.563) has poor Caco-2 permeability. Ligand B (-5.434) is even worse.

**Aqueous Solubility:** Both ligands have negative solubility values (-0.959 and -1.661), indicating poor aqueous solubility, which could be a formulation challenge.

**hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.305 and 0.131).

**Microsomal Clearance:** Ligand A (38.143) has moderate clearance, while Ligand B (1.098) has very low clearance, suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (14.77 hours) has a reasonable half-life. Ligand B (3.647 hours) has a shorter half-life.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.005 and 0.021), which is positive for CNS penetration.

**Binding Affinity:** Ligand B (-8.1 kcal/mol) has a significantly stronger binding affinity than Ligand A (-7.2 kcal/mol), a difference of 0.9 kcal/mol. This is a substantial advantage.

**Overall Assessment:**

While Ligand A excels in BBB penetration and has a much lower DILI risk, Ligand B's significantly stronger binding affinity (-8.1 vs -7.2 kcal/mol) is a major advantage for a GPCR target. The difference in affinity is likely to outweigh the slightly higher TPSA, lower BBB, and higher DILI risk of Ligand B, especially considering the low P-gp efflux for both. The poor Caco-2 permeability and solubility are concerns for both, but can potentially be addressed through formulation strategies. The improved metabolic stability of Ligand B is also a plus.

Output:
1
2025-04-17 04:57:59,438 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (362.748 and 370.519 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (100.92) is higher than the preferred <90 for CNS targets, while Ligand B (76.46) is well within the range. This is a significant advantage for Ligand B.

**3. logP:** Ligand A (3.502) is at the upper end of the optimal 1-3 range, while Ligand B (1.177) is slightly below. While Ligand A's logP isn't *bad*, Ligand B's lower value could improve solubility.

**4. H-Bond Donors:** Ligand A (2) and Ligand B (1) both meet the HBD <=5 criteria.

**5. H-Bond Acceptors:** Ligand A (4) and Ligand B (6) both meet the HBA <=10 criteria.

**6. QED:** Both ligands have good QED scores (0.547 and 0.669), indicating drug-like properties.

**7. DILI:** Ligand A (95.502) has a very high DILI risk, which is a major concern. Ligand B (30.632) has a low DILI risk, a significant advantage.

**8. BBB:** Ligand A (59.519) has a moderate BBB penetration, while Ligand B (38.891) is lower. Both are below the desirable >70 for CNS targets, but Ligand A is better.

**9. Caco-2:** Both ligands have negative Caco-2 values (-4.882 and -5.108), which is unusual and suggests poor permeability. This is a concern for both.

**10. Solubility:** Ligand A (-4.808) and Ligand B (-1.561) both have negative solubility values, indicating poor aqueous solubility. Ligand B is slightly better.

**11. hERG:** Ligand A (0.648) has a slightly elevated hERG risk, while Ligand B (0.058) has a very low risk. This is a strong advantage for Ligand B.

**12. Cl_mic:** Ligand A (46.906) has a lower microsomal clearance than Ligand B (65.797), suggesting better metabolic stability.

**13. t1/2:** Ligand A (55.493) has a longer in vitro half-life than Ligand B (28.598), which is preferable.

**14. Pgp:** Ligand A (0.534) has lower P-gp efflux liability than Ligand B (0.029), which is better for CNS exposure.

**15. Binding Affinity:** Ligand B (-6.4 kcal/mol) has a significantly stronger binding affinity than Ligand A (-10.2 kcal/mol). This is a substantial advantage for Ligand B, potentially outweighing some of its ADME drawbacks.

**Overall Assessment:**

Despite Ligand A having a slightly better BBB and Pgp profile, the significantly higher DILI risk, coupled with the weaker binding affinity, makes it a less desirable candidate. Ligand B has a much better safety profile (low DILI, low hERG), a significantly stronger binding affinity, and a more favorable TPSA. While its BBB penetration is not ideal, the strong affinity and better ADME properties overall make it the more promising candidate. The negative Caco-2 and solubility values are concerning for both, but can be addressed with formulation strategies.

Output:
1
2025-04-17 04:57:59,438 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (379.913 and 359.861 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (71.09) is slightly higher than Ligand B (64.34). Both are below the 90 A^2 threshold for CNS targets, which is good. Ligand B is preferable here.

**3. logP:** Both ligands have a logP around 4.07-4.08, which is at the upper limit of the optimal range (1-3). This could potentially lead to solubility issues or off-target interactions, but is not a dealbreaker.

**4. H-Bond Donors:** Ligand A has 2 HBDs and Ligand B has 1. Both are within the acceptable limit of <=5. Ligand B is slightly better.

**5. H-Bond Acceptors:** Ligand A has 4 HBAs and Ligand B has 6. Both are within the acceptable limit of <=10.

**6. QED:** Both ligands have similar QED values (0.711 and 0.718), indicating good drug-like properties.

**7. DILI:** Both ligands have very similar DILI risk (77.782 and 77.705 percentile), indicating a moderate risk. This isn't ideal, but not disqualifying.

**8. BBB:** Ligand B (62.699%) has a better BBB penetration percentile than Ligand A (52.656%). This is a *critical* factor for a CNS target like DRD2.

**9. Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and suggests poor permeability. Ligand A (-5.062) is slightly worse than Ligand B (-4.702).

**10. Aqueous Solubility:** Both ligands have very poor aqueous solubility (-5.149 and -4.403). This is a significant concern.

**11. hERG Inhibition:** Both ligands show low hERG inhibition risk (0.719 and 0.833 percentile), which is good.

**12. Microsomal Clearance:** Both ligands have similar microsomal clearance (74.676 and 75.657 mL/min/kg), indicating moderate metabolic stability.

**13. In vitro Half-Life:** Ligand B (64.847 hours) has a significantly longer in vitro half-life than Ligand A (46.382 hours). This is a positive attribute.

**14. P-gp Efflux:** Both ligands show low P-gp efflux liability (0.492 and 0.665), which is favorable for CNS penetration.

**15. Binding Affinity:** Ligand A (-8.9 kcal/mol) has a significantly stronger binding affinity than Ligand B (-7.8 kcal/mol). This is a substantial advantage (1.1 kcal/mol difference).

**Overall Assessment:**

While both ligands have some drawbacks (poor solubility, moderate DILI risk), the key differences lie in BBB penetration and binding affinity. Ligand B has a significantly better BBB percentile, which is crucial for a CNS target. However, Ligand A has a much stronger binding affinity. The 1.1 kcal/mol difference in binding affinity is substantial and likely outweighs the slightly lower BBB penetration, especially considering the low P-gp efflux for both. The poor solubility is a concern for both, but could be addressed with formulation strategies.

Output:
0
2025-04-17 04:57:59,438 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (352.435 and 385.814 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (89.71) is better than Ligand B (78.59), both are below the 90 A^2 threshold for CNS targets.

**3. logP:** Ligand B (2.041) is optimal (1-3), while Ligand A (0.56) is a bit low, potentially hindering membrane permeability.

**4. H-Bond Donors:** Ligand A (1) is preferable to Ligand B (2). Fewer HBDs generally improve permeability.

**5. H-Bond Acceptors:** Ligand A (7) is preferable to Ligand B (5), but both are within the acceptable range of <=10.

**6. QED:** Both ligands have similar, good QED values (0.771 and 0.785, respectively).

**7. DILI:** Both ligands have low DILI risk (36.06 and 34.665 percentiles, respectively).

**8. BBB:** Ligand B (68.36%) is better than Ligand A (57.774%), but both are below the desirable >70% threshold for CNS targets. This is a critical factor for DRD2.

**9. Caco-2 Permeability:** Ligand A (-4.842) is significantly worse than Ligand B (-4.68), indicating lower intestinal absorption.

**10. Aqueous Solubility:** Ligand A (-0.939) is better than Ligand B (-2.824), indicating higher solubility.

**11. hERG Inhibition:** Ligand A (0.099) is much better than Ligand B (0.409), suggesting a lower risk of cardiotoxicity.

**12. Microsomal Clearance:** Ligand A (8.6 mL/min/kg) is significantly better than Ligand B (22.217 mL/min/kg), indicating better metabolic stability.

**13. In vitro Half-Life:** Ligand A (27.818 hours) is much better than Ligand B (6.481 hours), suggesting a longer duration of action.

**14. P-gp Efflux:** Ligand A (0.03) is significantly better than Ligand B (0.332), indicating lower P-gp efflux and potentially better CNS exposure.

**15. Binding Affinity:** Ligand A (-7.9 kcal/mol) is significantly better than Ligand B (-6.6 kcal/mol). This is a substantial difference in potency, and a >1.5 kcal/mol advantage can outweigh other concerns.

**Overall Assessment:**

While Ligand B has a better logP and Caco-2 permeability, Ligand A excels in almost all other critical parameters, especially binding affinity, metabolic stability (Cl_mic, t1/2), P-gp efflux, and hERG inhibition. The significantly stronger binding affinity of Ligand A (-7.9 vs -6.6 kcal/mol) is a major advantage. The better P-gp efflux and BBB penetration (though still suboptimal) of Ligand A are also crucial for a CNS target like DRD2. The lower logP of Ligand A is a minor drawback that might be addressed through further optimization, but the substantial benefits of the other properties outweigh this concern.

Output:
1
2025-04-17 04:57:59,438 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (352.503 and 354.447 Da) fall comfortably within the ideal 200-500 Da range.

**TPSA:** Ligand A (23.55) is excellent, well below the 90 A^2 threshold for CNS targets. Ligand B (104.73) is higher, but still potentially acceptable, though less ideal for brain penetration.

**logP:** Ligand A (4.414) is slightly high, potentially leading to solubility issues or off-target interactions. Ligand B (0.89) is quite low, which could hinder membrane permeability and brain penetration.

**H-Bond Donors/Acceptors:** Ligand A (0 HBD, 2 HBA) is favorable. Ligand B (3 HBD, 5 HBA) is also acceptable, though slightly higher.

**QED:** Both ligands have reasonable QED values (0.719 and 0.533), indicating good drug-like properties.

**DILI:** Both ligands have similar, low DILI risk (37.689 and 37.495 percentile), which is positive.

**BBB:** This is a crucial parameter for a CNS target like DRD2. Ligand A has a very good BBB penetration score (79.411 percentile). Ligand B's BBB score (31.834 percentile) is significantly lower and concerning.

**Caco-2 Permeability:** Ligand A (-4.717) has poor Caco-2 permeability. Ligand B (-5.21) also has poor Caco-2 permeability.

**Aqueous Solubility:** Both ligands have very poor aqueous solubility (-4.993 and -1.952). This is a significant drawback.

**hERG Inhibition:** Ligand A (0.944) has a slightly elevated hERG risk, but manageable. Ligand B (0.076) has very low hERG risk, which is excellent.

**Microsomal Clearance:** Ligand A (100.737) has a high microsomal clearance, indicating rapid metabolism. Ligand B (-0.617) has a negative clearance, which is unusual and might indicate an issue with the prediction or a very stable compound.

**In vitro Half-Life:** Ligand A (28.544 hours) has a reasonable half-life. Ligand B (-12.316 hours) has a negative half-life, which is not physically possible and indicates a problem with the data.

**P-gp Efflux:** Ligand A (0.481) has moderate P-gp efflux, which is acceptable. Ligand B (0.092) has very low P-gp efflux, which is favorable for CNS penetration.

**Binding Affinity:** Ligand B (-8.6 kcal/mol) has a significantly stronger binding affinity than Ligand A (-7.7 kcal/mol). This 1.5 kcal/mol difference is substantial and could outweigh some ADME drawbacks.

**Overall Assessment:**

Ligand B has a much stronger binding affinity and lower P-gp efflux. However, it suffers from a poor BBB score, low logP, and a nonsensical negative half-life. Ligand A has a better BBB score and a reasonable half-life, but its high logP, poor Caco-2 permeability, and high metabolic clearance are concerning. Given the importance of BBB penetration for a CNS target, and the significant affinity advantage of Ligand B, I would still lean towards Ligand B *if* the negative half-life and low logP can be addressed through structural modifications. The negative half-life is a major red flag suggesting a data error. However, assuming that is an error, the strong binding and low P-gp efflux make it a more promising starting point.

Output:
1
2025-04-17 04:57:59,438 - INFO - Reasoning:

Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight (MW):** Both ligands (342.4 & 359.5 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (94.05) is slightly above the optimal <90 for CNS targets, but still reasonable. Ligand B (66.65) is excellent, well below 90.

**3. logP:** Ligand A (3.696) is at the upper end of the optimal 1-3 range, while Ligand B (2.633) is comfortably within it.

**4. H-Bond Donors (HBD):** Both ligands are acceptable (1 and 0 respectively), staying within the recommended limit of 5.

**5. H-Bond Acceptors (HBA):** Both ligands are acceptable (6 and 5 respectively), staying within the recommended limit of 10.

**6. QED:** Both ligands have good QED scores (0.777 and 0.787), indicating good drug-like properties.

**7. DILI:** Ligand A (72.043) has a higher DILI risk than Ligand B (40.132). Ligand B is preferable here.

**8. BBB:** Ligand B (85.964) has a significantly better BBB penetration percentile than Ligand A (72.082). This is a crucial advantage for a CNS target like DRD2.

**9. Caco-2 Permeability:** Both have negative values, indicating poor permeability. Ligand A (-4.907) is worse than Ligand B (-5.107).

**10. Aqueous Solubility:** Both have negative values, indicating poor solubility. Ligand A (-4.293) is slightly better than Ligand B (-2.814).

**11. hERG Inhibition:** Both ligands show low hERG inhibition risk (0.49 and 0.167). Ligand B is preferable.

**12. Microsomal Clearance:** Ligand A (86.181) has higher microsomal clearance than Ligand B (45.363), suggesting lower metabolic stability. Ligand B is preferable.

**13. In vitro Half-Life:** Ligand B (-6.352) has a longer *predicted* half-life than Ligand A (44.644). This is a significant advantage.

**14. P-gp Efflux:** Ligand A (0.423) has slightly lower P-gp efflux liability than Ligand B (0.108), which is desirable.

**15. Binding Affinity:** Ligand B (-6.8 kcal/mol) has a stronger binding affinity than Ligand A (-9.5 kcal/mol). This is a substantial advantage, potentially outweighing some of the minor ADME drawbacks.

**Overall Assessment:**

Ligand B is the superior candidate. While Ligand A has slightly better P-gp efflux, Ligand B excels in the critical areas for a CNS-targeting GPCR: BBB penetration, binding affinity, metabolic stability (lower Cl_mic, longer t1/2), and lower DILI risk. The lower TPSA and logP values of Ligand B are also favorable. The slight solubility issues are less critical given the strong affinity and good BBB penetration.

Output:
1
2025-04-17 04:57:59,439 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (363.483 and 353.419 Da) fall within the ideal range of 200-500 Da.

**TPSA:** Ligand A (84.08) is better than Ligand B (88.18), both are below the 90 A^2 threshold desirable for CNS targets.

**logP:** Ligand A (2.629) is optimal (1-3). Ligand B (0.363) is low, potentially hindering permeation. This is a significant drawback for CNS penetration.

**H-Bond Donors:** Ligand A (2) and Ligand B (1) are both acceptable (<=5).

**H-Bond Acceptors:** Both ligands (5) are within the acceptable range (<=10).

**QED:** Both ligands have good QED scores (0.741 and 0.771, both >= 0.5).

**DILI:** Ligand A (63.552) has a higher DILI risk than Ligand B (34.161). This favors Ligand B.

**BBB:** Ligand A (65.762) has a better BBB percentile than Ligand B (59.636), but both are below the desirable >70 for CNS targets.

**Caco-2 Permeability:** Ligand A (-5.488) is worse than Ligand B (-4.9), indicating lower intestinal absorption.

**Aqueous Solubility:** Ligand A (-2.564) is worse than Ligand B (-1.37), indicating lower solubility.

**hERG Inhibition:** Ligand A (0.579) has a slightly higher hERG risk than Ligand B (0.173), favoring Ligand B.

**Microsomal Clearance:** Ligand A (46.174) has a lower (better) microsomal clearance than Ligand B (-35.175). This suggests better metabolic stability for Ligand A.

**In vitro Half-Life:** Ligand A (22.544) has a longer half-life than Ligand B (-4.699), which is preferable.

**P-gp Efflux:** Ligand A (0.496) has lower P-gp efflux than Ligand B (0.014), which is favorable for CNS exposure.

**Binding Affinity:** Both ligands have very similar binding affinities (-8.5 and -8.3 kcal/mol), and both are excellent. The difference is negligible.

**Overall Assessment:**

Ligand B has advantages in terms of lower DILI risk, better solubility, and lower hERG inhibition. However, its significantly lower logP is a major concern for CNS penetration. Ligand A, while having a higher DILI risk, possesses a much more favorable logP, better metabolic stability (lower Cl_mic, longer t1/2), and lower P-gp efflux, all crucial for CNS drug candidates. Given the GPCR-specific priorities, the logP and P-gp efflux are more critical than the slightly higher DILI risk.

Output:
1
2025-04-17 04:57:59,439 - INFO - Reasoning:

Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (362.308 Da and 348.443 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (127.32) is higher than the preferred <90 for CNS targets, while Ligand B (86.71) is comfortably below. This is a significant advantage for Ligand B.

**3. logP:** Ligand A (0.12) is quite low, potentially hindering membrane permeability. Ligand B (0.583) is better, but still on the lower side of the optimal 1-3 range.

**4. H-Bond Donors:** Ligand A (3) and Ligand B (2) are both acceptable, being less than 5.

**5. H-Bond Acceptors:** Ligand A (5) and Ligand B (4) are both acceptable, being less than 10.

**6. QED:** Both ligands have good QED scores (0.566 and 0.731), suggesting good drug-like properties.

**7. DILI:** Ligand A (41.915) has a slightly higher DILI risk than Ligand B (15.626), though both are below the concerning threshold of 60.

**8. BBB:** Ligand A (74.564) has a better BBB percentile than Ligand B (61.535), which is a critical factor for a CNS target like DRD2.

**9. Caco-2:** Both have negative Caco-2 values which is unusual and suggests a problem with the data.

**10. Solubility:** Both have negative solubility values which is unusual and suggests a problem with the data.

**11. hERG:** Both ligands show very low hERG inhibition liability (0.093 and 0.057), which is excellent.

**12. Cl_mic:** Ligand B (10.948) has a significantly lower microsomal clearance than Ligand A (26.493), indicating better metabolic stability.

**13. t1/2:** Ligand B (-11.384) has a longer in vitro half-life than Ligand A (-4.571).

**14. Pgp:** Both ligands have very low P-gp efflux liability (0.016 and 0.028).

**15. Binding Affinity:** Both ligands have identical binding affinities (-8.4 kcal/mol), which is excellent.

**Overall Assessment:**

While Ligand A has a slightly better BBB score, Ligand B is superior in almost every other crucial aspect for a CNS-targeting GPCR ligand. Specifically, Ligand B has a much lower TPSA, lower DILI risk, better metabolic stability (lower Cl_mic and longer t1/2), and a slightly better logP. The significantly lower TPSA and improved metabolic properties of Ligand B outweigh the small difference in BBB penetration. The negative Caco-2 and solubility values are concerning and would need to be investigated, but based on the available data, Ligand B is the more promising candidate.

Output:
1
2025-04-17 04:57:59,439 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (354.447 and 342.527 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (93.73) is borderline but acceptable for CNS penetration, while Ligand B (32.34) is excellent, well below the 90 A^2 threshold. This favors Ligand B.

**logP:** Ligand A (1.298) is within the optimal range (1-3). Ligand B (4.124) is slightly above, potentially leading to solubility issues and off-target effects, but not drastically so.

**H-Bond Donors/Acceptors:** Ligand A has 2 HBD and 5 HBA, which are reasonable. Ligand B has 1 HBD and 2 HBA, also acceptable.

**QED:** Both ligands have good QED scores (0.531 and 0.732), indicating drug-like properties.

**DILI:** Ligand A (33.656) has a lower DILI risk than Ligand B (14.23), which is preferable.

**BBB:** This is a crucial parameter for CNS targets. Ligand A (41.373) has a poor BBB percentile, while Ligand B (87.127) is excellent, exceeding the desirable >70 threshold. This is a significant advantage for Ligand B.

**Caco-2 Permeability:** Ligand A (-5.068) has poor Caco-2 permeability, suggesting poor absorption. Ligand B (-4.578) is also poor, but slightly better than A.

**Aqueous Solubility:** Both ligands have poor aqueous solubility (-1.301 and -4.376).

**hERG Inhibition:** Ligand A (0.103) has a very low hERG risk, which is excellent. Ligand B (0.776) has a moderate hERG risk, which is less desirable.

**Microsomal Clearance:** Ligand A (0.091) has very low clearance, indicating good metabolic stability. Ligand B (81.051) has high clearance, suggesting rapid metabolism. This favors Ligand A.

**In vitro Half-Life:** Ligand A (-4.384) has a very short half-life. Ligand B (22.834) has a longer half-life, which is preferable.

**P-gp Efflux:** Ligand A (0.033) has low P-gp efflux, which is good for CNS penetration. Ligand B (0.512) has moderate P-gp efflux.

**Binding Affinity:** Ligand B (-9.0 kcal/mol) has a significantly stronger binding affinity than Ligand A (-7.5 kcal/mol). This >1.5 kcal/mol difference is substantial and can outweigh some ADME drawbacks.

**Overall Assessment:**

Ligand B excels in BBB penetration and binding affinity, two critical factors for a DRD2 ligand targeting CNS disorders. While its logP is slightly high and clearance is high, the strong affinity and excellent BBB penetration are compelling. Ligand A has better DILI and metabolic stability, but its poor BBB penetration and weaker affinity are major drawbacks. The poor solubility and permeability of both compounds are concerns, but can potentially be addressed through formulation strategies. Given the GPCR-specific priorities, the superior affinity and BBB penetration of Ligand B make it the more promising candidate.

Output:
1
2025-04-17 04:57:59,439 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (352.32 and 347.415 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (80.65) is excellent, well below the 90 A^2 threshold for CNS targets. Ligand B (102.76) is still reasonable but less optimal, being above 90 A^2.

**logP:** Ligand A (2.851) is within the optimal 1-3 range. Ligand B (-0.138) is significantly below 1, which could hinder permeation.

**H-Bond Donors/Acceptors:** Ligand A (2 HBD, 6 HBA) and Ligand B (3 HBD, 5 HBA) both have acceptable numbers of H-bond donors and acceptors.

**QED:** Both ligands have good QED scores (0.713 and 0.688), indicating drug-like properties.

**DILI:** Ligand A (80.07) has a higher DILI risk than Ligand B (37.96). This is a concern for Ligand A.

**BBB:** Ligand A (60.527) has a moderate BBB penetration, while Ligand B (41.722) is lower. Both are below the desirable >70 for CNS targets, but Ligand A is better.

**Caco-2:** Ligand A (-4.916) and Ligand B (-5.338) both have negative Caco-2 values, suggesting poor intestinal absorption. This is a significant drawback for both.

**Aqueous Solubility:** Ligand A (-4.559) and Ligand B (-1.632) both have negative solubility values, indicating poor solubility. Ligand B is slightly better.

**hERG:** Both ligands have very low hERG inhibition risk (0.426 and 0.074).

**Microsomal Clearance:** Ligand A (38.119) has higher microsomal clearance than Ligand B (-13.378), indicating lower metabolic stability.

**In vitro Half-Life:** Ligand B (4.93) has a positive half-life, while Ligand A (-33.206) has a negative half-life, suggesting very rapid metabolism.

**P-gp Efflux:** Both ligands show low P-gp efflux liability (0.237 and 0.014).

**Binding Affinity:** Both ligands have excellent binding affinities (-8.9 and -8.0 kcal/mol). Ligand A is slightly better.

**Overall Assessment:**

Ligand A has a better TPSA, logP, and binding affinity. However, it suffers from higher DILI risk, higher microsomal clearance, and a very poor in vitro half-life. Ligand B has better solubility, lower DILI, and better metabolic stability, but its logP is concerningly low, and its BBB penetration is also lower.

Given the GPCR-specific priorities, BBB penetration and logP are crucial. While both are suboptimal, Ligand A's superior binding affinity and better (though still not ideal) BBB penetration, combined with a more favorable logP, make it slightly more promising. The poor metabolic stability of Ligand A is a significant concern, but could potentially be addressed through structural modifications. The low logP of Ligand B is a more fundamental issue that would be harder to fix without significantly altering its binding affinity.

Output:
0
2025-04-17 04:57:59,440 - INFO - Batch 158 complete. Total preferences: 2528
2025-04-17 04:57:59,440 - INFO - Processing batch 159/512...
2025-04-17 04:58:40,354 - INFO - Reasoning:

Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (348.49 & 349.44 Da) fall comfortably within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (58.64) is excellent, well below the 90 Angstroms threshold for CNS targets. Ligand B (88.81) is higher but still acceptable, though less ideal.

**3. logP:** Ligand A (2.654) is optimal (1-3). Ligand B (0.098) is quite low, which could hinder membrane permeability and potentially reduce binding affinity.

**4. H-Bond Donors:** Both ligands have 1 HBD, which is within the ideal range (<=5).

**5. H-Bond Acceptors:** Ligand A has 3 HBAs, and Ligand B has 6. Both are within the acceptable limit of <=10, but Ligand B is approaching the upper end.

**6. QED:** Both ligands have good QED scores (0.686 and 0.762), indicating drug-like properties.

**7. DILI:** Ligand A (16.91) has a much lower DILI risk than Ligand B (31.91), indicating better predicted liver safety.

**8. BBB:** Ligand A (64.48) has a significantly better BBB penetration prediction than Ligand B (46.38). This is *critical* for a CNS target like DRD2.

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.888 and -4.878), which is unusual and suggests poor permeability. However, these values are on a log scale and are likely indicating very low permeability.

**10. Aqueous Solubility:** Both ligands have negative solubility values (-2.958 and -0.902), also likely indicating very low solubility.

**11. hERG Inhibition:** Both ligands have low hERG inhibition risk (0.366 and 0.138).

**12. Microsomal Clearance:** Ligand A (42.47) has higher predicted clearance than Ligand B (6.23), suggesting lower metabolic stability.

**13. In vitro Half-Life:** Ligand B (15.82) has a significantly longer predicted half-life than Ligand A (6.93).

**14. P-gp Efflux:** Both ligands have low P-gp efflux liability (0.147 and 0.012), which is favorable for CNS penetration.

**15. Binding Affinity:** Ligand A (-8.3 kcal/mol) has a stronger binding affinity than Ligand B (-7.5 kcal/mol). This 0.8 kcal/mol difference is substantial and can outweigh some ADME drawbacks.

**Overall Assessment:**

Despite Ligand B's longer half-life, Ligand A is the superior candidate. The significantly better BBB penetration, lower DILI risk, and *much* stronger binding affinity outweigh the slightly higher clearance. Ligand B's extremely low logP is a major concern, likely impacting permeability and potentially reducing its ability to reach the target in vivo. The negative Caco-2 and solubility values for both are concerning, but the affinity advantage of A is substantial.

Output:
1
2025-04-17 04:58:40,354 - INFO - Reasoning:

Let's analyze Ligand A and Ligand B for their potential as DRD2 drug candidates, considering the provided guidelines and GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (351.491 and 366.458 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (72.88) is better than Ligand B (75.27). Both are reasonably low, and below the 90 A^2 threshold for CNS targets, but A is closer to the ideal.

**3. logP:** Ligand B (2.56) is better than Ligand A (0.987). Both are within the optimal 1-3 range, but B is closer to the sweet spot. A's logP is a bit low and could hinder permeation.

**4. H-Bond Donors:** Both ligands have 2 HBD, which is within the acceptable limit of <=5.

**5. H-Bond Acceptors:** Ligand A has 4 HBA, and Ligand B has 3. Both are within the acceptable limit of <=10.

**6. QED:** Both ligands have good QED scores (0.748 and 0.841, respectively), indicating good drug-like properties.

**7. DILI:** Ligand A (5.118%) has a significantly lower DILI risk than Ligand B (61.497%). This is a major advantage for Ligand A.

**8. BBB:** Ligand B (74.06%) has a substantially better BBB penetration score than Ligand A (30.942%). This is critical for a CNS target like DRD2.

**9. Caco-2 Permeability:** Ligand A (-5.017) has a worse Caco-2 permeability than Ligand B (-4.682). Both are negative, indicating poor permeability, but B is slightly better.

**10. Aqueous Solubility:** Ligand A (-1.086) has better aqueous solubility than Ligand B (-3.762). This is a slight advantage for A.

**11. hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.37 and 0.252, respectively).

**12. Microsomal Clearance:** Ligand A (25.251) has lower microsomal clearance than Ligand B (58.82), indicating better metabolic stability.

**13. In vitro Half-Life:** Ligand A (18.008 hours) has a better in vitro half-life than Ligand B (-6.541 hours).

**14. P-gp Efflux:** Ligand A (0.028) has significantly lower P-gp efflux liability than Ligand B (0.305). This is a major advantage for A, particularly for CNS penetration.

**15. Binding Affinity:** Ligand B (-9.7 kcal/mol) has a significantly stronger binding affinity than Ligand A (-7.6 kcal/mol). This is a substantial advantage for Ligand B, exceeding the 1.5 kcal/mol difference threshold.

**Overall Assessment:**

While Ligand A has advantages in DILI risk, metabolic stability, P-gp efflux, and solubility, Ligand B's superior BBB penetration and *significantly* stronger binding affinity are decisive. For a CNS GPCR target like DRD2, strong binding and good brain penetration are paramount. The 1.5 kcal/mol difference in binding affinity is substantial and likely outweighs the drawbacks of slightly higher P-gp efflux and DILI risk for Ligand B. The better BBB score is also crucial.

Output:
1
2025-04-17 04:58:40,355 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (348.45 & 350.42 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (107.11) is significantly better than Ligand B (131.26). For CNS targets, we want TPSA <= 90, so Ligand A is closer to this threshold, suggesting better CNS penetration potential.

**logP:** Both ligands have good logP values (1.46 and 1.01), falling within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Both have 4 HBDs, which is acceptable. Ligand B has 7 HBAs, slightly higher than Ligand A's 4, potentially impacting permeability.

**QED:** Both ligands have similar and acceptable QED scores (0.507 and 0.514).

**DILI:** Ligand A (33.93%) has a considerably lower DILI risk than Ligand B (41.41%). This is a significant advantage.

**BBB:** Ligand B (77.16%) shows a much higher BBB penetration percentile than Ligand A (29.28%). This is a *major* advantage for a CNS target like DRD2.

**Caco-2 Permeability:** Both have negative Caco-2 values (-5.544 and -5.532), which is unusual and suggests poor permeability. However, these values are on a scale where negative values are possible and don't necessarily disqualify a compound.

**Aqueous Solubility:** Both have negative solubility values (-1.639 and -2.5), indicating poor aqueous solubility. This could pose formulation challenges.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.455 and 0.321).

**Microsomal Clearance:** Ligand B (37.85) has higher microsomal clearance than Ligand A (26.32), indicating faster metabolism and potentially lower *in vivo* exposure.

**In vitro Half-Life:** Ligand A (-14.44) has a significantly longer (less negative) half-life than Ligand B (0.78).

**P-gp Efflux:** Ligand B (0.015) shows very low P-gp efflux, which is excellent for CNS penetration. Ligand A (0.213) has moderate P-gp efflux.

**Binding Affinity:** Ligand B (-8.1 kcal/mol) has a stronger binding affinity than Ligand A (-7.5 kcal/mol). This is a 0.6 kcal/mol difference, which is substantial and could outweigh some ADME drawbacks.

**Overall Assessment:**

While Ligand A has better TPSA, DILI, and metabolic stability (lower Cl_mic, longer t1/2), Ligand B's significantly higher BBB penetration (77% vs 29%) and stronger binding affinity (-8.1 vs -7.5 kcal/mol) are critical advantages for a CNS-targeting GPCR like DRD2. The lower P-gp efflux of Ligand B further supports its potential for good CNS exposure. The slightly higher DILI risk and faster metabolism of Ligand B are concerns, but the improved potency and CNS penetration are likely to be more impactful for this target.

Output:
1
2025-04-17 04:58:40,355 - INFO - Reasoning:

Let's analyze Ligand A and Ligand B based on the provided guidelines, prioritizing GPCR-specific properties (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (355.341 and 354.535 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (102.76) is higher than the preferred <90 for CNS targets, while Ligand B (58.64) is well within the range. This is a significant advantage for Ligand B.

**3. logP:** Ligand A (0.442) is quite low, potentially hindering permeability. Ligand B (3.229) is within the optimal 1-3 range. This favors Ligand B.

**4. H-Bond Donors:** Ligand A (3) is acceptable, while Ligand B (1) is even better.

**5. H-Bond Acceptors:** Ligand A (5) is acceptable, while Ligand B (3) is even better.

**6. QED:** Both ligands have good QED scores (0.727 and 0.763), indicating good drug-like properties.

**7. DILI:** Ligand A (52.191) has a moderate DILI risk. Ligand B (16.479) has a much lower DILI risk, which is highly desirable.

**8. BBB:** Ligand A (52.772) has a moderate BBB penetration, while Ligand B (70.609) is excellent, exceeding the >70 threshold for CNS targets. This is a major advantage for Ligand B.

**9. Caco-2:** Ligand A (-5.017) and Ligand B (-4.474) both have negative values, which is unusual and suggests poor permeability. However, the scale isn't defined, so it's hard to interpret.

**10. Solubility:** Both ligands have poor aqueous solubility (-2.388 and -3.314). Solubility is a concern for both, but not a deciding factor.

**11. hERG:** Both ligands have low hERG inhibition liability (0.168 and 0.513), which is good.

**12. Cl_mic:** Ligand A (-21.156) has a lower (better) microsomal clearance than Ligand B (88.919), indicating greater metabolic stability. This favors Ligand A.

**13. t1/2:** Ligand A (-30.698) has a negative in vitro half-life, which is not possible. This is a red flag. Ligand B (5.13) has a short but positive half-life.

**14. Pgp:** Ligand A (0.006) has very low P-gp efflux, which is excellent. Ligand B (0.074) also has low P-gp efflux, but slightly higher than A.

**15. Binding Affinity:** Ligand B (-7.5 kcal/mol) has a slightly better binding affinity than Ligand A (-7.9 kcal/mol). Although the difference is small, it's still a positive for Ligand B.

**Overall Assessment:**

Ligand B is clearly the more promising candidate. While Ligand A has better metabolic stability and slightly lower Pgp efflux, it suffers from a very low logP, a higher TPSA, moderate DILI risk, a moderate BBB score, and an impossible half-life value. Ligand B excels in crucial GPCR-specific properties like TPSA, logP, and BBB penetration, and has a lower DILI risk. The slightly better affinity of Ligand B further strengthens its position. The negative half-life for Ligand A is a significant issue.

Output:
1
2025-04-17 04:58:40,355 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (356.323 and 356.495 Da) fall comfortably within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (51.02) is significantly better than Ligand B (62.98). For CNS targets, we want TPSA <= 90, and ideally closer to 60. Ligand A is much closer to this ideal.

**3. logP:** Both ligands have acceptable logP values (3.065 and 4.505), falling within the 1-3 range, although Ligand B is slightly higher.

**4. H-Bond Donors:** Ligand A (0) is preferable to Ligand B (2). Fewer HBDs generally improve permeability.

**5. H-Bond Acceptors:** Ligand A (4) is better than Ligand B (6). Lower HBA counts are generally preferred for CNS penetration.

**6. QED:** Both ligands have similar QED values (0.774 and 0.712), indicating good drug-likeness.

**7. DILI:** Ligand A (64.095) has a slightly higher DILI risk than Ligand B (56.146), but both are reasonably acceptable.

**8. BBB:** This is a critical parameter for a CNS target like DRD2. Ligand A has a significantly higher BBB penetration percentile (95.812) compared to Ligand B (69.95). This is a major advantage for Ligand A.

**9. Caco-2 Permeability:** Ligand A (-4.388) has a worse Caco-2 permeability than Ligand B (-5.282). Lower (more negative) values indicate lower permeability.

**10. Aqueous Solubility:** Both ligands have poor aqueous solubility (-3.561 and -4.748). This is a potential formulation challenge for both.

**11. hERG Inhibition:** Both ligands have low hERG inhibition risk (0.5 and 0.73), which is good.

**12. Microsomal Clearance:** Ligand B (80.18) has a higher microsomal clearance than Ligand A (32.097), suggesting lower metabolic stability.

**13. In vitro Half-Life:** Ligand A (-17.178) has a much longer in vitro half-life than Ligand B (78.824). This is a significant advantage for Ligand A.

**14. P-gp Efflux:** Ligand A (0.275) has lower P-gp efflux liability than Ligand B (0.353), which is favorable for CNS exposure.

**15. Binding Affinity:** Both ligands have excellent binding affinities (-9.8 and -8.4 kcal/mol). Ligand A has a 1.4 kcal/mol advantage, which is substantial and can outweigh some of the ADME drawbacks.

**Overall Assessment:**

Ligand A is the better candidate. While both have acceptable MW, logP, QED, and hERG, Ligand A excels in the critical GPCR-specific parameters for CNS targets: TPSA, BBB, P-gp efflux, and in vitro half-life. The significantly better BBB penetration (95.812 vs 69.95) and longer half-life are particularly important. The stronger binding affinity of Ligand A further solidifies its position as the more promising candidate. The slightly worse Caco-2 permeability and aqueous solubility are concerns, but potentially addressable through formulation strategies.



Output:
0
2025-04-17 04:58:40,355 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B based on the provided guidelines, prioritizing GPCR-specific properties (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (349.475 Da) is slightly lower, which can be beneficial for permeability.

**TPSA:** Ligand A (60.93) is significantly better than Ligand B (105.64). For CNS targets, we want TPSA <= 90, and Ligand A comfortably meets this, while Ligand B is above.

**logP:** Ligand A (1.291) is within the optimal range (1-3), while Ligand B (0.456) is a bit low, potentially hindering permeation.

**H-Bond Donors/Acceptors:** Ligand A (0 HBD, 4 HBA) is preferable to Ligand B (2 HBD, 5 HBA) as it has fewer potential issues with permeability. Both are within acceptable limits.

**QED:** Both ligands have similar and good QED scores (0.702 and 0.73).

**DILI:** Ligand A (25.436) has a much lower DILI risk than Ligand B (22.451), indicating better potential for liver safety.

**BBB:** This is a critical parameter for CNS targets. Ligand A (71.772) has a good BBB percentile, exceeding the desirable >70 threshold. Ligand B (54.478) is significantly lower, raising concerns about CNS penetration.

**Caco-2 Permeability:** Ligand A (-4.537) has a negative Caco-2 value, which is unusual and suggests poor permeability. Ligand B (-5.659) is even worse. This is a concern for both, but less critical given the BBB data.

**Aqueous Solubility:** Both ligands have very poor aqueous solubility (-0.971 and -1.921). This could pose formulation challenges.

**hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.315 and 0.045).

**Microsomal Clearance:** Ligand A (31.537) has a higher microsomal clearance than Ligand B (0.937), suggesting lower metabolic stability.

**In vitro Half-Life:** Ligand B (-8.628) has a significantly longer in vitro half-life than Ligand A (3.889), which is advantageous.

**P-gp Efflux:** Ligand A (0.065) has slightly higher P-gp efflux liability than Ligand B (0.014), meaning it may be pumped out of cells more readily, reducing CNS exposure.

**Binding Affinity:** Ligand B (-8.1 kcal/mol) has a substantially stronger binding affinity than Ligand A (-0.0 kcal/mol). This is a major advantage for Ligand B, potentially outweighing some of its ADME drawbacks.

**Overall Assessment:**

Despite Ligand B's superior binding affinity, Ligand A is the more promising candidate. The critical factor is the BBB penetration. Ligand A's BBB percentile (71.772) is good, suggesting it can reach the CNS. Ligand B's BBB percentile (54.478) is too low for a CNS-targeted drug. While Ligand B has a better half-life and affinity, the poor BBB penetration is a significant hurdle. The TPSA of Ligand A is also much better. The solubility issues are a concern for both, but can be addressed through formulation strategies.



Output:
0
2025-04-17 04:58:40,356 - INFO - Reasoning:

Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (370.362 and 350.507 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (49.41) is significantly better than Ligand B (68.3). For CNS targets, we want TPSA <= 90, and ideally lower. Ligand A is much closer to the optimal range.

**3. logP:** Both ligands have good logP values (2.973 and 3.485), falling within the 1-3 range.

**4. H-Bond Donors:** Both ligands have acceptable HBD counts (1 and 2 respectively), well below the threshold of 5.

**5. H-Bond Acceptors:** Ligand B (6) is slightly higher than Ligand A (2), but both are below the 10 threshold.

**6. QED:** Both ligands have similar QED values (0.774 and 0.711), indicating good drug-likeness.

**7. DILI:** Ligand A (19.62) has a much lower DILI risk than Ligand B (35.905). Lower is better, and Ligand A is well below the concerning threshold of 60.

**8. BBB:** Ligand A (93.098) has a significantly higher BBB penetration percentile than Ligand B (76.774). This is *critical* for a CNS target like DRD2. A value >70 is desirable, and Ligand A is closer to 100.

**9. Caco-2 Permeability:** Both have negative values, which is unusual and suggests poor permeability. However, the scale is not specified, so it's hard to interpret.

**10. Aqueous Solubility:** Both have negative values, again making interpretation difficult.

**11. hERG Inhibition:** Both ligands have low hERG inhibition risk (0.609 and 0.854).

**12. Microsomal Clearance:** Ligand A (6.292) has a much lower microsomal clearance than Ligand B (59.453), indicating better metabolic stability.

**13. In vitro Half-Life:** Ligand A (-22.928) has a *much* longer in vitro half-life than Ligand B (49.569). This is a significant advantage.

**14. P-gp Efflux:** Ligand A (0.033) has a much lower P-gp efflux liability than Ligand B (0.275). Lower is better for CNS exposure.

**15. Binding Affinity:** Ligand B (-7.7) has a slightly better binding affinity than Ligand A (-9.2). However, the difference is not substantial enough to outweigh the significant ADME advantages of Ligand A. A 1.5 kcal/mol advantage is typically needed to overcome substantial ADME issues.

**Overall Assessment:**

Ligand A is the superior candidate. It demonstrates significantly better predicted ADME properties, particularly BBB penetration, metabolic stability (lower Cl_mic, longer t1/2), and lower P-gp efflux. While Ligand B has slightly better binding affinity, the ADME profile of Ligand A is far more favorable for a CNS-targeting drug. The substantial improvements in BBB, DILI, and metabolic stability outweigh the minor difference in binding affinity.

Output:
1
2025-04-17 04:58:40,356 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (363.487 and 363.439 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (81.07) is better than Ligand B (84.67). Both are below the 90 A^2 threshold for CNS targets, but A is closer to the ideal.

**3. logP:** Ligand A (3.301) is within the optimal 1-3 range. Ligand B (4.015) is slightly higher, potentially increasing off-target effects and decreasing solubility.

**4. H-Bond Donors:** Ligand A (3) is higher than Ligand B (1), but both are acceptable (<=5).

**5. H-Bond Acceptors:** Both ligands have 6 HBA, which is within the acceptable range (<=10).

**6. QED:** Ligand B (0.83) has a significantly better QED score than Ligand A (0.629), indicating a more drug-like profile.

**7. DILI:** Ligand A (80.109) has a lower DILI risk than Ligand B (84.141), which is preferable.

**8. BBB:** Ligand B (77.627) has a better BBB penetration percentile than Ligand A (52.423). This is *critical* for a CNS target like DRD2.

**9. Caco-2 Permeability:** Ligand A (-5.121) has better Caco-2 permeability than Ligand B (-4.775).

**10. Aqueous Solubility:** Ligand A (-3.231) has better aqueous solubility than Ligand B (-4.858).

**11. hERG Inhibition:** Ligand A (0.18) has a lower hERG inhibition risk than Ligand B (0.302), which is favorable.

**12. Microsomal Clearance:** Ligand B (108.347) has a significantly higher microsomal clearance than Ligand A (52.159), suggesting lower metabolic stability.

**13. In vitro Half-Life:** Ligand A (52.598) has a better in vitro half-life than Ligand B (2.431).

**14. P-gp Efflux:** Ligand A (0.277) has lower P-gp efflux liability than Ligand B (0.188), which is beneficial for CNS penetration.

**15. Binding Affinity:** Ligand B (-7.8 kcal/mol) has a slightly better binding affinity than Ligand A (-8.5 kcal/mol). While A is better, the difference is not substantial enough to outweigh other factors.

**Overall Assessment:**

Ligand A has advantages in TPSA, logP, DILI, solubility, hERG, clearance, half-life, and P-gp efflux. However, Ligand B has a significantly better BBB penetration (77.627 vs 52.423) and QED score, and slightly better binding affinity. For a CNS target like DRD2, BBB penetration is paramount. The improved QED also suggests a more generally drug-like molecule. While Ligand A has a better binding affinity, the difference is not large enough to overcome the significant advantage of Ligand B in BBB penetration.

Output:
1
2025-04-17 04:58:40,356 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (383.704 and 368.499 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (67.01) is significantly better than Ligand B (76.66). For CNS targets, we want TPSA <= 90, and A is closer to the ideal <=60 range. B is pushing the upper limit.

**3. logP:** Ligand A (3.835) is good, within the 1-3 range. Ligand B (1.111) is a bit low, potentially hindering permeability.

**4. H-Bond Donors:** Both have 2 HBD, which is acceptable (<=5).

**5. H-Bond Acceptors:** Ligand A has 3 HBA, Ligand B has 5. Both are within the acceptable limit of <=10, but A is preferable.

**6. QED:** Both ligands have similar QED values (0.609 and 0.628), indicating good drug-likeness.

**7. DILI:** Ligand A (66.15) has a higher DILI risk than Ligand B (32.687). This is a drawback for A.

**8. BBB:** Ligand A (65.529) has a slightly better BBB percentile than Ligand B (62.35), but both are reasonably good for a CNS target, though ideally >70.

**9. Caco-2:** Ligand A (-4.932) has a worse Caco-2 permeability than Ligand B (-5.237). Lower values are less desirable.

**10. Solubility:** Ligand A (-4.575) has slightly worse solubility than Ligand B (-2.757).

**11. hERG:** Both ligands have very low hERG inhibition liability (0.566 and 0.219), which is excellent.

**12. Cl_mic:** Ligand A (24.841) has significantly lower microsomal clearance than Ligand B (41.794), indicating better metabolic stability.

**13. t1/2:** Ligand A (-7.354) has a much longer in vitro half-life than Ligand B (12.72). This is a significant advantage for A.

**14. Pgp:** Ligand A (0.386) has lower P-gp efflux liability than Ligand B (0.024), which is very favorable for CNS penetration.

**15. Binding Affinity:** Ligand A (-8.9 kcal/mol) has a stronger binding affinity than Ligand B (-7.8 kcal/mol). This is a substantial difference (>1.5 kcal/mol) and is a major driver in the decision.

**Overall Assessment:**

Despite Ligand A's higher DILI risk, its superior TPSA, logP, metabolic stability (Cl_mic, t1/2), P-gp efflux, and *significantly* stronger binding affinity outweigh the drawbacks. The better TPSA and logP values are particularly important for CNS penetration. The affinity difference is large enough to potentially overcome the DILI concern with further optimization. Ligand B's lower logP and higher Pgp efflux are significant negatives for a CNS target.

Output:
1
2025-04-17 04:58:40,356 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (348.49 and 364.52 Da) fall within the ideal 200-500 Da range.

**TPSA:** Both ligands have TPSA values (75.27 and 74.33) that are acceptable for oral absorption but slightly high for optimal CNS penetration (ideally <90, but closer to 60-70 is better).

**logP:** Ligand A (2.585) is optimal, while Ligand B (1.633) is a bit low, potentially hindering membrane permeability.

**H-Bond Donors/Acceptors:** Both have reasonable HBD (2) and HBA (3 for A, 5 for B) counts, within acceptable limits.

**QED:** Both ligands have good QED scores (0.637 and 0.735), indicating drug-like properties.

**DILI:** Ligand A (18.922) has a slightly higher DILI risk than Ligand B (22.722), but both are below the concerning threshold of 60.

**BBB:** This is a critical parameter for a CNS target like DRD2. Ligand A has a significantly better BBB penetration percentile (59.791) compared to Ligand B (41.644). While neither is >70, A is considerably closer.

**Caco-2 Permeability:** Ligand A (-4.916) shows better Caco-2 permeability than Ligand B (-5.56), suggesting better intestinal absorption.

**Aqueous Solubility:** Ligand A (-3.056) has better aqueous solubility than Ligand B (-0.799).

**hERG:** Both ligands have very low hERG inhibition risk (0.239 and 0.207).

**Microsomal Clearance:** Ligand B (-17.009) has a much lower (better) microsomal clearance than Ligand A (40.221), indicating greater metabolic stability.

**In vitro Half-Life:** Ligand B (6.069) has a longer in vitro half-life than Ligand A (-8.468).

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.162 and 0.024), which is favorable for CNS penetration.

**Binding Affinity:** Both ligands have excellent binding affinity (-8.9 and -8.5 kcal/mol). The difference of 0.4 kcal/mol is not substantial enough to outweigh other factors.

**Conclusion:**

Considering the GPCR-specific priorities, Ligand A is slightly favored. While Ligand B has better metabolic stability and half-life, Ligand A's superior BBB penetration, logP, Caco-2 permeability, and solubility are more critical for a CNS-targeting drug. The binding affinity difference is minimal.

Output:
1
2025-04-17 04:58:40,356 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (379.404 and 354.439 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (84.08) is excellent, well below the 90 A^2 threshold for CNS targets. Ligand B (94.8) is still reasonable but less optimal.

**3. logP:** Both ligands (2.449 and 2.158) are within the optimal 1-3 range.

**4. H-Bond Donors:** Ligand A (2) and Ligand B (1) both meet the <=5 criteria.

**5. H-Bond Acceptors:** Ligand A (5) and Ligand B (7) both meet the <=10 criteria.

**6. QED:** Both ligands have good QED scores (0.768 and 0.907), indicating drug-like properties.

**7. DILI:** Ligand A (66.654) is better than Ligand B (80.07), both are acceptable but A is preferred.

**8. BBB:** Ligand A (68.282) and Ligand B (62.97) are both below the desirable >70 for CNS targets, but Ligand A is better.

**9. Caco-2:** Ligand A (-4.949) and Ligand B (-5.27) are both negative, indicating poor permeability.

**10. Solubility:** Ligand A (-4.128) and Ligand B (-4.625) are both negative, indicating poor solubility.

**11. hERG:** Ligand A (0.424) and Ligand B (0.787) are both low, indicating low cardiotoxicity risk.

**12. Cl_mic:** Ligand A (70.693) has higher clearance than Ligand B (32.769), indicating lower metabolic stability. This is a significant drawback for A.

**13. t1/2:** Ligand B (17.962) has a much longer half-life than Ligand A (-11.277), which is a major advantage.

**14. Pgp:** Ligand A (0.085) has lower P-gp efflux liability than Ligand B (0.121), which is favorable for CNS penetration.

**15. Binding Affinity:** Ligand A (-7.5) has a significantly stronger binding affinity than Ligand B (0). This is a very substantial advantage.

**Overall Assessment:**

While Ligand A has a better binding affinity and lower Pgp efflux, Ligand B has superior metabolic stability (lower Cl_mic, longer t1/2) and a slightly better DILI score. The significantly stronger binding affinity of Ligand A is a major advantage that can potentially outweigh some of its ADME drawbacks. However, the poor metabolic stability of Ligand A is a serious concern. Considering the balance, the stronger binding affinity of Ligand A is the deciding factor, especially for a GPCR target where potency is crucial.

Output:
1
2025-04-17 04:58:40,357 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (350.369 and 344.499 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (68.18) is slightly higher than Ligand B (58.2). Both are below the 90 A^2 threshold for CNS targets, which is good. Ligand B is preferable here.

**3. logP:** Both ligands have good logP values (2.877 and 3.489), falling within the optimal 1-3 range. Ligand B is slightly higher, potentially improving membrane permeability.

**4. H-Bond Donors:** Both have 2 HBD, which is within the acceptable limit of <=5.

**5. H-Bond Acceptors:** Ligand A has 4 HBA, and Ligand B has 2. Both are below the 10 threshold. Ligand B is preferable here.

**6. QED:** Both ligands have reasonable QED values (0.871 and 0.75), indicating good drug-like properties.

**7. DILI:** Ligand A (73.982) has a higher DILI risk than Ligand B (26.871). This is a significant advantage for Ligand B.

**8. BBB:** Ligand A (90.617) has a significantly better BBB penetration percentile than Ligand B (64.25). This is *critical* for a CNS target like DRD2.

**9. Caco-2 Permeability:** Both have negative Caco-2 values (-4.78 and -4.785). This is unusual and suggests poor permeability. However, these values are on the same scale, so don't differentiate the ligands.

**10. Aqueous Solubility:** Both have negative solubility values (-4.044 and -4.204). This is also unusual and suggests poor solubility. Again, these values are similar.

**11. hERG Inhibition:** Both have very low hERG inhibition liability (0.451 and 0.126). Ligand B is slightly better.

**12. Microsomal Clearance:** Ligand A (19.135) has lower microsomal clearance than Ligand B (49.391), indicating better metabolic stability.

**13. In vitro Half-Life:** Ligand A (52.866) has a much longer in vitro half-life than Ligand B (7.668). This is a substantial advantage for Ligand A.

**14. P-gp Efflux:** Both have very low P-gp efflux liability (0.166 and 0.153).

**15. Binding Affinity:** Both have excellent binding affinities (-9.7 and -9.0 kcal/mol). Ligand A has a 0.7 kcal/mol advantage, which is significant.

**Overall Assessment:**

Ligand A excels in BBB penetration, binding affinity, and metabolic stability (lower Cl_mic, longer t1/2). Ligand B has a lower DILI risk and slightly better logP and fewer HBA. The critical factor for a CNS target is BBB penetration, and Ligand A has a substantial advantage (90.617 vs 64.25). The affinity difference (0.7 kcal/mol) is also significant and can outweigh some of the ADME drawbacks. While Ligand B's lower DILI is attractive, the superior BBB and affinity of Ligand A make it the more promising candidate.

Output:
1
2025-04-17 04:58:40,357 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (476.115 Da) is towards the upper end, while Ligand B (371.547 Da) is more favorably positioned.

**TPSA:** Ligand A (42.43) is excellent for CNS penetration, well below the 90 A^2 threshold. Ligand B (78.51) is higher but still reasonable, though less optimal for CNS targets.

**logP:** Ligand A (4.568) is slightly high, potentially leading to solubility issues and off-target interactions. Ligand B (1.029) is quite low, which could hinder membrane permeability.

**H-Bond Donors/Acceptors:** Ligand A (0 HBD, 3 HBA) is favorable. Ligand B (2 HBD, 4 HBA) is also acceptable.

**QED:** Both ligands have good QED scores (A: 0.611, B: 0.731), indicating drug-like properties.

**DILI:** Ligand A has a significantly higher DILI risk (75.029%) compared to Ligand B (14.967%), which is a major concern.

**BBB:** Ligand A exhibits excellent BBB penetration (89.298%), crucial for a CNS target. Ligand B's BBB penetration (66.576%) is lower, though not terrible.

**Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and suggests a potential issue with the data or modeling. However, we'll proceed assuming these represent low permeability.

**Aqueous Solubility:** Both ligands have very poor aqueous solubility (-5.208 and -1.986, respectively). This is a significant drawback, especially given Ligand A's already high logP.

**hERG Inhibition:** Ligand A (0.666) has a slightly higher hERG risk than Ligand B (0.22), but both are relatively low.

**Microsomal Clearance:** Ligand B (-6.076) has a negative clearance, which is not physically possible and indicates a modeling issue. Ligand A (47.804) has a moderate clearance.

**In vitro Half-Life:** Ligand B (-3.059) has a negative half-life, also indicating a modeling issue. Ligand A (-4.948) is also negative.

**P-gp Efflux:** Ligand A (0.49) has a lower P-gp efflux liability than Ligand B (0.023), which is beneficial for CNS exposure.

**Binding Affinity:** Ligand A (-9.4 kcal/mol) has a substantially stronger binding affinity than Ligand B (-7.2 kcal/mol). This is a significant advantage, potentially outweighing some of its ADME drawbacks.

**Overall Assessment:**

Ligand A has a much stronger binding affinity and excellent BBB penetration, which are critical for a CNS GPCR target. However, it suffers from a high DILI risk, poor solubility, and a relatively high logP. Ligand B has a better safety profile (lower DILI) and better solubility, but its affinity is weaker and its BBB penetration is less favorable. The negative values for Caco-2, clearance, and half-life for Ligand B are concerning and suggest potential issues with the data.

Despite the drawbacks, the significantly superior binding affinity of Ligand A, coupled with its good BBB penetration, makes it the more promising candidate *provided* the DILI risk can be mitigated through structural modifications. The issues with the data for Ligand B are also a concern.

Output:
1
2025-04-17 04:58:40,357 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (353.344 and 366.615 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (63.13) is higher than the preferred <90 for CNS targets, but still reasonable. Ligand B (23.55) is excellent, well below 90.

**3. logP:** Ligand A (3.132) is within the optimal 1-3 range. Ligand B (4.722) is slightly above, potentially leading to solubility issues and off-target interactions, but not drastically so.

**4. H-Bond Donors:** Ligand A (2) is good. Ligand B (0) is also acceptable.

**5. H-Bond Acceptors:** Both ligands (A: 3, B: 3) are within the acceptable limit of 10.

**6. QED:** Ligand A (0.867) is excellent, indicating high drug-likeness. Ligand B (0.581) is acceptable, but less optimal.

**7. DILI:** Ligand A (64.288) shows a moderate risk of DILI. Ligand B (8.802) has a very low DILI risk, a significant advantage.

**8. BBB:** Ligand A (76.813) has a good BBB penetration percentile. Ligand B (88.329) is excellent, indicating very good CNS penetration. This is crucial for a DRD2 ligand.

**9. Caco-2:** Both ligands have negative Caco-2 values (-4.778 and -4.714), which is unusual and suggests poor permeability. This is a significant concern for both.

**10. Solubility:** Both ligands have negative solubility values (-3.981 and -4.24), indicating very poor aqueous solubility. This is a major drawback.

**11. hERG:** Both ligands (0.772 and 0.736) have relatively low hERG inhibition liability, which is good.

**12. Cl_mic:** Ligand A (22.051) has lower microsomal clearance, suggesting better metabolic stability than Ligand B (122.513).

**13. t1/2:** Ligand A (47.872) has a longer in vitro half-life than Ligand B (35.112), which is preferable.

**14. Pgp:** Ligand A (0.431) has lower P-gp efflux liability than Ligand B (0.516), which is beneficial for CNS exposure.

**15. Binding Affinity:** Ligand A (-8.2 kcal/mol) has significantly stronger binding affinity than Ligand B (-0.0 kcal/mol). This is a major advantage for Ligand A.

**Overall Assessment:**

Despite the poor Caco-2 and solubility for both compounds, Ligand A is the stronger candidate. Its significantly superior binding affinity (-8.2 vs -0.0 kcal/mol) is a decisive factor, especially for a GPCR target. It also has better metabolic stability (lower Cl_mic, longer t1/2), lower Pgp efflux, and a slightly better BBB score. While Ligand B has a lower DILI risk, the affinity difference is too large to ignore. The solubility and permeability issues would need to be addressed through formulation or further chemical modification, but the potency of Ligand A provides a better starting point.

Output:
1
2025-04-17 04:58:40,357 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (353.394 and 367.471 Da) fall within the ideal range of 200-500 Da.

**TPSA:** Ligand A (102.66) is slightly above the optimal <90 for CNS targets, while Ligand B (87.74) is within the desired range. This gives a slight edge to Ligand B.

**logP:** Ligand A (0.65) is a bit low, potentially hindering permeation. Ligand B (1.071) is better, falling within the 1-3 optimal range. Ligand B is favored.

**H-Bond Donors/Acceptors:** Both have 2 HBD and 5 HBA, which are acceptable values.

**QED:** Both ligands have similar QED values (0.73 and 0.719), indicating good drug-likeness.

**DILI:** Ligand A (31.601) has a lower DILI risk than Ligand B (25.087), which is preferable.

**BBB:** Ligand B (65.878) has a significantly better BBB penetration percentile than Ligand A (58.007). This is a crucial advantage for a CNS target like DRD2.

**Caco-2 Permeability:** Ligand A (-4.839) has poorer Caco-2 permeability than Ligand B (-5.351), indicating lower intestinal absorption.

**Aqueous Solubility:** Ligand A (-1.111) has slightly better solubility than Ligand B (-1.994).

**hERG Inhibition:** Ligand B (0.099) has a lower hERG inhibition liability than Ligand A (0.395), which is a safety advantage.

**Microsomal Clearance:** Ligand A (1.887) has a lower microsomal clearance, suggesting better metabolic stability, than Ligand B (5.542).

**In vitro Half-Life:** Ligand A (11.855) has a longer half-life than Ligand B (7.319), which is preferable.

**P-gp Efflux:** Ligand A (0.028) has lower P-gp efflux liability than Ligand B (0.017), which is better for CNS exposure.

**Binding Affinity:** Ligand B (-7.6 kcal/mol) has a stronger binding affinity than Ligand A (-8.2 kcal/mol). While A has slightly better affinity, the difference is not substantial enough to outweigh the other factors.

**Overall Assessment:**

Ligand B demonstrates a more favorable profile for a CNS-targeting GPCR ligand. It has better logP, TPSA, BBB penetration, Caco-2 permeability, and hERG inhibition. While Ligand A has slightly better DILI, clearance, half-life, and P-gp efflux, the benefits of Ligand B in terms of CNS penetration and key ADME properties outweigh these minor drawbacks. The stronger binding affinity of Ligand B is also a positive factor.

Output:
1
2025-04-17 04:58:40,358 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (363.889 Da) is slightly lower, which could be advantageous for permeability.

**TPSA:** Both ligands have TPSA values below the 90 A^2 threshold desirable for CNS targets. Ligand B (72.88 A^2) is slightly better than Ligand A (81.99 A^2).

**logP:** Both ligands have logP values within the optimal range (1-3). Ligand B (2.136) is slightly lower than Ligand A (3.148), which could be beneficial for solubility but might slightly compromise membrane permeability.

**H-Bond Donors/Acceptors:** Both have acceptable HBD (2) and HBA (3/4) counts, well within the guidelines.

**QED:** Both ligands have similar QED values (0.76 and 0.742), indicating good drug-like properties.

**DILI:** Ligand B (25.087) has a significantly lower DILI risk than Ligand A (32.299), which is a substantial advantage.

**BBB:** Ligand B (76.464) has a considerably higher BBB penetration percentile than Ligand A (60.76). This is *critical* for a CNS target like DRD2.

**Caco-2 Permeability:** Ligand A (-4.799) has better Caco-2 permeability than Ligand B (-5.433).

**Aqueous Solubility:** Ligand A (-4.433) has better aqueous solubility than Ligand B (-3.778).

**hERG Inhibition:** Ligand B (0.925) has a slightly higher hERG inhibition liability than Ligand A (0.451), which is less desirable.

**Microsomal Clearance:** Ligand B (42.976) has lower microsomal clearance than Ligand A (57.816), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand B (-12.244) has a negative half-life, which is unusual and suggests very rapid metabolism or a problem with the assay. Ligand A (13.982) has a reasonable half-life.

**P-gp Efflux:** Ligand A (0.134) has lower P-gp efflux liability than Ligand B (0.086), which is favorable for CNS penetration.

**Binding Affinity:** Both ligands have very similar and strong binding affinities (-8.5 and -8.3 kcal/mol). The difference is negligible.

**Overall Assessment:**

Ligand B is the stronger candidate. While Ligand A has better Caco-2 permeability, solubility, and P-gp efflux, Ligand B's significantly better BBB penetration, lower DILI risk, and improved metabolic stability (lower Cl_mic) outweigh these factors, especially given the CNS target. The negative half-life for Ligand B is concerning, but its other advantages are substantial. The affinity is comparable between the two.

Output:
1
2025-04-17 04:58:40,358 - INFO - Batch 159 complete. Total preferences: 2544
2025-04-17 04:58:40,358 - INFO - Processing batch 160/512...
2025-04-17 04:59:22,170 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 drug candidates, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (350.503 and 347.459 Da) fall comfortably within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (58.64) is significantly better than Ligand B (78.51). For CNS targets, we want TPSA <= 90, and A is much closer to the optimal <=60 range. B is pushing the upper limit.

**3. logP:** Ligand A (2.735) is optimal (1-3). Ligand B (0.853) is a bit low, potentially hindering membrane permeability.

**4. H-Bond Donors:** Both ligands have acceptable HBD counts (1 and 2, respectively), well below the threshold of 5.

**5. H-Bond Acceptors:** Both ligands have acceptable HBA counts (3 and 4, respectively), well below the threshold of 10.

**6. QED:** Both ligands have good QED values (0.848 and 0.747), indicating good drug-like properties.

**7. DILI:** Ligand A (19.426) has a much lower DILI risk than Ligand B (8.453). Both are below 40, which is good.

**8. BBB:** Ligand A (84.141) has a significantly better BBB penetration percentile than Ligand B (64.87).  >70 is desirable for CNS targets, and A is closer to that threshold.

**9. Caco-2 Permeability:** Ligand A (-4.562) has a negative value, which is unusual and suggests poor permeability. Ligand B (-5.394) is also negative and similarly poor. This is a concern for both, but the scale is unclear, so it's hard to compare directly.

**10. Aqueous Solubility:** Ligand A (-3.833) and Ligand B (-1.235) both have negative solubility values, indicating poor solubility. B is slightly better.

**11. hERG Inhibition:** Both ligands have low hERG inhibition liability (0.386 and 0.176), which is good.

**12. Microsomal Clearance:** Ligand A (59.636) has higher microsomal clearance than Ligand B (-15.698). This suggests Ligand B is more metabolically stable.

**13. In vitro Half-Life:** Ligand A (-5.829) has a negative half-life, which is impossible and suggests an issue with the data. Ligand B (-3.734) is also negative, indicating a data issue for both.

**14. P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.092 and 0.007), which is favorable for CNS penetration.

**15. Binding Affinity:** Ligand B (-8.8 kcal/mol) has a slightly better binding affinity than Ligand A (-7.9 kcal/mol). This is a 0.9 kcal/mol difference, which is significant but not overwhelming.

**Overall Assessment:**

Despite the slightly better affinity of Ligand B, Ligand A is the more promising candidate. The key advantages of Ligand A are its significantly better TPSA, BBB penetration, and lower DILI risk. While both have issues with Caco-2 permeability and solubility, the CNS target prioritizes BBB penetration, and A excels in this area. The negative half-life values are concerning for both, but the other properties of A are more favorable for a CNS-targeting GPCR ligand.

Output:
1
2025-04-17 04:59:22,170 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight (MW):** Both ligands (353.275 and 356.463 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (66.63) is better than Ligand B (68.31), both are below the 90 A^2 threshold for CNS targets, which is good.

**3. logP:** Ligand A (3.128) is optimal (1-3), while Ligand B (0.771) is a bit low, potentially hindering permeation.

**4. H-Bond Donors (HBD):** Ligand A (2) and Ligand B (0) are both within the acceptable limit of <=5.

**5. H-Bond Acceptors (HBA):** Ligand A (4) and Ligand B (5) are both within the acceptable limit of <=10.

**6. QED:** Both ligands have similar QED values (0.711 and 0.703), indicating good drug-likeness.

**7. DILI:** Ligand A (69.794) has a higher DILI risk than Ligand B (21.326). This is a significant drawback for Ligand A.

**8. BBB:** Ligand A (57.619) and Ligand B (64.831) are both reasonably good, but Ligand B is better, and closer to the desirable >70 for CNS targets.

**9. Caco-2:** Both have negative Caco-2 values, which is unusual and difficult to interpret without further context. However, the values are similar.

**10. Solubility:** Both have negative solubility values, which is also unusual. The values are similar.

**11. hERG:** Ligand A (0.772) has a slightly higher hERG risk than Ligand B (0.23), but both are relatively low.

**12. Cl_mic:** Ligand A (57.932) has a higher microsomal clearance than Ligand B (27.935), suggesting lower metabolic stability.

**13. t1/2:** Ligand B (-7.867) has a more negative in vitro half-life, which is not ideal. Ligand A (-30.649) is even worse. Both are problematic.

**14. Pgp:** Ligand A (0.432) has lower P-gp efflux liability than Ligand B (0.012), which is favorable for CNS penetration.

**15. Binding Affinity:** Ligand A (-9.1 kcal/mol) has significantly stronger binding affinity than Ligand B (-6.6 kcal/mol). This is a substantial advantage.

**Overall Assessment:**

While Ligand A boasts a much superior binding affinity, its higher DILI risk and higher microsomal clearance are significant concerns. Ligand B, despite its weaker affinity, presents a much better safety profile (lower DILI) and potentially better metabolic stability. The slightly better BBB penetration of Ligand B is also advantageous for a CNS target. The Pgp value is better for Ligand A, but the affinity difference is so large that it likely outweighs this.

Considering the GPCR-specific priorities, and the fact that the affinity difference is >1.5 kcal/mol, I would initially lean towards Ligand A. However, the high DILI risk is a major red flag. Further investigation into the metabolic pathways and potential for off-target effects would be crucial for Ligand A.

Output:
1
2025-04-17 04:59:22,171 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (344.5 and 334.4 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (58.2) is better than Ligand B (45.4). Both are below the 90 Angstrom threshold for CNS targets, which is excellent.

**3. logP:** Both ligands have good logP values (3.04 and 3.93), falling within the optimal 1-3 range. Ligand B is slightly higher, which *could* be a minor concern for solubility, but is not a major drawback.

**4. H-Bond Donors:** Ligand A has 2 HBD, which is acceptable. Ligand B has 0, also acceptable.

**5. H-Bond Acceptors:** Ligand A has 2 HBA, and Ligand B has 5. Both are within the acceptable limit of 10.

**6. QED:** Both ligands have similar QED values (0.665 and 0.676), indicating good drug-like properties.

**7. DILI:** Ligand A (15.2%) has a significantly lower DILI risk than Ligand B (73.2%). This is a major advantage for Ligand A.

**8. BBB:** Ligand B (89.1%) has a substantially better BBB penetration score than Ligand A (70.4%). This is a critical factor for a CNS target like DRD2.

**9. Caco-2 Permeability:** Ligand A (-4.46) is better than Ligand B (-5.05), indicating better intestinal absorption.

**10. Aqueous Solubility:** Ligand A (-4.03) is better than Ligand B (-4.57), indicating better aqueous solubility.

**11. hERG Inhibition:** Ligand A (0.37) has a lower hERG inhibition liability than Ligand B (0.96), which is preferable.

**12. Microsomal Clearance:** Ligand A (52.07) has lower microsomal clearance than Ligand B (111.84), suggesting better metabolic stability.

**13. In vitro Half-Life:** Ligand B (37.72) has a longer in vitro half-life than Ligand A (4.76). This is a positive for Ligand B.

**14. P-gp Efflux:** Ligand A (0.085) has significantly lower P-gp efflux liability than Ligand B (0.653), which is crucial for CNS penetration.

**15. Binding Affinity:** Ligand B (-9.0 kcal/mol) has a stronger binding affinity than Ligand A (-8.3 kcal/mol). This is a substantial difference (0.7 kcal/mol), and a key driver in the decision.

**Overall Assessment:**

Ligand B has a significantly better BBB score and binding affinity, which are paramount for a CNS GPCR target. The longer half-life is also a benefit. However, it suffers from higher DILI risk and P-gp efflux. Ligand A has a better safety profile (DILI, hERG) and permeability characteristics, but weaker affinity and lower BBB penetration.

The affinity difference of 0.7 kcal/mol is significant enough to outweigh the drawbacks of Ligand B, particularly given the importance of strong binding for GPCR ligands. The higher BBB penetration also supports CNS activity. While the DILI and P-gp efflux are concerns, they may be addressable through further optimization.

Output:
1
2025-04-17 04:59:22,171 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (342.443) is slightly lower, which could be beneficial for permeability.

**TPSA:** Ligand A (65.54) is significantly better than Ligand B (104.73). For CNS targets, TPSA should be <= 90, and A is comfortably within this range, while B is pushing the limit.

**logP:** Both ligands have acceptable logP values (A: 1.518, B: 0.745), falling within the optimal range of 1-3.

**H-Bond Donors/Acceptors:** Ligand A (HBD=1, HBA=4) is preferable to Ligand B (HBD=3, HBA=5) as it has fewer hydrogen bond donors and acceptors, generally improving permeability.

**QED:** Ligand A (0.728) has a better QED score than Ligand B (0.524), indicating a more drug-like profile.

**DILI:** Ligand B (32.183) has a slightly lower DILI risk than Ligand A (19.659), but both are well below the concerning threshold of 60.

**BBB:** Ligand A (89.957) has a much higher BBB percentile than Ligand B (63.746). This is a *critical* advantage for a CNS target like DRD2.

**Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and suggests a potential issue with the prediction method or the molecules themselves. However, the magnitude is similar.

**Aqueous Solubility:** Both ligands have similar, very poor aqueous solubility (-1.24 and -1.292). This could pose formulation challenges.

**hERG Inhibition:** Both ligands show very low hERG inhibition liability (0.276 and 0.223), which is excellent.

**Microsomal Clearance:** Ligand B (25.665) has lower microsomal clearance than Ligand A (31.268), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (35.974) has a better in vitro half-life than Ligand B (-48.31), which is a significant advantage.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.024 and 0.027), which is favorable for CNS penetration.

**Binding Affinity:** Both ligands have excellent binding affinities (-7.9 and -7.7 kcal/mol). The difference of 0.2 kcal/mol is not substantial enough to outweigh the other differences.

**Overall Assessment:**

Ligand A is the stronger candidate. Its superior TPSA, BBB penetration, QED, and in vitro half-life, combined with comparable binding affinity and low hERG risk, make it more likely to be a viable drug candidate for DRD2. While Ligand B has slightly better metabolic stability (lower Cl_mic), the CNS-critical properties of Ligand A are significantly better. The solubility is a concern for both, but can be addressed with formulation strategies.

Output:
1
2025-04-17 04:59:22,171 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (350.409 and 383.514 Da) fall within the ideal range of 200-500 Da.

**TPSA:** Ligand A (32.78) is excellent, well below the 90 A^2 threshold for CNS targets. Ligand B (66.06) is still reasonable, but less optimal.

**logP:** Both ligands have good logP values (2.392 and 3.644), falling within the 1-3 range. Ligand B is slightly higher, which *could* be a minor concern for solubility, but isn't a dealbreaker.

**H-Bond Donors/Acceptors:** Ligand A (0 HBD, 3 HBA) is very favorable. Ligand B (1 HBD, 5 HBA) is also acceptable, but slightly less so.

**QED:** Ligand A (0.839) has a very strong drug-like profile. Ligand B (0.53) is still above the 0.5 threshold, but less impressive.

**DILI:** Ligand A (8.763) has a very low DILI risk. Ligand B (64.133) is higher, indicating a moderate risk of liver injury.

**BBB:** Ligand A (91.508) has excellent predicted BBB penetration, exceeding the 70% threshold. Ligand B (74.292) is still good, but significantly lower than Ligand A. This is a crucial factor for a CNS target like DRD2.

**Caco-2 Permeability:** Ligand A (-4.264) has poor Caco-2 permeability. Ligand B (-5.415) is even worse. This is a concern for oral bioavailability, but less critical for a CNS target where direct delivery or other routes might be considered.

**Aqueous Solubility:** Ligand A (-1.602) has poor solubility. Ligand B (-4.121) is even worse. This could pose formulation challenges.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.675 and 0.848).

**Microsomal Clearance:** Ligand A (12.539) has lower microsomal clearance, suggesting better metabolic stability, which is good. Ligand B (81.147) has much higher clearance, indicating faster metabolism.

**In vitro Half-Life:** Ligand A (-4.906) has a negative half-life, which is unusual and likely indicates a very short half-life. Ligand B (22.895) has a much more reasonable half-life.

**P-gp Efflux:** Ligand A (0.049) has very low P-gp efflux, which is excellent for CNS penetration. Ligand B (0.607) has a moderate P-gp efflux.

**Binding Affinity:** Ligand A (-9.4 kcal/mol) has significantly stronger binding affinity than Ligand B (-7.5 kcal/mol). The difference of 1.9 kcal/mol is substantial and can outweigh many ADME drawbacks.

**Overall Assessment:**

Ligand A excels in key areas for a CNS GPCR target: TPSA, BBB penetration, P-gp efflux, and, most importantly, binding affinity. While its solubility and Caco-2 permeability are poor, and its half-life is very short, the strong affinity and excellent CNS penetration properties are highly valuable. Ligand B has a more reasonable half-life, but suffers from lower affinity, poorer BBB penetration, higher DILI risk, and higher metabolic clearance. The significantly stronger binding affinity of Ligand A makes it the more promising candidate, despite its ADME liabilities, as these can potentially be addressed through further optimization.

Output:
1
2025-04-17 04:59:22,171 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 drug candidates, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (348.451 and 344.455 Da) fall within the ideal range of 200-500 Da.

**TPSA:** Ligand A (83.36) is slightly above the optimal <90 for CNS targets, but still reasonable. Ligand B (62.55) is excellent, well below 90.

**logP:** Ligand A (0.266) is quite low, potentially hindering permeability. Ligand B (3.229) is within the optimal 1-3 range. This is a significant advantage for Ligand B.

**H-Bond Donors/Acceptors:** Both have 1 HBD, which is good. Ligand A has 6 HBA, acceptable. Ligand B has 3 HBA, also acceptable.

**QED:** Both ligands have good QED scores (0.826 and 0.773), indicating good drug-like properties.

**DILI:** Ligand A (28.577) has a lower DILI risk than Ligand B (42.769), which is a positive.

**BBB:** Ligand A (59.946) has a BBB penetration percentile below the desirable >70 for CNS targets. Ligand B (66.382) is also below 70, but closer.

**Caco-2 Permeability:** Both have negative Caco-2 values (-4.875 and -4.656). This is unusual and suggests poor permeability.

**Aqueous Solubility:** Both have negative solubility values (-1.255 and -2.636), indicating poor aqueous solubility.

**hERG:** Both ligands have very low hERG inhibition risk (0.106 and 0.423), which is excellent.

**Microsomal Clearance:** Ligand A (8.212) has a lower microsomal clearance than Ligand B (76.416), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand B (68.701) has a significantly longer in vitro half-life than Ligand A (12.966), which is a major advantage.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.007 and 0.324), which is favorable for CNS penetration.

**Binding Affinity:** Ligand B (-8.5 kcal/mol) has a slightly better binding affinity than Ligand A (-7.9 kcal/mol). While the difference is less than the 1.5 kcal/mol threshold, it contributes to the overall assessment.

**Overall Assessment:**

Ligand B is the better candidate. While both have issues with Caco-2 and solubility, Ligand B's superior logP, longer half-life, and slightly better affinity outweigh Ligand A's lower DILI risk. The low logP of Ligand A is a significant concern for CNS penetration, while the longer half-life of Ligand B is crucial for a GPCR target. The BBB values for both are suboptimal, but Ligand B is closer to the desired threshold.

Output:
1
2025-04-17 04:59:22,171 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (455.256 Da) is higher, but still acceptable. Ligand B (368.487 Da) is slightly preferable.

**TPSA:** Both ligands have TPSA values below the 90 A^2 threshold desirable for CNS targets. Ligand A (89.35) is better than Ligand B (59.29).

**logP:** Ligand A (1.435) is within the optimal range (1-3). Ligand B (4.4) is higher, potentially leading to solubility issues and off-target interactions. This is a significant negative for Ligand B.

**H-Bond Donors/Acceptors:** Both ligands have 1 HBD and 6 HBA, which are within acceptable limits.

**QED:** Both ligands have QED values above 0.5, indicating good drug-likeness.

**DILI:** Ligand A (73.09) has a lower DILI risk than Ligand B (90.461), making it more favorable.

**BBB:** Ligand A (53.974) has a better BBB penetration percentile than Ligand B (39.55). This is crucial for a CNS target like DRD2.

**Caco-2 Permeability:** Ligand A (-4.934) has a lower Caco-2 permeability than Ligand B (-5.159), but both are quite poor.

**Aqueous Solubility:** Ligand A (-2.679) has better solubility than Ligand B (-4.608).

**hERG Inhibition:** Both ligands have very low hERG inhibition risk.

**Microsomal Clearance:** Ligand A (39.706) has lower microsomal clearance than Ligand B (68.768), indicating better metabolic stability.

**In vitro Half-Life:** Ligand B (48.724) has a longer in vitro half-life than Ligand A (18.798).

**P-gp Efflux:** Ligand A (0.265) has lower P-gp efflux than Ligand B (0.36), which is favorable for CNS penetration.

**Binding Affinity:** Ligand B (-8.9 kcal/mol) has a slightly better binding affinity than Ligand A (-8.5 kcal/mol). While a 1.5 kcal/mol difference is significant, other factors need to be considered.

**Overall Assessment:**

Ligand A is significantly better overall. While Ligand B has slightly better affinity and half-life, Ligand A excels in crucial areas for a CNS-targeting GPCR ligand: BBB penetration, lower DILI risk, better solubility, lower P-gp efflux, and lower microsomal clearance. Ligand B's high logP is a major concern, potentially hindering its ability to reach the brain and increasing the risk of off-target effects. The difference in affinity, while present, is likely outweighed by the superior ADME properties of Ligand A.

Output:
0
2025-04-17 04:59:22,172 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (355.435 and 357.376 Da) fall within the ideal range of 200-500 Da.

**TPSA:** Ligand A (118.97) is better than Ligand B (62.3). Both are below the 90 A^2 threshold for CNS targets, which is excellent.

**logP:** Ligand B (2.321) is within the optimal 1-3 range, while Ligand A (-0.692) is below 1, which could hinder permeation. This is a significant advantage for Ligand B.

**H-Bond Donors/Acceptors:** Ligand A has 4 HBD and 5 HBA, while Ligand B has 1 HBD and 3 HBA. Both are within acceptable limits, but Ligand B is slightly more favorable due to fewer potential off-target interactions.

**QED:** Ligand B (0.85) has a much higher QED score than Ligand A (0.387), indicating a more drug-like profile.

**DILI:** Both ligands have similar, relatively low DILI risk (17.449 and 17.798 percentile).

**BBB:** Ligand B (82.202) has a significantly higher BBB penetration percentile than Ligand A (20.822). This is *critical* for a CNS target like DRD2.

**Caco-2 Permeability:** Ligand A (-5.595) and Ligand B (-4.791) both have negative values, which is unusual and suggests poor permeability. However, the scale isn't specified, so it's difficult to interpret.

**Aqueous Solubility:** Both ligands have negative solubility values (-1.249 and -2.488), indicating poor solubility. This could be a formulation challenge.

**hERG:** Ligand A (0.034) has a very low hERG risk, while Ligand B (0.594) is slightly higher, but still relatively low.

**Microsomal Clearance:** Ligand B (-8.882) has a *negative* microsomal clearance, which is highly unusual and suggests very high metabolic stability. Ligand A (8.875) has a moderate clearance.

**In vitro Half-Life:** Ligand B (-4.173) also has a negative half-life, which is impossible and likely an error in the data. Ligand A (-7.535) is also negative, indicating an error.

**P-gp Efflux:** Ligand A (0.01) has very low P-gp efflux liability, which is favorable for CNS penetration. Ligand B (0.043) is slightly higher, but still low.

**Binding Affinity:** Ligand B (-9.2 kcal/mol) has a significantly stronger binding affinity than Ligand A (-7.1 kcal/mol). This difference of 2.1 kcal/mol is substantial and can outweigh some ADME drawbacks.

**Overall Assessment:**

Despite the questionable negative values for Caco-2, solubility, and half-life, Ligand B is the superior candidate. Its significantly better BBB penetration, optimal logP, higher QED, and *much* stronger binding affinity outweigh the slightly higher hERG risk and the potentially problematic negative clearance/half-life values (which likely indicate data errors). Ligand A's low logP is a major drawback for a CNS target. The affinity difference is also substantial.

Output:
1
2025-04-17 04:59:22,172 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (347.375 and 341.459 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (129.37) is slightly above the optimal <90 for CNS targets, but still reasonable. Ligand B (71.1) is excellent, well below 90.

**logP:** Ligand A (-0.162) is quite low, potentially hindering membrane permeability. Ligand B (2.775) is within the optimal 1-3 range. This is a significant advantage for Ligand B.

**H-Bond Donors/Acceptors:** Ligand A (4 HBD, 7 HBA) is acceptable. Ligand B (3 HBD, 6 HBA) is also acceptable and slightly better.

**QED:** Both ligands have good QED scores (0.574 and 0.719), indicating drug-like properties.

**DILI:** Ligand A (42.536) has a lower DILI risk than Ligand B (63.668), which is a positive attribute.

**BBB:** Ligand B (88.29) has a significantly higher BBB penetration percentile than Ligand A (9.306). This is *crucial* for a CNS target like DRD2.

**Caco-2 Permeability:** Both have negative values (-5.639 and -5.329), which is unusual and suggests poor permeability. However, these values are on a scale where negative values are possible and don't necessarily preclude activity.

**Aqueous Solubility:** Both ligands have negative values (-1.841 and -2.648), indicating poor solubility. This could be a formulation challenge.

**hERG Inhibition:** Ligand A (0.036) has a very low hERG risk, which is excellent. Ligand B (0.941) has a moderate hERG risk.

**Microsomal Clearance:** Ligand A (-0.282) has a very low (and likely favorable) microsomal clearance. Ligand B (31.233) has a higher clearance, suggesting faster metabolism.

**In vitro Half-Life:** Ligand B (73.891) has a much longer in vitro half-life than Ligand A (14.382).

**P-gp Efflux:** Ligand A (0.005) has very low P-gp efflux, which is excellent for CNS penetration. Ligand B (0.132) has slightly higher efflux, but still reasonable.

**Binding Affinity:** Ligand B (-9.3 kcal/mol) has a significantly stronger binding affinity than Ligand A (-8.1 kcal/mol). This 1.2 kcal/mol difference is substantial and can outweigh some ADME drawbacks.

**Overall Assessment:**

Ligand B is the stronger candidate. While Ligand A has a lower DILI risk and hERG inhibition, Ligand B's superior BBB penetration, significantly better binding affinity, and longer half-life are critical advantages for a CNS-targeting GPCR like DRD2. The slightly higher DILI and hERG risks associated with Ligand B could be addressed through further optimization. The logP value of Ligand B is also much more favorable.



Output:
1
2025-04-17 04:59:22,172 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (376.762 Da) is slightly higher than Ligand B (345.443 Da), but both are acceptable.

**TPSA:** Ligand A (67.43) is better than Ligand B (78.51). For CNS targets, we want TPSA <= 90, and ideally lower. Ligand A is closer to the ideal range.

**logP:** Both ligands have good logP values (Ligand A: 1.997, Ligand B: 0.981), falling within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Both have 2 HBD and 3 HBA, which are within acceptable limits.

**QED:** Ligand A (0.746) has a significantly better QED score than Ligand B (0.443), indicating a more drug-like profile.

**DILI:** Ligand A (61.109) has a higher DILI risk than Ligand B (23.226). This is a negative for Ligand A.

**BBB:** Ligand A (90.074) has a much better BBB penetration percentile than Ligand B (52.268). This is *critical* for a CNS target like DRD2.

**Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and difficult to interpret without knowing the scale. However, we can't strongly weigh this against either compound.

**Aqueous Solubility:** Both have negative solubility values, again making comparison difficult.

**hERG:** Both ligands have very low hERG inhibition liability (Ligand A: 0.652, Ligand B: 0.044), which is excellent.

**Microsomal Clearance:** Ligand B (29.294) has a higher microsomal clearance than Ligand A (14.18), suggesting Ligand A is more metabolically stable.

**In vitro Half-Life:** Ligand A (12.03) has a positive half-life, while Ligand B (-17.421) has a negative one. This is concerning for Ligand B.

**P-gp Efflux:** Both ligands show low P-gp efflux liability (Ligand A: 0.145, Ligand B: 0.018).

**Binding Affinity:** Both ligands have excellent binding affinities (Ligand A: -9 kcal/mol, Ligand B: -8.6 kcal/mol). Ligand A is slightly better.

**Overall Assessment:**

Ligand A is superior due to its significantly better BBB penetration, higher QED, better metabolic stability (lower Cl_mic, positive t1/2), and slightly better binding affinity. While Ligand A has a higher DILI risk, the crucial BBB penetration for a CNS target outweighs this concern. Ligand B's poor BBB penetration and negative half-life are major drawbacks.

Output:
1
2025-04-17 04:59:22,172 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (358.498 and 352.385 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (58.64) is excellent, well below the 90 A^2 threshold for CNS targets. Ligand B (69.3) is still reasonable, but less optimal.

**logP:** Ligand A (3.073) is optimal. Ligand B (1.544) is a bit low, potentially hindering membrane permeability.

**H-Bond Donors/Acceptors:** Both ligands have 1 HBD and 3 HBA, which are within acceptable limits.

**QED:** Both ligands have good QED scores (0.761 and 0.897), indicating drug-like properties.

**DILI:** Both ligands have acceptable DILI risk (30.322 and 41.566), below the 60 threshold.

**BBB:** Ligand A (91.392) has a significantly better BBB penetration score than Ligand B (80.419). This is a critical advantage for a CNS target like DRD2.

**Caco-2 Permeability:** Ligand A (-4.257) and Ligand B (-4.852) both have negative Caco-2 values, which is unusual and suggests poor permeability. However, the scale is not specified, so it's difficult to interpret.

**Aqueous Solubility:** Both ligands have poor aqueous solubility (-3.496 and -2.154). This could pose formulation challenges.

**hERG Inhibition:** Both ligands show low hERG inhibition risk (0.681 and 0.42).

**Microsomal Clearance:** Ligand A (46.709) has a higher microsomal clearance than Ligand B (26.229), suggesting lower metabolic stability.

**In vitro Half-Life:** Ligand B (-45.633) has a very negative half-life, indicating extremely rapid metabolism/poor stability. Ligand A (3.53) is better, but still not ideal.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.16 and 0.063), which is favorable for CNS penetration.

**Binding Affinity:** Ligand B (-8.2 kcal/mol) has a significantly stronger binding affinity than Ligand A (-7.2 kcal/mol). This is a substantial advantage (1 kcal/mol difference).

**Overall Assessment:**

While Ligand B boasts superior binding affinity, Ligand A is the more promising candidate due to its significantly better BBB penetration (91.392 vs 80.419) and more reasonable metabolic stability (Cl_mic and t1/2). The difference in binding affinity, while notable, can potentially be overcome with further optimization. The poor solubility and Caco-2 values are concerns for both, but can be addressed during lead optimization. Given the GPCR target and the importance of CNS penetration, the higher BBB score of Ligand A is a decisive factor.

Output:
0
2025-04-17 04:59:22,172 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B based on the provided guidelines, prioritizing GPCR-specific properties (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (352.479 and 359.467 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (90.54) is excellent for CNS penetration, being below 90. Ligand B (113.17) is still reasonable but less optimal, being above 90.

**logP:** Ligand A (0.254) is quite low, potentially hindering membrane permeability. Ligand B (-0.019) is also low, but slightly better than A. Both are below the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A has 3 HBD and 4 HBA, which are within acceptable limits. Ligand B has 2 HBD and 5 HBA, also acceptable.

**QED:** Both ligands have similar QED values (0.584 and 0.532), indicating good drug-likeness.

**DILI:** Ligand A (10.392) has a significantly lower DILI risk than Ligand B (12.214), which is a positive attribute.

**BBB:** Ligand A (46.336) has a slightly better BBB percentile than Ligand B (44.591), but both are below the desirable >70 for CNS targets.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.396 and -5.175), which is unusual and suggests very poor permeability. This is a major concern for both.

**Aqueous Solubility:** Both ligands have negative solubility values (-1.035 and -0.748), indicating very poor aqueous solubility. This is also a significant issue.

**hERG Inhibition:** Ligand A (0.081) has a much lower hERG inhibition risk than Ligand B (0.346), which is a substantial advantage.

**Microsomal Clearance:** Ligand B (44.422) has a much higher microsomal clearance than Ligand A (18.272), suggesting lower metabolic stability.

**In vitro Half-Life:** Ligand A (-2.235) has a slightly better (less negative) in vitro half-life than Ligand B (-16.456).

**P-gp Efflux:** Ligand A (0.001) exhibits minimal P-gp efflux, which is highly desirable for CNS penetration. Ligand B (0.058) shows slightly higher efflux, but still relatively low.

**Binding Affinity:** Ligand A (-7.4) has a significantly stronger binding affinity than Ligand B (-6.2), a difference of 1.2 kcal/mol. This is a substantial advantage that could outweigh some of the ADME deficiencies.

**Overall Assessment:**

Despite both ligands having significant ADME issues (poor permeability, solubility), Ligand A is the more promising candidate. Its superior binding affinity (-7.4 vs -6.2 kcal/mol), lower DILI risk, lower hERG risk, better metabolic stability (lower Cl_mic), and minimal P-gp efflux outweigh the slightly lower BBB and logP values. The strong binding affinity suggests that even with limited permeability, sufficient drug concentration at the target site might be achievable. The poor permeability and solubility would need to be addressed through formulation strategies or further chemical modifications, but the core scaffold of Ligand A appears more favorable.

Output:
0
2025-04-17 04:59:22,173 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (361.291 and 357.483 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (60.7) is better than Ligand B (63.91). Both are below the 90 A^2 threshold desirable for CNS targets, but lower is preferable.

**logP:** Ligand A (3.387) is optimal (1-3), while Ligand B (2.285) is slightly lower but still acceptable.

**H-Bond Donors/Acceptors:** Ligand A (1 HBD, 4 HBA) is better than Ligand B (0 HBD, 6 HBA). Both are within acceptable limits.

**QED:** Ligand A (0.655) is slightly better than Ligand B (0.536), indicating a more drug-like profile. Both are above the 0.5 threshold.

**DILI:** Ligand B (48.895) has a significantly lower DILI risk than Ligand A (80.031). This is a substantial advantage for Ligand B.

**BBB:** Ligand A (96.006) has excellent BBB penetration, while Ligand B (61.613) is lower, though still not terrible. This is a major advantage for Ligand A, given the CNS target.

**Caco-2 Permeability:** Ligand A (-4.641) has worse Caco-2 permeability than Ligand B (-5.135). Lower values indicate poorer permeability.

**Aqueous Solubility:** Ligand A (-4.576) has worse solubility than Ligand B (-2.821).

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.871 and 0.488, respectively).

**Microsomal Clearance:** Ligand A (29.393) has lower microsomal clearance than Ligand B (36.918), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (74.852) has a significantly longer half-life than Ligand B (10.884). This is a strong advantage for Ligand A.

**P-gp Efflux:** Ligand A (0.445) has lower P-gp efflux than Ligand B (0.218), meaning better CNS exposure.

**Binding Affinity:** Ligand A (-9.2 kcal/mol) has a significantly stronger binding affinity than Ligand B (-7.0 kcal/mol). This is a substantial advantage for Ligand A, exceeding the 1.5 kcal/mol difference threshold.

**Overall Assessment:**

Ligand A excels in BBB penetration, binding affinity, metabolic stability (lower Cl_mic), and half-life. The strong binding affinity is a major driver. While its DILI risk is higher and solubility/permeability are lower than Ligand B, the superior affinity and BBB penetration outweigh these drawbacks for a CNS target like DRD2. Ligand B has better safety (DILI) and solubility/permeability, but its weaker affinity and lower BBB penetration are significant liabilities.

Output:
1
2025-04-17 04:59:22,173 - INFO - Reasoning:

Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (358.419 and 368.587 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (69.68) is higher than Ligand B (58.2). For a CNS target like DRD2, we ideally want TPSA <= 90, so both are acceptable, but B is better.

**3. logP:** Both ligands have good logP values (3.712 and 3.603), falling within the optimal range of 1-3.

**4. H-Bond Donors:** Ligand A (1) is better than Ligand B (2). Lower HBDs generally improve permeability.

**5. H-Bond Acceptors:** Ligand A (7) is higher than Ligand B (3). Lower HBAs are preferred for permeability.

**6. QED:** Both ligands have similar QED values (0.678 and 0.675), indicating good drug-like properties.

**7. DILI:** Ligand A (96.51) has a significantly higher DILI risk than Ligand B (17.371). This is a major concern for Ligand A.

**8. BBB:** Ligand B (70.997) has a better BBB penetration percentile than Ligand A (63.358). Both are above the 70% threshold, but B is preferable.

**9. Caco-2 Permeability:** Ligand A (-4.676) has better Caco-2 permeability than Ligand B (-4.941).

**10. Aqueous Solubility:** Ligand A (-5.843) has slightly better aqueous solubility than Ligand B (-4.042).

**11. hERG Inhibition:** Both ligands have low hERG inhibition risk (0.685 and 0.594).

**12. Microsomal Clearance:** Ligand B (76.779) has a lower microsomal clearance than Ligand A (154.848), indicating better metabolic stability.

**13. In vitro Half-Life:** Ligand B (15.548) has a significantly longer in vitro half-life than Ligand A (2.317).

**14. P-gp Efflux:** Ligand A (0.257) has lower P-gp efflux than Ligand B (0.145), which is favorable for CNS penetration.

**15. Binding Affinity:** Both ligands have very similar and excellent binding affinities (-8.3 and -8.4 kcal/mol). The difference is negligible.

**Overall Assessment:**

While Ligand A has slightly better Caco-2 permeability and P-gp efflux, its significantly higher DILI risk, lower BBB penetration, and higher microsomal clearance are major drawbacks. Ligand B excels in crucial areas for a CNS-targeting GPCR ligand: lower DILI risk, better BBB penetration, and improved metabolic stability (lower Cl_mic and longer t1/2). The slight advantage of A in permeability is outweighed by the substantial safety and PK advantages of B.

Output:
1
2025-04-17 04:59:22,173 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (338.411) is slightly lower, which could be beneficial for permeability, but both are acceptable.

**TPSA:** Ligand A (78.09) is better than Ligand B (56.07), falling comfortably below the 90 A^2 threshold for CNS targets. Ligand B is also good, but A is preferable.

**logP:** Both ligands have good logP values (A: 2.087, B: 2.698), falling within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A has 2 HBD and 3 HBA, while Ligand B has 0 HBD and 6 HBA. Both are within acceptable limits (<=5 HBD and <=10 HBA).

**QED:** Both ligands have reasonable QED scores (A: 0.82, B: 0.751), indicating good drug-like properties.

**DILI:** Ligand A (63.397) has a higher DILI risk than Ligand B (35.867). This is a significant negative for Ligand A.

**BBB:** This is a critical parameter for a CNS target like DRD2. Ligand B (95.308) has excellent BBB penetration, significantly better than Ligand A (38.581).

**Caco-2 Permeability:** Ligand A (-5.045) has poor Caco-2 permeability, while Ligand B (-4.646) is also poor, but slightly better.

**Aqueous Solubility:** Both ligands have poor aqueous solubility (-3.348 and -3.505 respectively). This could pose formulation challenges, but isn't a dealbreaker if other properties are favorable.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (A: 0.481, B: 0.595).

**Microsomal Clearance:** Ligand A (17.522) has lower microsomal clearance than Ligand B (24.522), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (-11.092) has a significantly longer in vitro half-life than Ligand B (-4.014).

**P-gp Efflux:** Ligand A (0.043) has much lower P-gp efflux liability than Ligand B (0.215), which is highly desirable for CNS penetration.

**Binding Affinity:** Ligand A (-8.8 kcal/mol) has a stronger binding affinity than Ligand B (-7.5 kcal/mol). This is a substantial advantage (1.3 kcal/mol difference).

**Overall Assessment:**

Despite Ligand A's superior binding affinity and metabolic stability, Ligand B is the more promising candidate. The significantly better BBB penetration (95.308 vs 38.581) and lower DILI risk (35.867 vs 63.397) outweigh the slightly weaker binding and higher P-gp efflux. The strong affinity of Ligand A is attractive, but its poor BBB and higher DILI risk are major concerns for a CNS drug. The lower P-gp efflux of Ligand A is a positive, but not enough to overcome the other drawbacks.



Output:
1
2025-04-17 04:59:22,173 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (356.413 and 363.531 Da) fall within the ideal range of 200-500 Da.

**TPSA:** Ligand A (58.64) is excellent, well below the 90 A^2 threshold for CNS targets. Ligand B (70.15) is still reasonable, but less optimal.

**logP:** Ligand A (1.815) is within the optimal 1-3 range. Ligand B (2.739) is also acceptable, leaning towards the higher end but still within range.

**H-Bond Donors/Acceptors:** Ligand A (1 HBD, 3 HBA) and Ligand B (2 HBD, 6 HBA) both have acceptable numbers of H-bond donors and acceptors.

**QED:** Both ligands have good QED scores (0.533 and 0.842), indicating drug-like properties. Ligand B is slightly better here.

**DILI:** Ligand A (25.553) has a significantly lower DILI risk than Ligand B (51.26). This is a major advantage for Ligand A.

**BBB:** Ligand A (89.376) has a very good BBB penetration percentile, exceeding the desirable >70% threshold for CNS targets. Ligand B (74.835) is still reasonable, but lower.

**Caco-2 Permeability:** Ligand A (-4.414) and Ligand B (-5.261) both have negative Caco-2 values, which is unusual and suggests poor permeability. However, these values are on a scale where negative values are possible and don't necessarily disqualify a compound.

**Aqueous Solubility:** Both ligands have poor aqueous solubility (-2.237 and -3.217). This could pose formulation challenges, but is less critical than BBB penetration for a CNS target.

**hERG Inhibition:** Both ligands show low hERG inhibition liability (0.571 and 0.27), which is positive.

**Microsomal Clearance:** Ligand A (26.547) has a higher microsomal clearance than Ligand B (11.626), indicating lower metabolic stability. Ligand B is better here.

**In vitro Half-Life:** Ligand B (32.629) has a longer in vitro half-life than Ligand A (-21.711), suggesting better stability.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.123 and 0.105), which is favorable for CNS penetration.

**Binding Affinity:** Ligand B (-9.2 kcal/mol) has a significantly stronger binding affinity than Ligand A (-7.6 kcal/mol). This is a substantial advantage, potentially outweighing some of the ADME drawbacks. The difference is >1.5 kcal/mol.

**Overall Assessment:**

While Ligand A has better DILI and BBB penetration, the significantly stronger binding affinity of Ligand B (-9.2 vs -7.6 kcal/mol) is a crucial factor, especially for a GPCR target. The improved half-life of Ligand B is also beneficial. The slightly higher DILI risk and lower BBB for Ligand B are acceptable trade-offs given the potency advantage.

Output:
1
2025-04-17 04:59:22,174 - INFO - Batch 160 complete. Total preferences: 2560
2025-04-17 04:59:22,174 - INFO - Processing batch 161/512...
2025-04-17 05:00:04,037 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (344.363) is slightly lower, which could be beneficial for permeability, but both are acceptable.

**TPSA:** Ligand A (74.97) is much better than Ligand B (29.54) for CNS penetration, falling well below the 90 A^2 threshold. Ligand B is excellent.

**logP:** Both ligands have acceptable logP values (Ligand A: 2.784, Ligand B: 4.376). Ligand A is optimal, while Ligand B is approaching the upper limit, potentially raising concerns about solubility and off-target effects.

**H-Bond Donors/Acceptors:** Ligand A (0 HBD, 6 HBA) and Ligand B (0 HBD, 3 HBA) both have reasonable numbers of H-bond donors and acceptors, well within the guidelines.

**QED:** Both ligands have acceptable QED values (Ligand A: 0.777, Ligand B: 0.665), indicating good drug-like properties.

**DILI:** Ligand A (63.086) has a higher DILI risk than Ligand B (10.896). This is a significant drawback for Ligand A.

**BBB:** Ligand B (90.849) has a significantly better BBB penetration score than Ligand A (80.419). This is crucial for a CNS target like DRD2.

**Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and suggests poor permeability. However, the scale is not specified, so it's difficult to interpret.

**Aqueous Solubility:** Both ligands have negative solubility values, indicating poor solubility. Again, the scale is not specified.

**hERG Inhibition:** Ligand A (0.389) has a slightly higher hERG risk than Ligand B (0.897), but both are relatively low.

**Microsomal Clearance:** Ligand B (94.799) has a higher microsomal clearance than Ligand A (77.787), suggesting faster metabolism and potentially lower in vivo exposure.

**In vitro Half-Life:** Ligand A (-14.481) has a negative half-life, which is not possible. This is a major red flag. Ligand B (20.68) has a reasonable half-life.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (Ligand A: 0.579, Ligand B: 0.485), which is favorable for CNS penetration.

**Binding Affinity:** Ligand B (-7.3 kcal/mol) has a significantly stronger binding affinity than Ligand A (-9.0 kcal/mol). This is a substantial advantage.

**Overall Assessment:**

Ligand B is clearly superior. While its logP is slightly higher, its significantly better BBB penetration, much lower DILI risk, reasonable half-life, and *much* stronger binding affinity outweigh any potential drawbacks. Ligand A has a nonsensical half-life value and a concerning DILI risk. The superior binding affinity of Ligand B is a decisive factor, especially for a GPCR target where potency is critical.

Output:
1
2025-04-17 05:00:04,037 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (354.479 and 350.459 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (51.02) is significantly better than Ligand B (75.71). For CNS targets, we want TPSA <= 90, and A is comfortably within that range, while B is approaching the upper limit.

**3. logP:** Ligand A (3.313) is optimal (1-3), while Ligand B (1.668) is on the lower side. While not terrible, lower logP can sometimes indicate permeability issues.

**4. H-Bond Donors:** Ligand A (0) is preferable to Ligand B (1). Fewer HBDs generally improve permeability.

**5. H-Bond Acceptors:** Ligand A (5) is better than Ligand B (4). Both are within the acceptable limit of <=10.

**6. QED:** Both ligands have good QED scores (0.661 and 0.74), indicating drug-like properties.

**7. DILI:** Ligand A (60.062) is higher risk than Ligand B (9.306). This is a significant drawback for Ligand A.

**8. BBB:** Both ligands have excellent BBB penetration (73.827 and 75.107), exceeding the desirable >70 threshold for CNS targets.

**9. Caco-2 Permeability:** Ligand A (-5.112) and Ligand B (-4.816) both have negative Caco-2 values, which is unusual and suggests poor permeability. However, the scale isn't defined, so we can't interpret this definitively.

**10. Aqueous Solubility:** Ligand A (-2.543) and Ligand B (-1.48) both have negative solubility values, indicating poor solubility.

**11. hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.675 and 0.164).

**12. Microsomal Clearance:** Ligand A (51.876) has higher clearance than Ligand B (6.554), indicating lower metabolic stability.

**13. In vitro Half-Life:** Ligand A (-19.841) has a negative half-life, which is not possible. This is a major red flag. Ligand B (-12.455) also has a negative half-life, also a major red flag.

**14. P-gp Efflux:** Both ligands have low P-gp efflux (0.705 and 0.027), which is good for CNS exposure.

**15. Binding Affinity:** Both ligands have similar and strong binding affinities (-8.8 and -8.1 kcal/mol). The difference of 0.7 kcal/mol is not substantial enough to override other factors.

**Overall Assessment:**

Ligand B is significantly better. While both have issues with solubility and Caco-2 permeability, Ligand A has a much higher DILI risk and a nonsensical negative in vitro half-life. Ligand B's lower DILI, better logP, and lower clearance make it the more promising candidate, despite the shared solubility and permeability concerns.

Output:
1
2025-04-17 05:00:04,037 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (356.463 and 355.454 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (99.1) is higher than Ligand B (70.67). For CNS targets, TPSA should be <= 90. Ligand B is preferable here.

**logP:** Ligand A (0.146) is quite low, potentially hindering membrane permeability. Ligand B (1.0) is within the optimal 1-3 range. This is a significant advantage for Ligand B.

**H-Bond Donors/Acceptors:** Ligand A has 3 HBD and 5 HBA, while Ligand B has 2 HBD and 4 HBA. Both are within acceptable limits (<=5 HBD and <=10 HBA).

**QED:** Both ligands have good QED scores (0.546 and 0.746, respectively), indicating drug-likeness. Ligand B is slightly better.

**DILI:** Ligand A (10.081) has a lower DILI risk than Ligand B (16.014), which is preferable.

**BBB:** Ligand B (74.447) has a significantly higher BBB penetration percentile than Ligand A (57.387). This is *critical* for a CNS target like DRD2, giving Ligand B a major advantage.

**Caco-2 Permeability:** Both have negative Caco-2 values (-4.831 and -4.877), which is unusual and suggests poor permeability. This is a concern for both.

**Aqueous Solubility:** Both have negative solubility values (-0.844 and -1.648), which is also unusual and suggests poor solubility. This is a concern for both.

**hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.199 and 0.22), which is excellent.

**Microsomal Clearance:** Ligand A (19.421) has a higher microsomal clearance than Ligand B (-16.469 - note the negative value indicates stability). Lower clearance is better for metabolic stability, making Ligand B preferable.

**In vitro Half-Life:** Ligand B (14.732 hours) has a significantly longer half-life than Ligand A (2.506 hours). This is a substantial advantage for Ligand B.

**P-gp Efflux:** Both have very low P-gp efflux liability (0.021 and 0.013), which is good.

**Binding Affinity:** Both ligands have the same binding affinity (-7.6 kcal/mol), which is excellent and meets the criteria.

**Overall Assessment:**

Ligand B is clearly the better candidate. While Ligand A has a slightly lower DILI risk, Ligand B excels in the key GPCR-specific properties: significantly better BBB penetration, a more optimal logP, better metabolic stability (lower Cl_mic, longer t1/2), and a slightly higher QED. The negative Caco-2 and solubility values are concerning for both, but the superior CNS penetration and pharmacokinetic profile of Ligand B outweigh this concern.

Output:
1
2025-04-17 05:00:04,038 - INFO - Reasoning:

Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (390.481 and 366.571 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (76.88) is slightly above the preferred <90 for CNS targets, but still reasonable. Ligand B (49.41) is excellent, well below 90.

**3. logP:** Both ligands have good logP values (2.808 and 3.596), falling within the optimal 1-3 range.

**4. H-Bond Donors:** Both have 1 HBD, which is acceptable.

**5. H-Bond Acceptors:** Ligand A has 6 HBA, and Ligand B has 3. Both are within the acceptable limit of <=10.

**6. QED:** Ligand A (0.852) has a better QED score than Ligand B (0.678), indicating a more drug-like profile.

**7. DILI:** Ligand A (78.325) has a higher DILI risk than Ligand B (13.339). This is a significant drawback for Ligand A.

**8. BBB:** Ligand A (82.047) has a better BBB penetration percentile than Ligand B (76.154), which is important for a CNS target.

**9. Caco-2 Permeability:** Ligand A (-4.968) has worse Caco-2 permeability than Ligand B (-5.27). Lower values are less desirable.

**10. Aqueous Solubility:** Ligand A (-4.095) has worse aqueous solubility than Ligand B (-3.414).

**11. hERG Inhibition:** Both ligands have low hERG inhibition risk (0.491 and 0.555).

**12. Microsomal Clearance:** Ligand B (75.288) has significantly higher microsomal clearance than Ligand A (28.516), suggesting lower metabolic stability.

**13. In vitro Half-Life:** Ligand A (35.83) has a longer in vitro half-life than Ligand B (7.968).

**14. P-gp Efflux:** Ligand A (0.499) has lower P-gp efflux than Ligand B (0.231), which is favorable for CNS penetration.

**15. Binding Affinity:** Ligand B (-7.4) has a significantly stronger binding affinity than Ligand A (-9.1). This is a crucial advantage, exceeding the 1.5 kcal/mol threshold.

**Overall Assessment:**

While Ligand A has better BBB penetration and P-gp efflux, the significantly higher DILI risk, poorer solubility, and lower binding affinity are major concerns. Ligand B, despite slightly lower BBB, exhibits a much more favorable safety profile (low DILI), stronger binding affinity, and acceptable ADME properties. The strong binding affinity of Ligand B is a substantial advantage that outweighs the minor drawbacks in BBB and P-gp efflux.

Output:
1
2025-04-17 05:00:04,038 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (348.447 and 346.391 Da) fall comfortably within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (95.42) is better than Ligand B (123.21). For CNS targets, we want TPSA <= 90, so Ligand A is closer to this threshold. Ligand B is significantly higher.

**3. logP:** Ligand A (1.975) is within the optimal range (1-3). Ligand B (-1.105) is below 1, which could hinder permeation.

**4. H-Bond Donors:** Both ligands have 2 HBD, which is acceptable (<=5).

**5. H-Bond Acceptors:** Ligand A has 5 HBA, and Ligand B has 6. Both are within the acceptable range (<=10).

**6. QED:** Ligand A (0.819) has a better QED score than Ligand B (0.648), indicating a more drug-like profile.

**7. DILI:** Ligand A (43.66) has a slightly higher DILI risk than Ligand B (30.826), but both are below the concerning threshold of 60.

**8. BBB:** Both ligands have good BBB penetration (Ligand A: 51.26, Ligand B: 54.711). However, >70 is desirable for CNS targets. Both are acceptable, but not optimal.

**9. Caco-2:** Both have negative Caco-2 values, which is unusual and suggests poor permeability. This is a significant concern for both.

**10. Solubility:** Both have negative solubility values, which is also unusual and suggests poor aqueous solubility. This is a significant concern for both.

**11. hERG:** Both ligands have very low hERG risk (Ligand A: 0.245, Ligand B: 0.041).

**12. Cl_mic:** Ligand B (-20.794) has a lower (better) microsomal clearance than Ligand A (29.361), indicating greater metabolic stability.

**13. t1/2:** Ligand B (-2.619) has a negative in vitro half-life, which is not physically possible and indicates a problem with the data. Ligand A (-10.931) also has a negative half-life. Both are problematic.

**14. Pgp:** Both ligands have very low P-gp efflux liability (Ligand A: 0.05, Ligand B: 0.006).

**15. Binding Affinity:** Ligand B (-8.2 kcal/mol) has a significantly better binding affinity than Ligand A (-7.4 kcal/mol). This is a >1 kcal/mol advantage, which is substantial.

**Overall Assessment:**

Despite the issues with Caco-2, solubility, and half-life for both, Ligand B is the more promising candidate. The significantly stronger binding affinity (-8.2 vs -7.4 kcal/mol) outweighs the slightly higher DILI risk and the poorer logP. The lower microsomal clearance of Ligand B is also a positive. The TPSA is higher, but the affinity difference is substantial. The negative values for Caco-2 and solubility are concerning and would need to be investigated further, but the binding affinity is the most critical factor here.

Output:
1
2025-04-17 05:00:04,038 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (346.471 and 346.431 Da) fall comfortably within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (53.76) is excellent, well below the 90 A^2 threshold for CNS targets. Ligand B (87.32) is higher but still acceptable, though less optimal.

**3. logP:** Ligand A (3.479) is within the optimal 1-3 range. Ligand B (1.887) is on the lower side, potentially impacting permeability.

**4. H-Bond Donors:** Ligand A (0) is good. Ligand B (2) is also acceptable.

**5. H-Bond Acceptors:** Ligand A (3) is good. Ligand B (4) is also acceptable.

**6. QED:** Both ligands (0.842 and 0.738) have good drug-like properties.

**7. DILI:** Ligand A (31.601) has a lower DILI risk than Ligand B (46.064), indicating a safer profile.

**8. BBB:** Ligand A (71.888) has a good BBB penetration percentile, exceeding the 70% threshold for CNS targets. Ligand B (57.774) is significantly lower, which is a major concern for a CNS target like DRD2.

**9. Caco-2 Permeability:** Both are negative, indicating poor permeability. However, the scale is not defined, so this is difficult to interpret.

**10. Aqueous Solubility:** Both are negative, indicating poor solubility. Again, the scale is not defined.

**11. hERG Inhibition:** Ligand A (0.704) has a lower hERG risk than Ligand B (0.242), which is preferable.

**12. Microsomal Clearance:** Ligand A (52.272) has lower clearance, suggesting better metabolic stability. Ligand B (64.248) has higher clearance.

**13. In vitro Half-Life:** Ligand A (30.377) has a reasonable half-life. Ligand B (-44.409) has a negative half-life, which is not possible and likely indicates an issue with the data or scale.

**14. P-gp Efflux:** Ligand A (0.65) has lower P-gp efflux, which is favorable for CNS penetration. Ligand B (0.09) has very low P-gp efflux, which is good.

**15. Binding Affinity:** Ligand B (-8.4 kcal/mol) has a significantly stronger binding affinity than Ligand A (-0.0 kcal/mol). This is a substantial advantage.

**Overall Assessment:**

While Ligand B boasts a much stronger binding affinity, its significantly lower BBB penetration (57.774% vs. 71.888% for A) is a critical drawback for a CNS target. The negative in vitro half-life is also highly concerning. Ligand A, although with weaker affinity, presents a more balanced profile with good BBB penetration, lower DILI risk, better metabolic stability, and a reasonable half-life. Given the GPCR-specific priorities, and the importance of CNS penetration for DRD2, Ligand A is the more promising candidate.

Output:
0
2025-04-17 05:00:04,038 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (354.451 and 352.454 Da) fall comfortably within the ideal 200-500 Da range.

**TPSA:** Ligand A (103.26) is higher than Ligand B (75.19). For CNS targets, TPSA < 90 is preferred, so Ligand B is better here.

**logP:** Ligand A (-0.113) is quite low, potentially hindering membrane permeability. Ligand B (2.67) is within the optimal 1-3 range. This is a significant advantage for Ligand B.

**H-Bond Donors/Acceptors:** Ligand A has 3 HBD and 6 HBA, while Ligand B has 1 HBD and 4 HBA. Both are within acceptable limits (<=5 HBD and <=10 HBA).

**QED:** Both ligands have good QED scores (0.501 and 0.657, respectively), indicating drug-like properties.

**DILI:** Ligand A (12.796) has a much lower DILI risk than Ligand B (46.297). This is a positive for Ligand A.

**BBB:** Ligand A (22.606) has a very poor BBB percentile, making CNS penetration unlikely. Ligand B (86.041) has an excellent BBB percentile, crucial for a DRD2 ligand. This is a major advantage for Ligand B.

**Caco-2 Permeability:** Both are negative, but Ligand B (-4.611) is less negative than Ligand A (-5.376), suggesting slightly better permeability.

**Aqueous Solubility:** Both have negative solubility values, indicating poor solubility. Ligand A (-0.131) is slightly better than Ligand B (-3.53).

**hERG:** Both ligands have low hERG inhibition liability (0.092 and 0.725, respectively).

**Microsomal Clearance:** Ligand A (-2.539) has a negative clearance, which is unusual and might indicate an issue with the calculation or a very stable compound. Ligand B (80.579) has a high clearance, suggesting rapid metabolism.

**In vitro Half-Life:** Ligand A (-3.67) has a negative half-life, which is also unusual. Ligand B (-3.033) has a negative half-life as well.

**P-gp Efflux:** Ligand A (0.014) has very low P-gp efflux liability, which is good. Ligand B (0.539) has moderate P-gp efflux.

**Binding Affinity:** Ligand B (-7.7 kcal/mol) has a slightly better binding affinity than Ligand A (-7.2 kcal/mol). While both are good, the 0.5 kcal/mol difference is noticeable.

**Overall Assessment:**

Ligand B is the stronger candidate. Its excellent BBB penetration, optimal logP, and slightly better binding affinity are crucial for a DRD2 ligand. While Ligand A has a lower DILI risk and better P-gp efflux, the poor BBB penetration and low logP are significant drawbacks that outweigh these benefits. The unusual negative values for clearance and half-life for both compounds are concerning and would require further investigation, but do not change the overall ranking.

Output:
1
2025-04-17 05:00:04,038 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (345.334 and 344.499 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (101.38) is borderline for CNS penetration, being above the preferred <90, but not drastically so. Ligand B (40.62) is excellent, well below the threshold. This favors Ligand B.

**3. logP:** Ligand A (1.201) is within the optimal range (1-3). Ligand B (4.104) is slightly high, potentially leading to solubility issues and off-target interactions. This favors Ligand A.

**4. H-Bond Donors:** Ligand A (2) is acceptable. Ligand B (0) is also acceptable, and potentially better for BBB penetration.

**5. H-Bond Acceptors:** Ligand A (6) is acceptable. Ligand B (2) is also acceptable.

**6. QED:** Both ligands (0.724 and 0.747) have good drug-likeness scores, exceeding the 0.5 threshold.

**7. DILI:** Ligand A (90.617) has a higher DILI risk than Ligand B (18.922). This is a significant drawback for Ligand A.

**8. BBB:** Ligand B (97.829) has excellent BBB penetration, a critical factor for a CNS target like DRD2. Ligand A (57.464) is considerably lower, making CNS exposure less likely. This strongly favors Ligand B.

**9. Caco-2:** Both are negative values, which is unusual. Assuming these are log values, they are similar and don't provide much differentiation.

**10. Solubility:** Both have negative solubility values, also unusual. Assuming these are logS values, they are similar and don't provide much differentiation.

**11. hERG:** Ligand A (0.199) has a slightly lower hERG risk than Ligand B (0.919), which is preferable.

**12. Cl_mic:** Ligand A (18.273) has a much lower microsomal clearance, indicating better metabolic stability, than Ligand B (70.301). This favors Ligand A.

**13. t1/2:** Ligand A (-22.712) has a negative half-life, which is nonsensical. Ligand B (8.894) has a reasonable in vitro half-life. This is a major issue for Ligand A.

**14. Pgp:** Ligand A (0.083) has lower P-gp efflux, which is beneficial for CNS penetration. Ligand B (0.611) has moderate P-gp efflux. This favors Ligand A.

**15. Binding Affinity:** Ligand B (-8.2 kcal/mol) has a slightly better binding affinity than Ligand A (-9.3 kcal/mol). While A is better, the difference isn't huge enough to overcome other issues.

**Overall Assessment:**

Ligand B is the stronger candidate. Its excellent BBB penetration, low DILI risk, and good binding affinity outweigh its slightly higher logP and Pgp efflux. Ligand A has concerning issues with its negative half-life, high DILI risk, and suboptimal BBB penetration. While its lower Cl_mic and Pgp efflux are positive, they are not enough to compensate for the significant drawbacks.

Output:
1
2025-04-17 05:00:04,038 - INFO - Reasoning:

Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (347.459 and 345.487 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (78.51) is better than Ligand B (43.86). For CNS targets, we want TPSA <= 90. Both are within this range, but A is closer to the upper limit, which might slightly hinder BBB penetration compared to B.

**3. logP:** Both ligands have acceptable logP values (1.197 and 2.052), falling within the optimal 1-3 range.

**4. H-Bond Donors:** Ligand A has 2 HBD, and Ligand B has 0. Both are within the acceptable limit of <=5.

**5. H-Bond Acceptors:** Both ligands have 3 HBA, which is well within the acceptable limit of <=10.

**6. QED:** Ligand A (0.805) has a significantly better QED score than Ligand B (0.581), indicating a more drug-like profile.

**7. DILI:** Ligand A (27.453) has a much lower DILI risk than Ligand B (13.649), suggesting it is less likely to cause liver injury.

**8. BBB:** This is crucial for a CNS target. Ligand B (78.519) has a substantially higher BBB percentile than Ligand A (45.909). This is a major advantage for Ligand B.

**9. Caco-2 Permeability:** Ligand A (-5.107) has a more negative Caco-2 value than Ligand B (-4.526), implying lower intestinal absorption.

**10. Aqueous Solubility:** Ligand A (-3.238) has a more negative solubility value than Ligand B (-1.782), suggesting lower aqueous solubility.

**11. hERG Inhibition:** Ligand A (0.066) has a lower hERG inhibition liability than Ligand B (0.525), which is favorable.

**12. Microsomal Clearance:** Ligand B (44.733) has a higher microsomal clearance than Ligand A (12.561), meaning it will be metabolized faster. This is a negative for Ligand B.

**13. In vitro Half-Life:** Ligand A (7.31) has a positive in vitro half-life, while Ligand B (-11.683) has a negative value, which is concerning.

**14. P-gp Efflux:** Ligand A (0.03) has a lower P-gp efflux liability than Ligand B (0.153), which is desirable for CNS penetration.

**15. Binding Affinity:** Ligand A (-8.2 kcal/mol) has a significantly stronger binding affinity than Ligand B (-7.1 kcal/mol). This 1.1 kcal/mol difference is substantial and can outweigh some of the ADME drawbacks.

**Overall Assessment:**

Ligand B excels in BBB penetration, which is paramount for a CNS-targeting GPCR like DRD2. However, it suffers from higher DILI risk, faster clearance, a negative in vitro half-life, and a weaker binding affinity. Ligand A has a superior drug-like profile (QED), lower DILI risk, better metabolic stability (lower Cl_mic, positive t1/2), lower P-gp efflux, and a *much* stronger binding affinity. While its BBB penetration is lower, the significantly improved binding affinity and ADME properties (especially metabolic stability) are likely to outweigh this disadvantage. The stronger binding affinity suggests a lower dose may be required, potentially mitigating the BBB concern.

Output:
1
2025-04-17 05:00:04,038 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B based on the provided guidelines, prioritizing GPCR-specific properties (BBB, logP, Pgp, TPSA, and affinity) for DRD2.

**Molecular Weight:** Both ligands (342.439 Da and 354.447 Da) fall within the ideal range of 200-500 Da.

**TPSA:** Ligand A (58.64) is excellent, well below the 90 A^2 threshold for CNS targets. Ligand B (106.94) is higher but still reasonable, though less optimal.

**logP:** Ligand A (1.488) is within the optimal 1-3 range. Ligand B (0.52) is slightly low, potentially hindering permeability.

**H-Bond Donors/Acceptors:** Ligand A (HBD=1, HBA=3) is favorable. Ligand B (HBD=3, HBA=5) is also acceptable, but slightly higher.

**QED:** Both ligands have similar QED values (0.608 and 0.56), indicating good drug-likeness.

**DILI:** Ligand A (15.626) has a much lower DILI risk than Ligand B (14.928), suggesting better hepatotoxicity potential.

**BBB:** Ligand A (52.811) has a better BBB percentile than Ligand B (41.256), which is crucial for a CNS target like DRD2. While both are below the desirable >70, A is significantly better.

**Caco-2 Permeability:** Ligand A (-4.738) has a worse Caco-2 permeability than Ligand B (-5.209).

**Aqueous Solubility:** Ligand A (-2.544) has better aqueous solubility than Ligand B (-0.432).

**hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.104 and 0.062).

**Microsomal Clearance:** Ligand A (12.824) has higher microsomal clearance than Ligand B (-7.539), indicating lower metabolic stability. This is a significant drawback for Ligand A.

**In vitro Half-Life:** Ligand B (-20.448) has a much longer in vitro half-life than Ligand A (3.509), which is preferable.

**P-gp Efflux:** Ligand A (0.046) has lower P-gp efflux liability than Ligand B (0.017), which is beneficial for CNS penetration.

**Binding Affinity:** Both ligands have very similar and strong binding affinities (-8.3 kcal/mol and -7.9 kcal/mol). The difference of 0.4 kcal/mol is not substantial enough to override other ADME considerations.

**Overall Assessment:**

Ligand A excels in TPSA, BBB, DILI, solubility and P-gp efflux. However, it suffers from higher microsomal clearance and a shorter half-life. Ligand B has better Caco-2 permeability and a significantly longer half-life, but has a higher DILI risk, lower BBB penetration, and higher P-gp efflux.

Given the CNS target (DRD2), BBB penetration is paramount. Ligand A has a significantly better BBB percentile. The longer half-life of Ligand B is attractive, but the lower BBB and higher DILI risk are concerning. The slight advantage in Caco-2 permeability is less important for a CNS drug. The similar binding affinities make ADME properties the deciding factor.

Output:
0
2025-04-17 05:00:04,038 - INFO - Reasoning:

Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (338.411 and 355.366 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (76.02) is significantly better than Ligand B (109.66). For CNS targets, we want TPSA <= 90, and A is comfortably within that range, while B is pushing the limit.

**3. logP:** Ligand A (1.027) is within the optimal range (1-3). Ligand B (-0.892) is slightly below 1, which *could* indicate permeability issues, although not drastically.

**4. H-Bond Donors:** Ligand A (2) and Ligand B (3) are both acceptable (<=5).

**5. H-Bond Acceptors:** Ligand A (4) and Ligand B (6) are both acceptable (<=10).

**6. QED:** Both ligands have good QED scores (A: 0.549, B: 0.635), indicating good drug-like properties.

**7. DILI:** Ligand A (49.477) has a lower DILI risk than Ligand B (58.976), which is preferable.

**8. BBB:** Ligand A (45.095) has a lower BBB penetration percentile than Ligand B (56.65). While both are below the desirable >70 for CNS targets, B is better.

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.092 and -5.014). This is unusual and suggests poor permeability. However, these values are on a scale where negative values are possible, and direct comparison is difficult without knowing the scale's specifics.

**10. Aqueous Solubility:** Both ligands have negative solubility values (-2.301 and -1.395), indicating poor aqueous solubility. Similar to Caco-2, the scale is unknown, making direct comparison difficult.

**11. hERG Inhibition:** Both ligands have very low hERG inhibition risk (A: 0.176, B: 0.198).

**12. Microsomal Clearance:** Ligand A (18.571) has a higher microsomal clearance than Ligand B (-4.369). This suggests Ligand B is more metabolically stable, which is desirable.

**13. In vitro Half-Life:** Ligand A (9.689) has a shorter in vitro half-life than Ligand B (-9.624). Again, B is preferable.

**14. P-gp Efflux:** Both ligands have low P-gp efflux liability (A: 0.065, B: 0.03). B is slightly better.

**15. Binding Affinity:** Ligand B (-7.9 kcal/mol) has a slightly better binding affinity than Ligand A (-7.5 kcal/mol). While the difference is not huge, it is >1.5 kcal/mol, which can outweigh some ADME drawbacks.

**Overall Assessment:**

Considering the GPCR-specific priorities, Ligand B emerges as the more promising candidate. While Ligand A has a better TPSA, Ligand B has superior BBB penetration, metabolic stability (lower Cl_mic, longer t1/2), P-gp efflux, and a slightly better binding affinity. The slightly lower logP of Ligand B is a minor concern, but the stronger binding and improved CNS penetration potential are more critical for a DRD2 ligand. The negative Caco-2 and solubility values are concerning for both, but the other factors favor Ligand B.

Output:
1
2025-04-17 05:00:04,039 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (348.531 and 354.491 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (49.41) is significantly better than Ligand B (67.87). For CNS targets, we want TPSA <= 90, and A is comfortably within this range, while B is approaching the upper limit.

**logP:** Ligand A (3.89) is slightly higher than Ligand B (2.116), both are within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Both have 1 HBD, which is good. Ligand A has 2 HBA, and Ligand B has 4 HBA, both are acceptable (<=10).

**QED:** Both ligands have similar QED values (0.723 and 0.61), indicating good drug-likeness.

**DILI:** Ligand A (12.679) has a much lower DILI risk than Ligand B (17.138), both are good (<40 is preferred).

**BBB:** Ligand A (78.015) has a good BBB penetration percentile, while Ligand B (88.29) is even better. Both are >70, which is desirable for CNS targets.

**Caco-2 Permeability:** Ligand A (-4.549) and Ligand B (-4.569) have similar, very poor Caco-2 permeability.

**Aqueous Solubility:** Ligand A (-4.278) and Ligand B (-1.578) have poor aqueous solubility. Ligand B is slightly better.

**hERG Inhibition:** Ligand A (0.657) has a slightly higher hERG inhibition risk than Ligand B (0.479), but both are acceptable.

**Microsomal Clearance:** Ligand A (83.792) has a higher microsomal clearance than Ligand B (58.358), indicating lower metabolic stability.

**In vitro Half-Life:** Ligand A (17.747 hours) has a longer half-life than Ligand B (12.155 hours).

**P-gp Efflux:** Ligand A (0.214) has lower P-gp efflux liability than Ligand B (0.065), which is favorable for CNS penetration.

**Binding Affinity:** Ligand B (-7.3 kcal/mol) has a slightly better binding affinity than Ligand A (-8.0 kcal/mol). However, the difference is relatively small.

**Overall Assessment:**

Ligand A excels in TPSA, DILI, P-gp efflux, and in vitro half-life. Ligand B has better BBB penetration and binding affinity, and slightly better solubility. However, the significantly better TPSA and lower P-gp efflux of Ligand A are crucial for CNS penetration, and its lower DILI risk is also a significant advantage. The binding affinity difference is not large enough to outweigh these factors.

Output:
1
2025-04-17 05:00:04,039 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (370.758 Da and 364.515 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (41.57) is significantly better than Ligand B (75.19). For CNS targets, we want TPSA <= 90, and ideally closer to 60. Ligand A is much closer to this ideal. Ligand B is higher and could present permeability issues.

**logP:** Ligand A (4.356) is slightly above the optimal 1-3 range, but still potentially acceptable. Ligand B (2.95) is within the optimal range. However, for a GPCR, a slightly higher logP can be tolerated if other properties are favorable.

**H-Bond Donors/Acceptors:** Both ligands have 1 HBD, which is good. Ligand A has 2 HBA, and Ligand B has 5 HBA. Both are acceptable, but fewer HBA are generally preferred.

**QED:** Both ligands have reasonable QED values (0.853 and 0.755), indicating good drug-like properties.

**DILI:** Ligand A has a significantly higher DILI risk (91.431) compared to Ligand B (37.456). This is a major concern for Ligand A.

**BBB:** Ligand A (83.211) has a better BBB penetration prediction than Ligand B (78.79). Both are reasonably good, but Ligand A is preferable for a CNS target.

**Caco-2 Permeability:** Ligand A (-4.256) has a very poor Caco-2 permeability, indicating poor intestinal absorption. Ligand B (-4.963) is also poor, but slightly better than A.

**Aqueous Solubility:** Both ligands have very poor aqueous solubility (-5.879 and -3.459). This could pose formulation challenges, but is less critical for CNS drugs that can cross the BBB.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.658 and 0.465).

**Microsomal Clearance:** Ligand A (90.186) has a higher microsomal clearance than Ligand B (57.419), meaning it's likely to be metabolized more quickly. Lower clearance is preferred.

**In vitro Half-Life:** Ligand A (48.036) has a longer half-life than Ligand B (8.378). This is a positive for Ligand A.

**P-gp Efflux:** Both ligands show low P-gp efflux liability (0.491 and 0.499).

**Binding Affinity:** Ligand A (-9.7 kcal/mol) has a significantly stronger binding affinity than Ligand B (-7.5 kcal/mol). This is a substantial advantage, potentially outweighing some of the ADME concerns. A difference of >1.5 kcal/mol is considered significant.

**Overall Assessment:**

Ligand A has a much stronger binding affinity and better BBB penetration, which are crucial for a CNS GPCR target. However, it suffers from a high DILI risk, poor Caco-2 permeability, and higher metabolic clearance. Ligand B has a better safety profile (lower DILI) and slightly better Caco-2, but significantly weaker binding affinity.

Given the importance of potency for GPCRs, and the fact that the affinity difference is substantial, I would prioritize Ligand A *despite* its drawbacks. The high DILI risk is a concern, but could potentially be mitigated through structural modifications during lead optimization. The poor Caco-2 is less critical for a CNS target.

Output:
1
2025-04-17 05:00:04,039 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (345.443 Da) is slightly lower, which could be advantageous for permeability. Ligand B (358.467 Da) is also good.

**TPSA:** Ligand A (87.3) is better than Ligand B (67.23). Both are below the 90 A^2 threshold for CNS targets, but A is closer to the ideal range.

**logP:** Both ligands have good logP values (A: 2.461, B: 2.777), falling within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A has 3 HBD and 3 HBA, while Ligand B has 1 HBD and 5 HBA. Both are within acceptable limits (<=5 HBD and <=10 HBA).

**QED:** Both ligands have good QED scores (A: 0.601, B: 0.914), indicating good drug-like properties. Ligand B is significantly better.

**DILI:** Ligand A (51.338) has a lower DILI risk than Ligand B (67.623), which is preferable.

**BBB:** Ligand A (76.774) has a better BBB percentile than Ligand B (64.87). This is a critical factor for CNS targets like DRD2.

**Caco-2 Permeability:** Ligand A (-4.793) has a worse Caco-2 permeability than Ligand B (-5.238), indicating lower intestinal absorption.

**Aqueous Solubility:** Both have similar, poor aqueous solubility (-4.059 and -3.728).

**hERG:** Both ligands have similar, low hERG inhibition liability (0.561 and 0.522).

**Microsomal Clearance:** Ligand B (24.986) has lower microsomal clearance than Ligand A (31.011), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand B (17.03) has a longer half-life than Ligand A (14.264).

**P-gp Efflux:** Both ligands have similar P-gp efflux liability (0.104 and 0.218).

**Binding Affinity:** Ligand B (-7.8 kcal/mol) has a significantly stronger binding affinity than Ligand A (-8.6 kcal/mol). This is a substantial advantage.

**Overall Assessment:**

Ligand B is superior due to its significantly stronger binding affinity (-7.8 vs -8.6 kcal/mol) and better metabolic stability (lower Cl_mic and longer t1/2). While Ligand A has a slightly better BBB score and lower DILI risk, the affinity difference is substantial enough to outweigh these minor advantages, especially for a GPCR target where potent binding is crucial. The QED score is also much better for Ligand B.

Output:
1
2025-04-17 05:00:04,039 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (348.49 and 356.39 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (75.27) is higher than Ligand B (58.2). For CNS targets, TPSA should be <=90, so both are acceptable, but B is better.

**logP:** Both ligands (2.58 and 3.01) are within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Both have 2 HBD and 3/2 HBA, respectively, which are within acceptable limits.

**QED:** Both ligands have good QED scores (0.708 and 0.789), indicating drug-like properties.

**DILI:** Ligand A (24.54) has a significantly lower DILI risk than Ligand B (30.05), which is a positive attribute.

**BBB:** This is a crucial parameter for CNS targets. Ligand B (85.96) has a much higher BBB penetration percentile than Ligand A (61.92). This is a major advantage for B.

**Caco-2 Permeability:** Ligand A (-4.932) has better Caco-2 permeability than Ligand B (-4.58), suggesting better intestinal absorption. However, for a CNS target, intestinal absorption is less critical than BBB penetration.

**Aqueous Solubility:** Ligand A (-2.736) has slightly better solubility than Ligand B (-3.831).

**hERG:** Ligand A (0.119) has a lower hERG inhibition liability than Ligand B (0.544), indicating a lower risk of cardiotoxicity.

**Microsomal Clearance:** Ligand A (9.56) has significantly lower microsomal clearance than Ligand B (43.41), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand B (-9.266) has a longer in vitro half-life than Ligand A (-7.097).

**P-gp Efflux:** Ligand A (0.186) has lower P-gp efflux liability than Ligand B (0.07), which is beneficial for CNS exposure.

**Binding Affinity:** Both ligands have excellent binding affinity (-8.8 and -8.9 kcal/mol), with a very slight edge to Ligand B. The affinity difference is minimal and unlikely to be decisive.

**Overall Assessment:**

Ligand B excels in BBB penetration and in vitro half-life, which are critical for a CNS-targeting GPCR ligand. While Ligand A has advantages in DILI, hERG, microsomal clearance, and Caco-2 permeability, the superior BBB penetration of Ligand B outweighs these benefits. The slight advantage in binding affinity for Ligand B further supports this conclusion.

Output:
1
2025-04-17 05:00:04,039 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B based on the provided guidelines, prioritizing GPCR-specific properties (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (354.338 and 356.256 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (130.4) is slightly above the optimal <90 for CNS targets, but still reasonable. Ligand B (87.61) is excellent, well below 90. This favors Ligand B.

**logP:** Ligand A (-0.39) is a bit low, potentially hindering permeability. Ligand B (2.424) is within the optimal 1-3 range. This strongly favors Ligand B.

**H-Bond Donors:** Ligand A (3) is acceptable. Ligand B (0) is also good, potentially improving permeability.

**H-Bond Acceptors:** Ligand A (6) is acceptable. Ligand B (7) is also within the reasonable limit of 10.

**QED:** Both ligands have good QED scores (0.572 and 0.76), indicating good drug-like properties.

**DILI:** Ligand A (58.395) is better than Ligand B (88.794), indicating a lower risk of drug-induced liver injury. This favors Ligand A.

**BBB:** Both ligands have good BBB penetration (73.517 and 76.347), exceeding the 70% threshold for CNS targets. Ligand B is slightly better.

**Caco-2 Permeability:** Ligand A (-5.433) is very poor, indicating very low intestinal absorption. Ligand B (-4.263) is also poor, but less so than Ligand A. This favors Ligand B.

**Aqueous Solubility:** Both ligands have poor aqueous solubility (-2.408 and -4.218). This is a concern for both, but less critical given the CNS target.

**hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.083 and 0.283).

**Microsomal Clearance:** Ligand A (-5.831) has a lower (better) microsomal clearance, suggesting greater metabolic stability. Ligand B (84.228) has high clearance. This favors Ligand A.

**In vitro Half-Life:** Ligand A (11.903) has a shorter half-life than Ligand B (-27.05). A negative value for half-life is unusual and suggests a very rapid degradation. This strongly favors Ligand A.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.01 and 0.194).

**Binding Affinity:** Both ligands have the same binding affinity (-8.4 kcal/mol), which is excellent.

**Overall Assessment:**

Ligand B excels in key GPCR properties like TPSA and logP. While its DILI score is higher and clearance is worse, the significantly better logP and TPSA, combined with comparable BBB and affinity, make it a more promising candidate. Ligand A has a better DILI and clearance profile, but its poor logP and Caco-2 permeability are significant drawbacks for a CNS drug. The negative half-life for Ligand B is concerning, but the overall profile is still better than Ligand A.

Output:
1
2025-04-17 05:00:04,039 - INFO - Batch 161 complete. Total preferences: 2576
2025-04-17 05:00:04,039 - INFO - Processing batch 162/512...
2025-04-17 05:00:45,111 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (340.423 and 351.487 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (53.35) is slightly higher than Ligand B (48). Both are below the 90 Angstroms threshold desirable for CNS targets, but B is better.

**3. logP:** Both ligands have good logP values (2.829 and 2.193), falling within the optimal 1-3 range.

**4. H-Bond Donors:** Both have 0 HBD, which is acceptable.

**5. H-Bond Acceptors:** Ligand A has 5 HBA, and Ligand B has 4. Both are within the acceptable limit of <=10.

**6. QED:** Both ligands have similar QED values (0.786 and 0.736), indicating good drug-like properties.

**7. DILI:** Ligand A (56.107) has a significantly higher DILI risk than Ligand B (13.532). This is a major concern for Ligand A.

**8. BBB:** Both ligands have excellent BBB penetration (90.074 and 83.443), exceeding the >70% threshold for CNS targets.

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 values, which is unusual and suggests a potential issue with the data or a very poor permeability. However, we'll proceed assuming this is a data artifact and focus on the other parameters.

**10. Aqueous Solubility:** Both ligands have negative solubility values, which is also unusual. Again, we will proceed with caution.

**11. hERG Inhibition:** Both ligands show low hERG inhibition risk (0.613 and 0.677).

**12. Microsomal Clearance:** Ligand A (68.749) has higher microsomal clearance than Ligand B (57.487), indicating lower metabolic stability.

**13. In vitro Half-Life:** Ligand B (22.115) has a significantly longer in vitro half-life than Ligand A (-14.686). This is a substantial advantage for Ligand B.

**14. P-gp Efflux:** Ligand A (0.641) shows slightly higher P-gp efflux than Ligand B (0.114). Lower P-gp efflux is preferred for CNS penetration, favoring Ligand B.

**15. Binding Affinity:** Ligand B (-7.0) has a significantly stronger binding affinity than Ligand A (-9.6). This is a crucial advantage, exceeding the 1.5 kcal/mol difference threshold.

**Overall Assessment:**

Ligand B is clearly the superior candidate. While both have good MW, logP, BBB, and hERG profiles, Ligand B excels in critical areas: significantly lower DILI risk, longer half-life, lower P-gp efflux, and, most importantly, a much stronger binding affinity. The negative solubility and Caco-2 values are concerning, but the other advantages of Ligand B outweigh these issues, especially given the strong affinity. Ligand A's high DILI risk and lower affinity are significant drawbacks.

Output:
1
2025-04-17 05:00:45,112 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight (MW):** Both ligands (352.435 and 356.463 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (90.98) is excellent, falling below the 90 threshold for CNS targets. Ligand B (99.1) is still reasonable but less optimal, being closer to the 140 threshold for oral absorption.

**3. logP:** Ligand A (0.51) is a bit low, potentially hindering permeation. Ligand B (0.288) is even lower, raising concerns about membrane permeability.

**4. H-Bond Donors (HBD):** Both ligands (A: 2, B: 3) are within the acceptable limit of <=5.

**5. H-Bond Acceptors (HBA):** Both ligands (A: 4, B: 5) are within the acceptable limit of <=10.

**6. QED:** Both ligands have good QED scores (A: 0.538, B: 0.675), indicating drug-like properties.

**7. DILI:** Ligand A (46.762) has a slightly higher DILI risk than Ligand B (30.322), but both are below the concerning threshold of 60.

**8. BBB:** This is a critical parameter for a CNS target like DRD2. Ligand A (70.88) has a good BBB percentile, exceeding the desirable >70 threshold. Ligand B (35.401) has a very poor BBB percentile, making CNS penetration unlikely.

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.035 and -4.987), which is unusual and suggests poor permeability. However, these values are on a logarithmic scale and may not be directly comparable.

**10. Aqueous Solubility:** Both ligands have negative solubility values (-1.657 and -1.091), indicating poor aqueous solubility.

**11. hERG Inhibition:** Both ligands have very low hERG inhibition risk (A: 0.476, B: 0.134).

**12. Microsomal Clearance:** Ligand A (-12.633) exhibits significantly lower (better) microsomal clearance than Ligand B (16.803), suggesting greater metabolic stability.

**13. In vitro Half-Life:** Ligand A (5.208 hours) has a shorter half-life than Ligand B (8.815 hours), but both are reasonable.

**14. P-gp Efflux:** Both ligands have very low P-gp efflux liability (A: 0.01, B: 0.018), which is favorable for CNS penetration.

**15. Binding Affinity:** Ligand A (-8.8 kcal/mol) has a significantly stronger binding affinity than Ligand B (0.0 kcal/mol). This is a substantial advantage.

**Overall Assessment:**

Ligand A is the superior candidate. While both have issues with solubility and Caco-2 permeability, Ligand A's significantly better BBB penetration, much stronger binding affinity, and improved metabolic stability outweigh its slightly higher DILI risk and lower logP. The strong binding affinity (-8.8 kcal/mol) is particularly compelling and could compensate for some of the ADME deficiencies. Ligand B's extremely poor BBB penetration is a deal-breaker for a CNS target.

Output:
1
2025-04-17 05:00:45,112 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (353.463 and 365.455 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (96.53) is slightly above the optimal <90 for CNS targets, but still reasonable. Ligand B (71.97) is well within the desired range. This favors Ligand B.

**3. logP:** Both ligands have good logP values (1.734 and 1.294), falling within the 1-3 range.

**4. H-Bond Donors:** Ligand A has 3 HBD, which is acceptable. Ligand B has 0, which is also acceptable.

**5. H-Bond Acceptors:** Ligand A has 4 HBA, acceptable. Ligand B has 6, also acceptable.

**6. QED:** Both ligands have good QED scores (0.607 and 0.76), indicating good drug-like properties.

**7. DILI:** Both ligands have acceptable DILI risk (33.307 and 43.932), below the 60 threshold.

**8. BBB:** Both ligands show good BBB penetration (70.415 and 78.868), exceeding the 70% threshold desirable for CNS targets. Ligand B is slightly better.

**9. Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and suggests poor permeability. However, these values are on a log scale and negative values are common.

**10. Aqueous Solubility:** Both have negative solubility values, which is also unusual.

**11. hERG:** Both ligands have very low hERG inhibition risk (0.18 and 0.162).

**12. Microsomal Clearance:** Ligand A has a higher Cl_mic (64.847) than Ligand B (28.34), indicating potentially lower metabolic stability. This favors Ligand B.

**13. In vitro Half-Life:** Ligand B has a significantly better (less negative) in vitro half-life (-1.988 hours) compared to Ligand A (-23.896 hours). This is a strong advantage for Ligand B.

**14. P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.024 and 0.121).

**15. Binding Affinity:** Both ligands have excellent binding affinity (-8.1 and -8.0 kcal/mol), with Ligand A being slightly better (-8.1 kcal/mol).

**Overall Assessment:**

While Ligand A has a slightly better binding affinity, Ligand B demonstrates superior ADME properties, particularly in terms of metabolic stability (lower Cl_mic) and half-life. The TPSA value is also more favorable for CNS penetration. Given the GPCR-specific priorities, the improved ADME profile of Ligand B outweighs the minor difference in binding affinity.

Output:
1
2025-04-17 05:00:45,113 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (348.451 and 361.427 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (82.5) is significantly better than Ligand B (120.91). For CNS targets, we want TPSA <= 90, and A is comfortably within this range, while B is pushing the limit.

**3. logP:** Both ligands have acceptable logP values (2.267 and 0.832, respectively), falling within the 1-3 range. Ligand A is slightly preferred.

**4. H-Bond Donors:** Both have 2 HBD, which is within the acceptable limit of <=5.

**5. H-Bond Acceptors:** Ligand A has 4 HBA, while Ligand B has 7. Both are within the acceptable limit of <=10, but A is better.

**6. QED:** Both ligands have reasonable QED values (0.879 and 0.749), indicating good drug-like properties.

**7. DILI:** Both have similar DILI risk (60.489 and 67.429), both are above the 60 threshold, indicating higher risk. This is a concern for both.

**8. BBB:** Ligand A (68.941) has a significantly better BBB percentile than Ligand B (48.003). For a CNS target like DRD2, >70 is desirable, but A is closer to that goal.

**9. Caco-2:** Both have negative Caco-2 values (-4.864 and -5.488), which is unusual and suggests poor permeability. This is a significant drawback for both.

**10. Solubility:** Both have negative solubility values (-3.247 and -2.946), indicating very poor aqueous solubility. This is a major issue for both.

**11. hERG:** Both have low hERG inhibition liability (0.34 and 0.475), which is good.

**12. Cl_mic:** Ligand A (26.08) has a higher microsomal clearance than Ligand B (15.127), meaning it's metabolized faster. This is less desirable.

**13. t1/2:** Ligand B (-10.011) has a negative in vitro half-life, which is not physically possible and indicates a problem with the data or the molecule. Ligand A (12.682) has a reasonable half-life.

**14. Pgp:** Both have very low Pgp efflux liability (0.04 and 0.027), which is excellent for CNS penetration.

**15. Binding Affinity:** Ligand A (-9.0) has a slightly better binding affinity than Ligand B (-8.4). While both are good, the 0.6 kcal/mol difference is noticeable.

**Overall Assessment:**

Considering the GPCR-specific priorities, Ligand A is the better candidate. Its superior TPSA, BBB penetration, and binding affinity outweigh its slightly higher Cl_mic. Ligand B's negative half-life is a major red flag, and its lower BBB penetration is a significant drawback for a CNS target. Both compounds have solubility and permeability issues, but these might be addressed with formulation strategies. The DILI risk is concerning for both, but can be investigated further.

Output:
1
2025-04-17 05:00:45,113 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (354.439 and 338.411 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (96.45) is slightly above the optimal <90 for CNS targets, but still reasonable. Ligand B (83.12) is well within the desired range.

**logP:** Both ligands (2.368 and 2.603) are within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A (2 HBD, 6 HBA) and Ligand B (3 HBD, 3 HBA) both have acceptable numbers of H-bond donors and acceptors, well below the thresholds of 5 and 10, respectively.

**QED:** Both ligands have good QED scores (0.75 and 0.783), indicating good drug-like properties.

**DILI:** Ligand A (80.535) has a higher DILI risk than Ligand B (59.325). While both are above the preferred <40, Ligand B is significantly better.

**BBB:** This is a critical parameter for a CNS target like DRD2. Ligand B (65.801) has a considerably better BBB percentile than Ligand A (49.205). This is a major advantage for Ligand B.

**Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and suggests poor permeability. However, the scale is not defined, so it's difficult to interpret.

**Aqueous Solubility:** Both have negative solubility values, also unusual and suggesting poor solubility. Again, the scale is undefined.

**hERG:** Both ligands have very low hERG inhibition liability (0.123 and 0.354), which is excellent.

**Microsomal Clearance:** Ligand A (24.718) has a higher microsomal clearance than Ligand B (15.646), suggesting lower metabolic stability.

**In vitro Half-Life:** Ligand B (51.506) has a significantly longer in vitro half-life than Ligand A (-11.611). This is a substantial advantage.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.309 and 0.019), which is good for CNS penetration.

**Binding Affinity:** Both ligands have the same binding affinity (-9.5 kcal/mol), which is excellent and strong.

**Overall Assessment:**

While both ligands have excellent binding affinity and acceptable physicochemical properties, Ligand B is the superior candidate due to its significantly better BBB penetration (65.801 vs 49.205), lower DILI risk (59.325 vs 80.535), and longer in vitro half-life (51.506 vs -11.611). The lower microsomal clearance of Ligand B also contributes to its improved profile. The negative values for Caco-2 and solubility are concerning for both, but the other advantages of Ligand B outweigh these concerns.



Output:
1
2025-04-17 05:00:45,113 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (361.47 and 345.36 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (80.2) is excellent for CNS penetration, being well below 90. Ligand B (124.69) is higher, but still potentially acceptable, though less optimal.

**logP:** Ligand A (2.878) is within the optimal 1-3 range. Ligand B (0.566) is quite low, potentially hindering membrane permeability and CNS penetration.

**H-Bond Donors/Acceptors:** Ligand A (2 HBD, 4 HBA) is well within acceptable limits. Ligand B (4 HBD, 6 HBA) is also acceptable, though slightly higher.

**QED:** Both ligands have reasonable QED values (0.83 and 0.628), indicating good drug-like properties.

**DILI:** Both ligands have acceptable DILI risk (68.28 and 56.73), below the 60 threshold.

**BBB:** This is a critical parameter for a CNS target like DRD2. Ligand A has a BBB percentile of 54.09, which is moderate but not ideal. Ligand B has a very low BBB percentile of 12.06, making CNS penetration a significant concern.

**Caco-2 Permeability:** Ligand A (-4.839) has poor predicted Caco-2 permeability. Ligand B (-5.863) is even worse.

**Aqueous Solubility:** Ligand A (-3.704) has poor predicted solubility. Ligand B (-2.327) is also poor.

**hERG Inhibition:** Both ligands show very low hERG inhibition risk (0.314 and 0.095).

**Microsomal Clearance:** Ligand A (15.454) has moderate clearance, while Ligand B (-3.496) has negative clearance, which is unusual and suggests high metabolic stability.

**In vitro Half-Life:** Ligand A (70.761) has a good in vitro half-life. Ligand B (-13.568) has a negative half-life, which is not possible and indicates a problem with the prediction.

**P-gp Efflux:** Ligand A (0.17) shows low P-gp efflux, which is favorable for CNS penetration. Ligand B (0.011) also shows very low P-gp efflux.

**Binding Affinity:** Both ligands have excellent binding affinities (-9.5 and -8.9 kcal/mol). The difference of 0.6 kcal/mol is not substantial enough to override other significant differences.

**Overall Assessment:**

Ligand A is better despite the poor Caco-2 and solubility. The primary concern for DRD2 is CNS penetration. While Ligand A's BBB is only moderate, Ligand B's is extremely low, making it unlikely to reach the target in the brain. Ligand A also has a more reasonable half-life prediction. The slightly better logP of Ligand A also supports better permeability.

Output:
1
2025-04-17 05:00:45,113 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B based on the provided guidelines, prioritizing GPCR-specific properties (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (346.43) is slightly lower, which could be advantageous for permeability.

**TPSA:** Ligand A (78.87) is significantly better than Ligand B (103.79). For a CNS target like DRD2, TPSA < 90 is preferred, and Ligand A comfortably meets this, while Ligand B is close to the upper limit.

**logP:** Ligand A (1.504) is within the optimal range (1-3), while Ligand B (0.444) is slightly below 1. This lower logP for Ligand B could hinder its ability to cross cell membranes, including the BBB.

**H-Bond Donors/Acceptors:** Ligand A (HBD=2, HBA=4) and Ligand B (HBD=3, HBA=7) both fall within acceptable limits.

**QED:** Both ligands have similar QED values (A: 0.816, B: 0.713), indicating good drug-like properties.

**DILI:** Ligand A (21.753) has a much lower DILI risk than Ligand B (71.694). This is a significant advantage for Ligand A.

**BBB:** Ligand A (51.183) has a better BBB percentile than Ligand B (36.487), although both are not ideal (>70 is desirable). However, given the CNS target, Ligand A's higher BBB score is a considerable benefit.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.336 and -5.146), which is unusual and suggests poor permeability. This is a concern for both, but the values are very similar.

**Aqueous Solubility:** Both ligands have negative solubility values (-1.257 and -1.851), indicating poor solubility. This could pose formulation challenges.

**hERG Inhibition:** Ligand A (0.068) has a much lower hERG inhibition risk than Ligand B (0.224), which is a crucial safety consideration.

**Microsomal Clearance:** Ligand A (-7.21) has a lower (better) microsomal clearance than Ligand B (-13.794), indicating greater metabolic stability.

**In vitro Half-Life:** Ligand A (1.842) has a shorter half-life than Ligand B (17.557). This is a drawback for Ligand A, as a longer half-life is generally preferred.

**P-gp Efflux:** Ligand A (0.008) has a much lower P-gp efflux liability than Ligand B (0.021), meaning it's less likely to be pumped out of the brain, improving CNS exposure.

**Binding Affinity:** Ligand B (-7.9) has a significantly stronger binding affinity than Ligand A (-0.0). This is a major advantage for Ligand B, and could potentially outweigh some of its ADME drawbacks.

**Overall Assessment:**

While Ligand B boasts a superior binding affinity, Ligand A demonstrates a much more favorable ADME profile, particularly regarding CNS penetration (BBB, P-gp), safety (DILI, hERG), and metabolic stability (Cl_mic). The significantly better TPSA and logP of Ligand A also support its potential for CNS drug development. The weaker binding affinity of Ligand A is a concern, but the substantial improvements in other critical parameters make it a more promising candidate overall. The negative Caco-2 and solubility values are concerning for both, and would need to be addressed through formulation strategies or further chemical modifications.

Output:
0
2025-04-17 05:00:45,114 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (367.475 and 370.519 Da) fall within the ideal range of 200-500 Da.

**TPSA:** Ligand A (106.45) is slightly above the preferred <90 for CNS targets, while Ligand B (84.3) is well within the range. This favors Ligand B.

**logP:** Both ligands have good logP values (2.194 and 1.682), falling within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A has 0 HBD and 5 HBA, while Ligand B has 1 HBD and 6 HBA. Both are within acceptable limits (<=5 HBD and <=10 HBA).

**QED:** Ligand B (0.824) has a significantly higher QED score than Ligand A (0.422), indicating better overall drug-likeness.

**DILI:** Both ligands have similar and acceptable DILI risk (34.548 and 35.479 percentile).

**BBB:** Ligand B (75.107 percentile) has a substantially better BBB score than Ligand A (51.415 percentile). This is a critical advantage for a CNS target like DRD2.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values, which is unusual and problematic. It suggests poor intestinal absorption. However, for a CNS target, this is less critical than BBB penetration.

**Aqueous Solubility:** Both ligands have negative solubility values, indicating poor solubility. This is a concern for formulation and bioavailability.

**hERG Inhibition:** Ligand A (0.071) has a slightly lower hERG risk than Ligand B (0.395), which is preferable.

**Microsomal Clearance:** Ligand B (1.163 mL/min/kg) has significantly lower microsomal clearance than Ligand A (32.852 mL/min/kg), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand B (22.937 hours) has a much longer in vitro half-life than Ligand A (-27.204 hours - a negative value is concerning).

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.03 and 0.088), which is good for CNS exposure.

**Binding Affinity:** Ligand B (-8.6 kcal/mol) has a significantly stronger binding affinity than Ligand A (-6.3 kcal/mol). This difference of 2.3 kcal/mol is substantial and can outweigh minor ADME drawbacks.

**Overall Assessment:**

Ligand B is the stronger candidate. While both have issues with solubility and Caco-2 permeability, Ligand B excels in the most important parameters for a CNS-targeting GPCR: BBB penetration, binding affinity, metabolic stability (lower Cl_mic and longer t1/2), and QED. The higher affinity of Ligand B is a significant advantage.



Output:
1
2025-04-17 05:00:45,114 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (367.833 and 348.491 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (78.95) is better than Ligand B (47.1). Both are below the 90 A^2 threshold desirable for CNS targets, but Ligand B is significantly lower, which is favorable.

**logP:** Ligand A (1.291) is within the optimal 1-3 range. Ligand B (0.482) is slightly below 1, which *could* indicate permeability issues, but isn't a dealbreaker.

**H-Bond Donors/Acceptors:** Ligand A has 1 HBD and 4 HBA, while Ligand B has 0 HBD and 4 HBA. Both are within acceptable limits (<=5 HBD and <=10 HBA).

**QED:** Ligand A (0.813) has a better QED score than Ligand B (0.64), indicating a more drug-like profile.

**DILI:** Ligand B (3.296) has a *much* lower DILI risk than Ligand A (76.89). This is a significant advantage for Ligand B.

**BBB:** Ligand B (90.074) has a significantly better BBB penetration percentile than Ligand A (70.299). This is crucial for a CNS target like DRD2.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.483 and -4.912), which is unusual and suggests poor permeability. It's difficult to interpret these values without knowing the scale.

**Aqueous Solubility:** Both ligands have negative solubility values (-3.17 and -0.576), which is also unusual and suggests poor solubility.

**hERG Inhibition:** Ligand A (0.273) has a lower hERG inhibition risk than Ligand B (0.621), which is preferable.

**Microsomal Clearance:** Ligand B (21.551) has lower microsomal clearance than Ligand A (27.408), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand B (-11.213) has a longer in vitro half-life than Ligand A (-10.2), which is desirable.

**P-gp Efflux:** Ligand A (0.142) has lower P-gp efflux than Ligand B (0.01), which is favorable for CNS penetration.

**Binding Affinity:** Ligand B (-7.9) has a slightly better binding affinity than Ligand A (-8.6). While both are excellent, the difference is minor.

**Overall Assessment:**

Ligand B is the stronger candidate. While Ligand A has a slightly better affinity and lower P-gp efflux, Ligand B excels in critical areas for a CNS GPCR target: significantly better BBB penetration, much lower DILI risk, and better metabolic stability (lower Cl_mic and longer t1/2). The TPSA is also more favorable for CNS penetration. The slightly lower logP of Ligand B is a minor concern, but outweighed by its other advantages. The negative Caco-2 and solubility values are concerning for both, but may be artifacts of the prediction method.

Output:
1
2025-04-17 05:00:45,114 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (345.443 and 344.415 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (73.74) is slightly higher than Ligand B (67.67). Both are below the 90 A^2 threshold for CNS targets, which is good.

**3. logP:** Ligand A (1.234) and Ligand B (0.925) are both within the optimal 1-3 range.

**4. H-Bond Donors:** Ligand A has 1 HBD, while Ligand B has 0. Both are acceptable (<=5).

**5. H-Bond Acceptors:** Ligand A has 4 HBA, and Ligand B has 5. Both are within the acceptable limit of <=10.

**6. QED:** Ligand A (0.871) has a slightly better QED score than Ligand B (0.765), indicating a more drug-like profile. Both are above the 0.5 threshold.

**7. DILI:** Ligand B (46.064) has a significantly lower DILI risk than Ligand A (19.426), which is a major advantage.

**8. BBB:** Ligand B (83.637) has a much higher BBB penetration percentile than Ligand A (55.487). This is *critical* for a CNS target like DRD2.

**9. Caco-2 Permeability:** Ligand A (-4.803) and Ligand B (-4.391) both have negative values, which is unusual and suggests poor permeability. However, the scale isn't specified, so it's hard to interpret.

**10. Aqueous Solubility:** Ligand A (-0.991) and Ligand B (-2.155) both have negative solubility values, indicating poor solubility.

**11. hERG Inhibition:** Ligand A (0.225) and Ligand B (0.378) have low hERG inhibition liability, which is good.

**12. Microsomal Clearance:** Ligand B (60.929) has a higher microsomal clearance than Ligand A (13.321), meaning it's cleared more quickly. Ligand A is preferable here.

**13. In vitro Half-Life:** Ligand A (-10.098) has a longer in vitro half-life than Ligand B (-22.568). This is a significant advantage.

**14. P-gp Efflux:** Ligand A (0.036) has lower P-gp efflux liability than Ligand B (0.087), which is favorable for CNS penetration.

**15. Binding Affinity:** Ligand B (-9.0 kcal/mol) has a slightly better binding affinity than Ligand A (-8.1 kcal/mol). This is a substantial advantage, potentially outweighing some ADME drawbacks.

**Overall Assessment:**

While Ligand A has better metabolic stability (lower Cl_mic, longer t1/2) and lower P-gp efflux, Ligand B excels in crucial areas for a CNS-targeting GPCR ligand: significantly better BBB penetration (83.6% vs 55.5%), lower DILI risk, and slightly better binding affinity. The difference in binding affinity (-9.0 vs -8.1) is substantial enough to be a key deciding factor. The poor solubility and permeability of both are concerning, but can potentially be addressed with formulation strategies.

Output:
1
2025-04-17 05:00:45,114 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (351.403 and 357.495 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (115.03) is higher than Ligand B (78.95). For CNS targets, TPSA should be <= 90, so Ligand B is significantly better here.

**logP:** Ligand A (-1.299) is lower than the optimal 1-3 range, potentially hindering permeability. Ligand B (1.269) is within the optimal range. This favors Ligand B.

**H-Bond Donors/Acceptors:** Ligand A has 4 HBD and 6 HBA, while Ligand B has 1 HBD and 5 HBA. Both are within acceptable limits (<=5 HBD and <=10 HBA).

**QED:** Both ligands have good QED scores (0.538 and 0.596, respectively), indicating good drug-like properties.

**DILI:** Ligand A (23.226) has a much lower DILI risk than Ligand B (13.067), which is a significant advantage.

**BBB:** This is crucial for a CNS target like DRD2. Ligand A (11.4) has a very poor BBB percentile, while Ligand B (57.154) is much better, although still not ideal (>70 is desirable).

**Caco-2 Permeability:** Both have negative values (-5.554 and -4.707), which is unusual and difficult to interpret without knowing the scale. However, the values are similar.

**Aqueous Solubility:** Both ligands have very poor aqueous solubility (-0.445 and -0.676). This could pose formulation challenges.

**hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.027 and 0.242).

**Microsomal Clearance:** Ligand A (-9.167) has a much lower (better) microsomal clearance than Ligand B (66.347), indicating better metabolic stability.

**In vitro Half-Life:** Ligand A (-4.359) has a negative half-life, which is not possible. Ligand B (-19.385) also has a negative half-life, indicating an issue with the data.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.006).

**Binding Affinity:** Both ligands have the same binding affinity (-7.1 kcal/mol), which is excellent.

**Overall Assessment:**

Ligand B is superior in terms of TPSA, logP, and crucially, BBB penetration. However, Ligand A has a much lower DILI risk and better metabolic stability (lower Cl_mic). The negative half-life values are concerning for both, suggesting potential data errors. Given the importance of BBB penetration for a CNS target, and the acceptable logP of Ligand B, it is the more promising candidate despite the higher DILI risk. The strong binding affinity is equal for both, so this doesn't differentiate them.

Output:
1
2025-04-17 05:00:45,115 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (358.379 and 351.837 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (103.18) is higher than the preferred <90 for CNS targets, but not drastically so. Ligand B (56.99) is excellent, well below the threshold.

**3. logP:** Ligand A (1.494) is within the optimal 1-3 range. Ligand B (3.857) is at the higher end of optimal, but still acceptable.

**4. H-Bond Donors:** Ligand A (1) is good. Ligand B (0) is also good.

**5. H-Bond Acceptors:** Ligand A (8) is within the acceptable limit of <=10. Ligand B (3) is also good.

**6. QED:** Both ligands (0.709 and 0.621) have good drug-likeness scores, exceeding the 0.5 threshold.

**7. DILI:** Ligand A (98.72) has a very high DILI risk, which is a major concern. Ligand B (60.45) is elevated, but significantly lower than Ligand A.

**8. BBB:** Ligand A (71.772) has a decent BBB penetration score, but could be better. Ligand B (52.889) is lower, indicating poorer predicted brain penetration.

**9. Caco-2:** Both ligands have negative Caco-2 values (-4.843 and -4.738), which is unusual and difficult to interpret without more context. This suggests poor permeability.

**10. Solubility:** Both ligands have negative solubility values (-3.409 and -5.181), which is also unusual and suggests poor solubility.

**11. hERG:** Both ligands have low hERG inhibition liability (0.272 and 0.562), which is positive.

**12. Cl_mic:** Ligand A (74.853) has moderate clearance. Ligand B (98.629) has higher clearance, indicating lower metabolic stability.

**13. t1/2:** Ligand A (20.867) has a longer half-life than Ligand B (11.337), which is preferable.

**14. Pgp:** Both ligands have low Pgp efflux liability (0.401 and 0.363), which is good for CNS penetration.

**15. Binding Affinity:** Ligand B (-7.9 kcal/mol) has a significantly stronger binding affinity than Ligand A (-9.5 kcal/mol). The difference of 1.6 kcal/mol is substantial and can outweigh some ADME drawbacks.

**Overall Assessment:**

Despite the unusual Caco-2 and solubility values for both, Ligand B is the more promising candidate. While its BBB is lower than Ligand A, its significantly higher binding affinity (-7.9 vs -9.5 kcal/mol) is a major advantage for a GPCR target. The DILI risk is also considerably lower for Ligand B. The lower half-life and higher clearance of Ligand B are drawbacks, but potentially addressable through structural modifications. Ligand A's extremely high DILI risk is a significant red flag.

Output:
1
2025-04-17 05:00:45,115 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (396.843 and 368.434 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (84.5) is better than Ligand B (75.63). Both are below the 90 A^2 threshold for CNS targets, which is excellent.

**logP:** Ligand A (2.735) is optimal, while Ligand B (1.379) is a bit low, potentially hindering permeability.

**H-Bond Donors:** Ligand A (2) is good, while Ligand B (0) is also acceptable.

**H-Bond Acceptors:** Ligand A (4) is good, while Ligand B (6) is also acceptable.

**QED:** Both ligands have similar QED values (0.801 and 0.785), indicating good drug-likeness.

**DILI:** Ligand A (69.523) has a slightly higher DILI risk than Ligand B (54.634), but both are below the concerning threshold of 60.

**BBB:** Ligand B (75.843) has a better BBB penetration percentile than Ligand A (70.648), though both are above the desirable 70% threshold for CNS targets.

**Caco-2 Permeability:** Ligand A (-4.947) has worse Caco-2 permeability than Ligand B (-4.573), indicating potentially lower intestinal absorption.

**Aqueous Solubility:** Ligand A (-3.94) has worse solubility than Ligand B (-1.702).

**hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.27 and 0.142).

**Microsomal Clearance:** Ligand A (-4.03) has significantly lower microsomal clearance than Ligand B (34.793), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (26.488) has a longer half-life than Ligand B (-7.806).

**P-gp Efflux:** Ligand A (0.174) has lower P-gp efflux than Ligand B (0.036), meaning better CNS exposure.

**Binding Affinity:** Ligand B (-7.5 kcal/mol) has a slightly better binding affinity than Ligand A (-8.8 kcal/mol).

**Overall Assessment:**

Ligand B has a better BBB score, Caco-2 permeability, solubility, and binding affinity. However, Ligand A has better metabolic stability (lower Cl_mic, longer half-life) and lower P-gp efflux. Considering the GPCR-specific priorities, BBB and affinity are crucial. While Ligand A has a slightly better affinity, the difference isn't substantial enough to outweigh the advantages of Ligand B's superior BBB penetration and solubility. The lower P-gp efflux of Ligand A is also a plus, but the better overall profile of Ligand B makes it more promising.

Output:
1
2025-04-17 05:00:45,115 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (354.357 and 350.503 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (93.21) is slightly above the preferred <90 for CNS targets, but still reasonable. Ligand B (58.64) is well within the optimal range. This favors Ligand B.

**3. logP:** Both ligands have good logP values (1.902 and 2.452), falling within the 1-3 range.

**4. H-Bond Donors:** Ligand A (2) and Ligand B (1) are both within the acceptable limit of <=5. Ligand B is slightly better.

**5. H-Bond Acceptors:** Ligand A (5) and Ligand B (3) are both within the acceptable limit of <=10. Ligand B is slightly better.

**6. QED:** Both ligands have acceptable QED values (0.761 and 0.616), indicating good drug-like properties.

**7. DILI:** Ligand A (54.362) has a moderate DILI risk, while Ligand B (9.19) has a very low risk. This significantly favors Ligand B.

**8. BBB:** Ligand A (89.725) has a good BBB penetration percentile, while Ligand B (71.074) is also good, but less so. This favors Ligand A.

**9. Caco-2:** Both have negative values which is unusual. Assuming these are logP values, they are both poor.

**10. Solubility:** Both ligands have poor solubility (-2.541 and -3.393). This is a concern for both, but slightly worse for Ligand B.

**11. hERG:** Both ligands have low hERG inhibition risk (0.104 and 0.45).

**12. Cl_mic:** Ligand A (21.546) has a lower microsomal clearance than Ligand B (72.332), indicating better metabolic stability. This favors Ligand A.

**13. t1/2:** Ligand B (12.218) has a longer in vitro half-life than Ligand A (7.179). This favors Ligand B.

**14. Pgp:** Both ligands have very low P-gp efflux liability (0.037 and 0.043).

**15. Binding Affinity:** Ligand A (-8.6 kcal/mol) has a significantly stronger binding affinity than Ligand B (-6.9 kcal/mol). This is a major advantage for Ligand A. The 1.7 kcal/mol difference is substantial and can outweigh some ADME drawbacks.

**Overall Assessment:**

Considering the GPCR-specific priorities, the stronger binding affinity of Ligand A is a critical factor. While Ligand B has better TPSA, DILI, and half-life, the substantial difference in binding affinity (-8.6 vs -6.9 kcal/mol) is likely to be decisive. The slightly higher TPSA of Ligand A is not a major concern, and its metabolic stability is reasonable. The BBB penetration of Ligand A is also quite good.

Output:
1
2025-04-17 05:00:45,115 - INFO - Reasoning:

Let's analyze Ligand A and Ligand B against the provided guidelines, prioritizing GPCR-specific properties (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (360.445) is slightly lower, which is generally favorable for permeability.

**TPSA:** Ligand A (67.43) is significantly better than Ligand B (80.32). For CNS targets, TPSA should be <=90, and A is closer to the optimal <=60 range. B is pushing the upper limit.

**logP:** Both ligands have good logP values (A: 3.622, B: 2.272) falling within the 1-3 range. A is slightly higher, which could potentially lead to off-target effects, but is still acceptable.

**H-Bond Donors/Acceptors:** Both have acceptable HBD counts (2). Ligand B has a higher HBA count (5 vs 3), which *could* slightly hinder permeability, but isn't a major concern.

**QED:** Both ligands have similar, good QED values (A: 0.787, B: 0.752), indicating good drug-like properties.

**DILI:** Ligand A (33.656) has a much lower DILI risk than Ligand B (67.507). This is a significant advantage for A.

**BBB:** This is a critical parameter for a CNS target like DRD2. Ligand A (89.453) has a significantly better BBB percentile than Ligand B (51.881). A is very close to the desirable >70 threshold.

**Caco-2 Permeability:** Ligand A (-4.222) shows better Caco-2 permeability than Ligand B (-5.372), indicating better intestinal absorption.

**Aqueous Solubility:** Ligand A (-4.059) shows better aqueous solubility than Ligand B (-3.296).

**hERG:** Both ligands have low hERG inhibition liability (A: 0.614, B: 0.241), which is good.

**Microsomal Clearance:** Ligand A (61.17) has a higher microsomal clearance than Ligand B (27.126), suggesting lower metabolic stability. This is a drawback for A.

**In vitro Half-Life:** Ligand B (41.049) has a longer in vitro half-life than Ligand A (-11.102), which is a significant advantage for B.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (A: 0.055, B: 0.056), which is excellent for CNS penetration.

**Binding Affinity:** Ligand B (-7.6) has a slightly better binding affinity than Ligand A (-7.9). However, the difference is small (0.3 kcal/mol) and may not be decisive.

**Overall Assessment:**

Ligand A is superior due to its significantly better TPSA, BBB penetration, DILI risk, Caco-2 permeability, and aqueous solubility. While Ligand A has a higher microsomal clearance and a slightly weaker binding affinity, the improvements in ADME properties, particularly BBB, are crucial for a CNS-targeting drug. The small difference in binding affinity is unlikely to outweigh the substantial advantages in pharmacokinetic properties.

Output:
1
2025-04-17 05:00:45,115 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (422.308 Da) is slightly higher, but acceptable. Ligand B (358.804 Da) is also good.

**TPSA:** Both ligands have TPSA values below the 90 A^2 threshold desirable for CNS targets. Ligand A (82.19 A^2) is better than Ligand B (76.95 A^2).

**logP:** Both ligands have logP values within the optimal range (1-3). Ligand A (2.231) is slightly better than Ligand B (3.608), as higher logP can sometimes lead to off-target effects.

**H-Bond Donors/Acceptors:** Ligand A (HBD=1, HBA=5) is better than Ligand B (HBD=3, HBA=3). Fewer H-bonds generally improve membrane permeability.

**QED:** Both ligands have similar QED values (0.7 and 0.714), indicating good drug-like properties.

**DILI:** Ligand A (92.672) has a higher DILI risk than Ligand B (76.076). This is a significant negative for Ligand A.

**BBB:** Both ligands have acceptable BBB penetration (Ligand A: 60.372, Ligand B: 65.374). However, for a CNS target like DRD2, we ideally want >70. Ligand B is slightly better.

**Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and suggests poor permeability. Ligand A (-5.041) is slightly better than Ligand B (-4.569), but both are concerning.

**Aqueous Solubility:** Both ligands have negative solubility values, which is also unusual and suggests poor solubility. Ligand A (-4.859) is slightly better than Ligand B (-5.817).

**hERG Inhibition:** Both ligands have low hERG inhibition risk (Ligand A: 0.823, Ligand B: 0.62).

**Microsomal Clearance:** Ligand B (4.519 mL/min/kg) has significantly lower microsomal clearance than Ligand A (73.414 mL/min/kg), indicating better metabolic stability.

**In vitro Half-Life:** Ligand B (56.781 hours) has a much longer in vitro half-life than Ligand A (-41.71 hours). This is a major advantage for Ligand B.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (Ligand A: 0.209, Ligand B: 0.157).

**Binding Affinity:** Ligand B (-10.0 kcal/mol) has a significantly stronger binding affinity than Ligand A (-8.3 kcal/mol). This is a crucial factor, as a >1.5 kcal/mol advantage can outweigh other drawbacks.

**Overall Assessment:**

Ligand B is the better candidate. While both have issues with Caco-2 and solubility, Ligand B has a much stronger binding affinity, better metabolic stability (lower Cl_mic, longer t1/2), lower DILI risk, and slightly better BBB penetration. The significantly improved affinity outweighs the slightly higher logP and the comparable BBB values.

Output:
1
2025-04-17 05:00:45,116 - INFO - Batch 162 complete. Total preferences: 2592
2025-04-17 05:00:45,116 - INFO - Processing batch 163/512...
2025-04-17 05:01:33,643 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (350.459 Da and 344.455 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (98.66) is slightly above the optimal <90 for CNS targets, but still reasonable. Ligand B (53.76) is excellent, well below 90.

**logP:** Both ligands have good logP values (2.122 and 3.016), falling within the 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A has 4 HBD and 4 HBA, which is acceptable. Ligand B has 0 HBD and 3 HBA, also acceptable.

**QED:** Both ligands have good QED scores (0.605 and 0.715), indicating good drug-like properties.

**DILI:** Both ligands have low DILI risk (20.008 and 23.885), below the 40 threshold.

**BBB:** This is a critical parameter for a CNS target like DRD2. Ligand B (67.778) is significantly better than Ligand A (21.404). A value >70 is desirable, but 67.778 is a substantial advantage.

**Caco-2 Permeability:** Ligand A (-5.455) has poor Caco-2 permeability, suggesting poor intestinal absorption. Ligand B (-4.638) is also poor, but slightly better than A.

**Aqueous Solubility:** Both ligands have poor aqueous solubility (-2.724 and -2.249). This could pose formulation challenges.

**hERG Inhibition:** Both ligands show low hERG inhibition risk (0.424 and 0.466).

**Microsomal Clearance:** Ligand A (37.968) has lower microsomal clearance than Ligand B (64.199), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand B (21.462) has a longer in vitro half-life than Ligand A (-19.606), which is a positive attribute.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.077 and 0.371), which is favorable for CNS penetration.

**Binding Affinity:** Ligand B (-7.9 kcal/mol) has a slightly better binding affinity than Ligand A (-8.6 kcal/mol). While both are excellent, the difference is significant.

**Overall Assessment:**

Ligand B is the stronger candidate. Its superior BBB penetration (67.778 vs 21.404) is a major advantage for a CNS target. It also has a better half-life and slightly better binding affinity. While Ligand A has better metabolic stability, the BBB and half-life advantages of Ligand B outweigh this. The poor solubility of both compounds is a concern, but can potentially be addressed with formulation strategies.

Output:
1
2025-04-17 05:01:33,643 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (342.37 Da) is slightly lower, which could be beneficial for permeability. Ligand B (364.408 Da) is also good.

**TPSA:** Ligand A (63.45) is slightly above the optimal <90 for CNS targets, but still reasonable. Ligand B (58.64) is excellent, well below 90.

**logP:** Ligand A (3.989) is at the upper end of the optimal range (1-3), potentially raising concerns about solubility and off-target effects. Ligand B (2.295) is ideal.

**H-Bond Donors/Acceptors:** Ligand A has 0 HBD and 3 HBA, which is good. Ligand B has 1 HBD and 3 HBA, also good. Both are within acceptable limits.

**QED:** Both ligands have good QED values (A: 0.623, B: 0.787), indicating drug-like properties. Ligand B is slightly better.

**DILI:** Ligand A (70.841) has a higher DILI risk than Ligand B (16.789). This is a significant advantage for Ligand B.

**BBB:** Ligand A (83.249) has good BBB penetration, but Ligand B (96.084) is *excellent* and much more desirable for a CNS target like DRD2.

**Caco-2 Permeability:** Both have negative Caco-2 values (-4.541 and -4.363). This is unusual and requires further investigation, but doesn't immediately disqualify either.

**Aqueous Solubility:** Both have negative solubility values (-5.313 and -2.197). Again, unusual and requires further investigation. Ligand B is better.

**hERG Inhibition:** Both ligands show low hERG inhibition risk (A: 0.812, B: 0.661).

**Microsomal Clearance:** Ligand A (83.779) has higher microsomal clearance than Ligand B (14.801), suggesting lower metabolic stability. Ligand B is significantly better.

**In vitro Half-Life:** Ligand A (21.38 hours) has a reasonable half-life, but Ligand B (-11.593 hours) has a negative half-life, which is not possible and indicates a problem with the data or the molecule.

**P-gp Efflux:** Both have low P-gp efflux (A: 0.52, B: 0.033). Ligand B is significantly better.

**Binding Affinity:** Ligand A (-9.5 kcal/mol) has a slightly better binding affinity than Ligand B (-8.2 kcal/mol). However, the difference is not substantial enough to outweigh the other significant advantages of Ligand B.

**Overall:**

Ligand B is clearly superior. It has a better logP, significantly lower DILI risk, *much* better BBB penetration, lower microsomal clearance, and lower P-gp efflux. While Ligand A has a slightly better binding affinity, the other ADME properties of Ligand B are far more favorable for CNS drug development, especially considering the importance of BBB penetration for DRD2. The negative half-life for Ligand B is concerning and needs to be investigated, but the other advantages are strong enough to still favor it over Ligand A.

Output:
1
2025-04-17 05:01:33,644 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (358.383 and 360.885 Da) fall within the ideal range of 200-500 Da.

**TPSA:** Ligand A (125.79) is slightly above the optimal <90 for CNS targets, but still reasonable. Ligand B (59.47) is excellent, well below 90.

**logP:** Ligand A (0.903) is a bit low, potentially hindering permeation. Ligand B (4.64) is high, potentially causing solubility issues or off-target effects.

**H-Bond Donors/Acceptors:** Ligand A (HBD=3, HBA=8) is within acceptable limits. Ligand B (HBD=1, HBA=3) is also good.

**QED:** Both ligands have good QED scores (A: 0.636, B: 0.863), indicating drug-like properties.

**DILI:** Ligand A has a very high DILI risk (98.061), which is a major red flag. Ligand B has a much lower, acceptable DILI risk (31.989).

**BBB:** Ligand A has a poor BBB penetration score (26.638), making it unlikely to reach the target in the CNS. Ligand B has a very good BBB score (75.998), which is crucial for a DRD2 ligand.

**Caco-2 Permeability:** Both show poor Caco-2 permeability (-5.428 and -4.782).

**Aqueous Solubility:** Both have poor aqueous solubility (-3.599 and -3.565).

**hERG Inhibition:** Both ligands show low hERG inhibition risk (0.107 and 0.767).

**Microsomal Clearance:** Ligand A has a very low (good) microsomal clearance (-28.833). Ligand B has a higher clearance (8.92), indicating faster metabolism.

**In vitro Half-Life:** Ligand B has a very long in vitro half-life (98.682), while ligand A has a short half-life (1.278).

**P-gp Efflux:** Ligand A shows very low P-gp efflux (0.043), which is favorable for CNS penetration. Ligand B shows moderate P-gp efflux (0.543).

**Binding Affinity:** Both ligands have excellent binding affinities (-9.9 and -8.7 kcal/mol). The difference of 1.2 kcal/mol is significant, favoring Ligand A, but not enough to overcome its other serious flaws.

**Overall Assessment:**

Ligand A has a strong binding affinity and low P-gp efflux, but its extremely high DILI risk and poor BBB penetration are deal-breakers. The low logP and short half-life are also concerning.

Ligand B has a good BBB score, acceptable DILI, and a very long half-life. While its logP is high and Caco-2 permeability is low, these can potentially be addressed with further optimization. The moderate P-gp efflux is also manageable.

Considering the GPCR-specific priorities, especially BBB penetration for a CNS target like DRD2, Ligand B is the more promising candidate despite the higher logP.

Output:
1
2025-04-17 05:01:33,644 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (348.418 Da) is slightly lower, which can be advantageous for permeability.

**TPSA:** Ligand A (72.63) is significantly better than Ligand B (36.36) for CNS penetration, falling well below the 90 A^2 threshold. Ligand B is also good, but A is superior.

**logP:** Ligand A (2.215) is optimal, while Ligand B (4.634) is pushing the upper limit. High logP can lead to solubility issues and off-target interactions.

**H-Bond Donors/Acceptors:** Both ligands have 1 HBD and 4 HBA, which are within acceptable limits.

**QED:** Ligand A (0.85) has a better QED score than Ligand B (0.625), indicating a more drug-like profile.

**DILI:** Ligand A (20.706) has a lower DILI risk than Ligand B (16.634), which is preferable.

**BBB:** Ligand A (89.027) has a significantly better BBB penetration percentile than Ligand B (68.166). This is *crucial* for a CNS target like DRD2.

**Caco-2 Permeability:** Ligand A (-4.489) has worse Caco-2 permeability than Ligand B (-5.246). However, given the CNS target, this is less critical than BBB.

**Aqueous Solubility:** Ligand A (-2.414) has better aqueous solubility than Ligand B (-3.815).

**hERG:** Both ligands have relatively low hERG inhibition risk (0.711 and 0.979, respectively).

**Microsomal Clearance:** Ligand A (38.281) has lower microsomal clearance than Ligand B (121.584), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (-1.39) has a shorter half-life than Ligand B (29.059). This is a drawback for Ligand A, but potentially mitigated by its lower clearance.

**P-gp Efflux:** Ligand A (0.098) has significantly lower P-gp efflux liability than Ligand B (0.829), which is highly desirable for CNS penetration.

**Binding Affinity:** Ligand B (-7.1) has a slightly better binding affinity than Ligand A (-8.9). However, the difference is not substantial enough to outweigh the significant ADME advantages of Ligand A.

**Overall:** Ligand A is the stronger candidate. It excels in critical GPCR/CNS properties: TPSA, BBB, P-gp efflux, and has better solubility, DILI risk, and metabolic stability. While Ligand B has slightly better affinity and half-life, the ADME profile of Ligand A is far superior and more likely to translate to *in vivo* efficacy for a CNS target.

Output:
0
2025-04-17 05:01:33,644 - INFO - Reasoning:

Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (381.259 and 359.352 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (67.43) is excellent for CNS penetration, being well below 90. Ligand B (96.01) is still reasonable, but less optimal.

**logP:** Ligand A (4.149) is a bit high, potentially leading to solubility issues or off-target interactions. Ligand B (1.413) is on the lower side, which could impact permeability.

**H-Bond Donors/Acceptors:** Ligand A (2 HBD, 3 HBA) and Ligand B (3 HBD, 5 HBA) both have acceptable counts.

**QED:** Both ligands have similar QED values (0.79 and 0.64), indicating good drug-likeness.

**DILI:** Ligand A (80.109) has a higher DILI risk than Ligand B (54.052). This is a significant concern.

**BBB:** Ligand B (76.076) has a substantially better BBB percentile than Ligand A (54.556). This is *critical* for a CNS target like DRD2.

**Caco-2 Permeability:** Ligand A (-4.779) has poor Caco-2 permeability, while Ligand B (-5.234) also has poor permeability. Both are unfavorable.

**Aqueous Solubility:** Ligand A (-5.303) has very poor solubility, likely due to its high logP. Ligand B (-2.985) is better, but still problematic.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.462 and 0.275).

**Microsomal Clearance:** Ligand B (47.194) has a higher microsomal clearance than Ligand A (32.152), suggesting faster metabolism.

**In vitro Half-Life:** Ligand A (56.371) has a longer in vitro half-life than Ligand B (-3.336).

**P-gp Efflux:** Ligand A (0.294) has lower P-gp efflux, which is favorable for CNS penetration. Ligand B (0.028) has even lower P-gp efflux, which is even more favorable.

**Binding Affinity:** Ligand B (-7.9 kcal/mol) has a significantly stronger binding affinity than Ligand A (-9.5 kcal/mol). This is a substantial advantage.

**Overall Assessment:**

While Ligand A has a slightly better half-life and lower clearance, its high logP, poor solubility, higher DILI risk, and significantly lower BBB penetration are major drawbacks. Ligand B, despite its slightly higher clearance, excels in the most critical areas for a CNS GPCR target: strong binding affinity, good BBB penetration, and lower DILI risk. The lower P-gp efflux for Ligand B is also a significant advantage. The slightly lower logP of Ligand B is also preferable.

Output:
1
2025-04-17 05:01:33,644 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (384.303 Da) is slightly higher than Ligand B (352.341 Da), but both are acceptable.

**TPSA:** Ligand A (38.77) is excellent for CNS penetration, well below the 90 A^2 threshold. Ligand B (80.37) is higher, but still potentially acceptable, though less ideal.

**logP:** Ligand A (4.385) is slightly high, potentially leading to solubility issues or off-target effects. Ligand B (2.006) is within the optimal range (1-3).

**H-Bond Donors/Acceptors:** Ligand A (0 HBD, 4 HBA) and Ligand B (1 HBD, 5 HBA) both have reasonable numbers of H-bond donors and acceptors, staying within the guidelines.

**QED:** Both ligands have good QED scores (Ligand A: 0.725, Ligand B: 0.893), indicating drug-like properties.

**DILI:** Ligand A (34.587) has a lower DILI risk than Ligand B (60.14), which is approaching a higher risk category.

**BBB:** Ligand A (74.37) has a significantly better BBB penetration percentile than Ligand B (55.797). This is a critical factor for a CNS target like DRD2.

**Caco-2 Permeability:** Ligand A (-4.571) and Ligand B (-5.054) both have negative Caco-2 values, which is unusual and suggests poor permeability. This is a concern for both.

**Aqueous Solubility:** Ligand A (-4.865) and Ligand B (-2.146) both have poor aqueous solubility.

**hERG:** Both ligands have low hERG inhibition risk (Ligand A: 0.595, Ligand B: 0.47).

**Microsomal Clearance:** Ligand A (64.262) has a higher microsomal clearance than Ligand B (-15.749). This means Ligand B is likely more metabolically stable.

**In vitro Half-Life:** Ligand B (7.187 hours) has a longer in vitro half-life than Ligand A (2.657 hours).

**P-gp Efflux:** Both ligands have low P-gp efflux liability (Ligand A: 0.224, Ligand B: 0.036), which is good for CNS exposure.

**Binding Affinity:** Ligand B (-8.2 kcal/mol) has a slightly better binding affinity than Ligand A (-7.6 kcal/mol). While both are good, the 0.6 kcal/mol difference is notable.

**Overall Assessment:**

Ligand B has a better binding affinity and metabolic stability (lower Cl_mic, longer t1/2). However, Ligand A has a significantly better BBB penetration score and lower DILI risk. The high logP of Ligand A is a concern, but the superior BBB penetration is crucial for a CNS target. The poor Caco-2 and solubility for both are problematic, but can potentially be addressed through formulation strategies. Considering the GPCR-specific priorities, BBB penetration is paramount.

Output:
1
2025-04-17 05:01:33,645 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (356.413 and 353.419 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (60.85) is excellent, well below the 90 A^2 threshold for CNS targets. Ligand B (124.6) is higher, but still potentially acceptable, though less ideal.

**logP:** Ligand A (1.952) is optimal (1-3). Ligand B (-0.399) is below 1, which could hinder permeation.

**H-Bond Donors/Acceptors:** Ligand A (HBD=1, HBA=3) is favorable. Ligand B (HBD=4, HBA=5) is also acceptable, though slightly higher.

**QED:** Ligand A (0.766) is very good, indicating strong drug-likeness. Ligand B (0.464) is lower, suggesting a less optimal drug-like profile.

**DILI:** Ligand A (16.208) has a low DILI risk. Ligand B (22.993) is slightly higher, but still relatively low.

**BBB:** Ligand A (89.608) has excellent BBB penetration potential. Ligand B (46.762) is significantly lower, a major concern for a CNS target like DRD2.

**Caco-2 Permeability:** Ligand A (-4.636) is poor. Ligand B (-5.788) is also poor.

**Aqueous Solubility:** Both ligands have poor aqueous solubility (-1.977 and -1.653 respectively). This could pose formulation challenges.

**hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.537 and 0.038 respectively).

**Microsomal Clearance:** Ligand A (1.543) has lower clearance, indicating better metabolic stability. Ligand B (-24.383) has very high clearance, a significant drawback.

**In vitro Half-Life:** Ligand A (-15.77) has a very long half-life (negative value indicates longer than the scale). Ligand B (-4.112) has a shorter half-life.

**P-gp Efflux:** Ligand A (0.095) has low P-gp efflux, which is good for CNS penetration. Ligand B (0.005) has even lower efflux, which is also favorable.

**Binding Affinity:** Both ligands have strong binding affinities (-7.9 and -8.6 kcal/mol). Ligand B is slightly better (-8.6 vs -7.9), but the difference is not huge.

**Overall Assessment:**

Ligand A is significantly better due to its superior BBB penetration (89.6% vs 46.8%), better metabolic stability (lower Cl_mic), longer half-life, and better QED score. While both have poor solubility and Caco-2 permeability, the CNS target necessitates excellent BBB penetration, which Ligand A possesses. The slightly better affinity of Ligand B is outweighed by its poor BBB and metabolic stability.

Output:
1
2025-04-17 05:01:33,645 - INFO - Reasoning:

Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (345.447 and 343.471 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (81.59) is slightly above the optimal <90 for CNS targets, but still reasonable. Ligand B (64.41) is excellent, well below 90.

**3. logP:** Ligand A (0.954) is a bit low, potentially hindering permeability. Ligand B (2.732) is within the optimal 1-3 range.

**4. H-Bond Donors:** Ligand A (2) and Ligand B (0) are both acceptable, below the threshold of 5.

**5. H-Bond Acceptors:** Ligand A (5) and Ligand B (3) are both acceptable, below the threshold of 10.

**6. QED:** Both ligands have reasonable QED values (0.853 and 0.737), indicating good drug-like properties.

**7. DILI:** Ligand A (8.647) has a very low DILI risk, excellent. Ligand B (17.41) is also low, but higher than A.

**8. BBB:** Ligand A (68.321) is below the desirable >70 for CNS targets, which is a significant drawback. Ligand B (81.543) is much better, exceeding 70 and indicating good potential for brain penetration.

**9. Caco-2:** Both have negative values, which is unusual. Assuming these are percentile scores, lower is worse. Ligand A (-5.05) is worse than Ligand B (-4.542).

**10. Solubility:** Both have negative values, which is also unusual. Assuming these are percentile scores, lower is worse. Ligand A (-0.813) is worse than Ligand B (-3.527).

**11. hERG:** Both ligands have very low hERG risk (0.343 and 0.406).

**12. Cl_mic:** Ligand A (-35.351) has a much lower (better) microsomal clearance than Ligand B (49.441), suggesting greater metabolic stability.

**13. t1/2:** Ligand A (9.787) has a longer half-life than Ligand B (-4.651).

**14. Pgp:** Both ligands have very low Pgp efflux liability (0.004 and 0.09).

**15. Binding Affinity:** Ligand B (-7.4) has a significantly stronger binding affinity than Ligand A (-9.7). This is a substantial advantage.

**Overall Assessment:**

While Ligand A has better metabolic stability (lower Cl_mic, longer t1/2) and lower DILI risk, its poor BBB penetration is a critical flaw for a CNS target like DRD2. Ligand B, despite slightly higher DILI and lower metabolic stability, has a significantly better BBB score and a much stronger binding affinity. The stronger binding affinity can potentially compensate for the slightly less favorable ADME properties. Given the GPCR-specific prioritization of BBB and affinity, Ligand B is the more promising candidate.

Output:
1
2025-04-17 05:01:33,645 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (354.45 & 343.47 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (79.31) is better than Ligand B (81.99), both are below the 90 A^2 threshold for CNS targets, which is good.

**logP:** Ligand A (0.117) is quite low, potentially hindering permeation. Ligand B (3.551) is within the optimal 1-3 range. This is a significant advantage for Ligand B.

**H-Bond Donors/Acceptors:** Ligand A (1 HBD, 5 HBA) and Ligand B (2 HBD, 3 HBA) both have reasonable numbers, well within the guidelines.

**QED:** Both ligands have acceptable QED values (0.759 and 0.681, respectively), indicating good drug-like properties.

**DILI:** Both ligands have elevated DILI risk (13.84 & 56.19), but Ligand A is significantly lower.

**BBB:** Ligand A (55.87) is better than Ligand B (41.53) in terms of BBB penetration, which is critical for a CNS target like DRD2.

**Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and requires further investigation. It's difficult to interpret these values without knowing the scale.

**Aqueous Solubility:** Both have negative solubility values, which is also unusual and requires further investigation.

**hERG:** Ligand A (0.304) has a much lower hERG inhibition liability than Ligand B (0.686), making it safer from a cardiotoxicity perspective.

**Microsomal Clearance:** Ligand B (58.99) has a higher microsomal clearance than Ligand A (25.63), suggesting faster metabolism and potentially lower exposure.

**In vitro Half-Life:** Ligand B (36.14) has a significantly longer half-life than Ligand A (2.70), which is desirable.

**P-gp Efflux:** Ligand A (0.028) has much lower P-gp efflux liability than Ligand B (0.226), which is crucial for CNS penetration.

**Binding Affinity:** Ligand B (-7.8 kcal/mol) has a 0.7 kcal/mol stronger binding affinity than Ligand A (-7.1 kcal/mol). This is a substantial difference and a major advantage for Ligand B.

**Overall Assessment:**

While Ligand A has better BBB penetration and lower DILI/hERG/P-gp, its very low logP is a major concern. The low logP suggests poor membrane permeability, potentially negating the benefit of good BBB prediction. Ligand B, despite having a slightly lower BBB score, has a much more favorable logP, better metabolic stability (lower Cl_mic), and a significantly stronger binding affinity. The stronger binding affinity can often compensate for minor ADME deficiencies. The longer half-life is also a plus.

Considering the GPCR-specific priorities, the stronger binding affinity and better logP of Ligand B outweigh the slightly lower BBB score and higher P-gp efflux.

Output:
1
2025-04-17 05:01:33,645 - INFO - Reasoning:

Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight (MW):** Both ligands (363.439 Da and 372.487 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Both ligands have TPSA values (86.88 and 84.94) below the 90 A^2 threshold desirable for CNS targets, which is excellent.

**3. logP:** Ligand A (2.414) is within the optimal range (1-3). Ligand B (0.815) is slightly below, which *could* hinder permeation, but isn't a major concern.

**4. H-Bond Donors (HBD):** Both ligands have 1 HBD, well within the acceptable limit of 5.

**5. H-Bond Acceptors (HBA):** Both ligands have 6 HBA, also within the acceptable limit of 10.

**6. QED:** Both ligands have QED values above 0.7, indicating good drug-like properties.

**7. DILI:** Ligand A (52.385) has a slightly higher DILI risk than Ligand B (46.452), but both are below the concerning threshold of 60.

**8. BBB:** This is a critical parameter for a CNS target like DRD2. Ligand A (66.615) has a significantly better BBB percentile than Ligand B (46.452). This is a major advantage for Ligand A.

**9. Caco-2 Permeability:** Both have negative values, which is unusual. However, the magnitude is similar, and we'll consider this a neutral point.

**10. Aqueous Solubility:** Both have negative values, indicating poor solubility. This could pose formulation challenges, but is not a deal-breaker.

**11. hERG Inhibition:** Both ligands show very low hERG inhibition risk (0.081 and 0.121).

**12. Microsomal Clearance (Cl_mic):** Ligand A (-14.177) has a *much* lower (better) Cl_mic than Ligand B (68.342), suggesting significantly improved metabolic stability.

**13. In vitro Half-Life:** Ligand A (-2.617) has a negative half-life, which is unusual and likely indicates a very stable compound. Ligand B (-5.167) is also negative and similarly stable.

**14. P-gp Efflux:** Ligand A (0.025) has very low P-gp efflux liability, which is excellent for CNS penetration. Ligand B (0.039) is also low, but slightly higher.

**15. Binding Affinity:** Ligand A (-8.3 kcal/mol) has a substantially stronger binding affinity than Ligand B (-0.0 kcal/mol). This is a decisive advantage.

**Overall Assessment:**

Ligand A is clearly superior. While both ligands have acceptable physicochemical properties, Ligand A excels in the most critical areas for a CNS-targeting GPCR: **BBB penetration, metabolic stability (Cl_mic), and, most importantly, binding affinity.** The significantly stronger binding affinity of Ligand A (-8.3 kcal/mol vs -0.0 kcal/mol) is a major advantage that can compensate for any minor drawbacks in solubility. The improved BBB and lower Cl_mic further solidify its position as the more promising candidate.



Output:
1
2025-04-17 05:01:33,646 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (341.419 and 349.475 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (100.27) is slightly above the optimal <90 for CNS targets, but still reasonable. Ligand B (72.88) is excellent, well below 90, suggesting better CNS penetration potential.

**3. logP:** Both ligands (1.004 and 0.908) are within the optimal 1-3 range.

**4. H-Bond Donors:** Both have 2 HBD, which is acceptable.

**5. H-Bond Acceptors:** Ligand A has 7 HBA, acceptable. Ligand B has 4 HBA, also acceptable and potentially slightly better.

**6. QED:** Both ligands have good QED scores (0.808 and 0.74), indicating drug-like properties.

**7. DILI:** Both have low DILI risk (51.648 and 5.235), both are good. Ligand B is significantly better here.

**8. BBB:** Both ligands have the same BBB penetration (57.425), which is not ideal (>70 is desirable), but not a major differentiating factor here.

**9. Caco-2 Permeability:** Ligand A (-5.472) has poor Caco-2 permeability, which is a concern. Ligand B (-4.957) is slightly better, but still not great.

**10. Aqueous Solubility:** Ligand A (-2.415) has poor aqueous solubility, while Ligand B (-1.367) is better, but still not ideal.

**11. hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.249 and 0.155).

**12. Microsomal Clearance:** Ligand A (29.506) has higher microsomal clearance than Ligand B (-6.515). This suggests Ligand B is more metabolically stable.

**13. In vitro Half-Life:** Ligand B (-12.002) has a significantly longer in vitro half-life than Ligand A (5.132), which is a major advantage.

**14. P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.009 and 0.008).

**15. Binding Affinity:** Both ligands have very similar and strong binding affinities (-8.6 and -8.4 kcal/mol). The difference is less than 1.5 kcal/mol and therefore not a deciding factor.

**Overall Assessment:**

While both ligands have good binding affinity and acceptable physicochemical properties, Ligand B is superior. It has a lower TPSA, better DILI score, better metabolic stability (lower Cl_mic, longer t1/2), and slightly better solubility. Ligand A's poor Caco-2 permeability is a significant drawback. Given the GPCR-specific priorities, the improved ADME profile of Ligand B makes it the more promising drug candidate.

Output:
1
2025-04-17 05:01:33,646 - INFO - Okay, let's analyze these two ligands for their potential as DRD2 drug candidates. DRD2 is a GPCR in the CNS, so BBB penetration, logP, Pgp efflux, TPSA, and binding affinity are key.

**Ligand A:** [385.247, 84.63, 3.474, 2, 5, 0.392, 54.75, 47.15, -4.924, -4.344, 0.943, 25.597, 25.476, 0.8, -8.4]
**Ligand B:** [365.583, 40.54, 4.374, 1, 3, 0.661, 18.108, 48.701, -4.77, -4.816, 0.949, 105.351, 39.152, 0.912, -7.2]

Here's a breakdown of each property:

1. **MW:** Both are within the ideal range (200-500 Da). A (385.247) is slightly higher than B (365.583).
2. **TPSA:** A (84.63) is better than B (40.54) for CNS penetration, being closer to the <90 target. B is excellent.
3. **logP:** Both are good (between 1-3), with A (3.474) being slightly more optimal than B (4.374), which is approaching the upper limit.
4. **HBD:** A (2) and B (1) are both acceptable, well under the limit of 5.
5. **HBA:** A (5) and B (3) are both acceptable, well under the limit of 10.
6. **QED:** A (0.392) is quite poor, indicating a less drug-like profile. B (0.661) is better, exceeding the 0.5 threshold.
7. **DILI:** A (54.75) is moderate, but acceptable. B (18.108) is very good, indicating a low risk of liver injury.
8. **BBB:** Both are reasonably good, but B (48.701) is slightly better than A (47.15). Both are below the desirable >70 for CNS targets, but not dramatically so.
9. **Caco-2:** Both are negative, indicating poor permeability.
10. **Solubility:** Both are negative, indicating poor solubility.
11. **hERG:** Both are very low (0.943 and 0.949), indicating minimal hERG inhibition risk.
12. **Cl_mic:** A (25.597) is significantly better than B (105.351), suggesting better metabolic stability.
13. **t1/2:** A (25.476) is better than B (39.152), indicating a longer half-life.
14. **Pgp:** Both are low (0.8 and 0.912), suggesting minimal P-gp efflux.
15. **Binding Affinity:** A (-8.4) is significantly stronger than B (-7.2), a difference of 1.2 kcal/mol. This is a substantial advantage.

**Overall Assessment:**

Ligand A has a significantly better binding affinity (-8.4 kcal/mol vs -7.2 kcal/mol). This is a major advantage, potentially outweighing some of its weaknesses. It also has better metabolic stability (lower Cl_mic) and a longer half-life. However, its QED is poor, and its TPSA is higher than ideal, and BBB is lower.

Ligand B has a better QED, lower DILI risk, and slightly better BBB penetration. However, it suffers from significantly worse metabolic stability (higher Cl_mic) and a weaker binding affinity.

Given the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity), and the substantial difference in binding affinity, **Ligand A is the more promising candidate**. The strong binding affinity is likely to be a critical factor for efficacy, and the other parameters, while not ideal, are not disqualifying. Further optimization could focus on improving the QED and TPSA of Ligand A.

1
2025-04-17 05:01:33,646 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B based on the provided guidelines, prioritizing GPCR-specific properties (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (356.482) is slightly lower, which could be advantageous for permeability, but both are acceptable.

**TPSA:** Ligand A (78.43) is excellent for CNS penetration, well below the 90 A^2 threshold. Ligand B (111.06) is higher, but still potentially acceptable, though less ideal.

**logP:** Both ligands have good logP values (A: 2.348, B: 2.466), falling within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A (HBD=3, HBA=3) is better balanced than Ligand B (HBD=1, HBA=5). While both are within acceptable limits, excessive HBA can sometimes hinder permeability.

**QED:** Ligand A (0.526) has a better QED score than Ligand B (0.376), indicating a more drug-like profile.

**DILI:** Ligand B (75.301) has a higher DILI risk than Ligand A (8.53), which is a significant concern.

**BBB:** Ligand A (76.464) has a substantially better BBB penetration percentile than Ligand B (41.722). This is *crucial* for a CNS target like DRD2.

**Caco-2 Permeability:** Both have negative Caco-2 values which is unusual and suggests a potential issue with the data or the compounds. However, we must proceed with the available information.

**Aqueous Solubility:** Both have negative solubility values, which is also unusual.

**hERG Inhibition:** Both ligands have low hERG inhibition liability (A: 0.465, B: 0.261), which is good.

**Microsomal Clearance:** Ligand B (6.711) has a lower microsomal clearance than Ligand A (36.064), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (-11.024) has a negative half-life, which is impossible. Ligand B (-14.786) also has a negative half-life. This is a major data quality issue.

**P-gp Efflux:** Ligand A (0.105) has lower P-gp efflux liability than Ligand B (0.26), which is favorable for CNS exposure.

**Binding Affinity:** Both ligands have very similar binding affinities (A: -7.4 kcal/mol, B: -7.3 kcal/mol). The difference is negligible.

**Overall Assessment:**

Ligand A is clearly the superior candidate. Its significantly better BBB penetration, lower DILI risk, better QED score, and lower P-gp efflux outweigh the slightly higher microsomal clearance and the questionable half-life data. The negative half-life values for both compounds raise concerns about the data quality, but the other factors strongly favor Ligand A. The TPSA is also much better for CNS penetration.

Output:
1
2025-04-17 05:01:33,646 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 drug candidates, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (362.392 Da) is slightly higher than Ligand B (351.447 Da), but both are acceptable.

**TPSA:** Ligand A (58.64) is excellent for CNS penetration, well below the 90 A^2 threshold. Ligand B (98.74) is higher, but still potentially acceptable, though less ideal.

**logP:** Ligand A (1.758) is optimal. Ligand B (0.03) is very low, potentially hindering membrane permeability and CNS entry.

**H-Bond Donors/Acceptors:** Ligand A (HBD=1, HBA=3) is good. Ligand B (HBD=3, HBA=4) is also acceptable, though slightly higher.

**QED:** Ligand A (0.751) is excellent, indicating good drug-like properties. Ligand B (0.537) is acceptable, but lower.

**DILI:** Ligand A (29.042) has a very low DILI risk. Ligand B (12.641) also has a low DILI risk.

**BBB:** Ligand A (90.074) has excellent BBB penetration potential. Ligand B (25.32) is significantly lower, raising concerns about CNS exposure. This is a critical factor for a DRD2 targeting drug.

**Caco-2 Permeability:** Ligand A (-4.57) is negative, indicating poor permeability. Ligand B (-5.129) is also negative and similarly poor.

**Aqueous Solubility:** Ligand A (-2.659) is poor. Ligand B (-1.555) is also poor.

**hERG Inhibition:** Ligand A (0.584) has a low risk of hERG inhibition. Ligand B (0.081) also has a low risk.

**Microsomal Clearance:** Ligand A (32.164) has moderate clearance. Ligand B (-0.305) has very low clearance, suggesting high metabolic stability.

**In vitro Half-Life:** Ligand A (10.931) has a moderate half-life. Ligand B (-21.165) has a very long half-life, which is a significant advantage.

**P-gp Efflux:** Ligand A (0.04) has low P-gp efflux, which is favorable for CNS penetration. Ligand B (0.008) has even lower P-gp efflux, which is even more favorable.

**Binding Affinity:** Ligand A (-6.7 kcal/mol) has good binding affinity. Ligand B (-7.0 kcal/mol) has slightly better binding affinity. The difference is less than 1.5 kcal/mol.

**Overall Assessment:**

Ligand A excels in BBB penetration and has a good overall profile. However, its Caco-2 permeability and aqueous solubility are poor. Ligand B has slightly better affinity and metabolic stability (lower Cl_mic, longer t1/2), and even lower P-gp efflux, but its major drawback is the significantly lower BBB penetration (25.32 vs 90.074). For a CNS target like DRD2, BBB penetration is paramount. While Ligand B has a slight affinity advantage, the poor BBB score is a deal-breaker. Ligand A, despite its permeability/solubility issues, is more likely to reach the target in the brain.

Output:
1
2025-04-17 05:01:33,647 - INFO - Okay, let's analyze these two ligands for their potential as DRD2 drug candidates. DRD2 is a GPCR in the CNS, so BBB penetration, logP, Pgp efflux, TPSA, and binding affinity are paramount.

**Ligand A:** [349.391, 121.23 ,   1.641,   2.   ,   5.   ,   0.459,  63.94 ,  71.268, -5.017,  -3.423,   0.27 ,   8.305, -25.044,   0.118,  -7.8  ]
**Ligand B:** [356.438,  70.08 ,   1.116,   1.   ,   4.   ,   0.823,  30.826,  78.945, -4.466,  -0.905,   0.39 ,   4.738,  15.292,   0.051,   0.   ]

**1. Molecular Weight:** Both are within the ideal range (200-500 Da). A is 349.391, B is 356.438. No significant difference.

**2. TPSA:** A (121.23) is slightly higher than the ideal <90 for CNS targets, but still reasonable. B (70.08) is excellent, well below 90. B is significantly better here.

**3. logP:** Both are within the optimal 1-3 range. A (1.641) and B (1.116) are both good, but B is slightly lower, potentially impacting permeability.

**4. H-Bond Donors:** A (2) and B (1) are both acceptable (<=5). B is slightly better.

**5. H-Bond Acceptors:** A (5) and B (4) are both acceptable (<=10). B is slightly better.

**6. QED:** A (0.459) is below the desired 0.5, indicating a less drug-like profile. B (0.823) is excellent, well above 0.5. B is significantly better.

**7. DILI:** A (63.94) is moderately high, suggesting potential liver toxicity risk. B (30.826) is low, indicating a much lower risk. B is significantly better.

**8. BBB:** Both have good BBB penetration, exceeding the 70% threshold. A (71.268) and B (78.945). B is slightly better.

**9. Caco-2:** A (-5.017) and B (-4.466) are both negative. This is unusual and suggests poor permeability. The absolute value is important here. A is slightly worse.

**10. Solubility:** A (-3.423) and B (-0.905) are both negative, indicating poor solubility. B is better.

**11. hERG:** Both are low (A: 0.27, B: 0.39), indicating low cardiotoxicity risk. No significant difference.

**12. Cl_mic:** A (8.305) is higher than B (4.738), indicating faster metabolic clearance and lower metabolic stability. B is better.

**13. t1/2:** A (-25.044) is very negative, suggesting a very short half-life. B (15.292) is positive, indicating a longer half-life. B is significantly better.

**14. Pgp:** A (0.118) is slightly higher than B (0.051), indicating more P-gp efflux and potentially reduced CNS exposure. B is better.

**15. Binding Affinity:** A (-7.8) is slightly better than B (-0.0). However, the difference is substantial, and a strong affinity can sometimes overcome other deficiencies.

**Overall Assessment:**

While Ligand A has a slightly better binding affinity, Ligand B is superior in almost every other crucial ADME-Tox property. Specifically, B has a much better QED score, lower DILI risk, better metabolic stability (lower Cl_mic, longer t1/2), lower P-gp efflux, and a significantly better TPSA. The slightly lower logP of B is a minor concern, but the overall profile is far more favorable for development as a CNS-active drug. The substantial difference in half-life and DILI risk are particularly important.

Output:
1
2025-04-17 05:01:33,647 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (366.889 and 351.422 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (78.43) is significantly better than Ligand B (93.45). For CNS targets, we want TPSA <= 90, so Ligand A is preferable.

**logP:** Ligand A (3.361) is within the optimal range (1-3), while Ligand B (1.705) is on the lower end. Lower logP can hinder permeation.

**H-Bond Donors/Acceptors:** Both have 3 HBD, which is good. Ligand A has 3 HBA, and Ligand B has 4. Both are acceptable, being under the 10 HBA limit.

**QED:** Ligand A (0.722) has a better QED score than Ligand B (0.466), indicating a more drug-like profile.

**DILI:** Both ligands have acceptable DILI risk (Ligand A: 35.828, Ligand B: 39.977), below the 40 threshold.

**BBB:** Ligand B (83.986) has a significantly higher BBB penetration percentile than Ligand A (67.623). This is a *major* advantage for a CNS target like DRD2.

**Caco-2 Permeability:** Ligand A (-4.762) has a worse Caco-2 permeability than Ligand B (-5.005). Lower values indicate lower permeability.

**Aqueous Solubility:** Ligand A (-4.052) has a worse aqueous solubility than Ligand B (-2.774).

**hERG:** Both ligands have relatively low hERG inhibition liability (Ligand A: 0.35, Ligand B: 0.687).

**Microsomal Clearance:** Ligand B (22.687) has a lower microsomal clearance than Ligand A (32.911), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (44.435) has a longer in vitro half-life than Ligand B (9.827).

**P-gp Efflux:** Both ligands have low P-gp efflux liability (Ligand A: 0.092, Ligand B: 0.094).

**Binding Affinity:** Both ligands have very similar and excellent binding affinities (Ligand A: -9.0 kcal/mol, Ligand B: -8.0 kcal/mol). Ligand A is slightly better, but the difference is not huge.

**Overall Assessment:**

Ligand A has advantages in QED, in vitro half-life, and binding affinity, and TPSA. However, Ligand B excels in BBB penetration and has better metabolic stability (lower Cl_mic). Given the CNS target (DRD2), BBB penetration is *critical*. While Ligand A's TPSA is acceptable, Ligand B's superior BBB score outweighs its slightly higher TPSA and lower half-life. The binding affinity difference is small enough to be considered negligible.

Output:
1
2025-04-17 05:01:33,647 - INFO - Batch 163 complete. Total preferences: 2608
2025-04-17 05:01:33,647 - INFO - Processing batch 164/512...
2025-04-17 05:02:13,777 - INFO - Reasoning:

Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (342.443 and 351.378 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (67.23) is significantly better than Ligand B (91.76). For CNS targets, we want TPSA <= 90, so Ligand A is preferable.

**3. logP:** Both ligands have good logP values (2.154 and 1.528), falling within the optimal 1-3 range.

**4. H-Bond Donors:** Ligand A (1) and Ligand B (2) are both acceptable, being <= 5.

**5. H-Bond Acceptors:** Ligand A (4) and Ligand B (5) are both acceptable, being <= 10.

**6. QED:** Both ligands have good QED scores (0.61 and 0.811), indicating good drug-like properties.

**7. DILI:** Both ligands have acceptable DILI risk (35.324 and 40.287), both below the 40 threshold.

**8. BBB:** Ligand B (72.974) is significantly better than Ligand A (52.772) in terms of BBB penetration. For a CNS target like DRD2, >70 is desirable, but Ligand B is much closer than Ligand A.

**9. Caco-2 Permeability:** Both have negative Caco-2 values (-4.659 and -4.822), which is unusual and suggests poor permeability. This is a significant drawback for both.

**10. Aqueous Solubility:** Both have negative solubility values (-2.546 and -2.828), also suggesting poor solubility. This is a concern for bioavailability.

**11. hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.121 and 0.205).

**12. Microsomal Clearance:** Ligand B (6.465) has a lower microsomal clearance than Ligand A (12.065), indicating better metabolic stability.

**13. In vitro Half-Life:** Ligand B (-33.405) has a much longer in vitro half-life than Ligand A (-5.554). This is a significant advantage.

**14. P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.026 and 0.035), which is good for CNS exposure.

**15. Binding Affinity:** Both ligands have excellent binding affinity (-7.7 and -7.8 kcal/mol). The difference is minimal.

**Overall Assessment:**

While both ligands have good affinity, Ligand B is superior due to its significantly better BBB penetration, lower microsomal clearance (better metabolic stability), and longer in vitro half-life. The TPSA is higher for Ligand B, but still within a reasonable range. The negative Caco-2 and solubility values are concerning for both, but the other advantages of Ligand B outweigh this drawback. Given the GPCR-specific priorities, the improved BBB and metabolic stability of Ligand B make it the more promising candidate.

Output:
1
2025-04-17 05:02:13,778 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (358.385 and 370.559 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (84.5) is better than Ligand B (69.64). Both are below the 90 A^2 threshold for CNS targets, but A is slightly higher.

**3. logP:** Both ligands have good logP values (1.408 and 2.28), falling within the optimal 1-3 range. Ligand B is slightly higher, potentially aiding membrane permeability.

**4. H-Bond Donors:** Both have 2 HBD, which is within the acceptable limit of <=5.

**5. H-Bond Acceptors:** Both have 4 HBA, also within the acceptable limit of <=10.

**6. QED:** Ligand B (0.688) has a better QED score than Ligand A (0.371), indicating a more drug-like profile.

**7. DILI:** Ligand B (15.083) has a significantly lower DILI risk than Ligand A (39.434). This is a major advantage for Ligand B.

**8. BBB:** Ligand A (89.686) has a better BBB penetration percentile than Ligand B (73.711), which is crucial for a CNS target like DRD2.

**9. Caco-2 Permeability:** Ligand A (-4.628) has a worse Caco-2 permeability than Ligand B (-5.077). Lower values indicate poorer permeability.

**10. Aqueous Solubility:** Both have poor aqueous solubility (-2.93 and -3.097). This could pose formulation challenges, but is less critical than BBB for a CNS target.

**11. hERG Inhibition:** Ligand A (0.256) has a lower hERG inhibition liability than Ligand B (0.474), which is preferable.

**12. Microsomal Clearance:** Ligand B (50.269) has a lower microsomal clearance than Ligand A (56.8), suggesting better metabolic stability.

**13. In vitro Half-Life:** Ligand A (-15.5) has a longer in vitro half-life than Ligand B (-7.357), which is a positive attribute.

**14. P-gp Efflux:** Ligand A (0.078) has lower P-gp efflux liability than Ligand B (0.17), meaning it's less likely to be pumped out of the brain, improving CNS exposure.

**15. Binding Affinity:** Ligand A (-7.9) has a slightly better binding affinity than Ligand B (-7.0). While both are good, the 0.9 kcal/mol difference is significant.

**Overall Assessment:**

Ligand A excels in BBB penetration, binding affinity, P-gp efflux, and in vitro half-life. However, Ligand B demonstrates a superior safety profile with a much lower DILI risk and better metabolic stability (lower Cl_mic). While Ligand A has a slightly better affinity, the difference might be outweighed by the safety and metabolic advantages of Ligand B, especially considering the potential for chronic use in CNS disorders. The slightly better BBB of ligand A is important, but the difference isn't huge.

Considering the GPCR-specific priorities, and the importance of safety and metabolic stability for CNS drugs, Ligand B appears to be the more promising candidate.

Output:
1
2025-04-17 05:02:13,778 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (363.487 and 363.571 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (78.43) is significantly higher than Ligand B (41.15). For a CNS target like DRD2, TPSA should ideally be <=90, so both are acceptable, but B is much better.

**3. logP:** Ligand A (1.301) is within the optimal range (1-3). Ligand B (4.422) is slightly high, potentially leading to solubility issues and off-target interactions.

**4. H-Bond Donors:** Both ligands have 1 HBD, which is acceptable (<=5).

**5. H-Bond Acceptors:** Ligand A has 6 HBA, and Ligand B has 4. Both are within the acceptable range (<=10).

**6. QED:** Ligand A (0.798) has a better QED score than Ligand B (0.679), indicating a more drug-like profile.

**7. DILI:** Ligand A (35.828) has a lower DILI risk than Ligand B (17.449), which is preferable.

**8. BBB:** Both ligands have excellent BBB penetration (Ligand A: 75.533, Ligand B: 77.317), exceeding the desirable threshold of >70.

**9. Caco-2 Permeability:** Both have negative Caco-2 values (-5.279 and -5.305), which is unusual and suggests poor permeability. However, these values are on a log scale and the negative values are not directly comparable.

**10. Aqueous Solubility:** Both ligands have very poor aqueous solubility (-2.129 and -3.122). This is a significant concern.

**11. hERG Inhibition:** Ligand A (0.38) shows lower hERG inhibition risk than Ligand B (0.917), which is favorable.

**12. Microsomal Clearance:** Ligand A (12.846) has a lower microsomal clearance than Ligand B (40.548), indicating better metabolic stability.

**13. In vitro Half-Life:** Ligand B (43.877) has a longer in vitro half-life than Ligand A (23.255), which is generally desirable.

**14. P-gp Efflux:** Ligand A (0.059) has significantly lower P-gp efflux liability than Ligand B (0.569), which is crucial for CNS penetration.

**15. Binding Affinity:** Ligand A (-8.6 kcal/mol) has a significantly stronger binding affinity than Ligand B (-7.4 kcal/mol). This >1.5 kcal/mol difference is substantial and can outweigh some ADME drawbacks.

**Overall Assessment:**

While both compounds have issues with solubility and Caco-2 permeability, Ligand A is the stronger candidate. Its superior binding affinity, lower DILI risk, lower hERG inhibition, lower P-gp efflux, and better metabolic stability outweigh the slightly higher TPSA and lower in vitro half-life compared to Ligand B. The strong binding affinity is a key advantage for a GPCR target.



Output:
0
2025-04-17 05:02:13,778 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (348.443 and 361.511 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (68.82) is slightly higher than Ligand B (61.44), but both are below the 90 A^2 threshold desirable for CNS targets.

**3. logP:** Both ligands have good logP values (2.34 and 2.803), falling within the optimal 1-3 range.

**4. H-Bond Donors:** Both ligands have 2 HBD, which is within the acceptable limit of <=5.

**5. H-Bond Acceptors:** Ligand A has 5 HBA, and Ligand B has 6. Both are within the acceptable limit of <=10.

**6. QED:** Both ligands have QED values above 0.7, indicating good drug-likeness.

**7. DILI:** Ligand A (43.234) has a slightly better DILI percentile than Ligand B (56.301), indicating a lower risk of liver injury. Both are below the concerning 60 threshold.

**8. BBB:** Both ligands have excellent BBB penetration (77.162 and 78.829), exceeding the desirable >70 threshold for CNS targets.

**9. Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and suggests a potential issue with the data or modeling. However, the values are similar (-5.072 and -4.971).

**10. Aqueous Solubility:** Both ligands have very poor aqueous solubility (-1.753 and -4.166). This is a significant drawback.

**11. hERG Inhibition:** Both ligands have low hERG inhibition risk (0.487 and 0.866).

**12. Microsomal Clearance:** Ligand A (-38.71) has significantly lower (better) microsomal clearance than Ligand B (13.225), indicating greater metabolic stability.

**13. In vitro Half-Life:** Ligand A (11.026) has a slightly better in vitro half-life than Ligand B (63.512).

**14. P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.053 and 0.35), which is favorable for CNS penetration.

**15. Binding Affinity:** Ligand B (-8.9) has a slightly better binding affinity than Ligand A (-8.4), although both are excellent (below -7.0 kcal/mol).

**Overall Assessment:**

Both ligands have many favorable properties, particularly regarding BBB penetration and binding affinity. However, the poor aqueous solubility is a major concern for both. Ligand A has advantages in DILI risk, microsomal clearance, and in vitro half-life. The slightly better binding affinity of Ligand B is unlikely to outweigh the ADME advantages of Ligand A, especially given the similar affinities.

Output:
1
2025-04-17 05:02:13,778 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (347.463 and 348.462 Da) fall comfortably within the ideal 200-500 Da range.

**TPSA:** Ligand A (61.68) is slightly higher than Ligand B (58.2). Both are below the 90 A^2 threshold desirable for CNS targets, but Ligand B is preferable.

**logP:** Ligand A (0.486) is quite low, potentially hindering membrane permeability. Ligand B (3.05) is within the optimal 1-3 range. This is a significant advantage for Ligand B.

**H-Bond Donors/Acceptors:** Ligand A has 0 HBD and 5 HBA, while Ligand B has 2 HBD and 2 HBA. Both are within acceptable limits, but Ligand B's values are slightly more balanced.

**QED:** Both ligands have reasonable QED values (0.795 and 0.629, respectively), indicating good drug-like properties.

**DILI:** Ligand A (18.922) has a slightly higher DILI risk than Ligand B (12.641), but both are below the concerning threshold of 40.

**BBB:** Ligand B (83.637) has a significantly higher BBB penetration percentile than Ligand A (56.262). This is a crucial advantage for a CNS target like DRD2.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.852 and -4.761). These values are unusual and suggest poor permeability.

**Aqueous Solubility:** Ligand A (-0.113) has slightly better aqueous solubility than Ligand B (-3.333).

**hERG Inhibition:** Ligand A (0.167) shows slightly lower hERG inhibition liability than Ligand B (0.445), which is preferable.

**Microsomal Clearance:** Ligand A (9.465) has a lower microsomal clearance than Ligand B (28.256), indicating better metabolic stability.

**In vitro Half-Life:** Ligand A (9.959) has a slightly longer in vitro half-life than Ligand B (6.114).

**P-gp Efflux:** Ligand A (0.021) has much lower P-gp efflux liability than Ligand B (0.088), which is highly desirable for CNS penetration.

**Binding Affinity:** Ligand B (-8.6 kcal/mol) has a slightly better binding affinity than Ligand A (-8.1 kcal/mol). While the difference is not huge, it is still a positive factor.

**Overall Assessment:**

Ligand B is the stronger candidate. Its superior BBB penetration, optimal logP, and slightly better binding affinity outweigh the advantages of Ligand A in terms of metabolic stability and P-gp efflux. The low logP of Ligand A is a significant concern for CNS penetration. While both have poor Caco-2 permeability, the other factors favor Ligand B.

Output:
1
2025-04-17 05:02:13,779 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands are within the acceptable range (200-500 Da). Ligand A (453.2 Da) is slightly higher than Ligand B (391.465 Da), but not concerningly so.

**2. TPSA:** Ligand A (127.68) is higher than the ideal <90 for CNS targets, while Ligand B (79.37) is well within the desired range. This is a significant advantage for Ligand B.

**3. logP:** Both ligands have good logP values (A: 1.419, B: 1.79), falling within the optimal 1-3 range.

**4. H-Bond Donors:** Both ligands are acceptable (A: 2, B: 1).

**5. H-Bond Acceptors:** Both ligands are acceptable (A: 8, B: 5).

**6. QED:** Both ligands have reasonable QED values (A: 0.442, B: 0.75), but Ligand B is significantly better, indicating a more drug-like profile.

**7. DILI:** Ligand A has a very high DILI risk (98.953), which is a major concern. Ligand B's DILI risk (60.527) is elevated but less alarming.

**8. BBB:** Ligand B has a much better BBB penetration percentile (83.443) than Ligand A (45.134). This is crucial for a CNS target like DRD2.

**9. Caco-2 Permeability:** Both have negative values, which is unusual. Assuming these are logP values, they indicate poor permeability.

**10. Aqueous Solubility:** Both have negative values, indicating poor solubility.

**11. hERG Inhibition:** Both ligands show low hERG inhibition liability (A: 0.3, B: 0.387), which is good.

**12. Microsomal Clearance:** Ligand A (47.383) has higher clearance than Ligand B (39.559), suggesting lower metabolic stability.

**13. In vitro Half-Life:** Ligand B has a negative half-life (-22.42), which is impossible. This is a significant red flag and suggests an issue with the data. Ligand A has a half-life of 21.234.

**14. P-gp Efflux:** Both ligands have low P-gp efflux liability (A: 0.171, B: 0.195), which is favorable for CNS penetration.

**15. Binding Affinity:** Ligand B (-8.2 kcal/mol) has a slightly better binding affinity than Ligand A (-7.9 kcal/mol), although the difference is relatively small.

**Overall Assessment:**

Despite the questionable half-life value for Ligand B, it is the more promising candidate. Ligand A has a very high DILI risk, which is a major drawback. Ligand B excels in TPSA, BBB penetration, QED, and has slightly better affinity. The negative half-life for Ligand B is concerning and needs investigation, but the other factors strongly favor it.

Output:
1
2025-04-17 05:02:13,779 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (344.415 and 337.431 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (96.97) is better than Ligand B (70.9). Both are below the 90 A^2 threshold desirable for CNS targets, but Ligand B is significantly lower, which is a positive.

**logP:** Both ligands have good logP values (2.249 and 1.949), falling within the optimal 1-3 range.

**H-Bond Donors:** Both have 2 HBD, which is acceptable.

**H-Bond Acceptors:** Ligand A has 5 HBA, while Ligand B has 7. Both are within the acceptable limit of 10, but Ligand A is slightly preferred.

**QED:** Both ligands have identical QED scores (0.716), indicating good drug-likeness.

**DILI:** Ligand A (72.043) has a slightly higher DILI risk than Ligand B (62.35). Ligand B is preferable here.

**BBB:** Ligand B (76.309) has a significantly better BBB penetration percentile than Ligand A (57.425). This is a crucial advantage for a CNS target like DRD2.

**Caco-2 Permeability:** Both have negative Caco-2 values (-5.03 and -5.413), which is unusual and suggests poor permeability. This is a significant concern for both.

**Aqueous Solubility:** Both have negative solubility values (-3.267 and -2.027), indicating very poor aqueous solubility. This is a major drawback for both.

**hERG Inhibition:** Ligand A (0.271) has a lower hERG inhibition liability than Ligand B (0.952), making it safer from a cardiotoxicity perspective.

**Microsomal Clearance:** Ligand B (29.155) has a much lower microsomal clearance than Ligand A (58.659), indicating better metabolic stability.

**In vitro Half-Life:** Ligand A (-38.623) has a negative half-life, which is not possible. This suggests a very rapid degradation or an error in the data. Ligand B (0.853) has a very short half-life, but is still preferable to a negative value.

**P-gp Efflux:** Ligand A (0.168) has lower P-gp efflux liability than Ligand B (0.042), which is a positive for CNS penetration.

**Binding Affinity:** Both ligands have very similar and strong binding affinities (-8.1 and -8.2 kcal/mol). The difference is negligible.

**Overall Assessment:**

While both compounds have significant drawbacks (poor solubility and permeability), Ligand B is more promising due to its superior BBB penetration (76.309 vs 57.425) and better metabolic stability (lower Cl_mic). The lower DILI risk is also a benefit. The negative half-life for Ligand A is a critical flaw. Although Ligand A has slightly better hERG and P-gp profiles, the CNS target prioritization makes BBB and metabolic stability more important.

Output:
1
2025-04-17 05:02:13,779 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (347.459 and 348.403 Da) fall comfortably within the ideal 200-500 Da range.

**TPSA:** Ligand A (63.69) is significantly better than Ligand B (88.02). For CNS targets, we want TPSA <= 90, and A is much closer to the ideal <=60. B is pushing the upper limit.

**logP:** Ligand A (2.84) is optimal (1-3). Ligand B (0.635) is below 1, which could hinder permeation.

**H-Bond Donors/Acceptors:** Both have 1 HBD, which is good. Ligand A has 4 HBA, and Ligand B has 7. Both are acceptable (<=10), but A is preferable.

**QED:** Both ligands have similar, good QED values (0.89 and 0.833), indicating good drug-like properties.

**DILI:** Ligand A (30.748) has a much lower DILI risk than Ligand B (64.366). This is a significant advantage for A.

**BBB:** Ligand A (71.035) has a good BBB penetration percentile, exceeding the desirable >70 threshold for CNS targets. Ligand B (54.634) is considerably lower and less likely to achieve sufficient brain exposure.

**Caco-2 Permeability:** Both are negative, indicating poor permeability. This is a concern for both, but the lower value for B (-5.188) is worse than A (-4.67).

**Aqueous Solubility:** Both are negative, indicating poor solubility. This is a concern for both, but the lower value for B (-1.959) is worse than A (-1.98).

**hERG:** Both have low hERG inhibition liability (0.394 and 0.191), which is good.

**Microsomal Clearance:** Ligand A (12.402) has higher clearance than Ligand B (6.982), meaning B is more metabolically stable.

**In vitro Half-Life:** Ligand A (11.299) has a longer half-life than Ligand B (0.574), which is preferable.

**P-gp Efflux:** Both have very low P-gp efflux liability (0.044 and 0.004), which is excellent.

**Binding Affinity:** Ligand A (-8.8 kcal/mol) has *significantly* stronger binding affinity than Ligand B (0.0 kcal/mol). This difference in affinity is substantial and likely outweighs many of the minor ADME drawbacks.

**Overall Assessment:**

Ligand A is the clear winner. While both have issues with Caco-2 permeability and solubility, Ligand A excels in the most critical areas for a CNS-targeting GPCR ligand: BBB penetration, binding affinity, and DILI risk. The significantly stronger binding affinity of Ligand A (-8.8 vs 0.0) is a major advantage. The better TPSA and logP of Ligand A also contribute to its superior profile.



Output:
1
2025-04-17 05:02:13,779 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (352.391 and 356.51 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (104.98) is better than Ligand B (64.52), both are below the 90 A^2 threshold for CNS targets.

**logP:** Ligand A (-0.041) is slightly low, potentially hindering permeability, while Ligand B (3.623) is within the optimal 1-3 range. This favors Ligand B.

**H-Bond Donors:** Ligand A (1) is good, while Ligand B (4) is acceptable, but closer to the upper limit of 5.

**H-Bond Acceptors:** Ligand A (6) is good, while Ligand B (4) is also good.

**QED:** Ligand A (0.604) is significantly better than Ligand B (0.327), indicating a more drug-like profile.

**DILI:** Ligand A (62.66) has a higher DILI risk than Ligand B (9.81), which is a significant concern.

**BBB:** Ligand A (43.815) has a lower BBB penetration than Ligand B (34.277), which is a major drawback for a CNS target.

**Caco-2 Permeability:** Ligand A (-4.92) is very poor, while Ligand B (-6.022) is also poor.

**Aqueous Solubility:** Both ligands have very poor aqueous solubility (-1.538 and -1.489 respectively).

**hERG Inhibition:** Ligand A (0.075) has a lower hERG inhibition risk than Ligand B (0.96), which is preferable.

**Microsomal Clearance:** Ligand A (18.257) has a higher microsomal clearance than Ligand B (-13.727), indicating lower metabolic stability.

**In vitro Half-Life:** Ligand A (-11.541) has a shorter half-life than Ligand B (5.867).

**P-gp Efflux:** Ligand A (0.012) has much lower P-gp efflux liability than Ligand B (0.423), which is highly desirable for CNS penetration.

**Binding Affinity:** Ligand B (-8.4) has a slightly better binding affinity than Ligand A (-7.7), although the difference is not huge.

**Overall Assessment:**

Ligand B has a better logP, better BBB penetration, and better binding affinity. However, Ligand A has a better QED, lower P-gp efflux, and lower hERG inhibition. The poor BBB penetration of Ligand A is a critical flaw for a CNS target like DRD2. The higher DILI risk for Ligand A is also concerning. While Ligand B's solubility and Caco-2 permeability are poor, these can potentially be addressed with formulation strategies. The slightly better affinity of Ligand B, combined with its favorable BBB and logP, outweighs the other drawbacks.

Output:
1
2025-04-17 05:02:13,779 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 drug candidates, considering the provided guidelines and GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight (MW):** Both ligands (360.527 and 380.411 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (68.16) is better than Ligand B (72.11). Both are below the 90 A^2 threshold for CNS targets, which is good.

**3. logP:** Both ligands have good logP values (4.094 and 3.433), falling within the optimal 1-3 range. Ligand B is slightly better.

**4. H-Bond Donors (HBD):** Both ligands are acceptable (2 and 1 respectively), well below the 5 limit.

**5. H-Bond Acceptors (HBA):** Both ligands are acceptable (4 and 5 respectively), below the 10 limit.

**6. QED:** Both ligands have reasonable QED scores (0.849 and 0.702), indicating good drug-like properties. Ligand A is better.

**7. DILI:** Both ligands have low DILI risk (35.673 and 39.201 percentiles), which is favorable.

**8. BBB:** Ligand B (93.912) has a significantly better BBB penetration percentile than Ligand A (88.29). This is a crucial advantage for a CNS target like DRD2.

**9. Caco-2 Permeability:** Ligand A (-5.074) has slightly better Caco-2 permeability than Ligand B (-4.621).

**10. Aqueous Solubility:** Both have very poor aqueous solubility (-4.169 and -4.806). This is a concern, but can sometimes be mitigated with formulation strategies.

**11. hERG Inhibition:** Both ligands show low hERG inhibition liability (0.917 and 0.783), which is good.

**12. Microsomal Clearance:** Ligand A (17.764) has lower microsomal clearance than Ligand B (34.292), suggesting better metabolic stability.

**13. In vitro Half-Life:** Ligand A (41.135) has a longer in vitro half-life than Ligand B (15.006). This is a significant advantage.

**14. P-gp Efflux:** Ligand A (0.485) has lower P-gp efflux than Ligand B (0.249), which is favorable for CNS exposure.

**15. Binding Affinity:** Ligand A (-8.3 kcal/mol) has a significantly stronger binding affinity than Ligand B (-7.2 kcal/mol). This is a substantial advantage, exceeding the 1.5 kcal/mol threshold.

**Overall Assessment:**

While Ligand B has a better BBB score, the superior binding affinity (-8.3 vs -7.2 kcal/mol) of Ligand A is a critical factor, especially for a GPCR target. The stronger binding is likely to outweigh the slightly lower BBB penetration. Additionally, Ligand A demonstrates better metabolic stability (lower Cl_mic, longer t1/2) and lower P-gp efflux. Both have poor solubility, but this is a formulation challenge. Considering the GPCR-specific priorities, the stronger affinity and favorable ADME properties of Ligand A make it the more promising candidate.

Output:
1
2025-04-17 05:02:13,780 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (348.447 and 368.547 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (88.33) is excellent, falling well below the 90 A^2 threshold for CNS targets. Ligand B (50.6) is even better, indicating potentially improved brain penetration.

**logP:** Both ligands have good logP values (1.712 and 2.38), within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A has 1 HBD and 5 HBA, while Ligand B has 0 HBD and 6 HBA. Both are within acceptable limits (<=5 HBD and <=10 HBA).

**QED:** Ligand A (0.723) has a better QED score than Ligand B (0.469), suggesting a more drug-like profile.

**DILI:** Ligand A (29.042) has a significantly lower DILI risk than Ligand B (12.33), which is a major advantage.

**BBB:** Both ligands exhibit good BBB penetration (81% and 79.411%), exceeding the 70% threshold for CNS targets. Ligand A is slightly better.

**Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and difficult to interpret without knowing the scale. However, the values are similar.

**Aqueous Solubility:** Both ligands have negative solubility values, again, difficult to interpret without knowing the scale. The values are similar.

**hERG Inhibition:** Both ligands have low hERG inhibition liability (0.376 and 0.682), which is favorable.

**Microsomal Clearance:** Ligand A (47.701) has lower microsomal clearance than Ligand B (58.724), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (-5.082) has a much longer in vitro half-life than Ligand B (13.798).

**P-gp Efflux:** Ligand A (0.08) has significantly lower P-gp efflux liability than Ligand B (0.254), which is crucial for CNS penetration.

**Binding Affinity:** Ligand A (-8.4 kcal/mol) has a substantially stronger binding affinity than Ligand B (-6.0 kcal/mol). This difference of 2.4 kcal/mol is very significant and can outweigh minor ADME drawbacks.

**Overall Assessment:**

Ligand A is superior to Ligand B across most critical parameters. It has a better QED score, significantly lower DILI risk, lower P-gp efflux, better metabolic stability, longer half-life, and, most importantly, a much stronger binding affinity. While both have acceptable BBB penetration and logP values, the combination of improved ADME properties and substantially higher affinity makes Ligand A the more promising drug candidate.

Output:
1
2025-04-17 05:02:13,780 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (345.403 and 354.491 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (92.77) is better than Ligand B (98.66). Both are below the 140 A^2 threshold for oral absorption and reasonably close to the 90 A^2 target for CNS penetration, but A is preferable.

**3. logP:** Ligand A (-0.721) is slightly lower than the optimal 1-3 range, potentially hindering permeability. Ligand B (1.488) is within the optimal range. This favors Ligand B.

**4. H-Bond Donors:** Ligand A (2) is preferable to Ligand B (4), as fewer HBDs generally improve permeability.

**5. H-Bond Acceptors:** Ligand A (5) is preferable to Ligand B (4).

**6. QED:** Both ligands have acceptable QED values (0.751 and 0.581, respectively), indicating good drug-like properties.

**7. DILI:** Ligand A (25.165) has a significantly lower DILI risk than Ligand B (15.045), which is a major advantage.

**8. BBB:** Ligand A (35.595) has a better BBB penetration percentile than Ligand B (20.512). This is *critical* for a CNS target like DRD2.

**9. Caco-2 Permeability:** Both have negative Caco-2 values which is unusual and suggests poor permeability.

**10. Aqueous Solubility:** Both ligands have negative solubility values, which is also unusual and suggests poor solubility.

**11. hERG Inhibition:** Ligand A (0.36) has a lower hERG inhibition risk than Ligand B (0.099).

**12. Microsomal Clearance:** Ligand A (-5.023) shows better metabolic stability (lower clearance) than Ligand B (4.172).

**13. In vitro Half-Life:** Ligand A (0.602) has a slightly better in vitro half-life than Ligand B (-3.77).

**14. P-gp Efflux:** Ligand A (0.008) has significantly lower P-gp efflux liability than Ligand B (0.014), which is favorable for CNS exposure.

**15. Binding Affinity:** Ligand B (-8.1 kcal/mol) has a stronger binding affinity than Ligand A (-7.6 kcal/mol). This is a significant advantage, potentially outweighing some of the ADME drawbacks. The difference is >1.5 kcal/mol.

**Overall Assessment:**

While Ligand B has a better binding affinity and logP, Ligand A demonstrates superior ADME properties, particularly regarding BBB penetration, DILI risk, P-gp efflux, and metabolic stability. Given the CNS target (DRD2), BBB penetration is paramount. The stronger binding affinity of Ligand B is attractive, but the significantly better ADME profile of Ligand A, especially its lower DILI and P-gp efflux, makes it the more promising candidate.

Output:
0
2025-04-17 05:02:13,780 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (351.447 & 361.511 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (87.74) is better than Ligand B (57.84) as it is closer to the ideal range for CNS targets (<=90). Ligand B is quite low, which *could* indicate poor binding, but isn't necessarily a dealbreaker.

**3. logP:** Ligand A (1.418) is within the optimal 1-3 range. Ligand B (3.322) is at the higher end of optimal, but still acceptable.

**4. H-Bond Donors:** Ligand A (2) and Ligand B (1) are both within the acceptable limit of <=5.

**5. H-Bond Acceptors:** Ligand A (4) and Ligand B (5) are both within the acceptable limit of <=10.

**6. QED:** Both ligands have good QED scores (0.726 and 0.889, respectively), indicating drug-like properties.

**7. DILI:** Ligand A (17.449) has a significantly lower DILI risk than Ligand B (29.159), which is a substantial advantage.

**8. BBB:** Both ligands have excellent BBB penetration (75.843 and 76.464), exceeding the desirable >70% threshold for CNS targets.

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.589 and -4.687), which is unusual and suggests poor permeability. This is a concern for both.

**10. Aqueous Solubility:** Both ligands have negative solubility values (-2.179 and -3.601), also unusual and concerning for formulation.

**11. hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.261 and 0.628).

**12. Microsomal Clearance:** Ligand A (25.258) has a lower (better) microsomal clearance than Ligand B (65.88), suggesting greater metabolic stability.

**13. In vitro Half-Life:** Ligand A (-16.815) has a negative half-life, which is not physically possible and indicates a potential issue with the data or model. Ligand B (-13.191) also has a negative half-life.

**14. P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.012 and 0.504), which is excellent for CNS exposure.

**15. Binding Affinity:** Ligand A (-7.6) has a slightly better (more negative) binding affinity than Ligand B (-7.0). While both are good, the 0.6 kcal/mol difference is meaningful.

**Overall Assessment:**

Ligand A is the better candidate. While both have issues with Caco-2 and solubility, Ligand A has a significantly lower DILI risk, better metabolic stability (lower Cl_mic), and slightly better binding affinity. The negative half-life values are concerning for both, but the other advantages of Ligand A outweigh the slightly better P-gp efflux of Ligand B. The TPSA of Ligand A is also more favorable for CNS penetration.

Output:
1
2025-04-17 05:02:13,780 - INFO - Reasoning:

Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (390.795 Da) is slightly higher, but still acceptable. Ligand B (338.411 Da) is a bit lower, potentially favoring permeability.

**TPSA:** Both ligands have TPSA values below the 90 A^2 threshold for CNS targets. Ligand A (80.52 A^2) is better than Ligand B (66.71 A^2).

**logP:** Ligand A (4.05) is at the upper end of the optimal range (1-3), potentially leading to solubility issues or off-target interactions. Ligand B (1.713) is well within the optimal range.

**H-Bond Donors/Acceptors:** Ligand A (0 HBD, 4 HBA) and Ligand B (1 HBD, 4 HBA) both have reasonable numbers of H-bond donors and acceptors, well below the thresholds of 5 and 10 respectively.

**QED:** Both ligands have good QED scores (Ligand A: 0.569, Ligand B: 0.844), indicating drug-like properties. Ligand B's score is significantly better.

**DILI:** Ligand A (84.684) has a higher DILI risk than Ligand B (50.136). Ligand B is well below the 60% high-risk threshold.

**BBB:** Ligand A (64.482) and Ligand B (53.354) both fall short of the >70% desirable BBB penetration for CNS targets. However, Ligand A is closer.

**Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and suggests poor permeability. This is a significant concern for both.

**Aqueous Solubility:** Both ligands have very poor aqueous solubility (-5.754 and -3.525, respectively). This is a major drawback.

**hERG Inhibition:** Both ligands have low hERG inhibition liability (0.696 and 0.215), which is good.

**Microsomal Clearance:** Ligand A (48.584) has a higher microsomal clearance than Ligand B (14.882), indicating lower metabolic stability.

**In vitro Half-Life:** Ligand B (-12.542) has a negative in vitro half-life, which is not possible and indicates a problem with the data or the molecule itself. Ligand A (76.06) has a reasonable half-life.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.498 and 0.05).

**Binding Affinity:** Both ligands have the same binding affinity (-9.1 kcal/mol), which is excellent.

**Overall Assessment:**

While both ligands have excellent binding affinity, Ligand B is generally more favorable based on the ADME properties. It has a better logP, QED, DILI score, and lower microsomal clearance. However, the negative in vitro half-life for Ligand B is a critical flaw. The poor Caco-2 and solubility for both are major concerns. Ligand A has a better BBB score, but its higher logP and DILI risk are problematic. Given the choice, and acknowledging the questionable half-life of B, I would lean towards Ligand A due to its more reasonable (though still not ideal) ADME profile and the critical importance of BBB penetration for a CNS target. However, both require significant optimization.

Output:
1
2025-04-17 05:02:13,780 - INFO - Reasoning:

Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (373.787 and 364.917 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (78.51) is higher than Ligand B (40.62). For a CNS target like DRD2, TPSA should ideally be below 90. Ligand B is significantly better here.

**3. logP:** Ligand A (1.663) and Ligand B (3.405) are both within the optimal 1-3 range. Ligand B is slightly higher, potentially offering better membrane permeability.

**4. H-Bond Donors:** Ligand A (2) and Ligand B (0) are both acceptable, being less than 5.

**5. H-Bond Acceptors:** Ligand A (3) and Ligand B (2) are both acceptable, being less than 10.

**6. QED:** Both ligands have good QED scores (0.608 and 0.75), indicating drug-like properties.

**7. DILI:** Ligand A (54.75) has a higher DILI risk than Ligand B (12.524). This is a significant advantage for Ligand B.

**8. BBB:** Ligand B (91.508) has a much higher BBB penetration percentile than Ligand A (77.937). This is *critical* for a CNS target like DRD2.

**9. Caco-2 Permeability:** Ligand A (-5.148) and Ligand B (-4.793) are both negative, indicating poor permeability. This is a concern for both, but the values are similar.

**10. Aqueous Solubility:** Both ligands have poor aqueous solubility (-3.531 and -3.946). This could pose formulation challenges.

**11. hERG Inhibition:** Both ligands have low hERG inhibition risk (0.692 and 0.508).

**12. Microsomal Clearance:** Ligand B (44.069) has a significantly lower microsomal clearance than Ligand A (17.569), suggesting better metabolic stability.

**13. In vitro Half-Life:** Ligand A (23.384) has a longer half-life than Ligand B (1.184). This is a positive for Ligand A, but the difference is substantial and could be offset by other factors.

**14. P-gp Efflux:** Ligand A (0.123) has lower P-gp efflux than Ligand B (0.161), which is favorable for CNS penetration.

**15. Binding Affinity:** Ligand B (-8.6) has a slightly better binding affinity than Ligand A (-9.4). While both are excellent, the difference is small.

**Overall Assessment:**

Ligand B is the stronger candidate. Its superior BBB penetration (91.5 vs 77.9), lower DILI risk (12.5 vs 54.8), and better metabolic stability (lower Cl_mic) are crucial advantages for a CNS-targeting GPCR. While Ligand A has a longer half-life and slightly better P-gp efflux, the benefits of Ligand B in terms of CNS exposure and safety outweigh these factors. The slightly better binding affinity of Ligand B is also a plus.



Output:
1
2025-04-17 05:02:13,781 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (342.41 and 362.539 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (35.53) is excellent, well below the 90 A^2 threshold for CNS targets. Ligand B (49.41) is still reasonable but less optimal.

**logP:** Ligand A (4.29) is slightly high, potentially leading to solubility issues or off-target interactions. Ligand B (3.178) is within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A (0 HBD, 3 HBA) and Ligand B (1 HBD, 3 HBA) both have favorable counts, well within the guidelines.

**QED:** Both ligands have good QED scores (0.704 and 0.845), indicating good drug-like properties.

**DILI:** Ligand A (60.217) is approaching a concerning DILI risk, while Ligand B (35.479) has a much lower and favorable risk.

**BBB:** Ligand A (84.025) has a very good BBB penetration percentile, exceeding the 70% threshold. Ligand B (70.027) is acceptable but less favorable.

**Caco-2 Permeability:** Both have negative Caco-2 values which is unusual. Assuming these are logP values, Ligand A (-4.142) is very poor, and Ligand B (-5.007) is even worse. This suggests very poor intestinal absorption.

**Aqueous Solubility:** Both ligands have negative solubility values, which is also unusual. Assuming these are logS values, both are very poorly soluble.

**hERG:** Both ligands have low hERG inhibition liability (0.619 and 0.59), which is good.

**Microsomal Clearance:** Ligand A (97.786) has high microsomal clearance, suggesting rapid metabolism. Ligand B (84.904) is better, but still relatively high.

**In vitro Half-Life:** Ligand A (-10.595) has a very short half-life, which is concerning. Ligand B (-3.068) is better, but still short.

**P-gp Efflux:** Ligand A (0.439) has moderate P-gp efflux, while Ligand B (0.462) is similar. Both are acceptable, but lower would be better for CNS penetration.

**Binding Affinity:** Ligand A (-9.0) has significantly stronger binding affinity than Ligand B (-0.0). This is a substantial advantage.

**Overall Assessment:**

Despite Ligand A's higher logP and DILI risk, its *significantly* stronger binding affinity (-9.0 kcal/mol vs -0.0 kcal/mol) is a major advantage. The high BBB penetration (84.025) is also very favorable for a CNS target like DRD2. However, the poor Caco-2 permeability, solubility, high clearance, and short half-life are serious drawbacks. Ligand B has better ADME properties overall (lower DILI, better logP), but its binding affinity is extremely weak.

Given the importance of affinity for GPCRs, and the potential to mitigate ADME issues through further optimization, Ligand A is the more promising starting point, *provided* the Caco-2 and solubility issues can be addressed. The large affinity difference outweighs the ADME concerns at this stage.

Output:
1
2025-04-17 05:02:13,781 - INFO - Batch 164 complete. Total preferences: 2624
2025-04-17 05:02:13,781 - INFO - Processing batch 165/512...
2025-04-17 05:02:54,726 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (392.859 Da) is slightly higher than Ligand B (350.459 Da), but both are acceptable.

**TPSA:** Ligand A (56.75) is excellent for CNS penetration, well below the 90 A^2 threshold. Ligand B (71.78) is still reasonable, but less optimal.

**logP:** Ligand A (1.809) is within the optimal range (1-3). Ligand B (3.142) is at the higher end of the optimal range, potentially raising concerns about solubility and off-target effects, but still acceptable.

**H-Bond Donors/Acceptors:** Both ligands have acceptable HBD (0/1) and HBA (5/5) counts, falling within the recommended limits.

**QED:** Both ligands have similar QED values (0.784 and 0.765), indicating good drug-likeness.

**DILI:** Ligand A (52.423) has a slightly higher DILI risk than Ligand B (37.069), but both are below the concerning threshold of 60.

**BBB:** This is a critical parameter for CNS targets. Ligand A (80.419) has a significantly better BBB percentile than Ligand B (67.197). This is a major advantage for Ligand A.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values, which is unusual and suggests poor permeability. However, the scale is not specified, so it's hard to interpret.

**Aqueous Solubility:** Both ligands have negative solubility values, which is also unusual and suggests poor solubility.

**hERG Inhibition:** Both ligands show low hERG inhibition liability (0.445 and 0.277), which is good.

**Microsomal Clearance:** Ligand B (92.41) has a much higher microsomal clearance than Ligand A (8.812), indicating faster metabolism and potentially lower in vivo exposure.

**In vitro Half-Life:** Ligand A (10.152 hours) has a significantly longer half-life than Ligand B (36.079 hours).

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.194 and 0.137), which is favorable for CNS penetration.

**Binding Affinity:** Ligand A (-7.2 kcal/mol) has a stronger binding affinity than Ligand B (-6.6 kcal/mol). The difference of 0.6 kcal/mol is substantial and could outweigh some of the minor ADME drawbacks of Ligand A.

**Overall Assessment:**

Considering the GPCR-specific priorities, Ligand A is the more promising candidate. It has a better BBB score, longer half-life, lower clearance, and significantly stronger binding affinity. While Ligand B has slightly lower DILI risk, the superior CNS penetration and potency of Ligand A are more critical for a DRD2 ligand targeting CNS disorders. The negative values for Caco-2 and solubility are concerning for both, but the other advantages of Ligand A make it the better choice.

Output:
1
2025-04-17 05:02:54,726 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (383.876 Da) is slightly higher than Ligand B (350.507 Da), but both are acceptable.

**TPSA:** Ligand A (44.81) is better than Ligand B (50.6). Both are below the 90 A^2 threshold for CNS targets, which is good.

**logP:** Ligand A (3.899) is within the optimal range (1-3), while Ligand B (2.449) is towards the lower end. A higher logP is generally preferred for GPCRs to aid membrane permeability, giving a slight edge to Ligand A.

**H-Bond Donors/Acceptors:** Ligand A has 1 HBD and 4 HBA, while Ligand B has 0 HBD and 5 HBA. Both are within acceptable limits (<=5 HBD and <=10 HBA).

**QED:** Ligand A (0.87) has a significantly better QED score than Ligand B (0.65), indicating a more drug-like profile.

**DILI:** Ligand B (7.755) has a much lower DILI risk than Ligand A (64.909), which is a significant advantage.

**BBB:** Ligand B (90.772) has a substantially higher BBB penetration percentile than Ligand A (84.413). This is a crucial factor for a CNS target like DRD2, favoring Ligand B.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.749 and -4.296), which is unusual and suggests poor permeability. However, these values are on a different scale and hard to interpret directly.

**Aqueous Solubility:** Both ligands have negative solubility values (-4.771 and -1.298), indicating poor solubility. Ligand B is slightly better.

**hERG Inhibition:** Ligand A (0.889) has a slightly higher hERG risk than Ligand B (0.45), which is preferable for Ligand B.

**Microsomal Clearance:** Ligand B (76.548) has a higher microsomal clearance than Ligand A (62.106), meaning Ligand A is more metabolically stable.

**In vitro Half-Life:** Ligand A (-5.73) has a longer in vitro half-life than Ligand B (3.796), which is desirable.

**P-gp Efflux:** Ligand A (0.491) has lower P-gp efflux liability than Ligand B (0.048), which is better for CNS exposure.

**Binding Affinity:** Both ligands have similar binding affinities (-7.6 kcal/mol and -5.7 kcal/mol). Ligand A is significantly more potent. The 1.9 kcal/mol difference in affinity is substantial and can outweigh some ADME drawbacks.

**Overall Assessment:**

Ligand A has a significantly better binding affinity and metabolic stability (lower Cl_mic, longer t1/2) and lower P-gp efflux. However, Ligand B excels in BBB penetration, has a much lower DILI risk, and a better hERG profile. The superior affinity of Ligand A is a major advantage, especially for a GPCR where potency is critical. While Ligand B has better CNS penetration, the substantial affinity difference of Ligand A might allow it to achieve sufficient brain exposure despite slightly lower BBB values. The DILI risk for Ligand A is concerning, but the overall profile, particularly the binding affinity, makes it a more promising candidate.

Output:
1
2025-04-17 05:02:54,727 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (350.394 and 347.459 Da) fall within the ideal range of 200-500 Da.

**TPSA:** Ligand A (68.62) is better than Ligand B (70.67). Both are below the 90 A^2 threshold for CNS targets, but A is closer to the optimal range.

**logP:** Ligand A (1.926) is within the optimal 1-3 range. Ligand B (0.664) is slightly low, potentially hindering permeation.

**H-Bond Donors/Acceptors:** Ligand A has 1 HBD and 5 HBA, while Ligand B has 2 HBD and 4 HBA. Both are within acceptable limits.

**QED:** Both ligands have similar QED values (0.79 and 0.664), indicating good drug-likeness.

**DILI:** Ligand A (47.848) has a moderate DILI risk, while Ligand B (18.728) has a very low DILI risk, which is a significant advantage.

**BBB:** Ligand A (82.086) has a good BBB penetration percentile, exceeding the 70% threshold for CNS targets. Ligand B (54.866) is considerably lower and less desirable for CNS activity.

**Caco-2 Permeability:** Ligand A (-4.308) has poor Caco-2 permeability, while Ligand B (-5.049) is even worse. This is a concern for oral bioavailability.

**Aqueous Solubility:** Ligand A (-2.237) has slightly better solubility than Ligand B (-1.22), but both are poor.

**hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.492 and 0.208).

**Microsomal Clearance:** Ligand A (78.303) has higher microsomal clearance than Ligand B (1.846), indicating lower metabolic stability. Ligand B is much more metabolically stable.

**In vitro Half-Life:** Ligand A (-2.479) has a shorter half-life than Ligand B (6.452).

**P-gp Efflux:** Ligand A (0.069) has lower P-gp efflux than Ligand B (0.014), which is favorable for CNS exposure.

**Binding Affinity:** Ligand A (-7.7 kcal/mol) has a significantly stronger binding affinity than Ligand B (-6.6 kcal/mol). This 1.1 kcal/mol difference is substantial and can outweigh some ADME drawbacks.

**Overall Assessment:**

Ligand A excels in binding affinity and BBB penetration, crucial for a CNS-targeting GPCR. However, it suffers from poor Caco-2 permeability and higher metabolic clearance. Ligand B has a much better safety profile (lower DILI, lower clearance, longer half-life) and better metabolic stability, but its lower logP and significantly reduced BBB penetration are major drawbacks for a CNS target. The difference in binding affinity is also considerable.

Given the importance of BBB penetration and strong binding for CNS GPCR targets, and the substantial affinity difference, Ligand A is the more promising candidate, despite its ADME liabilities. Optimization efforts could focus on improving its Caco-2 permeability and metabolic stability.

Output:
1
2025-04-17 05:02:54,727 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (354.491 and 355.435 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (98.66) is slightly higher than Ligand B (96.97), but both are below the 140 threshold for oral absorption and reasonably close to the 90 target for CNS penetration.

**logP:** Ligand A (1.203) is within the optimal 1-3 range. Ligand B (-0.188) is slightly below 1, which *could* indicate permeability issues, but is not a major concern at this stage.

**H-Bond Donors/Acceptors:** Ligand A has 4 HBD and 4 HBA, while Ligand B has 2 HBD and 5 HBA. Both are within acceptable limits (<=5 HBD and <=10 HBA).

**QED:** Both ligands have good QED scores (0.526 and 0.629, respectively), indicating drug-like properties.

**DILI:** Both ligands have similar DILI risk (8.298 and 41.644 percentile), with Ligand B being slightly higher, but both are below the concerning 60 threshold.

**BBB:** This is a critical parameter for a CNS target like DRD2. Ligand B (58.085) has a significantly better BBB penetration percentile than Ligand A (40.093). This is a major advantage for Ligand B.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.08 and -4.938), which is unusual and suggests poor permeability. However, these values are on a log scale, and the negative values are not directly comparable without knowing the scale.

**Aqueous Solubility:** Both ligands have negative solubility values (-2.561 and -1.481), which is also unusual and suggests poor solubility. Similar to Caco-2, the scale is unknown.

**hERG:** Both ligands have very low hERG inhibition liability (0.117 and 0.062), which is excellent.

**Microsomal Clearance:** Ligand A (21.892) has a higher microsomal clearance than Ligand B (-2.885), indicating lower metabolic stability. Ligand B is predicted to be more metabolically stable.

**In vitro Half-Life:** Ligand B (3.165) has a positive half-life, while Ligand A (-3.861) has a negative half-life. This suggests Ligand B is more stable *in vitro*.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.032 and 0.008), which is favorable for CNS penetration.

**Binding Affinity:** Both ligands have very similar and strong binding affinities (-7.8 and -7.7 kcal/mol). The difference is negligible.

**Overall Assessment:**

Ligand B is the more promising candidate. While both ligands have good affinity and acceptable physicochemical properties, Ligand B demonstrates significantly better predicted BBB penetration (58.085 vs 40.093) and improved metabolic stability (lower Cl_mic, positive half-life). The slightly better BBB penetration is crucial for a CNS-targeting drug. The slightly lower logP of Ligand B is a minor concern, but the strong affinity and other favorable properties outweigh this. The negative Caco-2 and solubility values are concerning for both, but these may be artifacts of the prediction method or scale.

Output:
1
2025-04-17 05:02:54,727 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 drug candidates, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (346.406 and 348.447 Da) fall within the ideal range of 200-500 Da.

**TPSA:** Ligand A (88.99) is better than Ligand B (85.77), both are below the 90 A^2 threshold for CNS targets.

**logP:** Ligand A (2.222) is optimal (1-3), while Ligand B (0.199) is quite low, potentially hindering membrane permeability.

**H-Bond Donors:** Both ligands have 2 HBD, which is within the acceptable limit of <=5.

**H-Bond Acceptors:** Ligand A has 3 HBA, and Ligand B has 5 HBA, both are within the acceptable limit of <=10.

**QED:** Both ligands have good QED scores (0.586 and 0.735, respectively), indicating drug-like properties.

**DILI:** Ligand A (54.478) has a moderate DILI risk, while Ligand B (16.44) has a very low DILI risk, which is a significant advantage.

**BBB:** Ligand A (68.67) has a decent BBB penetration, but Ligand B (28.655) is significantly lower. This is a critical factor for a CNS target like DRD2.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.002 and -5.09), which is unusual and suggests poor permeability. However, these values are on a log scale and may not be directly comparable.

**Aqueous Solubility:** Both ligands have negative solubility values (-3.949 and -0.193), indicating poor solubility.

**hERG Inhibition:** Ligand A (0.814) has a slightly higher hERG inhibition risk than Ligand B (0.244), but both are relatively low.

**Microsomal Clearance:** Ligand A (28.243) has moderate clearance, while Ligand B (-20.557) has negative clearance, which is not possible. This is likely an error in the data, but suggests Ligand B is highly metabolically stable.

**In vitro Half-Life:** Ligand A (-5.908) has a negative half-life, which is impossible. Ligand B (4.664) has a short half-life.

**P-gp Efflux:** Ligand A (0.366) has lower P-gp efflux liability than Ligand B (0.013), which is preferable for CNS penetration.

**Binding Affinity:** Ligand B (-8.2 kcal/mol) has a significantly stronger binding affinity than Ligand A (-7.1 kcal/mol). This 1.1 kcal/mol difference is substantial and can outweigh some ADME drawbacks.

**Overall Assessment:**

Ligand B has a much better binding affinity and lower DILI risk. However, its BBB penetration is significantly lower than Ligand A, and its logP is very low, which could hinder permeability. The negative values for clearance and half-life are concerning and likely data errors. Ligand A has better BBB and P-gp efflux, but its affinity is weaker and DILI risk is higher.

Given the importance of binding affinity for GPCRs, and the fact that the difference is substantial (1.1 kcal/mol), I would lean towards Ligand B *if* the negative clearance and half-life values are corrected. The low logP is a concern, but could potentially be addressed through structural modifications. The low DILI risk is also a significant benefit.

Output:
1
2025-04-17 05:02:54,727 - INFO - Reasoning:

Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (348.487 and 347.459 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (75.27) is slightly higher than Ligand B (72.36). Both are below the 90 A^2 threshold desirable for CNS targets, but Ligand B is preferable.

**3. logP:** Ligand A (2.749) and Ligand B (1.712) are both within the optimal 1-3 range. Ligand A is slightly better.

**4. H-Bond Donors:** Both ligands have 2 HBD, which is within the acceptable limit of <=5.

**5. H-Bond Acceptors:** Ligand A has 3 HBA, and Ligand B has 4. Both are below the 10 limit, but Ligand A is preferable.

**6. QED:** Both ligands have good QED scores (0.725 and 0.789, respectively), indicating drug-like properties. Ligand B is slightly better.

**7. DILI:** Ligand A (24.157) has a significantly lower DILI risk than Ligand B (39.201). This is a major advantage for Ligand A.

**8. BBB:** Both ligands have good BBB penetration (67.623% and 69.794%). Ligand B is slightly better.

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.776 and -5.013). This is unusual and suggests poor permeability. Ligand B is slightly worse.

**10. Aqueous Solubility:** Both ligands have negative solubility values (-3.378 and -2.517). This is also unusual and suggests poor solubility. Ligand B is slightly better.

**11. hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.071 and 0.34). Ligand A is preferable.

**12. Microsomal Clearance:** Both ligands have similar microsomal clearance values (54.965 and 53.761 mL/min/kg).

**13. In vitro Half-Life:** Ligand A (-27.959) has a significantly longer (less negative) in vitro half-life than Ligand B (0.944). This is a significant advantage for Ligand A.

**14. P-gp Efflux:** Both ligands have low P-gp efflux liability (0.071 and 0.181). Ligand A is preferable.

**15. Binding Affinity:** Ligand B (-7.9 kcal/mol) has a slightly better binding affinity than Ligand A (-8.6 kcal/mol). This is a key advantage for Ligand B.

**Overall Assessment:**

While Ligand B has a slightly better binding affinity and BBB penetration, Ligand A demonstrates superior safety (DILI), metabolic stability (half-life), and P-gp efflux. The slightly better affinity of Ligand B is outweighed by the significant advantages of Ligand A in terms of safety and pharmacokinetics. Given the CNS target, a lower DILI risk and longer half-life are crucial. The negative Caco-2 and solubility values are concerning for both, but can be addressed through formulation strategies.

Output:
0
2025-04-17 05:02:54,728 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (358.467 and 371.478 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (75.19) is better than Ligand B (88.16). For CNS targets, we want TPSA <= 90, both are within this range, but A is preferable.

**3. logP:** Both ligands have good logP values (2.659 and 1.721), falling within the optimal 1-3 range. Ligand A is slightly higher, which could be beneficial for membrane permeability.

**4. H-Bond Donors:** Ligand A (1) is better than Ligand B (2). Lower HBD generally favors permeability.

**5. H-Bond Acceptors:** Ligand A (6) is better than Ligand B (4). Lower HBA generally favors permeability.

**6. QED:** Both ligands have reasonable QED values (0.823 and 0.692), indicating good drug-like properties. Ligand A is better.

**7. DILI:** Ligand A (73.129) has a higher DILI risk than Ligand B (41.838). This is a significant drawback for Ligand A.

**8. BBB:** Both ligands have good BBB penetration (79.139 and 74.292), exceeding the 70% threshold for CNS targets. Ligand A is slightly better.

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.272 and -5.283). This is unusual and suggests poor permeability. This is a significant concern for both.

**10. Aqueous Solubility:** Both ligands have very poor aqueous solubility (-3.126 and -2.132). This is a major issue for both compounds.

**11. hERG Inhibition:** Both ligands show low hERG inhibition liability (0.532 and 0.225), which is good. Ligand B is better.

**12. Microsomal Clearance:** Ligand A (60.545) has a higher microsomal clearance than Ligand B (8.631), indicating lower metabolic stability. This is a significant drawback for Ligand A.

**13. In vitro Half-Life:** Ligand B (-18.905) has a much longer in vitro half-life than Ligand A (2.698). This is a major advantage for Ligand B.

**14. P-gp Efflux:** Ligand A (0.122) has lower P-gp efflux than Ligand B (0.085), which is preferable for CNS exposure.

**15. Binding Affinity:** Both ligands have excellent binding affinity (-8.1 and -8.3 kcal/mol). The difference is minimal.

**Overall Assessment:**

While Ligand A has slightly better TPSA, logP, BBB, and P-gp efflux, Ligand B is significantly better in several crucial areas: DILI risk, metabolic stability (lower Cl_mic and much longer t1/2), and hERG inhibition. The poor Caco-2 and solubility are concerning for both, but can potentially be addressed with formulation strategies. The lower DILI risk and improved metabolic stability of Ligand B are more critical for overall drug development success, especially considering the CNS target.

Output:
1
2025-04-17 05:02:54,728 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (343.471 and 345.403 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (64.41) is significantly better than Ligand B (102.05). For CNS targets, TPSA should be <= 90, and A is comfortably within this range, while B exceeds it.

**logP:** Both ligands have acceptable logP values (2.589 and 1.322), falling within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A (0 HBD, 3 HBA) is preferable to Ligand B (2 HBD, 6 HBA). Lower values generally improve permeability.

**QED:** Both ligands have good QED scores (0.721 and 0.851), indicating good drug-like properties.

**DILI:** Ligand A (17.449) has a much lower DILI risk than Ligand B (49.826). This is a significant advantage.

**BBB:** Ligand A (83.443) has a substantially higher BBB penetration percentile than Ligand B (54.44). This is *critical* for a CNS target like DRD2.

**Caco-2 Permeability:** Ligand A (-4.467) has a worse Caco-2 permeability than Ligand B (-5.215). However, this is less important than BBB for a CNS target.

**Aqueous Solubility:** Ligand A (-2.657) has a slightly worse solubility than Ligand B (-1.992). Solubility is important, but can often be addressed with formulation.

**hERG:** Both ligands have very low hERG inhibition liability (0.462 and 0.173), which is excellent.

**Microsomal Clearance:** Ligand A (41.617) has a higher microsomal clearance than Ligand B (2.278), suggesting lower metabolic stability. This is a drawback for A.

**In vitro Half-Life:** Ligand B (1.494) has a slightly longer half-life than Ligand A (-16.833).

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.063 and 0.035).

**Binding Affinity:** Both ligands have very similar and excellent binding affinities (-8.2 and -8.3 kcal/mol). The difference is negligible.

**Overall Assessment:**

Ligand A is significantly better due to its superior TPSA, DILI, and *especially* BBB penetration. While Ligand A has a higher microsomal clearance and slightly worse solubility, these are less critical concerns than the CNS penetration and safety profile. The similar binding affinities make the ADME properties the deciding factor.

Output:
1
2025-04-17 05:02:54,728 - INFO - Reasoning:

Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (346.471 and 379.482 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (67.43) is slightly higher than Ligand B (63.25), but both are below the 90 A^2 threshold desirable for CNS targets.

**3. logP:** Ligand A (2.15) is within the optimal 1-3 range. Ligand B (3.964) is approaching the upper limit, potentially raising concerns about solubility and off-target effects, but still acceptable.

**4. H-Bond Donors:** Both ligands have 2 HBD, which is within the acceptable limit of <=5.

**5. H-Bond Acceptors:** Ligand A has 3 HBA, and Ligand B has 6 HBA. Both are within the acceptable limit of <=10, but Ligand B is higher.

**6. QED:** Both ligands have QED values above 0.5 (0.724 and 0.636), indicating good drug-like properties.

**7. DILI:** Ligand A (31.601) has a significantly lower DILI risk than Ligand B (88.329). This is a major advantage for Ligand A.

**8. BBB:** Ligand B (70.027) has a slightly better BBB penetration score than Ligand A (65.801), but both are above the 70% threshold for CNS targets.

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.856 and -4.812). This is unusual and suggests poor permeability.

**10. Aqueous Solubility:** Both ligands have negative solubility values (-3.417 and -4.136). This is also unusual and suggests poor solubility.

**11. hERG Inhibition:** Ligand A (0.369) has a lower hERG inhibition liability than Ligand B (0.864), indicating a lower risk of cardiotoxicity.

**12. Microsomal Clearance:** Ligand B (98.502) has a higher microsomal clearance than Ligand A (48.305), suggesting lower metabolic stability.

**13. In vitro Half-Life:** Ligand A (-8.733) has a more negative in vitro half-life than Ligand B (54.026), suggesting a longer half-life.

**14. P-gp Efflux:** Ligand A (0.177) has a lower P-gp efflux liability than Ligand B (0.849), which is favorable for CNS exposure.

**15. Binding Affinity:** Both ligands have very similar and strong binding affinities (-7.7 and -8.6 kcal/mol). The difference is less than 1.5 kcal/mol, so it's not a decisive factor.

**Overall Assessment:**

While Ligand B has slightly better BBB penetration and a marginally better binding affinity, Ligand A is significantly better in terms of safety (DILI, hERG) and ADME properties (microsomal clearance, P-gp efflux, half-life). The poor Caco-2 and solubility values are concerning for both, but the other advantages of Ligand A outweigh the slight benefit of Ligand B's BBB score. For a CNS target like DRD2, minimizing potential toxicity and optimizing ADME properties are crucial.

Output:
0
2025-04-17 05:02:54,728 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (349.471 Da) is slightly lower, which could be beneficial for permeability. Ligand B (370.406 Da) is also acceptable.

**TPSA:** Ligand A (56.79) is excellent, well below the 90 A^2 threshold for CNS targets. Ligand B (109.33) is higher, but still reasonable, though less favorable for CNS penetration.

**logP:** Ligand A (3.808) is within the optimal range (1-3), while Ligand B (-0.086) is significantly below 1, raising concerns about permeability. This is a major strike against Ligand B.

**H-Bond Donors/Acceptors:** Both ligands have 1 HBD, which is good. Ligand A has 4 HBA, and Ligand B has 6 HBA. Both are within the acceptable limit of 10.

**QED:** Both ligands have similar QED values (0.736 and 0.719), indicating good drug-likeness.

**DILI:** Ligand A (42.458) has a lower DILI risk than Ligand B (64.676), which is preferable.

**BBB:** Both ligands have good BBB penetration (Ligand A: 74.874, Ligand B: 77.705), exceeding the 70% threshold for CNS targets.

**Caco-2 Permeability:** Ligand A (-4.154) and Ligand B (-4.58) both have negative values, which is unusual and suggests poor permeability. However, the scale isn't specified, so it's hard to interpret.

**Aqueous Solubility:** Both ligands have negative solubility values (-4.437 and -2.229), indicating poor aqueous solubility. This could be a formulation challenge.

**hERG Inhibition:** Ligand A (0.486) has a lower hERG risk than Ligand B (0.066), which is preferable.

**Microsomal Clearance:** Ligand A (90.231) has a higher microsomal clearance than Ligand B (1.651), meaning it's less metabolically stable. Ligand B is much more stable.

**In vitro Half-Life:** Ligand A (-6.498) has a negative half-life, which is impossible. This is a significant data quality issue. Ligand B (12.041) has a reasonable half-life.

**P-gp Efflux:** Ligand A (0.436) has lower P-gp efflux than Ligand B (0.012), which is favorable for CNS exposure.

**Binding Affinity:** Both ligands have identical binding affinities (-7.7 kcal/mol), which is excellent.

**Overall Assessment:**

Ligand A has a better logP, lower DILI risk, and lower P-gp efflux. However, its microsomal clearance is higher (less stable), and its in vitro half-life is nonsensical. Ligand B has better metabolic stability and a plausible half-life, but its very low logP is a major concern for permeability and CNS penetration. Given the importance of logP for GPCRs and CNS targets, and the questionable half-life of Ligand A, Ligand B is slightly more promising, *assuming* the negative Caco-2 and solubility values aren't indicative of a larger data quality issue. The negative half-life for Ligand A is a red flag.

Output:
1
2025-04-17 05:02:54,728 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (346.43 & 347.39 Da) fall comfortably within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (89.87) is better than Ligand B (91.22) as both are below the 90 A^2 threshold for CNS targets.

**3. logP:** Both ligands have acceptable logP values (1.6 & 2.463), falling within the optimal range of 1-3. Ligand B is slightly higher, which could potentially lead to some solubility issues, but is still within range.

**4. H-Bond Donors:** Ligand A (3) and Ligand B (2) are both within the acceptable limit of <=5.

**5. H-Bond Acceptors:** Both ligands have 4 H-bond acceptors, well below the limit of 10.

**6. QED:** Both ligands have good QED scores (0.707 & 0.827), indicating good drug-like properties.

**7. DILI:** Ligand A (39.473) has a significantly lower DILI risk than Ligand B (53.781). This is a substantial advantage.

**8. BBB:** Ligand B (72.237) has a much better BBB penetration percentile than Ligand A (42.226). This is a critical factor for a CNS target like DRD2.

**9. Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and suggests poor permeability. However, the scale is not specified, so it's hard to interpret.

**10. Aqueous Solubility:** Both ligands have negative solubility values, which is also unusual and suggests poor solubility.

**11. hERG Inhibition:** Both ligands have low hERG inhibition risk (0.347 & 0.524).

**12. Microsomal Clearance:** Ligand A (20.475) has a lower microsomal clearance than Ligand B (55.153), indicating better metabolic stability.

**13. In vitro Half-Life:** Ligand A (-5.106) has a more negative in vitro half-life, which is unusual and suggests a shorter half-life. Ligand B (-0.23) is better.

**14. P-gp Efflux:** Both ligands have low P-gp efflux liability (0.273 & 0.117).

**15. Binding Affinity:** Ligand A (-8.3 kcal/mol) has a slightly better binding affinity than Ligand B (-7.9 kcal/mol). While the difference is less than the 1.5 kcal/mol threshold, it's still a positive.

**Overall Assessment:**

Ligand B is clearly superior regarding BBB penetration, which is paramount for a CNS target. It also has a better in vitro half-life. However, Ligand A has a significantly lower DILI risk and better metabolic stability (lower Cl_mic). The affinity difference is minor. The unusual negative values for Caco-2 and solubility are concerning for both, but the difference in BBB is the most important factor.

Output:
1
2025-04-17 05:02:54,729 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (345.4 and 358.4 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (82.97) is slightly higher than Ligand B (76.14), but both are below the 90 A^2 threshold desirable for CNS targets.

**logP:** Ligand A (0.296) is quite low, potentially hindering permeability. Ligand B (2.37) is within the optimal 1-3 range. This is a significant advantage for Ligand B.

**H-Bond Donors/Acceptors:** Ligand A has 1 HBD and 5 HBA, while Ligand B has 2 HBD and 5 HBA. Both are within acceptable limits (<=5 HBD and <=10 HBA).

**QED:** Both ligands have high QED scores (0.83 and 0.845), indicating good drug-like properties.

**DILI:** Ligand A (24.78) has a much lower DILI risk than Ligand B (52.39). This is a positive for Ligand A.

**BBB:** Ligand B (85.54) has a significantly higher BBB penetration percentile than Ligand A (72.66). This is a crucial advantage for a CNS target like DRD2.

**Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and requires further investigation, but doesn't immediately disqualify either.

**Aqueous Solubility:** Both have negative solubility values, which is also unusual and requires further investigation, but doesn't immediately disqualify either.

**hERG:** Both ligands have low hERG inhibition liability (0.409 and 0.294), which is good.

**Microsomal Clearance:** Ligand A (5.56) has a much lower microsomal clearance than Ligand B (13.52), indicating better metabolic stability.

**In vitro Half-Life:** Ligand B (15.63) has a longer in vitro half-life than Ligand A (6.96), which is desirable.

**P-gp Efflux:** Both have very low P-gp efflux liability (0.025 and 0.033), which is favorable for CNS penetration.

**Binding Affinity:** Ligand B (-8.7 kcal/mol) has a stronger binding affinity than Ligand A (-7.9 kcal/mol). This difference of 0.8 kcal/mol is substantial and can outweigh some ADME drawbacks.

**Overall Assessment:**

Ligand B is the stronger candidate. While Ligand A has a lower DILI risk and better metabolic stability, Ligand B excels in the most critical areas for a CNS-targeting GPCR ligand: BBB penetration and binding affinity. The higher logP of Ligand B is also beneficial for permeability. The 0.8 kcal/mol difference in binding affinity is significant.

Output:
1
2025-04-17 05:02:54,729 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B based on the provided guidelines, prioritizing GPCR-specific properties (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (407.769 Da) is slightly higher than Ligand B (371.503 Da), but both are acceptable.

**TPSA:** Ligand A (81.7) is borderline for CNS targets (ideally <90), while Ligand B (73.32) is well within the desired range. This favors Ligand B.

**logP:** Ligand A (2.861) is optimal. Ligand B (-0.508) is significantly below the optimal range and could indicate poor membrane permeability. This favors Ligand A.

**H-Bond Donors/Acceptors:** Both ligands have acceptable HBD (1) and HBA (5/6) counts.

**QED:** Both ligands have reasonable QED scores (0.407 and 0.678), with Ligand B being slightly more drug-like.

**DILI:** Ligand A (80.962) has a higher DILI risk than Ligand B (26.871). This is a significant drawback for Ligand A.

**BBB:** Ligand A (60.644) has a moderate BBB penetration, while Ligand B (41.605) is quite low. For a CNS target like DRD2, a higher BBB value is crucial. Ligand A is favored here, but both are not optimal.

**Caco-2 Permeability:** Ligand A (-4.781) and Ligand B (-5.004) both have negative Caco-2 permeability values, indicating poor intestinal absorption. This is concerning for both.

**Aqueous Solubility:** Ligand A (-4.693) and Ligand B (-1.275) both have negative solubility values, which is problematic. Ligand B is slightly better.

**hERG:** Both ligands have low hERG inhibition liability (0.536 and 0.349), which is good.

**Microsomal Clearance:** Ligand A (74.073) has higher microsomal clearance than Ligand B (12.463), indicating lower metabolic stability. Ligand B is favored.

**In vitro Half-Life:** Ligand B (13.512 hours) has a longer half-life than Ligand A (10.109 hours), which is desirable.

**P-gp Efflux:** Ligand A (0.211) has lower P-gp efflux than Ligand B (0.042), which is favorable for CNS penetration.

**Binding Affinity:** Ligand A (-7.5 kcal/mol) has a significantly stronger binding affinity than Ligand B (-6.8 kcal/mol). This is a substantial advantage for Ligand A, potentially outweighing some of its ADME drawbacks.

**Overall Assessment:**

Ligand A has a superior binding affinity and better (though still not great) BBB penetration and P-gp efflux. However, it has a higher DILI risk and lower metabolic stability. Ligand B has better ADME properties (lower DILI, better metabolic stability, longer half-life, better TPSA) but significantly weaker binding affinity.

Given the importance of potency for GPCR targets, and the >1.5 kcal/mol difference in binding affinity, I believe Ligand A is the more promising candidate, despite its ADME liabilities. Further optimization could focus on addressing the DILI and metabolic stability issues.

Output:
1
2025-04-17 05:02:54,729 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (343.362 and 352.431 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (101.21) is slightly above the optimal <90 for CNS targets, but still reasonable. Ligand B (84.94) is well within the desired range.

**logP:** Both ligands have good logP values (1.75 and 1.518), falling within the 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A has 2 HBD and 5 HBA, while Ligand B has 1 HBD and 5 HBA. Both are acceptable.

**QED:** Ligand A (0.827) has a significantly better QED score than Ligand B (0.579), suggesting a more drug-like profile.

**DILI:** Ligand A has a concerningly high DILI risk (85.964%), indicating potential liver toxicity. Ligand B has a much lower and acceptable DILI risk (33.812%).

**BBB:** Both ligands have reasonable BBB penetration (62.233% and 68.282%), but neither exceeds the desirable >70% threshold.

**Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and suggests poor permeability. This is a significant concern for both.

**Aqueous Solubility:** Both have negative solubility values, indicating very poor aqueous solubility. This is a major drawback.

**hERG Inhibition:** Both have very low hERG inhibition risk (0.399 and 0.077), which is excellent.

**Microsomal Clearance:** Both have relatively low microsomal clearance (2.076 and 2.358 mL/min/kg), suggesting reasonable metabolic stability.

**In vitro Half-Life:** Ligand A has a very poor in vitro half-life (-17.79 hours), which is unrealistic. Ligand B has a short but positive half-life (0.791 hours).

**P-gp Efflux:** Both have very low P-gp efflux liability (0.013 and 0.017), which is favorable for CNS penetration.

**Binding Affinity:** Ligand B has a significantly stronger binding affinity (-7.6 kcal/mol) compared to Ligand A (-9.0 kcal/mol). This is a substantial advantage.

**Overall Assessment:**

Ligand A has a better QED score and slightly better affinity, but suffers from a very high DILI risk, extremely poor solubility, an unrealistic half-life, and questionable Caco-2 permeability. Ligand B, while having a lower QED, exhibits a much lower DILI risk, better binding affinity, and slightly better BBB penetration. The poor solubility and Caco-2 values are concerning for both, but the DILI risk and affinity are the most critical factors here. Given the CNS target, a lower DILI risk and stronger binding are more important than a slightly better QED.

Output:
1
2025-04-17 05:02:54,729 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (347.463 and 368.84 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (90.98) is slightly above the optimal <90 for CNS targets, but acceptable. Ligand B (73.38) is well within the desired range.

**logP:** Both ligands have good logP values (1.981 and 2.862), falling within the 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A has 2 HBD and 4 HBA, which are within acceptable limits. Ligand B has 1 HBD and 5 HBA, also acceptable.

**QED:** Both ligands have similar and good QED scores (0.738 and 0.763), indicating good drug-likeness.

**DILI:** Ligand A (38.387) has a lower DILI risk than Ligand B (54.75), which is preferable.

**BBB:** This is a critical parameter for CNS targets. Ligand B (81.504) has a significantly higher BBB penetration percentile than Ligand A (41.218). This is a major advantage for Ligand B.

**Caco-2 Permeability:** Ligand A (-5.493) has a negative value, indicating poor permeability. Ligand B (-4.752) is also poor, but slightly better than A.

**Aqueous Solubility:** Both ligands have poor aqueous solubility (-1.791 and -3.418). This could pose formulation challenges, but is less critical than BBB for a CNS target.

**hERG Inhibition:** Ligand A (0.086) has a very low hERG risk, which is excellent. Ligand B (0.718) is higher, but still relatively low.

**Microsomal Clearance:** Ligand A (8.732) has lower microsomal clearance than Ligand B (51.339), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand B (47.025) has a much longer in vitro half-life than Ligand A (-3.844), which is a significant advantage.

**P-gp Efflux:** Ligand A (0.108) has lower P-gp efflux than Ligand B (0.323), which is preferable for CNS penetration.

**Binding Affinity:** Ligand B (-7.6) has a significantly stronger binding affinity than Ligand A (0.0). This is a crucial factor, and the 1.6 kcal/mol difference is substantial enough to outweigh some of the ADME drawbacks.

**Overall Assessment:**

Ligand B is the stronger candidate. While Ligand A has a lower DILI risk and better P-gp efflux, Ligand B's significantly higher BBB penetration and, most importantly, its *much* stronger binding affinity (-7.6 vs 0.0 kcal/mol) make it the more promising drug candidate. The longer half-life is also a considerable benefit. The slightly higher DILI and P-gp efflux are less concerning given the strong affinity and BBB penetration.



Output:
1
2025-04-17 05:02:54,730 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B based on the provided guidelines, prioritizing GPCR-specific properties (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (363.487 and 363.502 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (104.11) is higher than the preferred <90 for CNS targets, while Ligand B (36.44) is excellent. This is a significant advantage for Ligand B.

**logP:** Both ligands have acceptable logP values (2.091 and 3.713), falling within the 1-3 range. Ligand B is slightly higher, which could be beneficial for membrane permeability, but isn't a major concern for either.

**H-Bond Donors/Acceptors:** Ligand A has 3 HBD and 5 HBA, which are reasonable. Ligand B has 0 HBD and 4 HBA, also acceptable.

**QED:** Both ligands have good QED scores (0.7 and 0.752), indicating good drug-like properties.

**DILI:** Ligand A (66.421) has a higher DILI risk than Ligand B (21.946). This is a clear advantage for Ligand B.

**BBB:** Ligand B (94.029) has a significantly higher BBB penetration score than Ligand A (43.273). This is *critical* for a CNS target like DRD2.

**Caco-2 Permeability:** Ligand A (-5.593) has poor Caco-2 permeability, while Ligand B (-4.501) is slightly better, but still not great.

**Aqueous Solubility:** Both ligands have very poor aqueous solubility (-2.843 and -3.395). This could pose formulation challenges, but is less critical than BBB for CNS targets.

**hERG Inhibition:** Ligand A (0.219) has a slightly lower hERG risk than Ligand B (0.793), but both are relatively low.

**Microsomal Clearance:** Ligand B (53.901) has a lower microsomal clearance than Ligand A (39.857), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand B (44.095) has a longer in vitro half-life than Ligand A (12.453), which is desirable.

**P-gp Efflux:** Ligand A (0.037) has much lower P-gp efflux liability than Ligand B (0.364), which is a significant advantage for CNS exposure.

**Binding Affinity:** Ligand A (-8.7 kcal/mol) has a significantly stronger binding affinity than Ligand B (-7.1 kcal/mol). This is a substantial advantage for Ligand A.

**Overall Assessment:**

While Ligand A has superior binding affinity, Ligand B excels in crucial ADME properties for a CNS-targeting GPCR. The significantly higher BBB penetration (94.029 vs 43.273), lower DILI risk (21.946 vs 66.421), and better metabolic stability (lower Cl_mic and longer t1/2) of Ligand B outweigh the affinity difference. The lower P-gp efflux for Ligand A is a plus, but the TPSA of Ligand A is concerning. The affinity difference of 1.6 kcal/mol is substantial, but can potentially be optimized in later stages of drug development. Given the importance of CNS penetration for DRD2, Ligand B is the more promising candidate.

Output:
1
2025-04-17 05:02:54,730 - INFO - Batch 165 complete. Total preferences: 2640
2025-04-17 05:02:54,730 - INFO - Processing batch 166/512...
2025-04-17 05:03:36,799 - INFO - Reasoning:

Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight (MW):** Both ligands (351.403 and 351.382 Da) fall comfortably within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (102.69) is slightly higher than Ligand B (96.33). Both are below the 140 A^2 threshold for oral absorption and reasonably close to the 90 A^2 target for CNS penetration. Ligand B is slightly better here.

**3. logP:** Ligand A (1.015) is within the optimal 1-3 range. Ligand B (-0.246) is slightly below 1, which *could* indicate potential permeability issues, though not drastically. Ligand A is better here.

**4. H-Bond Donors (HBD):** Both ligands have 2 HBD, which is within the acceptable limit of <=5.

**5. H-Bond Acceptors (HBA):** Both ligands have 6 HBA, also within the acceptable limit of <=10.

**6. QED:** Both ligands have good QED scores (0.725 and 0.763, respectively), indicating good drug-like properties.

**7. DILI:** Ligand A (55.176) has a lower DILI risk than Ligand B (72.741). This is a significant advantage for Ligand A.

**8. BBB:** Both ligands have excellent BBB penetration (71.772 and 75.262, respectively), exceeding the desirable >70% threshold for CNS targets. Ligand B is slightly better.

**9. Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and requires further investigation. However, the magnitude of the negative value for Ligand A (-5.068) is larger than Ligand B (-5.055), suggesting potentially lower permeability for Ligand A.

**10. Aqueous Solubility:** Both have negative solubility values, which is also unusual and suggests very poor aqueous solubility. Ligand B (-2.944) is slightly less negative than Ligand A (-1.97), indicating slightly better solubility.

**11. hERG Inhibition:** Ligand A (0.094) has a very low hERG inhibition risk, significantly lower than Ligand B (0.349). This is a major advantage for Ligand A.

**12. Microsomal Clearance:** Ligand A (23.104) has a higher microsomal clearance than Ligand B (-1.532). This suggests Ligand B is more metabolically stable.

**13. In vitro Half-Life:** Ligand A (-7.055) has a longer in vitro half-life than Ligand B (6.95).

**14. P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.027 and 0.032), which is favorable for CNS exposure.

**15. Binding Affinity:** Ligand B (-9.0 kcal/mol) has a significantly stronger binding affinity than Ligand A (-7.9 kcal/mol). This is a substantial advantage for Ligand B, exceeding the 1.5 kcal/mol difference threshold.

**Overall Assessment:**

While Ligand A has advantages in DILI risk and hERG inhibition, the significantly stronger binding affinity of Ligand B (-9.0 vs -7.9 kcal/mol) is a decisive factor, especially for a GPCR target. The slightly better BBB penetration and metabolic stability of Ligand B also contribute to its favorability. The unusual Caco-2 and solubility values for both ligands are concerning and would require experimental validation, but the potency advantage of Ligand B is likely to outweigh these concerns.

Output:
1
2025-04-17 05:03:36,799 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (363.405 Da and 344.415 Da) fall within the ideal range of 200-500 Da.

**TPSA:** Ligand A (107.53) is slightly above the preferred <90 for CNS targets, while Ligand B (84.42) is comfortably within the range. This gives a slight edge to Ligand B.

**logP:** Ligand A (0.32) is quite low, potentially hindering membrane permeability. Ligand B (1.243) is better, falling within the optimal 1-3 range. This is a significant advantage for Ligand B.

**H-Bond Donors/Acceptors:** Ligand A has 4 HBD and 4 HBA, which are acceptable. Ligand B has 1 HBD and 5 HBA, also acceptable.

**QED:** Ligand B (0.785) has a considerably higher QED score than Ligand A (0.448), indicating better overall drug-likeness.

**DILI:** Ligand A (29.159) has a lower DILI risk than Ligand B (47.034), which is favorable.

**BBB:** Both ligands have good BBB penetration (Ligand A: 69.213, Ligand B: 70.648), though ideally, we'd want >70. They are comparable here.

**Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and suggests poor permeability. However, the scale isn't defined, so it's hard to interpret.

**Aqueous Solubility:** Both have negative solubility values, which is also unusual. Again, the scale is undefined.

**hERG Inhibition:** Both ligands have very low hERG inhibition risk (Ligand A: 0.263, Ligand B: 0.207).

**Microsomal Clearance:** Ligand A (9.408) has significantly lower microsomal clearance than Ligand B (38.883), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (-14.129) has a negative half-life, which is not possible. Ligand B (-2.776) is also negative, indicating a problem with the data.

**P-gp Efflux:** Both have very low P-gp efflux liability (Ligand A: 0.009, Ligand B: 0.032).

**Binding Affinity:** Ligand B (-9.3 kcal/mol) has a significantly stronger binding affinity than Ligand A (-7.0 kcal/mol). This is a crucial advantage, exceeding the 1.5 kcal/mol threshold.

**Overall Assessment:**

Ligand B is the stronger candidate. While Ligand A has a lower DILI risk and better metabolic stability, Ligand B excels in key GPCR-relevant properties: better logP, higher QED, and *significantly* stronger binding affinity. The slightly higher TPSA of Ligand A is less concerning than the poor logP. The negative values for Caco-2 and solubility are concerning for both, but the affinity difference is substantial enough to favor Ligand B.

Output:
1
2025-04-17 05:03:36,799 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (345.403 and 361.324 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (118.09) is better than Ligand B (124.24). Both are reasonably good for CNS penetration, being below the 140 A^2 threshold, but A is closer to the preferred <90 A^2 for CNS targets.

**logP:** Ligand B (0.849) is better than Ligand A (0.379). A logP of 0.379 is quite low and could hinder membrane permeability. Ligand B is closer to the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Both have 3 HBDs and 4 HBAs, which are acceptable.

**QED:** Both ligands have similar QED values (0.662 and 0.666), indicating good drug-likeness.

**DILI:** Ligand B (39.667) has a lower DILI risk than Ligand A (46.956), making it preferable. Both are below the concerning 60 threshold.

**BBB:** Ligand B (72.237) significantly outperforms Ligand A (28.306) in BBB penetration. This is *critical* for a CNS target like DRD2.

**Caco-2 Permeability:** Both have negative Caco-2 values (-5.437 and -5.342), which is unusual and suggests poor permeability. However, these values are on a scale where negative values are possible and don't necessarily disqualify a compound.

**Aqueous Solubility:** Both have negative solubility values (-2.576 and -2.992), which is also unusual and suggests poor solubility. This could be a formulation challenge.

**hERG:** Both ligands have low hERG inhibition liability (0.419 and 0.302), which is good.

**Microsomal Clearance:** Ligand A (-35.059) has much lower (better) microsomal clearance than Ligand B (-0.028). This suggests better metabolic stability for Ligand A.

**In vitro Half-Life:** Ligand B (8.529) has a significantly longer in vitro half-life than Ligand A (4.206), which is desirable.

**P-gp Efflux:** Both have very low P-gp efflux liability (0.019 and 0.043), which is favorable for CNS penetration.

**Binding Affinity:** Ligand A (-8.3 kcal/mol) has a substantially stronger binding affinity than Ligand B (-6.6 kcal/mol). This is a significant advantage, exceeding the 1.5 kcal/mol threshold.

**Overall Assessment:**

While Ligand A has superior binding affinity and metabolic stability, Ligand B excels in BBB penetration, which is paramount for a CNS target. The significantly lower logP of Ligand A is a major concern, potentially hindering its ability to cross cell membranes. The improved BBB, DILI, and half-life of Ligand B outweigh the affinity difference, especially considering the affinity of Ligand B is still quite good.

Output:
1
2025-04-17 05:03:36,800 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (349.358 and 349.351 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (83.91) is excellent, well below the 90 A^2 threshold for CNS targets. Ligand B (139.27) is approaching the upper limit for good oral absorption (140 A^2) and is less favorable for CNS penetration.

**logP:** Ligand A (2.315) is within the optimal 1-3 range. Ligand B (-1.926) is below 1, which could hinder permeation.

**H-Bond Donors/Acceptors:** Ligand A (HBD=1, HBA=4) and Ligand B (HBD=2, HBA=9) both fall within acceptable ranges, although Ligand B's HBA is closer to the upper limit.

**QED:** Ligand A (0.886) has a very strong drug-like profile. Ligand B (0.636) is still acceptable, but less ideal.

**DILI:** Both ligands have relatively high DILI risk (Ligand A: 75.766, Ligand B: 65.568), but are still within a range that isn't immediately disqualifying.

**BBB:** Ligand A (65.025) is reasonably good, but not exceptional. Ligand B (24.002) is very poor for a CNS target. This is a major drawback.

**Caco-2 Permeability:** Ligand A (-4.537) and Ligand B (-5.701) both have negative values, which is unusual. These values are likely on a log scale and indicate poor permeability. However, the negative values don't allow for direct comparison.

**Aqueous Solubility:** Ligand A (-3.094) and Ligand B (-1.205) also have negative values, indicating poor solubility. Again, the negative values don't allow for direct comparison.

**hERG Inhibition:** Both ligands show very low hERG inhibition risk (Ligand A: 0.049, Ligand B: 0.031).

**Microsomal Clearance:** Ligand A (2.865) has lower clearance than Ligand B (6.117), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (-33.336) has a significantly longer half-life than Ligand B (15.073), which is a major advantage.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (Ligand A: 0.042, Ligand B: 0.011).

**Binding Affinity:** Ligand A (-9.6 kcal/mol) has a substantially stronger binding affinity than Ligand B (-0.0 kcal/mol). This is a decisive advantage.

**Overall Assessment:**

Ligand A is clearly superior. Its favorable TPSA, logP, QED, metabolic stability (Cl_mic, t1/2), and *especially* its significantly stronger binding affinity and better BBB penetration outweigh any concerns about its DILI risk. Ligand B's poor logP and extremely low BBB penetration are dealbreakers for a CNS-targeting drug, even with a slightly lower DILI risk. The large difference in binding affinity is also a critical factor.

Output:
0
2025-04-17 05:03:36,800 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (370.515 Da) and Ligand B (345.403 Da) are both acceptable.

**TPSA:** Ligand A (67.87) is excellent, well below the 90 A^2 threshold for CNS targets. Ligand B (108.63) is still reasonable but higher, potentially impacting BBB penetration.

**logP:** Ligand A (1.431) is optimal. Ligand B (-0.359) is slightly low, which could hinder membrane permeability.

**H-Bond Donors/Acceptors:** Ligand A (1 HBD, 5 HBA) and Ligand B (2 HBD, 5 HBA) both meet the criteria of <=5 HBD and <=10 HBA.

**QED:** Both ligands have acceptable QED values (Ligand A: 0.766, Ligand B: 0.685), indicating good drug-like properties.

**DILI:** Both ligands have similar and acceptable DILI risk (Ligand A: 45.056, Ligand B: 48.662), both below the 60 threshold.

**BBB:** This is a crucial parameter for a CNS target like DRD2. Ligand A (67.08) is considerably better than Ligand B (38.813). A value >70 is desirable, and Ligand A is closer.

**Caco-2 Permeability:** Ligand A (-4.977) and Ligand B (-5.016) both have negative values, which is unusual. It's difficult to interpret without knowing the scale, but they appear similarly poor.

**Aqueous Solubility:** Ligand A (-3.067) and Ligand B (-1.425) both have negative values, suggesting poor aqueous solubility. Ligand B is slightly better.

**hERG Inhibition:** Both ligands have very low hERG risk (Ligand A: 0.353, Ligand B: 0.13).

**Microsomal Clearance:** Ligand A (29.833) has a lower clearance than Ligand B (6.093), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (10.884) has a longer half-life than Ligand B (-24.786). The negative value for Ligand B is concerning and likely an error or indicates very rapid degradation.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (Ligand A: 0.063, Ligand B: 0.006), which is favorable for CNS penetration.

**Binding Affinity:** Ligand B (-7.5 kcal/mol) has a slightly better binding affinity than Ligand A (-7.2 kcal/mol), but the difference is not substantial.

**Overall Assessment:**

Ligand A is superior due to its significantly better BBB penetration (67.08 vs 38.813), better metabolic stability (higher half-life and lower clearance), and more favorable TPSA. While Ligand B has a slightly better binding affinity, the ADME properties of Ligand A are more promising for a CNS-targeting drug. The negative half-life value for Ligand B is a major red flag.

Output:
0
2025-04-17 05:03:36,800 - INFO - Reasoning:

Let's analyze Ligand A and Ligand B based on the provided guidelines, prioritizing GPCR-specific properties (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (351.359 and 344.499 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (110.11) is higher than the optimal <90 for CNS targets, while Ligand B (49.41) is excellent. This is a significant advantage for Ligand B.

**logP:** Ligand A (0.111) is quite low, potentially hindering permeability. Ligand B (3.298) is within the optimal 1-3 range. This is a strong advantage for Ligand B.

**H-Bond Donors/Acceptors:** Ligand A has 2 HBD and 6 HBA, acceptable values. Ligand B has 1 HBD and 2 HBA, also acceptable.

**QED:** Both ligands have reasonable QED scores (0.779 and 0.628), indicating good drug-like properties.

**DILI:** Ligand A (57.929) has a moderate DILI risk, while Ligand B (29.236) has a low risk. This favors Ligand B.

**BBB:** Ligand A (50.679) has a moderate BBB penetration, below the desirable >70 for CNS targets. Ligand B (73.672) is excellent, exceeding the 70% threshold. This is a major advantage for Ligand B.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.87 and -4.821), which is unusual and suggests poor permeability. However, these values are on a scale where negative values are possible, and direct comparison is difficult without knowing the scale's specifics.

**Aqueous Solubility:** Both ligands have negative solubility values (-2.308 and -3.446), again suggesting poor solubility. Similar to Caco-2, the scale is unknown.

**hERG:** Both ligands have low hERG inhibition liability (0.128 and 0.245), which is good.

**Microsomal Clearance:** Ligand A (-40.235) has a lower (better) microsomal clearance than Ligand B (47.179), indicating greater metabolic stability.

**In vitro Half-Life:** Ligand A (8.194) has a shorter half-life than Ligand B (-11.256). A negative half-life is unusual and likely indicates a very stable compound.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.009 and 0.131), which is favorable for CNS penetration.

**Binding Affinity:** Ligand B (-8.2 kcal/mol) has a slightly better binding affinity than Ligand A (-7.7 kcal/mol), although the difference is not huge.

**Overall Assessment:**

Ligand B is significantly better suited as a drug candidate for a CNS target like DRD2. Its superior TPSA, logP, BBB penetration, and lower DILI risk outweigh the slightly worse microsomal clearance and half-life. The better binding affinity also contributes to its favorability. While both ligands have issues with Caco-2 and solubility, the CNS-specific properties are paramount for a DRD2 ligand, and Ligand B excels in these areas.

Output:
1
2025-04-17 05:03:36,800 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (351.443 and 367.921 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (95.86) is slightly above the optimal <90 for CNS targets, but still reasonable. Ligand B (58.36) is excellent, well below 90.

**3. logP:** Both ligands have good logP values (2.242 and 3.389), falling within the 1-3 range.

**4. H-Bond Donors:** Ligand A has 3 HBD, which is acceptable. Ligand B has 1 HBD, also acceptable.

**5. H-Bond Acceptors:** Both ligands have 4 HBA, which is within the acceptable limit of <=10.

**6. QED:** Both ligands have good QED scores (0.601 and 0.838), indicating good drug-like properties.

**7. DILI:** Ligand A (34.742) has a slightly higher DILI risk than Ligand B (19.736), but both are below the concerning threshold of 60.

**8. BBB:** This is a crucial parameter for a CNS target like DRD2. Ligand A (25.746) has a low BBB percentile, which is a significant drawback. Ligand B (62.97) has a much better BBB percentile, exceeding 60 and indicating good potential for CNS penetration.

**9. Caco-2 Permeability:** Ligand A (-5.301) has poor Caco-2 permeability. Ligand B (-4.662) is also poor, but slightly better than Ligand A.

**10. Aqueous Solubility:** Both ligands have poor aqueous solubility (-1.85 and -3.13). This could pose formulation challenges.

**11. hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.046 and 0.594).

**12. Microsomal Clearance:** Ligand A (15.071) has lower microsomal clearance than Ligand B (61.903), suggesting better metabolic stability.

**13. In vitro Half-Life:** Ligand A (-22.274) has a negative half-life, which is not possible. This is likely an error in the data. Ligand B (16.819) has a reasonable in vitro half-life.

**14. P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.02 and 0.666), which is favorable for CNS penetration.

**15. Binding Affinity:** Both ligands have very similar and excellent binding affinities (-7.7 and -7.8 kcal/mol). The difference is negligible.

**Overall Assessment:**

Despite Ligand A's slightly better metabolic stability, its extremely poor BBB penetration and questionable half-life are major concerns for a CNS drug. Ligand B excels in BBB penetration and has a reasonable half-life, making it a much more promising candidate despite slightly higher metabolic clearance. The similar binding affinities make the ADME properties the deciding factor.

Output:
1
2025-04-17 05:03:36,800 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (352.391 and 356.438 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (102.88) is slightly above the optimal <90 for CNS targets, but still reasonable. Ligand B (84.5) is well within the desired range. This favors Ligand B.

**3. logP:** Both ligands have logP values within the optimal 1-3 range (1.068 and 1.664). Ligand B is slightly higher, potentially aiding membrane permeability.

**4. H-Bond Donors:** Ligand A (1) and Ligand B (2) are both acceptable, below the threshold of 5.

**5. H-Bond Acceptors:** Ligand A (7) and Ligand B (4) are both below the threshold of 10.

**6. QED:** Ligand A (0.864) has a significantly better QED score than Ligand B (0.68), indicating a more drug-like profile overall.

**7. DILI:** Ligand A (68.98) has a slightly higher DILI risk than Ligand B (56.844), but both are acceptable (<60 is good).

**8. BBB:** Ligand B (80.574) has a substantially better BBB penetration percentile than Ligand A (71.811). This is a crucial factor for a CNS target like DRD2, strongly favoring Ligand B.

**9. Caco-2 Permeability:** Ligand A (-4.309) and Ligand B (-4.995) both have negative values, which is unusual. Assuming these are log scale values, lower values indicate lower permeability. Ligand B is slightly worse here.

**10. Aqueous Solubility:** Ligand A (-2.959) and Ligand B (-2.332) both have negative values, indicating poor solubility. Ligand B is slightly better.

**11. hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.152 and 0.194).

**12. Microsomal Clearance:** Ligand B (20.907) has a lower microsomal clearance than Ligand A (36.936), suggesting better metabolic stability.

**13. In vitro Half-Life:** Ligand B (2.448) has a slightly longer in vitro half-life than Ligand A (-18.976).

**14. P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.032 and 0.052).

**15. Binding Affinity:** Ligand B (-8.5 kcal/mol) has a significantly stronger binding affinity than Ligand A (-7.3 kcal/mol). This 1.2 kcal/mol difference is substantial and can outweigh minor ADME drawbacks.

**Overall Assessment:**

While Ligand A has a better QED score, Ligand B excels in the most critical parameters for a CNS-targeting GPCR ligand: BBB penetration and binding affinity. The lower microsomal clearance and slightly improved half-life also contribute to its favorability. The slightly lower TPSA is also beneficial. The small differences in solubility and Caco-2 permeability are less concerning given the strong affinity and BBB score.

Output:
1
2025-04-17 05:03:36,801 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (352.45 and 340.423 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (61.8) is better than Ligand B (71.34). Both are below the 90 A^2 threshold for CNS targets, but A is closer to the ideal.

**3. logP:** Both ligands (3.049 and 2.737) are within the optimal 1-3 range.

**4. H-Bond Donors:** Both have 2 HBD, which is acceptable (<=5).

**5. H-Bond Acceptors:** Ligand A has 4 HBA, and Ligand B has 3. Both are below the 10 threshold.

**6. QED:** Both ligands have similar QED values (0.826 and 0.782), indicating good drug-likeness.

**7. DILI:** Ligand A (13.843) has a significantly lower DILI risk than Ligand B (35.401). This is a substantial advantage.

**8. BBB:** Ligand B (75.301) has a better BBB penetration percentile than Ligand A (68.282). While both are good, B is closer to the desirable >70 for CNS targets.

**9. Caco-2 Permeability:** Both have negative Caco-2 values (-4.678 and -4.828), which is unusual and suggests poor permeability. However, these values are on a scale where negative values are possible, and direct comparison is difficult without knowing the scale's specifics.

**10. Aqueous Solubility:** Both have negative solubility values (-2.731 and -3.107), also unusual. Similar to Caco-2, interpretation is limited without knowing the scale.

**11. hERG Inhibition:** Ligand A (0.807) has a slightly higher hERG risk than Ligand B (0.505), but both are relatively low.

**12. Microsomal Clearance:** Ligand B (61.232) has a higher microsomal clearance than Ligand A (32.21), indicating lower metabolic stability.

**13. In vitro Half-Life:** Ligand B (64.892) has a longer in vitro half-life than Ligand A (22.616).

**14. P-gp Efflux:** Ligand A (0.142) has a lower P-gp efflux liability than Ligand B (0.284), which is favorable for CNS penetration.

**15. Binding Affinity:** Ligand B (-9.1 kcal/mol) has a significantly stronger binding affinity than Ligand A (-7.9 kcal/mol). This >1.5 kcal/mol difference is a major advantage.

**Overall Assessment:**

Ligand B has a superior binding affinity and better BBB penetration. However, it has a higher DILI risk and higher microsomal clearance. Ligand A has a much lower DILI risk and better metabolic stability (lower Cl_mic), and lower P-gp efflux. The difference in binding affinity is significant, and for a GPCR target, strong binding is paramount. The slightly higher DILI risk of Ligand B might be manageable with further optimization, while improving the affinity of Ligand A to reach -9.1 kcal/mol could be more challenging. Given the importance of affinity for GPCRs, and the acceptable (though not ideal) DILI risk for Ligand B, I favor Ligand B.

Output:
1
2025-04-17 05:03:36,801 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 drug candidates, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (347.463 and 343.471 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (70.59) is better than Ligand B (52.65). For CNS targets, we want TPSA <= 90, both are within this range, but A is closer to the upper limit.

**3. logP:** Ligand B (2.585) is better than Ligand A (0.92). The optimal range is 1-3, and B falls comfortably within it. A is slightly below 1, which *could* indicate permeability issues.

**4. H-Bond Donors:** Both ligands have 1 HBD, which is acceptable (<=5).

**5. H-Bond Acceptors:** Ligand A has 6 HBA, and Ligand B has 3. Both are within the acceptable range of <=10.

**6. QED:** Ligand A (0.825) has a significantly better QED score than Ligand B (0.491), indicating a more drug-like profile.

**7. DILI:** Ligand A (19.038) has a much lower DILI risk than Ligand B (46.801). This is a significant advantage for Ligand A.

**8. BBB:** Ligand A (81.582) has a better BBB penetration percentile than Ligand B (79.256). Both are good (>70), but A is slightly better.

**9. Caco-2 Permeability:** Ligand A (-5.146) has worse Caco-2 permeability than Ligand B (-4.525). Lower (more negative) values indicate lower permeability.

**10. Aqueous Solubility:** Ligand A (-0.7) has better aqueous solubility than Ligand B (-3.446). Higher values indicate better solubility.

**11. hERG Inhibition:** Both ligands have low hERG inhibition liability (0.436 and 0.661, respectively).

**12. Microsomal Clearance:** Ligand A (-7.222) has significantly lower microsomal clearance than Ligand B (48.429), indicating better metabolic stability.

**13. In vitro Half-Life:** Ligand A (11.173) has a longer in vitro half-life than Ligand B (7.047).

**14. P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.014 and 0.424, respectively).

**15. Binding Affinity:** Ligand B (-8.3) has a slightly better binding affinity than Ligand A (-8.0). While the difference is small, it's still a factor.

**Overall Assessment:**

Ligand A excels in key areas for a CNS-targeting GPCR drug: QED, DILI risk, BBB penetration, metabolic stability (Cl_mic & t1/2), and solubility. While its logP is slightly lower and Caco-2 permeability is worse than Ligand B, the advantages in the other critical parameters outweigh these drawbacks. Ligand B has a slightly better binding affinity and logP, but its higher DILI risk and lower metabolic stability are concerning. The difference in binding affinity is not large enough to overcome the significant ADME advantages of Ligand A.

Output:
1
2025-04-17 05:03:36,801 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (350.511 and 367.555 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (94.99) is better than Ligand B (38.77). For CNS targets, we want TPSA <= 90, so Ligand A is closer to this threshold.

**3. logP:** Both ligands have acceptable logP values (2.97 and 4.755), falling within the 1-3 range, but Ligand B is pushing the upper limit.

**4. H-Bond Donors:** Ligand A (4) is acceptable, while Ligand B (0) is also good.

**5. H-Bond Acceptors:** Both ligands have acceptable HBA counts (7 and 4 respectively), well below the threshold of 10.

**6. QED:** Both ligands have good QED scores (0.515 and 0.599), indicating drug-like properties.

**7. DILI:** Ligand A (38.348) has a slightly higher DILI risk than Ligand B (22.024), but both are below the concerning threshold of 60.

**8. BBB:** Ligand B (89.957) has a significantly better BBB penetration percentile than Ligand A (77.821). This is a *critical* factor for a CNS target like DRD2.

**9. Caco-2:** Both ligands have negative Caco-2 values, which is unusual and suggests poor permeability. However, the scale is not defined, so it's difficult to interpret.

**10. Solubility:** Both ligands have negative solubility values, which is also unusual. Again, the scale is undefined, making interpretation difficult.

**11. hERG:** Both ligands have low hERG inhibition liability (0.729 and 0.821), which is favorable.

**12. Cl_mic:** Ligand A (74.323) has a lower microsomal clearance than Ligand B (104.662), suggesting better metabolic stability.

**13. t1/2:** Ligand A (44.833) has a longer in vitro half-life than Ligand B (35.305), which is desirable.

**14. Pgp:** Ligand A (0.049) has significantly lower P-gp efflux liability than Ligand B (0.888), meaning it's less likely to be pumped out of the brain. This is crucial for CNS penetration.

**15. Binding Affinity:** Ligand B (-7.1 kcal/mol) has a slightly better binding affinity than Ligand A (-8.1 kcal/mol). While a difference of 1.0 kcal/mol is notable, the ADME properties are more concerning.

**Overall Assessment:**

While Ligand B has slightly better binding affinity, Ligand A is the superior candidate. The key advantages of Ligand A are its lower P-gp efflux, lower microsomal clearance, and longer half-life. Critically, its TPSA is also more favorable for CNS penetration. Ligand B's higher logP and P-gp efflux are concerning, potentially limiting brain exposure. The superior BBB penetration of Ligand B is a positive, but is outweighed by the other factors.



Output:
0
2025-04-17 05:03:36,801 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 drug candidates, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (342.443 and 348.443 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (75.19) is better than Ligand B (80.57). Both are below the 90 A^2 threshold desirable for CNS targets, but A is closer to the optimal range.

**logP:** Ligand A (1.71) is within the optimal 1-3 range. Ligand B (2.964) is also acceptable, but closer to the upper limit.

**H-Bond Donors:** Ligand A (1) is preferable to Ligand B (2). Lower HBD generally improves permeability.

**H-Bond Acceptors:** Both ligands have 4 HBA, which is acceptable (<=10).

**QED:** Ligand B (0.719) has a slightly better QED score than Ligand A (0.548), indicating a more drug-like profile.

**DILI:** Ligand A (35.169) has a significantly lower DILI risk than Ligand B (50.33). This is a major advantage for Ligand A.

**BBB:** Ligand A (58.821) has a better BBB penetration percentile than Ligand B (47.15), though both are below the desirable >70 for CNS targets.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.205 and -5.017), which is unusual and suggests poor permeability. This is a significant concern for both.

**Aqueous Solubility:** Ligand A (-0.936) is better than Ligand B (-3.269), indicating better solubility.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.293 and 0.441).

**Microsomal Clearance:** Ligand A (5.654) has a much lower microsomal clearance than Ligand B (68.586), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (-11.247) has a negative half-life, which is not possible and likely an error. Ligand B (18.439) has a reasonable in vitro half-life.

**P-gp Efflux:** Ligand A (0.036) has much lower P-gp efflux liability than Ligand B (0.426), which is crucial for CNS penetration.

**Binding Affinity:** Ligand B (-8.2) has a slightly better binding affinity than Ligand A (-7.9). However, the difference is relatively small (0.3 kcal/mol).

**Overall Assessment:**

Despite the slightly better affinity of Ligand B, Ligand A is the more promising candidate. Ligand A has significantly better DILI risk, lower P-gp efflux, lower microsomal clearance, better solubility, and a more favorable TPSA. The negative half-life for Ligand A is a data quality issue that needs to be resolved, but the other advantages are substantial. Both ligands have poor Caco-2 permeability, which is a concern, but the other ADME properties of Ligand A are more favorable for CNS drug development. The slightly better affinity of Ligand B is unlikely to outweigh the other benefits of Ligand A.

Output:
0
2025-04-17 05:03:36,801 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 drug candidates, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (341.426 Da) is slightly lower, which is generally favorable for permeability.

**2. TPSA:** Ligand A (29.54) is excellent, well below the 90 Angstroms threshold for CNS targets. Ligand B (58.64) is higher but still reasonable, though less ideal for CNS penetration.

**3. logP:** Both ligands have good logP values (A: 3.973, B: 3.125), falling within the optimal 1-3 range.

**4. H-Bond Donors:** Both ligands have acceptable HBD counts (A: 0, B: 1).

**5. H-Bond Acceptors:** Both ligands have acceptable HBA counts (A: 2, B: 4).

**6. QED:** Both ligands have high QED values (A: 0.842, B: 0.873), indicating good drug-like properties.

**7. DILI:** Both ligands have acceptable DILI risk (A: 50.989, B: 47.15), below the concerning threshold of 60.

**8. BBB:** This is a critical parameter for a CNS target like DRD2. Ligand A (82.047) has a significantly higher BBB percentile than Ligand B (63.009). This is a major advantage for Ligand A.

**9. Caco-2 Permeability:** Both have negative values, indicating a scale rather than a percentile. Without knowing the scale, it's difficult to interpret.

**10. Aqueous Solubility:** Both have negative values, indicating a scale rather than a percentile. Without knowing the scale, it's difficult to interpret.

**11. hERG Inhibition:** Both ligands show low hERG inhibition liability (A: 0.835, B: 0.445), which is good.

**12. Microsomal Clearance:** Ligand B (37.291) has significantly lower microsomal clearance than Ligand A (82.832), suggesting better metabolic stability.

**13. In vitro Half-Life:** Ligand B (20.654 hours) has a much longer in vitro half-life than Ligand A (-11.503 hours). This is a substantial advantage for Ligand B.

**14. P-gp Efflux:** Both ligands show low P-gp efflux liability (A: 0.798, B: 0.376). Ligand B has a lower value, suggesting less efflux.

**15. Binding Affinity:** Both ligands have strong binding affinities (A: -9.7 kcal/mol, B: -8.5 kcal/mol). Ligand A has a 1.2 kcal/mol advantage, which is significant and can outweigh some ADME drawbacks.

**Overall Assessment:**

Ligand A excels in BBB penetration and binding affinity, which are crucial for a CNS GPCR target. Ligand B has better metabolic stability (lower Cl_mic, longer t1/2) and lower P-gp efflux, but its BBB penetration is significantly lower. The 1.2 kcal/mol difference in binding affinity is substantial. Given the importance of CNS penetration for DRD2, and the strong affinity of Ligand A, it is the more promising candidate.

Output:
1
2025-04-17 05:03:36,802 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (389.901 and 343.431 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (80.75) is slightly above the optimal <90 for CNS targets, but still reasonable. Ligand B (71.33) is excellent, well below 90.

**3. logP:** Ligand A (2.936) is within the optimal 1-3 range. Ligand B (1.047) is at the lower end, potentially impacting permeability.

**4. H-Bond Donors:** Both have 0 HBD, which is acceptable.

**5. H-Bond Acceptors:** Both have 5 HBA, which is acceptable.

**6. QED:** Both ligands have good QED scores (0.723 and 0.769), indicating drug-like properties.

**7. DILI:** Ligand A (66.615) has a higher DILI risk than Ligand B (43.66). This is a concern for Ligand A.

**8. BBB:** Ligand B (81.776) has a significantly better BBB penetration percentile than Ligand A (56.34). This is *critical* for a CNS target like DRD2.

**9. Caco-2 Permeability:** Ligand A (-4.376) has poor Caco-2 permeability, suggesting poor absorption. Ligand B (-4.971) is also poor, but slightly worse.

**10. Aqueous Solubility:** Ligand A (-2.964) and Ligand B (-1.582) both have poor aqueous solubility.

**11. hERG Inhibition:** Both ligands show very low hERG inhibition risk (0.123 and 0.099).

**12. Microsomal Clearance:** Ligand A (67.392) has higher microsomal clearance than Ligand B (36.481), indicating lower metabolic stability.

**13. In vitro Half-Life:** Ligand B (-0.495) has a negative half-life, which is unusual and suggests very rapid metabolism or an issue with the assay. Ligand A (76.498) has a good half-life.

**14. P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.232 and 0.163).

**15. Binding Affinity:** Ligand B (-8.5 kcal/mol) has a significantly stronger binding affinity than Ligand A (-7.6 kcal/mol). This is a substantial advantage (>1.5 kcal/mol difference).

**Overall Assessment:**

While Ligand A has a better in vitro half-life, Ligand B is superior overall, particularly due to its significantly better BBB penetration (81.776 vs 56.34) and binding affinity (-8.5 vs -7.6 kcal/mol). The lower DILI risk for Ligand B is also a positive. The slightly lower logP of Ligand B is a minor concern, but the strong affinity and excellent BBB penetration outweigh this. The negative half-life for Ligand B is concerning and would need further investigation, but the other properties are so favorable that it still appears to be the better candidate.

Output:
1
2025-04-17 05:03:36,802 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (407.352 and 376.806 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (41.57) is slightly higher than Ligand B (37.49). Both are below the 90 A^2 threshold for CNS targets, which is good.

**3. logP:** Both ligands have logP values (4.86 and 4.434) that are a bit high, potentially leading to solubility issues or off-target interactions. Ligand A is slightly higher.

**4. H-Bond Donors:** Both have 1 HBD, which is acceptable.

**5. H-Bond Acceptors:** Ligand A has 2 HBA, and Ligand B has 3. Both are within the acceptable limit of <=10.

**6. QED:** Both ligands have good QED scores (0.709 and 0.838), indicating good drug-like properties.

**7. DILI:** Ligand A (39.938) has a slightly better DILI score than Ligand B (47.732), indicating a lower risk of liver injury. Both are below the concerning threshold of 60.

**8. BBB:** Both ligands have excellent BBB penetration (88.988 and 90.035), which is crucial for a CNS target like DRD2. Ligand B is marginally better.

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.217 and -4.631). This is unusual and suggests poor permeability. However, these values are on a strange scale and may not be directly comparable.

**10. Aqueous Solubility:** Both ligands have very poor aqueous solubility (-5.876 and -4.765). This is a significant concern, especially given their relatively high logP values.

**11. hERG Inhibition:** Ligand A (0.731) has a slightly lower hERG inhibition liability than Ligand B (0.939), which is preferable.

**12. Microsomal Clearance:** Ligand A (94.487) has a significantly higher microsomal clearance than Ligand B (29.759), indicating lower metabolic stability. This is a major drawback for Ligand A.

**13. In vitro Half-Life:** Ligand B (-6.38) has a much longer in vitro half-life than Ligand A (44.187). This is a substantial advantage for Ligand B.

**14. P-gp Efflux:** Ligand A (0.476) has lower P-gp efflux than Ligand B (0.754), which is beneficial for CNS exposure.

**15. Binding Affinity:** Ligand B (-8.4 kcal/mol) has a significantly stronger binding affinity than Ligand A (-7.3 kcal/mol). This is a crucial advantage, as a >1.5 kcal/mol difference can outweigh other drawbacks.

**Overall Assessment:**

Ligand B is the more promising candidate. While both have solubility concerns and questionable Caco-2 permeability, Ligand B's significantly stronger binding affinity, much better metabolic stability (lower Cl_mic, longer t1/2), and slightly better BBB penetration outweigh the slightly higher P-gp efflux and DILI risk. The affinity difference is substantial enough to potentially overcome the solubility issues through formulation strategies. Ligand A's high metabolic clearance is a major concern.

Output:
1
2025-04-17 05:03:36,802 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (361.423 and 353.471 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (97.39) is better than Ligand B (127.08). For CNS targets, we want TPSA <= 90, so Ligand A is closer to this threshold.

**3. logP:** Both ligands have good logP values (2.001 and 2.237), falling within the optimal 1-3 range.

**4. H-Bond Donors:** Ligand A (2) is preferable to Ligand B (4). Lower HBD generally improves permeability.

**5. H-Bond Acceptors:** Ligand A (6) is preferable to Ligand B (8). Lower HBA generally improves permeability.

**6. QED:** Both ligands have similar QED values (0.627 and 0.613), indicating good drug-like properties.

**7. DILI:** Ligand A (81.039) has a higher DILI risk than Ligand B (57.425). This is a negative for Ligand A.

**8. BBB:** Both ligands have good BBB penetration (69.794 and 70.997). Both are above the 70% threshold desirable for CNS targets.

**9. Caco-2 Permeability:** Ligand A (-4.559) has worse Caco-2 permeability than Ligand B (-5.071). Lower values suggest poorer absorption.

**10. Aqueous Solubility:** Ligand A (-3.592) has better aqueous solubility than Ligand B (-4.368).

**11. hERG Inhibition:** Ligand A (0.223) has a lower hERG inhibition risk than Ligand B (0.453). This is a positive for Ligand A.

**12. Microsomal Clearance:** Ligand B (82.372) has higher microsomal clearance than Ligand A (61.365), indicating faster metabolism and lower metabolic stability. This is a negative for Ligand B.

**13. In vitro Half-Life:** Ligand A (14.987) has a longer half-life than Ligand B (1.953). This is a significant positive for Ligand A.

**14. P-gp Efflux:** Ligand A (0.16) has lower P-gp efflux liability than Ligand B (0.013). Lower P-gp efflux is better for CNS exposure.

**15. Binding Affinity:** Ligand B (-7.6 kcal/mol) has a slightly better binding affinity than Ligand A (-8.7 kcal/mol). While both are excellent, the difference is 1.1 kcal/mol.

**Overall Assessment:**

Ligand A is generally better. It has a lower TPSA, fewer H-bonds, better metabolic stability (lower Cl_mic and longer t1/2), lower P-gp efflux, and lower hERG risk. While Ligand B has slightly better binding affinity and lower DILI risk, the ADME properties of Ligand A are more favorable, especially for a CNS target like DRD2. The 1.1 kcal/mol difference in binding affinity is unlikely to outweigh the significant improvements in ADME properties.

Output:
0
2025-04-17 05:03:36,802 - INFO - Batch 166 complete. Total preferences: 2656
2025-04-17 05:03:36,802 - INFO - Processing batch 167/512...
2025-04-17 05:04:19,777 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 drug candidates, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (353.5 and 369.5 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (72.88) is significantly better than Ligand B (95.58). For CNS targets, we want TPSA <= 90, so Ligand A is preferable.

**logP:** Ligand A (1.399) is within the optimal 1-3 range. Ligand B (0.673) is a bit low, potentially hindering permeability.

**H-Bond Donors/Acceptors:** Both have 2 HBD and 4 HBA, which are acceptable.

**QED:** Both ligands have good QED scores (0.615 and 0.745), indicating drug-likeness.

**DILI:** Ligand A (4.382) has a slightly better DILI score than Ligand B (41.838), indicating lower potential for liver injury. Both are below the concerning threshold of 60.

**BBB:** Both ligands have acceptable BBB penetration (54.013 and 55.215). While >70 is desirable, these are reasonable, and not a major differentiating factor.

**Caco-2:** Ligand A (-4.939) and Ligand B (-5.522) both have negative Caco-2 values, which is unusual and suggests very poor permeability. This is a significant concern for both.

**Solubility:** Ligand A (-1.23) is better than Ligand B (-2.359), indicating slightly better aqueous solubility.

**hERG:** Both ligands have very low hERG inhibition risk (0.298 and 0.123).

**Microsomal Clearance:** Ligand A (11.272) has a much lower microsomal clearance than Ligand B (26.836), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (11.969) has a positive half-life, while Ligand B (-21.441) has a negative half-life, which is not physically possible. This is a major red flag for Ligand B.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.037 and 0.022).

**Binding Affinity:** Ligand B (-8.0) has a significantly better binding affinity than Ligand A (-6.9). This is a substantial advantage (1.1 kcal/mol difference).

**Overall Assessment:**

Ligand B has a significantly better binding affinity, which is a crucial factor. However, it has a negative in vitro half-life, which is a dealbreaker. Ligand A has a more favorable ADME profile overall (better TPSA, lower clearance, positive half-life, better solubility, and slightly better DILI), but its binding affinity is weaker. The poor Caco-2 values for both are concerning, but the negative half-life of Ligand B is a more critical issue.

Given the importance of affinity for GPCRs, and acknowledging the poor Caco-2 values, Ligand B's superior binding affinity *would* be compelling if its other properties weren't so problematic. However, the negative half-life makes it an unviable candidate. Therefore, Ligand A is the more promising candidate, despite its weaker binding. Further optimization would focus on improving the affinity of Ligand A while maintaining its favorable ADME properties.

Output:
0
2025-04-17 05:04:19,777 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (355.523 and 345.403 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (101.29) is better than Ligand B (108.88). Both are reasonably close to the 90 A^2 threshold for CNS targets, but A is preferable.

**3. logP:** Ligand A (2.217) is optimal (1-3). Ligand B (0.366) is quite low, potentially hindering permeation. This is a significant drawback for B.

**4. H-Bond Donors:** Both ligands have 3 HBD, which is within the acceptable limit of <=5.

**5. H-Bond Acceptors:** Ligand A has 3 HBA, while Ligand B has 5. Both are within the acceptable limit of <=10, but A is slightly better.

**6. QED:** Both ligands have similar QED values (0.622 and 0.673), indicating good drug-likeness.

**7. DILI:** Ligand A (12.485) has a much lower DILI risk than Ligand B (47.421). This is a substantial advantage for A.

**8. BBB:** Ligand A (59.403) has a better BBB percentile than Ligand B (26.91). While neither is >70, A is significantly better, which is critical for a CNS target like DRD2.

**9. Caco-2:** Ligand A (-5.243) and Ligand B (-5.674) both have negative Caco-2 values, which is unusual and suggests poor permeability.

**10. Solubility:** Ligand A (-3.068) and Ligand B (-2.42) both have negative solubility values, which is also unusual and suggests poor solubility.

**11. hERG:** Both ligands have very low hERG inhibition liability (0.214 and 0.124), which is excellent.

**12. Cl_mic:** Ligand B (-6.665) has a *negative* microsomal clearance, which is impossible. This is a red flag, and suggests an error in the data. Ligand A (58.459) has a reasonable clearance.

**13. t1/2:** Ligand A (-16.049) has a negative half-life, which is impossible. Ligand B (12.832) has a reasonable half-life.

**14. Pgp:** Both ligands have very low Pgp efflux liability (0.003 and 0.027), which is favorable.

**15. Binding Affinity:** Ligand B (-8.8 kcal/mol) has a slightly better binding affinity than Ligand A (-8.0 kcal/mol). However, the difference (0.8 kcal/mol) is not large enough to overcome the significant ADME deficiencies of Ligand B.

**Overall Assessment:**

Ligand A is the more promising candidate despite the unusual Caco-2 and Solubility values, and the impossible half-life. Ligand B has a negative microsomal clearance, which is a critical flaw. Ligand A has better BBB penetration, lower DILI risk, and a more reasonable (though still problematic) ADME profile. The slightly better affinity of Ligand B does not outweigh the substantial drawbacks.

Output:
0
2025-04-17 05:04:19,778 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (347.449 and 346.435 Da) are within the ideal 200-500 Da range.

**TPSA:** Ligand A (12.47) is excellent, well below the 90 A^2 threshold for CNS targets. Ligand B (92.15) is significantly higher, exceeding the ideal range and potentially hindering BBB penetration.

**logP:** Ligand A (4.879) is slightly high, potentially leading to solubility issues or off-target interactions, but still within a manageable range. Ligand B (0.303) is very low, which is problematic for membrane permeability and CNS penetration.

**H-Bond Donors/Acceptors:** Ligand A (0 HBD, 2 HBA) is favorable. Ligand B (2 HBD, 6 HBA) is also acceptable, though slightly higher.

**QED:** Ligand B (0.8) has a better QED score than Ligand A (0.491), suggesting a more drug-like profile overall.

**DILI:** Ligand A (11.245) has a much lower DILI risk than Ligand B (51.842), which is a significant advantage.

**BBB:** Ligand A (88.29) shows excellent BBB penetration potential, exceeding the 70% threshold. Ligand B (63.474) is considerably lower, raising concerns about sufficient CNS exposure.

**Caco-2 Permeability:** Ligand A (-4.426) has poor Caco-2 permeability. Ligand B (-5.279) is even worse.

**Aqueous Solubility:** Ligand A (-4.605) has poor aqueous solubility. Ligand B (-1.565) is better, but still not ideal.

**hERG:** Both ligands have low hERG inhibition liability (0.964 and 0.2, respectively), which is positive.

**Microsomal Clearance:** Ligand A (45.075) has higher microsomal clearance than Ligand B (13.537), indicating lower metabolic stability.

**In vitro Half-Life:** Ligand B (23.265) has a much longer in vitro half-life than Ligand A (-4.3), which is a significant advantage.

**P-gp Efflux:** Ligand A (0.685) has moderate P-gp efflux liability. Ligand B (0.011) has very low P-gp efflux liability, which is highly desirable for CNS penetration.

**Binding Affinity:** Both ligands have comparable binding affinities (-8.4 and -8.8 kcal/mol). The difference is minimal and doesn't strongly favor either molecule.

**Overall Assessment:**

Considering the GPCR-specific priorities, Ligand A excels in BBB penetration and has a much lower DILI risk. However, its poor Caco-2 permeability, aqueous solubility, and higher metabolic clearance are concerning. Ligand B has a better QED score, lower P-gp efflux, and longer half-life, but suffers from poor BBB penetration and a higher DILI risk.

Given the importance of CNS penetration for a DRD2 target (involved in CNS disorders), and the relatively small difference in binding affinity, **Ligand A is the more promising candidate despite its drawbacks.** The poor permeability and solubility can potentially be addressed through formulation strategies, while achieving sufficient brain exposure is critical for efficacy.

Output:
0
2025-04-17 05:04:19,778 - INFO - Reasoning:

Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (362.333 and 369.487 Da) fall comfortably within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (116.93) is slightly higher than Ligand B (109.57). Both are below the 140 A^2 threshold for oral absorption, and reasonably close to the 90 A^2 target for CNS penetration, but Ligand B is preferable.

**3. logP:** Ligand A (1.079) is within the optimal 1-3 range. Ligand B (0.356) is a bit low, potentially hindering permeability. This favors Ligand A.

**4. H-Bond Donors:** Ligand A (3) and Ligand B (2) are both acceptable, below the 5 limit.

**5. H-Bond Acceptors:** Ligand A (6) and Ligand B (4) are both acceptable, below the 10 limit.

**6. QED:** Ligand A (0.722) has a better QED score than Ligand B (0.498), indicating a more drug-like profile.

**7. DILI:** Ligand B (21.908) has a significantly lower DILI risk than Ligand A (49.321), which is a major advantage.

**8. BBB:** Ligand A (82.435) has a better BBB penetration percentile than Ligand B (58.123). This is crucial for a CNS target like DRD2, and strongly favors Ligand A.

**9. Caco-2:** Ligand A (-4.786) and Ligand B (-5.32) both have negative Caco-2 values, which is unusual and suggests poor permeability. This is a concern for both, but the values are similar.

**10. Solubility:** Ligand A (-2.223) and Ligand B (-2.32) have similar, poor aqueous solubility.

**11. hERG:** Both ligands have very low hERG inhibition risk (0.374 and 0.113 respectively).

**12. Cl_mic:** Ligand A (-11.399) has a lower (better) microsomal clearance than Ligand B (-5.083), indicating greater metabolic stability.

**13. t1/2:** Ligand A (-35.643) has a longer in vitro half-life than Ligand B (-24.545), which is favorable.

**14. Pgp:** Both ligands have very low P-gp efflux liability (0.029 and 0.014 respectively).

**15. Binding Affinity:** Ligand A (-8.2 kcal/mol) has a significantly stronger binding affinity than Ligand B (-7.8 kcal/mol). This is a substantial advantage, potentially outweighing some of the ADME drawbacks.

**Overall Assessment:**

Ligand A excels in binding affinity and BBB penetration, both critical for a CNS GPCR target. It also has better QED, metabolic stability, and half-life. However, Ligand B has a much lower DILI risk. The difference in binding affinity (0.4 kcal/mol) is significant, and the improved BBB of Ligand A is also very important. While Ligand B's lower DILI is attractive, the stronger binding and better CNS penetration of Ligand A are more critical for DRD2 targeting.

Output:
1
2025-04-17 05:04:19,778 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (348.45 & 357.49 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (88.67) is excellent for CNS penetration, being well below 90. Ligand B (29.54) is even better.

**logP:** Ligand A (0.44) is quite low, potentially hindering membrane permeability. Ligand B (4.503) is slightly high, potentially causing solubility issues or off-target effects, but is within an acceptable range.

**H-Bond Donors/Acceptors:** Ligand A has 3 HBD and 4 HBA, which are reasonable. Ligand B has 0 HBD and 2 HBA, also acceptable.

**QED:** Both ligands have good QED scores (0.696 and 0.7), indicating drug-likeness.

**DILI:** Ligand A (16.91) has a lower DILI risk than Ligand B (11.52), which is preferable.

**BBB:** This is crucial for a CNS target. Ligand A (20.24) has a very poor BBB percentile. Ligand B (96.08) is excellent, indicating high brain penetration.

**Caco-2 Permeability:** Ligand A (-5.472) has very poor Caco-2 permeability, consistent with its low logP. Ligand B (-4.507) is also poor, but better than A.

**Aqueous Solubility:** Ligand A (-1.402) and Ligand B (-4.294) both have poor aqueous solubility.

**hERG Inhibition:** Ligand A (0.368) has a lower hERG risk than Ligand B (0.892).

**Microsomal Clearance:** Ligand A (-30.781) has very low microsomal clearance, suggesting high metabolic stability. Ligand B (72.939) has higher clearance, meaning faster metabolism.

**In vitro Half-Life:** Ligand A (6.245 hours) has a shorter half-life than Ligand B (-2.97 hours, which is unusual and likely indicates a very long half-life).

**P-gp Efflux:** Ligand A (0.012) has very low P-gp efflux, which is excellent for CNS penetration. Ligand B (0.577) has moderate P-gp efflux.

**Binding Affinity:** Ligand B (-8.1 kcal/mol) has significantly better binding affinity than Ligand A (-0.0 kcal/mol). This is a substantial advantage.

**Overall Assessment:**

Ligand A suffers from extremely poor BBB penetration, low logP, and very weak binding affinity. While it has good metabolic stability and low P-gp efflux, these are overshadowed by its major deficiencies.

Ligand B, despite slightly higher logP and moderate P-gp efflux, excels in BBB penetration and, crucially, has a much stronger binding affinity. The higher affinity is likely to outweigh the minor ADME drawbacks.

Output:
1
2025-04-17 05:04:19,778 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (338.371 and 344.459 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (93.96) is slightly above the preferred <90 for CNS targets, but still reasonable. Ligand B (70.4) is excellent, well below 90.

**3. logP:** Both ligands have good logP values (2.549 and 3.731), falling within the optimal 1-3 range. Ligand B is slightly higher, potentially increasing permeability but also raising concerns about off-target effects.

**4. H-Bond Donors:** Both have 2 HBD, which is within the acceptable limit of <=5.

**5. H-Bond Acceptors:** Ligand A has 7 HBA, and Ligand B has 4. Both are within the acceptable limit of <=10.

**6. QED:** Both ligands have good QED scores (0.687 and 0.89), indicating drug-like properties. Ligand B is slightly better.

**7. DILI:** Ligand A (84.606) has a higher DILI risk than Ligand B (41.179). This is a significant negative for Ligand A.

**8. BBB:** Ligand B (87.864) has a substantially better BBB penetration score than Ligand A (72.237). This is a critical advantage for a CNS target like DRD2.

**9. Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and likely indicates a problem with the prediction method, or a very poor permeability.

**10. Aqueous Solubility:** Both have negative solubility values, which is also unusual and likely indicates a problem with the prediction method, or a very poor solubility.

**11. hERG Inhibition:** Both ligands have low hERG inhibition risk (0.198 and 0.811).

**12. Microsomal Clearance:** Ligand A (35.897) has lower microsomal clearance than Ligand B (42.124), suggesting better metabolic stability.

**13. In vitro Half-Life:** Ligand B (72.584) has a significantly longer in vitro half-life than Ligand A (9.603). This is a major advantage.

**14. P-gp Efflux:** Both ligands have low P-gp efflux liability (0.368 and 0.124). Ligand B is slightly better.

**15. Binding Affinity:** Both ligands have excellent binding affinities (-9.4 and -8.9 kcal/mol). Ligand A is slightly better (-9.4 vs -8.9), but the difference is less than 1.5 kcal/mol, so it's not decisive.

**Overall Assessment:**

Ligand B is the stronger candidate. While Ligand A has slightly better binding affinity and metabolic stability, Ligand B excels in crucial areas for a CNS-targeting GPCR: significantly better BBB penetration, lower DILI risk, and a much longer in vitro half-life. The TPSA value for Ligand B is also more favorable. The negative Caco-2 and solubility values are concerning for both, but the other advantages of Ligand B outweigh this.

Output:
1
2025-04-17 05:04:19,778 - INFO - Reasoning:

Let's analyze Ligand A and Ligand B for their potential as DRD2 drug candidates, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (343.43 & 345.49 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (84.23) is better than Ligand B (43.86). For CNS targets, we want TPSA <= 90, both are within this range, but A is closer to the upper limit.

**3. logP:** Both ligands have good logP values (2.335 & 1.742), falling within the optimal 1-3 range. Ligand B is slightly lower, which *could* indicate slightly better solubility, but isn't a major concern.

**4. H-Bond Donors:** Ligand A has 2 HBD, and Ligand B has 0. Both are acceptable (<=5).

**5. H-Bond Acceptors:** Ligand A has 4 HBA, Ligand B has 3. Both are acceptable (<=10).

**6. QED:** Both ligands have similar QED values (0.756 & 0.732), indicating good drug-like properties.

**7. DILI:** Ligand A has a DILI risk of 60.3%, which is borderline high. Ligand B has a much lower DILI risk of 7.2%, a significant advantage.

**8. BBB:** This is critical for a CNS target like DRD2. Ligand B (91.043%) is *excellent*, exceeding the >70% threshold. Ligand A (54.595%) is considerably lower and less desirable.

**9. Caco-2 Permeability:** Both have negative Caco-2 values (-4.888 & -4.711). These values are unusual and suggest poor permeability. However, these are likely reported as logP values, and negative values simply mean permeability is very low.

**10. Aqueous Solubility:** Ligand A (-3.84) is slightly better than Ligand B (-1.795), indicating slightly better solubility.

**11. hERG Inhibition:** Ligand A (0.157) has a slightly lower hERG inhibition risk than Ligand B (0.518), which is good.

**12. Microsomal Clearance:** Ligand B (28.229) has significantly lower microsomal clearance than Ligand A (81.631), indicating better metabolic stability.

**13. In vitro Half-Life:** Ligand B (7.529) has a longer half-life than Ligand A (32.34), which is desirable.

**14. P-gp Efflux:** Ligand A (0.288) has lower P-gp efflux than Ligand B (0.096), which is preferable for CNS penetration.

**15. Binding Affinity:** Ligand B (-7.5 kcal/mol) has a significantly stronger binding affinity than Ligand A (-9.3 kcal/mol). This is a substantial advantage, potentially outweighing some of the minor ADME drawbacks of Ligand A.

**Overall Assessment:**

While Ligand A has slightly better solubility and P-gp efflux, Ligand B is clearly superior. Its significantly better BBB penetration, lower DILI risk, improved metabolic stability (lower Cl_mic and longer t1/2), and *much* stronger binding affinity make it the more promising drug candidate. The strong binding affinity of Ligand B (-7.5 kcal/mol) is a major advantage.

Output:
1
2025-04-17 05:04:19,779 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (335.37 and 348.44 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (101.88) is slightly above the optimal <90 for CNS targets, but still reasonable. Ligand B (78.87) is excellent, well below 90.

**logP:** Both ligands have good logP values (1.33 and 0.85), falling within the 1-3 range.

**H-Bond Donors/Acceptors:** Both have 2 HBD and 4 HBA, which are within acceptable limits.

**QED:** Ligand A (0.883) has a significantly better QED score than Ligand B (0.551), indicating a more drug-like profile.

**DILI:** Ligand A (67.78) has a higher DILI risk than Ligand B (18.73), which is a negative for A.

**BBB:** Ligand A (35.98) has a very low BBB penetration percentile, making it less desirable for a CNS target. Ligand B (28.85) is also low, but slightly better than A. Both are far from the >70 desirable for CNS targets.

**Caco-2:** Both ligands have negative Caco-2 values, which is unusual and suggests poor permeability.

**Solubility:** Both ligands have negative solubility values, which is also unusual and suggests poor solubility.

**hERG:** Both ligands have very low hERG inhibition liability, which is positive.

**Microsomal Clearance:** Ligand A (-6.31) has a much lower (better) microsomal clearance than Ligand B (2.18), suggesting greater metabolic stability.

**In vitro Half-Life:** Ligand A (-25.62) has a much longer in vitro half-life than Ligand B (-1.53), which is a significant advantage.

**P-gp efflux:** Both ligands have very low P-gp efflux liability, which is positive.

**Binding Affinity:** Ligand A (-8.4 kcal/mol) has a significantly stronger binding affinity than Ligand B (-7.8 kcal/mol). The 0.6 kcal/mol difference is substantial and can outweigh some ADME drawbacks.

**Overall Assessment:**

Despite Ligand A's higher DILI risk and poor BBB penetration, its significantly stronger binding affinity (-8.4 vs -7.8 kcal/mol), better QED, lower Cl_mic, and longer half-life are compelling advantages, especially considering the GPCR target class. The affinity difference is the most important factor here. While BBB is critical for CNS targets, a potent ligand might still show some CNS effect even with limited BBB penetration, especially if efflux is low. The poor Caco-2 and solubility are concerning, but could potentially be addressed with formulation strategies. Ligand B's lower DILI and slightly better BBB are overshadowed by its weaker binding affinity and lower QED.

Output:
1
2025-04-17 05:04:19,779 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (366.49 Da and 360.38 Da) are within the ideal 200-500 Da range.

**TPSA:** Ligand A (67.67) is significantly better than Ligand B (81.34). For CNS targets, we want TPSA <= 90, and A is closer to the ideal <=60 range. B is pushing the upper limit.

**logP:** Ligand A (1.744) is good, falling within the optimal 1-3 range. Ligand B (3.092) is also acceptable, but closer to the upper end, potentially increasing off-target interactions.

**H-Bond Donors/Acceptors:** Ligand A (0 HBD, 6 HBA) and Ligand B (1 HBD, 5 HBA) both have reasonable numbers of H-bonds.

**QED:** Both ligands have similar QED values (0.812 and 0.77), indicating good drug-likeness.

**DILI:** Ligand A (42.924) has a lower DILI risk than Ligand B (52.734), which is preferable. Both are below the concerning threshold of 60.

**BBB:** Ligand B (87.941) has a substantially better BBB penetration percentile than Ligand A (71.501). This is a critical factor for a CNS target like DRD2.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.664 and -4.507). This is unusual and suggests poor permeability. However, negative values are sometimes artifacts of the prediction method and shouldn't be heavily weighted without experimental data.

**Aqueous Solubility:** Both ligands have negative solubility values (-1.539 and -3.683), again suggesting poor solubility. Similar to Caco-2, these values are suspect and require experimental validation.

**hERG Inhibition:** Ligand A (0.247) has a lower hERG inhibition liability than Ligand B (0.676), making it safer from a cardiotoxicity perspective.

**Microsomal Clearance:** Ligand A (70.189) has a higher microsomal clearance than Ligand B (53.737), indicating faster metabolism and potentially lower in vivo exposure.

**In vitro Half-Life:** Ligand B (-10.9) has a significantly longer in vitro half-life than Ligand A (-2.755), which is a positive attribute.

**P-gp Efflux:** Ligand A (0.107) has lower P-gp efflux liability than Ligand B (0.267), which is beneficial for CNS penetration.

**Binding Affinity:** Ligand A (-7.8 kcal/mol) has a slightly better binding affinity than Ligand B (-6.9 kcal/mol). While both are good, the 0.9 kcal/mol difference is significant.

**Overall Assessment:**

Ligand A excels in TPSA, DILI, hERG, P-gp efflux, and binding affinity. Ligand B shines in BBB penetration and in vitro half-life. Given the importance of BBB penetration for a CNS target like DRD2, Ligand B appears more promising *despite* its slightly worse TPSA and higher DILI/hERG risk. However, the superior affinity of Ligand A is a significant advantage. The negative Caco-2 and solubility values for both are concerning, but could be prediction artifacts. Considering the balance, the stronger binding affinity of Ligand A, combined with its better safety profile (lower hERG and DILI) and acceptable BBB, makes it the slightly better candidate.

Output:
0
2025-04-17 05:04:19,779 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (363.38 and 366.483 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (101.29) is slightly higher than Ligand B (91.57). Both are below the 140 A^2 threshold for oral absorption, and reasonably close to the 90 A^2 target for CNS penetration, but Ligand B is better.

**3. logP:** Both ligands have good logP values (1.384 and 2.179), falling within the optimal 1-3 range. Ligand B is slightly higher, which could be beneficial for membrane permeability.

**4. H-Bond Donors:** Both have 3 HBD, which is within the acceptable limit of <=5.

**5. H-Bond Acceptors:** Ligand A has 3 HBA, while Ligand B has 5. Both are within the acceptable limit of <=10.

**6. QED:** Both ligands have similar QED values (0.607 and 0.614), indicating good drug-likeness.

**7. DILI:** Both ligands have low DILI risk (32.997 and 31.563), both well below the 40 threshold.

**8. BBB:** This is a critical parameter for a CNS target like DRD2. Ligand A has a significantly higher BBB penetration percentile (83.172) compared to Ligand B (62.233). This is a major advantage for Ligand A.

**9. Caco-2 Permeability:** Both have negative values (-5.341 and -5.082). This is unusual and may indicate issues with the modeling or data quality. It's difficult to interpret without further context, but it doesn't immediately disqualify either.

**10. Aqueous Solubility:** Both have negative values (-3.426 and -3.357). Similar to Caco-2 permeability, this is unusual and requires caution in interpretation.

**11. hERG Inhibition:** Both ligands show very low hERG inhibition risk (0.28 and 0.239), which is excellent.

**12. Microsomal Clearance:** Ligand A has a lower microsomal clearance (20.074) than Ligand B (39.018), suggesting better metabolic stability.

**13. In vitro Half-Life:** Ligand A has a longer in vitro half-life (13.78 hours) than Ligand B (3.247 hours), which is a significant advantage.

**14. P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.046 and 0.075).

**15. Binding Affinity:** Both ligands have strong binding affinities (-8.4 and -8.1 kcal/mol). Ligand A is slightly better (-8.4 kcal/mol).

**Overall Assessment:**

Ligand A is the better candidate. While both ligands have good overall profiles, Ligand A excels in the critical areas for CNS GPCR targets: **BBB penetration (83.2% vs 62.2%)**, **microsomal clearance (lower = better)**, and **in vitro half-life (longer = better)**. The slightly better binding affinity of Ligand A further supports this conclusion. The unusual negative values for Caco-2 and solubility are a concern for both, but the other advantages of Ligand A outweigh this.

Output:
0
2025-04-17 05:04:19,779 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (357.439 and 368.88 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (92.42) is slightly above the optimal <90 for CNS targets, but still reasonable. Ligand B (49.41) is excellent, well below the 90 threshold.

**logP:** Ligand A (1.477) is within the optimal 1-3 range. Ligand B (3.319) is at the higher end of optimal, but still acceptable.

**H-Bond Donors/Acceptors:** Both ligands have acceptable HBD (1) and HBA (6 for A, 2 for B) counts, well within the guidelines.

**QED:** Ligand A (0.895) has a very strong drug-like profile. Ligand B (0.553) is acceptable, but less ideal.

**DILI:** Ligand A (75.766) has a moderate DILI risk. Ligand B (28.112) has a very low DILI risk, which is a significant advantage.

**BBB:** Ligand A (75.107) has good BBB penetration, but Ligand B (90.112) is excellent, exceeding the >70 desirable threshold for CNS targets.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.865 and -4.909), which is unusual and suggests poor permeability. This is a concern for both.

**Aqueous Solubility:** Both ligands have negative solubility values (-2.955 and -4.276), indicating very poor aqueous solubility, a major drawback.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.219 and 0.378).

**Microsomal Clearance:** Ligand A (11.673) has lower microsomal clearance, suggesting better metabolic stability than Ligand B (38.194).

**In vitro Half-Life:** Ligand A (-26.729) has a very negative half-life, which is concerning. Ligand B (-6.522) is also negative, but less so.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.085 and 0.171), which is favorable for CNS penetration.

**Binding Affinity:** Ligand B (-8.1 kcal/mol) has a significantly stronger binding affinity than Ligand A (-7.3 kcal/mol). This >1.5 kcal/mol difference is substantial and can outweigh some ADME drawbacks.

**Overall Assessment:**

Ligand B is the more promising candidate. While both have poor solubility and Caco-2 permeability, Ligand B's significantly stronger binding affinity, excellent BBB penetration, and lower DILI risk are compelling advantages. The better BBB penetration is particularly crucial for a CNS target like DRD2. Although Ligand A has better metabolic stability, the affinity difference and reduced toxicity risk of Ligand B are more important in this context. The negative half-life values are concerning for both, and would require further investigation, but the superior binding of Ligand B makes it the better starting point for optimization.

Output:
1
2025-04-17 05:04:19,779 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (380.853 and 378.529 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (86.71) is better than Ligand B (49.41) as it is closer to the ideal range for CNS targets (<=90). Ligand B is excellent.

**3. logP:** Both ligands have good logP values (3.146 and 3.554), falling within the optimal 1-3 range.

**4. H-Bond Donors:** Ligand A (2) and Ligand B (1) are both acceptable, being less than 5.

**5. H-Bond Acceptors:** Ligand A (4) and Ligand B (3) are both acceptable, being less than 10.

**6. QED:** Both ligands have reasonable QED scores (0.856 and 0.719), indicating good drug-like properties.

**7. DILI:** Ligand A (89.841) has a higher DILI risk than Ligand B (23.653). This is a significant negative for Ligand A.

**8. BBB:** Ligand B (90.306) has a significantly better BBB penetration score than Ligand A (25.126). This is crucial for a CNS target like DRD2.

**9. Caco-2 Permeability:** Ligand A (-5.106) has poor Caco-2 permeability, while Ligand B (-4.825) is also poor, but slightly better.

**10. Aqueous Solubility:** Ligand A (-4.552) and Ligand B (-3.8) both have poor aqueous solubility.

**11. hERG Inhibition:** Ligand A (0.448) has a slightly better hERG profile than Ligand B (0.883), indicating lower cardiotoxicity risk.

**12. Microsomal Clearance:** Ligand B (50.899) has a higher microsomal clearance than Ligand A (10.424), suggesting faster metabolism and potentially lower *in vivo* exposure.

**13. In vitro Half-Life:** Ligand A (-13.329) has a slightly longer in vitro half-life than Ligand B (-12.977).

**14. P-gp Efflux:** Ligand A (0.148) has lower P-gp efflux liability than Ligand B (0.204), which is favorable for CNS penetration.

**15. Binding Affinity:** Ligand A (-9.5 kcal/mol) has a significantly stronger binding affinity than Ligand B (-7.8 kcal/mol). This is a substantial advantage.

**Overall Assessment:**

While Ligand A has a superior binding affinity, its significantly higher DILI risk and much lower BBB penetration are major drawbacks for a CNS drug candidate. Ligand B, despite having a slightly weaker affinity, exhibits a much better safety profile (lower DILI) and excellent BBB penetration, which are critical for targeting DRD2. The better BBB and lower DILI of Ligand B outweigh the affinity difference.

Output:
1
2025-04-17 05:04:19,780 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (362.357 Da) and Ligand B (347.411 Da) are both acceptable.

**2. TPSA:**  For CNS targets, we want TPSA <= 90. Ligand A (68.29) is excellent, well below the threshold. Ligand B (81.7) is slightly higher, but still reasonably good.

**3. logP:** Optimal is 1-3. Ligand A (4.273) is a bit high, potentially leading to solubility issues and off-target interactions. Ligand B (3.09) is within the optimal range.

**4. H-Bond Donors:** Both ligands have 1 HBD, which is good.

**5. H-Bond Acceptors:** Both ligands have 5 HBA, which is good.

**6. QED:** Both ligands have good QED scores (A: 0.704, B: 0.828), indicating drug-like properties.

**7. DILI:** Lower is better. Ligand A (96.937) has a significantly higher DILI risk than Ligand B (72.043). This is a major concern for Ligand A.

**8. BBB:** Both ligands have excellent BBB penetration (A: 80.264, B: 83.986), exceeding the desirable >70 threshold for CNS targets.

**9. Caco-2 Permeability:** Both have negative values, which is unusual and suggests very poor permeability. However, the scale is not specified, so it is difficult to interpret.

**10. Aqueous Solubility:** Both have negative values, which is also unusual and suggests very poor solubility. Again, the scale is not specified.

**11. hERG Inhibition:** Both have low hERG inhibition risk (A: 0.621, B: 0.305).

**12. Microsomal Clearance:** Ligand A (93.358) has a higher clearance than Ligand B (104.545), indicating lower metabolic stability.

**13. In vitro Half-Life:** Ligand B (-9.486) has a *much* longer half-life than Ligand A (53.814). This is a significant advantage for Ligand B.

**14. P-gp Efflux:** Both have low P-gp efflux liability (A: 0.435, B: 0.164).

**15. Binding Affinity:** Ligand A (-9.1 kcal/mol) has a significantly stronger binding affinity than Ligand B (-7.8 kcal/mol). This is a substantial advantage.

**Overall Assessment:**

While Ligand A boasts a superior binding affinity, its significantly higher DILI risk and higher microsomal clearance are major drawbacks. Ligand B, despite a slightly weaker affinity, presents a much more favorable ADME-Tox profile, with lower DILI risk, better metabolic stability (longer half-life), and a logP within the optimal range. Given the GPCR-specific priorities, and the importance of a clean safety profile for CNS drugs, Ligand B is the more promising candidate. The affinity difference, while notable, might be overcome with further optimization of Ligand B.



Output:
1
2025-04-17 05:04:19,780 - INFO - Reasoning:

Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (422.308 Da) is slightly higher than Ligand B (380.945 Da), but both are acceptable.

**2. TPSA:** Ligand A (82.19) is higher than Ligand B (58.95). For CNS targets, we want TPSA <= 90. Both are under this threshold, but Ligand B is significantly better.

**3. logP:** Ligand A (2.231) is within the optimal range (1-3). Ligand B (4.411) is above this range, potentially leading to solubility issues and off-target interactions.

**4. H-Bond Donors:** Both ligands have acceptable HBD counts (Ligand A: 1, Ligand B: 2), well below the limit of 5.

**5. H-Bond Acceptors:** Both ligands have acceptable HBA counts (Ligand A: 5, Ligand B: 4), well below the limit of 10.

**6. QED:** Both ligands have similar QED values (Ligand A: 0.7, Ligand B: 0.667), indicating good drug-like properties.

**7. DILI:** Ligand A (92.672) has a higher DILI risk than Ligand B (50.33). This is a significant concern for Ligand A.

**8. BBB:** Both ligands have reasonable BBB penetration (Ligand A: 60.372, Ligand B: 63.048). While neither exceeds the desirable >70% for CNS targets, they are comparable.

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.041 and -5.148). This is unusual and suggests poor permeability. However, these values are on a log scale and negative values are not uncommon, indicating very low permeability.

**10. Aqueous Solubility:** Both ligands have negative solubility values (-4.859 and -4.37). This indicates very low solubility, which is a concern.

**11. hERG Inhibition:** Both ligands have low hERG inhibition risk (Ligand A: 0.823, Ligand B: 0.617).

**12. Microsomal Clearance:** Ligand A (73.414) has higher microsomal clearance than Ligand B (64.097), suggesting lower metabolic stability.

**13. In vitro Half-Life:** Ligand B (75.57) has a longer in vitro half-life than Ligand A (-41.71), indicating better stability.

**14. P-gp Efflux:** Both ligands have low P-gp efflux liability (Ligand A: 0.209, Ligand B: 0.269).

**15. Binding Affinity:** Both ligands have excellent binding affinities (Ligand A: -8.3 kcal/mol, Ligand B: -8.7 kcal/mol). Ligand B has a slightly better affinity.

**Overall Assessment:**

Ligand B is the more promising candidate. While both have poor solubility and permeability, Ligand B has a better logP, lower DILI risk, longer half-life, and slightly better binding affinity. The higher logP of Ligand A is a significant drawback, potentially leading to off-target effects and formulation challenges. The lower DILI risk for Ligand B is also a crucial advantage. Although both have similar BBB penetration, the other factors favor Ligand B.

Output:
1
2025-04-17 05:04:19,780 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (357.41 and 353.463 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (64.11) is excellent, well below the 90 A^2 threshold for CNS targets. Ligand B (87.74) is still reasonable but less optimal, approaching the 90 A^2 limit.

**logP:** Ligand A (4.27) is slightly high, potentially leading to solubility issues or off-target interactions. Ligand B (0.54) is quite low, which could hinder membrane permeability and CNS penetration.

**H-Bond Donors/Acceptors:** Ligand A has 1 HBD and 5 HBA, which are acceptable. Ligand B has 2 HBD and 4 HBA, also acceptable.

**QED:** Both ligands have similar QED values (0.693 and 0.699), indicating good drug-like properties.

**DILI:** Ligand A has a high DILI risk (98.216%), which is a significant concern. Ligand B has a very low DILI risk (8.104%), a major advantage.

**BBB:** Ligand A has a good BBB penetration percentile (68.786%), but could be better. Ligand B's BBB penetration (59.636%) is lower and less desirable for a CNS target like DRD2.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.678 and -4.857), which is unusual and suggests poor permeability. This is a red flag for both.

**Aqueous Solubility:** Both ligands have very poor aqueous solubility (-5.822 and -1.712). This is a major drawback.

**hERG Inhibition:** Ligand A (0.438) shows some hERG inhibition risk, while Ligand B (0.158) has a lower risk.

**Microsomal Clearance:** Ligand A has very high microsomal clearance (100.435), indicating rapid metabolism. Ligand B has much lower clearance (8.788), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A has a moderate half-life (43.924 hours). Ligand B has a very short half-life (-4.83 hours), which is a significant negative.

**P-gp Efflux:** Ligand A has moderate P-gp efflux (0.469). Ligand B has very low P-gp efflux (0.004), which is highly desirable for CNS penetration.

**Binding Affinity:** Ligand A (-9.3 kcal/mol) has significantly stronger binding affinity than Ligand B (-7.4 kcal/mol). This is a substantial advantage, potentially outweighing some of its ADME drawbacks.

**Overall Assessment:**

Ligand A has a much better binding affinity and acceptable TPSA and BBB, but suffers from very high DILI risk, high metabolic clearance, and poor solubility. Ligand B has a much better safety profile (low DILI, low hERG, low P-gp efflux, better metabolic stability), but weaker affinity, lower BBB penetration, and poor solubility.

Given the CNS target (DRD2), a good binding affinity is crucial. While Ligand A's DILI risk is concerning, the substantial difference in binding affinity (-9.3 vs -7.4 kcal/mol) is a significant advantage. The poor solubility of both is a concern, but formulation strategies could potentially address this. The lower P-gp efflux of Ligand B is attractive, but the weaker affinity is a major drawback.

Considering the balance of properties and prioritizing affinity for a GPCR target, Ligand A is the more promising candidate, *despite* its DILI risk. Further optimization would focus on mitigating the DILI liability while preserving the strong binding affinity.

Output:
0
2025-04-17 05:04:19,780 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B based on the provided guidelines, prioritizing GPCR-specific properties (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (345.403 Da) is slightly lower, which could be beneficial for permeability, but both are acceptable.

**TPSA:** Ligand B (60.89) is significantly better than Ligand A (108.88). For CNS targets, TPSA should be <= 90. Ligand B comfortably meets this, while Ligand A is approaching the upper limit. This is a significant advantage for Ligand B.

**logP:** Ligand B (2.365) is optimal (1-3), while Ligand A (0.366) is quite low, potentially hindering permeation. This is a major drawback for Ligand A.

**H-Bond Donors/Acceptors:** Ligand A has 3 HBD and 5 HBA, while Ligand B has 0 HBD and 6 HBA. Both are within acceptable limits.

**QED:** Both ligands have good QED scores (A: 0.673, B: 0.707), indicating drug-like properties.

**DILI:** Ligand B (36.487) has a lower DILI risk than Ligand A (47.421), both are acceptable.

**BBB:** Ligand B (75.107) is excellent for CNS penetration, exceeding the desirable >70 threshold. Ligand A (26.91) is very poor, making CNS exposure unlikely. This is a critical difference given the target is DRD2.

**Caco-2 Permeability:** Ligand A (-5.674) has very poor Caco-2 permeability, while Ligand B (-4.775) is also poor, but better than A.

**Aqueous Solubility:** Both have negative solubility values, indicating poor solubility. Ligand B (-1.809) is slightly better than Ligand A (-2.42).

**hERG Inhibition:** Both ligands have low hERG inhibition risk (A: 0.124, B: 0.439).

**Microsomal Clearance:** Ligand A (-6.665) has a much lower (better) microsomal clearance than Ligand B (43.41). This suggests better metabolic stability for Ligand A.

**In vitro Half-Life:** Ligand B (22.746) has a longer half-life than Ligand A (12.832).

**P-gp Efflux:** Ligand A (0.027) has very low P-gp efflux, which is favorable for CNS penetration. Ligand B (0.094) is also low, but higher than A.

**Binding Affinity:** Ligand A (-8.8 kcal/mol) has a significantly stronger binding affinity than Ligand B (-5.9 kcal/mol). This is a substantial advantage for Ligand A, potentially outweighing some of its ADME deficiencies. However, the difference is not *massive*.

**Overall Assessment:**

While Ligand A has superior binding affinity and metabolic stability, its extremely poor logP and BBB penetration are major concerns for a CNS target like DRD2. Ligand B, despite weaker affinity, possesses a much more favorable profile for CNS penetration (excellent BBB, acceptable TPSA, optimal logP) and better Caco-2 permeability. The difference in affinity, while significant, might be overcome with further optimization of Ligand B, while fixing Ligand A's permeability issues would be a much larger undertaking.

Output:
1
2025-04-17 05:04:19,781 - INFO - Batch 167 complete. Total preferences: 2672
2025-04-17 05:04:19,781 - INFO - Processing batch 168/512...
2025-04-17 05:05:00,895 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (345.4) is slightly lower, which could be beneficial for permeability.

**TPSA:** Ligand A (95.41) is better than Ligand B (40.54) for CNS penetration, falling comfortably below the 90 A^2 threshold. Ligand B is excellent, but A is still very good.

**logP:** Ligand A (1.128) is within the optimal range, while Ligand B (4.481) is high. High logP can lead to solubility issues and off-target interactions.

**H-Bond Donors/Acceptors:** Ligand A has 2 HBD and 4 HBA, while Ligand B has 1 HBD and 3 HBA. Both are within acceptable limits.

**QED:** Both ligands have similar QED values (0.803 and 0.79), indicating good drug-likeness.

**DILI:** Ligand A (72.59) has a higher DILI risk than Ligand B (31.29), but both are below the concerning 60 threshold.

**BBB:** Ligand A (60.14) has a moderate BBB penetration, while Ligand B (56.15) is also moderate. Neither are ideal (>70), but this is less critical if other properties are strong.

**Caco-2 Permeability:** Ligand A (-4.667) has better Caco-2 permeability than Ligand B (-5.026).

**Aqueous Solubility:** Ligand A (-3.488) has better aqueous solubility than Ligand B (-4.491).

**hERG:** Ligand A (0.14) has a lower hERG inhibition liability than Ligand B (0.934), which is a significant advantage.

**Microsomal Clearance:** Ligand A (23.904) has lower microsomal clearance than Ligand B (113.262), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (-59.051) has a much longer in vitro half-life than Ligand B (-3.46). This is a substantial advantage.

**P-gp Efflux:** Ligand A (0.095) has lower P-gp efflux than Ligand B (0.617), which is favorable for CNS exposure.

**Binding Affinity:** Ligand B (-7.9) has a slightly better binding affinity than Ligand A (-8.5). However, the difference is relatively small (0.6 kcal/mol) and can be outweighed by other factors.

**Overall Assessment:**

Ligand A demonstrates a more balanced profile, particularly regarding ADME properties crucial for CNS penetration. It has better solubility, lower hERG risk, lower clearance, longer half-life, and lower P-gp efflux. While Ligand B has slightly better binding affinity, Ligand A's superior ADME properties, especially its lower logP and better metabolic stability, make it the more promising candidate for development as a DRD2-targeting drug.

Output:
0
2025-04-17 05:05:00,896 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (341.43 and 347.42 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (48.99) is excellent, well below the 90 A^2 threshold for CNS targets. Ligand B (110.44) is higher, but still potentially acceptable, although less desirable.

**logP:** Ligand A (3.988) is at the upper end of the optimal range (1-3), while Ligand B (0.762) is below the optimal range and could have permeability issues.

**H-Bond Donors/Acceptors:** Ligand A (1 HBD, 2 HBA) is favorable. Ligand B (2 HBD, 6 HBA) is also acceptable, but the higher HBA count could slightly impact permeability.

**QED:** Both ligands have similar QED values (0.898 and 0.786), indicating good drug-like properties.

**DILI:** Ligand A (33.773) has a much lower DILI risk than Ligand B (58.395), making it safer from a liver toxicity perspective.

**BBB:** Ligand A (96.937) has excellent BBB penetration, highly desirable for a CNS target like DRD2. Ligand B (69.407) is significantly lower, which is a major drawback.

**Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and suggests issues with the prediction method or the compounds themselves. However, the absolute value for Ligand A (-5.104) is less negative than Ligand B (-5.431), suggesting slightly better permeability.

**Aqueous Solubility:** Both have negative solubility values, again suggesting issues with the prediction. Ligand A (-3.418) is slightly better.

**hERG:** Ligand A (0.929) has a lower hERG risk than Ligand B (0.36), which is preferable.

**Microsomal Clearance:** Ligand A (30.402) has higher microsomal clearance than Ligand B (14.125), meaning Ligand B is more metabolically stable.

**In vitro Half-Life:** Ligand A (-23.55) has a negative half-life, which is not physically possible. Ligand B (-0.33) is also negative, indicating issues with the prediction.

**P-gp Efflux:** Ligand A (0.661) has lower P-gp efflux than Ligand B (0.013). Lower efflux is better for CNS exposure.

**Binding Affinity:** Ligand A (-10.4 kcal/mol) has a significantly stronger binding affinity than Ligand B (0.0 kcal/mol). This is a crucial advantage.

**Overall Assessment:**

Ligand A is clearly superior. Its excellent BBB penetration, strong binding affinity, lower DILI risk, and favorable TPSA and logP values outweigh the concerns about its higher clearance and questionable solubility/half-life predictions. Ligand B's poor BBB penetration and very weak binding affinity are significant liabilities, even considering its better metabolic stability. The negative values for Caco-2 and half-life for both compounds are concerning and would require experimental validation, but the overall profile of Ligand A is much more promising for a CNS-targeting drug.

Output:
1
2025-04-17 05:05:00,896 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (356.363 and 347.419 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (136.89) is slightly above the optimal <90 for CNS targets, but still reasonable. Ligand B (94.11) is excellent, well within the desired range.

**logP:** Ligand A (2.011) is optimal. Ligand B (-0.687) is significantly below the optimal range, potentially hindering membrane permeability.

**H-Bond Donors & Acceptors:** Ligand A (HBD=1, HBA=6) and Ligand B (HBD=2, HBA=5) both have acceptable numbers of H-bond donors and acceptors.

**QED:** Both ligands (A=0.621, B=0.596) have good drug-likeness scores, exceeding the 0.5 threshold.

**DILI:** Ligand A (89.376) has a higher DILI risk than Ligand B (24.855), which is a significant concern.

**BBB:** Ligand A (38.465) has a poor BBB penetration percentile. Ligand B (28.538) is also low, but slightly better than A. Both are far from the desirable >70 for CNS targets.

**Caco-2 Permeability:** Ligand A (-4.888) shows poor Caco-2 permeability. Ligand B (-5.272) is similarly poor.

**Aqueous Solubility:** Ligand A (-4.514) has poor aqueous solubility. Ligand B (-1.823) is also poor, but better than A.

**hERG Inhibition:** Both ligands have very low hERG inhibition risk (A=0.629, B=0.064).

**Microsomal Clearance:** Ligand A (34.456) has moderate clearance. Ligand B (-21.834) has negative clearance, which is not physically possible and likely indicates an issue with the prediction or data.

**In vitro Half-Life:** Ligand A (-9.321) has a negative half-life, which is also not physically possible. Ligand B (-6.173) is also negative.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (A=0.161, B=0.002), which is favorable for CNS penetration.

**Binding Affinity:** Ligand A (-8.2 kcal/mol) has a slightly better binding affinity than Ligand B (-7.9 kcal/mol), but the difference is not substantial.

**Overall Assessment:**

Ligand A has a better binding affinity and logP, but suffers from significantly higher DILI risk, poor BBB penetration, poor solubility, and impossible half-life and clearance values. Ligand B has a better TPSA, lower DILI, and lower P-gp efflux, but its logP is suboptimal and it also has impossible half-life and clearance values. The negative values for clearance and half-life are a major red flag for both compounds, indicating potential issues with the prediction method or data quality. However, given the GPCR-specific emphasis on BBB and logP, and the substantial DILI risk associated with Ligand A, Ligand B is slightly preferable despite its low logP. The negative clearance and half-life would need to be investigated and corrected before further optimization.

Output:
1
2025-04-17 05:05:00,896 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (363.37 and 369.491 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (105.32) is higher than the preferred <90 for CNS targets, but still potentially acceptable. Ligand B (88.52) is better, falling comfortably under 90.

**3. logP:** Ligand A (2.928) is within the optimal 1-3 range. Ligand B (0.809) is slightly below 1, which could indicate permeability issues, although not drastically.

**4. H-Bond Donors:** Ligand A (2) is acceptable. Ligand B (0) is also good.

**5. H-Bond Acceptors:** Ligand A (6) is acceptable. Ligand B (8) is also acceptable.

**6. QED:** Both ligands (0.738 and 0.77) have good drug-likeness scores, exceeding 0.5.

**7. DILI:** Ligand A (98.371) has a very high DILI risk, which is a major concern. Ligand B (63.086) is still elevated, but significantly lower than Ligand A.

**8. BBB:** Ligand A (21.946) has very poor BBB penetration, making it less suitable for a CNS target like DRD2. Ligand B (84.451) has excellent BBB penetration, a crucial advantage.

**9. Caco-2 Permeability:** Ligand A (-5.09) has poor Caco-2 permeability. Ligand B (-4.649) also has poor Caco-2 permeability.

**10. Aqueous Solubility:** Both ligands have poor aqueous solubility (-4.144 and -2.616). This could pose formulation challenges.

**11. hERG Inhibition:** Ligand A (0.634) has a slightly elevated hERG risk, but is acceptable. Ligand B (0.442) has a lower hERG risk, which is preferable.

**12. Microsomal Clearance:** Ligand A (31.098) has moderate clearance. Ligand B (44.085) has higher clearance, indicating lower metabolic stability.

**13. In vitro Half-Life:** Ligand A (-13.296) has a very short half-life. Ligand B (5.467) has a short half-life, but is better than Ligand A.

**14. P-gp Efflux:** Ligand A (0.232) has low P-gp efflux, which is good for CNS penetration. Ligand B (0.04) has very low P-gp efflux, even better.

**15. Binding Affinity:** Ligand B (-7.7 kcal/mol) has a significantly stronger binding affinity than Ligand A (-10.5 kcal/mol). This is a substantial advantage, potentially outweighing some of its ADME drawbacks.

**Overall Assessment:**

Ligand B is the superior candidate. While both have solubility and permeability concerns, Ligand B excels in the critical areas for a CNS-targeting GPCR: excellent BBB penetration, strong binding affinity, and lower DILI risk. Ligand A's extremely high DILI risk and poor BBB penetration are disqualifying factors. The better affinity of Ligand B further solidifies its advantage.

Output:
1
2025-04-17 05:05:00,897 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (366.849 and 372.487 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (76.46) is significantly better than Ligand B (92.78). For CNS targets, we want TPSA <= 90, so Ligand A is preferable.

**3. logP:** Both ligands have acceptable logP values (1.08 and 0.547), falling within the 1-3 range. Ligand A is slightly better.

**4. H-Bond Donors:** Both have 1 HBD, which is within the acceptable limit of <=5.

**5. H-Bond Acceptors:** Both have 5 HBA, which is within the acceptable limit of <=10.

**6. QED:** Both ligands have good QED scores (0.578 and 0.672), indicating drug-like properties. Ligand B is slightly better.

**7. DILI:** Both have similar and acceptable DILI risk (43.66 and 42.575 percentile), well below the 60 threshold.

**8. BBB:** Ligand B (71.307) has a significantly better BBB penetration percentile than Ligand A (58.24). This is a *critical* factor for a CNS target like DRD2.

**9. Caco-2 Permeability:** Both have negative Caco-2 values (-4.967 and -4.987), which is unusual and suggests poor permeability. This is a concern for both.

**10. Aqueous Solubility:** Both have negative solubility values (-2.436 and -2.541), indicating poor aqueous solubility. This is a concern for both.

**11. hERG Inhibition:** Both have very low hERG inhibition risk (0.34 and 0.187), which is excellent.

**12. Microsomal Clearance:** Ligand A (6.451) has a lower microsomal clearance than Ligand B (46.789), suggesting better metabolic stability.

**13. In vitro Half-Life:** Ligand A (4.786) has a better in vitro half-life than Ligand B (-34.833).

**14. P-gp Efflux:** Ligand A (0.245) has lower P-gp efflux than Ligand B (0.074), which is favorable for CNS penetration.

**15. Binding Affinity:** Ligand B (-7.7 kcal/mol) has a slightly better binding affinity than Ligand A (-8.1 kcal/mol). While the difference is small, it's still a positive for Ligand B.

**Overall Assessment:**

While Ligand A has advantages in TPSA, metabolic stability (Cl_mic and t1/2), and P-gp efflux, Ligand B *significantly* outperforms it in BBB penetration (71.307 vs 58.24). For a CNS target like DRD2, BBB penetration is paramount. The slightly better affinity of Ligand B further strengthens its position. The poor Caco-2 and solubility are concerning for both, but can potentially be addressed with formulation strategies.

Output:
1
2025-04-17 05:05:00,897 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (347.365 and 364.408 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (63.25) is better than Ligand B (67.43). Both are below the 90 A^2 threshold desirable for CNS targets, but A is closer to optimal.

**logP:** Both ligands have good logP values (3.032 and 2.688), falling within the 1-3 range.

**H-Bond Donors/Acceptors:** Both have 2 HBD and 3 HBA, which are within acceptable limits.

**QED:** Ligand A (0.874) has a significantly higher QED score than Ligand B (0.73), indicating better overall drug-likeness.

**DILI:** Ligand A (61.07) has a higher DILI risk than Ligand B (29.43). This is a significant drawback for Ligand A.

**BBB:** Both ligands have excellent BBB penetration (86.817 and 83.792), exceeding the >70% threshold for CNS targets.

**Caco-2:** Both have negative Caco-2 permeability values, which is unusual and suggests poor intestinal absorption. This is a concern for both.

**Solubility:** Both ligands have very poor aqueous solubility (-3.926 and -3.616). This is a major issue for both.

**hERG:** Both ligands have low hERG inhibition risk (0.274 and 0.366).

**Microsomal Clearance:** Ligand B (45.009) has lower microsomal clearance than Ligand A (56.877), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand B (-7.375) has a longer in vitro half-life than Ligand A (-25.522).

**P-gp Efflux:** Both have very low P-gp efflux liability (0.099 and 0.083), which is good for CNS penetration.

**Binding Affinity:** Both ligands have very strong binding affinity (-9.7 and -9.1 kcal/mol). The difference of 0.6 kcal/mol is not substantial enough to outweigh other factors.

**Overall Assessment:**

Ligand B is the better candidate. While both have solubility and Caco-2 permeability issues, Ligand B has a significantly lower DILI risk, better metabolic stability (lower Cl_mic), and a longer half-life. The slightly lower QED and affinity are less concerning given these advantages. The CNS penetration is excellent for both, and the hERG risk is low. The solubility and Caco-2 issues would need to be addressed through formulation or structural modification, but Ligand B starts from a better position.

Output:
1
2025-04-17 05:05:00,897 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (337.379) is slightly lower, which could be beneficial for permeability, but both are acceptable.

**TPSA:** Both ligands have TPSA values below the 90 A^2 threshold desirable for CNS targets. Ligand A (87.14) is better than Ligand B (96.69).

**logP:** Both ligands have logP values within the optimal range (1-3). Ligand A (2.609) is slightly higher than Ligand B (1.134), which is preferable for CNS penetration.

**H-Bond Donors/Acceptors:** Ligand A (HBD=2, HBA=4) and Ligand B (HBD=1, HBA=5) both fall within acceptable limits.

**QED:** Both ligands have good QED scores (A: 0.901, B: 0.863), indicating drug-like properties.

**DILI:** Both ligands have DILI risk below 60, indicating relatively low liver injury risk. Ligand B (63.862) is slightly higher than Ligand A (67.429), but both are acceptable.

**BBB:** Both ligands have good BBB penetration (A: 68.282, B: 61.225), but Ligand A is better. While both are below the ideal >70, they are reasonably good.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values which is unusual. This suggests poor permeability.

**Aqueous Solubility:** Both ligands have negative solubility values, which is also unusual and suggests poor solubility.

**hERG:** Both ligands have very low hERG inhibition liability (A: 0.81, B: 0.153), which is excellent.

**Microsomal Clearance:** Ligand A (14.576) has a higher microsomal clearance than Ligand B (5.786), suggesting lower metabolic stability. This is a negative for Ligand A.

**In vitro Half-Life:** Ligand A (40.147) has a longer in vitro half-life than Ligand B (43.558), which is preferable.

**P-gp Efflux:** Ligand A (0.291) has lower P-gp efflux liability than Ligand B (0.076), which is a significant advantage for CNS penetration.

**Binding Affinity:** Ligand A (-9.9 kcal/mol) has a significantly stronger binding affinity than Ligand B (-8.4 kcal/mol). This is a major advantage for Ligand A, potentially outweighing some of its ADME drawbacks.

**Overall Assessment:**

Considering the GPCR-specific priorities, Ligand A is the more promising candidate. Its superior binding affinity (-9.9 vs -8.4 kcal/mol) is a key advantage. It also has better TPSA and logP values, and lower P-gp efflux. While its microsomal clearance is higher (less stable) than Ligand B, the strong binding affinity and better CNS penetration properties (BBB, P-gp) make it the more likely candidate to succeed. The negative Caco-2 and solubility values are concerning for both, but can be addressed during lead optimization.



Output:
1
2025-04-17 05:05:00,897 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (346.431 and 352.391 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (87.32) is excellent, being below the 90 A^2 threshold for CNS targets. Ligand B (127.84) is higher, but still potentially acceptable, though less ideal.

**3. logP:** Ligand A (1.091) is within the optimal range of 1-3. Ligand B (-1.093) is slightly below 1, which could hinder permeation, but not drastically.

**4. H-Bond Donors:** Ligand A (2) and Ligand B (4) are both within the acceptable limit of <=5.

**5. H-Bond Acceptors:** Ligand A (4) and Ligand B (5) are both within the acceptable limit of <=10.

**6. QED:** Ligand A (0.724) has a significantly better QED score than Ligand B (0.181), indicating a more drug-like profile.

**7. DILI:** Both ligands have similar, low DILI risk (32.183 and 33.385 percentile).

**8. BBB:** Both ligands have similar, reasonable BBB penetration (36.371 and 37.573 percentile). While not exceeding the desirable >70, they are comparable.

**9. Caco-2 Permeability:** Ligand A (-4.984) has a worse Caco-2 permeability than Ligand B (-5.634), suggesting lower intestinal absorption.

**10. Aqueous Solubility:** Both ligands have poor aqueous solubility (-1.776 and -1.6). This is a concern, but can be addressed with formulation strategies.

**11. hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.089 and 0.044 percentile).

**12. Microsomal Clearance:** Ligand A (-19.624) has a lower (better) microsomal clearance than Ligand B (-26.687), indicating better metabolic stability.

**13. In vitro Half-Life:** Ligand A (-5.716) has a slightly better in vitro half-life than Ligand B (-4.543).

**14. P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.027 and 0.006 percentile).

**15. Binding Affinity:** Ligand A (-7.8 kcal/mol) has slightly better binding affinity than Ligand B (-7.5 kcal/mol). While the difference is not huge, it's a positive factor.

**Overall Assessment:**

Ligand A is superior due to its better TPSA, QED, microsomal clearance, and slightly better binding affinity. While its Caco-2 permeability is worse, the other advantages, especially the higher QED and lower clearance, make it the more promising candidate. The similar BBB values and low DILI/hERG risks are positive for both. Given the GPCR target and the need for CNS penetration, the lower TPSA and better predicted metabolic stability of Ligand A are particularly important.

Output:
1
2025-04-17 05:05:00,898 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (368.503 and 361.433 Da) are within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (84.42) is slightly above the optimal <90 for CNS targets, but still reasonable. Ligand B (70.67) is excellent, well below 90.

**3. logP:** Both ligands have good logP values (2.02 and 1.152), falling within the 1-3 range.

**4. H-Bond Donors:** Ligand A (1) and Ligand B (2) are both acceptable, being less than 5.

**5. H-Bond Acceptors:** Ligand A (6) and Ligand B (4) are both acceptable, being less than 10.

**6. QED:** Both ligands have similar QED values (0.759 and 0.745), indicating good drug-likeness.

**7. DILI:** Ligand A (42.962) and Ligand B (31.02) both have low DILI risk, below the 40 threshold, which is good.

**8. BBB:** This is a crucial parameter for CNS targets. Ligand A (57.852) is moderate, while Ligand B (74.021) is excellent, exceeding the desirable >70 threshold.

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.851 and -4.72), which is unusual and suggests poor permeability. This is a significant concern.

**10. Aqueous Solubility:** Both ligands have negative solubility values (-2.463 and -1.394), indicating very poor aqueous solubility. This is also a significant concern.

**11. hERG Inhibition:** Both ligands have low hERG inhibition risk (0.33 and 0.387).

**12. Microsomal Clearance:** Ligand A (18.501) has higher clearance than Ligand B (2.467), indicating lower metabolic stability.

**13. In vitro Half-Life:** Ligand B (-11.662) has a significantly longer half-life than Ligand A (31.797).

**14. P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.277 and 0.015).

**15. Binding Affinity:** Ligand B (-8.4 kcal/mol) has a slightly better binding affinity than Ligand A (-7.6 kcal/mol), exceeding the 1.5 kcal/mol advantage threshold.

**Overall Assessment:**

While both ligands have issues with Caco-2 permeability and aqueous solubility, Ligand B is the more promising candidate. It has a significantly better BBB score, longer half-life, slightly better affinity, and lower microsomal clearance. The better BBB penetration is particularly important for a CNS target like DRD2. The slightly better binding affinity further strengthens its position. Although both have poor solubility and permeability, these can potentially be addressed through formulation strategies.

Output:
1
2025-04-17 05:05:00,898 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (362.308 Da and 347.39 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (84.43) is better than Ligand B (71.53), both are below the 90 A^2 threshold desirable for CNS targets.

**3. logP:** Both ligands have good logP values (2.001 and 1.368, respectively), falling within the optimal 1-3 range.

**4. H-Bond Donors:** Ligand A (0) is preferable to Ligand B (1) as fewer HBDs generally improve permeability.

**5. H-Bond Acceptors:** Ligand A (8) is slightly higher than Ligand B (4), but both are within the acceptable limit of 10.

**6. QED:** Both ligands have good QED values (0.777 and 0.844), indicating good drug-like properties.

**7. DILI:** Ligand B (24.157) has a significantly lower DILI risk than Ligand A (70.88), which is a major advantage.

**8. BBB:** Ligand A (87.786) has a better BBB penetration percentile than Ligand B (82.706), though both are reasonably good.

**9. Caco-2 Permeability:** Ligand A (-4.779) is slightly better than Ligand B (-4.388), indicating better intestinal absorption.

**10. Aqueous Solubility:** Ligand A (-3.305) is slightly worse than Ligand B (-2.328), but both are quite poor.

**11. hERG Inhibition:** Ligand A (0.121) has a slightly lower hERG inhibition liability than Ligand B (0.457), which is preferable.

**12. Microsomal Clearance:** Ligand B (17.599) has lower microsomal clearance than Ligand A (25.877), suggesting better metabolic stability.

**13. In vitro Half-Life:** Ligand B (-3.832) has a longer in vitro half-life than Ligand A (-12.813), which is a significant advantage.

**14. P-gp Efflux:** Ligand A (0.113) has lower P-gp efflux liability than Ligand B (0.034), which is preferable for CNS penetration.

**15. Binding Affinity:** Both ligands have very similar and excellent binding affinities (-8.8 kcal/mol and -8.3 kcal/mol, respectively). The difference of 0.5 kcal/mol is not substantial enough to outweigh other factors.

**Overall Assessment:**

While Ligand A has slightly better BBB penetration and P-gp efflux, Ligand B demonstrates a significantly better safety profile (lower DILI) and improved pharmacokinetic properties (lower Cl_mic and longer t1/2). Given the importance of safety and PK in drug development, and the relatively similar binding affinities, Ligand B is the more promising candidate.

Output:
1
2025-04-17 05:05:00,898 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (370.852 Da) is slightly better positioned.

**TPSA:** Ligand A (69.64) is excellent for CNS penetration, well below the 90 A^2 threshold. Ligand B (109.85) is higher, but still potentially acceptable, though less ideal.

**logP:** Ligand A (2.607) is optimal. Ligand B (-0.436) is significantly lower, which could hinder membrane permeability and CNS penetration.

**H-Bond Donors/Acceptors:** Ligand A (HBD=2, HBA=3) and Ligand B (HBD=1, HBA=6) both fall within acceptable ranges.

**QED:** Ligand A (0.775) has a better QED score than Ligand B (0.496), indicating a more drug-like profile.

**DILI:** Ligand A (38.775) has a lower DILI risk than Ligand B (43.66), both are acceptable.

**BBB:** Ligand B (77.821) has a much better BBB percentile than Ligand A (53.781). This is a significant advantage for a CNS target.

**Caco-2 Permeability:** Ligand A (-4.783) has very poor Caco-2 permeability. Ligand B (-5.266) is also poor, but slightly better.

**Aqueous Solubility:** Ligand A (-3.006) and Ligand B (-2.436) both have poor aqueous solubility.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.625 and 0.536 respectively).

**Microsomal Clearance:** Ligand A (2.441) has a lower microsomal clearance, suggesting better metabolic stability than Ligand B (27.238).

**In vitro Half-Life:** Ligand A (22.917 hours) has a significantly longer half-life than Ligand B (-27.578 hours - which is a negative value and indicates very rapid degradation).

**P-gp Efflux:** Ligand A (0.303) has lower P-gp efflux liability than Ligand B (0.029), which is favorable for CNS exposure.

**Binding Affinity:** Ligand A (-8.8 kcal/mol) has a significantly stronger binding affinity than Ligand B (-6.5 kcal/mol). This is a major advantage.

**Overall Assessment:**

While Ligand B has a better BBB score, Ligand A is superior in most other critical parameters. The significantly stronger binding affinity (-8.8 vs -6.5 kcal/mol) of Ligand A is a substantial advantage, and can often compensate for minor ADME deficiencies. Ligand A also has better QED, metabolic stability, half-life, and P-gp efflux. The poor Caco-2 permeability and solubility of both are concerns, but can be addressed with formulation strategies. The lower logP of Ligand B is a significant drawback for CNS penetration.

Output:
1
2025-04-17 05:05:00,898 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (340.379 and 348.443 Da) fall comfortably within the ideal 200-500 Da range.

**TPSA:** Ligand A (85.36) is better than Ligand B (87.66), both are below the 90 A^2 threshold for CNS targets.

**logP:** Ligand A (1.788) is optimal, while Ligand B (0.731) is slightly low, potentially hindering permeation.

**H-Bond Donors/Acceptors:** Ligand A (1 HBD, 5 HBA) is better than Ligand B (3 HBD, 4 HBA). Both are within acceptable limits, but fewer H-bonds generally improve permeability.

**QED:** Ligand A (0.81) has a significantly better QED score than Ligand B (0.592), indicating a more drug-like profile.

**DILI:** Ligand A (71.888) has a higher DILI risk than Ligand B (22.257), which is a significant drawback.

**BBB:** Ligand A (66.654) has a better BBB penetration percentile than Ligand B (46.762), which is crucial for a CNS target like DRD2.

**Caco-2 Permeability:** Ligand A (-4.68) is significantly worse than Ligand B (-5.109).

**Aqueous Solubility:** Ligand A (-3.675) is slightly better than Ligand B (-2.015).

**hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.047 and 0.089, respectively).

**Microsomal Clearance:** Ligand A (67.527) has a higher microsomal clearance than Ligand B (-5.968), suggesting lower metabolic stability.

**In vitro Half-Life:** Ligand A (-12.415) has a shorter half-life than Ligand B (9.05).

**P-gp Efflux:** Ligand A (0.037) has lower P-gp efflux liability than Ligand B (0.022), which is favorable for CNS exposure.

**Binding Affinity:** Ligand B (-7.1 kcal/mol) has a significantly stronger binding affinity than Ligand A (-10.1 kcal/mol). This is a substantial advantage.

**Overall Assessment:**

Ligand B demonstrates a significantly stronger binding affinity, which is the most important factor. While it has a slightly lower logP and a higher DILI risk than Ligand A, the substantial affinity difference outweighs these concerns. The lower BBB penetration is a concern, but not insurmountable. Ligand A has better BBB and Pgp, but its affinity is much weaker. Considering the GPCR-specific priorities, the higher affinity of Ligand B is the deciding factor.

Output:
1
2025-04-17 05:05:00,898 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, considering the provided guidelines and GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (347.327 and 356.457 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (97.41) is slightly above the optimal <90 for CNS targets, but still reasonable. Ligand B (43.78) is excellent, well below the threshold.

**logP:** Ligand A (0.325) is quite low, potentially hindering permeability. Ligand B (3.661) is within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Both ligands have 1 HBD, which is good. Ligand A has 6 HBA, acceptable. Ligand B has 3 HBA, also acceptable.

**QED:** Both ligands have good QED scores (0.735 and 0.773), indicating drug-like properties.

**DILI:** Ligand A has a concerning DILI risk (80.225), indicating a high potential for liver injury. Ligand B has a very low DILI risk (13.532), a significant advantage.

**BBB:** Ligand A's BBB penetration (57.231) is below the desirable >70 for CNS targets. Ligand B has a much better BBB penetration (71.074), exceeding the threshold.

**Caco-2 Permeability:** Both have negative Caco-2 values (-4.478 and -4.621), which is unusual and suggests poor permeability. However, these are likely reported as log values, and negative values indicate low permeability.

**Aqueous Solubility:** Both have very poor aqueous solubility (-3.023 and -3.143). This is a significant drawback for both.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.185 and 0.896), which is positive.

**Microsomal Clearance:** Ligand A has a lower Cl_mic (3.7 mL/min/kg) than Ligand B (83.716 mL/min/kg), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A has a very long in vitro half-life (-12.02 hours), which is good. Ligand B has a shorter half-life (-5.056 hours).

**P-gp Efflux:** Ligand A has very low P-gp efflux (0.03), which is excellent for CNS penetration. Ligand B has higher P-gp efflux (0.165), which is less desirable.

**Binding Affinity:** Ligand A has a significantly stronger binding affinity (-9.1 kcal/mol) than Ligand B (-6.8 kcal/mol). This is a substantial advantage, potentially outweighing some of the ADME concerns.

**Overall Assessment:**

Ligand A has a superior binding affinity and better metabolic stability and P-gp efflux. However, its low logP, poor BBB penetration, and high DILI risk are major concerns. Ligand B has a much better logP, lower DILI risk, and better BBB penetration, but its affinity is weaker, and it has higher P-gp efflux and faster clearance.

Given the GPCR-specific priorities for CNS targets, BBB penetration and logP are critical. While Ligand A's affinity is very strong, the combination of poor BBB penetration, low logP, and high DILI risk makes it a less viable candidate. Ligand B, despite the weaker affinity, presents a more balanced profile with better ADME properties, particularly for CNS penetration and safety. The 1.5 kcal/mol advantage in binding affinity is not enough to overcome the significant ADME liabilities of Ligand A.

Output:
1
2025-04-17 05:05:00,899 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (348.451 and 344.43 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (83.36) is better than Ligand B (49.41). Both are below the 90 A^2 threshold for CNS targets, but Ligand A is slightly higher and could be a minor concern.

**logP:** Ligand B (2.532) is optimal (1-3), while Ligand A (0.431) is below 1, which could hinder permeation. This is a significant drawback for Ligand A.

**H-Bond Donors:** Both ligands have 1 HBD, which is within the acceptable limit of <=5.

**H-Bond Acceptors:** Ligand A has 6 HBA, while Ligand B has 2. Both are within the acceptable limit of <=10.

**QED:** Both ligands have good QED scores (0.737 and 0.779, respectively), indicating good drug-like properties.

**DILI:** Both ligands have low DILI risk (29.779 and 27.608 percentiles), which is favorable.

**BBB:** Ligand B (98.022) has excellent BBB penetration, exceeding the desirable >70% threshold. Ligand A (54.595) is significantly lower and may have limited CNS exposure. This is a critical difference for a CNS target like DRD2.

**Caco-2 Permeability:** Ligand A (-5.752) has poor Caco-2 permeability, while Ligand B (-4.684) is better, but still not great.

**Aqueous Solubility:** Ligand A (-0.803) has poor aqueous solubility, while Ligand B (-3.463) is even worse. Both are concerning, but Ligand B is worse.

**hERG Inhibition:** Ligand A (0.13) has a very low hERG risk, which is excellent. Ligand B (0.55) is slightly higher, but still acceptable.

**Microsomal Clearance:** Ligand A (-9.483) has very low microsomal clearance, indicating good metabolic stability. Ligand B (29.448) has higher clearance, suggesting faster metabolism.

**In vitro Half-Life:** Ligand A (4.421) has a short in vitro half-life, while Ligand B (-18.145) has a very long half-life.

**P-gp Efflux:** Ligand A (0.008) has very low P-gp efflux, which is highly desirable for CNS penetration. Ligand B (0.286) has higher P-gp efflux, which could limit CNS exposure.

**Binding Affinity:** Ligand B (-8.9 kcal/mol) has a slightly better binding affinity than Ligand A (-7.8 kcal/mol). While both are good, the 1.1 kcal/mol difference is notable.

**Overall Assessment:**

Ligand B is the stronger candidate. While it has poorer solubility than Ligand A, it excels in crucial areas for a CNS-targeting GPCR ligand: excellent BBB penetration, good binding affinity, and a long in vitro half-life. Ligand A suffers from a low logP, poor Caco-2 permeability, and a significantly lower BBB percentile, which are major drawbacks. The superior metabolic stability of Ligand A is outweighed by its poor pharmacokinetic properties.

Output:
1
2025-04-17 05:05:00,899 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (381.347) is slightly higher, but acceptable.

**TPSA:** Ligand A (32.34) is excellent for CNS penetration, well below 90. Ligand B (88.91) is higher but still potentially acceptable, though less optimal.

**logP:** Ligand A (4.609) is a bit high, potentially leading to solubility issues or off-target interactions. Ligand B (1.033) is on the lower side, which could hinder permeability.

**H-Bond Donors/Acceptors:** Ligand A (HBD=1, HBA=2) is favorable. Ligand B (HBD=2, HBA=6) is also acceptable, but the higher HBA count could slightly impact permeability.

**QED:** Both ligands have similar QED values (A: 0.812, B: 0.804), indicating good drug-like properties.

**DILI:** Ligand A (31.059) has a much lower DILI risk than Ligand B (69.678), which is a significant advantage.

**BBB:** Ligand A (81.078) has a very good BBB percentile, highly desirable for a CNS target. Ligand B (45.638) is considerably lower, raising concerns about CNS exposure.

**Caco-2 Permeability:** Ligand A (-4.945) and Ligand B (-5.643) both have negative values, indicating poor permeability.

**Aqueous Solubility:** Ligand A (-4.589) and Ligand B (-2.604) both have negative values, indicating poor solubility.

**hERG Inhibition:** Ligand A (0.768) has a slightly higher hERG risk than Ligand B (0.139), but both are relatively low.

**Microsomal Clearance:** Ligand A (42.587) has a higher microsomal clearance than Ligand B (20.556), suggesting lower metabolic stability.

**In vitro Half-Life:** Ligand A (42.117) has a longer half-life than Ligand B (9.467), which is preferable.

**P-gp Efflux:** Ligand A (0.588) has lower P-gp efflux than Ligand B (0.017), which is beneficial for CNS penetration.

**Binding Affinity:** Ligand B (-8.6 kcal/mol) has a significantly stronger binding affinity than Ligand A (-7.4 kcal/mol) - a 1.2 kcal/mol difference. This is a substantial advantage.

**Overall Assessment:**

While Ligand B boasts superior binding affinity, Ligand A has a much more favorable ADME profile, particularly regarding BBB penetration (critical for a CNS target like DRD2), DILI risk, and P-gp efflux. Ligand A's slightly higher logP is a concern, but the strong BBB penetration and lower toxicity risk outweigh this. The difference in affinity, while significant, might be overcome with further optimization of Ligand A. Ligand B's poor BBB and higher DILI risk are major drawbacks.

Output:
0
2025-04-17 05:05:00,899 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (365.5) is slightly higher than Ligand B (345.4).

**TPSA:** Ligand A (71.53) is excellent for CNS penetration, well below the 90 A^2 threshold. Ligand B (116.42) is higher, but still potentially acceptable, although less ideal.

**logP:** Ligand A (2.235) is optimal. Ligand B (-0.039) is slightly negative, which could hinder membrane permeability.

**H-Bond Donors & Acceptors:** Ligand A (1 HBD, 5 HBA) and Ligand B (3 HBD, 5 HBA) both fall within acceptable ranges.

**QED:** Both ligands have good QED scores (A: 0.839, B: 0.531), indicating drug-like properties.

**DILI:** Both ligands have the same DILI risk (82.28%), which is quite high and a significant concern.

**BBB:** Ligand A (82.28%) shows excellent BBB penetration, exceeding the 70% threshold. Ligand B (39.705%) is considerably lower, making CNS exposure less likely. This is a critical difference for a DRD2 ligand.

**Caco-2 Permeability:** Ligand A (-4.971) has poor Caco-2 permeability, while Ligand B (-5.436) is also poor.

**Aqueous Solubility:** Ligand A (-2.726) and Ligand B (-3.415) both have poor aqueous solubility.

**hERG:** Both ligands have low hERG inhibition risk (A: 0.528, B: 0.224).

**Microsomal Clearance:** Ligand A (17.821) has a moderate clearance, while Ligand B (-14.808) has negative clearance, which is not possible and indicates an error or outlier. We will assume this is an error and proceed with caution.

**In vitro Half-Life:** Ligand A (8.174 hours) has a reasonable half-life, while Ligand B (1.284 hours) is very short.

**P-gp Efflux:** Ligand A (0.101) has low P-gp efflux, which is favorable. Ligand B (0.01) also has very low P-gp efflux.

**Binding Affinity:** Ligand B (-8.6 kcal/mol) has a significantly stronger binding affinity than Ligand A (-7.1 kcal/mol) - a difference of 1.5 kcal/mol. This is a substantial advantage.

**Overall Assessment:**

Despite the high DILI risk for both compounds, Ligand B stands out due to its superior binding affinity. The negative clearance value is concerning, but the affinity difference is significant enough to warrant further investigation, assuming the clearance data is inaccurate. Ligand A's excellent BBB penetration is a plus, but the weaker affinity and poor Caco-2 permeability are drawbacks. Given the GPCR target and the importance of CNS penetration, the stronger binding affinity of Ligand B is the deciding factor, even with the questionable clearance data.

Output:
1
2025-04-17 05:05:00,899 - INFO - Batch 168 complete. Total preferences: 2688
2025-04-17 05:05:00,899 - INFO - Processing batch 169/512...
2025-04-17 05:05:42,220 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (358.295 and 341.503 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (60.25) is excellent, well below the 90 Angstroms threshold for CNS targets. Ligand B (73.63) is still reasonable, but less optimal.

**3. logP:** Ligand A (1.864) is within the optimal 1-3 range. Ligand B (4.619) is higher, potentially leading to solubility issues and off-target interactions, although not drastically so.

**4. H-Bond Donors:** Ligand A (0) is good. Ligand B (2) is acceptable.

**5. H-Bond Acceptors:** Both ligands have 5 HBA, which is within the acceptable limit of 10.

**6. QED:** Ligand A (0.766) has a better QED score than Ligand B (0.48), indicating better overall drug-likeness.

**7. DILI:** Ligand A (61.187) has a slightly higher DILI risk than Ligand B (51.028), but both are within an acceptable range (<60 is good).

**8. BBB:** Ligand A (92.71) has significantly better predicted BBB penetration than Ligand B (79.217). This is *critical* for a CNS target like DRD2.

**9. Caco-2 Permeability:** Ligand A (-4.505) has a worse Caco-2 permeability than Ligand B (-5.034). Lower values indicate lower permeability.

**10. Aqueous Solubility:** Ligand A (-3.31) has better aqueous solubility than Ligand B (-4.881).

**11. hERG Inhibition:** Ligand A (0.319) has a lower hERG inhibition risk than Ligand B (0.937).

**12. Microsomal Clearance:** Ligand B (90.796) has a higher microsomal clearance than Ligand A (33.171), indicating faster metabolism and potentially lower *in vivo* exposure.

**13. In vitro Half-Life:** Ligand B (52.936) has a longer in vitro half-life than Ligand A (-18.804).

**14. P-gp Efflux:** Ligand A (0.206) has lower P-gp efflux than Ligand B (0.711), which is favorable for CNS penetration.

**15. Binding Affinity:** Ligand A (-9.4 kcal/mol) has *significantly* stronger binding affinity than Ligand B (-0.0 kcal/mol). This is a decisive advantage.

**Overall Assessment:**

Ligand A is the superior candidate. While Ligand B has a slightly longer half-life and better Caco-2 permeability, Ligand A excels in the most important parameters for a CNS-targeting GPCR ligand: **BBB penetration, binding affinity, TPSA, and P-gp efflux**. The significantly stronger binding affinity of Ligand A (-9.4 vs -0.0 kcal/mol) is a major advantage that can compensate for minor ADME drawbacks. The better QED and lower hERG risk also contribute to its favorability.



Output:
1
2025-04-17 05:05:42,220 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (346.475 and 354.491 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (64.68) is significantly better than Ligand B (87.66). For CNS targets, TPSA should be <= 90, and A is comfortably within this range, while B is approaching the upper limit.

**3. logP:** Both ligands have good logP values (2.911 and 2.064), falling within the optimal 1-3 range.

**4. H-Bond Donors:** Both ligands have acceptable HBD counts (2 and 3 respectively), below the threshold of 5.

**5. H-Bond Acceptors:** Both ligands have acceptable HBA counts (3 and 4 respectively), below the threshold of 10.

**6. QED:** Ligand A (0.884) has a much better QED score than Ligand B (0.524), indicating a more drug-like profile.

**7. DILI:** Ligand A (19.581) has a significantly lower DILI risk than Ligand B (30.748). Both are below the 40 threshold, but A is preferable.

**8. BBB:** This is a critical parameter for CNS targets. Ligand A (72.547) has a much higher BBB penetration percentile than Ligand B (45.444). A score >70 is desirable, and A is closer to that mark.

**9. Caco-2 Permeability:** Ligand A (-4.628) has a worse Caco-2 permeability than Ligand B (-5.224). Lower values are less desirable.

**10. Aqueous Solubility:** Ligand A (-2.854) has a slightly better solubility than Ligand B (-2.515).

**11. hERG Inhibition:** Both ligands have low hERG inhibition risk (0.608 and 0.243).

**12. Microsomal Clearance:** Ligand A (-18.441) has a much lower (better) microsomal clearance than Ligand B (44.016), suggesting greater metabolic stability.

**13. In vitro Half-Life:** Ligand A (5.901) has a shorter half-life than Ligand B (13.613).

**14. P-gp Efflux:** Ligand A (0.01) has a much lower P-gp efflux liability than Ligand B (0.165), which is favorable for CNS penetration.

**15. Binding Affinity:** Both ligands have similar and strong binding affinities (-8.2 and -8.0 kcal/mol). The difference is negligible.

**Overall Assessment:**

Ligand A is significantly better than Ligand B. While B has a slightly better Caco-2 permeability and half-life, A excels in crucial areas for a CNS-targeting GPCR ligand: TPSA, QED, DILI, BBB, microsomal clearance, and P-gp efflux. The similar binding affinities make these differences decisive. Ligand A's superior predicted CNS penetration and safety profile outweigh the minor drawbacks.

Output:
1
2025-04-17 05:05:42,220 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (347.375) is slightly lower, which could be beneficial for permeability, but both are acceptable.

**TPSA:** Ligand A (111.15) is better than Ligand B (58.64) as it is closer to the ideal range for CNS targets (<=90). Ligand B is quite low, which might suggest reduced hydrogen bonding and potentially lower aqueous solubility.

**logP:** Ligand B (2.749) is optimal (1-3), while Ligand A (-0.318) is significantly below this range. This is a major drawback for Ligand A, as it may struggle with membrane permeability.

**H-Bond Donors/Acceptors:** Ligand A (2 HBD, 7 HBA) and Ligand B (1 HBD, 4 HBA) both fall within acceptable limits (<=5 HBD, <=10 HBA).

**QED:** Both ligands have similar and good QED values (0.77 and 0.76).

**DILI:** Ligand B (32.261) has a much lower DILI risk than Ligand A (63.823), making it safer from a liver toxicity perspective.

**BBB:** Ligand B (67.468) has a significantly better BBB penetration percentile than Ligand A (34.548). This is *critical* for a CNS target like DRD2.

**Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and suggests poor permeability. However, the scale is not specified, so it's hard to interpret.

**Aqueous Solubility:** Both ligands have very poor aqueous solubility (-1.632 and -4.035). This is a concern for both, but could be mitigated with formulation strategies.

**hERG Inhibition:** Ligand A (0.02) has a slightly lower hERG inhibition risk than Ligand B (0.5), which is preferable.

**Microsomal Clearance:** Ligand A (-20.177) has a much lower (better) microsomal clearance than Ligand B (40.395), indicating better metabolic stability.

**In vitro Half-Life:** Ligand A (28.365) has a better in vitro half-life than Ligand B (-7.633).

**P-gp Efflux:** Ligand A (0.009) has significantly lower P-gp efflux liability than Ligand B (0.162), which is highly desirable for CNS penetration.

**Binding Affinity:** Both ligands have comparable and strong binding affinities (-8.2 and -8.4 kcal/mol). The difference is negligible.

**Overall Assessment:**

While Ligand A has advantages in metabolic stability (Cl_mic, t1/2) and P-gp efflux, its poor logP and significantly lower BBB penetration are major drawbacks for a CNS-targeting GPCR. Ligand B, despite its higher DILI and slightly higher hERG, exhibits a much more favorable profile for CNS penetration due to its optimal logP and superior BBB score. The strong binding affinity is comparable for both. Given the GPCR-specific priorities, BBB penetration and logP are paramount.

Output:
1
2025-04-17 05:05:42,220 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (338.386 and 345.487 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (47.09) is slightly higher than Ligand B (43.86), but both are well below the 90 A^2 threshold for CNS targets.

**3. logP:** Ligand A (3.504) is optimal, while Ligand B (1.742) is on the lower end. While still acceptable, lower logP can sometimes hinder permeability.

**4. H-Bond Donors:** Both have 0 HBD, which is good.

**5. H-Bond Acceptors:** Ligand A has 5 HBA, and Ligand B has 3. Both are within the acceptable limit of 10.

**6. QED:** Both ligands have similar QED values (0.73 and 0.732), indicating good drug-likeness.

**7. DILI:** Ligand A (56.96) has a higher DILI risk than Ligand B (7.212). This is a significant concern for Ligand A.

**8. BBB:** Ligand B (91.043) has a significantly better BBB penetration percentile than Ligand A (86.08). This is crucial for a CNS target like DRD2.

**9. Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and suggests a potential issue with the data. However, the magnitude is similar.

**10. Aqueous Solubility:** Both have negative solubility values, which is also unusual. Again, the magnitudes are similar.

**11. hERG Inhibition:** Ligand A (0.921) has a slightly higher hERG inhibition liability than Ligand B (0.518), but both are reasonably low.

**12. Microsomal Clearance:** Ligand B (28.229) has much lower microsomal clearance than Ligand A (76.42), indicating better metabolic stability.

**13. In vitro Half-Life:** Ligand B (7.529) has a much longer in vitro half-life than Ligand A (-49.268). This is a major advantage for Ligand B.

**14. P-gp Efflux:** Ligand A (-9.5) has a lower P-gp efflux liability than Ligand B (0.096), which is favorable for CNS penetration.

**15. Binding Affinity:** Ligand B (-7.5 kcal/mol) has a significantly stronger binding affinity than Ligand A (-9.5 kcal/mol). This difference in affinity is substantial.

**Overall Assessment:**

Ligand B is the more promising candidate. While Ligand A has slightly better P-gp efflux, Ligand B excels in several critical areas: significantly better BBB penetration, much lower DILI risk, superior metabolic stability (lower Cl_mic and longer t1/2), and a substantially stronger binding affinity. The lower logP of Ligand B is a minor concern, but the benefits outweigh this drawback, especially considering the importance of CNS penetration for a DRD2 ligand.

Output:
1
2025-04-17 05:05:42,221 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (344.459 and 356.373 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (67.23) is significantly better than Ligand B (87.32). For CNS targets, we want TPSA <= 90, and A is comfortably within this range, while B is approaching the upper limit.

**3. logP:** Both ligands have good logP values (2.257 and 1.059), falling within the optimal 1-3 range. Ligand A is slightly better.

**4. H-Bond Donors:** Ligand A (1) is better than Ligand B (2). Lower HBD is generally preferred.

**5. H-Bond Acceptors:** Both ligands have the same HBA count (4), which is acceptable (<=10).

**6. QED:** Ligand A (0.805) has a much better QED score than Ligand B (0.485), indicating a more drug-like profile.

**7. DILI:** Ligand A (33.501) has a lower DILI risk than Ligand B (52.85), both are acceptable but A is preferred.

**8. BBB:** Both ligands have good BBB penetration (75.611 and 84.296), exceeding the 70% threshold for CNS targets. Ligand B is slightly better.

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.753 and -4.934), which is unusual and suggests poor permeability. This is a significant concern for both.

**10. Aqueous Solubility:** Both ligands have negative solubility values (-2.708 and -2.162), which is also concerning. Poor solubility can hinder bioavailability.

**11. hERG Inhibition:** Ligand A (0.086) has a much lower hERG inhibition risk than Ligand B (0.453). This is a crucial safety parameter.

**12. Microsomal Clearance:** Ligand A (45.299) has a better (lower) microsomal clearance than Ligand B (9.402), indicating better metabolic stability.

**13. In vitro Half-Life:** Ligand A (8.561) has a better half-life than Ligand B (-15.821).

**14. P-gp Efflux:** Ligand A (0.073) has a lower P-gp efflux liability than Ligand B (0.031), which is beneficial for CNS exposure.

**15. Binding Affinity:** Ligand A (-8.0) has slightly better binding affinity than Ligand B (-7.7). While the difference is small, it's still a positive factor.

**Overall Assessment:**

Ligand A is significantly better across most crucial parameters, especially QED, DILI, hERG, metabolic stability (Cl_mic and t1/2), and P-gp efflux. While both have concerning Caco-2 and solubility values, Ligand A's superior profile in other areas makes it the more promising candidate. The slightly better affinity of A, combined with its better ADME properties, outweighs the slightly better BBB penetration of B.

Output:
1
2025-04-17 05:05:42,221 - INFO - Reasoning:

Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (362.417 and 360.351 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (87.66) is better than Ligand B (42.43). For CNS targets, TPSA should be <= 90, both meet this.

**3. logP:** Ligand A (1.22) is within the optimal 1-3 range. Ligand B (3.326) is at the higher end of optimal, but still acceptable.

**4. H-Bond Donors:** Ligand A (3) is acceptable. Ligand B (0) is also acceptable.

**5. H-Bond Acceptors:** Ligand A (4) is acceptable. Ligand B (3) is also acceptable.

**6. QED:** Ligand A (0.635) is good, exceeding the 0.5 threshold. Ligand B (0.278) is below the threshold and indicates a less drug-like profile.

**7. DILI:** Both ligands have similar, low DILI risk (32.803 and 32.997 percentile).

**8. BBB:** Ligand B (97.131) significantly outperforms Ligand A (82.009) in BBB penetration, which is crucial for a CNS target like DRD2.

**9. Caco-2 Permeability:** Ligand A (-4.904) is worse than Ligand B (-4.271), indicating lower intestinal absorption.

**10. Aqueous Solubility:** Ligand A (-1.658) is better than Ligand B (-3.39), indicating better solubility.

**11. hERG Inhibition:** Ligand A (0.347) has a lower hERG inhibition liability than Ligand B (0.723), which is preferable.

**12. Microsomal Clearance:** Ligand A (8.374) has significantly lower clearance than Ligand B (55.116), indicating better metabolic stability.

**13. In vitro Half-Life:** Ligand A (-6.051) has a longer half-life than Ligand B (-5.791).

**14. P-gp Efflux:** Ligand A (0.011) has much lower P-gp efflux than Ligand B (0.207), which is beneficial for CNS exposure.

**15. Binding Affinity:** Ligand A (-8.2 kcal/mol) has a slightly better binding affinity than Ligand B (-7.5 kcal/mol). While both are good, the 0.7 kcal/mol difference is noteworthy.

**Overall Assessment:**

Ligand B excels in BBB penetration, a critical factor for CNS drug development. However, it suffers from a lower QED score, higher P-gp efflux, and significantly higher microsomal clearance. Ligand A has a better overall ADME profile (QED, P-gp, Cl_mic, t1/2, solubility, hERG) and comparable binding affinity. The slightly better affinity of Ligand A, combined with its superior ADME properties, makes it the more promising candidate despite the slightly lower BBB score. The difference in BBB isn't large enough to outweigh the other advantages of Ligand A.

Output:
1
2025-04-17 05:05:42,221 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (372.401 and 338.459 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (85.17) is better than Ligand B (79.42). Both are below the 90 A^2 threshold desirable for CNS targets, indicating good potential for brain penetration.

**logP:** Ligand A (1.718) is within the optimal 1-3 range. Ligand B (3.351) is at the higher end of the optimal range, potentially increasing off-target interactions and decreasing solubility.

**H-Bond Donors/Acceptors:** Both ligands have acceptable HBD (1) and HBA (7/6) counts, well within the guidelines.

**QED:** Both ligands have similar QED values (0.864 and 0.837), indicating good drug-likeness.

**DILI:** Ligand A (73.943) has a higher DILI risk than Ligand B (37.999). This is a significant negative for Ligand A.

**BBB:** Ligand B (82.125) has a slightly better BBB penetration percentile than Ligand A (78.247), though both are reasonably good for a CNS target.

**Caco-2 Permeability:** Ligand A (-4.879) has a worse Caco-2 permeability than Ligand B (-5.094). Both are negative values, which is unusual and suggests poor permeability.

**Aqueous Solubility:** Ligand A (-2.616) has slightly better aqueous solubility than Ligand B (-3.977).

**hERG Inhibition:** Ligand A (0.076) has a lower hERG inhibition liability than Ligand B (0.433), which is favorable.

**Microsomal Clearance:** Ligand B (34.87) has a slightly lower microsomal clearance than Ligand A (27.436), indicating better metabolic stability.

**In vitro Half-Life:** Ligand A (26.366) has a longer in vitro half-life than Ligand B (-5.133). This is a positive for Ligand A.

**P-gp Efflux:** Ligand A (0.084) has a lower P-gp efflux liability than Ligand B (0.399), which is favorable for CNS penetration.

**Binding Affinity:** Ligand A (-8.9 kcal/mol) has a significantly stronger binding affinity than Ligand B (-6.9 kcal/mol). This is a substantial advantage, exceeding the 1.5 kcal/mol difference threshold.

**Overall Assessment:**

The most critical factor for a CNS GPCR target is brain penetration and affinity. While both ligands have acceptable TPSA and BBB values, Ligand A's significantly stronger binding affinity (-8.9 vs -6.9 kcal/mol) is a major advantage. This difference in affinity could potentially overcome some of the drawbacks of Ligand A, such as the higher DILI risk. Ligand B has better metabolic stability and lower DILI, but the weaker binding affinity is a significant concern. Given the importance of potency for GPCRs, and the substantial difference in affinity, Ligand A is the more promising candidate.

Output:
1
2025-04-17 05:05:42,221 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (358.419 and 362.451 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (70.54) is better than Ligand B (71.78), both are below the 90 A^2 threshold for CNS targets, which is good.

**logP:** Ligand A (3.464) is optimal, while Ligand B (1.3) is a bit low, potentially hindering permeation.

**H-Bond Donors/Acceptors:** Ligand A (0 HBD, 7 HBA) and Ligand B (1 HBD, 5 HBA) both fall within acceptable ranges.

**QED:** Ligand B (0.8) is better than Ligand A (0.454), indicating a more drug-like profile.

**DILI:** Ligand B (63.823) has a lower DILI risk than Ligand A (79.682), which is preferable.

**BBB:** Ligand A (73.711) has significantly better BBB penetration than Ligand B (51.842). This is a *critical* advantage for a CNS target like DRD2.

**Caco-2 Permeability:** Both have negative values, indicating poor permeability.

**Aqueous Solubility:** Both have negative values, indicating poor solubility.

**hERG:** Both ligands have very low hERG inhibition liability, which is good.

**Microsomal Clearance:** Ligand B (29.459) has much lower microsomal clearance than Ligand A (112.831), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand B (27.757) has a longer in vitro half-life than Ligand A (-29.256), which is desirable.

**P-gp Efflux:** Ligand B (0.117) shows lower P-gp efflux liability than Ligand A (0.64), which is beneficial for CNS exposure.

**Binding Affinity:** Ligand B (-7.6 kcal/mol) has a slightly better binding affinity than Ligand A (-8.1 kcal/mol). While the difference isn't huge, it's still a positive.

**Overall Assessment:**

While Ligand B has better QED, DILI, metabolic stability, half-life, and P-gp efflux, the *superior BBB penetration of Ligand A* is the deciding factor for a CNS target. The slightly better affinity of Ligand B is not enough to overcome the significant difference in BBB. The poor solubility and permeability of both compounds are concerning, but can be addressed in later optimization stages. Given the importance of CNS penetration for DRD2, Ligand A is the more promising candidate.

Output:
0
2025-04-17 05:05:42,221 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (351.451 and 361.471 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (93.78) is better than Ligand B (101.02). Both are below the 140 A^2 threshold for oral absorption, and importantly, Ligand A is below the 90 A^2 threshold desirable for CNS targets.

**logP:** Ligand A (-1.477) is lower than the optimal 1-3 range, potentially hindering permeability. Ligand B (1.428) is within the optimal range. This is a significant advantage for Ligand B.

**H-Bond Donors/Acceptors:** Both have 3 HBDs, which is acceptable. Ligand A has 5 HBAs, and Ligand B has 4. Both are within the acceptable range of <=10.

**QED:** Ligand B (0.738) has a higher QED score than Ligand A (0.464), indicating a more drug-like profile.

**DILI:** Ligand A (12.059) has a much lower DILI risk than Ligand B (47.344). This is a substantial advantage for Ligand A.

**BBB:** Ligand A (28.693) has a very low BBB penetration percentile, making it unlikely to effectively engage the DRD2 receptor in the CNS. Ligand B (44.668) is also low, but better than Ligand A. Both are far from the >70% desired for CNS GPCRs.

**Caco-2 Permeability:** Both have negative Caco-2 values (-5.919 and -5.301), which is unusual and suggests poor permeability.

**Aqueous Solubility:** Both have negative solubility values (-0.667 and -3.464), which is also unusual and suggests poor solubility.

**hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.124 and 0.261).

**Microsomal Clearance:** Ligand A (-25.067) has a much lower (better) microsomal clearance than Ligand B (17.333), suggesting greater metabolic stability.

**In vitro Half-Life:** Ligand B (17.735 hours) has a significantly longer half-life than Ligand A (7.044 hours).

**P-gp Efflux:** Both have very low P-gp efflux liability (0.001 and 0.027).

**Binding Affinity:** Ligand A (-7.8 kcal/mol) has a stronger binding affinity than Ligand B (-6.9 kcal/mol). This is a 0.9 kcal/mol difference, which is significant.

**Overall Assessment:**

While Ligand A has a superior binding affinity and lower DILI risk and microsomal clearance, its extremely poor BBB penetration is a critical drawback for a CNS target like DRD2. Ligand B has better logP and QED, and a longer half-life, but suffers from a higher DILI risk and weaker binding affinity. The poor BBB penetration for both is concerning. However, the affinity difference is substantial, and the better logP of Ligand B could potentially be optimized to improve BBB penetration. Given the GPCR-specific emphasis on BBB, logP, and affinity, and the significant affinity advantage of Ligand A, it's still the better candidate *if* BBB penetration can be improved through structural modifications. However, considering the current data, Ligand B's better logP and QED make it a slightly more promising starting point for optimization, despite its weaker binding.

Output:
1
2025-04-17 05:05:42,222 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (352.45 and 346.475 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (58.64) is significantly better than Ligand B (67.23). For CNS targets, we want TPSA <= 90, and ideally closer to 60. Ligand A is much closer to the ideal range.

**3. logP:** Ligand A (4.22) is slightly higher than optimal (1-3), but still potentially acceptable. Ligand B (2.306) is well within the optimal range. However, for a GPCR, a slightly higher logP can be tolerated if other properties are favorable.

**4. H-Bond Donors:** Both ligands have 1 HBD, which is within the acceptable limit of <= 5.

**5. H-Bond Acceptors:** Ligand A has 3 HBAs, and Ligand B has 4. Both are within the acceptable limit of <= 10.

**6. QED:** Both ligands have similar QED values (0.863 and 0.785), indicating good drug-like properties.

**7. DILI:** Ligand A (38.387) has a slightly higher DILI risk than Ligand B (21.753), but both are below the concerning threshold of 60.

**8. BBB:** Ligand B (79.217) has a significantly better BBB penetration percentile than Ligand A (64.948). This is a crucial factor for a CNS target like DRD2.

**9. Caco-2 Permeability:** Ligand A (-4.174) has a worse Caco-2 permeability than Ligand B (-4.972). Lower values indicate poorer permeability.

**10. Aqueous Solubility:** Ligand A (-4.614) has worse solubility than Ligand B (-2.288).

**11. hERG Inhibition:** Both ligands have similar, low hERG inhibition risk (0.705 and 0.612).

**12. Microsomal Clearance:** Ligand A (99.603) has a much higher microsomal clearance than Ligand B (50.806), indicating lower metabolic stability.

**13. In vitro Half-Life:** Ligand B (-23.876) has a significantly longer in vitro half-life than Ligand A (19.035).

**14. P-gp Efflux:** Both ligands have similar, low P-gp efflux liability (0.154 and 0.262).

**15. Binding Affinity:** Both ligands have the same binding affinity (-7.8 kcal/mol), which is excellent.

**Overall Assessment:**

While Ligand B has better logP, BBB, Caco-2, solubility, and metabolic stability (lower Cl_mic, longer t1/2), Ligand A has a lower TPSA. Given the GPCR-specific priorities, BBB penetration is paramount for a CNS target. Ligand B's significantly higher BBB percentile (79.217 vs 64.948) and better ADME properties outweigh the slightly higher TPSA and logP. The equal binding affinity makes the ADME profile the deciding factor.

Output:
1
2025-04-17 05:05:42,222 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 drug candidates, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight (MW):** Both ligands are within the ideal range (200-500 Da). Ligand A (352.425 Da) is slightly lower, which *could* be beneficial for permeability, but both are acceptable.

**2. TPSA:** Ligand A (58.2) is excellent, well below the 90 Angstrom threshold for CNS targets. Ligand B (78.87) is still reasonable but less optimal.

**3. logP:** Ligand A (3.227) is within the optimal range (1-3). Ligand B (1.261) is at the lower end, potentially hindering permeation.

**4. H-Bond Donors (HBD):** Both ligands have 2 HBD, which is within the desirable limit of <=5.

**5. H-Bond Acceptors (HBA):** Ligand A has 2 HBA, while Ligand B has 5. Both are within the acceptable limit of <=10, but Ligand A is more favorable.

**6. QED:** Both ligands have similar QED values (0.792 and 0.611), indicating reasonable drug-likeness.

**7. DILI:** Both ligands have low DILI risk (37.728 and 36.293), which is good.

**8. BBB:** Ligand A has a significantly higher BBB penetration percentile (89.066) compared to Ligand B (61.342). This is a *critical* advantage for a CNS target like DRD2.

**9. Caco-2 Permeability:** Ligand A (-4.483) and Ligand B (-4.717) both have negative values, which is unusual and requires careful interpretation. Assuming these are logP-like scales, lower values suggest poorer permeability.

**10. Aqueous Solubility:** Ligand A (-3.939) and Ligand B (-2.174) both have negative values, indicating poor solubility.

**11. hERG Inhibition:** Both ligands have low hERG inhibition risk (0.615 and 0.481).

**12. Microsomal Clearance (Cl_mic):** Ligand A (42.534) has a higher clearance than Ligand B (5.678), suggesting lower metabolic stability.

**13. In vitro Half-Life:** Ligand B (17.19 hours) has a much longer half-life than Ligand A (3.555 hours). This is a significant advantage.

**14. P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.137 and 0.173), which is favorable for CNS penetration.

**15. Binding Affinity:** Ligand B (-7.1 kcal/mol) has a slightly better binding affinity than Ligand A (-9.0 kcal/mol). However, the difference is not substantial enough to outweigh other factors.

**Overall Assessment:**

Ligand A excels in TPSA and BBB penetration, both crucial for CNS GPCR targets. While its metabolic stability (Cl_mic) and half-life are less favorable, its superior BBB penetration and TPSA, combined with acceptable logP and affinity, make it the more promising candidate. Ligand B has a better half-life, but its lower BBB penetration and logP are significant drawbacks.

Output:
1
2025-04-17 05:05:42,222 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight (MW):** Both ligands (348.443 and 345.487 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (67.87) is slightly higher than Ligand B (52.65). Both are below the 90 A^2 threshold for CNS targets, but B is preferable.

**3. logP:** Both ligands have good logP values (1.401 and 1.765), falling within the optimal 1-3 range.

**4. H-Bond Donors (HBD):** Both have 1 HBD, which is within the acceptable limit of <=5.

**5. H-Bond Acceptors (HBA):** Ligand A has 4 HBAs, and Ligand B has 3. Both are below the limit of <=10.

**6. QED:** Both ligands have high QED scores (0.815 and 0.826), indicating good drug-like properties.

**7. DILI:** Ligand A (12.292) has a significantly lower DILI risk than Ligand B (15.936). This is a substantial advantage for Ligand A.

**8. BBB:** Both ligands have excellent BBB penetration (71.772 and 71.733), exceeding the desirable threshold of >70 for CNS targets.

**9. Caco-2 Permeability:** Both have negative values (-4.733 and -4.904), indicating poor permeability. This is a concern for both, but they are similar.

**10. Aqueous Solubility:** Both have negative values (-1.829 and -2.127), indicating poor solubility. This is a concern for both, but they are similar.

**11. hERG Inhibition:** Both ligands show low hERG inhibition liability (0.267 and 0.381), which is favorable.

**12. Microsomal Clearance (Cl_mic):** Ligand B (4.303) has significantly lower microsomal clearance than Ligand A (16.688), indicating better metabolic stability. This is a significant advantage for Ligand B.

**13. In vitro Half-Life:** Ligand B (23.125) has a much longer in vitro half-life than Ligand A (11.497), which is desirable. This is a significant advantage for Ligand B.

**14. P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.014 and 0.094), which is excellent for CNS exposure.

**15. Binding Affinity:** Ligand A (-8.4 kcal/mol) has a substantially stronger binding affinity than Ligand B (-0.0 kcal/mol). This is a major advantage for Ligand A, potentially outweighing some of its ADME drawbacks.

**Overall Assessment:**

Ligand A has a significantly better binding affinity, a lower DILI risk, and similar BBB penetration. However, Ligand B has better metabolic stability (lower Cl_mic) and a longer half-life. Considering the importance of potency for GPCR ligands, and the substantial difference in binding affinity (-8.4 vs -0.0 kcal/mol), the stronger binding of Ligand A is the most critical factor. While the ADME properties of Ligand B are better, the affinity difference is so large that it's likely Ligand A can be optimized to address its metabolic stability issues.

Output:
0
2025-04-17 05:05:42,222 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (348.4 and 356.4 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (93.73) is better than Ligand B (108.33). For CNS targets, we want TPSA <= 90, so Ligand A is closer to this threshold.

**3. logP:** Ligand A (0.491) is slightly better than Ligand B (-0.801), but both are a bit low. A logP between 1-3 is optimal. The low logP could hinder permeation, but isn't a dealbreaker if other properties are strong.

**4. H-Bond Donors:** Ligand A (2) is preferable to Ligand B (3). Lower HBDs generally improve permeability.

**5. H-Bond Acceptors:** Ligand A (5) is preferable to Ligand B (6). Lower HBAs generally improve permeability.

**6. QED:** Both ligands have similar QED values (0.527 and 0.491), indicating reasonable drug-likeness.

**7. DILI:** Ligand B (23.8) has a significantly lower DILI risk than Ligand A (49.6). This is a substantial advantage for Ligand B.

**8. BBB:** Both ligands have similar BBB penetration (29.8% and 32.0%). Neither is outstanding, but both are below the desirable >70% for CNS targets.

**9. Caco-2:** Both ligands have negative Caco-2 values (-5.259 and -5.246), which is unusual and suggests poor permeability.

**10. Solubility:** Both ligands have negative solubility values (-1.579 and -0.488), which is also unusual and suggests poor solubility.

**11. hERG:** Both ligands have very low hERG inhibition risk (0.137 and 0.089). This is excellent.

**12. Cl_mic:** Ligand B (-6.231) has a much *lower* (better) microsomal clearance than Ligand A (17.94). This suggests better metabolic stability for Ligand B.

**13. t1/2:** Ligand B (7.607) has a significantly longer in vitro half-life than Ligand A (-4.298). This is a major advantage for Ligand B.

**14. Pgp:** Both ligands have very low P-gp efflux liability (0.037 and 0.02). This is excellent for CNS penetration.

**15. Binding Affinity:** Ligand A (-8.9 kcal/mol) has a significantly stronger binding affinity than Ligand B (-7.1 kcal/mol). This is a substantial advantage for Ligand A. A >1.5 kcal/mol advantage is considered significant.

**Overall Assessment:**

While Ligand A has a superior binding affinity, Ligand B demonstrates a much better ADME profile. Specifically, its lower DILI risk, lower Cl_mic, and longer t1/2 are highly desirable. The TPSA of Ligand A is better, but the difference isn't substantial enough to overcome the ADME advantages of Ligand B. The low logP and Caco-2/Solubility values are concerning for both, but the improved metabolic stability and safety profile of Ligand B make it a more promising starting point for optimization. The strong binding affinity of Ligand A is tempting, but a compound with poor ADME properties is less likely to succeed.

Output:
1
2025-04-17 05:05:42,223 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (352.32 and 343.471 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (80.65) is slightly above the preferred <90 for CNS targets, but acceptable. Ligand B (61.44) is well within the desired range.

**logP:** Both ligands have good logP values (2.851 and 2.174), falling within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Both have 2 HBDs, which is good. Ligand A has 6 HBAs, while Ligand B has 3. Both are within the acceptable limit of 10.

**QED:** Both ligands have good QED scores (0.713 and 0.76), indicating good drug-like properties.

**DILI:** Ligand A has a DILI risk of 80.07, which is high. Ligand B has a much lower DILI risk of 15.394, which is excellent.

**BBB:** Ligand A has a BBB penetration of 60.527%, which is below the desirable >70% for CNS targets. Ligand B has a BBB penetration of 69.794%, which is closer to the target but still slightly below.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.916 and -5.011), which is unusual and indicates poor permeability. This is a significant concern for both.

**Aqueous Solubility:** Both ligands have negative solubility values (-4.559 and -2.544), indicating very poor aqueous solubility. This is a major drawback.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.426 and 0.611).

**Microsomal Clearance:** Ligand A has a higher microsomal clearance (38.119) than Ligand B (2.708), suggesting Ligand B is more metabolically stable.

**In vitro Half-Life:** Ligand A has a negative in vitro half-life (-33.206), which is not physically meaningful and suggests rapid degradation or an issue with the assay. Ligand B has a very short half-life (2.483 hours).

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.237 and 0.036), which is favorable for CNS penetration.

**Binding Affinity:** Ligand B (-9.0 kcal/mol) has a significantly stronger binding affinity than Ligand A (-8.9 kcal/mol). While the difference is small, it's still a factor.

**Overall Assessment:**

Ligand B is the more promising candidate despite the poor Caco-2 and solubility. Its significantly lower DILI risk, better metabolic stability (lower Cl_mic), slightly better BBB penetration, and stronger binding affinity outweigh the slightly higher TPSA. Ligand A's high DILI risk and negative half-life are major red flags. The poor solubility and permeability are concerns for both, but can potentially be addressed with formulation strategies. The affinity difference, while small, favors Ligand B.

Output:
1
2025-04-17 05:05:42,223 - INFO - Reasoning:

Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (348.45 & 368.54 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (96.25) is better than Ligand B (49.85). For CNS targets, TPSA should be <= 90, and Ligand A is closer to this threshold. This is a significant advantage for brain penetration.

**3. logP:** Both ligands have good logP values (1.39 & 3.12), falling within the optimal 1-3 range. Ligand B is slightly higher, which *could* indicate a potential for off-target interactions, but isn't a major concern.

**4. H-Bond Donors:** Ligand A has 3 HBD, and Ligand B has 0. Both are within the acceptable limit of <=5.

**5. H-Bond Acceptors:** Ligand A has 5 HBA, and Ligand B has 4. Both are within the acceptable limit of <=10.

**6. QED:** Both ligands have similar QED values (0.724 & 0.748), indicating good drug-like properties.

**7. DILI:** Both ligands have acceptable DILI risk (47.96 & 38.58), well below the 60 threshold.

**8. BBB:** This is a crucial parameter for a CNS target like DRD2. Ligand B (69.48%) is significantly better than Ligand A (40.56%). A BBB percentile >70 is desirable, but 69.48% is a substantial improvement over 40.56%.

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.953 & -4.502), which is unusual and suggests poor permeability. This is a concern for both compounds, but doesn't immediately disqualify them.

**10. Aqueous Solubility:** Both ligands have very poor aqueous solubility (-3.313 & -3.232). This is a significant drawback that would require formulation strategies.

**11. hERG Inhibition:** Both ligands show very low hERG inhibition risk (0.055 & 0.311), which is excellent.

**12. Microsomal Clearance:** Ligand A (27.96) has a much lower (better) microsomal clearance than Ligand B (113.17). Lower clearance indicates greater metabolic stability.

**13. In vitro Half-Life:** Both ligands have similar in vitro half-lives (2.88 & 2.81 hours).

**14. P-gp Efflux:** Ligand A (0.039) has significantly lower P-gp efflux liability than Ligand B (0.355). Lower P-gp efflux is highly desirable for CNS penetration.

**15. Binding Affinity:** Both ligands have very similar and excellent binding affinities (-8.2 & -8.3 kcal/mol). The difference is negligible.

**Overall Assessment:**

Ligand A excels in TPSA, microsomal clearance, and P-gp efflux, all critical for CNS penetration and metabolic stability. Ligand B has a significantly better BBB score. Both have poor solubility and Caco-2 permeability. The affinity is comparable.

Considering the GPCR-specific priorities, the lower TPSA, lower P-gp efflux, and lower Cl_mic of Ligand A are more valuable than the slightly better BBB of Ligand B. The poor solubility and permeability are concerns for both, but can be addressed through formulation. The improved metabolic stability and reduced efflux of Ligand A give it a higher probability of achieving sufficient brain exposure.

Output:
0
2025-04-17 05:05:42,223 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (348.531 Da) is slightly lower, which is generally favorable for permeability.

**TPSA:** Ligand A (49.41) is significantly better than Ligand B (80.37). For CNS targets, we want TPSA <= 90, and ideally closer to 60. Ligand A is well within this range, while Ligand B is pushing the upper limit and may have reduced brain penetration.

**logP:** Both ligands have acceptable logP values (Ligand A: 3.887, Ligand B: 2.264), falling within the optimal range of 1-3. Ligand A is slightly higher, which could potentially lead to off-target interactions, but is still reasonable.

**H-Bond Donors/Acceptors:** Both have 1 HBD, which is good. Ligand A has 2 HBA, while Ligand B has 5. Higher HBA can sometimes hinder permeability.

**QED:** Both ligands have good QED scores (Ligand A: 0.838, Ligand B: 0.882), indicating good drug-like properties.

**DILI:** Ligand A (14.889) has a much lower DILI risk than Ligand B (61.846). This is a significant advantage for Ligand A.

**BBB:** Ligand A (93.098) has excellent BBB penetration, exceeding the desirable threshold of >70. Ligand B (46.142) is considerably lower and would likely have limited CNS exposure. This is a critical factor for a DRD2 ligand.

**Caco-2 Permeability:** Ligand A (-4.626) and Ligand B (-5.086) both have negative values, which is unusual. This suggests poor permeability. However, the scale is not specified, so it's difficult to interpret.

**Aqueous Solubility:** Ligand A (-4.659) and Ligand B (-3.094) also have negative values, suggesting poor solubility.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (Ligand A: 0.533, Ligand B: 0.166), which is good.

**Microsomal Clearance:** Ligand A (44.74) has higher clearance than Ligand B (18.162), indicating lower metabolic stability.

**In vitro Half-Life:** Ligand B (34.735) has a significantly longer half-life than Ligand A (1.161). This is a positive for Ligand B.

**P-gp Efflux:** Ligand A (0.233) has lower P-gp efflux than Ligand B (0.085), which is beneficial for CNS exposure.

**Binding Affinity:** Both ligands have very similar and strong binding affinities (Ligand A: -7.8 kcal/mol, Ligand B: -7.7 kcal/mol). The difference is negligible.

**Overall Assessment:**

Considering all factors, **Ligand A is the more promising drug candidate.** While Ligand B has a better half-life, Ligand A excels in crucial areas for a CNS-targeting GPCR ligand: significantly better BBB penetration, lower DILI risk, and lower P-gp efflux. The TPSA is also much more favorable for Ligand A. The slightly higher logP and clearance of Ligand A are less concerning given its superior CNS properties.



Output:
0
2025-04-17 05:05:42,223 - INFO - Batch 169 complete. Total preferences: 2704
2025-04-17 05:05:42,224 - INFO - Processing batch 170/512...
2025-04-17 05:06:31,336 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands fall within the ideal range (200-500 Da). Ligand A (493.221 Da) is at the higher end, while Ligand B (346.471 Da) is comfortably within.

**TPSA:** Both ligands have TPSA values below the 140 A^2 threshold for good oral absorption. Ligand A (93.45 A^2) is better suited for CNS penetration as it's below the 90 A^2 target, while Ligand B (78.43 A^2) is also favorable.

**logP:** Both ligands have logP values within the optimal range (1-3). Ligand A (3.331) is slightly higher, potentially raising concerns about off-target effects, but still acceptable. Ligand B (2.945) is ideal.

**H-Bond Donors/Acceptors:** Both ligands have 3 HBDs and 3-5 HBAs, which are within the acceptable limits.

**QED:** Both ligands have reasonable QED scores (Ligand A: 0.388, Ligand B: 0.677). Ligand B has a significantly better QED score, indicating a more drug-like profile.

**DILI:** Ligand A (75.339 percentile) has a higher DILI risk than Ligand B (21.326 percentile). This is a significant negative for Ligand A.

**BBB:** Ligand A (61.923 percentile) has a moderate BBB penetration, while Ligand B (51.454 percentile) is lower. While both are below the desirable >70% for CNS targets, Ligand A is better.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values, which is unusual and suggests poor permeability. Ligand A (-5.291) is slightly better than Ligand B (-4.723).

**Aqueous Solubility:** Both ligands have negative solubility values, indicating very poor aqueous solubility. Ligand A (-4.236) is slightly better than Ligand B (-3.185).

**hERG Inhibition:** Both ligands show low hERG inhibition risk (Ligand A: 0.853, Ligand B: 0.335). Ligand B has a lower hERG risk.

**Microsomal Clearance:** Ligand A (59.788 mL/min/kg) has a higher microsomal clearance than Ligand B (30.89 mL/min/kg), indicating lower metabolic stability.

**In vitro Half-Life:** Ligand A (10.322 hours) has a longer half-life than Ligand B (5.995 hours).

**P-gp Efflux:** Both ligands show low P-gp efflux liability (Ligand A: 0.326, Ligand B: 0.071). Ligand B has a lower P-gp efflux, which is favorable for CNS penetration.

**Binding Affinity:** Ligand B (-8.7 kcal/mol) has slightly better binding affinity than Ligand A (-8.4 kcal/mol). While the difference is small, it's still a factor.

**Overall Assessment:**

Ligand B is the more promising candidate. It has a better QED score, significantly lower DILI risk, lower P-gp efflux, and slightly better binding affinity. While Ligand A has a slightly better BBB penetration and half-life, the superior ADME profile of Ligand B, particularly the lower DILI and P-gp efflux, outweigh these advantages. The poor Caco-2 and solubility are concerning for both, but can be addressed with formulation strategies.

Output:
1
2025-04-17 05:06:31,337 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (346.431 Da) is slightly lower, which is generally favorable for permeability.

**TPSA:** Ligand A (96.11) is better than Ligand B (58.2). For CNS targets, TPSA should be <=90, and Ligand A is closer to this threshold.

**logP:** Both ligands have good logP values (A: 1.501, B: 3.139), falling within the optimal range of 1-3. Ligand B is slightly higher, which could potentially lead to off-target effects, but is still acceptable.

**H-Bond Donors/Acceptors:** Ligand A (HBD=3, HBA=4) and Ligand B (HBD=2, HBA=2) both have reasonable numbers of H-bond donors and acceptors, well within the recommended limits.

**QED:** Both ligands have similar QED values (A: 0.727, B: 0.768), indicating good drug-like properties.

**DILI:** Ligand A (43.971) has a slightly higher DILI risk than Ligand B (36.448), but both are below the concerning threshold of 60.

**BBB:** Ligand A (57.929) and Ligand B (61.962) both show reasonable BBB penetration, but Ligand B is slightly better. A value >70 is desirable for CNS targets, and neither quite reaches that, but >50 is acceptable.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.102 and -5.075). This is unusual and suggests poor permeability. However, these values are on a logarithmic scale and are likely indicating very low permeability.

**Aqueous Solubility:** Both ligands have negative solubility values (-4.099 and -3.859), indicating very poor aqueous solubility. This is a significant drawback.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (A: 0.222, B: 0.434).

**Microsomal Clearance:** Ligand A (32.532) has a higher microsomal clearance than Ligand B (17.183), suggesting lower metabolic stability.

**In vitro Half-Life:** Ligand B (20.936) has a significantly longer in vitro half-life than Ligand A (0.338), which is a major advantage.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (A: 0.112, B: 0.262), which is favorable for CNS penetration.

**Binding Affinity:** Ligand A (-10.1 kcal/mol) has a significantly stronger binding affinity than Ligand B (-9.5 kcal/mol). This is a substantial advantage, potentially outweighing some of the ADME drawbacks.

**Overall Assessment:**

While both compounds have issues with solubility and Caco-2 permeability, the significantly stronger binding affinity of Ligand A (-10.1 kcal/mol vs -9.5 kcal/mol) is a critical factor. The slightly better TPSA and acceptable BBB penetration also favor Ligand A. Although Ligand B has a better half-life, the potency difference is substantial. Given the GPCR target and the importance of affinity, Ligand A is the more promising candidate, despite its slightly higher DILI and clearance.

Output:
0
2025-04-17 05:06:31,337 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (349.475 and 343.431 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (72.88) is significantly better than Ligand B (90.98). For CNS targets, we want TPSA <= 90, so Ligand A is preferable.

**logP:** Ligand A (0.764) is a bit low, potentially hindering permeability. Ligand B (2.115) is within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Both have 2 HBD and 4 HBA, which are acceptable.

**QED:** Both ligands have good QED scores (0.695 and 0.84), indicating drug-likeness.

**DILI:** Both have low DILI risk (10.392 and 62.35), with Ligand A being slightly better.

**BBB:** Ligand A (61.691) is better than Ligand B (55.874), but neither are above the desirable 70% threshold for CNS targets. However, given that we must choose between the two, A is better.

**Caco-2 Permeability:** Both have negative Caco-2 values (-5.152 and -5.161), which is unusual and suggests poor permeability. This is a significant drawback for both.

**Aqueous Solubility:** Both have negative solubility values (-1.695 and -3.209), indicating very poor solubility. This is a major concern for both compounds.

**hERG Inhibition:** Both have low hERG inhibition risk (0.399 and 0.677).

**Microsomal Clearance:** Ligand A (15.065) has lower clearance than Ligand B (20.002), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (12.127 hours) has a significantly longer half-life than Ligand B (-7.832 hours).

**P-gp Efflux:** Ligand A (0.056) has much lower P-gp efflux liability than Ligand B (0.102), which is crucial for CNS penetration.

**Binding Affinity:** Both have excellent binding affinities (-8.7 and -8.5 kcal/mol). The difference of 0.2 kcal/mol is not substantial enough to outweigh other factors.

**Overall Assessment:**

Considering the GPCR-specific priorities, Ligand A is more promising. It has a lower TPSA, better BBB penetration, lower P-gp efflux, better metabolic stability (lower Cl_mic and longer t1/2), and slightly lower DILI risk. While both have poor solubility and Caco-2 permeability, the other advantages of Ligand A make it the better candidate. The slightly lower logP of Ligand A is a concern, but not as critical as the other factors favoring it.

Output:
0
2025-04-17 05:06:31,337 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (344.5 and 346.4 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (45.48) is significantly better than Ligand B (60.03). For CNS targets, we want TPSA <= 90, and ideally closer to 60. Ligand A is much closer to this ideal.

**3. logP:** Ligand A (4.527) is higher than optimal (1-3), but still potentially manageable. Ligand B (1.305) is quite low, which could hinder permeability.

**4. H-Bond Donors:** Both ligands have 1 HBD, which is within the acceptable limit of <=5.

**5. H-Bond Acceptors:** Ligand A has 3 HBAs, while Ligand B has 5. Both are acceptable (<=10), but Ligand A is slightly preferred.

**6. QED:** Both ligands have good QED scores (0.825 and 0.891), indicating good drug-like properties.

**7. DILI:** Ligand A (15.161) has a much lower DILI risk than Ligand B (40.713). This is a significant advantage for Ligand A.

**8. BBB:** Ligand A (85.227) has a significantly higher BBB penetration percentile than Ligand B (46.607). This is *critical* for a CNS target like DRD2.

**9. Caco-2 Permeability:** Ligand A (-5.029) has worse Caco-2 permeability than Ligand B (-4.704), but both are negative values, indicating poor permeability.

**10. Aqueous Solubility:** Ligand A (-3.731) has worse solubility than Ligand B (-0.998). Solubility is important, but can often be addressed with formulation.

**11. hERG Inhibition:** Ligand A (0.925) has a slightly higher hERG risk than Ligand B (0.323), but both are relatively low.

**12. Microsomal Clearance:** Ligand B (-35.812) has significantly lower (better) microsomal clearance than Ligand A (30.722), indicating greater metabolic stability.

**13. In vitro Half-Life:** Ligand A (45.806) has a longer half-life than Ligand B (18.963).

**14. P-gp Efflux:** Ligand A (0.571) has lower P-gp efflux than Ligand B (0.054), which is favorable for CNS penetration.

**15. Binding Affinity:** Ligand B (-9.7 kcal/mol) has a slightly better binding affinity than Ligand A (-8.8 kcal/mol). While affinity is crucial, the difference of 0.9 kcal/mol is not substantial enough to outweigh the significant ADME advantages of Ligand A.

**Overall Assessment:**

Ligand A is the more promising candidate. Its superior BBB penetration, lower DILI risk, and lower P-gp efflux are particularly important for a CNS GPCR target. While Ligand B has slightly better affinity and metabolic stability, the ADME profile of Ligand A is far more favorable for achieving sufficient brain exposure and minimizing potential toxicity. The slightly lower solubility of Ligand A is a concern, but potentially addressable through formulation strategies.

Output:
1
2025-04-17 05:06:31,337 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (353.344 and 378.877 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (52.98) is significantly better than Ligand B (60.44). For CNS targets, we want TPSA <= 90, both are within this range, but A is closer to the optimal < 60 range.

**3. logP:** Both ligands have good logP values (2.56 and 3.989), falling within the optimal 1-3 range. Ligand B is slightly higher, which *could* present solubility issues, but is still acceptable.

**4. H-Bond Donors:** Both have 0 HBD, which is good.

**5. H-Bond Acceptors:** Ligand A has 3 HBA, and Ligand B has 4. Both are acceptable, being <= 10.

**6. QED:** Both ligands have reasonable QED values (0.835 and 0.755), indicating good drug-like properties.

**7. DILI:** Ligand A (53.47) has a lower DILI risk than Ligand B (84.917). This is a significant advantage for Ligand A.

**8. BBB:** Ligand A (96.627) has a *much* higher BBB penetration percentile than Ligand B (61.962). This is a critical factor for a CNS target like DRD2.

**9. Caco-2:** Both have negative Caco-2 values (-4.49 and -4.74). This is unusual and suggests poor permeability. However, these values are on a scale where negative values are possible and don't necessarily indicate a complete block.

**10. Solubility:** Both have negative solubility values (-3.477 and -5.065). Similar to Caco-2, this is not ideal but doesn't automatically disqualify them.

**11. hERG:** Both have low hERG inhibition liability (0.483 and 0.351).

**12. Cl_mic:** Ligand A (16.002) has a lower microsomal clearance than Ligand B (49.217), indicating better metabolic stability.

**13. t1/2:** Ligand A (-14.076) has a negative in vitro half-life, which is concerning. Ligand B (14.111) has a positive, and therefore more reasonable, half-life.

**14. Pgp:** Both have very low P-gp efflux liability (0.107 and 0.353).

**15. Binding Affinity:** Both have strong binding affinities (-10.0 and -9.4 kcal/mol). The difference of 0.6 kcal/mol, while present, is not substantial enough to outweigh the other significant advantages of Ligand A.

**Overall Assessment:**

Ligand A is significantly better due to its superior BBB penetration, lower DILI risk, and better metabolic stability (lower Cl_mic). While its in vitro half-life is concerning (negative value), the other advantages, especially the high BBB value, are crucial for a CNS-targeting drug. Ligand B's higher DILI risk and lower BBB penetration are significant drawbacks. The slightly better half-life of Ligand B is not enough to compensate for these issues.

Output:
0
2025-04-17 05:06:31,338 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (344.415 and 353.438 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (91.4) is slightly above the preferred <90 for CNS targets, but still reasonable. Ligand B (64.09) is well within the ideal range.

**logP:** Ligand A (0.595) is a bit low, potentially hindering permeation. Ligand B (0.276) is even lower, raising concerns about membrane permeability.

**H-Bond Donors/Acceptors:** Ligand A has 2 HBD and 4 HBA, which are acceptable. Ligand B has 1 HBD and 4 HBA, also acceptable.

**QED:** Both ligands have good QED scores (0.56 and 0.697), indicating good drug-like properties.

**DILI:** Ligand A (32.261) has a slightly higher DILI risk than Ligand B (16.402), but both are below the concerning threshold of 60.

**BBB:** This is crucial for a CNS target. Ligand B (80.419) has a significantly better BBB penetration score than Ligand A (60.876).

**Caco-2 Permeability:** Ligand A (-5.398) and Ligand B (-4.69) both have negative Caco-2 values, which is unusual and suggests poor permeability.

**Aqueous Solubility:** Ligand A (-2.135) and Ligand B (-0.963) both have negative solubility values, which is also unusual and suggests poor solubility.

**hERG Inhibition:** Ligand A (0.08) has a very low hERG risk, which is excellent. Ligand B (0.566) has a slightly higher, but still relatively low, hERG risk.

**Microsomal Clearance:** Ligand A (-5.8) has a negative clearance, which is not physically possible and likely indicates an error or unusual behavior in the prediction. Ligand B (14.118) has a moderate clearance.

**In vitro Half-Life:** Ligand B (6.344) has a longer half-life than Ligand A (-3.209), which is preferable. Again, the negative value for Ligand A is concerning.

**P-gp Efflux:** Ligand A (0.018) has very low P-gp efflux, which is excellent for CNS penetration. Ligand B (0.035) also has low P-gp efflux.

**Binding Affinity:** Ligand B (-7.3 kcal/mol) has a slightly better binding affinity than Ligand A (-8.1 kcal/mol). While A is slightly better, the difference is not substantial enough to overcome other issues.

**Overall Assessment:**

Ligand B is the more promising candidate. While its logP is low, its significantly better BBB penetration (80.419 vs 60.876), longer half-life, and lower DILI risk outweigh the slightly weaker binding affinity. The negative values for clearance and half-life of Ligand A are highly suspect and raise serious concerns about its reliability. Both ligands have permeability and solubility issues, but Ligand B is better positioned for CNS delivery due to its superior BBB score and lower efflux.

Output:
1
2025-04-17 05:06:31,338 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B based on the provided guidelines, prioritizing GPCR-specific properties (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (345.418 Da) is slightly lower, which could be beneficial for permeability. Ligand B (366.487 Da) is also good.

**TPSA:** Ligand A (53.51) is excellent for CNS penetration, well below the 90 A^2 threshold. Ligand B (90.54) is at the upper limit for CNS targets, potentially hindering BBB penetration.

**logP:** Ligand A (2.575) is optimal. Ligand B (1.481) is a little low, potentially impacting permeability.

**H-Bond Donors/Acceptors:** Ligand A (0 HBD, 4 HBA) is favorable. Ligand B (3 HBD, 4 HBA) is also acceptable, but the 3 HBDs could slightly reduce permeability.

**QED:** Both ligands have similar QED values (A: 0.787, B: 0.712), indicating good drug-likeness.

**DILI:** Ligand A (64.327) has a higher DILI risk than Ligand B (29.081). This is a significant drawback for Ligand A.

**BBB:** Ligand A (90.074) has excellent BBB penetration, exceeding the 70% threshold. Ligand B (53.664) is significantly lower, a major concern for a CNS target like DRD2.

**Caco-2 Permeability:** Ligand A (-4.585) has poor Caco-2 permeability, which is concerning. Ligand B (-5.559) is also poor, but slightly worse.

**Aqueous Solubility:** Both ligands have poor aqueous solubility (A: -2.786, B: -1.845). This could pose formulation challenges.

**hERG Inhibition:** Both ligands show low hERG inhibition risk (A: 0.41, B: 0.23).

**Microsomal Clearance:** Ligand A (66.905) has higher microsomal clearance, suggesting lower metabolic stability. Ligand B (-15.485) has negative clearance, which is unusual and suggests very high stability.

**In vitro Half-Life:** Ligand A (-35.375) has a negative half-life, which is also unusual and suggests very high stability. Ligand B (25.714) has a reasonable half-life.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (A: 0.526, B: 0.014), which is good for CNS exposure. Ligand B is significantly lower, which is a positive.

**Binding Affinity:** Ligand A (-8.2 kcal/mol) has a significantly stronger binding affinity than Ligand B (-7.8 kcal/mol). This 0.4 kcal/mol difference is substantial and could outweigh some of the ADME drawbacks.

**Overall Assessment:**

Despite Ligand A's superior binding affinity and excellent BBB penetration, its higher DILI risk and poor Caco-2 permeability are significant concerns. Ligand B, while having a slightly weaker affinity, presents a much better ADME profile, particularly with its lower DILI risk, very high metabolic stability, and low P-gp efflux. The TPSA is a concern, but the binding affinity is still good. Given the CNS target, the lower DILI risk and better metabolic stability of Ligand B are crucial.

Output:
1
2025-04-17 05:06:31,338 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (350.503 and 381.929 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (69.64) is slightly above the optimal <90 for CNS targets, but still reasonable. Ligand B (62.3) is well within the desired range.

**3. logP:** Both ligands have good logP values (2.328 and 3.488), falling within the optimal 1-3 range. Ligand B is slightly higher, which could be beneficial for membrane permeability but needs to be balanced against solubility.

**4. H-Bond Donors:** Ligand A has 2 HBD, and Ligand B has 1. Both are acceptable (<=5).

**5. H-Bond Acceptors:** Ligand A has 3 HBA, and Ligand B has 4. Both are acceptable (<=10).

**6. QED:** Both ligands have good QED values (0.67 and 0.868), indicating good drug-like properties.

**7. DILI:** Ligand A (6.941) has a significantly lower DILI risk than Ligand B (53.044). This is a major advantage for Ligand A.

**8. BBB:** Ligand B (73.75) has a much better BBB penetration percentile than Ligand A (64.017). This is crucial for a CNS target like DRD2.

**9. Caco-2 Permeability:** Ligand A (-4.88) shows poor Caco-2 permeability, while Ligand B (-5.071) is also poor, but slightly better.

**10. Aqueous Solubility:** Ligand A (-2.038) has slightly better aqueous solubility than Ligand B (-4.193).

**11. hERG Inhibition:** Both ligands have low hERG inhibition risk (0.461 and 0.405).

**12. Microsomal Clearance:** Ligand A (27.923) has lower microsomal clearance than Ligand B (37.175), indicating better metabolic stability.

**13. In vitro Half-Life:** Ligand B (-5.333) has a significantly longer in vitro half-life than Ligand A (0.46).

**14. P-gp Efflux:** Both ligands have low P-gp efflux liability (0.115 and 0.529).

**15. Binding Affinity:** Both ligands have excellent binding affinities (-8 and -9 kcal/mol). Ligand B is slightly more potent.

**Overall Assessment:**

Ligand B has a significantly better BBB penetration (73.75 vs 64.017) and a longer half-life (-5.333 vs 0.46), which are important for CNS drug development. It also has a slightly better binding affinity (-9 vs -8 kcal/mol). However, Ligand A has a much lower DILI risk (6.941 vs 53.044).

Given the GPCR-specific priorities, BBB penetration is critical. While DILI is important, the superior BBB and half-life of Ligand B, combined with its slightly better potency, outweigh the higher DILI risk. The difference in binding affinity is not substantial enough to favor Ligand A.

Output:
1
2025-04-17 05:06:31,338 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the acceptable range (200-500 Da). Ligand A (369.384 Da) is slightly lower, which could be advantageous for permeability.

**TPSA:** Ligand B (81.22) is significantly better than Ligand A (101.9). For CNS targets, we want TPSA <= 90, so Ligand B is preferable.

**logP:** Ligand B (2.368) is within the optimal range (1-3), while Ligand A (-0.378) is quite low. Low logP can hinder membrane permeability. This is a significant advantage for Ligand B.

**H-Bond Donors/Acceptors:** Ligand A has 4 HBD and 5 HBA, while Ligand B has 1 HBD and 5 HBA. Both are acceptable, but Ligand B's lower HBD count is slightly preferable for permeability.

**QED:** Ligand B (0.782) has a better QED score than Ligand A (0.467), indicating a more drug-like profile.

**DILI:** Ligand B (60.295) has a higher DILI risk than Ligand A (9.965). This is a concern for Ligand B, but not a dealbreaker at this stage.

**BBB:** Ligand B (82.939) has a much higher BBB penetration percentile than Ligand A (48.119). This is *critical* for a CNS target like DRD2, making Ligand B far more promising.

**Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and suggests poor permeability. However, the scale isn't defined, so it's hard to interpret.

**Aqueous Solubility:** Both have negative solubility values, again unusual.

**hERG:** Both ligands have low hERG inhibition liability (0.225 and 0.305 respectively), which is good.

**Microsomal Clearance:** Ligand A (-12.912) has a much lower (better) microsomal clearance than Ligand B (41.945), suggesting greater metabolic stability.

**In vitro Half-Life:** Ligand A (-32.298) has a negative half-life, which is impossible. Ligand B (14.783) has a reasonable half-life. This is a major red flag for Ligand A.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.006 and 0.361 respectively), which is favorable for CNS penetration.

**Binding Affinity:** Both ligands have the same binding affinity (-7 kcal/mol), which is excellent.

**Overall Assessment:**

Ligand B is significantly better despite the higher DILI risk. The superior BBB penetration, optimal logP, better TPSA, and better QED outweigh the DILI concern. Ligand A has a problematic negative in vitro half-life and a very low logP, making it less likely to reach the target in the brain. The binding affinity is the same for both, so the ADME properties become the deciding factors.

Output:
1
2025-04-17 05:06:31,338 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 drug candidates, considering the provided guidelines and GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (478.308 Da) is towards the higher end, while Ligand B (348.403 Da) is comfortably within the range.

**TPSA:** Ligand A (77.43) is better than Ligand B (114.69). For CNS targets, we want TPSA <= 90, and A is closer to that threshold.

**logP:** Ligand A (3.131) is optimal (1-3). Ligand B (0.935) is a bit low, potentially hindering permeation.

**H-Bond Donors/Acceptors:** Ligand A (0 HBD, 7 HBA) and Ligand B (3 HBD, 6 HBA) both fall within acceptable limits (<=5 HBD and <=10 HBA).

**QED:** Both ligands have good QED scores (A: 0.493, B: 0.644), indicating reasonable drug-likeness. Ligand B is slightly better.

**DILI:** Ligand A (56.689) has a higher DILI risk than Ligand B (25.436). This is a significant advantage for B.

**BBB:** Ligand A (75.107) has a much better BBB percentile than Ligand B (40.132). This is *critical* for a CNS target like DRD2.

**Caco-2 Permeability:** Ligand A (-4.77) has a worse Caco-2 permeability than Ligand B (-5.573). Both are negative, indicating poor permeability, but B is slightly better.

**Aqueous Solubility:** Ligand A (-4.027) has worse aqueous solubility than Ligand B (-3.09). Both are poor, but B is slightly better.

**hERG Inhibition:** Both ligands have very low hERG inhibition risk (A: 0.552, B: 0.514).

**Microsomal Clearance:** Ligand A (69.912) has higher microsomal clearance than Ligand B (32.761), suggesting lower metabolic stability. This favors Ligand B.

**In vitro Half-Life:** Ligand A (22.146 hours) has a longer half-life than Ligand B (4.758 hours). This is a significant advantage for A.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (A: 0.57, B: 0.015). Ligand B is significantly lower, which is favorable for CNS penetration.

**Binding Affinity:** Ligand A (-7.9 kcal/mol) has a slightly better binding affinity than Ligand B (-7.0 kcal/mol). This is a substantial advantage for A, potentially outweighing some ADME drawbacks.

**Overall Assessment:**

Ligand A excels in binding affinity and BBB penetration, and has a longer half-life. However, it has a higher DILI risk, worse TPSA, and higher clearance. Ligand B has better ADME properties (lower DILI, better clearance, lower P-gp efflux), but weaker binding affinity and significantly lower BBB penetration.

Given the GPCR-specific priorities, especially BBB for a CNS target, and the substantial affinity difference, **Ligand A is the more promising candidate**. The stronger binding affinity (-7.9 vs -7.0) is a significant advantage that can potentially be optimized through further structural modifications to address the ADME concerns. The good BBB value is also a major plus.

Output:
1
2025-04-17 05:06:31,339 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B based on the provided guidelines, prioritizing GPCR-specific properties (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (370.603 and 352.463 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (40.62) is significantly better than Ligand B (57.95). For CNS targets, TPSA should be <= 90, both are well within this range, but A is preferable.

**logP:** Both ligands (4.041 and 4.166) are slightly above the optimal 1-3 range, but still acceptable. This might raise concerns about solubility and off-target effects, but is not a major differentiator here.

**H-Bond Donors/Acceptors:** Ligand A (0 HBD, 3 HBA) is better than Ligand B (1 HBD, 5 HBA) in terms of balancing solubility and permeability.

**QED:** Both ligands have similar QED values (0.545 and 0.542), indicating good drug-likeness.

**DILI:** Ligand A (14.347) has a much lower DILI risk than Ligand B (52.772). This is a significant advantage for Ligand A.

**BBB:** Ligand A (83.986) has a substantially better BBB penetration percentile than Ligand B (68.903). This is *critical* for a CNS target like DRD2. A value >70 is desirable, and A is closer to that threshold.

**Caco-2 Permeability:** Ligand A (-4.832) has a worse Caco-2 permeability than Ligand B (-5.806), indicating potentially lower intestinal absorption. However, for a CNS target, intestinal absorption is less critical than BBB penetration.

**Aqueous Solubility:** Ligand A (-3.587) has slightly better aqueous solubility than Ligand B (-3.004).

**hERG:** Both ligands have similar, low hERG inhibition liability (0.866 and 0.882).

**Microsomal Clearance:** Ligand A (94.544) has a higher microsomal clearance than Ligand B (49.639), suggesting lower metabolic stability. This is a drawback for Ligand A.

**In vitro Half-Life:** Ligand B (23.851) has a significantly longer in vitro half-life than Ligand A (-6.373). This is a major advantage for Ligand B.

**P-gp Efflux:** Both ligands have similar P-gp efflux liability (0.728 and 0.533), indicating moderate efflux.

**Binding Affinity:** Ligand B (-8.3 kcal/mol) has a stronger binding affinity than Ligand A (-7.1 kcal/mol). This is a substantial difference (>1.5 kcal/mol), and a significant advantage for Ligand B.

**Overall Assessment:**

While Ligand A has advantages in TPSA, DILI, and BBB, the stronger binding affinity of Ligand B (-8.3 vs -7.1 kcal/mol) is a major factor, especially for a GPCR target. The longer half-life of Ligand B is also a significant benefit. The higher DILI risk for Ligand B is a concern, but the substantial affinity advantage, combined with acceptable BBB penetration, likely outweighs this risk.

Output:
1
2025-04-17 05:06:31,339 - INFO - Reasoning:

Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (347.354 and 351.359 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (107.97) is better than Ligand B (110.97). Both are reasonably good for CNS penetration, being below the 140 A^2 threshold, but closer to the preferred <90 A^2 for CNS targets is better.

**3. logP:** Ligand B (-0.041) is slightly better than Ligand A (0.13), but both are quite low. A logP between 1-3 is optimal, and these are both below 1, which could hinder permeation.

**4. H-Bond Donors:** Both ligands have 1 HBD, which is within the acceptable limit of <=5.

**5. H-Bond Acceptors:** Ligand A has 6 HBAs, while Ligand B has 7. Both are within the acceptable limit of <=10.

**6. QED:** Ligand A (0.824) has a significantly better QED score than Ligand B (0.565), indicating a more drug-like profile.

**7. DILI:** Ligand B (64.793) has a lower DILI risk than Ligand A (76.386), which is favorable.

**8. BBB:** Ligand A (68.67) and Ligand B (65.452) are both below the desirable >70 percentile for CNS targets. However, Ligand A is slightly better.

**9. Caco-2:** Both ligands have negative Caco-2 values (-4.937 and -4.825). This is unusual and suggests poor intestinal absorption.

**10. Solubility:** Both ligands have negative solubility values (-1.601 and -2.755), which is also unusual and suggests poor aqueous solubility.

**11. hERG:** Both ligands have very low hERG inhibition liability (0.059 and 0.093), which is excellent.

**12. Cl_mic:** Ligand A (4.808) has a much lower microsomal clearance than Ligand B (41.841), indicating better metabolic stability.

**13. t1/2:** Ligand A (-8.125) has a negative in vitro half-life, which is not possible. This is a red flag. Ligand B (11.078) has a reasonable half-life.

**14. Pgp:** Both ligands have very low P-gp efflux liability (0.035 and 0.03), which is excellent for CNS penetration.

**15. Binding Affinity:** Ligand A (-8.3 kcal/mol) has a significantly stronger binding affinity than Ligand B (-6.9 kcal/mol). This is a substantial advantage.

**Overall Assessment:**

Despite the low logP and Caco-2/Solubility issues for both, Ligand A possesses a significantly stronger binding affinity (-8.3 vs -6.9 kcal/mol) and better metabolic stability (lower Cl_mic). The QED score is also much higher for Ligand A. However, the negative in vitro half-life for Ligand A is a major concern and likely indicates an error in the data or a highly unstable compound. Ligand B has a more reasonable half-life. Considering the importance of affinity for GPCRs, and the relatively small difference in BBB, Ligand A *would* be preferred if the half-life data were accurate. However, given the impossible half-life value, I must favor Ligand B.

Output:
1
2025-04-17 05:06:31,339 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (350.503 and 357.382 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (78.43) is significantly better than Ligand B (104.81). For CNS targets, we want TPSA <= 90, and A is comfortably within that range, while B is pushing the limit.

**logP:** Ligand A (2.375) is optimal (1-3), while Ligand B (-0.338) is below 1, which could hinder permeation. This is a significant disadvantage for B.

**H-Bond Donors/Acceptors:** Ligand A (HBD=3, HBA=3) and Ligand B (HBD=2, HBA=5) both have reasonable numbers of H-bond donors and acceptors, well within the guidelines.

**QED:** Both ligands have acceptable QED values (0.617 and 0.517, respectively), indicating good drug-like properties.

**DILI:** Ligand A (10.198) has a much lower DILI risk than Ligand B (36.758). This is a clear advantage for A.

**BBB:** Ligand A (53.974) has a moderate BBB penetration, while Ligand B (65.452) is better. While both are not ideal (>70 is desirable), B is better here.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.729 and -4.967), which is unusual and suggests poor permeability. However, the scale isn't clearly defined, so we will proceed with caution.

**Aqueous Solubility:** Both ligands have negative solubility values (-3.039 and -2.141), also unusual. Similar to Caco-2, we'll proceed cautiously.

**hERG:** Both ligands have very low hERG inhibition liability (0.37 and 0.161), which is excellent.

**Microsomal Clearance:** Ligand A (49.367) has higher microsomal clearance than Ligand B (13.965), indicating lower metabolic stability. B is preferable here.

**In vitro Half-Life:** Ligand B (-28.34) has a longer in vitro half-life than Ligand A (-18.619), which is a positive attribute.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.09 and 0.014), which is good for CNS penetration.

**Binding Affinity:** Both ligands have similar, strong binding affinities (-8.6 and -8.0 kcal/mol). The difference is less than 1.5 kcal/mol, so this doesn't strongly favor either compound.

**Overall Assessment:**

Considering the GPCR-specific priorities, Ligand A is the stronger candidate. While Ligand B has better BBB penetration and metabolic stability, Ligand A's significantly better logP, lower DILI risk, and more favorable TPSA outweigh these advantages. The negative Caco-2 and solubility values are concerning for both, but the other properties of A are more aligned with a viable CNS drug candidate.

Output:
1
2025-04-17 05:06:31,339 - INFO - Reasoning:

Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (383.5 and 377.5 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Both ligands have TPSA values (107.2 and 105.3) that are above the optimal <90 for CNS targets, but not drastically so. This is a moderate concern for both.

**3. logP:** Ligand A (0.188) has a very low logP, which is suboptimal for membrane permeability and CNS penetration. Ligand B (-1.209) is also low, but slightly better than A. Both are below the optimal 1-3 range.

**4. H-Bond Donors:** Ligand A (3) is slightly higher than ideal, but acceptable. Ligand B (1) is excellent.

**5. H-Bond Acceptors:** Both ligands (6) are within the acceptable limit of <=10.

**6. QED:** Both ligands have good QED scores (0.58 and 0.645), indicating good drug-like properties.

**7. DILI:** Ligand A (60.9%) has a higher DILI risk than Ligand B (56.6%), but both are within an acceptable range (<60 is preferred).

**8. BBB:** Ligand B (51.6%) has a significantly better BBB percentile than Ligand A (41.6%). This is a crucial advantage for a CNS target like DRD2.

**9. Caco-2:** Both ligands have negative Caco-2 values (-5.986 and -5.209), which is unusual and suggests very poor permeability. This is a significant drawback for both.

**10. Solubility:** Both ligands have negative solubility values (-2.839 and -1.702), indicating poor aqueous solubility. This is a concern for formulation and bioavailability.

**11. hERG:** Both ligands have very low hERG inhibition risk (0.068 and 0.124).

**12. Cl_mic:** Ligand A (11.279) has a lower microsomal clearance than Ligand B (23.301), suggesting better metabolic stability.

**13. t1/2:** Ligand B (-46.171) has a much longer in vitro half-life than Ligand A (-14.662), which is a significant advantage.

**14. Pgp:** Both ligands have very low P-gp efflux liability (0.019 and 0.011).

**15. Binding Affinity:** Ligand B (-8.2 kcal/mol) has a stronger binding affinity than Ligand A (-7.6 kcal/mol). This 0.6 kcal/mol difference is substantial and can outweigh some ADME drawbacks.

**Overall Assessment:**

Ligand B is the more promising candidate. While both have issues with TPSA, Caco-2, and Solubility, Ligand B demonstrates significantly better BBB penetration, a longer half-life, and a stronger binding affinity. The lower logP of Ligand B, while still suboptimal, is better than Ligand A's. The improved metabolic stability of Ligand A is a plus, but the other advantages of Ligand B are more critical for a CNS-targeting GPCR.

Output:
1
2025-04-17 05:06:31,340 - INFO - Here's a step-by-step comparison of Ligand A and Ligand B, followed by my final decision:

**1. Molecular Weight (MW):**
*   Ligand A: 413.36 Da - Within the ideal range (200-500 Da).
*   Ligand B: 366.824 Da - Also within the ideal range.
*   *No clear advantage.*

**2. Topological Polar Surface Area (TPSA):**
*   Ligand A: 76.14  - Excellent for CNS penetration (well below 90).
*   Ligand B: 86.88 - Still good for CNS penetration, but slightly higher than A.
*   *Ligand A slightly favored.*

**3. Lipophilicity (logP):**
*   Ligand A: 4.351 - A bit high, potentially leading to solubility issues or off-target interactions.
*   Ligand B: 2.839 - Optimal range (1-3).
*   *Ligand B favored.*

**4. H-Bond Donors (HBD):**
*   Ligand A: 2 - Acceptable.
*   Ligand B: 3 - Acceptable.
*   *No clear advantage.*

**5. H-Bond Acceptors (HBA):**
*   Ligand A: 5 - Acceptable.
*   Ligand B: 3 - Acceptable.
*   *No clear advantage.*

**6. QED:**
*   Ligand A: 0.768 - Excellent drug-likeness.
*   Ligand B: 0.658 - Good drug-likeness, but slightly lower than A.
*   *Ligand A favored.*

**7. DILI Risk:**
*   Ligand A: 37.728 - Low risk.
*   Ligand B: 77.394 - Moderate risk.
*   *Ligand A favored.*

**8. BBB Penetration:**
*   Ligand A: 86.002 - Very good for CNS targets.
*   Ligand B: 60.76 - Acceptable, but significantly lower than A.
*   *Ligand A strongly favored (critical for DRD2).*

**9. Caco-2 Permeability:**
*   Ligand A: -4.67 - Poor permeability.
*   Ligand B: -5.238 - Poor permeability.
*   *No clear advantage.*

**10. Aqueous Solubility:**
*   Ligand A: -4.385 - Poor solubility.
*   Ligand B: -4.053 - Poor solubility.
*   *No clear advantage.*

**11. hERG Inhibition:**
*   Ligand A: 0.426 - Low risk.
*   Ligand B: 0.595 - Slightly higher risk than A.
*   *Ligand A favored.*

**12. Microsomal Clearance:**
*   Ligand A: 72.735 - Moderate clearance.
*   Ligand B: 43.217 - Lower clearance, indicating better metabolic stability.
*   *Ligand B favored.*

**13. In vitro Half-Life:**
*   Ligand A: 31.706 - Moderate half-life.
*   Ligand B: 56.454 - Longer half-life, potentially allowing for less frequent dosing.
*   *Ligand B favored.*

**14. P-gp Efflux:**
*   Ligand A: 0.148 - Low efflux, good for CNS exposure.
*   Ligand B: 0.496 - Higher efflux, potentially limiting CNS exposure.
*   *Ligand A favored (critical for DRD2).*

**15. Binding Affinity:**
*   Ligand A: -9.5 kcal/mol - Excellent binding affinity.
*   Ligand B: -9.4 kcal/mol - Also excellent, but slightly weaker than A.
*   *Ligand A favored.*

**Overall Assessment:**

Given that DRD2 is a CNS target (GPCR), BBB penetration is paramount. Ligand A has a significantly higher BBB percentile (86%) compared to Ligand B (60%).  Ligand A also demonstrates superior DILI risk, QED, hERG inhibition, P-gp efflux, and binding affinity. While Ligand B has better metabolic stability (lower Cl_mic, longer t1/2) and a more optimal logP, the CNS-related properties of Ligand A are far more critical for this target. The slightly higher logP of Ligand A is a manageable concern compared to the substantial difference in BBB penetration.

1
2025-04-17 05:06:31,340 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B based on the provided guidelines, prioritizing GPCR-specific properties (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (347.375 Da) is slightly lower, which could be beneficial for permeability.

**TPSA:** Ligand B (76.88) is significantly better than Ligand A (124.52). For CNS targets, TPSA < 90 is preferred, and Ligand B comfortably meets this, while Ligand A is approaching the upper limit.

**logP:** Ligand B (2.939) is optimal (1-3), whereas Ligand A (-0.422) is quite low, potentially hindering membrane permeability and CNS penetration.

**H-Bond Donors/Acceptors:** Ligand A has 3 HBD and 6 HBA, while Ligand B has 1 HBD and 7 HBA. Both are within acceptable limits, though Ligand B's lower HBD count is slightly favorable.

**QED:** Both ligands have acceptable QED values (A: 0.454, B: 0.747), indicating reasonable drug-likeness. Ligand B is better.

**DILI:** Both have similar DILI risk (A: 59.519, B: 61.497), and are within an acceptable range (<60 is good).

**BBB:** Ligand B (62.156) has a better BBB percentile than Ligand A (53.742), though neither are above the highly desirable >70 threshold. This is a critical factor for a CNS target like DRD2.

**Caco-2 Permeability:** Both have negative values, which is unusual. Assuming these are logP-scale values, lower values indicate poorer permeability. Ligand A (-6.015) is worse than Ligand B (-5.695).

**Aqueous Solubility:** Both have negative values, also unusual. Again, assuming logS values, lower values indicate lower solubility. Ligand A (-1.185) is slightly better than Ligand B (-2.56).

**hERG Inhibition:** Both have very low hERG inhibition risk (A: 0.022, B: 0.367), which is excellent.

**Microsomal Clearance:** Ligand A (-5.876) has a lower (better) microsomal clearance than Ligand B (9.447), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand B (63.791) has a significantly longer half-life than Ligand A (16.773), which is a major advantage.

**P-gp Efflux:** Ligand A (0.003) has a much lower P-gp efflux liability than Ligand B (0.279), indicating better potential for CNS exposure.

**Binding Affinity:** Ligand B (-9.0) has a considerably stronger binding affinity than Ligand A (-8.5). A 0.5 kcal/mol difference is significant and can outweigh some ADME drawbacks.

**Overall Assessment:**

Ligand B is the stronger candidate. While Ligand A has better metabolic stability and P-gp efflux, Ligand B excels in crucial areas for a CNS GPCR target: TPSA, logP, BBB penetration, and, most importantly, binding affinity. The stronger binding affinity of Ligand B (-9.0 kcal/mol) is a substantial advantage. The longer half-life also contributes to its favorability. The slightly higher logP and lower TPSA of Ligand B are more aligned with CNS penetration requirements.



Output:
1
2025-04-17 05:06:31,340 - INFO - Batch 170 complete. Total preferences: 2720
2025-04-17 05:06:31,340 - INFO - Processing batch 171/512...
2025-04-17 05:07:13,651 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (344.459 and 356.457 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (74.33) is better than Ligand B (43.78) as it is closer to the ideal range for CNS targets (<=90). Ligand B is excellent.

**3. logP:** Both ligands have acceptable logP values (1.818 and 3.661), falling within the optimal 1-3 range. Ligand B is slightly higher, potentially leading to some solubility concerns, but still within an acceptable range.

**4. H-Bond Donors:** Both ligands have reasonable HBD counts (2 and 1 respectively), well below the threshold of 5.

**5. H-Bond Acceptors:** Both ligands have reasonable HBA counts (4 and 3 respectively), well below the threshold of 10.

**6. QED:** Both ligands have good QED scores (0.754 and 0.773), indicating good drug-like properties.

**7. DILI:** Ligand A (49.011) has a slightly higher DILI risk than Ligand B (13.532). Ligand B is significantly better here.

**8. BBB:** Both ligands have good BBB penetration (76.658 and 71.074), exceeding the desirable threshold of 70 for CNS targets. Ligand A is slightly better.

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.762 and -4.621). This is unusual and suggests poor permeability. However, these values are on the same scale, so this doesn't differentiate the ligands.

**10. Aqueous Solubility:** Both ligands have negative solubility values (-3.149 and -3.143). This is also unusual and suggests poor solubility. Again, these values are similar.

**11. hERG Inhibition:** Both ligands have low hERG inhibition risk (0.653 and 0.896).

**12. Microsomal Clearance:** Ligand B (83.716) has a significantly higher microsomal clearance than Ligand A (47.564), indicating lower metabolic stability. Ligand A is better here.

**13. In vitro Half-Life:** Ligand A (17.469) has a longer in vitro half-life than Ligand B (-5.056). This is a significant advantage for Ligand A.

**14. P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.074 and 0.165), which is favorable for CNS penetration.

**15. Binding Affinity:** Ligand A (-8.0) has a slightly better binding affinity than Ligand B (-6.8). This 1.2 kcal/mol difference is substantial and can outweigh minor ADME drawbacks.

**Overall Assessment:**

Considering the GPCR-specific priorities, Ligand A is the better candidate. While Ligand B has a lower DILI risk, Ligand A has a significantly better binding affinity, longer half-life, and lower microsomal clearance. The slightly better BBB penetration of Ligand A is also a plus. The similar poor solubility and permeability values are concerning for both, but the superior potency and metabolic stability of Ligand A make it the more promising candidate.

Output:
0
2025-04-17 05:07:13,651 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (345.355 and 359.411 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (93.9) is excellent, falling below the 90 A^2 threshold for CNS targets. Ligand B (121.18) is higher, but still potentially acceptable, though less optimal.

**logP:** Ligand A (1.874) is within the optimal 1-3 range. Ligand B (0.376) is a bit low, potentially hindering membrane permeability.

**H-Bond Donors/Acceptors:** Ligand A (1 HBD, 6 HBA) and Ligand B (3 HBD, 6 HBA) both have reasonable numbers of H-bond donors and acceptors, well within the guidelines.

**QED:** Ligand A (0.854) has a very strong drug-like profile. Ligand B (0.681) is still acceptable, but less favorable.

**DILI:** Ligand A (77.433) and Ligand B (83.443) both have acceptable DILI risk, below the concerning 60 percentile.

**BBB:** This is crucial for a CNS target. Ligand A (74.292) has a good BBB percentile. Ligand B (45.909) is significantly lower, indicating poor predicted brain penetration.

**Caco-2 Permeability:** Ligand A (-4.501) has poor Caco-2 permeability. Ligand B (-5.595) is even worse.

**Aqueous Solubility:** Both ligands (-3.305 and -3.135) have poor aqueous solubility.

**hERG Inhibition:** Both ligands (0.18 and 0.385) show low hERG inhibition risk, which is good.

**Microsomal Clearance:** Ligand A (95.704) has high microsomal clearance, suggesting rapid metabolism. Ligand B (-6.554) has *negative* clearance, which is not physically possible and indicates an outlier or error in the data. However, even if we interpret this as very low clearance, it's a strong positive.

**In vitro Half-Life:** Ligand A (-33.21) has a negative half-life, which is not physically possible and indicates an outlier or error in the data. Ligand B (-26.371) also has a negative half-life.

**P-gp Efflux:** Both ligands (0.16 and 0.017) have low P-gp efflux, which is favorable for CNS penetration.

**Binding Affinity:** Ligand B (-8.6 kcal/mol) has significantly stronger binding affinity than Ligand A (0.0 kcal/mol). This is a substantial advantage.

**Overall Assessment:**

Despite the poor solubility and Caco-2 permeability for both compounds, Ligand B stands out due to its significantly superior binding affinity and potentially better metabolic stability (indicated by the negative clearance value, which should be investigated further). The biggest drawback for Ligand B is its lower BBB penetration compared to Ligand A. However, the substantial affinity advantage (-8.6 vs 0.0 kcal/mol) can often outweigh moderate ADME deficiencies, especially if further optimization can improve BBB penetration. Ligand A's poor affinity makes it a less promising candidate. The negative values for half-life and clearance for both compounds are concerning and should be verified.

Output:
1
2025-04-17 05:07:13,652 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (367.812 and 344.411 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (90.12) is slightly above the optimal <90 for CNS targets, but still reasonable. Ligand B (76.66) is well within the desired range.

**logP:** Ligand A (2.206) is within the optimal 1-3 range. Ligand B (0.218) is quite low, potentially hindering membrane permeability.

**H-Bond Donors/Acceptors:** Both ligands have acceptable HBD (3 & 2) and HBA (4 & 4) counts, well below the thresholds of 5 and 10, respectively.

**QED:** Both ligands have similar QED scores (0.699 and 0.618), indicating good drug-likeness.

**DILI:** Ligand A (68.437) has a higher DILI risk than Ligand B (29.236). This is a significant negative for Ligand A.

**BBB:** Ligand A (63.164) has a moderate BBB penetration, while Ligand B (54.75) is lower. Both are below the desirable >70 for CNS targets, but Ligand A is better.

**Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and suggests a potential issue with the data or the compounds themselves. This is difficult to interpret without further information.

**Aqueous Solubility:** Both ligands have negative solubility values, which is also unusual and requires further investigation.

**hERG:** Both ligands show very low hERG inhibition liability (0.653 and 0.074), which is excellent.

**Microsomal Clearance:** Ligand A (19.947) has a higher microsomal clearance than Ligand B (5.521), suggesting lower metabolic stability.

**In vitro Half-Life:** Ligand A (76.874) has a significantly longer half-life than Ligand B (2.816), which is a major advantage.

**P-gp Efflux:** Ligand A (0.041) has very low P-gp efflux, which is favorable for CNS penetration. Ligand B (0.02) is even lower, but both are excellent.

**Binding Affinity:** Ligand A (-8.3 kcal/mol) has a substantially stronger binding affinity than Ligand B (-6.9 kcal/mol) - a difference of 1.4 kcal/mol. This is a significant advantage that can outweigh some of the ADME drawbacks.

**Overall Assessment:**

Ligand A has a significantly better binding affinity and a longer half-life, and better BBB penetration. However, it has a higher DILI risk and higher microsomal clearance. Ligand B has a lower DILI risk and better TPSA, but suffers from a very low logP and a much weaker binding affinity.

Given the GPCR-specific priorities, the strong binding affinity of Ligand A is a critical factor. While the DILI risk is a concern, it might be mitigated through structural modifications during lead optimization. The lower logP of Ligand B is a more fundamental issue that would be harder to address without significantly altering the core structure and potentially losing affinity.

Output:
1
2025-04-17 05:07:13,652 - INFO - Reasoning:

Let's analyze Ligand A and Ligand B based on the provided guidelines, prioritizing GPCR-specific properties (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (343.427 Da) is slightly lower, which could be beneficial for permeability, but both are acceptable.

**TPSA:** Ligand A (87.13) is better than Ligand B (53.33) as it is closer to the ideal range for CNS targets (<=90).

**logP:** Ligand A (3.132) is within the optimal range (1-3). Ligand B (4.703) is slightly higher, potentially leading to solubility issues or off-target interactions.

**H-Bond Donors/Acceptors:** Ligand A has 3 HBD and 3 HBA, while Ligand B has 0 HBD and 4 HBA. Both are within acceptable limits (<=5 HBD, <=10 HBA).

**QED:** Both ligands have similar QED values (0.779 and 0.673), indicating good drug-like properties.

**DILI:** Ligand A (62.156) has a higher DILI risk than Ligand B (39.628). This is a negative for Ligand A.

**BBB:** Ligand B (76.696) has a significantly better BBB penetration percentile than Ligand A (52.85). This is a crucial advantage for a CNS target like DRD2.

**Caco-2 Permeability:** Ligand A (-5.121) has a worse Caco-2 permeability than Ligand B (-4.795).

**Aqueous Solubility:** Ligand A (-3.78) has a slightly better aqueous solubility than Ligand B (-5.478).

**hERG Inhibition:** Ligand A (0.528) has a lower hERG inhibition liability than Ligand B (0.898), which is favorable.

**Microsomal Clearance:** Ligand B (86.346) has a higher microsomal clearance than Ligand A (40.122), suggesting lower metabolic stability.

**In vitro Half-Life:** Ligand A (74.705) has a longer in vitro half-life than Ligand B (47.229), which is desirable.

**P-gp Efflux:** Ligand A (0.269) has lower P-gp efflux liability than Ligand B (0.819), which is beneficial for CNS exposure.

**Binding Affinity:** Ligand B (-7.1 kcal/mol) has a significantly stronger binding affinity than Ligand A (-9.4 kcal/mol). This is a substantial advantage, potentially outweighing some of the ADME drawbacks.

**Overall Assessment:**

While Ligand A has better solubility, lower hERG risk, lower P-gp efflux, and longer half-life, Ligand B's superior BBB penetration and significantly stronger binding affinity are critical for a CNS GPCR target. The slightly higher logP and DILI risk of Ligand B are less concerning given the strong binding and better CNS penetration. The difference in binding affinity (-7.1 vs -9.4) is substantial.

Output:
1
2025-04-17 05:07:13,652 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (380.857 Da) is slightly higher than Ligand B (350.459 Da), but both are acceptable.

**TPSA:** Both ligands have TPSA values below the 140 A^2 threshold for oral absorption. Ligand A (92.09 A^2) is slightly higher than Ligand B (87.66 A^2), but both are reasonably good for CNS penetration, being below the stricter 90 A^2 target.

**logP:** Ligand A (3.174) is within the optimal range (1-3), while Ligand B (1.114) is at the lower end. Lower logP can sometimes hinder permeability, which is a concern for CNS targets.

**H-Bond Donors/Acceptors:** Ligand A has 1 HBD and 5 HBA, while Ligand B has 3 HBD and 4 HBA. Both are within acceptable limits (<=5 HBD and <=10 HBA).

**QED:** Both ligands have similar QED values (0.686 and 0.67), indicating good drug-like properties.

**DILI:** Ligand A has a DILI risk of 77.782%, which is moderately high. Ligand B has a significantly lower DILI risk of 23.769%, which is much more favorable.

**BBB:** This is a critical parameter for CNS targets. Ligand A has a BBB penetration percentile of 57.193%, which is acceptable but not ideal. Ligand B has a much lower BBB penetration of 35.673%, which is a significant drawback.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.039 and -5.401). This is unusual and suggests poor intestinal absorption, but the scale is not clearly defined.

**Aqueous Solubility:** Both ligands have negative solubility values (-4.876 and -1.453). Again, the scale is unclear, but suggests poor solubility.

**hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.368% and 0.14%), which is excellent.

**Microsomal Clearance:** Ligand A (56.237 mL/min/kg) has a moderate clearance, while Ligand B (-15.738 mL/min/kg) has a negative value, which is not physically possible. This is a major red flag for Ligand B, suggesting a potential issue with the data or a highly unstable compound.

**In vitro Half-Life:** Ligand A has a negative half-life (-11.556 hours), which is not physically possible. Ligand B has a half-life of 30.379 hours, which is good.

**P-gp Efflux:** Ligand A (0.11) has low P-gp efflux, which is favorable for CNS penetration. Ligand B (0.041) also has low P-gp efflux.

**Binding Affinity:** Ligand A has a significantly stronger binding affinity (-7.8 kcal/mol) than Ligand B (-9.0 kcal/mol). This is a substantial difference and a major advantage for Ligand A.

**Overall Assessment:**

Despite the questionable solubility and Caco-2 values for both, Ligand A is the more promising candidate. It has a significantly better binding affinity, acceptable BBB penetration, low P-gp efflux, and a manageable (though elevated) DILI risk. Ligand B has a very concerning negative microsomal clearance and a poor BBB score, making it less likely to be a viable drug candidate. The negative half-life for Ligand A is a data error, but the strong affinity makes it worth further investigation.

Output:
0
2025-04-17 05:07:13,652 - INFO - Reasoning:

Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight (MW):** Both ligands (370.515 and 354.447 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (70.08) is significantly better than Ligand B (87.15). For CNS targets, we want TPSA <= 90, and A is closer to the ideal <= 60-70 range. B is pushing the upper limit and could have reduced brain penetration.

**3. logP:** Both ligands have acceptable logP values (1.838 and 0.593). The optimal range is 1-3, and A is within this range, while B is slightly below, which *could* indicate permeability issues, though not critically.

**4. H-Bond Donors (HBD):** Both have 1 HBD, which is good.

**5. H-Bond Acceptors (HBA):** Both have 5 HBA, which is good.

**6. QED:** Both ligands have reasonable QED scores (0.8 and 0.689), indicating good drug-like properties.

**7. DILI:** Ligand A (38.503) has a slightly higher DILI risk than Ligand B (24.544), but both are below the concerning threshold of 60.

**8. BBB:** This is crucial for a CNS target like DRD2. Ligand B (55.215) has a much better BBB percentile than Ligand A (28.655). This is a major advantage for B.

**9. Caco-2 Permeability:** Both have negative Caco-2 values (-4.57 and -4.639), which is unusual and suggests poor permeability. This is a concern for both, but doesn't necessarily disqualify them.

**10. Aqueous Solubility:** Both have negative solubility values (-2.046 and -0.95), also unusual and suggesting poor solubility. This is a concern for both, but doesn't necessarily disqualify them.

**11. hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.155 and 0.141).

**12. Microsomal Clearance:** Ligand B (19.898) has significantly lower microsomal clearance than Ligand A (43.521), indicating better metabolic stability.

**13. In vitro Half-Life:** Ligand B (2.407) has a longer half-life than Ligand A (-2.6).

**14. P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.167 and 0.058).

**15. Binding Affinity:** Ligand B (-7.6 kcal/mol) has a slightly better binding affinity than Ligand A (-7.2 kcal/mol). While the difference is not huge, it's within the range where it could outweigh minor ADME drawbacks.

**Overall Assessment:**

Ligand B is the more promising candidate. While both have issues with Caco-2 and solubility, Ligand B excels in BBB penetration, metabolic stability (lower Cl_mic, longer t1/2), and has a slightly better binding affinity. The TPSA value for Ligand A is a concern for CNS penetration, and the lower BBB score further diminishes its potential. The slightly better DILI score of Ligand B is also a plus. Given the GPCR-specific priorities, the superior BBB and metabolic stability of Ligand B are decisive.

Output:
1
2025-04-17 05:07:13,653 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (336.479 and 352.865 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (32.34) is excellent, well below the 90 A^2 threshold for CNS targets. Ligand B (45.15) is still reasonable, but less optimal.

**3. logP:** Ligand A (3.945) is within the optimal 1-3 range, while Ligand B (4.937) is slightly higher. While still acceptable, higher logP can sometimes lead to off-target effects.

**4. H-Bond Donors:** Both ligands have acceptable HBD counts (1 and 2 respectively), well below the 5 threshold.

**5. H-Bond Acceptors:** Both ligands have acceptable HBA counts (2 and 3 respectively), well below the 10 threshold.

**6. QED:** Ligand A (0.897) has a very strong drug-like profile, significantly better than Ligand B (0.683).

**7. DILI:** Ligand A (19.504) has a much lower DILI risk than Ligand B (32.571).

**8. BBB:** This is a critical parameter for CNS targets. Ligand A (87.67) has a very good BBB penetration percentile, exceeding the desirable >70 threshold. Ligand B (15.432) is very poor for CNS penetration.

**9. Caco-2 Permeability:** Both have negative values, which is unusual and suggests a problem with the data or modeling. However, the magnitude of the negative value for Ligand A (-4.915) is less extreme than for Ligand B (-5.263), suggesting slightly better permeability.

**10. Aqueous Solubility:** Both have negative values, which is also unusual. Ligand A (-3.37) is slightly better than Ligand B (-4.711).

**11. hERG Inhibition:** Both have low hERG inhibition risk (0.977 and 0.757).

**12. Microsomal Clearance:** Ligand A (3.5) has significantly lower microsomal clearance than Ligand B (85.282), indicating better metabolic stability.

**13. In vitro Half-Life:** Ligand A (15.957) has a better in vitro half-life than Ligand B (17.072).

**14. P-gp Efflux:** Ligand A (0.649) has lower P-gp efflux liability than Ligand B (0.3), which is favorable for CNS exposure.

**15. Binding Affinity:** Both ligands have excellent binding affinities (-9.9 and -8.9 kcal/mol). Ligand A is slightly better (-9.9 kcal/mol).

**Overall Assessment:**

Ligand A is significantly superior to Ligand B. It has a better QED score, much lower DILI risk, excellent BBB penetration, better metabolic stability (lower Cl_mic), lower P-gp efflux, and slightly better binding affinity. While both have unusual solubility and Caco-2 permeability values, Ligand A is better in both respects. The combination of these factors makes Ligand A a much more promising drug candidate for targeting DRD2, a CNS target.

Output:
1
2025-04-17 05:07:13,653 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (408.384 Da) is slightly higher than Ligand B (348.487 Da), but both are acceptable.

**2. TPSA:** Ligand A (49.57) is better than Ligand B (58.64). For CNS targets, we want TPSA <= 90, and ideally closer to 60. Both are within the acceptable range, but A is preferable.

**3. logP:** Both ligands have good logP values (A: 3.624, B: 2.799), falling within the optimal 1-3 range.

**4. H-Bond Donors:** Both have 1 HBD, which is good.

**5. H-Bond Acceptors:** Both have 3 HBA, which is good.

**6. QED:** Ligand A (0.828) has a significantly better QED score than Ligand B (0.686), indicating a more drug-like profile.

**7. DILI:** Ligand A (10.896) has a much lower DILI risk than Ligand B (15.471), which is a significant advantage.

**8. BBB:** Ligand A (91.198) has a substantially higher BBB penetration percentile than Ligand B (81.815). This is *critical* for a CNS target like DRD2.

**9. Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual. However, the magnitude of negativity is similar (-5.226 for A, -4.747 for B), so this isn't a major differentiator.

**10. Aqueous Solubility:** Both have negative solubility values, which is also unusual. Again, the values are similar (-3.267 for A, -3.083 for B).

**11. hERG Inhibition:** Both ligands have low hERG inhibition risk (A: 0.939, B: 0.444), which is good.

**12. Microsomal Clearance:** Ligand A (36.808) has lower microsomal clearance than Ligand B (61.723), suggesting better metabolic stability.

**13. In vitro Half-Life:** Ligand A (19.878) has a longer in vitro half-life than Ligand B (11.445), which is desirable.

**14. P-gp Efflux:** Both ligands have low P-gp efflux liability (A: 0.345, B: 0.141).

**15. Binding Affinity:** Ligand A (-9.7 kcal/mol) has a significantly stronger binding affinity than Ligand B (-8.0 kcal/mol). This is a substantial advantage, exceeding the 1.5 kcal/mol threshold.

**Overall Assessment:**

Ligand A consistently outperforms Ligand B across most critical parameters, especially for a CNS target. Its superior BBB penetration, lower DILI risk, better metabolic stability (lower Cl_mic, longer t1/2), higher QED, and significantly stronger binding affinity make it the more promising drug candidate. While both have unusual solubility and Caco-2 values, the other advantages of Ligand A outweigh these concerns.

Output:
1
2025-04-17 05:07:13,653 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B based on the provided guidelines, prioritizing GPCR-specific properties (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (372.795) is slightly higher than Ligand B (355.435), but both are acceptable.

**TPSA:** Ligand A (52.6) is excellent for CNS penetration, well below the 90 A^2 threshold. Ligand B (88.18) is higher, but still potentially acceptable, though less ideal.

**logP:** Ligand A (4.202) is slightly high, potentially leading to solubility issues or off-target effects. Ligand B (0.319) is quite low, which could hinder membrane permeability and CNS penetration.

**H-Bond Donors/Acceptors:** Ligand A (0 HBD, 4 HBA) is favorable. Ligand B (1 HBD, 5 HBA) is also acceptable.

**QED:** Both ligands have similar QED values (0.587 and 0.58), indicating good drug-likeness.

**DILI:** Ligand A (59.364) has a moderate DILI risk, while Ligand B (35.712) has a lower risk.

**BBB:** Ligand A (85.498) has a significantly better BBB percentile than Ligand B (60.799). This is a crucial factor for a CNS target like DRD2.

**Caco-2 Permeability:** Ligand A (-4.147) has poor Caco-2 permeability, which is concerning. Ligand B (-4.886) is also poor, but slightly worse.

**Aqueous Solubility:** Ligand A (-5.67) has very poor aqueous solubility, likely due to its high logP. Ligand B (-1.347) is also poor, but better than Ligand A.

**hERG Inhibition:** Ligand A (0.391) has a very low hERG risk, which is excellent. Ligand B (0.14) is even lower, also excellent.

**Microsomal Clearance:** Ligand A (93.695) has high microsomal clearance, indicating poor metabolic stability. Ligand B (-8.189) has negative clearance, which is highly unusual and likely indicates *very* high metabolic stability.

**In vitro Half-Life:** Ligand A (37.648) has a moderate in vitro half-life. Ligand B (-9.92) has a negative half-life, which is not physically possible and suggests an error or unusual behavior.

**P-gp Efflux:** Ligand A (0.411) has low P-gp efflux, which is favorable for CNS penetration. Ligand B (0.006) has extremely low P-gp efflux, which is even more favorable.

**Binding Affinity:** Ligand B (-7.5 kcal/mol) has a significantly stronger binding affinity than Ligand A (0 kcal/mol). This is a major advantage, potentially outweighing some ADME drawbacks.

**Overall Assessment:**

Ligand B has a much stronger binding affinity, extremely low P-gp efflux, and lower DILI risk. However, it suffers from a low logP and poor Caco-2 permeability. Ligand A has better BBB penetration, but suffers from poor solubility, high metabolic clearance, and a very weak binding affinity.

Given the importance of binding affinity for GPCRs, and the need for CNS penetration, Ligand B is the more promising candidate *despite* its low logP. The strong binding affinity could compensate for some permeability issues, and the extremely low P-gp efflux will help with brain exposure. The negative values for clearance and half-life are concerning and would need further investigation, but the affinity advantage is significant.



Output:
1
2025-04-17 05:07:13,653 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (345.389 and 366.571 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (49.33) is significantly better than Ligand B (40.62), both are below the 90 A^2 threshold for CNS targets.

**3. logP:** Both ligands have good logP values (3.626 and 3.571) falling within the optimal 1-3 range.

**4. H-Bond Donors:** Ligand A has 2 HBD, which is acceptable. Ligand B has 0, also acceptable.

**5. H-Bond Acceptors:** Ligand A has 2 HBA, and Ligand B has 3. Both are within the acceptable limit of 10.

**6. QED:** Ligand A (0.869) has a better QED score than Ligand B (0.675), indicating better overall drug-likeness.

**7. DILI:** Ligand A (35.712) has a slightly higher DILI risk than Ligand B (22.257), but both are below the concerning threshold of 60.

**8. BBB:** Ligand A (75.107) has a slightly better BBB penetration percentile than Ligand B (71.229), both are above the 70% threshold for CNS targets.

**9. Caco-2:** Both ligands have negative Caco-2 values (-4.464 and -4.685), which is unusual and suggests poor permeability. This is a significant concern.

**10. Solubility:** Both ligands have negative solubility values (-4.378 and -3.551), indicating very poor aqueous solubility, which is a major drawback.

**11. hERG:** Both ligands have low hERG inhibition liability (0.733 and 0.567), which is good.

**12. Cl_mic:** Ligand B (94.906) has a significantly higher microsomal clearance than Ligand A (40.809), indicating lower metabolic stability. This is a major negative for Ligand B.

**13. t1/2:** Ligand A (8.458) has a slightly longer in vitro half-life than Ligand B (7.264).

**14. Pgp:** Both ligands have low Pgp efflux liability (0.285 and 0.412), which is favorable for CNS penetration.

**15. Binding Affinity:** Ligand A (-9.8 kcal/mol) has a significantly stronger binding affinity than Ligand B (-7.8 kcal/mol). This is a substantial advantage, exceeding the 1.5 kcal/mol difference threshold.

**Overall Assessment:**

Despite the poor Caco-2 and solubility values for both, Ligand A is the better candidate. Its significantly stronger binding affinity (-9.8 vs -7.8 kcal/mol) is a major advantage that can potentially outweigh the ADME concerns. Additionally, Ligand A has a better QED score, slightly better BBB penetration, and lower microsomal clearance (better metabolic stability) than Ligand B. The solubility and permeability issues would need to be addressed through formulation strategies, but the potency advantage of Ligand A makes it a more promising starting point.

Output:
0
2025-04-17 05:07:13,653 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (355.356 and 349.431 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (55.4) is excellent, well below the 90 A^2 threshold for CNS targets. Ligand B (84.67) is higher but still reasonable, though less favorable.

**logP:** Ligand A (3.767) is optimal. Ligand B (1.691) is on the lower side, potentially hindering membrane permeability.

**H-Bond Donors/Acceptors:** Both ligands have 1 HBD, which is good. Ligand A has 3 HBA, and Ligand B has 5 HBA. Both are within the acceptable range of <=10.

**QED:** Both ligands have good QED scores (0.791 and 0.845), indicating drug-like properties.

**DILI:** Ligand A (54.323) has a slightly higher DILI risk than Ligand B (36.758), but both are below the concerning threshold of 60.

**BBB:** Ligand A (95.386) has excellent BBB penetration, exceeding the desirable 70% threshold. Ligand B (77.705) is good, but not as favorable. This is a crucial factor for a CNS target like DRD2.

**Caco-2 Permeability:** Ligand A (-4.182) and Ligand B (-4.653) both have negative values, which is unusual and likely indicates poor permeability. However, the scale is not specified, so it's difficult to interpret.

**Aqueous Solubility:** Ligand A (-4.958) and Ligand B (-1.504) both have negative values, which suggests poor solubility. Again, the scale is not specified.

**hERG:** Both ligands have low hERG inhibition risk (0.651 and 0.172).

**Microsomal Clearance:** Ligand A (75.321) has higher microsomal clearance than Ligand B (25.016), suggesting lower metabolic stability.

**In vitro Half-Life:** Ligand B (-12.369) has a significantly longer in vitro half-life than Ligand A (-2.906).

**P-gp Efflux:** Ligand A (0.174) has lower P-gp efflux than Ligand B (0.03), which is desirable for CNS penetration.

**Binding Affinity:** Ligand A (-8.7 kcal/mol) has a slightly better binding affinity than Ligand B (-7.9 kcal/mol). The difference is 0.8 kcal/mol, which is significant.

**Overall Assessment:**

Ligand A excels in BBB penetration and binding affinity, two critical factors for a CNS GPCR target. While its DILI risk and microsomal clearance are slightly higher, the superior BBB and affinity likely outweigh these drawbacks. Ligand B has a better half-life and lower DILI, but its lower logP and BBB penetration are significant concerns. The difference in binding affinity, while not huge, favors Ligand A.

Output:
1
2025-04-17 05:07:13,654 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (343.391 and 349.435 Da) fall comfortably within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (111.19) is slightly higher than Ligand B (107.45), but both are below the 140 A^2 threshold for good oral absorption and reasonably close to the 90 A^2 target for CNS penetration.

**3. logP:** Ligand A (0.879) is within the optimal range (1-3), while Ligand B (-0.134) is slightly below 1. This is a significant difference; lower logP can hinder membrane permeability.

**4. H-Bond Donors:** Ligand A (2) and Ligand B (3) are both acceptable, being less than 5.

**5. H-Bond Acceptors:** Ligand A (8) and Ligand B (6) are both within the desired range of less than 10.

**6. QED:** Ligand A (0.832) has a better QED score than Ligand B (0.603), indicating a more drug-like profile.

**7. DILI:** Ligand A (70.88) has a higher DILI risk than Ligand B (25.087). This is a concern for Ligand A.

**8. BBB:** Ligand A (58.782) has a significantly better BBB penetration percentile than Ligand B (11.749). This is *critical* for a CNS target like DRD2.

**9. Caco-2 Permeability:** Ligand A (-5.352) and Ligand B (-5.522) both have negative Caco-2 values, which is unusual and suggests poor permeability. However, the scale isn't specified, so it's hard to interpret.

**10. Aqueous Solubility:** Ligand A (-2.492) and Ligand B (-0.846) both have negative solubility values, indicating poor solubility.

**11. hERG Inhibition:** Both ligands have low hERG inhibition risk (0.331 and 0.189, respectively).

**12. Microsomal Clearance:** Ligand A (-21.004) has a lower (better) microsomal clearance than Ligand B (-12.097), suggesting greater metabolic stability.

**13. In vitro Half-Life:** Ligand A (-16.324) has a longer half-life than Ligand B (11.404), which is desirable.

**14. P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.015 and 0.01, respectively).

**15. Binding Affinity:** Ligand A (-9.2 kcal/mol) has a significantly stronger binding affinity than Ligand B (-8.1 kcal/mol). This is a substantial advantage (1.1 kcal/mol difference).

**Overall Assessment:**

Ligand A has a superior binding affinity and better BBB penetration, which are paramount for a CNS GPCR target. It also exhibits better metabolic stability (lower Cl_mic) and a longer half-life. While its DILI risk is higher, the substantial advantage in affinity and BBB penetration likely outweighs this concern, *especially* given the poor BBB penetration of Ligand B. Ligand B's lower logP is a significant drawback, potentially hindering its ability to cross cell membranes.

Output:
1
2025-04-17 05:07:13,654 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B based on the provided guidelines, prioritizing GPCR-specific properties (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (370.471 and 357.479 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (104.73) is higher than Ligand B (71.09). For CNS targets, TPSA should be <= 90. Ligand B is preferable here.

**logP:** Both ligands (2.758 and 3.007) are within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A has 3 HBD and 5 HBA, while Ligand B has 2 HBD and 4 HBA. Both are within acceptable limits.

**QED:** Both ligands have good QED scores (0.711 and 0.864), indicating good drug-like properties.

**DILI:** Ligand A (79.992) has a higher DILI risk than Ligand B (48.895). Lower is better, so Ligand B is preferable.

**BBB:** Ligand B (58.278) has a significantly better BBB penetration percentile than Ligand A (46.064). This is a critical factor for a CNS target like DRD2.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.282 and -5.048), which is unusual and suggests poor permeability. However, these values are on a scale where negative values are possible, and direct comparison is difficult without knowing the scale's specifics.

**Aqueous Solubility:** Both ligands have negative solubility values (-3.055 and -3.022), again indicating poor solubility. Similar to Caco-2, the scale is unclear.

**hERG Inhibition:** Ligand A (0.047) has a slightly lower hERG inhibition liability than Ligand B (0.414), which is preferable.

**Microsomal Clearance:** Ligand A (7.655) has a lower microsomal clearance than Ligand B (11.934), indicating better metabolic stability.

**In vitro Half-Life:** Ligand B (35.777) has a significantly longer in vitro half-life than Ligand A (-25.442). This is a substantial advantage.

**P-gp Efflux:** Ligand A (0.022) has a much lower P-gp efflux liability than Ligand B (0.119), which is crucial for CNS penetration.

**Binding Affinity:** Ligand B (-9.2 kcal/mol) has a stronger binding affinity than Ligand A (-7.7 kcal/mol). The difference is >1.5 kcal/mol, making this a significant advantage.

**Overall Assessment:**

Ligand B is the stronger candidate. While both have issues with Caco-2 and solubility, Ligand B excels in the most critical areas for a CNS-targeting GPCR: BBB penetration, binding affinity, and in vitro half-life. It also has a lower DILI risk. The lower P-gp efflux of Ligand A is a positive, but the substantial affinity advantage of Ligand B outweighs this.

Output:
1
2025-04-17 05:07:13,654 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (354.431 and 354.441 Da) fall comfortably within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (60.67) is slightly higher than Ligand B (49.41). Both are below the 90 A^2 threshold for CNS targets, but B is preferable.

**3. logP:** Ligand A (3.55) is at the upper end of the optimal range (1-3), while Ligand B (2.762) is well within it. Ligand B is slightly better here.

**4. H-Bond Donors:** Ligand A (0) is ideal, while Ligand B (1) is acceptable.

**5. H-Bond Acceptors:** Ligand A (6) is good, while Ligand B (2) is excellent.

**6. QED:** Both ligands have good QED scores (0.658 and 0.825, respectively), indicating drug-like properties. Ligand B is better.

**7. DILI:** Ligand A (65.723) has a significantly higher DILI risk than Ligand B (11.283). This is a major concern for Ligand A.

**8. BBB:** Both ligands have excellent BBB penetration (79.411 and 87.01, respectively), exceeding the >70% threshold for CNS targets. Ligand B is slightly better.

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 values, which is unusual and suggests poor permeability. However, the scale is not specified, so it's difficult to interpret.

**10. Aqueous Solubility:** Both ligands have negative solubility values, which is also unusual and suggests poor solubility. Again, the scale is not specified.

**11. hERG Inhibition:** Both ligands show low hERG inhibition risk (0.264 and 0.569, respectively).

**12. Microsomal Clearance:** Ligand A (101.065) has a higher microsomal clearance than Ligand B (29.335), indicating lower metabolic stability.

**13. In vitro Half-Life:** Ligand B (-6.27) has a longer half-life than Ligand A (-16.753).

**14. P-gp Efflux:** Both ligands have low P-gp efflux liability (0.6 and 0.109, respectively), which is good for CNS exposure. Ligand B is better.

**15. Binding Affinity:** Both ligands have similar and strong binding affinities (-9.6 and -9.2 kcal/mol, respectively). The difference is less than 1.5 kcal/mol, so it's not a deciding factor.

**Overall Assessment:**

Ligand B is clearly superior. It has a significantly lower DILI risk, better logP, better TPSA, better QED, better metabolic stability (lower Cl_mic), longer half-life, and lower P-gp efflux. While both have good BBB penetration and binding affinity, the ADME properties of Ligand B make it a much more promising drug candidate. The unusual negative values for Caco-2 and solubility are a concern for both, but the other advantages of Ligand B outweigh this.

Output:
1
2025-04-17 05:07:13,654 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (346.435 and 358.429 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (107.83) is higher than the preferred <90 for CNS targets, but still potentially acceptable. Ligand B (58.64) is excellent, well below the 90 threshold.

**logP:** Both ligands (1.794 and 2.344) are within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A has 2 HBD and 6 HBA, which are acceptable. Ligand B has 1 HBD and 3 HBA, also acceptable.

**QED:** Both ligands have good QED scores (0.71 and 0.821), indicating good drug-like properties.

**DILI:** Ligand A (52.346) has a moderate DILI risk, while Ligand B (25.242) has a low DILI risk, which is favorable.

**BBB:** This is a crucial parameter for a CNS target like DRD2. Ligand A has a BBB percentile of 68.554, which is okay but not great. Ligand B has a significantly higher BBB percentile of 95.502, making it much more likely to reach the brain.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.195 and -4.59), which is unusual and suggests poor permeability. However, these values are on a log scale and can be difficult to interpret directly without knowing the base of the log.

**Aqueous Solubility:** Both ligands have negative solubility values (-2.34 and -2.779), indicating poor aqueous solubility. This could be a formulation challenge.

**hERG Inhibition:** Ligand A (0.06) has a very low hERG risk, which is excellent. Ligand B (0.459) has a slightly higher, but still relatively low, hERG risk.

**Microsomal Clearance:** Ligand A (21.329) has a moderate microsomal clearance, suggesting moderate metabolic stability. Ligand B (0.241) has very low clearance, indicating excellent metabolic stability.

**In vitro Half-Life:** Ligand A (-1.237) has a negative half-life, which is not physically possible and indicates an issue with the data or experimental setup. Ligand B (4.375) has a good in vitro half-life.

**P-gp Efflux:** Ligand A (0.214) has low P-gp efflux, which is good. Ligand B (0.046) has very low P-gp efflux, even better.

**Binding Affinity:** Ligand B (-7.7 kcal/mol) has a slightly better binding affinity than Ligand A (-8.5 kcal/mol). While both are good, the difference is not substantial enough to outweigh other factors.

**Overall Assessment:**

Ligand B is the stronger candidate. It excels in BBB penetration, metabolic stability (low Cl_mic, good t1/2), P-gp efflux, and has a lower DILI risk. While both have solubility and permeability concerns, the superior CNS penetration and metabolic profile of Ligand B make it more likely to be a viable drug candidate for a CNS target like DRD2. The negative half-life for Ligand A is a significant red flag.

Output:
1
2025-04-17 05:07:13,655 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (366.49 & 360.42 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Both ligands (59.31 & 58.2) are below the 90 A^2 threshold for CNS targets, which is excellent.

**3. logP:** Ligand A (0.845) is slightly below the optimal 1-3 range, potentially hindering permeability. Ligand B (3.022) is within the optimal range. This favors Ligand B.

**4. H-Bond Donors:** Ligand A (0) is ideal. Ligand B (2) is acceptable, but more donors can sometimes reduce permeability.

**5. H-Bond Acceptors:** Ligand A (8) is within the acceptable range. Ligand B (2) is also good.

**6. QED:** Both ligands (0.646 & 0.664) have good drug-likeness scores, exceeding the 0.5 threshold.

**7. DILI:** Both ligands have low DILI risk (39.55 & 30.63), which is favorable. Ligand B is slightly better.

**8. BBB:** Both ligands show good BBB penetration (78.40 & 83.91), exceeding the 70% threshold for CNS targets. Ligand B is slightly better.

**9. Caco-2 Permeability:** Both have negative Caco-2 values (-4.733 & -4.628), which is unusual and suggests poor permeability *in vitro*. This is a concern for both.

**10. Aqueous Solubility:** Both have negative solubility values (-1.014 & -4.411), indicating very poor aqueous solubility. This is a significant drawback for both.

**11. hERG Inhibition:** Both ligands have low hERG inhibition risk (0.881 & 0.561).

**12. Microsomal Clearance:** Ligand A (39.07) has higher clearance than Ligand B (29.29), suggesting lower metabolic stability. This favors Ligand B.

**13. In vitro Half-Life:** Ligand B (17.37) has a longer half-life than Ligand A (13.34), which is preferable.

**14. P-gp Efflux:** Both ligands have low P-gp efflux liability (0.124 & 0.117), which is good for CNS penetration.

**15. Binding Affinity:** Ligand B (-8.0 kcal/mol) has a stronger binding affinity than Ligand A (-7.3 kcal/mol). This 0.7 kcal/mol difference is significant and can outweigh some of the ADME drawbacks.

**Overall Assessment:**

While both ligands have significant solubility and permeability issues (negative Caco-2 and solubility values), Ligand B is superior due to its better logP, lower microsomal clearance, longer half-life, and significantly stronger binding affinity. The stronger affinity is a key advantage for a GPCR ligand. The slightly better BBB and DILI scores also contribute to its favorability.

Output:
1
2025-04-17 05:07:13,655 - INFO - Batch 171 complete. Total preferences: 2736
2025-04-17 05:07:13,655 - INFO - Processing batch 172/512...
2025-04-17 05:07:53,997 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (405.684 and 492.689 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (42.31) is excellent, well below the 90 A^2 threshold for CNS targets. Ligand B (56.75) is still reasonable but higher, potentially impacting BBB penetration.

**3. logP:** Both ligands (4.345 and 4.256) are slightly above the optimal 1-3 range, but not drastically so. This could potentially lead to some off-target effects or solubility issues, but is not a major concern.

**4. H-Bond Donors:** Both have 0 HBD, which is acceptable.

**5. H-Bond Acceptors:** Ligand A has 4 HBA, and Ligand B has 6 HBA. Both are within the acceptable range of <=10.

**6. QED:** Both ligands have good QED scores (0.549 and 0.584), indicating good drug-like properties.

**7. DILI:** Both ligands have similar DILI risk (62.001 and 63.862), placing them in a moderate risk category. This isn't a deal-breaker, but warrants further investigation.

**8. BBB:** Ligand A has a significantly better BBB penetration score (92.71%) than Ligand B (83.87%). This is a *critical* advantage for a CNS target like DRD2.

**9. Caco-2 Permeability:** Ligand A (-4.284) has better Caco-2 permeability than Ligand B (-5.028).

**10. Aqueous Solubility:** Ligand A (-4.794) has better aqueous solubility than Ligand B (-5.962).

**11. hERG Inhibition:** Both ligands have low hERG inhibition liability (0.695 and 0.936), which is favorable.

**12. Microsomal Clearance:** Ligand A (89.063) has higher microsomal clearance than Ligand B (76.439), meaning it's metabolized faster and has lower metabolic stability.

**13. In vitro Half-Life:** Ligand B (30.968) has a longer in vitro half-life than Ligand A (62.13). This is a positive for Ligand B.

**14. P-gp Efflux:** Ligand A (0.775) has lower P-gp efflux than Ligand B (0.834), which is beneficial for CNS exposure.

**15. Binding Affinity:** Ligand B (-11.0 kcal/mol) has *significantly* stronger binding affinity than Ligand A (-8.5 kcal/mol). This is a substantial advantage, potentially outweighing some of the ADME drawbacks. A difference of 2.5 kcal/mol is considerable.

**Overall Assessment:**

While Ligand B has a superior binding affinity and better metabolic stability (longer half-life), Ligand A demonstrates significantly better BBB penetration, Caco-2 permeability, and solubility, and lower P-gp efflux. Given that DRD2 is a CNS target, BBB penetration is paramount. The substantial affinity difference of Ligand B is tempting, but the lower BBB penetration is a major concern. The better ADME profile of Ligand A, particularly the BBB score, makes it the more promising candidate despite the slightly weaker binding.

Output:
0
2025-04-17 05:07:53,998 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (342.414 and 362.55 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (61.36) is better than Ligand B (66.4) as it is closer to the ideal <90 for CNS targets.

**3. logP:** Ligand B (2.362) is better than Ligand A (4.506). Ligand A's logP is quite high, potentially leading to solubility issues and off-target interactions. Ligand B is within the optimal 1-3 range.

**4. H-Bond Donors:** Ligand A (3) is reasonable, while Ligand B (0) is also acceptable.

**5. H-Bond Acceptors:** Ligand A (2) and Ligand B (4) are both within the acceptable limit of 10.

**6. QED:** Both ligands have similar QED values (0.766 and 0.771), indicating good drug-like properties.

**7. DILI:** Ligand B (37.999) has a significantly lower DILI risk than Ligand A (60.644). This is a major advantage for Ligand B.

**8. BBB:** Both ligands have very similar and good BBB penetration (68.127 and 68.864), exceeding the desirable >70% threshold for CNS targets.

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.945 and -4.481). These values are unusual and suggest poor permeability, but are likely reported on a log scale where negative values indicate low permeability.

**10. Aqueous Solubility:** Ligand B (-2.95) is better than Ligand A (-5.456). Both are poor, but B is less poor.

**11. hERG Inhibition:** Ligand B (0.223) has a much lower hERG inhibition liability than Ligand A (0.836), a critical safety advantage.

**12. Microsomal Clearance:** Ligand B (67.178) has lower microsomal clearance than Ligand A (85.943), indicating better metabolic stability.

**13. In vitro Half-Life:** Ligand A (20.061) has a longer half-life than Ligand B (7.68).

**14. P-gp Efflux:** Ligand B (0.062) has significantly lower P-gp efflux liability than Ligand A (0.348). This is highly favorable for CNS penetration.

**15. Binding Affinity:** Ligand A (-10.4 kcal/mol) has a substantially stronger binding affinity than Ligand B (0.0 kcal/mol). This is a significant advantage for Ligand A.

**Overall Assessment:**

While Ligand A boasts a much stronger binding affinity, its high logP, higher DILI risk, higher hERG inhibition, and higher P-gp efflux are significant drawbacks. Ligand B, despite weaker binding, exhibits a far superior ADME-Tox profile, particularly regarding safety (DILI, hERG) and CNS penetration (P-gp, BBB). For a CNS target like DRD2, achieving adequate brain exposure is paramount. The substantial difference in binding affinity *might* be overcome with further optimization of Ligand B, while mitigating the ADME issues of Ligand A would be more challenging.

Output:
1
2025-04-17 05:07:53,998 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight (MW):** Both ligands (351.422 and 363.531 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (69.72) is better than Ligand B (63.91). Both are below 90, which is favorable for CNS penetration.

**3. logP:** Ligand A (1.661) is within the optimal 1-3 range. Ligand B (3.829) is approaching the upper limit, potentially raising concerns about solubility and off-target effects, but still acceptable.

**4. H-Bond Donors (HBD):** Both ligands have acceptable HBD counts (1 and 0, respectively), well below the threshold of 5.

**5. H-Bond Acceptors (HBA):** Ligand A (3) and Ligand B (6) are both below the 10 threshold.

**6. QED:** Both ligands have reasonable QED values (0.724 and 0.635), indicating good drug-like properties.

**7. DILI:** Ligand A (36.293) has a lower DILI risk than Ligand B (53.276), which is a significant advantage.

**8. BBB:** Both ligands show excellent BBB penetration (Ligand A: 81.815, Ligand B: 83.017), exceeding the desirable >70 threshold for CNS targets.

**9. Caco-2 Permeability:** Ligand A (-4.509) is worse than Ligand B (-5.298). Lower values here indicate lower permeability.

**10. Aqueous Solubility:** Ligand A (-1.353) is better than Ligand B (-3.446). Higher values are preferred.

**11. hERG Inhibition:** Both ligands have low hERG inhibition liability (0.573 and 0.43, respectively), which is good.

**12. Microsomal Clearance (Cl_mic):** Ligand A (39.175) has lower clearance than Ligand B (81.055), suggesting better metabolic stability.

**13. In vitro Half-Life:** Ligand B (33.868) has a much longer half-life than Ligand A (5.858). This is a significant advantage.

**14. P-gp Efflux:** Ligand A (0.063) has significantly lower P-gp efflux than Ligand B (0.833), which is crucial for CNS exposure.

**15. Binding Affinity:** Ligand B (-6.9 kcal/mol) has a slightly better binding affinity than Ligand A (-8.0 kcal/mol). While A is better, the difference isn't massive.

**Overall Assessment:**

Ligand A excels in several key areas: lower DILI risk, better solubility, lower P-gp efflux, and lower microsomal clearance. Ligand B has a longer half-life and slightly better affinity. Given the importance of minimizing toxicity (DILI) and maximizing CNS penetration (low P-gp efflux, good BBB), and considering the relatively small difference in binding affinity, Ligand A appears to be the more promising candidate. The better metabolic stability (lower Cl_mic) is also a plus.

Output:
0
2025-04-17 05:07:53,998 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (345.447 and 344.455 Da) fall comfortably within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (80.12) is better than Ligand B (67.43). Both are below the 90 A^2 threshold desirable for CNS targets, but A is slightly higher and could potentially impact BBB penetration.

**3. logP:** Both ligands have good logP values (0.903 and 1.477), falling within the optimal 1-3 range. Ligand B is slightly better.

**4. H-Bond Donors:** Ligand A has 1 HBD, while Ligand B has 2. Both are within the acceptable limit of <=5.

**5. H-Bond Acceptors:** Ligand A has 5 HBA, and Ligand B has 3. Both are within the acceptable limit of <=10.

**6. QED:** Ligand A (0.86) has a better QED score than Ligand B (0.717), indicating a more drug-like profile.

**7. DILI:** Ligand A (19.659) has a significantly lower DILI risk than Ligand B (34.471). This is a major advantage for Ligand A.

**8. BBB:** Both ligands have similar BBB penetration (62.854 and 62.117). Neither reaches the >70 percentile desirable for CNS targets, but they are reasonably close.

**9. Caco-2 Permeability:** Ligand A (-5.136) has worse Caco-2 permeability than Ligand B (-4.709).

**10. Aqueous Solubility:** Ligand A (-1.29) has worse aqueous solubility than Ligand B (-2.78).

**11. hERG Inhibition:** Ligand A (0.07) has a lower hERG inhibition liability than Ligand B (0.241), which is preferable.

**12. Microsomal Clearance:** Ligand A (18.51) has higher microsomal clearance than Ligand B (15.062), suggesting lower metabolic stability.

**13. In vitro Half-Life:** Ligand A (-4.468) has a shorter in vitro half-life than Ligand B (2.333).

**14. P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.03 and 0.033), which is good for CNS penetration.

**15. Binding Affinity:** Ligand A (-9.5 kcal/mol) has a significantly stronger binding affinity than Ligand B (-7.5 kcal/mol). This is a substantial advantage, exceeding the 1.5 kcal/mol difference threshold.

**Overall Assessment:**

While Ligand B has slightly better logP, Caco-2 permeability, and solubility, Ligand A is superior due to its significantly stronger binding affinity (-9.5 vs -7.5 kcal/mol) and much lower DILI risk (19.66 vs 34.47). The stronger binding affinity is likely to outweigh the minor ADME drawbacks of Ligand A, especially considering the importance of potency for GPCR targets. The lower DILI risk is also a critical factor for drug development. The BBB penetration is similar for both, and both have acceptable P-gp efflux.

Output:
1
2025-04-17 05:07:53,998 - INFO - Reasoning:

Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (349.431 and 347.459 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (71.44) is significantly better than Ligand B (84.66). For CNS targets, we want TPSA <= 90, and A is closer to the ideal <= 60. B is pushing the upper limit.

**3. logP:** Both ligands have acceptable logP values (1.049 and 2.434), falling within the optimal 1-3 range. Ligand B is slightly higher, which could potentially lead to some solubility issues, but is still within range.

**4. H-Bond Donors:** Ligand A (0) is preferable to Ligand B (2). Fewer HBDs generally improve permeability.

**5. H-Bond Acceptors:** Ligand A (5) is preferable to Ligand B (4). Both are within the acceptable range of <=10.

**6. QED:** Both ligands have similar QED values (0.714 and 0.672), indicating good drug-like properties.

**7. DILI:** Both ligands have acceptable DILI risk (38.852 and 43.971), well below the concerning threshold of 60.

**8. BBB:** Both ligands show good BBB penetration (78.054 and 81.233), exceeding the desirable 70% for CNS targets. Ligand B is slightly better.

**9. Caco-2 Permeability:** Ligand A (-4.252) has a worse Caco-2 permeability than Ligand B (-4.646). Lower values are less desirable, but both are negative, indicating poor permeability.

**10. Aqueous Solubility:** Ligand A (-2.148) has better aqueous solubility than Ligand B (-3.643). Higher values are preferred.

**11. hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.253 and 0.664), which is excellent.

**12. Microsomal Clearance:** Ligand A (48.69) has lower microsomal clearance than Ligand B (65.87), indicating better metabolic stability.

**13. In vitro Half-Life:** Ligand A (16.031) has a longer in vitro half-life than Ligand B (-29.14). A negative value for B is concerning.

**14. P-gp Efflux:** Ligand A (0.12) has significantly lower P-gp efflux liability than Ligand B (0.096). Lower efflux is crucial for CNS exposure.

**15. Binding Affinity:** Both ligands have very similar and strong binding affinities (-8.0 and -7.6 kcal/mol). The difference of 0.4 kcal/mol isn't significant enough to override other ADME properties.

**Overall Assessment:**

Ligand A is the better candidate. While both have good affinity and BBB penetration, Ligand A excels in TPSA, HBD, solubility, metabolic stability (lower Cl_mic, longer t1/2), and P-gp efflux. Ligand B has slightly better BBB and Caco-2 permeability, but the negative value for half-life is a major concern. For a CNS target like DRD2, minimizing P-gp efflux and maximizing metabolic stability are critical, and Ligand A performs better in these areas. The lower TPSA and HBD of Ligand A also contribute to better predicted permeability.

Output:
1
2025-04-17 05:07:53,999 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (346.43 & 358.43 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (87.66) is better than Ligand B (58.64). Both are below the 90 A^2 threshold for CNS targets, but A is closer to the upper limit.

**logP:** Both ligands have good logP values (1.65 & 2.34), falling within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A (HBD=3, HBA=4) is slightly higher in both counts than Ligand B (HBD=1, HBA=3), but both are within acceptable limits.

**QED:** Both ligands have good QED scores (0.668 & 0.821), indicating good drug-like properties.

**DILI:** Ligand A (35.29) has a slightly higher DILI risk than Ligand B (25.24), but both are below the concerning threshold of 40.

**BBB:** This is a critical parameter for a CNS target like DRD2. Ligand B (95.50) significantly outperforms Ligand A (65.84), exceeding the desirable >70% threshold.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.76 & -4.59), which is unusual and suggests poor permeability. This is a significant drawback for both.

**Aqueous Solubility:** Both ligands have negative solubility values (-2.69 & -2.78), indicating poor aqueous solubility. This is a concern for formulation and bioavailability.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.28 & 0.46).

**Microsomal Clearance:** Ligand A (17.64) has a higher microsomal clearance than Ligand B (0.24), indicating lower metabolic stability.

**In vitro Half-Life:** Ligand B (4.38) has a longer half-life than Ligand A (16.22), which is preferable.

**P-gp Efflux:** Ligand A (0.21) has lower P-gp efflux liability than Ligand B (0.05), which is better for CNS exposure.

**Binding Affinity:** Ligand B (-7.7 kcal/mol) has a slightly better binding affinity than Ligand A (-8.2 kcal/mol). While the difference is small, it's still a positive for Ligand B.

**Overall Assessment:**

While Ligand A has slightly better TPSA and P-gp efflux, Ligand B excels in the most critical areas for a CNS-targeting GPCR: **BBB penetration (95.50% vs. 65.84%)** and **binding affinity (-7.7 vs -8.2 kcal/mol)**. Ligand B also has a better half-life and lower clearance. The poor Caco-2 and solubility are concerning for both, but can be addressed with formulation strategies. Given the importance of BBB penetration for CNS drugs, Ligand B is the more promising candidate.

Output:
1
2025-04-17 05:07:53,999 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B based on the provided guidelines, prioritizing GPCR-specific properties (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (347.46 and 352.56 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (65.79) is higher than Ligand B (40.62). For CNS targets, TPSA should be <=90, both are within this range, but B is significantly better.

**logP:** Ligand A (2.183) is within the optimal 1-3 range. Ligand B (4.502) is higher, potentially leading to solubility issues and off-target interactions.

**H-Bond Donors/Acceptors:** Ligand A has 1 HBD and 4 HBA, while Ligand B has 0 HBD and 2 HBA. Both are acceptable.

**QED:** Ligand A (0.907) has a very strong drug-like profile, while Ligand B (0.429) is below the desirable threshold of 0.5.

**DILI:** Ligand A (15.63) has a lower DILI risk than Ligand B (17.1). Both are good, but A is slightly better.

**BBB:** Ligand A (69.41) is good, but Ligand B (86.20) is excellent, exceeding the >70% threshold for CNS targets. This is a significant advantage for B.

**Caco-2 Permeability:** Both have negative values, indicating poor permeability. Ligand A (-4.977) is slightly worse than Ligand B (-4.332).

**Aqueous Solubility:** Both have negative values, indicating poor solubility. Ligand A (-1.6) is slightly better than Ligand B (-3.699).

**hERG Inhibition:** Ligand A (0.615) has a slightly higher hERG risk than Ligand B (0.852). Lower is better.

**Microsomal Clearance:** Ligand A (0.977) has a much lower clearance than Ligand B (118.02), indicating better metabolic stability.

**In vitro Half-Life:** Ligand A (20.73) has a shorter half-life than Ligand B (29.61).

**P-gp Efflux:** Ligand A (0.075) has much lower P-gp efflux liability than Ligand B (0.614), which is crucial for CNS penetration.

**Binding Affinity:** Ligand B (-7.1) has a slightly better binding affinity than Ligand A (-8.0). However, the difference is less than 1.5 kcal/mol and can be outweighed by other factors.

**Overall Assessment:**

Ligand B excels in BBB penetration and has slightly better binding affinity. However, it suffers from a higher logP, lower QED, higher P-gp efflux, and significantly higher microsomal clearance. Ligand A has a superior drug-like profile (QED), lower DILI risk, better metabolic stability (lower Cl_mic), lower P-gp efflux, and slightly better solubility. Considering the importance of BBB for CNS targets, Ligand B's high BBB is attractive, but the other ADME liabilities, particularly the high P-gp efflux and poor metabolic stability, are concerning. Ligand A, despite a slightly lower BBB, presents a more balanced and favorable profile overall, particularly for oral bioavailability and CNS exposure.

Output:
0
2025-04-17 05:07:53,999 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (346.431 and 385.295 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (87.46) is better than Ligand B (80.04) as it is closer to the <90 A^2 threshold for CNS targets.

**3. logP:** Ligand B (2.775) is better than Ligand A (0.541). Ligand A's logP is quite low, potentially hindering membrane permeability. Ligand B is within the optimal 1-3 range.

**4. H-Bond Donors:** Both ligands have 2 HBD, which is within the acceptable limit of <=5.

**5. H-Bond Acceptors:** Both ligands have 5 HBA, which is within the acceptable limit of <=10.

**6. QED:** Ligand A (0.815) has a slightly better QED than Ligand B (0.768), indicating a more drug-like profile.

**7. DILI:** Ligand A (36.797) has a significantly lower DILI risk than Ligand B (52.966). This is a substantial advantage for Ligand A.

**8. BBB:** Ligand A (32.765) has a much better BBB penetration percentile than Ligand B (22.218). This is critical for a CNS target like DRD2.

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.186 and -5.039). This is unusual and suggests poor permeability. However, these values are on a scale where negative values are possible, and direct comparison is difficult without knowing the scale's specifics.

**10. Aqueous Solubility:** Both ligands have negative solubility values (-1.259 and -3.184). Similar to Caco-2, this is unusual and requires caution.

**11. hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.139 and 0.14).

**12. Microsomal Clearance:** Ligand A (9.784) has a much lower microsomal clearance than Ligand B (30.522), indicating better metabolic stability.

**13. In vitro Half-Life:** Ligand B (40.628) has a significantly longer in vitro half-life than Ligand A (0.91). This is a positive for Ligand B.

**14. P-gp Efflux:** Both ligands have low P-gp efflux liability (0.057 and 0.088).

**15. Binding Affinity:** Ligand B (-9.0 kcal/mol) has a slightly better binding affinity than Ligand A (-8.7 kcal/mol). While the difference is not huge, it is still a factor.

**Overall Assessment:**

Considering the GPCR-specific priorities, Ligand A is the more promising candidate. Its superior BBB penetration, lower DILI risk, and lower microsomal clearance are significant advantages for a CNS drug. While Ligand B has better logP and half-life, the substantial benefits of Ligand A in terms of CNS penetration and safety outweigh these factors. The low logP of Ligand A is a concern, but the strong affinity (-8.7 kcal/mol) suggests it can still bind effectively.

Output:
0
2025-04-17 05:07:53,999 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (364.47 and 342.44 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (93.61) is slightly higher than Ligand B (76.02). For CNS targets, we want TPSA <= 90, so both are acceptable, but B is better.

**logP:** Both ligands have good logP values (1.766 and 2.068), falling within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A has 1 HBD and 5 HBA, while Ligand B has 2 HBD and 4 HBA. Both are within acceptable limits (<=5 HBD and <=10 HBA).

**QED:** Ligand A (0.835) has a much better QED score than Ligand B (0.472), indicating better overall drug-likeness.

**DILI:** Both ligands have similar, acceptable DILI risk (53.35 and 50.14 percentile).

**BBB:** Ligand A (67.93) has a significantly better BBB penetration percentile than Ligand B (57.15).  This is *critical* for a CNS target like DRD2.

**Caco-2 Permeability:** Ligand A (-5.157) has worse Caco-2 permeability than Ligand B (-4.742), indicating potentially lower intestinal absorption.

**Aqueous Solubility:** Both have very poor aqueous solubility (-3.007 and -3.662). This is a concern for both, but not a deciding factor between the two.

**hERG Inhibition:** Ligand A (0.673) has a slightly higher hERG inhibition risk than Ligand B (0.078), which is preferable.

**Microsomal Clearance:** Both have similar, relatively low microsomal clearance (30.59 and 28.90 mL/min/kg), suggesting reasonable metabolic stability.

**In vitro Half-Life:** Ligand A (-23.50) has a much longer in vitro half-life than Ligand B (2.13), which is a significant advantage.

**P-gp Efflux:** Ligand A (0.205) has a lower P-gp efflux liability than Ligand B (0.095), which is beneficial for CNS exposure.

**Binding Affinity:** Both ligands have very similar and strong binding affinities (-8.7 and -8.3 kcal/mol). The difference is less than the 1.5 kcal/mol threshold.

**Overall Assessment:**

Ligand A is superior due to its significantly better BBB penetration (67.93 vs 57.15), higher QED (0.835 vs 0.472), lower P-gp efflux (0.205 vs 0.095), and longer in vitro half-life (-23.50 vs 2.13). While Ligand B has slightly better Caco-2 permeability and lower hERG risk, the CNS target prioritization makes BBB and P-gp crucial. The slightly better solubility of Ligand B is not enough to offset the other advantages of Ligand A.



Output:
1
2025-04-17 05:07:54,000 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (363.483 and 354.535 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (91.32) is slightly above the optimal <90 for CNS targets, but still reasonable. Ligand B (78.43) is well within the desired range.

**3. logP:** Both ligands have good logP values (1.937 and 2.868), falling within the 1-3 range.

**4. H-Bond Donors:** Both have 3 HBD, which is acceptable.

**5. H-Bond Acceptors:** Ligand A has 5 HBA, and Ligand B has 3 HBA, both are within the acceptable limit of <=10.

**6. QED:** Ligand A (0.72) has a better QED score than Ligand B (0.528), indicating better overall drug-likeness.

**7. DILI:** Ligand A (51.997) has a higher DILI risk than Ligand B (16.014). This is a significant drawback for Ligand A.

**8. BBB:** Ligand B (59.946) has a substantially better BBB penetration percentile than Ligand A (27.026). This is *critical* for a CNS target like DRD2.

**9. Caco-2 Permeability:** Ligand A (-5.135) has worse Caco-2 permeability than Ligand B (-4.541).

**10. Aqueous Solubility:** Ligand A (-2.29) has slightly better solubility than Ligand B (-3.137).

**11. hERG Inhibition:** Ligand A (0.187) has a slightly lower hERG inhibition risk than Ligand B (0.607).

**12. Microsomal Clearance:** Ligand B (53.967) has a lower microsomal clearance than Ligand A (8.408), suggesting better metabolic stability.

**13. In vitro Half-Life:** Ligand B (5.338) has a longer in vitro half-life than Ligand A (2.509).

**14. P-gp Efflux:** Ligand A (0.18) has lower P-gp efflux than Ligand B (0.288), which is favorable for CNS penetration.

**15. Binding Affinity:** Ligand A (-8.6 kcal/mol) has a significantly stronger binding affinity than Ligand B (-7.7 kcal/mol). This is a substantial advantage.

**Overall Assessment:**

While Ligand A boasts a superior binding affinity, the significantly higher DILI risk and much poorer BBB penetration are major concerns. For a CNS target, BBB penetration is paramount. Ligand B, despite having slightly weaker affinity, presents a much more favorable ADME-Tox profile, particularly its excellent BBB penetration, lower DILI, and better metabolic stability. The 0.9 kcal/mol difference in affinity might be overcome with further optimization of Ligand B, but the poor ADME properties of Ligand A are harder to fix.

Output:
1
2025-04-17 05:07:54,000 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (348.531 Da) is slightly lower, which could be beneficial for permeability. Ligand B (388.599 Da) is also acceptable.

**TPSA:** Ligand A (40.62) is excellent, well below the 90 A^2 threshold for CNS targets. Ligand B (66.48) is higher but still reasonable, though less optimal for CNS penetration.

**logP:** Ligand A (3.841) is at the upper end of the optimal range (1-3), but still acceptable. Ligand B (2.028) is closer to the lower end, potentially impacting permeability.

**H-Bond Donors/Acceptors:** Ligand A (0 HBD, 2 HBA) is very favorable. Ligand B (1 HBD, 4 HBA) is also acceptable, but slightly higher counts could potentially affect permeability.

**QED:** Both ligands have good QED scores (A: 0.732, B: 0.783), indicating good drug-like properties.

**DILI:** Ligand A (18.108) has a significantly lower DILI risk than Ligand B (31.563), which is a major advantage.

**BBB:** This is critical for a CNS target. Ligand A (87.088) has a very good BBB percentile, exceeding the desirable >70 threshold. Ligand B (45.909) is considerably lower, suggesting poor brain penetration.

**Caco-2 Permeability:** Both have negative values, which is unusual and suggests these are percentile scores where lower values indicate poorer permeability. Ligand A (-4.69) is better than Ligand B (-4.963), but both are poor.

**Aqueous Solubility:** Both have negative values, indicating percentile scores. Ligand A (-3.943) is slightly better than Ligand B (-2.57).

**hERG Inhibition:** Ligand A (0.641) has a lower hERG risk than Ligand B (0.148), which is preferable.

**Microsomal Clearance:** Ligand A (77.937) has higher clearance than Ligand B (37.383), indicating lower metabolic stability.

**In vitro Half-Life:** Ligand A (-2.204) has a shorter half-life than Ligand B (-3.373), which is less desirable.

**P-gp Efflux:** Ligand A (0.484) has lower P-gp efflux liability than Ligand B (0.052), which is beneficial for CNS exposure.

**Binding Affinity:** Both ligands have excellent binding affinity (-7.0 and -8.0 kcal/mol). Ligand B is slightly better, but the difference is likely not enough to overcome the other significant drawbacks.

**Overall Assessment:**

Ligand A is the superior candidate. While Ligand B has slightly better affinity and lower clearance, Ligand A excels in critical areas for a CNS-targeting GPCR: significantly lower DILI risk, much better BBB penetration, lower P-gp efflux, and a more favorable TPSA. The slightly lower half-life and higher clearance of Ligand A are less concerning than the poor BBB penetration of Ligand B.



Output:
0
2025-04-17 05:07:54,000 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B based on the provided guidelines, prioritizing GPCR-specific properties (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (347.463 Da) is slightly lower, which could be beneficial for permeability.

**TPSA:** Ligand A (78.43) is significantly better than Ligand B (91.32). For CNS targets, TPSA should be <= 90, so Ligand A is preferable.

**logP:** Both ligands have acceptable logP values (Ligand A: 1.06, Ligand B: 2.156), falling within the optimal range of 1-3.

**H-Bond Donors/Acceptors:** Ligand A (HBD=1, HBA=5) is slightly better than Ligand B (HBD=3, HBA=5) regarding the number of hydrogen bond donors, but both are within acceptable limits.

**QED:** Ligand A (0.832) has a higher QED score than Ligand B (0.658), indicating a more drug-like profile.

**DILI:** Ligand B (42.109) has a lower DILI risk than Ligand A (16.13), which is a positive attribute.

**BBB:** Ligand A (60.527) has a better BBB penetration percentile than Ligand B (42.575). While ideally >70 for CNS targets, Ligand A is closer.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.174 and -5.018), which is unusual and suggests poor permeability. This is a significant concern for both.

**Aqueous Solubility:** Both ligands have negative solubility values (-1.243 and -2.469), indicating very poor aqueous solubility. This is a major drawback for both.

**hERG Inhibition:** Both ligands have very low hERG inhibition liability (0.119 and 0.083), which is excellent.

**Microsomal Clearance:** Ligand A (-10.276) has significantly lower microsomal clearance than Ligand B (18.778), indicating better metabolic stability.

**In vitro Half-Life:** Ligand A (-2.853) has a shorter in vitro half-life than Ligand B (10.194).

**P-gp Efflux:** Ligand A (0.006) has much lower P-gp efflux liability than Ligand B (0.11), which is crucial for CNS penetration.

**Binding Affinity:** Ligand B (-8.0) has a slightly better binding affinity than Ligand A (-7.5), a difference of 0.5 kcal/mol.

**Overall Assessment:**

Despite the slightly better affinity of Ligand B, Ligand A is the more promising candidate. The key advantages of Ligand A are its significantly better TPSA, lower P-gp efflux, lower microsomal clearance, and higher QED and BBB penetration. The poor Caco-2 and solubility are concerning for both, but can potentially be addressed through formulation strategies. The better metabolic stability and reduced efflux liability of Ligand A are particularly important for CNS drug development. The 0.5 kcal/mol difference in binding affinity is unlikely to outweigh the ADME advantages of Ligand A.

Output:
1
2025-04-17 05:07:54,000 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (358.804 and 351.416 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (76.95) is higher than the preferred <90 for CNS targets, but still reasonable. Ligand B (21.06) is *excellent*, well below the threshold. This favors Ligand B.

**3. logP:** Ligand A (3.608) is within the optimal 1-3 range. Ligand B (4.565) is slightly above, potentially raising concerns about solubility and off-target effects, but not drastically.

**4. H-Bond Donors:** Ligand A (3) is acceptable. Ligand B (0) is also good.

**5. H-Bond Acceptors:** Both ligands (A: 3, B: 3) are well within the acceptable limit of 10.

**6. QED:** Both ligands (A: 0.714, B: 0.736) have good drug-likeness scores, exceeding the 0.5 threshold.

**7. DILI:** Ligand A (76.076) has a higher DILI risk than Ligand B (21.753). This is a significant advantage for Ligand B.

**8. BBB:** Ligand A (65.374) is below the desirable >70 for CNS targets. Ligand B (97.053) is *excellent*, exceeding the threshold. This is a major advantage for Ligand B.

**9. Caco-2:** Both have negative values, which is unusual. Assuming these are logP values, they are both poor.

**10. Aqueous Solubility:** Both ligands have negative solubility values, which is also unusual.

**11. hERG:** Ligand A (0.62) has a slightly higher hERG risk than Ligand B (0.854). Lower is better, so Ligand B is preferable.

**12. Cl_mic:** Ligand A (4.519) has lower microsomal clearance, indicating better metabolic stability, which is good. Ligand B (62.229) has significantly higher clearance, a potential drawback.

**13. t1/2:** Ligand A (56.781) has a longer in vitro half-life than Ligand B (6.494). This is a strong advantage for Ligand A.

**14. Pgp:** Ligand A (0.157) has lower P-gp efflux, which is beneficial for CNS penetration. Ligand B (0.563) has higher efflux, potentially limiting brain exposure. This favors Ligand A.

**15. Binding Affinity:** Ligand B (-8.5 kcal/mol) has a significantly stronger binding affinity than Ligand A (-10.0 kcal/mol). This is a substantial advantage, potentially outweighing some of the ADME concerns with Ligand B.

**Overall Assessment:**

Ligand B excels in key GPCR properties for CNS targets: TPSA, BBB, and, most importantly, binding affinity. While its metabolic stability (Cl_mic) and P-gp efflux are less favorable than Ligand A, the superior binding affinity and excellent BBB penetration are likely to be more critical for efficacy. Ligand A has better metabolic stability and P-gp properties, but its lower BBB penetration and weaker binding affinity are significant drawbacks. The DILI risk is also lower for Ligand B.

Output:
1
2025-04-17 05:07:54,000 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (340.387 and 350.463 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (112.66) is slightly above the optimal <90 for CNS targets, but still reasonable. Ligand B (96.11) is excellent, well within the desired range.

**logP:** Ligand A (1.295) and Ligand B (2.221) are both within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Both ligands have 3 HBD and 5/4 HBA, respectively, which are acceptable.

**QED:** Both ligands have similar QED scores (0.627 and 0.603), indicating good drug-likeness.

**DILI:** Ligand A (64.56) has a higher DILI risk than Ligand B (37.456). This is a significant negative for Ligand A.

**BBB:** Ligand A (41.14) has a low BBB penetration percentile, which is a major concern for a CNS target like DRD2. Ligand B (33.54) is also low, but slightly better. Both are far from the desirable >70.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values, which is unusual and suggests poor permeability. However, these values are on a log scale, and negative values are possible.

**Aqueous Solubility:** Both ligands have negative solubility values, indicating poor aqueous solubility.

**hERG Inhibition:** Both ligands show very low hERG inhibition risk (0.104 and 0.212).

**Microsomal Clearance:** Ligand A (3.152) has a lower microsomal clearance than Ligand B (5.43), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (1.809) has a shorter half-life than Ligand B (-0.97).

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.011 and 0.042).

**Binding Affinity:** Ligand B (-7.7 kcal/mol) has a slightly better binding affinity than Ligand A (-7.5 kcal/mol), although the difference is small.

**Overall Assessment:**

Given the GPCR-specific priorities, BBB penetration is crucial for DRD2. Ligand A's low BBB percentile (41.14) is a significant drawback. While Ligand B also has a low BBB percentile (33.54), it compensates with a lower DILI risk and slightly better binding affinity. The lower DILI risk is a substantial advantage, and the slightly improved binding affinity, while small, adds to its favorability. Both have poor solubility and permeability, but these can potentially be addressed with formulation strategies.

Output:
1
2025-04-17 05:07:54,001 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B based on the provided guidelines, prioritizing GPCR-specific properties (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (348.443 and 354.495 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (68.82) is excellent, well below the 90 A^2 threshold for CNS targets. Ligand B (95.74) is still reasonable but closer to the 140 A^2 limit for oral absorption and less ideal for CNS penetration.

**logP:** Ligand A (2.389) is optimal (1-3). Ligand B (0.585) is a bit low, potentially hindering membrane permeability.

**H-Bond Donors/Acceptors:** Both ligands have 2 HBD and 4 HBA, which are within acceptable limits.

**QED:** Both ligands have good QED scores (0.708 and 0.633, respectively), indicating drug-like properties.

**DILI:** Ligand A (33.889) has a significantly lower DILI risk than Ligand B (10.392), indicating a safer profile.

**BBB:** Ligand A (73.401) has a much better BBB penetration percentile than Ligand B (64.56). This is a crucial factor for a CNS target like DRD2.

**Caco-2 Permeability:** Ligand A (-4.77) and Ligand B (-5.359) both have negative values, indicating poor permeability. However, the scale isn't clearly defined, so it's hard to interpret the difference.

**Aqueous Solubility:** Both ligands have negative solubility values (-2.62 and -1.217), indicating poor solubility.

**hERG:** Both ligands have very low hERG inhibition liability (0.465 and 0.161), which is excellent.

**Microsomal Clearance:** Ligand A (32.573) has a higher microsomal clearance than Ligand B (17.956), suggesting faster metabolism and potentially lower in vivo exposure.

**In vitro Half-Life:** Ligand B (-19.749) has a negative half-life, which is not physically possible. This is likely an error in the data, and makes it difficult to assess. Ligand A (22.552) has a reasonable half-life.

**P-gp Efflux:** Ligand A (0.043) has very low P-gp efflux liability, which is favorable for CNS penetration. Ligand B (0.001) is even lower, but the difference is minimal.

**Binding Affinity:** Ligand A (-8.3 kcal/mol) has a significantly stronger binding affinity than Ligand B (-7.2 kcal/mol). This 1.1 kcal/mol difference is substantial and can outweigh minor ADME drawbacks.

**Conclusion:**

Considering all factors, especially the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity), **Ligand A is the more promising drug candidate.** It has superior BBB penetration, better logP, lower DILI risk, and significantly stronger binding affinity. While both have solubility and Caco-2 permeability issues, the stronger affinity and better CNS properties of Ligand A make it the preferred choice. The negative half-life value for Ligand B is also a major concern.

Output:
1
2025-04-17 05:07:54,001 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (360.414 and 342.355 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (64.16) is excellent, well below the 90 A^2 threshold for CNS targets. Ligand B (98.39) is higher, but still potentially acceptable, though less ideal.

**3. logP:** Both ligands have good logP values (3.114 and 2.758), falling within the optimal 1-3 range.

**4. H-Bond Donors:** Ligand A (0) is good. Ligand B (2) is also acceptable.

**5. H-Bond Acceptors:** Both ligands have 6 HBA, which is within the acceptable limit of <=10.

**6. QED:** Both ligands have similar QED values (0.672 and 0.695), indicating good drug-likeness.

**7. DILI:** Both ligands have high DILI risk (85.615 and 93.292), which is a concern. However, this is often a later-stage consideration, and can sometimes be mitigated with structural modifications.

**8. BBB:** Ligand A has a significantly better BBB penetration percentile (84.839) compared to Ligand B (59.674). This is *critical* for a CNS target like DRD2.

**9. Caco-2 Permeability:** Both have negative Caco-2 values which is unusual and suggests poor permeability.

**10. Aqueous Solubility:** Both have negative solubility values, which is also unusual.

**11. hERG:** Both ligands have very low hERG inhibition liability (0.379 and 0.346), which is excellent.

**12. Microsomal Clearance:** Both have similar microsomal clearance (73.855 and 78.593), suggesting moderate metabolic stability.

**13. In vitro Half-Life:** Ligand B has a much longer in vitro half-life (112.215 hours) than Ligand A (26.821 hours). This is a significant advantage.

**14. P-gp Efflux:** Both ligands have low P-gp efflux liability (0.271 and 0.126), which is good for CNS penetration.

**15. Binding Affinity:** Both ligands have very similar and excellent binding affinities (-8.9 and -8.7 kcal/mol). The difference is negligible.

**Overall Assessment:**

Given the GPCR-specific priorities, the most important factor here is BBB penetration. Ligand A has a substantially higher BBB percentile (84.839) than Ligand B (59.674). While Ligand B has a better half-life, the improved CNS exposure potential of Ligand A outweighs this benefit. The similar affinities and acceptable ADME profiles (aside from the DILI and solubility concerns, which are common early on) make Ligand A the more promising candidate.

Output:
1
2025-04-17 05:07:54,001 - INFO - Batch 172 complete. Total preferences: 2752
2025-04-17 05:07:54,001 - INFO - Processing batch 173/512...
2025-04-17 05:08:37,214 - INFO - Reasoning:

Let's analyze Ligand A and Ligand B based on the provided guidelines, prioritizing GPCR-specific properties (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight (MW):** Both ligands (358.36 and 348.462 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (61.8) is slightly higher than Ligand B (49.41). Both are below the 90 A^2 threshold desirable for CNS targets, but B is better.

**3. logP:** Both ligands have good logP values (3.203 and 3.49), falling within the optimal 1-3 range.

**4. H-Bond Donors (HBD):** Ligand A (2) and Ligand B (1) are both within the acceptable limit of <=5.

**5. H-Bond Acceptors (HBA):** Ligand A (3) and Ligand B (2) are both within the acceptable limit of <=10.

**6. QED:** Both ligands have acceptable QED scores (0.869 and 0.767), indicating good drug-like properties.

**7. DILI:** Ligand A (15.781) has a significantly lower DILI risk than Ligand B (32.61). This is a substantial advantage for A.

**8. BBB:** Both ligands have excellent BBB penetration (89.957 and 89.802), exceeding the desirable >70 threshold for CNS targets.

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.333 and -4.602). This is unusual and suggests poor permeability. However, since these are negative values, a *less* negative value is better. Ligand A (-4.333) is slightly better than Ligand B (-4.602).

**10. Aqueous Solubility:** Both ligands have negative solubility values (-3.277 and -3.693). Similar to Caco-2, a *less* negative value is better. Ligand A (-3.277) is slightly better than Ligand B (-3.693).

**11. hERG Inhibition:** Ligand A (0.674) has a slightly lower hERG inhibition risk than Ligand B (0.914).

**12. Microsomal Clearance (Cl_mic):** Ligand A (9.831) has significantly lower microsomal clearance than Ligand B (46.499), indicating better metabolic stability.

**13. In vitro Half-Life:** Ligand A (-26.035) has a much longer in vitro half-life than Ligand B (-6.614). This is a significant advantage for A.

**14. P-gp Efflux:** Ligand A (0.123) has lower P-gp efflux liability than Ligand B (0.7), which is favorable for CNS exposure.

**15. Binding Affinity:** Ligand B (-9.2) has a slightly better binding affinity than Ligand A (-8.6). This is a 1.6 kcal/mol difference, which is significant.

**Overall Assessment:**

While Ligand B has a slightly better binding affinity, Ligand A demonstrates superior ADME properties, particularly regarding safety (DILI), metabolic stability (Cl_mic, t1/2), and P-gp efflux. The lower DILI risk and improved metabolic stability are crucial for drug development. The slightly better BBB penetration is similar for both. Given the GPCR target and the importance of CNS penetration, the combination of favorable ADME properties outweighs the small difference in binding affinity.

Output:
0
2025-04-17 05:08:37,215 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (351.447 and 351.418 Da) fall within the ideal range of 200-500 Da.

**TPSA:** Ligand A (89.95) is excellent, falling below the 90 A^2 threshold for CNS targets. Ligand B (55.84) is even better, further enhancing its potential for brain penetration.

**logP:** Ligand A (-0.058) is slightly low, potentially hindering membrane permeability. Ligand B (3.101) is within the optimal range of 1-3. This is a significant advantage for Ligand B.

**H-Bond Donors/Acceptors:** Ligand A has 2 HBD and 5 HBA, which are acceptable. Ligand B has 0 HBD and 4 HBA, also acceptable.

**QED:** Both ligands have good QED scores (0.655 and 0.686), indicating drug-like properties.

**DILI:** Ligand A (23.769) has a lower DILI risk than Ligand B (32.183), which is preferable.

**BBB:** Ligand A (26.25) has a very low BBB penetration percentile, making it unlikely to reach the target in the CNS effectively. Ligand B (87.553) has excellent BBB penetration, a critical factor for a DRD2 ligand.

**Caco-2 Permeability:** Both have negative values, which is unusual. Assuming these represent logP-like scales, both are poor.

**Aqueous Solubility:** Ligand A (-0.719) has poor solubility, while Ligand B (-2.16) is even worse. Solubility could be a formulation challenge for both.

**hERG Inhibition:** Ligand A (0.026) has a very low hERG risk, a significant advantage. Ligand B (0.488) has a slightly higher, but still relatively low, hERG risk.

**Microsomal Clearance:** Ligand A (13.359) has lower microsomal clearance, indicating better metabolic stability than Ligand B (71.605).

**In vitro Half-Life:** Ligand A (-14.339) has a negative half-life, which is impossible, indicating a data error. Ligand B (9.424) has a reasonable half-life.

**P-gp Efflux:** Ligand A (0.009) has very low P-gp efflux, which is favorable for CNS penetration. Ligand B (0.266) has slightly higher P-gp efflux, but still reasonable.

**Binding Affinity:** Ligand A (-7.8) has a slightly better binding affinity than Ligand B (-7.4). However, the difference is less than 1.5 kcal/mol.

**Overall Assessment:**

Despite Ligand A's slightly better affinity and lower DILI/P-gp efflux, its extremely poor BBB penetration and questionable half-life are major drawbacks for a CNS target like DRD2. Ligand B excels in BBB penetration (87.553) and has an acceptable logP, making it far more likely to reach the target. While its DILI risk is slightly higher and solubility is poor, these can potentially be addressed through further optimization. The affinity difference is small enough to be outweighed by the significant ADME advantages of Ligand B.

Output:
1
2025-04-17 05:08:37,215 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (351.535 and 361.471 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (52.65) is significantly better than Ligand B (92.94). For CNS targets, we want TPSA <= 90, and A is comfortably within that range, while B is approaching the upper limit.

**logP:** Both ligands have acceptable logP values (2.508 and 3.204), falling within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A (HBD=1, HBA=3) is preferable to Ligand B (HBD=2, HBA=7). Lower HBD/HBA generally improves permeability.

**QED:** Both ligands have good QED scores (0.658 and 0.701), indicating good drug-like properties.

**DILI:** Ligand A (7.871) has a much lower DILI risk than Ligand B (76.309). This is a significant advantage for A.

**BBB:** Ligand A (83.288) has a better BBB penetration percentile than Ligand B (72.315). Both are above 70, which is desirable for CNS targets, but A is better.

**Caco-2 Permeability:** Ligand A (-4.786) has a worse Caco-2 permeability than Ligand B (-5.484). Lower values indicate lower permeability.

**Aqueous Solubility:** Ligand A (-2.29) has better aqueous solubility than Ligand B (-3.688).

**hERG:** Ligand A (0.67) has a lower hERG inhibition liability than Ligand B (0.374), indicating a lower risk of cardiotoxicity.

**Microsomal Clearance:** Ligand A (71.968) has a lower microsomal clearance than Ligand B (78.006), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (-9.662) has a significantly longer in vitro half-life than Ligand B (31.21). This is a major advantage for A.

**P-gp Efflux:** Ligand A (0.085) has lower P-gp efflux liability than Ligand B (0.332), which is beneficial for CNS exposure.

**Binding Affinity:** Both ligands have excellent binding affinities (-8.0 and -7.8 kcal/mol). The difference of 0.2 kcal/mol is not substantial enough to outweigh the other significant advantages of Ligand A.

**Overall Assessment:**

Ligand A consistently outperforms Ligand B across most critical ADME properties, particularly DILI risk, BBB penetration, metabolic stability (Cl_mic and t1/2), and P-gp efflux. While Ligand B has slightly better Caco-2 permeability, the other advantages of Ligand A, especially for a CNS target like DRD2, make it the more promising candidate. The similar binding affinities further solidify this conclusion.

Output:
1
2025-04-17 05:08:37,215 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (368.46 and 369.49 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (92.58) is slightly above the optimal <90 for CNS targets, but still reasonable. Ligand B (79.81) is well within the desired range.

**logP:** Ligand A (-0.276) is quite low, potentially hindering membrane permeability. Ligand B (1.856) is within the optimal 1-3 range. This is a significant advantage for Ligand B.

**H-Bond Donors/Acceptors:** Both ligands have 0 HBD and 6 HBA, which are acceptable values.

**QED:** Ligand A (0.689) has a better QED score than Ligand B (0.464), indicating better overall drug-likeness.

**DILI:** Both ligands have acceptable DILI risk (45.64 and 52.42, respectively), below the 60 threshold.

**BBB:** Ligand A (86.35) shows significantly better BBB penetration potential than Ligand B (58.82). This is a crucial factor for a CNS target like DRD2.

**Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and suggests poor permeability. However, the scale is not specified, so it's hard to interpret.

**Aqueous Solubility:** Both ligands have very poor aqueous solubility (-1.24 and -1.03). This is a concern for both.

**hERG Inhibition:** Both ligands show low hERG inhibition risk (0.282 and 0.179).

**Microsomal Clearance:** Ligand A (2.54) has much lower microsomal clearance than Ligand B (99.67), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (9.21) has a longer half-life than Ligand B (-1.20), which is preferable.

**P-gp Efflux:** Both ligands show low P-gp efflux liability (0.058 and 0.107).

**Binding Affinity:** Ligand A (-7.8 kcal/mol) has a significantly stronger binding affinity than Ligand B (-6.5 kcal/mol). This is a substantial advantage, potentially outweighing some of the ADME drawbacks.

**Overall Assessment:**

Ligand A has a superior binding affinity and better metabolic stability (lower Cl_mic, longer t1/2) and BBB penetration. However, its low logP and poor solubility are concerning. Ligand B has a better logP and TPSA, but significantly weaker binding affinity and poorer metabolic stability.

Given the GPCR-specific priorities, the strong binding affinity and acceptable BBB penetration of Ligand A are critical. While the low logP and solubility are drawbacks, they might be addressable through formulation strategies or further chemical modifications. The 1.3 kcal/mol difference in binding affinity is substantial and likely to be more impactful than the ADME differences, especially for a CNS target where achieving sufficient target engagement is paramount.

Output:
1
2025-04-17 05:08:37,215 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (343.431 Da) is slightly lower, which could be beneficial for permeability. Ligand B (381.9 Da) is also good.

**TPSA:** Ligand A (79.06) is better than Ligand B (37.38) for CNS penetration, being closer to the ideal <90 A^2 for CNS targets. Ligand B is still acceptable, but A has a clear advantage.

**logP:** Ligand A (1.927) is within the optimal range (1-3). Ligand B (4.812) is higher, potentially leading to solubility issues and off-target effects. This is a significant drawback for Ligand B.

**H-Bond Donors/Acceptors:** Ligand A (HBD=1, HBA=5) and Ligand B (HBD=0, HBA=3) both have reasonable numbers of H-bond donors and acceptors.

**QED:** Ligand A (0.906) has a much better QED score than Ligand B (0.625), indicating a more drug-like profile.

**DILI:** Both ligands have low DILI risk (Ligand A: 38.736, Ligand B: 35.673), which is good.

**BBB:** Ligand B (73.401) has a slightly better BBB percentile than Ligand A (68.67), but both are reasonably good for a CNS target.

**Caco-2 Permeability:** Ligand A (-5.327) has a much worse Caco-2 permeability than Ligand B (-4.753).

**Aqueous Solubility:** Ligand A (-2.08) has a slightly better aqueous solubility than Ligand B (-4.514).

**hERG:** Both ligands have very low hERG inhibition liability (Ligand A: 0.103, Ligand B: 0.666).

**Microsomal Clearance:** Ligand A (2.769) has a significantly lower microsomal clearance than Ligand B (76.77), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand B (60.908) has a much longer in vitro half-life than Ligand A (15.488).

**P-gp Efflux:** Ligand A (0.04) has a much lower P-gp efflux liability than Ligand B (0.811), which is crucial for CNS penetration.

**Binding Affinity:** Ligand A (-8.6 kcal/mol) has a significantly stronger binding affinity than Ligand B (-7.2 kcal/mol). This >1.5 kcal/mol difference is substantial and can outweigh some ADME drawbacks.

**Overall Assessment:**

Ligand A is the stronger candidate. While Ligand B has better BBB penetration and in vitro half-life, Ligand A excels in critical areas: significantly higher binding affinity, lower logP (reducing potential issues), better TPSA, better QED, lower P-gp efflux, and lower microsomal clearance. The strong binding affinity of Ligand A is a major advantage, and its other properties are generally more favorable for a CNS-targeting GPCR ligand. The lower Caco-2 permeability is a concern, but the strong affinity and favorable CNS properties likely outweigh this.

Output:
1
2025-04-17 05:08:37,216 - INFO - Reasoning:

Let's analyze Ligand A and Ligand B against the provided guidelines, prioritizing GPCR-specific properties (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (409.284 Da) is higher, but still acceptable. Ligand B (342.374 Da) is slightly better.

**TPSA:** Both ligands are below the 140 A^2 threshold for oral absorption, and importantly, below the 90 A^2 threshold for CNS targets. Ligand B (74.33 A^2) is significantly better than Ligand A (93.21 A^2).

**logP:** Both ligands have logP values between 1-3 (Ligand A: 2.753, Ligand B: 3.3), which is optimal. Ligand B is slightly higher, potentially increasing permeability.

**H-Bond Donors/Acceptors:** Both have acceptable HBD (2) and HBA (Ligand A: 6, Ligand B: 3) counts. Ligand B is better here.

**QED:** Both ligands have good QED scores (Ligand A: 0.684, Ligand B: 0.899), indicating drug-like properties. Ligand B is better.

**DILI:** Both have acceptable DILI risk (Ligand A: 78.402, Ligand B: 70.686), though lower is preferable. Ligand B is slightly better.

**BBB:** Both ligands have good BBB penetration (Ligand A: 68.088, Ligand B: 70.88). Ligand B is slightly better.

**Caco-2 Permeability:** Both have negative Caco-2 permeability values, which is unusual and suggests poor permeability. Ligand A (-4.716) is slightly better than Ligand B (-4.776).

**Aqueous Solubility:** Both have negative solubility values, indicating very poor solubility. Ligand A (-3.519) is slightly better than Ligand B (-4.496).

**hERG Inhibition:** Both have low hERG inhibition risk (Ligand A: 0.451, Ligand B: 0.627). Ligand B is slightly better.

**Microsomal Clearance:** Ligand A (103.734 mL/min/kg) has significantly higher clearance than Ligand B (-33.824 mL/min/kg). This suggests Ligand B is more metabolically stable.

**In vitro Half-Life:** Ligand B (41.623 hours) has a much longer half-life than Ligand A (66.437 hours).

**P-gp Efflux:** Both have very low P-gp efflux liability (Ligand A: 0.054, Ligand B: 0.062).

**Binding Affinity:** Ligand B (-9.5 kcal/mol) has significantly stronger binding affinity than Ligand A (-7.7 kcal/mol). This is a substantial advantage, potentially outweighing minor ADME drawbacks.

**Overall Assessment:**

Ligand B consistently outperforms Ligand A across most relevant parameters for a CNS-targeting GPCR ligand. While both have poor Caco-2 and solubility, the significantly improved metabolic stability (lower Cl_mic, longer t1/2), better TPSA, QED, and *much* stronger binding affinity of Ligand B make it the more promising candidate. The slightly better BBB and DILI scores also contribute to its favorability.



Output:
1
2025-04-17 05:08:37,216 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (347.459 Da and 354.43 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (70.67) is significantly better than Ligand B (101.8). For CNS targets, TPSA should be <=90, and A is comfortably within this range, while B is pushing the limit.

**logP:** Both ligands (0.689 and 0.802) are within the optimal 1-3 range, but are on the lower side. This could potentially impact permeability, but isn't a major concern.

**H-Bond Donors/Acceptors:** Both have 2 HBDs, which is good. Ligand A has 4 HBAs, and Ligand B has 6. Both are acceptable, but fewer is generally preferred.

**QED:** Both ligands have good QED scores (0.525 and 0.754), indicating good drug-like properties.

**DILI:** Ligand A (15.471) has a much lower DILI risk than Ligand B (45.522). This is a significant advantage for A.

**BBB:** Ligand B (76.696) has a substantially better BBB penetration percentile than Ligand A (40.364). This is a critical factor for a CNS target like DRD2.

**Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and suggests poor permeability. This is a concern for both, but the magnitude of negativity is similar.

**Aqueous Solubility:** Both ligands have negative solubility values, which is also unusual and indicates poor solubility. This is a concern for both.

**hERG:** Both ligands have very low hERG inhibition liability (0.291 and 0.051), which is excellent.

**Microsomal Clearance:** Ligand A (10.007) has much lower microsomal clearance than Ligand B (25.464), indicating better metabolic stability.

**In vitro Half-Life:** Ligand A (-0.904) has a slightly better (less negative) in vitro half-life than Ligand B (-25.246).

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.012 and 0.045), which is favorable.

**Binding Affinity:** Both ligands have very similar and excellent binding affinities (-7.6 and -7.7 kcal/mol). The difference is negligible.

**Overall Assessment:**

Ligand B has a significantly better BBB score, which is paramount for a CNS target. However, it suffers from higher DILI risk, higher microsomal clearance, and a worse TPSA value. Ligand A has better TPSA, DILI, metabolic stability, and half-life. The similar binding affinities mean that the ADME properties become the deciding factor. While BBB is critical, the combination of lower DILI and better metabolic stability for Ligand A makes it the more promising candidate, despite the lower BBB score. The poor Caco-2 and solubility are concerns for both, but can be addressed with formulation strategies.

Output:
0
2025-04-17 05:08:37,216 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (344.455 and 348.418 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (60.85) is significantly better than Ligand B (71.34). For CNS targets, TPSA should be <= 90, both are within this range, but A is preferable.

**3. logP:** Both ligands have good logP values (2.078 and 2.918), falling within the optimal 1-3 range.

**4. H-Bond Donors:** Ligand A (1) is better than Ligand B (2). Lower HBD generally improves permeability.

**5. H-Bond Acceptors:** Both ligands have the same number of HBA (3), which is acceptable (<=10).

**6. QED:** Both ligands have high QED scores (0.91 and 0.83), indicating good drug-like properties.

**7. DILI:** Ligand A (13.687) has a much lower DILI risk than Ligand B (37.767). This is a significant advantage for Ligand A.

**8. BBB:** Ligand B (76.541) has a better BBB penetration percentile than Ligand A (68.67). While both are reasonably good, B is better here. This is a critical factor for a CNS target like DRD2.

**9. Caco-2 Permeability:** Ligand A (-4.495) has better Caco-2 permeability than Ligand B (-4.654), although both are negative values which is unusual.

**10. Aqueous Solubility:** Ligand A (-1.59) has better aqueous solubility than Ligand B (-3.59).

**11. hERG Inhibition:** Ligand A (0.602) has a slightly better hERG profile than Ligand B (0.324), indicating lower cardiotoxicity risk.

**12. Microsomal Clearance:** Ligand A (19.813) has higher microsomal clearance than Ligand B (14.817), indicating lower metabolic stability. This is a disadvantage for Ligand A.

**13. In vitro Half-Life:** Ligand B (31.657) has a significantly longer in vitro half-life than Ligand A (3.585). This is a major advantage for Ligand B.

**14. P-gp Efflux:** Ligand A (0.17) has lower P-gp efflux than Ligand B (0.123), which is favorable for CNS penetration.

**15. Binding Affinity:** Ligand B (-8.8 kcal/mol) has a slightly better binding affinity than Ligand A (-8.1 kcal/mol). While the difference is not huge, it's enough to consider.

**Overall Assessment:**

Ligand B has a better BBB score, longer half-life, and slightly better binding affinity. Ligand A has better DILI risk, solubility, and P-gp efflux. Considering the GPCR-specific priorities, BBB penetration is crucial for CNS targets. The improved half-life of Ligand B is also a significant advantage. While Ligand A's lower DILI is attractive, the benefits of Ligand B's CNS penetration and metabolic stability outweigh this.

Output:
1
2025-04-17 05:08:37,216 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (357.426 and 348.422 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (98.74) is slightly higher than the ideal <90 for CNS targets, but still reasonable. Ligand B (78.09) is excellent, well below 90.

**3. logP:** Ligand A (0.261) is quite low, potentially hindering membrane permeability. Ligand B (2.67) is within the optimal 1-3 range. This is a significant advantage for Ligand B.

**4. H-Bond Donors:** Ligand A (3) and Ligand B (2) are both acceptable, below the threshold of 5.

**5. H-Bond Acceptors:** Ligand A (4) and Ligand B (3) are both acceptable, below the threshold of 10.

**6. QED:** Both ligands have good QED scores (0.58 and 0.731), indicating drug-like properties.

**7. DILI:** Ligand A (18.302) has a much lower DILI risk than Ligand B (50.136), which is a positive.

**8. BBB:** Ligand B (82.474) has a significantly better BBB penetration score than Ligand A (65.413). This is crucial for a CNS target like DRD2.

**9. Caco-2 Permeability:** Ligand A (-5.24) has poor Caco-2 permeability, which is concerning. Ligand B (-4.864) is also poor, but slightly better.

**10. Aqueous Solubility:** Ligand A (-1.105) and Ligand B (-2.939) both have poor aqueous solubility.

**11. hERG Inhibition:** Ligand A (0.058) has very low hERG inhibition risk, a strong advantage. Ligand B (0.864) has a moderate risk.

**12. Microsomal Clearance:** Ligand A (-15.58) has a very low (good) microsomal clearance, indicating high metabolic stability. Ligand B (35.23) has a higher clearance, suggesting faster metabolism.

**13. In vitro Half-Life:** Ligand A (0.574) has a very short half-life. Ligand B (52.689) has a much longer half-life, which is desirable.

**14. P-gp Efflux:** Ligand A (0.012) has very low P-gp efflux, which is excellent for CNS penetration. Ligand B (0.29) has moderate P-gp efflux.

**15. Binding Affinity:** Both ligands have the same binding affinity (-7.7 kcal/mol), which is excellent.

**Overall Assessment:**

While Ligand A has advantages in DILI, hERG, P-gp efflux, and microsomal clearance, its low logP and poor Caco-2 permeability are major drawbacks. The low logP will severely limit its ability to cross cell membranes, including the BBB. Ligand B, despite a higher DILI risk and moderate P-gp efflux, has a much better logP and significantly better BBB penetration. The longer half-life is also a plus. Given the GPCR-specific priorities for DRD2, the improved permeability and BBB penetration of Ligand B outweigh the slightly higher DILI and P-gp efflux.

Output:
1
2025-04-17 05:08:37,216 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (416.218 Da) is slightly higher than Ligand B (378.435 Da), but both are acceptable.

**TPSA:** Ligand A (68.53) is excellent for CNS penetration, well below the 90 A^2 threshold. Ligand B (114.19) is higher, but still potentially acceptable, though less ideal.

**logP:** Both ligands have good logP values (A: 2.692, B: 1.791), falling within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A (HBD=1, HBA=5) and Ligand B (HBD=2, HBA=7) both have reasonable numbers of H-bond donors and acceptors, within the suggested limits.

**QED:** Both ligands have similar and acceptable QED values (A: 0.601, B: 0.648), indicating good drug-like properties.

**DILI:** Ligand A (55.215) has a lower DILI risk than Ligand B (92.672). This is a significant advantage.

**BBB:** This is a critical parameter for CNS targets. Ligand A has a very good BBB percentile (71.656), exceeding the desirable >70 threshold. Ligand B's BBB percentile (38.775) is considerably lower and concerning for CNS penetration.

**Caco-2 Permeability:** Both have negative Caco-2 values which is unusual and likely indicates an issue with the model or data.

**Aqueous Solubility:** Both have negative solubility values which is also unusual and likely indicates an issue with the model or data.

**hERG:** Both ligands show low hERG inhibition liability (A: 0.688, B: 0.265), which is favorable.

**Microsomal Clearance:** Ligand A (77.831) has a higher microsomal clearance than Ligand B (0.174), suggesting lower metabolic stability. This is a drawback for Ligand A.

**In vitro Half-Life:** Ligand B (42.258) has a significantly longer in vitro half-life than Ligand A (14.068), which is a positive attribute.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (A: 0.627, B: 0.065). Ligand B is better.

**Binding Affinity:** Both ligands have excellent binding affinities (A: -8.0 kcal/mol, B: -8.3 kcal/mol). Ligand B is slightly better, but the difference is small and may not be crucial given the other factors.

**Overall Assessment:**

Ligand A excels in TPSA and BBB penetration, crucial for a CNS-targeting GPCR. However, it suffers from higher DILI risk, higher microsomal clearance (lower metabolic stability), and a shorter half-life.

Ligand B has a better DILI profile, better metabolic stability (lower Cl_mic and longer t1/2), and lower P-gp efflux. However, its TPSA is higher, and its BBB penetration is significantly worse.

Considering the GPCR-specific priorities, the **BBB penetration is paramount for a CNS target like DRD2**. Ligand A's strong BBB value outweighs its other drawbacks, particularly given the similar binding affinities. The lower DILI risk of ligand B is attractive, but can be addressed during further optimization.

Output:
1
2025-04-17 05:08:37,217 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (345.487 and 354.491 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (54.46) is significantly better than Ligand B (81.08). For a CNS target like DRD2, TPSA should be <= 90, and ideally lower. Ligand A is well within this range, while Ligand B is approaching the upper limit and less favorable.

**logP:** Ligand A (3.07) is optimal, while Ligand B (1.107) is a bit low. A logP between 1-3 is preferred, and Ligand B's value might indicate permeability issues.

**H-Bond Donors/Acceptors:** Ligand A has 1 HBD and 4 HBA, while Ligand B has 2 HBD and 4 HBA. Both are within acceptable limits (<=5 HBD and <=10 HBA).

**QED:** Both ligands have similar QED values (0.891 and 0.792), indicating good drug-likeness.

**DILI:** Both ligands have low DILI risk (29.624 and 27.414), which is good.

**BBB:** This is a critical parameter for CNS targets. Ligand A has a BBB percentile of 92.361, which is excellent. Ligand B has a very low BBB percentile of 20.512, making it unlikely to effectively reach the target in the brain.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.953 and -4.624). This is unusual and requires further investigation, but it's not a primary decision-making factor here given the other strong differences.

**Aqueous Solubility:** Both ligands have negative solubility values (-2.842 and -1.369). Similar to Caco-2, this is unusual and warrants further investigation, but is less critical than BBB.

**hERG:** Both ligands have low hERG inhibition liability (0.706 and 0.401), which is favorable.

**Microsomal Clearance:** Ligand A (63.404) has higher clearance than Ligand B (16.85), meaning Ligand B is more metabolically stable.

**In vitro Half-Life:** Ligand B (10.115) has a slightly longer half-life than Ligand A (9.596).

**P-gp Efflux:** Ligand A (0.391) has lower P-gp efflux liability than Ligand B (0.106), which is beneficial for CNS penetration.

**Binding Affinity:** Ligand A (-9.3 kcal/mol) has a significantly stronger binding affinity than Ligand B (-0.0 kcal/mol). This is a substantial difference and a major advantage for Ligand A.

**Conclusion:**

Considering all factors, especially the GPCR-specific priorities, **Ligand A is significantly more promising**. Its excellent BBB penetration, optimal logP, strong binding affinity, and acceptable TPSA outweigh the slightly higher microsomal clearance. Ligand B's extremely poor BBB penetration and weak binding affinity make it a much less viable candidate, despite its better metabolic stability and half-life.

Output:
1
2025-04-17 05:08:37,217 - INFO - Reasoning:

Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (350.459 Da and 348.531 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (81.08) is better than Ligand B (40.62) as it is closer to the <90 A^2 threshold for CNS targets. Ligand B is very low, which *could* indicate poor binding, but isn't necessarily a dealbreaker.

**3. logP:** Ligand A (0.619) is suboptimal, being below the preferred 1-3 range. Ligand B (4.031) is at the upper end of the range, potentially causing solubility issues, but is still within acceptable limits.

**4. H-Bond Donors:** Ligand A (2) is reasonable. Ligand B (0) is also acceptable.

**5. H-Bond Acceptors:** Ligand A (4) is good. Ligand B (2) is also good.

**6. QED:** Ligand A (0.731) is better than Ligand B (0.559), indicating a more drug-like profile.

**7. DILI:** Ligand A (27.336) has a much lower DILI risk than Ligand B (11.128), which is a significant advantage.

**8. BBB:** Ligand B (88.096) is significantly better than Ligand A (36.371) regarding BBB penetration, a critical factor for CNS targets like DRD2. This is a major point in favor of Ligand B.

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.451 and -4.533), which is unusual and suggests poor permeability. This is a concern for both.

**10. Aqueous Solubility:** Both ligands have negative solubility values (-0.877 and -3.35). This is also a significant concern, potentially hindering formulation and bioavailability. Ligand B is worse.

**11. hERG Inhibition:** Ligand A (0.428) has a lower hERG risk than Ligand B (0.748), which is preferable.

**12. Microsomal Clearance:** Ligand A (-2.799) has a lower (better) microsomal clearance than Ligand B (63.22). This suggests better metabolic stability for Ligand A.

**13. In vitro Half-Life:** Ligand A (-14.613) has a negative half-life, which is not possible. This is a major red flag. Ligand B (4.344) is reasonable.

**14. P-gp Efflux:** Ligand A (0.079) exhibits lower P-gp efflux than Ligand B (0.395), which is favorable for CNS penetration.

**15. Binding Affinity:** Ligand A (-8.2) has a significantly stronger binding affinity than Ligand B (-6.7). This is a substantial advantage, potentially outweighing some of its ADME drawbacks.

**Overall Assessment:**

Ligand A has a much better binding affinity, lower DILI risk, better metabolic stability, and lower P-gp efflux. However, it has a very poor (and impossible) in vitro half-life, and a significantly lower BBB penetration. Ligand B has excellent BBB penetration, but weaker binding affinity, higher DILI risk, and poorer metabolic stability.

Given the importance of BBB penetration for a CNS target like DRD2, and the fact that the affinity difference is substantial (1.5 kcal/mol), Ligand B is the more promising candidate *despite* its other shortcomings. The poor solubility and permeability of both compounds would need to be addressed through formulation or further chemical modifications, but the strong BBB penetration of Ligand B is a key advantage. The negative half-life of Ligand A is a showstopper.

Output:
1
2025-04-17 05:08:37,217 - INFO - Reasoning:

Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (335.323 and 347.434 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (124.07) is borderline, but acceptable for CNS penetration, while Ligand B (54.34) is excellent, well below the 90 A^2 threshold. This favors Ligand B.

**3. logP:** Both ligands have good logP values (2.379 and 1.811), falling within the optimal 1-3 range.

**4. H-Bond Donors:** Ligand A has 3 HBD, which is acceptable. Ligand B has 1 HBD, also acceptable.

**5. H-Bond Acceptors:** Ligand A has 7 HBA, acceptable. Ligand B has 3 HBA, also acceptable.

**6. QED:** Both ligands have good QED scores (0.625 and 0.883), indicating good drug-like properties. Ligand B is slightly better.

**7. DILI:** Ligand A has a high DILI risk (97.596), which is a significant concern. Ligand B has a very low DILI risk (15.083), a major advantage.

**8. BBB:** Ligand B has a much higher BBB penetration percentile (94.455) than Ligand A (20.318). This is crucial for a CNS target like DRD2 and strongly favors Ligand B.

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.92 and -4.866). This is unusual and suggests poor permeability, but the scale is not defined, so it's hard to interpret.

**10. Aqueous Solubility:** Both ligands have negative solubility values (-5.15 and -2.44). Similar to Caco-2, this is unusual and suggests poor solubility, but the scale is not defined.

**11. hERG Inhibition:** Both ligands have low hERG inhibition risk (0.505 and 0.4), which is good.

**12. Microsomal Clearance:** Ligand B has a lower microsomal clearance (9.112 mL/min/kg) than Ligand A (34.599 mL/min/kg), indicating better metabolic stability.

**13. In vitro Half-Life:** Ligand B has a longer in vitro half-life (-6.835 hours) than Ligand A (-2.571 hours).

**14. P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.069 and 0.079).

**15. Binding Affinity:** Both ligands have excellent binding affinities (-9.6 and -8.0 kcal/mol). Ligand A is slightly more potent.

**Overall Assessment:**

While Ligand A has slightly better binding affinity, the significant drawbacks of high DILI risk and poor BBB penetration outweigh this advantage. Ligand B excels in key areas for a CNS GPCR target: excellent BBB penetration, low DILI risk, better metabolic stability, and a longer half-life. The slightly lower affinity is a reasonable trade-off for the improved ADME properties.

Output:
1
2025-04-17 05:08:37,218 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (349.431 and 363.567 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (95.58) is higher than the preferred <90 for CNS targets, while Ligand B (40.54) is excellent. This is a significant advantage for Ligand B.

**logP:** Ligand A (0.378) is quite low, potentially hindering membrane permeability. Ligand B (3.411) is within the optimal 1-3 range. This favors Ligand B.

**H-Bond Donors/Acceptors:** Ligand A has 2 HBD and 4 HBA, which are acceptable. Ligand B has 1 HBD and 3 HBA, also acceptable.

**QED:** Both ligands have good QED scores (0.75 and 0.814), indicating good drug-like properties.

**DILI:** Ligand A (24.544) has a slightly higher DILI risk than Ligand B (15.316), but both are below the concerning threshold of 60.

**BBB:** This is critical for a CNS target. Ligand A (45.444) has a poor BBB percentile, while Ligand B (77.511) is very good, exceeding the desirable >70 threshold. This is a major advantage for Ligand B.

**Caco-2 Permeability:** Both have negative Caco-2 values (-5.257 and -5.123), which is unusual and suggests poor permeability. However, these values are on a log scale and difficult to interpret without further context.

**Aqueous Solubility:** Both ligands have very poor aqueous solubility (-1.681 and -4.232). This is a significant drawback for both.

**hERG Inhibition:** Ligand A (0.022) has a very low hERG risk, which is excellent. Ligand B (0.739) has a moderate hERG risk, but is still relatively low.

**Microsomal Clearance:** Ligand A (-10.797) has a negative clearance, which is not physically possible and likely an error in the data. Ligand B (83.551) has a high microsomal clearance, indicating rapid metabolism. This is a disadvantage for Ligand B.

**In vitro Half-Life:** Ligand A (-13.368) has a negative half-life, which is not physically possible and likely an error in the data. Ligand B (23.823) has a moderate half-life.

**P-gp Efflux:** Ligand A (0.007) has very low P-gp efflux, which is favorable for CNS penetration. Ligand B (0.617) has moderate P-gp efflux.

**Binding Affinity:** Ligand B (-7.2 kcal/mol) has a slightly better binding affinity than Ligand A (-8.4 kcal/mol), although both are strong binders.

**Overall Assessment:**

Despite the strong binding affinity of Ligand A, its extremely poor BBB penetration, questionable ADME properties (negative clearance and half-life), and low logP make it a very unlikely drug candidate. Ligand B, while having a higher clearance and moderate P-gp efflux, possesses a significantly better TPSA, logP, and crucially, a good BBB penetration. The slightly weaker affinity of Ligand B is likely outweighed by its superior pharmacokinetic properties for a CNS target. The negative values for Caco-2, clearance, and half-life for Ligand A are concerning and suggest potential data errors.

Output:
1
2025-04-17 05:08:37,218 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (368.543 and 353.507 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (58.64) is significantly better than Ligand B (81.67). For CNS targets, we want TPSA <= 90, and A is comfortably within that range, while B is approaching the upper limit.

**3. logP:** Both ligands have good logP values (2.464 and 1.447), falling within the optimal 1-3 range.

**4. H-Bond Donors:** Ligand A (1) is preferable to Ligand B (3). Fewer HBDs generally improve permeability.

**5. H-Bond Acceptors:** Both ligands have 4 HBA, which is acceptable (<=10).

**6. QED:** Both ligands have reasonable QED values (0.635 and 0.548), indicating good drug-like properties.

**7. DILI:** Ligand A (17.759) has a much lower DILI risk than Ligand B (5.312), suggesting better hepatotoxicity potential. Both are below the 40 threshold.

**8. BBB:** Ligand A (71.035) has a significantly better BBB penetration score than Ligand B (46.452). For a CNS target like DRD2, >70 is desirable, but A is much closer than B.

**9. Caco-2:** Ligand A (-4.837) has a worse Caco-2 permeability than Ligand B (-5.164). However, Caco-2 is less critical than BBB for CNS targets.

**10. Solubility:** Ligand A (-2.848) has slightly better solubility than Ligand B (-1.385).

**11. hERG:** Both ligands have very low hERG inhibition risk (0.357 and 0.243).

**12. Cl_mic:** Ligand B (3.305) has a much lower microsomal clearance than Ligand A (68.139), indicating better metabolic stability.

**13. t1/2:** Ligand B (-7.347) has a slightly longer in vitro half-life than Ligand A (-4.875).

**14. Pgp:** Ligand A (0.104) has lower P-gp efflux liability than Ligand B (0.024), which is favorable for CNS penetration.

**15. Binding Affinity:** Both ligands have excellent binding affinity (-7.0 and -7.5 kcal/mol). Ligand B is slightly better, but the difference is not substantial enough to outweigh other factors.

**Overall Assessment:**

Ligand A is the better candidate. While Ligand B has slightly better metabolic stability and half-life, Ligand A excels in crucial areas for a CNS-targeting GPCR ligand: TPSA, BBB penetration, DILI risk, and Pgp efflux. The slightly lower Caco-2 permeability of Ligand A is less concerning given the CNS target. The affinity difference is minimal. The combination of these factors makes Ligand A the more promising drug candidate.

Output:
1
2025-04-17 05:08:37,218 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (366.849 Da) is slightly lower, which could be advantageous for permeability.

**TPSA:** Ligand A (76.46) is significantly better than Ligand B (98.49). For CNS targets, we want TPSA <= 90, so Ligand A is preferable.

**logP:** Ligand A (3.421) is optimal (1-3), while Ligand B (1.949) is on the lower end. Lower logP can hinder permeation, making Ligand A more promising.

**H-Bond Donors/Acceptors:** Ligand A (HBD=1, HBA=5) and Ligand B (HBD=2, HBA=4) both fall within acceptable ranges.

**QED:** Ligand A (0.902) has a superior QED score compared to Ligand B (0.638), indicating better overall drug-likeness.

**DILI:** Ligand A (71.656) has a higher DILI risk than Ligand B (45.677), but both are reasonably acceptable.

**BBB:** Ligand A (71.307) and Ligand B (69.794) are both reasonably good, but slightly below the >70 desirable for CNS targets.

**Caco-2 Permeability:** Ligand A (-4.359) is worse than Ligand B (-5.012), indicating lower intestinal absorption.

**Aqueous Solubility:** Ligand A (-3.877) is worse than Ligand B (-2.658).

**hERG Inhibition:** Both ligands have similar, low hERG inhibition liability (0.454 and 0.568).

**Microsomal Clearance:** Ligand A (83.319) has higher clearance than Ligand B (27.994), meaning Ligand B is more metabolically stable.

**In vitro Half-Life:** Ligand B (-28.756) has a negative half-life, which is unusual and suggests a very rapid degradation. Ligand A (66.29) is much better.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.288 and 0.144).

**Binding Affinity:** Both ligands have excellent binding affinity (-8.3 and -8.2 kcal/mol). The difference is minimal.

**Overall Assessment:**

Ligand A excels in TPSA, logP, and QED, which are crucial for CNS penetration and drug-likeness. While its Caco-2 permeability and aqueous solubility are worse than Ligand B, its superior TPSA and logP are more important for a CNS target. Ligand B has better metabolic stability and solubility, but its lower logP and higher TPSA are less favorable. The negative half-life of Ligand B is a major red flag.

Output:
1
2025-04-17 05:08:37,218 - INFO - Batch 173 complete. Total preferences: 2768
2025-04-17 05:08:37,218 - INFO - Processing batch 174/512...
2025-04-17 05:09:21,279 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (359.354 and 352.431 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (119.24) is slightly above the optimal <90 for CNS targets, but still reasonable. Ligand B (81.01) is well within the desired range. This favors Ligand B.

**3. logP:** Ligand A (-1.551) is a bit low, potentially hindering permeability. Ligand B (1.785) is within the optimal 1-3 range. This strongly favors Ligand B.

**4. H-Bond Donors:** Both ligands have 1 HBD, which is acceptable.

**5. H-Bond Acceptors:** Ligand A has 6 HBA, and Ligand B has 5. Both are within the acceptable limit of <=10.

**6. QED:** Both ligands have reasonable QED values (0.453 and 0.771), indicating acceptable drug-likeness. Ligand B is better here.

**7. DILI:** Both ligands have low DILI risk (44.552 and 40.869), below the 60 threshold.

**8. BBB:** Ligand A has a good BBB penetration percentile (79.062), while Ligand B is lower (65.452). This favors Ligand A, but the difference isn't huge.

**9. Caco-2 Permeability:** Both have negative Caco-2 values which is unusual and suggests poor permeability.

**10. Aqueous Solubility:** Both have negative solubility values which is unusual and suggests poor solubility.

**11. hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.171 and 0.232).

**12. Microsomal Clearance:** Ligand A has a lower Cl_mic (2.993) than Ligand B (24.962), indicating better metabolic stability. This favors Ligand A.

**13. In vitro Half-Life:** Ligand A has a significantly longer half-life (-34.976) than Ligand B (19.874), which is a major advantage.

**14. P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.026 and 0.065).

**15. Binding Affinity:** Ligand A (-7.7 kcal/mol) has a slightly better binding affinity than Ligand B (-6.9 kcal/mol). While both are good, the 0.8 kcal/mol difference is significant.

**Overall Assessment:**

Considering the GPCR-specific priorities, Ligand A is more promising. While Ligand B has better logP and TPSA, Ligand A's superior binding affinity, metabolic stability (lower Cl_mic), longer half-life, and reasonable BBB penetration outweigh these drawbacks. The slightly lower logP of Ligand A can be addressed through further optimization, but a 0.8 kcal/mol difference in binding affinity is substantial.

Output:
1
2025-04-17 05:09:21,279 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (368.39 Da) is slightly lower, which could be advantageous for permeability. Ligand B (407.312 Da) is also acceptable.

**TPSA:** Ligand A (112.49) is borderline for CNS penetration, being slightly above the preferred <90 threshold. Ligand B (67.35) is excellent, well below 90, and highly favorable for CNS penetration.

**logP:** Both ligands have good logP values (A: 1.361, B: 2.163), falling within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A has 2 HBD and 6 HBA, which is acceptable. Ligand B has 1 HBD and 5 HBA, also acceptable.

**QED:** Both ligands have similar and good QED scores (A: 0.763, B: 0.733), indicating good drug-like properties.

**DILI:** Ligand A (71.384) has a higher DILI risk than Ligand B (43.35), although both are below the concerning 60 threshold.

**BBB:** This is a critical parameter for a CNS target like DRD2. Ligand B (80.535) has a significantly better BBB percentile than Ligand A (38.891). This is a major advantage for Ligand B.

**Caco-2 Permeability:** Ligand A (-4.918) shows poor Caco-2 permeability, indicating potential absorption issues. Ligand B (-5.109) is also poor, but similar to A.

**Aqueous Solubility:** Both ligands have very poor aqueous solubility (-3.505 and -3.028 respectively). This could pose formulation challenges.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (A: 0.143, B: 0.596).

**Microsomal Clearance:** Ligand B (47.239) has a higher microsomal clearance than Ligand A (30.584), suggesting lower metabolic stability.

**In vitro Half-Life:** Ligand A (-31.056) has a shorter in vitro half-life than Ligand B (27.483).

**P-gp Efflux:** Both ligands show low P-gp efflux liability (A: 0.1, B: 0.059), which is favorable for CNS exposure.

**Binding Affinity:** Ligand B (-8.4 kcal/mol) has a slightly better binding affinity than Ligand A (-9.1 kcal/mol). While the difference is relatively small, it's still a positive for Ligand B.

**Overall Assessment:**

Ligand B is significantly more promising due to its superior BBB penetration (80.5% vs 38.9%), and slightly better binding affinity. While both have poor solubility and Caco-2 permeability, the BBB is the most critical factor for a CNS target. The slightly higher metabolic clearance of Ligand B is a concern, but the strong BBB penetration and affinity outweigh this drawback.

Output:
1
2025-04-17 05:09:21,279 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (360.57 and 366.51 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (23.55) is excellent, well below the 90 A^2 threshold for CNS targets. Ligand B (54.18) is higher, but still reasonable, though less favorable.

**logP:** Both ligands have good logP values (3.869 and 3.302), falling within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A (0 HBD, 3 HBA) is better than Ligand B (1 HBD, 6 HBA) in terms of balancing solubility and permeability.

**QED:** Both ligands have similar and good QED values (0.769 and 0.779), indicating good drug-like properties.

**DILI:** Ligand A (19.271 percentile) has a significantly lower DILI risk than Ligand B (36.603 percentile). This is a substantial advantage.

**BBB:** Both ligands have excellent BBB penetration (92.4% and 82.862%), exceeding the desirable >70% threshold for CNS targets. Ligand A is slightly better.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.904 and -4.697), which is unusual and suggests poor permeability. This is a significant concern for both.

**Aqueous Solubility:** Both ligands have negative solubility values (-3.986 and -3.451), indicating very poor aqueous solubility. This is a major drawback for both.

**hERG Inhibition:** Both ligands show low hERG inhibition liability (0.904 and 0.607), which is favorable.

**Microsomal Clearance:** Ligand A (79.408 mL/min/kg) has a higher microsomal clearance than Ligand B (59.245 mL/min/kg), suggesting lower metabolic stability.

**In vitro Half-Life:** Ligand B (-7.103 hours) has a negative half-life, which is not possible. This is a major red flag. Ligand A (10.65 hours) has a reasonable half-life.

**P-gp Efflux:** Both ligands show low P-gp efflux liability (0.752 and 0.57), which is good for CNS exposure.

**Binding Affinity:** Ligand A (-7.3 kcal/mol) has a slightly better binding affinity than Ligand B (-7.0 kcal/mol), although the difference is small.

**Overall Assessment:**

Despite the poor Caco-2 and solubility for both, Ligand A is the more promising candidate. It has a significantly lower DILI risk, a slightly better BBB score, a better half-life, and a slightly better binding affinity. Ligand B's negative in vitro half-life is a critical flaw. The TPSA and logP values are acceptable for both. The poor solubility and permeability would need to be addressed through formulation strategies, but the other ADME properties of Ligand A are more favorable.

Output:
0
2025-04-17 05:09:21,280 - INFO - Reasoning:

Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (367.47 & 347.42 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (72.91) is excellent, well below the 90 A^2 threshold for CNS targets. Ligand B (78.87) is still reasonable, but less optimal.

**3. logP:** Ligand A (2.269) is within the optimal 1-3 range. Ligand B (0.108) is quite low, potentially hindering membrane permeability and CNS penetration.

**4. H-Bond Donors:** Both have 0 HBD, which is acceptable.

**5. H-Bond Acceptors:** Ligand A has 5 HBA, and Ligand B has 6 HBA, both within the acceptable limit of <=10.

**6. QED:** Both ligands have similar QED values (0.771 and 0.769), indicating good drug-likeness.

**7. DILI:** Both ligands have low DILI risk (49.40 and 45.10 percentiles), which is favorable.

**8. BBB:** Ligand A has a significantly higher BBB penetration percentile (84.141) than Ligand B (68.282). This is a *critical* advantage for a CNS target like DRD2.

**9. Caco-2 Permeability:** Ligand A (-4.439) and Ligand B (-4.503) have similar, and very poor, Caco-2 permeability.

**10. Aqueous Solubility:** Ligand A (-3.101) and Ligand B (-0.668) have poor aqueous solubility.

**11. hERG Inhibition:** Both ligands show very low hERG inhibition risk (0.346 and 0.246), which is excellent.

**12. Microsomal Clearance:** Ligand A (65.187) has higher microsomal clearance than Ligand B (-5.29). This suggests Ligand B is more metabolically stable.

**13. In vitro Half-Life:** Ligand A (13.078) has a longer half-life than Ligand B (1.036).

**14. P-gp Efflux:** Ligand A (0.251) has lower P-gp efflux than Ligand B (0.021), indicating better potential for CNS exposure.

**15. Binding Affinity:** Ligand B (-7.6 kcal/mol) has a slightly better binding affinity than Ligand A (-8.1 kcal/mol). While a 0.5 kcal/mol difference is noticeable, it is not a huge advantage and can be overcome by other factors.

**Overall Assessment:**

Ligand A is significantly better suited as a DRD2 ligand. The superior BBB penetration (84.141 vs 68.282), combined with lower P-gp efflux, outweigh the slightly weaker binding affinity and higher clearance. The low logP of Ligand B is a major concern for CNS penetration. While both have poor solubility and Caco-2 permeability, these can potentially be addressed through formulation strategies. The GPCR-specific priorities heavily favor Ligand A.

Output:
1
2025-04-17 05:09:21,280 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (389.901) is slightly higher than Ligand B (348.487), but both are acceptable.

**TPSA:** Both ligands have TPSA values below the 90 A^2 threshold desirable for CNS targets. Ligand A (80.75) is better than Ligand B (58.64), suggesting potentially better brain penetration.

**logP:** Both ligands have logP values within the optimal range (1-3). Ligand A (2.936) and Ligand B (3.313) are both good, but Ligand A is slightly preferred.

**H-Bond Donors/Acceptors:** Ligand A has 0 HBD and 5 HBA, while Ligand B has 1 HBD and 3 HBA. Both are within acceptable limits (<=5 HBD and <=10 HBA).

**QED:** Both ligands have good QED scores (A: 0.723, B: 0.749), indicating a generally drug-like profile.

**DILI:** Ligand A (66.615) has a higher DILI risk than Ligand B (36.681). This is a significant drawback for Ligand A.

**BBB:** Ligand B (63.746) has a slightly better BBB percentile than Ligand A (56.34), but both are below the desirable >70 for CNS targets.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values which is unusual and indicates poor permeability. Ligand A (-4.376) is slightly better than Ligand B (-4.572).

**Aqueous Solubility:** Both ligands have negative solubility values, which is also unusual and indicates poor solubility. Ligand A (-2.964) is slightly better than Ligand B (-2.739).

**hERG:** Both ligands have very low hERG inhibition liability (A: 0.123, B: 0.169), which is excellent.

**Microsomal Clearance:** Ligand B (77.667) has a higher microsomal clearance than Ligand A (67.392), indicating lower metabolic stability.

**In vitro Half-Life:** Ligand A (76.498) has a significantly longer in vitro half-life than Ligand B (18.039), which is a major advantage.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (A: 0.232, B: 0.149), which is good.

**Binding Affinity:** Ligand B (-7.8 kcal/mol) has a slightly better binding affinity than Ligand A (-7.6 kcal/mol). While the difference is small, it's still a factor.

**Overall Assessment:**

Ligand B has a better DILI score, slightly better BBB penetration, and a slightly better binding affinity. However, Ligand A has a significantly longer half-life and better TPSA. The lower DILI risk and better affinity of Ligand B are important, but the significantly longer half-life of Ligand A is a substantial advantage for a CNS drug, potentially allowing for less frequent dosing. The negative Caco-2 and Solubility values are concerning for both, and would require further investigation. Considering the GPCR-specific priorities, the slightly better affinity and lower toxicity of Ligand B outweigh the longer half-life of Ligand A.

Output:
1
2025-04-17 05:09:21,280 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 drug candidates, considering the provided guidelines and GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight (MW):** Both ligands (339.4 & 351.4 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (85.35) is excellent, well below the 90 target for CNS drugs. Ligand B (93.45) is still reasonable but less optimal.

**3. logP:** Ligand A (0.895) is a bit low, potentially hindering permeability. Ligand B (1.705) is better, falling within the optimal 1-3 range.

**4. H-Bond Donors (HBD):** Both ligands (A: 2, B: 3) are within the acceptable limit of <=5.

**5. H-Bond Acceptors (HBA):** Both ligands (A: 5, B: 4) are within the acceptable limit of <=10.

**6. QED:** Ligand A (0.791) has a good drug-likeness score, while Ligand B (0.466) is below the desirable threshold of 0.5.

**7. DILI:** Ligand A (75.38) has a higher DILI risk than Ligand B (39.98), which is preferred.

**8. BBB:** Ligand B (83.99) has a significantly better BBB penetration score than Ligand A (20.86). This is *crucial* for a CNS target like DRD2.

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 values, which is unusual and suggests poor permeability. However, the scale is not specified, so it's difficult to interpret.

**10. Aqueous Solubility:** Both ligands have negative solubility values, which is also unusual and suggests poor solubility.

**11. hERG Inhibition:** Both ligands (A: 0.551, B: 0.687) have relatively low hERG inhibition risk.

**12. Microsomal Clearance:** Ligand A (-21.03) has a much lower (better) microsomal clearance than Ligand B (22.69), indicating greater metabolic stability.

**13. In vitro Half-Life:** Ligand B (9.83) has a significantly longer half-life than Ligand A (-2.34).

**14. P-gp Efflux:** Both ligands have very low P-gp efflux liability (A: 0.025, B: 0.094), which is positive for CNS penetration.

**15. Binding Affinity:** Both ligands have similar and strong binding affinities (-8.3 and -8.0 kcal/mol). The difference is less than the 1.5 kcal/mol threshold.

**Overall Assessment:**

While Ligand A has better metabolic stability (lower Cl_mic) and a higher QED score, Ligand B is significantly better regarding BBB penetration (83.99 vs 20.86), which is paramount for a CNS target. The slightly lower DILI risk for Ligand B is also favorable. The comparable binding affinities make the superior ADME properties of Ligand B the deciding factor. The negative solubility and Caco-2 values are concerning for both, but the BBB score is the most critical factor here.

Output:
1
2025-04-17 05:09:21,280 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 drug candidates, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (345.443 and 350.419 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (63.69) is significantly better than Ligand B (126.46). For CNS targets, TPSA should be <= 90, and A is comfortably within this range, while B is considerably above.

**logP:** Both ligands have good logP values (1.74 and 1.212), falling within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A (HBD=1, HBA=5) is better than Ligand B (HBD=4, HBA=4) in terms of balancing solubility and permeability. While both are acceptable, fewer H-bonds generally favor permeability.

**QED:** Ligand A (0.901) has a much higher QED score than Ligand B (0.526), indicating a more drug-like profile.

**DILI:** Ligand A (10.237) has a significantly lower DILI risk than Ligand B (36.797), which is a substantial advantage.

**BBB:** Ligand A (76.696) has a much better BBB penetration percentile than Ligand B (55.138). A value >70 is desirable for CNS targets, and A is closer to this threshold.

**Caco-2 Permeability:** Ligand A (-4.73) has a better Caco-2 permeability than Ligand B (-5.582), indicating better intestinal absorption.

**Aqueous Solubility:** Ligand A (-0.927) has better aqueous solubility than Ligand B (-2.29), which is beneficial for formulation and bioavailability.

**hERG Inhibition:** Ligand A (0.316) has a lower hERG inhibition liability than Ligand B (0.086), reducing the risk of cardiotoxicity.

**Microsomal Clearance:** Ligand A (4.762) has a lower microsomal clearance than Ligand B (21.952), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (3.385) has a shorter half-life than Ligand B (27.836). This is a drawback for A, but the other favorable properties may outweigh this.

**P-gp Efflux:** Ligand A (0.012) has a much lower P-gp efflux liability than Ligand B (0.007), which is crucial for CNS exposure.

**Binding Affinity:** Ligand B (-7.6) has a slightly better binding affinity than Ligand A (-7.1), a difference of 0.5 kcal/mol. While affinity is important, the other ADME properties are more concerning for Ligand B.

**Overall:**

Ligand A consistently outperforms Ligand B across most critical ADME properties, especially those prioritized for GPCRs targeting the CNS (BBB, TPSA, Pgp). The only significant drawback for Ligand A is the shorter in vitro half-life, but its superior overall profile, particularly the much better BBB penetration, lower DILI risk, and lower P-gp efflux, makes it the more promising candidate. The 0.5 kcal/mol difference in binding affinity is unlikely to overcome the substantial ADME advantages of Ligand A.

Output:
0
2025-04-17 05:09:21,281 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (350.415 and 346.435 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (79.31) is better than Ligand B (89.07). Both are below the 90 A^2 threshold desirable for CNS targets, but A is closer to the optimal range.

**3. logP:** Ligand B (1.028) is better than Ligand A (-0.374). A logP of -0.374 is quite low and may hinder membrane permeability. Ligand B is within the optimal 1-3 range.

**4. H-Bond Donors:** Both ligands have 1 HBD, which is acceptable.

**5. H-Bond Acceptors:** Ligand B (7) is slightly higher than Ligand A (5), but both are within the acceptable limit of 10.

**6. QED:** Ligand B (0.809) has a significantly better QED score than Ligand A (0.54), indicating a more drug-like profile.

**7. DILI:** Ligand A (25.087) has a lower DILI risk than Ligand B (52.385), which is favorable.

**8. BBB:** Both ligands have similar BBB penetration (Ligand A: 55.099, Ligand B: 55.138). Neither is ideal (>70), but this is less critical if other properties are strong.

**9. Caco-2:** Both ligands have negative Caco-2 values (-4.511 and -5.002). This is unusual and suggests poor permeability.

**10. Solubility:** Both ligands have negative solubility values (-1.721 and -1.402). This is also unusual and suggests poor solubility.

**11. hERG:** Both ligands have low hERG inhibition risk (0.294 and 0.244).

**12. Cl_mic:** Ligand A (-5.286) has a much lower (better) microsomal clearance than Ligand B (26.554), indicating better metabolic stability.

**13. t1/2:** Ligand B (50.6) has a significantly longer in vitro half-life than Ligand A (-5.189).

**14. Pgp:** Both ligands have low Pgp efflux liability (0.075 and 0.227).

**15. Binding Affinity:** Ligand B (-8.1 kcal/mol) has a significantly stronger binding affinity than Ligand A (-6.7 kcal/mol). This is a >1.5 kcal/mol difference, which is a substantial advantage.

**Overall Assessment:**

Ligand B is the stronger candidate despite the higher DILI risk. The significantly better binding affinity (-8.1 vs -6.7 kcal/mol) and longer half-life are major advantages. While Ligand A has a lower DILI risk and better metabolic stability, the poor logP value and weaker binding affinity are significant drawbacks, especially for a CNS target. The similar BBB values and low Pgp efflux for both are positive. The negative Caco-2 and solubility values are concerning for both, but can be addressed with formulation strategies. The stronger affinity of Ligand B is likely to outweigh these concerns.

Output:
1
2025-04-17 05:09:21,281 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (341.386 Da) is slightly better than Ligand B (383.187 Da) as it's closer to the lower end, potentially aiding permeability.

**TPSA:** Ligand A (65.2) is significantly better than Ligand B (81.91). For CNS targets, TPSA should be <=90, and A is comfortably within this range, while B is approaching the upper limit. This favors A.

**logP:** Both ligands have acceptable logP values (A: 2.533, B: 3.789), falling within the optimal 1-3 range. B is slightly higher, which *could* indicate potential off-target effects or solubility issues, but isn't a major concern.

**H-Bond Donors/Acceptors:** Ligand A (HBD=2, HBA=2) is preferable to Ligand B (HBD=0, HBA=5). While both are within acceptable limits, a balance of donors and acceptors can be beneficial for binding.

**QED:** Ligand A (0.901) has a much higher QED score than Ligand B (0.431), indicating a significantly more drug-like profile. This is a substantial advantage for A.

**DILI:** Ligand B (81.039) has a higher DILI risk than Ligand A (63.513), suggesting a greater potential for liver toxicity. This favors A.

**BBB:** Ligand A (89.492) has a significantly better BBB penetration percentile than Ligand B (78.79). This is *critical* for a CNS target like DRD2, making A much more promising.

**Caco-2 Permeability:** Ligand A (-5.064) shows better Caco-2 permeability than Ligand B (-4.559), suggesting better intestinal absorption.

**Aqueous Solubility:** Both ligands have poor aqueous solubility (-4.556 and -5.755 respectively), which could pose formulation challenges.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (A: 0.571, B: 0.71), which is good.

**Microsomal Clearance:** Ligand A (20.487) has a lower microsomal clearance than Ligand B (55.274), indicating better metabolic stability. This is a significant advantage for A.

**In vitro Half-Life:** Ligand A (20.767) has a longer in vitro half-life than Ligand B (8.714), which is desirable for less frequent dosing.

**P-gp Efflux:** Ligand A (0.115) exhibits lower P-gp efflux liability than Ligand B (0.503), which is favorable for CNS exposure.

**Binding Affinity:** Both ligands have excellent binding affinities (A: -9.4 kcal/mol, B: -8.5 kcal/mol). Ligand A is 0.9 kcal/mol more potent, which is a substantial advantage and can outweigh minor ADME drawbacks.

**Overall:** Ligand A consistently outperforms Ligand B across most critical parameters, especially those prioritized for GPCRs targeting the CNS (BBB, TPSA, Pgp) and key ADME properties (QED, DILI, Cl_mic, t1/2). The significantly stronger binding affinity of A further solidifies its position as the superior candidate.

Output:
0
2025-04-17 05:09:21,281 - INFO - Reasoning:

Let's analyze Ligand A and Ligand B based on the provided guidelines, prioritizing GPCR-specific properties (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (375.837 and 378.387 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (90.27) is excellent for CNS penetration, being under the 90 threshold. Ligand B (126.61) is higher, but still potentially acceptable, though less ideal.

**logP:** Both ligands have good logP values (2.921 and 3.309), falling within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A (1 HBD, 4 HBA) and Ligand B (2 HBD, 6 HBA) both have reasonable numbers of H-bond donors and acceptors, well within the guidelines.

**QED:** Ligand A (0.892) has a significantly better QED score than Ligand B (0.518), indicating a more drug-like profile.

**DILI:** Both ligands have high DILI risk (94.882 and 99.729), which is a concern. However, this is often a later-stage optimization parameter.

**BBB:** Ligand A (38.426) has a very poor BBB percentile, making CNS penetration unlikely. Ligand B (30.71) is also poor, but slightly lower, indicating slightly less efflux.

**Caco-2 Permeability:** Ligand A (-4.873) and Ligand B (-5.47) both have negative Caco-2 values, which is unusual and suggests poor permeability.

**Aqueous Solubility:** Both ligands have poor aqueous solubility (-5.08 and -4.164).

**hERG Inhibition:** Ligand A (0.594) has a slightly better hERG profile than Ligand B (0.115), indicating lower cardiotoxicity risk.

**Microsomal Clearance:** Ligand A (11.021) has higher microsomal clearance than Ligand B (1.4), suggesting lower metabolic stability.

**In vitro Half-Life:** Ligand B (88.317) has a significantly longer in vitro half-life than Ligand A (76.967).

**P-gp Efflux:** Ligand A (0.277) has lower P-gp efflux than Ligand B (0.106), which is beneficial for CNS penetration.

**Binding Affinity:** Both ligands have excellent binding affinities (-9.5 and -8.8 kcal/mol). Ligand A is slightly better (-9.5 kcal/mol).

**Overall Assessment:**

Given the GPCR-specific priorities, the most critical factors are BBB, logP, TPSA, Pgp, and affinity. While both ligands have good logP and affinity, Ligand A has a better TPSA and P-gp efflux profile. However, its BBB is very poor. Ligand B has a slightly better half-life, but worse TPSA and P-gp efflux. The poor BBB for both is a significant drawback for a CNS target. Considering the slightly better affinity, TPSA, and P-gp efflux of Ligand A, and the slightly better half-life of Ligand B, the affinity difference is small enough that the better ADME properties of Ligand A give it a slight edge.

Output:
0
2025-04-17 05:09:21,281 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (342.439 and 352.479 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (78.43) is significantly better than Ligand B (96.25). For CNS targets, we want TPSA <= 90, so Ligand A is preferable.

**3. logP:** Both ligands have good logP values (2.358 and 1.538), falling within the optimal 1-3 range. Ligand A is slightly higher, which could be beneficial for membrane permeability.

**4. H-Bond Donors:** Both have 3 HBD, which is acceptable.

**5. H-Bond Acceptors:** Ligand A has 3 HBA, while Ligand B has 5. Lower HBA is generally preferred for better permeability, giving a slight edge to Ligand A.

**6. QED:** Both ligands have similar QED values (0.603 and 0.595), indicating good drug-likeness.

**7. DILI:** Ligand A (19.969) has a considerably lower DILI risk than Ligand B (27.491). This is a significant advantage for Ligand A.

**8. BBB:** Ligand A (42.497) has a lower BBB penetration percentile than Ligand B (50.679). While both are below the desirable >70 for CNS targets, Ligand B is better in this regard.

**9. Caco-2:** Both have negative Caco-2 values (-5.135 and -5.2), which is unusual and difficult to interpret without knowing the scale. Assuming these are logP-like scales, lower values suggest poor permeability.

**10. Solubility:** Both have negative solubility values (-2.689 and -1.958), again unusual and difficult to interpret. Lower values suggest poor solubility.

**11. hERG:** Both ligands have low hERG inhibition liability (0.307 and 0.173), which is good.

**12. Cl_mic:** Both have similar microsomal clearance values (43.417 and 46.659), suggesting comparable metabolic stability.

**13. t1/2:** Ligand B (21.257) has a slightly longer in vitro half-life than Ligand A (19.728), which is a minor advantage.

**14. Pgp:** Both have very low P-gp efflux liability (0.198 and 0.075), which is excellent, especially for CNS penetration.

**15. Binding Affinity:** Ligand A (-8.7 kcal/mol) has a significantly stronger binding affinity than Ligand B (-7.3 kcal/mol). This is a substantial advantage, as a >1.5 kcal/mol difference can outweigh other drawbacks.

**Overall Assessment:**

Considering the GPCR-specific priorities, Ligand A is the more promising candidate. Its superior binding affinity (-8.7 vs -7.3 kcal/mol) is a major factor. While Ligand B has slightly better BBB penetration, Ligand A compensates with a lower TPSA, lower DILI risk, and comparable logP and Pgp efflux. The unusual Caco-2 and solubility values for both compounds are concerning and would require further investigation, but the strong affinity of Ligand A makes it the better choice for further optimization.

Output:
1
2025-04-17 05:09:21,281 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B based on the provided guidelines, prioritizing GPCR-specific properties (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (373.446 and 353.463 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (72.91) is significantly better than Ligand B (96.53). For CNS targets, TPSA should be <= 90, and A is comfortably within this range, while B is close to the upper limit.

**logP:** Both ligands have similar and optimal logP values (1.645 and 1.57), falling within the 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A (0 HBD, 5 HBA) is slightly better than Ligand B (3 HBD, 4 HBA). Both are within acceptable limits, but fewer HBDs generally improve permeability.

**QED:** Both ligands have reasonable QED scores (0.758 and 0.519), indicating good drug-like properties.

**DILI:** Ligand A (53.625) has a higher DILI risk than Ligand B (24.544). This is a drawback for Ligand A.

**BBB:** Both ligands have excellent BBB penetration (83.56% and 80.419%), exceeding the desirable >70% threshold for CNS targets.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.237 and -4.733), which is unusual and suggests poor permeability. However, these values are on a scale where negative values are possible, and direct comparison is difficult without knowing the scale's specifics.

**Aqueous Solubility:** Both ligands have negative solubility values (-1.855 and -2.41), again suggesting poor solubility. Similar to Caco-2, the scale is unclear.

**hERG Inhibition:** Both ligands exhibit low hERG inhibition liability (0.498 and 0.342), which is favorable.

**Microsomal Clearance:** Ligand A (8.174) has significantly lower microsomal clearance than Ligand B (52.188), indicating better metabolic stability.

**In vitro Half-Life:** Ligand A (13.233 hours) has a much longer half-life than Ligand B (-28.96 hours). The negative value for B is concerning and likely indicates very rapid metabolism.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.19 and 0.066), which is good for CNS exposure.

**Binding Affinity:** Ligand B (-7.4 kcal/mol) has a slightly better binding affinity than Ligand A (-7.0 kcal/mol), although the difference is small (0.4 kcal/mol).

**Overall Assessment:**

Ligand A excels in TPSA, metabolic stability (Cl_mic, t1/2), and has a lower DILI risk. Ligand B has a slightly better binding affinity, but suffers from a significantly higher DILI risk, very poor in vitro half-life, and higher microsomal clearance. Given the importance of BBB penetration for CNS targets (which both fulfill), and the need for metabolic stability, Ligand A appears to be the more promising candidate. The slightly better affinity of Ligand B is unlikely to outweigh the substantial ADME deficiencies.

Output:
1
2025-04-17 05:09:21,282 - INFO - Okay, let's analyze these two ligands for their potential as DRD2 drug candidates. DRD2 is a GPCR in the CNS, so BBB penetration, logP, Pgp efflux, TPSA, and binding affinity are paramount.

**Ligand A: [337.379, 86.45, 2.59, 1, 5, 0.926, 50.33, 46.84, -4.57, -3.398, 0.718, -5.222, 3.005, 0.165, -8.9]**
**Ligand B: [341.455, 73.99, 2.763, 3, 2, 0.636, 26.173, 65.374, -5.171, -3.13, 0.312, 23.075, -20.267, 0.12, -8.6]**

Here's a breakdown of each property:

1. **MW:** Both ligands are within the ideal range (200-500 Da).
2. **TPSA:** Ligand A (86.45) is slightly higher than ideal for CNS targets (<90), but acceptable. Ligand B (73.99) is excellent, well below the threshold.
3. **logP:** Both ligands have good logP values (2.59 & 2.763), falling within the optimal 1-3 range.
4. **HBD:** Ligand A (1) is preferable to Ligand B (3). Lower HBD generally improves permeability.
5. **HBA:** Ligand A (5) is preferable to Ligand B (2). Lower HBA generally improves permeability.
6. **QED:** Ligand A (0.926) has a significantly better QED score than Ligand B (0.636), indicating a more drug-like profile.
7. **DILI:** Ligand A (50.33) has a higher DILI risk than Ligand B (26.173). This is a negative for Ligand A.
8. **BBB:** Ligand B (65.374) has a much better BBB percentile than Ligand A (46.84). This is a *major* advantage for Ligand B, given the CNS target.
9. **Caco-2:** Ligand A (-4.57) has a worse Caco-2 permeability than Ligand B (-5.171). Lower values are less desirable.
10. **Solubility:** Both have poor solubility (-3.398 and -3.13). This is a concern for both, but not a deciding factor.
11. **hERG:** Both ligands have low hERG risk (0.718 and 0.312).
12. **Cl_mic:** Ligand A (-5.222) has a lower (better) microsomal clearance than Ligand B (23.075), suggesting better metabolic stability.
13. **t1/2:** Ligand B (-20.267) has a much longer in vitro half-life than Ligand A (3.005). This is a significant advantage for Ligand B.
14. **Pgp:** Both ligands have low Pgp efflux liability (0.165 and 0.12).
15. **Binding Affinity:** Both ligands have very similar, strong binding affinities (-8.9 and -8.6 kcal/mol). The difference is not substantial enough to override other factors.

**Overall Assessment:**

While Ligand A has a better QED and metabolic stability (lower Cl_mic), Ligand B is significantly better in terms of BBB penetration, half-life, and DILI risk. The superior BBB penetration is *critical* for a CNS target like DRD2. The longer half-life is also a major benefit. The slightly lower QED and higher DILI risk of Ligand B are less concerning than the poor BBB penetration of Ligand A.

Output:
1
2025-04-17 05:09:21,282 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (344.455 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (60.85) is slightly higher than Ligand B (58.64), but both are well below the 90 Angstroms threshold desirable for CNS targets.

**3. logP:** Ligand A (1.424) is within the optimal range (1-3), while Ligand B (2.527) is closer to the upper end. Both are acceptable, but A is slightly preferred.

**4. H-Bond Donors:** Both ligands have 1 HBD, which is within the acceptable limit of <=5.

**5. H-Bond Acceptors:** Both ligands have 3 HBA, which is within the acceptable limit of <=10.

**6. QED:** Ligand B (0.863) has a higher QED score than Ligand A (0.606), indicating a more drug-like profile.

**7. DILI:** Ligand A (8.414%) has a significantly lower DILI risk than Ligand B (31.563%). This is a substantial advantage for Ligand A.

**8. BBB:** Ligand B (78.751%) has a better BBB penetration score than Ligand A (61.109%). This is a critical factor for a CNS target like DRD2, favoring Ligand B.

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 values, which is unusual and suggests poor permeability. Ligand A (-4.638) is slightly worse than Ligand B (-4.587).

**10. Aqueous Solubility:** Both ligands have negative solubility values, indicating poor aqueous solubility. Ligand A (-2.341) is slightly better than Ligand B (-2.882).

**11. hERG Inhibition:** Ligand A (0.31) has a lower hERG inhibition liability than Ligand B (0.549), which is preferable.

**12. Microsomal Clearance:** Ligand B (49.696) has a lower microsomal clearance than Ligand A (16.939), suggesting better metabolic stability. This favors Ligand B.

**13. In vitro Half-Life:** Ligand B (-21.029) has a significantly longer in vitro half-life than Ligand A (-3.825), which is a major advantage.

**14. P-gp Efflux:** Ligand A (0.091) has lower P-gp efflux liability than Ligand B (0.429), which is beneficial for CNS penetration.

**15. Binding Affinity:** Ligand B (-9.2 kcal/mol) has a stronger binding affinity than Ligand A (-7.9 kcal/mol). This is a significant advantage, potentially outweighing some ADME drawbacks. The difference of 1.3 kcal/mol is substantial.

**Overall Assessment:**

Ligand B has a superior binding affinity, better BBB penetration, improved metabolic stability (lower Cl_mic, longer t1/2), and a higher QED score. While Ligand A has a lower DILI risk and P-gp efflux, the difference in affinity and BBB penetration for a CNS target like DRD2 are more critical. The negative Caco-2 and solubility values are concerning for both, but can potentially be addressed with formulation strategies. The stronger binding affinity of Ligand B is likely to translate to greater efficacy.

Output:
1
2025-04-17 05:09:21,282 - INFO - Reasoning:

Let's analyze Ligand A and Ligand B against the provided guidelines, prioritizing GPCR-specific properties (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (348.403 and 353.463 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (116.48) is slightly above the optimal <90 for CNS targets, while Ligand B (111.45) is closer but still above. This is a minor concern for both.

**logP:** Ligand A (-0.637) is quite low, potentially hindering permeation. Ligand B (1.115) is within the optimal 1-3 range. This is a significant advantage for Ligand B.

**H-Bond Donors/Acceptors:** Ligand A has 4 HBD and 6 HBA, which are acceptable. Ligand B has 3 HBD and 5 HBA, also acceptable.

**QED:** Both ligands have reasonable QED values (0.489 and 0.545), indicating decent drug-likeness.

**DILI:** Ligand A (54.634) has a moderate DILI risk, while Ligand B (7.794) has a very low risk. This is a substantial advantage for Ligand B.

**BBB:** Ligand A (28.383) has a poor BBB percentile, making CNS penetration unlikely. Ligand B (66.615) has a much better BBB percentile, increasing the likelihood of CNS exposure. This is a critical advantage for Ligand B, given the target is DRD2.

**Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and suggests poor permeability. However, the scale isn't specified, so it's hard to interpret.

**Aqueous Solubility:** Both have negative solubility values, also unusual and suggesting poor solubility.

**hERG:** Both ligands have low hERG inhibition liability (0.125 and 0.25), which is good.

**Microsomal Clearance:** Ligand A (-3.242) has a negative clearance, which is not physically possible and likely an error. Ligand B (32.51) has a moderate clearance.

**In vitro Half-Life:** Ligand A (30.721) has a reasonable half-life, while Ligand B (-19.911) has a negative half-life, which is not physically possible and likely an error.

**P-gp Efflux:** Both have low P-gp efflux liability (0.026 and 0.004), which is favorable for CNS penetration.

**Binding Affinity:** Ligand B (-7.1 kcal/mol) has a slightly better binding affinity than Ligand A (-8.5 kcal/mol). While A is better, the difference is not substantial enough to overcome the other significant drawbacks.

**Overall Assessment:**

Ligand B is significantly more promising. It has a better logP, a much lower DILI risk, and a substantially higher BBB percentile. While both have issues with Caco-2 and solubility, the BBB is paramount for a CNS target like DRD2. The negative values for clearance and half-life for Ligand B are concerning and likely errors in the data, but even discounting those, Ligand B is superior. Ligand A's low logP and poor BBB make it a less viable candidate.

Output:
1
2025-04-17 05:09:21,282 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (349.431 and 338.411 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (86.88) is better than Ligand B (66.71). Both are below the 90 A^2 threshold desirable for CNS targets.

**logP:** Ligand A (1.28) and Ligand B (1.855) are both within the optimal 1-3 range.

**H-Bond Donors:** Both ligands have 1 HBD, which is acceptable.

**H-Bond Acceptors:** Ligand A has 5 HBA, and Ligand B has 4. Both are below the 10 threshold.

**QED:** Both ligands have good QED scores (0.836 and 0.925), indicating good drug-like properties.

**DILI:** Ligand A (29.159) has a significantly lower DILI risk than Ligand B (54.634). This is a substantial advantage.

**BBB:** Ligand B (73.013) has a much better BBB penetration score than Ligand A (56.029). This is a critical factor for a CNS target like DRD2.

**Caco-2 Permeability:** Ligand A (-4.834) has worse Caco-2 permeability than Ligand B (-5.071). Both are quite poor.

**Aqueous Solubility:** Ligand A (-1.182) has better aqueous solubility than Ligand B (-2.959).

**hERG:** Ligand A (0.144) has a lower hERG risk than Ligand B (0.428).

**Microsomal Clearance:** Ligand B (21.429) has lower microsomal clearance than Ligand A (27.533), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (14.31) has a longer in vitro half-life than Ligand B (-4.049).

**P-gp Efflux:** Ligand A (0.071) has lower P-gp efflux than Ligand B (0.073), which is slightly better.

**Binding Affinity:** Ligand B (-8.6) has a slightly stronger binding affinity than Ligand A (-9.0). However, the difference is small, and Ligand A is already at a very strong binding affinity.

**Overall Assessment:**

Ligand B excels in BBB penetration and has slightly better affinity and metabolic stability. However, Ligand A has a significantly lower DILI risk, better solubility and a longer half-life. Given the importance of minimizing toxicity (DILI) and the need for reasonable solubility for formulation, and the already excellent binding affinity of Ligand A, I favor Ligand A. The difference in BBB is concerning, but not insurmountable with further optimization.

Output:
1
2025-04-17 05:09:21,283 - INFO - Batch 174 complete. Total preferences: 2784
2025-04-17 05:09:21,283 - INFO - Processing batch 175/512...
2025-04-17 05:10:02,738 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight (MW):** Both ligands are within the ideal range (200-500 Da). Ligand A (355.523) is slightly lower, which could be beneficial for permeability.

**2. TPSA:** Both ligands have TPSA values around 60-61, well below the 90 A^2 threshold for CNS targets. This is excellent for brain penetration.

**3. logP:** Ligand A (1.887) is optimal, while Ligand B (3.436) is towards the higher end of the optimal range. Both are acceptable, but A is slightly preferred.

**4. H-Bond Donors (HBD):** Both are within the acceptable limit of <=5. Ligand A has 1 HBD, and Ligand B has 0.

**5. H-Bond Acceptors (HBA):** Both are within the acceptable limit of <=10. Ligand A has 4 HBA, and Ligand B has 6.

**6. QED:** Both have similar QED values (0.65 and 0.664), indicating good drug-likeness.

**7. DILI:** Ligand A (5.467) has a significantly lower DILI risk than Ligand B (55.448). This is a major advantage for Ligand A.

**8. BBB:** Ligand A (81.233) has a noticeably better BBB penetration percentile than Ligand B (73.362). This is crucial for a CNS target like DRD2.

**9. Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and suggests poor permeability. However, the scale is not specified, so it's difficult to interpret.

**10. Aqueous Solubility:** Both have negative solubility values, indicating poor solubility. This is a concern, but can sometimes be overcome with formulation strategies.

**11. hERG Inhibition:** Both ligands have low hERG inhibition risk (0.481 and 0.43).

**12. Microsomal Clearance:** Ligand B (74.576) has a much higher microsomal clearance than Ligand A (19.897), indicating faster metabolism and potentially lower exposure.

**13. In vitro Half-Life:** Ligand B (60.669) has a significantly longer half-life than Ligand A (-3.95). This is a positive for Ligand B, but the negative value is concerning.

**14. P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.025 and 0.747).

**15. Binding Affinity:** Ligand A (-6.8 kcal/mol) has a slightly better binding affinity than Ligand B (-6.3 kcal/mol). While the difference is not huge, it's still a factor.

**Overall Assessment:**

Ligand A is the stronger candidate. It has a lower DILI risk, better BBB penetration, a slightly better binding affinity, and lower microsomal clearance (meaning better metabolic stability). While both have poor solubility and Caco-2 permeability, the advantages of Ligand A in terms of safety (DILI) and CNS penetration (BBB) are critical for a DRD2 target. The longer half-life of Ligand B is a potential benefit, but the negative value is concerning.

Output:
0
2025-04-17 05:10:02,738 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (351.535 and 349.391 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (52.65) is excellent, well below the 90 A^2 threshold for CNS targets. Ligand B (115.3) is higher, but still potentially acceptable, though less optimal.

**3. logP:** Ligand A (2.22) is within the optimal range of 1-3. Ligand B (0.817) is slightly below 1, which *could* indicate permeability issues, but isn't a dealbreaker.

**4. H-Bond Donors:** Ligand A (1) and Ligand B (2) are both within the acceptable limit of <=5.

**5. H-Bond Acceptors:** Ligand A (3) is well within the limit of <=10. Ligand B (8) is also acceptable, but approaching the upper limit.

**6. QED:** Both ligands have similar QED values (0.693 and 0.644), indicating good drug-like properties.

**7. DILI:** Ligand A (5.428) has a significantly lower DILI risk than Ligand B (61.07). This is a substantial advantage for Ligand A.

**8. BBB:** Ligand A (85.033) has a much higher BBB penetration percentile than Ligand B (52.423). This is *critical* for a CNS target like DRD2.

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.794 and -4.951), which is unusual and suggests poor permeability. However, these values are on a log scale and can be misleading; we'll consider them less heavily.

**10. Aqueous Solubility:** Both ligands have negative solubility values (-2.11 and -2.181), also on a log scale, suggesting poor solubility. This is a concern, but formulation strategies can sometimes mitigate this.

**11. hERG Inhibition:** Ligand A (0.719) has a slightly higher hERG risk than Ligand B (0.152). However, both are relatively low.

**12. Microsomal Clearance:** Ligand A (31.9) has a higher microsomal clearance than Ligand B (26.108), indicating lower metabolic stability.

**13. In vitro Half-Life:** Ligand B (19.901) has a longer in vitro half-life than Ligand A (0.377). This is a positive for Ligand B.

**14. P-gp Efflux:** Ligand A (0.076) has lower P-gp efflux liability than Ligand B (0.07). This is a slight advantage for Ligand A.

**15. Binding Affinity:** Ligand B (-7.8 kcal/mol) has a significantly stronger binding affinity than Ligand A (-6.8 kcal/mol). This is a 1.0 kcal/mol difference, which is substantial and can outweigh some ADME drawbacks.

**Overall Assessment:**

While Ligand B has a superior binding affinity and better metabolic stability (longer half-life), Ligand A is significantly better in terms of predicted safety (DILI) and, crucially, BBB penetration. For a CNS target like DRD2, BBB penetration is paramount. The lower DILI risk is also a significant advantage. The slightly lower affinity of Ligand A is a concern, but could potentially be addressed through further optimization. The logP of Ligand B is a slight concern.

Output:
0
2025-04-17 05:10:02,738 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (375.782 Da) is slightly higher than Ligand B (344.423 Da), but both are acceptable.

**TPSA:** Ligand A (81.84) is excellent for CNS penetration, falling well below the 90 A^2 threshold. Ligand B (118.01) is higher, but still potentially acceptable, though less ideal.

**logP:** Ligand A (3.902) is at the upper end of the optimal range (1-3), but still acceptable. Ligand B (0.36) is quite low, potentially hindering membrane permeability and CNS penetration.

**H-Bond Donors/Acceptors:** Both ligands have reasonable HBD (3) and HBA (Ligand A: 3, Ligand B: 9) counts, generally within acceptable limits. Ligand B's HBA is higher, which could slightly impact permeability.

**QED:** Both ligands have good QED scores (Ligand A: 0.578, Ligand B: 0.687), indicating good drug-like properties.

**DILI:** Ligand A (75.649) has a higher DILI risk than Ligand B (58.705), but both are below the concerning threshold of 60.

**BBB:** Ligand A (64.25) has a moderate BBB penetration, while Ligand B (58.123) is also moderate. Both are below the desirable >70 for CNS targets, but Ligand A is better.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.108 and -5.639), which is unusual and suggests poor permeability. This is a significant concern for both.

**Aqueous Solubility:** Both ligands have negative solubility values (-4.899 and -2.161), indicating very poor aqueous solubility. This is a major drawback for both compounds.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (Ligand A: 0.569, Ligand B: 0.458), which is positive.

**Microsomal Clearance:** Ligand A (22.813 mL/min/kg) has higher clearance than Ligand B (16.42 mL/min/kg), meaning Ligand B is more metabolically stable.

**In vitro Half-Life:** Ligand A (22.752 hours) has a longer half-life than Ligand B (2.819 hours), which is a significant advantage.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (Ligand A: 0.315, Ligand B: 0.008), which is good for CNS exposure. Ligand B is slightly better.

**Binding Affinity:** Ligand A (-9.2 kcal/mol) has significantly better binding affinity than Ligand B (-8.7 kcal/mol). This 0.5 kcal/mol difference is substantial and can outweigh some ADME drawbacks.

**Overall Assessment:**

Despite both ligands having significant drawbacks (poor solubility and permeability), Ligand A is the more promising candidate. Its superior binding affinity (-9.2 vs -8.7 kcal/mol) is a critical advantage for a GPCR target. While Ligand B has slightly better metabolic stability and P-gp efflux, the substantial difference in binding affinity, combined with a better TPSA and acceptable (though not ideal) BBB, makes Ligand A the preferred choice. The poor solubility and permeability would need to be addressed through formulation or further chemical modifications, but the potency advantage of Ligand A provides a stronger starting point.

Output:
1
2025-04-17 05:10:02,739 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (373.469 and 371.821 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (62.3) is excellent, well below the 90 A^2 threshold for CNS targets. Ligand B (120.52) is higher, but still potentially acceptable, though less ideal.

**logP:** Ligand A (2.864) is optimal (1-3). Ligand B (0.218) is quite low, which could hinder membrane permeability and CNS penetration.

**H-Bond Donors/Acceptors:** Ligand A (HBD=1, HBA=4) is favorable. Ligand B (HBD=4, HBA=5) is also reasonable, but slightly higher.

**QED:** Ligand A (0.762) is good, indicating strong drug-likeness. Ligand B (0.365) is below the 0.5 threshold, suggesting a less drug-like profile.

**DILI:** Both ligands have similar DILI risk (37.805 and 38.736), both being acceptable (<40).

**BBB:** Ligand A (73.245) has a good BBB percentile, exceeding the 70% threshold for CNS targets. Ligand B (30.554) is significantly lower, indicating poor predicted brain penetration. This is a major drawback for a DRD2 ligand.

**Caco-2 Permeability:** Ligand A (-4.614) is poor, indicating low intestinal absorption. Ligand B (-5.602) is even worse.

**Aqueous Solubility:** Both ligands have negative solubility values (-2.883 and -2.156), which is unusual and suggests poor solubility. This could be a formulation challenge.

**hERG Inhibition:** Both ligands have low hERG risk (0.378 and 0.101).

**Microsomal Clearance:** Ligand A (28.802) has moderate clearance. Ligand B (-1.747) has very low clearance, suggesting high metabolic stability, which is a positive.

**In vitro Half-Life:** Ligand A (-10.455) has a negative half-life, which doesn't make sense and indicates an issue with the prediction. Ligand B (21.067) is reasonable.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.099 and 0.032), which is good for CNS penetration.

**Binding Affinity:** Ligand B (-7.9 kcal/mol) has a slightly better binding affinity than Ligand A (-8.1 kcal/mol). However, the difference is small and may not be enough to overcome the other significant drawbacks of Ligand B.

**Overall Assessment:**

Ligand A is superior despite the poor Caco-2 permeability and questionable half-life. Its excellent TPSA, optimal logP, good QED, and crucially, its good BBB penetration make it a much more promising candidate for a CNS-targeting DRD2 ligand. Ligand B's low logP and very poor BBB penetration are major liabilities, even with its slightly better affinity and improved metabolic stability. The negative half-life prediction for Ligand A is concerning, but the other factors outweigh this issue.

Output:
1
2025-04-17 05:10:02,739 - INFO - Reasoning:

Let's analyze Ligand A and Ligand B based on the provided guidelines, prioritizing GPCR-specific properties (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (345.378 Da) is slightly lower, which could be beneficial for permeability.

**TPSA:** Both ligands have TPSA values below the 90 A^2 threshold desirable for CNS targets. Ligand B (77.24 A^2) is lower than Ligand A (90.98 A^2), making it slightly more favorable for brain penetration.

**logP:** Ligand A (1.286) is within the optimal range (1-3), while Ligand B (4.224) is a bit high. A logP > 4 can lead to solubility issues and off-target interactions. This favors Ligand A.

**H-Bond Donors & Acceptors:** Both have acceptable HBD (2) and HBA (4 & 5) counts, falling within the recommended limits.

**QED:** Both ligands have QED values above 0.5, indicating good drug-like properties.

**DILI:** Ligand A (50.446) has a lower DILI risk than Ligand B (60.915), which is preferable.

**BBB:** This is a critical parameter for CNS targets. Ligand A has a significantly higher BBB percentile (72.896) than Ligand B (54.983). This is a major advantage for Ligand A.

**Caco-2 Permeability:** Both have negative values, which is unusual. However, the magnitude of the negative value for Ligand A (-5.024) is smaller than that for Ligand B (-4.954), suggesting slightly better permeability for A.

**Aqueous Solubility:** Both have negative values, indicating poor solubility. Ligand B (-4.333) is slightly better than Ligand A (-2.801), but both are concerning.

**hERG Inhibition:** Both ligands have low hERG inhibition liability (0.679 and 0.433), which is good.

**Microsomal Clearance:** Ligand A (-5.994) has a much lower (better) microsomal clearance than Ligand B (54.92). This suggests greater metabolic stability for Ligand A.

**In vitro Half-Life:** Ligand A (-25.231) has a much longer half-life than Ligand B (22.225), which is desirable.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.018 and 0.486), which is favorable for CNS penetration. Ligand A is slightly better.

**Binding Affinity:** Ligand B (-8.1 kcal/mol) has a slightly better binding affinity than Ligand A (-9.0 kcal/mol). While affinity is important, the difference here is not substantial enough to outweigh the significant ADME advantages of Ligand A.

**Overall:**

Ligand A is significantly better overall, particularly regarding BBB penetration, metabolic stability (lower Cl_mic, longer t1/2), and DILI risk. While Ligand B has slightly better binding affinity and solubility, the ADME properties of Ligand A are far more favorable for a CNS-targeting drug, especially considering it's a GPCR. The higher logP of Ligand B is also a concern.

Output:
0
2025-04-17 05:10:02,739 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (339.439 and 362.451 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Both ligands (71.09 and 69.68) are below the 90 A^2 threshold for CNS targets, which is excellent.

**3. logP:** Ligand A (2.064) is optimal, while Ligand B (3.703) is approaching the upper limit of the optimal range.

**4. H-Bond Donors:** Ligand A (2) and Ligand B (1) are both within the acceptable limit of <=5.

**5. H-Bond Acceptors:** Ligand A (3) and Ligand B (6) are both within the acceptable limit of <=10.

**6. QED:** Both ligands have good QED scores (0.78 and 0.878), indicating drug-like properties.

**7. DILI:** Ligand A (46.879) has a significantly lower DILI risk than Ligand B (85.227). This is a major advantage for Ligand A.

**8. BBB:** Both ligands have reasonably good BBB penetration (63.086 and 67.468), but neither exceeds the desirable >70% threshold.

**9. Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and suggests poor permeability. This is a concern for both.

**10. Aqueous Solubility:** Both have negative solubility values, indicating poor solubility. This is a concern for both.

**11. hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.263 and 0.347).

**12. Microsomal Clearance:** Ligand A (57.766) has higher microsomal clearance than Ligand B (49.816), suggesting lower metabolic stability.

**13. In vitro Half-Life:** Ligand A (-22.391) has a significantly shorter in vitro half-life than Ligand B (-14.932). This is a disadvantage for Ligand A.

**14. P-gp Efflux:** Both ligands have low P-gp efflux liability (0.165 and 0.186), which is good for CNS penetration.

**15. Binding Affinity:** Ligand B (-9.0 kcal/mol) has a slightly better binding affinity than Ligand A (-8.8 kcal/mol). While the difference isn't huge, it's a positive for Ligand B.

**Overall Assessment:**

Ligand A has a much better safety profile (lower DILI) and a more optimal logP. However, it suffers from higher metabolic clearance and a shorter half-life. Ligand B has a slightly better binding affinity and a longer half-life, but a significantly higher DILI risk. Given the importance of minimizing toxicity for CNS drugs, and the relatively small difference in binding affinity, the lower DILI risk of Ligand A is a critical advantage. The poor Caco-2 and solubility for both are concerning, but can potentially be addressed through formulation strategies.

Output:
0
2025-04-17 05:10:02,739 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (342.53 and 346.39 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (23.55) is excellent, well below the 90 A^2 threshold for CNS targets. Ligand B (123.21) is higher, but still within an acceptable range, though less favorable.

**logP:** Ligand A (4.423) is slightly high, potentially leading to solubility issues or off-target interactions. Ligand B (-1.105) is quite low, which could hinder membrane permeability and CNS penetration.

**H-Bond Donors/Acceptors:** Ligand A (0 HBD, 2 HBA) is optimal. Ligand B (2 HBD, 6 HBA) is acceptable, but higher numbers can sometimes impact permeability.

**QED:** Both ligands have similar QED values (0.79 and 0.648), indicating good drug-like properties.

**DILI:** Ligand A (20.32) has a significantly lower DILI risk than Ligand B (30.83), which is a major advantage.

**BBB:** Ligand A (92.90) has excellent BBB penetration, crucial for a CNS target like DRD2. Ligand B (54.71) is considerably lower, raising concerns about reaching the target in the brain.

**Caco-2 Permeability:** Ligand A (-4.606) has poor Caco-2 permeability. Ligand B (-5.908) is also poor.

**Aqueous Solubility:** Ligand A (-3.739) has poor aqueous solubility. Ligand B (-1.373) is also poor.

**hERG Inhibition:** Ligand A (0.915) has a low risk of hERG inhibition. Ligand B (0.041) has a very low risk of hERG inhibition.

**Microsomal Clearance:** Ligand A (69.06) has moderate microsomal clearance. Ligand B (-20.794) has negative clearance, which is not possible and indicates a data error or unusual behavior.

**In vitro Half-Life:** Ligand A (17.042) has a reasonable half-life. Ligand B (-2.619) has a negative half-life, which is not possible and indicates a data error or unusual behavior.

**P-gp Efflux:** Both ligands show low P-gp efflux (0.808 and 0.006), which is favorable for CNS penetration.

**Binding Affinity:** Ligand B (-8.2 kcal/mol) has a significantly stronger binding affinity than Ligand A (-0.0 kcal/mol). This is a substantial advantage.

**Overall Assessment:**

Despite Ligand A's excellent TPSA and BBB penetration, its poor Caco-2 permeability, aqueous solubility, and very weak binding affinity are major drawbacks. Ligand B has a much stronger binding affinity, which is a critical factor for GPCR ligands. However, its low logP and lower BBB penetration are concerns. The negative values for clearance and half-life for Ligand B are concerning and suggest data issues.

Considering the priorities for GPCRs, the strong binding affinity of Ligand B outweighs its lower BBB penetration and logP, *assuming the negative clearance and half-life values are errors*. The DILI risk is higher for Ligand B, but the difference isn't drastic.

Output:
1
2025-04-17 05:10:02,739 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (362.495 and 351.466 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (67.43) is higher than Ligand B (47.36). For CNS targets, we want TPSA <= 90, both are within this range, but B is better.

**logP:** Both ligands have good logP values (2.85 and 3.353), falling within the optimal 1-3 range.

**H-Bond Donors:** Ligand A has 2 HBD, and Ligand B has 0. Both are acceptable (<=5).

**H-Bond Acceptors:** Both ligands have 4 HBA, which is within the acceptable range (<=10).

**QED:** Both ligands have reasonable QED scores (0.795 and 0.607), indicating good drug-like properties.

**DILI:** Ligand A (61.807) has a higher DILI risk than Ligand B (31.524). Lower is better, so B is preferable.

**BBB:** Ligand B (94.804) has a significantly higher BBB penetration percentile than Ligand A (70.531). This is a crucial advantage for a CNS target like DRD2.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.051 and -4.053). This is unusual and suggests poor permeability. However, these values are on a log scale, so the absolute difference is important. -4.053 is better than -5.051.

**Aqueous Solubility:** Both ligands have negative solubility values (-3.607 and -3.419). This is also concerning, indicating poor solubility. -3.419 is slightly better.

**hERG Inhibition:** Ligand A (0.197) has a slightly lower hERG inhibition risk than Ligand B (0.778), which is preferable.

**Microsomal Clearance:** Ligand B (80.583) has a higher microsomal clearance than Ligand A (50.661), suggesting lower metabolic stability. A is preferable.

**In vitro Half-Life:** Ligand A (45.935) has a longer in vitro half-life than Ligand B (20.908), which is desirable.

**P-gp Efflux:** Ligand A (0.355) has lower P-gp efflux than Ligand B (0.46), which is better for CNS exposure.

**Binding Affinity:** Ligand A (-9.6 kcal/mol) has a significantly stronger binding affinity than Ligand B (-6.6 kcal/mol). This is a substantial advantage, potentially outweighing some of the ADME drawbacks. A difference of 3 kcal/mol is significant.

**Overall Assessment:**

While Ligand B excels in BBB penetration and has a lower DILI risk, Ligand A's significantly stronger binding affinity (-9.6 vs -6.6 kcal/mol) is a major advantage. The improved half-life, lower P-gp efflux, and lower clearance of Ligand A also contribute to its favorability. The solubility and permeability issues are concerning for both, but the potency advantage of A is likely to be more impactful in driving efficacy. Given the GPCR-specific priorities, the strong affinity of Ligand A is the deciding factor.

Output:
1
2025-04-17 05:10:02,740 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (362.352 and 360.885 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (76.46) is better than Ligand B (64.35). Both are below the 90 A^2 threshold desirable for CNS targets, but A is closer to the upper limit.

**logP:** Ligand A (0.735) is suboptimal, being slightly below the 1-3 range. Ligand B (4.765) is significantly high, potentially leading to solubility issues and off-target interactions.

**H-Bond Donors/Acceptors:** Ligand A (HBD=1, HBA=5) is preferable to Ligand B (HBD=2, HBA=3) as it's closer to the ideal ranges.

**QED:** Ligand A (0.838) has a significantly better QED score than Ligand B (0.677), indicating a more drug-like profile.

**DILI:** Ligand A (38.62) has a lower DILI risk than Ligand B (47.732), both are acceptable but A is better.

**BBB:** Ligand A (88.096) has a much higher BBB penetration percentile than Ligand B (69.523). This is a *critical* advantage for a CNS target like DRD2.

**Caco-2 Permeability:** Ligand A (-4.668) and Ligand B (-5.056) both have negative values, indicating poor permeability.

**Aqueous Solubility:** Ligand A (-1.099) is better than Ligand B (-4.701), indicating better solubility.

**hERG Inhibition:** Ligand A (0.098) has a much lower hERG inhibition liability than Ligand B (0.797), which is a significant safety advantage.

**Microsomal Clearance:** Ligand A (2.357) has a much lower microsomal clearance than Ligand B (59.053), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (6.828) has a shorter half-life than Ligand B (76.9), but this is less critical than metabolic stability.

**P-gp Efflux:** Ligand A (0.06) shows much lower P-gp efflux liability than Ligand B (0.565), which is crucial for CNS penetration.

**Binding Affinity:** Ligand B (-8.9 kcal/mol) has a slightly better binding affinity than Ligand A (-7.9 kcal/mol), a 1.0 kcal/mol difference. While affinity is important, the other ADME properties of Ligand A are far superior.

**Conclusion:**

Despite the slightly better binding affinity of Ligand B, Ligand A is the far more promising drug candidate. Its superior BBB penetration, lower logP, better solubility, lower hERG risk, lower DILI, lower P-gp efflux, and better metabolic stability outweigh the small difference in binding affinity. For a CNS GPCR target, optimizing for brain penetration and safety is paramount, and Ligand A excels in these areas.

Output:
0
2025-04-17 05:10:02,740 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (350.415 Da) is slightly lower, which is generally favorable for permeability. Ligand B (364.873 Da) is also good.

**TPSA:** Ligand A (96.89) is better than Ligand B (58.73) as it is closer to the ideal range for CNS targets (<=90). Ligand B is still acceptable.

**logP:** Ligand A (0.392) is quite low, potentially hindering membrane permeability. Ligand B (4.539) is high, potentially causing solubility issues and off-target effects. This is a significant drawback for Ligand B.

**H-Bond Donors/Acceptors:** Ligand A has 3 HBD and 5 HBA, which are within acceptable limits. Ligand B has 1 HBD and 5 HBA, also acceptable.

**QED:** Both ligands have good QED scores (A: 0.599, B: 0.627), indicating drug-like properties.

**DILI:** Both ligands have relatively low DILI risk (A: 18.108, B: 16.867), which is positive.

**BBB:** Both ligands have moderate BBB penetration (A: 55.332, B: 58.24). Neither is ideal (>70), but this isn't a dealbreaker if other properties are strong.

**Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and suggests poor permeability. This is a concern for both.

**Aqueous Solubility:** Both ligands have very poor aqueous solubility (-1.651 and -4.237). This is a significant issue for both, potentially impacting bioavailability.

**hERG Inhibition:** Ligand A (0.129) has a very low hERG risk, which is excellent. Ligand B (0.808) has a slightly higher risk, but still relatively low.

**Microsomal Clearance:** Ligand A (11.881) has lower clearance, indicating better metabolic stability than Ligand B (85.781).

**In vitro Half-Life:** Ligand A (-5.468) has a negative half-life, which is unusual and suggests rapid metabolism or instability. Ligand B (38.714) has a much better half-life.

**P-gp Efflux:** Ligand A (0.02) has very low P-gp efflux, which is favorable for CNS penetration. Ligand B (0.458) has moderate P-gp efflux.

**Binding Affinity:** Ligand B (-7.0 kcal/mol) has a significantly better binding affinity than Ligand A (-8.5 kcal/mol). This is a substantial advantage.

**Overall Assessment:**

Ligand B has a much stronger binding affinity, which is the most important factor. However, its high logP is a major concern. Ligand A has a better TPSA, lower clearance, and lower P-gp efflux, but its very low logP and negative half-life are problematic. The poor solubility of both is also a concern.

Despite the high logP, the significantly improved binding affinity of Ligand B is likely to outweigh the drawbacks, especially considering the potential for optimization of the logP through structural modifications. The negative half-life of ligand A is a significant red flag.

Output:
1
2025-04-17 05:10:02,740 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (342.399 and 350.459 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (116.29) is higher than the preferred <90 for CNS targets, while Ligand B (59.08) is well within the range. This is a significant advantage for Ligand B.

**logP:** Ligand A (0.329) is quite low, potentially hindering membrane permeability. Ligand B (1.291) is better, falling within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A has 2 HBD and 4 HBA, which are acceptable. Ligand B has 0 HBD and 4 HBA, also acceptable.

**QED:** Ligand A (0.775) has a better QED score than Ligand B (0.489), indicating a more drug-like profile overall.

**DILI:** Ligand A (28.073) has a much lower DILI risk than Ligand B (14.851), which is a substantial advantage.

**BBB:** Ligand B (66.344) has a significantly better BBB penetration score than Ligand A (39.511). This is critical for a CNS target like DRD2.

**Caco-2 Permeability:** Ligand A (-5.327) shows poor Caco-2 permeability, while Ligand B (-4.482) is slightly better, but still not great.

**Aqueous Solubility:** Ligand A (-3.264) and Ligand B (-1.541) both have poor aqueous solubility.

**hERG Inhibition:** Ligand A (0.131) has a lower hERG inhibition risk than Ligand B (0.404).

**Microsomal Clearance:** Ligand A (-12.695) has a much lower (better) microsomal clearance than Ligand B (27.458), indicating greater metabolic stability.

**In vitro Half-Life:** Ligand B (9.716) has a significantly longer in vitro half-life than Ligand A (-5.48).

**P-gp Efflux:** Ligand A (0.007) has a much lower P-gp efflux liability than Ligand B (0.094), which is beneficial for CNS penetration.

**Binding Affinity:** Ligand B (-7.2 kcal/mol) has a slightly better binding affinity than Ligand A (-8.4 kcal/mol). While A is better, the difference is not substantial enough to outweigh other factors.

**Overall Assessment:**

Ligand B excels in BBB penetration and has a longer half-life, both crucial for CNS drug development. Its TPSA is also much more favorable. However, it has a higher DILI risk, worse metabolic stability, and higher P-gp efflux. Ligand A has a better QED, lower DILI, better metabolic stability, and lower P-gp efflux, but suffers from poor BBB penetration and low logP.

Given the GPCR-specific priorities, particularly BBB penetration for a CNS target, and the relatively small difference in binding affinity, **Ligand B is the more promising candidate**. The poor BBB of Ligand A is a major drawback that is difficult to overcome. While the DILI risk is a concern for Ligand B, it might be mitigated through structural modifications.

Output:
1
2025-04-17 05:10:02,740 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (350.459 and 376.85 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (67.87) is higher than Ligand B (32.34). For CNS targets, TPSA should be <= 90, so both are acceptable, but Ligand B is significantly better.

**logP:** Ligand A (1.335) is within the optimal 1-3 range. Ligand B (4.488) is slightly high, potentially leading to solubility issues and off-target interactions.

**H-Bond Donors/Acceptors:** Both ligands have 1 HBD, which is good. Ligand A has 4 HBA, and Ligand B has 2 HBA, both within the acceptable limit of <=10.

**QED:** Both ligands have similar QED values (0.812 and 0.839), indicating good drug-likeness.

**DILI:** Both ligands have similar, low DILI risk (20.9 and 21.171 percentile).

**BBB:** Ligand B (89.492) has a significantly higher BBB penetration percentile than Ligand A (63.164). This is a crucial advantage for a CNS target like DRD2.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.846 and -4.725). This is unusual and suggests poor permeability. However, the values are very similar.

**Aqueous Solubility:** Both ligands have negative solubility values (-1.469 and -5.059). This is also concerning, but again, the values are comparable.

**hERG Inhibition:** Ligand A (0.189) has a lower hERG inhibition liability than Ligand B (0.877), which is preferable.

**Microsomal Clearance:** Ligand A (9.74 mL/min/kg) has a lower microsomal clearance than Ligand B (27.099 mL/min/kg), indicating better metabolic stability.

**In vitro Half-Life:** Ligand A (8.589 hours) has a longer half-life than Ligand B (4.497 hours).

**P-gp Efflux:** Ligand A (0.041) has a much lower P-gp efflux liability than Ligand B (0.359), which is highly desirable for CNS penetration.

**Binding Affinity:** Both ligands have very similar and strong binding affinities (-8.4 and -8.6 kcal/mol). The difference is negligible.

**Overall Assessment:**

Ligand B excels in BBB penetration, a critical factor for CNS drug targets. However, it suffers from higher logP, higher P-gp efflux, and higher microsomal clearance compared to Ligand A. Ligand A has better ADME properties (lower logP, lower P-gp, lower Cl_mic, longer t1/2, lower hERG) and a comparable binding affinity. While both have poor Caco-2 and solubility, the ADME profile of Ligand A is more favorable overall, especially considering the importance of BBB penetration and metabolic stability for a CNS-acting GPCR ligand.

Output:
0
2025-04-17 05:10:02,741 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (351.451 Da) is slightly lower, which is generally favorable for permeability. Ligand B (364.555 Da) is also good.

**TPSA:** Ligand A (84.99) is excellent for CNS penetration, well below the 90 A^2 threshold. Ligand B (49.41) is even better, further enhancing the likelihood of BBB penetration.

**logP:** Ligand A (0.302) is quite low, potentially hindering membrane permeability and reducing binding affinity. Ligand B (3.229) is within the optimal range (1-3), indicating good partitioning properties.

**H-Bond Donors/Acceptors:** Ligand A has 2 HBD and 3 HBA, which are acceptable. Ligand B has 1 HBD and 3 HBA, also acceptable.

**QED:** Both ligands have good QED scores (A: 0.75, B: 0.833), suggesting good drug-like properties.

**DILI:** Ligand A (32.571) has a lower DILI risk than Ligand B (40.054), which is a positive attribute. Both are below the 40% threshold.

**BBB:** Ligand B (74.564) has a significantly higher BBB percentile than Ligand A (60.527). This is a crucial advantage for a CNS target like DRD2.

**Caco-2 Permeability:** Ligand A (-4.713) has poor Caco-2 permeability, which is concerning. Ligand B (-5.078) also has poor Caco-2 permeability, but is comparable to Ligand A.

**Aqueous Solubility:** Both ligands have poor aqueous solubility (-1.629 and -3.896 respectively).

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.325 and 0.421 respectively).

**Microsomal Clearance:** Ligand A (-14.638) has a lower (better) microsomal clearance than Ligand B (87.229), indicating better metabolic stability.

**In vitro Half-Life:** Ligand A (-14.299) has a very short half-life, while Ligand B (-0.389) has a slightly longer half-life.

**P-gp Efflux:** Both have very low P-gp efflux liability (0.009 and 0.345 respectively).

**Binding Affinity:** Ligand A (-8.8 kcal/mol) has a significantly stronger binding affinity than Ligand B (0.0 kcal/mol). This is a major advantage.

**Overall Assessment:**

Despite Ligand A's superior binding affinity, its very low logP and poor Caco-2 permeability are major drawbacks. These properties will likely hinder its ability to reach the target in the brain. Ligand B, while having weaker binding affinity, possesses a much better logP and significantly higher BBB penetration, making it more likely to achieve therapeutic concentrations in the CNS. The better metabolic stability (lower Cl_mic) of Ligand A is a plus, but the affinity difference is substantial enough to potentially overcome that with formulation strategies.

Output:
1
2025-04-17 05:10:02,741 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (364.837 and 364.555 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (115.56) is higher than the preferred <90 for CNS targets, but not drastically so. Ligand B (42.43) is excellent, well below the threshold. This favors Ligand B.

**3. logP:** Ligand A (1.73) is within the optimal 1-3 range. Ligand B (4.361) is slightly above, potentially leading to solubility issues and off-target interactions, but still within a tolerable range.

**4. H-Bond Donors:** Ligand A (4) is acceptable. Ligand B (0) is also good, potentially improving membrane permeability.

**5. H-Bond Acceptors:** Both ligands (4) are within the acceptable limit of 10.

**6. QED:** Both ligands have good QED scores (0.534 and 0.688), indicating drug-like properties. Ligand B is slightly better.

**7. DILI:** Ligand A (67.39) has a higher DILI risk than Ligand B (8.143). This is a significant advantage for Ligand B.

**8. BBB:** Ligand A (15.316) has very poor predicted BBB penetration, a critical drawback for a CNS target. Ligand B (90.539) has excellent BBB penetration, a major advantage.

**9. Caco-2 Permeability:** Ligand A (-5.741) shows poor permeability. Ligand B (-4.492) is better, but still not great.

**10. Aqueous Solubility:** Ligand A (-2.392) has poor solubility. Ligand B (-4.502) is also poor.

**11. hERG Inhibition:** Ligand A (0.113) has a slightly higher hERG risk than Ligand B (0.704).

**12. Microsomal Clearance:** Ligand B (93.933) has much higher microsomal clearance than Ligand A (6.778), suggesting lower metabolic stability. This is a drawback for Ligand B.

**13. In vitro Half-Life:** Ligand B (11.063) has a significantly longer half-life than Ligand A (-0.717). This is a positive for Ligand B.

**14. P-gp Efflux:** Ligand A (0.067) has lower P-gp efflux, which is favorable for CNS penetration. Ligand B (0.1) is slightly higher.

**15. Binding Affinity:** Ligand A (-8.4 kcal/mol) has a significantly stronger binding affinity than Ligand B (-6.6 kcal/mol). This is a substantial advantage for Ligand A, potentially outweighing some of its ADME drawbacks.

**Overall Assessment:**

While Ligand A has superior binding affinity, its extremely poor BBB penetration is a deal-breaker for a CNS target like DRD2. Ligand B, despite its weaker affinity, possesses excellent BBB penetration, a much lower DILI risk, and a longer half-life. The slightly higher logP and clearance are less concerning than the poor BBB of Ligand A. The strong affinity of Ligand A is tempting, but without adequate CNS exposure, it's unlikely to be effective *in vivo*.

Output:
1
2025-04-17 05:10:02,741 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (352.415 and 352.519 Da) fall within the ideal range of 200-500 Da.

**TPSA:** Ligand A (68.29) is slightly above the optimal <90 for CNS targets, but still reasonable. Ligand B (58.64) is well within the desired range.

**logP:** Ligand A (4.274) is a bit high, potentially leading to solubility issues and off-target effects. Ligand B (3.124) is within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Both ligands have 1 HBD, which is good. Ligand A has 5 HBA, acceptable. Ligand B has 3 HBA, also acceptable.

**QED:** Both ligands have similar QED values (0.696 and 0.657), indicating good drug-likeness.

**DILI:** Ligand A has a very high DILI risk (98.759), which is a major red flag. Ligand B has a much lower DILI risk (19.31), which is excellent.

**BBB:** Ligand A's BBB penetration (45.677) is suboptimal for a CNS target. Ligand B has excellent BBB penetration (82.086), a significant advantage.

**Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and difficult to interpret without knowing the scale. However, the magnitude suggests poor permeability for both.

**Aqueous Solubility:** Both have negative solubility values, indicating poor solubility.

**hERG Inhibition:** Both ligands show some hERG inhibition risk (0.42 and 0.583), but these values aren't excessively high.

**Microsomal Clearance:** Ligand A (66.57) and Ligand B (70.729) have similar microsomal clearance values, suggesting comparable metabolic stability.

**In vitro Half-Life:** Ligand B has a slightly longer in vitro half-life (1.294 hours) than Ligand A (-3.201 hours).

**P-gp Efflux:** Ligand A (0.74) shows moderate P-gp efflux, while Ligand B (0.346) shows lower efflux, which is preferable for CNS penetration.

**Binding Affinity:** Ligand A (-9.4 kcal/mol) has a slightly better binding affinity than Ligand B (-8.2 kcal/mol), a difference of 1.2 kcal/mol. While this is a positive for Ligand A, it is likely outweighed by its other significant drawbacks.

**Overall Assessment:**

Ligand A has a superior binding affinity, but its extremely high DILI risk, poor BBB penetration, and moderate P-gp efflux make it a very poor candidate. Ligand B, despite slightly weaker binding, has a much more favorable ADME profile, particularly its excellent BBB penetration, low DILI risk, and lower P-gp efflux. Given the GPCR-specific priorities for CNS targets, Ligand B is the more promising candidate.

Output:
1
2025-04-17 05:10:02,741 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (364.917 Da) is slightly higher than Ligand B (345.399 Da), but both are acceptable.

**TPSA:** Ligand A (40.62) is excellent for CNS penetration, well below the 90 A^2 threshold. Ligand B (91.76) is higher, approaching the upper limit for CNS targets, potentially hindering BBB penetration.

**logP:** Ligand A (3.405) is within the optimal range (1-3). Ligand B (0.497) is quite low, potentially causing permeability issues and reduced binding.

**H-Bond Donors/Acceptors:** Ligand A (0 HBD, 2 HBA) is favorable. Ligand B (2 HBD, 5 HBA) is also acceptable, though slightly higher.

**QED:** Both ligands have good QED scores (A: 0.75, B: 0.811), indicating drug-like properties.

**DILI:** Ligand A (12.524) has a significantly lower DILI risk than Ligand B (55.448), which is a substantial advantage.

**BBB:** Ligand A (91.508) has excellent BBB penetration potential, exceeding the 70% threshold. Ligand B (37.069) is considerably lower, raising concerns about CNS exposure.

**Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and suggests potential issues with the calculation or data quality. However, since both are similarly affected, this is less discriminatory.

**Aqueous Solubility:** Both have negative solubility values, again suggesting potential data quality issues. This is less discriminatory.

**hERG:** Both ligands show low hERG inhibition liability (A: 0.508, B: 0.17), which is good.

**Microsomal Clearance:** Ligand A (44.069) has higher microsomal clearance than Ligand B (19.722), suggesting lower metabolic stability.

**In vitro Half-Life:** Ligand B (5.877 hours) has a longer in vitro half-life than Ligand A (1.184 hours), which is preferable.

**P-gp Efflux:** Ligand A (0.161) shows lower P-gp efflux liability than Ligand B (0.033), which is beneficial for CNS exposure.

**Binding Affinity:** Both ligands have very similar binding affinities (-8.6 kcal/mol and -8.5 kcal/mol). The difference is negligible.

**Conclusion:**

Considering the GPCR-specific priorities, Ligand A is the more promising candidate. It has superior BBB penetration, a much lower DILI risk, and better P-gp efflux properties. While Ligand B has a slightly longer half-life, the significant advantages of Ligand A in BBB, DILI, and P-gp outweigh this benefit. Ligand B's low logP is also a concern.

Output:
0
2025-04-17 05:10:02,742 - INFO - Batch 175 complete. Total preferences: 2800
2025-04-17 05:10:02,742 - INFO - Processing batch 176/512...
2025-04-17 05:10:47,023 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (350.547 and 349.475 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (40.62) is significantly better than Ligand B (71). For a CNS target like DRD2, TPSA should be <= 90, and ideally closer to 60. Ligand A is well within this range, while Ligand B is pushing the upper limit and less favorable.

**3. logP:** Both ligands have good logP values (4.088 and 2.354), falling within the optimal 1-3 range. Ligand A is slightly higher, which could potentially lead to off-target effects, but it's not a major concern.

**4. H-Bond Donors:** Ligand A (0) and Ligand B (1) are both acceptable.

**5. H-Bond Acceptors:** Ligand A (2) and Ligand B (4) are both acceptable.

**6. QED:** Both ligands have similar and good QED values (0.694 and 0.717), indicating good drug-like properties.

**7. DILI:** Ligand A (13.649) has a much lower DILI risk than Ligand B (18.302). This is a significant advantage for Ligand A.

**8. BBB:** Ligand A (95.657) has a significantly higher BBB penetration percentile than Ligand B (73.943). This is *critical* for a CNS target like DRD2.

**9. Caco-2 Permeability:** Both have negative values, which is unusual. Assuming these are logP-like scales, lower values indicate poorer permeability. Ligand A (-4.451) is worse than Ligand B (-4.685), but both are poor.

**10. Aqueous Solubility:** Both have negative values, indicating poor aqueous solubility. Ligand A (-4.058) is slightly better than Ligand B (-2.404).

**11. hERG Inhibition:** Both ligands have low hERG inhibition risk (0.601 and 0.322).

**12. Microsomal Clearance:** Ligand A (84.488) has higher microsomal clearance than Ligand B (45.655), indicating lower metabolic stability. This is a disadvantage for Ligand A.

**13. In vitro Half-Life:** Ligand A (3.452) has a longer half-life than Ligand B (1.811).

**14. P-gp Efflux:** Ligand A (0.391) has lower P-gp efflux than Ligand B (0.076), which is favorable for CNS penetration.

**15. Binding Affinity:** Ligand B (-8.8 kcal/mol) has a significantly stronger binding affinity than Ligand A (-7.3 kcal/mol). This is a substantial advantage for Ligand B. A >1.5 kcal/mol difference in affinity can often outweigh other ADME concerns.

**Overall Assessment:**

While Ligand A excels in BBB penetration, DILI risk, and P-gp efflux, Ligand B's *much* stronger binding affinity (-8.8 vs -7.3 kcal/mol) is a decisive factor. The affinity difference is large enough to compensate for the slightly higher TPSA and lower BBB. The lower metabolic stability of Ligand A is also a concern. Given the GPCR-specific priorities, and the importance of affinity, Ligand B is the more promising candidate.

Output:
1
2025-04-17 05:10:47,024 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (347.463 and 371.88 Da) fall within the ideal 200-500 Da range.

**TPSA:** Both ligands (61.68 and 60.77) are below the 90 A^2 threshold desirable for CNS targets, which is good.

**logP:** Ligand A (1.06) is optimal, while Ligand B (4.047) is approaching the upper limit and could potentially cause solubility issues or off-target interactions.

**H-Bond Donors/Acceptors:** Ligand A (0 HBD, 5 HBA) and Ligand B (2 HBD, 3 HBA) both have reasonable numbers of H-bond donors and acceptors, well within the guidelines.

**QED:** Ligand A (0.82) has a better QED score than Ligand B (0.652), indicating a more drug-like profile.

**DILI:** Ligand A (34.161) has a significantly lower DILI risk than Ligand B (10.237), which is a major advantage.

**BBB:** Ligand A (70.027) has a good BBB penetration percentile, exceeding the 70% threshold for CNS targets. Ligand B (56.34) is significantly lower and less favorable for CNS penetration.

**Caco-2 Permeability:** Both have negative values, which is unusual. Assuming these are logP values, they are very poor, but it is difficult to interpret without knowing the units.

**Aqueous Solubility:** Ligand A (-0.78) has slightly better solubility than Ligand B (-3.611), although both are quite poor.

**hERG:** Ligand A (0.303) has a much lower hERG inhibition liability than Ligand B (0.867), reducing the risk of cardiotoxicity.

**Microsomal Clearance:** Ligand B (84.008) has a much higher microsomal clearance than Ligand A (17.453), indicating lower metabolic stability.

**In vitro Half-Life:** Ligand B (44.684) has a longer half-life than Ligand A (20.28), which is a positive.

**P-gp Efflux:** Ligand A (0.081) has lower P-gp efflux liability than Ligand B (0.472), which is beneficial for CNS exposure.

**Binding Affinity:** Ligand B (-6.8 kcal/mol) has a significantly stronger binding affinity than Ligand A (0.0 kcal/mol). This is a substantial advantage.

**Overall Assessment:**

Ligand B has a much stronger binding affinity, which is a critical factor for GPCR ligands. However, it suffers from higher logP, higher DILI risk, lower BBB penetration, higher hERG inhibition, and higher microsomal clearance. Ligand A has a better overall ADME profile (BBB, DILI, hERG, clearance, Pgp) and a more drug-like QED score, but its binding affinity is very weak.

Given the importance of BBB penetration for a CNS target like DRD2, and the significant differences in DILI and hERG risk, Ligand A is the more promising starting point, despite the weaker affinity. The affinity could be improved through further optimization, while addressing the ADME liabilities of Ligand B might be more challenging.

Output:
0
2025-04-17 05:10:47,024 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B against the provided guidelines, prioritizing GPCR-specific properties (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (373.406 Da) is slightly lower, which could be favorable for permeability, but both are acceptable.

**TPSA:** Ligand A (117.62) is better than Ligand B (76.19) as it is closer to the ideal range for CNS targets (<=90). Ligand B is still acceptable.

**logP:** Ligand A (-0.042) is slightly low, potentially hindering permeation. Ligand B (2.415) is within the optimal range (1-3). This is a significant advantage for Ligand B.

**H-Bond Donors/Acceptors:** Ligand A (3 HBD, 6 HBA) and Ligand B (1 HBD, 6 HBA) both fall within acceptable limits (<=5 HBD and <=10 HBA).

**QED:** Both ligands have reasonable QED values (Ligand A: 0.435, Ligand B: 0.795). Ligand B's score is significantly higher, indicating better overall drug-likeness.

**DILI:** Both ligands have acceptable DILI risk (Ligand A: 71.152, Ligand B: 51.493), though Ligand B is better.

**BBB:** Ligand B (68.05) is better than Ligand A (52.966), but both are below the desirable threshold of >70 for CNS targets. This is a weakness for both, but less so for Ligand B.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.101 and -5.322), which is unusual and suggests poor permeability. This is a significant drawback for both.

**Aqueous Solubility:** Both ligands have negative solubility values (-2.242 and -2.554) which is also unusual and suggests poor solubility. This is a significant drawback for both.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (Ligand A: 0.314, Ligand B: 0.208), which is good.

**Microsomal Clearance:** Ligand A (28.236) has lower clearance than Ligand B (62.065), indicating better metabolic stability.

**In vitro Half-Life:** Ligand A (-49.598) has a negative half-life, which is not possible. Ligand B (42.494) is a more reasonable value.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (Ligand A: 0.062, Ligand B: 0.163), which is favorable for CNS penetration.

**Binding Affinity:** Ligand B (-7.1 kcal/mol) has a significantly stronger binding affinity than Ligand A (-8.3 kcal/mol). This is a crucial advantage, as a >1.5 kcal/mol difference can outweigh other drawbacks.

**Overall Assessment:**

Ligand B is the more promising candidate. While both have issues with Caco-2 permeability and aqueous solubility, Ligand B excels in key areas for a CNS-targeting GPCR: better logP, higher QED, better BBB penetration, and *significantly* stronger binding affinity. The better metabolic stability of Ligand A is a plus, but the affinity difference is substantial. The negative half-life for Ligand A is also a major concern.

Output:
1
2025-04-17 05:10:47,024 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (368.503 and 366.487 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (96.25) is better than Ligand B (100.28). Both are below the 140 A^2 threshold for oral absorption, and closer to the <90 A^2 target for CNS penetration.

**3. logP:** Ligand A (0.825) is slightly outside the optimal 1-3 range, being a bit low. Ligand B (2.621) is within the optimal range. This favors Ligand B.

**4. H-Bond Donors:** Both ligands have 3 HBD, which is acceptable (<=5).

**5. H-Bond Acceptors:** Ligand A has 6 HBA, and Ligand B has 7. Both are within the acceptable limit of <=10.

**6. QED:** Both ligands have similar QED values (0.532 and 0.559), indicating good drug-likeness.

**7. DILI:** Ligand A (32.765) has a significantly lower DILI risk than Ligand B (60.915). This is a major advantage for Ligand A.

**8. BBB:** Ligand A (36.332) has a very poor BBB percentile, while Ligand B (46.724) is still low, but better. This is a critical disadvantage for Ligand A, given DRD2 is a CNS target.

**9. Caco-2 Permeability:** Both have negative values (-5.597 and -5.244), which is unusual and suggests poor permeability. However, these values are on a scale where negative values are possible, and direct comparison is difficult without knowing the scale's specifics.

**10. Aqueous Solubility:** Both have negative values (-1.392 and -2.328) indicating poor solubility.

**11. hERG Inhibition:** Ligand A (0.211) has a lower hERG risk than Ligand B (0.692). This is a positive for Ligand A.

**12. Microsomal Clearance:** Ligand A (21.576) has a lower microsomal clearance than Ligand B (60.968), suggesting better metabolic stability. This is a significant advantage for Ligand A.

**13. In vitro Half-Life:** Ligand A (-20.439) has a negative half-life, which is not possible. This is a major red flag and likely an error in the data. Ligand B (24.009) has a reasonable half-life.

**14. P-gp Efflux:** Ligand A (0.043) has very low P-gp efflux, which is excellent for CNS penetration. Ligand B (0.567) has moderate P-gp efflux.

**15. Binding Affinity:** Ligand A (-7.5 kcal/mol) has a slightly better binding affinity than Ligand B (-6.9 kcal/mol). While both are good, the 0.6 kcal/mol difference is not huge.

**Overall Assessment:**

Ligand A has advantages in DILI risk, hERG inhibition, P-gp efflux, and binding affinity, and metabolic stability. However, its extremely poor BBB penetration and impossible half-life are major drawbacks. Ligand B has a better logP and a reasonable half-life, but suffers from higher DILI risk, greater P-gp efflux, and slightly lower affinity.

Considering the GPCR-specific priorities, BBB penetration is crucial for a CNS target like DRD2. While Ligand A's affinity is slightly better, its extremely low BBB value makes it unlikely to reach the target in the brain. The negative half-life is also a showstopper. Ligand B, despite its flaws, has a more plausible profile for CNS exposure.

Output:
1
2025-04-17 05:10:47,024 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (353.463 and 372.491 Da) fall within the ideal range of 200-500 Da.

**TPSA:** Ligand A (89.95) is excellent, falling below the 90 A^2 threshold for CNS targets. Ligand B (102.32) is still reasonable but less optimal.

**logP:** Ligand A (0.227) is quite low, potentially hindering membrane permeability. Ligand B (0.663) is better, but still on the lower side of the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Both ligands have 2 HBDs, which is good. Ligand A has 4 HBAs, and Ligand B has 6 HBAs. Both are acceptable, being under the 10 HBA limit.

**QED:** Both ligands have a QED of 0.66, indicating good drug-likeness.

**DILI:** Ligand A (18.185) has a significantly lower DILI risk than Ligand B (54.944), which is a major advantage.

**BBB:** Ligand A (38.465) has a poor BBB penetration percentile. Ligand B (57.193) is better, but still not ideal (we want >70 for CNS targets).

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.154 and -5.075), which is unusual and suggests poor permeability.

**Aqueous Solubility:** Both ligands have negative solubility values (-0.953 and -1.869), which is also concerning.

**hERG Inhibition:** Ligand A (0.152) shows very low hERG inhibition risk, a significant advantage. Ligand B (0.318) is slightly higher but still acceptable.

**Microsomal Clearance:** Ligand A (4.092) has a lower microsomal clearance, suggesting better metabolic stability than Ligand B (43.03).

**In vitro Half-Life:** Ligand A (-4.348) has a negative half-life, which is not physically possible and indicates a potential data error or a very rapidly metabolized compound. Ligand B (-35.317) is also negative, and similarly problematic.

**P-gp Efflux:** Ligand A (0.022) has very low P-gp efflux liability, which is excellent for CNS penetration. Ligand B (0.059) is slightly higher, but still low.

**Binding Affinity:** Ligand A (-8.1 kcal/mol) has a significantly stronger binding affinity than Ligand B (-7.5 kcal/mol). This 1.6 kcal/mol difference is substantial and could outweigh some of the ADME drawbacks.

**Overall Assessment:**

Despite the problematic negative values for Caco-2 and Solubility, Ligand A is the more promising candidate. Its significantly better binding affinity (-8.1 vs -7.5 kcal/mol), lower DILI risk, lower hERG risk, lower microsomal clearance, and lower P-gp efflux liability are all highly favorable. While its BBB penetration is not ideal, the strong binding affinity and favorable ADME properties (excluding the negative values which need investigation) suggest it has a higher probability of success. Ligand B's higher DILI, higher clearance, and weaker binding affinity make it less attractive. The negative half-life values for both compounds are concerning and require further investigation.

Output:
0
2025-04-17 05:10:47,025 - INFO - Reasoning:

Let's analyze Ligand A and Ligand B based on the provided guidelines, prioritizing GPCR-specific properties (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (344.499 Da) is slightly lower, which could be beneficial for permeability.

**TPSA:** Ligand A (49.41) is significantly better than Ligand B (63.91). For a CNS target like DRD2, TPSA < 90 is preferred, and A is comfortably within that range, while B is approaching the upper limit.

**logP:** Both ligands have good logP values (A: 3.278, B: 3.079), falling within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A (HBD=1, HBA=2) has a more favorable profile than Ligand B (HBD=0, HBA=5). Lower HBD/HBA generally improves permeability.

**QED:** Both ligands have acceptable QED values (A: 0.594, B: 0.78), indicating good drug-like properties.

**DILI:** Ligand A (37.146) has a lower DILI risk than Ligand B (59.054), which is preferable. Both are below the concerning threshold of 60, but A is better.

**BBB:** Ligand B (88.639) has a significantly higher BBB penetration percentile than Ligand A (76.464). This is a crucial factor for CNS targets, giving B an advantage.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.781 and -4.864). These values are unusual and difficult to interpret without further context. Typically, higher values are better.

**Aqueous Solubility:** Both ligands have negative solubility values (-4.137 and -2.999), again unusual. Higher values are preferred.

**hERG:** Both ligands have low hERG inhibition liability (A: 0.293, B: 0.372), which is good.

**Microsomal Clearance:** Ligand B (51.309) has lower microsomal clearance than Ligand A (78.137), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand B (-22.791) has a longer in vitro half-life than Ligand A (-13.404). This is a positive attribute.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (A: 0.463, B: 0.36), which is favorable for CNS penetration.

**Binding Affinity:** Ligand B (-8.8 kcal/mol) has a stronger binding affinity than Ligand A (-7.9 kcal/mol). This is a significant advantage, as a >1.5 kcal/mol difference can outweigh other factors.

**Overall Assessment:**

Ligand B excels in BBB penetration and binding affinity, two critical factors for a CNS GPCR target. It also demonstrates better metabolic stability (lower Cl_mic) and a longer half-life. While Ligand A has a slightly better TPSA and DILI profile, the superior affinity and BBB penetration of Ligand B are more impactful for DRD2 targeting. The negative Caco-2 and solubility values are concerning for both, but the stronger binding and CNS penetration of B make it the more promising candidate.

Output:
1
2025-04-17 05:10:47,025 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (352.479 and 360.42 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (96.25) is better than Ligand B (58.2). Both are below the 90 A^2 threshold for CNS targets, which is excellent.

**logP:** Both ligands have good logP values (1.548 and 3.022, respectively), falling within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A has 3 HBD and 5 HBA, while Ligand B has 2 HBD and 2 HBA. Both are within acceptable limits (<=5 HBD and <=10 HBA).

**QED:** Both ligands have acceptable QED scores (0.595 and 0.664, respectively), indicating good drug-like properties.

**DILI:** Both ligands have low DILI risk (33.695 and 30.632 percentiles, respectively), which is favorable.

**BBB:** This is a critical parameter for a CNS target like DRD2. Ligand B (83.908) significantly outperforms Ligand A (33.036). A value >70 is desirable, and Ligand B is approaching that, while Ligand A is quite low.

**Caco-2 Permeability:** Ligand A (-5.198) and Ligand B (-4.628) both have negative values, which is unusual. It's difficult to interpret these without knowing the scale, but lower values generally indicate poorer permeability.

**Aqueous Solubility:** Both ligands have poor aqueous solubility (-2.215 and -4.411, respectively). This could pose formulation challenges.

**hERG Inhibition:** Both ligands show low hERG inhibition risk (0.294 and 0.561, respectively).

**Microsomal Clearance:** Ligand A (22.67) has a lower microsomal clearance than Ligand B (29.289), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (41.428) has a longer in vitro half-life than Ligand B (17.374), which is desirable.

**P-gp Efflux:** Ligand A (0.092) shows lower P-gp efflux than Ligand B (0.117), which is favorable for CNS penetration.

**Binding Affinity:** Ligand B (-8.0 kcal/mol) has a slightly better binding affinity than Ligand A (-7.5 kcal/mol). While both are good, the 0.5 kcal/mol difference is notable.

**Overall Assessment:**

Ligand B is significantly better regarding BBB penetration, a crucial factor for CNS targets. It also has a slightly better binding affinity. While Ligand A has better metabolic stability (lower Cl_mic, longer t1/2) and lower P-gp efflux, the substantial advantage of Ligand B in BBB penetration outweighs these benefits. The solubility of both is poor, but this can be addressed through formulation strategies.

Output:
1
2025-04-17 05:10:47,025 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 drug candidates, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight (MW):** Both ligands are within the ideal range (200-500 Da). Ligand A (369.864 Da) and Ligand B (350.467 Da) are both acceptable.

**2. TPSA:** Ligand A (55.4) is excellent, well below the 90 A^2 threshold for CNS targets. Ligand B (110.2) is higher but still potentially acceptable, though less ideal.

**3. logP:** Ligand A (4.04) is at the upper end of the optimal range (1-3) and could potentially cause solubility issues or off-target interactions. Ligand B (2.103) is within the optimal range.

**4. H-Bond Donors (HBD):** Both ligands have acceptable HBD counts (Ligand A: 1, Ligand B: 2), well below the threshold of 5.

**5. H-Bond Acceptors (HBA):** Both ligands have acceptable HBA counts (Ligand A: 3, Ligand B: 4), below the threshold of 10.

**6. QED:** Ligand A (0.797) has a very good drug-likeness score. Ligand B (0.397) is significantly lower, suggesting a less drug-like profile.

**7. DILI:** Ligand A (46.258) has a low DILI risk. Ligand B (16.673) also has a low DILI risk.

**8. BBB:** This is crucial for a CNS target like DRD2. Ligand A (83.172) has a very good BBB penetration percentile. Ligand B (46.879) is considerably lower, indicating poor predicted brain penetration.

**9. Caco-2 Permeability:** Ligand A (-4.267) has poor Caco-2 permeability. Ligand B (-5.248) is even worse.

**10. Aqueous Solubility:** Ligand A (-4.935) has poor aqueous solubility. Ligand B (-1.087) is better, but still poor.

**11. hERG Inhibition:** Both ligands have low hERG inhibition risk (Ligand A: 0.46, Ligand B: 0.103).

**12. Microsomal Clearance:** Ligand A (114.945) has relatively high microsomal clearance, suggesting faster metabolism. Ligand B (8.288) has much lower clearance, indicating better metabolic stability.

**13. In vitro Half-Life:** Ligand A (15.632) has a moderate in vitro half-life. Ligand B (10.068) has a shorter half-life.

**14. P-gp Efflux:** Both ligands have very low P-gp efflux liability (Ligand A: 0.467, Ligand B: 0.007).

**15. Binding Affinity:** Ligand B (-6.7 kcal/mol) has significantly better binding affinity than Ligand A (0.0 kcal/mol). This is a substantial advantage.

**Overall Assessment:**

Ligand B has a much stronger binding affinity, which is a major advantage. It also exhibits better metabolic stability (lower Cl_mic) and lower P-gp efflux. However, its BBB penetration is significantly worse than Ligand A, and its QED score is lower. Ligand A has excellent BBB penetration and a good QED score, but its binding affinity is very weak, and it has higher metabolic clearance.

Given the GPCR-specific priorities, BBB penetration is critical for CNS targets. While Ligand B's affinity is much better, the poor BBB penetration is a major drawback. The difference in affinity (6.7 kcal/mol) is substantial, but the poor CNS exposure of Ligand B makes it less likely to be a viable drug candidate. Ligand A, despite its weak binding, has a much better chance of reaching the target in the brain.

Output:
1
2025-04-17 05:10:47,025 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (355.435 and 351.531 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (102.34) is better than Ligand B (38.77) as it is closer to the ideal range for CNS targets (<=90). Ligand B is excellent.

**logP:** Ligand A (-1.586) is suboptimal, being below the preferred 1-3 range. This could hinder permeability. Ligand B (4.397) is high, potentially causing solubility issues and off-target effects, but acceptable.

**H-Bond Donors/Acceptors:** Ligand A has 3 HBD and 6 HBA, which are within acceptable limits. Ligand B has 0 HBD and 3 HBA, also acceptable.

**QED:** Both ligands have good QED scores (0.509 and 0.682), indicating drug-like properties.

**DILI:** Ligand A (11.4) has a much lower DILI risk than Ligand B (17.642), which is a significant advantage.

**BBB:** Ligand B (91.392) has a significantly higher BBB penetration percentile than Ligand A (18.883). This is *critical* for a CNS target like DRD2.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values, which is unusual and suggests poor permeability. However, the scale is not defined, so it's difficult to interpret.

**Aqueous Solubility:** Both ligands have negative solubility values, indicating poor solubility.

**hERG Inhibition:** Ligand A (0.087) has a very low hERG inhibition liability, which is excellent. Ligand B (0.828) is higher, posing a potential cardiotoxicity risk.

**Microsomal Clearance:** Ligand A (-6.74) suggests very slow clearance and high metabolic stability. Ligand B (128.637) indicates rapid clearance, which is a major drawback.

**In vitro Half-Life:** Ligand A (9.804) has a better half-life than Ligand B (0.154).

**P-gp Efflux:** Ligand A (0.003) has very low P-gp efflux, which is favorable for CNS penetration. Ligand B (0.806) has moderate P-gp efflux.

**Binding Affinity:** Ligand A (-7.5) has a slightly better binding affinity than Ligand B (-6.5). While both are good, the 1 kcal/mol difference is notable.

**Overall Assessment:**

Ligand B excels in BBB penetration, which is paramount for a CNS target. However, it suffers from high logP, rapid clearance, moderate P-gp efflux, and a higher DILI risk. Ligand A has better metabolic stability, lower DILI risk, lower P-gp efflux, and a slightly better binding affinity, but its low logP and poor BBB penetration are significant concerns.

Despite the superior affinity of Ligand A, the critical importance of BBB penetration for a CNS target like DRD2, combined with the significantly better BBB score of Ligand B, tips the balance. While Ligand B's other properties are less ideal, these could potentially be improved through further optimization. The poor BBB penetration of Ligand A is a more difficult property to address.

Output:
1
2025-04-17 05:10:47,026 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 drug candidates, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (364.515 and 365.905 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (76.02) is better than Ligand B (61.38). Both are below the 90 A^2 threshold for CNS targets, which is good.

**3. logP:** Ligand A (1.649) is within the optimal range (1-3). Ligand B (3.462) is at the higher end of the optimal range, potentially increasing off-target effects.

**4. H-Bond Donors:** Both ligands have 2 HBD, which is acceptable (<=5).

**5. H-Bond Acceptors:** Ligand A has 5 HBA, and Ligand B has 4. Both are within the acceptable range (<=10).

**6. QED:** Both ligands have similar QED values (0.735 and 0.752), indicating good drug-like properties.

**7. DILI:** Ligand A (43.234) has a slightly higher DILI risk than Ligand B (37.922), but both are below the concerning threshold of 60.

**8. BBB:** Ligand A (59.364) and Ligand B (63.164) are both reasonably good, but neither exceeds the desirable 70% threshold for CNS targets. Ligand B is slightly better.

**9. Caco-2 Permeability:** Both have negative Caco-2 values (-5.701 and -5.391), which is unusual and suggests poor permeability. This is a significant concern for both.

**10. Aqueous Solubility:** Both have negative solubility values (-2.246 and -3.575), which is also a significant concern.

**11. hERG Inhibition:** Ligand A (0.11) has a much lower hERG inhibition liability than Ligand B (0.91), making it safer from a cardiotoxicity perspective.

**12. Microsomal Clearance:** Both ligands have similar microsomal clearance values (29.691 and 30.274), indicating similar metabolic stability.

**13. In vitro Half-Life:** Ligand B (109.046) has a significantly longer half-life than Ligand A (2.828), which is a major advantage.

**14. P-gp Efflux:** Ligand A (0.093) has lower P-gp efflux liability than Ligand B (0.771), which is beneficial for CNS penetration.

**15. Binding Affinity:** Ligand B (-7.6 kcal/mol) has a significantly stronger binding affinity than Ligand A (-8.0 kcal/mol). This is a substantial advantage, potentially outweighing some of the ADME drawbacks.

**Overall Assessment:**

While Ligand B has a superior binding affinity and longer half-life, Ligand A exhibits a better safety profile (lower hERG, lower P-gp efflux) and slightly better TPSA. The poor Caco-2 and solubility for both are concerning. However, the stronger binding affinity of Ligand B is a critical factor for GPCR targets. Given the importance of affinity for GPCRs, and the relatively minor differences in other parameters, Ligand B is the more promising candidate, despite the higher P-gp efflux and hERG risk. Further optimization would be needed to address the solubility and permeability issues.

Output:
1
2025-04-17 05:10:47,026 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (344.459 and 368.478 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (76.02) is better than Ligand B (67.35) as it is closer to the ideal range of <=90 for CNS targets.

**3. logP:** Both ligands have good logP values (1.813 and 2.048), falling within the optimal 1-3 range.

**4. H-Bond Donors:** Ligand A (2) is slightly higher than Ligand B (1), but both are within the acceptable limit of <=5.

**5. H-Bond Acceptors:** Ligand A (4) is lower than Ligand B (6), both are within the acceptable limit of <=10.

**6. QED:** Ligand A (0.706) has a better QED score than Ligand B (0.587), indicating a more drug-like profile.

**7. DILI:** Ligand A (21.908) has a significantly lower DILI risk than Ligand B (47.654), which is a major advantage.

**8. BBB:** Ligand B (77.084) has a substantially better BBB penetration percentile than Ligand A (53.276). This is a critical factor for a CNS target like DRD2.

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.791 and -4.986). This is unusual and suggests poor permeability.

**10. Aqueous Solubility:** Both ligands have negative solubility values (-3.176 and -3.321), indicating very poor solubility.

**11. hERG Inhibition:** Both ligands have low hERG inhibition liability (0.057 and 0.479), which is good.

**12. Microsomal Clearance:** Ligand B (57.641) has a higher microsomal clearance than Ligand A (30.013), indicating lower metabolic stability.

**13. In vitro Half-Life:** Ligand A (-16.095) has a longer in vitro half-life than Ligand B (3.245).

**14. P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.024 and 0.077), which is favorable for CNS penetration.

**15. Binding Affinity:** Ligand B (-8.7) has a slightly better binding affinity than Ligand A (-8.0), although both are excellent.

**Overall Assessment:**

While Ligand B has a significantly better BBB score and slightly better binding affinity, Ligand A has advantages in DILI risk, QED, metabolic stability (lower Cl_mic, longer t1/2), and solubility (although both are poor). Given the importance of minimizing toxicity (DILI) and maintaining a reasonable metabolic profile for a CNS drug, and the relatively small difference in binding affinity, Ligand A appears to be the more promising candidate. The poor solubility and permeability are concerning for both, but could be addressed with formulation strategies.

Output:
0
2025-04-17 05:10:47,026 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (344.415 and 353.423 Da) fall within the ideal range of 200-500 Da.

**TPSA:** Ligand A (73.91) is excellent, well below the 90 A^2 threshold for CNS targets. Ligand B (129.23) is higher but still acceptable, though less ideal.

**logP:** Ligand A (1.126) is within the optimal range of 1-3. Ligand B (-0.197) is slightly below 1, which *could* indicate permeability issues, but isn't a dealbreaker.

**H-Bond Donors/Acceptors:** Ligand A (2 HBD, 5 HBA) and Ligand B (4 HBD, 6 HBA) both have reasonable numbers of H-bonds, within the suggested limits.

**QED:** Both ligands have acceptable QED values (0.86 and 0.512, respectively), indicating good drug-like properties.

**DILI:** Both ligands have low DILI risk (41.024 and 39.395 percentile), which is favorable.

**BBB:** This is a crucial parameter for a CNS target like DRD2. Ligand A has a very high BBB penetration percentile (89.027), which is excellent. Ligand B's BBB penetration (28.655) is significantly lower and a major concern.

**Caco-2 Permeability:** Both have negative values, which is unusual. Assuming these are logP-like scales, lower values indicate poorer permeability. Ligand A (-5.057) is worse than Ligand B (-5.618) in this regard, but both are poor.

**Aqueous Solubility:** Both ligands have negative solubility values, which is also unusual. Assuming these are logS-like scales, lower values indicate poorer solubility. Ligand A (-2.176) is better than Ligand B (-1.041).

**hERG:** Both ligands have very low hERG inhibition liability (0.576 and 0.057), which is excellent.

**Microsomal Clearance:** Ligand A has a very low (and therefore good) microsomal clearance (-13.702), indicating high metabolic stability. Ligand B's clearance (0.875) is much higher, suggesting faster metabolism.

**In vitro Half-Life:** Ligand A has a good in vitro half-life (24.53 hours). Ligand B's half-life (6.812 hours) is shorter.

**P-gp Efflux:** Ligand A has no P-gp efflux liability (0.028), which is ideal for CNS penetration. Ligand B has some P-gp efflux liability (0.01), but it's very low.

**Binding Affinity:** Ligand B (-8.1 kcal/mol) has a significantly stronger binding affinity than Ligand A (-0.0 kcal/mol). This is a substantial advantage.

**Overall Assessment:**

While Ligand B boasts a much stronger binding affinity, the significantly lower BBB penetration and higher microsomal clearance are major drawbacks for a CNS-targeting drug. Ligand A, despite its weaker binding affinity, has excellent BBB penetration, low P-gp efflux, and good metabolic stability. The combination of these factors makes Ligand A a more promising candidate, especially considering the importance of CNS exposure for DRD2. The poor Caco-2 and solubility values for both are concerning but could be addressed with formulation strategies.

Output:
0
2025-04-17 05:10:47,026 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (354.447 and 352.435 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (107.89) is higher than Ligand B (74.68). For CNS targets, we prefer TPSA <= 90. Ligand B is significantly better in this regard.

**logP:** Ligand A (-0.054) is slightly lower than the optimal 1-3 range, potentially hindering permeability. Ligand B (-0.354) is also a bit low, but closer to the desired range.

**H-Bond Donors:** Ligand A has 4 HBD, which is acceptable. Ligand B has 0, which is also acceptable.

**H-Bond Acceptors:** Ligand A has 5 HBA, acceptable. Ligand B has 6, also acceptable.

**QED:** Both ligands have reasonable QED values (0.535 and 0.499), indicating good drug-like properties.

**DILI:** Ligand A (19.232) has a lower DILI risk than Ligand B (24.583), which is preferable.

**BBB:** Both ligands have similar BBB penetration (52.268 and 53.393). While not ideal (>70), they are comparable.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.262 and -4.676). This is unusual and suggests poor permeability.

**Aqueous Solubility:** Both ligands have negative solubility values (-1.359 and -0.92). This is also unusual and suggests poor solubility.

**hERG:** Both ligands have low hERG inhibition liability (0.146 and 0.291), which is good.

**Microsomal Clearance:** Ligand A (14.718) has lower microsomal clearance than Ligand B (19.055), indicating better metabolic stability.

**In vitro Half-Life:** Ligand A (13.337 hours) has a longer half-life than Ligand B (1.838 hours), which is a significant advantage.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.007 and 0.026), which is excellent for CNS penetration.

**Binding Affinity:** Both ligands have the same binding affinity (-7.3 kcal/mol), which is excellent.

**Overall Assessment:**

Given the GPCR-specific priorities, TPSA is a crucial factor for CNS targets. Ligand B has a significantly lower TPSA (74.68) than Ligand A (107.89). While both have issues with Caco-2 and solubility, the lower TPSA of Ligand B, combined with its slightly better logP, gives it a slight edge. The longer half-life and lower clearance of Ligand A are attractive, but the TPSA difference is more critical for a CNS target like DRD2. The similar binding affinity makes this a secondary consideration.

Output:
1
2025-04-17 05:10:47,027 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (379.837 and 343.383 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (114.58) is slightly above the optimal <90 for CNS targets, but still reasonable. Ligand B (104.46) is better, falling comfortably under 90.

**3. logP:** Both ligands have good logP values (1.897 and 1.5), falling within the 1-3 range.

**4. H-Bond Donors:** Both have 3 HBD, which is within the acceptable limit of <=5.

**5. H-Bond Acceptors:** Ligand A has 9 HBA, right at the upper limit of the acceptable range. Ligand B has 5 HBA, which is excellent.

**6. QED:** Both ligands have good QED scores (0.58 and 0.661), indicating good drug-like properties.

**7. DILI:** Ligand A has a DILI risk of 96.976, which is very high and a significant concern. Ligand B has a much lower DILI risk of 55.448, which is still moderately high but significantly better.

**8. BBB:** Ligand A has a BBB penetration of 65.801, which is okay but not ideal for a CNS target. Ligand B has a significantly lower BBB penetration of 36.642, which is a major drawback.

**9. Caco-2:** Both have negative Caco-2 values (-5.255 and -5.233), which is unusual and suggests poor permeability. This is a red flag for both.

**10. Solubility:** Both have negative solubility values (-4.089 and -2.693), indicating very poor aqueous solubility. This is a significant issue for both.

**11. hERG:** Both ligands have very low hERG inhibition liability (0.063 and 0.336), which is excellent.

**12. Cl_mic:** Ligand A has a lower microsomal clearance (39.684) than Ligand B (48.298), suggesting better metabolic stability.

**13. t1/2:** Ligand A has a longer in vitro half-life (45.664) than Ligand B (7.951), which is preferable.

**14. Pgp:** Both ligands have low P-gp efflux liability (0.157 and 0.216), which is good for CNS penetration.

**15. Binding Affinity:** Ligand B (-7.9 kcal/mol) has a slightly better binding affinity than Ligand A (-8.2 kcal/mol). While the difference is small, it's still a factor.

**Overall Assessment:**

Ligand A has a major drawback with its very high DILI risk. While it has better metabolic stability and half-life, the DILI risk is a significant concern. Ligand B has a lower DILI risk, but suffers from very poor BBB penetration and a shorter half-life. Both have poor solubility and permeability.

Considering the GPCR-specific priorities, BBB penetration is crucial for CNS targets. While Ligand B has a slightly better affinity, the significantly lower BBB penetration makes it less likely to reach the target in the brain. The high DILI risk of Ligand A is a showstopper.

Output:
0
2025-04-17 05:10:47,027 - INFO - Reasoning:

Let's analyze Ligand A and Ligand B based on the provided guidelines, keeping in mind DRD2 is a CNS-relevant GPCR.

**1. Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (339.355) is slightly lower, which could be beneficial for permeability, but both are acceptable.

**2. TPSA:** This is critical for CNS penetration. Ligand A (112.91) is better, being closer to the ideal <90, while Ligand B (51.66) is excellent.

**3. logP:** Both ligands have good logP values (A: 1.414, B: 3.154), falling within the optimal 1-3 range.

**4. H-Bond Donors:** Ligand A (3) is reasonable. Ligand B (0) is also good, potentially improving membrane permeability.

**5. H-Bond Acceptors:** Both ligands have acceptable HBA counts (A: 5, B: 6).

**6. QED:** Both ligands have similar QED values (A: 0.65, B: 0.612), indicating good drug-like properties.

**7. DILI:** Ligand A (81.621) has a higher DILI risk than Ligand B (43.117), which is preferable.

**8. BBB:** Ligand B (82.551) has a significantly better BBB penetration percentile than Ligand A (45.909). This is a *major* advantage for a CNS target like DRD2.

**9. Caco-2 Permeability:** Ligand A (-5.582) shows poor Caco-2 permeability, while Ligand B (-4.902) is slightly better, but still not ideal.

**10. Aqueous Solubility:** Both ligands have poor aqueous solubility (-3.284 and -2.468 respectively). This could pose formulation challenges.

**11. hERG Inhibition:** Both ligands have low hERG inhibition risk (A: 0.403, B: 0.436).

**12. Microsomal Clearance:** Ligand A (18.743) has lower microsomal clearance, suggesting better metabolic stability than Ligand B (55.209).

**13. In vitro Half-Life:** Ligand A (-7.151) has a significantly longer in vitro half-life than Ligand B (-2.402).

**14. P-gp Efflux:** Both ligands have low P-gp efflux liability (A: 0.177, B: 0.243).

**15. Binding Affinity:** Ligand A (-8.2) has a stronger binding affinity than Ligand B (-6.8). This is a substantial difference (1.4 kcal/mol) and a significant advantage.

**Overall Assessment:**

While Ligand A has better metabolic stability (lower Cl_mic, longer t1/2) and a significantly stronger binding affinity, Ligand B excels in properties crucial for CNS penetration: TPSA and, most importantly, BBB. The substantial difference in BBB penetration (82.551 vs 45.909) outweighs the benefits of Ligand A's slightly better metabolic profile and affinity. The lower DILI risk for Ligand B is also a positive factor. The poor Caco-2 permeability is a concern for both, but less critical for a CNS target where direct absorption isn't the primary route of exposure.

Output:
1
2025-04-17 05:10:47,027 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (341.367 and 350.459 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (88.6) is better than Ligand B (66.92). Both are below the 90 A^2 threshold for CNS targets, which is excellent.

**logP:** Ligand B (1.991) is optimal (1-3), while Ligand A (0.347) is quite low, potentially hindering membrane permeability.

**H-Bond Donors/Acceptors:** Ligand A has 1 HBD and 5 HBA, while Ligand B has 0 HBD and 4 HBA. Both are within acceptable limits.

**QED:** Both ligands have reasonable QED values (0.617 and 0.562), indicating good drug-like properties.

**DILI:** Ligand B (30.748) has a significantly lower DILI risk than Ligand A (61.342), making it safer.

**BBB:** Ligand B (73.672) has a much better BBB penetration score than Ligand A (47.926). This is *critical* for a CNS target like DRD2.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.518 and -4.481). This is unusual and suggests poor permeability. However, these values are on a log scale, and the absolute difference is small.

**Aqueous Solubility:** Both ligands have negative solubility values (-2.636 and -2.342). This indicates poor aqueous solubility.

**hERG:** Both ligands have low hERG inhibition liability (0.097 and 0.295), which is good.

**Microsomal Clearance:** Ligand B (71.137) has a much higher microsomal clearance than Ligand A (12.428), suggesting faster metabolism and potentially lower in vivo exposure.

**In vitro Half-Life:** Ligand A (-17.176) has a negative half-life, which is not possible and indicates a significant issue with the data or the compound's stability. Ligand B (-9.274) also has a negative half-life, but it is less extreme.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.01 and 0.172), which is favorable for CNS penetration.

**Binding Affinity:** Both ligands have similar and strong binding affinities (-8.0 and -6.9 kcal/mol). Ligand A is slightly better, but the difference is not huge.

**Overall Assessment:**

Ligand B is significantly better due to its superior BBB penetration (73.672 vs 47.926), lower DILI risk (30.748 vs 61.342), and more reasonable logP (1.991 vs 0.347). While both have issues with solubility and Caco-2 permeability, the BBB is paramount for a CNS target. The negative half-life values are concerning for both, but less so for Ligand B. The slightly better affinity of Ligand A is outweighed by the other factors.

Output:
1
2025-04-17 05:10:47,027 - INFO - Batch 176 complete. Total preferences: 2816
2025-04-17 05:10:47,027 - INFO - Processing batch 177/512...
2025-04-17 05:11:27,883 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (347.503 and 345.418 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (52.65) is significantly better than Ligand B (62.3). For CNS targets, we want TPSA <= 90, and ideally closer to 60. Ligand A is much closer to the ideal range.

**3. logP:** Both ligands have acceptable logP values (1.733 and 2.157), falling within the 1-3 range.

**4. H-Bond Donors:** Both have 1 HBD, which is within the acceptable limit of <= 5.

**5. H-Bond Acceptors:** Both have 3 HBA, also within the acceptable limit of <= 10.

**6. QED:** Both ligands have good QED scores (0.51 and 0.657), indicating good drug-like properties.

**7. DILI:** Ligand A (4.886) has a much lower DILI risk than Ligand B (27.608). This is a significant advantage for Ligand A.

**8. BBB:** Both ligands have excellent BBB penetration (79.992 and 82.474), exceeding the desirable threshold of >70 for CNS targets.

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.87 and -4.424). This is unusual and suggests poor permeability. However, the values are similar.

**10. Aqueous Solubility:** Both ligands have negative solubility values (-1.131 and -2.454), indicating poor aqueous solubility. Ligand B is slightly worse.

**11. hERG Inhibition:** Both ligands have low hERG inhibition risk (0.702 and 0.579).

**12. Microsomal Clearance:** Ligand A (1.6 mL/min/kg) has significantly lower microsomal clearance than Ligand B (25.966 mL/min/kg), indicating better metabolic stability.

**13. In vitro Half-Life:** Ligand A (6.365 hours) has a better in vitro half-life than Ligand B (-32.255 hours). The negative value for Ligand B is concerning.

**14. P-gp Efflux:** Ligand A (0.028) has much lower P-gp efflux than Ligand B (0.125), which is crucial for CNS exposure.

**15. Binding Affinity:** Ligand B (-8.3 kcal/mol) has a slightly better binding affinity than Ligand A (-7.8 kcal/mol). While affinity is important, the difference of 0.5 kcal/mol is not substantial enough to outweigh the numerous ADME advantages of Ligand A.

**Overall Assessment:**

Ligand A is the superior candidate. It demonstrates significantly better DILI risk, metabolic stability (lower Cl_mic, better t1/2), lower P-gp efflux, and a more favorable TPSA. While Ligand B has slightly better binding affinity, the ADME profile of Ligand A is far more promising, particularly for a CNS target like DRD2. The negative Caco-2 and solubility values are concerning for both, but the other advantages of Ligand A make it the better choice for further optimization.

Output:
1
2025-04-17 05:11:27,884 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (400.327 Da) is slightly higher than Ligand B (344.499 Da), but both are acceptable.

**TPSA:** Ligand A (55.4) is higher than Ligand B (49.41). For CNS targets, we want TPSA <= 90, so both are good, but B is slightly better.

**logP:** Both ligands have good logP values (A: 3.61, B: 3.132), falling within the optimal range of 1-3.

**H-Bond Donors/Acceptors:** Both ligands have acceptable HBD (1) and HBA (A: 3, B: 2) counts.

**QED:** Both ligands have good QED scores (A: 0.737, B: 0.855), indicating good drug-like properties.

**DILI:** Ligand A (58.511) has a higher DILI risk than Ligand B (25.785). This is a significant advantage for Ligand B.

**BBB:** Ligand B (84.606) has a significantly better BBB penetration percentile than Ligand A (56.068). This is *critical* for a CNS target like DRD2.

**Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and suggests a potential issue with the modeling or data. However, we can't rely on this value too heavily.

**Aqueous Solubility:** Both have negative solubility values, again suggesting a potential issue with the modeling or data.

**hERG:** Both ligands have low hERG inhibition liability (A: 0.813, B: 0.48), which is good.

**Microsomal Clearance:** Ligand B (72.056) has a higher microsomal clearance than Ligand A (61.914), meaning A is more metabolically stable.

**In vitro Half-Life:** Ligand A (16.191) has a longer half-life than Ligand B (-4.436). This is a positive for A.

**P-gp Efflux:** Ligand B (0.22) has significantly lower P-gp efflux liability than Ligand A (0.62). Lower P-gp efflux is highly desirable for CNS penetration.

**Binding Affinity:** Ligand B (-8.4 kcal/mol) has a slightly better binding affinity than Ligand A (-9.3 kcal/mol). While A is better, the difference is not substantial enough to outweigh the other factors.

**Overall Assessment:**

Ligand B is the superior candidate. Its significantly better BBB penetration (84.606 vs. 56.068) and lower P-gp efflux (0.22 vs. 0.62) are crucial for a CNS-targeting drug. The lower DILI risk (25.785 vs. 58.511) is also a major advantage. While Ligand A has better metabolic stability and half-life, the CNS penetration benefits of Ligand B are more important for DRD2. The small difference in binding affinity is not enough to overcome the ADME advantages of Ligand B.

Output:
1
2025-04-17 05:11:27,884 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (346.431 and 350.394 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (85.25) is better than Ligand B (95.42). Both are below 90, which is favorable for CNS penetration.

**3. logP:** Ligand A (0.855) is slightly lower than optimal (1-3), potentially impacting permeability. Ligand B (1.622) is within the optimal range.

**4. H-Bond Donors:** Both ligands have 2 HBD, which is acceptable.

**5. H-Bond Acceptors:** Both ligands have 5 HBA, which is acceptable.

**6. QED:** Both ligands have good QED scores (0.684 and 0.86), indicating good drug-like properties.

**7. DILI:** Ligand A (39.201) has a significantly lower DILI risk than Ligand B (57.193), which is a major advantage.

**8. BBB:** Ligand B (82.164) has a much better BBB percentile than Ligand A (42.187). This is critical for a CNS target like DRD2.

**9. Caco-2 Permeability:** Both have negative values, which is unusual. Assuming these are logP-scale values, lower is worse. Ligand A (-4.899) is worse than Ligand B (-4.775).

**10. Aqueous Solubility:** Both have negative values, which is unusual. Assuming these are logS-scale values, lower is worse. Ligand A (-1.849) is better than Ligand B (-3.094).

**11. hERG Inhibition:** Ligand A (0.049) has a much lower hERG inhibition liability than Ligand B (0.281), which is a significant safety advantage.

**12. Microsomal Clearance:** Ligand A (1.285) has a much lower microsomal clearance than Ligand B (17.475), indicating better metabolic stability.

**13. In vitro Half-Life:** Ligand A (-3.993) has a much longer in vitro half-life than Ligand B (-20.054).

**14. P-gp Efflux:** Ligand A (0.028) has a much lower P-gp efflux liability than Ligand B (0.072), which is beneficial for CNS exposure.

**15. Binding Affinity:** Ligand B (-9.4 kcal/mol) has a significantly stronger binding affinity than Ligand A (-7.2 kcal/mol). This is a substantial advantage, potentially outweighing some ADME concerns.

**Overall Assessment:**

Ligand B has a significantly better binding affinity and BBB penetration, which are crucial for a CNS GPCR target. However, it suffers from higher DILI risk, higher hERG inhibition, higher microsomal clearance, shorter half-life, and higher P-gp efflux. Ligand A has a much better safety profile (DILI, hERG), better metabolic stability (Cl_mic, t1/2), and lower P-gp efflux, but weaker binding affinity and lower BBB penetration.

The difference in binding affinity (-2.2 kcal/mol) is substantial. While Ligand A's ADME profile is more favorable, the stronger binding of Ligand B is likely to be more important for efficacy, especially considering the potential for optimization of ADME properties. The improved BBB penetration of Ligand B is also a significant advantage.

Output:
1
2025-04-17 05:11:27,884 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 drug candidates, considering the provided guidelines and GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (362.352 Da and 358.36 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (88.41) is better than Ligand B (67.43) as it's closer to the <90 A^2 threshold for CNS targets.

**3. logP:** Both ligands have good logP values (1.581 and 2.662), falling within the optimal 1-3 range. Ligand B is slightly higher, which could be a minor advantage.

**4. H-Bond Donors:** Ligand A (3) is slightly higher than Ligand B (2), but both are acceptable (<=5).

**5. H-Bond Acceptors:** Ligand A (6) is higher than Ligand B (3), but both are within the acceptable range (<=10).

**6. QED:** Both ligands have good QED scores (0.669 and 0.751), indicating good drug-like properties. Ligand B is slightly better.

**7. DILI:** Both ligands have acceptable DILI risk (54.323 and 45.677), well below the 60 threshold. Ligand B is slightly better.

**8. BBB:** Both ligands show good BBB penetration (70.648 and 78.209), exceeding the 70% threshold for CNS targets. Ligand B is better.

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.849 and -4.566), which is unusual and suggests poor permeability. This is a significant concern for both.

**10. Aqueous Solubility:** Both ligands have negative solubility values (-2.396 and -3.31), indicating very poor aqueous solubility. This is a major drawback for both.

**11. hERG Inhibition:** Both ligands have low hERG inhibition risk (0.501 and 0.535), which is good.

**12. Microsomal Clearance:** Ligand B (22.185) has significantly lower microsomal clearance than Ligand A (49.17), suggesting better metabolic stability.

**13. In vitro Half-Life:** Ligand B (-14.146) has a negative half-life, which is not physically possible and indicates a problem with the data or the molecule's stability. Ligand A (10.56) has a reasonable half-life.

**14. P-gp Efflux:** Both ligands have low P-gp efflux liability (0.09 and 0.089), which is favorable for CNS penetration.

**15. Binding Affinity:** Ligand B (-8.8 kcal/mol) has a slightly better binding affinity than Ligand A (-8.3 kcal/mol). While the difference is not huge, it's within the range where it could outweigh some ADME drawbacks.

**Overall Assessment:**

Both ligands have significant issues with Caco-2 permeability and aqueous solubility. However, considering the GPCR-specific priorities, Ligand B is slightly more promising. It has better BBB penetration, lower microsomal clearance (better metabolic stability), and a slightly better binding affinity. The negative half-life for Ligand B is a major red flag and suggests a potential instability issue that needs investigation. However, given the other factors, and assuming the half-life data is an error, Ligand B is the more viable candidate.

Output:
1
2025-04-17 05:11:27,885 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (356.369 and 356.463 Da) fall comfortably within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (78.87) is significantly better than Ligand B (88.1). For CNS targets, we want TPSA <= 90, and A is closer to the ideal.

**3. logP:** Both ligands have acceptable logP values (1.286 and 0.552), falling within the 1-3 range. Ligand A is slightly better.

**4. H-Bond Donors:** Both have 2 HBD, which is within the acceptable limit of <=5.

**5. H-Bond Acceptors:** Ligand A has 4 HBA, and Ligand B has 5. Both are within the acceptable limit of <=10.

**6. QED:** Both ligands have good QED scores (0.722 and 0.651), indicating good drug-like properties.

**7. DILI:** Ligand A (36.797) has a much lower DILI risk than Ligand B (8.492). This is a significant advantage for A.

**8. BBB:** Ligand A (76.464) has a substantially better BBB penetration percentile than Ligand B (45.715). For a CNS target like DRD2, this is a critical advantage.

**9. Caco-2 Permeability:** Ligand A (-4.409) has slightly better Caco-2 permeability than Ligand B (-4.782).

**10. Aqueous Solubility:** Ligand A (-2.062) has slightly better solubility than Ligand B (-1.187).

**11. hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.329 and 0.277).

**12. Microsomal Clearance:** Ligand A (36.338) has higher microsomal clearance than Ligand B (5.648), meaning B is more metabolically stable.

**13. In vitro Half-Life:** Ligand B (-1.858) has a better in vitro half-life than Ligand A (-20.321).

**14. P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.054 and 0.025).

**15. Binding Affinity:** Ligand A (-8.2 kcal/mol) has a significantly stronger binding affinity than Ligand B (-6.6 kcal/mol). This difference of 1.6 kcal/mol is substantial and can outweigh some ADME drawbacks.

**Overall Assessment:**

Ligand A is the superior candidate. While Ligand B has better metabolic stability and half-life, Ligand A excels in the most critical areas for a CNS-targeting GPCR ligand: BBB penetration, binding affinity, and DILI risk. The significantly stronger binding affinity of Ligand A (-8.2 vs -6.6) is a major advantage. The lower TPSA and DILI risk further strengthen its profile.

Output:
1
2025-04-17 05:11:27,885 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (337.383 and 344.415 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (85.84) is better than Ligand B (91.4) as it is closer to the <90 A^2 threshold for CNS targets.

**3. logP:** Both ligands have good logP values (2.504 and 1.296), falling within the optimal 1-3 range. Ligand A is slightly better.

**4. H-Bond Donors:** Ligand A (1) is preferable to Ligand B (2) as lower HBDs generally improve permeability.

**5. H-Bond Acceptors:** Both ligands have the same number of HBA (6), which is acceptable (<=10).

**6. QED:** Both ligands have good QED scores (0.747 and 0.824), indicating good drug-like properties.

**7. DILI:** Ligand A (69.058) has a slightly higher DILI risk than Ligand B (61.846), but both are still reasonably low.

**8. BBB:** Ligand B (84.839) has a significantly better BBB penetration percentile than Ligand A (74.641). This is a crucial factor for a CNS target like DRD2.

**9. Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and suggests poor permeability. However, the scale is not defined, so it's hard to interpret.

**10. Aqueous Solubility:** Both ligands have very poor aqueous solubility (-3.244 and -2.987). This is a significant drawback.

**11. hERG Inhibition:** Ligand A (0.116) has a lower hERG inhibition liability than Ligand B (0.499), which is preferable.

**12. Microsomal Clearance:** Ligand A (19.501) has a higher microsomal clearance than Ligand B (4.604), indicating lower metabolic stability.

**13. In vitro Half-Life:** Ligand B (7.22) has a slightly longer in vitro half-life than Ligand A (6.018).

**14. P-gp Efflux:** Ligand A (0.078) has lower P-gp efflux liability than Ligand B (0.101), which is beneficial for CNS penetration.

**15. Binding Affinity:** Ligand A (-7.8 kcal/mol) has a significantly stronger binding affinity than Ligand B (-0.0 kcal/mol). This is a major advantage, potentially outweighing some of the ADME drawbacks.

**Overall Assessment:**

While Ligand B has better BBB penetration and metabolic stability, Ligand A's significantly superior binding affinity (-7.8 vs -0.0 kcal/mol) is a decisive factor. The strong binding is likely to be more impactful than the slightly worse BBB and metabolic stability, especially considering the potential for further optimization. The lower P-gp efflux of Ligand A also supports better CNS exposure. The poor solubility of both is a concern, but can be addressed with formulation strategies.

Output:
1
2025-04-17 05:11:27,885 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 drug candidates, considering the provided guidelines and GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (355.395 and 362.463 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (124.44) is slightly above the optimal <90 for CNS targets, but still reasonable. Ligand B (95.57) is well within the preferred range for CNS penetration.

**logP:** Ligand A (0.342) is quite low, potentially hindering membrane permeability. Ligand B (2.218) is within the optimal 1-3 range. This is a significant advantage for Ligand B.

**H-Bond Donors/Acceptors:** Ligand A has 2 HBD and 8 HBA, which are acceptable. Ligand B has 1 HBD and 10 HBA, also acceptable, though the higher HBA count *could* slightly impact permeability.

**QED:** Both ligands have similar QED values (0.676 and 0.688), indicating good drug-likeness.

**DILI:** Ligand A (49.011) has a lower DILI risk than Ligand B (70.803), which is a positive.

**BBB:** Ligand A (61.923) has a moderate BBB penetration, while Ligand B (35.75) is quite poor. This is a major drawback for Ligand B, given DRD2 is a CNS target.

**Caco-2 Permeability:** Ligand A (-4.586) has poor Caco-2 permeability, consistent with its low logP. Ligand B (-5.169) also shows poor permeability.

**Aqueous Solubility:** Both ligands have very poor aqueous solubility (-2.437 and -2.714). This could pose formulation challenges.

**hERG Inhibition:** Ligand A (0.036) has a very low hERG risk, excellent. Ligand B (0.234) also shows low hERG risk.

**Microsomal Clearance:** Ligand A (71.401) has moderate clearance, while Ligand B (58.643) has lower clearance, suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (-10.267) has a very short half-life, a significant concern. Ligand B (-12.334) is even shorter.

**P-gp Efflux:** Ligand A (0.011) has very low P-gp efflux, which is favorable for CNS penetration. Ligand B (0.174) has slightly higher efflux, but still relatively low.

**Binding Affinity:** Ligand A (-7.0) and Ligand B (-5.9) both have good binding affinity, but Ligand A is significantly stronger (1.1 kcal/mol difference). This is a substantial advantage for Ligand A, potentially outweighing some of its ADME drawbacks.

**Overall Assessment:**

Ligand A has a significantly stronger binding affinity and a much lower P-gp efflux, which are critical for CNS GPCR targets. While its logP is low and BBB is only moderate, the strong affinity could compensate. Its DILI risk is also lower. Ligand B has a better logP and TPSA, but its significantly weaker affinity and poor BBB penetration are major drawbacks. The shorter half-life of both compounds is a concern, but the affinity difference is the deciding factor.

Output:
0
2025-04-17 05:11:27,885 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (421.257 Da) is slightly higher, but still acceptable. Ligand B (360.483 Da) is preferable.

**TPSA:** Both ligands have TPSA values above the optimal 90 A^2 for CNS targets. Ligand A (64.35 A^2) is better than Ligand B (69.3 A^2), but both are still relatively low and shouldn't be a major concern.

**logP:** Both ligands have good logP values (between 1-3). Ligand A (3.941) is at the higher end, potentially raising solubility concerns, while Ligand B (2.338) is closer to optimal.

**H-Bond Donors/Acceptors:** Ligand A has 2 HBD and 3 HBA, which is good. Ligand B has 1 HBD and 4 HBA, also acceptable.

**QED:** Both ligands have high QED values (A: 0.777, B: 0.91), indicating good drug-like properties. Ligand B is slightly better.

**DILI:** Ligand A (37.456) has a lower DILI risk than Ligand B (56.727), which is a significant advantage.

**BBB:** Ligand A (87.553) has a much better BBB percentile than Ligand B (34.122). This is *critical* for a CNS target like DRD2.

**Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and suggests poor permeability. Ligand A (-5.028) is slightly better than Ligand B (-5.254).

**Aqueous Solubility:** Both ligands have very poor aqueous solubility (-4.426 and -2.441 respectively). This is a significant drawback for both.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (A: 0.754, B: 0.585).

**Microsomal Clearance:** Ligand A (13.412 mL/min/kg) has a lower clearance than Ligand B (36.709 mL/min/kg), indicating better metabolic stability.

**In vitro Half-Life:** Ligand A (25.973 hours) has a much longer half-life than Ligand B (-32.423 hours, which is nonsensical and a major red flag).

**P-gp Efflux:** Ligand A (0.291) has lower P-gp efflux than Ligand B (0.184), which is preferable for CNS penetration.

**Binding Affinity:** Ligand B (-7.1 kcal/mol) has a slightly better binding affinity than Ligand A (-9.5 kcal/mol). However, the difference is not substantial enough to outweigh the other significant advantages of Ligand A.

**Overall Assessment:**

Ligand A is significantly better due to its superior BBB penetration (87.553 vs 34.122), longer half-life, lower DILI risk, and lower P-gp efflux. While Ligand B has a slightly better binding affinity, the other ADME properties of Ligand A are far more favorable for a CNS-targeting drug. The negative Caco-2 and solubility values are concerning for both, but can potentially be addressed through formulation strategies.



Output:
0
2025-04-17 05:11:27,885 - INFO - Reasoning:

Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight (MW):** Both ligands (358.463 and 386.283 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (69.64) is better than Ligand B (71.33). Both are reasonably good for CNS penetration, being below 90, but closer to the ideal.

**3. logP:** Both ligands (2.513 and 2.243) are within the optimal 1-3 range.

**4. H-Bond Donors (HBD):** Ligand A (2) is better than Ligand B (0). While both are acceptable, a small number of HBDs can aid permeability.

**5. H-Bond Acceptors (HBA):** Ligand A (4) is better than Ligand B (5). Both are acceptable, but lower is generally preferred.

**6. QED:** Both ligands have similar QED values (0.834 and 0.752), indicating good drug-like properties.

**7. DILI:** Ligand B (42.264) has a significantly lower DILI risk than Ligand A (54.556), which is a substantial advantage.

**8. BBB:** Ligand B (80.419) has a much higher BBB penetration percentile than Ligand A (64.793). This is *critical* for a CNS target like DRD2.

**9. Caco-2 Permeability:** Ligand A (-5.083) is better than Ligand B (-4.896). Higher values indicate better intestinal absorption.

**10. Aqueous Solubility:** Ligand A (-3.277) is better than Ligand B (-2.64). Higher values indicate better solubility.

**11. hERG Inhibition:** Both ligands have low hERG inhibition risk (0.579 and 0.411).

**12. Microsomal Clearance (Cl_mic):** Ligand B (34.624) has lower microsomal clearance than Ligand A (43.617), suggesting better metabolic stability.

**13. In vitro Half-Life:** Ligand A (34.829) has a longer half-life than Ligand B (-12.822). This is a positive attribute.

**14. P-gp Efflux:** Ligand A (0.54) has lower P-gp efflux than Ligand B (0.087), meaning it's less likely to be pumped out of the brain, improving CNS exposure.

**15. Binding Affinity:** Ligand A (-9.1 kcal/mol) has a significantly stronger binding affinity than Ligand B (-7.7 kcal/mol). This is a substantial advantage, potentially outweighing some ADME drawbacks.

**Overall Assessment:**

While Ligand A has a better binding affinity and half-life, Ligand B excels in crucial ADME properties for a CNS-targeting GPCR. Specifically, its significantly higher BBB penetration (80.419 vs 64.793) and lower DILI risk (42.264 vs 54.556) are major advantages. The lower P-gp efflux is also beneficial. The difference in binding affinity, while substantial, might be overcome with further optimization of Ligand B. Given the importance of CNS penetration and safety for a DRD2 ligand, Ligand B is the more promising candidate.

Output:
1
2025-04-17 05:11:27,886 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight (MW):** Both ligands (367.555 and 349.402 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Both ligands (55.4 and 55.84) are reasonably low, but slightly above the optimal <90 for CNS targets. This isn't a major concern, but it's a slight disadvantage.

**3. logP:** Both ligands have good logP values (3.617 and 3.03), falling within the optimal 1-3 range.

**4. H-Bond Donors (HBD):** Ligand A has 1 HBD, while Ligand B has 0. Both are acceptable (<=5).

**5. H-Bond Acceptors (HBA):** Ligand A has 3 HBA, and Ligand B has 4. Both are within the acceptable range (<=10).

**6. QED:** Both ligands have similar QED values (0.755 and 0.787), indicating good drug-likeness.

**7. DILI:** Ligand A (35.789) has a slightly better DILI score than Ligand B (44.242), indicating a lower risk of liver injury. Both are below the concerning threshold of 60.

**8. BBB:** This is a critical parameter for CNS targets. Ligand B (95.541) significantly outperforms Ligand A (57.774) in BBB penetration. This is a major advantage for Ligand B.

**9. Caco-2 Permeability:** Ligand A (-4.977) has a worse Caco-2 permeability than Ligand B (-3.921), suggesting lower intestinal absorption.

**10. Aqueous Solubility:** Ligand A (-5.392) has worse solubility than Ligand B (-3.226).

**11. hERG Inhibition:** Both ligands have similar, low hERG inhibition risk (0.617 and 0.676).

**12. Microsomal Clearance (Cl_mic):** Both ligands have similar Cl_mic values (53.538 and 54.069), suggesting similar metabolic stability.

**13. In vitro Half-Life:** Ligand B (8.708) has a significantly longer in vitro half-life than Ligand A (-31.774). This is a major advantage for Ligand B.

**14. P-gp Efflux:** Both ligands have low P-gp efflux liability (0.45 and 0.191). Ligand B is slightly better.

**15. Binding Affinity:** Ligand B (-8.9 kcal/mol) has a *much* stronger binding affinity than Ligand A (0.0 kcal/mol). This is a decisive factor.

**Overall Assessment:**

While Ligand A has a slightly better DILI score, Ligand B overwhelmingly outperforms it in the critical areas for a CNS-targeting GPCR ligand: BBB penetration, binding affinity, and in vitro half-life. The significantly stronger binding affinity of Ligand B (-8.9 kcal/mol vs 0.0 kcal/mol) is a huge advantage that can compensate for any minor drawbacks in TPSA or solubility. The superior BBB penetration (95.541 vs 57.774) is also crucial.

Output:
1
2025-04-17 05:11:27,886 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (346.43 and 369.58 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Both ligands have TPSA values (62.99 and 61.44) below the 90 A^2 threshold desirable for CNS targets, which is excellent.

**3. logP:** Both ligands have logP values (1.935 and 2.118) within the optimal 1-3 range.

**4. H-Bond Donors:** Ligand A (0 HBD) is preferable to Ligand B (2 HBD) as fewer HBDs generally improve permeability.

**5. H-Bond Acceptors:** Both ligands have the same number of HBA (4), which is acceptable (<=10).

**6. QED:** Ligand A (0.836) has a higher QED score than Ligand B (0.688), indicating a more drug-like profile.

**7. DILI:** Ligand A (28.62) has a significantly lower DILI risk than Ligand B (8.14), which is a major advantage.

**8. BBB:** Ligand A (88.06%) has a much higher BBB penetration percentile than Ligand B (64.83%). This is *critical* for a CNS target like DRD2.

**9. Caco-2 Permeability:** Ligand A (-4.209) has a lower Caco-2 permeability than Ligand B (-5.524). Lower values are less desirable.

**10. Aqueous Solubility:** Ligand A (-2.822) has lower solubility than Ligand B (-1.931). Solubility is important, but not as critical as BBB for a CNS target.

**11. hERG Inhibition:** Both ligands have low hERG inhibition risk (0.545 and 0.394).

**12. Microsomal Clearance:** Ligand A (73.098) has higher microsomal clearance than Ligand B (26.457), meaning it's less metabolically stable. This is a drawback for Ligand A.

**13. In vitro Half-Life:** Ligand A (21.108 hours) has a longer half-life than Ligand B (15.93 hours). This is a positive for Ligand A.

**14. P-gp Efflux:** Ligand A (0.288) has lower P-gp efflux than Ligand B (0.009), which is favorable for CNS penetration.

**15. Binding Affinity:** Ligand B (-7.5 kcal/mol) has a slightly better binding affinity than Ligand A (-8.6 kcal/mol). While affinity is important, the difference of 1.1 kcal/mol is not substantial enough to outweigh the other significant advantages of Ligand A.

**Overall Assessment:**

Ligand A is the more promising candidate. Its significantly better BBB penetration, lower DILI risk, higher QED, and lower P-gp efflux outweigh its slightly lower solubility, higher clearance, and slightly weaker binding affinity. For a CNS target like DRD2, achieving good brain exposure is paramount, and Ligand A excels in this regard.

Output:
1
2025-04-17 05:11:27,886 - INFO - Reasoning:

Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (386.949 and 347.371 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (66.4) is significantly better than Ligand B (102.69). For CNS targets, we want TPSA <= 90, so Ligand A is much closer to this threshold.

**3. logP:** Both ligands have similar logP values (2.159 and 2.144), falling within the optimal 1-3 range.

**4. H-Bond Donors:** Ligand A (0) is preferable to Ligand B (2). Fewer HBDs generally improve permeability.

**5. H-Bond Acceptors:** Both ligands have the same number of HBA (6), which is acceptable (<=10).

**6. QED:** Both ligands have good QED scores (0.739 and 0.795), indicating good drug-like properties.

**7. DILI:** Ligand A (34.471) has a much lower DILI risk than Ligand B (73.013). This is a significant advantage for Ligand A.

**8. BBB:** Ligand A (88.445) has a considerably higher BBB penetration percentile than Ligand B (68.282). This is *critical* for a CNS target like DRD2.

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.91 and -4.854). This is unusual and suggests poor permeability. However, the absolute values are similar.

**10. Aqueous Solubility:** Both ligands have negative solubility values (-2.709 and -3.653). This is also concerning and suggests poor solubility. Ligand B is slightly worse.

**11. hERG Inhibition:** Ligand A (0.676) has a slightly lower hERG inhibition risk than Ligand B (0.495). Lower is better.

**12. Microsomal Clearance:** Ligand A (-9.356) has a much lower (better) microsomal clearance than Ligand B (20.446). This indicates greater metabolic stability for Ligand A.

**13. In vitro Half-Life:** Ligand B (69.331) has a significantly longer in vitro half-life than Ligand A (6.808). This is a positive for Ligand B.

**14. P-gp Efflux:** Ligand A (0.24) has a lower P-gp efflux liability than Ligand B (0.295), which is beneficial for CNS penetration.

**15. Binding Affinity:** Ligand B (-8.0) has a slightly better binding affinity than Ligand A (-7.4). While affinity is important, the difference of 0.6 kcal/mol is not substantial enough to outweigh the numerous advantages of Ligand A.

**Overall Assessment:**

Ligand A is the superior candidate. It has a significantly better safety profile (lower DILI), much better BBB penetration, better metabolic stability (lower Cl_mic), and lower P-gp efflux. While Ligand B has a slightly better binding affinity and half-life, the ADME properties of Ligand A are far more favorable for a CNS-targeting drug. The TPSA is also much more favorable for Ligand A.

Output:
1
2025-04-17 05:11:27,886 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (355.869 and 346.446 Da) fall within the ideal range of 200-500 Da.

**TPSA:** Ligand A (45.23) is significantly better than Ligand B (58.2). For CNS targets, we want TPSA <= 90, and A is much closer to the optimal range for brain penetration.

**logP:** Both ligands have good logP values (4.767 and 3.393), falling within the 1-3 range, suggesting good permeability. Ligand A is slightly higher, which could potentially lead to off-target effects, but is still acceptable.

**H-Bond Donors/Acceptors:** Ligand A (HBD=1, HBA=3) is preferable to Ligand B (HBD=2, HBA=2) as it has fewer hydrogen bond donors.

**QED:** Both ligands have acceptable QED values (0.804 and 0.709), indicating good drug-like properties.

**DILI:** Ligand B (23.885) has a much lower DILI risk than Ligand A (64.948), which is a significant advantage.

**BBB:** Both ligands have excellent BBB penetration (82.474 and 81.698), exceeding the desirable threshold of 70. This is crucial for a CNS target like DRD2.

**Caco-2 Permeability:** Both have negative Caco-2 values (-4.768 and -4.565). This is unusual and potentially problematic, suggesting poor intestinal absorption. However, for a CNS target, this is less critical as the primary route of exposure is expected to be via the blood-brain barrier.

**Aqueous Solubility:** Both ligands have very poor aqueous solubility (-4.555 and -3.852). This could pose formulation challenges.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.736 and 0.635), which is good.

**Microsomal Clearance:** Ligand B (77.967) has a higher microsomal clearance than Ligand A (61.482), meaning A is more metabolically stable.

**In vitro Half-Life:** Ligand A (68.489) has a significantly longer in vitro half-life than Ligand B (17.424), which is a major advantage.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.642 and 0.254), which is favorable for CNS penetration. Ligand B is slightly better here.

**Binding Affinity:** Both ligands have excellent binding affinity (-9.6 and -9.2 kcal/mol), well below the -7.0 kcal/mol threshold. Ligand A is slightly more potent.

**Overall Assessment:**

Ligand A excels in TPSA, metabolic stability (Cl_mic & t1/2), and binding affinity. Ligand B has a much better DILI score and slightly better P-gp efflux. The poor solubility and Caco-2 values are concerning for both, but less critical given the CNS target. The difference in half-life is substantial. Given the importance of metabolic stability and potency for GPCR ligands, and the relatively small difference in binding affinity, the longer half-life and better metabolic stability of Ligand A outweigh the DILI risk.

Output:
1
2025-04-17 05:11:27,887 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (364.515 and 363.487 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (78.09) is better than Ligand B (84.14). Both are below the 90 A^2 threshold for CNS targets, but A is closer to the ideal range.

**3. logP:** Both ligands have good logP values (1.837 and 1.336), falling within the optimal 1-3 range. Ligand B is slightly lower, which could slightly impact permeability.

**4. H-Bond Donors:** Ligand A (2) is acceptable, while Ligand B (1) is even better, both are below the 5 threshold.

**5. H-Bond Acceptors:** Ligand A (4) is good, while Ligand B (7) is also acceptable, being below the 10 threshold.

**6. QED:** Both ligands have good QED scores (0.738 and 0.863), indicating good drug-like properties.

**7. DILI:** Ligand A (26.91) has a significantly lower DILI risk than Ligand B (42.885). This is a substantial advantage for Ligand A.

**8. BBB:** Ligand B (73.517) has a better BBB penetration percentile than Ligand A (50.523). This is a critical factor for a CNS target like DRD2.

**9. Caco-2 Permeability:** Ligand A (-5.32) has a worse Caco-2 permeability than Ligand B (-4.976).

**10. Aqueous Solubility:** Ligand A (-1.626) has a worse aqueous solubility than Ligand B (-2.08).

**11. hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.222 and 0.767).

**12. Microsomal Clearance:** Ligand A (17.79) has a lower microsomal clearance than Ligand B (21.776), indicating better metabolic stability.

**13. In vitro Half-Life:** Ligand A (-17.536) has a much longer in vitro half-life than Ligand B (14.36).

**14. P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.036 and 0.081).

**15. Binding Affinity:** Ligand B (-8.8) has a slightly better binding affinity than Ligand A (-8.0). While the difference is not huge, it is still a positive for Ligand B.

**Overall Assessment:**

Ligand B has a significantly better BBB score and a slightly better binding affinity, which are crucial for a CNS GPCR target. However, Ligand A has a much lower DILI risk, better metabolic stability (lower Cl_mic, longer t1/2), and a better TPSA. The difference in binding affinity is not large enough to outweigh the safety and pharmacokinetic advantages of Ligand A. The better BBB of Ligand B is important, but the other properties of Ligand A make it a more promising candidate overall.

Output:
1
2025-04-17 05:11:27,887 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (384.929 and 382.961 Da) fall comfortably within the ideal 200-500 Da range.

**2. TPSA:** Both ligands have TPSA values (50.8 and 51.02) slightly above the optimal <90 for CNS targets, but still reasonable.

**3. logP:** Ligand A (3.334) is within the optimal 1-3 range. Ligand B (4.616) is a bit higher, potentially leading to solubility issues or off-target interactions, but not drastically so.

**4. H-Bond Donors:** Ligand A (1) is good. Ligand B (0) is also acceptable.

**5. H-Bond Acceptors:** Ligand A (4) and Ligand B (5) are both within the acceptable limit of <=10.

**6. QED:** Both ligands have QED values (0.868 and 0.702) above 0.5, indicating good drug-like properties.

**7. DILI:** Ligand A (60.644) is approaching a concerning DILI risk, while Ligand B (45.328) is better, falling well below the 60% threshold.

**8. BBB:** Ligand A (75.533) has a better BBB percentile than Ligand B (66.731), which is crucial for a CNS target like DRD2.

**9. Caco-2:** Both ligands have negative Caco-2 values (-4.817 and -4.852), which is unusual and suggests very poor permeability. This is a significant drawback for both.

**10. Solubility:** Both ligands have negative solubility values (-4.213 and -4.544), indicating very poor aqueous solubility. This is also a significant drawback.

**11. hERG:** Ligand A (0.466) has a lower hERG risk than Ligand B (0.737), which is preferable.

**12. Cl_mic:** Ligand A (51.744) has a lower microsomal clearance than Ligand B (74.005), indicating better metabolic stability.

**13. t1/2:** Ligand B (55.584) has a longer in vitro half-life than Ligand A (38.195), which is generally desirable.

**14. Pgp:** Ligand A (0.178) has lower P-gp efflux liability than Ligand B (0.699), which is beneficial for CNS penetration.

**15. Binding Affinity:** Ligand A (-8.4 kcal/mol) has a significantly stronger binding affinity than Ligand B (-7.2 kcal/mol). This >1.5 kcal/mol difference is a major advantage, potentially outweighing some of the ADME drawbacks.

**Overall Assessment:**

Despite the poor Caco-2 and solubility for both compounds, Ligand A is the more promising candidate. Its significantly stronger binding affinity (-8.4 vs -7.2 kcal/mol) is a key advantage for a GPCR target. It also has better BBB penetration, lower DILI risk, lower hERG risk, lower Pgp efflux, and better metabolic stability. While Ligand B has a slightly longer half-life, the superior binding and CNS properties of Ligand A make it the preferred choice.

Output:
0
2025-04-17 05:11:27,887 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (379.873 and 351.491 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (96.87) is slightly higher than Ligand B (89.45). Both are below the 90 A^2 threshold desirable for CNS targets, but Ligand B is preferable.

**3. logP:** Both ligands have a logP of approximately 2.4, which is within the optimal 1-3 range.

**4. H-Bond Donors:** Ligand A (2) is better than Ligand B (3).

**5. H-Bond Acceptors:** Ligand A (6) is better than Ligand B (4).

**6. QED:** Ligand A (0.831) has a significantly higher QED score than Ligand B (0.604), indicating better overall drug-likeness.

**7. DILI:** Ligand A (83.676) has a much higher DILI risk than Ligand B (15.2). This is a major concern for Ligand A.

**8. BBB:** Ligand A (57.193) has a better BBB percentile than Ligand B (46.413), but both are below the desirable >70 for CNS targets.

**9. Caco-2 Permeability:** Ligand A (-5.355) has worse Caco-2 permeability than Ligand B (-4.887). Lower (more negative) values indicate poorer permeability.

**10. Aqueous Solubility:** Ligand A (-3.206) has worse aqueous solubility than Ligand B (-1.945).

**11. hERG Inhibition:** Ligand A (0.276) has a slightly lower hERG inhibition risk than Ligand B (0.545).

**12. Microsomal Clearance:** Ligand B (-0.875) has a lower (better) microsomal clearance than Ligand A (1.569), suggesting greater metabolic stability.

**13. In vitro Half-Life:** Ligand B (-15.313) has a significantly longer in vitro half-life than Ligand A (31.397).

**14. P-gp Efflux:** Ligand A (0.09) has a lower P-gp efflux liability than Ligand B (0.235), which is favorable for CNS penetration.

**15. Binding Affinity:** Both ligands have a binding affinity of -7 kcal/mol, so this parameter doesn't differentiate them.

**Overall Assessment:**

While Ligand A has a better QED and slightly better P-gp efflux, its significantly higher DILI risk, poorer solubility, and worse Caco-2 permeability are major drawbacks. Ligand B, despite a lower QED, exhibits a much more favorable safety profile (lower DILI), better metabolic stability (lower Cl_mic, longer t1/2), and better permeability. Given the GPCR-specific priorities and the importance of safety and metabolic stability for CNS drugs, Ligand B is the more promising candidate.

Output:
1
2025-04-17 05:11:27,887 - INFO - Batch 177 complete. Total preferences: 2832
2025-04-17 05:11:27,887 - INFO - Processing batch 178/512...
2025-04-17 05:12:10,080 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (349.435 and 346.431 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (107.19) is higher than Ligand B (85.25). For CNS targets, TPSA < 90 is preferred. Ligand B is better here.

**3. logP:** Ligand A (0.249) is quite low, potentially hindering membrane permeability. Ligand B (0.709) is better, though still on the lower side of the optimal 1-3 range.

**4. H-Bond Donors:** Ligand A (3) is acceptable, while Ligand B (2) is also good.

**5. H-Bond Acceptors:** Ligand A (4) and Ligand B (5) are both within the acceptable limit of 10.

**6. QED:** Both ligands have good QED scores (0.625 and 0.712), indicating drug-like properties.

**7. DILI:** Ligand A (51.881) has a slightly higher DILI risk than Ligand B (32.61). Both are below the concerning threshold of 60, but lower is better.

**8. BBB:** Ligand A (60.876) and Ligand B (50.795) are both below the desirable >70 percentile for CNS targets. However, Ligand A is better.

**9. Caco-2 Permeability:** Both have negative Caco-2 values (-5.301 and -5.235), which is unusual and suggests poor permeability. This is a significant concern for both.

**10. Aqueous Solubility:** Both have negative solubility values (-2.259 and -1.065), indicating poor aqueous solubility. This is also a significant concern.

**11. hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.268 and 0.1).

**12. Microsomal Clearance:** Ligand A (37.429) has higher microsomal clearance than Ligand B (8.025), suggesting lower metabolic stability. Ligand B is better.

**13. In vitro Half-Life:** Ligand A (26.342) has a longer half-life than Ligand B (1.805).

**14. P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.045 and 0.021), which is good for CNS penetration.

**15. Binding Affinity:** Ligand A (-8.5 kcal/mol) has a slightly better binding affinity than Ligand B (-7.8 kcal/mol). This 0.7 kcal/mol difference is significant.

**Overall Assessment:**

While both ligands have significant drawbacks (poor Caco-2 and solubility), Ligand A has a substantially better binding affinity. The slightly better BBB penetration and longer half-life also contribute to its favorability. The lower logP of Ligand A is a concern, but the stronger binding may compensate. Ligand B has better TPSA and metabolic stability, but the weaker binding affinity is a major disadvantage for a GPCR target. Given the GPCR-specific priorities, the affinity advantage of Ligand A outweighs its other shortcomings.

Output:
1
2025-04-17 05:12:10,080 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (345.49 and 368.46 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (56.15) is excellent, well below the 90 A^2 threshold for CNS targets. Ligand B (113.44) is higher, but still potentially acceptable, though less ideal.

**logP:** Ligand A (3.23) is optimal (1-3). Ligand B (0.022) is very low, which is a significant concern for permeability and CNS penetration.

**H-Bond Donors/Acceptors:** Ligand A (1 HBD, 5 HBA) is good. Ligand B (3 HBD, 7 HBA) is also acceptable, but slightly higher.

**QED:** Both ligands have reasonable QED values (0.446 and 0.652), indicating drug-like properties. Ligand B is slightly better.

**DILI:** Ligand A (12.6%) has a much lower DILI risk than Ligand B (55.2%). This is a substantial advantage for Ligand A.

**BBB:** Ligand A (81.7%) shows excellent BBB penetration, exceeding the desirable 70% threshold. Ligand B (35.7%) is poor, likely due to the low logP.

**Caco-2 Permeability:** Ligand A (-4.96) is negative, which is unusual and suggests poor permeability. Ligand B (-5.72) is also negative, but slightly worse.

**Aqueous Solubility:** Both ligands have negative solubility values, which is also unusual and suggests poor solubility. Ligand A (-3.15) is slightly better than Ligand B (-1.51).

**hERG:** Ligand A (0.64) has a low hERG risk. Ligand B (0.03) has a very low hERG risk, but this is less critical given other issues.

**Microsomal Clearance:** Ligand A (70.75) has moderate clearance. Ligand B (-6.47) has negative clearance, which is impossible and indicates a data error or unusual behavior.

**In vitro Half-Life:** Ligand A (-2.31) has a negative half-life, which is impossible and indicates a data error or unusual behavior. Ligand B (15.58) has a reasonable half-life.

**P-gp Efflux:** Ligand A (0.45) has low P-gp efflux, which is good. Ligand B (0.04) also has low P-gp efflux.

**Binding Affinity:** Ligand B (-8.3 kcal/mol) has a significantly stronger binding affinity than Ligand A (-7.8 kcal/mol). This is a 1.5 kcal/mol difference, which is substantial.

**Overall Assessment:**

Despite the stronger binding affinity of Ligand B, its extremely low logP and poor BBB penetration are major drawbacks for a CNS target like DRD2. The negative values for clearance and half-life are also concerning and likely indicate data issues. Ligand A, while having slightly weaker affinity, possesses a much more favorable profile regarding logP, BBB, and DILI risk. The negative Caco-2 and solubility values are concerning, but might be addressable with formulation strategies. The negative values for clearance and half-life are also concerning and likely indicate data issues.

Considering the GPCR-specific priorities and the overall balance of properties, Ligand A is the more promising candidate.

Output:
1
2025-04-17 05:12:10,080 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (368.352 and 370.559 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (99.1) is higher than the preferred <90 for CNS targets, while Ligand B (49.85) is well within the range. This is a significant advantage for Ligand B.

**logP:** Ligand A (-0.196) is quite low, potentially hindering membrane permeability. Ligand B (2.783) is within the optimal 1-3 range. This favors Ligand B.

**H-Bond Donors/Acceptors:** Ligand A has 3 HBD and 5 HBA, acceptable values. Ligand B has 0 HBD and 4 HBA, also acceptable.

**QED:** Both ligands have good QED scores (0.603 and 0.721, respectively), indicating drug-like properties.

**DILI:** Ligand A (37.728) has a slightly higher DILI risk than Ligand B (25.475), but both are below the concerning threshold of 60.

**BBB:** Ligand B (69.407) has a better BBB percentile than Ligand A (57.968). While both are not ideal (>70), Ligand B is closer to the desired range for a CNS target.

**Caco-2 Permeability:** Both have negative Caco-2 values (-4.869 and -4.615), which is unusual and suggests poor permeability. However, these values are on a log scale and likely represent very low permeability.

**Aqueous Solubility:** Both ligands have negative solubility values (-1.623 and -2.28), indicating very poor aqueous solubility. This is a significant drawback for both.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.235 and 0.297).

**Microsomal Clearance:** Ligand A (-1.407) has a lower (better) microsomal clearance than Ligand B (53.592), suggesting better metabolic stability. This is a strong point for Ligand A.

**In vitro Half-Life:** Ligand A (-42.248) has a very negative half-life, which is not interpretable. Ligand B (12.292) has a reasonable half-life.

**P-gp Efflux:** Ligand A (0.023) has a lower P-gp efflux liability than Ligand B (0.206), which is favorable for CNS penetration.

**Binding Affinity:** Ligand B (0.0) has a significantly better binding affinity than Ligand A (-6.8). This is a crucial advantage, as a difference of >1.5 kcal/mol can outweigh other drawbacks.

**Overall Assessment:**

Ligand B is the more promising candidate. It has a much better logP, TPSA, BBB penetration, and, most importantly, binding affinity. While both have poor solubility and Caco-2 permeability, the strong affinity of Ligand B and its better CNS properties outweigh the drawbacks. Ligand A's better metabolic stability is a plus, but the significantly weaker binding and unfavorable logP are major concerns.

Output:
1
2025-04-17 05:12:10,080 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (364.392 and 352.475 Da) fall within the ideal range of 200-500 Da.

**TPSA:** Ligand A (52.89) is excellent, well below the 90 A^2 threshold for CNS targets. Ligand B (76.66) is still reasonable, but less optimal, being closer to the 140 A^2 threshold for oral absorption.

**logP:** Ligand A (3.839) is at the higher end of the optimal range (1-3), while Ligand B (1.797) is at the lower end. While both are within range, higher logP can sometimes be problematic for solubility, but is less of a concern given the other parameters.

**H-Bond Donors/Acceptors:** Ligand A (1 HBD, 3 HBA) and Ligand B (2 HBD, 4 HBA) both have acceptable numbers of H-bond donors and acceptors, well within the guidelines.

**QED:** Both ligands have QED values (0.76 and 0.621) above the 0.5 threshold, indicating good drug-like properties.

**DILI:** Ligand A (53.432) has a moderate DILI risk, while Ligand B (13.843) has a very low DILI risk. This is a significant advantage for Ligand B.

**BBB:** Ligand A (83.443) has a very good BBB penetration percentile, exceeding the desirable >70% threshold for CNS targets. Ligand B (70.803) is close, but slightly below this threshold.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.74 and -4.941), which is unusual and suggests poor permeability. This is a concern for both.

**Aqueous Solubility:** Both ligands have very poor aqueous solubility (-5.189 and -1.656). This is a major drawback for both compounds.

**hERG Inhibition:** Ligand A (0.941) has a slightly higher hERG risk than Ligand B (0.292), which is preferable.

**Microsomal Clearance:** Ligand A (67.573) has a higher microsomal clearance than Ligand B (36.158), indicating lower metabolic stability.

**In vitro Half-Life:** Ligand B (-2.431) has a negative in vitro half-life, which is not physically possible and likely an error or outlier. Ligand A (8.678) has a reasonable half-life.

**P-gp Efflux:** Ligand A (0.343) has lower P-gp efflux than Ligand B (0.031), which is beneficial for CNS penetration.

**Binding Affinity:** Ligand A (-9.4 kcal/mol) has a significantly stronger binding affinity than Ligand B (-7.4 kcal/mol). This is a substantial advantage, exceeding the 1.5 kcal/mol difference threshold.

**Overall Assessment:**

Ligand A excels in binding affinity and BBB penetration, which are critical for a CNS-targeting GPCR. However, it has moderate DILI risk and higher metabolic clearance. Ligand B has a much lower DILI risk and better metabolic stability, but its binding affinity is weaker and its BBB penetration is slightly lower. The negative half-life for Ligand B is a major red flag. While both have poor solubility and permeability, the superior binding affinity of Ligand A is likely to outweigh its other drawbacks, especially given the importance of potency for GPCR ligands.

Output:
1
2025-04-17 05:12:10,081 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (386.5 and 363.5 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (121.6) is slightly above the optimal <90 for CNS targets, but still reasonable. Ligand B (78.51) is excellent, well below 90.

**logP:** Ligand A (0.453) is quite low, potentially hindering permeability. Ligand B (2.327) is within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A has 3 HBD and 5 HBA, acceptable. Ligand B has 2 HBD and 4 HBA, also acceptable.

**QED:** Both ligands have good QED scores (0.695 and 0.862), indicating drug-like properties.

**DILI:** Both have low DILI risk (49.6 and 39.7), which is good.

**BBB:** Both have good BBB penetration (65.5% and 68.4%), but ideally, we'd like to see >70% for a CNS target. Ligand B is slightly better here.

**Caco-2:** Both have negative Caco-2 values, which is unusual and problematic. It suggests poor permeability.

**Solubility:** Both have negative solubility values, also unusual and problematic. It suggests poor solubility.

**hERG:** Both have very low hERG risk (0.122 and 0.256).

**Microsomal Clearance:** Ligand A has a high negative clearance (-26.99), indicating very slow clearance and good metabolic stability. Ligand B has a low clearance (1.393), which is less favorable.

**In vitro Half-Life:** Ligand A has a longer half-life (17.39 hours) than Ligand B (9.76 hours).

**P-gp Efflux:** Both have very low P-gp efflux (0.025 and 0.067), which is favorable for CNS penetration.

**Binding Affinity:** Ligand B (-8.2 kcal/mol) has a slightly better binding affinity than Ligand A (-7.8 kcal/mol), but the difference is relatively small.

**Overall Assessment:**

Ligand B is the better candidate. While both have issues with Caco-2 and solubility, Ligand B has a more favorable logP, TPSA, and slightly better BBB penetration. The difference in binding affinity is not substantial enough to overcome Ligand A's poor logP. The improved metabolic stability of Ligand A is a plus, but the other ADME properties of Ligand B are more aligned with the requirements for a CNS-active GPCR ligand.

Output:
1
2025-04-17 05:12:10,081 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 drug candidates, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (335.367 and 347.459 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (102.16) is higher than the preferred <90 for CNS targets, while Ligand B (71.53) is well within the range. This is a significant advantage for Ligand B.

**logP:** Ligand A (3.386) is at the upper end of the optimal 1-3 range, while Ligand B (2.174) is comfortably within it. Both are acceptable, but Ligand B is slightly better.

**H-Bond Donors/Acceptors:** Ligand A has 3 HBD and 5 HBA, which are acceptable. Ligand B has 1 HBD and 4 HBA, also acceptable.

**QED:** Both ligands have similar QED values (0.663 and 0.695), indicating good drug-likeness.

**DILI:** Ligand A has a high DILI risk (95.812 percentile), which is a major concern. Ligand B has a much lower DILI risk (19.891 percentile), a significant advantage.

**BBB:** Ligand A (62.621 percentile) is below the desirable >70 for CNS targets, while Ligand B (80.419 percentile) is excellent. This is a crucial difference given DRD2's role in CNS disorders.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.99 and -4.367), which is unusual and suggests poor permeability. However, these values are on a scale where negative values are possible and don't necessarily disqualify a compound.

**Aqueous Solubility:** Both ligands have very poor aqueous solubility (-4.73 and -1.839). This could pose formulation challenges.

**hERG Inhibition:** Both ligands show low hERG inhibition risk (0.612 and 0.534), which is good.

**Microsomal Clearance:** Ligand A (36.536) has lower clearance than Ligand B (46.076), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand B (-1.714) has a negative half-life, which is not physically possible and indicates a data error or unusual behavior. Ligand A (17.353) has a reasonable half-life.

**P-gp Efflux:** Both ligands show low P-gp efflux liability (0.13 and 0.109), which is favorable for CNS penetration.

**Binding Affinity:** Ligand B (-7.1 kcal/mol) has a slightly better binding affinity than Ligand A (-9.6 kcal/mol). While A is stronger, the difference is less than the 1.5 kcal/mol threshold that could outweigh other issues.

**Overall Assessment:**

Ligand B is the superior candidate. It has a much better BBB score, significantly lower DILI risk, a more favorable TPSA, and a slightly better logP. The negative half-life for Ligand B is a red flag, but the other advantages are substantial. Ligand A's high DILI risk and suboptimal BBB penetration are major drawbacks. Although Ligand A has a better binding affinity, the other ADME properties of Ligand B make it a more promising starting point for drug development.

Output:
1
2025-04-17 05:12:10,081 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B based on the provided guidelines, prioritizing GPCR-specific properties (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (354.475 and 365.543 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (51.96) is slightly higher than Ligand B (47.36), but both are below the 90 A^2 threshold desirable for CNS targets.

**logP:** Ligand A (4.08) is slightly higher than the optimal range (1-3), while Ligand B (3.182) is within the optimal range. This favors Ligand B.

**H-Bond Donors/Acceptors:** Both have acceptable HBD (0) and HBA (4 for A, 5 for B) counts, well within the guidelines.

**QED:** Both ligands have acceptable QED scores (0.709 and 0.664), indicating good drug-like properties.

**DILI:** Ligand A (80.923) has a higher DILI risk than Ligand B (26.638). This is a significant advantage for Ligand B.

**BBB:** Ligand B (83.249) has a substantially better BBB penetration score than Ligand A (60.566). This is *critical* for a CNS target like DRD2 and heavily favors Ligand B.

**Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and difficult to interpret without knowing the scale. However, they are similarly poor.

**Aqueous Solubility:** Both ligands have very poor aqueous solubility (-4.162 and -3.464). This is a concern for both, but may be less critical if BBB penetration is high.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.479 and 0.649).

**Microsomal Clearance:** Ligand B (93.131) has a higher microsomal clearance than Ligand A (27.207), suggesting faster metabolism and lower metabolic stability. This favors Ligand A.

**In vitro Half-Life:** Ligand A (59.679) has a longer in vitro half-life than Ligand B (29.854), which is preferable.

**P-gp Efflux:** Ligand A (0.59) has lower P-gp efflux than Ligand B (0.365), which is beneficial for CNS exposure.

**Binding Affinity:** Ligand B (-6.6 kcal/mol) has a significantly stronger binding affinity than Ligand A (-10.2 kcal/mol). This is a major advantage for Ligand B, and can potentially offset some of the ADME drawbacks.

**Overall Assessment:**

Ligand B is the stronger candidate. While Ligand A has better metabolic stability and P-gp efflux, Ligand B's superior BBB penetration, significantly better binding affinity, and lower DILI risk outweigh these drawbacks, especially given the CNS target. The slightly higher logP of Ligand A is less concerning than the substantial difference in BBB penetration. The poor solubility is a concern for both, but can be addressed with formulation strategies.

Output:
1
2025-04-17 05:12:10,081 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (349.475 and 356.396 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (64.09) is slightly above the optimal <90 for CNS targets, but still reasonable. Ligand B (58.87) is excellent, well below 90.

**3. logP:** Ligand A (1.001) is at the lower end of the optimal 1-3 range, potentially hindering permeability. Ligand B (3.38) is well within the optimal range.

**4. H-Bond Donors:** Both ligands have 1 HBD, which is acceptable (<=5).

**5. H-Bond Acceptors:** Ligand A has 4 HBAs, and Ligand B has 6 HBAs, both are within the acceptable limit of <=10.

**6. QED:** Both ligands have similar QED values (0.769 and 0.786), indicating good drug-likeness.

**7. DILI:** Ligand A (5.894) has a very low DILI risk, significantly better than Ligand B (43.66).

**8. BBB:** Ligand B (74.719) has a significantly better BBB percentile than Ligand A (62.621). This is a crucial factor for a CNS target like DRD2.

**9. Caco-2 Permeability:** Ligand A (-4.773) has poor Caco-2 permeability, suggesting poor intestinal absorption. Ligand B (-5.018) is also poor, but slightly worse.

**10. Aqueous Solubility:** Ligand A (-0.496) has slightly better aqueous solubility than Ligand B (-3.529).

**11. hERG Inhibition:** Ligand A (0.125) has a very low hERG inhibition risk, much better than Ligand B (0.728).

**12. Microsomal Clearance:** Ligand A (6.02) has lower microsomal clearance, indicating better metabolic stability, compared to Ligand B (36.627).

**13. In vitro Half-Life:** Ligand B (23.813) has a significantly longer in vitro half-life than Ligand A (5.644).

**14. P-gp Efflux:** Ligand A (0.022) has very low P-gp efflux, which is favorable for CNS penetration. Ligand B (0.16) is slightly higher, but still reasonable.

**15. Binding Affinity:** Both ligands have very similar and excellent binding affinities (-8.1 and -8.3 kcal/mol). The difference is negligible.

**Overall Assessment:**

Ligand B excels in BBB penetration and in vitro half-life, both critical for CNS drug development. Its logP is also more optimal. However, it has a higher DILI risk and hERG inhibition liability. Ligand A has a superior safety profile (DILI, hERG) and metabolic stability, but suffers from lower BBB penetration and Caco-2 permeability.

Considering the GPCR-specific priorities, BBB is paramount for DRD2. While Ligand A's safety profile is appealing, Ligand B's superior BBB penetration outweighs its slightly higher risk profile. The similar binding affinity makes this the deciding factor.

Output:
1
2025-04-17 05:12:10,082 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (352.381 and 362.832 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (61.19) is better than Ligand B (41.57). Both are below the 90 A^2 threshold desirable for CNS targets.

**logP:** Both ligands have good logP values (3.463 and 3.169), falling within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A (0 HBD, 5 HBA) is slightly better than Ligand B (1 HBD, 3 HBA) in terms of balancing solubility and permeability. Both are within acceptable limits.

**QED:** Both ligands have good QED scores (0.762 and 0.888), indicating good drug-like properties.

**DILI:** Ligand A (30.05) has a significantly lower DILI risk than Ligand B (52.423), which is a substantial advantage.

**BBB:** Ligand A (96.472) has a much higher BBB penetration percentile than Ligand B (87.515). This is *critical* for a CNS target like DRD2.

**Caco-2 Permeability:** Ligand A (-4.178) is better than Ligand B (-4.743), indicating better intestinal absorption.

**Aqueous Solubility:** Ligand A (-3.699) is better than Ligand B (-3.965), which is a slight advantage.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.598 and 0.799).

**Microsomal Clearance:** Ligand B (43.597) has lower microsomal clearance than Ligand A (56.455), indicating better metabolic stability.

**In vitro Half-Life:** Ligand B (11.428) has a longer in vitro half-life than Ligand A (-19.655). This is a significant advantage.

**P-gp Efflux:** Ligand A (0.645) has lower P-gp efflux liability than Ligand B (0.229), which is favorable for CNS exposure.

**Binding Affinity:** Ligand B (-8.3 kcal/mol) has a slightly better binding affinity than Ligand A (-9.3 kcal/mol). While the difference is small, it's still a positive for Ligand B.

**Overall Assessment:**

While Ligand B has slightly better affinity and metabolic stability (lower Cl_mic, longer t1/2), Ligand A is significantly better in several crucial areas for a CNS-targeting GPCR: BBB penetration, DILI risk, and P-gp efflux. The higher BBB score for Ligand A is a major advantage, as it directly addresses the need for CNS exposure. The lower DILI risk is also a significant safety benefit. The affinity difference is small enough to be outweighed by these ADME/Tox advantages.

Output:
0
2025-04-17 05:12:10,082 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B based on the provided guidelines, prioritizing GPCR-specific properties (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (341.411 Da) is slightly lower, which *could* be beneficial for permeability, but both are acceptable.

**TPSA:** Ligand A (82.27) is excellent for CNS penetration, well below the 90 threshold. Ligand B (29.54) is even better, indicating potentially improved brain exposure.

**logP:** Ligand A (1.375) is within the optimal range. Ligand B (3.971) is approaching the upper limit, potentially raising concerns about solubility and off-target effects, but still acceptable.

**H-Bond Donors/Acceptors:** Ligand A has 2 HBD and 3 HBA, which are reasonable. Ligand B has 0 HBD and 3 HBA, also acceptable.

**QED:** Both ligands have similar QED values (A: 0.466, B: 0.491), indicating moderate drug-likeness.

**DILI:** Both ligands show low DILI risk (A: 38.309, B: 31.136), which is positive.

**BBB:** This is a critical parameter for a CNS target like DRD2. Ligand B (90.074) has a significantly higher BBB percentile than Ligand A (35.673). This is a major advantage for Ligand B.

**Caco-2 Permeability:** Ligand A (-4.967) shows poor Caco-2 permeability, which is a concern. Ligand B (-5.02) is also poor, but similar to A.

**Aqueous Solubility:** Both ligands exhibit poor aqueous solubility (A: -2.484, B: -4.264). This could pose formulation challenges.

**hERG Inhibition:** Ligand A (0.362) has a lower hERG risk than Ligand B (0.918), which is preferable.

**Microsomal Clearance:** Ligand A (-2.243) has a lower (better) microsomal clearance, suggesting greater metabolic stability, than Ligand B (85.557).

**In vitro Half-Life:** Ligand B (10.33) has a longer half-life than Ligand A (-24.15), which is desirable.

**P-gp Efflux:** Ligand A (0.11) has significantly lower P-gp efflux liability than Ligand B (0.667), meaning more drug will likely reach the brain.

**Binding Affinity:** Ligand A (-8.9 kcal/mol) has a substantially stronger binding affinity than Ligand B (-6.9 kcal/mol). This is a significant advantage, potentially outweighing some of the ADME drawbacks.

**Overall Assessment:**

Ligand B excels in BBB penetration and has a longer half-life. However, Ligand A has a much stronger binding affinity and lower P-gp efflux, and better metabolic stability. The strong binding affinity of Ligand A is a key factor, especially for a GPCR where achieving sufficient receptor occupancy is crucial. While Ligand B's BBB is excellent, the difference in affinity is substantial. The poor solubility and Caco-2 permeability of both are concerns, but these can potentially be addressed through formulation strategies. The lower hERG risk of Ligand A is also a benefit.

Output:
0
2025-04-17 05:12:10,082 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (349.431 and 357.451 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (101.3) is slightly above the optimal <90 for CNS targets, but still reasonable. Ligand B (91.34) is better, falling comfortably under 90.

**logP:** Ligand A (1.542) is within the optimal 1-3 range. Ligand B (-0.931) is slightly below 1, which *could* indicate permeability issues, but isn't a hard disqualifier.

**H-Bond Donors/Acceptors:** Both ligands have 2 HBD and 5-6 HBA, which are acceptable values.

**QED:** Both ligands have similar QED scores (0.574 and 0.583), indicating good drug-likeness.

**DILI:** Ligand A (43.66) has a moderate DILI risk, while Ligand B (14.385) has a very low DILI risk, a significant advantage.

**BBB:** This is crucial for a CNS target. Ligand A has a BBB percentile of 63.048, which is okay, but not great. Ligand B has a much lower BBB percentile of 28.344, which is concerning for CNS penetration.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.755 and -4.913), which is unusual and suggests poor permeability. This is a red flag for both.

**Aqueous Solubility:** Both ligands have negative solubility values (-2.715 and -0.311), indicating poor aqueous solubility. This is also a concern.

**hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.084 and 0.191).

**Microsomal Clearance:** Ligand A (47.912) has a higher microsomal clearance than Ligand B (-11.472). This suggests Ligand B is more metabolically stable.

**In vitro Half-Life:** Ligand B (-5.942) has a slightly better (less negative) in vitro half-life than Ligand A (-18.537).

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.048 and 0.006), which is favorable for CNS penetration.

**Binding Affinity:** Ligand A (-8.2 kcal/mol) has a significantly stronger binding affinity than Ligand B (-7.0 kcal/mol). This is a substantial advantage.

**Overall Assessment:**

Ligand A has a much stronger binding affinity, which is a major plus. However, its BBB penetration is only moderate. Ligand B has a significantly better safety profile (lower DILI) and metabolic stability, but its binding affinity is weaker and its BBB penetration is poor. The poor Caco-2 and solubility for both are concerning, but can sometimes be addressed with formulation strategies. Given the GPCR-specific prioritization of BBB and affinity, and the substantial difference in binding affinity, Ligand A is the more promising candidate *despite* the moderate BBB score. The strong binding affinity could potentially overcome some of the permeability issues.

Output:
1
2025-04-17 05:12:10,082 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands fall within the ideal range (200-500 Da). Ligand A (415.288 Da) is slightly higher than Ligand B (353.463 Da), but both are acceptable.

**TPSA:** Ligand A (96.74) is closer to the upper limit for CNS targets (<=90), but still reasonable. Ligand B (78.95) is excellent, well below the 90 threshold.

**logP:** Ligand A (2.837) is within the optimal range (1-3). Ligand B (0.777) is a bit low, potentially hindering permeability.

**H-Bond Donors/Acceptors:** Ligand A (HBD=2, HBA=5) and Ligand B (HBD=1, HBA=4) both have acceptable numbers of H-bond donors and acceptors.

**QED:** Both ligands have good QED scores (Ligand A: 0.527, Ligand B: 0.664), indicating drug-like properties.

**DILI:** Ligand A (39.434) has a slightly higher DILI risk than Ligand B (14.541), but both are below the concerning threshold of 60.

**BBB:** Ligand A (84.025) has a significantly better BBB penetration percentile than Ligand B (63.862). This is a critical advantage for a CNS target like DRD2.

**Caco-2 Permeability:** Ligand A (-5.031) and Ligand B (-4.976) have similar, and very poor, Caco-2 permeability values.

**Aqueous Solubility:** Both ligands have poor aqueous solubility (-3.023 and -0.746 respectively).

**hERG Inhibition:** Ligand A (0.816) has a slightly higher hERG risk than Ligand B (0.179), but both are relatively low.

**Microsomal Clearance:** Ligand A (-19.54) has a much lower (better) microsomal clearance than Ligand B (30.221), indicating greater metabolic stability.

**In vitro Half-Life:** Ligand A (23.371) has a longer in vitro half-life than Ligand B (-2.294).

**P-gp Efflux:** Ligand A (0.076) shows lower P-gp efflux liability than Ligand B (0.01), which is favorable for CNS penetration.

**Binding Affinity:** Ligand A (-8.8 kcal/mol) has a significantly stronger binding affinity than Ligand B (-7.0 kcal/mol). This is a substantial advantage.

**Conclusion:**

Considering the GPCR-specific priorities, Ligand A is the more promising candidate. It has a significantly better BBB score, a much stronger binding affinity, better metabolic stability (lower Cl_mic, longer t1/2), and lower P-gp efflux. While Ligand B has a slightly better logP and lower DILI, the superior CNS penetration and binding affinity of Ligand A outweigh these minor advantages. The poor Caco-2 and solubility are concerns for both, but can be addressed with formulation strategies.

Output:
1
2025-04-17 05:12:10,083 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (384.933 and 379.595 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (52.29) is better than Ligand B (48.99). Both are below the 90 A^2 threshold for CNS targets, which is excellent.

**3. logP:** Ligand A (2.844) is within the optimal range (1-3). Ligand B (4.187) is slightly higher, potentially increasing off-target effects and decreasing solubility, but still acceptable.

**4. H-Bond Donors:** Ligand A (0) is preferable to Ligand B (1). Fewer HBDs generally improve permeability.

**5. H-Bond Acceptors:** Ligand A (6) is slightly higher than Ligand B (4), but both are within the acceptable limit of 10.

**6. QED:** Both ligands have good QED scores (0.591 and 0.772), indicating good drug-like properties. Ligand B is slightly better.

**7. DILI:** Both ligands have low DILI risk (34.587 and 37.185), below the 40% threshold.

**8. BBB:** Ligand A (68.166) has a better BBB percentile than Ligand B (55.797). This is a *critical* factor for a CNS target like DRD2. While both are not ideal (>70), Ligand A is significantly closer.

**9. Caco-2:** Ligand A (-4.988) and Ligand B (-5.601) both have negative Caco-2 values which is unusual and suggests poor permeability.

**10. Solubility:** Both ligands have very poor aqueous solubility (-2.418 and -3.893). This is a significant drawback.

**11. hERG:** Both ligands have low hERG risk (0.56 and 0.658).

**12. Cl_mic:** Ligand A (75.019) has a slightly higher microsomal clearance than Ligand B (69.202), suggesting slightly lower metabolic stability.

**13. t1/2:** Ligand B (-18.46) has a *much* longer in vitro half-life than Ligand A (39.386). This is a substantial advantage.

**14. Pgp:** Both ligands have low P-gp efflux liability (0.352 and 0.396).

**15. Binding Affinity:** Ligand B (-6.6) has a slightly better binding affinity than Ligand A (-6.2). While the difference is small (0.4 kcal/mol), it's still a positive.

**Overall Assessment:**

Ligand A excels in BBB penetration and TPSA, which are crucial for CNS GPCR targets. However, Ligand B has a significantly longer half-life and slightly better binding affinity. Both have poor solubility and Caco-2 permeability. The better BBB of Ligand A is a significant advantage, but the longer half-life of Ligand B could allow for less frequent dosing. Considering the balance, the improved BBB of Ligand A is more important for CNS penetration, outweighing the slightly better affinity and half-life of Ligand B.

Output:
0
2025-04-17 05:12:10,083 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (412.209) is slightly higher than Ligand B (346.431), but both are acceptable.

**TPSA:** Ligand A (47.04) is excellent for CNS penetration, well below the 90 A^2 threshold. Ligand B (84.42) is higher, but still potentially acceptable, although less ideal.

**logP:** Ligand A (4.787) is a bit high, potentially leading to solubility issues or off-target interactions. Ligand B (1.321) is within the optimal range (1-3).

**H-Bond Donors/Acceptors:** Both ligands have acceptable HBD (1) and HBA (4 for A, 5 for B) counts.

**QED:** Both ligands have good QED scores (0.633 and 0.869), indicating good drug-like properties.

**DILI:** Ligand A (93.835) has a high DILI risk, which is a significant concern. Ligand B (44.862) has a much lower, and acceptable, DILI risk.

**BBB:** Ligand A (81.698) has a good BBB percentile, desirable for a CNS target. Ligand B (58.976) is lower, which is a drawback.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.754 and -4.94), which is unusual and suggests poor permeability. This is a significant concern for both.

**Aqueous Solubility:** Both ligands have very poor aqueous solubility (-5.547 and -1.533). This is a major issue, especially given Ligand A's already high logP.

**hERG Inhibition:** Ligand A (0.847) has a slightly higher hERG risk than Ligand B (0.17), but both are relatively low.

**Microsomal Clearance:** Ligand A (82.185) has a higher microsomal clearance, indicating faster metabolism. Ligand B (-10.635) has a negative clearance, which is not physically possible and likely indicates an issue with the prediction method or the molecule itself.

**In vitro Half-Life:** Ligand A (63.056) has a moderate half-life. Ligand B (11.002) has a very short half-life.

**P-gp Efflux:** Ligand A (0.552) has moderate P-gp efflux. Ligand B (0.029) has very low P-gp efflux, which is favorable for CNS penetration.

**Binding Affinity:** Both ligands have very similar and excellent binding affinities (-8.9 and -8.7 kcal/mol). The difference is not substantial enough to outweigh other factors.

**Overall Assessment:**

Ligand A has a good BBB score and affinity, but suffers from a high DILI risk, high logP, poor solubility, and moderate P-gp efflux. Ligand B has a lower DILI risk and P-gp efflux, better logP, but a significantly lower BBB score, very short half-life, and questionable permeability and clearance values.

Despite the similar affinities, Ligand B is slightly favored due to the significantly lower DILI risk and P-gp efflux. However, the negative Caco-2 and clearance values for Ligand B are concerning and suggest potential issues with the prediction model or the molecule itself. The poor solubility of both is a major hurdle.

Given the severe DILI risk associated with Ligand A, and the questionable ADME properties of Ligand B, neither is an ideal candidate. However, Ligand B is marginally better due to the lower DILI risk and P-gp efflux, despite the other issues.

Output:
1
2025-04-17 05:12:10,083 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (347.361 and 358.844 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (66.4) is higher than Ligand B (44.1). For a CNS target like DRD2, TPSA should ideally be <=90, so both are acceptable, but B is better.

**logP:** Both ligands have logP values (4.034 and 4.797) that are slightly above the optimal 1-3 range, but still within a reasonable range. Ligand B is slightly higher, which *could* present solubility issues, but isn't a dealbreaker.

**H-Bond Donors/Acceptors:** Ligand A has 2 HBD and 2 HBA, while Ligand B has 0 HBD and 2 HBA. Both are within acceptable limits (<=5 HBD and <=10 HBA).

**QED:** Ligand A (0.829) has a better QED score than Ligand B (0.713), indicating a more drug-like profile.

**DILI:** Ligand A (78.247) has a higher DILI risk than Ligand B (45.173). This is a significant negative for Ligand A.

**BBB:** Ligand B (75.921) has a considerably better BBB penetration percentile than Ligand A (41.218). This is *critical* for a CNS target like DRD2.

**Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and suggests poor permeability. However, these values are on a strange scale, and the absolute value is less important than the trend.

**Aqueous Solubility:** Both ligands have very poor aqueous solubility (-3.398 and -5.431). This is a concern, but can sometimes be overcome with formulation strategies.

**hERG Inhibition:** Ligand A (0.208) has a slightly lower hERG inhibition liability than Ligand B (0.927), which is preferable.

**Microsomal Clearance:** Ligand B (69.862) has a higher microsomal clearance than Ligand A (20.829), meaning Ligand A is more metabolically stable.

**In vitro Half-Life:** Ligand A (5.945) has a longer half-life than Ligand B (0.892).

**P-gp Efflux:** Ligand A (0.074) has lower P-gp efflux liability than Ligand B (0.458), which is beneficial for CNS penetration.

**Binding Affinity:** Ligand B (-8.5 kcal/mol) has a significantly stronger binding affinity than Ligand A (-9.0 kcal/mol). This is a substantial advantage, potentially outweighing some of the ADME drawbacks.

**Overall Assessment:**

Ligand B is the stronger candidate. While it has a slightly higher logP and P-gp efflux, its significantly better BBB penetration, lower DILI risk, and *much* stronger binding affinity are decisive advantages for a CNS GPCR target like DRD2. Ligand A has better metabolic stability and lower P-gp efflux, but the poor BBB penetration and higher DILI risk are significant drawbacks. The affinity difference is also substantial.

Output:
1
2025-04-17 05:12:10,083 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (338.415 Da) is slightly lower, which could be beneficial for permeability. Ligand B (366.502 Da) is also good.

**TPSA:** Ligand A (98.72) is borderline for CNS targets, being slightly above the preferred <90. Ligand B (53.33) is excellent, well below the threshold. This is a significant advantage for Ligand B.

**logP:** Ligand A (0.982) is a little low, potentially hindering permeation. Ligand B (3.335) is optimal.

**H-Bond Donors/Acceptors:** Ligand A has 2 HBD and 6 HBA, which is acceptable. Ligand B has 0 HBD and 4 HBA, also acceptable.

**QED:** Both ligands have good QED scores (A: 0.626, B: 0.7), indicating drug-like properties.

**DILI:** Ligand A (55.603) has a moderate DILI risk, while Ligand B (20.9) has a very low risk. This favors Ligand B.

**BBB:** Ligand A (60.838) has a moderate BBB penetration, which is not ideal for a CNS target. Ligand B (95.851) has excellent BBB penetration, a major advantage.

**Caco-2 Permeability:** Ligand A (-5.991) has poor Caco-2 permeability, which is concerning. Ligand B (-4.688) is better, but still not great.

**Aqueous Solubility:** Ligand A (-1.143) has poor solubility. Ligand B (-5.285) has very poor solubility.

**hERG:** Both ligands have low hERG inhibition risk (A: 0.363, B: 0.605).

**Microsomal Clearance:** Ligand A (18.809) has lower clearance, suggesting better metabolic stability than Ligand B (93.245).

**In vitro Half-Life:** Ligand A (7.715) has a shorter half-life than Ligand B (-9.598 - indicating a very long half-life).

**P-gp Efflux:** Ligand A (0.068) has low P-gp efflux, which is favorable for CNS exposure. Ligand B (0.206) is slightly higher, but still reasonable.

**Binding Affinity:** Ligand B (-7.1 kcal/mol) has a significantly stronger binding affinity than Ligand A (-9.3 kcal/mol). This is a crucial advantage.

**Overall Assessment:**

Ligand B clearly outperforms Ligand A. While both have acceptable MW and QED, Ligand B excels in key areas for a CNS-targeting GPCR ligand: TPSA, logP, BBB penetration, DILI risk, and, most importantly, binding affinity. Although solubility and Caco-2 permeability are poor for both, the strong affinity and excellent BBB penetration of Ligand B are likely to outweigh these drawbacks. Ligand A's lower affinity and moderate BBB penetration make it a less promising candidate.

Output:
1
2025-04-17 05:12:10,083 - INFO - Batch 178 complete. Total preferences: 2848
2025-04-17 05:12:10,084 - INFO - Processing batch 179/512...
2025-04-17 05:12:50,293 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (347.459 and 349.475 Da) fall within the ideal range of 200-500 Da.

**TPSA:** Ligand A (73.64) is slightly higher than Ligand B (64.09). Both are below the 90 A^2 threshold desirable for CNS targets, but Ligand B is closer to the optimal range.

**logP:** Ligand A (1.967) is within the optimal range (1-3). Ligand B (0.552) is slightly below 1, which *could* indicate permeability issues, though not drastically.

**H-Bond Donors/Acceptors:** Both ligands have 0/4 HBD/HBA, which is acceptable and balances solubility and permeability.

**QED:** Both ligands have good QED scores (0.629 and 0.712), indicating drug-like properties.

**DILI:** Ligand A (18.418) has a slightly higher DILI risk than Ligand B (13.532), but both are well below the concerning threshold of 60.

**BBB:** This is a critical parameter for a CNS target like DRD2. Ligand A has a significantly better BBB penetration percentile (85.459) compared to Ligand B (42.109). This is a major advantage for Ligand A.

**Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and suggests a potential issue with the data or modeling. However, we will proceed with the other parameters.

**Aqueous Solubility:** Both have negative solubility values, which is also unusual.

**hERG Inhibition:** Both ligands show very low hERG inhibition liability (0.418 and 0.37), which is excellent.

**Microsomal Clearance:** Ligand A (73.797) has higher microsomal clearance than Ligand B (10.665), indicating lower metabolic stability.

**In vitro Half-Life:** Ligand B (-10.691) has a slightly better (less negative) in vitro half-life than Ligand A (-12.056).

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.094), which is favorable for CNS penetration.

**Binding Affinity:** Both ligands have excellent binding affinity (-7.0 and -7.1 kcal/mol). The difference is negligible.

**Overall Assessment:**

Ligand A excels in BBB penetration, a crucial factor for DRD2 targeting. While it has slightly higher DILI risk and lower metabolic stability, the significant advantage in BBB outweighs these drawbacks. Ligand B has a slightly better logP and metabolic stability, but its poor BBB penetration makes it less likely to reach the target in the brain. Given the GPCR-specific priorities, particularly BBB, Ligand A is the more promising candidate.

Output:
1
2025-04-17 05:12:50,293 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (343.383) is slightly lower, which could be beneficial for permeability, but both are acceptable.

**TPSA:** Ligand A (84.67) is better than Ligand B (62.3) as it is closer to the ideal range for CNS targets (<=90). Ligand B is quite good as well.

**logP:** Ligand A (1.85) is within the optimal range (1-3), while Ligand B (3.246) is at the higher end. While still acceptable, higher logP can sometimes lead to off-target effects.

**H-Bond Donors/Acceptors:** Both ligands have 1 HBD and a reasonable number of HBAs (5 and 4 respectively). This is favorable for both solubility and permeability.

**QED:** Ligand A (0.895) has a higher QED score than Ligand B (0.758), indicating a more drug-like profile.

**DILI:** Ligand B (42.148) has a lower DILI risk than Ligand A (57.154), making it slightly preferable from a toxicity standpoint. Both are below the concerning threshold of 60.

**BBB:** Ligand B (68.282) has a significantly better BBB penetration percentile than Ligand A (51.803). This is a *critical* factor for a CNS target like DRD2.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values, which is unusual and potentially problematic. However, the scale isn't defined, so it's hard to interpret.

**Aqueous Solubility:** Both ligands have negative solubility values, which is also unusual and potentially problematic.

**hERG Inhibition:** Both ligands have very low hERG inhibition liability, which is excellent.

**Microsomal Clearance:** Ligand A (14.387) has a lower microsomal clearance than Ligand B (75.421), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (-6.052) has a longer in vitro half-life than Ligand B (-5.444).

**P-gp Efflux:** Ligand A (0.041) has a lower P-gp efflux liability than Ligand B (0.272), which is beneficial for CNS exposure.

**Binding Affinity:** Ligand B (-7.8 kcal/mol) has a slightly better binding affinity than Ligand A (-8.6 kcal/mol). While A is better, the difference is not substantial enough to outweigh other factors.

**Overall Assessment:**

Ligand B is the more promising candidate. The significantly better BBB penetration (68.282 vs 51.803) is the most important factor for a CNS target. While Ligand A has slightly better metabolic stability and P-gp efflux, the improved brain penetration of Ligand B is crucial. The slightly better affinity of Ligand B is also a plus.

Output:
1
2025-04-17 05:12:50,294 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (362.455 and 343.515 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (97.12) is higher than the preferred <90 for CNS targets, but still potentially acceptable. Ligand B (37.27) is excellent, well below the threshold.

**3. logP:** Ligand A (1.93) is within the optimal 1-3 range. Ligand B (3.758) is slightly higher but still acceptable.

**4. H-Bond Donors:** Ligand A (2) and Ligand B (1) are both within the acceptable limit of <=5.

**5. H-Bond Acceptors:** Ligand A (6) and Ligand B (3) are both within the acceptable limit of <=10.

**6. QED:** Both ligands have good QED values (0.784 and 0.854), indicating good drug-like properties.

**7. DILI:** Ligand A (69.135) has a higher DILI risk than Ligand B (11.09). This is a significant negative for Ligand A.

**8. BBB:** Ligand B (91.198) has a much better BBB penetration percentile than Ligand A (52.191). This is *critical* for a CNS target like DRD2.

**9. Caco-2 Permeability:** Ligand A (-5.247) has poor Caco-2 permeability, suggesting poor absorption. Ligand B (-4.655) is also poor, but slightly better than A.

**10. Aqueous Solubility:** Both ligands have very poor aqueous solubility (-2.812 and -3.886). This is a concern for both, but potentially manageable with formulation strategies.

**11. hERG Inhibition:** Ligand A (0.102) has a slightly lower hERG risk than Ligand B (0.638), but both are relatively low.

**12. Microsomal Clearance:** Ligand B (59.149) has a lower microsomal clearance than Ligand A (36.2), suggesting better metabolic stability.

**13. In vitro Half-Life:** Ligand B (43.993) has a longer in vitro half-life than Ligand A (-12.789), which is a significant advantage.

**14. P-gp Efflux:** Both ligands have low P-gp efflux liability (0.16 and 0.165), which is good.

**15. Binding Affinity:** Ligand A (-8.1) has a slightly better binding affinity than Ligand B (-7.0). However, the difference is less than 1.5 kcal/mol, so it's not a decisive factor.

**Overall Assessment:**

Ligand B is significantly better overall, primarily due to its superior BBB penetration (91.198 vs 52.191), lower DILI risk (11.09 vs 69.135), and better metabolic stability (lower Cl_mic and longer t1/2). While Ligand A has slightly better binding affinity, the ADME properties of Ligand B are far more favorable for a CNS-targeting drug. The poor Caco-2 permeability and solubility are concerns for both, but are secondary to the critical BBB and safety profiles.

Output:
1
2025-04-17 05:12:50,294 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (346.471 and 348.451 Da) fall comfortably within the ideal 200-500 Da range.

**TPSA:** Ligand A (67.43) is significantly better than Ligand B (110.2). For CNS targets, we want TPSA <= 90, and A is well within that, while B exceeds it. This is a substantial advantage for A.

**logP:** Both ligands have acceptable logP values (2.15 and 1.428), falling within the optimal 1-3 range. Ligand A is slightly higher, which could be beneficial for membrane permeability.

**H-Bond Donors/Acceptors:** Both have 2 HBD and a reasonable number of HBA (3 for A, 4 for B). This isn't a major differentiating factor.

**QED:** Ligand A (0.724) has a significantly better QED score than Ligand B (0.412), indicating a more drug-like profile.

**DILI:** Ligand A (31.601) has a much lower DILI risk than Ligand B (15.355). Both are below 40, which is good, but A is considerably safer.

**BBB:** Ligand A (65.801) has a better BBB percentile than Ligand B (59.131). While both are not ideal (>70 is desired), A is closer to the threshold. This is a critical factor for a CNS target like DRD2.

**Caco-2:** Ligand A (-4.856) has a worse Caco-2 permeability than Ligand B (-5.51). This suggests B might have slightly better intestinal absorption, but the difference isn't huge and is less important for a CNS target.

**Solubility:** Ligand A (-3.417) has better solubility than Ligand B (-1.617).

**hERG:** Both ligands have low hERG inhibition liability (0.369 and 0.259), which is good.

**Microsomal Clearance:** Ligand A (48.305) has a higher microsomal clearance than Ligand B (5.852), suggesting lower metabolic stability. This is a disadvantage for A.

**In vitro Half-Life:** Ligand A (-8.733) has a significantly longer in vitro half-life than Ligand B (16.134). This is a strong advantage for A.

**P-gp Efflux:** Ligand A (0.177) has lower P-gp efflux than Ligand B (0.008), which is favorable for CNS penetration.

**Binding Affinity:** Both ligands have very similar and excellent binding affinities (-7.7 and -7.8 kcal/mol). The difference is negligible.

**Overall Assessment:**

Ligand A is superior despite the slightly higher Cl_mic. The advantages of A are substantial: significantly better TPSA, QED, DILI, BBB, solubility, and P-gp efflux, and a longer half-life. These factors are particularly important for a CNS GPCR target like DRD2. While B has slightly better Caco-2 permeability, this is less critical given the target. The similar binding affinities mean the ADME properties will largely dictate which ligand is more promising.

Output:
1
2025-04-17 05:12:50,294 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (348.397 and 361.507 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (41.37) is slightly higher than Ligand B (38.77), but both are well below the 90 A^2 threshold for CNS targets.

**3. logP:** Both ligands have good logP values (3.019 and 3.391), falling within the optimal 1-3 range.

**4. H-Bond Donors:** Both have 0 HBD, which is acceptable.

**5. H-Bond Acceptors:** Both have 4 HBA, which is also acceptable.

**6. QED:** Ligand A (0.856) has a significantly better QED score than Ligand B (0.499), indicating a more drug-like profile.

**7. DILI:** Ligand A (41.877) has a higher DILI risk than Ligand B (21.675). This is a negative for Ligand A.

**8. BBB:** Both ligands have excellent BBB penetration (90.733 and 90.074), exceeding the desirable >70 threshold for CNS targets.

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 values, which is unusual and suggests poor permeability. However, these values are on a strange scale and are difficult to interpret without more context.

**10. Aqueous Solubility:** Both ligands have negative solubility values, which is also unusual and suggests poor solubility. Again, the scale is unclear.

**11. hERG Inhibition:** Both ligands have low hERG inhibition risk (0.892 and 0.736).

**12. Microsomal Clearance:** Ligand B (104.233) has significantly higher microsomal clearance than Ligand A (49.756), indicating lower metabolic stability.

**13. In vitro Half-Life:** Ligand A (-25.031) has a negative half-life, which is not possible. Ligand B (2.253) has a very short half-life.

**14. P-gp Efflux:** Both ligands have low P-gp efflux liability (0.512 and 0.561).

**15. Binding Affinity:** Ligand B (-7.2 kcal/mol) has a significantly stronger binding affinity than Ligand A (-0.0 kcal/mol). This is a crucial difference.

**Overall Assessment:**

Despite Ligand A's better QED and lower microsomal clearance, the overwhelmingly stronger binding affinity of Ligand B (-7.2 vs -0.0 kcal/mol) is the deciding factor. A 7.2 kcal/mol difference in binding is substantial and can often outweigh minor ADME drawbacks. While the negative solubility and permeability values are concerning, they are present for both compounds. The DILI risk is also lower for Ligand B. The half-life for Ligand A is impossible, and the half-life for Ligand B is very short, but these can be addressed through structural modifications.

Output:
1
2025-04-17 05:12:50,294 - INFO - Reasoning:

Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (353.419 and 364.515 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (99.18) is higher than Ligand B (58.44). For a CNS target like DRD2, TPSA should be <=90. Ligand B is much closer to this threshold and therefore preferable.

**3. logP:** Ligand A (0.263) is quite low, potentially hindering membrane permeability. Ligand B (2.015) is within the optimal 1-3 range. This is a significant advantage for Ligand B.

**4. H-Bond Donors:** Ligand A has 2 HBD, which is acceptable. Ligand B has 0, also acceptable.

**5. H-Bond Acceptors:** Both ligands have 5 HBA, which is within the acceptable range of <=10.

**6. QED:** Both ligands have good QED scores (0.707 and 0.802), indicating good drug-like properties.

**7. DILI:** Ligand A (28.306) has a lower DILI risk than Ligand B (52.772), which is favorable.

**8. BBB:** Ligand B (77.2) has a significantly higher BBB penetration percentile than Ligand A (62.195). This is *critical* for a CNS target like DRD2.

**9. Caco-2 Permeability:** Ligand A (-4.906) has worse Caco-2 permeability than Ligand B (-4.87). Both are negative, indicating poor permeability, but A is slightly worse.

**10. Aqueous Solubility:** Ligand A (-0.965) has slightly better solubility than Ligand B (-2.35), but both are poor.

**11. hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.142 and 0.259).

**12. Microsomal Clearance:** Ligand B (77.656) has a much higher microsomal clearance than Ligand A (5.815), indicating faster metabolism and lower metabolic stability. This is a significant drawback for Ligand B.

**13. In vitro Half-Life:** Ligand A (-28.526) has a much longer in vitro half-life than Ligand B (-7.177), which is favorable.

**14. P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.014 and 0.234).

**15. Binding Affinity:** Ligand A (-7.9) has a slightly better binding affinity than Ligand B (-7.0). While both are good, the 0.9 kcal/mol difference is notable.

**Overall Assessment:**

Despite Ligand A's slightly better affinity and lower DILI, Ligand B is the more promising candidate. The critical factor is the significantly higher BBB penetration (77.2 vs 62.195) and better logP (2.015 vs 0.263) of Ligand B. These properties are paramount for CNS drug development. While Ligand B has a higher clearance and shorter half-life, these can potentially be addressed through structural modifications during lead optimization. The poor logP of Ligand A is a more difficult property to improve significantly.

Output:
1
2025-04-17 05:12:50,294 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B based on the provided guidelines, prioritizing GPCR-specific properties (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (421.173 Da) is slightly higher, but still acceptable. Ligand B (351.466 Da) is preferable.

**TPSA:**  Ligand A (97.11) is borderline for CNS targets (<=90 is preferred), while Ligand B (73.2) is well within the desired range. This favors Ligand B.

**logP:** Both ligands have good logP values (A: 2.16, B: 2.952), falling within the optimal 1-3 range. Ligand B is slightly higher, potentially offering better membrane permeability.

**H-Bond Donors/Acceptors:** Ligand A (HBD=2, HBA=5) and Ligand B (HBD=1, HBA=3) both have acceptable numbers of H-bond donors and acceptors.

**QED:** Both ligands have reasonable QED values (A: 0.746, B: 0.649), indicating good drug-like properties.

**DILI:** Ligand A has a significantly higher DILI risk (85.964%) compared to Ligand B (16.906%). This is a major concern for Ligand A.

**BBB:** Ligand B (89.725%) has a much better BBB penetration score than Ligand A (52.966%). This is critical for a CNS target like DRD2.

**Caco-2 Permeability:** Ligand A (-5.745) has poor Caco-2 permeability, while Ligand B (-4.723) is slightly better, but still not great.

**Aqueous Solubility:** Both ligands have poor aqueous solubility (A: -2.75, B: -3.363). This could pose formulation challenges, but is less critical than BBB penetration for a CNS drug.

**hERG Inhibition:** Ligand A (0.019) has very low hERG inhibition risk, while Ligand B (0.843) is slightly higher.

**Microsomal Clearance:** Ligand B (41.494 mL/min/kg) has a much lower microsomal clearance than Ligand A (4.146 mL/min/kg), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand B (-11.769 hours) has a longer in vitro half-life than Ligand A (-15.241 hours).

**P-gp Efflux:** Ligand A (0.034) has lower P-gp efflux liability than Ligand B (0.302), which is favorable for CNS exposure.

**Binding Affinity:** Ligand A (-8.7 kcal/mol) has a slightly better binding affinity than Ligand B (-7.5 kcal/mol). However, the difference is not substantial enough to outweigh the significant ADME/Tox advantages of Ligand B.

**Overall Assessment:**

Ligand B is the superior candidate. While Ligand A has slightly better binding affinity and P-gp efflux, Ligand B excels in critical areas for a CNS-targeting GPCR: significantly lower DILI risk, much better BBB penetration, improved metabolic stability (lower Cl_mic, longer t1/2), and a more favorable TPSA. The poor Caco-2 permeability and solubility are drawbacks for both, but less critical for a CNS-focused drug.



Output:
1
2025-04-17 05:12:50,295 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (353.5 & 341.5 Da) fall within the ideal 200-500 Da range.

**TPSA:** Both ligands (61.88 & 62.3) are slightly above the optimal <90 for CNS targets, but still reasonably acceptable.

**logP:** Ligand A (1.5) is optimal, while Ligand B (2.715) is also within the preferred 1-3 range.

**H-Bond Donors/Acceptors:** Both ligands have acceptable HBD (1) and HBA (4 & 3) counts, well within the guidelines.

**QED:** Both ligands have good QED scores (0.682 & 0.809), indicating drug-like properties.

**DILI:** Ligand A (5.584) has a very low DILI risk, significantly better than Ligand B (27.065). This is a substantial advantage.

**BBB:** Ligand B (72.78) has a significantly better BBB penetration percentile than Ligand A (61.962). This is crucial for a CNS target like DRD2.

**Caco-2 Permeability:** Both have negative values, indicating poor permeability.

**Aqueous Solubility:** Both ligands have very poor aqueous solubility (-0.513 and -3.269). This is a significant drawback for both.

**hERG Inhibition:** Both ligands show low hERG inhibition risk (0.348 & 0.385).

**Microsomal Clearance:** Ligand A (5.622) has a much lower microsomal clearance than Ligand B (70.074), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (4.039) has a positive half-life, while Ligand B (-13.083) has a negative half-life, indicating very poor stability.

**P-gp Efflux:** Both ligands show low P-gp efflux liability (0.007 & 0.074).

**Binding Affinity:** Ligand B (-9.2 kcal/mol) has a stronger binding affinity than Ligand A (-7.7 kcal/mol), with a difference of 1.5 kcal/mol. This is a substantial advantage that can potentially offset some ADME weaknesses.

**Overall Assessment:**

Ligand B has a significantly better binding affinity and BBB penetration, which are critical for a CNS GPCR target. However, it suffers from a much higher DILI risk, very poor in vitro half-life, and higher microsomal clearance. Ligand A has a much better safety profile (DILI), metabolic stability (Cl_mic, t1/2), and acceptable BBB. While its affinity is lower, the 1.5 kcal/mol difference might be overcome with further optimization. The solubility is a concern for both, but can be addressed with formulation strategies.

Considering the balance of properties, and prioritizing safety and metabolic stability alongside affinity for a CNS target, Ligand A appears to be the more viable drug candidate, despite the slightly weaker binding. The poor solubility is a concern for both, but the other ADME properties of Ligand A are considerably more favorable.

Output:
1
2025-04-17 05:12:50,295 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 drug candidates, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (399.559 and 344.415 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (83.47) is better than Ligand B (87.32). Both are below the 90 A^2 threshold desirable for CNS targets, but A is closer to the optimal range.

**logP:** Ligand A (2.566) is within the optimal 1-3 range. Ligand B (0.928) is slightly below 1, which *could* indicate permeability issues.

**H-Bond Donors/Acceptors:** Both have 2 HBDs, which is good. Ligand A has 6 HBAs, while Ligand B has 4. Both are within acceptable limits (<=10).

**QED:** Both ligands have good QED scores (0.633 and 0.854), indicating good drug-like properties.

**DILI:** Ligand A (71.694) has a higher DILI risk than Ligand B (36.293). This is a significant negative for Ligand A.

**BBB:** Ligand B (57.076) has a significantly better BBB penetration percentile than Ligand A (46.219). While neither are >70, BBB is a critical factor for CNS targets like DRD2.

**Caco-2 Permeability:** Both have negative Caco-2 values (-5.6 and -5.081), which is unusual and suggests poor permeability. This is a concern for both.

**Aqueous Solubility:** Both have negative solubility values (-2.83 and -2.47), also suggesting poor solubility.

**hERG:** Both have low hERG inhibition liability (0.465 and 0.296), which is good.

**Microsomal Clearance:** Ligand B (10.251) has a much lower microsomal clearance than Ligand A (28.382), indicating better metabolic stability.

**In vitro Half-Life:** Ligand B (9.921) has a longer in vitro half-life than Ligand A (26.014).

**P-gp Efflux:** Ligand A (0.465) has lower P-gp efflux than Ligand B (0.011), which is preferable for CNS penetration.

**Binding Affinity:** Ligand B (-9.6 kcal/mol) has a significantly stronger binding affinity than Ligand A (-7.3 kcal/mol). This >1.5 kcal/mol difference is substantial and can outweigh some ADME drawbacks.

**Overall Assessment:**

Ligand B is the stronger candidate. While both have issues with Caco-2 and solubility, Ligand B excels in key areas for a CNS GPCR target: significantly better BBB penetration, much better metabolic stability (lower Cl_mic, longer t1/2), and a *much* stronger binding affinity. The lower DILI risk for Ligand B is also a major advantage. Although Ligand A has better P-gp efflux, the other benefits of Ligand B outweigh this.



Output:
1
2025-04-17 05:12:50,295 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (366.542 and 352.41 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (94.22) is slightly above the optimal <90 for CNS targets, while Ligand B (74.57) is well within the desired range. This favors Ligand B.

**logP:** Ligand A (0.253) is quite low, potentially hindering permeation. Ligand B (1.666) is within the optimal 1-3 range. This is a significant advantage for Ligand B.

**H-Bond Donors:** Ligand A (2) is acceptable. Ligand B (0) is also good, potentially improving membrane permeability.

**H-Bond Acceptors:** Both ligands have 5 HBA, which is acceptable.

**QED:** Both ligands have good QED scores (0.704 and 0.775), indicating drug-like properties.

**DILI:** Both ligands have low DILI risk (43.622 and 40.403), which is positive.

**BBB:** Ligand A (34.161) has a poor BBB percentile, a major drawback for a CNS target. Ligand B (92.943) has an excellent BBB percentile, a significant advantage.

**Caco-2 Permeability:** Ligand A (-5.479) shows very poor Caco-2 permeability, which is concerning. Ligand B (-4.63) is slightly better, but still not ideal.

**Aqueous Solubility:** Both ligands have very poor aqueous solubility (-2.148 and -2.637). This could pose formulation challenges, but might be mitigated with appropriate excipients.

**hERG:** Both ligands have low hERG inhibition liability (0.097 and 0.358), which is good.

**Microsomal Clearance:** Ligand A (24.834) has moderate clearance, while Ligand B (15.901) has lower clearance, suggesting better metabolic stability. This favors Ligand B.

**In vitro Half-Life:** Ligand A (-18.667) has a negative half-life, which is not physically possible and indicates a significant issue with the data or the molecule. Ligand B (11.271) has a reasonable half-life.

**P-gp Efflux:** Both ligands have very low P-gp efflux (0.013 and 0.07), which is beneficial for CNS penetration.

**Binding Affinity:** Ligand B (-7.5 kcal/mol) has a significantly stronger binding affinity than Ligand A (0.0 kcal/mol). This is a crucial advantage, as a >1.5 kcal/mol difference can outweigh other drawbacks.

**Overall Assessment:**

Ligand B is clearly the superior candidate. It excels in key GPCR-specific properties: high BBB penetration, optimal logP, strong binding affinity, and lower microsomal clearance. While solubility is a concern for both, Ligand A's extremely poor Caco-2 permeability and non-sensical half-life, combined with its very weak binding affinity and poor BBB penetration, make it a much less viable candidate.



Output:
1
2025-04-17 05:12:50,295 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight (MW):** Both ligands (344.411 and 350.503 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (75.71) is higher than Ligand B (58.64). For CNS targets, we want TPSA <= 90, so both are acceptable, but B is better.

**3. logP:** Ligand A (1.336) is within the optimal range (1-3), while Ligand B (2.593) is also good, leaning towards the higher end.

**4. H-Bond Donors (HBD):** Both ligands have 1 HBD, which is within the acceptable limit of <=5.

**5. H-Bond Acceptors (HBA):** Ligand A has 4 HBAs, and Ligand B has 3. Both are within the acceptable limit of <=10.

**6. QED:** Ligand B (0.732) has a significantly better QED score than Ligand A (0.464), indicating a more drug-like profile.

**7. DILI:** Ligand A (32.067) has a lower DILI risk than Ligand B (14.967), which is favorable.

**8. BBB:** Ligand B (66.576) has a much better BBB penetration percentile than Ligand A (46.026). This is *critical* for a CNS target like DRD2.

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.678 and -4.738), which is unusual and suggests poor permeability. This is a significant concern for both.

**10. Aqueous Solubility:** Both ligands have negative solubility values (-2.588 and -2.25), indicating very poor aqueous solubility. This is a major drawback.

**11. hERG Inhibition:** Ligand A (0.074) shows slightly lower hERG inhibition risk than Ligand B (0.405), which is preferable.

**12. Microsomal Clearance:** Ligand A (33.169) has lower microsomal clearance than Ligand B (43.826), suggesting better metabolic stability.

**13. In vitro Half-Life:** Ligand B (-8.649) has a significantly longer in vitro half-life than Ligand A (3.571). This is a positive attribute.

**14. P-gp Efflux:** Ligand A (0.017) has lower P-gp efflux liability than Ligand B (0.169), which is beneficial for CNS penetration.

**15. Binding Affinity:** Both ligands have very similar and strong binding affinities (-8.6 and -8.5 kcal/mol). The difference is negligible.

**Overall Assessment:**

While Ligand A has advantages in DILI, hERG, and P-gp efflux, Ligand B is significantly better regarding BBB penetration, QED, and in vitro half-life. The poor Caco-2 and solubility for both are concerning, but the BBB is paramount for a CNS target. Given the GPCR-specific priorities, the improved BBB and QED of Ligand B outweigh the slight advantages of Ligand A.

Output:
1
2025-04-17 05:12:50,295 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities: BBB, logP, Pgp, TPSA, and affinity.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (378.881 Da) is slightly higher, but still acceptable.

**TPSA:** Ligand A (68.29) is excellent for CNS penetration, well below the 90 A^2 threshold. Ligand B (94.8) is higher, but still potentially acceptable, though less ideal.

**logP:** Both ligands have good logP values (A: 2.869, B: 1.432) falling within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Both have acceptable HBD (1) and HBA (A: 5, B: 6) counts, balancing solubility and permeability.

**QED:** Both ligands have good QED scores (A: 0.715, B: 0.802), indicating drug-like properties.

**DILI:** Ligand A (70.221) is slightly higher risk, but still moderate. Ligand B (44.552) is better, falling well below the 60 threshold.

**BBB:** Ligand A (42.924) is lower than ideal for a CNS target. Ligand B (46.336) is also low. This is a significant concern for both.

**Caco-2 Permeability:** Both have negative Caco-2 values (-4.926 and -5.302), which is unusual and suggests poor permeability. This is a major red flag.

**Aqueous Solubility:** Both ligands have negative solubility values (-3.937 and -1.817), also unusual and indicating very poor aqueous solubility. This is a significant drawback.

**hERG Inhibition:** Both have low hERG risk (A: 0.373, B: 0.502).

**Microsomal Clearance:** Ligand A (91.309) has higher clearance, suggesting lower metabolic stability. Ligand B (3.662) has very low clearance, indicating high metabolic stability.

**In vitro Half-Life:** Ligand A (-0.803) has a negative half-life, which is not physically meaningful and suggests issues with the prediction. Ligand B (-3.726) also has a negative half-life.

**P-gp Efflux:** Both have very low P-gp efflux liability (A: 0.135, B: 0.007), which is good for CNS exposure.

**Binding Affinity:** Ligand B (-8.6 kcal/mol) has a slightly better binding affinity than Ligand A (-8.1 kcal/mol). While the difference is not huge, it's a factor.

**Overall Assessment:**

Both compounds have significant issues with predicted permeability and solubility. The negative Caco-2 and solubility values are concerning. However, given the GPCR-specific priorities, we need to focus on BBB, logP, Pgp, TPSA, and affinity. While both have poor BBB scores, Ligand B has better metabolic stability (lower Cl_mic), slightly better affinity, and a lower DILI risk. Ligand A's higher clearance and slightly higher DILI risk are negatives. The negative half-life predictions for both are problematic, but the other ADME properties lean slightly towards Ligand B.

Output:
1
2025-04-17 05:12:50,296 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (368.5 and 337.5 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (87.32) is better than Ligand B (62.73). For CNS targets, we want TPSA <= 90, and both meet this criterion, but A is closer to the upper limit.

**3. logP:** Ligand A (1.463) is within the optimal 1-3 range. Ligand B (4.32) is higher, potentially leading to solubility issues and off-target interactions.

**4. H-Bond Donors:** Both ligands have 2 HBD, which is acceptable (<=5).

**5. H-Bond Acceptors:** Both ligands have 5 HBA, which is acceptable (<=10).

**6. QED:** Both ligands have good QED scores (0.725 and 0.796), indicating good drug-like properties.

**7. DILI:** Both ligands have low DILI risk (47.421 and 45.173), below the 60 threshold.

**8. BBB:** Ligand B (66.925) is slightly better than Ligand A (63.358), but both are below the desirable >70 for CNS targets. This is a concern for both, but less so for B.

**9. Caco-2 Permeability:** Both have negative values (-5.322 and -5.101), which is unusual and suggests poor permeability. This is a significant drawback for both.

**10. Aqueous Solubility:** Both have negative values (-2.685 and -4.054), indicating poor solubility. This is a concern, especially given Ligand B's higher logP.

**11. hERG Inhibition:** Ligand A (0.402) has a lower hERG risk than Ligand B (0.718), which is preferable.

**12. Microsomal Clearance:** Ligand A (11.186) has significantly lower clearance than Ligand B (43.981), suggesting better metabolic stability.

**13. In vitro Half-Life:** Ligand A (-9.32) has a negative half-life, which is impossible. Ligand B (41.842) has a reasonable half-life. This is a major red flag for Ligand A.

**14. P-gp Efflux:** Ligand A (0.036) has much lower P-gp efflux liability than Ligand B (0.154), which is beneficial for CNS penetration.

**15. Binding Affinity:** Ligand A (-7.9) has significantly stronger binding affinity than Ligand B (-0.0). This is a substantial advantage.

**Overall Assessment:**

Despite the poor Caco-2 and solubility values for both, Ligand A is the more promising candidate. Its significantly stronger binding affinity (-7.9 vs -0.0) is a major advantage that can potentially outweigh some of the ADME drawbacks. Furthermore, Ligand A has better hERG inhibition, lower microsomal clearance, and lower P-gp efflux. The negative half-life for Ligand A is a critical issue that needs investigation, but the overall profile is still better than Ligand B. Ligand B's high logP and poor metabolic stability are significant concerns.

Output:
1
2025-04-17 05:12:50,296 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 drug candidates, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight (MW):** Both ligands (352.494 and 363.849 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (49.41) is significantly better than Ligand B (72.28). For CNS targets, we want TPSA <= 90, and ideally closer to 60. Ligand A is well within this range, while Ligand B is pushing the upper limit and less favorable.

**3. logP:** Ligand A (3.614) is slightly higher than the optimal 1-3 range, but acceptable. Ligand B (1.824) is on the lower side, potentially hindering permeability.

**4. H-Bond Donors (HBD):** Both ligands have 1 HBD, which is within the acceptable limit of <=5.

**5. H-Bond Acceptors (HBA):** Ligand A has 2 HBA, and Ligand B has 6 HBA. Both are within the limit of <=10, but Ligand B is higher and could potentially impact permeability.

**6. QED:** Both ligands have good QED scores (0.742 and 0.877), indicating good drug-like properties.

**7. DILI:** Ligand A (15.898) has a much lower DILI risk than Ligand B (76.076). This is a significant advantage for Ligand A.

**8. BBB:** Ligand A (91.663) has excellent BBB penetration, exceeding the desirable >70% threshold for CNS targets. Ligand B (57.193) is considerably lower, raising concerns about CNS exposure.

**9. Caco-2:** Both ligands have negative Caco-2 values (-4.74 and -4.64), which is unusual and suggests poor permeability. This is a significant drawback for both.

**10. Solubility:** Both ligands have negative solubility values (-3.138 and -3.04), which is also unusual and suggests poor solubility. This is a significant drawback for both.

**11. hERG:** Both ligands have low hERG inhibition liability (0.594 and 0.241), which is good.

**12. Cl_mic:** Ligand A (24.629) has lower microsomal clearance than Ligand B (29.134), indicating better metabolic stability.

**13. t1/2:** Ligand A (-16.672) has a negative in vitro half-life, while Ligand B (0.493) is very short. Both are problematic, indicating rapid metabolism.

**14. Pgp:** Ligand A (0.304) has lower P-gp efflux liability than Ligand B (0.08), suggesting better CNS exposure and oral bioavailability.

**15. Binding Affinity:** Both ligands have very similar binding affinities (-8.5 and -8.4 kcal/mol), which are excellent and comparable.

**Overall Assessment:**

Considering the GPCR-specific priorities, Ligand A is the superior candidate. Its significantly better BBB penetration, lower DILI risk, lower Pgp efflux, and lower microsomal clearance outweigh the slightly higher logP. While both ligands have issues with Caco-2 permeability, solubility and in vitro half-life, the ADME profile of Ligand A is considerably more favorable for a CNS-targeting drug. The affinity is comparable, so the better ADME properties of Ligand A make it the more promising candidate.

Output:
0
2025-04-17 05:12:50,296 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (348.378 Da) is slightly better positioned.

**TPSA:** Ligand A (89.16) is excellent for CNS penetration, being well below 90. Ligand B (65.49) is also very good.

**logP:** Ligand A (2.256) is optimal. Ligand B (4.277) is pushing the upper limit and could potentially lead to solubility issues or off-target interactions.

**H-Bond Donors/Acceptors:** Ligand A (2 HBD, 5 HBA) is well within acceptable ranges. Ligand B (0 HBD, 7 HBA) is also acceptable, but the lack of HBDs might slightly hinder aqueous solubility.

**QED:** Ligand A (0.867) has a strong drug-like profile. Ligand B (0.38) is significantly lower, indicating a less desirable overall drug-likeness.

**DILI:** Ligand A (71.423) has a moderate DILI risk, but still acceptable. Ligand B (97.635) has a very high DILI risk, which is a major concern.

**BBB:** Ligand A (68.205) is reasonably good for BBB penetration, but could be better. Ligand B (54.827) is lower and less favorable for a CNS target.

**Caco-2 Permeability:** Both have negative values, indicating poor permeability. This is unusual and requires further investigation, but we'll proceed assuming these are percentile scores and lower is worse. Ligand A (-5.023) is slightly better than Ligand B (-4.764).

**Aqueous Solubility:** Both have negative values, again indicating poor solubility. Ligand A (-3.546) is slightly better than Ligand B (-5.812).

**hERG Inhibition:** Ligand A (0.084) has very low hERG inhibition risk. Ligand B (0.276) is slightly higher but still relatively low.

**Microsomal Clearance:** Ligand A (26.051) has a lower clearance, suggesting better metabolic stability. Ligand B (112.79) has a very high clearance, indicating rapid metabolism.

**In vitro Half-Life:** Ligand A (43.732) has a reasonable half-life. Ligand B (-20.915) has a negative half-life, which is not physically possible and indicates a significant issue.

**P-gp Efflux:** Ligand A (0.019) has very low P-gp efflux, which is excellent for CNS exposure. Ligand B (0.676) has moderate P-gp efflux.

**Binding Affinity:** Ligand B (-8.6 kcal/mol) has a slightly better binding affinity than Ligand A (-7.9 kcal/mol). However, the difference is not substantial enough to overcome the significant ADME deficiencies of Ligand B.

**Overall Assessment:**

Ligand A is significantly better overall. It has a better QED score, lower DILI risk, better metabolic stability, lower P-gp efflux, and a more favorable balance of physicochemical properties for CNS penetration. While Ligand B has slightly better binding affinity, its poor drug-likeness, high DILI risk, rapid metabolism, and questionable half-life make it a much less viable candidate. The negative values for Caco-2 and Solubility are concerning for both, but less critical than the other issues with Ligand B.

Output:
0
2025-04-17 05:12:50,296 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (352.475 and 360.443 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (84.5) is excellent, well below the 90 A^2 threshold for CNS targets. Ligand B (114.12) is still reasonable, but less optimal, being above 100.

**logP:** Both ligands (2.106 and 2.364) are within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A has 2 HBD and 4 HBA, which are good values. Ligand B has 1 HBD and 6 HBA, also acceptable, but slightly higher HBA count.

**QED:** Ligand A (0.665) has a significantly better QED score than Ligand B (0.348), indicating a more drug-like profile.

**DILI:** Ligand A (18.418) has a much lower DILI risk than Ligand B (50.097), which is a significant advantage.

**BBB:** Ligand A (56.34) has a better BBB penetration percentile than Ligand B (43.117), although both are below the desirable >70% for CNS targets.

**Caco-2 Permeability:** Ligand A (-4.744) has a worse Caco-2 permeability than Ligand B (-5.003). Both are quite poor.

**Aqueous Solubility:** Ligand A (-1.825) has better solubility than Ligand B (-2.413).

**hERG Inhibition:** Ligand A (0.088) has a lower hERG inhibition risk than Ligand B (0.42).

**Microsomal Clearance:** Ligand A (24.288) has lower microsomal clearance, suggesting better metabolic stability than Ligand B (30.029).

**In vitro Half-Life:** Ligand B (13.978) has a longer in vitro half-life than Ligand A (8.396).

**P-gp Efflux:** Ligand A (0.06) has lower P-gp efflux liability than Ligand B (0.051), suggesting better CNS exposure.

**Binding Affinity:** Ligand A (-8.0) has a significantly stronger binding affinity than Ligand B (-6.2). This is a crucial advantage, exceeding the 1.5 kcal/mol difference threshold.

**Overall Assessment:**

Ligand A is clearly superior. It has a better QED, lower DILI risk, better BBB penetration, lower hERG risk, better metabolic stability, lower P-gp efflux, and, most importantly, a significantly stronger binding affinity. While Ligand B has a slightly longer half-life and marginally better Caco-2 permeability, the advantages of Ligand A outweigh these minor benefits, especially considering the GPCR-specific focus on affinity and CNS penetration. The stronger binding affinity of Ligand A could potentially compensate for the less-than-ideal BBB value.

Output:
1
2025-04-17 05:12:50,297 - INFO - Batch 179 complete. Total preferences: 2864
2025-04-17 05:12:50,297 - INFO - Processing batch 180/512...
2025-04-17 05:13:36,278 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (346.387 and 344.459 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (106.34) is slightly above the optimal <90 for CNS targets, but still reasonable. Ligand B (67.23) is well within the desired range. This favors Ligand B.

**3. logP:** Ligand A (-0.219) is a bit low, potentially hindering permeability. Ligand B (2.541) is within the optimal 1-3 range. This strongly favors Ligand B.

**4. H-Bond Donors:** Both have acceptable HBD counts (2 and 1, respectively), well below the threshold of 5.

**5. H-Bond Acceptors:** Both have acceptable HBA counts (4 each), below the threshold of 10.

**6. QED:** Both ligands have similar and good QED values (0.772 and 0.773).

**7. DILI:** Ligand A (49.864) has a slightly higher DILI risk than Ligand B (32.377), but both are below the concerning threshold of 60.

**8. BBB:** This is a critical parameter for a CNS target like DRD2. Ligand B (74.719) has a significantly better BBB percentile than Ligand A (50.679). This is a major advantage for Ligand B.

**9. Caco-2 Permeability:** Both have negative Caco-2 values (-4.944 and -4.872), which is unusual and suggests poor permeability. However, these values are on a scale where negative values are possible, and direct comparison is difficult without knowing the scale's specifics.

**10. Aqueous Solubility:** Both have negative solubility values (-2.999 and -3.118), indicating poor aqueous solubility. Similar to Caco-2, the scale is unknown.

**11. hERG Inhibition:** Both ligands show low hERG inhibition risk (0.122 and 0.34).

**12. Microsomal Clearance:** Ligand A (-15.014) has much lower (better) microsomal clearance than Ligand B (31.552), indicating greater metabolic stability. This favors Ligand A.

**13. In vitro Half-Life:** Ligand A (-3.417) has a negative half-life, which is not physically possible and suggests an issue with the data or scale. Ligand B (-1.39) also has a negative half-life, indicating similar data quality concerns.

**14. P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.008 and 0.048), which is favorable for CNS penetration.

**15. Binding Affinity:** Both ligands have similar and strong binding affinities (-9.0 and -7.9 kcal/mol). Ligand A is slightly better (-9.0 kcal/mol), but the difference is less than the 1.5 kcal/mol threshold that would override other issues.

**Overall Assessment:**

Ligand B is the more promising candidate. While both have issues with Caco-2 and solubility, Ligand B excels in the critical GPCR-specific parameters for CNS targets: TPSA and, most importantly, BBB penetration. Its logP is also more favorable. Although Ligand A has better metabolic stability (lower Cl_mic), the superior BBB penetration of Ligand B outweighs this advantage. The negative half-life values for both are concerning and require further investigation, but don't fundamentally change the ranking based on the available data.

Output:
1
2025-04-17 05:13:36,279 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 drug candidates, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (356.411 and 375.481 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (92.49) is better than Ligand B (57.61). For CNS targets, we want TPSA <= 90, so Ligand A is marginally above this, while Ligand B is well within the desired range.

**3. logP:** Ligand A (1.107) is within the optimal 1-3 range. Ligand B (4.038) is slightly high, potentially leading to solubility issues and off-target interactions.

**4. H-Bond Donors:** Both ligands have 1 HBD, which is acceptable (<=5).

**5. H-Bond Acceptors:** Ligand A has 7 HBAs, and Ligand B has 4. Both are within the acceptable range (<=10).

**6. QED:** Ligand A (0.756) has a better QED score than Ligand B (0.663), indicating a more drug-like profile.

**7. DILI:** Ligand A (89.841) has a higher DILI risk than Ligand B (26.328). This is a significant drawback for Ligand A.

**8. BBB:** Ligand B (80.031) has a significantly better BBB penetration percentile than Ligand A (39.511). This is crucial for a CNS target like DRD2.

**9. Caco-2 Permeability:** Ligand A (-5.358) has poor Caco-2 permeability, while Ligand B (-4.54) is slightly better, but still not ideal.

**10. Aqueous Solubility:** Both ligands have poor aqueous solubility (-3.067 and -3.296). This could be a formulation challenge, but is less critical than BBB penetration for a CNS drug.

**11. hERG Inhibition:** Ligand A (0.111) has a lower hERG inhibition liability than Ligand B (0.726), which is favorable.

**12. Microsomal Clearance:** Ligand B (77.76) has a significantly higher microsomal clearance than Ligand A (25.885), indicating lower metabolic stability.

**13. In vitro Half-Life:** Ligand B (4.655) has a slightly longer in vitro half-life than Ligand A (3.144).

**14. P-gp Efflux:** Ligand A (0.035) has much lower P-gp efflux liability than Ligand B (0.506). Lower P-gp efflux is highly desirable for CNS penetration.

**15. Binding Affinity:** Ligand A (-8.6 kcal/mol) has a significantly stronger binding affinity than Ligand B (-6.4 kcal/mol). The 2.2 kcal/mol difference is substantial and can outweigh some ADME drawbacks.

**Overall Assessment:**

While Ligand A has superior binding affinity and lower P-gp efflux, its significantly higher DILI risk and poor BBB penetration are major concerns. Ligand B, despite its weaker affinity, has a much better safety profile (lower DILI), excellent BBB penetration, and acceptable P-gp efflux. Given the GPCR-specific priorities for DRD2 (BBB, logP, Pgp, TPSA, and affinity), and the substantial difference in BBB penetration, Ligand B is the more promising candidate. The affinity difference, while significant, might be overcome with further optimization of Ligand B.

Output:
1
2025-04-17 05:13:36,279 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (337.423 and 354.51 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (54.46) is slightly higher than Ligand B (49.41), but both are below the 90 A^2 threshold desirable for CNS targets.

**3. logP:** Both ligands have logP values (3.819 and 4.006) within the optimal 1-3 range, though approaching the upper limit.

**4. H-Bond Donors:** Both have 1 HBD, which is acceptable.

**5. H-Bond Acceptors:** Ligand A has 4 HBA, and Ligand B has 2. Both are within the acceptable range of <=10.

**6. QED:** Ligand A (0.921) has a significantly better QED score than Ligand B (0.476), indicating a more drug-like profile.

**7. DILI:** Ligand A (62.35) has a higher DILI risk than Ligand B (17.255). This is a concern for Ligand A.

**8. BBB:** Ligand B (83.288) has a significantly higher BBB penetration percentile than Ligand A (77.239). This is a crucial advantage for a CNS target like DRD2.

**9. Caco-2 Permeability:** Both have negative Caco-2 values (-4.403 and -4.6), which is unusual and suggests poor permeability. However, these values are on a scale where negative values are possible and don't necessarily preclude development.

**10. Aqueous Solubility:** Both have negative solubility values (-5.204 and -3.905), indicating poor aqueous solubility. This could pose formulation challenges.

**11. hERG Inhibition:** Both ligands have low hERG inhibition risk (0.715 and 0.83).

**12. Microsomal Clearance:** Ligand B (83.843) has a higher microsomal clearance than Ligand A (76.928), suggesting faster metabolism and potentially lower *in vivo* exposure.

**13. In vitro Half-Life:** Ligand A (38.336) has a much longer half-life than Ligand B (7.708). This is a significant advantage for dosing convenience.

**14. P-gp Efflux:** Both ligands have low P-gp efflux liability (0.431 and 0.556).

**15. Binding Affinity:** Ligand A (-8.4 kcal/mol) has a slightly better binding affinity than Ligand B (-7.7 kcal/mol). The difference is 0.7 kcal/mol, which is a meaningful advantage.

**Overall Assessment:**

Ligand A has a better QED score, longer half-life, and slightly better binding affinity. However, it has a higher DILI risk and lower BBB penetration than Ligand B. Given that DRD2 is a CNS target, BBB penetration is paramount. Ligand B's significantly higher BBB score (83.288 vs 77.239) outweighs the benefits of Ligand A's slightly better affinity and half-life, especially considering the affinity difference isn't huge. The lower DILI risk of Ligand B is also a positive. While both have solubility and permeability concerns, these can be addressed with formulation strategies.

Output:
1
2025-04-17 05:13:36,279 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (350.369 Da and 347.415 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (82.62) is significantly better than Ligand B (102.76). For CNS targets, we want TPSA <= 90, and A is comfortably within this range, while B is slightly above.

**logP:** Ligand A (2.699) is optimal (1-3). Ligand B (0.835) is a bit low, potentially hindering permeation.

**H-Bond Donors/Acceptors:** Ligand A (HBD=1, HBA=5) and Ligand B (HBD=3, HBA=5) both have reasonable numbers of H-bond donors and acceptors.

**QED:** Both ligands have good QED scores (0.325 and 0.749), with B being preferable.

**DILI:** Ligand A (58.511) has a higher DILI risk than Ligand B (35.091). B is clearly better here.

**BBB:** Ligand A (77.705) has a much better BBB penetration percentile than Ligand B (23.149). This is a *critical* factor for a CNS target like DRD2.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.1 and -5.06), which is unusual and suggests poor permeability. However, these values are on a scale where negative values are possible and don't necessarily disqualify a compound.

**Aqueous Solubility:** Both ligands have negative solubility values (-3.124 and -1.985), indicating poor aqueous solubility. This could be a formulation challenge.

**hERG Inhibition:** Ligand A (0.866) has a slightly higher hERG inhibition risk than Ligand B (0.169). B is significantly better here.

**Microsomal Clearance:** Ligand A (45.936) has a higher microsomal clearance than Ligand B (6.432), indicating lower metabolic stability. B is preferable.

**In vitro Half-Life:** Ligand B (-24.813) has a longer in vitro half-life than Ligand A (-18.489) which is favorable.

**P-gp Efflux:** Ligand A (0.886) has slightly lower P-gp efflux liability than Ligand B (0.011). Lower is better, so A is preferable.

**Binding Affinity:** Both ligands have the same binding affinity (-8.5 kcal/mol), which is excellent.

**Overall Assessment:**

While Ligand B has better DILI, hERG, clearance, and half-life, Ligand A's significantly superior BBB penetration (77.7 vs 23.1) and better TPSA (82.62 vs 102.76) are decisive for a CNS-targeting GPCR like DRD2. The affinity is the same, so we prioritize the CNS penetration and permeability characteristics. The slightly higher P-gp efflux for B is also a concern.

Output:
0
2025-04-17 05:13:36,279 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, considering the provided guidelines and GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (352.415 Da) is slightly lower, which could be beneficial for permeability. Ligand B (369.384 Da) is also good.

**TPSA:** Ligand A (68.29) is excellent, well below the 90 A^2 threshold for CNS targets. Ligand B (101.9) is higher but still reasonable, though less optimal for CNS penetration.

**logP:** Ligand A (4.274) is at the upper end of the optimal range, potentially leading to solubility issues or off-target interactions. Ligand B (-0.378) is significantly lower, which is undesirable as it may hinder membrane permeability.

**H-Bond Donors/Acceptors:** Ligand A (HBD=1, HBA=5) is within the acceptable ranges. Ligand B (HBD=4, HBA=5) is also acceptable, but the higher HBD count could slightly impact permeability.

**QED:** Ligand A (0.696) has a better QED score, indicating better drug-likeness, than Ligand B (0.467).

**DILI:** Ligand A (98.759) has a very high DILI risk, which is a major concern. Ligand B (9.965) has a very low DILI risk, which is excellent.

**BBB:** Both ligands have reasonable BBB penetration (Ligand A: 45.677, Ligand B: 48.119). However, neither reaches the >70 percentile desirable for CNS targets.

**Caco-2 Permeability:** Ligand A (-4.798) shows poor Caco-2 permeability, indicating poor intestinal absorption. Ligand B (-5.379) also shows poor Caco-2 permeability.

**Aqueous Solubility:** Ligand A (-5.939) has very poor aqueous solubility, consistent with its high logP. Ligand B (-0.673) has slightly better solubility, but still not ideal.

**hERG Inhibition:** Ligand A (0.42) has a low hERG inhibition risk, which is good. Ligand B (0.225) also has a low hERG inhibition risk.

**Microsomal Clearance:** Ligand A (66.57) has moderate microsomal clearance. Ligand B (-12.912) has negative clearance, which is not physically possible and likely indicates an issue with the prediction or data quality.

**In vitro Half-Life:** Ligand A (-3.201) has a negative half-life, which is not physically possible and indicates a data issue. Ligand B (-32.298) also has a negative half-life, indicating a data issue.

**P-gp Efflux:** Ligand A (0.74) has moderate P-gp efflux. Ligand B (0.006) has very low P-gp efflux, which is favorable for CNS penetration.

**Binding Affinity:** Ligand A (-9.4 kcal/mol) has significantly stronger binding affinity than Ligand B (-7.0 kcal/mol). This is a substantial advantage.

**Overall Assessment:**

Ligand A has a much stronger binding affinity, a better QED score, and a lower hERG risk. However, its extremely high DILI risk, poor solubility, and poor Caco-2 permeability are major drawbacks. The negative values for half-life and clearance are concerning and suggest data quality issues.

Ligand B has a much lower DILI risk and very low P-gp efflux, which are significant advantages. However, its low logP is a major concern for permeability, and its binding affinity is considerably weaker. The negative values for half-life and clearance are concerning and suggest data quality issues.

Despite the data quality issues, the substantial difference in binding affinity for Ligand A is compelling. While the DILI risk is a serious concern, it might be mitigated through structural modifications. The poor solubility and permeability could also be addressed with prodrug strategies or formulation techniques. The negative values for half-life and clearance are a red flag, but if these were corrected to reasonable values, Ligand A would be the better candidate.

Output:
1
2025-04-17 05:13:36,280 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (385.863 Da) is slightly higher than Ligand B (357.445 Da), but both are acceptable.

**TPSA:** Ligand A (46.17) is excellent for CNS penetration, well below the 90 A^2 threshold. Ligand B (61.44) is still reasonable, but less optimal.

**logP:** Ligand A (4.308) is a bit high, potentially leading to solubility issues or off-target interactions. Ligand B (1.776) is within the optimal range (1-3).

**H-Bond Donors/Acceptors:** Ligand A (HBD=1, HBA=2) and Ligand B (HBD=2, HBA=3) both have acceptable numbers of hydrogen bond donors and acceptors.

**QED:** Both ligands have similar QED values (A: 0.779, B: 0.73), indicating good drug-likeness.

**DILI:** Ligand A (63.086) has a higher DILI risk than Ligand B (9.849). This is a significant concern.

**BBB:** Ligand B (89.957) has a substantially better BBB penetration score than Ligand A (70.105). This is crucial for a CNS target like DRD2.

**Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and suggests a potential issue with the data or modeling. However, the values are similar in magnitude.

**Aqueous Solubility:** Both ligands have poor aqueous solubility (A: -5.172, B: -1.934).

**hERG Inhibition:** Both ligands have low hERG inhibition risk (A: 0.637, B: 0.752).

**Microsomal Clearance:** Ligand B (-15.101) has significantly lower microsomal clearance than Ligand A (38.164), indicating better metabolic stability.

**In vitro Half-Life:** Ligand B (7.283) has a shorter in vitro half-life than Ligand A (39.474). This is less ideal, but the difference might be manageable.

**P-gp Efflux:** Ligand A (0.225) has lower P-gp efflux than Ligand B (0.015), which is favorable for CNS penetration.

**Binding Affinity:** Ligand B (-8.6 kcal/mol) has a slightly better binding affinity than Ligand A (-8.3 kcal/mol), although the difference is small.

**Overall Assessment:**

Ligand B is the more promising candidate. While its solubility and half-life are not ideal, its significantly better BBB penetration, lower DILI risk, and improved metabolic stability outweigh the slightly weaker affinity and higher P-gp efflux. Ligand A's high logP and DILI risk are major drawbacks. The GPCR-specific priorities strongly favor Ligand B due to its superior BBB score.

Output:
1
2025-04-17 05:13:36,280 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight (MW):** Both ligands (360.445 and 351.403 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (49.85) is significantly better than Ligand B (101.83). For CNS targets, we want TPSA <= 90, and Ligand A is comfortably within this range, while Ligand B exceeds it.

**3. logP:** Both ligands have similar logP values (2.195 and 2.266), falling within the optimal 1-3 range.

**4. H-Bond Donors (HBD):** Both are low (0 and 1), which is good.

**5. H-Bond Acceptors (HBA):** Ligand A (3) is preferable to Ligand B (7), as lower HBA generally improves permeability.

**6. QED:** Both have good QED scores (0.699 and 0.778), indicating drug-like properties.

**7. DILI:** Ligand A (11.128) has a much lower DILI risk than Ligand B (44.591). This is a significant advantage.

**8. BBB:** Ligand A (96.084) has a substantially higher BBB penetration percentile than Ligand B (70.027). This is *critical* for a CNS target like DRD2.

**9. Caco-2 Permeability:** Both have negative values (-4.291 and -4.399), which is unusual and hard to interpret without knowing the scale. However, the values are similar.

**10. Aqueous Solubility:** Both have similar, very low solubility values (-1.76 and -1.768). This could be a formulation challenge for both.

**11. hERG Inhibition:** Ligand A (0.684) shows slightly lower hERG inhibition liability than Ligand B (0.239), which is preferable.

**12. Microsomal Clearance:** Ligand A (33.714) has lower microsomal clearance than Ligand B (57.189), indicating better metabolic stability.

**13. In vitro Half-Life:** Ligand A (-5.148) has a slightly better (less negative) in vitro half-life than Ligand B (-8.82).

**14. P-gp Efflux:** Ligand A (0.097) has significantly lower P-gp efflux liability than Ligand B (0.247), which is beneficial for CNS exposure.

**15. Binding Affinity:** Ligand A (-7.5 kcal/mol) has a slightly better binding affinity than Ligand B (-7.2 kcal/mol). While the difference is not huge, it adds to the overall advantage of Ligand A.

**Overall Assessment:**

Ligand A is clearly superior. It excels in crucial areas for a CNS-targeting GPCR ligand: TPSA, BBB penetration, DILI risk, P-gp efflux, and metabolic stability. While both have similar logP and QED, Ligand A's better ADME profile and slightly improved affinity make it the more promising drug candidate. The solubility is a concern for both, but can be addressed with formulation strategies.

Output:
1
2025-04-17 05:13:36,280 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B based on the provided guidelines, prioritizing GPCR-specific properties (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (371.434 and 356.495 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (102.76) is slightly above the optimal <90 for CNS targets, but still reasonable. Ligand B (61.88) is well within the desirable range.

**logP:** Ligand A (0.335) is quite low, potentially hindering permeation. Ligand B (3.549) is near the upper end of the optimal range (1-3), but still acceptable.

**H-Bond Donors/Acceptors:** Ligand A has 3 HBD and 6 HBA, which are acceptable. Ligand B has 1 HBD and 4 HBA, also acceptable.

**QED:** Both ligands have good QED scores (0.669 and 0.735), indicating good drug-like properties.

**DILI:** Ligand A (38.736) has a lower DILI risk than Ligand B (44.087), both are acceptable.

**BBB:** Ligand A (65.839) is below the desirable >70 for CNS targets, while Ligand B (70.027) just meets the threshold. This is a significant advantage for Ligand B.

**Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and could indicate issues with the measurement or the compounds themselves. However, the values are similar, so this isn't a major differentiator.

**Aqueous Solubility:** Both have negative solubility values, also unusual. Again, similar values.

**hERG:** Ligand A (0.118) has a lower hERG risk than Ligand B (0.633), which is a positive.

**Microsomal Clearance:** Ligand A (-24.017) has a much lower (better) microsomal clearance than Ligand B (62.91), indicating better metabolic stability.

**In vitro Half-Life:** Ligand A (-2.074) has a negative half-life, which is not physically possible and indicates a problem with the data. Ligand B (2.135) is a reasonable half-life.

**P-gp Efflux:** Ligand A (0.025) has very low P-gp efflux, which is excellent for CNS penetration. Ligand B (0.347) has moderate P-gp efflux.

**Binding Affinity:** Ligand B (-7.6 kcal/mol) has a significantly stronger binding affinity than Ligand A (-8.2 kcal/mol). The difference of 0.6 kcal/mol is substantial and can outweigh some ADME drawbacks.

**Overall Assessment:**

Ligand B is the better candidate. While Ligand A has better P-gp efflux and lower hERG risk, the significantly stronger binding affinity of Ligand B (-7.6 vs -8.2 kcal/mol) is a major advantage. Furthermore, Ligand B meets the BBB threshold, while Ligand A does not. The metabolic stability of Ligand A is better, but the negative half-life value is a red flag. The slightly higher logP of Ligand B is acceptable, and the other ADME properties are reasonably balanced.

Output:
1
2025-04-17 05:13:36,280 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (339.395 and 347.415 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (74.69) is excellent, well below the 90 A^2 threshold for CNS targets. Ligand B (95.67) is still reasonable but closer to the upper limit and less favorable.

**logP:** Ligand A (2.985) is optimal (1-3). Ligand B (0.899) is slightly low, potentially hindering membrane permeability, though not drastically.

**H-Bond Donors/Acceptors:** Both ligands have 2 HBD and 4-5 HBA, which are within acceptable limits.

**QED:** Both ligands have QED values above 0.7, indicating good drug-likeness.

**DILI:** Both ligands have low DILI risk (36.797 and 39.473 percentile), which is positive.

**BBB:** Ligand A (65.529) is moderate, while Ligand B (46.84) is considerably lower. For a CNS target like DRD2, a higher BBB penetration is highly desirable. This is a significant advantage for Ligand A.

**Caco-2 Permeability:** Ligand A (-4.995) and Ligand B (-5.065) both have negative Caco-2 values which are not ideal.

**Aqueous Solubility:** Ligand A (-3.849) and Ligand B (-1.2) both have negative solubility values which are not ideal.

**hERG Inhibition:** Both ligands show very low hERG inhibition risk (0.381 and 0.085 percentile).

**Microsomal Clearance:** Ligand A (43.081) has higher clearance than Ligand B (4.959), indicating lower metabolic stability. This is a negative for Ligand A.

**In vitro Half-Life:** Ligand B (-12.354) has a much longer in vitro half-life than Ligand A (5.535), which is a significant advantage.

**P-gp Efflux:** Both ligands show very low P-gp efflux liability (0.041 and 0.027 percentile).

**Binding Affinity:** Ligand A (-8.5 kcal/mol) has a slightly better binding affinity than Ligand B (-7.8 kcal/mol). While the difference is not huge, it's a positive for Ligand A.

**Overall Assessment:**

Ligand A excels in TPSA and binding affinity, and has a moderately acceptable BBB score. However, it suffers from higher microsomal clearance and a shorter half-life. Ligand B has a better half-life and lower clearance, but its BBB penetration is significantly lower, and its logP is less optimal. Given the importance of BBB penetration for a CNS target like DRD2, and the relatively small difference in binding affinity, Ligand A is the more promising candidate. The slightly lower metabolic stability of Ligand A could be addressed through structural modifications.

Output:
1
2025-04-17 05:13:36,281 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B against the provided guidelines, with a focus on GPCR properties (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (352.475 Da) is slightly lower, which could be beneficial for permeability.

**TPSA:** Both ligands have TPSA values below the 90 A^2 threshold desirable for CNS targets. Ligand B (54.46 A^2) is slightly higher than Ligand A (59.08 A^2), but both are acceptable.

**logP:** Ligand A (1.701) is within the optimal range (1-3), while Ligand B (3.427) is at the higher end. While still acceptable, higher logP can sometimes lead to off-target effects.

**H-Bond Donors/Acceptors:** Ligand A (0 HBD, 4 HBA) and Ligand B (1 HBD, 5 HBA) both fall within acceptable limits.

**QED:** Both ligands have reasonable QED values, with Ligand B (0.676) being slightly better than Ligand A (0.444), indicating a more drug-like profile.

**DILI:** Ligand A (9.461) has a significantly lower DILI risk than Ligand B (26.444), which is a major advantage.

**BBB:** Both ligands exhibit excellent BBB penetration (Ligand A: 81.582%, Ligand B: 91.431%). Ligand B is slightly better, which is crucial for a CNS target like DRD2.

**Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and suggests poor permeability. However, the scale is not defined, so it's hard to interpret.

**Aqueous Solubility:** Both have negative solubility values, again unusual and suggesting poor solubility.

**hERG:** Both ligands have low hERG inhibition liability (Ligand A: 0.394, Ligand B: 0.873), which is good.

**Microsomal Clearance:** Ligand A (67.076) has a higher microsomal clearance than Ligand B (61.148), suggesting potentially lower metabolic stability.

**In vitro Half-Life:** Ligand B (-8.516) has a better (longer) in vitro half-life than Ligand A (-11.604).

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (Ligand A: 0.069, Ligand B: 0.678), which is beneficial for CNS penetration.

**Binding Affinity:** Ligand A (-6.8 kcal/mol) has a slightly better binding affinity than Ligand B (-6.5 kcal/mol), although the difference is relatively small.

**Overall Assessment:**

Ligand A has a significant advantage in terms of DILI risk and slightly better binding affinity. Ligand B has better QED, BBB penetration, and in vitro half-life. The solubility and Caco-2 values are concerning for both, but the negative values make comparison difficult. Given the importance of minimizing toxicity (DILI) and achieving CNS penetration for a DRD2 target, and the small affinity difference, Ligand A appears to be the more promising candidate.

Output:
0
2025-04-17 05:13:36,281 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (343.471 Da) is slightly lower, which could be advantageous for permeability.

**2. TPSA:** Ligand A (71.09) is better than Ligand B (43.78), falling comfortably below the 90 A^2 threshold for CNS targets. Ligand B is excellent.

**3. logP:** Both ligands have good logP values (A: 2.795, B: 3.47), falling within the optimal 1-3 range.

**4. H-Bond Donors:** Ligand A (2) and Ligand B (1) are both acceptable.

**5. H-Bond Acceptors:** Ligand A (3) and Ligand B (4) are both acceptable.

**6. QED:** Both ligands have good QED scores (A: 0.507, B: 0.799), indicating drug-like properties. Ligand B is better.

**7. DILI:** Ligand A (34.393) has a slightly higher DILI risk than Ligand B (22.993), but both are below the concerning threshold of 60.

**8. BBB:** This is critical for a CNS target like DRD2. Ligand B (69.95) is significantly better than Ligand A (55.293), approaching the desirable >70 percentile.

**9. Caco-2 Permeability:** Both have negative values, which is unusual and suggests a potential issue with the data. However, the magnitude is important. Ligand A (-4.983) is worse than Ligand B (-4.708).

**10. Aqueous Solubility:** Both have negative values, which is also unusual. Ligand A (-2.365) is slightly better than Ligand B (-3.72).

**11. hERG Inhibition:** Both have low hERG risk (A: 0.489, B: 0.831).

**12. Microsomal Clearance:** Ligand A (53.208) has lower clearance than Ligand B (78.108), suggesting better metabolic stability.

**13. In vitro Half-Life:** Ligand B (61.161) has a significantly longer half-life than Ligand A (14.072).

**14. P-gp Efflux:** Ligand A (0.104) has much lower P-gp efflux than Ligand B (0.687), which is favorable for CNS penetration.

**15. Binding Affinity:** Ligand B (-7.3 kcal/mol) has a stronger binding affinity than Ligand A (-8.0 kcal/mol). While A is slightly better, the difference is not substantial enough to overcome other issues.

**Overall Assessment:**

Ligand B is the stronger candidate. While Ligand A has slightly better metabolic stability and P-gp efflux, Ligand B excels in the most critical areas for a CNS-targeting GPCR: BBB penetration, QED, and binding affinity. The longer half-life of Ligand B is also a significant advantage. The unusual negative values for Caco-2 and Solubility are concerning, but the overall profile of Ligand B is more promising.

Output:
1
2025-04-17 05:13:36,281 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (369.531 and 352.475 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Both ligands have TPSA values around 70 (70.67 and 70.08). This is above the optimal <90 for CNS targets, but not drastically so.

**3. logP:** Both ligands have logP values around 1.1 (1.027 and 1.127), which is within the optimal 1-3 range.

**4. H-Bond Donors:** Ligand A has 2 HBD, and Ligand B has 1. Both are acceptable (<=5).

**5. H-Bond Acceptors:** Ligand A has 5 HBA, and Ligand B has 4. Both are acceptable (<=10).

**6. QED:** Ligand B (0.827) has a significantly better QED score than Ligand A (0.445), indicating a more drug-like profile.

**7. DILI:** Ligand A (17.371) has a lower DILI risk than Ligand B (20.706), which is preferable.

**8. BBB:** This is a critical parameter for a CNS target like DRD2. Ligand B (81.698) has a much higher BBB percentile than Ligand A (35.673). This is a major advantage for Ligand B.

**9. Caco-2 Permeability:** Ligand A (-5.565) has a worse Caco-2 permeability than Ligand B (-4.145), suggesting lower intestinal absorption.

**10. Aqueous Solubility:** Ligand A (-1.282) has slightly better aqueous solubility than Ligand B (-1.929), but both are poor.

**11. hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.398 and 0.383).

**12. Microsomal Clearance:** Ligand A (10.69) has lower microsomal clearance than Ligand B (35.958), suggesting better metabolic stability.

**13. In vitro Half-Life:** Ligand B (-6.896) has a negative half-life, which is unusual and likely indicates very rapid degradation. Ligand A (3.48) has a more reasonable half-life.

**14. P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.032 and 0.111).

**15. Binding Affinity:** Ligand B (-7.5 kcal/mol) has a slightly better binding affinity than Ligand A (-7.2 kcal/mol). While the difference is not huge, it's still a positive for Ligand B.

**Overall Assessment:**

Ligand B excels in BBB penetration and has a better QED score and slightly better affinity. However, it has a concerningly low (negative) in vitro half-life and higher DILI risk. Ligand A has better metabolic stability (lower Cl_mic, better t1/2), lower DILI, and slightly better solubility. The significantly better BBB penetration of Ligand B is a strong advantage for a CNS target, but the poor half-life is a major drawback. Considering the balance, the better BBB penetration of Ligand B is likely to outweigh the other factors, assuming the half-life issue can be addressed through structural modifications.

Output:
1
2025-04-17 05:13:36,281 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (359.459 and 349.362 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (111.61) is better than Ligand B (117.59). Both are reasonably good for CNS penetration, being under 140, but closer to the ideal <90 is preferred.

**3. logP:** Ligand A (2.569) is better than Ligand B (1.078). Ligand B is a bit low, potentially hindering membrane permeability. Ligand A is within the optimal 1-3 range.

**4. H-Bond Donors:** Ligand A (2) is preferable to Ligand B (4). Fewer HBDs generally improve permeability.

**5. H-Bond Acceptors:** Ligand A (8) is preferable to Ligand B (5). Fewer HBAs generally improve permeability.

**6. QED:** Both ligands have acceptable QED values (0.727 and 0.558), indicating reasonable drug-likeness.

**7. DILI:** Ligand A (91.431) has a higher DILI risk than Ligand B (48.313). This is a significant drawback for Ligand A.

**8. BBB:** Ligand A (62.699) has a better BBB percentile than Ligand B (52.074), which is important for a CNS target like DRD2. However, both are below the desirable >70 threshold.

**9. Caco-2:** Both ligands have negative Caco-2 values (-5.2 and -5.36), which is unusual and likely indicates poor permeability. This is a significant concern for both.

**10. Solubility:** Both ligands have negative solubility values (-3.537 and -2.59), indicating very poor aqueous solubility. This is a major issue for both.

**11. hERG:** Both ligands have low hERG inhibition liability (0.595 and 0.627), which is good.

**12. Cl_mic:** Ligand B (7.925) has significantly lower microsomal clearance than Ligand A (31.041), suggesting better metabolic stability.

**13. t1/2:** Both ligands have similar in vitro half-lives (44.339 and 45.444 hours).

**14. Pgp:** Both ligands have very low Pgp efflux liability (0.16 and 0.104), which is favorable for CNS penetration.

**15. Binding Affinity:** Ligand B (-9.2 kcal/mol) has a slightly better binding affinity than Ligand A (-8.7 kcal/mol). While the difference is not huge, it's enough to consider, especially given the other factors.

**Overall Assessment:**

Ligand A has better BBB penetration, logP, and H-bonding characteristics, but suffers from a significantly higher DILI risk and higher metabolic clearance. Ligand B has a better DILI profile, lower clearance, and slightly better binding affinity. However, its logP is suboptimal. The poor Caco-2 and solubility for both are concerning and would require significant optimization.

Considering the GPCR-specific priorities and the overall profile, **Ligand B** is the more promising candidate. The lower DILI risk and better metabolic stability outweigh the slightly lower BBB and logP values, especially since the binding affinity is slightly better. The solubility and permeability issues are critical for both, but can potentially be addressed through formulation or further structural modifications.

Output:
1
2025-04-17 05:13:36,281 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (350.511 and 359.495 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Both ligands have TPSA values around 59.3-59.2 A^2, which is excellent for CNS penetration (well below the 90 A^2 threshold).

**3. logP:** Ligand A (1.92) is optimal, while Ligand B (4.534) is pushing the upper limit. High logP can lead to off-target effects and solubility issues.

**4. H-Bond Donors:** Both ligands have 0 HBD, which is acceptable.

**5. H-Bond Acceptors:** Ligand A has 7 HBA, and Ligand B has 5 HBA, both within the acceptable limit of 10.

**6. QED:** Both ligands have good QED scores (0.749 and 0.804), indicating drug-like properties.

**7. DILI:** Ligand A (15.2 percentile) has a significantly lower DILI risk than Ligand B (55.68 percentile). This is a major advantage for Ligand A.

**8. BBB:** Both ligands have excellent BBB penetration (87.553% and 84.917%), exceeding the desirable threshold of 70%.

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 values, indicating poor permeability. This is concerning, but can sometimes be overcome with formulation strategies.

**10. Aqueous Solubility:** Ligand A (-1.58) has slightly better solubility than Ligand B (-4.075), though both are quite poor.

**11. hERG Inhibition:** Both ligands have low hERG inhibition risk (0.546 and 0.448).

**12. Microsomal Clearance:** Ligand A (25.838 mL/min/kg) has significantly lower microsomal clearance than Ligand B (66.462 mL/min/kg), suggesting better metabolic stability.

**13. In vitro Half-Life:** Ligand A (7.331 hours) has a better in vitro half-life than Ligand B (-32.372 hours - a negative value is unusual and suggests very rapid degradation).

**14. P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.073 and 0.453), which is favorable for CNS exposure.

**15. Binding Affinity:** Ligand B (-7.9 kcal/mol) has a significantly stronger binding affinity than Ligand A (-5.9 kcal/mol). This is a substantial advantage, potentially outweighing some of the ADME drawbacks.

**Overall Assessment:**

Ligand B has a superior binding affinity, which is crucial for GPCR targets. However, it suffers from higher logP, higher DILI risk, and significantly worse metabolic stability (higher Cl_mic and lower t1/2). Ligand A has a more balanced profile with better ADME properties (lower DILI, lower Cl_mic, longer t1/2, better solubility) and acceptable affinity. Given the CNS target and the importance of a balanced profile for *in vivo* efficacy, the better ADME properties of Ligand A are more compelling, despite the weaker binding. The difference in affinity (-2 kcal/mol) is not large enough to overcome the significant ADME liabilities of Ligand B.

Output:
0
2025-04-17 05:13:36,282 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (364.43 and 377.51 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (108.56) is higher than Ligand B (70.12). For CNS targets, TPSA should be <= 90. Ligand B is significantly better in this regard.

**logP:** Ligand A (0.946) is suboptimal, being slightly below the preferred 1-3 range, potentially hindering permeation. Ligand B (4.125) is at the higher end but still acceptable, though it could raise concerns about off-target effects.

**H-Bond Donors/Acceptors:** Ligand A has 2 HBD and 7 HBA, while Ligand B has 1 HBD and 5 HBA. Both are within acceptable limits (<=5 HBD and <=10 HBA).

**QED:** Both have reasonable QED values (0.818 and 0.769), indicating good drug-like properties.

**DILI:** Ligand A (64.68%) has a higher DILI risk than Ligand B (55.87%), although both are reasonably acceptable.

**BBB:** This is crucial for a CNS target like DRD2. Ligand B (73.75%) shows significantly better BBB penetration potential than Ligand A (45.44%).

**Caco-2 Permeability:** Ligand A (-5.461) has poor Caco-2 permeability, while Ligand B (-4.744) is slightly better, but still not great.

**Aqueous Solubility:** Both ligands have poor aqueous solubility (-2.19 and -4.622). This could present formulation challenges.

**hERG Inhibition:** Ligand A (0.263) has a lower hERG inhibition risk than Ligand B (0.883), which is preferable.

**Microsomal Clearance:** Ligand B (66.68) has a higher microsomal clearance than Ligand A (12.51), indicating faster metabolism and potentially lower *in vivo* exposure.

**In vitro Half-Life:** Ligand B (26.912 hours) has a much longer half-life than Ligand A (-8.065 hours), which is a significant advantage.

**P-gp Efflux:** Ligand A (0.079) shows lower P-gp efflux liability than Ligand B (0.3), which is favorable for CNS penetration.

**Binding Affinity:** Ligand A (-9.1 kcal/mol) has a significantly stronger binding affinity than Ligand B (-6.7 kcal/mol). This is a substantial advantage, potentially outweighing some of the ADME drawbacks.

**Overall Assessment:**

Ligand A has a superior binding affinity and lower P-gp efflux, but suffers from poor Caco-2 permeability, a higher DILI risk, and a significantly shorter half-life. Ligand B excels in BBB penetration, has a longer half-life, and a lower DILI risk, but its binding affinity is considerably weaker, and it has higher P-gp efflux.

Given the importance of CNS penetration for a DRD2 ligand, and the substantial affinity difference, the stronger binding of Ligand A is the deciding factor. While its ADME properties are less ideal, optimization efforts could focus on improving its permeability, metabolic stability, and reducing DILI risk. The large affinity difference (-2.4 kcal/mol) is likely to be more impactful than the other differences.

Output:
0
2025-04-17 05:13:36,282 - INFO - Reasoning:

Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight (MW):** Both ligands (348.395 and 352.494 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (82.06) is better than Ligand B (49.41). For CNS targets, we want TPSA <= 90, both are within range, but A is closer to the upper limit.

**3. logP:** Both ligands have good logP values (2.313 and 3.819), falling within the optimal 1-3 range. Ligand B is slightly higher, which could potentially lead to some off-target effects, but is still acceptable.

**4. H-Bond Donors (HBD):** Both have 1 HBD, which is within the acceptable limit of <=5.

**5. H-Bond Acceptors (HBA):** Ligand A has 6 HBA, while Ligand B has 2. Both are within the acceptable limit of <=10.

**6. QED:** Ligand A (0.823) has a higher QED score than Ligand B (0.722), indicating better overall drug-likeness.

**7. DILI:** Both ligands have low DILI risk (34.393 and 33.773 percentile), which is good.

**8. BBB:** Ligand B (84.141) has a significantly better BBB penetration percentile than Ligand A (77.239). This is a *critical* factor for a CNS target like DRD2.

**9. Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and suggests poor permeability. However, the scale is not specified, so it's difficult to interpret.

**10. Aqueous Solubility:** Both have negative solubility values, which is also unusual and suggests poor solubility. Again, the scale is not specified.

**11. hERG Inhibition:** Both ligands have low hERG inhibition liability (0.275 and 0.68), which is favorable.

**12. Microsomal Clearance:** Ligand A (54.332) has lower microsomal clearance than Ligand B (77.284), suggesting better metabolic stability.

**13. In vitro Half-Life:** Ligand A (-15.709) has a negative half-life, which is not physically possible. This is a major red flag. Ligand B (13.066) has a reasonable half-life.

**14. P-gp Efflux:** Both ligands have low P-gp efflux liability (0.11 and 0.462), which is good for CNS penetration.

**15. Binding Affinity:** Both ligands have very similar and strong binding affinities (-8.8 kcal/mol and -8.5 kcal/mol). The difference of 0.3 kcal/mol is unlikely to be decisive.

**Conclusion:**

Despite Ligand A having a slightly better QED and lower clearance, the negative in vitro half-life is a deal-breaker. This indicates rapid metabolism and a very short duration of action. Ligand B, while having a slightly lower QED and higher clearance, has a significantly better BBB score and a plausible half-life. Given the GPCR-specific priority of BBB penetration for CNS targets, and the critical importance of a reasonable half-life, **Ligand B is the more viable drug candidate.**

Output:
1
2025-04-17 05:13:36,282 - INFO - Batch 180 complete. Total preferences: 2880
2025-04-17 05:13:36,282 - INFO - Processing batch 181/512...
2025-04-17 05:14:17,616 - INFO - Reasoning:

Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (356.46 & 344.38 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (49.41) is excellent, well below the 90 A^2 threshold for CNS targets. Ligand B (124.1) is higher, but still acceptable, though less ideal for CNS penetration.

**3. logP:** Ligand A (3.355) is optimal (1-3). Ligand B (0.496) is quite low, potentially hindering membrane permeability and CNS penetration.

**4. H-Bond Donors:** Ligand A (1) is good. Ligand B (3) is acceptable, but higher HBD can sometimes reduce permeability.

**5. H-Bond Acceptors:** Ligand A (2) is good. Ligand B (6) is higher, which could impact permeability.

**6. QED:** Both ligands (0.793 & 0.701) have good drug-likeness scores (>0.5).

**7. DILI:** Ligand A (10.59) has a much lower DILI risk than Ligand B (43.39). This is a significant advantage for Ligand A.

**8. BBB:** Ligand A (96.74) has excellent BBB penetration potential, exceeding the desirable >70% threshold. Ligand B (43.58) is considerably lower, raising concerns about reaching the target in the CNS.

**9. Caco-2:** Both have negative values, which is unusual. Assuming these represent logP-scaled Caco-2 permeability, the values suggest poor permeability. However, the negative values make direct comparison difficult.

**10. Solubility:** Both have negative values, which is unusual. Assuming these represent logS, the values suggest poor solubility.

**11. hERG:** Both ligands have low hERG inhibition risk (0.687 & 0.249).

**12. Cl_mic:** Ligand A (18.63) has a higher microsomal clearance than Ligand B (6.64), suggesting faster metabolism and potentially lower exposure.

**13. t1/2:** Ligand B (-13.48) has a longer in vitro half-life than Ligand A (-12.67), which is a slight advantage.

**14. Pgp:** Ligand A (0.077) has lower P-gp efflux liability than Ligand B (0.006), meaning it's less likely to be pumped out of the brain, improving CNS exposure.

**15. Binding Affinity:** Both ligands have similar strong binding affinities (-8.2 and -8.8 kcal/mol). The difference is minor.

**Overall Assessment:**

Considering the GPCR-specific priorities, Ligand A is the far superior candidate. Its excellent BBB penetration, optimal logP, lower DILI risk, and lower P-gp efflux liability outweigh the slightly higher microsomal clearance and shorter half-life. Ligand B's low logP and poor BBB penetration are major drawbacks for a CNS-targeted drug. The similar binding affinities make the ADME properties the deciding factor.

Output:
1
2025-04-17 05:14:17,616 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (346.381 and 347.39 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (57.26) is significantly better than Ligand B (80.32). For CNS targets, we want TPSA <= 90, and A is comfortably within that range, while B is approaching the upper limit.

**3. logP:** Ligand A (3.642) is optimal (1-3), while Ligand B (1.797) is on the lower side. While not terrible, lower logP can sometimes indicate permeability issues.

**4. H-Bond Donors:** Both have 2 HBD, which is acceptable (<=5).

**5. H-Bond Acceptors:** Ligand A has 3 HBA, and Ligand B has 4. Both are within the acceptable range (<=10).

**6. QED:** Both ligands have QED values above 0.7, indicating good drug-like properties.

**7. DILI:** Ligand A (60.062) is slightly higher risk than Ligand B (49.399), but both are below the concerning threshold of 60.

**8. BBB:** Both ligands have a BBB percentile of 77.2, which is excellent and meets the >70 requirement for CNS targets.

**9. Caco-2 Permeability:** Both have negative values, which is unusual. Assuming these are logP-scale values, lower values indicate lower permeability. Ligand A (-4.697) is worse than Ligand B (-4.408), but both are poor.

**10. Aqueous Solubility:** Both have negative values, indicating poor solubility. Ligand A (-3.741) is slightly worse than Ligand B (-2.634).

**11. hERG Inhibition:** Ligand A (0.811) is better than Ligand B (0.108), indicating lower cardiotoxicity risk.

**12. Microsomal Clearance:** Ligand A (-2.146) has a negative clearance, which is not physically possible. This is likely an error or a very stable compound. Ligand B (33.582) has a higher clearance, suggesting faster metabolism.

**13. In vitro Half-Life:** Ligand A (15.187 hours) has a much longer half-life than Ligand B (5.109 hours).

**14. P-gp Efflux:** Ligand A (0.119) has lower P-gp efflux than Ligand B (0.026), which is beneficial for CNS penetration.

**15. Binding Affinity:** Ligand B (-7.2 kcal/mol) has a significantly stronger binding affinity than Ligand A (-10.0 kcal/mol). This is a substantial difference, and a >1.5 kcal/mol advantage often outweighs other drawbacks.

**Overall Assessment:**

Despite Ligand A's better TPSA, logP, hERG, P-gp efflux, and half-life, the overwhelmingly stronger binding affinity of Ligand B (-7.2 vs -10.0 kcal/mol) is the deciding factor. The affinity difference is large enough to compensate for its slightly higher TPSA and clearance. The BBB penetration is identical for both. The Caco-2 and solubility are poor for both, but can be addressed with formulation strategies. The negative clearance for Ligand A is a red flag.

Output:
1
2025-04-17 05:14:17,617 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (421.259 Da) is slightly higher, but acceptable. Ligand B (391.339 Da) is also good.

**2. TPSA:** Ligand A (71.06) is higher than Ligand B (58.64). For a CNS target like DRD2, we want TPSA <= 90, so both are acceptable, but B is better.

**3. logP:** Ligand A (3.502) is at the upper end of the optimal range (1-3), while Ligand B (2.742) is well within it.  Higher logP can sometimes lead to off-target effects, so B is slightly favored.

**4. H-Bond Donors:** Ligand A (0) is ideal, while Ligand B (1) is acceptable.

**5. H-Bond Acceptors:** Ligand A (6) is good, while Ligand B (3) is excellent.

**6. QED:** Both ligands have good QED scores (A: 0.473, B: 0.679), indicating reasonable drug-likeness. Ligand B is better.

**7. DILI:** Ligand A (55.68) has a moderate DILI risk, while Ligand B (12.02) has a very low risk. This is a significant advantage for Ligand B.

**8. BBB:** Both ligands have excellent BBB penetration (A: 74.99, B: 75.882), exceeding the 70% threshold for CNS targets. Very similar.

**9. Caco-2 Permeability:** Ligand A (-4.138) has poor Caco-2 permeability, while Ligand B (-5.024) is also poor. This is not ideal, but not a dealbreaker given the BBB scores.

**10. Aqueous Solubility:** Ligand A (-4.582) has poor solubility, while Ligand B (-3.462) is also poor. This could pose formulation challenges.

**11. hERG Inhibition:** Both ligands have low hERG inhibition risk (A: 0.664, B: 0.518).

**12. Microsomal Clearance:** Ligand A (117.577) has higher clearance than Ligand B (28.571), indicating lower metabolic stability. B is significantly better.

**13. In vitro Half-Life:** Ligand A (14.163) has a longer half-life than Ligand B (2.066). This is a positive for A.

**14. P-gp Efflux:** Both ligands have low P-gp efflux (A: 0.309, B: 0.203), which is good for CNS exposure. B is slightly better.

**15. Binding Affinity:** Ligand B (-8.6 kcal/mol) has a significantly stronger binding affinity than Ligand A (-7.1 kcal/mol). This is a crucial advantage, as a >1.5 kcal/mol difference can outweigh other drawbacks.

**Overall Assessment:**

Ligand B is the superior candidate. While both have poor Caco-2 and solubility, Ligand B excels in crucial areas: significantly lower DILI risk, better metabolic stability (lower Cl_mic, though half-life is shorter), and *much* stronger binding affinity. The better logP and TPSA values also contribute to its favorability. The affinity difference is large enough to compensate for the shorter half-life.

Output:
1
2025-04-17 05:14:17,617 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 drug candidates, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (380.432 and 364.45 Da) fall within the ideal 200-500 Da range.

**TPSA:** Both ligands have TPSA values (78.43 and 76.8) below the 90 A^2 threshold for CNS targets, which is excellent.

**logP:** Ligand A (1.454) is within the optimal 1-3 range. Ligand B (2.793) is also within the optimal range, but closer to the upper limit.

**H-Bond Donors/Acceptors:** Ligand A has 3 HBD and 4 HBA, both acceptable. Ligand B has 0 HBD and 7 HBA, also acceptable.

**QED:** Both ligands have good QED scores (0.625 and 0.834), indicating good drug-like properties.

**DILI:** Ligand A (18.728) has a significantly lower DILI risk than Ligand B (73.09), which is a major advantage.

**BBB:** Ligand B (87.941) has a much higher BBB penetration percentile than Ligand A (69.252). This is a critical factor for a CNS target like DRD2.

**Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual. However, the absolute values (-5.474 and -5.062) are similar and don't strongly differentiate the two.

**Aqueous Solubility:** Both have negative solubility values, which is also unusual. Again, the absolute values (-2.457 and -3.093) are similar.

**hERG:** Both ligands have very low hERG inhibition liability (0.289 and 0.067), which is excellent.

**Microsomal Clearance:** Ligand A (3.857) has a much lower microsomal clearance than Ligand B (34.739), indicating better metabolic stability.

**In vitro Half-Life:** Ligand A (-8.323) has a more negative (longer) in vitro half-life than Ligand B (-0.476).

**P-gp Efflux:** Ligand A (0.072) has lower P-gp efflux liability than Ligand B (0.241), which is favorable for CNS penetration.

**Binding Affinity:** Both ligands have very similar and excellent binding affinities (-7.8 and -8.1 kcal/mol). The difference of 0.3 kcal/mol is unlikely to be decisive.

**Overall Assessment:**

Ligand B has a superior BBB score, which is highly desirable for a CNS target. However, it suffers from significantly higher DILI risk, higher P-gp efflux, and much higher microsomal clearance. Ligand A has a much better safety profile (lower DILI), better metabolic stability, lower P-gp efflux, and a longer half-life. While Ligand B has a slightly better binding affinity and BBB score, the overall profile of Ligand A is more favorable for drug development due to the critical importance of safety and pharmacokinetic properties.

Output:
0
2025-04-17 05:14:17,617 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (362.539 and 363.443 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (58.2) is excellent, well below the 90 A^2 threshold for CNS targets. Ligand B (105.98) is higher, but still potentially acceptable, though less ideal.

**3. logP:** Ligand A (4.064) is at the upper end of the optimal range (1-3), potentially leading to solubility issues. Ligand B (1.241) is a bit low, potentially hindering permeation.

**4. H-Bond Donors:** Both ligands have 2 HBD, which is within the acceptable limit of <=5.

**5. H-Bond Acceptors:** Ligand A has 3 HBA, and Ligand B has 6 HBA, both are within the acceptable limit of <=10.

**6. QED:** Both ligands have good QED scores (0.651 and 0.734), indicating good drug-like properties.

**7. DILI:** Ligand A (44.552) has a lower DILI risk than Ligand B (76.076), making it more favorable.

**8. BBB:** Ligand A (68.864) has a significantly better BBB penetration percentile than Ligand B (48.158). This is *crucial* for a CNS target like DRD2.

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.039 and -5.284). This is unusual and suggests poor permeability. However, these values are on a scale where negative values are possible, and direct comparison is difficult without knowing the scale's specifics.

**10. Aqueous Solubility:** Both ligands have negative solubility values (-4.06 and -2.965). Similar to Caco-2, these are on a scale where negative values are possible, and direct comparison is difficult without knowing the scale's specifics.

**11. hERG Inhibition:** Both ligands have low hERG inhibition liability (0.663 and 0.097), which is good.

**12. Microsomal Clearance:** Ligand A (79.655) has higher microsomal clearance than Ligand B (-3.506), suggesting lower metabolic stability.

**13. In vitro Half-Life:** Ligand A (37.092) has a longer half-life than Ligand B (18.154).

**14. P-gp Efflux:** Ligand A (0.702) has slightly higher P-gp efflux liability than Ligand B (0.022). Lower P-gp efflux is desirable for CNS penetration, favoring Ligand B.

**15. Binding Affinity:** Both ligands have excellent binding affinities (-8.8 and -8.7 kcal/mol), very close to each other. The difference is negligible.

**Overall Assessment:**

Ligand A is superior due to its much better BBB penetration (68.864 vs 48.158) and lower DILI risk (44.552 vs 76.076). While Ligand A has higher microsomal clearance and P-gp efflux, the critical factor for a CNS target is BBB penetration, which Ligand A significantly outperforms. The slight advantage in half-life also contributes to its favorability. The negative Caco-2 and solubility values are concerning for both, but the difference in BBB is a deciding factor.

Output:
1
2025-04-17 05:14:17,617 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (336.41 Da) is slightly lower, which could be beneficial for permeability.

**TPSA:** Ligand A (34.03) is excellent for CNS penetration, well below the 90 A^2 threshold. Ligand B (83.22) is higher, but still potentially acceptable, though less ideal.

**logP:** Both ligands have good logP values (A: 4.036, B: 2.562), falling within the 1-3 range. Ligand B is closer to the optimal range.

**H-Bond Donors/Acceptors:** Ligand A (HBD=1, HBA=2) is better than Ligand B (HBD=3, HBA=4) in terms of balancing solubility and permeability.

**QED:** Both ligands have similar and acceptable QED values (A: 0.724, B: 0.73).

**DILI:** Ligand A (53.432) has a slightly higher DILI risk than Ligand B (46.297), but both are below the concerning 60 threshold.

**BBB:** Ligand A (69.794) has a better BBB percentile than Ligand B (54.556). While >70 is desirable, 69.794 is still reasonably good for a CNS target.

**Caco-2 Permeability:** Ligand A (-4.932) has a more negative Caco-2 value, indicating *lower* permeability than Ligand B (-5.104). This is a negative for Ligand A.

**Aqueous Solubility:** Ligand A (-4.477) has lower solubility than Ligand B (-2.407). Solubility is important, but can be addressed with formulation.

**hERG:** Both ligands have low hERG inhibition risk (A: 0.876, B: 0.617).

**Microsomal Clearance:** Ligand B (22.973) has significantly lower microsomal clearance than Ligand A (74.847), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand B (13.555 hours) has a longer half-life than Ligand A (25.012 hours). This is a positive for Ligand B.

**P-gp Efflux:** Ligand A (0.574) has lower P-gp efflux liability than Ligand B (0.061), which is desirable for CNS exposure.

**Binding Affinity:** Ligand B (-7.7 kcal/mol) has a significantly stronger binding affinity than Ligand A (-9.7 kcal/mol). This is a substantial advantage, potentially outweighing some of the ADME drawbacks.

**Overall Assessment:**

Ligand B is the more promising candidate. While Ligand A has better BBB and P-gp properties, Ligand B's significantly stronger binding affinity (-7.7 vs -9.7 kcal/mol) and improved metabolic stability (lower Cl_mic and longer half-life) are crucial for a GPCR drug candidate. The slightly higher TPSA of Ligand B is not a major concern, and the differences in solubility and Caco-2 permeability could be addressed during optimization. The affinity difference is large enough to prioritize Ligand B.

Output:
1
2025-04-17 05:14:17,617 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (346.43 & 348.44 Da) fall comfortably within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (91.57) is slightly above the preferred <90 for CNS targets, while Ligand B (87.66) is closer to the ideal. This gives a slight edge to Ligand B.

**3. logP:** Both ligands (1.48 & 1.57) are within the optimal 1-3 range, suggesting good permeability and reasonable solubility.

**4. H-Bond Donors:** Both have 3 HBD, which is acceptable.

**5. H-Bond Acceptors:** Both have 4 HBA, which is acceptable.

**6. QED:** Ligand A (0.652) has a slightly better QED score than Ligand B (0.56), indicating a more drug-like profile.

**7. DILI:** Ligand A (27.34) has a significantly lower DILI risk than Ligand B (34.16), which is a substantial advantage.

**8. BBB:** Ligand A (40.56) has a slightly better BBB percentile than Ligand B (36.80), although both are below the desirable >70 for CNS targets. This is a critical factor for DRD2.

**9. Caco-2:** Both have negative Caco-2 values (-4.75 and -4.95), which is unusual and suggests poor permeability. This is a significant drawback for both.

**10. Solubility:** Both have negative solubility values (-2.12 and -2.34), indicating very poor aqueous solubility. This is a major concern for both compounds.

**11. hERG:** Ligand A (0.13) has a much lower hERG inhibition liability than Ligand B (0.43), indicating a lower risk of cardiotoxicity.

**12. Cl_mic:** Ligand B (51.48) has a higher microsomal clearance than Ligand A (15.74), meaning Ligand A is more metabolically stable.

**13. t1/2:** Ligand A (-9.65) has a more negative in vitro half-life than Ligand B (-16.65), suggesting a longer half-life.

**14. Pgp:** Ligand A (0.044) has a much lower P-gp efflux liability than Ligand B (0.243), which is beneficial for CNS penetration.

**15. Binding Affinity:** Both ligands have very similar and strong binding affinities (-8.7 and -8.3 kcal/mol). The difference is less than the 1.5 kcal/mol threshold.

**Overall Assessment:**

While both compounds have strong binding affinities, Ligand A is the more promising candidate. It exhibits a lower DILI risk, lower hERG liability, better metabolic stability (lower Cl_mic, longer t1/2), lower P-gp efflux, and a slightly better BBB penetration. The slightly higher TPSA of Ligand A is less concerning than the poorer ADME properties of Ligand B. The poor Caco-2 and solubility for both are concerning and would require significant optimization. However, considering the GPCR-specific priorities, Ligand A is the better starting point.

Output:
0
2025-04-17 05:14:17,617 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (348.451 and 353.419 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (93.01) is slightly above the optimal <90 for CNS targets, but still reasonable. Ligand B (79.39) is excellent, well below 90.

**logP:** Ligand A (1.334) is within the optimal 1-3 range. Ligand B (0.315) is a bit low, potentially hindering membrane permeability.

**H-Bond Donors/Acceptors:** Ligand A has 1 HBD and 6 HBA, both acceptable. Ligand B has 0 HBD and 5 HBA, also acceptable.

**QED:** Both ligands have similar QED values (0.716 and 0.727), indicating good drug-likeness.

**DILI:** Ligand A (64.288) has a higher DILI risk than Ligand B (38.736), which is preferable.

**BBB:** Ligand A (56.999) has a lower BBB penetration percentile than Ligand B (62.97). While neither are *high* (>70), Ligand B is better.

**Caco-2 Permeability:** Ligand A (-5.21) has very poor Caco-2 permeability, a significant drawback. Ligand B (-4.553) is also poor, but slightly better.

**Aqueous Solubility:** Both ligands have poor aqueous solubility (-2.041 and -0.8, respectively). This could pose formulation challenges.

**hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.075 and 0.15), which is excellent.

**Microsomal Clearance:** Ligand A (40.744) has higher microsomal clearance than Ligand B (1.181), suggesting lower metabolic stability.

**In vitro Half-Life:** Both ligands have negative in vitro half-lives (-6.54 and -6.009), which is unusual and suggests rapid degradation. Ligand B is slightly better.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.091 and 0.037), which is highly desirable for CNS penetration.

**Binding Affinity:** Ligand A (-7.9 kcal/mol) has a significantly stronger binding affinity than Ligand B (-0.0 kcal/mol). This is a substantial advantage.

**Overall Assessment:**

Despite Ligand A's higher DILI risk and poor Caco-2 permeability, its *much* stronger binding affinity (-7.9 vs -0.0 kcal/mol) is a decisive factor. A 7.9 kcal/mol advantage is substantial and can often outweigh minor ADME drawbacks, especially for a GPCR target where potency is crucial. Ligand B's slightly better BBB and lower DILI are positives, but the lack of significant binding affinity makes it unlikely to be a viable candidate. The poor solubility and half-lives are concerns for both, but can be addressed with formulation strategies.

Output:
1
2025-04-17 05:14:17,617 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 drug candidates, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (367.471 and 340.446 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (78.95) is better than Ligand B (49.84). For CNS targets, we want TPSA <= 90, both are within this range, but A is closer to the upper limit.

**3. logP:** Ligand A (1.046) is optimal (1-3), while Ligand B (4.432) is high. High logP can lead to solubility issues and off-target interactions.

**4. H-Bond Donors:** Ligand A (1) and Ligand B (2) are both acceptable (<=5).

**5. H-Bond Acceptors:** Ligand A (5) and Ligand B (4) are both acceptable (<=10).

**6. QED:** Both ligands have similar QED values (0.787 and 0.783), indicating good drug-likeness.

**7. DILI:** Ligand A (71.694) has a higher DILI risk than Ligand B (40.093). This is a concern for Ligand A.

**8. BBB:** Ligand B (80.07) has a significantly better BBB penetration percentile than Ligand A (68.786). This is *critical* for a CNS target like DRD2.

**9. Caco-2:** Both have negative values, which is unusual. Assuming these are percentile scores, Ligand B (-4.921) is slightly better than Ligand A (-3.391).

**10. Solubility:** Both have negative values, indicating poor solubility. Ligand A (-3.391) is slightly better than Ligand B (-4.812).

**11. hERG:** Ligand A (0.692) has a lower hERG risk than Ligand B (0.904), which is preferable.

**12. Cl_mic:** Ligand B (55.466) has lower microsomal clearance than Ligand A (68.63), suggesting better metabolic stability.

**13. t1/2:** Ligand B (60.161) has a longer in vitro half-life than Ligand A (21.766), which is desirable.

**14. Pgp:** Ligand A (0.21) has significantly lower P-gp efflux liability than Ligand B (0.593). Lower Pgp is better for CNS exposure.

**15. Binding Affinity:** Ligand B (-9.8 kcal/mol) has a significantly stronger binding affinity than Ligand A (-8.3 kcal/mol). A 1.5 kcal/mol difference is substantial and can outweigh some ADME drawbacks.

**Overall Assessment:**

While Ligand A has a slightly better hERG profile and Pgp efflux, Ligand B is superior overall. The critical factors driving this decision are:

*   **BBB:** Ligand B's much higher BBB penetration is crucial for a CNS target.
*   **Affinity:** The significantly stronger binding affinity of Ligand B (-9.8 vs -8.3 kcal/mol) is a major advantage.
*   **Metabolic Stability/Half-life:** Ligand B exhibits better metabolic stability and a longer half-life.
*   **DILI:** Ligand B has a lower DILI risk.
*   **logP:** Ligand A's logP is optimal, while Ligand B's is high, but the affinity difference is large enough to compensate.

Output:
1
2025-04-17 05:14:17,617 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (353.34 and 345.403 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (57.61) is excellent, well below the 90 A^2 threshold for CNS targets. Ligand B (103.25) is higher, but still potentially acceptable, though less optimal.

**logP:** Ligand A (2.919) is within the optimal 1-3 range. Ligand B (0.556) is quite low, potentially hindering membrane permeability and CNS penetration.

**H-Bond Donors/Acceptors:** Ligand A (1 HBD, 2 HBA) is very favorable. Ligand B (3 HBD, 5 HBA) is also acceptable, but slightly less ideal.

**QED:** Both ligands have decent QED scores (0.85 and 0.682), indicating good drug-like properties.

**DILI:** Ligand A (53.276) has a moderate DILI risk, while Ligand B (40.287) has a lower, more favorable DILI risk.

**BBB:** Ligand A (78.79) has a good BBB percentile, exceeding the 70% threshold for CNS targets. Ligand B (17.371) is very poor for CNS penetration.

**Caco-2 Permeability:** Ligand A (-4.701) has poor Caco-2 permeability, which is concerning. Ligand B (-5.517) is also poor.

**Aqueous Solubility:** Both ligands have very poor aqueous solubility (-3.287 and -1.997, respectively). This could present formulation challenges.

**hERG Inhibition:** Both ligands show very low hERG inhibition risk (0.144 and 0.223).

**Microsomal Clearance:** Ligand A (-6.919) shows excellent metabolic stability (negative value indicates low clearance). Ligand B (-10.084) is even better.

**In vitro Half-Life:** Ligand A (0.445) has a very short half-life. Ligand B (-12.706) has an extremely long half-life, which is very favorable.

**P-gp Efflux:** Both ligands show very low P-gp efflux liability (0.073 and 0.007).

**Binding Affinity:** Ligand A (-9.0) has a significantly stronger binding affinity than Ligand B (-8.6). The difference is 0.4 kcal/mol, which is substantial.

**Overall Assessment:**

Ligand A excels in TPSA, logP, BBB, metabolic stability, P-gp efflux, and *especially* binding affinity. However, it has poor Caco-2 permeability and a short half-life. Ligand B has better DILI and half-life, but suffers from a very low logP and poor BBB penetration, making it unlikely to reach the CNS target effectively. The strong affinity of Ligand A, combined with its acceptable BBB, outweighs its permeability and half-life concerns, especially for a CNS target where getting across the BBB is paramount. Optimization could focus on improving permeability and half-life.

Output:
1
2025-04-17 05:14:17,618 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (349.431 and 344.455 Da) fall comfortably within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (71.11) and Ligand B (69.64) are both below the 90 A^2 threshold desirable for CNS targets, which is excellent.

**3. logP:** Both ligands have logP values (2.193 and 2.127) within the optimal 1-3 range.

**4. H-Bond Donors:** Ligand A has 1 HBD, and Ligand B has 2. Both are within the acceptable limit of <=5.

**5. H-Bond Acceptors:** Ligand A has 4 HBA, and Ligand B has 3. Both are within the acceptable limit of <=10.

**6. QED:** Ligand B (0.822) has a significantly better QED score than Ligand A (0.519), suggesting a more drug-like profile.

**7. DILI:** Both ligands have acceptable DILI risk, with Ligand A at 42.575 and Ligand B at 37.767 (both < 40 is good). Ligand B is slightly better.

**8. BBB:** Ligand A (68.36) has a better BBB percentile than Ligand B (45.56). This is a *critical* factor for a CNS target like DRD2.

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.651 and -4.603), which is unusual and suggests poor permeability. This is a concern for both.

**10. Aqueous Solubility:** Both ligands have negative solubility values (-1.791 and -2.468), indicating very poor aqueous solubility. This is a significant drawback.

**11. hERG Inhibition:** Both ligands have low hERG inhibition risk (0.39 and 0.559).

**12. Microsomal Clearance:** Ligand B (31.461) has lower microsomal clearance than Ligand A (43.732), indicating better metabolic stability.

**13. In vitro Half-Life:** Ligand B (5.119 hours) has a slightly better in vitro half-life than Ligand A (-22.555 hours - note the negative value is concerning).

**14. P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.026 and 0.171).

**15. Binding Affinity:** Ligand B (-8.8 kcal/mol) has a significantly stronger binding affinity than Ligand A (-7.4 kcal/mol). This >1.5 kcal/mol difference is substantial and can outweigh some ADME drawbacks.

**Overall Assessment:**

While both ligands have issues with solubility and Caco-2 permeability, Ligand B is superior due to its significantly better binding affinity, QED, metabolic stability, and half-life. The improved binding affinity is a major advantage for a GPCR target. Ligand A has a better BBB score, which is important, but the affinity difference is more critical. The poor solubility and permeability would need to be addressed in further optimization, but the stronger binding makes Ligand B a more promising starting point.

Output:
1
2025-04-17 05:14:17,618 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (376.475 and 361.877 Da) are within the ideal range of 200-500 Da.

**TPSA:** Ligand A (121.8) is slightly above the optimal <90 for CNS targets, but still reasonable. Ligand B (64.86) is excellent, well below 90.

**logP:** Ligand A (-0.495) is a bit low, potentially hindering membrane permeability. Ligand B (3.805) is very good, falling within the optimal 1-3 range.

**H-Bond Donors:** Ligand A (3) is acceptable. Ligand B (1) is also good.

**H-Bond Acceptors:** Both ligands (6) are within the acceptable limit of <=10.

**QED:** Both ligands have good QED scores (0.491 and 0.897), indicating drug-like properties. Ligand B is significantly better.

**DILI:** Ligand A (39.201) has a lower DILI risk than Ligand B (62.35), which is approaching a moderate risk.

**BBB:** Ligand B (83.986) has a much higher BBB penetration score than Ligand A (47.926). This is a *critical* advantage for a CNS target like DRD2.

**Caco-2 Permeability:** Both are negative, indicating poor permeability. This is concerning, but can be mitigated if other properties are favorable.

**Aqueous Solubility:** Both are negative, indicating poor solubility. This is a concern for formulation.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.085 and 0.261).

**Microsomal Clearance:** Ligand A (19.919) has lower microsomal clearance, suggesting better metabolic stability than Ligand B (45.11).

**In vitro Half-Life:** Ligand A (13.514) has a longer half-life than Ligand B (7.162).

**P-gp Efflux:** Ligand A (0.034) has significantly lower P-gp efflux liability than Ligand B (0.459), which is a major advantage for CNS penetration.

**Binding Affinity:** Ligand B (-7.6) has a slightly better binding affinity than Ligand A (-7.2). While the difference is not huge (0.4 kcal/mol), it's still a positive.

**Overall Assessment:**

Ligand B excels in key properties for a CNS-targeting GPCR ligand: excellent TPSA, optimal logP, high BBB penetration, and slightly better binding affinity. While its DILI risk is higher and P-gp efflux is worse than Ligand A, the superior BBB penetration and logP are likely to outweigh these drawbacks. Ligand A has better metabolic stability and lower P-gp efflux, but its poor logP and lower BBB penetration are significant liabilities. The Caco-2 and solubility issues are shared by both, and would need to be addressed in further optimization.

Output:
1
2025-04-17 05:14:17,618 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (355.316 and 348.422 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (77.25) is slightly higher than Ligand B (75.19), but both are below the 90 A^2 threshold desirable for CNS targets.

**3. logP:** Both ligands have good logP values (2.885 and 1.976), falling within the optimal 1-3 range. Ligand B is slightly lower, which *could* indicate better solubility but potentially reduced membrane permeability.

**4. H-Bond Donors:** Both ligands have 1 HBD, which is within the acceptable limit of <=5.

**5. H-Bond Acceptors:** Ligand A has 5 HBA, and Ligand B has 4. Both are within the acceptable limit of <=10.

**6. QED:** Ligand A (0.913) has a significantly higher QED score than Ligand B (0.798), indicating a more drug-like profile.

**7. DILI:** Ligand A (74.796) has a higher DILI risk than Ligand B (39.511). This is a significant drawback for Ligand A.

**8. BBB:** Ligand A (93.253) has a much better BBB penetration percentile than Ligand B (81.776). This is a critical advantage for a CNS target like DRD2.

**9. Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and suggests poor permeability. However, the scale isn't specified, so it's hard to interpret. Ligand A (-4.291) is slightly worse than Ligand B (-4.748).

**10. Aqueous Solubility:** Both ligands have negative solubility values, which is also unusual. Ligand B (-2.511) is slightly better than Ligand A (-4.413).

**11. hERG Inhibition:** Both ligands have low hERG inhibition risk (0.346 and 0.47), which is good.

**12. Microsomal Clearance:** Ligand B (54.618) has a significantly higher microsomal clearance than Ligand A (19.919), implying lower metabolic stability.

**13. In vitro Half-Life:** Ligand A (-8.789) has a longer in vitro half-life than Ligand B (-5.731).

**14. P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.116 and 0.091), which is favorable for CNS penetration.

**15. Binding Affinity:** Both ligands have excellent binding affinities (-9.2 and -8.0 kcal/mol). Ligand A is slightly more potent.

**Overall Assessment:**

Ligand A excels in BBB penetration, binding affinity, and metabolic stability (lower Cl_mic, longer t1/2). However, it has a significantly higher DILI risk. Ligand B has a lower DILI risk and slightly better solubility, but suffers from lower BBB penetration and poorer metabolic stability.

Given the CNS target (DRD2), BBB penetration is paramount. The 1.2 kcal/mol difference in binding affinity is less critical than the substantial difference in BBB. While the DILI risk for Ligand A is concerning, it might be mitigated through structural modifications during lead optimization. The poor solubility and permeability scores are concerning for both, but could be addressed through formulation strategies.

Output:
1
2025-04-17 05:14:17,618 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (352.291 and 368.949 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (63.84) is higher than the preferred <90 for CNS targets, but still reasonable. Ligand B (33.73) is excellent, well below 90.

**3. logP:** Both ligands have logP values (4.21 and 4.492) slightly above the optimal 1-3 range, potentially raising concerns about solubility and off-target effects. However, for a GPCR, some lipophilicity is often tolerated and can aid membrane permeability.

**4. H-Bond Donors:** Both have 1 HBD, which is within the acceptable limit of <=5.

**5. H-Bond Acceptors:** Ligand A has 5 HBAs, and Ligand B has 4, both within the acceptable limit of <=10.

**6. QED:** Both ligands have QED values (0.713 and 0.617) above 0.5, indicating good drug-like properties.

**7. DILI:** Ligand A has a high DILI risk (92.439%), which is a significant concern. Ligand B has a very low DILI risk (9.112%), a major advantage.

**8. BBB:** Ligand A (71.035%) has a good BBB penetration percentile. Ligand B (80.031%) is even better, exceeding the desirable >70% threshold for CNS targets.

**9. Caco-2:** Both ligands have negative Caco-2 values (-4.702 and -4.777), which is unusual and suggests poor permeability. This is a red flag for both.

**10. Solubility:** Both ligands have very poor aqueous solubility (-5.358 and -2.727). This is a significant drawback.

**11. hERG:** Ligand A (0.589) has a slightly elevated hERG risk, while Ligand B (0.945) has a higher risk. Both are concerning, but Ligand A is better.

**12. Cl_mic:** Ligand A (77.421) has a higher microsomal clearance, indicating faster metabolism. Ligand B (51.263) has a lower clearance, suggesting better metabolic stability.

**13. t1/2:** Ligand A has a negative in vitro half-life (-19.525), which is impossible and likely an error in the data. Ligand B has a reasonable half-life of 41.16 hours.

**14. Pgp:** Ligand A (0.249) has lower P-gp efflux, which is favorable for CNS penetration. Ligand B (0.433) has higher P-gp efflux.

**15. Binding Affinity:** Ligand A (-10.7 kcal/mol) has a significantly stronger binding affinity than Ligand B (-8.0 kcal/mol). This is a substantial advantage.

**Overall Assessment:**

Despite the strong binding affinity of Ligand A, its extremely high DILI risk and impossible half-life are dealbreakers. The poor solubility and Caco-2 values for both are concerning, but the DILI and half-life issues with Ligand A are far more serious. Ligand B, while having a weaker affinity, possesses a much better safety profile (low DILI), better BBB penetration, better metabolic stability, and a reasonable half-life. The lower Pgp efflux is less ideal, but the other advantages outweigh this.

Output:
1
2025-04-17 05:14:17,618 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (349.431 Da) is slightly lower, which could be beneficial for permeability. Ligand B (368.503 Da) is also good.

**TPSA:** Ligand A (98.7) is slightly above the optimal <90 for CNS targets, but still reasonable. Ligand B (65.98) is excellent, well below 90, suggesting better CNS penetration potential.

**logP:** Both ligands have good logP values (A: 2.829, B: 1.02), falling within the 1-3 range. Ligand A is slightly better.

**H-Bond Donors/Acceptors:** Ligand A (HBD=1, HBA=6) and Ligand B (HBD=0, HBA=6) both have acceptable numbers of H-bond donors and acceptors.

**QED:** Both ligands have good QED scores (A: 0.51, B: 0.791), indicating drug-like properties. Ligand B is better here.

**DILI:** Both ligands have acceptable DILI risk (A: 45.56, B: 54.75), below the 60 threshold.

**BBB:** Ligand A (76.231) has a good BBB percentile, exceeding the 70% target. Ligand B (68.748) is lower, which is a concern for a CNS target.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.941 and -4.574), which is unusual and suggests poor permeability. This is a significant drawback for both.

**Aqueous Solubility:** Both ligands have negative solubility values (-4.166 and -2.3), indicating very poor aqueous solubility. This is a major issue for both.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (A: 0.917, B: 0.715).

**Microsomal Clearance:** Ligand A (43.467) has a higher microsomal clearance than Ligand B (25.556), suggesting lower metabolic stability. Ligand B is preferable here.

**In vitro Half-Life:** Ligand B (-13.034) has a significantly longer in vitro half-life than Ligand A (-4.441), which is a major advantage.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (A: 0.362, B: 0.052). Ligand B is better.

**Binding Affinity:** Both ligands have excellent binding affinities (A: -7.2 kcal/mol, B: -7.3 kcal/mol). Ligand B is slightly better.

**Overall Assessment:**

While both compounds have issues with solubility and Caco-2 permeability, Ligand B emerges as the more promising candidate. Its superior BBB penetration (though still not ideal), lower microsomal clearance, longer half-life, and slightly better binding affinity outweigh the slightly higher DILI risk and lower logP. The poor solubility and permeability are significant hurdles for both, but can potentially be addressed with formulation strategies. The CNS target prioritization heavily favors the better BBB score of Ligand B.

Output:
1
2025-04-17 05:14:17,619 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (346.471 Da) is slightly lower, which could be beneficial for permeability. Ligand B (381.567 Da) is also good.

**TPSA:** Ligand A (53.76) is excellent, well below the 90 A^2 threshold for CNS targets. Ligand B (66.32) is still acceptable, but less optimal.

**logP:** Ligand A (3.099) is within the optimal range (1-3). Ligand B (4.259) is slightly higher, potentially raising concerns about solubility and off-target effects, but not critically so.

**H-Bond Donors/Acceptors:** Ligand A (0 HBD, 3 HBA) is favorable. Ligand B (1 HBD, 6 HBA) is also acceptable, but the higher HBA count could slightly impact permeability.

**QED:** Both ligands have reasonable QED values (A: 0.842, B: 0.705), indicating good drug-like properties.

**DILI:** Ligand A (17.914) has a significantly lower DILI risk than Ligand B (36.099), which is a major advantage.

**BBB:** Ligand A (70.686) has a good BBB penetration percentile, exceeding the desirable threshold for CNS targets. Ligand B (52.617) is lower, suggesting reduced CNS exposure. This is a critical difference given the target (DRD2).

**Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and suggests a potential issue with the data or a very poor permeability. However, we'll proceed with the other parameters for now.

**Aqueous Solubility:** Both have negative solubility values, which is also unusual.

**hERG Inhibition:** Ligand A (0.55) has a lower hERG risk than Ligand B (0.8).

**Microsomal Clearance:** Ligand A (68.134) and Ligand B (64.579) have similar microsomal clearance values.

**In vitro Half-Life:** Ligand B (61.404) has a significantly longer half-life than Ligand A (23.39), which is a positive attribute.

**P-gp Efflux:** Ligand A (0.254) has a much lower P-gp efflux liability than Ligand B (0.626), which is crucial for CNS penetration.

**Binding Affinity:** Ligand B (-6.2 kcal/mol) has a substantially stronger binding affinity than Ligand A (0.0 kcal/mol). This is a very significant advantage.

**Overall Assessment:**

While Ligand B boasts a significantly better binding affinity and a longer half-life, Ligand A has superior properties regarding safety (DILI), CNS penetration (BBB, P-gp), and TPSA. The combination of good BBB penetration, low P-gp efflux, and acceptable TPSA for Ligand A is highly favorable for a CNS-targeting GPCR like DRD2. The much lower DILI risk is also a significant benefit. The significantly weaker binding affinity of Ligand A is a concern, but the other factors outweigh this. The negative Caco-2 and solubility values are concerning for both, but the other properties suggest Ligand A is the better starting point for optimization.

Output:
0
2025-04-17 05:14:17,619 - INFO - Batch 181 complete. Total preferences: 2896
2025-04-17 05:14:17,619 - INFO - Processing batch 182/512...
2025-04-17 05:15:00,129 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (378.219 and 364.515 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (92.41) is slightly above the optimal <90 for CNS targets, but still reasonable. Ligand B (74.33) is well within the desired range.

**logP:** Both ligands have good logP values (2.813 and 2.657), falling within the 1-3 optimal range.

**H-Bond Donors/Acceptors:** Both have 2 HBD and 6/5 HBA, respectively, which are acceptable.

**QED:** Both ligands have good QED scores (0.731 and 0.778), indicating good drug-like properties.

**DILI:** Ligand A has a significantly higher DILI risk (94.106 percentile) than Ligand B (57.076 percentile). This is a major concern for Ligand A.

**BBB:** Ligand B has a much better BBB penetration score (51.066 percentile) than Ligand A (33.036 percentile). This is crucial for a CNS target like DRD2.

**Caco-2 Permeability:** Both have negative Caco-2 values (-5.18 and -5.264) which is unusual and suggests poor permeability. However, these values are on a scale where negative values are possible and don't necessarily disqualify the compounds.

**Aqueous Solubility:** Both have negative solubility values (-4.492 and -2.694) which is also unusual and suggests poor solubility.

**hERG:** Both ligands have low hERG inhibition liability (0.291 and 0.372), which is good.

**Microsomal Clearance:** Ligand B has a higher microsomal clearance (36.329) than Ligand A (26.973), indicating potentially lower metabolic stability. However, both are reasonably stable.

**In vitro Half-Life:** Ligand B has a significantly longer in vitro half-life (46.509 hours) than Ligand A (12.893 hours). This is a significant advantage for Ligand B.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.106 and 0.043), which is favorable for CNS penetration.

**Binding Affinity:** Ligand A has a significantly better binding affinity (-10.1 kcal/mol) than Ligand B (-8.0 kcal/mol). This is a substantial advantage.

**Overall Assessment:**

While Ligand A boasts a superior binding affinity, its high DILI risk and poor BBB penetration are major drawbacks. Ligand B, despite a slightly weaker binding affinity, has a much better safety profile (lower DILI), significantly better BBB penetration, and a longer half-life. For a CNS target like DRD2, BBB penetration and safety are paramount. The 2.1 kcal/mol difference in binding affinity can potentially be overcome with further optimization of Ligand B.

Output:
1
2025-04-17 05:15:00,129 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (347.459 and 362.583 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (83.71) is better than Ligand B (23.55) as it is closer to the <90 A^2 threshold for CNS targets. Ligand B is very low, which *could* indicate poor interactions, but isn't necessarily a dealbreaker.

**3. logP:** Ligand A (1.451) is optimal (1-3). Ligand B (4.277) is slightly high, potentially leading to solubility issues and off-target interactions, but still within a tolerable range.

**4. H-Bond Donors:** Ligand A (1) and Ligand B (0) are both acceptable (<=5).

**5. H-Bond Acceptors:** Both ligands (A: 3, B: 3) are within the acceptable range (<=10).

**6. QED:** Both ligands have good QED scores (A: 0.506, B: 0.655), indicating drug-like properties. Ligand B is slightly better.

**7. DILI:** Ligand A (26.173) has a significantly lower DILI risk than Ligand B (10.896), which is a major advantage.

**8. BBB:** Ligand B (92.943) has a much higher BBB penetration score than Ligand A (61.923). This is *critical* for a CNS target like DRD2.

**9. Caco-2 Permeability:** Ligand A (-4.769) and Ligand B (-4.505) are both very poor.

**10. Aqueous Solubility:** Ligand A (-1.959) is better than Ligand B (-4.146).

**11. hERG Inhibition:** Ligand A (0.336) is better than Ligand B (0.862), indicating lower cardiotoxicity risk.

**12. Microsomal Clearance:** Ligand A (22.499) has lower clearance than Ligand B (110.998), suggesting better metabolic stability.

**13. In vitro Half-Life:** Ligand A (-14.111) is better than Ligand B (40.78).

**14. P-gp Efflux:** Ligand A (0.154) has lower P-gp efflux liability than Ligand B (0.201), which is favorable for CNS exposure.

**15. Binding Affinity:** Ligand A (-7.2 kcal/mol) has a slightly better binding affinity than Ligand B (-6.2 kcal/mol). This 1 kcal/mol difference is significant.

**Overall Assessment:**

Ligand B excels in BBB penetration, which is paramount for a DRD2 ligand. However, it suffers from higher DILI risk, higher logP, higher microsomal clearance, and higher P-gp efflux. Ligand A has a better safety profile (lower DILI, hERG), better metabolic stability, and slightly better affinity. The difference in binding affinity (1 kcal/mol) is substantial enough to outweigh the BBB advantage of Ligand B, especially considering the other favorable properties of Ligand A.

Output:
0
2025-04-17 05:15:00,130 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (332.407 and 349.435 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (50.16) is excellent, well below the 90 A^2 threshold for CNS targets. Ligand B (104.29) is higher, but still potentially acceptable, though less ideal.

**logP:** Ligand A (4.358) is slightly high, potentially leading to solubility issues or off-target interactions, but not drastically so. Ligand B (0.492) is quite low, which could hinder membrane permeability and CNS penetration.

**H-Bond Donors/Acceptors:** Ligand A (HBD=1, HBA=3) is favorable. Ligand B (HBD=2, HBA=5) is also acceptable, though slightly higher in HBA.

**QED:** Both ligands have reasonable QED values (0.755 and 0.675), indicating good drug-like properties.

**DILI:** Ligand A (75.184) has a higher DILI risk than Ligand B (35.169). This is a concern for Ligand A.

**BBB:** Ligand A (70.919) has a good BBB percentile, exceeding the desirable >70% threshold for CNS targets. Ligand B (53.974) is significantly lower, indicating poor predicted brain penetration. This is a major drawback for a DRD2 ligand.

**Caco-2 Permeability:** Ligand A (-4.743) has poor Caco-2 permeability. Ligand B (-5.457) is also poor, but slightly worse.

**Aqueous Solubility:** Ligand A (-4.796) has poor aqueous solubility. Ligand B (-0.839) has slightly better solubility, but still poor.

**hERG Inhibition:** Ligand A (0.882) has a low hERG risk. Ligand B (0.053) has a very low hERG risk, which is excellent.

**Microsomal Clearance:** Ligand A (74.192) has moderate microsomal clearance. Ligand B (13.906) has very low clearance, suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (-6.508) has a short half-life. Ligand B (17.779) has a longer half-life, which is desirable.

**P-gp Efflux:** Ligand A (0.482) has low P-gp efflux, which is good for CNS penetration. Ligand B (0.002) has very low P-gp efflux, even better.

**Binding Affinity:** Ligand A (-9.0) has significantly stronger binding affinity than Ligand B (-7.7). This is a substantial advantage.

**Overall Assessment:**

While Ligand A has a higher DILI risk and poor solubility/permeability, its *much* stronger binding affinity (-9.0 vs -7.7 kcal/mol) and good BBB penetration are compelling advantages, especially for a CNS target like DRD2. The affinity difference is large enough to potentially overcome the ADME liabilities, particularly if formulation strategies can address the solubility issues. Ligand B's biggest weakness is its poor BBB penetration, which is critical for a CNS drug. Its better ADME profile is less valuable if it can't reach the target.

Output:
1
2025-04-17 05:15:00,130 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (343.335 Da) is slightly lower, which could be beneficial for permeability.

**2. TPSA:** Ligand A (112.93) is excellent for CNS penetration, being well below the 90 A^2 threshold. Ligand B (59.08) is also very good.

**3. logP:** Both ligands have optimal logP values (Ligand A: 2.338, Ligand B: 1.632), falling within the 1-3 range.

**4. H-Bond Donors:** Ligand A has 3 HBD, which is acceptable. Ligand B has 0, which is also acceptable.

**5. H-Bond Acceptors:** Ligand A has 4 HBA, acceptable. Ligand B has 5, also acceptable.

**6. QED:** Both ligands have reasonable QED values (Ligand A: 0.711, Ligand B: 0.606), indicating good drug-like properties.

**7. DILI:** Ligand A has a DILI risk of 89.88, which is high and concerning. Ligand B has a much lower DILI risk of 15.51, which is excellent.

**8. BBB:** Ligand A has a BBB penetration of 29.275, which is low and a significant drawback for a CNS target. Ligand B has a BBB penetration of 76.696, which is very good and desirable.

**9. Caco-2 Permeability:** Ligand A has a negative Caco-2 value (-5.351), which is unusual and suggests poor permeability. Ligand B also has a negative value (-4.632) but is slightly better.

**10. Aqueous Solubility:** Both ligands have negative solubility values (Ligand A: -3.128, Ligand B: -2.125), which is problematic. However, given the logP values, this isn't entirely unexpected and might be manageable with formulation strategies.

**11. hERG Inhibition:** Ligand A has a very low hERG risk (0.056), which is excellent. Ligand B has a slightly higher, but still acceptable, hERG risk (0.561).

**12. Microsomal Clearance:** Ligand A has a negative clearance (-0.875), which is unusual. Ligand B has a higher clearance (50.762), which is less desirable, indicating faster metabolism.

**13. In vitro Half-Life:** Ligand A has a very short half-life (-15.95), which is a major drawback. Ligand B has a slightly better, but still short, half-life (-3.175).

**14. P-gp Efflux:** Ligand A has very low P-gp efflux (0.026), which is excellent for CNS penetration. Ligand B has slightly higher efflux (0.072), which is still good.

**15. Binding Affinity:** Ligand A has a better binding affinity (-9.2 kcal/mol) than Ligand B (-6.8 kcal/mol). This is a significant advantage.

**Overall Assessment:**

Despite Ligand A's superior binding affinity, its high DILI risk, poor BBB penetration, negative Caco-2 permeability, and very short half-life make it a less viable candidate. Ligand B, while having a slightly weaker affinity, presents a much more favorable ADME profile, particularly its good BBB penetration, low DILI risk, and acceptable P-gp efflux. For a CNS GPCR target like DRD2, BBB penetration and safety (DILI) are critical. The affinity difference, while notable, might be overcome with further optimization of Ligand B.

Output:
1
2025-04-17 05:15:00,130 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B based on the provided guidelines, prioritizing GPCR-specific properties (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (360.351 and 362.348 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (49.41) is significantly better than Ligand B (98.66). For CNS targets, TPSA should be <=90, and A is comfortably within this range, while B is above.

**logP:** Both ligands have acceptable logP values (2.821 and 1.561, respectively), falling within the 1-3 optimal range. Ligand A is slightly better.

**H-Bond Donors/Acceptors:** Ligand A (HBD=1, HBA=2) has fewer H-bonds than Ligand B (HBD=4, HBA=4). This generally favors permeability.

**QED:** Ligand A (0.821) has a significantly better QED score than Ligand B (0.475), indicating a more drug-like profile.

**DILI:** Both ligands have acceptable DILI risk (35.983 and 42.187, respectively), both below the 60 threshold.

**BBB:** Ligand A (79.333) has a much better BBB percentile than Ligand B (49.903). This is *critical* for a CNS target like DRD2; a value >70 is desirable, and A is closer to that.

**Caco-2 Permeability:** Ligand A (-4.408) has better Caco-2 permeability than Ligand B (-5.173).

**Aqueous Solubility:** Both ligands have poor solubility (-3.032 and -2.789 respectively). This is a concern, but can sometimes be overcome with formulation strategies.

**hERG Inhibition:** Both ligands have similar, low hERG inhibition risk (0.714 and 0.747).

**Microsomal Clearance:** Both ligands have similar microsomal clearance (8.716 and 8.48).

**In vitro Half-Life:** Ligand A (5.223) has a shorter half-life than Ligand B (18.941). This is a drawback for A, but potentially manageable.

**P-gp Efflux:** Both ligands have similar P-gp efflux liability (0.027 and 0.165).

**Binding Affinity:** Ligand B (-7.9 kcal/mol) has a significantly better binding affinity than Ligand A (-9.4 kcal/mol). This is a substantial advantage. However, the difference is not large enough to overcome the other significant deficiencies of Ligand B.

**Overall Assessment:**

While Ligand B has a better binding affinity, Ligand A is superior overall, particularly regarding properties crucial for CNS penetration (BBB, TPSA). The significantly better BBB and TPSA of Ligand A, combined with its superior QED and comparable safety profiles, outweigh the affinity difference. The longer half-life of Ligand B is a plus, but not enough to overcome its poor CNS penetration properties.

Output:
0
2025-04-17 05:15:00,130 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight (MW):** Both ligands (362.47 and 357.479 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (58.2) is slightly higher than Ligand B (54.79). Both are below the 90 A^2 threshold desirable for CNS targets, which is good.

**3. logP:** Ligand A (4.145) is slightly higher than Ligand B (3.746). Ligand A is approaching the upper limit of the optimal range (1-3), while Ligand B is comfortably within it.

**4. H-Bond Donors (HBD):** Ligand A (2) and Ligand B (0) are both within the acceptable limit of <=5.

**5. H-Bond Acceptors (HBA):** Ligand A (3) and Ligand B (5) are both within the acceptable limit of <=10.

**6. QED:** Both ligands have similar QED values (0.811 and 0.791), indicating good drug-like properties.

**7. DILI:** Ligand A (65.529) has a higher DILI risk than Ligand B (54.323). Both are acceptable, but B is preferable.

**8. BBB:** Ligand A (69.252) has a slightly better BBB penetration percentile than Ligand B (61.419). Both are reasonably good, but ideally >70 for CNS targets.

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.702 and -4.598). This is unusual and suggests poor permeability.

**10. Aqueous Solubility:** Both ligands have negative solubility values (-4.431 and -3.547), indicating very poor aqueous solubility. This is a significant concern.

**11. hERG Inhibition:** Ligand A (0.756) has a higher hERG inhibition liability than Ligand B (0.264). Ligand B is significantly better in this regard.

**12. Microsomal Clearance:** Ligand A (75.866) has higher microsomal clearance than Ligand B (53.792), suggesting lower metabolic stability.

**13. In vitro Half-Life:** Ligand A (56.79) has a longer half-life than Ligand B (27.131).

**14. P-gp Efflux:** Ligand A (0.457) has lower P-gp efflux than Ligand B (0.358), which is favorable for CNS penetration.

**15. Binding Affinity:** Ligand B (-7.9 kcal/mol) has a significantly stronger binding affinity than Ligand A (-9.0 kcal/mol). This is a substantial advantage.

**Overall Assessment:**

While Ligand A has a slightly better BBB and P-gp efflux, Ligand B is superior overall. The most critical factor is the significantly stronger binding affinity of Ligand B. It also has lower DILI risk and hERG inhibition liability, and better metabolic stability (lower Cl_mic). The poor Caco-2 and solubility for both are concerning, but the strong binding affinity of B may compensate for these issues.

Output:
1
2025-04-17 05:15:00,130 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B based on the provided guidelines, prioritizing GPCR properties (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (366.849 and 368.865 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (87.32) is slightly above the preferred <90 for CNS targets, while Ligand B (76.72) is well within the range. This favors Ligand B.

**logP:** Both ligands have good logP values (2.486 and 1.457), falling within the optimal 1-3 range. Ligand B is slightly lower, which could slightly improve solubility.

**H-Bond Donors/Acceptors:** Ligand A has 2 HBD and 4 HBA, while Ligand B has 1 HBD and 3 HBA. Both are within acceptable limits (<=5 HBD and <=10 HBA).

**QED:** Ligand B (0.854) has a significantly better QED score than Ligand A (0.42), indicating a more drug-like profile.

**DILI:** Ligand A (59.519) has a higher DILI risk than Ligand B (35.983). This is a significant advantage for Ligand B.

**BBB:** Ligand B (58.434) has a better BBB percentile than Ligand A (44.668), although both are below the desirable >70 for CNS targets. This is a moderate advantage for Ligand B.

**Caco-2 Permeability:** Ligand A (-5.338) has a more negative Caco-2 value than Ligand B (-4.911), suggesting lower intestinal permeability.

**Aqueous Solubility:** Ligand A (-3.191) has a more negative solubility value than Ligand B (-2.198), indicating lower aqueous solubility.

**hERG:** Both ligands have low hERG inhibition liability (0.415 and 0.255), which is good.

**Microsomal Clearance:** Ligand B (-13.974) has a lower (better) microsomal clearance than Ligand A (7.159), indicating greater metabolic stability.

**In vitro Half-Life:** Ligand B (-3.466) has a more negative (better) in vitro half-life than Ligand A (-16.682), indicating a longer half-life.

**P-gp Efflux:** Ligand A (0.092) has a slightly higher P-gp efflux liability than Ligand B (0.015), which is unfavorable.

**Binding Affinity:** Ligand B (-8.7 kcal/mol) has a slightly better binding affinity than Ligand A (-7.9 kcal/mol). While the difference is less than the 1.5 kcal/mol threshold, it is still a positive factor.

**Overall Assessment:**

Ligand B consistently outperforms Ligand A across most critical ADME properties (DILI, BBB, solubility, metabolic stability, P-gp efflux) and has a slightly better binding affinity and QED score. While both ligands have acceptable MW, logP, and hERG values, Ligand B's superior profile makes it the more promising drug candidate for targeting DRD2.

Output:
1
2025-04-17 05:15:00,130 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (339.487 Da) is slightly better, being closer to the lower end which can aid permeability.

**TPSA:** Ligand A (46.84) is excellent, well below the 90 A^2 threshold for CNS targets. Ligand B (132.44) is higher, but still potentially acceptable, though less ideal.

**logP:** Ligand A (3.691) is optimal. Ligand B (-0.594) is significantly lower, which is a major concern for CNS penetration. A negative logP often indicates poor membrane permeability.

**H-Bond Donors/Acceptors:** Ligand A (0 HBD, 5 HBA) is better. Ligand B (2 HBD, 7 HBA) is acceptable, but more potential for off-target interactions and permeability issues.

**QED:** Both ligands have reasonable QED values (A: 0.837, B: 0.593), indicating good drug-like properties.

**DILI:** Ligand A (46.297) has a slightly better DILI score than Ligand B (52.152), indicating lower potential for liver injury. Both are acceptable.

**BBB:** Ligand A (87.553) is excellent, exceeding the desirable 70% threshold for CNS targets. Ligand B (58.782) is significantly lower, raising concerns about brain penetration.

**Caco-2 Permeability:** Ligand A (-4.882) is very poor, indicating very low intestinal absorption. Ligand B (-5.107) is also poor, but slightly better than A.

**Aqueous Solubility:** Both ligands have poor aqueous solubility (-2.83 and -1.831 respectively). This could pose formulation challenges.

**hERG Inhibition:** Ligand A (0.86) is better than Ligand B (0.08), indicating lower cardiotoxicity risk.

**Microsomal Clearance:** Ligand A (65.449) has higher clearance than Ligand B (27.782), suggesting lower metabolic stability.

**In vitro Half-Life:** Ligand B (-3.661) has a negative half-life, which is not possible. This is likely an error in the data, and makes the assessment of this parameter unreliable. Ligand A (6.077) is acceptable.

**P-gp Efflux:** Ligand A (0.577) is better than Ligand B (0.015), indicating lower P-gp efflux and potentially better CNS exposure.

**Binding Affinity:** Ligand A (-8.9 kcal/mol) has a significantly stronger binding affinity than Ligand B (-7.4 kcal/mol). This is a substantial advantage, potentially outweighing some of the ADME drawbacks.

**Overall Assessment:**

Ligand A is the stronger candidate. While its Caco-2 permeability is poor and its microsomal clearance is higher, its superior BBB penetration, significantly better binding affinity, lower hERG risk, and better P-gp efflux profile make it more likely to succeed as a CNS-targeting DRD2 ligand. Ligand B's negative logP is a major red flag, severely hindering its potential for brain penetration. The questionable half-life data for Ligand B further reduces its attractiveness. The substantial affinity difference (-8.9 vs -7.4) is a key driver in this decision.

Output:
1
2025-04-17 05:15:00,130 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (356.46 & 374.88 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (49.41) is significantly better than Ligand B (67.43). For CNS targets, we want TPSA <= 90, and ideally closer to 60. Ligand A is much closer to this ideal.

**logP:** Both ligands have good logP values (3.36 & 2.37), falling within the 1-3 optimal range.

**H-Bond Donors/Acceptors:** Ligand A (HBD=1, HBA=2) is slightly better than Ligand B (HBD=2, HBA=3) in terms of minimizing potential permeability issues. Both are within acceptable limits.

**QED:** Both ligands have similar QED values (0.79 & 0.70), indicating good drug-likeness.

**DILI:** Both ligands have low DILI risk (29.8 & 32.8), which is favorable.

**BBB:** Both ligands have excellent BBB penetration (89.3% & 85.0%), which is crucial for a CNS target like DRD2.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.58 & -4.73). This is unusual and suggests a potential issue with in vitro permeability. However, these values are on a scale where negative values are possible, and don't necessarily disqualify the compounds.

**Aqueous Solubility:** Both ligands have poor aqueous solubility (-3.53 & -3.89). This could pose formulation challenges, but is not a deal-breaker if other properties are strong.

**hERG:** Both ligands have low hERG inhibition risk (0.68 & 0.52).

**Microsomal Clearance:** Ligand A (26.4) has significantly lower microsomal clearance than Ligand B (45.4), indicating better metabolic stability.

**In vitro Half-Life:** Ligand A (-10.4) has a negative half-life, which is concerning and likely an artifact of the prediction method. Ligand B (26.6) has a reasonable half-life.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.15 & 0.22), which is good for CNS exposure.

**Binding Affinity:** Ligand A (-8.6 kcal/mol) has a significantly stronger binding affinity than Ligand B (-7.6 kcal/mol). This 1.0 kcal/mol difference is substantial and can outweigh minor ADME drawbacks.

**Overall Assessment:**

Ligand A is the stronger candidate. While its in vitro half-life is problematic (and needs experimental verification), its superior TPSA, lower microsomal clearance, and significantly better binding affinity outweigh the slightly worse solubility and the questionable half-life prediction. The excellent BBB penetration for both is a positive, but the stronger binding of Ligand A to DRD2 is the most critical factor for a GPCR target.

Output:
1
2025-04-17 05:15:00,130 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (341.371 and 341.411 Da) fall comfortably within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (112.95) is slightly higher than Ligand B (80.32). For CNS targets, TPSA should be <= 90. Ligand B is significantly better here.

**3. logP:** Both ligands have good logP values (1.192 and 1.821), falling within the optimal 1-3 range. Ligand B is slightly better.

**4. H-Bond Donors:** Both have 2 HBD, which is acceptable (<=5).

**5. H-Bond Acceptors:** Ligand A has 6 HBA, while Ligand B has 4. Both are within the acceptable range (<=10).

**6. QED:** Both ligands have high QED scores (0.819 and 0.856), indicating good drug-like properties.

**7. DILI:** Ligand A (61.07) has a higher DILI risk than Ligand B (38.813). Lower is better, and Ligand B is preferable.

**8. BBB:** Both ligands have similar BBB penetration (53.819 and 53.044). While not exceptional (>70 desirable), they are reasonable.

**9. Caco-2 Permeability:** Both have negative Caco-2 values (-5.091 and -4.971), which is unusual. This suggests poor permeability.

**10. Aqueous Solubility:** Both have negative solubility values (-3.627 and -2.336), indicating very low solubility. This is a significant concern.

**11. hERG Inhibition:** Both ligands show low hERG inhibition risk (0.101 and 0.192).

**12. Microsomal Clearance:** Ligand A (3.097) has lower microsomal clearance than Ligand B (29.194), suggesting better metabolic stability.

**13. In vitro Half-Life:** Ligand A (31.236 hours) has a significantly longer half-life than Ligand B (2.141 hours).

**14. P-gp Efflux:** Both have very low P-gp efflux liability (0.038 and 0.023).

**15. Binding Affinity:** Ligand B (-9.4 kcal/mol) has a significantly stronger binding affinity than Ligand A (-8.1 kcal/mol). This is a crucial advantage.

**Overall Assessment:**

While both compounds have issues with solubility and Caco-2 permeability, Ligand B is the more promising candidate. Its superior binding affinity (-9.4 vs -8.1 kcal/mol) is a major advantage, and it has a lower DILI risk. Although Ligand A has better metabolic stability and half-life, the affinity difference outweighs these benefits, especially for a GPCR target where strong binding is critical. The similar BBB values aren't decisive. The poor solubility and permeability are concerns that would need to be addressed through formulation or further structural modifications, but the starting point is better with Ligand B.

Output:
1
2025-04-17 05:15:00,131 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (335.407 and 348.418 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (66.89) is slightly higher than the ideal <90 for CNS targets, but still reasonable. Ligand B (58.64) is excellent, well below 90.

**logP:** Ligand A (4.005) is at the upper end of the optimal range (1-3) and could potentially cause solubility issues. Ligand B (2.334) is ideal.

**H-Bond Donors/Acceptors:** Ligand A (2 HBD, 3 HBA) and Ligand B (1 HBD, 3 HBA) both have acceptable numbers of H-bond donors and acceptors.

**QED:** Both ligands have good QED scores (0.759 and 0.823), indicating good drug-like properties.

**DILI:** Ligand A (75.688) has a higher DILI risk than Ligand B (33.618). This is a significant negative for Ligand A.

**BBB:** Ligand A (68.554) is below the desirable >70 for CNS targets, while Ligand B (72.974) is above it. This is a crucial advantage for Ligand B.

**Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and suggests poor permeability. However, the scale isn't specified, so it's difficult to interpret.

**Aqueous Solubility:** Both have negative solubility values, again making interpretation difficult.

**hERG:** Both ligands have low hERG inhibition liability (0.689 and 0.508), which is good.

**Microsomal Clearance:** Ligand A (33.774) has lower microsomal clearance than Ligand B (66.513), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (65.992) has a significantly longer half-life than Ligand B (6.751), which is a positive.

**P-gp Efflux:** Ligand A (0.508) has lower P-gp efflux than Ligand B (0.184), which is favorable for CNS penetration.

**Binding Affinity:** Both ligands have strong binding affinities (-9.8 and -8.7 kcal/mol). Ligand A is 1.1 kcal/mol stronger, which is a substantial difference and could outweigh some of its ADME drawbacks.

**Overall Assessment:**

Ligand B excels in key GPCR properties: logP, BBB, and DILI. While Ligand A has a slightly better binding affinity and metabolic stability (lower Cl_mic, longer t1/2) and lower P-gp efflux, its higher DILI risk and lower BBB penetration are significant concerns for a CNS target. The difference in binding affinity (1.1 kcal/mol) is considerable, but the ADME profile of Ligand B is more favorable for CNS drug development.

Output:
1
2025-04-17 05:15:00,131 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (339.443) is slightly lower, which could be beneficial for permeability, but both are acceptable.

**TPSA:** Ligand A (63.91) is better than Ligand B (40.62) as it is closer to the optimal range for CNS targets (<=90).

**logP:** Both ligands have good logP values (Ligand A: 2.032, Ligand B: 3.945), falling within the 1-3 range. Ligand B is closer to the upper limit, which *could* raise concerns about solubility or off-target effects, but isn't a dealbreaker.

**H-Bond Donors/Acceptors:** Ligand A has 0 HBD and 5 HBA, while Ligand B has 0 HBD and 2 HBA. Both are within acceptable limits (<=5 HBD, <=10 HBA).

**QED:** Ligand A (0.855) has a significantly better QED score than Ligand B (0.554), indicating a more drug-like profile.

**DILI:** Ligand A (42.613) has a slightly higher DILI risk than Ligand B (21.869), but both are below the concerning threshold of 60.

**BBB:** Ligand B (97.674) has a *much* better BBB penetration score than Ligand A (81.97). This is a critical advantage for a CNS target like DRD2.

**Caco-2 Permeability:** Ligand A (-5.107) has a negative Caco-2 value, which is concerning. Ligand B (-4.224) is also negative, but less so.

**Aqueous Solubility:** Ligand A (-1.043) has slightly better aqueous solubility than Ligand B (-3.887).

**hERG Inhibition:** Ligand A (0.268) has a lower hERG inhibition risk than Ligand B (0.91).

**Microsomal Clearance:** Ligand B (74.9) has a higher microsomal clearance than Ligand A (32.246), meaning Ligand A is more metabolically stable.

**In vitro Half-Life:** Ligand A (-4.693) has a longer in vitro half-life than Ligand B (3.676).

**P-gp Efflux:** Ligand A (0.07) has significantly lower P-gp efflux liability than Ligand B (0.445), which is favorable for CNS penetration.

**Binding Affinity:** Ligand B (-7.8) has a significantly stronger binding affinity than Ligand A (-9.1). This is a substantial advantage, potentially outweighing some of the ADME drawbacks.

**Overall Assessment:**

Ligand B excels in BBB penetration and binding affinity, which are paramount for a CNS GPCR target. While it has a slightly higher logP and P-gp efflux, the strong affinity and excellent BBB penetration are likely to compensate. Ligand A has better metabolic stability and lower P-gp efflux, but its significantly weaker binding affinity and lower BBB penetration are major drawbacks. The negative Caco-2 values for both are concerning, but the superior binding and CNS penetration of Ligand B make it the more promising candidate.

Output:
1
2025-04-17 05:15:00,131 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (411.34 Da) is slightly higher than Ligand B (353.809 Da), but both are acceptable.

**2. TPSA:** Ligand A (67.43) is higher than Ligand B (50.75). For CNS targets, we prefer TPSA <= 90. Both are within this range, but Ligand B is better.

**3. logP:** Ligand A (3.405) and Ligand B (4.454) are both within the optimal range of 1-3, but Ligand B is pushing the upper limit. Higher logP can sometimes lead to off-target effects, but is less of a concern than poor CNS penetration.

**4. H-Bond Donors:** Ligand A (2) is acceptable, while Ligand B (0) is also good.

**5. H-Bond Acceptors:** Ligand A (3) and Ligand B (4) are both within the acceptable limit of <=10.

**6. QED:** Ligand A (0.706) is better than Ligand B (0.498). A higher QED suggests better drug-like properties.

**7. DILI:** Ligand A (48.158) has a lower DILI risk than Ligand B (71.113). This is a significant advantage for Ligand A.

**8. BBB:** Ligand A (74.952) has a better BBB penetration percentile than Ligand B (64.211). This is *critical* for a CNS target like DRD2.

**9. Caco-2 Permeability:** Ligand A (-4.453) and Ligand B (-5.196) both have negative values, indicating poor permeability. This is a concern for both, but Ligand A is slightly better.

**10. Aqueous Solubility:** Ligand A (-4.532) and Ligand B (-3.907) both have negative values, indicating poor solubility. This is a concern for both, but Ligand B is slightly better.

**11. hERG Inhibition:** Ligand A (0.328) has a lower hERG inhibition risk than Ligand B (0.702). This is a significant advantage for Ligand A.

**12. Microsomal Clearance:** Ligand A (93.424) has higher microsomal clearance than Ligand B (77.615), meaning it's less metabolically stable. This favors Ligand B.

**13. In vitro Half-Life:** Ligand A (9.871) has a shorter half-life than Ligand B (96.773). This favors Ligand B.

**14. P-gp Efflux:** Ligand A (0.332) has lower P-gp efflux than Ligand B (0.79). Lower P-gp efflux is desirable for CNS penetration, favoring Ligand A.

**15. Binding Affinity:** Both ligands have very strong binding affinities (-9.5 and -9.6 kcal/mol). The difference is negligible.

**Overall Assessment:**

Ligand A excels in key areas for a CNS-targeting GPCR: BBB penetration, lower DILI risk, lower hERG inhibition, and lower P-gp efflux. While its metabolic stability (Cl_mic) and half-life are less favorable than Ligand B, the superior CNS penetration profile and safety parameters outweigh these drawbacks, especially given the very similar binding affinities. Ligand B has better metabolic stability and half-life, but its lower BBB penetration and higher DILI/hERG risks are significant concerns.

Output:
0
2025-04-17 05:15:00,131 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (349.431 and 344.499 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (83.8) is better than Ligand B (49.41). Both are below the 90 A^2 threshold for CNS targets.

**logP:** Ligand A (0.769) is slightly below the optimal 1-3 range, potentially hindering permeability. Ligand B (3.444) is within the optimal range.

**H-Bond Donors/Acceptors:** Ligand A (2 HBD, 5 HBA) and Ligand B (1 HBD, 2 HBA) both have reasonable numbers of H-bond donors and acceptors, well within the guidelines.

**QED:** Both ligands have similar QED values (0.795 and 0.777), indicating good drug-like properties.

**DILI:** Ligand A (42.148) has a slightly higher DILI risk than Ligand B (22.722), but both are below the concerning threshold of 60.

**BBB:** This is a crucial parameter for a CNS target like DRD2. Ligand B (73.711) significantly outperforms Ligand A (33.23) in BBB penetration, exceeding the desirable >70% threshold.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values, which is unusual and suggests poor permeability. However, the scale is not specified, so it's hard to interpret.

**Aqueous Solubility:** Both ligands have negative solubility values, which is also unusual.

**hERG:** Ligand A (0.168) has a lower hERG inhibition liability than Ligand B (0.505), indicating a lower risk of cardiotoxicity.

**Microsomal Clearance:** Ligand B (54.931) has a much higher microsomal clearance than Ligand A (8.562), suggesting lower metabolic stability.

**In vitro Half-Life:** Ligand A (34.195) has a longer in vitro half-life than Ligand B (-13.812), which is a positive attribute.

**P-gp Efflux:** Ligand A (0.041) exhibits lower P-gp efflux liability than Ligand B (0.351), which is favorable for CNS penetration.

**Binding Affinity:** Ligand A (-8.1 kcal/mol) has a significantly stronger binding affinity than Ligand B (0.0 kcal/mol). This is a substantial advantage.

**Overall Assessment:**

While Ligand A has a better binding affinity, longer half-life, lower P-gp efflux, and lower hERG risk, Ligand B excels in BBB penetration and has a more favorable logP. The significantly stronger binding affinity of Ligand A (-8.1 kcal/mol vs 0 kcal/mol) is a major advantage that can potentially overcome some of its ADME drawbacks. Given the importance of CNS penetration for a DRD2 target, and the substantial difference in affinity, Ligand A is the more promising candidate.

Output:
1
2025-04-17 05:15:00,131 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (380.455 Da) is slightly higher than Ligand B (343.391 Da), but both are acceptable.

**TPSA:** Ligand A (111.77) is better than Ligand B (123.95). For CNS targets, we want TPSA <= 90, so both are above this ideal, but A is closer.

**logP:** Both ligands have acceptable logP values (A: 0.845, B: 1.313), falling within the optimal range of 1-3. Ligand B is slightly better.

**H-Bond Donors:** Both have 1 HBD, which is good.

**H-Bond Acceptors:** Ligand A has 9 HBAs, which is acceptable. Ligand B has 5 HBAs, which is also acceptable.

**QED:** Ligand A (0.702) has a significantly better QED score than Ligand B (0.331), indicating a more drug-like profile.

**DILI:** Ligand A (98.216) has a higher DILI risk than Ligand B (41.915). This is a significant drawback for Ligand A.

**BBB:** Ligand A (29.508) has a very poor BBB penetration percentile, while Ligand B (40.675) is also low, but better than A. For a CNS target like DRD2, >70 is desirable. Both are far from this, but A is worse.

**Caco-2 Permeability:** Both have negative Caco-2 values, indicating poor permeability. Ligand A (-5.493) is slightly better than Ligand B (-4.93).

**Aqueous Solubility:** Both have negative solubility values, indicating poor solubility. Ligand A (-2.438) is slightly better than Ligand B (-1.443).

**hERG Inhibition:** Both ligands have low hERG inhibition risk (A: 0.111, B: 0.196).

**Microsomal Clearance:** Ligand A (-11.21) has a significantly lower (better) microsomal clearance than Ligand B (28.233), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (47.81) has a better in vitro half-life than Ligand B (-14.109).

**P-gp Efflux:** Ligand A (0.098) has lower P-gp efflux liability than Ligand B (0.015), which is favorable for CNS penetration.

**Binding Affinity:** Ligand B (-7.1 kcal/mol) has a slightly better binding affinity than Ligand A (-9.1 kcal/mol). However, the difference is not substantial enough to outweigh other factors.

**Overall Assessment:**

Ligand A has a better QED, metabolic stability (Cl_mic, t1/2), and P-gp efflux. However, it has a significantly higher DILI risk and a much poorer BBB penetration. Ligand B has a slightly better binding affinity and a lower DILI risk, but suffers from poor metabolic stability and a lower QED.

Given the importance of BBB penetration for a CNS target like DRD2, and the significant DILI risk associated with Ligand A, **Ligand B is the more promising candidate despite its lower QED and metabolic stability.** The slightly better binding affinity also contributes to this decision. Further optimization of Ligand B could focus on improving its metabolic stability and QED.

Output:
1
2025-04-17 05:15:00,131 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (368.861 and 380.901 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (60.03) is significantly better than Ligand B (86.88). For CNS targets, we want TPSA <= 90, and A is comfortably within that, while B is approaching the upper limit.

**3. logP:** Both ligands have good logP values (3.78 and 3.363), falling within the optimal 1-3 range.

**4. H-Bond Donors:** Ligand A (1) is preferable to Ligand B (3). Lower HBD generally improves permeability.

**5. H-Bond Acceptors:** Ligand A (5) is preferable to Ligand B (4). Lower HBA generally improves permeability.

**6. QED:** Both ligands have acceptable QED values (0.876 and 0.743), indicating good drug-like properties.

**7. DILI:** Ligand A (60.489) has a slightly better DILI score than Ligand B (73.672), indicating a lower risk of liver injury. Both are acceptable, but lower is better.

**8. BBB:** This is a critical parameter for CNS targets. Ligand A (91.431) is *much* better than Ligand B (48.468). A value >70 is desirable, and A is close, while B is significantly lower.

**9. Caco-2 Permeability:** Ligand A (-4.485) is better than Ligand B (-5.23), indicating better intestinal absorption.

**10. Aqueous Solubility:** Ligand A (-4.854) is better than Ligand B (-4.527), indicating better solubility.

**11. hERG Inhibition:** Ligand A (0.763) is better than Ligand B (0.305), indicating lower cardiotoxicity risk.

**12. Microsomal Clearance:** Ligand B (34.91) has lower microsomal clearance than Ligand A (43.481), suggesting better metabolic stability.

**13. In vitro Half-Life:** Ligand B (13.791) has a longer half-life than Ligand A (24.618).

**14. P-gp Efflux:** Ligand A (0.441) is better than Ligand B (0.293), indicating lower P-gp efflux and potentially better CNS exposure.

**15. Binding Affinity:** Ligand B (-9.3) has a significantly stronger binding affinity than Ligand A (-8.0). This is a substantial advantage.

**Overall Assessment:**

While Ligand B has a superior binding affinity and better metabolic stability (lower Cl_mic and longer t1/2), Ligand A excels in almost all other crucial ADME properties, *especially* BBB penetration (91.431 vs 48.468). For a CNS target like DRD2, BBB penetration is paramount. The difference in binding affinity (-9.3 vs -8.0) is significant, but the substantial improvement in BBB, TPSA, and other ADME properties with Ligand A likely outweighs this difference. A slightly weaker but more bioavailable ligand is often preferable to a potent ligand that cannot reach its target in the brain.

Output:
0
2025-04-17 05:15:00,132 - INFO - Batch 182 complete. Total preferences: 2912
2025-04-17 05:15:00,132 - INFO - Processing batch 183/512...
2025-04-17 05:15:44,397 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 drug candidates, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (342.403 Da and 354.422 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (93.01) is slightly above the preferred <90 for CNS targets, but still reasonable. Ligand B (68.73) is well within the optimal range for CNS penetration.

**3. logP:** Ligand A (1.337) is within the optimal 1-3 range. Ligand B (2.742) is also good, leaning towards the higher end but still acceptable.

**4. H-Bond Donors:** Ligand A (1) is good. Ligand B (0) is also good.

**5. H-Bond Acceptors:** Ligand A (6) is good. Ligand B (5) is good.

**6. QED:** Ligand A (0.908) is excellent, indicating high drug-likeness. Ligand B (0.646) is still acceptable, above the 0.5 threshold.

**7. DILI:** Ligand A (60.721) is approaching a concerning level, indicating moderate liver injury risk. Ligand B (29.314) has a much lower and favorable DILI risk.

**8. BBB:** Ligand A (75.649) is good, exceeding the 70% threshold for CNS targets. Ligand B (82.396) is even better, suggesting excellent brain penetration potential.

**9. Caco-2:** Both ligands have negative Caco-2 values (-4.998 and -4.037), which is unusual and suggests poor permeability. This is a significant drawback for both.

**10. Solubility:** Both ligands have negative solubility values (-2.722 and -1.668), which is also unusual and suggests poor aqueous solubility. This is a significant drawback for both.

**11. hERG:** Both ligands have very low hERG inhibition liability (0.361 and 0.303), which is excellent.

**12. Cl_mic:** Ligand A (17.112) has a lower microsomal clearance, suggesting better metabolic stability than Ligand B (81.569).

**13. t1/2:** Ligand A (4.43) has a slightly longer half-life than Ligand B (2.884).

**14. Pgp:** Both ligands have very low P-gp efflux liability (0.023 and 0.096), which is excellent for CNS penetration.

**15. Binding Affinity:** Ligand A (-8.7 kcal/mol) has a significantly stronger binding affinity than Ligand B (-6.7 kcal/mol). This is a substantial advantage.

**Overall Assessment:**

While both ligands have issues with Caco-2 permeability and aqueous solubility, Ligand A's significantly stronger binding affinity (-8.7 vs -6.7 kcal/mol) is a major advantage that could potentially outweigh its slightly higher DILI risk and less favorable TPSA. Ligand B has better DILI and TPSA, but its weaker binding affinity is a substantial drawback, especially for a GPCR target where potency is crucial. The superior BBB penetration of Ligand B is also a positive, but the affinity difference is larger.

Output:
1
2025-04-17 05:15:44,397 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (345.443 and 351.531 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (75.44) is slightly higher than Ligand B (60.77). Both are below the 90 A^2 threshold desirable for CNS targets, but Ligand B is better.

**3. logP:** Ligand A (2.559) and Ligand B (3.211) are both within the optimal 1-3 range. Ligand B is slightly higher, which could be beneficial for membrane permeability but needs to be balanced against solubility.

**4. H-Bond Donors:** Ligand A (1) is preferable to Ligand B (2). Lower HBD generally improves permeability.

**5. H-Bond Acceptors:** Ligand A (4) is preferable to Ligand B (3). Lower HBA generally improves permeability.

**6. QED:** Ligand A (0.851) has a significantly better QED score than Ligand B (0.67), indicating a more drug-like profile.

**7. DILI:** Ligand A (53.276) has a higher DILI risk than Ligand B (9.151). This is a significant drawback for Ligand A.

**8. BBB:** Both ligands have excellent BBB penetration (Ligand A: 74.254, Ligand B: 74.564), exceeding the >70% threshold for CNS targets.

**9. Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and suggests a potential issue with the data or modeling. However, the values are similar (-4.769 and -4.453) and don't strongly differentiate the ligands.

**10. Aqueous Solubility:** Both ligands have negative solubility values, which is also unusual and suggests a potential issue with the data or modeling. Ligand B (-2.95) is slightly better than Ligand A (-3.703).

**11. hERG Inhibition:** Ligand A (0.28) has a lower hERG inhibition risk than Ligand B (0.761), which is favorable.

**12. Microsomal Clearance:** Ligand A (44.711) has significantly lower microsomal clearance than Ligand B (65.355), indicating better metabolic stability.

**13. In vitro Half-Life:** Ligand A (-3.903) has a negative half-life, which is an issue. Ligand B (26.035) has a reasonable half-life.

**14. P-gp Efflux:** Ligand A (0.287) has lower P-gp efflux than Ligand B (0.699), which is beneficial for CNS exposure.

**15. Binding Affinity:** Ligand A (-8.4 kcal/mol) has a significantly stronger binding affinity than Ligand B (-7.3 kcal/mol). This is a substantial advantage, potentially outweighing some of the ADME drawbacks.

**Overall Assessment:**

Ligand A has a superior binding affinity, better QED, lower P-gp efflux, lower microsomal clearance, and lower hERG risk. However, it has a higher DILI risk and a negative in vitro half-life. Ligand B has a lower DILI risk and a reasonable half-life, but its binding affinity is weaker, and its QED is lower.

Given the importance of binding affinity for GPCRs, and the acceptable BBB penetration of both, Ligand A is the more promising candidate *despite* the DILI and half-life concerns. These issues could potentially be addressed through further structural modifications. The significant affinity advantage is a strong driver.

Output:
1
2025-04-17 05:15:44,397 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 drug candidates, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (361.515 and 356.457 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (66.81) is higher than Ligand B (43.78). For CNS targets, TPSA should be <=90, both are within this range, but B is better.

**logP:** Ligand A (2.556) and Ligand B (3.661) are both within the optimal 1-3 range. Ligand B is slightly higher, which could be beneficial for membrane permeability, but needs to be balanced against solubility.

**H-Bond Donors:** Both ligands have 1 HBD, which is within the acceptable limit of <=5.

**H-Bond Acceptors:** Ligand A has 5 HBA, and Ligand B has 3. Both are below the acceptable limit of <=10.

**QED:** Both ligands have good QED scores (0.745 and 0.773), indicating good drug-like properties.

**DILI:** Ligand A (15.743) has a slightly higher DILI risk than Ligand B (13.532), but both are well below the concerning threshold of 60.

**BBB:** This is a critical parameter for CNS targets. Ligand B (71.074) has a significantly better BBB percentile than Ligand A (54.556). This is a major advantage for Ligand B.

**Caco-2 Permeability:** Ligand A (-5.601) has worse Caco-2 permeability than Ligand B (-4.621).

**Aqueous Solubility:** Both ligands have poor aqueous solubility (-1.834 and -3.143). This could pose formulation challenges, but is not a dealbreaker if other properties are favorable.

**hERG Inhibition:** Ligand A (0.479) has a slightly lower hERG inhibition risk than Ligand B (0.896), which is preferable.

**Microsomal Clearance:** Ligand B (83.716) has a significantly higher microsomal clearance than Ligand A (38.858), indicating faster metabolism and potentially lower *in vivo* exposure.

**In vitro Half-Life:** Ligand A (-11.799) has a longer in vitro half-life than Ligand B (-5.056).

**P-gp Efflux:** Ligand A (0.056) has lower P-gp efflux than Ligand B (0.165), which is favorable for CNS penetration.

**Binding Affinity:** Both ligands have similar binding affinities (-6.7 and -6.8 kcal/mol), which are both excellent. The difference is negligible.

**Overall Assessment:**

Ligand B has a clear advantage due to its significantly better BBB penetration (71.074 vs 54.556). While it has slightly higher P-gp efflux and hERG risk, and worse metabolic stability (higher Cl_mic, shorter t1/2), the improved BBB is paramount for a CNS-targeting drug. The binding affinities are comparable. Ligand A has a slight edge in hERG and metabolic stability, but the BBB difference outweighs these benefits.

Output:
1
2025-04-17 05:15:44,398 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (339.414 Da) is slightly preferred due to being closer to the lower end, potentially aiding permeability.

**TPSA:** Ligand A (38.13) is excellent for CNS penetration, well below 90. Ligand B (70.67) is higher but still potentially acceptable, though less ideal.

**logP:** Ligand A (3.52) is optimal. Ligand B (1.027) is a bit low, potentially hindering membrane permeability.

**H-Bond Donors & Acceptors:** Ligand A (0 HBD, 3 HBA) is very favorable. Ligand B (2 HBD, 5 HBA) is also reasonable, but slightly higher counts could affect permeability.

**QED:** Ligand A (0.84) is excellent, indicating high drug-likeness. Ligand B (0.445) is below the desirable threshold of 0.5, suggesting a less favorable overall drug-like profile.

**DILI:** Ligand A (50.33) has a moderate risk, but is acceptable. Ligand B (17.371) is very good, indicating low liver injury risk.

**BBB:** Ligand A (94.029) is *excellent* for CNS penetration. Ligand B (35.673) is poor and a major drawback for a CNS target like DRD2.

**Caco-2 Permeability:** Ligand A (-4.466) is poor. Ligand B (-5.565) is also poor. Both are negative values, indicating low permeability.

**Aqueous Solubility:** Ligand A (-4.421) is poor. Ligand B (-1.282) is also poor, but slightly better than Ligand A.

**hERG Inhibition:** Ligand A (0.791) is acceptable. Ligand B (0.398) is very good, indicating low cardiotoxicity risk.

**Microsomal Clearance:** Ligand A (66.662) is relatively high, suggesting faster metabolism. Ligand B (10.69) is very low, indicating good metabolic stability.

**In vitro Half-Life:** Ligand A (-20.113) is poor, indicating a short half-life. Ligand B (3.48) is poor, indicating a short half-life.

**P-gp Efflux:** Ligand A (0.476) is good, indicating low efflux. Ligand B (0.032) is excellent, indicating very low efflux.

**Binding Affinity:** Ligand B (-7.2 kcal/mol) is significantly more potent than Ligand A (-10.5 kcal/mol). This is a substantial advantage.

**Overall Assessment:**

Despite Ligand B's superior binding affinity, the extremely poor BBB penetration (35.673) is a critical flaw for a CNS target. Ligand A, while having a weaker affinity, boasts excellent BBB penetration (94.029), a good QED score, and acceptable DILI and hERG risk. The lower logP and Caco-2 permeability of Ligand B are also concerning. The better metabolic stability of Ligand B is a plus, but can be addressed through structural modifications. The strong affinity of Ligand B is tempting, but it's unlikely to translate into *in vivo* efficacy without better brain exposure.

Output:
0
2025-04-17 05:15:44,398 - INFO - Reasoning:

Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (376.475 Da) is slightly higher than Ligand B (340.383 Da), but both are acceptable.

**2. TPSA:** Ligand A (121.8) is borderline for CNS penetration, slightly above the optimal <90. Ligand B (99.23) is well within the desired range for CNS targets. This is a significant advantage for Ligand B.

**3. logP:** Ligand A (-0.495) is quite low, potentially hindering membrane permeability. Ligand B (1.496) is within the optimal range (1-3). This is a clear advantage for Ligand B.

**4. H-Bond Donors:** Ligand A (3) is acceptable. Ligand B (1) is even better, potentially improving permeability.

**5. H-Bond Acceptors:** Ligand A (6) is acceptable. Ligand B (5) is also good.

**6. QED:** Both ligands have good QED scores (Ligand A: 0.491, Ligand B: 0.819). Ligand B is significantly better, indicating a more drug-like profile.

**7. DILI:** Ligand A (39.201) has a lower DILI risk than Ligand B (56.805), which is good.

**8. BBB:** Ligand A (47.926) has a moderate BBB penetration, while Ligand B (60.295) is better, but still not ideal (>70 is preferred).

**9. Caco-2:** Both have negative Caco-2 values, which is unusual and suggests poor permeability. This is a concern for both.

**10. Solubility:** Both ligands have negative solubility values, which is also unusual and suggests poor solubility. This is a concern for both.

**11. hERG:** Ligand A (0.085) has a very low hERG risk. Ligand B (0.415) is slightly higher, but still relatively low.

**12. Cl_mic:** Ligand A (19.919) has a lower microsomal clearance, suggesting better metabolic stability than Ligand B (39.417).

**13. t1/2:** Ligand A (13.514) has a longer in vitro half-life than Ligand B (4.855). This is a significant advantage for Ligand A.

**14. Pgp:** Ligand A (0.034) has very low P-gp efflux, which is excellent for CNS penetration. Ligand B (0.105) is slightly higher, but still relatively low.

**15. Binding Affinity:** Ligand B (-8.8 kcal/mol) has a significantly stronger binding affinity than Ligand A (-7.2 kcal/mol). This >1.5 kcal/mol difference is substantial and can outweigh some ADME drawbacks.

**Overall Assessment:**

While Ligand A has advantages in DILI, metabolic stability (Cl_mic), half-life, and P-gp efflux, Ligand B excels in key GPCR-relevant properties: TPSA, logP, QED, and, crucially, binding affinity. The significantly stronger binding affinity of Ligand B (-8.8 kcal/mol vs -7.2 kcal/mol) is a major factor. The lower TPSA and better logP of Ligand B also suggest better CNS penetration potential despite the moderate BBB score. The negative Caco-2 and solubility values are concerning for both, but the affinity difference is large enough to prioritize Ligand B for further optimization.

Output:
1
2025-04-17 05:15:44,398 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (344.46 and 349.37 Da) fall comfortably within the ideal 200-500 Da range.

**TPSA:** Ligand A (59.65) is significantly better than Ligand B (96.25). For CNS targets, TPSA should be <= 90, so Ligand A is preferable.

**logP:** Both ligands have acceptable logP values (1.50 and 0.996), falling within the 1-3 range.

**H-Bond Donors/Acceptors:** Both have 1 HBD, which is good. Ligand B has 6 HBA, slightly higher than Ligand A's 3, but both are within the acceptable limit of <=10.

**QED:** Both ligands have similar QED scores (0.824 and 0.794), indicating good drug-likeness.

**DILI:** Ligand A (12.49) has a much lower DILI risk than Ligand B (56.65), which is a significant advantage.

**BBB:** Ligand B (80.34) has a better BBB penetration percentile than Ligand A (66.93), but both are reasonably good for a CNS target.

**Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and suggests poor permeability. However, the scale is not specified, so it's hard to interpret.

**Aqueous Solubility:** Both have negative solubility values, which is also unusual and suggests poor solubility. Again, the scale is not specified.

**hERG:** Both ligands show low hERG inhibition liability (0.41 and 0.23), which is positive.

**Microsomal Clearance:** Ligand A (-7.23) shows significantly better metabolic stability (lower clearance) than Ligand B (2.39).

**In vitro Half-Life:** Ligand A (-10.07) has a much longer predicted half-life than Ligand B (0.26).

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.03 and 0.02), which is excellent for CNS penetration.

**Binding Affinity:** Ligand B (-7.5) has a slightly better binding affinity than Ligand A (-8.3). However, the difference is relatively small (0.8 kcal/mol) and may not outweigh the other significant advantages of Ligand A.

**Overall:** Considering all factors, especially the GPCR-specific priorities, Ligand A is the more promising candidate. It has a significantly better TPSA, lower DILI risk, better metabolic stability (lower Cl_mic and longer t1/2), and comparable BBB penetration and affinity to Ligand B. While Ligand B has slightly better affinity and BBB penetration, the other advantages of Ligand A make it a more favorable starting point for further optimization.

Output:
1
2025-04-17 05:15:44,398 - INFO - Reasoning:

Let's analyze Ligand A and Ligand B based on the provided guidelines, prioritizing GPCR-specific properties (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (340.343 Da) is slightly lower, which *could* be beneficial for permeability, but both are acceptable.

**TPSA:** Ligand A (115.92) is better than Ligand B (127.23). For CNS targets, we want TPSA <= 90, so Ligand A is closer to this target.

**logP:** Ligand A (1.211) is within the optimal range (1-3), while Ligand B (-0.033) is slightly below 1. This is a significant drawback for Ligand B, potentially hindering membrane permeability.

**H-Bond Donors/Acceptors:** Ligand A (HBD=1, HBA=8) and Ligand B (HBD=2, HBA=7) both have reasonable numbers of H-bond donors and acceptors.

**QED:** Ligand A (0.712) has a better QED score than Ligand B (0.425), indicating a more drug-like profile.

**DILI:** Ligand B (61.07) has a higher DILI risk than Ligand A (96.549), which is undesirable.

**BBB:** Ligand B (58.511) has a better BBB penetration percentile than Ligand A (46.219). This is a critical factor for CNS targets like DRD2. However, both are below the desirable >70 threshold.

**Caco-2 Permeability:** Ligand A (-4.964) has significantly *better* Caco-2 permeability than Ligand B (-5.615).

**Aqueous Solubility:** Ligand A (-2.642) has slightly better solubility than Ligand B (-1.965).

**hERG:** Both ligands have very low hERG inhibition liability (0.361 and 0.075, respectively), which is excellent.

**Microsomal Clearance:** Ligand B (5.431) has a much lower microsomal clearance than Ligand A (50.644), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand B (83.79) has a significantly longer in vitro half-life than Ligand A (-13.845), which is a major advantage.

**P-gp Efflux:** Ligand A (0.02) has significantly lower P-gp efflux liability than Ligand B (0.068), which is beneficial for CNS penetration.

**Binding Affinity:** Ligand B (-7.6 kcal/mol) has a slightly better binding affinity than Ligand A (-8.6 kcal/mol). While both are excellent, the 1.0 kcal/mol difference is noteworthy.

**Overall Assessment:**

Ligand A has better physicochemical properties (TPSA, logP, QED, Caco-2, solubility, P-gp efflux) and a lower DILI risk. However, Ligand B has superior BBB penetration and metabolic stability (lower Cl_mic, longer t1/2), and a slightly better binding affinity.

Given the GPCR target (DRD2) and the importance of CNS penetration, BBB is a crucial factor. While Ligand B's BBB is still not ideal, it's significantly better than Ligand A's. The improved metabolic stability and binding affinity of Ligand B also contribute to its potential. The lower logP of Ligand B is a concern, but the slightly better affinity may compensate.

Output:
1
2025-04-17 05:15:44,398 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (348.443 and 354.401 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (68.82) is slightly higher than Ligand B (58.44). Both are below the 90 A^2 threshold for CNS targets, which is good. Ligand B is preferable here.

**3. logP:** Ligand A (2.34) and Ligand B (1.694) are both within the optimal 1-3 range. Ligand A is slightly better.

**4. H-Bond Donors:** Ligand A (2) is better than Ligand B (0). While both are acceptable, a small number of HBDs can aid solubility.

**5. H-Bond Acceptors:** Ligand A (5) and Ligand B (4) are both within the acceptable limit of 10.

**6. QED:** Both ligands have very similar QED values (0.826 and 0.827), indicating good drug-likeness.

**7. DILI:** Ligand B (34.432) has a significantly lower DILI risk than Ligand A (43.234). This is a substantial advantage for Ligand B.

**8. BBB:** Ligand B (92.943) has a much higher predicted BBB penetration than Ligand A (77.162). This is *critical* for a CNS target like DRD2, making Ligand B highly preferable.

**9. Caco-2 Permeability:** Ligand A (-5.072) has better Caco-2 permeability than Ligand B (-4.531).

**10. Aqueous Solubility:** Both ligands have very poor aqueous solubility (-1.753 and -1.77). This is a concern for both, but not a deciding factor given the other properties.

**11. hERG Inhibition:** Both ligands have similar, low hERG inhibition risk (0.487 and 0.516).

**12. Microsomal Clearance:** Ligand A (-38.71) has a lower (better) microsomal clearance than Ligand B (29.086), suggesting greater metabolic stability.

**13. In vitro Half-Life:** Ligand B (-26.67) has a much longer in vitro half-life than Ligand A (11.026). This is a significant advantage.

**14. P-gp Efflux:** Both ligands have very similar P-gp efflux liability (0.053 and 0.052).

**15. Binding Affinity:** Both ligands have excellent binding affinities (-8.4 and -8.7 kcal/mol). The difference is minimal.

**Overall Assessment:**

Ligand B is the stronger candidate. While Ligand A has slightly better Caco-2 permeability and microsomal clearance, Ligand B's significantly better BBB penetration, lower DILI risk, and longer half-life outweigh these minor drawbacks. For a CNS GPCR target, BBB penetration is paramount, and Ligand B excels in this area. The higher half-life is also a significant benefit.

Output:
1
2025-04-17 05:15:44,398 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B based on the provided guidelines, prioritizing GPCR-specific properties (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (348.491 and 347.375 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (67.65) is significantly better than Ligand B (127.51). For CNS targets, we want TPSA <= 90, and Ligand A is comfortably within that range, while Ligand B exceeds it. This is a major advantage for A.

**logP:** Ligand A (1.575) is within the optimal 1-3 range. Ligand B (-1.055) is below 1, which could hinder permeation. This favors Ligand A.

**H-Bond Donors/Acceptors:** Ligand A (0 HBD, 4 HBA) is preferable to Ligand B (2 HBD, 6 HBA). Both are within acceptable limits, but fewer H-bonds generally improve permeability.

**QED:** Both ligands have similar QED values (0.7 and 0.675), indicating good drug-likeness.

**DILI:** Ligand A (9.383) has a much lower DILI risk than Ligand B (61.729). This is a significant advantage for A.

**BBB:** Ligand A (69.717) has a better BBB percentile than Ligand B (59.674). While both are not ideal (>70 is desirable), A is closer. This is crucial for a CNS target like DRD2.

**Caco-2 Permeability:** Ligand A (-4.745) and Ligand B (-5.525) both have negative values, which is unusual and suggests poor permeability. However, the scale is not specified, so it's difficult to interpret.

**Aqueous Solubility:** Both ligands have poor solubility (-1.134 and -1.765). This is a potential issue for both, but not a deciding factor.

**hERG:** Ligand A (0.754) has a lower hERG risk than Ligand B (0.061). This is a positive for A.

**Microsomal Clearance:** Ligand A (20.762) has a higher (worse) microsomal clearance than Ligand B (-16.099). This suggests Ligand B is more metabolically stable.

**In vitro Half-Life:** Ligand A (-7.712) has a significantly longer in vitro half-life than Ligand B (0.277). This is a strong advantage for A.

**P-gp Efflux:** Ligand A (0.041) has a lower P-gp efflux liability than Ligand B (0.002). Lower efflux is better, especially for CNS penetration, favoring A.

**Binding Affinity:** Ligand B (-8.0 kcal/mol) has a slightly better binding affinity than Ligand A (-7.2 kcal/mol). While a 1.5 kcal/mol advantage is often significant, the other ADME properties of A are much more favorable.

**Overall Assessment:**

Considering the GPCR-specific priorities, Ligand A is the superior candidate. Its significantly better TPSA, logP, BBB, DILI, hERG, P-gp efflux, and in vitro half-life outweigh the slightly weaker binding affinity. Ligand B's higher TPSA, lower logP, and higher DILI risk are major drawbacks.



Output:
0
2025-04-17 05:15:44,398 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (352.41 and 353.438 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (107.11) is slightly above the optimal <90 for CNS targets, while Ligand B (91.32) is within the preferred range. This gives a slight edge to Ligand B.

**3. logP:** Both ligands have logP values within the optimal range (1.197 and 1.919).

**4. H-Bond Donors:** Ligand A (4) and Ligand B (3) are both acceptable, being less than 5.

**5. H-Bond Acceptors:** Both ligands have 4 H-bond acceptors, which is within the acceptable limit of 10.

**6. QED:** Both ligands have similar QED values (0.639 and 0.623), indicating good drug-likeness.

**7. DILI:** Ligand A (61.691) has a higher DILI risk than Ligand B (36.642). This is a significant advantage for Ligand B.

**8. BBB:** Ligand A (53.664) and Ligand B (62.233) both have reasonable BBB penetration, but Ligand B is better, exceeding 60%. This is crucial for a CNS target like DRD2.

**9. Caco-2 Permeability:** Ligand A (-5.316) has poorer Caco-2 permeability compared to Ligand B (-4.957), suggesting lower intestinal absorption.

**10. Aqueous Solubility:** Both ligands have poor aqueous solubility (-3.142 and -2.525). While not ideal, this isn't a primary concern if BBB penetration is good.

**11. hERG Inhibition:** Both ligands have low hERG inhibition risk (0.34 and 0.253).

**12. Microsomal Clearance:** Ligand A (-12.363) has a much lower (better) microsomal clearance than Ligand B (39.431), indicating better metabolic stability.

**13. In vitro Half-Life:** Ligand B (18.76) has a significantly longer in vitro half-life than Ligand A (-2.006). This is a substantial advantage.

**14. P-gp Efflux:** Both ligands have very low P-gp efflux (0.06 and 0.071).

**15. Binding Affinity:** Ligand A (-9.7 kcal/mol) has a slightly better binding affinity than Ligand B (-7.8 kcal/mol). However, the difference is less than 1.5 kcal/mol, so it doesn't necessarily outweigh other ADME differences.

**Overall Assessment:**

Ligand B is the more promising candidate. While Ligand A has slightly better binding affinity, Ligand B demonstrates superior ADME properties crucial for CNS drug development: lower DILI risk, better BBB penetration, improved Caco-2 permeability, and a significantly longer half-life. The TPSA value is also more favorable for CNS penetration. The improved metabolic stability of Ligand A is a plus, but the other advantages of Ligand B are more critical for a GPCR target in the CNS.

Output:
1
2025-04-17 05:15:44,398 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (351.397 Da) is slightly lower, which could be advantageous for permeability.

**TPSA:** Ligand A (54.34) is significantly better than Ligand B (63.25). For CNS targets, we want TPSA <= 90, and ideally closer to 60. Ligand A is well within this range, while Ligand B is approaching the upper limit.

**logP:** Both ligands have acceptable logP values (Ligand A: 2.092, Ligand B: 3.463), falling within the optimal 1-3 range. Ligand B is a bit higher, potentially increasing off-target interactions or solubility issues.

**H-Bond Donors/Acceptors:** Ligand A (HBD=1, HBA=3) has a more favorable profile than Ligand B (HBD=2, HBA=5). Lower values generally improve permeability.

**QED:** Ligand A (0.903) has a much higher QED score than Ligand B (0.73), indicating a more drug-like profile.

**DILI:** Ligand A (22.8) has a significantly lower DILI risk than Ligand B (52.152), suggesting better hepatic safety.

**BBB:** Ligand A (95.967) has excellent BBB penetration, exceeding the desirable >70 threshold. Ligand B (83.249) is still good, but not as promising. This is a critical factor for a CNS target like DRD2.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.677 and -4.522). These values are unusual and suggest poor permeability. However, the scale isn't specified, so it's difficult to interpret precisely.

**Aqueous Solubility:** Both ligands have negative solubility values (-2.851 and -4.711). Again, the scale is unspecified, making interpretation difficult. Poor solubility can hinder bioavailability.

**hERG Inhibition:** Both ligands show low hERG inhibition liability (Ligand A: 0.397, Ligand B: 0.564), which is good.

**Microsomal Clearance:** Ligand A (4.128) has significantly lower microsomal clearance than Ligand B (53.182), indicating better metabolic stability.

**In vitro Half-Life:** Ligand A (-0.26) has a slightly negative half-life, while Ligand B (33.907) has a long half-life. Negative half-life is unusual.

**P-gp Efflux:** Ligand A (0.042) has very low P-gp efflux, which is highly desirable for CNS penetration. Ligand B (0.277) is higher, potentially limiting brain exposure.

**Binding Affinity:** Ligand A (-8.7 kcal/mol) has a significantly stronger binding affinity than Ligand B (-6.7 kcal/mol). This >1.5 kcal/mol difference in binding is a substantial advantage, potentially outweighing some of the ADME concerns.

**Overall Assessment:**

Ligand A is clearly the superior candidate. It excels in key areas for CNS GPCR targets: BBB penetration, TPSA, P-gp efflux, metabolic stability (Cl_mic), and, most importantly, binding affinity. While both ligands have questionable solubility and Caco-2 permeability values, the strong affinity and favorable CNS properties of Ligand A make it the more promising drug candidate.



Output:
1
2025-04-17 05:15:44,399 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (344.415 and 360.401 Da) are within the ideal 200-500 Da range.

**TPSA:** Ligand A (78.27) is better than Ligand B (67.87). Both are below the 90 A^2 threshold desirable for CNS targets.

**logP:** Both ligands have good logP values (2.156 and 1.358), falling within the optimal 1-3 range. Ligand B is slightly lower, which *could* indicate slightly better solubility, but isn't a major concern.

**H-Bond Donors/Acceptors:** Both ligands have 1 HBD, which is good. Ligand A has 6 HBA, while Ligand B has 4. Both are within the acceptable limit of 10.

**QED:** Ligand A (0.899) has a significantly better QED score than Ligand B (0.696), indicating a more drug-like profile.

**DILI:** Ligand A (73.09) has a higher DILI risk than Ligand B (43.622). This is a significant negative for Ligand A.

**BBB:** Ligand B (90.617) has a substantially higher BBB penetration percentile than Ligand A (77.2). This is a crucial advantage for a CNS target like DRD2.

**Caco-2 Permeability:** Ligand A (-4.672) and Ligand B (-4.307) have similar, negative Caco-2 permeability values, indicating poor intestinal absorption. This isn't a primary concern for a CNS target where direct delivery is possible.

**Aqueous Solubility:** Ligand A (-3.322) has slightly better solubility than Ligand B (-2.276), but both are poor.

**hERG:** Both ligands have low hERG inhibition liability (0.303 and 0.376), which is good.

**Microsomal Clearance:** Ligand A (26.593) has lower microsomal clearance than Ligand B (28.121), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand B (-24.973) has a significantly longer in vitro half-life than Ligand A (6.988). This is a major advantage.

**P-gp Efflux:** Ligand A (0.129) has lower P-gp efflux than Ligand B (0.059), which is favorable for CNS penetration.

**Binding Affinity:** Ligand A (-9.6 kcal/mol) has a slightly better binding affinity than Ligand B (-8.5 kcal/mol). This difference of 1.1 kcal/mol is significant, but must be weighed against the other factors.

**Overall Assessment:**

Ligand A has better affinity, QED, solubility, and metabolic stability, and lower P-gp efflux. However, it has a significantly higher DILI risk and lower BBB penetration. Ligand B excels in BBB penetration and has a much better safety profile (lower DILI), and a longer half-life. Given the CNS target (DRD2), BBB penetration is paramount. The 1.1 kcal/mol difference in binding affinity is likely surmountable with further optimization, whereas mitigating the DILI risk of Ligand A could be challenging.

Output:
1
2025-04-17 05:15:44,399 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (354.466 and 337.379 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (78.43) is significantly better than Ligand B (91.32). For CNS targets, we want TPSA <= 90, so Ligand A is preferable.

**3. logP:** Both ligands have good logP values (2.077 and 2.622), falling within the optimal 1-3 range.

**4. H-Bond Donors:** Both have 3 HBD, which is acceptable.

**5. H-Bond Acceptors:** Ligand A has 3 HBA, while Ligand B has 4. Both are within the acceptable limit of <=10.

**6. QED:** Both ligands have similar QED values (0.655 and 0.578), both above the 0.5 threshold, indicating good drug-likeness.

**7. DILI:** Ligand A (22.761) has a much lower DILI risk than Ligand B (51.842). This is a significant advantage for Ligand A.

**8. BBB:** Ligand A (77.821) has a considerably higher BBB penetration percentile than Ligand B (54.478).  This is *critical* for a CNS target like DRD2, and favors Ligand A strongly.

**9. Caco-2 Permeability:** Ligand A (-4.789) and Ligand B (-5.152) both have negative values, which is unusual and suggests poor permeability. However, the scale is not specified, so it's hard to interpret.

**10. Aqueous Solubility:** Ligand A (-2.699) and Ligand B (-4.317) both have negative solubility values, indicating poor solubility.

**11. hERG Inhibition:** Ligand A (0.521) has a slightly higher hERG risk than Ligand B (0.202), but both are relatively low.

**12. Microsomal Clearance:** Ligand B (31.72) has a lower microsomal clearance than Ligand A (24.959), suggesting better metabolic stability.

**13. In vitro Half-Life:** Ligand B (-21.984) has a negative half-life, which is not possible. This is a major red flag and suggests a data error or a very rapidly metabolized compound. Ligand A (26.055) has a reasonable half-life.

**14. P-gp Efflux:** Ligand A (0.078) has lower P-gp efflux than Ligand B (0.044), which is desirable for CNS penetration.

**15. Binding Affinity:** Ligand B (-9.8 kcal/mol) has a significantly stronger binding affinity than Ligand A (-8.0 kcal/mol). This is a substantial advantage for Ligand B.

**Overall Assessment:**

While Ligand B has a better binding affinity, the issues with its negative in vitro half-life and higher DILI risk, coupled with significantly lower BBB penetration, make it a less desirable candidate. Ligand A, despite slightly weaker binding, has a much more favorable ADME profile, particularly its BBB penetration, lower DILI risk, and reasonable half-life. Given the CNS target, BBB penetration is paramount.

Output:
0
2025-04-17 05:15:44,399 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (343.47 and 348.45 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (38.77) is excellent, well below the 90 A^2 threshold for CNS targets. Ligand B (95.42) is significantly higher, exceeding the ideal range and potentially hindering BBB penetration.

**logP:** Ligand A (3.764) is at the upper end of the optimal range (1-3), while Ligand B (1.82) is at the lower end. While both are within the range, a higher logP can be beneficial for GPCR ligands.

**H-Bond Donors/Acceptors:** Ligand A (0 HBD, 4 HBA) is favorable. Ligand B (2 HBD, 5 HBA) is also acceptable, but slightly higher counts could impact permeability.

**QED:** Both ligands have good QED scores (0.763 and 0.846), indicating drug-likeness.

**DILI:** Ligand A (18.19%) has a much lower DILI risk than Ligand B (39.74%), making it safer.

**BBB:** Ligand A (83.25%) shows excellent BBB penetration, crucial for a CNS target like DRD2. Ligand B (61.38%) is considerably lower, raising concerns about reaching the target in the brain.

**Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and suggests a potential issue with the calculation or data. However, the magnitude of negativity is similar.

**Aqueous Solubility:** Both have negative solubility values, which is also unusual.

**hERG:** Both ligands have very low hERG inhibition liability (0.906 and 0.189), which is excellent.

**Microsomal Clearance:** Ligand A (91.76 mL/min/kg) has higher clearance than Ligand B (22.72 mL/min/kg), suggesting lower metabolic stability.

**In vitro Half-Life:** Both have negative half-life values, which is also unusual.

**P-gp Efflux:** Both have low P-gp efflux liability (0.562 and 0.036), which is positive for CNS penetration.

**Binding Affinity:** Both ligands have similar and strong binding affinities (-8.8 and -8.5 kcal/mol). The difference is less than the 1.5 kcal/mol threshold.

**Conclusion:**

Considering the GPCR-specific priorities, Ligand A is significantly more promising. Its superior TPSA, BBB penetration, and lower DILI risk outweigh the slightly higher microsomal clearance. While both have unusual solubility and half-life values, the other properties of Ligand A make it a better candidate for further development targeting DRD2.

Output:
1
2025-04-17 05:15:44,399 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (340.423 and 349.475 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (62.4) is better than Ligand B (64.09). Both are below the 90 A^2 threshold for CNS targets, which is good.

**logP:** Ligand A (3.376) is within the optimal 1-3 range. Ligand B (0.857) is slightly below 1, which could potentially hinder permeation.

**H-Bond Donors:** Both ligands have 1 HBD, which is acceptable.

**H-Bond Acceptors:** Ligand A has 3 HBA, and Ligand B has 4. Both are below the 10 threshold.

**QED:** Ligand A (0.871) has a slightly better QED than Ligand B (0.765), indicating a more drug-like profile.

**DILI:** Ligand A (59.984) has a higher DILI risk than Ligand B (7.135). This is a significant drawback for Ligand A.

**BBB:** Ligand A (75.107) has a significantly better BBB penetration percentile than Ligand B (52.191). This is crucial for a CNS target like DRD2.

**Caco-2 Permeability:** Ligand A (-4.631) has a worse Caco-2 permeability than Ligand B (-4.786). Both are negative, indicating poor permeability.

**Aqueous Solubility:** Ligand A (-4.848) is slightly better than Ligand B (-0.771). Both are negative, indicating poor solubility.

**hERG Inhibition:** Ligand A (0.738) has a slightly lower hERG inhibition liability than Ligand B (0.363), which is favorable.

**Microsomal Clearance:** Ligand A (78.001) has a higher microsomal clearance than Ligand B (24.78), suggesting lower metabolic stability.

**In vitro Half-Life:** Ligand A (-32.378) has a much shorter in vitro half-life than Ligand B (-0.526). This is a significant disadvantage for Ligand A.

**P-gp Efflux:** Ligand A (0.482) has a lower P-gp efflux liability than Ligand B (0.039), which is beneficial for CNS penetration.

**Binding Affinity:** Both ligands have very similar binding affinities (-7.7 and -7.6 kcal/mol), which are both excellent and meet the > -7.0 kcal/mol criterion. The difference is negligible.

**Overall Assessment:**

Ligand A excels in BBB penetration and P-gp efflux, which are critical for CNS GPCR targets. However, it suffers from higher DILI risk, higher microsomal clearance (lower metabolic stability), and a shorter half-life. Ligand B has a much better safety profile (lower DILI) and better metabolic stability, but its BBB penetration is significantly lower, and its logP is suboptimal.

Considering the balance, the better BBB penetration of Ligand A is a strong advantage for a CNS target, and the affinity is comparable. While the DILI risk is a concern, it might be mitigated with further structural modifications. The lower metabolic stability and half-life are also concerns, but potentially addressable. The poor logP of Ligand B is a more fundamental issue.

Output:
0
2025-04-17 05:15:44,399 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 drug candidates, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (352.431 and 365.419 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (95.94) is better than Ligand B (127.87). For CNS targets, we want TPSA <= 90, so Ligand A is closer to this threshold. Ligand B is significantly higher, potentially hindering BBB penetration.

**3. logP:** Ligand A (0.105) is quite low, potentially causing permeability issues. Ligand B (1.581) is within the optimal 1-3 range. This is a significant advantage for Ligand B.

**4. H-Bond Donors:** Both ligands have 2 HBD, which is acceptable (<=5).

**5. H-Bond Acceptors:** Ligand A has 5 HBA, while Ligand B has 9. Both are within the acceptable range (<=10), but Ligand A is slightly better.

**6. QED:** Ligand A (0.646) has a better QED score than Ligand B (0.563), indicating better overall drug-likeness.

**7. DILI:** Ligand A (23.846) has a much lower DILI risk than Ligand B (84.839). This is a major advantage for Ligand A.

**8. BBB:** Ligand A (42.226) has a lower BBB penetration percentile than Ligand B (70.027). For a CNS target like DRD2, >70 is desirable, making Ligand B significantly better in this regard.

**9. Caco-2 Permeability:** Ligand A (-4.989) has poor Caco-2 permeability, while Ligand B (-5.222) is also poor, but slightly better.

**10. Aqueous Solubility:** Ligand A (-0.927) has poor solubility, while Ligand B (-4.117) is even worse.

**11. hERG Inhibition:** Ligand A (0.042) has very low hERG inhibition risk, while Ligand B (0.29) is slightly higher, but still relatively low.

**12. Microsomal Clearance:** Ligand A (7.87) has lower microsomal clearance than Ligand B (35.671), suggesting better metabolic stability.

**13. In vitro Half-Life:** Ligand A (1.601) has a shorter half-life than Ligand B (29.244), which is a significant advantage for Ligand B.

**14. P-gp Efflux:** Ligand A (0.04) has very low P-gp efflux liability, while Ligand B (0.194) is higher. This is a strong advantage for Ligand A.

**15. Binding Affinity:** Ligand A (-8.5 kcal/mol) has a slightly better binding affinity than Ligand B (-7.7 kcal/mol). While both are good, the 1.5 kcal/mol difference could be significant.

**Overall Assessment:**

Ligand A excels in DILI risk, P-gp efflux, hERG inhibition, and binding affinity, and has a better TPSA and QED. However, its low logP, poor Caco-2 permeability and BBB penetration are major drawbacks for a CNS target.

Ligand B has a better logP, BBB penetration, and in vitro half-life. However, it has a higher DILI risk, higher P-gp efflux, and lower QED.

Considering the GPCR-specific priorities, BBB penetration is crucial for CNS targets. Ligand B's significantly higher BBB (70.027) outweighs its other drawbacks, especially given its acceptable logP. The better half-life is also a significant plus. While the DILI risk is higher, it's not excessively so. The slightly weaker binding affinity can potentially be optimized in further iterations.

Output:
1
2025-04-17 05:15:44,399 - INFO - Batch 183 complete. Total preferences: 2928
2025-04-17 05:15:44,399 - INFO - Processing batch 184/512...
2025-04-17 05:16:30,290 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (346.387 and 347.459 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (116.34) is higher than the preferred <90 for CNS targets, while Ligand B (66.65) is well within the range. This is a significant advantage for Ligand B.

**logP:** Ligand A (1.126) is at the lower end of optimal, potentially impacting permeability. Ligand B (2.803) is well within the 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A has 4 HBD and 5 HBA, acceptable values. Ligand B has 0 HBD and 4 HBA, also acceptable.

**QED:** Both ligands have good QED scores (0.535 and 0.742), indicating drug-likeness.

**DILI:** Ligand A (47.732) has a moderate DILI risk, while Ligand B (21.404) has a low DILI risk.

**BBB:** Ligand A (25.242) has very poor predicted BBB penetration. Ligand B (81.737) has excellent predicted BBB penetration, a crucial factor for a CNS target like DRD2.

**Caco-2 Permeability:** Ligand A (-5.901) shows poor permeability. Ligand B (-4.595) is slightly better, but still not ideal.

**Aqueous Solubility:** Both ligands have poor aqueous solubility (-3.257 and -2.109). This could pose formulation challenges.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.342 and 0.155).

**Microsomal Clearance:** Ligand A (9.271) has lower clearance, suggesting better metabolic stability than Ligand B (50.488).

**In vitro Half-Life:** Ligand A (-23.325) has a very long half-life, which is positive. Ligand B (14.766) has a moderate half-life.

**P-gp Efflux:** Ligand A (0.037) shows very low P-gp efflux, which is favorable for CNS penetration. Ligand B (0.142) shows slightly higher P-gp efflux, but still relatively low.

**Binding Affinity:** Ligand B (-7.1 kcal/mol) has a significantly stronger binding affinity than Ligand A (-8.6 kcal/mol). While both are good, the 1.5 kcal/mol difference is substantial and can outweigh some ADME drawbacks.

**Overall Assessment:**

Ligand B is the superior candidate. Its excellent BBB penetration, favorable logP, lower DILI risk, and significantly stronger binding affinity outweigh its slightly higher microsomal clearance and moderate Caco-2 permeability. Ligand A's poor BBB penetration and permeability are major drawbacks for a CNS target, despite its metabolic stability and long half-life. The affinity difference is also important, and Ligand B's affinity is strong enough to compensate for its other weaknesses.

Output:
1
2025-04-17 05:16:30,291 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (389.905 Da) is slightly higher than Ligand B (350.507 Da), but both are acceptable.

**TPSA:** Ligand A (78.95) is better than Ligand B (47.1). For CNS targets, we want TPSA <= 90, and ideally lower. Both are well within this range, but Ligand B is closer to the ideal.

**logP:** Both ligands have good logP values (Ligand A: 1.414, Ligand B: 0.872), falling within the optimal 1-3 range.

**H-Bond Donors:** Ligand A has 1 HBD, while Ligand B has 0. Both are acceptable (<=5).

**H-Bond Acceptors:** Both ligands have 4 HBAs, which is within the acceptable range (<=10).

**QED:** Both ligands have similar QED values (Ligand A: 0.797, Ligand B: 0.713), indicating good drug-like properties (>=0.5).

**DILI:** Ligand A (58.627) has a higher DILI risk than Ligand B (5.584). This is a significant advantage for Ligand B.

**BBB:** Ligand B (61.535) has a slightly better BBB penetration percentile than Ligand A (59.093), though both are below the desirable >70 for CNS targets.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.887 and -4.808), which is unusual and suggests poor permeability. This is a concern for both.

**Aqueous Solubility:** Both ligands have negative solubility values (-2.808 and -0.13), which is also concerning and suggests poor solubility. Ligand B is slightly better.

**hERG Inhibition:** Both ligands show low hERG inhibition liability (Ligand A: 0.529, Ligand B: 0.421), which is good.

**Microsomal Clearance:** Ligand A (25.187) has a higher microsomal clearance than Ligand B (-5.448). This means Ligand B is likely to have better metabolic stability.

**In vitro Half-Life:** Ligand B (3.028) has a longer in vitro half-life than Ligand A (-5.507). This is a significant advantage for Ligand B.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (Ligand A: 0.088, Ligand B: 0.017). Ligand B is slightly better.

**Binding Affinity:** Ligand B (-7.8 kcal/mol) has a slightly better binding affinity than Ligand A (-7.6 kcal/mol). While the difference is small, it's within the range where it could outweigh minor ADME drawbacks.

**Overall Assessment:**

Ligand B is the better candidate. It has a significantly lower DILI risk, better metabolic stability (lower Cl_mic, longer t1/2), slightly better BBB penetration, and a slightly better binding affinity. While both have concerning Caco-2 and solubility values, the ADME profile of Ligand B is superior, especially regarding safety (DILI) and metabolic stability. The small advantage in binding affinity further supports choosing Ligand B.

Output:
1
2025-04-17 05:16:30,291 - INFO - Okay, let's analyze these two ligands for their potential as DRD2 drug candidates. DRD2 is a GPCR in the CNS, so BBB penetration, logP, Pgp efflux, TPSA, and binding affinity are key.

**Ligand A:** [343.427, 75.44, 2.15, 1, 4, 0.831, 31.136, 67.235, -4.664, -3.081, 0.093, 5.664, -2.317, 0.057, -7.5]
**Ligand B:** [344.459, 75.19, 2.641, 1, 4, 0.609, 41.877, 70.88, -5.08, -2.149, 0.342, 37.09, -13.804, 0.154, -8.3]

Here's a breakdown comparing each property:

1. **MW:** Both ligands are within the ideal range (343-344 Da).
2. **TPSA:** Both are good (75.44 & 75.19), and below the 90 A^2 threshold for CNS targets.
3. **logP:** Both are within the optimal range (2.15 & 2.641). Ligand B is slightly higher, which *could* be beneficial for membrane permeability, but isn't a huge difference.
4. **HBD:** Both have 1 HBD, which is good.
5. **HBA:** Both have 4 HBA, which is good.
6. **QED:** Ligand A (0.831) is significantly better than Ligand B (0.609), indicating a more drug-like profile.
7. **DILI:** Ligand A (31.136) has a much lower DILI risk than Ligand B (41.877). This is a significant advantage.
8. **BBB:** Ligand B (70.88) has a better BBB percentile than Ligand A (67.235). While both are above the 70% threshold, the difference is noticeable.
9. **Caco-2:** Ligand A (-4.664) has a worse Caco-2 value than Ligand B (-5.08). Lower values are less desirable.
10. **Solubility:** Ligand B (-2.149) has better solubility than Ligand A (-3.081).
11. **hERG:** Both have very low hERG risk (0.093 and 0.342).
12. **Cl_mic:** Ligand A (5.664) has a lower microsomal clearance than Ligand B (37.09), suggesting better metabolic stability.
13. **t1/2:** Ligand B (-13.804) has a much longer in vitro half-life than Ligand A (-2.317). This is a significant advantage.
14. **Pgp:** Both have low Pgp efflux liability (0.057 and 0.154).
15. **Binding Affinity:** Ligand B (-8.3) has a slightly better binding affinity than Ligand A (-7.5). The difference is 0.8 kcal/mol, which is a reasonable advantage.

**Overall Assessment:**

Ligand B has a better BBB, longer half-life, better solubility, and slightly better affinity. However, Ligand A has a significantly better QED score, much lower DILI risk, and better metabolic stability.

Considering the GPCR-specific priorities, the BBB is important, but not at the expense of safety (DILI) and metabolic stability. The 0.8 kcal/mol difference in binding affinity is not large enough to outweigh the substantial benefits of Ligand A's improved safety profile and metabolic stability. A longer half-life is desirable, but can often be improved through further optimization.

Therefore, I believe **Ligand A** is the more promising drug candidate.

1
2025-04-17 05:16:30,291 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (345.487 and 353.482 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (43.86) is significantly better than Ligand B (47.36), both being below the 90 A^2 threshold for CNS targets.

**3. logP:** Ligand A (1.576) is within the optimal 1-3 range. Ligand B (3.545) is at the higher end of optimal, but still acceptable.

**4. H-Bond Donors:** Both have 0 HBD, which is good.

**5. H-Bond Acceptors:** Ligand A has 3 HBA, and Ligand B has 4. Both are acceptable (<=10).

**6. QED:** Both ligands have similar QED values (0.763 and 0.735), indicating good drug-likeness.

**7. DILI:** Ligand A (6.282) has a much lower DILI risk than Ligand B (12.098), which is a significant advantage.

**8. BBB:** Ligand B (95.657) has a substantially better BBB penetration percentile than Ligand A (72.741). This is a *critical* factor for a CNS target like DRD2.

**9. Caco-2 Permeability:** Ligand A (-4.692) has a worse Caco-2 permeability than Ligand B (-4.184).

**10. Aqueous Solubility:** Ligand A (-2.579) has better aqueous solubility than Ligand B (-4.096).

**11. hERG Inhibition:** Both ligands have low hERG inhibition risk (0.477 and 0.625).

**12. Microsomal Clearance:** Ligand B (75.708) has a higher microsomal clearance than Ligand A (33.835), indicating lower metabolic stability.

**13. In vitro Half-Life:** Ligand A (14.901) has a longer in vitro half-life than Ligand B (-2.854).

**14. P-gp Efflux:** Ligand A (0.013) has significantly lower P-gp efflux liability than Ligand B (0.306), which is favorable for CNS penetration.

**15. Binding Affinity:** Ligand A (-7.5) has a slightly better binding affinity than Ligand B (0.0).

**Overall Assessment:**

Ligand B excels in BBB penetration, which is paramount for a CNS GPCR target. However, it suffers from higher DILI risk, higher P-gp efflux, and lower metabolic stability. Ligand A has a better safety profile (lower DILI), better metabolic stability, lower P-gp efflux, and comparable binding affinity. The difference in BBB is significant, but the combined benefits of Ligand A's other properties, particularly the lower DILI and P-gp efflux, make it the more promising candidate. The slightly better affinity of Ligand A further supports this conclusion.

Output:
0
2025-04-17 05:16:30,291 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (363.439 and 349.475 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (100.55) is slightly above the optimal <90 for CNS targets, but still reasonable. Ligand B (74.58) is excellent, well below 90.

**3. logP:** Both ligands (2.472 and 2.115) are within the optimal 1-3 range.

**4. H-Bond Donors:** Ligand A (3) and Ligand B (2) are both acceptable, below the threshold of 5.

**5. H-Bond Acceptors:** Ligand A (6) and Ligand B (4) are both acceptable, below the threshold of 10.

**6. QED:** Both ligands have good QED scores (0.685 and 0.825), indicating drug-like properties.

**7. DILI:** Ligand A (84.102) has a higher DILI risk than Ligand B (34.703). This is a significant negative for Ligand A.

**8. BBB:** Ligand B (64.948) has a better BBB penetration percentile than Ligand A (49.903). While neither is >70, Ligand B is considerably better. This is crucial for a CNS target like DRD2.

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.821 and -4.778), which is unusual and suggests poor permeability. This is a concern for both.

**10. Aqueous Solubility:** Both ligands have negative solubility values (-3.567 and -2.24). This is also a concern, indicating poor solubility.

**11. hERG Inhibition:** Both ligands have low hERG inhibition risk (0.298 and 0.495).

**12. Microsomal Clearance:** Ligand A (77.238) has higher microsomal clearance than Ligand B (18.911), indicating lower metabolic stability.

**13. In vitro Half-Life:** Ligand B (48.202) has a longer in vitro half-life than Ligand A (24.208).

**14. P-gp Efflux:** Both ligands have low P-gp efflux liability (0.415 and 0.093).

**15. Binding Affinity:** Ligand A (-8.9 kcal/mol) has a significantly stronger binding affinity than Ligand B (-7.8 kcal/mol). This is a 1.1 kcal/mol difference, which is substantial and can outweigh some ADME drawbacks.

**Overall Assessment:**

While Ligand A has a superior binding affinity, Ligand B is clearly the better candidate. The significantly lower DILI risk, better BBB penetration, and improved metabolic stability (lower Cl_mic and longer t1/2) of Ligand B are crucial advantages for a CNS-targeting drug. The poor Caco-2 and solubility for both are concerning, but can potentially be addressed through formulation strategies. The affinity difference, while notable, is likely surmountable with further optimization of Ligand B.

Output:
1
2025-04-17 05:16:30,291 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (364.555 and 345.447 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (32.78) is excellent, well below the 90 A^2 threshold for CNS targets. Ligand B (71.33) is higher, but still potentially acceptable, though less optimal.

**3. logP:** Ligand A (3.653) is within the optimal 1-3 range. Ligand B (1.645) is on the lower end, potentially hindering permeability.

**4. H-Bond Donors:** Both have 0 HBD, which is good.

**5. H-Bond Acceptors:** Ligand A has 4 HBA, and Ligand B has 5. Both are within the acceptable limit of 10.

**6. QED:** Both ligands have good QED scores (0.593 and 0.761), indicating drug-like properties.

**7. DILI:** Ligand A (36.138) has a lower DILI risk than Ligand B (44.591), both are acceptable.

**8. BBB:** Ligand A (73.711) has a significantly better BBB penetration percentile than Ligand B (64.521). This is a crucial advantage for a CNS target like DRD2.

**9. Caco-2 Permeability:** Both have negative Caco-2 values (-4.971 and -4.951), which is unusual and suggests poor permeability. However, these values are very close, so this isn't a major differentiator.

**10. Aqueous Solubility:** Both have negative solubility values (-3.699 and -1.698), indicating poor solubility. Again, these are similar.

**11. hERG Inhibition:** Ligand A (0.958) has a slightly higher hERG risk than Ligand B (0.124). This is a potential concern for Ligand A.

**12. Microsomal Clearance:** Ligand A (109.962) has a higher microsomal clearance than Ligand B (17.768), indicating lower metabolic stability.

**13. In vitro Half-Life:** Ligand B (6.804) has a longer in vitro half-life than Ligand A (-28.326).

**14. P-gp Efflux:** Ligand A (0.799) has a slightly lower P-gp efflux liability than Ligand B (0.071), which is favorable for CNS penetration.

**15. Binding Affinity:** Both ligands have excellent binding affinities (-7.8 and -7.0 kcal/mol). Ligand A is slightly better, but the difference is less than 1.5 kcal/mol.

**Overall Assessment:**

Ligand A excels in TPSA and BBB penetration, which are critical for CNS GPCR targets. While it has slightly higher hERG risk and lower metabolic stability, its superior BBB penetration and comparable affinity outweigh these drawbacks. Ligand B has better metabolic stability and lower hERG risk, but its significantly lower BBB penetration is a major disadvantage for a DRD2 ligand.

Output:
1
2025-04-17 05:16:30,291 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (346.299 and 351.407 Da) fall within the ideal range of 200-500 Da.

**TPSA:** Ligand A (125.59) is slightly above the optimal <90 for CNS targets, but still reasonable. Ligand B (104.73) is well within the desired range.

**logP:** Ligand A (1.288) is within the optimal 1-3 range. Ligand B (-0.068) is slightly below 1, which *could* indicate permeability issues, though not drastically.

**H-Bond Donors/Acceptors:** Both ligands have acceptable HBD (1) and HBA (8 for A, 6 for B) counts, well below the thresholds of 5 and 10, respectively.

**QED:** Both ligands have good QED scores (0.491 and 0.625), indicating reasonable drug-likeness. Ligand B is slightly better.

**DILI:** Ligand A (88.368) has a higher DILI risk than Ligand B (59.48). This is a significant negative for Ligand A.

**BBB:** Ligand A (70.143) has a good BBB penetration percentile, meeting the >70 threshold for CNS targets. Ligand B (56.417) is lower, which is a concern for CNS penetration.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.948 and -4.945), which is unusual and difficult to interpret without further context. However, it suggests poor permeability.

**Aqueous Solubility:** Both ligands have very poor aqueous solubility (-3.95 and -1.494). This is a significant drawback for both.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.312 and 0.234).

**Microsomal Clearance:** Ligand A (40.63) has lower microsomal clearance than Ligand B (44.466), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand B (-32.995) has a significantly longer in vitro half-life than Ligand A (-3.312). This is a major advantage for Ligand B.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.234 and 0.012), which is good for CNS exposure. Ligand B is slightly better.

**Binding Affinity:** Ligand B (-7.2 kcal/mol) has a significantly stronger binding affinity than Ligand A (-8.8 kcal/mol). This is a crucial advantage, exceeding the 1.5 kcal/mol difference threshold.

**Overall Assessment:**

Ligand B is the more promising candidate. While its logP is slightly low and Caco-2 permeability is poor, its significantly stronger binding affinity (-7.2 vs -8.8 kcal/mol), better BBB penetration (56.4 vs 70.1, though still suboptimal), lower DILI risk (59.5 vs 88.4), and much longer in vitro half-life outweigh the minor drawbacks. The poor solubility is a concern for both, but can be addressed with formulation strategies. The stronger affinity of Ligand B suggests it may be more potent and require a lower dose, potentially mitigating solubility issues.

Output:
1
2025-04-17 05:16:30,291 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (361.442 and 365.459 Da) fall comfortably within the ideal 200-500 Da range.

**TPSA:** Ligand A (63.25) is significantly better than Ligand B (101.53). For CNS targets, we want TPSA <= 90, so Ligand A is preferable.

**logP:** Ligand A (2.724) is optimal (1-3). Ligand B (-0.36) is too low, potentially hindering permeation. This is a significant drawback for Ligand B.

**H-Bond Donors/Acceptors:** Ligand A (HBD=2, HBA=5) and Ligand B (HBD=1, HBA=6) both have acceptable counts.

**QED:** Both ligands have good QED scores (0.828 and 0.768, respectively), indicating generally drug-like properties.

**DILI:** Ligand A (61.807) has a higher DILI risk than Ligand B (40.209), but both are reasonably acceptable.

**BBB:** Ligand A (70.531) has a good BBB penetration percentile, exceeding the 70% threshold for CNS targets. Ligand B (37.224) is considerably lower and less desirable.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.194 and -5.515), which is unusual and suggests poor permeability. However, these values are on a log scale and are difficult to interpret without knowing the original units.

**Aqueous Solubility:** Both ligands have negative solubility values (-3.366 and -2.303), indicating poor aqueous solubility. This could be a formulation challenge.

**hERG Inhibition:** Ligand A (0.618) has a slightly higher hERG risk than Ligand B (0.055), but both are relatively low.

**Microsomal Clearance:** Ligand A (28.607) has higher clearance than Ligand B (4.079), suggesting lower metabolic stability.

**In vitro Half-Life:** Ligand A (16.392) has a longer half-life than Ligand B (-0.945), which is preferable.

**P-gp Efflux:** Ligand A (0.124) has lower P-gp efflux than Ligand B (0.014), which is favorable for CNS penetration.

**Binding Affinity:** Ligand B (-7.5 kcal/mol) has a significantly stronger binding affinity than Ligand A (-9.0 kcal/mol). This is a substantial advantage.

**Overall Assessment:**

While Ligand B has a superior binding affinity, its significantly negative logP and low BBB penetration are major concerns for a CNS target like DRD2. Ligand A, despite a slightly weaker affinity, has a much better logP, TPSA, and BBB score, making it more likely to reach the target in the brain. The slightly higher DILI and clearance for Ligand A are less concerning than the permeability issues of Ligand B. The negative Caco-2 and solubility values are problematic for both, but can potentially be addressed through formulation strategies.

Output:
1
2025-04-17 05:16:30,291 - INFO - Okay, let's analyze these two ligands for their potential as DRD2 drug candidates. DRD2 is a GPCR in the CNS, so BBB penetration, logP, Pgp efflux, TPSA, and binding affinity are key.

**Ligand A:** [399.288, 38.5, 4.505, 0, 4, 0.612, 58.705, 81.698, -5.18, -4.802, 0.922, 97.189, -32.821, 0.792, -8.2]
**Ligand B:** [345.399, 106.57, 1.167, 2, 5, 0.833, 33.695, 67.274, -4.819, -3.396, 0.47, 23.186, 18.498, 0.028, -8.2]

**1. Molecular Weight:** Both are within the ideal range (200-500 Da). Ligand A (399.288) is slightly higher, but acceptable.
**2. TPSA:** Ligand A (38.5) is excellent for CNS penetration (well below 90). Ligand B (106.57) is higher, but still potentially acceptable, though less ideal.
**3. logP:** Ligand A (4.505) is a bit high, potentially leading to solubility issues and off-target interactions. Ligand B (1.167) is closer to the optimal range, but on the lower side, which might affect permeability.
**4. H-Bond Donors:** Ligand A (0) is good. Ligand B (2) is acceptable.
**5. H-Bond Acceptors:** Ligand A (4) is good. Ligand B (5) is acceptable.
**6. QED:** Both are good (A: 0.612, B: 0.833), indicating drug-like properties. Ligand B is slightly better.
**7. DILI:** Ligand A (58.705) is moderate risk. Ligand B (33.695) is low risk, a significant advantage.
**8. BBB:** Ligand A (81.698) is very good, exceeding the 70% threshold. Ligand B (67.274) is below this threshold, which is a concern for a CNS target.
**9. Caco-2:** Both are negative, which is unusual and suggests a potential issue with the data or a very poor permeability.
**10. Solubility:** Both are negative, which is also unusual and suggests a potential issue with the data or a very poor solubility.
**11. hERG:** Both are low risk (A: 0.922, B: 0.47).
**12. Cl_mic:** Ligand A (97.189) has high metabolic clearance, suggesting rapid metabolism. Ligand B (23.186) has lower clearance, indicating better metabolic stability.
**13. t1/2:** Ligand A (-32.821) has a very short half-life, which is undesirable. Ligand B (18.498) has a better half-life.
**14. Pgp:** Ligand A (0.792) has moderate P-gp efflux. Ligand B (0.028) has very low P-gp efflux, which is a significant advantage for CNS penetration.
**15. Binding Affinity:** Both have the same binding affinity (-8.2 kcal/mol), which is excellent.

**Overall Assessment:**

While both ligands have excellent binding affinity, Ligand B is the more promising candidate. Its lower DILI risk, lower P-gp efflux, and better metabolic stability (lower Cl_mic, longer t1/2) outweigh the slightly higher TPSA and lower logP. The BBB score for Ligand B is a concern, but the low Pgp efflux could help to mitigate this. The negative values for Caco-2 and solubility are concerning and would require further investigation. Ligand A's high metabolic clearance and short half-life are major drawbacks.

Output:
1
2025-04-17 05:16:30,292 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (345.443 & 358.435 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (61.88) is significantly better than Ligand B (94.17). For CNS targets, we prefer TPSA <= 90, so Ligand A is much more favorable.

**3. logP:** Ligand A (1.65) is within the optimal 1-3 range. Ligand B (0.344) is slightly low, potentially hindering permeation.

**4. H-Bond Donors:** Both ligands have 1 HBD, which is acceptable.

**5. H-Bond Acceptors:** Ligand A has 3 HBA, while Ligand B has 6. Both are within the acceptable limit of <= 10, but Ligand A is preferable.

**6. QED:** Ligand A (0.906) has a much better QED score than Ligand B (0.566), indicating a more drug-like profile.

**7. DILI:** Ligand A (34.393) has a lower DILI risk than Ligand B (26.638), suggesting better hepatotoxicity potential.

**8. BBB:** Ligand A (76.735) has a significantly higher BBB percentile than Ligand B (60.062). This is *critical* for a CNS target like DRD2.

**9. Caco-2 Permeability:** Both have negative values, which is unusual. However, the magnitude of Ligand A (-4.466) is less negative than Ligand B (-4.727), suggesting slightly better permeability.

**10. Aqueous Solubility:** Both have negative values, which is unusual. However, the magnitude of Ligand A (-1.508) is less negative than Ligand B (-0.802), suggesting slightly better solubility.

**11. hERG Inhibition:** Both ligands show very low hERG inhibition liability (0.247 and 0.1 respectively), which is excellent.

**12. Microsomal Clearance:** Ligand A (-2.32) has a lower (better) microsomal clearance than Ligand B (56.776), indicating greater metabolic stability.

**13. In vitro Half-Life:** Ligand A (-4.835) has a longer half-life than Ligand B (-6.743), which is desirable.

**14. P-gp Efflux:** Both ligands show very low P-gp efflux liability (0.041 and 0.01 respectively), which is excellent.

**15. Binding Affinity:** Ligand B (-6.6 kcal/mol) has a significantly stronger binding affinity than Ligand A (-0.0 kcal/mol). This is a substantial advantage.

**Overall Assessment:**

While Ligand B has a much stronger binding affinity, Ligand A is superior in almost every other ADME-Tox property, *especially* BBB penetration (76.735 vs 60.062) and TPSA (61.88 vs 94.17), both of which are crucial for CNS GPCR targets. The significantly better QED, DILI, metabolic stability, and half-life of Ligand A also contribute to its favorability. The difference in binding affinity, while large, might be overcome with further optimization of Ligand A, while improving the ADME profile of Ligand B would be much more challenging given its already high TPSA and lower BBB.

Output:
1
2025-04-17 05:16:30,292 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (350.503 and 375.416 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (69.64) is better than Ligand B (47.48). Both are below the 90 A^2 threshold for CNS targets, which is excellent.

**logP:** Both ligands have good logP values (2.471 and 3.374), falling within the optimal 1-3 range. Ligand B is slightly higher, which could potentially lead to some solubility issues, but is still acceptable.

**H-Bond Donors/Acceptors:** Ligand A has 2 HBD and 3 HBA, while Ligand B has 0 HBD and 6 HBA. Both are within acceptable limits (<=5 HBD and <=10 HBA).

**QED:** Both ligands have similar QED values (0.773 and 0.673), indicating good drug-likeness.

**DILI:** Ligand A (13.494) has a significantly lower DILI risk than Ligand B (31.95). This is a major advantage for Ligand A.

**BBB:** Ligand B (87.708) has a much higher BBB penetration percentile than Ligand A (62.078). This is a critical factor for a CNS target like DRD2, and favors Ligand B.

**Caco-2 Permeability:** Both have negative Caco-2 values (-4.816 and -4.448), which is unusual and suggests poor permeability. However, these values are on a scale where negative values are possible and don't necessarily disqualify the compounds.

**Aqueous Solubility:** Both have negative solubility values (-3.508 and -3.604), indicating poor aqueous solubility. This is a concern for both, but potentially manageable with formulation strategies.

**hERG Inhibition:** Ligand A (0.375) shows lower hERG inhibition liability than Ligand B (0.732), which is a positive attribute.

**Microsomal Clearance:** Ligand B (75.336) has a higher microsomal clearance than Ligand A (65.045), indicating lower metabolic stability.

**In vitro Half-Life:** Ligand A (-1.455) has a longer in vitro half-life than Ligand B (-4.967).

**P-gp Efflux:** Ligand A (0.25) has lower P-gp efflux liability than Ligand B (0.173), which is beneficial for CNS penetration.

**Binding Affinity:** Ligand A (-7.8 kcal/mol) has a significantly stronger binding affinity than Ligand B (-6.5 kcal/mol). This 1.3 kcal/mol difference is substantial and can outweigh some ADME drawbacks.

**Overall Assessment:**

Ligand A excels in binding affinity, DILI risk, hERG inhibition, and metabolic stability (lower Cl_mic, longer t1/2). Ligand B's main advantage is its superior BBB penetration. However, the substantial difference in binding affinity (-7.8 vs -6.5 kcal/mol) and the lower DILI risk of Ligand A are compelling. While BBB is important, a significantly stronger binder is more likely to be effective *in vivo*, and the BBB penetration of Ligand A (62.078) is still reasonable. The poor Caco-2 and solubility for both compounds are drawbacks that would need to be addressed during lead optimization, but the potency advantage of Ligand A is more critical at this stage.

Output:
0
2025-04-17 05:16:30,292 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (347.46 and 348.49 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (61.88) is significantly better than Ligand B (69.64). For CNS targets, we want TPSA <= 90, and ideally closer to 60. Ligand A is much closer to this ideal.

**3. logP:** Both ligands have acceptable logP values (1.815 and 2.247), falling within the 1-3 range.

**4. H-Bond Donors:** Ligand A (1) is preferable to Ligand B (2). Fewer HBDs generally improve permeability.

**5. H-Bond Acceptors:** Both ligands have 3 HBA, which is acceptable.

**6. QED:** Ligand A (0.854) has a substantially higher QED than Ligand B (0.723), indicating a more drug-like profile.

**7. DILI:** Ligand A (26.87) has a much lower DILI risk than Ligand B (15.01). Both are below 40, which is good, but A is significantly better.

**8. BBB:** Ligand A (77.90) has a much better BBB penetration percentile than Ligand B (45.13). For a CNS target like DRD2, >70 is desirable, and A is closer to that threshold.

**9. Caco-2 Permeability:** Ligand A (-4.549) is better than Ligand B (-4.859), suggesting slightly better intestinal absorption.

**10. Aqueous Solubility:** Ligand A (-1.928) is better than Ligand B (-3.004), indicating better solubility.

**11. hERG Inhibition:** Both ligands have low hERG inhibition risk (0.447 and 0.266).

**12. Microsomal Clearance:** Ligand A (41.5) has slightly better metabolic stability than Ligand B (38.46).

**13. In vitro Half-Life:** Ligand A (-9.498) has a significantly longer half-life than Ligand B (4.96).

**14. P-gp Efflux:** Ligand A (0.054) has much lower P-gp efflux liability than Ligand B (0.127). Lower P-gp efflux is crucial for CNS penetration.

**15. Binding Affinity:** Both ligands have strong binding affinities (-9.2 and -8.1 kcal/mol). Ligand A is 1.1 kcal/mol better, which is a substantial difference and can outweigh some ADME drawbacks.

**Overall Assessment:**

Ligand A consistently outperforms Ligand B across most critical parameters, especially those prioritized for GPCRs targeting the CNS. The significantly better BBB penetration, lower P-gp efflux, higher QED, lower DILI risk, and longer half-life, combined with a superior binding affinity, make Ligand A the more promising drug candidate.

Output:
1
2025-04-17 05:16:30,292 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B based on the provided guidelines, prioritizing GPCR-specific properties (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (348.403 Da) is slightly lower, which could be beneficial for permeability.

**TPSA:** Ligand B (88.16) is significantly better than Ligand A (104.65). For CNS targets, TPSA < 90 is preferred, and Ligand B meets this criterion while Ligand A is close but less desirable.

**logP:** Ligand B (1.989) is within the optimal range (1-3), while Ligand A (-0.098) is slightly below 1, potentially hindering permeation.

**H-Bond Donors/Acceptors:** Both ligands have similar and acceptable HBD (2) and HBA (6/5) counts.

**QED:** Both ligands have similar and good QED scores (0.744 and 0.723).

**DILI:** Ligand A (37.922) has a much lower DILI risk than Ligand B (72.703), which is a significant advantage.

**BBB:** Ligand A (64.056) has a better BBB penetration percentile than Ligand B (59.713), although both are below the desirable >70 for CNS targets.

**Caco-2 Permeability:** Ligand A (-4.986) has a slightly better (less negative) Caco-2 permeability than Ligand B (-5.386).

**Aqueous Solubility:** Ligand B (-3.06) has worse solubility than Ligand A (-1.319).

**hERG:** Both ligands show low hERG inhibition liability, with Ligand A (0.181) being slightly better than Ligand B (0.369).

**Microsomal Clearance:** Ligand A (-3.086) has significantly lower microsomal clearance than Ligand B (14.525), indicating better metabolic stability.

**In vitro Half-Life:** Ligand A (8.057 hours) has a better in vitro half-life than Ligand B (-8.77 hours).

**P-gp Efflux:** Ligand A (0.006) has much lower P-gp efflux liability than Ligand B (0.137), which is crucial for CNS penetration.

**Binding Affinity:** Ligand B (-9.0 kcal/mol) has a significantly stronger binding affinity than Ligand A (-7.8 kcal/mol). This is a substantial advantage, potentially outweighing some of the ADME drawbacks.

**Overall Assessment:**

Ligand B has a superior binding affinity, which is paramount for GPCR targeting. However, it suffers from higher DILI risk, poorer BBB penetration, worse solubility, higher P-gp efflux, and higher microsomal clearance. Ligand A has better ADME properties across the board (BBB, DILI, solubility, P-gp, clearance, half-life), but its affinity is weaker.

Given the importance of CNS penetration for a DRD2 target, and the substantial difference in binding affinity, the stronger binding of Ligand B is likely to be more impactful, *provided* that the ADME issues can be addressed through further optimization. The lower TPSA of Ligand B is also favorable.

Output:
1
2025-04-17 05:16:30,292 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (362.861 Da and 386.945 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (88.32) is better than Ligand B (69.64) as it is closer to the optimal range for CNS targets (<=90).

**3. logP:** Both ligands have good logP values (2.396 and 2.668), falling within the 1-3 range.

**4. H-Bond Donors:** Both have 2 HBD, which is acceptable.

**5. H-Bond Acceptors:** Both have 4 HBA, which is acceptable.

**6. QED:** Ligand A (0.787) has a slightly better QED score than Ligand B (0.606), indicating a more drug-like profile.

**7. DILI:** Ligand A (53.625) has a higher DILI risk than Ligand B (30.71), but both are below the concerning threshold of 60.

**8. BBB:** Ligand A (72.237) has a significantly better BBB penetration percentile than Ligand B (34.742). This is a crucial factor for a CNS target like DRD2.

**9. Caco-2 Permeability:** Ligand A (-5.146) has worse Caco-2 permeability than Ligand B (-4.944), but both are negative, indicating poor permeability.

**10. Aqueous Solubility:** Ligand A (-3.425) has slightly worse solubility than Ligand B (-3.279), but both are poor.

**11. hERG Inhibition:** Both ligands have low hERG inhibition risk (0.611 and 0.708).

**12. Microsomal Clearance:** Ligand A (13.683) has lower microsomal clearance than Ligand B (60.305), suggesting better metabolic stability.

**13. In vitro Half-Life:** Ligand A (-21.623) has a negative half-life, which is concerning, while Ligand B (20.979) has a positive half-life.

**14. P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.078 and 0.212).

**15. Binding Affinity:** Ligand B (-7.3) has a significantly better binding affinity than Ligand A (-9.0). This is a substantial advantage.

**Overall Assessment:**

While Ligand A has better TPSA, QED, and metabolic stability, Ligand B's superior binding affinity (-7.3 vs -9.0 kcal/mol) and significantly better BBB penetration (34.742 vs 72.237) are decisive for a CNS GPCR target. The better affinity can potentially compensate for the slightly lower BBB and solubility. The positive half-life of Ligand B is also a major advantage.

Output:
1
2025-04-17 05:16:30,293 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (364.515 and 358.454 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Both ligands have TPSA values (67.23 and 67.87) slightly above the optimal <90 for CNS targets, but still reasonable.

**3. logP:** Ligand A (2.296) is within the optimal 1-3 range. Ligand B (1.246) is on the lower end, potentially impacting permeability.

**4. H-Bond Donors:** Both have 1 HBD, which is acceptable.

**5. H-Bond Acceptors:** Ligand A has 5 HBA, and Ligand B has 4. Both are below the acceptable limit of 10.

**6. QED:** Ligand A (0.841) has a significantly better QED score than Ligand B (0.638), indicating better overall drug-likeness.

**7. DILI:** Ligand A (63.629) has a higher DILI risk than Ligand B (9.306). This is a significant drawback for Ligand A.

**8. BBB:** Ligand B (91.043) has a much higher BBB percentile than Ligand A (56.805). This is *critical* for a CNS target like DRD2.

**9. Caco-2 Permeability:** Ligand A (-5.21) has worse Caco-2 permeability than Ligand B (-4.548), but both are negative values indicating poor permeability.

**10. Aqueous Solubility:** Ligand A (-3.239) has worse aqueous solubility than Ligand B (-1.63).

**11. hERG Inhibition:** Ligand A (0.121) has slightly higher hERG inhibition liability than Ligand B (0.389), but both are relatively low.

**12. Microsomal Clearance:** Ligand A (66.036) has higher microsomal clearance than Ligand B (10.737), suggesting lower metabolic stability.

**13. In vitro Half-Life:** Ligand B (-17.989) has a significantly longer in vitro half-life than Ligand A (56.957).

**14. P-gp Efflux:** Ligand A (0.117) has lower P-gp efflux liability than Ligand B (0.024), which is favorable for CNS penetration.

**15. Binding Affinity:** Ligand A (-8.1 kcal/mol) has a significantly stronger binding affinity than Ligand B (-6.5 kcal/mol). This is a substantial advantage.

**Overall Assessment:**

While Ligand A boasts a superior binding affinity, its significantly higher DILI risk, lower BBB penetration, and poorer metabolic stability are major concerns. Ligand B, despite a weaker affinity, presents a much more favorable ADME-Tox profile, particularly its excellent BBB penetration (91%), low DILI risk (9.3%), and longer half-life. For a CNS target like DRD2, achieving good brain exposure is paramount. The 1.6 kcal/mol difference in binding affinity may be overcome with further optimization of Ligand B, while mitigating the liabilities of Ligand A would be more challenging.

Output:
1
2025-04-17 05:16:30,293 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (342.374 and 368.499 Da) fall within the ideal 200-500 Da range.

**TPSA:** Both ligands (76.02 and 76.66) are below the 90 A^2 threshold for CNS targets, which is excellent.

**logP:** Both ligands (2.503 and 2.337) are within the optimal 1-3 range.

**H-Bond Donors:** Both have 2 HBD, well within the acceptable limit of 5.

**H-Bond Acceptors:** Ligand A has 4 HBA, and Ligand B has 5. Both are below the 10 limit.

**QED:** Ligand A (0.88) has a higher QED than Ligand B (0.622), indicating a more drug-like profile.

**DILI:** Ligand A (70.686) has a higher DILI risk than Ligand B (38.503). This is a significant negative for Ligand A.

**BBB:** Both ligands have excellent BBB penetration (70.997 and 70.648 percentile), meeting the >70% target for CNS drugs.

**Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and suggests a potential issue with the data or modeling. However, the values are similar.

**Aqueous Solubility:** Both have negative solubility values, which is also unusual. Again, values are similar.

**hERG Inhibition:** Both have low hERG inhibition risk (0.359 and 0.594).

**Microsomal Clearance:** Ligand A (4.27 mL/min/kg) has significantly lower microsomal clearance than Ligand B (32.298 mL/min/kg), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (59.045) has a much longer in vitro half-life than Ligand B (15.024), which is highly desirable.

**P-gp Efflux:** Both have very low P-gp efflux liability (0.181 and 0.185).

**Binding Affinity:** Ligand B (-7.5 kcal/mol) has a significantly stronger binding affinity than Ligand A (-10.0 kcal/mol). This is a substantial advantage.

**Overall Assessment:**

Ligand B's significantly stronger binding affinity (-7.5 vs -10.0 kcal/mol) is a major advantage that could outweigh some of its slightly less favorable ADME properties. While Ligand A has better metabolic stability and half-life, Ligand B's lower DILI risk is also a critical factor. Both have good BBB penetration and acceptable logP/TPSA values. The unusual negative solubility and Caco-2 values are a concern for both, but the difference in binding affinity is the deciding factor.

Output:
1
2025-04-17 05:16:30,293 - INFO - Batch 184 complete. Total preferences: 2944
2025-04-17 05:16:30,293 - INFO - Processing batch 185/512...
2025-04-17 05:17:13,561 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (360.523 and 342.487 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (34.59) is significantly better than Ligand B (54.18). For CNS targets, we want TPSA <= 90, and ideally lower. Ligand A is excellent, while Ligand B is approaching the upper limit and could present permeability challenges.

**3. logP:** Ligand A (4.161) is slightly higher than the optimal 1-3 range, but still acceptable. Ligand B (3.29) is within the optimal range. However, for a GPCR, a slightly higher logP isn't as detrimental as a high TPSA.

**4. H-Bond Donors:** Ligand A (0) is preferable to Ligand B (1). Fewer H-bond donors generally improve membrane permeability.

**5. H-Bond Acceptors:** Both ligands have 5 H-bond acceptors, which is within the acceptable limit of <= 10.

**6. QED:** Both ligands have similar QED values (0.742 and 0.785), indicating good drug-like properties.

**7. DILI:** Both ligands have very low DILI risk (24.195 and 23.963 percentile), which is excellent.

**8. BBB:** Ligand A (83.482) has a significantly better BBB penetration prediction than Ligand B (78.247). While both are good (>70), the difference is noticeable for a CNS target.

**9. Caco-2 Permeability:** Ligand A (-5.033) has worse Caco-2 permeability than Ligand B (-4.625). However, this is less critical than BBB for CNS targets.

**10. Aqueous Solubility:** Ligand A (-3.887) has slightly worse solubility than Ligand B (-3.325), but both are poor. Solubility can be improved with formulation.

**11. hERG Inhibition:** Both ligands have low hERG inhibition risk (0.803 and 0.686).

**12. Microsomal Clearance:** Ligand B (51.3) has lower microsomal clearance than Ligand A (58.929), suggesting better metabolic stability.

**13. In vitro Half-Life:** Ligand B (50.018) has a significantly longer in vitro half-life than Ligand A (22.883). This is a substantial advantage.

**14. P-gp Efflux:** Ligand A (0.695) has lower P-gp efflux than Ligand B (0.638), which is favorable for CNS penetration.

**15. Binding Affinity:** Ligand A (-6.5 kcal/mol) has a significantly stronger binding affinity than Ligand B (-0.0 kcal/mol). This is the most critical factor. A difference of 6.5 kcal/mol is enormous and likely outweighs the benefits of Ligand B's better metabolic stability and half-life.

**Overall Assessment:**

Ligand A is the stronger candidate despite some drawbacks (slightly higher logP, lower half-life, and poorer solubility). The significantly superior binding affinity (-6.5 vs -0.0 kcal/mol) and excellent BBB penetration (83.482) are crucial for a CNS-targeting GPCR like DRD2. The lower TPSA of Ligand A is also a significant advantage. While Ligand B has better metabolic stability, the potency difference is too large to ignore.

Output:
1
2025-04-17 05:17:13,562 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (353.39 and 342.531 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (73.86) is higher than Ligand B (41.05). For a CNS target like DRD2, TPSA should be <= 90, so both are acceptable, but B is significantly better.

**3. logP:** Ligand A (3.016) is within the optimal 1-3 range. Ligand B (4.584) is slightly above, potentially leading to solubility issues or off-target interactions.

**4. H-Bond Donors:** Both ligands have 1 HBD, which is acceptable (<=5).

**5. H-Bond Acceptors:** Ligand A has 6 HBA, and Ligand B has 4. Both are within the acceptable range (<=10).

**6. QED:** Both ligands have similar QED values (0.76 and 0.736), indicating good drug-like properties.

**7. DILI:** Ligand A (63.552) has a higher DILI risk than Ligand B (39.046). This is a significant advantage for Ligand B.

**8. BBB:** Ligand A (86.08) and Ligand B (94.339) both show good BBB penetration, but B is better (>70 desirable). This is crucial for a CNS target.

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.025 and -4.776), which is unusual and suggests poor permeability. However, these values are on a logarithmic scale, and the absolute value is more important. B has a slightly more negative value, indicating potentially worse permeability.

**10. Aqueous Solubility:** Both ligands have negative solubility values (-4.679 and -5.242), again indicating poor solubility. B is slightly worse.

**11. hERG Inhibition:** Ligand A (0.625) has a slightly higher hERG risk than Ligand B (0.936). Lower is better, so B is preferable.

**12. Microsomal Clearance:** Ligand A (112.525) has higher microsomal clearance than Ligand B (96.116), meaning it's less metabolically stable. B is better.

**13. In vitro Half-Life:** Ligand B (61.517) has a longer in vitro half-life than Ligand A (42.943), which is desirable.

**14. P-gp Efflux:** Ligand A (0.435) has higher P-gp efflux than Ligand B (0.586), meaning less CNS exposure. B is better.

**15. Binding Affinity:** Ligand A (-8.2 kcal/mol) has a significantly stronger binding affinity than Ligand B (-0.0 kcal/mol). This is a substantial advantage for A, potentially outweighing some of its ADME drawbacks.

**Overall Assessment:**

While Ligand B has better ADME properties across the board (lower DILI, better BBB, better metabolic stability, lower P-gp efflux), Ligand A's *much* stronger binding affinity (-8.2 vs -0.0 kcal/mol) is a critical factor. A difference of this magnitude is likely to be decisive, even with the slightly less favorable ADME profile of Ligand A. The improved BBB penetration of both ligands is encouraging, and the ADME issues might be addressable through further optimization.

Output:
1
2025-04-17 05:17:13,562 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (352.41 and 343.431 Da) fall comfortably within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (93.21) is slightly above the preferred <90 for CNS targets, but still reasonable. Ligand B (79.38) is excellent, well below 90.

**3. logP:** Both ligands have good logP values (1.919 and 2.013), falling within the optimal 1-3 range.

**4. H-Bond Donors:** Both have 2 HBD, which is within the acceptable limit of <=5.

**5. H-Bond Acceptors:** Ligand A has 5 HBA, and Ligand B has 6. Both are within the acceptable limit of <=10.

**6. QED:** Both ligands have high QED scores (0.844 and 0.871), indicating good drug-like properties.

**7. DILI:** Ligand A (60.605) is approaching the upper limit of acceptable DILI risk, while Ligand B (51.028) is better.

**8. BBB:** Both ligands exhibit excellent BBB penetration (80.147% and 88.445%), which is crucial for a CNS target like DRD2. Ligand B is slightly better.

**9. Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and suggests poor permeability. This is a significant concern.

**10. Aqueous Solubility:** Both have very poor aqueous solubility (-2.392 and -3.664). This is a major drawback.

**11. hERG Inhibition:** Both have very low hERG inhibition risk (0.076 and 0.61).

**12. Microsomal Clearance:** Ligand A (45.357) has lower clearance than Ligand B (63.28), suggesting better metabolic stability.

**13. In vitro Half-Life:** Ligand B has a significantly longer half-life (11.466 hours) than Ligand A (-13.549 hours). The negative value for Ligand A is concerning and likely an artifact of the prediction method.

**14. P-gp Efflux:** Both have very low P-gp efflux (0.023 and 0.039), which is favorable for CNS penetration.

**15. Binding Affinity:** Ligand B (-9.9 kcal/mol) has a substantially stronger binding affinity than Ligand A (-7.3 kcal/mol). This difference of 2.6 kcal/mol is significant and can outweigh some of the ADME drawbacks.

**Overall Assessment:**

While both compounds have issues with solubility and Caco-2 permeability, Ligand B is the more promising candidate. It has a significantly better binding affinity, better BBB penetration, lower DILI risk, and a much more reasonable in vitro half-life. The lower microsomal clearance of Ligand A is a plus, but the stronger binding affinity of Ligand B is a more critical factor for a GPCR target. The poor solubility and permeability would need to be addressed through formulation or structural modifications, but the starting point is better with Ligand B.

Output:
1
2025-04-17 05:17:13,562 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (352.479 and 368.865 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (65.12) is significantly better than Ligand B (81.75). For CNS targets, TPSA should be <= 90, and A is comfortably within this range, while B is approaching the upper limit.

**logP:** Ligand A (-0.069) is slightly lower than optimal (1-3), potentially hindering permeability. Ligand B (0.896) is closer to the optimal range, but still on the lower side.

**H-Bond Donors/Acceptors:** Ligand A (HBD=1, HBA=5) is better than Ligand B (HBD=2, HBA=3) in terms of maintaining a balance between solubility and permeability.

**QED:** Both ligands have good QED values (A: 0.695, B: 0.756), indicating a generally drug-like profile.

**DILI:** Ligand A (12.641) has a much lower DILI risk than Ligand B (23.575), a significant advantage.

**BBB:** Ligand B (77.549) has a substantially better BBB penetration score than Ligand A (56.417). This is a critical factor for a CNS target like DRD2.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.848 and -4.901), which is unusual and suggests poor permeability. This is a concern for both.

**Aqueous Solubility:** Both ligands have negative solubility values (-0.318 and -2.471), which is also unusual and indicates poor solubility.

**hERG:** Both ligands have low hERG inhibition liability (A: 0.282, B: 0.245), which is good.

**Microsomal Clearance:** Ligand A (0.034) has a much lower microsomal clearance than Ligand B (-4.157), indicating better metabolic stability.

**In vitro Half-Life:** Ligand A (-3.526) has a much longer in vitro half-life than Ligand B (6.046), which is desirable.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (A: 0.006, B: 0.011), which is good for CNS penetration.

**Binding Affinity:** Ligand B (-8.2 kcal/mol) has a stronger binding affinity than Ligand A (-7.3 kcal/mol). This is a significant advantage, exceeding the 1.5 kcal/mol threshold.

**Overall Assessment:**

While Ligand A has better ADME properties (DILI, metabolic stability, half-life, TPSA), Ligand B's significantly stronger binding affinity (-8.2 vs -7.3 kcal/mol) and better BBB penetration (77.5 vs 56.4) are crucial for a CNS GPCR target. The affinity difference is substantial enough to outweigh the ADME concerns, especially considering the relatively acceptable (though not ideal) values for those properties in Ligand B. The poor Caco-2 and solubility for both are concerning, but can be addressed with formulation strategies.

Output:
1
2025-04-17 05:17:13,562 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (388.823 Da) is slightly higher than Ligand B (349.431 Da), but both are acceptable.

**2. TPSA:** Ligand A (67.43) is better than Ligand B (84.67). For CNS targets, we want TPSA <= 90, both are within this range, but A is preferable.

**3. logP:** Ligand A (4.464) is higher than the optimal range (1-3), potentially causing solubility issues and off-target effects. Ligand B (1.59) is within the optimal range. This is a significant advantage for Ligand B.

**4. H-Bond Donors:** Both ligands have acceptable HBD counts (Ligand A: 2, Ligand B: 1).

**5. H-Bond Acceptors:** Both ligands have acceptable HBA counts (Ligand A: 3, Ligand B: 5).

**6. QED:** Both ligands have good QED values (Ligand A: 0.767, Ligand B: 0.873), indicating drug-like properties.

**7. DILI:** Ligand A (81.504) has a higher DILI risk than Ligand B (35.983). This is a substantial negative for Ligand A.

**8. BBB:** Ligand A (79.488) has a better BBB penetration score than Ligand B (51.493). This is a crucial factor for a CNS target like DRD2, favoring Ligand A.

**9. Caco-2:** Ligand A (-4.757) and Ligand B (-5.093) both have negative Caco-2 values, which is unusual and suggests poor permeability. The values are similar, so this isn't a major differentiator.

**10. Solubility:** Ligand A (-5.85) has very poor solubility, while Ligand B (-0.997) is slightly better, but still poor.

**11. hERG:** Ligand A (0.766) has a slightly higher hERG risk than Ligand B (0.099). This favors Ligand B.

**12. Cl_mic:** Ligand B (16.924) has a lower microsomal clearance, indicating better metabolic stability, than Ligand A (31.404).

**13. t1/2:** Ligand A (69.693) has a significantly longer in vitro half-life than Ligand B (-1.749). This is a strong positive for Ligand A.

**14. Pgp:** Ligand A (0.434) has lower P-gp efflux, which is beneficial for CNS penetration, than Ligand B (0.054).

**15. Binding Affinity:** Ligand B (-8.6 kcal/mol) has a stronger binding affinity than Ligand A (-9.0 kcal/mol). While both are excellent, the difference is small.

**Overall Assessment:**

Ligand A has advantages in BBB penetration, in vitro half-life, and P-gp efflux. However, it suffers from high DILI risk, poor solubility, and a high logP. Ligand B has a better logP, lower DILI risk, better metabolic stability, and lower hERG risk, but a lower BBB score.

Given the GPCR-specific priorities, BBB is critical. While Ligand A has a better BBB score, its significantly higher DILI risk and poor solubility are major concerns. The slightly better binding affinity of Ligand A is unlikely to overcome these significant liabilities. Ligand B's more balanced profile, particularly its lower risk profile (DILI, hERG) and better metabolic stability, makes it the more promising candidate, despite the lower BBB score.

Output:
1
2025-04-17 05:17:13,563 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 drug candidates, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (360.4 and 359.5 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (135.76) is borderline for CNS penetration, just above the preferred <90, but still potentially acceptable. Ligand B (55.2) is excellent, well below 90, indicating good potential for CNS penetration.

**logP:** Both ligands have good logP values (1.057 and 3.237), falling within the optimal 1-3 range. Ligand B is slightly better, closer to the upper end of the range, which can be beneficial for membrane permeability.

**H-Bond Donors/Acceptors:** Ligand A has 3 HBD and 6 HBA, which are reasonable. Ligand B has 0 HBD and 5 HBA, also reasonable.

**QED:** Both ligands have good QED scores (0.625 and 0.727), indicating good drug-like properties.

**DILI:** Ligand A has a high DILI risk (96.51%), which is a significant concern. Ligand B has a much lower, and acceptable, DILI risk (47.654%).

**BBB:** Ligand A has a poor BBB penetration score (40.791%). Ligand B has a very good BBB penetration score (87.127%), crucial for a CNS target like DRD2.

**Caco-2 Permeability:** Ligand A has a negative Caco-2 value (-5.431), suggesting poor permeability. Ligand B has a negative value as well (-4.942), but is slightly better.

**Aqueous Solubility:** Both ligands have negative solubility values (-3.479 and -4.255), suggesting poor solubility. This is a potential issue, but can sometimes be overcome with formulation strategies.

**hERG Inhibition:** Ligand A has a very low hERG risk (0.227), which is excellent. Ligand B has a slightly higher, but still acceptable, hERG risk (0.617).

**Microsomal Clearance:** Ligand A has a relatively low microsomal clearance (17.505), suggesting better metabolic stability. Ligand B has a significantly higher clearance (82.182), indicating faster metabolism.

**In vitro Half-Life:** Ligand A has a negative half-life (-17.169), which is problematic. Ligand B has a positive half-life (17.213), which is better.

**P-gp Efflux:** Ligand A has very low P-gp efflux (0.04), which is excellent for CNS penetration. Ligand B has a higher P-gp efflux (0.704), which could limit CNS exposure.

**Binding Affinity:** Ligand A has a significantly better binding affinity (-8.9 kcal/mol) than Ligand B (-7.8 kcal/mol). This is a substantial advantage.

**Overall Assessment:**

Despite the superior binding affinity of Ligand A, its extremely high DILI risk, poor BBB penetration, and negative half-life are major drawbacks. Ligand B, while having slightly weaker affinity, possesses a much more favorable ADME profile, particularly its excellent BBB penetration, lower DILI risk, and acceptable half-life. For a CNS target like DRD2, BBB penetration and safety (DILI) are paramount. The affinity difference, while significant, might be overcome with further optimization of Ligand B.

Output:
1
2025-04-17 05:17:13,563 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (363.479 and 356.373 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (64.63) is significantly better than Ligand B (86.63).  For CNS targets, we want TPSA <= 90, and A is comfortably within that, while B is approaching the upper limit.

**3. logP:** Ligand A (3.368) is optimal (1-3), while Ligand B (1.238) is on the lower side. Lower logP can hinder permeation, especially across the BBB.

**4. H-Bond Donors:** Both ligands have 1 HBD, which is within the acceptable limit of <= 5.

**5. H-Bond Acceptors:** Ligand A has 4 HBAs, and Ligand B has 5, both within the acceptable limit of <= 10.

**6. QED:** Both ligands have good QED scores (0.731 and 0.829), indicating good drug-like properties.

**7. DILI:** Ligand A (67.507) has a higher DILI risk than Ligand B (49.632).  While both are acceptable, B is preferable.

**8. BBB:** Ligand B (84.451) has a significantly better BBB penetration percentile than Ligand A (35.905). This is *critical* for a CNS target like DRD2.

**9. Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and suggests a potential issue with the modeling or data quality. However, the magnitude of negativity is similar.

**10. Aqueous Solubility:** Both have negative solubility values, again suggesting a potential issue with the modeling or data quality. The magnitude of negativity is similar.

**11. hERG Inhibition:** Ligand A (0.673) has a slightly higher hERG risk than Ligand B (0.286), but both are relatively low.

**12. Microsomal Clearance:** Ligand B (20.504) has significantly lower microsomal clearance than Ligand A (81.984), indicating better metabolic stability.

**13. In vitro Half-Life:** Ligand B (-30.481) has a much longer in vitro half-life than Ligand A (-14.434).

**14. P-gp Efflux:** Ligand A (0.474) has lower P-gp efflux liability than Ligand B (0.048), which is favorable for CNS penetration.

**15. Binding Affinity:** Ligand B (-7.3 kcal/mol) has a slightly better binding affinity than Ligand A (-9.0 kcal/mol). While A is stronger, the difference is not substantial enough to outweigh other factors.

**Overall Assessment:**

Despite the stronger binding affinity of Ligand A, Ligand B is the more promising candidate. The significantly better BBB penetration (84.451 vs 35.905), lower microsomal clearance, longer half-life, and lower DILI risk outweigh the slightly weaker binding. The logP value of Ligand A is also more optimal. Given the GPCR target and the need for CNS penetration, Ligand B is the superior choice.



Output:
1
2025-04-17 05:17:13,563 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B based on the provided guidelines, prioritizing GPCR-specific properties (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (349.406 and 350.463 Da) fall within the ideal range of 200-500 Da.

**TPSA:** Ligand A (78.51) is excellent for CNS penetration, being well below 90. Ligand B (102.3) is still reasonable but less optimal.

**logP:** Both ligands have good logP values (0.844 and 1.052), falling within the 1-3 range.

**H-Bond Donors/Acceptors:** Both ligands have acceptable HBD (2) and HBA (3 & 4) counts, well within the limits.

**QED:** Both ligands have good QED scores (0.698 and 0.716), indicating drug-like properties.

**DILI:** Ligand A (35.285) has a significantly lower DILI risk than Ligand B (13.92), which is a substantial advantage.

**BBB:** This is a crucial parameter for a CNS target like DRD2. Ligand A has a very high BBB penetration percentile (84.219), while Ligand B is considerably lower (62.621).

**Caco-2 Permeability:** Both have negative values, which is unusual. Assuming these are logP values, they are very poor.

**Aqueous Solubility:** Both have negative values, which is unusual.

**hERG:** Both ligands have very low hERG inhibition liability (0.182 and 0.089), indicating a low risk of cardiotoxicity.

**Microsomal Clearance:** Ligand A (33.131) has a higher microsomal clearance than Ligand B (24.978), suggesting potentially lower metabolic stability.

**In vitro Half-Life:** Ligand B (0.005) has a very short half-life, which is a major drawback. Ligand A (5.531) is better, but still not ideal.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.017 and 0.002), which is favorable for CNS exposure.

**Binding Affinity:** Ligand B (-8.0 kcal/mol) has a slightly better binding affinity than Ligand A (-7.9 kcal/mol), but the difference is minimal (0.1 kcal/mol).

**Overall Assessment:**

Ligand A is significantly better due to its superior BBB penetration, much lower DILI risk, and better in vitro half-life. While Ligand B has slightly better binding affinity, the difference is not substantial enough to overcome the significant advantages of Ligand A in terms of safety (DILI) and CNS penetration (BBB). The poor Caco-2 and solubility values are concerning for both, but the CNS target prioritizes BBB over intestinal absorption.

Output:
1
2025-04-17 05:17:13,563 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (375.778 and 389.239 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (56.15) is excellent, well below the 90 A^2 threshold for CNS targets. Ligand B (104.65) is higher, but still potentially acceptable, though less ideal.

**logP:** Ligand A (3.729) is at the upper end of the optimal 1-3 range. Ligand B (0.886) is quite low, potentially hindering permeability.

**H-Bond Donors/Acceptors:** Ligand A (HBD=1, HBA=4) is favorable. Ligand B (HBD=2, HBA=6) is also acceptable, but slightly higher.

**QED:** Both ligands have reasonable QED values (0.866 and 0.725), indicating good drug-like properties.

**DILI:** Both ligands have similar DILI risk (66.15 and 70.686), both are moderately high, but not alarming.

**BBB:** Ligand A (71.927) has a good BBB percentile, exceeding the 70% threshold for CNS targets. Ligand B (45.366) is significantly lower, raising concerns about CNS penetration. This is a critical difference given DRD2's role in CNS disorders.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.54 and -4.9), which is unusual and suggests poor permeability. However, these values are on a log scale and could be interpreted differently depending on the experimental setup.

**Aqueous Solubility:** Both ligands have negative solubility values (-4.475 and -2.179), indicating poor solubility. This is a concern for bioavailability.

**hERG Inhibition:** Ligand A (0.412) has a very low hERG risk. Ligand B (0.169) is even lower, but both are good.

**Microsomal Clearance:** Ligand A (70.477) has a higher clearance than Ligand B (10.46). Ligand B is much more metabolically stable.

**In vitro Half-Life:** Ligand B (-21.014) has a significantly longer half-life than Ligand A (13.193).

**P-gp Efflux:** Ligand A (0.594) has moderate P-gp efflux. Ligand B (0.053) has very low P-gp efflux, which is highly desirable for CNS penetration.

**Binding Affinity:** Ligand A (-8.3 kcal/mol) has a slightly better binding affinity than Ligand B (-7.5 kcal/mol). The difference is 0.8 kcal/mol, which is substantial, but may be outweighed by other factors.

**Overall Assessment:**

Ligand A has a better BBB score and slightly better binding affinity, but suffers from higher metabolic clearance and P-gp efflux. Ligand B has superior metabolic stability, lower P-gp efflux, and a longer half-life, but its logP is low and its BBB penetration is significantly compromised.

Given the importance of BBB penetration for a DRD2 ligand targeting CNS disorders, and the relatively small difference in binding affinity, **Ligand A is the more promising candidate**. The slightly better affinity combined with the significantly better BBB score outweighs the drawbacks of higher clearance and P-gp efflux.

Output:
0
2025-04-17 05:17:13,563 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (380.861 Da) is slightly higher than Ligand B (354.455 Da), but both are acceptable.

**TPSA:** Ligand A (95.91) is better than Ligand B (135.16). For CNS targets, we want TPSA <= 90, so Ligand A is closer to this threshold. Ligand B is significantly higher, potentially hindering BBB penetration.

**logP:** Ligand A (1.762) is within the optimal range (1-3). Ligand B (0.209) is quite low, potentially causing permeability issues.

**H-Bond Donors/Acceptors:** Ligand A (HBD=2, HBA=6) and Ligand B (HBD=4, HBA=7) are both within acceptable limits (<=5 HBD and <=10 HBA).

**QED:** Ligand A (0.788) has a better QED score than Ligand B (0.5), indicating a more drug-like profile.

**DILI:** Ligand A (75.262) has a higher DILI risk than Ligand B (49.011), but both are below the concerning threshold of 60.

**BBB:** Ligand A (77.821) has a significantly better BBB percentile than Ligand B (47.693). This is a crucial factor for a CNS target like DRD2.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.158 and -5.51). This is unusual and suggests poor permeability, but it's difficult to interpret without knowing the scale.

**Aqueous Solubility:** Both ligands have negative solubility values (-4.68 and -2.118), which is also unusual and suggests poor solubility.

**hERG Inhibition:** Both ligands have very low hERG inhibition liability (0.24 and 0.278), which is excellent.

**Microsomal Clearance:** Ligand A (8.438) has a much lower (better) microsomal clearance than Ligand B (18.236), indicating greater metabolic stability.

**In vitro Half-Life:** Ligand A (-4.132) has a slightly better (less negative) in vitro half-life than Ligand B (1.17), suggesting better stability.

**P-gp Efflux:** Ligand A (0.126) has lower P-gp efflux liability than Ligand B (0.074), which is favorable for CNS penetration.

**Binding Affinity:** Ligand A (-7.9 kcal/mol) has a slightly better binding affinity than Ligand B (-7.3 kcal/mol). While both are good, the 0.6 kcal/mol difference is significant and can outweigh some ADME drawbacks.

**Overall Assessment:**

Ligand A is the superior candidate. It has better TPSA, logP, BBB penetration, QED, metabolic stability (lower Cl_mic, better t1/2), lower P-gp efflux, and slightly better binding affinity. While Ligand A has a higher DILI risk, it's still within an acceptable range. The combination of improved CNS penetration properties (BBB, TPSA, logP, Pgp) and binding affinity makes Ligand A the more promising drug candidate for targeting DRD2.

Output:
1
2025-04-17 05:17:13,564 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (348.531 and 349.479 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (49.41) is excellent, well below the 90 A^2 threshold for CNS targets. Ligand B (102.04) is higher, but still potentially acceptable, though less optimal.

**3. logP:** Ligand A (3.482) is within the optimal 1-3 range. Ligand B (1.989) is at the lower end of optimal, potentially impacting permeability.

**4. H-Bond Donors:** Ligand A (1) is good. Ligand B (3) is acceptable, but higher.

**5. H-Bond Acceptors:** Ligand A (2) is good. Ligand B (5) is acceptable, but higher.

**6. QED:** Ligand A (0.716) is excellent, indicating strong drug-likeness. Ligand B (0.562) is still acceptable, but less favorable.

**7. DILI:** Ligand A (12.718) has a very low DILI risk. Ligand B (39.201) is also relatively low, but higher than A.

**8. BBB:** Both ligands have good BBB penetration (Ligand A: 86.274%, Ligand B: 81.272%). Ligand A is slightly better.

**9. Caco-2 Permeability:** Ligand A (-4.407) has poor Caco-2 permeability. Ligand B (-5.364) is even worse. Both are concerning.

**10. Aqueous Solubility:** Both ligands have poor aqueous solubility (-3.9 and -3.25 respectively). This could pose formulation challenges.

**11. hERG Inhibition:** Ligand A (0.394) has a very low hERG risk. Ligand B (0.702) is slightly higher, but still relatively low.

**12. Microsomal Clearance:** Ligand A (74.079) has higher clearance, indicating lower metabolic stability. Ligand B (52.162) has lower clearance and better metabolic stability.

**13. In vitro Half-Life:** Ligand A (16.399) has a shorter half-life. Ligand B (1.964) has a very short half-life. Both are poor.

**14. P-gp Efflux:** Ligand A (0.028) has very low P-gp efflux, which is excellent for CNS penetration. Ligand B (0.426) has moderate P-gp efflux.

**15. Binding Affinity:** Ligand B (-8.0 kcal/mol) has a significantly stronger binding affinity than Ligand A (-7.4 kcal/mol). This is a substantial advantage (1.6 kcal/mol difference).

**Overall Assessment:**

Ligand B's superior binding affinity is a major advantage, potentially outweighing some of its ADME drawbacks. However, the poor Caco-2 permeability for both is a significant concern. Ligand A has better TPSA, QED, DILI, and P-gp efflux, but its metabolic stability is worse. Considering the GPCR-specific priorities, BBB penetration is good for both. The difference in affinity is large enough to favor Ligand B, *assuming* formulation strategies can address the solubility and permeability issues.

Output:
1
2025-04-17 05:17:13,564 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (366.571 and 351.447 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (40.62) is excellent, well below the 90 A^2 threshold for CNS targets. Ligand B (98.74) is higher, but still potentially acceptable, though less ideal.

**logP:** Ligand A (3.404) is optimal (1-3). Ligand B (0.171) is significantly low, which could hinder membrane permeability and CNS penetration.

**H-Bond Donors/Acceptors:** Ligand A (0 HBD, 3 HBA) is excellent. Ligand B (3 HBD, 4 HBA) is within acceptable limits, but higher than A.

**QED:** Both ligands have reasonable QED values (0.648 and 0.58), indicating good drug-like properties.

**DILI:** Both ligands have low DILI risk (13.843 and 12.796), which is favorable.

**BBB:** Ligand A has a very high BBB penetration score (92.478), which is excellent for a CNS target like DRD2. Ligand B's BBB score (35.052) is poor, making CNS exposure unlikely.

**Caco-2 Permeability:** Ligand A (-5.079) and Ligand B (-5.157) both show poor Caco-2 permeability, indicating potential absorption issues.

**Aqueous Solubility:** Both ligands have poor aqueous solubility (-3.232 and -1.8). This could pose formulation challenges.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.804 and 0.086), which is good.

**Microsomal Clearance:** Ligand A (61.336) has moderate clearance, while Ligand B (13.551) has lower clearance, suggesting better metabolic stability.

**In vitro Half-Life:** Ligand B (11.524 hours) has a significantly longer half-life than Ligand A (-2.335 hours).

**P-gp Efflux:** Ligand A (0.497) has lower P-gp efflux liability than Ligand B (0.02), which is beneficial for CNS penetration.

**Binding Affinity:** Ligand B (-8.1 kcal/mol) has a slightly better binding affinity than Ligand A (-7.7 kcal/mol), but the difference is not substantial enough to overcome the significant ADME deficiencies.

**Overall Assessment:**

Considering the GPCR-specific priorities, Ligand A is significantly more promising. Its excellent BBB penetration, optimal logP, and lower P-gp efflux outweigh its slightly weaker binding affinity and poor solubility/permeability. Ligand B's extremely low logP and poor BBB penetration are major drawbacks for a CNS drug, despite its slightly better affinity and metabolic stability. The poor Caco-2 permeability for both is a concern, but can potentially be addressed with formulation strategies.

Output:
1
2025-04-17 05:17:13,564 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (353.86 and 364.47 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (56.84) is excellent, well below the 90 A^2 threshold for CNS targets. Ligand B (96.67) is higher, but still potentially acceptable, though less ideal.

**logP:** Ligand A (3.93) is optimal. Ligand B (0.65) is quite low, potentially hindering membrane permeability and CNS penetration.

**H-Bond Donors/Acceptors:** Both ligands have 2 HBDs, which is good. Ligand A has 4 HBAs, and Ligand B has 6 HBAs. Both are within the acceptable range of <=10.

**QED:** Both ligands have good QED scores (0.746 and 0.773), indicating drug-like properties.

**DILI:** Ligand A (71.07%) has a higher DILI risk than Ligand B (30.83%), which is a significant concern.

**BBB:** Ligand A (91.39%) shows excellent BBB penetration, critical for a CNS target like DRD2. Ligand B (31.49%) has very poor predicted BBB penetration.

**Caco-2 Permeability:** Ligand A (-4.892) has poor Caco-2 permeability, which is concerning. Ligand B (-5.197) is also poor.

**Aqueous Solubility:** Ligand A (-4.437) has poor aqueous solubility. Ligand B (-1.442) is also poor.

**hERG:** Both ligands have low hERG inhibition risk (0.901 and 0.638).

**Microsomal Clearance:** Ligand A (33.67 mL/min/kg) has moderate clearance. Ligand B (-19.87) has negative clearance, which is not physically possible and likely indicates an error or extrapolation issue in the prediction. This is a major red flag.

**In vitro Half-Life:** Ligand A (-4.86 hours) has a very short half-life. Ligand B (18.21 hours) has a much more reasonable half-life.

**P-gp Efflux:** Ligand A (0.187) has low P-gp efflux, which is good for CNS penetration. Ligand B (0.058) also has low P-gp efflux.

**Binding Affinity:** Ligand A (-9.2 kcal/mol) has significantly stronger binding affinity than Ligand B (-7.0 kcal/mol). This is a substantial advantage.

**Overall Assessment:**

Ligand A excels in BBB penetration and binding affinity, which are crucial for a DRD2 ligand. However, it suffers from poor Caco-2 permeability, poor aqueous solubility, a higher DILI risk, and a very short half-life. Ligand B has a better DILI profile and a longer half-life, but its low logP and extremely poor BBB penetration are major drawbacks for a CNS target. The negative microsomal clearance for Ligand B is also a critical issue.

Despite the drawbacks of Ligand A, the significantly stronger binding affinity and excellent BBB penetration outweigh its other issues *more* than the issues with Ligand B. The poor solubility and permeability of Ligand A could potentially be addressed through formulation strategies. The negative clearance of Ligand B is a showstopper.

Output:
1
2025-04-17 05:17:13,564 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (348.49 and 353.43 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (49.85) is excellent, well below the 90 A^2 threshold for CNS targets. Ligand B (130.47) is higher, but still potentially acceptable, though less ideal.

**logP:** Ligand A (2.3) is optimal (1-3). Ligand B (-1.031) is below 1, which could hinder permeation. This is a significant drawback.

**H-Bond Donors/Acceptors:** Ligand A (0 HBD, 3 HBA) is favorable. Ligand B (2 HBD, 8 HBA) is also acceptable, but higher HBA could slightly impact permeability.

**QED:** Both ligands have similar QED values (0.74 and 0.668), indicating good drug-likeness.

**DILI:** Ligand A (6.359) has a much lower DILI risk than Ligand B (69.29), which is a major concern.

**BBB:** Ligand A (93.718) has excellent BBB penetration, exceeding the desirable >70% threshold. Ligand B (43.815) is significantly lower, raising concerns about CNS exposure.

**Caco-2 Permeability:** Ligand A (-4.463) has poor Caco-2 permeability. Ligand B (-5.377) is also poor.

**Aqueous Solubility:** Both ligands have negative solubility values (-1.894 and -1.608), indicating poor aqueous solubility. This could pose formulation challenges.

**hERG Inhibition:** Ligand A (0.658) has a lower hERG risk than Ligand B (0.157), which is a positive.

**Microsomal Clearance:** Ligand A (55.779) has a moderate clearance, while Ligand B (7.619) has a very low clearance, suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (-7.289) has a longer half-life than Ligand B (0.099), which is desirable.

**P-gp Efflux:** Ligand A (0.161) has lower P-gp efflux than Ligand B (0.042), which is favorable for CNS penetration.

**Binding Affinity:** Both ligands have comparable and strong binding affinities (-8.4 and -8.0 kcal/mol). The difference is less than the 1.5 kcal/mol threshold.

**Conclusion:**

Considering the GPCR-specific priorities, Ligand A is the more promising candidate. Its superior BBB penetration, lower DILI risk, and better P-gp efflux profile outweigh its slightly poorer Caco-2 permeability and solubility. While Ligand B has better metabolic stability, its significantly lower logP and BBB penetration are major drawbacks for a CNS target like DRD2. The affinity difference is not substantial enough to overcome these ADME deficiencies.

Output:
1
2025-04-17 05:17:13,565 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B based on the provided guidelines, prioritizing GPCR-specific properties (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (350.463 and 386.283 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (81.75) is slightly higher than Ligand B (71.33), but both are below the 90 A^2 threshold desirable for CNS targets.

**logP:** Ligand A (0.945) is a bit low, potentially hindering permeation, while Ligand B (2.243) is within the optimal 1-3 range. This favors Ligand B.

**H-Bond Donors/Acceptors:** Ligand A has 2 HBD and 3 HBA, while Ligand B has 0 HBD and 5 HBA. Both are within acceptable limits.

**QED:** Both ligands have similar QED values (0.774 and 0.752), indicating good drug-likeness.

**DILI:** Ligand A (21.908) has a significantly lower DILI risk than Ligand B (42.264), which is a strong advantage for Ligand A.

**BBB:** Ligand B (80.419) has a better BBB percentile than Ligand A (70.143), which is crucial for CNS targets. This is a significant advantage for Ligand B.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.86 and -4.896). These values are unusual and difficult to interpret without more context, but suggest poor permeability.

**Aqueous Solubility:** Both ligands have negative solubility values (-1.709 and -2.64). These values are also unusual and suggest poor solubility.

**hERG Inhibition:** Both ligands have low hERG inhibition liability (0.24 and 0.411), which is good.

**Microsomal Clearance:** Ligand A (5.279) has a lower microsomal clearance than Ligand B (34.624), indicating better metabolic stability. This favors Ligand A.

**In vitro Half-Life:** Ligand B (-12.822) has a much longer in vitro half-life than Ligand A (-2.283), which is a significant advantage.

**P-gp Efflux:** Both ligands show very low P-gp efflux liability (0.024 and 0.087).

**Binding Affinity:** Ligand B (-7.7 kcal/mol) has a substantially stronger binding affinity than Ligand A (0 kcal/mol). This is a major advantage for Ligand B, potentially outweighing some of its ADME drawbacks.

**Overall Assessment:**

Ligand B excels in BBB penetration and binding affinity, which are critical for a CNS-targeting GPCR like DRD2. The longer half-life is also beneficial. While its DILI risk is higher and logP is at the upper end of optimal, the strong affinity likely compensates for these. Ligand A has a better safety profile (lower DILI) and metabolic stability, but its significantly weaker binding affinity is a major drawback. Given the importance of potency for GPCRs, and the substantial difference in affinity, Ligand B is the more promising candidate.

Output:
1
2025-04-17 05:17:13,565 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 drug candidates, considering the provided guidelines and GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (346.387 Da) is slightly lower, which could be favorable for permeability, while Ligand B (364.515 Da) is also good.

**2. TPSA:** Ligand A (95.34) is better than Ligand B (74.33). For CNS targets, TPSA < 90 is preferred, so Ligand A is closer to the ideal.

**3. logP:** Both ligands have acceptable logP values (Ligand A: 1.111, Ligand B: 1.633), falling within the optimal range of 1-3.

**4. H-Bond Donors:** Ligand A (1) is better than Ligand B (2). Lower is generally preferred.

**5. H-Bond Acceptors:** Ligand A (8) is better than Ligand B (5). Both are acceptable, but lower is better.

**6. QED:** Both ligands have good QED scores (Ligand A: 0.565, Ligand B: 0.735), indicating drug-like properties. Ligand B is slightly better.

**7. DILI:** Ligand A (51.377) has a higher DILI risk than Ligand B (22.722). This is a significant advantage for Ligand B.

**8. BBB:** Ligand A (69.407) has a better BBB percentile than Ligand B (41.644). For a CNS target like DRD2, >70 is desirable, and Ligand A is closer to that threshold.

**9. Caco-2 Permeability:** Both have negative values, which is unusual. However, the magnitude of the negative value is important. Ligand A (-5.033) is less negative than Ligand B (-5.56), suggesting slightly better permeability.

**10. Aqueous Solubility:** Both have negative values, indicating poor solubility. Ligand A (-1.673) is slightly better than Ligand B (-0.799).

**11. hERG Inhibition:** Both ligands have low hERG inhibition risk (Ligand A: 0.22, Ligand B: 0.207).

**12. Microsomal Clearance:** Ligand A (70.118) has a higher clearance than Ligand B (-17.009). A negative clearance suggests very high metabolic stability, which is a significant advantage for Ligand B.

**13. In vitro Half-Life:** Ligand A (1.269) has a shorter half-life than Ligand B (6.069). Longer half-life is preferred.

**14. P-gp Efflux:** Both ligands have very low P-gp efflux liability (Ligand A: 0.158, Ligand B: 0.024). Ligand B is slightly better.

**15. Binding Affinity:** Ligand B (-8.5 kcal/mol) has a stronger binding affinity than Ligand A (-7.4 kcal/mol). This is a 1.1 kcal/mol difference, which is substantial and can outweigh some ADME drawbacks.

**Overall Assessment:**

Ligand B has a significantly better safety profile (lower DILI), better metabolic stability (negative Cl_mic), longer half-life, and stronger binding affinity. While Ligand A has a slightly better BBB score and TPSA, the advantages of Ligand B in safety, metabolic stability, and potency are more critical for a CNS drug candidate targeting a GPCR. The stronger binding affinity of Ligand B is a major advantage.

Output:
1
2025-04-17 05:17:13,565 - INFO - Batch 185 complete. Total preferences: 2960
2025-04-17 05:17:13,565 - INFO - Processing batch 186/512...
2025-04-17 05:17:55,234 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (351.382 and 345.443 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (96.33) is slightly above the optimal <90 for CNS targets, but still reasonable. Ligand B (69.72) is excellent, well below 90.

**logP:** Ligand A (-0.246) is a bit low, potentially hindering membrane permeability. Ligand B (1.503) is within the optimal 1-3 range. This is a significant advantage for Ligand B.

**H-Bond Donors/Acceptors:** Ligand A (2 HBD, 6 HBA) and Ligand B (1 HBD, 3 HBA) both have acceptable numbers of H-bond donors and acceptors.

**QED:** Both ligands have good QED scores (0.763 and 0.814), indicating drug-like properties.

**DILI:** Ligand A (72.741) has a higher DILI risk than Ligand B (31.33). This is a clear advantage for Ligand B.

**BBB:** Both ligands have good BBB penetration (75.262 and 74.796), exceeding the 70% threshold for CNS targets.

**Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and suggests a potential issue with the data or modeling. However, given the other parameters, we'll proceed with caution.

**Aqueous Solubility:** Both have negative solubility values, which is also unusual.

**hERG:** Both ligands have low hERG inhibition liability (0.349 and 0.211), which is good.

**Microsomal Clearance:** Ligand A (-1.532) has a negative microsomal clearance, which is not physically possible. This is a major red flag. Ligand B (60.726) has a high clearance, indicating poor metabolic stability.

**In vitro Half-Life:** Ligand A (6.95 hours) is reasonable, but Ligand B (-16.086 hours) is not physically possible.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.032 and 0.026), which is favorable for CNS penetration.

**Binding Affinity:** Ligand A (-9.0 kcal/mol) has a significantly stronger binding affinity than Ligand B (-7.8 kcal/mol). This is a substantial advantage for Ligand A, potentially outweighing some of its other drawbacks.

**Overall Assessment:**

Ligand A has a much stronger binding affinity, which is paramount for GPCR ligands. However, it has a physically impossible microsomal clearance and half-life, and a slightly low logP. Ligand B has better physicochemical properties (logP, TPSA, DILI) and more realistic ADME properties, but its binding affinity is weaker.

Despite the strong affinity of Ligand A, the impossible ADME values raise serious concerns about the reliability of the data or the molecule's inherent properties. It's highly likely these values are errors. Given the choice between a potentially flawed but highly potent ligand and a less potent but more reasonable ligand, I would lean towards Ligand B. The better ADME profile of Ligand B, especially the lower DILI risk and acceptable logP, makes it a more viable starting point for optimization.

Output:
1
2025-04-17 05:17:55,234 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (348.451 Da) is slightly lower, which is generally favorable for permeability.

**2. TPSA:** Ligand A (101.8) is better than Ligand B (78.43). For CNS targets, TPSA should be <= 90. Ligand B is well within this range, and Ligand A is slightly above, but still acceptable.

**3. logP:** Ligand A (0.82) is a bit low, potentially hindering permeation. Ligand B (1.957) is closer to the optimal range of 1-3.

**4. H-Bond Donors:** Ligand A (2) and Ligand B (1) are both acceptable (<=5).

**5. H-Bond Acceptors:** Ligand A (6) and Ligand B (7) are both acceptable (<=10).

**6. QED:** Both ligands have reasonable QED values (A: 0.724, B: 0.653), indicating good drug-like properties.

**7. DILI:** Ligand A (33.656) has a lower DILI risk than Ligand B (42.807), which is preferable.

**8. BBB:** This is a crucial parameter for CNS targets. Ligand A (71.966) has a significantly better BBB percentile than Ligand B (52.501). A value >70 is desirable, and Ligand A is closer to this threshold.

**9. Caco-2 Permeability:** Both have negative values, which is unusual. Lower values indicate poorer permeability. Ligand A (-5.436) is better than Ligand B (-5.188), but both are problematic.

**10. Aqueous Solubility:** Both have negative values, which is also unusual. Lower values indicate poorer solubility. Ligand A (-1.975) is better than Ligand B (-2.324), but both are problematic.

**11. hERG Inhibition:** Both have very low hERG inhibition risk (A: 0.023, B: 0.24), which is excellent.

**12. Microsomal Clearance:** Ligand A (27.538) has lower clearance than Ligand B (70.376), suggesting better metabolic stability.

**13. In vitro Half-Life:** Ligand A (5.644) has a shorter half-life than Ligand B (31.689). Longer half-life is generally preferred.

**14. P-gp Efflux:** Both have very low P-gp efflux liability (A: 0.013, B: 0.099), which is excellent.

**15. Binding Affinity:** Ligand A (-7.7 kcal/mol) has a significantly stronger binding affinity than Ligand B (-6.2 kcal/mol). This difference of 1.5 kcal/mol is substantial and can outweigh some of the ADME drawbacks.

**Overall Assessment:**

Ligand A is the stronger candidate. While its logP and Caco-2/Solubility are less ideal, its superior BBB penetration, lower DILI risk, better metabolic stability (lower Cl_mic), and *significantly* stronger binding affinity outweigh these concerns. The strong binding affinity is particularly important for a GPCR target. Ligand B's better logP is offset by its poorer BBB, higher DILI, and weaker binding.

Output:
0
2025-04-17 05:17:55,234 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 drug candidates, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (338.451 and 347.507 Da) fall well within the ideal 200-500 Da range.

**TPSA:** Ligand A (42.43) is significantly better than Ligand B (64.86). For CNS targets, we want TPSA <= 90, and A is much closer to the ideal <= 60 range. B is pushing the upper limit.

**logP:** Ligand A (4.049) is slightly higher than the optimal 1-3 range, but still acceptable. Ligand B (2.895) is within the optimal range.

**H-Bond Donors/Acceptors:** Ligand A (0 HBD, 4 HBA) is preferable to Ligand B (1 HBD, 6 HBA). Lower counts generally improve permeability.

**QED:** Both ligands have similar and good QED values (0.772 and 0.783).

**DILI:** Both ligands have low DILI risk (23.187 and 21.753), which is excellent.

**BBB:** Both ligands have good BBB penetration (75.843 and 79.256), exceeding the desirable >70 threshold for CNS targets. Ligand B is slightly better.

**Caco-2 Permeability:** Ligand A (-4.898) has poor Caco-2 permeability, while Ligand B (-5.09) is also poor. Both are negative values, indicating low permeability.

**Aqueous Solubility:** Ligand A (-3.936) has slightly better solubility than Ligand B (-2.386), but both are quite poor.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.879 and 0.452).

**Microsomal Clearance:** Ligand A (81.185) has significantly higher microsomal clearance than Ligand B (34.02). This suggests Ligand B is more metabolically stable.

**In vitro Half-Life:** Ligand B (13.987 hours) has a much longer half-life than Ligand A (-10.453 hours). A negative half-life is not physically possible and suggests a significant issue with the prediction for Ligand A.

**P-gp Efflux:** Ligand A (0.524) has lower P-gp efflux than Ligand B (0.267), which is favorable for CNS exposure.

**Binding Affinity:** Ligand B (-7.5 kcal/mol) has a stronger binding affinity than Ligand A (-8.8 kcal/mol). While A is stronger, the difference is not substantial enough to overcome its other weaknesses.

**Overall Assessment:**

Ligand B is the better candidate. While Ligand A has slightly better affinity and P-gp efflux, it suffers from poor Caco-2 permeability, high microsomal clearance, and an implausible negative in vitro half-life. Ligand B has better metabolic stability (lower Cl_mic, longer t1/2), a more favorable logP, and a slightly better BBB score. The TPSA of Ligand A is better, but the other ADME properties of Ligand B are more promising for a CNS-targeting drug.



Output:
1
2025-04-17 05:17:55,234 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (361.825 Da) and Ligand B (339.395 Da) are both acceptable.

**2. TPSA:**  Ligand A (75.63) is higher than the preferred <90 for CNS targets, but still within a reasonable range. Ligand B (54.78) is excellent, well below 90.

**3. logP:** Ligand A (4.506) is slightly high, potentially leading to solubility issues and off-target effects. Ligand B (0.65) is quite low, which could hinder permeability.

**4. H-Bond Donors:** Ligand A (2) is good. Ligand B (0) is also acceptable.

**5. H-Bond Acceptors:** Ligand A (3) is good. Ligand B (4) is also good.

**6. QED:** Both ligands have similar and acceptable QED values (A: 0.725, B: 0.74).

**7. DILI:** Ligand A (77.588) has a higher DILI risk than Ligand B (32.842), which is preferable.

**8. BBB:** This is critical for a CNS target. Ligand A (25.126) has a very low BBB penetration percentile, making it unlikely to reach the target in the brain. Ligand B (62.97) is better, though still not ideal (we want >70).

**9. Caco-2:** Both ligands have negative Caco-2 values which is unusual and suggests poor permeability.

**10. Solubility:** Both ligands have negative solubility values which is also unusual and suggests poor solubility.

**11. hERG:** Both ligands have very low hERG inhibition liability (A: 0.118, B: 0.102), which is excellent.

**12. Cl_mic:** Ligand A (-12.367) has a negative clearance, which is not possible and indicates an issue with the data. Ligand B (10.347) is reasonable.

**13. t1/2:** Ligand A (22.992) has a longer half-life than Ligand B (8.157), which is generally desirable.

**14. Pgp:** Both ligands have very low Pgp efflux liability (A: 0.055, B: 0.025), which is good for CNS penetration.

**15. Binding Affinity:** Both ligands have similar and strong binding affinities (A: -8.7 kcal/mol, B: -8.0 kcal/mol). Ligand A has a slight advantage.

**Overall Assessment:**

Ligand A has a better binding affinity and half-life, but suffers from a very poor BBB prediction, high DILI risk, and a questionable clearance value. Ligand B has a better BBB prediction, lower DILI risk, and a reasonable clearance, but its logP is quite low and its affinity is slightly weaker.

Given the importance of BBB penetration for a CNS target like DRD2, and the significant concerns with Ligand A's BBB score, I would favor **Ligand B**, despite its lower logP and slightly weaker affinity. The lower DILI risk is also a significant advantage. The low logP could potentially be addressed through medicinal chemistry optimization. The negative values for Caco-2 and solubility are concerning and need to be investigated further, but are less critical than the BBB score at this stage.

Output:
1
2025-04-17 05:17:55,235 - INFO - Reasoning:

Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (359.861 and 356.451 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (71.01) is significantly better than Ligand B (83.98). For CNS targets, we want TPSA <= 90, and A is closer to the optimal <= 60 range. B is pushing the upper limit.

**3. logP:** Ligand A (3.889) is slightly higher than Ligand B (2.415), both are within the optimal 1-3 range, but A is closer to the upper limit.

**4. H-Bond Donors:** Ligand A (1) is preferable to Ligand B (2). Lower HBD generally improves permeability.

**5. H-Bond Acceptors:** Ligand A (4) is preferable to Ligand B (5). Lower HBA generally improves permeability.

**6. QED:** Both ligands have similar QED values (0.898 and 0.862), indicating good drug-like properties.

**7. DILI:** Ligand B (70.182) has a slightly higher DILI risk than Ligand A (61.729), but both are acceptable.

**8. BBB:** Ligand A (83.094) has a significantly better BBB penetration percentile than Ligand B (49.011). This is *critical* for a CNS target like DRD2.

**9. Caco-2 Permeability:** Ligand A (-4.944) has better Caco-2 permeability than Ligand B (-5.367), though both are negative values which is unusual.

**10. Aqueous Solubility:** Ligand A (-3.922) has better aqueous solubility than Ligand B (-3.192), though both are negative values which is unusual.

**11. hERG:** Both ligands have very low hERG inhibition liability (0.323 and 0.136), which is excellent.

**12. Microsomal Clearance:** Ligand B (-0.307) has significantly lower microsomal clearance than Ligand A (28.624), indicating better metabolic stability. This is a strong point for B.

**13. In vitro Half-Life:** Ligand A (27.371) has a slightly longer in vitro half-life than Ligand B (25.411).

**14. P-gp Efflux:** Ligand A (0.076) has lower P-gp efflux liability than Ligand B (0.063), which is preferable for CNS penetration.

**15. Binding Affinity:** Ligand A (-9.6 kcal/mol) has a significantly stronger binding affinity than Ligand B (-8.5 kcal/mol). This is a substantial advantage (1.1 kcal/mol difference).

**Overall Assessment:**

Ligand A is the stronger candidate. While Ligand B has better metabolic stability (lower Cl_mic), the significantly superior BBB penetration, TPSA, binding affinity, and slightly better solubility and permeability of Ligand A outweigh this advantage. The strong binding affinity of Ligand A (-9.6 kcal/mol) is a major positive, and the good BBB score (83.094) is essential for a CNS-targeting drug.



Output:
1
2025-04-17 05:17:55,235 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (371.463 and 362.495 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (131.44) is borderline for CNS penetration, being slightly above the preferred <90 cutoff, but still reasonable. Ligand B (55.57) is excellent, well below 90.

**logP:** Ligand A (-0.615) is a bit low, potentially hindering membrane permeability. Ligand B (3.582) is optimal.

**H-Bond Donors/Acceptors:** Ligand A has 4 HBD and 7 HBA, which are acceptable. Ligand B has 0 HBD and 5 HBA, also acceptable.

**QED:** Both ligands have reasonable QED scores (0.448 and 0.682), indicating drug-like properties, with Ligand B being better.

**DILI:** Both ligands have low DILI risk (41.877 and 39.201), which is good.

**BBB:** This is a critical parameter for a CNS target. Ligand A has a BBB percentile of 14.541, which is very poor. Ligand B has a BBB percentile of 96.316, which is excellent.

**Caco-2 Permeability:** Ligand A (-6.223) has very poor Caco-2 permeability. Ligand B (-4.729) is also poor, but better than Ligand A.

**Aqueous Solubility:** Ligand A (-1.657) and Ligand B (-4.284) both have poor aqueous solubility.

**hERG Inhibition:** Ligand A (0.053) has a very low hERG risk, which is excellent. Ligand B (0.762) has a slightly elevated, but still acceptable, hERG risk.

**Microsomal Clearance:** Ligand A (-9.408) has excellent metabolic stability (negative value indicates low clearance). Ligand B (125.244) has high microsomal clearance, suggesting rapid metabolism.

**In vitro Half-Life:** Ligand A (-11.524) has a very long half-life (negative value indicates long half-life). Ligand B (41.043) has a moderate half-life.

**P-gp Efflux:** Ligand A (0.01) has very low P-gp efflux, which is excellent. Ligand B (0.662) has moderate P-gp efflux.

**Binding Affinity:** Both ligands have comparable binding affinities (-7.0 and -7.4 kcal/mol). Ligand B is slightly better.

**Overall Assessment:**

Ligand B is significantly better due to its excellent BBB penetration, optimal logP, and acceptable ADME properties. While its solubility and Caco-2 permeability are not ideal, the strong BBB penetration and good affinity outweigh these drawbacks for a CNS target like DRD2. Ligand A's extremely poor BBB penetration is a major disqualifier, despite its good metabolic stability and low P-gp efflux. The slightly better affinity of Ligand B is a bonus.

Output:
1
2025-04-17 05:17:55,235 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (350.459 Da and 342.443 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (87.66) is better than Ligand B (78.09) as both are below the 90 A^2 threshold for CNS targets.

**logP:** Ligand B (2.123) is slightly higher than Ligand A (1.141), placing it more optimally within the 1-3 range. Ligand A is a bit low, potentially hindering permeation.

**H-Bond Donors/Acceptors:** Ligand A has 3 HBD and 4 HBA, while Ligand B has 2 HBD and 3 HBA. Both are within acceptable limits (<=5 HBD and <=10 HBA).

**QED:** Ligand B (0.823) has a significantly better QED score than Ligand A (0.582), indicating a more drug-like profile.

**DILI:** Ligand A (14.424) has a much lower DILI risk than Ligand B (38.813), which is a significant advantage.

**BBB:** Ligand A (55.176) has a better BBB percentile than Ligand B (42.032), although neither are above the desirable 70% threshold for CNS targets.

**Caco-2 Permeability:** Ligand A (-4.806) has a better Caco-2 permeability than Ligand B (-5.146).

**Aqueous Solubility:** Ligand B (-3.307) has a better aqueous solubility than Ligand A (-1.772).

**hERG:** Both ligands have very low hERG inhibition liability (0.183 and 0.422, respectively), which is excellent.

**Microsomal Clearance:** Ligand A (19.05) has a lower microsomal clearance than Ligand B (25.587), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (0.399) has a shorter in vitro half-life than Ligand B (-23.283), which is a disadvantage.

**P-gp Efflux:** Ligand A (0.123) has a lower P-gp efflux liability than Ligand B (0.197), which is beneficial for CNS exposure.

**Binding Affinity:** Ligand B (-8.7) has a slightly better binding affinity than Ligand A (-8.2), although the difference is relatively small (0.5 kcal/mol).

**Overall Assessment:**

Ligand B has a better QED, logP, solubility, and binding affinity. However, Ligand A has a significantly lower DILI risk, better BBB penetration, lower P-gp efflux, and better metabolic stability. The slightly better binding affinity of Ligand B is not enough to outweigh the advantages of Ligand A, especially considering the importance of minimizing toxicity (DILI) and maximizing CNS exposure (BBB, P-gp) for a DRD2 ligand.

Output:
0
2025-04-17 05:17:55,235 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (357.439 and 366.893 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (99.81) is slightly higher than Ligand B (86.88). Both are below the 140 A^2 threshold for oral absorption, and closer to the desirable <90 A^2 for CNS targets. Ligand B is preferable here.

**logP:** Ligand A (1.856) and Ligand B (2.903) are both within the optimal 1-3 range. Ligand B is slightly better.

**H-Bond Donors/Acceptors:** Ligand A has 2 HBD and 6 HBA, while Ligand B has 3 HBD and 3 HBA. Both are within acceptable limits (<=5 HBD and <=10 HBA).

**QED:** Both ligands have similar QED values (0.79 and 0.693), indicating good drug-likeness.

**DILI:** Ligand A (52.772) has a lower DILI risk than Ligand B (61.962), which is a positive for Ligand A.

**BBB:** This is a critical parameter for a CNS target like DRD2. Ligand B (64.482) has a significantly higher BBB penetration percentile than Ligand A (43.777). This is a major advantage for Ligand B.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.416 and -5.188), which is unusual and suggests poor permeability. This is a concern for both.

**Aqueous Solubility:** Both ligands have negative solubility values (-2.795 and -4.517), indicating poor aqueous solubility. This is a drawback for both, but more pronounced for Ligand A.

**hERG Inhibition:** Ligand A (0.535) has a slightly higher hERG inhibition liability than Ligand B (0.313), meaning Ligand B is preferable.

**Microsomal Clearance:** Ligand A (-0.882) has a lower (better) microsomal clearance than Ligand B (33.691), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (10.473) has a shorter half-life than Ligand B (29.222), which is a negative for Ligand A.

**P-gp Efflux:** Ligand A (0.019) has significantly lower P-gp efflux liability than Ligand B (0.367), which is a strong advantage for Ligand A.

**Binding Affinity:** Ligand B (-8.6 kcal/mol) has a slightly better binding affinity than Ligand A (-8.1 kcal/mol). While the difference is not huge, it's still a positive for Ligand B.

**Overall Assessment:**

Ligand B excels in BBB penetration and binding affinity, two crucial factors for a CNS-targeting GPCR ligand. While it has higher DILI and P-gp efflux, the superior BBB and affinity likely outweigh these drawbacks. Ligand A has better metabolic stability (lower Cl_mic) and lower P-gp efflux, but its significantly lower BBB penetration is a major disadvantage. The poor Caco-2 and solubility are concerns for both, but can potentially be addressed with formulation strategies.

Output:
1
2025-04-17 05:17:55,235 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (346.515 and 349.387 Da) fall comfortably within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (58.2) is significantly better than Ligand B (101.74). For CNS targets, we want TPSA <= 90, and A is well within that, while B is above. This is a substantial advantage for A.

**3. logP:** Ligand A (3.569) is optimal (1-3), while Ligand B (0.918) is a bit low, potentially hindering permeation.

**4. H-Bond Donors:** Both ligands have acceptable HBD counts (2 and 1, respectively), well below the threshold of 5.

**5. H-Bond Acceptors:** Ligand B (6) is slightly higher than Ligand A (2), but both are within the acceptable limit of 10.

**6. QED:** Both ligands have good QED values (0.722 and 0.749), indicating good drug-like properties.

**7. DILI:** Both ligands have acceptable DILI risk (36.448 and 44.552), both below the 60 threshold.

**8. BBB:** Both ligands have good BBB penetration (61.458 and 69.988). Ligand B is slightly better, but both are reasonably good for a CNS target. A value >70 is preferred, but not essential.

**9. Caco-2:** Both have negative Caco-2 values (-4.883 and -4.925). This is unusual and requires further investigation, but it doesn't immediately disqualify either.

**10. Solubility:** Both have negative solubility values (-4.452 and -2.144). Similar to Caco-2, this is concerning and needs further investigation.

**11. hERG:** Both ligands have very low hERG inhibition liability (0.255 and 0.035), which is excellent.

**12. Cl_mic:** Ligand B (4.796) has significantly lower microsomal clearance than Ligand A (53.965), suggesting better metabolic stability. This is a significant advantage for B.

**13. t1/2:** Ligand B (-23.734) has a much longer in vitro half-life than Ligand A (4.163). This is a major advantage for B, potentially allowing for less frequent dosing.

**14. Pgp:** Both have low P-gp efflux liability (0.286 and 0.062), which is good for CNS exposure.

**15. Binding Affinity:** Both ligands have the same binding affinity (-8.3 kcal/mol), which is excellent and well below the -7.0 kcal/mol threshold.

**Overall Assessment:**

While Ligand B has superior metabolic stability (Cl_mic, t1/2) and slightly better BBB penetration, Ligand A has a much more favorable TPSA and logP, which are critical for CNS penetration and overall drug-like properties. The negative Caco-2 and solubility values are concerning for both, but the TPSA and logP differences are more impactful for a GPCR target in the CNS. Given the importance of TPSA and logP for CNS targets, and the strong binding affinity being equal, Ligand A is the slightly better candidate.

Output:
0
2025-04-17 05:17:55,236 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (335.407 and 348.462 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (66.89) is better than Ligand B (49.41) as it's closer to the <90 threshold for CNS targets. Ligand B is excellent.

**3. logP:** Both ligands have good logP values (4.005 and 2.838), falling within the optimal 1-3 range. Ligand B is slightly better.

**4. H-Bond Donors:** Ligand A (2) and Ligand B (1) are both acceptable, being less than 5. Ligand B is slightly better.

**5. H-Bond Acceptors:** Ligand A (3) and Ligand B (2) are both acceptable, being less than 10. Ligand B is slightly better.

**6. QED:** Both ligands have reasonable QED values (0.759 and 0.627), indicating good drug-like properties. Ligand A is better.

**7. DILI:** Ligand A (75.688) has a higher DILI risk than Ligand B (29.701). Ligand B is significantly better here.

**8. BBB:** Both ligands have good BBB penetration (68.554 and 74.913), exceeding the 70% threshold for CNS targets. Ligand B is slightly better.

**9. Caco-2:** Both ligands have negative Caco-2 values (-5.014 and -4.607) which is unusual and suggests poor permeability. This is a significant drawback for both.

**10. Solubility:** Both ligands have negative solubility values (-5.4 and -3.824), indicating very poor aqueous solubility. This is a major concern for both.

**11. hERG:** Both ligands have low hERG inhibition risk (0.689 and 0.355). Ligand B is better.

**12. Cl_mic:** Both ligands have similar microsomal clearance values (33.774 and 32.526).

**13. t1/2:** Ligand A (65.992) has a significantly longer in vitro half-life than Ligand B (-22.32). This is a major advantage for Ligand A.

**14. Pgp:** Ligand A (0.508) has lower P-gp efflux liability than Ligand B (0.23). This is better for CNS exposure.

**15. Binding Affinity:** Ligand B (-7.3 kcal/mol) has a significantly stronger binding affinity than Ligand A (-9.8 kcal/mol). This is a substantial advantage, potentially outweighing some ADME drawbacks.

**Overall Assessment:**

While Ligand A has a longer half-life and lower Pgp efflux, Ligand B demonstrates a significantly stronger binding affinity (-7.3 vs -9.8 kcal/mol), lower DILI risk, and slightly better BBB penetration. The negative Caco-2 and solubility values are concerning for both, but the superior affinity of Ligand B is a critical factor for a GPCR target. Given the importance of potency for GPCRs, and the relatively better ADME profile of Ligand B (especially the lower DILI), it is the more promising candidate.

Output:
1
2025-04-17 05:17:55,236 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (343.43 and 384.86 Da) fall within the ideal range of 200-500 Da.

**TPSA:** Both ligands have TPSA values (74.59 and 72.63) below the 90 A^2 threshold desirable for CNS targets, which is excellent.

**logP:** Both ligands have logP values (2.013 and 2.78) within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Both ligands have acceptable HBD (1) and HBA (5/4) counts, well below the thresholds of 5 and 10, respectively.

**QED:** Both ligands have good QED scores (0.885 and 0.86), indicating good drug-likeness.

**DILI:** Ligand A (28.31) has a significantly lower DILI risk than Ligand B (56.73), placing it in the desirable <40 percentile. Ligand B is moderately risky.

**BBB:** Ligand A (83.99) has a much better BBB penetration score than Ligand B (64.87). This is a critical advantage for a CNS target like DRD2.

**Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and suggests poor permeability. However, the scale is not specified, so it's difficult to interpret.

**Aqueous Solubility:** Both ligands have negative solubility values, again, the scale is not specified, making interpretation difficult.

**hERG:** Both ligands have low hERG inhibition liability (0.876 and 0.746), which is favorable.

**Microsomal Clearance:** Ligand A (24.37) has a higher microsomal clearance than Ligand B (10.01), suggesting lower metabolic stability.

**In vitro Half-Life:** Ligand B (-10.04) has a negative half-life, which is not possible. This is likely an error in the data and raises concerns about the reliability of this value for Ligand B. Ligand A has a reasonable half-life of 33.70 hours.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.042 and 0.37), which is excellent for CNS penetration.

**Binding Affinity:** Ligand B (-9.7 kcal/mol) has a slightly better binding affinity than Ligand A (-7.8 kcal/mol). However, the difference is 1.9 kcal/mol, which is significant but might be outweighed by other factors.

**Overall Assessment:**

Ligand A is the more promising candidate. While Ligand B has slightly better binding affinity, Ligand A excels in crucial ADME properties for a CNS-targeting GPCR. Specifically, its significantly lower DILI risk and substantially better BBB penetration are major advantages. The questionable half-life value for Ligand B further diminishes its appeal. The slightly higher clearance of Ligand A is a minor concern that could potentially be addressed through structural modifications.

Output:
1
2025-04-17 05:17:55,236 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (342.443 and 352.431 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (88.32) is better than Ligand B (74.03) as it is closer to the ideal <90 for CNS targets.

**logP:** Both ligands have good logP values (2.153 and 1.666), falling within the optimal 1-3 range. Ligand B is slightly lower, which *could* indicate slightly better solubility but potentially reduced permeability.

**H-Bond Donors/Acceptors:** Ligand A has 2 HBD and 4 HBA, while Ligand B has 0 HBD and 6 HBA. Both are within acceptable limits (<=5 HBD and <=10 HBA).

**QED:** Both ligands have similar QED values (0.743 and 0.673), indicating good drug-like properties.

**DILI:** Ligand A (37.611) has a slightly higher DILI risk than Ligand B (31.989), but both are below the concerning threshold of 60.

**BBB:** Ligand A (78.519) has a better BBB penetration score than Ligand B (74.254), which is crucial for a CNS target like DRD2. Both are reasonably good, but A is preferable.

**Caco-2 Permeability:** Ligand A (-5.207) has worse Caco-2 permeability than Ligand B (-4.72).

**Aqueous Solubility:** Ligand A (-2.634) has worse aqueous solubility than Ligand B (-1.169).

**hERG Inhibition:** Both ligands show low hERG inhibition risk (0.563 and 0.421).

**Microsomal Clearance:** Ligand A (-12.79) has significantly lower (better) microsomal clearance than Ligand B (50.166), indicating better metabolic stability.

**In vitro Half-Life:** Ligand A (-11.997) has a longer in vitro half-life than Ligand B (25.414), which is desirable.

**P-gp Efflux:** Ligand A (0.028) has much lower P-gp efflux liability than Ligand B (0.142), which is very important for CNS penetration.

**Binding Affinity:** Ligand A (-8.9 kcal/mol) has a significantly stronger binding affinity than Ligand B (-6.7 kcal/mol). This >1.5 kcal/mol difference is a major advantage, potentially outweighing some ADME drawbacks.

**Overall Assessment:**

Ligand A is the stronger candidate. While Ligand B has slightly better solubility and Caco-2 permeability, Ligand A excels in the most critical areas for a CNS-targeting GPCR ligand: significantly higher binding affinity, better BBB penetration, lower P-gp efflux, and improved metabolic stability (lower Cl_mic and longer t1/2). The slightly higher DILI risk is less concerning given the strong affinity and CNS penetration properties.



Output:
1
2025-04-17 05:17:55,236 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (342.395 and 351.466 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (74.45) is slightly above the optimal <90 for CNS targets, but still reasonable. Ligand B (52.65) is excellent, well below 90.

**logP:** Ligand A (3.367) is at the upper end of the optimal 1-3 range, but acceptable. Ligand B (1.713) is good, falling comfortably within the range.

**H-Bond Donors/Acceptors:** Ligand A (0 HBD, 6 HBA) is favorable. Ligand B (1 HBD, 3 HBA) is also good. Both are within the recommended limits.

**QED:** Both ligands have good QED scores (0.567 and 0.793), indicating good drug-like properties.

**DILI:** Ligand A (73.09) has a higher DILI risk than Ligand B (10.624). This is a significant negative for Ligand A.

**BBB:** Ligand A (81.776) has a good BBB penetration percentile, exceeding the 70% threshold. Ligand B (91.896) is even better, indicating excellent potential for CNS exposure.

**Caco-2 Permeability:** Ligand A (-4.784) has poor Caco-2 permeability. Ligand B (-5.023) also has poor Caco-2 permeability.

**Aqueous Solubility:** Ligand A (-4.029) has poor aqueous solubility. Ligand B (-1.992) has slightly better, but still poor aqueous solubility.

**hERG Inhibition:** Ligand A (0.141) has a very low hERG inhibition risk. Ligand B (0.516) has a slightly higher, but still acceptable hERG risk.

**Microsomal Clearance:** Ligand A (68.982) has moderate microsomal clearance. Ligand B (-4.564) has negative clearance, which is excellent (indicates very high metabolic stability).

**In vitro Half-Life:** Ligand A (-1.216) has a negative half-life, which is excellent. Ligand B (16.011) has a reasonable half-life.

**P-gp Efflux:** Ligand A (0.315) has low P-gp efflux, which is favorable for CNS penetration. Ligand B (0.046) has very low P-gp efflux, even better.

**Binding Affinity:** Ligand B (-7.9 kcal/mol) has a significantly stronger binding affinity than Ligand A (-8.9 kcal/mol). While both are excellent, the 1 kcal/mol difference is substantial.

**Overall Assessment:**

Ligand B is the superior candidate. While both have poor Caco-2 and solubility, Ligand B excels in key areas for a CNS-targeting GPCR ligand: significantly better metabolic stability (Cl_mic), excellent BBB penetration, very low P-gp efflux, and a slightly stronger binding affinity. Ligand A's higher DILI risk is also a concern.

Output:
1
2025-04-17 05:17:55,237 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (334.419 and 349.431 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (45.33) is excellent for CNS penetration, well below the 90 A^2 threshold. Ligand B (84.67) is higher but still reasonable, though less optimal for CNS targets.

**logP:** Ligand A (4.371) is slightly high, potentially leading to solubility issues or off-target interactions. Ligand B (1.767) is within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Both ligands have acceptable HBD (1) and HBA (2 for A, 5 for B) counts, staying within the guidelines.

**QED:** Both ligands have good QED scores (0.77 and 0.895), indicating drug-like properties.

**DILI:** Ligand A (75.107) has a concerningly high DILI risk (above the 60 threshold). Ligand B (33.075) has a very favorable DILI profile.

**BBB:** Both ligands have good BBB penetration (69.407 and 65.335), but Ligand A is slightly better. However, both are below the desirable >70 for CNS targets.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.845 and -4.664), which is unusual and suggests poor permeability. This is a significant drawback for both.

**Aqueous Solubility:** Both ligands have negative solubility values (-6.165 and -2.493), indicating poor aqueous solubility. This is a concern, especially given Ligand A's higher logP.

**hERG:** Ligand A (0.796) has a slightly elevated hERG risk, while Ligand B (0.23) is very low, indicating a much lower risk of cardiotoxicity.

**Microsomal Clearance:** Ligand A (57.796) has a higher microsomal clearance than Ligand B (17.769), suggesting lower metabolic stability.

**In vitro Half-Life:** Ligand A (23.464) has a shorter half-life than Ligand B (8.694), which is less desirable.

**P-gp Efflux:** Ligand A (0.695) has lower P-gp efflux than Ligand B (0.089), which is favorable for CNS exposure.

**Binding Affinity:** Ligand B (-7.5 kcal/mol) has a significantly stronger binding affinity than Ligand A (-9.5 kcal/mol). This 1.5 kcal/mol difference is substantial and can outweigh some ADME drawbacks.

**Overall Assessment:**

Ligand B is the better candidate. While both have issues with Caco-2 and solubility, Ligand B has a much better safety profile (lower DILI, lower hERG), better metabolic stability (lower Cl_mic, longer t1/2), and, critically, significantly higher binding affinity. Ligand A's higher logP, DILI risk, and shorter half-life are major concerns. The stronger binding affinity of Ligand B is a significant advantage for a GPCR target like DRD2.

Output:
1
2025-04-17 05:17:55,237 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight (MW):** Both ligands (356.482 and 361.511 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (67.43) is slightly higher than Ligand B (59.23). Both are below the 90 A^2 threshold for CNS targets, which is good. Ligand B is preferable here.

**3. logP:** Ligand A (3.572) and Ligand B (4.064) are both within the optimal 1-3 range, but Ligand B is pushing the upper limit.

**4. H-Bond Donors (HBD):** Ligand A has 2 HBD, and Ligand B has 0. Both are acceptable (<=5).

**5. H-Bond Acceptors (HBA):** Ligand A has 3 HBA, and Ligand B has 5. Both are acceptable (<=10).

**6. QED:** Both ligands have similar QED values (0.733 and 0.746), indicating good drug-likeness.

**7. DILI:** Ligand A (19.698) has a significantly lower DILI risk than Ligand B (38.697). This is a substantial advantage for Ligand A.

**8. BBB:** Both ligands have excellent BBB penetration (Ligand A: 82.862, Ligand B: 83.831), exceeding the >70% threshold for CNS targets. They are comparable here.

**9. Caco-2 Permeability:** Both have negative Caco-2 values (-4.302 and -4.907). This is unusual and suggests poor permeability. However, these values are on a scale where negative values are possible, and their relative comparison is important. Ligand B is slightly worse.

**10. Aqueous Solubility:** Both ligands have negative solubility values (-3.63 and -3.486), indicating poor aqueous solubility. Again, relative comparison is important. Ligand B is slightly worse.

**11. hERG Inhibition:** Both have low hERG inhibition risk (0.664 and 0.338), which is good. Ligand B is preferable here.

**12. Microsomal Clearance:** Ligand A (57.528) has lower microsomal clearance than Ligand B (91.401), indicating better metabolic stability. This is a significant advantage for Ligand A.

**13. In vitro Half-Life:** Ligand A (-3.609) has a much more favorable in vitro half-life than Ligand B (-14.666). This is a major advantage for Ligand A.

**14. P-gp Efflux:** Both ligands have low P-gp efflux liability (0.187 and 0.493), which is good for CNS exposure. Ligand A is preferable here.

**15. Binding Affinity:** Both ligands have excellent binding affinity (-8.2 and -8.0 kcal/mol). The difference is minimal, and both are well below the -7.0 kcal/mol threshold.

**Overall Assessment:**

While Ligand B has a slightly better logP and hERG profile, Ligand A significantly outperforms it in crucial ADME properties: DILI risk, microsomal clearance, and in vitro half-life.  The comparable BBB penetration and excellent binding affinity of both compounds are positives. Given the GPCR-specific focus, and the importance of metabolic stability and reduced toxicity for CNS drugs, Ligand A is the more promising candidate. The negative Caco-2 and solubility values are concerning for both, but the other advantages of Ligand A outweigh this concern.

Output:
0
2025-04-17 05:17:55,237 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (354.491 and 350.375 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (89.87) is excellent, being below the 90 Angstroms threshold for CNS targets. Ligand B (119.51) is higher, but still potentially acceptable, though less ideal.

**3. logP:** Ligand A (1.299) is within the optimal range of 1-3. Ligand B (0.063) is quite low, potentially hindering membrane permeability.

**4. H-Bond Donors:** Both ligands have acceptable HBD counts (3 and 2, respectively), well below the 5 threshold.

**5. H-Bond Acceptors:** Ligand A (4) is good. Ligand B (7) is also acceptable, being below the 10 threshold.

**6. QED:** Both ligands have similar and acceptable QED values (0.671 and 0.636, both > 0.5).

**7. DILI:** Ligand A (6.592) has a significantly lower DILI risk than Ligand B (72.819), which is quite high. This is a major advantage for Ligand A.

**8. BBB:** Ligand A (48.158) has a moderate BBB penetration score, while Ligand B (54.478) is also moderate. Both are below the desirable >70 for CNS targets, but Ligand B is slightly better.

**9. Caco-2:** Both ligands have negative Caco-2 values (-4.871 and -4.83), which is unusual and suggests poor permeability.

**10. Solubility:** Both ligands have negative solubility values (-1.627 and -2.965), indicating poor aqueous solubility.

**11. hERG:** Both ligands have very low hERG inhibition liability (0.252 and 0.029).

**12. Cl_mic:** Ligand A (17.686) has a lower microsomal clearance than Ligand B (55.993), suggesting better metabolic stability.

**13. t1/2:** Ligand A (-19.615) has a more negative in vitro half-life, which is unusual and suggests a very short half-life. Ligand B (-21.245) is even worse.

**14. Pgp:** Both ligands have very low P-gp efflux liability (0.04 and 0.029).

**15. Binding Affinity:** Ligand B (-7.2 kcal/mol) has a slightly better binding affinity than Ligand A (-8.0 kcal/mol). However, the difference is relatively small.

**Overall Assessment:**

Considering the GPCR-specific priorities, Ligand A is the more promising candidate. While both have issues with Caco-2 and solubility, Ligand A has a significantly lower DILI risk, better metabolic stability (lower Cl_mic), and a more favorable logP. The slightly better affinity of Ligand B is unlikely to outweigh the substantial risks associated with its high DILI score and poor metabolic stability. The BBB values for both are suboptimal, but this can potentially be addressed through further optimization.

Output:
1
2025-04-17 05:17:55,237 - INFO - Batch 186 complete. Total preferences: 2976
2025-04-17 05:17:55,237 - INFO - Processing batch 187/512...
2025-04-17 05:18:46,857 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (347.459 Da) is slightly lower, which could be beneficial for permeability. Ligand B (364.442 Da) is also good.

**TPSA:** Ligand A (93.43) is better than Ligand B (51.66). For CNS targets, TPSA should be <= 90, and Ligand A is right on the cusp, while Ligand B is well within the range.

**logP:** Ligand A (1.763) is optimal, while Ligand B (3.552) is approaching the upper limit. Higher logP can sometimes lead to off-target effects.

**H-Bond Donors/Acceptors:** Ligand A has 2 HBD and 4 HBA, which is a good balance. Ligand B has 0 HBD and 5 HBA, also reasonable.

**QED:** Both ligands have good QED values (A: 0.622, B: 0.719), indicating good drug-like properties.

**DILI:** Ligand A (12.292) has a much lower DILI risk than Ligand B (36.06). This is a significant advantage for Ligand A.

**BBB:** Ligand B (89.957) has a significantly higher BBB penetration percentile than Ligand A (29.74). This is a *critical* factor for a CNS target like DRD2.

**Caco-2 Permeability:** Ligand A (-4.99) and Ligand B (-4.249) both have negative values, which is unusual and suggests poor permeability. However, the scale isn't specified, so it's hard to interpret.

**Aqueous Solubility:** Ligand A (-1.266) has slightly better solubility than Ligand B (-4.543).

**hERG Inhibition:** Ligand A (0.366) has a lower hERG inhibition liability than Ligand B (0.669), which is preferable.

**Microsomal Clearance:** Ligand A (-0.543) has a lower (better) microsomal clearance than Ligand B (89.519), indicating better metabolic stability.

**In vitro Half-Life:** Ligand A (-7.227) has a much longer in vitro half-life than Ligand B (-14.462).

**P-gp Efflux:** Ligand A (0.022) has a much lower P-gp efflux liability than Ligand B (0.304), which is crucial for CNS penetration.

**Binding Affinity:** Ligand A (-7.7 kcal/mol) has a slightly better binding affinity than Ligand B (-6.9 kcal/mol). While both are good, the difference is significant enough to consider.

**Overall Assessment:**

Ligand A excels in metabolic stability (Cl_mic, t1/2), DILI risk, P-gp efflux, hERG, and has slightly better binding affinity. Ligand B's primary advantage is its significantly higher BBB penetration. However, the combination of lower DILI, better metabolic stability, lower efflux, and comparable affinity makes Ligand A a more promising candidate. The lower BBB score for Ligand A is a concern, but can potentially be addressed with further modifications. The poor Caco-2 values for both are concerning and would require investigation.

Output:
0
2025-04-17 05:18:46,858 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (370.881 and 352.431 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Both ligands (76.58 and 77.1) are below the 90 A^2 threshold for CNS targets, which is good.

**3. logP:** Ligand A (3.265) is optimal, while Ligand B (1.187) is slightly low, potentially hindering permeation.

**4. H-Bond Donors:** Both ligands have 1 HBD, which is within the acceptable limit of <=5.

**5. H-Bond Acceptors:** Ligand A has 6 HBAs, and Ligand B has 5. Both are within the acceptable limit of <=10.

**6. QED:** Ligand A (0.823) has a significantly better QED score than Ligand B (0.457), indicating a more drug-like profile.

**7. DILI:** Ligand A (59.519) has a slightly higher DILI risk than Ligand B (45.483), but both are below the concerning threshold of 60.

**8. BBB:** Both ligands have good BBB penetration (Ligand A: 70.609, Ligand B: 68.36), but Ligand A is slightly better.

**9. Caco-2 Permeability:** Both have negative values, which is unusual. Assuming these are logP-like scales, lower values suggest poorer permeability. Ligand A (-4.514) is worse than Ligand B (-4.861).

**10. Aqueous Solubility:** Both have negative values, indicating poor solubility. Ligand A (-3.763) is slightly better than Ligand B (-1.704).

**11. hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.214 and 0.211).

**12. Microsomal Clearance:** Ligand B (11.247) has significantly lower microsomal clearance than Ligand A (61.489), suggesting better metabolic stability.

**13. In vitro Half-Life:** Ligand B (-3.876) has a negative half-life, which is not possible. This is likely an error in the data. Ligand A (2.689) has a reasonable half-life.

**14. P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.05 and 0.032).

**15. Binding Affinity:** Ligand B (-7.6 kcal/mol) has a slightly better binding affinity than Ligand A (-7.1 kcal/mol), with a 0.5 kcal/mol advantage.

**Overall Assessment:**

Despite Ligand B's slightly better binding affinity and lower clearance, Ligand A is the more promising candidate. The significantly better QED score of Ligand A suggests a more balanced and drug-like profile. While Ligand B has better metabolic stability, the negative half-life value is concerning. Ligand A also has a slightly better BBB score and a more optimal logP value. The Caco-2 and solubility values are poor for both, but Ligand A is marginally better. The 0.5 kcal/mol difference in binding affinity is not substantial enough to outweigh the other advantages of Ligand A, especially considering the importance of ADME properties for CNS drugs.

Output:
1
2025-04-17 05:18:46,858 - INFO - Reasoning:

Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (355.419 Da and 344.371 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (84.34) is excellent, well below the 90 A^2 threshold for CNS targets. Ligand B (108.55) is still reasonable but less optimal, being above 90 A^2.

**logP:** Ligand A (3.87) is at the upper end of the optimal range (1-3), but acceptable. Ligand B (1.77) is at the lower end, potentially impacting permeability.

**H-Bond Donors/Acceptors:** Both have 2 HBD and 6 HBA, which are within acceptable limits (<=5 and <=10 respectively).

**QED:** Both ligands have good QED scores (0.726 and 0.878), indicating good drug-like properties.

**DILI:** Ligand A (94.649) has a concerningly high DILI risk (above 60). Ligand B (77.2) is better, but still warrants attention.

**BBB:** Both ligands have very low BBB penetration (19.542 and 19.038), which is a major drawback for a CNS target like DRD2. This is a critical failure for both.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.035 and -5.109), which is unusual and suggests poor permeability.

**Aqueous Solubility:** Both ligands have negative solubility values (-4.699 and -2.801), which is also concerning and suggests poor solubility.

**hERG Inhibition:** Ligand A (0.442) has a slightly higher hERG risk than Ligand B (0.015), but both are relatively low.

**Microsomal Clearance:** Ligand A (57.181) has higher clearance than Ligand B (4.809), indicating lower metabolic stability.

**In vitro Half-Life:** Ligand B (2.361) has a slightly longer half-life than Ligand A (-4.395).

**P-gp Efflux:** Ligand A (0.45) has slightly higher P-gp efflux than Ligand B (0.011).

**Binding Affinity:** Ligand A (-9.9 kcal/mol) has a significantly stronger binding affinity than Ligand B (-8.5 kcal/mol). The difference of 1.4 kcal/mol is substantial and could outweigh some ADME concerns.

**Overall Assessment:**

Despite the significantly better binding affinity of Ligand A, the extremely poor BBB penetration of *both* compounds is a deal-breaker for a CNS target. The high DILI risk for Ligand A is also a major concern. While Ligand B has slightly better ADME properties (lower DILI, lower clearance, longer half-life, lower P-gp efflux), its lower affinity and poor BBB penetration are still problematic.

However, the substantial difference in binding affinity (-9.9 vs -8.5 kcal/mol) is a significant factor. If we *had* to choose, and assuming further optimization could address the BBB and DILI issues, Ligand A's stronger binding makes it the slightly more promising starting point. But, realistically, both compounds require substantial modification to become viable drug candidates.

Output:
0
2025-04-17 05:18:46,858 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (361.511 and 365.459 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (65.36) is excellent, well below the 90 A^2 threshold for CNS targets. Ligand B (117.42) is higher, but still potentially acceptable, though less ideal.

**3. logP:** Ligand A (3.39) is optimal. Ligand B (0.238) is quite low, which could hinder membrane permeability and CNS penetration.

**4. H-Bond Donors:** Ligand A (1) is good. Ligand B (3) is acceptable, but higher.

**5. H-Bond Acceptors:** Both ligands (A: 5, B: 5) are within the acceptable range (<=10).

**6. QED:** Ligand A (0.815) is excellent, indicating high drug-likeness. Ligand B (0.641) is still reasonable, but lower.

**7. DILI:** Ligand A (29.857) has a significantly lower DILI risk than Ligand B (47.344).

**8. BBB:** Ligand A (60.372) has a moderate BBB penetration, while Ligand B (52.811) is lower. Both are below the desirable >70 for CNS targets, but A is better.

**9. Caco-2 Permeability:** Ligand A (-4.811) has poor Caco-2 permeability. Ligand B (-5.609) is even worse.

**10. Aqueous Solubility:** Ligand A (-3.822) has poor aqueous solubility. Ligand B (-2.221) is slightly better, but still poor.

**11. hERG Inhibition:** Ligand A (0.86) has a slightly higher hERG risk than Ligand B (0.039), but both are relatively low.

**12. Microsomal Clearance:** Ligand A (55.34) has moderate clearance. Ligand B (-6.396) has negative clearance, which is unusual and suggests potential instability or an issue with the prediction method.

**13. In vitro Half-Life:** Ligand A (21.463) has a reasonable half-life. Ligand B (-4.302) has a negative half-life, which is not possible and indicates a problem with the prediction.

**14. P-gp Efflux:** Ligand A (0.222) has low P-gp efflux, which is good for CNS penetration. Ligand B (0.009) has very low P-gp efflux, which is even better.

**15. Binding Affinity:** Ligand A (-7.5 kcal/mol) has a slightly better binding affinity than Ligand B (-7.1 kcal/mol). While the difference is not huge, it is still a factor.

**Overall Assessment:**

Ligand A is superior despite its poor Caco-2 and solubility. Its better logP, QED, DILI, and slightly better affinity are significant advantages. Ligand B's extremely low logP is a major concern, and the negative values for clearance and half-life are red flags indicating unreliable predictions or inherent instability. Although both have poor Caco-2 and solubility, these can be addressed with formulation strategies. The negative values for Ligand B are more concerning.

Output:
1
2025-04-17 05:18:46,858 - INFO - Okay, let's analyze these two ligands for their potential as DRD2 drug candidates. DRD2 is a GPCR in the CNS, so BBB penetration, logP, Pgp efflux, TPSA, and binding affinity are paramount.

**Ligand A: [363.439, 86.88, 2.414, 1, 6, 0.848, 52.385, 66.615, -5.253, -1.788, 0.081, -14.177, -2.617, 0.025, -8.3]**

*   **MW:** 363.439 Da - Within the ideal range (200-500).
*   **TPSA:** 86.88 - Good for CNS penetration, below the 90 threshold.
*   **logP:** 2.414 - Excellent, within the optimal 1-3 range.
*   **HBD:** 1 - Acceptable.
*   **HBA:** 6 - Acceptable.
*   **QED:** 0.848 - Very good, indicating high drug-likeness.
*   **DILI:** 52.385 - Low risk of liver injury.
*   **BBB:** 66.615 - Good, but could be better for a CNS target. Ideally >70.
*   **Caco-2:** -5.253 - Negative value is unusual and suggests very poor permeability. This is a significant concern.
*   **Solubility:** -1.788 - Very poor solubility. A major drawback.
*   **hERG:** 0.081 - Very low risk of hERG inhibition.
*   **Cl_mic:** -14.177 - Negative value is unusual and suggests very high metabolic stability.
*   **t1/2:** -2.617 - Negative value is unusual and suggests very long half-life.
*   **Pgp:** 0.025 - Very low P-gp efflux, which is excellent for CNS penetration.
*   **Affinity:** -8.3 kcal/mol - Excellent binding affinity.

**Ligand B: [339.395, 73.64, 1.273, 0, 4, 0.578, 51.221, 56.883, -4.311, -1.8, 0.679, 8.816, -2.095, 0.118, -7.5]**

*   **MW:** 339.395 Da - Within the ideal range (200-500).
*   **TPSA:** 73.64 - Good for CNS penetration, below the 90 threshold.
*   **logP:** 1.273 - Acceptable, but on the lower end of the optimal range.
*   **HBD:** 0 - Acceptable.
*   **HBA:** 4 - Acceptable.
*   **QED:** 0.578 - Acceptable drug-likeness.
*   **DILI:** 51.221 - Low risk of liver injury.
*   **BBB:** 56.883 - Moderate, but not ideal for a CNS target.
*   **Caco-2:** -4.311 - Negative value is unusual and suggests very poor permeability. This is a significant concern.
*   **Solubility:** -1.8 - Very poor solubility. A major drawback.
*   **hERG:** 0.679 - Low risk of hERG inhibition.
*   **Cl_mic:** 8.816 - Moderate metabolic clearance.
*   **t1/2:** -2.095 - Negative value is unusual and suggests very long half-life.
*   **Pgp:** 0.118 - Low P-gp efflux, which is good for CNS penetration.
*   **Affinity:** -7.5 kcal/mol - Good binding affinity, but 0.8 kcal/mol weaker than Ligand A.

**Comparison and Decision:**

Both ligands have significant issues with Caco-2 permeability and solubility. The negative values are concerning and likely indicate errors in the prediction or unusual behavior. However, Ligand A has a substantially better binding affinity (-8.3 vs -7.5 kcal/mol). It also has a slightly better BBB score, lower Pgp efflux, and a better QED score. The negative values for Cl_mic and t1/2 are unusual, but suggest potentially favorable metabolic stability and long half-life. While the solubility and permeability are problematic for both, the superior affinity of Ligand A, combined with its other slightly better properties, makes it the more promising candidate *assuming the negative values are not indicative of fundamental flaws*. Further investigation into the solubility and permeability predictions would be crucial.

1
2025-04-17 05:18:46,858 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (379.517 Da) is slightly higher than Ligand B (355.479 Da), but both are acceptable.

**TPSA:** Ligand A (52.65) is significantly better than Ligand B (93.11). For CNS targets, we want TPSA <= 90, so Ligand A is much more favorable.

**logP:** Ligand A (1.926) is optimal (1-3). Ligand B (-0.187) is below 1, which could hinder permeation. This is a significant drawback for Ligand B.

**H-Bond Donors/Acceptors:** Ligand A (HBD=1, HBA=4) and Ligand B (HBD=3, HBA=5) both fall within acceptable ranges.

**QED:** Both ligands have similar and good QED values (0.63 and 0.636).

**DILI:** Ligand A (31.95) has a much lower DILI risk than Ligand B (7.871), indicating better predicted liver safety.

**BBB:** Ligand A (74.137) has a good BBB percentile, exceeding the desirable threshold of 70. Ligand B (11.012) is very poor, suggesting limited CNS penetration. This is a critical disadvantage for a DRD2 ligand.

**Caco-2 Permeability:** Both have negative values, which is unusual and likely indicates a scaling issue. However, Ligand A (-5.004) is less negative than Ligand B (-5.169), potentially suggesting slightly better permeability.

**Aqueous Solubility:** Both have negative values, which is also unusual. Ligand A (-2.015) is slightly better than Ligand B (-0.77).

**hERG:** Ligand A (0.687) has a lower hERG risk than Ligand B (0.321), which is preferable.

**Microsomal Clearance:** Ligand A (16.74) has a higher clearance than Ligand B (-2.28). This suggests Ligand B is more metabolically stable, which is a positive.

**In vitro Half-Life:** Ligand A (-2.126) has a shorter half-life than Ligand B (-2.638), which is less desirable.

**P-gp Efflux:** Ligand A (0.046) has lower P-gp efflux than Ligand B (0.019), which is better for CNS exposure.

**Binding Affinity:** Both ligands have excellent binding affinities (-7.1 and -7.2 kcal/mol). The difference is minimal and doesn't outweigh the other significant differences.

**Conclusion:**

Considering the GPCR-specific priorities and the overall profile, **Ligand A is the more promising drug candidate**. It has a much better TPSA, logP, BBB penetration, and DILI risk profile. While Ligand B has slightly better metabolic stability and half-life, the poor BBB penetration and logP are significant drawbacks for a CNS target like DRD2. The comparable binding affinity makes the superior ADME properties of Ligand A decisive.

Output:
1
2025-04-17 05:18:46,859 - INFO - Reasoning:

Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (362.411 and 350.507 Da) fall within the ideal range of 200-500 Da.

**TPSA:** Ligand A (108.47) is higher than the ideal <90 for CNS targets, while Ligand B (58.44) is well within the desired range. This is a significant advantage for Ligand B.

**logP:** Ligand A (0.791) is a bit low, potentially hindering permeation. Ligand B (3.067) is near the optimal range of 1-3.

**H-Bond Donors/Acceptors:** Ligand A has 2 HBD and 7 HBA, which are acceptable. Ligand B has 0 HBD and 4 HBA, also acceptable.

**QED:** Both ligands have reasonable QED values (0.754 and 0.688), indicating good drug-like properties.

**DILI:** Ligand A (74.68) has a higher DILI risk than Ligand B (25.785). This is a negative for Ligand A.

**BBB:** Ligand B (79.992) has a significantly better BBB penetration score than Ligand A (57.968). This is crucial for a CNS target like DRD2.

**Caco-2 Permeability:** Ligand A (-5.363) has poor Caco-2 permeability, while Ligand B (-4.418) is slightly better, but still not ideal.

**Aqueous Solubility:** Ligand A (-3.703) has poor solubility, while Ligand B (-1.956) is better, but still not great.

**hERG Inhibition:** Ligand A (0.062) has a very low hERG risk, which is excellent. Ligand B (0.813) has a slightly elevated, but still acceptable, hERG risk.

**Microsomal Clearance:** Ligand A (29.36) has lower clearance than Ligand B (76.056), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand B (7.303) has a longer half-life than Ligand A (-4.918).

**P-gp Efflux:** Ligand A (0.238) has lower P-gp efflux than Ligand B (0.435), which is favorable for CNS penetration.

**Binding Affinity:** Ligand B (-7.1) has a slightly better binding affinity than Ligand A (-8.0). While A is better, the difference is not large enough to overcome the other deficiencies.

**Overall Assessment:**

Ligand B is the stronger candidate. It excels in BBB penetration, has a better logP, lower DILI risk, and a longer half-life. While its Caco-2 and solubility are not ideal, these can be addressed through formulation strategies. Ligand A suffers from poor BBB penetration, low logP, and poor solubility, which are significant drawbacks for a CNS-targeted GPCR. The slightly better affinity of Ligand A is outweighed by the superior ADME properties of Ligand B.

Output:
1
2025-04-17 05:18:46,859 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (360.885 and 360.332 Da) fall comfortably within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (51.22) is significantly better than Ligand B (79.82). For CNS targets, we want TPSA <= 90, and A is much closer to the ideal <=60. B is pushing the upper limit and could have reduced brain penetration.

**3. logP:** Ligand A (4.625) is a bit high, potentially leading to solubility issues or off-target interactions, but still within a reasonable range. Ligand B (2.133) is excellent, falling squarely within the optimal 1-3 range.

**4. H-Bond Donors:** Ligand A (1) is preferable to Ligand B (3). Fewer HBDs generally improve permeability.

**5. H-Bond Acceptors:** Ligand A (3) is preferable to Ligand B (4). Fewer HBAs generally improve permeability.

**6. QED:** Ligand A (0.817) is superior to Ligand B (0.696), indicating a more drug-like profile.

**7. DILI:** Ligand A (65.374) has a higher DILI risk than Ligand B (47.693), but both are acceptable (below 60).

**8. BBB:** Ligand B (78.868) has a significantly better BBB percentile than Ligand A (50.407). This is *crucial* for a CNS target like DRD2.

**9. Caco-2:** Both ligands have negative Caco-2 values (-4.841 and -4.963), which is unusual and suggests poor permeability. This is a significant drawback for both.

**10. Solubility:** Both ligands have negative solubility values (-5.763 and -2.881), which is also unusual and suggests poor aqueous solubility. This is a significant drawback for both.

**11. hERG:** Both ligands have low hERG risk (0.428 and 0.594).

**12. Cl_mic:** Ligand B (11.104) has a much lower microsomal clearance than Ligand A (104.891), indicating better metabolic stability.

**13. t1/2:** Ligand B (15.567) has a longer in vitro half-life than Ligand A (22.832).

**14. Pgp:** Ligand A (0.362) has lower P-gp efflux liability than Ligand B (0.046), which is beneficial for CNS penetration.

**15. Binding Affinity:** Ligand B (-7.9 kcal/mol) has a substantially stronger binding affinity than Ligand A (-9.8 kcal/mol). A difference of >1.5 kcal/mol is significant and can outweigh other drawbacks.

**Overall Assessment:**

While Ligand A has better QED, fewer H-bonds, and lower Pgp efflux, Ligand B is the stronger candidate. The most important factors for a CNS-targeting GPCR are BBB penetration and binding affinity. Ligand B has a much higher BBB percentile (78.868 vs 50.407) and a significantly better binding affinity (-7.9 vs -9.8 kcal/mol). The lower Cl_mic and longer t1/2 of Ligand B also contribute to its improved profile. The negative Caco-2 and solubility values are concerning for both, but the superior affinity and BBB penetration of Ligand B make it the more promising candidate, assuming these solubility/permeability issues can be addressed through formulation or further modification.

Output:
1
2025-04-17 05:18:46,859 - INFO - Reasoning:

Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight (MW):** Both ligands (370.471 and 372.487 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (68.31) is significantly better than Ligand B (84.94). For CNS targets, we want TPSA <= 90, and A is comfortably within that range, while B is approaching the upper limit.

**3. logP:** Both ligands have acceptable logP values (1.481 and 0.815), falling within the optimal range of 1-3.

**4. H-Bond Donors (HBD):** Both ligands have a low number of HBDs (0 and 1, respectively), which is favorable.

**5. H-Bond Acceptors (HBA):** Both ligands have the same number of HBAs (6), which is acceptable (<=10).

**6. QED:** Both ligands have similar and good QED scores (0.759 and 0.719), indicating good drug-like properties.

**7. DILI:** Both ligands have reasonably low DILI risk (54.944 and 46.452), both below the 60 threshold.

**8. BBB:** Ligand A (66.925) has a better BBB percentile than Ligand B (46.452).  For a CNS target like DRD2, a BBB > 70 is desirable, but A is significantly closer than B.

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.526 and -4.988). This is unusual and suggests poor permeability. However, these values are on a log scale, and the negative values indicate very low permeability.

**10. Aqueous Solubility:** Both ligands have poor aqueous solubility (-1.472 and -2.502). This is a concern for bioavailability.

**11. hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.179 and 0.121).

**12. Microsomal Clearance (Cl_mic):** Ligand A (43.086) has lower microsomal clearance than Ligand B (68.342), suggesting better metabolic stability.

**13. In vitro Half-Life:** Ligand A (27.903) has a longer in vitro half-life than Ligand B (-5.167). The negative value for B is concerning and indicates very rapid degradation.

**14. P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.121 and 0.039).

**15. Binding Affinity:** Ligand A (0) has a slightly better binding affinity than Ligand B (0).

**Overall Assessment:**

Ligand A is superior to Ligand B. While both have issues with solubility and Caco-2 permeability, Ligand A excels in key areas for a CNS GPCR target: better TPSA, significantly better BBB penetration, lower microsomal clearance, and a longer half-life. The slightly better binding affinity also contributes to its favorability. The poor permeability and solubility are drawbacks that would need to be addressed in further optimization, but the other properties make Ligand A a more promising starting point.

Output:
1
2025-04-17 05:18:46,859 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B based on the provided guidelines, prioritizing GPCR-specific properties (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (348.447) is slightly better, being closer to the lower end which can aid permeability.

**TPSA:** Ligand A (67.67) is significantly better than Ligand B (103.95). For CNS targets, TPSA should be <= 90, and Ligand A comfortably meets this, while Ligand B is close to the upper limit.

**logP:** Both ligands have acceptable logP values (Ligand A: 1.104, Ligand B: 2.222), falling within the optimal range of 1-3. Ligand B is slightly higher, which could potentially lead to off-target effects, but is still reasonable.

**H-Bond Donors/Acceptors:** Ligand A (HBD=0, HBA=5) is preferable to Ligand B (HBD=3, HBA=5). Fewer H-bond donors generally improve permeability.

**QED:** Ligand A (0.799) has a better QED score than Ligand B (0.573), indicating a more drug-like profile.

**DILI:** Ligand A (28.306) has a much lower DILI risk than Ligand B (83.792). This is a significant advantage for Ligand A.

**BBB:** Ligand A (59.364) has a better BBB percentile than Ligand B (43.815), though neither are above the desirable >70% for CNS targets. However, given DRD2 is a CNS target, Ligand A is clearly favored.

**Caco-2 Permeability:** Ligand A (-4.621) has a worse Caco-2 permeability than Ligand B (-5.626). Lower values suggest lower permeability.

**Aqueous Solubility:** Ligand A (-1.128) has slightly better solubility than Ligand B (-2.63).

**hERG Inhibition:** Ligand A (0.161) has a lower hERG inhibition liability than Ligand B (0.632), which is a significant safety advantage.

**Microsomal Clearance:** Ligand A (20.619) has a lower microsomal clearance than Ligand B (46.708), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (14.792) has a better in vitro half-life than Ligand B (1.776).

**P-gp Efflux:** Ligand A (0.026) has significantly lower P-gp efflux liability than Ligand B (0.302), which is crucial for CNS penetration.

**Binding Affinity:** Ligand B (-8.4) has a slightly better binding affinity than Ligand A (-7.4). This is a 1.0 kcal/mol difference, which is significant, but needs to be weighed against the other ADME properties.

**Overall Assessment:**

While Ligand B has a slightly better binding affinity, Ligand A is significantly superior in almost all other critical ADME properties, particularly those important for CNS drug development (BBB, TPSA, Pgp, DILI, hERG, metabolic stability). The better BBB, lower P-gp efflux, and lower DILI/hERG risks of Ligand A are compelling advantages that outweigh the slightly weaker binding affinity. The substantial difference in predicted toxicity (DILI) and safety (hERG) heavily favor Ligand A.

Output:
0
2025-04-17 05:18:46,860 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (348.403 and 348.407 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (85.69) is excellent, well below the 90 A^2 threshold for CNS targets. Ligand B (120.08) is still acceptable but less optimal, being closer to the 140 A^2 threshold for oral absorption.

**3. logP:** Ligand A (0.171) is quite low, potentially hindering membrane permeability. Ligand B (-0.457) is also low, but slightly better than A. Both are below the optimal 1-3 range.

**4. H-Bond Donors:** Ligand A (1) is good. Ligand B (3) is acceptable, but higher HBDs can sometimes reduce permeability.

**5. H-Bond Acceptors:** Ligand A (6) is good. Ligand B (5) is also good.

**6. QED:** Both ligands have reasonable QED values (0.838 and 0.622), indicating good drug-like properties.

**7. DILI:** Both ligands have acceptable DILI risk (55.719 and 52.346), below the 60 threshold.

**8. BBB:** This is a critical parameter for a CNS target like DRD2. Ligand A has a very good BBB penetration percentile (74.913). Ligand B's BBB penetration (30.748) is significantly lower and concerning.

**9. Caco-2 Permeability:** Ligand A (-4.589) has poor Caco-2 permeability, consistent with its low logP. Ligand B (-5.76) is also poor, but slightly worse.

**10. Aqueous Solubility:** Both ligands have very poor aqueous solubility (-1.982 and -1.942). This could pose formulation challenges.

**11. hERG Inhibition:** Both ligands show very low hERG inhibition risk (0.136 and 0.063).

**12. Microsomal Clearance:** Ligand A (16.543) has moderate clearance. Ligand B (-28.122) has *very* high clearance, indicating poor metabolic stability.

**13. In vitro Half-Life:** Ligand A (64.516) has a reasonable half-life. Ligand B (11.078) has a short half-life, consistent with its high clearance.

**14. P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.014 and 0.011), which is favorable for CNS penetration.

**15. Binding Affinity:** Ligand A (-8.8 kcal/mol) has significantly stronger binding affinity than Ligand B (-0.0 kcal/mol). This is a substantial difference.

**Overall Assessment:**

Ligand A is clearly superior. While its logP and solubility are suboptimal, its *much* stronger binding affinity and significantly better BBB penetration outweigh these drawbacks. The poor Caco-2 permeability is less critical for a CNS target. Ligand B suffers from poor BBB penetration and very high metabolic clearance, making it a less viable candidate despite having slightly better logP and HBD/HBA counts. The affinity difference is dramatic.

Output:
1
2025-04-17 05:18:46,860 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B based on the provided guidelines, prioritizing GPCR-specific properties (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (344.379 Da) is slightly lower, which *could* be beneficial for permeability, but both are acceptable.

**TPSA:** Ligand A (127.93) is borderline for CNS targets (ideally <90), while Ligand B (107.34) is better positioned for CNS penetration.

**logP:** Ligand A (0.02) is quite low, potentially hindering permeation. Ligand B (1.958) is much better, falling within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A has 4 HBD and 6 HBA, which are reasonable. Ligand B has 1 HBD and 5 HBA, also acceptable.

**QED:** Both ligands have good QED scores (A: 0.605, B: 0.775), indicating drug-like properties. Ligand B is slightly better.

**DILI:** Ligand A (80.651) has a higher DILI risk than Ligand B (64.521), although both are within an acceptable range.

**BBB:** Ligand A (43.699) has a poor BBB percentile, a significant drawback for a CNS target like DRD2. Ligand B (50.523) is better, but still not ideal (aim for >70).

**Caco-2 Permeability:** Ligand A (-5.664) shows poor permeability. Ligand B (-4.649) is better, but still low.

**Aqueous Solubility:** Both ligands exhibit poor aqueous solubility (-2.389 and -3.527 respectively). This could pose formulation challenges.

**hERG Inhibition:** Ligand A (0.064) has a very low hERG risk, which is excellent. Ligand B (0.341) is slightly higher, but still relatively low.

**Microsomal Clearance:** Ligand A (-7.093) has excellent metabolic stability (negative value indicates low clearance). Ligand B (18.421) has a significantly higher clearance, suggesting faster metabolism.

**In vitro Half-Life:** Ligand B (97.702) has a very long in vitro half-life, which is a major advantage. Ligand A (9.262) has a shorter half-life.

**P-gp Efflux:** Ligand A (0.004) shows very low P-gp efflux, which is favorable for CNS penetration. Ligand B (0.114) has slightly higher efflux, but still relatively low.

**Binding Affinity:** Ligand B (-7.8 kcal/mol) has a slightly better binding affinity than Ligand A (-8.8 kcal/mol). While A is stronger, the difference is not substantial enough to overcome its other weaknesses.

**Overall Assessment:**

Ligand A suffers from a very low logP and poor BBB penetration, which are critical for a CNS-targeting GPCR. Its poor Caco-2 permeability also raises concerns. While it has excellent metabolic stability and a slightly better binding affinity, these advantages are outweighed by its ADME liabilities.

Ligand B, while not perfect, has a much more favorable profile for CNS penetration with a better logP, BBB, and a significantly longer half-life. The higher clearance is a concern, but potentially manageable.

Output:
1
2025-04-17 05:18:46,860 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B based on the provided guidelines, prioritizing GPCR-specific properties (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (341.455 and 343.431 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (56.27) is excellent for CNS penetration, well below the 90 A^2 threshold. Ligand B (101.21) is higher, but still potentially acceptable, though less ideal.

**logP:** Ligand A (4.665) is slightly high, potentially leading to solubility issues or off-target effects. Ligand B (1.526) is quite low, which could hinder membrane permeability.

**H-Bond Donors/Acceptors:** Ligand A (HBD=1, HBA=5) and Ligand B (HBD=2, HBA=5) both have reasonable H-bond characteristics.

**QED:** Both ligands have good QED scores (A: 0.793, B: 0.807), indicating good drug-like properties.

**DILI:** Both ligands have acceptable DILI risk (A: 49.787, B: 51.881), below the 60 threshold.

**BBB:** Both ligands exhibit excellent BBB penetration (A: 74.835, B: 78.868), exceeding the 70% threshold, which is critical for a CNS target like DRD2.

**Caco-2 Permeability:** Ligand A (-4.414) and Ligand B (-5.118) both have negative Caco-2 permeability values, which is unusual and suggests poor intestinal absorption. This is less critical for a CNS target where direct delivery is possible, but still a concern.

**Aqueous Solubility:** Both ligands have poor aqueous solubility (A: -4.972, B: -3.332). This is a concern, especially with Ligand A's higher logP.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (A: 0.652, B: 0.17), which is favorable.

**Microsomal Clearance:** Ligand A (75.764) has higher microsomal clearance than Ligand B (35.566), suggesting lower metabolic stability.

**In vitro Half-Life:** Ligand B (-22.391) has a significantly negative in vitro half-life, which is highly unfavorable. Ligand A (1.794) is better, but still relatively short.

**P-gp Efflux:** Ligand A (0.284) has lower P-gp efflux liability than Ligand B (0.013), which is beneficial for CNS penetration.

**Binding Affinity:** Ligand B (-9.0 kcal/mol) has a substantially stronger binding affinity than Ligand A (-8.9 kcal/mol). This 0.1 kcal/mol difference, while seemingly small, is significant and could outweigh some of the ADME drawbacks.

**Overall Assessment:**

Ligand B is the stronger binder, which is paramount for GPCR targets. While its logP is low and its in vitro half-life is very poor, the excellent BBB penetration and strong binding affinity are compelling. Ligand A has a better logP and P-gp efflux profile, but its weaker binding affinity and higher clearance are less desirable. The poor solubility of both is a concern, but can potentially be addressed with formulation strategies. Given the importance of affinity for GPCRs, and the acceptable BBB penetration for both, Ligand B is the more promising candidate despite its drawbacks.

Output:
1
2025-04-17 05:18:46,860 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (348.359 Da) is slightly better positioned.

**TPSA:** Ligand B (84.73) is significantly better than Ligand A (128.53). For CNS targets, we want TPSA <= 90, and Ligand B comfortably meets this, while Ligand A is pushing the limit.

**logP:** Ligand B (2.623) is optimal (1-3), while Ligand A (0.546) is quite low, potentially hindering membrane permeability.

**H-Bond Donors/Acceptors:** Ligand A has 3 HBD and 6 HBA, while Ligand B has 2 HBD and 8 HBA. Both are within acceptable limits.

**QED:** Both ligands have similar, good QED values (0.67 and 0.689).

**DILI:** Ligand A (50.136) has a much lower DILI risk than Ligand B (92.865). This is a significant advantage for Ligand A.

**BBB:** Ligand B (53.858) has a much better BBB penetration percentile than Ligand A (19.542). This is *critical* for a CNS target like DRD2.

**Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and suggests poor permeability. However, the scale is not specified, so it's hard to interpret.

**Aqueous Solubility:** Both have negative solubility values, also unusual. Again, the scale is unknown.

**hERG:** Both ligands have very low hERG inhibition liability (0.133 and 0.683).

**Microsomal Clearance:** Ligand A (-0.505) has much lower (better) microsomal clearance than Ligand B (35.779), indicating better metabolic stability.

**In vitro Half-Life:** Ligand B (7.91) has a longer half-life than Ligand A (-34.157), which is a positive.

**P-gp Efflux:** Ligand A (0.032) has significantly lower P-gp efflux liability than Ligand B (0.097), which is favorable for CNS penetration.

**Binding Affinity:** Both ligands have the same binding affinity (-8.3 kcal/mol), which is excellent.

**Overall Assessment:**

Ligand B excels in BBB penetration and has a longer half-life. However, its high DILI risk and higher P-gp efflux are concerning. Ligand A has a better safety profile (lower DILI), better metabolic stability (lower Cl_mic), and lower P-gp efflux. The biggest drawback of Ligand A is its low logP and borderline TPSA, which could limit permeability. However, given the excellent binding affinity, and the importance of BBB penetration and safety for a CNS drug, the better metabolic stability and lower efflux of Ligand A are more valuable.

Output:
0
2025-04-17 05:18:46,860 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (349.431 and 355.471 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (64.96) is significantly better than Ligand B (82.62). For CNS targets, we want TPSA <= 90, and A is comfortably within this range, while B is approaching the upper limit.

**logP:** Ligand B (3.014) is optimal (1-3), while Ligand A (0.498) is quite low, potentially hindering membrane permeability. This is a significant drawback for A.

**H-Bond Donors/Acceptors:** Ligand A (HBD=1, HBA=6) and Ligand B (HBD=2, HBA=7) both have reasonable numbers of H-bond donors and acceptors, falling within the suggested limits.

**QED:** Both ligands have acceptable QED values (A: 0.839, B: 0.749), indicating good drug-like properties.

**DILI:** Ligand A (36.06) has a much lower DILI risk than Ligand B (84.451). This is a substantial advantage for A.

**BBB:** Ligand B (68.786) has a better BBB penetration score than Ligand A (44.126). While both are not ideal (>70 is desirable), B is closer. This is a critical factor for a CNS target like DRD2.

**Caco-2 Permeability:** Ligand A (-4.891) has a very poor Caco-2 permeability, while Ligand B (-5.389) is also poor, but slightly better.

**Aqueous Solubility:** Ligand A (-1.244) has slightly better solubility than Ligand B (-3.715).

**hERG Inhibition:** Ligand A (0.323) has a lower hERG inhibition liability than Ligand B (0.737), which is preferable.

**Microsomal Clearance:** Ligand A (-9.831) has a much lower (better) microsomal clearance than Ligand B (39.303), indicating better metabolic stability.

**In vitro Half-Life:** Ligand A (45.554) has a longer half-life than Ligand B (0.981).

**P-gp Efflux:** Ligand A (0.02) has significantly lower P-gp efflux liability than Ligand B (0.108), which is crucial for CNS penetration.

**Binding Affinity:** Both ligands have excellent binding affinities (A: -8.1 kcal/mol, B: -9.9 kcal/mol). Ligand B is slightly better, but the difference is not massive.

**Overall Assessment:**

Ligand B has a better logP and BBB, which are important for CNS targets. However, it suffers from significantly higher DILI risk, higher P-gp efflux, and higher microsomal clearance. Ligand A, while having a suboptimal logP, excels in safety (DILI, hERG), metabolic stability (Cl_mic, t1/2), and efflux (Pgp). The strong binding affinity of both is comparable. Given the GPCR-specific priorities, the lower TPSA and significantly improved safety/ADME profile of Ligand A outweigh its lower logP and BBB.

Output:
0
2025-04-17 05:18:46,861 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (355.454 and 356.419 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (53.09) is excellent, well below the 90 A^2 threshold for CNS targets. Ligand B (108.33) is higher, but still potentially acceptable, though less optimal.

**3. logP:** Ligand A (1.046) is within the optimal 1-3 range. Ligand B (-0.801) is slightly below 1, which could indicate potential permeability issues, but not a dealbreaker.

**4. H-Bond Donors:** Ligand A (0) is good. Ligand B (3) is acceptable.

**5. H-Bond Acceptors:** Ligand A (4) is good. Ligand B (6) is acceptable.

**6. QED:** Ligand A (0.74) is excellent, indicating good drug-like properties. Ligand B (0.491) is lower, suggesting a less ideal overall profile.

**7. DILI:** Ligand A (18.147) has a low DILI risk. Ligand B (23.808) is also relatively low, but higher than A.

**8. BBB:** Ligand A (78.247) has a good BBB penetration percentile. Ligand B (31.989) is significantly lower, which is a major concern for a CNS target like DRD2.

**9. Caco-2 Permeability:** Ligand A (-4.377) is poor. Ligand B (-5.246) is also poor.

**10. Aqueous Solubility:** Ligand A (-1.058) is poor. Ligand B (-0.488) is also poor.

**11. hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.346 and 0.089 respectively).

**12. Microsomal Clearance:** Ligand A (18.767) has moderate clearance. Ligand B (-6.231) has negative clearance, which is not possible and likely indicates an error in the data or a very stable compound.

**13. In vitro Half-Life:** Ligand A (8.423) has a reasonable half-life. Ligand B (7.607) is similar.

**14. P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.027 and 0.02 respectively).

**15. Binding Affinity:** Ligand B (-7.1 kcal/mol) has a slightly better binding affinity than Ligand A (-6.9 kcal/mol), but the difference is not huge.

**Overall Assessment:**

Considering the GPCR-specific priorities, Ligand A is significantly more promising. The biggest advantage is its much higher BBB penetration (78.25% vs 31.99%). While both have poor Caco-2 and solubility, BBB is critical for CNS targets. Ligand B's slightly better affinity is outweighed by its poor BBB score and potentially erroneous negative clearance value. Ligand A also has a better QED score and lower DILI risk.

Output:
1
2025-04-17 05:18:46,861 - INFO - Batch 187 complete. Total preferences: 2992
2025-04-17 05:18:46,861 - INFO - Processing batch 188/512...
2025-04-17 05:19:28,998 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 drug candidates, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (349.387 and 357.485 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (92.95) is slightly above the preferred <90 for CNS targets, but still reasonable. Ligand B (29.54) is excellent, well below the threshold.

**logP:** Ligand A (0.742) is a bit low, potentially hindering permeability. Ligand B (4.358) is higher, approaching the upper limit, but still acceptable.

**H-Bond Donors/Acceptors:** Ligand A has 0 HBD and 6 HBA, which is acceptable. Ligand B has 0 HBD and 2 HBA, also acceptable.

**QED:** Both ligands have reasonable QED scores (0.703 and 0.646), indicating good drug-like properties.

**DILI:** Ligand A (38.62) has a slightly higher DILI risk than Ligand B (19.31), but both are below the concerning threshold of 60.

**BBB:** Ligand A (76.813) is good, but Ligand B (96.859) is *excellent* for CNS penetration, a critical factor for DRD2.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.25 and -4.147), which is unusual and suggests poor permeability. This is a significant concern.

**Aqueous Solubility:** Both ligands have negative solubility values (-1.254 and -4.81), which is also unusual and suggests poor solubility. This is a significant concern.

**hERG Inhibition:** Both ligands show very low hERG inhibition risk (0.028 and 0.877).

**Microsomal Clearance:** Ligand A (66.044) has lower clearance than Ligand B (91.022), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (-17.227) has a negative half-life, which is not physically meaningful. Ligand B (19.1) has a reasonable half-life.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.023 and 0.433), which is favorable for CNS exposure.

**Binding Affinity:** Ligand B (-7.6 kcal/mol) has a significantly stronger binding affinity than Ligand A (-6.5 kcal/mol). This 1.1 kcal/mol difference is substantial and can outweigh minor ADME drawbacks.

**Overall Assessment:**

Despite the concerning negative values for Caco-2 and solubility, Ligand B is the more promising candidate. Its superior BBB penetration (96.859 vs 76.813), significantly stronger binding affinity (-7.6 vs -6.5 kcal/mol), and lower DILI risk outweigh the slightly higher microsomal clearance. The negative half-life for Ligand A is a major red flag. While both have issues with predicted permeability and solubility, the stronger binding and better CNS penetration of Ligand B make it the better starting point for optimization.

Output:
1
2025-04-17 05:19:28,998 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (364.4 and 366.5 Da) fall comfortably within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (92.34) is slightly higher than Ligand B (76.58). For CNS targets, we prefer TPSA <= 90, so Ligand B is better here.

**3. logP:** Both ligands have good logP values (1.663 and 2.576), falling within the optimal 1-3 range. Ligand B is slightly better.

**4. H-Bond Donors:** Ligand A has 2 HBD, and Ligand B has 1. Both are within the acceptable limit of <=5.

**5. H-Bond Acceptors:** Ligand A has 4 HBA, and Ligand B has 7. Both are within the acceptable limit of <=10, but Ligand A is preferable.

**6. QED:** Both ligands have reasonable QED values (0.815 and 0.724), indicating good drug-like properties.

**7. DILI:** Ligand A (80.923) has a higher DILI risk than Ligand B (60.954). This favors Ligand B.

**8. BBB:** Ligand B (79.217) has a significantly better BBB penetration percentile than Ligand A (67.119). This is a *critical* advantage for a CNS target like DRD2.

**9. Caco-2 Permeability:** Both have negative values, which is unusual. However, the magnitude is similar, and this doesn't strongly differentiate them.

**10. Aqueous Solubility:** Both have negative values, which is also unusual. The magnitude is similar, and this doesn't strongly differentiate them.

**11. hERG Inhibition:** Ligand A (0.344) has a lower hERG inhibition risk than Ligand B (0.754). This favors Ligand A.

**12. Microsomal Clearance:** Ligand B (66.949) has a higher microsomal clearance than Ligand A (37.246), indicating lower metabolic stability. This favors Ligand A.

**13. In vitro Half-Life:** Both have similar in vitro half-lives (63.649 and 63.228 hours).

**14. P-gp Efflux:** Ligand A (0.294) has lower P-gp efflux liability than Ligand B (0.314). Lower efflux is preferred for CNS penetration, favoring Ligand A.

**15. Binding Affinity:** Ligand B (-7.2 kcal/mol) has a significantly stronger binding affinity than Ligand A (-10.2 kcal/mol). This is a *major* advantage, potentially outweighing some of the ADME drawbacks of Ligand B.

**Overall Assessment:**

While Ligand A has better metabolic stability, lower P-gp efflux, and lower hERG risk, Ligand B's superior BBB penetration and *significantly* stronger binding affinity are decisive. For a CNS GPCR target, achieving good brain exposure (BBB) and potent binding are paramount. The 1.5 kcal/mol difference in binding affinity is substantial and likely to translate to greater efficacy. The slightly higher DILI risk and P-gp efflux of Ligand B are acceptable trade-offs given its superior potency and BBB.

Output:
1
2025-04-17 05:19:28,999 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (356.413 and 361.364 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (49.85) is excellent, well below the 90 A^2 threshold for CNS targets. Ligand B (69.72) is still reasonable, but less optimal.

**3. logP:** Ligand A (2.423) is within the optimal 1-3 range. Ligand B (0.77) is a bit low, potentially hindering membrane permeability.

**4. H-Bond Donors:** Both have acceptable HBD counts (0 for A, 1 for B), well below the 5 limit.

**5. H-Bond Acceptors:** Both have acceptable HBA counts (3 for A and B), well below the 10 limit.

**6. QED:** Both ligands have similar and good QED values (0.704 and 0.739), indicating good drug-like properties.

**7. DILI:** Both have low DILI risk (22.722 and 29.43), which is favorable.

**8. BBB:** Ligand A (97.131) has excellent BBB penetration, exceeding the desirable >70% threshold. Ligand B (82.435) is good, but significantly lower than A. This is a critical advantage for a CNS target like DRD2.

**9. Caco-2 Permeability:** Both have negative Caco-2 values (-4.241 and -4.787), which is unusual and suggests poor permeability. This is a significant concern for both.

**10. Aqueous Solubility:** Both have negative solubility values (-2.694 and -2.463), which is also unusual and suggests poor solubility. This is a significant concern for both.

**11. hERG Inhibition:** Both have very low hERG inhibition risk (0.461 and 0.361), which is excellent.

**12. Microsomal Clearance:** Ligand A (42.444) has higher clearance than Ligand B (1.935), suggesting lower metabolic stability.

**13. In vitro Half-Life:** Ligand B (-3.144) has a longer half-life than Ligand A (-9.142), which is favorable.

**14. P-gp Efflux:** Ligand A (0.124) has lower P-gp efflux liability than Ligand B (0.017), which is beneficial for CNS exposure.

**15. Binding Affinity:** Ligand B (0.0 kcal/mol) has significantly *better* binding affinity than Ligand A (-6.7 kcal/mol). This is a substantial advantage.

**Overall Assessment:**

Despite the unusual Caco-2 and solubility values, the superior binding affinity of Ligand B, combined with its longer half-life, makes it the more promising candidate. The significantly better BBB penetration of Ligand A is a strong point, but the much stronger binding of Ligand B likely outweighs this advantage, especially considering the potential for optimization of permeability and solubility. The lower clearance of Ligand B is also a positive.

Output:
1
2025-04-17 05:19:28,999 - INFO - Reasoning:

Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (380.5) is slightly higher than Ligand B (354.5), but both are acceptable.

**2. TPSA:** Ligand A (105.31) is higher than Ligand B (81.75). For CNS targets, we prefer TPSA <= 90. Ligand B is better in this regard.

**3. logP:** Ligand A (1.516) and Ligand B (0.596) are both within the optimal range (1-3), but Ligand B is on the lower side. Ligand A is preferable here.

**4. H-Bond Donors:** Ligand A (1) is better than Ligand B (2). Lower HBD generally improves permeability.

**5. H-Bond Acceptors:** Ligand A (8) is higher than Ligand B (4). Lower HBA is generally preferred. Ligand B is better.

**6. QED:** Both ligands have acceptable QED values (A: 0.862, B: 0.635), indicating good drug-like properties.

**7. DILI:** Ligand A (63.668) has a higher DILI risk than Ligand B (9.965). This is a significant advantage for Ligand B.

**8. BBB:** Ligand A (82.978) has a much better BBB penetration percentile than Ligand B (36.487). This is *critical* for a CNS target like DRD2.

**9. Caco-2 Permeability:** Both have negative values, which is unusual and likely indicates a scaling issue. We can't reliably compare these values.

**10. Aqueous Solubility:** Both have negative values, again indicating a scaling issue. We can't reliably compare these values.

**11. hERG Inhibition:** Both ligands have very low hERG inhibition risk (A: 0.474, B: 0.156), which is excellent.

**12. Microsomal Clearance:** Ligand A (17.049) has higher microsomal clearance than Ligand B (5.362), meaning it's less metabolically stable. Ligand B is preferable.

**13. In vitro Half-Life:** Ligand A (6.842) has a longer half-life than Ligand B (-1.157). This is a positive for Ligand A, but the negative value for B is concerning.

**14. P-gp Efflux:** Ligand A (0.198) has lower P-gp efflux liability than Ligand B (0.005), which is beneficial for CNS exposure.

**15. Binding Affinity:** Both ligands have the same excellent binding affinity (-7.4 kcal/mol).

**Overall Assessment:**

Ligand A excels in BBB penetration, P-gp efflux, and in vitro half-life. However, it has a higher DILI risk and higher microsomal clearance. Ligand B has a better TPSA, lower DILI, lower clearance, and fewer H-bonds. The significantly better BBB value for Ligand A is the deciding factor for a CNS target. While Ligand B has a better safety profile (DILI, clearance), getting the drug into the brain is paramount. The slightly lower logP of Ligand B is a minor concern, but the strong affinity should compensate.

Output:
1
2025-04-17 05:19:28,999 - INFO - Reasoning:

Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (348.487 and 385.917 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (67.43) is better than Ligand B (71.53). Both are below the 90 A^2 threshold desirable for CNS targets, but A is closer to optimal.

**3. logP:** Both ligands (2.701 and 2.89) are within the optimal 1-3 range.

**4. H-Bond Donors:** Ligand A (2) is slightly higher than Ligand B (1), but both are well within the acceptable limit of 5.

**5. H-Bond Acceptors:** Ligand A (3) is lower than Ligand B (5), both are within the acceptable limit of 10.

**6. QED:** Both ligands have good QED scores (0.695 and 0.764), indicating good drug-like properties.

**7. DILI:** Ligand A (34.277) has a significantly lower DILI risk than Ligand B (74.021). This is a major advantage for Ligand A.

**8. BBB:** Ligand A (62.233) has a better BBB penetration percentile than Ligand B (57.736), although both are below the desirable >70 for CNS targets.

**9. Caco-2 Permeability:** Ligand A (-5.164) has a worse Caco-2 permeability than Ligand B (-4.746).

**10. Aqueous Solubility:** Both ligands have very poor aqueous solubility (-3.281 and -3.288). This is a concern for both, but not a deciding factor.

**11. hERG Inhibition:** Both ligands have low hERG inhibition risk (0.203 and 0.195).

**12. Microsomal Clearance:** Ligand A (45.873) has a lower microsomal clearance than Ligand B (48.922), suggesting better metabolic stability.

**13. In vitro Half-Life:** Ligand B (21.269) has a significantly longer in vitro half-life than Ligand A (7.403). This is a notable advantage for Ligand B.

**14. P-gp Efflux:** Both ligands have low P-gp efflux liability (0.121 and 0.265).

**15. Binding Affinity:** Ligand B (-7.9 kcal/mol) has a stronger binding affinity than Ligand A (-8.4 kcal/mol). While A is slightly better, the difference is not substantial.

**Overall Assessment:**

Considering the GPCR-specific priorities, Ligand A is the more promising candidate. While Ligand B has a better binding affinity and half-life, Ligand A's significantly lower DILI risk and better BBB penetration are crucial for a CNS-targeting drug. The TPSA is also more favorable for Ligand A. The solubility is poor for both, but can be addressed with formulation strategies. The slightly lower Caco-2 permeability of A is less concerning than the higher DILI risk of B.



Output:
0
2025-04-17 05:19:28,999 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (348.45 & 362.50 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (76.12) is significantly better than Ligand B (82.11). For CNS targets, we want TPSA <= 90, and A is closer to the ideal <= 60. B is approaching a less desirable range.

**logP:** Ligand A (-0.993) is suboptimal, being slightly below the 1-3 range. Ligand B (2.985) is within the optimal range. This is a significant advantage for B.

**H-Bond Donors/Acceptors:** Both have 2 HBDs and 5 HBAs, which are acceptable.

**QED:** Both ligands have good QED scores (0.685 and 0.857), indicating good drug-like properties.

**DILI:** Ligand A (12.37) has a much lower DILI risk than Ligand B (28.31), a clear advantage.

**BBB:** Ligand A (39.55) has a poor BBB penetration percentile, while Ligand B (48.04) is also low, but better than A. Both are far from the desirable >70 for CNS targets.

**Caco-2 Permeability:** Both have negative Caco-2 values (-5.13 and -5.164), which is unusual and suggests poor permeability. This is a concern for both.

**Aqueous Solubility:** Both have negative solubility values (-1.237 and -3.209), indicating poor aqueous solubility. This is a concern for both.

**hERG:** Ligand A (0.274) has a lower hERG inhibition liability than Ligand B (0.675), which is preferable.

**Microsomal Clearance:** Ligand A (14.81) has lower microsomal clearance than Ligand B (18.16), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (18.74) has a positive half-life, while Ligand B (-21.01) has a negative half-life, which is not physically possible and suggests a data error or a very rapidly metabolized compound. This is a major red flag for Ligand B.

**P-gp Efflux:** Ligand A (0.005) has very low P-gp efflux, which is excellent for CNS penetration. Ligand B (0.302) has moderate P-gp efflux.

**Binding Affinity:** Ligand A (-7.8) has a significantly stronger binding affinity than Ligand B (-7.1). This is a substantial advantage for A, potentially outweighing some of its ADME shortcomings.

**Overall Assessment:**

While Ligand B has a better logP, the negative half-life is a critical flaw. The poor BBB penetration of both is a concern, but can sometimes be overcome with formulation strategies. Ligand A's superior binding affinity, lower DILI risk, lower hERG risk, better metabolic stability, and very low P-gp efflux make it the more promising candidate despite the suboptimal logP and BBB. The strong binding affinity could potentially compensate for the lower logP.

Output:
0
2025-04-17 05:19:28,999 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (340.423 and 345.403 Da) fall comfortably within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (58.64) is significantly better than Ligand B (108.21). For CNS targets, we want TPSA <= 90, and A is well within this range, while B exceeds it. This is a substantial advantage for A.

**3. logP:** Ligand A (2.085) is optimal (1-3). Ligand B (0.746) is a bit low, potentially hindering permeation.

**4. H-Bond Donors:** Both ligands have 1 HBD, which is within the acceptable limit of <=5.

**5. H-Bond Acceptors:** Ligand A has 3 HBAs, and Ligand B has 6. Both are within the acceptable limit of <=10, but A is preferable.

**6. QED:** Both ligands have similar QED values (0.893 and 0.815), indicating good drug-likeness.

**7. DILI:** Ligand A (57.697) has a slightly higher DILI risk than Ligand B (48.275), but both are below the concerning threshold of 60.

**8. BBB:** Ligand A (67.274) has a better BBB percentile than Ligand B (44.668). While >70 is desirable, A is closer to that target, which is critical for a CNS target like DRD2.

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.697 and -4.884). These values are unusual and likely indicate poor permeability *in vitro*. However, the values are similar, so this doesn't differentiate the two significantly.

**10. Aqueous Solubility:** Both ligands have negative solubility values (-3.219 and -2.217). These values are also unusual and suggest poor aqueous solubility. Again, the values are similar, so this doesn't differentiate the two significantly.

**11. hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.373 and 0.114).

**12. Microsomal Clearance:** Ligand A (27.305) has a higher microsomal clearance than Ligand B (11.214), indicating lower metabolic stability. This is a drawback for A.

**13. In vitro Half-Life:** Ligand B (-8.306) has a longer in vitro half-life than Ligand A (-5.013). This is a benefit for B.

**14. P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.08 and 0.01).

**15. Binding Affinity:** Ligand A (-9.2 kcal/mol) has a significantly stronger binding affinity than Ligand B (-7.7 kcal/mol). This is a substantial advantage for A, exceeding the 1.5 kcal/mol difference threshold.

**Overall Assessment:**

Despite Ligand A's slightly higher DILI risk and higher microsomal clearance, its superior TPSA, logP, BBB penetration, and *significantly* stronger binding affinity outweigh these drawbacks. The lower TPSA and better logP of Ligand A are particularly important for CNS penetration, and the strong affinity is crucial for efficacy. Ligand B's better metabolic stability and half-life are positives, but the weaker affinity and higher TPSA are significant liabilities.

Output:
1
2025-04-17 05:19:29,000 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (348.443 and 352.431 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (98.66) is slightly higher than Ligand B (88.1). Both are below the 140 threshold for oral absorption and reasonably close to the 90 target for CNS penetration, but Ligand B is better.

**3. logP:** Ligand A (1.873) is within the optimal 1-3 range. Ligand B (-0.084) is slightly below 1, which *could* indicate potential permeability issues.

**4. H-Bond Donors:** Ligand A (4) and Ligand B (2) are both acceptable, below the 5 limit.

**5. H-Bond Acceptors:** Ligand A (4) and Ligand B (5) are both acceptable, below the 10 limit.

**6. QED:** Both ligands have good QED scores (0.631 and 0.722, respectively), indicating drug-like properties.

**7. DILI:** Ligand A (37.03) has a lower DILI risk than Ligand B (15.432), which is a significant advantage.

**8. BBB:** Ligand A (51.493) has a better BBB penetration percentile than Ligand B (43.273), which is crucial for a CNS target like DRD2.

**9. Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and suggests poor permeability. However, these values are on a strange scale and difficult to interpret without more context.

**10. Aqueous Solubility:** Both have negative solubility values, also unusual and difficult to interpret.

**11. hERG:** Both ligands have very low hERG inhibition liability (0.359 and 0.137), which is excellent.

**12. Microsomal Clearance:** Ligand B (-11.428) has significantly lower (better) microsomal clearance than Ligand A (26.019), suggesting greater metabolic stability.

**13. In vitro Half-Life:** Ligand B (29.271) has a longer in vitro half-life than Ligand A (15.379), which is desirable.

**14. P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.096 and 0.008), which is good for CNS exposure.

**15. Binding Affinity:** Ligand A (-8.8 kcal/mol) has a slightly better binding affinity than Ligand B (-8.1 kcal/mol). While the difference is not huge (less than 1.5 kcal/mol), it is a factor.

**Overall Assessment:**

Ligand A has advantages in DILI risk, BBB penetration, and binding affinity. Ligand B has advantages in metabolic stability (Cl_mic), half-life, and slightly better TPSA. The negative Caco-2 and solubility values are concerning for both, but the differences in other parameters are more significant. Given the importance of BBB penetration for a CNS target like DRD2, and the slightly better binding affinity, Ligand A appears to be the more promising candidate, despite the higher Cl_mic.

Output:
1
2025-04-17 05:19:29,000 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (367.515 and 358.551 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (82.43) is better than Ligand B (33.2). For CNS targets, TPSA should be <=90, both meet this.

**3. logP:** Ligand A (1.802) is optimal (1-3), while Ligand B (4.512) is slightly high, potentially leading to solubility issues and off-target interactions.

**4. H-Bond Donors:** Ligand A (1) is good, Ligand B (0) is also acceptable.

**5. H-Bond Acceptors:** Ligand A (5) is good, Ligand B (3) is also acceptable.

**6. QED:** Both ligands have good QED scores (0.596 and 0.726, respectively), indicating drug-like properties.

**7. DILI:** Ligand A (27.724) has a lower DILI risk than Ligand B (17.371), which is preferable.

**8. BBB:** Ligand B (74.641) has a significantly better BBB penetration percentile than Ligand A (64.793). This is a *critical* factor for a CNS target like DRD2.

**9. Caco-2 Permeability:** Ligand A (-5.017) is worse than Ligand B (-4.663), suggesting lower intestinal absorption for A.

**10. Aqueous Solubility:** Ligand A (-2.422) is better than Ligand B (-5.228), which is important for formulation.

**11. hERG Inhibition:** Both ligands have low hERG inhibition risk (0.588 and 0.517).

**12. Microsomal Clearance:** Ligand A (29.66) has a lower clearance than Ligand B (62.544), indicating better metabolic stability.

**13. In vitro Half-Life:** Ligand B (17.811) has a longer half-life than Ligand A (2.541), which is generally desirable.

**14. P-gp Efflux:** Ligand A (0.137) has lower P-gp efflux than Ligand B (0.605), which is beneficial for CNS exposure.

**15. Binding Affinity:** Ligand B (-7.8 kcal/mol) has a significantly stronger binding affinity than Ligand A (-6.5 kcal/mol). This >1.5 kcal/mol difference is substantial and can outweigh some ADME drawbacks.

**Overall Assessment:**

While Ligand A has better solubility, lower DILI risk, and lower P-gp efflux, Ligand B's *much* stronger binding affinity (-7.8 vs -6.5 kcal/mol) and significantly better BBB penetration (74.641 vs 64.793) are decisive. The slightly higher logP of Ligand B is a concern, but the strong affinity suggests it might still be effective. The longer half-life of Ligand B is also a plus. Given the GPCR-specific priorities, particularly BBB and affinity, Ligand B is the more promising candidate.

Output:
1
2025-04-17 05:19:29,000 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 drug candidates, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (344.411 and 339.399 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (66.9) is significantly better than Ligand B (95.84). For CNS targets, we want TPSA <= 90, so A is preferable.

**3. logP:** Both ligands have good logP values (2.816 and 2.641), falling within the optimal 1-3 range.

**4. H-Bond Donors:** Ligand A (0) is better than Ligand B (3). Fewer HBDs generally improve permeability.

**5. H-Bond Acceptors:** Ligand A (4) is better than Ligand B (6). Fewer HBAs generally improve permeability.

**6. QED:** Both ligands have acceptable QED values (0.808 and 0.612), indicating good drug-like properties.

**7. DILI:** Ligand A (24.157) has a much lower DILI risk than Ligand B (69.484). This is a significant advantage for A.

**8. BBB:** Ligand A (77.976) has a substantially better BBB penetration percentile than Ligand B (29.546). This is *critical* for a CNS target like DRD2.

**9. Caco-2 Permeability:** Ligand A (-4.656) is better than Ligand B (-5.644), indicating better intestinal absorption.

**10. Aqueous Solubility:** Ligand A (-2.149) is better than Ligand B (-3.746), indicating better solubility.

**11. hERG Inhibition:** Both ligands have similar hERG inhibition liabilities (0.614 and 0.813), and are relatively low risk.

**12. Microsomal Clearance:** Ligand A (21.641) has lower microsomal clearance than Ligand B (54.31), suggesting better metabolic stability.

**13. In vitro Half-Life:** Ligand B (52.58) has a significantly longer in vitro half-life than Ligand A (3.836). This is a potential advantage for B.

**14. P-gp Efflux:** Ligand A (0.286) has a much lower P-gp efflux liability than Ligand B (0.153). Lower P-gp efflux is highly desirable for CNS penetration.

**15. Binding Affinity:** Ligand B (-9.3) has a slightly better binding affinity than Ligand A (-8.3). While a 1 kcal/mol difference is noticeable, the other ADME properties are more concerning for Ligand B.

**Overall Assessment:**

Ligand A is clearly the superior candidate. While Ligand B has a slightly better binding affinity, Ligand A excels in almost all crucial ADME properties, particularly those prioritized for GPCRs targeting the CNS: TPSA, BBB, P-gp efflux, and DILI. The significantly better BBB penetration and lower P-gp efflux of Ligand A are especially important for ensuring sufficient drug exposure in the brain. The better metabolic stability (lower Cl_mic) and solubility also contribute to its favorability. The longer half-life of Ligand B is a plus, but can likely be addressed through further optimization.



Output:
0
2025-04-17 05:19:29,000 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (341.371 and 356.457 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (106.94) is better than Ligand B (43.78). For CNS targets, we want TPSA <= 90, and both meet this criterion, but A is closer to the ideal.

**logP:** Both ligands have good logP values (2.952 and 3.661), falling within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Both have 1 HBD, which is good. Ligand A has 7 HBA, while Ligand B has 3. Both are within the acceptable limit of <=10, but B is better.

**QED:** Both ligands have good QED scores (0.704 and 0.773), indicating good drug-likeness.

**DILI:** Ligand A has a concerning DILI risk (81.233), indicating a higher potential for liver injury. Ligand B has a much lower and acceptable DILI risk (13.532). This is a significant advantage for Ligand B.

**BBB:** Both ligands have excellent BBB penetration (79.721 and 71.074), exceeding the desirable >70 threshold for CNS targets.

**Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and suggests poor permeability. However, the scale isn't specified, so it's hard to interpret.

**Aqueous Solubility:** Both have negative solubility values, which is also unusual and suggests poor solubility.

**hERG:** Both ligands have low hERG inhibition liability (0.267 and 0.896), which is favorable.

**Microsomal Clearance:** Ligand A has a lower Cl_mic (37.976) than Ligand B (83.716), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A has a longer half-life (19.507) than Ligand B (-5.056). This is a significant advantage for Ligand A.

**P-gp Efflux:** Ligand A has a lower Pgp efflux liability (0.229) than Ligand B (0.165), suggesting better CNS exposure.

**Binding Affinity:** Ligand A has a significantly better binding affinity (-9.4 kcal/mol) than Ligand B (-6.8 kcal/mol). This is a substantial advantage, potentially outweighing some ADME drawbacks.

**Overall Assessment:**

Ligand A has a superior binding affinity and better metabolic stability (lower Cl_mic, longer t1/2), and P-gp efflux. However, it has a significantly higher DILI risk. Ligand B has a much better safety profile (lower DILI) and slightly better HBA count. The difference in binding affinity is substantial (2.6 kcal/mol), which is a large advantage. Given the importance of potency for GPCR ligands, and the potential to mitigate DILI risk through structural modifications, Ligand A is the more promising candidate.

Output:
1
2025-04-17 05:19:29,000 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (348.462 Da) is slightly lower, which is generally favorable for permeability.

**TPSA:** Ligand A (49.41) is significantly better than Ligand B (67.87). For CNS targets, we want TPSA <= 90, and ideally closer to 60. Ligand A is much closer to this ideal.

**logP:** Both ligands have good logP values (A: 2.692, B: 1.843) falling within the optimal range of 1-3.

**H-Bond Donors/Acceptors:** Both have acceptable HBD (1) counts. Ligand A has 2 HBA, while Ligand B has 5. Lower HBA is generally preferred.

**QED:** Both ligands have reasonable QED scores (A: 0.794, B: 0.626), indicating drug-like properties, but A is better.

**DILI:** Ligand A (14.889) has a much lower DILI risk than Ligand B (30.322). This is a significant advantage.

**BBB:** This is critical for a CNS target like DRD2. Ligand A (91.896) has excellent BBB penetration, exceeding the desirable >70% threshold. Ligand B (52.811) is considerably lower and less promising for CNS exposure.

**Caco-2 Permeability:** Both are negative, indicating poor permeability. This is a concern for both.

**Aqueous Solubility:** Both are negative, indicating poor solubility. This is a concern for both.

**hERG:** Both ligands have low hERG inhibition risk (A: 0.465, B: 0.139).

**Microsomal Clearance:** Ligand A (2.678) has a much lower microsomal clearance than Ligand B (46.481), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (-0.687) has a slightly better (less negative) in vitro half-life than Ligand B (-3.096).

**P-gp Efflux:** Ligand A (0.163) has lower P-gp efflux liability than Ligand B (0.036), which is favorable for CNS penetration and bioavailability.

**Binding Affinity:** Ligand A (-10.3 kcal/mol) has a significantly stronger binding affinity than Ligand B (-6.8 kcal/mol). This is a substantial advantage, and can often outweigh minor ADME drawbacks. The difference is >1.5 kcal/mol.

**Overall Assessment:**

Ligand A is clearly superior. It excels in critical areas for a CNS-targeting GPCR ligand: BBB penetration, metabolic stability (low Cl_mic), lower DILI risk, and significantly stronger binding affinity. While both have issues with Caco-2 and solubility, the superior CNS properties and binding affinity of Ligand A make it the much more promising candidate.

Output:
1
2025-04-17 05:19:29,001 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (371.438 and 348.422 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (96.33) is slightly above the optimal <90 for CNS targets, but still reasonable. Ligand B (75.19) is well within the desired range.

**3. logP:** Ligand A (0.117) is quite low, potentially hindering membrane permeability. Ligand B (2.117) is within the optimal 1-3 range. This is a significant advantage for Ligand B.

**4. H-Bond Donors:** Ligand A (2) is acceptable. Ligand B (1) is even better.

**5. H-Bond Acceptors:** Ligand A (6) is acceptable. Ligand B (4) is also good.

**6. QED:** Both ligands have good QED scores (0.71 and 0.904), indicating drug-like properties.

**7. DILI:** Ligand A (63.862) has a higher DILI risk than Ligand B (41.218), though both are reasonably low.

**8. BBB:** This is critical for a CNS target. Ligand A (49.205) has a moderate BBB penetration, while Ligand B (83.908) has excellent predicted BBB penetration. This is a major advantage for Ligand B.

**9. Caco-2 Permeability:** Ligand A (-5.314) shows poor permeability. Ligand B (-4.756) is slightly better but still not great.

**10. Aqueous Solubility:** Both ligands have very poor predicted aqueous solubility (-2.495 and -3.274). This could pose formulation challenges.

**11. hERG Inhibition:** Ligand A (0.07) has very low hERG inhibition risk. Ligand B (0.402) is slightly higher, but still relatively low.

**12. Microsomal Clearance:** Ligand A (10.261) has lower clearance, indicating better metabolic stability. Ligand B (37.154) has significantly higher clearance.

**13. In vitro Half-Life:** Ligand A (24.539) has a reasonable half-life. Ligand B (-6.949) has a very short predicted half-life, which is a significant drawback.

**14. P-gp Efflux:** Ligand A (0.018) has very low P-gp efflux, which is favorable for CNS penetration. Ligand B (0.12) is slightly higher, but still relatively low.

**15. Binding Affinity:** Ligand A (-7.3) has slightly better binding affinity than Ligand B (-0.0). This is a substantial advantage for Ligand A.

**Overall Assessment:**

While Ligand A has a slightly better binding affinity and lower P-gp efflux, Ligand B is the stronger candidate. The critical factors driving this decision are:

*   **BBB Penetration:** Ligand B's significantly higher BBB penetration (83.908%) is crucial for a CNS target like DRD2.
*   **logP:** Ligand B's logP (2.117) is within the optimal range, while Ligand A's is too low (0.117).
*   **Metabolic Stability:** Ligand A has better metabolic stability. However, the difference in binding affinity is larger than the difference in metabolic stability.

The poor solubility of both compounds is a concern, but can potentially be addressed through formulation strategies. The short half-life of Ligand B is also a concern, but could be improved through structural modifications.

Output:
1
2025-04-17 05:19:29,001 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (339.439 and 361.32 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (47.36) is excellent, well below the 90 A^2 threshold for CNS targets. Ligand B (87.74) is higher but still acceptable, though less ideal.

**logP:** Ligand A (2.968) is optimal (1-3). Ligand B (0.687) is a bit low, potentially hindering membrane permeability.

**H-Bond Donors/Acceptors:** Both have reasonable HBD (0/2) and HBA (4/4) counts, well within acceptable limits.

**QED:** Both ligands have good QED scores (0.864 and 0.709), indicating drug-like properties.

**DILI:** Ligand A (42.807) has a slightly higher DILI risk than Ligand B (56.805), but both are below the concerning 60 percentile.

**BBB:** Both ligands show excellent BBB penetration (91.431 and 91.392), which is crucial for a CNS target like DRD2.

**Caco-2 Permeability:** Ligand A (-4.726) and Ligand B (-5.042) have negative values, which is unusual and suggests poor permeability. This is a significant concern.

**Aqueous Solubility:** Both ligands have very poor aqueous solubility (-2.954 and -2.872). This could present formulation challenges.

**hERG:** Both ligands have low hERG inhibition liability (0.726 and 0.139), which is positive.

**Microsomal Clearance:** Ligand A (81.263) has a higher microsomal clearance than Ligand B (5.569), indicating lower metabolic stability. Ligand B is much more stable.

**In vitro Half-Life:** Ligand B (33.441) has a significantly longer in vitro half-life than Ligand A (8.979), which is desirable.

**P-gp Efflux:** Ligand A (0.614) has a slightly higher P-gp efflux liability than Ligand B (0.011). Lower P-gp efflux is preferred for CNS penetration.

**Binding Affinity:** Ligand B (-8.7 kcal/mol) has a significantly stronger binding affinity than Ligand A (-7.9 kcal/mol). This 0.8 kcal/mol difference is substantial and can outweigh some ADME drawbacks.

**Conclusion:**

While both ligands have good BBB penetration and acceptable DILI/hERG profiles, Ligand B is the more promising candidate. Its significantly stronger binding affinity (-8.7 vs -7.9 kcal/mol) is a major advantage. Furthermore, it exhibits much better metabolic stability (lower Cl_mic, longer t1/2) and lower P-gp efflux. The lower logP of Ligand B is a concern, but the superior affinity and pharmacokinetic properties outweigh this drawback. The poor Caco-2 and solubility for both are problematic and would require formulation work, but are less critical than potency and metabolic stability for a CNS target.

Output:
1
2025-04-17 05:19:29,001 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 drug candidates, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (352.406 and 342.491 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (59.08) is excellent, well below the 90 target for CNS drugs. Ligand B (68.87) is still reasonable, but less optimal.

**3. logP:** Ligand A (1.492) is within the optimal 1-3 range. Ligand B (3.168) is at the higher end of optimal, but still acceptable.

**4. H-Bond Donors:** Ligand A (0) is good. Ligand B (3) is also acceptable, staying under the 5 threshold.

**5. H-Bond Acceptors:** Ligand A (4) is good, under the 10 threshold. Ligand B (5) is also acceptable.

**6. QED:** Both ligands (0.746 and 0.752) have excellent drug-likeness scores.

**7. DILI:** Ligand A (46.026) has a lower DILI risk than Ligand B (51.26), both are good (<60).

**8. BBB:** Both ligands have very high BBB penetration (89.531 and 89.066), which is crucial for a CNS target like DRD2.

**9. Caco-2 Permeability:** Ligand A (-4.27) has a worse Caco-2 permeability than Ligand B (-5.44). Lower values indicate lower permeability.

**10. Aqueous Solubility:** Ligand A (-1.464) has better aqueous solubility than Ligand B (-3.001).

**11. hERG Inhibition:** Ligand A (0.354) has a lower hERG risk than Ligand B (0.933).

**12. Microsomal Clearance:** Ligand A (12.571) has significantly lower microsomal clearance than Ligand B (31.617), indicating better metabolic stability.

**13. In vitro Half-Life:** Ligand A (4.629) has a shorter half-life than Ligand B (15.323).

**14. P-gp Efflux:** Ligand A (0.047) has much lower P-gp efflux liability than Ligand B (0.167), which is highly desirable for CNS penetration.

**15. Binding Affinity:** Ligand B (-9.0) has a significantly stronger binding affinity than Ligand A (-7.6). This is a >1.5 kcal/mol advantage, which can outweigh some ADME drawbacks.

**Overall Assessment:**

Ligand B has a substantially better binding affinity, which is the most important factor. While Ligand A has better metabolic stability (lower Cl_mic) and P-gp efflux, the difference in affinity is significant. The slightly higher logP and P-gp efflux of Ligand B are not major concerns given the excellent BBB penetration observed for both. The slightly worse solubility and Caco-2 permeability of Ligand B are also less critical than the strong binding affinity.

Output:
1
2025-04-17 05:19:29,001 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 drug candidates, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight (MW):** Both ligands (348.487 and 363.531 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (49.85) is excellent, well below the 90 Angstroms threshold for CNS targets. Ligand B (63.91) is still reasonable, but less optimal.

**3. logP:** Both ligands have good logP values (2.751 and 3.829), falling within the 1-3 range. Ligand B is slightly higher, which could potentially lead to off-target effects, but is not a major concern.

**4. H-Bond Donors (HBD):** Both ligands have 0 HBD, which is acceptable.

**5. H-Bond Acceptors (HBA):** Ligand A has 3 HBA, and Ligand B has 6 HBA. Both are within the acceptable limit of 10.

**6. QED:** Both ligands have good QED scores (0.501 and 0.635), indicating good drug-like properties.

**7. DILI:** Ligand A (13.3) has a significantly lower DILI risk than Ligand B (53.276). This is a major advantage for Ligand A.

**8. BBB:** Both ligands have excellent BBB penetration (89.88 and 83.017), exceeding the desirable >70 threshold for CNS targets.

**9. Caco-2 Permeability:** Ligand A (-4.655) has poor Caco-2 permeability, while Ligand B (-5.298) is also poor. This is a potential issue for both, suggesting limited intestinal absorption.

**10. Aqueous Solubility:** Both ligands have very poor aqueous solubility (-2.481 and -3.446). This could pose formulation challenges.

**11. hERG Inhibition:** Both ligands have low hERG inhibition risk (0.602 and 0.43).

**12. Microsomal Clearance:** Ligand A (66.685) has lower microsomal clearance than Ligand B (81.055), suggesting better metabolic stability.

**13. In vitro Half-Life:** Ligand A (-15.544) has a negative half-life, which is not possible and likely an error in the data. Ligand B (33.868) has a reasonable half-life.

**14. P-gp Efflux:** Both ligands have low P-gp efflux liability (0.296 and 0.833), which is favorable for CNS penetration.

**15. Binding Affinity:** Ligand A (-7.8 kcal/mol) has a slightly better binding affinity than Ligand B (-6.9 kcal/mol). This difference of 0.9 kcal/mol is significant, potentially outweighing some of the ADME drawbacks.

**Overall Assessment:**

Ligand A is more promising despite the negative half-life value, which is likely an error. It has a significantly better DILI profile, slightly better binding affinity, and lower microsomal clearance. While both have poor solubility and Caco-2 permeability, the superior safety profile and binding affinity of Ligand A make it the better candidate. The negative half-life for Ligand A is a critical data point that would need to be verified, but assuming it is an error, A is the preferred choice.

Output:
1
2025-04-17 05:19:29,001 - INFO - Batch 188 complete. Total preferences: 3008
2025-04-17 05:19:29,002 - INFO - Processing batch 189/512...
2025-04-17 05:20:10,039 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (345.4 and 350.4 Da) fall comfortably within the ideal 200-500 Da range.

**TPSA:** Ligand A (84.67) is significantly better than Ligand B (105.48). For CNS targets, we want TPSA <= 90, so Ligand A is preferable.

**logP:** Ligand A (1.163) is within the optimal 1-3 range, while Ligand B (0.619) is slightly below 1. While not a hard cutoff, lower logP can hinder permeation. Ligand A is better.

**H-Bond Donors/Acceptors:** Ligand A (1 HBD, 5 HBA) is more favorable than Ligand B (3 HBD, 6 HBA). Both are within acceptable limits, but fewer H-bonds generally improve permeability.

**QED:** Ligand A (0.81) has a much better QED score than Ligand B (0.471), indicating a more drug-like profile.

**DILI:** Both ligands have similar DILI risk (54.6 and 59.2), both being acceptable (below 60).

**BBB:** Both ligands have identical BBB penetration (57.4%). This is below the desirable >70 for CNS targets, but not a major differentiating factor here.

**Caco-2 Permeability:** Ligand A (-4.646) has a slightly better Caco-2 permeability than Ligand B (-5.224), though both are negative values which is unusual and difficult to interpret without knowing the scale.

**Aqueous Solubility:** Both ligands have similar, very poor aqueous solubility (-2.124 and -2.115). This could pose formulation challenges.

**hERG Inhibition:** Ligand A (0.052) has a much lower hERG inhibition liability than Ligand B (0.371), which is a significant advantage.

**Microsomal Clearance:** Ligand A (11.524) has a significantly lower microsomal clearance than Ligand B (37.959), indicating better metabolic stability.

**In vitro Half-Life:** Ligand A (-9.596) has a much longer in vitro half-life than Ligand B (-23.651).

**P-gp Efflux:** Ligand A (0.024) has a much lower P-gp efflux liability than Ligand B (0.103). Lower P-gp efflux is crucial for CNS penetration.

**Binding Affinity:** Ligand A (-8.8 kcal/mol) has a slightly better binding affinity than Ligand B (-8.1 kcal/mol). While the difference is not huge, it's still a positive for Ligand A.

**Overall Assessment:**

Ligand A consistently outperforms Ligand B across most critical ADME properties, especially TPSA, QED, hERG, microsomal clearance, half-life, and P-gp efflux. While both have poor solubility and sub-optimal BBB, Ligand A's superior ADME profile, combined with slightly better affinity, makes it the more promising drug candidate.



Output:
0
2025-04-17 05:20:10,039 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (358.869 and 342.374 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (51.22) is significantly better than Ligand B (83.98). For CNS targets, we want TPSA <= 90, and ideally closer to 60. Ligand A is much closer to this ideal.

**3. logP:** Ligand A (3.914) is within the optimal 1-3 range, while Ligand B (1.544) is at the lower end. While not terrible, lower logP can hinder permeability.

**4. H-Bond Donors:** Ligand A (1) and Ligand B (2) are both acceptable, being <=5.

**5. H-Bond Acceptors:** Ligand A (3) and Ligand B (4) are both acceptable, being <=10.

**6. QED:** Both ligands have similar and good QED values (0.816 and 0.834, respectively), indicating good drug-like properties.

**7. DILI:** Ligand A (29.391) has a much lower DILI risk than Ligand B (65.723). This is a significant advantage for Ligand A.

**8. BBB:** Both ligands have good BBB penetration (73.827 and 77.588), exceeding the desirable >70 threshold for CNS targets. Ligand B is slightly better.

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.737 and -4.777). This is unusual and suggests poor permeability. However, these values are on a scale where negative values are possible and don't necessarily preclude development.

**10. Aqueous Solubility:** Both ligands have negative solubility values (-4.58 and -2.581). Similar to Caco-2, this suggests poor solubility, which could be a formulation challenge.

**11. hERG Inhibition:** Both ligands have very low hERG risk (0.54 and 0.143).

**12. Microsomal Clearance:** Ligand A (95.384) has significantly higher microsomal clearance than Ligand B (22.746), meaning it's metabolized faster. This is a disadvantage for Ligand A.

**13. In vitro Half-Life:** Ligand A (0.378) has a very short half-life compared to Ligand B (-25.58). This is a major disadvantage for Ligand A.

**14. P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.246 and 0.046).

**15. Binding Affinity:** Both ligands have excellent binding affinity (-9.5 and -9.7 kcal/mol). The difference is minimal.

**Overall Assessment:**

Ligand A has advantages in TPSA and DILI risk. However, Ligand B has a better logP, significantly better metabolic stability (lower Cl_mic), and a much longer in vitro half-life. The BBB penetration is comparable. Given the GPCR-specific priorities, the improved metabolic stability and half-life of Ligand B are crucial. While both have solubility and permeability concerns, these can potentially be addressed through formulation strategies. The slightly better logP of Ligand A is outweighed by the pharmacokinetic advantages of Ligand B.

Output:
1
2025-04-17 05:20:10,040 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (339.4) is slightly preferred due to being lower.

**2. TPSA:** Ligand A (99.77) is better than Ligand B (105.83). Both are reasonably good for CNS penetration, but A is closer to the ideal <90 for CNS targets.

**3. logP:** Ligand A (0.604) is suboptimal, being below the preferred 1-3 range. Ligand B (0.874) is also low, but slightly better. Both could suffer from permeability issues.

**4. H-Bond Donors:** Ligand A (3) is acceptable. Ligand B (1) is excellent.

**5. H-Bond Acceptors:** Ligand A (4) is acceptable. Ligand B (7) is also acceptable, but higher.

**6. QED:** Both ligands have good QED scores (A: 0.583, B: 0.741), indicating drug-like properties. Ligand B is better here.

**7. DILI:** Ligand A (40.87) has a better DILI score than Ligand B (61.07), indicating lower liver injury risk.

**8. BBB:** Ligand B (70.997) is significantly better than Ligand A (15.704) in terms of BBB penetration, a critical factor for CNS targets like DRD2.

**9. Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and suggests poor permeability. This is concerning for both.

**10. Aqueous Solubility:** Both have negative solubility values, which is also unusual and suggests poor solubility. This is concerning for both.

**11. hERG Inhibition:** Ligand A (0.122) shows a lower hERG inhibition risk than Ligand B (0.565), which is favorable.

**12. Microsomal Clearance:** Ligand A (-32.593) has much lower (better) microsomal clearance than Ligand B (25.735), indicating greater metabolic stability.

**13. In vitro Half-Life:** Ligand B (-12.445) has a longer half-life than Ligand A (-1.949), which is desirable.

**14. P-gp Efflux:** Ligand A (0.007) has significantly lower P-gp efflux than Ligand B (0.078), which is crucial for CNS penetration.

**15. Binding Affinity:** Ligand B (-7.1) has a slightly better binding affinity than Ligand A (-8.1). While A is better, the difference is not large enough to outweigh other factors.

**Overall Assessment:**

Ligand B excels in BBB penetration and in vitro half-life, both important for CNS drug development. It also has a better QED score. However, it suffers from higher DILI risk and P-gp efflux. Ligand A has better DILI, hERG, P-gp efflux, and metabolic stability. The low logP values for both are a concern, but the superior BBB penetration of Ligand B, combined with its slightly better affinity, makes it the more promising candidate, despite its other drawbacks. The difference in binding affinity isn't large enough to overcome the significant advantage of Ligand B's BBB penetration.

Output:
1
2025-04-17 05:20:10,040 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B based on the provided guidelines, prioritizing GPCR-specific properties (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (379.479 and 361.433 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (136.82) is slightly above the optimal <90 for CNS targets, but still reasonable. Ligand B (87.3) is excellent, well below 90.

**logP:** Ligand A (-1.028) is quite low, potentially hindering permeability. Ligand B (1.739) is within the optimal 1-3 range. This is a significant advantage for Ligand B.

**H-Bond Donors/Acceptors:** Both have 3 HBD and are within acceptable limits. Ligand A has 6 HBA, while Ligand B has 3 HBA, both are acceptable.

**QED:** Both ligands have acceptable QED scores (0.469 and 0.554, respectively), indicating reasonable drug-likeness.

**DILI:** Ligand A (39.511) has a slightly higher DILI risk than Ligand B (23.924), but both are below the concerning threshold of 60.

**BBB:** This is crucial for a CNS target like DRD2. Ligand A (36.371) has a poor BBB percentile. Ligand B (80.613) is excellent, exceeding the desirable >70 threshold.

**Caco-2 Permeability:** Both have negative values, indicating poor permeability.

**Aqueous Solubility:** Both have negative values, indicating poor solubility.

**hERG:** Both ligands have low hERG inhibition liability (0.116 and 0.224), which is good.

**Microsomal Clearance:** Ligand A (26.422) has a higher microsomal clearance than Ligand B (16.591), suggesting lower metabolic stability.

**In vitro Half-Life:** Both have negative values, indicating poor half-life.

**P-gp Efflux:** Both have very low P-gp efflux liability (0.01 and 0.015), which is favorable.

**Binding Affinity:** Ligand B (-8 kcal/mol) has a slightly better binding affinity than Ligand A (-7 kcal/mol). While the difference is not huge, it's a positive factor.

**Overall Assessment:**

Ligand B is significantly better suited as a drug candidate for DRD2. Its superior BBB penetration, optimal logP, and slightly better binding affinity outweigh the minor drawbacks in Caco-2 permeability and aqueous solubility. Ligand A's low logP and poor BBB penetration are major concerns for a CNS-targeting drug.

Output:
1
2025-04-17 05:20:10,040 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (376.389 and 347.379 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (109.22) is better than Ligand B (126.45). For CNS targets, we want TPSA <= 90, so both are above this ideal, but A is closer.

**3. logP:** Both ligands (-1.243 and -1.455) are a bit low. Optimal is 1-3. Lower logP can hinder permeation.

**4. H-Bond Donors:** Both have 2 HBD, which is within the acceptable limit of <=5.

**5. H-Bond Acceptors:** Ligand A has 7 HBA, and Ligand B has 6. Both are within the acceptable limit of <=10.

**6. QED:** Both ligands have good QED scores (0.601 and 0.691), indicating drug-like properties.

**7. DILI:** Ligand A (75.882) has a higher DILI risk than Ligand B (44.63). Lower is better, so B is preferable here.

**8. BBB:** Ligand B (77.433) has a significantly better BBB penetration percentile than Ligand A (54.634). This is *critical* for a CNS target like DRD2.

**9. Caco-2 Permeability:** Both have negative Caco-2 values (-5.421 and -5.295), which is unusual and suggests poor permeability.

**10. Aqueous Solubility:** Both have negative solubility values (-1.744 and -2.206), also unusual and suggesting poor solubility.

**11. hERG Inhibition:** Both have very low hERG inhibition risk (0.049 and 0.072).

**12. Microsomal Clearance:** Ligand B (-12.497) has lower (better) microsomal clearance than Ligand A (14.619), indicating greater metabolic stability.

**13. In vitro Half-Life:** Ligand B (6.382) has a longer half-life than Ligand A (-10.634).

**14. P-gp Efflux:** Both have very low P-gp efflux liability (0.016 and 0.004).

**15. Binding Affinity:** Ligand B (-8.0 kcal/mol) has a slightly better binding affinity than Ligand A (-7.4 kcal/mol). While both are good, the 0.6 kcal/mol difference is notable.

**Overall Assessment:**

While both compounds have issues with solubility and Caco-2 permeability, Ligand B is the stronger candidate. The significantly better BBB penetration (77.433 vs 54.634), lower DILI risk, improved metabolic stability (lower Cl_mic), longer half-life, and slightly better binding affinity outweigh the minor drawbacks. The GPCR-specific priority of BBB penetration is a major factor in this decision.

Output:
1
2025-04-17 05:20:10,040 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (344.371 and 344.459 Da) fall comfortably within the ideal 200-500 Da range.

**2. TPSA:** Both ligands have TPSA values (87.76 and 86.88) below the 90 A^2 threshold desirable for CNS targets, which is good.

**3. logP:** Ligand A (1.025) is closer to the optimal 1-3 range than Ligand B (2.137). While both are acceptable, A is slightly favored.

**4. H-Bond Donors:** Ligand A (1) is preferable to Ligand B (3) as lower HBD generally improves permeability.

**5. H-Bond Acceptors:** Both ligands have a reasonable number of HBA (5 and 3, respectively), well below the 10 limit.

**6. QED:** Ligand A (0.895) has a significantly higher QED score than Ligand B (0.641), indicating a more drug-like profile.

**7. DILI:** Ligand A (86.778) has a higher DILI risk than Ligand B (26.755). This is a significant drawback for Ligand A.

**8. BBB:** Ligand B (56.96) has a substantially better BBB penetration percentile than Ligand A (39.24). This is a *critical* advantage for a CNS target like DRD2.

**9. Caco-2 Permeability:** Ligand A (-4.714) has slightly better Caco-2 permeability than Ligand B (-5.341), but both are quite poor.

**10. Aqueous Solubility:** Both ligands have poor aqueous solubility (-3.111 and -2.946 respectively).

**11. hERG Inhibition:** Both ligands show very low hERG inhibition risk (0.362 and 0.365).

**12. Microsomal Clearance:** Ligand B (30.213) has a much higher microsomal clearance than Ligand A (7.645), suggesting lower metabolic stability. This is a negative for Ligand B.

**13. In vitro Half-Life:** Ligand A (-9.515) has a much longer in vitro half-life than Ligand B (-19.273). This is a significant advantage for Ligand A.

**14. P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.033 and 0.123).

**15. Binding Affinity:** Ligand B (-8.0 kcal/mol) has a slightly better binding affinity than Ligand A (-7.6 kcal/mol), but the difference is not substantial enough to outweigh other factors.

**Overall Assessment:**

While Ligand A has better QED, half-life, and Caco-2 permeability, Ligand B excels in the most crucial areas for a CNS GPCR target: BBB penetration and DILI risk. The significantly lower DILI risk and higher BBB penetration of Ligand B are more important than the slight advantages of Ligand A. The higher metabolic clearance of Ligand B is a concern, but could be addressed with structural modifications.

Output:
1
2025-04-17 05:20:10,041 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (347.39 Da) is slightly lower, which could be beneficial for permeability, while Ligand B (380.897 Da) is also good.

**TPSA:** Ligand A (82.53) is better than Ligand B (51.66) as it is closer to the ideal range for CNS targets (<=90). Ligand B is quite low, which might suggest reduced hydrogen bonding and potentially lower solubility.

**logP:** Ligand A (1.321) is within the optimal range (1-3). Ligand B (3.433) is at the higher end of the optimal range, but still acceptable.

**H-Bond Donors/Acceptors:** Ligand A has 2 HBD and 4 HBA, while Ligand B has 0 HBD and 5 HBA. Both are within acceptable limits, but Ligand A's HBD count might contribute to better solubility.

**QED:** Both ligands have similar QED values (0.761 and 0.69), indicating good drug-like properties.

**DILI:** Ligand A (35.595) has a significantly lower DILI risk than Ligand B (52.772), which is a major advantage.

**BBB:** Ligand B (83.094) has a substantially better BBB penetration score than Ligand A (64.87). This is a critical factor for a CNS target like DRD2.

**Caco-2 Permeability:** Ligand A (-4.949) has a worse Caco-2 permeability score than Ligand B (-4.636).

**Aqueous Solubility:** Ligand A (-1.917) has a worse aqueous solubility score than Ligand B (-3.786).

**hERG:** Ligand A (0.102) has a lower hERG inhibition liability than Ligand B (0.57), which is preferable.

**Microsomal Clearance:** Ligand B (81.517) has a much higher microsomal clearance than Ligand A (3.694), indicating lower metabolic stability.

**In vitro Half-Life:** Ligand A (-14.921) has a much longer in vitro half-life than Ligand B (39.829), which is a significant advantage.

**P-gp Efflux:** Ligand A (0.034) has a much lower P-gp efflux liability than Ligand B (0.443), which is crucial for CNS penetration.

**Binding Affinity:** Ligand A (-7.7 kcal/mol) has a slightly better binding affinity than Ligand B (-6.8 kcal/mol). While the difference is not huge, it's still a positive point for Ligand A.

**Overall Assessment:**

Ligand B excels in BBB penetration, which is paramount for a CNS target. However, it suffers from higher DILI risk, higher microsomal clearance (lower metabolic stability), higher P-gp efflux, and lower in vitro half-life. Ligand A, while having a lower BBB score, compensates with significantly better safety (DILI), metabolic stability, P-gp efflux, half-life, and a slightly improved binding affinity. Considering the balance of properties, and prioritizing metabolic stability and safety alongside CNS penetration, Ligand A appears to be the more promising candidate.

Output:
0
2025-04-17 05:20:10,041 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B based on the provided guidelines, prioritizing GPCR-specific properties (BBB, logP, Pgp, TPSA, and affinity) for DRD2.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (338.367 Da) is slightly lower than Ligand B (355.479 Da), which is acceptable.

**TPSA:** Both ligands have TPSA values below the 90 A^2 threshold for CNS targets. Ligand A (83.04 A^2) is slightly higher than Ligand B (79.9 A^2), but both are good.

**logP:** Ligand A (3.367) is within the optimal range (1-3). Ligand B (0.248) is significantly *below* the optimal range, which could hinder permeation. This is a major drawback for Ligand B.

**H-Bond Donors/Acceptors:** Ligand A (0 HBD, 7 HBA) and Ligand B (2 HBD, 5 HBA) both fall within acceptable limits (<=5 HBD, <=10 HBA).

**QED:** Both ligands have similar QED values (Ligand A: 0.663, Ligand B: 0.62), indicating good drug-like properties.

**DILI:** Ligand A (78.402) has a moderate DILI risk, while Ligand B (11.206) has a very low DILI risk. This favors Ligand B.

**BBB:** Ligand A (82.474) has excellent BBB penetration (above 70%), crucial for a CNS target like DRD2. Ligand B (62.854) has a significantly lower BBB penetration, which is a major concern.

**Caco-2 Permeability:** Both have negative Caco-2 values which is unusual and suggests a problem with the data or modeling.

**Aqueous Solubility:** Both have negative solubility values which is unusual and suggests a problem with the data or modeling.

**hERG:** Both ligands have very low hERG inhibition risk (Ligand A: 0.095, Ligand B: 0.352).

**Microsomal Clearance:** Ligand A (111.337) has higher microsomal clearance than Ligand B (37.578), indicating lower metabolic stability. Ligand B is preferred here.

**In vitro Half-Life:** Ligand A (-42.512) has a negative half-life, which is not physically possible and indicates a problem with the data. Ligand B (-6.98) is also negative, but less so.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (Ligand A: 0.3, Ligand B: 0.003), which is good for CNS penetration.

**Binding Affinity:** Ligand A (-8.7 kcal/mol) has a significantly stronger binding affinity than Ligand B (-7.5 kcal/mol). This is a substantial advantage for Ligand A, potentially outweighing some of its ADME drawbacks.

**Overall Assessment:**

Ligand A excels in binding affinity and BBB penetration, both critical for a DRD2 ligand. While its DILI risk is higher and its metabolic stability is lower, the strong affinity and good BBB penetration are significant advantages. Ligand B has a better DILI and metabolic stability profile, but its very low logP and poor BBB penetration are major drawbacks for a CNS-targeting drug. The negative half-life values for both are concerning and suggest data quality issues, but the difference in binding affinity is substantial enough to favor Ligand A.

Output:
1
2025-04-17 05:20:10,041 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (349.39 and 365.46 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (88.18) is excellent for CNS penetration, being well below 90. Ligand B (104.36) is still reasonable, but less optimal.

**logP:** Ligand A (-0.109) is a bit low, potentially hindering membrane permeability. Ligand B (1.63) is within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A (1 HBD, 5 HBA) and Ligand B (2 HBD, 6 HBA) both have acceptable numbers of hydrogen bond donors and acceptors.

**QED:** Ligand A (0.703) has a better QED score than Ligand B (0.482), indicating a more drug-like profile.

**DILI:** Both ligands have similar DILI risk (Ligand A: 42.54, Ligand B: 49.13), both being relatively low and acceptable.

**BBB:** Ligand A (47.11) has a significantly better BBB percentile than Ligand B (36.45). This is crucial for a CNS target like DRD2.

**Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and suggests poor permeability. However, the scale is not specified, so it's hard to interpret.

**Aqueous Solubility:** Both ligands have negative solubility values, which is also unusual.

**hERG:** Both ligands have very low hERG risk (Ligand A: 0.085, Ligand B: 0.568).

**Microsomal Clearance:** Ligand A (-23.54) has a much lower (better) microsomal clearance than Ligand B (57.16). This suggests better metabolic stability.

**In vitro Half-Life:** Ligand A (-25.73) has a much longer half-life than Ligand B (22.29).

**P-gp Efflux:** Ligand A (0.006) has a much lower P-gp efflux liability than Ligand B (0.099), which is highly desirable for CNS penetration.

**Binding Affinity:** Ligand B (-7.1) has a slightly better binding affinity than Ligand A (-8.2). However, the difference is not substantial enough to overcome the other significant ADME advantages of Ligand A.

**Overall Assessment:**

Ligand A demonstrates a superior ADME profile, particularly regarding BBB penetration, metabolic stability (low Cl_mic, long t1/2), and P-gp efflux. While Ligand B has slightly better binding affinity, the differences in other critical parameters, especially for a CNS target, strongly favor Ligand A. The low logP of Ligand A is a concern, but the other advantages are substantial.

Output:
1
2025-04-17 05:20:10,041 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (337.427 and 343.427 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (90.75) is slightly above the preferred <90 for CNS targets, but still reasonable. Ligand B (73.74) is well within the ideal range.

**logP:** Ligand A (4.39) is a bit high, potentially leading to solubility issues and off-target effects. Ligand B (1.081) is excellent, falling within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Both ligands have acceptable HBD (1) and HBA (3 & 4) counts, well below the thresholds of 5 and 10, respectively.

**QED:** Ligand B (0.891) has a significantly better QED score than Ligand A (0.498), indicating a more drug-like profile.

**DILI:** Ligand A (58.434) has a moderate DILI risk, while Ligand B (25.436) has a very low risk.

**BBB:** Both ligands have good BBB penetration (Ligand A: 74.254, Ligand B: 70.609), but Ligand A is slightly better. Both are above the 70% threshold for CNS targets.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.954 and -4.632), which is unusual and suggests poor permeability. This is a significant concern for both.

**Aqueous Solubility:** Both ligands have negative solubility values (-4.801 and -1.798), indicating very poor aqueous solubility. This is a major drawback.

**hERG Inhibition:** Both ligands show low hERG inhibition risk (0.841 and 0.276).

**Microsomal Clearance:** Ligand A (62.934) has higher microsomal clearance than Ligand B (17.753), suggesting lower metabolic stability.

**In vitro Half-Life:** Ligand B (-2.48) has a negative half-life, which is not physically possible and indicates a problem with the data or the molecule's stability. Ligand A (12.356) has a reasonable half-life.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.462 and 0.118), which is favorable for CNS penetration.

**Binding Affinity:** Both ligands have excellent binding affinity (-9.9 and -9.6 kcal/mol), with Ligand A being slightly stronger. The difference is less than 1.5 kcal/mol, so it's not a decisive factor.

**Overall Assessment:**

Ligand B is the better candidate despite the negative Caco-2 and solubility values. Its superior QED, lower DILI risk, lower microsomal clearance, and acceptable BBB penetration outweigh the slightly weaker binding affinity and the concerning solubility/permeability issues. Ligand A's higher logP and higher DILI risk are less desirable. The negative half-life for Ligand B is a major red flag, but assuming this is a data error, the other properties make it more promising. Both compounds require significant work to improve solubility and permeability, but Ligand B starts from a better position.

Output:
1
2025-04-17 05:20:10,041 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 drug candidates, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (350.503 and 370.471 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (49.85) is excellent, well below the 90 A^2 threshold for CNS targets. Ligand B (92.78) is higher, but still potentially acceptable, although less ideal for CNS penetration.

**logP:** Ligand A (2.831) is optimal (1-3). Ligand B (1.462) is on the lower end, potentially hindering permeability.

**H-Bond Donors/Acceptors:** Ligand A (0 HBD, 3 HBA) is favorable. Ligand B (1 HBD, 6 HBA) is also acceptable, but slightly higher.

**QED:** Both ligands have similar QED values (0.766 and 0.762), indicating good drug-likeness.

**DILI:** Ligand A (13.3) has a significantly lower DILI risk than Ligand B (63.707), which is a substantial advantage.

**BBB:** Ligand A (89.531) has excellent BBB penetration potential, exceeding the 70% threshold. Ligand B (30.167) is poor, making CNS exposure unlikely. This is a critical difference for a DRD2 target.

**Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and suggests a potential issue with the data or modeling. However, the magnitude of the negative value for Ligand A (-4.226) is smaller than for Ligand B (-4.844), suggesting slightly better permeability.

**Aqueous Solubility:** Both have negative solubility values, which is also unusual. The values are similar, so this isn't a major differentiator.

**hERG Inhibition:** Ligand A (0.482) has a lower hERG risk than Ligand B (0.077), which is preferable.

**Microsomal Clearance:** Ligand A (67.885) has higher clearance than Ligand B (58.589), indicating lower metabolic stability.

**In vitro Half-Life:** Ligand A (0.313) has a very short half-life compared to Ligand B (-3.071), which is a significant drawback.

**P-gp Efflux:** Ligand A (0.113) has lower P-gp efflux liability than Ligand B (0.046), which is beneficial for CNS exposure.

**Binding Affinity:** Ligand B (-8.0 kcal/mol) has a significantly stronger binding affinity than Ligand A (-6.9 kcal/mol). This is a 1.1 kcal/mol difference, which is substantial and could potentially overcome some ADME deficiencies.

**Overall Assessment:**

Ligand B has a superior binding affinity, which is a major advantage. However, its poor BBB penetration (30.167) is a critical flaw for a CNS target like DRD2. Ligand A, while having a weaker affinity, exhibits excellent BBB penetration (89.531), lower DILI risk, and lower P-gp efflux. The shorter half-life and higher clearance of Ligand A are concerns, but these can potentially be addressed through structural modifications. The negative Caco-2 and solubility values are concerning for both, but the relative differences are small.

Given the importance of BBB penetration for CNS GPCR targets, and the substantial difference in this property between the two ligands, I favor Ligand A. The affinity difference, while significant, may be overcome with further optimization, while poor BBB penetration is much harder to fix.

Output:
0
2025-04-17 05:20:10,042 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (340.335 and 346.471 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (102.46) is higher than Ligand B (71.34). For CNS targets, TPSA should be <=90. Ligand B is significantly better here.

**3. logP:** Both ligands have good logP values (3.673 and 3.21), falling within the optimal 1-3 range.

**4. H-Bond Donors:** Ligand A has 0 HBD, while Ligand B has 2. Both are acceptable (<=5).

**5. H-Bond Acceptors:** Ligand A has 6 HBA, and Ligand B has 3. Both are within the acceptable range (<=10).

**6. QED:** Both ligands have good QED values (0.451 and 0.796), indicating reasonable drug-likeness. Ligand B is better.

**7. DILI:** Ligand A has a DILI risk of 80.341, which is relatively high. Ligand B has a DILI risk of 43.195, which is much better (below the 60 threshold).

**8. BBB:** Ligand A has a BBB penetration of 56.766, while Ligand B has 70.299. For a CNS target like DRD2, >70 is desirable, making Ligand B significantly better.

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.282 and -4.538). This is unusual and suggests poor permeability. However, the scale isn't specified, so it's hard to interpret.

**10. Aqueous Solubility:** Both ligands have negative solubility values (-6.103 and -3.972). Again, the scale is unspecified, making interpretation difficult.

**11. hERG Inhibition:** Both ligands have low hERG inhibition risk (0.697 and 0.312).

**12. Microsomal Clearance:** Ligand A (71.187) has higher microsomal clearance than Ligand B (49.323), suggesting lower metabolic stability.

**13. In vitro Half-Life:** Ligand B (62.362) has a longer in vitro half-life than Ligand A (5.843), which is desirable.

**14. P-gp Efflux:** Both ligands have low P-gp efflux liability (0.497 and 0.311).

**15. Binding Affinity:** Both ligands have the same binding affinity (-8.5 kcal/mol), which is excellent.

**Overall Assessment:**

Ligand B is clearly superior. While both have excellent binding affinity, Ligand B demonstrates significantly better ADME properties crucial for CNS penetration. Specifically, its lower TPSA, lower DILI risk, higher BBB penetration, and longer half-life make it a much more promising candidate. The negative values for Caco-2 and solubility are concerning for both, but the other advantages of Ligand B outweigh these issues.

Output:
1
2025-04-17 05:20:10,042 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (351.403 and 349.41 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (111.89) is better than Ligand B (101.21). Both are below the 140 A^2 threshold for oral absorption and reasonably close to the 90 A^2 target for CNS penetration.

**logP:** Ligand B (1.308) is within the optimal 1-3 range, while Ligand A (-0.411) is slightly below, potentially hindering permeation.

**H-Bond Donors/Acceptors:** Both have 2 HBD and are within the acceptable limits. Ligand A has 6 HBA, and Ligand B has 5. Both are acceptable.

**QED:** Both ligands have good QED scores (0.673 and 0.806), indicating drug-like properties.

**DILI:** Ligand A (28.306) has a significantly lower DILI risk than Ligand B (49.283), which is a substantial advantage.

**BBB:** Ligand B (90.772) has a much higher BBB penetration percentile than Ligand A (29.391). This is a critical factor for a CNS target like DRD2.

**Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and suggests potential issues with intestinal absorption. However, the scale is not specified, so it's hard to interpret.

**Aqueous Solubility:** Both have negative solubility values, which is also unusual and suggests poor solubility.

**hERG:** Both have low hERG inhibition liability (0.179 and 0.377), which is good.

**Microsomal Clearance:** Ligand A (-7.121) shows much better metabolic stability (lower clearance) than Ligand B (2.823).

**In vitro Half-Life:** Ligand A (22.357 hours) has a longer half-life than Ligand B (-20.936 hours).

**P-gp Efflux:** Ligand A (0.007) shows very low P-gp efflux, which is excellent for CNS penetration. Ligand B (0.023) is also low, but higher than A.

**Binding Affinity:** Ligand A (-0.0 kcal/mol) has a significantly better binding affinity than Ligand B (-8.1 kcal/mol). This is the most important factor.

**Overall Assessment:**

While Ligand B has a much better BBB score, the significantly stronger binding affinity of Ligand A (-0.0 kcal/mol vs -8.1 kcal/mol) is a decisive advantage, especially for a GPCR target. The better DILI score, metabolic stability, longer half-life, and lower P-gp efflux of Ligand A further support its selection. The slightly lower logP of Ligand A is a minor concern, but can potentially be addressed through further optimization. The unusual negative values for Caco-2 and solubility are concerning and would require further investigation, but the binding affinity difference is substantial enough to favor Ligand A.

Output:
0
2025-04-17 05:20:10,042 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (368.35 and 377.941 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (69.81) is excellent, well below the 90 A^2 threshold for CNS targets. Ligand B (41.19) is also very good, comfortably under the threshold.

**3. logP:** Ligand A (3.497) is optimal. Ligand B (4.429) is slightly higher, potentially raising concerns about solubility and off-target effects, but still within a reasonable range.

**4. H-Bond Donors:** Ligand A (3) is acceptable. Ligand B (0) is also acceptable, and potentially beneficial for membrane permeability.

**5. H-Bond Acceptors:** Ligand A (2) is good. Ligand B (5) is also acceptable, being within the <10 guideline.

**6. QED:** Both ligands have good QED scores (0.509 and 0.649), indicating drug-like properties.

**7. DILI:** Ligand A (38.62) has a lower DILI risk than Ligand B (19.542), which is preferable.

**8. BBB:** Ligand A (82.784) has a slightly better BBB penetration percentile than Ligand B (79.449), which is important for a CNS target like DRD2.

**9. Caco-2 Permeability:** Ligand A (-5.211) has poor Caco-2 permeability, which is a significant drawback. Ligand B (-4.943) also has poor permeability, but slightly better than A.

**10. Aqueous Solubility:** Both ligands have very poor aqueous solubility (-3.362 and -5.148). This is a concern for formulation and bioavailability.

**11. hERG Inhibition:** Both ligands have low hERG inhibition risk (0.888 and 0.856).

**12. Microsomal Clearance:** Ligand A (8.589) has lower microsomal clearance, suggesting better metabolic stability, compared to Ligand B (60.938).

**13. In vitro Half-Life:** Ligand B (45.529) has a significantly longer in vitro half-life than Ligand A (3.962), which is a major advantage.

**14. P-gp Efflux:** Both ligands have low P-gp efflux liability (0.355 and 0.754).

**15. Binding Affinity:** Ligand A (-9.1 kcal/mol) has a significantly stronger binding affinity than Ligand B (-6.6 kcal/mol). This is a substantial advantage, potentially outweighing some of the ADME drawbacks.

**Overall Assessment:**

Ligand A has a superior binding affinity and better DILI and BBB scores, but suffers from poor Caco-2 permeability and a short half-life. Ligand B has a longer half-life, but weaker binding affinity and a higher DILI risk. The significantly stronger binding affinity of Ligand A is a critical factor for GPCR targets. While the poor permeability and half-life are concerns, these can potentially be addressed through formulation strategies or further chemical modifications. The substantial affinity advantage is likely to translate to greater efficacy.

Output:
1
2025-04-17 05:20:10,042 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (336.355 and 349.381 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (95.34) is slightly above the optimal <90 for CNS targets, but still reasonable. Ligand B (62.3) is well within the desired range. This favors Ligand B.

**3. logP:** Both ligands have good logP values (1.445 and 2.294), falling within the 1-3 range.

**4. H-Bond Donors:** Both have 1 HBD, which is acceptable.

**5. H-Bond Acceptors:** Ligand A has 7 HBAs, which is acceptable. Ligand B has 3 HBAs, which is also good.

**6. QED:** Both ligands have good QED scores (0.768 and 0.83), indicating good drug-like properties.

**7. DILI:** Ligand A has a very high DILI risk (98.565), which is a significant concern. Ligand B has a much lower DILI risk (32.028), making it more favorable.

**8. BBB:** Ligand B has a significantly higher BBB penetration percentile (96.123) compared to Ligand A (19.349). This is *critical* for a CNS target like DRD2.

**9. Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and difficult to interpret without knowing the scale. However, the magnitude is similar.

**10. Aqueous Solubility:** Both have negative solubility values, again making direct comparison difficult.

**11. hERG:** Both ligands have low hERG inhibition liability (0.098 and 0.552), which is good.

**12. Microsomal Clearance:** Both have similar microsomal clearance values (22.997 and 25.332), indicating moderate metabolic stability.

**13. In vitro Half-Life:** Ligand B has a significantly longer half-life (-15.648) than Ligand A (-4.208). This is a positive attribute.

**14. P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.006 and 0.025), which is favorable for CNS penetration.

**15. Binding Affinity:** Both ligands have very similar and excellent binding affinities (-8.8 and -8.7 kcal/mol). The difference is negligible.

**Overall Assessment:**

Ligand B is significantly better due to its much higher BBB penetration (96.123 vs 19.349), lower DILI risk (32.028 vs 98.565), and longer in vitro half-life (-15.648 vs -4.208). While Ligand A has a slightly lower TPSA, the other factors overwhelmingly favor Ligand B. The similar binding affinities make the ADME properties the deciding factor.

Output:
1
2025-04-17 05:20:10,043 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (357.5 and 351.4 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (90.9) is slightly above the preferred <90 for CNS targets, but acceptable. Ligand B (78.95) is well within the ideal range.

**logP:** Ligand A (1.068) is at the lower end of optimal, potentially impacting permeability. Ligand B (0.531) is even lower, raising concerns about membrane permeability.

**H-Bond Donors/Acceptors:** Ligand A (3 HBD, 5 HBA) is within acceptable limits. Ligand B (1 HBD, 4 HBA) is also good.

**QED:** Both ligands have good QED scores (0.537 and 0.805), indicating drug-like properties.

**DILI:** Ligand A (12.1%) has a significantly lower DILI risk than Ligand B (28.7%). This is a substantial advantage.

**BBB:** Ligand A (46.2%) is below the desirable >70% for CNS targets, but not drastically so. Ligand B (51.2%) is also below 70%, but slightly better than A.

**Caco-2 Permeability:** Ligand A (-5.314) and Ligand B (-4.598) both have negative values, indicating poor permeability.

**Aqueous Solubility:** Both ligands have negative solubility values (-0.816 and -1.53), suggesting poor solubility.

**hERG:** Both ligands have very low hERG risk (0.231 and 0.117).

**Microsomal Clearance:** Ligand A (-2.464) has a lower (better) microsomal clearance than Ligand B (10.773), indicating greater metabolic stability.

**In vitro Half-Life:** Ligand A (-10.006) has a much longer in vitro half-life than Ligand B (-7.906).

**P-gp Efflux:** Both ligands show very low P-gp efflux liability (0.006 and 0.024).

**Binding Affinity:** Ligand B (-8.9 kcal/mol) has a slightly better binding affinity than Ligand A (-7.0 kcal/mol), a difference of 1.9 kcal/mol. This is a significant advantage that could potentially offset some ADME liabilities.

**Overall Assessment:**

While Ligand B has a better binding affinity, Ligand A demonstrates a significantly better safety profile (lower DILI) and improved metabolic stability (lower Cl_mic, longer t1/2). Both have permeability and solubility concerns, and suboptimal BBB penetration. However, the substantial difference in DILI risk and metabolic stability, combined with acceptable (though not ideal) BBB penetration, makes Ligand A the more promising candidate. The affinity difference, while notable, is less critical than avoiding potential liver toxicity and ensuring sufficient drug exposure through metabolic stability.

Output:
0
2025-04-17 05:20:10,043 - INFO - Batch 189 complete. Total preferences: 3024
2025-04-17 05:20:10,043 - INFO - Processing batch 190/512...
2025-04-17 05:20:57,790 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (340.358 Da) is slightly lower, which could be advantageous for permeability. Ligand B (365.499 Da) is also acceptable.

**TPSA:** Both ligands have TPSA values below the 140 A^2 threshold for good oral absorption. More importantly, both are below the 90 A^2 threshold desirable for CNS targets. Ligand A (86.02 A^2) is slightly better than Ligand B (91.32 A^2).

**logP:** Both ligands have optimal logP values (1-3). Ligand A (2.988) is closer to the upper end, while Ligand B (1.739) is closer to the lower end. This is a slight advantage for Ligand A.

**H-Bond Donors/Acceptors:** Ligand A (4 HBD, 2 HBA) and Ligand B (3 HBD, 5 HBA) both fall within acceptable limits.

**QED:** Both ligands have QED values above 0.5, indicating good drug-like properties. Ligand A (0.588) is slightly better.

**DILI:** Ligand A (90.694) has a higher DILI risk than Ligand B (42.613). This is a significant drawback for Ligand A.

**BBB:** Ligand A (67.313) has a better BBB percentile than Ligand B (50.679), which is crucial for a CNS target like DRD2.

**Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and suggests a potential issue with the data or modeling. However, we'll proceed assuming these represent low permeability.

**Aqueous Solubility:** Both ligands have negative solubility values, which is also unusual and suggests poor solubility.

**hERG:** Both ligands have very low hERG inhibition liability, which is good. Ligand B (0.152) is slightly better.

**Microsomal Clearance:** Ligand A (6.159) has significantly lower microsomal clearance than Ligand B (28.035), indicating better metabolic stability.

**In vitro Half-Life:** Ligand A (100.987) has a much longer in vitro half-life than Ligand B (-12.486), which is a major advantage.

**P-gp Efflux:** Ligand A (0.201) has lower P-gp efflux liability than Ligand B (0.108), which is favorable for CNS penetration.

**Binding Affinity:** Ligand A (-11 kcal/mol) has a significantly stronger binding affinity than Ligand B (-8.2 kcal/mol). This is a substantial advantage that can outweigh some of the ADME drawbacks.

**Overall Assessment:**

Ligand A has a superior binding affinity, better BBB penetration, lower clearance, longer half-life, and lower P-gp efflux. However, it has a significantly higher DILI risk. Ligand B has a lower DILI risk but weaker affinity, poorer BBB penetration, higher clearance, and a shorter half-life.

Given the importance of affinity and CNS penetration for a DRD2 ligand, and the fact that the affinity difference is substantial (2.8 kcal/mol), Ligand A is the more promising candidate despite the higher DILI risk. DILI risk can potentially be mitigated through structural modifications during lead optimization. The strong binding and favorable CNS properties of Ligand A are more difficult to achieve through later-stage modifications.

Output:
0
2025-04-17 05:20:57,790 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (355.435 Da) is slightly lower, which could be beneficial for permeability. Ligand B (366.487 Da) is also good.

**TPSA:** Ligand A (99.18) is closer to the ideal range for CNS targets (<=90), though still slightly above. Ligand B (69.48) is excellent, well within the desired range. This favors Ligand B.

**logP:** Ligand A (-0.641) is quite low, potentially hindering membrane permeability and brain penetration. Ligand B (2.997) is nearly ideal. This is a significant advantage for Ligand B.

**H-Bond Donors/Acceptors:** Ligand A has 2 HBD and 5 HBA, which are acceptable. Ligand B has 0 HBD and 7 HBA, also acceptable.

**QED:** Both ligands have similar QED values (0.683 and 0.682), indicating good drug-likeness.

**DILI:** Ligand A (31.291) has a much lower DILI risk than Ligand B (57.154). This is a positive for Ligand A.

**BBB:** Ligand A (29.74) has a very low BBB penetration percentile, making it unlikely to reach the target in the CNS effectively. Ligand B (54.013) is better, but still not ideal (aim for >70). This is a major drawback for Ligand A.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.138 and -4.663), which is unusual and suggests poor permeability. However, these values are on a strange scale, and the absolute value is what matters. Ligand B appears slightly better.

**Aqueous Solubility:** Both ligands have very poor aqueous solubility (-0.27 and -2.256). This could pose formulation challenges.

**hERG Inhibition:** Ligand A (0.063) has a very low hERG risk, which is excellent. Ligand B (0.654) is higher, representing a potential cardiotoxicity concern. This favors Ligand A.

**Microsomal Clearance:** Ligand A (2.31) has a lower microsomal clearance, indicating better metabolic stability. Ligand B (84.523) has very high clearance, suggesting rapid metabolism. This is a significant advantage for Ligand A.

**In vitro Half-Life:** Ligand A (25.235) has a reasonable half-life. Ligand B (-16.513) has a negative half-life, which is impossible and indicates a problem with the data or the molecule's stability.

**P-gp Efflux:** Ligand A (0.016) has very low P-gp efflux, which is favorable for CNS penetration. Ligand B (0.28) has slightly higher efflux.

**Binding Affinity:** Ligand B (-6.3 kcal/mol) has a significantly stronger binding affinity than Ligand A (-0.0). This is a crucial advantage, potentially outweighing some of the ADME drawbacks.

**Overall Assessment:**

Ligand B has a much better logP, TPSA, and binding affinity, which are critical for a CNS GPCR target. However, it suffers from high DILI risk, high metabolic clearance, a problematic half-life, and a less favorable BBB score. Ligand A has better safety profiles (DILI, hERG) and metabolic stability, and lower P-gp efflux, but its low logP and extremely poor BBB penetration are major concerns.

Despite the strong affinity of Ligand B, the poor BBB penetration of Ligand A and the questionable half-life and high clearance of Ligand B make both problematic. However, the affinity difference is substantial. Given the importance of affinity for GPCRs, and the possibility of optimizing the ADME properties of Ligand B, I would choose Ligand B as the more promising starting point for further optimization.

Output:
1
2025-04-17 05:20:57,791 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (346.431 Da) is slightly lower, which could be advantageous for permeability.

**TPSA:** Ligand A (84.42) is excellent for CNS penetration, well below the 90 A^2 threshold. Ligand B (40.62) is also very good.

**logP:** Ligand A (1.207) is within the optimal range. Ligand B (2.185) is also good, though slightly higher.

**H-Bond Donors/Acceptors:** Ligand A has 1 HBD and 5 HBA, which are acceptable. Ligand B has 0 HBD and 3 HBA, also acceptable.

**QED:** Both ligands have reasonable QED scores (A: 0.866, B: 0.769), indicating good drug-like properties.

**DILI:** Both ligands have similar and acceptable DILI risk (A: 34.432, B: 36.603), both below the 40 threshold.

**BBB:** Ligand B (90.617) has a significantly higher BBB percentile than Ligand A (66.964). This is a crucial advantage for a CNS target like DRD2.

**Caco-2 Permeability:** Ligand A (-5.109) has a negative Caco-2 value, which is unusual and suggests very poor permeability. Ligand B (-4.86) is also negative, but slightly less so.

**Aqueous Solubility:** Ligand A (-1.009) has poor aqueous solubility. Ligand B (-3.602) is even worse.

**hERG Inhibition:** Ligand A (0.076) has very low hERG inhibition risk. Ligand B (0.699) is slightly higher, but still relatively low.

**Microsomal Clearance:** Ligand A (-1.218) has negative clearance, which is not physically possible and indicates an issue with the data or prediction. Ligand B (45.449) has a high microsomal clearance, suggesting rapid metabolism.

**In vitro Half-Life:** Ligand A (7.906) has a reasonable half-life. Ligand B (-14.848) has a negative half-life, which is not physically possible.

**P-gp Efflux:** Ligand A (0.008) has very low P-gp efflux, which is excellent for CNS penetration. Ligand B (0.374) has slightly higher efflux, but still relatively low.

**Binding Affinity:** Ligand B (-9.3 kcal/mol) has a slightly better binding affinity than Ligand A (-8.6 kcal/mol), although both are very good.

**Overall Assessment:**

Ligand B is clearly superior due to its significantly higher BBB penetration (90.617 vs 66.964). While Ligand A has better P-gp efflux and hERG, the BBB is paramount for a CNS target. The negative values for Caco-2 and half-life for Ligand B are concerning, but the affinity is better. However, the negative clearance for Ligand A is a fatal flaw. The data for ligand A seems suspect due to the negative clearance.

Output:
1
2025-04-17 05:20:57,791 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (339.41 and 344.455 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (41.49) is significantly better than Ligand B (60.85). For CNS targets, we want TPSA <= 90, and ideally closer to 60. Ligand A is much closer to this ideal.

**3. logP:** Ligand A (3.674) is optimal (1-3), while Ligand B (1.424) is on the lower side, potentially hindering permeability.

**4. H-Bond Donors:** Both have acceptable HBD counts (2 and 1 respectively), staying within the <=5 guideline.

**5. H-Bond Acceptors:** Both have acceptable HBA counts (3 each), staying within the <=10 guideline.

**6. QED:** Both have reasonable QED values (0.789 and 0.606), indicating drug-like properties, with Ligand A being slightly better.

**7. DILI:** Ligand A (40.287) has a slightly higher DILI risk than Ligand B (8.414), but both are below the concerning threshold of 60.

**8. BBB:** Ligand A (70.027) is better than Ligand B (61.109) in terms of BBB penetration, but both are reasonably good. A value >70 is desirable for CNS targets.

**9. Caco-2 Permeability:** Ligand A (-4.528) and Ligand B (-4.638) both have negative values, which is unusual and suggests poor permeability. However, the scale is not specified, so it's difficult to interpret.

**10. Aqueous Solubility:** Ligand A (-4.314) and Ligand B (-2.341) both have negative values, which also suggests poor solubility.

**11. hERG Inhibition:** Ligand A (0.931) has a slightly higher hERG risk than Ligand B (0.31), but both are relatively low.

**12. Microsomal Clearance:** Ligand A (38.156) has a higher microsomal clearance than Ligand B (16.939), indicating lower metabolic stability.

**13. In vitro Half-Life:** Ligand B (-3.825) has a negative half-life, which is impossible. This is a major red flag. Ligand A (50.054) has a reasonable half-life.

**14. P-gp Efflux:** Ligand A (0.876) has a slightly higher P-gp efflux liability than Ligand B (0.091). Lower is better for CNS exposure.

**15. Binding Affinity:** Ligand A (-9.4 kcal/mol) has a significantly stronger binding affinity than Ligand B (-7.9 kcal/mol). This is a crucial advantage, potentially outweighing some of the ADME drawbacks.

**Overall Assessment:**

Ligand A is the stronger candidate. While it has a slightly higher DILI risk and P-gp efflux, its superior TPSA, logP, BBB penetration, and *significantly* better binding affinity make it more likely to be a viable drug candidate for DRD2. The negative half-life for Ligand B is a deal-breaker. The affinity difference of 1.5 kcal/mol is substantial and justifies accepting some minor ADME compromises.

Output:
1
2025-04-17 05:20:57,791 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (350.46 and 358.48 Da) fall within the ideal 200-500 Da range.

**TPSA:** Both ligands have TPSA values (89.87 and 85.35) below the 90 A^2 threshold desirable for CNS targets. This is a good sign for both.

**logP:** Ligand A (0.828) is slightly low, potentially hindering permeation. Ligand B (-1.16) is even lower, raising more concerns about permeability. Both are below the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A (HBD=3, HBA=4) is within acceptable limits. Ligand B (HBD=2, HBA=6) is also acceptable, although the higher HBA might slightly impact permeability.

**QED:** Ligand A (0.655) has a better QED score than Ligand B (0.541), indicating a more drug-like profile.

**DILI:** Ligand A (19.97) has a significantly higher DILI risk than Ligand B (5.31), which is a major concern.

**BBB:** Both ligands have reasonable BBB penetration (Ligand A: 23.03, Ligand B: 22.84), but are not exceptionally high.

**Caco-2 Permeability:** Both ligands have negative Caco-2 permeability values (-5.104 and -5.024), which is unusual and suggests poor intestinal absorption. This is a significant drawback for both.

**Aqueous Solubility:** Both ligands have negative solubility values (-1.862 and -0.133), which is also unusual and suggests poor aqueous solubility.

**hERG Inhibition:** Ligand A (0.077) has a very low hERG risk, a significant advantage. Ligand B (0.217) has a slightly higher, but still relatively low, hERG risk.

**Microsomal Clearance:** Ligand A (2.85 mL/min/kg) has a much lower microsomal clearance than Ligand B (30.271 mL/min/kg), indicating better metabolic stability.

**In vitro Half-Life:** Ligand A (10.46 hours) has a significantly longer half-life than Ligand B (-11.341 hours). The negative value for Ligand B is concerning.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.034 and 0.004), which is favorable for CNS penetration.

**Binding Affinity:** Ligand A (-7.5 kcal/mol) has a slightly better binding affinity than Ligand B (-6.5 kcal/mol). This 1 kcal/mol difference is noteworthy.

**Overall Assessment:**

Ligand A has a better binding affinity, QED, metabolic stability (lower Cl_mic, longer t1/2), and a much lower hERG risk. However, its DILI risk is significantly higher. Ligand B has a lower DILI risk but suffers from poorer predicted metabolic stability, a shorter half-life, and a weaker binding affinity. The negative Caco-2 and solubility values are concerning for both.

Given the GPCR-specific priorities, and the importance of CNS penetration, the better binding affinity and metabolic stability of Ligand A, despite the higher DILI risk, make it a slightly more promising starting point. The DILI risk can potentially be mitigated through structural modifications. The poor Caco-2 and solubility for both ligands would need to be addressed.

Output:
0
2025-04-17 05:20:57,791 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (338.415 and 348.407 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (98.72) is excellent, being below the 90 A^2 threshold for CNS targets. Ligand B (120.12) is still reasonable, but less optimal, being above 90 A^2.

**logP:** Ligand A (0.982) is at the lower end of the optimal range (1-3), potentially impacting permeability. Ligand B (-0.508) is below 1, which is a concern for permeation.

**H-Bond Donors/Acceptors:** Both ligands have 2 HBD and 6 HBA, which are within acceptable limits.

**QED:** Both ligands have similar QED scores (0.626 and 0.623), indicating good drug-likeness.

**DILI:** Ligand A (55.603) has a higher DILI risk than Ligand B (30.942). This is a negative for Ligand A.

**BBB:** Ligand A (60.838) has a better BBB penetration percentile than Ligand B (38.852). This is a significant advantage for CNS targeting.

**Caco-2 Permeability:** Ligand A (-5.991) has significantly worse Caco-2 permeability than Ligand B (-5.455), suggesting poorer intestinal absorption.

**Aqueous Solubility:** Both ligands have poor aqueous solubility (-1.143 and -1.579).

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.363 and 0.074).

**Microsomal Clearance:** Ligand A (18.809) has higher microsomal clearance than Ligand B (6.301), indicating lower metabolic stability.

**In vitro Half-Life:** Ligand B (32.844) has a significantly longer in vitro half-life than Ligand A (7.715), which is a major advantage.

**P-gp Efflux:** Ligand A (0.068) has lower P-gp efflux liability than Ligand B (0.007), which is favorable for CNS exposure.

**Binding Affinity:** Ligand B (-7.2 kcal/mol) has a significantly stronger binding affinity than Ligand A (-9.3 kcal/mol). This is a substantial advantage, potentially outweighing some ADME drawbacks.

**Overall Assessment:**

While Ligand A has better BBB penetration and lower P-gp efflux, Ligand B excels in several critical areas: significantly stronger binding affinity, a longer half-life, and lower DILI risk. The lower logP and TPSA of Ligand B are less ideal, but the substantial affinity advantage, combined with better metabolic stability, makes it the more promising candidate. The poor solubility of both is a formulation challenge that would need to be addressed, but is secondary to the potency and stability differences.

Output:
1
2025-04-17 05:20:57,791 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B based on the provided guidelines, prioritizing GPCR-specific properties (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (346.431 Da) is slightly lower, which could be beneficial for permeability. Ligand B (378.607 Da) is also acceptable.

**TPSA:** Ligand A (76.46) is much better than Ligand B (33.2). For a CNS target like DRD2, a TPSA below 90 is preferred, and Ligand A is well within this range. Ligand B is also acceptable, but higher TPSA can sometimes hinder BBB penetration.

**logP:** Ligand A (0.965) is within the optimal range (1-3), but on the lower side. Ligand B (4.299) is higher, potentially causing solubility issues or off-target interactions.

**H-Bond Donors/Acceptors:** Ligand A has 1 HBD and 5 HBA, which are reasonable. Ligand B has 0 HBD and 4 HBA, also acceptable.

**QED:** Ligand A (0.779) has a better QED score than Ligand B (0.632), indicating a more drug-like profile.

**DILI:** Ligand A (45.173) has a slightly higher DILI risk than Ligand B (22.722), but both are below the concerning threshold of 60.

**BBB:** This is a critical parameter for CNS targets. Ligand B (87.941) has a significantly higher BBB penetration percentile than Ligand A (65.374). This is a major advantage for Ligand B.

**Caco-2 Permeability:** Both are negative, which is unusual and potentially problematic. However, the scale is not specified, so it's hard to interpret.

**Aqueous Solubility:** Both ligands have negative solubility values, which is also unusual.

**hERG Inhibition:** Ligand A (0.166) shows a lower hERG inhibition liability than Ligand B (0.803), which is preferable.

**Microsomal Clearance:** Ligand B (86.718) has a much higher microsomal clearance than Ligand A (2.928), suggesting lower metabolic stability.

**In vitro Half-Life:** Ligand A (6.32 hours) has a longer half-life than Ligand B (-5.812 hours). The negative value for B is concerning.

**P-gp Efflux:** Ligand A (0.03) has a much lower P-gp efflux liability than Ligand B (0.685), which is beneficial for CNS exposure.

**Binding Affinity:** Ligand A (-7.8 kcal/mol) has a slightly better binding affinity than Ligand B (-7.0 kcal/mol). While both are good, the 1.8 kcal/mol difference is significant.

**Overall Assessment:**

Ligand B excels in BBB penetration, a crucial factor for a CNS target. However, it suffers from higher logP, higher P-gp efflux, higher hERG inhibition, and significantly higher microsomal clearance (lower metabolic stability). Ligand A has a better overall ADME profile, with lower P-gp efflux, lower hERG, better metabolic stability, and a slightly better binding affinity. The slightly lower BBB penetration of Ligand A is a concern, but the superior ADME properties and binding affinity outweigh this drawback.

Output:
0
2025-04-17 05:20:57,792 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B based on the provided guidelines, prioritizing GPCR-specific properties (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (398.985 Da) is closer to the upper end, while Ligand B (349.406 Da) is a bit lower. This isn't a major differentiating factor.

**TPSA:** Ligand A (66.91) is excellent for CNS penetration, well below the 90 A^2 threshold. Ligand B (83.22) is still reasonable but less optimal, approaching the 100 A^2 limit.

**logP:** Ligand A (4.826) is high, potentially causing solubility issues or off-target interactions. Ligand B (2.048) is within the optimal 1-3 range. This is a significant advantage for Ligand B.

**H-Bond Donors/Acceptors:** Ligand A (2 HBD, 5 HBA) and Ligand B (3 HBD, 3 HBA) both fall within acceptable limits.

**QED:** Both ligands have good QED scores (A: 0.655, B: 0.704), indicating drug-like properties.

**DILI:** Ligand A (72.354) has a higher DILI risk than Ligand B (51.26), though both are below the concerning 60 threshold.

**BBB:** Both ligands exhibit good BBB penetration (A: 70.57, B: 79.294), exceeding the 70% threshold for CNS targets. Ligand B is slightly better.

**Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and suggests a potential issue with the data or modeling. However, we'll proceed assuming this reflects poor permeability.

**Aqueous Solubility:** Both ligands have very poor aqueous solubility (A: -5.781, B: -3.195). This is a significant drawback for both.

**hERG Inhibition:** Both ligands show low hERG inhibition risk (A: 0.438, B: 0.419).

**Microsomal Clearance:** Ligand A (85.286) has a higher microsomal clearance than Ligand B (20.783), indicating lower metabolic stability. This is a clear advantage for Ligand B.

**In vitro Half-Life:** Ligand A (70.052) has a longer half-life than Ligand B (13.63), which is desirable.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (A: 0.375, B: 0.071). Ligand B is significantly lower, suggesting better CNS exposure.

**Binding Affinity:** Ligand B (-8.8 kcal/mol) has a slightly better binding affinity than Ligand A (-8.3 kcal/mol). While the difference is not huge, it's enough to be considered.

**Overall Assessment:**

Ligand B is the more promising candidate. While both have poor solubility, Ligand B has a more favorable logP, lower DILI risk, significantly better metabolic stability (lower Cl_mic, longer t1/2), lower P-gp efflux, and slightly better binding affinity. Ligand A's primary advantage is its longer half-life, but this is outweighed by its higher logP and clearance. Given the GPCR target and the need for CNS penetration, the combination of better ADME properties and comparable affinity makes Ligand B the preferred choice.

Output:
1
2025-04-17 05:20:57,792 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B based on the provided guidelines, prioritizing GPCR-specific properties (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (350.344 Da) is slightly lower, which is generally favorable for permeability, but both are acceptable.

**TPSA:** Ligand A (49.33) is excellent for CNS penetration, well below the 90 A^2 threshold. Ligand B (93.11) is higher, potentially hindering BBB penetration, though still not drastically outside acceptable limits.

**logP:** Ligand A (2.511) is optimal. Ligand B (-0.528) is significantly lower, which could lead to poor membrane permeability and reduced CNS exposure. This is a major drawback.

**H-Bond Donors/Acceptors:** Ligand A (0 HBD, 4 HBA) is favorable. Ligand B (3 HBD, 5 HBA) is also acceptable, but slightly higher counts could impact permeability.

**QED:** Both ligands have reasonable QED values (A: 0.85, B: 0.563), indicating good drug-like properties.

**DILI:** Ligand A (45.677) has a slightly higher DILI risk than Ligand B (18.573), but both are below the concerning threshold of 60.

**BBB:** Ligand A (96.045) has excellent BBB penetration potential. Ligand B (39.899) is significantly lower, raising concerns about reaching the CNS target. This is a critical difference given DRD2 is a CNS target.

**Caco-2 Permeability:** Ligand A (-4.503) has poor Caco-2 permeability. Ligand B (-5.186) is also poor, but slightly worse.

**Aqueous Solubility:** Ligand A (-2.479) has poor aqueous solubility. Ligand B (-0.673) is also poor, but slightly better.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (A: 0.907, B: 0.473).

**Microsomal Clearance:** Ligand B (-17.624) has a lower (better) microsomal clearance than Ligand A (23.712), suggesting greater metabolic stability.

**In vitro Half-Life:** Ligand B (-9.449) has a longer half-life than Ligand A (-19.361), which is desirable.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (A: 0.277, B: 0.008), which is good for CNS exposure.

**Binding Affinity:** Both ligands have very similar binding affinities (A: -8.6 kcal/mol, B: -8.1 kcal/mol). The difference of 0.5 kcal/mol is not substantial enough to overcome the significant ADME deficiencies of Ligand B.

**Conclusion:**

Ligand A is the more promising candidate. While it has poor Caco-2 permeability and solubility, its superior logP and, critically, its excellent BBB penetration make it much more likely to reach the DRD2 target in the CNS. Ligand B's negative logP and lower BBB penetration are significant drawbacks that outweigh its slightly better metabolic stability and half-life. Given the GPCR-specific priorities, BBB penetration is paramount for a CNS drug like this.

Output:
1
2025-04-17 05:20:57,792 - INFO - Reasoning:

Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (423.16 Da) is slightly higher than Ligand B (362.514 Da), but both are acceptable.

**2. TPSA:** Ligand A (81.59) is higher than Ligand B (36.36). For CNS targets, TPSA should be <= 90. Both are within this range, but Ligand B is significantly better.

**3. logP:** Both ligands have good logP values (A: 4.34, B: 4.634), falling within the optimal 1-3 range, although slightly above. Ligand B is marginally higher.

**4. H-Bond Donors:** Ligand A has 4 HBD, which is acceptable. Ligand B has only 1, which is also good.

**5. H-Bond Acceptors:** Both ligands have a reasonable number of HBA (A: 3, B: 4).

**6. QED:** Both ligands have acceptable QED values (A: 0.438, B: 0.625), with Ligand B being more drug-like.

**7. DILI:** Ligand A has a DILI risk of 68.9%, which is considered high risk. Ligand B has a much lower DILI risk of 16.6%, which is good.

**8. BBB:** Ligand A has a BBB penetration of 46.4%, which is below the desirable threshold of 70% for CNS targets. Ligand B has a BBB penetration of 68.2%, which is also below 70% but significantly better than Ligand A.

**9. Caco-2:** Both ligands have negative Caco-2 values (-5.384 and -5.246), which is unusual and suggests poor permeability. This is a significant concern for both.

**10. Solubility:** Both ligands have very poor aqueous solubility (-4.929 and -3.815). This is a major drawback.

**11. hERG:** Both ligands have low hERG inhibition liability (A: 0.747, B: 0.979), which is good.

**12. Cl_mic:** Ligand A has a lower microsomal clearance (41.834) than Ligand B (121.584), indicating better metabolic stability.

**13. t1/2:** Both ligands have similar in vitro half-lives (A: 30.344, B: 29.059).

**14. Pgp:** Ligand A has a low Pgp efflux liability (0.289), which is favorable for CNS penetration. Ligand B has a higher Pgp efflux liability (0.829).

**15. Binding Affinity:** Ligand B (-7.1 kcal/mol) has a significantly better binding affinity than Ligand A (-9.7 kcal/mol). This is a substantial advantage.

**Overall Assessment:**

While both ligands have issues with Caco-2 permeability and solubility, Ligand B is the better candidate. It has a significantly better binding affinity, a much lower DILI risk, and a better QED score. Although its BBB penetration is still below the ideal threshold, it's considerably better than Ligand A. Ligand A's high DILI risk and lower affinity are major drawbacks. The better metabolic stability of Ligand A is outweighed by the other factors.

Output:
1
2025-04-17 05:20:57,792 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (387.311 Da) is slightly higher than Ligand B (355.479 Da), but both are acceptable.

**TPSA:** Ligand A (68.7) is excellent for CNS penetration, well below the 90 Angstrom threshold. Ligand B (101.9) is higher, but still potentially acceptable, though less ideal.

**logP:** Ligand A (2.69) is optimal. Ligand B (0.005) is very low, which could hinder membrane permeability and CNS penetration.

**H-Bond Donors/Acceptors:** Ligand A (HBD=2, HBA=4) and Ligand B (HBD=4, HBA=5) both fall within acceptable ranges.

**QED:** Ligand A (0.78) has a better drug-likeness score than Ligand B (0.515).

**DILI:** Ligand A (19.969) has a significantly lower DILI risk than Ligand B (4.149), which is a substantial advantage.

**BBB:** Ligand A (47.848) has a better BBB percentile than Ligand B (25.397), although both are below the desirable >70% for CNS targets.

**Caco-2 Permeability:** Ligand A (-5.105) has a more negative Caco-2 value, suggesting lower permeability. Ligand B (-5.598) is also low, but slightly worse.

**Aqueous Solubility:** Ligand A (-2.193) has slightly better solubility than Ligand B (-0.874).

**hERG:** Both ligands have very low hERG inhibition liability (0.623 and 0.1 respectively), which is good.

**Microsomal Clearance:** Ligand A (-21.954) has a much lower (better) microsomal clearance than Ligand B (-18.136), indicating greater metabolic stability.

**In vitro Half-Life:** Ligand A (74.584) has a significantly longer in vitro half-life than Ligand B (-6.626).

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.061 and 0.003 respectively).

**Binding Affinity:** Both ligands have the same binding affinity (-8.3 kcal/mol), which is excellent.

**Overall Assessment:**

Ligand A is superior to Ligand B. While both have good binding affinity, Ligand A excels in crucial ADME properties for a CNS-targeting GPCR ligand. Specifically, it has a better logP, significantly lower DILI risk, better BBB penetration, lower microsomal clearance, and a longer half-life. The slightly lower Caco-2 permeability of Ligand A is less concerning given the CNS target and the overall superior profile. Ligand B's very low logP is a significant drawback, likely hindering its ability to cross the blood-brain barrier despite the low P-gp efflux.

Output:
1
2025-04-17 05:20:57,792 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (353.419 and 346.515 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (102.17) is slightly above the optimal <90 for CNS targets, but still reasonable. Ligand B (49.41) is excellent, well below 90.

**logP:** Ligand A (-0.493) is a bit low, potentially hindering permeability. Ligand B (3.215) is within the optimal 1-3 range.

**H-Bond Donors:** Both ligands have 1 HBD, which is acceptable.

**H-Bond Acceptors:** Ligand A has 5 HBA, acceptable. Ligand B has 2 HBA, also acceptable.

**QED:** Both ligands have good QED scores (0.593 and 0.72), indicating drug-like properties.

**DILI:** Ligand A (22.993) has a very low DILI risk, excellent. Ligand B (13.106) also has a low DILI risk, also excellent.

**BBB:** Ligand A (84.335) has a good BBB penetration percentile, desirable for a CNS target. Ligand B (72.354) is also good, but slightly lower.

**Caco-2:** Both ligands have negative Caco-2 values (-5.097 and -4.593). This is unusual and suggests poor permeability. However, these values are on a scale where negative values are possible, and the absolute magnitude is important.

**Solubility:** Both ligands have negative solubility values (-1.603 and -4.119). This is also unusual, and suggests poor aqueous solubility.

**hERG:** Both ligands have low hERG inhibition liability (0.192 and 0.394), which is positive.

**Microsomal Clearance:** Ligand A (22.596) has lower clearance than Ligand B (60.117), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (7.327) has a longer half-life than Ligand B (-3.093), which is preferable.

**P-gp Efflux:** Ligand A (0.013) has very low P-gp efflux, which is excellent for CNS penetration. Ligand B (0.151) has slightly higher P-gp efflux, but still reasonably low.

**Binding Affinity:** Ligand B (-8.2 kcal/mol) has a significantly stronger binding affinity than Ligand A (-7.2 kcal/mol). This 1 kcal/mol difference is substantial and can outweigh some ADME drawbacks.

**Overall Assessment:**

Ligand B has a superior binding affinity and a more favorable logP. While Ligand A has better BBB penetration and lower clearance, the significantly stronger binding of Ligand B is a major advantage, especially for a GPCR target. The negative Caco-2 and solubility values are concerning for both, but the potency advantage of Ligand B is likely to be more impactful in early-stage optimization.

Output:
1
2025-04-17 05:20:57,793 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (362.392 and 348.447 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (67.43) is better than Ligand B (78.67). Both are below 90, which is good for CNS penetration, but A is significantly closer to the ideal range.

**logP:** Ligand A (2.711) is optimal (1-3), while Ligand B (1.097) is on the lower side. Lower logP can hinder permeation.

**H-Bond Donors/Acceptors:** Ligand A (2 HBD, 3 HBA) and Ligand B (1 HBD, 5 HBA) both have acceptable numbers of H-bond donors and acceptors.

**QED:** Ligand B (0.864) has a better QED score than Ligand A (0.376), indicating a more drug-like profile overall.

**DILI:** Ligand B (17.604) has a much lower DILI risk than Ligand A (23.963), making it safer from a liver toxicity perspective.

**BBB:** Ligand A (83.676) has a significantly better BBB penetration percentile than Ligand B (69.523). This is a crucial factor for a CNS target like DRD2.

**Caco-2 Permeability:** Ligand A (-4.736) has a worse Caco-2 permeability than Ligand B (-4.63). Lower values indicate lower permeability.

**Aqueous Solubility:** Ligand A (-3.606) has better aqueous solubility than Ligand B (-0.273).

**hERG Inhibition:** Ligand A (0.543) has a lower hERG inhibition risk than Ligand B (0.244), which is preferable.

**Microsomal Clearance:** Ligand B (-0.442) has a lower (better) microsomal clearance than Ligand A (8.054), suggesting greater metabolic stability.

**In vitro Half-Life:** Ligand B (-2.877) has a longer in vitro half-life than Ligand A (-13.493), which is desirable.

**P-gp Efflux:** Ligand A (0.035) has a lower P-gp efflux liability than Ligand B (0.047), which is better for CNS exposure.

**Binding Affinity:** Ligand B (-8.2) has a slightly better binding affinity than Ligand A (-7.9). While the difference is small, it's still a positive.

**Overall Assessment:**

Ligand A excels in BBB penetration and has slightly better solubility and lower P-gp efflux. However, Ligand B demonstrates superior drug-likeness (QED), safety (DILI), metabolic stability (Cl_mic, t1/2), and a slightly better binding affinity. The lower logP of Ligand B is a concern, but the better overall ADME profile and comparable affinity make it the more promising candidate. Given the GPCR-specific priorities, the better BBB of Ligand A is important, but the other ADME properties of Ligand B are more favorable, and the affinity difference is small enough to be outweighed.

Output:
1
2025-04-17 05:20:57,793 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (349.435 and 352.435 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (96.33) is slightly higher than Ligand B (83.47). Both are below the 90 A^2 threshold desirable for CNS targets, but Ligand B is preferable.

**3. logP:** Ligand A (0.447) is a bit low, potentially hindering permeability. Ligand B (-0.167) is even lower, raising concerns about permeability. Both are suboptimal, but Ligand B is slightly worse.

**4. H-Bond Donors:** Ligand A (2) and Ligand B (1) are both within the acceptable limit of <=5. Ligand B is slightly better.

**5. H-Bond Acceptors:** Ligand A (5) and Ligand B (6) are both within the acceptable limit of <=10.

**6. QED:** Both ligands have good QED scores (0.552 and 0.718, respectively), indicating drug-like properties. Ligand B is better.

**7. DILI:** Ligand A (38.852) has a slightly higher DILI risk than Ligand B (24.932). Ligand B is preferable.

**8. BBB:** This is a critical parameter for CNS targets. Ligand A (41.14) has a low BBB penetration percentile, which is a significant drawback. Ligand B (55.099) is much better, exceeding 50% and moving closer to the desirable >70% range.

**9. Caco-2 Permeability:** Ligand A (-5.508) has very poor Caco-2 permeability. Ligand B (-4.795) is slightly better, but still poor.

**10. Aqueous Solubility:** Ligand A (-1.135) and Ligand B (-0.98) both have poor aqueous solubility.

**11. hERG Inhibition:** Both ligands have low hERG inhibition liability (0.087 and 0.2, respectively), which is good.

**12. Microsomal Clearance:** Ligand A (17.396) has lower microsomal clearance than Ligand B (9.63), suggesting better metabolic stability.

**13. In vitro Half-Life:** Ligand A (20.606) has a longer in vitro half-life than Ligand B (24.058), which is desirable.

**14. P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.015 and 0.013, respectively), which is excellent.

**15. Binding Affinity:** Ligand A (-8.5 kcal/mol) has a significantly stronger binding affinity than Ligand B (-7.5 kcal/mol). This is a substantial advantage (1.0 kcal/mol difference).

**Overall Assessment:**

While Ligand A has better metabolic stability and a much stronger binding affinity, its extremely poor BBB penetration is a major concern for a CNS target like DRD2. Ligand B, despite having slightly less favorable logP and solubility, exhibits significantly better BBB penetration (55.099 vs 41.14), which is paramount for CNS drug development. The 1.0 kcal/mol difference in binding affinity can potentially be overcome with further optimization of Ligand B, but improving BBB penetration for Ligand A would be far more challenging.

Output:
1
2025-04-17 05:20:57,793 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (380.857 Da) is slightly higher than Ligand B (349.391 Da), but both are acceptable.

**TPSA:** Ligand A (92.09) is better than Ligand B (115.47). For CNS targets, we want TPSA <= 90, so Ligand A is closer to this threshold. Ligand B is significantly higher, potentially hindering BBB penetration.

**logP:** Ligand A (3.174) is optimal (1-3). Ligand B (-0.688) is quite low, which could lead to poor membrane permeability and bioavailability.

**H-Bond Donors/Acceptors:** Ligand A (1 HBD, 5 HBA) and Ligand B (2 HBD, 5 HBA) are both within acceptable limits (<=5 HBD and <=10 HBA).

**QED:** Both ligands have similar QED values (0.686 and 0.603), indicating reasonable drug-likeness.

**DILI:** Ligand A (77.782) has a higher DILI risk than Ligand B (45.56). While both are below 60 (good), Ligand B is preferable.

**BBB:** Ligand A (57.193) and Ligand B (53.742) are both below the desirable threshold of >70 for CNS targets. However, this is less critical if other properties are favorable.

**Caco-2 Permeability:** Both have negative Caco-2 values (-5.039 and -5.602), which is unusual and indicates very poor permeability. This is a significant drawback for both.

**Aqueous Solubility:** Both have negative solubility values (-4.876 and -2.172), indicating very poor solubility. This is also a significant drawback for both.

**hERG Inhibition:** Ligand A (0.368) has a slightly higher hERG risk than Ligand B (0.022), but both are low and acceptable.

**Microsomal Clearance:** Ligand A (56.237) has a higher clearance than Ligand B (-18.727), suggesting lower metabolic stability. Ligand B is much more stable.

**In vitro Half-Life:** Ligand A (-11.556) has a negative half-life, which is not possible. Ligand B (-19.745) also has a negative half-life, indicating issues with the data.

**P-gp Efflux:** Ligand A (0.11) has lower P-gp efflux liability than Ligand B (0.004), which is favorable for CNS penetration.

**Binding Affinity:** Ligand B (-8.0 kcal/mol) has a significantly stronger binding affinity than Ligand A (-7.8 kcal/mol). This 1.5+ kcal/mol difference is substantial and can outweigh some ADME drawbacks.

**Overall Assessment:**

Despite both ligands having issues with Caco-2 and solubility, Ligand B is the better candidate. Its significantly stronger binding affinity (-8.0 vs -7.8 kcal/mol) is a major advantage. It also has better metabolic stability (lower Cl_mic, more negative t1/2), lower DILI risk, and lower P-gp efflux. While its logP is low, the strong binding affinity might compensate. Ligand A's higher TPSA and lower P-gp efflux are not enough to overcome the affinity difference and other ADME liabilities.

Output:
1
2025-04-17 05:20:57,793 - INFO - Okay, let's analyze these two ligands for their potential as DRD2 drug candidates. DRD2 is a GPCR in the CNS, so BBB penetration, logP, Pgp efflux, TPSA, and binding affinity are paramount.

**Ligand A: [359.264, 119.23 ,   0.5  ,   2.   ,   8.   ,   0.746,  79.915,  71.229, -5.022,  -2.925,   0.044,  43.995, -17.294,   0.018,  -8.5  ]**

*   **MW:** 359.264 Da - Acceptable.
*   **TPSA:** 119.23  - Good for general absorption, but borderline for CNS targets (ideally <90).
*   **logP:** 0.5 - Low. May struggle with membrane permeability.
*   **HBD:** 2 - Acceptable.
*   **HBA:** 8 - Acceptable.
*   **QED:** 0.746 - Good drug-like properties.
*   **DILI:** 79.915 - Relatively high DILI risk.
*   **BBB:** 71.229 - Good BBB penetration, meeting the >70% threshold for CNS targets.
*   **Caco-2:** -5.022 - Very poor Caco-2 permeability.
*   **Solubility:** -2.925 - Very poor solubility.
*   **hERG:** 0.044 - Very low hERG risk.
*   **Cl_mic:** 43.995 - Moderate metabolic clearance.
*   **t1/2:** -17.294 - Very short half-life.
*   **Pgp:** 0.018 - Low P-gp efflux, which is good.
*   **Affinity:** -8.5 kcal/mol - Excellent binding affinity.

**Ligand B: [341.455,  54.34 ,   2.553,   1.   ,   3.   ,   0.859,  35.905,  66.499, -4.817,  -3.099,   0.179,  41.046,  -4.466,   0.186,  -9.   ]**

*   **MW:** 341.455 Da - Acceptable.
*   **TPSA:** 54.34 - Excellent for CNS penetration.
*   **logP:** 2.553 - Optimal.
*   **HBD:** 1 - Acceptable.
*   **HBA:** 3 - Acceptable.
*   **QED:** 0.859 - Excellent drug-like properties.
*   **DILI:** 35.905 - Low DILI risk.
*   **BBB:** 66.499 - Acceptable, but not ideal for a CNS target (below 70%).
*   **Caco-2:** -4.817 - Poor Caco-2 permeability.
*   **Solubility:** -3.099 - Poor solubility.
*   **hERG:** 0.179 - Low hERG risk.
*   **Cl_mic:** 41.046 - Moderate metabolic clearance.
*   **t1/2:** -4.466 - Short half-life, but better than Ligand A.
*   **Pgp:** 0.186 - Low P-gp efflux, which is good.
*   **Affinity:** -9.0 kcal/mol - Exceptional binding affinity, 0.5 kcal/mol better than Ligand A.

**Comparison and Decision:**

While Ligand A has excellent binding affinity and good BBB penetration, its extremely poor solubility, Caco-2 permeability, and short half-life are major drawbacks. The high DILI risk is also concerning. Ligand B, despite a slightly lower BBB score, presents a much more balanced profile. It has a better logP, lower TPSA, excellent QED, a lower DILI risk, and a superior binding affinity. Both have poor solubility and Caco-2 permeability, but these can potentially be addressed with formulation strategies. The better overall ADME profile and superior affinity of Ligand B make it the more promising candidate.

1
2025-04-17 05:20:57,794 - INFO - Batch 190 complete. Total preferences: 3040
2025-04-17 05:20:57,794 - INFO - Processing batch 191/512...
2025-04-17 05:21:39,586 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 drug candidates, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (348.531 and 351.378 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (58.2) is excellent, well below the 90 A^2 threshold for CNS targets. Ligand B (91.5) is higher, approaching the upper limit for good oral absorption (140) but less ideal for CNS penetration.

**logP:** Ligand A (4.104) is slightly above the optimal 1-3 range, potentially leading to solubility issues, but still within a manageable range. Ligand B (1.031) is quite low, potentially hindering membrane permeability.

**H-Bond Donors/Acceptors:** Both have 2 HBD, which is good. Ligand A has 2 HBA, also good. Ligand B has 4 HBA, which is acceptable but slightly higher.

**QED:** Both ligands have similar QED values (0.68 and 0.749), indicating good drug-likeness.

**DILI:** Ligand A (22.761) has a much lower DILI risk than Ligand B (67.313), indicating a safer profile.

**BBB:** Ligand A (76.425) has a significantly better BBB percentile than Ligand B (67.158). This is a crucial advantage for a CNS target like DRD2.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.592 and -4.893), which is unusual and suggests poor permeability. However, these values are on a log scale and may not be directly comparable without further context.

**Aqueous Solubility:** Both ligands have negative solubility values (-4.626 and -2.739), indicating poor aqueous solubility. This is a concern, but can potentially be addressed through formulation.

**hERG Inhibition:** Ligand A (0.507) has a slightly higher hERG risk than Ligand B (0.35), but both are relatively low.

**Microsomal Clearance:** Ligand A (76.207) has a higher microsomal clearance than Ligand B (47.55), suggesting faster metabolism and potentially lower *in vivo* exposure.

**In vitro Half-Life:** Ligand B (-34.847) has a significantly longer *in vitro* half-life than Ligand A (-1.999). This is a major advantage.

**P-gp Efflux:** Ligand A (0.296) has lower P-gp efflux liability than Ligand B (0.071), which is beneficial for CNS exposure.

**Binding Affinity:** Ligand B (-7.9) has a slightly better binding affinity than Ligand A (-8.5). While both are excellent, the 1.5 kcal/mol difference is noteworthy.

**Overall Assessment:**

Considering the GPCR-specific priorities, Ligand A is the more promising candidate. Its superior BBB penetration, lower DILI risk, and lower P-gp efflux outweigh the slightly lower half-life and higher logP. The affinity difference is small enough that the ADME advantages of Ligand A are more impactful. While both have solubility concerns, these can be addressed with formulation strategies.

Output:
0
2025-04-17 05:21:39,587 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (345.443 and 351.451 Da) fall comfortably within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (81.67) is slightly higher than Ligand B (72.72). Both are below the 90 A^2 threshold desirable for CNS targets, but Ligand B is preferable.

**3. logP:** Ligand A (1.534) is within the optimal 1-3 range. Ligand B (0.435) is slightly below 1, which *could* indicate potential permeability issues, though not drastically. Ligand A is better here.

**4. H-Bond Donors:** Ligand A has 3 HBD, which is acceptable. Ligand B has 0, also acceptable. No clear advantage.

**5. H-Bond Acceptors:** Ligand A has 3 HBA, while Ligand B has 7. Both are below the 10 threshold, but Ligand A is better.

**6. QED:** Both ligands have similar QED values (0.757 and 0.71), indicating good drug-like properties.

**7. DILI:** Both ligands have low DILI risk (25.204 and 26.871 percentile), which is good.

**8. BBB:** Ligand B (67.313%) has a better BBB penetration score than Ligand A (58.278%). This is a crucial factor for a CNS target like DRD2.

**9. Caco-2 Permeability:** Ligand A (-4.811) has a significantly *better* Caco-2 permeability score than Ligand B (-4.919).

**10. Aqueous Solubility:** Ligand A (-1.4) is better than Ligand B (0.034) in terms of aqueous solubility.

**11. hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.354 and 0.223), which is excellent.

**12. Microsomal Clearance:** Ligand A (-17.061) has a much *lower* (better) microsomal clearance than Ligand B (18.44). This suggests greater metabolic stability for Ligand A.

**13. In vitro Half-Life:** Ligand A (30.521) has a longer in vitro half-life than Ligand B (8.296).

**14. P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.027 and 0.044).

**15. Binding Affinity:** Ligand A (-9.6 kcal/mol) has a significantly stronger binding affinity than Ligand B (-7.1 kcal/mol). This is a substantial advantage (2.5 kcal/mol difference).

**Overall Assessment:**

While Ligand B has a slightly better BBB score and TPSA, Ligand A overwhelmingly wins on several critical parameters. The significantly stronger binding affinity (-9.6 vs -7.1 kcal/mol) is a major advantage. Furthermore, Ligand A demonstrates superior metabolic stability (lower Cl_mic, longer t1/2), better Caco-2 permeability, and better solubility. The slightly lower BBB score for Ligand A is less concerning given its overall superior profile, and can potentially be addressed through further optimization.

Output:
1
2025-04-17 05:21:39,587 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (334.379 and 349.387 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Both ligands (86.88 and 88.18) are below the 90 A^2 threshold desirable for CNS targets, which is excellent.

**3. logP:** Ligand A (1.562) is within the optimal 1-3 range. Ligand B (-0.109) is slightly below 1, which *could* indicate permeability issues, though not drastically.

**4. H-Bond Donors:** Ligand A (3) and Ligand B (1) both meet the <=5 criteria.

**5. H-Bond Acceptors:** Ligand A (3) and Ligand B (5) both meet the <=10 criteria.

**6. QED:** Both ligands have good QED scores (0.553 and 0.703), indicating good drug-like properties.

**7. DILI:** Ligand A (62.389) has a higher DILI risk than Ligand B (42.536), but both are below the concerning 60 threshold.

**8. BBB:** Both ligands have acceptable BBB penetration (49.67% and 47.111%), but are below the 70% target. This is a moderate concern, but not disqualifying.

**9. Caco-2 Permeability:** Ligand A (-5.017) has poor Caco-2 permeability, while Ligand B (-4.467) is also poor, but slightly better.

**10. Aqueous Solubility:** Both ligands have poor aqueous solubility (-3.712 and -1.857). This could pose formulation challenges.

**11. hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.074 and 0.085).

**12. Microsomal Clearance:** Ligand A (-1.849) has lower (better) microsomal clearance than Ligand B (-23.537), indicating better metabolic stability.

**13. In vitro Half-Life:** Ligand A (-14.044) has a longer half-life than Ligand B (-25.726), which is favorable.

**14. P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.022 and 0.006). This is excellent for CNS penetration.

**15. Binding Affinity:** Both ligands have strong binding affinities (-9.2 and -8.2 kcal/mol). Ligand A is 1 kcal/mol stronger, which is a significant advantage.

**Overall Assessment:**

Ligand A is slightly better overall. While both have poor solubility and Caco-2 permeability, Ligand A has a significantly better binding affinity (-9.2 vs -8.2 kcal/mol), better metabolic stability (lower Cl_mic), and a longer half-life. The slightly higher DILI risk is a concern, but the affinity advantage is substantial enough to outweigh this, especially for a CNS target where good BBB penetration is critical (and both are reasonably close). Ligand B's lower logP is a slight negative.

Output:
1
2025-04-17 05:21:39,587 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (351.451 and 344.455 Da) fall within the ideal range of 200-500 Da.

**TPSA:** Ligand A (84.99) is better than Ligand B (58.64). Both are below the 90 A^2 threshold desirable for CNS targets, but Ligand B is closer to optimal.

**logP:** Ligand B (2.527) is within the optimal 1-3 range. Ligand A (0.302) is significantly lower, which could hinder membrane permeability and potentially reduce binding affinity.

**H-Bond Donors/Acceptors:** Ligand A has 2 HBD and 3 HBA, while Ligand B has 1 HBD and 3 HBA. Both are acceptable.

**QED:** Both ligands have good QED scores (0.75 and 0.863), indicating good drug-like properties.

**DILI:** Both ligands have low DILI risk (32.571 and 31.563), which is favorable.

**BBB:** Ligand B (78.751) has a significantly better BBB penetration percentile than Ligand A (60.527). This is a crucial advantage for a CNS target like DRD2.

**Caco-2 Permeability:** Ligand A (-4.713) and Ligand B (-4.587) have negative values, indicating poor permeability.

**Aqueous Solubility:** Both ligands have very poor aqueous solubility (-1.629 and -2.882). This is a concern for formulation and bioavailability.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.325 and 0.549).

**Microsomal Clearance:** Ligand A (-14.638) has a much lower (better) microsomal clearance than Ligand B (49.696), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (-14.299) has a negative half-life, which is unrealistic. Ligand B (-21.029) also has a negative half-life, which is unrealistic.

**P-gp Efflux:** Ligand A (0.009) has very low P-gp efflux, which is excellent for CNS penetration. Ligand B (0.429) has slightly higher efflux, but still relatively low.

**Binding Affinity:** Ligand B (-9.2 kcal/mol) has a slightly better binding affinity than Ligand A (-8.8 kcal/mol). While both are good, the difference is not substantial enough to overcome the other drawbacks of Ligand B.

**Overall Assessment:**

Ligand A has better metabolic stability (lower Cl_mic) and P-gp efflux, but suffers from a very low logP and a lower BBB percentile. Ligand B has a better logP and significantly better BBB penetration, but has a higher Cl_mic. Considering DRD2 is a CNS target, BBB penetration is paramount. The slightly better affinity of Ligand B is a bonus. Although both have poor solubility and permeability, the CNS focus makes the better BBB penetration of Ligand B more important.

Output:
1
2025-04-17 05:21:39,587 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (372.531 and 345.407 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (67.87) is significantly better than Ligand B (115.99). For CNS targets, we want TPSA <= 90, and A is comfortably within this range, while B exceeds it.

**logP:** Both ligands have good logP values (1.843 and 1.537), falling within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Both have 1 HBD and 5 HBA, which are acceptable.

**QED:** Ligand A (0.626) has a better QED score than Ligand B (0.495), indicating a more drug-like profile.

**DILI:** Ligand A (30.322) has a much lower DILI risk than Ligand B (58.395). Both are below 60, but A is significantly preferred.

**BBB:** Ligand A (52.811) has a lower BBB penetration percentile than Ligand B (62.311). While both are not ideal (>70), B is better here.

**Caco-2 Permeability:** Ligand A (-4.862) has worse Caco-2 permeability than Ligand B (-5.092). Both are very poor, but B is slightly better.

**Aqueous Solubility:** Ligand A (-1.936) has better aqueous solubility than Ligand B (-2.641).

**hERG:** Both ligands have very low hERG inhibition liability (0.139 and 0.152), which is excellent.

**Microsomal Clearance:** Ligand A (46.481) has significantly better microsomal clearance (lower) than Ligand B (8.004), indicating better metabolic stability.

**In vitro Half-Life:** Ligand A (-3.096) has a longer in vitro half-life than Ligand B (2.49).

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.036 and 0.031).

**Binding Affinity:** Ligand B (-7.2 kcal/mol) has a slightly better binding affinity than Ligand A (-6.8 kcal/mol). This is a 0.4 kcal/mol difference, which is notable but not overwhelming.

**Overall Assessment:**

Considering the GPCR-specific priorities, Ligand A is the more promising candidate. While Ligand B has slightly better BBB penetration and binding affinity, Ligand A excels in crucial areas like TPSA, DILI, metabolic stability (Cl_mic and t1/2), and QED. The lower TPSA of Ligand A is particularly important for CNS penetration, and the lower DILI risk is a significant safety advantage. The difference in binding affinity (0.4 kcal/mol) can potentially be optimized during lead optimization, whereas improving TPSA or reducing DILI risk is often more challenging.

Output:
1
2025-04-17 05:21:39,587 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 drug candidates, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (370.603 and 350.463 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (49.41) is significantly better than Ligand B (80.48). For CNS targets, TPSA should be <= 90, and A is comfortably within this range, while B is approaching the upper limit.

**3. logP:** Ligand A (3.947) is optimal (1-3), while Ligand B (1.57) is on the lower side. Lower logP can hinder permeation, particularly across the BBB.

**4. H-Bond Donors:** Both ligands have 1 HBD, which is within the acceptable limit of <=5.

**5. H-Bond Acceptors:** Ligand A has 3 HBAs, and Ligand B has 6. Both are within the acceptable limit of <=10, but Ligand A is preferable.

**6. QED:** Ligand B (0.807) has a slightly better QED score than Ligand A (0.593), indicating a more drug-like profile overall.

**7. DILI:** Ligand A (9.926) has a much lower DILI risk than Ligand B (38.813), which is a significant advantage.

**8. BBB:** Ligand A (84.257) has a significantly higher BBB penetration percentile than Ligand B (64.211). This is *critical* for a CNS target like DRD2. A value >70 is desirable, and A is closer to that threshold.

**9. Caco-2 Permeability:** Both have negative values (-4.977 and -4.848). This is unusual and requires further investigation, but the values are similar.

**10. Aqueous Solubility:** Both have negative values (-4.056 and -1.891). This is also unusual and suggests poor solubility. Ligand B is slightly better.

**11. hERG Inhibition:** Ligand A (0.862) has a slightly higher hERG risk than Ligand B (0.128), but both are relatively low.

**12. Microsomal Clearance:** Ligand A (88.598) has a higher microsomal clearance than Ligand B (27.521), indicating faster metabolism and lower metabolic stability. This is a drawback for Ligand A.

**13. In vitro Half-Life:** Ligand B (-9.55) has a much longer in vitro half-life than Ligand A (15.116). This is a significant advantage for Ligand B.

**14. P-gp Efflux:** Ligand A (0.3) has lower P-gp efflux liability than Ligand B (0.154), which is preferable for CNS exposure.

**15. Binding Affinity:** Ligand B (-8.1) has a slightly better binding affinity than Ligand A (-7.4), although both are strong binders (< -7.0). The difference of 0.7 kcal/mol is not substantial enough to outweigh other significant differences.

**Overall Assessment:**

Considering the GPCR-specific priorities, Ligand A is the more promising candidate. Its superior BBB penetration, lower DILI risk, and better logP outweigh its slightly higher microsomal clearance and lower QED. The binding affinity difference is minimal. While both ligands have solubility issues, the CNS target makes BBB penetration and metabolic stability paramount, favoring Ligand A.

Output:
1
2025-04-17 05:21:39,588 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (366.483 and 368.413 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (67.87) is significantly better than Ligand B (85.94). For CNS targets, we want TPSA <= 90, and A is comfortably within this range, while B is approaching the upper limit.

**3. logP:** Both ligands have good logP values (2.186 and 1.508), falling within the optimal 1-3 range. Ligand A is slightly higher, which could be beneficial for membrane permeability.

**4. H-Bond Donors:** Ligand A (1) is preferable to Ligand B (3). Fewer HBDs generally improve permeability.

**5. H-Bond Acceptors:** Ligand A (5) is preferable to Ligand B (6). Fewer HBAs generally improve permeability.

**6. QED:** Both ligands have acceptable QED values (0.751 and 0.67), indicating good drug-like properties.

**7. DILI:** Ligand A (56.883) has a lower DILI risk than Ligand B (82.435), making it safer from a liver toxicity perspective.

**8. BBB:** Ligand A (69.407) has a lower BBB penetration than Ligand B (75.533). While both are reasonably good, B is better for a CNS target.

**9. Caco-2 Permeability:** Ligand A (-4.974) has a worse Caco-2 permeability than Ligand B (-5.559). Lower values indicate lower permeability.

**10. Aqueous Solubility:** Ligand A (-2.014) has better aqueous solubility than Ligand B (-3.884).

**11. hERG Inhibition:** Ligand A (0.225) has a much lower hERG inhibition risk than Ligand B (0.854). This is a significant advantage for A.

**12. Microsomal Clearance:** Ligand B (29.482) has significantly lower microsomal clearance than Ligand A (48.578), suggesting better metabolic stability.

**13. In vitro Half-Life:** Ligand B (8.403) has a longer in vitro half-life than Ligand A (37.236).

**14. P-gp Efflux:** Ligand A (0.158) has lower P-gp efflux liability than Ligand B (0.05). Lower efflux is better for CNS exposure.

**15. Binding Affinity:** Both ligands have excellent binding affinities (-7.7 and -7.8 kcal/mol). The difference is negligible.

**Overall Assessment:**

Ligand A excels in TPSA, H-bonding, DILI, hERG inhibition, solubility, and P-gp efflux. Ligand B has better BBB penetration and metabolic stability (lower Cl_mic and longer t1/2). Given the GPCR-specific priority for BBB penetration, Ligand B is slightly favored. However, the significantly lower hERG risk and better overall ADME profile of Ligand A (especially the lower DILI) are compelling. The small difference in binding affinity is not a deciding factor. Considering the balance, and the critical need to minimize off-target effects like hERG inhibition, I lean towards Ligand A.

Output:
1
2025-04-17 05:21:39,588 - INFO - Reasoning:

Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (343.358 and 339.395 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (75.29) is higher than Ligand B (54.78). For a CNS target like DRD2, TPSA should ideally be <=90. Both are acceptable, but B is better.

**3. logP:** Ligand A (2.407) is within the optimal 1-3 range. Ligand B (0.65) is slightly low, potentially hindering permeation.

**4. H-Bond Donors:** Ligand A (1) is good. Ligand B (0) is also acceptable.

**5. H-Bond Acceptors:** Both ligands have 4 HBA, which is within the acceptable limit of <=10.

**6. QED:** Both ligands have good QED scores (0.668 and 0.74), indicating drug-like properties.

**7. DILI:** Ligand A (72.586) has a higher DILI risk than Ligand B (32.842). B is significantly better here.

**8. BBB:** Ligand A (67.584) and Ligand B (62.97) are both below the desirable >70 percentile for CNS targets. However, A is slightly better.

**9. Caco-2 Permeability:** Ligand A (-4.399) and Ligand B (-4.341) both have negative values, which is unusual and suggests poor permeability. This is a concern for both.

**10. Aqueous Solubility:** Ligand A (-3.863) and Ligand B (-2.404) both have negative values, indicating poor solubility. This is a concern for both.

**11. hERG Inhibition:** Ligand A (0.614) and Ligand B (0.102) are both relatively low, suggesting low cardiotoxicity risk. B is better.

**12. Microsomal Clearance:** Ligand A (40.931) has a higher microsomal clearance than Ligand B (10.347), meaning it's less metabolically stable. B is better.

**13. In vitro Half-Life:** Ligand A (-21.143) has a negative half-life, which is not physically possible and indicates a problem with the data or the molecule. Ligand B (8.157) is reasonable.

**14. P-gp Efflux:** Ligand A (0.156) has lower P-gp efflux than Ligand B (0.025), which is favorable for CNS penetration. A is better.

**15. Binding Affinity:** Ligand B (-8.0 kcal/mol) has a slightly better binding affinity than Ligand A (-7.7 kcal/mol). While both are good, the difference is not huge.

**Overall Assessment:**

Ligand B is the better candidate. While both have issues with Caco-2 permeability and solubility, Ligand B has a significantly lower DILI risk, better metabolic stability (lower Cl_mic, positive t1/2), and better hERG inhibition profile. The slightly lower logP is a concern, but the superior safety and PK properties outweigh this. The negative half-life for Ligand A is a major red flag.



Output:
1
2025-04-17 05:21:39,588 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (335.451 Da) is slightly lower, which is generally favorable for permeability. Ligand B (362.461 Da) is also acceptable.

**TPSA:** Ligand A (41.29) is excellent, well below the 90 A^2 threshold for CNS targets. Ligand B (58.64) is still reasonable, but less optimal.

**logP:** Ligand A (3.995) is at the higher end of the optimal range (1-3), potentially raising concerns about solubility and off-target effects. Ligand B (2.838) is well within the optimal range.

**H-Bond Donors/Acceptors:** Both ligands have acceptable HBD (1) and HBA (4 for A, 3 for B) counts, well below the thresholds of 5 and 10, respectively.

**QED:** Both ligands have similar and good QED values (0.71 and 0.722), indicating good drug-like properties.

**DILI:** Ligand A (54.478) has a moderate DILI risk, while Ligand B (18.922) has a very low DILI risk, which is a significant advantage.

**BBB:** This is crucial for a CNS target like DRD2. Ligand A (55.332) has a moderate BBB penetration, while Ligand B (88.6) has excellent BBB penetration, exceeding the desirable >70 threshold.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values, which is unusual and suggests poor permeability. However, these values are on a log scale, and the negative values are likely representing very low permeability.

**Aqueous Solubility:** Both ligands have negative solubility values, indicating poor aqueous solubility. This is a potential issue for formulation and bioavailability.

**hERG Inhibition:** Ligand A (0.973) has a slightly higher hERG risk than Ligand B (0.672), although both are relatively low.

**Microsomal Clearance:** Ligand A (52.122) has a higher microsomal clearance than Ligand B (16.153), indicating lower metabolic stability.

**In vitro Half-Life:** Ligand B (-2.248) has a negative half-life, which is impossible. This is likely an error in the data. Ligand A (26.658) has a reasonable half-life.

**P-gp Efflux:** Ligand A (0.906) has a moderate P-gp efflux liability, while Ligand B (0.075) has very low P-gp efflux, which is highly desirable for CNS penetration.

**Binding Affinity:** Ligand B (-7.6 kcal/mol) has a significantly stronger binding affinity than Ligand A (-9.0 kcal/mol). This difference of 1.4 kcal/mol is substantial and can outweigh some of the ADME drawbacks of Ligand A.

**Overall Assessment:**

Ligand B is the superior candidate. While both have issues with solubility and Caco-2 permeability, Ligand B excels in the critical areas for a CNS GPCR target: significantly better BBB penetration, lower DILI risk, lower P-gp efflux, and *much* stronger binding affinity. The questionable half-life value for Ligand B is concerning, but the other advantages are substantial. Ligand A's higher logP and clearance are also less favorable.



Output:
1
2025-04-17 05:21:39,588 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (352.475 and 363.527 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (75.71) is better than Ligand B (62.3). Both are below the 90 A^2 threshold for CNS targets, but A is slightly higher, potentially impacting BBB penetration less favorably.

**3. logP:** Ligand B (3.481) is slightly higher than Ligand A (2.119), pushing it toward the upper end of the optimal 1-3 range. Ligand A is good, but B is better for membrane permeability.

**4. H-Bond Donors:** Both have 1 HBD, which is within the acceptable limit of <=5.

**5. H-Bond Acceptors:** Both have 4 HBA, which is within the acceptable limit of <=10.

**6. QED:** Ligand B (0.755) has a better QED score than Ligand A (0.587), indicating a more drug-like profile.

**7. DILI:** Ligand A (12.136) has a significantly lower DILI risk than Ligand B (49.011). This is a substantial advantage for Ligand A.

**8. BBB:** Ligand A (78.092) has a better BBB penetration percentile than Ligand B (63.009). While both are reasonably good, A is closer to the desirable >70 threshold for CNS targets.

**9. Caco-2 Permeability:** Ligand A (-4.497) has better Caco-2 permeability than Ligand B (-5.014).

**10. Aqueous Solubility:** Ligand A (-2.524) has better aqueous solubility than Ligand B (-3.782).

**11. hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.394 and 0.201 respectively).

**12. Microsomal Clearance:** Ligand A (53.758) has lower microsomal clearance than Ligand B (63.397), suggesting better metabolic stability.

**13. In vitro Half-Life:** Ligand A (-14.178) has a longer in vitro half-life than Ligand B (-15.966).

**14. P-gp Efflux:** Ligand A (0.031) has lower P-gp efflux than Ligand B (0.264), which is highly favorable for CNS exposure.

**15. Binding Affinity:** Ligand B (-7.5 kcal/mol) has a slightly better binding affinity than Ligand A (-8.3 kcal/mol). While A is already very good, the 0.8 kcal/mol difference is noteworthy.

**Overall Assessment:**

Ligand A has a superior safety profile (lower DILI) and better ADME properties (BBB, solubility, permeability, metabolic stability, P-gp efflux). Ligand B has a slightly better logP and binding affinity. However, the ADME advantages of Ligand A, particularly its better BBB penetration and lower P-gp efflux, are crucial for a CNS-targeting drug like a DRD2 ligand. The affinity difference is not large enough to overcome the ADME benefits of Ligand A.

Output:
0
2025-04-17 05:21:39,589 - INFO - Okay, let's analyze these two ligands for their potential as DRD2 drug candidates. DRD2 is a GPCR in the CNS, so BBB penetration, logP, Pgp efflux, TPSA, and binding affinity are paramount.

**Ligand A: [366.334, 39.68, 2.928, 0., 3., 0.773, 38.93, 88.445, -4.499, -2.879, 0.485, 29.915, 11.297, 0.064, -7.9]**
**Ligand B: [343.471, 71.09, 3.146, 2., 3., 0.747, 27.336, 59.287, -4.938, -2.261, 0.237, 24.471, 11.87, 0.055, -8.]**

Here's a breakdown of each property:

1. **MW:** Both are within the ideal range (200-500 Da). A (366.334) is slightly higher than B (343.471), but both are acceptable.
2. **TPSA:** A (39.68) is excellent, well below the 90 A^2 threshold for CNS targets. B (71.09) is higher, but still reasonable.
3. **logP:** Both are within the optimal 1-3 range. A (2.928) and B (3.146) are both good.
4. **HBD:** A (0) is preferable to B (2). Fewer HBDs generally improve permeability.
5. **HBA:** Both have 3 HBA, which is acceptable.
6. **QED:** Both are good (A: 0.773, B: 0.747), indicating drug-like properties.
7. **DILI:** A (38.93) is better than B (27.336), indicating lower potential for liver injury.
8. **BBB:** This is *critical* for a CNS target. A (88.445) is excellent, exceeding the 70% threshold. B (59.287) is significantly lower and concerning.
9. **Caco-2:** Both are negative, indicating poor permeability. This is a significant drawback for both.
10. **Solubility:** Both are negative, indicating poor solubility. This is a significant drawback for both.
11. **hERG:** Both are very low (A: 0.485, B: 0.237), suggesting minimal cardiotoxicity risk.
12. **Cl_mic:** A (29.915) is slightly higher than B (24.471), suggesting slightly lower metabolic stability.
13. **t1/2:** Both are similar (A: 11.297, B: 11.87), and acceptable.
14. **Pgp:** Both are very low (A: 0.064, B: 0.055), indicating minimal P-gp efflux.
15. **Affinity:** B (-8.0) is slightly better than A (-7.9), but the difference is small.

**Overall Assessment:**

Ligand A is superior due to its significantly better BBB penetration (88.4% vs. 59.3%). While both have issues with Caco-2 permeability and solubility, the ability to cross the blood-brain barrier is paramount for a DRD2 ligand targeting CNS disorders. The slightly better DILI score for A is also a plus. The small affinity difference is outweighed by the BBB advantage.

Output:
1
2025-04-17 05:21:39,589 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B against the provided guidelines, prioritizing GPCR-specific properties (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (362.308 Da) is slightly lower, which could be beneficial for permeability.

**TPSA:** Ligand A (93.53) is better than Ligand B (135.92). For CNS targets, TPSA should be <=90, so Ligand A is closer to this target.

**logP:** Both ligands have acceptable logP values (A: 0.102, B: 1.278), falling within the 1-3 range. Ligand B is better here.

**H-Bond Donors/Acceptors:** Both have 1 HBD, which is good. Ligand A has 6 HBA, and Ligand B has 7 HBA, both are acceptable (<=10).

**QED:** Ligand A (0.77) has a better QED score than Ligand B (0.45), indicating a more drug-like profile.

**DILI:** Ligand A (46.956) has a significantly lower DILI risk than Ligand B (83.443). This is a major advantage for Ligand A.

**BBB:** Both ligands have good BBB penetration (A: 74.564, B: 70.415), exceeding the 70% threshold for CNS targets. Ligand A is slightly better.

**Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual. It's difficult to interpret without knowing the scale.

**Aqueous Solubility:** Both have negative solubility values, which is also unusual. It's difficult to interpret without knowing the scale.

**hERG:** Both ligands have low hERG inhibition risk (A: 0.421, B: 0.438), which is good.

**Microsomal Clearance:** Ligand A (2.326) has much lower microsomal clearance than Ligand B (61.675), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (-29.609) has a negative half-life, which is not possible. Ligand B (30.486) is more reasonable.

**P-gp Efflux:** Both have low P-gp efflux liability (A: 0.035, B: 0.157), which is good for CNS penetration. Ligand A is better.

**Binding Affinity:** Ligand B (-8.0) has a slightly better binding affinity than Ligand A (-7.5), but the difference is less than 1.5 kcal/mol.

**Overall Assessment:**

Considering all factors, **Ligand A** is the more promising candidate. It has a better TPSA, QED, DILI risk, BBB penetration, microsomal clearance, and P-gp efflux liability. While Ligand B has a slightly better logP and binding affinity, the advantages of Ligand A in ADME properties, especially the significantly lower DILI risk and better metabolic stability, outweigh this small difference in potency. The negative values for Caco-2 and solubility are concerning for both, but the other advantages of Ligand A make it the preferred choice.

Output:
0
2025-04-17 05:21:39,589 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the acceptable range (200-500 Da). Ligand A (344.459 Da) is slightly better positioned.

**TPSA:** Ligand A (69.3) is significantly better than Ligand B (42.43). For CNS targets, we want TPSA <= 90, and ideally lower. Ligand A is well within this range, while Ligand B is also acceptable, but less optimal.

**logP:** Ligand A (2.339) is optimal (1-3). Ligand B (4.568) is pushing the upper limit and could potentially lead to solubility issues or off-target interactions.

**H-Bond Donors/Acceptors:** Ligand A (HBD=1, HBA=3) and Ligand B (HBD=0, HBA=3) are both acceptable.

**QED:** Ligand A (0.915) is excellent, indicating high drug-likeness. Ligand B (0.611) is still acceptable, but less favorable.

**DILI:** Ligand A (15.2) has a much lower DILI risk than Ligand B (75.029). This is a significant advantage for Ligand A.

**BBB:** Ligand A (61.535) is borderline for good CNS penetration, while Ligand B (89.298) is excellent. This is a major advantage for Ligand B.

**Caco-2 Permeability:** Ligand A (-5.196) is poor, indicating low intestinal absorption. Ligand B (-4.604) is also poor, but slightly better than A.

**Aqueous Solubility:** Ligand A (-1.374) is poor, while Ligand B (-5.208) is even worse. Both have solubility concerns.

**hERG Inhibition:** Ligand A (0.387) has a lower hERG risk than Ligand B (0.666), which is preferable.

**Microsomal Clearance:** Ligand A (-4.403) indicates low clearance and good metabolic stability, which is a significant advantage. Ligand B (47.804) suggests rapid clearance.

**In vitro Half-Life:** Ligand A (-16.129) indicates a long half-life, which is desirable. Ligand B (-4.948) suggests a shorter half-life.

**P-gp Efflux:** Ligand A (0.05) has very low P-gp efflux, which is excellent for CNS exposure. Ligand B (0.49) has moderate P-gp efflux.

**Binding Affinity:** Ligand B (-9.4 kcal/mol) has a slightly better binding affinity than Ligand A (-8.6 kcal/mol). While a 1.5 kcal/mol difference is usually significant, the other ADME properties of Ligand A are more favorable.

**Overall Assessment:**

While Ligand B has better BBB penetration and binding affinity, Ligand A demonstrates superior drug-like properties across several critical ADME parameters, including lower DILI risk, better metabolic stability (lower Cl_mic, longer t1/2), lower P-gp efflux, and a better QED score. The slightly lower BBB penetration of Ligand A is a concern, but the other advantages, particularly the improved safety profile and metabolic stability, outweigh this drawback. Given the GPCR-specific priorities, and the importance of a balanced ADME profile, Ligand A is the more promising candidate.

Output:
0
2025-04-17 05:21:39,589 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (349.475 and 335.415 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (69.72) is better than Ligand B (62.97) as it is closer to the <90 A^2 threshold for CNS targets.

**logP:** Both ligands have good logP values (1.707 and 1.375), falling within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A (1 HBD, 3 HBA) is slightly better than Ligand B (0 HBD, 7 HBA) in terms of balancing solubility and permeability.

**QED:** Both ligands have similar and acceptable QED values (0.678 and 0.702), indicating good drug-likeness.

**DILI:** Ligand A (12.796) has a significantly lower DILI risk than Ligand B (42.846), which is a major advantage.

**BBB:** Ligand A (69.407) has a slightly better BBB penetration percentile than Ligand B (64.676), though both are below the desirable >70 for CNS targets.

**Caco-2 Permeability:** Ligand A (-4.634) has a worse Caco-2 permeability than Ligand B (-5.032).

**Aqueous Solubility:** Both ligands have very poor aqueous solubility (-1.248 and -1.25). This is a concern for both, but can be mitigated with formulation strategies.

**hERG Inhibition:** Ligand A (0.115) has a much lower hERG inhibition liability than Ligand B (0.711), a critical safety advantage.

**Microsomal Clearance:** Ligand A (39.203) has a better (lower) microsomal clearance than Ligand B (11.224), indicating better metabolic stability.

**In vitro Half-Life:** Ligand A (3.408) has a positive half-life, while Ligand B (-39.054) has a negative half-life. This is a major advantage for Ligand A.

**P-gp Efflux:** Ligand A (0.014) has significantly lower P-gp efflux liability than Ligand B (0.029), which is crucial for CNS penetration.

**Binding Affinity:** Ligand B (-9.5 kcal/mol) has a significantly stronger binding affinity than Ligand A (-7.5 kcal/mol). This is a substantial advantage for Ligand B. The difference of 2 kcal/mol is significant enough to potentially offset some ADME liabilities.

**Overall Assessment:**

While Ligand B boasts a superior binding affinity, Ligand A demonstrates a much more favorable safety profile (lower DILI, hERG, and P-gp efflux) and better metabolic stability (lower Cl_mic, positive t1/2). Both have poor solubility and sub-optimal BBB penetration. However, the safety and metabolic advantages of Ligand A are significant, particularly for a CNS target like DRD2. The 2 kcal/mol difference in binding affinity, while notable, may be addressable through further optimization of Ligand A.

Output:
0
2025-04-17 05:21:39,589 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (355.385 and 352.435 Da) fall comfortably within the ideal 200-500 Da range.

**TPSA:** Ligand A (69.41) is excellent, well below the 90 A^2 threshold for CNS targets. Ligand B (87.78) is still reasonable, but closer to the 90 A^2 limit.

**logP:** Ligand A (3.584) is optimal. Ligand B (-0.195) is significantly suboptimal, being below 1, which could hinder permeation.

**H-Bond Donors/Acceptors:** Both have 1 HBD and 6 HBA, which are within acceptable limits.

**QED:** Both ligands have very similar QED values (0.78 and 0.795), indicating good drug-likeness.

**DILI:** Ligand A (42.924) has a slightly higher DILI risk than Ligand B (21.326), but both are below the concerning threshold of 60.

**BBB:** Ligand A (80.264) has a good BBB penetration percentile. Ligand B (46.917) is significantly lower, which is a major concern for a CNS target like DRD2.

**Caco-2 Permeability:** Both have negative Caco-2 values (-4.684 and -4.674), which is unusual and suggests poor permeability. This is a red flag for both.

**Aqueous Solubility:** Both have negative solubility values (-4.005 and -0.37), suggesting poor aqueous solubility. This could pose formulation challenges.

**hERG:** Both ligands have low hERG inhibition liability (0.563 and 0.387).

**Microsomal Clearance:** Ligand A (35.795) has a higher microsomal clearance than Ligand B (3.917), meaning it's likely to be metabolized faster. Ligand B appears to have better metabolic stability.

**In vitro Half-Life:** Ligand B (-15.041) has a negative half-life, which is not possible and indicates a significant issue with the data or the compound's stability. Ligand A (4.465) has a reasonable half-life.

**P-gp Efflux:** Both have very low P-gp efflux liability (0.181 and 0.06).

**Binding Affinity:** Both ligands have the same binding affinity (-8.2 kcal/mol), which is excellent.

**Overall Assessment:**

Given the GPCR-specific priorities, BBB penetration is crucial. Ligand A has a much better BBB score (80.264) compared to Ligand B (46.917). While Ligand B has better metabolic stability and lower DILI, its poor logP and significantly lower BBB penetration are major drawbacks for a CNS drug. The negative Caco-2 and solubility values are concerning for both, but can potentially be addressed with formulation strategies. The negative half-life for Ligand B is a showstopper.

Output:
1
2025-04-17 05:21:39,590 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (370.274 Da and 364.555 Da) fall within the ideal range of 200-500 Da.

**TPSA:** Ligand A (98.66) is slightly above the optimal <90 for CNS targets, but still reasonable. Ligand B (42.43) is excellent, well below the threshold.

**logP:** Ligand A (1.137) is within the optimal range of 1-3. Ligand B (4.617) is a bit high, potentially leading to solubility issues and off-target interactions.

**H-Bond Donors:** Ligand A (4) is acceptable. Ligand B (0) is also acceptable.

**H-Bond Acceptors:** Both ligands (4) are within the acceptable limit of <=10.

**QED:** Both ligands have good QED scores (0.461 and 0.676), indicating reasonable drug-likeness. Ligand B is better.

**DILI:** Ligand A (43.66) has a slightly higher DILI risk than Ligand B (31.291), but both are below the concerning threshold of 60.

**BBB:** This is crucial for a CNS target. Ligand B (81.698) has a significantly better BBB penetration percentile than Ligand A (54.517). This is a major advantage for Ligand B.

**Caco-2 Permeability:** Ligand A (-5.021) has poor Caco-2 permeability, indicating poor intestinal absorption. Ligand B (-4.565) is also poor, but slightly better than A.

**Aqueous Solubility:** Both ligands have very poor aqueous solubility (-2.744 and -5.006). This is a concern for both, but more so for Ligand B given its higher logP.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.411 and 0.773).

**Microsomal Clearance:** Ligand A (17.869) has lower microsomal clearance, suggesting better metabolic stability than Ligand B (94.832).

**In vitro Half-Life:** Ligand A (-14.032) has a negative half-life, which is not possible. This is a red flag. Ligand B (18.278) has a reasonable half-life.

**P-gp Efflux:** Ligand A (0.095) has lower P-gp efflux, which is favorable for CNS penetration. Ligand B (0.86) has higher P-gp efflux, which is less desirable.

**Binding Affinity:** Ligand B (-7.4) has a slightly better binding affinity than Ligand A (-7.9), although both are excellent.

**Overall Assessment:**

Ligand B is the stronger candidate. While its logP is a bit high and solubility is poor, its significantly better BBB penetration, acceptable DILI, and reasonable half-life outweigh these drawbacks. The negative half-life reported for Ligand A is a critical flaw. The better affinity of Ligand B further supports its selection.

Output:
1
2025-04-17 05:21:39,590 - INFO - Batch 191 complete. Total preferences: 3056
2025-04-17 05:21:39,590 - INFO - Processing batch 192/512...
2025-04-17 05:22:19,991 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (354.491 and 342.403 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (67.87) is excellent, well below the 90 A^2 threshold for CNS targets. Ligand B (106.77) is higher, but still potentially acceptable, though less ideal.

**logP:** Ligand A (2.114) is optimal. Ligand B (0.957) is slightly low, potentially hindering membrane permeability.

**H-Bond Donors/Acceptors:** Ligand A (HBD=1, HBA=4) and Ligand B (HBD=3, HBA=4) both have reasonable H-bond characteristics.

**QED:** Both ligands (0.76 and 0.68) have good drug-likeness scores.

**DILI:** Ligand A (7.794) has a very low DILI risk, significantly better than Ligand B (54.207), which is moderately risky.

**BBB:** This is crucial for a CNS target. Ligand A (69.523) is good, though not exceptional. Ligand B (31.834) is poor, indicating limited brain penetration.

**Caco-2 Permeability:** Ligand A (-4.544) is poor, indicating low intestinal absorption. Ligand B (-5.688) is also poor.

**Aqueous Solubility:** Both ligands have poor aqueous solubility (-1.711 and -2.183 respectively).

**hERG Inhibition:** Both ligands show very low hERG inhibition risk (0.366 and 0.067).

**Microsomal Clearance:** Ligand A (7.029) has a moderate clearance. Ligand B (-17.892) has a *negative* clearance, which is impossible and suggests an error in the data or a very unusual metabolic profile. This is a major red flag.

**In vitro Half-Life:** Ligand A (5.244) has a moderate half-life. Ligand B (-10.696) has a negative half-life, which is impossible and further reinforces the data quality concerns.

**P-gp Efflux:** Both ligands show very low P-gp efflux liability (0.029 and 0.01).

**Binding Affinity:** Both ligands have excellent binding affinity (-8.0 and -8.1 kcal/mol), with Ligand B being slightly better. However, the affinity difference is small and likely less important than the ADME issues.

**Overall Assessment:**

Ligand A has a better overall profile, particularly regarding DILI risk and BBB penetration. While its Caco-2 permeability and solubility are poor, these can potentially be addressed through formulation strategies. Ligand B, despite slightly better binding affinity, has serious issues with its negative clearance and half-life values, indicating a fundamental problem with the data or the molecule's stability. The poor BBB penetration is also a major drawback for a CNS target.

Output:
1
2025-04-17 05:22:19,991 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (366.487 Da) is slightly higher than Ligand B (347.459 Da), but both are acceptable.

**TPSA:** Both ligands have TPSA values below 90, which is good for CNS penetration. Ligand B (75.44) is better than Ligand A (83.56).

**logP:** Both ligands have logP values within the optimal range (1-3). Ligand A (1.261) is slightly lower, while Ligand B (2.858) is closer to the upper end, which could potentially lead to solubility issues, but is still acceptable.

**H-Bond Donors/Acceptors:** Ligand A has 2 HBD and 6 HBA, while Ligand B has 1 HBD and 4 HBA. Both are within the acceptable limits (<=5 HBD and <=10 HBA).

**QED:** Both ligands have good QED scores (A: 0.759, B: 0.858), indicating good drug-like properties.

**DILI:** Ligand A (31.291) has a significantly lower DILI risk than Ligand B (41.373), which is a substantial advantage.

**BBB:** Ligand B (84.606) has a much higher BBB penetration percentile than Ligand A (60.023). This is a critical factor for a CNS target like DRD2.

**Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and suggests poor permeability. However, the scale isn't specified, so it's difficult to interpret.

**Aqueous Solubility:** Both have negative solubility values, which is also unusual. Again, the scale is unspecified, making interpretation difficult.

**hERG:** Both ligands have low hERG inhibition liability (A: 0.212, B: 0.357), which is good.

**Microsomal Clearance:** Ligand A (-13.349) exhibits significantly lower microsomal clearance than Ligand B (47.424). This suggests better metabolic stability for Ligand A.

**In vitro Half-Life:** Ligand A (11.153 hours) has a longer half-life than Ligand B (-19.822 hours). The negative value for B is concerning.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (A: 0.034, B: 0.282), which is favorable for CNS penetration.

**Binding Affinity:** Ligand B (-9.4 kcal/mol) has a significantly stronger binding affinity than Ligand A (-7.6 kcal/mol). This is a substantial advantage, potentially outweighing some of the ADME drawbacks.

**Overall Assessment:**

Ligand B excels in BBB penetration and binding affinity, two crucial factors for a CNS GPCR target. However, it has a higher DILI risk, a concerning negative in vitro half-life, and higher microsomal clearance. Ligand A has a better safety profile (lower DILI), better metabolic stability (lower Cl_mic, longer t1/2), and lower Pgp efflux, but its BBB penetration and binding affinity are weaker.

Given the importance of strong binding affinity for GPCRs, and the relatively modest difference in BBB between the two, the stronger affinity of Ligand B is the deciding factor. While the ADME properties of Ligand B are less ideal, optimization could potentially address these issues. The substantial affinity difference is more difficult to overcome through modification.

Output:
1
2025-04-17 05:22:19,992 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (346.383 and 345.403 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (88.85) is excellent, falling well below the 90 Angstroms threshold for CNS targets. Ligand B (106.1) is still reasonable, but less optimal.

**3. logP:** Both ligands have good logP values (1.711 and 1.074), within the 1-3 range.

**4. H-Bond Donors:** Ligand A (1) and Ligand B (2) are both acceptable, being less than 5.

**5. H-Bond Acceptors:** Ligand A (5) and Ligand B (6) are both acceptable, being less than 10.

**6. QED:** Both ligands have similar QED values (0.792 and 0.741), indicating good drug-likeness.

**7. DILI:** Ligand A (59.984) has a better DILI score than Ligand B (74.564), indicating lower potential for liver injury. Both are acceptable, but A is preferred.

**8. BBB:** Ligand B (61.962) has a slightly better BBB score than Ligand A (50.523), but both are below the desirable >70 for CNS targets. This is a critical factor, and we'll revisit it.

**9. Caco-2 Permeability:** Ligand A (-4.384) has better Caco-2 permeability than Ligand B (-5.198). Higher values (less negative) indicate better absorption.

**10. Aqueous Solubility:** Ligand A (-2.509) has better aqueous solubility than Ligand B (-2.877).

**11. hERG Inhibition:** Ligand A (0.032) has a much lower hERG inhibition liability than Ligand B (0.322), which is a significant safety advantage.

**12. Microsomal Clearance:** Ligand B (46.448) has lower microsomal clearance than Ligand A (62.831), suggesting better metabolic stability.

**13. In vitro Half-Life:** Ligand B (23.614) has a longer half-life than Ligand A (18.745).

**14. P-gp Efflux:** Ligand A (0.02) has lower P-gp efflux than Ligand B (0.046), which is favorable for CNS penetration.

**15. Binding Affinity:** Ligand B (-7.8 kcal/mol) has a significantly better binding affinity than Ligand A (-6.9 kcal/mol). This is a 0.9 kcal/mol difference, which is substantial and can outweigh some ADME drawbacks.

**Overall Assessment:**

While Ligand B has a better binding affinity and metabolic stability (lower Cl_mic, longer t1/2), Ligand A excels in several key areas crucial for a CNS-targeting GPCR drug: lower TPSA, better solubility, significantly lower hERG risk, and lower P-gp efflux. The BBB values for both are suboptimal, but Ligand A's other properties suggest it might overcome this limitation more effectively. The improved safety profile (lower DILI and hERG) of Ligand A is also a major advantage. The affinity difference, while significant, might be addressable with further optimization of Ligand A.

Output:
0
2025-04-17 05:22:19,992 - INFO - Reasoning:

Let's analyze Ligand A and Ligand B based on the provided guidelines, prioritizing GPCR-specific properties (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (358.467 and 348.393 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (67.23) is higher than Ligand B (49.41). For CNS targets, TPSA should be <=90, both are within this range, but B is preferable.

**logP:** Both ligands have good logP values (1.838 and 2.747), falling within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Both have acceptable HBD (1) and Ligand B has fewer HBA (2 vs 5). This is slightly favorable for B.

**QED:** Ligand A (0.83) has a higher QED score than Ligand B (0.635), indicating better overall drug-likeness.

**DILI:** Ligand A (64.056) has a slightly higher DILI risk than Ligand B (44.668), but both are reasonably acceptable.

**BBB:** This is a crucial parameter for CNS targets. Ligand B (87.088) has a significantly higher BBB percentile than Ligand A (57.891). This is a major advantage for B.

**Caco-2 Permeability:** Ligand A (-5.168) has worse Caco-2 permeability than Ligand B (-4.624).

**Aqueous Solubility:** Ligand A (-2.636) has worse aqueous solubility than Ligand B (-3.232).

**hERG:** Both ligands have low hERG inhibition liability (0.239 and 0.497).

**Microsomal Clearance:** Ligand A (44.449) and Ligand B (43.795) have similar microsomal clearance values.

**In vitro Half-Life:** Ligand B (-4.056) has a negative half-life, which is unusual and suggests very rapid metabolism. Ligand A (27.217) has a much more reasonable half-life.

**P-gp Efflux:** Ligand A (0.249) has lower P-gp efflux than Ligand B (0.18), which is favorable for CNS penetration.

**Binding Affinity:** Both ligands have the same binding affinity (-8.1 kcal/mol), which is excellent.

**Overall Assessment:**

While Ligand A has a better QED and in vitro half-life, Ligand B excels in the most critical areas for a CNS-targeting GPCR ligand: significantly higher BBB penetration and lower TPSA. The better Caco-2 permeability and solubility of Ligand B also contribute to its favorability. The negative half-life of Ligand B is a significant concern. However, the strong affinity is maintained, and the BBB advantage is substantial. Given the importance of CNS penetration for DRD2, Ligand B is the more promising candidate, assuming the negative half-life can be addressed through structural modifications.

Output:
1
2025-04-17 05:22:19,992 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (350.46 and 354.45 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (75.71) is significantly better than Ligand B (93.73). For CNS targets, we want TPSA <= 90, so Ligand A is preferable.

**3. logP:** Both ligands have acceptable logP values (1.59 and 0.87), falling within the 1-3 range. Ligand A is slightly better.

**4. H-Bond Donors:** Ligand A (1) is better than Ligand B (2). Lower HBD generally improves permeability.

**5. H-Bond Acceptors:** Ligand A (4) is better than Ligand B (5). Lower HBA generally improves permeability.

**6. QED:** Ligand A (0.708) has a better QED score than Ligand B (0.599), indicating a more drug-like profile.

**7. DILI:** Ligand A (18.65) has a much lower DILI risk than Ligand B (29.31), which is a significant advantage.

**8. BBB:** Ligand A (73.25) has a better BBB penetration percentile than Ligand B (63.36). Both are reasonably good, but A is better, and >70 is desirable for CNS targets.

**9. Caco-2 Permeability:** Ligand A (-4.74) is better than Ligand B (-5). Higher values indicate better absorption.

**10. Aqueous Solubility:** Ligand A (-1.74) is better than Ligand B (-1.93). Higher solubility is preferred.

**11. hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.31 and 0.17 respectively).

**12. Microsomal Clearance:** Ligand A (44.54) has lower microsomal clearance than Ligand B (53.70), suggesting better metabolic stability.

**13. In vitro Half-Life:** Ligand A (-22.89) has a much longer in vitro half-life than Ligand B (-5.86), which is a significant advantage.

**14. P-gp Efflux:** Both have very low P-gp efflux liability (0.081 and 0.012 respectively).

**15. Binding Affinity:** Ligand A (-8.8) has a slightly better binding affinity than Ligand B (-7.8). While both are good, the difference of 1 kcal/mol is noticeable.

**Overall Assessment:**

Ligand A consistently outperforms Ligand B across most critical parameters, particularly TPSA, DILI, BBB, metabolic stability (Cl_mic and t1/2), and QED. While both ligands have acceptable logP and hERG values, Ligand A's superior ADME properties and slightly better binding affinity make it the more promising drug candidate for targeting DRD2.

Output:
1
2025-04-17 05:22:19,992 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (341.411 and 350.463 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (68.5) is excellent, well below the 90 A^2 threshold for CNS targets. Ligand B (76.58) is still reasonable, but less optimal.

**logP:** Ligand A (4.159) is slightly high, potentially leading to solubility issues or off-target effects. Ligand B (1.802) is within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A (0 HBD, 5 HBA) is good. Ligand B (1 HBD, 6 HBA) is also acceptable.

**QED:** Both ligands have good QED scores (0.603 and 0.808), indicating drug-like properties.

**DILI:** Ligand A (80.69) has a higher DILI risk than Ligand B (48.623). This is a significant negative for Ligand A.

**BBB:** Both ligands have excellent BBB penetration (76.309 and 83.831), exceeding the desirable >70 threshold for CNS targets.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values, which is unusual and suggests a potential issue with the data or modeling. However, we'll proceed assuming these represent low permeability.

**Aqueous Solubility:** Both ligands have negative solubility values, which is also unusual and suggests poor solubility.

**hERG:** Ligand A (0.697) has a slightly higher hERG risk than Ligand B (0.323), but both are relatively low.

**Microsomal Clearance:** Ligand A (73.32) has higher microsomal clearance than Ligand B (63.147), indicating faster metabolism and potentially lower *in vivo* exposure.

**In vitro Half-Life:** Ligand A (-8.663) has a significantly longer in vitro half-life than Ligand B (17.319). This is a positive for Ligand A.

**P-gp Efflux:** Ligand A (0.4) has lower P-gp efflux than Ligand B (0.041), which is favorable for CNS penetration.

**Binding Affinity:** Ligand A (-8.7 kcal/mol) has a slightly better binding affinity than Ligand B (-8.1 kcal/mol). The difference is 0.6 kcal/mol, which is not huge, but still noticeable.

**Overall Assessment:**

Ligand A has a better binding affinity, lower P-gp efflux, and longer half-life. However, it suffers from a higher DILI risk and a higher logP, which could lead to solubility and off-target issues. Ligand B has a more favorable logP, lower DILI risk, and better metabolic stability, but its binding affinity is slightly weaker and P-gp efflux is higher.

Considering the GPCR-specific priorities, BBB is excellent for both. The slightly better affinity and P-gp profile of Ligand A are attractive, but the significantly higher DILI risk is a major concern. The lower DILI risk of Ligand B, coupled with a reasonable logP, makes it the more promising candidate despite the slightly weaker binding. The negative solubility and Caco-2 values are concerning for both, but could be addressed with formulation strategies.

Output:
1
2025-04-17 05:22:19,992 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 drug candidates, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (372.447 and 351.397 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (110.6) is higher than the preferred <90 for CNS targets, while Ligand B (70.23) is well within the range. This is a significant advantage for Ligand B.

**logP:** Ligand A (0.876) is a bit low, potentially hindering permeation. Ligand B (2.774) is within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A has 1 HBD and 7 HBA, which are acceptable. Ligand B has 3 HBD and 2 HBA, also acceptable.

**QED:** Both ligands have reasonable QED scores (0.843 and 0.73), indicating good drug-like properties.

**DILI:** Ligand A (69.135) has a slightly higher DILI risk than Ligand B (60.682), but both are reasonably low.

**BBB:** Ligand B (81.466) has a significantly higher BBB penetration percentile than Ligand A (68.67). This is crucial for a CNS target like DRD2.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.814 and -4.708), which is unusual and suggests poor permeability. However, these values are on a scale where negative values are possible, and direct comparison is difficult without knowing the scale's specifics.

**Aqueous Solubility:** Both ligands have negative solubility values (-2.929 and -4.274), again suggesting poor solubility. Similar to Caco-2, the scale is unclear.

**hERG Inhibition:** Ligand A (0.081) has a very low hERG risk, which is excellent. Ligand B (0.322) has a slightly higher, but still acceptable, hERG risk.

**Microsomal Clearance:** Ligand A (30.006) has a higher microsomal clearance than Ligand B (23.177), meaning it's likely to be metabolized faster.

**In vitro Half-Life:** Ligand B (6.658) has a longer in vitro half-life than Ligand A (4.692).

**P-gp Efflux:** Ligand A (0.022) has very low P-gp efflux liability, which is favorable for CNS penetration. Ligand B (0.104) has a slightly higher P-gp efflux, but still relatively low.

**Binding Affinity:** Ligand B (-9.2 kcal/mol) has a significantly stronger binding affinity than Ligand A (-7.3 kcal/mol). This difference of 1.9 kcal/mol is substantial and can outweigh some ADME drawbacks.

**Conclusion:**

Considering the GPCR-specific priorities, Ligand B is the more promising candidate. Its superior BBB penetration, better logP, longer half-life, and significantly stronger binding affinity outweigh the slightly higher DILI and P-gp efflux compared to Ligand A. The TPSA value of Ligand B is also much more favorable for CNS penetration. While both ligands have issues with Caco-2 and solubility, the strong affinity and BBB penetration of Ligand B make it the better choice.

Output:
1
2025-04-17 05:22:19,993 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (344.455 and 348.359 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (53.76) is excellent, well below the 90 A^2 threshold for CNS targets. Ligand B (134.85) is higher, but still potentially acceptable, though less ideal.

**3. logP:** Ligand A (3.231) is optimal (1-3). Ligand B (-1.453) is significantly lower, potentially hindering membrane permeability and CNS penetration.

**4. H-Bond Donors:** Ligand A (0) is good. Ligand B (3) is acceptable, but higher HBD can sometimes reduce permeability.

**5. H-Bond Acceptors:** Ligand A (3) is good. Ligand B (6) is higher, potentially impacting permeability.

**6. QED:** Both ligands have acceptable QED values (0.828 and 0.575, both >0.5).

**7. DILI:** Ligand A (31.989) has a much lower DILI risk than Ligand B (54.75). Both are below 60, but A is preferable.

**8. BBB:** Ligand A (78.48) has a good BBB percentile, exceeding the 70% target for CNS drugs. Ligand B (39.511) is significantly lower, raising concerns about CNS exposure.

**9. Caco-2:** Ligand A (-4.509) and Ligand B (-5.593) both have negative values, which is unusual and difficult to interpret without knowing the scale. However, lower values generally indicate lower permeability.

**10. Solubility:** Ligand A (-3.563) and Ligand B (-2.04) both have negative values, which is unusual and difficult to interpret without knowing the scale. However, lower values generally indicate lower solubility.

**11. hERG:** Ligand A (0.55) has a slightly higher hERG risk than Ligand B (0.025), but both are very low.

**12. Cl_mic:** Ligand A (71.332) has a higher microsomal clearance than Ligand B (-20.118). The negative value for Ligand B is unusual and suggests very high metabolic stability.

**13. t1/2:** Ligand A (40.409) has a longer in vitro half-life than Ligand B (7.158).

**14. Pgp:** Ligand A (0.441) has lower P-gp efflux liability than Ligand B (0.004), which is favorable for CNS penetration.

**15. Binding Affinity:** Both ligands have excellent binding affinities (-8.2 and -8.0 kcal/mol), with a very small difference.

**Overall Assessment:**

Ligand A is significantly better suited as a CNS-targeting drug candidate. While both have good binding affinity, Ligand A excels in crucial ADME properties for CNS penetration: TPSA, logP, BBB, and Pgp efflux. It also has a lower DILI risk and longer half-life. Ligand B's low logP and BBB percentile are major drawbacks. The unusual negative values for Caco-2 and Solubility are concerning and would require further investigation, but the other factors strongly favor Ligand A.

Output:
1
2025-04-17 05:22:19,993 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (373.387 and 368.474 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (135.92) is better than Ligand B (67.43) as it is closer to the ideal value of <90 for CNS targets. Ligand B is very low and might indicate reduced hydrogen bonding potential, potentially impacting binding.

**logP:** Ligand A (1.278) is within the optimal 1-3 range. Ligand B (3.215) is at the higher end of the optimal range, but still acceptable.

**H-Bond Donors/Acceptors:** Ligand A has 1 HBD and 7 HBA, while Ligand B has 2 HBD and 4 HBA. Both are within acceptable limits (<=5 HBD, <=10 HBA).

**QED:** Both ligands have good QED scores (0.45 and 0.665, respectively), indicating drug-like properties. Ligand B is slightly better.

**DILI:** Ligand A (83.443) has a higher DILI risk than Ligand B (47.732). This is a significant drawback for Ligand A.

**BBB:** Both ligands have good BBB penetration (70.415 and 73.672, respectively). Ligand B is slightly better.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.8 and -4.525). This is unusual and suggests poor permeability. However, these values are on a scale where negative values are possible, and direct comparison is difficult without knowing the scale's specifics.

**Aqueous Solubility:** Both ligands have negative solubility values (-3.549 and -4.627). Similar to Caco-2, this is unusual and suggests poor solubility.

**hERG:** Both ligands have low hERG risk (0.438).

**Microsomal Clearance:** Ligand A (61.675) has lower microsomal clearance than Ligand B (72.491), indicating better metabolic stability.

**In vitro Half-Life:** Ligand A (30.486) has a shorter half-life than Ligand B (-18.138). The negative value for ligand B is concerning and likely an error or indicates very rapid metabolism.

**P-gp Efflux:** Both ligands have low P-gp efflux (0.157).

**Binding Affinity:** Ligand B (-7.5 kcal/mol) has a slightly better binding affinity than Ligand A (-8.0 kcal/mol). While the difference is small, it's still a positive for Ligand B.

**Overall Assessment:**

Ligand B is the better candidate. While both have issues with Caco-2 and solubility, Ligand B has a significantly lower DILI risk, better binding affinity, and a slightly better BBB score. The negative half-life for ligand B is concerning, but the other factors outweigh this issue. Ligand A's higher DILI risk is a major concern.

Output:
1
2025-04-17 05:22:19,993 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (343.427 and 348.491 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (66.65) is significantly better than Ligand B (79.3). For CNS targets, we want TPSA <= 90, and A is closer to the ideal <=60 range. B is pushing the upper limit.

**3. logP:** Both ligands have acceptable logP values (2.028 and 3.118), falling within the optimal 1-3 range. Ligand B is slightly higher, which *could* indicate potential solubility issues, but isn't a major concern.

**4. H-Bond Donors:** Ligand A (0) is preferable to Ligand B (3). Fewer HBDs generally improve permeability.

**5. H-Bond Acceptors:** Ligand A (4) is better than Ligand B (6). Lower HBA is generally favorable for CNS penetration.

**6. QED:** Ligand A (0.839) has a significantly better QED score than Ligand B (0.595), indicating a more drug-like profile.

**7. DILI:** Both ligands have very similar and acceptable DILI risk (27.608 and 27.104 percentile).

**8. BBB:** Ligand A (76.541) has a substantially better BBB penetration prediction than Ligand B (60.644). This is *critical* for a CNS target like DRD2. A score >70 is desirable, and A is closer.

**9. Caco-2:** Both have negative Caco-2 values (-4.84 and -4.951). This is unusual and suggests potential issues with intestinal absorption. However, given the CNS target, intestinal absorption is less critical than BBB penetration.

**10. Solubility:** Both have negative solubility values (-1.705 and -2.639). This is also unusual and indicates poor aqueous solubility. This could be a formulation challenge, but is less critical than BBB for a CNS target.

**11. hERG:** Both ligands have low hERG inhibition liability (0.099 and 0.812), which is good.

**12. Cl_mic:** Ligand B (22.119) has lower microsomal clearance than Ligand A (31.759), suggesting better metabolic stability.

**13. t1/2:** Ligand B (45.928) has a significantly longer in vitro half-life than Ligand A (-12.148). This is a strong advantage for B.

**14. Pgp:** Ligand A (0.067) has lower P-gp efflux liability than Ligand B (0.174), which is favorable for CNS exposure.

**15. Binding Affinity:** Both ligands have very similar and strong binding affinities (-8.7 and -8.5 kcal/mol). The difference is negligible.

**Overall Assessment:**

Ligand A is clearly superior due to its significantly better TPSA, BBB penetration, QED, and Pgp efflux liability. While Ligand B has better metabolic stability (lower Cl_mic and longer t1/2), the CNS target prioritization makes BBB penetration and low Pgp efflux far more important. The slightly better QED score of A also contributes to its overall drug-likeness. The negative Caco-2 and solubility values are concerning for both, but less critical for a CNS-focused drug.

Output:
0
2025-04-17 05:22:19,993 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (362.495 and 344.499 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (69.64) is higher than Ligand B (40.62). For a CNS target like DRD2, TPSA should ideally be <= 90. Both are acceptable, but B is significantly better.

**3. logP:** Both ligands have good logP values (2.613 and 3.372), falling within the optimal 1-3 range.

**4. H-Bond Donors:** Ligand A (2) is slightly higher than Ligand B (0). Both are within the acceptable limit of <=5.

**5. H-Bond Acceptors:** Ligand A (4) is higher than Ligand B (2). Both are within the acceptable limit of <=10.

**6. QED:** Both ligands have reasonable QED values (0.865 and 0.737), indicating good drug-like properties.

**7. DILI:** Ligand A (42.885) has a slightly higher DILI risk than Ligand B (15.2). Both are below the concerning threshold of 60, but B is preferable.

**8. BBB:** This is a critical parameter for CNS targets. Ligand B (91.663) has a significantly higher BBB penetration percentile than Ligand A (67.584). This is a major advantage for B.

**9. Caco-2 Permeability:** Ligand A (-5.077) and Ligand B (-4.644) both have negative values, which is unusual and suggests poor permeability. However, the scale isn't specified, so it's hard to interpret.

**10. Aqueous Solubility:** Both ligands have very poor aqueous solubility (-2.503 and -3.21). This is a significant drawback for both, potentially impacting bioavailability.

**11. hERG Inhibition:** Both ligands show low hERG inhibition risk (0.311 and 0.444).

**12. Microsomal Clearance:** Ligand B (50.939) has a higher microsomal clearance than Ligand A (15.889), indicating faster metabolism and potentially lower exposure.

**13. In vitro Half-Life:** Ligand A (16.09) has a longer in vitro half-life than Ligand B (2.232). This is an advantage for A.

**14. P-gp Efflux:** Both ligands show low P-gp efflux liability (0.18 and 0.277), which is good for CNS penetration.

**15. Binding Affinity:** Both ligands have very similar and excellent binding affinities (-8.9 and -8.7 kcal/mol). The difference is negligible.

**Overall Assessment:**

Ligand B is the more promising candidate. While both have poor solubility, Ligand B excels in BBB penetration (91.663 vs 67.584), a critical factor for a CNS target like DRD2. It also has a lower DILI risk and a better TPSA value. Although Ligand A has a longer half-life and lower clearance, the superior BBB penetration of Ligand B outweighs these benefits. The similar binding affinities mean that the ADME advantages of B are more important.

Output:
1
2025-04-17 05:22:19,994 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (358.467 and 362.316 Da) fall comfortably within the ideal 200-500 Da range.

**TPSA:** Ligand A (67.23) is significantly better than Ligand B (122.76). For CNS targets, we want TPSA <= 90, and A is well within this range, while B is considerably above. This is a major advantage for A.

**logP:** Both ligands have good logP values (1.838 and 1.085), falling within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A (HBD=1, HBA=5) is preferable to Ligand B (HBD=3, HBA=9). Lower HBD/HBA generally improves permeability.

**QED:** Ligand A (0.83) has a significantly better QED score than Ligand B (0.601), indicating a more drug-like profile.

**DILI:** Both ligands have relatively high DILI risk (64.056 and 68.825), but are still below the concerning threshold of 60.

**BBB:** Ligand A (57.891) and Ligand B (61.535) are both below the desirable >70 percentile for CNS targets. However, this is less critical than other factors when the difference is small.

**Caco-2 Permeability:** Both have negative Caco-2 values (-5.168 and -5.478), which is unusual and suggests poor permeability. This is a concern for both.

**Aqueous Solubility:** Both ligands have very poor aqueous solubility (-2.636 and -2.787). This could pose formulation challenges.

**hERG:** Both ligands have low hERG risk (0.239 and 0.138), which is good.

**Microsomal Clearance:** Ligand A (44.449) has a higher (worse) microsomal clearance than Ligand B (18.132), suggesting lower metabolic stability.

**In vitro Half-Life:** Ligand B (-23.202) has a negative half-life, which is impossible and likely an error in the data. Ligand A (27.217) has a reasonable half-life.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.249 and 0.012), which is favorable for CNS exposure.

**Binding Affinity:** Both ligands have excellent binding affinity (-8.1 and -8.0 kcal/mol), with Ligand A being slightly better. The affinity difference is small enough that it doesn't overwhelmingly favor one ligand.

**Overall Assessment:**

Ligand A is significantly better due to its lower TPSA, better QED, and a reasonable in vitro half-life. While both have poor solubility and Caco-2 permeability, the TPSA advantage of A is crucial for CNS penetration. Ligand B's negative half-life is a significant red flag, suggesting a data error or a very unstable compound. The slightly better affinity of A is a bonus.

Output:
0
2025-04-17 05:22:19,994 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (351.447 and 345.403 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (89.95) is excellent, being below the 90 A^2 threshold for CNS targets. Ligand B (108.88) is still reasonable but less optimal.

**logP:** Ligand A (-0.016) is slightly below the optimal 1-3 range, potentially hindering permeability. Ligand B (0.595) is also on the lower side, but closer to the desired range.

**H-Bond Donors/Acceptors:** Ligand A (HBD=2, HBA=4) and Ligand B (HBD=3, HBA=5) both have acceptable numbers of H-bond donors and acceptors.

**QED:** Both ligands have good QED scores (0.682 and 0.651), indicating drug-like properties.

**DILI:** Ligand A (22.024) has a significantly lower DILI risk than Ligand B (60.295), which is a considerable advantage.

**BBB:** Ligand A (29.275) has a low BBB penetration percentile, which is a major drawback for a CNS target. Ligand B (32.765) is also low, but slightly better.

**Caco-2:** Both have negative Caco-2 values, which is unusual and suggests poor permeability.

**Solubility:** Both ligands have negative solubility values, indicating poor aqueous solubility.

**hERG:** Both ligands have very low hERG inhibition liability (0.121 and 0.152), which is good.

**Microsomal Clearance:** Both have similar microsomal clearance values (10.175 and 10.905), suggesting similar metabolic stability.

**In vitro Half-Life:** Ligand A (-29.722) has a very negative half-life, which is concerning. Ligand B (-19.397) is also negative, but less so.

**P-gp Efflux:** Both have very low P-gp efflux liability (0.009 and 0.025), which is good.

**Binding Affinity:** Ligand B (-8.2 kcal/mol) has a slightly better binding affinity than Ligand A (-7.8 kcal/mol), but the difference is not substantial.

**Overall Assessment:**

Considering the GPCR-specific priorities, BBB penetration is critical for DRD2. While both ligands have poor BBB scores, Ligand A's DILI risk is much lower. However, the extremely poor in vitro half-life of Ligand A is a major concern. Ligand B, despite the higher DILI risk, has a slightly better BBB score, a better binding affinity, and a less problematic half-life. The poor solubility and Caco-2 values for both are concerning but could potentially be addressed with formulation strategies. Given the importance of CNS penetration and the significant difference in DILI risk, Ligand B appears to be the more promising candidate, despite its drawbacks.

Output:
1
2025-04-17 05:22:19,994 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (343.431 Da) is slightly preferred due to being closer to the lower end, potentially aiding permeability.

**TPSA:** Both ligands have TPSA values below 90 (A: 71.33, B: 67.87), which is excellent for CNS penetration. No significant difference here.

**logP:** Both ligands have logP values within the optimal range (1-3). Ligand B (2.082) is slightly higher, which could be beneficial for membrane permeability, but isn't a major advantage.

**H-Bond Donors/Acceptors:** Ligand A (0 HBD, 5 HBA) is slightly better than Ligand B (1 HBD, 4 HBA) in terms of balancing solubility and permeability.

**QED:** Both ligands have acceptable QED scores (A: 0.769, B: 0.645), indicating good drug-like properties. Ligand A is slightly better.

**DILI:** Ligand A (43.66) has a higher DILI risk than Ligand B (22.761). This is a significant advantage for Ligand B.

**BBB:** Ligand A (81.776) has a significantly better BBB penetration percentile than Ligand B (61.962). This is a crucial factor for a CNS target like DRD2.

**Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and suggests poor permeability. However, the scale is not specified, so it's hard to interpret.

**Aqueous Solubility:** Both ligands have negative solubility values, indicating poor solubility. Again, the scale is unspecified.

**hERG Inhibition:** Ligand A (0.099) has a lower hERG inhibition liability than Ligand B (0.37), which is preferable.

**Microsomal Clearance:** Ligand B (45.227) has a slightly higher microsomal clearance than Ligand A (36.481), indicating potentially lower metabolic stability.

**In vitro Half-Life:** Ligand A (-0.495) has a negative half-life, which is not possible. This is a red flag. Ligand B (6.346) has a reasonable half-life.

**P-gp Efflux:** Ligand A (0.163) has lower P-gp efflux liability than Ligand B (0.042), which is beneficial for CNS exposure.

**Binding Affinity:** Ligand B (-7.1 kcal/mol) has a slightly better binding affinity than Ligand A (-8.5 kcal/mol). While A has a better affinity, the difference is not substantial enough to overcome the other issues.

**Overall Assessment:**

Ligand A has a better BBB score, lower P-gp efflux, and better affinity, but suffers from a nonsensical half-life value and higher DILI risk. Ligand B has a better DILI profile, a reasonable half-life, and acceptable BBB penetration, and a very good binding affinity. The negative half-life for Ligand A is a major concern, and the DILI risk is also significant. While Ligand A's affinity is slightly better, the other factors strongly favor Ligand B.

Output:
1
2025-04-17 05:22:19,994 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (349.425 and 350.415 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (35.58) is excellent, well below the 90 A^2 threshold for CNS targets. Ligand B (77.1) is higher, but still potentially acceptable, though less ideal.

**3. logP:** Ligand A (2.536) is within the optimal 1-3 range. Ligand B (-0.064) is slightly below 1, which could indicate permeability issues.

**4. H-Bond Donors:** Both ligands have 1 HBD, which is good.

**5. H-Bond Acceptors:** Ligand A has 3 HBA, and Ligand B has 5 HBA. Both are within the acceptable range of <=10.

**6. QED:** Ligand A (0.891) has a very strong drug-like profile. Ligand B (0.679) is still acceptable, but less optimal.

**7. DILI:** Ligand A (13.532) has a low DILI risk. Ligand B (30.399) is higher, but still relatively low risk.

**8. BBB:** This is crucial for a CNS target. Ligand A (87.088) has excellent BBB penetration potential. Ligand B (52.617) is significantly lower, which is a major drawback.

**9. Caco-2:** Both ligands have negative Caco-2 values (-4.755 and -4.874), which is unusual and suggests poor permeability. However, these values are on a scale where negative values are possible, and direct comparison is difficult without knowing the scale's specifics.

**10. Solubility:** Both ligands have negative solubility values (-2.241 and -1.313), again suggesting poor aqueous solubility. Similar to Caco-2, the scale is unclear.

**11. hERG:** Both ligands have very low hERG risk (0.897 and 0.102).

**12. Cl_mic:** Ligand A (-33.01) has a lower (better) microsomal clearance, suggesting greater metabolic stability. Ligand B (-17.865) is higher.

**13. t1/2:** Ligand A (11.147) has a moderate in vitro half-life. Ligand B (17.903) has a longer half-life, which is generally desirable.

**14. Pgp:** Both ligands have very low Pgp efflux liability (0.08 and 0.012).

**15. Binding Affinity:** Ligand A (-9.3 kcal/mol) has a significantly stronger binding affinity than Ligand B (-7.7 kcal/mol). This >1.5 kcal/mol difference is substantial.

**Overall Assessment:**

Ligand A is clearly superior. While both have issues with Caco-2 and solubility, Ligand A's significantly better BBB penetration, stronger binding affinity, and lower microsomal clearance outweigh the slightly lower QED and the solubility/permeability concerns. The strong affinity suggests that even with some permeability limitations, sufficient drug could reach the target. Ligand B's poor BBB penetration is a major concern for a CNS target like DRD2.

Output:
1
2025-04-17 05:22:19,995 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (340.383 Da) is slightly preferred as it's closer to the lower end, potentially aiding permeability.

**TPSA:** Both ligands have TPSA values below 90, which is good for CNS penetration. Ligand A (79.58) is better than Ligand B (67.43) in this regard.

**logP:** Ligand A (2.712) is optimal (1-3), while Ligand B (4.637) is pushing the upper limit. High logP can lead to solubility issues and off-target effects.

**H-Bond Donors/Acceptors:** Ligand A (0 HBD, 5 HBA) and Ligand B (2 HBD, 3 HBA) both fall within acceptable ranges.

**QED:** Both ligands have good QED scores (A: 0.634, B: 0.759), indicating drug-like properties.

**DILI:** Ligand A (75.184) has a higher DILI risk than Ligand B (49.864). This is a significant drawback for Ligand A.

**BBB:** Ligand A (89.957) has a significantly better BBB penetration score than Ligand B (77.821), which is crucial for a CNS target like DRD2.

**Caco-2 Permeability:** Both show poor Caco-2 permeability (-4.396 and -4.431). This suggests potential absorption issues, but is less critical given the CNS target.

**Aqueous Solubility:** Both have poor aqueous solubility (-3.72 and -4.961). This is a concern, but can sometimes be mitigated with formulation strategies.

**hERG Inhibition:** Both ligands show low hERG inhibition liability (0.538 and 0.534).

**Microsomal Clearance:** Ligand B (98.648) has a higher microsomal clearance than Ligand A (83.888), indicating faster metabolism and potentially lower *in vivo* exposure.

**In vitro Half-Life:** Ligand B (48.298) has a much longer half-life than Ligand A (2.218). This is a significant advantage for Ligand B.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.408 and 0.258).

**Binding Affinity:** Ligand B (-8.1 kcal/mol) has a *much* stronger binding affinity than Ligand A (-0.0 kcal/mol). This difference in affinity is substantial and likely outweighs many of the other drawbacks.

**Overall Assessment:**

While Ligand A has better TPSA and BBB, Ligand B's significantly stronger binding affinity (-8.1 vs -0.0 kcal/mol) is the dominant factor. The improved half-life and lower DILI risk of Ligand B further solidify its position as the more promising candidate. The higher logP and clearance are concerns, but the potency advantage is likely to be decisive, and these can be addressed through further optimization.

Output:
1
2025-04-17 05:22:19,995 - INFO - Batch 192 complete. Total preferences: 3072
2025-04-17 05:22:19,995 - INFO - Processing batch 193/512...
2025-04-17 05:23:03,545 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (342.399 and 355.429 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (80.37) is excellent, well below the 90 A^2 threshold for CNS targets. Ligand B (47.36) is even better, further increasing its potential for brain penetration.

**3. logP:** Both ligands have good logP values (1.774 and 2.926), falling within the optimal 1-3 range.

**4. H-Bond Donors:** Ligand A has 1 HBD, which is acceptable. Ligand B has 0, also acceptable.

**5. H-Bond Acceptors:** Ligand A has 5 HBA, within the limit. Ligand B has 4 HBA, also within the limit.

**6. QED:** Both ligands have similar QED values (0.793 and 0.756), indicating good drug-like properties.

**7. DILI:** Ligand A (48.313) has a slightly higher DILI risk than Ligand B (35.285), but both are below the concerning threshold of 60.

**8. BBB:** This is a critical parameter for CNS targets. Ligand B (97.751) is significantly better than Ligand A (68.554), exceeding the desirable >70 percentile.

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.94 and -4.58), which is unusual and suggests poor permeability. This is a significant drawback for both.

**10. Aqueous Solubility:** Both ligands have negative solubility values (-2.229 and -2.705), indicating very poor aqueous solubility, which is a major concern for bioavailability.

**11. hERG Inhibition:** Ligand A (0.151) has a slightly lower hERG risk than Ligand B (0.669), which is favorable.

**12. Microsomal Clearance:** Ligand A (40.928) has a higher microsomal clearance than Ligand B (35.896), suggesting lower metabolic stability.

**13. In vitro Half-Life:** Ligand B (6.95) has a significantly longer in vitro half-life than Ligand A (-8.893), which is a substantial advantage.

**14. P-gp Efflux:** Ligand A (0.096) has lower P-gp efflux liability than Ligand B (0.18), which is better for CNS exposure.

**15. Binding Affinity:** Ligand B (-7.2 kcal/mol) has a better binding affinity than Ligand A (-8.4 kcal/mol). While A is slightly better, the difference is not substantial enough to outweigh other factors.

**Overall Assessment:**

Despite both ligands having issues with Caco-2 permeability and aqueous solubility, Ligand B is the more promising candidate. Its significantly higher BBB penetration (97.751 vs 68.554), longer half-life (6.95 vs -8.893), and better binding affinity (-7.2 vs -8.4) outweigh the slightly higher P-gp efflux and hERG risk. The lower DILI risk is also a positive. The poor permeability and solubility are serious concerns that would need to be addressed through formulation or structural modifications, but the superior CNS penetration profile of Ligand B makes it the better starting point.

Output:
1
2025-04-17 05:23:03,545 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (339.4 and 337.4 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (84.83) is better than Ligand B (63.13). Both are below the 90 A^2 threshold desirable for CNS targets.

**3. logP:** Both ligands (2.643 and 2.549) are within the optimal 1-3 range.

**4. H-Bond Donors:** Both ligands have 2 HBD, which is acceptable (<=5).

**5. H-Bond Acceptors:** Ligand A has 6 HBA, and Ligand B has 3. Both are within the acceptable range of <=10.

**6. QED:** Both ligands have the same QED (0.763), indicating good drug-likeness.

**7. DILI:** Ligand A (88.251) has a higher DILI risk than Ligand B (52.772). This is a significant negative for Ligand A.

**8. BBB:** Ligand A (57.736) has a better BBB penetration percentile than Ligand B (36.409). This is a crucial factor for a CNS target like DRD2.

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.183 and -5.021). This is unusual and suggests poor permeability.

**10. Aqueous Solubility:** Both ligands have negative solubility values (-4.462 and -3.343), indicating poor aqueous solubility.

**11. hERG Inhibition:** Ligand A (0.756) has a slightly higher hERG inhibition risk than Ligand B (0.369), but both are relatively low.

**12. Microsomal Clearance:** Both ligands have similar microsomal clearance (32.694 and 32.907), suggesting similar metabolic stability.

**13. In vitro Half-Life:** Ligand A (22.438) has a longer half-life than Ligand B (13.479), which is favorable.

**14. P-gp Efflux:** Ligand A (0.082) has lower P-gp efflux liability than Ligand B (0.161), which is beneficial for CNS penetration.

**15. Binding Affinity:** Ligand B (-8.7 kcal/mol) has slightly better binding affinity than Ligand A (-8.5 kcal/mol), although the difference is small.

**Overall Assessment:**

While Ligand A has better BBB penetration and lower P-gp efflux, the significantly higher DILI risk is a major concern. Ligand B, despite slightly lower BBB and higher P-gp efflux, has a much more favorable safety profile (lower DILI). The binding affinity difference is minimal. Considering the GPCR-specific priorities and the importance of safety for CNS drugs, Ligand B is the more promising candidate. The poor Caco-2 and solubility for both compounds are concerning and would need to be addressed during optimization, but the DILI risk is harder to fix later in development.

Output:
1
2025-04-17 05:23:03,546 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (350.379 and 347.455 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (118.45) is better than Ligand B (55.84). For CNS targets, we want TPSA <= 90, and both are within this range, but A is closer to the upper limit.

**logP:** Ligand B (2.684) is optimal (1-3), while Ligand A (-0.31) is below 1, potentially hindering permeation. This is a significant drawback for A.

**H-Bond Donors/Acceptors:** Ligand A (2 HBD, 7 HBA) is slightly better than Ligand B (0 HBD, 5 HBA) in terms of balancing solubility and permeability, although both are acceptable.

**QED:** Ligand A (0.703) has a better QED score than Ligand B (0.561), indicating a more drug-like profile.

**DILI:** Ligand B (14.114) has a much lower DILI risk than Ligand A (54.711), which is a substantial advantage.

**BBB:** Ligand B (81.466) has a significantly higher BBB penetration percentile than Ligand A (70.182). Both are good, but B is preferable for a CNS target like DRD2.

**Caco-2 Permeability:** Ligand A (-4.964) has worse Caco-2 permeability than Ligand B (-4.468), but both are negative values which is unusual and suggests poor permeability.

**Aqueous Solubility:** Ligand A (-1.437) has better aqueous solubility than Ligand B (-3.252).

**hERG:** Ligand A (0.032) has a lower hERG risk than Ligand B (0.894), a positive attribute.

**Microsomal Clearance:** Ligand B (68.215) has a better (lower) microsomal clearance than Ligand A (28.788), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand B (-13.144) has a much longer in vitro half-life than Ligand A (-1.835), which is a significant advantage.

**P-gp Efflux:** Ligand A (0.011) has much lower P-gp efflux liability than Ligand B (0.557), which is crucial for CNS penetration.

**Binding Affinity:** Both ligands have similar binding affinities (-8.2 and -7.9 kcal/mol), which are both excellent. The difference of 0.3 kcal/mol is not substantial enough to outweigh other factors.

**Overall Assessment:**

Ligand B is the stronger candidate. While Ligand A has a better QED, P-gp efflux, and hERG profile, Ligand B excels in critical areas for a CNS-targeting GPCR: BBB penetration, metabolic stability (lower Cl_mic, longer t1/2), and lower DILI risk. The suboptimal logP of Ligand A is a major concern, potentially limiting its ability to cross cell membranes. The superior BBB penetration of Ligand B is particularly important given the target is DRD2.

Output:
1
2025-04-17 05:23:03,546 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 drug candidates, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (348.443 and 360.845 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (76.66) is better than Ligand B (78.35). Both are below the 90 A^2 threshold for CNS targets, which is good.

**3. logP:** Ligand A (1.354) is within the optimal 1-3 range. Ligand B (2.472) is also acceptable, but slightly higher.

**4. H-Bond Donors:** Both ligands have 2 HBD, which is well within the acceptable limit of <=5.

**5. H-Bond Acceptors:** Ligand A has 4 HBA, and Ligand B has 5. Both are below the acceptable limit of <=10.

**6. QED:** Ligand B (0.875) has a better QED score than Ligand A (0.661), indicating a more drug-like profile.

**7. DILI:** Ligand A (31.989) has a significantly lower DILI risk than Ligand B (55.68), which is a substantial advantage.

**8. BBB:** Ligand A (57.929) has a better BBB penetration percentile than Ligand B (35.13). This is *critical* for a CNS target like DRD2.

**9. Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and suggests poor permeability. However, the scale is not clearly defined, so it's difficult to interpret.

**10. Aqueous Solubility:** Both ligands have very poor aqueous solubility (-2.157 and -3.873 respectively). This is a significant drawback.

**11. hERG Inhibition:** Both ligands have low hERG inhibition risk (0.292 and 0.412).

**12. Microsomal Clearance:** Ligand A (41.269) has lower microsomal clearance than Ligand B (63.564), indicating better metabolic stability.

**13. In vitro Half-Life:** Ligand A (6.539) has a shorter half-life than Ligand B (-7.602). The negative value for Ligand B is concerning and likely an error or indicates very rapid degradation.

**14. P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.05 and 0.055).

**15. Binding Affinity:** Ligand B (-9.0 kcal/mol) has a significantly better binding affinity than Ligand A (-8.2 kcal/mol). This is a >1.5 kcal/mol advantage, which can outweigh some ADME drawbacks.

**Overall Assessment:**

Despite Ligand B's superior binding affinity, Ligand A is the more promising candidate. The critical factors are the significantly better BBB penetration (57.93 vs 35.13) and lower DILI risk (31.99 vs 55.68) for Ligand A. The poor solubility of both is a concern that would need to be addressed through formulation strategies, but the CNS penetration and safety profile are more difficult to improve later in development. The negative half-life value for Ligand B is also a red flag. While the affinity difference is substantial, it's less important than achieving brain exposure and avoiding liver toxicity.

Output:
0
2025-04-17 05:23:03,546 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (345.487 and 372.799 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (81.99) is better than Ligand B (62.55) as it is closer to the ideal <90 for CNS targets.

**logP:** Both ligands (2.641 and 2.947) are within the optimal 1-3 range.

**H-Bond Donors:** Ligand A (2) is slightly higher than Ligand B (1), but both are acceptable (<=5).

**H-Bond Acceptors:** Both ligands (3) are well within the acceptable limit of <=10.

**QED:** Both ligands have good QED scores (0.696 and 0.864), indicating good drug-like properties.

**DILI:** Both ligands have low DILI risk (29.973 and 35.983), both under the 40 threshold.

**BBB:** Ligand B (86.778) significantly outperforms Ligand A (58.899) in BBB penetration, which is crucial for a CNS target like DRD2.

**Caco-2:** Ligand A (-4.63) and Ligand B (-4.547) are both very poor, suggesting very low intestinal absorption. This is not a major concern for a CNS target where direct delivery or high permeability across the BBB is prioritized.

**Solubility:** Both ligands have poor solubility (-3.91 and -4.244). This could be a formulation challenge, but is less critical than BBB penetration for CNS drugs.

**hERG:** Both ligands have low hERG risk (0.372 and 0.506).

**Microsomal Clearance:** Ligand B (10.315) has a significantly lower microsomal clearance than Ligand A (53.814), indicating better metabolic stability.

**In vitro Half-Life:** Ligand B (22.318) has a much longer in vitro half-life than Ligand A (-11.395), which is a substantial advantage.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.167 and 0.087), which is good for CNS penetration.

**Binding Affinity:** Both ligands have comparable and strong binding affinities (-8.1 and -8.4 kcal/mol). The difference is minimal.

**Overall Assessment:**

Ligand B is the better candidate. While both have similar affinities and acceptable physicochemical properties, Ligand B's superior BBB penetration (86.778 vs 58.899), lower microsomal clearance, and longer half-life are critical advantages for a CNS-targeting drug. The slightly better TPSA of Ligand A is outweighed by the significant advantage of Ligand B in BBB penetration.

Output:
1
2025-04-17 05:23:03,546 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B based on the provided guidelines, prioritizing GPCR-specific properties (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (342.483 and 348.447 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (40.62) is significantly better than Ligand B (78.68). For CNS targets, we want TPSA <= 90, and A is comfortably within this range, while B is approaching the upper limit.

**logP:** Ligand A (2.984) is optimal (1-3), while Ligand B (1.197) is on the lower side, potentially hindering permeability.

**H-Bond Donors/Acceptors:** Ligand A (0 HBD, 2 HBA) is preferable to Ligand B (1 HBD, 5 HBA). Lower values are generally better for CNS penetration.

**QED:** Both ligands have good QED scores (0.721 and 0.865), indicating good drug-like properties.

**DILI:** Ligand A (27.065) has a lower DILI risk than Ligand B (18.651), which is favorable.

**BBB:** Ligand A (70.997) has a better BBB percentile than Ligand B (62.97), although both are reasonably good. A score >70 is desirable for CNS targets, and A is closer to this threshold.

**Caco-2 Permeability:** Ligand A (-4.533) has a negative value, which is unusual and suggests very poor permeability. Ligand B (-5.228) is also poor, but slightly worse.

**Aqueous Solubility:** Ligand A (-3.536) has poor solubility, and Ligand B (-1.021) is also poor.

**hERG:** Ligand A (0.527) has a lower hERG risk than Ligand B (0.108), which is preferable.

**Microsomal Clearance:** Ligand A (42.862) has a higher clearance than Ligand B (-0.586), indicating lower metabolic stability. Ligand B is much more metabolically stable.

**In vitro Half-Life:** Ligand A (13.108) has a longer half-life than Ligand B (5.658), which is desirable.

**P-gp Efflux:** Ligand A (0.34) has lower P-gp efflux than Ligand B (0.033), which is better for CNS exposure.

**Binding Affinity:** Ligand B (-0.0 kcal/mol) has a significantly weaker binding affinity than Ligand A (-7.0 kcal/mol). This is a crucial difference. A >1.5 kcal/mol advantage in binding often outweighs other ADME concerns.

**Overall Assessment:**

Despite Ligand A's poor Caco-2 and solubility, its significantly superior binding affinity (-7.0 kcal/mol vs -0.0 kcal/mol) and better BBB penetration, lower DILI risk, and lower P-gp efflux are decisive advantages for a CNS-targeting GPCR. The stronger binding is likely to overcome the permeability issues, especially considering the importance of potency for GPCR ligands. Ligand B's better metabolic stability is a plus, but the extremely weak binding makes it unlikely to be effective.

Output:
1
2025-04-17 05:23:03,547 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (350.423 and 347.415 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (120.08) is slightly above the preferred <90 for CNS targets, but still reasonable. Ligand B (100.45) is better, falling comfortably under 90.

**3. logP:** Ligand A (-0.385) is a bit low, potentially hindering membrane permeability. Ligand B (1.073) is within the optimal 1-3 range. This is a significant advantage for Ligand B.

**4. H-Bond Donors:** Ligand A (3) and Ligand B (2) are both acceptable, being less than 5.

**5. H-Bond Acceptors:** Both ligands (5) are within the acceptable limit of 10.

**6. QED:** Both ligands (0.56 and 0.696) have good drug-likeness scores, exceeding 0.5.

**7. DILI:** Ligand A (36.409) and Ligand B (42.264) both have low DILI risk, below the 40 threshold.

**8. BBB:** Both ligands have similar BBB penetration (45.405 and 44.824), which is not ideal (below 70), but not a dealbreaker as DRD2 is not exclusively a CNS target.

**9. Caco-2 Permeability:** Both have negative values, indicating poor permeability. Ligand A (-5.545) is slightly worse than Ligand B (-4.889).

**10. Aqueous Solubility:** Both have negative values, indicating poor solubility. Ligand A (-1.973) is slightly worse than Ligand B (-2.366).

**11. hERG Inhibition:** Ligand A (0.024) has very low hERG risk, which is excellent. Ligand B (0.622) is higher, but still relatively low.

**12. Microsomal Clearance:** Ligand A (8.803) has lower clearance, suggesting better metabolic stability than Ligand B (35.953).

**13. In vitro Half-Life:** Ligand A (-13.748) has a negative half-life, which is concerning and likely an error. Ligand B (35.656) has a reasonable half-life.

**14. P-gp Efflux:** Both ligands have very low P-gp efflux (0.007 and 0.052), which is good for CNS penetration.

**15. Binding Affinity:** Both ligands have very similar and strong binding affinities (-7.3 and -7.2 kcal/mol). The difference is negligible.

**Overall Assessment:**

Ligand B is the better candidate. While Ligand A has slightly better metabolic stability and a lower hERG risk, Ligand B has a significantly better logP value, which is crucial for GPCR ligands. The negative half-life for Ligand A is a major red flag. The slightly better TPSA for Ligand B is also favorable. The similar affinities mean that the ADME properties become the deciding factor.

Output:
1
2025-04-17 05:23:03,547 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (347.415 and 366.458 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Both ligands (74.61 and 75.27) are reasonably close to the 90 A^2 threshold for CNS targets, though ideally lower.

**3. logP:** Both ligands (2.854 and 2.56) fall within the optimal 1-3 range.

**4. H-Bond Donors:** Ligand A has 1 HBD, and Ligand B has 2. Both are acceptable (<=5).

**5. H-Bond Acceptors:** Ligand A has 7 HBA, and Ligand B has 3. Both are acceptable (<=10).

**6. QED:** Both ligands have good QED scores (0.776 and 0.841), indicating drug-like properties.

**7. DILI:** Both have moderately high DILI risk (64.986 and 61.497), but are still below the concerning 60 threshold.

**8. BBB:** Ligand B has a significantly better BBB penetration percentile (74.06) than Ligand A (57.619). This is a *critical* advantage for a CNS target like DRD2.

**9. Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual. It suggests poor permeability.

**10. Aqueous Solubility:** Both have negative solubility values, which is also unusual and suggests poor solubility.

**11. hERG Inhibition:** Both ligands show low hERG inhibition risk (0.409 and 0.252).

**12. Microsomal Clearance:** Ligand A has higher microsomal clearance (92.553) than Ligand B (58.82), indicating lower metabolic stability.

**13. In vitro Half-Life:** Ligand B has a longer in vitro half-life (-6.541 hours) than Ligand A (6.644 hours).

**14. P-gp Efflux:** Ligand A has a higher P-gp efflux liability (0.118) than Ligand B (0.305), which is unfavorable for CNS penetration.

**15. Binding Affinity:** Ligand B has a significantly stronger binding affinity (-9.7 kcal/mol) compared to Ligand A (-7.5 kcal/mol). This is a substantial advantage (a difference of 2.2 kcal/mol).

**Overall Assessment:**

Ligand B is the superior candidate. While both have some concerning ADME properties (negative Caco-2 and solubility), Ligand B excels in the most critical areas for a CNS-targeting GPCR: significantly better BBB penetration, stronger binding affinity, and improved metabolic stability (lower Cl_mic and longer t1/2). The lower P-gp efflux also contributes to better CNS exposure. The affinity difference is large enough to potentially offset the ADME concerns.

Output:
1
2025-04-17 05:23:03,547 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 drug candidates, considering the provided guidelines and GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (351.793 and 356.463 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (71.09) is excellent, well below the 90 A^2 threshold for CNS targets. Ligand B (99.1) is higher, but still potentially acceptable, though less ideal.

**logP:** Ligand A (3.723) is at the upper end of the optimal range (1-3), but still acceptable. Ligand B (0.575) is quite low, which could hinder permeability and potentially binding affinity.

**H-Bond Donors/Acceptors:** Ligand A (HBD=2, HBA=4) and Ligand B (HBD=3, HBA=5) both meet the criteria of <=5 HBD and <=10 HBA.

**QED:** Both ligands have good QED scores (A: 0.543, B: 0.646), indicating drug-like properties.

**DILI:** Ligand A has a high DILI risk (96.82%), which is a significant concern. Ligand B has a very low DILI risk (7.445%), a major advantage.

**BBB:** Ligand A (55.487%) is borderline for good CNS penetration, while Ligand B (60.954%) is also borderline. Neither is >70%, but B is slightly better.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.864 and -4.993), which is unusual and suggests poor permeability. This is concerning for both.

**Aqueous Solubility:** Both ligands have negative solubility values (-5.877 and -0.934), indicating very poor aqueous solubility. This is a significant drawback for both.

**hERG:** Both ligands have very low hERG inhibition liability (A: 0.279, B: 0.101), which is excellent.

**Microsomal Clearance:** Ligand A (34.48) has moderate clearance, while Ligand B (-2.265) has negative clearance, which is not physically meaningful but suggests very high metabolic stability.

**In vitro Half-Life:** Ligand A (101.147) has a good half-life, while Ligand B (-7.626) has a negative half-life, which is not physically meaningful.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (A: 0.289, B: 0.018), which is favorable for CNS penetration.

**Binding Affinity:** Ligand A (-9.4 kcal/mol) has significantly stronger binding affinity than Ligand B (-6.3 kcal/mol). This is a substantial advantage for Ligand A.

**Overall Assessment:**

Ligand A has a much stronger binding affinity, which is a critical factor for GPCRs. However, its extremely high DILI risk is a major red flag. Its BBB penetration is also suboptimal. Ligand B has a much better safety profile (low DILI), slightly better BBB, and excellent P-gp efflux properties. However, its logP is very low, its binding affinity is significantly weaker, and its Caco-2 permeability and solubility are poor.

Despite the superior affinity of Ligand A, the high DILI risk is a dealbreaker. While the other ADME properties of Ligand B are not ideal, they are less concerning than a high risk of liver injury. The weaker affinity of Ligand B could potentially be improved through further optimization, while mitigating DILI risk is often very challenging.

Output:
1
2025-04-17 05:23:03,547 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (360.776 and 356.463 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (94.04) is slightly above the optimal <90 for CNS targets, but still reasonable. Ligand B (85.89) is well within the desired range.

**3. logP:** Ligand A (3.602) is at the higher end of the optimal range (1-3), while Ligand B (1.069) is at the lower end. While a lower logP can sometimes indicate poor membrane permeability, for a GPCR, it's not a dealbreaker if other properties are favorable.

**4. H-Bond Donors:** Both ligands have 2 HBD, which is within the acceptable limit of <=5.

**5. H-Bond Acceptors:** Both ligands have 5 HBA, also within the acceptable limit of <=10.

**6. QED:** Both ligands have similar QED values (0.693 and 0.604), indicating good drug-like properties.

**7. DILI:** Ligand A has a significantly higher DILI risk (97.984%) compared to Ligand B (27.453%). This is a major concern for Ligand A.

**8. BBB:** Ligand B (72.237%) has a better BBB penetration percentile than Ligand A (65.684%), which is crucial for a CNS target like DRD2.

**9. Caco-2 Permeability:** Both have negative Caco-2 values (-4.856 and -4.855), which is unusual and suggests poor permeability. However, these values are very similar, so this isn't a differentiating factor.

**10. Aqueous Solubility:** Ligand B (-1.865) has better aqueous solubility than Ligand A (-4.698).

**11. hERG Inhibition:** Both ligands have low hERG inhibition risk (0.441 and 0.214).

**12. Microsomal Clearance:** Both have similar microsomal clearance values (36.34 and 36.318 mL/min/kg), indicating comparable metabolic stability.

**13. In vitro Half-Life:** Ligand B (-3.24) has a negative half-life, which is not possible. This is a red flag. Ligand A (52.453) has a reasonable half-life.

**14. P-gp Efflux:** Ligand A (0.176) exhibits lower P-gp efflux than Ligand B (0.023), which is favorable for CNS penetration.

**15. Binding Affinity:** Ligand B (-7.4 kcal/mol) has a significantly stronger binding affinity than Ligand A (-10.6 kcal/mol). This is a substantial advantage.

**Overall Assessment:**

Despite the negative Caco-2 values for both, Ligand B is the more promising candidate. It has a significantly better BBB score, lower DILI risk, better solubility, and *much* stronger binding affinity. The negative in vitro half-life for Ligand B is a major concern and needs investigation, but the affinity difference is so large that it could potentially be overcome with structural modifications. Ligand A's high DILI risk is a significant drawback. The slightly higher TPSA of Ligand A is less concerning than the DILI and affinity issues.



Output:
1
2025-04-17 05:23:03,548 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (361.558 and 353.369 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (46.61) is excellent, well below the 90 A^2 threshold for CNS targets. Ligand B (84.23) is higher, but still potentially acceptable, though less ideal.

**logP:** Ligand A (3.564) is optimal (1-3). Ligand B (2.045) is on the lower end, potentially hindering permeation.

**H-Bond Donors/Acceptors:** Ligand A (0 HBD, 4 HBA) is favorable. Ligand B (2 HBD, 4 HBA) is also acceptable.

**QED:** Both ligands have good QED scores (0.403 and 0.82), indicating drug-like properties. Ligand B is significantly better.

**DILI:** Ligand A (20.202) has a very low DILI risk, excellent. Ligand B (36.293) is still reasonably low, but higher than A.

**BBB:** Ligand A (77.821) has a good BBB penetration score, desirable for a CNS target. Ligand B (89.957) is even better, exceeding the 70% threshold.

**Caco-2 Permeability:** Both have negative Caco-2 values (-4.605 and -4.694), which is unusual and problematic. This suggests poor intestinal absorption, but could be an artifact of the prediction method.

**Aqueous Solubility:** Both ligands have negative solubility values (-4.556 and -3.549), indicating very poor aqueous solubility. This is a significant concern for bioavailability.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.831 and 0.522).

**Microsomal Clearance:** Ligand A (92.54) has higher microsomal clearance, suggesting faster metabolism and lower metabolic stability. Ligand B (38.033) has much lower clearance, indicating better metabolic stability.

**In vitro Half-Life:** Ligand A (-6.233) has a negative half-life, which is not physically meaningful. Ligand B (6.243) has a reasonable half-life.

**P-gp Efflux:** Ligand A (0.846) has low P-gp efflux, which is favorable for CNS exposure. Ligand B (0.063) has extremely low P-gp efflux, even better.

**Binding Affinity:** Ligand B (-9.6 kcal/mol) has a significantly stronger binding affinity than Ligand A (-6.233 kcal/mol). This >1.5 kcal/mol difference is substantial and can outweigh some ADME drawbacks.

**Overall Assessment:**

Ligand B is the stronger candidate. While both have solubility and Caco-2 permeability issues, Ligand B's superior binding affinity, excellent BBB penetration, low P-gp efflux, and better metabolic stability outweigh the slightly higher DILI risk and less optimal logP. The negative half-life of Ligand A is a major red flag. The large affinity difference is the deciding factor.

Output:
1
2025-04-17 05:23:03,548 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (355.389 and 358.404 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (88.91) is excellent, falling well below the 90 A^2 threshold for CNS targets. Ligand B (42.43) is also very good, comfortably under the threshold.

**3. logP:** Ligand A (1.415) is optimal. Ligand B (3.656) is also within the optimal range, though approaching the upper limit.

**4. H-Bond Donors:** Ligand A (2) is good. Ligand B (0) is also acceptable.

**5. H-Bond Acceptors:** Ligand A (5) is good. Ligand B (3) is also good.

**6. QED:** Both ligands have acceptable QED values (0.738 and 0.677, respectively), indicating reasonable drug-likeness.

**7. DILI:** Ligand A (56.727) has a moderate DILI risk, but is still acceptable. Ligand B (20.163) has a very low DILI risk, which is a significant advantage.

**8. BBB:** This is a critical parameter for CNS targets. Ligand A (74.486) is good, exceeding 70%. Ligand B (96.161) is *excellent*, very close to 100%. This is a major point in favor of Ligand B.

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.14 and -4.106), which is unusual and suggests poor permeability. However, these values are on a strange scale and difficult to interpret without knowing the scale's specifics.

**10. Aqueous Solubility:** Both ligands have negative solubility values (-2.865 and -3.775), again suggesting poor solubility. Similar to Caco-2, the scale is unclear.

**11. hERG Inhibition:** Ligand A (0.093) has very low hERG inhibition risk. Ligand B (0.636) has a slightly higher, but still relatively low, risk.

**12. Microsomal Clearance:** Ligand A (0.019) has very low clearance, indicating high metabolic stability. Ligand B (67.514) has a high clearance, suggesting rapid metabolism. This is a significant drawback for Ligand B.

**13. In vitro Half-Life:** Ligand A (-7.003) has a very long half-life. Ligand B (-6.615) has a shorter, but still reasonable, half-life.

**14. P-gp Efflux:** Ligand A (0.018) has very low P-gp efflux, which is ideal for CNS penetration. Ligand B (0.215) has slightly higher efflux, but still relatively low.

**15. Binding Affinity:** Both ligands have very good binding affinities (-7.9 and -6.9 kcal/mol). Ligand A is slightly better (-7.9 kcal/mol). However, the difference is less than 1.5 kcal/mol, so it's not decisive.

**Overall Assessment:**

Ligand B excels in BBB penetration (96.161%) and has a very low DILI risk (20.163). However, it suffers from high microsomal clearance (67.514), suggesting poor metabolic stability. Ligand A has slightly better affinity and metabolic stability, but its BBB penetration is lower (74.486%).

Given the importance of BBB penetration for a CNS target like DRD2, and the relatively small difference in binding affinity, **Ligand B is the more promising candidate**. The high BBB value is a significant advantage that could outweigh the concern about its higher clearance, which might be addressed through structural modifications.

Output:
1
2025-04-17 05:23:03,548 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (368.396 Da) is slightly higher than Ligand B (344.499 Da), but both are acceptable.

**TPSA:** Ligand A (67.87) is better than Ligand B (40.62). For CNS targets, we want TPSA <= 90, both are well within this range. Ligand B is preferable here.

**logP:** Ligand A (1.593) is within the optimal range (1-3). Ligand B (3.232) is at the higher end of the optimal range. Both are acceptable, but Ligand A is slightly better.

**H-Bond Donors:** Ligand A (1) is good. Ligand B (0) is also good. No significant difference.

**H-Bond Acceptors:** Ligand A (4) is good. Ligand B (2) is also good. No significant difference.

**QED:** Ligand A (0.636) is better than Ligand B (0.446), indicating a more drug-like profile.

**DILI:** Ligand A (21.869) is significantly better than Ligand B (13.339), indicating a lower risk of drug-induced liver injury.

**BBB:** Ligand A (89.841) is much better than Ligand B (77.627). For CNS targets, >70 is desirable, and Ligand A is closer to this threshold. This is a major advantage for Ligand A.

**Caco-2 Permeability:** Both are negative, indicating poor permeability. However, the scale isn't specified, so it's difficult to interpret.

**Aqueous Solubility:** Both are negative, indicating poor solubility. Again, the scale is unspecified.

**hERG Inhibition:** Both are low (0.534 and 0.692), indicating low cardiotoxicity risk. No significant difference.

**Microsomal Clearance:** Ligand A (32.334) is better than Ligand B (49.342), indicating better metabolic stability.

**In vitro Half-Life:** Ligand A (-7.781) is much better than Ligand B (18.043), indicating a longer half-life.

**P-gp Efflux:** Ligand A (0.042) is much better than Ligand B (0.322), indicating lower P-gp efflux and better CNS exposure.

**Binding Affinity:** Ligand A (-7.3) is slightly better than Ligand B (-0.0). This is a significant advantage, as affinity is a primary driver.

**Overall Assessment:**

Ligand A consistently outperforms Ligand B across most critical parameters, especially for a CNS target like DRD2. It has a better BBB score, lower DILI risk, better metabolic stability, longer half-life, lower P-gp efflux, and superior binding affinity. While both have poor Caco-2 and solubility, the strong advantages of Ligand A outweigh these drawbacks.

Output:
1
2025-04-17 05:23:03,548 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (353.344 and 364.917 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (58.36) is better than Ligand B (49.41). Both are below the 90 A^2 threshold desirable for CNS targets.

**logP:** Both ligands have good logP values (2.627 and 3.597), falling within the optimal 1-3 range. Ligand B is slightly higher, which *could* be a minor drawback if it impacts solubility, but is not a major concern.

**H-Bond Donors/Acceptors:** Both have 1 HBD, which is good. Ligand A has 4 HBA, and Ligand B has 2 HBA. Both are within the acceptable limits (<=10).

**QED:** Both ligands have similar QED values (0.833 and 0.782), indicating good drug-likeness.

**DILI:** Ligand A (48.158) has a slightly higher DILI risk than Ligand B (29.43). This is a point in favor of Ligand B.

**BBB:** Ligand A (88.135) has a significantly better BBB penetration percentile than Ligand B (75.805). This is a *major* advantage for a CNS target like DRD2.

**Caco-2 Permeability:** Ligand A (-4.396) has better Caco-2 permeability than Ligand B (-4.673).

**Aqueous Solubility:** Ligand A (-3.404) has better solubility than Ligand B (-4.3).

**hERG:** Both ligands have low hERG inhibition liability (0.61 and 0.44), which is good.

**Microsomal Clearance:** Ligand B (71.087) has significantly higher microsomal clearance than Ligand A (26.34). This suggests Ligand A is more metabolically stable.

**In vitro Half-Life:** Ligand A (-5.482) has a much longer in vitro half-life than Ligand B (14.694).

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.21 and 0.217), which is excellent for CNS penetration.

**Binding Affinity:** Both ligands have very similar and excellent binding affinities (-8.4 and -8.3 kcal/mol). The difference is negligible.

**Overall Assessment:**

Ligand A is superior due to its significantly better BBB penetration (88.135 vs 75.805), better metabolic stability (lower Cl_mic, longer t1/2), and better solubility. While Ligand B has a slightly lower DILI risk, the BBB advantage of Ligand A is paramount for a CNS target. The binding affinities are essentially the same, so the ADME properties become the deciding factors.

Output:
1
2025-04-17 05:23:03,548 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (341.455 and 350.419 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (73.99) is significantly better than Ligand B (96.69). For CNS targets, we want TPSA <= 90, so Ligand A is preferable.

**logP:** Ligand A (2.389) is optimal (1-3), while Ligand B (0.499) is a bit low, potentially hindering permeation.

**H-Bond Donors/Acceptors:** Ligand A (3 HBD, 2 HBA) and Ligand B (2 HBD, 6 HBA) both fall within acceptable ranges.

**QED:** Both ligands have good QED scores (0.695 and 0.754, respectively), indicating good drug-like properties.

**DILI:** Both ligands have relatively low DILI risk (29.081 and 51.493), but Ligand A is better.

**BBB:** Ligand A (50.407) is better than Ligand B (36.448), although both are below the desirable >70 for CNS targets. This is a critical factor for DRD2.

**Caco-2:** Ligand A (-4.822) and Ligand B (-5.249) both have negative values, which is unusual and suggests very poor permeability. This is a significant concern for both.

**Solubility:** Ligand A (-3.739) and Ligand B (-1.978) both have negative values, indicating poor solubility.

**hERG:** Both ligands have very low hERG risk (0.364 and 0.126).

**Microsomal Clearance:** Ligand B (-5.033) has a negative clearance, which is not physically possible and likely indicates a very slow clearance rate (highly stable). Ligand A (16.348) has a moderate clearance.

**In vitro Half-Life:** Ligand B (17.241) has a longer half-life than Ligand A (1.867).

**P-gp Efflux:** Ligand A (0.111) has lower P-gp efflux than Ligand B (0.013), which is favorable for CNS penetration.

**Binding Affinity:** Ligand B (-7.8 kcal/mol) has a slightly better binding affinity than Ligand A (-8.5 kcal/mol). However, the difference is relatively small.

**Overall Assessment:**

Ligand A is better overall. While Ligand B has slightly better affinity and a longer half-life, Ligand A excels in crucial properties for a CNS-targeting GPCR ligand: TPSA, logP, BBB, and P-gp efflux. The better logP and TPSA of Ligand A suggest it will have better permeability, despite the poor Caco-2 and solubility values for both. The slightly better BBB score for Ligand A is also important. The negative clearance for Ligand B is a red flag.

Output:
0
2025-04-17 05:23:03,549 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (341.43 and 354.441 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (46.09) is better than Ligand B (40.62) as both are below the 90 A^2 threshold for CNS targets.

**3. logP:** Ligand A (3.857) is slightly higher than Ligand B (2.919), both within the optimal 1-3 range. Ligand B is closer to the lower bound, which could slightly impact permeability.

**4. H-Bond Donors:** Both have 0 HBD, which is good.

**5. H-Bond Acceptors:** Ligand A has 3 HBA, and Ligand B has 2. Both are well within the acceptable limit of 10.

**6. QED:** Both ligands have similar QED values (0.801 and 0.782), indicating good drug-like properties.

**7. DILI:** Ligand A (31.369) has a significantly lower DILI risk than Ligand B (13.804), which is a major advantage.

**8. BBB:** Ligand B (93.563) has a slightly better BBB penetration percentile than Ligand A (89.066), but both are excellent (>70).

**9. Caco-2 Permeability:** Ligand A (-4.589) and Ligand B (-4.483) have similar, negative values, which is not ideal. This suggests poor intestinal absorption.

**10. Aqueous Solubility:** Both ligands have similar, very poor aqueous solubility (-3.401 and -3.484). This is a concern for formulation and bioavailability.

**11. hERG Inhibition:** Both ligands show low hERG inhibition liability (0.754 and 0.674), which is good.

**12. Microsomal Clearance:** Ligand B (46.117) has a lower microsomal clearance than Ligand A (63.66), indicating better metabolic stability.

**13. In vitro Half-Life:** Ligand B (-23.86) has a significantly longer in vitro half-life than Ligand A (-0.914), which is a substantial advantage.

**14. P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.218 and 0.193), which is excellent for CNS penetration.

**15. Binding Affinity:** Ligand B (-9.0) has a significantly stronger binding affinity than Ligand A (-7.8), a difference of 1.2 kcal/mol. This is a substantial advantage that can outweigh some of the ADME drawbacks.

**Overall Assessment:**

While Ligand A has a better DILI score and slightly better TPSA, Ligand B's superior binding affinity (-9.0 vs -7.8 kcal/mol), better BBB penetration, and significantly improved metabolic stability (lower Cl_mic and longer t1/2) are more critical for a CNS-targeting GPCR like DRD2. The difference in binding affinity is substantial. The solubility and Caco-2 permeability are poor for both, but these can potentially be addressed with formulation strategies.

Output:
1
2025-04-17 05:23:03,549 - INFO - Batch 193 complete. Total preferences: 3088
2025-04-17 05:23:03,549 - INFO - Processing batch 194/512...
2025-04-17 05:23:45,466 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 drug candidates, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (406.328 Da) is slightly higher than Ligand B (344.415 Da), but both are acceptable.

**TPSA:** Ligand A (62.53) is better than Ligand B (93.21). For CNS targets, we want TPSA <= 90, so Ligand A is preferable.

**logP:** Both ligands have good logP values (Ligand A: 3.157, Ligand B: 2.597), falling within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Both have reasonable HBD/HBA counts (Ligand A: 1/5, Ligand B: 2/5), well within the recommended limits.

**QED:** Both ligands have similar and good QED values (Ligand A: 0.848, Ligand B: 0.801), indicating good drug-like properties.

**DILI:** Ligand A (58.395) has a slightly higher DILI risk than Ligand B (45.134), but both are below the concerning threshold of 60.

**BBB:** Ligand A (89.608) has a significantly better BBB penetration score than Ligand B (78.48). This is a critical factor for a CNS target like DRD2.

**Caco-2 Permeability:** Ligand A (-5.187) shows poorer Caco-2 permeability compared to Ligand B (-4.733). However, this is less important than BBB for CNS targets.

**Aqueous Solubility:** Both ligands have very poor aqueous solubility (-3.289 and -3.414 respectively). This could pose formulation challenges, but is not a dealbreaker if other properties are favorable.

**hERG Inhibition:** Ligand A (0.799) has a slightly higher hERG inhibition risk than Ligand B (0.236). This is a concern, but not a major one given the other properties.

**Microsomal Clearance:** Ligand A (72.631) has higher microsomal clearance than Ligand B (49.81), meaning it's metabolized faster. Lower clearance is preferred.

**In vitro Half-Life:** Ligand B (23.366) has a longer in vitro half-life than Ligand A (17.545). This is desirable.

**P-gp Efflux:** Ligand A (0.601) shows lower P-gp efflux than Ligand B (0.026), which is beneficial for CNS penetration.

**Binding Affinity:** Both ligands have the same excellent binding affinity (-8.4 kcal/mol).

**Overall Assessment:**

Ligand A excels in BBB penetration and P-gp efflux, which are crucial for CNS GPCR targets. While it has slightly higher DILI and hERG risk and faster clearance, the strong BBB penetration and comparable binding affinity outweigh these drawbacks. Ligand B has better Caco-2 permeability, lower DILI, hERG, and clearance, and longer half-life, but its significantly lower BBB penetration is a major disadvantage for a CNS target.

Output:
1
2025-04-17 05:23:45,466 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (426.738 Da) is slightly higher, but acceptable. Ligand B (382.507 Da) is good.

**TPSA:** Ligand A (30.93) is excellent for CNS penetration, well below the 90 A^2 threshold. Ligand B (82.78) is higher, but still potentially acceptable, though less ideal for CNS targets.

**logP:** Ligand A (4.477) is a bit high, potentially leading to solubility issues and off-target effects. Ligand B (2.185) is within the optimal range (1-3).

**H-Bond Donors/Acceptors:** Ligand A (0 HBD, 4 HBA) is favorable. Ligand B (2 HBD, 6 HBA) is also acceptable.

**QED:** Both ligands have good QED values (A: 0.681, B: 0.8), indicating good drug-like properties.

**DILI:** Ligand A (37.611) has a lower DILI risk than Ligand B (69.678), which is a significant advantage.

**BBB:** Ligand A (78.48) has a much better BBB percentile than Ligand B (27.259). This is a crucial factor for a CNS target like DRD2.

**Caco-2 Permeability:** Ligand A (-4.826) has poor Caco-2 permeability. Ligand B (-5.353) also has poor Caco-2 permeability.

**Aqueous Solubility:** Both ligands have very poor aqueous solubility (A: -5.452, B: -3.455).

**hERG Inhibition:** Both ligands have low hERG inhibition risk (A: 0.957, B: 0.626).

**Microsomal Clearance:** Ligand A (49.977) has a higher microsomal clearance than Ligand B (32.029), indicating lower metabolic stability.

**In vitro Half-Life:** Ligand B (48.482) has a significantly longer in vitro half-life than Ligand A (7.692).

**P-gp Efflux:** Ligand A (0.763) has slightly lower P-gp efflux than Ligand B (0.182), which is favorable for CNS penetration.

**Binding Affinity:** Ligand A (-7.9 kcal/mol) has a slightly better binding affinity than Ligand B (-7.4 kcal/mol), although the difference is not huge.

**Overall Assessment:**

Ligand A excels in BBB penetration, DILI risk, and binding affinity. However, it suffers from high logP, poor Caco-2 permeability, and higher metabolic clearance. Ligand B has a better logP, longer half-life, and lower clearance, but significantly poorer BBB penetration and a higher DILI risk.

Given the CNS target (DRD2), BBB penetration is paramount. Ligand A's substantially higher BBB percentile (78.48 vs 27.259) outweighs its other drawbacks, especially considering the only moderate difference in binding affinity. While the solubility and permeability are concerns for both, these can potentially be addressed with formulation strategies. The lower DILI risk of Ligand A is also a significant advantage.

Output:
0
2025-04-17 05:23:45,467 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (382.5 and 406.3 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (66.92) is significantly better than Ligand B (79.46). For CNS targets, we want TPSA <= 90, and A is comfortably within that range, while B is approaching the upper limit.

**logP:** Both ligands have good logP values (3.064 and 3.746), falling within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A (0 HBD, 5 HBA) is slightly better than Ligand B (3 HBD, 3 HBA) in terms of balancing solubility and permeability.

**QED:** Both have acceptable QED scores (0.738 and 0.656), indicating good drug-like properties.

**DILI:** Both ligands have relatively high DILI risk (77.55 and 71.77), but these are percentile scores, and a direct comparison is difficult without knowing the distribution of scores in the dataset.

**BBB:** Ligand B (77.821) has a better BBB penetration score than Ligand A (65.607). This is a critical factor for CNS targets like DRD2.

**Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and suggests a potential issue with the data or modeling. However, the values are similar (-4.621 vs -4.997).

**Aqueous Solubility:** Both ligands have very poor aqueous solubility (-4.137 and -4.762). This is a significant drawback.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.669 and 0.694).

**Microsomal Clearance:** Ligand A (105.779) has a higher microsomal clearance than Ligand B (40.769), indicating lower metabolic stability. This is a significant disadvantage for Ligand A.

**In vitro Half-Life:** Ligand B (75.308) has a much longer in vitro half-life than Ligand A (8.357).

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.213 and 0.21).

**Binding Affinity:** Ligand B (-9.5 kcal/mol) has a significantly stronger binding affinity than Ligand A (-7.0 kcal/mol). This >1.5 kcal/mol difference is a major advantage for Ligand B, potentially outweighing some of its ADME drawbacks.

**Overall Assessment:**

While Ligand A has a better TPSA, Ligand B excels in the most crucial areas for a CNS-targeting GPCR ligand: BBB penetration, binding affinity, and metabolic stability (lower Cl_mic and higher t1/2). The significantly stronger binding affinity of Ligand B is a decisive factor. The poor solubility of both is a concern, but can potentially be addressed with formulation strategies.

Output:
1
2025-04-17 05:23:45,467 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (365.543 and 365.455 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (61.44) is significantly better than Ligand B (86.88). For CNS targets, we want TPSA <= 90, and A is comfortably within that range, while B is approaching the upper limit. This favors A.

**3. logP:** Both ligands have good logP values (1.793 and 2.065), falling within the optimal 1-3 range.

**4. H-Bond Donors:** Ligand A (2) is slightly higher than Ligand B (1), but both are acceptable (<=5).

**5. H-Bond Acceptors:** Ligand A (4) is lower than Ligand B (6), which is preferable. We want <=10, and both are within this range, but A is better.

**6. QED:** Both ligands have good QED scores (0.722 and 0.812), indicating good drug-like properties.

**7. DILI:** Ligand A (16.44) has a much lower DILI risk than Ligand B (49.554). Lower is better, and A is well below the 40% threshold, while B is approaching a moderate risk. This is a significant advantage for A.

**8. BBB:** Ligand A (70.415) has a significantly higher BBB penetration percentile than Ligand B (30.748). For a CNS target like DRD2, >70% is desirable, and A meets this criterion, while B falls far short. This is a crucial advantage for A.

**9. Caco-2 Permeability:** Ligand A (-5.235) and Ligand B (-4.836) both have negative values, which is unusual. It's difficult to interpret without knowing the scale, but generally, higher values are better.

**10. Aqueous Solubility:** Ligand A (-2.939) and Ligand B (-1.883) both have negative values, which is also unusual. Again, higher values are better.

**11. hERG Inhibition:** Both ligands have low hERG inhibition risk (0.348 and 0.296), which is good.

**12. Microsomal Clearance:** Ligand A (74.94) has higher microsomal clearance than Ligand B (43.844), indicating faster metabolism and potentially lower *in vivo* exposure. This favors B.

**13. In vitro Half-Life:** Ligand B (71.526) has a longer in vitro half-life than Ligand A (24.657), which is preferable.

**14. P-gp Efflux:** Both ligands have low P-gp efflux liability (0.1 and 0.283), which is good for CNS penetration.

**15. Binding Affinity:** Ligand A (-8.9 kcal/mol) has a significantly stronger binding affinity than Ligand B (-7.7 kcal/mol). A difference of >1.5 kcal/mol is considered substantial and can outweigh minor ADME drawbacks.

**Overall Assessment:**

Ligand A is the superior candidate. While Ligand B has slightly better metabolic stability and half-life, Ligand A excels in the critical areas for a CNS GPCR target: TPSA, BBB penetration, DILI risk, and, most importantly, binding affinity. The significantly stronger affinity of Ligand A (-8.9 vs -7.7 kcal/mol) is a major advantage. The lower TPSA and DILI, combined with excellent BBB penetration, make it a much more promising drug candidate.

Output:
1
2025-04-17 05:23:45,467 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight (MW):** Both ligands (340.427 and 344.499 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (76.02) is better than Ligand B (49.41). For CNS targets, we want TPSA <= 90, both are well within this range. Ligand A is slightly higher, but still acceptable.

**3. logP:** Ligand B (3.42) is higher than Ligand A (1.024). While both are within the optimal 1-3 range, Ligand B is approaching the upper limit.

**4. H-Bond Donors (HBD):** Both ligands have acceptable HBD counts (2 and 1 respectively), well below the threshold of 5.

**5. H-Bond Acceptors (HBA):** Both ligands have acceptable HBA counts (4 and 2 respectively), well below the threshold of 10.

**6. QED:** Both ligands have good QED scores (0.575 and 0.795), indicating drug-like properties. Ligand B is slightly better.

**7. DILI:** Ligand A (37.456) has a lower DILI risk than Ligand B (13.532), which is a significant advantage. Both are below the 40 threshold, but lower is always preferred.

**8. BBB:** Ligand B (76.154) has a much better BBB penetration percentile than Ligand A (48.313). This is *critical* for a CNS target like DRD2.

**9. Caco-2 Permeability:** Ligand A (-4.933) is better than Ligand B (-4.82). Higher values indicate better intestinal absorption.

**10. Aqueous Solubility:** Ligand A (-2.456) is better than Ligand B (-3.86). Higher values indicate better solubility.

**11. hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.086 and 0.385), which is excellent.

**12. Microsomal Clearance (Cl_mic):** Ligand A (6.104) has a lower clearance than Ligand B (39.431), indicating better metabolic stability. This is a significant advantage.

**13. In vitro Half-Life:** Ligand A (-7.355) has a longer half-life than Ligand B (-6.632).

**14. P-gp Efflux:** Ligand A (0.039) has lower P-gp efflux liability than Ligand B (0.098), which is favorable for CNS penetration.

**15. Binding Affinity:** Ligand B (-8.9 kcal/mol) has a stronger binding affinity than Ligand A (-8.2 kcal/mol). This is a 0.7 kcal/mol difference, which is substantial.

**Overall Assessment:**

Ligand B has a significantly better BBB penetration and binding affinity, which are the most important factors for a CNS GPCR target. However, Ligand A has better DILI, Cl_mic, solubility, and P-gp efflux. The difference in binding affinity (0.7 kcal/mol) is substantial enough to outweigh the advantages of Ligand A, especially given the importance of CNS penetration for DRD2.

Output:
1
2025-04-17 05:23:45,467 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B based on the provided guidelines, prioritizing GPCR-specific properties (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (362.308 Da) is slightly lower than Ligand B (383.543 Da), which is generally favorable for permeability.

**TPSA:** Ligand A (84.43) is significantly better than Ligand B (92.93). For CNS targets, TPSA should be <=90. Ligand A is comfortably within this range, while Ligand B is close to the upper limit.

**logP:** Both ligands have good logP values (A: 2.001, B: 1.785), falling within the optimal range of 1-3.

**H-Bond Donors/Acceptors:** Ligand A (HBD=0, HBA=8) and Ligand B (HBD=2, HBA=8) both have acceptable numbers of H-bond donors and acceptors.

**QED:** Ligand A (0.777) has a higher QED score than Ligand B (0.608), indicating a more drug-like profile.

**DILI:** Ligand A (70.88) has a slightly higher DILI risk than Ligand B (65.491), but both are still reasonably low.

**BBB:** This is a critical parameter for CNS targets like DRD2. Ligand A (87.786) has a *much* higher BBB percentile than Ligand B (16.014). This is a major advantage for Ligand A.

**Caco-2 Permeability:** Ligand A (-4.779) has a lower (worse) Caco-2 permeability than Ligand B (-5.733). However, given the strong BBB score for A, this is less critical.

**Aqueous Solubility:** Ligand A (-3.305) has slightly better solubility than Ligand B (-2.093).

**hERG:** Both ligands have very low hERG inhibition risk (A: 0.121, B: 0.154).

**Microsomal Clearance:** Ligand B (31.946) has a higher microsomal clearance than Ligand A (25.877), suggesting lower metabolic stability.

**In vitro Half-Life:** Ligand A (-12.813) has a longer in vitro half-life than Ligand B (-0.845), indicating better stability.

**P-gp Efflux:** Ligand A (0.113) has lower P-gp efflux liability than Ligand B (0.067), which is favorable for CNS penetration.

**Binding Affinity:** Ligand A (-8.8 kcal/mol) has a significantly stronger binding affinity than Ligand B (-7.4 kcal/mol). This difference of 1.4 kcal/mol is substantial and can outweigh minor ADME drawbacks.

**Conclusion:**

Ligand A is the superior candidate. While Ligand B has slightly better Caco-2 permeability, Ligand A excels in the most crucial areas for a CNS-targeting GPCR ligand: significantly better BBB penetration, stronger binding affinity, better QED, longer half-life, and lower P-gp efflux. The TPSA value is also more favorable for Ligand A.



Output:
1
2025-04-17 05:23:45,467 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (350.419 and 351.382 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (87.91) is better than Ligand B (95.5). Both are below the 90 A^2 threshold for CNS targets, but A is closer to the optimal range.

**3. logP:** Ligand A (0.66) is slightly better than Ligand B (-0.447). Both are a bit low, potentially hindering permeation, but still within an acceptable range.

**4. H-Bond Donors:** Both ligands have 1 HBD, which is within the ideal limit of <=5.

**5. H-Bond Acceptors:** Ligand A has 6 HBAs, and Ligand B has 5. Both are within the ideal limit of <=10.

**6. QED:** Both ligands have similar QED values (0.727 and 0.718), indicating good drug-like properties.

**7. DILI:** Ligand A (36.099) has a significantly lower DILI risk than Ligand B (61.07). This is a major advantage for Ligand A.

**8. BBB:** Ligand B (73.827) has a better BBB penetration percentile than Ligand A (64.986). This is important for CNS targets like DRD2.

**9. Caco-2 Permeability:** Ligand A (-4.894) has worse Caco-2 permeability than Ligand B (-5.096). Both are quite poor, but B is slightly better.

**10. Aqueous Solubility:** Ligand A (-0.804) has slightly better aqueous solubility than Ligand B (-0.982).

**11. hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.153 and 0.067).

**12. Microsomal Clearance:** Ligand B (1.546) has a much lower microsomal clearance than Ligand A (14.799), indicating better metabolic stability.

**13. In vitro Half-Life:** Ligand B (6.763) has a significantly longer in vitro half-life than Ligand A (1.623).

**14. P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.009 and 0.008).

**15. Binding Affinity:** Both ligands have the same binding affinity (-7.6 kcal/mol), which is excellent.

**Overall Assessment:**

While Ligand B has better BBB penetration and metabolic stability (lower Cl_mic, longer t1/2), Ligand A has a significantly lower DILI risk and slightly better TPSA and solubility. The binding affinity is identical. Given the GPCR-specific priorities, BBB is crucial, but DILI is a major concern. The substantial difference in DILI risk tips the balance in favor of Ligand A. The slightly lower BBB score for A is less concerning than the higher DILI risk for B.

Output:
0
2025-04-17 05:23:45,468 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight (MW):** Both ligands (353.379 and 349.391 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Both ligands (120.77 and 117.7) are below the 140 A^2 threshold for good oral absorption, but slightly above the more stringent 90 A^2 for CNS targets. This isn't a major concern, but something to note.

**3. logP:** Ligand A (-0.296) is a bit low, potentially hindering permeation. Ligand B (-0.01) is better, falling closer to the optimal 1-3 range.

**4. H-Bond Donors (HBD):** Both ligands have acceptable HBD counts (2 and 3, respectively), well within the limit of 5.

**5. H-Bond Acceptors (HBA):** Both ligands have acceptable HBA counts (6 each), within the limit of 10.

**6. QED:** Both ligands have good QED scores (0.77 and 0.668), indicating good drug-like properties.

**7. DILI:** Both ligands have relatively high DILI risk (60.644 and 65.917). This is a concern, and further investigation would be needed.

**8. BBB:** Ligand A (40.946) has a significantly better BBB percentile than Ligand B (35.556). For a CNS target like DRD2, this is a crucial advantage.

**9. Caco-2 Permeability:** Both have negative Caco-2 values (-5.017 and -5.378), which is unusual and suggests very poor permeability. This is a significant drawback for both.

**10. Aqueous Solubility:** Both have negative solubility values (-1.094 and -2.725), also unusual and indicating poor solubility. This is a significant drawback for both.

**11. hERG Inhibition:** Both ligands have very low hERG inhibition liability (0.059 and 0.121), which is excellent.

**12. Microsomal Clearance (Cl_mic):** Ligand A (-23.63) has a much lower (better) microsomal clearance than Ligand B (16.253), indicating better metabolic stability.

**13. In vitro Half-Life:** Ligand A (13.991) has a longer half-life than Ligand B (7.988), which is generally desirable.

**14. P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.003 and 0.022), which is favorable for CNS penetration.

**15. Binding Affinity:** Both ligands have the same binding affinity (-8.5 kcal/mol), which is excellent and strong.

**Overall Assessment:**

Despite both compounds having excellent binding affinity, Ligand A is the more promising candidate. Its significantly better BBB penetration (40.946 vs 35.556) and lower microsomal clearance (-23.63 vs 16.253) are critical advantages for a CNS-targeting GPCR like DRD2. While both have poor Caco-2 and solubility, the improved metabolic stability and BBB penetration of Ligand A outweigh the slightly lower logP. The DILI risk is a concern for both, but can be addressed in subsequent optimization.

Output:
0
2025-04-17 05:23:45,468 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (347.415 and 366.487 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (90.29) is excellent, falling below the 90 threshold for CNS targets. Ligand B (100.19) is slightly higher but still reasonable.

**3. logP:** Both ligands have good logP values (0.89 and 1.267), within the optimal 1-3 range.

**4. H-Bond Donors:** Ligand A (1) is good. Ligand B (3) is acceptable, but higher HBD can sometimes reduce permeability.

**5. H-Bond Acceptors:** Ligand A (6) and Ligand B (5) are both within the acceptable limit of 10.

**6. QED:** Both ligands have similar QED values (0.799 and 0.706), indicating good drug-like properties.

**7. DILI:** Ligand A (54.323) has a higher DILI risk than Ligand B (34.703), but both are below the concerning 60 threshold.

**8. BBB:** This is crucial for a CNS target like DRD2. Ligand A (72.005) has a significantly better BBB percentile than Ligand B (39.705).

**9. Caco-2:** Ligand A (-4.817) and Ligand B (-5.424) both have negative values, which is unusual. It suggests poor Caco-2 permeability.

**10. Solubility:** Both ligands have very poor aqueous solubility (-1.547 and -1.582). This is a significant drawback.

**11. hERG:** Both ligands have very low hERG inhibition risk (0.176 and 0.029).

**12. Cl_mic:** Ligand A (48.769) has a higher microsomal clearance than Ligand B (1.321), indicating lower metabolic stability.

**13. t1/2:** Ligand A (12.613) has a longer in vitro half-life than Ligand B (4.302).

**14. Pgp:** Both ligands have very low P-gp efflux liability (0.058 and 0.013).

**15. Binding Affinity:** Ligand A (-8.9 kcal/mol) has a significantly stronger binding affinity than Ligand B (-7.9 kcal/mol). This is a substantial advantage.

**Overall Assessment:**

While both compounds have issues with solubility and Caco-2 permeability, Ligand A is the more promising candidate. Its significantly stronger binding affinity (-8.9 vs -7.9 kcal/mol) and much better BBB penetration (72 vs 39.7) outweigh its slightly higher DILI risk and lower metabolic stability (higher Cl_mic). The affinity difference is >1 kcal/mol, which is a significant advantage. For a CNS target, BBB penetration is paramount, and Ligand A excels in this area.

Output:
1
2025-04-17 05:23:45,468 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (354.793 and 342.439 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (60.45) and Ligand B (58.64) are both below the 90 A^2 threshold desirable for CNS targets, indicating good potential for brain penetration.

**3. logP:** Ligand A (4.057) is at the upper end of the optimal range (1-3), while Ligand B (1.465) is at the lower end. Ligand B's lower logP might hinder permeability.

**4. H-Bond Donors:** Both ligands have 1 HBD, which is within the acceptable limit of <=5.

**5. H-Bond Acceptors:** Ligand A has 4 HBAs, and Ligand B has 3, both within the acceptable limit of <=10.

**6. QED:** Both ligands have similar QED values (0.754 and 0.773), indicating good drug-likeness.

**7. DILI:** Ligand A has a significantly higher DILI risk (93.951%) compared to Ligand B (29.624%). This is a major concern for Ligand A.

**8. BBB:** Ligand A (74.758%) has a better BBB percentile than Ligand B (60.644%), which is important for CNS targets.

**9. Caco-2:** Both ligands have negative Caco-2 values (-4.614 and -4.642). These values are unusual and suggest poor permeability. This is a significant drawback for both.

**10. Solubility:** Ligand A (-5.636) and Ligand B (-3.672) both have negative solubility values, indicating poor aqueous solubility.

**11. hERG:** Ligand A (0.692) has a slightly higher hERG risk than Ligand B (0.344), but both are relatively low.

**12. Cl_mic:** Ligand A (65.052) has a higher microsomal clearance than Ligand B (17.499), indicating lower metabolic stability.

**13. t1/2:** Ligand A (41.861) has a longer in vitro half-life than Ligand B (10.474).

**14. Pgp:** Ligand A (0.47) has lower P-gp efflux liability than Ligand B (0.055), which is favorable for CNS penetration.

**15. Binding Affinity:** Ligand A (-10.7 kcal/mol) has a significantly stronger binding affinity than Ligand B (-8.4 kcal/mol). This is a substantial advantage.

**Overall Assessment:**

Ligand A has a significantly better binding affinity and BBB penetration, and lower Pgp efflux, but suffers from a very high DILI risk, higher metabolic clearance, and poor solubility. Ligand B has a much lower DILI risk and better metabolic stability, but weaker binding affinity and lower BBB penetration.

Given the importance of binding affinity for GPCRs, and the fact that the difference in affinity is substantial (>1.5 kcal/mol), Ligand A is initially more promising *despite* its drawbacks. However, the extremely high DILI risk for Ligand A is a major red flag. While optimization could potentially mitigate the DILI risk, it's a significant hurdle. The poor solubility and Caco-2 values for both are concerning and would need to be addressed.

Considering the balance, and prioritizing the strong affinity of Ligand A, I would initially favor it, but with a strong caveat that DILI mitigation is critical.

Output:
1
2025-04-17 05:23:45,468 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (369.868 and 369.491 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (52.65) is significantly better than Ligand B (91.42). For CNS targets, we want TPSA <= 90, so Ligand A is much more favorable.

**3. logP:** Both ligands have acceptable logP values (2.542 and 1.017), falling within the optimal 1-3 range. Ligand A is slightly better.

**4. H-Bond Donors:** Both have 1 HBD, which is good.

**5. H-Bond Acceptors:** Ligand A has 3 HBAs, and Ligand B has 6. Both are acceptable (<=10), but Ligand A is preferable.

**6. QED:** Both ligands have similar QED values (0.803 and 0.722), indicating good drug-likeness.

**7. DILI:** Ligand A (38.736) has a significantly lower DILI risk than Ligand B (67.235).  Below 40 is good, so Ligand A is much better here.

**8. BBB:** Ligand A (83.831) has a much higher BBB penetration percentile than Ligand B (42.342).  >70 is desirable for CNS targets, and Ligand A is closer to this threshold.

**9. Caco-2:** Both have negative Caco-2 values, which is unusual and difficult to interpret without knowing the scale. However, it doesn't strongly influence the decision given other factors.

**10. Solubility:** Both have negative solubility values, again making direct comparison difficult.

**11. hERG:** Both ligands have low hERG inhibition liability (0.803 and 0.233), which is good.

**12. Cl_mic:** Ligand A (3.908) has a lower microsomal clearance than Ligand B (45.079), indicating better metabolic stability.

**13. t1/2:** Ligand A (40.91) has a much longer in vitro half-life than Ligand B (-20.345). This is a significant advantage.

**14. Pgp:** Ligand A (0.097) has lower P-gp efflux liability than Ligand B (0.087), which is favorable for CNS penetration.

**15. Binding Affinity:** Ligand A (-7.6 kcal/mol) has a slightly better binding affinity than Ligand B (-6.9 kcal/mol). While both are good, the difference is meaningful.

**Overall Assessment:**

Ligand A consistently outperforms Ligand B across most critical parameters, especially those prioritized for GPCRs targeting the CNS. Specifically, Ligand A has a significantly better TPSA, BBB, DILI risk, metabolic stability (Cl_mic, t1/2), and slightly better affinity. While both have acceptable logP and H-bond properties, the superior ADME profile of Ligand A makes it the more promising drug candidate.

Output:
1
2025-04-17 05:23:45,468 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (363.929 and 342.399 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (49.33) is significantly better than Ligand B (89.32). For CNS targets, we want TPSA <= 90, and A is comfortably within this range, while B is approaching the upper limit.

**3. logP:** Both ligands have good logP values (4.66 and 4.054), falling within the optimal 1-3 range, though slightly high.

**4. H-Bond Donors:** Both have 2 HBD, which is acceptable.

**5. H-Bond Acceptors:** Ligand A has 2 HBA, while Ligand B has 6. Lower HBA is generally preferred for better permeability, giving an edge to Ligand A.

**6. QED:** Ligand A (0.772) has a better QED score than Ligand B (0.583), indicating a more drug-like profile.

**7. DILI:** Ligand A (22.257) has a much lower DILI risk than Ligand B (73.129). This is a significant advantage for Ligand A.

**8. BBB:** Ligand A (76.774) has a substantially better BBB penetration percentile than Ligand B (55.603). This is *critical* for a CNS target like DRD2.

**9. Caco-2 Permeability:** Both have negative values (-4.76 and -4.675). These values are unusual and require further investigation, but they are similar.

**10. Aqueous Solubility:** Both have negative values (-4.931 and -5.182). Similar to Caco-2, these values are unusual and require further investigation.

**11. hERG Inhibition:** Both have low hERG inhibition risk (0.653 and 0.553).

**12. Microsomal Clearance:** Ligand A (68.24) has a higher microsomal clearance than Ligand B (63.772), indicating potentially lower metabolic stability, but the difference is not huge.

**13. In vitro Half-Life:** Ligand A (16.75) has a longer half-life than Ligand B (8.719), which is desirable.

**14. P-gp Efflux:** Ligand A (0.707) has lower P-gp efflux liability than Ligand B (0.146), meaning it's less likely to be pumped out of the brain, improving CNS exposure.

**15. Binding Affinity:** Ligand B (-8.8 kcal/mol) has a slightly better binding affinity than Ligand A (-10 kcal/mol). While affinity is important, the difference of 1.2 kcal/mol is unlikely to outweigh the significant ADME advantages of Ligand A.

**Overall Assessment:**

Ligand A is the superior candidate. It excels in key properties for CNS drug development: TPSA, BBB, DILI, QED, P-gp efflux, and in vitro half-life. While Ligand B has slightly better binding affinity, the ADME profile of Ligand A is far more favorable, particularly its predicted brain penetration and lower toxicity risk. The slightly higher logP of both compounds is a minor concern, but manageable.

Output:
0
2025-04-17 05:23:45,469 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 drug candidates, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (364.515 Da and 336.399 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (67.23) is significantly better than Ligand B (94.8). For CNS targets, we want TPSA <= 90, so Ligand A is preferable.

**logP:** Both ligands have good logP values (2.325 and 1.758), falling within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Both have 1 HBD, which is good. Ligand A has 5 HBA, while Ligand B has 6. Both are acceptable, being <= 10.

**QED:** Both ligands have high QED scores (0.806 and 0.914), indicating good drug-like properties.

**DILI:** Ligand A (27.685) has a much lower DILI risk than Ligand B (54.285). Both are below 60, but A is clearly better.

**BBB:** This is critical for a CNS target. Ligand A has a BBB percentile of 88.135, excellent. Ligand B is significantly lower at 51.687, which is less desirable.

**Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and suggests poor permeability. However, the scale isn't specified, so it's hard to interpret.

**Aqueous Solubility:** Both have negative solubility values, which is also unusual and suggests poor solubility.

**hERG:** Both ligands have very low hERG inhibition liability (0.502 and 0.237), which is excellent.

**Microsomal Clearance:** Ligand A (52.889) has a moderate clearance, while Ligand B (-14.188) has a negative clearance, which is not physically possible and likely indicates an error or outlier in the data. This is a major red flag for Ligand B.

**In vitro Half-Life:** Both have similar in vitro half-lives (15.087 and 15.432 hours), which are reasonable.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.07 and 0.007), which is favorable for CNS penetration.

**Binding Affinity:** Ligand A (-7.9 kcal/mol) has a significantly stronger binding affinity than Ligand B (-5.9 kcal/mol). This difference of 2 kcal/mol is substantial and can outweigh minor ADME drawbacks.

**Overall Assessment:**

Ligand A is clearly superior. It has better TPSA, lower DILI risk, significantly better BBB penetration, and a much stronger binding affinity. The negative values for Caco-2 and solubility are concerning for both, but the other advantages of Ligand A, especially the BBB and affinity, make it the more promising candidate. Ligand B's negative microsomal clearance is a serious issue.

Output:
1
2025-04-17 05:23:45,469 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (348.487 and 350.459 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (67.43) is significantly better than Ligand B (76.66). For CNS targets, we want TPSA <= 90, and ideally closer to 60. Ligand A is much closer to this ideal.

**3. logP:** Both ligands have good logP values (2.537 and 1.385), falling within the optimal range of 1-3. Ligand A is slightly better.

**4. H-Bond Donors:** Both have 2 HBD, which is within the acceptable limit of <=5.

**5. H-Bond Acceptors:** Ligand A has 3 HBA, and Ligand B has 4, both within the acceptable limit of <=10.

**6. QED:** Ligand A (0.673) has a better QED score than Ligand B (0.512), indicating a more drug-like profile. Both are above the 0.5 threshold.

**7. DILI:** Ligand A (13.61) has a significantly lower DILI risk than Ligand B (18.651). Both are below 40, which is good.

**8. BBB:** This is crucial for a CNS target like DRD2. Ligand A (71.811) has a much better BBB penetration percentile than Ligand B (50.872). A value >70 is desirable, and Ligand A is closer to that threshold.

**9. Caco-2 Permeability:** Both have negative values (-4.66 and -4.951), indicating poor permeability. This is a concern for both, but doesn't differentiate them significantly.

**10. Aqueous Solubility:** Both have negative values (-2.633 and -2.259), suggesting poor solubility. This is also a concern for both.

**11. hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.351 and 0.23).

**12. Microsomal Clearance:** Ligand B (13.303) has lower microsomal clearance than Ligand A (40.337), suggesting better metabolic stability.

**13. In vitro Half-Life:** Ligand B (9.407) has a significantly longer in vitro half-life than Ligand A (3.395).

**14. P-gp Efflux:** Both have very low P-gp efflux liability (0.044 and 0.04).

**15. Binding Affinity:** Ligand A (-7.9 kcal/mol) has a slightly better binding affinity than Ligand B (-7.5 kcal/mol). While both are excellent, the 0.4 kcal/mol difference is noticeable.

**Overall Assessment:**

Considering the GPCR-specific priorities, Ligand A is the better candidate. Its superior BBB penetration, lower TPSA, better QED, and slightly better binding affinity outweigh Ligand B's better metabolic stability and half-life. The CNS target necessitates good brain penetration, which Ligand A provides to a greater extent. While both have solubility and permeability issues, these can be addressed through formulation strategies. The DILI risk is also lower for Ligand A.

Output:
1
2025-04-17 05:23:45,469 - INFO - Reasoning:

Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (422.714 Da) is higher, but still acceptable. Ligand B (344.415 Da) is slightly lower, potentially aiding permeability.

**2. TPSA:** Both ligands have TPSA values around 65, which is slightly above the optimal <90 for CNS targets but still reasonable.

**3. logP:** Ligand A (3.695) is within the optimal range (1-3). Ligand B (0.381) is significantly *below* the optimal range, which is a major concern for CNS penetration. Low logP often translates to poor membrane permeability.

**4. H-Bond Donors:** Ligand A (1) and Ligand B (0) are both acceptable.

**5. H-Bond Acceptors:** Ligand A (5) and Ligand B (4) are both acceptable.

**6. QED:** Both ligands have good QED scores (A: 0.591, B: 0.779), indicating good drug-like properties.

**7. DILI:** Ligand A (77.743) has a higher DILI risk than Ligand B (42.575). This is a negative for Ligand A.

**8. BBB:** Ligand A (58.976) has a lower BBB penetration percentile than Ligand B (62.195). While neither is *excellent* (>70), Ligand B is better.

**9. Caco-2 Permeability:** Ligand A (-5.331) has poor Caco-2 permeability, while Ligand B (-4.517) is slightly better. Both are negative values, indicating low permeability.

**10. Aqueous Solubility:** Ligand A (-3.914) and Ligand B (-1.25) both have negative solubility values, suggesting poor solubility.

**11. hERG Inhibition:** Ligand A (0.846) has a slightly higher hERG risk than Ligand B (0.206), but both are relatively low.

**12. Microsomal Clearance:** Ligand A (61.007) has higher microsomal clearance than Ligand B (30.622), indicating lower metabolic stability.

**13. In vitro Half-Life:** Ligand A (43.874) has a longer half-life than Ligand B (-1.986).

**14. P-gp Efflux:** Ligand A (0.738) shows moderate P-gp efflux, while Ligand B (0.066) has very low P-gp efflux, which is highly desirable for CNS penetration.

**15. Binding Affinity:** Ligand A (-8.6 kcal/mol) has a significantly stronger binding affinity than Ligand B (-7.6 kcal/mol). This is a substantial advantage for Ligand A.

**Overall Assessment:**

Despite the better binding affinity of Ligand A, its significantly lower logP and higher DILI risk are major drawbacks. The low logP is particularly concerning for a CNS target like DRD2, as it will likely hinder BBB penetration. Ligand B, while having a weaker affinity, has a more favorable logP, lower DILI, better P-gp efflux, and better BBB penetration. The affinity difference of 1 kcal/mol, while noticeable, is likely outweighed by the ADME advantages of Ligand B, especially for a CNS target.

Output:
1
2025-04-17 05:23:45,469 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (344.455 and 348.491 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (58.64) is excellent, well below the 90 A^2 threshold for CNS targets. Ligand B (86.88) is still reasonable but less optimal.

**logP:** Ligand A (1.283) is within the optimal 1-3 range. Ligand B (2.632) is also within range, but approaching the higher end.

**H-Bond Donors/Acceptors:** Ligand A (HBD=1, HBA=3) and Ligand B (HBD=3, HBA=3) both have acceptable numbers of H-bond donors and acceptors.

**QED:** Ligand A (0.782) has a better QED score than Ligand B (0.641), indicating a more drug-like profile.

**DILI:** Ligand A (32.493) has a significantly lower DILI risk than Ligand B (12.369), which is a substantial advantage.

**BBB:** Ligand A (78.79) has a much better BBB penetration percentile than Ligand B (67.701). This is critical for a CNS target like DRD2.

**Caco-2 Permeability:** Ligand A (-4.52) and Ligand B (-5.221) both have negative Caco-2 values, which is unusual and suggests poor permeability. However, the scale is not specified, so it's difficult to interpret.

**Aqueous Solubility:** Ligand A (-3.079) and Ligand B (-2.42) both have negative solubility values, indicating poor solubility. Again, the scale is not specified.

**hERG:** Ligand A (0.508) has a slightly higher hERG risk than Ligand B (0.302), but both are relatively low.

**Microsomal Clearance:** Ligand A (28.854) has a lower microsomal clearance than Ligand B (30.212), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (-7.326) has a significantly longer in vitro half-life than Ligand B (-32.846).

**P-gp Efflux:** Ligand A (0.157) has lower P-gp efflux liability than Ligand B (0.046), which is favorable for CNS penetration.

**Binding Affinity:** Ligand B (-7.7 kcal/mol) has a slightly better binding affinity than Ligand A (-8.4 kcal/mol). While affinity is important, the difference of 0.7 kcal/mol isn't substantial enough to outweigh the other significant advantages of Ligand A.

**Overall:** Ligand A demonstrates a superior profile across multiple critical parameters for a CNS-targeting GPCR. It has better BBB penetration, lower DILI risk, better metabolic stability, longer half-life, and lower P-gp efflux. While Ligand B has slightly better binding affinity, the other advantages of Ligand A make it the more promising drug candidate.

Output:
0
2025-04-17 05:23:45,470 - INFO - Batch 194 complete. Total preferences: 3104
2025-04-17 05:23:45,470 - INFO - Processing batch 195/512...
2025-04-17 05:24:28,855 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (339.483 and 344.459 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (46.06) is excellent, well below the 90 A^2 threshold for CNS targets. Ligand B (67.23) is still reasonable, but higher, potentially impacting BBB penetration.

**3. logP:** Ligand A (4.218) is slightly high, potentially leading to solubility issues or off-target interactions. Ligand B (2.144) is within the optimal range of 1-3.

**4. H-Bond Donors:** Ligand A (2) and Ligand B (1) both meet the criteria of <=5.

**5. H-Bond Acceptors:** Ligand A (2) and Ligand B (4) both meet the criteria of <=10.

**6. QED:** Both ligands have acceptable QED values (0.729 and 0.609, both >=0.5).

**7. DILI:** Both ligands have low DILI risk (27.918 and 30.981, both <40).

**8. BBB:** Ligand A shines with a BBB percentile of 96.782, excellent for a CNS target. Ligand B's BBB (74.758) is good, but significantly lower than Ligand A.

**9. Caco-2:** Ligand A (-4.675) and Ligand B (-5.114) both have negative values, indicating poor Caco-2 permeability. This is a concern for oral bioavailability.

**10. Solubility:** Ligand A (-4.031) and Ligand B (-1.03) both have negative values, indicating poor solubility.

**11. hERG:** Both ligands have low hERG risk (0.902 and 0.446).

**12. Cl_mic:** Ligand A (48.357) has a higher microsomal clearance than Ligand B (26.313), suggesting lower metabolic stability.

**13. t1/2:** Ligand B (-18.565) has a negative half-life, which is concerning. Ligand A (45.691) has a more reasonable in vitro half-life.

**14. Pgp:** Both ligands have low Pgp efflux liability (0.692 and 0.102).

**15. Binding Affinity:** Both ligands have excellent binding affinities (-9.0 and -8.2 kcal/mol). The difference is 0.8 kcal/mol, which is not enough to overcome the other ADME differences.

**Overall Assessment:**

Ligand A is superior due to its significantly better BBB penetration (96.782 vs 74.758) and more reasonable in vitro half-life (45.691 vs -18.565). While Ligand A's logP is slightly higher, the strong BBB penetration is critical for a CNS-targeting drug. Ligand B's negative half-life is a major red flag. The small difference in binding affinity is not enough to overcome the other deficiencies of Ligand B.

Output:
1
2025-04-17 05:24:28,856 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (352.387 and 352.475 Da) fall comfortably within the ideal 200-500 Da range.

**TPSA:** Ligand A (117.87) is slightly above the optimal <90 for CNS targets, but still reasonable. Ligand B (81.08) is excellent, well below 90.

**logP:** Ligand A (0.166) is quite low, potentially hindering permeability. Ligand B (1.314) is within the optimal 1-3 range. This is a significant advantage for Ligand B.

**H-Bond Donors/Acceptors:** Ligand A has 3 HBD and 6 HBA, acceptable values. Ligand B has 2 HBD and 4 HBA, also acceptable and slightly more favorable.

**QED:** Both ligands have good QED scores (0.574 and 0.707), indicating good drug-like properties.

**DILI:** Ligand A (49.477) has a moderate DILI risk, while Ligand B (19.698) has a very low DILI risk. This favors Ligand B.

**BBB:** Ligand A (52.268) has a moderate BBB penetration, which is not ideal for a CNS target. Ligand B (65.839) has a significantly better BBB penetration, exceeding 60%. This is a major advantage for Ligand B.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.886 and -4.639). This is unusual and suggests poor permeability based on this metric. However, the absolute values are similar.

**Aqueous Solubility:** Both ligands have negative solubility values (-1.655 and -1.464), which is also unusual and suggests poor solubility. Again, the values are similar.

**hERG:** Both ligands have low hERG inhibition liability (0.209 and 0.322), which is good.

**Microsomal Clearance:** Ligand A (41.744) has a higher microsomal clearance than Ligand B (8.009), indicating lower metabolic stability. Ligand B is significantly better here.

**In vitro Half-Life:** Both ligands have similar in vitro half-lives (4.047 and 4.843 hours).

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.093 and 0.131), which is favorable for CNS penetration.

**Binding Affinity:** Ligand B (-7.7 kcal/mol) has a slightly better binding affinity than Ligand A (-7.4 kcal/mol). While the difference is small (0.3 kcal/mol), it's enough to be considered, especially given the other advantages of Ligand B.

**Overall:** Ligand B is clearly superior. It has a better logP, significantly lower DILI risk, substantially better BBB penetration, lower microsomal clearance, and slightly better binding affinity. While the Caco-2 and solubility values are concerning for both, the other advantages of Ligand B, particularly its CNS-relevant properties, make it the more promising candidate.

Output:
1
2025-04-17 05:24:28,856 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B based on the provided guidelines, prioritizing GPCR-specific properties (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (346.39 and 348.53 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (105.82) is higher than the preferred <90 for CNS targets, while Ligand B (41.57) is well within the range. This is a significant advantage for Ligand B.

**logP:** Ligand A (1.484) is within the optimal 1-3 range. Ligand B (3.663) is at the higher end, but still acceptable.

**H-Bond Donors/Acceptors:** Ligand A has 2 HBD and 6 HBA, which are reasonable. Ligand B has 1 HBD and 3 HBA, also reasonable.

**QED:** Both ligands have similar QED values (0.812 and 0.771), indicating good drug-likeness.

**DILI:** Ligand A (50.14) has a moderate DILI risk, while Ligand B (13.80) has a very low risk. This favors Ligand B.

**BBB:** Ligand A (49.79) has a poor BBB penetration percentile, which is a major drawback for a CNS target like DRD2. Ligand B (89.61) has excellent BBB penetration. This is a critical advantage for Ligand B.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.144 and -4.729), which is unusual and suggests poor permeability. However, the scale is not clearly defined, so it's difficult to interpret.

**Aqueous Solubility:** Both ligands have negative solubility values (-2.436 and -3.5), which is also concerning. Again, the scale is unclear.

**hERG:** Ligand A (0.062) has a very low hERG risk, while Ligand B (0.702) has a slightly elevated risk, but still relatively low.

**Microsomal Clearance:** Ligand A (-14.38) has a negative clearance, which is not physically possible. This is likely an error in the data. Ligand B (75.84) has a high clearance, indicating rapid metabolism.

**In vitro Half-Life:** Ligand A (25.43) has a moderate half-life. Ligand B (7.06) has a short half-life.

**P-gp Efflux:** Ligand A (0.029) has very low P-gp efflux, which is favorable for CNS penetration. Ligand B (0.458) has moderate P-gp efflux.

**Binding Affinity:** Ligand A (-8.9 kcal/mol) has significantly stronger binding affinity than Ligand B (-0.0 kcal/mol). This is a substantial advantage for Ligand A.

**Overall Assessment:**

Despite the strong binding affinity of Ligand A, its poor BBB penetration and questionable clearance data are major concerns. Ligand B, while having weaker affinity, exhibits excellent BBB penetration, low DILI risk, and acceptable logP and TPSA values. The negative values for Caco-2 and solubility are concerning for both, but the CNS target makes BBB penetration the most critical factor. The large difference in binding affinity is a concern, but can potentially be overcome with further optimization.

Output:
1
2025-04-17 05:24:28,856 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (344.46 and 351.41 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (68.44) is significantly better than Ligand B (120.58). For CNS targets, TPSA should be <= 90, and A is comfortably within this range, while B exceeds it.

**logP:** Ligand A (1.643) is within the optimal 1-3 range. Ligand B (-0.533) is slightly below 1, which *could* hinder permeation, though not drastically.

**H-Bond Donors/Acceptors:** Ligand A (HBD=2, HBA=3) and Ligand B (HBD=3, HBA=7) both have reasonable values, within the suggested limits.

**QED:** Both ligands have similar QED values (0.609 and 0.607), indicating good drug-likeness.

**DILI:** Ligand A (21.95) has a much lower DILI risk than Ligand B (46.22), which is preferable. Both are below the concerning threshold of 60.

**BBB:** This is critical for a CNS target like DRD2. Ligand A (51.11) is considerably better than Ligand B (31.21). A value >70 is desirable, but A is a better starting point.

**Caco-2 Permeability:** Both have negative values (-5.609 and -5.276), which is unusual and suggests poor permeability. However, these values are on a scale where negative values are possible and don't necessarily disqualify a compound outright.

**Aqueous Solubility:** Both have negative values (-1.27 and -1.505), suggesting poor solubility. This could be a formulation challenge.

**hERG:** Both ligands have very low hERG inhibition liability (0.182 and 0.048), which is excellent.

**Microsomal Clearance:** Ligand A (-5.954) shows better metabolic stability (lower clearance) than Ligand B (-9.832).

**In vitro Half-Life:** Ligand A (-0.1) has a very short half-life, which is concerning. Ligand B (4.522) is much better.

**P-gp Efflux:** Both have very low P-gp efflux liability (0.035 and 0.02).

**Binding Affinity:** Ligand B (-8.2 kcal/mol) has a significantly stronger binding affinity than Ligand A (-0.0 kcal/mol). This is a substantial advantage. A difference of >1.5 kcal/mol can often outweigh other ADME drawbacks.

**Overall Assessment:**

While Ligand A has better TPSA, DILI, and metabolic stability, the overwhelmingly stronger binding affinity of Ligand B (-8.2 vs -0.0 kcal/mol) is the decisive factor. The lower BBB penetration and higher TPSA of Ligand B are concerns, but these could potentially be addressed through further optimization. The significantly improved affinity suggests a higher probability of achieving efficacy. The half-life of Ligand B is also much better than that of Ligand A.



Output:
1
2025-04-17 05:24:28,856 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (343.427 Da) is slightly preferred as it's closer to the lower end, potentially aiding permeability.

**TPSA:** Ligand A (71.53) is significantly better than Ligand B (117.28). For CNS targets, TPSA should be <= 90, and A comfortably meets this, while B exceeds it. This is a major advantage for A.

**logP:** Ligand A (1.946) is within the optimal range (1-3). Ligand B (-2.544) is quite low, potentially hindering membrane permeability and CNS penetration.

**H-Bond Donors/Acceptors:** Ligand A (HBD=1, HBA=4) and Ligand B (HBD=2, HBA=7) both have reasonable values.

**QED:** Ligand A (0.887) has a much better QED score than Ligand B (0.429), indicating a more drug-like profile.

**DILI:** Both ligands have low DILI risk (A: 37.728, B: 32.067), which is good.

**BBB:** Ligand A (66.499) has a better BBB percentile than Ligand B (54.246), although ideally, we want >70 for CNS targets. A is closer to this threshold.

**Caco-2:** Ligand A (-4.816) and Ligand B (-5.553) both have negative Caco-2 values, which is unusual and suggests poor permeability. This is a concern for both.

**Solubility:** Ligand A (-2.011) and Ligand B (-0.563) both have negative solubility values, indicating poor aqueous solubility. This is a concern for both.

**hERG:** Both ligands have very low hERG risk (A: 0.221, B: 0.051), which is excellent.

**Microsomal Clearance:** Ligand A (47.824) has a higher (worse) microsomal clearance than Ligand B (3.192), suggesting faster metabolism. This favors B.

**In vitro Half-Life:** Ligand B (-47.561) has a very negative half-life, which is concerning and likely indicates very rapid degradation. Ligand A (15.758) is much better.

**Pgp Efflux:** Both ligands have low Pgp efflux liability (A: 0.099, B: 0.001), which is good for CNS penetration.

**Binding Affinity:** Ligand A (-8.8 kcal/mol) has a significantly stronger binding affinity than Ligand B (-6.1 kcal/mol). This is a substantial advantage for A, potentially outweighing some of its ADME drawbacks. A difference of >1.5 kcal/mol is considered significant.

**Overall Assessment:**

Ligand A is the stronger candidate. While both have issues with Caco-2 and solubility, A excels in crucial areas for a CNS-targeting GPCR ligand: TPSA, logP, QED, BBB, and, most importantly, binding affinity. The significantly stronger binding affinity of A (-8.8 vs -6.1 kcal/mol) is a major advantage. Although B has better metabolic stability (lower Cl_mic), A's superior affinity and more favorable CNS properties make it the more promising candidate.

Output:
1
2025-04-17 05:24:28,856 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B based on the provided guidelines, prioritizing GPCR-specific properties (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (336.435 Da) is slightly lower, which could be beneficial for permeability.

**TPSA:** Ligand A (40.62) is excellent for CNS penetration, well below the 90 A^2 threshold. Ligand B (72.88) is higher, but still reasonable, though less optimal for CNS targets.

**logP:** Ligand A (3.002) is optimal. Ligand B (1.378) is a bit low, potentially hindering permeation.

**H-Bond Donors/Acceptors:** Ligand A (0 HBD, 2 HBA) is very favorable. Ligand B (2 HBD, 4 HBA) is acceptable, but slightly higher counts could impact permeability.

**QED:** Both ligands have good QED scores (A: 0.626, B: 0.691), indicating drug-likeness.

**DILI:** Ligand A (25.785) has a very low DILI risk. Ligand B (8.996) also has a low DILI risk, but slightly higher than A.

**BBB:** This is a critical parameter for DRD2. Ligand A (92.012) has excellent BBB penetration potential. Ligand B (42.226) is significantly lower, which is a major drawback for a CNS target.

**Caco-2 Permeability:** Ligand A (-4.352) has poor Caco-2 permeability. Ligand B (-4.953) is also poor, but slightly worse than A.

**Aqueous Solubility:** Both ligands have poor aqueous solubility (-3.338 and -1.662 respectively).

**hERG:** Both ligands have low hERG risk (0.457 and 0.508 respectively).

**Microsomal Clearance:** Ligand A (25.502) has higher clearance than Ligand B (18.633), suggesting lower metabolic stability.

**In vitro Half-Life:** Ligand B (-1.161) has a slightly better (less negative) in vitro half-life than Ligand A (-17.26), indicating better stability.

**P-gp Efflux:** Ligand A (0.256) has lower P-gp efflux, which is beneficial for CNS penetration. Ligand B (0.088) has even lower P-gp efflux, which is even better.

**Binding Affinity:** Ligand A (-8.9 kcal/mol) has significantly stronger binding affinity than Ligand B (0.0 kcal/mol). This is a substantial advantage.

**Overall Assessment:**

Despite Ligand A's poor Caco-2 permeability and higher clearance, its *significantly* superior binding affinity (-8.9 vs 0.0 kcal/mol) and excellent BBB penetration (92.012%) outweigh its drawbacks. The strong binding affinity suggests a lower dose could be effective, potentially mitigating solubility issues. Ligand B's low logP and poor BBB penetration are major concerns for a CNS-targeting drug.

Output:
1
2025-04-17 05:24:28,856 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (340.423 and 353.463 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (67.43) is significantly better than Ligand B (87.74). For CNS targets, we want TPSA <= 90, and A is comfortably within that, while B is approaching the upper limit.

**logP:** Ligand A (3.377) is within the optimal 1-3 range. Ligand B (0.847) is below 1, which could hinder permeation.

**H-Bond Donors/Acceptors:** Both have acceptable HBD (2) and HBA (3 for A, 4 for B) counts, well within the guidelines.

**QED:** Both ligands have reasonable QED scores (0.877 and 0.602), indicating good drug-like properties.

**DILI:** Ligand A (81.311) has a higher DILI risk than Ligand B (23.614). This is a significant negative for A.

**BBB:** Ligand B (67.507) has a better BBB penetration percentile than Ligand A (53.199). While both are not ideal (>70 desirable), B is better.

**Caco-2 Permeability:** Ligand A (-4.586) has a worse Caco-2 permeability than Ligand B (-4.894). Lower values indicate poorer permeability.

**Aqueous Solubility:** Ligand A (-4.882) has a worse aqueous solubility than Ligand B (-1.147).

**hERG:** Ligand A (0.698) has a slightly higher hERG risk than Ligand B (0.091). Lower is better here.

**Microsomal Clearance:** Ligand A (70.514) has a higher microsomal clearance than Ligand B (36.277), indicating lower metabolic stability.

**In vitro Half-Life:** Ligand B (-6.431) has a longer in vitro half-life than Ligand A (-12.485).

**P-gp Efflux:** Ligand A (0.272) has a lower P-gp efflux liability than Ligand B (0.021), which is favorable for CNS penetration.

**Binding Affinity:** Ligand B (-7.5) has a significantly stronger binding affinity than Ligand A (-9.8). This is a crucial advantage, exceeding the 1.5 kcal/mol threshold.

**Overall Assessment:**

Ligand B is the stronger candidate. While its BBB isn't ideal, its significantly better binding affinity (-7.5 vs -9.8 kcal/mol), lower DILI risk, better metabolic stability (lower Cl_mic, longer t1/2), and better solubility outweigh the slightly lower BBB and higher P-gp efflux. Ligand A's high DILI risk and poorer metabolic stability are major concerns. The TPSA and logP values of Ligand A are better, but the affinity difference is substantial and more important for a GPCR target.

Output:
1
2025-04-17 05:24:28,857 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (402.248 Da) is slightly higher, but acceptable. Ligand B (348.403 Da) is also good.

**2. TPSA:** Ligand A (73.22) is excellent for CNS penetration, falling well below the 90 A^2 threshold. Ligand B (84.74) is still reasonable but less optimal.

**3. logP:** Ligand A (3.858) is at the upper end of the optimal range (1-3) but still acceptable. Ligand B (1.694) is on the lower side, which *could* indicate permeability issues, but isn't a hard disqualifier.

**4. H-Bond Donors:** Ligand A (1) and Ligand B (0) are both within the acceptable limit of <=5.

**5. H-Bond Acceptors:** Ligand A (5) and Ligand B (6) are both within the acceptable limit of <=10.

**6. QED:** Both ligands have similar QED values (0.673 and 0.611), indicating good drug-like properties.

**7. DILI:** Ligand A (98.682) has a very high DILI risk, which is a significant concern. Ligand B (78.945) is much better, indicating a lower risk of liver injury.

**8. BBB:** Ligand A (80.962) has good BBB penetration, exceeding the 70% threshold for CNS targets. Ligand B (95.192) is *excellent* with very high predicted BBB penetration.

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.754 and -4.274), which is unusual and suggests poor permeability. This is a significant red flag for both. However, these values are often unreliable and can be misleading.

**10. Aqueous Solubility:** Both ligands have very poor aqueous solubility (-5.72 and -3.305). This is a major formulation challenge.

**11. hERG Inhibition:** Ligand A (0.606) has a slightly elevated hERG risk, while Ligand B (0.061) has a very low risk.

**12. Microsomal Clearance:** Ligand A (130.734) has higher microsomal clearance, suggesting faster metabolism. Ligand B (64.076) has lower clearance, indicating better metabolic stability.

**13. In vitro Half-Life:** Ligand A (95.559) has a longer half-life, which is desirable. Ligand B (14.38) has a very short half-life.

**14. P-gp Efflux:** Ligand A (0.735) has moderate P-gp efflux, while Ligand B (0.058) has very low P-gp efflux, which is highly desirable for CNS penetration.

**15. Binding Affinity:** Ligand A (-8.3 kcal/mol) has a significantly stronger binding affinity than Ligand B (-7.5 kcal/mol). This 1.8 kcal/mol difference is substantial and could outweigh some of the ADME drawbacks.

**Overall Assessment:**

Despite the poor solubility and Caco-2 values for both, Ligand A's superior binding affinity and acceptable BBB penetration are attractive. *However*, the extremely high DILI risk is a major concern and likely disqualifies it. Ligand B, while having a weaker affinity, has a much better safety profile (lower DILI, lower hERG, lower P-gp efflux) and excellent BBB penetration. The lower clearance and shorter half-life are drawbacks, but potentially addressable through structural modifications.

Considering the GPCR-specific priorities and the overall risk-benefit profile, Ligand B is the more viable drug candidate.

Output:
1
2025-04-17 05:24:28,857 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (347.503 Da) is slightly lower, which could be advantageous for permeability.

**TPSA:** Ligand A (63.13) is slightly higher than Ligand B (58.2). Both are below the 90 A^2 threshold desirable for CNS targets, but Ligand B is closer to the optimal range.

**logP:** Both ligands have good logP values (A: 3.175, B: 2.988), falling within the 1-3 range.

**H-Bond Donors/Acceptors:** Both have 2 HBD and 3 HBA, which are within acceptable limits.

**QED:** Ligand A (0.674) has a better QED score than Ligand B (0.482), indicating better overall drug-likeness.

**DILI:** Both ligands have low DILI risk (A: 25.204, B: 29.624), well below the 40 threshold.

**BBB:** Ligand B (83.443) has a significantly higher BBB percentile than Ligand A (70.919). This is a crucial advantage for a CNS target like DRD2.

**Caco-2 Permeability:** Ligand A (-4.758) has a worse Caco-2 permeability than Ligand B (-5.094). Lower values indicate poorer permeability.

**Aqueous Solubility:** Both have very poor aqueous solubility (-3.218 and -3.858). This is a concern for both, but could be mitigated with formulation strategies.

**hERG:** Both ligands have low hERG inhibition liability (A: 0.696, B: 0.622).

**Microsomal Clearance:** Ligand A (48.947) has lower microsomal clearance than Ligand B (56.85), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (13.759) has a longer in vitro half-life than Ligand B (-5.929). This is a significant advantage.

**P-gp Efflux:** Ligand A (0.394) has lower P-gp efflux liability than Ligand B (0.151), suggesting better CNS exposure.

**Binding Affinity:** Ligand B (-8.0 kcal/mol) has a slightly better binding affinity than Ligand A (-7.7 kcal/mol). This difference, while not huge, is meaningful.

**Overall Assessment:**

Ligand B excels in BBB penetration and binding affinity, which are paramount for a CNS GPCR target. While Ligand A has better QED, metabolic stability, half-life, and P-gp efflux, the superior BBB and affinity of Ligand B outweigh these advantages. The solubility is a concern for both, but can potentially be addressed.

Output:
1
2025-04-17 05:24:28,857 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (474.172 Da) is at the higher end, while Ligand B (348.447 Da) is closer to the middle.

**TPSA:** Ligand A (59.81) is better than Ligand B (85.57). For CNS targets, we want TPSA <= 90, both are within this range, but A is preferable.

**logP:** Ligand A (4.794) is high, potentially leading to solubility issues and off-target effects. Ligand B (1.561) is optimal. This is a significant advantage for B.

**H-Bond Donors/Acceptors:** Both have acceptable HBD (1) and HBA (4 for A, 5 for B) counts.

**QED:** Both ligands have good QED scores (0.655 and 0.836), indicating drug-like properties.

**DILI:** Ligand A (64.599) has a higher DILI risk than Ligand B (15.122). This is a substantial advantage for B.

**BBB:** Ligand A (83.288) has a good BBB penetration percentile, exceeding the 70% threshold for CNS targets. Ligand B (59.248) is lower, which is a significant drawback for a CNS target like DRD2.

**Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and suggests poor permeability. However, the scale is not defined, so it is hard to interpret.

**Aqueous Solubility:** Both have negative solubility values, suggesting poor solubility. Again, the scale is not defined.

**hERG Inhibition:** Ligand A (0.537) has a slightly higher hERG inhibition risk than Ligand B (0.151).

**Microsomal Clearance:** Ligand A (42.336) has lower clearance than Ligand B (15.371), indicating better metabolic stability.

**In vitro Half-Life:** Ligand A (71.344) has a longer half-life than Ligand B (13.452).

**P-gp Efflux:** Ligand A (0.662) has lower P-gp efflux than Ligand B (0.015), which is favorable for CNS penetration.

**Binding Affinity:** Ligand A (-9.1 kcal/mol) has significantly stronger binding affinity than Ligand B (0.0 kcal/mol). This is a major advantage for A, potentially outweighing some of its ADME drawbacks.

**Overall Assessment:**

Ligand A has a much better binding affinity and better BBB penetration and P-gp efflux. However, its high logP, higher DILI risk, and questionable solubility are concerning. Ligand B has better ADME properties (logP, DILI, P-gp, hERG), but its binding affinity is extremely weak.

Given the importance of affinity for GPCR ligands, and the substantial difference in binding energy (-9.1 vs 0.0 kcal/mol), Ligand A is the more promising candidate *despite* its ADME liabilities. The strong binding could potentially be optimized through further medicinal chemistry efforts to improve its ADME profile. The weak binding of Ligand B makes it unlikely to be a viable starting point.

Output:
1
2025-04-17 05:24:28,857 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (348.447 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (78.68) and Ligand B (77.32) are both below the 90 Angstroms threshold desirable for CNS targets, which is excellent.

**3. logP:** Ligand A (0.912) is slightly below the optimal 1-3 range, potentially impacting permeability. Ligand B (2.103) is within the optimal range.

**4. H-Bond Donors:** Ligand A (1) and Ligand B (0) are both acceptable, below the threshold of 5.

**5. H-Bond Acceptors:** Ligand A (5) and Ligand B (6) are both acceptable, below the threshold of 10.

**6. QED:** Ligand A (0.827) has a higher QED score than Ligand B (0.615), indicating a more drug-like profile overall.

**7. DILI:** Ligand A (11.128) has a significantly lower DILI risk than Ligand B (48.701), which is a major advantage.

**8. BBB:** Ligand A (71.772) has a better BBB percentile than Ligand B (51.066), which is crucial for a CNS target like DRD2.

**9. Caco-2:** Both ligands have negative Caco-2 values (-4.887 and -4.331), which is unusual and suggests poor permeability. However, these values are on a scale where negative values are possible and don't necessarily disqualify the compounds.

**10. Solubility:** Ligand A (-0.756) and Ligand B (-2.975) both have negative solubility values, suggesting poor aqueous solubility. This could be a formulation challenge.

**11. hERG:** Both ligands have very low hERG inhibition risk (0.056 and 0.097).

**12. Cl_mic:** Ligand A (4.158) has a much lower microsomal clearance than Ligand B (98.404), indicating better metabolic stability.

**13. t1/2:** Ligand A (4.925) has a positive in vitro half-life, while Ligand B (-13.979) has a negative value, which is concerning.

**14. Pgp:** Both ligands have very low P-gp efflux liability (0.006 and 0.066).

**15. Binding Affinity:** Ligand B (-7.8) has a slightly better binding affinity than Ligand A (-7.6), but the difference is small (0.2 kcal/mol).

**Overall Assessment:**

Ligand A is the more promising candidate. While Ligand B has slightly better binding affinity, Ligand A excels in crucial ADME properties, particularly DILI risk, BBB penetration, metabolic stability (lower Cl_mic), and in vitro half-life. The slightly lower logP of Ligand A is a minor concern that could potentially be addressed through further optimization, but the significant advantages in safety (DILI) and CNS penetration (BBB) outweigh this drawback. The negative solubility and Caco-2 values are concerning for both, but could be addressed with formulation strategies.

Output:
0
2025-04-17 05:24:28,858 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (362.417 and 363.477 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (78.87) is much better than Ligand B (21.06). For a CNS target like DRD2, TPSA should be <=90, and lower is preferable. Ligand A is comfortably within this range, while Ligand B is exceptionally low, which *could* indicate a lack of necessary interactions.

**logP:** Ligand A (1.315) is optimal, while Ligand B (4.865) is high. While logP < 4 is generally acceptable, 4.865 is pushing the upper limit and could lead to solubility issues and off-target binding.

**H-Bond Donors/Acceptors:** Ligand A has 2 HBD and 4 HBA, which are reasonable. Ligand B has 0 HBD and 4 HBA, also acceptable, but the lack of HBDs might affect solubility.

**QED:** Ligand A (0.747) has a better QED score than Ligand B (0.57), indicating a more drug-like profile.

**DILI:** Ligand A (14.696) has a significantly lower DILI risk than Ligand B (46.064). This is a major advantage for Ligand A.

**BBB:** Ligand B (92.71) has a much higher BBB penetration percentile than Ligand A (63.978). This is a critical factor for a CNS target, and Ligand B excels here.

**Caco-2 Permeability:** Ligand A (-4.93) has poor Caco-2 permeability, while Ligand B (-5.039) is similarly poor. This is not ideal, but not a dealbreaker if BBB penetration is high.

**Aqueous Solubility:** Ligand A (-1.162) has slightly better aqueous solubility than Ligand B (-4.026).

**hERG Inhibition:** Ligand A (0.453) has a lower hERG inhibition liability than Ligand B (0.976), which is favorable.

**Microsomal Clearance:** Ligand A (-12.524) has a much lower (better) microsomal clearance than Ligand B (54.019), indicating greater metabolic stability.

**In vitro Half-Life:** Ligand B (65.435) has a significantly longer in vitro half-life than Ligand A (-6.489). This is a significant advantage for Ligand B.

**P-gp Efflux:** Ligand A (0.047) has lower P-gp efflux liability than Ligand B (0.909), which is beneficial for CNS exposure.

**Binding Affinity:** Ligand B (-7.5 kcal/mol) has a slightly better binding affinity than Ligand A (-8.1 kcal/mol). While the difference is not huge, it is still a positive for Ligand B.

**Overall Assessment:**

Ligand A has a better overall ADME profile (lower DILI, better solubility, lower hERG, better metabolic stability, lower P-gp efflux). However, Ligand B has significantly better BBB penetration and a slightly better binding affinity, and a longer half-life. Given the CNS target (DRD2), BBB penetration is paramount. The slightly better affinity of Ligand B, coupled with its excellent BBB score, outweighs the ADME drawbacks, especially considering optimization could potentially improve those parameters.

Output:
1
2025-04-17 05:24:28,858 - INFO - Reasoning:

Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (361.785 and 347.459 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (113.68) is borderline for CNS targets, slightly above the preferred <90, but potentially acceptable. Ligand B (66.65) is excellent, well below 90, indicating good potential for CNS penetration.

**3. logP:** Both ligands have good logP values (2.301 and 2.902), falling within the optimal 1-3 range.

**4. H-Bond Donors:** Ligand A has 4 HBD, acceptable. Ligand B has 0 HBD, also acceptable.

**5. H-Bond Acceptors:** Both ligands have 4 HBA, which is within the acceptable limit of <=10.

**6. QED:** Both ligands have reasonable QED values (0.669 and 0.711), indicating good drug-like properties.

**7. DILI:** Ligand A (79.062) has a higher DILI risk than Ligand B (48.313). This is a significant drawback for Ligand A.

**8. BBB:** Ligand B (79.76) has a considerably better BBB percentile than Ligand A (63.048). This is a critical advantage for a CNS target like DRD2.

**9. Caco-2:** Both have negative Caco-2 values, which is unusual and suggests potential issues with permeability prediction. This is a data quality concern, but we'll proceed assuming it indicates poor permeability.

**10. Solubility:** Both have negative solubility values, which is also unusual. This suggests poor aqueous solubility.

**11. hERG:** Both ligands have very low hERG inhibition liability (0.352 and 0.262), which is excellent.

**12. Cl_mic:** Ligand A (-22.983) has a *negative* microsomal clearance, which is impossible. This is a data error. Ligand B (76.92) has a high microsomal clearance, indicating rapid metabolism.

**13. t1/2:** Ligand A (53.463) has a better in vitro half-life than Ligand B (-20.072). However, the negative value for Ligand B is a data error.

**14. Pgp:** Both ligands have very low Pgp efflux liability (0.065 and 0.457), which is favorable for CNS penetration.

**15. Binding Affinity:** Ligand A (-9.7 kcal/mol) has a significantly stronger binding affinity than Ligand B (-7.8 kcal/mol). This is a substantial advantage, potentially outweighing some ADME concerns.

**Overall Assessment:**

Despite the questionable Caco-2 and solubility data, the most significant factors are the binding affinity and BBB penetration. Ligand A has a much stronger binding affinity, which is crucial for GPCR targets. However, Ligand B has a much better BBB percentile and lower DILI risk. The negative values for Cl_mic and t1/2 for Ligand B are data errors and make it difficult to assess its metabolic stability. The negative Cl_mic for Ligand A is also a data error.

Considering the GPCR-specific priorities and the substantial affinity advantage of Ligand A, I would tentatively favor Ligand A, *assuming the negative Cl_mic value is a data error*. The stronger binding affinity is likely to be more impactful than the slightly lower BBB and higher DILI risk, especially if further optimization can address those issues. However, the data quality issues are concerning and would require verification.

Output:
1
2025-04-17 05:24:28,858 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (343.475 and 368.478 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (62.19) is significantly better than Ligand B (67.35) as both are below the 90 A^2 threshold for CNS targets.

**logP:** Ligand A (4.253) is slightly higher than the optimal range (1-3), while Ligand B (2.048) is within the optimal range. Higher logP can sometimes lead to off-target effects, but is less concerning than very low logP.

**H-Bond Donors/Acceptors:** Ligand A (2 HBD, 4 HBA) and Ligand B (1 HBD, 6 HBA) both have acceptable numbers of H-bond donors and acceptors.

**QED:** Ligand A (0.753) has a better QED score than Ligand B (0.587), indicating a more drug-like profile.

**DILI:** Ligand B (47.654) has a much lower DILI risk than Ligand A (63.862), which is a significant advantage.

**BBB:** Ligand B (77.084) has a considerably better BBB penetration percentile than Ligand A (68.554). This is crucial for a CNS target like DRD2.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.85 and -4.986), which is unusual and suggests poor permeability. This is a significant concern for both.

**Aqueous Solubility:** Both ligands exhibit poor aqueous solubility (-4.768 and -3.321).

**hERG Inhibition:** Ligand A (0.733) has a slightly higher hERG inhibition risk than Ligand B (0.479), but both are relatively low.

**Microsomal Clearance:** Both ligands have similar microsomal clearance values (58.554 and 57.641 mL/min/kg), suggesting comparable metabolic stability.

**In vitro Half-Life:** Ligand B (3.245 hours) has a significantly shorter half-life than Ligand A (129.704 hours). This is a substantial advantage for Ligand A.

**P-gp Efflux:** Ligand A (0.548) has lower P-gp efflux liability than Ligand B (0.077), which is favorable for CNS penetration.

**Binding Affinity:** Ligand B (-8.7 kcal/mol) has a slightly better binding affinity than Ligand A (-8.3 kcal/mol). While the difference is not huge, it is still a factor.

**Overall Assessment:**

Ligand B excels in BBB penetration, DILI risk, and binding affinity, which are critical for a CNS GPCR target. Ligand A has a better QED score, longer half-life, and lower P-gp efflux. However, the poor Caco-2 permeability for both is a major concern. The superior BBB and DILI profile of Ligand B, combined with its slightly better affinity, outweigh the advantages of Ligand A, despite the shorter half-life. The longer half-life of Ligand A could be addressed through structural modifications, but improving BBB penetration is often more challenging.

Output:
1
2025-04-17 05:24:28,858 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (338.37) is slightly better, being closer to the lower end, which can aid permeability.

**TPSA:** Ligand A (82.18) is excellent, well below the 90 A^2 threshold for CNS targets. Ligand B (131.44) is higher, but still potentially acceptable, though less ideal.

**logP:** Ligand A (1.946) is optimal. Ligand B (-0.615) is below 1, which could hinder permeation. This is a significant drawback.

**H-Bond Donors/Acceptors:** Ligand A (HBD=1, HBA=6) is favorable. Ligand B (HBD=4, HBA=7) is also acceptable, but slightly higher, potentially impacting permeability.

**QED:** Ligand A (0.786) is very good, indicating strong drug-likeness. Ligand B (0.448) is lower, suggesting a less favorable drug-like profile.

**DILI:** Ligand A (74.331) has a higher DILI risk than Ligand B (41.877), but both are below the concerning threshold of 60.

**BBB:** Ligand A (71.501) has good BBB penetration, exceeding the 70% threshold. Ligand B (14.541) has very poor BBB penetration, a critical flaw for a CNS target.

**Caco-2:** Ligand A (-5.063) and Ligand B (-6.223) both have negative values, which is unusual and difficult to interpret without knowing the scale. However, lower values generally suggest poor permeability.

**Solubility:** Ligand A (-3.105) and Ligand B (-1.657) both have negative solubility values, which is also unusual. Lower values suggest poor solubility.

**hERG:** Ligand A (0.591) has a low hERG risk. Ligand B (0.053) has an even lower hERG risk, which is positive.

**Microsomal Clearance:** Ligand A (57.899) has moderate clearance. Ligand B (-9.408) has negative clearance which is unusual and likely an error.

**In vitro Half-Life:** Ligand A (6.94) has a moderate half-life. Ligand B (-11.524) has a negative half-life which is impossible and likely an error.

**Pgp Efflux:** Ligand A (0.306) has low Pgp efflux, which is good. Ligand B (0.01) has very low Pgp efflux, which is excellent.

**Binding Affinity:** Ligand A (-10 kcal/mol) has significantly stronger binding affinity than Ligand B (-7 kcal/mol). This is a substantial advantage.

**Overall Assessment:**

Ligand A is clearly superior. While its DILI risk is slightly higher, its excellent TPSA, optimal logP, good BBB penetration, strong binding affinity, and favorable Pgp efflux outweigh this concern. Ligand B suffers from poor logP, very poor BBB penetration, and questionable values for clearance and half-life. The significantly stronger binding affinity of Ligand A is a decisive factor, as a >3 kcal/mol advantage can often compensate for minor ADME issues.

Output:
0
2025-04-17 05:24:28,858 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B based on the provided guidelines, prioritizing GPCR-specific properties (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (362.426 and 343.475 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (57.69) is slightly higher than Ligand B (55.47), but both are below the 90 A^2 threshold desirable for CNS targets.

**logP:** Ligand A (2.815) is within the optimal 1-3 range. Ligand B (1.169) is at the lower end, potentially impacting permeability.

**H-Bond Donors/Acceptors:** Ligand A (0 HBD, 3 HBA) and Ligand B (1 HBD, 4 HBA) both have acceptable numbers of H-bond donors and acceptors.

**QED:** Both ligands have good QED scores (0.84 and 0.895), indicating good drug-like properties.

**DILI:** Ligand A (79.837) has a higher DILI risk than Ligand B (10.779). This is a significant negative for Ligand A.

**BBB:** Both ligands exhibit excellent BBB penetration (Ligand A: 85.033, Ligand B: 89.027).

**Caco-2 Permeability:** Both ligands have negative Caco-2 values, which is unusual. However, the magnitude suggests Ligand B (-4.94) has slightly better (less negative) permeability than Ligand A (-4.392).

**Aqueous Solubility:** Ligand A (-4.365) has slightly better solubility than Ligand B (-1.126).

**hERG:** Both ligands have similar hERG inhibition liability (0.802 and 0.804).

**Microsomal Clearance:** Ligand B (-6.906) has significantly lower (better) microsomal clearance than Ligand A (37.832), indicating greater metabolic stability.

**In vitro Half-Life:** Ligand B (-3.884) has a longer half-life than Ligand A (9.345).

**P-gp Efflux:** Ligand A (0.377) has lower P-gp efflux than Ligand B (0.051), which is favorable for CNS penetration.

**Binding Affinity:** Both ligands have excellent binding affinities (-9.6 and -8.9 kcal/mol). Ligand A is slightly stronger, but the difference is less than 1.5 kcal/mol.

**Overall Assessment:**

Ligand B is the stronger candidate. While Ligand A has a slightly better binding affinity and P-gp efflux, Ligand B significantly outperforms it in critical ADME properties: much lower DILI risk, significantly better metabolic stability (lower Cl_mic and longer t1/2), and slightly better Caco-2 permeability. The lower logP of Ligand B is a minor concern, but the overall profile is more favorable for development, especially considering the target is a CNS GPCR. The substantial difference in DILI risk is a key deciding factor.

Output:
1
2025-04-17 05:24:28,859 - INFO - Batch 195 complete. Total preferences: 3120
2025-04-17 05:24:28,859 - INFO - Processing batch 196/512...
2025-04-17 05:25:13,994 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (378.826 Da) is slightly higher than Ligand B (345.363 Da), but both are acceptable.

**TPSA:** Ligand A (57.26) is excellent for CNS penetration, being well below 90. Ligand B (118.17) is higher, but still potentially acceptable, though less ideal.

**logP:** Ligand A (2.838) is optimal (1-3). Ligand B (-0.862) is significantly lower, which could hinder membrane permeability and CNS penetration.

**H-Bond Donors/Acceptors:** Both ligands have 2 HBD and are within the acceptable range of <=5. Ligand A has 4 HBA, and Ligand B has 8 HBA, both are within the acceptable range of <=10.

**QED:** Both ligands have similar QED values (0.716 and 0.744), indicating good drug-likeness.

**DILI:** Ligand A (34.742) has a lower DILI risk than Ligand B (50.097), which is preferable.

**BBB:** Ligand A (70.997) has a much better BBB percentile than Ligand B (50.795). This is a critical advantage for a CNS target like DRD2.

**Caco-2 Permeability:** Both have negative values, indicating poor permeability. However, the scale is not specified, so it's difficult to interpret.

**Aqueous Solubility:** Both ligands have negative values, indicating poor solubility. Again, the scale is not specified.

**hERG Inhibition:** Ligand A (0.749) has a slightly higher hERG risk than Ligand B (0.049), but both are relatively low.

**Microsomal Clearance:** Ligand A (15.996) has higher clearance than Ligand B (-1.941), indicating lower metabolic stability. This is a negative for Ligand A.

**In vitro Half-Life:** Ligand A (33.182) has a longer half-life than Ligand B (-1.027), which is a positive for Ligand A.

**P-gp Efflux:** Ligand A (0.153) has lower P-gp efflux liability than Ligand B (0.01), which is preferable for CNS penetration.

**Binding Affinity:** Both ligands have the same binding affinity (-7.9 kcal/mol), which is excellent.

**Overall Assessment:**

Ligand A is superior due to its significantly better BBB penetration, lower DILI risk, and lower P-gp efflux. While it has slightly higher microsomal clearance, the benefits of better CNS exposure outweigh this drawback. Ligand B's low logP is a major concern, potentially limiting its ability to cross the blood-brain barrier despite its acceptable TPSA. The similar binding affinity makes the ADME properties the deciding factor.

Output:
1
2025-04-17 05:25:13,994 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (349.289 Da) is slightly lower, which is generally favorable for permeability.

**TPSA:** Ligand A (78.63) is better than Ligand B (47.36) as it is closer to the ideal range for CNS targets (<=90). Ligand B is quite low, which *could* indicate poor interactions with the target.

**logP:** Both ligands have good logP values (A: 2.533, B: 3.718), falling within the optimal 1-3 range. Ligand B is slightly higher, potentially increasing off-target interactions, but still acceptable.

**H-Bond Donors/Acceptors:** Both ligands have acceptable HBD (0) and HBA (A: 6, B: 4) counts, falling within the recommended limits.

**QED:** Both ligands have good QED scores (A: 0.623, B: 0.722), indicating a drug-like profile.

**DILI:** Ligand A (84.762) has a significantly higher DILI risk than Ligand B (23.769). This is a major concern for Ligand A.

**BBB:** Both ligands exhibit excellent BBB penetration (A: 85.731, B: 89.027), which is crucial for a CNS target like DRD2. Ligand B is slightly better.

**Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and suggests a potential issue with the data or modeling. However, we can still compare them relatively. Ligand A (-3.871) is slightly better than Ligand B (-4.793).

**Aqueous Solubility:** Both ligands have poor aqueous solubility (A: -4.29, B: -3.008). This could present formulation challenges.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (A: 0.275, B: 0.539), which is positive.

**Microsomal Clearance:** Ligand B (68.353) has significantly lower microsomal clearance than Ligand A (118.049), indicating better metabolic stability.

**In vitro Half-Life:** Ligand B (-4.936) has a slightly longer in vitro half-life than Ligand A (-34.453).

**P-gp Efflux:** Both ligands have low P-gp efflux liability (A: 0.426, B: 0.301), which is favorable for CNS exposure.

**Binding Affinity:** Ligand B (-7.3 kcal/mol) has a slightly better binding affinity than Ligand A (-8.2 kcal/mol). While A is better, the difference is not substantial enough to overcome the other issues.

**Overall Assessment:**

Ligand B is the more promising candidate. While both have poor solubility and Caco-2 permeability, Ligand B has a significantly lower DILI risk, better metabolic stability (lower Cl_mic, longer t1/2), and slightly better binding affinity. The TPSA of Ligand A is better, but the DILI risk is a major red flag. For a CNS target, the BBB penetration is excellent for both, but the other ADME properties of Ligand B make it a more viable starting point for optimization.

Output:
1
2025-04-17 05:25:13,995 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (443.285 Da) is slightly higher, but still acceptable.

**2. TPSA:** Both ligands have a TPSA of 75.27, which is above the optimal <90 for CNS targets, but not drastically so.

**3. logP:** Both ligands have good logP values (A: 3.09, B: 2.052), falling within the 1-3 range.

**4. H-Bond Donors:** Both have 2 HBD, which is within the acceptable limit of <=5.

**5. H-Bond Acceptors:** Both have 3 HBA, within the acceptable limit of <=10.

**6. QED:** Ligand A (0.735) has a better QED score than Ligand B (0.597), indicating a more drug-like profile.

**7. DILI:** Ligand A (43.66) has a significantly lower DILI risk than Ligand B (64.754), making it safer from a liver toxicity perspective.

**8. BBB:** This is a crucial parameter for a CNS target like DRD2. Ligand A (85.072) has a much higher BBB percentile than Ligand B (77.821). This is a significant advantage for Ligand A.

**9. Caco-2 Permeability:** Both have negative Caco-2 values, suggesting poor permeability.

**10. Aqueous Solubility:** Both have negative solubility values, suggesting poor solubility.

**11. hERG Inhibition:** Both ligands have low hERG inhibition liability (A: 0.716, B: 0.582).

**12. Microsomal Clearance:** Ligand B (11.037) has a higher microsomal clearance than Ligand A (5.089), indicating faster metabolism and potentially lower *in vivo* exposure.

**13. In vitro Half-Life:** Ligand A (57.348) has a significantly longer half-life than Ligand B (-24.643), which is a major advantage.

**14. P-gp Efflux:** Both ligands have low P-gp efflux liability (A: 0.326, B: 0.08).

**15. Binding Affinity:** Both ligands have the same binding affinity (-9.1 kcal/mol), which is excellent.

**Overall Assessment:**

While both ligands have good binding affinity, Ligand A is the superior candidate. It has a better QED score, significantly lower DILI risk, a higher BBB percentile, and a much longer half-life. The slightly higher molecular weight is a minor drawback compared to these advantages. The poor Caco-2 and solubility are concerns for both, but can be addressed with formulation strategies. Given the importance of BBB penetration for a CNS target, Ligand A is clearly the more promising drug candidate.

Output:
1
2025-04-17 05:25:13,995 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (352.431 and 354.411 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (96.89) is better than Ligand B (103.63). Both are below the 140 A^2 threshold for oral absorption, and importantly, below the 90 A^2 target for CNS penetration.

**3. logP:** Ligand A (0.273) is slightly better than Ligand B (-0.246) but both are quite low. A logP between 1-3 is optimal, and these are both below 1, potentially hindering permeation.

**4. H-Bond Donors:** Ligand A (3) is higher than Ligand B (1), but both are within the acceptable limit of 5.

**5. H-Bond Acceptors:** Ligand A (5) is lower than Ligand B (9), which is closer to the upper limit of 10.

**6. QED:** Both ligands have good QED scores (0.572 and 0.715, respectively), indicating good drug-like properties. Ligand B is slightly better.

**7. DILI:** Ligand A (33.773) has a significantly lower DILI risk than Ligand B (47.693). This is a substantial advantage for Ligand A.

**8. BBB:** Ligand B (74.098) has a much higher BBB penetration percentile than Ligand A (41.566). This is a critical advantage for a CNS target like DRD2.

**9. Caco-2 Permeability:** Ligand A (-5.388) has a much worse Caco-2 permeability than Ligand B (-4.894).

**10. Aqueous Solubility:** Ligand A (-1.664) has worse solubility than Ligand B (-0.765).

**11. hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.115 and 0.044, respectively).

**12. Microsomal Clearance:** Ligand A (3.896) has a lower microsomal clearance than Ligand B (10.556), indicating better metabolic stability.

**13. In vitro Half-Life:** Ligand A (22.393) has a longer in vitro half-life than Ligand B (6.05).

**14. P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.02 and 0.025, respectively).

**15. Binding Affinity:** Ligand A (-7.9 kcal/mol) has a significantly stronger binding affinity than Ligand B (-6.3 kcal/mol). This is a substantial advantage.

**Overall Assessment:**

Ligand A excels in binding affinity, DILI risk, metabolic stability, and half-life. Ligand B shines in BBB penetration and has slightly better QED and Caco-2 permeability. However, the significantly stronger binding affinity of Ligand A (-7.9 vs -6.3) is a major advantage that can potentially overcome its lower BBB and solubility. Given the importance of affinity for GPCRs, and the relatively acceptable BBB value for Ligand A (41.566 is not terrible), Ligand A is the more promising candidate. The lower DILI risk and improved metabolic stability further strengthen its profile.

Output:
1
2025-04-17 05:25:13,995 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (347.415 Da) is slightly lower, which could be beneficial for permeability.

**TPSA:** Ligand A (91.76) is preferable to Ligand B (118.61). For CNS targets, TPSA should be <= 90, and A is closer to this threshold.

**logP:** Ligand B (0.947) is slightly better than Ligand A (0.508). Both are a bit low, potentially hindering membrane permeability, but still within an acceptable range.

**H-Bond Donors/Acceptors:** Both have 2 HBDs, which is good. Ligand B has 8 HBAs, while Ligand A has 5.  Ligand A is better here, as higher HBA counts can sometimes reduce permeability.

**QED:** Ligand A (0.782) has a better QED score than Ligand B (0.617), indicating a more drug-like profile.

**DILI:** Ligand A (29.43) has a significantly lower DILI risk than Ligand B (56.262), a major advantage.

**BBB:** Ligand A (66.266) has a better BBB percentile than Ligand B (35.13). While >70 is desirable for CNS targets, 66.266 is still considerably better than 35.13. This is a crucial factor for DRD2.

**Caco-2 Permeability:** Ligand A (-4.681) has a better (more positive) Caco-2 permeability score than Ligand B (-6.183).

**Aqueous Solubility:** Ligand A (-1.688) has a better (less negative) solubility score than Ligand B (-1.375).

**hERG Inhibition:** Ligand A (0.145) has a much lower hERG inhibition risk than Ligand B (0.523).

**Microsomal Clearance:** Ligand A (-8.946) has a much lower (better) microsomal clearance than Ligand B (-2.444), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (7.28 hours) has a significantly longer in vitro half-life than Ligand B (-18.053 hours).

**P-gp Efflux:** Ligand A (0.044) has a much lower P-gp efflux liability than Ligand B (0.024), which is beneficial for CNS penetration.

**Binding Affinity:** Ligand B (-6.9 kcal/mol) has a slightly better binding affinity than Ligand A (-7.6 kcal/mol). However, the difference is relatively small (0.7 kcal/mol), and the other advantages of Ligand A likely outweigh this.

**Overall:** Ligand A is significantly better across most ADME-Tox properties (DILI, BBB, solubility, hERG, clearance, half-life, P-gp efflux) and has a good QED score. While Ligand B has slightly better affinity, the substantial improvements in other critical parameters for a CNS-targeting GPCR make Ligand A the more promising candidate.



Output:
0
2025-04-17 05:25:13,995 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (339.37 and 358.85 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (48.31) is significantly better than Ligand B (44.81) as both are below the 90 A^2 threshold for CNS targets.

**3. logP:** Both ligands have good logP values (3.669 and 4.416) within the optimal 1-3 range, although Ligand B is slightly higher.

**4. H-Bond Donors:** Both have 1 HBD, which is acceptable.

**5. H-Bond Acceptors:** Ligand A has 5 HBA, and Ligand B has 3 HBA, both within the acceptable limit of 10.

**6. QED:** Both ligands have similar QED scores (0.77 and 0.709), indicating good drug-likeness.

**7. DILI:** Ligand A (76.541) has a higher DILI risk than Ligand B (44.746). Ligand B is preferred here.

**8. BBB:** Ligand A (83.211) has a significantly better BBB penetration score than Ligand B (66.344). This is a crucial advantage for a CNS target like DRD2.

**9. Caco-2:** Both have negative Caco-2 values, which is unusual and suggests poor permeability. Ligand A (-4.994) is slightly worse than Ligand B (-5.213).

**10. Solubility:** Both have negative solubility values, which is also unusual. Ligand A (-4.448) is slightly better than Ligand B (-3.959).

**11. hERG:** Both ligands have low hERG inhibition liability (0.787 and 0.911), which is good.

**12. Cl_mic:** Ligand A (58.205) has a slightly lower microsomal clearance than Ligand B (53.463), suggesting better metabolic stability.

**13. t1/2:** Ligand B (39.037) has a significantly longer in vitro half-life than Ligand A (3.082). This is a significant advantage.

**14. Pgp:** Both ligands have low P-gp efflux liability (0.445 and 0.45).

**15. Binding Affinity:** Ligand A (-9.1 kcal/mol) has a stronger binding affinity than Ligand B (-8.5 kcal/mol). This is a substantial difference, exceeding the 1.5 kcal/mol advantage threshold.

**Overall Assessment:**

While Ligand B has a better DILI score and longer half-life, Ligand A's significantly stronger binding affinity (-9.1 vs -8.5 kcal/mol) and superior BBB penetration (83.211 vs 66.344) are critical for a CNS GPCR target. The affinity difference is likely to outweigh the slightly higher DILI risk and shorter half-life, especially given the importance of target engagement in the brain. The TPSA is also better for Ligand A.

Output:
1
2025-04-17 05:25:13,995 - INFO - Okay, let's analyze these two ligands (A and B) for their potential as DRD2 drug candidates, keeping in mind the provided guidelines and GPCR-specific priorities.

**Step-by-step comparison:**

1. **MW:** Ligand A (413.36 Da) is within the ideal range (200-500 Da). Ligand B (348.349 Da) is also within the ideal range. No clear advantage here.

2. **TPSA:** Ligand A (76.14) is slightly above the optimal <90 for CNS targets, but still reasonable. Ligand B (72.05) is excellent, well below 90. **Advantage: B**

3. **logP:** Ligand A (4.351) is a bit high, potentially leading to solubility issues or off-target interactions. Ligand B (3.252) is within the optimal 1-3 range. **Advantage: B**

4. **HBD:** Ligand A (2) is acceptable. Ligand B (1) is also acceptable. No clear advantage.

5. **HBA:** Ligand A (5) is acceptable. Ligand B (4) is also acceptable. No clear advantage.

6. **QED:** Both Ligand A (0.768) and Ligand B (0.861) have good drug-like scores (>0.5). **Advantage: B (slightly)**

7. **DILI:** Ligand A (37.728) has a lower DILI risk than Ligand B (70.919). **Advantage: A**

8. **BBB:** Both ligands have excellent BBB penetration (A: 86.002, B: 85.731). No clear advantage.

9. **Caco-2:** Both ligands have negative Caco-2 values, which is unusual and suggests poor permeability. This is concerning for both.

10. **Solubility:** Both ligands have very poor aqueous solubility (A: -4.385, B: -4.857). This is a significant drawback for both.

11. **hERG:** Both ligands have low hERG inhibition risk (A: 0.426, B: 0.449). No clear advantage.

12. **Cl_mic:** Ligand A (72.735) has a higher microsomal clearance than Ligand B (40.851), suggesting lower metabolic stability. **Advantage: B**

13. **t1/2:** Ligand B (-11.771) has a negative in vitro half-life, which is not possible. This is a major red flag. Ligand A (31.706) is reasonable. **Advantage: A**

14. **Pgp:** Both ligands have low P-gp efflux liability (A: 0.148, B: 0.334). No clear advantage.

15. **Binding Affinity:** Ligand A (-9.5 kcal/mol) has a significantly stronger binding affinity than Ligand B (-10.3 kcal/mol). This is a substantial advantage. **Advantage: A**

**Overall Assessment:**

Considering the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity), Ligand A appears to be the more promising candidate despite some drawbacks. While Ligand B has better TPSA and logP, Ligand A's significantly superior binding affinity (-9.5 vs -10.3 kcal/mol) is a major factor. The DILI risk is also lower for Ligand A. The negative half-life for Ligand B is a showstopper. Both have poor solubility and Caco-2 permeability, which would need to be addressed in further optimization, but the stronger binding of Ligand A provides a better starting point.

Output:
1
2025-04-17 05:25:13,996 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (357.426 and 375.47 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (73.32) is significantly better than Ligand B (99). For CNS targets, TPSA < 90 is preferred, and A is comfortably within this range, while B is approaching the upper limit.

**logP:** Ligand A (-0.372) is slightly lower than optimal (1-3), but not drastically so. Ligand B (0.406) is better, falling within the desired range.

**H-Bond Donors/Acceptors:** Both have 1 HBD, which is good. Ligand A has 5 HBA, acceptable. Ligand B has 8 HBA, which is higher but still within the generally acceptable limit of 10.

**QED:** Both ligands have good QED scores (0.73 and 0.795), indicating good drug-like properties.

**DILI:** Ligand A (20.9) has a much lower DILI risk than Ligand B (53.276). This is a significant advantage for A.

**BBB:** Ligand A (43.583) has a lower BBB penetration percentile than Ligand B (72.392). For a CNS target like DRD2, >70 is desirable, and B is closer to this target.

**Caco-2 Permeability:** Both have negative values (-4.613 and -4.918), which is unusual and suggests poor permeability.

**Aqueous Solubility:** Both have negative values (-0.376 and -2.514), suggesting poor aqueous solubility.

**hERG:** Both ligands have very low hERG inhibition liability (0.234 and 0.065), which is excellent.

**Microsomal Clearance:** Ligand A (-15.948) has a much lower (better) microsomal clearance than Ligand B (12.066). This suggests greater metabolic stability for A.

**In vitro Half-Life:** Ligand A (-17.706) has a much longer in vitro half-life than Ligand B (5.975), indicating better stability.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.033 and 0.043), which is good for CNS penetration.

**Binding Affinity:** Ligand B (-7.2) has a slightly better binding affinity than Ligand A (-7.6). However, the difference is only 0.4 kcal/mol, which is not a huge advantage considering the other factors.

**Overall Assessment:**

Ligand A excels in DILI risk, metabolic stability (Cl_mic and t1/2), and TPSA. While its BBB penetration is lower, its superior safety profile and metabolic properties are very attractive. Ligand B has better logP and BBB penetration, but suffers from higher DILI risk and poorer metabolic stability. Given the GPCR-specific priorities and the relatively small difference in binding affinity, the improved safety and pharmacokinetic properties of Ligand A make it the more promising candidate.

Output:
0
2025-04-17 05:25:13,996 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (404.308 Da) is slightly higher than Ligand B (368.543 Da), but both are acceptable.

**TPSA:** Ligand A (56.15) is excellent for CNS penetration, well below 90. Ligand B (67.43) is still reasonable, but less optimal.

**logP:** Ligand A (3.725) is within the optimal range (1-3). Ligand B (2.512) is also within range, but closer to the lower bound.

**H-Bond Donors/Acceptors:** Ligand A (HBD=1, HBA=4) and Ligand B (HBD=2, HBA=4) both have acceptable numbers of hydrogen bond donors and acceptors.

**QED:** Ligand A (0.827) has a significantly better QED score than Ligand B (0.51), indicating a more drug-like profile.

**DILI:** Ligand A (53.548) has a moderate DILI risk, but is better than Ligand B (29.779) which is very good.

**BBB:** Both ligands have good BBB penetration (Ligand A: 65.529, Ligand B: 60.411), but Ligand A is slightly better. While both are below the ideal >70, they are still reasonable.

**Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and suggests a potential issue with permeability prediction. However, the values are close enough to not be a major differentiator.

**Aqueous Solubility:** Both have negative solubility values, again suggesting issues with the prediction method, and are not useful for comparison.

**hERG:** Both ligands have very low hERG risk (0.329 and 0.325 respectively).

**Microsomal Clearance:** Ligand A (81.022) has higher microsomal clearance than Ligand B (50.312), suggesting lower metabolic stability.

**In vitro Half-Life:** Ligand B (-11.343) has a negative half-life, which is not physically possible and indicates a problem with the prediction. Ligand A (42.928) has a reasonable half-life.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.677 and 0.19 respectively), which is favorable for CNS penetration. Ligand B is better in this regard.

**Binding Affinity:** Ligand A (-8.2 kcal/mol) has a significantly stronger binding affinity than Ligand B (-7.4 kcal/mol). This 0.8 kcal/mol difference is substantial and can outweigh some ADME drawbacks.

**Overall Assessment:**

Considering the GPCR-specific priorities, Ligand A is the better candidate. While Ligand B has slightly better P-gp efflux and DILI, Ligand A has a significantly stronger binding affinity, a better QED score, and a more reasonable in vitro half-life. The slightly higher TPSA and clearance of Ligand A are less concerning given the strong binding affinity and acceptable BBB penetration. The negative values for Caco-2 and Solubility are concerning for both, but don't definitively rule either out.



Output:
1
2025-04-17 05:25:13,996 - INFO - Okay, let's analyze these two ligands for their potential as DRD2 drug candidates. DRD2 is a GPCR in the CNS, so BBB penetration, logP, Pgp efflux, TPSA, and binding affinity are paramount.

**Ligand A:** [340.423, 60.45, 3.352, 1, 5, 0.783, 37.185, 71.966, -4.391, -4.177, 0.504, 104.857, -27.932, 0.181, -8.1]
**Ligand B:** [364.364, 87.66, 0.595, 3, 4, 0.624, 35.789, 47.499, -5.061, -1.967, 0.281, 1.716, -16.384, 0.03, -6.9]

Here's a breakdown of each property:

1. **MW:** Both are within the ideal range (200-500 Da). A (340.423) is slightly preferred.
2. **TPSA:** A (60.45) is excellent for CNS penetration (well below 90). B (87.66) is still reasonable, but less optimal.
3. **logP:** A (3.352) is optimal. B (0.595) is too low and could hinder membrane permeability.
4. **HBD:** Both are acceptable (A: 1, B: 3), within the guideline of <=5.
5. **HBA:** Both are acceptable (A: 5, B: 4), within the guideline of <=10.
6. **QED:** Both are good (A: 0.783, B: 0.624), indicating drug-like properties.
7. **DILI:** Both have low DILI risk (A: 37.185, B: 35.789), both are below the 40% threshold.
8. **BBB:** A (71.966) is very good, exceeding the 70% threshold for CNS targets. B (47.499) is significantly lower and a concern.
9. **Caco-2:** A (-4.391) and B (-5.061) are both negative values, which is unusual. Assuming these are log scale values, lower values indicate poorer permeability. B is slightly worse.
10. **Solubility:** A (-4.177) and B (-1.967) are both negative values, indicating poor solubility. B is slightly better.
11. **hERG:** Both have low hERG risk (A: 0.504, B: 0.281).
12. **Cl_mic:** A (104.857) is higher than B (1.716), indicating faster metabolism and lower stability. B is much preferred.
13. **t1/2:** A (-27.932) and B (-16.384) are both negative values, which is unusual. Assuming these are log scale values, lower values indicate shorter half-life. B is slightly better.
14. **Pgp:** A (0.181) is lower than B (0.03), indicating less P-gp efflux and better CNS exposure. A is preferred.
15. **Affinity:** A (-8.1) is significantly better than B (-6.9), a difference of 1.2 kcal/mol. This is a substantial advantage.

**Overall Assessment:**

Ligand A is clearly superior. While Ligand B has better metabolic stability (lower Cl_mic) and slightly better solubility, Ligand A excels in the critical areas for a CNS-targeting GPCR: TPSA, logP, BBB penetration, Pgp efflux, and *especially* binding affinity. The 1.2 kcal/mol difference in binding affinity is substantial enough to outweigh the ADME drawbacks of A. The BBB penetration of A is also a major advantage.

Output:
1
2025-04-17 05:25:13,996 - INFO - Reasoning:

Let's analyze Ligand A and Ligand B based on the provided guidelines, prioritizing GPCR-specific properties (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (336.395 and 343.431 Da) fall within the ideal range of 200-500 Da.

**TPSA:** Both ligands have a TPSA of approximately 80, which is acceptable for general drug-likeness but slightly high for a CNS target (ideally <90, but closer to <70 is preferred).

**logP:** Ligand A (3.487) is optimal, while Ligand B (0.982) is a bit low, potentially hindering membrane permeability.

**H-Bond Donors/Acceptors:** Both ligands have reasonable HBD (2 and 1 respectively) and HBA (5) counts, falling within acceptable limits.

**QED:** Both ligands have good QED scores (0.72 and 0.781), indicating good drug-like properties.

**DILI:** Ligand A (79.449) has a higher DILI risk than Ligand B (40.636). This is a significant negative for Ligand A.

**BBB:** Ligand B (84.568) has a significantly better BBB penetration score than Ligand A (47.189). This is a *critical* advantage for a CNS target like DRD2.

**Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and suggests a potential issue with the data or modeling. However, we can assume they are both low.

**Aqueous Solubility:** Both ligands have negative solubility values, which is also unusual.

**hERG:** Both ligands have very low hERG inhibition liability, which is positive.

**Microsomal Clearance:** Ligand B (30.07 mL/min/kg) has lower microsomal clearance than Ligand A (41.808 mL/min/kg), indicating better metabolic stability.

**In vitro Half-Life:** Ligand B (-8.633 hours) has a longer half-life than Ligand A (63.278 hours).

**P-gp Efflux:** Ligand B (0.108) has lower P-gp efflux liability than Ligand A (0.408), which is beneficial for CNS penetration.

**Binding Affinity:** Both ligands have excellent binding affinities (-9.5 and -8.4 kcal/mol). Ligand A is slightly better (-9.5 kcal/mol), but the difference is less than 1.5 kcal/mol, so it's not a decisive factor.

**Overall Assessment:**

Ligand B is the more promising candidate. While Ligand A has a slightly better binding affinity, Ligand B excels in crucial ADME properties for a CNS-targeting GPCR: significantly better BBB penetration, lower DILI risk, lower P-gp efflux, and better metabolic stability. The lower logP of Ligand B is a minor concern, but the substantial benefits in CNS penetration and safety outweigh this drawback.

Output:
1
2025-04-17 05:25:13,997 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (348.49 and 356.46 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (69.64) is significantly better than Ligand B (76.15). For CNS targets, we want TPSA <= 90, and ideally closer to 60. Ligand A is much closer to the ideal.

**logP:** Both ligands have good logP values (2.08 and 1.45), falling within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A has 2 HBD and 3 HBA, while Ligand B has 0 HBD and 5 HBA. Both are within acceptable limits (<=5 HBD and <=10 HBA).

**QED:** Ligand A (0.799) has a much better QED score than Ligand B (0.51), indicating a more drug-like profile.

**DILI:** Ligand A (9.19) has a significantly lower DILI risk than Ligand B (32.07), which is a substantial advantage.

**BBB:** Both ligands have reasonably good BBB penetration (64.79% and 67.58%), but neither exceeds the desirable >70% threshold. Ligand B is slightly better.

**Caco-2 Permeability:** Both have negative Caco-2 values (-4.91 and -4.35). This is unusual and suggests poor permeability. However, these values are on a log scale, so the difference is not huge.

**Aqueous Solubility:** Both have negative solubility values (-2.16 and -0.92). Again, unusual and suggesting poor solubility. Ligand B is slightly better.

**hERG:** Both ligands have low hERG inhibition risk (0.44 and 0.53).

**Microsomal Clearance:** Ligand A (22.75) has a much lower microsomal clearance than Ligand B (57.81), indicating better metabolic stability.

**In vitro Half-Life:** Ligand A (9.82) has a longer in vitro half-life than Ligand B (-5.46), which is a significant advantage.

**P-gp Efflux:** Ligand A (0.125) has a much lower P-gp efflux liability than Ligand B (0.094), meaning it's less likely to be pumped out of the brain, improving CNS exposure.

**Binding Affinity:** Ligand A (-9.1 kcal/mol) has a significantly stronger binding affinity than Ligand B (0.0 kcal/mol). This is the most important factor, and the difference is substantial.

**Overall Assessment:**

Ligand A is clearly superior. It has a better TPSA, QED, DILI, microsomal clearance, in vitro half-life, P-gp efflux, and *much* stronger binding affinity. While both have issues with Caco-2 and solubility, the substantial advantage in binding affinity and the more favorable ADME properties of Ligand A outweigh these concerns. The stronger binding affinity is particularly important for a GPCR target.

Output:
1
2025-04-17 05:25:13,997 - INFO - Reasoning:

Let's analyze Ligand A and Ligand B against the provided guidelines, prioritizing GPCR-specific properties (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (366.889 and 344.467 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (58.64) is excellent, well below the 90 A^2 threshold for CNS targets. Ligand B (76.69) is still reasonable but less optimal, approaching the 140 A^2 limit for oral absorption.

**logP:** Ligand A (2.009) is within the optimal 1-3 range. Ligand B (0.808) is slightly below 1, which *could* indicate permeability issues, though not severely.

**H-Bond Donors/Acceptors:** Both ligands have 1 HBD, which is good. Ligand A has 3 HBA, and Ligand B has 8 HBA. While both are within the acceptable range, Ligand A is preferable.

**QED:** Both ligands have QED values above 0.5 (0.809 and 0.714), indicating good drug-like properties.

**DILI:** Both ligands have low DILI risk (23.265 and 20.434 percentiles), which is positive.

**BBB:** Both ligands have good BBB penetration (74.758 and 70.027 percentiles), but Ligand A is slightly better. This is crucial for a DRD2 ligand targeting CNS disorders.

**Caco-2 Permeability:** Ligand A (-4.629) has poor Caco-2 permeability, while Ligand B (-5.623) is also poor. This is a concern for both, but less critical given the focus on CNS penetration.

**Aqueous Solubility:** Both ligands have very poor aqueous solubility (-3.013 and -0.599). This could be a formulation challenge.

**hERG:** Both ligands have low hERG inhibition liability (0.246 and 0.271), which is good.

**Microsomal Clearance:** Ligand A (44.902) has moderate clearance, while Ligand B (-20) has *very* low clearance (negative value suggests very stable). This is a significant advantage for Ligand B.

**In vitro Half-Life:** Ligand A (11.967 hours) has a reasonable half-life. Ligand B (1.409 hours) has a very short half-life, which is a major drawback.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.158 and 0.033), which is favorable for CNS penetration. Ligand B is slightly better.

**Binding Affinity:** Ligand A (-8.4 kcal/mol) has a significantly stronger binding affinity than Ligand B (-6.9 kcal/mol). This 1.5 kcal/mol difference is substantial and can outweigh some ADME concerns.

**Overall Assessment:**

Ligand A excels in TPSA, BBB penetration, and *especially* binding affinity. Its Caco-2 permeability and aqueous solubility are concerning, but the strong affinity and good BBB suggest it might overcome these issues. Ligand B has better metabolic stability (lower Cl_mic, lower Pgp) but suffers from a weaker binding affinity and a very short half-life. For a CNS GPCR target like DRD2, strong binding affinity and BBB penetration are paramount. The difference in affinity is substantial enough to favor Ligand A.

Output:
1
2025-04-17 05:25:13,997 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B based on the provided guidelines, prioritizing GPCR-specific properties (BBB, logP, Pgp, TPSA, and affinity).

**Ligand A:**

*   **MW:** 344.371 Da - Good (within 200-500 range)
*   **TPSA:** 117.09 A<sup>2</sup> - Acceptable, but pushing the limit for CNS targets (ideally <90).
*   **logP:** 0.62 - Low. May have permeability issues.
*   **HBD:** 3 - Good.
*   **HBA:** 5 - Good.
*   **QED:** 0.71 - Excellent.
*   **DILI:** 58.55 - Acceptable risk.
*   **BBB:** 39.279 - Poor. Significantly below the desirable >70 for CNS targets.
*   **Caco-2:** -5.398 - Very poor permeability.
*   **Solubility:** -2.189 - Poor solubility.
*   **hERG:** 0.099 - Very low risk.
*   **Cl_mic:** 1.851 mL/min/kg - Low clearance, good metabolic stability.
*   **t1/2:** -38.368 hours - Excellent in vitro half-life.
*   **Pgp:** 0.025 - Low efflux, favorable for CNS penetration.
*   **Affinity:** -8.9 kcal/mol - Excellent binding affinity.

**Ligand B:**

*   **MW:** 358.551 Da - Good (within 200-500 range)
*   **TPSA:** 33.2 A<sup>2</sup> - Excellent for CNS penetration.
*   **logP:** 4.442 - High. Could lead to solubility issues or off-target effects.
*   **HBD:** 0 - Good, but potentially impacts solubility.
*   **HBA:** 3 - Good.
*   **QED:** 0.78 - Excellent.
*   **DILI:** 21.171 - Very low risk.
*   **BBB:** 87.515 - Excellent, highly desirable for CNS targets.
*   **Caco-2:** -5.281 - Very poor permeability.
*   **Solubility:** -3.766 - Poor solubility.
*   **hERG:** 0.669 - Moderate risk.
*   **Cl_mic:** 93.514 mL/min/kg - High clearance, poor metabolic stability.
*   **t1/2:** -5.862 hours - Poor in vitro half-life.
*   **Pgp:** 0.628 - Moderate efflux.
*   **Affinity:** -7.5 kcal/mol - Good binding affinity, but 1.4 kcal/mol weaker than Ligand A.

**Comparison and Decision:**

Both ligands have significant drawbacks regarding solubility and Caco-2 permeability. However, given the target is a CNS GPCR (DRD2), BBB penetration is paramount. Ligand B has a significantly better BBB score (87.515) compared to Ligand A (39.279). While Ligand A boasts superior binding affinity (-8.9 vs -7.5 kcal/mol) and better metabolic stability (lower Cl_mic), the poor BBB penetration is a major hurdle for CNS drug development. Ligand B's higher logP and moderate hERG risk are concerns, but these can potentially be addressed through further optimization. The substantial difference in BBB penetration outweighs the affinity advantage of Ligand A.

Output:
1
2025-04-17 05:25:13,997 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (365.459 and 370.368 Da) fall within the ideal range of 200-500 Da.

**TPSA:** Ligand A (104.71) is slightly above the preferred <90 for CNS targets, while Ligand B (96.89) is closer to the ideal range.

**logP:** Ligand A (1.366) is within the optimal 1-3 range. Ligand B (0.364) is a bit low, potentially hindering membrane permeability.

**H-Bond Donors/Acceptors:** Both have 3 HBDs, which is acceptable. Ligand A has 7 HBAs, while Ligand B has 5. Both are within the acceptable limit of <=10.

**QED:** Ligand A (0.706) has a better QED score than Ligand B (0.573), indicating a more drug-like profile.

**DILI:** Ligand B (23.304) has a significantly lower DILI risk than Ligand A (66.576), which is a major advantage.

**BBB:** Ligand B (61.07) has a slightly better BBB penetration percentile than Ligand A (54.207), though both are not optimal (>70).

**Caco-2 Permeability:** Ligand A (-5.329) has worse Caco-2 permeability than Ligand B (-5.228), indicating lower intestinal absorption.

**Aqueous Solubility:** Ligand A (-2.607) has slightly worse solubility than Ligand B (-1.544).

**hERG:** Both ligands have very low hERG inhibition risk (0.269 and 0.35 respectively).

**Microsomal Clearance:** Ligand B (6.013) shows better metabolic stability (lower clearance) than Ligand A (11.491).

**In vitro Half-Life:** Ligand A (42.336) has a significantly longer half-life than Ligand B (4.253).

**P-gp Efflux:** Both ligands show low P-gp efflux liability (0.069 and 0.023).

**Binding Affinity:** Ligand B (-7.4 kcal/mol) has a stronger binding affinity than Ligand A (-8.2 kcal/mol). While A has a slightly better affinity, the difference is small.

**Overall Assessment:**

Ligand B is the better candidate. While Ligand A has a slightly better binding affinity and longer half-life, Ligand B excels in crucial areas for a CNS-targeting GPCR ligand: lower DILI risk, better metabolic stability (lower Cl_mic), slightly better BBB penetration, and a more favorable logP. The superior ADMET properties of Ligand B outweigh the minor difference in binding affinity.

Output:
1
2025-04-17 05:25:13,997 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (344.459 and 349.431 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (50.6) is significantly better than Ligand B (96.53). For CNS targets, TPSA < 90 is preferred, and A is comfortably within this range, while B is close to the upper limit and less desirable.

**3. logP:** Ligand A (1.685) is optimal (1-3), while Ligand B (0.259) is quite low, potentially hindering membrane permeability.

**4. H-Bond Donors:** Ligand A (0) is excellent. Ligand B (3) is acceptable but less ideal.

**5. H-Bond Acceptors:** Ligand A (5) is good. Ligand B (4) is also good.

**6. QED:** Both ligands have similar QED values (0.8 and 0.641), indicating good drug-like properties.

**7. DILI:** Ligand A (18.651) has a much lower DILI risk than Ligand B (25.94). Both are below 40, indicating low risk, but A is preferable.

**8. BBB:** Ligand A (89.027) has a significantly higher BBB penetration percentile than Ligand B (43.699). For a CNS target like DRD2, >70 is desirable, and A is closer to this threshold.

**9. Caco-2 Permeability:** Ligand A (-4.759) is better than Ligand B (-5.32), indicating better intestinal absorption.

**10. Aqueous Solubility:** Ligand A (-0.503) is better than Ligand B (-1.667), though both are negative, suggesting poor solubility.

**11. hERG Inhibition:** Both ligands have very low hERG inhibition liability (0.641 and 0.099), which is excellent.

**12. Microsomal Clearance:** Ligand A (3.742) has a lower (better) microsomal clearance than Ligand B (-5.441).

**13. In vitro Half-Life:** Ligand A (24.859) has a longer half-life than Ligand B (10.074), which is preferable.

**14. P-gp Efflux:** Ligand A (0.169) has lower P-gp efflux liability than Ligand B (0.013), which is better for CNS exposure.

**15. Binding Affinity:** Both ligands have similar and strong binding affinities (-8.4 and -8.7 kcal/mol). The difference is negligible.

**Overall Assessment:**

Ligand A is significantly better than Ligand B. It excels in critical GPCR properties like TPSA, logP, and BBB penetration. It also has lower DILI risk, better Caco-2 permeability, lower microsomal clearance, and a longer half-life. While both have good affinity and low hERG risk, the superior ADME properties of Ligand A make it a much more promising drug candidate for targeting DRD2.

Output:
1
2025-04-17 05:25:13,998 - INFO - Batch 196 complete. Total preferences: 3136
2025-04-17 05:25:13,998 - INFO - Processing batch 197/512...
2025-04-17 05:25:59,114 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B based on the provided guidelines, prioritizing GPCR-specific properties (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (337.379 and 346.406 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (97.37) is slightly above the optimal <90 for CNS targets, but still reasonable. Ligand B (65.54) is excellent, well below 90.

**logP:** Ligand A (2.575) is within the optimal 1-3 range. Ligand B (0.683) is a bit low, potentially hindering permeability.

**H-Bond Donors/Acceptors:** Ligand A has 2 HBD and 5 HBA, which are acceptable. Ligand B has 1 HBD and 4 HBA, also acceptable.

**QED:** Both ligands have good QED scores (0.836 and 0.77), indicating good drug-like properties.

**DILI:** Ligand A (77.356) has a higher DILI risk than Ligand B (29.546). This is a significant negative for Ligand A.

**BBB:** Ligand A (57.193) has a moderate BBB penetration, while Ligand B (70.803) is better, exceeding the desirable >70 threshold for CNS targets. This is a major advantage for Ligand B.

**Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and difficult to interpret without context. However, we can assume lower values are worse.

**Aqueous Solubility:** Both have negative solubility values, which is also unusual and difficult to interpret.

**hERG:** Ligand A (0.899) has a slightly higher hERG risk than Ligand B (0.285).

**Microsomal Clearance:** Ligand A (37.796) has a moderate clearance, while Ligand B (-10.366) has a *negative* clearance, which is highly unusual and suggests exceptional metabolic stability.

**In vitro Half-Life:** Ligand A (25.126) has a reasonable half-life. Ligand B (-13.398) has a negative half-life, again indicating exceptional stability.

**P-gp Efflux:** Ligand A (0.344) has lower P-gp efflux than Ligand B (0.025), which is favorable for CNS penetration.

**Binding Affinity:** Both ligands have the same excellent binding affinity (-7.9 kcal/mol).

**Overall Assessment:**

While both ligands have excellent binding affinity, Ligand B is significantly better overall. It has a much lower DILI risk, better BBB penetration, superior metabolic stability (negative clearance and half-life), and lower P-gp efflux. Ligand A's higher DILI risk and lower BBB penetration are significant drawbacks, despite its slightly better P-gp efflux. The unusual negative values for Caco-2 and solubility are concerning for both, but the other advantages of B outweigh this.

Output:
1
2025-04-17 05:25:59,114 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 drug candidates, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (348.403 and 337.471 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (110.26) is higher than the preferred <90 for CNS targets, while Ligand B (62.73) is well within the range. This is a significant advantage for Ligand B.

**logP:** Ligand A (2.382) is within the optimal 1-3 range. Ligand B (3.739) is slightly higher but still acceptable, although approaching the upper limit where solubility issues could arise.

**H-Bond Donors/Acceptors:** Both ligands have 2 HBD and 6/5 HBA, respectively, which are within acceptable limits.

**QED:** Both ligands have good QED scores (0.758 and 0.841), indicating good drug-like properties.

**DILI:** Ligand A (70.686) has a higher DILI risk than Ligand B (48.623), although both are below the concerning >60 threshold.

**BBB:** This is a critical parameter for a CNS target like DRD2. Ligand B (82.047) has a significantly better BBB percentile than Ligand A (54.517). This is a major advantage for Ligand B.

**Caco-2 Permeability:** Ligand A (-5.049) shows poor Caco-2 permeability, suggesting poor intestinal absorption. Ligand B (-4.93) is also poor, but slightly better than A.

**Aqueous Solubility:** Both ligands have negative solubility values, indicating poor aqueous solubility. Ligand B (-4.053) is slightly better than Ligand A (-2.9).

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.203 and 0.722).

**Microsomal Clearance:** Ligand A (66.417) has lower microsomal clearance than Ligand B (75.095), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand B (36.36) has a longer in vitro half-life than Ligand A (-22.619), which is a positive attribute.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.14 and 0.171).

**Binding Affinity:** Ligand B (-8.5 kcal/mol) has a slightly better binding affinity than Ligand A (-7.8 kcal/mol). While the difference is not huge, it's a positive factor.

**Overall Assessment:**

Ligand B is the more promising candidate. It excels in the critical GPCR-specific parameters of TPSA and BBB penetration. While Ligand A has better metabolic stability (lower Cl_mic), the superior BBB penetration and slightly better affinity of Ligand B outweigh this advantage, especially for a CNS target. The solubility issues are a concern for both, but can be addressed with formulation strategies.

Output:
1
2025-04-17 05:25:59,115 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (352.475 and 345.426 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (87.66) is better than Ligand B (73.45). Both are below the 90 A^2 threshold for CNS targets, but A is slightly higher, which could potentially impact BBB penetration.

**3. logP:** Both ligands have good logP values (1.506 and 1.777), falling within the optimal 1-3 range.

**4. H-Bond Donors:** Ligand A (3) is slightly higher than Ligand B (1), but both are within the acceptable limit of <=5.

**5. H-Bond Acceptors:** Ligand A (4) is lower than Ligand B (7), which is preferable.

**6. QED:** Both ligands have similar and acceptable QED values (0.648 and 0.701), indicating good drug-like properties.

**7. DILI:** Ligand A (16.44) has a significantly lower DILI risk than Ligand B (37.999). This is a major advantage for Ligand A.

**8. BBB:** Ligand B (85.731) has a much higher BBB penetration percentile than Ligand A (25.94). This is a critical factor for a CNS target like DRD2, and heavily favors Ligand B.

**9. Caco-2 Permeability:** Ligand A (-4.901) shows poor Caco-2 permeability, while Ligand B (-5.282) is also poor. Both are unfavorable.

**10. Aqueous Solubility:** Ligand A (-1.702) shows poor aqueous solubility, while Ligand B (-2.116) is also poor. Both are unfavorable.

**11. hERG Inhibition:** Both ligands have low hERG inhibition risk (0.151 and 0.263).

**12. Microsomal Clearance:** Ligand A (10.518) and Ligand B (11.869) have similar microsomal clearance values.

**13. In vitro Half-Life:** Ligand B (-6.563) has a significantly longer in vitro half-life than Ligand A (11.617). This is a considerable advantage for Ligand B.

**14. P-gp Efflux:** Both ligands have low P-gp efflux liability (0.024 and 0.178).

**15. Binding Affinity:** Ligand B (-7.2 kcal/mol) has a slightly better binding affinity than Ligand A (-8.0 kcal/mol). While A is slightly better, the difference is not substantial enough to outweigh other factors.

**Overall Assessment:**

Ligand B is significantly better regarding BBB penetration and in vitro half-life, both crucial for CNS drug development. While Ligand A has a lower DILI risk, the superior BBB and half-life of Ligand B are more critical for targeting DRD2. The slightly better affinity of Ligand A is not enough to compensate for the significant difference in BBB.

Output:
1
2025-04-17 05:25:59,115 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (356.373 and 359.451 Da) are within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (76.46) is significantly better than Ligand B (82.53). For CNS targets, we want TPSA <= 90, and A is closer to the optimal range.

**3. logP:** Both ligands have good logP values (2.618 and 2.578), falling within the 1-3 optimal range.

**4. H-Bond Donors:** Ligand A (1) is preferable to Ligand B (2). Lower HBD generally improves permeability.

**5. H-Bond Acceptors:** Both ligands have 5 HBA, which is acceptable (<=10).

**6. QED:** Both ligands have similar, good QED values (0.884 and 0.86).

**7. DILI:** Ligand A (64.754) has a higher DILI risk than Ligand B (42.536). This is a negative for Ligand A.

**8. BBB:** This is crucial for a CNS target like DRD2. Ligand A (87.747) has a much higher BBB percentile than Ligand B (31.756). This is a major advantage for Ligand A.

**9. Caco-2 Permeability:** Ligand A (-4.251) has a worse Caco-2 permeability than Ligand B (-5.3). Lower values indicate lower permeability.

**10. Aqueous Solubility:** Ligand A (-4.373) has worse solubility than Ligand B (-2.853).

**11. hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.264 and 0.28).

**12. Microsomal Clearance:** Ligand B (-9.574) has a lower (better) microsomal clearance than Ligand A (64.48). This suggests better metabolic stability for Ligand B.

**13. In vitro Half-Life:** Ligand B (-0.334) has a longer half-life than Ligand A (-10.97).

**14. P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.056 and 0.054).

**15. Binding Affinity:** Both ligands have excellent binding affinities (-8.2 and -8.7 kcal/mol). Ligand B is slightly better (-8.7 kcal/mol).

**Overall Assessment:**

While Ligand B has slightly better affinity, metabolic stability, half-life, and lower DILI risk, Ligand A's significantly superior BBB penetration (87.747 vs 31.756) and lower TPSA are critical for a CNS-targeting drug. The higher DILI risk for Ligand A is a concern, but potentially mitigatable with further optimization. The improved BBB penetration is likely to translate to greater CNS exposure and efficacy, outweighing the other minor drawbacks.

Output:
1
2025-04-17 05:25:59,115 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight (MW):** Both ligands (344.46 and 354.46 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (78.09) is significantly better than Ligand B (135.16). For CNS targets, we want TPSA <= 90, and A is comfortably within that range, while B is above.

**3. logP:** Ligand A (2.16) is optimal (1-3), while Ligand B (0.209) is quite low, potentially hindering membrane permeability.

**4. H-Bond Donors (HBD):** Both are acceptable (A=2, B=4), staying within the <=5 guideline.

**5. H-Bond Acceptors (HBA):** Both are acceptable (A=3, B=7), staying within the <=10 guideline.

**6. QED:** Ligand A (0.859) has a much better QED score than Ligand B (0.5), indicating a more drug-like profile.

**7. DILI:** Ligand A (34.82) has a lower DILI risk than Ligand B (49.011), which is preferable. Both are below the 60 threshold, but A is significantly better.

**8. BBB:** Ligand A (59.87) is better than Ligand B (47.69). While both are below the ideal >70 for CNS targets, A is closer.

**9. Caco-2:** Both have negative values, indicating poor permeability. This is concerning, but we need to consider other factors.

**10. Solubility:** Both have negative values, indicating poor solubility. This is also concerning.

**11. hERG:** Both ligands have low hERG inhibition risk (A=0.308, B=0.278).

**12. Cl_mic:** Ligand B (18.24) has a significantly lower microsomal clearance than Ligand A (35.78), suggesting better metabolic stability.

**13. t1/2:** Ligand B (1.17) has a slightly better in vitro half-life than Ligand A (-15.31), but the negative value for A is concerning and likely an error.

**14. Pgp:** Ligand A (0.146) has much lower P-gp efflux liability than Ligand B (0.074), which is crucial for CNS penetration.

**15. Binding Affinity:** Ligand B (-7.3) has a slightly better binding affinity than Ligand A (-8.4). However, the difference is only 0.1 kcal/mol, which is not substantial enough to outweigh the significant ADME advantages of Ligand A.

**Overall Assessment:**

Considering the GPCR-specific priorities, Ligand A is the more promising candidate. It has a significantly better TPSA, logP, QED, DILI, and Pgp efflux profile, all critical for CNS penetration and drug-likeness. While Ligand B has slightly better affinity and metabolic stability, the substantial advantages of Ligand A in other key areas outweigh these benefits. The negative half-life for Ligand A is a red flag, but the other properties are more critical for initial ranking.

Output:
1
2025-04-17 05:25:59,115 - INFO - Reasoning:

Let's analyze Ligand A and Ligand B based on the provided guidelines, prioritizing GPCR properties (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (339.4 and 349.5 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (84.83) is better than Ligand B (73.2). Both are below the 90 A^2 threshold desirable for CNS targets.

**logP:** Ligand B (3.496) is slightly higher than Ligand A (2.643), but both are within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A has 2 HBD and 6 HBA, while Ligand B has 1 HBD and 3 HBA. Both are within acceptable limits.

**QED:** Both ligands have similar QED values (0.763 and 0.682), indicating good drug-likeness.

**DILI:** Ligand A (88.251) has a significantly higher DILI risk than Ligand B (10.469). This is a major concern for Ligand A.

**BBB:** Ligand B (77.239) has a much better BBB penetration score than Ligand A (57.736). This is crucial for a CNS target like DRD2.

**Caco-2 Permeability:** Ligand A (-5.183) has a worse Caco-2 permeability than Ligand B (-4.414).

**Aqueous Solubility:** Ligand A (-4.462) has a worse aqueous solubility than Ligand B (-2.941).

**hERG:** Both ligands have similar, low hERG inhibition liability (0.756 and 0.729).

**Microsomal Clearance:** Ligand B (60.039) has a higher microsomal clearance than Ligand A (32.694), indicating lower metabolic stability.

**In vitro Half-Life:** Ligand A (22.438) has a longer half-life than Ligand B (0.911).

**P-gp Efflux:** Both ligands have similar P-gp efflux liability (0.082 and 0.083).

**Binding Affinity:** Ligand A (-8.5 kcal/mol) has a significantly stronger binding affinity than Ligand B (-7.6 kcal/mol). This is a 0.9 kcal/mol difference, which is substantial.

**Overall Assessment:**

While Ligand A boasts superior binding affinity, its significantly higher DILI risk and poorer BBB penetration are major drawbacks for a CNS drug candidate. Ligand B, despite slightly weaker binding, presents a much more favorable ADME-Tox profile, particularly its excellent BBB score and low DILI risk. The affinity difference, while notable, might be overcome with further optimization of Ligand B. Given the GPCR-specific priorities, and the importance of CNS penetration and safety, Ligand B is the more promising candidate.

Output:
1
2025-04-17 05:25:59,115 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 drug candidates, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (339.435 and 360.523 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (58.56) is better than Ligand B (40.62). Both are below the 90 A^2 threshold for CNS targets, which is excellent.

**3. logP:** Ligand A (3.773) is slightly higher than Ligand B (2.952), both are within the optimal range of 1-3.

**4. H-Bond Donors:** Ligand A (2) is better than Ligand B (0). While both are acceptable, having some HBD can aid solubility.

**5. H-Bond Acceptors:** Both ligands have 3 HBA, which is well within the acceptable limit of 10.

**6. QED:** Both ligands have similar QED values (0.842 and 0.783), indicating good drug-like properties.

**7. DILI:** Ligand A (24.04) has a significantly lower DILI risk than Ligand B (39.201). This is a substantial advantage.

**8. BBB:** Ligand B (82.474) has a much better BBB penetration percentile than Ligand A (58.007). This is a critical factor for a CNS target like DRD2.

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 values, which is unusual and suggests poor permeability. However, the scale is not specified, so it's difficult to interpret.

**10. Aqueous Solubility:** Both ligands have negative solubility values, which is also unusual and suggests poor solubility. Again, the scale is not specified.

**11. hERG Inhibition:** Both ligands have low hERG inhibition risk (0.874 and 0.75), which is favorable.

**12. Microsomal Clearance:** Ligand B (99.262) has higher microsomal clearance than Ligand A (92.62), indicating lower metabolic stability.

**13. In vitro Half-Life:** Ligand A (3.881) has a slightly longer half-life than Ligand B (1.847).

**14. P-gp Efflux:** Ligand A (0.439) has lower P-gp efflux than Ligand B (0.506), which is beneficial for CNS penetration.

**15. Binding Affinity:** Ligand B (-8.2 kcal/mol) has a significantly stronger binding affinity than Ligand A (-9.6 kcal/mol). This is a major advantage, potentially outweighing some ADME drawbacks.

**Overall Assessment:**

The key trade-off is between Ligand B's superior binding affinity and BBB penetration versus Ligand A's lower DILI risk and slightly better metabolic stability. Given that this is a CNS target (DRD2), BBB penetration is paramount. The 1.6 kcal/mol difference in binding affinity is significant, and likely to overcome the slightly higher DILI risk of Ligand B. The negative Caco-2 and solubility values are concerning for both, but can be addressed during lead optimization.

Output:
1
2025-04-17 05:25:59,116 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (351.382 and 370.469 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (102.05) is slightly above the optimal <90 for CNS targets, but still reasonable. Ligand B (58.12) is excellent, well below 90.

**3. logP:** Ligand A (1.535) is within the optimal 1-3 range. Ligand B (3.315) is at the higher end of optimal, but still acceptable.

**4. H-Bond Donors:** Ligand A (2) and Ligand B (1) are both within the acceptable limit of <=5.

**5. H-Bond Acceptors:** Ligand A (6) and Ligand B (5) are both within the acceptable limit of <=10.

**6. QED:** Both ligands have similar QED values (0.751 and 0.712), indicating good drug-like properties.

**7. DILI:** Both ligands have similar DILI risk (62.35 and 57.193), indicating moderate risk. This isn't a major differentiating factor.

**8. BBB:** Ligand B (86.351) has a significantly better BBB percentile than Ligand A (61.923). This is a *critical* advantage for a CNS target like DRD2.

**9. Caco-2 Permeability:** Ligand A (-5.118) has poor Caco-2 permeability, while Ligand B (-4.944) is slightly better, but still poor.

**10. Aqueous Solubility:** Ligand A (-2.513) has poor aqueous solubility, while Ligand B (-4.125) is even worse.

**11. hERG Inhibition:** Ligand A (0.205) has a lower hERG inhibition risk than Ligand B (0.902), which is favorable.

**12. Microsomal Clearance:** Ligand A (27.644) has much lower microsomal clearance than Ligand B (79.188), suggesting better metabolic stability.

**13. In vitro Half-Life:** Ligand B (30.645) has a longer in vitro half-life than Ligand A (7.503), which is desirable.

**14. P-gp Efflux:** Ligand A (0.047) has significantly lower P-gp efflux liability than Ligand B (0.275), which is a major advantage for CNS penetration.

**15. Binding Affinity:** Ligand A (-8.1) has a stronger binding affinity than Ligand B (-7.3). This is a substantial advantage (0.8 kcal/mol difference).

**Overall Assessment:**

While Ligand A has better affinity and metabolic stability (lower Cl_mic, lower Pgp efflux), Ligand B excels in BBB penetration. Given that DRD2 is a CNS target, BBB penetration is paramount. The stronger affinity of Ligand A is a significant plus, but can potentially be overcome with further optimization of Ligand B. The poor solubility and Caco-2 permeability of both compounds are concerns, but can be addressed through formulation strategies or structural modifications. The lower hERG risk of Ligand A is also a positive. However, the substantially better BBB score of Ligand B, combined with acceptable (though not ideal) other properties, makes it the more promising candidate.

Output:
1
2025-04-17 05:25:59,116 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (346.471 and 353.467 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (49.85) is excellent, well below the 90 A^2 threshold for CNS targets. Ligand B (113.49) is higher, but still potentially acceptable, though less ideal.

**logP:** Ligand A (2.527) is optimal (1-3). Ligand B (1.248) is on the lower side, potentially hindering permeability.

**H-Bond Donors/Acceptors:** Ligand A (0 HBD, 3 HBA) is favorable. Ligand B (3 HBD, 6 HBA) is also acceptable, though slightly higher counts.

**QED:** Both ligands have reasonable QED scores (0.735 and 0.583), indicating drug-like properties.

**DILI:** Ligand A (29.081) has a much lower DILI risk than Ligand B (41.915), which is a significant advantage.

**BBB:** Ligand A (83.172) has a substantially better BBB penetration percentile than Ligand B (70.26). This is *critical* for a CNS target like DRD2.

**Caco-2 Permeability:** Ligand A (-4.416) has poor Caco-2 permeability, while Ligand B (-5.358) is also poor. This is a concern for both.

**Aqueous Solubility:** Both ligands have very poor aqueous solubility (-2.092 and -1.989). This could present formulation challenges.

**hERG:** Both ligands have low hERG inhibition risk (0.331 and 0.391).

**Microsomal Clearance:** Ligand A (32.041) and Ligand B (39.334) have moderate microsomal clearance.

**In vitro Half-Life:** Ligand A (6.955) has a better in vitro half-life than Ligand B (-3.689).

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.112 and 0.017).

**Binding Affinity:** Ligand A (-9.2 kcal/mol) has a significantly stronger binding affinity than Ligand B (-7.6 kcal/mol). This is a substantial advantage, potentially outweighing some of the ADME drawbacks.

**Overall Assessment:**

Ligand A is the stronger candidate. While both have poor solubility and Caco-2 permeability, Ligand A boasts a significantly better binding affinity, a much lower DILI risk, and superior BBB penetration. The better half-life is also a plus. For a CNS GPCR target, strong affinity and good BBB penetration are paramount, and Ligand A excels in these areas. The lower DILI risk is also a major benefit.

Output:
1
2025-04-17 05:25:59,116 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (335.407 and 349.479 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (57.84) is significantly better than Ligand B (79.26). For CNS targets, we want TPSA <= 90, and A is comfortably within this range, while B is approaching the upper limit.

**3. logP:** Ligand A (3.153) is optimal (1-3), while Ligand B (1.176) is a bit low, potentially hindering permeability.

**4. H-Bond Donors:** Ligand A (1) and Ligand B (2) are both acceptable (<=5).

**5. H-Bond Acceptors:** Ligand A (4) and Ligand B (5) are both acceptable (<=10).

**6. QED:** Both ligands have similar QED values (0.796 and 0.775), indicating good drug-likeness.

**7. DILI:** Ligand A (51.648) has a higher DILI risk than Ligand B (21.753), but both are below the concerning threshold of 60.

**8. BBB:** Both ligands have similar and good BBB penetration (48.662 and 49.205). While >70 is desirable, these are reasonably good and comparable.

**9. Caco-2 Permeability:** Both have negative Caco-2 values (-5.222 and -5.324). This is unusual and suggests a potential issue with the prediction method or the molecules themselves. However, the values are very close, so this doesn't strongly favor one over the other.

**10. Aqueous Solubility:** Both have negative solubility values (-2.972 and -1.219). Similar to Caco-2, this is concerning, but the values are close.

**11. hERG Inhibition:** Both ligands show low hERG inhibition liability (0.371 and 0.294), which is favorable.

**12. Microsomal Clearance:** Ligand B (-15.914) has significantly lower (better) microsomal clearance than Ligand A (18.777), indicating greater metabolic stability.

**13. In vitro Half-Life:** Ligand B (17.501) has a much longer in vitro half-life than Ligand A (-2.554), which is a significant advantage.

**14. P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.334 and 0.008), which is excellent for CNS penetration.

**15. Binding Affinity:** Both ligands have strong binding affinities (-9.1 and -8.4 kcal/mol). Ligand A is slightly better (-9.1 vs -8.4), but the difference is less than 1.5 kcal/mol, so it doesn't overwhelmingly favor A.

**Overall Assessment:**

Considering the GPCR-specific priorities, Ligand A has a better TPSA and slightly better affinity, but Ligand B excels in metabolic stability (lower Cl_mic, longer t1/2) and has a lower DILI risk. The logP of Ligand A is more optimal. The negative Caco-2 and solubility values are concerning for both, but similar. Given the importance of metabolic stability and reduced toxicity for CNS drugs, and the relatively small affinity difference, Ligand B appears to be the more promising candidate.

Output:
1
2025-04-17 05:25:59,116 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (353.419 and 347.394 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (96.97) is slightly above the optimal <90 for CNS targets, but still reasonable. Ligand B (72.16) is well within the desired range.

**3. logP:** Ligand A (-0.719) is a bit low, potentially hindering membrane permeability. Ligand B (1.347) is within the optimal 1-3 range.

**4. H-Bond Donors:** Ligand A (2) and Ligand B (1) are both acceptable, below the threshold of 5.

**5. H-Bond Acceptors:** Both ligands (A: 5, B: 5) are below the threshold of 10.

**6. QED:** Both ligands have good QED scores (A: 0.698, B: 0.769), indicating drug-likeness.

**7. DILI:** Ligand A (34.432) has a significantly lower DILI risk than Ligand B (55.758). This is a substantial advantage for Ligand A.

**8. BBB:** Ligand B (75.029) has a much better BBB penetration score than Ligand A (27.065). This is *critical* for a CNS target like DRD2.

**9. Caco-2 Permeability:** Both have negative values, indicating poor permeability. Ligand A (-5.339) is worse than Ligand B (-4.576).

**10. Aqueous Solubility:** Both ligands have negative solubility values, indicating poor solubility. Ligand A (-0.804) is slightly better than Ligand B (-1.019).

**11. hERG Inhibition:** Ligand A (0.093) has a very low hERG risk, significantly better than Ligand B (0.371).

**12. Microsomal Clearance:** Ligand A (-11.378) has a *much* lower (better) microsomal clearance than Ligand B (33.391), suggesting greater metabolic stability.

**13. In vitro Half-Life:** Ligand A (22.676) has a reasonable half-life, while Ligand B (25.675) is slightly better.

**14. P-gp Efflux:** Ligand A (0.006) has almost no P-gp efflux liability, which is excellent for CNS penetration. Ligand B (0.178) has a moderate P-gp efflux liability.

**15. Binding Affinity:** Ligand A (-0.0) has a very weak binding affinity, while Ligand B (-8.2) has a strong binding affinity. This is a major deciding factor.

**Overall Assessment:**

Ligand B clearly wins on binding affinity and BBB penetration, two crucial factors for a CNS GPCR target. While Ligand A has advantages in DILI, hERG, P-gp efflux, and metabolic stability, the significantly weaker binding affinity (-0.0 kcal/mol) is a major drawback. The strong affinity of Ligand B (-8.2 kcal/mol) likely outweighs the slightly higher DILI and P-gp efflux liabilities. The better BBB penetration of Ligand B is also very important.

Output:
1
2025-04-17 05:25:59,117 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (346.402 and 361.408 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (71.34) and Ligand B (69.22) are both below the 90 A^2 threshold desirable for CNS targets, which is excellent.

**3. logP:** Both ligands have logP values (3.114 and 2.983) within the optimal 1-3 range.

**4. H-Bond Donors:** Both have 2 HBD, which is acceptable.

**5. H-Bond Acceptors:** Both have 3 HBA, which is acceptable.

**6. QED:** Both ligands have QED values (0.844 and 0.748) above 0.5, indicating good drug-like properties.

**7. DILI:** Ligand A (57.076) has a higher DILI risk than Ligand B (15.898). Ligand B is significantly better here, falling well below the 40 threshold.

**8. BBB:** Both ligands have excellent BBB penetration (89.531 and 82.396), exceeding the >70% target for CNS drugs.

**9. Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and potentially problematic. However, given the context of these being predictions, we'll proceed with caution and consider other factors.

**10. Aqueous Solubility:** Both have negative solubility values, which is also unusual and potentially problematic. Again, we'll proceed with caution.

**11. hERG Inhibition:** Both have low hERG inhibition risk (0.736 and 0.773).

**12. Microsomal Clearance:** Ligand A (28.217) has a higher microsomal clearance than Ligand B (25.712), indicating potentially lower metabolic stability.

**13. In vitro Half-Life:** Ligand B (-30.946) has a *much* longer predicted in vitro half-life than Ligand A (88.617). This is a significant advantage.

**14. P-gp Efflux:** Ligand A (0.274) has lower P-gp efflux liability than Ligand B (0.051), which is favorable for CNS exposure.

**15. Binding Affinity:** Ligand A (-9.6 kcal/mol) has a significantly stronger binding affinity than Ligand B (-6.4 kcal/mol). This is a >3 kcal/mol difference, which is substantial and can outweigh some ADME drawbacks.

**Overall Assessment:**

While Ligand A has superior binding affinity and lower P-gp efflux, Ligand B demonstrates a much better safety profile (DILI) and significantly improved metabolic stability (half-life). The negative solubility and Caco-2 values are concerning for both, but the large difference in binding affinity is a major factor. Given the importance of affinity for GPCR ligands, and the fact that both have acceptable BBB penetration, the stronger binding of Ligand A is likely to be more impactful. The lower DILI risk of Ligand B is attractive, but the substantial difference in affinity tilts the balance towards Ligand A.

Output:
1
2025-04-17 05:25:59,117 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (347.455 Da) is slightly lower, which could be beneficial for permeability.

**2. TPSA:** Ligand A (56.79) is excellent for CNS penetration, well below the 90 A^2 threshold. Ligand B (127.32) is higher, but still potentially acceptable, though less ideal.

**3. logP:** Ligand A (3.322) is optimal. Ligand B (0.12) is significantly low, which is a major concern for membrane permeability and CNS penetration.

**4. H-Bond Donors:** Ligand A (1) is good. Ligand B (3) is acceptable, but higher.

**5. H-Bond Acceptors:** Ligand A (4) is good. Ligand B (5) is acceptable, but higher.

**6. QED:** Both ligands have reasonable QED values (A: 0.858, B: 0.566), indicating good drug-like properties.

**7. DILI:** Ligand A (54.75) has a slightly higher DILI risk than Ligand B (41.915), but both are below the concerning threshold of 60.

**8. BBB:** Ligand A (44.397) has a lower BBB penetration percentile than Ligand B (74.564). This is a significant advantage for Ligand B, given DRD2 is a CNS target.

**9. Caco-2 Permeability:** Ligand A (-4.802) has poor Caco-2 permeability, which is concerning. Ligand B (-5.58) is also poor, but similar to A.

**10. Aqueous Solubility:** Ligand A (-3.678) has poor aqueous solubility. Ligand B (-2.973) is also poor, but slightly better than A.

**11. hERG Inhibition:** Both ligands have very low hERG inhibition risk (A: 0.431, B: 0.093).

**12. Microsomal Clearance:** Ligand A (23.902) has lower microsomal clearance, suggesting better metabolic stability than Ligand B (26.493).

**13. In vitro Half-Life:** Ligand A (30.646) has a longer in vitro half-life than Ligand B (-4.571). This is a significant advantage for Ligand A.

**14. P-gp Efflux:** Ligand A (0.235) has lower P-gp efflux, which is beneficial for CNS exposure, compared to Ligand B (0.016).

**15. Binding Affinity:** Both ligands have comparable and strong binding affinities (A: -8.8 kcal/mol, B: -8.4 kcal/mol). The difference of 0.4 kcal/mol is not substantial enough to outweigh other significant differences.

**Overall Assessment:**

Ligand B has a significantly better BBB penetration score, which is crucial for a CNS target like DRD2. However, its very low logP is a major drawback, likely hindering its ability to cross cell membranes and reach the brain. Ligand A, while having a lower BBB score, possesses a much more favorable logP, better metabolic stability (lower Cl_mic, longer t1/2), and lower P-gp efflux. The poor Caco-2 and solubility of both are concerns, but can potentially be addressed through formulation strategies. Considering the importance of CNS penetration and the critical role of logP in achieving it, Ligand A is the more promising candidate despite its slightly lower BBB score.

Output:
0
2025-04-17 05:25:59,117 - INFO - Reasoning:

Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (345.483 and 341.415 Da) fall comfortably within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (49.77) is excellent, well below the 90 A^2 threshold for CNS targets. Ligand B (94.46) is higher, but still potentially acceptable, though less ideal.

**3. logP:** Ligand A (3.103) is optimal. Ligand B (1.967) is a bit low, potentially hindering membrane permeability, but not drastically.

**4. H-Bond Donors:** Ligand A (1) is good. Ligand B (3) is acceptable, but approaching the upper limit.

**5. H-Bond Acceptors:** Both ligands (A: 3, B: 3) are within the ideal range.

**6. QED:** Ligand A (0.916) is excellent, indicating high drug-likeness. Ligand B (0.779) is still good, but less so than A.

**7. DILI:** Ligand A (14.153) has a very low DILI risk, which is highly desirable. Ligand B (58.589) has a moderate DILI risk, which is a concern.

**8. BBB:** Ligand A (91.508) has excellent BBB penetration, crucial for a CNS target like DRD2. Ligand B (77.782) is lower, suggesting reduced CNS exposure.

**9. Caco-2:** Both ligands have negative Caco-2 values, which is unusual and suggests a potential issue with the data or a very poor permeability. However, we will proceed with the analysis assuming these values represent permeability on a specific scale and focus on relative comparison. Ligand A (-4.234) is better than Ligand B (-5.132).

**10. Solubility:** Both ligands have negative solubility values, which is also unusual. Ligand A (-3.031) is better than Ligand B (-3.575).

**11. hERG:** Both ligands have low hERG inhibition risk (A: 0.839, B: 0.697).

**12. Cl_mic:** Ligand A (38.393) has a moderate clearance, while Ligand B (-31.795) has a negative clearance, which is not physically possible and indicates a data issue. Assuming this is a percentile, it suggests very high metabolic stability, which is a positive.

**13. t1/2:** Ligand A (21.355) has a reasonable in vitro half-life. Ligand B (5.367) has a shorter half-life, potentially requiring more frequent dosing.

**14. Pgp:** Ligand A (0.584) has lower P-gp efflux, which is favorable for CNS penetration. Ligand B (0.022) has very low P-gp efflux, which is extremely favorable.

**15. Binding Affinity:** Ligand B (-9.1 kcal/mol) has a significantly stronger binding affinity than Ligand A (-8.3 kcal/mol). This 0.8 kcal/mol difference is substantial and could outweigh some of the ADME drawbacks.

**Overall Assessment:**

Ligand B has a superior binding affinity, very low P-gp efflux, and potentially very high metabolic stability. However, it has a higher TPSA, lower logP, a moderate DILI risk, and lower BBB penetration compared to Ligand A. Ligand A excels in BBB penetration, DILI risk, and QED. The negative Caco-2 and solubility values for both are concerning and would require further investigation.

Given the GPCR-specific priorities for DRD2 (BBB, logP, Pgp, TPSA, and affinity), the stronger affinity of Ligand B is a major advantage. The lower BBB penetration is a concern, but the very low P-gp efflux could partially compensate for this by increasing brain exposure. The moderate DILI risk is a concern, but could be mitigated with further optimization.

Output:
1
2025-04-17 05:25:59,117 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, considering the provided guidelines and GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (347.503 and 351.403 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (52.65) is excellent, well below the 90 A^2 threshold for CNS targets. Ligand B (116.76) is higher, but still potentially acceptable, though less ideal.

**logP:** Ligand A (1.899) is optimal (1-3). Ligand B (-1.327) is below 1, which may impede permeation.

**H-Bond Donors/Acceptors:** Ligand A (HBD=1, HBA=3) is within the desirable ranges. Ligand B (HBD=4, HBA=5) is also acceptable.

**QED:** Ligand A (0.512) is good, exceeding the 0.5 threshold. Ligand B (0.443) is slightly below, indicating a less drug-like profile.

**DILI:** Ligand A (4.188) has a very low DILI risk. Ligand B (21.908) has a moderate DILI risk, but is still acceptable.

**BBB:** Ligand A (67.197) has a reasonable BBB penetration, but could be better. Ligand B (35.324) has poor predicted BBB penetration, a significant drawback for a CNS target.

**Caco-2 Permeability:** Ligand A (-4.75) has poor Caco-2 permeability. Ligand B (-5.668) also has poor Caco-2 permeability.

**Aqueous Solubility:** Ligand A (-1.498) has poor aqueous solubility. Ligand B (-2.217) has even poorer aqueous solubility.

**hERG:** Ligand A (0.501) has a low hERG risk. Ligand B (0.096) has a very low hERG risk.

**Microsomal Clearance:** Ligand A (2.597) has a relatively low clearance, suggesting better metabolic stability. Ligand B (-1.459) has negative clearance, which is not physically possible and indicates an issue with the prediction.

**In vitro Half-Life:** Ligand A (-8.081) has a negative half-life, which is not physically possible and indicates an issue with the prediction. Ligand B (20.994) has a long half-life.

**P-gp Efflux:** Ligand A (0.018) has very low P-gp efflux, which is favorable for CNS penetration. Ligand B (0.002) also has very low P-gp efflux.

**Binding Affinity:** Ligand B (-8.3 kcal/mol) has a significantly stronger binding affinity than Ligand A (-7.0 kcal/mol). This is a substantial advantage.

**Overall Assessment:**

While Ligand A has better TPSA and DILI, Ligand B's significantly stronger binding affinity (-8.3 vs -7.0 kcal/mol) is a major advantage, and outweighs the drawbacks in TPSA and solubility. The poor BBB penetration of Ligand B is concerning, but the strong affinity could potentially overcome this. The negative values for clearance and half-life for Ligand A are problematic and suggest issues with the prediction.

Output:
1
2025-04-17 05:25:59,118 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (365.949 and 354.475 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (44.37) is excellent, well below the 90 A^2 threshold for CNS targets. Ligand B (58.2) is still reasonable but less favorable.

**logP:** Ligand A (4.397) is slightly high, potentially leading to solubility issues or off-target interactions, but still within a tolerable range. Ligand B (3.493) is optimal.

**H-Bond Donors/Acceptors:** Both ligands have 2 HBD and a reasonable number of HBA (2 for A, 3 for B), satisfying the <5 HBD and <10 HBA guidelines.

**QED:** Ligand A (0.717) has a better QED score than Ligand B (0.591), indicating a more drug-like profile.

**DILI:** Ligand A (22.102) has a significantly lower DILI risk than Ligand B (65.723), a major advantage.

**BBB:** Ligand A (88.717) has a much better BBB penetration percentile than Ligand B (75.107), crucial for a CNS target like DRD2.

**Caco-2 Permeability:** Ligand A (-4.597) has a negative Caco-2 value, which is unusual and suggests poor permeability. Ligand B (-5.253) is also poor, but slightly worse.

**Aqueous Solubility:** Both ligands have very poor aqueous solubility (-3.255 and -4.037 respectively). This is a concern, but can sometimes be mitigated with formulation strategies.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.849 and 0.644), which is good.

**Microsomal Clearance:** Ligand A (34.117) has a lower microsomal clearance than Ligand B (89.706), indicating better metabolic stability.

**In vitro Half-Life:** Ligand A (109.248) has a significantly longer in vitro half-life than Ligand B (8.589), which is highly desirable.

**P-gp Efflux:** Ligand A (0.398) has lower P-gp efflux liability than Ligand B (0.56), suggesting better CNS exposure.

**Binding Affinity:** Ligand B (-9.6 kcal/mol) has a significantly stronger binding affinity than Ligand A (-7.8 kcal/mol). This is a substantial advantage, potentially outweighing some of the ADME drawbacks.

**Overall Assessment:**

Ligand B has a much stronger binding affinity, which is a primary driver for GPCR drug candidates. However, Ligand A demonstrates superior ADME properties, particularly in BBB penetration, DILI risk, metabolic stability, and half-life. The poor Caco-2 permeability for both is a concern. Given the importance of CNS penetration for DRD2 and the substantial difference in binding affinity, Ligand B is the more promising candidate, despite its higher DILI risk and lower ADME scores. Formulation strategies could be explored to address solubility and permeability issues.

Output:
1
2025-04-17 05:25:59,118 - INFO - Batch 197 complete. Total preferences: 3152
2025-04-17 05:25:59,118 - INFO - Processing batch 198/512...
2025-04-17 05:26:42,175 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (356.5 and 354.4 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (81.08) is excellent, well below the 90 target for CNS drugs. Ligand B (99.1) is still reasonable but less optimal.

**logP:** Ligand A (1.809) is within the optimal 1-3 range. Ligand B (0.042) is quite low, potentially hindering membrane permeability and CNS penetration.

**H-Bond Donors/Acceptors:** Ligand A (2 HBD, 4 HBA) and Ligand B (3 HBD, 5 HBA) both have acceptable numbers of H-bond donors and acceptors.

**QED:** Both ligands have acceptable QED scores (0.462 and 0.648, respectively), indicating reasonable drug-likeness. Ligand B is slightly better.

**DILI:** Ligand A (10.198) has a very low DILI risk, which is excellent. Ligand B (25.165) is also acceptable, but higher.

**BBB:** This is critical for a CNS target. Ligand A (55.099) is moderate, while Ligand B (34.044) is significantly lower. This is a major drawback for Ligand B.

**Caco-2 Permeability:** Both have negative Caco-2 values (-4.578 and -4.978). This is unusual and suggests poor permeability. However, these values are on a log scale, and the negative values suggest very poor permeability.

**Aqueous Solubility:** Both have negative solubility values (-0.824 and -1.226). This is also concerning, indicating poor aqueous solubility.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.518 and 0.098).

**Microsomal Clearance:** Ligand A (56.985) has a higher clearance than Ligand B (4.738), suggesting lower metabolic stability.

**In vitro Half-Life:** Both have similar in vitro half-lives (3.651 and 3.138 hours).

**P-gp Efflux:** Ligand A (0.091) has lower P-gp efflux liability than Ligand B (0.018), which is favorable for CNS penetration.

**Binding Affinity:** Ligand B (-9.3 kcal/mol) has a significantly stronger binding affinity than Ligand A (-6.6 kcal/mol). This is a substantial advantage.

**Overall Assessment:**

Despite the poor Caco-2 and solubility values for both, Ligand B's significantly higher binding affinity (-9.3 vs -6.6 kcal/mol) is a major advantage that could potentially overcome some of its ADME liabilities. However, its low BBB penetration is a serious concern. Ligand A has better BBB penetration and a lower DILI risk, but its weaker binding affinity is a significant drawback. Given the GPCR-specific emphasis on affinity, and assuming the binding assay is reliable, the stronger affinity of Ligand B is likely to be more important. The poor permeability and solubility would need to be addressed through formulation or further chemical modifications, but a strong starting point is crucial.

Output:
1
2025-04-17 05:26:42,175 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (363.479 Da and 339.414 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (72.47) is better than Ligand B (41.15). For CNS targets, we want TPSA <= 90, both meet this criterion, but Ligand B is significantly lower and thus more favorable for brain penetration.

**logP:** Ligand A (3.532) is within the optimal 1-3 range. Ligand B (4.123) is slightly higher, potentially leading to solubility issues, but still acceptable.

**H-Bond Donors/Acceptors:** Both ligands have 1 HBD and a reasonable number of HBAs (5 and 3 respectively), satisfying the criteria of <=5 HBD and <=10 HBA.

**QED:** Both ligands have good QED scores (0.593 and 0.704), indicating drug-like properties.

**DILI:** Ligand A (56.805) has a higher DILI risk than Ligand B (35.479). This is a significant advantage for Ligand B.

**BBB:** Both ligands have excellent BBB penetration (88.794 and 85.459), exceeding the desirable >70 threshold for CNS targets.

**Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and suggests a potential issue with the data or modeling. However, the values are relatively close.

**Aqueous Solubility:** Both ligands have very poor aqueous solubility (-5.238 and -4.705). This is a concern, but can sometimes be mitigated with formulation strategies.

**hERG Inhibition:** Ligand A (0.206) has a slightly lower hERG risk than Ligand B (0.978), which is preferable.

**Microsomal Clearance:** Ligand A (81.721) has a higher microsomal clearance than Ligand B (58.634), indicating faster metabolism and potentially lower *in vivo* exposure.

**In vitro Half-Life:** Ligand B (-6.452) has a longer half-life than Ligand A (-3.312), which is desirable.

**P-gp Efflux:** Both ligands show strong P-gp efflux liability (0.251 and 0.759), which is not ideal for CNS penetration.

**Binding Affinity:** Ligand A (-9.0 kcal/mol) has a significantly stronger binding affinity than Ligand B (-8.9 kcal/mol). This 0.1 kcal/mol difference, while seemingly small, is potentially significant.

**Overall Assessment:**

Ligand B is generally more favorable due to its lower DILI risk, better metabolic stability (lower Cl_mic, longer t1/2), and lower P-gp efflux. However, Ligand A has a slightly better hERG profile and a significantly better binding affinity. The affinity difference is the most critical factor for a GPCR target. While the solubility and P-gp efflux are concerns for both, the stronger binding of Ligand A could potentially overcome these issues.

Output:
1
2025-04-17 05:26:42,176 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (367.427 and 343.435 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (121.53) is slightly above the optimal <90 for CNS targets, but still reasonable. Ligand B (87.97) is excellent, well within the desired range.

**logP:** Both ligands have good logP values (1.077 and 1.351), falling within the 1-3 range.

**H-Bond Donors & Acceptors:** Ligand A has 3 HBD and 6 HBA, both acceptable. Ligand B has 2 HBD and 7 HBA, also acceptable.

**QED:** Both ligands have good QED scores (0.642 and 0.875), indicating good drug-like properties.

**DILI:** Ligand A (86.002) has a higher DILI risk than Ligand B (77.627), though both are still relatively moderate.

**BBB:** This is critical for a CNS target. Ligand A has a BBB percentile of 28.887, which is quite low and concerning. Ligand B has a significantly better BBB percentile of 72.896, exceeding the desirable >70 threshold.

**Caco-2 Permeability:** Both have negative Caco-2 values (-5.463 and -4.991), which is unusual and suggests poor permeability. However, these values are on a log scale and can be difficult to interpret without knowing the base of the log.

**Aqueous Solubility:** Both ligands have very poor aqueous solubility (-2.449 and -2.823). This is a significant drawback.

**hERG Inhibition:** Both ligands show low hERG inhibition risk (0.152 and 0.481).

**Microsomal Clearance:** Ligand A (24.757) has lower microsomal clearance than Ligand B (43.276), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (38.603) has a longer in vitro half-life than Ligand B (5.921), which is preferable.

**P-gp Efflux:** Ligand A (0.177) has lower P-gp efflux than Ligand B (0.076), indicating better potential for CNS exposure.

**Binding Affinity:** Ligand A (-8.7 kcal/mol) has a significantly stronger binding affinity than Ligand B (-7.4 kcal/mol). This is a substantial advantage (1.3 kcal/mol difference).

**Overall Assessment:**

While Ligand A has superior binding affinity and better metabolic stability and P-gp efflux, its extremely poor BBB penetration is a major deal-breaker for a CNS target like DRD2. Ligand B, despite slightly weaker binding, has a much more favorable BBB profile (72.896), which is paramount for CNS drug development. The solubility is poor for both, but this can potentially be addressed with formulation strategies. The Caco-2 values are concerning, but the strong BBB value for Ligand B outweighs this.

Output:
1
2025-04-17 05:26:42,176 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (366.53 and 350.46 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (60.85) is significantly better than Ligand B (78.87). For CNS targets, we want TPSA <= 90, and A is much closer to the ideal <=60 range.

**3. logP:** Both ligands have good logP values (1.597 and 1.403), falling within the optimal 1-3 range.

**4. H-Bond Donors:** Ligand A (1) is preferable to Ligand B (2). Lower HBD generally improves permeability.

**5. H-Bond Acceptors:** Both ligands have the same number of HBA (4), which is acceptable (<=10).

**6. QED:** Ligand A (0.821) has a higher QED than Ligand B (0.681), indicating better overall drug-likeness.

**7. DILI:** Ligand A (23.77) has a much lower DILI risk than Ligand B (13.42). Both are good, but A is better.

**8. BBB:** Ligand A (65.45) is better than Ligand B (47.19), though ideally we want >70 for CNS targets. A is closer.

**9. Caco-2:** Both have negative Caco-2 values (-4.904 and -4.838). This is unusual and suggests poor permeability. However, the values are similar.

**10. Solubility:** Ligand A (-3.22) is slightly better than Ligand B (-1.875), but both are poor.

**11. hERG:** Ligand A (0.631) has a slightly higher hERG risk than Ligand B (0.099). This is a point in favor of B.

**12. Cl_mic:** Ligand A (56.51) has a higher microsomal clearance than Ligand B (30.64), indicating lower metabolic stability. This favors B.

**13. t1/2:** Ligand A (3.155) has a longer half-life than Ligand B (1.171). This is a positive for A.

**14. Pgp:** Ligand A (0.367) has a lower P-gp efflux liability than Ligand B (0.056), which is crucial for CNS penetration. This is a significant advantage for A.

**15. Binding Affinity:** Ligand B (-7.7 kcal/mol) has a significantly stronger binding affinity than Ligand A (-0.0 kcal/mol). This is a *major* advantage for B, potentially outweighing some ADME drawbacks.

**Overall Assessment:**

While Ligand A has better overall ADME properties (TPSA, QED, DILI, BBB, Pgp, t1/2), Ligand B's substantially stronger binding affinity (-7.7 vs -0.0 kcal/mol) is a decisive factor. The affinity difference is large enough to compensate for the slightly worse ADME profile of Ligand B. The lower Pgp efflux and better metabolic stability of B are also beneficial.

Output:
1
2025-04-17 05:26:42,176 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (340.471 Da) is slightly lower, which can be advantageous for permeability. Ligand B (379.551 Da) is also acceptable.

**TPSA:** Ligand A (44.39) is excellent, well below the 90 A^2 threshold for CNS targets. Ligand B (62.3) is still reasonable but less optimal, potentially hindering BBB penetration.

**logP:** Both ligands have a logP around 2.7-2.8, falling within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Both ligands have 1 HBD, which is good. Ligand A has 4 HBA, and Ligand B has 5 HBA, both acceptable.

**QED:** Ligand A (0.929) has a significantly better QED score than Ligand B (0.772), indicating a more drug-like profile.

**DILI:** Ligand A (10.857) has a much lower DILI risk than Ligand B (29.585), a significant advantage.

**BBB:** Ligand A (77.705) has a better BBB percentile than Ligand B (68.67), crucial for a CNS target like DRD2.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.181 and -5.151). This is unusual and suggests poor permeability. However, the scale isn't defined, so it's hard to interpret.

**Aqueous Solubility:** Both ligands have negative solubility values (-2.219 and -3.575), which is also concerning. Again, the scale is undefined.

**hERG Inhibition:** Ligand A (0.944) has a slightly higher hERG risk than Ligand B (0.428), but both are relatively low.

**Microsomal Clearance:** Ligand A (-2.222) has a much lower (better) microsomal clearance than Ligand B (59.211), indicating greater metabolic stability.

**In vitro Half-Life:** Ligand A (-1.696) has a negative half-life, which is unusual. Ligand B (5.238) has a reasonable half-life.

**P-gp Efflux:** Ligand A (0.107) has a significantly lower P-gp efflux liability than Ligand B (0.184), which is beneficial for CNS penetration.

**Binding Affinity:** Ligand B (-8.0) has a substantially stronger binding affinity than Ligand A (0.0). This is a major advantage, potentially outweighing some of the ADME drawbacks. A difference of 8 kcal/mol is very significant.

**Overall Assessment:**

Ligand B has a much stronger binding affinity, which is the most important factor for GPCRs. However, Ligand A demonstrates superior ADME properties, particularly regarding BBB penetration, DILI risk, metabolic stability, and P-gp efflux. The negative solubility and Caco-2 values are concerning for both, but the substantial affinity difference of Ligand B is likely to be more impactful.

Output:
1
2025-04-17 05:26:42,176 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (380.861 and 348.447 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (105.31) is slightly above the optimal <90 for CNS targets, but still reasonable. Ligand B (84.3) is well within the desired range.

**3. logP:** Both ligands have good logP values (1.546 and 1.183), falling within the 1-3 optimal range.

**4. H-Bond Donors:** Both have 1 HBD, which is acceptable.

**5. H-Bond Acceptors:** Ligand A has 7 HBAs, and Ligand B has 5. Both are within the acceptable limit of <=10.

**6. QED:** Both ligands have similar QED values (0.847 and 0.802), indicating good drug-likeness.

**7. DILI:** Ligand A has a DILI risk of 84.141, which is high. Ligand B has a much lower DILI risk of 42.536, which is preferable.

**8. BBB:** This is crucial for a CNS target like DRD2. Ligand A has a BBB penetration of 58.821%, which is below the desirable >70%. Ligand B has a significantly better BBB penetration of 74.176%.

**9. Caco-2 Permeability:** Ligand A (-5.125) and Ligand B (-4.669) have negative values, which is unusual. It's difficult to interpret without knowing the scale, but lower values generally indicate poorer permeability.

**10. Aqueous Solubility:** Both ligands have negative solubility values (-2.682 and -2.086), indicating poor aqueous solubility. This could pose formulation challenges.

**11. hERG Inhibition:** Both ligands show low hERG inhibition risk (0.194 and 0.236).

**12. Microsomal Clearance:** Ligand A has very low (and negative) microsomal clearance (-0.058), suggesting high metabolic stability. Ligand B has a much higher clearance (45.83), indicating faster metabolism.

**13. In vitro Half-Life:** Ligand A has a negative half-life (-0.416), which is not physically meaningful. Ligand B has a half-life of -5.697, also not physically meaningful.

**14. P-gp Efflux:** Both ligands show low P-gp efflux (0.04 and 0.092), which is good for CNS penetration.

**15. Binding Affinity:** Ligand B (-8.3 kcal/mol) has a significantly stronger binding affinity than Ligand A (0 kcal/mol). This is a substantial advantage.

**Overall Assessment:**

While Ligand A has better metabolic stability (lower Cl_mic) and a similar QED, its high DILI risk, poor BBB penetration, and *extremely* weak binding affinity are major drawbacks. Ligand B, despite having a higher Cl_mic, excels in the most critical areas for a CNS GPCR target: significantly better binding affinity, a good BBB score, and a lower DILI risk. The negative half-life values for both are concerning and would require further investigation, but the affinity difference is a major deciding factor.

Output:
1
2025-04-17 05:26:42,177 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (360.391 and 346.431 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (108.58) is slightly above the preferred <90 for CNS targets, while Ligand B (92.15) is closer to the ideal range. This gives a slight edge to Ligand B.

**logP:** Both ligands have good logP values (2.042 and 1.837), falling within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A has 1 HBD and 8 HBA, while Ligand B has 2 HBD and 5 HBA. Both are within acceptable limits (<=5 HBD and <=10 HBA).

**QED:** Both ligands have similar QED values (0.785 and 0.719), indicating good drug-likeness.

**DILI:** Ligand A has a higher DILI risk (83.443 percentile) compared to Ligand B (36.293 percentile). This is a significant negative for Ligand A.

**BBB:** Ligand A shows a very good BBB penetration (82.823 percentile), while Ligand B is also good, but lower (66.77 percentile). This favors Ligand A.

**Caco-2 Permeability:** Ligand A (-4.955) and Ligand B (-5.418) both have negative Caco-2 values, which is unusual and suggests poor permeability. However, these values are on a scale where negative values are expected and lower values indicate better permeability. Ligand B is slightly better here.

**Aqueous Solubility:** Ligand A (-4.69) and Ligand B (-2.014) both have negative solubility values, which is also unusual and suggests good solubility. Ligand B is better here.

**hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.285 and 0.13 percentile), which is excellent.

**Microsomal Clearance:** Ligand A (53.683 mL/min/kg) has a higher microsomal clearance than Ligand B (13.74 mL/min/kg), indicating lower metabolic stability. This favors Ligand B.

**In vitro Half-Life:** Ligand A (-28.223 hours) has a negative half-life, which is unusual. Ligand B (28.104 hours) has a reasonable half-life.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.129 and 0.048 percentile), which is excellent.

**Binding Affinity:** Both ligands have the same binding affinity (-8.3 kcal/mol), which is very strong.

**Overall Assessment:**

Ligand B is the better candidate. While Ligand A has better BBB penetration, Ligand B excels in several critical areas: significantly lower DILI risk, better metabolic stability (lower Cl_mic), a more reasonable in vitro half-life, and better solubility. The TPSA is also more favorable for CNS penetration. The similar binding affinity means the ADME properties become the deciding factors.

Output:
1
2025-04-17 05:26:42,177 - INFO - Reasoning:

Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (349.479 Da and 367.471 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (80.12) is better than Ligand B (84.67) as it is closer to the <90 A^2 threshold for CNS targets.

**3. logP:** Both ligands have good logP values (1.782 and 1.329), falling within the optimal range of 1-3.

**4. H-Bond Donors:** Both have 1 HBD, which is acceptable.

**5. H-Bond Acceptors:** Ligand A has 5 HBAs, and Ligand B has 6. Both are within the acceptable limit of <=10.

**6. QED:** Both ligands have similar QED values (0.898 and 0.817), indicating good drug-likeness.

**7. DILI:** Ligand A (35.789) has a significantly lower DILI risk than Ligand B (52.772). This is a substantial advantage.

**8. BBB:** Ligand A (64.172) has a slightly better BBB percentile than Ligand B (61.38), although both are below the desirable >70 for CNS targets.

**9. Caco-2:** Ligand A (-4.691) has a worse Caco-2 permeability than Ligand B (-4.989), but both are negative values, indicating poor permeability.

**10. Solubility:** Ligand A (-2.512) has better solubility than Ligand B (-3.241).

**11. hERG:** Both ligands show low hERG inhibition liability (0.264 and 0.385).

**12. Cl_mic:** Ligand B (43.372) has lower microsomal clearance than Ligand A (50.622), suggesting better metabolic stability.

**13. t1/2:** Ligand B (11.577) has a much longer in vitro half-life than Ligand A (-7.662). This is a significant advantage.

**14. Pgp:** Ligand A (0.138) has lower P-gp efflux liability than Ligand B (0.127), which is favorable for CNS penetration.

**15. Binding Affinity:** Ligand B (-8.4) has a significantly stronger binding affinity than Ligand A (-7.662). This is a >1.5 kcal/mol advantage, which can outweigh other drawbacks.

**Overall Assessment:**

While Ligand A has better TPSA, DILI, solubility and Pgp efflux, Ligand B's significantly stronger binding affinity (-8.4 vs -7.662 kcal/mol) and longer half-life are critical advantages, especially for a GPCR target like DRD2. The lower DILI risk of Ligand A is appealing, but the substantial affinity difference of Ligand B is likely to be more impactful. The slightly lower BBB for Ligand B is a concern, but not insurmountable.

Output:
1
2025-04-17 05:26:42,177 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (345.359 Da) is slightly lower, which could be beneficial for permeability. Ligand B (383.254 Da) is also acceptable.

**TPSA:** Ligand A (119.24) is excellent, falling well below the 90 A^2 threshold for CNS targets. Ligand B (47.09) is also very good, well below the threshold.

**logP:** Ligand A (0.143) is quite low, potentially hindering membrane permeability and CNS penetration. Ligand B (4.539) is high, potentially causing solubility issues and off-target interactions.

**H-Bond Donors/Acceptors:** Ligand A has 2 HBD and 7 HBA, which are acceptable. Ligand B has 0 HBD and 5 HBA, also acceptable.

**QED:** Both ligands have reasonable QED values (A: 0.791, B: 0.601), indicating good drug-like properties.

**DILI:** Ligand A (76.464) has a higher DILI risk than Ligand B (47.421), which is preferable.

**BBB:** Ligand B (70.57) has a significantly better BBB penetration percentile than Ligand A (53.587). This is a critical advantage for a CNS target like DRD2.

**Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and suggests potential issues with the prediction method or the molecules themselves. However, the values are close enough to not be a major differentiator.

**Aqueous Solubility:** Both ligands have negative solubility values, which is also unusual.

**hERG Inhibition:** Ligand A (0.039) shows very low hERG inhibition risk, a major advantage. Ligand B (0.919) has a higher risk.

**Microsomal Clearance:** Ligand B (70.495) has a higher microsomal clearance than Ligand A (11.865), indicating faster metabolism and potentially lower exposure.

**In vitro Half-Life:** Ligand B (9.672) has a longer half-life than Ligand A (6.284), which is generally desirable.

**P-gp Efflux:** Ligand A (0.008) has very low P-gp efflux liability, which is excellent for CNS penetration. Ligand B (0.751) has moderate P-gp efflux.

**Binding Affinity:** Ligand B (-7.7 kcal/mol) has a slightly better binding affinity than Ligand A (-8.3 kcal/mol). While the difference is not huge, it's a positive for Ligand B.

**Overall Assessment:**

Ligand A has a better safety profile (lower DILI, lower hERG) and P-gp efflux, but suffers from a very low logP and consequently, poor BBB penetration. Ligand B has better BBB penetration, a longer half-life, and slightly better affinity, but has a higher logP, higher DILI risk, and higher hERG risk.

Given the importance of BBB penetration for a CNS target like DRD2, and the relatively small difference in binding affinity, **Ligand B is the more promising candidate**. The higher logP and associated risks could be addressed through further structural modifications, but achieving good BBB penetration is often more challenging.

Output:
1
2025-04-17 05:26:42,177 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight (MW):** Both ligands (351.447 and 345.334 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (102.66) is slightly above the optimal <90 for CNS targets, while Ligand B (95.93) is closer to the ideal range. This gives a slight edge to Ligand B.

**3. logP:** Ligand A (0.819) is a bit low, potentially hindering permeability. Ligand B (1.974) is better, falling within the optimal 1-3 range. Ligand B is favored.

**4. H-Bond Donors (HBD):** Both ligands have acceptable HBD counts (2 and 0, respectively), well below the threshold of 5.

**5. H-Bond Acceptors (HBA):** Both ligands have acceptable HBA counts (5 and 8, respectively), below the threshold of 10.

**6. QED:** Both ligands have reasonable QED scores (0.674 and 0.576), indicating good drug-like properties.

**7. DILI:** Ligand A (13.804) has a significantly lower DILI risk than Ligand B (78.402). This is a major advantage for Ligand A.

**8. BBB:** Ligand B (76.309) has a much better BBB penetration score than Ligand A (54.789). This is crucial for a CNS target like DRD2, and strongly favors Ligand B.

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 values, which is unusual and suggests poor permeability. However, the scale is not specified, so it's difficult to interpret.

**10. Aqueous Solubility:** Both ligands have negative solubility values, which is also unusual. Again, the scale is unknown.

**11. hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.252 and 0.244).

**12. Microsomal Clearance (Cl_mic):** Ligand A (2.236) has much lower microsomal clearance than Ligand B (71.419), indicating better metabolic stability. This is a significant advantage for Ligand A.

**13. In vitro Half-Life:** Ligand A (-8.108) has a much longer in vitro half-life than Ligand B (-18.932), indicating better stability. This is a significant advantage for Ligand A.

**14. P-gp Efflux:** Both ligands have low P-gp efflux liability (0.008 and 0.123).

**15. Binding Affinity:** Ligand B (-8.2) has a slightly better binding affinity than Ligand A (-7.4). While a 0.8 kcal/mol difference is noticeable, it's not overwhelmingly large.

**Overall Assessment:**

Ligand B excels in BBB penetration and binding affinity, both critical for a CNS GPCR target. However, it suffers from a high DILI risk and poor metabolic stability (high Cl_mic, short half-life).

Ligand A has a lower DILI risk, better metabolic stability (lower Cl_mic, longer half-life), and a reasonable BBB score. Its logP is a bit low, and its binding affinity is slightly weaker, but the improvements in safety and metabolic properties are substantial.

Considering the balance of properties, and prioritizing metabolic stability and safety (DILI) alongside CNS penetration, **Ligand A is the more promising drug candidate.** The slightly weaker binding affinity can potentially be optimized in later stages of drug development.

Output:
0
2025-04-17 05:26:42,177 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (341.411 and 358.429 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Both ligands have TPSA values (68.46 and 67.43) below the 90 A^2 threshold desirable for CNS targets, indicating good potential for brain penetration.

**3. logP:** Both ligands have logP values (2.725 and 2.763) within the optimal 1-3 range.

**4. H-Bond Donors:** Ligand A (0 HBD) is slightly better than Ligand B (2 HBD) as fewer HBDs generally improve permeability.

**5. H-Bond Acceptors:** Ligand A (5 HBA) is slightly better than Ligand B (3 HBA). Both are below the 10 HBA threshold.

**6. QED:** Both ligands have acceptable QED values (0.808 and 0.767), indicating good drug-like properties.

**7. DILI:** Ligand B (31.989 percentile) has a significantly lower DILI risk than Ligand A (43.117 percentile). This is a substantial advantage.

**8. BBB:** Both ligands have excellent BBB penetration (79.992% and 77.2%), exceeding the desirable >70% threshold for CNS targets.

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.905 and -4.684). These values are unusual and likely indicate poor permeability in this assay. However, the BBB values suggest they *can* cross biological membranes, so this discrepancy needs further investigation but doesn't immediately disqualify either.

**10. Aqueous Solubility:** Both ligands have poor aqueous solubility (-2.827 and -2.613). This could pose formulation challenges.

**11. hERG Inhibition:** Both ligands show very low hERG inhibition liability (0.171 and 0.342), which is excellent.

**12. Microsomal Clearance:** Ligand B (47.938) has slightly higher microsomal clearance than Ligand A (41.986), meaning A is slightly more metabolically stable.

**13. In vitro Half-Life:** Ligand A (-16.285) has a slightly longer in vitro half-life than Ligand B (-15.13), which is preferable.

**14. P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.494 and 0.091). Ligand B is significantly better here, which is crucial for CNS exposure.

**15. Binding Affinity:** Both ligands have comparable, strong binding affinities (-9.1 and -9.3 kcal/mol). The difference is negligible.

**Overall Assessment:**

While Ligand A has a slightly better half-life and metabolic stability, Ligand B demonstrates a significantly lower DILI risk and substantially lower P-gp efflux. For a CNS target like DRD2, minimizing P-gp efflux is critical for ensuring sufficient brain exposure. The lower DILI risk is also a major advantage. The comparable binding affinities make the ADME properties the deciding factors.

Output:
1
2025-04-17 05:26:42,178 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 drug candidates, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (359.773 and 360.361 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (110.0) is slightly above the optimal <90 for CNS targets, but still reasonable. Ligand B (107.69) is better, falling closer to the desired range.

**3. logP:** Ligand A (1.962) is within the optimal 1-3 range. Ligand B (-0.532) is below 1, which could hinder permeation.

**4. H-Bond Donors:** Ligand A (2) and Ligand B (3) are both acceptable, being less than 5.

**5. H-Bond Acceptors:** Both ligands (6) are within the acceptable limit of 10.

**6. QED:** Both ligands (0.72 and 0.606) have good drug-likeness scores, exceeding 0.5.

**7. DILI:** Ligand A (96.782) has a high DILI risk, exceeding the 60 threshold. Ligand B (45.483) has a much lower, and acceptable, DILI risk. This is a significant negative for Ligand A.

**8. BBB:** Ligand A (33.579) has a very poor BBB penetration score. Ligand B (52.811) is better, but still below the desirable >70 for CNS targets.

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.686 and -5.18), which is unusual and suggests poor permeability. However, these values are on a scale where negative values are possible and don't necessarily disqualify a compound.

**10. Aqueous Solubility:** Both ligands have negative solubility values (-3.032 and -1.205), indicating poor solubility. This could pose formulation challenges.

**11. hERG Inhibition:** Ligand A (0.033) has a very low hERG risk, which is excellent. Ligand B (0.312) has a slightly higher, but still relatively low, hERG risk.

**12. Microsomal Clearance:** Ligand A (-4.19) has a negative clearance, suggesting high metabolic stability (which is good). Ligand B (-3.359) also has negative clearance, indicating good metabolic stability.

**13. In vitro Half-Life:** Ligand A (9.077) has a reasonable half-life. Ligand B (-13.791) has a negative half-life, which is not physically possible and likely indicates an issue with the data or model.

**14. P-gp Efflux:** Ligand A (0.043) has very low P-gp efflux, which is favorable for CNS penetration. Ligand B (0.02) also has very low P-gp efflux.

**15. Binding Affinity:** Both ligands have excellent binding affinities (-8.4 and -8.0 kcal/mol). The difference of 0.4 kcal/mol is not substantial enough to outweigh other factors.

**Overall Assessment:**

Ligand A has a strong binding affinity and low hERG/P-gp, but is severely hampered by its high DILI risk and very poor BBB penetration. The negative Caco-2 and solubility values are also concerning.

Ligand B has a better DILI profile and slightly better TPSA, but its logP is too low, potentially leading to poor membrane permeability. The negative half-life is a major red flag, indicating a data quality issue.

Despite the issues with both compounds, Ligand A is slightly more promising due to its better BBB score (although still poor) and the critical importance of avoiding high DILI risk. However, the DILI risk is substantial.

Output:
0
2025-04-17 05:26:42,178 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (352.322 and 360.483 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (118.73) is better than Ligand B (76.14) as it is closer to the optimal range for CNS targets (<=90). Ligand B is excellent.

**logP:** Ligand A (-0.355) is suboptimal, being below 1, which might hinder permeation. Ligand B (2.757) is within the optimal 1-3 range. This is a significant advantage for Ligand B.

**H-Bond Donors/Acceptors:** Ligand A has 3 HBD and 8 HBA, while Ligand B has 2 HBD and 6 HBA. Both are within acceptable limits (<=5 HBD and <=10 HBA).

**QED:** Both ligands have similar QED values (0.623 and 0.67), indicating good drug-likeness.

**DILI:** Ligand A (81.078) has a higher DILI risk than Ligand B (63.746), though both are acceptable.

**BBB:** Ligand A (41.838) has a low BBB penetration percentile, which is a major drawback for a CNS target. Ligand B (59.325) is better, but still not ideal (we want >70).

**Caco-2 Permeability:** Both ligands have similar, very poor Caco-2 permeability (-5.169 and -5.162). This suggests potential absorption issues for both.

**Aqueous Solubility:** Both ligands have poor aqueous solubility (-2.093 and -3.746).

**hERG Inhibition:** Ligand A (0.085) has a lower hERG inhibition liability than Ligand B (0.466), which is favorable.

**Microsomal Clearance:** Ligand A (-6.099) has a lower (better) microsomal clearance than Ligand B (94.451), indicating greater metabolic stability.

**In vitro Half-Life:** Ligand A (23.503) has a longer half-life than Ligand B (-1.152), which is desirable.

**P-gp Efflux:** Ligand A (0.02) has significantly lower P-gp efflux liability than Ligand B (0.185), which is crucial for CNS penetration.

**Binding Affinity:** Both ligands have comparable and excellent binding affinities (-7.7 and -7.8 kcal/mol). The difference is negligible.

**Overall Assessment:**

Ligand B has a significantly better logP value, which is critical for GPCRs. However, its BBB penetration is still suboptimal. Ligand A suffers from a poor logP and BBB penetration, but has better metabolic stability, lower P-gp efflux, and a slightly longer half-life. Considering the importance of BBB penetration for a CNS target like DRD2, and the fact that both ligands have comparable affinity, Ligand B is slightly favored due to its better logP. However, the poor BBB and Caco-2 permeability are concerning. Ligand A's lower P-gp efflux is a significant advantage, potentially compensating for the lower logP. Given the balance, and prioritizing CNS penetration, I lean towards Ligand A.

Output:
0
2025-04-17 05:26:42,178 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 drug candidates, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (362.455 and 348.447 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (97.12) is better than Ligand B (107.5). Both are below the 140 A^2 threshold for oral absorption, and closer to the <90 A^2 ideal for CNS targets.

**3. logP:** Ligand A (1.93) is slightly better than Ligand B (0.889), both falling within the optimal 1-3 range.

**4. H-Bond Donors:** Ligand A (2) is slightly higher than Ligand B (1), but both are acceptable (<=5).

**5. H-Bond Acceptors:** Ligand A (6) is higher than Ligand B (4), but both are within the acceptable range (<=10).

**6. QED:** Both ligands have similar QED values (0.784 and 0.769), indicating good drug-likeness.

**7. DILI:** Ligand A (69.135) has a significantly higher DILI risk than Ligand B (17.449). This is a major concern for Ligand A.

**8. BBB:** Ligand B (60.566) has a better BBB penetration percentile than Ligand A (52.191). While neither is >70, Ligand B is closer. This is critical for a CNS target like DRD2.

**9. Caco-2 Permeability:** Both have negative Caco-2 values (-5.247 and -5.069), which is unusual and suggests poor permeability. This is a red flag for both.

**10. Aqueous Solubility:** Both have negative solubility values (-2.812 and -1.881), indicating very poor aqueous solubility. This is a significant formulation challenge for both.

**11. hERG Inhibition:** Both ligands have low hERG inhibition risk (0.102 and 0.299).

**12. Microsomal Clearance:** Ligand B (4.42) has much lower microsomal clearance than Ligand A (36.2), suggesting better metabolic stability.

**13. In vitro Half-Life:** Ligand B (-4.704) has a better (less negative) in vitro half-life than Ligand A (-12.789), indicating better stability.

**14. P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.16 and 0.006).

**15. Binding Affinity:** Ligand A (-8.1 kcal/mol) has a slightly better binding affinity than Ligand B (-7.1 kcal/mol). However, the difference is less than 1.5 kcal/mol, so it doesn't necessarily outweigh other significant differences.

**Overall Assessment:**

Despite Ligand A having a slightly better binding affinity, Ligand B is the more promising candidate. Ligand A's significantly higher DILI risk is a major drawback. Ligand B has better BBB penetration, lower DILI, and significantly improved metabolic stability (lower Cl_mic and better half-life). While both have poor Caco-2 and solubility, the other factors make Ligand B more likely to succeed.

Output:
1
2025-04-17 05:26:42,178 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (350.459 and 348.443 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (67.87) is significantly better than Ligand B (78.87). For CNS targets, we want TPSA <= 90, and A is closer to the optimal <=60 range. B is pushing the upper limit.

**3. logP:** Both ligands have good logP values (1.501 and 0.825), falling within the optimal 1-3 range. Ligand A is slightly better.

**4. H-Bond Donors:** Both have acceptable HBD counts (1 and 2, respectively), well below the limit of 5.

**5. H-Bond Acceptors:** Both ligands have 4 HBA, which is acceptable (<=10).

**6. QED:** Both have good QED scores (0.737 and 0.789), indicating good drug-like properties.

**7. DILI:** Ligand A (21.636) has a much lower DILI risk than Ligand B (12.524). This is a significant advantage.

**8. BBB:** Ligand A (65.801) has a better BBB penetration percentile than Ligand B (46.607). While both are not ideal (>70 desirable), A is closer. This is crucial for a CNS target like DRD2.

**9. Caco-2 Permeability:** Both have negative Caco-2 values (-4.662 and -4.847), which is unusual and suggests poor permeability. This is a concern for both, but the values are similar.

**10. Aqueous Solubility:** Both have negative solubility values (-1.925 and -2.087), indicating very poor aqueous solubility. This is a significant drawback for both.

**11. hERG Inhibition:** Both have low hERG inhibition risk (0.129 and 0.26).

**12. Microsomal Clearance:** Ligand A (45.253) has higher microsomal clearance than Ligand B (13.923), meaning it's less metabolically stable. This favors Ligand B.

**13. In vitro Half-Life:** Ligand B (40.349) has a longer in vitro half-life than Ligand A (24.288), which is desirable.

**14. P-gp Efflux:** Both have very low P-gp efflux liability (0.03 and 0.011), which is good for CNS penetration.

**15. Binding Affinity:** Ligand B (-8.4 kcal/mol) has a significantly stronger binding affinity than Ligand A (-7.0 kcal/mol). This is a substantial advantage, potentially outweighing some of the ADME drawbacks.

**Overall Assessment:**

Ligand B has a significantly better binding affinity, longer half-life, and lower microsomal clearance. However, Ligand A has a much better safety profile (lower DILI), better BBB penetration, and lower TPSA. The poor solubility and Caco-2 permeability are concerns for both. Given the GPCR-specific priorities, the stronger binding affinity of Ligand B is a major advantage that likely outweighs the slightly higher DILI risk and lower BBB. The difference in affinity (1.4 kcal/mol) is substantial.

Output:
1
2025-04-17 05:26:42,179 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (410.268 Da) is slightly higher than Ligand B (352.519 Da), but both are acceptable.

**2. TPSA:** Ligand A (100.45) is borderline for CNS targets (ideally <90), while Ligand B (67.43) is well within the desired range. This is a significant advantage for Ligand B.

**3. logP:** Both ligands have good logP values (A: 2.799, B: 3.195), falling within the optimal 1-3 range.

**4. H-Bond Donors:** Both ligands have 2 HBD, which is within the acceptable limit of <=5.

**5. H-Bond Acceptors:** Ligand A has 5 HBA, and Ligand B has 3. Both are below the acceptable limit of <=10.

**6. QED:** Both ligands have reasonable QED scores (A: 0.798, B: 0.692), indicating good drug-like properties.

**7. DILI:** Ligand A (74.99) has a higher DILI risk than Ligand B (29.391). This is a clear advantage for Ligand B.

**8. BBB:** Ligand A (57.193) has a moderate BBB penetration, while Ligand B (60.876) is also moderate. Both are below the desirable >70 for CNS targets, but not dramatically so.

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.636 and -4.794), which is unusual and suggests poor permeability. This is a concern for both.

**10. Aqueous Solubility:** Both ligands have negative solubility values (-4.514 and -3.268), indicating very poor aqueous solubility. This is a significant drawback for both.

**11. hERG Inhibition:** Both ligands have low hERG inhibition risk (A: 0.563, B: 0.362), which is good.

**12. Microsomal Clearance:** Ligand A (50.135) has lower microsomal clearance than Ligand B (63.361), suggesting better metabolic stability.

**13. In vitro Half-Life:** Both ligands have similar in vitro half-lives (A: 14.494, B: 15.512).

**14. P-gp Efflux:** Both ligands have low P-gp efflux liability (A: 0.096, B: 0.08), which is favorable for CNS penetration.

**15. Binding Affinity:** Ligand B (-7.9 kcal/mol) has a significantly stronger binding affinity than Ligand A (-7.1 kcal/mol). This is a >1.5 kcal/mol advantage, which can outweigh some ADME drawbacks.

**Overall Assessment:**

Ligand B is the better candidate. While both have concerning solubility and permeability issues, Ligand B has a significantly stronger binding affinity, lower DILI risk, and a more favorable TPSA. The stronger affinity is a crucial advantage for a GPCR ligand, and the lower DILI risk is important for safety. Although both have suboptimal BBB penetration, the other advantages of Ligand B make it more promising.

Output:
1
2025-04-17 05:26:42,179 - INFO - Batch 198 complete. Total preferences: 3168
2025-04-17 05:26:42,179 - INFO - Processing batch 199/512...
2025-04-17 05:27:24,642 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (356.535 and 349.431 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (25.24) is excellent, well below the 90 A^2 threshold for CNS targets. Ligand B (111.45) is higher, but still potentially acceptable, though less ideal.

**logP:** Ligand A (4.867) is slightly high, potentially leading to solubility issues or off-target interactions. Ligand B (0.477) is quite low, which could hinder membrane permeability and CNS penetration.

**H-Bond Donors/Acceptors:** Ligand A (0 HBD, 3 HBA) is favorable. Ligand B (3 HBD, 5 HBA) is also reasonable, though slightly higher.

**QED:** Ligand A (0.77) is good, indicating a drug-like profile. Ligand B (0.59) is acceptable, but less optimal.

**DILI:** Ligand A (41.954) has a low DILI risk. Ligand B (16.906) has an even lower DILI risk, which is excellent.

**BBB:** This is critical for a CNS target. Ligand A (92.051) has excellent BBB penetration. Ligand B (32.687) has very poor predicted BBB penetration.

**Caco-2 Permeability:** Ligand A (-4.899) shows poor permeability. Ligand B (-5.125) is also poor.

**Aqueous Solubility:** Ligand A (-4.756) has poor solubility. Ligand B (-1.872) has slightly better solubility, but still not great.

**hERG Inhibition:** Ligand A (0.778) has a low risk of hERG inhibition. Ligand B (0.217) has a very low risk.

**Microsomal Clearance:** Ligand A (75.59) has moderate clearance. Ligand B (-9.857) has a negative clearance, which is not physically possible and likely indicates an issue with the prediction or the molecule itself. It's likely a very stable compound *in vitro*.

**In vitro Half-Life:** Ligand A (26.204 hours) has a reasonable half-life. Ligand B (31.594 hours) has a longer half-life, which is favorable.

**P-gp Efflux:** Ligand A (0.883) has moderate P-gp efflux. Ligand B (0.017) has very low P-gp efflux, which is highly desirable for CNS penetration.

**Binding Affinity:** Ligand A (0.0) has weak binding affinity. Ligand B (-7.2) has very strong binding affinity.

**Overall Assessment:**

Ligand B stands out due to its significantly stronger binding affinity (-7.2 kcal/mol vs 0.0 kcal/mol for A) and very low P-gp efflux. While its logP is low and TPSA is higher than ideal, the exceptional binding affinity and favorable BBB penetration (despite the low logP) outweigh these drawbacks, especially for a GPCR target. Ligand A has better TPSA and a lower logP, but its weak binding affinity is a major disadvantage. The negative clearance for Ligand B is a flag, but the strong affinity and low P-gp efflux are compelling.

Output:
1
2025-04-17 05:27:24,642 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (358.829 and 365.861 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (69.04) is slightly above the optimal <90 for CNS targets, but still reasonable. Ligand B (53.09) is excellent, well below the threshold.

**logP:** Ligand A (3.511) is at the upper end of the optimal range (1-3), potentially raising concerns about solubility and off-target effects. Ligand B (2.243) is well within the optimal range.

**H-Bond Donors/Acceptors:** Ligand A (HBD=1, HBA=5) and Ligand B (HBD=0, HBA=4) both have acceptable numbers of H-bond donors and acceptors.

**QED:** Both ligands have similar QED values (0.757 and 0.751), indicating good drug-like properties.

**DILI:** Ligand A (84.18) has a higher DILI risk than Ligand B (47.693). This is a significant negative for Ligand A.

**BBB:** Ligand B (94.261) has a significantly higher BBB penetration percentile than Ligand A (49.593). This is *critical* for a CNS target like DRD2.

**Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and requires further investigation. However, the magnitude is similar.

**Aqueous Solubility:** Both have negative solubility values, which is also unusual and requires further investigation. The magnitude is similar.

**hERG:** Both ligands have low hERG inhibition liability (0.385 and 0.535), which is good.

**Microsomal Clearance:** Ligand A (74.528) has a higher microsomal clearance than Ligand B (7.086), suggesting lower metabolic stability.

**In vitro Half-Life:** Ligand B (2.95) has a slightly longer in vitro half-life than Ligand A (57.225), though the scale is different and this is hard to compare.

**P-gp Efflux:** Ligand A (0.384) has slightly lower P-gp efflux liability than Ligand B (0.091), which is favorable.

**Binding Affinity:** Ligand B (-8.4 kcal/mol) has a slightly better binding affinity than Ligand A (-9.2 kcal/mol). While both are excellent, the difference is not huge.

**Overall Assessment:**

Ligand B is the superior candidate. Its significantly higher BBB penetration, lower DILI risk, and better logP profile outweigh the slightly lower P-gp efflux and slightly weaker binding affinity. The higher metabolic stability (lower Cl_mic) and longer half-life are also beneficial. While the Caco-2 and solubility values are concerning for both, the other factors strongly favor Ligand B for development as a CNS-active DRD2 ligand.

Output:
1
2025-04-17 05:27:24,643 - INFO - Reasoning:

Let's analyze Ligand A and Ligand B for their potential as DRD2 drug candidates, considering the provided guidelines and GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (346.391 and 344.455 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (116.12) is higher than the optimal <90 for CNS targets, but not drastically so. Ligand B (62.55) is excellent, well below the threshold. This favors Ligand B.

**3. logP:** Ligand A (0.478) is quite low, potentially hindering permeability. Ligand B (3.296) is within the optimal 1-3 range. This strongly favors Ligand B.

**4. H-Bond Donors:** Ligand A (2) and Ligand B (1) are both acceptable (<=5).

**5. H-Bond Acceptors:** Ligand A (6) and Ligand B (3) are both acceptable (<=10).

**6. QED:** Both ligands have good QED scores (0.666 and 0.834), indicating drug-like properties.

**7. DILI:** Both ligands have acceptable DILI risk (54.168 and 41.877, both <60).

**8. BBB:** Ligand A (32.648) has a poor BBB percentile, making CNS penetration unlikely. Ligand B (69.407) is good, exceeding the >70 target for CNS GPCRs. This is a major advantage for Ligand B.

**9. Caco-2 Permeability:** Ligand A (-5.649) has very poor Caco-2 permeability. Ligand B (-4.344) is also poor, but slightly better than A.

**10. Aqueous Solubility:** Ligand A (-1.883) and Ligand B (-3.477) both have poor aqueous solubility.

**11. hERG Inhibition:** Both ligands show very low hERG inhibition risk (0.065 and 0.099).

**12. Microsomal Clearance:** Ligand A (-6.776) shows better metabolic stability (lower clearance) than Ligand B (57.112).

**13. In vitro Half-Life:** Ligand B (49.071) has a longer half-life than Ligand A (24.236).

**14. P-gp Efflux:** Ligand A (0.007) shows very low P-gp efflux, which is excellent. Ligand B (0.193) shows slightly higher, but still acceptable, P-gp efflux.

**15. Binding Affinity:** Ligand B (-7.7) has a significantly stronger binding affinity than Ligand A (-8.0). While A is slightly better, the difference is not substantial enough to overcome the other deficiencies.

**Overall Assessment:**

Ligand B is the superior candidate. While both have solubility issues, Ligand B excels in key areas for a CNS-targeting GPCR: logP, BBB penetration, and binding affinity. Ligand A's very low logP and poor BBB penetration are significant drawbacks. The longer half-life of Ligand B is also a plus. Although Ligand A has better metabolic stability, the other advantages of Ligand B outweigh this.

Output:
1
2025-04-17 05:27:24,643 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (346.471 and 347.415 Da) fall comfortably within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (49.85) is significantly better than Ligand B (99.5). For CNS targets, TPSA <= 90 is preferred, and A is well within this range, while B is slightly above.

**3. logP:** Ligand A (2.365) is optimal (1-3), while Ligand B (0.843) is a bit low, potentially hindering membrane permeability.

**4. H-Bond Donors:** Both have acceptable HBD counts (0 for A, 1 for B), well below the threshold of 5.

**5. H-Bond Acceptors:** Both have acceptable HBA counts (3 for A, 5 for B), well below the threshold of 10.

**6. QED:** Both ligands have good QED values (0.385 and 0.76), indicating reasonable drug-likeness. Ligand B is better here.

**7. DILI:** Both ligands have low DILI risk (31.059 and 35.052), both under the 40% threshold.

**8. BBB:** Ligand A (69.794) is better than Ligand B (56.65), although both are not ideal. A value >70 is desirable for CNS targets. Ligand A is closer to this threshold.

**9. Caco-2:** Both have negative Caco-2 values (-4.519 and -4.535), which is unusual and difficult to interpret without more context. It suggests poor permeability.

**10. Solubility:** Both have negative solubility values (-2.195 and -2.182), again unusual and suggesting poor aqueous solubility.

**11. hERG:** Both ligands have very low hERG risk (0.415 and 0.213).

**12. Cl_mic:** Both have similar microsomal clearance (26.288 and 26.229), suggesting similar metabolic stability.

**13. t1/2:** Ligand A (8.515) has a longer in vitro half-life than Ligand B (-3.625). This is a significant advantage.

**14. Pgp:** Ligand A (0.286) has lower P-gp efflux liability than Ligand B (0.016), which is crucial for CNS penetration.

**15. Binding Affinity:** Ligand B (-7.3) has a significantly stronger binding affinity than Ligand A (0). This is a major advantage, exceeding the 1.5 kcal/mol difference threshold.

**Overall Assessment:**

While Ligand B has a much better binding affinity, Ligand A has superior properties regarding CNS penetration (lower TPSA, better BBB, lower Pgp efflux) and metabolic stability (longer half-life). Ligand B's low logP and poor BBB are significant drawbacks for a CNS target. The substantial affinity difference of Ligand B is tempting, but the ADME properties of Ligand A are more favorable for a DRD2 ligand targeting CNS disorders.

Output:
0
2025-04-17 05:27:24,643 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (340.379 and 351.535 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (88.52) is better than Ligand B (52.65) as it is closer to the optimal range for CNS targets (<=90). Ligand B is quite low, which could potentially reduce binding affinity.

**3. logP:** Both ligands have good logP values (3.166 and 2.649), falling within the 1-3 range.

**4. H-Bond Donors:** Ligand A (2) and Ligand B (1) are both acceptable.

**5. H-Bond Acceptors:** Ligand A (4) and Ligand B (3) are both acceptable.

**6. QED:** Both ligands have similar and good QED values (0.892 and 0.8), indicating good drug-like properties.

**7. DILI:** Ligand A (87.01) has a significantly higher DILI risk than Ligand B (11.09). This is a major concern for Ligand A.

**8. BBB:** Ligand B (68.592) has a much better BBB penetration percentile than Ligand A (34.548). For a CNS target like DRD2, this is a critical advantage.

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.87 and -4.621), which is unusual and suggests poor permeability. However, these values are on a log scale, so the absolute difference is not huge.

**10. Aqueous Solubility:** Both ligands have negative solubility values (-4.306 and -2.202), indicating poor aqueous solubility. This could pose formulation challenges.

**11. hERG Inhibition:** Both ligands have low hERG inhibition risk (0.154 and 0.364).

**12. Microsomal Clearance:** Ligand B (43.532) has significantly higher microsomal clearance than Ligand A (6.35). This suggests Ligand A is more metabolically stable.

**13. In vitro Half-Life:** Ligand A (18.44) has a longer half-life than Ligand B (4.964).

**14. P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.077 and 0.09).

**15. Binding Affinity:** Ligand B (-7.5 kcal/mol) has a stronger binding affinity than Ligand A (-9.4 kcal/mol). While Ligand A has a better affinity, the difference is not substantial enough to overcome its other drawbacks.

**Overall Assessment:**

Ligand B is the more promising candidate. While both have poor solubility and Caco-2 permeability, Ligand B excels in BBB penetration, has a significantly lower DILI risk, and a better binding affinity. The improved BBB penetration is crucial for a CNS target like DRD2. Although Ligand A has better metabolic stability and half-life, the higher DILI risk and poor BBB penetration are significant liabilities.

Output:
1
2025-04-17 05:27:24,643 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (337.379 and 349.475 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (70.27) is slightly higher than Ligand B (67.6), but both are below the 90 A^2 threshold desirable for CNS targets.

**3. logP:** Both ligands have good logP values (3.604 and 3.041), falling within the optimal range of 1-3.

**4. H-Bond Donors:** Ligand A has 0 HBD, while Ligand B has 1. Both are acceptable.

**5. H-Bond Acceptors:** Ligand A has 6 HBA, and Ligand B has 5. Both are within the acceptable limit of <=10.

**6. QED:** Both ligands have good QED scores (0.614 and 0.855), indicating good drug-like properties. Ligand B is slightly better.

**7. DILI:** Ligand A has a DILI risk of 76.037, which is concerning (high risk >60). Ligand B has a much lower DILI risk of 17.1, which is excellent.

**8. BBB:** Ligand A has a BBB penetration of 68.941, which is below the desirable threshold of >70 for CNS targets. Ligand B has a significantly higher BBB penetration of 89.725, which is very promising.

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.761 and -4.73), which is unusual and suggests poor permeability. This is a significant drawback for both.

**10. Aqueous Solubility:** Both ligands have negative solubility values (-4.841 and -2.917), indicating very poor aqueous solubility. This is a major concern for both.

**11. hERG Inhibition:** Both ligands have low hERG inhibition risk (0.556 and 0.562).

**12. Microsomal Clearance:** Ligand A has a higher microsomal clearance (51.545) than Ligand B (39.676), suggesting lower metabolic stability.

**13. In vitro Half-Life:** Ligand B has a longer in vitro half-life (12.851 hours) than Ligand A (-9.485 hours).

**14. P-gp Efflux:** Ligand A has a higher P-gp efflux liability (0.444) than Ligand B (0.214), which is unfavorable for CNS penetration.

**15. Binding Affinity:** Ligand B has a better binding affinity (-7.1 kcal/mol) than Ligand A (-8.5 kcal/mol). While A is slightly better, the difference is not substantial enough to overcome other issues.

**Overall Assessment:**

Ligand B is significantly better than Ligand A. While both have poor Caco-2 and solubility, Ligand B excels in critical areas for CNS drug development: lower DILI risk, much higher BBB penetration, longer half-life, lower P-gp efflux, and better binding affinity. Ligand A's high DILI risk and lower BBB penetration are major drawbacks.

Output:
1
2025-04-17 05:27:24,643 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (352.48 Da and 352.41 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (87.47) is better than Ligand B (95.42). Both are below the 90 A^2 threshold desirable for CNS targets, but A is closer to the optimal range.

**logP:** Ligand A (2.187) is within the optimal 1-3 range. Ligand B (0.946) is slightly below 1, which *could* indicate potential permeability issues.

**H-Bond Donors/Acceptors:** Both ligands have 2 HBD and 5 HBA, which are acceptable.

**QED:** Both ligands have good QED scores (0.711 and 0.795, respectively), indicating drug-like properties.

**DILI:** Both ligands have low DILI risk (25.553 and 26.871 percentiles), which is favorable.

**BBB:** Ligand B (71.19) has a significantly better BBB penetration percentile than Ligand A (55.215). This is a *major* advantage for a CNS target like DRD2.

**Caco-2 Permeability:** Ligand A (-5.077) has a worse Caco-2 permeability than Ligand B (-4.791), suggesting lower intestinal absorption.

**Aqueous Solubility:** Both ligands have poor aqueous solubility (-1.473 and -1.394). This is a concern, but can sometimes be mitigated with formulation strategies.

**hERG:** Both ligands have low hERG inhibition liability (0.378 and 0.462), which is good.

**Microsomal Clearance:** Ligand A (49.925) has a better (lower) microsomal clearance than Ligand B (-14.217). This suggests better metabolic stability for Ligand A.

**In vitro Half-Life:** Ligand A (23.732) has a better (longer) in vitro half-life than Ligand B (-13.059).

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.034 and 0.021).

**Binding Affinity:** Ligand B (-8.6 kcal/mol) has a significantly stronger binding affinity than Ligand A (-7.1 kcal/mol). This is a substantial advantage (1.5 kcal/mol difference).

**Overall Assessment:**

While Ligand A has better metabolic stability and half-life, Ligand B excels in the most critical areas for a CNS GPCR target: **BBB penetration and binding affinity**. The significantly stronger binding affinity of Ligand B (-8.6 vs -7.1) is a major driver, and the improved BBB (71.19 vs 55.215) is crucial for CNS exposure. The slightly lower logP of Ligand B is a minor concern, but the benefits outweigh this drawback.

Output:
1
2025-04-17 05:27:24,644 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 drug candidates, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (349.519 and 362.901 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (43.86) is significantly better than Ligand B (49.41). For CNS targets, we want TPSA <= 90, both are well within this range, but A is preferable.

**logP:** Both ligands have acceptable logP values (2.356 and 3.95), falling within the optimal 1-3 range. Ligand B is slightly higher, which *could* indicate potential off-target issues, but isn't a major concern.

**H-Bond Donors/Acceptors:** Ligand A (0 HBD, 3 HBA) and Ligand B (1 HBD, 2 HBA) both have low numbers of HBD and HBA, which is favorable for permeability.

**QED:** Both ligands have good QED scores (0.765 and 0.798), indicating good drug-like properties.

**DILI:** Ligand A (11.4) has a much lower DILI risk than Ligand B (35.673). This is a significant advantage for Ligand A.

**BBB:** Both ligands have excellent BBB penetration (84.878 and 81.466), exceeding the desirable >70 threshold for CNS targets.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.368 and -4.784). This is unusual and suggests poor permeability. However, these values are on a log scale, and a more negative value indicates *lower* permeability.

**Aqueous Solubility:** Ligand A (-1.587) has better (less negative) solubility than Ligand B (-4.528).

**hERG:** Both ligands have low hERG inhibition liability (0.684 and 0.67), which is good.

**Microsomal Clearance:** Ligand A (36.998) has significantly lower microsomal clearance than Ligand B (62.087), indicating better metabolic stability.

**In vitro Half-Life:** Ligand A (-2.535) has a longer in vitro half-life than Ligand B (-1.365).

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.219 and 0.602), which is favorable for CNS exposure.

**Binding Affinity:** Ligand B (-8.5 kcal/mol) has a stronger binding affinity than Ligand A (-7.4 kcal/mol). This is a 1.1 kcal/mol difference, which is substantial and could outweigh some ADME drawbacks.

**Overall Assessment:**

While Ligand B has a better binding affinity, Ligand A demonstrates significantly better ADME properties, particularly regarding DILI risk, metabolic stability (lower Cl_mic, longer t1/2), and solubility. The difference in binding affinity (1.1 kcal/mol) is important, but the superior ADME profile of Ligand A, especially the lower DILI risk, makes it the more promising candidate. Given the CNS target, BBB penetration is excellent for both, but the other ADME properties are more critical for overall viability.

Output:
0
2025-04-17 05:27:24,644 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (362.5 and 348.5 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (76.02) is higher than Ligand B (49.41). For a CNS target like DRD2, TPSA should ideally be <= 90, so both are acceptable, but Ligand B is significantly better.

**3. logP:** Both ligands have good logP values (3.123 and 3.889), falling within the optimal 1-3 range. Ligand B is slightly higher, which could be beneficial for membrane permeability but needs to be balanced against solubility.

**4. H-Bond Donors:** Ligand A has 2 HBD, and Ligand B has 1. Both are within the acceptable limit of <=5.

**5. H-Bond Acceptors:** Ligand A has 5 HBA, and Ligand B has 2. Both are within the acceptable limit of <=10.

**6. QED:** Both ligands have good QED scores (0.709 and 0.792), indicating good drug-like properties.

**7. DILI:** Ligand A (32.38%) has a slightly higher DILI risk than Ligand B (22.8%). Both are below the 40% threshold, indicating low risk.

**8. BBB:** Ligand B (79.68%) has a significantly better BBB penetration percentile than Ligand A (59.09%). This is a *critical* factor for a CNS target like DRD2.

**9. Caco-2 Permeability:** Ligand A (-5.401) and Ligand B (-4.766) both have negative values, which is unusual and suggests poor permeability. However, the scale isn't specified, so it's hard to interpret.

**10. Aqueous Solubility:** Ligand A (-1.995) and Ligand B (-4.141) both have negative values, suggesting poor solubility. This is a potential concern, but can sometimes be overcome with formulation strategies.

**11. hERG Inhibition:** Both ligands have low hERG inhibition risk (0.66 and 0.517).

**12. Microsomal Clearance:** Ligand B (54.954) has a higher microsomal clearance than Ligand A (39.283), indicating faster metabolism and potentially lower *in vivo* exposure.

**13. In vitro Half-Life:** Ligand A (24.566) has a longer half-life than Ligand B (-7.369). This is a positive attribute.

**14. P-gp Efflux:** Both ligands have low P-gp efflux liability (0.199 and 0.356).

**15. Binding Affinity:** Ligand B (-7.9 kcal/mol) has a slightly better binding affinity than Ligand A (-8.4 kcal/mol). While both are excellent, a difference of 0.5 kcal/mol is meaningful.

**Overall Assessment:**

Ligand B is the more promising candidate. While Ligand A has a longer half-life, Ligand B excels in the critical areas for a CNS GPCR target: significantly better BBB penetration (79.7% vs 59.1%), a lower TPSA, and slightly better binding affinity. The higher metabolic clearance of Ligand B is a concern, but the superior BBB penetration and affinity are likely to outweigh this drawback.

Output:
1
2025-04-17 05:27:24,644 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (365.5) is slightly higher than Ligand B (334.4).

**2. TPSA:** Ligand A (78.51) is better than Ligand B (60.67) for CNS penetration, being closer to the <90 target.

**3. logP:** Ligand A (1.238) is optimal, while Ligand B (3.889) is approaching the upper limit of the optimal range.

**4. H-Bond Donors:** Ligand A (2) is good, while Ligand B (0) is also acceptable.

**5. H-Bond Acceptors:** Ligand A (4) is good, and Ligand B (5) is also acceptable.

**6. QED:** Both ligands have similar, good QED values (0.666 and 0.679).

**7. DILI:** Ligand A (41.024) has a significantly lower DILI risk than Ligand B (64.909). This is a substantial advantage.

**8. BBB:** Ligand B (61.768) has a slightly better BBB percentile than Ligand A (50.679), but both are below the desirable >70 for CNS targets.

**9. Caco-2 Permeability:** Ligand A (-5.536) has a more negative Caco-2 value, which is less favorable than Ligand B (-4.855).

**10. Aqueous Solubility:** Ligand A (-2.718) has better aqueous solubility than Ligand B (-4.486).

**11. hERG Inhibition:** Both ligands have low hERG inhibition risk (0.106 and 0.257).

**12. Microsomal Clearance:** Ligand A (35.19) has a lower microsomal clearance, indicating better metabolic stability, than Ligand B (71.576).

**13. In vitro Half-Life:** Ligand B (-8.258) has a more negative in vitro half-life, suggesting a longer half-life than Ligand A (1.35).

**14. P-gp Efflux:** Ligand A (0.051) has a significantly lower P-gp efflux liability than Ligand B (0.545), which is crucial for CNS penetration.

**15. Binding Affinity:** Ligand B (-9.9) has a substantially stronger binding affinity than Ligand A (-8.2). This is a 1.7 kcal/mol difference, which is a significant advantage.

**Overall Assessment:**

While Ligand B has a superior binding affinity and slightly better BBB penetration and in vitro half-life, Ligand A demonstrates a more favorable ADME profile overall. Specifically, Ligand A has a lower DILI risk, lower P-gp efflux, better solubility, and better metabolic stability. For a CNS target like DRD2, minimizing efflux and DILI risk are critical. The affinity difference, while substantial, might be overcome with further optimization of Ligand A, whereas improving the ADME properties of Ligand B would likely be more challenging. Considering the GPCR-specific priorities, Ligand A is the more promising candidate.

Output:
0
2025-04-17 05:27:24,644 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (343.471 and 352.479 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (61.44) is significantly better than Ligand B (95.74). For CNS targets, we want TPSA <= 90, so Ligand A is much closer to this threshold.

**3. logP:** Ligand A (2.186) is optimal (1-3), while Ligand B (0.48) is a bit low, potentially hindering permeation.

**4. H-Bond Donors:** Both have 2 HBD, which is acceptable (<=5).

**5. H-Bond Acceptors:** Ligand A has 3 HBA, and Ligand B has 4. Both are within the acceptable limit of <=10.

**6. QED:** Both ligands have similar QED values (0.798 and 0.752), indicating good drug-likeness.

**7. DILI:** Ligand A (21.869) has a lower DILI risk than Ligand B (12.33), which is preferable.

**8. BBB:** This is crucial for a CNS target like DRD2. Ligand A (62.233) is significantly better than Ligand B (43.311). A value >70 is desirable, but 62.233 is a much more promising starting point than 43.311.

**9. Caco-2 Permeability:** Ligand A (-4.825) is better than Ligand B (-5.378). Higher values are better.

**10. Aqueous Solubility:** Ligand A (-2.31) is better than Ligand B (-1.58). Higher values are better.

**11. hERG Inhibition:** Ligand A (0.49) has a lower hERG risk than Ligand B (0.101), which is preferable.

**12. Microsomal Clearance:** Ligand B (-6.2) has a significantly lower (better) microsomal clearance than Ligand A (17.456). This suggests better metabolic stability for Ligand B.

**13. In vitro Half-Life:** Ligand A (7.995) has a better in vitro half-life than Ligand B (-7.723).

**14. P-gp Efflux:** Ligand B (0.005) has much lower P-gp efflux than Ligand A (0.089). Lower efflux is highly desirable for CNS penetration.

**15. Binding Affinity:** Ligand A (-8.2) has a significantly stronger binding affinity than Ligand B (-0.0). This is a major advantage, and a difference of >1.5 kcal/mol can often outweigh other ADME concerns.

**Overall Assessment:**

Ligand A excels in binding affinity, TPSA, BBB penetration, and has a lower DILI risk. While Ligand B has better metabolic stability (lower Cl_mic) and P-gp efflux, the substantial difference in binding affinity and the significantly better BBB score of Ligand A make it the more promising candidate. The slightly higher TPSA of Ligand A is less concerning than the poor BBB and low logP of Ligand B. The strong binding affinity of Ligand A (-8.2 kcal/mol) is a critical advantage for a GPCR target.

Output:
1
2025-04-17 05:27:24,645 - INFO - Reasoning:

Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (355.429 and 352.366 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (58.37) is excellent, well below the 90 A^2 threshold for CNS targets. Ligand B (124.44) is higher, but still potentially acceptable, though less ideal.

**3. logP:** Ligand A (3.732) is within the optimal 1-3 range. Ligand B (-1.038) is significantly lower, which could hinder membrane permeability and CNS penetration.

**4. H-Bond Donors:** Ligand A (1) is good. Ligand B (4) is higher, potentially impacting permeability.

**5. H-Bond Acceptors:** Ligand A (4) is good. Ligand B (6) is higher, potentially impacting permeability.

**6. QED:** Ligand A (0.722) is excellent, indicating good drug-like properties. Ligand B (0.443) is lower, suggesting a less favorable overall profile.

**7. DILI:** Ligand A (25.126) has a very low DILI risk. Ligand B (46.258) is higher, indicating a moderate risk.

**8. BBB:** Ligand A (98.061) has excellent predicted BBB penetration. Ligand B (36.177) is significantly lower, a major concern for a CNS target like DRD2.

**9. Caco-2:** Ligand A (-4.69) and Ligand B (-5.228) both have negative values, which is unusual. Assuming these are logP values, they indicate very poor permeability. However, since Caco-2 is listed as a separate property, it's likely these are percentile scores, and lower values indicate poor permeability.

**10. Solubility:** Ligand A (-2.762) and Ligand B (-1.793) both have negative solubility scores. This is concerning, and suggests formulation challenges.

**11. hERG:** Ligand A (0.944) has a low hERG risk. Ligand B (0.138) also has a low hERG risk.

**12. Cl_mic:** Ligand A (26.052) has a moderate clearance. Ligand B (-1.787) has a very low (and potentially unrealistic) clearance, suggesting very high metabolic stability.

**13. t1/2:** Ligand A (-17.456) has a negative half-life, which is impossible. Assuming this is a percentile score, it indicates very poor in vitro stability. Ligand B (-3.92) also has a negative half-life, indicating very poor in vitro stability.

**14. Pgp:** Ligand A (0.575) has moderate P-gp efflux. Ligand B (0.042) has very low P-gp efflux, which is favorable for CNS penetration.

**15. Binding Affinity:** Ligand A (-8.6 kcal/mol) has a significantly stronger binding affinity than Ligand B (-7.9 kcal/mol). The 0.7 kcal/mol difference is substantial and could outweigh some ADME drawbacks.

**Overall Assessment:**

Despite the questionable half-life and solubility values for both compounds, Ligand A is the superior candidate. Its significantly better BBB penetration, higher QED, lower DILI risk, and, crucially, stronger binding affinity make it more likely to succeed as a DRD2-targeting drug. Ligand B's poor logP and BBB penetration are major liabilities for a CNS-focused drug. The very low clearance and Pgp efflux for Ligand B are positives, but are outweighed by the other deficiencies.

Output:
1
2025-04-17 05:27:24,645 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (357.5 and 351.5 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (82.11) is slightly higher than Ligand B (61.88). For CNS targets, we prefer TPSA <= 90, so both are acceptable, but B is better.

**logP:** Both ligands have good logP values (1.018 and 1.415), falling within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A has 2 HBD and 5 HBA, while Ligand B has 1 HBD and 4 HBA. Both are within acceptable limits (<=5 HBD and <=10 HBA).

**QED:** Both ligands have good QED scores (0.634 and 0.735), indicating good drug-like properties.

**DILI:** Both ligands have low DILI risk (23.77 and 20.71), which is favorable.

**BBB:** This is a critical parameter for CNS targets. Ligand B (62.16) is significantly better than Ligand A (30.59), exceeding the desirable >70 threshold, while A is far from it.

**Caco-2 Permeability:** Ligand A (-5.039) and Ligand B (-4.659) both have negative values, which is unusual and indicates poor permeability. However, the scale isn't defined, so it's hard to interpret.

**Aqueous Solubility:** Both ligands have poor aqueous solubility (-1.577 and -1.181). This could be a formulation challenge, but not a deal-breaker if other properties are strong.

**hERG Inhibition:** Both ligands show very low hERG inhibition risk (0.265 and 0.1), which is excellent.

**Microsomal Clearance:** Ligand A (14.197) has a lower (better) microsomal clearance than Ligand B (30.179), indicating better metabolic stability.

**In vitro Half-Life:** Ligand B (-19.628) has a much longer (better) in vitro half-life than Ligand A (-1.481).

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.021 and 0.033), which is favorable for CNS penetration.

**Binding Affinity:** Ligand B (-7.4 kcal/mol) has a significantly stronger binding affinity than Ligand A (-6.3 kcal/mol). This 1.1 kcal/mol difference is substantial and can outweigh some ADME drawbacks.

**Conclusion:**

Ligand B is the stronger candidate. While both have issues with solubility and Caco-2 permeability, Ligand B's superior BBB penetration and significantly improved binding affinity are decisive. The longer half-life is also a benefit. The slightly higher clearance of B is less concerning given the strong affinity. Given the GPCR target and the importance of CNS penetration, the BBB score is paramount.

Output:
1
2025-04-17 05:27:24,645 - INFO - Reasoning:

Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (340.47 and 353.46 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (58.2) is excellent, well below the 90 A^2 threshold for CNS targets. Ligand B (78.95) is still reasonable but less optimal.

**logP:** Ligand A (3.702) is within the optimal 1-3 range. Ligand B (0.491) is quite low, potentially hindering membrane permeability and CNS penetration.

**H-Bond Donors/Acceptors:** Ligand A has 2 HBD and 2 HBA, well within acceptable limits. Ligand B has 1 HBD and 5 HBA, also acceptable, though the higher HBA count could slightly impact permeability.

**QED:** Ligand A (0.504) has a good drug-likeness score. Ligand B (0.371) is lower, suggesting a less favorable overall drug-like profile.

**DILI:** Ligand A (36.681) has a low DILI risk. Ligand B (6.863) also has a very low DILI risk.

**BBB:** Ligand A (68.321) is good, but ideally >70 for CNS targets. Ligand B (72.858) is better, exceeding the 70% threshold.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.811 and -4.931), which is unusual and suggests poor permeability. However, these values are on a log scale, and negative values simply indicate permeability below the detection limit.

**Aqueous Solubility:** Both ligands have negative solubility values (-4.085 and -1.079), indicating very poor aqueous solubility. This is a significant concern for bioavailability.

**hERG Inhibition:** Ligand A (0.71) has a lower hERG risk than Ligand B (0.412).

**Microsomal Clearance:** Ligand A (48.703) has moderate clearance. Ligand B (13.328) has significantly lower clearance, indicating better metabolic stability.

**In vitro Half-Life:** Ligand A (-1.445) has a very short half-life. Ligand B (-34.013) has an extremely long half-life.

**P-gp Efflux:** Ligand A (0.221) has low P-gp efflux, which is favorable for CNS penetration. Ligand B (0.017) has very low P-gp efflux, even more favorable.

**Binding Affinity:** Ligand A (-8.4 kcal/mol) has a significantly stronger binding affinity than Ligand B (-6.6 kcal/mol). This is a substantial advantage.

**Overall Assessment:**

Ligand A excels in binding affinity and has a good TPSA and acceptable BBB penetration. Its main drawbacks are its poor solubility and short half-life. Ligand B has a better BBB, lower clearance, and extremely long half-life, but suffers from a significantly weaker binding affinity and a very low logP, which is a major concern for CNS penetration.

Given the importance of binding affinity for GPCRs, and the fact that the difference in affinity is >1.5 kcal/mol, Ligand A is the more promising candidate despite its solubility and half-life issues. These ADME properties can be addressed through further optimization. The low logP of Ligand B is a more difficult property to improve without sacrificing affinity.

Output:
1
2025-04-17 05:27:24,645 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight (MW):** Both ligands (339.439 and 350.503 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (53.51) is significantly better than Ligand B (78.43). For CNS targets, we want TPSA <= 90, and A is much closer to the optimal <=60 range. B is pushing the upper limit.

**3. logP:** Both ligands have good logP values (2.396 and 2.232), falling within the 1-3 range.

**4. H-Bond Donors (HBD):** Both ligands are acceptable (0 and 3 respectively), staying within the <=5 guideline.

**5. H-Bond Acceptors (HBA):** Both ligands are acceptable (3 and 3 respectively), staying within the <=10 guideline.

**6. QED:** Ligand A (0.85) has a significantly better QED score than Ligand B (0.628), indicating a more drug-like profile.

**7. DILI:** Both ligands have similar and acceptable DILI risk (16.44 and 16.208 percentile).

**8. BBB:** This is crucial for a CNS target like DRD2. Ligand A (89.027) is excellent, exceeding the desirable >70 threshold. Ligand B (56.029) is considerably lower, suggesting poorer brain penetration.

**9. Caco-2 Permeability:** Both are negative, which is unusual. This suggests poor intestinal absorption. However, for a CNS target, this is less critical than BBB.

**10. Aqueous Solubility:** Both are negative, suggesting poor solubility. This could be a formulation challenge, but is less critical for CNS targets if BBB penetration is good.

**11. hERG Inhibition:** Both ligands have low hERG inhibition risk (0.29 and 0.357).

**12. Microsomal Clearance:** Ligand A (32.029) has lower clearance than Ligand B (46.503), indicating better metabolic stability.

**13. In vitro Half-Life:** Ligand A (2.376) has a slightly better half-life than Ligand B (-4.89), although both are not ideal.

**14. P-gp Efflux:** Both ligands have low P-gp efflux liability (0.125 and 0.259), which is good for CNS penetration.

**15. Binding Affinity:** Ligand B (-8.5 kcal/mol) has a slightly better binding affinity than Ligand A (-7.9 kcal/mol). However, the difference (0.6 kcal/mol) is not substantial enough to outweigh the significant advantages of Ligand A in other key ADME properties.

**Overall Assessment:**

Ligand A is the superior candidate. While Ligand B has slightly better binding affinity, Ligand A excels in crucial properties for a CNS-targeting GPCR ligand: significantly better TPSA, a much higher BBB score, better QED, and lower microsomal clearance. The improved BBB and TPSA are particularly important for DRD2, as they suggest better brain exposure and potentially higher efficacy.



Output:
0
2025-04-17 05:27:24,646 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (352.479 and 368.369 Da) fall within the ideal range of 200-500 Da.

**TPSA:** Ligand A (90.54) is excellent for CNS penetration, being under the 90 threshold. Ligand B (100.97) is still reasonable but less optimal.

**logP:** Ligand A (0.398) is quite low, potentially hindering membrane permeability. Ligand B (0.708) is slightly better but still on the lower side of the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A has 3 HBD and 4 HBA, which are acceptable. Ligand B has 1 HBD and 7 HBA, also acceptable, though the higher HBA count could slightly impact permeability.

**QED:** Both ligands have good QED scores (0.56 and 0.806), indicating generally drug-like properties. Ligand B is better here.

**DILI:** Ligand A (9.849) has a very low DILI risk, which is excellent. Ligand B (84.296) has a significantly higher DILI risk, which is a major concern.

**BBB:** Ligand A (43.117) has a poor BBB penetration percentile. Ligand B (71.307) is much better, exceeding the desirable >70 threshold for CNS targets. This is a critical advantage for Ligand B.

**Caco-2 Permeability:** Both have negative Caco-2 values (-5.724 and -5.413), which is unusual and suggests poor permeability. However, these values are on a scale where negative values are possible, and the absolute values are similar.

**Aqueous Solubility:** Both ligands have poor aqueous solubility (-0.611 and -2.544).

**hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.148 and 0.102).

**Microsomal Clearance:** Ligand A (-15.463) has a very low (and likely good) microsomal clearance, indicating high metabolic stability. Ligand B (4.379) has a positive clearance, suggesting faster metabolism.

**In vitro Half-Life:** Ligand A (5.483) has a relatively short half-life. Ligand B (-3.74) has a negative half-life, which is unusual and potentially problematic.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.005 and 0.049).

**Binding Affinity:** Both ligands have strong binding affinities (-8.2 and -7.9 kcal/mol), with Ligand A being slightly better. The difference (0.3 kcal/mol) isn't huge enough to overcome other significant drawbacks.

**Overall Assessment:**

Ligand B is significantly better regarding BBB penetration, a crucial factor for a CNS target like DRD2. While its DILI risk is higher, the strong binding affinity and acceptable QED score are positives. Ligand A has a better DILI profile and slightly better affinity, but its extremely poor BBB penetration and lower logP are major drawbacks. The negative half-life for Ligand B is concerning, but could be an artifact of the modeling. The low logP for Ligand A is a significant issue for CNS penetration.

Output:
1
2025-04-17 05:27:24,646 - INFO - Batch 199 complete. Total preferences: 3184
2025-04-17 05:27:24,646 - INFO - Processing batch 200/512...
2025-04-17 05:28:05,512 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (341.411 and 348.491 Da) are within the ideal 200-500 Da range.

**TPSA:** Ligand A (71.53) is better than Ligand B (47.1). Both are below 90, which is favorable for CNS penetration.

**logP:** Ligand A (1.207) is within the optimal 1-3 range. Ligand B (0.195) is slightly low, potentially hindering permeation.

**H-Bond Donors:** Ligand A (1) is better than Ligand B (0). Lower is generally preferred for BBB penetration.

**H-Bond Acceptors:** Both ligands have 4 HBA, which is acceptable.

**QED:** Ligand A (0.817) is better than Ligand B (0.712), indicating a more drug-like profile.

**DILI:** Ligand A (59.907) has a higher DILI risk than Ligand B (5.157). This is a significant drawback for Ligand A.

**BBB:** Ligand B (80.07) is significantly better than Ligand A (52.889) in terms of predicted BBB penetration, which is crucial for a CNS target like DRD2.

**Caco-2 Permeability:** Ligand A (-4.589) and Ligand B (-4.791) both have negative values, suggesting poor permeability.

**Aqueous Solubility:** Ligand A (-3.029) is slightly better than Ligand B (-0.316), but both are poor.

**hERG:** Ligand A (0.084) has a slightly lower hERG risk than Ligand B (0.467).

**Microsomal Clearance:** Ligand B (-3.726) has a lower (better) microsomal clearance than Ligand A (3.227), indicating greater metabolic stability.

**In vitro Half-Life:** Ligand B (-3.211) has a longer half-life than Ligand A (6.352), which is desirable.

**P-gp Efflux:** Ligand A (0.028) has a lower P-gp efflux liability than Ligand B (0.008), which is better for CNS exposure.

**Binding Affinity:** Ligand B (-8.6 kcal/mol) has a significantly stronger binding affinity than Ligand A (-7.8 kcal/mol). This >1.5 kcal/mol difference is substantial and can outweigh some ADME drawbacks.

**Overall Assessment:**

Ligand B is the more promising candidate. While its logP is slightly low and solubility is poor, its *significantly* better BBB penetration, stronger binding affinity, lower DILI risk, and improved metabolic stability/half-life outweigh the drawbacks. The strong binding affinity is a major advantage for a GPCR target. Ligand A's higher DILI risk and lower BBB penetration are significant concerns.

Output:
1
2025-04-17 05:28:05,512 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 drug candidates, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (362.86 and 353.42 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (78.43) is significantly better than Ligand B (96.97). For CNS targets, we want TPSA <= 90, so Ligand A is preferable.

**logP:** Ligand A (3.34) is optimal (1-3), while Ligand B (1.10) is on the lower side, potentially hindering permeation.

**H-Bond Donors/Acceptors:** Ligand A has 3 HBD and 3 HBA, while Ligand B has 2 HBD and 5 HBA. Both are within acceptable limits (<=5 HBD, <=10 HBA).

**QED:** Both ligands have good QED scores (0.567 and 0.668, respectively), indicating drug-like properties.

**DILI:** Both ligands have acceptable DILI risk (46.96 and 49.71, both <60).

**BBB:** Both ligands have reasonably good BBB penetration (58.24% and 55.14%). While >70 is desirable, these are not disqualifying, and the difference is small.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.132 and -5.22). This is unusual and suggests poor permeability. However, these values are on a scale where negative values are possible and don't necessarily mean zero permeability.

**Aqueous Solubility:** Both ligands have negative solubility values (-4.728 and -2.505). Again, this is on a scale where negative values are possible, and doesn't necessarily mean zero solubility.

**hERG:** Both ligands have low hERG inhibition liability (0.298 and 0.134), which is good.

**Microsomal Clearance:** Ligand A (42.16) has a higher (worse) microsomal clearance than Ligand B (-17.30). This suggests Ligand B is more metabolically stable.

**In vitro Half-Life:** Ligand B (-8.83) has a longer in vitro half-life than Ligand A (5.5).

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.155 and 0.025), which is favorable for CNS penetration.

**Binding Affinity:** Ligand A (-8.3 kcal/mol) has a slightly better binding affinity than Ligand B (-7.8 kcal/mol). While the difference is less than the 1.5 kcal/mol threshold that would overwhelmingly favor one ligand, it's still a positive for Ligand A.

**Overall Assessment:**

Ligand A is superior due to its more favorable TPSA and logP values, which are critical for CNS penetration. While Ligand B has better metabolic stability and half-life, the slight advantage in binding affinity of Ligand A, combined with its better TPSA and logP, makes it the more promising candidate. The negative Caco-2 and solubility values are concerning for both, but not necessarily disqualifying without further investigation.

Output:
1
2025-04-17 05:28:05,513 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (368.302 and 354.397 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (51.66) is significantly better than Ligand B (78.43). For CNS targets, we want TPSA <= 90, and A is much closer to the ideal <=60 range. B is pushing the upper limit.

**3. logP:** Both ligands have good logP values (3.143 and 2.759), falling within the optimal 1-3 range.

**4. H-Bond Donors:** Ligand A (0) is preferable to Ligand B (3). Fewer HBDs generally improve permeability.

**5. H-Bond Acceptors:** Ligand A (5) is preferable to Ligand B (3).

**6. QED:** Both ligands have good QED scores (0.57 and 0.761), indicating good drug-like properties.

**7. DILI:** Both ligands have acceptable DILI risk (39.434 and 31.059), both below the 40 threshold.

**8. BBB:** Ligand A (85.731) has a significantly better BBB percentile than Ligand B (74.564). For a CNS target like DRD2, a BBB > 70 is highly desirable, and A is closer to this target.

**9. Caco-2 Permeability:** Ligand A (-4.507) is better than Ligand B (-4.883), though both are negative. Higher values are better.

**10. Aqueous Solubility:** Ligand A (-3.819) is better than Ligand B (-3.566), though both are negative. Higher values are better.

**11. hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.561 and 0.496), which is excellent.

**12. Microsomal Clearance:** Ligand B (47.385) has lower microsomal clearance than Ligand A (53.576), suggesting better metabolic stability.

**13. In vitro Half-Life:** Ligand B (-27.566) has a significantly longer in vitro half-life than Ligand A (-16.802). This is a major advantage.

**14. P-gp Efflux:** Both ligands have low P-gp efflux liability (0.131 and 0.061), which is good for CNS penetration.

**15. Binding Affinity:** Both ligands have excellent binding affinity (-8 and -9 kcal/mol). Ligand B is slightly better.

**Overall Assessment:**

While Ligand B has a slightly better binding affinity and a significantly longer half-life, Ligand A is superior in terms of TPSA and BBB penetration, both crucial for CNS drug development. The lower TPSA and better BBB of Ligand A are more important than the slight affinity advantage of Ligand B. The lower HBD and HBA are also beneficial.

Output:
1
2025-04-17 05:28:05,513 - INFO - Reasoning:

Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (361.833 and 359.333 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (88.91) is excellent, well below the 90 A^2 threshold for CNS targets. Ligand B (127.42) is higher but still reasonable, though less optimal for CNS penetration.

**3. logP:** Ligand A (1.275) is within the optimal 1-3 range. Ligand B (-0.996) is slightly below 1, potentially hindering permeation.

**4. H-Bond Donors:** Ligand A (2) and Ligand B (4) are both acceptable, below the 5 threshold.

**5. H-Bond Acceptors:** Both ligands (A: 5, B: 5) are below the 10 threshold.

**6. QED:** Ligand A (0.811) has a significantly better QED score than Ligand B (0.502), indicating a more drug-like profile.

**7. DILI:** Ligand A (70.57) has a higher DILI risk than Ligand B (53.47), but both are below the concerning 60 threshold.

**8. BBB:** Ligand A (64.599) has a better BBB percentile than Ligand B (36.371). This is a *critical* factor for a CNS target like DRD2.

**9. Caco-2 Permeability:** Both have negative values, which is unusual. Assuming these are logP-scale values, lower values indicate poorer permeability. Ligand A (-5.244) is worse than Ligand B (-5.461).

**10. Aqueous Solubility:** Both have negative values, indicating poor solubility. Ligand A (-3.381) is slightly better than Ligand B (-1.983).

**11. hERG:** Both ligands have very low hERG inhibition risk (0.201 and 0.233).

**12. Microsomal Clearance:** Ligand B (-37.477) has a much lower (better) microsomal clearance than Ligand A (37.16). This suggests better metabolic stability for Ligand B.

**13. In vitro Half-Life:** Ligand B (-25.591) has a longer in vitro half-life than Ligand A (34.163).

**14. P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.195 and 0.011).

**15. Binding Affinity:** Ligand A (-9.7 kcal/mol) has a significantly stronger binding affinity than Ligand B (-8.6 kcal/mol). This is a substantial difference.

**Overall Assessment:**

While Ligand B shows advantages in metabolic stability (Cl_mic, t1/2) and has a lower DILI risk, Ligand A is superior overall, particularly due to its *much* stronger binding affinity (-9.7 vs -8.6 kcal/mol) and significantly better BBB penetration (64.6 vs 36.4). The stronger affinity can potentially overcome some of the ADME drawbacks. The TPSA of Ligand A is also much more favorable for CNS penetration. The slightly lower logP of Ligand B is a concern. For a CNS GPCR target, high affinity and good BBB penetration are paramount, and Ligand A excels in these areas.

Output:
1
2025-04-17 05:28:05,513 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight (MW):** Both ligands (345.403 and 345.447 Da) fall comfortably within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (106.07) is better than Ligand B (62.63). For CNS targets, we want TPSA <= 90, so Ligand B is preferable.

**3. logP:** Ligand B (2.53) is more optimal than Ligand A (0.894). The ideal range is 1-3, and Ligand A is slightly below 1, which could hinder permeation.

**4. H-Bond Donors (HBD):** Both ligands are within the acceptable limit of <=5 (Ligand A: 2, Ligand B: 1).

**5. H-Bond Acceptors (HBA):** Both ligands are within the acceptable limit of <=10 (Ligand A: 7, Ligand B: 5).

**6. QED:** Both ligands have good QED scores (Ligand A: 0.805, Ligand B: 0.925), indicating drug-like properties.

**7. DILI:** Ligand A (44.94) has a considerably lower DILI risk than Ligand B (56.844). Lower is better, and both are acceptable, but A is preferred.

**8. BBB:** Ligand B (78.674) has a significantly better BBB penetration score than Ligand A (24.389). This is *critical* for a CNS target like DRD2, making Ligand B strongly favored.

**9. Caco-2 Permeability:** Ligand A (-5.273) has a worse Caco-2 permeability than Ligand B (-4.646). Higher is better.

**10. Aqueous Solubility:** Both ligands have very poor aqueous solubility (-1.66 and -1.789). This is a concern for both, but not a deciding factor.

**11. hERG Inhibition:** Both ligands show very low hERG inhibition risk (Ligand A: 0.028, Ligand B: 0.872).

**12. Microsomal Clearance:** Ligand A (-16.928) has a much lower (better) microsomal clearance than Ligand B (24.866), indicating greater metabolic stability.

**13. In vitro Half-Life:** Ligand B (31.199) has a longer half-life than Ligand A (25.951).

**14. P-gp Efflux:** Both ligands show very low P-gp efflux liability (Ligand A: 0.015, Ligand B: 0.078).

**15. Binding Affinity:** Both ligands have very similar and excellent binding affinities (Ligand A: -8.9 kcal/mol, Ligand B: -8.3 kcal/mol). The difference is less than 1.5 kcal/mol, so it's not a major deciding factor.

**Overall Assessment:**

Ligand B is clearly superior due to its significantly better BBB penetration (78.674 vs 24.389) and more optimal logP (2.53 vs 0.894). While Ligand A has a lower DILI risk and better metabolic stability, the BBB and logP are paramount for CNS GPCR targets. The slightly longer half-life of Ligand B is also a plus.



Output:
1
2025-04-17 05:28:05,513 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (348.447 and 352.475 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (95.42) is slightly above the preferred <90 for CNS targets, but still reasonable. Ligand B (66.92) is well within the ideal range. This favors Ligand B.

**3. logP:** Both ligands have good logP values (2.136 and 1.869), falling within the optimal 1-3 range.

**4. H-Bond Donors:** Ligand A has 2 HBD, which is acceptable. Ligand B has 0, also acceptable.

**5. H-Bond Acceptors:** Ligand A has 5 HBA, within the limit. Ligand B has 4, also within the limit.

**6. QED:** Ligand A (0.787) has a better QED score than Ligand B (0.594), indicating a more drug-like profile.

**7. DILI:** Ligand A (41.605) has a slightly higher DILI risk than Ligand B (15.471), but both are below the concerning threshold of 60. This favors Ligand B.

**8. BBB:** Ligand B (76.192) has a significantly better BBB penetration percentile than Ligand A (57.619). This is a crucial advantage for a CNS target like DRD2.

**9. Caco-2 Permeability:** Ligand A (-4.899) has worse Caco-2 permeability than Ligand B (-4.24). Lower values are less desirable. This favors Ligand B.

**10. Aqueous Solubility:** Ligand A (-2.906) has worse aqueous solubility than Ligand B (-0.884). Lower values are less desirable. This favors Ligand B.

**11. hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.087 and 0.337), which is excellent.

**12. Microsomal Clearance:** Ligand A (55.125) has lower microsomal clearance than Ligand B (63.399), suggesting better metabolic stability. This favors Ligand A.

**13. In vitro Half-Life:** Ligand A (-9.795) has a longer in vitro half-life than Ligand B (-4.998). This favors Ligand A.

**14. P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.093 and 0.099), which is desirable.

**15. Binding Affinity:** Ligand B (-7.6 kcal/mol) has a slightly better binding affinity than Ligand A (-7.3 kcal/mol). While the difference is small, it's enough to consider.

**Overall Assessment:**

Ligand B clearly outperforms Ligand A in several critical areas for a CNS-targeting GPCR ligand: BBB penetration, TPSA, DILI risk, Caco-2 permeability, and aqueous solubility. While Ligand A has advantages in metabolic stability (Cl_mic) and half-life, the improved CNS penetration and safety profile of Ligand B are more important for DRD2. The slightly better binding affinity of Ligand B further solidifies its position as the more promising candidate.

Output:
1
2025-04-17 05:28:05,514 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B based on the provided guidelines, prioritizing GPCR-specific properties (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (344.46 and 363.53 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (74.33) is better than Ligand B (62.3). Both are below the 90 A^2 threshold desirable for CNS targets.

**logP:** Ligand A (2.143) is within the optimal 1-3 range. Ligand B (3.45) is slightly higher, potentially increasing off-target effects, but still acceptable.

**H-Bond Donors/Acceptors:** Ligand A has 2 HBD and 4 HBA, while Ligand B has 1 HBD and 4 HBA. Both are within acceptable limits.

**QED:** Ligand B (0.842) has a significantly better QED score than Ligand A (0.532), indicating a more drug-like profile.

**DILI:** Ligand A (33.23) has a lower DILI risk than Ligand B (47.732), which is preferable.

**BBB:** Both ligands have excellent BBB penetration (Ligand A: 71.074, Ligand B: 70.415), exceeding the >70% threshold for CNS targets.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.021 and -5.061), which is unusual and suggests poor permeability. However, these values are on the same scale, so don't differentiate the compounds.

**Aqueous Solubility:** Both ligands have negative solubility values (-2.794 and -3.197), also unusual and suggesting poor solubility. Again, these are similar.

**hERG:** Both ligands have very low hERG inhibition liability (0.65 and 0.427), which is excellent.

**Microsomal Clearance:** Ligand B (35.484) has lower microsomal clearance than Ligand A (50.012), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (58.995) has a significantly longer in vitro half-life than Ligand B (12.262), which is a strong advantage.

**P-gp Efflux:** Ligand A (0.06) has much lower P-gp efflux liability than Ligand B (0.483), which is crucial for CNS penetration.

**Binding Affinity:** Ligand B (-8.9 kcal/mol) has a significantly stronger binding affinity than Ligand A (-7.9 kcal/mol). This 1 kcal/mol difference is substantial and can outweigh some ADME drawbacks.

**Overall Assessment:**

Ligand B has a superior binding affinity and a better QED score, and lower microsomal clearance. However, Ligand A has a lower DILI risk, lower P-gp efflux, and a significantly longer half-life. Given the CNS target (DRD2), strong binding affinity and good BBB penetration are paramount. The 1 kcal/mol difference in binding affinity is a significant advantage for Ligand B, and the slightly higher P-gp efflux and DILI are less concerning given the excellent BBB values. The longer half-life of Ligand A is attractive, but the significantly stronger binding of Ligand B is more important for efficacy.

Output:
1
2025-04-17 05:28:05,514 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B based on the provided guidelines, prioritizing GPCR-specific properties (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (364.511 Da) is slightly better, being closer to the lower end which can aid permeability.

**TPSA:** Ligand A (78.43) is significantly better than Ligand B (103.78). For CNS targets, TPSA should be <=90, and A is comfortably within that range, while B is pushing the limit.

**logP:** Both ligands have acceptable logP values (A: 2.943, B: 1.838), falling within the optimal 1-3 range. A is slightly better, being closer to the upper end of the range, potentially aiding membrane permeability.

**H-Bond Donors/Acceptors:** Ligand A (HBD=3, HBA=4) is better than Ligand B (HBD=1, HBA=10). While both are within acceptable limits, B has a high number of HBA which could hinder permeability.

**QED:** Both ligands have reasonable QED values (A: 0.696, B: 0.488), indicating drug-likeness, but A is superior.

**DILI:** Both ligands have acceptable DILI risk (A: 31.524, B: 75.107), but A is significantly lower, indicating a lower risk of liver injury.

**BBB:** This is a crucial parameter for CNS targets. Ligand A (76.347) is excellent, exceeding the desirable >70 threshold. Ligand B (54.827) is considerably lower, suggesting poor brain penetration.

**Caco-2 Permeability:** Ligand A (-4.803) is better than Ligand B (-5.707), indicating better intestinal absorption.

**Aqueous Solubility:** Ligand A (-3.188) is better than Ligand B (-1.44), suggesting better solubility.

**hERG Inhibition:** Both ligands show low hERG inhibition liability (A: 0.437, B: 0.258), which is good.

**Microsomal Clearance:** Ligand A (68.26) is higher than Ligand B (30.087), indicating lower metabolic stability. This is a drawback for A.

**In vitro Half-Life:** Ligand A (35.607) is slightly better than Ligand B (31.832), suggesting a slightly longer half-life.

**P-gp Efflux:** Ligand A (0.297) is better than Ligand B (0.311), indicating lower P-gp efflux and better potential for CNS exposure.

**Binding Affinity:** Ligand A (-8.0) has a significantly stronger binding affinity than Ligand B (-6.6). This >1.5 kcal/mol difference is substantial and can outweigh some ADME drawbacks.

**Overall Assessment:**

Ligand A is clearly superior. It excels in key GPCR-relevant properties like TPSA, BBB, and binding affinity. While its microsomal clearance is a concern, the significantly stronger binding affinity and superior BBB penetration outweigh this drawback. Ligand B's lower BBB penetration is a major disadvantage for a CNS target.

Output:
1
2025-04-17 05:28:05,514 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (362.539 and 359.905 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (40.62) is significantly better than Ligand B (46.84).  For CNS targets, we want TPSA <= 90, and ideally lower. Ligand A is closer to the ideal range.

**3. logP:** Both ligands have good logP values (3.954 and 3.754), falling within the optimal 1-3 range.

**4. H-Bond Donors:** Both have 0 HBD, which is acceptable.

**5. H-Bond Acceptors:** Ligand A has 3 HBA, and Ligand B has 5. Both are within the acceptable limit of <=10.

**6. QED:** Both ligands have good QED scores (0.737 and 0.788), indicating good drug-like properties.

**7. DILI:** Ligand A (26.057) has a lower DILI risk than Ligand B (15.82). Both are below 40, indicating low risk.

**8. BBB:** Ligand A (89.608) has a significantly better BBB penetration percentile than Ligand B (78.79).  For CNS targets, >70 is desirable, and Ligand A is closer to this threshold.

**9. Caco-2 Permeability:** Ligand A (-4.744) has worse Caco-2 permeability than Ligand B (-5.02). Lower values are less desirable.

**10. Aqueous Solubility:** Both ligands have very poor aqueous solubility (-3.357 and -3.59). This is a concern for both, but not a deciding factor given the CNS target.

**11. hERG Inhibition:** Both ligands have low hERG inhibition risk (0.626 and 0.502).

**12. Microsomal Clearance:** Ligand A (69.741) has higher microsomal clearance than Ligand B (37.348).  Lower clearance is preferred for metabolic stability, so Ligand B is better.

**13. In vitro Half-Life:** Both have similar in vitro half-lives (7.377 and 7.882 hours).

**14. P-gp Efflux:** Ligand A (0.61) has lower P-gp efflux than Ligand B (0.23). Lower efflux is preferred for CNS exposure, making Ligand A better.

**15. Binding Affinity:** Both ligands have very similar and excellent binding affinities (-8.5 and -8.4 kcal/mol). The difference is negligible.

**Overall Assessment:**

Considering the GPCR-specific priorities, Ligand A is the better candidate. While Ligand B has slightly better metabolic stability (lower Cl_mic), Ligand A excels in crucial areas for CNS penetration: significantly better BBB (89.6 vs 78.8), and lower P-gp efflux (0.61 vs 0.23).  The TPSA is also more favorable for Ligand A. The slight difference in Caco-2 permeability is less important for a CNS target.  The similar binding affinities make these ADME properties the deciding factors.

Output:
1
2025-04-17 05:28:05,514 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (350.503 and 355.538 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (58.64) is higher than the preferred <90 for CNS targets, but still reasonable. Ligand B (29.54) is excellent, well below the threshold.

**3. logP:** Ligand A (2.45) is optimal (1-3). Ligand B (4.842) is slightly high, potentially leading to solubility issues and off-target interactions, but not drastically so.

**4. H-Bond Donors:** Ligand A (1) is good. Ligand B (0) is also acceptable.

**5. H-Bond Acceptors:** Ligand A (3) is good. Ligand B (2) is also acceptable.

**6. QED:** Ligand A (0.684) is good (>0.5). Ligand B (0.554) is acceptable, but less ideal.

**7. DILI:** Ligand A (15.665) is very good (low risk). Ligand B (10.585) is also good.

**8. BBB:** This is a crucial parameter for a CNS target like DRD2. Ligand A (54.634) is moderate, while Ligand B (96.743) is excellent, exceeding the >70 desirable threshold.

**9. Caco-2 Permeability:** Both ligands have negative values which is unusual, but we can interpret these as very poor permeability.

**10. Aqueous Solubility:** Both ligands have negative values which is unusual, but we can interpret these as very poor solubility.

**11. hERG Inhibition:** Ligand A (0.439) is very low risk. Ligand B (0.892) is slightly higher, but still relatively low risk.

**12. Microsomal Clearance:** Ligand A (43.85) is moderate. Ligand B (110.759) is high, indicating faster metabolism and potentially lower *in vivo* exposure.

**13. In vitro Half-Life:** Ligand A (1.087) is short. Ligand B (18.909) is much longer, a significant advantage.

**14. P-gp Efflux:** Ligand A (0.088) is very low efflux, which is good for CNS penetration. Ligand B (0.857) is higher, potentially limiting CNS exposure.

**15. Binding Affinity:** Ligand B (-7.0) has a slightly better binding affinity than Ligand A (-6.9), but the difference is small.

**Overall Assessment:**

Ligand B is the stronger candidate. While its logP is slightly elevated, its exceptional BBB penetration (96.743), longer half-life (18.909), and slightly better binding affinity (-7.0 kcal/mol) outweigh the drawbacks. The lower P-gp efflux of Ligand A is a positive, but the significantly better BBB score of Ligand B is more critical for a CNS target. The higher metabolic clearance of Ligand B is a concern, but could potentially be addressed through structural modifications.

Output:
1
2025-04-17 05:28:05,515 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (346.43 & 351.54 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (62.99) is slightly higher than Ligand B (52.65). Both are below the 90 A^2 threshold desirable for CNS targets, but Ligand B is preferable.

**3. logP:** Both ligands have good logP values (1.935 & 2.22), falling within the optimal 1-3 range.

**4. H-Bond Donors:** Ligand A (0) has fewer HBD than Ligand B (1). Lower is generally preferred for BBB penetration, making Ligand A slightly better.

**5. H-Bond Acceptors:** Ligand A (4) has more HBA than Ligand B (3). Lower is generally preferred for BBB penetration, making Ligand B slightly better.

**6. QED:** Both ligands have acceptable QED values (0.836 & 0.693), indicating good drug-like properties.

**7. DILI:** Ligand A (28.62) has a significantly lower DILI risk than Ligand B (5.43), a major advantage.

**8. BBB:** Both ligands have excellent BBB penetration (88.06% & 85.03%), exceeding the >70% threshold for CNS targets. Ligand A is slightly better.

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 permeability values (-4.209 & -4.794). This is unusual and suggests poor permeability. However, these values are on a log scale, so the magnitude is important. Ligand B is slightly worse.

**10. Aqueous Solubility:** Both ligands have negative solubility values (-2.822 & -2.11). This is also unusual and indicates very poor aqueous solubility. Ligand B is slightly better.

**11. hERG Inhibition:** Both ligands have low hERG inhibition risk (0.545 & 0.719).

**12. Microsomal Clearance:** Ligand A (73.098) has a higher microsomal clearance than Ligand B (31.9), indicating lower metabolic stability. Ligand B is preferable.

**13. In vitro Half-Life:** Ligand A (21.108) has a longer half-life than Ligand B (0.377), which is a significant advantage.

**14. P-gp Efflux:** Both ligands have low P-gp efflux liability (0.288 & 0.076), which is good for CNS exposure. Ligand B is slightly better.

**15. Binding Affinity:** Ligand A (-8.6 kcal/mol) has a significantly stronger binding affinity than Ligand B (-6.8 kcal/mol). This is a substantial advantage, potentially outweighing some ADME drawbacks.

**Overall Assessment:**

Ligand A has a much stronger binding affinity and lower DILI risk, and slightly better BBB penetration. However, it has higher microsomal clearance and lower in vitro half-life. Ligand B has better TPSA, slightly better Pgp efflux, and lower clearance, but significantly weaker binding affinity and higher DILI risk.

Given the importance of potency for GPCR ligands, and the substantial difference in binding affinity (-8.6 vs -6.8 kcal/mol), the stronger binding of Ligand A is the most critical factor. The lower DILI risk further strengthens its profile. While the higher clearance is a concern, it might be addressable through structural modifications. The poor solubility and permeability are concerning but might be improved with formulation strategies.

Output:
1
2025-04-17 05:28:05,515 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, considering the provided guidelines and GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (353.369 and 342.399 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (73.22) is significantly better than Ligand B (84.3). For CNS targets, we want TPSA <= 90, and A is closer to the optimal <= 60 range. B is pushing the upper limit.

**logP:** Ligand A (2.553) is within the optimal 1-3 range. Ligand B (0.489) is a bit low, potentially hindering membrane permeability.

**H-Bond Donors/Acceptors:** Both have 1 HBD and 5 HBA, which are acceptable.

**QED:** Both ligands have good QED values (0.74 and 0.789), indicating drug-like properties.

**DILI:** Both have acceptable DILI risk (59.984 and 55.293), below the 60 threshold.

**BBB:** Ligand A (82.435) has a much better BBB penetration percentile than Ligand B (63.048).  For a CNS target like DRD2, >70 is desirable, and A is closer.

**Caco-2 Permeability:** Ligand A (-4.292) is better than Ligand B (-4.816), indicating better intestinal absorption.

**Aqueous Solubility:** Both have poor aqueous solubility (-2.557 and -2.44). This could pose formulation challenges, but is less critical than BBB for CNS drugs.

**hERG Inhibition:** Ligand A (0.568) has a slightly higher hERG risk than Ligand B (0.067). B is much better here.

**Microsomal Clearance:** Ligand B (25.787) has significantly lower microsomal clearance than Ligand A (89.099), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand B (-13.385) has a negative half-life, which is problematic. Ligand A (6.289) is reasonable.

**P-gp Efflux:** Ligand A (0.391) has better P-gp efflux properties than Ligand B (0.045). Lower P-gp efflux is preferred for CNS penetration.

**Binding Affinity:** Both ligands have excellent binding affinity (-8.6 and -8.0 kcal/mol). The difference is 0.6 kcal/mol, which isn't substantial enough to outweigh the other significant differences.

**Overall Assessment:**

Ligand A is superior due to its significantly better BBB penetration, more favorable TPSA, better Caco-2 permeability, and reasonable metabolic stability. While Ligand B has better hERG and lower Cl_mic, the critical factor for a CNS target is getting the drug into the brain, where Ligand A excels. The negative half-life of Ligand B is also a major red flag.

Output:
1
2025-04-17 05:28:05,515 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (352.479 and 349.475 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (95.74) is slightly above the optimal <90 for CNS targets, but still reasonable. Ligand B (81.67) is well within the desired range.

**logP:** Both ligands have acceptable logP values (1.175 and 1.785), falling within the 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A (HBD=2, HBA=3) and Ligand B (HBD=3, HBA=4) both have reasonable numbers of H-bond donors and acceptors, well below the limits of 5 and 10 respectively.

**QED:** Ligand A (0.751) has a better QED score than Ligand B (0.601), indicating a more drug-like profile.

**DILI:** Ligand A (20.744) has a significantly lower DILI risk than Ligand B (13.3), which is a substantial advantage.

**BBB:** Ligand A (84.606) has a much higher BBB penetration percentile than Ligand B (40.403). This is *critical* for a CNS target like DRD2.

**Caco-2 Permeability:** Ligand A (-4.966) has worse Caco-2 permeability than Ligand B (-5.188), but both are quite poor.

**Aqueous Solubility:** Ligand A (-2.096) has slightly better solubility than Ligand B (-0.894), though both are quite poor.

**hERG:** Both ligands have low hERG inhibition liability (0.163 and 0.411), which is good.

**Microsomal Clearance:** Ligand A (18.264) has higher microsomal clearance than Ligand B (7.762), indicating lower metabolic stability.

**In vitro Half-Life:** Ligand B (47.908) has a significantly longer in vitro half-life than Ligand A (-20.369), which is a major advantage.

**P-gp Efflux:** Ligand A (0.019) has significantly lower P-gp efflux liability than Ligand B (0.113), which is desirable for CNS penetration.

**Binding Affinity:** Ligand B (-7.8) has a slightly better binding affinity than Ligand A (-8.4). While A is better, the difference is not substantial.

**Overall Assessment:**

Ligand A excels in BBB penetration, DILI risk, and P-gp efflux, all crucial for CNS drug development. Ligand B has a better half-life. However, the significantly better BBB and lower DILI of Ligand A outweigh the half-life advantage of Ligand B, especially considering the modest affinity difference. The poor Caco-2 and solubility of both are concerns, but can potentially be addressed through formulation strategies.

Output:
1
2025-04-17 05:28:05,515 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (343.354 and 349.387 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (78.79) is significantly better than Ligand B (101.74). For CNS targets, we want TPSA <= 90, so Ligand A is preferable.

**3. logP:** Both ligands have acceptable logP values (2.329 and 0.918), falling within the 1-3 range. Ligand A is slightly better.

**4. H-Bond Donors:** Ligand A (3) is slightly higher than Ligand B (1), but both are within the acceptable limit of <=5.

**5. H-Bond Acceptors:** Ligand A (4) is lower than Ligand B (6), which is preferable. We want <=10.

**6. QED:** Both ligands have good QED scores (0.641 and 0.749), indicating good drug-like properties.

**7. DILI:** Both ligands have similar and acceptable DILI risk (44.63 and 44.552 percentile).

**8. BBB:** Ligand B (69.988) has a significantly higher BBB penetration percentile than Ligand A (29.12). This is a *critical* advantage for a CNS target like DRD2.

**9. Caco-2 Permeability:** Ligand A (-5.31) has a worse Caco-2 permeability than Ligand B (-4.925), indicating lower intestinal absorption.

**10. Aqueous Solubility:** Ligand A (-2.913) has a worse aqueous solubility than Ligand B (-2.144).

**11. hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.408 and 0.035).

**12. Microsomal Clearance:** Ligand B (4.796) has a lower microsomal clearance than Ligand A (8.688), suggesting better metabolic stability.

**13. In vitro Half-Life:** Ligand B (-23.734) has a much longer in vitro half-life than Ligand A (-5.493). This is a significant advantage.

**14. P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.068 and 0.062).

**15. Binding Affinity:** Both ligands have the same binding affinity (-8.3 kcal/mol), which is excellent.

**Overall Assessment:**

While Ligand A has a slightly better TPSA and logP, Ligand B excels in crucial ADME properties for a CNS drug: significantly higher BBB penetration, better metabolic stability (lower Cl_mic, longer t1/2), and better Caco-2 permeability and solubility. The equal binding affinity removes that as a differentiating factor. Given the GPCR-specific priorities, the superior BBB penetration and ADME profile of Ligand B make it the more promising drug candidate.

Output:
1
2025-04-17 05:28:05,516 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (345.4 & 349.4 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (80.76) is significantly better than Ligand B (116.19). For CNS targets, we want TPSA <= 90, and A is comfortably within this range, while B exceeds it.

**3. logP:** Both ligands have acceptable logP values (1.587 & 2.356), falling within the optimal 1-3 range.

**4. H-Bond Donors:** Ligand A (1) is preferable to Ligand B (2). Lower HBD generally improves permeability.

**5. H-Bond Acceptors:** Ligand A (5) is preferable to Ligand B (4). Lower HBA generally improves permeability.

**6. QED:** Ligand A (0.847) has a much better QED score than Ligand B (0.288), indicating a more drug-like profile.

**7. DILI:** Both ligands have low DILI risk (41.411 & 35.479), both being below the 40 threshold.

**8. BBB:** Ligand A (77.898) has a significantly better BBB percentile than Ligand B (43.815).  A value >70 is desirable for CNS targets, and A is closer to that mark.

**9. Caco-2 Permeability:** Ligand A (-4.645) is better than Ligand B (-5.214), indicating better intestinal absorption.

**10. Aqueous Solubility:** Ligand A (-3.344) is better than Ligand B (-1.994), indicating better solubility.

**11. hERG:** Both ligands have very low hERG inhibition risk (0.24 & 0.202).

**12. Microsomal Clearance:** Ligand A (15.383) has a lower microsomal clearance than Ligand B (27.67), suggesting better metabolic stability.

**13. In vitro Half-Life:** Ligand A (-7.559) has a better in vitro half-life than Ligand B (23.982).

**14. P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.024 & 0.021).

**15. Binding Affinity:** Both ligands have excellent binding affinity (-8.1 & -8.2 kcal/mol). The difference is minimal.

**Overall Assessment:**

Ligand A is superior to Ligand B across most key ADME properties, particularly TPSA, BBB, QED, solubility, and metabolic stability. While both have excellent binding affinity, the improved pharmacokinetic profile of Ligand A makes it a much more promising drug candidate for a CNS target like DRD2. The lower TPSA and higher BBB are critical for brain penetration.

Output:
0
2025-04-17 05:28:05,516 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (350.419 and 393.359 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (107.55) is better than Ligand B (115.81). Both are below the 140 A^2 threshold for oral absorption, but closer to the 90 A^2 target for CNS penetration.

**logP:** Ligand A (0.121) is quite low, potentially hindering membrane permeability. Ligand B (-1.238) is also low, but slightly better than A. Both are below the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Both ligands have 3 HBDs and 5 HBAs, which are acceptable.

**QED:** Ligand A (0.675) has a significantly better QED score than Ligand B (0.446), indicating a more drug-like profile.

**DILI:** Ligand A (52.113) has a slightly higher DILI risk than Ligand B (44.552), but both are below the concerning 60 percentile.

**BBB:** Both ligands have similar BBB penetration (Ligand A: 36.371, Ligand B: 38.852). Both are below the desirable >70 percentile for CNS targets, but not drastically so.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.737 and -5.643), which is unusual and suggests poor permeability.

**Aqueous Solubility:** Both ligands have very poor aqueous solubility (-1.614 and -1.684).

**hERG:** Both ligands have very low hERG inhibition risk (0.177 and 0.174).

**Microsomal Clearance:** Ligand A (2.877) has a much lower (better) microsomal clearance than Ligand B (-16.347). This suggests better metabolic stability for Ligand A.

**In vitro Half-Life:** Ligand A (25.748) has a significantly longer half-life than Ligand B (-46.705).

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.015 and 0.006), which is favorable for CNS penetration.

**Binding Affinity:** Ligand B (-7.9 kcal/mol) has a slightly better binding affinity than Ligand A (-8.4 kcal/mol). However, the difference is relatively small.

**Overall Assessment:**

Ligand A is superior due to its better QED, lower microsomal clearance, longer half-life, and slightly lower DILI risk. While both have poor logP and aqueous solubility, the improved ADME properties of Ligand A outweigh the slightly better affinity of Ligand B. The negative Caco-2 values are concerning for both, but can be addressed through formulation strategies. Given the CNS target, the acceptable (though not ideal) BBB values combined with low P-gp efflux are promising for both.

Output:
1
2025-04-17 05:28:05,516 - INFO - Batch 200 complete. Total preferences: 3200
2025-04-17 05:28:05,516 - INFO - Processing batch 201/512...
2025-04-17 05:28:48,154 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (353.507 and 346.435 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (70.67) is significantly better than Ligand B (84.22). For CNS targets, we want TPSA <= 90, and A is closer to the optimal <= 60 range. B is pushing the upper limit.

**3. logP:** Both ligands have good logP values (1.544 and 0.621), falling within the 1-3 range. Ligand A is slightly better.

**4. H-Bond Donors:** Ligand A (2) is reasonable, while Ligand B (0) is also acceptable.

**5. H-Bond Acceptors:** Ligand A (4) is good, and Ligand B (6) is also acceptable, though slightly higher.

**6. QED:** Both ligands have good QED values (0.694 and 0.798), indicating good drug-like properties.

**7. DILI:** Ligand A (8.802) has a much lower DILI risk than Ligand B (32.881). This is a significant advantage for A.

**8. BBB:** Ligand B (76.658) has a better BBB penetration percentile than Ligand A (58.278). This is a key factor for CNS targets like DRD2.

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.941 and -5.202). These values are unusual and suggest poor permeability. However, the scale isn't specified, so it's difficult to interpret.

**10. Aqueous Solubility:** Both ligands have negative solubility values (-1.012 and -1.405), again indicating poor solubility.

**11. hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.32 and 0.065).

**12. Microsomal Clearance:** Both ligands have similar microsomal clearance values (24.483 and 24.221).

**13. In vitro Half-Life:** Ligand B (-6.01) has a longer in vitro half-life than Ligand A (-3.575).

**14. P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.009 and 0.086).

**15. Binding Affinity:** Ligand B (-8.9 kcal/mol) has a significantly stronger binding affinity than Ligand A (-7.2 kcal/mol). This is a substantial advantage, exceeding the 1.5 kcal/mol difference threshold.

**Overall Assessment:**

Ligand B has a much stronger binding affinity and better BBB penetration, which are critical for a CNS GPCR target like DRD2. However, Ligand A has a significantly lower DILI risk and a better TPSA value. The poor Caco-2 and solubility values are concerning for both, but the affinity difference is substantial. Given the importance of affinity for GPCRs, and the relatively good BBB penetration of Ligand B, it outweighs the slightly higher DILI risk.

Output:
1
2025-04-17 05:28:48,154 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (336.443 and 354.491 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (60.56) is significantly better than Ligand B (75.71). For CNS targets, TPSA should be <= 90, both are within this range, but A is preferred.

**logP:** Both ligands have good logP values (3.485 and 2.652), falling within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Both have acceptable HBD (1) and HBA (6 & 4) counts, well within the guidelines.

**QED:** Ligand A (0.775) has a much better QED score than Ligand B (0.483), indicating a more drug-like profile.

**DILI:** Ligand A (62.66) has a higher DILI risk than Ligand B (18.108). This is a significant drawback for Ligand A.

**BBB:** Both ligands have good BBB penetration (79.256 and 77.162), exceeding the desirable >70 threshold for CNS targets.

**Caco-2:** Ligand A (-5.142) has a worse Caco-2 permeability than Ligand B (-4.379). Lower values suggest poorer absorption.

**Solubility:** Ligand A (-3.338) has worse solubility than Ligand B (-2.597).

**hERG:** Both ligands have low hERG inhibition liability (0.581 and 0.459), which is good.

**Microsomal Clearance:** Ligand B (92.362) has a much higher microsomal clearance than Ligand A (34.876), suggesting lower metabolic stability.

**In vitro Half-Life:** Ligand A (5.875) has a better in vitro half-life than Ligand B (-17.64).

**P-gp Efflux:** Ligand A (0.489) has lower P-gp efflux than Ligand B (0.107), which is favorable for CNS penetration.

**Binding Affinity:** Ligand A (-8.6 kcal/mol) has a significantly stronger binding affinity than Ligand B (-7.3 kcal/mol). This is a substantial advantage.

**Overall Assessment:**

Ligand A has a superior binding affinity, better TPSA, QED, half-life, and P-gp efflux. However, it suffers from higher DILI risk, poorer Caco-2 permeability, and solubility. Ligand B has better DILI, solubility, and Caco-2 permeability, but weaker binding affinity, lower QED, and higher P-gp efflux.

Given the importance of binding affinity for GPCRs, and the acceptable BBB penetration for both, the stronger affinity of Ligand A is a major advantage. While the DILI risk is a concern, it might be mitigated through structural modifications. The lower solubility and permeability could also be addressed through formulation strategies. The difference in affinity (1.3 kcal/mol) is substantial enough to outweigh the ADME drawbacks, especially considering the CNS target.

Output:
1
2025-04-17 05:28:48,155 - INFO - Reasoning:

Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (340.354 and 338.371 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (60.45) is excellent, well below the 90 A^2 threshold for CNS targets. Ligand B (89.07) is approaching the upper limit but still acceptable.

**3. logP:** Ligand A (3.781) is at the higher end of the optimal range (1-3), but still reasonable. Ligand B (1.393) is at the lower end, potentially hindering permeability.

**4. H-Bond Donors:** Both ligands have 1 HBD, which is within the acceptable limit of <=5.

**5. H-Bond Acceptors:** Ligand A has 5 HBA, and Ligand B has 7 HBA, both within the acceptable limit of <=10.

**6. QED:** Both ligands have good QED scores (0.716 and 0.773), indicating good drug-like properties.

**7. DILI:** Ligand A (91.819) has a higher DILI risk than Ligand B (79.604). This is a concern for Ligand A.

**8. BBB:** Ligand A (75.107) has a good BBB penetration percentile, desirable for a CNS target. Ligand B (46.219) has a significantly lower BBB penetration, which is a major drawback.

**9. Caco-2 Permeability:** Ligand A (-4.226) has poor Caco-2 permeability, while Ligand B (-5.335) is even worse. Both are negative values, indicating low permeability.

**10. Aqueous Solubility:** Ligand A (-5.575) has poor aqueous solubility, while Ligand B (-1.96) is slightly better.

**11. hERG Inhibition:** Ligand A (0.754) has slightly higher hERG inhibition risk than Ligand B (0.052). Ligand B is very low risk.

**12. Microsomal Clearance:** Ligand A (131.387) has higher microsomal clearance, suggesting lower metabolic stability, compared to Ligand B (35.493).

**13. In vitro Half-Life:** Ligand A (20.944) has a moderate in vitro half-life. Ligand B (-19.607) has a negative half-life, which is not physically possible and suggests an issue with the data or the molecule's stability.

**14. P-gp Efflux:** Ligand A (0.259) has lower P-gp efflux, which is favorable for CNS penetration. Ligand B (0.051) has even lower P-gp efflux.

**15. Binding Affinity:** Both ligands have excellent binding affinities (-9.5 and -8.8 kcal/mol). The difference of 0.7 kcal/mol is not substantial enough to outweigh other significant differences.

**Overall Assessment:**

Ligand A has a better BBB score and lower P-gp efflux, which are crucial for CNS targets. However, it suffers from higher DILI risk, poor Caco-2 permeability, poor solubility, and higher metabolic clearance. Ligand B has a significantly lower BBB score, which is a critical drawback for a CNS-targeted drug. The negative in vitro half-life is also a major red flag. Despite its better hERG profile, the poor BBB penetration and the unrealistic half-life make it a less viable candidate.

Considering the GPCR-specific priorities, the better BBB penetration of Ligand A, despite its other drawbacks, makes it the more promising candidate. Further optimization would be needed to address the DILI risk, permeability, solubility, and metabolic stability.

Output:
1
2025-04-17 05:28:48,155 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (348.422 and 348.487 Da) fall comfortably within the ideal 200-500 Da range.

**2. TPSA:** Both ligands have a TPSA of approximately 66.5 A<sup>2</sup>, which is acceptable for oral absorption but slightly high for optimal CNS penetration (ideally <90 A<sup>2</sup>, and even better <60 A<sup>2</sup>).

**3. logP:** Ligand A (2.257) and Ligand B (2.845) both have logP values within the optimal 1-3 range. Ligand B is slightly more lipophilic, which could be beneficial for BBB penetration, but also carries a slightly higher risk of off-target interactions.

**4. H-Bond Donors:** Ligand A has 0 HBD, while Ligand B has 1. Both are within the acceptable limit of <=5.

**5. H-Bond Acceptors:** Ligand A has 4 HBA, and Ligand B has 3. Both are within the acceptable limit of <=10.

**6. QED:** Ligand A (0.791) has a higher QED score than Ligand B (0.686), indicating a more drug-like profile.

**7. DILI:** Ligand A (32.299) has a slightly higher DILI risk than Ligand B (27.608), but both are below the concerning threshold of 60.

**8. BBB:** This is a critical parameter for a CNS target like DRD2. Ligand A has a significantly higher BBB penetration percentile (95.89%) compared to Ligand B (70.609%). This is a major advantage for Ligand A.

**9. Caco-2 Permeability:** Both ligands show poor Caco-2 permeability (-4.103 and -4.616 respectively). This suggests potential absorption issues.

**10. Aqueous Solubility:** Both ligands have very poor aqueous solubility (-2.809 and -2.833 respectively). This could pose formulation challenges.

**11. hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.345 and 0.145 respectively).

**12. Microsomal Clearance:** Ligand A (54.74 mL/min/kg) has a lower microsomal clearance than Ligand B (62.786 mL/min/kg), suggesting better metabolic stability.

**13. In vitro Half-Life:** Ligand A (-13.079 hours) has a significantly longer in vitro half-life than Ligand B (-19.252 hours). This is a positive attribute.

**14. P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.02 and 0.244 respectively).

**15. Binding Affinity:** Ligand B (-7.7 kcal/mol) has a stronger binding affinity than Ligand A (-6.7 kcal/mol). This is a 1.0 kcal/mol difference, which is substantial and could potentially outweigh some of the ADME drawbacks.

**Overall Assessment:**

While Ligand B boasts a better binding affinity, Ligand A has a significantly superior BBB penetration (95.89% vs 70.609%), better metabolic stability (lower Cl_mic), longer half-life, and a higher QED score. For a CNS target like DRD2, BBB penetration is paramount. The 1.0 kcal/mol difference in binding affinity, while significant, might be overcome with further optimization of Ligand A. The poor solubility and Caco-2 permeability are concerns for both, but formulation strategies can potentially address these.

Output:
0
2025-04-17 05:28:48,155 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 drug candidates, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (363.483 and 346.431 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (82.53) is significantly better than Ligand B (101.05). For CNS targets, we want TPSA <= 90, so Ligand A is preferable.

**3. logP:** Both ligands have similar logP values (1.897 and 1.906), both falling within the optimal 1-3 range.

**4. H-Bond Donors:** Both ligands have 2 HBD, which is acceptable (<=5).

**5. H-Bond Acceptors:** Both ligands have 5 HBA, which is acceptable (<=10).

**6. QED:** Ligand A (0.723) has a better QED score than Ligand B (0.498). A QED >= 0.5 is desirable, and A is comfortably above this threshold.

**7. DILI:** Ligand A (46.258) has a lower DILI risk than Ligand B (60.295). Both are acceptable (<60 is good), but A is better.

**8. BBB:** Ligand A (46.84) has a lower BBB penetration percentile than Ligand B (59.674). While both are not ideal (>70 is desirable for CNS targets), B is significantly better. This is a critical factor for DRD2.

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.381 and -5.06). This is unusual and suggests poor permeability. However, the values are close, so this is not a major differentiator.

**10. Aqueous Solubility:** Both ligands have negative solubility values (-3.42 and -3.351). This indicates poor aqueous solubility, which could be a formulation challenge. Again, they are similar.

**11. hERG Inhibition:** Both ligands have low hERG inhibition liability (0.34 and 0.21). This is good.

**12. Microsomal Clearance:** Ligand A (21.938) has a lower microsomal clearance than Ligand B (40.184), suggesting better metabolic stability.

**13. In vitro Half-Life:** Ligand A (-14.435) has a negative half-life, which is not physically possible and likely an error. Ligand B (3.022) has a short half-life, but a realistic value.

**14. P-gp Efflux:** Both ligands have low P-gp efflux liability (0.076 and 0.215). This is good, especially for CNS targets.

**15. Binding Affinity:** Ligand B (-8.7 kcal/mol) has a significantly stronger binding affinity than Ligand A (-7.4 kcal/mol). This is a substantial advantage (>1.5 kcal/mol difference).

**Overall Assessment:**

Ligand B has a significantly better binding affinity and a better BBB score, which are the most important factors for a CNS-targeting GPCR like DRD2. While Ligand A has better TPSA, QED, DILI, and metabolic stability, the superior affinity and BBB penetration of Ligand B outweigh these advantages. The negative half-life for Ligand A is a major red flag, indicating a potential data error or a highly unstable compound.

Output:
1
2025-04-17 05:28:48,155 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 drug candidates, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (340.379) is slightly better, being closer to the lower end which can aid permeability.

**TPSA:** Ligand A (81.86) is excellent for CNS penetration, falling well below the 90 A^2 threshold. Ligand B (96.17) is still reasonable but less optimal.

**logP:** Both ligands have good logP values (A: 2.259, B: 1.391), falling within the 1-3 range. Ligand A is slightly better.

**H-Bond Donors/Acceptors:** Ligand A (HBD=1, HBA=5) is better than Ligand B (HBD=2, HBA=9) in terms of balancing solubility and permeability.

**QED:** Both ligands have good QED scores (A: 0.682, B: 0.752), indicating good drug-like properties.

**DILI:** Ligand A (77.782) has a higher DILI risk than Ligand B (69.135), but both are acceptable.

**BBB:** Both ligands have excellent BBB penetration (A: 78.519, B: 71.888), exceeding the 70% threshold.

**Caco-2 Permeability:** Ligand A (-4.732) shows better Caco-2 permeability than Ligand B (-5.761), suggesting better intestinal absorption.

**Aqueous Solubility:** Ligand A (-4.49) has slightly better solubility than Ligand B (-2.7).

**hERG:** Ligand A (0.708) has a slightly higher hERG risk than Ligand B (0.056). This is a significant advantage for Ligand B.

**Microsomal Clearance:** Ligand B (23.011) has significantly lower microsomal clearance than Ligand A (48.365), indicating better metabolic stability.

**In vitro Half-Life:** Ligand B (6.626) has a much longer in vitro half-life than Ligand A (-16.27). This is a major advantage for Ligand B.

**P-gp Efflux:** Ligand A (0.411) has lower P-gp efflux than Ligand B (0.091), which is favorable for CNS exposure.

**Binding Affinity:** Ligand B (-7.2) has a significantly stronger binding affinity than Ligand A (-8.6). This is a crucial advantage, as a 1.5 kcal/mol difference can outweigh other drawbacks.

**Overall Assessment:**

While Ligand A has some advantages in terms of TPSA, logP, and P-gp efflux, Ligand B excels in critical areas for a CNS-targeting GPCR drug. Its significantly stronger binding affinity (-7.2 vs -8.6 kcal/mol), lower microsomal clearance, and longer half-life are substantial benefits. The lower hERG risk is also a significant advantage. The slightly higher TPSA and P-gp efflux are less concerning given the strong affinity and improved metabolic stability.

Output:
1
2025-04-17 05:28:48,155 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B based on the provided guidelines, prioritizing GPCR-specific properties (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (360.401 and 364.471 Da) fall within the ideal range of 200-500 Da.

**TPSA:** Ligand A (78.87) is significantly better than Ligand B (91.4). For CNS targets, TPSA should be <= 90, so Ligand A is preferable.

**logP:** Ligand A (0.64) is a bit low, potentially hindering permeation. Ligand B (0.946) is slightly better, but still on the lower side of the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Both have 2 HBD and are within acceptable limits. Ligand B has 5 HBA, while Ligand A has 4. Both are acceptable.

**QED:** Both ligands have good QED scores (0.698 and 0.761, respectively), indicating drug-likeness.

**DILI:** Ligand A (22.8) has a much lower DILI risk than Ligand B (49.011). This is a significant advantage for Ligand A.

**BBB:** Ligand A (77.821) has a significantly higher BBB penetration percentile than Ligand B (41.722). This is *crucial* for a CNS target like DRD2.

**Caco-2 Permeability:** Ligand A (-4.857) and Ligand B (-5.232) both have negative values, indicating low permeability.

**Aqueous Solubility:** Ligand A (-1.573) and Ligand B (-2.88) both have negative values, indicating low solubility.

**hERG:** Both ligands have low hERG inhibition liability (0.475 and 0.296, respectively), which is good.

**Microsomal Clearance:** Ligand A (-10.253) has much lower microsomal clearance than Ligand B (13.485), indicating better metabolic stability.

**In vitro Half-Life:** Ligand A (11.391) has a shorter half-life than Ligand B (18.067), but both are reasonable.

**P-gp Efflux:** Ligand A (0.045) has lower P-gp efflux liability than Ligand B (0.051), which is favorable for CNS penetration.

**Binding Affinity:** Ligand A (-8.3 kcal/mol) has a slightly better binding affinity than Ligand B (-7.9 kcal/mol). While the difference is not huge, it adds to the overall advantage of Ligand A.

**Conclusion:**

Ligand A is the superior candidate. It excels in the most important parameters for a CNS-targeting GPCR: BBB penetration, TPSA, DILI risk, and metabolic stability. Although its logP and Caco-2 permeability are not ideal, the strong advantages in CNS penetration and safety outweigh these drawbacks. The slightly better binding affinity further supports this conclusion.

Output:
0
2025-04-17 05:28:48,156 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (356.463 and 381.223 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (84.94) is excellent, well below the 90 A^2 threshold for CNS targets. Ligand B (99.25) is still reasonable but less optimal.

**logP:** Ligand A (2.48) is within the optimal 1-3 range. Ligand B (3.059) is slightly higher but still acceptable.

**H-Bond Donors/Acceptors:** Ligand A (1 HBD, 5 HBA) and Ligand B (3 HBD, 5 HBA) both have reasonable numbers of H-bond donors and acceptors, well within the guidelines.

**QED:** Both ligands have similar QED values (0.708 and 0.707), indicating good drug-likeness.

**DILI:** Ligand A (46.956) has a much lower DILI risk than Ligand B (97.829). This is a significant advantage.

**BBB:** Ligand A (78.054) has a significantly better BBB penetration score than Ligand B (60.876). This is crucial for a CNS target like DRD2.

**Caco-2 Permeability:** Ligand A (-4.317) and Ligand B (-4.784) have similar, negative Caco-2 permeability values. This is not ideal, but not a dealbreaker.

**Aqueous Solubility:** Ligand A (-2.391) has better aqueous solubility than Ligand B (-5.15).

**hERG:** Both ligands have very low hERG inhibition liability (0.299 and 0.116), which is excellent.

**Microsomal Clearance:** Ligand A (43.844) has a moderate microsomal clearance, while Ligand B (10.783) has a very low clearance, suggesting better metabolic stability.

**In vitro Half-Life:** Ligand B (20.454) has a significantly longer in vitro half-life than Ligand A (-4.142). This is a substantial advantage.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.077 and 0.033).

**Binding Affinity:** Ligand B (-9.5 kcal/mol) has a significantly stronger binding affinity than Ligand A (-7.6 kcal/mol). This is a >1.5 kcal/mol difference, which can outweigh some ADME drawbacks.

**Overall Assessment:**

Ligand B has a superior binding affinity and better metabolic stability (lower Cl_mic and longer t1/2). However, Ligand A has a much better safety profile (lower DILI) and significantly better BBB penetration, which is paramount for a CNS target. While Ligand B's affinity is strong, the difference isn't so overwhelming that it completely negates the advantages of Ligand A's improved CNS penetration and reduced toxicity. Considering the GPCR-specific priorities, the BBB score is critical.

Output:
0
2025-04-17 05:28:48,156 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (360.395 and 350.419 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (32.34) is excellent, well below the 90 A^2 threshold for CNS targets. Ligand B (102.44) is higher, but still potentially acceptable, though less ideal.

**logP:** Ligand A (4.363) is slightly high, potentially leading to solubility issues or off-target interactions, but not drastically so. Ligand B (0.379) is quite low, which could hinder membrane permeability and CNS penetration.

**H-Bond Donors/Acceptors:** Ligand A (1 HBD, 1 HBA) is optimal. Ligand B (2 HBD, 6 HBA) is acceptable, but the higher HBA count could slightly impact permeability.

**QED:** Both ligands have good QED scores (0.593 and 0.703), indicating generally drug-like properties.

**DILI:** Ligand A (29.159) has a very favorable DILI score. Ligand B (41.838) is also reasonably good, but slightly higher.

**BBB:** This is crucial for a CNS target. Ligand A excels with a BBB percentile of 95.076. Ligand B's BBB percentile is significantly lower at 63.009, which is less desirable.

**Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and likely indicates a problem with the prediction method or the molecule itself. However, we can still compare them. Ligand A (-4.519) is better than Ligand B (-4.886).

**Aqueous Solubility:** Both ligands have negative solubility values, again suggesting a potential issue with the prediction. Ligand A (-4.363) is slightly better than Ligand B (-1.297).

**hERG Inhibition:** Ligand A (0.929) has a low hERG risk. Ligand B (0.171) also has a low hERG risk.

**Microsomal Clearance:** Ligand A (48.86) has moderate clearance. Ligand B (17.045) has lower clearance, suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (-10.19) has a negative half-life, which is problematic. Ligand B (20.451) has a reasonable half-life.

**P-gp Efflux:** Ligand A (0.672) has moderate P-gp efflux. Ligand B (0.003) has very low P-gp efflux, which is highly desirable for CNS penetration.

**Binding Affinity:** Ligand B (-7.5 kcal/mol) has a significantly stronger binding affinity than Ligand A (-9.1 kcal/mol). This is a substantial advantage.

**Overall Assessment:**

Ligand B has a significantly better binding affinity, lower P-gp efflux, and better metabolic stability. However, its logP is very low and its BBB penetration is considerably lower than Ligand A. Ligand A has excellent BBB penetration, a favorable DILI score, and a good TPSA. The negative half-life for Ligand A is a major concern.

Despite the lower BBB, the superior affinity of Ligand B, combined with its lower P-gp efflux, is likely to result in sufficient CNS exposure. The low logP is a concern, but the strong binding may compensate. The better metabolic stability is also a plus. The negative half-life of Ligand A is a dealbreaker.

Output:
1
2025-04-17 05:28:48,156 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (342.37 and 347.419 Da) fall comfortably within the ideal 200-500 Da range.

**TPSA:** Ligand A (49.85) is excellent, well below the 90 A^2 threshold for CNS targets. Ligand B (81.77) is higher, but still potentially acceptable, though less optimal.

**logP:** Ligand A (2.922) is within the optimal 1-3 range. Ligand B (-0.413) is significantly lower, which is a concern for membrane permeability and CNS penetration.

**H-Bond Donors/Acceptors:** Ligand A (0 HBD, 3 HBA) is favorable. Ligand B (1 HBD, 5 HBA) is also acceptable, though slightly higher.

**QED:** Both ligands have similar QED values (0.858 and 0.801), indicating good drug-likeness.

**DILI:** Ligand A (77.123) has a higher DILI risk than Ligand B (36.448), but both are within a reasonable range.

**BBB:** Ligand A (89.492) has excellent BBB penetration, exceeding the 70% threshold. Ligand B (36.448) has very poor predicted BBB penetration, a major drawback for a CNS target.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.13 and -4.895), which is unusual and suggests poor permeability. However, these values are on a log scale and may not be directly comparable.

**Aqueous Solubility:** Both ligands have negative solubility values (-2.945 and -0.988), indicating poor aqueous solubility.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.708 and 0.494).

**Microsomal Clearance:** Ligand A (33.385) has a higher microsomal clearance than Ligand B (9.657), suggesting lower metabolic stability.

**In vitro Half-Life:** Ligand A (-23.973) has a negative half-life, which is not physically meaningful and suggests a very rapid clearance. Ligand B (-10.83) is also negative, but less so.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.369 and 0.022), which is favorable for CNS penetration.

**Binding Affinity:** Ligand A (-8.8 kcal/mol) has a significantly stronger binding affinity than Ligand B (-7.7 kcal/mol). This 1.1 kcal/mol difference is substantial and could outweigh some ADME drawbacks.

**Overall Assessment:**

Ligand A is significantly better despite the higher DILI and clearance. The superior BBB penetration (89.492 vs 36.448) and much stronger binding affinity (-8.8 vs -7.7 kcal/mol) are crucial for a CNS-targeting GPCR like DRD2. The poor solubility and permeability are concerns for both, but can be addressed with formulation strategies. The negative half-life values are concerning but could be due to modeling artifacts. Ligand B's very low logP and poor BBB penetration are major liabilities that are difficult to overcome.

Output:
0
2025-04-17 05:28:48,156 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B against the provided guidelines, prioritizing GPCR-specific properties (BBB, logP, Pgp, TPSA, and affinity) for DRD2.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (363.414 Da) and Ligand B (348.397 Da) are both acceptable.

**TPSA:** Ligand A (85.13) is slightly above the optimal <90 for CNS targets, but still reasonable. Ligand B (41.37) is excellent, well below 90.

**logP:** Ligand A (4.351) is a bit high, potentially leading to solubility issues and off-target interactions. Ligand B (3.019) is within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A (1 HBD, 5 HBA) is good. Ligand B (0 HBD, 4 HBA) is also good.

**QED:** Both ligands have good QED scores: Ligand A (0.611) and Ligand B (0.856).

**DILI:** Ligand A (79.256) has a higher DILI risk than Ligand B (41.877), which is preferable.

**BBB:** Ligand A (82.319) is good, but Ligand B (90.733) is excellent, exceeding the >70 desirable threshold for CNS targets. This is a significant advantage for Ligand B.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.685 and -4.58), which is unusual and suggests poor permeability. However, the scale is not defined, so we can't interpret this definitively.

**Aqueous Solubility:** Both ligands have negative solubility values (-5.693 and -2.84), which is also unusual. Again, the scale is undefined.

**hERG:** Ligand A (0.546) has a slightly higher hERG risk than Ligand B (0.892), which is preferable.

**Microsomal Clearance:** Ligand A (54.429) has moderate clearance, while Ligand B (49.756) is slightly better. Lower is preferred.

**In vitro Half-Life:** Ligand A (18.604) has a shorter half-life than Ligand B (-25.031), which is unusual.

**P-gp Efflux:** Ligand A (0.513) has moderate P-gp efflux, while Ligand B (0.512) is similar. Lower is preferred for CNS penetration.

**Binding Affinity:** Ligand A (-9.3 kcal/mol) has a significantly stronger binding affinity than Ligand B (0.0 kcal/mol). This is a major advantage for Ligand A. A difference of >1.5 kcal/mol can outweigh other drawbacks.

**Overall Assessment:**

Ligand B excels in key GPCR properties: TPSA, logP, and especially BBB penetration. It also has a lower DILI risk. However, its binding affinity is significantly weaker than Ligand A.

Ligand A's primary advantage is its much stronger binding affinity. While its logP is higher and DILI risk is greater, the substantial improvement in binding affinity (-9.3 vs 0.0 kcal/mol) is likely to outweigh these drawbacks, especially for a GPCR target where potency is crucial. The unusual negative values for Caco-2 and solubility are concerning, but the strong binding affinity makes Ligand A the more promising candidate, assuming these values are not indicative of significant issues.

Output:
1
2025-04-17 05:28:48,156 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (370.471 and 362.832 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (98.15) is better than Ligand B (46.34). For CNS targets, TPSA should be <=90, so Ligand A is closer to the ideal range.

**logP:** Ligand A (-0.151) is significantly lower than the optimal 1-3 range, potentially hindering membrane permeability. Ligand B (4.742) is too high, potentially causing solubility issues and off-target effects.

**H-Bond Donors/Acceptors:** Ligand A (2 HBD, 6 HBA) is reasonable. Ligand B (0 HBD, 3 HBA) is also acceptable.

**QED:** Both ligands have similar, good QED values (0.675 and 0.697).

**DILI:** Ligand A (32.377) has a lower DILI risk than Ligand B (42.497), which is preferable. Both are below the 60 threshold.

**BBB:** Ligand B (91.857) has a *much* higher BBB penetration percentile than Ligand A (28.848). This is a critical advantage for a CNS target like DRD2.

**Caco-2 Permeability:** Both have negative values, which is unusual and suggests poor permeability. Ligand A (-5.165) is slightly better than Ligand B (-4.718).

**Aqueous Solubility:** Both have negative values, indicating poor solubility. Ligand A (-1.55) is slightly better than Ligand B (-4.644).

**hERG Inhibition:** Ligand A (0.016) has a very low hERG risk, which is excellent. Ligand B (0.733) is higher, indicating some potential for cardiotoxicity.

**Microsomal Clearance:** Ligand A (23.507) has a lower microsomal clearance than Ligand B (81.635), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand B (24.269) has a significantly longer in vitro half-life than Ligand A (-2.77), which is desirable.

**P-gp Efflux:** Ligand A (0.013) has a much lower P-gp efflux liability than Ligand B (0.727), which is crucial for CNS penetration.

**Binding Affinity:** Ligand B (-8.4 kcal/mol) has a stronger binding affinity than Ligand A (-6.6 kcal/mol). This is a substantial difference (1.8 kcal/mol), and a strong affinity can often compensate for some ADME deficiencies.

**Overall Assessment:**

Ligand B excels in BBB penetration and binding affinity, both critical for a CNS GPCR target. While its logP is high, the strong affinity might overcome this. Ligand A has better TPSA, DILI, hERG, and P-gp efflux, but its low BBB and weaker affinity are significant drawbacks. Given the importance of CNS penetration for DRD2 and the substantial affinity advantage of Ligand B, it is the more promising candidate.

Output:
1
2025-04-17 05:28:48,157 - INFO - Reasoning:

Let's analyze Ligand A and Ligand B based on the provided guidelines, prioritizing GPCR-specific properties (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (352.475 and 348.443 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (67.87) is significantly better than Ligand B (78.87). For CNS targets, we want TPSA <= 90, both are within this range, but A is closer to the optimal value.

**logP:** Both ligands have acceptable logP values (2.302 and 1.034), falling within the 1-3 range. Ligand A is slightly better.

**H-Bond Donors/Acceptors:** Ligand A (HBD=1, HBA=4) and Ligand B (HBD=2, HBA=4) both have reasonable H-bond characteristics.

**QED:** Ligand B (0.778) has a better QED score than Ligand A (0.484), suggesting a more drug-like profile overall.

**DILI:** Ligand A (10.896) has a much lower DILI risk than Ligand B (34.277), a significant advantage.

**BBB:** This is crucial for a CNS target like DRD2. Ligand A (81.698) has a substantially higher BBB penetration percentile than Ligand B (38.387). This is a major point in favor of Ligand A.

**Caco-2 Permeability:** Both have negative values which is unusual and suggests poor permeability.

**Aqueous Solubility:** Both have negative values which is unusual and suggests poor solubility.

**hERG:** Both ligands show low hERG inhibition liability (0.437 and 0.073), which is good.

**Microsomal Clearance:** Ligand B (16.667) has a lower microsomal clearance than Ligand A (12.146), indicating potentially better metabolic stability.

**In vitro Half-Life:** Ligand A (-9.104) has a significantly longer in vitro half-life than Ligand B (-18.877).

**P-gp Efflux:** Ligand A (0.052) has lower P-gp efflux liability than Ligand B (0.027), which is favorable for CNS penetration.

**Binding Affinity:** Ligand B (0.0) has no binding affinity, while Ligand A (-7.4) has a strong binding affinity. This is the most important factor.

**Overall Assessment:**

Ligand A is the clear winner. While Ligand B has a slightly better QED and microsomal clearance, Ligand A excels in the most critical areas for a CNS-targeting GPCR: **BBB penetration, binding affinity, and DILI risk**. The significantly stronger binding affinity of Ligand A (-7.4 kcal/mol) is a major advantage that can outweigh minor ADME drawbacks. The high BBB penetration (81.698) is also crucial for CNS efficacy. The low DILI risk is a significant safety advantage.

Output:
1
2025-04-17 05:28:48,157 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, considering the provided guidelines and GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (353.463 Da) is slightly lower, which could be advantageous for permeability. Ligand B (371.535 Da) is also good.

**TPSA:** Ligand A (87.74) is excellent, falling well below the 90 Angstroms threshold for CNS targets. Ligand B (53.94) is also very good, further supporting CNS penetration.

**logP:** Ligand A (0.681) is a bit low, potentially hindering membrane permeability. Ligand B (4.03) is at the higher end of the optimal range, which could lead to solubility issues or off-target interactions, but is acceptable.

**H-Bond Donors/Acceptors:** Ligand A (HBD=2, HBA=4) is well within the acceptable limits. Ligand B (HBD=1, HBA=7) is also good.

**QED:** Both ligands have similar QED values (A: 0.705, B: 0.747), indicating good drug-like properties.

**DILI:** Ligand A (15.2) has a significantly lower DILI risk than Ligand B (80.651). This is a major advantage for Ligand A.

**BBB:** Ligand B (77.976) has a better BBB penetration percentile than Ligand A (50.019). This is crucial for a CNS target like DRD2.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.121 and -5.196), which is unusual and suggests poor permeability. However, these values are on a scale where negative values are possible, and the absolute values are similar.

**Aqueous Solubility:** Both ligands have poor aqueous solubility (-0.862 and -4.235). This could pose formulation challenges.

**hERG Inhibition:** Ligand A (0.089) shows very low hERG inhibition risk, a significant advantage. Ligand B (0.834) has a higher, though not alarming, hERG risk.

**Microsomal Clearance:** Ligand B (94.637) has a much higher microsomal clearance than Ligand A (8.858), indicating lower metabolic stability.

**In vitro Half-Life:** Ligand A (10.292) has a slightly shorter half-life than Ligand B (11.697), but both are reasonable.

**P-gp Efflux:** Ligand A (0.009) has very low P-gp efflux liability, which is excellent for CNS penetration. Ligand B (0.381) has moderate P-gp efflux.

**Binding Affinity:** Ligand B (-8.6 kcal/mol) has a stronger binding affinity than Ligand A (-7.8 kcal/mol). This is a 1.5 kcal/mol difference, which is substantial and can outweigh some ADME drawbacks.

**Overall Assessment:**

Ligand B has a stronger binding affinity and better BBB penetration, which are critical for a CNS GPCR target. However, it suffers from significantly higher DILI risk, higher microsomal clearance (lower metabolic stability), and moderate P-gp efflux. Ligand A has a much better safety profile (lower DILI, lower hERG, lower P-gp), better metabolic stability, but weaker affinity and lower BBB penetration.

Given the importance of safety and metabolic stability in drug development, and the fact that the affinity difference, while significant, isn't enormous, I would lean towards **Ligand A** as the more viable drug candidate. The lower DILI and P-gp efflux, coupled with reasonable metabolic stability, are strong advantages. Further optimization could focus on improving the affinity of Ligand A while maintaining its favorable ADMET properties.

Output:
0
2025-04-17 05:28:48,157 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (366.571 and 359.495 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (40.62) is significantly better than Ligand B (73.2). For CNS targets, we want TPSA <= 90, and ideally closer to 60. Ligand A is much closer to this ideal. Ligand B is higher and could hinder BBB penetration.

**logP:** Both ligands have good logP values (3.404 and 3.026), falling within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A (0 HBD, 3 HBA) is preferable to Ligand B (1 HBD, 4 HBA). Fewer hydrogen bonds generally improve membrane permeability. Both are within acceptable limits.

**QED:** Both ligands have good QED scores (0.648 and 0.901), indicating good drug-like properties.

**DILI:** Ligand A (13.843) has a much lower DILI risk than Ligand B (50.136). This is a significant advantage for Ligand A.

**BBB:** Ligand A (92.478) has excellent BBB penetration predicted, exceeding the desirable >70 threshold. Ligand B (60.682) is considerably lower, which is a major concern for a CNS target like DRD2.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.079 and -4.989). These values are unusual and difficult to interpret without further context, but suggest poor permeability.

**Aqueous Solubility:** Both ligands have negative solubility values (-3.232 and -3.464). Similar to Caco-2, these values are unusual and indicate poor solubility.

**hERG:** Both ligands have low hERG risk (0.804 and 0.604).

**Microsomal Clearance:** Ligand A (61.336) has higher microsomal clearance than Ligand B (21.015), suggesting faster metabolism and potentially lower *in vivo* exposure.

**In vitro Half-Life:** Ligand B (1.511 hours) has a shorter half-life than Ligand A (-2.335 hours). The negative value for Ligand A is unusual and requires further investigation, but generally, longer half-lives are preferred.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.497 and 0.297), which is good for CNS penetration.

**Binding Affinity:** Ligand B (-8.8 kcal/mol) has a significantly stronger binding affinity than Ligand A (-7.7 kcal/mol). This is a 1.1 kcal/mol difference, which is substantial and could potentially outweigh some of the ADME drawbacks of Ligand B.

**Overall Assessment:**

Despite the stronger binding affinity of Ligand B, Ligand A is the more promising candidate. The critical factors are the significantly better predicted BBB penetration (92.5% vs 60.7%), lower DILI risk (13.8% vs 50.1%), and more favorable TPSA (40.6 vs 73.2). While both have poor predicted solubility and permeability, the CNS target necessitates prioritizing BBB penetration, and Ligand A excels in this area. The affinity difference, while notable, is unlikely to overcome the substantial ADME advantages of Ligand A.

Output:
0
2025-04-17 05:28:48,158 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (348.487 and 345.487 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (58.64) is significantly better than Ligand B (63.13). For CNS targets, we want TPSA <= 90, both are well within this range, but A is preferable.

**3. logP:** Both ligands have good logP values (2.513 and 3.029), falling within the optimal 1-3 range. Ligand B is slightly higher, which could potentially lead to reduced solubility, but it's not a major concern.

**4. H-Bond Donors:** Ligand A (1) is better than Ligand B (2). Lower HBD generally improves permeability.

**5. H-Bond Acceptors:** Both ligands have the same number of HBA (3), which is acceptable (<=10).

**6. QED:** Both ligands have good QED scores (0.651 and 0.798), indicating good drug-like properties. Ligand B is slightly better.

**7. DILI:** Ligand A (12.641) has a higher DILI risk than Ligand B (20.202). This is a significant advantage for Ligand B.

**8. BBB:** Both ligands have good BBB penetration (64.831 and 66.576). While >70 is desirable, both are acceptable, and the difference is minor.

**9. Caco-2:** Both ligands have negative Caco-2 permeability values (-4.647 and -4.776). This is unusual and suggests poor intestinal absorption. This is a significant drawback for both, but doesn't necessarily disqualify them for CNS targets.

**10. Solubility:** Both ligands have negative solubility values (-2.842 and -2.916). This is also concerning and suggests poor aqueous solubility. This is a significant drawback for both, but less critical for CNS targets if BBB penetration is good.

**11. hERG:** Both ligands have very low hERG inhibition risk (0.393 and 0.261). This is excellent.

**12. Cl_mic:** Ligand B (28.194) has significantly lower microsomal clearance than Ligand A (71.872), indicating better metabolic stability. This is a major advantage for Ligand B.

**13. t1/2:** Ligand B (16.407) has a much longer in vitro half-life than Ligand A (3.398). This is a significant advantage for Ligand B, potentially allowing for less frequent dosing.

**14. Pgp:** Both ligands have low P-gp efflux liability (0.267 and 0.077). Ligand B is slightly better.

**15. Binding Affinity:** Both ligands have excellent binding affinity (-8.3 and -8.1 kcal/mol). The difference of 0.2 kcal/mol is not substantial enough to outweigh other factors.

**Overall Assessment:**

Ligand B is the superior candidate. While both have issues with Caco-2 and solubility, Ligand B demonstrates significantly better metabolic stability (lower Cl_mic, longer t1/2), lower DILI risk, and slightly better Pgp efflux profile. The TPSA and QED are also slightly better for Ligand B. The affinity difference is minimal. Given the GPCR target and CNS focus, metabolic stability and safety (DILI) are particularly important, making Ligand B the more promising candidate.

Output:
1
2025-04-17 05:28:48,158 - INFO - Batch 201 complete. Total preferences: 3216
2025-04-17 05:28:48,158 - INFO - Processing batch 202/512...
2025-04-17 05:29:28,955 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (347.419 and 362.836 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (130.23) is borderline acceptable for CNS penetration, being slightly above the preferred <90, but still reasonable. Ligand B (51.02) is excellent, well below the 90 threshold.

**logP:** Ligand A (0.401) is quite low, potentially hindering membrane permeability. Ligand B (3.417) is optimal, falling within the 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A has 4 HBD and 6 HBA, which are within acceptable limits. Ligand B has 0 HBD and 4 HBA, also acceptable.

**QED:** Both ligands have good QED scores (0.528 and 0.766), indicating drug-like properties.

**DILI:** Ligand A (54.75) has a moderate DILI risk, while Ligand B (63.629) has a higher DILI risk, but both are not critically high.

**BBB:** This is crucial for a CNS target. Ligand A (57.774) has a moderate BBB penetration, while Ligand B (84.451) has excellent BBB penetration.

**Caco-2 Permeability:** Ligand A (-5.47) has poor Caco-2 permeability, likely due to the low logP. Ligand B (-4.614) is also poor, but slightly better than A.

**Aqueous Solubility:** Both ligands have poor aqueous solubility (-2.303 and -3.449). This could pose formulation challenges.

**hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.127 and 0.309).

**Microsomal Clearance:** Ligand A (15.247) has lower microsomal clearance, suggesting better metabolic stability than Ligand B (48.497).

**In vitro Half-Life:** Ligand A (-14.457) has a negative half-life, which is unusual and likely indicates rapid degradation. Ligand B (-27.301) also has a negative half-life, but is even more negative.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.007 and 0.527), which is favorable for CNS penetration.

**Binding Affinity:** Ligand B (-8.9 kcal/mol) has a significantly stronger binding affinity than Ligand A (-7.8 kcal/mol). This 1.1 kcal/mol difference is substantial and can outweigh some ADME drawbacks.

**Overall Assessment:**

Ligand B is the stronger candidate. While both have solubility and half-life concerns, Ligand B excels in key areas for a CNS GPCR target: significantly better logP, excellent BBB penetration, and a substantially higher binding affinity. The slightly higher DILI risk is less concerning than the poor permeability and weaker binding of Ligand A. The negative half-life values are concerning for both, and would require further investigation (perhaps indicating an issue with the assay or a very rapid degradation pathway). However, the potency advantage of Ligand B is significant.

Output:
1
2025-04-17 05:29:28,956 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (354.447 and 348.447 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (84.94) and Ligand B (81.75) are both below the 90 A^2 threshold desirable for CNS targets, which is excellent.

**3. logP:** Both ligands have logP values within the optimal range (1.109 and 1.03, respectively).

**4. H-Bond Donors:** Ligand A has 1 HBD, and Ligand B has 2. Both are acceptable (<=5).

**5. H-Bond Acceptors:** Ligand A has 5 HBA, and Ligand B has 3. Both are acceptable (<=10).

**6. QED:** Both ligands have similar QED values (0.692 and 0.643), indicating good drug-likeness.

**7. DILI:** Ligand A (23.575) has a lower DILI risk than Ligand B (27.801), which is preferable. Both are below the 40 threshold.

**8. BBB:** This is a critical parameter for CNS targets. Ligand B (66.188) has a significantly higher BBB percentile than Ligand A (46.336). This is a major advantage for Ligand B.

**9. Caco-2 Permeability:** Both have negative values (-4.575 and -4.964), which is unusual and suggests very poor permeability. This is a significant concern for both.

**10. Aqueous Solubility:** Both have negative values (-1.262 and -1.527), indicating poor aqueous solubility. This is a drawback for both.

**11. hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.137 and 0.086).

**12. Microsomal Clearance:** Ligand B (11.71) has lower microsomal clearance than Ligand A (15.647), suggesting better metabolic stability.

**13. In vitro Half-Life:** Ligand B (9.841) has a longer in vitro half-life than Ligand A (-1.948), which is desirable.

**14. P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.015 and 0.005), which is good for CNS penetration.

**15. Binding Affinity:** Ligand A (-7.8 kcal/mol) has a significantly stronger binding affinity than Ligand B (-6.3 kcal/mol). This is a substantial advantage for Ligand A, potentially outweighing some of its ADME drawbacks. The difference is >1.5 kcal/mol.

**Overall Assessment:**

While Ligand B exhibits superior BBB penetration and metabolic stability, the significantly stronger binding affinity of Ligand A (-7.8 vs -6.3 kcal/mol) is a decisive factor. The difference in binding affinity is large enough to potentially overcome the lower BBB and shorter half-life of Ligand A. The poor Caco-2 and solubility are concerns for both, but can be addressed with formulation strategies. Given the importance of potency for GPCR ligands, and the substantial affinity difference, Ligand A is the more promising candidate.

Output:
0
2025-04-17 05:29:28,956 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (345.378 Da) is slightly lower, which could be beneficial for permeability. Ligand B (369.853 Da) is also good.

**TPSA:** Both ligands have TPSA values around 94-96 A^2, which is close to the upper limit for CNS penetration (<=90 A^2). Ligand A (93.88) is slightly better in this regard.

**logP:** Both ligands have optimal logP values (around 0.95), falling within the 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A has 3 HBD and 3 HBA, while Ligand B has 1 HBD and 5 HBA. Both are within acceptable limits (<=5 HBD and <=10 HBA).

**QED:** Both ligands have similar QED values (0.68 and 0.699), indicating good drug-likeness.

**DILI:** Ligand A (39.55) has a significantly lower DILI risk than Ligand B (56.495). This is a substantial advantage.

**BBB:** Ligand A (75.107) has a much better BBB penetration percentile than Ligand B (49.011). This is *critical* for a CNS target like DRD2.

**Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and suggests issues with the prediction method. However, the values are similar.

**Aqueous Solubility:** Both ligands have negative solubility values, again suggesting issues with the prediction. The values are similar.

**hERG:** Both ligands have low hERG inhibition liability (0.616 and 0.134). Ligand B is slightly better.

**Microsomal Clearance:** Ligand A has a much lower (better) microsomal clearance (-9.595) than Ligand B (42.183). This indicates better metabolic stability.

**In vitro Half-Life:** Ligand A has a longer half-life (-28.643) than Ligand B (26.895).

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.02 and 0.015).

**Binding Affinity:** Ligand B (-7.4 kcal/mol) has a slightly better binding affinity than Ligand A (-9.0 kcal/mol). This is a 1.6 kcal/mol difference, which is significant.

**Overall Assessment:**

While Ligand B has a slightly better binding affinity, Ligand A is superior overall, especially considering the GPCR-specific priorities for a CNS target. Ligand A has significantly better BBB penetration, lower DILI risk, better metabolic stability (lower Cl_mic and longer t1/2), and a slightly better TPSA. The affinity difference, while notable, is likely outweighed by the substantial advantages in ADME properties, particularly BBB penetration, which is crucial for CNS drug development.

Output:
1
2025-04-17 05:29:28,956 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (345.447 and 340.387 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (82.42) is excellent for CNS penetration, being well below 90. Ligand B (100.97) is still reasonable but less optimal.

**logP:** Ligand A (2.482) is within the optimal 1-3 range. Ligand B (0.857) is slightly below 1, which *could* indicate permeability issues, though not severely.

**H-Bond Donors/Acceptors:** Ligand A has 3 HBD and 5 HBA, both within acceptable limits. Ligand B has 1 HBD and 6 HBA, also acceptable.

**QED:** Both ligands have good QED scores (0.673 and 0.886), indicating drug-likeness.

**DILI:** Ligand A (70.686) has a higher DILI risk than Ligand B (58.395), though both are below the concerning 60 threshold.

**BBB:** Ligand B (67.08) has a significantly better BBB percentile than Ligand A (44.901). This is a critical advantage for a CNS target like DRD2.

**Caco-2 Permeability:** Ligand A (-4.656) shows poor Caco-2 permeability, suggesting absorption issues. Ligand B (-5.161) is also poor, but slightly better than A.

**Aqueous Solubility:** Both ligands have very poor aqueous solubility (-2.77 and -1.76). This could pose formulation challenges.

**hERG:** Both ligands have low hERG inhibition risk (0.433 and 0.271).

**Microsomal Clearance:** Ligand B (-3.586) has a *much* lower (better) microsomal clearance than Ligand A (44.524), indicating greater metabolic stability.

**In vitro Half-Life:** Ligand B (20.68) has a better in vitro half-life than Ligand A (39.12).

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.059 and 0.01).

**Binding Affinity:** Both ligands have similar, excellent binding affinities (-8.4 and -8.2 kcal/mol). The difference is negligible.

**Conclusion:**

While both ligands exhibit strong binding affinity, Ligand B is the superior candidate. Its significantly better BBB penetration, lower microsomal clearance, longer half-life, and lower DILI risk outweigh the slightly lower logP and Caco-2 permeability. The TPSA is also more favorable. For a CNS target like DRD2, BBB penetration and metabolic stability are paramount.

Output:
1
2025-04-17 05:29:28,956 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (365.5) is slightly higher than Ligand B (339.4).

**TPSA:** Both ligands have TPSA values below the 140 A^2 threshold for oral absorption, but are above the 90 A^2 ideal for CNS targets. Ligand B (92.42) is better than Ligand A (105.21) in this regard.

**logP:** Ligand A (3.137) is within the optimal range (1-3), while Ligand B (0.701) is slightly below, potentially hindering permeation.

**H-Bond Donors/Acceptors:** Both ligands have acceptable HBD/HBA counts. Ligand A has 2 HBD and 5 HBA, while Ligand B has 1 HBD and 5 HBA.

**QED:** Both ligands have similar QED values (0.654 and 0.646), indicating good drug-likeness.

**DILI:** Both ligands have elevated DILI risk (Ligand A: 63.591, Ligand B: 68.825), but are not excessively high.

**BBB:** Both ligands show moderate BBB penetration (Ligand A: 57.619, Ligand B: 64.87). While neither is >70, Ligand B is better.

**Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and suggests poor permeability. Ligand A (-5.141) is slightly better than Ligand B (-4.775).

**Aqueous Solubility:** Both have negative solubility values, indicating poor solubility. Ligand A (-3.486) is slightly better than Ligand B (-2.601).

**hERG Inhibition:** Both ligands have low hERG inhibition liability (Ligand A: 0.648, Ligand B: 0.126). Ligand B is significantly better.

**Microsomal Clearance:** Ligand A (46.795) has a much more favorable microsomal clearance than Ligand B (12.6), indicating better metabolic stability.

**In vitro Half-Life:** Ligand A (6.06 hours) has a better in vitro half-life than Ligand B (-37.05 hours - likely an error or very rapid clearance).

**P-gp Efflux:** Ligand A (0.332) has lower P-gp efflux liability than Ligand B (0.015), which is favorable for CNS exposure.

**Binding Affinity:** Ligand A (-8.3 kcal/mol) has a significantly better binding affinity than Ligand B (-7.9 kcal/mol). This 0.4 kcal/mol difference is substantial.

**Overall Assessment:**

Ligand A has a significantly better binding affinity and metabolic stability (lower Cl_mic, longer t1/2) and lower P-gp efflux. While Ligand B has a slightly better TPSA and hERG profile, the superior affinity and ADME properties of Ligand A outweigh these minor advantages, especially considering the importance of potency for GPCR ligands. The negative Caco-2 and solubility values are concerning for both, but can be addressed with formulation strategies.

Output:
1
2025-04-17 05:29:28,957 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (356.394 and 347.415 Da) fall within the ideal 200-500 Da range.

**TPSA:** Both ligands (99.1 and 100.55) are slightly above the optimal <90 for CNS targets, but still reasonable.

**logP:** Ligand A (-0.933) is a bit low, potentially hindering membrane permeability. Ligand B (0.797) is better, falling within the 1-3 range.

**H-Bond Donors/Acceptors:** Both have 3 HBD and 5 HBA, which are acceptable.

**QED:** Both ligands have good QED scores (0.591 and 0.604), indicating drug-likeness.

**DILI:** Ligand A (14.618) has a significantly lower DILI risk than Ligand B (41.915). This is a substantial advantage.

**BBB:** Ligand A (46.336) has a slightly better BBB penetration percentile than Ligand B (43.505), but both are below the desirable >70 for CNS targets.

**Caco-2 Permeability:** Both have negative Caco-2 values (-5.23 and -4.901), which is unusual and suggests poor permeability. This is a concern for both.

**Aqueous Solubility:** Both have negative solubility values (-1.088 and -2.111), indicating very poor aqueous solubility. This is a significant drawback for both.

**hERG Inhibition:** Both have very low hERG inhibition risk (0.282 and 0.047).

**Microsomal Clearance:** Ligand A (-9.604) has much lower (better) microsomal clearance than Ligand B (3.904), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (7.215 hours) has a better in vitro half-life than Ligand B (-32.27 hours). The negative value for Ligand B is concerning and likely an error or indicates very rapid degradation.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.008 and 0.046), which is good.

**Binding Affinity:** Both ligands have excellent binding affinity (-8.1 and -8.3 kcal/mol). The difference is minimal.

**Overall Assessment:**

Ligand A is the better candidate. While both have issues with solubility and Caco-2 permeability, Ligand A demonstrates significantly better metabolic stability (lower Cl_mic, longer t1/2), lower DILI risk, and a slightly better BBB percentile. The logP is a concern, but the superior ADME properties outweigh this drawback, especially considering the comparable binding affinities. The negative half-life for ligand B is a major red flag.

Output:
0
2025-04-17 05:29:28,957 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B based on the provided guidelines, prioritizing GPCR-specific properties (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (369.849 Da) is slightly higher than Ligand B (347.434 Da), but both are acceptable.

**TPSA:** Ligand A (74.87) is slightly higher than Ligand B (62.3). Both are below the 90 A^2 threshold desirable for CNS targets, but Ligand B is preferable.

**logP:** Ligand A (1.537) is within the optimal range (1-3). Ligand B (2.936) is also within range, leaning towards the higher end. Both are acceptable, but Ligand A is slightly better.

**H-Bond Donors/Acceptors:** Both ligands have 1 HBD and a reasonable number of HBAs (4 for A, 3 for B). This is favorable for both.

**QED:** Both ligands have good QED scores (0.873 for A, 0.805 for B), indicating good drug-like properties.

**DILI:** Ligand A (70.919) has a higher DILI risk than Ligand B (35.091). This is a significant drawback for Ligand A.

**BBB:** Ligand B (84.374) has a much higher BBB penetration score than Ligand A (58.511). This is a *critical* advantage for a CNS target like DRD2.

**Caco-2 Permeability:** Both have negative Caco-2 values which is unusual and suggests poor permeability. Ligand A (-4.766) is worse than Ligand B (-4.528).

**Aqueous Solubility:** Both have negative solubility values, which is also unusual and suggests poor solubility. Ligand A (-3.079) is worse than Ligand B (-2.541).

**hERG:** Ligand A (0.219) has a slightly lower hERG inhibition liability than Ligand B (0.638), which is preferable.

**Microsomal Clearance:** Ligand B (28.884) has a much higher microsomal clearance than Ligand A (1.568). This means Ligand A is more metabolically stable.

**In vitro Half-Life:** Ligand A (16.429 hours) has a significantly longer half-life than Ligand B (-6.226 hours). This is a major advantage for Ligand A.

**P-gp Efflux:** Ligand B (0.194) has lower P-gp efflux liability than Ligand A (0.102), which is beneficial for CNS penetration.

**Binding Affinity:** Ligand A (-7.8 kcal/mol) has a slightly better binding affinity than Ligand B (-0.0 kcal/mol). This is a substantial advantage for Ligand A.

**Overall Assessment:**

Ligand A has a better binding affinity, metabolic stability (lower Cl_mic), and longer half-life. However, Ligand B excels in BBB penetration, has a significantly lower DILI risk, and lower P-gp efflux. Given that this is a CNS target (DRD2), BBB penetration is paramount. The lower DILI risk of Ligand B is also a significant advantage. While Ligand A's affinity is better, the difference might be overcome with further optimization of Ligand B. The negative Caco-2 and solubility values are concerning for both, but are less critical than BBB for a CNS target.

Output:
1
2025-04-17 05:29:28,957 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (353.463 and 340.379 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (78.95) and Ligand B (75.69) are both below the 90 A^2 threshold desirable for CNS targets, which is excellent.

**3. logP:** Ligand A (0.492) is quite low, potentially hindering membrane permeability. Ligand B (2.749) is within the optimal 1-3 range. This is a significant advantage for Ligand B.

**4. H-Bond Donors:** Both ligands have 1 HBD, which is acceptable.

**5. H-Bond Acceptors:** Ligand A has 5 HBA, and Ligand B has 4 HBA, both are within the acceptable range of <=10.

**6. QED:** Both ligands have similar QED values (0.643 and 0.671), indicating good drug-likeness.

**7. DILI:** Ligand A (12.214) has a much lower DILI risk than Ligand B (64.521). This is a significant advantage for Ligand A.

**8. BBB:** Both ligands have similar BBB penetration (44.668 and 45.715). Neither is above the 70% threshold, but they are comparable.

**9. Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and suggests poor permeability. However, the scale is not specified, so it's difficult to interpret.

**10. Aqueous Solubility:** Both have negative solubility values, again, the scale is unspecified making interpretation difficult.

**11. hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.201 and 0.236).

**12. Microsomal Clearance:** Ligand A (-13.842) has a much lower (better) microsomal clearance than Ligand B (42.281), indicating better metabolic stability.

**13. In vitro Half-Life:** Ligand A (-10.542) has a negative half-life, which is not possible. This is a red flag. Ligand B (27.368) has a reasonable half-life.

**14. P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.01 and 0.131), which is favorable for CNS penetration.

**15. Binding Affinity:** Ligand B (-8.4 kcal/mol) has a slightly better binding affinity than Ligand A (-7.7 kcal/mol). While the difference is less than the 1.5 kcal/mol threshold, it's still a positive for Ligand B.

**Overall Assessment:**

Ligand A has advantages in DILI risk and metabolic stability (Cl_mic). However, its extremely low logP and negative half-life are major concerns. The negative half-life is a showstopper. Ligand B, while having a higher DILI risk, has a much more favorable logP, a reasonable half-life, and slightly better binding affinity. Given the GPCR-specific priorities, especially logP and BBB, and the critical importance of a positive half-life, Ligand B is the more promising candidate.

Output:
1
2025-04-17 05:29:28,957 - INFO - Reasoning:

Let's analyze Ligand A and Ligand B based on the provided guidelines, prioritizing GPCR-specific properties (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (352.387) is slightly lower, which *could* be beneficial for permeability, but both are acceptable.

**TPSA:** Ligand B (75.27) is significantly better than Ligand A (102.96). For CNS targets, TPSA should be <=90. Ligand B is comfortably within this range, while Ligand A is pushing the upper limit. This favors Ligand B.

**logP:** Ligand B (2.822) is optimal (1-3), while Ligand A (0.224) is quite low, potentially hindering membrane permeability. This is a significant advantage for Ligand B.

**H-Bond Donors/Acceptors:** Both have acceptable HBD (2) and relatively low HBA (Ligand A: 6, Ligand B: 3). No strong preference here.

**QED:** Both have reasonable QED values (Ligand A: 0.368, Ligand B: 0.645), but Ligand B is considerably better, indicating a more drug-like profile.

**DILI:** Both ligands have similar DILI risk (Ligand A: 51.338, Ligand B: 51.842), and are both acceptable (<60).

**BBB:** Ligand B (76.735) is significantly better than Ligand A (60.45). A BBB percentile >70 is desirable for CNS targets, and Ligand B is closer to that threshold. This is a major advantage for Ligand B.

**Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and suggests a potential issue with the data or modeling. However, the magnitude is worse for Ligand A (-5.494) than Ligand B (-4.966).

**Aqueous Solubility:** Both have negative solubility values, which is also unusual. Again, the magnitude is worse for Ligand A (-1.878) than Ligand B (-4.223).

**hERG:** Both have very low hERG inhibition liability (Ligand A: 0.098, Ligand B: 0.609), which is excellent.

**Microsomal Clearance:** Ligand A (20.695) has lower microsomal clearance than Ligand B (41.339), indicating better metabolic stability. This favors Ligand A.

**In vitro Half-Life:** Ligand A (-17.196) has a more negative in vitro half-life, which is not ideal. Ligand B (-15.917) is better, but still indicates a short half-life.

**P-gp Efflux:** Both have very low P-gp efflux liability (Ligand A: 0.044, Ligand B: 0.187), which is desirable for CNS penetration.

**Binding Affinity:** Ligand B (-7.6) has slightly better binding affinity than Ligand A (-7.8), but the difference is minimal (0.2 kcal/mol).

**Overall Assessment:**

Ligand B is clearly superior. It excels in key GPCR properties: TPSA, logP, and BBB. While Ligand A has better metabolic stability (lower Cl_mic), the significant advantages of Ligand B in permeability (logP), CNS penetration (BBB, TPSA), and drug-likeness (QED) outweigh this benefit. The slight difference in binding affinity is negligible. The unusual negative solubility and Caco-2 values are concerning for both, but less so for Ligand B given its other favorable properties.

Output:
1
2025-04-17 05:29:28,958 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (347.415 and 343.431 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (102.76) is better than Ligand B (110) as it is closer to the desirable <90 TPSA for CNS targets. Ligand B is still acceptable, but A is preferred.

**3. logP:** Ligand B (1.572) is slightly better than Ligand A (0.886). Both are within the optimal 1-3 range, but A is a bit low, potentially hindering membrane permeability.

**4. H-Bond Donors:** Both ligands have 3 HBD, which is within the acceptable limit of <=5.

**5. H-Bond Acceptors:** Both ligands have 5 HBA, which is within the acceptable limit of <=10.

**6. QED:** Both ligands have similar QED values (0.663 and 0.651), indicating good drug-like properties.

**7. DILI:** Ligand A (25.94) has a significantly lower DILI risk than Ligand B (51.221). This is a major advantage for Ligand A.

**8. BBB:** Ligand B (63.629) has a much better BBB penetration percentile than Ligand A (12.292). This is a critical factor for a CNS target like DRD2.

**9. Caco-2 Permeability:** Both have negative Caco-2 values (-5.34 and -5.3), which is unusual and suggests poor permeability. This is a concern for both.

**10. Aqueous Solubility:** Both have negative solubility values (-1.732 and -3.383), indicating very poor aqueous solubility. This is a significant drawback for both.

**11. hERG Inhibition:** Ligand A (0.048) has a lower hERG inhibition risk than Ligand B (0.189), which is preferable.

**12. Microsomal Clearance:** Ligand A (1.61) has significantly lower microsomal clearance than Ligand B (19.674), indicating better metabolic stability.

**13. In vitro Half-Life:** Ligand A (-21.815) has a much longer in vitro half-life than Ligand B (-4.908), which is a significant advantage.

**14. P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.02 and 0.017), which is good.

**15. Binding Affinity:** Ligand B (-8.5 kcal/mol) has a slightly better binding affinity than Ligand A (-7.9 kcal/mol). While A's affinity is good, the 0.6 kcal/mol difference is not huge.

**Overall Assessment:**

Ligand B excels in BBB penetration and binding affinity, which are crucial for a CNS GPCR target. However, it suffers from a higher DILI risk, higher metabolic clearance, and shorter half-life. Ligand A has a much better safety profile (lower DILI, hERG), better metabolic stability (lower Cl_mic, longer t1/2), and acceptable TPSA, but its BBB penetration is very poor.

Considering the balance, the improved safety and pharmacokinetic properties of Ligand A outweigh the slightly weaker binding affinity, especially given that the affinity is still in a good range. The poor solubility and permeability are concerns for both, but can potentially be addressed through formulation strategies. The BBB penetration of Ligand A is a major drawback, but the other advantages are substantial.

Output:
0
2025-04-17 05:29:28,958 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 drug candidates, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight (MW):** Both ligands are within the ideal range (200-500 Da). Ligand A (343.427 Da) is slightly lower, which could be beneficial for permeability.

**2. TPSA:** Both are reasonably good, but Ligand A (91.32) is better than Ligand B (95.07) for CNS penetration as it's closer to the <90 threshold.

**3. logP:** Both ligands have acceptable logP values (Ligand A: 1.241, Ligand B: 2.419), falling within the 1-3 range. Ligand B is slightly higher, which might raise concerns about off-target effects, but isn't critical.

**4. H-Bond Donors (HBD):** Ligand A (3) is preferable to Ligand B (1) as it is within the ideal range.

**5. H-Bond Acceptors (HBA):** Ligand A (4) is preferable to Ligand B (9) as it is within the ideal range.

**6. QED:** Both ligands have reasonable QED scores (Ligand A: 0.702, Ligand B: 0.505), indicating good drug-like properties. Ligand A is slightly better.

**7. DILI:** Ligand A (39.899) has a significantly lower DILI risk than Ligand B (77.588), which is a major advantage.

**8. BBB:** Both ligands have moderate BBB penetration (Ligand A: 40.481, Ligand B: 43.815). Neither is ideal (>70), but this is less critical if other properties are strong.

**9. Caco-2:** Both have negative Caco-2 values, which is unusual and suggests poor permeability.

**10. Solubility:** Both have negative solubility values, which is also unusual and suggests poor solubility.

**11. hERG:** Both ligands have very low hERG inhibition risk (Ligand A: 0.063, Ligand B: 0.044).

**12. Cl_mic:** Ligand A (0.419) has much lower microsomal clearance than Ligand B (97.357), indicating better metabolic stability.

**13. t1/2:** Ligand A (-11.79) has a negative half-life, which is impossible. Ligand B (23.029) has a reasonable half-life.

**14. Pgp:** Ligand A (0.045) has lower P-gp efflux liability than Ligand B (0.252), which is beneficial for CNS exposure.

**15. Binding Affinity:** Ligand A (-9.2 kcal/mol) has a significantly stronger binding affinity than Ligand B (-7.0 kcal/mol). This is a substantial advantage, potentially outweighing some of the ADME drawbacks.

**Overall Assessment:**

Despite the unusual negative values for Caco-2 and solubility, Ligand A is the more promising candidate. It has a significantly better binding affinity, lower DILI risk, lower microsomal clearance (better metabolic stability), and lower P-gp efflux. The TPSA is also slightly better. While the BBB penetration isn't ideal for either, the superior binding affinity and ADME properties of Ligand A make it the better choice. The negative half-life for Ligand A is a major concern, and would need to be investigated.

Output:
0
2025-04-17 05:29:28,958 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (364.515 and 366.889 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (75.19) is higher than Ligand B (57.69). For CNS targets, we prefer TPSA <= 90, so both are acceptable, but B is better.

**logP:** Both ligands have a logP of approximately 2.7, which is within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A has 1 HBD and 5 HBA, while Ligand B has 0 HBD and 3 HBA. Both are within acceptable limits (<=5 HBD and <=10 HBA).

**QED:** Ligand A (0.872) has a higher QED than Ligand B (0.771), indicating a more drug-like profile.

**DILI:** Ligand A (51.881) has a slightly higher DILI risk than Ligand B (37.611), but both are below the concerning threshold of 60.

**BBB:** This is a crucial parameter for CNS targets. Ligand B (77.278) has a significantly higher BBB penetration percentile than Ligand A (62.97). This is a major advantage for B.

**Caco-2 Permeability:** Ligand A (-4.858) has lower Caco-2 permeability than Ligand B (-4.407), suggesting potentially poorer intestinal absorption for A.

**Aqueous Solubility:** Ligand A (-3.685) has lower aqueous solubility than Ligand B (-2.517).

**hERG Inhibition:** Both ligands show low hERG inhibition liability (0.305 and 0.14 respectively), which is good.

**Microsomal Clearance:** Ligand A (59.641) has higher microsomal clearance than Ligand B (35.749), indicating lower metabolic stability for A.

**In vitro Half-Life:** Ligand A (11.759) has a longer half-life than Ligand B (1.128). This is a positive for A, but the large difference in half-life is concerning for B.

**P-gp Efflux:** Ligand A (0.463) has higher P-gp efflux liability than Ligand B (0.188). Lower P-gp efflux is preferred, especially for CNS targets, giving an advantage to B.

**Binding Affinity:** Ligand B (-8.8) has a slightly better binding affinity than Ligand A (-8.0). While both are excellent, the 0.8 kcal/mol difference is significant.

**Overall Assessment:**

Ligand B is the stronger candidate. Its superior BBB penetration (77.28 vs 62.97), lower P-gp efflux, better Caco-2 permeability, lower microsomal clearance, and slightly better binding affinity outweigh Ligand A's higher QED and longer half-life. The difference in half-life for B is concerning, but can be addressed through structural modifications. The BBB penetration is critical for a CNS target like DRD2, and Ligand B excels in this area.

Output:
1
2025-04-17 05:29:28,958 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (346.471 and 356.423 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (50.8) is significantly better than Ligand B (108.05). For CNS targets, TPSA should be <= 90, and A is comfortably within this range, while B exceeds it. This is a major advantage for A.

**logP:** Ligand A (3.322) is optimal (1-3), while Ligand B (-0.868) is quite low, potentially hindering membrane permeability. This favors A.

**H-Bond Donors/Acceptors:** Ligand A (HBD=1, HBA=3) and Ligand B (HBD=2, HBA=5) are both acceptable, staying within the recommended limits.

**QED:** Ligand A (0.86) has a much better QED score than Ligand B (0.475), indicating a more drug-like profile.

**DILI:** Ligand B (39.511) has a slightly higher DILI risk than Ligand A (22.8), but both are below the concerning threshold of 60.

**BBB:** Ligand A (89.027) has a significantly higher BBB penetration percentile than Ligand B (33.656). This is *critical* for a CNS target like DRD2, making A far more promising.

**Caco-2 Permeability:** Ligand A (-4.278) and Ligand B (-5.248) both have negative Caco-2 values, which is unusual and requires further investigation. However, the difference is small.

**Aqueous Solubility:** Ligand A (-3.152) and Ligand B (-1.135) both have negative solubility values, which is also unusual and requires further investigation. The difference is small.

**hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.561 and 0.062 respectively).

**Microsomal Clearance:** Ligand A (41.018) has a higher microsomal clearance than Ligand B (2.461), suggesting faster metabolism and potentially lower in vivo exposure. This favors B.

**In vitro Half-Life:** Ligand B (-10.074) has a negative half-life, which is impossible. This is a major red flag for Ligand B. Ligand A (2.776) is reasonable.

**P-gp Efflux:** Ligand A (0.094) has slightly higher P-gp efflux liability than Ligand B (0.008), but both are very low.

**Binding Affinity:** Ligand A (-8.4 kcal/mol) has a stronger binding affinity than Ligand B (-6.8 kcal/mol). This is a substantial difference (1.6 kcal/mol), and can often outweigh minor ADME concerns.

**Overall Assessment:**

Ligand A is significantly better across most critical parameters for a CNS-targeting GPCR. Its superior TPSA, logP, QED, and *especially* BBB penetration, combined with a much stronger binding affinity, outweigh its slightly higher microsomal clearance. Ligand B has a problematic negative in vitro half-life and a poor logP and BBB.



Output:
1
2025-04-17 05:29:28,959 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (363.288 and 366.527 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (90.93) is better than Ligand B (58.64). For CNS targets, we want TPSA <= 90, so Ligand A is right on the edge while Ligand B is well within the range.

**3. logP:** Both ligands have good logP values (1.924 and 2.708), falling within the optimal 1-3 range.

**4. H-Bond Donors:** Both have 1 HBD, which is acceptable.

**5. H-Bond Acceptors:** Ligand A has 6 HBA, and Ligand B has 4. Both are below the acceptable threshold of 10.

**6. QED:** Both ligands have good QED scores (0.561 and 0.731), indicating good drug-like properties.

**7. DILI:** Ligand A (75.456) has a higher DILI risk than Ligand B (13.532). This is a significant advantage for Ligand B.

**8. BBB:** Both ligands have excellent BBB penetration (89.104 and 82.202), exceeding the desirable >70 threshold for CNS targets.

**9. Caco-2 Permeability:** Both have negative Caco-2 values (-4.942 and -4.933). This is unusual and could indicate issues with the prediction method or the compounds themselves. However, since both are similarly poor, it doesn't differentiate them.

**10. Aqueous Solubility:** Ligand A (-3.96) has slightly worse solubility than Ligand B (-2.067), but both are poor.

**11. hERG Inhibition:** Both ligands have low hERG inhibition risk (0.67 and 0.558).

**12. Microsomal Clearance:** Ligand A (58.136) has higher microsomal clearance than Ligand B (25.682), indicating lower metabolic stability. Ligand B is preferable here.

**13. In vitro Half-Life:** Ligand B (9.271) has a significantly longer in vitro half-life than Ligand A (-2.173). This is a major advantage for Ligand B.

**14. P-gp Efflux:** Both ligands have low P-gp efflux liability (0.26 and 0.139).

**15. Binding Affinity:** Ligand B (-8.2 kcal/mol) has a slightly better binding affinity than Ligand A (-7.8 kcal/mol). While the difference is less than the 1.5 kcal/mol threshold that would overwhelmingly favor one ligand, it contributes to the overall picture.

**Overall Assessment:**

Ligand B is the more promising candidate. It has a significantly lower DILI risk, better metabolic stability (lower Cl_mic, longer t1/2), and slightly better binding affinity. While Ligand A has a slightly better TPSA, the advantages of Ligand B in safety (DILI) and pharmacokinetics (Cl_mic, t1/2) outweigh this minor difference. Both have acceptable BBB penetration and logP values.

Output:
1
2025-04-17 05:29:28,959 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B based on the provided guidelines, prioritizing GPCR-specific properties (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (348.4 and 350.3 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (82.81) is significantly better than Ligand B (128.54). For CNS targets, TPSA should be <=90, and A is comfortably within this range, while B is pushing the limit.

**logP:** Ligand A (1.711) is within the optimal 1-3 range. Ligand B (-2.098) is quite low, potentially hindering membrane permeability and CNS penetration.

**H-Bond Donors/Acceptors:** Both have acceptable HBD (1) and HBA (7 for A, 9 for B) counts, being within the recommended limits.

**QED:** Both ligands have similar QED values (0.658 and 0.612), indicating good drug-likeness.

**DILI:** Ligand A (26.483) has a much lower DILI risk than Ligand B (69.252). This is a significant advantage for A.

**BBB:** Ligand A (38.232) has a low BBB percentile, which is a major concern for a CNS target like DRD2. Ligand B (61.846) is better, but still not ideal (aim for >70).

**Caco-2 Permeability:** Ligand A (-4.588) and Ligand B (-5.058) both have negative Caco-2 values, which is unusual and suggests poor permeability.

**Aqueous Solubility:** Both ligands have negative solubility values (-1.879 and -1.054), indicating very poor aqueous solubility. This could be a formulation challenge.

**hERG Inhibition:** Ligand A (0.569) has a slightly higher hERG risk than Ligand B (0.005). This favors B.

**Microsomal Clearance:** Ligand B (-14.953) has a much lower (better) microsomal clearance than Ligand A (56.17), indicating greater metabolic stability.

**In vitro Half-Life:** Ligand B (3.926) has a slightly longer half-life than Ligand A (-24.762), which is preferable.

**P-gp Efflux:** Ligand A (0.304) has lower P-gp efflux liability than Ligand B (0.018), which is a positive for CNS penetration.

**Binding Affinity:** Ligand B (-8.7 kcal/mol) has a slightly better binding affinity than Ligand A (-7.9 kcal/mol). While A is still good, the 0.8 kcal/mol difference is notable.

**Overall Assessment:**

Despite Ligand B's better affinity and metabolic stability, Ligand A is the more promising candidate. The critical factor is the CNS target. Ligand A's lower TPSA and lower P-gp efflux are beneficial for brain penetration, despite its lower BBB percentile. Ligand B's very low logP is a major drawback, severely limiting its ability to cross the blood-brain barrier. Furthermore, Ligand A has a significantly lower DILI risk. While both have poor solubility and Caco-2 permeability, these can potentially be addressed with formulation strategies. The affinity difference is not large enough to overcome the significant permeability issues of Ligand B.

Output:
0
2025-04-17 05:29:28,959 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (376.503 and 346.391 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (76.13) is significantly better than Ligand B (114.94). For CNS targets, we want TPSA <= 90, and A is comfortably within that range, while B is pushing the limit.

**logP:** Both ligands have good logP values (1.978 and 1.102), falling within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A (HBD=1, HBA=5) is slightly better than Ligand B (HBD=2, HBA=7) in terms of adhering to the <=5 and <=10 rules, respectively.

**QED:** Both ligands have acceptable QED values (0.836 and 0.74), indicating good drug-like properties.

**DILI:** Both ligands have similar DILI risk (67.584 and 69.911), which is moderately high but not alarming.

**BBB:** Ligand A (69.833) has a better BBB percentile than Ligand B (57.193). For a CNS target like DRD2, >70 is desirable, but A is closer to that threshold than B.

**Caco-2 Permeability:** Both have negative Caco-2 values (-5.329 and -5.148), which is unusual and suggests poor permeability. This is a significant drawback for both.

**Aqueous Solubility:** Both ligands have poor aqueous solubility (-2.803 and -2.694).

**hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.134 and 0.078).

**Microsomal Clearance:** Ligand A (30.113) has lower microsomal clearance than Ligand B (43.476), indicating better metabolic stability.

**In vitro Half-Life:** Ligand A (-1.569) has a negative half-life, which is not possible. Ligand B (-20.067) also has a negative half-life. This is a major red flag for both compounds.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.339 and 0.048), which is good for CNS penetration.

**Binding Affinity:** Ligand A (-9.3 kcal/mol) has significantly better binding affinity than Ligand B (-8.0 kcal/mol). This is a substantial difference, exceeding the 1.5 kcal/mol advantage threshold.

**Overall Assessment:**

Despite the poor Caco-2 and half-life values for both, Ligand A is the more promising candidate. Its superior TPSA, BBB penetration, metabolic stability (lower Cl_mic), and *significantly* stronger binding affinity outweigh the similar DILI and solubility issues. The negative half-life values are concerning and would need to be investigated further (likely an experimental error or data artifact), but the binding affinity difference is substantial enough to prioritize A for further optimization.

Output:
1
2025-04-17 05:29:28,959 - INFO - Batch 202 complete. Total preferences: 3232
2025-04-17 05:29:28,959 - INFO - Processing batch 203/512...
2025-04-17 05:30:10,696 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (370.358 Da and 354.447 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (121.72) is slightly above the optimal <90 for CNS targets, but still reasonable. Ligand B (110.1) is better, falling comfortably under 140 and closer to the CNS target.

**logP:** Ligand A (1.574) is within the optimal 1-3 range. Ligand B (-0.224) is slightly low, potentially hindering permeability.

**H-Bond Donors/Acceptors:** Ligand A (1 HBD, 7 HBA) is excellent. Ligand B (4 HBD, 5 HBA) is also acceptable, but higher HBD count could slightly impact permeability.

**QED:** Both ligands have reasonable QED scores (0.793 and 0.545), indicating good drug-like properties.

**DILI:** Ligand A (94.804) has a high DILI risk, which is a significant concern. Ligand B (22.024) has a very low DILI risk, a major advantage.

**BBB:** Ligand A (83.87) has good BBB penetration, desirable for a CNS target. Ligand B (10.392) has very poor BBB penetration, a major drawback.

**Caco-2 Permeability:** Ligand A (-4.589) has poor Caco-2 permeability. Ligand B (-5.372) also has poor Caco-2 permeability.

**Aqueous Solubility:** Ligand A (-3.301) has poor solubility. Ligand B (-1.785) has slightly better solubility.

**hERG:** Both ligands have low hERG inhibition risk (0.133 and 0.101).

**Microsomal Clearance:** Ligand A (-8.459) has very low (good) microsomal clearance, indicating good metabolic stability. Ligand B (-13.162) has even lower clearance, suggesting excellent metabolic stability.

**In vitro Half-Life:** Both ligands have similar in vitro half-lives (21.887 and 20.571 hours).

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.104 and 0.02).

**Binding Affinity:** Both ligands have excellent binding affinity (-9.3 and -8.1 kcal/mol). Ligand A is slightly better (-9.3 kcal/mol).

**Overall Assessment:**

While Ligand A has slightly better affinity and BBB penetration, its extremely high DILI risk and poor Caco-2 permeability are major red flags. Ligand B, despite the lower logP and BBB, has a remarkably low DILI risk and excellent metabolic stability. For a CNS target, a low DILI risk is paramount, and the difference in affinity (1.2 kcal/mol) can potentially be overcome with further optimization. The poor BBB of ligand B is a concern, but can be addressed with structural modifications.

Output:
1
2025-04-17 05:30:10,696 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (368.449 and 356.463 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (46.38) is excellent, well below the 90 A^2 threshold for CNS targets. Ligand B (99.1) is higher, but still potentially acceptable, though less ideal.

**logP:** Ligand A (4.59) is slightly high, potentially causing solubility issues or off-target interactions. Ligand B (0.456) is quite low, which could hinder membrane permeability and CNS penetration.

**H-Bond Donors/Acceptors:** Ligand A (0 HBD, 4 HBA) is favorable. Ligand B (3 HBD, 5 HBA) is also reasonable.

**QED:** Ligand B (0.601) has a better QED score than Ligand A (0.232), indicating better overall drug-likeness.

**DILI:** Ligand B (19.271) has a significantly lower DILI risk than Ligand A (36.216), which is a major advantage.

**BBB:** Ligand A (86.196) has a much better BBB penetration percentile than Ligand B (49.128). This is critical for a CNS target like DRD2.

**Caco-2 Permeability:** Both have negative values, which is unusual and suggests a potential issue with the data. However, the magnitude of the negative value for Ligand A (-4.592) is smaller than for Ligand B (-4.775), suggesting slightly better permeability.

**Aqueous Solubility:** Both ligands have very poor aqueous solubility (-5.26 and -1.474). This is a significant concern for both.

**hERG Inhibition:** Ligand A (0.881) has a slightly higher hERG risk than Ligand B (0.303), but both are relatively low.

**Microsomal Clearance:** Ligand B (7.205) has a much lower microsomal clearance than Ligand A (49.644), indicating better metabolic stability.

**In vitro Half-Life:** Ligand B (-14.712) has a significantly longer in vitro half-life than Ligand A (-1.37), which is a major positive.

**P-gp Efflux:** Ligand A (0.394) has lower P-gp efflux liability than Ligand B (0.023), meaning it's less likely to be pumped out of the brain.

**Binding Affinity:** Ligand A (-8.1 kcal/mol) has a significantly stronger binding affinity than Ligand B (-6.5 kcal/mol). This is a substantial advantage, potentially outweighing some of its other drawbacks.

**Overall Assessment:**

Ligand A excels in binding affinity and BBB penetration, which are crucial for a CNS GPCR target. However, its high logP, poor solubility, and higher DILI risk are concerning. Ligand B has better drug-likeness (QED), lower DILI, better metabolic stability, and longer half-life, but suffers from poor BBB penetration and significantly weaker binding affinity.

Given the importance of strong binding affinity for GPCRs, and the critical need for BBB penetration for CNS targets, the stronger affinity and better BBB of Ligand A are decisive. While its other properties are less ideal, optimization efforts could focus on improving solubility and reducing logP/DILI risk. The weaker affinity of Ligand B is a more difficult hurdle to overcome.

Output:
0
2025-04-17 05:30:10,696 - INFO - Reasoning:

Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (354.466 and 359.451 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (60.85) is significantly better than Ligand B (73.74). For CNS targets, we want TPSA <= 90, and A is comfortably within that, while B is approaching the upper limit.

**3. logP:** Both ligands have good logP values (2.293 and 1.931), falling within the optimal 1-3 range.

**4. H-Bond Donors:** Both have 1 HBD, which is acceptable.

**5. H-Bond Acceptors:** Ligand A has 3 HBA, and Ligand B has 5. Both are within the acceptable limit of <=10, but A is preferable.

**6. QED:** Ligand B (0.909) has a significantly better QED score than Ligand A (0.537), indicating a more drug-like profile overall.

**7. DILI:** Ligand A (11.516) has a much lower DILI risk than Ligand B (60.489). This is a substantial advantage for Ligand A.

**8. BBB:** Ligand A (79.915) has a significantly better BBB penetration percentile than Ligand B (32.803). This is *critical* for a CNS target like DRD2.

**9. Caco-2:** Both have negative Caco-2 values, which is unusual and suggests poor permeability. However, the scale is not specified, so it is hard to interpret.

**10. Solubility:** Both have negative solubility values, which is also unusual.

**11. hERG:** Both ligands have low hERG inhibition liability (0.558 and 0.314), which is good.

**12. Cl_mic:** Ligand B (25.442) has lower microsomal clearance than Ligand A (45.308), suggesting better metabolic stability.

**13. t1/2:** Ligand B (5.93) has a longer in vitro half-life than Ligand A (-23.647). This is a significant advantage for Ligand B.

**14. Pgp:** Ligand A (0.253) has lower P-gp efflux liability than Ligand B (0.181), which is favorable for CNS penetration.

**15. Binding Affinity:** Both ligands have excellent binding affinities (-8.1 and -8.4 kcal/mol). Ligand B is slightly better, but the difference is small.

**Overall Assessment:**

While Ligand B has a better QED and in vitro half-life, Ligand A is significantly better in terms of BBB penetration, DILI risk, and TPSA. For a CNS target like DRD2, BBB penetration is paramount. The lower DILI risk is also a major advantage. The slightly better affinity of Ligand B is unlikely to outweigh the substantial benefits of Ligand A regarding CNS penetration and safety.

Output:
0
2025-04-17 05:30:10,697 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (346.431 and 347.409 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (90.54) is borderline acceptable for CNS targets (<=90), while Ligand B (45.23) is well within the desired range, suggesting better potential for brain penetration.

**3. logP:** Ligand A (0.379) is quite low, potentially hindering membrane permeability. Ligand B (3.278) is within the optimal 1-3 range.

**4. H-Bond Donors:** Ligand A (3) and Ligand B (1) are both acceptable, being less than or equal to 5.

**5. H-Bond Acceptors:** Both ligands (A: 3, B: 3) are well below the limit of 10.

**6. QED:** Both ligands have good QED scores (A: 0.629, B: 0.923), indicating drug-like properties. Ligand B is superior here.

**7. DILI:** Ligand A (19.387) has a significantly lower DILI risk than Ligand B (54.789), which is a considerable advantage.

**8. BBB:** Ligand B (89.957) has a better BBB percentile than Ligand A (72.974), though both are reasonably good for a CNS target.

**9. Caco-2:** Both have negative values, which is unusual. Assuming these are log values, a higher value indicates better permeability. Comparing the absolute values, Ligand A (-5.15) appears to have slightly better Caco-2 permeability than Ligand B (-4.466).

**10. Solubility:** Both ligands have poor solubility scores (A: -2.437, B: -3.604).

**11. hERG:** Ligand A (0.118) has a lower hERG risk than Ligand B (0.817), which is preferable.

**12. Cl_mic:** Ligand A (-5.327) has much lower (better) microsomal clearance than Ligand B (32.669), indicating better metabolic stability.

**13. t1/2:** Ligand B (35.235) has a significantly longer in vitro half-life than Ligand A (9.849).

**14. Pgp:** Ligand A (0.013) exhibits much lower P-gp efflux liability than Ligand B (0.466), which is crucial for CNS penetration.

**15. Binding Affinity:** Both ligands have strong binding affinities (A: -9.4 kcal/mol, B: -8.7 kcal/mol), with Ligand A being slightly more potent. The 1.5 kcal/mol difference is significant.

**Overall Assessment:**

Ligand A has a superior binding affinity, lower DILI risk, lower hERG risk, lower microsomal clearance (better metabolic stability), and lower P-gp efflux. However, its logP is quite low, and its BBB penetration is lower than Ligand B. Ligand B has a better TPSA, logP, BBB, and in vitro half-life.

Given the GPCR-specific priorities, BBB penetration and logP are important. While Ligand B has a better BBB and logP, the significantly stronger binding affinity of Ligand A (-9.4 vs -8.7 kcal/mol) and its favorable ADME properties (DILI, hERG, Cl_mic, Pgp) outweigh the slightly lower BBB and logP. The stronger binding is likely to translate to efficacy at lower doses, potentially mitigating permeability issues.

Output:
1
2025-04-17 05:30:10,697 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (381.885 Da) is slightly higher than Ligand B (353.507 Da), but both are acceptable.

**TPSA:** Ligand A (80.32) is better than Ligand B (61.88) for CNS penetration, falling comfortably below the 90 A^2 threshold.

**logP:** Ligand A (3.48) is optimal, while Ligand B (1.641) is on the lower side. A logP below 1 can hinder permeation.

**H-Bond Donors/Acceptors:** Ligand A (HBD=2, HBA=5) and Ligand B (HBD=1, HBA=4) both have reasonable numbers of H-bond donors and acceptors, well within the guidelines.

**QED:** Both ligands have similar QED values (0.686 and 0.684), indicating good drug-likeness.

**DILI:** Ligand A (72.199) has a higher DILI risk than Ligand B (8.104). This is a significant drawback for Ligand A.

**BBB:** Both ligands have good BBB penetration (Ligand A: 61.962, Ligand B: 64.482), but neither exceeds the desirable 70% threshold.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values, which is unusual and suggests poor permeability. However, the values are similar.

**Aqueous Solubility:** Both have poor aqueous solubility, with negative values.

**hERG Inhibition:** Both ligands exhibit low hERG inhibition risk (Ligand A: 0.443, Ligand B: 0.227).

**Microsomal Clearance:** Ligand B (9.944) has significantly lower microsomal clearance than Ligand A (59.741), indicating better metabolic stability.

**In vitro Half-Life:** Ligand B (-7.356) has a negative half-life, which is not possible. This is a major red flag. Ligand A (66.282) has a reasonable half-life.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (Ligand A: 0.156, Ligand B: 0.04).

**Binding Affinity:** Ligand B (-8.5 kcal/mol) has a slightly better binding affinity than Ligand A (-8.1 kcal/mol), although the difference is small.

**Overall Assessment:**

Ligand B has a better logP, lower DILI risk, and lower microsomal clearance. However, the negative in vitro half-life is a critical issue. Ligand A has a higher DILI risk and higher clearance, but a reasonable half-life. Given the importance of metabolic stability and the unphysical half-life of Ligand B, and the relatively small difference in binding affinity, Ligand A is the more promising candidate *despite* its higher DILI risk. Further optimization could address the DILI concern.

Output:
0
2025-04-17 05:30:10,697 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (345.447 and 349.475 Da) fall comfortably within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (71.33) is slightly higher than Ligand B (65.79). Both are below the 90 A^2 threshold for CNS targets, which is good.

**3. logP:** Ligand A (1.482) and Ligand B (2.203) are both within the optimal 1-3 range.

**4. H-Bond Donors:** Ligand A (0) has fewer HBD than Ligand B (1). Lower is generally preferred for BBB penetration.

**5. H-Bond Acceptors:** Ligand A (5) has more HBA than Ligand B (4). Both are within the acceptable limit of 10.

**6. QED:** Both ligands have good QED scores (0.775 and 0.855, respectively), indicating good drug-like properties.

**7. DILI:** Ligand A (33.075) has a slightly higher DILI risk than Ligand B (21.093), but both are below the concerning threshold of 60.

**8. BBB:** This is a critical parameter for a CNS target like DRD2. Ligand A (71.035) has a significantly better BBB percentile than Ligand B (63.94).

**9. Caco-2 Permeability:** Both have negative values, indicating poor permeability. This is concerning, but less critical than BBB for a CNS target.

**10. Aqueous Solubility:** Both have negative values, indicating poor solubility. This is a drawback, but can be addressed with formulation strategies.

**11. hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.277 and 0.746, respectively).

**12. Microsomal Clearance:** Ligand A (36.838) has higher microsomal clearance than Ligand B (0.305), suggesting lower metabolic stability. This is a significant disadvantage.

**13. In vitro Half-Life:** Ligand A (-7.276) has a much lower in vitro half-life than Ligand B (27.795). This is a major drawback for Ligand A.

**14. P-gp Efflux:** Both ligands show low P-gp efflux liability (0.081 and 0.194, respectively).

**15. Binding Affinity:** Both have excellent binding affinities (-9.0 and -8.0 kcal/mol). Ligand A is slightly better, but the difference is less than 1.5 kcal/mol, so it doesn't overwhelmingly outweigh other factors.

**Conclusion:**

Considering the GPCR-specific priorities, Ligand B is the more promising candidate. While Ligand A has slightly better affinity, Ligand B has a significantly better BBB percentile, lower microsomal clearance (better metabolic stability), and a much longer in vitro half-life. The lower DILI risk is also a plus. The slightly lower affinity of Ligand B can potentially be optimized in subsequent iterations.

Output:
1
2025-04-17 05:30:10,697 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (364.5 and 353.4 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (74.33) is significantly better than Ligand B (121.23). For CNS targets, we want TPSA <= 90, and A is comfortably within that, while B exceeds it. This is a substantial advantage for A.

**logP:** Both ligands have good logP values (1.633 and 1.887), falling within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Both have 2 HBD and 5 HBA, which are acceptable.

**QED:** Ligand A (0.735) has a better QED score than Ligand B (0.518), indicating a more drug-like profile.

**DILI:** Ligand A (22.722) has a much lower DILI risk than Ligand B (62.233). This is a significant advantage for A.

**BBB:** Ligand B (66.925) has a better BBB penetration score than Ligand A (41.644). While >70 is desirable, 66.925 is still reasonably good. However, the difference isn't large enough to overcome other significant advantages of A.

**Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and suggests poor permeability. However, the scale is not specified, so it's hard to interpret.

**Aqueous Solubility:** Both have negative solubility values, which is also unusual and suggests poor solubility. Again, the scale is not specified.

**hERG:** Ligand A (0.207) has a slightly better hERG profile than Ligand B (0.562), indicating lower cardiotoxicity risk.

**Microsomal Clearance:** Ligand A (-17.009) has a significantly *lower* (better) microsomal clearance than Ligand B (37.279), suggesting greater metabolic stability.

**In vitro Half-Life:** Ligand B (19.572) has a longer half-life than Ligand A (6.069). This is a positive for B, but not enough to outweigh the other issues.

**P-gp Efflux:** Ligand A (0.024) has a much lower P-gp efflux liability than Ligand B (0.202), which is crucial for CNS penetration.

**Binding Affinity:** Ligand A (-8.5 kcal/mol) has a slightly better binding affinity than Ligand B (-7.9 kcal/mol). While the difference is less than the 1.5 kcal/mol threshold, it adds to the overall advantage of A.

**Overall:**

Ligand A is superior. It excels in TPSA, DILI, metabolic stability (Cl_mic), P-gp efflux, and has a slightly better affinity and hERG profile. While Ligand B has a better BBB score and half-life, the advantages of Ligand A, particularly its lower TPSA, DILI, and P-gp efflux, are more critical for a CNS-targeting GPCR ligand like a DRD2 modulator. The solubility and Caco-2 values are concerning for both, but the other properties of A make it the more promising candidate.

Output:
0
2025-04-17 05:30:10,698 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (365.539 and 347.455 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (63.24) is slightly higher than Ligand B (56.79). Both are below the 90 A^2 threshold desirable for CNS targets, but Ligand B is preferable.

**3. logP:** Ligand A (3.811) is slightly higher than Ligand B (2.956), both are within the optimal 1-3 range.

**4. H-Bond Donors:** Both ligands have 1 HBD, which is within the acceptable limit of <=5.

**5. H-Bond Acceptors:** Ligand A has 3 HBAs, and Ligand B has 4. Both are below the acceptable limit of <=10.

**6. QED:** Both ligands have good QED scores (0.686 and 0.804, respectively), indicating good drug-like properties. Ligand B is slightly better.

**7. DILI:** Both ligands have similar, low DILI risk (37.456% and 37.379%), indicating a low risk of liver injury.

**8. BBB:** Both ligands have excellent BBB penetration (78.092% and 77.433%), which is crucial for CNS targets like DRD2. The difference is negligible.

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.849 and -4.775). This is unusual and suggests poor permeability. However, these values are on a scale where negative values are possible, and direct comparison is difficult without knowing the scale's specifics.

**10. Aqueous Solubility:** Both ligands have very poor aqueous solubility (-3.948 and -3.567). This is a significant concern for bioavailability.

**11. hERG Inhibition:** Both ligands have low hERG inhibition risk (0.607% and 0.776%).

**12. Microsomal Clearance:** Ligand B (76.434) has a higher microsomal clearance than Ligand A (62.147), indicating faster metabolism and potentially lower in vivo exposure.

**13. In vitro Half-Life:** Ligand A (18.627 hours) has a longer in vitro half-life than Ligand B (16.017 hours).

**14. P-gp Efflux:** Both ligands have low P-gp efflux liability (0.526 and 0.659), which is favorable for CNS penetration.

**15. Binding Affinity:** Ligand B (-8.5 kcal/mol) has a slightly better binding affinity than Ligand A (-8.2 kcal/mol). While the difference is small, it's within the range where it could outweigh minor ADME drawbacks.

**Overall Assessment:**

Both ligands have good QED, low DILI and hERG risk, and excellent BBB penetration. The biggest concerns are the poor aqueous solubility and potentially poor Caco-2 permeability for both. Ligand B has a slightly better binding affinity, a better TPSA, and a better QED score, but a higher microsomal clearance and shorter half-life. Given the importance of binding affinity for GPCRs and the small advantage of Ligand B in this regard, along with the slightly better TPSA and QED, it is the more promising candidate.

Output:
1
2025-04-17 05:30:10,698 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, considering the provided guidelines and GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (371.482 and 361.467 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (88.91) is better than Ligand B (69.72), both are below the 90 A^2 threshold for CNS targets.

**logP:** Ligand A (1.159) and Ligand B (0.942) are both within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A (2 HBD, 6 HBA) and Ligand B (1 HBD, 4 HBA) both meet the criteria of <=5 HBD and <=10 HBA.

**QED:** Both ligands have similar QED values (0.603 and 0.587), indicating good drug-likeness.

**DILI:** Both ligands have relatively high DILI risk (61.807 and 65.723), but are still within a range that isn't immediately disqualifying.

**BBB:** Ligand A (73.788) has a significantly better BBB penetration percentile than Ligand B (62.854). This is a crucial factor for a CNS target like DRD2.

**Caco-2 Permeability:** Ligand A (-5.501) and Ligand B (-4.884) both have negative values, suggesting poor permeability.

**Aqueous Solubility:** Both ligands have very poor aqueous solubility (-2.002 and -3.253). This is a significant drawback.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.192 and 0.15).

**Microsomal Clearance:** Ligand A (15.574) has a much lower microsomal clearance than Ligand B (34.683), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (-2.677) has a negative half-life, which is unusual and suggests rapid degradation or an issue with the assay. Ligand B (-31.726) is even worse.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.074 and 0.129), which is favorable for CNS penetration.

**Binding Affinity:** Ligand B (-8.1 kcal/mol) has a slightly better binding affinity than Ligand A (-7.5 kcal/mol). The difference is 0.6 kcal/mol, which is not substantial enough to overcome other significant drawbacks.

**Overall Assessment:**

Considering the GPCR-specific priorities, BBB penetration is paramount for a CNS target. Ligand A has a significantly better BBB percentile (73.788) than Ligand B (62.854). Furthermore, Ligand A exhibits better metabolic stability (lower Cl_mic) and a more reasonable (though still poor) in vitro half-life. While both ligands have poor solubility and Caco-2 permeability, the superior BBB and metabolic stability of Ligand A make it the more promising candidate. The slightly better affinity of Ligand B does not outweigh these factors.

Output:
0
2025-04-17 05:30:10,698 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (346.289 Da) is slightly preferred as it's closer to the lower end, potentially aiding permeability.

**TPSA:** Ligand A (89.16) is excellent for CNS penetration, being well below 90. Ligand B (109.41) is still reasonable but less optimal.

**logP:** Ligand A (1.353) is within the optimal range (1-3). Ligand B (0.189) is quite low, which could hinder membrane permeability and potentially reduce binding affinity.

**H-Bond Donors/Acceptors:** Ligand A (0 HBD, 6 HBA) is favorable. Ligand B (2 HBD, 5 HBA) is also acceptable, but the higher number of HBDs could slightly impact permeability.

**QED:** Both ligands have reasonable QED scores (A: 0.737, B: 0.56), indicating good drug-like properties.

**DILI:** Ligand A (79.566) has a lower DILI risk than Ligand B (49.903), which is a significant advantage.

**BBB:** Both ligands exhibit good BBB penetration (A: 78.519, B: 72.586), but Ligand A is slightly better.

**Caco-2 Permeability:** Ligand A (-4.123) shows better Caco-2 permeability than Ligand B (-5.545), indicating better intestinal absorption.

**Aqueous Solubility:** Ligand A (-3.531) has slightly better aqueous solubility than Ligand B (-2.604).

**hERG Inhibition:** Both ligands have low hERG inhibition risk (A: 0.268, B: 0.399).

**Microsomal Clearance:** Ligand A (73.277) has a higher microsomal clearance than Ligand B (0.93), meaning Ligand B is more metabolically stable.

**In vitro Half-Life:** Ligand B (-8.509) has a longer in vitro half-life than Ligand A (-6.155), which is favorable.

**P-gp Efflux:** Both ligands have low P-gp efflux (A: 0.305, B: 0.03), which is good for CNS exposure. Ligand B is slightly better.

**Binding Affinity:** Ligand A (-8.7 kcal/mol) has a slightly better binding affinity than Ligand B (-7.7 kcal/mol). While both are good, the 1 kcal/mol difference is significant.

**Overall Assessment:**

Considering the GPCR-specific priorities, Ligand A is the more promising candidate. It has a better logP, TPSA, DILI score, Caco-2 permeability, aqueous solubility, and binding affinity. Although Ligand B has better metabolic stability and a slightly longer half-life, the superior CNS penetration properties (TPSA, BBB) and binding affinity of Ligand A are more critical for a DRD2 ligand. The slightly lower DILI risk of Ligand A is also a significant advantage.

Output:
1
2025-04-17 05:30:10,698 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (345.451 and 362.539 Da) fall within the ideal range of 200-500 Da.

**TPSA:** Ligand A (89.66) is excellent, being below the 90 A^2 threshold for CNS targets. Ligand B (40.62) is also very good.

**logP:** Both ligands have logP values (3.452 and 3.954) within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A has 2 HBD and 6 HBA, which are acceptable. Ligand B has 0 HBD and 3 HBA, also acceptable.

**QED:** Both ligands have similar QED values (0.767 and 0.737), indicating good drug-likeness.

**DILI:** Ligand A (56.223) has a moderate DILI risk, while Ligand B (26.057) has a significantly lower risk, which is a strong advantage.

**BBB:** Both ligands exhibit excellent BBB penetration (81.815 and 89.608), exceeding the desirable >70 percentile for CNS targets. Ligand B is slightly better.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.737 and -4.744), which is unusual and suggests poor permeability. This is a concern for both.

**Aqueous Solubility:** Both ligands have negative solubility values (-4.953 and -3.357), indicating very poor aqueous solubility. This is a significant drawback for both.

**hERG Inhibition:** Ligand A (0.297) has a slightly lower hERG risk than Ligand B (0.626), which is preferable.

**Microsomal Clearance:** Ligand B (69.741) has a higher microsomal clearance than Ligand A (57.406), meaning it is less metabolically stable.

**In vitro Half-Life:** Ligand A (36.918) has a considerably longer half-life than Ligand B (7.377), which is a major advantage.

**P-gp Efflux:** Ligand A (0.115) has a lower P-gp efflux liability than Ligand B (0.61), which is favorable for CNS penetration.

**Binding Affinity:** Ligand B (-8.5 kcal/mol) has a slightly stronger binding affinity than Ligand A (-9.0 kcal/mol). While the difference is small, it's still a positive for Ligand B.

**Overall Assessment:**

Ligand B has a better binding affinity and lower DILI risk, and slightly better BBB penetration. However, Ligand A has a significantly longer half-life and lower P-gp efflux, which are crucial for CNS drugs. Both have poor solubility and Caco-2 permeability. Considering the GPCR-specific priorities, the longer half-life and lower P-gp efflux of Ligand A are more critical for achieving sufficient brain exposure, outweighing the slightly better affinity and DILI profile of Ligand B.

Output:
0
2025-04-17 05:30:10,699 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (356.463 and 348.447 Da) fall within the ideal range of 200-500 Da.

**TPSA:** Both ligands have TPSA values (90.31 and 87.46) below the 90 threshold for CNS targets, which is excellent.

**logP:** Ligand A (0.264) is quite low, potentially hindering permeation. Ligand B (1.347) is better, falling within the optimal 1-3 range. This is a significant advantage for Ligand B.

**H-Bond Donors/Acceptors:** Both have 2 HBDs and 5 HBAs, which are within acceptable limits.

**QED:** Both ligands have good QED scores (0.579 and 0.779), indicating drug-like properties.

**DILI:** Ligand A (24.234) has a lower DILI risk than Ligand B (37.922), which is favorable.

**BBB:** Both ligands have reasonably good BBB penetration (51.609 and 53.858), but neither exceeds the desirable >70% threshold.

**Caco-2 Permeability:** Both have negative Caco-2 values, indicating poor permeability.

**Aqueous Solubility:** Both have negative solubility values, indicating poor solubility.

**hERG Inhibition:** Both ligands show low hERG inhibition liability (0.306 and 0.241).

**Microsomal Clearance:** Ligand A (42.479) has higher microsomal clearance than Ligand B (18.371), suggesting lower metabolic stability. Ligand B is significantly better here.

**In vitro Half-Life:** Ligand B (15.906) has a much longer in vitro half-life than Ligand A (-0.76), which is a substantial advantage.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.174 and 0.026), which is good for CNS penetration.

**Binding Affinity:** Ligand B (-8.1 kcal/mol) has a significantly stronger binding affinity than Ligand A (-6.9 kcal/mol) - a difference of 1.2 kcal/mol. This is a major advantage that can outweigh some of the ADME drawbacks.

**Overall Assessment:**

Ligand B is the more promising candidate. While both have issues with Caco-2 permeability and aqueous solubility, Ligand B excels in key areas for a CNS-targeting GPCR ligand: better logP, significantly improved metabolic stability (lower Cl_mic, longer t1/2), and, most importantly, a substantially higher binding affinity. The slightly higher DILI risk for Ligand B is a concern, but the potency advantage is likely to be more impactful in early development.

Output:
1
2025-04-17 05:30:10,699 - INFO - Reasoning:

Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (337.47 & 351.44 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (57.78) is significantly better than Ligand B (79.63). For CNS targets, we want TPSA <= 90, and A is comfortably within that, while B is approaching the upper limit.

**3. logP:** Both ligands have similar logP values (3.97 and 3.89), both within the optimal 1-3 range.

**4. H-Bond Donors:** Both have 2 HBD, which is acceptable.

**5. H-Bond Acceptors:** Ligand A has 2 HBA, while Ligand B has 6.  Lower HBA is generally preferred for better permeability, making A more favorable.

**6. QED:** Ligand A (0.887) has a much better QED score than Ligand B (0.492), indicating a more drug-like profile.

**7. DILI:** Ligand A (25.09) has a significantly lower DILI risk than Ligand B (85.23). This is a major advantage for A.

**8. BBB:** Both ligands have reasonably good BBB penetration (68.63% and 67.47%), but neither exceeds the desirable >70% threshold. This isn't a decisive factor here as they are close.

**9. Caco-2:** Ligand A (-4.983) is better than Ligand B (-5.53), indicating better intestinal absorption.

**10. Solubility:** Ligand A (-4.307) is better than Ligand B (-4.712), indicating better aqueous solubility.

**11. hERG:** Both ligands have similar hERG inhibition liability (0.697 and 0.753), which is acceptable.

**12. Cl_mic:** Ligand A (47.29) has lower microsomal clearance than Ligand B (81.32), suggesting better metabolic stability.

**13. t1/2:** Ligand A (-31.904) has a significantly *longer* in vitro half-life than Ligand B (-14.57). This is a substantial advantage.

**14. Pgp:** Both ligands have the same Pgp efflux liability (0.233 and 0.591).

**15. Binding Affinity:** Both ligands have the same binding affinity (-10.2 kcal/mol). This eliminates affinity as a differentiating factor.

**Overall Assessment:**

Ligand A consistently outperforms Ligand B across most key ADME properties, including TPSA, QED, DILI, solubility, metabolic stability (Cl_mic), and half-life. While both have acceptable logP and BBB, the superior profile of Ligand A makes it the more promising drug candidate. The lower TPSA and HBA, combined with the significantly reduced DILI risk and improved metabolic stability, outweigh any minor differences in BBB penetration.

Output:
1
2025-04-17 05:30:10,699 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (369.487 and 361.471 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (78.95) is significantly better than Ligand B (99.77). For CNS targets, we want TPSA <= 90, and A is comfortably within that range, while B is close to the upper limit and less desirable.

**logP:** Both ligands have acceptable logP values (1.077 and 1.821), falling within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A has 1 HBD and 5 HBA, while Ligand B has 3 HBD and 5 HBA. Both are within acceptable limits (<=5 HBD and <=10 HBA).

**QED:** Both ligands have similar, good QED values (0.726 and 0.731), indicating good drug-like properties.

**DILI:** Ligand A (42.536) has a lower DILI risk than Ligand B (58.395). Both are below 60, but A is preferable.

**BBB:** This is a critical parameter for a CNS target. Ligand A has a BBB percentile of 63.125, which is reasonable, while Ligand B's BBB percentile is only 30.477, which is significantly lower and a major drawback.

**Caco-2 Permeability:** Ligand A (-4.993) is better than Ligand B (-5.782), indicating better intestinal absorption.

**Aqueous Solubility:** Both ligands have the same poor aqueous solubility (-2.318). This is a potential issue for both, but not a deciding factor.

**hERG Inhibition:** Ligand A (0.143) has a much lower hERG inhibition liability than Ligand B (0.525). This is a significant advantage for Ligand A.

**Microsomal Clearance:** Ligand A (12.605) has a higher (worse) microsomal clearance than Ligand B (-9.188). This suggests Ligand B is more metabolically stable.

**In vitro Half-Life:** Ligand B (-11.8) has a much longer in vitro half-life than Ligand A (1.208). This is a significant advantage for Ligand B.

**P-gp Efflux:** Ligand A (0.026) has a much lower P-gp efflux liability than Ligand B (0.062), which is favorable for CNS penetration.

**Binding Affinity:** Ligand A (-7.7) has slightly better binding affinity than Ligand B (-8.2). While both are excellent, the difference is minor.

**Overall Assessment:**

Ligand A is the better candidate. While Ligand B has better metabolic stability and half-life, Ligand A excels in crucial areas for a CNS-targeting GPCR ligand: significantly better TPSA, a much higher BBB percentile, lower hERG inhibition, and lower P-gp efflux. The slightly better affinity of Ligand A further supports this conclusion. The solubility is a concern for both, but can be addressed with formulation strategies.

Output:
0
2025-04-17 05:30:10,699 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (405.311 Da) is slightly higher than Ligand B (348.531 Da), but both are acceptable.

**TPSA:** Ligand A (41.13) is excellent for CNS penetration, well below the 90 A^2 threshold. Ligand B (58.2) is still reasonable but less optimal.

**logP:** Ligand A (4.736) is a bit high, potentially leading to solubility issues or off-target interactions. Ligand B (3.793) is much better, falling within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Both ligands have 2 HBDs and 1-2 HBAs, which are within acceptable limits.

**QED:** Both ligands have QED values above 0.5 (0.742 and 0.688), indicating good drug-like properties.

**DILI:** Ligand A (38.852) has a slightly higher DILI risk than Ligand B (27.685), but both are below the concerning threshold of 60.

**BBB:** Ligand A (89.066) has a significantly better BBB penetration percentile than Ligand B (71.539), which is a crucial factor for a CNS target like DRD2.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.696 and -4.679), which is unusual and suggests poor permeability. This is a significant drawback for both.

**Aqueous Solubility:** Both ligands have very poor aqueous solubility (-5.511 and -4.778). This is a major concern for bioavailability.

**hERG Inhibition:** Ligand A (0.875) has a slightly higher hERG inhibition risk than Ligand B (0.351), but both are relatively low.

**Microsomal Clearance:** Ligand A (79.622) has a higher microsomal clearance than Ligand B (63.466), suggesting lower metabolic stability.

**In vitro Half-Life:** Ligand B (-1.624) has a negative half-life, which is not physically possible and indicates a significant issue with the data or the compound. Ligand A (71.101) has a reasonable half-life.

**P-gp Efflux:** Ligand A (0.493) has a lower P-gp efflux liability than Ligand B (0.237), which is favorable for CNS exposure.

**Binding Affinity:** Ligand A (-10.0 kcal/mol) has a *much* stronger binding affinity than Ligand B (-0.0 kcal/mol). This is a decisive advantage, as a >1.5 kcal/mol difference can outweigh other drawbacks.

**Overall Assessment:**

Despite the poor solubility and Caco-2 permeability for both, Ligand A is the superior candidate due to its significantly higher binding affinity (-10.0 vs -0.0 kcal/mol) and better BBB penetration (89.066 vs 71.539). The stronger binding is likely to be the most important factor, and the better BBB will help ensure sufficient CNS exposure. The negative half-life for Ligand B is a fatal flaw. While Ligand A's logP is a bit high and clearance is higher, these can potentially be addressed through further optimization.

Output:
1
2025-04-17 05:30:10,700 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (352.475 and 355.498 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (67.87) is slightly above the optimal <90 for CNS targets, but still reasonable. Ligand B (61.44) is excellent, well below 90.

**3. logP:** Ligand A (1.746) is within the optimal 1-3 range. Ligand B (2.258) is also good, falling within the same range.

**4. H-Bond Donors:** Ligand A (1) is good. Ligand B (2) is also acceptable.

**5. H-Bond Acceptors:** Ligand A (4) is good. Ligand B (3) is also good.

**6. QED:** Both ligands have acceptable QED values (0.74 and 0.667), indicating good drug-like properties.

**7. DILI:** Ligand A (36.177) has a low DILI risk, well below the 40 threshold. Ligand B (5.777) has an even lower DILI risk, which is excellent.

**8. BBB:** This is a critical parameter for CNS targets. Ligand A (57.464) is below the desirable >70 threshold. Ligand B (75.107) is *excellent*, exceeding the 70% threshold.

**9. Caco-2 Permeability:** Ligand A (-4.587) has poor Caco-2 permeability. Ligand B (-5.02) also has poor Caco-2 permeability. Both are negative values, indicating low permeability.

**10. Aqueous Solubility:** Ligand A (-2.526) has poor aqueous solubility. Ligand B (-1.733) has slightly better, but still poor, aqueous solubility.

**11. hERG Inhibition:** Both ligands have low hERG inhibition risk (0.234 and 0.472).

**12. Microsomal Clearance:** Ligand A (30.038) has moderate clearance. Ligand B (-4.863) has *negative* clearance, which is highly unusual and suggests exceptional metabolic stability.

**13. In vitro Half-Life:** Ligand A (9.784) has a moderate half-life. Ligand B (-16.427) has a negative half-life, which is not physically possible and likely indicates an issue with the data or model. However, given the negative clearance, it strongly suggests very high stability.

**14. P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.06 and 0.019).

**15. Binding Affinity:** Ligand B (-7.1 kcal/mol) has a slightly better binding affinity than Ligand A (-6.9 kcal/mol). While the difference is small, it's within the range where it can outweigh minor ADME drawbacks.

**Overall Assessment:**

Ligand B is the stronger candidate. While both have poor solubility and permeability, Ligand B excels in crucial areas for a CNS-targeting GPCR ligand: significantly better BBB penetration (75.107% vs 57.464%), exceptional metabolic stability (negative clearance and half-life), and slightly improved binding affinity. The lower P-gp efflux for both is also beneficial. The DILI risk is very low for both. The slight difference in affinity, combined with the substantial improvement in BBB and metabolic stability, makes Ligand B the more promising drug candidate.

Output:
1
2025-04-17 05:30:10,700 - INFO - Batch 203 complete. Total preferences: 3248
2025-04-17 05:30:10,700 - INFO - Processing batch 204/512...
2025-04-17 05:30:51,974 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (393.236 Da) is slightly higher than Ligand B (353.463 Da), but both are acceptable.

**TPSA:** Ligand A (47.28) is excellent for CNS penetration, well below the 90 A^2 threshold. Ligand B (96.53) is higher, but still potentially acceptable, though less ideal.

**logP:** Ligand A (4.81) is a bit high, potentially leading to solubility issues or off-target interactions. Ligand B (1.711) is within the optimal range (1-3).

**H-Bond Donors/Acceptors:** Ligand A (HBD=2, HBA=3) and Ligand B (HBD=3, HBA=4) both have reasonable numbers of H-bond donors and acceptors, falling within the guidelines.

**QED:** Both ligands have similar QED values (A: 0.741, B: 0.677), indicating good drug-like properties.

**DILI:** Ligand A (28.732) has a significantly lower DILI risk than Ligand B (43.389), which is a substantial advantage.

**BBB:** Ligand A (70.415) has a good BBB percentile, desirable for a CNS target. Ligand B (55.293) is lower, suggesting reduced CNS exposure. This is a critical difference given the target.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.892 and -4.986). This is unusual and suggests poor permeability, but the scale is not specified, so it's hard to interpret.

**Aqueous Solubility:** Both ligands have negative solubility values (-4.178 and -2.809). Similar to Caco-2, the scale is unknown.

**hERG Inhibition:** Ligand A (0.964) has a slightly higher hERG risk than Ligand B (0.096), but both are relatively low.

**Microsomal Clearance:** Ligand A (28.581) has a higher microsomal clearance than Ligand B (18.193), meaning it's likely to be metabolized faster.

**In vitro Half-Life:** Ligand B (-27.162) has a significantly *longer* in vitro half-life than Ligand A (15.966). This is a major advantage.

**P-gp Efflux:** Ligand A (0.681) has lower P-gp efflux liability than Ligand B (0.031), which is favorable for CNS penetration.

**Binding Affinity:** Ligand A (-8.7 kcal/mol) has a slightly better binding affinity than Ligand B (-7.9 kcal/mol). This 0.8 kcal/mol difference is significant and could outweigh some ADME drawbacks.

**Overall Assessment:**

Ligand A excels in binding affinity and BBB penetration, crucial for a CNS GPCR target. It also has a lower DILI risk and lower P-gp efflux. However, its logP is high, and its metabolic clearance is higher, leading to a shorter half-life. Ligand B has a better half-life, lower logP, and lower hERG risk, but its BBB penetration is significantly worse, and its binding affinity is weaker.

Given the importance of CNS penetration for a DRD2 ligand, and the relatively small difference in binding affinity, Ligand A is the more promising candidate. The higher logP and clearance can be addressed through further optimization.



Output:
1
2025-04-17 05:30:51,975 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (337.383 and 360.447 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (99.77) is better than Ligand B (104.02). Both are reasonably close to the 90 A^2 threshold for CNS targets, but A is preferable.

**3. logP:** Both ligands have acceptable logP values (0.796 and 0.613), falling within the 1-3 range.

**4. H-Bond Donors:** Both have 3 HBD, which is within the acceptable limit of <=5.

**5. H-Bond Acceptors:** Ligand A (4) is better than Ligand B (10). Ligand B is at the upper limit of acceptable HBA count, potentially impacting permeability.

**6. QED:** Ligand A (0.679) has a slightly better QED score than Ligand B (0.563), indicating a more drug-like profile.

**7. DILI:** Ligand A (60.682) has a lower DILI risk than Ligand B (83.753). This is a significant advantage for Ligand A.

**8. BBB:** Ligand B (32.416) has a better BBB penetration percentile than Ligand A (20.357). This is a crucial factor for a CNS target like DRD2, and initially favors Ligand B.

**9. Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and suggests poor permeability. However, the scale is not specified, so it's difficult to interpret.

**10. Aqueous Solubility:** Both have negative solubility values, which is also unusual. Again, the scale is unknown, making interpretation difficult.

**11. hERG Inhibition:** Ligand A (0.115) has a significantly lower hERG inhibition liability than Ligand B (0.471), a major safety advantage.

**12. Microsomal Clearance:** Ligand A (-27.048) has a much lower (better) microsomal clearance than Ligand B (20.261), indicating greater metabolic stability.

**13. In vitro Half-Life:** Ligand B (53.795) has a significantly longer in vitro half-life than Ligand A (-19.15). This is a positive for Ligand B.

**14. P-gp Efflux:** Ligand A (0.015) has a much lower P-gp efflux liability than Ligand B (0.006), which is beneficial for CNS penetration.

**15. Binding Affinity:** Ligand B (-7.6 kcal/mol) has a slightly better binding affinity than Ligand A (-8.8 kcal/mol). While a difference of 1.2 kcal/mol is notable, it's not overwhelmingly large.

**Overall Assessment:**

Considering the GPCR-specific priorities, Ligand A is the more promising candidate. While Ligand B has a better BBB score and half-life, Ligand A excels in crucial areas like DILI risk, hERG inhibition, metabolic stability (Cl_mic), and P-gp efflux. The slightly weaker binding affinity of Ligand A can potentially be optimized in subsequent iterations, whereas mitigating the higher DILI and hERG risks of Ligand B would be more challenging. The lower TPSA and HBA of Ligand A are also favorable.

Output:
0
2025-04-17 05:30:51,975 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (366.805 and 366.824 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (108.47) is higher than the preferred <90 for CNS targets, while Ligand B (60.25) is well within the optimal range. This is a significant advantage for Ligand B.

**3. logP:** Both ligands have logP values within the optimal range (2.006 and 2.96).

**4. H-Bond Donors:** Ligand A has 2 HBD, which is acceptable. Ligand B has 0, which is also acceptable.

**5. H-Bond Acceptors:** Ligand A has 7 HBA, which is acceptable. Ligand B has 5, which is also acceptable.

**6. QED:** Both ligands have reasonable QED values (0.757 and 0.532), indicating good drug-like properties. Ligand A is slightly better.

**7. DILI:** Ligand A (87.243) has a higher DILI risk than Ligand B (65.839), though both are not alarming.

**8. BBB:** Ligand B (81.233) has a significantly better BBB penetration score than Ligand A (57.968). This is crucial for a CNS target like DRD2.

**9. Caco-2 Permeability:** Ligand A (-5.084) has a worse Caco-2 permeability than Ligand B (-4.339).

**10. Aqueous Solubility:** Ligand A (-4.028) has a worse aqueous solubility than Ligand B (-2.838).

**11. hERG Inhibition:** Both ligands have low hERG inhibition risk (0.228 and 0.328).

**12. Microsomal Clearance:** Ligand A (47.009) has lower microsomal clearance, suggesting better metabolic stability, than Ligand B (73.705).

**13. In vitro Half-Life:** Ligand B (21.85) has a much longer in vitro half-life than Ligand A (-5.925).

**14. P-gp Efflux:** Both ligands have low P-gp efflux liability (0.177 and 0.381).

**15. Binding Affinity:** Both ligands have excellent binding affinity (-8.1 and -8.2 kcal/mol), with Ligand B being slightly better.

**Overall Assessment:**

While Ligand A has slightly better QED and microsomal clearance, Ligand B significantly outperforms it in key areas for a CNS GPCR target: TPSA, BBB penetration, and in vitro half-life. The better TPSA and BBB scores are particularly important for DRD2. The slightly better binding affinity of Ligand B further strengthens its position. The solubility and Caco-2 permeability are better for Ligand B as well.

Output:
1
2025-04-17 05:30:51,975 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (370.494 and 345.487 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (67.23) is slightly above the optimal <90 for CNS targets, but still reasonable. Ligand B (52.65) is well within the desired range.

**logP:** Both ligands have good logP values (1.86 and 1.483), falling within the 1-3 range.

**H-Bond Donors/Acceptors:** Both have 1 HBD, which is good. Ligand A has 5 HBA, while Ligand B has 3. Both are acceptable (<=10).

**QED:** Both ligands have good QED scores (0.72 and 0.768), indicating good drug-like properties.

**DILI:** Ligand A (54.75) has a moderate DILI risk, while Ligand B (23.032) has a very low risk. This is a significant advantage for Ligand B.

**BBB:** Ligand A (66.537) is below the desirable >70 for CNS targets, while Ligand B (73.827) is excellent. This is a crucial difference given DRD2's role in CNS disorders.

**Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and suggests poor permeability. However, the scale is not specified, so it's difficult to interpret.

**Aqueous Solubility:** Both have negative solubility values, which is also unusual. Again, the scale is not specified.

**hERG:** Both ligands have low hERG inhibition liability (0.291 and 0.48), which is good.

**Microsomal Clearance:** Ligand A (43.252) has a moderate clearance, while Ligand B (6.785) has a very low clearance, suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (-7.897) has a very long half-life, while Ligand B (16.756) has a moderate half-life.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.119 and 0.075), which is favorable for CNS penetration.

**Binding Affinity:** Both ligands have excellent binding affinity (-7.5 and -7.8 kcal/mol). Ligand B is slightly better, but the difference is small.

**Overall Assessment:**

Ligand B is the superior candidate. While both have good affinity and drug-like properties, Ligand B excels in key areas for a CNS-targeting GPCR ligand: significantly lower DILI risk, much better BBB penetration, and lower microsomal clearance. The slightly longer half-life of Ligand A is a minor advantage compared to the other benefits of Ligand B. The unusual negative values for Caco-2 and solubility are concerning, but the other factors strongly favor Ligand B.

Output:
1
2025-04-17 05:30:51,975 - INFO - Reasoning:

Let's analyze Ligand A and Ligand B against the provided guidelines, prioritizing GPCR-specific properties (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (346.431 Da) is slightly lower, which *could* be beneficial for permeability, but both are acceptable.

**TPSA:** Ligand A (78.67) is excellent for CNS penetration, well below the 90 A^2 threshold. Ligand B (134.67) is higher, approaching the 140 A^2 limit for oral absorption, and less ideal for CNS targets.

**logP:** Ligand A (0.788) is a little low, potentially hindering permeation. Ligand B (0.921) is also on the lower side of optimal, but slightly better than A.

**H-Bond Donors/Acceptors:** Ligand A (1 HBD, 5 HBA) is better than Ligand B (3 HBD, 7 HBA) regarding the balance between solubility and permeability.

**QED:** Ligand A (0.859) has a significantly better QED score than Ligand B (0.646), indicating a more drug-like profile.

**DILI:** Ligand A (28.655) has a much lower DILI risk than Ligand B (81.427), a significant advantage.

**BBB:** Ligand A (47.615) has a better BBB percentile than Ligand B (37.418), although both are not optimal. For a CNS target like DRD2, we want >70%.

**Caco-2 Permeability:** Ligand A (-4.823) has a worse Caco-2 permeability than Ligand B (-5.343), but both are very poor.

**Aqueous Solubility:** Ligand A (-0.975) is better than Ligand B (-3.142), indicating better solubility.

**hERG Inhibition:** Ligand A (0.375) has a lower hERG risk than Ligand B (0.083), which is preferable.

**Microsomal Clearance:** Ligand A (34.241) has a higher microsomal clearance than Ligand B (18.17), indicating lower metabolic stability.

**In vitro Half-Life:** Ligand A (-16.956) has a worse in vitro half-life than Ligand B (6.51).

**P-gp Efflux:** Ligand A (0.111) has a lower P-gp efflux liability than Ligand B (0.071), which is favorable for CNS penetration.

**Binding Affinity:** Ligand B (-8.6 kcal/mol) has a slightly better binding affinity than Ligand A (-7.6 kcal/mol). This 1.0 kcal/mol difference is significant and could potentially outweigh some of the ADME drawbacks of Ligand B.

**Overall Assessment:**

Ligand A has a superior profile in terms of drug-likeness (QED, DILI, Solubility, hERG, Pgp) and crucial CNS properties (TPSA, BBB). While its logP is slightly low and Caco-2 permeability is poor, its overall balance is better. Ligand B's main advantage is its slightly higher binding affinity, but it suffers from higher DILI risk, lower QED, poorer BBB penetration, and worse solubility. Considering the GPCR-specific priorities and the importance of CNS penetration for DRD2, the benefits of Ligand A outweigh the slightly better affinity of Ligand B.

Output:
0
2025-04-17 05:30:51,976 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (345.403 and 355.385 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (97.62) is slightly above the optimal <90 for CNS targets, while Ligand B (85.4) is comfortably below. This favors Ligand B.

**logP:** Both ligands have acceptable logP values (0.948 and 1.716), falling within the 1-3 range. Ligand B is slightly better.

**H-Bond Donors/Acceptors:** Ligand A has 2 HBD and 6 HBA, while Ligand B has 1 HBD and 4 HBA. Both are within acceptable limits (<=5 HBD and <=10 HBA).

**QED:** Both ligands have good QED scores (0.521 and 0.685), indicating good drug-like properties. Ligand B is better.

**DILI:** Ligand A (65.878) has a higher DILI risk than Ligand B (35.983). This is a significant advantage for Ligand B.

**BBB:** Ligand B (92.71) shows excellent BBB penetration, exceeding the desirable >70% threshold. Ligand A (57.852) is below this threshold, which is a major drawback for a CNS target.

**Caco-2 Permeability:** Ligand A (-5.37) has poor Caco-2 permeability, while Ligand B (-4.489) is slightly better, but still not great.

**Aqueous Solubility:** Both ligands have poor aqueous solubility (-1.791 and -2.835). This could pose formulation challenges, but is less critical than BBB penetration for a CNS drug.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.248 and 0.192).

**Microsomal Clearance:** Ligand A (49.798) has a higher microsomal clearance than Ligand B (38.228), indicating lower metabolic stability.

**In vitro Half-Life:** Ligand B (-4.703) has a negative half-life, which is unusual and likely indicates very rapid metabolism. Ligand A (18.675) has a more reasonable half-life, though not exceptionally long.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.081 and 0.023), which is favorable for CNS penetration.

**Binding Affinity:** Both ligands have strong binding affinities (-8.0 and -6.8 kcal/mol). Ligand A has a 1.2 kcal/mol advantage, which is substantial and could potentially outweigh some of its ADME drawbacks.

**Overall Assessment:**

While Ligand A has a superior binding affinity, Ligand B is significantly better in terms of crucial ADME properties for a CNS-targeting GPCR. Specifically, the excellent BBB penetration (92.71%) and lower DILI risk (35.983) of Ligand B are major advantages. The slightly better TPSA and logP also contribute to its favorability. Although Ligand B's half-life is concerning, the strong binding affinity (-6.8 kcal/mol) and low P-gp efflux suggest it may still achieve sufficient brain exposure. The poor Caco-2 and solubility are drawbacks, but less critical for a CNS target. The affinity difference, while significant, may be overcome with further optimization of Ligand B.

Output:
1
2025-04-17 05:30:51,976 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 drug candidates, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (347.5) is slightly better, being closer to the lower end which can aid permeability.

**2. TPSA:** Ligand A (75.86) is significantly better than Ligand B (84.5). For CNS targets, we want TPSA <= 90, and A is comfortably within that range, while B is approaching the upper limit.

**3. logP:** Both ligands have good logP values (A: 2.586, B: 3.164), falling within the optimal 1-3 range. B is slightly higher, which *could* indicate potential off-target issues, but isn't a major concern.

**4. H-Bond Donors:** Both have 2 HBD, which is acceptable (<=5).

**5. H-Bond Acceptors:** Ligand A has 6 HBA, and Ligand B has 4. Both are within the acceptable range (<=10).

**6. QED:** Both ligands have reasonable QED values (A: 0.756, B: 0.663), indicating good drug-like properties. A is slightly better.

**7. DILI:** Both have relatively low DILI risk (A: 11.632, B: 70.958), but A is significantly lower, suggesting a better safety profile.

**8. BBB:** This is *critical* for a CNS target like DRD2. Ligand A has a BBB percentile of 70.88, which is desirable (>70). Ligand B is much lower at 42.032, which is a significant drawback.

**9. Caco-2 Permeability:** Both have negative values (-5.27 and -4.809), indicating poor permeability. This is concerning, but can sometimes be overcome with formulation strategies.

**10. Aqueous Solubility:** Both have negative values (-3.28 and -4.139), indicating poor solubility. Similar to Caco-2, this is a formulation challenge.

**11. hERG Inhibition:** Both have low hERG inhibition liability (A: 0.31, B: 0.536), which is good.

**12. Microsomal Clearance:** Ligand A (33.935) has lower clearance than Ligand B (65.568), suggesting better metabolic stability.

**13. In vitro Half-Life:** Ligand A (18.939) has a shorter half-life than Ligand B (28.56), but both are reasonable.

**14. P-gp Efflux:** Both have low P-gp efflux liability (A: 0.107, B: 0.241), which is favorable for CNS penetration.

**15. Binding Affinity:** Ligand B (-8.4 kcal/mol) has a significantly stronger binding affinity than Ligand A (-6.4 kcal/mol). This is a substantial advantage. A difference of >1.5 kcal/mol can often outweigh other ADME concerns.

**Overall Assessment:**

While Ligand B has a superior binding affinity, Ligand A is significantly better in several critical ADME properties for a CNS-targeting GPCR: TPSA, BBB penetration, DILI risk, and microsomal clearance. The lower BBB penetration of Ligand B is a major concern, as it will severely limit its ability to reach the target in the brain. The stronger binding of B is attractive, but the poor BBB and higher DILI risk are substantial liabilities. Ligand A, despite its weaker binding, has a more balanced profile and a much higher probability of achieving sufficient brain exposure.

Output:
0
2025-04-17 05:30:51,976 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (362.495 Da and 341.415 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (58.64) is significantly better than Ligand B (91.02). A TPSA under 90 is preferred for CNS targets, and Ligand A is comfortably within that range, while Ligand B is nearing the upper limit.

**logP:** Both ligands have good logP values (2.214 and 1.411), falling within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Both have 1 HBD, which is good. Ligand A has 4 HBA, and Ligand B has 5. Both are acceptable, being under the 10 limit.

**QED:** Both ligands have similar, good QED values (0.874 and 0.876), indicating drug-like properties.

**DILI:** Ligand A (25.553) has a much lower DILI risk than Ligand B (36.06). Both are below 40, which is good, but A is preferable.

**BBB:** This is a crucial parameter for a CNS target like DRD2. Ligand A has a BBB percentile of 80.264, which is excellent (>70). Ligand B's BBB percentile is only 54.052, which is considerably lower and less desirable.

**Caco-2 Permeability:** Both have negative Caco-2 values (-5.201 and -5.137), which is unusual and suggests poor permeability. However, these values are on a scale where negative values are possible, and direct comparison is difficult without knowing the scale's specifics.

**Aqueous Solubility:** Both have negative solubility values (-3.434 and -1.895), also unusual, and suggesting poor solubility.

**hERG:** Both ligands have low hERG inhibition liability (0.583 and 0.259), which is good.

**Microsomal Clearance:** Ligand A (28.793) has a higher microsomal clearance than Ligand B (-14.625). This suggests Ligand B is more metabolically stable, which is a positive.

**In vitro Half-Life:** Ligand A (5.359) has a slightly longer half-life than Ligand B (3.769), which is favorable.

**P-gp Efflux:** Ligand A (0.157) has lower P-gp efflux liability than Ligand B (0.025), meaning it is less likely to be pumped out of the brain, improving CNS exposure.

**Binding Affinity:** Both ligands have very similar and strong binding affinities (-8.8 kcal/mol and -8.6 kcal/mol). The difference of 0.2 kcal/mol is not substantial enough to outweigh other significant differences.

**Conclusion:**

Considering the GPCR-specific priorities, Ligand A is the more promising candidate. Its superior BBB penetration (80.264 vs 54.052), lower DILI risk, and lower P-gp efflux liability are significant advantages. While Ligand B has better metabolic stability (lower Cl_mic), the CNS exposure benefits of Ligand A outweigh this. The similar affinities mean that the ADME properties are the deciding factors.

Output:
0
2025-04-17 05:30:51,976 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (366.53 and 351.42 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (57.69) is significantly better than Ligand B (80.32). For CNS targets, we want TPSA <= 90, and A is comfortably within that range, while B is approaching the upper limit.

**3. logP:** Both ligands have similar logP values (2.36 and 2.29), both falling within the optimal 1-3 range.

**4. H-Bond Donors:** Ligand A (0) is preferable to Ligand B (2). Fewer HBDs generally improve permeability.

**5. H-Bond Acceptors:** Both ligands have the same number of HBA (4), which is acceptable (<=10).

**6. QED:** Ligand B (0.753) has a slightly better QED score than Ligand A (0.535), indicating a more drug-like profile. However, this difference is not substantial enough to outweigh other factors.

**7. DILI:** Ligand A (39.28) has a slightly better DILI score than Ligand B (45.17), indicating lower potential for liver injury. Both are below the 60% threshold, so the risk is acceptable for both.

**8. BBB:** Ligand B (85.46) demonstrates significantly better BBB penetration than Ligand A (74.84). This is a *critical* factor for a CNS target like DRD2.

**9. Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and suggests a potential issue with the data. However, the values are similar (-4.85 and -4.08).

**10. Aqueous Solubility:** Both ligands have similar, very poor aqueous solubility (-3.49 and -3.43). This could pose formulation challenges.

**11. hERG Inhibition:** Both ligands have low hERG inhibition risk (0.28 and 0.46).

**12. Microsomal Clearance:** Ligand B (78.11) has a higher microsomal clearance than Ligand A (62.72), suggesting faster metabolism and potentially lower *in vivo* exposure.

**13. In vitro Half-Life:** Ligand A (-33.57) has a longer in vitro half-life than Ligand B (-28.48), which is favorable.

**14. P-gp Efflux:** Ligand A (0.331) has lower P-gp efflux than Ligand B (0.126), which is desirable for CNS penetration.

**15. Binding Affinity:** Ligand B (-8.5 kcal/mol) has a significantly stronger binding affinity than Ligand A (-6.2 kcal/mol). This is a substantial advantage (2.3 kcal/mol difference), and can often outweigh minor ADME drawbacks.

**Overall Assessment:**

While Ligand A has better TPSA, HBD, DILI, half-life, and P-gp efflux, Ligand B's superior BBB penetration and *much* stronger binding affinity are decisive. The difference in binding affinity is substantial enough to overcome the slightly less favorable BBB and other ADME properties. The BBB score for Ligand B is already quite good (85.46%).

Output:
1
2025-04-17 05:30:51,977 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight (MW):** Both ligands (372.575 and 360.523 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Both ligands have a TPSA of around 53, which is acceptable for general oral absorption but slightly high for optimal CNS penetration (ideally <90, but aiming for <60 is better for CNS).

**3. logP:** Ligand A (2.086) is within the optimal range (1-3). Ligand B (4.148) is at the upper end, potentially raising concerns about solubility and off-target effects.

**4. H-Bond Donors (HBD):** Both ligands are acceptable (1 and 0, respectively), well below the limit of 5.

**5. H-Bond Acceptors (HBA):** Both ligands are acceptable (5 and 4, respectively), well below the limit of 10.

**6. QED:** Both ligands have good QED scores (0.672 and 0.766), indicating good drug-like properties.

**7. DILI:** Ligand A (9.965%) has a significantly lower DILI risk than Ligand B (20.667%). This is a substantial advantage.

**8. BBB:** Ligand B (83.172%) has a much better BBB penetration score than Ligand A (65.413%). This is crucial for a CNS target like DRD2.

**9. Caco-2 Permeability:** Both have negative values, which is unusual. Assuming these are logP-scaled values, lower (more negative) values indicate poorer permeability. Both are poor.

**10. Aqueous Solubility:** Both have negative values, suggesting poor aqueous solubility.

**11. hERG Inhibition:** Both ligands show low hERG inhibition risk (0.792 and 0.668, respectively).

**12. Microsomal Clearance (Cl_mic):** Ligand A (54.324) has a lower microsomal clearance than Ligand B (77.032), suggesting better metabolic stability.

**13. In vitro Half-Life:** Ligand A (18.755 hours) has a significantly longer half-life than Ligand B (4.665 hours).

**14. P-gp Efflux:** Both ligands show low P-gp efflux liability (0.563 and 0.627, respectively).

**15. Binding Affinity:** Ligand B (-7.8 kcal/mol) has a significantly stronger binding affinity than Ligand A (-5.7 kcal/mol). This is a substantial advantage, potentially outweighing some ADME drawbacks.

**Overall Assessment:**

Ligand B excels in binding affinity and BBB penetration, which are critical for a CNS-targeting GPCR. However, it has a higher DILI risk, higher logP, and a shorter half-life. Ligand A has a better safety profile (lower DILI), better metabolic stability (lower Cl_mic, longer t1/2), and a more favorable logP, but its affinity and BBB penetration are lower.

The difference in binding affinity (-7.8 vs -5.7 kcal/mol) is substantial (2.1 kcal/mol). Given the importance of potency for GPCRs, and the fact that we can potentially mitigate some of the ADME concerns with Ligand B through formulation or structural modifications, I believe Ligand B is the more promising candidate. The superior BBB penetration further supports this decision.

Output:
1
2025-04-17 05:30:51,977 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (348.487 Da) is slightly preferred as it's closer to the lower end, potentially aiding permeability.

**TPSA:** Ligand A (58.64) is excellent for CNS penetration, well below the 90 A^2 threshold. Ligand B (95.58) is higher, but still potentially acceptable, though less ideal.

**logP:** Ligand A (2.37) is optimal. Ligand B (0.241) is quite low, which could hinder membrane permeability and CNS entry. This is a significant drawback.

**H-Bond Donors/Acceptors:** Ligand A (HBD=1, HBA=3) and Ligand B (HBD=2, HBA=6) both fall within acceptable ranges.

**QED:** Both ligands have good QED scores (A: 0.514, B: 0.547), indicating drug-like properties.

**DILI:** Both ligands have the same low DILI risk (23.885).

**BBB:** Ligand A has a significantly better BBB percentile (52.927) than Ligand B (43.156). This is crucial for a CNS target like DRD2.

**Caco-2 Permeability:** Ligand A (-4.42) and Ligand B (-5.823) both have negative values, which is unusual and suggests poor permeability. However, the scale isn't specified, so it's hard to interpret definitively.

**Aqueous Solubility:** Ligand A (-2.722) and Ligand B (-1.508) both have negative values, which is also unusual.

**hERG Inhibition:** Both ligands show very low hERG inhibition risk (A: 0.271, B: 0.134).

**Microsomal Clearance:** Ligand B (-14.867) has a much lower (better) microsomal clearance than Ligand A (41.649), suggesting greater metabolic stability.

**In vitro Half-Life:** Ligand B (-8.676) has a slightly longer in vitro half-life than Ligand A (-7.492).

**P-gp Efflux:** Both ligands show very low P-gp efflux liability (A: 0.081, B: 0.007).

**Binding Affinity:** Both ligands have comparable and strong binding affinities (A: -7.6 kcal/mol, B: -7.0 kcal/mol). Ligand A is slightly better.

**Overall Assessment:**

Ligand A is superior due to its better logP, significantly better BBB penetration, and slightly better binding affinity. While Ligand B has better metabolic stability (lower Cl_mic) and half-life, the poor logP and lower BBB penetration are major concerns for a CNS-targeting drug. The GPCR-specific priorities heavily favor Ligand A.

Output:
1
2025-04-17 05:30:51,977 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (352.41 and 358.404 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (88.67) is excellent, falling well below the 90 A^2 threshold for CNS targets. Ligand B (49.41) is also very good.

**3. logP:** Ligand A (0.187) is quite low, potentially hindering permeability. Ligand B (2.44) is within the optimal 1-3 range. This is a significant advantage for Ligand B.

**4. H-Bond Donors:** Ligand A (3) is acceptable. Ligand B (1) is even better.

**5. H-Bond Acceptors:** Ligand A (4) is acceptable. Ligand B (2) is also good.

**6. QED:** Both ligands have good QED scores (0.682 and 0.793), indicating drug-like properties.

**7. DILI:** Both ligands have relatively low DILI risk (20.396 and 27.491 percentiles), which is positive.

**8. BBB:** Ligand B (87.01) is excellent, exceeding the 70% threshold for CNS targets. Ligand A (42.846) is considerably lower and concerning for CNS penetration. This is a major advantage for Ligand B.

**9. Caco-2 Permeability:** Ligand A (-5.145) shows poor permeability. Ligand B (-4.615) is also poor, but slightly better than A.

**10. Aqueous Solubility:** Both ligands have poor aqueous solubility (-1.049 and -3.676). This could pose formulation challenges, but is less critical than BBB for a CNS target.

**11. hERG Inhibition:** Both ligands have low hERG inhibition risk (0.418 and 0.45).

**12. Microsomal Clearance:** Ligand A (-35.478) has very low (good) microsomal clearance, suggesting high metabolic stability. Ligand B (19.383) has moderate clearance.

**13. In vitro Half-Life:** Ligand A (-6.957) has a very long half-life, which is highly desirable. Ligand B (11.549) has a moderate half-life.

**14. P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.007 and 0.172), which is favorable for CNS penetration.

**15. Binding Affinity:** Both ligands have the same binding affinity (-8.3 kcal/mol), which is excellent.

**Overall Assessment:**

While Ligand A has superior metabolic stability and half-life, its low logP and poor BBB penetration are major drawbacks for a CNS target like DRD2. Ligand B, despite slightly higher clearance, excels in key areas for CNS drugs: logP, BBB, and acceptable permeability. The equal binding affinity means the ADME properties become the deciding factor.

Output:
1
2025-04-17 05:30:51,978 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (355.479 and 348.447 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (62.32) is significantly better than Ligand B (103.95). For CNS targets, TPSA should be <=90, and A is comfortably within that range, while B is nearing the upper limit.

**logP:** Both ligands have similar logP values (1.424 and 1.385), falling within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A (0 HBD, 5 HBA) is preferable to Ligand B (3 HBD, 4 HBA). Lower HBD generally improves BBB penetration.

**QED:** Both ligands have similar, acceptable QED values (0.675 and 0.692), indicating good drug-like properties.

**DILI:** Ligand A (10.12) has a much lower DILI risk than Ligand B (48.507). This is a significant advantage.

**BBB:** Ligand A (89.763) has a substantially higher BBB penetration percentile than Ligand B (55.215). This is *critical* for a CNS target like DRD2.

**Caco-2 Permeability:** Ligand A (-4.284) is better than Ligand B (-5.074), indicating better intestinal absorption, but both are negative values which is unusual.

**Aqueous Solubility:** Ligand A (-0.333) is better than Ligand B (-3.385), indicating better solubility.

**hERG:** Ligand A (0.736) has a lower hERG inhibition liability than Ligand B (0.119), indicating a lower risk of cardiotoxicity.

**Microsomal Clearance:** Both ligands have similar microsomal clearance values (27.799 and 29.5 mL/min/kg).

**In vitro Half-Life:** Ligand A (-30.566) has a worse in vitro half-life than Ligand B (-24.933).

**P-gp Efflux:** Ligand A (0.044) has a lower P-gp efflux liability than Ligand B (0.038), which is favorable.

**Binding Affinity:** Ligand B (-8.3) has a slightly better binding affinity than Ligand A (-7.7), but the difference is less than 1.5 kcal/mol.

**Overall Assessment:**

Ligand A is significantly better overall, particularly due to its superior BBB penetration, lower DILI risk, and lower hERG liability. While Ligand B has slightly better binding affinity, the ADME properties of Ligand A are far more favorable for a CNS-targeting drug. The difference in binding affinity is not large enough to overcome the substantial advantages of Ligand A in terms of safety and CNS exposure.

Output:
1
2025-04-17 05:30:51,978 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (353.463 and 351.447 Da) fall comfortably within the ideal 200-500 Da range.

**TPSA:** Ligand A (87.74) is better than Ligand B (76.83). Both are below the 90 A^2 threshold for CNS targets, which is excellent.

**logP:** Ligand A (0.823) is slightly lower than optimal (1-3), potentially hindering permeation. Ligand B (1.701) is within the optimal range.

**H-Bond Donors/Acceptors:** Ligand A (2 HBD, 4 HBA) and Ligand B (1 HBD, 6 HBA) both have reasonable numbers of H-bond donors and acceptors, well within the suggested limits.

**QED:** Ligand A (0.766) has a slightly better QED score than Ligand B (0.647), indicating a more drug-like profile. Both are above the 0.5 threshold.

**DILI:** Ligand A (22.334) has a significantly lower DILI risk than Ligand B (27.181), which is a major advantage. Both are below the 40 threshold.

**BBB:** Ligand B (77.239) has a substantially better BBB penetration score than Ligand A (63.94). This is a critical factor for a CNS target like DRD2.

**Caco-2 Permeability:** Ligand A (-5.046) has a worse Caco-2 permeability than Ligand B (-4.866). Both are negative, which is not ideal, but B is better.

**Aqueous Solubility:** Both ligands have poor aqueous solubility (-1.049 and -1.381 respectively).

**hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.128 and 0.276 respectively).

**Microsomal Clearance:** Ligand A (-0.183) has a much lower (better) microsomal clearance than Ligand B (47.828), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand B (9.175) has a significantly longer in vitro half-life than Ligand A (-2.078).

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.014 and 0.049 respectively).

**Binding Affinity:** Ligand B (-7.1 kcal/mol) has a significantly stronger binding affinity than Ligand A (0.0 kcal/mol). This is a decisive advantage.

**Overall Assessment:**

Ligand B excels in the most critical areas for a CNS-targeting GPCR ligand: BBB penetration and binding affinity. While Ligand A has a better DILI score and metabolic stability, the superior affinity and BBB penetration of Ligand B outweigh these benefits. The slightly lower logP of Ligand A is a concern, and the significantly weaker binding affinity is a dealbreaker.

Output:
1
2025-04-17 05:30:51,978 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (346.43 and 344.46 Da) fall comfortably within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (84.5) is better than Ligand B (65.54). Both are below the 90 A^2 threshold for CNS targets, but Ligand B is closer to optimal.

**3. logP:** Both ligands have good logP values (1.16 and 1.99), falling within the 1-3 range. Ligand B is slightly better.

**4. H-Bond Donors:** Ligand A has 2 HBD, and Ligand B has 1. Both are within the acceptable limit of 5.

**5. H-Bond Acceptors:** Both ligands have 4 HBA, well below the limit of 10.

**6. QED:** Ligand B (0.783) has a significantly better QED score than Ligand A (0.392), indicating a more drug-like profile.

**7. DILI:** Ligand B (19.5%) has a much lower DILI risk than Ligand A (32.3%). This is a significant advantage.

**8. BBB:** Ligand B (80.4%) has a substantially better BBB penetration score than Ligand A (49.4%). This is *critical* for a CNS target like DRD2.

**9. Caco-2 Permeability:** Ligand A (-5.29) has a lower Caco-2 permeability than Ligand B (-4.86), suggesting slightly poorer intestinal absorption.

**10. Aqueous Solubility:** Ligand A (-2.21) has slightly better aqueous solubility than Ligand B (-1.34).

**11. hERG Inhibition:** Ligand A (0.091) has a slightly lower hERG inhibition risk than Ligand B (0.374).

**12. Microsomal Clearance:** Ligand B (10.6) has a slightly lower microsomal clearance than Ligand A (12.7), indicating better metabolic stability.

**13. In vitro Half-Life:** Ligand B (3.09) has a longer in vitro half-life than Ligand A (-8.87).

**14. P-gp Efflux:** Ligand A (0.048) has a lower P-gp efflux liability than Ligand B (0.062), which is favorable for CNS penetration.

**15. Binding Affinity:** Ligand B (-7.7 kcal/mol) has a slightly better binding affinity than Ligand A (-8.0 kcal/mol). Although the difference is small, it's still a positive.

**Overall Assessment:**

Ligand B is the superior candidate. While Ligand A has slightly better P-gp efflux and hERG inhibition, Ligand B excels in the most critical areas for a CNS-targeting GPCR ligand: BBB penetration, DILI risk, QED, and in vitro half-life. The slightly better binding affinity of Ligand B further supports this conclusion. The lower TPSA of Ligand B is also beneficial.

Output:
1
2025-04-17 05:30:51,978 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (344.5 & 364.6 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Both ligands have a TPSA of 49.41, which is good for permeability and acceptable for a CNS target, being below the 90 Angstrom threshold.

**3. logP:** Both ligands have a logP around 3.2 (3.276 and 3.228), which is optimal for good absorption and CNS penetration.

**4. H-Bond Donors:** Both have 1 HBD, which is within the acceptable limit of 5.

**5. H-Bond Acceptors:** Ligand A has 2 HBA, and Ligand B has 3 HBA, both are within the acceptable limit of 10.

**6. QED:** Both ligands have QED values above 0.7, indicating good drug-likeness.

**7. DILI:** Ligand A (18.1%) has a lower DILI risk than Ligand B (19.5%), both are good.

**8. BBB:** Ligand A (82.4%) has significantly better predicted BBB penetration than Ligand B (72.0%). This is a crucial factor for a CNS target like DRD2.

**9. Caco-2 Permeability:** Ligand A (-4.87) and Ligand B (-5.091) both have negative Caco-2 permeability values, which is unusual and indicates poor permeability. This is a concern for both.

**10. Aqueous Solubility:** Both ligands have very poor aqueous solubility (-3.837 and -4.069). This is a significant drawback.

**11. hERG Inhibition:** Both ligands show low hERG inhibition risk (0.409 and 0.385).

**12. Microsomal Clearance:** Ligand B (72.271) has a higher microsomal clearance than Ligand A (46.774), suggesting Ligand A is more metabolically stable.

**13. In vitro Half-Life:** Ligand A (-6.222 hours) has a longer half-life than Ligand B (-15.615 hours).

**14. P-gp Efflux:** Both ligands have low P-gp efflux liability (0.226 and 0.177), which is favorable for CNS penetration.

**15. Binding Affinity:** Ligand A (-9.3 kcal/mol) has a significantly stronger binding affinity than Ligand B (-7.8 kcal/mol). This is a substantial advantage, exceeding the 1.5 kcal/mol difference threshold.

**Conclusion:**

Despite the poor solubility and Caco-2 permeability for both, Ligand A is the more promising candidate. Its superior BBB penetration, metabolic stability (lower Cl_mic, longer t1/2), and significantly stronger binding affinity to DRD2 outweigh the shared drawbacks. The strong binding affinity is particularly important for a GPCR target, and the better BBB score is critical for CNS activity.

Output:
1
2025-04-17 05:30:51,979 - INFO - Batch 204 complete. Total preferences: 3264
2025-04-17 05:30:51,979 - INFO - Processing batch 205/512...
2025-04-17 05:31:35,773 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (342.483 and 347.419 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (49.41) is excellent, well below the 90 A^2 threshold for CNS targets. Ligand B (94.11) is higher, but still potentially acceptable, though less ideal.

**logP:** Ligand A (3.173) is optimal (1-3). Ligand B (-0.687) is significantly lower, which could hinder membrane permeability and CNS penetration.

**H-Bond Donors/Acceptors:** Ligand A (HBD=1, HBA=2) is favorable. Ligand B (HBD=2, HBA=5) is also within acceptable limits, but slightly higher.

**QED:** Ligand A (0.798) is excellent, indicating high drug-likeness. Ligand B (0.596) is acceptable, but lower.

**DILI:** Ligand A (19.465) has a very low DILI risk. Ligand B (24.855) is also relatively low, but higher than A.

**BBB:** This is crucial for a CNS target. Ligand A (73.943) is good, exceeding the 70% threshold. Ligand B (28.538) is poor, indicating limited brain penetration.

**Caco-2 Permeability:** Ligand A (-4.945) is negative, indicating poor permeability. Ligand B (-5.272) is also negative and similarly poor.

**Aqueous Solubility:** Ligand A (-4.47) and Ligand B (-1.823) both have negative solubility values, indicating poor solubility.

**hERG Inhibition:** Ligand A (0.293) is very low risk. Ligand B (0.064) is also very low risk.

**Microsomal Clearance:** Ligand A (47.904) is moderate. Ligand B (-21.834) is negative, which is unusual and likely indicates very high metabolic stability (potentially problematic, as it could suggest poor metabolism and accumulation).

**In vitro Half-Life:** Ligand A (12.177 hours) is good. Ligand B (-6.173 hours) is negative, which is also unusual and likely indicates very short half-life.

**P-gp Efflux:** Ligand A (0.18) is low, suggesting minimal P-gp efflux. Ligand B (0.002) is extremely low, suggesting negligible P-gp efflux.

**Binding Affinity:** Ligand A (-8.7 kcal/mol) is excellent. Ligand B (-7.9 kcal/mol) is also good, but 0.8 kcal/mol weaker.

**Overall Assessment:**

Ligand A is significantly better suited as a drug candidate. While both have poor Caco-2 and solubility, Ligand A's superior BBB penetration, better logP, and slightly better binding affinity outweigh the other drawbacks. Ligand B's poor logP and BBB penetration are major concerns for a CNS target. The negative values for clearance and half-life in Ligand B are also concerning and suggest potential issues with the data or the molecule itself.

Output:
0
2025-04-17 05:31:35,773 - INFO - Reasoning:

Let's analyze Ligand A and Ligand B for their potential as DRD2 drug candidates, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight (MW):** Both ligands are within the ideal range (200-500 Da). Ligand A (392.263 Da) is slightly higher, but still acceptable. Ligand B (347.419 Da) is also good.

**2. TPSA:** Ligand A (67.16) is excellent, falling well below the 90 Angstroms threshold for CNS targets. Ligand B (87.54) is higher, but still potentially acceptable, though less ideal.

**3. logP:** Ligand A (4.927) is high, potentially leading to solubility issues and off-target interactions. Ligand B (0.246) is very low, which could hinder membrane permeability.

**4. H-Bond Donors (HBD):** Both ligands have acceptable HBD counts (Ligand A: 0, Ligand B: 1).

**5. H-Bond Acceptors (HBA):** Both ligands have acceptable HBA counts (Ligand A: 4, Ligand B: 5).

**6. QED:** Both ligands have good QED scores (Ligand A: 0.591, Ligand B: 0.827), indicating good drug-like properties. Ligand B is better here.

**7. DILI:** Ligand A (93.68) has a high DILI risk, which is a significant concern. Ligand B (58.085) has a moderate DILI risk, which is preferable.

**8. BBB:** Ligand A (28.887) has very poor predicted BBB penetration, making it unlikely to reach the target in the CNS. Ligand B (53.974) has moderate BBB penetration, which is better, but still not ideal.

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.354 and -4.937), which is unusual and suggests potential issues with intestinal absorption. However, these values are on a log scale and can be difficult to interpret directly.

**10. Aqueous Solubility:** Both ligands have very poor predicted aqueous solubility (-6.478 and -1.553). This is a concern, particularly for Ligand A given its high logP.

**11. hERG Inhibition:** Ligand A (0.655) has a slightly elevated hERG risk, while Ligand B (0.136) has a very low risk.

**12. Microsomal Clearance:** Ligand A (1.642) has low microsomal clearance, suggesting good metabolic stability. Ligand B (21.205) has high microsomal clearance, indicating rapid metabolism.

**13. In vitro Half-Life:** Ligand A (72.73) has a long in vitro half-life, which is desirable. Ligand B (19.176) has a shorter half-life.

**14. P-gp Efflux:** Ligand A (0.355) has low P-gp efflux, which is good for CNS penetration. Ligand B (0.014) has very low P-gp efflux, which is even better.

**15. Binding Affinity:** Ligand B (-7.8 kcal/mol) has significantly stronger binding affinity than Ligand A (-9.6 kcal/mol). This is a substantial advantage.

**Overall Assessment:**

While Ligand A has better metabolic stability and a longer half-life, its high logP, poor BBB penetration, and high DILI risk are major drawbacks. Ligand B, despite its faster metabolism, has a significantly better binding affinity, lower DILI risk, better P-gp efflux, and a more reasonable (though still not ideal) logP and BBB score. The strong binding affinity of Ligand B can potentially compensate for its pharmacokinetic liabilities, and further optimization could address those issues. The poor BBB score for Ligand B is a concern, but the strong affinity might allow for efficacy even with reduced brain exposure.

Output:
1
2025-04-17 05:31:35,774 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (399.208 and 371.415 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (94.18) is better than Ligand B (114.04). For CNS targets, we want TPSA <= 90, so Ligand A is closer to this threshold.

**logP:** Ligand A (1.894) is within the optimal 1-3 range. Ligand B (-0.029) is slightly below 1, which *could* indicate permeability issues, although not drastically.

**H-Bond Donors/Acceptors:** Ligand A (HBD=1, HBA=7) and Ligand B (HBD=2, HBA=7) are both acceptable, well within the guidelines of <=5 HBD and <=10 HBA.

**QED:** Both ligands have good QED scores (A: 0.556, B: 0.63), indicating good drug-like properties.

**DILI:** Ligand A (98.527) has a very high DILI risk, exceeding the >60 threshold. Ligand B (78.054) is still elevated, but significantly lower and more acceptable. This is a major concern for Ligand A.

**BBB:** Both ligands have reasonable BBB penetration (A: 49.903, B: 51.997), but neither exceeds the desirable >70 for CNS targets. This isn't a deciding factor, but it's a point against both.

**Caco-2 Permeability:** Both have negative Caco-2 values (-5.292 and -5.113), which is unusual and suggests poor permeability. This is a significant drawback for both.

**Aqueous Solubility:** Both ligands have very poor aqueous solubility (-3.78 and -2.598). This could hinder formulation and bioavailability.

**hERG Inhibition:** Ligand A (0.561) is better than Ligand B (0.078), indicating a lower risk of cardiotoxicity.

**Microsomal Clearance:** Ligand A (36.482) has lower clearance than Ligand B (53.512), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (36.643) has a longer half-life than Ligand B (-5.597). The negative value for B is concerning and likely an artifact or error.

**P-gp Efflux:** Ligand A (0.536) has lower P-gp efflux than Ligand B (0.018), which is favorable for CNS exposure.

**Binding Affinity:** Ligand A (-10.2 kcal/mol) has *significantly* stronger binding affinity than Ligand B (-7.0 kcal/mol). This is a substantial advantage.

**Overall Assessment:**

Ligand A has a much stronger binding affinity, better TPSA, lower P-gp efflux, lower microsomal clearance, and longer half-life. However, its extremely high DILI risk is a major red flag. Ligand B has a better DILI profile, but weaker affinity, higher P-gp efflux, and a questionable in vitro half-life.

Given the GPCR-specific priorities, and the importance of CNS penetration for a DRD2 target, the strong affinity of Ligand A is very compelling. While the DILI risk is concerning, it might be mitigated through structural modifications during lead optimization. The poor solubility and Caco-2 permeability are shared issues that could be addressed. The significantly weaker binding of Ligand B makes it less attractive, even with a better DILI profile.

Output:
1
2025-04-17 05:31:35,774 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 drug candidates, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight (MW):** Both ligands (352.391 and 358.385 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (115.46) is slightly above the optimal <90 for CNS targets, but still reasonable. Ligand B (59.08) is excellent, well below 90. This favors Ligand B.

**3. logP:** Both ligands have good logP values (0.92 and 1.061), falling within the 1-3 range.

**4. H-Bond Donors (HBD):** Both ligands are acceptable (2 and 0 respectively), being less than 5.

**5. H-Bond Acceptors (HBA):** Both ligands are acceptable (7 and 4 respectively), being less than 10.

**6. QED:** Both ligands have good QED scores (0.814 and 0.708), indicating good drug-like properties.

**7. DILI:** Both ligands have acceptable DILI risk (56.068 and 45.328), below the concerning threshold of 60.

**8. BBB:** Ligand B (89.492) has a significantly better BBB percentile than Ligand A (72.237). This is a crucial advantage for a CNS target like DRD2.

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.481 and -4.36). This is unusual and suggests poor permeability. However, these values are on a scale where negative values are possible, and the absolute magnitude isn't directly comparable without knowing the scale's specifics. We will proceed with caution.

**10. Aqueous Solubility:** Both ligands have negative solubility values (-3.185 and -2.007), again suggesting poor solubility. Similar to Caco-2, the scale is unknown.

**11. hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.058 and 0.349), which is excellent.

**12. Microsomal Clearance (Cl_mic):** Ligand B (25.14) has a lower Cl_mic than Ligand A (39.245), suggesting better metabolic stability.

**13. In vitro Half-Life:** Both ligands have negative half-life values (-16.064 and -15.462), which is not physically possible. This indicates an issue with the data or the scale used.

**14. P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.018 and 0.084), which is favorable for CNS penetration.

**15. Binding Affinity:** Both ligands have excellent binding affinities (-8 and -9 kcal/mol). Ligand B is slightly better (-9 kcal/mol).

**Overall Assessment:**

Ligand B is the stronger candidate. It has a significantly better BBB percentile (89.492 vs 72.237), lower Cl_mic (better metabolic stability), and slightly better binding affinity. While both have concerning negative values for Caco-2 and solubility, the superior BBB penetration of Ligand B is particularly important for a CNS-targeting drug like a DRD2 ligand. The negative half-life values are concerning and would need to be investigated, but the other factors strongly favor Ligand B.

Output:
1
2025-04-17 05:31:35,774 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (348.403 and 335.415 Da) fall within the ideal range of 200-500 Da.

**TPSA:** Ligand A (113.44) is borderline for CNS penetration, slightly above the ideal <90, but acceptable. Ligand B (78.86) is excellent, well below 90.

**logP:** Ligand A (-0.111) is quite low, potentially hindering membrane permeability. Ligand B (2.557) is within the optimal 1-3 range. This is a significant advantage for Ligand B.

**H-Bond Donors/Acceptors:** Ligand A (3 HBD, 6 HBA) is good. Ligand B (2 HBD, 7 HBA) is also acceptable.

**QED:** Both ligands have similar QED values (0.684 and 0.687), indicating good drug-likeness.

**DILI:** Both ligands have similar DILI risk (63.397 and 63.086), indicating moderate risk, but not alarming.

**BBB:** Ligand A (27.142) has poor predicted BBB penetration, a major drawback for a CNS target. Ligand B (40.675) is still not ideal, but significantly better than Ligand A.

**Caco-2 Permeability:** Both ligands have very poor Caco-2 permeability (-5.399 and -5.358), suggesting poor intestinal absorption. This isn't a primary concern for CNS targets where direct delivery or BBB penetration is prioritized.

**Aqueous Solubility:** Both ligands have poor aqueous solubility (-2.096 and -3.062).

**hERG Inhibition:** Ligand A (0.09) has a slightly lower hERG risk than Ligand B (0.729), but both are relatively low.

**Microsomal Clearance:** Ligand A (-5.592) has a lower (better) microsomal clearance than Ligand B (67.547), indicating better metabolic stability.

**In vitro Half-Life:** Ligand B (45.932) has a significantly longer half-life than Ligand A (18.004).

**P-gp Efflux:** Both ligands have very low P-gp efflux (0.016 and 0.014), which is favorable for CNS penetration.

**Binding Affinity:** Ligand B (-9.0 kcal/mol) has a substantially stronger binding affinity than Ligand A (-7.5 kcal/mol). This difference of 1.5 kcal/mol is significant and can outweigh some ADME drawbacks.

**Conclusion:**

Considering the GPCR-specific priorities, Ligand B is the more promising candidate. While both have issues with solubility and Caco-2 permeability, Ligand B's superior logP, BBB penetration, binding affinity, and half-life outweigh Ligand A's slightly better metabolic stability and lower hERG risk. The significantly stronger binding affinity of Ligand B is a key factor, and its improved logP and BBB are crucial for a CNS-targeting drug.

Output:
1
2025-04-17 05:31:35,774 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (367.471 Da) and Ligand B (350.459 Da) are both acceptable.

**TPSA:** Ligand A (91.76) is slightly above the preferred <90 for CNS targets, but still reasonable. Ligand B (66.92) is excellent, well below the 90 threshold.

**logP:** Both ligands have good logP values (A: 1.041, B: 2.134), falling within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A has 2 HBD and 6 HBA, which are acceptable. Ligand B has 0 HBD and 4 HBA, also acceptable.

**QED:** Both ligands have reasonable QED scores (A: 0.751, B: 0.563), indicating good drug-like properties.

**DILI:** Ligand A (42.187) has a slightly higher DILI risk than Ligand B (21.675), but both are below the concerning threshold of 60.

**BBB:** This is a crucial parameter for a CNS target like DRD2. Ligand B (77.162) has a significantly better BBB percentile than Ligand A (39.511). This is a major advantage for Ligand B.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values, which is unusual and requires further investigation. However, the values are similar (-4.88 for A, -4.385 for B), so this doesn't strongly favor either.

**Aqueous Solubility:** Both ligands have negative solubility values, which is also unusual. Again, the values are similar (-1.153 for A, -2.49 for B) and don't heavily influence the decision.

**hERG Inhibition:** Both ligands have very low hERG inhibition risk (A: 0.245, B: 0.267).

**Microsomal Clearance:** Ligand A (-0.578) shows better metabolic stability (lower clearance) than Ligand B (64.986). This is a significant advantage for Ligand A.

**In vitro Half-Life:** Ligand B (-2.161) has a negative half-life, which is not physically possible and indicates a potential issue with the data. Ligand A (6.235) has a reasonable half-life.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (A: 0.029, B: 0.079).

**Binding Affinity:** Ligand B (-7.9 kcal/mol) has a significantly stronger binding affinity than Ligand A (-6.9 kcal/mol). This 1.0 kcal/mol difference is substantial and can outweigh some ADME drawbacks.

**Overall Assessment:**

Ligand B is superior due to its significantly better BBB penetration and substantially stronger binding affinity. While Ligand A has better metabolic stability and a more reasonable half-life, the importance of CNS penetration and potency for a DRD2 ligand outweighs these factors. The negative half-life value for ligand B is concerning and would need to be investigated, but the affinity advantage is substantial.

Output:
1
2025-04-17 05:31:35,775 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B against the provided guidelines, prioritizing GPCR-specific properties (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (348.34 and 348.45 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (132.03) is slightly above the optimal <90 for CNS targets, but still reasonable. Ligand B (96.11) is excellent, well within the desired range.

**logP:** Ligand A (0.259) is quite low, potentially hindering permeability. Ligand B (1.728) is much better, falling within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A has 5 HBD and 5 HBA. Ligand B has 3 HBD and 4 HBA. Both are acceptable, within the guidelines.

**QED:** Both ligands have good QED scores (0.541 and 0.654, respectively), indicating drug-like properties.

**DILI:** Ligand A (78.95) has a higher DILI risk than Ligand B (58.16), though both are not alarmingly high.

**BBB:** This is a critical parameter for a CNS target like DRD2. Ligand A has a BBB percentile of 60.99, which is below the desirable >70 threshold. Ligand B has a BBB percentile of 35.44, also below the desired threshold, but significantly lower than Ligand A.

**Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and suggests poor permeability. However, the scale is not explicitly defined, so we must be cautious. Ligand A (-5.224) is worse than Ligand B (-4.704).

**Aqueous Solubility:** Both have negative solubility values, also unusual. Ligand A (-3.687) is slightly worse than Ligand B (-3.317).

**hERG:** Both ligands have low hERG inhibition liability (0.243 and 0.318), which is good.

**Microsomal Clearance:** Ligand A (-5.518) has a lower (better) microsomal clearance than Ligand B (37.124), indicating better metabolic stability.

**In vitro Half-Life:** Ligand A (43.576) has a longer half-life than Ligand B (-28.386), which is desirable.

**P-gp Efflux:** Ligand A (0.055) has lower P-gp efflux than Ligand B (0.124), which is favorable for CNS penetration.

**Binding Affinity:** Ligand B (-7.6 kcal/mol) has a significantly stronger binding affinity than Ligand A (-9.3 kcal/mol). This is a substantial advantage.

**Overall Assessment:**

Despite Ligand A having better metabolic stability, half-life, and P-gp efflux, Ligand B is the superior candidate. The most important factors are binding affinity and logP. Ligand B's significantly stronger binding affinity (-7.6 vs -9.3 kcal/mol) outweighs the slightly worse ADME properties. Its logP is also much more favorable for CNS penetration. While both have suboptimal BBB penetration, Ligand B's better logP suggests it might have a better chance of crossing the BBB *in vivo* than Ligand A, which has a very low logP.

Output:
1
2025-04-17 05:31:35,775 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B based on the provided guidelines, prioritizing GPCR-specific properties (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (350.48 and 349.43 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (40.62) is significantly better than Ligand B (84.67). For CNS targets, TPSA should be <= 90, and ideally <= 60. Ligand A is well within this range, while Ligand B is approaching the upper limit and less desirable.

**logP:** Ligand A (3.034) is optimal (1-3), while Ligand B (1.403) is on the lower side. While not terrible, lower logP can hinder membrane permeability.

**H-Bond Donors/Acceptors:** Ligand A (0 HBD, 2 HBA) is preferable to Ligand B (1 HBD, 5 HBA). Lower counts are generally better for CNS penetration.

**QED:** Both ligands have good QED scores (0.631 and 0.839), indicating drug-like properties.

**DILI:** Ligand A (18.11) has a much lower DILI risk than Ligand B (32.65), which is a significant advantage.

**BBB:** Ligand A (94.42) has excellent BBB penetration (highly desirable for a CNS target), while Ligand B (69.79) is lower, though still reasonable.

**Caco-2 Permeability:** Both have negative Caco-2 values (-4.679 and -4.545), which is unusual and requires further investigation. However, the values are similar.

**Aqueous Solubility:** Both have negative solubility values (-3.26 and -1.697), which is also unusual and requires further investigation. The values are similar.

**hERG:** Ligand A (0.783) has a lower hERG risk than Ligand B (0.146), which is preferable.

**Microsomal Clearance:** Ligand A (52.07) has higher microsomal clearance than Ligand B (26.60), indicating lower metabolic stability.

**In vitro Half-Life:** Ligand B (7.375) has a significantly longer half-life than Ligand A (1.491), which is a positive attribute.

**P-gp Efflux:** Ligand A (0.369) has lower P-gp efflux than Ligand B (0.039), which is favorable for CNS exposure.

**Binding Affinity:** Ligand B (-7.7 kcal/mol) has slightly better binding affinity than Ligand A (-7.9 kcal/mol). However, the difference is small and may not outweigh other factors.

**Overall Assessment:**

Ligand A is the stronger candidate. Its superior TPSA, logP, DILI risk, and BBB penetration are critical for a CNS-targeting GPCR. While Ligand B has a slightly better affinity and half-life, the advantages of Ligand A in key ADME properties, particularly BBB and TPSA, are more important for CNS drug development. The lower P-gp efflux for Ligand A also contributes to better CNS exposure.

Output:
1
2025-04-17 05:31:35,775 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (347.415 and 364.833 Da) fall within the ideal 200-500 Da range.

**TPSA:** Both ligands have TPSA values (82.71 and 80.37) below the 90 A^2 threshold desirable for CNS targets, which is excellent.

**logP:** Ligand A (1.339) is within the optimal 1-3 range. Ligand B (2.48) is also within the optimal range, but closer to the upper limit.

**H-Bond Donors/Acceptors:** Both ligands have acceptable HBD (1) and HBA (4/5) counts, well within the guidelines.

**QED:** Both ligands have good QED scores (0.833 and 0.903), indicating good drug-like properties.

**DILI:** Ligand A (39.899) has a much lower DILI risk than Ligand B (63.397), placing it in the 'good' category while Ligand B is approaching the 'high risk' threshold.

**BBB:** Ligand A (48.662) has a significantly better BBB penetration score than Ligand B (35.052). This is a *critical* factor for a CNS target like DRD2.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values, which is unusual and suggests poor permeability. However, the scale is not specified, so it's hard to interpret.

**Aqueous Solubility:** Both ligands have negative solubility values, indicating poor aqueous solubility. This is a concern for bioavailability.

**hERG:** Both ligands have very low hERG inhibition liability (0.271 and 0.139), which is excellent.

**Microsomal Clearance:** Ligand A (35.7 mL/min/kg) has a lower (better) microsomal clearance than Ligand B (16.298 mL/min/kg), suggesting greater metabolic stability.

**In vitro Half-Life:** Ligand A (-14.274 hours) has a negative half-life, which is not possible. Ligand B (44.171 hours) has a good in vitro half-life. This is a major red flag for Ligand A.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.057 and 0.221), which is favorable for CNS penetration.

**Binding Affinity:** Ligand B (-7.8 kcal/mol) has a slightly better binding affinity than Ligand A (-8.3 kcal/mol). While the difference is not huge, it's a positive for Ligand B.

**Overall Assessment:**

Ligand A has a better BBB score, lower DILI risk, and better metabolic stability. However, it has a nonsensical negative half-life. Ligand B has a slightly better binding affinity and a reasonable half-life, but a higher DILI risk and poorer BBB penetration. Given the importance of BBB penetration for a CNS target like DRD2, and the concerning negative half-life of Ligand A, Ligand B is the more promising candidate, despite its slightly higher DILI risk. The solubility issues of both compounds would need to be addressed through formulation strategies.

Output:
1
2025-04-17 05:31:35,775 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B based on the provided guidelines, prioritizing GPCR-specific properties (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (346.431 and 362.499 Da) fall within the ideal range of 200-500 Da.

**TPSA:** Both ligands have TPSA values (76.46 and 74.33) below the 90 A^2 threshold desirable for CNS targets, which is excellent.

**logP:** Both ligands have logP values (1.528 and 1.895) within the optimal range of 1-3.

**H-Bond Donors/Acceptors:** Ligand A (1 HBD, 5 HBA) and Ligand B (2 HBD, 5 HBA) both meet the criteria of <=5 HBD and <=10 HBA.

**QED:** Both ligands have QED values (0.793 and 0.756) above 0.5, indicating good drug-likeness.

**DILI:** Ligand A (40.054) and Ligand B (34.781) both have low DILI risk, well below the 60 threshold. Ligand B is slightly better here.

**BBB:** Both ligands have acceptable BBB penetration (58.976 and 61.652). While not exceeding the desirable >70, they are reasonably good.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.51 and -5.135). This is unusual and suggests poor permeability. However, these values are on a scale where negative values are possible, and the absolute magnitude is important. Ligand B has a slightly more negative value, indicating potentially worse permeability.

**Aqueous Solubility:** Both ligands have negative solubility values (-2.693 and -3.135). Again, this is unusual, but indicates poor aqueous solubility. Ligand B is slightly worse.

**hERG:** Both ligands have low hERG inhibition liability (0.115 and 0.389), which is favorable. Ligand A is slightly better.

**Microsomal Clearance:** Ligand A (61.676) has a higher microsomal clearance than Ligand B (46.268), suggesting lower metabolic stability. Ligand B is better here.

**In vitro Half-Life:** Ligand B (-8.112) has a longer in vitro half-life than Ligand A (-22.942), which is a significant advantage.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.053 and 0.081), which is good for CNS penetration. Ligand A is slightly better.

**Binding Affinity:** Ligand B (-8.7 kcal/mol) has a slightly stronger binding affinity than Ligand A (-7.6 kcal/mol). This 1.1 kcal/mol difference is substantial and can outweigh some ADME drawbacks.

**Overall Assessment:**

Ligand B is slightly better overall. While both have issues with Caco-2 and solubility, Ligand B has a significantly better binding affinity, longer half-life, and lower microsomal clearance. The slightly better DILI score is also a plus. The stronger binding affinity is a key advantage for a GPCR target.

Output:
1
2025-04-17 05:31:35,776 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (335.407 Da) is slightly lower, which could be beneficial for permeability. Ligand B (377.457 Da) is also acceptable.

**TPSA:** Ligand A (57.84) is excellent, well below the 90 A^2 threshold for CNS targets. Ligand B (78.51) is still reasonable, but less optimal.

**logP:** Ligand A (3.153) is within the optimal range (1-3). Ligand B (1.174) is at the lower end, potentially hindering permeability.

**H-Bond Donors/Acceptors:** Both ligands have acceptable HBD (1 & 2 respectively) and HBA (4 each) counts.

**QED:** Ligand A (0.796) has a better QED score than Ligand B (0.561), indicating a more drug-like profile.

**DILI:** Ligand B (35.052) has a significantly lower DILI risk than Ligand A (51.648), which is a substantial advantage.

**BBB:** Ligand B (69.794) has a much higher BBB penetration percentile than Ligand A (48.662). This is crucial for a CNS target like DRD2.

**Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and suggests poor permeability. However, the scale is not specified, so it's difficult to interpret.

**Aqueous Solubility:** Both have negative solubility values, indicating poor solubility. This is a concern for both compounds.

**hERG:** Both ligands have very low hERG inhibition risk (0.371 and 0.246 respectively).

**Microsomal Clearance:** Ligand B (22.555) has a slightly higher microsomal clearance than Ligand A (18.777), suggesting potentially lower metabolic stability.

**In vitro Half-Life:** Ligand B (-6.521) has a much lower in vitro half-life than Ligand A (-2.554). This is a significant drawback.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.334 and 0.029 respectively). Ligand B is better here.

**Binding Affinity:** Ligand B (-7.4 kcal/mol) has a significantly stronger binding affinity than Ligand A (-9.1 kcal/mol). This is a major advantage, potentially outweighing some ADME drawbacks.

**Overall Assessment:**

Ligand B is the stronger candidate despite some ADME liabilities. The significantly improved binding affinity (-7.4 vs -9.1 kcal/mol) is a major advantage for a GPCR target. Critically, it also has a much better BBB penetration (69.794 vs 48.662) and lower DILI risk (35.052 vs 51.648). While its solubility and half-life are worse, the strong affinity and BBB penetration are more critical for CNS drug development. Ligand A's better TPSA and QED are less impactful given the affinity and CNS penetration advantages of Ligand B.

Output:
1
2025-04-17 05:31:35,776 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (356.5 and 345.4 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (89.87) is better than Ligand B (54.78) as it is closer to the ideal <90 for CNS targets. Ligand B is excellent.

**logP:** Both ligands (1.688 and 1.518) are within the optimal 1-3 range.

**H-Bond Donors:** Ligand A has 3 HBD, which is acceptable. Ligand B has 0, which is also acceptable.

**H-Bond Acceptors:** Both ligands have 4 HBA, which is within the acceptable limit of <=10.

**QED:** Both ligands have similar QED values (0.556 and 0.53), indicating good drug-likeness.

**DILI:** Ligand A (7.949) has a significantly lower DILI risk than Ligand B (18.457), indicating a safer profile.

**BBB:** Ligand B (72.974) has a much better BBB penetration score than Ligand A (42.885). This is a critical factor for a CNS target like DRD2.

**Caco-2 Permeability:** Ligand A (-4.795) has slightly better Caco-2 permeability than Ligand B (-4.371), suggesting better intestinal absorption.

**Aqueous Solubility:** Ligand A (-1.383) has slightly better aqueous solubility than Ligand B (-1.032).

**hERG Inhibition:** Ligand A (0.22) has a lower hERG inhibition liability than Ligand B (0.414), which is favorable.

**Microsomal Clearance:** Ligand B (21.385) has slightly lower microsomal clearance than Ligand A (23.1), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand B (7.744) has a longer in vitro half-life than Ligand A (4.028), which is desirable.

**P-gp Efflux:** Ligand A (0.044) has a lower P-gp efflux liability than Ligand B (0.112), which is beneficial for CNS exposure.

**Binding Affinity:** Ligand A (-7.2) has a stronger binding affinity than Ligand B (-6.7). This is a significant advantage, as a >1.5 kcal/mol difference can outweigh minor ADME drawbacks.

**Overall Assessment:**

Ligand A has a better binding affinity, lower DILI risk, better Caco-2 permeability, better aqueous solubility, and lower hERG inhibition. However, Ligand B excels in BBB penetration and has slightly better metabolic stability and half-life. Given that this is a CNS target (DRD2), BBB penetration is paramount. The 1.5 kcal/mol difference in binding affinity is substantial, but the significant improvement in BBB for Ligand B, coupled with acceptable other parameters, makes it the more promising candidate.

Output:
1
2025-04-17 05:31:35,776 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (353.403 and 356.419 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (68.46) is excellent, well below the 90 A^2 threshold for CNS targets. Ligand B (117.12) is higher, but still potentially acceptable, though less ideal.

**logP:** Ligand A (3.861) is optimal. Ligand B (-0.899) is significantly lower, which could hinder membrane permeability and CNS penetration.

**H-Bond Donors/Acceptors:** Ligand A (0 HBD, 7 HBA) is favorable. Ligand B (4 HBD, 6 HBA) is also reasonable, though the 4 HBDs are approaching the upper limit.

**QED:** Both ligands have acceptable QED values (0.519 and 0.419), indicating reasonable drug-likeness.

**DILI:** Ligand A (96.316) has a high DILI risk, which is a significant concern. Ligand B (31.64) has a very low DILI risk, a major advantage.

**BBB:** Ligand A (87.088) has excellent BBB penetration potential, crucial for a CNS target. Ligand B (44.94) has poor BBB penetration, a major drawback.

**Caco-2 Permeability:** Ligand A (-4.878) has poor Caco-2 permeability, which is concerning. Ligand B (-5.445) is also poor, but similar to A.

**Aqueous Solubility:** Ligand A (-5.291) has poor solubility. Ligand B (-0.879) is also poor, but slightly better than A.

**hERG Inhibition:** Ligand A (0.492) has a low hERG risk. Ligand B (0.08) is even lower, indicating very little cardiotoxicity risk.

**Microsomal Clearance:** Ligand A (113.72) has moderate clearance. Ligand B (-0.982) has negative clearance, which is not physically possible and likely indicates an issue with the data or prediction method. We'll treat this as very low clearance for now, suggesting high metabolic stability.

**In vitro Half-Life:** Ligand A (32.963 hours) has a reasonable half-life. Ligand B (8.501 hours) has a shorter half-life, which may require more frequent dosing.

**P-gp Efflux:** Ligand A (0.632) has moderate P-gp efflux. Ligand B (0.02) has very low P-gp efflux, which is highly desirable for CNS penetration.

**Binding Affinity:** Ligand A (-9.8 kcal/mol) has significantly stronger binding affinity than Ligand B (-7.2 kcal/mol). This is a substantial advantage, potentially outweighing some of its other drawbacks.

**Overall Assessment:**

Ligand A has excellent affinity and BBB penetration, but suffers from high DILI risk, poor solubility, and moderate Caco-2 permeability. Ligand B has a much better safety profile (low DILI, low hERG, low P-gp efflux) and slightly better solubility, but significantly weaker affinity and poor BBB penetration.

Given the GPCR-specific priorities, particularly the need for good BBB penetration and a balance of ADME properties, the stronger affinity of Ligand A is a compelling factor. However, the high DILI risk is a major concern. While affinity is important, a high DILI risk often leads to attrition during development. Ligand B's lower affinity is a drawback, but its superior safety profile and lower efflux make it a more promising starting point for optimization.

Output:
1
2025-04-17 05:31:35,776 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 drug candidates, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (388.251 Da) is slightly higher than Ligand B (336.395 Da), but both are acceptable.

**TPSA:** Both ligands have TPSA values below 90, which is good for CNS penetration. Ligand A (80.76) is better than Ligand B (86.88).

**logP:** Ligand A (3.319) is optimal, while Ligand B (1.599) is on the lower side. Lower logP can hinder permeation.

**H-Bond Donors/Acceptors:** Ligand A (HBD=1, HBA=5) and Ligand B (HBD=3, HBA=3) both fall within acceptable limits.

**QED:** Both ligands have good QED scores (A: 0.632, B: 0.725), indicating drug-like properties.

**DILI:** Ligand A (82.668) has a higher DILI risk than Ligand B (59.248). This is a concern for Ligand A.

**BBB:** Ligand A (48.391) has a moderate BBB penetration, while Ligand B (37.96) is lower. Both are below the desirable >70 for CNS targets, but Ligand A is better.

**Caco-2 Permeability:** Ligand A (-4.469) has significantly better Caco-2 permeability than Ligand B (-5.154).

**Aqueous Solubility:** Both have poor aqueous solubility (-3.997 and -3.601 respectively).

**hERG:** Both ligands have very low hERG inhibition risk (0.1 and 0.199 respectively).

**Microsomal Clearance:** Ligand B (-33.206) exhibits significantly lower microsomal clearance, suggesting better metabolic stability, compared to Ligand A (88.091).

**In vitro Half-Life:** Ligand B (6.728 hours) has a slightly longer half-life than Ligand A (22.264 hours).

**P-gp Efflux:** Both ligands show low P-gp efflux liability (0.083 and 0.021 respectively).

**Binding Affinity:** Ligand B (-9 kcal/mol) has a stronger binding affinity than Ligand A (-7 kcal/mol). This is a significant advantage.

**Overall Assessment:**

Ligand B has a stronger binding affinity, better metabolic stability (lower Cl_mic), and lower DILI risk. However, Ligand A has better Caco-2 permeability and a slightly better BBB score. The affinity difference is substantial (2 kcal/mol), and for a GPCR, this difference can often outweigh minor ADME drawbacks. While both have poor solubility, this can be addressed with formulation strategies. Given the importance of potency and metabolic stability for GPCR targets, Ligand B is the more promising candidate.

Output:
1
2025-04-17 05:31:35,776 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (344.5 and 348.5 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (40.62) is significantly better than Ligand B (60.85). For CNS targets, we want TPSA <= 90, and ideally closer to 60. Ligand A is much closer to this ideal.

**3. logP:** Both ligands have good logP values (3.23 and 2.06), falling within the 1-3 range.

**4. H-Bond Donors:** Ligand A (0) is preferable to Ligand B (1). Fewer H-bond donors generally improve permeability.

**5. H-Bond Acceptors:** Ligand A (2) is better than Ligand B (3). Lower is better for permeability.

**6. QED:** Both ligands have acceptable QED values (0.735 and 0.683), indicating good drug-like properties.

**7. DILI:** Ligand A (20.124) has a much lower DILI risk than Ligand B (6.747), which is a significant advantage.

**8. BBB:** Ligand A (89.88) has a substantially better BBB penetration percentile than Ligand B (61.419). A value >70 is desirable for CNS targets, and Ligand A is close, while B is considerably lower.

**9. Caco-2 Permeability:** Both have negative values, which is unusual and suggests a potential issue with the data. However, the magnitude of the negative value is similar.

**10. Aqueous Solubility:** Both have negative values, again suggesting a potential data issue.

**11. hERG:** Both ligands have low hERG inhibition liability (0.53 and 0.445), which is good.

**12. Microsomal Clearance:** Ligand A (60.229) has higher microsomal clearance than Ligand B (54.714), meaning it's cleared faster and has lower metabolic stability. This is a negative for Ligand A.

**13. In vitro Half-Life:** Ligand B (-21.746) has a much longer in vitro half-life than Ligand A (1.871). This is a significant advantage for Ligand B.

**14. P-gp Efflux:** Both ligands have low P-gp efflux liability (0.467 and 0.323), which is good for CNS penetration.

**15. Binding Affinity:** Ligand A (-8.3 kcal/mol) has a slightly better binding affinity than Ligand B (-7.5 kcal/mol). This 0.8 kcal/mol difference is significant, and can outweigh some ADME drawbacks.

**Overall Assessment:**

Ligand A excels in key GPCR properties like TPSA, BBB penetration, and binding affinity, and has a much lower DILI risk. However, its higher microsomal clearance and shorter half-life are concerns. Ligand B has a better half-life and lower clearance, but suffers from a higher TPSA, lower BBB penetration, and a higher DILI risk.

Given the importance of BBB penetration for a CNS target like DRD2, and the significant advantage in binding affinity, Ligand A is the more promising candidate *despite* its metabolic liability. The improved affinity and BBB penetration are likely to translate to better in vivo efficacy, and metabolic stability can be improved through structural modifications.

Output:
1
2025-04-17 05:31:35,777 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (363.479 and 347.503 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (72.47) is excellent, well below the 90 A^2 threshold for CNS targets. Ligand B (81.99) is still reasonable, but less optimal.

**3. logP:** Both ligands have a logP around 3.4-3.5, which is within the optimal 1-3 range.

**4. H-Bond Donors:** Ligand A (1) and Ligand B (2) are both acceptable, below the 5 threshold.

**5. H-Bond Acceptors:** Ligand A (5) and Ligand B (3) are both acceptable, below the 10 threshold.

**6. QED:** Both ligands have good QED scores (0.593 and 0.74).

**7. DILI:** Ligand A (56.805) has a moderate DILI risk, but is acceptable. Ligand B (21.714) has a very low DILI risk, which is a significant advantage.

**8. BBB:** Ligand A (88.794) has excellent BBB penetration, exceeding the 70% threshold. Ligand B (63.784) is below this threshold, which is a major drawback for a CNS target.

**9. Caco-2:** Both have negative Caco-2 values, which is unusual and suggests poor permeability. However, these values are on a strange scale, and may not be directly comparable.

**10. Solubility:** Both have negative solubility values, which is also unusual.

**11. hERG:** Both have low hERG inhibition liability (0.206 and 0.442).

**12. Cl_mic:** Ligand A (81.721) has a higher microsomal clearance than Ligand B (67.575), indicating lower metabolic stability.

**13. t1/2:** Ligand B (-11.187) has a significantly longer in vitro half-life than Ligand A (-3.312).

**14. Pgp:** Ligand A (0.251) has a lower P-gp efflux liability than Ligand B (0.139). Lower Pgp is better for CNS penetration.

**15. Binding Affinity:** Ligand A (-9.0) has a substantially stronger binding affinity than Ligand B (-0.0). This is a crucial advantage, potentially outweighing some ADME concerns.

**Overall Assessment:**

Ligand A has a much stronger binding affinity and better BBB penetration, which are critical for a CNS GPCR target like DRD2. While its DILI risk is slightly higher and metabolic stability is lower, the significantly improved affinity and BBB penetration are likely to be more important. Ligand B has a better safety profile (lower DILI) and metabolic stability, but its poor BBB penetration is a major limitation.

Output:
1
2025-04-17 05:31:35,777 - INFO - Batch 205 complete. Total preferences: 3280
2025-04-17 05:31:35,777 - INFO - Processing batch 206/512...
2025-04-17 05:32:17,823 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (480.736 Da) is at the higher end, while Ligand B (385.251 Da) is more favorably positioned.

**2. TPSA:** Ligand A (97.38) is pushing the upper limit for CNS targets (<=90), while Ligand B (71.58) is well within the desired range. This favors Ligand B.

**3. logP:** Both ligands have good logP values (A: 2.4, B: 2.697), falling within the optimal 1-3 range.

**4. H-Bond Donors:** Ligand A has 1 HBD, and Ligand B has 0. Both are acceptable (<=5).

**5. H-Bond Acceptors:** Both ligands have 5 HBAs, which is acceptable (<=10).

**6. QED:** Both ligands have good QED scores (A: 0.527, B: 0.797), indicating drug-like properties. Ligand B is slightly better.

**7. DILI:** Both ligands have high DILI risk (A: 96.394, B: 71.19), but Ligand B is considerably lower, suggesting a better safety profile.

**8. BBB:** Both ligands have reasonable BBB penetration (A: 58.782, B: 59.519). Neither is exceptional (>70), but they are comparable.

**9. Caco-2 Permeability:** Both have negative Caco-2 values (-4.939 and -4.84). This is unusual and suggests poor permeability.

**10. Aqueous Solubility:** Both have negative solubility values (-3.471 and -3.165), indicating very poor aqueous solubility. This is a significant concern.

**11. hERG Inhibition:** Both have very low hERG inhibition risk (A: 0.157, B: 0.209), which is excellent.

**12. Microsomal Clearance:** Ligand A has a negative clearance (-9.58), which is not physically meaningful and likely an error. Ligand B has a clearance of 42.123, which is relatively high, suggesting faster metabolism.

**13. In vitro Half-Life:** Ligand A has a long half-life (72.926), which is desirable. Ligand B has a shorter half-life (35.776).

**14. P-gp Efflux:** Ligand A has very low P-gp efflux (0.379), which is favorable for CNS penetration. Ligand B also has low P-gp efflux (0.274).

**15. Binding Affinity:** Ligand A has a significantly stronger binding affinity (-9.3 kcal/mol) compared to Ligand B (-0.0 kcal/mol). This is a major advantage for Ligand A.

**Overall Assessment:**

Despite the poor solubility and permeability of both compounds, Ligand A's substantially stronger binding affinity (-9.3 kcal/mol vs -0.0 kcal/mol) is a decisive factor. The affinity difference is large enough to potentially overcome the ADME liabilities, especially given the GPCR target class where potency is paramount. Ligand B has a better DILI score and a longer half-life, but the lack of binding affinity makes it unlikely to be a viable candidate. The negative values for Caco-2 and solubility are concerning for both, and would need to be addressed through structural modifications.

Output:
1
2025-04-17 05:32:17,824 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (379.964 Da) is slightly higher than Ligand B (355.471 Da), but both are acceptable.

**TPSA:** Ligand A (64.11) is excellent for CNS penetration, well below the 90 A^2 threshold. Ligand B (82.62) is still reasonable, but less optimal.

**logP:** Ligand A (4.744) is a bit high, potentially leading to solubility issues and off-target interactions. Ligand B (3.014) is within the optimal range (1-3).

**H-Bond Donors/Acceptors:** Ligand A (HBD=1, HBA=5) and Ligand B (HBD=2, HBA=7) are both within acceptable limits.

**QED:** Both ligands have good QED scores (A: 0.6, B: 0.749), indicating drug-like properties.

**DILI:** Ligand A (70.299) has a higher DILI risk than Ligand B (84.451), which is concerning.

**BBB:** Both ligands show good BBB penetration (A: 60.295, B: 68.786), but Ligand B is slightly better. A value >70 is highly desirable for CNS targets, and neither quite reaches that.

**Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and suggests poor permeability. This is a significant concern for both.

**Aqueous Solubility:** Both ligands have very poor aqueous solubility (A: -5.877, B: -3.715). This is a major drawback.

**hERG Inhibition:** Ligand A (0.602) has a slightly higher hERG risk than Ligand B (0.737), but both are reasonably low.

**Microsomal Clearance:** Ligand A (120.578) has a higher microsomal clearance than Ligand B (39.303), indicating lower metabolic stability.

**In vitro Half-Life:** Ligand A (93.236) has a much longer in vitro half-life than Ligand B (0.981), which is a significant advantage.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (A: 0.382, B: 0.108), which is favorable for CNS penetration.

**Binding Affinity:** Ligand B (-9.9 kcal/mol) has significantly stronger binding affinity than Ligand A (-0.0 kcal/mol). This is a decisive factor.

**Overall Assessment:**

Ligand B is the better candidate despite its slightly higher TPSA and poor solubility. The significantly stronger binding affinity (-9.9 kcal/mol vs -0.0 kcal/mol) outweighs the drawbacks. The better logP, lower DILI risk, and lower clearance also contribute to its favorability. While both have poor Caco-2 permeability and solubility, the potency advantage of Ligand B is substantial.

Output:
1
2025-04-17 05:32:17,824 - INFO - Reasoning:

Let's analyze Ligand A and Ligand B against the provided guidelines, keeping in mind DRD2 is a CNS-relevant GPCR.

**1. Molecular Weight:** Both ligands (368.503 and 359.352 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (94.56) is slightly higher than Ligand B (80.12). Both are below the 90 A^2 threshold desirable for CNS targets, but B is preferable.

**3. logP:** Both ligands have good logP values (1.003 and 0.769), falling within the 1-3 range.

**4. H-Bond Donors:** Ligand A (3) is higher than Ligand B (1). Both are within the acceptable limit of <=5.

**5. H-Bond Acceptors:** Ligand A (6) is higher than Ligand B (5). Both are within the acceptable limit of <=10.

**6. QED:** Ligand B (0.842) has a higher QED score than Ligand A (0.636), indicating better overall drug-likeness.

**7. DILI:** Ligand A (33.23) has a significantly lower DILI risk than Ligand B (60.644). This is a substantial advantage for Ligand A.

**8. BBB:** Ligand B (70.105) has a better BBB penetration percentile than Ligand A (33.579). This is a *critical* factor for a CNS target like DRD2.

**9. Caco-2 Permeability:** Both have negative values, which is unusual. Assuming these are logP-like scales, lower values indicate poorer permeability. Ligand B (-5.071) is worse than Ligand A (-5.55).

**10. Aqueous Solubility:** Both have negative values, indicating poor solubility. Ligand A (-1.003) is slightly better than Ligand B (-2.603).

**11. hERG Inhibition:** Both have very low hERG inhibition risk (0.174 and 0.183).

**12. Microsomal Clearance:** Ligand A (-29.142) has a much lower (better) microsomal clearance than Ligand B (1.76). This suggests greater metabolic stability for Ligand A.

**13. In vitro Half-Life:** Ligand A (24.156) has a longer half-life than Ligand B (-9.619).

**14. P-gp Efflux:** Both have very low P-gp efflux liability (0.039 and 0.018).

**15. Binding Affinity:** Ligand B (-8.5 kcal/mol) has a slightly better binding affinity than Ligand A (-7.8 kcal/mol). The difference is 0.7 kcal/mol, which is not a huge advantage.

**Overall Assessment:**

For a CNS GPCR target, BBB penetration is paramount. Ligand B excels in this area (70.105 vs 33.579). However, Ligand A has significantly better DILI and metabolic stability (lower Cl_mic, longer t1/2). The affinity difference is relatively small. Considering the importance of minimizing toxicity and ensuring sufficient exposure in the brain, the better BBB penetration of Ligand B outweighs the advantages of Ligand A.

Output:
1

2025-04-17 05:32:17,824 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (347.5 and 350.5 Da) fall comfortably within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (63.13) is significantly better than Ligand B (75.71). For CNS targets, we want TPSA <= 90, and A is closer to the optimal <=60 range. B is pushing the upper limit.

**3. logP:** Both ligands have acceptable logP values (3.175 and 1.524), falling within the 1-3 range. Ligand A is slightly better, being closer to the optimal range.

**4. H-Bond Donors:** Ligand A (2) and Ligand B (1) are both within the acceptable limit of <=5.

**5. H-Bond Acceptors:** Ligand A (3) and Ligand B (4) are both within the acceptable limit of <=10.

**6. QED:** Both ligands have good QED scores (0.674 and 0.788), indicating good drug-like properties.

**7. DILI:** Ligand A (25.2) has a lower DILI risk than Ligand B (19.7), which is preferable.

**8. BBB:** Both ligands have excellent BBB penetration (70.9% and 74.1%), exceeding the desirable >70% threshold for CNS targets.

**9. Caco-2 Permeability:** Ligand A (-4.758) has worse Caco-2 permeability than Ligand B (-4.753). However, both are negative, indicating poor permeability.

**10. Aqueous Solubility:** Ligand A (-3.218) has slightly worse aqueous solubility than Ligand B (-2.216). Both are quite poor.

**11. hERG Inhibition:** Ligand A (0.696) has a slightly higher hERG risk than Ligand B (0.184). B is much better here.

**12. Microsomal Clearance:** Ligand A (48.95) has higher microsomal clearance than Ligand B (21.09), indicating lower metabolic stability. B is preferable.

**13. In vitro Half-Life:** Ligand A (13.76) has a longer half-life than Ligand B (-5.30). This is a significant advantage for A.

**14. P-gp Efflux:** Ligand A (0.394) has lower P-gp efflux than Ligand B (0.053), which is better for CNS exposure.

**15. Binding Affinity:** Ligand A (-7.7 kcal/mol) has a slightly better binding affinity than Ligand B (-7.2 kcal/mol). While both are excellent, the 0.5 kcal/mol difference is noteworthy.

**Overall Assessment:**

Ligand A excels in binding affinity, BBB penetration, P-gp efflux, and in vitro half-life. However, it suffers from poorer Caco-2 permeability and higher microsomal clearance. Ligand B has better hERG, DILI, and metabolic stability. Considering the GPCR-specific priorities, BBB penetration and affinity are paramount. The slightly better affinity of A, combined with its excellent BBB and P-gp properties, outweigh its slightly worse metabolic stability and permeability. The difference in affinity is also significant.

Output:
1
2025-04-17 05:32:17,824 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (335.319 and 347.434 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (105.06) is higher than Ligand B (52.65). For CNS targets, TPSA should be <= 90. Ligand B is significantly better in this regard.

**logP:** Ligand A (2.411) is within the optimal 1-3 range. Ligand B (0.799) is slightly below 1, which might hinder permeation.

**H-Bond Donors/Acceptors:** Ligand A has 2 HBD and 5 HBA, which are acceptable. Ligand B has 1 HBD and 3 HBA, also acceptable.

**QED:** Both ligands have similar QED values (0.765 and 0.723), indicating good drug-likeness.

**DILI:** Ligand A has a high DILI risk (98.527), which is a major concern. Ligand B has a very low DILI risk (6.592), a significant advantage.

**BBB:** Ligand A has a BBB penetration of 61.342, which is below the desirable >70 for CNS targets. Ligand B has a much better BBB penetration (72.237), exceeding the threshold.

**Caco-2 Permeability:** Both have negative Caco-2 values (-4.653 and -4.767), which is unusual and suggests poor permeability. However, these values are on a log scale and are difficult to interpret without context.

**Aqueous Solubility:** Both have negative solubility values (-5.675 and -1.633), indicating poor aqueous solubility.

**hERG:** Both ligands have low hERG inhibition liability (0.239 and 0.354), which is good.

**Microsomal Clearance:** Ligand A has a moderate Cl_mic (5.553), while Ligand B has a negative Cl_mic (-9.686), which is unusual and suggests very high metabolic stability.

**In vitro Half-Life:** Ligand A has a moderate half-life (14.383 hours). Ligand B has a very long half-life (-24.553 hours), which is a strong positive.

**P-gp Efflux:** Ligand A has a low P-gp efflux liability (0.196). Ligand B also has very low P-gp efflux (0.011).

**Binding Affinity:** Ligand A has a significantly stronger binding affinity (-10.2 kcal/mol) compared to Ligand B (-8.0 kcal/mol). This is a substantial difference.

**Overall Assessment:**

While Ligand A has a much better binding affinity, its extremely high DILI risk and suboptimal BBB penetration are major drawbacks. Ligand B, despite having a weaker affinity, possesses a significantly better safety profile (low DILI), excellent BBB penetration, and very high metabolic stability. For a CNS target like DRD2, a good safety profile and brain penetration are crucial. The affinity difference, while substantial, might be overcome with further optimization of Ligand B.

Output:
1
2025-04-17 05:32:17,824 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (349.387 and 352.475 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (95.61) is slightly higher than Ligand B (84.5). Both are below the 140 A^2 threshold for oral absorption, and closer to the desirable <90 A^2 for CNS targets. Ligand B is preferable here.

**logP:** Ligand A (0.383) is quite low, potentially hindering membrane permeability. Ligand B (2.023) is within the optimal 1-3 range. This is a significant advantage for Ligand B.

**H-Bond Donors/Acceptors:** Ligand A has 1 HBD and 7 HBA, while Ligand B has 2 HBD and 4 HBA. Both are within acceptable limits (<=5 HBD and <=10 HBA).

**QED:** Both ligands have reasonable QED values (0.826 and 0.716), indicating good drug-like properties.

**DILI:** Ligand A (60.799) has a higher DILI risk than Ligand B (19.155). This is a substantial negative for Ligand A.

**BBB:** Ligand A (53.083) has a slightly better BBB penetration percentile than Ligand B (49.011), but both are below the desirable >70 for CNS targets.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.538 and -4.446), which is unusual and suggests poor permeability. This is a concern for both, but doesn't differentiate them significantly.

**Aqueous Solubility:** Both have negative solubility values (-0.709 and -2.641), indicating poor aqueous solubility. Ligand B is worse.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.302 and 0.189).

**Microsomal Clearance:** Ligand A (-11.912) has a lower (better) microsomal clearance than Ligand B (69.043), suggesting better metabolic stability.

**In vitro Half-Life:** Both have negative half-life values (-20.323 and -21.907), which is not physically meaningful. This suggests issues with the data or the model used to generate these values.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.039 and 0.054), which is favorable for CNS penetration.

**Binding Affinity:** Ligand B (-8.7 kcal/mol) has a stronger binding affinity than Ligand A (-7.5 kcal/mol). This difference of 1.2 kcal/mol is significant and can outweigh some ADME drawbacks.

**Overall Assessment:**

Ligand B is the more promising candidate. While both have issues with solubility and Caco-2 permeability, Ligand B has a significantly better logP, a much lower DILI risk, and a substantially stronger binding affinity. The slightly lower BBB penetration of Ligand B is less concerning given its superior logP and affinity. The better metabolic stability of Ligand A is a plus, but the other factors favor Ligand B.

Output:
1
2025-04-17 05:32:17,825 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (346.431 and 348.487 Da) fall comfortably within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (67.67) is slightly higher than Ligand B (58.64). For a CNS target like DRD2, we ideally want TPSA <= 90, so both are acceptable, but B is better.

**3. logP:** Ligand A (1.484) is within the optimal 1-3 range. Ligand B (2.801) is also good.

**4. H-Bond Donors:** Ligand A (0) is preferable to Ligand B (1). Fewer HBDs generally improve permeability.

**5. H-Bond Acceptors:** Ligand A (5) is better than Ligand B (3). Both are within the acceptable range of <=10.

**6. QED:** Both ligands have similar QED values (0.758 and 0.751), indicating good drug-likeness.

**7. DILI:** Ligand A (38.116) has a lower DILI risk than Ligand B (9.771), which is a significant advantage.

**8. BBB:** This is crucial for a CNS target. Ligand B (85.459) has a substantially higher BBB penetration percentile than Ligand A (66.615). This is a major point in favor of Ligand B.

**9. Caco-2 Permeability:** Ligand A (-4.581) has better Caco-2 permeability than Ligand B (-4.697).

**10. Aqueous Solubility:** Ligand A (-0.927) has better aqueous solubility than Ligand B (-2.51).

**11. hERG Inhibition:** Ligand A (0.252) shows lower hERG inhibition liability than Ligand B (0.512), which is preferable.

**12. Microsomal Clearance:** Ligand A (17.859) has lower microsomal clearance than Ligand B (45.531), indicating better metabolic stability.

**13. In vitro Half-Life:** Ligand A (9.751) has a longer in vitro half-life than Ligand B (-0.846).

**14. P-gp Efflux:** Ligand A (0.041) has lower P-gp efflux liability than Ligand B (0.176), which is beneficial for CNS exposure.

**15. Binding Affinity:** Both ligands have the same binding affinity (-8.2 kcal/mol), so this parameter doesn't differentiate them.

**Overall Assessment:**

Ligand B excels in BBB penetration, a critical factor for DRD2 targeting. However, Ligand A demonstrates superior ADME properties across several parameters: lower DILI risk, better solubility, lower hERG inhibition, better metabolic stability (lower Cl_mic and longer t1/2), and lower P-gp efflux. While BBB is a priority, the combined advantages of Ligand A's ADME profile, particularly the lower DILI and better metabolic stability, make it a more promising candidate. The slightly higher TPSA of Ligand A is a minor drawback compared to the significant benefits in other areas.

Output:
0
2025-04-17 05:32:17,825 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 drug candidates, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (350.415 and 344.455 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (84.94) is better than Ligand B (58.64) as it is closer to the ideal range for CNS targets (<=90). Ligand B is excellent.

**3. logP:** Both ligands have good logP values (2.0 and 1.9), falling within the optimal 1-3 range.

**4. H-Bond Donors:** Both ligands have 1 HBD, which is within the acceptable limit of <=5.

**5. H-Bond Acceptors:** Ligand A has 5 HBA, and Ligand B has 3. Both are within the acceptable limit of <=10.

**6. QED:** Both ligands have good QED scores (0.544 and 0.793), indicating good drug-like properties. Ligand B is slightly better.

**7. DILI:** Ligand A (50.291) has a moderate DILI risk, while Ligand B (15.743) has a very low DILI risk. This is a significant advantage for Ligand B.

**8. BBB:** Ligand A (81.892) has a good BBB penetration percentile, but Ligand B (75.572) is slightly lower. Both are acceptable, but >70 is desirable.

**9. Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and requires further investigation. However, the magnitude is similar.

**10. Aqueous Solubility:** Both have negative solubility values, which is also unusual and requires further investigation. Ligand B is slightly worse.

**11. hERG Inhibition:** Both ligands have low hERG inhibition risk (0.627 and 0.151). Ligand B is better.

**12. Microsomal Clearance:** Ligand A (86.392) has higher clearance than Ligand B (55.158), suggesting lower metabolic stability. Ligand B is better.

**13. In vitro Half-Life:** Ligand B (10.305 hours) has a significantly longer half-life than Ligand A (-41.06 hours). This is a major advantage for Ligand B.

**14. P-gp Efflux:** Ligand A (0.101) has lower P-gp efflux than Ligand B (0.04), which is better for CNS exposure.

**15. Binding Affinity:** Ligand B (-8.6 kcal/mol) has a significantly stronger binding affinity than Ligand A (-7.4 kcal/mol). This is a substantial advantage, potentially outweighing minor ADME drawbacks.

**Overall Assessment:**

Ligand B is the superior candidate. While Ligand A has a slightly better BBB score and P-gp efflux, Ligand B excels in critical areas: significantly stronger binding affinity, much lower DILI risk, longer half-life, and lower microsomal clearance. The lower DILI and improved metabolic stability are particularly important for drug development. The affinity difference is also significant (>1.2 kcal/mol).

Output:
1
2025-04-17 05:32:17,825 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (347.415 and 351.447 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (102.68) is higher than Ligand B (78.95). For CNS targets, TPSA should be <=90. Ligand B is preferable here.

**3. logP:** Both ligands have good logP values (1.28 and 1.538), falling within the optimal 1-3 range.

**4. H-Bond Donors:** Ligand A (3) is higher than Ligand B (1). Both are acceptable, but lower is generally better for permeability. Ligand B is preferable.

**5. H-Bond Acceptors:** Ligand A (5) is higher than Ligand B (4). Both are within the acceptable limit of <=10, but Ligand B is preferable.

**6. QED:** Both ligands have similar and good QED values (0.719 and 0.736), indicating good drug-like properties.

**7. DILI:** Ligand A (60.45) has a higher DILI risk than Ligand B (28.306). Ligand B is significantly better here.

**8. BBB:** Ligand A (64.599) and Ligand B (71.811) both have acceptable BBB penetration, but Ligand B is better, exceeding 70% which is desirable for CNS targets.

**9. Caco-2 Permeability:** Ligand A (-5.241) has worse Caco-2 permeability than Ligand B (-4.552). Higher is better. Ligand B is preferable.

**10. Aqueous Solubility:** Ligand A (-2.263) has worse solubility than Ligand B (-1.678). Higher is better. Ligand B is preferable.

**11. hERG Inhibition:** Both ligands have low hERG inhibition risk (0.387 and 0.198), which is good. Ligand B is slightly better.

**12. Microsomal Clearance:** Ligand A (-26.375) has a much lower (better) microsomal clearance than Ligand B (1.405), suggesting greater metabolic stability. Ligand A is preferable.

**13. In vitro Half-Life:** Ligand A (9.629) has a shorter half-life than Ligand B (-18.62). Longer is generally better. Ligand B is preferable.

**14. P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.016 and 0.031), which is good for CNS penetration.

**15. Binding Affinity:** Both ligands have excellent binding affinity (-7.8 and -7.9 kcal/mol). The difference is minimal.

**Overall Assessment:**

Ligand B consistently outperforms Ligand A in most key ADME properties relevant for a CNS-targeting GPCR, including TPSA, DILI, BBB, Caco-2 permeability, solubility, and half-life. While Ligand A has better metabolic stability (lower Cl_mic), the other advantages of Ligand B, particularly its superior BBB penetration and lower toxicity risk, outweigh this benefit. The binding affinity is comparable.

Output:
1
2025-04-17 05:32:17,825 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (371.38 Da) is slightly higher than Ligand B (356.423 Da), but both are acceptable.

**TPSA:** Ligand A (55.4) is significantly better than Ligand B (108.05). For CNS targets, TPSA should be <=90, so Ligand A is much more favorable.

**logP:** Ligand A (3.086) is optimal (1-3). Ligand B (-0.868) is quite low, potentially hindering membrane permeability and CNS penetration.

**H-Bond Donors/Acceptors:** Ligand A (HBD=1, HBA=3) and Ligand B (HBD=2, HBA=5) both fall within acceptable ranges.

**QED:** Ligand A (0.822) is excellent, indicating high drug-likeness. Ligand B (0.475) is below the desirable threshold of 0.5.

**DILI:** Ligand A (72.043) has a higher DILI risk than Ligand B (39.511), but both are reasonably low.

**BBB:** Ligand A (77.937) is good for CNS penetration, exceeding the 70% threshold. Ligand B (33.656) is significantly lower and less favorable.

**Caco-2 Permeability:** Ligand A (-4.728) and Ligand B (-5.248) both have negative values, which is unusual. Lower values indicate lower permeability. However, the difference is small.

**Aqueous Solubility:** Ligand A (-4.6) and Ligand B (-1.135) both have negative values, indicating low solubility. Ligand B is slightly better.

**hERG Inhibition:** Ligand A (0.77) is much lower risk than Ligand B (0.062). Lower is better.

**Microsomal Clearance:** Ligand A (51.365) has higher clearance than Ligand B (2.461), indicating lower metabolic stability.

**In vitro Half-Life:** Ligand A (25.209) has a longer half-life than Ligand B (-10.074).

**P-gp Efflux:** Ligand A (0.499) has lower P-gp efflux than Ligand B (0.008), which is more favorable for CNS penetration.

**Binding Affinity:** Ligand A (-10.2 kcal/mol) has significantly stronger binding affinity than Ligand B (-6.8 kcal/mol). This is a substantial difference and a major advantage for Ligand A.

**Overall Assessment:**

Ligand A is clearly superior. It excels in key GPCR properties like TPSA, logP, BBB, and, crucially, binding affinity. While its DILI and Cl_mic are slightly worse than Ligand B, the strong affinity and favorable CNS penetration properties of Ligand A outweigh these drawbacks. Ligand B's low logP and poor BBB penetration are major concerns for a CNS-targeting drug.



Output:
1
2025-04-17 05:32:17,826 - INFO - Reasoning:

Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (362.308 and 359.495 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (84.43) is better than Ligand B (62.3). Both are below the 90 A^2 threshold for CNS targets, which is excellent.

**3. logP:** Both ligands have a logP around 2.0 (2.001 and 2.015), which is optimal for permeability and solubility.

**4. H-Bond Donors:** Ligand A (0) is preferable to Ligand B (1). Fewer HBDs generally improve permeability.

**5. H-Bond Acceptors:** Ligand A (8) is slightly higher than Ligand B (4), but both are within the acceptable limit of 10.

**6. QED:** Both ligands have good QED scores (0.777 and 0.874), indicating good drug-like properties.

**7. DILI:** Ligand B (27.918) has a significantly lower DILI risk than Ligand A (70.88), making it safer from a liver toxicity perspective. This is a significant advantage for Ligand B.

**8. BBB:** Ligand A (87.786) has a substantially better BBB penetration score than Ligand B (67.197). This is *critical* for a CNS target like DRD2.

**9. Caco-2 Permeability:** Ligand A (-4.779) shows better Caco-2 permeability than Ligand B (-5.318), suggesting better intestinal absorption.

**10. Aqueous Solubility:** Both ligands have very poor aqueous solubility (-3.305 and -3.175). This is a concern for both.

**11. hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.121 and 0.159).

**12. Microsomal Clearance:** Ligand B (21.839) has lower microsomal clearance than Ligand A (25.877), indicating better metabolic stability.

**13. In vitro Half-Life:** Ligand A (-12.813) has a longer in vitro half-life than Ligand B (-7.503), which is desirable.

**14. P-gp Efflux:** Ligand A (0.113) has lower P-gp efflux than Ligand B (0.039), meaning it is less likely to be pumped out of the brain, improving CNS exposure.

**15. Binding Affinity:** Ligand B (-7.5) has a slightly better binding affinity than Ligand A (-8.8). While A is stronger, the difference is not massive (1.3 kcal/mol) and can be overcome by other factors.

**Overall Assessment:**

The decision hinges on the balance between BBB penetration (Ligand A is significantly better) and DILI risk (Ligand B is significantly better). For a CNS target, BBB penetration is paramount. While Ligand B has a better safety profile (DILI) and metabolic stability, Ligand A's superior BBB penetration is the deciding factor. The slightly better affinity of Ligand B is not enough to offset the lower BBB score.

Output:
0
2025-04-17 05:32:17,826 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (358.454 and 348.487 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (78.87) is higher than Ligand B (49.85). For a CNS target like DRD2, we ideally want TPSA <= 90, so both are acceptable, but B is significantly better.

**3. logP:** Both ligands have good logP values (1.409 and 2.895), falling within the optimal 1-3 range.

**4. H-Bond Donors:** Ligand A has 2 HBD, and Ligand B has 0. Both are within the acceptable limit of <= 5.

**5. H-Bond Acceptors:** Ligand A has 4 HBA, and Ligand B has 3. Both are within the acceptable limit of <= 10.

**6. QED:** Ligand A (0.752) has a better QED score than Ligand B (0.475), indicating a more drug-like profile.

**7. DILI:** Ligand A (20.861) has a lower DILI risk than Ligand B (17.836), which is preferable.

**8. BBB:** Ligand B (92.827) has a significantly higher BBB penetration percentile than Ligand A (70.609). This is a *critical* advantage for a CNS target like DRD2.

**9. Caco-2 Permeability:** Both have negative values (-4.706 and -4.684), which is unusual. This likely indicates a scale where lower values represent lower permeability. Both are similarly poor.

**10. Aqueous Solubility:** Both have negative values (-1.934 and -1.912), again suggesting a scale where lower values indicate lower solubility. Both are similarly poor.

**11. hERG Inhibition:** Ligand A (0.484) shows slightly lower hERG inhibition liability than Ligand B (0.678), which is favorable.

**12. Microsomal Clearance:** Ligand B (63.647) has a higher microsomal clearance than Ligand A (11.882), indicating faster metabolism and potentially lower *in vivo* exposure.

**13. In vitro Half-Life:** Ligand A (15.102) has a longer in vitro half-life than Ligand B (-8.118). This is a significant advantage.

**14. P-gp Efflux:** Ligand A (0.081) has much lower P-gp efflux liability than Ligand B (0.458). Lower P-gp efflux is crucial for CNS penetration.

**15. Binding Affinity:** Ligand B (-8.4 kcal/mol) has a slightly better binding affinity than Ligand A (-7.2 kcal/mol). This is a 1.2 kcal/mol advantage, which is substantial and can outweigh some ADME drawbacks.

**Overall Assessment:**

While Ligand A has better QED, DILI, hERG, metabolic stability (lower Cl_mic and longer t1/2), and P-gp efflux, Ligand B's *significantly* higher BBB penetration (92.827 vs 70.609) and slightly better binding affinity (-8.4 vs -7.2) are decisive for a CNS target like DRD2. The better affinity is also a strong point. The slightly worse ADME properties of Ligand B can potentially be addressed through further optimization, but achieving good BBB penetration is often challenging.

Output:
1
2025-04-17 05:32:17,826 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (347.463 and 359.535 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (77.37) is significantly better than Ligand B (29.54). For CNS targets, we want TPSA <= 90, and Ligand B is much closer to the ideal range for brain penetration. Ligand A is still acceptable but less optimal.

**logP:** Ligand A (1.562) is within the optimal 1-3 range. Ligand B (4.284) is slightly high, potentially leading to solubility issues and off-target interactions.

**H-Bond Donors/Acceptors:** Ligand A has 1 HBD and 5 HBA, which is reasonable. Ligand B has 0 HBD and 3 HBA, also acceptable.

**QED:** Both ligands have reasonable QED values (0.784 and 0.681), indicating good drug-like properties.

**DILI:** Both ligands have relatively low DILI risk (20.047 and 26.638), which is positive.

**BBB:** Ligand B (83.831) has a significantly higher BBB percentile than Ligand A (68.282). This is a crucial advantage for a CNS target like DRD2.

**Caco-2 Permeability:** Ligand A (-4.986) shows poor permeability, while Ligand B (-5.172) is also poor. This is a concern for oral bioavailability, but less critical for a CNS target where direct delivery or other routes might be considered.

**Aqueous Solubility:** Ligand A (-1.768) has slightly better solubility than Ligand B (-4.863), but both are quite poor.

**hERG Inhibition:** Ligand A (0.104) has a very low hERG risk, a significant advantage. Ligand B (0.767) is higher, suggesting a potential cardiotoxicity concern.

**Microsomal Clearance:** Ligand A (-2.172) has a negative clearance, which is excellent (meaning very stable). Ligand B (125.288) has high clearance, indicating rapid metabolism.

**In vitro Half-Life:** Ligand A (2.52) has a shorter half-life than Ligand B (4.025), but both are relatively low.

**P-gp Efflux:** Ligand A (0.008) has very low P-gp efflux, which is excellent for CNS penetration. Ligand B (0.736) has moderate P-gp efflux, which could limit brain exposure.

**Binding Affinity:** Ligand B (-8.2 kcal/mol) has a significantly stronger binding affinity than Ligand A (-7.0 kcal/mol). This is a substantial advantage, potentially outweighing some of the ADME drawbacks.

**Overall Assessment:**

Ligand B excels in binding affinity and BBB penetration, which are paramount for a CNS GPCR target. However, it suffers from higher logP, higher hERG risk, and higher metabolic clearance. Ligand A has better TPSA, lower hERG, and better metabolic stability, but its affinity and BBB penetration are lower.

The difference in binding affinity (-8.2 vs -7.0) is significant (1.2 kcal/mol), and the improved BBB penetration of Ligand B are strong arguments in its favor. While the higher logP and hERG risk are concerns, they might be addressable through further optimization. The superior affinity and BBB penetration are more difficult to achieve through later-stage modifications.

Output:
1
2025-04-17 05:32:17,826 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B based on the provided guidelines, prioritizing GPCR-specific properties (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (343.387 Da) is slightly lower, which can be beneficial for permeability, while Ligand B (392.204 Da) is still acceptable.

**TPSA:** Ligand A (100.21) is borderline for CNS targets (ideally <90), while Ligand B (29.54) is excellent, well below the threshold. This is a significant advantage for Ligand B.

**logP:** Ligand A (0.259) is quite low, potentially hindering membrane permeability. Ligand B (4.62) is high, potentially causing solubility issues or off-target effects, but within a tolerable range.

**H-Bond Donors/Acceptors:** Ligand A has 2 HBD and 5 HBA, which are acceptable. Ligand B has 0 HBD and 2 HBA, also acceptable, and potentially favoring permeability due to fewer hydrogen bonds.

**QED:** Both ligands have reasonable QED values (Ligand A: 0.811, Ligand B: 0.644), indicating good drug-like properties.

**DILI:** Both ligands have similar DILI risk (Ligand A: 65.374, Ligand B: 63.978), indicating moderate risk.

**BBB:** Ligand A (47.499) has a poor BBB percentile, making CNS penetration unlikely. Ligand B (82.164) has a very good BBB percentile, which is crucial for a DRD2 ligand. This is a major advantage for Ligand B.

**Caco-2 Permeability:** Ligand A (-5.362) shows very poor permeability. Ligand B (-4.238) is also poor, but slightly better than A.

**Aqueous Solubility:** Both ligands have poor aqueous solubility (Ligand A: -2.181, Ligand B: -5.532).

**hERG Inhibition:** Ligand A (0.02) has very low hERG inhibition risk, which is excellent. Ligand B (0.833) has a moderate risk, which is a concern.

**Microsomal Clearance:** Ligand A (-16.6) suggests very low clearance and high metabolic stability. Ligand B (94.508) suggests rapid clearance and low metabolic stability, a significant drawback.

**In vitro Half-Life:** Ligand A (4.432) has a short half-life. Ligand B (35.55) has a significantly longer half-life, which is desirable.

**P-gp Efflux:** Ligand A (0.029) has low P-gp efflux, which is good. Ligand B (0.729) has moderate P-gp efflux, which could limit CNS exposure.

**Binding Affinity:** Ligand B (-8.3 kcal/mol) has a significantly stronger binding affinity than Ligand A (0.0 kcal/mol). This is a crucial factor, as a >1.5 kcal/mol advantage can outweigh other drawbacks.

**Overall Assessment:**

Ligand B is the superior candidate despite some drawbacks. Its strong binding affinity, excellent BBB penetration, and longer half-life outweigh its higher logP, moderate P-gp efflux, and moderate hERG risk. Ligand A's extremely low logP, poor BBB penetration, and very weak binding affinity make it a poor candidate, even with its favorable hERG profile and metabolic stability. The DRD2 target is in the CNS, making BBB penetration and affinity paramount.

Output:
1
2025-04-17 05:32:17,826 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (355.523 and 349.431 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (72.88) is excellent, well below the 90 A^2 threshold for CNS targets. Ligand B (84.67) is still acceptable, but less optimal.

**logP:** Both ligands (1.479 and 1.629) are within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A (2 HBD, 4 HBA) and Ligand B (1 HBD, 5 HBA) both have reasonable H-bond characteristics, well within the guidelines.

**QED:** Both ligands have good QED scores (0.657 and 0.809), indicating drug-like properties.

**DILI:** Ligand A (3.218) has a very low DILI risk. Ligand B (39.046) is higher, but still considered acceptable.

**BBB:** This is critical for a CNS target. Ligand A (52.811) is moderate, while Ligand B (75.727) is significantly better, exceeding the 70% threshold.

**Caco-2 Permeability:** Both have negative values (-4.926 and -4.499), which is unusual and suggests poor permeability. This is a significant concern for both.

**Aqueous Solubility:** Both ligands have negative solubility values (-0.676 and -2.588), which is also concerning, indicating poor aqueous solubility.

**hERG:** Both ligands have low hERG risk (0.427 and 0.302).

**Microsomal Clearance:** Ligand A (18.191) has lower clearance than Ligand B (51.796), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (-0.157) has a very short half-life, while Ligand B (-15.186) is also short, but worse.

**P-gp Efflux:** Both have very low P-gp efflux liability (0.019 and 0.134) which is good.

**Binding Affinity:** Ligand B (-8.2 kcal/mol) has a significantly stronger binding affinity than Ligand A (-6.4 kcal/mol) - a difference of 1.8 kcal/mol. This is a substantial advantage.

**Overall Assessment:**

Ligand B is the stronger candidate. While both have issues with Caco-2 and aqueous solubility, Ligand B's superior BBB penetration and significantly improved binding affinity outweigh the slightly higher DILI risk and worse metabolic stability. The stronger binding affinity is a crucial factor for GPCRs, and the better BBB penetration is essential for CNS activity. The solubility and permeability issues would need to be addressed in further optimization, but the core pharmacodynamic and pharmacokinetic properties of Ligand B are more promising.

Output:
1
2025-04-17 05:32:17,827 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B based on the provided guidelines, prioritizing GPCR-specific properties (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (343.427 Da) is slightly lower, which could be beneficial for permeability.

**TPSA:** Both ligands have TPSA values below the 90 A^2 threshold desirable for CNS targets. Ligand B (56.59 A^2) is slightly lower than Ligand A (61.88 A^2), which is favorable.

**logP:** Ligand A (1.405) is within the optimal range (1-3), while Ligand B (3.456) is at the higher end. While still acceptable, higher logP can sometimes lead to off-target effects.

**H-Bond Donors/Acceptors:** Ligand A (1 HBD, 4 HBA) and Ligand B (2 HBD, 5 HBA) both have reasonable numbers of H-bond donors and acceptors, well within the suggested limits.

**QED:** Ligand A (0.901) has a significantly higher QED score than Ligand B (0.749), indicating a more drug-like profile.

**DILI:** Ligand A (53.936) has a higher DILI risk than Ligand B (13.843). This is a significant drawback for Ligand A.

**BBB:** Both ligands exhibit good BBB penetration (Ligand A: 73.517%, Ligand B: 76.076%), exceeding the 70% threshold for CNS targets. Ligand B is slightly better.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values, which is unusual and potentially indicates issues with the prediction method. However, we can still compare them relatively. Ligand A (-4.627) is slightly better than Ligand B (-4.994).

**Aqueous Solubility:** Both ligands have negative solubility values, again suggesting a potential issue with the prediction method. Ligand A (-3.047) is slightly better than Ligand B (-3.818).

**hERG Inhibition:** Ligand A (0.389) has a lower hERG inhibition risk than Ligand B (0.856), which is preferable.

**Microsomal Clearance:** Ligand A (-20.942) has a much lower (better) microsomal clearance than Ligand B (52.564), indicating greater metabolic stability.

**In vitro Half-Life:** Ligand A (7.876 hours) has a longer half-life than Ligand B (2.006 hours), which is generally desirable.

**P-gp Efflux:** Ligand A (0.018) shows very low P-gp efflux, which is excellent for CNS penetration. Ligand B (0.589) shows moderate P-gp efflux.

**Binding Affinity:** Ligand B (-7.1 kcal/mol) has a significantly stronger binding affinity than Ligand A (-9.4 kcal/mol). This is a substantial advantage, potentially outweighing some of the ADME drawbacks.

**Overall Assessment:**

Ligand B has a significantly better binding affinity, which is crucial for a GPCR target. It also has a lower DILI risk and slightly better BBB penetration. However, it has a higher logP, a lower QED, and a higher P-gp efflux. Ligand A has a better QED, lower DILI, better metabolic stability, and very low P-gp efflux, but its binding affinity is considerably weaker.

Given the importance of binding affinity for GPCRs, and the acceptable (though not ideal) ADME profile of Ligand B, I believe **Ligand B** is the more promising drug candidate. The stronger binding is likely to be more impactful than the slightly less favorable ADME properties, especially considering optimization can address those issues.

Output:
1
2025-04-17 05:32:17,827 - INFO - Batch 206 complete. Total preferences: 3296
2025-04-17 05:32:17,827 - INFO - Processing batch 207/512...
2025-04-17 05:32:59,255 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (375.485 Da) is slightly higher than Ligand B (347.415 Da), but both are acceptable.

**TPSA:** Ligand A (71.09) is better than Ligand B (84.67). For CNS targets, TPSA should be <=90, both are within this range, but A is preferable.

**logP:** Ligand A (3.013) is optimal (1-3), while Ligand B (1.588) is at the lower end of the range. This is a significant advantage for Ligand A as it suggests better membrane permeability.

**H-Bond Donors/Acceptors:** Ligand A (HBD=2, HBA=4) and Ligand B (HBD=1, HBA=5) both fall within acceptable limits (<=5 HBD, <=10 HBA).

**QED:** Both ligands have similar QED values (0.734 and 0.733), indicating good drug-likeness.

**DILI:** Ligand A (44.591) has a slightly higher DILI risk than Ligand B (38.309), but both are below the concerning threshold of 60.

**BBB:** Ligand B (74.254) has a significantly better BBB penetration percentile than Ligand A (58.317). This is a crucial factor for a CNS target like DRD2.

**Caco-2 Permeability:** Ligand A (-4.907) has better Caco-2 permeability than Ligand B (-4.51), suggesting better intestinal absorption.

**Aqueous Solubility:** Ligand A (-3.316) has better aqueous solubility than Ligand B (-2.705).

**hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.363 and 0.177).

**Microsomal Clearance:** Ligand B (40.371) has slightly lower microsomal clearance than Ligand A (45.238), indicating better metabolic stability.

**In vitro Half-Life:** Ligand B (8.494) has a longer in vitro half-life than Ligand A (4.856).

**P-gp Efflux:** Ligand A (0.089) has lower P-gp efflux liability than Ligand B (0.057), which is favorable for CNS penetration.

**Binding Affinity:** Ligand B (-7.5 kcal/mol) has a slightly better binding affinity than Ligand A (-7.0 kcal/mol). This 0.5 kcal/mol difference is significant.

**Overall Assessment:**

Ligand B excels in BBB penetration and binding affinity, two critical factors for a CNS GPCR target. While Ligand A has advantages in logP, solubility, and Caco-2 permeability, the superior BBB and affinity of Ligand B outweigh these benefits. The slightly better metabolic stability and half-life of Ligand B are also advantageous.

Output:
1
2025-04-17 05:32:59,255 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (356.403 and 336.395 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (82.29) is better than Ligand B (86.88) as it is closer to the ideal <90 for CNS targets.

**logP:** Ligand A (3.465) is optimal (1-3), while Ligand B (1.599) is on the lower side, potentially hindering permeation.

**H-Bond Donors/Acceptors:** Ligand A (0 HBD, 7 HBA) and Ligand B (3 HBD, 3 HBA) both fall within acceptable limits (<=5 HBD, <=10 HBA).

**QED:** Both ligands have good QED scores (0.603 and 0.725, respectively), indicating drug-like properties.

**DILI:** Ligand A (87.049) has a higher DILI risk than Ligand B (59.248). This is a negative for Ligand A.

**BBB:** Ligand A (59.597) is better than Ligand B (37.96) but both are below the desirable >70 for CNS targets.

**Caco-2 Permeability:** Ligand A (-4.857) is significantly worse than Ligand B (-5.154). Lower values indicate poor permeability.

**Aqueous Solubility:** Ligand A (-4.158) is slightly better than Ligand B (-3.601).

**hERG:** Both ligands have very low hERG risk (0.153 and 0.199).

**Microsomal Clearance:** Ligand B (-33.206) has a much lower (better) microsomal clearance than Ligand A (107.701), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand B (6.728) has a longer half-life than Ligand A (-23.587).

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.65 and 0.021).

**Binding Affinity:** Both ligands have the same binding affinity (-9 kcal/mol), which is excellent.

**Overall Assessment:**

While Ligand A has a slightly better TPSA and solubility, Ligand B is superior in most critical ADME properties. The lower logP of Ligand B is a concern, but the significantly better metabolic stability (lower Cl_mic, longer t1/2), lower DILI risk, and better Caco-2 permeability outweigh this drawback. The binding affinity is identical, so potency is not a differentiating factor. Given the importance of BBB penetration for a CNS target like DRD2, the better overall ADME profile of Ligand B makes it the more promising candidate.

Output:
1
2025-04-17 05:32:59,256 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (372.893 and 343.479 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (78.87) is better than Ligand B (73.45) as it is closer to the <90 target for CNS penetration. Both are acceptable.

**3. logP:** Ligand A (2.379) is optimal (1-3). Ligand B (3.472) is slightly higher, but still within an acceptable range.

**4. H-Bond Donors:** Ligand A (2) and Ligand B (1) are both good, well below the threshold of 5.

**5. H-Bond Acceptors:** Ligand A (4) is good, while Ligand B (7) is slightly higher but still acceptable (<10).

**6. QED:** Both ligands have good QED scores (0.506 and 0.665, respectively), indicating drug-like properties. Ligand B is slightly better.

**7. DILI:** Ligand A (33.424) has a significantly lower DILI risk than Ligand B (59.907). This is a major advantage for Ligand A.

**8. BBB:** Ligand B (78.209) has a better BBB penetration score than Ligand A (67.817), which is crucial for a CNS target like DRD2.

**9. Caco-2:** Both have negative Caco-2 values, which is unusual and suggests poor permeability. This is a concern for both, but the scale used is unclear.

**10. Solubility:** Both have negative solubility values, which is also unusual and suggests poor solubility. This is a concern for both, but the scale used is unclear.

**11. hERG:** Ligand A (0.402) has a much lower hERG inhibition liability than Ligand B (0.144), reducing the risk of cardiotoxicity.

**12. Cl_mic:** Ligand A (6.816) has a much lower microsomal clearance than Ligand B (74.49), indicating better metabolic stability.

**13. t1/2:** Ligand A (1.585) has a slightly better in vitro half-life than Ligand B (-4.044).

**14. Pgp:** Ligand A (0.125) has a much lower P-gp efflux liability than Ligand B (0.264), improving CNS exposure.

**15. Binding Affinity:** Ligand A (-7.5) has a slightly better binding affinity than Ligand B (0.0).

**Overall Assessment:**

Ligand A is significantly better overall. While Ligand B has a better BBB score, Ligand A excels in almost all other critical parameters, especially safety (DILI, hERG) and ADME properties (Cl_mic, Pgp). The superior binding affinity of Ligand A further strengthens its position. The negative Caco-2 and solubility values are concerning for both, but the other advantages of Ligand A outweigh this.

Output:
1
2025-04-17 05:32:59,256 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 drug candidates, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (336.4) is slightly better being closer to the middle of the range.

**TPSA:** Ligand B (71.53) is significantly better than Ligand A (101.62). For CNS targets, we want TPSA <= 90, and Ligand B is much closer to this threshold.

**logP:** Both ligands have good logP values (Ligand A: 2.32, Ligand B: 1.812), falling within the optimal 1-3 range. Ligand B is slightly lower, which could potentially improve solubility.

**H-Bond Donors/Acceptors:** Ligand A has 3 HBD and 5 HBA, while Ligand B has 1 HBD and 5 HBA. Both are acceptable, but Ligand B's lower HBD count is slightly favorable for permeability.

**QED:** Both ligands have good QED scores (A: 0.68, B: 0.826), indicating drug-likeness. Ligand B is better.

**DILI:** Ligand B (43.622) has a lower DILI risk than Ligand A (68.36), which is a significant advantage.

**BBB:** Ligand B (85.498) has a much higher BBB penetration score than Ligand A (45.715). This is *critical* for a CNS target like DRD2.

**Caco-2 Permeability:** Ligand A (-5.621) has better Caco-2 permeability than Ligand B (-4.8). However, given the importance of CNS penetration, this is less crucial.

**Aqueous Solubility:** Ligand A (-3.138) has better aqueous solubility than Ligand B (-2.322).

**hERG Inhibition:** Both ligands have low hERG inhibition risk (A: 0.741, B: 0.165), which is good. Ligand B is better.

**Microsomal Clearance:** Ligand B (-3.967) has significantly lower microsomal clearance than Ligand A (-16.902), indicating better metabolic stability.

**In vitro Half-Life:** Ligand A (28.896) has a longer in vitro half-life than Ligand B (-1.731). This is a positive for Ligand A, but the other advantages of Ligand B are more impactful.

**P-gp Efflux:** Ligand A (0.132) has lower P-gp efflux than Ligand B (0.042). Lower is better, so Ligand A is slightly better here.

**Binding Affinity:** Ligand B (-9.1 kcal/mol) has a slightly better binding affinity than Ligand A (-8.3 kcal/mol). While both are good, the difference is significant enough to consider.

**Overall Assessment:**

Ligand B is the superior candidate. While Ligand A has slightly better Caco-2 permeability, in vitro half-life, and P-gp efflux, Ligand B excels in the most important parameters for a CNS-targeting GPCR: TPSA, BBB penetration, DILI risk, and metabolic stability (Cl_mic). The slightly better binding affinity of Ligand B further solidifies its advantage.



Output:
1
2025-04-17 05:32:59,256 - INFO - Reasoning:

Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (348.443 and 372.466 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (87.66) is better than Ligand B (98.58). Both are below the 90 A^2 threshold desirable for CNS targets, but A is closer to optimal.

**3. logP:** Ligand A (1.362) is slightly better than Ligand B (0.741), both are within the optimal 1-3 range, but B is closer to the lower limit which might affect permeability.

**4. H-Bond Donors:** Both ligands have 3 HBD, which is acceptable (<=5).

**5. H-Bond Acceptors:** Ligand A has 4 HBA, while Ligand B has 7. Ligand A is preferable as it's closer to the ideal of <=10.

**6. QED:** Both ligands have similar QED values (0.694 and 0.677), indicating good drug-likeness.

**7. DILI:** Ligand A (22.955) has a significantly lower DILI risk than Ligand B (58.976). This is a major advantage for Ligand A.

**8. BBB:** Ligand A (31.873) has a lower BBB percentile than Ligand B (43.505). While both are not ideal (>70), B is better for CNS penetration.

**9. Caco-2:** Both have negative Caco-2 values, which is unusual and requires further investigation. However, the magnitude of negativity is similar.

**10. Solubility:** Both have negative solubility values, also unusual and requiring further investigation. Again, the magnitude is similar.

**11. hERG:** Both ligands have low hERG inhibition liability (0.247 and 0.429), which is good.

**12. Cl_mic:** Ligand B (21.768) has a lower microsomal clearance than Ligand A (36.38), indicating better metabolic stability.

**13. t1/2:** Ligand B (-24.001) has a negative in vitro half-life, which is not possible. This is a red flag. Ligand A (18.066) has a reasonable half-life.

**14. Pgp:** Both ligands have very low Pgp efflux liability (0.045 and 0.074), which is favorable for CNS exposure.

**15. Binding Affinity:** Both ligands have similar binding affinities (-8.0 and -7.9 kcal/mol), which are excellent. The difference is negligible.

**Overall Assessment:**

While Ligand B has slightly better BBB penetration and metabolic stability, the significantly lower DILI risk and more reasonable in vitro half-life of Ligand A are crucial advantages. The negative values for Caco-2 and solubility are concerning for both, but the more significant issue is the impossible half-life for Ligand B. Given the GPCR-specific priorities, and the importance of minimizing toxicity (DILI) for CNS drugs, Ligand A is the more promising candidate.

Output:
1
2025-04-17 05:32:59,256 - INFO - Reasoning:

Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (349.471 and 343.387 Da) are within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (59.0) is excellent, falling well below the 90 Angstroms threshold for CNS targets. Ligand B (101.22) is higher, but still potentially acceptable, though less ideal.

**3. logP:** Both ligands have good logP values (2.857 and 1.364), falling within the optimal 1-3 range. Ligand A is slightly more lipophilic, which could aid in membrane permeability.

**4. H-Bond Donors:** Both have 1 HBD, which is within the acceptable limit of <=5.

**5. H-Bond Acceptors:** Ligand A has 4 HBA, and Ligand B has 6 HBA, both within the acceptable limit of <=10.

**6. QED:** Both ligands have similar QED values (0.822 and 0.814), indicating good drug-likeness.

**7. DILI:** Ligand A (18.224) has a significantly lower DILI risk than Ligand B (60.605). This is a major advantage for Ligand A.

**8. BBB:** Ligand B (74.37) has a better BBB penetration percentile than Ligand A (41.528). This is a critical factor for a CNS target like DRD2.

**9. Caco-2 Permeability:** Ligand A (-4.422) has a worse Caco-2 permeability than Ligand B (-4.78).

**10. Aqueous Solubility:** Both have negative solubility values, indicating poor solubility. Ligand A (-2.676) is slightly better than Ligand B (-2.047).

**11. hERG Inhibition:** Both ligands have low hERG inhibition liability (0.749 and 0.258), which is good.

**12. Microsomal Clearance:** Ligand B (56.445) has lower microsomal clearance than Ligand A (70.92), suggesting better metabolic stability.

**13. In vitro Half-Life:** Ligand A (15.195) has a longer in vitro half-life than Ligand B (-21.792).

**14. P-gp Efflux:** Ligand A (0.497) has lower P-gp efflux than Ligand B (0.053), which is favorable for CNS penetration.

**15. Binding Affinity:** Ligand B (-7.9 kcal/mol) has a slightly better binding affinity than Ligand A (-7.4 kcal/mol), a 0.5 kcal/mol difference.

**Overall Assessment:**

Ligand B has a better BBB score and binding affinity, which are crucial for a CNS GPCR target. However, Ligand A has a significantly lower DILI risk, better P-gp efflux, and a longer half-life. The difference in binding affinity (0.5 kcal/mol) is not substantial enough to outweigh the safety concerns associated with Ligand B's higher DILI risk. The better BBB of Ligand B is important, but the P-gp efflux of Ligand A is also beneficial for CNS exposure. Considering the balance of properties, and prioritizing safety (DILI) alongside CNS penetration, Ligand A appears to be the more promising candidate.

Output:
0
2025-04-17 05:32:59,256 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (348.49 and 349.43 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (75.27) is significantly better than Ligand B (104.46). For CNS targets, we want TPSA <= 90, and A is comfortably within that range, while B exceeds it. This is a significant advantage for A.

**3. logP:** Both ligands have good logP values (2.58 and 1.90), falling within the optimal 1-3 range.

**4. H-Bond Donors:** Ligand A (2) and Ligand B (3) are both acceptable, being <= 5.

**5. H-Bond Acceptors:** Ligand A (3) and Ligand B (5) are both acceptable, being <= 10.

**6. QED:** Both ligands have similar QED values (0.708 and 0.665), indicating good drug-likeness.

**7. DILI:** Ligand A (24.54) has a much lower DILI risk than Ligand B (46.92). This is a substantial advantage for A.

**8. BBB:** Ligand A (61.92) has a better BBB percentile than Ligand B (46.45). While both are below the ideal >70 for CNS targets, A is closer. This is a key factor for DRD2.

**9. Caco-2:** Both ligands have negative Caco-2 values (-4.932 and -4.999), which is unusual and suggests poor permeability. This is a concern for both.

**10. Solubility:** Both ligands have negative solubility values (-2.736 and -3.205), indicating poor aqueous solubility. This is a concern for both.

**11. hERG:** Both ligands have low hERG inhibition liability (0.119 and 0.143), which is good.

**12. Cl_mic:** Ligand A (9.564) has significantly lower microsomal clearance than Ligand B (16.248), indicating better metabolic stability.

**13. t1/2:** Ligand A (-7.097) has a much longer in vitro half-life than Ligand B (14.924). This is a significant advantage for A.

**14. Pgp:** Both ligands have low P-gp efflux liability (0.186 and 0.247), which is good.

**15. Binding Affinity:** Ligand A (-8.8) has a slightly better binding affinity than Ligand B (-8.1). While both are excellent (below -7.0), the 0.7 kcal/mol difference is meaningful.

**Overall Assessment:**

Ligand A is superior to Ligand B. It has a better TPSA, lower DILI risk, better BBB penetration, lower microsomal clearance, longer half-life, and slightly better binding affinity. While both have issues with Caco-2 and solubility, the improvements in ADME properties and CNS penetration for Ligand A make it the more promising drug candidate for targeting DRD2.

Output:
1
2025-04-17 05:32:59,257 - INFO - Reasoning:

Let's analyze Ligand A and Ligand B for their potential as DRD2 drug candidates, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight (MW):** Both ligands (344.415 and 354.523 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (84.42) is excellent, well below the 90 A^2 threshold for CNS targets. Ligand B (41.91) is even better, further increasing the likelihood of BBB penetration.

**3. logP:** Ligand A (1.706) is within the optimal 1-3 range. Ligand B (3.981) is approaching the upper limit but still acceptable.

**4. H-Bond Donors (HBD):** Both ligands have acceptable HBD counts (1 and 0, respectively), well below the 5 threshold.

**5. H-Bond Acceptors (HBA):** Both ligands have acceptable HBA counts (5 each), below the 10 threshold.

**6. QED:** Ligand A (0.899) has a very strong drug-like profile. Ligand B (0.752) is also good, but slightly lower.

**7. DILI:** Ligand A (63.125) has a moderate DILI risk. Ligand B (40.016) has a lower, more favorable DILI risk.

**8. BBB:** Ligand A (67.895) has a reasonable BBB penetration potential, but Ligand B (81.621) is significantly better, exceeding 80% and being highly desirable for a CNS target like DRD2.

**9. Caco-2 Permeability:** Both have negative values, which is unusual. Assuming these are logP-scaled values, lower values indicate poorer permeability. Ligand A (-4.692) is worse than Ligand B (-5.421).

**10. Aqueous Solubility:** Both have negative values, indicating poor solubility. Ligand A (-3.116) is slightly better than Ligand B (-3.028).

**11. hERG Inhibition:** Both ligands show very low hERG inhibition risk (0.196 and 0.805 respectively).

**12. Microsomal Clearance (Cl_mic):** Ligand A (32.254) has lower clearance, suggesting better metabolic stability than Ligand B (65.521).

**13. In vitro Half-Life:** Ligand A (-19.331) has a negative half-life, which is not physically possible. This is a red flag. Ligand B (12.168) has a reasonable half-life.

**14. P-gp Efflux:** Both ligands have low P-gp efflux liability (0.13 and 0.495 respectively).

**15. Binding Affinity:** Ligand B (-7.5 kcal/mol) has a significantly stronger binding affinity than Ligand A (-9.0 kcal/mol). This is a substantial advantage.

**Overall Assessment:**

While Ligand A has a better QED and lower Cl_mic, the negative half-life is a critical flaw. Ligand B excels in key areas for a CNS GPCR target: superior BBB penetration, strong binding affinity, and a reasonable half-life. The slightly higher DILI risk and lower QED are less concerning given the strong affinity and BBB properties. The Caco-2 permeability is poor for both, but this is less critical for a CNS target.

Output:
1
2025-04-17 05:32:59,257 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 drug candidates, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (342.483 and 340.427 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (40.62) is significantly better than Ligand B (67.23). For CNS targets, we want TPSA <= 90, and ideally closer to 60. Ligand A is much closer to this ideal.

**3. logP:** Both ligands have good logP values (3.123 and 2.06), falling within the optimal 1-3 range.

**4. H-Bond Donors:** Ligand A (0) is preferable to Ligand B (1). Fewer HBDs generally improve permeability.

**5. H-Bond Acceptors:** Ligand A (2) is better than Ligand B (4). Lower HBA counts are generally favored for CNS penetration.

**6. QED:** Both ligands have good QED scores (0.74 and 0.806), indicating good drug-like properties.

**7. DILI:** Ligand A (25.281) has a lower DILI risk than Ligand B (32.028), which is desirable.

**8. BBB:** This is a critical parameter for a CNS target like DRD2. Ligand A (82.823) has a significantly higher BBB percentile than Ligand B (55.099). A value >70 is desirable, and Ligand A is closer to that threshold.

**9. Caco-2 Permeability:** Ligand A (-4.781) and Ligand B (-5.048) both have negative values, which is unusual and suggests poor permeability. However, the difference is minimal.

**10. Aqueous Solubility:** Ligand A (-3.915) and Ligand B (-2.425) both have negative values, indicating poor solubility. This is a concern, but can be addressed with formulation strategies.

**11. hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.249 and 0.238).

**12. Microsomal Clearance:** Ligand B (13.956) has lower microsomal clearance than Ligand A (43.245), suggesting better metabolic stability.

**13. In vitro Half-Life:** Ligand B (-12.353) has a negative half-life, which is not possible. This is a significant red flag and suggests a very rapid metabolism or an error in the data. Ligand A (13.81) has a reasonable half-life.

**14. P-gp Efflux:** Both ligands have low P-gp efflux liability (0.276 and 0.042). Ligand B is slightly better here.

**15. Binding Affinity:** Ligand B (-9.0) has a slightly better binding affinity than Ligand A (-8.5). However, the difference is only 0.5 kcal/mol, which is not substantial enough to overcome the other significant drawbacks of Ligand B.

**Overall Assessment:**

Ligand A is the more promising candidate. It has a much better TPSA, significantly higher BBB penetration, a lower DILI risk, and a reasonable in vitro half-life. While Ligand B has slightly better affinity and P-gp efflux, its very poor (and impossible) half-life and lower BBB penetration are major concerns. The difference in binding affinity is not large enough to outweigh the other advantages of Ligand A, especially considering the importance of CNS penetration for a DRD2 target.

Output:
1
2025-04-17 05:32:59,257 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight (MW):** Both ligands (348.368 and 350.478 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (32.34) is significantly better than Ligand B (49.41). For CNS targets, we want TPSA <= 90, and ideally closer to 90. Ligand A is much closer to this ideal.

**3. logP:** Both ligands have acceptable logP values (4.498 and 3.285), falling within the 1-3 range, although Ligand A is a bit high.

**4. H-Bond Donors (HBD):** Both have 1 HBD, which is good.

**5. H-Bond Acceptors (HBA):** Both have 2 HBA, which is good.

**6. QED:** Both ligands have reasonable QED scores (0.834 and 0.799), indicating good drug-like properties.

**7. DILI:** Ligand A (56.689) has a higher DILI risk than Ligand B (15.2). This is a significant drawback for Ligand A.

**8. BBB:** Both ligands have excellent BBB penetration (90.617 and 96.045), exceeding the desirable >70 threshold for CNS targets.

**9. Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and suggests poor permeability. However, these values are on a strange scale, so it's hard to interpret.

**10. Aqueous Solubility:** Both have negative solubility values, which is also unusual and suggests poor solubility. Again, the scale is unclear.

**11. hERG Inhibition:** Ligand A (0.946) has a slightly higher hERG risk than Ligand B (0.604), but both are reasonably low.

**12. Microsomal Clearance (Cl_mic):** Ligand B (43.834) has a lower (better) microsomal clearance than Ligand A (35.856), indicating greater metabolic stability.

**13. In vitro Half-Life:** Ligand B (-2.493) has a longer in vitro half-life than Ligand A (1.662).

**14. P-gp Efflux:** Ligand A (0.554) has lower P-gp efflux than Ligand B (0.105), which is favorable for CNS penetration.

**15. Binding Affinity:** Ligand A (-10.4 kcal/mol) has a significantly stronger binding affinity than Ligand B (-8.7 kcal/mol). This is a substantial advantage.

**Overall Assessment:**

Ligand A has a much stronger binding affinity, which is a critical factor for GPCRs. It also has better TPSA and P-gp efflux. However, its DILI risk is considerably higher, and its metabolic stability is lower. Ligand B has a better safety profile (lower DILI) and better metabolic stability. The solubility and Caco-2 values are problematic for both, but the affinity difference is substantial. Given the importance of affinity for GPCRs, and the acceptable BBB penetration of both, the stronger affinity of Ligand A outweighs its drawbacks, *provided* the DILI risk can be mitigated through further optimization.

Output:
1
2025-04-17 05:32:59,257 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (379.913 Da) is slightly lower, which is generally favorable for permeability. Ligand B (402.607 Da) is also acceptable.

**TPSA:** Ligand A (71.09) is better than Ligand B (58.64) as it is closer to the ideal range for CNS targets (<=90).

**logP:** Both ligands have good logP values (A: 3.285, B: 2.385), falling within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A (HBD=2, HBA=4) and Ligand B (HBD=1, HBA=6) both have reasonable numbers of H-bond donors and acceptors, well within the recommended limits.

**QED:** Both ligands have good QED scores (A: 0.572, B: 0.643), indicating good drug-like properties.

**DILI:** Ligand A (68.088) has a higher DILI risk than Ligand B (36.991). This is a significant drawback for Ligand A.

**BBB:** Ligand B (56.611) has a better BBB penetration percentile than Ligand A (47.15). While neither is >70, Ligand B is closer. This is crucial for a CNS target like DRD2.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.07 and -5.08), which is unusual and suggests very poor permeability. This is a major concern for both.

**Aqueous Solubility:** Both ligands have negative solubility values (-4.22 and -3.095), indicating very poor solubility. This is a significant issue for both, potentially hindering bioavailability.

**hERG Inhibition:** Both ligands have low hERG inhibition liability (A: 0.297, B: 0.356), which is good.

**Microsomal Clearance:** Ligand B (66.756) has a slightly lower microsomal clearance than Ligand A (74.323), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand B (12.39 hours) has a significantly longer half-life than Ligand A (36.84 hours). This is a substantial advantage for Ligand B.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (A: 0.328, B: 0.183). Ligand B is slightly better here.

**Binding Affinity:** Ligand A (-8.7 kcal/mol) has a significantly stronger binding affinity than Ligand B (-7.4 kcal/mol). This is a substantial advantage for Ligand A, potentially outweighing some of its ADME drawbacks.

**Overall Assessment:**

Ligand A has a significantly better binding affinity, which is a major plus. However, it suffers from higher DILI risk and lower BBB penetration. Ligand B has better ADME properties (lower DILI, better BBB, longer half-life, lower P-gp efflux), but its binding affinity is weaker. Given the GPCR-specific priorities, and the fact that the affinity difference is substantial (>1.5 kcal/mol), the stronger binding of Ligand A is likely to be more important, *assuming* the DILI risk can be mitigated through structural modifications. The poor Caco-2 and solubility are concerning for both, but can potentially be addressed with formulation strategies.

Output:
0
2025-04-17 05:32:59,258 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (346.431 and 348.443 Da) fall comfortably within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (93.51) is slightly higher than Ligand B (67.87). For CNS targets, we ideally want TPSA <= 90. Ligand A is borderline, while Ligand B is well within the desired range. This favors Ligand B.

**3. logP:** Both ligands have good logP values (1.546 and 1.421), falling within the optimal 1-3 range.

**4. H-Bond Donors:** Both have 1 HBD, which is acceptable.

**5. H-Bond Acceptors:** Ligand A has 6 HBA, and Ligand B has 4. Both are below the acceptable limit of 10.

**6. QED:** Ligand A (0.873) has a significantly higher QED score than Ligand B (0.582), indicating better overall drug-likeness. This favors Ligand A.

**7. DILI:** Ligand A (42.187) has a slightly higher DILI risk than Ligand B (35.052), but both are below the concerning threshold of 60.

**8. BBB:** Ligand A (88.872) has a significantly better BBB penetration prediction than Ligand B (71.501). This is a critical factor for a CNS target like DRD2, strongly favoring Ligand A.

**9. Caco-2:** Both have negative Caco-2 values (-4.585 and -4.587), which is unusual and difficult to interpret without further context. However, it doesn't appear to be a major differentiating factor.

**10. Solubility:** Both have negative solubility values (-2.879 and -2.592), also unusual. Again, not a major differentiator.

**11. hERG:** Both have very low hERG inhibition liability (0.86 and 0.138), indicating a low risk of cardiotoxicity. Ligand B is slightly better here.

**12. Cl_mic:** Ligand A (3.998) has a lower microsomal clearance than Ligand B (29.301), suggesting better metabolic stability. This favors Ligand A.

**13. t1/2:** Ligand A (40.774) has a much longer in vitro half-life than Ligand B (-3.507), which is a significant advantage. This favors Ligand A.

**14. Pgp:** Ligand A (0.093) has lower P-gp efflux liability than Ligand B (0.047), indicating better potential for CNS exposure. This favors Ligand A.

**15. Binding Affinity:** Ligand B (-7.3 kcal/mol) has a slightly better binding affinity than Ligand A (-6.7 kcal/mol). This is a 0.6 kcal/mol difference, which is notable, but may not outweigh other ADME considerations.

**Overall Assessment:**

While Ligand B has a slightly better binding affinity and marginally lower hERG risk, Ligand A is significantly superior in terms of BBB penetration, metabolic stability (lower Cl_mic, longer t1/2), P-gp efflux, and QED.  The TPSA of Ligand A is borderline, but the substantial advantages in CNS penetration and metabolic properties outweigh this minor drawback. Given the GPCR-specific priorities for DRD2 (BBB, logP, Pgp, TPSA, and affinity), Ligand A is the more promising drug candidate.

Output:
1
2025-04-17 05:32:59,258 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (350.419 and 351.466 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (116.48) is higher than the preferred <90 for CNS targets, while Ligand B (58.36) is well within the range. This is a significant advantage for Ligand B.

**3. logP:** Ligand A (-0.49) is below the optimal range of 1-3, potentially hindering permeation. Ligand B (2.945) is nearly ideal.

**4. H-Bond Donors:** Ligand A (4) is acceptable, while Ligand B (1) is even better, potentially improving permeability.

**5. H-Bond Acceptors:** Both ligands (A: 6, B: 4) are within the acceptable limit of <=10.

**6. QED:** Both ligands have good QED scores (A: 0.495, B: 0.696), indicating reasonable drug-likeness. Ligand B is better.

**7. DILI:** Both ligands have low DILI risk (A: 23.769, B: 19.969), which is positive.

**8. BBB:** Ligand A (28.81) has a poor BBB percentile, making CNS penetration unlikely. Ligand B (78.79) has a very good BBB percentile, crucial for a DRD2 ligand.

**9. Caco-2 Permeability:** Ligand A (-5.464) has very poor Caco-2 permeability, while Ligand B (-4.583) is slightly better, but still not ideal.

**10. Aqueous Solubility:** Both ligands have poor aqueous solubility (-1.552 and -2.578 respectively).

**11. hERG Inhibition:** Both ligands have low hERG inhibition risk (A: 0.106, B: 0.718).

**12. Microsomal Clearance:** Ligand A (12.119) has lower clearance than Ligand B (51.681), suggesting better metabolic stability.

**13. In vitro Half-Life:** Ligand A (-19.505) has a negative half-life, which is not physically possible and indicates a problem with the data or the molecule's stability. Ligand B (-6.967) is also negative, but less so.

**14. P-gp Efflux:** Both ligands have very low P-gp efflux liability (A: 0.012, B: 0.344), which is favorable for CNS penetration.

**15. Binding Affinity:** Both ligands have similar, strong binding affinities (A: -8.4 kcal/mol, B: -7.4 kcal/mol). Ligand A is slightly better.

**Overall Assessment:**

Despite Ligand A having a slightly better binding affinity, Ligand B is the superior candidate. The critical factors are the significantly better BBB penetration (78.79 vs 28.81) and TPSA (58.36 vs 116.48) for a CNS target like DRD2. Ligand A's poor BBB and high TPSA, combined with its low logP and poor Caco-2 permeability, make it unlikely to reach the target in the brain. The negative half-life values are concerning for both, but less critical than the permeability issues with Ligand A.

Output:
1
2025-04-17 05:32:59,258 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (381.738 Da) is slightly higher than Ligand B (352.41 Da), but both are acceptable.

**TPSA:** Ligand A (109.7) is higher than Ligand B (83.56). For CNS targets, we prefer TPSA <= 90. Ligand B is better in this regard.

**logP:** Both ligands have good logP values (Ligand A: 2.474, Ligand B: 1.677), falling within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Both have 2 HBD and 5/4 HBA respectively, which are within acceptable limits.

**QED:** Both ligands have similar QED values (A: 0.615, B: 0.662), indicating good drug-likeness.

**DILI:** Ligand A (50.989) has a slightly higher DILI risk than Ligand B (41.915), but both are below the concerning threshold of 60.

**BBB:** Both ligands exhibit excellent BBB penetration (Ligand A: 81.582, Ligand B: 85.072), exceeding the desirable >70% threshold for CNS targets.

**Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and suggests a potential issue with intestinal absorption. However, the scale is not specified, so it's difficult to interpret.

**Aqueous Solubility:** Both have negative solubility values, indicating poor aqueous solubility. This is a concern for formulation and bioavailability.

**hERG Inhibition:** Both ligands show low hERG inhibition liability (Ligand A: 0.679, Ligand B: 0.291), which is favorable.

**Microsomal Clearance:** Ligand A (7.606) has significantly lower microsomal clearance than Ligand B (51.601), indicating better metabolic stability.

**In vitro Half-Life:** Ligand A (4.461) has a longer in vitro half-life than Ligand B (-14.961), which is a significant advantage. The negative value for Ligand B is concerning.

**P-gp Efflux:** Ligand A (0.464) has lower P-gp efflux liability than Ligand B (0.035), which is beneficial for CNS exposure.

**Binding Affinity:** Ligand B (-7.3) has a slightly better binding affinity than Ligand A (-7.2), but the difference is small (0.1 kcal/mol).

**Overall Assessment:**

While Ligand B has a slightly better TPSA and binding affinity, Ligand A is superior in several critical ADME properties. Specifically, Ligand A demonstrates significantly better metabolic stability (lower Cl_mic, longer t1/2) and lower P-gp efflux, both crucial for CNS drug development. The slightly higher DILI risk for Ligand A is less concerning than the poor metabolic stability and potential efflux issues of Ligand B. The negative solubility and Caco-2 values are concerning for both, but can be addressed with formulation strategies. Given the GPCR-specific priorities, the improved ADME profile of Ligand A outweighs the minor affinity difference.

Output:
1
2025-04-17 05:32:59,258 - INFO - Reasoning:

Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (354.519 Da and 346.391 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (32.34) is excellent, well below the 90 A^2 threshold for CNS targets. Ligand B (109.22) is higher, but still potentially acceptable, though less ideal.

**logP:** Ligand A (4.747) is slightly high, potentially leading to solubility issues or off-target interactions. Ligand B (-0.772) is too low, which could hinder membrane permeability and brain penetration.

**H-Bond Donors/Acceptors:** Ligand A (HBD=1, HBA=3) is optimal. Ligand B (HBD=2, HBA=6) is acceptable, but the higher HBA count could slightly impact permeability.

**QED:** Both ligands have similar QED values (0.76 and 0.681), indicating good drug-likeness.

**DILI:** Ligand A (44.63) has a lower DILI risk than Ligand B (56.689), which is preferable.

**BBB:** This is a critical parameter for DRD2. Ligand A (93.602) has excellent BBB penetration potential. Ligand B (58.666) is significantly lower, raising concerns about reaching the target in the CNS.

**Caco-2 Permeability:** Both have negative values, indicating poor permeability. However, these values are on a different scale and difficult to directly compare.

**Aqueous Solubility:** Both have negative values, indicating poor solubility.

**hERG Inhibition:** Ligand A (0.964) shows a slightly higher risk of hERG inhibition than Ligand B (0.041), but both are relatively low.

**Microsomal Clearance:** Ligand A (103.529) has higher clearance, suggesting faster metabolism. Ligand B (-6.464) has negative clearance, which is not physically possible and likely an error in the data. This is a major red flag.

**In vitro Half-Life:** Ligand A (50.768) has a reasonable half-life. Ligand B (6.556) has a very short half-life, indicating rapid degradation.

**P-gp Efflux:** Ligand A (0.77) shows moderate P-gp efflux. Ligand B (0.013) shows very low P-gp efflux, which is favorable for CNS penetration.

**Binding Affinity:** Ligand A (-9.7 kcal/mol) has significantly stronger binding affinity than Ligand B (-8.3 kcal/mol). The 1.4 kcal/mol difference is substantial and can outweigh some ADME drawbacks.

**Overall Assessment:**

Ligand A excels in key areas for a CNS-targeting GPCR ligand: excellent TPSA, good BBB penetration, and significantly stronger binding affinity. While its logP is slightly high and clearance is moderate, the strong binding and favorable CNS penetration are compelling. Ligand B has a problematic negative clearance value, a poor BBB score, and weaker binding affinity, making it a less attractive candidate.

Output:
1
2025-04-17 05:32:59,259 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (414.296 Da) is slightly higher, but acceptable. Ligand B (348.462 Da) is also good.

**TPSA:** Ligand A (81.7) is borderline for CNS targets (ideally <90), but still reasonable. Ligand B (41.57) is excellent, well below the 90 threshold.

**logP:** Both ligands have logP values around 4 (A: 3.932, B: 4.125). This is slightly above the optimal range of 1-3, potentially leading to solubility issues or off-target interactions, but not dramatically so.

**H-Bond Donors/Acceptors:** Both have acceptable HBD (1) and Ligand A has 5 HBA, while Ligand B has 2 HBA. Both are within the recommended limits.

**QED:** Both ligands have good QED scores (A: 0.714, B: 0.84), indicating drug-like properties.

**DILI:** Ligand A has a DILI risk of 64.521, which is moderately high. Ligand B has a much lower DILI risk of 18.961, which is very favorable.

**BBB:** Ligand B (94.378) has excellent BBB penetration, exceeding the desirable >70% threshold. Ligand A (68.941) is below this threshold, which is a significant drawback for a CNS target.

**Caco-2 Permeability:** Both have negative Caco-2 values (-4.467 and -4.39). These values are unusual and likely indicate poor permeability. However, negative values are often artifacts of the prediction method.

**Aqueous Solubility:** Both have negative solubility values (-4.935 and -3.547), which is also concerning. Similar to Caco-2, these values are likely prediction artifacts.

**hERG Inhibition:** Ligand A (0.505) has a slightly higher hERG risk than Ligand B (0.844), but both are relatively low.

**Microsomal Clearance:** Ligand A (102.18) has a higher microsomal clearance than Ligand B (41.629), suggesting lower metabolic stability.

**In vitro Half-Life:** Ligand B (16.627 hours) has a longer half-life than Ligand A (37.394 hours).

**P-gp Efflux:** Ligand A (0.14) has lower P-gp efflux than Ligand B (0.451), which is beneficial for CNS exposure.

**Binding Affinity:** Ligand B (-8.5 kcal/mol) has a slightly better binding affinity than Ligand A (-7.8 kcal/mol), although both are strong binders. The 1.5 kcal/mol difference is significant.

**Overall Assessment:**

Considering the GPCR-specific priorities, Ligand B is the superior candidate. Its excellent BBB penetration (94.378), lower DILI risk (18.961), better metabolic stability (lower Cl_mic), longer half-life, and slightly improved binding affinity (-8.5 kcal/mol) outweigh the slightly higher P-gp efflux. While both ligands have questionable solubility and permeability predictions, the CNS target makes BBB penetration paramount. Ligand A's lower BBB score is a major disadvantage.



Output:
1
2025-04-17 05:32:59,259 - INFO - Batch 207 complete. Total preferences: 3312
2025-04-17 05:32:59,259 - INFO - Processing batch 208/512...
2025-04-17 05:33:40,296 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (354.426 and 349.431 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (76.46) is significantly better than Ligand B (104.46). For CNS targets, we want TPSA <= 90, and A is comfortably within this range, while B is above.

**3. logP:** Both ligands have good logP values (1.631 and 1.155), falling within the optimal 1-3 range.

**4. H-Bond Donors:** Ligand A (1) is better than Ligand B (3). Lower HBDs generally improve permeability.

**5. H-Bond Acceptors:** Both ligands have 5 HBA, which is acceptable (<=10).

**6. QED:** Both ligands have good QED scores (0.596 and 0.685), indicating drug-like properties.

**7. DILI:** Both ligands have low DILI risk (39.744 and 34.238), both well below the 40 threshold.

**8. BBB:** This is a crucial parameter for a CNS target like DRD2. Ligand A has a significantly higher BBB penetration percentile (91.431) compared to Ligand B (58.821). A value >70 is desirable, and A meets this criterion while B does not.

**9. Caco-2 Permeability:** Both have negative values (-5.019 and -5.157), which is unusual and difficult to interpret without knowing the scale. However, the values are very similar.

**10. Aqueous Solubility:** Both have negative values (-2.095 and -2.075), again unusual and difficult to interpret. They are very similar.

**11. hERG Inhibition:** Both ligands show very low hERG inhibition liability (0.536 and 0.044), which is excellent.

**12. Microsomal Clearance:** Ligand A (1.917) has a much lower microsomal clearance than Ligand B (41.904). Lower clearance indicates better metabolic stability.

**13. In vitro Half-Life:** Ligand A (-8.24) has a much longer in vitro half-life than Ligand B (-22.882). This is a significant advantage.

**14. P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.047 and 0.052), which is good.

**15. Binding Affinity:** Both ligands have comparable and excellent binding affinities (-7.8 and -7.9 kcal/mol). The difference is negligible.

**Overall Assessment:**

Ligand A is significantly better than Ligand B. While both have good potency, Ligand A excels in crucial ADME properties for a CNS drug targeting a GPCR. Specifically, its superior TPSA, BBB penetration, lower microsomal clearance, and longer half-life make it a much more promising candidate. The similar logP, HBA, DILI, hERG, and P-gp values further support this conclusion.

Output:
1
2025-04-17 05:33:40,297 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B based on the provided guidelines, prioritizing GPCR-specific properties (BBB, logP, Pgp, TPSA, and affinity) for DRD2.

**Molecular Weight:** Both ligands (351.403 and 353.463 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (111.89) is slightly above the optimal <90 for CNS targets, but still reasonable. Ligand B (87.74) is excellent, well below 90.

**logP:** Ligand A (-0.411) is a bit low, potentially hindering permeability. Ligand B (1.522) is within the optimal 1-3 range. This is a significant advantage for Ligand B.

**H-Bond Donors/Acceptors:** Both have 2 HBD and are within acceptable limits. Ligand A has 6 HBA, while Ligand B has 4. Both are acceptable (<10).

**QED:** Both ligands have acceptable QED scores (0.673 and 0.583, both > 0.5).

**DILI:** Ligand A (28.306) has a lower DILI risk than Ligand B (22.8), which is favorable.

**BBB:** This is critical for a CNS target. Ligand A (29.391) has a very poor BBB percentile. Ligand B (82.435) is excellent, exceeding the >70 desirable threshold. This is a major advantage for Ligand B.

**Caco-2 Permeability:** Ligand A (-4.867) indicates poor permeability. Ligand B (-4.491) is slightly better, but still not great.

**Aqueous Solubility:** Both ligands have poor aqueous solubility (-1.781 and -2.152).

**hERG:** Both ligands have low hERG risk (0.179 and 0.311).

**Microsomal Clearance:** Ligand A (-7.121) indicates very low clearance and excellent metabolic stability. Ligand B (59.715) suggests faster clearance, which is a drawback.

**In vitro Half-Life:** Ligand A (22.357) has a reasonable half-life. Ligand B (-25.535) has a negative half-life, which is not physically possible and likely indicates an issue with the data or prediction.

**P-gp Efflux:** Ligand A (0.007) has very low P-gp efflux, which is excellent for CNS penetration. Ligand B (0.047) is also low, but slightly higher.

**Binding Affinity:** Ligand A (-0.0) has a very weak binding affinity. Ligand B (-6.9) has a strong binding affinity, well below the -7.0 threshold. This is a significant advantage for Ligand B.

**Overall Assessment:**

Ligand B is clearly the superior candidate. While Ligand A has better DILI and metabolic stability, Ligand B's significantly better BBB penetration, logP, and *much* stronger binding affinity outweigh these drawbacks. The negative half-life for Ligand B is a red flag, but the strong affinity suggests it's worth investigating further to determine the source of this prediction. Ligand A's extremely poor BBB penetration and weak affinity make it unlikely to be a viable CNS drug candidate.

Output:
1
2025-04-17 05:33:40,297 - INFO - Reasoning:

Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (343.471 and 353.463 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (44.81) is significantly better than Ligand B (87.74). For CNS targets, TPSA should be <= 90, and A is comfortably within this range, while B is approaching the upper limit. This favors A.

**3. logP:** Ligand A (2.505) is optimal (1-3). Ligand B (0.683) is a bit low, potentially hindering permeation. This favors A.

**4. H-Bond Donors:** Both ligands have acceptable HBD counts (1 and 2, respectively), well below the limit of 5.

**5. H-Bond Acceptors:** Both ligands have acceptable HBA counts (3 and 4, respectively), well below the limit of 10.

**6. QED:** Both ligands have similar and good QED values (0.583 and 0.659), indicating good drug-like properties.

**7. DILI:** Ligand A (12.33) has a lower DILI risk than Ligand B (10.702), which is preferable.

**8. BBB:** Ligand A (71.539) has a better BBB penetration percentile than Ligand B (64.25). While both are reasonably good, A is closer to the desirable >70 threshold for CNS targets. This strongly favors A.

**9. Caco-2:** Both have negative Caco-2 values, which is unusual and difficult to interpret without knowing the scale. However, the values are similar and don't strongly differentiate the two.

**10. Solubility:** Both have negative solubility values, again making comparison difficult. The values are similar.

**11. hERG:** Both ligands have low hERG inhibition liability (0.839 and 0.2), which is good.

**12. Cl_mic:** Ligand A (-6.802) has a *much* lower (better) microsomal clearance than Ligand B (-3.423). This suggests greater metabolic stability for A. This is a significant advantage for A.

**13. t1/2:** Ligand A (0.251) has a very short in vitro half-life, while Ligand B (-16.652) has a very long in vitro half-life. This is a significant advantage for B.

**14. Pgp:** Both ligands have very low P-gp efflux liability (0.048 and 0.012), which is good for CNS penetration.

**15. Binding Affinity:** Ligand B (-7.5) has a slightly better binding affinity than Ligand A (-7.3). However, the difference is only 0.2 kcal/mol, which is not substantial enough to outweigh the numerous advantages of Ligand A.

**Overall Assessment:**

Ligand A is the superior candidate. It excels in critical GPCR properties like TPSA, logP, BBB penetration, and metabolic stability (Cl_mic). While Ligand B has slightly better affinity and a longer half-life, the advantages of A in terms of CNS penetration and metabolic stability are more important for a DRD2 ligand targeting CNS disorders. The short half-life of A could be addressed through structural modifications during lead optimization.

Output:
1
2025-04-17 05:33:40,297 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (378.925 and 348.531 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Both ligands have a TPSA of 41.57, which is acceptable, but ideally should be lower for CNS penetration (target <90).

**3. logP:** Ligand A (4.443) is slightly higher than Ligand B (3.351). While both are within the optimal 1-3 range, Ligand A is approaching the upper limit and could potentially have solubility issues.

**4. H-Bond Donors:** Both have 1 HBD, which is good.

**5. H-Bond Acceptors:** Both have 3 HBA, which is good.

**6. QED:** Both ligands have high QED scores (0.807 and 0.847), indicating good drug-like properties.

**7. DILI:** Ligand A (48.391) has a higher DILI risk than Ligand B (6.049). This is a significant advantage for Ligand B.

**8. BBB:** Ligand B (94.184) has a substantially better BBB penetration score than Ligand A (78.48). This is *critical* for a CNS target like DRD2.

**9. Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and potentially problematic. However, the values are similar (-4.805 vs -4.653).

**10. Aqueous Solubility:** Both have negative solubility values, which is also unusual. Again, the values are similar (-4.82 vs -4.134).

**11. hERG Inhibition:** Both have low hERG inhibition liability (0.81 and 0.705), which is good.

**12. Microsomal Clearance:** Ligand A (63.814) has a higher microsomal clearance than Ligand B (41.74), indicating lower metabolic stability.

**13. In vitro Half-Life:** Ligand B (7.31) has a longer in vitro half-life than Ligand A (18.794). This is a significant advantage.

**14. P-gp Efflux:** Ligand A (0.632) has higher P-gp efflux than Ligand B (0.055). Lower P-gp efflux is preferred for CNS penetration, giving Ligand B a clear advantage.

**15. Binding Affinity:** Ligand A (-9.4 kcal/mol) has a significantly stronger binding affinity than Ligand B (-6.7 kcal/mol). This is a substantial advantage for Ligand A. The difference of 2.7 kcal/mol is large enough to potentially overcome some ADME liabilities.

**Overall Assessment:**

While Ligand A boasts a much stronger binding affinity, Ligand B has a significantly better safety profile (lower DILI), better BBB penetration, lower P-gp efflux, and improved metabolic stability (lower Cl_mic, longer t1/2). For a CNS target like DRD2, BBB penetration and minimizing efflux are paramount. The substantial difference in binding affinity *might* be enough to overcome the ADME advantages of Ligand B, but the improved CNS properties of Ligand B are very compelling. Given the importance of CNS penetration for DRD2, and the relatively small difference in solubility/permeability, Ligand B is the more promising candidate.

Output:
1
2025-04-17 05:33:40,297 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (357.479 and 351.491 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (71.09) is slightly higher than Ligand B (67.59). Both are below the 90 A^2 threshold desirable for CNS targets, but Ligand B is preferable.

**3. logP:** Both ligands have good logP values (3.0 and 2.769), falling within the optimal 1-3 range.

**4. H-Bond Donors:** Ligand A (2) is slightly higher than Ligand B (1), but both are within the acceptable limit of <=5.

**5. H-Bond Acceptors:** Ligand A (4) and Ligand B (5) are both within the acceptable limit of <=10.

**6. QED:** Both ligands have acceptable QED values (0.827 and 0.782), indicating good drug-like properties.

**7. DILI:** Ligand A (65.684) has a higher DILI risk than Ligand B (31.059). This is a significant advantage for Ligand B.

**8. BBB:** Ligand A (61.497) has a slightly better BBB penetration percentile than Ligand B (54.362). However, both are below the desirable >70 for CNS targets.

**9. Caco-2 Permeability:** Ligand A (-4.819) has worse Caco-2 permeability than Ligand B (-4.57). Lower values are less desirable.

**10. Aqueous Solubility:** Ligand A (-3.784) has worse aqueous solubility than Ligand B (-2.404). Lower values are less desirable.

**11. hERG Inhibition:** Ligand A (0.139) has a slightly better hERG inhibition profile than Ligand B (0.482), meaning lower risk of cardiotoxicity.

**12. Microsomal Clearance:** Ligand A (47.891) has lower microsomal clearance than Ligand B (40.162), suggesting better metabolic stability.

**13. In vitro Half-Life:** Ligand A (-3.524) has a much worse in vitro half-life than Ligand B (39.692). This is a substantial advantage for Ligand B.

**14. P-gp Efflux:** Ligand A (0.156) has slightly better P-gp efflux liability than Ligand B (0.158), meaning it's less likely to be pumped out of the brain.

**15. Binding Affinity:** Ligand A (-9.9 kcal/mol) has a significantly stronger binding affinity than Ligand B (-6.3 kcal/mol). This is a >3.5 kcal/mol advantage, which can outweigh some ADME drawbacks.

**Overall Assessment:**

While Ligand A has a superior binding affinity, Ligand B demonstrates a much more favorable ADME profile, specifically regarding DILI risk, in vitro half-life, and aqueous solubility. The stronger binding affinity of Ligand A is attractive, but the poor half-life and higher DILI risk are concerning. For a CNS target like DRD2, a balance between potency and good brain penetration/safety is crucial. Ligand B's better ADME properties, particularly the lower DILI and improved half-life, make it a more promising starting point for optimization, even with the slightly lower affinity.

Output:
1
2025-04-17 05:33:40,297 - INFO - Reasoning:

Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (346.431 and 349.362 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (77.41) is significantly better than Ligand B (117.59). For CNS targets, we want TPSA <= 90, and Ligand A is comfortably within this range, while Ligand B is above.

**3. logP:** Both ligands have good logP values (1.782 and 1.078), falling within the optimal 1-3 range.

**4. H-Bond Donors:** Ligand A (2) is preferable to Ligand B (4). Lower HBD generally improves permeability.

**5. H-Bond Acceptors:** Both ligands have 5 HBA, which is acceptable (<=10).

**6. QED:** Ligand A (0.726) has a higher QED score than Ligand B (0.558), indicating a more drug-like profile.

**7. DILI:** Ligand A (32.765) has a lower DILI risk than Ligand B (48.313), which is favorable. Both are below the concerning threshold of 60.

**8. BBB:** Ligand A (60.644) has a better BBB penetration percentile than Ligand B (52.074). While both are below the ideal >70 for CNS targets, A is closer.

**9. Caco-2 Permeability:** Ligand A (-4.928) has better Caco-2 permeability than Ligand B (-5.36). Higher values are better.

**10. Aqueous Solubility:** Ligand A (-2.128) has better aqueous solubility than Ligand B (-2.59). Higher values are better.

**11. hERG Inhibition:** Ligand A (0.288) has a lower hERG inhibition liability than Ligand B (0.627), which is a significant advantage.

**12. Microsomal Clearance:** Ligand A (28.977) has lower microsomal clearance than Ligand B (7.925), suggesting better metabolic stability.

**13. In vitro Half-Life:** Ligand A (41.038) has a longer in vitro half-life than Ligand B (45.444).

**14. P-gp Efflux:** Ligand A (0.019) has significantly lower P-gp efflux liability than Ligand B (0.104). Lower efflux is crucial for CNS exposure.

**15. Binding Affinity:** Ligand B (-9.2) has a slightly stronger binding affinity than Ligand A (-8.0). However, the difference is not substantial enough to overcome the numerous ADME advantages of Ligand A.

**Overall Assessment:**

Ligand A consistently outperforms Ligand B across most critical ADME properties, especially TPSA, BBB, P-gp efflux, hERG, and metabolic stability. While Ligand B has slightly better binding affinity, the overall profile of Ligand A is far more promising for development as a CNS-active drug targeting DRD2. The lower TPSA and P-gp efflux of Ligand A are particularly important for brain penetration.



Output:
0
2025-04-17 05:33:40,297 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B based on the provided guidelines, prioritizing GPCR-specific properties (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (350.478 and 347.375 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (49.41) is excellent, well below the 90 A^2 threshold for CNS targets. Ligand B (116.42) is higher but still potentially acceptable, though less ideal.

**logP:** Ligand A (3.512) is optimal (1-3). Ligand B (-0.259) is significantly lower, which is a major concern for CNS penetration as it may struggle to cross cell membranes.

**H-Bond Donors/Acceptors:** Ligand A (1 HBD, 2 HBA) is favorable. Ligand B (3 HBD, 5 HBA) is slightly higher, but still within acceptable limits.

**QED:** Both ligands have similar QED values (0.797 and 0.694), indicating good drug-likeness.

**DILI:** Ligand A (20.822) has a much lower DILI risk than Ligand B (53.936), which is a significant advantage.

**BBB:** Ligand A (96.161) has excellent BBB penetration potential, exceeding the desirable >70 percentile. Ligand B (53.044) is considerably lower, raising concerns about reaching the CNS target.

**Caco-2 Permeability:** Ligand A (-4.674) is negative, which is unusual and potentially problematic, suggesting poor permeability. Ligand B (-5.36) is also negative and similarly concerning.

**Aqueous Solubility:** Ligand A (-3.903) and Ligand B (-2.616) both have negative solubility values, indicating poor aqueous solubility. This could pose formulation challenges.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.644 and 0.06), which is positive.

**Microsomal Clearance:** Ligand A (31.187) has a moderate clearance, while Ligand B (-42.152) has a negative clearance, which is not physically possible and likely indicates an error in the data or a very stable compound.

**In vitro Half-Life:** Ligand A (-1.145) has a negative half-life, which is not physically possible and likely indicates an error in the data. Ligand B (-25.624) also has a negative half-life, indicating an error.

**P-gp Efflux:** Ligand A (0.27) has low P-gp efflux, which is favorable for CNS penetration. Ligand B (0.003) also has very low P-gp efflux.

**Binding Affinity:** Both ligands have comparable and strong binding affinities (-7.9 and -7.8 kcal/mol). The difference is minimal and unlikely to be decisive.

**Overall Assessment:**

Despite the unusual negative values for Caco-2 permeability and in vitro half-life, Ligand A is the more promising candidate. Its superior BBB penetration, lower DILI risk, and optimal logP outweigh the concerns about permeability and solubility. Ligand B's very low logP is a major drawback for a CNS-targeting drug, and its higher DILI risk is also concerning. The negative clearance and half-life values for both compounds are suspect and would need further investigation, but the other properties strongly favor Ligand A.

Output:
0
2025-04-17 05:33:40,297 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (344.459 and 348.495 Da) fall comfortably within the ideal 200-500 Da range.

**TPSA:** Ligand A (66.4) is significantly better than Ligand B (77.15). For CNS targets, we want TPSA <= 90, and A is closer to the optimal <=60 range. B is approaching a less desirable range.

**logP:** Both ligands have good logP values (2.286 and 1.709), falling within the 1-3 optimal range.

**H-Bond Donors/Acceptors:** Ligand A (0 HBD, 4 HBA) is preferable to Ligand B (2 HBD, 5 HBA). Lower counts generally improve permeability.

**QED:** Both ligands have similar, good QED scores (0.825 and 0.847), indicating good drug-like properties.

**DILI:** Ligand A (35.789) has a lower DILI risk than Ligand B (44.048), both are acceptable, but A is better.

**BBB:** Ligand A (80.574) has a significantly better BBB penetration score than Ligand B (75.805). For a CNS target like DRD2, >70 is desirable, and A is closer.

**Caco-2 Permeability:** Ligand A (-4.692) has a worse Caco-2 permeability than Ligand B (-5.241). Lower values are worse.

**Aqueous Solubility:** Ligand A (-2.035) has better aqueous solubility than Ligand B (-2.23). Higher values are better.

**hERG:** Both ligands have similar, low hERG inhibition liability (0.436 and 0.578), indicating low cardiotoxicity risk.

**Microsomal Clearance:** Ligand A (39.753) has lower microsomal clearance than Ligand B (44.729), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (-0.653) has a much better in vitro half-life than Ligand B (-16.091).

**P-gp Efflux:** Ligand A (0.196) has a lower P-gp efflux liability than Ligand B (0.066), which is favorable for CNS penetration.

**Binding Affinity:** Ligand A (-8.9 kcal/mol) has a significantly stronger binding affinity than Ligand B (-7.4 kcal/mol). This >1.5 kcal/mol difference is substantial and can outweigh minor ADME drawbacks.

**Overall Assessment:**

Ligand A is clearly superior. It has a better TPSA, BBB, DILI, microsomal clearance, in vitro half-life, P-gp efflux, and *significantly* better binding affinity. While Ligand B has slightly better Caco-2 permeability and solubility, the substantial advantages of Ligand A, particularly its binding affinity and CNS penetration properties, make it the more promising drug candidate for a CNS target like DRD2.

Output:
1
2025-04-17 05:33:40,298 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (354.447 and 370.515 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (88.1) is better than Ligand B (75.71). Both are below the 90 A^2 threshold for CNS targets, which is excellent.

**3. logP:** Ligand B (0.959) is slightly better than Ligand A (0.511), being closer to the optimal 1-3 range. Ligand A is a bit low, potentially hindering permeation.

**4. H-Bond Donors:** Ligand B (1) is preferable to Ligand A (2). Lower HBD generally improves permeability.

**5. H-Bond Acceptors:** Both ligands have 5 HBA, which is acceptable (<=10).

**6. QED:** Both ligands have good QED scores (0.696 and 0.754, respectively), indicating drug-like properties.

**7. DILI:** Ligand A (13.61) has a significantly lower DILI risk than Ligand B (35.479). This is a major advantage for Ligand A.

**8. BBB:** Both ligands have excellent BBB penetration (70.686 and 76.309, respectively), exceeding the desirable >70 threshold for CNS targets.

**9. Caco-2 Permeability:** Ligand A (-4.82) has a more negative Caco-2 value than Ligand B (-5.098), suggesting slightly better permeability.

**10. Aqueous Solubility:** Ligand B (-2.399) has better aqueous solubility than Ligand A (-1.167).

**11. hERG Inhibition:** Both ligands have low hERG inhibition risk (0.188 and 0.311, respectively).

**12. Microsomal Clearance:** Ligand A (15.281) has significantly lower microsomal clearance than Ligand B (37.623), indicating better metabolic stability.

**13. In vitro Half-Life:** Ligand B (16.787) has a slightly longer half-life than Ligand A (19.414).

**14. P-gp Efflux:** Ligand A (0.042) has significantly lower P-gp efflux liability than Ligand B (0.154), which is crucial for CNS exposure.

**15. Binding Affinity:** Ligand A (-8.1 kcal/mol) has a significantly stronger binding affinity than Ligand B (0.0 kcal/mol). This is a critical advantage.

**Overall Assessment:**

Ligand A is clearly superior. While Ligand B has slightly better solubility and half-life, Ligand A excels in the most critical parameters for a CNS-targeting GPCR ligand: significantly stronger binding affinity, lower DILI risk, lower P-gp efflux, and lower microsomal clearance. The slightly lower logP of Ligand A is a minor concern outweighed by its other advantages.

Output:
1
2025-04-17 05:33:40,298 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B based on the provided guidelines, prioritizing GPCR-specific properties (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (358.873 and 367.427 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (50.16) is significantly better than Ligand B (117.84). For CNS targets, we want TPSA <= 90, and A is comfortably within that range, while B exceeds it. This is a major advantage for A.

**logP:** Ligand A (2.981) is optimal (1-3). Ligand B (0.374) is quite low, potentially hindering permeation.

**H-Bond Donors/Acceptors:** Ligand A (HBD=1, HBA=4) and Ligand B (HBD=2, HBA=5) both have acceptable numbers of H-bond donors and acceptors.

**QED:** Both ligands have reasonable QED values (A: 0.863, B: 0.729), indicating good drug-like properties.

**DILI:** Both ligands have similar and acceptable DILI risk (A: 45.638, B: 48.313), both below the 60 threshold.

**BBB:** Ligand A (82.435) has a much better BBB percentile than Ligand B (54.595). For a CNS target like DRD2, >70 is desirable, and A is closer to this target.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.208 and -5.169). This is unusual and could indicate issues with the prediction method or the compounds themselves. However, the values are similar.

**Aqueous Solubility:** Both ligands have negative solubility values (-3.269 and -1.613). Similar to Caco-2, this is concerning, but again, the values are comparable.

**hERG Inhibition:** Ligand A (0.845) has a slightly higher hERG risk than Ligand B (0.077), but both are relatively low.

**Microsomal Clearance:** Ligand A (18.477) has a higher (worse) microsomal clearance than Ligand B (1.91). This suggests B is more metabolically stable.

**In vitro Half-Life:** Ligand B (60.92) has a significantly longer in vitro half-life than Ligand A (33.624), which is a positive for B.

**P-gp Efflux:** Ligand A (0.442) has lower P-gp efflux liability than Ligand B (0.033), which is beneficial for CNS penetration.

**Binding Affinity:** Ligand B (-7.9 kcal/mol) has a significantly stronger binding affinity than Ligand A (-9.1 kcal/mol). This is a substantial advantage for B.

**Overall Assessment:**

While Ligand B has a superior binding affinity and better metabolic stability (lower Cl_mic, longer t1/2), Ligand A excels in properties crucial for CNS penetration: TPSA, logP, and BBB. The lower logP of B is a significant concern, potentially limiting its ability to cross the blood-brain barrier despite the P-gp efflux data. The higher TPSA of B is also unfavorable. The affinity difference is 1.2 kcal/mol, which is substantial, but the CNS properties of A are so much better that it outweighs the affinity difference.

Output:
0
2025-04-17 05:33:40,298 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (357.41 Da) and Ligand B (342.443 Da) are both acceptable.

**TPSA:**  Both ligands have TPSA values above the optimal 90 A^2 for CNS targets, but are still within a reasonable range for GPCRs. Ligand A (64.11 A^2) is better than Ligand B (66.71 A^2).

**logP:** Ligand A (4.27) is slightly high, potentially leading to solubility issues or off-target interactions. Ligand B (2.173) is within the optimal 1-3 range. This favors Ligand B.

**H-Bond Donors/Acceptors:** Both ligands have acceptable HBD (1) and HBA (5/4) counts.

**QED:** Both ligands have good QED scores (0.693 and 0.905), indicating good drug-like properties. Ligand B is slightly better.

**DILI:** Ligand A has a very high DILI risk (98.216%), which is a significant concern. Ligand B has a much lower and acceptable DILI risk (34.432%). This is a major advantage for Ligand B.

**BBB:** Both ligands have reasonably good BBB penetration (68.786% and 70.764%). Ligand B is slightly better.

**Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and suggests poor permeability. However, the scale is not specified, so it is difficult to interpret.

**Aqueous Solubility:** Both ligands have very poor aqueous solubility (-5.822 and -2.302). This is a concern, but potentially manageable with formulation strategies.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.438 and 0.275).

**Microsomal Clearance:** Ligand A has very high microsomal clearance (100.435), indicating poor metabolic stability. Ligand B has much lower clearance (28.74), suggesting better metabolic stability. This is a significant advantage for Ligand B.

**In vitro Half-Life:** Ligand A has a moderate half-life (43.924 hours), while Ligand B has a very short half-life (-2.039 hours). This favors Ligand A, but the negative value for Ligand B is concerning and may indicate an error.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.469 and 0.057), which is good for CNS penetration. Ligand B is better.

**Binding Affinity:** Both ligands have strong binding affinities (-9.3 and -8.8 kcal/mol). Ligand A has a slightly better affinity, but the difference (0.5 kcal/mol) is not substantial enough to outweigh its other drawbacks.

**Overall:**

Ligand B is significantly better due to its much lower DILI risk, better logP, and lower microsomal clearance. While Ligand A has slightly better affinity and half-life, the high DILI risk and poor metabolic stability are major liabilities. The slightly better BBB penetration of Ligand B also supports its selection.

Output:
1
2025-04-17 05:33:40,298 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (350.459 Da) is slightly lower, which could be advantageous for permeability, but both are acceptable.

**TPSA:** Ligand A (87.66) is better than Ligand B (102.76). For CNS targets, we want TPSA <= 90, so Ligand A is preferable.

**logP:** Both ligands have good logP values (A: 1.262, B: 0.991), falling within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Both have 3 HBD, which is good. Ligand A has 4 HBA, and Ligand B has 6 HBA. Both are acceptable, but lower is generally better.

**QED:** Both ligands have good QED scores (A: 0.584, B: 0.642), indicating drug-like properties.

**DILI:** Ligand A (12.253) has a significantly lower DILI risk than Ligand B (65.413). This is a major advantage for Ligand A.

**BBB:** Ligand A (56.65) has a better BBB percentile than Ligand B (26.406). While >70 is desirable, 56.65 is still reasonably good, and much better than 26.406, which is a significant concern for a CNS target.

**Caco-2 Permeability:** Ligand A (-4.846) has a worse Caco-2 permeability than Ligand B (-5.298), but both are quite poor.

**Aqueous Solubility:** Ligand A (-1.851) has better solubility than Ligand B (-3.057).

**hERG:** Both ligands have low hERG inhibition liability (A: 0.163, B: 0.332).

**Microsomal Clearance:** Ligand A (23.354) has higher microsomal clearance than Ligand B (13.093), meaning it's less metabolically stable. This is a drawback for Ligand A.

**In vitro Half-Life:** Ligand A (12.26) has a longer half-life than Ligand B (8.68), which is preferable.

**P-gp Efflux:** Ligand A (0.035) has much lower P-gp efflux liability than Ligand B (0.093). This is a significant advantage for CNS penetration.

**Binding Affinity:** Ligand B (-9.1) has a slightly better binding affinity than Ligand A (-8.3). However, the difference is only 0.8 kcal/mol, and can be overcome by better ADME properties.

**Overall Assessment:**

Ligand A is significantly better overall. It has a much lower DILI risk, better BBB penetration, and lower P-gp efflux. While Ligand B has slightly better binding affinity and a slightly longer half-life, the ADME advantages of Ligand A, particularly for a CNS target like DRD2, outweigh this difference. The TPSA of Ligand A is also more favorable.

Output:
1
2025-04-17 05:33:40,298 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (382.551 Da) is slightly higher than Ligand B (362.373 Da), but both are acceptable.

**TPSA:** Ligand A (58.64) is significantly better than Ligand B (93.73). For CNS targets, we want TPSA <= 90, so Ligand A is much more favorable.

**logP:** Both ligands have acceptable logP values (Ligand A: 1.859, Ligand B: 0.622), falling within the optimal 1-3 range. Ligand A is preferable due to being closer to the middle of the range.

**H-Bond Donors/Acceptors:** Ligand A (HBD=1, HBA=5) is slightly better than Ligand B (HBD=2, HBA=5) in terms of HBD count, but both are within acceptable limits.

**QED:** Both ligands have reasonable QED values (Ligand A: 0.804, Ligand B: 0.676), indicating good drug-like properties. Ligand A is better here.

**DILI:** Ligand A (36.681) has a lower DILI risk than Ligand B (49.128), which is preferable. Both are below the 60 threshold, but lower is better.

**BBB:** Ligand A (65.568) and Ligand B (74.796) both have good BBB penetration, but Ligand B is better. A value >70 is desirable, and Ligand B is closer to that.

**Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and suggests poor permeability. However, the absolute value of Ligand A (-5.071) is smaller than Ligand B (-4.982), suggesting slightly better permeability.

**Aqueous Solubility:** Both ligands have very poor aqueous solubility (-3.129 and -1.981, respectively). This is a significant drawback for both.

**hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.163 and 0.236, respectively). This is excellent.

**Microsomal Clearance:** Ligand A (36.31) has a higher microsomal clearance than Ligand B (23.208), suggesting lower metabolic stability. Ligand B is preferable here.

**In vitro Half-Life:** Ligand B (3.189 hours) has a slightly longer half-life than Ligand A (21.1 hours), which is preferable.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.028 and 0.021, respectively). This is excellent.

**Binding Affinity:** Both ligands have excellent binding affinity (-8.1 and -8.3 kcal/mol, respectively). Ligand B is slightly better (-8.3 kcal/mol).

**Overall Assessment:**

Considering the GPCR-specific priorities, Ligand A is slightly better. It has a much lower TPSA, lower DILI risk, and a better QED score. While Ligand B has better BBB penetration and slightly better affinity, the lower TPSA of Ligand A is crucial for CNS penetration, and the lower DILI risk is important for safety. The solubility is poor for both, but this can be addressed with formulation strategies.

Output:
1
2025-04-17 05:33:40,298 - INFO - Reasoning:

Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (354.407 and 353.507 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (117.79) is borderline, but acceptable for CNS penetration, while Ligand B (61.88) is excellent, well below the 90 A^2 threshold. This favors Ligand B.

**3. logP:** Both ligands have good logP values (1.847 and 1.498), falling within the optimal 1-3 range.

**4. H-Bond Donors:** Ligand A has 2 HBD, and Ligand B has 1. Both are within the acceptable limit of <=5.

**5. H-Bond Acceptors:** Ligand A has 7 HBA, and Ligand B has 4. Both are within the acceptable limit of <=10.

**6. QED:** Both ligands have reasonable QED values (0.847 and 0.718), indicating good drug-like properties.

**7. DILI:** Ligand A has a DILI risk of 52.772, which is acceptable (below 60). Ligand B has a very low DILI risk of 10.198, which is excellent. This favors Ligand B.

**8. BBB:** Both ligands have good BBB penetration (77.821 and 70.531), but Ligand A is slightly better, exceeding 70%.

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.647 and -4.586), which is unusual and suggests poor permeability. This is a concern for both, but doesn't differentiate them.

**10. Aqueous Solubility:** Both ligands have negative solubility values (-3.072 and -0.969), indicating poor aqueous solubility. This is a significant drawback for both, but Ligand B is slightly better.

**11. hERG Inhibition:** Both ligands have low hERG inhibition risk (0.113 and 0.344), which is good.

**12. Microsomal Clearance:** Ligand A has a lower Cl_mic (29.498) than Ligand B (55.526), suggesting better metabolic stability. This favors Ligand A.

**13. In vitro Half-Life:** Ligand A has a negative half-life (-25.232), which is problematic. Ligand B has a negative half-life as well (-0.661), but it's closer to zero, suggesting slightly better stability. Both are concerning.

**14. P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.019 and 0.013), which is excellent for CNS penetration.

**15. Binding Affinity:** Ligand A has a stronger binding affinity (-8.1 kcal/mol) than Ligand B (-7.7 kcal/mol). This is a significant advantage for Ligand A (a 0.4 kcal/mol difference).

**Overall Assessment:**

While Ligand B excels in TPSA, DILI, and P-gp efflux, Ligand A has a significantly stronger binding affinity and better metabolic stability (lower Cl_mic). The stronger binding affinity is a major advantage for a GPCR ligand, and can often outweigh some ADME liabilities. The negative half-life for both is concerning, but the affinity difference is substantial. Considering the GPCR-specific priorities, the stronger affinity of Ligand A makes it the more promising candidate, despite its slightly higher TPSA and DILI risk.

Output:
1
2025-04-17 05:33:40,299 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (385.433) is slightly higher than Ligand B (350.459), but both are acceptable.

**TPSA:** Ligand A (121.01) is borderline for CNS penetration, being slightly above the preferred <90. Ligand B (66.92) is excellent, well below 90, suggesting better CNS penetration potential.

**logP:** Ligand A (-0.479) is a bit low, potentially hindering membrane permeability. Ligand B (1.825) is within the optimal range (1-3).

**H-Bond Donors/Acceptors:** Ligand A has 2 HBD and 5 HBA, which are reasonable. Ligand B has 0 HBD and 4 HBA, also acceptable.

**QED:** Both ligands have good QED scores (A: 0.64, B: 0.71), indicating drug-like properties.

**DILI:** Ligand A (39.628) has a moderate DILI risk, but is still acceptable. Ligand B (12.718) shows a very low DILI risk, which is a significant advantage.

**BBB:** Ligand A (64.211) is below the desirable threshold of >70 for CNS targets. Ligand B (76.541) is excellent, exceeding the 70% threshold.

**Caco-2 Permeability:** Both have negative values, which is unusual. Assuming these are percentile scores, Ligand B (-4.36) is slightly better than Ligand A (-5.044).

**Aqueous Solubility:** Both have negative values, which is unusual. Assuming these are percentile scores, Ligand A (-1.775) is slightly better than Ligand B (-1.67).

**hERG Inhibition:** Both ligands have low hERG inhibition risk (A: 0.25, B: 0.283).

**Microsomal Clearance:** Ligand A (-21.848) shows lower clearance and better metabolic stability than Ligand B (77.294).

**In vitro Half-Life:** Ligand A (-27.126) shows a longer half-life than Ligand B (-19.347).

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (A: 0.024, B: 0.038).

**Binding Affinity:** Ligand B (-8.2 kcal/mol) has a significantly stronger binding affinity than Ligand A (-6.7 kcal/mol). This >1.5 kcal/mol difference is substantial and can outweigh some ADME drawbacks.

**Overall Assessment:**

Ligand B is the stronger candidate. While Ligand A has better metabolic stability and half-life, Ligand B excels in the critical GPCR-specific properties: significantly higher binding affinity, a much better BBB score, a lower TPSA, and a lower DILI risk. The slightly lower metabolic stability of Ligand B is a concern, but the superior affinity and CNS penetration potential are more important for a DRD2 target.

Output:
1
2025-04-17 05:33:40,299 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (355.435 and 354.491 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (99.18) is slightly above the optimal <90 for CNS targets, but still reasonable. Ligand B (78.87) is well within the desired range.

**logP:** Ligand A (-0.786) is a bit low, potentially hindering membrane permeability. Ligand B (1.707) is within the optimal 1-3 range. This is a significant advantage for Ligand B.

**H-Bond Donors/Acceptors:** Both have 2 HBD and are within the acceptable range. Ligand A has 5 HBA, while Ligand B has 4. Both are acceptable.

**QED:** Both ligands have good QED scores (0.624 and 0.729), indicating drug-like properties.

**DILI:** Both have low DILI risk (32.299 and 22.838), which is favorable.

**BBB:** Ligand B (62.931) has a significantly better BBB percentile than Ligand A (41.528). This is crucial for a CNS target like DRD2.

**Caco-2 Permeability:** Both have negative Caco-2 values (-4.949 and -4.792). These values are difficult to interpret without knowing the scale, but suggest poor permeability.

**Aqueous Solubility:** Both have negative solubility values (-0.649 and -1.774). Similar to Caco-2, these values are difficult to interpret, but suggest poor solubility.

**hERG:** Both have low hERG risk (0.065 and 0.304).

**Microsomal Clearance:** Ligand A (27.577) has lower microsomal clearance than Ligand B (45.873), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (-9.953) has a negative half-life, which is problematic. Ligand B (17.748) has a reasonable half-life.

**P-gp Efflux:** Ligand A (0.017) shows very low P-gp efflux, which is excellent for CNS penetration. Ligand B (0.112) also shows low P-gp efflux, but slightly higher than Ligand A.

**Binding Affinity:** Ligand A (-6.3 kcal/mol) has a better binding affinity than Ligand B (0.0 kcal/mol). This is a substantial advantage for Ligand A.

**Overall Assessment:**

Ligand A has a better binding affinity and lower P-gp efflux and microsomal clearance, but suffers from a low logP, negative half-life, and a less favorable BBB penetration. Ligand B has a better logP, BBB penetration, and half-life, but its binding affinity is very poor.

Given the GPCR-specific priorities, BBB penetration and logP are critical. Ligand B's significantly better BBB (62.931 vs 41.528) and logP (1.707 vs -0.786) outweigh Ligand A's superior binding affinity, especially considering the negative half-life for Ligand A. While the binding affinity of Ligand A is good, a binding affinity of 0 kcal/mol is not useful.

Output:
1
2025-04-17 05:33:40,299 - INFO - Batch 208 complete. Total preferences: 3328
2025-04-17 05:33:40,299 - INFO - Processing batch 209/512...
2025-04-17 05:34:23,755 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (349.381 and 370.49 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (62.3) is significantly better than Ligand B (69.64). For CNS targets, we want TPSA <= 90, and lower is preferable. Ligand A is well within this range, while Ligand B is approaching the upper limit.

**3. logP:** Both ligands have good logP values (2.153 and 1.487), falling within the optimal 1-3 range.

**4. H-Bond Donors:** Ligand A (1) is better than Ligand B (2). Lower HBD generally improves permeability.

**5. H-Bond Acceptors:** Ligand A (3) is better than Ligand B (4). Similar to HBD, lower HBA is generally preferred.

**6. QED:** Ligand A (0.906) has a much better QED score than Ligand B (0.743), indicating a more drug-like profile.

**7. DILI:** Ligand A (41.101) has a slightly higher DILI risk than Ligand B (20.9), but both are below the concerning threshold of 60.

**8. BBB:** Ligand A (90.617) has a significantly better BBB penetration prediction than Ligand B (70.919). This is *critical* for a CNS target like DRD2.

**9. Caco-2:** Ligand A (-4.818) and Ligand B (-5.148) both have negative values, which is unusual and suggests very poor permeability. This is a significant concern for both.

**10. Solubility:** Both ligands have poor aqueous solubility (-2.572 and -3.073). This could pose formulation challenges.

**11. hERG:** Both ligands have low hERG inhibition risk (0.441 and 0.432).

**12. Cl_mic:** Ligand B (-2.095) has a lower (better) microsomal clearance than Ligand A (6.101), suggesting better metabolic stability.

**13. t1/2:** Ligand B (-1.168) has a longer in vitro half-life than Ligand A (-9.575).

**14. Pgp:** Ligand A (0.028) has a much lower P-gp efflux liability than Ligand B (0.064), which is favorable for CNS penetration.

**15. Affinity:** Ligand A (-8.9 kcal/mol) has a significantly stronger binding affinity than Ligand B (-7.0 kcal/mol). This is a substantial advantage, potentially outweighing some of the ADME drawbacks.

**Overall Assessment:**

Ligand A is the stronger candidate. While both have poor solubility and Caco-2 permeability, Ligand A excels in the most critical areas for a CNS GPCR target: BBB penetration, binding affinity, and P-gp efflux. Its superior QED score also supports its drug-likeness. Although Ligand B has better metabolic stability and half-life, the difference in binding affinity and BBB penetration is too significant to ignore. The strong binding affinity of Ligand A (-8.9 kcal/mol) is a major advantage.

Output:
1
2025-04-17 05:34:23,755 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (350.47 and 346.39 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (92.62) is better than Ligand B (102.74). Both are below the 140 A^2 threshold for oral absorption, and Ligand A is closer to the desirable <90 A^2 for CNS targets.

**logP:** Ligand A (1.726) is within the optimal 1-3 range. Ligand B (-0.578) is below 1, potentially hindering permeation. This is a significant drawback for Ligand B.

**H-Bond Donors/Acceptors:** Ligand A (0 HBD, 4 HBA) and Ligand B (1 HBD, 5 HBA) are both reasonable, falling within the acceptable limits.

**QED:** Ligand B (0.737) has a better QED score than Ligand A (0.379), suggesting a more drug-like profile overall.

**DILI:** Ligand A (26.444) has a much lower DILI risk than Ligand B (48.275), indicating a safer profile.

**BBB:** Ligand A (77.627) has significantly better BBB penetration potential than Ligand B (46.064). This is crucial for a CNS target like DRD2.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.721 and -4.933), which is unusual and suggests poor permeability. However, these values are on a log scale and difficult to interpret without further context.

**Aqueous Solubility:** Both ligands have negative solubility values (-0.581 and -1.802), indicating poor aqueous solubility. This could pose formulation challenges.

**hERG:** Both ligands have very low hERG inhibition risk (0.361 and 0.114).

**Microsomal Clearance:** Ligand B (-17.681) has a lower (better) microsomal clearance than Ligand A (56.287), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand B (24.579) has a longer in vitro half-life than Ligand A (-25.633), which is favorable.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.03 and 0.011).

**Binding Affinity:** Ligand B (-7.8 kcal/mol) has a slightly better binding affinity than Ligand A (-7.2 kcal/mol). This 0.6 kcal/mol difference is notable, but not overwhelmingly decisive.

**Overall Assessment:**

Ligand A excels in BBB penetration, TPSA, and DILI risk, all critical for a CNS GPCR target. Its logP is within the optimal range. While its solubility and Caco-2 permeability are poor, the strong BBB score mitigates some of the permeability concerns.

Ligand B has a better QED, metabolic stability, and half-life, and slightly better binding affinity. However, its poor logP and significantly lower BBB penetration are major drawbacks for a CNS drug.

Considering the GPCR-specific priorities, particularly BBB penetration for a CNS target, **Ligand A is the more promising candidate**. The slightly weaker binding affinity can potentially be optimized in subsequent iterations, but improving BBB penetration is often much more challenging.

Output:
0
2025-04-17 05:34:23,755 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (346.431 and 344.419 Da) fall comfortably within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (87.46) is excellent, falling well below the 90 A^2 threshold for CNS targets. Ligand B (111.06) is still reasonable but less optimal, being above 100.

**3. logP:** Both ligands have good logP values (1.027 and 2.066), within the optimal 1-3 range.

**4. H-Bond Donors:** Ligand A (2) and Ligand B (1) both meet the HBD <= 5 criteria.

**5. H-Bond Acceptors:** Ligand A (5) and Ligand B (4) both meet the HBA <= 10 criteria.

**6. QED:** Ligand A (0.852) has a very strong drug-like profile. Ligand B (0.484) is lower, indicating a less ideal overall drug-likeness.

**7. DILI:** Both ligands have acceptable DILI risk (26.173 and 30.593), well below the 40% threshold.

**8. BBB:** This is a critical parameter for a CNS target like DRD2. Ligand A (67.895) is better than Ligand B (52.966), although both are below the desirable >70% threshold.

**9. Caco-2:** Both have negative values (-5.123 and -5.113), which is unusual and likely indicates a scale where lower values represent lower permeability. This is a potential concern for both.

**10. Solubility:** Both have negative values (-2.514 and -1.971) which is also unusual and likely indicates a scale where lower values represent lower solubility. This is a potential concern for both.

**11. hERG:** Both ligands show very low hERG inhibition liability (0.143 and 0.134), which is excellent.

**12. Cl_mic:** Ligand B (5.658) has significantly lower microsomal clearance than Ligand A (38.598), suggesting better metabolic stability.

**13. t1/2:** Ligand B (-14.075) has a longer in vitro half-life than Ligand A (-20.83), which is also a positive.

**14. Pgp:** Both ligands show very low P-gp efflux liability (0.032 and 0.01), which is excellent for CNS penetration.

**15. Binding Affinity:** Ligand A (-9.4 kcal/mol) has a significantly stronger binding affinity than Ligand B (-6.9 kcal/mol). This is a substantial difference (2.5 kcal/mol) and can outweigh some ADME drawbacks.

**Overall Assessment:**

Ligand A excels in TPSA, QED, and, most importantly, binding affinity. While its BBB penetration is not ideal, it's better than Ligand B's. Ligand B has better metabolic stability (lower Cl_mic) and a longer half-life, but its lower affinity and poorer QED are significant drawbacks. Given the strong emphasis on affinity for GPCRs, and the substantial difference in binding energy, Ligand A is the more promising candidate, despite its slightly lower BBB score.

Output:
1
2025-04-17 05:34:23,756 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (347.459 and 352.431 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (75.44) is better than Ligand B (77.1), both are below the 90 A^2 threshold for CNS targets, which is good.

**3. logP:** Ligand A (2.928) is optimal (1-3), while Ligand B (0.18) is quite low, potentially hindering membrane permeability. This is a significant drawback for Ligand B.

**4. H-Bond Donors:** Both have 1 HBD, which is within the acceptable limit of <=5.

**5. H-Bond Acceptors:** Ligand A has 4 HBAs, and Ligand B has 5. Both are within the acceptable limit of <=10.

**6. QED:** Both ligands have good QED scores (0.823 and 0.764, respectively), indicating drug-like properties.

**7. DILI:** Ligand A (21.791) has a significantly lower DILI risk than Ligand B (29.779), both are acceptable but A is preferable.

**8. BBB:** Ligand A (91.392) has excellent BBB penetration (above 70), crucial for a CNS target like DRD2. Ligand B (52.579) is considerably lower, which is a major concern.

**9. Caco-2:** Both have negative Caco-2 values, which is unusual and difficult to interpret without further context.

**10. Solubility:** Both have negative solubility values, which is also unusual and difficult to interpret without further context.

**11. hERG:** Both ligands have low hERG inhibition liability (0.416 and 0.216), which is positive.

**12. Cl_mic:** Ligand A (54.47) has a higher microsomal clearance than Ligand B (19.734), suggesting faster metabolism. This is a slight negative for Ligand A.

**13. t1/2:** Ligand B (21.014) has a longer in vitro half-life than Ligand A (-29.12), which is a positive for Ligand B, but the negative value for A is concerning.

**14. Pgp:** Ligand A (0.159) has lower P-gp efflux liability than Ligand B (0.017), which is preferable for CNS penetration.

**15. Binding Affinity:** Ligand B (-7.2) has a slightly better binding affinity than Ligand A (-7.7), but the difference is small, and other factors are more important.

**Overall Assessment:**

Ligand A is the better candidate. While Ligand B has slightly better affinity and half-life, Ligand A excels in crucial areas for a CNS-targeting GPCR ligand: significantly better logP, much higher BBB penetration, and lower DILI risk. The lower Pgp efflux for Ligand A also supports better CNS exposure. The negative values for Caco-2 and solubility are concerning for both, but the other benefits of Ligand A outweigh these issues.

Output:
1
2025-04-17 05:34:23,756 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (348.403 and 349.475 Da) fall comfortably within the ideal 200-500 Da range.

**TPSA:** Ligand A (96.55) is better than Ligand B (63.57). Both are below the 90 A^2 threshold for CNS targets, but Ligand A is slightly higher and could potentially impact BBB penetration.

**logP:** Ligand A (0.71) is a bit low, potentially hindering permeability. Ligand B (2.051) is within the optimal 1-3 range. This is a significant advantage for Ligand B.

**H-Bond Donors/Acceptors:** Ligand A has 2 HBD and 5 HBA, while Ligand B has 1 HBD and 4 HBA. Both are within acceptable limits.

**QED:** Ligand A (0.789) has a better QED score than Ligand B (0.658), indicating a more drug-like profile.

**DILI:** Both ligands have low DILI risk (Ligand A: 29.857, Ligand B: 31.563), both below the 40 threshold.

**BBB:** Both ligands have similar BBB penetration (Ligand A: 56.301, Ligand B: 56.805). These are acceptable, but not ideal (>70) for a CNS target.

**Caco-2 Permeability:** Ligand A (-4.827) has worse Caco-2 permeability than Ligand B (-4.568).

**Aqueous Solubility:** Ligand A (-2.246) has slightly better solubility than Ligand B (-1.639).

**hERG Inhibition:** Both ligands have very low hERG inhibition risk (Ligand A: 0.18, Ligand B: 0.293).

**Microsomal Clearance:** Ligand A (-5.783) has significantly lower (better) microsomal clearance than Ligand B (59.623), indicating better metabolic stability.

**In vitro Half-Life:** Ligand A (-8.458) has a much longer in vitro half-life than Ligand B (14.323). This is a major advantage for Ligand A.

**P-gp Efflux:** Ligand A (0.014) has significantly lower P-gp efflux than Ligand B (0.125), which is crucial for CNS penetration.

**Binding Affinity:** Ligand A (-7.8 kcal/mol) has slightly better binding affinity than Ligand B (-7.5 kcal/mol). While the difference is not huge, it's still a positive for Ligand A.

**Overall Assessment:**

Ligand A excels in metabolic stability (Cl_mic, t1/2), P-gp efflux, and binding affinity. Its QED is also slightly better. However, its logP is suboptimal, and Caco-2 permeability is lower. Ligand B has a better logP, but suffers from higher P-gp efflux, lower metabolic stability, and a shorter half-life.

Given the GPCR-specific priorities, particularly BBB penetration and metabolic stability, and the relatively small difference in binding affinity, **Ligand A appears to be the more promising candidate.** The lower P-gp efflux and improved metabolic profile are critical for CNS drug development, and the slightly better affinity helps to compensate for the lower logP.

Output:
0
2025-04-17 05:34:23,756 - INFO - Reasoning:
Let's analyze both ligands against the given criteria, prioritizing GPCR-specific properties (BBB, logP, Pgp, TPSA, and affinity).

**Ligand A:**

*   **MW:** 350.503 Da - Good (within 200-500 range)
*   **TPSA:** 60.85 - Excellent (well below 90 for CNS targets)
*   **logP:** 2.425 - Good (within 1-3 range)
*   **HBD:** 1 - Good (<=5)
*   **HBA:** 3 - Good (<=10)
*   **QED:** 0.847 - Excellent (>=0.5)
*   **DILI:** 8.104 - Excellent (low risk, <40)
*   **BBB:** 71.733 - Good (above 70, desirable for CNS)
*   **Caco-2:** -4.499 - Poor (negative value suggests very low permeability)
*   **Solubility:** -1.699 - Poor (negative value suggests very low solubility)
*   **hERG:** 0.492 - Good (low risk)
*   **Cl_mic:** 48.407 - Moderate (relatively low clearance)
*   **t1/2:** -8.522 - Excellent (long half-life)
*   **Pgp:** 0.053 - Excellent (low efflux, good for CNS exposure)
*   **Affinity:** -8.4 kcal/mol - Excellent (strong binding)

**Ligand B:**

*   **MW:** 377.897 Da - Good (within 200-500 range)
*   **TPSA:** 71.09 - Acceptable (slightly above 60, but still potentially okay for CNS)
*   **logP:** 4.211 - Marginal (slightly above optimal range, potential solubility issues)
*   **HBD:** 2 - Good (<=5)
*   **HBA:** 4 - Good (<=10)
*   **QED:** 0.759 - Good (>=0.5)
*   **DILI:** 69.135 - Moderate (higher risk, >60)
*   **BBB:** 76.192 - Excellent (above 70, desirable for CNS)
*   **Caco-2:** -4.931 - Poor (negative value suggests very low permeability)
*   **Solubility:** -5.049 - Very Poor (negative value suggests extremely low solubility)
*   **hERG:** 0.379 - Good (low risk)
*   **Cl_mic:** 46.435 - Moderate (relatively low clearance)
*   **t1/2:** 46.14 - Good (long half-life)
*   **Pgp:** 0.29 - Good (low efflux, good for CNS exposure)
*   **Affinity:** -8.9 kcal/mol - Excellent (very strong binding, 0.5 kcal/mol better than Ligand A)

**Comparison and Decision:**

Both ligands have excellent binding affinity and good BBB penetration, which are critical for a CNS-targeting GPCR like DRD2. Ligand B has a slightly better binding affinity (-8.9 vs -8.4 kcal/mol). However, both ligands exhibit very poor Caco-2 permeability and aqueous solubility. Ligand B also has a higher DILI risk.

Ligand A has a better TPSA, logP, and DILI score than Ligand B. While both have poor solubility and permeability, the lower TPSA and logP of Ligand A suggest it *might* be slightly more amenable to optimization in these areas. The significantly lower DILI risk is also a major advantage. The 0.5 kcal/mol difference in binding affinity is unlikely to overcome the more significant ADME liabilities of Ligand B.

Therefore, I would choose **Ligand A** as the more viable drug candidate.

Output:
0
2025-04-17 05:34:23,756 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B based on the provided guidelines, prioritizing GPCR-specific properties (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (365.463 and 374.941 Da) fall within the ideal range of 200-500 Da.

**TPSA:** Ligand A (117.59) is better than Ligand B (49.84). For CNS targets, we want TPSA <= 90, so both are acceptable, but A is closer to the upper limit.

**logP:** Ligand A (0.232) is quite low, potentially hindering permeation. Ligand B (4.97) is higher, bordering on being too high, but still within a reasonable range. This favors Ligand B.

**H-Bond Donors/Acceptors:** Ligand A has 3 HBD and 7 HBA, while Ligand B has 2 HBD and 5 HBA. Both are within acceptable limits (<=5 HBD and <=10 HBA).

**QED:** Both ligands have similar QED values (0.555 and 0.529), indicating good drug-likeness.

**DILI:** Ligand A (77.2) has a higher DILI risk than Ligand B (69.407). Lower is better, so Ligand B is preferred.

**BBB:** This is crucial for a CNS target like DRD2. Ligand A (32.416) has a very poor BBB penetration percentile. Ligand B (86.002) has excellent BBB penetration. This is a major advantage for Ligand B.

**Caco-2 Permeability:** Ligand A (-6.239) has very poor Caco-2 permeability. Ligand B (-5.079) is also poor, but slightly better.

**Aqueous Solubility:** Ligand A (-2.285) has poor solubility. Ligand B (-4.89) is also poor, but slightly better.

**hERG Inhibition:** Ligand A (0.025) has a very low hERG risk, which is excellent. Ligand B (0.858) has a moderate hERG risk. Ligand A is preferred here.

**Microsomal Clearance:** Ligand A (20.422) has lower clearance, indicating better metabolic stability than Ligand B (86.457). This favors Ligand A.

**In vitro Half-Life:** Ligand A (-3.869) has a negative half-life, which is not physically possible and indicates an issue with the data. Ligand B (67.813) has a good in vitro half-life.

**P-gp Efflux:** Ligand A (0.068) has low P-gp efflux, which is good for CNS penetration. Ligand B (0.514) has moderate P-gp efflux. Ligand A is preferred.

**Binding Affinity:** Ligand B (-8.6 kcal/mol) has a significantly stronger binding affinity than Ligand A (-7.3 kcal/mol). This is a substantial advantage for Ligand B, potentially outweighing some of its ADME drawbacks.

**Overall Assessment:**

Ligand B clearly wins on the most important criteria for a CNS-targeting GPCR ligand: BBB penetration and binding affinity. While Ligand A has better hERG and P-gp profiles, the poor BBB penetration is a deal-breaker. The slightly higher logP of Ligand B is acceptable, and its better affinity is a significant advantage. The issues with Ligand A's half-life are also concerning.

Output:
1
2025-04-17 05:34:23,756 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (339.4) is slightly lower, which could be advantageous for permeability.

**TPSA:** Ligand A (85.35) is better than Ligand B (61.94) as it is closer to the ideal range for CNS targets (<=90). Ligand B is quite low, which might indicate reduced hydrogen bonding and potentially lower aqueous solubility.

**logP:** Ligand A (0.895) is a bit low, potentially hindering membrane permeability. Ligand B (3.414) is within the optimal range (1-3).

**H-Bond Donors/Acceptors:** Ligand A has 2 HBD and 5 HBA, which is reasonable. Ligand B has 0 HBD and 6 HBA. Both are acceptable, but the lack of HBD in B might affect solubility.

**QED:** Both ligands have similar QED values (0.791 and 0.774), indicating good drug-like properties.

**DILI:** Ligand A (75.38) has a higher DILI risk than Ligand B (60.41), which is preferable.

**BBB:** Ligand B (95.81) significantly outperforms Ligand A (20.86) in BBB penetration, a critical factor for CNS targets like DRD2. This is a major advantage for Ligand B.

**Caco-2 Permeability:** Ligand A (-4.979) shows better Caco-2 permeability than Ligand B (-4.255), suggesting better intestinal absorption. However, given the target is in the CNS, this is less important than BBB penetration.

**Aqueous Solubility:** Ligand A (-2.39) has better aqueous solubility than Ligand B (-4.085).

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.551 and 0.214).

**Microsomal Clearance:** Ligand A (-21.03) has a much lower (better) microsomal clearance than Ligand B (66.66), indicating better metabolic stability.

**In vitro Half-Life:** Ligand A (-2.335) has a shorter half-life than Ligand B (-32.003).

**P-gp Efflux:** Both ligands show low P-gp efflux liability (0.025 and 0.341).

**Binding Affinity:** Both ligands have similar, strong binding affinities (-8.3 and -8.7 kcal/mol). The difference is negligible.

**Overall Assessment:**

Ligand B is the stronger candidate. While Ligand A has better metabolic stability (lower Cl_mic) and solubility, Ligand B's *exceptional* BBB penetration (95.81%) is the deciding factor for a CNS target like DRD2. The slightly higher logP of Ligand B is also beneficial. The lower DILI risk of Ligand B is also a plus. Although Ligand A has better Caco-2 permeability, this is less crucial for a CNS-acting drug.

Output:
1
2025-04-17 05:34:23,757 - INFO - Reasoning:

Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (356.423 and 366.527 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (127.84) is higher than the preferred <90 for CNS targets, but still potentially acceptable. Ligand B (78.43) is excellent, well below 90, suggesting better CNS penetration potential.

**3. logP:** Ligand A (-0.511) is quite low, potentially hindering membrane permeability. Ligand B (1.714) is within the optimal 1-3 range. This is a significant advantage for Ligand B.

**4. H-Bond Donors:** Ligand A (4) is at the upper limit of the preferred range, while Ligand B (3) is good.

**5. H-Bond Acceptors:** Both ligands have 5 and 4 acceptors, respectively, both within acceptable limits.

**6. QED:** Both ligands have reasonable QED values (0.392 and 0.572), with Ligand B being slightly more drug-like.

**7. DILI:** Ligand A (51.842) has a moderate DILI risk, while Ligand B (27.065) has a lower, more favorable risk profile.

**8. BBB:** Both ligands have similar BBB penetration percentiles (52.268 and 50.252). Neither is exceptional (>70), but they are not terrible either.

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.497 and -5.674), which is unusual and suggests poor permeability. This is a concern for both.

**10. Aqueous Solubility:** Both ligands have negative solubility values (-1.663 and -2.779), which is also unusual and suggests poor solubility. This is a concern for both.

**11. hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.054 and 0.245).

**12. Microsomal Clearance:** Ligand A (4.615) has a lower clearance than Ligand B (23.316), indicating better metabolic stability.

**13. In vitro Half-Life:** Ligand B (31.375) has a significantly longer half-life than Ligand A (3.229). This is a major advantage for Ligand B, potentially allowing for less frequent dosing.

**14. P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.008 and 0.116).

**15. Binding Affinity:** Ligand B (-7.8 kcal/mol) has a stronger binding affinity than Ligand A (-7.1 kcal/mol). The 0.7 kcal/mol difference is substantial and can outweigh some ADME drawbacks.

**Overall Assessment:**

While both ligands have issues with Caco-2 permeability and solubility, Ligand B is the stronger candidate. Its superior logP, lower DILI risk, significantly longer half-life, and stronger binding affinity outweigh the slightly higher TPSA and lower metabolic stability compared to Ligand A. For a CNS target like DRD2, the better logP and affinity of Ligand B are particularly important.

Output:
1
2025-04-17 05:34:23,757 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (356.413 and 357.47 Da) fall comfortably within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (67.43) is slightly higher than Ligand B (64.09), but both are below the 90 A^2 threshold desirable for CNS targets.

**3. logP:** Ligand A (1.863) is within the optimal 1-3 range. Ligand B (0.743) is a bit low, potentially impacting permeability.

**4. H-Bond Donors:** Ligand A (2) and Ligand B (1) are both acceptable, below the 5 limit.

**5. H-Bond Acceptors:** Ligand A (3) and Ligand B (4) are both below the 10 limit.

**6. QED:** Both ligands have similar QED values (0.685 and 0.696), indicating good drug-like properties.

**7. DILI:** Ligand A (31.059) has a significantly lower DILI risk than Ligand B (8.724), which is a substantial advantage.

**8. BBB:** Ligand A (81.466) has a better BBB penetration percentile than Ligand B (76.696). While both are reasonably good, A is closer to the desirable >70 threshold for CNS targets.

**9. Caco-2 Permeability:** Ligand A (-4.657) has worse Caco-2 permeability than Ligand B (-4.579), but both are very poor.

**10. Aqueous Solubility:** Ligand A (-2.969) has worse aqueous solubility than Ligand B (-1.073).

**11. hERG Inhibition:** Both ligands have low hERG inhibition risk (0.322 and 0.471).

**12. Microsomal Clearance:** Ligand A (3.435) has significantly lower microsomal clearance than Ligand B (32.521), suggesting better metabolic stability.

**13. In vitro Half-Life:** Ligand A (1.013) has a shorter half-life than Ligand B (-13.59), which is a significant drawback.

**14. P-gp Efflux:** Ligand A (0.02) has much lower P-gp efflux than Ligand B (0.067), which is favorable for CNS penetration.

**15. Binding Affinity:** Ligand A (-8.7 kcal/mol) has a slightly better binding affinity than Ligand B (-7.8 kcal/mol). The difference is 0.9 kcal/mol, which is substantial.

**Overall Assessment:**

Ligand A is the stronger candidate. While it has poorer Caco-2 permeability and in vitro half-life, its superior binding affinity, significantly lower DILI risk, better BBB penetration, lower P-gp efflux, and lower microsomal clearance outweigh these drawbacks, especially considering the target is a CNS GPCR. The affinity difference is also significant. Ligand B's lower logP is a concern for permeability, and its higher DILI risk is a major flag.

Output:
1
2025-04-17 05:34:23,757 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (347.455 and 350.419 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (64.63) is significantly better than Ligand B (115.57). For CNS targets, we want TPSA <= 90, so Ligand A is much closer to this threshold. Ligand B is considerably higher and may struggle with brain penetration.

**3. logP:** Ligand A (3.454) is within the optimal range (1-3). Ligand B (0.342) is quite low, potentially hindering membrane permeability and CNS entry.

**4. H-Bond Donors:** Ligand A (1) is good. Ligand B (3) is acceptable, but higher HBD can sometimes reduce permeability.

**5. H-Bond Acceptors:** Ligand A (4) is good. Ligand B (6) is higher, potentially impacting permeability.

**6. QED:** Ligand A (0.801) is excellent, indicating strong drug-likeness. Ligand B (0.582) is acceptable, but lower.

**7. DILI:** Both ligands have similar DILI risk (53.974 and 53.276), both falling under the 'good' category (<60).

**8. BBB:** Ligand A (64.831) is reasonable, but not optimal. Ligand B (73.401) is better, exceeding the 70% threshold desirable for CNS targets. This is a key advantage for Ligand B.

**9. Caco-2:** Ligand A (-4.457) and Ligand B (-5.376) both have negative values, which is unusual. Without knowing the scale, it's hard to interpret, but lower values generally indicate poorer permeability.

**10. Solubility:** Ligand A (-5.264) and Ligand B (-2.087) both have negative solubility values, which is also unusual. Lower values indicate poorer solubility.

**11. hERG:** Ligand A (0.735) is better than Ligand B (0.288), indicating lower risk of cardiotoxicity.

**12. Cl_mic:** Ligand A (108.65) has a higher clearance than Ligand B (-2.726).  Negative clearance is unusual and likely indicates high metabolic stability. Ligand B is significantly better in this regard.

**13. t1/2:** Ligand A (9.2) is better than Ligand B (0.474). A longer half-life is generally preferred.

**14. Pgp:** Ligand A (0.647) is better than Ligand B (0.005), indicating lower P-gp efflux. Lower efflux is crucial for CNS penetration.

**15. Affinity:** Ligand A (-7.9) has a slightly better binding affinity than Ligand B (-7.6). While both are good, the 0.3 kcal/mol difference isn't huge.

**Overall Assessment:**

Ligand B excels in BBB penetration and metabolic stability (Cl_mic), which are critical for CNS GPCR targets. However, it suffers from a low logP and higher TPSA, potentially hindering permeability. Ligand A has a more favorable logP and TPSA, better solubility, and a slightly better binding affinity, but its BBB penetration is less promising and its metabolic stability is lower.

Considering the GPCR-specific priorities, the balance tips toward **Ligand B** due to its superior BBB penetration and metabolic stability. While the lower logP is a concern, the strong affinity and excellent BBB may compensate for this, especially with potential optimization.

Output:
1
2025-04-17 05:34:23,757 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight (MW):** Both ligands are within the ideal range (200-500 Da). Ligand A (353.463 Da) is slightly lower, which could be beneficial for permeability.

**2. TPSA:** Ligand A (87.74) is excellent, falling well below the 90 Angstrom threshold for CNS targets. Ligand B (104.05) is still reasonable but less optimal.

**3. logP:** Both ligands have good logP values (A: 0.849, B: 0.777), falling within the 1-3 range.

**4. H-Bond Donors (HBD):** Both are acceptable (A: 2, B: 1), well below the limit of 5.

**5. H-Bond Acceptors (HBA):** Ligand A (4) is good. Ligand B (9) is approaching the upper limit of 10, potentially impacting permeability.

**6. QED:** Both have acceptable QED scores (A: 0.45, B: 0.772), with Ligand B being significantly more drug-like.

**7. DILI:** Ligand A (7.29) has a much lower DILI risk than Ligand B (77.2), which is quite high. This is a significant advantage for Ligand A.

**8. BBB:** Ligand A (66.499) has a better BBB percentile than Ligand B (57.425), though both are not ideal (>70 is preferred).

**9. Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and suggests poor permeability. However, the scale is not specified, so it's difficult to interpret.

**10. Aqueous Solubility:** Both have negative solubility values, again making interpretation difficult without knowing the scale.

**11. hERG Inhibition:** Both have low hERG inhibition liability (A: 0.237, B: 0.128).

**12. Microsomal Clearance:** Ligand A (9.159) has significantly lower microsomal clearance than Ligand B (40.462), indicating better metabolic stability.

**13. In vitro Half-Life:** Ligand A (-14.978) has a much longer in vitro half-life than Ligand B (11.835).

**14. P-gp Efflux:** Both have very low P-gp efflux liability (A: 0.012, B: 0.051).

**15. Binding Affinity:** Ligand B (-8.3 kcal/mol) has a slightly better binding affinity than Ligand A (-7.3 kcal/mol). The difference is 1 kcal/mol, which is a notable, but not overwhelming advantage.

**Overall Assessment:**

While Ligand B has a slightly better binding affinity and QED, Ligand A is significantly better across several critical ADME properties. Specifically, its lower DILI risk, better BBB penetration, lower microsomal clearance, and longer half-life are highly desirable, especially for a CNS target like DRD2. The TPSA of Ligand A is also more favorable. The slight difference in binding affinity is likely surmountable with further optimization, while the ADME advantages of Ligand A are more difficult to improve later in the drug discovery process.

Output:
0
2025-04-17 05:34:23,758 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (366.483 Da) is slightly higher than Ligand B (349.479 Da), but both are acceptable.

**TPSA:** Ligand A (75.71) is significantly better than Ligand B (94.14). For CNS targets, we want TPSA <= 90, so Ligand A is preferable.

**logP:** Both ligands have good logP values (A: 1.846, B: 1.731), falling within the optimal range of 1-3.

**H-Bond Donors/Acceptors:** Ligand A (HBD=1, HBA=4) is better than Ligand B (HBD=3, HBA=5). Lower values are generally preferred for better permeability.

**QED:** Both ligands have similar and good QED values (A: 0.747, B: 0.77), indicating good drug-like properties.

**DILI:** Ligand A (37.146) has a much lower DILI risk than Ligand B (29.43). Both are good, but A is better.

**BBB:** This is a crucial parameter for CNS targets. Ligand A (81.698) has a significantly higher BBB penetration percentile than Ligand B (57.619). This is a major advantage for Ligand A.

**Caco-2 Permeability:** Ligand A (-4.65) is better than Ligand B (-5.197), indicating better intestinal absorption.

**Aqueous Solubility:** Ligand A (-1.979) is better than Ligand B (-2.387), indicating better solubility.

**hERG Inhibition:** Both ligands have very low hERG inhibition risk (A: 0.547, B: 0.233).

**Microsomal Clearance:** Ligand A (32.42) has a higher (worse) microsomal clearance than Ligand B (14.992). This suggests Ligand B is more metabolically stable.

**In vitro Half-Life:** Ligand B (-21.867) has a much longer in vitro half-life than Ligand A (-7.872). This is a significant advantage for Ligand B.

**P-gp Efflux:** Ligand A (0.399) has lower P-gp efflux than Ligand B (0.056), meaning it is less likely to be pumped out of the brain, improving CNS exposure.

**Binding Affinity:** Ligand A (-8.9 kcal/mol) has a slightly better binding affinity than Ligand B (-7.6 kcal/mol). While both are good, the 1.3 kcal/mol difference is significant and can outweigh some ADME drawbacks.

**Overall Assessment:**

Ligand A excels in TPSA, BBB, DILI, solubility, and binding affinity. Its P-gp efflux is also better. Ligand B has better metabolic stability (lower Cl_mic) and a longer half-life. However, the superior BBB penetration and binding affinity of Ligand A, combined with its acceptable ADME profile, make it the more promising candidate for a CNS-targeting drug like a DRD2 ligand. The difference in binding affinity is substantial enough to compensate for the slightly higher Cl_mic.

Output:
1
2025-04-17 05:34:23,758 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (368.499 and 368.459 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (82.78) is significantly better than Ligand B (101.49). For CNS targets, we want TPSA <= 90, so Ligand A is preferable.

**3. logP:** Ligand A (2.059) is within the optimal range (1-3). Ligand B (0.346) is quite low, potentially hindering membrane permeability and CNS penetration.

**4. H-Bond Donors:** Both ligands have acceptable HBD counts (2 and 1, respectively), well below the threshold of 5.

**5. H-Bond Acceptors:** Both ligands have acceptable HBA counts (5 and 6, respectively), well below the threshold of 10.

**6. QED:** Both ligands have similar and good QED values (0.77 and 0.745), indicating good drug-like properties.

**7. DILI:** Both ligands have elevated DILI risk (61.07 and 66.499), but are still within acceptable range (<60 is good, >60 is high risk).

**8. BBB:** Ligand B (75.029) has a notably better BBB percentile than Ligand A (34.548). This is a critical factor for CNS targets like DRD2.

**9. Caco-2 Permeability:** Ligand A (-5.149) shows poor Caco-2 permeability, while Ligand B (-4.74) is slightly better, but still poor.

**10. Aqueous Solubility:** Both ligands have very poor aqueous solubility (-3.148 and -3.097).

**11. hERG Inhibition:** Both ligands have low hERG inhibition risk (0.315 and 0.258).

**12. Microsomal Clearance:** Ligand B (43.223) has lower microsomal clearance than Ligand A (55.44), suggesting better metabolic stability.

**13. In vitro Half-Life:** Ligand A (52.235) has a longer in vitro half-life than Ligand B (-52.89), which is a positive attribute.

**14. P-gp Efflux:** Both ligands have low P-gp efflux liability (0.314 and 0.044).

**15. Binding Affinity:** Ligand B (-8.2 kcal/mol) has a significantly stronger binding affinity than Ligand A (-7.7 kcal/mol). The difference of 0.5 kcal/mol is substantial and can outweigh some ADME drawbacks.

**Overall Assessment:**

Ligand B has a significantly better binding affinity and a much improved BBB penetration, which are crucial for a CNS-targeting GPCR like DRD2. While Ligand A has a better TPSA and in vitro half-life, the superior affinity and BBB of Ligand B are more important. The lower logP of Ligand B is a concern, but the strong binding affinity might compensate for it. The similar DILI risk and low hERG inhibition are acceptable for both.

Output:
1
2025-04-17 05:34:23,758 - INFO - Reasoning:

Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (358.31 and 390.546 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (41.99) is excellent, well below the 90 A^2 threshold for CNS targets. Ligand B (58.64) is still reasonable but less optimal.

**3. logP:** Ligand A (4.599) is a bit high, potentially leading to solubility issues or off-target interactions. Ligand B (1.705) is within the optimal range of 1-3.

**4. H-Bond Donors:** Both ligands have 1 HBD, which is acceptable.

**5. H-Bond Acceptors:** Ligand A has 2 HBA, and Ligand B has 5. Both are below the 10 threshold, but Ligand A is preferable.

**6. QED:** Both ligands have good QED scores (0.627 and 0.774), indicating drug-like properties.

**7. DILI:** Ligand A has a DILI risk of 65.491, which is moderately high. Ligand B has a much lower DILI risk of 37.069, which is preferable.

**8. BBB:** Both ligands have excellent BBB penetration (84.917 and 81.349), exceeding the 70% threshold for CNS targets.

**9. Caco-2 Permeability:** Both have negative Caco-2 values (-4.601 and -4.755), which is unusual and suggests poor permeability. This is a significant concern for both.

**10. Aqueous Solubility:** Both ligands have very poor aqueous solubility (-5.276 and -3.136). This is a major drawback, especially given Ligand A's already high logP.

**11. hERG Inhibition:** Ligand A (0.761) has a slightly higher hERG risk than Ligand B (0.388), though both are relatively low.

**12. Microsomal Clearance:** Ligand A (67.028) has a higher microsomal clearance than Ligand B (33.397), indicating lower metabolic stability.

**13. In vitro Half-Life:** Ligand A (-5.468) has a shorter in vitro half-life than Ligand B (-3.687).

**14. P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.151 and 0.074), which is good for CNS penetration.

**15. Binding Affinity:** Ligand B (-8.2 kcal/mol) has significantly stronger binding affinity than Ligand A (-9.0 kcal/mol). This is a substantial advantage.

**Overall Assessment:**

While both ligands have poor solubility and Caco-2 permeability, Ligand B is the stronger candidate. It has a better logP, a much lower DILI risk, better metabolic stability (lower Cl_mic, longer t1/2), and, crucially, significantly higher binding affinity. The higher affinity could potentially compensate for the ADME deficiencies, and formulation strategies might be employed to address the solubility issue. Ligand A's high logP and DILI risk, coupled with its weaker binding, make it less attractive.

Output:
1
2025-04-17 05:34:23,758 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (387.238 Da) is slightly higher than Ligand B (338.411 Da), but both are acceptable.

**TPSA:** Ligand A (59.59) is excellent for CNS penetration, well below the 90 A^2 threshold. Ligand B (75.19) is still reasonable, but less optimal.

**logP:** Ligand A (4.019) is at the upper end of the optimal range, potentially raising concerns about solubility and off-target effects. Ligand B (2.128) is well within the optimal range.

**H-Bond Donors/Acceptors:** Ligand A (HBD=2, HBA=3) and Ligand B (HBD=1, HBA=4) both have reasonable numbers of H-bond donors and acceptors, falling within the guidelines.

**QED:** Both ligands have good QED scores (Ligand A: 0.706, Ligand B: 0.927), indicating good drug-like properties.

**DILI:** Ligand A (68.088) has a higher DILI risk than Ligand B (49.399), suggesting potential liver toxicity concerns.

**BBB:** Ligand A (74.99) has a very good BBB penetration percentile, exceeding the desirable threshold of 70. Ligand B (57.774) is lower, which is a significant drawback for a CNS target.

**Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and likely indicates an issue with the prediction method or the molecule itself. It's hard to draw conclusions from this.

**Aqueous Solubility:** Both have negative solubility values, which is also unusual. Again, hard to draw conclusions.

**hERG:** Ligand A (0.86) has a slightly higher hERG risk than Ligand B (0.357), but both are relatively low.

**Microsomal Clearance:** Ligand A (71.882) has higher microsomal clearance, indicating faster metabolism and potentially lower exposure. Ligand B (15.426) has much lower clearance, suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (33.68) has a shorter half-life than Ligand B (6.942), which is less desirable.

**P-gp Efflux:** Ligand A (0.537) has lower P-gp efflux than Ligand B (0.03), which is favorable for CNS penetration.

**Binding Affinity:** Ligand B (-8.2 kcal/mol) has a significantly stronger binding affinity than Ligand A (-9.3 kcal/mol). This is a substantial advantage.

**Overall Assessment:**

While Ligand A has good BBB penetration and P-gp efflux, its higher logP, DILI risk, faster clearance, shorter half-life, and weaker binding affinity are concerning. Ligand B, despite a lower BBB score, is superior in most other key parameters, especially its significantly stronger binding affinity and improved metabolic stability. The difference in affinity is substantial enough to outweigh the lower BBB score, especially considering the other favorable properties.

Output:
1
2025-04-17 05:34:23,758 - INFO - Batch 209 complete. Total preferences: 3344
2025-04-17 05:34:23,759 - INFO - Processing batch 210/512...
2025-04-17 05:35:05,180 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (370.515 Da) and Ligand B (348.462 Da) are both acceptable.

**TPSA:** Ligand A (81.08) is better than Ligand B (41.57). For CNS targets, we want TPSA <= 90, both are within range, but A is closer to the upper limit.

**logP:** Ligand B (3.846) is higher than Ligand A (0.712). While 0.712 isn't terrible, it's on the lower side and might hinder membrane permeability. 3.846 is approaching the upper limit of the optimal range, but still acceptable.

**H-Bond Donors/Acceptors:** Ligand A has 2 HBD and 5 HBA, while Ligand B has 1 HBD and 3 HBA. Both are within acceptable limits (<=5 HBD, <=10 HBA).

**QED:** Ligand A (0.72) has a slightly better QED score than Ligand B (0.544), indicating a more drug-like profile.

**DILI:** Ligand A (14.424) has a significantly lower DILI risk than Ligand B (18.651), which is a major advantage.

**BBB:** Ligand B (87.088) has a much higher BBB penetration percentile than Ligand A (43.117). This is *critical* for a CNS target like DRD2.

**Caco-2 Permeability:** Ligand A (-5.085) has a negative value, which is unusual and suggests very poor permeability. Ligand B (-4.606) is also poor, but less so.

**Aqueous Solubility:** Ligand A (-1.725) has very poor solubility, while Ligand B (-4.038) is also poor.

**hERG Inhibition:** Ligand A (0.299) has a lower hERG inhibition risk than Ligand B (0.948), which is favorable.

**Microsomal Clearance:** Ligand B (62.439) has higher clearance than Ligand A (33.75), meaning A is more metabolically stable.

**In vitro Half-Life:** Ligand A (-4.576) has a shorter half-life than Ligand B (25.21).

**P-gp Efflux:** Ligand A (0.022) has much lower P-gp efflux liability than Ligand B (0.418), which is highly desirable for CNS penetration.

**Binding Affinity:** Ligand B (-7.1) has slightly better binding affinity than Ligand A (-7.3), but the difference is small (0.2 kcal/mol).

**Overall Assessment:**

Ligand B excels in BBB penetration and has slightly better binding affinity. However, Ligand A has significantly better DILI risk, lower P-gp efflux, lower microsomal clearance (better metabolic stability), and a better QED score. The poor Caco-2 and solubility of both are concerning, but the strong BBB penetration of Ligand B is a major advantage for a CNS target. The difference in affinity is small enough to be potentially overcome with further optimization. Given the importance of BBB penetration for DRD2, and the relatively small difference in binding affinity, Ligand B is the more promising candidate.

Output:
1
2025-04-17 05:35:05,181 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (338.411 Da) is slightly lower, which is generally favorable for permeability.

**TPSA:** Ligand A (73.47) is significantly better than Ligand B (114.99). For CNS targets, TPSA should be <=90, and A is comfortably within this range, while B is pushing the limit.

**logP:** Ligand A (3.813) is optimal (1-3), while Ligand B (-0.739) is quite low, potentially hindering membrane permeability and brain penetration.

**H-Bond Donors/Acceptors:** Both have acceptable HBD counts (3). Ligand B has a higher HBA count (6) compared to A (2), which could slightly impact permeability.

**QED:** Ligand A (0.775) has a better QED score than Ligand B (0.468), indicating a more drug-like profile.

**DILI:** Ligand B (44.203) has a much lower DILI risk than Ligand A (79.449), which is a significant advantage.

**BBB:** Ligand A (61.807) is better than Ligand B (51.105), but both are below the desirable >70 percentile for CNS targets. However, given the other factors, this is less critical.

**Caco-2 Permeability:** Ligand A (-4.935) is better than Ligand B (-5.682), indicating better intestinal absorption.

**Aqueous Solubility:** Ligand A (-4.707) is better than Ligand B (-1.63), which is important for formulation.

**hERG:** Ligand A (0.545) has a slightly higher hERG risk than Ligand B (0.1), which is a concern.

**Microsomal Clearance:** Ligand B (-8.546) has a significantly *lower* (better) microsomal clearance than Ligand A (7.258), indicating greater metabolic stability.

**In vitro Half-Life:** Ligand B (14.687) has a longer half-life than Ligand A (57.514), which is generally desirable.

**P-gp Efflux:** Ligand A (0.221) has a lower P-gp efflux liability than Ligand B (0.004), which is crucial for CNS penetration.

**Binding Affinity:** Ligand A (-10.1 kcal/mol) has a significantly stronger binding affinity than Ligand B (-7.3 kcal/mol). This is a substantial advantage, potentially outweighing some of the ADME drawbacks.

**Overall Assessment:**

Ligand A has a superior binding affinity and better permeability characteristics (TPSA, logP, Caco-2, P-gp). However, it has a higher DILI risk and hERG inhibition liability. Ligand B has better metabolic stability (lower Cl_mic, longer t1/2) and lower DILI/hERG risks, but suffers from poor logP and a weaker binding affinity.

Given the GPCR-specific priorities, the strong binding affinity of Ligand A is a major advantage. While the DILI and hERG risks are concerns, they might be mitigated through structural modifications. The poor logP of Ligand B is a more fundamental issue that would be harder to address without significantly impacting affinity.

Output:
1
2025-04-17 05:35:05,181 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 drug candidates, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (350.459 Da and 364.471 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (66.92) is significantly better than Ligand B (85.25). For CNS targets, we want TPSA <= 90, and A is comfortably within this range, while B is approaching the upper limit.

**logP:** Both ligands have acceptable logP values (1.825 and 0.879), falling within the 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A (0 HBD, 4 HBA) is preferable to Ligand B (2 HBD, 6 HBA). Lower values generally improve permeability.

**QED:** Both ligands have good QED scores (0.71 and 0.783), indicating good drug-like properties.

**DILI:** Ligand A (12.718) has a much lower DILI risk than Ligand B (63.746). This is a significant advantage for A.

**BBB:** Ligand A (76.541) has a substantially better BBB penetration score than Ligand B (52.036).  A score >70 is desirable for CNS targets, and A is closer to this threshold.

**Caco-2 Permeability:** Ligand A (-4.36) has better Caco-2 permeability than Ligand B (-5.561), though both are negative values which is unusual and requires further investigation.

**Aqueous Solubility:** Ligand B (-2.097) has slightly better aqueous solubility than Ligand A (-1.67), but both are poor. Solubility isn't a major concern if permeability is good.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.283 and 0.449).

**Microsomal Clearance:** Ligand B (28.671) has lower microsomal clearance than Ligand A (77.294), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand B (21.702) has a longer in vitro half-life than Ligand A (-19.347). This is a significant advantage for B.

**P-gp Efflux:** Ligand A (0.038) has significantly lower P-gp efflux than Ligand B (0.07). Lower P-gp efflux is preferred, especially for CNS targets.

**Binding Affinity:** Ligand B (-7.6) has a slightly better binding affinity than Ligand A (-8.2). However, the difference is relatively small (0.6 kcal/mol), and other factors are more important.

**Overall Assessment:**

Ligand A is the more promising candidate. While Ligand B has better metabolic stability and half-life, Ligand A excels in crucial areas for CNS GPCR targets: TPSA, BBB penetration, DILI risk, and P-gp efflux. The slightly better affinity of Ligand B is unlikely to outweigh the advantages of Ligand A regarding CNS penetration and safety.

Output:
0
2025-04-17 05:35:05,181 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (342.403 and 348.495 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (87.12) is better than Ligand B (77.15) as it is closer to the ideal range of <=90 for CNS targets.

**3. logP:** Both ligands (1.36 and 1.631) are within the optimal range of 1-3, suggesting good permeability and avoiding solubility issues. Ligand B is slightly higher, which could be beneficial, but not significantly.

**4. H-Bond Donors:** Ligand A (1) is better than Ligand B (2). Lower HBD is generally preferred for CNS penetration.

**5. H-Bond Acceptors:** Both ligands have the same number of HBA (5), which is within the acceptable limit of <=10.

**6. QED:** Both ligands have similar QED values (0.859 and 0.817), indicating good drug-likeness.

**7. DILI:** Ligand A (59.907) has a higher DILI risk than Ligand B (8.414). This is a significant drawback for Ligand A.

**8. BBB:** Both ligands have similar BBB penetration (51.415 and 58.278). Neither is above the desirable threshold of >70, but they are comparable.

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.303 and -5.522), which is unusual and suggests poor permeability. This is a concern for both.

**10. Aqueous Solubility:** Both ligands have negative solubility values (-1.986 and -1.324), indicating poor aqueous solubility. This is a concern for both.

**11. hERG Inhibition:** Both ligands have low hERG inhibition risk (0.507 and 0.33).

**12. Microsomal Clearance:** Ligand A (18.732) has a higher microsomal clearance than Ligand B (-8.728). This means Ligand B is more metabolically stable, which is desirable.

**13. In vitro Half-Life:** Ligand A (-24.777) has a significantly shorter in vitro half-life than Ligand B (-0.487). This is a major drawback for Ligand A.

**14. P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.04 and 0.02).

**15. Binding Affinity:** Ligand A (-7.9) has slightly better binding affinity than Ligand B (-8.3). However, the difference is relatively small (0.4 kcal/mol) and may not outweigh other significant ADME differences.

**Overall Assessment:**

Ligand B is the more promising candidate. While both have issues with Caco-2 permeability and aqueous solubility, Ligand B demonstrates significantly better metabolic stability (lower Cl_mic, longer t1/2) and a much lower DILI risk. The slightly better affinity of Ligand A is not enough to compensate for these substantial drawbacks. Given the GPCR-specific focus on BBB, logP, Pgp, TPSA, and affinity, Ligand B's superior ADME profile makes it a better starting point for further optimization.

Output:
1
2025-04-17 05:35:05,181 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (355.435 and 376.523 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (96.97) is excellent, falling well below the 90 A^2 threshold for CNS targets. Ligand B (121.6) is still reasonable but less optimal, exceeding the 90 A^2 threshold.

**logP:** Ligand A (-0.449) is slightly low, potentially hindering permeability. Ligand B (0.371) is better, falling within the 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A (2 HBD, 5 HBA) and Ligand B (3 HBD, 4 HBA) both have acceptable counts, within the recommended limits.

**QED:** Both ligands have reasonable QED scores (0.546 and 0.477), indicating good drug-like properties.

**DILI:** Ligand A (20.706) has a significantly lower DILI risk than Ligand B (33.695), which is a substantial advantage.

**BBB:** Ligand A (54.246) has a moderate BBB penetration, while Ligand B (43.815) has a lower BBB penetration. While both are below the ideal >70, A is better.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.22 and -5.38), which is unusual and suggests poor permeability. This is a significant concern for both.

**Aqueous Solubility:** Both ligands have negative solubility values (-0.714 and -1.785), indicating poor aqueous solubility. This is a concern for both.

**hERG Inhibition:** Both ligands have very low hERG inhibition liability (0.076 and 0.219), which is excellent.

**Microsomal Clearance:** Ligand A (32.979) has lower microsomal clearance compared to Ligand B (40.419), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (-21.335) has a negative half-life, which is not possible. Ligand B (-7.543) also has a negative half-life, which is not possible. This is a major red flag for both.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.007 and 0.006), which is favorable for CNS penetration.

**Binding Affinity:** Ligand A (-7.4 kcal/mol) has a slightly better binding affinity than Ligand B (-7.1 kcal/mol), although the difference is relatively small.

**Overall Assessment:**

Ligand A is the better candidate. While both have issues with Caco-2 permeability, solubility, and half-life, Ligand A has a significantly lower DILI risk, better TPSA, slightly better BBB penetration, and slightly better binding affinity. The lower microsomal clearance is also a plus. The negative half-life values are concerning for both, but the other advantages of Ligand A make it the more promising starting point for optimization.

Output:
0
2025-04-17 05:35:05,181 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (407.327 Da) is slightly higher than Ligand B (369.412 Da), but both are acceptable.

**2. TPSA:**  Both ligands have TPSA values below the 90 A^2 threshold for CNS targets, which is good. Ligand A (41.13 A^2) is a bit higher than Ligand B (36.44 A^2), but both are favorable.

**3. logP:** Both ligands have logP values within the optimal range (1-3). Ligand A (4.891) is slightly above this range, potentially raising concerns about solubility and off-target effects. Ligand B (2.992) is ideal.

**4. H-Bond Donors:** Ligand A (2) is within the acceptable limit of <=5. Ligand B (0) is also good.

**5. H-Bond Acceptors:** Ligand A (1) is well within the acceptable limit of <=10. Ligand B (4) is also good.

**6. QED:** Both ligands have QED values above 0.5, indicating good drug-like properties. Ligand B (0.813) is slightly better than Ligand A (0.631).

**7. DILI:** Both ligands have acceptable DILI risk, below 40. Ligand B (42.109) is slightly higher than Ligand A (46.297), but both are reasonably low.

**8. BBB:** Both ligands demonstrate good BBB penetration, with Ligand B (88.833) being significantly better than Ligand A (78.751). This is a crucial factor for a CNS target like DRD2.

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 permeability values, which is unusual and suggests a potential issue with intestinal absorption. However, these values are on a strange scale and may not be directly comparable.

**10. Aqueous Solubility:** Both ligands have negative solubility values, which is also unusual and suggests poor solubility. Again, the scale is unclear.

**11. hERG Inhibition:** Both ligands have low hERG inhibition liability, which is good. Ligand A (0.936) is slightly higher than Ligand B (0.738), but both are acceptable.

**12. Microsomal Clearance:** Ligand A (87.472) has significantly higher microsomal clearance than Ligand B (27.48), indicating lower metabolic stability.

**13. In vitro Half-Life:** Ligand A (77.15) has a longer in vitro half-life than Ligand B (2.227), which is generally desirable.

**14. P-gp Efflux:** Ligand A (0.738) has lower P-gp efflux than Ligand B (0.174), which is favorable for CNS penetration.

**15. Binding Affinity:** Ligand B (-7.9 kcal/mol) has a significantly stronger binding affinity than Ligand A (-10 kcal/mol). This is a substantial advantage.

**Overall Assessment:**

Ligand B is the stronger candidate. While Ligand A has a slightly longer half-life and lower P-gp efflux, Ligand B's superior binding affinity (-7.9 vs -10 kcal/mol) and significantly better BBB penetration (88.833 vs 78.751) outweigh the drawbacks. The lower microsomal clearance of Ligand B is also a significant advantage, suggesting better metabolic stability. Ligand A's higher logP is a concern.

Output:
1
2025-04-17 05:35:05,181 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (346.471 and 345.491 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (69.64) is slightly higher than Ligand B (61.36). Both are below the 90 A^2 threshold desirable for CNS targets, but Ligand B is preferable.

**3. logP:** Both ligands have a logP around 2.68-2.69, which is within the optimal 1-3 range.

**4. H-Bond Donors:** Ligand A has 2 HBD, and Ligand B has 1. Both are acceptable (<=5).

**5. H-Bond Acceptors:** Ligand A has 3 HBA, and Ligand B has 5. Both are acceptable (<=10).

**6. QED:** Ligand B (0.889) has a significantly better QED score than Ligand A (0.676), indicating better overall drug-likeness.

**7. DILI:** Ligand A (35.983) has a lower DILI risk than Ligand B (50.33), which is favorable.

**8. BBB:** Ligand B (89.027) has a much higher BBB penetration percentile than Ligand A (66.615). This is *critical* for a CNS target like DRD2.

**9. Caco-2 Permeability:** Both have negative values, indicating poor permeability. Ligand A (-4.519) is slightly worse than Ligand B (-4.848).

**10. Aqueous Solubility:** Both ligands have negative solubility values, indicating poor solubility. Ligand A (-2.825) is slightly better than Ligand B (-2.587).

**11. hERG Inhibition:** Both ligands have low hERG inhibition risk (0.598 and 0.639).

**12. Microsomal Clearance:** Both have similar microsomal clearance (74.427 and 71.977).

**13. In vitro Half-Life:** Ligand B (-1.038) has a negative half-life, which is concerning. Ligand A (27.972) has a reasonable half-life.

**14. P-gp Efflux:** Both ligands have low P-gp efflux liability (0.606 and 0.294). Ligand B is better.

**15. Binding Affinity:** Ligand B (-9.1 kcal/mol) has a significantly stronger binding affinity than Ligand A (-8.4 kcal/mol). This >1.5 kcal/mol difference is substantial and can outweigh some ADME drawbacks.

**Overall Assessment:**

While Ligand A has a better DILI score and in vitro half-life, Ligand B is significantly better in several key areas for a CNS-targeting GPCR: superior BBB penetration, higher QED, stronger binding affinity, and lower P-gp efflux. The stronger binding affinity is a major advantage. The negative half-life of Ligand B is a concern, but could potentially be addressed through structural modifications. The poor Caco-2 and solubility are shared issues.

Output:
1
2025-04-17 05:35:05,181 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (349.475 and 350.459 Da) are within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (72.88) is slightly higher than Ligand B (70.08), but both are below the 90 A^2 threshold desirable for CNS targets.

**3. logP:** Both ligands have good logP values (0.905 and 0.881), falling within the optimal range of 1-3.

**4. H-Bond Donors:** Ligand A (2) is slightly higher than Ligand B (1), but both are within the acceptable limit of <=5.

**5. H-Bond Acceptors:** Both ligands have the same number of H-bond acceptors (4), which is well within the acceptable limit of <=10.

**6. QED:** Both ligands have good QED scores (0.67 and 0.772), indicating good drug-like properties.

**7. DILI:** Ligand A (8.957) has a significantly lower DILI risk than Ligand B (11.361). This is a substantial advantage.

**8. BBB:** Ligand B (61.535) has a much better BBB penetration percentile than Ligand A (36.409). This is a critical factor for a CNS target like DRD2.

**9. Caco-2 Permeability:** Ligand A (-4.847) has slightly better Caco-2 permeability than Ligand B (-4.466), but both are negative values, indicating poor permeability.

**10. Aqueous Solubility:** Ligand A (-1.019) has slightly poorer aqueous solubility than Ligand B (-0.643), but both are negative, indicating poor solubility.

**11. hERG Inhibition:** Both ligands have low hERG inhibition risk (0.141 and 0.215).

**12. Microsomal Clearance:** Ligand B (4.442) has significantly lower microsomal clearance than Ligand A (18.077), suggesting better metabolic stability.

**13. In vitro Half-Life:** Ligand B (2.997) has a slightly longer in vitro half-life than Ligand A (5.612).

**14. P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.028 and 0.072).

**15. Binding Affinity:** Ligand B (-7.8 kcal/mol) has a slightly better binding affinity than Ligand A (-8.0 kcal/mol). While the difference is small, it's still a positive for Ligand B.

**Overall Assessment:**

Ligand B is the better candidate. While Ligand A has a slightly better binding affinity and Caco-2 permeability, Ligand B excels in the most critical areas for a CNS-targeting GPCR: BBB penetration and metabolic stability (lower Cl_mic). The lower DILI risk of Ligand A is a plus, but the superior BBB penetration of Ligand B outweighs this benefit, given the CNS target. The slightly better affinity of Ligand B also contributes to its overall advantage.

Output:
1
2025-04-17 05:35:05,181 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (390.795 and 381.402 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (88.52) is excellent, falling well below the 90 A^2 threshold for CNS targets. Ligand B (107.97) is still reasonable but less optimal, being above 90 A^2.

**3. logP:** Ligand A (3.607) is within the optimal 1-3 range. Ligand B (0.284) is quite low, potentially hindering membrane permeability and CNS penetration.

**4. H-Bond Donors:** Both ligands have acceptable HBD counts (2 and 1, respectively), well below the 5 threshold.

**5. H-Bond Acceptors:** Ligand A (5) is good. Ligand B (8) is higher but still acceptable, being below the 10 threshold.

**6. QED:** Both ligands have reasonable QED values (0.786 and 0.581), indicating drug-like properties. Ligand A is slightly better.

**7. DILI:** Both ligands have high DILI risk (93.525 and 87.902). This is a concern, but can be addressed in later optimization stages.

**8. BBB:** Ligand A (36.293) has a poor BBB percentile, which is a significant drawback for a CNS target. Ligand B (46.336) is also low, but slightly better than Ligand A.

**9. Caco-2:** Both ligands have negative Caco-2 values (-5.086 and -5.765). This is unusual and suggests poor intestinal absorption.

**10. Solubility:** Both ligands have negative solubility values (-3.701 and -2.821). This is also unusual and suggests poor aqueous solubility.

**11. hERG:** Both ligands have very low hERG inhibition risk (0.053 and 0.154), which is excellent.

**12. Cl_mic:** Ligand A (0.719) has a very low microsomal clearance, indicating good metabolic stability. Ligand B (28.952) has a much higher clearance, suggesting faster metabolism.

**13. t1/2:** Ligand A (-23.968) has a very long in vitro half-life, which is highly desirable. Ligand B (-17.302) has a shorter half-life.

**14. Pgp:** Both ligands have low P-gp efflux liability (0.159 and 0.035), which is favorable for CNS penetration.

**15. Binding Affinity:** Ligand A (-8.4 kcal/mol) has a significantly stronger binding affinity than Ligand B (-7.8 kcal/mol). The 0.6 kcal/mol difference is substantial and could outweigh some of the ADME drawbacks.

**Overall Assessment:**

Despite both ligands having issues with DILI, solubility, and Caco-2 permeability, Ligand A is the more promising candidate. Its superior binding affinity, lower clearance, longer half-life, and better TPSA outweigh the slightly worse BBB score compared to Ligand B. The low logP of Ligand B is a major concern, as it will likely hinder its ability to cross the blood-brain barrier. The strong binding affinity of Ligand A provides a good starting point for optimization, and the ADME properties can be improved through structural modifications.

Output:
1
2025-04-17 05:35:05,182 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (357.445 and 348.447 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (52.65) is significantly better than Ligand B (76.46). For CNS targets, we want TPSA <= 90, and ideally closer to 60. Ligand A is much closer to the ideal range.

**3. logP:** Both ligands have good logP values (1.871 and 1.371), falling within the optimal 1-3 range.

**4. H-Bond Donors:** Both have 1 HBD, which is acceptable.

**5. H-Bond Acceptors:** Ligand A has 3 HBA, while Ligand B has 5. Both are within the acceptable limit of <= 10, but lower is generally preferred.

**6. QED:** Both ligands have reasonable QED scores (0.836 and 0.755), indicating good drug-like properties.

**7. DILI:** Ligand A has a DILI risk of 8.337, which is excellent (low risk). Ligand B's DILI risk is 30.865, still acceptable but higher.

**8. BBB:** This is crucial for a CNS target like DRD2. Ligand A has a BBB penetration of 87.553%, which is excellent. Ligand B has 74.99%, which is good but less desirable.

**9. Caco-2 Permeability:** Both have negative Caco-2 values (-4.914 and -4.801). This is unusual and suggests poor permeability. However, these values are on a log scale and can be difficult to interpret without knowing the exact scale used.

**10. Aqueous Solubility:** Both have negative solubility values (-1.522 and -1.144), again suggesting poor solubility. This is a concern for bioavailability.

**11. hERG Inhibition:** Both ligands show low hERG inhibition liability (0.615 and 0.549), which is good.

**12. Microsomal Clearance:** Ligand A has a significantly lower (better) microsomal clearance (-32.822) than Ligand B (14.377). Lower clearance indicates greater metabolic stability.

**13. In vitro Half-Life:** Ligand A has a shorter half-life (-12.515) than Ligand B (-5.745). This is a negative for Ligand A, but the large difference in clearance is more concerning.

**14. P-gp Efflux:** Both have very low P-gp efflux liability (0.02 and 0.076), which is excellent for CNS penetration.

**15. Binding Affinity:** Ligand A (-8.3 kcal/mol) has a slightly better binding affinity than Ligand B (-7.8 kcal/mol). While both are good, the 0.5 kcal/mol difference is notable.

**Overall Assessment:**

Ligand A is the stronger candidate. It excels in TPSA, BBB penetration, DILI risk, and microsomal clearance. Its binding affinity is also slightly better. While both have poor solubility and Caco-2 permeability, the superior ADME properties of Ligand A, especially its BBB penetration and metabolic stability, are critical for a CNS-targeting drug. The slightly shorter half-life of Ligand A is a minor concern compared to the other advantages.

Output:
1
2025-04-17 05:35:05,182 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (365.503 and 362.451 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (61.68) is significantly better than Ligand B (91.57). For CNS targets, we want TPSA <= 90, so Ligand A is preferable.

**3. logP:** Ligand A (-0.073) is slightly lower than optimal (1-3), but still acceptable. Ligand B (3.634) is within the optimal range.

**4. H-Bond Donors:** Ligand A (0) is excellent, minimizing potential issues with permeability. Ligand B (3) is acceptable.

**5. H-Bond Acceptors:** Ligand A (6) is good. Ligand B (5) is also good.

**6. QED:** Both ligands have similar QED values (0.731 and 0.624), both above the 0.5 threshold, indicating good drug-like properties.

**7. DILI:** Ligand A (25.126) has a much lower DILI risk than Ligand B (65.064). This is a significant advantage for Ligand A.

**8. BBB:** Ligand A (53.781) is better than Ligand B (36.526), but both are below the desirable >70 percentile for CNS targets. However, Ligand A is closer.

**9. Caco-2 Permeability:** Both have negative values (-5.181 and -5.612), which is unusual and suggests poor permeability. This is a concern for both.

**10. Aqueous Solubility:** Both have negative values (-0.897 and -4.793), indicating poor aqueous solubility. This is a concern for both.

**11. hERG Inhibition:** Ligand A (0.143) has a lower hERG risk than Ligand B (0.608), which is preferable.

**12. Microsomal Clearance:** Ligand A (16.683) has a lower microsomal clearance than Ligand B (54.582), suggesting better metabolic stability.

**13. In vitro Half-Life:** Ligand B (30.642) has a significantly longer half-life than Ligand A (1.751). This is a substantial advantage for Ligand B.

**14. P-gp Efflux:** Ligand A (0.019) has much lower P-gp efflux liability than Ligand B (0.288), which is crucial for CNS penetration.

**15. Binding Affinity:** Ligand B (-8.5 kcal/mol) has a significantly stronger binding affinity than Ligand A (-6.9 kcal/mol). This is a substantial advantage for Ligand B, potentially outweighing some ADME drawbacks.

**Overall Assessment:**

Ligand B has a significantly better binding affinity and a longer half-life. However, Ligand A excels in TPSA, DILI risk, P-gp efflux, and hERG risk. Both have poor Caco-2 and solubility. Considering the GPCR-specific priorities, BBB penetration is important, and while neither is ideal, Ligand A is better. The strong affinity of Ligand B is a major plus, and a difference of 1.6 kcal/mol is significant. The lower DILI and P-gp efflux of Ligand A are also very attractive. Given the importance of affinity for GPCRs, and the substantial difference in binding, I would lean towards Ligand B despite its other drawbacks. Further optimization could address the DILI and P-gp issues.

Output:
1
2025-04-17 05:35:05,182 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (372.491 and 384.376 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (115.97) is slightly above the optimal <90 for CNS targets, but still reasonable. Ligand B (88.85) is excellent, well below 90.

**logP:** Ligand A (-1.233) is quite low, potentially hindering permeability. Ligand B (1.44) is within the optimal 1-3 range. This is a significant advantage for Ligand B.

**H-Bond Donors/Acceptors:** Ligand A has 3 HBD and 6 HBA, both acceptable. Ligand B has 1 HBD and 5 HBA, also acceptable.

**QED:** Both ligands have good QED scores (0.515 and 0.685), indicating good drug-like properties.

**DILI:** Ligand A (11.283) has a very low DILI risk, excellent. Ligand B (46.181) is moderate, but still acceptable.

**BBB:** Ligand A (14.541) has a very poor BBB penetration percentile. Ligand B (64.948) is moderate, but significantly better than Ligand A, and approaching the desirable >70 for CNS targets. This is a critical advantage for Ligand B.

**Caco-2 Permeability:** Ligand A (-5.978) is very poor. Ligand B (-4.924) is also poor, but slightly better.

**Aqueous Solubility:** Both ligands have poor aqueous solubility (-0.806 and -2.865). This could pose formulation challenges.

**hERG Inhibition:** Ligand A (0.07) has very low hERG inhibition risk. Ligand B (0.516) is slightly higher, but still relatively low.

**Microsomal Clearance:** Ligand A (-11.696) suggests very low clearance and high metabolic stability, excellent. Ligand B (35.109) has moderate clearance, which is less desirable.

**In vitro Half-Life:** Ligand A (-7.902) suggests a very long half-life, excellent. Ligand B (-10.369) also suggests a long half-life, but slightly shorter than Ligand A.

**P-gp Efflux:** Both ligands show no P-gp efflux liability (0.007 and 0.037), which is favorable for CNS penetration.

**Binding Affinity:** Ligand A (0) has no binding affinity. Ligand B (-7.9) has a strong binding affinity.

**Overall Assessment:**

Ligand B is the superior candidate. While both have solubility issues, Ligand B excels in key areas for a CNS-targeting GPCR ligand: logP, BBB penetration, and, crucially, binding affinity. Ligand A's extremely low logP and poor BBB penetration are major drawbacks, despite its favorable metabolic stability and low DILI. The strong binding affinity of Ligand B (-7.9 kcal/mol) is a significant advantage that can potentially offset its moderate DILI and clearance.

Output:
1
2025-04-17 05:35:05,182 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (365.5 and 341.4 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (91.32) is slightly above the optimal <90 for CNS targets, but still reasonable. Ligand B (82.68) is well within the desired range.

**logP:** Both ligands have good logP values (1.819 and 1.443), falling within the 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A has 3 HBD and 5 HBA, which is acceptable. Ligand B has 1 HBD and 8 HBA, also acceptable.

**QED:** Both ligands have QED values above 0.6, indicating good drug-likeness.

**DILI:** Ligand A (41.062) has a lower DILI risk than Ligand B (62.776), which is a significant advantage.

**BBB:** Ligand A (47.654) has a lower BBB penetration percentile than Ligand B (67.352). While neither are *high* (>70), Ligand B is considerably better for CNS penetration.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values, which is unusual and suggests poor permeability. However, the scale isn't specified, so it's hard to interpret.

**Aqueous Solubility:** Both ligands have negative solubility values, which is also unusual. Again, scale is unspecified, but suggests poor solubility.

**hERG Inhibition:** Both ligands have very low hERG inhibition risk.

**Microsomal Clearance:** Ligand A (-10.592) has *much* lower (better) microsomal clearance than Ligand B (17.472), indicating greater metabolic stability.

**In vitro Half-Life:** Ligand A (28.208) has a longer half-life than Ligand B (-3.382).

**P-gp Efflux:** Ligand A (0.043) has lower P-gp efflux liability than Ligand B (0.103), which is favorable for CNS exposure.

**Binding Affinity:** Ligand A (-8.9 kcal/mol) has a significantly stronger binding affinity than Ligand B (-6.6 kcal/mol). This >1.5 kcal/mol difference is substantial and can outweigh some ADME drawbacks.

**Overall Assessment:**

Ligand A has a superior binding affinity and better metabolic stability (lower Cl_mic, longer t1/2), lower DILI risk, and lower P-gp efflux. While its BBB penetration is lower than Ligand B, the significantly stronger binding affinity and improved metabolic properties are more critical for a GPCR target like DRD2. The negative Caco-2 and solubility values are concerning for both, but the strong binding of A might allow for lower doses, potentially mitigating these issues.

Output:
1
2025-04-17 05:35:05,182 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B based on the provided guidelines, prioritizing GPCR-specific properties (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (370.431 and 379.482 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (129.56) is slightly above the optimal <90 for CNS targets, but still reasonable. Ligand B (63.25) is excellent, well below 90.

**logP:** Ligand A (-1.007) is quite low, potentially hindering permeability. Ligand B (3.964) is very good, close to the optimal range of 1-3.

**H-Bond Donors/Acceptors:** Both ligands have 2 HBDs and around 6-7 HBAs, which are acceptable.

**QED:** Both ligands have similar QED scores (0.679 and 0.636), indicating good drug-likeness.

**DILI:** Ligand A (60.954) is borderline, indicating moderate risk. Ligand B (88.329) is significantly higher, suggesting a higher DILI risk.

**BBB:** This is crucial for a DRD2 ligand. Ligand A (19.814) has a very poor BBB penetration score. Ligand B (70.027) is excellent, exceeding the desirable >70 threshold.

**Caco-2 Permeability:** Both have negative values, which is unusual. Assuming these are percentile scores, Ligand A (-5.462) is extremely poor, and Ligand B (-4.812) is also very poor.

**Aqueous Solubility:** Both ligands have negative solubility values, which is also unusual. Assuming these are percentile scores, both are very poor.

**hERG:** Ligand A (0.063) has a very low hERG risk, which is excellent. Ligand B (0.864) has a moderate hERG risk.

**Microsomal Clearance:** Ligand A (-18.175) has a negative clearance, which is not physically possible. This suggests an error in the data. Ligand B (98.502) has very high clearance, indicating poor metabolic stability.

**In vitro Half-Life:** Ligand A (14.55) has a moderate half-life. Ligand B (54.026) has a much longer half-life, which is favorable.

**P-gp Efflux:** Ligand A (0.008) shows very little P-gp efflux, which is excellent for CNS penetration. Ligand B (0.849) shows moderate P-gp efflux.

**Binding Affinity:** Ligand A (0.0) has very weak binding affinity. Ligand B (-8.6) has excellent binding affinity, significantly better than Ligand A.

**Overall Assessment:**

Ligand B is the superior candidate despite the higher DILI risk. Its strong binding affinity, excellent BBB penetration, favorable logP, and longer half-life outweigh the DILI concern. The poor Caco-2 and solubility values are concerning for both, but can be addressed with formulation strategies. Ligand A's extremely poor BBB penetration and weak binding affinity are deal-breakers, even with its favorable hERG profile. The negative clearance value for Ligand A is also a data quality issue.

Output:
1
2025-04-17 05:35:05,183 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B based on the provided guidelines, prioritizing GPCR-specific properties (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (346.471 Da) is slightly lower, which could be beneficial for permeability.

**TPSA:** Ligand A (69.64) is significantly better than Ligand B (83.36). For CNS targets, TPSA should be <=90, and A is comfortably within this range, while B is approaching the upper limit.

**logP:** Ligand A (3.704) is optimal (1-3), while Ligand B (-0.152) is significantly low, potentially hindering permeation. This is a major disadvantage for B.

**H-Bond Donors/Acceptors:** Both have acceptable HBD counts (2). Ligand B has a higher HBA count (7 vs 3), which could slightly impact permeability, but is still within reasonable limits.

**QED:** Both ligands have similar QED values (0.825 and 0.625), indicating good drug-likeness.

**DILI:** Ligand A (19.504) has a much lower DILI risk than Ligand B (34.238), which is a significant advantage.

**BBB:** Ligand A (76.658) has a substantially better BBB penetration score than Ligand B (58.55). This is *critical* for a CNS target like DRD2.

**Caco-2 Permeability:** Ligand A (-4.783) is better than Ligand B (-5.446), indicating better intestinal absorption.

**Aqueous Solubility:** Ligand A (-4.418) is better than Ligand B (-1.165), which is important for formulation.

**hERG Inhibition:** Ligand A (0.654) has a lower hERG inhibition liability than Ligand B (0.027), reducing cardiotoxicity risk.

**Microsomal Clearance:** Ligand A (92.127) has a higher (worse) microsomal clearance than Ligand B (3.831), suggesting lower metabolic stability.

**In vitro Half-Life:** Ligand B (45.521) has a significantly longer in vitro half-life than Ligand A (2.485).

**P-gp Efflux:** Ligand A (0.15) has lower P-gp efflux liability than Ligand B (0.011), which is favorable for CNS exposure.

**Binding Affinity:** Ligand B (-7.3) has a slightly better binding affinity than Ligand A (-8.3). However, the difference is only 0.1 kcal/mol, and the other advantages of Ligand A likely outweigh this small difference.

**Overall:**

Ligand A is clearly the superior candidate. While Ligand B has a slightly better binding affinity and half-life, Ligand A excels in crucial areas for a CNS-targeting GPCR: TPSA, logP, BBB penetration, DILI risk, hERG inhibition, and P-gp efflux. The significantly better logP and BBB values for Ligand A are particularly important. The higher clearance of Ligand A is a concern, but can potentially be addressed through structural modifications.



Output:
1
2025-04-17 05:35:05,183 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (363.839 and 350.415 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (29.85) is excellent, well below the 90 A^2 threshold for CNS targets. Ligand B (90.31) is at the upper limit for CNS targets but still acceptable.

**logP:** Ligand A (4.927) is slightly high, potentially leading to solubility issues or off-target interactions. Ligand B (-0.64) is quite low, which could hinder membrane permeability and CNS penetration.

**H-Bond Donors/Acceptors:** Ligand A (1 HBD, 3 HBA) and Ligand B (2 HBD, 5 HBA) both have reasonable numbers of H-bond donors and acceptors, falling within acceptable limits.

**QED:** Both ligands have acceptable QED values (0.834 and 0.661, respectively), indicating good drug-like properties.

**DILI:** Ligand A (58.976) has a moderate DILI risk, while Ligand B (38.62) has a lower, more favorable DILI risk.

**BBB:** This is a critical parameter for CNS targets. Ligand A excels with a BBB percentile of 91.508, indicating excellent brain penetration potential. Ligand B's BBB percentile is significantly lower at 42.032, raising concerns about reaching the target in the brain.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.475 and -4.503), which is unusual and suggests poor intestinal absorption. However, for a CNS target, intestinal absorption is less critical than BBB penetration.

**Aqueous Solubility:** Both ligands have very poor aqueous solubility (-5.99 and -1.202). This is a concern, but can potentially be addressed with formulation strategies.

**hERG Inhibition:** Ligand A (0.752) shows a slightly higher risk of hERG inhibition than Ligand B (0.182).

**Microsomal Clearance:** Ligand A (51.495) has a higher microsomal clearance than Ligand B (2.269), suggesting faster metabolism and potentially lower in vivo exposure.

**In vitro Half-Life:** Ligand B (-1.592) has a negative half-life, which is impossible and indicates a significant issue with the data or the compound's stability. Ligand A (16.237) has a reasonable half-life.

**P-gp Efflux:** Ligand A (0.258) has lower P-gp efflux liability than Ligand B (0.047), which is favorable for CNS penetration.

**Binding Affinity:** Ligand A (-9.6 kcal/mol) has a significantly stronger binding affinity than Ligand B (-7.3 kcal/mol). This 2.3 kcal/mol difference is substantial and can outweigh some of the ADME drawbacks.

**Conclusion:**

Despite Ligand A's slightly higher logP and DILI risk, its *significantly* superior BBB penetration (91.5 vs 42.0), much stronger binding affinity (-9.6 vs -7.3), and more reasonable half-life, make it the more promising candidate for a DRD2-targeting drug. Ligand B's very low logP and negative half-life are major red flags. The strong affinity of Ligand A is a key advantage for a GPCR target, and its good BBB score is crucial for CNS activity.

Output:
1
2025-04-17 05:35:05,183 - INFO - Batch 210 complete. Total preferences: 3360
2025-04-17 05:35:05,183 - INFO - Processing batch 211/512...
2025-04-17 05:35:47,732 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (374.853 and 362.455 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (70.25) is better than Ligand B (75.51). Both are below the 90 A^2 threshold for CNS targets, but A is closer to the ideal.

**3. logP:** Ligand A (2.927) is optimal (1-3). Ligand B (-0.148) is significantly lower, potentially hindering permeation. This is a major drawback for B.

**4. H-Bond Donors:** Ligand A (2) is good. Ligand B (0) is also acceptable.

**5. H-Bond Acceptors:** Ligand A (4) is good. Ligand B (5) is also acceptable.

**6. QED:** Both ligands have good QED scores (0.622 and 0.747, respectively), indicating drug-likeness.

**7. DILI:** Both ligands have the same DILI risk (91.082 and 35.169 percentile), which is relatively high. This is a concern for both, but not a deciding factor between them.

**8. BBB:** Ligand B (71.617) has a significantly better BBB penetration score than Ligand A (35.169). This is a critical advantage for a CNS target like DRD2.

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.037 and -5.024), which is unusual and suggests poor permeability. This is a concern for both.

**10. Aqueous Solubility:** Both ligands have negative solubility values (-4.509 and -1.776), indicating very poor solubility. This is a significant issue for both, potentially hindering bioavailability.

**11. hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.285 and 0.089).

**12. Microsomal Clearance:** Both ligands have similar microsomal clearance (17.369 and 16.883 mL/min/kg), suggesting moderate metabolic stability.

**13. In vitro Half-Life:** Ligand A (31.972) has a much longer half-life than Ligand B (2.702).

**14. P-gp Efflux:** Ligand A (0.252) has lower P-gp efflux than Ligand B (0.032), which is favorable for CNS exposure.

**15. Binding Affinity:** Ligand A (-8.7 kcal/mol) has a slightly better binding affinity than Ligand B (-8.0 kcal/mol). While both are excellent, the 0.7 kcal/mol difference is noteworthy.

**Overall Assessment:**

Ligand B has a much better BBB score, which is paramount for a CNS target. However, its significantly negative logP is a major concern, likely hindering its ability to cross cell membranes. Ligand A has a more favorable logP, better half-life, and slightly better affinity, despite the lower BBB score. Considering the GPCR-specific priorities, the better logP and affinity of Ligand A, combined with acceptable (though not ideal) TPSA, outweigh the BBB disadvantage. The poor solubility and permeability are concerns for both, but can be addressed with formulation strategies.

Output:
1
2025-04-17 05:35:47,733 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B against the provided guidelines, prioritizing GPCR-specific properties (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (351.447) is slightly lower, which could be beneficial for permeability, but both are acceptable.

**TPSA:** Ligand A (95.67) is better than Ligand B (37.83) as it is closer to the ideal range for CNS targets (<=90). Ligand B is very low, which might suggest good BBB penetration, but could also indicate poor interactions.

**logP:** Ligand A (1.958) is within the optimal range (1-3). Ligand B (3.499) is at the higher end, potentially leading to solubility issues or off-target interactions, but still acceptable.

**H-Bond Donors/Acceptors:** Ligand A has 2 HBD and 5 HBA, while Ligand B has 0 HBD and 6 HBA. Both are within acceptable limits.

**QED:** Both ligands have reasonable QED scores (A: 0.783, B: 0.631), indicating good drug-like properties.

**DILI:** Ligand A (39.434) has a slightly higher DILI risk than Ligand B (5.7), but both are below the concerning threshold of 60.

**BBB:** This is a critical parameter for CNS targets. Ligand B (90.074) significantly outperforms Ligand A (44.979) in BBB penetration, which is a major advantage.

**Caco-2 Permeability:** Both have negative Caco-2 values, suggesting poor permeability. This is unusual and could indicate issues with the prediction method or the molecules themselves.

**Aqueous Solubility:** Both ligands have negative solubility values, which is also unusual and suggests poor solubility.

**hERG Inhibition:** Ligand A (0.372) has a lower hERG risk than Ligand B (0.903), which is preferable.

**Microsomal Clearance:** Ligand B (41.21) has a higher microsomal clearance than Ligand A (26.043), indicating faster metabolism and potentially lower in vivo exposure.

**In vitro Half-Life:** Ligand A (-2.958) has a longer in vitro half-life than Ligand B (-1.829), which is a positive attribute.

**P-gp Efflux:** Ligand A (0.138) has lower P-gp efflux liability than Ligand B (0.175), which is favorable for CNS penetration.

**Binding Affinity:** Ligand A (-7.9 kcal/mol) has a significantly stronger binding affinity than Ligand B (-6.7 kcal/mol). This 1.2 kcal/mol difference is substantial and can often outweigh minor ADME drawbacks.

**Overall Assessment:**

While Ligand B has a much better BBB score, Ligand A's superior binding affinity (-7.9 vs -6.7 kcal/mol) is a significant advantage, especially for a GPCR target like DRD2. The stronger binding is likely to translate to greater efficacy. Although Ligand A has a lower BBB score, its lower P-gp efflux and better half-life could partially compensate. The slightly higher DILI risk for Ligand A is not a major concern given the other favorable properties. The unusual negative values for Caco-2 and solubility are concerning, but the affinity difference is substantial enough to prioritize Ligand A.

Output:
1
2025-04-17 05:35:47,733 - INFO - Reasoning:

Let's analyze Ligand A and Ligand B based on the provided guidelines, prioritizing GPCR-specific properties (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (350.39 and 369.491 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (87.66) is excellent, being below the 90 A^2 threshold for CNS targets. Ligand B (107.45) is still reasonable, but less optimal.

**logP:** Ligand A (1.99) is within the optimal 1-3 range. Ligand B (0.397) is a bit low, potentially hindering permeation.

**H-Bond Donors/Acceptors:** Both ligands have 3 HBDs, which is acceptable. Ligand A has 4 HBAs, and Ligand B has 7 HBAs. Both are within the acceptable range of <=10, but Ligand A is preferable.

**QED:** Both ligands have QED values above 0.5 (0.685 and 0.573), indicating good drug-like properties.

**DILI:** Ligand A (47.926) has a lower DILI risk than Ligand B (38.736), which is better.

**BBB:** This is a crucial parameter for a CNS target like DRD2. Ligand A has a BBB percentile of 71.501, which is very good (>70). Ligand B has a significantly lower BBB percentile of 14.192, which is a major drawback.

**Caco-2 Permeability:** Both have negative values, which is unusual. A higher value is better, but we can't draw strong conclusions from these negative values.

**Aqueous Solubility:** Both have negative values, which is also unusual. Higher is better, but again, we can't draw strong conclusions.

**hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.419 and 0.048).

**Microsomal Clearance:** Ligand A (-6.053) has a much lower (better) microsomal clearance than Ligand B (18.618), indicating greater metabolic stability.

**In vitro Half-Life:** Ligand A (-1.997) has a slightly better in vitro half-life than Ligand B (-0.713).

**P-gp Efflux:** Ligand A (0.081) has lower P-gp efflux than Ligand B (0.036), which is preferable for CNS penetration.

**Binding Affinity:** Ligand A (-9.1 kcal/mol) has a significantly stronger binding affinity than Ligand B (-6.6 kcal/mol). This is a substantial advantage, exceeding the 1.5 kcal/mol threshold.

**Conclusion:**

Considering all factors, especially the critical GPCR-specific properties (BBB, logP, Pgp, TPSA, and affinity), **Ligand A is the far more promising drug candidate.** Its superior BBB penetration, better logP, lower P-gp efflux, excellent TPSA, significantly stronger binding affinity, and improved metabolic stability outweigh any minor drawbacks. Ligand B's poor BBB penetration is a major obstacle for a CNS-targeted drug.

Output:
1
2025-04-17 05:35:47,733 - INFO - Reasoning:

Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (352.435 and 347.415 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (127.34) is higher than the preferred <90 for CNS targets, while Ligand B (84.67) is within the desirable range. This is a significant advantage for Ligand B.

**3. logP:** Ligand A (0.467) is quite low, potentially hindering membrane permeability. Ligand B (1.479) is better, falling within the optimal 1-3 range.

**4. H-Bond Donors:** Ligand A (5) is at the upper limit of the preferred range, while Ligand B (1) is excellent.

**5. H-Bond Acceptors:** Both ligands have 5 HBA, which is acceptable.

**6. QED:** Both ligands have similar QED values (0.465 and 0.512), indicating reasonable drug-likeness.

**7. DILI:** Ligand A (29.43) has a lower DILI risk than Ligand B (35.983), which is a positive.

**8. BBB:** This is crucial for a CNS target like DRD2. Ligand A (17.565) has a very poor BBB penetration percentile, while Ligand B (72.78) is excellent, exceeding the >70 desirable threshold. This is a major advantage for Ligand B.

**9. Caco-2 Permeability:** Ligand A (-5.577) has very poor Caco-2 permeability, consistent with its low logP. Ligand B (-4.406) is better, but still not ideal.

**10. Aqueous Solubility:** Both ligands have poor aqueous solubility (-1.805 and -2.155). This could pose formulation challenges, but is less critical than BBB penetration for a CNS drug.

**11. hERG Inhibition:** Ligand A (0.061) has a very low hERG risk, which is excellent. Ligand B (0.243) is slightly higher, but still acceptable.

**12. Microsomal Clearance:** Ligand A (-5.878) suggests very low clearance and high metabolic stability, which is good. Ligand B (24.876) has a higher clearance, indicating faster metabolism.

**13. In vitro Half-Life:** Ligand A (-14.444) suggests a very long half-life, while Ligand B (20.701) has a shorter, but still reasonable, half-life.

**14. P-gp Efflux:** Ligand A (0.017) has very low P-gp efflux, which is favorable for CNS penetration. Ligand B (0.166) has slightly higher efflux, but still acceptable.

**15. Binding Affinity:** Ligand B (-7.4 kcal/mol) has a stronger binding affinity than Ligand A (-8.5 kcal/mol). While A has a slightly better affinity, the difference is not substantial enough to outweigh the other significant drawbacks.

**Overall Assessment:**

Ligand B is significantly more promising due to its superior BBB penetration, better logP, and acceptable TPSA. While Ligand A has a slightly better affinity and lower DILI risk, its extremely poor BBB penetration and low logP are major liabilities for a CNS-targeted drug. The stronger binding affinity of Ligand B, combined with its favorable ADME properties, makes it the more viable candidate.

Output:
1
2025-04-17 05:35:47,733 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (381.391 Da) is slightly higher than Ligand B (349.479 Da), but both are acceptable.

**TPSA:** Ligand A (46.61) is excellent for CNS penetration, well below the 90 A^2 threshold. Ligand B (72.28) is still reasonable, but less optimal.

**logP:** Ligand A (3.34) is within the optimal range (1-3). Ligand B (1.759) is on the lower end, potentially impacting permeability.

**H-Bond Donors/Acceptors:** Ligand A (0 HBD, 3 HBA) is favorable. Ligand B (1 HBD, 6 HBA) is also acceptable, but slightly higher.

**QED:** Both ligands have similar QED values (A: 0.752, B: 0.735), indicating good drug-likeness.

**DILI:** Ligand A (46.995) has a slightly higher DILI risk than Ligand B (34.781), but both are below the concerning threshold of 60.

**BBB:** Ligand A (96.355) shows excellent BBB penetration, exceeding the desirable 70% threshold. Ligand B (77.472) is also good, but less so than A. This is a critical advantage for a CNS target like DRD2.

**Caco-2 Permeability:** Ligand A (-4.51) has poor Caco-2 permeability. Ligand B (-5.144) is also poor.

**Aqueous Solubility:** Both ligands have poor aqueous solubility (-4.567 and -1.35 respectively).

**hERG Inhibition:** Ligand A (0.786) has a slightly higher hERG risk than Ligand B (0.165), which is preferable.

**Microsomal Clearance:** Ligand A (50.127) has higher microsomal clearance, suggesting lower metabolic stability, compared to Ligand B (33.699).

**In vitro Half-Life:** Ligand A (-39.088) has a very short in vitro half-life, which is a significant drawback. Ligand B (27.582) is better, but still not ideal.

**P-gp Efflux:** Ligand A (0.257) has lower P-gp efflux, which is favorable for CNS exposure. Ligand B (0.067) has even lower efflux, which is excellent.

**Binding Affinity:** Ligand B (-7.2 kcal/mol) has a significantly stronger binding affinity than Ligand A (-9.0 kcal/mol). This is a substantial advantage, potentially outweighing some ADME concerns.

**Overall Assessment:**

While Ligand B has better P-gp efflux and a significantly better binding affinity, Ligand A has a superior BBB score. Given the CNS target, BBB is paramount. However, the substantial affinity difference of Ligand B (-7.2 vs -9.0) is very important. The poor solubility and permeability of both compounds are concerns, but can be addressed with formulation strategies. The short half-life of Ligand A is a major drawback. Considering the balance, the stronger binding affinity of Ligand B is more likely to translate to *in vivo* efficacy, and its other properties are acceptable.

Output:
1
2025-04-17 05:35:47,733 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (343.43 & 362.46 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (65.79) is significantly better than Ligand B (106.32). For CNS targets, we want TPSA <= 90, so Ligand A is much more favorable.

**logP:** Ligand A (1.715) is within the optimal range (1-3), while Ligand B (0.706) is a bit low, potentially hindering permeation.

**H-Bond Donors/Acceptors:** Ligand A (HBD=1, HBA=4) and Ligand B (HBD=2, HBA=6) both have reasonable numbers of H-bond donors and acceptors, falling within the guidelines.

**QED:** Both ligands have similar QED values (0.846 and 0.772), indicating good drug-like properties.

**DILI:** Ligand A (36.293) has a lower DILI risk than Ligand B (63.513), making it safer.

**BBB:** This is a crucial parameter for a CNS target like DRD2. Ligand A has a BBB percentile of 72.237, which is excellent (>70). Ligand B's BBB percentile is only 20.318, which is very poor.

**Caco-2 Permeability:** Both have negative values, which is unusual. However, the magnitude of the negative value for Ligand A (-4.806) is smaller than that of Ligand B (-5.242), suggesting slightly better permeability.

**Aqueous Solubility:** Both have negative values, which is also unusual. Ligand A (-1.807) is slightly better than Ligand B (-2.871).

**hERG:** Both ligands have low hERG inhibition liability (0.388 and 0.303), which is good.

**Microsomal Clearance:** Ligand A (54.289) has a higher (worse) microsomal clearance than Ligand B (11.718), suggesting lower metabolic stability.

**In vitro Half-Life:** Ligand B (4.595 hours) has a slightly longer half-life than Ligand A (3.667 hours).

**P-gp Efflux:** Ligand A (0.121) has lower P-gp efflux liability than Ligand B (0.045), which is favorable for CNS penetration.

**Binding Affinity:** Ligand B (-7.6 kcal/mol) has a slightly better binding affinity than Ligand A (-8.0 kcal/mol). However, the difference is relatively small, and the other factors are more important.

**Overall Assessment:**

Ligand A is significantly better due to its superior TPSA, BBB penetration, lower DILI risk, and lower P-gp efflux. While Ligand B has slightly better binding affinity and half-life, the critical CNS-related properties of Ligand A outweigh these minor advantages. The poor BBB penetration of Ligand B is a major drawback for a DRD2 targeting drug.

Output:
1
2025-04-17 05:35:47,733 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (341.455 Da) is slightly lower, which could be beneficial for permeability. Ligand B (382.835 Da) is also good.

**TPSA:** Ligand A (58.37) is excellent, well below the 90 A^2 threshold for CNS targets. Ligand B (87.66) is still reasonable, but less optimal for brain penetration.

**logP:** Ligand A (3.005) is within the optimal range (1-3). Ligand B (1.398) is at the lower end, potentially hindering permeability.

**H-Bond Donors/Acceptors:** Ligand A (HBD=1, HBA=4) and Ligand B (HBD=3, HBA=4) both have acceptable numbers of hydrogen bond donors and acceptors.

**QED:** Ligand A (0.908) has a very strong drug-like profile. Ligand B (0.606) is still acceptable, but less ideal.

**DILI:** Ligand A (14.424) has a very low DILI risk. Ligand B (28.616) is higher, indicating a moderate risk, but still within an acceptable range.

**BBB:** Both ligands have good BBB penetration (Ligand A: 72.354, Ligand B: 70.182), exceeding the desirable threshold of >70.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.094 and -5.209). This is unusual and suggests poor permeability, but these values can be unreliable.

**Aqueous Solubility:** Both ligands have negative solubility values (-2.477 and -1.978). This is also unusual and suggests poor solubility, which could be problematic for bioavailability.

**hERG Inhibition:** Both ligands have low hERG inhibition liability (Ligand A: 0.67, Ligand B: 0.311), which is good.

**Microsomal Clearance:** Ligand A (29.452) has a moderate clearance, while Ligand B (-9.934) has a *negative* clearance, which is not physically possible and likely indicates an issue with the prediction method. This suggests significantly better metabolic stability for Ligand B.

**In vitro Half-Life:** Ligand A (10.481) has a reasonable half-life. Ligand B (17.651) has a longer half-life, which is desirable.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (Ligand A: 0.31, Ligand B: 0.032), which is favorable for CNS exposure. Ligand B is better.

**Binding Affinity:** Ligand B (-7.6 kcal/mol) has a significantly stronger binding affinity than Ligand A (0 kcal/mol). This is a major advantage, potentially outweighing some of the ADME drawbacks.

**Overall Assessment:**

Ligand B is the stronger candidate. While Ligand A has a better QED and lower DILI risk, Ligand B's significantly higher binding affinity (-7.6 vs 0 kcal/mol) is a decisive factor for a GPCR target. The negative clearance for Ligand B is a red flag, but the longer half-life and lower P-gp efflux suggest good pharmacokinetic properties. The slightly higher TPSA and lower logP of Ligand B are less concerning given the strong affinity. The negative Caco-2 and solubility values are concerning for both, but can be addressed through formulation strategies.



Output:
1
2025-04-17 05:35:47,733 - INFO - Reasoning:

Let's analyze Ligand A and Ligand B against the provided guidelines, prioritizing GPCR-specific properties (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (364.398 and 348.447 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (92.34) is slightly above the optimal <90 for CNS targets, but still reasonable. Ligand B (76.12) is well within the desired range.

**logP:** Ligand A (1.663) is within the optimal 1-3 range. Ligand B (-0.993) is slightly below 1, which *could* indicate permeability issues, but isn't a hard cutoff.

**H-Bond Donors/Acceptors:** Both ligands have 2 HBD and acceptable HBA counts (4 and 5 respectively).

**QED:** Both ligands have acceptable QED scores (0.815 and 0.685, both >0.5).

**DILI:** Ligand A (80.923) has a higher DILI risk than Ligand B (12.369). This is a significant negative for Ligand A.

**BBB:** Ligand A (67.119) has a better BBB percentile than Ligand B (39.55). This is a key advantage for a CNS target like DRD2.

**Caco-2 Permeability:** Ligand A (-4.922) has poor Caco-2 permeability, suggesting poor intestinal absorption. Ligand B (-5.13) is similarly poor.

**Aqueous Solubility:** Ligand A (-3.502) has poor aqueous solubility. Ligand B (-1.237) is also poor, but slightly better than Ligand A.

**hERG:** Both ligands have low hERG inhibition risk (0.344 and 0.274).

**Microsomal Clearance:** Ligand A (37.246) has higher microsomal clearance than Ligand B (14.808), indicating lower metabolic stability.

**In vitro Half-Life:** Ligand A (63.649) has a longer half-life than Ligand B (18.738).

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.294 and 0.005).

**Binding Affinity:** Ligand B (-7.8 kcal/mol) has a significantly stronger binding affinity than Ligand A (-10.2 kcal/mol). This is a substantial advantage, potentially outweighing some ADME concerns.

**Overall Assessment:**

Ligand B is the stronger candidate. While its BBB penetration is lower than Ligand A, its *much* stronger binding affinity (-7.8 vs -10.2 kcal/mol) is a critical advantage for a GPCR target. Additionally, Ligand B has a significantly lower DILI risk and better metabolic stability (lower Cl_mic). The slightly lower logP of Ligand B is a minor concern, but the strong affinity likely compensates for this. Ligand A's poor Caco-2 permeability and solubility are also concerning.

Output:
1
2025-04-17 05:35:47,733 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (349.475 and 355.454 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (101.29) is slightly above the optimal <90 for CNS targets, but still reasonable. Ligand B (92.5) is better, falling comfortably below 90.

**3. logP:** Both ligands (1.478 and 1.834) are within the optimal 1-3 range.

**4. H-Bond Donors:** Ligand A (3) and Ligand B (2) are both acceptable, being less than 5.

**5. H-Bond Acceptors:** Both ligands (3) are acceptable, being less than 10.

**6. QED:** Ligand A (0.7) is significantly better than Ligand B (0.462), indicating a more drug-like profile.

**7. DILI:** Both ligands have similar, low DILI risk (30.826 and 31.563 percentile).

**8. BBB:** This is a crucial parameter for CNS targets. Ligand B (92.943) has a much higher BBB penetration percentile than Ligand A (48.74). This is a major advantage for Ligand B.

**9. Caco-2 Permeability:** Both have negative values, indicating poor permeability. Ligand A (-5.305) is slightly worse than Ligand B (-5.185).

**10. Aqueous Solubility:** Both ligands have negative solubility values, indicating poor solubility. Ligand A (-2.92) is slightly better than Ligand B (-3.177).

**11. hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.091 and 0.524).

**12. Microsomal Clearance:** Ligand B (23.138) has lower microsomal clearance than Ligand A (27.557), suggesting better metabolic stability.

**13. In vitro Half-Life:** Ligand B (-9.18) has a negative half-life, which is problematic. Ligand A (2.071) has a short, but positive half-life.

**14. P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.032 and 0.315).

**15. Binding Affinity:** Both ligands have very similar and excellent binding affinities (-7.7 and -7.6 kcal/mol). The difference is negligible.

**Overall Assessment:**

While Ligand A has a better QED and slightly better solubility and half-life, Ligand B significantly outperforms it in BBB penetration, which is paramount for a CNS-targeting drug. The slightly better metabolic stability of Ligand B is also a plus. The similar binding affinities mean that the ADME advantages of Ligand B outweigh the minor QED advantage of Ligand A.

Output:
1
2025-04-17 05:35:47,733 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (351.403 and 344.379 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (115.03) is slightly above the optimal <90 for CNS targets, but still reasonable. Ligand B (110.83) is also slightly above, but similar to A.

**3. logP:** Ligand A (-1.299) is a bit low, potentially hindering permeability. Ligand B (-0.059) is better, falling within the 1-3 range, though on the lower end.

**4. H-Bond Donors:** Ligand A (4) is acceptable. Ligand B (1) is excellent.

**5. H-Bond Acceptors:** Ligand A (6) is acceptable. Ligand B (8) is also acceptable, but higher.

**6. QED:** Both ligands have good QED scores (0.538 and 0.672), indicating drug-like properties.

**7. DILI:** Ligand A (23.226) has a very favorable DILI score, indicating low liver injury risk. Ligand B (65.723) is significantly higher, suggesting a higher risk.

**8. BBB:** Ligand A (11.4) has a very poor BBB penetration score. Ligand B (58.55) is much better, though still not ideal (>70 is preferred). This is a critical factor for a CNS target like DRD2.

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.554 and -5.208), which is unusual and suggests poor permeability. This is concerning.

**10. Aqueous Solubility:** Both ligands have negative solubility values (-0.445 and -2.315), which is also unusual and suggests poor solubility.

**11. hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.027 and 0.07).

**12. Microsomal Clearance:** Ligand A (-9.167) has a very low (good) microsomal clearance, indicating high metabolic stability. Ligand B (40.492) has a much higher clearance, suggesting faster metabolism.

**13. In vitro Half-Life:** Both have similar negative half-lives (-4.359 and -4.116), which is unusual.

**14. P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.006 and 0.055), which is positive for CNS penetration.

**15. Binding Affinity:** Ligand B (-8.0 kcal/mol) has a significantly stronger binding affinity than Ligand A (-7.1 kcal/mol). This is a substantial advantage.

**Overall Assessment:**

While Ligand B has a better binding affinity and a much better BBB score than Ligand A, it has a significantly higher DILI risk and faster metabolic clearance. Ligand A has a much better safety profile (DILI) and metabolic stability, but suffers from poor BBB penetration and a weaker binding affinity.

Given the GPCR-specific priorities, BBB penetration is crucial for DRD2. However, the substantial difference in binding affinity (-8.0 vs -7.1) and the concerning DILI risk of Ligand B are major drawbacks. The poor Caco-2 and solubility for both are also concerning, but might be addressable through formulation.

Considering these factors, I would lean towards **Ligand A** due to its significantly lower DILI risk and better metabolic stability. While its BBB penetration is poor, this might be improved through structural modifications without sacrificing the safety profile. The affinity difference, while noticeable, is not so large that it completely outweighs the safety concerns associated with Ligand B.

Output:
0
2025-04-17 05:35:47,734 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (363.483 and 349.391 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (62.74) is excellent, well below the 90 A^2 threshold for CNS targets. Ligand B (120.54) is higher, but still potentially acceptable, though less ideal.

**logP:** Both ligands have good logP values (2.017 and 1.643), falling within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A has 0 HBD and 5 HBA, while Ligand B has 1 HBD and 5 HBA. Both are within acceptable limits.

**QED:** Ligand A (0.803) has a significantly better QED score than Ligand B (0.435), indicating a more drug-like profile.

**DILI:** Both ligands have low DILI risk (33.346 and 30.516 percentile), which is favorable.

**BBB:** This is a critical parameter for a CNS target like DRD2. Ligand A has a very good BBB penetration score (86.39%), exceeding the desirable >70% threshold. Ligand B's BBB penetration (43.815%) is significantly lower and concerning.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values, which is unusual and suggests poor permeability. However, the scale is not specified, so it's difficult to interpret.

**Aqueous Solubility:** Both ligands have negative solubility values, which is also unusual and suggests poor solubility. Again, the scale is not specified.

**hERG:** Both ligands have low hERG inhibition liability (0.464 and 0.109), which is good.

**Microsomal Clearance:** Ligand A (54.469) has higher microsomal clearance than Ligand B (11.336), suggesting lower metabolic stability.

**In vitro Half-Life:** Ligand B has a longer in vitro half-life (9.34 hours) compared to Ligand A (-16.52 hours). The negative value for Ligand A is concerning and likely an error or indicates very rapid degradation.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.212 and 0.017), which is favorable for CNS penetration.

**Binding Affinity:** Ligand A (-8.7 kcal/mol) has a significantly stronger binding affinity than Ligand B (-7.5 kcal/mol). This 1.2 kcal/mol difference is substantial and can outweigh some ADME drawbacks.

**Overall Assessment:**

Ligand A is the stronger candidate. While it has a higher microsomal clearance and a negative in vitro half-life (which needs investigation), its superior BBB penetration, significantly better binding affinity, and higher QED score make it more promising. Ligand B's poor BBB penetration is a major drawback for a CNS-targeted drug. The negative solubility and permeability values for both compounds are concerning and require further investigation, but the affinity and BBB differences are decisive.

Output:
1
2025-04-17 05:35:47,734 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 drug candidates, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (338.451 Da) is slightly preferred due to being closer to the lower end, potentially aiding permeability.

**TPSA:** Ligand A (40.62) is significantly better than Ligand B (53.94). For CNS targets, we want TPSA <= 90, and lower is better. Ligand A is well within this range, while Ligand B is approaching the upper limit.

**logP:** Both ligands have good logP values (A: 3.27, B: 3.342), falling within the optimal 1-3 range. No significant difference here.

**H-Bond Donors/Acceptors:** Ligand A (HBD=0, HBA=2) is better than Ligand B (HBD=1, HBA=7). Fewer H-bonds generally improve permeability.

**QED:** Both ligands have similar QED values (A: 0.806, B: 0.805), indicating good drug-likeness.

**DILI:** Ligand A (52.734) has a much lower DILI risk than Ligand B (86.002). This is a significant advantage for Ligand A.

**BBB:** Ligand A (90.112) has a substantially better BBB penetration prediction than Ligand B (72.974). This is *critical* for a CNS target like DRD2.

**Caco-2 Permeability:** Both are negative, indicating poor permeability. However, the scale is not specified, so it's hard to interpret.

**Aqueous Solubility:** Both are negative, indicating poor solubility. Again, the scale is not specified.

**hERG:** Both ligands have low hERG inhibition liability (A: 0.629, B: 0.733), which is good.

**Microsomal Clearance:** Ligand B (50.63) has lower microsomal clearance than Ligand A (61.323), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand B (4.514) has a slightly longer half-life than Ligand A (5.097), which is a minor advantage.

**P-gp Efflux:** Ligand A (0.432) has lower P-gp efflux liability than Ligand B (0.222). Lower P-gp efflux is desirable for CNS penetration.

**Binding Affinity:** Ligand B (-7.7 kcal/mol) has a significantly stronger binding affinity than Ligand A (-9.5 kcal/mol). This is a substantial advantage, potentially outweighing some of the ADME drawbacks of Ligand B. However, the difference is not *huge*.

**Overall Assessment:**

While Ligand B has a better binding affinity, Ligand A is superior in almost all ADME properties crucial for CNS drug development, particularly BBB penetration and DILI risk. The difference in binding affinity (-7.7 vs -9.5) is not large enough to overcome the significant advantages Ligand A has in terms of safety and brain exposure. Given the GPCR-specific priorities, the better BBB, lower DILI, and lower P-gp efflux of Ligand A make it the more promising candidate.

Output:
0
2025-04-17 05:35:47,734 - INFO - Reasoning:

Let's analyze Ligand A and Ligand B based on the provided guidelines, prioritizing GPCR-specific properties (BBB, logP, Pgp, TPSA, and affinity) for DRD2.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (342.443 Da) is slightly lower, which could be beneficial for permeability. Ligand B (355.538 Da) is also good.

**TPSA:** Ligand A (88.32) is excellent for CNS penetration, falling well below the 90 A^2 threshold. Ligand B (29.54) is even better, suggesting superior BBB penetration potential.

**logP:** Ligand A (2.131) is within the optimal range (1-3). Ligand B (4.842) is higher, potentially leading to solubility issues and off-target interactions, though not drastically so.

**H-Bond Donors/Acceptors:** Ligand A has 2 HBD and 4 HBA, which are acceptable. Ligand B has 0 HBD and 2 HBA, also acceptable.

**QED:** Ligand A (0.877) has a better QED score than Ligand B (0.554), indicating a more drug-like profile overall.

**DILI:** Ligand A (48.895) has a slightly higher DILI risk than Ligand B (10.585), but both are below the concerning threshold of 60.

**BBB:** This is a critical parameter for DRD2. Ligand A (81.621) is good, but Ligand B (96.743) is *excellent*, significantly increasing the likelihood of CNS exposure.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values, which is unusual and suggests a potential issue with the data or modeling. However, we can still compare relative values. Ligand A (-4.951) is slightly better than Ligand B (-4.286).

**Aqueous Solubility:** Both ligands have negative solubility values, which is also unusual. Ligand A (-3.525) is slightly better than Ligand B (-4.381).

**hERG:** Ligand A (0.565) has a slightly lower hERG risk than Ligand B (0.892), which is preferable.

**Microsomal Clearance:** Ligand A (23.759) has a lower clearance, suggesting better metabolic stability than Ligand B (110.759).

**In vitro Half-Life:** Ligand A (-25.77) has a negative half-life, which is not physically possible and indicates an issue with the data. Ligand B (18.909) is reasonable.

**P-gp Efflux:** Ligand A (0.052) has significantly lower P-gp efflux liability than Ligand B (0.857), which is crucial for CNS penetration.

**Binding Affinity:** Ligand B (-7.0) has a slightly better binding affinity than Ligand A (-8.4). However, the difference is not substantial enough to overcome the other significant advantages of Ligand A.

**Overall Assessment:**

Ligand B excels in BBB penetration and binding affinity. However, it has a higher logP, significantly higher P-gp efflux, and worse metabolic stability. Ligand A has a better overall drug-like profile (QED), lower DILI risk, lower P-gp efflux, better metabolic stability, and acceptable BBB penetration. The issues with the negative Caco-2 and solubility values are concerning, but the relative comparison still favors Ligand A. Given the importance of BBB penetration and metabolic stability for a CNS-targeting GPCR like DRD2, and considering the more favorable ADME profile of Ligand A, it is the more promising candidate.

Output:
1
2025-04-17 05:35:47,734 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B based on the provided guidelines, prioritizing GPCR-specific properties (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (389.323 Da) is slightly higher than Ligand B (367.471 Da), but both are acceptable.

**TPSA:** Ligand A (58.64) is excellent for CNS penetration, well below the 90 A^2 threshold. Ligand B (96.53) is higher, but still potentially acceptable, though less ideal.

**logP:** Ligand A (3.149) is optimal. Ligand B (1.44) is on the lower side, potentially hindering permeability.

**H-Bond Donors/Acceptors:** Ligand A (HBD=1, HBA=3) is favorable. Ligand B (HBD=3, HBA=5) is also acceptable, but slightly higher counts could impact permeability.

**QED:** Both ligands have reasonable QED values (A: 0.759, B: 0.576), indicating good drug-like properties.

**DILI:** Ligand A (27.336) has a significantly lower DILI risk than Ligand B (42.924), which is a substantial advantage.

**BBB:** This is a critical parameter for a CNS target like DRD2. Ligand A (78.286) shows good BBB penetration. Ligand B (55.797) is considerably lower, raising concerns about sufficient CNS exposure.

**Caco-2 Permeability:** Ligand A (-4.952) is poor, while Ligand B (-5.346) is also poor. This is a concern for both, but less critical given the focus on BBB for CNS targets.

**Aqueous Solubility:** Both ligands have very poor solubility (-3.393 and -1.98 respectively). This could pose formulation challenges.

**hERG:** Both ligands have low hERG risk (0.405 and 0.325 respectively).

**Microsomal Clearance:** Ligand A (27.746) has a higher clearance than Ligand B (17.603), indicating lower metabolic stability.

**In vitro Half-Life:** Ligand B (-11.821) has a negative half-life, which is not possible. This is a red flag and suggests an issue with the data or the compound itself. Ligand A (19.319) has a reasonable half-life.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.211 and 0.122 respectively), which is favorable for CNS penetration.

**Binding Affinity:** Both ligands have strong binding affinities (-8.0 and -7.6 kcal/mol respectively). Ligand A is slightly better (-8.0 kcal/mol), but the difference is relatively small.

**Overall Assessment:**

Ligand A is the stronger candidate. It has a better BBB score, lower DILI risk, better logP, and a slightly better binding affinity. While both have poor solubility and Caco-2 permeability, the BBB is paramount for a CNS target. The negative half-life for Ligand B is a major concern, making Ligand A the clear choice.

Output:
1
2025-04-17 05:35:47,734 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (344.415 and 353.507 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (80.49) is better than Ligand B (72.88) as it is closer to the <90 A^2 threshold for CNS targets.

**logP:** Both ligands have good logP values (1.5 and 1.377), falling within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A (HBD=1, HBA=6) is slightly better than Ligand B (HBD=2, HBA=4) regarding the number of hydrogen bond donors and acceptors.

**QED:** Both ligands have similar and acceptable QED values (0.767 and 0.757), indicating good drug-likeness.

**DILI:** Ligand A (46.646) has a slightly higher DILI risk than Ligand B (6.282), but both are below the concerning threshold of 60.

**BBB:** Ligand A (74.874) has a significantly better BBB penetration score than Ligand B (44.436). This is a crucial factor for a CNS target like DRD2.

**Caco-2 Permeability:** Ligand A (-5.153) shows better Caco-2 permeability than Ligand B (-4.917).

**Aqueous Solubility:** Both ligands have poor aqueous solubility (-1.47 and -1.695).

**hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.217 and 0.386).

**Microsomal Clearance:** Ligand B (13.379) has a lower microsomal clearance than Ligand A (18.178), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand B (-6.373) has a longer in vitro half-life than Ligand A (-1.36), which is favorable.

**P-gp Efflux:** Ligand B (0.012) has significantly lower P-gp efflux liability than Ligand A (0.074), which is highly desirable for CNS penetration.

**Binding Affinity:** Ligand A (-8.0) has a superior binding affinity to Ligand B (-0.0). This difference is substantial.

**Overall Assessment:**

While Ligand B has advantages in metabolic stability (lower Cl_mic), half-life, and P-gp efflux, the significantly stronger binding affinity of Ligand A (-8.0 kcal/mol vs -0.0 kcal/mol) and its better BBB penetration (74.874 vs 44.436) outweigh these benefits. The affinity difference is massive, and for a GPCR, strong binding is paramount. The slightly higher DILI risk of Ligand A is not a major concern given the other favorable properties.

Output:
1
2025-04-17 05:35:47,734 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (346.471 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (69.64) is slightly higher than Ligand B (58.64). For CNS targets, we want TPSA <= 90, so both are acceptable, but B is better.

**3. logP:** Both ligands have good logP values (A: 2.311, B: 2.924), falling within the optimal 1-3 range.

**4. H-Bond Donors:** Ligand A (2) is slightly higher than Ligand B (1), but both are within the acceptable limit of <=5.

**5. H-Bond Acceptors:** Both ligands have the same number of H-bond acceptors (3), well below the limit of 10.

**6. QED:** Both ligands have similar QED values (A: 0.751, B: 0.721), indicating good drug-like properties (>=0.5).

**7. DILI:** Ligand B (41.411) has a significantly lower DILI risk than Ligand A (14.541). This is a major advantage for B.

**8. BBB:** Ligand B (65.103) has a considerably better BBB penetration percentile than Ligand A (52.617). This is crucial for a CNS target like DRD2.

**9. Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and suggests poor permeability. However, the values are similar (-4.866 for A, -4.704 for B).

**10. Aqueous Solubility:** Both have negative solubility values, indicating very poor solubility. Again, values are similar (-2.057 for A, -3.21 for B).

**11. hERG Inhibition:** Both ligands show low hERG inhibition liability (A: 0.148, B: 0.271).

**12. Microsomal Clearance:** Ligand B (93.491) has a much higher microsomal clearance than Ligand A (20.797), meaning it's metabolized faster. This is a disadvantage for B.

**13. In vitro Half-Life:** Ligand B (-17.625) has a negative half-life, which is not physically possible and suggests a problem with the data or the molecule's stability. Ligand A (-0.513) is also negative, but less so.

**14. P-gp Efflux:** Both ligands have low P-gp efflux liability (A: 0.146, B: 0.412).

**15. Binding Affinity:** Both ligands have very similar and strong binding affinities (A: -9.3 kcal/mol, B: -8.6 kcal/mol). The difference of 0.7 kcal/mol is not substantial enough to override other factors.

**Overall Assessment:**

While both ligands have good MW, logP, QED, and hERG profiles, and strong binding affinities, Ligand B is significantly better due to its lower DILI risk and, critically, much better BBB penetration. The major drawback for Ligand B is its higher microsomal clearance and the nonsensical negative half-life. However, the BBB advantage is so important for a CNS target that it outweighs the metabolic concerns, *assuming the negative half-life is a data error*. Ligand A's higher DILI risk is a significant concern.

Output:
1
2025-04-17 05:35:47,734 - INFO - Batch 211 complete. Total preferences: 3376
2025-04-17 05:35:47,734 - INFO - Processing batch 212/512...
2025-04-17 05:36:29,896 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (344.459 Da and 338.455 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (74.33) is better than Ligand B (50.16). Both are below the 90 A^2 threshold desirable for CNS targets, but Ligand B is closer to optimal.

**3. logP:** Ligand A (1.355) is within the optimal 1-3 range. Ligand B (3.142) is at the higher end of the optimal range, potentially increasing off-target effects, but still acceptable.

**4. H-Bond Donors:** Ligand A (2) and Ligand B (1) are both acceptable (<=5).

**5. H-Bond Acceptors:** Both ligands (A: 4, B: 4) are within the acceptable range (<=10).

**6. QED:** Both ligands have good QED scores (A: 0.817, B: 0.88), indicating drug-like properties.

**7. DILI:** Ligand A (21.908) has a significantly lower DILI risk than Ligand B (30.516), making it safer.

**8. BBB:** Ligand B (89.104) has a much higher BBB penetration percentile than Ligand A (59.093). This is a *critical* advantage for a CNS target like DRD2.

**9. Caco-2 Permeability:** Ligand A (-5.104) has a worse Caco-2 permeability than Ligand B (-4.898). Both are negative, which is unusual and indicates poor permeability.

**10. Aqueous Solubility:** Ligand A (-1.93) has better aqueous solubility than Ligand B (-3.058).

**11. hERG Inhibition:** Ligand A (0.396) has a lower hERG inhibition liability than Ligand B (0.875), indicating a lower risk of cardiotoxicity.

**12. Microsomal Clearance:** Ligand A (8.117) has a lower microsomal clearance than Ligand B (69.731), suggesting better metabolic stability.

**13. In vitro Half-Life:** Ligand A (1.834) has a shorter in vitro half-life than Ligand B (6.653).

**14. P-gp Efflux:** Ligand A (0.014) shows significantly lower P-gp efflux liability than Ligand B (0.639), which is beneficial for CNS exposure.

**15. Binding Affinity:** Both ligands have very similar and strong binding affinities (A: -8.4 kcal/mol, B: -8.2 kcal/mol). The difference is less than 1.5 kcal/mol, so it's not a deciding factor.

**Overall Assessment:**

Ligand B excels in BBB penetration, which is paramount for a CNS target. However, it suffers from higher DILI risk, higher P-gp efflux, and faster clearance. Ligand A has a better safety profile (lower DILI, hERG, P-gp), better metabolic stability (lower clearance), and better solubility. While its BBB penetration is lower, the other advantages, particularly the lower efflux, make it a more promising candidate. The slight difference in binding affinity is negligible given the other factors.

Output:
0
2025-04-17 05:36:29,896 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (347.415 and 348.447 Da) fall comfortably within the ideal 200-500 Da range.

**TPSA:** Ligand A (78.95) is significantly better than Ligand B (88.76). For CNS targets, we want TPSA <= 90, and A is closer to the ideal.

**logP:** Both ligands have acceptable logP values (0.736 and 1.399, respectively), falling within the optimal 1-3 range. Ligand B is slightly better.

**H-Bond Donors/Acceptors:** Both have 1 HBD, which is good. Ligand A has 4 HBA, and Ligand B has 5. Both are acceptable, being <= 10.

**QED:** Both ligands have good QED scores (0.764 and 0.869), indicating good drug-like properties.

**DILI:** Ligand A (29.391) has a much lower DILI risk than Ligand B (38.852). This is a significant advantage.

**BBB:** Ligand B (78.209) has a better BBB penetration percentile than Ligand A (65.723). While both are reasonably good, >70 is preferred for CNS targets.

**Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and suggests poor permeability. Ligand A (-4.3) is slightly better than Ligand B (-4.926), but both are concerning.

**Aqueous Solubility:** Both have negative solubility values, which is also unusual and suggests poor solubility. Ligand A (-2.308) is slightly better than Ligand B (-0.708).

**hERG:** Both ligands show very low hERG inhibition liability (0.106 and 0.396), which is excellent.

**Microsomal Clearance:** Ligand A (16.027) has a higher microsomal clearance than Ligand B (0.917), indicating lower metabolic stability. This is a disadvantage for Ligand A.

**In vitro Half-Life:** Ligand A (-22.023) has a much longer in vitro half-life than Ligand B (12.775). This is a significant advantage for Ligand A.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.011 and 0.015), which is excellent.

**Binding Affinity:** Ligand B (-8.1 kcal/mol) has a slightly better binding affinity than Ligand A (-7.6 kcal/mol). While the difference is not huge, it's a positive for Ligand B.

**Overall Assessment:**

Considering the GPCR-specific priorities, the key differentiating factors are BBB, TPSA, DILI, and affinity. Ligand B has a better BBB score and affinity, which are crucial for CNS targets. However, Ligand A has a significantly lower DILI risk, better TPSA, and a longer half-life. The negative Caco-2 and solubility values are concerning for both, but the better affinity of Ligand B is a strong point. Given the slight edge in affinity and better BBB, I would lean towards Ligand B, but the poor permeability/solubility would require significant optimization.

Output:
1
2025-04-17 05:36:29,896 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (340.47 & 344.50 Da) fall comfortably within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (50.36) is significantly better than Ligand B (58.2). For CNS targets, we want TPSA <= 90, and ideally lower. Ligand A is much closer to the ideal range.

**3. logP:** Ligand A (4.489) is higher than Ligand B (2.728). While both are within the 1-3 range, Ligand A is approaching the upper limit. This *could* present solubility issues, but is not a dealbreaker.

**4. H-Bond Donors:** Both ligands have 2 HBD, which is acceptable (<=5).

**5. H-Bond Acceptors:** Both ligands have 2 HBA, which is acceptable (<=10).

**6. QED:** Ligand A (0.842) has a considerably higher QED score than Ligand B (0.698), indicating better overall drug-likeness.

**7. DILI:** Ligand A (49.48) has a higher DILI risk than Ligand B (15.86). This is a significant advantage for Ligand B.

**8. BBB:** Ligand A (73.40) has a much better BBB penetration percentile than Ligand B (54.25). This is *critical* for a CNS target like DRD2.

**9. Caco-2 Permeability:** Both ligands have very poor Caco-2 permeability (-4.655 and -4.652). This suggests poor intestinal absorption, but is less critical for a CNS target where direct delivery is possible.

**10. Aqueous Solubility:** Both ligands have very poor aqueous solubility (-4.841 and -4.868). This is a concern, but can be addressed with formulation strategies.

**11. hERG Inhibition:** Ligand A (0.804) has a slightly higher hERG inhibition risk than Ligand B (0.123). This is a clear advantage for Ligand B.

**12. Microsomal Clearance:** Ligand A (83.14) has a higher microsomal clearance than Ligand B (12.63), indicating lower metabolic stability. This favors Ligand B.

**13. In vitro Half-Life:** Ligand B (6.83 hours) has a significantly longer in vitro half-life than Ligand A (-3.02 hours). This is a strong advantage for Ligand B.

**14. P-gp Efflux:** Ligand A (0.287) has lower P-gp efflux than Ligand B (0.066), which is favorable for CNS penetration.

**15. Binding Affinity:** Ligand A (-8.8 kcal/mol) has a significantly stronger binding affinity than Ligand B (-7.7 kcal/mol). This is a substantial advantage, potentially outweighing some of the ADME concerns.

**Overall Assessment:**

Ligand A has a significantly better binding affinity and BBB penetration, which are crucial for a CNS GPCR target. However, it suffers from higher DILI risk, higher hERG inhibition, faster clearance, and shorter half-life. Ligand B has a better safety profile (lower DILI, hERG) and better metabolic stability, but weaker affinity and lower BBB penetration.

The difference in binding affinity (-8.8 vs -7.7 kcal/mol) is substantial (1.1 kcal/mol). Given the importance of potency for GPCRs, and the possibility of mitigating some ADME issues through formulation or structural modifications, the stronger affinity of Ligand A makes it the more promising candidate. The improved BBB penetration further supports this.

Output:
0
2025-04-17 05:36:29,896 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B against the provided guidelines, prioritizing GPCR-specific properties (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (340.383 Da) is slightly lower, which isn't a major concern.

**TPSA:** Ligand A (79.54) is better than Ligand B (41.37) as it is closer to the ideal range for CNS targets (<=90).

**logP:** Ligand B (3.241) is higher than Ligand A (1.753). While both are within the optimal range of 1-3, Ligand B is approaching the upper limit, which could raise concerns about solubility and off-target effects.

**H-Bond Donors/Acceptors:** Both ligands have a reasonable number of HBD (0) and HBA (5/4), falling within acceptable limits.

**QED:** Both ligands have similar QED values (0.832 and 0.803), indicating good drug-likeness.

**DILI:** Ligand B (21.908) has a significantly lower DILI risk than Ligand A (63.668), which is a substantial advantage.

**BBB:** Ligand B (89.337) has a much higher BBB penetration percentile than Ligand A (44.591). This is *critical* for a CNS target like DRD2.

**Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and suggests a potential issue with the data or modeling. However, the values are similar.

**Aqueous Solubility:** Both ligands have negative solubility values, which is also unusual. Again, the values are similar.

**hERG Inhibition:** Ligand A (0.242) has a slightly lower hERG inhibition liability than Ligand B (0.589), but both are relatively low risk.

**Microsomal Clearance:** Ligand B (56.837) has a higher microsomal clearance than Ligand A (25.622), indicating faster metabolism and potentially lower exposure.

**In vitro Half-Life:** Ligand A (29.064) has a longer in vitro half-life than Ligand B (16.711), which is preferable.

**P-gp Efflux:** Ligand A (0.146) has a lower P-gp efflux liability than Ligand B (0.573), which is beneficial for CNS penetration.

**Binding Affinity:** Ligand B (-7.5 kcal/mol) has a significantly stronger binding affinity than Ligand A (-9.1 kcal/mol). This is a major advantage, potentially outweighing some of the ADME drawbacks.

**Overall Assessment:**

While Ligand A has better TPSA, P-gp efflux, and half-life, Ligand B excels in the most critical areas for a CNS-targeting GPCR: **BBB penetration and binding affinity**. The significantly stronger binding affinity (-7.5 vs -9.1 kcal/mol) is a substantial advantage. The lower DILI risk for Ligand B is also a positive factor. The higher logP and clearance of Ligand B are concerns, but the strong affinity and excellent BBB penetration are likely to be more impactful for efficacy.

Output:
1
2025-04-17 05:36:29,896 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (357.42 and 345.443 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (35.58) is excellent, well below the 90 A^2 target for CNS drugs. Ligand B (71.53) is higher, but still potentially acceptable, though less ideal.

**logP:** Ligand A (3.304) is optimal. Ligand B (1.466) is at the lower end of the optimal range, potentially impacting permeability.

**H-Bond Donors/Acceptors:** Both have 1 HBD, which is good. Ligand A has 3 HBA, and Ligand B has 4 HBA, both are within the acceptable limit of 10.

**QED:** Both ligands have good QED scores (0.898 and 0.812), indicating good drug-like properties.

**DILI:** Ligand A (27.724) has a very low DILI risk. Ligand B (9.771) also has a low DILI risk, but slightly higher than A.

**BBB:** This is crucial for a CNS target. Ligand A (92.516) has excellent BBB penetration. Ligand B (71.772) is acceptable but significantly lower than A, which is a major drawback.

**Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and requires further investigation. However, we'll proceed with the assumption that lower values indicate poorer permeability.

**Aqueous Solubility:** Both have negative solubility values, also unusual. We'll assume lower values indicate poorer solubility.

**hERG:** Both ligands have low hERG risk (0.936 and 0.156), which is favorable.

**Microsomal Clearance:** Ligand A (22.02) is moderate, while Ligand B (0.174) is very low, suggesting better metabolic stability for B.

**In vitro Half-Life:** Ligand A (-0.448) has a very short half-life. Ligand B (-6.426) has a longer half-life.

**P-gp Efflux:** Ligand A (0.246) has lower P-gp efflux, which is good for CNS penetration. Ligand B (0.017) has very low P-gp efflux, even better.

**Binding Affinity:** Ligand B (-7.8 kcal/mol) has a slightly better binding affinity than Ligand A (-7.4 kcal/mol). The difference is 0.4 kcal/mol, which is not huge, but noticeable.

**Overall Assessment:**

Ligand A excels in BBB penetration and has a lower DILI risk. However, it has a short half-life and moderate metabolic clearance. Ligand B has better metabolic stability (lower Cl_mic, longer t1/2) and slightly better binding affinity, and very low P-gp efflux. The biggest drawback of Ligand B is its lower BBB penetration compared to Ligand A.

Given the GPCR-specific prioritization, BBB penetration is critical for CNS targets like DRD2. While Ligand B has a slightly better affinity and metabolic profile, Ligand A's significantly higher BBB penetration makes it the more promising candidate.

Output:
1
2025-04-17 05:36:29,896 - INFO - Reasoning:

Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (365.5 and 361.5 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Both ligands (55.8 and 56.7 A^2) are below the 90 A^2 threshold desirable for CNS targets, which is excellent.

**3. logP:** Both ligands have good logP values (2.87 and 3.25), falling within the optimal 1-3 range. Ligand B is slightly more lipophilic.

**4. H-Bond Donors:** Ligand A has 0 HBD, while Ligand B has 1. Both are acceptable (<=5).

**5. H-Bond Acceptors:** Ligand A has 4 HBA, and Ligand B has 5. Both are within the acceptable range (<=10).

**6. QED:** Both ligands have good QED scores (0.728 and 0.858), indicating good drug-like properties.

**7. DILI:** Ligand A has a DILI risk of 33.5%, while Ligand B has 23.8%. Both are good (below 40%), but Ligand B is slightly better.

**8. BBB:** Ligand A has a BBB penetration of 53.7%, and Ligand B has 59.1%. While both are reasonable, neither exceeds the desirable 70% threshold for CNS targets. Ligand B is better.

**9. Caco-2 Permeability:** Both have negative Caco-2 values (-4.53 and -4.79). This is unusual and suggests poor permeability. However, these values are on a strange scale and difficult to interpret without further information.

**10. Aqueous Solubility:** Both have negative solubility values (-4.64 and -2.64). This is also unusual and suggests poor solubility. Again, the scale is unclear.

**11. hERG Inhibition:** Both ligands have low hERG inhibition risk (0.58 and 0.45), which is good.

**12. Microsomal Clearance:** Ligand A has a Cl_mic of 65.5 mL/min/kg, while Ligand B has 78.1 mL/min/kg.  Higher clearance is less desirable, so Ligand A is better here.

**13. In vitro Half-Life:** Ligand A has a negative half-life (-24.9 hours), which is impossible. Ligand B has a half-life of 12.9 hours, which is reasonable. This is a major red flag for Ligand A.

**14. P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.195 and 0.071), which is excellent for CNS penetration. Ligand B is slightly better.

**15. Binding Affinity:** Ligand A has a binding affinity of -8.1 kcal/mol, while Ligand B has -7.2 kcal/mol. Ligand A has a significantly stronger binding affinity, exceeding the >1.5 kcal/mol advantage threshold.

**Overall Assessment:**

Ligand A has a significantly better binding affinity, which is a crucial factor for GPCRs. However, its negative half-life is a critical flaw. The negative solubility and Caco-2 values are also concerning. Ligand B has a more reasonable ADME profile (better DILI, BBB, half-life, and P-gp efflux) but a weaker binding affinity.

Despite the strong affinity of Ligand A, the unrealistic half-life and questionable solubility/permeability make it a highly improbable drug candidate. Ligand B, while not perfect, presents a more balanced profile and is more likely to be a viable starting point for optimization.

Output:
1
2025-04-17 05:36:29,897 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (368.5 and 355.4 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (89.87) is excellent, falling below the 90 A^2 threshold for CNS targets. Ligand B (116.76) is higher, but still potentially acceptable, though less optimal.

**logP:** Ligand A (1.861) is within the optimal 1-3 range. Ligand B (0.664) is slightly low, which *could* hinder permeability, but isn't a dealbreaker.

**H-Bond Donors/Acceptors:** Ligand A (3 HBD, 5 HBA) and Ligand B (2 HBD, 8 HBA) both have reasonable numbers of H-bond donors and acceptors, well within the guidelines.

**QED:** Both ligands have similar QED values (0.713 and 0.66), indicating good drug-like properties.

**DILI:** Ligand A (36.293) has a much lower DILI risk than Ligand B (92.982). This is a significant advantage for Ligand A.

**BBB:** Ligand A (19.038) has a very poor BBB percentile. Ligand B (45.638) is better, but still not ideal (aim for >70 for CNS targets).

**Caco-2 Permeability:** Both have negative Caco-2 values (-5.824 and -5.63), which is unusual and suggests poor permeability. However, these values are on a log scale, and the absolute values are close, so this isn't a major differentiator.

**Aqueous Solubility:** Both have negative solubility values (-1.578 and -4.017), indicating poor aqueous solubility. This could pose formulation challenges.

**hERG:** Ligand A (0.047) has a very low hERG risk, while Ligand B (0.464) is slightly higher.

**Microsomal Clearance:** Ligand B (19.069) has a higher microsomal clearance than Ligand A (8.733), suggesting faster metabolism and potentially lower *in vivo* exposure.

**In vitro Half-Life:** Ligand A (-20.517) has a very negative half-life, which is concerning. Ligand B (7.617) is positive, suggesting a longer half-life.

**P-gp Efflux:** Ligand A (0.044) has very low P-gp efflux liability, which is excellent for CNS penetration. Ligand B (0.09) is slightly higher, but still relatively low.

**Binding Affinity:** Ligand B (-9.3 kcal/mol) has a significantly stronger binding affinity than Ligand A (-6.8 kcal/mol). This is a substantial advantage, potentially outweighing some of the ADME drawbacks.

**Overall Assessment:**

Ligand A has better DILI, hERG, and P-gp efflux profiles, but suffers from very poor BBB penetration and a concerningly short *in vitro* half-life. Ligand B has a much stronger binding affinity, a better (though still suboptimal) BBB score, and a longer half-life. The biggest drawback for Ligand B is its higher DILI risk.

Given the GPCR target and the importance of CNS penetration, the stronger binding affinity of Ligand B is a critical factor. While the DILI risk is higher, it might be mitigated through structural modifications during lead optimization. The poor BBB of Ligand A is a major hurdle that would be difficult to overcome.

Output:
1
2025-04-17 05:36:29,897 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (355.385 and 353.423 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (66.65) is significantly better than Ligand B (116.05). For CNS targets, TPSA should be <=90. Ligand A is within this range, while Ligand B is considerably above. This is a major advantage for Ligand A.

**3. logP:** Ligand A (2.1) is within the optimal range of 1-3. Ligand B (-1.029) is below 1, which could hinder permeation. This favors Ligand A.

**4. H-Bond Donors:** Both have acceptable HBD counts (0 for A, 2 for B, both <=5).

**5. H-Bond Acceptors:** Both have 4 HBAs, which is acceptable (<=10).

**6. QED:** Ligand A (0.811) has a higher QED than Ligand B (0.657), indicating a more drug-like profile.

**7. DILI:** Ligand A (44.048) has a slightly higher DILI risk than Ligand B (25.824), but both are below the concerning threshold of 60.

**8. BBB:** Ligand A (86.39) has a much better BBB penetration percentile than Ligand B (54.13). For a CNS target like DRD2, >70 is desirable, and A is closer to that target. This is a significant advantage for Ligand A.

**9. Caco-2 Permeability:** Ligand A (-4.536) has a negative value, which is unusual and suggests poor permeability. Ligand B (-5.373) is also negative and similarly poor. This is a weakness for both, but doesn't differentiate them.

**10. Aqueous Solubility:** Ligand A (-1.539) and Ligand B (-1.153) both have negative solubility values, indicating poor solubility. This is a drawback for both.

**11. hERG Inhibition:** Ligand A (0.274) has a lower hERG risk than Ligand B (0.058), which is preferable.

**12. Microsomal Clearance:** Ligand B (-16.44) has a lower (better) microsomal clearance than Ligand A (26.74), indicating greater metabolic stability.

**13. In vitro Half-Life:** Ligand A (-38.236) has a very negative half-life, which is problematic. Ligand B (1.782) is better, though still relatively short.

**14. P-gp Efflux:** Ligand A (0.094) has lower P-gp efflux liability than Ligand B (0.002), which is favorable for CNS penetration.

**15. Binding Affinity:** Ligand B (-7.5 kcal/mol) has a slightly better binding affinity than Ligand A (-8.3 kcal/mol). While a difference of 0.8 kcal/mol is not huge, it is noticeable.

**Overall Assessment:**

Despite the slightly better affinity of Ligand B, Ligand A is the more promising candidate. The key advantages of Ligand A are its superior TPSA, logP, BBB penetration, and P-gp efflux liability. These are crucial for CNS drug development. While Ligand A has a concerningly negative in vitro half-life and Caco-2 permeability, these issues might be addressable through further optimization. Ligand B's low logP and poor BBB penetration are more fundamental issues that would be harder to overcome.

Output:
1
2025-04-17 05:36:29,897 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (351.451 and 359.423 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (89.35) is excellent, falling well below the 90 A^2 threshold for CNS targets. Ligand B (131.19) is higher, but still potentially acceptable, though less ideal.

**logP:** Ligand A (0.528) is a bit low, potentially hindering membrane permeability. Ligand B (-1.371) is even lower, raising concerns about permeability. Both are below the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A (1 HBD, 6 HBA) is good. Ligand B (3 HBD, 6 HBA) is also acceptable.

**QED:** Ligand A (0.701) is strong, indicating good drug-like properties. Ligand B (0.441) is lower, suggesting a less favorable overall drug-likeness profile.

**DILI:** Ligand A (39.899) has a very low DILI risk. Ligand B (11.283) also has a low DILI risk.

**BBB:** Ligand A (55.642) has a moderate BBB penetration score. Ligand B (45.715) is lower, which is a significant drawback for a CNS target like DRD2.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.068 and -5.677), which is unusual and suggests poor permeability. This is a red flag.

**Aqueous Solubility:** Both ligands have negative solubility values (-1.073 and -1.647), indicating very poor aqueous solubility, which is a major formulation challenge.

**hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.069 and 0.125).

**Microsomal Clearance:** Ligand A (16.505) has a moderate clearance, while Ligand B (0.513) has a very low clearance, suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (9.177) has a moderate half-life. Ligand B (-4.74) has a negative half-life, which is not physically possible and indicates a problem with the data or the molecule's stability.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.027 and 0.006), which is favorable for CNS penetration.

**Binding Affinity:** Ligand A (-7.5 kcal/mol) has a slightly better binding affinity than Ligand B (-6.2 kcal/mol). The difference is 1.3 kcal/mol, which is significant enough to potentially overcome some ADME drawbacks.

**Overall Assessment:**

Despite the poor Caco-2 and solubility values for both, Ligand A is the better candidate. It has a superior QED score, a better (though still moderate) BBB score, and a slightly stronger binding affinity. Ligand B's negative in vitro half-life is a critical flaw. The low logP values for both are concerning, but the stronger affinity of Ligand A and its better overall profile make it the more promising starting point, assuming solubility and permeability can be addressed through structural modifications.

Output:
0
2025-04-17 05:36:29,897 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (349.431 and 341.411 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (98.7) is slightly higher than Ligand B (84.23). Both are below the 140 threshold for oral absorption and acceptable for CNS targets, but Ligand B is better positioned.

**logP:** Both ligands have good logP values (2.829 and 2.751), falling within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A has 1 HBD and 6 HBA, while Ligand B has 2 HBD and 4 HBA. Both are within acceptable limits (<=5 HBD and <=10 HBA).

**QED:** Ligand B (0.811) has a significantly higher QED score than Ligand A (0.51), indicating a more drug-like profile.

**DILI:** Ligand A (45.56) has a lower DILI risk than Ligand B (52.966), which is preferable.

**BBB:** Ligand A (76.231) has a substantially better BBB penetration percentile than Ligand B (65.839). This is a *critical* advantage for a CNS target like DRD2.

**Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and suggests poor permeability. However, the scale is not defined, so it's hard to interpret.

**Aqueous Solubility:** Both have negative solubility values, again, the scale is undefined, but suggests poor solubility.

**hERG:** Ligand A (0.917) has a slightly higher hERG risk than Ligand B (0.311), making Ligand B safer from a cardiotoxicity perspective.

**Microsomal Clearance:** Ligand A (43.467) has a higher microsomal clearance than Ligand B (30.646), meaning Ligand B is more metabolically stable.

**In vitro Half-Life:** Ligand B (22.526) has a significantly longer in vitro half-life than Ligand A (-4.441), which is a major advantage.

**P-gp Efflux:** Ligand A (0.362) has lower P-gp efflux liability than Ligand B (0.243), which is better for CNS exposure.

**Binding Affinity:** Ligand B (-9.3 kcal/mol) has a *much* stronger binding affinity than Ligand A (-7.2 kcal/mol). This difference of 2.1 kcal/mol is substantial and can outweigh many ADME drawbacks.

**Overall Assessment:**

While Ligand A has better BBB penetration and lower DILI risk, Ligand B excels in almost every other crucial parameter, especially binding affinity and metabolic stability. The significantly stronger binding affinity of Ligand B (-9.3 vs -7.2 kcal/mol) is a decisive factor. The longer half-life and better QED also contribute to its superior profile. The slightly higher P-gp efflux is a minor concern compared to the affinity advantage. For a CNS target, the BBB value for Ligand A is good, but the overall profile of Ligand B is more promising.

Output:
1
2025-04-17 05:36:29,897 - INFO - Reasoning:

Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (354.407 and 345.443 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (117.79) is better than Ligand B (62.62). For CNS targets, we want TPSA <= 90, so both are acceptable, but A is closer to the upper limit.

**3. logP:** Both ligands have a logP of approximately 1.85, which is optimal (1-3).

**4. H-Bond Donors:** Ligand A has 2 HBD, and Ligand B has 0. Both are within the acceptable limit of <=5.

**5. H-Bond Acceptors:** Ligand A has 7 HBA, and Ligand B has 4. Both are within the acceptable limit of <=10.

**6. QED:** Ligand A (0.847) has a significantly better QED score than Ligand B (0.618), indicating a more drug-like profile.

**7. DILI:** Both ligands have relatively similar DILI risk (52.772 and 57.154), both being acceptable (<60).

**8. BBB:** Ligand A (77.821) has a slightly better BBB percentile than Ligand B (74.564). Both are good, but A is closer to the desirable >70 threshold for CNS targets.

**9. Caco-2 Permeability:** Ligand A (-4.647) has worse Caco-2 permeability than Ligand B (-4.5). Lower values are less desirable.

**10. Aqueous Solubility:** Ligand A (-3.072) has worse aqueous solubility than Ligand B (-2.744). Lower values are less desirable.

**11. hERG Inhibition:** Both ligands have low hERG inhibition liability (0.113 and 0.252), which is good.

**12. Microsomal Clearance:** Ligand A (29.498) has lower microsomal clearance than Ligand B (49.941), suggesting better metabolic stability.

**13. In vitro Half-Life:** Ligand A (-25.232) has a longer in vitro half-life than Ligand B (-19.931).

**14. P-gp Efflux:** Ligand A (0.019) has significantly lower P-gp efflux liability than Ligand B (0.399), which is crucial for CNS penetration.

**15. Binding Affinity:** Both ligands have the same binding affinity (-8.0 kcal/mol), which is excellent.

**Overall Assessment:**

While both ligands have excellent binding affinity and acceptable logP values, Ligand A is superior due to its better QED, slightly better BBB penetration, significantly lower P-gp efflux, lower microsomal clearance, and longer half-life. The slightly worse Caco-2 and solubility of Ligand A are less critical given the CNS target and the overall superior ADME profile. The lower P-gp efflux is a significant advantage for CNS exposure.

Output:
1
2025-04-17 05:36:29,897 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (364.423 and 343.431 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (93.73) is slightly above the optimal <90 for CNS targets, while Ligand B (80.12) is comfortably within the range. This favors Ligand B.

**logP:** Both ligands have good logP values (2.22 and 1.13), falling within the 1-3 range. Ligand B is slightly lower, which could potentially affect permeability, but is still acceptable.

**H-Bond Donors/Acceptors:** Ligand A has 2 HBD and 5 HBA, while Ligand B has 1 HBD and 5 HBA. Both are within acceptable limits (<=5 HBD, <=10 HBA).

**QED:** Both ligands have good QED scores (0.701 and 0.785), indicating good drug-like properties.

**DILI:** Ligand A (83.598) has a higher DILI risk than Ligand B (51.493). This is a significant advantage for Ligand B.

**BBB:** Ligand B (70.57) has a better BBB penetration percentile than Ligand A (65.607). While both are above 70, the higher value for B is preferable for a CNS target.

**Caco-2 Permeability:** Ligand A (-4.963) has a worse Caco-2 permeability than Ligand B (-5.33). Lower values indicate lower permeability.

**Aqueous Solubility:** Ligand A (-4.049) has worse solubility than Ligand B (-2.448).

**hERG Inhibition:** Ligand B (0.106) has a much lower hERG inhibition liability than Ligand A (0.556), which is a critical safety advantage.

**Microsomal Clearance:** Ligand B (33.363) has a slightly lower microsomal clearance than Ligand A (37.616), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand B (-1.647) has a slightly longer in vitro half-life than Ligand A (-12.319).

**P-gp Efflux:** Ligand B (0.071) has a much lower P-gp efflux liability than Ligand A (0.229), which is crucial for CNS penetration.

**Binding Affinity:** Ligand B (-7.8 kcal/mol) has a slightly better binding affinity than Ligand A (-8.4 kcal/mol). Although the difference is small, it's still a positive factor for Ligand B.

**Overall Assessment:**

Ligand B consistently outperforms Ligand A across several critical ADME-Tox properties, including DILI, BBB, hERG, P-gp efflux, and solubility. While Ligand A has a slightly better binding affinity and a slightly better TPSA, the improvements in safety and CNS penetration for Ligand B are more significant for a DRD2 (CNS target) drug candidate.

Output:
1
2025-04-17 05:36:29,897 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (344.411 and 343.398 Da) fall comfortably within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (64.68) is higher than Ligand B (52.33). For a CNS target like DRD2, a TPSA <= 90 is preferred, and ideally closer to 60. Ligand B is better here.

**3. logP:** Ligand A (2.312) is within the optimal 1-3 range. Ligand B (4.636) is higher, potentially leading to solubility issues and off-target interactions. Ligand A is better.

**4. H-Bond Donors:** Both have 0 HBD, which is acceptable.

**5. H-Bond Acceptors:** Ligand A has 5, and Ligand B has 4. Both are within the acceptable limit of <=10.

**6. QED:** Ligand A (0.854) has a better QED score than Ligand B (0.742), indicating a more drug-like profile.

**7. DILI:** Ligand A (38.852) has a lower DILI risk than Ligand B (48.313), which is preferable.

**8. BBB:** Ligand B (88.057) has a significantly higher BBB penetration percentile than Ligand A (70.803). This is a *critical* advantage for a CNS target.

**9. Caco-2 Permeability:** Both have negative Caco-2 values (-4.33 and -4.352), which is unusual and suggests poor permeability. This is a concern for both.

**10. Aqueous Solubility:** Ligand A (-2.85) has better solubility than Ligand B (-5.984).

**11. hERG Inhibition:** Both have low hERG inhibition liability (0.583 and 0.412).

**12. Microsomal Clearance:** Ligand B (97.151) has a higher microsomal clearance than Ligand A (50.728), indicating lower metabolic stability. Ligand A is better.

**13. In vitro Half-Life:** Ligand A (47.762) has a much longer in vitro half-life than Ligand B (0.229). This is a significant advantage.

**14. P-gp Efflux:** Both have low P-gp efflux liability (0.442 and 0.424).

**15. Binding Affinity:** Ligand B (-8.5 kcal/mol) has a *much* stronger binding affinity than Ligand A (-0.0 kcal/mol). This is a substantial advantage, potentially outweighing some of the ADME concerns.

**Overall Assessment:**

While Ligand A has better ADME properties (solubility, metabolic stability, half-life, DILI), Ligand B's significantly stronger binding affinity (-8.5 vs -0.0 kcal/mol) and excellent BBB penetration (88.06%) are decisive. The higher logP of Ligand B is a concern, but the potency advantage is substantial. The poor Caco-2 values are concerning for both, but for a CNS target, oral bioavailability is less critical than brain penetration and target engagement.

Output:
1
2025-04-17 05:36:29,897 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight (MW):** Both ligands (375.259 and 356.392 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (58.12) is better than Ligand B (61.88). Both are below the 90 A^2 threshold for CNS targets, which is good.

**3. logP:** Both ligands have good logP values (3.021 and 4.065), falling within the optimal 1-3 range. Ligand B is slightly higher, potentially increasing off-target interactions, but not drastically.

**4. H-Bond Donors (HBD):** Both ligands have 1 HBD, well within the acceptable limit of <=5.

**5. H-Bond Acceptors (HBA):** Ligand A has 4 HBA, and Ligand B has 3. Both are below the limit of <=10.

**6. QED:** Both ligands have high QED scores (0.835 and 0.849), indicating good drug-like properties.

**7. DILI:** Ligand A (76.154) has a higher DILI risk than Ligand B (45.444). This is a significant drawback for Ligand A.

**8. BBB:** Ligand B (84.219) has a substantially better BBB penetration score than Ligand A (68.748). This is *critical* for a CNS target like DRD2.

**9. Caco-2 Permeability:** Both have negative values (-4.738 and -4.694), which is unusual and suggests poor permeability. However, these values are on a scale where negative values are possible, and direct comparison is difficult without knowing the scale's specifics.

**10. Aqueous Solubility:** Both have negative values (-4.467 and -4.199), suggesting poor aqueous solubility. Similar to Caco-2, the scale is unknown.

**11. hERG Inhibition:** Both ligands have low hERG inhibition risk (0.706 and 0.796).

**12. Microsomal Clearance (Cl_mic):** Ligand B (37.736) has a higher microsomal clearance than Ligand A (25.793), suggesting faster metabolism and potentially lower exposure.

**13. In vitro Half-Life:** Ligand B (17.871) has a longer in vitro half-life than Ligand A (9.9). This is a positive for Ligand B.

**14. P-gp Efflux:** Ligand A (0.278) has lower P-gp efflux than Ligand B (0.135), which is beneficial for CNS penetration.

**15. Binding Affinity:** Ligand A (-9.5 kcal/mol) has a significantly stronger binding affinity than Ligand B (-8.0 kcal/mol). This is a substantial advantage.

**Overall Assessment:**

While Ligand A has a superior binding affinity, the significantly higher DILI risk and lower BBB penetration are major concerns. For a CNS target like DRD2, BBB penetration is paramount. Ligand B, despite a slightly weaker affinity, has a much better safety profile (lower DILI) and significantly improved BBB penetration, along with a longer half-life. The difference in affinity is substantial (1.5 kcal/mol), but the ADME/Tox profile of Ligand B is far more favorable for development.

Output:
1
2025-04-17 05:36:29,898 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (349.435 and 352.406 Da) are within the ideal range of 200-500 Da.

**TPSA:** Ligand A (107.4) is borderline for CNS penetration, being above the preferred <90, but still potentially acceptable. Ligand B (59.08) is excellent, well below the 90 threshold.

**logP:** Both ligands have good logP values (2.164 and 1.492), falling within the optimal 1-3 range.

**H-Bond Donors:** Ligand A has 1 HBD, which is good. Ligand B has 0, also good.

**H-Bond Acceptors:** Both ligands have 4 HBAs, which is within the acceptable limit of <=10.

**QED:** Ligand B (0.746) has a significantly better QED score than Ligand A (0.355), indicating a more drug-like profile.

**DILI:** Both ligands have acceptable DILI risk (42.613 and 46.026), both below the 60 threshold.

**BBB:** Ligand B (89.531) has a much better BBB penetration percentile than Ligand A (70.919). This is a crucial advantage for a CNS target like DRD2.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.607 and -4.27), which is unusual and suggests poor permeability. This is a significant concern for both.

**Aqueous Solubility:** Both ligands have negative solubility values (-2.355 and -1.464), indicating very poor aqueous solubility. This is a major drawback for both.

**hERG Inhibition:** Both ligands show low hERG inhibition liability (0.22 and 0.354), which is positive.

**Microsomal Clearance:** Ligand A (39.227) has a higher microsomal clearance than Ligand B (12.571), suggesting lower metabolic stability.

**In vitro Half-Life:** Ligand B (4.629) has a longer in vitro half-life than Ligand A (2.672).

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.076 and 0.047), which is favorable for CNS penetration.

**Binding Affinity:** Ligand A (-8.4 kcal/mol) has a slightly better binding affinity than Ligand B (-7.6 kcal/mol). However, the difference is less than 1.5 kcal/mol, so the ADME properties become more important.

**Overall Assessment:**

While Ligand A has slightly better binding affinity, Ligand B is the more promising candidate. Ligand B exhibits significantly better QED, BBB penetration, and in vitro half-life, and lower microsomal clearance. The poor Caco-2 and solubility are concerning for both, but the superior CNS-related properties of Ligand B outweigh the small affinity difference. For a CNS target like DRD2, BBB penetration is paramount, and Ligand B excels in this area.

Output:
1
2025-04-17 05:36:29,898 - INFO - Reasoning:

Let's analyze Ligand A and Ligand B for their potential as DRD2 drug candidates, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (336.351 Da) is slightly better, being closer to the lower end which can aid permeability.

**TPSA:** Ligand A (95.3) is excellent, falling well below the 90 A^2 threshold for CNS targets. Ligand B (124.42) is higher, potentially hindering BBB penetration.

**logP:** Ligand A (3.068) is optimal (1-3). Ligand B (0.327) is quite low, which could severely limit its ability to cross cell membranes, including the BBB.

**H-Bond Donors/Acceptors:** Ligand A (HBD=1, HBA=6) is favorable. Ligand B (HBD=3, HBA=4) is also acceptable, but slightly less optimal.

**QED:** Both ligands have similar QED values (A: 0.786, B: 0.71), indicating good drug-like properties.

**DILI:** Ligand A (81.427) has a higher DILI risk than Ligand B (57.348), but both are within an acceptable range.

**BBB:** Ligand A (71.733) has a good BBB percentile, desirable for a CNS target. Ligand B (57.193) is significantly lower, raising concerns about CNS exposure.

**Caco-2 Permeability:** Ligand A (-4.994) is better than Ligand B (-5.468), indicating better intestinal absorption.

**Aqueous Solubility:** Ligand A (-4.74) is better than Ligand B (-3.3), indicating better solubility.

**hERG:** Both ligands have very low hERG inhibition liability (A: 0.892, B: 0.139), which is excellent.

**Microsomal Clearance:** Ligand A (48.562) has a moderate clearance, while Ligand B (-25.392) has a negative value, suggesting very slow clearance and high metabolic stability. This is a significant advantage for Ligand B.

**In vitro Half-Life:** Ligand A (33.063) has a reasonable half-life, while Ligand B (-10.636) has a negative value, suggesting a very long half-life.

**P-gp Efflux:** Both ligands exhibit low P-gp efflux liability (A: 0.438, B: 0.009), which is favorable for CNS penetration.

**Binding Affinity:** Both ligands have the same binding affinity (-8.5 kcal/mol), which is excellent and strong.

**Overall Assessment:**

While Ligand B has superior metabolic stability and a longer half-life, its low logP and lower BBB penetration are major drawbacks for a CNS-targeting drug. Ligand A, despite a slightly higher DILI risk and moderate clearance, has a much more favorable profile for BBB penetration (critical for DRD2), better solubility, and a good logP value. The equal binding affinity makes the ADME properties the deciding factor.

Output:
1
2025-04-17 05:36:29,898 - INFO - Batch 212 complete. Total preferences: 3392
2025-04-17 05:36:29,898 - INFO - Processing batch 213/512...
2025-04-17 05:37:11,494 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B based on the provided guidelines, prioritizing GPCR-specific properties (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (342.399 and 351.353 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (89.32) is better than Ligand B (73.48), both are below the 90 A^2 threshold for CNS targets.

**logP:** Ligand A (4.054) is higher than the optimal range (1-3), while Ligand B (1.146) is slightly below. This is a significant advantage for Ligand B.

**H-Bond Donors/Acceptors:** Ligand A (HBD=2, HBA=6) and Ligand B (HBD=1, HBA=3) both have acceptable numbers of H-bond donors and acceptors.

**QED:** Ligand B (0.809) has a better QED score than Ligand A (0.583), indicating a more drug-like profile.

**DILI:** Ligand B (39.667) has a much lower DILI risk than Ligand A (73.129).

**BBB:** Ligand B (90.151) has a significantly higher BBB penetration percentile than Ligand A (55.603). This is a critical advantage for a CNS target like DRD2.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values, which is unusual and suggests potential issues with permeability prediction. However, the values are similar (-4.675 vs -4.723).

**Aqueous Solubility:** Both ligands have negative solubility values, which is also unusual. Ligand A (-5.182) is slightly worse than Ligand B (-2.326).

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.553 and 0.249).

**Microsomal Clearance:** Ligand B (-12.574) has a much lower (better) microsomal clearance than Ligand A (63.772), indicating greater metabolic stability.

**In vitro Half-Life:** Ligand B (-37.445) has a much longer in vitro half-life than Ligand A (8.719).

**P-gp Efflux:** Ligand B (0.029) has a much lower P-gp efflux liability than Ligand A (0.146), which is favorable for CNS penetration.

**Binding Affinity:** Ligand A (-8.8 kcal/mol) has a slightly better binding affinity than Ligand B (-7.1 kcal/mol). However, the difference is less than 1.5 kcal/mol, and can be outweighed by the superior ADME properties of Ligand B.

**Overall Assessment:**

Ligand B consistently outperforms Ligand A in crucial ADME properties, especially BBB penetration, DILI risk, metabolic stability, and P-gp efflux. While Ligand A has slightly better binding affinity, the ADME advantages of Ligand B are more important for a CNS-targeting GPCR like DRD2. The negative solubility and Caco-2 values are concerning for both, but Ligand B's other properties are significantly more favorable.

Output:
1
2025-04-17 05:37:11,494 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (348.447 and 347.423 Da) fall comfortably within the ideal 200-500 Da range.

**TPSA:** Ligand A (76.46) is excellent, well below the 90 A^2 threshold for CNS targets. Ligand B (90.96) is slightly higher but still acceptable.

**logP:** Ligand A (1.863) is optimal. Ligand B (0.927) is a bit low, potentially hindering membrane permeability, but still within a reasonable range.

**H-Bond Donors/Acceptors:** Ligand A (1 HBD, 5 HBA) is favorable. Ligand B (0 HBD, 8 HBA) is also acceptable.

**QED:** Both ligands have similar QED values (0.763 and 0.74), indicating good drug-like properties.

**DILI:** Ligand A (32.067) has a much lower DILI risk than Ligand B (59.131), which is a significant advantage.

**BBB:** Ligand A (91.508) has excellent BBB penetration, exceeding the desirable 70% threshold. Ligand B (70.88) is at the lower end of acceptable for a CNS target.

**Caco-2 Permeability:** Ligand A (-4.875) has poor Caco-2 permeability, which is a concern. Ligand B (-4.635) is also poor, but slightly better.

**Aqueous Solubility:** Both ligands have very poor aqueous solubility (-2.448 and -1.514). This could pose formulation challenges.

**hERG Inhibition:** Ligand A (0.324) has a very low hERG risk. Ligand B (0.046) is even lower, which is excellent.

**Microsomal Clearance:** Ligand A (40.827) has lower microsomal clearance than Ligand B (54.594), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (-6.627) has a longer in vitro half-life than Ligand B (21.313), which is a positive attribute.

**P-gp Efflux:** Ligand A (0.281) has lower P-gp efflux than Ligand B (0.19), indicating better potential for CNS exposure.

**Binding Affinity:** Both ligands have the same excellent binding affinity (-7.9 kcal/mol).

**Overall Assessment:**

Ligand A is superior due to its significantly lower DILI risk, much better BBB penetration, lower P-gp efflux, and better metabolic stability (lower Cl_mic and longer t1/2). While both have poor Caco-2 permeability and solubility, the CNS target prioritizes BBB penetration and minimizing off-target effects (DILI). The slightly lower logP of Ligand B is less concerning than the higher DILI and lower BBB.

Output:
0
2025-04-17 05:37:11,494 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (347.415 and 357.391 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (84.67) is excellent for CNS penetration, being well below 90. Ligand B (20.31) is even better, indicating very good potential for crossing the blood-brain barrier.

**logP:** Ligand A (1.368) is within the optimal 1-3 range. Ligand B (4.488) is slightly higher, potentially leading to solubility issues or off-target interactions, but still within a tolerable range.

**H-Bond Donors/Acceptors:** Ligand A has 1 HBD and 5 HBA, which are acceptable. Ligand B has 0 HBD and 1 HBA, which is also good, potentially improving membrane permeability.

**QED:** Both ligands have reasonable QED values (0.786 and 0.687), suggesting good drug-like properties.

**DILI:** Both ligands have low DILI risk (36.681 and 26.173 percentiles), which is favorable.

**BBB:** This is a critical parameter for a CNS target like DRD2. Ligand A has a BBB percentile of 54.362, which is okay, but not great. Ligand B shines here with a BBB percentile of 94.261, indicating a very high probability of CNS penetration.

**Caco-2 Permeability:** Ligand A (-4.945) has poor Caco-2 permeability, which is concerning. Ligand B (-4.259) is also poor, but slightly better than Ligand A.

**Aqueous Solubility:** Both ligands have poor aqueous solubility (-1.854 and -5.323), which could pose formulation challenges.

**hERG Inhibition:** Ligand A (0.077) has a very low hERG risk, which is excellent. Ligand B (0.825) has a slightly elevated hERG risk, but still relatively low.

**Microsomal Clearance:** Ligand A (26.292 mL/min/kg) has a lower clearance than Ligand B (58.752 mL/min/kg), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand B (15.617 hours) has a significantly longer half-life than Ligand A (7.635 hours), which is a major advantage.

**P-gp Efflux:** Ligand A (0.035) has very low P-gp efflux, which is ideal for CNS penetration. Ligand B (0.616) has moderate P-gp efflux, which could limit CNS exposure.

**Binding Affinity:** Both ligands have excellent binding affinities (-9.0 and -8.5 kcal/mol). The difference of 0.5 kcal/mol is not substantial enough to outweigh other factors.

**Overall Assessment:**

Ligand B is the stronger candidate. While it has slightly higher logP and P-gp efflux, its overwhelmingly superior BBB penetration, longer half-life, and still-excellent binding affinity make it more likely to succeed as a CNS-active DRD2 ligand. Ligand A's poor Caco-2 permeability is a significant drawback, and its lower BBB value is concerning. The better metabolic stability of Ligand A is a plus, but can be addressed through structural modifications if needed.

Output:
1
2025-04-17 05:37:11,494 - INFO - Reasoning:

Let's analyze Ligand A and Ligand B for their potential as DRD2 drug candidates, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (399.705) is slightly higher, but acceptable. Ligand B (348.491) is also good.

**2. TPSA:** Ligand A (43.78) is excellent, well below the 90 Angstroms threshold for CNS targets. Ligand B (67.23) is higher, but still potentially acceptable, though less ideal.

**3. logP:** Ligand A (4.31) is slightly high, potentially leading to solubility issues or off-target interactions. Ligand B (2.49) is optimal.

**4. H-Bond Donors:** Both ligands have 1 HBD, which is within the acceptable limit of 5.

**5. H-Bond Acceptors:** Ligand A has 3 HBAs, and Ligand B has 4. Both are within the acceptable limit of 10.

**6. QED:** Both ligands have similar QED values (0.782 and 0.745), indicating good drug-like properties.

**7. DILI:** Ligand A (54.634) has a moderate DILI risk, while Ligand B (19.155) has a very low DILI risk, a significant advantage.

**8. BBB:** Ligand A (62.815) has a moderate BBB penetration, while Ligand B (70.686) has a good BBB penetration. This is a crucial factor for a CNS target like DRD2, favoring Ligand B.

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.961 and -4.791). This is unusual and suggests poor permeability. However, these values are on a logarithmic scale, and the absolute values are close, making it difficult to differentiate based on this metric alone.

**10. Aqueous Solubility:** Both ligands have negative solubility values (-4.632 and -1.749), indicating poor aqueous solubility. Ligand B is better than Ligand A.

**11. hERG Inhibition:** Ligand A (0.94) has a slightly higher hERG inhibition risk than Ligand B (0.275), which is preferable.

**12. Microsomal Clearance:** Ligand A (49.04) has a moderate clearance, while Ligand B (57.886) has a higher clearance, suggesting lower metabolic stability.

**13. In vitro Half-Life:** Ligand A (-10.484) has a very short half-life, while Ligand B (-4.721) has a better half-life.

**14. P-gp Efflux:** Ligand A (0.597) has moderate P-gp efflux, while Ligand B (0.158) has low P-gp efflux. Lower P-gp efflux is desirable for CNS penetration, favoring Ligand B.

**15. Binding Affinity:** Ligand A (-8.4 kcal/mol) has a slightly better binding affinity than Ligand B (-7.6 kcal/mol). This 0.8 kcal/mol difference is significant and could potentially outweigh some of the ADME drawbacks of Ligand A.

**Overall Assessment:**

While Ligand A has a slightly better binding affinity, Ligand B demonstrates a superior ADME profile, particularly regarding BBB penetration, DILI risk, P-gp efflux, and hERG inhibition.  For a CNS target like DRD2, good BBB penetration is critical. The lower DILI risk and P-gp efflux of Ligand B are also significant advantages. The slightly lower affinity of Ligand B is likely surmountable with further optimization.

Output:
1
2025-04-17 05:37:11,494 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 drug candidates, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (359.495 and 353.419 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (49.17) is excellent, well below the 90 A^2 threshold for CNS targets. Ligand B (88.18) is higher, but still acceptable, though less ideal for CNS penetration.

**logP:** Ligand A (4.201) is slightly high, potentially leading to solubility issues or off-target interactions. Ligand B (-0.482) is quite low, which could hinder membrane permeability and CNS entry.

**H-Bond Donors/Acceptors:** Ligand A (0 HBD, 6 HBA) is favorable. Ligand B (1 HBD, 5 HBA) is also acceptable.

**QED:** Both ligands have good QED scores (0.595 and 0.69), indicating drug-like properties.

**DILI:** Ligand A (53.625) has a moderate DILI risk, but is acceptable. Ligand B (39.395) has a lower, and thus preferable, DILI risk.

**BBB:** Ligand A (72.896) has a good BBB percentile, exceeding the 70% threshold for CNS targets. Ligand B (53.974) is lower, which is a significant drawback for a CNS target like DRD2.

**Caco-2 Permeability:** Both have negative Caco-2 values (-5.115 and -4.458), which is unusual and suggests poor permeability. This is a red flag for both, but the negative values are difficult to interpret directly.

**Aqueous Solubility:** Both ligands have negative solubility values (-4.096 and -1.007), indicating poor aqueous solubility. This is a concern, but can sometimes be overcome with formulation strategies.

**hERG Inhibition:** Both ligands show very low hERG inhibition risk (0.257 and 0.07).

**Microsomal Clearance:** Ligand A (63.595) has moderate clearance, while Ligand B (8.36) has very low clearance, indicating better metabolic stability.

**In vitro Half-Life:** Ligand B (-12.555) has a significantly longer predicted half-life than Ligand A (-9.342).

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.619 and 0.012), which is positive for CNS penetration.

**Binding Affinity:** Ligand A (-7.4 kcal/mol) has a slightly better binding affinity than Ligand B (-6.5 kcal/mol), though both are good.

**Overall Assessment:**

Ligand A excels in BBB penetration and binding affinity, crucial for a CNS GPCR target. However, its logP is a bit high, and its metabolic clearance is moderate. Ligand B has better metabolic stability, lower DILI risk, and a longer half-life, but its low logP and significantly lower BBB penetration are major drawbacks for a CNS target. Given the importance of BBB penetration for DRD2, Ligand A is the more promising candidate despite its slightly less favorable logP and clearance.

Output:
1
2025-04-17 05:37:11,495 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (344.455 and 343.471 Da) fall within the ideal range of 200-500 Da.

**TPSA:** Ligand A (60.85) is significantly better than Ligand B (81.99). For CNS targets, we want TPSA <= 90, and A is comfortably within this range, while B is approaching the upper limit.

**logP:** Ligand A (1.873) is optimal, while Ligand B (3.318) is slightly higher but still acceptable (1-3 is optimal).

**H-Bond Donors/Acceptors:** Ligand A (HBD=1, HBA=3) and Ligand B (HBD=2, HBA=3) both have reasonable numbers of H-bond donors and acceptors, well within the guidelines.

**QED:** Both ligands have similar QED values (0.795 and 0.759), indicating good drug-like properties.

**DILI:** Ligand A (13.339) has a much lower DILI risk than Ligand B (39.667), which is a significant advantage.

**BBB:** Ligand A (63.552) has a better BBB penetration percentile than Ligand B (50.407). While >70 is desirable, A is still better positioned for CNS activity.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.707 and -4.639), which is unusual and suggests poor permeability. This is a concern for both.

**Aqueous Solubility:** Both ligands have negative solubility values (-1.723 and -3.976), also unusual and suggesting poor solubility. This is a concern for both.

**hERG Inhibition:** Ligand A (0.23) has a lower hERG inhibition liability than Ligand B (0.723), indicating a lower risk of cardiotoxicity.

**Microsomal Clearance:** Ligand A (23.688) has a lower microsomal clearance than Ligand B (57.015), indicating better metabolic stability.

**In vitro Half-Life:** Ligand B (45.64) has a longer in vitro half-life than Ligand A (13.739), which is a positive attribute.

**P-gp Efflux:** Ligand A (0.081) has a lower P-gp efflux liability than Ligand B (0.115), which is favorable for CNS penetration.

**Binding Affinity:** Both ligands have the same binding affinity (-8.7 kcal/mol), which is excellent and strong enough to outweigh some of the ADME drawbacks.

**Overall Assessment:**

Considering the GPCR-specific priorities, Ligand A is the better candidate. It has a significantly lower DILI risk, better BBB penetration, lower hERG inhibition, lower P-gp efflux, and better metabolic stability (lower Cl_mic). While both have poor Caco-2 and solubility, the other advantages of Ligand A, particularly the improved safety profile and CNS penetration potential, make it the more promising drug candidate. The equal binding affinity removes that as a differentiating factor.

Output:
0
2025-04-17 05:37:11,495 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (357.426 and 362.451 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (87.74) is better than Ligand B (69.68) as it is closer to the ideal range of <90 for CNS targets.

**logP:** Ligand B (3.703) is higher than Ligand A (0.383). While a logP of 3.7 is approaching the upper limit, it's still acceptable. Ligand A's very low logP (0.383) is a significant concern, suggesting poor membrane permeability.

**H-Bond Donors/Acceptors:** Ligand A has 2 HBD and 4 HBA, while Ligand B has 1 HBD and 6 HBA. Both are within acceptable limits (<=5 HBD and <=10 HBA).

**QED:** Both ligands have good QED scores (0.69 and 0.878), indicating drug-like properties.

**DILI:** Ligand A (28.189) has a much lower DILI risk than Ligand B (85.227). This is a substantial advantage for Ligand A.

**BBB:** Ligand A (75.572) has a better BBB percentile than Ligand B (67.468), although both are reasonably good.

**Caco-2 Permeability:** Ligand A (-4.821) has a lower Caco-2 permeability than Ligand B (-4.644), but the difference is small.

**Aqueous Solubility:** Ligand A (-1.693) has better aqueous solubility than Ligand B (-4.018).

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.285 and 0.347).

**Microsomal Clearance:** Ligand A (-1.121) has a lower (better) microsomal clearance than Ligand B (49.816), indicating better metabolic stability.

**In vitro Half-Life:** Ligand A (6.945) has a shorter half-life than Ligand B (-14.932). This is a drawback for Ligand A.

**P-gp Efflux:** Ligand A (0.015) has significantly lower P-gp efflux liability than Ligand B (0.186), which is crucial for CNS penetration.

**Binding Affinity:** Ligand B (-9.0) has a stronger binding affinity than Ligand A (-8.4). This is a 0.6 kcal/mol difference, which is significant.

**Overall Assessment:**

Ligand A excels in several key areas for a CNS-targeting GPCR ligand: lower DILI risk, better BBB penetration, better solubility, lower P-gp efflux, and better metabolic stability. However, its low logP is a major concern. Ligand B has a superior binding affinity and better half-life, but suffers from higher DILI risk, poorer BBB penetration, higher P-gp efflux, and worse metabolic stability.

Given the importance of CNS penetration for DRD2, and the significant advantage Ligand A has in BBB, P-gp efflux, and DILI, I believe it is the more promising candidate *despite* the lower logP and binding affinity. The lower logP could potentially be addressed through structural modifications, but mitigating the higher DILI and P-gp efflux of Ligand B would be more challenging. The affinity difference, while notable, may be overcome with further optimization.

Output:
0
2025-04-17 05:37:11,495 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (370.446 and 365.411 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (70.08) is significantly better than Ligand B (101.74). For CNS targets, TPSA should be <=90, and A is comfortably within that range, while B is pushing the limit.

**logP:** Both ligands have similar logP values (1.749 and 1.69), both within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Both have 1 HBD, which is good. Ligand A has 5 HBA, while Ligand B has 7. Both are acceptable (<=10), but A is slightly preferred.

**QED:** Ligand A (0.877) has a better QED score than Ligand B (0.749), indicating a more drug-like profile.

**DILI:** Ligand A (42.885) has a much lower DILI risk than Ligand B (82.862). This is a significant advantage for A.

**BBB:** Ligand A (69.407) has a better BBB penetration percentile than Ligand B (38.813). This is *critical* for a CNS target like DRD2.

**Caco-2 Permeability:** Both have negative Caco-2 values (-4.571 and -4.761), which is unusual and suggests poor permeability. This is a concern for both, but doesn't differentiate them significantly.

**Aqueous Solubility:** Both have negative solubility values (-2.435 and -2.556), also unusual and indicating poor solubility. Similar to Caco-2, this doesn't help differentiate.

**hERG:** Ligand A (0.616) has a slightly higher hERG risk than Ligand B (0.093). B is significantly better here.

**Microsomal Clearance:** Ligand B (56.18) has lower microsomal clearance than Ligand A (30.764), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand B (42.693) has a significantly longer in vitro half-life than Ligand A (12.508).

**P-gp Efflux:** Ligand A (0.178) has lower P-gp efflux than Ligand B (0.12), which is favorable for CNS penetration.

**Binding Affinity:** Ligand B (-7.4 kcal/mol) has a stronger binding affinity than Ligand A (-8.2 kcal/mol). This is a substantial advantage for B.

**Overall Assessment:**

While Ligand B has a better binding affinity and metabolic stability (lower Cl_mic, longer t1/2), Ligand A is superior in almost all other crucial ADME properties, especially those critical for CNS penetration: TPSA, BBB, DILI, and P-gp efflux. The difference in binding affinity (-7.4 vs -8.2) is not large enough to overcome the significant advantages of Ligand A in terms of CNS penetration and safety. The poor Caco-2 and solubility are concerns for both, but can potentially be addressed through formulation strategies. Given the DRD2 target and the need for CNS exposure, Ligand A is the more promising candidate.

Output:
0
2025-04-17 05:37:11,495 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (345.4 and 352.5 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (98.74) is higher than Ligand B (60.85). For CNS targets, TPSA should be <= 90. Ligand A is borderline, while Ligand B is well within the desired range. This favors Ligand B.

**logP:** Ligand A (0.777) is slightly low, potentially hindering permeation. Ligand B (2.669) is within the optimal 1-3 range. This favors Ligand B.

**H-Bond Donors/Acceptors:** Ligand A has 3 HBD and 4 HBA, while Ligand B has 1 HBD and 3 HBA. Both are within acceptable limits (<=5 HBD and <=10 HBA).

**QED:** Both ligands have good QED scores (0.709 and 0.827, respectively), indicating good drug-like properties.

**DILI:** Ligand A (32.261) has a slightly higher DILI risk than Ligand B (12.33), but both are below the concerning threshold of 60.

**BBB:** Ligand A (63.629) has a better BBB penetration percentile than Ligand B (58.085), but both are below the desirable >70 for CNS targets.

**Caco-2 Permeability:** Ligand A (-5.22) has significantly worse Caco-2 permeability than Ligand B (-4.403). Higher values are better.

**Aqueous Solubility:** Both ligands have poor aqueous solubility (-2.394 and -2.547). This is a potential issue for both, but not a deciding factor.

**hERG Inhibition:** Ligand A (0.126) has a slightly lower hERG inhibition risk than Ligand B (0.68), which is preferable.

**Microsomal Clearance:** Ligand A (-22.081) has much lower microsomal clearance (better metabolic stability) than Ligand B (38.762). This is a significant advantage for Ligand A.

**In vitro Half-Life:** Ligand A (15.313 hours) has a longer half-life than Ligand B (2.421 hours). This is a significant advantage for Ligand A.

**P-gp Efflux:** Ligand A (0.016) has much lower P-gp efflux liability than Ligand B (0.204), which is crucial for CNS penetration.

**Binding Affinity:** Both ligands have similar and strong binding affinities (-8.7 and -8.3 kcal/mol). The difference is less than the 1.5 kcal/mol threshold.

**Overall Assessment:**

While Ligand A has better metabolic stability (lower Cl_mic, longer t1/2), lower P-gp efflux, and slightly lower hERG risk, Ligand B excels in TPSA and logP, which are critical for CNS penetration. The lower TPSA and better logP of Ligand B are more important for a CNS target like DRD2, despite the slightly lower BBB score. Ligand A's poor Caco-2 permeability is also a concern. The affinity difference is minimal.

Output:
1
2025-04-17 05:37:11,495 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (364.368 and 344.459 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (98.32) is slightly above the optimal <90 for CNS targets, but still reasonable. Ligand B (58.44) is excellent, well below 90.

**logP:** Ligand A (1.39) is within the optimal 1-3 range. Ligand B (2.149) is also good, within the optimal range.

**H-Bond Donors:** Ligand A (3) is acceptable. Ligand B (0) is also acceptable, potentially aiding permeability.

**H-Bond Acceptors:** Both ligands (A: 4, B: 4) are well within the acceptable limit of 10.

**QED:** Both ligands have good QED scores (A: 0.577, B: 0.79), indicating drug-like properties. Ligand B is slightly better.

**DILI:** Both ligands have low DILI risk (A: 35.479, B: 26.406), which is favorable. Ligand B is slightly better.

**BBB:** Both ligands show good BBB penetration (A: 67.041, B: 74.176). Ligand B is better, exceeding 70%.

**Caco-2 Permeability:** Ligand A (-5.198) is poor, indicating poor intestinal absorption. Ligand B (-4.651) is also poor, but slightly better than A.

**Aqueous Solubility:** Both ligands have very poor aqueous solubility (-1.609 and -1.71). This is a significant concern for both.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (A: 0.645, B: 0.409), which is good. Ligand B is slightly better.

**Microsomal Clearance:** Ligand A (11.801) has lower clearance than Ligand B (23.128), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (-29.935) has a much longer half-life than Ligand B (1.102). This is a significant advantage for Ligand A.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (A: 0.15, B: 0.082). Ligand B is slightly better.

**Binding Affinity:** Ligand B (-9.5 kcal/mol) has significantly stronger binding affinity than Ligand A (-7.7 kcal/mol). This is a >1.5 kcal/mol difference, which is a major advantage.

**Overall Assessment:**

While Ligand A has better metabolic stability (lower Cl_mic, longer t1/2), Ligand B excels in several key areas for a CNS-targeting GPCR ligand: better BBB penetration, slightly lower DILI and hERG risk, and *significantly* stronger binding affinity. The poor solubility and Caco-2 permeability are concerns for both, but the strong binding affinity of Ligand B outweighs these drawbacks, especially considering the importance of potency for GPCR ligands. The slightly better TPSA and P-gp efflux of Ligand B are also beneficial.

Output:
1
2025-04-17 05:37:11,495 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (366.333 Da) and Ligand B (348.531 Da) are both acceptable.

**TPSA:** Ligand A (104.21) is slightly above the preferred <90 for CNS targets, but still reasonable. Ligand B (49.41) is excellent, well below the threshold.

**logP:** Both ligands have acceptable logP values (Ligand A: 1.589, Ligand B: 3.912). Ligand B is closer to the upper limit but still within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A has 3 HBD and 5 HBA, which are both acceptable. Ligand B has 1 HBD and 2 HBA, also acceptable.

**QED:** Both ligands have good QED values (Ligand A: 0.674, Ligand B: 0.766), indicating drug-like properties.

**DILI:** Ligand A (70.027) has a moderate DILI risk, while Ligand B (11.245) has a very low risk. This is a significant advantage for Ligand B.

**BBB:** Ligand B (83.366) has a much better BBB penetration percentile than Ligand A (53.587). This is crucial for a CNS target like DRD2.

**Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and suggests a potential issue with permeability prediction. However, the magnitude is similar.

**Aqueous Solubility:** Both ligands have very poor predicted aqueous solubility (-3.058 and -3.818 respectively). This is a concern for both, but may be mitigated by formulation strategies.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (Ligand A: 0.328, Ligand B: 0.596).

**Microsomal Clearance:** Ligand B (57.061) has a higher microsomal clearance than Ligand A (27.44), suggesting faster metabolism and potentially lower *in vivo* exposure.

**In vitro Half-Life:** Ligand A (40.026) has a longer in vitro half-life than Ligand B (-12.983), which is a positive attribute.

**P-gp Efflux:** Ligand A (0.067) has lower P-gp efflux liability than Ligand B (0.318), which is favorable for CNS penetration.

**Binding Affinity:** Ligand A (-9.6 kcal/mol) has a significantly stronger binding affinity than Ligand B (-8.0 kcal/mol). This is a substantial advantage, potentially outweighing some of the ADME drawbacks.

**Overall Assessment:**

Ligand B excels in BBB penetration and DILI risk, which are critical for a CNS GPCR target. However, its metabolic stability (higher Cl_mic, shorter half-life) is a concern. Ligand A, despite having a less favorable BBB and higher DILI, boasts a significantly stronger binding affinity. The 1.6 kcal/mol difference in binding affinity is substantial and likely to have a major impact on efficacy. Given the importance of potency for GPCRs, and the fact that formulation strategies *might* address solubility issues, the stronger binding affinity of Ligand A is the deciding factor.

Output:
1
2025-04-17 05:37:11,495 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (380.413 Da) is slightly higher than Ligand B (352.494 Da), but both are acceptable.

**TPSA:** Ligand A (104.73) is above the optimal 90 for CNS targets, while Ligand B (58.2) is well below. This is a significant advantage for Ligand B.

**logP:** Ligand A (0.228) is quite low, potentially hindering membrane permeability. Ligand B (3.496) is within the optimal range (1-3). This favors Ligand B.

**H-Bond Donors/Acceptors:** Ligand A has 3 HBD and 6 HBA, which are acceptable. Ligand B has 2 HBD and 2 HBA, also acceptable, and potentially better for permeability due to fewer hydrogen bonds.

**QED:** Ligand B (0.737) has a significantly better QED score than Ligand A (0.37), indicating a more drug-like profile.

**DILI:** Ligand A (35.285) has a slightly higher DILI risk than Ligand B (17.759), but both are below the concerning threshold of 60.

**BBB:** Ligand B (89.919) has a much higher predicted BBB penetration than Ligand A (59.364). This is crucial for a CNS target like DRD2, making Ligand B highly preferable.

**Caco-2 Permeability:** Ligand A (-5.384) has poor predicted Caco-2 permeability, likely due to its low logP and higher TPSA. Ligand B (-4.592) is also not great, but slightly better.

**Aqueous Solubility:** Ligand A (-1.71) has poor aqueous solubility, while Ligand B (-4.132) is even worse. This could pose formulation challenges for both, but is less critical than BBB penetration for a CNS drug.

**hERG Inhibition:** Both ligands have low predicted hERG inhibition risk (Ligand A: 0.108, Ligand B: 0.429).

**Microsomal Clearance:** Ligand A (31.616) has lower microsomal clearance than Ligand B (46.263), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (-31.826) has a very negative half-life, which is concerning. Ligand B (10.88) is better.

**P-gp Efflux:** Ligand A (0.022) has very low P-gp efflux, which is favorable for CNS penetration. Ligand B (0.142) has slightly higher efflux, but still acceptable.

**Binding Affinity:** Ligand B (-7.6 kcal/mol) has a significantly stronger binding affinity than Ligand A (-6.2 kcal/mol). This 1.4 kcal/mol difference is substantial and can outweigh some of the ADME drawbacks of Ligand B.

**Overall:**

Ligand B is the superior candidate. While both have solubility issues, Ligand B excels in critical areas for a CNS-targeting GPCR ligand: significantly better BBB penetration, a more favorable logP, a higher QED score, and a substantially stronger binding affinity. The slightly higher metabolic clearance of Ligand B is a minor concern compared to the advantages it offers.

Output:
1
2025-04-17 05:37:11,495 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (367.764 Da) is slightly higher than Ligand B (336.395 Da), but both are acceptable.

**TPSA:** Both ligands have TPSA values below 90 (Ligand A: 89.55, Ligand B: 80.05), which is favorable for CNS penetration.

**logP:** Both ligands have logP values between 1-3 (Ligand A: 2.861, Ligand B: 3.34), which is optimal.

**H-Bond Donors/Acceptors:** Both ligands have 2 HBD and 5/4 HBA, respectively, fitting within the desirable ranges.

**QED:** Both ligands have good QED scores (Ligand A: 0.605, Ligand B: 0.723), indicating drug-like properties.

**DILI:** Ligand A has a higher DILI risk (95.386 percentile) than Ligand B (64.521 percentile). This is a significant concern for Ligand A.

**BBB:** Both ligands have reasonable BBB penetration (Ligand A: 54.595, Ligand B: 50.679), but these values are below the desirable >70% for CNS targets.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values which is unusual and suggests poor permeability.

**Aqueous Solubility:** Both ligands have negative solubility values which is unusual and suggests poor solubility.

**hERG:** Both ligands have low hERG inhibition liability (Ligand A: 0.346, Ligand B: 0.425).

**Microsomal Clearance:** Ligand B has lower microsomal clearance (34.23 mL/min/kg) than Ligand A (80.03 mL/min/kg), suggesting better metabolic stability.

**In vitro Half-Life:** Both ligands have similar in vitro half-lives (Ligand A: 43.439, Ligand B: 43.995).

**P-gp Efflux:** Both ligands have low P-gp efflux liability (Ligand A: 0.111, Ligand B: 0.042), which is good for CNS exposure.

**Binding Affinity:** Ligand B has a significantly stronger binding affinity (-9.9 kcal/mol) compared to Ligand A (-8.6 kcal/mol). This difference of 1.3 kcal/mol is substantial and can outweigh some ADME drawbacks.

**Overall Assessment:**

Ligand B is the more promising candidate. While both ligands have suboptimal BBB penetration and Caco-2/solubility values, Ligand B's significantly stronger binding affinity and lower DILI risk are major advantages. The lower microsomal clearance also contributes to its better profile. Ligand A's high DILI risk is a significant red flag, making it less likely to progress as a drug candidate.

Output:
1
2025-04-17 05:37:11,495 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (345.4 and 346.5 Da) fall comfortably within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (88.7) is slightly higher than Ligand B (78.4). Both are below the 90 Angstrom threshold desirable for CNS targets, but Ligand B is preferable.

**3. logP:** Both ligands have good logP values (2.97 and 2.38), falling within the optimal 1-3 range.

**4. H-Bond Donors:** Ligand A has 1 HBD, while Ligand B has 3. Both are within the acceptable limit of 5.

**5. H-Bond Acceptors:** Ligand A has 6 HBA, and Ligand B has 3. Both are below the 10 limit.

**6. QED:** Ligand A (0.92) has a significantly better QED score than Ligand B (0.51), indicating a more drug-like profile.

**7. DILI:** Ligand A (65.8%) has a higher DILI risk than Ligand B (24.0%). This is a significant advantage for Ligand B.

**8. BBB:** Ligand A (62.4%) has a better BBB penetration percentile than Ligand B (49.0%). This is a crucial factor for a CNS target like DRD2.

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 values, which is unusual and suggests potential issues with permeability prediction. However, Ligand B (-4.84) is slightly less negative than Ligand A (-4.53).

**10. Aqueous Solubility:** Both ligands have negative solubility values, again indicating prediction issues. Ligand B (-2.44) is slightly better.

**11. hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.20 and 0.06, respectively).

**12. Microsomal Clearance:** Ligand A (22.1) and Ligand B (25.2) have similar microsomal clearance values. Lower is better, so Ligand A is slightly preferred.

**13. In vitro Half-Life:** Ligand A (2.98) has a positive half-life, while Ligand B (-18.39) has a negative half-life, which is problematic. This is a major advantage for Ligand A.

**14. P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.11 and 0.08, respectively).

**15. Binding Affinity:** Ligand B (-7.5 kcal/mol) has a significantly stronger binding affinity than Ligand A (-9.0 kcal/mol). This is a substantial advantage that could outweigh some ADME drawbacks.

**Overall Assessment:**

While Ligand A has a better QED, half-life, and BBB, Ligand B's significantly stronger binding affinity (-7.5 vs -9.0 kcal/mol) and much lower DILI risk are critical advantages, especially for a GPCR target. The slightly lower BBB for Ligand B is a concern, but the potency difference is substantial. The negative solubility and Caco-2 values are concerning for both, but the binding affinity is the most important factor here.

Output:
1
2025-04-17 05:37:11,496 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (379.81 and 350.503 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (90.37) is slightly above the optimal <90 for CNS targets, but still reasonable. Ligand B (78.43) is well within the desired range.

**logP:** Both ligands (2.23 and 2.375) are within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Both ligands have 3 HBD and 4/3 HBA, respectively, which are acceptable values.

**QED:** Both ligands have QED values (0.731 and 0.629) above the 0.5 threshold, indicating good drug-likeness.

**DILI:** Ligand A (25.591) has a significantly lower DILI risk than Ligand B (15.006), indicating a safer profile.

**BBB:** This is a critical parameter for a CNS target like DRD2. Ligand A (77.317) has a good BBB percentile, while Ligand B (53.432) is considerably lower, suggesting poorer brain penetration.

**Caco-2 Permeability:** Ligand A (-5.162) has a negative value, which is unusual and suggests very poor permeability. Ligand B (-4.799) also has a negative value, but slightly less negative.

**Aqueous Solubility:** Both ligands have very poor aqueous solubility (-3.026 and -3.07). This could pose formulation challenges.

**hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.659 and 0.277).

**Microsomal Clearance:** Ligand A (-8.242) has a much lower (better) microsomal clearance than Ligand B (50.178), indicating greater metabolic stability.

**In vitro Half-Life:** Ligand A (18.712) has a longer half-life than Ligand B (-10.609).

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.118 and 0.202).

**Binding Affinity:** Both ligands have very similar and strong binding affinities (-8.9 and -8.5 kcal/mol). The difference is less than 1.5 kcal/mol, so it's not a deciding factor.

**Overall Assessment:**

Ligand A is superior due to its significantly better BBB penetration (77.3 vs 53.4), lower DILI risk (25.6 vs 15.0), and much improved metabolic stability (lower Cl_mic and longer half-life). While both have poor solubility and Caco-2 permeability, the CNS target prioritizes BBB penetration. The slightly higher TPSA of Ligand A is a minor concern compared to the substantial benefits in other key ADME properties.

Output:
1
2025-04-17 05:37:11,496 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (351.407 and 342.447 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (139.2) is very close to the upper limit for good oral absorption and acceptable for CNS targets, while Ligand B (67.98) is well below the 90 threshold for CNS targets, which is a significant advantage.

**logP:** Ligand A (-0.162) is a bit low, potentially hindering permeability. Ligand B (1.338) is within the optimal 1-3 range. This favors Ligand B.

**H-Bond Donors/Acceptors:** Ligand A has 4 HBD and 5 HBA, acceptable values. Ligand B has 1 HBD and 6 HBA, also acceptable.

**QED:** Both ligands have good QED scores (0.458 and 0.805), indicating drug-like properties. Ligand B is significantly better.

**DILI:** Ligand A (42.536) has a slightly higher DILI risk than Ligand B (29.081), but both are below the concerning threshold of 60.

**BBB:** Ligand A (52.772) has a moderate BBB penetration, while Ligand B (37.263) is lower. While both are not ideal (>70), this is less critical if other properties strongly favor a compound.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.929 and -4.777), which is unusual and suggests poor permeability. This is a significant drawback for both.

**Aqueous Solubility:** Both ligands have negative solubility values (-2.632 and -2.091), indicating poor solubility. This is also a significant drawback for both.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.213 and 0.181).

**Microsomal Clearance:** Ligand A (-1.341) has a negative clearance, which is unusual and suggests very high metabolic stability. Ligand B (19.685) has a moderate clearance.

**In vitro Half-Life:** Ligand A (-5.038) has a negative half-life, which is also unusual and suggests extremely long half-life. Ligand B (12.736) has a reasonable half-life.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.009 and 0.031), which is favorable for CNS penetration.

**Binding Affinity:** Ligand A (-7.8 kcal/mol) has a slightly better binding affinity than Ligand B (-6.8 kcal/mol). This 1.0 kcal/mol difference is substantial.

**Overall Assessment:**

While Ligand A boasts a slightly better binding affinity and potentially excellent metabolic stability and half-life (negative values are suspect and require further investigation), its poor logP and Caco-2 permeability are major concerns. Ligand B, despite slightly weaker binding, has a much better logP, TPSA, QED, and lower DILI risk. The negative permeability and solubility values for both are concerning and would need to be addressed through formulation or structural modifications. However, considering the GPCR-specific priorities, Ligand B's superior physicochemical properties, particularly the more favorable logP and TPSA, make it a more promising starting point for optimization, even with the slightly lower affinity. The unusual negative values for clearance and half-life for Ligand A raise concerns about the reliability of the predictions.

Output:
1
2025-04-17 05:37:11,496 - INFO - Batch 213 complete. Total preferences: 3408
2025-04-17 05:37:11,496 - INFO - Processing batch 214/512...
2025-04-17 05:37:52,514 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (350.503 and 344.419 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (49.85) is excellent, well below the 90 A^2 threshold for CNS targets. Ligand B (90.89) is at the upper limit, but still acceptable.

**logP:** Both ligands (2.712 and 2.018) are within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A (0 HBD, 3 HBA) is favorable. Ligand B (1 HBD, 8 HBA) is also acceptable, though slightly higher in HBA count.

**QED:** Both ligands have good QED scores (0.692 and 0.802), indicating good drug-like properties.

**DILI:** Ligand A (16.479) has a significantly lower DILI risk than Ligand B (55.719). This is a major advantage for Ligand A.

**BBB:** Ligand A (78.48) has a better BBB penetration percentile than Ligand B (69.988), which is crucial for a CNS target like DRD2. While both are reasonably good, A is preferred.

**Caco-2 Permeability:** Ligand A (-4.287) has poor Caco-2 permeability, while Ligand B (-5.549) is also poor. This is a concern for both, but less critical for CNS targets where direct absorption isn't as vital.

**Aqueous Solubility:** Both ligands have poor aqueous solubility (-1.925 and -2.189). This could pose formulation challenges, but is not a deal-breaker.

**hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.393 and 0.073).

**Microsomal Clearance:** Ligand A (47.212) has higher microsomal clearance than Ligand B (25.508), indicating lower metabolic stability. This is a disadvantage for Ligand A.

**In vitro Half-Life:** Ligand B (-1.431) has a slightly better in vitro half-life than Ligand A (-11.62).

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.058 and 0.072).

**Binding Affinity:** Both ligands have very similar and strong binding affinities (-7.8 and -7.6 kcal/mol). The difference is negligible.

**Overall Assessment:**

Ligand A excels in TPSA, DILI risk, and BBB penetration, which are particularly important for a CNS GPCR target. While its Caco-2 permeability and microsomal clearance are less favorable, the strong affinity and superior CNS-related properties outweigh these drawbacks. Ligand B has slightly better metabolic stability and half-life, but the higher DILI risk and lower BBB penetration are significant concerns.

Output:
1
2025-04-17 05:37:52,515 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (345.487 and 351.451 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (81.99) is significantly better than Ligand B (90.7), being closer to the desirable <90 for CNS targets. Ligand B is pushing the upper limit.

**logP:** Ligand A (2.764) is optimal (1-3). Ligand B (0.347) is quite low, potentially hindering membrane permeability and CNS penetration.

**H-Bond Donors:** Both have 2 HBD, which is within the acceptable limit of <=5.

**H-Bond Acceptors:** Ligand A has 3 HBA, while Ligand B has 5. Both are within the acceptable limit of <=10.

**QED:** Both ligands have similar QED values (0.804 and 0.774), indicating good drug-likeness.

**DILI:** Ligand A (29.081) has a much lower DILI risk than Ligand B (18.108), indicating better predicted liver safety.

**BBB:** Ligand A (56.921) has a significantly better BBB percentile than Ligand B (46.762). While neither is >70, A is closer and more favorable for a CNS target.

**Caco-2 Permeability:** Both have negative Caco-2 values (-4.821 and -4.842), which is unusual and suggests poor permeability. However, these values are on the same scale, so don't differentiate the ligands.

**Aqueous Solubility:** Both have negative solubility values (-3.499 and -0.434). Again, these are on the same scale, so don't differentiate the ligands.

**hERG:** Both ligands have low hERG inhibition liability (0.435 and 0.26), which is good.

**Microsomal Clearance:** Ligand A (21.529) has higher microsomal clearance than Ligand B (5.76), meaning it is less metabolically stable.

**In vitro Half-Life:** Ligand B (-2.158) has a slightly better (longer) in vitro half-life than Ligand A (16.182).

**P-gp Efflux:** Ligand A (0.141) has lower P-gp efflux liability than Ligand B (0.007), which is highly desirable for CNS penetration.

**Binding Affinity:** Ligand B (-7.1) has a slightly better binding affinity than Ligand A (-9.2). However, the difference is not substantial enough to outweigh the other significant differences.

**Overall Assessment:**

Ligand A is significantly better overall. While Ligand B has a slightly better binding affinity and half-life, Ligand A excels in critical areas for a CNS-targeting GPCR ligand: TPSA, logP, BBB penetration, DILI risk, and P-gp efflux. The lower logP of Ligand B is a major concern, as it will likely limit its ability to cross the blood-brain barrier. The better TPSA and BBB of Ligand A are crucial for CNS activity. The lower DILI risk is also a significant advantage.

Output:
0
2025-04-17 05:37:52,515 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (428.689 Da) is higher, but still acceptable. Ligand B (346.471 Da) is slightly lower, potentially aiding permeability.

**TPSA:** Both ligands have TPSA values (61.44 and 62.55) slightly above the optimal 90 for CNS targets, but still reasonable. This isn't a major differentiating factor.

**logP:** Ligand A (4.265) is slightly above the optimal range (1-3), potentially leading to solubility issues or off-target interactions. Ligand B (3.748) is within the optimal range.

**H-Bond Donors/Acceptors:** Ligand A (HBD=2, HBA=2) and Ligand B (HBD=1, HBA=3) both have acceptable numbers of H-bond donors and acceptors.

**QED:** Both ligands have good QED scores (0.764 and 0.883), indicating good drug-like properties.

**DILI:** Ligand A has a significantly higher DILI risk (79.333%) compared to Ligand B (40.364%). This is a major concern for Ligand A.

**BBB:** Ligand A (73.517%) has a better BBB penetration score than Ligand B (64.637%), which is crucial for a CNS target like DRD2.

**Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and suggests poor permeability. However, the scale is not specified, so it's difficult to interpret.

**Aqueous Solubility:** Both ligands have very poor aqueous solubility (-5.806 and -3.961). This is a significant drawback for both, but potentially more problematic for Ligand A due to its higher logP.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.763 and 0.391).

**Microsomal Clearance:** Ligand A (46.377) has a higher microsomal clearance than Ligand B (32.598), suggesting lower metabolic stability.

**In vitro Half-Life:** Ligand A (88.421) has a longer in vitro half-life than Ligand B (29.24), which is favorable.

**P-gp Efflux:** Ligand A (0.221) has lower P-gp efflux liability than Ligand B (0.359), which is beneficial for CNS penetration.

**Binding Affinity:** Ligand B (-7.8 kcal/mol) has a significantly stronger binding affinity than Ligand A (-9.1 kcal/mol). This is a substantial advantage, potentially outweighing some of the ADME drawbacks.

**Overall Assessment:**

Ligand B is the stronger candidate. While both have poor solubility and Caco-2 permeability, Ligand B has a significantly better binding affinity, lower DILI risk, and a more favorable logP. The better affinity is a key advantage for a GPCR target. Ligand A's higher DILI risk and higher clearance are significant liabilities. Although Ligand A has better BBB and P-gp efflux, the superior affinity of Ligand B is more important.



Output:
1
2025-04-17 05:37:52,515 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (349.475 and 354.539 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (62.83) is slightly higher than the ideal <90 for CNS targets, but still reasonable. Ligand B (55.89) is better, falling comfortably below 90.

**logP:** Both ligands have good logP values (2.002 and 1.554), within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A has 2 HBD and 4 HBA, while Ligand B has 1 HBD and 4 HBA. Both are within acceptable limits (<=5 HBD and <=10 HBA).

**QED:** Both ligands have reasonable QED scores (0.716 and 0.647), indicating good drug-like properties.

**DILI:** Ligand A has a DILI risk of 13.339, which is excellent (low risk). Ligand B has a DILI risk of 3.18, also very good.

**BBB:** This is crucial for a CNS target like DRD2. Ligand A has a BBB penetration of 64.637%, while Ligand B has 57.115%. Ligand A is better here, but both are below the desirable >70% threshold.

**Caco-2 Permeability:** Ligand A (-4.873) and Ligand B (-5.246) both have negative values, indicating poor permeability. This is a concern.

**Aqueous Solubility:** Ligand A (-1.639) and Ligand B (0.17) both have poor solubility.

**hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.472 and 0.436).

**Microsomal Clearance:** Ligand A (18.424) has a moderate clearance, while Ligand B (-20.611) has a negative clearance, which is unusual and suggests very high metabolic stability. This is a significant advantage for Ligand B.

**In vitro Half-Life:** Ligand A (36.051 hours) has a reasonable half-life. Ligand B (-2.036 hours) has a negative half-life, which is nonsensical and indicates a potential data error or a very rapidly metabolized compound.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.011 and 0.003), which is favorable for CNS penetration.

**Binding Affinity:** Ligand A (-7.9 kcal/mol) has a slightly better binding affinity than Ligand B (-7.4 kcal/mol), though both are excellent. The 0.5 kcal/mol difference is potentially significant.

**Overall Assessment:**

Ligand A has a better BBB score and binding affinity. However, Ligand B has significantly better metabolic stability (negative clearance) and a very low P-gp efflux. The negative half-life for Ligand B is a major red flag and likely an error. Considering the importance of metabolic stability for CNS drugs, and the fact that both ligands have acceptable (though not ideal) BBB penetration, Ligand A is the more viable candidate, despite the slightly lower metabolic stability.

Output:
0
2025-04-17 05:37:52,515 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 drug candidates, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (365.865 and 364.486 Da) are within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (85.09) is better than Ligand B (40.62). For CNS targets, TPSA <= 90 is preferred, both are within this range, but A is closer to the upper limit.

**3. logP:** Ligand B (3.338) is slightly higher than Ligand A (1.446). Both are within the optimal 1-3 range, but B is approaching the upper limit.

**4. H-Bond Donors:** Ligand A (2) is better than Ligand B (0). While both are acceptable, a small number of HBDs can improve permeability.

**5. H-Bond Acceptors:** Ligand A (7) is higher than Ligand B (3). Both are acceptable.

**6. QED:** Both ligands have good QED scores (0.736 and 0.825), indicating good drug-like properties.

**7. DILI:** Both ligands have similar DILI risk (47.421 and 49.128), and are both below the concerning threshold of 60.

**8. BBB:** Ligand B (96.006) significantly outperforms Ligand A (55.991). This is *critical* for a CNS target like DRD2.

**9. Caco-2 Permeability:** Ligand A (-5.589) is better than Ligand B (-4.727), indicating better intestinal absorption.

**10. Aqueous Solubility:** Ligand A (-1.812) is better than Ligand B (-4.079).

**11. hERG Inhibition:** Both ligands have low hERG inhibition risk (0.28 and 0.622).

**12. Microsomal Clearance:** Ligand B (51.396) has higher clearance than Ligand A (6.167), suggesting lower metabolic stability.

**13. In vitro Half-Life:** Ligand A (36.625) has a longer half-life than Ligand B (22.78).

**14. P-gp Efflux:** Ligand A (0.211) has lower P-gp efflux than Ligand B (0.597), which is favorable for CNS penetration.

**15. Binding Affinity:** Ligand B (-9.4) has a significantly stronger binding affinity than Ligand A (-8.8). This is a 0.6 kcal/mol difference, which is substantial and can outweigh some ADME drawbacks.

**Overall Assessment:**

While Ligand A has better ADME properties (TPSA, solubility, Caco-2, P-gp efflux, metabolic stability, half-life), Ligand B's *much* stronger binding affinity (-9.4 vs -8.8 kcal/mol) and excellent BBB penetration (96%) are decisive. For a CNS GPCR target, strong affinity and BBB penetration are paramount. The slightly less favorable ADME profile of Ligand B can potentially be addressed through further optimization, but it's difficult to significantly improve binding affinity.

Output:
1
2025-04-17 05:37:52,515 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (351.451 and 345.487 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (97.28) is slightly above the optimal <90 for CNS targets, but still reasonable. Ligand B (73.99) is excellent, well below 90.

**3. logP:** Ligand A (1.246) is within the optimal 1-3 range. Ligand B (3.687) is at the higher end of optimal, but still acceptable.

**4. H-Bond Donors:** Both ligands have 3 HBD, which is within the acceptable limit of <=5.

**5. H-Bond Acceptors:** Ligand A has 5 HBA, and Ligand B has 2 HBA, both are within the acceptable limit of <=10.

**6. QED:** Both ligands have QED values above 0.5 (0.672 and 0.597), indicating good drug-like properties.

**7. DILI:** Both ligands have similar DILI risk (40.83 and 41.76), both are good (low risk).

**8. BBB:** Ligand A has a significantly better BBB penetration percentile (71.268) compared to Ligand B (63.862). This is a crucial factor for a CNS target like DRD2.

**9. Caco-2 Permeability:** Ligand A (-4.826) has a worse Caco-2 permeability than Ligand B (-5.069). Lower values indicate lower permeability.

**10. Aqueous Solubility:** Ligand A (-1.782) has better aqueous solubility than Ligand B (-4.226).

**11. hERG Inhibition:** Ligand A (0.044) has a much lower hERG inhibition liability than Ligand B (0.722), which is a significant advantage.

**12. Microsomal Clearance:** Ligand A (27.812) has a lower microsomal clearance than Ligand B (62.427), suggesting better metabolic stability.

**13. In vitro Half-Life:** Ligand A (37.695) has a longer in vitro half-life than Ligand B (9.41).

**14. P-gp Efflux:** Ligand A (0.018) has a much lower P-gp efflux liability than Ligand B (0.507), which is beneficial for CNS exposure.

**15. Binding Affinity:** Ligand B (-8.7) has a significantly stronger binding affinity than Ligand A (0.0). This is a substantial advantage. The difference of 8.7 kcal/mol is very large and likely outweighs some of the ADME drawbacks of Ligand B.

**Overall Assessment:**

While Ligand A has better BBB, solubility, hERG, clearance, and P-gp properties, Ligand B's *much* stronger binding affinity (-8.7 kcal/mol vs 0.0 kcal/mol) is a decisive factor. For a GPCR target, strong binding is paramount. The slightly worse ADME properties of Ligand B can potentially be addressed through further optimization, but a weak binder is unlikely to become a viable drug.

Output:
1
2025-04-17 05:37:52,516 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (349.431 and 369.446 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (78.95) is better than Ligand B (64.43). Both are below the 90 A^2 threshold desirable for CNS targets.

**3. logP:** Ligand B (2.835) is optimal (1-3), while Ligand A (0.143) is significantly low, potentially hindering membrane permeability.

**4. H-Bond Donors:** Ligand A (1) is better than Ligand B (0). Both are within the acceptable limit of <=5.

**5. H-Bond Acceptors:** Ligand A (4) is better than Ligand B (5). Both are within the acceptable limit of <=10.

**6. QED:** Both ligands have similar QED values (0.683 and 0.628), indicating good drug-like properties.

**7. DILI:** Ligand B (14.23) has a much lower DILI risk than Ligand A (23.032), making it safer from a liver toxicity perspective.

**8. BBB:** Ligand B (83.094) has a significantly higher BBB penetration percentile than Ligand A (54.944). This is *critical* for a CNS target like DRD2.

**9. Caco-2 Permeability:** Ligand A (-4.727) has better Caco-2 permeability than Ligand B (-4.451). However, this is less important than BBB for CNS targets.

**10. Aqueous Solubility:** Both ligands have similar and poor aqueous solubility (-1.939 and -1.827).

**11. hERG Inhibition:** Ligand A (0.148) has a slightly lower hERG inhibition liability than Ligand B (0.445), which is preferable.

**12. Microsomal Clearance:** Ligand B (64.97) has a significantly higher microsomal clearance than Ligand A (6.138), indicating lower metabolic stability.

**13. In vitro Half-Life:** Ligand B (13.649) has a longer in vitro half-life than Ligand A (9.696).

**14. P-gp Efflux:** Ligand A (0.011) has much lower P-gp efflux liability than Ligand B (0.218), which is favorable for CNS penetration.

**15. Binding Affinity:** Ligand A (-8.8 kcal/mol) has a significantly stronger binding affinity than Ligand B (-6.4 kcal/mol). This is a substantial advantage.

**Overall Assessment:**

While Ligand A has superior binding affinity and lower P-gp efflux, Ligand B excels in critical areas for a CNS-targeting GPCR: BBB penetration and DILI risk. The low logP of Ligand A is a major concern, potentially severely limiting its ability to cross cell membranes and reach the brain, even with low P-gp efflux. The much higher BBB value for Ligand B outweighs the affinity difference, especially given the affinity of Ligand B is still quite good. The better DILI profile of Ligand B is also a significant advantage. The metabolic stability of Ligand B is a concern, but can be addressed with structural modifications.

Output:
1
2025-04-17 05:37:52,516 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (350.434 and 348.487 Da) fall comfortably within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (69.64) is slightly higher than Ligand B (58.64). Both are below the 90 A^2 threshold desirable for CNS targets, but Ligand B is preferable.

**3. logP:** Both ligands have good logP values (2.076 and 2.679), falling within the optimal 1-3 range. Ligand B is slightly higher, which could be beneficial for membrane permeability.

**4. H-Bond Donors:** Ligand A has 2 HBD, and Ligand B has 1. Both are within the acceptable limit of <=5. Ligand B is slightly better.

**5. H-Bond Acceptors:** Both ligands have 3 HBA, well within the limit of <=10.

**6. QED:** Ligand A (0.721) has a slightly higher QED than Ligand B (0.542), suggesting a more drug-like profile overall.

**7. DILI:** Both ligands have low DILI risk (26.134 and 21.52), well below the concerning threshold of 60. Ligand B is slightly better.

**8. BBB:** Both ligands exhibit excellent BBB penetration (89.608 and 81.233), exceeding the desirable >70 threshold for CNS targets. Ligand A is slightly better.

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.595 and -4.393). This is unusual and suggests a potential issue with intestinal absorption. However, the values are very close.

**10. Aqueous Solubility:** Both ligands have negative solubility values (-2.315 and -2.391). This is also unusual and suggests poor aqueous solubility. Again, the values are very close.

**11. hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.563 and 0.242). Ligand B is significantly better.

**12. Microsomal Clearance:** Ligand A (18.505) has a lower (better) microsomal clearance than Ligand B (62.47), indicating greater metabolic stability.

**13. In vitro Half-Life:** Both ligands have negative in vitro half-life values (-1.096 and -8.074). This is highly unusual and suggests a problem with the data or the compounds themselves. Ligand B is significantly worse.

**14. P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.056 and 0.051). This is good for CNS exposure.

**15. Binding Affinity:** Ligand B (-7.5 kcal/mol) has a slightly better binding affinity than Ligand A (-8.0 kcal/mol). While the difference is small, it's within the range where it could outweigh minor ADME drawbacks.

**Overall Assessment:**

Ligand B has a slight edge due to its better logP, lower hERG inhibition, and slightly better binding affinity. However, Ligand A has a better QED, BBB, and microsomal clearance. The negative values for Caco-2 and solubility are concerning for both, but are similar. The negative half-life values are problematic for both and require further investigation. Considering the GPCR-specific priorities, the slightly stronger binding affinity of Ligand B, combined with its favorable logP and hERG profile, makes it a marginally better candidate.

Output:
1
2025-04-17 05:37:52,516 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (367.768 and 342.443 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (88.49) is better than Ligand B (69.3). Both are below the 90 A^2 threshold desirable for CNS targets.

**logP:** Both ligands have good logP values (2.772 and 2.122), falling within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A has 2 HBD and 5 HBA, while Ligand B has 1 HBD and 3 HBA. Both are within acceptable limits.

**QED:** Both ligands have high QED scores (0.85 and 0.915), indicating good drug-like properties.

**DILI:** Ligand A has a high DILI risk (96.704 percentile), which is a significant concern. Ligand B has a much lower DILI risk (34.548 percentile), a major advantage.

**BBB:** Ligand A (58.666) and Ligand B (55.332) are both below the 70% threshold for desirable BBB penetration, but not drastically.

**Caco-2 Permeability:** Ligand A (-4.659) and Ligand B (-5.113) both have negative values, indicating poor permeability.

**Aqueous Solubility:** Ligand A (-4.581) and Ligand B (-3.092) both have negative values, indicating poor solubility.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.158 and 0.388).

**Microsomal Clearance:** Ligand B (29.397) has a lower microsomal clearance than Ligand A (16.56), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand B (-9.619) has a negative half-life, which is concerning. Ligand A (38.852) is positive, indicating a longer half-life.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.084 and 0.072).

**Binding Affinity:** Ligand A (-9.5 kcal/mol) has a significantly stronger binding affinity than Ligand B (-7.4 kcal/mol). This is a substantial advantage, potentially outweighing some ADME concerns.

**Overall Assessment:**

While Ligand A boasts a superior binding affinity, its extremely high DILI risk is a major red flag. The DILI risk alone makes it a less viable candidate. Ligand B, while having a weaker binding affinity, has a much more favorable safety profile (low DILI) and better metabolic stability. The slight difference in BBB penetration is less critical than the significant difference in DILI.

Output:
1
2025-04-17 05:37:52,516 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (350.419 and 352.301 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (107.55) is better than Ligand B (127.24). For CNS targets, we want TPSA <= 90, so both are above this ideal, but A is closer.

**3. logP:** Ligand B (0.629) is better than Ligand A (0.121). While both are on the low side, ligand B is closer to the optimal 1-3 range. A's low logP could hinder membrane permeability.

**4. H-Bond Donors:** Ligand A (3) is slightly higher than Ligand B (2), but both are acceptable (<=5).

**5. H-Bond Acceptors:** Ligand B (7) is higher than Ligand A (5), but both are within the acceptable range (<=10).

**6. QED:** Ligand B (0.826) is significantly better than Ligand A (0.675), indicating a more drug-like profile.

**7. DILI:** Ligand A (52.113) has a much lower DILI risk than Ligand B (84.18). This is a significant advantage for Ligand A.

**8. BBB:** Ligand B (70.997) is significantly better than Ligand A (36.371). For a CNS target like DRD2, >70% BBB penetration is highly desirable. This is a major advantage for Ligand B.

**9. Caco-2:** Both ligands have negative Caco-2 values (-5.737 and -5.349), which is unusual and suggests poor permeability. This is a concern for both.

**10. Solubility:** Both ligands have negative solubility values (-1.614 and -3.163), which is also unusual and suggests poor solubility. This is a concern for both.

**11. hERG:** Both ligands have very low hERG inhibition risk (0.177 and 0.19).

**12. Cl_mic:** Ligand B (-10.235) has a much lower (better) microsomal clearance than Ligand A (2.877), suggesting greater metabolic stability.

**13. t1/2:** Ligand B (-19.177) has a much longer in vitro half-life than Ligand A (25.748), which is a significant advantage.

**14. Pgp:** Both ligands have very low P-gp efflux liability (0.015 and 0.006).

**15. Binding Affinity:** Both ligands have similar and strong binding affinities (-8.4 and -8.6 kcal/mol). The difference is negligible.

**Overall Assessment:**

Ligand B excels in BBB penetration, metabolic stability (Cl_mic), and in vitro half-life, which are crucial for a CNS-targeting GPCR. It also has a better QED score and logP. Ligand A has a lower DILI risk, but the significantly lower BBB penetration is a major drawback. Given the importance of CNS penetration for DRD2, Ligand B is the more promising candidate despite the higher DILI risk. The negative Caco-2 and solubility values are concerning for both, and would require further investigation/optimization.

Output:
1
2025-04-17 05:37:52,516 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (368.861 and 348.451 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (68.73) is excellent, well below the 90 A^2 threshold for CNS targets. Ligand B (74.57) is still reasonable but less optimal.

**logP:** Ligand A (3.331) is within the optimal 1-3 range. Ligand B (0.479) is quite low, potentially hindering membrane permeability and CNS penetration.

**H-Bond Donors/Acceptors:** Both ligands have a reasonable number of HBD (0) and HBA (5 and 6 respectively), staying within the suggested limits.

**QED:** Both ligands have acceptable QED scores (0.762 and 0.699), indicating good drug-likeness.

**DILI:** Ligand A (46.297) has a slightly higher DILI risk than Ligand B (21.442), but both are below the concerning threshold of 60.

**BBB:** Both ligands have excellent BBB penetration (73.672 and 76.425), exceeding the desirable >70% for CNS targets.

**Caco-2 Permeability:** Ligand A (-4.438) and Ligand B (-4.799) both have negative Caco-2 values, which is unusual and suggests poor permeability. However, the scale is not defined, so it's hard to interpret.

**Aqueous Solubility:** Both ligands have very poor aqueous solubility (-3.553 and -0.393). This is a significant drawback.

**hERG Inhibition:** Both ligands show low hERG inhibition liability (0.418 and 0.107), which is positive.

**Microsomal Clearance:** Ligand A (66.133) has a higher microsomal clearance than Ligand B (8.84), indicating lower metabolic stability.

**In vitro Half-Life:** Ligand B (0.407) has a very short in vitro half-life, while Ligand A (6.431) is better, but still relatively short.

**P-gp Efflux:** Both ligands show low P-gp efflux (0.149 and 0.014), which is favorable for CNS penetration.

**Binding Affinity:** Ligand A (-7.9 kcal/mol) has a slightly better binding affinity than Ligand B (-7.6 kcal/mol), although the difference is not huge.

**Overall Assessment:**

Considering the GPCR-specific priorities, Ligand A is more promising. While both have poor solubility, Ligand A has a better logP, which is crucial for CNS penetration. Its slightly better affinity and lower clearance are also advantages. Ligand B's very low logP is a major concern, potentially limiting its ability to cross the blood-brain barrier despite the high BBB percentile. The poor Caco-2 values for both are concerning, but the other factors favor Ligand A.

Output:
1
2025-04-17 05:37:52,517 - INFO - Reasoning:

Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (348.399 and 348.443 Da) fall comfortably within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (85.89) is slightly higher than Ligand B (67.87). Both are below the 90 A^2 threshold desirable for CNS targets, but B is better.

**3. logP:** Both ligands have good logP values (1.331 and 2.288), falling within the optimal 1-3 range. Ligand B is slightly better.

**4. H-Bond Donors:** Ligand A (2) and Ligand B (1) are both within the acceptable limit of <=5. Ligand B is slightly better.

**5. H-Bond Acceptors:** Ligand A (5) and Ligand B (4) are both within the acceptable limit of <=10. Ligand B is slightly better.

**6. QED:** Ligand A (0.758) has a significantly better QED score than Ligand B (0.549), indicating a more drug-like profile.

**7. DILI:** Ligand A (65.917) has a higher DILI risk than Ligand B (35.595). This is a significant drawback for Ligand A.

**8. BBB:** Ligand B (74.254) has a better BBB penetration percentile than Ligand A (67.468). Both are above the 70% threshold, but B is preferable for a CNS target.

**9. Caco-2 Permeability:** Ligand A (-4.619) has worse Caco-2 permeability than Ligand B (-5.176). Lower values are less desirable.

**10. Aqueous Solubility:** Ligand A (-2.329) has slightly better aqueous solubility than Ligand B (-2.205).

**11. hERG Inhibition:** Ligand A (0.101) has a lower hERG inhibition liability than Ligand B (0.669), which is a positive.

**12. Microsomal Clearance:** Ligand A (-2.476) has a lower (better) microsomal clearance than Ligand B (32.428), suggesting greater metabolic stability.

**13. In vitro Half-Life:** Ligand A (19.802) has a longer in vitro half-life than Ligand B (-15.413). This is a significant advantage for Ligand A.

**14. P-gp Efflux:** Ligand A (0.037) has much lower P-gp efflux liability than Ligand B (0.189), which is crucial for CNS penetration.

**15. Binding Affinity:** Both ligands have very similar binding affinities (-8.6 and -8.1 kcal/mol). The difference is less than the 1.5 kcal/mol threshold.

**Overall Assessment:**

While Ligand A has a better QED, longer half-life, and lower P-gp efflux, the significantly higher DILI risk and slightly lower BBB penetration are major concerns. Ligand B, despite a lower QED, exhibits a much more favorable safety profile (lower DILI) and better BBB penetration, which are critical for a CNS-targeting drug. The slight advantage in logP and TPSA for Ligand B also contribute to its favorability. The similar binding affinities make the ADME/Tox properties the deciding factors.

Output:
1
2025-04-17 05:37:52,517 - INFO - Reasoning:

Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight (MW):** Both ligands (378.796 and 344.499 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (61.19) is slightly above the optimal <90 for CNS targets, but still reasonable. Ligand B (40.62) is excellent, well below 90.

**3. logP:** Ligand A (4.28) is a bit high, potentially leading to solubility issues or off-target interactions. Ligand B (3.108) is within the optimal 1-3 range.

**4. H-Bond Donors (HBD):** Both ligands have 0 HBD, which is acceptable.

**5. H-Bond Acceptors (HBA):** Ligand A has 5 HBA, and Ligand B has 2 HBA, both are within the acceptable range of <=10.

**6. QED:** Both ligands have good QED scores (0.575 and 0.719, respectively), indicating drug-like properties.

**7. DILI:** Ligand A (61.807) has a higher DILI risk than Ligand B (21.598). This is a significant negative for Ligand A.

**8. BBB:** Ligand B (87.282) has a significantly better BBB penetration percentile than Ligand A (67.197). This is crucial for a CNS target like DRD2.

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 values, which is unusual and suggests poor permeability. However, the scale is not specified, so the absolute impact is uncertain.

**10. Aqueous Solubility:** Both ligands have negative solubility values, which is also unusual. This suggests poor solubility.

**11. hERG Inhibition:** Both ligands have low hERG inhibition liability (0.479 and 0.487).

**12. Microsomal Clearance (Cl_mic):** Ligand B (50.158) has lower microsomal clearance, indicating better metabolic stability, compared to Ligand A (74.709).

**13. In vitro Half-Life:** Ligand B (-12.792) has a negative half-life, which is problematic and likely indicates rapid degradation. Ligand A (1.987) has a short, but positive, half-life.

**14. P-gp Efflux:** Both ligands have low P-gp efflux liability (0.665 and 0.228).

**15. Binding Affinity:** Ligand B (-8.3 kcal/mol) has a slightly better binding affinity than Ligand A (-7.9 kcal/mol). While the difference is not huge, it's a positive for Ligand B.

**Overall Assessment:**

Considering the GPCR-specific priorities, Ligand B is the more promising candidate. Its superior BBB penetration, lower DILI risk, better metabolic stability (lower Cl_mic), and slightly better binding affinity outweigh the negative half-life. Ligand A's higher logP and DILI risk are concerning. The negative Caco-2 and solubility values for both are problematic and would require further investigation, but the other factors favor Ligand B.

Output:
1
2025-04-17 05:37:52,517 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 drug candidates, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (352.523 Da and 369.849 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (55.89) is significantly better than Ligand B (80.76). For CNS targets, we want TPSA <= 90, and A is comfortably within this range, while B is approaching the upper limit.

**3. logP:** Both ligands have acceptable logP values (1.166 and 1.507, respectively), falling within the optimal 1-3 range.

**4. H-Bond Donors:** Both have 1 HBD, which is good.

**5. H-Bond Acceptors:** Ligand A has 4 HBA, and Ligand B has 5. Both are acceptable (<=10).

**6. QED:** Both ligands have good QED scores (0.712 and 0.822), indicating drug-like properties.

**7. DILI:** Ligand A (6.747) has a much lower DILI risk than Ligand B (56.185). This is a significant advantage for A.

**8. BBB:** Ligand A (54.556) has a lower BBB penetration percentile than Ligand B (69.523). While both are not ideal (>70 is desirable), B is better in this regard.

**9. Caco-2 Permeability:** Both have negative Caco-2 values (-4.885 and -4.79), which is unusual and suggests poor permeability. This is a concern for both, but the values are similar.

**10. Aqueous Solubility:** Both have negative solubility values (-0.897 and -2.145), indicating poor aqueous solubility. B is worse than A.

**11. hERG Inhibition:** Ligand A (0.619) has a lower hERG inhibition risk than Ligand B (0.211), which is preferable.

**12. Microsomal Clearance:** Ligand A (12.918) has a lower microsomal clearance than Ligand B (6.695), suggesting better metabolic stability.

**13. In vitro Half-Life:** Ligand A (-7.078) has a much longer in vitro half-life than Ligand B (26.487). This is a significant advantage for A.

**14. P-gp Efflux:** Ligand A (0.009) has significantly lower P-gp efflux than Ligand B (0.082), which is crucial for CNS penetration.

**15. Binding Affinity:** Ligand A (-7.4) has a slightly better binding affinity than Ligand B (0).

**Overall Assessment:**

Considering the GPCR-specific priorities, Ligand A is the stronger candidate. While Ligand B has better BBB penetration, Ligand A excels in critical areas like DILI risk, metabolic stability (Cl_mic and t1/2), P-gp efflux, and hERG inhibition. The slightly better binding affinity of A is also a plus. The poor Caco-2 and solubility are concerns for both, but can be addressed with formulation strategies. The lower TPSA of A is also beneficial for CNS penetration.

Output:
0
2025-04-17 05:37:52,517 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (347.415 Da) is slightly lower, which could be beneficial for permeability, while Ligand B (384.889 Da) is still well within the range.

**TPSA:** Both ligands have TPSA values below the 90 A^2 threshold desirable for CNS targets. Ligand B (84.42 A^2) is better than Ligand A (96.53 A^2).

**logP:** Both ligands have logP values within the optimal range (1-3). Ligand A (0.736) is on the lower side, potentially hindering permeation, while Ligand B (1.229) is better positioned.

**H-Bond Donors/Acceptors:** Ligand A has 3 HBD and 4 HBA, which are acceptable. Ligand B has 1 HBD and 6 HBA, also acceptable.

**QED:** Both ligands have good QED scores (>0.5), indicating drug-like properties. Ligand B (0.843) is better than Ligand A (0.604).

**DILI:** Ligand A (52.113) has a lower DILI risk than Ligand B (84.219), which is a significant advantage.

**BBB:** Ligand A (68.205) has a significantly better BBB penetration percentile than Ligand B (40.675). This is *critical* for a CNS target like DRD2.

**Caco-2 Permeability:** Ligand A (-4.739) shows poor Caco-2 permeability, while Ligand B (-5.116) is also poor, but slightly better.

**Aqueous Solubility:** Both ligands have very poor aqueous solubility (-2.606 and -3.229 respectively). This is a concern for both.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.083 and 0.203 respectively).

**Microsomal Clearance:** Ligand A (17.73 mL/min/kg) has a lower microsomal clearance than Ligand B (32.543 mL/min/kg), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (5.912 hours) has a longer in vitro half-life than Ligand B (2.278 hours).

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.025 and 0.079 respectively), which is good for CNS penetration.

**Binding Affinity:** Ligand B (-0.0 kcal/mol) has a significantly weaker binding affinity than Ligand A (-8.0 kcal/mol). This is a *major* difference. A difference of >1.5 kcal/mol often outweighs minor ADME drawbacks.

**Overall Assessment:**

While Ligand B has better physicochemical properties (TPSA, logP, QED) and lower DILI risk, the dramatically superior binding affinity of Ligand A (-8.0 kcal/mol vs -0.0 kcal/mol) is the deciding factor. The strong binding of Ligand A, coupled with acceptable BBB penetration (68.205), and better metabolic stability (lower Cl_mic and longer t1/2) makes it the more promising candidate, despite its lower Caco-2 permeability and solubility. The solubility and permeability issues might be addressable through formulation strategies. The lack of binding affinity for Ligand B is a much more difficult hurdle to overcome.



Output:
1
2025-04-17 05:37:52,518 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (341.411 and 349.362 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (73.1) is excellent, well below the 90 A^2 threshold for CNS targets. Ligand B (105.82) is still reasonable, but less optimal, being above 90.

**logP:** Ligand A (2.397) is within the optimal 1-3 range. Ligand B (0.494) is a bit low, potentially hindering membrane permeability.

**H-Bond Donors/Acceptors:** Ligand A (1 HBD, 5 HBA) is good. Ligand B (3 HBD, 5 HBA) is also acceptable, but the higher HBD count could slightly impact permeability.

**QED:** Both ligands have good QED scores (0.928 and 0.721, respectively), indicating drug-like properties.

**DILI:** Ligand A (64.754) has a higher DILI risk than Ligand B (36.138), which is a significant concern.

**BBB:** Ligand A (75.572) has a good BBB penetration percentile, exceeding the 70% threshold for CNS targets. Ligand B (48.197) is significantly lower, which is problematic for a CNS target like DRD2.

**Caco-2 Permeability:** Both have negative Caco-2 values (-4.509 and -4.813), which is unusual and suggests poor permeability. This is a red flag for both compounds.

**Aqueous Solubility:** Both have negative solubility values (-3.369 and -1.915), which is also unusual and suggests poor solubility.

**hERG:** Both ligands show low hERG inhibition liability (0.443 and 0.468), which is favorable.

**Microsomal Clearance:** Ligand A (10.426) has a lower (better) microsomal clearance than Ligand B (-33.166). This indicates better metabolic stability for Ligand A.

**In vitro Half-Life:** Ligand B (37.781) has a significantly longer in vitro half-life than Ligand A (11.631), which is a positive attribute.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.193 and 0.022), which is good for CNS penetration.

**Binding Affinity:** Both ligands have the same binding affinity (-8.9 kcal/mol), which is excellent and strong.

**Overall Assessment:**

Despite the equal binding affinity, Ligand A is the more promising candidate. The critical factors are the significantly better BBB penetration (75.6% vs 48.2%) and lower microsomal clearance (10.4 vs -33.2). While Ligand A has a higher DILI risk, this can be addressed through structural modifications. The poor Caco-2 and solubility values are concerning for both, but the strong affinity might allow for formulation strategies to overcome these issues. Ligand B's poor BBB penetration is a major drawback for a CNS target.

Output:
1
2025-04-17 05:37:52,518 - INFO - Batch 214 complete. Total preferences: 3424
2025-04-17 05:37:52,518 - INFO - Processing batch 215/512...
2025-04-17 05:38:36,230 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 drug candidates, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (335.407 Da) is slightly lower, which could be advantageous for permeability.

**TPSA:** Both are reasonably low, but Ligand A (54.46) is significantly better than Ligand B (58.64), falling well below the 90 A^2 threshold for CNS targets. Ligand B is approaching the 140 A^2 limit for oral absorption.

**logP:** Both have good logP values (A: 2.966, B: 1.948) within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Both have 1 HBD and 4 HBA, which are within acceptable limits.

**QED:** Both ligands have high QED scores (A: 0.937, B: 0.832), indicating good drug-like properties.

**DILI:** Ligand A (43.04) has a slightly higher DILI risk than Ligand B (36.293), but both are below the concerning 60 percentile.

**BBB:** This is a critical parameter for a CNS target like DRD2. Ligand A has a significantly higher BBB penetration percentile (88.29) compared to Ligand B (61.613). This is a major advantage for Ligand A.

**Caco-2 Permeability:** Ligand A (-4.818) has a worse Caco-2 permeability than Ligand B (-5.229), but both are quite poor.

**Aqueous Solubility:** Both have poor aqueous solubility (-3.403 and -3.142 respectively).

**hERG:** Both ligands have low hERG inhibition liability (A: 0.726, B: 0.232), which is favorable.

**Microsomal Clearance:** Ligand B (45.216) has a higher microsomal clearance than Ligand A (21.53), suggesting Ligand A is more metabolically stable.

**In vitro Half-Life:** Ligand A (-2.816) has a longer in vitro half-life than Ligand B (8.571).

**P-gp Efflux:** Ligand A (0.212) shows lower P-gp efflux liability than Ligand B (0.112), which is beneficial for CNS exposure.

**Binding Affinity:** Ligand B (-8.2 kcal/mol) has a significantly stronger binding affinity than Ligand A (-10.1 kcal/mol). This is a substantial advantage, potentially outweighing some of the ADME drawbacks of Ligand B. However, the difference is not *that* large.

**Overall Assessment:**

Ligand A excels in properties crucial for CNS penetration (BBB, TPSA, Pgp, metabolic stability, half-life) and has a good overall drug-like profile. Ligand B has a stronger binding affinity, but suffers from poorer BBB penetration, higher metabolic clearance, and lower half-life. Given the importance of CNS penetration for a DRD2 ligand, and the relatively modest affinity difference, Ligand A is the more promising candidate.

Output:
0
2025-04-17 05:38:36,231 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (345.487 and 353.388 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Both ligands have TPSA values (56.15 and 56.99) below the 90 A^2 threshold desirable for CNS targets, which is excellent.

**3. logP:** Both ligands have logP values (3.227 and 3.843) within the optimal range of 1-3. Ligand B is slightly higher, which could potentially lead to some off-target effects, but is still acceptable.

**4. H-Bond Donors:** Ligand A has 1 HBD, and Ligand B has 0. Both are within the acceptable limit of <=5.

**5. H-Bond Acceptors:** Ligand A has 5 HBA, and Ligand B has 3. Both are within the acceptable limit of <=10.

**6. QED:** Ligand B (0.781) has a significantly better QED score than Ligand A (0.446), indicating a more drug-like profile.

**7. DILI:** Ligand A has a DILI risk of 12.602, which is very good (low risk). Ligand B has a DILI risk of 24.195, also good, but higher than Ligand A.

**8. BBB:** Ligand B (96.006) has a much higher BBB penetration percentile than Ligand A (81.698). This is a critical advantage for a CNS target like DRD2.

**9. Caco-2 Permeability:** Both have negative values (-4.956 and -4.216), which is unusual and suggests poor permeability. However, these values are on a scale where negative values are possible and don't necessarily disqualify the compounds.

**10. Aqueous Solubility:** Both ligands have very poor aqueous solubility (-3.153 and -4.069). This is a significant concern for bioavailability.

**11. hERG Inhibition:** Both ligands have low hERG inhibition risk (0.635 and 0.637).

**12. Microsomal Clearance:** Ligand B (55.729) has a lower microsomal clearance than Ligand A (70.754), suggesting better metabolic stability.

**13. In vitro Half-Life:** Ligand B (-24.018) has a significantly longer in vitro half-life than Ligand A (-2.314). This is a major advantage.

**14. P-gp Efflux:** Both ligands have low P-gp efflux liability (0.449 and 0.19). Ligand B is slightly better.

**15. Binding Affinity:** Ligand B (-8.0 kcal/mol) has a slightly better binding affinity than Ligand A (-7.8 kcal/mol). While the difference is small, it's still a positive factor.

**Overall Assessment:**

Ligand B is the superior candidate. While both have poor solubility and Caco-2 permeability, Ligand B excels in crucial areas for a CNS-targeting GPCR: significantly better BBB penetration, longer half-life, better metabolic stability (lower Cl_mic), and a slightly improved binding affinity. Its QED score is also considerably higher, indicating a more favorable drug-like profile. The slightly higher logP of Ligand B is a minor concern, but the benefits outweigh this potential drawback.

Output:
1
2025-04-17 05:38:36,231 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (352.387 Da and 360.439 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (117.87) is slightly above the optimal <90 for CNS targets, but still reasonable. Ligand B (88.44) is excellent, well below 90.

**3. logP:** Ligand A (0.166) is quite low, potentially hindering membrane permeability. Ligand B (1.954) is much better, falling within the optimal 1-3 range.

**4. H-Bond Donors:** Ligand A (3) is acceptable. Ligand B (1) is even better.

**5. H-Bond Acceptors:** Ligand A (6) is acceptable. Ligand B (7) is also acceptable.

**6. QED:** Both ligands have good QED scores (0.574 and 0.847), indicating drug-likeness. Ligand B is superior.

**7. DILI:** Ligand A (49.477) has a lower DILI risk than Ligand B (66.886), which is preferable.

**8. BBB:** Ligand A (52.268) and Ligand B (55.603) are both below the desirable >70 for CNS targets. However, this is less critical if other properties are favorable.

**9. Caco-2:** Both have negative Caco-2 values, which is unusual and suggests poor permeability. This is a significant concern for both.

**10. Solubility:** Both have negative solubility values, which is also unusual and suggests poor solubility. This is a significant concern for both.

**11. hERG:** Both ligands have low hERG risk (0.209 and 0.306).

**12. Cl_mic:** Ligand B (36.411) has a lower microsomal clearance, indicating better metabolic stability than Ligand A (41.744).

**13. t1/2:** Ligand B (-5.911) has a negative half-life, which is not possible and indicates a problem with the data. Ligand A (4.047) has a reasonable half-life.

**14. Pgp:** Both ligands have low P-gp efflux liability (0.093 and 0.102), which is good for CNS penetration.

**15. Binding Affinity:** Ligand A (-7.4) has a slightly better binding affinity than Ligand B (-7.2), but the difference is small (0.2 kcal/mol).

**Overall Assessment:**

Despite Ligand A's slightly better affinity and lower DILI risk, Ligand B is the more promising candidate. Ligand A's very low logP is a major concern, likely leading to poor permeability. Ligand B has a better logP, better QED, and better metabolic stability. The negative Caco-2 and solubility values are concerning for both, but the other properties of Ligand B are more favorable overall. The negative half-life for Ligand B is a data issue that would need to be investigated.

Output:
1
2025-04-17 05:38:36,231 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 drug candidates, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (413.262 Da) is slightly higher than Ligand B (371.478 Da), but both are acceptable.

**TPSA:** Ligand A (51.1) is significantly better than Ligand B (80.32). For CNS targets, we want TPSA <= 90, and ideally closer to 60. Ligand A is much closer to this ideal.

**logP:** Both ligands have good logP values (A: 4.006, B: 2.489), falling within the optimal range of 1-3. Ligand B is slightly preferred here as it is closer to the center of the range.

**H-Bond Donors/Acceptors:** Ligand A (HBD=1, HBA=3) is more favorable than Ligand B (HBD=2, HBA=5). Lower values are generally preferred for better permeability.

**QED:** Ligand A (0.806) has a much better QED score than Ligand B (0.397), indicating a more drug-like profile.

**DILI:** Ligand B (44.552) has a lower DILI risk than Ligand A (63.397), which is a positive attribute.

**BBB:** Both ligands have good BBB penetration (A: 75.107, B: 73.245), exceeding the desirable threshold of >70 for CNS targets.

**Caco-2 Permeability:** Ligand A (-4.689) has a worse Caco-2 permeability compared to Ligand B (-5.301), indicating lower intestinal absorption.

**Aqueous Solubility:** Ligand A (-4.882) has worse solubility than Ligand B (-3.442).

**hERG Inhibition:** Ligand A (0.71) has a slightly higher hERG inhibition liability than Ligand B (0.377), but both are reasonably low risk.

**Microsomal Clearance:** Ligand B (75.817) has a higher microsomal clearance than Ligand A (55.72), indicating faster metabolism and potentially lower exposure.

**In vitro Half-Life:** Ligand A (65.282) has a significantly longer in vitro half-life than Ligand B (-20.665). This is a major advantage.

**P-gp Efflux:** Ligand A (0.573) has lower P-gp efflux liability than Ligand B (0.074), which is beneficial for CNS exposure.

**Binding Affinity:** Ligand A (-8.7 kcal/mol) has a significantly stronger binding affinity than Ligand B (-7.4 kcal/mol). This is a substantial advantage, potentially outweighing some of the ADME drawbacks. A difference of 1.3 kcal/mol is significant.

**Overall Assessment:**

Ligand A excels in key areas for a CNS-targeting GPCR: TPSA, QED, BBB, P-gp efflux, and, crucially, binding affinity. While it has slightly worse solubility, Caco-2 permeability and a higher DILI risk, the strong binding affinity and favorable CNS penetration properties are compelling. Ligand B has better DILI and logP, but its significantly lower QED, higher P-gp efflux, and weaker binding affinity are major drawbacks. The longer half-life of Ligand A is also a significant benefit.

Output:
1
2025-04-17 05:38:36,231 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (350.463 and 345.443 Da) are within the ideal 200-500 Da range.

**TPSA:** Ligand A (96.11) is slightly above the optimal <90 for CNS targets, while Ligand B (90.27) is closer to the threshold.

**logP:** Both ligands have good logP values (1.971 and 1.649), falling within the 1-3 range.

**H-Bond Donors:** Ligand A has 3 HBD, which is acceptable. Ligand B has only 1, which is also good.

**H-Bond Acceptors:** Both ligands have 4 HBA, well within the acceptable limit of 10.

**QED:** Both ligands have good QED scores (0.731 and 0.842), indicating good drug-like properties.

**DILI:** Ligand A (50.795) has a slightly higher DILI risk than Ligand B (31.989), but both are below the concerning threshold of 60.

**BBB:** Both ligands have excellent BBB penetration (73.672 and 72.082), exceeding the desirable >70 for CNS targets.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.651 and -4.749). This is unusual and suggests poor permeability. However, these values are on a log scale and are likely representing very low permeability.

**Aqueous Solubility:** Both ligands have negative solubility values (-3.841 and -2.605), indicating poor aqueous solubility. This is a concern for bioavailability.

**hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.266 and 0.229).

**Microsomal Clearance:** Ligand B (10.874) has significantly lower microsomal clearance than Ligand A (56.139), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand B (-12.081) has a longer in vitro half-life than Ligand A (-49.717), which is a positive attribute.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.057 and 0.063), which is favorable for CNS exposure.

**Binding Affinity:** Ligand B (-8.5 kcal/mol) has a slightly better binding affinity than Ligand A (-8.0 kcal/mol). While the difference is not huge, it's within the range where a 1.5 kcal/mol advantage can be significant.

**Conclusion:**

Considering all factors, **Ligand B** is the more promising candidate. While both ligands have good BBB penetration and acceptable logP values, Ligand B demonstrates superior metabolic stability (lower Cl_mic), longer half-life, lower DILI risk, and slightly better binding affinity. The poor solubility and permeability are concerns for both, but the improved ADME profile of Ligand B outweighs the marginal affinity difference.

Output:
1
2025-04-17 05:38:36,232 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B based on the provided guidelines, prioritizing GPCR-specific properties (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (356.373 and 348.403 Da) fall within the ideal range of 200-500 Da.

**TPSA:** Ligand A (75.63) is significantly better than Ligand B (104.53). For CNS targets, TPSA should be <= 90, so Ligand A is within range, while Ligand B is slightly above.

**logP:** Ligand A (2.496) is optimal (1-3), while Ligand B (-0.463) is below 1, potentially hindering permeation. This is a significant drawback for Ligand B.

**H-Bond Donors/Acceptors:** Ligand A (0 HBD, 5 HBA) and Ligand B (2 HBD, 6 HBA) both fall within acceptable ranges.

**QED:** Both ligands have reasonable QED values (0.832 and 0.694), indicating good drug-like properties.

**DILI:** Ligand A (53.315) has a slightly higher DILI risk than Ligand B (35.634), but both are below the concerning threshold of 60.

**BBB:** Ligand A (90.074) has excellent BBB penetration, exceeding the desirable >70% for CNS targets. Ligand B (31.214) has poor BBB penetration, a major disadvantage for a DRD2 ligand.

**Caco-2 Permeability:** Ligand A (-4.102) and Ligand B (-5.257) both have negative values, indicating poor permeability.

**Aqueous Solubility:** Ligand A (-2.195) and Ligand B (-1.138) both have negative values, indicating poor solubility.

**hERG:** Both ligands have very low hERG inhibition risk (0.202 and 0.037).

**Microsomal Clearance:** Ligand A (36.149) has higher clearance than Ligand B (21.802), suggesting lower metabolic stability.

**In vitro Half-Life:** Ligand A (-11.367) has a negative half-life, which is not possible, and suggests a problem with the data. Ligand B (-7.207) also has a negative half-life.

**P-gp Efflux:** Both ligands show minimal P-gp efflux liability (0.058 and 0.009).

**Binding Affinity:** Both ligands have excellent binding affinity (-8.0 and -8.1 kcal/mol), with Ligand B being slightly better. However, the affinity difference is small and can be outweighed by other factors.

**Conclusion:**

Considering the GPCR-specific priorities, Ligand A is the more promising candidate. Its superior TPSA, logP, and, crucially, BBB penetration outweigh the slightly higher DILI risk and clearance. Ligand B's poor logP and extremely low BBB penetration are significant liabilities for a CNS-targeting drug. The negative half-life values for both compounds are concerning and would require further investigation, but do not change the overall ranking based on the other properties.

Output:
1
2025-04-17 05:38:36,232 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (389.279 and 347.423 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (78.87) is excellent, well below the 90 A^2 target for CNS penetration. Ligand B (118.06) is still reasonable but less optimal, exceeding the preferred threshold.

**logP:** Ligand A (2.982) is within the optimal 1-3 range. Ligand B (1.738) is slightly lower, which *could* indicate potential permeability issues, but isn't a major concern.

**H-Bond Donors/Acceptors:** Ligand A has 2 HBD and 4 HBA, fitting the <5 and <10 rules. Ligand B has 1 HBD and 4 HBA, also favorable.

**QED:** Ligand A (0.83) has a very strong drug-like profile. Ligand B (0.479) is lower, suggesting a less ideal overall drug-likeness.

**DILI:** Ligand A (36.603) has a low DILI risk. Ligand B (43.622) is slightly higher, but still acceptable.

**BBB:** Ligand A (51.842) has a moderate BBB penetration, while Ligand B (55.099) is also moderate. Both are below the desirable >70 for CNS targets, but not dramatically so.

**Caco-2:** Ligand A (-4.498) and Ligand B (-5.157) both have negative Caco-2 values, which is unusual and suggests poor permeability. This is a significant concern for both.

**Solubility:** Ligand A (-3.602) and Ligand B (-2.086) have negative solubility values, indicating very poor aqueous solubility. This is a major drawback for both compounds.

**hERG:** Both ligands have very low hERG inhibition risk (0.587 and 0.167, respectively).

**Microsomal Clearance:** Ligand A (34.954) has a higher microsomal clearance than Ligand B (11.592), suggesting lower metabolic stability.

**In vitro Half-Life:** Ligand A (-8.856) has a longer in vitro half-life than Ligand B (-5.878).

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.196 and 0.016, respectively), which is good for CNS exposure.

**Binding Affinity:** Ligand B (-7.3 kcal/mol) has a significantly stronger binding affinity than Ligand A (-8.5 kcal/mol). This is a substantial advantage.

**Overall Assessment:**

While both compounds have significant drawbacks (poor Caco-2 and solubility), Ligand B's substantially stronger binding affinity (-7.3 vs -8.5 kcal/mol) is a critical advantage for a GPCR target like DRD2. The difference of 1.2 kcal/mol is large enough to potentially overcome the ADME liabilities, *especially* if formulation strategies can be employed to address the solubility issues. Ligand A has better QED and slightly better metabolic stability, but the affinity difference is decisive.

Output:
1
2025-04-17 05:38:36,232 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (339.4) is slightly lower, which is generally favorable for permeability.

**TPSA:** Ligand A (84.98) is excellent for CNS penetration, falling well below the 90 A^2 threshold. Ligand B (99.1) is still reasonable but less optimal.

**logP:** Ligand A (2.678) is within the optimal range (1-3). Ligand B (0.21) is quite low, potentially hindering membrane permeability and CNS entry.

**H-Bond Donors/Acceptors:** Both ligands have acceptable HBD (2 & 3) and HBA (5) counts.

**QED:** Both ligands have reasonable QED scores (0.723 and 0.568), indicating drug-like properties.

**DILI:** Ligand A (66.615) has a higher DILI risk than Ligand B (11.206). This is a concern for Ligand A, but not a deal-breaker at this stage.

**BBB:** Ligand A (60.799) has a moderate BBB penetration, while Ligand B (29.508) is quite low. This is a significant advantage for Ligand A, given that DRD2 is a CNS target.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values, which is unusual and suggests potential issues with the data or the model. However, we can still compare them relatively.

**Aqueous Solubility:** Both ligands have negative solubility values, again suggesting potential data issues.

**hERG:** Both ligands have very low hERG inhibition risk, which is positive.

**Microsomal Clearance:** Ligand A (39.271) has a higher microsomal clearance than Ligand B (3.993), suggesting lower metabolic stability.

**In vitro Half-Life:** Ligand B (3.199) has a slightly longer half-life than Ligand A (5.433).

**P-gp Efflux:** Ligand A (0.147) has a much lower P-gp efflux liability than Ligand B (0.03), which is highly desirable for CNS penetration.

**Binding Affinity:** Ligand A (-9.3 kcal/mol) has a slightly better binding affinity than Ligand B (-8.5 kcal/mol). While both are good, the 0.8 kcal/mol difference is meaningful.

**Overall Assessment:**

Considering the GPCR-specific priorities, Ligand A is the more promising candidate. Its superior TPSA, logP, BBB penetration, and P-gp efflux profile are crucial for CNS drug development. While its DILI risk and microsomal clearance are higher, the significantly better binding affinity and CNS penetration properties outweigh these concerns. Ligand B's low logP and poor BBB penetration are major drawbacks.

Output:
0
2025-04-17 05:38:36,232 - INFO - Reasoning:

Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (364.471 and 351.451 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (79.96) is significantly better than Ligand B (122.27). For CNS targets, we want TPSA <= 90, and A is comfortably within that range, while B exceeds it. This is a significant advantage for A.

**3. logP:** Ligand A (2.439) is optimal (1-3), while Ligand B (0.424) is a bit low, potentially hindering permeation.

**4. H-Bond Donors:** Ligand A (1) is good. Ligand B (4) is acceptable but higher, potentially impacting permeability.

**5. H-Bond Acceptors:** Ligand A (7) is good. Ligand B (6) is also good.

**6. QED:** Both ligands have reasonable QED values (0.821 and 0.592), indicating good drug-like properties.

**7. DILI:** Ligand A (56.146) has a slightly higher DILI risk than Ligand B (43.932), but both are below the concerning threshold of 60.

**8. BBB:** Ligand A (69.639) is better than Ligand B (63.358) but both are below the desired >70 for CNS targets. However, A is closer.

**9. Caco-2:** Ligand A (-4.764) is worse than Ligand B (-5.456), indicating lower intestinal absorption.

**10. Solubility:** Ligand A (-2.833) is worse than Ligand B (-2.325).

**11. hERG:** Both ligands have very low hERG inhibition risk (0.586 and 0.252).

**12. Cl_mic:** Ligand B (4.102) has significantly lower microsomal clearance than Ligand A (54.479), suggesting better metabolic stability.

**13. t1/2:** Ligand B (0.687) has a very short half-life, while Ligand A (-24.638) has a negative value, which is unusual and likely indicates a very rapid clearance.

**14. Pgp:** Ligand A (0.331) has lower P-gp efflux liability than Ligand B (0.022), which is favorable for CNS penetration.

**15. Binding Affinity:** Ligand B (-8.5 kcal/mol) has a stronger binding affinity than Ligand A (-7.9 kcal/mol). This is a 0.6 kcal/mol difference, which is significant.

**Overall Assessment:**

Considering the GPCR-specific priorities, Ligand A has a clear advantage in TPSA and logP, which are critical for CNS penetration. It also has better Pgp properties. However, Ligand B has a significantly better binding affinity, lower clearance, and slightly better DILI risk. The biggest drawback of Ligand A is its poor Caco-2 and solubility. The negative in vitro half-life is also concerning. While the affinity difference is important, the TPSA and logP values of Ligand A are more crucial for a CNS target like DRD2.

Output:
1
2025-04-17 05:38:36,232 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (363.483 and 380.539 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (75.44) is slightly higher than Ligand B (68.21). Both are below the 90 A^2 threshold for CNS targets, which is good.

**3. logP:** Both ligands have good logP values (2.953 and 3.081), falling within the optimal range of 1-3.

**4. H-Bond Donors:** Ligand A has 1 HBD, and Ligand B has 0. Both are within the acceptable limit of <=5.

**5. H-Bond Acceptors:** Ligand A has 5 HBA, and Ligand B has 7. Both are within the acceptable limit of <=10.

**6. QED:** Both ligands have acceptable QED values (0.782 and 0.593), indicating good drug-like properties.

**7. DILI:** Ligand A (50.446) has a slightly higher DILI risk than Ligand B (23.769). This favors Ligand B.

**8. BBB:** Both ligands have excellent BBB penetration (71.19% and 78.868%), exceeding the desirable threshold of >70% for CNS targets. Ligand B is slightly better.

**9. Caco-2 Permeability:** Both have negative values (-5.103 and -5.048) which is unusual and suggests poor permeability. This is a concern for both.

**10. Aqueous Solubility:** Both have negative values (-2.403 and -2.069) which is also unusual and suggests poor solubility. This is a concern for both.

**11. hERG Inhibition:** Both ligands show low hERG inhibition liability (0.528 and 0.477), which is favorable.

**12. Microsomal Clearance:** Ligand A (87.92) has a higher microsomal clearance than Ligand B (72.291), indicating lower metabolic stability. This favors Ligand B.

**13. In vitro Half-Life:** Ligand A (8.008 hours) has a longer half-life than Ligand B (1.369 hours). This favors Ligand A.

**14. P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.272 and 0.291), which is excellent for CNS exposure.

**15. Binding Affinity:** Ligand A (-8.0 kcal/mol) has a significantly stronger binding affinity than Ligand B (-6.2 kcal/mol). This is a substantial advantage, exceeding the 1.5 kcal/mol difference threshold.

**Overall Assessment:**

While Ligand B has a better safety profile (lower DILI) and metabolic stability (lower Cl_mic), the significantly stronger binding affinity of Ligand A (-8.0 vs -6.2 kcal/mol) is a decisive factor. The affinity difference is large enough to potentially overcome the slightly higher DILI risk and shorter half-life, especially considering the excellent BBB penetration of both compounds. The poor Caco-2 and solubility values are concerning for both, but can be addressed with formulation strategies.

Output:
1
2025-04-17 05:38:36,233 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (357.451 and 345.491 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (107.97) is higher than Ligand B (64.86). For CNS targets, TPSA < 90 is preferred. Ligand B is significantly better here.

**logP:** Ligand A (0.635) is below the optimal 1-3 range, potentially hindering permeation. Ligand B (2.818) is within the optimal range. This favors Ligand B.

**H-Bond Donors & Acceptors:** Ligand A has 3 HBD and 5 HBA, which are acceptable. Ligand B has 1 HBD and 6 HBA, also acceptable.

**QED:** Both ligands have good QED scores (0.591 and 0.859), indicating drug-like properties. Ligand B is slightly better.

**DILI:** Both ligands have relatively low DILI risk (33.501 and 37.611), below the 40 threshold.

**BBB:** Ligand A (51.415) has a moderate BBB penetration, while Ligand B (74.06) is much better, exceeding the desirable >70 threshold for CNS targets. This is a significant advantage for Ligand B.

**Caco-2 Permeability:** Ligand A (-4.937) has poor Caco-2 permeability, while Ligand B (-5.363) is also poor.

**Aqueous Solubility:** Both ligands have poor aqueous solubility (-1.512 and -3.022).

**hERG Inhibition:** Both ligands show low hERG inhibition risk (0.229 and 0.285).

**Microsomal Clearance:** Ligand A (24.253) and Ligand B (26.235) have similar microsomal clearance values.

**In vitro Half-Life:** Ligand A (-23.698) has a significantly longer in vitro half-life than Ligand B (7.654). This is a positive for Ligand A.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.03 and 0.134).

**Binding Affinity:** Ligand B (-7.6 kcal/mol) has a slightly better binding affinity than Ligand A (-7.1 kcal/mol). While the difference is not huge, it's a positive for Ligand B.

**Overall Assessment:**

Considering the GPCR-specific priorities, Ligand B is the more promising candidate. It has a significantly better BBB score, a more favorable logP, and a slightly better binding affinity. While Ligand A has a longer half-life, the improved CNS penetration and logP of Ligand B outweigh this advantage. The poor Caco-2 and solubility for both are concerns that would need to be addressed in further optimization, but are less critical for a CNS target.

Output:
1
2025-04-17 05:38:36,233 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (346.5 and 351.5 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (58.2) is excellent, well below the 90 A^2 threshold for CNS targets. Ligand B (101.6) is higher, but still potentially acceptable, though less ideal.

**logP:** Ligand A (3.694) is optimal (1-3). Ligand B (-0.32) is significantly outside the optimal range and is concerningly low, potentially hindering membrane permeability.

**H-Bond Donors/Acceptors:** Ligand A (2 HBD, 2 HBA) is well within acceptable limits. Ligand B (3 HBD, 5 HBA) is also acceptable, but slightly higher.

**QED:** Both ligands have good QED values (0.52 and 0.596), indicating good drug-like properties.

**DILI:** Ligand A (21.9%) has a much lower DILI risk than Ligand B (15.5%). Both are acceptable, but A is preferable.

**BBB:** Ligand A (65.4%) shows reasonable BBB penetration, while Ligand B (16.4%) is very poor. This is a critical factor for a CNS target like DRD2.

**Caco-2 Permeability:** Ligand A (-4.65) is poor, while Ligand B (-5.602) is even worse. Both are undesirable.

**Aqueous Solubility:** Ligand A (-4.567) is poor, while Ligand B (-0.83) is also poor, but slightly better.

**hERG Inhibition:** Ligand A (0.407) has a low hERG risk, while Ligand B (0.069) has a very low hERG risk. Both are good.

**Microsomal Clearance:** Ligand A (41.96) has moderate clearance, while Ligand B (-9.064) has excellent metabolic stability (negative value indicates very slow clearance).

**In vitro Half-Life:** Ligand A (6.75 hours) is reasonable, while Ligand B (-26.2 hours) is excellent.

**P-gp Efflux:** Ligand A (0.345) has low P-gp efflux, which is good for CNS penetration. Ligand B (0.003) has very low P-gp efflux, even better.

**Binding Affinity:** Ligand A (-8.4 kcal/mol) has a significantly stronger binding affinity than Ligand B (-7.5 kcal/mol). This 1.9 kcal/mol difference is substantial.

**Overall Assessment:**

Ligand A excels in binding affinity, TPSA, DILI, and P-gp efflux. Its BBB penetration is reasonable. The main drawbacks are moderate Caco-2 permeability and aqueous solubility.

Ligand B has excellent metabolic stability and very low P-gp efflux, but suffers from a very poor logP, very poor BBB penetration, and a weaker binding affinity. The low logP is a major concern as it will severely limit its ability to cross cell membranes and reach the brain.

Given the GPCR-specific priorities, particularly BBB penetration and affinity, and the substantial difference in binding affinity, **Ligand A is the more promising candidate.** The better affinity and reasonable BBB penetration outweigh the concerns about solubility and Caco-2 permeability, which can be addressed through formulation strategies.

Output:
1
2025-04-17 05:38:36,233 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (336.347 Da) is slightly lower, which could be beneficial for permeability.

**TPSA:** Ligand A (68.71) is excellent for CNS penetration, well below the 90 A^2 threshold. Ligand B (79.72) is still reasonable but less optimal.

**logP:** Ligand A (3.997) is at the higher end of the optimal range (1-3), potentially leading to some solubility issues. Ligand B (2.638) is well within the optimal range.

**H-Bond Donors/Acceptors:** Ligand A (0 HBD, 6 HBA) is favorable. Ligand B (1 HBD, 8 HBA) is also acceptable, but slightly higher counts could impact permeability.

**QED:** Both ligands have good QED scores (A: 0.525, B: 0.755), indicating drug-like properties. Ligand B is better.

**DILI:** Both have relatively high DILI risk, but Ligand B (81.621) is lower than Ligand A (95.89).

**BBB:** This is crucial for a CNS target. Ligand A (76.037) has a good BBB percentile, exceeding the 70% threshold. Ligand B (48.779) is significantly lower, raising concerns about CNS exposure.

**Caco-2 Permeability:** Ligand A (-4.477) has poor Caco-2 permeability, which is a significant drawback. Ligand B (-5.34) is also poor, but slightly worse than A.

**Aqueous Solubility:** Both have very poor aqueous solubility (-6.505 for A, -3.001 for B). This is a concern for formulation and bioavailability.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (A: 0.815, B: 0.498).

**Microsomal Clearance:** Ligand B (55.557) has significantly lower microsomal clearance than Ligand A (134.103), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (65.546) has a longer half-life than Ligand B (1.212).

**P-gp Efflux:** Ligand A (0.736) has lower P-gp efflux than Ligand B (0.026), which is favorable for CNS penetration.

**Binding Affinity:** Ligand B (-9.0 kcal/mol) has a substantially stronger binding affinity than Ligand A (-8.3 kcal/mol). This difference of 0.7 kcal/mol is significant and can outweigh some ADME drawbacks.

**Overall Assessment:**

While Ligand A has a better BBB score and P-gp efflux, its poor Caco-2 permeability and higher DILI risk are major concerns. Ligand B, despite a lower BBB score, boasts significantly better metabolic stability (lower Cl_mic), a much stronger binding affinity, and a lower DILI risk. The strong binding affinity of Ligand B is a critical advantage for a GPCR target, and the lower clearance suggests it might achieve sufficient brain exposure despite the lower BBB prediction. The solubility issues are a concern for both, but can be addressed with formulation strategies.

Output:
1
2025-04-17 05:38:36,233 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (361.833 Da) and Ligand B (341.459 Da) are both acceptable.

**TPSA:**  Ligand A (88.08) is better than Ligand B (62.31). Both are below the 90 A^2 threshold desirable for CNS targets, but Ligand A is closer to the ideal range.

**logP:** Ligand A (2.116) and Ligand B (3.109) are both within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A (HBD=1, HBA=5) and Ligand B (HBD=2, HBA=6) both have acceptable numbers of H-bond donors and acceptors.

**QED:** Both ligands have good QED scores (Ligand A: 0.763, Ligand B: 0.807), indicating good drug-like properties.

**DILI:** Both ligands have elevated DILI risk (Ligand A: 59.364, Ligand B: 63.513). Ligand A is slightly better, but both are approaching the concerning >60 threshold.

**BBB:** This is a critical parameter for CNS targets. Ligand B (92.051) significantly outperforms Ligand A (46.84). This is a major advantage for Ligand B.

**Caco-2 Permeability:** Both have negative values, which is unusual. A more negative value indicates lower permeability. Ligand A (-5.162) is slightly better than Ligand B (-4.75).

**Aqueous Solubility:** Both ligands have negative solubility values, which is also unusual. Ligand A (-2.464) is slightly better than Ligand B (-3.181).

**hERG Inhibition:** Both ligands have low hERG inhibition risk (Ligand A: 0.488, Ligand B: 0.947). Ligand B is slightly higher, but both are acceptable.

**Microsomal Clearance:** Ligand B (34.468) has a significantly lower microsomal clearance than Ligand A (56.353), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand B (36.285) has a longer in vitro half-life than Ligand A (19.086), which is desirable.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (Ligand A: 0.041, Ligand B: 0.083).

**Binding Affinity:** Both ligands have the same binding affinity (-8.2 kcal/mol), which is excellent.

**Conclusion:**

While Ligand A has slightly better TPSA, Caco-2 permeability, and solubility, Ligand B is superior due to its significantly higher BBB penetration (92.051 vs 46.84), lower microsomal clearance, and longer half-life. Given the CNS target (DRD2), BBB penetration is paramount. The improved metabolic stability and half-life of Ligand B further strengthen its profile. The slightly higher DILI risk of Ligand B is a concern, but the substantial advantage in BBB penetration outweighs this drawback.

Output:
1
2025-04-17 05:38:36,233 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (349.431 Da) is slightly lower, which could be beneficial for permeability. Ligand B (364.823 Da) is also good.

**TPSA:** Ligand A (101.9) is borderline for CNS targets, being slightly above the preferred <90. Ligand B (33.2) is excellent, well below the threshold, suggesting good CNS penetration potential.

**logP:** Ligand A (1.169) is within the optimal range. Ligand B (4.192) is a bit high, potentially leading to solubility issues and off-target interactions, but still within acceptable limits.

**H-Bond Donors/Acceptors:** Ligand A has 4 HBD and 5 HBA, which are acceptable. Ligand B has 0 HBD and 2 HBA, which is also good.

**QED:** Both ligands have good QED scores (A: 0.592, B: 0.72), indicating drug-like properties.

**DILI:** Both ligands have low DILI risk (A: 42.769, B: 33.773), which is favorable.

**BBB:** This is a critical parameter for a CNS target like DRD2. Ligand A has a BBB percentile of 12.292, which is very low and a significant drawback. Ligand B has a much higher BBB percentile of 93.718, indicating excellent potential for brain penetration.

**Caco-2 Permeability:** Ligand A (-5.511) shows poor permeability. Ligand B (-4.319) is also poor, but slightly better than A.

**Aqueous Solubility:** Both ligands have negative solubility values (-2.189 and -5.039), indicating poor aqueous solubility. This is a concern, but can sometimes be mitigated through formulation.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (A: 0.356, B: 0.677).

**Microsomal Clearance:** Ligand A (-1.941) has negative clearance, which is unusual and suggests very high metabolic stability. Ligand B (55.945) has a high clearance, indicating faster metabolism.

**In vitro Half-Life:** Ligand A (-0.065) has a very short half-life, which is undesirable. Ligand B (0.826) has a slightly better half-life, but still not ideal.

**P-gp Efflux:** Ligand A (0.021) has very low P-gp efflux, which is good for CNS exposure. Ligand B (0.449) has slightly higher P-gp efflux, but still relatively low.

**Binding Affinity:** Both ligands have similar and strong binding affinities (A: -8.3 kcal/mol, B: -8.5 kcal/mol). The difference is small and doesn't significantly favor one over the other.

**Conclusion:**

Despite Ligand A's slightly better MW and comparable affinity, Ligand B is the superior candidate. The overwhelmingly positive BBB score (93.718) for Ligand B is crucial for a CNS target. While its logP is higher and solubility lower than Ligand A, the poor BBB penetration of Ligand A (12.292) is a deal-breaker. The better TPSA of Ligand B also contributes to its favorability. Although Ligand B has higher Cl_mic, the strong binding affinity and excellent BBB penetration outweigh this drawback.

Output:
1
2025-04-17 05:38:36,234 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 drug candidates, considering the provided guidelines and GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (344.371 and 359.451 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (110.26) is higher than the preferred <90 for CNS targets, while Ligand B (82.53) is closer to the ideal range. This favors Ligand B.

**3. logP:** Both ligands have good logP values (1.362 and 2.06), falling within the optimal 1-3 range.

**4. H-Bond Donors:** Both have 2 HBD, which is acceptable (<=5).

**5. H-Bond Acceptors:** Ligand A has 6 HBA, and Ligand B has 5. Both are within the acceptable limit of <=10.

**6. QED:** Both have good QED scores (0.7 and 0.875), indicating good drug-like properties.

**7. DILI:** Both ligands have elevated DILI risk (62.854 and 65.413), but are still below the concerning >60 threshold. This isn't a major differentiator.

**8. BBB:** This is critical for a CNS target like DRD2. Ligand A has a BBB percentile of 45.909, while Ligand B has a significantly lower value of 26.095. Ligand A is considerably better in this regard.

**9. Caco-2 Permeability:** Both have negative Caco-2 values (-5.049 and -5.215), which is unusual and suggests poor permeability. This is a concern for both, but the values are similar.

**10. Aqueous Solubility:** Both ligands have negative solubility values (-2.558 and -3.524), indicating very poor aqueous solubility. This is a significant drawback for both.

**11. hERG Inhibition:** Ligand A (0.069) has a very low hERG risk, while Ligand B (0.347) has a slightly higher, but still low, risk. This favors Ligand A.

**12. Microsomal Clearance:** Ligand A (27.392) has moderate clearance, while Ligand B (1.888) has very low clearance, suggesting better metabolic stability. This favors Ligand B.

**13. In vitro Half-Life:** Ligand A (-22.909) has a negative half-life, which is not physically possible and indicates a problem with the data or the molecule. Ligand B has a half-life of 41.931 hours, which is good. This strongly favors Ligand B.

**14. P-gp Efflux:** Ligand A (0.047) has very low P-gp efflux, which is desirable for CNS penetration. Ligand B (0.188) has slightly higher efflux, but still relatively low. This favors Ligand A.

**15. Binding Affinity:** Ligand A (-8.4 kcal/mol) has a significantly stronger binding affinity than Ligand B (-0.0 kcal/mol). This is a major advantage for Ligand A, potentially outweighing some of its ADME drawbacks.

**Overall Assessment:**

Ligand A has a much stronger binding affinity and better BBB penetration and P-gp efflux. However, it has a nonsensical half-life value and moderate clearance. Ligand B has better TPSA, metabolic stability, and a reasonable half-life, but its binding affinity is extremely weak and its BBB penetration is poor.

Given the importance of binding affinity for GPCRs, and the need for CNS penetration, Ligand A is the more promising candidate *despite* its ADME liabilities. The extremely weak binding of Ligand B is a deal-breaker. The negative half-life for Ligand A is concerning, but could be an artifact of the prediction method. Further investigation is needed to confirm this value.

Output:
0
2025-04-17 05:38:36,234 - INFO - Batch 215 complete. Total preferences: 3440
2025-04-17 05:38:36,234 - INFO - Processing batch 216/512...
2025-04-17 05:39:18,122 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (360.5 and 359.4 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (23.55) is excellent, well below the 90 A^2 threshold for CNS targets. Ligand B (108.05) is higher, but still potentially acceptable, though less ideal.

**logP:** Ligand A (4.174) is slightly high, potentially leading to solubility issues or off-target interactions. Ligand B (0.19) is very low, which could hinder membrane permeability and CNS penetration.

**H-Bond Donors/Acceptors:** Ligand A (0 HBD, 3 HBA) is favorable. Ligand B (2 HBD, 6 HBA) is also reasonable.

**QED:** Both ligands have good QED scores (0.706 and 0.81), indicating good drug-like properties.

**DILI:** Both ligands have acceptable DILI risk (57.3 and 61.9 percentile), below the concerning 60 threshold.

**BBB:** Ligand A excels with a BBB penetration of 81.7%, highly desirable for a CNS target. Ligand B's BBB penetration is significantly lower at 39.7%, a major drawback.

**Caco-2 Permeability:** Ligand A (-4.745) has poor Caco-2 permeability. Ligand B (-5.675) also has poor Caco-2 permeability.

**Aqueous Solubility:** Ligand A (-4.375) has poor aqueous solubility. Ligand B (-2.707) has better aqueous solubility than Ligand A, but is still not ideal.

**hERG:** Both ligands have low hERG inhibition liability (0.95 and 0.172), which is positive.

**Microsomal Clearance:** Ligand A (121.38) has a relatively high microsomal clearance, suggesting faster metabolism. Ligand B (-12.043) has a negative value, which is unusual and likely represents very high metabolic stability.

**In vitro Half-Life:** Ligand A (33.9 hours) has a reasonable half-life. Ligand B (-24.32 hours) also has a negative value, which is unusual and likely represents a very long half-life.

**P-gp Efflux:** Ligand A (0.728) has moderate P-gp efflux. Ligand B (0.009) has very low P-gp efflux, which is highly desirable for CNS penetration.

**Binding Affinity:** Both ligands have excellent binding affinities (-8.2 and -9.3 kcal/mol). Ligand B is slightly better.

**Overall Assessment:**

Ligand B has a superior binding affinity and very low P-gp efflux, which are crucial for CNS GPCR targets. However, its low logP and poor Caco-2 permeability are significant concerns. Ligand A has a better logP and BBB penetration, but its Caco-2 permeability and microsomal clearance are less favorable. Given the importance of BBB penetration for a CNS target like DRD2, and the slightly better affinity of Ligand B, I would lean towards Ligand B despite its permeability concerns. The low logP could potentially be addressed through structural modifications, while improving BBB penetration is often more challenging.

Output:
1
2025-04-17 05:39:18,123 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B based on the provided guidelines, prioritizing GPCR-specific properties (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (360.479 and 375.965 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (78.43) is better than Ligand B (12.47). For CNS targets, TPSA should be <=90, both are well within this range, but A is closer to the optimal value.

**logP:** Ligand A (2.844) is within the optimal 1-3 range. Ligand B (4.971) is slightly higher, potentially leading to solubility issues and off-target effects.

**H-Bond Donors/Acceptors:** Ligand A has 3 HBD and 4 HBA, while Ligand B has 0 HBD and 3 HBA. Both are acceptable, but the presence of some HBDs in Ligand A can improve solubility.

**QED:** Both ligands have the same QED (0.677), indicating similar drug-likeness.

**DILI:** Ligand A (33.307) has a slightly higher DILI risk than Ligand B (25.436), but both are below the 40 threshold, indicating low risk.

**BBB:** This is a critical parameter for a CNS target like DRD2. Ligand B (95.851) has a significantly higher BBB penetration percentile than Ligand A (28.189). This is a major advantage for Ligand B.

**Caco-2 Permeability:** Ligand A (-5.436) and Ligand B (-5.227) both have negative values, which is unusual. Assuming these are percentile scores, lower values indicate poor permeability.

**Aqueous Solubility:** Ligand A (-2.976) has slightly better solubility than Ligand B (-4.57), but both are poor.

**hERG Inhibition:** Ligand A (0.339) has a lower hERG inhibition liability than Ligand B (0.956), which is favorable.

**Microsomal Clearance:** Ligand B (53.375) has a higher microsomal clearance than Ligand A (47.544), suggesting lower metabolic stability.

**In vitro Half-Life:** Ligand B (9.973) has a significantly longer half-life than Ligand A (-5.437).

**P-gp Efflux:** Ligand A (0.101) has lower P-gp efflux liability than Ligand B (0.884), which is beneficial for CNS exposure.

**Binding Affinity:** Ligand A (-8.7 kcal/mol) has a slightly better binding affinity than Ligand B (-8.3 kcal/mol), though the difference is relatively small.

**Overall Assessment:**

Ligand B excels in BBB penetration and has a longer half-life. These are crucial for CNS drug development. While Ligand A has slightly better solubility, lower hERG risk, and a marginally better binding affinity, the significant advantage of Ligand B in BBB penetration outweighs these factors. The higher logP of Ligand B is a concern, but the strong BBB penetration suggests it can still reach the target in the brain.

Output:
1
2025-04-17 05:39:18,123 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (372.475 and 347.419 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (69.04) is excellent, well below the 90 A^2 threshold for CNS targets. Ligand B (89.35) is approaching the upper limit, but still acceptable.

**3. logP:** Ligand A (3.527) is optimal. Ligand B (0.088) is very low, which is a significant concern for permeability and CNS penetration.

**4. H-Bond Donors:** Both ligands have 1 HBD, which is within the acceptable limit of <=5.

**5. H-Bond Acceptors:** Ligand A has 7 HBAs, and Ligand B has 6. Both are within the acceptable limit of <=10.

**6. QED:** Both ligands have similar QED values (0.71 and 0.706), indicating good drug-likeness.

**7. DILI:** Ligand A (90.733) has a high DILI risk, which is a major drawback. Ligand B (50.523) has a moderate DILI risk, which is preferable.

**8. BBB:** Ligand A (72.276) has a good BBB percentile, desirable for a CNS target. Ligand B (37.146) has a poor BBB percentile, a significant negative.

**9. Caco-2:** Both have negative Caco-2 values, which are unusual and difficult to interpret without further context. However, the magnitude suggests poor permeability for both.

**10. Solubility:** Both have negative solubility values, again unusual.

**11. hERG:** Ligand A (0.615) has a low hERG risk, which is good. Ligand B (0.103) also has a low hERG risk.

**12. Cl_mic:** Ligand A (79.635) has a relatively high microsomal clearance, suggesting lower metabolic stability. Ligand B (-2.025) has a *very* low (and likely unrealistic) clearance, indicating very high metabolic stability.

**13. t1/2:** Ligand A (25.571) has a moderate in vitro half-life. Ligand B (-8.86) has a very long (and likely unrealistic) half-life.

**14. Pgp:** Ligand A (0.801) has moderate P-gp efflux. Ligand B (0.012) has very low P-gp efflux, which is highly desirable for CNS penetration.

**15. Binding Affinity:** Ligand A (-9.0) has significantly stronger binding affinity than Ligand B (-7.1). This is a substantial advantage.

**Overall Assessment:**

Ligand A has a much better binding affinity and acceptable BBB penetration, but suffers from high DILI risk and moderate P-gp efflux. Ligand B has a lower affinity, poor BBB penetration, but lower DILI risk and very low P-gp efflux.

Despite the high DILI risk, the significantly stronger binding affinity of Ligand A is a crucial factor for a GPCR target. The difference in binding affinity (-9.0 vs -7.1 kcal/mol) is substantial and could outweigh the DILI concern, especially if further optimization can reduce the DILI risk. The low logP of Ligand B is a major impediment to CNS penetration, making it less likely to be a viable candidate.

Output:
1
2025-04-17 05:39:18,123 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (348.4 and 350.4 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (93.73) is better than Ligand B (95.42). Both are below the 90 A^2 threshold desirable for CNS targets, but A is closer.

**logP:** Ligand B (1.622) is better than Ligand A (0.491). A logP of 0.491 is quite low and may hinder membrane permeability. Ligand B is within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Both ligands have 2 HBD and 5 HBA, which are acceptable.

**QED:** Ligand B (0.86) has a significantly better QED score than Ligand A (0.527), indicating a more drug-like profile.

**DILI:** Ligand A (49.632) has a slightly better DILI percentile than Ligand B (57.193), but both are acceptable (below 60).

**BBB:** Ligand B (82.164) is *much* better than Ligand A (29.779) in terms of predicted BBB penetration. This is a critical factor for a CNS target like DRD2.

**Caco-2 Permeability:** Ligand A (-5.259) has a worse Caco-2 permeability than Ligand B (-4.775), suggesting lower intestinal absorption.

**Aqueous Solubility:** Ligand A (-1.579) has better aqueous solubility than Ligand B (-3.094).

**hERG:** Both ligands have low hERG inhibition liability (0.137 and 0.281, respectively).

**Microsomal Clearance:** Ligand B (17.475) has a slightly better microsomal clearance than Ligand A (17.94), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand B (-20.054) has a significantly longer in vitro half-life than Ligand A (-4.298).

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.037 and 0.072, respectively).

**Binding Affinity:** Both ligands have excellent binding affinities (-8.9 and -9.4 kcal/mol), with Ligand B being slightly better. The difference is less than 0.5 kcal/mol, so it's not a decisive factor on its own.

**Overall Assessment:**

While Ligand A has slightly better solubility and DILI, Ligand B is superior in almost every other critical parameter, especially for a CNS target. Its significantly better BBB penetration, QED, Caco-2 permeability, in vitro half-life, and logP outweigh the minor advantages of Ligand A. The binding affinity difference is negligible. Given the GPCR-specific prioritization, Ligand B is the more promising drug candidate.

Output:
1
2025-04-17 05:39:18,123 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (348.487 and 351.407 Da) fall comfortably within the ideal 200-500 Da range.

**TPSA:** Ligand A (69.64) is excellent, well below the 90 A^2 threshold for CNS targets. Ligand B (102.06) is still reasonable, but less optimal, being above 90.

**logP:** Ligand A (2.103) is within the optimal 1-3 range. Ligand B (-1.547) is below 1, which could hinder permeation.

**H-Bond Donors & Acceptors:** Both ligands have 2 HBD and a reasonable number of HBA (3 for A, 4 for B), satisfying the <5 HBD and <10 HBA guidelines.

**QED:** Both ligands have acceptable QED values (0.748 and 0.605), indicating good drug-like properties.

**DILI:** Both ligands have low DILI risk (23.614 and 29.042 percentiles), which is favorable.

**BBB:** Ligand A (65.452) is borderline for good CNS penetration, while Ligand B (56.572) is lower and less desirable. This is a significant point in favor of A.

**Caco-2 Permeability:** Ligand A (-4.756) and Ligand B (-5.099) have negative Caco-2 values, which is unusual and suggests poor permeability. However, these values are on a scale where negative values are possible, and direct comparison is difficult without knowing the scale's specifics.

**Aqueous Solubility:** Both ligands have negative solubility values (-2.407 and -1.246), which is also unusual and suggests poor solubility. Similar to Caco-2, interpretation is limited without knowing the scale.

**hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.212 and 0.085), which is excellent.

**Microsomal Clearance:** Ligand A (41.909) has a moderate clearance, while Ligand B (-9.761) has a negative clearance, suggesting high metabolic stability. This is a strong point for B.

**In vitro Half-Life:** Ligand A (-37.687) has a negative half-life, which is not physically possible and likely indicates an issue with the data or model. Ligand B (5.721) has a short half-life.

**P-gp Efflux:** Both ligands show very low P-gp efflux (0.168 and 0.001), which is favorable for CNS penetration.

**Binding Affinity:** Ligand A (-8.3 kcal/mol) has a significantly stronger binding affinity than Ligand B (-7.6 kcal/mol). This 0.7 kcal/mol difference is substantial and can outweigh some ADME drawbacks.

**Overall Assessment:**

Ligand A is favored due to its superior TPSA, logP, and significantly better binding affinity. While its BBB penetration is borderline, it's still better than Ligand B. The negative values for Caco-2 and solubility are concerning for both, but the affinity advantage of A is substantial. Ligand B has better metabolic stability (negative Cl_mic), but its lower logP and weaker binding affinity are significant drawbacks, especially for a CNS target. The nonsensical half-life value for ligand A is a red flag, but the overall profile is still better than B.

Output:
1
2025-04-17 05:39:18,124 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (350.503 and 350.507 Da) fall comfortably within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (69.64) is slightly above the optimal <90 for CNS targets, but still reasonable. Ligand B (50.6) is excellent, well below 90.

**3. logP:** Both ligands (2.491 and 2.249) are within the optimal 1-3 range.

**4. H-Bond Donors:** Ligand A (2) and Ligand B (0) are both acceptable, below the limit of 5.

**5. H-Bond Acceptors:** Ligand A (3) and Ligand B (5) are both acceptable, below the limit of 10.

**6. QED:** Both ligands (0.693 and 0.757) have good drug-likeness scores, exceeding the 0.5 threshold.

**7. DILI:** Ligand A (13.3) and Ligand B (12.796) both have very low DILI risk, well below the 40 threshold.

**8. BBB:** This is a critical parameter for a CNS target like DRD2. Ligand A (67.546) is decent, but Ligand B (80.884) is significantly better, exceeding the desirable >70 threshold.

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.914 and -4.664), which is unusual and suggests poor permeability. However, these values are on a log scale and are difficult to interpret without knowing the original units. We'll need to consider this with caution.

**10. Aqueous Solubility:** Both ligands have negative solubility values (-2.81 and -0.637), which is also unusual. Similar to Caco-2, these values are on a log scale and are difficult to interpret without knowing the original units.

**11. hERG Inhibition:** Both ligands (0.225 and 0.57) have low hERG inhibition liability, which is favorable.

**12. Microsomal Clearance:** Ligand A (39.267) and Ligand B (42.095) have moderate microsomal clearance. Lower is preferred, but these aren't alarmingly high.

**13. In vitro Half-Life:** Ligand A (0.851) has a very short half-life, which is a significant drawback. Ligand B (11.737) has a much more reasonable half-life.

**14. P-gp Efflux:** Both ligands (0.075 and 0.067) have low P-gp efflux, which is good for CNS penetration.

**15. Binding Affinity:** Ligand A (-7.9 kcal/mol) has a significantly stronger binding affinity than Ligand B (-6.7 kcal/mol). This is a substantial difference (1.2 kcal/mol), which can outweigh some ADME concerns.

**Overall Assessment:**

While Ligand A has superior binding affinity, Ligand B has a much better BBB penetration score, a longer half-life, and a more favorable TPSA. The negative Caco-2 and solubility values for both are concerning, but the significant affinity advantage of Ligand A is compelling. However, the extremely short half-life of Ligand A is a major issue, as it would likely require very frequent dosing. Considering the GPCR-specific priorities, BBB penetration is crucial for CNS targets, and Ligand B excels in this area. The affinity difference, while substantial, might be overcome with further optimization of Ligand B.

Output:
1
2025-04-17 05:39:18,124 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (349.406) is slightly lower, which could be beneficial for permeability.

**TPSA:** Ligand A (66.65) is excellent for CNS penetration, well below the 90 A^2 threshold. Ligand B (93.99) is higher, but still potentially acceptable, though less ideal.

**logP:** Ligand A (2.036) is optimal. Ligand B (4.25) is pushing the upper limit and could present solubility issues or off-target interactions.

**H-Bond Donors/Acceptors:** Ligand A (0 HBD, 4 HBA) is favorable. Ligand B (1 HBD, 5 HBA) is also acceptable, but slightly higher.

**QED:** Ligand A (0.834) is very good, indicating high drug-likeness. Ligand B (0.483) is lower, suggesting a less favorable overall drug-like profile.

**DILI:** Ligand A (34.277) has a low DILI risk. Ligand B (50.291) is slightly higher, but still within an acceptable range.

**BBB:** Ligand A (83.288) has excellent BBB penetration potential. Ligand B (69.833) is lower, which is a significant drawback for a CNS target like DRD2.

**Caco-2 Permeability:** Ligand A (-4.709) is poor. Ligand B (-5.185) is also poor, but slightly worse.

**Aqueous Solubility:** Both ligands have poor aqueous solubility (-1.87 and -3.387 respectively).

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.372 and 0.298 respectively).

**Microsomal Clearance:** Ligand A (32.467) and Ligand B (35.748) are similar, indicating moderate metabolic clearance.

**In vitro Half-Life:** Ligand A (-9.132) has a longer half-life than Ligand B (1.907).

**P-gp Efflux:** Ligand A (0.147) has low P-gp efflux, which is good for CNS penetration. Ligand B (0.185) also has low P-gp efflux.

**Binding Affinity:** Ligand A (-9.2 kcal/mol) has a significantly stronger binding affinity than Ligand B (-8.4 kcal/mol). This 0.8 kcal/mol difference is substantial and can outweigh some ADME drawbacks.

**Overall Assessment:**

Ligand A is superior due to its excellent BBB penetration, optimal logP, very good QED, strong binding affinity, and low DILI risk. While both have poor Caco-2 permeability and solubility, the strong affinity and CNS penetration potential of Ligand A make it a more promising candidate for a DRD2-targeting drug. Ligand B's higher logP and lower BBB penetration are significant concerns.

Output:
1
2025-04-17 05:39:18,124 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands are within the acceptable range (200-500 Da). Ligand A (354.395 Da) is slightly lower, which can be advantageous for permeability.

**2. TPSA:** Both ligands have TPSA values below 140, suggesting reasonable oral absorption. However, for a CNS target like DRD2, we ideally want TPSA < 90. Ligand A (93.87) is closer to this threshold than Ligand B (97.19).

**3. logP:** Both ligands have logP values between 1 and 3 (1.464 and 1.684 respectively), which is optimal.

**4. H-Bond Donors:** Both ligands are within the acceptable limit of 5. Ligand A has 0 HBD, while Ligand B has 1.

**5. H-Bond Acceptors:** Both ligands are within the acceptable limit of 10. Ligand A has 8 HBA, and Ligand B has 7.

**6. QED:** Both ligands have QED values above 0.5, indicating good drug-like properties (0.659 and 0.755 respectively).

**7. DILI:** Both ligands have relatively high DILI risk, but Ligand B (86.855) is lower than Ligand A (94.106), indicating a slightly lower potential for liver injury.

**8. BBB:** This is a critical parameter for CNS targets. Ligand A has a BBB percentile of 51.687, while Ligand B has 39.24. Ligand A is significantly better in terms of BBB penetration.

**9. Caco-2 Permeability:** Both have negative values, which is unusual. Lower values indicate poorer permeability. Ligand A (-5.051) is slightly better than Ligand B (-5.24).

**10. Aqueous Solubility:** Both ligands have very poor aqueous solubility (-2.65 and -3.139 respectively). This is a significant drawback.

**11. hERG Inhibition:** Both ligands have low hERG inhibition risk (0.185 and 0.216 respectively).

**12. Microsomal Clearance:** Ligand B (54.731) has higher microsomal clearance than Ligand A (29.986), suggesting lower metabolic stability.

**13. In vitro Half-Life:** Ligand A (-35.969) has a much longer in vitro half-life than Ligand B (-13.099).

**14. P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.19 and 0.106 respectively), which is good for CNS penetration.

**15. Binding Affinity:** Both ligands have very similar and strong binding affinities (-8.7 and -8.5 kcal/mol). The difference is less than the 1.5 kcal/mol threshold.

**Overall Assessment:**

While both ligands have good binding affinity and acceptable logP values, Ligand A is preferable due to its better BBB penetration, longer half-life, lower microsomal clearance, and slightly better Caco-2 permeability. The slightly higher DILI risk for Ligand A is a concern, but the improvements in CNS-relevant properties outweigh this drawback. The poor solubility of both compounds is a major issue that would need to be addressed during lead optimization.

Output:
0
2025-04-17 05:39:18,124 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (346.391 and 346.475 Da) fall comfortably within the ideal 200-500 Da range.

**TPSA:** Ligand A (134.65) is slightly above the optimal <90 for CNS targets, but still reasonable. Ligand B (78.35) is excellent, well below 90.

**logP:** Ligand A (-0.687) is a bit low, potentially hindering permeability. Ligand B (1.898) is within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Both ligands have acceptable HBD (3 and 2 respectively) and HBA (5 each) counts, well within the guidelines.

**QED:** Both ligands have good QED scores (0.666 and 0.752), indicating good drug-like properties.

**DILI:** Ligand A (44.126) has a moderate DILI risk, while Ligand B (13.532) has a very low risk. This is a significant advantage for Ligand B.

**BBB:** Ligand A (58.511) has a BBB penetration percentile that is below the desirable >70 for CNS targets. Ligand B (68.282) is closer, but still below the ideal threshold.

**Caco-2 Permeability:** Both have negative Caco-2 values (-5.406 and -5.043), which is unusual and indicates poor permeability. This is a major concern for both.

**Aqueous Solubility:** Both ligands have negative solubility values (-1.838 and -2.25), which is also concerning and suggests poor solubility.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.152 and 0.281).

**Microsomal Clearance:** Ligand A (-17.951) has a much lower (better) microsomal clearance than Ligand B (33.473), suggesting greater metabolic stability.

**In vitro Half-Life:** Ligand A (-11.261) has a negative half-life, which is not possible and indicates an issue with the data. Ligand B (5.019) has a short half-life, which is less desirable.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.002 and 0.103), which is good for CNS penetration.

**Binding Affinity:** Ligand B (-7.5 kcal/mol) has a significantly stronger binding affinity than Ligand A (-9.1 kcal/mol). This is a substantial advantage, potentially outweighing some ADME concerns.

**Overall Assessment:**

Ligand B is the more promising candidate. While both have issues with Caco-2 permeability and solubility, Ligand B has a significantly better binding affinity, lower DILI risk, and a more favorable logP. The slightly better BBB penetration of Ligand B is also a plus. Ligand A's negative half-life is a data quality issue and raises concerns. The superior affinity of Ligand B is a key factor, as a strong binding advantage can often compensate for minor ADME deficiencies, especially in the context of GPCR targets where achieving sufficient target engagement is crucial.

Output:
1
2025-04-17 05:39:18,124 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (347.375 and 359.817 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (111.28) is slightly above the optimal <90 for CNS targets, but still reasonable. Ligand B (95.84) is excellent, well within the desired range.

**3. logP:** Ligand A (1.186) is within the optimal 1-3 range. Ligand B (3.133) is at the higher end of optimal, but still acceptable.

**4. H-Bond Donors:** Ligand A (2) and Ligand B (3) are both within the acceptable limit of <=5.

**5. H-Bond Acceptors:** Ligand A (7) and Ligand B (5) are both within the acceptable limit of <=10.

**6. QED:** Ligand A (0.812) has a significantly better QED score than Ligand B (0.628), indicating higher overall drug-likeness.

**7. DILI:** Both ligands have similar and acceptable DILI risk (77.549 and 77.976 percentile).

**8. BBB:** Ligand A (65.529) has a lower BBB penetration percentile than Ligand B (71.229). While both are not ideal (>70), Ligand B is better.

**9. Caco-2 Permeability:** Both ligands have the same, very poor Caco-2 permeability (-5.196). This is a significant concern for oral bioavailability.

**10. Aqueous Solubility:** Both ligands have very poor aqueous solubility (-2.599 and -4.128). This is a major drawback for formulation and bioavailability.

**11. hERG Inhibition:** Ligand A (0.139) has a much lower hERG inhibition risk than Ligand B (0.813), which is a significant advantage.

**12. Microsomal Clearance:** Ligand A (31.875) has a lower microsomal clearance than Ligand B (39.005), indicating better metabolic stability.

**13. In vitro Half-Life:** Ligand B (36.154) has a significantly longer in vitro half-life than Ligand A (2.016). This is a positive attribute.

**14. P-gp Efflux:** Ligand A (0.022) has a much lower P-gp efflux liability than Ligand B (0.417), which is crucial for CNS penetration.

**15. Binding Affinity:** Ligand B (-9.1 kcal/mol) has a slightly better binding affinity than Ligand A (-8.9 kcal/mol). While the difference is small, it's a factor.

**Overall Assessment:**

Ligand B has a better BBB penetration and longer half-life. However, Ligand A demonstrates superior drug-likeness (QED), lower hERG risk, lower P-gp efflux, and better metabolic stability (lower Cl_mic). The slightly better affinity of Ligand B is outweighed by the more favorable ADME properties of Ligand A, especially the lower P-gp efflux which is critical for CNS targets. Both compounds have poor solubility and Caco-2 permeability, which would need to be addressed during optimization.

Output:
0
2025-04-17 05:39:18,125 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (374.522 and 371.547 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (69.64) is significantly better than Ligand B (78.51). For CNS targets, we want TPSA <= 90, and A is closer to the optimal <=60 range. B is pushing the upper limit.

**3. logP:** Both ligands have good logP values (1.841 and 1.618), falling within the 1-3 optimal range.

**4. H-Bond Donors:** Both have 2 HBD, which is acceptable (<=5).

**5. H-Bond Acceptors:** Both have 4 HBA, which is acceptable (<=10).

**6. QED:** Both have good QED scores (0.573 and 0.604), indicating drug-likeness.

**7. DILI:** Ligand A (13.843) has a much lower DILI risk than Ligand B (19.271). Both are below 40, which is good, but A is preferable.

**8. BBB:** This is crucial for a CNS target like DRD2. Ligand A (81.233) has a significantly higher BBB penetration percentile than Ligand B (62.699). A value >70 is desirable, and A is much closer.

**9. Caco-2 Permeability:** Both have negative values (-5.039 and -5.478), indicating poor permeability. This is a concern for both, but the values are similar.

**10. Aqueous Solubility:** Both have negative values (-2.592 and -2.118), indicating poor solubility. This is a concern for both, but the values are similar.

**11. hERG Inhibition:** Both ligands have low hERG inhibition liability (0.71 and 0.638), which is good.

**12. Microsomal Clearance:** Ligand A (38.692) has higher microsomal clearance than Ligand B (24.196), meaning faster metabolism and potentially lower *in vivo* exposure. This favors Ligand B.

**13. In vitro Half-Life:** Ligand B (-31.835) has a much longer in vitro half-life than Ligand A (-12.028). This is a significant advantage for B.

**14. P-gp Efflux:** Both have very low P-gp efflux liability (0.203 and 0.071), which is good for CNS penetration.

**15. Binding Affinity:** Ligand B (-8.5 kcal/mol) has a slightly better binding affinity than Ligand A (-7.7 kcal/mol). While A is still good, the 0.8 kcal/mol difference is notable.

**Overall Assessment:**

Ligand A excels in TPSA, BBB, and DILI risk, which are highly important for a CNS GPCR target. Ligand B has a better binding affinity and a longer half-life, and lower Cl_mic. However, the superior BBB penetration of Ligand A is a critical advantage for targeting DRD2 in the brain. The slightly better affinity of B is less important than the improved CNS exposure predicted for A. The poor Caco-2 and solubility for both are drawbacks that would need to be addressed in further optimization, but are less critical than CNS penetration for this target.

Output:
1
2025-04-17 05:39:18,125 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 drug candidates, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (343.471 and 371.865 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (73.99) is significantly better than Ligand B (87.74). For CNS targets, we want TPSA <= 90, and A is closer to the ideal.

**3. logP:** Both ligands have good logP values (2.972 and 1.907), falling within the optimal 1-3 range. Ligand A is slightly higher, which could be beneficial for membrane permeability.

**4. H-Bond Donors:** Both ligands have a reasonable number of HBDs (3 and 2 respectively), well within the acceptable limit of <=5.

**5. H-Bond Acceptors:** Ligand A (2) is better than Ligand B (4), keeping the total H-bond count lower, which is generally favorable for permeability.

**6. QED:** Both ligands have good QED scores (0.571 and 0.715), indicating good drug-like properties.

**7. DILI:** Ligand A (27.026) has a lower DILI risk than Ligand B (35.983), which is preferable. Both are below the concerning threshold of 60.

**8. BBB:** Ligand B (75.107) has a slightly better BBB penetration percentile than Ligand A (69.484), but both are reasonably good, exceeding the 70% threshold.

**9. Caco-2 Permeability:** Ligand A (-4.824) has a worse Caco-2 permeability than Ligand B (-4.657). Higher values are better.

**10. Aqueous Solubility:** Ligand A (-3.844) has a worse aqueous solubility than Ligand B (-2.124). Higher values are better.

**11. hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.415 and 0.2), which is excellent.

**12. Microsomal Clearance:** Ligand A (54.021) has lower microsomal clearance than Ligand B (61.427), suggesting better metabolic stability.

**13. In vitro Half-Life:** Ligand B (8.235) has a better in vitro half-life than Ligand A (-13.24).

**14. P-gp Efflux:** Both ligands have low P-gp efflux liability (0.096 and 0.086), which is good for CNS penetration.

**15. Binding Affinity:** Ligand B (-7.7) has a slightly better binding affinity than Ligand A (-8.0). While both are excellent, the difference is minimal.

**Overall Assessment:**

Ligand A excels in TPSA, DILI, and metabolic stability (Cl_mic). Ligand B has a slightly better BBB, half-life, and Caco-2 permeability. The binding affinity difference is negligible. Given the importance of CNS penetration for a DRD2 target, and the slightly better BBB score of Ligand B, combined with its better half-life, it appears to be a slightly more promising candidate. However, the lower TPSA and DILI of Ligand A are also very attractive. Ultimately, the slightly better BBB and half-life of Ligand B outweigh the advantages of Ligand A.

Output:
1
2025-04-17 05:39:18,125 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (382.291 and 362.495 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Both ligands have TPSA values (71.09 and 69.64) below the 90 A^2 threshold for CNS targets, which is excellent.

**3. logP:** Both ligands have logP values (2.954 and 2.434) within the optimal 1-3 range.

**4. H-Bond Donors:** Both have 2 HBD, which is acceptable.

**5. H-Bond Acceptors:** Ligand A has 3 HBA, and Ligand B has 4 HBA, both are below the 10 threshold.

**6. QED:** Both ligands have good QED scores (0.77 and 0.791), indicating good drug-like properties.

**7. DILI:** Ligand A (44.552) has a slightly higher DILI risk than Ligand B (32.61), but both are below the concerning 60 percentile.

**8. BBB:** Ligand A (67.623) has a better BBB penetration percentile than Ligand B (60.333). While both are reasonably good, DRD2 is a CNS target, so higher BBB is preferred.

**9. Caco-2 Permeability:** Both have negative Caco-2 values (-5.047 and -5.034), which is unusual and suggests poor permeability. This is a significant concern.

**10. Aqueous Solubility:** Both have negative solubility values (-4.249 and -3.824), indicating very poor aqueous solubility. This is a major drawback.

**11. hERG Inhibition:** Both ligands have low hERG inhibition liability (0.331 and 0.405), which is positive.

**12. Microsomal Clearance:** Ligand A (12.496) has significantly lower microsomal clearance than Ligand B (53.497), suggesting better metabolic stability.

**13. In vitro Half-Life:** Ligand A (13.876 hours) has a much longer in vitro half-life than Ligand B (6.695 hours), which is a significant advantage.

**14. P-gp Efflux:** Both ligands have low P-gp efflux liability (0.083 and 0.107), which is favorable for CNS penetration.

**15. Binding Affinity:** Ligand A (-9.4 kcal/mol) has a significantly stronger binding affinity than Ligand B (-7.5 kcal/mol). This is a substantial advantage (1.9 kcal/mol difference), potentially outweighing some of the ADME drawbacks.

**Overall Assessment:**

Despite the poor Caco-2 and solubility for both, Ligand A is the more promising candidate. Its superior binding affinity (-9.4 vs -7.5 kcal/mol), better BBB penetration (67.623 vs 60.333), lower microsomal clearance (12.496 vs 53.497), and longer half-life (13.876 vs 6.695) make it a more attractive starting point for optimization. While the solubility and permeability issues need to be addressed, the strong affinity and favorable CNS properties of Ligand A are more likely to lead to a viable drug candidate for a CNS target like DRD2.

Output:
1
2025-04-17 05:39:18,125 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight (MW):** Both ligands (341.415 and 352.431 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (90.98) is excellent, falling below the 90 threshold for CNS targets. Ligand B (96.89) is still reasonable but slightly higher.

**3. logP:** Ligand A (1.404) is optimal. Ligand B (0.273) is quite low, potentially hindering membrane permeability.

**4. H-Bond Donors (HBD):** Both ligands are within the acceptable limit of 5 (A: 2, B: 3).

**5. H-Bond Acceptors (HBA):** Both ligands are within the acceptable limit of 10 (A: 4, B: 5).

**6. QED:** Both ligands have acceptable QED values (A: 0.831, B: 0.572), indicating good drug-like properties.

**7. DILI:** Both ligands have low DILI risk (A: 52.385, B: 33.773), which is favorable.

**8. BBB:** Ligand B (41.566) has a better BBB percentile than Ligand A (29.934). This is a critical factor for CNS targets like DRD2.

**9. Caco-2:** Both have negative Caco-2 values, which is unusual and suggests poor permeability. This is a concern for both.

**10. Solubility:** Both have negative solubility values, suggesting poor solubility. This is a concern for both.

**11. hERG:** Both have very low hERG risk (A: 0.44, B: 0.115).

**12. Cl_mic:** Ligand A (-19.716) has significantly lower (better) microsomal clearance than Ligand B (3.896). This indicates better metabolic stability for Ligand A.

**13. t1/2:** Ligand B (22.393) has a longer in vitro half-life than Ligand A (-15.196).

**14. Pgp:** Both have very low Pgp efflux liability (A: 0.026, B: 0.02).

**15. Binding Affinity:** Ligand B (-7.9) has a slightly better binding affinity than Ligand A (-8.7). However, the difference is relatively small.

**Overall Assessment:**

Ligand B has a better BBB penetration and slightly better binding affinity, which are important for a CNS GPCR target. However, its low logP is a significant concern, potentially leading to poor permeability. Ligand A has a better logP and significantly better metabolic stability (lower Cl_mic), but its BBB penetration is lower. Considering the importance of BBB for CNS targets, and the relatively small difference in binding affinity, Ligand B is slightly more promising, *assuming* the low logP can be addressed through structural modifications. However, the negative Caco-2 and solubility values are concerning for both.

Output:
1
2025-04-17 05:39:18,126 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (429.742 Da) is higher, but still acceptable. Ligand B (361.848 Da) is slightly better.

**TPSA:** Both ligands have TPSA values (A: 49.85, B: 45.23) below the 90 A^2 threshold for CNS targets, which is excellent. Ligand B is slightly preferable.

**logP:** Both ligands have logP values within the optimal range (1-3). Ligand A (3.483) is at the higher end, while Ligand B (4.763) is slightly above the ideal range. This could potentially lead to solubility issues for Ligand B, but it's not a severe concern.

**H-Bond Donors & Acceptors:** Ligand A (0 HBD, 3 HBA) and Ligand B (1 HBD, 2 HBA) both fall within the acceptable ranges (<=5 HBD, <=10 HBA).

**QED:** Both ligands have good QED scores (A: 0.736, B: 0.783), indicating good drug-like properties. Ligand B is slightly better.

**DILI:** Both ligands have DILI risk above 40, but below 60, indicating moderate risk. Ligand A (58.976) is slightly higher than Ligand B (60.14), but the difference is minimal.

**BBB:** This is crucial for a CNS target like DRD2. Ligand A (73.168) and Ligand B (85.072) both have good BBB penetration, but Ligand B is significantly better, exceeding 80%.

**Caco-2 Permeability:** Both ligands show poor Caco-2 permeability (A: -4.833, B: -4.6). This suggests potential absorption issues.

**Aqueous Solubility:** Both ligands have poor aqueous solubility (A: -4.317, B: -6.356). Ligand B is worse.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (A: 0.562, B: 0.35), which is favorable. Ligand B is slightly better.

**Microsomal Clearance:** Ligand A (41.638 mL/min/kg) has a lower clearance than Ligand B (74.31 mL/min/kg), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (13.622 hours) has a longer half-life than Ligand B (-0.978 hours). This is a significant advantage for Ligand A.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (A: 0.688, B: 0.269). Ligand B is significantly better, indicating better potential for CNS exposure.

**Binding Affinity:** This is the most important factor. Ligand B (-9.4 kcal/mol) has a significantly stronger binding affinity than Ligand A (-7.5 kcal/mol) - a difference of 1.9 kcal/mol. This difference is substantial enough to outweigh some of the ADME drawbacks of Ligand B.

**Overall:**

Ligand B excels in key GPCR properties: BBB penetration, P-gp efflux, and, most importantly, binding affinity. While it has slightly worse solubility and higher logP, the significantly stronger binding affinity and better CNS penetration make it the more promising candidate. Ligand A has better metabolic stability and half-life, but the affinity difference is too large to ignore.

Output:
1
2025-04-17 05:39:18,126 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (339.351 Da) is slightly preferred due to being closer to the lower end, potentially aiding permeability.

**TPSA:** Ligand A (102.66) is better than Ligand B (58.2). For CNS targets, TPSA should be <=90. Both are within this range, but Ligand B is significantly lower, which is highly favorable for brain penetration.

**logP:** Ligand A (0.678) is suboptimal, being below the preferred 1-3 range. Ligand B (3.934) is excellent, falling right within the optimal range. This is a significant advantage for Ligand B.

**H-Bond Donors/Acceptors:** Both have 2 HBDs, which is good. Ligand A has 5 HBAs, while Ligand B has 2. Lower HBA is generally preferred for better permeability, giving Ligand B an edge.

**QED:** Ligand A (0.788) has a better QED score than Ligand B (0.487), indicating a more drug-like profile.

**DILI:** Ligand A (76.154) has a higher DILI risk than Ligand B (42.148). Ligand B is clearly preferred here.

**BBB:** Ligand A (33.579) has a very poor BBB penetration score. Ligand B (82.513) is excellent, exceeding the desirable >70 threshold for CNS targets. This is a critical advantage for Ligand B.

**Caco-2:** Both have negative Caco-2 values, which is unusual and difficult to interpret without knowing the scale. We'll proceed cautiously, noting this as a potential issue for both.

**Solubility:** Both have negative solubility values, again, making interpretation difficult.

**hERG:** Both ligands have low hERG inhibition liability (0.306 and 0.425 respectively), which is good.

**Microsomal Clearance:** Ligand A (-19.04) has a much lower (better) microsomal clearance than Ligand B (53.171). This suggests better metabolic stability for Ligand A.

**In vitro Half-Life:** Ligand A (-15.03) has a negative half-life, which is problematic. Ligand B (18.172) has a reasonable half-life.

**P-gp Efflux:** Ligand A (0.035) has very low P-gp efflux, which is excellent. Ligand B (0.343) is also relatively low, but higher than Ligand A.

**Binding Affinity:** Ligand A (-9.6) has a significantly stronger binding affinity than Ligand B (-8.0). This is a substantial advantage for Ligand A, potentially outweighing some ADME drawbacks.

**Overall Assessment:**

Ligand B excels in properties crucial for CNS penetration (logP, BBB, TPSA) and has a better safety profile (lower DILI). However, Ligand A has a significantly stronger binding affinity and better metabolic stability (lower Cl_mic and P-gp efflux). The negative half-life for Ligand A is a major concern. The superior binding affinity of Ligand A (-9.6 vs -8.0 kcal/mol) is a substantial advantage, and could potentially overcome some of the ADME liabilities, *if* the half-life issue can be addressed through structural modification. However, the excellent BBB penetration of Ligand B is a huge advantage for a CNS target like DRD2. Considering the importance of BBB penetration for CNS drugs, and the concerning negative half-life of Ligand A, I favor Ligand B.

Output:
1
2025-04-17 05:39:18,126 - INFO - Batch 216 complete. Total preferences: 3456
2025-04-17 05:39:18,126 - INFO - Processing batch 217/512...
2025-04-17 05:39:58,648 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (349.475 and 348.443 Da) fall comfortably within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (74.57) and Ligand B (75.71) are both below the 90 A^2 threshold desirable for CNS targets, which is excellent.

**3. logP:** Both ligands have logP values within the optimal range (Ligand A: 1.699, Ligand B: 1.508).

**4. H-Bond Donors:** Ligand A has 2 HBD, and Ligand B has 1. Both are within the acceptable limit of <=5.

**5. H-Bond Acceptors:** Both ligands have 4 HBA, well below the limit of <=10.

**6. QED:** Ligand A (0.85) has a significantly better QED score than Ligand B (0.448), indicating a more drug-like profile.

**7. DILI:** Ligand A (16.092) has a much lower DILI risk than Ligand B (25.785), suggesting better potential for avoiding liver toxicity.

**8. BBB:** Ligand B (63.009) has a better BBB penetration percentile than Ligand A (53.974), which is a key consideration for a CNS target like DRD2.

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.875 and -4.641), which is unusual and suggests poor permeability. However, these values are on a scale where negative values are possible, and direct comparison is difficult without knowing the scale's specifics.

**10. Aqueous Solubility:** Both ligands have negative solubility values (-2.176 and -2.038), which is also unusual and suggests poor solubility. Similar to Caco-2, the scale is unknown, making direct comparison difficult.

**11. hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.168 and 0.113).

**12. Microsomal Clearance:** Ligand A (11.481) has a significantly lower microsomal clearance than Ligand B (40.883), indicating better metabolic stability.

**13. In vitro Half-Life:** Ligand A (-12.658) has a negative half-life which is not possible. Ligand B (-19.274) also has a negative half-life. This is a major red flag for both compounds.

**14. P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.056 and 0.043), which is favorable for CNS penetration.

**15. Binding Affinity:** Ligand A (-8.3 kcal/mol) has a better binding affinity than Ligand B (-6.4 kcal/mol). This is a substantial difference (1.9 kcal/mol) and can outweigh some ADME drawbacks.

**Overall Assessment:**

Despite the unusual negative values for Caco-2 and Solubility, Ligand A is the more promising candidate. Its significantly better QED, lower DILI risk, lower microsomal clearance (better metabolic stability), and substantially stronger binding affinity to DRD2 outweigh Ligand B's slightly better BBB penetration. The negative half-life values are concerning for both, but the superior binding affinity of Ligand A makes it the better starting point for optimization, assuming the negative half-life can be addressed.

Output:
0
2025-04-17 05:39:58,648 - INFO - Reasoning:

Let's analyze Ligand A and Ligand B for their potential as DRD2 drug candidates, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (370.739 and 344.459 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (77.4) is slightly above the optimal <90 for CNS targets, but still reasonable. Ligand B (65.54) is well within the desired range.

**3. logP:** Both ligands have good logP values (2.865 and 2.201), falling within the 1-3 range.

**4. H-Bond Donors:** Both have 1 HBD, which is acceptable.

**5. H-Bond Acceptors:** Ligand A has 5 HBAs, and Ligand B has 4. Both are within the acceptable limit of <=10.

**6. QED:** Both ligands have high QED scores (0.821 and 0.889), indicating good drug-like properties.

**7. DILI:** Ligand A has a DILI risk of 87.01, which is high. Ligand B has a much lower DILI risk of 42.536, which is preferable.

**8. BBB:** Ligand A has a BBB penetration of 68.941, which is borderline for a CNS target. Ligand B has a significantly better BBB penetration of 81.97, making it more promising for CNS activity.

**9. Caco-2 Permeability:** Both have negative Caco-2 values (-4.723 and -4.711), which is unusual and suggests poor permeability. However, these values are on a log scale and can be misleading without context.

**10. Aqueous Solubility:** Both have negative solubility values (-4.299 and -2.557), suggesting poor aqueous solubility. This is a concern for bioavailability.

**11. hERG Inhibition:** Both have low hERG inhibition liability (0.308 and 0.454), which is good.

**12. Microsomal Clearance:** Ligand A (45.462) has higher microsomal clearance than Ligand B (31.428), indicating lower metabolic stability.

**13. In vitro Half-Life:** Ligand A (48.988) has a longer in vitro half-life than Ligand B (16.779), which is a positive.

**14. P-gp Efflux:** Both have low P-gp efflux liability (0.252 and 0.03), which is favorable for CNS penetration.

**15. Binding Affinity:** Ligand A (-8.6 kcal/mol) has a significantly stronger binding affinity than Ligand B (-7.6 kcal/mol). This is a substantial advantage, potentially outweighing some of its ADME drawbacks.

**Overall Assessment:**

While Ligand A boasts a superior binding affinity, its high DILI risk and borderline BBB penetration are significant concerns. Ligand B, despite a slightly weaker affinity, presents a much more favorable ADME profile, particularly with its lower DILI risk and better BBB penetration. Given the GPCR-specific priorities for CNS targets, and the importance of minimizing toxicity, Ligand B is the more promising candidate. The difference in binding affinity (1 kcal/mol) is not large enough to overcome the substantial ADME advantages of Ligand B.

Output:
1
2025-04-17 05:39:58,649 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (351.451 and 345.487 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (97.28) is slightly above the optimal <90 for CNS targets, but still reasonable. Ligand B (52.65) is excellent, well below 90.

**logP:** Both ligands have good logP values (1.246 and 1.788), falling within the 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A has 3 HBD and 5 HBA, which are acceptable. Ligand B has 1 HBD and 3 HBA, also acceptable.

**QED:** Both ligands have good QED scores (0.672 and 0.773), indicating good drug-like properties.

**DILI:** Ligand A (40.83) has a slightly higher DILI risk than Ligand B (9.151), but both are below the concerning threshold of 60.

**BBB:** Ligand B (83.676) has a significantly better BBB penetration score than Ligand A (71.268). This is a crucial advantage for a CNS target like DRD2.

**Caco-2 Permeability:** Both have negative Caco-2 values which is unusual and suggests poor permeability. However, the values are close enough that this isn't a major differentiator.

**Aqueous Solubility:** Both ligands have poor aqueous solubility (-1.782 and -2.656). This could pose formulation challenges.

**hERG Inhibition:** Ligand A (0.044) has a very low hERG inhibition risk, which is excellent. Ligand B (0.393) has a slightly higher, but still relatively low, hERG risk.

**Microsomal Clearance:** Both ligands have similar microsomal clearance values (27.812 and 28.763), suggesting comparable metabolic stability.

**In vitro Half-Life:** Ligand B (15.07) has a shorter half-life than Ligand A (37.695). This is a drawback for Ligand B.

**P-gp Efflux:** Ligand A (0.018) has very low P-gp efflux, which is excellent for CNS penetration. Ligand B (0.065) also has low P-gp efflux, but slightly higher than A.

**Binding Affinity:** Ligand B (-8.2 kcal/mol) has a significantly stronger binding affinity than Ligand A (-0.0 kcal/mol). This is a major advantage, potentially outweighing some of the other drawbacks.

**Conclusion:**

While Ligand A has a better half-life and slightly better P-gp efflux, Ligand B's superior BBB penetration and *much* stronger binding affinity are decisive. The strong binding affinity of Ligand B is a significant advantage for a GPCR target, and the high BBB score suggests it will reach the target in the CNS. The slightly shorter half-life and higher DILI risk are less concerning than the poor affinity of Ligand A.

Output:
1
2025-04-17 05:39:58,649 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 drug candidates, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (338.331 Da) is slightly lower, which could be beneficial for permeability.

**TPSA:** Ligand A (129.65) is closer to the ideal range for CNS targets (<=90) than Ligand B (58.12). This suggests better potential for brain penetration.

**logP:** Ligand A (-0.674) is a bit low, potentially hindering permeation. Ligand B (3.573) is within the optimal range (1-3).

**H-Bond Donors/Acceptors:** Ligand A (HBD=2, HBA=7) and Ligand B (HBD=1, HBA=5) both fall within acceptable limits.

**QED:** Both ligands have good QED scores (A: 0.645, B: 0.805), indicating drug-like properties.

**DILI:** Ligand A (85.576) has a higher DILI risk than Ligand B (50.174). This is a significant drawback for Ligand A.

**BBB:** Ligand B (83.637) has a substantially better BBB percentile than Ligand A (23.071). This is a critical advantage for a CNS target like DRD2.

**Caco-2 Permeability:** Both have negative values, indicating poor permeability. Ligand A (-5.767) is slightly better than Ligand B (-4.761) but both are concerning.

**Aqueous Solubility:** Both have negative values, indicating poor solubility. Ligand A (-2.59) is slightly better than Ligand B (-4.841).

**hERG Inhibition:** Both have low hERG inhibition risk (A: 0.134, B: 0.262).

**Microsomal Clearance:** Ligand A (-6.287) has much lower (better) microsomal clearance than Ligand B (76.588), indicating greater metabolic stability.

**In vitro Half-Life:** Ligand B (43.996) has a significantly longer half-life than Ligand A (-1.56).

**P-gp Efflux:** Both ligands have very low P-gp efflux (A: 0.003, B: 0.4).

**Binding Affinity:** Both ligands have excellent binding affinities (A: -8.8 kcal/mol, B: -9.1 kcal/mol). The difference is minimal.

**Overall Assessment:**

Ligand B is the stronger candidate. While Ligand A has better metabolic stability (lower Cl_mic), the significantly better BBB penetration, lower DILI risk, and longer half-life of Ligand B outweigh this advantage. The slightly higher logP of Ligand B is also favorable. Although both have poor Caco-2 and solubility, the CNS target prioritizes BBB penetration, and Ligand B excels in this area. The affinities are comparable, so the ADME properties are the deciding factor.

Output:
1
2025-04-17 05:39:58,649 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (366.53 and 350.55 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (67.43) is slightly higher than the ideal <90 for CNS targets, but still reasonable. Ligand B (58.2) is excellent, well below 90.

**3. logP:** Both ligands have logP values within the optimal range (2.55 and 4.04). Ligand B is a bit higher, potentially raising concerns about solubility and off-target effects, but not critically.

**4. H-Bond Donors:** Both ligands have 2 HBD, which is within the acceptable limit of <=5.

**5. H-Bond Acceptors:** Ligand A has 4 HBA, and Ligand B has 2 HBA, both are within the acceptable limit of <=10.

**6. QED:** Both ligands have QED values above 0.5 (0.785 and 0.694), indicating good drug-like properties.

**7. DILI:** Ligand A (47.15) has a higher DILI risk than Ligand B (18.30). This is a significant advantage for Ligand B.

**8. BBB:** Ligand B (84.22) has a significantly better BBB penetration score than Ligand A (68.75). This is crucial for a CNS target like DRD2.

**9. Caco-2 Permeability:** Ligand A (-5.169) has a negative Caco-2 value, which is unusual and suggests poor permeability. Ligand B (-4.542) is also negative, but less so.

**10. Aqueous Solubility:** Both ligands have negative solubility values, indicating poor aqueous solubility. Ligand A (-3.638) is slightly better than Ligand B (-4.76).

**11. hERG Inhibition:** Both ligands have low hERG inhibition risk (0.178 and 0.533).

**12. Microsomal Clearance:** Ligand A (63.3) has lower microsomal clearance than Ligand B (82.7), suggesting better metabolic stability.

**13. In vitro Half-Life:** Ligand A (22.05) has a longer half-life than Ligand B (4.05).

**14. P-gp Efflux:** Both ligands have low P-gp efflux liability (0.107 and 0.161).

**15. Binding Affinity:** Both ligands have very similar and strong binding affinities (-8.3 and -8.1 kcal/mol). The difference is negligible.

**Overall Assessment:**

Ligand B is the stronger candidate. While Ligand A has slightly better metabolic stability and half-life, Ligand B excels in the most critical areas for a CNS GPCR target: BBB penetration (84.22 vs 68.75) and DILI risk (18.30 vs 47.15). The TPSA is also more favorable for Ligand B. The Caco-2 permeability is poor for both, but the overall profile of Ligand B is more promising for CNS drug development.

Output:
1
2025-04-17 05:39:58,649 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (353.467 and 348.447 Da) are within the ideal 200-500 Da range.

**TPSA:** Ligand A (107.77) is borderline for CNS penetration, being above the preferred <90, but still potentially acceptable. Ligand B (67.67) is excellent, well below 90, suggesting good CNS penetration.

**logP:** Ligand A (-0.96) is a bit low, potentially hindering membrane permeability. Ligand B (0.755) is within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A has 3 HBD and 5 HBA, which are reasonable. Ligand B has 0 HBD and 5 HBA, also reasonable.

**QED:** Ligand B (0.805) has a significantly better QED score than Ligand A (0.495), indicating a more drug-like profile.

**DILI:** Ligand A (5.196) has a very low DILI risk. Ligand B (24.351) is still acceptable, but higher than A.

**BBB:** Ligand B (63.474) has a better BBB percentile than Ligand A (42.458), although both are not optimal (>70 is preferred).

**Caco-2 Permeability:** Ligand A (-6.188) has poor Caco-2 permeability, indicating poor intestinal absorption. Ligand B (-4.68) is also poor, but slightly better than A.

**Aqueous Solubility:** Ligand A (-1.145) has poor aqueous solubility. Ligand B (0.045) is slightly better, but still low.

**hERG:** Both ligands have very low hERG inhibition risk (0.048 and 0.126).

**Microsomal Clearance:** Ligand A (-17.433) has a much lower (better) microsomal clearance than Ligand B (8.779), suggesting greater metabolic stability.

**In vitro Half-Life:** Ligand A (-23.452) has a much longer in vitro half-life than Ligand B (1.774), which is highly desirable.

**P-gp Efflux:** Both ligands show minimal P-gp efflux liability (0.0 and 0.03).

**Binding Affinity:** Ligand B (-8.5) has a slightly better binding affinity than Ligand A (-7.9), although the difference is not huge.

**Overall Assessment:**

Ligand B excels in TPSA, QED, and BBB, which are crucial for CNS GPCR targets. However, it suffers from poor Caco-2 permeability and aqueous solubility, and has a higher DILI risk and lower metabolic stability compared to Ligand A. Ligand A, while having a lower logP and BBB, compensates with significantly better metabolic stability (lower Cl_mic, longer t1/2), lower DILI risk, and better solubility. The slightly better affinity of Ligand B is unlikely to outweigh the ADME deficiencies. Considering the importance of metabolic stability and lower toxicity for CNS drugs, and the modest affinity difference, Ligand A appears to be the more promising candidate.

Output:
1
2025-04-17 05:39:58,650 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 drug candidates, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (348.393 and 361.511 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (61.36) is better than Ligand B (47.36) as it is closer to the ideal range of <90 for CNS targets.

**3. logP:** Both ligands have logP values around 4 (3.801 and 4.001). While slightly above the optimal 1-3 range, they aren't drastically high enough to be immediately concerning.

**4. H-Bond Donors:** Ligand A has 3 HBD, while Ligand B has 0. Both are within the acceptable limit of <=5.

**5. H-Bond Acceptors:** Ligand A has 2 HBA, and Ligand B has 5. Both are within the acceptable limit of <=10.

**6. QED:** Both ligands have good QED scores (0.667 and 0.714), indicating drug-like properties.

**7. DILI:** Ligand B (20.396) has a significantly lower DILI risk than Ligand A (44.281). This is a substantial advantage for Ligand B.

**8. BBB:** Ligand B (76.696) has a much better BBB penetration score than Ligand A (45.715). This is *critical* for a CNS target like DRD2.

**9. Caco-2 Permeability:** Ligand A (-4.972) shows better Caco-2 permeability than Ligand B (-4.578), but both are negative values which is unusual and requires further investigation.

**10. Aqueous Solubility:** Both ligands have similar poor aqueous solubility (-4.056 and -4.142). This could pose formulation challenges.

**11. hERG Inhibition:** Ligand A (0.878) has slightly higher hERG inhibition risk than Ligand B (0.527), but both are relatively low.

**12. Microsomal Clearance:** Ligand B (101.832) has significantly higher microsomal clearance than Ligand A (70.399), meaning it will be metabolized more quickly.

**13. In vitro Half-Life:** Ligand A (0.384) has a much shorter in vitro half-life than Ligand B (20.406). This is a significant drawback for Ligand A.

**14. P-gp Efflux:** Ligand A (0.611) has lower P-gp efflux than Ligand B (0.323), suggesting better CNS exposure.

**15. Binding Affinity:** Ligand A (-10.1 kcal/mol) has a *much* stronger binding affinity than Ligand B (-6.5 kcal/mol). This is a substantial advantage for Ligand A.

**Overall Assessment:**

While Ligand A boasts a significantly better binding affinity, Ligand B has superior ADME properties crucial for CNS drug development. Specifically, the much higher BBB penetration and lower DILI risk of Ligand B are very attractive. The longer half-life of Ligand B is also a major benefit. The higher metabolic clearance of Ligand B is a concern, but could potentially be addressed through structural modifications. The stronger affinity of Ligand A is tempting, but the poor BBB penetration and shorter half-life are significant hurdles. Given the GPCR-specific priorities, and the importance of CNS penetration for DRD2, Ligand B is the more promising candidate.

Output:
1
2025-04-17 05:39:58,650 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (341.415 and 352.475 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (90.98) is better than Ligand B (67.87). Both are below the 90 A^2 threshold for CNS targets, which is excellent.

**3. logP:** Both ligands have good logP values (1.891 and 1.725), falling within the optimal 1-3 range.

**4. H-Bond Donors:** Ligand A (2) is slightly higher than Ligand B (1), but both are within the acceptable limit of <=5.

**5. H-Bond Acceptors:** Both ligands have 4 H-bond acceptors, well within the acceptable limit of <=10.

**6. QED:** Both ligands have acceptable QED values (0.717 and 0.642), indicating good drug-like properties.

**7. DILI:** Ligand A (58.55) has a higher DILI risk than Ligand B (15.471). This is a significant advantage for Ligand B.

**8. BBB:** Both ligands have good BBB penetration (65.878% and 67.08%), exceeding the desirable threshold of >70% for CNS targets. While neither *exceeds* 70%, they are both reasonably good.

**9. Caco-2 Permeability:** Ligand A (-5.078) has worse Caco-2 permeability than Ligand B (-4.868). Higher values are better, so B is slightly preferred.

**10. Aqueous Solubility:** Ligand A (-3.582) has worse aqueous solubility than Ligand B (-2.157). Higher values are better, so B is slightly preferred.

**11. hERG Inhibition:** Ligand A (0.417) has a slightly lower hERG inhibition risk than Ligand B (0.621), which is preferable.

**12. Microsomal Clearance:** Ligand A (32.6) has slightly better microsomal clearance than Ligand B (30.247). Lower clearance is better, indicating greater metabolic stability.

**13. In vitro Half-Life:** Ligand A (-3.326) has a much longer in vitro half-life than Ligand B (11.343). This is a significant advantage for Ligand A.

**14. P-gp Efflux:** Ligand A (0.067) has lower P-gp efflux liability than Ligand B (0.154). Lower efflux is better, especially for CNS targets.

**15. Binding Affinity:** Ligand A (-8.8 kcal/mol) has a significantly stronger binding affinity than Ligand B (-7.7 kcal/mol). This >1.5 kcal/mol difference is a major advantage, potentially outweighing some ADME drawbacks.

**Overall Assessment:**

Ligand A has a significantly better binding affinity and longer half-life, along with better P-gp efflux and microsomal clearance. However, Ligand B has a much lower DILI risk and slightly better solubility and Caco-2 permeability. The strong binding affinity of Ligand A is a critical factor for GPCR ligands. The longer half-life is also very desirable. While the DILI risk for Ligand A is a concern, the substantial binding affinity advantage likely outweighs this risk, especially in early-stage drug discovery where optimization can address toxicity concerns.

Output:
1
2025-04-17 05:39:58,650 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (346.471 and 367.471 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (58.64) is excellent, well below the 90 A^2 threshold for CNS targets. Ligand B (91.76) is above this threshold, which is less favorable for CNS penetration.

**logP:** Ligand A (2.575) is within the optimal 1-3 range. Ligand B (0.735) is slightly below 1, potentially hindering permeation.

**H-Bond Donors/Acceptors:** Ligand A (1 HBD, 3 HBA) is good. Ligand B (3 HBD, 6 HBA) is also acceptable, but higher counts can sometimes impact permeability.

**QED:** Both ligands have good QED scores (0.569 and 0.645, respectively), indicating drug-like properties.

**DILI:** Ligand A (28.461) has a much lower DILI risk than Ligand B (72.199), which is a significant advantage.

**BBB:** Ligand A (75.107) has a good BBB percentile, exceeding the 70% threshold for CNS targets. Ligand B (18.961) is very low, indicating poor predicted brain penetration. This is a critical drawback for a DRD2 ligand.

**Caco-2 Permeability:** Both have negative values, which is unusual and could indicate issues with the prediction method or the molecule itself. However, the magnitude of the negative value for Ligand A (-4.805) is smaller than for Ligand B (-5.102), suggesting slightly better permeability.

**Aqueous Solubility:** Both have negative values, which is also unusual. Ligand A (-2.421) is slightly better than Ligand B (-1.694).

**hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.216 and 0.155).

**Microsomal Clearance:** Ligand A (35.914) has a moderate clearance, while Ligand B (0.102) has extremely low clearance, suggesting very high metabolic stability.

**In vitro Half-Life:** Ligand A (-2.108) has a negative half-life, which is not possible and likely an artifact of the prediction. Ligand B (4.656) has a reasonable half-life.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.135 and 0.034).

**Binding Affinity:** Ligand B (-6.5 kcal/mol) has a slightly better binding affinity than Ligand A (-8.0 kcal/mol). However, the difference is not substantial enough to overcome the significant ADME disadvantages of Ligand B.

**Overall Assessment:**

Ligand A is the stronger candidate. While Ligand B has slightly better binding affinity and metabolic stability, Ligand A excels in crucial properties for a CNS-targeting GPCR ligand: TPSA, BBB penetration, and DILI risk. The problematic negative values for Caco-2 and solubility are concerning for both, but less so for Ligand A. The negative half-life for Ligand A is a red flag, but could be an artifact of the prediction. The poor BBB penetration of Ligand B is a deal-breaker for a DRD2 ligand.



Output:
0
2025-04-17 05:39:58,650 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (349.427 and 361.349 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (90.23) is excellent for CNS penetration, being below the 90 threshold. Ligand B (124.47) is higher, but still potentially acceptable, though less ideal.

**3. logP:** Ligand A (0.786) is a bit low, potentially hindering permeability. Ligand B (1.094) is better, falling within the optimal 1-3 range.

**4. H-Bond Donors:** Ligand A (3) is within the acceptable limit of <=5. Ligand B (1) is even better.

**5. H-Bond Acceptors:** Both ligands (A: 5, B: 5) are within the acceptable limit of <=10.

**6. QED:** Ligand A (0.731) is good, indicating strong drug-like properties. Ligand B (0.217) is poor, suggesting potential issues.

**7. DILI:** Both ligands have low DILI risk (A: 30.438, B: 35.091), below the 40 threshold.

**8. BBB:** This is crucial for a CNS target. Ligand A (60.644) is moderate, while Ligand B (78.054) is significantly better, exceeding the desirable >70 threshold.

**9. Caco-2 Permeability:** Both have negative values (-5.014 and -4.714), which is unusual and difficult to interpret without more context. However, we can assume lower (more negative) values indicate poorer permeability.

**10. Aqueous Solubility:** Both ligands have negative values (-1.84 and -1.052), again unusual. Lower values suggest lower solubility.

**11. hERG Inhibition:** Both ligands show low hERG inhibition liability (A: 0.47, B: 0.237).

**12. Microsomal Clearance:** Ligand A (15.54) has lower clearance, indicating better metabolic stability than Ligand B (46.917).

**13. In vitro Half-Life:** Ligand A (40.627) has a longer half-life than Ligand B (-28.417), which is a significant advantage.

**14. P-gp Efflux:** Ligand A (0.26) has lower P-gp efflux, which is favorable for CNS penetration. Ligand B (0.023) is even lower, which is excellent.

**15. Binding Affinity:** Both ligands have strong binding affinities (A: -8 kcal/mol, B: -6.9 kcal/mol). Ligand A is slightly better (-8 vs -6.9).

**Overall Assessment:**

Ligand B excels in BBB penetration and P-gp efflux, critical for CNS targets. However, it suffers from a poor QED score and higher microsomal clearance. Ligand A has a better QED, longer half-life, and lower clearance, but its BBB penetration is only moderate and logP is a bit low. The affinity difference is relatively small (1.1 kcal/mol), and the benefits of better ADME properties for Ligand A, combined with its slightly better affinity, outweigh the superior BBB of Ligand B.

Output:
1
2025-04-17 05:39:58,650 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (341.415 and 348.487 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (90.98) is better than Ligand B (67.43). Both are below the 90 A^2 threshold desirable for CNS targets.

**3. logP:** Both ligands have good logP values (1.733 and 2.108), falling within the optimal 1-3 range.

**4. H-Bond Donors:** Both ligands have 2 HBD, which is within the acceptable limit of <=5.

**5. H-Bond Acceptors:** Ligand A has 4 HBA, and Ligand B has 3. Both are within the acceptable limit of <=10.

**6. QED:** Ligand A (0.866) has a significantly better QED score than Ligand B (0.66), indicating a more drug-like profile.

**7. DILI:** Ligand A (52.656) has a higher DILI risk than Ligand B (20.861). Ligand B is preferable here.

**8. BBB:** Ligand B (59.674) has a significantly better BBB percentile than Ligand A (46.336). This is a crucial factor for a CNS target like DRD2.

**9. Caco-2 Permeability:** Both have negative values which is unusual. Assuming these are percentile scores, Ligand B (-4.779) is slightly better than Ligand A (-5).

**10. Aqueous Solubility:** Both have negative values which is unusual. Assuming these are percentile scores, Ligand A (-2.69) is slightly better than Ligand B (-3.066).

**11. hERG Inhibition:** Ligand A (0.087) has a lower hERG inhibition liability than Ligand B (0.225), which is preferable.

**12. Microsomal Clearance:** Ligand A (12.833) has a lower microsomal clearance than Ligand B (24.379), suggesting better metabolic stability.

**13. In vitro Half-Life:** Ligand A (-5.702) has a longer in vitro half-life than Ligand B (7.573).

**14. P-gp Efflux:** Ligand A (0.011) has significantly lower P-gp efflux liability than Ligand B (0.046), which is very important for CNS penetration.

**15. Binding Affinity:** Both ligands have the same binding affinity (-7.9 kcal/mol), which is excellent.

**Overall Assessment:**

Ligand B excels in BBB penetration and has a lower DILI risk. However, Ligand A demonstrates superior drug-likeness (QED), metabolic stability (Cl_mic, t1/2), lower P-gp efflux, and lower hERG inhibition. The difference in BBB is significant, but the combination of favorable ADME properties in Ligand A, coupled with equal binding affinity, makes it a more promising candidate. The lower P-gp efflux of Ligand A is particularly important for CNS targets, potentially overcoming any slight disadvantage in BBB.

Output:
1
2025-04-17 05:39:58,651 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (354.447 and 346.475 Da) fall within the ideal range of 200-500 Da.

**TPSA:** Ligand A (96.89) is better than Ligand B (78.09) as it is closer to the ideal range for CNS targets (<=90).

**logP:** Ligand B (2.074) is optimal (1-3), while Ligand A (0.066) is quite low, potentially hindering permeation. This is a significant drawback for Ligand A.

**H-Bond Donors/Acceptors:** Ligand A has 3 HBD and 5 HBA, while Ligand B has 2 HBD and 3 HBA. Both are within acceptable limits.

**QED:** Ligand B (0.742) has a better QED score than Ligand A (0.509), indicating a more drug-like profile.

**DILI:** Ligand B (23.769) has a lower DILI risk than Ligand A (18.883), which is preferable.

**BBB:** Ligand A (57.968) has a significantly better BBB penetration percentile than Ligand B (42.226). This is a crucial factor for a CNS target like DRD2.

**Caco-2 Permeability:** Both ligands have the same Caco-2 permeability (-5.333), which is not ideal.

**Aqueous Solubility:** Both ligands have the same aqueous solubility (-1.666), which is not ideal.

**hERG Inhibition:** Ligand A (0.266) shows a lower hERG inhibition liability than Ligand B (0.387), which is better for cardiac safety.

**Microsomal Clearance:** Ligand B (12.705) has a lower microsomal clearance than Ligand A (18.841), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand B (-25.513) has a significantly longer in vitro half-life than Ligand A (7.977), which is desirable.

**P-gp Efflux:** Ligand A (0.031) has a lower P-gp efflux liability than Ligand B (0.156), which is favorable for CNS exposure.

**Binding Affinity:** Ligand A (-8.1 kcal/mol) has a stronger binding affinity than Ligand B (-7.9 kcal/mol). This is a substantial advantage, potentially outweighing some ADME drawbacks.

**Overall Assessment:**

Ligand A excels in binding affinity and BBB penetration, and has lower P-gp efflux and hERG inhibition. However, its low logP is a major concern, potentially limiting its ability to cross cell membranes. Ligand B has better ADME properties (QED, DILI, metabolic stability, half-life) and a good logP, but its binding affinity is slightly weaker and its BBB penetration is considerably lower.

Given the importance of CNS penetration for a DRD2 ligand, and the relatively small difference in binding affinity (0.2 kcal/mol), the superior BBB value of Ligand A, coupled with its lower P-gp efflux, makes it the more promising candidate. The low logP is a concern, but could potentially be addressed with prodrug strategies or formulation approaches.

Output:
0
2025-04-17 05:39:58,651 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B based on the provided guidelines, prioritizing GPCR-specific properties (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (348.4 and 366.5 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (93.73) is slightly above the optimal <90 for CNS targets, but still reasonable. Ligand B (74.77) is excellent, well below 90.

**logP:** Ligand A (0.491) is a bit low, potentially hindering permeability. Ligand B (1.112) is better, falling within the 1-3 optimal range.

**H-Bond Donors/Acceptors:** Ligand A (2 HBD, 5 HBA) and Ligand B (1 HBD, 6 HBA) both have acceptable numbers of H-bond donors and acceptors.

**QED:** Both ligands have good QED scores (0.527 and 0.782), indicating drug-like properties.

**DILI:** Ligand A (49.632) has a slightly higher DILI risk than Ligand B (36.293), but both are below the concerning threshold of 60.

**BBB:** This is a critical parameter for a CNS target like DRD2. Ligand B (65.258) shows a significantly better BBB penetration percentile than Ligand A (29.779).

**Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and suggests a potential issue with the data or modeling. However, we'll proceed with the other parameters.

**Aqueous Solubility:** Both have negative solubility values, also unusual.

**hERG Inhibition:** Both ligands show very low hERG inhibition risk (0.137 and 0.126).

**Microsomal Clearance:** Ligand A (17.94) has a lower (better) microsomal clearance than Ligand B (-16.457), suggesting greater metabolic stability. However, the negative value for Ligand B is concerning.

**In vitro Half-Life:** Ligand A (-4.298) has a negative half-life, which is impossible. Ligand B (0.564) is very short, which is not ideal.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.037 and 0.049), which is favorable for CNS penetration.

**Binding Affinity:** Ligand A (-8.9 kcal/mol) has a slightly better binding affinity than Ligand B (-7.9 kcal/mol), a difference of 1 kcal/mol.

**Overall Assessment:**

Despite Ligand A's slightly better binding affinity, Ligand B is the more promising candidate. The significantly higher BBB penetration (65.258 vs 29.779) is crucial for a CNS-targeting drug. Ligand B also has a better logP, lower DILI risk, and a more reasonable TPSA. The negative values for Caco-2 and solubility are concerning for both, but the other advantages of Ligand B outweigh this. The negative half-life for Ligand A is a major red flag, and the negative clearance for Ligand B is also concerning. The 1 kcal/mol difference in binding affinity is unlikely to overcome these ADME deficiencies.

Output:
1
2025-04-17 05:39:58,651 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (339.439 and 348.487 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (53.51) is significantly better than Ligand B (67.43). For CNS targets, we want TPSA <= 90, and A is comfortably within that range, while B is approaching the upper limit.

**3. logP:** Both ligands have good logP values (2.396 and 2.908), falling within the optimal 1-3 range.

**4. H-Bond Donors:** Ligand A (0) is preferable to Ligand B (2). Fewer H-bond donors generally improve permeability.

**5. H-Bond Acceptors:** Both ligands have 3 H-bond acceptors, which is acceptable.

**6. QED:** Ligand A (0.85) has a much better QED score than Ligand B (0.597), indicating a more drug-like profile.

**7. DILI:** Ligand A (16.44) has a significantly lower DILI risk than Ligand B (26.367).

**8. BBB:** Ligand A (89.027) has a substantially better BBB penetration percentile than Ligand B (69.678). This is *critical* for a CNS target like DRD2.

**9. Caco-2 Permeability:** Ligand A (-4.563) is better than Ligand B (-4.959), indicating slightly better intestinal absorption.

**10. Aqueous Solubility:** Ligand A (-2.197) is better than Ligand B (-3.115).

**11. hERG Inhibition:** Both ligands have low hERG inhibition risk (0.29 and 0.408).

**12. Microsomal Clearance:** Ligand A (32.029) has a lower microsomal clearance than Ligand B (71.886), suggesting better metabolic stability.

**13. In vitro Half-Life:** Ligand A (2.376) has a better in vitro half-life than Ligand B (-24.091).

**14. P-gp Efflux:** Ligand A (0.125) has a much lower P-gp efflux liability than Ligand B (0.533), which is favorable for CNS penetration.

**15. Binding Affinity:** Ligand B (-8.3) has a slightly better binding affinity than Ligand A (-7.9), but the difference is less than 1.5 kcal/mol and can be outweighed by other factors.

**Overall Assessment:**

Ligand A is significantly superior to Ligand B across most ADME-Tox properties, *especially* those crucial for CNS drug development (BBB, TPSA, Pgp). While Ligand B has a slightly better binding affinity, the substantial advantages of Ligand A in terms of predicted brain penetration, metabolic stability, and lower toxicity make it the more promising drug candidate.

Output:
0
2025-04-17 05:39:58,651 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (348.447 and 349.391 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (72.96) is significantly better than Ligand B (107.77). For CNS targets, we want TPSA <= 90, and A is comfortably within this range, while B is pushing the limit.

**logP:** Ligand A (-0.33) is slightly lower than optimal (1-3), but not drastically so. Ligand B (-1.264) is also below optimal, but still within a reasonable range.

**H-Bond Donors/Acceptors:** Ligand A (1 HBD, 4 HBA) is preferable to Ligand B (2 HBD, 6 HBA). Lower counts generally improve permeability. Both are within acceptable limits.

**QED:** Both ligands have similar QED values (0.706 and 0.69), indicating good drug-likeness.

**DILI:** Ligand A (35.789) has a lower DILI risk than Ligand B (25.553), which is favorable.

**BBB:** This is a critical parameter for a CNS target like DRD2. Ligand A (64.637) has a significantly higher BBB percentile than Ligand B (49.011). A value >70 is desirable, and A is closer to that threshold.

**Caco-2 Permeability:** Ligand A (-4.568) and Ligand B (-5.197) both have negative Caco-2 values, which is unusual and suggests poor permeability. However, these values are on a scale where negative values are possible, and the absolute difference isn't huge.

**Aqueous Solubility:** Both ligands have very poor aqueous solubility (-1.017 and -0.795). This could pose formulation challenges.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.147 and 0.204), which is good.

**Microsomal Clearance:** Ligand B (-8.111) shows better metabolic stability (lower clearance) than Ligand A (20.352).

**In vitro Half-Life:** Ligand B (-3.856) has a slightly longer in vitro half-life than Ligand A (-26.762), which is favorable.

**P-gp Efflux:** Both ligands show low P-gp efflux liability (0.012 and 0.013).

**Binding Affinity:** Ligand B (-8.5 kcal/mol) has a stronger binding affinity than Ligand A (-6.8 kcal/mol). This is a substantial difference (>1.5 kcal/mol) and a significant advantage.

**Overall Assessment:**

While Ligand B has a superior binding affinity and better metabolic stability, Ligand A has a much more favorable TPSA and significantly better BBB penetration. Given that DRD2 is a CNS target, BBB penetration is paramount. The stronger binding of Ligand B *could* potentially overcome the lower BBB, but the difference in TPSA is also substantial. The lower DILI risk of Ligand A is also a plus. Considering the GPCR-specific priorities, the improved CNS penetration of Ligand A is more critical than the slightly stronger binding of Ligand B.

Output:
0
2025-04-17 05:39:58,652 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B based on the provided guidelines, prioritizing GPCR-specific properties (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands fall within the ideal range (200-500 Da). Ligand A (387.307 Da) is slightly higher than Ligand B (350.344 Da), but both are acceptable.

**TPSA:** Both ligands have TPSA values below 90, which is favorable for CNS penetration (Ligand A: 51.13, Ligand B: 49.33).

**logP:** Ligand A (4.989) is slightly above the optimal range (1-3) but still potentially manageable. Ligand B (2.511) is well within the optimal range. This favors Ligand B.

**H-Bond Donors/Acceptors:** Both ligands have 0 HBD and 4 HBA, which are within acceptable limits.

**QED:** Both ligands have good QED scores (Ligand A: 0.54, Ligand B: 0.85), indicating drug-likeness. Ligand B is better here.

**DILI:** Both ligands have acceptable DILI risk (Ligand A: 53.005, Ligand B: 45.677), below the 60 threshold. Ligand B is slightly better.

**BBB:** This is a critical parameter for CNS targets. Ligand B (96.045) has a significantly higher BBB percentile than Ligand A (70.841). This is a major advantage for Ligand B.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values, which is unusual and suggests poor permeability. This is a concern for both.

**Aqueous Solubility:** Both have negative solubility values, indicating very poor aqueous solubility. This is a significant drawback for both.

**hERG Inhibition:** Both ligands have low hERG inhibition liability (Ligand A: 0.57, Ligand B: 0.907), which is good.

**Microsomal Clearance:** Ligand A (54.805) has higher microsomal clearance than Ligand B (23.712), suggesting lower metabolic stability. This favors Ligand B.

**In vitro Half-Life:** Ligand B (-19.361) has a negative half-life, which is not physically possible and suggests a problem with the data. Ligand A (1.779) has a very short half-life. Both are problematic, but the negative value for B is a clear data issue.

**P-gp Efflux:** Ligand A (0.5) has lower P-gp efflux liability than Ligand B (0.277), which is favorable for CNS exposure.

**Binding Affinity:** Ligand B (-8.6 kcal/mol) has a slightly better binding affinity than Ligand A (-7.6 kcal/mol). While both are good, the 1 kcal/mol difference is noteworthy.

**Overall Assessment:**

Ligand B consistently outperforms Ligand A in key areas for a CNS-targeting GPCR ligand: BBB penetration, logP, DILI, and microsomal clearance. The binding affinity is also slightly better for Ligand B. The negative half-life for Ligand B is a data quality concern, but the other advantages are substantial. Both ligands have poor solubility and Caco-2 permeability, which would require formulation strategies to address. The lower P-gp efflux for Ligand A is a minor advantage, but doesn't outweigh the other benefits of Ligand B.

Output:
1
2025-04-17 05:39:58,652 - INFO - Batch 217 complete. Total preferences: 3472
2025-04-17 05:39:58,652 - INFO - Processing batch 218/512...
2025-04-17 05:40:47,424 - INFO - Reasoning:

Let's analyze Ligand A and Ligand B based on the provided guidelines, prioritizing GPCR-specific properties (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (364.825 and 350.503 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (64.99) is significantly better than Ligand B (78.43). For CNS targets, TPSA should be <= 90, both are within this range, but A is closer to the optimal <60 range.

**logP:** Ligand A (3.392) is slightly higher than Ligand B (2.375), both are within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A has 1 HBD and 5 HBA, while Ligand B has 3 HBD and 3 HBA. Both are acceptable, within the recommended limits.

**QED:** Both ligands have similar QED values (0.727 and 0.617), indicating good drug-likeness.

**DILI:** Ligand A (52.385) has a higher DILI risk than Ligand B (10.198). This is a significant drawback for Ligand A.

**BBB:** Ligand B (53.974) has a substantially better BBB penetration percentile than Ligand A (30.981). This is *critical* for a CNS target like DRD2.

**Caco-2 Permeability:** Ligand A (-4.563) has better Caco-2 permeability than Ligand B (-4.729), but both are negative, indicating poor permeability.

**Aqueous Solubility:** Ligand A (-4.445) has slightly better solubility than Ligand B (-3.039), but both are poor.

**hERG Inhibition:** Ligand A (0.677) has a slightly higher hERG inhibition liability than Ligand B (0.37), but both are relatively low risk.

**Microsomal Clearance:** Ligand B (49.367) has lower microsomal clearance than Ligand A (93.639), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand B (-18.619) has a much longer in vitro half-life than Ligand A (13.417).

**P-gp Efflux:** Ligand A (0.531) has lower P-gp efflux liability than Ligand B (0.09), which is favorable for CNS penetration.

**Binding Affinity:** Both ligands have very similar and strong binding affinities (-9 and -8.6 kcal/mol). The difference is negligible.

**Overall Assessment:**

Ligand B is the more promising candidate. While Ligand A has slightly better Caco-2 permeability and P-gp efflux, Ligand B excels in the most critical areas for a CNS-targeting GPCR: significantly better BBB penetration, lower DILI risk, and improved metabolic stability (lower Cl_mic and longer t1/2). The similar binding affinities make these ADME properties the deciding factors.

Output:
1
2025-04-17 05:40:47,424 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B based on the provided guidelines, prioritizing GPCR-specific properties (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (374.453 and 367.515 Da) fall within the ideal range of 200-500 Da.

**TPSA:** Ligand A (69.64) is slightly above the optimal <90 for CNS targets, but still reasonable. Ligand B (54.9) is excellent, well below 90.

**logP:** Both ligands have good logP values (1.538 and 2.247), falling within the 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A (2 HBD, 4 HBA) and Ligand B (0 HBD, 6 HBA) both have acceptable numbers of H-bond donors and acceptors.

**QED:** Both ligands have similar and good QED scores (0.786 and 0.772), indicating good drug-likeness.

**DILI:** Ligand A (39.201) has a slightly higher DILI risk than Ligand B (28.693), but both are below the concerning threshold of 60.

**BBB:** This is a critical parameter for CNS targets like DRD2. Ligand B (84.606) has a significantly higher BBB percentile than Ligand A (69.717). This is a major advantage for Ligand B.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values, which is unusual and suggests poor permeability. This is a concern for both.

**Aqueous Solubility:** Both ligands have negative solubility values, which is also unusual and suggests poor solubility. This is a concern for both.

**hERG Inhibition:** Ligand A (0.287) has a lower hERG inhibition liability than Ligand B (0.551), which is preferable.

**Microsomal Clearance:** Ligand A (-14.244) has a much lower (better) microsomal clearance than Ligand B (56.695), indicating greater metabolic stability.

**In vitro Half-Life:** Ligand A (1.226 hours) has a shorter half-life than Ligand B (-3.645 hours, which is unusual and potentially indicates a problem with the calculation or data).

**P-gp Efflux:** Ligand A (0.042) has a much lower P-gp efflux liability than Ligand B (0.137), which is favorable for CNS penetration.

**Binding Affinity:** Ligand A (-7.1 kcal/mol) has a slightly better binding affinity than Ligand B (-6.6 kcal/mol), although both are good (below -7.0). The difference is 0.5 kcal/mol, which is significant.

**Overall Assessment:**

Ligand B excels in BBB penetration, a crucial factor for a DRD2 ligand. However, it suffers from higher P-gp efflux, worse metabolic stability (higher Cl_mic), and a shorter half-life. Ligand A, while having a slightly lower BBB score, compensates with significantly better metabolic stability, lower P-gp efflux, and a slightly better binding affinity. The negative solubility and permeability values are a concern for both, but can potentially be addressed with formulation strategies. Considering the importance of CNS penetration and metabolic stability for a DRD2 ligand, and the relatively small difference in binding affinity, Ligand A is the more promising candidate.

Output:
0
2025-04-17 05:40:47,424 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (369.38 and 354.44 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (73.45) is significantly better than Ligand B (86.8), being well below the 90 A^2 threshold for CNS targets. Ligand B is approaching the 140 A^2 limit for oral absorption, which is less ideal.

**logP:** Both ligands have acceptable logP values (1.77 and 2.62), falling within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A (HBD=1, HBA=8) and Ligand B (HBD=2, HBA=6) both meet the criteria of <=5 HBDs and <=10 HBAs.

**QED:** Both ligands have similar QED scores (0.756 and 0.752), indicating good drug-likeness.

**DILI:** Both ligands have relatively low DILI risk (83.29 and 80.19 percentile), suggesting acceptable liver safety profiles.

**BBB:** Ligand A (77.82%) has a slightly better BBB penetration prediction than Ligand B (72.82%), though both are reasonably good for a CNS target.

**Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and suggests a potential issue with the prediction method. However, we can still compare the values; Ligand A (-5.024) is slightly better than Ligand B (-5.324).

**Aqueous Solubility:** Both ligands have very poor predicted aqueous solubility (-3.263 and -4.329). This is a significant concern.

**hERG Inhibition:** Both ligands show low hERG inhibition liability (0.29 and 0.47), which is favorable.

**Microsomal Clearance:** Ligand A (31.07) has a higher microsomal clearance than Ligand B (25.89), indicating potentially lower metabolic stability.

**In vitro Half-Life:** Ligand B (14.00) has a significantly longer predicted half-life than Ligand A (-23.60), which is a major advantage.

**P-gp Efflux:** Both ligands show low P-gp efflux liability (0.233 and 0.211), which is good for CNS penetration.

**Binding Affinity:** Ligand B (-9.4 kcal/mol) has a significantly stronger binding affinity than Ligand A (-7.9 kcal/mol). This is a substantial difference (>1.5 kcal/mol) and likely outweighs some of the ADME drawbacks.

**Overall Assessment:**

While Ligand A has a better TPSA and slightly better BBB prediction, Ligand B's superior binding affinity (-9.4 vs -7.9 kcal/mol) is a critical advantage for a GPCR target. The longer half-life of Ligand B is also a significant positive. The solubility is poor for both, but the binding affinity difference is substantial enough to prioritize Ligand B.

Output:
1
2025-04-17 05:40:47,425 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (340.467 and 352.519 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (52.57) is slightly higher than Ligand B (49.85), but both are well below the 90 A^2 threshold for CNS targets.

**3. logP:** Both ligands have excellent logP values (2.705 and 2.589), falling within the optimal 1-3 range.

**4. H-Bond Donors:** Ligand A has 2 HBD, and Ligand B has 0. Both are acceptable (<=5).

**5. H-Bond Acceptors:** Ligand A has 3 HBA, and Ligand B has 4. Both are acceptable (<=10).

**6. QED:** Ligand A (0.783) has a better QED score than Ligand B (0.606), indicating a more drug-like profile.

**7. DILI:** Ligand A (12.718) has a slightly higher DILI risk than Ligand B (2.171), but both are well below the concerning threshold of 40.

**8. BBB:** Ligand B (86.468) has a significantly better BBB penetration percentile than Ligand A (81.698). This is a crucial factor for a CNS target like DRD2.

**9. Caco-2 Permeability:** Both have negative values, indicating poor permeability. However, the scale is not specified, so it's difficult to interpret.

**10. Aqueous Solubility:** Both have negative values, indicating poor solubility. Again, the scale is not specified.

**11. hERG Inhibition:** Both ligands have low hERG inhibition risk (0.754 and 0.614).

**12. Microsomal Clearance:** Ligand B (17.672) has a lower microsomal clearance than Ligand A (24.134), suggesting better metabolic stability.

**13. In vitro Half-Life:** Ligand A (9.818) has a longer in vitro half-life than Ligand B (-9.277). However, the negative value for Ligand B is concerning and likely indicates a very short half-life.

**14. P-gp Efflux:** Ligand A (0.217) has lower P-gp efflux than Ligand B (0.041), which is favorable for CNS penetration.

**15. Binding Affinity:** Ligand A (-8.5 kcal/mol) has a significantly stronger binding affinity than Ligand B (-6.8 kcal/mol). This is a substantial advantage, potentially outweighing some ADME drawbacks.

**Overall Assessment:**

While Ligand B has a better BBB score and lower clearance, Ligand A's significantly stronger binding affinity (-8.5 vs -6.8 kcal/mol) is a major advantage, especially for a GPCR target where potency is critical. The slightly higher DILI risk and lower BBB for Ligand A are less concerning given the substantial affinity difference. The longer half-life of Ligand A is also a positive. The P-gp efflux is also better for Ligand A.

Output:
1
2025-04-17 05:40:47,425 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (347.415 Da) is slightly lower, which could be advantageous for permeability, while Ligand B (384.395 Da) is also good.

**TPSA:** Ligand A (104.46) is better than Ligand B (49.85) as it is closer to the <90 threshold for CNS targets. Ligand B is quite low, which could be a concern for selectivity.

**logP:** Both ligands have good logP values (A: 1.682, B: 2.021), falling within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A has 3 HBD and 5 HBA, which is acceptable. Ligand B has 0 HBD and 4 HBA, also acceptable.

**QED:** Both ligands have similar QED values (A: 0.679, B: 0.696), indicating good drug-likeness.

**DILI:** Both ligands have low DILI risk (A: 45.948, B: 35.983), which is favorable.

**BBB:** This is a critical parameter for a CNS target like DRD2. Ligand B (93.912) significantly outperforms Ligand A (58.085) in BBB penetration. This is a major advantage for Ligand B.

**Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and suggests a potential issue with the data or modeling. However, the values are similar (-4.96 for A, -4.462 for B).

**Aqueous Solubility:** Both ligands have negative solubility values, which is also unusual. Again, values are similar (-2.444 for A, -3.401 for B).

**hERG Inhibition:** Both ligands have very low hERG inhibition risk (A: 0.068, B: 0.588), which is excellent.

**Microsomal Clearance:** Ligand A (37.732) has lower microsomal clearance than Ligand B (51.715), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (-30.976) has a longer in vitro half-life than Ligand B (-26.136).

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (A: 0.076, B: 0.054), which is excellent for CNS penetration.

**Binding Affinity:** Both ligands have strong binding affinities (A: -9.1 kcal/mol, B: -8.7 kcal/mol). Ligand A is slightly better (-9.1 vs -8.7). However, the difference is not substantial enough to outweigh other factors.

**Overall Assessment:**

Ligand B is superior due to its significantly better BBB penetration (93.912 vs 58.085). While Ligand A has slightly better affinity and metabolic stability, the BBB is paramount for a CNS-targeting drug. The TPSA of Ligand B is also lower, which could be beneficial. The unusual negative values for Caco-2 and solubility are a concern for both, but the difference in BBB is decisive.

Output:
1
2025-04-17 05:40:47,425 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight (MW):** Both ligands (339.439 and 368.861 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (54.46) is significantly better than Ligand B (60.03). For CNS targets, we want TPSA <= 90, and ideally closer to 60. Both are acceptable, but A is preferred.

**3. logP:** Both ligands have good logP values (3.95 and 3.78), falling within the optimal 1-3 range.

**4. H-Bond Donors (HBD):** Both have 1 HBD, well within the acceptable limit of <=5.

**5. H-Bond Acceptors (HBA):** Both have 5 HBA, also within the acceptable limit of <=10.

**6. QED:** Both ligands have high QED scores (0.836 and 0.876), indicating good drug-like properties.

**7. DILI:** Both ligands have similar DILI risk (62.776 and 60.489), placing them in a moderate risk category. This isn't a major differentiating factor.

**8. BBB:** Ligand B (91.431) has a substantially better BBB percentile than Ligand A (61.419). This is *critical* for a CNS target like DRD2.

**9. Caco-2 Permeability:** Both have negative Caco-2 values (-4.648 and -4.485), which is unusual and suggests poor permeability. However, these values are on a scale where negative values are possible, and direct comparison is difficult without knowing the scale's specifics.

**10. Aqueous Solubility:** Both have negative solubility values (-4.462 and -4.854), again indicating poor solubility. Similar to Caco-2, the scale is unknown.

**11. hERG Inhibition:** Both ligands have low hERG inhibition risk (0.75 and 0.763), which is good.

**12. Microsomal Clearance (Cl_mic):** Ligand B (43.481) has significantly lower microsomal clearance than Ligand A (96.394), suggesting better metabolic stability. This is a positive for B.

**13. In vitro Half-Life:** Ligand B (24.618) has a slightly longer half-life than Ligand A (21.905), which is favorable.

**14. P-gp Efflux:** Both ligands have similar P-gp efflux liability (0.363 and 0.441), suggesting moderate efflux.

**15. Binding Affinity:** Both ligands have excellent binding affinities (-8.9 and -8.0 kcal/mol). Ligand A has a 0.9 kcal/mol advantage, which is significant.

**Overall Assessment:**

While Ligand A has a better affinity and TPSA, Ligand B excels in BBB penetration and metabolic stability (lower Cl_mic) and has a slightly longer half-life. For a CNS target like DRD2, BBB penetration is paramount. The 30% difference in BBB percentile is substantial. The affinity difference, while noticeable, might be overcome with further optimization. The similar DILI, hERG, and P-gp profiles don't strongly favor either compound. The poor Caco-2 and solubility values are concerning for both, but can potentially be addressed through formulation strategies.

Output:
1
2025-04-17 05:40:47,425 - INFO - Okay, let's analyze these two ligands for their potential as DRD2 drug candidates. DRD2 is a GPCR in the CNS, so BBB penetration, logP, Pgp efflux, TPSA, and binding affinity are paramount.

**Ligand A: [421.173, 97.11, 2.16, 2, 5, 0.746, 85.964, 52.966, -5.745, -2.75, 0.019, 4.146, -15.241, 0.034, -8.7]**

*   **MW:** 421.173 Da - Acceptable.
*   **TPSA:** 97.11 - Borderline. A bit high for optimal CNS penetration, but not disqualifying.
*   **logP:** 2.16 - Good. Within the optimal range.
*   **HBD:** 2 - Acceptable.
*   **HBA:** 5 - Acceptable.
*   **QED:** 0.746 - Excellent. Highly drug-like.
*   **DILI:** 85.964 - High risk. This is a significant concern.
*   **BBB:** 52.966 - Moderate. Below the desirable >70% for CNS targets.
*   **Caco-2:** -5.745 - Very poor. Indicates very low intestinal absorption.
*   **Solubility:** -2.75 - Very poor. A significant issue for formulation.
*   **hERG:** 0.019 - Very low risk. Excellent.
*   **Cl_mic:** 4.146 - Low. Good metabolic stability.
*   **t1/2:** -15.241 - Very short half-life. A major drawback.
*   **Pgp:** 0.034 - Low efflux. Good.
*   **Affinity:** -8.7 kcal/mol - Excellent. Very strong binding.

**Ligand B: [339.439, 53.51, 2.396, 0, 3, 0.85, 16.44, 89.027, -4.563, -2.197, 0.29, 32.029, 2.376, 0.125, -7.9]**

*   **MW:** 339.439 Da - Acceptable.
*   **TPSA:** 53.51 - Excellent. Well within the range for CNS penetration.
*   **logP:** 2.396 - Good. Within the optimal range.
*   **HBD:** 0 - Acceptable.
*   **HBA:** 3 - Acceptable.
*   **QED:** 0.85 - Excellent. Highly drug-like.
*   **DILI:** 16.44 - Very low risk. Excellent.
*   **BBB:** 89.027 - Excellent. Highly likely to cross the BBB.
*   **Caco-2:** -4.563 - Poor, but better than Ligand A.
*   **Solubility:** -2.197 - Poor, but better than Ligand A.
*   **hERG:** 0.29 - Very low risk. Excellent.
*   **Cl_mic:** 32.029 - Moderate. Acceptable, but not ideal.
*   **t1/2:** 2.376 - Short, but better than Ligand A.
*   **Pgp:** 0.125 - Low efflux. Good.
*   **Affinity:** -7.9 kcal/mol - Very good. Strong binding.

**Comparison and Decision:**

While Ligand A boasts a slightly better binding affinity (-8.7 vs -7.9 kcal/mol), its significant liabilities in DILI risk, BBB penetration, Caco-2 permeability, and solubility are major red flags. The extremely short half-life is also a critical issue.

Ligand B, despite a slightly weaker binding affinity, presents a far more favorable ADME-Tox profile. Its excellent BBB penetration, low DILI risk, and acceptable metabolic stability make it a much more promising starting point for drug development. The Caco-2 and solubility are still poor, but are less concerning than the issues with Ligand A.

Given the GPCR-specific priorities (BBB, logP, Pgp, TPSA, affinity) and the overall balance of properties, **Ligand B is the more viable drug candidate.**

1
2025-04-17 05:40:47,426 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (354.45 & 355.45 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (88.1) is better than Ligand B (92.5). Both are below the 90 A^2 threshold for CNS targets, which is good.

**logP:** Both ligands have a logP around 1.2-1.3, which is optimal (1-3).

**H-Bond Donors/Acceptors:** Both have 2 HBDs, which is acceptable. Ligand A has 6 HBAs, while Ligand B has 3. Both are within the acceptable limit of 10.

**QED:** Ligand A (0.743) has a better QED score than Ligand B (0.686), indicating better overall drug-likeness.

**DILI:** Ligand A (10.59) has a significantly lower DILI risk than Ligand B (16.32). This is a substantial advantage.

**BBB:** Ligand B (92.83) has a much higher BBB penetration percentile than Ligand A (73.75). This is a critical advantage for a CNS target like DRD2.

**Caco-2 Permeability:** Ligand A (-4.642) has better Caco-2 permeability than Ligand B (-5.219), indicating better intestinal absorption.

**Aqueous Solubility:** Ligand A (-1.827) has better aqueous solubility than Ligand B (-3.066).

**hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.482 and 0.492).

**Microsomal Clearance:** Ligand B (10.623) has higher microsomal clearance than Ligand A (5.952), meaning it will be metabolized faster. This is a disadvantage.

**In vitro Half-Life:** Ligand A (-6.519) has a significantly longer in vitro half-life than Ligand B (-17.146). This is a major advantage.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.032 and 0.028).

**Binding Affinity:** Ligand A (-8.4 kcal/mol) has a stronger binding affinity than Ligand B (-7.2 kcal/mol). This is a significant advantage. The difference of 1.2 kcal/mol is substantial enough to potentially overcome minor ADME drawbacks.

**Overall Assessment:**

While Ligand B has a superior BBB score, Ligand A excels in most other critical parameters, particularly DILI risk, metabolic stability (lower Cl_mic, longer t1/2), solubility, and *significantly* stronger binding affinity. The stronger affinity of Ligand A is a major factor, and the lower DILI risk is also very important. The difference in BBB is notable, but can potentially be addressed through formulation strategies. Given the GPCR-specific priorities, the combination of strong affinity, favorable ADME properties (especially metabolic stability and reduced toxicity), and acceptable BBB makes Ligand A the more promising candidate.

Output:
1
2025-04-17 05:40:47,426 - INFO - Reasoning:

Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight (MW):** Both ligands (363.849 and 369.531 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (102.04) is higher than the preferred <90 for CNS targets, while Ligand B (69.72) is well within the desired range. This is a significant advantage for Ligand B.

**3. logP:** Ligand A (3.597) is at the upper end of the optimal range (1-3), but still acceptable. Ligand B (1.494) is slightly lower, but still within the range.

**4. H-Bond Donors (HBD):** Both ligands have acceptable HBD counts (3 and 1, respectively), well below the threshold of 5.

**5. H-Bond Acceptors (HBA):** Both ligands have acceptable HBA counts (4 each), below the threshold of 10.

**6. QED:** Both ligands have similar and good QED values (0.773 and 0.738, respectively), indicating good drug-like properties.

**7. DILI:** Ligand A (78.247) has a higher DILI risk than Ligand B (27.104). This is a considerable advantage for Ligand B.

**8. BBB:** Both ligands have reasonably good BBB penetration (64.095% and 62.233%), but neither exceeds the desirable 70% threshold.

**9. Caco-2 Permeability:** Ligand A (-4.836) has poor Caco-2 permeability, while Ligand B (-5.155) also has poor Caco-2 permeability. Both are negative values, suggesting low permeability.

**10. Aqueous Solubility:** Ligand A (-5.052) has poor aqueous solubility, while Ligand B (-2.542) is slightly better, but still poor.

**11. hERG Inhibition:** Both ligands show low hERG inhibition risk (0.341 and 0.175, respectively).

**12. Microsomal Clearance:** Both ligands have similar microsomal clearance values (56.676 and 55.456 mL/min/kg).

**13. In vitro Half-Life:** Ligand A (85.904) has a much longer in vitro half-life than Ligand B (-1.604). This is a significant advantage for Ligand A.

**14. P-gp Efflux:** Ligand A (0.218) has a lower P-gp efflux liability than Ligand B (0.036). Lower is better, so this favors Ligand A.

**15. Binding Affinity:** Ligand A (-8.4 kcal/mol) has a significantly stronger binding affinity than Ligand B (0.0 kcal/mol). This is a major advantage for Ligand A. A difference of >1.5 kcal/mol can outweigh other drawbacks, and here the difference is enormous.

**Overall Assessment:**

Despite Ligand A's higher TPSA and DILI risk, its significantly superior binding affinity (-8.4 vs 0.0 kcal/mol), longer half-life, and lower P-gp efflux outweigh these concerns. The large difference in binding affinity is the most critical factor, especially for a GPCR target where achieving sufficient receptor occupancy is crucial. While Ligand B has better TPSA and DILI, the lack of significant binding affinity makes it unlikely to be a viable candidate.

Output:
1
2025-04-17 05:40:47,426 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, considering the provided guidelines and GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (352.435 Da and 344.499 Da) fall within the ideal range of 200-500 Da.

**TPSA:** Ligand A (107.69) is borderline for CNS penetration, being above the preferred <90, but not drastically so. Ligand B (40.62) is excellent, well below the 90 threshold.

**logP:** Ligand A (-0.173) is quite low, potentially hindering membrane permeability. Ligand B (3.539) is optimal, falling within the 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A has 3 HBD and 6 HBA, which are acceptable. Ligand B has 0 HBD and 2 HBA, also acceptable, and potentially favoring permeability due to fewer hydrogen bonds.

**QED:** Both ligands have similar QED values (0.659 and 0.716), indicating good drug-likeness.

**DILI:** Ligand A (38.348) has a slightly higher DILI risk than Ligand B (13.843), but both are below the concerning threshold of 60.

**BBB:** This is a critical parameter for CNS targets. Ligand A (26.212) has a poor BBB percentile, while Ligand B (76.464) is very good, exceeding the desirable >70 threshold.

**Caco-2 Permeability:** Ligand A (-5.194) shows poor permeability, consistent with its low logP. Ligand B (-4.774) is also low, but less so than Ligand A.

**Aqueous Solubility:** Both ligands have negative solubility values (-1.091 and -3.504), indicating poor aqueous solubility. This could be a formulation challenge, but is less critical than permeability for CNS targets.

**hERG Inhibition:** Both ligands show low hERG inhibition risk (0.103 and 0.315).

**Microsomal Clearance:** Ligand A (-2.243) has a negative clearance, suggesting very slow metabolism and high stability. Ligand B (52.904) has a high clearance, indicating rapid metabolism.

**In vitro Half-Life:** Ligand A (1.922) has a short half-life, consistent with its clearance. Ligand B (-8.986) has a very long half-life, consistent with its clearance.

**P-gp Efflux:** Ligand A (0.015) has very low P-gp efflux, which is favorable for CNS penetration. Ligand B (0.264) has slightly higher P-gp efflux, but still relatively low.

**Binding Affinity:** Ligand A (-8.2 kcal/mol) has a slightly better binding affinity than Ligand B (-7.7 kcal/mol), but the difference is not substantial.

**Overall Assessment:**

Ligand B is the superior candidate. While Ligand A has slightly better binding affinity, its poor logP, low BBB penetration, and poor Caco-2 permeability are significant drawbacks for a CNS-targeting drug. Ligand B excels in the critical GPCR-specific parameters: excellent BBB penetration, optimal logP, and acceptable P-gp efflux. Its higher metabolic clearance is a concern, but could potentially be addressed through structural modifications. The difference in binding affinity (0.5 kcal/mol) is unlikely to outweigh the substantial ADME advantages of Ligand B.

Output:
1
2025-04-17 05:40:47,426 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (346.471 and 363.487 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (42.01) is significantly better than Ligand B (98.17). For CNS targets, TPSA should be <= 90, and A is comfortably within that range, while B is approaching the upper limit and could hinder BBB penetration.

**3. logP:** Both ligands have similar logP values (3.099 and 3.184), falling within the optimal 1-3 range.

**4. H-Bond Donors:** Ligand A (0) is preferable to Ligand B (1). Fewer HBDs generally improve membrane permeability.

**5. H-Bond Acceptors:** Both ligands have the same number of HBA (4), which is acceptable (<=10).

**6. QED:** Ligand A (0.822) has a much better QED score than Ligand B (0.457), indicating a more drug-like profile.

**7. DILI:** Ligand A (10.702) has a significantly lower DILI risk than Ligand B (43.079). This is a major advantage for A.

**8. BBB:** Ligand A (77.588) has a substantially higher BBB percentile than Ligand B (41.218). This is *critical* for a CNS target like DRD2.

**9. Caco-2 Permeability:** Ligand A (-4.61) has a more favorable Caco-2 permeability than Ligand B (-5.175), although both are negative values which is unusual and requires further investigation.

**10. Aqueous Solubility:** Ligand B (-2.407) has slightly better solubility than Ligand A (-1.215), but solubility isn't a primary concern here given the other factors.

**11. hERG Inhibition:** Both ligands have low hERG inhibition risk (0.779 and 0.226), which is good.

**12. Microsomal Clearance:** Ligand A (6.517) has lower microsomal clearance than Ligand B (32.921), suggesting better metabolic stability.

**13. In vitro Half-Life:** Ligand A (-6.306) has a longer in vitro half-life than Ligand B (14.855), which is desirable.

**14. P-gp Efflux:** Ligand A (0.14) has lower P-gp efflux liability than Ligand B (0.133), which is slightly better for CNS exposure.

**15. Binding Affinity:** Ligand B (-7.1) has a slightly better binding affinity than Ligand A (-7.8). However, the difference of 0.7 kcal/mol is unlikely to overcome the significant ADME advantages of Ligand A.

**Overall:** Ligand A is significantly superior to Ligand B. It has a better QED score, lower DILI risk, much higher BBB penetration, better metabolic stability, longer half-life, and lower P-gp efflux. While Ligand B has slightly better binding affinity, the ADME properties of Ligand A are far more favorable for a CNS-targeting drug candidate.

Output:
0
2025-04-17 05:40:47,426 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (364.555 Da) is slightly higher than Ligand B (352.435 Da), but both are acceptable.

**TPSA:** Ligand A (49.41) is excellent for CNS penetration, well below the 90 A^2 threshold. Ligand B (99.77) is higher, but still potentially acceptable, though less ideal.

**logP:** Ligand A (3.206) is optimal. Ligand B (-0.836) is significantly lower, which could hinder membrane permeability and CNS penetration.

**H-Bond Donors/Acceptors:** Ligand A (HBD=1, HBA=3) and Ligand B (HBD=3, HBA=5) both fall within acceptable ranges.

**QED:** Ligand A (0.815) has a very strong drug-like profile. Ligand B (0.555) is acceptable, but less favorable.

**DILI:** Ligand A (22.993) has a very low DILI risk. Ligand B (14.773) also has a low DILI risk, but is slightly higher.

**BBB:** Ligand A (75.301) has a good BBB percentile, exceeding the 70% threshold for CNS targets. Ligand B (43.311) is considerably lower, suggesting limited brain penetration. This is a major drawback for a DRD2 ligand.

**Caco-2 Permeability:** Both have negative values, which is unusual. Assuming these are logP-like scales, Ligand A (-4.313) is better than Ligand B (-0.749) in terms of permeability.

**Aqueous Solubility:** Both have negative values, which is unusual. Assuming these are logS-like scales, Ligand A (-4.313) is better than Ligand B (-0.749) in terms of solubility.

**hERG:** Both ligands have very low hERG risk (0.314 and 0.051, respectively).

**Microsomal Clearance:** Ligand B (-25.561) has a significantly lower (better) microsomal clearance than Ligand A (62.673), indicating greater metabolic stability.

**In vitro Half-Life:** Ligand B (1.908) has a slightly longer half-life than Ligand A (-4.062).

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.185 and 0.002, respectively).

**Binding Affinity:** Both ligands have the same binding affinity (-7.0 kcal/mol), which is excellent.

**Conclusion:**

Despite Ligand B's better metabolic stability and half-life, Ligand A is the more promising candidate. The critical factors are the significantly better BBB penetration (75.3% vs 43.3%) and more favorable logP (3.206 vs -0.836) of Ligand A. These properties are crucial for CNS drug development, especially for a GPCR target like DRD2. The higher TPSA of Ligand B is also a concern. While Ligand B has a better clearance profile, the importance of CNS penetration outweighs this benefit in this case.

Output:
1
2025-04-17 05:40:47,427 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (353.5 and 343.4 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (70.67) is slightly higher than Ligand B (62.3). Both are below the 90 A^2 threshold desirable for CNS targets, but Ligand B is preferable.

**logP:** Ligand A (1.256) is within the optimal range (1-3), while Ligand B (2.594) is towards the higher end. Both are acceptable, but A is slightly better.

**H-Bond Donors/Acceptors:** Ligand A (2 HBD, 4 HBA) and Ligand B (1 HBD, 3 HBA) both have reasonable values, well below the thresholds of 5 and 10 respectively. Ligand B is slightly better here.

**QED:** Ligand B (0.877) has a significantly higher QED score than Ligand A (0.58), indicating better overall drug-likeness.

**DILI:** Ligand A (19.7%) has a much lower DILI risk than Ligand B (52.6%). This is a significant advantage for Ligand A.

**BBB:** Ligand B (75.1%) has a substantially higher BBB penetration score than Ligand A (29.0%). This is *critical* for a CNS target like DRD2, making Ligand B strongly favored.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.751 and -4.432), which is unusual and suggests poor permeability. However, these values are on a log scale and the difference is small.

**Aqueous Solubility:** Both ligands have negative solubility values (-2.346 and -2.592), indicating poor aqueous solubility. This is a concern for both.

**hERG Inhibition:** Ligand A (0.208) has a lower hERG inhibition liability than Ligand B (0.605), which is preferable.

**Microsomal Clearance:** Ligand A (35.9) has a lower microsomal clearance than Ligand B (55.1), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand B (29.7) has a much longer in vitro half-life than Ligand A (-5.864). This is a significant advantage for Ligand B.

**P-gp Efflux:** Ligand A (0.033) has a much lower P-gp efflux liability than Ligand B (0.164), which is beneficial for CNS penetration.

**Binding Affinity:** Ligand B (-9.3 kcal/mol) has a significantly stronger binding affinity than Ligand A (-6.4 kcal/mol). This is a major advantage for Ligand B, potentially outweighing some of the ADME drawbacks. The difference of 2.9 kcal/mol is substantial.

**Overall Assessment:**

While Ligand A has advantages in DILI, hERG, P-gp efflux, and metabolic stability, Ligand B's superior BBB penetration (75.1% vs 29.0%) and significantly stronger binding affinity (-9.3 vs -6.4 kcal/mol) are decisive for a CNS GPCR target. The longer half-life of Ligand B is also a positive. The slightly higher logP and DILI risk of Ligand B are acceptable trade-offs given its strong affinity and BBB penetration.

Output:
1
2025-04-17 05:40:47,427 - INFO - Reasoning:

Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (351.422 and 348.443 Da) fall comfortably within the ideal 200-500 Da range.

**2. TPSA:** Both ligands have TPSA values (71.53 and 71.78) that are acceptable for oral absorption (<140) but slightly higher than optimal for CNS penetration (<90). This is a minor concern, as other factors are more critical for CNS targets.

**3. logP:** Both ligands have logP values (2.065 and 2.594) within the optimal 1-3 range, suggesting good permeability and reasonable solubility.

**4. H-Bond Donors & Acceptors:** Both ligands have 1 HBD and 4 HBA, which are within acceptable limits.

**5. QED:** Both ligands have good QED scores (0.778 and 0.888), indicating a generally drug-like profile.

**6. DILI:** Ligand A (32.842) has a slightly higher DILI risk than Ligand B (25.165), but both are below the concerning threshold of 60.

**7. BBB:** Ligand A (91.819) demonstrates significantly better predicted BBB penetration than Ligand B (70.919). This is a crucial advantage for a CNS target like DRD2.

**8. Caco-2 Permeability:** Ligand A (-3.889) shows slightly better Caco-2 permeability than Ligand B (-4.643), suggesting better intestinal absorption.

**9. Aqueous Solubility:** Both ligands have very poor aqueous solubility (-2.258 and -2.317). This could pose formulation challenges.

**10. hERG Inhibition:** Both ligands have low hERG inhibition risk (0.304 and 0.278).

**11. Microsomal Clearance:** Ligand B (11.377) has a significantly lower microsomal clearance than Ligand A (65.134), indicating better metabolic stability.

**12. In vitro Half-Life:** Ligand B (25.993 hours) has a much longer in vitro half-life than Ligand A (-23.167 hours). This is a major advantage, potentially allowing for less frequent dosing.

**13. P-gp Efflux:** Both ligands have low P-gp efflux liability (0.055 and 0.066), which is favorable for CNS exposure.

**14. Binding Affinity:** Ligand B (-8.7 kcal/mol) has a significantly stronger binding affinity than Ligand A (-7.4 kcal/mol). This 1.3 kcal/mol difference is substantial and can outweigh some of the ADME drawbacks.

**Overall Assessment:**

While Ligand A has better BBB penetration and Caco-2 permeability, Ligand B exhibits a significantly stronger binding affinity, better metabolic stability (lower Cl_mic), and a longer half-life. The stronger binding affinity is a critical factor for GPCR targets, and the improved metabolic stability and half-life address potential limitations of Ligand A. The slightly lower BBB score for Ligand B is less concerning given its superior potency. The solubility is a concern for both, but can be addressed through formulation strategies.

Output:
1
2025-04-17 05:40:47,427 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (346.427 Da) is slightly lower, which could be beneficial for permeability.

**TPSA:** Ligand A (67.87) is significantly better than Ligand B (105.28). For CNS targets, we want TPSA <= 90, and A is comfortably within that range, while B is above.

**logP:** Ligand A (1.9) is optimal, while Ligand B (-0.42) is below the preferred range of 1-3. This could hinder permeation for Ligand B.

**H-Bond Donors/Acceptors:** Ligand A (HBD=1, HBA=4) and Ligand B (HBD=2, HBA=7) both fall within acceptable limits, though B has a higher HBA count.

**QED:** Both ligands have reasonable QED values (A: 0.846, B: 0.764), indicating good drug-like properties.

**DILI:** Ligand B (63.203) has a higher DILI risk than Ligand A (31.718), though both are below the concerning threshold of 60.

**BBB:** This is a crucial parameter for a CNS target like DRD2. Ligand A (65.839) is significantly better than Ligand B (11.981). A value >70 is desirable, and A is closer to that target.

**Caco-2 Permeability:** Ligand A (-4.399) is better than Ligand B (-5.308). Higher values indicate better intestinal absorption.

**Aqueous Solubility:** Ligand A (-2.894) is better than Ligand B (-2.102).

**hERG:** Both ligands have very low hERG risk (A: 0.266, B: 0.054).

**Microsomal Clearance:** Ligand A (25.742) has a higher clearance than Ligand B (-1.675), suggesting lower metabolic stability. However, the negative value for B is unusual and may indicate very high stability.

**In vitro Half-Life:** Ligand A (-8.293) has a longer half-life than Ligand B (-5.915).

**P-gp Efflux:** Ligand A (0.07) shows lower P-gp efflux than Ligand B (0.034), which is favorable for CNS penetration.

**Binding Affinity:** Ligand B (-7.9 kcal/mol) has a slightly better binding affinity than Ligand A (-8.5 kcal/mol). However, the difference is small (0.6 kcal/mol) and may not be enough to overcome the ADME deficiencies of Ligand B.

**Overall Assessment:**

Ligand A is the stronger candidate. It excels in key GPCR properties like TPSA, logP, and especially BBB penetration. While Ligand B has slightly better binding affinity, its poor logP and extremely low BBB penetration are significant drawbacks for a CNS-targeting drug. The better ADME profile of Ligand A, particularly its favorable BBB score, outweighs the minor affinity difference.

Output:
1
2025-04-17 05:40:47,427 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 drug candidates, considering the provided guidelines and GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight (MW):** Both ligands (350.463 and 344.459 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (87.46) is better than Ligand B (67.23). Both are below the 90 A^2 threshold for CNS targets, but Ligand B is closer to optimal.

**3. logP:** Both ligands have good logP values (1.246 and 2.152), falling within the 1-3 range. Ligand B is slightly better.

**4. H-Bond Donors (HBD):** Both ligands are within the acceptable limit of <=5 (Ligand A: 2, Ligand B: 1).

**5. H-Bond Acceptors (HBA):** Both ligands are within the acceptable limit of <=10 (Ligand A: 5, Ligand B: 4).

**6. QED:** Both ligands have good QED scores (0.739 and 0.771), indicating good drug-like properties.

**7. DILI:** Both ligands have low DILI risk (32.299 and 36.681), well below the 40 threshold.

**8. BBB:** Ligand B (76.231) is significantly better than Ligand A (54.634) regarding BBB penetration, which is crucial for a CNS target like DRD2.

**9. Caco-2 Permeability:** Both have negative values, which is unusual. Assuming these are logP-scale values, lower values indicate poorer permeability. Ligand A (-4.724) is worse than Ligand B (-4.906).

**10. Aqueous Solubility:** Both have negative values, which is unusual. Assuming these are logS values, lower values indicate poorer solubility. Ligand A (-1.183) is better than Ligand B (-2.918).

**11. hERG Inhibition:** Both ligands have low hERG inhibition risk (0.192 and 0.408).

**12. Microsomal Clearance (Cl_mic):** Ligand A (12.831) has a lower clearance than Ligand B (43.887), indicating better metabolic stability.

**13. In vitro Half-Life:** Ligand A (12.018) has a longer half-life than Ligand B (7.815).

**14. P-gp Efflux:** Both ligands have low P-gp efflux liability (0.052 and 0.208).

**15. Binding Affinity:** Ligand B (-8.4 kcal/mol) has a significantly stronger binding affinity than Ligand A (-7.7 kcal/mol). The difference of 0.7 kcal/mol is substantial and can outweigh some ADME drawbacks.

**Overall Assessment:**

Ligand B is the more promising candidate. While Ligand A has better metabolic stability (lower Cl_mic, longer t1/2) and solubility, Ligand B excels in the most critical areas for a CNS-targeting GPCR: **BBB penetration and binding affinity**. The 0.7 kcal/mol difference in binding affinity is significant. The slightly lower metabolic stability of Ligand B can potentially be addressed through further optimization, but a strong binding affinity and good CNS penetration are harder to achieve.

Output:
1
2025-04-17 05:40:47,428 - INFO - Batch 218 complete. Total preferences: 3488
2025-04-17 05:40:47,428 - INFO - Processing batch 219/512...
2025-04-17 05:41:29,854 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (381.445 and 370.559 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (95.58) is slightly above the optimal <90 for CNS targets, but still reasonable. Ligand B (66.48) is well within the desired range.

**logP:** Ligand A (-0.576) is a bit low, potentially hindering permeation. Ligand B (2.769) is nearly ideal.

**H-Bond Donors/Acceptors:** Ligand A has 2 HBD and 5 HBA, which are acceptable. Ligand B has 1 HBD and 3 HBA, also acceptable.

**QED:** Both ligands have good QED scores (0.616 and 0.782), indicating good drug-like properties.

**DILI:** Both ligands have the same DILI risk (32.842 percentile), which is low and favorable.

**BBB:** Ligand B (87.941) has a significantly higher BBB penetration score than Ligand A (64.831). This is a crucial advantage for a CNS target like DRD2.

**Caco-2 Permeability:** Ligand A (-5.456) and Ligand B (-4.95) both have negative values, which is unusual and suggests very low permeability. This is a significant concern for both.

**Aqueous Solubility:** Ligand A (-1.557) and Ligand B (-4.204) both have negative values, indicating poor aqueous solubility. This could pose formulation challenges.

**hERG Inhibition:** Ligand A (0.113) has a very low hERG risk, which is excellent. Ligand B (0.627) is slightly higher, but still relatively low.

**Microsomal Clearance:** Ligand A (-12.298) has a negative clearance, which is not physically meaningful and likely indicates very high metabolic stability. Ligand B (80.023) has a high clearance, suggesting faster metabolism.

**In vitro Half-Life:** Ligand A (7.012 hours) has a reasonable half-life. Ligand B (-36.398 hours) has a negative half-life, which is not physically meaningful.

**P-gp Efflux:** Ligand A (0.008) has very low P-gp efflux, which is excellent for CNS penetration. Ligand B (0.146) has slightly higher efflux, but still relatively low.

**Binding Affinity:** Ligand B (-8.6 kcal/mol) has a slightly better binding affinity than Ligand A (-7.5 kcal/mol). While both are good, the 1.1 kcal/mol difference is notable.

**Overall Assessment:**

Ligand B is the stronger candidate. While both have issues with Caco-2 permeability and solubility, Ligand B excels in BBB penetration and has a better binding affinity. The higher logP is also favorable. Ligand A's negative clearance and half-life values are concerning and likely represent errors or limitations in the prediction methods. The better BBB score and affinity of Ligand B, combined with acceptable ADME properties, make it the more promising drug candidate for DRD2.

Output:
1
2025-04-17 05:41:29,854 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (344.371 and 354.51 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (106.35) is better than Ligand B (49.41). For CNS targets, TPSA should be <=90, and both meet this criteria, but A is closer to the upper limit.

**logP:** Ligand A (1.327) is within the optimal 1-3 range. Ligand B (3.408) is at the higher end of the optimal range, potentially raising concerns about off-target effects, but still acceptable.

**H-Bond Donors/Acceptors:** Ligand A has 2 HBD and 6 HBA, while Ligand B has 1 HBD and 2 HBA. Both are within acceptable limits (<=5 HBD and <=10 HBA).

**QED:** Ligand A (0.785) has a slightly better QED score than Ligand B (0.69), indicating better overall drug-likeness.

**DILI:** Ligand A (52.772) has a significantly lower DILI risk than Ligand B (19.038), which is a major advantage.

**BBB:** Ligand B (89.221) has a substantially higher BBB penetration score than Ligand A (62.854). This is *critical* for a CNS target like DRD2.

**Caco-2 Permeability:** Both have negative values (-4.674 and -4.31), which is unusual and suggests poor permeability. This is a concern for both, but the values are similar.

**Aqueous Solubility:** Both have negative values (-2.894 and -4.127), indicating poor aqueous solubility. This could pose formulation challenges.

**hERG Inhibition:** Ligand A (0.174) has a lower hERG inhibition risk than Ligand B (0.78). This is a positive for Ligand A.

**Microsomal Clearance:** Ligand B (74.078) has a much higher microsomal clearance than Ligand A (15.354), indicating lower metabolic stability.

**In vitro Half-Life:** Ligand A (21.244) has a longer in vitro half-life than Ligand B (-10.679). The negative value for B is concerning and likely an error or indicates very rapid metabolism.

**P-gp Efflux:** Ligand A (0.004) has a much lower P-gp efflux liability than Ligand B (0.351), which is beneficial for CNS penetration.

**Binding Affinity:** Both ligands have similar and strong binding affinities (-8.2 and -7.8 kcal/mol), both well below the -7.0 threshold. The difference of 0.4 kcal/mol is not substantial enough to outweigh other factors.

**Overall Assessment:**

Ligand A has advantages in DILI risk, hERG inhibition, metabolic stability (lower Cl_mic, longer t1/2), and P-gp efflux. However, Ligand B shines with its significantly better BBB penetration. Given that DRD2 is a CNS target, BBB penetration is paramount. While Ligand A has a better safety profile and metabolic stability, the superior BBB score of Ligand B is the deciding factor.

Output:
1
2025-04-17 05:41:29,855 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (367.823 and 347.411 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (30.49) is excellent, well below the 90 A^2 threshold for CNS targets. Ligand B (58.18) is higher, but still reasonable.

**logP:** Ligand A (4.906) is slightly high, potentially leading to solubility issues or off-target interactions. Ligand B (3.732) is within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Both have acceptable HBD counts (1). Ligand B has a higher HBA count (6) compared to Ligand A (3), but both are within the acceptable limit of 10.

**QED:** Both ligands have similar QED values (0.754 and 0.746), indicating good drug-likeness.

**DILI:** Ligand A (38.813) has a lower DILI risk than Ligand B (72.586), which is a significant advantage.

**BBB:** Ligand A (85.498) has a significantly better BBB penetration percentile than Ligand B (60.101). This is crucial for a CNS target like DRD2.

**Caco-2 Permeability:** Both have negative Caco-2 values (-4.736 and -4.597), which is unusual and suggests poor permeability. However, these values are on a scale where negative values are possible and don't necessarily disqualify a compound.

**Aqueous Solubility:** Both have negative solubility values (-4.925 and -4.404), indicating poor aqueous solubility. This is a concern, particularly for Ligand A with its higher logP.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.916 and 0.807).

**Microsomal Clearance:** Ligand A (39.561) has lower microsomal clearance than Ligand B (62.972), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (39.128) has a much longer in vitro half-life than Ligand B (2.712), which is highly desirable.

**P-gp Efflux:** Ligand A (0.628) has lower P-gp efflux liability than Ligand B (0.314), which is beneficial for CNS penetration.

**Binding Affinity:** Ligand A (-9.0 kcal/mol) has a significantly stronger binding affinity than Ligand B (-7.0 kcal/mol). This 1.5+ kcal/mol difference is substantial and can outweigh some ADME drawbacks.

**Overall Assessment:**

Ligand A is the superior candidate. While its logP is slightly elevated and solubility is low, its significantly stronger binding affinity, better BBB penetration, lower DILI risk, lower P-gp efflux, and longer half-life outweigh these concerns. The substantial affinity difference is particularly important for a GPCR target. Ligand B, while having a better logP, suffers from poorer BBB penetration, higher DILI risk, and significantly weaker binding.

Output:
1
2025-04-17 05:41:29,855 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 drug candidates, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight (MW):** Both ligands (346.39 and 346.52 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (104.54) is higher than the preferred <90 for CNS targets, while Ligand B (58.2) is well within the desirable range. This is a significant advantage for Ligand B.

**3. logP:** Ligand A (0.221) is quite low, potentially hindering membrane permeability. Ligand B (3.402) is within the optimal 1-3 range. This favors Ligand B.

**4. H-Bond Donors (HBD):** Both ligands have 2 HBD, which is acceptable.

**5. H-Bond Acceptors (HBA):** Ligand A has 5 HBA, acceptable. Ligand B has 2 HBA, also acceptable.

**6. QED:** Both ligands have good QED scores (0.655 and 0.819), indicating drug-like properties.

**7. DILI:** Both ligands have low DILI risk (38.97 and 33.23), which is good.

**8. BBB:** Ligand A (48.35%) has a moderate BBB penetration, while Ligand B (73.87%) has a very good BBB penetration. This is a critical advantage for Ligand B, given DRD2 is a CNS target.

**9. Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and requires further investigation, but doesn't immediately disqualify either.

**10. Aqueous Solubility:** Both have negative solubility values, which is also unusual and requires further investigation.

**11. hERG Inhibition:** Ligand A (0.028) has very low hERG inhibition risk, while Ligand B (0.415) has a slightly higher, but still acceptable, risk.

**12. Microsomal Clearance (Cl_mic):** Ligand A (27.34) has a slightly higher clearance than Ligand B (24.10), suggesting potentially lower metabolic stability.

**13. In vitro Half-Life:** Ligand A (-43.04) has a very negative half-life, which is concerning. Ligand B (38.02) has a positive half-life, indicating better stability.

**14. P-gp Efflux:** Ligand A (0.006) has very low P-gp efflux, which is good. Ligand B (0.142) has slightly higher P-gp efflux, but still relatively low.

**15. Binding Affinity:** Ligand B (-9.4 kcal/mol) has a significantly stronger binding affinity than Ligand A (-7.8 kcal/mol). This >1.5 kcal/mol difference is substantial and can outweigh minor ADME drawbacks.

**Overall Assessment:**

Ligand B is significantly more promising. It excels in key GPCR properties: TPSA, logP, BBB penetration, and, most importantly, binding affinity. While both have unusual solubility and Caco-2 values that warrant further investigation, Ligand B's superior CNS penetration and binding affinity make it the more viable candidate. Ligand A's low logP and negative half-life are significant drawbacks.

Output:
1
2025-04-17 05:41:29,855 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (344.455 and 352.395 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (58.64) is excellent, well below the 90 A^2 threshold for CNS targets. Ligand B (119.54) is higher, but still potentially acceptable, though less ideal.

**3. logP:** Ligand A (2.351) is optimal (1-3). Ligand B (-1.295) is quite low, potentially hindering membrane permeability and CNS penetration.

**4. H-Bond Donors:** Ligand A (1) is good. Ligand B (3) is acceptable, but approaching the upper limit.

**5. H-Bond Acceptors:** Ligand A (3) is good. Ligand B (5) is acceptable.

**6. QED:** Ligand A (0.753) is excellent. Ligand B (0.565) is acceptable, but lower.

**7. DILI:** Ligand A (24.661) has a very low DILI risk. Ligand B (49.321) is higher, indicating a moderate risk, but still not alarming.

**8. BBB:** Ligand A (69.407) is good, above the 70% threshold for CNS targets. Ligand B (42.032) is significantly lower, raising concerns about CNS penetration.

**9. Caco-2 Permeability:** Ligand A (-4.794) is concerningly low. Ligand B (-5.216) is similarly low. Both suggest poor intestinal absorption.

**10. Aqueous Solubility:** Ligand A (-2.819) is poor. Ligand B (-1.746) is also poor.

**11. hERG Inhibition:** Both ligands (0.183 and 0.19) show very low hERG inhibition liability, which is excellent.

**12. Microsomal Clearance:** Ligand A (36.769) has moderate clearance. Ligand B (-13.716) has negative clearance, which is unusual and likely an error or indicates very high metabolic stability.

**13. In vitro Half-Life:** Ligand A (1.37) has a short half-life. Ligand B (3.621) has a longer half-life.

**14. P-gp Efflux:** Both ligands (0.11 and 0.009) have low P-gp efflux, which is favorable for CNS penetration.

**15. Binding Affinity:** Ligand A (-8.9 kcal/mol) has significantly stronger binding affinity than Ligand B (-7.5 kcal/mol). This 1.4 kcal/mol difference is substantial.

**Overall Assessment:**

Ligand A is superior despite its poor Caco-2 and solubility. Its excellent TPSA, logP, BBB, QED, DILI, and *significantly* stronger binding affinity outweigh the concerns about permeability and solubility. The strong binding affinity suggests it might overcome permeability issues *in vivo*. Ligand B's low logP and poor BBB penetration are major drawbacks for a CNS target. While its half-life is better, the affinity is not strong enough to compensate for the other deficiencies.

Output:
1
2025-04-17 05:41:29,855 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (352.32 and 378.523 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (80.65) is better than Ligand B (68.21) as it is closer to the ideal <90 for CNS targets.

**3. logP:** Both ligands (2.851 and 2.864) are within the optimal 1-3 range.

**4. H-Bond Donors:** Ligand A (2) is preferable to Ligand B (0). While both are acceptable, a small number of HBDs can improve solubility without drastically impacting permeability.

**5. H-Bond Acceptors:** Ligand A (6) is slightly better than Ligand B (7). Both are within the acceptable range.

**6. QED:** Both ligands have similar QED values (0.713 and 0.704), indicating good drug-likeness.

**7. DILI:** Both ligands have similar DILI risk (80.07 and 60.954), with Ligand B being slightly better. Both are acceptable, but ideally, we'd want values below 60.

**8. BBB:** Ligand B (74.06) is significantly better than Ligand A (60.527) in terms of predicted BBB penetration, a crucial factor for CNS targets like DRD2.

**9. Caco-2 Permeability:** Ligand A (-4.916) is better than Ligand B (-4.979). Higher values indicate better absorption.

**10. Aqueous Solubility:** Ligand A (-4.559) is better than Ligand B (-3.101). Higher values are better.

**11. hERG Inhibition:** Both ligands show low hERG inhibition liability (0.426 and 0.291), which is good.

**12. Microsomal Clearance:** Ligand A (38.119) has lower microsomal clearance than Ligand B (62.36), suggesting better metabolic stability.

**13. In vitro Half-Life:** Ligand A (-33.206) has a much longer in vitro half-life than Ligand B (8.933), a significant advantage.

**14. P-gp Efflux:** Ligand A (0.237) has lower P-gp efflux than Ligand B (0.145), which is preferable for CNS exposure.

**15. Binding Affinity:** Ligand A (-8.9 kcal/mol) has a significantly stronger binding affinity than Ligand B (-6.6 kcal/mol). This is a substantial advantage, potentially outweighing some minor ADME drawbacks.

**Overall Assessment:**

While Ligand B has a better BBB score, Ligand A excels in several other critical areas, particularly binding affinity and metabolic stability (longer half-life, lower clearance). The significantly stronger binding affinity (-8.9 vs -6.6 kcal/mol) is a major advantage for a GPCR target. The improved solubility and Caco-2 permeability of Ligand A are also beneficial. The slightly higher TPSA is not a major concern given the strong affinity.

Output:
1
2025-04-17 05:41:29,856 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (451.68) is slightly higher, but still acceptable.

**2. TPSA:** Ligand A (68.29) is better than Ligand B (49.85) as it is closer to the ideal range for CNS targets (<=90).

**3. logP:** Both ligands have good logP values (A: 4.366, B: 3.115), falling within the optimal range of 1-3. Ligand B is slightly preferred here.

**4. H-Bond Donors:** Ligand A (1) is better than Ligand B (0).

**5. H-Bond Acceptors:** Ligand A (5) is better than Ligand B (4).

**6. QED:** Both ligands have good QED scores (A: 0.554, B: 0.748), indicating good drug-like properties. Ligand B is slightly preferred.

**7. DILI:** Ligand A (92.051) has a significantly higher DILI risk than Ligand B (38.581). This is a major concern for Ligand A.

**8. BBB:** Ligand A (81.466) has a better BBB penetration percentile than Ligand B (69.484), which is crucial for a CNS target like DRD2.

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 values, which is unusual and suggests poor permeability.

**10. Aqueous Solubility:** Both ligands have negative solubility values, suggesting poor solubility.

**11. hERG:** Both ligands have low hERG inhibition liability (A: 0.229, B: 0.311), which is good.

**12. Microsomal Clearance:** Ligand B (113.17) has a higher microsomal clearance than Ligand A (87.525), indicating lower metabolic stability.

**13. In vitro Half-Life:** Ligand A (39.856) has a longer in vitro half-life than Ligand B (2.812), which is preferable.

**14. P-gp Efflux:** Both ligands have low P-gp efflux liability (A: 0.454, B: 0.355), which is good for CNS penetration.

**15. Binding Affinity:** Both ligands have similar strong binding affinities (A: -8.6 kcal/mol, B: -8.3 kcal/mol). The difference is less than 1.5 kcal/mol, so it doesn't significantly sway the decision.

**Overall Assessment:**

Ligand A has a better BBB score and in vitro half-life, but a significantly higher DILI risk. Ligand B has a better QED, logP, and lower DILI risk, but a shorter half-life and lower BBB penetration. Given the importance of minimizing toxicity (DILI) and achieving CNS penetration for a DRD2 target, Ligand B is the more promising candidate. While the BBB score isn't ideal, it's less concerning than the high DILI risk associated with Ligand A. The slightly lower affinity of Ligand B is not a major drawback given the strong binding of both compounds.

Output:
1
2025-04-17 05:41:29,856 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (350.423 and 351.407 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (121.03) is better than Ligand B (129.37). Both are reasonably close to the 140 A^2 threshold for oral absorption, but for a CNS target like DRD2, we ideally want <90 A^2. Ligand A is closer to this target.

**3. logP:** Ligand A (0.957) is within the optimal range (1-3), but on the lower end. Ligand B (-1.015) is below 1, which could hinder permeation. This favors Ligand A.

**4. H-Bond Donors:** Both ligands have 4 HBD, which is acceptable (<=5).

**5. H-Bond Acceptors:** Ligand A has 5 HBA, and Ligand B has 7. Both are within the acceptable limit of <=10, but Ligand A is slightly better.

**6. QED:** Ligand A (0.603) has a better QED score than Ligand B (0.451), indicating a more drug-like profile.

**7. DILI:** Ligand B (27.801) has a significantly lower DILI risk than Ligand A (60.915). This is a substantial advantage for Ligand B.

**8. BBB:** Ligand A (69.794) has a better BBB penetration percentile than Ligand B (23.769). This is *critical* for a CNS target like DRD2, and is a major advantage for Ligand A.

**9. Caco-2:** Both have negative Caco-2 values (-5.282 and -5.659), which is unusual and suggests poor permeability. This is a concern for both, but doesn't differentiate them.

**10. Solubility:** Both have negative solubility values (-2.252 and -1.033), indicating poor aqueous solubility. This is a concern for both, but doesn't differentiate them.

**11. hERG:** Both ligands have very low hERG inhibition liability (0.038 and 0.034), which is excellent.

**12. Cl_mic:** Ligand B (-5.026) has a lower (better) microsomal clearance than Ligand A (-19.666), indicating greater metabolic stability.

**13. t1/2:** Ligand A (8.666) has a slightly longer in vitro half-life than Ligand B (6.536).

**14. Pgp:** Both ligands have very low Pgp efflux liability (0.005 and 0.002), which is favorable.

**15. Binding Affinity:** Ligand B (-7.8) has a significantly stronger binding affinity than Ligand A (-9.0). A 1.2 kcal/mol difference is substantial and can outweigh some ADME drawbacks.

**Overall Assessment:**

Ligand A excels in BBB penetration and has a better QED score, but suffers from a higher DILI risk and poorer metabolic stability. Ligand B has a much better safety profile (DILI) and metabolic stability, and a significantly stronger binding affinity, but its BBB penetration is poor.

Given the GPCR-specific priorities, *strong binding affinity and BBB penetration are paramount*. While Ligand A has better BBB, the substantial affinity advantage of Ligand B (-7.8 vs -9.0 kcal/mol) is a major factor. The better metabolic stability and lower DILI risk of Ligand B further support its selection. The poor logP of Ligand B is a concern, but the strong binding may compensate.

Output:
1
2025-04-17 05:41:29,856 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (347.46 and 357.43 Da) fall comfortably within the ideal 200-500 Da range.

**TPSA:** Ligand A (80.32) is significantly better than Ligand B (98.74). For CNS targets, we want TPSA <= 90, so Ligand A is preferable.

**logP:** Ligand A (2.388) is within the optimal 1-3 range. Ligand B (-0.022) is quite low, potentially hindering membrane permeability and CNS penetration. This is a significant drawback for a CNS target.

**H-Bond Donors/Acceptors:** Both have 2 HBDs and 4 HBAs, which are acceptable.

**QED:** Both ligands have reasonable QED scores (0.672 and 0.532), indicating decent drug-likeness.

**DILI:** Ligand A (32.61) has a lower DILI risk than Ligand B (45.25), which is favorable.

**BBB:** Ligand A (58.938) has a better BBB percentile than Ligand B (47.809), although both are below the desirable >70 for CNS targets. This is a critical point; we need good CNS penetration.

**Caco-2 Permeability:** Both have negative Caco-2 values (-4.766 and -4.749), which is unusual and suggests poor permeability. However, these values are on a log scale and difficult to interpret without context.

**Aqueous Solubility:** Both have negative solubility values (-2.592 and -1.751), also unusual and suggesting poor solubility.

**hERG:** Both ligands have low hERG risk (0.406 and 0.493).

**Microsomal Clearance:** Ligand A (68.1) has higher microsomal clearance than Ligand B (40.732), indicating faster metabolism and potentially lower *in vivo* exposure.

**In vitro Half-Life:** Ligand B (-31.209) has a very negative half-life, which is not physically meaningful and suggests instability. Ligand A (2.762) is more reasonable.

**P-gp Efflux:** Both have low P-gp efflux liability (0.051 and 0.216), which is good for CNS penetration.

**Binding Affinity:** Ligand A (-7.6 kcal/mol) has a slightly better binding affinity than Ligand B (-7.2 kcal/mol). While the difference is not huge, it's enough to consider, especially given the other factors.

**Overall Assessment:**

Ligand A is significantly better due to its more favorable logP, TPSA, DILI, and binding affinity. While its BBB penetration isn't ideal, it's better than Ligand B's. Ligand B's very low logP and negative half-life are major red flags. The solubility and Caco-2 values are concerning for both, but the other factors strongly favor Ligand A.

Output:
1
2025-04-17 05:41:29,856 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 drug candidates, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight (MW):** Both ligands (362.392 and 351.441 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (69.64) is better than Ligand B (41.15). Both are below the 90 A^2 threshold for CNS targets, but Ligand A is slightly higher and may present a minor permeability issue, while Ligand B is excellent.

**3. logP:** Ligand A (1.701) is within the optimal range (1-3), while Ligand B (3.758) is approaching the upper limit. This suggests Ligand B might have solubility issues.

**4. H-Bond Donors (HBD):** Both ligands have acceptable HBD counts (2 and 1, respectively), well below the limit of 5.

**5. H-Bond Acceptors (HBA):** Both ligands have acceptable HBA counts (3 each), well below the limit of 10.

**6. QED:** Both ligands have good QED scores (0.782 and 0.813), indicating good drug-like properties.

**7. DILI:** Ligand A (12.33) has a significantly lower DILI risk than Ligand B (15.626), which is a substantial advantage.

**8. BBB:** Ligand B (86.661) has a much higher BBB penetration percentile than Ligand A (74.254). This is a critical advantage for a CNS target like DRD2.

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.824 and -4.801), which is unusual and suggests poor permeability. However, these values are on the same scale, so this doesn't differentiate the two.

**10. Aqueous Solubility:** Both ligands have negative solubility values (-2.622 and -3.354), also unusual and indicating poor solubility. Again, similar for both.

**11. hERG Inhibition:** Both ligands have low hERG inhibition risk (0.417 and 0.928).

**12. Microsomal Clearance (Cl_mic):** Ligand A (7.515) has significantly lower microsomal clearance than Ligand B (38.972), indicating better metabolic stability.

**13. In vitro Half-Life:** Ligand A (-18.889) has a much longer in vitro half-life than Ligand B (0.893), which is a significant advantage.

**14. P-gp Efflux:** Ligand A (0.088) has a much lower P-gp efflux liability than Ligand B (0.519), which is beneficial for CNS exposure.

**15. Binding Affinity:** Both ligands have very similar and strong binding affinities (-8.9 and -8.1 kcal/mol). The difference of 0.8 kcal/mol is not substantial enough to outweigh other factors.

**Overall Assessment:**

Ligand B excels in BBB penetration, which is paramount for a CNS target. However, Ligand A demonstrates superior ADME properties: lower DILI risk, better metabolic stability (lower Cl_mic, longer t1/2), and lower P-gp efflux. While both have poor Caco-2 and solubility, the ADME advantages of Ligand A, combined with comparable binding affinity, make it the more promising candidate. The higher BBB of Ligand B is attractive, but the other ADME liabilities are concerning.

Output:
0
2025-04-17 05:41:29,856 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B based on the provided guidelines, prioritizing GPCR-specific properties (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (344.375 and 348.531 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (115.05) is borderline for CNS targets, being slightly above the preferred <90. Ligand B (41.57) is excellent, well below the threshold.

**logP:** Ligand A (0.116) is quite low, potentially hindering permeation. Ligand B (3.493) is optimal.

**H-Bond Donors/Acceptors:** Ligand A has 2 HBD and 5 HBA, which are acceptable. Ligand B has 1 HBD and 3 HBA, also acceptable.

**QED:** Both ligands have good QED scores (0.82 and 0.799), indicating drug-like properties.

**DILI:** Ligand A (54.207) has a moderate DILI risk, while Ligand B (12.136) has a very low risk.

**BBB:** This is crucial for a CNS target. Ligand A (23.381) has poor BBB penetration, while Ligand B (86.041) is excellent, exceeding the desirable >70 threshold.

**Caco-2 Permeability:** Ligand A (-5.058) has very poor Caco-2 permeability. Ligand B (-4.718) is also poor, but slightly better than A.

**Aqueous Solubility:** Both ligands have poor aqueous solubility (-2.494 and -3.998).

**hERG:** Ligand A (0.311) has a low hERG risk, which is good. Ligand B (0.716) has a slightly higher, but still acceptable, hERG risk.

**Microsomal Clearance:** Ligand A (-17.007) has very low microsomal clearance, suggesting high metabolic stability. Ligand B (61.409) has higher clearance, indicating faster metabolism.

**In vitro Half-Life:** Ligand A (0.857) has a very short half-life. Ligand B (11.318) has a much longer, and more desirable, half-life.

**P-gp Efflux:** Ligand A (0.023) has very low P-gp efflux, which is excellent for CNS penetration. Ligand B (0.264) has slightly higher efflux, but still relatively low.

**Binding Affinity:** Ligand B (-7.2 kcal/mol) has a significantly stronger binding affinity than Ligand A (-8.5 kcal/mol). While A is already quite good, B's affinity is superior.

**Overall Assessment:**

Ligand B is the stronger candidate. While both have solubility issues, Ligand B excels in key areas for a CNS-targeting GPCR: BBB penetration, logP, binding affinity, and DILI risk. Its longer half-life is also a significant advantage. Ligand A's low logP and poor BBB penetration are major drawbacks, despite its good metabolic stability and P-gp efflux profile. The superior affinity of Ligand B further solidifies its position as the more promising candidate.

Output:
1
2025-04-17 05:41:29,857 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (341.415 and 349.475 Da) fall comfortably within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (101.21) is slightly above the optimal <90 for CNS targets, but still reasonable. Ligand B (71) is excellent, well below 90. This favors Ligand B.

**3. logP:** Both ligands have good logP values (1.136 and 2.354), falling within the 1-3 range. Ligand B is slightly better.

**4. H-Bond Donors:** Ligand A (2) and Ligand B (1) are both within the acceptable limit of <=5. Ligand B is slightly better.

**5. H-Bond Acceptors:** Ligand A (5) and Ligand B (4) are both within the acceptable limit of <=10. Ligand B is slightly better.

**6. QED:** Both ligands have acceptable QED values (0.8 and 0.717), indicating good drug-like properties.

**7. DILI:** Ligand A (50.33) has a moderate DILI risk, while Ligand B (23.769) has a lower, more favorable DILI risk. This favors Ligand B.

**8. BBB:** Ligand A (92.672) shows excellent BBB penetration, exceeding the desirable >70 threshold. Ligand B (68.786) is below this threshold, which is a significant drawback for a CNS target. This favors Ligand A.

**9. Caco-2 Permeability:** Ligand A (-5.125) and Ligand B (-4.695) both have negative values, which is unusual. However, the scale isn't specified, so it's hard to interpret.

**10. Aqueous Solubility:** Both ligands have negative solubility values (-3.37 and -2.584), again, the scale is unknown.

**11. hERG Inhibition:** Both ligands have very low hERG inhibition liability (0.399 and 0.456), which is excellent.

**12. Microsomal Clearance:** Both ligands have similar microsomal clearance values (18.982 and 19.084 mL/min/kg), suggesting comparable metabolic stability.

**13. In vitro Half-Life:** Ligand A (-14.025) has a negative half-life, which is impossible. This is a major red flag. Ligand B (2.736) has a short, but positive half-life.

**14. P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.016 and 0.2), which is excellent for CNS penetration.

**15. Binding Affinity:** Ligand A (-9.4 kcal/mol) has a significantly stronger binding affinity than Ligand B (-8.7 kcal/mol). This is a substantial advantage.

**Overall Assessment:**

Ligand A has a major issue with its reported half-life being negative, which is physically impossible and suggests an error in the data. It also has a slightly higher TPSA. However, it excels in BBB penetration and, crucially, has a significantly stronger binding affinity. Ligand B has better TPSA, DILI and H-bonding characteristics, but its BBB penetration is suboptimal for a CNS target, and its binding affinity is weaker.

Given the importance of binding affinity for GPCRs, and the critical need for BBB penetration for CNS targets, the stronger affinity and better BBB penetration of Ligand A outweigh its other drawbacks, *assuming the negative half-life is a data error*. If the half-life is accurate, Ligand A is immediately disqualified.

Output:
1
2025-04-17 05:41:29,857 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (358.404 and 384.527 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (62.22) is excellent, well below the 90 A^2 threshold for CNS targets. Ligand B (92.26) is still reasonable but closer to the upper limit, potentially impacting BBB penetration.

**logP:** Ligand A (3.481) is optimal. Ligand B (1.584) is a bit low; while not drastically so, it could hinder membrane permeability.

**H-Bond Donors/Acceptors:** Ligand A (2 HBD, 3 HBA) is favorable. Ligand B (1 HBD, 6 HBA) is also acceptable, though the higher HBA count could slightly affect permeability.

**QED:** Both ligands have good QED scores (0.847 and 0.752), indicating generally drug-like properties.

**DILI:** Ligand A (22.024) has a significantly lower DILI risk than Ligand B (56.883), which is a substantial advantage.

**BBB:** Ligand A (84.413) shows excellent BBB penetration potential, exceeding the 70% threshold. Ligand B (73.401) is still decent, but less favorable.

**Caco-2 Permeability:** Ligand A (-4.556) has poor Caco-2 permeability. Ligand B (-5.055) is also poor, but slightly worse.

**Aqueous Solubility:** Both ligands have very poor aqueous solubility (-3.645 and -3.63). This is a significant drawback for both, potentially impacting bioavailability.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.521 and 0.242).

**Microsomal Clearance:** Ligand A (18.096) has a lower microsomal clearance, suggesting better metabolic stability than Ligand B (66.441).

**In vitro Half-Life:** Ligand A (-0.376) has a slightly longer in vitro half-life than Ligand B (-38.786).

**P-gp Efflux:** Ligand A (0.307) has lower P-gp efflux liability than Ligand B (0.229), which is beneficial for CNS exposure.

**Binding Affinity:** Both ligands have very similar and excellent binding affinities (-8.5 and -8.2 kcal/mol). The difference is less than the 1.5 kcal/mol threshold.

**Overall Assessment:**

Ligand A is the stronger candidate. While both have poor solubility and Caco-2 permeability, Ligand A excels in crucial areas for a CNS-targeting GPCR ligand: significantly lower DILI risk, better BBB penetration, lower P-gp efflux, and improved metabolic stability. The slightly better half-life is also a plus. Although the logP is optimal for A and slightly low for B, the other advantages of A outweigh this. The similar binding affinities make the ADME properties the deciding factor.

Output:
1
2025-04-17 05:41:29,857 - INFO - Reasoning:

Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (347.455 and 363.889 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (55.84) is significantly better than Ligand B (58.22). Both are below the 90 A^2 threshold desirable for CNS targets, but A is closer to optimal.

**3. logP:** Both ligands have good logP values (3.98 and 3.741), falling within the optimal 1-3 range.

**4. H-Bond Donors:** Ligand A (0) is preferable to Ligand B (1). Fewer HBDs generally improve permeability.

**5. H-Bond Acceptors:** Both ligands have 4 HBA, which is acceptable (<=10).

**6. QED:** Both ligands have similar QED values (0.73 and 0.698), indicating good drug-likeness.

**7. DILI:** Ligand A (31.989) has a lower DILI risk than Ligand B (39.434), both are acceptable (<40 is good).

**8. BBB:** This is a crucial parameter for a CNS target like DRD2. Ligand A (84.374) has a significantly higher BBB percentile than Ligand B (61.574). A value >70 is desirable, and A is much closer.

**9. Caco-2 Permeability:** Ligand A (-4.301) has a more favorable Caco-2 permeability than Ligand B (-5.061).

**10. Aqueous Solubility:** Both ligands have poor aqueous solubility (-4.638 and -4.158). This is a potential issue, but can be addressed with formulation strategies.

**11. hERG Inhibition:** Ligand A (0.773) has a slightly lower hERG inhibition risk than Ligand B (0.936), which is favorable.

**12. Microsomal Clearance:** Ligand B (73.622) has lower microsomal clearance than Ligand A (97.086), suggesting better metabolic stability.

**13. In vitro Half-Life:** Ligand B (29.945) has a longer in vitro half-life than Ligand A (-13.602), which is a significant advantage.

**14. P-gp Efflux:** Ligand A (0.393) has lower P-gp efflux than Ligand B (0.44), which is preferable for CNS penetration.

**15. Binding Affinity:** Ligand B (-7.5 kcal/mol) has a better binding affinity than Ligand A (-8.7 kcal/mol). This is a substantial difference (1.2 kcal/mol), and a strong affinity can often outweigh other less-than-ideal properties.

**Overall Assessment:**

While Ligand B has a better binding affinity and metabolic stability (lower Cl_mic, longer t1/2), Ligand A excels in properties critical for CNS penetration (BBB, TPSA, Pgp) and has a lower DILI risk. The significantly better BBB penetration of Ligand A is a major advantage for a DRD2 ligand. The affinity difference, while notable, might be overcome with further optimization of Ligand A. Given the GPCR-specific priorities, the superior CNS penetration profile of Ligand A makes it the more promising candidate.

Output:
0
2025-04-17 05:41:29,857 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (352.421 and 352.475 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (43.37) is significantly better than Ligand B (98.66). For CNS targets, TPSA should be <=90, and A is comfortably within this range, while B is close to the upper limit and less desirable.

**3. logP:** Ligand A (4.998) is higher than optimal (1-3), but still potentially acceptable given the strong affinity. Ligand B (0.811) is quite low, which could hinder membrane permeability and CNS penetration.

**4. H-Bond Donors:** Ligand A (0) is ideal. Ligand B (4) is acceptable, but higher HBD can sometimes reduce permeability.

**5. H-Bond Acceptors:** Ligand A (3) is good. Ligand B (4) is also acceptable.

**6. QED:** Both ligands have similar and acceptable QED values (0.535 and 0.545, respectively).

**7. DILI:** Ligand A (49.632) has a moderate DILI risk, but is much better than Ligand B (16.479) which is very low and favorable.

**8. BBB:** This is a critical parameter for CNS targets. Ligand A (90.965) has excellent BBB penetration, while Ligand B (30.554) is poor.

**9. Caco-2 Permeability:** Ligand A (-4.09) is poor, while Ligand B (-5.206) is even worse. Both are unfavorable.

**10. Aqueous Solubility:** Ligand A (-5.556) is poor, while Ligand B (-2.404) is slightly better, but still unfavorable.

**11. hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.273 and 0.216, respectively).

**12. Microsomal Clearance:** Ligand A (96.147) has high clearance, indicating poor metabolic stability. Ligand B (4.492) has very low clearance, which is highly desirable.

**13. In vitro Half-Life:** Ligand A (4.589) has a short half-life, consistent with the high clearance. Ligand B (16.311) has a much longer half-life, which is favorable.

**14. P-gp Efflux:** Both ligands have low P-gp efflux liability (0.368 and 0.049, respectively), which is good.

**15. Binding Affinity:** Ligand A (-9.5 kcal/mol) has significantly stronger binding affinity than Ligand B (-8.0 kcal/mol). This is a substantial difference (1.5 kcal/mol) and can outweigh some ADME drawbacks.

**Overall Assessment:**

Despite Ligand A having a higher logP and poorer Caco-2/Solubility, its *much* stronger binding affinity (-9.5 vs -8.0 kcal/mol) and excellent BBB penetration (90.965) make it the more promising candidate. The high clearance is a concern, but could potentially be addressed through structural modifications. Ligand B's poor BBB penetration and weak affinity are major drawbacks for a CNS target, even with its better metabolic stability.

Output:
1
2025-04-17 05:41:29,858 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B based on the provided guidelines, prioritizing GPCR-specific properties (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (374.413 Da) and Ligand B (361.383 Da) are comparable.

**TPSA:** Ligand A (93.21) is excellent for CNS penetration, being well below 90. Ligand B (136.81) is higher, but still potentially acceptable, though less ideal.

**logP:** Ligand A (1.08) is within the optimal range. Ligand B (-0.021) is slightly below 1, which *could* indicate permeability issues, but is not a severe concern.

**H-Bond Donors/Acceptors:** Ligand A (HBD=2, HBA=6) and Ligand B (HBD=4, HBA=6) are both reasonable, falling within the suggested limits.

**QED:** Both ligands have acceptable QED values (A: 0.664, B: 0.555), indicating good drug-like properties.

**DILI:** Ligand A (55.448) has a lower DILI risk than Ligand B (90.074), which is a significant advantage.

**BBB:** This is a critical parameter for a CNS target like DRD2. Ligand A (83.443) has a very good BBB percentile, while Ligand B (32.067) is quite poor, suggesting limited brain penetration.

**Caco-2 Permeability:** Both have negative values, which is unusual. Assuming these are logP-like scales, lower values indicate lower permeability. Ligand A (-5.041) is slightly better than Ligand B (-5.502).

**Aqueous Solubility:** Both ligands have very poor solubility (-2.853 and -3.741 respectively). This could pose formulation challenges.

**hERG Inhibition:** Both ligands show low hERG inhibition risk (0.418 and 0.286 respectively).

**Microsomal Clearance:** Ligand A (6.575) has significantly lower microsomal clearance than Ligand B (19.805), indicating better metabolic stability.

**In vitro Half-Life:** Ligand A (8.848) has a better in vitro half-life than Ligand B (-9.33).

**P-gp Efflux:** Ligand A (0.109) has lower P-gp efflux than Ligand B (0.047), which is favorable for CNS penetration.

**Binding Affinity:** Both ligands have the same binding affinity (-8.4 kcal/mol), which is excellent.

**Overall Assessment:**

Ligand A is clearly superior. While both have excellent binding affinity, Ligand A demonstrates significantly better predicted ADME properties, particularly regarding BBB penetration (83.443 vs 32.067), lower DILI risk (55.448 vs 90.074), and improved metabolic stability (lower Cl_mic and better half-life). The slightly better TPSA and P-gp efflux also contribute to its favorability. The solubility is poor for both, but can be addressed with formulation strategies. Given the CNS target, the substantial difference in BBB penetration is the deciding factor.

Output:
0
2025-04-17 05:41:29,859 - INFO - Batch 219 complete. Total preferences: 3504
2025-04-17 05:41:29,859 - INFO - Processing batch 220/512...
2025-04-17 05:42:10,063 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (387.527) is slightly lower, which could be beneficial for permeability.

**TPSA:** Ligand A (91.76) is borderline for CNS targets (ideally <90), while Ligand B (45.59) is well within the desired range. This is a significant advantage for Ligand B.

**logP:** Ligand A (1.229) is at the lower end of the optimal range, potentially hindering permeation. Ligand B (3.48) is well within the optimal range.

**H-Bond Donors/Acceptors:** Ligand A has 2 HBD and 7 HBA, which are acceptable. Ligand B has 1 HBD and 4 HBA, also acceptable.

**QED:** Both ligands have good QED scores (A: 0.684, B: 0.749), indicating drug-like properties.

**DILI:** Ligand A (66.421) has a higher DILI risk than Ligand B (10.314). This is a significant concern for Ligand A.

**BBB:** Ligand B (89.027) has a much higher BBB penetration percentile than Ligand A (17.72). This is crucial for a CNS target like DRD2 and strongly favors Ligand B.

**Caco-2 Permeability:** Ligand A (-5.067) has poor Caco-2 permeability, suggesting poor intestinal absorption. Ligand B (-5) also has poor Caco-2 permeability, but is slightly better than Ligand A.

**Aqueous Solubility:** Both ligands have poor aqueous solubility (-2.833 and -3.099 respectively). This could pose formulation challenges, but is less critical than BBB penetration for a CNS target.

**hERG Inhibition:** Ligand A (0.328) has a slightly lower hERG risk than Ligand B (0.895), but both are reasonably low.

**Microsomal Clearance:** Ligand A (16.161) has lower microsomal clearance than Ligand B (41), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand B (30.151) has a significantly longer in vitro half-life than Ligand A (-6.101), which is a major advantage.

**P-gp Efflux:** Ligand A (0.142) has lower P-gp efflux than Ligand B (0.658), which is favorable for CNS exposure.

**Binding Affinity:** Ligand B (-8.1 kcal/mol) has a significantly stronger binding affinity than Ligand A (-6.8 kcal/mol). This 1.3 kcal/mol difference is substantial and can outweigh some ADME drawbacks.

**Overall Assessment:**

Ligand B is clearly the superior candidate. While both have solubility issues, Ligand B excels in the critical areas for a CNS GPCR target: BBB penetration, binding affinity, and in vitro half-life. It also has a much lower DILI risk. Ligand A's lower TPSA, lower P-gp efflux, and better metabolic stability are not enough to compensate for its poor BBB penetration, weaker affinity, and higher DILI risk.

Output:
1
2025-04-17 05:42:10,063 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (351.447 and 350.419 Da) fall within the ideal range of 200-500 Da.

**TPSA:** Ligand A (89.95) is excellent, falling below the 90 A^2 threshold for CNS targets. Ligand B (112.58) is still reasonable but less optimal, being above 100.

**logP:** Ligand A (-0.058) is slightly low, potentially hindering permeation. Ligand B (0.145) is also on the lower side, but better than A. Both are within the 1-3 range, but closer to the lower bound.

**H-Bond Donors/Acceptors:** Ligand A (2 HBD, 5 HBA) is favorable. Ligand B (4 HBD, 6 HBA) is also acceptable, but slightly higher counts might affect permeability.

**QED:** Ligand A (0.655) has a better QED score than Ligand B (0.478), indicating a more drug-like profile.

**DILI:** Ligand A (23.769) has a significantly lower DILI risk than Ligand B (41.838), a major advantage.

**BBB:** Ligand A (26.25) has a very low BBB penetration percentile, which is a significant drawback for a CNS target like DRD2. Ligand B (53.819) is substantially better, though still not ideal (aim for >70).

**Caco-2 Permeability:** Both ligands show poor Caco-2 permeability (-5.016 and -4.982). This suggests potential absorption issues.

**Aqueous Solubility:** Both ligands have very low solubility (-0.719 and -2.323). This could present formulation challenges.

**hERG:** Both ligands have very low hERG inhibition liability (0.026 and 0.235), which is positive.

**Microsomal Clearance:** Ligand A (13.359) has a higher microsomal clearance than Ligand B (9.184), suggesting lower metabolic stability.

**In vitro Half-Life:** Ligand A (-14.339) has a very short in vitro half-life, while Ligand B (15.98) is better, but still not great.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.009 and 0.011), which is good for CNS penetration.

**Binding Affinity:** Ligand B (-7.2 kcal/mol) has a slightly better binding affinity than Ligand A (-7.8 kcal/mol). While the difference is relatively small, it's still a factor.

**Overall Assessment:**

Ligand A has a better QED and DILI profile, but suffers from extremely poor BBB penetration and a short half-life. Ligand B has a better BBB score and binding affinity, but a higher DILI risk and lower QED. Given the CNS target (DRD2), BBB penetration is crucial. While Ligand B's BBB score isn't ideal, it's significantly better than Ligand A's. The slightly better affinity of Ligand B also contributes. The DILI risk of Ligand B is a concern, but could be addressed with further optimization. The poor solubility and Caco-2 permeability of both are significant, but could potentially be improved with formulation strategies.

Output:
1
2025-04-17 05:42:10,064 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (344.375 and 347.459 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (122.03) is borderline for CNS penetration, slightly above the preferred <90. Ligand B (57) is excellent, well below 90.

**logP:** Ligand A (0.24) is quite low, potentially hindering permeability. Ligand B (1.991) is within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A has 3 HBD and 7 HBA, acceptable values. Ligand B has 0 HBD and 4 HBA, also acceptable.

**QED:** Both ligands have good QED scores (0.69 and 0.836), indicating drug-like properties.

**DILI:** Ligand A has a DILI risk of 68.825, which is moderately high. Ligand B has a much lower DILI risk of 20.9, a significant advantage.

**BBB:** Ligand A's BBB penetration (35.052) is poor for a CNS target. Ligand B's BBB penetration (59.131) is better, though still not ideal (aim for >70).

**Caco-2 Permeability:** Ligand A (-5.154) has very poor Caco-2 permeability. Ligand B (-4.609) is also poor, but slightly better than Ligand A.

**Aqueous Solubility:** Ligand A (-2.511) and Ligand B (-0.64) both have poor aqueous solubility.

**hERG Inhibition:** Ligand A (0.059) has a very low hERG risk, which is excellent. Ligand B (0.415) has a slightly higher, but still acceptable, hERG risk.

**Microsomal Clearance:** Ligand A (9.455) has a relatively low microsomal clearance, indicating better metabolic stability. Ligand B (8.452) is also good.

**In vitro Half-Life:** Ligand A (-3.268) has a negative half-life, which is concerning and likely an error or outlier. Ligand B (43.096) has a good in vitro half-life.

**P-gp Efflux:** Ligand A (0.005) has very low P-gp efflux, which is favorable for CNS penetration. Ligand B (0.13) has a slightly higher P-gp efflux, but still relatively low.

**Binding Affinity:** Both ligands have comparable and strong binding affinities (-7.5 and -7.0 kcal/mol). The difference of 0.5 kcal/mol is not substantial enough to override other significant differences.

**Overall Assessment:**

Ligand B is the superior candidate. While both have good affinity, Ligand B excels in several critical areas for a CNS-targeting GPCR: significantly lower DILI risk, better TPSA, better logP, and a much more reasonable in vitro half-life. Ligand A's low logP, poor Caco-2 permeability, and questionable half-life are major drawbacks. Although Ligand A has lower P-gp efflux, the other liabilities outweigh this benefit.

Output:
1
2025-04-17 05:42:10,064 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (337.379 Da) is slightly lower, which could be beneficial for permeability, while Ligand B (361.917 Da) is also good.

**TPSA:** Ligand A (83.48) is borderline for CNS penetration, being above the preferred <90 threshold, but still potentially acceptable. Ligand B (38.13) is excellent, well below the 90 threshold and highly favorable for CNS penetration.

**logP:** Both ligands have logP values within the optimal range (1-3). Ligand A (3.099) is closer to the upper limit, while Ligand B (4.032) is slightly above, which could raise concerns about solubility and off-target effects, but is still manageable.

**H-Bond Donors/Acceptors:** Ligand A has 3 HBD and 4 HBA, which are within acceptable limits. Ligand B has 0 HBD and 3 HBA, also good.

**QED:** Both ligands have QED values above 0.5 (Ligand A: 0.668, Ligand B: 0.742), indicating good drug-like properties.

**DILI:** Ligand A has a DILI risk of 83.133, which is relatively high and concerning. Ligand B has a much lower DILI risk of 25.126, which is excellent.

**BBB:** Ligand A has a BBB penetration of 41.722, which is not ideal for a CNS target like DRD2. Ligand B has a significantly higher BBB penetration of 83.637, which is very favorable.

**Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and likely indicates a problem with the prediction method. We'll have to rely on other parameters for permeability assessment.

**Aqueous Solubility:** Both ligands have negative solubility values, again indicating a potential issue with the prediction method.

**hERG Inhibition:** Both ligands show low hERG inhibition risk (Ligand A: 0.622, Ligand B: 0.568).

**Microsomal Clearance:** Ligand A has a lower microsomal clearance (28.071) than Ligand B (84.996), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A has a longer half-life (44.92 hours) than Ligand B (2.531 hours), which is a significant advantage.

**P-gp Efflux:** Ligand A shows low P-gp efflux (0.114), which is good. Ligand B also shows low P-gp efflux (0.453), also good.

**Binding Affinity:** Ligand B has a significantly stronger binding affinity (-7.1 kcal/mol) compared to Ligand A (-9.4 kcal/mol). This >1.5 kcal/mol difference in affinity is a major advantage, potentially outweighing some of the ADME drawbacks.

**Overall Assessment:**

Ligand B is the stronger candidate. While Ligand A has better metabolic stability and half-life, Ligand B excels in critical areas for a CNS-targeting GPCR ligand: significantly better BBB penetration, a much lower DILI risk, and a substantially stronger binding affinity. The slightly higher logP of Ligand B is a minor concern, but the superior affinity and CNS penetration properties are more important. The negative solubility and Caco-2 values are concerning, but may be artifacts of the prediction method.

Output:
1
2025-04-17 05:42:10,064 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (346.471 and 352.494 Da) fall comfortably within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (49.85) is better than Ligand B (40.62). Both are below the 90 A^2 threshold for CNS targets, which is excellent.

**3. logP:** Both ligands have good logP values (2.942 and 3.258), falling within the optimal 1-3 range.

**4. H-Bond Donors:** Both have 0 HBD, which is acceptable.

**5. H-Bond Acceptors:** Ligand A has 4 HBA, and Ligand B has 2. Both are below the 10 threshold.

**6. QED:** Both ligands have similar QED values (0.769 and 0.782), indicating good drug-likeness.

**7. DILI:** Ligand A (15.743) has a slightly higher DILI risk than Ligand B (12.292), but both are well below the concerning 60 percentile.

**8. BBB:** This is a critical parameter for a CNS target like DRD2. Ligand B (96.743) significantly outperforms Ligand A (73.245) in BBB penetration. This is a major advantage for Ligand B.

**9. Caco-2 Permeability:** Both have negative values, indicating poor permeability. Ligand A (-4.312) is slightly worse than Ligand B (-4.533).

**10. Aqueous Solubility:** Both ligands have negative solubility values, indicating poor solubility. Ligand A (-2.273) is slightly better than Ligand B (-3.671).

**11. hERG Inhibition:** Both ligands have low hERG inhibition risk (0.812 and 0.765).

**12. Microsomal Clearance:** Ligand B (56.523) has a higher clearance than Ligand A (44.944), meaning Ligand A is more metabolically stable.

**13. In vitro Half-Life:** Ligand A (22.419) has a significantly longer half-life than Ligand B (-13.183). This is a substantial advantage for Ligand A.

**14. P-gp Efflux:** Both ligands have low P-gp efflux liability (0.206 and 0.2).

**15. Binding Affinity:** Both ligands have excellent binding affinity (-8.2 and -8.0 kcal/mol). The difference of 0.2 kcal/mol is not substantial enough to outweigh other factors.

**Overall Assessment:**

While Ligand A has better metabolic stability (lower Cl_mic, longer t1/2) and slightly better solubility, Ligand B's significantly higher BBB penetration (96.743 vs 73.245) is the deciding factor for a CNS target like DRD2. The difference in BBB is substantial and outweighs the benefits of Ligand A's slightly improved metabolic properties. The binding affinities are nearly identical.

Output:
1
2025-04-17 05:42:10,064 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (344.459 Da) is slightly lower, which could be beneficial for permeability.

**TPSA:** Ligand A (67.23) is significantly better than Ligand B (121.44). For CNS targets, we want TPSA <= 90, and Ligand A is comfortably within this range, while Ligand B exceeds it.

**logP:** Both ligands have acceptable logP values (A: 1.677, B: 0.616), falling within the optimal 1-3 range. Ligand A is slightly better.

**H-Bond Donors/Acceptors:** Ligand A (HBD=1, HBA=4) is preferable to Ligand B (HBD=3, HBA=6). Lower counts are generally better for CNS penetration.

**QED:** Both ligands have similar and acceptable QED values (A: 0.576, B: 0.5).

**DILI:** Ligand A (24.777) has a much lower DILI risk than Ligand B (61.691). This is a significant advantage for Ligand A.

**BBB:** Ligand A (52.268) has a better BBB percentile than Ligand B (31.136), although both are below the desirable >70 for CNS targets. However, the difference is substantial.

**Caco-2 Permeability:** Both show poor Caco-2 permeability (-5.016 and -5.26). This is a concern for oral bioavailability, but less critical for a CNS target where direct delivery or other routes might be considered.

**Aqueous Solubility:** Both ligands have poor aqueous solubility (-1.49 and -2.036).

**hERG:** Both ligands have low hERG inhibition liability (A: 0.374, B: 0.193).

**Microsomal Clearance:** Ligand A (14.946) has a higher microsomal clearance than Ligand B (-6.235), suggesting lower metabolic stability. This is a drawback for Ligand A.

**In vitro Half-Life:** Ligand B (-6.571) has a better in vitro half-life than Ligand A (-11.192).

**P-gp Efflux:** Ligand A (0.092) has a lower P-gp efflux liability than Ligand B (0.014), which is favorable for CNS exposure.

**Binding Affinity:** Ligand B (-7.8 kcal/mol) has a slightly better binding affinity than Ligand A (-7.2 kcal/mol). This 0.6 kcal/mol difference is not large enough to overcome the other significant advantages of Ligand A.

**Overall Assessment:**

Considering the GPCR-specific priorities, Ligand A is the better candidate. Its significantly lower TPSA, lower DILI risk, better BBB penetration, and lower P-gp efflux outweigh the slightly worse microsomal clearance and slightly weaker binding affinity. The superior TPSA and BBB are crucial for CNS drug development.

Output:
0
2025-04-17 05:42:10,065 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (356.46 and 349.52 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (49.41) is better than Ligand B (52.65). Both are below the 90 A^2 threshold for CNS targets, which is good.

**3. logP:** Ligand A (3.52) is slightly higher than Ligand B (2.26). Both are within the optimal 1-3 range, but Ligand A is closer to the upper limit.

**4. H-Bond Donors:** Both ligands have 1 HBD, which is acceptable (<=5).

**5. H-Bond Acceptors:** Ligand A has 2 HBA, and Ligand B has 3. Both are below the 10 threshold.

**6. QED:** Both ligands have good QED scores (0.74 and 0.8), indicating drug-likeness.

**7. DILI:** Ligand A (31.33) has a significantly lower DILI risk than Ligand B (10.74). This is a major advantage for Ligand A.

**8. BBB:** Ligand A (93.76) has a much higher BBB penetration percentile than Ligand B (75.03). This is crucial for a CNS target like DRD2.

**9. Caco-2:** Ligand A (-4.36) and Ligand B (-4.82) both have negative values, which is unusual and suggests poor permeability. However, the scale is not specified, so it's hard to interpret.

**10. Solubility:** Ligand A (-3.84) and Ligand B (-1.59) both have negative values, suggesting poor solubility. Again, the scale is unclear.

**11. hERG:** Both ligands have relatively low hERG inhibition risk (0.595 and 0.726).

**12. Cl_mic:** Ligand A (32.68) has a lower microsomal clearance than Ligand B (55.83), indicating better metabolic stability.

**13. t1/2:** Ligand A (-5.82) has a longer in vitro half-life than Ligand B (2.16), which is preferable.

**14. Pgp:** Ligand A (0.224) has significantly lower P-gp efflux liability than Ligand B (0.069). Lower Pgp is better for CNS exposure.

**15. Binding Affinity:** Both ligands have excellent binding affinities (-9.7 and -9.0 kcal/mol). The difference is 0.7 kcal/mol, which is not substantial enough to outweigh the ADME advantages of Ligand A.

**Overall Assessment:**

Ligand A is clearly superior. It has a significantly better safety profile (lower DILI), much better BBB penetration, lower Pgp efflux, better metabolic stability (lower Cl_mic, longer t1/2), and comparable binding affinity to Ligand B. While both have issues with Caco-2 and solubility, the other advantages of Ligand A make it the more promising drug candidate for a CNS target like DRD2.

Output:
1
2025-04-17 05:42:10,065 - INFO - Reasoning:

Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (347.419 and 342.443 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (98.14) is slightly higher than Ligand B (78.92). For CNS targets, TPSA should be <= 90. Ligand B is better here.

**3. logP:** Ligand A (0.969) is a bit low, potentially hindering permeability. Ligand B (2.855) is within the optimal 1-3 range. Ligand B is clearly superior.

**4. H-Bond Donors:** Ligand A (2) and Ligand B (3) are both acceptable (<=5).

**5. H-Bond Acceptors:** Ligand A (6) and Ligand B (3) are both acceptable (<=10).

**6. QED:** Ligand B (0.755) has a better QED score than Ligand A (0.394), indicating a more drug-like profile.

**7. DILI:** Both ligands have similar, acceptable DILI risk (Ligand A: 46.879, Ligand B: 45.095, both <60).

**8. BBB:** Ligand B (65.064) has a significantly better BBB percentile than Ligand A (52.423). This is *critical* for a CNS target like DRD2.

**9. Caco-2 Permeability:** Both are negative, but Ligand B (-4.935) is less negative than Ligand A (-5.59), suggesting slightly better permeability.

**10. Aqueous Solubility:** Both are negative, suggesting poor solubility. Ligand A (-2.777) is slightly better than Ligand B (-3.994).

**11. hERG Inhibition:** Both have low hERG inhibition risk (Ligand A: 0.108, Ligand B: 0.414).

**12. Microsomal Clearance:** Both have similar microsomal clearance (Ligand A: 16.666, Ligand B: 16.06).

**13. In vitro Half-Life:** Ligand B (11.548) has a longer half-life than Ligand A (7.336).

**14. P-gp Efflux:** Both have very low P-gp efflux liability (Ligand A: 0.012, Ligand B: 0.126).

**15. Binding Affinity:** Ligand B (-8.6 kcal/mol) has a slightly better binding affinity than Ligand A (-8.0 kcal/mol). While both are good, the difference is meaningful.

**Overall Assessment:**

Ligand B is the superior candidate. It excels in key properties for a CNS-targeting GPCR ligand: better logP, significantly better BBB penetration, better QED, and slightly improved binding affinity and half-life. While Ligand A has slightly better solubility, the other advantages of Ligand B outweigh this minor drawback. The improved BBB and logP are particularly important for DRD2.

Output:
1
2025-04-17 05:42:10,065 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (386.54 and 361.56 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (89.87) is excellent for CNS penetration, being under the 90 A^2 threshold. Ligand B (46.09) is also very good.

**logP:** Ligand A (1.321) is within the optimal 1-3 range. Ligand B (4.536) is slightly high, potentially leading to solubility issues and off-target interactions, but not drastically so.

**H-Bond Donors/Acceptors:** Ligand A has 3 HBD and 6 HBA, which are acceptable. Ligand B has 0 HBD and 4 HBA, also acceptable.

**QED:** Both ligands have similar QED values (0.71 and 0.638), indicating good drug-likeness.

**DILI:** Both ligands have relatively low DILI risk (55.64 and 41.88), falling below the 60 threshold.

**BBB:** This is a critical parameter for a CNS target. Ligand A has a BBB percentile of 25.59, which is quite low and a significant drawback. Ligand B has a much higher BBB percentile of 78.02, which is very desirable.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.307 and -5.102), which is unusual and suggests poor permeability. However, these values are on a scale where negative values are possible and don't necessarily disqualify a compound.

**Aqueous Solubility:** Both ligands have negative solubility values (-3.239 and -4.082), indicating poor aqueous solubility. This could be a formulation challenge.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.271 and 0.474).

**Microsomal Clearance:** Ligand A (40.016) has a lower microsomal clearance than Ligand B (122.139), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (13.023) has a longer half-life than Ligand B (-1.291), which is preferable.

**P-gp Efflux:** Ligand A (0.1) has very low P-gp efflux, which is excellent for CNS penetration. Ligand B (0.539) has moderate P-gp efflux.

**Binding Affinity:** Ligand B (-7.2 kcal/mol) has a significantly stronger binding affinity than Ligand A (-6.6 kcal/mol). This 0.6 kcal/mol difference is substantial and can outweigh some ADME drawbacks.

**Overall Assessment:**

Ligand B is the more promising candidate. While its logP is slightly elevated and solubility is poor, its *significantly* better BBB penetration and stronger binding affinity are crucial for a CNS-targeting GPCR like DRD2. The lower metabolic stability and shorter half-life of Ligand B are concerns, but these can potentially be addressed through structural modifications. Ligand A's very poor BBB penetration is a major roadblock, despite its better metabolic properties.



Output:
1
2025-04-17 05:42:10,065 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (370.435 Da and 363.527 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (125.55) is slightly above the optimal <90 for CNS targets, but still reasonable. Ligand B (53.51) is excellent, well below the threshold.

**logP:** Ligand A (-0.911) is a bit low, potentially hindering permeability. Ligand B (3.061) is within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A has 3 HBD and 7 HBA, which are acceptable. Ligand B has 0 HBD and 4 HBA, also acceptable.

**QED:** Both ligands have good QED scores (0.616 and 0.826), indicating good drug-like properties.

**DILI:** Both ligands have similar DILI risk (63.552 and 61.691), placing them in a moderate risk category, but not alarmingly high.

**BBB:** Ligand B (78.247) shows significantly better BBB penetration potential than Ligand A (56.378). This is a crucial advantage for a CNS target like DRD2.

**Caco-2 Permeability:** Ligand A (-5.592) has poor Caco-2 permeability, while Ligand B (-4.712) is slightly better, but still not great.

**Aqueous Solubility:** Ligand A (-1.263) has poor aqueous solubility, while Ligand B (-3.365) is even worse. This could pose formulation challenges for both.

**hERG Inhibition:** Ligand A (0.021) has very low hERG inhibition risk, a significant advantage. Ligand B (0.462) has a slightly elevated risk, but still relatively low.

**Microsomal Clearance:** Ligand A (1.154) has lower microsomal clearance, suggesting better metabolic stability than Ligand B (85.862).

**In vitro Half-Life:** Ligand A (17.46) has a longer half-life than Ligand B (-12.399), which is beneficial.

**P-gp Efflux:** Ligand A (0.005) has very low P-gp efflux, which is excellent for CNS penetration. Ligand B (0.369) has a slightly higher, but still reasonable, P-gp efflux.

**Binding Affinity:** Ligand B (-7.6) has a significantly stronger binding affinity than Ligand A (-0). This is a major advantage, potentially outweighing some of its ADME drawbacks.

**Overall Assessment:**

Ligand B stands out due to its superior binding affinity and significantly better BBB penetration. While its solubility and Caco-2 permeability are not ideal, the strong binding and potential for CNS exposure are critical for a DRD2 ligand. Ligand A has a better safety profile (hERG, P-gp) and metabolic stability, but its weak binding affinity and poor BBB penetration are major drawbacks. The affinity difference is substantial (>1.5 kcal/mol), making Ligand B the more promising candidate.

Output:
1
2025-04-17 05:42:10,065 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (346.515 and 347.39 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (58.2) is excellent, well below the 90 A^2 threshold for CNS targets. Ligand B (78.51) is still reasonable but less optimal.

**3. logP:** Ligand A (3.592) is at the upper end of the optimal range (1-3), while Ligand B (1.013) is slightly below, potentially hindering permeation.

**4. H-Bond Donors:** Both ligands have 2 HBD, which is within the acceptable limit of <=5.

**5. H-Bond Acceptors:** Ligand A has 2 HBA, and Ligand B has 3 HBA, both within the acceptable limit of <=10.

**6. QED:** Both ligands have good QED scores (0.521 and 0.798, respectively), indicating drug-like properties. Ligand B is slightly better.

**7. DILI:** Both ligands have low DILI risk (37.728 and 40.83), which is favorable.

**8. BBB:** Both ligands have acceptable BBB penetration (60.915 and 66.886), but neither exceeds the desirable >70% threshold for CNS targets.

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.865 and -4.971), which is unusual and suggests poor permeability. This is a significant concern.

**10. Aqueous Solubility:** Both ligands have negative solubility values (-4.874 and -2.87), indicating very poor aqueous solubility. This is a major drawback.

**11. hERG Inhibition:** Both ligands have low hERG inhibition risk (0.253 and 0.318).

**12. Microsomal Clearance:** Ligand A has a high microsomal clearance (81.91 mL/min/kg), suggesting rapid metabolism. Ligand B has a much lower clearance (-24.298 mL/min/kg), indicating better metabolic stability.

**13. In vitro Half-Life:** Ligand A has a short half-life (3.682 hours), while Ligand B has a very short half-life (3.059 hours). Both are not ideal.

**14. P-gp Efflux:** Ligand A has no P-gp efflux (0.452), which is favorable. Ligand B has very low P-gp efflux (0.017), which is even more favorable.

**15. Binding Affinity:** Ligand B (-9.4 kcal/mol) has significantly stronger binding affinity than Ligand A (-0.0 kcal/mol). This is a crucial advantage.

**Overall Assessment:**

Despite both ligands having significant drawbacks (poor solubility and permeability), Ligand B is the more promising candidate. Its substantially stronger binding affinity outweighs the slightly less optimal logP and TPSA. The significantly lower microsomal clearance and P-gp efflux also contribute to its favorability. While the negative Caco-2 and solubility values are concerning, the strong binding affinity suggests that formulation strategies might be able to overcome these issues. Ligand A's very weak binding affinity makes it unlikely to be a viable candidate, regardless of its other properties.

Output:
1
2025-04-17 05:42:10,066 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B against the provided guidelines, prioritizing GPCR-specific properties (BBB, logP, Pgp, TPSA, and affinity) for DRD2.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (345.311 Da) is slightly lower, which could be beneficial for permeability, while Ligand B (362.495 Da) is also good.

**TPSA:** Ligand A (123.71) is closer to the ideal range for CNS targets (<=90) than Ligand B (50.8). This is a significant advantage for brain penetration.

**logP:** Both ligands have acceptable logP values (A: 1.282, B: 2.62), falling within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A has 2 HBD and 6 HBA, while Ligand B has 1 HBD and 4 HBA. Both are within acceptable limits.

**QED:** Ligand B (0.838) has a significantly better QED score than Ligand A (0.462), indicating a more drug-like profile.

**DILI:** Ligand B (21.908) has a much lower DILI risk than Ligand A (83.172), a substantial advantage.

**BBB:** Ligand B (86.351) has a considerably higher BBB penetration percentile than Ligand A (45.715). This is crucial for a CNS target like DRD2.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values, which is unusual and suggests a potential issue with the data or modeling. However, we can still compare the values. Ligand A (-4.91) is slightly worse than Ligand B (-4.638).

**Aqueous Solubility:** Both ligands have negative solubility values, again suggesting a potential data issue. Ligand B (-2.892) is slightly better than Ligand A (-4.124).

**hERG Inhibition:** Both ligands have low hERG inhibition risk (A: 0.511, B: 0.489).

**Microsomal Clearance:** Ligand B (20.532) has a slightly higher microsomal clearance than Ligand A (16.359), suggesting potentially lower metabolic stability.

**In vitro Half-Life:** Ligand A (46.784) has a significantly longer in vitro half-life than Ligand B (8.955).

**P-gp Efflux:** Ligand A (0.386) has a lower P-gp efflux liability than Ligand B (0.094), which is favorable for CNS penetration.

**Binding Affinity:** Ligand A (-9.0 kcal/mol) has a significantly stronger binding affinity than Ligand B (-6.7 kcal/mol). This is a major advantage, potentially outweighing some of the ADME drawbacks.

**Overall Assessment:**

Ligand A has a superior binding affinity and better P-gp efflux, but suffers from poor BBB penetration, high DILI risk, and a lower QED score. Ligand B excels in BBB penetration, DILI risk, and QED, but has weaker binding affinity. Given that this is a CNS target (DRD2), BBB penetration is paramount. The significantly better BBB score of Ligand B, coupled with its lower DILI risk and higher QED, makes it a more promising candidate despite the weaker binding affinity. The affinity difference, while substantial, might be addressable through further optimization, whereas improving BBB penetration is often more challenging.

Output:
1
2025-04-17 05:42:10,066 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (356.46 and 351.50 Da) fall comfortably within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (58.2) is significantly better than Ligand B (89.38). For CNS targets, we want TPSA <= 90, and A is much closer to the ideal <=60 range. B is pushing the upper limit and could suffer from reduced BBB penetration.

**3. logP:** Both ligands have good logP values (3.57 and 3.74), falling within the optimal 1-3 range.

**4. H-Bond Donors:** Ligand A has 2 HBD, which is acceptable. Ligand B has 0, which is also acceptable.

**5. H-Bond Acceptors:** Ligand A has 2 HBA, acceptable. Ligand B has 3 HBA, also acceptable.

**6. QED:** Ligand A (0.621) has a significantly better QED score than Ligand B (0.26), indicating a more drug-like profile.

**7. DILI:** Ligand A (41.9%) has a slightly higher DILI risk than Ligand B (15.9%), but both are below the concerning 60% threshold.

**8. BBB:** Ligand A (89.6%) has a better BBB percentile than Ligand B (80.1%), which is crucial for a CNS target like DRD2. Both are good, but A is preferable.

**9. Caco-2:** Both ligands have negative Caco-2 values (-4.6 and -4.7). These values are unusual and likely indicate poor permeability. However, since both are similarly poor, this doesn't differentiate them.

**10. Solubility:** Both ligands have negative solubility values (-4.5 and -2.4). Again, these are unusual and suggest poor solubility. The difference isn't significant enough to favor one over the other.

**11. hERG:** Both ligands have low hERG inhibition liability (0.55 and 0.69), which is good.

**12. Cl_mic:** Both ligands have similar microsomal clearance values (46.7 and 47.3), indicating comparable metabolic stability.

**13. t1/2:** Ligand A (-3.49) has a negative half-life, which is not possible. Ligand B (-21.34) also has a negative half-life, which is also not possible. This is a major red flag for both compounds.

**14. Pgp:** Both ligands have low Pgp efflux liability (0.21 and 0.16), which is favorable for CNS penetration.

**15. Binding Affinity:** Ligand A (-8.1 kcal/mol) has a significantly stronger binding affinity than Ligand B (-7.2 kcal/mol). This 0.9 kcal/mol difference is substantial and can outweigh minor ADME drawbacks.

**Overall Assessment:**

Ligand A is the stronger candidate. It has a better TPSA, QED, and significantly better binding affinity. While both have issues with solubility and Caco-2 permeability, and both have impossible half-life values, the superior binding affinity and better CNS-related properties (BBB, TPSA) of Ligand A make it the more promising starting point for optimization. The negative half-life values are concerning and need to be investigated further, but the binding affinity advantage is significant.

Output:
1
2025-04-17 05:42:10,066 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (343.383 and 345.487 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (87.68) is better than Ligand B (52.65), both are below the 90 A^2 threshold for CNS targets.

**logP:** Both ligands have acceptable logP values (1.15 and 1.624), falling within the 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A has 2 HBD and 5 HBA, while Ligand B has 1 HBD and 3 HBA. Both are within the acceptable ranges.

**QED:** Both ligands have reasonable QED scores (0.869 and 0.796), indicating good drug-likeness.

**DILI:** Both ligands have low DILI risk (54.827 and 5.273 percentile), which is favorable. Ligand B is significantly better.

**BBB:** Ligand B (71.888%) is significantly better than Ligand A (28.693%) in terms of BBB penetration, a crucial factor for CNS targets like DRD2.

**Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and suggests a potential issue with the data or modeling. However, we'll proceed assuming these represent low permeability.

**Aqueous Solubility:** Both have negative solubility values, also unusual. Again, we'll assume this indicates low solubility.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.289 and 0.529).

**Microsomal Clearance:** Ligand A (-12.896) has a lower (better) microsomal clearance than Ligand B (-7.854), suggesting greater metabolic stability.

**In vitro Half-Life:** Ligand A (19.649 hours) has a longer half-life than Ligand B (5.364 hours), which is preferable.

**P-gp Efflux:** Ligand A (0.045) has lower P-gp efflux than Ligand B (0.017), which is better for CNS exposure.

**Binding Affinity:** Ligand B (-8.7 kcal/mol) has a slightly better binding affinity than Ligand A (-9.5 kcal/mol). While the difference is small, it is still a factor.

**Overall Assessment:**

Ligand B is superior due to its significantly better BBB penetration (71.888% vs 28.693%). This is the most important factor for a CNS target like DRD2. While Ligand A has better metabolic stability and half-life, the improved CNS penetration of Ligand B outweighs these benefits. The slightly better affinity of Ligand B also contributes to its favorability. The unusual negative values for Caco-2 and solubility are concerning for both, but the difference in BBB is the deciding factor.

Output:
1
2025-04-17 05:42:10,066 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (346.431 Da) is slightly lower, which could be beneficial for permeability, but both are acceptable.

**TPSA:** Ligand A (98.32) is closer to the ideal range for CNS targets (<=90) than Ligand B (78.43). This is a slight advantage for A.

**logP:** Both ligands have logP values within the optimal range (1-3), with Ligand A (1.223) being slightly lower and Ligand B (2.598) being higher. Both are acceptable, but B is slightly better.

**H-Bond Donors/Acceptors:** Both have 3 HBD and 4 HBA, which are within acceptable limits.

**QED:** Both ligands have similar QED values (A: 0.675, B: 0.621), indicating good drug-likeness.

**DILI:** Both ligands have low DILI risk (A: 34.432, B: 36.06), which is good.

**BBB:** Both ligands have similar BBB penetration (A: 49.205, B: 48.003). Neither is above the desirable 70% threshold, which is a concern for CNS targets. However, this parameter is less critical if the compound demonstrates excellent potency.

**Caco-2 Permeability:** Both have negative Caco-2 values (-5.243 and -5.681), which is unusual and suggests poor permeability. This is a significant drawback for both.

**Aqueous Solubility:** Both have negative solubility values (-3.068 and -3.35), indicating poor aqueous solubility. This could pose formulation challenges.

**hERG Inhibition:** Both ligands have very low hERG inhibition risk (A: 0.234, B: 0.464), which is excellent.

**Microsomal Clearance:** Ligand A (-0.386) has significantly lower (better) microsomal clearance than Ligand B (89.06). This suggests better metabolic stability for Ligand A.

**In vitro Half-Life:** Ligand A (-14.83) has a very negative half-life, which is concerning. Ligand B (-13.638) is also negative, but less so. These values are likely errors or indicate very rapid degradation.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (A: 0.014, B: 0.083), which is favorable for CNS penetration.

**Binding Affinity:** Ligand A (-8.7 kcal/mol) has a slightly better binding affinity than Ligand B (-8.1 kcal/mol). While the difference is small (0.6 kcal/mol), it's within the range where it could outweigh minor ADME drawbacks.

**Overall Assessment:**

Despite both compounds having issues with permeability and solubility, Ligand A appears slightly more promising. It has a better binding affinity, lower microsomal clearance (better metabolic stability), and a slightly more favorable TPSA. The negative half-life values are concerning for both, but the affinity difference and metabolic stability edge give Ligand A a slight advantage. The BBB values are suboptimal for both.

Output:
0
2025-04-17 05:42:10,067 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (342.443 and 355.435 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (67.23) is significantly better than Ligand B (104.81). For CNS targets, we want TPSA <= 90, and A is comfortably within this range, while B is above.

**3. logP:** Ligand A (1.909) is optimal (1-3), while Ligand B (0.209) is quite low, potentially hindering permeation.

**4. H-Bond Donors:** Ligand A (1) and Ligand B (2) are both acceptable (<=5).

**5. H-Bond Acceptors:** Ligand A (4) and Ligand B (5) are both acceptable (<=10).

**6. QED:** Both ligands have reasonable QED values (0.803 and 0.502), indicating good drug-like properties.

**7. DILI:** Both ligands have low DILI risk (23.575 and 24.234), which is good.

**8. BBB:** Ligand B (66.499) is slightly better than Ligand A (61.535), but both are below the desirable >70 for CNS targets. However, given the other factors, this isn't a dealbreaker.

**9. Caco-2:** Ligand A (-5.04) and Ligand B (-4.558) are both negative, indicating poor permeability. This is a concern for both.

**10. Solubility:** Both ligands have poor aqueous solubility (-1.701 and -1.849). This could present formulation challenges.

**11. hERG:** Both ligands have very low hERG risk (0.374 and 0.081).

**12. Cl_mic:** Ligand A (18.444) has a much lower microsomal clearance than Ligand B (75.67), indicating better metabolic stability.

**13. t1/2:** Ligand B (-27.172) has a much longer in vitro half-life than Ligand A (-9.628). This is a significant advantage for B.

**14. Pgp:** Ligand A (0.028) has much lower P-gp efflux liability than Ligand B (0.006), which is favorable for CNS penetration.

**15. Binding Affinity:** Ligand A (-8.3) has a slightly better binding affinity than Ligand B (-7.6), although both are good (<-7.0).

**Overall Assessment:**

Considering the GPCR-specific priorities, Ligand A is more promising. Its superior TPSA and logP values are crucial for CNS penetration. While Ligand B has a longer half-life, the better permeability profile (even though still poor) and metabolic stability of Ligand A, combined with its slightly better affinity, outweigh this benefit. The lower Pgp efflux for A is also beneficial for CNS exposure. The solubility and Caco-2 values are problematic for both, but can be addressed with formulation strategies.

Output:
0
2025-04-17 05:42:10,067 - INFO - Batch 220 complete. Total preferences: 3520
2025-04-17 05:42:10,067 - INFO - Processing batch 221/512...
2025-04-17 05:42:50,454 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (352.475 and 354.491 Da) fall comfortably within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (70.08) is significantly better than Ligand B (87.66). For CNS targets, TPSA < 90 is preferred, and A is closer to the optimal <60 range. B is pushing the upper limit.

**3. logP:** Both ligands have good logP values (1.578 and 1.469), falling within the 1-3 range.

**4. H-Bond Donors:** Ligand A (1) is better than Ligand B (3). Lower HBD generally improves permeability.

**5. H-Bond Acceptors:** Both ligands have the same HBA count (4), which is acceptable (<=10).

**6. QED:** Both ligands have similar and good QED values (0.532 and 0.554), indicating good drug-like properties.

**7. DILI:** Ligand A (14.23) has a much lower DILI risk than Ligand B (10.237). This is a significant advantage.

**8. BBB:** Ligand A (64.482) has a better BBB percentile than Ligand B (57.736), but both are below the desirable >70 for CNS targets. However, A is closer.

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.597 and -4.716). This is unusual and suggests poor permeability. However, the values are very similar.

**10. Aqueous Solubility:** Both ligands have negative solubility values (-1.358 and -2.06). This is also unusual, suggesting poor aqueous solubility. B is worse than A.

**11. hERG Inhibition:** Both ligands have low hERG inhibition liability (0.467 and 0.328), which is good.

**12. Microsomal Clearance:** Ligand A (36.705) has lower microsomal clearance than Ligand B (42.626), suggesting better metabolic stability.

**13. In vitro Half-Life:** Ligand A (0.295) has a shorter half-life than Ligand B (4.856). This is a disadvantage for A.

**14. P-gp Efflux:** Ligand A (0.184) has lower P-gp efflux liability than Ligand B (0.086), which is favorable for CNS penetration.

**15. Binding Affinity:** Ligand B (-8.1 kcal/mol) has a slightly better binding affinity than Ligand A (-7.6 kcal/mol). This is a 0.5 kcal/mol difference, which is significant but not overwhelming.

**Overall Assessment:**

Considering the GPCR-specific priorities, Ligand A is the more promising candidate. While Ligand B has a slightly better binding affinity, Ligand A excels in crucial ADME properties for CNS drugs: lower TPSA, lower DILI risk, better BBB penetration, lower P-gp efflux, and better metabolic stability. The lower half-life of A is a concern, but can potentially be addressed through structural modifications. The poor Caco-2 and solubility are shared issues that would need attention in either case.

Output:
0
2025-04-17 05:42:50,455 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (343.471 and 341.371 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (81.99) is significantly better than Ligand B (108.31). For CNS targets, we want TPSA <= 90, and A is comfortably within that, while B is pushing the limit.

**logP:** Ligand A (2.662) is optimal (1-3), while Ligand B (1.437) is a bit low, potentially hindering permeation.

**H-Bond Donors/Acceptors:** Both have 2 HBD, which is good. Ligand A has 3 HBA, and Ligand B has 6 HBA. Lower HBA is generally preferred, making Ligand A slightly better.

**QED:** Both ligands have good QED scores (0.711 and 0.852), indicating good drug-like properties.

**DILI:** Ligand A (21.908) has a much lower DILI risk than Ligand B (63.552). This is a significant advantage for A.

**BBB:** Both have similar BBB penetration (Ligand A: 51.997, Ligand B: 56.301). Neither is ideal (>70), but this isn't a primary discriminator here as DRD2 is not exclusively a CNS target.

**Caco-2 Permeability:** Ligand A (-4.896) and Ligand B (-5.037) both have negative values, indicating poor permeability.

**Aqueous Solubility:** Both ligands have poor aqueous solubility (-3.727 and -3.157).

**hERG:** Both ligands have very low hERG inhibition risk (0.412 and 0.062).

**Microsomal Clearance:** Ligand B (20.171) has lower microsomal clearance than Ligand A (32.434), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand B (-24.143) has a significantly longer in vitro half-life than Ligand A (2.246). This is a substantial advantage for B.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.093 and 0.006).

**Binding Affinity:** Ligand B (-8.5) has a slightly better binding affinity than Ligand A (-8.1). While the difference is small (0.4 kcal/mol), it's within the range where it could outweigh some ADME drawbacks.

**Overall Assessment:**

Ligand A excels in TPSA, logP, and DILI risk. Ligand B has better metabolic stability (lower Cl_mic, longer t1/2) and slightly better binding affinity. The TPSA and DILI advantages of Ligand A are significant, especially for a GPCR target where CNS penetration (and therefore minimizing off-target effects) is important. While both have poor Caco-2 and solubility, the lower DILI risk of A is a strong point. The affinity difference is small.

Output:
1
2025-04-17 05:42:50,455 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (354.535 Da and 368.459 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (58.64) is excellent, well below the 90 A^2 threshold for CNS targets. Ligand B (91.84) is slightly above, but still potentially acceptable.

**3. logP:** Ligand A (3.229) is optimal (1-3). Ligand B (0.498) is low, potentially hindering permeation. This is a significant drawback.

**4. H-Bond Donors:** Both ligands have 1 HBD, which is within the acceptable limit of <=5.

**5. H-Bond Acceptors:** Ligand A has 3 HBAs, and Ligand B has 6. Both are within the acceptable limit of <=10.

**6. QED:** Both ligands have good QED values (0.691 and 0.757), indicating drug-like properties.

**7. DILI:** Ligand A (9.926) has a much lower DILI risk than Ligand B (62.001). This is a substantial advantage for Ligand A.

**8. BBB:** Ligand A (77.821) has a good BBB penetration percentile, desirable for a CNS target. Ligand B (55.254) is lower, which is a concern.

**9. Caco-2 Permeability:** Ligand A (-4.334) and Ligand B (-5.117) both have negative values, indicating poor permeability.

**10. Aqueous Solubility:** Both ligands have negative solubility values, indicating poor solubility.

**11. hERG Inhibition:** Ligand A (0.66) has a slightly higher hERG risk than Ligand B (0.153), but both are relatively low.

**12. Microsomal Clearance:** Ligand A (78.646) has a higher microsomal clearance than Ligand B (26.821), suggesting lower metabolic stability.

**13. In vitro Half-Life:** Ligand B (-19.307) has a negative half-life, which is not possible and suggests a very rapid clearance. Ligand A (5.314) has a reasonable half-life.

**14. P-gp Efflux:** Both ligands have low P-gp efflux liability (0.063 and 0.056), which is favorable for CNS penetration.

**15. Binding Affinity:** Ligand B (-8.1 kcal/mol) has a slightly better binding affinity than Ligand A (-7.3 kcal/mol). However, the difference is less than 1.5 kcal/mol, and other factors are more critical.

**Overall Assessment:**

Ligand A is the more promising candidate. While its binding affinity is slightly lower, it demonstrates significantly better ADME properties, particularly regarding BBB penetration, DILI risk, and metabolic stability. Ligand B's low logP and negative half-life are major red flags. The slightly better affinity of Ligand B is unlikely to overcome these significant drawbacks, especially for a CNS target like DRD2.

Output:
0
2025-04-17 05:42:50,455 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (361.419 and 351.418 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (81.7) is higher than Ligand B (51.91). For a CNS target like DRD2, TPSA should be <= 90, so both are acceptable, but B is significantly better.

**3. logP:** Both ligands have good logP values (2.069 and 3.065), falling within the optimal 1-3 range.

**4. H-Bond Donors:** Ligand A has 1 HBD, and Ligand B has 0. Both are within the acceptable limit of <=5.

**5. H-Bond Acceptors:** Ligand A has 5 HBA, and Ligand B has 4. Both are within the acceptable limit of <=10.

**6. QED:** Ligand A (0.882) has a better QED score than Ligand B (0.722), indicating a more drug-like profile.

**7. DILI:** Ligand A (93.292) has a significantly higher DILI risk than Ligand B (29.391). This is a major concern for Ligand A.

**8. BBB:** Ligand B (96.161) has a much higher BBB penetration percentile than Ligand A (56.65). This is *critical* for a CNS target like DRD2.

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.8 and -4.316). This is unusual and suggests poor permeability. However, the scale is not specified, so it's hard to interpret.

**10. Aqueous Solubility:** Both ligands have negative solubility values (-3.753 and -3.855), suggesting poor solubility. Similar to Caco-2, the scale is unclear.

**11. hERG Inhibition:** Both ligands have low hERG inhibition risk (0.426 and 0.582).

**12. Microsomal Clearance:** Ligand A (30.514) has lower microsomal clearance than Ligand B (44.171), suggesting better metabolic stability.

**13. In vitro Half-Life:** Ligand B (44.402) has a significantly longer in vitro half-life than Ligand A (13.717).

**14. P-gp Efflux:** Both ligands have low P-gp efflux liability (0.545 and 0.19). Ligand B is better.

**15. Binding Affinity:** Ligand B (-7.1 kcal/mol) has a significantly stronger binding affinity than Ligand A (-9.9 kcal/mol). This is a substantial advantage.

**Overall Assessment:**

Ligand B is the superior candidate. While both have issues with Caco-2 and solubility, Ligand B excels in the most important areas for a CNS GPCR target: BBB penetration (96.161 vs 56.65), binding affinity (-7.1 vs -9.9 kcal/mol), and has a much lower DILI risk (29.391 vs 93.292). The longer half-life and lower P-gp efflux are also beneficial. Ligand A's higher DILI risk is a significant red flag.

Output:
1
2025-04-17 05:42:50,455 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (343.358 Da) is slightly lower, which could be beneficial for permeability, but both are acceptable.

**TPSA:** Ligand A (75.48) is higher than Ligand B (58.64). For a CNS target like DRD2, we ideally want TPSA <= 90, so both are within range, but Ligand B is preferable.

**logP:** Both ligands have good logP values (Ligand A: 3.133, Ligand B: 2.234), falling within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Both have 1 HBD and 4 HBA, which are within acceptable limits.

**QED:** Both ligands have good QED scores (Ligand A: 0.683, Ligand B: 0.747), indicating good drug-like properties.

**DILI:** Ligand A (78.945) has a higher DILI risk than Ligand B (53.664). Lower DILI is preferred, giving an edge to Ligand B.

**BBB:** Both ligands have excellent BBB penetration (Ligand A: 81.582, Ligand B: 83.637), exceeding the desirable >70 threshold for CNS targets. This is a strong positive for both.

**Caco-2 Permeability:** Both have negative Caco-2 values (-4.921 and -4.677). This is unusual and suggests poor permeability. However, these values are on a scale where negative values are possible, and direct comparison is difficult without knowing the scale's specifics.

**Aqueous Solubility:** Both have negative solubility values (-4.566 and -3.088). Similar to Caco-2, these are on a scale where negative values are possible, making direct comparison difficult.

**hERG Inhibition:** Both ligands show low hERG inhibition risk (Ligand A: 0.785, Ligand B: 0.448). Lower is better, so Ligand B is slightly better here.

**Microsomal Clearance:** Ligand A (14.789) has significantly lower microsomal clearance than Ligand B (34.518), indicating better metabolic stability. This is a significant advantage for Ligand A.

**In vitro Half-Life:** Ligand A (18.308 hours) has a longer half-life than Ligand B (7.968 hours), which is generally desirable.

**P-gp Efflux:** Both ligands show low P-gp efflux liability (Ligand A: 0.29, Ligand B: 0.151). Lower is better, giving a slight edge to Ligand B.

**Binding Affinity:** Ligand B (-8.3 kcal/mol) has a slightly better binding affinity than Ligand A (-9.7 kcal/mol). While both are excellent, the difference of 1.4 kcal/mol is substantial and can outweigh minor ADME drawbacks.

**Overall Assessment:**

Ligand B has advantages in TPSA, DILI, hERG, P-gp efflux, and most importantly, binding affinity. Ligand A has advantages in metabolic stability (Cl_mic) and in vitro half-life. Given the importance of binding affinity for GPCRs, and the acceptable BBB penetration for both, Ligand B appears to be the more promising candidate. The slightly better ADME profile (lower DILI, hERG, Pgp) further supports this conclusion.

Output:
1
2025-04-17 05:42:50,455 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (343.471 and 363.527 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (79.19) is better than Ligand B (62.3). Both are below the 90 A^2 threshold for CNS targets, but Ligand B is closer to the ideal.

**3. logP:** Both ligands have good logP values (2.088 and 3.47), falling within the optimal 1-3 range. Ligand B is slightly higher, potentially leading to some solubility concerns, but not a major issue.

**4. H-Bond Donors:** Ligand A has 2 HBD, and Ligand B has 1. Both are within the acceptable limit of <=5.

**5. H-Bond Acceptors:** Ligand A has 3 HBA, and Ligand B has 4. Both are within the acceptable limit of <=10.

**6. QED:** Both ligands have similar and good QED values (0.819 and 0.871), indicating good drug-like properties.

**7. DILI:** Ligand A (25.126%) has a significantly lower DILI risk than Ligand B (44.397%). This is a substantial advantage for Ligand A.

**8. BBB:** Ligand B (77.278%) has a better BBB penetration score than Ligand A (63.474%). This is crucial for a CNS target like DRD2.

**9. Caco-2 Permeability:** Both have negative Caco-2 values (-5.051 and -4.966), which is unusual and suggests poor permeability. This is a concern for both.

**10. Aqueous Solubility:** Both have negative solubility values (-3.243 and -3.518), indicating poor aqueous solubility. This is a concern for both.

**11. hERG Inhibition:** Both ligands have low hERG inhibition risk (0.591 and 0.527).

**12. Microsomal Clearance:** Ligand A (-14.641) has much lower (better) microsomal clearance than Ligand B (56.309), indicating better metabolic stability.

**13. In vitro Half-Life:** Ligand A (-6.266) has a better in vitro half-life than Ligand B (-4.965).

**14. P-gp Efflux:** Both ligands have low P-gp efflux liability (0.108 and 0.295).

**15. Binding Affinity:** Both ligands have very similar and excellent binding affinities (-8.6 and -8.8 kcal/mol). The difference is negligible.

**Overall Assessment:**

Ligand B has a better BBB score, which is a high priority for a CNS target. However, Ligand A has significantly lower DILI risk, better metabolic stability (lower Cl_mic and better half-life), and a slightly better TPSA. The Caco-2 and solubility issues are present in both, but the superior safety and pharmacokinetic profile of Ligand A outweigh the slight advantage of Ligand B's BBB penetration. Given the similar binding affinities, the ADMET properties make Ligand A the more promising candidate.

Output:
0
2025-04-17 05:42:50,456 - INFO - Reasoning:

Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (363.443 and 350.459 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (100.35) is higher than the preferred <90 for CNS targets, while Ligand B (67.87) is well within the range. This is a significant advantage for Ligand B.

**3. logP:** Ligand A (0.385) is quite low, potentially hindering membrane permeability. Ligand B (1.215) is better, falling within the optimal 1-3 range.

**4. H-Bond Donors:** Both ligands have acceptable HBD counts (2 and 1, respectively), well below the limit of 5.

**5. H-Bond Acceptors:** Both ligands have acceptable HBA counts (7 and 4, respectively), below the limit of 10.

**6. QED:** Both ligands have good QED values (0.818 and 0.75), indicating good drug-like properties.

**7. DILI:** Ligand A (62.737) has a higher DILI risk than Ligand B (23.226). This favors Ligand B.

**8. BBB:** Ligand B (77.743) has a significantly higher BBB penetration percentile than Ligand A (11.943). This is a crucial advantage for a CNS target like DRD2.

**9. Caco-2 Permeability:** Ligand A (-5.239) has poor Caco-2 permeability, while Ligand B (-4.693) is slightly better, but still not ideal.

**10. Aqueous Solubility:** Both ligands have very poor aqueous solubility (-1.761 and -1.613). This could pose formulation challenges, but is less critical than BBB penetration for a CNS drug.

**11. hERG Inhibition:** Both ligands have low hERG inhibition risk (0.12 and 0.365).

**12. Microsomal Clearance:** Ligand A (-9.399) has a much lower (better) microsomal clearance than Ligand B (35.701), indicating greater metabolic stability.

**13. In vitro Half-Life:** Ligand A (-10.34) has a longer in vitro half-life than Ligand B (9.626).

**14. P-gp Efflux:** Both ligands have low P-gp efflux liability (0.051 and 0.039).

**15. Binding Affinity:** Both ligands have similar, strong binding affinities (-7.8 and -7.9 kcal/mol). The difference is negligible.

**Overall Assessment:**

While Ligand A has better metabolic stability and half-life, Ligand B is superior due to its significantly better BBB penetration (77.743 vs 11.943), lower TPSA (67.87 vs 100.35), and lower DILI risk (23.226 vs 62.737). The slightly lower logP of Ligand A is a concern for brain penetration. For a CNS GPCR target like DRD2, BBB penetration and a favorable safety profile (low DILI) are paramount. The similar binding affinities make these ADME properties the deciding factors.

Output:
1
2025-04-17 05:42:50,456 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight (MW):** Both ligands (338.411 and 345.487 Da) fall comfortably within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (75.19) is better than Ligand B (43.86). For CNS targets, we want TPSA <= 90, both are within this range, but A is closer to the upper limit.

**3. logP:** Both ligands have good logP values (1.087 and 1.864), falling within the optimal 1-3 range.

**4. H-Bond Donors (HBD):** Both ligands are acceptable. Ligand A has 1 HBD, and Ligand B has 0. Both are <=5.

**5. H-Bond Acceptors (HBA):** Both ligands are acceptable. Ligand A has 4 HBA, and Ligand B has 3. Both are <=10.

**6. QED:** Both ligands have similar QED values (0.755 and 0.731), indicating good drug-like properties (>=0.5).

**7. DILI:** Ligand B (10.818) has a significantly lower DILI risk than Ligand A (41.411). This is a substantial advantage for Ligand B.

**8. BBB:** Ligand A (63.009) has a better BBB percentile than Ligand B (59.325). While both are not ideal (>70), A is closer. This is critical for a CNS target like DRD2.

**9. Caco-2 Permeability:** Both have negative Caco-2 values (-4.594 and -4.685). This is unusual and suggests poor permeability.

**10. Aqueous Solubility:** Both have negative solubility values (-2.478 and -2.052). This is also unusual and suggests poor solubility.

**11. hERG Inhibition:** Both ligands have low hERG inhibition risk (0.12 and 0.381).

**12. Microsomal Clearance:** Ligand B (10.425) has lower microsomal clearance than Ligand A (16.002), indicating better metabolic stability.

**13. In vitro Half-Life:** Ligand B (6.064) has a longer in vitro half-life than Ligand A (-8.216).

**14. P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.021 and 0.047).

**15. Binding Affinity:** Ligand B (-7.4 kcal/mol) has a significantly stronger binding affinity than Ligand A (-8.2 kcal/mol). A difference of 0.8 kcal/mol is substantial.

**Overall Assessment:**

Ligand B is the more promising candidate. While Ligand A has a slightly better BBB penetration, Ligand B excels in several critical areas: significantly lower DILI risk, better metabolic stability (lower Cl_mic, longer t1/2), and, most importantly, a much stronger binding affinity. The affinity difference is large enough to outweigh the slightly lower BBB score. The negative Caco-2 and solubility values are concerning for both, but can be addressed during lead optimization.

Output:
1
2025-04-17 05:42:50,456 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (348.447 and 350.463 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (85.25) is slightly higher than Ligand B (78.68). Both are below the 90 A^2 threshold for CNS targets, which is good.

**3. logP:** Both ligands have similar logP values (1.424 and 1.445), falling within the optimal range of 1-3.

**4. H-Bond Donors:** Ligand A has 2 HBD, while Ligand B has 1. Both are within the acceptable limit of <=5.

**5. H-Bond Acceptors:** Both ligands have 5 HBA, which is within the acceptable limit of <=10.

**6. QED:** Ligand A (0.78) has a slightly better QED score than Ligand B (0.682), indicating a more drug-like profile.

**7. DILI:** Ligand A (28.228) has a significantly lower DILI risk than Ligand B (12.136). This is a substantial advantage for Ligand A.

**8. BBB:** Ligand A (57.464) has a slightly better BBB penetration percentile than Ligand B (54.711). While both are below the ideal >70 for CNS targets, Ligand A is closer.

**9. Caco-2 Permeability:** Ligand A (-4.931) has worse Caco-2 permeability than Ligand B (-5.452). Lower values are less desirable.

**10. Aqueous Solubility:** Ligand A (-1.375) has slightly better aqueous solubility than Ligand B (-0.453).

**11. hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.107 and 0.214).

**12. Microsomal Clearance:** Ligand A (17.329) has a higher microsomal clearance than Ligand B (0.132), indicating faster metabolism and lower metabolic stability. This is a significant drawback for Ligand A.

**13. In vitro Half-Life:** Ligand A (24.887) has a longer in vitro half-life than Ligand B (-9.449). This is a positive for Ligand A.

**14. P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.023 and 0.028).

**15. Binding Affinity:** Both ligands have very similar and excellent binding affinities (-7.4 and -7.5 kcal/mol). The difference is negligible.

**Overall Assessment:**

Ligand A has advantages in QED, DILI risk, aqueous solubility, and in vitro half-life. However, it suffers from higher microsomal clearance and worse Caco-2 permeability. Ligand B has better Caco-2 permeability and significantly better metabolic stability (lower Cl_mic). Considering the GPCR-specific priorities, BBB penetration is important, but metabolic stability is crucial for CNS drugs to achieve sufficient exposure. The lower DILI risk for Ligand A is also a significant benefit. Given the similar affinities and the importance of metabolic stability, Ligand B is slightly favored.

Output:
1
2025-04-17 05:42:50,456 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight (MW):** Both ligands (359.86 & 364.87 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (67.59) is higher than Ligand B (49.85). For a CNS target like DRD2, TPSA < 90 is preferred, so both are acceptable, but B is better.

**3. logP:** Both ligands have good logP values (3.20 & 2.01), falling within the optimal 1-3 range.

**4. H-Bond Donors (HBD):** Ligand A has 2 HBD, while Ligand B has 0. Both are within the acceptable limit of <=5.

**5. H-Bond Acceptors (HBA):** Ligand A has 4 HBA, and Ligand B has 3. Both are within the acceptable limit of <=10.

**6. QED:** Both ligands have reasonable QED scores (0.88 & 0.72), indicating good drug-like properties.

**7. DILI:** Ligand A (67.47%) has a significantly higher DILI risk than Ligand B (31.25%). This is a major concern for Ligand A.

**8. BBB:** Ligand A (66.42%) has a slightly lower BBB penetration than Ligand B (63.94%). While neither is outstanding (>70), BBB is a high priority for DRD2.

**9. Caco-2 Permeability:** Ligand A (-4.95) has worse Caco-2 permeability than Ligand B (-4.45).

**10. Aqueous Solubility:** Ligand A (-4.12) has worse solubility than Ligand B (-2.96).

**11. hERG Inhibition:** Both ligands have low hERG inhibition risk (0.59 & 0.45).

**12. Microsomal Clearance (Cl_mic):** Ligand A (-5.59) has much lower (better) microsomal clearance than Ligand B (16.11). This suggests better metabolic stability for Ligand A.

**13. In vitro Half-Life:** Ligand A (39.89) has a longer half-life than Ligand B (24.37).

**14. P-gp Efflux:** Ligand A (0.18) has a slightly higher P-gp efflux liability than Ligand B (0.18).

**15. Binding Affinity:** Ligand A (-9.4 kcal/mol) has a significantly stronger binding affinity than Ligand B (-0.0 kcal/mol). This is a very substantial difference.

**Overall Assessment:**

Ligand A has a much stronger binding affinity and better metabolic stability (lower Cl_mic, longer t1/2). However, its significantly higher DILI risk and lower BBB penetration are major drawbacks. Ligand B has a better safety profile (lower DILI) and slightly better BBB, but its binding affinity is extremely weak.

Given the importance of CNS penetration for a DRD2 ligand, and the substantial difference in binding affinity, the stronger affinity of Ligand A is likely to outweigh its drawbacks, *provided* the DILI risk can be mitigated through structural modifications. The weak affinity of Ligand B makes it a less promising starting point.

Output:
1
2025-04-17 05:42:50,456 - INFO - Reasoning:

Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (349.391 and 361.471 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (107.84) is slightly above the ideal <90 for CNS targets, but still reasonable. Ligand B (88.91) is excellent, well below 90.

**3. logP:** Ligand A (0.693) is a bit low, potentially hindering membrane permeability. Ligand B (1.41) is better, falling within the optimal 1-3 range.

**4. H-Bond Donors:** Ligand A (0) is ideal. Ligand B (2) is acceptable.

**5. H-Bond Acceptors:** Ligand A (5) is good. Ligand B (6) is also acceptable.

**6. QED:** Both ligands have good QED scores (0.423 and 0.707), indicating drug-like properties. Ligand B is better.

**7. DILI:** Both ligands have acceptable DILI risk (35.595 and 40.054), below the 40 threshold.

**8. BBB:** This is critical for a CNS target. Ligand A has a good BBB percentile (70.997), exceeding the desirable >70 threshold. Ligand B (56.883) is significantly lower and less favorable.

**9. Caco-2:** Ligand A (-4.911) and Ligand B (-5.431) both have negative Caco-2 values, which is unusual and suggests poor permeability. This is a concern for both, but the values are similar.

**10. Solubility:** Both ligands have poor aqueous solubility (-1.506 and -2.146). This is a significant drawback for both.

**11. hERG:** Both ligands show very low hERG inhibition liability (0.15 and 0.064), which is excellent.

**12. Cl_mic:** Ligand A (5.037) has a lower microsomal clearance, suggesting better metabolic stability than Ligand B (31.231).

**13. t1/2:** Ligand A (14.116) has a slightly longer in vitro half-life than Ligand B (12.114).

**14. Pgp:** Both ligands have very low P-gp efflux liability (0.012 and 0.097), which is excellent for CNS penetration.

**15. Binding Affinity:** Ligand B (-7.9 kcal/mol) has a significantly stronger binding affinity than Ligand A (-6.5 kcal/mol). This is a >1.5 kcal/mol advantage, which can outweigh some ADME drawbacks.

**Overall Assessment:**

Ligand B has a superior binding affinity and a better logP value. However, its BBB penetration is significantly lower than Ligand A's. Ligand A has a better BBB score and metabolic stability. Considering the GPCR-specific priorities, BBB is crucial for CNS targets like DRD2. While Ligand B's affinity is stronger, the lower BBB penetration is a major concern. The poor solubility and Caco-2 values are drawbacks for both, but can potentially be addressed with formulation strategies. Given the importance of CNS penetration for DRD2, and the fact that Ligand A meets the BBB threshold while Ligand B does not, Ligand A is the more promising candidate.

Output:
0
2025-04-17 05:42:50,457 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (343.402 and 344.455 Da) fall comfortably within the ideal range of 200-500 Da.

**2. TPSA:** Both ligands have TPSA values (63.25 and 62.55) below the 90 A^2 threshold desirable for CNS targets, which is excellent.

**3. logP:** Both ligands have logP values (3.015 and 3.077) within the optimal range of 1-3.

**4. H-Bond Donors:** Ligand A has 2 HBD, and Ligand B has 1. Both are acceptable (<=5).

**5. H-Bond Acceptors:** Both ligands have 3 HBA, well within the acceptable limit of <=10.

**6. QED:** Both ligands have high QED scores (0.812 and 0.807), indicating good drug-like properties.

**7. DILI:** Ligand A has a DILI risk of 40.403, which is just above the 'good' threshold of <40, but still reasonable. Ligand B has a significantly lower DILI risk of 27.065, which is excellent.

**8. BBB:** Both ligands have excellent BBB penetration percentiles (83.831 and 81.776), exceeding the desirable >70% for CNS targets.

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 permeability values (-4.427 and -4.4), which is unusual and suggests a potential issue with intestinal absorption. However, these values are on a scale where negative values can occur and don't necessarily preclude development.

**10. Aqueous Solubility:** Both ligands have very poor aqueous solubility (-3.698 and -3.133). This is a significant concern for formulation and bioavailability.

**11. hERG Inhibition:** Both ligands have low hERG inhibition liability (0.441 and 0.652), which is favorable.

**12. Microsomal Clearance:** Ligand A has a lower microsomal clearance (38.004) than Ligand B (74.633), indicating better metabolic stability.

**13. In vitro Half-Life:** Ligand B has a significantly longer in vitro half-life (77.174 hours) than Ligand A (26.433 hours), which is a major advantage.

**14. P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.085 and 0.442), which is excellent for CNS exposure.

**15. Binding Affinity:** Both ligands have very strong binding affinities (-9.6 and -9.2 kcal/mol). Ligand A is slightly better (-9.6 kcal/mol).

**Overall Assessment:**

Both ligands are very promising based on their strong binding affinity, good BBB penetration, and low P-gp efflux. However, the poor aqueous solubility of both is a major concern. Ligand B has a clear advantage in terms of DILI risk and in vitro half-life, outweighing the slightly weaker binding affinity compared to Ligand A. The lower metabolic clearance of Ligand A is positive, but the longer half-life of Ligand B is more impactful for dosing considerations.

Output:
1
2025-04-17 05:42:50,457 - INFO - Reasoning:

Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (336.355 Da) is slightly lower, which could be advantageous for permeability.

**2. TPSA:** Ligand B (71.97) is significantly better than Ligand A (112.7). For CNS targets, we want TPSA <= 90, and Ligand B is comfortably within this range, while Ligand A exceeds it. This is a significant advantage for Ligand B.

**3. logP:** Both ligands have similar and optimal logP values (around 1.3), falling within the 1-3 range.

**4. H-Bond Donors:** Ligand A has 2 HBD, and Ligand B has 0. Both are acceptable (<=5).

**5. H-Bond Acceptors:** Both ligands have 6 HBA, which is within the acceptable range (<=10).

**6. QED:** Ligand A (0.854) has a slightly better QED score than Ligand B (0.76), indicating a more drug-like profile.

**7. DILI:** Ligand A (75.339) has a higher DILI risk than Ligand B (43.932).  Ligand B is preferable here.

**8. BBB:** Ligand B (78.868) has a significantly better BBB penetration percentile than Ligand A (38.077). This is *critical* for a CNS target like DRD2.

**9. Caco-2 Permeability:** Ligand A (-5.055) has slightly better Caco-2 permeability than Ligand B (-4.957), but both are negative values, which is unusual and requires further investigation.

**10. Aqueous Solubility:** Ligand A (-3.683) has slightly better aqueous solubility than Ligand B (-2.265), but both are negative values, which is unusual and requires further investigation.

**11. hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.334 and 0.162, respectively), which is excellent.

**12. Microsomal Clearance:** Both ligands have similar microsomal clearance values (27.006 and 28.34 mL/min/kg), indicating comparable metabolic stability.

**13. In vitro Half-Life:** Ligand A (-3.505) has a slightly longer in vitro half-life than Ligand B (-1.988), which is preferable.

**14. P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.033 and 0.121, respectively), which is excellent.

**15. Binding Affinity:** Both ligands have excellent binding affinities (-8.4 and -8.0 kcal/mol). The difference of 0.4 kcal/mol is not substantial enough to outweigh the other ADME differences.

**Overall Assessment:**

Ligand B is the stronger candidate. While Ligand A has a slightly better QED and in vitro half-life, Ligand B excels in the crucial areas for a CNS-targeting GPCR: significantly lower TPSA, much better BBB penetration, and lower DILI risk. The similar logP and binding affinity further support this conclusion. The negative values for Caco-2 and solubility are concerning for both, but the other advantages of Ligand B make it the more promising candidate.

Output:
1
2025-04-17 05:42:50,457 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (366.531 and 362.539 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (75.19) is higher than Ligand B (49.41). For CNS targets, we prefer TPSA <= 90, so both are acceptable, but B is significantly better.

**3. logP:** Both ligands have similar logP values (2.855 and 2.839), falling within the optimal 1-3 range.

**4. H-Bond Donors:** Both have 1 HBD, which is good.

**5. H-Bond Acceptors:** Ligand A has 5 HBA, and Ligand B has 3. Both are within the acceptable limit of <=10.

**6. QED:** Both ligands have reasonable QED scores (0.805 and 0.765), indicating good drug-like properties.

**7. DILI:** Ligand A (30.167) has a slightly higher DILI risk than Ligand B (16.014), but both are below the concerning threshold of 40.

**8. BBB:** This is a critical parameter for CNS targets. Ligand B (80.264) has a significantly higher BBB percentile than Ligand A (67.197). This is a major advantage for B.

**9. Caco-2 Permeability:** Both have negative values (-5.07 and -5.168). This is unusual and suggests poor permeability. However, these values are on a scale where negative values are possible, and direct comparison is difficult without knowing the scale's specifics.

**10. Aqueous Solubility:** Both have negative values (-3.043 and -3.564), indicating poor aqueous solubility. Similar to Caco-2, the scale is unknown.

**11. hERG Inhibition:** Ligand A (0.209) has a slightly lower hERG inhibition liability than Ligand B (0.494), which is preferable.

**12. Microsomal Clearance:** Both have similar microsomal clearance values (53.792 and 51.866), indicating similar metabolic stability.

**13. In vitro Half-Life:** Ligand B (-7.596) has a negative half-life, which is not possible. This is likely an error in the data. Ligand A (9.338) has a reasonable half-life.

**14. P-gp Efflux:** Ligand A (0.105) has lower P-gp efflux than Ligand B (0.145), which is favorable for CNS penetration.

**15. Binding Affinity:** Ligand A (-8.2 kcal/mol) has a significantly stronger binding affinity than Ligand B (-0.0 kcal/mol). This is a substantial advantage for A, potentially outweighing some of its ADME drawbacks.

**Overall Assessment:**

While Ligand B has a much better BBB score and lower DILI risk, the dramatically superior binding affinity of Ligand A (-8.2 vs -0.0 kcal/mol) is a decisive factor. A strong binding affinity can often compensate for moderate ADME liabilities, especially if the compound can still reach the target in sufficient concentrations. The negative half-life for Ligand B is also a red flag, suggesting a data error. The slightly better hERG and Pgp profiles of Ligand A are also beneficial.

Output:
1
2025-04-17 05:42:50,457 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (355.364 Da) is slightly lower, which could be beneficial for permeability. Ligand B (371.503 Da) is also good.

**TPSA:** Ligand A (62.53) is excellent, well below the 90 A^2 threshold for CNS targets. Ligand B (87.74) is still reasonable, but less optimal.

**logP:** Both ligands have good logP values (A: 2.271, B: 1.37), falling within the 1-3 range.

**H-Bond Donors/Acceptors:** Both have acceptable HBD (A: 1, B: 2) and HBA (A: 5, B: 5) counts, fulfilling the criteria of <=5 and <=10 respectively.

**QED:** Ligand A (0.918) has a significantly better QED score than Ligand B (0.598), indicating a more drug-like profile.

**DILI:** Ligand A (49.05) has a slightly higher DILI risk than Ligand B (33.424), but both are below the concerning threshold of 60.

**BBB:** This is a crucial parameter for a CNS target like DRD2. Ligand A (97.208) has an excellent BBB percentile, while Ligand B (71.307) is good but lower.

**Caco-2 Permeability:** Both show poor Caco-2 permeability (A: -4.707, B: -4.973). This is a concern, but not a dealbreaker if other properties are favorable.

**Aqueous Solubility:** Both have very poor aqueous solubility (A: -2.168, B: -2.684). This could pose formulation challenges.

**hERG Inhibition:** Ligand A (0.853) has a slightly higher hERG risk than Ligand B (0.232), but both are relatively low.

**Microsomal Clearance:** Ligand A (-1.563) has a much lower (better) microsomal clearance than Ligand B (57.634), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (3.339) has a shorter half-life than Ligand B (-21.73), which is a negative.

**P-gp Efflux:** Ligand A (0.293) has significantly lower P-gp efflux liability than Ligand B (0.033), which is highly desirable for CNS penetration.

**Binding Affinity:** Ligand A (-8.7 kcal/mol) has a significantly stronger binding affinity than Ligand B (-6.8 kcal/mol). This >1.5 kcal/mol difference is substantial and can outweigh some ADME drawbacks.

**Overall Assessment:**

Ligand A is the stronger candidate. While it has a shorter half-life and slightly higher DILI risk, its superior BBB penetration, significantly better metabolic stability (lower Cl_mic), lower P-gp efflux, higher QED, and *much* stronger binding affinity outweigh these drawbacks. The TPSA is also excellent. Ligand B's lower affinity and poorer metabolic stability are significant concerns. The solubility and Caco-2 permeability are problematic for both, but can potentially be addressed with formulation strategies.



Output:
1
2025-04-17 05:42:50,458 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (349.362 Da) is slightly lower, which could be advantageous for permeability. Ligand B (364.452 Da) is also good.

**TPSA:** Ligand A (102.76) is borderline for CNS penetration, being above the preferred <90. Ligand B (49.41) is excellent, well below 90, and highly favorable for CNS targets.

**logP:** Ligand A (-0.312) is too low, potentially hindering membrane permeability and brain penetration. Ligand B (4.041) is at the upper end of the optimal range, which could lead to solubility issues but is generally acceptable.

**H-Bond Donors/Acceptors:** Ligand A (3 HBD, 5 HBA) is reasonable. Ligand B (1 HBD, 2 HBA) is even better, suggesting improved permeability.

**QED:** Both ligands have good QED scores (A: 0.586, B: 0.693), indicating drug-like properties.

**DILI:** Both ligands have acceptable DILI risk (A: 40.054, B: 35.75), below the 60 threshold.

**BBB:** This is a crucial parameter for a CNS target. Ligand A has a BBB percentile of 26.638, which is poor. Ligand B has a significantly better BBB percentile of 89.841, making it much more likely to reach the target in the brain.

**Caco-2 Permeability:** Both have negative Caco-2 values which is unusual and suggests poor permeability.

**Aqueous Solubility:** Both ligands have negative solubility values which is also unusual and suggests poor solubility.

**hERG Inhibition:** Ligand A (0.151) shows a very low risk of hERG inhibition, which is excellent. Ligand B (0.5) is slightly higher but still relatively low.

**Microsomal Clearance:** Ligand A (-26.971) has a negative clearance, which is not physically possible. This is likely an error in the data. Ligand B (67.516) has a high clearance, indicating rapid metabolism, which is a drawback.

**In vitro Half-Life:** Ligand A (-3.082) has a negative half-life, which is not physically possible. This is likely an error in the data. Ligand B (15.77) has a reasonable half-life.

**P-gp Efflux:** Ligand A (0.008) has very low P-gp efflux, which is favorable for CNS penetration. Ligand B (0.203) also has low P-gp efflux.

**Binding Affinity:** Ligand A (-7.4 kcal/mol) has a slightly better binding affinity than Ligand B (-0.0 kcal/mol). However, the difference in binding affinity is less important than the significant ADME differences.

**Overall Assessment:**

Despite Ligand A's slightly better binding affinity, Ligand B is the more promising candidate. Its superior TPSA, BBB penetration, and lower HBD/HBA counts are critical for a CNS-targeting GPCR ligand. The issues with the negative values for clearance and half-life for Ligand A are concerning and suggest data errors. While Ligand B's clearance is high, this can potentially be addressed through structural modifications. The poor logP of Ligand A is a major disadvantage.

Output:
1
2025-04-17 05:42:50,458 - INFO - Batch 221 complete. Total preferences: 3536
2025-04-17 05:42:50,458 - INFO - Processing batch 222/512...
2025-04-17 05:43:31,704 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 drug candidates, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (368.543 Da) is slightly higher than Ligand B (337.402 Da), but both are acceptable.

**TPSA:** Ligand A (75.27) is slightly higher than Ligand B (64.84). Both are below the 90 A^2 threshold for CNS targets, which is good.

**logP:** Ligand A (2.592) and Ligand B (3.331) are both within the optimal range of 1-3. Ligand B is slightly higher, which *could* be a minor concern for solubility, but not a major issue.

**H-Bond Donors/Acceptors:** Ligand A has 2 HBD and 3 HBA, while Ligand B has 1 HBD and 5 HBA. Both are within acceptable limits (<=5 HBD and <=10 HBA).

**QED:** Ligand B (0.927) has a significantly better QED score than Ligand A (0.614), indicating a more drug-like profile.

**DILI:** Both ligands have relatively high DILI risk, with Ligand A at 39.046 and Ligand B at 63.862. Ligand A is preferable here, having a lower risk. However, both are still within acceptable limits (<60 is good).

**BBB:** Ligand B (91.392) has a much higher BBB penetration percentile than Ligand A (65.025). This is a *critical* advantage for a CNS target like DRD2.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.071 and -4.872). This is unusual and suggests poor permeability. However, these values are on a strange scale, and are likely logP-related predictions that are not directly comparable.

**Aqueous Solubility:** Both ligands have very poor aqueous solubility (-3.77 and -4.866). This is a significant drawback and could hinder bioavailability.

**hERG Inhibition:** Ligand A (0.324) has a lower hERG inhibition liability than Ligand B (0.973), which is favorable.

**Microsomal Clearance:** Ligand B (72.795) has a higher microsomal clearance than Ligand A (57.385), suggesting faster metabolism and potentially lower exposure.

**In vitro Half-Life:** Ligand B (22.693) has a longer in vitro half-life than Ligand A (-14.3). This is a positive attribute.

**P-gp Efflux:** Ligand A (0.181) has lower P-gp efflux liability than Ligand B (0.34), which is beneficial for CNS penetration.

**Binding Affinity:** Ligand B (-8.6 kcal/mol) has a slightly better binding affinity than Ligand A (-7.8 kcal/mol). This difference of 0.8 kcal/mol is meaningful, but not overwhelming.

**Overall Assessment:**

Ligand B is the stronger candidate. While it has a higher DILI risk and slightly worse hERG, its significantly better BBB penetration (91.392 vs 65.025), longer half-life, and slightly improved binding affinity outweigh the drawbacks. The higher QED score also supports its drug-like properties. The poor solubility is a concern for both, but can potentially be addressed through formulation strategies. The negative Caco-2 values are concerning, but may be unreliable predictions.

Output:
1
2025-04-17 05:43:31,704 - INFO - Reasoning:

Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (359.312 and 350.547 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (106.85) is better than Ligand B (58.2). For CNS targets, we want TPSA <= 90, and A is closer to that threshold.

**3. logP:** Ligand A (1.3) is optimal (1-3), while Ligand B (4.183) is pushing the upper limit and could potentially lead to solubility issues or off-target interactions.

**4. H-Bond Donors:** Both ligands have 2 HBD, which is within the acceptable limit of <=5.

**5. H-Bond Acceptors:** Ligand A has 7 HBA, while Ligand B has 2. Both are within the acceptable limit of <=10.

**6. QED:** Ligand A (0.722) has a better QED score than Ligand B (0.655), indicating a more drug-like profile.

**7. DILI:** Ligand A (72.043) has a higher DILI risk than Ligand B (30.05). This is a negative for Ligand A.

**8. BBB:** Ligand A (83.715) has a significantly better BBB penetration percentile than Ligand B (71.927). This is a crucial advantage for a CNS target like DRD2.

**9. Caco-2:** Ligand A (-5.183) and Ligand B (-4.675) both have negative Caco-2 values, which is unusual and suggests poor permeability.

**10. Solubility:** Ligand A (-2.19) has slightly better solubility than Ligand B (-4.535), although both are poor.

**11. hERG:** Ligand A (0.115) has a lower hERG risk than Ligand B (0.523), which is favorable.

**12. Cl_mic:** Ligand A (26.632) has a lower microsomal clearance than Ligand B (67.042), indicating better metabolic stability.

**13. t1/2:** Ligand A (-10.423) has a negative in vitro half-life, which is concerning. Ligand B (13.073) has a positive half-life, which is better.

**14. Pgp:** Ligand A (0.124) has lower P-gp efflux liability than Ligand B (0.424), which is beneficial for CNS exposure.

**15. Binding Affinity:** Ligand B (-7.8 kcal/mol) has a slightly better binding affinity than Ligand A (-8.2 kcal/mol). While A is better, the difference is small.

**Overall Assessment:**

Despite the slightly better affinity of Ligand B, Ligand A is the more promising candidate. The key advantages of Ligand A are its significantly better BBB penetration, lower Pgp efflux, lower hERG risk, and lower microsomal clearance. While its DILI risk is higher, and solubility is poor, the CNS-focused priorities (BBB, Pgp) and metabolic stability outweigh these concerns. Ligand B's higher logP and poorer metabolic stability are significant drawbacks.

Output:
1
2025-04-17 05:43:31,705 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (356.438 and 362.499 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (76.66) is better than Ligand B (74.33). Both are below the 90 A^2 threshold desirable for CNS targets, but A is closer to the ideal.

**3. logP:** Both ligands have acceptable logP values (1.331 and 1.895), falling within the optimal 1-3 range.

**4. H-Bond Donors:** Both have 2 HBD, which is within the acceptable limit of <=5.

**5. H-Bond Acceptors:** Ligand A has 4 HBA, and Ligand B has 5. Both are below the 10 threshold.

**6. QED:** Both ligands have similar QED values (0.753 and 0.756), indicating good drug-likeness.

**7. DILI:** Both ligands have low DILI risk (30.361 and 34.781 percentile), which is favorable.

**8. BBB:** This is a critical parameter for CNS targets like DRD2. Ligand A has a significantly better BBB penetration (82.435%) compared to Ligand B (61.652%). Ligand A is much closer to the desirable >70% threshold.

**9. Caco-2 Permeability:** Ligand A (-4.945) is better than Ligand B (-5.135), indicating slightly better intestinal absorption.

**10. Aqueous Solubility:** Ligand A (-2.053) is better than Ligand B (-3.135), indicating better aqueous solubility.

**11. hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.434 and 0.389 percentile), which is excellent.

**12. Microsomal Clearance:** Ligand A (15.075 mL/min/kg) has a lower clearance than Ligand B (46.268 mL/min/kg), suggesting better metabolic stability.

**13. In vitro Half-Life:** Ligand A (26.298 hours) has a much longer half-life than Ligand B (-8.112 hours). This is a significant advantage.

**14. P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.043 and 0.081 percentile), which is favorable for CNS penetration.

**15. Binding Affinity:** Both ligands have the same binding affinity (-8.7 kcal/mol), which is excellent and well below the -7.0 kcal/mol threshold.

**Overall Assessment:**

While both ligands have good binding affinity and acceptable physicochemical properties, Ligand A is significantly better due to its superior BBB penetration (82.4% vs 61.7%), lower microsomal clearance, and longer in vitro half-life. These factors are particularly important for a CNS-targeting drug like a DRD2 ligand. The slightly better TPSA and solubility also contribute to its favorability.

Output:
1
2025-04-17 05:43:31,705 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (343.427 and 343.471 Da) fall comfortably within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (66.65) is slightly higher than Ligand B (61.44). Both are below the 90 A^2 threshold desirable for CNS targets, but Ligand B is closer to the ideal.

**3. logP:** Both ligands have good logP values (2.028 and 2.174), falling within the optimal 1-3 range.

**4. H-Bond Donors:** Ligand A has 0 HBD, while Ligand B has 2. Both are within the acceptable limit of <=5.

**5. H-Bond Acceptors:** Ligand A has 4 HBA, and Ligand B has 3. Both are within the acceptable limit of <=10.

**6. QED:** Ligand A (0.839) has a higher QED than Ligand B (0.76), suggesting a more drug-like profile.

**7. DILI:** Ligand A (27.608) has a significantly lower DILI risk than Ligand B (15.394). This is a major advantage for Ligand A.

**8. BBB:** Ligand A (76.541) has a better BBB penetration percentile than Ligand B (69.794). While both are reasonably good, Ligand A is closer to the desirable >70 threshold for CNS targets.

**9. Caco-2 Permeability:** Ligand A (-4.84) has a worse Caco-2 permeability than Ligand B (-5.011). Lower values indicate poorer permeability.

**10. Aqueous Solubility:** Ligand A (-1.705) has slightly better aqueous solubility than Ligand B (-2.544).

**11. hERG Inhibition:** Ligand A (0.099) has a lower hERG inhibition liability than Ligand B (0.611), indicating a lower risk of cardiotoxicity.

**12. Microsomal Clearance:** Ligand A (31.759) has a significantly higher microsomal clearance than Ligand B (2.708), meaning it's metabolized faster and has lower metabolic stability. This is a significant drawback for Ligand A.

**13. In vitro Half-Life:** Ligand A (-12.148) has a much shorter in vitro half-life than Ligand B (2.483). This is another significant drawback for Ligand A.

**14. P-gp Efflux:** Ligand A (0.067) has lower P-gp efflux liability than Ligand B (0.036), which is favorable for CNS penetration.

**15. Binding Affinity:** Ligand B (-9.0) has a slightly better binding affinity than Ligand A (-8.7). While both are strong binders, the 0.3 kcal/mol difference is not huge.

**Overall Assessment:**

Ligand A excels in BBB penetration, DILI risk, hERG inhibition, and P-gp efflux. However, it suffers from significantly higher microsomal clearance and a shorter half-life, which are critical drawbacks for a CNS drug. Ligand B, while slightly less favorable in some ADME properties, has much better metabolic stability and a longer half-life. Given the importance of metabolic stability and duration of action for CNS drugs, and the relatively small difference in binding affinity, Ligand B is the more promising candidate.

Output:
1
2025-04-17 05:43:31,705 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 drug candidates, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (367.423 and 346.402 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (94.09) is slightly above the optimal <90 for CNS targets, but still reasonable. Ligand B (69.64) is excellent, well below 90.

**3. logP:** Both ligands have good logP values (1.773 and 2.096), falling within the 1-3 range.

**4. H-Bond Donors:** Both have 2 HBD, which is within the acceptable limit of <=5.

**5. H-Bond Acceptors:** Ligand A has 6 HBA, and Ligand B has 3. Both are within the acceptable limit of <=10.

**6. QED:** Both ligands have good QED scores (0.702 and 0.881), indicating good drug-like properties.

**7. DILI:** Ligand A (54.401) has a slightly higher DILI risk than Ligand B (31.563), but both are below the concerning threshold of 60.

**8. BBB:** This is a critical parameter for CNS targets. Ligand B (67.468) has a significantly better BBB percentile than Ligand A (17.914). This is a major advantage for Ligand B.

**9. Caco-2 Permeability:** Both have negative values, which is unusual and suggests poor permeability. However, the scale is not specified, so it's difficult to interpret.

**10. Aqueous Solubility:** Both have negative values, indicating poor solubility.

**11. hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.551 and 0.552).

**12. Microsomal Clearance:** Ligand B (20.695) has lower microsomal clearance than Ligand A (32.228), suggesting better metabolic stability.

**13. In vitro Half-Life:** Ligand B (10.669) has a longer in vitro half-life than Ligand A (-40.278), which is a strong positive. The negative value for Ligand A is concerning.

**14. P-gp Efflux:** Both ligands have low P-gp efflux liability (0.138 and 0.109), which is favorable for CNS penetration.

**15. Binding Affinity:** Ligand B (-9.6 kcal/mol) has a significantly stronger binding affinity than Ligand A (-7.9 kcal/mol). This >1.5 kcal/mol difference is substantial and can outweigh minor ADME drawbacks.

**Overall Assessment:**

Ligand B clearly outperforms Ligand A. While both have acceptable MW, logP, HBD, HBA, QED, and hERG profiles, Ligand B excels in the critical areas for a CNS-targeting GPCR: BBB penetration, metabolic stability (lower Cl_mic, longer t1/2), and, most importantly, binding affinity. Ligand A's poor BBB penetration and negative in vitro half-life are significant drawbacks. The better affinity of Ligand B is a decisive factor.

Output:
1
2025-04-17 05:43:31,705 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (366.439 Da and 354.466 Da) fall within the ideal range of 200-500 Da.

**TPSA:** Ligand A (84.94) is better than Ligand B (67.43), both are below the 90 A^2 threshold for CNS targets.

**logP:** Ligand B (2.508) is more optimal than Ligand A (1.104). While A is within the 1-3 range, B is closer to the sweet spot.

**H-Bond Donors & Acceptors:** Ligand A has 1 HBD and 5 HBA, while Ligand B has 2 HBD and 3 HBA. Both are within acceptable limits.

**QED:** Ligand A (0.805) has a significantly better QED score than Ligand B (0.593), indicating better overall drug-likeness.

**DILI:** Ligand B (22.8) has a much lower DILI risk than Ligand A (56.844), which is a significant advantage.

**BBB:** Ligand B (87.941) has a much higher BBB penetration percentile than Ligand A (64.599). This is *critical* for a CNS target like DRD2.

**Caco-2 Permeability:** Ligand A (-4.811) has a lower Caco-2 permeability than Ligand B (-4.597), suggesting potentially poorer absorption.

**Aqueous Solubility:** Ligand A (-2.384) has better aqueous solubility than Ligand B (-3.18), which is a slight advantage.

**hERG Inhibition:** Ligand A (0.123) has a lower hERG inhibition liability than Ligand B (0.533), which is a positive.

**Microsomal Clearance:** Ligand A (-16.598) has a much lower microsomal clearance, indicating better metabolic stability than Ligand B (55.247).

**In vitro Half-Life:** Ligand A (60.091) has a longer in vitro half-life than Ligand B (-4.367), which is preferable.

**P-gp Efflux:** Ligand A (0.042) has a lower P-gp efflux liability than Ligand B (0.243), which is beneficial for CNS exposure.

**Binding Affinity:** Ligand B (-7.8 kcal/mol) has a significantly stronger binding affinity than Ligand A (0.0 kcal/mol). This is a major advantage, potentially outweighing some of the ADME drawbacks.

**Overall Assessment:**

Ligand B excels in the most critical areas for a CNS GPCR target: BBB penetration and binding affinity. While Ligand A has better QED, metabolic stability, and lower P-gp efflux, the superior affinity and BBB of Ligand B are decisive. The lower DILI risk for Ligand B is also a significant benefit. The slightly worse solubility and higher hERG risk of Ligand B can be addressed through further optimization.

Output:
1
2025-04-17 05:43:31,706 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (346.475 and 358.404 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (76.02) is significantly better than Ligand B (49.41). For CNS targets, we want TPSA <= 90, and ideally lower. Ligand A is borderline, while Ligand B is excellent.

**logP:** Both ligands have good logP values (2.261 and 3.094), falling within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A has 2 HBD and 4 HBA, while Ligand B has 1 HBD and 4 HBA. Both are within acceptable limits (<=5 HBD and <=10 HBA).

**QED:** Both ligands have similar QED scores (0.795 and 0.794), indicating good drug-likeness.

**DILI:** Ligand A (32.028) has a much lower DILI risk than Ligand B (57.697). This is a significant advantage for Ligand A.

**BBB:** Ligand B (93.757) has a substantially higher BBB penetration percentile than Ligand A (61.652). This is a *critical* advantage for a CNS target like DRD2.

**Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and suggests a problem with the data or the model. However, we can't rely on this metric.

**Aqueous Solubility:** Both have negative solubility values, which is also unusual. Again, we can't rely on this metric.

**hERG:** Ligand A (0.499) has a slightly lower hERG inhibition liability than Ligand B (0.916), which is preferable.

**Microsomal Clearance:** Ligand B (30.676) has lower microsomal clearance than Ligand A (41.819), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand B (36.116) has a significantly longer in vitro half-life than Ligand A (1.243). This is a considerable advantage.

**P-gp Efflux:** Ligand A (0.111) has a lower P-gp efflux liability than Ligand B (0.399), which is favorable for CNS penetration.

**Binding Affinity:** Ligand B (-9.4 kcal/mol) has a significantly stronger binding affinity than Ligand A (-8.7 kcal/mol). This >1.5 kcal/mol difference is a major advantage, potentially outweighing some ADME drawbacks.

**Overall Assessment:**

Ligand B excels in BBB penetration and binding affinity, the two most important factors for a CNS GPCR target. It also has better metabolic stability (lower Cl_mic) and a longer half-life. While Ligand A has a lower DILI risk and P-gp efflux, the superior affinity and BBB of Ligand B are decisive. The TPSA of Ligand B is also more favorable.

Output:
1
2025-04-17 05:43:31,706 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (346.431 and 352.41 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Both ligands have TPSA values (78.67 and 76.46) below the 90 A^2 threshold for CNS targets, which is excellent.

**3. logP:** Both ligands have logP values (0.698 and 0.507) which are a bit low, ideally we want between 1-3. This could potentially hinder permeability, but isn't a dealbreaker.

**4. H-Bond Donors:** Both ligands have 1 HBD, which is within the acceptable limit of <=5.

**5. H-Bond Acceptors:** Both ligands have 5 HBA, also within the acceptable limit of <=10.

**6. QED:** Both ligands have good QED scores (0.737 and 0.838), indicating good drug-like properties.

**7. DILI:** Both ligands have relatively low DILI risk (32.261 and 42.536), below the 40 threshold.

**8. BBB:** This is a critical parameter for a CNS target like DRD2. Ligand B (87.631) has a significantly higher BBB percentile than Ligand A (58.007). This is a major advantage for Ligand B.

**9. Caco-2 Permeability:** Both have negative values, indicating poor permeability. This is concerning, but can be overcome with formulation strategies.

**10. Aqueous Solubility:** Both have negative values, indicating poor solubility. This is also concerning, but can be overcome with formulation strategies.

**11. hERG Inhibition:** Both ligands show very low hERG inhibition risk (0.132 and 0.143).

**12. Microsomal Clearance:** Ligand A (37.568) has a higher microsomal clearance than Ligand B (5.736), suggesting Ligand B is more metabolically stable.

**13. In vitro Half-Life:** Ligand A (10.48) has a longer half-life than Ligand B (5.045).

**14. P-gp Efflux:** Both have very low P-gp efflux liability (0.014 and 0.015).

**15. Binding Affinity:** Ligand A (-7.0 kcal/mol) has a slightly better binding affinity than Ligand B (-0.0 kcal/mol). However, the difference is not substantial enough to outweigh the other factors.

**Overall Assessment:**

While Ligand A has slightly better binding affinity and a longer half-life, Ligand B is significantly better in terms of BBB penetration (87.631 vs 58.007) and metabolic stability (lower Cl_mic). For a CNS target like DRD2, BBB penetration is paramount. The better metabolic stability of Ligand B is also a significant advantage. The slightly lower affinity of Ligand B can potentially be optimized during lead optimization. The poor Caco-2 and solubility for both compounds are concerns, but can be addressed with formulation.

Output:
1
2025-04-17 05:43:31,706 - INFO - Reasoning:

Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (338.411 and 371.547 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (74.33) is better than Ligand B (78.51). Both are below the 90 A^2 threshold desirable for CNS targets, but A is closer to optimal.

**3. logP:** Both ligands have similar and good logP values (1.725 and 1.618), falling within the 1-3 range.

**4. H-Bond Donors:** Both have 2 HBD, which is acceptable (<=5).

**5. H-Bond Acceptors:** Both have 4 HBA, which is acceptable (<=10).

**6. QED:** Ligand A (0.871) has a significantly better QED score than Ligand B (0.604), indicating a more drug-like profile.

**7. DILI:** Ligand A (58.938) has a higher DILI risk than Ligand B (19.271). This is a significant drawback for Ligand A.

**8. BBB:** Ligand B (62.699) has a better BBB penetration percentile than Ligand A (54.052). While both are not ideal (>70), B is closer.

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 values, which is unusual and suggests poor permeability. Ligand A (-5.314) is slightly better than Ligand B (-5.478), but both are concerning.

**10. Aqueous Solubility:** Both ligands have negative solubility values, indicating poor aqueous solubility. Ligand B (-2.118) is slightly better than Ligand A (-2.501).

**11. hERG Inhibition:** Both ligands show low hERG inhibition liability (0.544 and 0.638), which is good.

**12. Microsomal Clearance:** Ligand A (-15.436) has significantly lower (better) microsomal clearance than Ligand B (24.196), indicating better metabolic stability.

**13. In vitro Half-Life:** Ligand A (33.958) has a much longer in vitro half-life than Ligand B (-31.835). This is a major advantage for Ligand A.

**14. P-gp Efflux:** Both ligands show low P-gp efflux liability (0.028 and 0.071), which is good.

**15. Binding Affinity:** Both ligands have very similar and strong binding affinities (-9.2 and -8.5 kcal/mol). The difference is less than 1.5 kcal/mol, so it's not a deciding factor.

**Overall Assessment:**

Ligand A has advantages in QED, metabolic stability (Cl_mic), and half-life. However, it has a significantly higher DILI risk and slightly lower BBB penetration. Ligand B has a lower DILI risk and better BBB penetration, but suffers from poorer metabolic stability and a shorter half-life.

Considering the GPCR-specific priorities, BBB is crucial for CNS targets. However, the substantial difference in DILI risk and metabolic stability (Cl_mic and t1/2) are more concerning. A high DILI risk can be a deal-breaker in drug development. While Ligand B's BBB is better, the improved metabolic stability and half-life of Ligand A, combined with acceptable (though not ideal) BBB, make it the more promising candidate. Further optimization could address the DILI risk.

Output:
0
2025-04-17 05:43:31,706 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (359.495 and 346.383 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (62.3) is significantly better than Ligand B (88.85). For CNS targets, TPSA should be <= 90, and A is comfortably within this range, while B is approaching the upper limit.

**logP:** Both ligands have good logP values (2.015 and 1.711), falling within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Both have 1 HBD, which is good. Ligand A has 4 HBA, and Ligand B has 5. Both are acceptable (<=10).

**QED:** Both ligands have reasonable QED scores (0.874 and 0.792), indicating good drug-like properties.

**DILI:** Ligand A (27.918) has a much lower DILI risk than Ligand B (59.984). This is a significant advantage for A.

**BBB:** Ligand A (67.197) has a better BBB penetration percentile than Ligand B (50.523). While >70 is desirable, 67.197 is a reasonable starting point, whereas 50.523 is less promising for a CNS target.

**Caco-2 Permeability:** Ligand A (-5.318) shows better Caco-2 permeability than Ligand B (-4.384), indicating better intestinal absorption.

**Aqueous Solubility:** Ligand A (-3.175) has slightly better aqueous solubility than Ligand B (-2.509).

**hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.159 and 0.032).

**Microsomal Clearance:** Ligand A (21.839) has significantly lower microsomal clearance than Ligand B (62.831), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (-7.503) has a substantially longer in vitro half-life than Ligand B (18.745).

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.039 and 0.02).

**Binding Affinity:** Ligand A (-7.5 kcal/mol) has a slightly better binding affinity than Ligand B (-6.9 kcal/mol). While the difference is less than the 1.5 kcal/mol threshold, it contributes to the overall preference for A.

**Overall Assessment:**

Ligand A consistently outperforms Ligand B across most critical ADME properties, especially BBB penetration, DILI risk, metabolic stability (Cl_mic and t1/2), and Caco-2 permeability. While both have acceptable logP and binding affinity, the superior ADME profile of Ligand A makes it the more promising drug candidate for targeting DRD2, a CNS GPCR.



Output:
1
2025-04-17 05:43:31,707 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (346.431 and 345.447 Da) fall well within the ideal range of 200-500 Da.

**2. TPSA:** Both ligands have TPSA values (87.46 and 87.22) that are acceptable for oral absorption (<140) and reasonably good for a CNS target (<90, though slightly above).

**3. logP:** Ligand A (0.637) is slightly low, potentially hindering permeation. Ligand B (2.418) is much better, falling within the optimal 1-3 range. This is a significant advantage for Ligand B.

**4. H-Bond Donors:** Both ligands have 2 HBD, which is within the acceptable limit of <=5.

**5. H-Bond Acceptors:** Ligand A has 5 HBA, and Ligand B has 6. Both are within the acceptable limit of <=10.

**6. QED:** Ligand A (0.758) has a better QED score than Ligand B (0.528), indicating a more drug-like profile.

**7. DILI:** Both ligands have low DILI risk (42.148 and 38.542 percentiles), which is good.

**8. BBB:** This is a crucial parameter for CNS targets. Ligand B (88.872) has a significantly higher BBB penetration percentile than Ligand A (35.324). This is a major advantage for Ligand B.

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.441 and -5.261). This is unusual and suggests poor permeability. However, these values are on a log scale and the negative values are not directly comparable without knowing the scale.

**10. Aqueous Solubility:** Both ligands have very poor aqueous solubility (-2.49 and -3.262). This is a significant drawback for both.

**11. hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.092 and 0.344), which is excellent.

**12. Microsomal Clearance:** Ligand A (22.131 mL/min/kg) has lower microsomal clearance than Ligand B (44.852 mL/min/kg), indicating better metabolic stability.

**13. In vitro Half-Life:** Ligand A (7.01 hours) has a positive half-life, while Ligand B (-9.52 hours) has a negative half-life, which is not possible. This is likely an error in the data, but it is a significant concern for Ligand B.

**14. P-gp Efflux:** Both ligands have low P-gp efflux liability (0.024 and 0.066), which is good.

**15. Binding Affinity:** Ligand A (-7.8 kcal/mol) has a slightly better binding affinity than Ligand B (-8.7 kcal/mol). While both are excellent, the difference is relatively small.

**Overall Assessment:**

Ligand B is the better candidate despite the questionable half-life value. Its significantly higher BBB penetration (88.872 vs 35.324) and more optimal logP (2.418 vs 0.637) are critical advantages for a CNS-targeting GPCR like DRD2. While Ligand A has a slightly better QED and metabolic stability, the improved CNS penetration of Ligand B outweighs these factors. The negative half-life for Ligand B is concerning and would require further investigation, but the other properties strongly favor it.

Output:
1
2025-04-17 05:43:31,707 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (350.419 and 354.447 Da) fall comfortably within the ideal 200-500 Da range.

**TPSA:** Ligand A (103.79) is better than Ligand B (107.89). Both are below the 140 A^2 threshold for oral absorption, but closer to the 90 A^2 target for CNS penetration.

**logP:** Ligand A (1.843) is optimal (1-3), while Ligand B (0.088) is quite low, potentially hindering permeation. This is a significant disadvantage for Ligand B.

**H-Bond Donors/Acceptors:** Ligand A has 3 HBD and 5 HBA, while Ligand B has 4 HBD and 5 HBA. Both are within acceptable limits.

**QED:** Ligand A (0.769) has a significantly better QED score than Ligand B (0.469), indicating better overall drug-likeness.

**DILI:** Ligand A (32.183) has a much lower DILI risk than Ligand B (15.2). This is a substantial advantage for Ligand A.

**BBB:** Ligand A (52.811) has a better BBB percentile than Ligand B (23.924). While neither is >70, A is significantly better. This is crucial for a CNS target like DRD2.

**Caco-2 Permeability:** Ligand A (-4.745) has a worse Caco-2 permeability than Ligand B (-5.389). Both are negative, indicating poor permeability.

**Aqueous Solubility:** Ligand A (-2.466) has a slightly better solubility than Ligand B (-1.285). Both are negative, indicating poor solubility.

**hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.171 and 0.116, respectively).

**Microsomal Clearance:** Ligand A (4.785) has a much lower microsomal clearance than Ligand B (-15.232). This suggests better metabolic stability for Ligand A.

**In vitro Half-Life:** Ligand A (-15.594) has a much longer in vitro half-life than Ligand B (38.588). This is a significant advantage for Ligand A.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.006 and 0.019, respectively).

**Binding Affinity:** Both ligands have similar binding affinities (-8.0 and -7.9 kcal/mol). The difference is negligible.

**Overall Assessment:**

Ligand A is clearly superior. It has better logP, QED, DILI, BBB, microsomal clearance, and in vitro half-life. While Caco-2 permeability and aqueous solubility are poor for both, the other advantages of Ligand A outweigh these drawbacks, especially given the importance of BBB penetration for a CNS target. The similar binding affinities mean that the ADME properties are the deciding factor.

Output:
1
2025-04-17 05:43:31,707 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B based on the provided guidelines, prioritizing GPCR-specific properties (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (365.5 and 355.5 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (78.51) is better than Ligand B (59.23). For CNS targets, we want TPSA <= 90, both are within this range, but A is closer to the upper limit.

**logP:** Ligand B (4.406) is higher than Ligand A (1.095). While 1-3 is optimal, Ligand B is pushing the upper limit. Ligand A is well within the optimal range.

**H-Bond Donors/Acceptors:** Ligand A has 2 HBD and 4 HBA, while Ligand B has 0 HBD and 5 HBA. Both are acceptable, falling within the recommended limits.

**QED:** Both ligands have similar QED values (0.662 and 0.657), indicating good drug-likeness.

**DILI:** Ligand A (39.162) has a lower DILI risk than Ligand B (57.736), which is preferable. Both are below the 60 threshold, but A is better.

**BBB:** Ligand A (59.209) has a slightly better BBB penetration percentile than Ligand B (55.021). While both are not ideal (>70 desirable), A is closer. This is a crucial factor for a CNS target like DRD2.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.233 and -5.172), which is unusual and suggests poor permeability. This is a significant drawback for both.

**Aqueous Solubility:** Both ligands have negative solubility values (-3.242 and -4.717), indicating very poor aqueous solubility. This is a major concern for bioavailability.

**hERG Inhibition:** Ligand A (0.198) has a lower hERG inhibition liability than Ligand B (0.514), which is better.

**Microsomal Clearance:** Ligand B (91.823) has a significantly higher microsomal clearance than Ligand A (28.322), indicating lower metabolic stability. This is a major disadvantage for Ligand B.

**In vitro Half-Life:** Ligand B (60.29) has a much longer in vitro half-life than Ligand A (2.234), which is a positive for Ligand B.

**P-gp Efflux:** Ligand A (0.026) has much lower P-gp efflux liability than Ligand B (0.741), which is highly desirable for CNS penetration.

**Binding Affinity:** Ligand B (-8.1 kcal/mol) has a slightly better binding affinity than Ligand A (-7.9 kcal/mol). This is a positive for Ligand B, but the difference is relatively small.

**Overall Assessment:**

Ligand A is superior despite the slightly weaker binding affinity. Its better BBB penetration, lower DILI risk, lower hERG inhibition, significantly lower microsomal clearance (better metabolic stability), and significantly lower P-gp efflux liability are crucial advantages for a CNS-targeting GPCR. While both have poor solubility and Caco-2 permeability, the ADME properties of Ligand A are much more favorable. The small affinity difference is outweighed by the substantial improvements in drug-like properties.

Output:
0
2025-04-17 05:43:31,707 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (362.367 and 347.503 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (125.88) is slightly above the optimal <90 for CNS targets, but still reasonable. Ligand B (53.51) is excellent, well below 90.

**logP:** Ligand A (0.742) is a bit low, potentially hindering permeability. Ligand B (3.445) is within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A (1 HBD, 8 HBA) is good. Ligand B (0 HBD, 3 HBA) is also very good. Both are within acceptable limits.

**QED:** Both ligands have similar QED values (0.663 and 0.687), indicating good drug-likeness.

**DILI:** Ligand A has a very high DILI risk (98.759), a significant concern. Ligand B has a low DILI risk (19.271), which is highly favorable.

**BBB:** Ligand A's BBB penetration (47.615) is suboptimal for a CNS target. Ligand B exhibits excellent BBB penetration (82.164), exceeding the >70 threshold.

**Caco-2 Permeability:** Ligand A shows poor Caco-2 permeability (-5.019). Ligand B shows poor Caco-2 permeability (-4.386).

**Aqueous Solubility:** Both ligands have poor aqueous solubility (-3.226 and -2.138).

**hERG Inhibition:** Ligand A has a very low hERG risk (0.128), which is excellent. Ligand B has a moderate hERG risk (0.773).

**Microsomal Clearance:** Ligand A has moderate clearance (57.007). Ligand B has higher clearance (75.371).

**In vitro Half-Life:** Ligand A has a negative half-life (-2.929), which is not possible. Ligand B has a reasonable half-life (28.533).

**P-gp Efflux:** Ligand A has low P-gp efflux (0.17), which is good. Ligand B has moderate P-gp efflux (0.346).

**Binding Affinity:** Ligand B (-7.7 kcal/mol) has a slightly better binding affinity than Ligand A (-8.2 kcal/mol), though the difference is small.

**Overall Assessment:**

Ligand A has a major drawback with its extremely high DILI risk and poor BBB penetration. While it has a slightly better binding affinity and lower P-gp efflux, these are outweighed by the significant safety concerns. The negative half-life is also a major red flag.

Ligand B, despite having slightly higher P-gp efflux and clearance, presents a much more favorable profile with excellent BBB penetration, low DILI risk, and good binding affinity. The solubility and Caco-2 permeability are concerns for both, but can be addressed with formulation strategies.

Output:
1
2025-04-17 05:43:31,707 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (359.451 and 370.871 Da) are within the ideal 200-500 Da range.

**TPSA:** Ligand A (66.65) is significantly higher than Ligand B (32.34). For CNS targets, TPSA should be <= 90, so both are acceptable, but B is much better.

**logP:** Ligand A (2.633) is within the optimal 1-3 range. Ligand B (4.56) is slightly above, potentially raising solubility concerns, but not drastically.

**H-Bond Donors/Acceptors:** Ligand A has 0 HBD and 5 HBA. Ligand B has 1 HBD and 2 HBA. Both are within acceptable limits.

**QED:** Both ligands have good QED values (0.787 and 0.824), indicating good drug-like properties.

**DILI:** Both ligands have low DILI risk (40.132 and 39.201), which is favorable.

**BBB:** Ligand B (93.408) has a much higher BBB penetration percentile than Ligand A (85.964). This is a *critical* advantage for a CNS target like DRD2.

**Caco-2 Permeability:** Both have negative values (-5.107 and -4.809), which is unusual and suggests poor permeability. However, the scale is not specified, so it's difficult to interpret.

**Aqueous Solubility:** Both have negative values (-2.814 and -4.684), again, the scale is not specified, making interpretation difficult.

**hERG:** Both ligands have very low hERG inhibition liability (0.167 and 0.757), which is excellent.

**Microsomal Clearance:** Both have similar microsomal clearance values (45.363 and 43.591), suggesting comparable metabolic stability.

**In vitro Half-Life:** Ligand B (32.613) has a significantly longer in vitro half-life than Ligand A (-6.352). This is a positive attribute.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.108 and 0.33), which is good, especially for CNS penetration.

**Binding Affinity:** Ligand B (-8.1 kcal/mol) has a significantly stronger binding affinity than Ligand A (-6.8 kcal/mol). This >1.5 kcal/mol difference is substantial and can outweigh some ADME drawbacks.

**Conclusion:**

Ligand B is the superior candidate. While both meet the basic drug-likeness criteria, Ligand B excels in the most important parameters for a CNS-targeting GPCR: significantly higher BBB penetration, stronger binding affinity, and a longer in vitro half-life. The slightly higher logP of Ligand B is a minor concern compared to these advantages. The negative Caco-2 and solubility values are concerning for both, but the superior binding and BBB penetration of B make it the better choice.

Output:
1
2025-04-17 05:43:31,708 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (342.483 and 346.523 Da) fall comfortably within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (49.41) is significantly better than Ligand B (56.32). For CNS targets, we want TPSA <= 90, and ideally closer to that value. Ligand A is much closer to the ideal range.

**3. logP:** Both ligands have a logP of approximately 2.57, which is within the optimal 1-3 range.

**4. H-Bond Donors:** Ligand A (1) is preferable to Ligand B (2). Fewer HBDs generally improve permeability.

**5. H-Bond Acceptors:** Ligand A (2) is better than Ligand B (6). Lower HBA counts are generally preferred for CNS penetration.

**6. QED:** Both ligands have decent QED values (0.617 and 0.791), indicating good drug-like properties. Ligand B is slightly better.

**7. DILI:** Ligand A (17.449) has a lower DILI risk than Ligand B (14.114), which is favorable.

**8. BBB:** Ligand B (80.69) has a better BBB percentile than Ligand A (71.966). This is a crucial factor for CNS targets, and Ligand B has a noticeable advantage here.

**9. Caco-2 Permeability:** Ligand A (-4.821) shows better Caco-2 permeability than Ligand B (-5.319). Higher values are better.

**10. Aqueous Solubility:** Ligand A (-2.886) has better aqueous solubility than Ligand B (-1.642).

**11. hERG Inhibition:** Ligand A (0.309) has a lower hERG inhibition liability than Ligand B (0.942), which is a significant safety advantage.

**12. Microsomal Clearance:** Ligand B (-4.579) has a lower (better) microsomal clearance than Ligand A (13.702), indicating greater metabolic stability.

**13. In vitro Half-Life:** Ligand B (26.194) has a significantly longer in vitro half-life than Ligand A (-3.137), which is a major advantage.

**14. P-gp Efflux:** Ligand A (0.217) has lower P-gp efflux liability than Ligand B (0.023). Lower efflux is better for CNS exposure.

**15. Binding Affinity:** Both ligands have very similar and excellent binding affinities (-8.4 and -8.8 kcal/mol). The difference is negligible.

**Overall Assessment:**

Ligand B excels in BBB penetration and metabolic stability (lower Cl_mic, longer t1/2). However, Ligand A has a better TPSA, solubility, lower hERG risk, and lower P-gp efflux. Considering the GPCR-specific priorities, BBB is critical. While Ligand A has several advantages in other ADME properties, the substantial difference in BBB (80.69 vs 71.966) and the longer half-life of Ligand B are compelling. The slightly higher DILI and hERG risk of Ligand B are acceptable given its superior CNS penetration and metabolic stability.

Output:
1
2025-04-17 05:43:31,708 - INFO - Batch 222 complete. Total preferences: 3552
2025-04-17 05:43:31,708 - INFO - Processing batch 223/512...
2025-04-17 05:44:12,682 - INFO - Reasoning:

Let's analyze Ligand A and Ligand B based on the provided guidelines, prioritizing GPCR-specific properties (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (351.324 and 364.408 Da) fall within the ideal range of 200-500 Da.

**TPSA:** Ligand A (38.77) is significantly better than Ligand B (58.64). For CNS targets, we want TPSA <= 90, and ideally lower. Ligand A is excellent, while Ligand B is approaching the upper limit.

**logP:** Both ligands have a logP around 3 (3.083 and 3.013), which is optimal.

**H-Bond Donors/Acceptors:** Ligand A (0 HBD, 3 HBA) and Ligand B (1 HBD, 3 HBA) both have acceptable numbers of H-bond donors and acceptors.

**QED:** Both ligands have reasonable QED scores (0.85 and 0.755), indicating good drug-like properties.

**DILI:** Ligand A (80.962) has a higher DILI risk than Ligand B (39.667). This is a significant drawback for Ligand A.

**BBB:** Ligand A (91.508) has a much better BBB penetration percentile than Ligand B (74.292). This is a critical advantage for a CNS target like DRD2.

**Caco-2 Permeability:** Ligand A (-4.068) and Ligand B (-4.566) both have negative Caco-2 values, which is unusual and suggests poor permeability. However, the scale is not specified, so it's hard to interpret.

**Aqueous Solubility:** Ligand A (-3.814) and Ligand B (-2.685) both have negative solubility values, which is also unusual and suggests poor solubility.

**hERG:** Both ligands have low hERG inhibition liability (0.546 and 0.603), which is good.

**Microsomal Clearance:** Ligand A (48.017) has lower microsomal clearance than Ligand B (60.59), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (-40.965) has a significantly longer in vitro half-life than Ligand B (-11.089). This is a major advantage.

**P-gp Efflux:** Ligand A (0.243) has lower P-gp efflux liability than Ligand B (0.147), meaning it's less likely to be pumped out of the brain, improving CNS exposure.

**Binding Affinity:** Ligand B (-8.1 kcal/mol) has a slightly better binding affinity than Ligand A (-7.3 kcal/mol). While >1.5 kcal/mol advantage is considered significant, the 0.8 kcal/mol difference isn't overwhelming, especially considering the other factors.

**Overall Assessment:**

Ligand A excels in BBB penetration, TPSA, metabolic stability (lower Cl_mic), and in vitro half-life, and P-gp efflux. Ligand B has a lower DILI risk and slightly better binding affinity. However, the superior CNS penetration properties of Ligand A, combined with its better metabolic stability and longer half-life, outweigh the slightly higher DILI risk and weaker binding. Given the CNS target (DRD2), BBB penetration is paramount, and Ligand A clearly wins in this regard.

Output:
1
2025-04-17 05:44:12,682 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (362.539 Da and 346.402 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (49.41) is significantly better than Ligand B (71.34). For CNS targets, we want TPSA <= 90, and ideally closer to 60. Ligand A is much closer to this ideal.

**3. logP:** Both ligands have good logP values (2.85 and 3.114), falling within the optimal 1-3 range.

**4. H-Bond Donors:** Ligand A (1) and Ligand B (2) are both acceptable, being <= 5.

**5. H-Bond Acceptors:** Both ligands have 3 H-bond acceptors, well within the acceptable limit of <= 10.

**6. QED:** Both ligands have good QED scores (0.765 and 0.844), indicating good drug-like properties.

**7. DILI:** Ligand A (29.818) has a much lower DILI risk than Ligand B (57.076). Both are below 60, but A is preferred.

**8. BBB:** Ligand B (89.531) has a significantly better BBB penetration score than Ligand A (76.231). This is a crucial factor for a CNS target like DRD2.

**9. Caco-2 Permeability:** Ligand A (-5.087) and Ligand B (-4.684) are both negative, indicating poor permeability. This is a concern for both, but not a deciding factor.

**10. Aqueous Solubility:** Both ligands have poor aqueous solubility (-3.775 and -3.817). This could pose formulation challenges, but is not a primary concern given the CNS target.

**11. hERG Inhibition:** Ligand A (0.399) has a lower hERG inhibition risk than Ligand B (0.736), which is preferable.

**12. Microsomal Clearance:** Ligand A (60.52) has higher microsomal clearance than Ligand B (28.217), indicating lower metabolic stability. This is a negative for Ligand A.

**13. In vitro Half-Life:** Ligand B (88.617) has a much longer in vitro half-life than Ligand A (-15.836). This is a significant advantage for Ligand B.

**14. P-gp Efflux:** Ligand A (0.28) has lower P-gp efflux than Ligand B (0.274). Lower efflux is better for CNS exposure.

**15. Binding Affinity:** Ligand B (-9.6 kcal/mol) has a significantly stronger binding affinity than Ligand A (-7.6 kcal/mol). This is a major advantage for Ligand B, potentially outweighing some of its ADME drawbacks.

**Overall Assessment:**

While Ligand A has advantages in TPSA, DILI, and hERG, Ligand B excels in the most critical areas for a CNS-targeting GPCR: **BBB penetration and binding affinity**. The significantly stronger binding affinity of Ligand B (-9.6 vs -7.6 kcal/mol) is a substantial advantage. The longer half-life is also a major benefit. Although Ligand B has a slightly higher DILI risk and lower metabolic stability, the superior CNS penetration and potency make it the more promising candidate.

Output:
1
2025-04-17 05:44:12,682 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (402.288 Da) is slightly higher than Ligand B (346.471 Da), but both are acceptable.

**2. TPSA:** Ligand A (47.56) is better than Ligand B (58.64). For CNS targets, TPSA should be <= 90, both are well within this range.

**3. logP:** Ligand A (3.587) is optimal, while Ligand B (2.5) is a bit lower but still acceptable.

**4. H-Bond Donors:** Both ligands have 1 HBD, which is good.

**5. H-Bond Acceptors:** Ligand A has 3 HBA, and Ligand B has 4 HBA, both are within the acceptable range of <=10.

**6. QED:** Both ligands have similar QED values (0.687 and 0.735), indicating good drug-likeness.

**7. DILI:** Ligand A (58.511) has a higher DILI risk than Ligand B (12.834). This is a significant drawback for Ligand A.

**8. BBB:** Ligand B (77.162) has a significantly better BBB penetration score than Ligand A (43.893). This is crucial for a CNS target like DRD2.

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.756 and -4.777), which is unusual and suggests poor permeability. However, these values are on a log scale, and the negative values are not directly comparable without knowing the scale. We'll consider this a neutral point for now.

**10. Aqueous Solubility:** Both ligands have negative solubility values (-5.079 and -2.845), again suggesting poor solubility. Similar to Caco-2, the scale isn't clear, making direct comparison difficult.

**11. hERG Inhibition:** Both ligands have low hERG inhibition risk (0.791 and 0.837).

**12. Microsomal Clearance:** Ligand B (36.109) has lower microsomal clearance than Ligand A (45.971), indicating better metabolic stability.

**13. In vitro Half-Life:** Ligand A (33.635) has a longer half-life than Ligand B (-5.511). This is a positive for Ligand A, but the negative value for Ligand B is concerning.

**14. P-gp Efflux:** Ligand A (0.472) has lower P-gp efflux than Ligand B (0.216), which is favorable for CNS penetration.

**15. Binding Affinity:** Both ligands have very similar, strong binding affinities (-9.1 and -8.7 kcal/mol). The difference of 0.4 kcal/mol is not substantial enough to override other factors.

**Overall Assessment:**

Ligand B is the more promising candidate. While both have issues with Caco-2 and solubility, Ligand B excels in BBB penetration (77.162 vs 43.893) and has a much lower DILI risk (12.834 vs 58.511). The slightly better metabolic stability of Ligand B is also a plus. The P-gp efflux is lower for Ligand A, but the superior BBB and safety profile of Ligand B outweigh this advantage. The affinity is comparable.

Output:
1
2025-04-17 05:44:12,682 - INFO - Reasoning:

Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (374.746 and 351.451 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (84.58) is excellent, well below the 90 A^2 threshold for CNS targets. Ligand B (107.19) is still reasonable, but less optimal.

**logP:** Ligand A (3.467) is within the optimal 1-3 range. Ligand B (0.445) is quite low, potentially hindering membrane permeability and CNS penetration.

**H-Bond Donors/Acceptors:** Both have 3 HBD and 4 HBA, which are acceptable.

**QED:** Both ligands have similar QED values (0.676 and 0.663), indicating good drug-likeness.

**DILI:** Ligand A (62.078) has a higher DILI risk than Ligand B (36.758). This is a negative for Ligand A.

**BBB:** Ligand A (46.375) has a significantly better BBB penetration percentile than Ligand B (19.581). This is a *critical* advantage for a CNS target like DRD2.

**Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and suggests poor permeability. However, the scale is not specified, so it's hard to interpret.

**Aqueous Solubility:** Both have negative solubility values, which is also unusual and suggests poor solubility. Again, the scale is not specified.

**hERG:** Ligand A (0.772) has a slightly higher hERG risk than Ligand B (0.026).

**Microsomal Clearance:** Ligand A (22.869) has a higher microsomal clearance than Ligand B (7.963), indicating lower metabolic stability.

**In vitro Half-Life:** Ligand A (13.086) has a longer half-life than Ligand B (-0.023).

**P-gp Efflux:** Ligand A (0.307) has lower P-gp efflux liability than Ligand B (0.006), which is favorable for CNS penetration.

**Binding Affinity:** Ligand B (-8.2 kcal/mol) has a slightly better binding affinity than Ligand A (-9.2 kcal/mol). While the difference is small, it's still a factor.

**Overall Assessment:**

Despite Ligand A having a higher DILI risk and slightly worse metabolic stability, its significantly better BBB penetration, lower P-gp efflux, and acceptable TPSA and logP make it the more promising candidate for a CNS-targeting drug like a DRD2 ligand. The affinity difference is small enough to be outweighed by the ADME advantages. Ligand B's very low logP is a major concern, as it will likely limit its ability to cross the blood-brain barrier.

Output:
1
2025-04-17 05:44:12,682 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B based on the provided guidelines, prioritizing GPCR-specific properties (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (352.431 and 344.455 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (95.94) is slightly above the optimal <90 for CNS targets, but still reasonable. Ligand B (53.76) is excellent, well below 90.

**logP:** Ligand A (0.455) is quite low, potentially hindering permeability. Ligand B (3.012) is optimal.

**H-Bond Donors/Acceptors:** Ligand A has 2 HBD and 5 HBA, acceptable. Ligand B has 0 HBD and 3 HBA, also acceptable.

**QED:** Both ligands have good QED scores (0.677 and 0.847), indicating drug-likeness.

**DILI:** Ligand A (18.108) has a much lower DILI risk than Ligand B (34.471), which is a significant advantage.

**BBB:** Ligand B (85.459) has a significantly higher BBB penetration score than Ligand A (39.977). This is a *critical* factor for a CNS target like DRD2.

**Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and suggests poor permeability. However, the scale is not specified, so the absolute values are hard to interpret.

**Aqueous Solubility:** Both have negative solubility values, also unusual. This is a potential concern for both.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.241 and 0.431).

**Microsomal Clearance:** Ligand A (28.388) has lower microsomal clearance, indicating better metabolic stability than Ligand B (47.953).

**In vitro Half-Life:** Ligand B (50.448) has a much longer in vitro half-life than Ligand A (2.739), which is desirable.

**P-gp Efflux:** Both ligands show very low P-gp efflux liability (0.008 and 0.369).

**Binding Affinity:** Ligand B (-8.8 kcal/mol) has a slightly better binding affinity than Ligand A (-8.0 kcal/mol), although the difference is not huge.

**Overall Assessment:**

Ligand B is superior due to its excellent BBB penetration, optimal logP, and longer half-life. While Ligand A has a lower DILI risk and better metabolic stability, the BBB score is a critical factor for CNS drug development. The slightly better affinity of Ligand B further supports its selection. The unusual negative permeability and solubility values are concerning for both, but the other advantages of Ligand B outweigh this.

Output:
1
2025-04-17 05:44:12,682 - INFO - Reasoning:

Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (355.385 and 344.455 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (82.27) is slightly higher than Ligand B (58.64). Both are below the 90 Angstrom threshold desirable for CNS targets, but B is significantly better.

**3. logP:** Both ligands have good logP values (1.317 and 2.019), falling within the optimal 1-3 range.

**4. H-Bond Donors:** Ligand A (2) and Ligand B (1) both meet the HBD criteria of <=5. Ligand B is slightly better.

**5. H-Bond Acceptors:** Both ligands have 3 HBA, well within the acceptable limit of <=10.

**6. QED:** Both ligands have similar QED values (0.807 and 0.794), indicating good drug-likeness.

**7. DILI:** Ligand A (29.43) has a slightly higher DILI risk than Ligand B (14.618), but both are below the concerning threshold of 60.

**8. BBB:** Both ligands exhibit excellent BBB penetration (74.176 and 78.519), exceeding the desirable >70 percentile for CNS targets. Ligand B is slightly better.

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.866 and -4.76), which is unusual and suggests poor permeability. This is a significant concern for both.

**10. Aqueous Solubility:** Both ligands have negative solubility values (-2.365 and -3.259), indicating very poor aqueous solubility. This is a major drawback for both.

**11. hERG Inhibition:** Both ligands have low hERG inhibition risk (0.378 and 0.211).

**12. Microsomal Clearance:** Ligand A (-29.744) has a much lower (better) microsomal clearance than Ligand B (21.058), suggesting greater metabolic stability.

**13. In vitro Half-Life:** Ligand A (-27.676) has a much longer in vitro half-life than Ligand B (0.249), which is highly desirable.

**14. P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.024 and 0.032), which is favorable for CNS penetration.

**15. Binding Affinity:** Both ligands have excellent binding affinities (-8.6 and -8.8 kcal/mol). Ligand B is slightly better.

**Overall Assessment:**

Both ligands have strong binding affinities and good BBB penetration, which are crucial for a CNS-targeting GPCR like DRD2. However, they both suffer from very poor predicted solubility and permeability. Ligand A has a significant advantage in metabolic stability (lower Cl_mic) and longer half-life, which are important for *in vivo* efficacy. While Ligand B has a slightly better TPSA and affinity, the metabolic liabilities of Ligand B are concerning. Considering the GPCR-specific priorities, the improved metabolic profile of Ligand A is more valuable than the marginal improvements in other parameters for Ligand B.

Output:
1
2025-04-17 05:44:12,683 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (348.4 & 342.4 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (41.37) is significantly better than Ligand B (61.61). For CNS targets, we want TPSA <= 90, and ideally closer to 60. Ligand A is much closer to this ideal.

**logP:** Both ligands have good logP values (3.019 & 2.57), falling within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A (0 HBD, 4 HBA) and Ligand B (1 HBD, 4 HBA) both have acceptable numbers of H-bond donors and acceptors.

**QED:** Both ligands have similar and good QED scores (0.856 & 0.852).

**DILI:** Ligand A (41.88%) has a much lower DILI risk than Ligand B (75.15%). This is a significant advantage.

**BBB:** Ligand A (90.73%) has a better BBB penetration percentile than Ligand B (85.46%). Both are good, but A is preferable for a CNS target.

**Caco-2 Permeability:** Both are negative, indicating poor permeability. This is a concern for both, but doesn't immediately disqualify either.

**Aqueous Solubility:** Both are negative, indicating poor solubility. This is a concern for both, but doesn't immediately disqualify either.

**hERG:** Ligand A (0.892) has a slightly higher hERG risk than Ligand B (0.578), but both are relatively low.

**Microsomal Clearance:** Ligand A (49.76) has a higher microsomal clearance than Ligand B (11.61), suggesting faster metabolism and lower metabolic stability. This is a disadvantage for Ligand A.

**In vitro Half-Life:** Ligand B (-12.32) has a longer in vitro half-life than Ligand A (-25.03), indicating better stability. This is a significant advantage for Ligand B.

**P-gp Efflux:** Ligand A (0.512) has a higher P-gp efflux liability than Ligand B (0.182). Lower P-gp efflux is preferred, especially for CNS targets, making Ligand B better.

**Binding Affinity:** Ligand B (-9.6 kcal/mol) has a significantly stronger binding affinity than Ligand A (-0.0 kcal/mol). This is a *major* advantage for Ligand B. A difference of >1.5 kcal/mol can outweigh other drawbacks.

**Overall Assessment:**

While Ligand A has advantages in TPSA, BBB, and DILI, Ligand B's significantly stronger binding affinity (-9.6 vs -0.0 kcal/mol) and better P-gp efflux, coupled with a longer half-life, outweigh the drawbacks of slightly higher TPSA and DILI. The strong binding affinity is crucial for a GPCR ligand, and the improved pharmacokinetic properties (P-gp, half-life) are highly desirable.

Output:
1
2025-04-17 05:44:12,683 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (348.531 and 349.475 Da) fall within the ideal range of 200-500 Da.

**TPSA:** Ligand A (58.2) is significantly better than Ligand B (92.5). For CNS targets, we want TPSA <= 90, and A is comfortably within that range, while B is close to the upper limit. This favors A.

**logP:** Ligand A (4.269) is a bit high, potentially leading to solubility issues, but still within an acceptable range. Ligand B (1.286) is on the lower side, which could hinder permeation. The optimal range is 1-3, so A is slightly preferred here, despite being higher.

**H-Bond Donors/Acceptors:** Both have 2 HBDs, which is good. Ligand A has 2 HBAs, while Ligand B has 3. Both are acceptable (<=10), but lower is generally better.

**QED:** Ligand B (0.757) has a better QED score than Ligand A (0.457), indicating a more drug-like profile overall. This favors B.

**DILI:** Ligand A (15.743) has a significantly lower DILI risk than Ligand B (19.426), which is a substantial advantage.

**BBB:** Both ligands have reasonably good BBB penetration (A: 67.623, B: 65.413), but neither exceeds the desirable >70 threshold. A is slightly better.

**Caco-2 Permeability:** Both have negative Caco-2 values (-4.788 and -5.12), which is unusual and suggests poor permeability. This is a concern for both, but the values are similar.

**Aqueous Solubility:** Both have negative solubility values (-3.862 and -3.107), indicating very poor aqueous solubility. This is a significant drawback for both.

**hERG Inhibition:** Ligand A (0.516) has a slightly higher hERG risk than Ligand B (0.102), which is a clear advantage for B.

**Microsomal Clearance:** Ligand A (53.264) has a higher microsomal clearance than Ligand B (29.341), meaning it's metabolized faster. Lower clearance is preferred, favoring B.

**In vitro Half-Life:** Ligand B (0.445) has a slightly longer in vitro half-life than Ligand A (-5.375), which is a slight advantage for B.

**P-gp Efflux:** Ligand A (0.398) has lower P-gp efflux than Ligand B (0.019), which is a significant advantage for A, especially for CNS targets.

**Binding Affinity:** Both ligands have very similar and excellent binding affinities (-8.6 and -8.7 kcal/mol). This is a tie.

**Overall Assessment:**

Considering the GPCR-specific priorities, Ligand A is slightly favored. While Ligand B has a better QED, lower hERG risk, and slightly better metabolic stability, Ligand A excels in TPSA (critical for CNS penetration), DILI risk (important for safety), and P-gp efflux (crucial for CNS exposure). The similar binding affinities mean that the ADME properties become the deciding factors. The lower TPSA and P-gp efflux of A are more important for a CNS target like DRD2, outweighing the slightly better QED and hERG profile of B. The solubility and permeability issues are concerning for both, but can potentially be addressed with formulation strategies.

Output:
0
2025-04-17 05:44:12,683 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (349.431 and 350.459 Da) fall within the ideal range of 200-500 Da.

**TPSA:** Ligand A (86.02) is better than Ligand B (67.87) as it is closer to the ideal range of <90 for CNS targets.

**logP:** Ligand B (1.198) is slightly better than Ligand A (0.651). Both are within the optimal range of 1-3, but A is a bit low, potentially hindering permeation.

**H-Bond Donors/Acceptors:** Ligand A has 2 HBD and 5 HBA, while Ligand B has 1 HBD and 4 HBA. Both are within acceptable limits.

**QED:** Ligand A (0.737) has a better QED score than Ligand B (0.501), indicating a more drug-like profile.

**DILI:** Ligand B (8.375) has a significantly lower DILI risk than Ligand A (40.132), which is a substantial advantage.

**BBB:** Ligand B (59.093) has a much better BBB penetration score than Ligand A (32.144). This is *critical* for a CNS target like DRD2.

**Caco-2 Permeability:** Ligand A (-5.108) has a worse Caco-2 permeability than Ligand B (-4.78). Both are negative, indicating poor permeability, but B is slightly better.

**Aqueous Solubility:** Ligand A (-0.671) has better solubility than Ligand B (-1.273).

**hERG:** Both ligands have low hERG inhibition risk (0.281 and 0.356, respectively).

**Microsomal Clearance:** Ligand A (7.05) has a lower microsomal clearance than Ligand B (4.522), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (21.713) has a longer in vitro half-life than Ligand B (2.255), which is preferable.

**P-gp Efflux:** Ligand A (0.164) has a lower P-gp efflux liability than Ligand B (0.026), meaning it is less likely to be pumped out of the brain.

**Binding Affinity:** Ligand A (-7.7 kcal/mol) has a slightly better binding affinity than Ligand B (-7.4 kcal/mol). This 0.3 kcal/mol difference, while noticeable, isn't huge.

**Overall Assessment:**

Ligand B is the stronger candidate. While Ligand A has a slightly better binding affinity, longer half-life, and lower P-gp efflux, Ligand B's significantly better BBB penetration (59.093 vs 32.144) and much lower DILI risk (8.375 vs 40.132) are decisive advantages for a CNS-targeting GPCR. The slightly lower logP of Ligand A is also a concern. The improved TPSA of Ligand B is also favorable.



Output:
1
2025-04-17 05:44:12,683 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (343.387 Da) is slightly lower, which could be beneficial for permeability, while Ligand B (375.921 Da) is still well within the acceptable range.

**TPSA:** Ligand A (109.14) is higher than the preferred <90 for CNS targets, but not drastically so. Ligand B (29.54) is excellent, well below the threshold, suggesting good CNS penetration potential.

**logP:** Ligand A (1.216) is within the optimal range (1-3). Ligand B (4.988) is high, potentially leading to solubility issues and off-target interactions.

**H-Bond Donors/Acceptors:** Ligand A has 3 HBD and 6 HBA, both acceptable. Ligand B has 0 HBD and 3 HBA, also acceptable.

**QED:** Both ligands have reasonable QED values (A: 0.756, B: 0.666), indicating good drug-like properties.

**DILI:** Ligand A (50.097) has a slightly higher DILI risk than Ligand B (29.042), but both are below the concerning threshold of 60.

**BBB:** Ligand B (45.793) has a significantly better BBB percentile than Ligand A (36.448). This is a critical advantage for a CNS target like DRD2.

**Caco-2 Permeability:** Ligand A (-5.117) has a negative Caco-2 value which is unusual and suggests very poor permeability. Ligand B (-4.574) also has a negative value, but is slightly better.

**Aqueous Solubility:** Both ligands have very poor aqueous solubility (-3.079 and -5.371 respectively).

**hERG Inhibition:** Both ligands show low hERG inhibition liability (0.132 and 0.686 respectively).

**Microsomal Clearance:** Ligand A (9.932) has a lower microsomal clearance than Ligand B (102.684), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (-27.038) has a negative half-life, which is not physically possible and indicates a significant issue. Ligand B (24.312) has a reasonable half-life.

**P-gp Efflux:** Ligand A (0.004) has very low P-gp efflux, which is favorable for CNS penetration. Ligand B (0.5) has moderate P-gp efflux.

**Binding Affinity:** Both ligands have the same binding affinity (-7.6 kcal/mol), which is excellent.

**Overall Assessment:**

While both ligands bind equally well, Ligand B is clearly the more promising candidate. Its superior BBB penetration, lower DILI risk, and reasonable half-life outweigh the higher logP. Ligand A has a very poor Caco-2 permeability and an impossible half-life, making it a non-starter. The high TPSA of Ligand A is also a concern. Although both have poor solubility, this can be addressed with formulation strategies.

Output:
1
2025-04-17 05:44:12,683 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (365.4 & 356.5 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (81.67) is slightly higher but still reasonable for a CNS target, while Ligand B (49.33) is excellent, well below the 90 A^2 threshold. This favors Ligand B.

**3. logP:** Ligand A (0.963) is a bit low, potentially hindering permeation. Ligand B (2.964) is optimal. This favors Ligand B.

**4. H-Bond Donors:** Ligand A (3) is acceptable. Ligand B (0) is also good, potentially improving permeability.

**5. H-Bond Acceptors:** Ligand A (4) is acceptable. Ligand B (5) is also good.

**6. QED:** Both ligands have good QED scores (0.532 and 0.848), indicating drug-like properties. Ligand B is slightly better.

**7. DILI:** Ligand A (11.75) has a much lower DILI risk than Ligand B (42.0). This favors Ligand A.

**8. BBB:** Ligand A (69.79) is reasonable, but Ligand B (77.82) is better, exceeding 70% which is desirable for CNS targets. This favors Ligand B.

**9. Caco-2:** Ligand A (-5.318) is very poor, suggesting poor intestinal absorption. Ligand B (-4.78) is also poor, but slightly better.

**10. Solubility:** Both ligands have poor aqueous solubility (-1.043 and -2.085). This is a concern for both, but less critical for CNS targets where BBB penetration is prioritized.

**11. hERG:** Ligand A (0.296) has a very low hERG risk, which is excellent. Ligand B (0.794) is higher, but still relatively low. This favors Ligand A.

**12. Cl_mic:** Ligand A (-1.026) has a negative clearance, indicating very high metabolic stability. Ligand B (42.009) has a high clearance, suggesting rapid metabolism. This strongly favors Ligand A.

**13. t1/2:** Ligand A (-29.271) has a very long half-life, which is excellent. Ligand B (-11.096) has a shorter half-life. This favors Ligand A.

**14. Pgp:** Ligand A (0.008) has very low P-gp efflux, which is excellent for CNS penetration. Ligand B (0.371) has moderate P-gp efflux. This favors Ligand A.

**15. Binding Affinity:** Ligand B (-8.7 kcal/mol) has a slightly better binding affinity than Ligand A (-7.6 kcal/mol). While a 1.1 kcal/mol difference is significant, the substantial advantages of Ligand A in ADME properties, particularly metabolic stability, BBB penetration, and P-gp efflux, outweigh this difference.

**Overall Assessment:**

Ligand A demonstrates a superior ADME profile, particularly regarding metabolic stability (Cl_mic, t1/2), BBB penetration, and P-gp efflux, all critical for a CNS-targeting GPCR ligand. While Ligand B has slightly better affinity and TPSA, Ligand A's lower DILI risk and superior metabolic properties make it the more promising drug candidate.

Output:
0
2025-04-17 05:44:12,683 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (351.447 and 348.487 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (87.74) is better than Ligand B (58.64). Both are below the 90 A^2 threshold for CNS targets, but A is closer to the upper limit.

**logP:** Ligand B (2.798) is optimal (1-3). Ligand A (0.293) is too low, potentially hindering membrane permeability.

**H-Bond Donors/Acceptors:** Ligand A (HBD=2, HBA=4) and Ligand B (HBD=1, HBA=3) both have acceptable numbers of H-bond donors and acceptors.

**QED:** Both ligands have good QED scores (A: 0.674, B: 0.777), indicating drug-like properties.

**DILI:** Both ligands have low DILI risk (A: 35.285, B: 33.773), below the 40 threshold.

**BBB:** Ligand B (85.537) significantly outperforms Ligand A (45.715) in BBB penetration, which is crucial for a CNS target like DRD2.

**Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and suggests a potential issue with the data or modeling. However, the values are similar (-4.78 and -4.363).

**Aqueous Solubility:** Both have negative solubility values, which is also unusual. Ligand A (-2.309) is slightly better than Ligand B (-3.589).

**hERG Inhibition:** Both ligands have very low hERG inhibition risk (A: 0.084, B: 0.256).

**Microsomal Clearance:** Ligand A (21.661) has lower microsomal clearance than Ligand B (47.552), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (-23.969) has a more negative half-life, which is not possible and indicates a data issue. Ligand B (-14.784) also has a negative value, but is slightly less problematic.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (A: 0.029, B: 0.182).

**Binding Affinity:** Ligand B (-8.1 kcal/mol) has a slightly better binding affinity than Ligand A (-7.1 kcal/mol). While both are good, the 1.0 kcal/mol difference is significant.

**Overall Assessment:**

Ligand B is the more promising candidate. Its superior BBB penetration (85.537 vs 45.715) is a major advantage for a CNS target. It also has a better logP value (2.798 vs 0.293) which will improve permeability. While Ligand A has better metabolic stability (lower Cl_mic), the difference in binding affinity (1.0 kcal/mol) and the critical importance of BBB penetration for DRD2 outweigh this benefit. The negative values for Caco-2 and solubility are concerning for both, but the overall profile of Ligand B is more favorable.

Output:
1
2025-04-17 05:44:12,683 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (362.901 and 363.498 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (52.57) is higher than Ligand B (40.54). For CNS targets, we prefer TPSA <= 90, both are within this range, but B is better.

**3. logP:** Ligand A (4.281) is slightly higher than Ligand B (3.685). Both are above the optimal 1-3 range, but still acceptable. Ligand B is preferable.

**4. H-Bond Donors:** Ligand A (2) is higher than Ligand B (1). Both are within the acceptable limit of <=5.

**5. H-Bond Acceptors:** Ligand A (2) is lower than Ligand B (3). Both are within the acceptable limit of <=10.

**6. QED:** Both ligands have similar QED values (0.771 and 0.784), indicating good drug-likeness.

**7. DILI:** Ligand A (34.161) has a higher DILI risk than Ligand B (19.969). Lower is better, so Ligand B is preferable.

**8. BBB:** Ligand B (86.545) has significantly better BBB penetration than Ligand A (70.997). This is a *critical* factor for a CNS target like DRD2.

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.411 and -4.559). This indicates poor permeability, which is a concern.

**10. Aqueous Solubility:** Both ligands have negative solubility values (-5.092 and -4.181), indicating poor solubility.

**11. hERG Inhibition:** Ligand A (0.765) has slightly lower hERG inhibition risk than Ligand B (0.85), but both are relatively low.

**12. Microsomal Clearance:** Ligand B (53.138) has a significantly higher microsomal clearance than Ligand A (17.483), indicating faster metabolism and lower metabolic stability. Ligand A is preferable.

**13. In vitro Half-Life:** Ligand A (37.114) has a longer half-life than Ligand B (4.49). This is a significant advantage for Ligand A.

**14. P-gp Efflux:** Ligand A (0.599) has lower P-gp efflux than Ligand B (0.715), which is preferable for CNS exposure.

**15. Binding Affinity:** Ligand A (-9.1 kcal/mol) has a significantly stronger binding affinity than Ligand B (-7.8 kcal/mol). This is a substantial advantage, potentially outweighing some ADME drawbacks.

**Overall Assessment:**

While Ligand A has some ADME liabilities (lower solubility, lower BBB, higher P-gp efflux), its *much* stronger binding affinity (-9.1 vs -7.8 kcal/mol) and better metabolic stability (lower Cl_mic, longer t1/2) are crucial. The significantly better BBB penetration of Ligand B is a strong point, but the affinity difference is substantial. Given the importance of affinity for GPCRs, and the fact that both ligands have concerning permeability and solubility, the stronger binding of Ligand A is the deciding factor.

Output:
1
2025-04-17 05:44:12,683 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (361.555 and 368.487 Da) fall comfortably within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (38.25) is significantly better than Ligand B (69.88). For CNS targets, we want TPSA <= 90, and ideally closer to 60. Ligand A is well within this range, while Ligand B is approaching the upper limit and less favorable.

**3. logP:** Both ligands have acceptable logP values (4.445 and 3.648), falling within the 1-3 range, though Ligand A is slightly higher.

**4. H-Bond Donors:** Both have 0 HBD, which is acceptable.

**5. H-Bond Acceptors:** Ligand A has 5, and Ligand B has 6. Both are within the acceptable limit of <=10.

**6. QED:** Both ligands have similar QED values (0.696 and 0.689), indicating good drug-like properties.

**7. DILI:** Ligand A (21.946) has a much lower DILI risk than Ligand B (81.078). This is a significant advantage for Ligand A.

**8. BBB:** Ligand A (85.459) has a substantially higher BBB penetration percentile than Ligand B (46.491). This is *critical* for a CNS target like DRD2.

**9. Caco-2 Permeability:** Both have negative values (-4.965 and -5.088), which is unusual and suggests poor permeability. However, the values are very similar.

**10. Aqueous Solubility:** Both have negative values (-3.534 and -3.555), indicating poor aqueous solubility. This is a concern, but can sometimes be overcome with formulation strategies.

**11. hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.85 and 0.403).

**12. Microsomal Clearance:** Ligand A (49.209) has lower microsomal clearance than Ligand B (63.138), suggesting better metabolic stability.

**13. In vitro Half-Life:** Ligand A (33.342) has a significantly longer in vitro half-life than Ligand B (8.995).

**14. P-gp Efflux:** Ligand A (0.653) has lower P-gp efflux liability than Ligand B (0.423), which is favorable for CNS penetration.

**15. Binding Affinity:** Ligand B (-8.6 kcal/mol) has a slightly better binding affinity than Ligand A (-7.6 kcal/mol). This is a 1.0 kcal/mol difference, which is notable, but not overwhelming given the other factors.

**Overall Assessment:**

Ligand A is clearly the more promising candidate. While Ligand B has slightly better binding affinity, Ligand A excels in almost all other crucial ADME-Tox properties, particularly BBB penetration (a key factor for CNS targets), DILI risk, metabolic stability, and P-gp efflux. The better TPSA of Ligand A also supports its potential for CNS entry. The solubility and Caco-2 permeability are poor for both, but these can potentially be addressed through formulation. The superior overall profile of Ligand A outweighs the modest affinity advantage of Ligand B.

Output:
1
2025-04-17 05:44:12,683 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (341.371 Da) is slightly lower, which could be advantageous for permeability.

**TPSA:** Ligand A (104.12) is better than Ligand B (40.85) as it is closer to the <90 A^2 threshold for CNS targets. Ligand B is very low, which might indicate poor interactions with the receptor.

**logP:** Both ligands have good logP values (A: 1.179, B: 2.957), falling within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A has 2 HBD and 5 HBA, while Ligand B has 0 HBD and 5 HBA. Both are within acceptable limits.

**QED:** Both ligands have similar QED values (A: 0.795, B: 0.758), indicating good drug-likeness.

**DILI:** Ligand A (67.197) has a higher DILI risk than Ligand B (26.483). This is a negative for Ligand A.

**BBB:** Ligand B (93.757) has a significantly higher BBB penetration percentile than Ligand A (61.846). This is a crucial advantage for a CNS target like DRD2.

**Caco-2 Permeability:** Both have negative values, which is unusual. However, the magnitude of the negative value for Ligand A (-5.16) is larger than for Ligand B (-4.849), suggesting potentially lower absorption for Ligand A.

**Aqueous Solubility:** Both ligands have negative solubility values, which is also unusual. Ligand B (-2.185) is slightly better than Ligand A (-3.196).

**hERG Inhibition:** Ligand A (0.064) has a lower hERG inhibition liability than Ligand B (0.838), indicating a lower risk of cardiotoxicity.

**Microsomal Clearance:** Ligand B (37.625) has a higher microsomal clearance than Ligand A (18.287), suggesting lower metabolic stability.

**In vitro Half-Life:** Ligand A (-7.636) has a longer in vitro half-life than Ligand B (-19.848).

**P-gp Efflux:** Ligand A (0.095) has lower P-gp efflux liability than Ligand B (0.458), which is beneficial for CNS exposure.

**Binding Affinity:** Ligand A (-9.2 kcal/mol) has a slightly better binding affinity than Ligand B (-7.4 kcal/mol). This 1.8 kcal/mol difference is substantial and can outweigh some ADME drawbacks.

**Overall Assessment:**

While Ligand A has better affinity and metabolic stability, Ligand B excels in BBB penetration, which is paramount for a CNS target. The lower DILI risk and P-gp efflux for Ligand B are also favorable. The slightly better solubility of Ligand B is also a plus. The affinity difference, while significant, can potentially be optimized in later stages of drug development. Given the importance of CNS penetration for DRD2, Ligand B is the more promising candidate.

Output:
1
2025-04-17 05:44:12,684 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B based on the provided guidelines, prioritizing GPCR-specific properties (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (342.399 Da) is slightly lower, which could be beneficial for permeability.

**TPSA:** Ligand A (96.25) is better than Ligand B (62.3). Both are below 90, which is good for CNS penetration. Ligand B is particularly favorable here.

**logP:** Both ligands have good logP values (A: 2.137, B: 3.163), falling within the optimal range of 1-3. Ligand B is slightly higher, potentially improving membrane permeability.

**H-Bond Donors/Acceptors:** Ligand A has 3 HBD and 5 HBA, while Ligand B has 1 HBD and 4 HBA. Both are within acceptable limits.

**QED:** Both ligands have good QED scores (A: 0.672, B: 0.82), indicating drug-likeness. Ligand B is slightly better.

**DILI:** Ligand A (55.68) is better than Ligand B (64.754) regarding DILI risk, being further from the concerning >60 percentile.

**BBB:** Ligand B (70.415) is significantly better than Ligand A (31.756) in terms of BBB penetration. This is a *critical* factor for a CNS target like DRD2.

**Caco-2 Permeability:** Ligand A (-5.457) is worse than Ligand B (-4.947). Higher values are better, so Ligand B is slightly preferred.

**Aqueous Solubility:** Both have negative solubility values, indicating poor solubility. Ligand A (-3.294) is slightly better than Ligand B (-3.781).

**hERG Inhibition:** Both ligands have low hERG inhibition risk (A: 0.64, B: 0.339), which is good. Ligand B is better.

**Microsomal Clearance:** Ligand A (22.998) has lower clearance than Ligand B (64.859), suggesting better metabolic stability. This is a significant advantage for Ligand A.

**In vitro Half-Life:** Ligand A (-29.011) has a much longer half-life than Ligand B (-7.479). This is a major advantage for Ligand A.

**P-gp Efflux:** Ligand A (0.097) has lower P-gp efflux than Ligand B (0.458), which is beneficial for CNS exposure.

**Binding Affinity:** Both ligands have comparable binding affinities (A: -8.7 kcal/mol, B: -8.6 kcal/mol). The difference is negligible.

**Overall Assessment:**

Ligand B excels in BBB penetration and has slightly better logP, QED, Caco-2 permeability, and hERG inhibition. However, Ligand A demonstrates significantly better metabolic stability (lower Cl_mic, longer t1/2), lower DILI risk, and lower P-gp efflux. Given the importance of CNS penetration for DRD2, Ligand B's superior BBB score is a major advantage. The metabolic stability and lower DILI risk of Ligand A are also important, but can potentially be addressed through further optimization. The similar binding affinities make these factors more decisive.

Output:
1
2025-04-17 05:44:12,684 - INFO - Batch 223 complete. Total preferences: 3568
2025-04-17 05:44:12,684 - INFO - Processing batch 224/512...
2025-04-17 05:44:55,260 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (387.33 and 369.502 Da) fall within the ideal range of 200-500 Da.

**TPSA:** Ligand A (79.37) is better than Ligand B (38.77) as it is closer to the ideal range for CNS targets (<=90). Ligand B is quite low, which might suggest a lack of necessary interactions.

**logP:** Ligand A (1.714) is optimal, while Ligand B (3.727) is approaching the upper limit.

**H-Bond Donors/Acceptors:** Ligand A has 1 HBD and 4 HBA, while Ligand B has 0 HBD and 4 HBA. Both are within acceptable limits.

**QED:** Both ligands have similar QED values (0.781 and 0.701), indicating good drug-likeness.

**DILI:** Ligand A (56.844) has a higher DILI risk than Ligand B (26.134), which is a negative for Ligand A.

**BBB:** Ligand B (94.261) significantly outperforms Ligand A (67.158) in predicted BBB penetration, a critical factor for CNS targets like DRD2.

**Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and difficult to interpret without further context. However, it doesn't strongly sway the decision.

**Aqueous Solubility:** Both ligands have very poor predicted aqueous solubility (-2.52 and -3.668). This is a concern for both, but can potentially be addressed with formulation strategies.

**hERG Inhibition:** Both ligands show low hERG inhibition risk (0.627 and 0.646).

**Microsomal Clearance:** Ligand A (-22.204) has a much lower (better) microsomal clearance than Ligand B (84.923), suggesting greater metabolic stability.

**In vitro Half-Life:** Ligand A (-30.813) has a longer in vitro half-life than Ligand B (44.132), which is desirable.

**P-gp Efflux:** Ligand A (0.034) has much lower P-gp efflux liability than Ligand B (0.58), which is beneficial for CNS penetration.

**Binding Affinity:** Ligand B (-7.4) has a slightly better binding affinity than Ligand A (-7.9). However, the difference is small (0.5 kcal/mol) and may not outweigh other factors.

**Overall Assessment:**

Ligand B clearly excels in BBB penetration and has a slightly better binding affinity. However, Ligand A has significantly better metabolic stability (lower Cl_mic, longer t1/2), lower P-gp efflux, and a lower DILI risk. The TPSA of Ligand A is also more favorable for CNS penetration. Given the importance of BBB penetration for a CNS target like DRD2, and the relatively small affinity difference, Ligand B is the more promising candidate.

Output:
1
2025-04-17 05:44:55,260 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (361.47 & 365.41 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (72.88) is better than Ligand B (56.67). Both are below the 90 A^2 threshold for CNS targets, which is excellent.

**logP:** Ligand A (1.93) is within the optimal 1-3 range. Ligand B (3.31) is at the higher end, but still acceptable.

**H-Bond Donors/Acceptors:** Ligand A has 2 HBD and 3 HBA, while Ligand B has 1 HBD and 5 HBA. Both are within acceptable limits (<=5 HBD, <=10 HBA).

**QED:** Both ligands have good QED scores (0.78 and 0.90), indicating good drug-like properties.

**DILI:** Both ligands have elevated DILI risk (60.06 and 68.90), which is a concern. However, this is not a dealbreaker at this stage.

**BBB:** Ligand B (71.85) is significantly better than Ligand A (20.63) in terms of predicted BBB penetration. This is a *critical* advantage for a CNS target like DRD2.

**Caco-2 Permeability:** Ligand A (-5.35) has poor Caco-2 permeability, while Ligand B (-4.68) is slightly better, but still poor.

**Aqueous Solubility:** Ligand A (-1.68) has slightly better aqueous solubility than Ligand B (-4.66).

**hERG Inhibition:** Ligand A (0.024) has a very low hERG risk, which is excellent. Ligand B (0.361) is slightly higher, but still relatively low.

**Microsomal Clearance:** Ligand A (4.64 mL/min/kg) has lower microsomal clearance, suggesting better metabolic stability, than Ligand B (54.52 mL/min/kg).

**In vitro Half-Life:** Ligand A (8.01 h) has a better in vitro half-life than Ligand B (-9.20 h).

**P-gp Efflux:** Ligand A (0.046) has lower P-gp efflux, which is favorable for CNS penetration, compared to Ligand B (0.239).

**Binding Affinity:** Ligand B (-9.7 kcal/mol) has a significantly stronger binding affinity than Ligand A (-8.0 kcal/mol). This is a substantial advantage (1.7 kcal/mol difference).

**Overall Assessment:**

While Ligand A has better metabolic stability (lower Cl_mic, longer t1/2), lower P-gp efflux, and lower hERG risk, Ligand B excels in the most critical areas for a CNS-targeting GPCR: **BBB penetration and binding affinity**. The 1.7 kcal/mol difference in binding affinity is significant and can often outweigh minor ADME drawbacks. The higher BBB value for Ligand B is crucial for ensuring sufficient drug exposure in the brain. The poor Caco-2 permeability of both is a concern, but can potentially be addressed with formulation strategies.

Output:
1
2025-04-17 05:44:55,260 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 drug candidates, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (354.43 and 349.39 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (83.56) is excellent, well below the 90 A^2 threshold for CNS targets. Ligand B (107.84) is still reasonable, but less optimal, being above 90 A^2.

**3. logP:** Both ligands have logP values (0.589 and 0.693) within the optimal 1-3 range.

**4. H-Bond Donors:** Ligand A has 2 HBD, which is good. Ligand B has 0, also acceptable.

**5. H-Bond Acceptors:** Both ligands have 5 HBA, which is within the acceptable limit of <=10.

**6. QED:** Ligand A (0.643) has a better QED score than Ligand B (0.423), indicating a more drug-like profile.

**7. DILI:** Both ligands have low DILI risk (30.32 and 35.60 percentiles), which is favorable.

**8. BBB:** Ligand A has a significantly better BBB penetration score (78.71%) than Ligand B (70.99%). While both are above 70%, the difference is noticeable for a CNS target.

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.583 and -4.911), which is unusual and suggests poor permeability. This is a significant concern for both.

**10. Aqueous Solubility:** Both ligands have negative solubility values (-0.482 and -1.506), indicating very poor aqueous solubility, which is a major drawback.

**11. hERG Inhibition:** Both ligands show low hERG inhibition risk (0.434 and 0.15), which is good.

**12. Microsomal Clearance:** Ligand A (29.76 mL/min/kg) has a higher, but still reasonable, clearance than Ligand B (5.04 mL/min/kg). Lower clearance is better, so B is slightly favored here.

**13. In vitro Half-Life:** Ligand B (14.12 hours) has a longer half-life than Ligand A (12.37 hours), which is preferable.

**14. P-gp Efflux:** Both ligands show very low P-gp efflux liability (0.024 and 0.012), which is excellent for CNS penetration.

**15. Binding Affinity:** Ligand A (-7.6 kcal/mol) has a significantly stronger binding affinity than Ligand B (-6.5 kcal/mol). This 1.1 kcal/mol difference is substantial and can outweigh some of the ADME drawbacks.

**Overall Assessment:**

Despite the poor Caco-2 and solubility for both, Ligand A is the more promising candidate. Its superior TPSA, QED, BBB penetration, and *significantly* stronger binding affinity to DRD2 outweigh the slightly higher clearance and shorter half-life compared to Ligand B. The strong affinity is particularly important for a GPCR target. Addressing the solubility and permeability issues would be crucial for further development, but the starting point with Ligand A is better.

Output:
1
2025-04-17 05:44:55,261 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (349.475 and 345.443 Da) fall comfortably within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (78.51) is higher than Ligand B (54.78). For a CNS target like DRD2, TPSA < 90 is preferred, so both are acceptable, but B is better.

**3. logP:** Both ligands have good logP values (1.777 and 1.518), falling within the optimal 1-3 range.

**4. H-Bond Donors:** Ligand A has 2 HBD, and Ligand B has 0. Both are within the acceptable limit of <=5.

**5. H-Bond Acceptors:** Ligand A has 3 HBA, and Ligand B has 4. Both are within the acceptable limit of <=10.

**6. QED:** Both ligands have similar QED values (0.543 and 0.53), indicating good drug-likeness.

**7. DILI:** Ligand A (27.724) has a lower DILI risk than Ligand B (18.457), which is favorable.

**8. BBB:** This is a crucial parameter for CNS targets. Ligand B (72.974) has a significantly higher BBB penetration percentile than Ligand A (53.121). This is a major advantage for B.

**9. Caco-2 Permeability:** Ligand A (-5.06) shows poor Caco-2 permeability, while Ligand B (-4.371) is slightly better, but still poor.

**10. Aqueous Solubility:** Ligand A (-2.367) has slightly better solubility than Ligand B (-1.032), but both are quite poor.

**11. hERG Inhibition:** Ligand A (0.084) has a lower hERG inhibition liability than Ligand B (0.414), which is preferable.

**12. Microsomal Clearance:** Ligand A (28.504) has a higher microsomal clearance than Ligand B (21.385), indicating lower metabolic stability.

**13. In vitro Half-Life:** Ligand B (7.744 hours) has a significantly longer half-life than Ligand A (-1.955 hours). This is a substantial advantage for B.

**14. P-gp Efflux:** Ligand A (0.03) has lower P-gp efflux liability than Ligand B (0.112), which is favorable.

**15. Binding Affinity:** Ligand A (-7.8 kcal/mol) has a slightly better binding affinity than Ligand B (-6.7 kcal/mol). The difference is 1.1 kcal/mol, which is significant.

**Overall Assessment:**

While Ligand A has better binding affinity and lower P-gp efflux, Ligand B demonstrates superior ADME properties critical for CNS penetration. Specifically, its significantly higher BBB penetration (72.974 vs 53.121) and longer half-life (7.744 vs -1.955) are major advantages. The lower DILI risk is also a plus. The affinity difference, while notable, can potentially be optimized in later stages of drug development. Given the GPCR-specific priorities, the improved pharmacokinetic profile of Ligand B outweighs the slightly better affinity of Ligand A.

Output:
1
2025-04-17 05:44:55,261 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (392.428 and 346.431 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (66.49) is better than Ligand B (76.46). For CNS targets, we want TPSA <= 90, both are within this range, but A is closer to the ideal.

**3. logP:** Both ligands have similar logP values (1.509 and 1.528), falling within the optimal 1-3 range.

**4. H-Bond Donors:** Ligand A has 2 HBD, while Ligand B has 1. Both are acceptable (<=5).

**5. H-Bond Acceptors:** Both ligands have 5 HBA, which is acceptable (<=10).

**6. QED:** Both ligands have good QED scores (0.741 and 0.793), indicating good drug-like properties.

**7. DILI:** Ligand A (83.947) has a significantly higher DILI risk than Ligand B (40.054). This is a major concern for Ligand A.

**8. BBB:** Ligand A (61.38) has a slightly better BBB percentile than Ligand B (58.976), but both are below the desirable >70 for CNS targets.

**9. Caco-2 Permeability:** Ligand A (-4.965) has a worse Caco-2 permeability than Ligand B (-4.51). Lower values indicate reduced permeability.

**10. Aqueous Solubility:** Ligand A (-3.351) has a worse aqueous solubility than Ligand B (-2.693). Lower values indicate reduced solubility.

**11. hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.453 and 0.115).

**12. Microsomal Clearance:** Ligand A (20.304) has a lower microsomal clearance than Ligand B (61.676), suggesting better metabolic stability.

**13. In vitro Half-Life:** Ligand A (25.847) has a longer in vitro half-life than Ligand B (-22.942). This is a positive attribute.

**14. P-gp Efflux:** Ligand A (0.269) has lower P-gp efflux liability than Ligand B (0.053), which is favorable for CNS penetration.

**15. Binding Affinity:** Both ligands have very similar binding affinities (-7.7 and -7.6 kcal/mol). The difference is negligible.

**Overall Assessment:**

While Ligand A has slightly better BBB, P-gp efflux, and metabolic stability, its significantly higher DILI risk and poorer solubility/permeability are major drawbacks. Ligand B, despite slightly lower BBB and higher P-gp efflux, presents a much more favorable safety profile (lower DILI) and better solubility/permeability. Given the importance of safety and ADME properties in drug development, and the relatively similar binding affinities, Ligand B is the more promising candidate.

Output:
1
2025-04-17 05:44:55,261 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (367.471 and 382.913 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (91.76) is slightly above the optimal <90 for CNS targets, but still reasonable. Ligand B (55.57) is excellent, well below the threshold.

**logP:** Ligand A (1.605) is within the optimal 1-3 range. Ligand B (4.494) is a bit high, potentially leading to solubility issues and off-target interactions.

**H-Bond Donors/Acceptors:** Ligand A has 2 HBD and 6 HBA, both acceptable. Ligand B has 0 HBD and 5 HBA, also acceptable.

**QED:** Both ligands have reasonable QED scores (0.414 and 0.707), with Ligand B being better.

**DILI:** Both ligands have similar DILI risk (50.95 and 50.136), indicating a moderate risk.

**BBB:** This is a critical parameter for CNS targets. Ligand A has a BBB percentile of 36.952, which is below the desirable >70. Ligand B has a significantly better BBB percentile of 72.315, exceeding the threshold.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.472 and -5.087), which is unusual and suggests poor permeability. However, these values are on a log scale and negative values are not necessarily indicative of poor permeability.

**Aqueous Solubility:** Both ligands have negative solubility values (-0.99 and -4.059), indicating poor aqueous solubility.

**hERG Inhibition:** Both ligands show low hERG inhibition liability (0.332 and 0.464), which is good.

**Microsomal Clearance:** Ligand A (-7.488) has a much lower (better) microsomal clearance than Ligand B (51.416), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand B (56.408) has a significantly longer half-life than Ligand A (5.844), which is a positive attribute.

**P-gp Efflux:** Ligand A has no P-gp efflux (0.088) while Ligand B has a moderate efflux (0.549). Lower P-gp efflux is preferred for CNS penetration.

**Binding Affinity:** Ligand B (-8.1 kcal/mol) has a substantially stronger binding affinity than Ligand A (-0.0 kcal/mol). This is a major advantage, potentially outweighing some of its ADME drawbacks.

**Overall Assessment:**

Ligand B is the stronger candidate. While it has a higher logP and moderate P-gp efflux, its significantly improved BBB penetration and, most importantly, *much* stronger binding affinity (-8.1 vs -0.0 kcal/mol) make it the more promising drug candidate. The better half-life is also a significant advantage. Ligand A's lower clearance is good, but its poor affinity and low BBB penetration are major drawbacks for a CNS target.

Output:
1
2025-04-17 05:44:55,261 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 drug candidates, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (362.411 and 357.495 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (106.39) is higher than Ligand B (90.9). Both are below the 140 A^2 threshold for oral absorption, but only Ligand B is below the 90 A^2 threshold preferred for CNS targets.

**logP:** Ligand A (4.362) is significantly higher than Ligand B (0.515). Ligand A is pushing the upper limit and could potentially have solubility issues or off-target effects. Ligand B is quite low, potentially hindering permeation.

**H-Bond Donors/Acceptors:** Ligand A has 2 HBD and 6 HBA, while Ligand B has 3 HBD and 5 HBA. Both are within acceptable ranges.

**QED:** Both ligands have similar QED values (0.586 and 0.496), indicating reasonable drug-likeness.

**DILI:** Ligand A has a high DILI risk (94.804 percentile), which is a major concern. Ligand B has a very low DILI risk (4.188 percentile), which is excellent.

**BBB:** Ligand A shows moderate BBB penetration (63.746 percentile). Ligand B has poor BBB penetration (36.371 percentile), which is a significant drawback for a CNS target.

**Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and suggests potential issues with the data or the compounds. However, the magnitude is different, with Ligand A (-4.57) being less negative than Ligand B (-5.235).

**Aqueous Solubility:** Ligand A has very poor aqueous solubility (-5.927 percentile). Ligand B has slightly better solubility (-0.281 percentile), but it's still quite low.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.247 and 0.258 percentile).

**Microsomal Clearance:** Ligand A has a moderate clearance (77.721 mL/min/kg), while Ligand B has very low clearance (-0.81 mL/min/kg), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A has a moderate half-life (19.794 hours). Ligand B has a short half-life (10.859 hours).

**P-gp Efflux:** Ligand A has moderate P-gp efflux (0.289 percentile), while Ligand B has very low P-gp efflux (0.016 percentile), which is beneficial for CNS penetration.

**Binding Affinity:** Ligand A has a significantly stronger binding affinity (-9.3 kcal/mol) than Ligand B (-7.4 kcal/mol). This is a substantial difference and a major advantage for Ligand A.

**Overall Assessment:**

Ligand A has a much stronger binding affinity, which is critical for GPCRs. However, it suffers from high DILI risk, poor solubility, and moderate BBB penetration. Ligand B has a better safety profile (low DILI, low P-gp efflux), better TPSA for CNS penetration, and better metabolic stability, but its binding affinity is significantly weaker and its BBB penetration is poor.

Given the strong emphasis on binding affinity for GPCRs, and the fact that the affinity difference is >1.5 kcal/mol, I would cautiously favor Ligand A *if* the DILI risk could be mitigated through structural modifications. The poor solubility is also a concern, but may be addressed through formulation strategies. The moderate BBB penetration is less concerning given the strong affinity. Ligand B's weak affinity makes it less likely to be a viable candidate, even with its better ADME properties.

Output:
1
2025-04-17 05:44:55,261 - INFO - Reasoning:

Let's analyze Ligand A and Ligand B based on the provided guidelines, prioritizing GPCR-specific properties (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (379.964 Da) is slightly higher than Ligand B (345.403 Da), but both are acceptable.

**TPSA:** Ligand A (64.11) is excellent for CNS penetration, well below the 90 A^2 threshold. Ligand B (109) is higher, but still potentially acceptable, though less ideal.

**logP:** Ligand A (4.744) is a bit high, potentially leading to solubility issues and off-target effects. Ligand B (-0.008) is very low, which could hinder membrane permeability and CNS penetration.

**H-Bond Donors/Acceptors:** Ligand A (HBD=1, HBA=5) and Ligand B (HBD=3, HBA=5) both fall within acceptable ranges.

**QED:** Both ligands have similar, good QED values (A: 0.6, B: 0.665).

**DILI:** Both ligands have similar, acceptable DILI risk (A: 70.299, B: 71.19).

**BBB:** Ligand A (60.295) is moderate, while Ligand B (40.791) is poor for CNS penetration. This is a significant drawback for a DRD2 ligand.

**Caco-2 Permeability:** Both have negative values, which is unusual. However, the magnitude suggests Ligand A (-4.658) has slightly better permeability than Ligand B (-5.332).

**Aqueous Solubility:** Both ligands have very poor aqueous solubility (A: -5.877, B: -2.046).

**hERG Inhibition:** Ligand A (0.602) has a slightly higher risk than Ligand B (0.043), but both are relatively low.

**Microsomal Clearance:** Ligand A (120.578) has higher clearance, indicating lower metabolic stability, compared to Ligand B (-19.878, indicating high stability).

**In vitro Half-Life:** Ligand A (93.236) has a longer half-life than Ligand B (-9.691, indicating very short half-life).

**P-gp Efflux:** Ligand A (0.382) has lower P-gp efflux, which is favorable for CNS exposure, while Ligand B (0.012) has very low efflux.

**Binding Affinity:** Ligand B (-8.4 kcal/mol) has significantly stronger binding affinity than Ligand A (0.0 kcal/mol). This is a substantial advantage.

**Overall Assessment:**

Ligand B has a much stronger binding affinity, and better metabolic stability. However, its low logP and poor BBB penetration are major concerns for a CNS target like DRD2. Ligand A has a better BBB score, and more reasonable logP, but its binding affinity is very weak.

Considering the GPCR-specific priorities, the strong affinity of Ligand B is a significant advantage that *could* be overcome with structural modifications to improve its logP and BBB penetration. The weak affinity of Ligand A is a more fundamental issue, and is less likely to be improved through optimization.

Output:
1
2025-04-17 05:44:55,262 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (368.587 and 346.515 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (40.62) is better than Ligand B (49.41). Both are below the 90 A^2 threshold for CNS targets, but A is closer to the ideal.

**3. logP:** Both ligands have a logP around 3.65 and 3.648, which is optimal (1-3).

**4. H-Bond Donors:** Ligand A (0) is preferable to Ligand B (1). Fewer HBDs generally improve permeability.

**5. H-Bond Acceptors:** Ligand A (3) is slightly better than Ligand B (2). Both are within the acceptable range (<=10).

**6. QED:** Ligand A (0.657) has a better QED score than Ligand B (0.512), indicating a more drug-like profile.

**7. DILI:** Ligand A (17.759) has a significantly lower DILI risk than Ligand B (8.259), which is a major advantage.

**8. BBB:** Both ligands have excellent BBB penetration (Ligand A: 85.925, Ligand B: 89.337). Ligand B is slightly better, but both are above the desirable 70% threshold for CNS targets.

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.75 and -4.768). This is unusual and suggests poor permeability. However, these values are on a log scale and can be interpreted as very low permeability.

**10. Aqueous Solubility:** Both ligands have negative solubility values (-3.347 and -3.796), indicating poor aqueous solubility. This could pose formulation challenges.

**11. hERG Inhibition:** Ligand A (0.601) shows slightly lower hERG inhibition liability than Ligand B (0.703), which is preferable.

**12. Microsomal Clearance:** Ligand A (82.217) has higher microsomal clearance than Ligand B (43.7), meaning it is less metabolically stable. This is a disadvantage for Ligand A.

**13. In vitro Half-Life:** Ligand B (3.498) has a longer in vitro half-life than Ligand A (1.957), which is a positive attribute.

**14. P-gp Efflux:** Ligand A (0.433) has lower P-gp efflux liability than Ligand B (0.309), which is favorable for CNS penetration.

**15. Binding Affinity:** Ligand B (-7.7 kcal/mol) has a significantly stronger binding affinity than Ligand A (-6.9 kcal/mol). This is a substantial advantage, potentially outweighing some of the ADME drawbacks.

**Overall Assessment:**

Ligand B has a significantly better binding affinity and a longer half-life. While Ligand A has better DILI risk and P-gp efflux, the affinity difference is substantial. Given the GPCR-specific prioritization of affinity, and the acceptable BBB penetration of both compounds, Ligand B is the more promising candidate, despite its slightly higher DILI risk and lower P-gp profile. The poor Caco-2 and solubility for both compounds are concerning, but can potentially be addressed through formulation strategies.

Output:
1
2025-04-17 05:44:55,262 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the acceptable range (200-500 Da). Ligand A (350.375 Da) is slightly lower, which could be beneficial for permeability. Ligand B (385.921 Da) is also good.

**TPSA:** Ligand A (114.97) is closer to the ideal range for CNS targets (<=90) than Ligand B (84.14). This is a significant advantage for brain penetration.

**logP:** Ligand A (-1.436) is a bit low, potentially hindering membrane permeability. Ligand B (2.992) is within the optimal range (1-3). This favors Ligand B.

**H-Bond Donors/Acceptors:** Ligand A has 3 HBD and 5 HBA, which are acceptable. Ligand B has 1 HBD and 7 HBA, also acceptable.

**QED:** Both ligands have good QED scores (A: 0.563, B: 0.717), indicating drug-likeness.

**DILI:** Both ligands have moderate DILI risk (A: 56.689, B: 60.062). Neither is a major concern, but lower is better.

**BBB:** Ligand B (43.505) has a significantly better BBB percentile than Ligand A (15.355). This is crucial for a CNS target like DRD2.

**Caco-2 Permeability:** Ligand A (-5.358) has poor Caco-2 permeability, while Ligand B (-4.97) is also poor, but slightly better.

**Aqueous Solubility:** Both have poor aqueous solubility (-1.562 and -2.672 respectively). This could pose formulation challenges.

**hERG:** Both ligands have very low hERG inhibition risk (A: 0.086, B: 0.2). This is excellent.

**Microsomal Clearance:** Ligand A (-30.38) has much lower microsomal clearance than Ligand B (36.565), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (-18.564) has a shorter half-life than Ligand B (34.408).

**P-gp Efflux:** Both have very low P-gp efflux liability (A: 0.005, B: 0.467).

**Binding Affinity:** Both ligands have comparable binding affinities (-8.0 and -7.0 kcal/mol, respectively). Ligand A is slightly better, but the difference is less than 1.5 kcal/mol.

**Overall Assessment:**

Ligand B excels in BBB penetration and has a more favorable logP. While Ligand A has slightly better affinity and metabolic stability, the poor BBB and lower logP are significant drawbacks for a CNS-targeting GPCR. The difference in affinity is not large enough to overcome these ADME deficiencies.

Output:
1
2025-04-17 05:44:55,262 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (338.411 Da) is slightly lower, which could be advantageous for permeability.

**TPSA:** Ligand A (67.23) is significantly better than Ligand B (81.75). For a CNS target like DRD2, TPSA should be <=90, and ideally lower. Ligand A is much closer to the optimal range.

**logP:** Both ligands have acceptable logP values (A: 1.366, B: 1.515), falling within the 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A (HBD=1, HBA=4) is preferable to Ligand B (HBD=0, HBA=6). While both are acceptable, fewer hydrogen bond donors can sometimes improve BBB penetration.

**QED:** Ligand A (0.919) has a substantially higher QED score than Ligand B (0.784), indicating a more drug-like profile.

**DILI:** Ligand B (59.907) has a slightly better DILI score than Ligand A (43.466), but both are below the concerning threshold of 60.

**BBB:** Ligand B (96.161) has a significantly higher BBB percentile than Ligand A (67.08). This is a *critical* advantage for a CNS target like DRD2.

**Caco-2 Permeability:** Ligand A (-5.097) has a worse Caco-2 permeability than Ligand B (-4.165), indicating potentially lower intestinal absorption.

**Aqueous Solubility:** Ligand A (-1.775) has a worse aqueous solubility than Ligand B (-2.902).

**hERG:** Both ligands have very low hERG inhibition liability (A: 0.255, B: 0.317), which is excellent.

**Microsomal Clearance:** Ligand A (16.216) has a significantly lower microsomal clearance than Ligand B (59.404), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (-5.245) has a much longer in vitro half-life than Ligand B (-15.882).

**P-gp Efflux:** Both ligands have low P-gp efflux liability (A: 0.127, B: 0.235).

**Binding Affinity:** Ligand B (-8.7 kcal/mol) has a stronger binding affinity than Ligand A (-7.4 kcal/mol). This is a substantial difference (>1.5 kcal/mol) and a major factor.

**Overall Assessment:**

Ligand B excels in BBB penetration and binding affinity, two crucial factors for a DRD2 ligand. While Ligand A has better TPSA, QED, metabolic stability and half-life, the superior affinity and BBB penetration of Ligand B outweigh these advantages. The slightly worse solubility and Caco-2 permeability of Ligand B are less concerning given the target is in the CNS.

Output:
1
2025-04-17 05:44:55,262 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B based on the provided guidelines, prioritizing GPCR-specific properties (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (347.419 and 348.422 Da) fall comfortably within the ideal 200-500 Da range.

**TPSA:** Ligand A (80.56) is better than Ligand B (58.44). Both are below 90, which is good for CNS targets.

**logP:** Ligand B (1.615) is better than Ligand A (0.303). A logP between 1-3 is optimal, and Ligand A is quite low, potentially hindering permeation.

**H-Bond Donors:** Both have 0 HBD, which is acceptable.

**H-Bond Acceptors:** Ligand A (6) is higher than Ligand B (4). Both are within the acceptable limit of 10.

**QED:** Both ligands have good QED scores (0.765 and 0.834), indicating drug-like properties.

**DILI:** Ligand B (31.563) has a significantly lower DILI risk than Ligand A (49.826). This is a substantial advantage.

**BBB:** Ligand B (98.255) is *much* better than Ligand A (74.564) in terms of BBB penetration. This is critical for a CNS target like DRD2.

**Caco-2 Permeability:** Ligand A (-4.637) and Ligand B (-4.749) are both very poor.

**Aqueous Solubility:** Ligand A (-1.79) is better than Ligand B (-2.935), but both are poor.

**hERG Inhibition:** Ligand A (0.105) has a lower hERG inhibition liability than Ligand B (0.346), which is preferable.

**Microsomal Clearance:** Ligand B (39.062) has a higher microsomal clearance than Ligand A (33.341), suggesting lower metabolic stability.

**In vitro Half-Life:** Ligand A (-6.015) has a longer half-life than Ligand B (-20.104).

**P-gp Efflux:** Ligand A (0.182) exhibits lower P-gp efflux than Ligand B (0.067), which is beneficial for CNS exposure.

**Binding Affinity:** Ligand B (-8.3 kcal/mol) has a slightly better binding affinity than Ligand A (-7.8 kcal/mol). While the difference is not huge, it's still a positive factor.

**Overall Assessment:**

Ligand B is the stronger candidate. Its superior BBB penetration (98.255 vs 74.564) and lower DILI risk (31.563 vs 49.826) are significant advantages for a CNS-targeting drug. The slightly better binding affinity (-8.3 vs -7.8) also contributes. While Ligand A has better solubility, P-gp efflux, and half-life, the BBB and DILI advantages of Ligand B outweigh these factors, especially given the target is a CNS GPCR. The logP of Ligand A is concerningly low.

Output:
1
2025-04-17 05:44:55,262 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 drug candidates, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (362.499 and 382.448 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (66.4) is better than Ligand B (67.43). Both are below the 90 A^2 threshold for CNS targets, which is good.

**3. logP:** Both ligands have good logP values (2.351 and 2.971), falling within the optimal 1-3 range. Ligand B is slightly higher, potentially increasing membrane permeability.

**4. H-Bond Donors:** Ligand A (0) is preferable to Ligand B (2). Fewer HBDs generally improve permeability.

**5. H-Bond Acceptors:** Ligand A (5) is preferable to Ligand B (4). Both are below the 10 threshold.

**6. QED:** Ligand A (0.575) has a significantly better QED score than Ligand B (0.346), indicating a more drug-like profile.

**7. DILI:** Ligand A (31.02) has a much lower DILI risk than Ligand B (43.622), suggesting better hepatotoxicity potential.

**8. BBB:** Ligand B (87.321) has a significantly higher BBB penetration percentile than Ligand A (74.176). This is a *critical* advantage for a CNS target like DRD2.

**9. Caco-2 Permeability:** Ligand A (-4.821) has a slightly better Caco-2 permeability than Ligand B (-5.394), but both are negative and therefore difficult to interpret without knowing the scale.

**10. Aqueous Solubility:** Ligand A (-1.946) has better aqueous solubility than Ligand B (-3.518).

**11. hERG Inhibition:** Both ligands have low hERG inhibition risk (0.415 and 0.609).

**12. Microsomal Clearance:** Ligand B (29.761) has lower microsomal clearance than Ligand A (33.808), suggesting better metabolic stability.

**13. In vitro Half-Life:** Ligand A (-9.24) has a much longer in vitro half-life than Ligand B (3.265).

**14. P-gp Efflux:** Ligand A (0.474) has lower P-gp efflux than Ligand B (0.148), which is favorable for CNS penetration.

**15. Binding Affinity:** Both ligands have very similar and excellent binding affinities (-7.7 and -7.8 kcal/mol). The difference is negligible.

**Overall Assessment:**

Ligand B excels in BBB penetration, a crucial factor for a CNS-targeting drug. It also has better metabolic stability (lower Cl_mic). However, Ligand A has a superior QED score, lower DILI risk, better solubility, and a longer half-life. The difference in P-gp efflux is also favorable for Ligand A. While BBB is paramount, the combination of better overall drug-likeness properties in Ligand A, coupled with acceptable BBB penetration, makes it the more promising candidate. The slightly better BBB of Ligand B is not enough to overcome the other advantages of Ligand A.

Output:
0
2025-04-17 05:44:55,263 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (346.471 and 352.479 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (58.64) is significantly better than Ligand B (72.96). For CNS targets, we want TPSA <= 90, and A is much closer to the optimal <=60 range. B is approaching a less desirable range.

**3. logP:** Ligand A (2.102) is optimal (1-3), while Ligand B (0.302) is a bit low, potentially hindering permeation.

**4. H-Bond Donors:** Both have 1 HBD, which is good.

**5. H-Bond Acceptors:** Ligand A has 3 HBA, and Ligand B has 4. Both are acceptable (<=10).

**6. QED:** Both ligands have similar QED values (0.793 and 0.773), indicating good drug-likeness.

**7. DILI:** Ligand A (22.8) has a much lower DILI risk than Ligand B (13.3). Both are good (<40), but A is preferable.

**8. BBB:** Ligand A (75.107) has a significantly better BBB penetration percentile than Ligand B (55.797). This is *critical* for a CNS target like DRD2.

**9. Caco-2 Permeability:** Ligand A (-4.514) is better than Ligand B (-4.971), indicating slightly improved intestinal absorption.

**10. Aqueous Solubility:** Ligand A (-3.5) is better than Ligand B (-1.013), indicating better solubility.

**11. hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.233 and 0.15).

**12. Microsomal Clearance:** Ligand B (9.18) has a higher clearance than Ligand A (3.366), suggesting lower metabolic stability.

**13. In vitro Half-Life:** Ligand A (10.954) has a longer half-life than Ligand B (-0.671).

**14. P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.039 and 0.01).

**15. Binding Affinity:** Both ligands have very similar and excellent binding affinities (-7.8 and -7.7 kcal/mol). The difference is negligible.

**Overall Assessment:**

Ligand A is superior to Ligand B. While both have good binding affinity and drug-like properties, Ligand A excels in crucial areas for a CNS-targeting GPCR ligand: TPSA, logP, BBB penetration, DILI risk, solubility, and metabolic stability (lower Cl_mic and longer t1/2). Ligand B's lower logP and poorer BBB penetration are significant drawbacks.



Output:
0
2025-04-17 05:44:55,263 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (336.435 Da) is slightly preferred due to being lower in weight.

**TPSA:** Ligand A (41.57) is significantly better than Ligand B (58.64). For CNS targets, we want TPSA <= 90, and A is much closer to the ideal range for brain penetration.

**logP:** Both ligands have good logP values (A: 3.705, B: 3.386), falling within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Both have acceptable HBD (1) and HBA (A: 3, B: 4) counts.

**QED:** Ligand A (0.925) has a superior QED score compared to Ligand B (0.771), indicating better overall drug-likeness.

**DILI:** Both have similar DILI risk (A: 54.789, B: 55.68), both being acceptable (<60).

**BBB:** Ligand A (91.586) has a much higher BBB percentile than Ligand B (82.862). This is a critical advantage for a CNS target like DRD2.

**Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and suggests poor permeability. This is a concern for both, but the values are similar.

**Aqueous Solubility:** Both have negative solubility values, which is also unusual and indicates very poor solubility. This is a concern for both, but the values are similar.

**hERG Inhibition:** Both ligands show low hERG inhibition liability (A: 0.919, B: 0.612), which is good.

**Microsomal Clearance:** Ligand A (92.773) has a significantly higher microsomal clearance than Ligand B (22.621), indicating faster metabolism and potentially lower *in vivo* exposure. This is a disadvantage for Ligand A.

**In vitro Half-Life:** Ligand B (-0.423) has a slightly longer half-life than Ligand A (5.171), which is preferable.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (A: 0.715, B: 0.285), which is good for CNS penetration. Ligand B is slightly better.

**Binding Affinity:** Ligand B (-8.4 kcal/mol) has a stronger binding affinity than Ligand A (-9.0 kcal/mol). This is a significant advantage.

**Overall Assessment:**

Despite Ligand A's better QED, TPSA, and BBB, Ligand B's significantly stronger binding affinity (-8.4 vs -9.0 kcal/mol) and lower microsomal clearance (22.621 vs 92.773) are more important for a GPCR target. While both have poor Caco-2 and solubility, the binding affinity and metabolic stability are more critical for initial optimization. The stronger binding of Ligand B suggests it will be more potent and potentially require a lower dose, which can mitigate some ADME concerns.

Output:
1
2025-04-17 05:44:55,263 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (346.351 Da) is slightly preferred as it's closer to the lower end, potentially aiding permeability.

**TPSA:** Ligand A (127.9) is borderline for CNS penetration, while Ligand B (58.2) is excellent, falling well below the 90 threshold. This is a significant advantage for Ligand B.

**logP:** Ligand A (-2.107) is quite low, potentially hindering membrane permeability. Ligand B (4.479) is high, potentially causing solubility issues or off-target interactions, but for a GPCR, a higher logP can be acceptable if other parameters are favorable.

**H-Bond Donors/Acceptors:** Ligand A (HBD=1, HBA=9) is reasonable. Ligand B (HBD=2, HBA=2) is also good, with fewer hydrogen bonding groups, which generally improves permeability.

**QED:** Ligand A (0.634) has a better QED score than Ligand B (0.428), indicating a more drug-like profile.

**DILI:** Ligand A (72.043) has a higher DILI risk than Ligand B (22.102). This is a significant advantage for Ligand B.

**BBB:** Ligand B (70.686) has a better BBB penetration score than Ligand A (43.815). This is crucial for a CNS target like DRD2.

**Caco-2 Permeability:** Ligand A (-5.61) has poor Caco-2 permeability, while Ligand B (-4.737) is also poor, but slightly better.

**Aqueous Solubility:** Ligand A (-1.721) has poor solubility, while Ligand B (-4.656) is even worse.

**hERG Inhibition:** Ligand A (0.013) has very low hERG inhibition risk, which is excellent. Ligand B (0.5) has a slightly elevated risk.

**Microsomal Clearance:** Ligand A (-0.737) has lower (better) microsomal clearance than Ligand B (74.609). This suggests better metabolic stability for Ligand A.

**In vitro Half-Life:** Ligand B (38.688) has a significantly longer half-life than Ligand A (7.551). This is a major advantage for Ligand B.

**P-gp Efflux:** Ligand A (0.025) has very low P-gp efflux, which is excellent for CNS penetration. Ligand B (0.303) has a slightly higher, but still reasonable, P-gp efflux.

**Binding Affinity:** Both ligands have very similar and strong binding affinities (-8.1 and -7.9 kcal/mol). The difference is less than the 1.5 kcal/mol threshold.

**Overall Assessment:**

Ligand B excels in BBB penetration, DILI risk, and in vitro half-life, all critical for a CNS GPCR target. While its logP is high and solubility is poor, the strong binding affinity and favorable BBB profile outweigh these concerns. Ligand A has a better QED, lower DILI, and better metabolic stability, but its poor BBB penetration and low logP are significant drawbacks for a CNS target. The TPSA of Ligand B is also much more favorable.

Output:
1
2025-04-17 05:44:55,263 - INFO - Batch 224 complete. Total preferences: 3584
2025-04-17 05:44:55,263 - INFO - Processing batch 225/512...
2025-04-17 05:45:36,809 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (358.435 and 350.507 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (106.12) is higher than Ligand B (58.44). For CNS targets, TPSA should be <= 90. Ligand B is much better in this regard.

**3. logP:** Ligand A (-0.269) is quite low, potentially hindering membrane permeability. Ligand B (3.067) is within the optimal range of 1-3. This is a significant advantage for Ligand B.

**4. H-Bond Donors:** Ligand A (3) is acceptable, while Ligand B (0) is also good.

**5. H-Bond Acceptors:** Ligand A (6) is acceptable, and Ligand B (4) is also good.

**6. QED:** Both ligands have good QED scores (0.579 and 0.688), indicating drug-like properties.

**7. DILI:** Ligand A (42.458) has a slightly higher DILI risk than Ligand B (25.785), but both are below the concerning threshold of 60.

**8. BBB:** Ligand B (79.992) has a much better BBB percentile than Ligand A (48.391). This is *critical* for a CNS target like DRD2.

**9. Caco-2 Permeability:** Ligand A (-5.315) has poor Caco-2 permeability, while Ligand B (-4.418) is also poor, but slightly better.

**10. Aqueous Solubility:** Both ligands have poor aqueous solubility (-0.906 and -1.956).

**11. hERG Inhibition:** Ligand A (0.063) has a very low hERG risk, while Ligand B (0.813) has a slightly elevated risk.

**12. Microsomal Clearance:** Ligand A (2.968) has a much lower microsomal clearance than Ligand B (76.056), indicating better metabolic stability.

**13. In vitro Half-Life:** Ligand A (12.322) has a longer half-life than Ligand B (7.303).

**14. P-gp Efflux:** Ligand A (0.028) has very low P-gp efflux, which is excellent for CNS penetration. Ligand B (0.435) has higher P-gp efflux.

**15. Binding Affinity:** Both ligands have excellent binding affinities (-7.4 and -7.1 kcal/mol), with Ligand A being slightly stronger. However, the 0.3 kcal/mol difference is unlikely to outweigh the ADME deficiencies of Ligand A.

**Overall Assessment:**

Ligand B is significantly better suited as a drug candidate. While Ligand A has slightly better binding affinity and metabolic stability, Ligand B excels in crucial properties for CNS penetration: TPSA, logP, and especially BBB. The lower P-gp efflux of Ligand A is a positive, but the poor logP and higher TPSA are major drawbacks. The better BBB penetration of Ligand B is paramount for targeting DRD2.

Output:
1
2025-04-17 05:45:36,809 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (337.335 and 348.447 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (97.36) is slightly above the preferred <90 for CNS targets, while Ligand B (78.53) is well within the range. This favors Ligand B.

**logP:** Both ligands (2.875 and 2.157) are within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A has 2 HBD and 5 HBA, while Ligand B has 1 HBD and 4 HBA. Both are within acceptable limits (<=5 HBD and <=10 HBA).

**QED:** Both ligands have good QED scores (0.674 and 0.766), indicating good drug-like properties.

**DILI:** Ligand A has a high DILI risk (93.176 percentile), which is a significant concern. Ligand B has a much lower DILI risk (47.111 percentile), making it more favorable.

**BBB:** Ligand B (69.407 percentile) has a better BBB penetration score than Ligand A (27.918 percentile). This is crucial for a CNS target like DRD2.

**Caco-2 Permeability:** Both have negative Caco-2 values (-5.251 and -5.085), which is unusual and suggests poor permeability. However, these values are on a log scale, and the absolute difference isn't huge.

**Aqueous Solubility:** Both ligands have negative solubility values (-3.62 and -2.662), indicating poor aqueous solubility. This could pose formulation challenges.

**hERG Inhibition:** Ligand A (0.11) has a slightly lower hERG inhibition risk than Ligand B (0.386), but both are relatively low.

**Microsomal Clearance:** Ligand B (20.684 mL/min/kg) has a significantly lower microsomal clearance than Ligand A (6.361 mL/min/kg), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand B (-12.422 hours) has a significantly longer half-life than Ligand A (-4.55 hours), which is desirable.

**P-gp Efflux:** Ligand A (0.041) has a lower P-gp efflux liability than Ligand B (0.094), indicating better potential for CNS exposure.

**Binding Affinity:** Ligand A (-8.6 kcal/mol) has a stronger binding affinity than Ligand B (-7.1 kcal/mol). This is a substantial difference (1.5 kcal/mol), which can outweigh some ADME drawbacks.

**Overall Assessment:**

While Ligand A has a superior binding affinity, its very high DILI risk and poor BBB penetration are major drawbacks for a CNS drug. Ligand B, despite having slightly weaker affinity, presents a much more favorable ADME profile, particularly its lower DILI risk, better BBB penetration, and improved metabolic stability (lower Cl_mic and longer t1/2). The difference in affinity, while significant, might be overcome with further optimization of Ligand B. Given the GPCR-specific priorities for CNS targets, Ligand B is the more promising candidate.

Output:
1
2025-04-17 05:45:36,810 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 drug candidates, considering the provided guidelines and GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (344.415 and 351.495 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (86.11) is excellent, well below the 90 A^2 threshold for CNS targets. Ligand B (106.96) is still reasonable but less optimal.

**logP:** Ligand A (2.202) is within the optimal 1-3 range. Ligand B (3.691) is slightly higher, potentially raising concerns about solubility and off-target effects, but still acceptable.

**H-Bond Donors/Acceptors:** Ligand A (HBD=1, HBA=6) is favorable. Ligand B (HBD=2, HBA=3) is also good.

**QED:** Ligand A (0.812) has a very strong drug-like profile. Ligand B (0.375) is significantly lower, suggesting potential issues.

**DILI:** Ligand A (80.225) has a higher DILI risk than Ligand B (27.142), which is a significant concern.

**BBB:** Both ligands have similar BBB penetration (Ligand A: 56.65, Ligand B: 58.821). These are below the desirable >70 for CNS targets, but not dramatically so.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.488 and -4.781). This is unusual and suggests poor permeability.

**Aqueous Solubility:** Both ligands have negative solubility values (-3.722 and -4.022), indicating very poor aqueous solubility.

**hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.164 and 0.329).

**Microsomal Clearance:** Ligand A (85.113) has higher microsomal clearance than Ligand B (62.31), indicating lower metabolic stability.

**In vitro Half-Life:** Ligand B (-2.752) has a slightly longer half-life than Ligand A (-26.32).

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.286 and 0.141).

**Binding Affinity:** Both ligands have strong binding affinities (-9.1 and -8.4 kcal/mol). Ligand A is slightly better (-9.1 kcal/mol).

**Overall Assessment:**

Ligand A has a better QED score and slightly better binding affinity, but significantly higher DILI risk and lower metabolic stability. Ligand B has a lower DILI risk and better metabolic stability but a lower QED score. The poor Caco-2 and solubility for both are major drawbacks. Considering the CNS target, BBB is important, and both are similar. Given the importance of minimizing toxicity (DILI) and maximizing metabolic stability for a CNS drug, and the relatively small difference in binding affinity, Ligand B is the more promising candidate despite its lower QED. The poor solubility and permeability would need to be addressed through formulation or structural modification.

Output:
1
2025-04-17 05:45:36,810 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight (MW):** Both ligands (346.471 and 358.429 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (69.64) and Ligand B (67.43) are both below the 90 A^2 threshold desirable for CNS targets, which is excellent.

**3. logP:** Both ligands have logP values within the optimal range (Ligand A: 2.001, Ligand B: 2.416, 1-3).

**4. H-Bond Donors (HBD):** Both ligands have 2 HBD, well within the acceptable limit of <=5.

**5. H-Bond Acceptors (HBA):** Both ligands have 3 HBA, also within the acceptable limit of <=10.

**6. QED:** Ligand A (0.765) has a better QED score than Ligand B (0.622), indicating a more drug-like profile.

**7. DILI:** Ligand A (15.471) has a significantly lower DILI risk than Ligand B (26.755), which is a major advantage.

**8. BBB:** Ligand B (90.074) has a much higher BBB percentile than Ligand A (48.197). This is a *critical* advantage for a CNS target like DRD2.

**9. Caco-2:** Both ligands have negative Caco-2 values (-4.953 and -4.862), which is unusual and suggests poor permeability. This is a concern for both.

**10. Solubility:** Both ligands have negative solubility values (-3.652 and -2.529), indicating poor aqueous solubility. This is a concern for both.

**11. hERG:** Both ligands have low hERG inhibition liability (Ligand A: 0.235, Ligand B: 0.313), which is good.

**12. Cl_mic:** Ligand B (29.284) has a lower microsomal clearance than Ligand A (45.286), suggesting better metabolic stability.

**13. t1/2:** Ligand B (-6.298) has a more negative in vitro half-life than Ligand A (-2.264). This is a concern for both, but more so for B.

**14. Pgp:** Both ligands have very low Pgp efflux liability (Ligand A: 0.135, Ligand B: 0.052), which is favorable for CNS penetration.

**15. Binding Affinity:** Ligand B (-7.8 kcal/mol) has a significantly stronger binding affinity than Ligand A (-9.9 kcal/mol). This is a substantial advantage, potentially outweighing some of the ADME drawbacks.

**Overall Assessment:**

Ligand B is the stronger binder, which is paramount for GPCRs. Its significantly improved BBB penetration is also a major plus for a CNS target. While it has a slightly higher DILI risk and lower metabolic stability than Ligand A, the substantial improvement in binding affinity and BBB penetration makes it the more promising candidate. The poor Caco-2 and solubility are concerns for both, but can be addressed with formulation strategies.

Output:
1
2025-04-17 05:45:36,810 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (360.772 and 354.401 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (82.45) is slightly higher than Ligand B (76.02). Both are below the 90 A^2 threshold desirable for CNS targets, but Ligand B is preferable.

**3. logP:** Ligand A (4.604) is higher than the optimal range (1-3), potentially causing solubility issues and off-target effects. Ligand B (2.649) is within the optimal range. This is a significant advantage for Ligand B.

**4. H-Bond Donors:** Ligand A (3) and Ligand B (2) are both acceptable, being less than 5.

**5. H-Bond Acceptors:** Both ligands (A: 4, B: 4) are within the acceptable limit of 10.

**6. QED:** Both ligands have good QED values (A: 0.633, B: 0.705), indicating drug-like properties. Ligand B is slightly better.

**7. DILI:** Ligand A (91.431) has a considerably higher DILI risk than Ligand B (52.85). This is a major concern for Ligand A.

**8. BBB:** Ligand B (85.498) has a much better BBB penetration percentile than Ligand A (11.632). This is critical for a CNS target like DRD2, making Ligand B far more promising.

**9. Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and suggests poor permeability. However, the scale is not specified, so it's hard to interpret.

**10. Aqueous Solubility:** Both have negative solubility values, also unusual. Again, the scale is unknown.

**11. hERG:** Both ligands have low hERG inhibition liability (A: 0.176, B: 0.241), which is good.

**12. Microsomal Clearance:** Ligand A (31.315) and Ligand B (35.514) have similar microsomal clearance values.

**13. In vitro Half-Life:** Ligand B (-1.328) has a negative half-life, which is not possible. This is a red flag. Ligand A (18.886) has a reasonable half-life.

**14. P-gp Efflux:** Both ligands have low P-gp efflux liability (A: 0.062, B: 0.145), which is desirable.

**15. Binding Affinity:** Both ligands have very similar and strong binding affinities (A: -8.6 kcal/mol, B: -8.4 kcal/mol). The difference is less than 1.5 kcal/mol, so it's not a deciding factor.

**Overall Assessment:**

Despite the unusual negative values for Caco-2 and Solubility, the critical factors for a CNS-targeting GPCR like DRD2 heavily favor Ligand B. Its significantly better BBB penetration, lower DILI risk, and acceptable logP outweigh the slightly better half-life of Ligand A and the similar binding affinities. The negative half-life for Ligand B is a significant concern, but the other factors are more important.

Output:
1
2025-04-17 05:45:36,810 - INFO - Reasoning:

Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (369.487 Da and 350.394 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (74.07) is slightly higher than Ligand B (67.67). Both are below the 90 A^2 threshold desirable for CNS targets, but Ligand B is preferable.

**3. logP:** Ligand A (1.242) and Ligand B (0.704) are both within the optimal 1-3 range. Ligand A is slightly better.

**4. H-Bond Donors:** Both ligands have 0 HBD, which is good.

**5. H-Bond Acceptors:** Both ligands have 5 HBA, which is acceptable (<=10).

**6. QED:** Both ligands have similar QED values (0.781 and 0.784), indicating good drug-likeness.

**7. DILI:** Ligand A (34.82) has a slightly lower DILI risk than Ligand B (38.736), both are good (<40).

**8. BBB:** This is a crucial parameter for a CNS target like DRD2. Ligand B (90.617) has a significantly higher BBB percentile than Ligand A (82.513). This is a major advantage for Ligand B.

**9. Caco-2 Permeability:** Ligand A (-4.735) has a lower Caco-2 permeability than Ligand B (-4.445). While both are negative, indicating poor permeability, Ligand B is slightly better.

**10. Aqueous Solubility:** Both ligands have very poor aqueous solubility (-2.039 and -1.821 respectively). This is a concern for both, but not a deciding factor.

**11. hERG Inhibition:** Ligand A (0.773) has a slightly higher hERG inhibition risk than Ligand B (0.286). Ligand B is preferable.

**12. Microsomal Clearance:** Ligand A (20.438) has a higher microsomal clearance than Ligand B (5.655), indicating lower metabolic stability. Ligand B is preferable.

**13. In vitro Half-Life:** Ligand A (-29.185) has a much shorter in vitro half-life than Ligand B (9.31). This is a significant disadvantage for Ligand A.

**14. P-gp Efflux:** Ligand A (0.129) has lower P-gp efflux than Ligand B (0.05). Lower P-gp efflux is better, so Ligand A is preferable.

**15. Binding Affinity:** Ligand A (-8.7 kcal/mol) has a slightly better binding affinity than Ligand B (-8.2 kcal/mol). This is a positive for Ligand A.

**Overall Assessment:**

While Ligand A has slightly better binding affinity and P-gp efflux, Ligand B demonstrates superior ADME properties crucial for CNS penetration and drug development. Specifically, its significantly higher BBB percentile, lower hERG risk, lower microsomal clearance (better metabolic stability), and longer in-vitro half-life outweigh the small difference in binding affinity. The poor solubility and Caco-2 permeability are concerns for both, but can be addressed with formulation strategies. Given the GPCR-specific priorities, Ligand B is the more promising candidate.

Output:
1
2025-04-17 05:45:36,810 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (349.5 and 355.4 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (43.86) is significantly better than Ligand B (100.89). For CNS targets, we want TPSA <= 90, and A is comfortably within this range, while B is above.

**logP:** Ligand A (2.356) is optimal (1-3), while Ligand B (0.084) is quite low, potentially hindering permeation.

**H-Bond Donors/Acceptors:** Ligand A (0 HBD, 3 HBA) is more favorable than Ligand B (1 HBD, 6 HBA). Both are within acceptable limits, but fewer H-bonds generally improve permeability.

**QED:** Both ligands have similar QED values (0.765 and 0.701), indicating good drug-likeness.

**DILI:** Ligand A (11.4) has a much lower DILI risk than Ligand B (55.68). This is a significant advantage for A.

**BBB:** Ligand A (84.88) has a better BBB penetration percentile than Ligand B (76.54). Both are reasonably good, but A is closer to the desirable >70 threshold for CNS targets.

**Caco-2 Permeability:** Both have negative values, indicating poor permeability. However, the magnitude of the negative value is smaller for Ligand A (-4.368) than for Ligand B (-4.985), suggesting slightly better absorption potential for A.

**Aqueous Solubility:** Both have negative values, indicating poor solubility. The value for Ligand A (-1.587) is better than for Ligand B (-2.173).

**hERG Inhibition:** Ligand A (0.684) has a lower hERG inhibition liability than Ligand B (0.39), which is preferable.

**Microsomal Clearance:** Ligand A (36.998) has a higher (worse) microsomal clearance than Ligand B (-25.925). This means Ligand B is likely more metabolically stable.

**In vitro Half-Life:** Ligand B (6.942) has a longer half-life than Ligand A (-2.535). This is a positive for B.

**P-gp Efflux:** Ligand A (0.219) has lower P-gp efflux liability than Ligand B (0.034), which is desirable for CNS penetration.

**Binding Affinity:** Ligand B (-7.7 kcal/mol) has a slightly better binding affinity than Ligand A (-7.4 kcal/mol), but the difference is relatively small (0.3 kcal/mol).

**Overall Assessment:**

Ligand A is superior due to its significantly better TPSA, logP, DILI risk, BBB penetration, and P-gp efflux. While Ligand B has slightly better affinity and metabolic stability, the ADME properties of Ligand A are much more favorable, especially for a CNS target like DRD2. The small affinity difference is unlikely to outweigh the substantial ADME advantages of Ligand A.

Output:
1
2025-04-17 05:45:36,811 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (346.431 and 354.451 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (87.47) is better than Ligand B (90.98). Both are below the 90 A^2 threshold for CNS targets, which is good.

**logP:** Ligand A (0.951) is slightly better than Ligand B (-0.804), falling within the optimal 1-3 range. Ligand B is a little low, which *could* impact permeability.

**H-Bond Donors/Acceptors:** Both have 2 HBD and 5 HBA, which are acceptable.

**QED:** Both ligands have reasonable QED scores (0.732 and 0.624), indicating good drug-like properties.

**DILI:** Both ligands have very similar, and low, DILI risk (13.416 and 13.261 percentile). This is excellent.

**BBB:** This is a critical parameter for a CNS target like DRD2. Ligand A has a significantly higher BBB penetration (84.257%) compared to Ligand B (24.738%). This is a major advantage for Ligand A.

**Caco-2 Permeability:** Both have negative Caco-2 values (-5.374 and -5.362), which is unusual and suggests poor permeability. However, these values are very close and may not be a significant differentiator.

**Aqueous Solubility:** Both have negative solubility values (-1.222 and -0.822), indicating poor aqueous solubility. This could pose formulation challenges.

**hERG Inhibition:** Ligand A (0.567) has a slightly better hERG profile than Ligand B (0.093), indicating lower cardiotoxicity risk.

**Microsomal Clearance:** Ligand B (-11.953) has a *much* lower (better) microsomal clearance than Ligand A (11.772). This suggests better metabolic stability for Ligand B.

**In vitro Half-Life:** Ligand B (3.056 hours) has a longer half-life than Ligand A (-1.156 hours). This is a significant advantage for Ligand B.

**P-gp Efflux:** Ligand A (0.025) has a much lower P-gp efflux liability than Ligand B (0.002), which is beneficial for CNS exposure.

**Binding Affinity:** Ligand A (-8.3 kcal/mol) has a slightly better binding affinity than Ligand B (-7.6 kcal/mol). While both are good, the 0.7 kcal/mol difference is notable.

**Overall Assessment:**

Ligand A excels in BBB penetration and binding affinity, which are crucial for a CNS GPCR target. Its P-gp efflux is also much lower. However, Ligand B demonstrates superior metabolic stability (lower Cl_mic) and a longer half-life. The solubility and Caco-2 permeability are poor for both.

Considering the GPCR-specific priorities, the superior BBB penetration of Ligand A is a decisive factor. While metabolic stability is important, a drug needs to *reach* the target in the brain. The slightly better affinity of Ligand A further strengthens its position.

Output:
1
2025-04-17 05:45:36,811 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (376.519 and 346.431 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Both ligands have TPSA values (96.89 and 95.42) that are acceptable for oral absorption (<140) but slightly high for optimal CNS penetration (<90). This is a minor drawback, but not disqualifying.

**3. logP:** Both ligands have logP values (1.104 and 1.412) within the optimal range of 1-3, suggesting good permeability and reasonable solubility.

**4. H-Bond Donors & Acceptors:** Ligand A has 3 HBD and 6 HBA, while Ligand B has 2 HBD and 5 HBA. Both are within acceptable limits.

**5. QED:** Ligand B (0.84) has a significantly higher QED score than Ligand A (0.494), indicating a more drug-like profile.

**6. DILI:** Ligand A (23.459) has a much lower DILI risk than Ligand B (45.25), which is a significant advantage.

**7. BBB:** Ligand B (51.997) has a considerably better BBB penetration percentile than Ligand A (34.626). This is a *critical* factor for a CNS target like DRD2.

**8. Caco-2 Permeability:** Ligand A (-5.448) has slightly better Caco-2 permeability than Ligand B (-4.983), but both are negative values, which is unusual and difficult to interpret without knowing the scale.

**9. Aqueous Solubility:** Both ligands have very poor aqueous solubility (-2.33 and -2.007). This could pose formulation challenges.

**10. hERG Inhibition:** Both ligands show very low hERG inhibition risk (0.173 and 0.085).

**11. Microsomal Clearance:** Ligand B (19.1) has lower microsomal clearance than Ligand A (22.728), suggesting better metabolic stability.

**12. In vitro Half-Life:** Ligand A (-7.27) has a much longer in vitro half-life than Ligand B (-2.235). This is a significant advantage.

**13. P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.031 and 0.016), which is favorable for CNS penetration.

**14. Binding Affinity:** Ligand B (-8.4 kcal/mol) has a significantly stronger binding affinity than Ligand A (-6.9 kcal/mol). This >1.5 kcal/mol difference is substantial and can outweigh some ADME drawbacks.

**Overall Assessment:**

While Ligand A has a better safety profile (lower DILI, longer half-life) and slightly better Caco-2 permeability, Ligand B is the stronger candidate due to its significantly improved BBB penetration and substantially higher binding affinity. For a CNS target like DRD2, BBB penetration and potency are paramount. The higher QED score for Ligand B also supports its drug-likeness. The solubility issues are a concern for both, but can potentially be addressed through formulation strategies.

Output:
1
2025-04-17 05:45:36,811 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (355.435 and 372.342 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (113.6) is slightly above the optimal <90 for CNS targets, but still reasonable. Ligand B (89.19) is excellent, well below 90.

**logP:** Ligand A (-0.031) is a bit low, potentially hindering permeability. Ligand B (2.17) is within the optimal 1-3 range. This is a significant advantage for Ligand B.

**H-Bond Donors/Acceptors:** Ligand A has 3 HBD and 5 HBA, which are acceptable. Ligand B has 2 HBD and 7 HBA, also acceptable.

**QED:** Both ligands have good QED scores (0.503 and 0.676), indicating good drug-like properties.

**DILI:** Ligand A (34.781) has a lower DILI risk than Ligand B (56.844), which is preferable.

**BBB:** Ligand B (83.87) has a significantly better BBB penetration score than Ligand A (43.815). This is *critical* for a CNS target like DRD2.

**Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and suggests poor permeability. However, the scale is not specified, so it's hard to interpret.

**Aqueous Solubility:** Both ligands have negative solubility values, which is also unusual.

**hERG Inhibition:** Ligand A (0.068) has a lower hERG risk than Ligand B (0.644), which is favorable.

**Microsomal Clearance:** Both ligands have similar microsomal clearance values (51.412 and 55.99), indicating moderate metabolic stability.

**In vitro Half-Life:** Ligand A (-17.638) has a negative half-life, which is not possible. This is a major red flag. Ligand B (-2.124) also has a negative half-life, but is less extreme.

**P-gp Efflux:** Ligand A (0.016) has very low P-gp efflux, which is excellent for CNS penetration. Ligand B (0.052) also has low P-gp efflux, but slightly higher than A.

**Binding Affinity:** Ligand B (-8.4 kcal/mol) has a slightly better binding affinity than Ligand A (-7.0 kcal/mol). While A is still good, the 1.4 kcal/mol difference is significant.

**Overall Assessment:**

Ligand B is the stronger candidate. Its superior logP and BBB penetration are crucial for a CNS GPCR target. The better binding affinity further strengthens its profile. While Ligand A has a slightly lower DILI risk and P-gp efflux, the negative in vitro half-life is a major concern. The negative half-life values for both compounds are suspect and would require experimental validation, but the other properties of Ligand B make it the more promising candidate.

Output:
1
2025-04-17 05:45:36,811 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (392.503 and 367.475 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (127.23) is higher than the preferred <90 for CNS targets, while Ligand B (89.35) is closer to the ideal range. This gives a slight edge to Ligand B.

**logP:** Ligand A (-0.033) is slightly below the optimal 1-3 range, potentially hindering permeability. Ligand B (0.155) is also on the lower side, but closer to the desired range.

**H-Bond Donors/Acceptors:** Ligand A has 2 HBD and 7 HBA, which are acceptable. Ligand B has 1 HBD and 7 HBA, also acceptable.

**QED:** Both ligands have reasonable QED scores (0.425 and 0.746), indicating drug-like properties, with Ligand B being better.

**DILI:** Both ligands have DILI risk around the 50-60 percentile, indicating moderate risk. This isn't a major differentiating factor.

**BBB:** Both ligands have similar BBB penetration (58.511 and 52.268), both below the desirable >70 for CNS targets. This is a weakness for both, but crucial for DRD2.

**Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and suggests poor permeability.

**Aqueous Solubility:** Both have negative solubility values, which is also unusual and suggests poor solubility.

**hERG:** Both ligands exhibit low hERG inhibition liability (0.075 and 0.076), which is good.

**Microsomal Clearance:** Ligand A (5.431) has significantly lower microsomal clearance than Ligand B (22.822), suggesting better metabolic stability. This is a significant advantage for Ligand A.

**In vitro Half-Life:** Ligand A (83.79) has a much longer half-life than Ligand B (4.367), which is a major advantage.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.068 and 0.031), which is favorable for CNS penetration.

**Binding Affinity:** Both ligands have the same binding affinity (-7.6 kcal/mol), which is excellent.

**Overall Assessment:**

While both ligands have good binding affinity, Ligand A is more favorable due to its significantly improved metabolic stability (lower Cl_mic) and longer half-life. Although Ligand B has a slightly better TPSA and QED, the pharmacokinetic advantages of Ligand A are more important for a CNS target like DRD2. The poor solubility and permeability are concerning for both, but the improved metabolic profile of Ligand A could potentially be optimized further.



Output:
1
2025-04-17 05:45:36,812 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (348.487 and 347.463 Da) fall comfortably within the ideal 200-500 Da range.

**TPSA:** Ligand A (78.43) is slightly higher than Ligand B (70.47). Both are below the 90 A^2 threshold desirable for CNS targets, but Ligand B is preferable.

**logP:** Ligand A (1.988) is optimal, while Ligand B (0.41) is a bit low, potentially hindering membrane permeability. This is a significant advantage for Ligand A.

**H-Bond Donors/Acceptors:** Ligand A has 3 HBD and 3 HBA, while Ligand B has 1 HBD and 5 HBA. Both are within acceptable limits (<=5 HBD and <=10 HBA).

**QED:** Ligand B (0.809) has a better QED score than Ligand A (0.528), indicating a more drug-like profile overall.

**DILI:** Both ligands have similar, low DILI risk (11.128 and 11.322 percentile).

**BBB:** Both ligands have similar BBB penetration (53.083 and 52.385 percentile). While not exceptional (>70), they are reasonable.

**Caco-2 Permeability:** Ligand A (-4.784) has a worse Caco-2 permeability than Ligand B (-5.24). Lower values indicate lower permeability.

**Aqueous Solubility:** Ligand A (-3.55) has better aqueous solubility than Ligand B (-0.057).

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.268 and 0.371 percentile).

**Microsomal Clearance:** Ligand A (40.518 mL/min/kg) has higher clearance than Ligand B (-1.957 mL/min/kg). This means Ligand B is likely more metabolically stable, a positive attribute.

**In vitro Half-Life:** Ligand B (-4.719 hours) has a longer half-life than Ligand A (-6.828 hours).

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.141 and 0.02). Ligand B is slightly better.

**Binding Affinity:** Ligand B (-8.0 kcal/mol) has a significantly stronger binding affinity than Ligand A (-7.6 kcal/mol). This 0.4 kcal/mol difference is substantial and can outweigh some ADME drawbacks.

**Overall Assessment:**

Ligand B demonstrates a superior binding affinity and better metabolic stability (lower Cl_mic, longer t1/2). While its logP is slightly lower, the stronger binding affinity is a key advantage for a GPCR target like DRD2. Ligand A has better solubility and a more optimal logP, but the affinity difference is critical. Considering the GPCR-specific priorities, the stronger affinity of Ligand B makes it the more promising candidate.

Output:
1
2025-04-17 05:45:36,812 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (348.443 and 370.563 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (60.03) is better than Ligand B (57.17). Both are below the 90 A^2 threshold desirable for CNS targets, indicating good potential for brain penetration.

**3. logP:** Ligand A (3.465) is slightly higher than Ligand B (1.807), placing it closer to the optimal 1-3 range. Ligand B is a bit low, potentially hindering permeation.

**4. H-Bond Donors:** Both ligands have 1 HBD, which is within the acceptable limit of <=5.

**5. H-Bond Acceptors:** Ligand A has 4 HBAs, while Ligand B has 6. Both are below the 10 limit, but Ligand A is preferable.

**6. QED:** Ligand A (0.905) has a significantly better QED score than Ligand B (0.595), suggesting a more drug-like profile.

**7. DILI:** Ligand A (46.142) has a higher DILI risk than Ligand B (6.282). This is a significant drawback for Ligand A.

**8. BBB:** Ligand A (80.651) has a better BBB percentile than Ligand B (71.617), which is crucial for a CNS target like DRD2.

**9. Caco-2 Permeability:** Ligand A (-4.45) has a worse Caco-2 permeability than Ligand B (-5.469). Lower values are less favorable.

**10. Aqueous Solubility:** Ligand A (-3.467) has a worse aqueous solubility than Ligand B (-1.734). Lower values are less favorable.

**11. hERG Inhibition:** Both ligands have similar hERG inhibition liabilities (0.655 and 0.743), indicating moderate risk.

**12. Microsomal Clearance:** Ligand A (43.916) has a higher microsomal clearance than Ligand B (5.144), meaning it's metabolized faster and has lower metabolic stability.

**13. In vitro Half-Life:** Ligand A (14.711) has a longer in vitro half-life than Ligand B (6.825), which is a positive attribute.

**14. P-gp Efflux:** Ligand A (0.219) has a lower P-gp efflux liability than Ligand B (0.046), which is desirable for CNS penetration.

**15. Binding Affinity:** Ligand A (-8.2 kcal/mol) has a significantly stronger binding affinity than Ligand B (-5.7 kcal/mol). This is a substantial advantage, potentially outweighing some of the ADME drawbacks.

**Overall Assessment:**

Ligand A has a much better binding affinity and BBB penetration, and lower P-gp efflux, which are critical for a CNS GPCR target. However, it has a higher DILI risk, worse Caco-2 permeability, and aqueous solubility, and higher microsomal clearance. Ligand B has a better safety profile (DILI) and permeability, but its lower affinity and BBB penetration are significant concerns. The substantial difference in binding affinity (-8.2 vs -5.7 kcal/mol) is a major factor. Given the importance of affinity for GPCRs, and the acceptable BBB for Ligand A, I believe Ligand A is the more promising candidate, despite its drawbacks. Further optimization could focus on mitigating the DILI risk and improving solubility/permeability.

Output:
1
2025-04-17 05:45:36,812 - INFO - Reasoning:

Let's analyze Ligand A and Ligand B based on the provided guidelines, prioritizing GPCR-specific properties (BBB, logP, Pgp, TPSA, and affinity) for DRD2.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (343.427 Da) is slightly lower, which could be beneficial for permeability.

**TPSA:** Ligand A (91.32) is better than Ligand B (118.36). For CNS targets, TPSA should be <=90, so Ligand A is preferable.

**logP:** Ligand A (2.361) is optimal (1-3), while Ligand B (0.775) is a bit low, potentially hindering permeation.

**H-Bond Donors/Acceptors:** Both have 3 HBD and 4 HBA, which are within acceptable limits.

**QED:** Both ligands have reasonable QED scores (0.692 and 0.592, both >0.5), indicating good drug-like properties.

**DILI:** Ligand A (23.071) has a significantly lower DILI risk than Ligand B (50.989). This is a major advantage for Ligand A.

**BBB:** Ligand A (35.983) has a poor BBB penetration percentile, while Ligand B (59.054) is better, but still not ideal (>70 is desirable). This is a significant drawback for Ligand A, given the CNS target.

**Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and suggests poor permeability. However, the scale isn't specified, so it's hard to interpret.

**Aqueous Solubility:** Both have negative solubility values, which is also unusual and suggests poor solubility. Again, the scale is missing.

**hERG:** Both have very low hERG inhibition liability (0.057 and 0.31), which is excellent.

**Microsomal Clearance:** Ligand A (20.09) has a lower microsomal clearance than Ligand B (3.691), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (-12.685) has a negative half-life, which is not possible. This is a major red flag. Ligand B (-20.503) also has a negative half-life, which is also problematic.

**P-gp Efflux:** Ligand A (0.028) has very low P-gp efflux liability, which is highly desirable for CNS penetration. Ligand B (0.091) is also low, but higher than Ligand A.

**Binding Affinity:** Both have strong binding affinities (-9.1 and -8.3 kcal/mol). Ligand A is slightly better (-9.1 kcal/mol), but the difference is not huge.

**Overall Assessment:**

Despite Ligand A having better TPSA, logP, DILI, and P-gp efflux, its extremely poor BBB penetration and impossible half-life are major concerns. The negative half-life is a critical flaw. Ligand B, while having a lower logP and higher DILI risk, has a better (though still suboptimal) BBB score. The negative half-life for Ligand B is also a major issue.

Given the issues with both compounds, and prioritizing a viable starting point, I would cautiously lean towards Ligand B *if* the negative half-life values are data errors. The slightly better BBB score, even if not ideal, is more valuable than the slightly better affinity of Ligand A, especially considering the impossible half-life of Ligand A.

However, the negative half-life values for both compounds are extremely concerning and suggest potential data quality issues.

Output:
1
2025-04-17 05:45:36,812 - INFO - Reasoning:

Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (364.408 and 357.401 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (58.64) is significantly better than Ligand B (75.44). For CNS targets, we want TPSA <= 90, and A is comfortably within that range, while B is approaching the upper limit.

**3. logP:** Both ligands have good logP values (2.295 and 2.415), falling within the optimal 1-3 range.

**4. H-Bond Donors:** Both have 1 HBD, which is acceptable.

**5. H-Bond Acceptors:** Ligand A has 3 HBAs, and Ligand B has 4. Both are within the acceptable limit of <= 10.

**6. QED:** Both have good QED scores (0.787 and 0.813), indicating good drug-like properties.

**7. DILI:** Ligand A (16.789) has a much lower DILI risk than Ligand B (34.277). This is a significant advantage for A.

**8. BBB:** Ligand A (96.084) has a significantly higher BBB penetration percentile than Ligand B (86.817). This is *critical* for a CNS target like DRD2.

**9. Caco-2 Permeability:** Both have negative Caco-2 values (-4.363 and -4.664). This is unusual and suggests poor permeability. However, the absolute values are similar.

**10. Aqueous Solubility:** Both have negative solubility values (-2.197 and -2.936), indicating poor solubility. Again, the values are similar.

**11. hERG Inhibition:** Both have low hERG inhibition liability (0.661 and 0.537), which is good.

**12. Microsomal Clearance:** Ligand A (14.801) has a lower microsomal clearance than Ligand B (35.233), suggesting better metabolic stability.

**13. In vitro Half-Life:** Ligand A (-11.593) has a more negative (longer) half-life than Ligand B (-21.314).

**14. P-gp Efflux:** Both have very low P-gp efflux liability (0.033 and 0.171), which is favorable for CNS penetration.

**15. Binding Affinity:** Both ligands have very similar and excellent binding affinities (-8.2 and -8.3 kcal/mol). The difference is negligible.

**Overall Assessment:**

Ligand A is clearly superior. While both ligands have good affinity, Ligand A excels in several key areas crucial for a CNS-targeting GPCR: significantly better TPSA, lower DILI risk, substantially higher BBB penetration, and improved metabolic stability (lower Cl_mic and longer t1/2). The similar Caco-2 and solubility values are concerning for both, but the other advantages of A outweigh these drawbacks.

Output:
1
2025-04-17 05:45:36,812 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 drug candidates, considering the provided guidelines and GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands are within the acceptable range (200-500 Da). Ligand A (354.378 Da) is slightly preferred as it's closer to the ideal range.

**2. TPSA:** Ligand A (104.73) is better than Ligand B (82.53). Both are below 140, but for a CNS target like DRD2, we want TPSA as close to 90 as possible. Ligand B is closer to this target.

**3. logP:** Both ligands have good logP values (A: 1.955, B: 3.085), falling within the optimal 1-3 range. Ligand B is slightly better.

**4. H-Bond Donors:** Ligand A (3) is slightly worse than Ligand B (2), but both are acceptable.

**5. H-Bond Acceptors:** Both ligands have the same number of H-bond acceptors (5), which is within the acceptable limit.

**6. QED:** Ligand B (0.592) has a better QED score than Ligand A (0.376), indicating a more drug-like profile.

**7. DILI:** Ligand A (39.395) has a lower DILI risk than Ligand B (53.781), which is preferable.

**8. BBB:** Ligand B (74.176) has a significantly better BBB penetration percentile than Ligand A (58.24). This is *critical* for a CNS target like DRD2.

**9. Caco-2 Permeability:** Both have negative values, which is unusual. Assuming these are log values, lower values indicate lower permeability. Ligand A (-5.16) is slightly better than Ligand B (-4.966).

**10. Aqueous Solubility:** Both have negative values, which is unusual. Assuming these are log values, lower values indicate lower solubility. Ligand A (-3.21) is slightly better than Ligand B (-4.897).

**11. hERG Inhibition:** Both ligands have similar hERG inhibition liability (A: 0.559, B: 0.818), and are within acceptable ranges.

**12. Microsomal Clearance:** Both ligands have similar microsomal clearance (A: 63.268, B: 65.542).

**13. In vitro Half-Life:** Ligand B (32.346) has a significantly longer in vitro half-life than Ligand A (-26.85). This is a major advantage.

**14. P-gp Efflux:** Both ligands have similar P-gp efflux liability (A: 0.065, B: 0.611).

**15. Binding Affinity:** Both ligands have similar binding affinities (A: -8.0 kcal/mol, B: -8.1 kcal/mol). The difference is negligible.

**Overall Assessment:**

While Ligand A has a slightly better DILI score and Caco-2/Solubility, Ligand B excels in the most crucial areas for a CNS GPCR target: BBB penetration and in vitro half-life. The better QED score also supports Ligand B. The slight advantage in logP is also beneficial. The similar binding affinities mean that the superior ADME properties of Ligand B outweigh any minor drawbacks.

Output:
1
2025-04-17 05:45:36,813 - INFO - Batch 225 complete. Total preferences: 3600
2025-04-17 05:45:36,813 - INFO - Processing batch 226/512...
2025-04-17 05:46:28,368 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (358.804 and 345.487 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (58.95) is significantly better than Ligand B (81.99). For CNS targets, we want TPSA <= 90, and A is comfortably within that range, while B is approaching the upper limit.

**3. logP:** Both ligands have good logP values (3.637 and 3.072), falling within the optimal 1-3 range.

**4. H-Bond Donors:** Both have 2 HBD, which is acceptable.

**5. H-Bond Acceptors:** Ligand A has 4 HBA, and Ligand B has 3. Both are within the acceptable limit of <= 10.

**6. QED:** Both ligands have good QED scores (0.732 and 0.821), indicating good drug-like properties.

**7. DILI:** Ligand A has a concerningly high DILI risk (94.649%), while Ligand B has a much lower and acceptable risk (34.781%). This is a major drawback for Ligand A.

**8. BBB:** Ligand B (63.474%) is better than Ligand A (57.27%), although neither is above the desirable 70% threshold for CNS targets. However, given the target is DRD2, BBB is a high priority.

**9. Caco-2:** Both have negative Caco-2 values, which is unusual and suggests poor permeability. This is a potential issue for both.

**10. Solubility:** Both have negative solubility values, indicating poor aqueous solubility. This is a potential issue for both.

**11. hERG:** Both ligands have low hERG inhibition liability (0.596 and 0.336), which is good.

**12. Cl_mic:** Ligand B (53.371) has a lower microsomal clearance than Ligand A (65.194), suggesting better metabolic stability.

**13. t1/2:** Ligand B has a negative in vitro half-life (-10.075), which is highly unusual and concerning. Ligand A has a more reasonable 55.301 hours.

**14. Pgp:** Ligand A (0.302) has lower P-gp efflux liability than Ligand B (0.1), which is favorable for CNS penetration.

**15. Binding Affinity:** Ligand A (-9.7 kcal/mol) has a significantly stronger binding affinity than Ligand B (-8.4 kcal/mol). This is a substantial advantage.

**Overall Assessment:**

Despite the strong affinity of Ligand A, its extremely high DILI risk is a major red flag. The lower DILI risk and better metabolic stability of Ligand B are significant advantages. While Ligand B's BBB penetration isn't ideal, it's better than Ligand A's. The negative Caco-2 and solubility values are concerning for both, but can potentially be addressed through formulation strategies. The unusual negative half-life for Ligand B is a significant concern.

Considering the GPCR-specific priorities, the balance of properties favors Ligand B, despite its weaker binding affinity. The DILI risk associated with Ligand A is too high to ignore, even with its superior binding.

Output:
1
2025-04-17 05:46:28,368 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B based on the provided guidelines, prioritizing GPCR-specific properties (BBB, logP, Pgp, TPSA, and affinity) for DRD2.

**Molecular Weight:** Both ligands (348.45 & 343.52 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (87.46) is better than Ligand B (37.27). For CNS targets, TPSA should be <=90, both are within this range, but A is closer to the upper limit.

**logP:** Ligand B (3.758) is higher than Ligand A (0.645). While 1-3 is optimal, B is slightly above, which *could* be problematic, but not severely. A is quite low, potentially hindering permeation.

**H-Bond Donors/Acceptors:** Ligand A (HBD=2, HBA=5) and Ligand B (HBD=1, HBA=3) both have acceptable numbers of H-bond donors and acceptors.

**QED:** Both ligands have good QED scores (A: 0.675, B: 0.854), indicating good drug-like properties.

**DILI:** Ligand A (19.97%) has a significantly lower DILI risk than Ligand B (11.09%). This is a substantial advantage for A.

**BBB:** Ligand B (91.20%) has a *much* higher BBB penetration score than Ligand A (37.46%). This is a critical advantage for a CNS target like DRD2.

**Caco-2 Permeability:** Ligand A (-5.103) has a negative Caco-2 value, which is concerning. Ligand B (-4.655) is also negative, but less so. Both suggest poor intestinal absorption, but A is worse.

**Aqueous Solubility:** Ligand A (-1.227) has slightly better solubility than Ligand B (-3.886).

**hERG Inhibition:** Ligand A (0.195) has a lower hERG inhibition liability than Ligand B (0.638), which is favorable.

**Microsomal Clearance:** Ligand A (9.176) has a lower microsomal clearance than Ligand B (59.149), indicating better metabolic stability.

**In vitro Half-Life:** Ligand B (43.993) has a much longer in vitro half-life than Ligand A (-4.216). This is a significant advantage for B.

**P-gp Efflux:** Ligand A (0.049) has lower P-gp efflux liability than Ligand B (0.165), which is good for CNS penetration.

**Binding Affinity:** Both ligands have similar, strong binding affinities (A: -7.9 kcal/mol, B: -7.0 kcal/mol). A has a slight advantage.

**Overall Assessment:**

Ligand B excels in BBB penetration and in vitro half-life, both crucial for a CNS GPCR target. Its logP is slightly elevated but manageable. Ligand A has better DILI and hERG profiles, lower P-gp efflux, and slightly better affinity, but suffers from very poor predicted Caco-2 permeability and a low BBB score. Given the importance of CNS penetration for DRD2, and the strong affinity of both compounds, Ligand B is the more promising candidate. The better BBB score outweighs the slightly higher logP and P-gp efflux.

Output:
1
2025-04-17 05:46:28,368 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (341.357 Da) is slightly better, being closer to the lower end which can aid permeability.

**TPSA:** Ligand A (42.24) is excellent, well below the 90 A^2 threshold for CNS targets. Ligand B (105.56) is higher, but still potentially acceptable, though less ideal.

**logP:** Ligand A (4.991) is a bit high, potentially leading to solubility issues or off-target interactions. Ligand B (1.361) is optimal.

**H-Bond Donors/Acceptors:** Ligand A (HBD=1, HBA=2) is excellent. Ligand B (HBD=2, HBA=7) is acceptable, but the higher HBA count could slightly impact permeability.

**QED:** Both ligands have similar QED values (A: 0.71, B: 0.721), indicating good drug-likeness.

**DILI:** Ligand A (79.333) is better than Ligand B (96.161). Both are above the 60 percentile, indicating a higher risk of liver injury, but A is significantly lower.

**BBB:** Ligand A (65.452) is better than Ligand B (40.016). A score >70 is desirable for CNS targets, and A is closer to this threshold. This is a critical factor for DRD2.

**Caco-2 Permeability:** Ligand A (-4.715) is better than Ligand B (-5.148). Higher values indicate better intestinal absorption.

**Aqueous Solubility:** Ligand A (-5.16) is better than Ligand B (-3.446). Higher values indicate better solubility.

**hERG Inhibition:** Ligand A (0.843) is better than Ligand B (0.143). Lower values are preferred to avoid cardiotoxicity.

**Microsomal Clearance:** Ligand A (59.33) is better than Ligand B (6.557). Lower clearance suggests greater metabolic stability.

**In vitro Half-Life:** Ligand A (48.311) is better than Ligand B (-31.201). Longer half-life is generally desirable.

**P-gp Efflux:** Ligand A (0.5) is better than Ligand B (0.096). Lower efflux improves CNS exposure.

**Binding Affinity:** Ligand A (-9.2 kcal/mol) is significantly better than Ligand B (-8.7 kcal/mol). A difference of 0.5 kcal/mol is substantial and can outweigh minor ADME drawbacks.

**Overall Assessment:**

Ligand A is superior to Ligand B. While Ligand A's logP is slightly high, its significantly better BBB penetration, binding affinity, lower DILI risk, better metabolic stability, and lower P-gp efflux outweigh this concern, especially considering the target is a CNS GPCR (DRD2). Ligand B has a better logP, but falls short in crucial areas like BBB penetration and binding affinity.

Output:
0
2025-04-17 05:46:28,369 - INFO - Reasoning:

Let's analyze Ligand A and Ligand B against the provided guidelines, prioritizing GPCR-specific properties (BBB, logP, Pgp, TPSA, and affinity) for DRD2.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (398.26 Da) is slightly higher than Ligand B (353.463 Da), but both are acceptable.

**TPSA:** Ligand A (71.09) is excellent for CNS penetration, well below the 90 A^2 threshold. Ligand B (84.32) is still reasonable, but less optimal.

**logP:** Ligand A (3.886) is within the optimal range (1-3). Ligand B (-0.479) is significantly below this range, potentially leading to poor membrane permeability and bioavailability.

**H-Bond Donors/Acceptors:** Both ligands have acceptable HBD (2) and HBA (3 for A, 5 for B) counts, falling within the recommended limits.

**QED:** Both ligands have good QED scores (0.701 and 0.674), indicating drug-like properties.

**DILI:** Ligand A (85.653) has a higher DILI risk than Ligand B (8.104). This is a significant drawback for Ligand A.

**BBB:** Ligand A (78.558) has a good BBB percentile, desirable for a CNS target. Ligand B (53.432) is considerably lower, suggesting limited brain penetration.

**Caco-2 Permeability:** Ligand A (-5.069) has poor Caco-2 permeability. Ligand B (-4.793) is also poor, but slightly better.

**Aqueous Solubility:** Both ligands have very poor aqueous solubility (-4.694 and -0.634). This could pose formulation challenges.

**hERG Inhibition:** Ligand A (0.641) has a slightly higher hERG risk than Ligand B (0.108), but both are relatively low.

**Microsomal Clearance:** Ligand A (65.989) has higher microsomal clearance than Ligand B (9.241), indicating lower metabolic stability.

**In vitro Half-Life:** Ligand A (86.255) has a longer half-life than Ligand B (16.214).

**P-gp Efflux:** Ligand A (0.43) has lower P-gp efflux than Ligand B (0.004), which is favorable for CNS penetration.

**Binding Affinity:** Ligand A (-10.9 kcal/mol) has significantly stronger binding affinity than Ligand B (-6.9 kcal/mol). This is a substantial advantage.

**Overall Assessment:**

Despite Ligand A's higher DILI risk and poor Caco-2 permeability, its significantly superior binding affinity (-10.9 vs -6.9 kcal/mol) and better BBB penetration (78.56 vs 53.43) outweigh the drawbacks, especially considering the target is a CNS GPCR (DRD2). The strong binding affinity suggests that a lower dose might be effective, potentially mitigating the DILI risk. The lower P-gp efflux also supports better CNS exposure. Ligand B's very low logP is a major concern, likely hindering its ability to cross cell membranes and reach the target in the brain.

Output:
1
2025-04-17 05:46:28,369 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight (MW):** Both ligands (346.43 & 349.48 Da) fall comfortably within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (76.66) is slightly higher than Ligand B (69.72). Both are below the 90 A^2 threshold desirable for CNS targets, but Ligand B is preferable.

**3. logP:** Both ligands have very similar logP values (1.593 & 1.542), falling within the optimal 1-3 range.

**4. H-Bond Donors (HBD):** Ligand A has 2 HBD, and Ligand B has 1. Both are within the acceptable limit of <=5. Ligand B is slightly better.

**5. H-Bond Acceptors (HBA):** Ligand A has 5 HBA, and Ligand B has 3. Both are within the acceptable limit of <=10. Ligand B is preferable.

**6. QED:** Both ligands have good QED scores (0.765 & 0.837), indicating good drug-like properties. Ligand B is slightly better.

**7. DILI:** Ligand A (25.79%) has a significantly lower DILI risk than Ligand B (9.85%). This is a substantial advantage for Ligand A.

**8. BBB:** Both ligands have reasonable BBB penetration (62.78% & 67.93%). While >70% is ideal, both are acceptable, and Ligand B is slightly better.

**9. Caco-2 Permeability:** Both have negative Caco-2 values (-5.389 & -4.882), which is unusual and suggests poor permeability. This is a concern for both.

**10. Aqueous Solubility:** Both have negative solubility values (-1.229 & -1.969), indicating very poor aqueous solubility. This is a significant drawback for both.

**11. hERG Inhibition:** Both ligands show very low hERG inhibition risk (0.545 & 0.312). This is excellent for both.

**12. Microsomal Clearance (Cl_mic):** Ligand A (5.467) has a much lower Cl_mic than Ligand B (14.379), indicating better metabolic stability. This is a significant advantage for Ligand A.

**13. In vitro Half-Life:** Ligand A (9.14) has a longer in vitro half-life than Ligand B (-5.234). This is a significant advantage for Ligand A.

**14. P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.045 & 0.034). This is excellent for both.

**15. Binding Affinity:** Both ligands have the same binding affinity (-9.1 kcal/mol), which is excellent.

**Overall Assessment:**

While Ligand B has slightly better TPSA, QED, and BBB, Ligand A demonstrates superior ADME properties. Specifically, its significantly lower DILI risk, lower microsomal clearance (better metabolic stability), and longer in vitro half-life are crucial advantages. The poor Caco-2 and aqueous solubility are concerning for both, but the metabolic and toxicity profiles of Ligand A are more favorable. Given the GPCR target and the need for CNS penetration, the improved ADME profile of Ligand A outweighs the slight advantages of Ligand B.

Output:
0
2025-04-17 05:46:28,369 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B based on the provided guidelines, prioritizing GPCR-specific properties (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (346.383) is slightly lower, which could be beneficial for permeability.

**TPSA:** Ligand A (90.65) is better than Ligand B (49.41) as it is closer to the ideal range for CNS targets (<=90). Ligand B is very low, which may indicate poor interactions with the target.

**logP:** Both ligands have acceptable logP values (A: 1.906, B: 2.536), falling within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Both have 1 HBD, which is good. Ligand A has 7 HBA, while Ligand B has 2. Both are within acceptable limits (<=10).

**QED:** Both are above 0.5, indicating good drug-likeness (A: 0.734, B: 0.602).

**DILI:** Ligand A (65.568) has a higher DILI risk than Ligand B (32.261). This is a negative for Ligand A.

**BBB:** Ligand B (70.376) has a significantly better BBB penetration score than Ligand A (63.319). This is a crucial advantage for a CNS target like DRD2.

**Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and suggests poor permeability. However, the scale is not specified, so it is hard to interpret the values.

**Aqueous Solubility:** Both have negative solubility values, which is also unusual.

**hERG:** Both have low hERG inhibition liability (A: 0.236, B: 0.56), which is good.

**Microsomal Clearance:** Ligand B (-0.197) has a much lower (better) microsomal clearance than Ligand A (112.336). This indicates better metabolic stability for Ligand B.

**In vitro Half-Life:** Ligand B (-29.697) has a much longer in vitro half-life than Ligand A (-11.436). This is a significant advantage for Ligand B.

**P-gp Efflux:** Ligand A (0.659) has a slightly higher P-gp efflux liability than Ligand B (0.052). Lower is better, favoring Ligand B.

**Binding Affinity:** Ligand B (-9.9 kcal/mol) has a substantially stronger binding affinity than Ligand A (-7.1 kcal/mol). This is a very important factor, as a >1.5 kcal/mol advantage can outweigh other drawbacks.

**Overall:**

Ligand B is superior due to its significantly better BBB penetration, metabolic stability (lower Cl_mic, longer t1/2), lower P-gp efflux, and, most importantly, much stronger binding affinity. While Ligand A has a slightly lower molecular weight and better TPSA, these advantages are overshadowed by Ligand B's superior ADME and potency. The DILI risk for Ligand A is also a concern.

Output:
1
2025-04-17 05:46:28,369 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (362.352 and 356.482 Da) fall within the ideal 200-500 Da range.

**TPSA:** Both ligands (76.46 and 78.43) are below the 90 A^2 threshold for CNS targets, which is excellent.

**logP:** Ligand A (0.735) is slightly low, potentially hindering permeation. Ligand B (2.609) is within the optimal 1-3 range. This favors Ligand B.

**H-Bond Donors/Acceptors:** Ligand A has 1 HBD and 5 HBA, while Ligand B has 3 HBD and 3 HBA. Both are within acceptable limits (<=5 HBD and <=10 HBA).

**QED:** Ligand A (0.838) has a better QED score than Ligand B (0.678), indicating a more drug-like profile.

**DILI:** Ligand A (38.62) has a slightly higher DILI risk than Ligand B (26.095), but both are below the concerning threshold of 60.

**BBB:** Ligand A (88.096) has a significantly better BBB penetration percentile than Ligand B (68.786). This is a crucial advantage for a CNS target like DRD2.

**Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and potentially indicates issues with the prediction method or the compounds themselves. However, the magnitude of the negative value is similar.

**Aqueous Solubility:** Both ligands have very poor predicted aqueous solubility (-1.099 and -2.584). This is a significant drawback.

**hERG Inhibition:** Ligand A (0.098) has a much lower hERG inhibition risk than Ligand B (0.338). This is a major advantage for Ligand A.

**Microsomal Clearance:** Ligand A (2.357) has a lower (better) microsomal clearance than Ligand B (5.711), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (6.828) has a positive half-life, while Ligand B has a negative half-life (-9.951). This is very concerning for Ligand B.

**P-gp Efflux:** Ligand A (0.06) has a much lower P-gp efflux liability than Ligand B (0.186), which is beneficial for CNS penetration.

**Binding Affinity:** Ligand A (-7.9 kcal/mol) has a slightly better binding affinity than Ligand B (-0.0 kcal/mol). This is a substantial difference and a key driver in the decision.

**Overall Assessment:**

Ligand A is superior. While both have solubility issues, Ligand A excels in critical areas for a CNS GPCR target: BBB penetration, hERG inhibition, metabolic stability, P-gp efflux, and, most importantly, binding affinity. The slightly lower logP of Ligand A is a minor concern compared to the significant advantages it holds. Ligand B's negative in vitro half-life is a major red flag.



Output:
1
2025-04-17 05:46:28,370 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (346.475 and 365.865 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (64.68) is significantly better than Ligand B (101.21). For CNS targets, we want TPSA <= 90, and A is closer to that threshold.

**3. logP:** Both ligands have good logP values (2.911 and 2.013), falling within the optimal 1-3 range.

**4. H-Bond Donors:** Both have 2 HBDs, which is acceptable.

**5. H-Bond Acceptors:** Ligand A has 3 HBAs, while Ligand B has 5. Both are within the acceptable limit of <=10, but A is preferable.

**6. QED:** Both have reasonable QED values (0.884 and 0.777), indicating good drug-like properties.

**7. DILI:** Ligand A (19.581) has a much lower DILI risk than Ligand B (49.864). This is a significant advantage for A.

**8. BBB:** Both ligands have excellent BBB penetration (72.547 and 78.364), exceeding the desirable >70 threshold for CNS targets.

**9. Caco-2 Permeability:** Ligand A (-4.628) has worse Caco-2 permeability than Ligand B (-5.169), but both are negative which is not ideal.

**10. Aqueous Solubility:** Ligand A (-2.854) has slightly better solubility than Ligand B (-3.349), but both are negative, indicating poor solubility.

**11. hERG Inhibition:** Both ligands have low hERG inhibition risk (0.608 and 0.404).

**12. Microsomal Clearance:** Ligand A (-18.441) has significantly lower (better) microsomal clearance than Ligand B (22.482), indicating greater metabolic stability.

**13. In vitro Half-Life:** Ligand A (5.901) has a longer half-life than Ligand B (0.433).

**14. P-gp Efflux:** Both ligands have very low P-gp efflux (0.01 and 0.021), which is good for CNS exposure.

**15. Binding Affinity:** Ligand B (-7.9 kcal/mol) has a slightly better binding affinity than Ligand A (-8.2 kcal/mol). While a >1.5 kcal/mol advantage is significant, the difference here is only 0.3 kcal/mol.

**Overall Assessment:**

Ligand A is the stronger candidate. Despite slightly weaker binding affinity, it excels in crucial ADME properties: lower DILI risk, significantly better metabolic stability (lower Cl_mic and longer t1/2), and a lower TPSA. These factors are particularly important for a CNS-targeting GPCR like DRD2. The better TPSA and DILI profiles outweigh the small difference in binding affinity.

Output:
1
2025-04-17 05:46:28,370 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (352.45 and 346.515 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (69.64) is slightly higher than Ligand B (49.41). Both are below the 90 A^2 threshold for CNS targets, but Ligand B is significantly better.

**3. logP:** Both ligands have good logP values (3.925 and 3.668) falling within the optimal 1-3 range.

**4. H-Bond Donors:** Ligand A has 2 HBD, and Ligand B has 1. Both are within the acceptable limit of <=5.

**5. H-Bond Acceptors:** Ligand A has 3 HBA, and Ligand B has 2. Both are within the acceptable limit of <=10.

**6. QED:** Both ligands have good QED scores (0.627 and 0.79), indicating good drug-like properties.

**7. DILI:** Ligand A (31.291) has a much lower DILI risk than Ligand B (10.585), which is a significant advantage.

**8. BBB:** Both ligands have excellent BBB penetration (72.78% and 81.737%), exceeding the desirable >70% threshold for CNS targets. Ligand B is slightly better.

**9. Caco-2 Permeability:** Both have negative Caco-2 values (-4.747 and -4.632). These values are unusual and suggest poor permeability. However, since these are negative values, it's difficult to directly compare.

**10. Aqueous Solubility:** Both have negative solubility values (-3.855 and -3.955), indicating very poor solubility. This is a significant drawback for both.

**11. hERG Inhibition:** Both ligands show low hERG inhibition liability (0.857 and 0.554), which is good.

**12. Microsomal Clearance:** Ligand A (92.211) has higher microsomal clearance than Ligand B (80.69), suggesting lower metabolic stability.

**13. In vitro Half-Life:** Ligand B (-8.852) has a much longer in vitro half-life than Ligand A (4.416), a major advantage.

**14. P-gp Efflux:** Both ligands have low P-gp efflux liability (0.514 and 0.151), which is favorable for CNS penetration. Ligand B is better.

**15. Binding Affinity:** Both ligands have excellent binding affinities (-8.2 and -8.8 kcal/mol). Ligand B is slightly more potent.

**Overall Assessment:**

While both ligands have desirable binding affinities and BBB penetration, Ligand B is the better candidate. It has a lower TPSA, a longer half-life, lower P-gp efflux, and slightly better binding affinity. Although Ligand A has a lower DILI risk, the benefits of Ligand B's improved pharmacokinetic properties (half-life, P-gp) and slightly better potency outweigh this difference, especially for a CNS target where good brain exposure is critical. The poor solubility and Caco-2 permeability are concerning for both, but can potentially be addressed with formulation strategies.

Output:
1
2025-04-17 05:46:28,370 - INFO - Here's a step-by-step comparison of Ligand A and Ligand B, followed by my final decision:

**1. Molecular Weight (MW):**
*   Ligand A: 372.451 Da - Within the ideal range (200-500 Da).
*   Ligand B: 363.454 Da - Within the ideal range (200-500 Da).
*   *Both are acceptable.*

**2. Topological Polar Surface Area (TPSA):**
*   Ligand A: 136.83  - Good for oral absorption, borderline for CNS targets (ideally <90).
*   Ligand B: 38.77 - Excellent for CNS penetration.
*   *Ligand B is significantly better for CNS targets.*

**3. Lipophilicity (logP):**
*   Ligand A: 1.645 - Optimal.
*   Ligand B: 4.129 - High. Could lead to solubility issues and off-target interactions.
*   *Ligand A is better.*

**4. H-Bond Donors (HBD):**
*   Ligand A: 1 - Acceptable.
*   Ligand B: 0 - Acceptable.
*   *Both are acceptable.*

**5. H-Bond Acceptors (HBA):**
*   Ligand A: 6 - Acceptable.
*   Ligand B: 4 - Acceptable.
*   *Both are acceptable.*

**6. Quantitative Estimate of Drug-likeness (QED):**
*   Ligand A: 0.445 - Below the desired threshold of 0.5.
*   Ligand B: 0.629 - Above the desired threshold of 0.5.
*   *Ligand B is better.*

**7. DILI Risk (DILI):**
*   Ligand A: 36.72 - Low risk.
*   Ligand B: 51.144 - Moderate risk, but still acceptable.
*   *Ligand A is better.*

**8. Blood-Brain Barrier Penetration (BBB):**
*   Ligand A: 75.107 - Good, but could be better for a CNS target.
*   Ligand B: 81.698 - Very good.
*   *Ligand B is better.*

**9. Caco-2 Permeability:**
*   Ligand A: -4.709 - Poor permeability.
*   Ligand B: -4.279 - Poor permeability.
*   *Both are poor, but B is slightly better.*

**10. Aqueous Solubility:**
*   Ligand A: -1.985 - Poor solubility.
*   Ligand B: -4.164 - Very poor solubility.
*   *Ligand A is better.*

**11. hERG Inhibition:**
*   Ligand A: 0.23 - Low risk.
*   Ligand B: 0.888 - Moderate risk.
*   *Ligand A is better.*

**12. Microsomal Clearance (Cl_mic):**
*   Ligand A: -23.113 - Low clearance, suggesting good metabolic stability.
*   Ligand B: 121.637 - High clearance, suggesting poor metabolic stability.
*   *Ligand A is significantly better.*

**13. In vitro Half-Life:**
*   Ligand A: 14.701 - Moderate.
*   Ligand B: 18.463 - Moderate.
*   *Both are acceptable.*

**14. P-gp Efflux:**
*   Ligand A: 0.012 - Very low efflux, favorable for CNS exposure.
*   Ligand B: 0.631 - Moderate efflux.
*   *Ligand A is significantly better.*

**15. Binding Affinity:**
*   Ligand A: -7.8 kcal/mol - Excellent.
*   Ligand B: -7.0 kcal/mol - Very good.
*   *Ligand A is better.*

**Overall Assessment & GPCR Prioritization:**

Given that the target is a CNS GPCR (DRD2), BBB penetration, logP, Pgp efflux, TPSA, and affinity are paramount. Ligand B excels in BBB penetration and has a better QED score. However, Ligand A demonstrates superior performance across most critical ADME properties (DILI, solubility, hERG, Cl_mic, Pgp efflux) *and* has a better binding affinity. The higher logP of Ligand B is a concern, potentially leading to solubility issues and off-target effects. While Ligand B's TPSA is excellent, the overall balance of properties favors Ligand A. The significantly better metabolic stability (lower Cl_mic) and lower P-gp efflux of Ligand A are particularly important for CNS drug development. The slightly lower BBB of Ligand A is a manageable drawback given its other advantages.

Output:
1
2025-04-17 05:46:28,370 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (347.39 and 349.431 Da) fall comfortably within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (69.72) is significantly better than Ligand B (91.65). For CNS targets, we want TPSA <= 90, so Ligand A is preferable.

**3. logP:** Ligand A (-0.063) is slightly lower than optimal (1-3), but still reasonable. Ligand B (1.534) is within the ideal range.

**4. H-Bond Donors:** Both have acceptable HBD counts (1 and 2 respectively), well below the limit of 5.

**5. H-Bond Acceptors:** Both have acceptable HBA counts (3 and 4 respectively), well below the limit of 10.

**6. QED:** Both ligands have good QED scores (0.684 and 0.696), indicating good drug-like properties.

**7. DILI:** Ligand A (21.946) has a much lower DILI risk than Ligand B (38.852). Both are below the 40 threshold, but A is better.

**8. BBB:** Both ligands have the same BBB penetration (58.24). This is a moderate value, and ideally, we'd like to see >70 for a CNS target like DRD2.

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.823 and -5.008). These values are unusual and suggest poor permeability.

**10. Aqueous Solubility:** Both ligands have negative solubility values (-1.85 and -1.567), indicating poor solubility.

**11. hERG Inhibition:** Both ligands have low hERG inhibition risk (0.181 and 0.421).

**12. Microsomal Clearance:** Ligand A (-17.753) has a significantly lower (better) microsomal clearance than Ligand B (-6.219). This suggests better metabolic stability for Ligand A.

**13. In vitro Half-Life:** Ligand A (-18.765) has a lower (worse) in vitro half-life than Ligand B (21.058).

**14. P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.011 and 0.173), which is good for CNS penetration.

**15. Binding Affinity:** Both ligands have the same binding affinity (-8.1 kcal/mol), which is excellent.

**Overall Assessment:**

Ligand A is superior due to its lower TPSA, lower DILI risk, and significantly better microsomal clearance. While Ligand B has a slightly better logP and in vitro half-life, the advantages of Ligand A in TPSA, DILI, and clearance are more important, especially considering the GPCR-specific priorities. The poor Caco-2 and solubility are concerning for both, but can potentially be addressed through formulation strategies. The equal BBB values are not decisive.

Output:
0
2025-04-17 05:46:28,370 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (356.4 and 343.4 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (96.7) is slightly higher than Ligand B (90.99). Both are below the 90 A^2 threshold desirable for CNS targets, which is good.

**logP:** Ligand A (0.313) is lower than the optimal 1-3 range, potentially hindering permeation. Ligand B (1.339) is within the optimal range. This favors Ligand B.

**H-Bond Donors/Acceptors:** Ligand A (2 HBD, 6 HBA) and Ligand B (3 HBD, 7 HBA) both have reasonable numbers of H-bond donors and acceptors, well within the guidelines.

**QED:** Both ligands have good QED scores (0.696 and 0.754), indicating good drug-like properties.

**DILI:** Ligand A (28.9%) has a significantly lower DILI risk than Ligand B (43.7%). This is a substantial advantage for Ligand A.

**BBB:** Ligand A (78.5%) has a better BBB penetration score than Ligand B (61.8%). This is crucial for a CNS target like DRD2 and strongly favors Ligand A.

**Caco-2 Permeability:** Ligand A (-4.872) has worse Caco-2 permeability than Ligand B (-5.461). Both are negative, indicating poor permeability, but B is slightly better.

**Aqueous Solubility:** Both ligands have very poor aqueous solubility (-2.079 and -1.682). This is a concern for both, but not a deciding factor.

**hERG Inhibition:** Ligand A (0.305) has a lower hERG inhibition liability than Ligand B (0.795), indicating a lower risk of cardiotoxicity. This favors Ligand A.

**Microsomal Clearance:** Ligand A (6.125) has a higher microsomal clearance than Ligand B (2.126), meaning it's less metabolically stable. This favors Ligand B.

**In vitro Half-Life:** Ligand A (7.904) has a slightly longer half-life than Ligand B (-0.184).

**P-gp Efflux:** Ligand A (0.027) has significantly lower P-gp efflux liability than Ligand B (0.01). Lower efflux is better, especially for CNS targets, and favors Ligand A.

**Binding Affinity:** Ligand B (-8.1 kcal/mol) has a stronger binding affinity than Ligand A (-7.5 kcal/mol). This is a 0.6 kcal/mol difference, which is significant, and is the biggest advantage for Ligand B.

**Overall Assessment:**

Ligand B has a better binding affinity and logP, and lower clearance. However, Ligand A has significantly better BBB penetration, lower DILI risk, lower hERG inhibition, and lower P-gp efflux. Given that this is a CNS target, BBB penetration and minimizing off-target effects (DILI, hERG) are paramount. The 0.6 kcal/mol difference in binding affinity, while significant, can potentially be optimized in later stages of drug development. The improved ADME properties of Ligand A, particularly its BBB score, make it the more promising candidate.

Output:
1
2025-04-17 05:46:28,371 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (348.487 and 364.921 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (67.43) is slightly above the optimal <90 for CNS targets, but still reasonable. Ligand B (54.18) is well within the desired range.

**3. logP:** Both ligands have good logP values (3.911 and 3.755), falling within the 1-3 range.

**4. H-Bond Donors:** Ligand A (2) and Ligand B (1) both meet the HBD <=5 criteria.

**5. H-Bond Acceptors:** Ligand A (3) and Ligand B (5) both meet the HBA <=10 criteria.

**6. QED:** Both ligands have acceptable QED values (0.673 and 0.736), indicating good drug-likeness.

**7. DILI:** Ligand A (39.589) has a slightly higher DILI risk than Ligand B (15.781), but both are below the concerning threshold of 60.

**8. BBB:** This is a critical parameter for a CNS target like DRD2. Ligand A (69.446) has a good BBB percentile, exceeding the 70% threshold. Ligand B (52.579) is significantly lower, which is a major drawback.

**9. Caco-2:** Ligand A (-4.506) and Ligand B (-5.108) both have negative Caco-2 values, which is unusual and suggests poor permeability. However, these values are on a scale where negative values are possible, and direct comparison is difficult without knowing the scale's specifics.

**10. Solubility:** Ligand A (-4.256) and Ligand B (-2.498) both have negative solubility values, which is also unusual and suggests poor solubility. Again, the scale is unknown.

**11. hERG:** Both ligands show low hERG inhibition liability (0.83 and 0.88), which is favorable.

**12. Cl_mic:** Ligand B (25.374) has a much lower microsomal clearance than Ligand A (87.009), indicating better metabolic stability.

**13. t1/2:** Ligand B (65.372) has a significantly longer in vitro half-life than Ligand A (17.757), which is a positive attribute.

**14. Pgp:** Both ligands have low P-gp efflux liability (0.354 and 0.482), which is good for CNS penetration.

**15. Binding Affinity:** Ligand B (-6.6 kcal/mol) has a stronger binding affinity than Ligand A (-8.4 kcal/mol). This is a substantial difference (1.8 kcal/mol), and a stronger affinity can often outweigh minor ADME concerns.

**Overall Assessment:**

While Ligand B has superior metabolic stability (lower Cl_mic, longer t1/2) and a stronger binding affinity, Ligand A's significantly better BBB penetration is a decisive advantage for a CNS-targeted DRD2 ligand. The negative Caco-2 and solubility values are concerning for both, but the BBB is paramount. The slightly higher DILI risk for Ligand A is acceptable given its superior BBB.

Output:
0
2025-04-17 05:46:28,371 - INFO - Reasoning:

Let's analyze Ligand A and Ligand B based on the provided guidelines, prioritizing GPCR-specific properties (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (369.868 and 352.395 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (71.09) is excellent for CNS penetration, well below the 90 A^2 threshold. Ligand B (109.66) is higher, but still potentially acceptable, though less ideal.

**logP:** Ligand A (3.278) is within the optimal 1-3 range. Ligand B (-1.266) is significantly lower, which is a concern for permeability and CNS penetration.

**H-Bond Donors/Acceptors:** Ligand A (2 HBD, 3 HBA) and Ligand B (1 HBD, 7 HBA) both fall within acceptable limits (<=5 HBD, <=10 HBA).

**QED:** Both ligands have similar QED values (0.701 and 0.684), indicating good drug-likeness.

**DILI:** Ligand A (40.054) has a slightly better DILI score than Ligand B (64.366), indicating lower potential for liver injury.

**BBB:** Ligand A (83.831) has a significantly higher BBB percentile than Ligand B (49.128). This is a *critical* advantage for a CNS target like DRD2.

**Caco-2 Permeability:** Both have negative values, which is unusual. Assuming these are logP-like scales, lower values indicate poorer permeability. Ligand A (-4.666) is worse than Ligand B (-4.952).

**Aqueous Solubility:** Both have negative values, indicating poor solubility. Ligand A (-4.002) is slightly better than Ligand B (-0.527).

**hERG:** Both ligands have very low hERG inhibition liability (0.381 and 0.059), which is excellent.

**Microsomal Clearance:** Ligand A (39.138) has higher microsomal clearance than Ligand B (11.585), suggesting faster metabolism and potentially lower in vivo exposure.

**In vitro Half-Life:** Ligand A (18.46) has a longer half-life than Ligand B (2.13), which is favorable.

**P-gp Efflux:** Ligand A (0.161) has lower P-gp efflux liability than Ligand B (0.014), which is beneficial for CNS exposure.

**Binding Affinity:** Both ligands have excellent binding affinities (-7.7 and -7.5 kcal/mol). The difference of 0.2 kcal/mol is not substantial enough to outweigh other significant differences.

**Overall Assessment:**

Ligand A is the stronger candidate. While its Caco-2 permeability is worse, its superior BBB penetration, better DILI score, lower P-gp efflux, and longer half-life are crucial advantages for a CNS-targeting GPCR. Ligand B's low logP is a major drawback, likely hindering both permeability and BBB penetration.



Output:
1
2025-04-17 05:46:28,371 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (368.46 and 360.52 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (101.49) is higher than the preferred <90 for CNS targets, but not drastically so. Ligand B (53.33) is well within the ideal range. This favors Ligand B.

**logP:** Ligand A (1.153) is within the optimal 1-3 range. Ligand B (4.148) is slightly above, potentially leading to solubility issues or off-target interactions, but still acceptable.

**H-Bond Donors/Acceptors:** Ligand A has 1 HBD and 7 HBA, which are reasonable. Ligand B has 0 HBD and 4 HBA, also reasonable.

**QED:** Both ligands have good QED scores (0.618 and 0.766), indicating good drug-like properties.

**DILI:** Ligand A (56.73) has a higher DILI risk than Ligand B (20.67). This favors Ligand B.

**BBB:** Ligand B (83.17) has significantly better predicted BBB penetration than Ligand A (54.25). This is a *critical* advantage for a CNS target like DRD2.

**Caco-2 Permeability:** Ligand A (-5.021) and Ligand B (-4.878) both have negative values, indicating poor permeability.

**Aqueous Solubility:** Both ligands have poor aqueous solubility (-2.127 and -3.701 respectively).

**hERG Inhibition:** Ligand A (0.03) has a very low hERG risk, which is excellent. Ligand B (0.668) has a slightly higher, but still relatively low, hERG risk.

**Microsomal Clearance:** Ligand A (32.39) has lower microsomal clearance, suggesting better metabolic stability than Ligand B (77.03).

**In vitro Half-Life:** Ligand A (-9.178) has a negative half-life, which is concerning. Ligand B (4.665) has a positive half-life, indicating better stability.

**P-gp Efflux:** Ligand A (0.034) has very low P-gp efflux, which is highly desirable for CNS penetration. Ligand B (0.627) has a higher, but still acceptable, P-gp efflux.

**Binding Affinity:** Ligand B (-7.8) has a slightly stronger binding affinity than Ligand A (-7.6), although the difference is relatively small.

**Overall Assessment:**

Ligand B is the stronger candidate. While Ligand A has a better hERG profile and lower Cl_mic, Ligand B excels in the most critical areas for a CNS GPCR target: BBB penetration and DILI risk. The slightly better affinity of Ligand B further supports this conclusion. The TPSA of Ligand B is also significantly better than that of Ligand A.



Output:
1
2025-04-17 05:46:28,371 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (340.423 and 364.471 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (71.34) is significantly better than Ligand B (92.57). For CNS targets, we want TPSA <= 90, so Ligand A is preferable.

**logP:** Both ligands have acceptable logP values (2.936 and 1.562), falling within the 1-3 range. Ligand A is slightly better.

**H-Bond Donors/Acceptors:** Both have 2 HBDs, which is good. Ligand A has 3 HBAs, while Ligand B has 5. Lower HBA is generally preferred, giving a slight edge to Ligand A.

**QED:** Both ligands have similar, good QED values (0.761 and 0.78), indicating good drug-like properties.

**DILI:** Ligand A (39.899) has a lower DILI risk than Ligand B (64.676). This is a significant advantage for Ligand A.

**BBB:** Ligand A (69.833) has a better BBB penetration percentile than Ligand B (59.403). While >70 is desirable, Ligand A is closer and thus preferred for a CNS target.

**Caco-2 Permeability:** Both have negative values, indicating poor permeability. Ligand A (-4.808) is slightly better than Ligand B (-5.091), but both are concerning.

**Aqueous Solubility:** Both have negative values, indicating poor solubility. Ligand A (-2.612) is slightly better than Ligand B (-3.548).

**hERG:** Both ligands have low hERG inhibition liability (0.642 and 0.431), which is good.

**Microsomal Clearance:** Ligand A (24.834) has significantly lower microsomal clearance than Ligand B (48.142), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (38.13) has a much longer half-life than Ligand B (-26.729). This is a major advantage for Ligand A.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.352 and 0.031). Ligand B is slightly better.

**Binding Affinity:** Both ligands have very similar and strong binding affinities (-9.5 and -9.2 kcal/mol). The difference is negligible.

**Overall Assessment:**

Ligand A consistently outperforms Ligand B in most crucial ADME properties, especially BBB, DILI, microsomal clearance, and half-life. While both have poor Caco-2 and solubility, the other benefits of Ligand A outweigh these drawbacks, particularly for a CNS target like DRD2. The similar binding affinities make the ADME profile the deciding factor.

Output:
1
2025-04-17 05:46:28,372 - INFO - Batch 226 complete. Total preferences: 3616
2025-04-17 05:46:28,372 - INFO - Processing batch 227/512...
2025-04-17 05:47:17,481 - INFO - Reasoning:

Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (341.386 and 354.523 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (71.09) is significantly better than Ligand B (41.91). For a CNS target like DRD2, a TPSA <= 90 is desirable, and Ligand A is closer to the optimal range for CNS penetration.

**3. logP:** Both ligands have acceptable logP values (2.438 and 3.981, respectively), falling within the 1-3 range. Ligand B is slightly higher, which *could* pose a minor solubility issue, but is not a major concern.

**4. H-Bond Donors:** Ligand A has 2 HBD, and Ligand B has 0. Both are within the acceptable limit of <=5.

**5. H-Bond Acceptors:** Ligand A has 3 HBA, and Ligand B has 5. Both are within the acceptable limit of <=10.

**6. QED:** Both ligands have reasonable QED values (0.848 and 0.752), indicating good drug-like properties.

**7. DILI:** Both ligands have low DILI risk (50.058 and 40.016 percentile), which is favorable.

**8. BBB:** Both ligands show good BBB penetration (83.249 and 81.621 percentile), which is crucial for a CNS target. Ligand A is slightly better.

**9. Caco-2 Permeability:** Ligand A (-4.698) has poor Caco-2 permeability, while Ligand B (-5.421) also has poor Caco-2 permeability. This is a concern for both, but the values are similar.

**10. Aqueous Solubility:** Both ligands have poor aqueous solubility (-3.675 and -3.028). This could present formulation challenges.

**11. hERG Inhibition:** Both ligands have low hERG inhibition risk (0.257 and 0.805 percentile), which is excellent.

**12. Microsomal Clearance:** Ligand A has lower microsomal clearance (37.217 mL/min/kg) than Ligand B (65.521 mL/min/kg), suggesting better metabolic stability.

**13. In vitro Half-Life:** Ligand A has a negative half-life (-20.1 hours), which is not physically possible and indicates a data error or unusual behavior. Ligand B has a more reasonable half-life of 12.168 hours.

**14. P-gp Efflux:** Both ligands have low P-gp efflux liability (0.108 and 0.495 percentile), which is good for CNS exposure.

**15. Binding Affinity:** Ligand B (-7.5 kcal/mol) has a significantly better binding affinity than Ligand A (-9.4 kcal/mol). A >1.5 kcal/mol advantage in binding is considered substantial.

**Overall Assessment:**

While Ligand A has a slightly better TPSA and BBB penetration, the negative in vitro half-life is a critical flaw. The significantly stronger binding affinity of Ligand B (-7.5 vs -9.4 kcal/mol) outweighs the slightly higher logP and worse TPSA. The better half-life of Ligand B is also a major advantage. The poor Caco-2 and solubility are concerns for both, but can be addressed with formulation strategies.

Output:
1
2025-04-17 05:47:17,481 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (353.507 and 351.491 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (53.09) is significantly better than Ligand B (70.67). For CNS targets, we want TPSA <= 90, and A is much closer to the preferred <=60 range. B is approaching a less desirable range.

**3. logP:** Both ligands have acceptable logP values (1.737 and 1.154), falling within the 1-3 optimal range.

**4. H-Bond Donors:** Ligand A (0) is preferable to Ligand B (2). Fewer HBDs generally improve permeability.

**5. H-Bond Acceptors:** Both ligands have 4 HBA, which is acceptable (<=10).

**6. QED:** Both ligands have similar QED values (0.7 and 0.58), both above the 0.5 threshold, indicating good drug-likeness.

**7. DILI:** Ligand A (10.392) has a much lower DILI risk than Ligand B (5.545), indicating a safer profile. Both are below the 40 threshold.

**8. BBB:** Ligand A (77.2) has a significantly higher BBB penetration percentile than Ligand B (54.983). This is *critical* for a CNS target like DRD2. A is approaching the desirable >70 range, while B is below.

**9. Caco-2 Permeability:** Ligand A (-4.398) is better than Ligand B (-5.228), indicating better intestinal absorption.

**10. Aqueous Solubility:** Ligand A (-0.521) is better than Ligand B (-0.842), indicating better solubility.

**11. hERG Inhibition:** Both ligands have similar, low hERG inhibition liability (0.384 and 0.492).

**12. Microsomal Clearance:** Ligand B (-8.58) has a *negative* clearance, which is unusual and likely an error in the data. Ligand A (27.887) is more reasonable. Lower clearance is better, suggesting greater metabolic stability.

**13. In vitro Half-Life:** Ligand B (8.37) has a longer half-life than Ligand A (-9.224). However, the negative value for A is suspect.

**14. P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.05 and 0.042), which is good.

**15. Binding Affinity:** Both ligands have very similar and excellent binding affinities (-7.5 and -7.0 kcal/mol). The difference is less than 1.5 kcal/mol, so it's not a deciding factor.

**Overall Assessment:**

Ligand A is clearly superior. It has a lower TPSA, lower DILI risk, significantly better BBB penetration, better Caco-2 permeability, and better aqueous solubility. While Ligand B has a slightly longer half-life, the negative value for A's half-life is suspect, and the other advantages of A outweigh this. The negative clearance value for B is a major red flag. Given the GPCR-specific priorities, particularly BBB penetration for a CNS target, Ligand A is the much more promising candidate.

Output:
1
2025-04-17 05:47:17,482 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (370.45 and 389.905 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (95.42) is better than Ligand B (108.39). Both are below the 140 A^2 threshold for oral absorption, but Ligand A is closer to the desirable <90 A^2 for CNS targets.

**3. logP:** Both ligands have acceptable logP values (1.068 and 1.914), falling within the 1-3 range.

**4. H-Bond Donors:** Ligand A (2) is preferable to Ligand B (3). Lower HBD generally improves permeability.

**5. H-Bond Acceptors:** Ligand A (6) is preferable to Ligand B (5).

**6. QED:** Ligand A (0.808) has a significantly better QED score than Ligand B (0.66), indicating a more drug-like profile.

**7. DILI:** Ligand A (51.725) has a lower DILI risk than Ligand B (55.021), though both are reasonably acceptable.

**8. BBB:** Ligand A (63.746) has a significantly better BBB penetration percentile than Ligand B (32.726). This is *crucial* for a CNS target like DRD2.

**9. Caco-2 Permeability:** Both have negative values, which is unusual. Assuming these are logP-scale values, lower values indicate lower permeability. Ligand A (-5.049) is slightly better than Ligand B (-5.187).

**10. Aqueous Solubility:** Both ligands have very poor aqueous solubility (-2.443 and -3.891). This is a concern, but can sometimes be mitigated with formulation strategies.

**11. hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.203 and 0.2).

**12. Microsomal Clearance:** Ligand A (0.922) has much lower microsomal clearance than Ligand B (31.967), indicating better metabolic stability.

**13. In vitro Half-Life:** Ligand A (-3.516) has a much longer in vitro half-life than Ligand B (-45.456).

**14. P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.071 and 0.026).

**15. Binding Affinity:** Both ligands have similar, strong binding affinities (-8.8 and -8.6 kcal/mol). The difference is less than the 1.5 kcal/mol threshold.

**Overall Assessment:**

Ligand A is significantly better than Ligand B. While both have good binding affinity, Ligand A excels in crucial ADME properties for a CNS-targeting GPCR: significantly better BBB penetration, lower microsomal clearance, longer half-life, and a higher QED score. The slightly better TPSA and H-bond characteristics also contribute to its favorability. The poor aqueous solubility is a concern for both, but the other advantages of Ligand A outweigh this drawback.

Output:
1
2025-04-17 05:47:17,482 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (404.308 Da) is slightly higher than Ligand B (367.515 Da), but both are acceptable.

**2. TPSA:** Ligand A (56.15) is significantly better than Ligand B (78.51). For CNS targets, we want TPSA <= 90, and ideally closer to 60. Ligand A is much closer to this ideal.

**3. logP:** Ligand A (3.725) is optimal, while Ligand B (1.896) is a bit low. A logP between 1-3 is preferred, and Ligand B is at the lower end, potentially hindering permeability.

**4. H-Bond Donors:** Both ligands have acceptable HBD counts (Ligand A: 1, Ligand B: 2), well below the threshold of 5.

**5. H-Bond Acceptors:** Both ligands have acceptable HBA counts (Ligand A: 4, Ligand B: 4), well below the threshold of 10.

**6. QED:** Both ligands have similar and good QED values (Ligand A: 0.827, Ligand B: 0.805), indicating good drug-like properties.

**7. DILI:** Both ligands have acceptable DILI risk (Ligand A: 53.548, Ligand B: 43.971), both below the 60 threshold.

**8. BBB:** Both ligands have good BBB penetration (Ligand A: 65.529, Ligand B: 61.846), but Ligand A is slightly better. For CNS targets, >70 is desirable, but both are reasonably good.

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 values, which is unusual and suggests a potential issue with the data. However, since both are similarly negative, this doesn't differentiate them.

**10. Aqueous Solubility:** Both ligands have negative solubility values, again suggesting a data issue. Similar to Caco-2, this doesn't help differentiate.

**11. hERG Inhibition:** Both ligands have very low hERG inhibition risk (Ligand A: 0.329, Ligand B: 0.292).

**12. Microsomal Clearance:** Ligand B (32.855) has significantly lower microsomal clearance than Ligand A (81.022), indicating better metabolic stability.

**13. In vitro Half-Life:** Ligand B (-17.249) has a negative half-life, which is impossible and indicates a data issue. Ligand A (42.928) has a reasonable half-life.

**14. P-gp Efflux:** Both ligands have low P-gp efflux liability (Ligand A: 0.677, Ligand B: 0.082). Ligand B is slightly better.

**15. Binding Affinity:** Both ligands have very similar and excellent binding affinities (Ligand A: -8.2 kcal/mol, Ligand B: -8.3 kcal/mol). The difference is negligible.

**Overall Assessment:**

Considering the GPCR-specific priorities, Ligand A is the better candidate. It has a more optimal logP, significantly lower TPSA, and a reasonable half-life. While Ligand B has better metabolic stability (lower Cl_mic) and slightly lower P-gp efflux, the TPSA and logP advantages of Ligand A are more crucial for CNS penetration and target engagement. The negative values for Caco-2 and solubility are concerning for both, but don't clearly favor one over the other. The negative half-life for Ligand B is a major red flag.

Output:
1
2025-04-17 05:47:17,482 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (346.431 and 346.439 Da) fall comfortably within the ideal 200-500 Da range.

**2. TPSA:** Both ligands have TPSA values (94.56 and 95.57) slightly above the optimal <90 for CNS targets, but still reasonable.

**3. logP:** Ligand A (0.784) is a bit low, potentially hindering permeability. Ligand B (1.107) is better, falling within the optimal 1-3 range.

**4. H-Bond Donors:** Ligand A (3) is acceptable. Ligand B (1) is even better, minimizing potential permeability issues.

**5. H-Bond Acceptors:** Ligand A (5) is acceptable. Ligand B (9) is at the upper limit but still within the acceptable range.

**6. QED:** Both ligands have good QED scores (0.605 and 0.75), indicating drug-like properties.

**7. DILI:** Ligand A (33.579) has a significantly lower DILI risk than Ligand B (63.048), which is a strong advantage.

**8. BBB:** Ligand B (65.607) has a considerably better BBB penetration percentile than Ligand A (27.608). This is *critical* for a CNS target like DRD2.

**9. Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and suggests poor permeability. However, these values are on a scale where negative values are possible.

**10. Aqueous Solubility:** Both have negative solubility values, also unusual.

**11. hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.159 and 0.056).

**12. Microsomal Clearance:** Ligand A (-16.376) has a much lower (better) microsomal clearance than Ligand B (25.165), indicating better metabolic stability.

**13. In vitro Half-Life:** Ligand A (11.513) has a longer half-life than Ligand B (7.287).

**14. P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.007 and 0.093).

**15. Binding Affinity:** Ligand A (-7.6 kcal/mol) has a slightly better binding affinity than Ligand B (-6.9 kcal/mol), a difference of 0.7 kcal/mol.

**Overall Assessment:**

While Ligand A has better metabolic stability (lower Cl_mic, longer t1/2), lower DILI risk, and slightly better affinity, Ligand B *significantly* outperforms it in BBB penetration (65.607 vs 27.608). For a CNS target like DRD2, BBB penetration is paramount. The 0.7 kcal/mol difference in affinity can likely be overcome with further optimization, but improving BBB penetration is much more challenging. The slightly better logP of Ligand B also contributes to better potential permeability.

Output:
1
2025-04-17 05:47:17,482 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 drug candidates, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (357.405 and 337.402 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (80.12) is better than Ligand B (64.84). Both are below the 90 A^2 threshold for CNS targets, which is excellent.

**3. logP:** Ligand A (1.111) is within the optimal 1-3 range. Ligand B (3.331) is at the higher end of optimal, but still acceptable.

**4. H-Bond Donors:** Both ligands have 1 HBD, which is within the acceptable limit of <=5.

**5. H-Bond Acceptors:** Both ligands have 5 HBA, which is within the acceptable limit of <=10.

**6. QED:** Ligand B (0.927) has a significantly higher QED score than Ligand A (0.718), indicating better overall drug-likeness.

**7. DILI:** Ligand A (30.244) has a much lower DILI risk than Ligand B (63.862). This is a significant advantage for Ligand A.

**8. BBB:** Ligand B (91.392) has a substantially higher BBB penetration percentile than Ligand A (79.682). This is a critical advantage for a CNS target like DRD2.

**9. Caco-2 Permeability:** Ligand A (-5.012) and Ligand B (-4.872) both have negative values, suggesting poor permeability. This is concerning, but not a dealbreaker if other properties are strong.

**10. Aqueous Solubility:** Ligand A (-2.166) and Ligand B (-4.866) both have negative values, suggesting poor solubility. This is also concerning.

**11. hERG Inhibition:** Ligand A (0.176) has a lower hERG inhibition liability than Ligand B (0.973), indicating a lower risk of cardiotoxicity.

**12. Microsomal Clearance:** Ligand B (72.795) has a much higher microsomal clearance than Ligand A (4.727), meaning it's metabolized more quickly and has lower metabolic stability.

**13. In vitro Half-Life:** Ligand A (3.674) has a shorter half-life than Ligand B (22.693).

**14. P-gp Efflux:** Ligand A (0.013) has a significantly lower P-gp efflux liability than Ligand B (0.34), which is beneficial for CNS exposure.

**15. Binding Affinity:** Ligand B (-8.6 kcal/mol) has a stronger binding affinity than Ligand A (-7.0 kcal/mol). This is a substantial advantage, exceeding the 1.5 kcal/mol threshold.

**Overall Assessment:**

Ligand B excels in BBB penetration and binding affinity, both crucial for a CNS GPCR target. However, it suffers from higher DILI risk, higher P-gp efflux, and faster metabolic clearance. Ligand A has a better safety profile (lower DILI, hERG, and P-gp) and better metabolic stability, but its BBB penetration and binding affinity are weaker.

Given the importance of strong binding affinity for GPCRs, and the relatively high BBB score of Ligand A (still >70), I believe **Ligand B** is the more promising candidate, despite its drawbacks. The affinity difference is substantial enough to potentially overcome the ADME liabilities through further optimization.

Output:
1
2025-04-17 05:47:17,483 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (340.354 Da and 353.507 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (82.19) is better than Ligand B (53.09). For CNS targets, we want TPSA <= 90, both are within this range, but A is closer to the upper limit.

**3. logP:** Ligand A (3.286) is optimal (1-3), while Ligand B (1.593) is on the lower end. Lower logP can hinder permeation.

**4. H-Bond Donors:** Ligand A (3) is acceptable (<=5), and Ligand B (0) is also good.

**5. H-Bond Acceptors:** Ligand A (2) is good (<=10), and Ligand B (4) is also acceptable.

**6. QED:** Both ligands have good QED values (0.666 and 0.728, both >= 0.5).

**7. DILI:** Ligand A (95.58) has a very high DILI risk, which is a major concern. Ligand B (11.206) has a very low DILI risk, which is excellent.

**8. BBB:** Ligand B (81.582) has a significantly better BBB penetration percentile than Ligand A (34.161). This is *critical* for a CNS target like DRD2.

**9. Caco-2:** Ligand A (-5.157) and Ligand B (-4.326) both have negative values, indicating poor permeability.

**10. Solubility:** Ligand A (-5.035) and Ligand B (-0.683) both have negative values, indicating poor solubility.

**11. hERG:** Ligand A (0.273) and Ligand B (0.414) both have low hERG inhibition liability, which is good.

**12. Cl_mic:** Ligand B (33.526) has a lower microsomal clearance than Ligand A (14.754), suggesting better metabolic stability.

**13. t1/2:** Ligand A (6.137) has a slightly better in vitro half-life than Ligand B (-17.99). However, the negative value for Ligand B is concerning and likely an error or indicates very rapid degradation.

**14. Pgp:** Ligand A (0.135) has lower P-gp efflux liability than Ligand B (0.052), which is favorable for CNS penetration.

**15. Binding Affinity:** Ligand A (-10.2 kcal/mol) has a significantly stronger binding affinity than Ligand B (-7.5 kcal/mol). This is a substantial advantage.

**Overall Assessment:**

Despite the superior binding affinity of Ligand A, its extremely high DILI risk and poor BBB penetration make it a very unfavorable candidate. Ligand B, while having a weaker binding affinity, exhibits a much better safety profile (low DILI), significantly improved BBB penetration, and better metabolic stability. For a CNS target like DRD2, BBB penetration and safety are paramount. The difference in affinity, while notable, can potentially be overcome with further optimization of Ligand B. The negative half-life for Ligand B is a red flag, but the other properties strongly favor it.

Output:
1
2025-04-17 05:47:17,483 - INFO - Reasoning:

Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (353.467 and 346.427 Da) fall comfortably within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (107.4) is slightly higher than Ligand B (80.57). For CNS targets, we prefer TPSA <= 90. Ligand B is better here.

**3. logP:** Both ligands have good logP values (2.634 and 2.287), falling within the optimal 1-3 range.

**4. H-Bond Donors:** Ligand A (1) and Ligand B (2) are both acceptable, being <=5.

**5. H-Bond Acceptors:** Both ligands have 4 H-bond acceptors, well within the acceptable limit of <=10.

**6. QED:** Both ligands have similar QED values (0.391 and 0.408), indicating moderate drug-likeness. Improvement is possible, but not a deciding factor.

**7. DILI:** Ligand A (19.659) has a significantly lower DILI risk than Ligand B (33.695). This is a substantial advantage for Ligand A.

**8. BBB:** Ligand A (70.609) has a much better BBB penetration percentile than Ligand B (56.805). This is *critical* for a CNS target like DRD2.

**9. Caco-2 Permeability:** Ligand A (-4.578) and Ligand B (-5.011) both have negative Caco-2 values, which is unusual and suggests poor permeability. However, the scale isn't clearly defined, so we'll consider this a neutral point.

**10. Aqueous Solubility:** Both ligands have very poor aqueous solubility (-1.846 and -1.986). This is a concern, but can potentially be addressed with formulation strategies.

**11. hERG Inhibition:** Both ligands show low hERG inhibition risk (0.209 and 0.288), which is good.

**12. Microsomal Clearance:** Ligand A (42.355) has a higher microsomal clearance than Ligand B (32.158), suggesting lower metabolic stability.

**13. In vitro Half-Life:** Ligand B (14.152) has a significantly longer in vitro half-life than Ligand A (-0.081). This is a significant advantage for Ligand B.

**14. P-gp Efflux:** Both ligands have low P-gp efflux liability (0.007 and 0.159), which is favorable for CNS penetration.

**15. Binding Affinity:** Ligand B (-8.2 kcal/mol) has a significantly stronger binding affinity than Ligand A (-6.8 kcal/mol). This is a 1.4 kcal/mol difference, which is substantial and can outweigh some ADME drawbacks.

**Overall Assessment:**

While Ligand A has better DILI and BBB penetration, the significantly stronger binding affinity of Ligand B (-8.2 vs -6.8 kcal/mol) is a major advantage, especially for a GPCR target. The longer half-life of Ligand B is also beneficial. The slightly higher DILI and lower BBB of Ligand B are less concerning given the potency advantage. Both have poor solubility, which is a formulation challenge.

Output:
1
2025-04-17 05:47:17,483 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (386.455 and 366.487 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (133.38) is slightly above the optimal <90 for CNS targets, but still reasonable. Ligand B (91.4) is excellent, well within the desired range.

**logP:** Ligand A (0.754) is a bit low, potentially hindering membrane permeability. Ligand B (2.732) is optimal.

**H-Bond Donors/Acceptors:** Both ligands have 2 HBD and a reasonable number of HBA (7 for A, 4 for B), satisfying the <5 HBD and <10 HBA guidelines.

**QED:** Both ligands have good QED scores (0.753 and 0.802, respectively), indicating drug-likeness.

**DILI:** Ligand A (97.867) has a concerningly high DILI risk. Ligand B (54.75) is much better, indicating a lower risk of liver injury.

**BBB:** Ligand A (39.473) has a very poor BBB penetration score, making it unlikely to effectively reach its CNS target. Ligand B (66.615) is better, but still not ideal (aim for >70).

**Caco-2 Permeability:** Ligand A (-5.158) has poor Caco-2 permeability. Ligand B (-4.608) is slightly better, but still low.

**Aqueous Solubility:** Both ligands have very poor aqueous solubility (-2.414 and -4.242). This could pose formulation challenges.

**hERG Inhibition:** Both ligands show very low hERG inhibition risk (0.054 and 0.24).

**Microsomal Clearance:** Ligand A (1.039) has lower microsomal clearance, suggesting better metabolic stability. Ligand B (56.38) has high clearance, indicating faster metabolism.

**In vitro Half-Life:** Ligand A (25.88 hours) has a better in vitro half-life than Ligand B (-7.472 hours).

**P-gp Efflux:** Both ligands show low P-gp efflux liability (0.105 and 0.089).

**Binding Affinity:** Ligand B (-9.6 kcal/mol) has a significantly stronger binding affinity than Ligand A (-8.2 kcal/mol). This >1.5 kcal/mol difference is substantial and can outweigh some ADME drawbacks.

**Overall Assessment:**

Ligand A suffers from a very poor BBB score and high DILI risk, making it a less attractive candidate despite its reasonable metabolic stability and half-life. Ligand B, while having lower metabolic stability and a less-than-ideal BBB score, possesses a significantly stronger binding affinity, a much lower DILI risk, and a more optimal logP. Given the GPCR-specific priorities, the strong affinity of Ligand B is a major advantage. While the BBB score isn't optimal, it's better than Ligand A's, and further optimization could potentially improve it.



Output:
1
2025-04-17 05:47:17,483 - INFO - Okay, let's analyze these two ligands for their potential as DRD2 drug candidates. DRD2 is a GPCR in the CNS, so BBB penetration, logP, Pgp efflux, TPSA, and binding affinity are paramount.

**Ligand A: [397.777, 55.4, 3.697, 1, 3, 0.756, 89.415, 56.65, -4.79, -5.46, 0.797, 64.643, -16.56, 0.283, -9.2]**

*   **MW:** 397.777 Da - Good, within the ideal range.
*   **TPSA:** 55.4 A<sup>2</sup> - Acceptable, but pushing the upper limit for CNS targets.
*   **logP:** 3.697 - Excellent, within the optimal range.
*   **HBD:** 1 - Good.
*   **HBA:** 3 - Good.
*   **QED:** 0.756 - Excellent, highly drug-like.
*   **DILI:** 89.415 - High risk of liver injury. This is a significant concern.
*   **BBB:** 56.65 - Moderate, below the desirable >70% for CNS targets.
*   **Caco-2:** -4.79 - Very poor permeability.
*   **Solubility:** -5.46 - Very poor solubility.
*   **hERG:** 0.797 - Low risk, good.
*   **Cl_mic:** 64.643 mL/min/kg - Moderate clearance, not ideal.
*   **t1/2:** -16.56 hours - Very short half-life.
*   **Pgp:** 0.283 - Low efflux, good.
*   **Affinity:** -9.2 kcal/mol - Excellent, very strong binding.

**Ligand B: [346.471, 49.85, 2.365, 0, 3, 0.385, 31.059, 69.794, -4.519, -2.195, 0.415, 26.288, 8.515, 0.286, 0]**

*   **MW:** 346.471 Da - Good, within the ideal range.
*   **TPSA:** 49.85 A<sup>2</sup> - Excellent, well within the ideal range for CNS targets.
*   **logP:** 2.365 - Good, within the optimal range.
*   **HBD:** 0 - Good.
*   **HBA:** 3 - Good.
*   **QED:** 0.385 - Moderate, less drug-like than Ligand A.
*   **DILI:** 31.059 - Low risk of liver injury.
*   **BBB:** 69.794 - Good, above the 70% threshold for CNS targets.
*   **Caco-2:** -4.519 - Very poor permeability.
*   **Solubility:** -2.195 - Poor solubility.
*   **hERG:** 0.415 - Low risk, good.
*   **Cl_mic:** 26.288 mL/min/kg - Low clearance, good metabolic stability.
*   **t1/2:** 8.515 hours - Moderate half-life.
*   **Pgp:** 0.286 - Low efflux, good.
*   **Affinity:** 0 kcal/mol - Very weak binding.

**Comparison & Decision:**

While Ligand A boasts a significantly superior binding affinity (-9.2 kcal/mol vs. 0 kcal/mol for Ligand B), its major drawbacks are the high DILI risk, poor Caco-2 permeability, and poor aqueous solubility. These factors would likely lead to significant development challenges. Ligand B, while having a very weak binding affinity, has a much better safety profile (low DILI), good BBB penetration, and acceptable logP and TPSA values. The poor permeability and solubility are still concerns, but potentially addressable through formulation strategies.

Given the GPCR-specific priorities and the critical importance of safety and CNS penetration for a DRD2 target, **Ligand B** is the more promising starting point, despite its weak binding affinity. The affinity can be optimized through further medicinal chemistry efforts, while mitigating the severe liabilities of Ligand A would be far more challenging.

1
2025-04-17 05:47:17,483 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (369.487 Da) is slightly higher than Ligand B (344.375 Da), but both are acceptable.

**TPSA:** Ligand A (80.76) is excellent for CNS penetration, being well below 90. Ligand B (124.16) is higher, but still potentially acceptable, though less ideal.

**logP:** Ligand A (3.297) is optimal. Ligand B (0.329) is quite low, potentially hindering membrane permeability and CNS entry.

**H-Bond Donors/Acceptors:** Ligand A (HBD=1, HBA=6) is favorable. Ligand B (HBD=3, HBA=7) is also acceptable, but slightly higher counts could impact permeability.

**QED:** Both ligands have good QED values (A: 0.746, B: 0.694), indicating good drug-like properties.

**DILI:** Ligand B (76.425) has a higher DILI risk than Ligand A (55.448), although both are moderate.

**BBB:** Ligand A (84.684) has a significantly better BBB percentile than Ligand B (58.317). This is a critical advantage for a CNS target like DRD2.

**Caco-2 Permeability:** Ligand A (-4.349) has a better Caco-2 permeability than Ligand B (-5.63), indicating better intestinal absorption.

**Aqueous Solubility:** Both have negative values, indicating low solubility. Ligand A (-3.553) is slightly better than Ligand B (-3.396).

**hERG Inhibition:** Both ligands have low hERG inhibition risk (A: 0.517, B: 0.227).

**Microsomal Clearance:** Ligand A (76.679) has higher microsomal clearance than Ligand B (27.73), indicating faster metabolism and potentially lower *in vivo* exposure.

**In vitro Half-Life:** Ligand B (-22.372) has a significantly longer in vitro half-life than Ligand A (31.112).

**P-gp Efflux:** Ligand A (0.261) has lower P-gp efflux than Ligand B (0.029), which is favorable for CNS penetration.

**Binding Affinity:** Ligand B (-8.8 kcal/mol) has a stronger binding affinity than Ligand A (-7.0 kcal/mol). This is a substantial advantage (1.8 kcal/mol difference).

**Overall Assessment:**

While Ligand B boasts a superior binding affinity, Ligand A is the more promising candidate overall. The critical factors for a CNS GPCR target are BBB penetration, logP, and P-gp efflux. Ligand A significantly outperforms Ligand B in BBB (84.684 vs 58.317) and P-gp efflux (0.261 vs 0.029), and has a more optimal logP (3.297 vs 0.329). The stronger affinity of Ligand B might be overcome with further optimization, but the poor CNS penetration properties are a major hurdle. Ligand A's better ADME profile, particularly its BBB penetration, makes it the more viable starting point for drug development.

Output:
0
2025-04-17 05:47:17,484 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (366.393 and 367.515 Da) fall comfortably within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (75.19) is slightly higher than Ligand B (54.9). For a CNS target like DRD2, TPSA < 90 is preferred, so both are acceptable, but B is better.

**3. logP:** Both ligands have similar logP values (2.239 and 2.247), falling within the optimal 1-3 range.

**4. H-Bond Donors:** Ligand A has 1 HBD, while Ligand B has 0. Both are within the acceptable limit of <=5.

**5. H-Bond Acceptors:** Ligand A has 5 HBA, and Ligand B has 6. Both are within the acceptable limit of <=10.

**6. QED:** Ligand A (0.904) has a significantly higher QED than Ligand B (0.772), indicating a more drug-like profile.

**7. DILI:** Ligand A (76.154) has a higher DILI risk than Ligand B (28.693). This is a significant advantage for Ligand B.

**8. BBB:** Both ligands have excellent BBB penetration (84.451 and 84.606 percentile), exceeding the desirable >70 threshold for CNS targets.

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.803 and -4.478). This is unusual and suggests poor permeability. However, these values are on a scale where negative values are possible, and direct comparison is difficult without knowing the scale's specifics.

**10. Aqueous Solubility:** Both ligands have negative solubility values (-3.566 and -2.138). Similar to Caco-2, this is unusual and makes direct comparison difficult.

**11. hERG Inhibition:** Both ligands have low hERG inhibition risk (0.378 and 0.551).

**12. Microsomal Clearance:** Ligand A (4.239) has significantly lower microsomal clearance than Ligand B (56.695), suggesting better metabolic stability.

**13. In vitro Half-Life:** Ligand A (6.407) has a longer in vitro half-life than Ligand B (-3.645). This is a substantial advantage for Ligand A.

**14. P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.167 and 0.137), which is favorable for CNS penetration.

**15. Binding Affinity:** Ligand A (-9.1 kcal/mol) has a significantly stronger binding affinity than Ligand B (-6.6 kcal/mol). This is a >1.5 kcal/mol advantage, which can outweigh minor ADME drawbacks.

**Overall Assessment:**

Ligand A has a substantially better binding affinity and metabolic stability (lower Cl_mic, longer t1/2) and a higher QED. While Ligand B has a lower DILI risk, the superior affinity of Ligand A is a critical factor for a GPCR target, especially considering both ligands exhibit good BBB penetration. The negative Caco-2 and solubility values are concerning for both, but the strong binding of A makes it more likely to overcome these issues.

Output:
1
2025-04-17 05:47:17,484 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (348.451 and 360.483 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (105.28) is slightly above the optimal <90 for CNS targets, but still reasonable. Ligand B (86.88) is excellent, well below 90.

**logP:** Ligand A (-0.851) is a bit low, potentially hindering permeability. Ligand B (2.17) is within the optimal 1-3 range. This is a significant advantage for Ligand B.

**H-Bond Donors/Acceptors:** Both have 3 HBD and acceptable HBA counts (6 and 4 respectively).

**QED:** Both ligands have similar QED values (0.643 and 0.599), indicating good drug-likeness.

**DILI:** Ligand A (14.696) has a much lower DILI risk than Ligand B (36.293). This is a positive for Ligand A.

**BBB:** Ligand A (35.052) has a poor BBB percentile, while Ligand B (37.069) is only marginally better. Both are below the desirable >70 for CNS targets.

**Caco-2 Permeability:** Both have negative Caco-2 values (-6.026 and -5.948), which is unusual and suggests poor permeability.

**Aqueous Solubility:** Both have negative solubility values (-0.339 and -1.686), also unusual and indicating very low solubility.

**hERG Inhibition:** Both ligands show very low hERG inhibition risk (0.185 and 0.286).

**Microsomal Clearance:** Ligand A (-37.098) has a significantly lower (better) microsomal clearance than Ligand B (30.481), indicating greater metabolic stability.

**In vitro Half-Life:** Both have similar, short in vitro half-lives (2.082 and 2.039 hours).

**P-gp Efflux:** Both show very low P-gp efflux liability (0.004 and 0.071).

**Binding Affinity:** Ligand B (-8.3 kcal/mol) has a slightly better binding affinity than Ligand A (-7.9 kcal/mol), although the difference is not huge (0.4 kcal/mol).

**Overall Assessment:**

Considering the GPCR-specific priorities, Ligand B is more promising. While both have issues with Caco-2 and solubility, Ligand B has a much better logP value, which is crucial for CNS penetration. The slightly better binding affinity of Ligand B is also a plus. Ligand A has a lower DILI risk and better metabolic stability, but the poor logP and BBB penetration are significant drawbacks for a CNS target. The difference in affinity is not large enough to overcome the logP/BBB issues of Ligand A.

Output:
1
2025-04-17 05:47:17,484 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (381.301 Da) is slightly higher than Ligand B (350.419 Da), but both are acceptable.

**TPSA:** Ligand A (54.88) is excellent for CNS penetration, well below the 90 A^2 threshold. Ligand B (106.6) is higher, but still potentially acceptable, though less ideal.

**logP:** Ligand A (4.618) is a bit high, potentially leading to solubility issues and off-target effects. Ligand B (1.102) is quite low, which could hinder membrane permeability.

**H-Bond Donors/Acceptors:** Ligand A has 1 HBD and 4 HBA, which are within acceptable limits. Ligand B has 2 HBD and 4 HBA, also acceptable.

**QED:** Both ligands have good QED scores (Ligand A: 0.624, Ligand B: 0.846), indicating drug-like properties. Ligand B is slightly better here.

**DILI:** Ligand A has a DILI risk of 86.933, which is high and concerning. Ligand B has a much lower DILI risk of 38.154, which is good.

**BBB:** Ligand A has a BBB penetration of 87.321, which is excellent for a CNS target. Ligand B has a BBB penetration of 32.92, which is poor and a significant drawback.

**Caco-2 Permeability:** Ligand A (-4.853) and Ligand B (-5.085) both have negative values, which is unusual and suggests very poor permeability. However, the scale isn't specified, so it's hard to interpret.

**Aqueous Solubility:** Both ligands have very poor aqueous solubility (-4.841 and -1.571 respectively). This is a concern, especially given Ligand A's high logP.

**hERG Inhibition:** Ligand A (0.484) has a slightly higher hERG risk than Ligand B (0.02), but both are relatively low.

**Microsomal Clearance:** Ligand A (49.401) has moderate clearance, while Ligand B (-14.098) has negative clearance, which is unusual and potentially indicates very high metabolic stability.

**In vitro Half-Life:** Ligand A (33.404 hours) has a reasonable half-life. Ligand B (-32.263 hours) has a negative half-life, which is not physically possible and indicates a problem with the data.

**P-gp Efflux:** Ligand A (0.429) has moderate P-gp efflux, while Ligand B (0.004) has very low P-gp efflux, which is favorable for CNS penetration.

**Binding Affinity:** Ligand A (-10.5 kcal/mol) has significantly stronger binding affinity than Ligand B (-7.2 kcal/mol). This is a substantial advantage.

**Overall Assessment:**

Ligand A has a very strong binding affinity and good BBB penetration, but suffers from high DILI risk, high logP, and poor solubility. Ligand B has a better safety profile (lower DILI) and lower P-gp efflux, but its binding affinity is significantly weaker and its BBB penetration is poor. The negative values for Caco-2 and in vitro half-life for Ligand B are also concerning and suggest data quality issues.

Given the GPCR-specific priorities, BBB penetration is crucial for CNS targets. While Ligand A's DILI risk is concerning, the significantly stronger binding affinity (-10.5 vs -7.2 kcal/mol) and excellent BBB penetration make it the more promising candidate, *assuming* the DILI risk can be mitigated through structural modifications. The large affinity difference could outweigh the ADME drawbacks with further optimization.

Output:
1
2025-04-17 05:47:17,484 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (374.869 Da) is slightly higher than Ligand B (348.487 Da), but both are acceptable.

**TPSA:** Ligand A (99.77) is closer to the upper limit for CNS targets (<=90), but still reasonable. Ligand B (53.76) is excellent, well below the threshold.

**logP:** Ligand A (0.979) is a bit low, potentially hindering permeation. Ligand B (3.723) is optimal.

**H-Bond Donors:** Ligand A (3) is acceptable. Ligand B (0) is also good.

**H-Bond Acceptors:** Ligand A (4) is acceptable. Ligand B (3) is also good.

**QED:** Both ligands have good QED scores (A: 0.435, B: 0.719), suggesting drug-like properties. Ligand B is better.

**DILI:** Both ligands have low DILI risk (A: 27.181, B: 28.965), which is positive.

**BBB:** Ligand A (70.376) meets the desirable threshold (>70) for CNS targets. Ligand B (85.149) is even better.

**Caco-2 Permeability:** Ligand A (-5.24) is very poor. Ligand B (-4.063) is also poor, but slightly better.

**Aqueous Solubility:** Both ligands have poor aqueous solubility (A: -2.187, B: -3.427).

**hERG Inhibition:** Both ligands have low hERG inhibition risk (A: 0.254, B: 0.602).

**Microsomal Clearance:** Ligand A (-11.567) indicates *low* clearance and therefore good metabolic stability. Ligand B (107.362) indicates *high* clearance and poor metabolic stability.

**In vitro Half-Life:** Ligand A (-16.699) indicates a very long half-life, which is desirable. Ligand B (50.431) is moderate.

**P-gp Efflux:** Both ligands have very low P-gp efflux (A: 0.005, B: 0.747), which is excellent for CNS penetration.

**Binding Affinity:** Both ligands have comparable binding affinities (A: -7.5 kcal/mol, B: -7.3 kcal/mol). Ligand A is slightly better.

**Overall Assessment:**

Ligand A has a slight edge in binding affinity and significantly better metabolic stability (lower Cl_mic, longer half-life) and P-gp efflux. However, its Caco-2 permeability is very poor, and its logP is suboptimal. Ligand B excels in TPSA, logP, and BBB penetration, but suffers from poor metabolic stability.

Given the GPCR-specific priorities, BBB penetration is crucial for a CNS target like DRD2. While Ligand B has a superior BBB score, the significantly better metabolic stability of Ligand A, coupled with its acceptable BBB and slightly better affinity, makes it the more promising candidate. The poor Caco-2 and logP of Ligand A could potentially be addressed through further optimization, whereas improving the metabolic stability of Ligand B might be more challenging.

Output:
0
2025-04-17 05:47:17,485 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (370.494 and 364.471 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (76.02) is significantly better than Ligand B (85.25). For CNS targets, we want TPSA <= 90, and A is closer to the optimal <=60 range.

**logP:** Both ligands have acceptable logP values (1.868 and 0.879), falling within the 1-3 range. Ligand A is slightly better.

**H-Bond Donors/Acceptors:** Both have 2 HBD and 5/6 HBA, which are within acceptable limits.

**QED:** Both ligands have good QED scores (0.732 and 0.783), indicating drug-likeness.

**DILI:** Ligand A (46.801) has a lower DILI risk than Ligand B (63.746), which is preferable.

**BBB:** Ligand A (63.629) has a better BBB percentile than Ligand B (52.036). While both are below the ideal >70, A is closer and more promising for a CNS target.

**Caco-2 Permeability:** Ligand A (-5.256) has a higher Caco-2 permeability than Ligand B (-5.561).

**Aqueous Solubility:** Ligand A (-3.249) has better solubility than Ligand B (-2.097).

**hERG:** Both ligands have low hERG inhibition risk (0.273 and 0.449).

**Microsomal Clearance:** Ligand B (28.671) has slightly lower microsomal clearance than Ligand A (31.666), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand B (21.702) has a significantly longer half-life than Ligand A (-1.989). This is a substantial advantage.

**P-gp Efflux:** Ligand A (0.045) has lower P-gp efflux than Ligand B (0.07), which is beneficial for CNS penetration.

**Binding Affinity:** Both ligands have excellent binding affinities (-7.8 and -7.6 kcal/mol). The difference of 0.2 kcal/mol is not substantial enough to outweigh other factors.

**Overall Assessment:**

Considering the GPCR-specific priorities, Ligand A is the more promising candidate. Its superior TPSA, BBB, solubility, and lower DILI risk are crucial for CNS drug development. While Ligand B has a better half-life and slightly better metabolic stability, the improvements in CNS penetration metrics for Ligand A are more important for a DRD2 ligand.

Output:
1
2025-04-17 05:47:17,485 - INFO - Batch 227 complete. Total preferences: 3632
2025-04-17 05:47:17,485 - INFO - Processing batch 228/512...
2025-04-17 05:48:08,513 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (369.443 and 362.495 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (110.86) is higher than the preferred <90 for CNS targets, while Ligand B (58.64) is well within the range. This is a significant advantage for Ligand B.

**logP:** Both ligands have good logP values (2.981 and 2.214), falling within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Both ligands have 1 HBD and a reasonable number of HBAs (6 and 4 respectively), satisfying the criteria.

**QED:** Both ligands have good QED scores (0.631 and 0.874), indicating drug-like properties.

**DILI:** Ligand A (65.219) has a higher DILI risk than Ligand B (25.553). This favors Ligand B.

**BBB:** Ligand B (80.264) has a significantly better BBB penetration score than Ligand A (70.531). This is a crucial advantage for a CNS target like DRD2.

**Caco-2 Permeability:** Ligand A (-4.379) has worse Caco-2 permeability than Ligand B (-5.201), indicating lower intestinal absorption.

**Aqueous Solubility:** Both ligands have similar, poor aqueous solubility (-3.702 and -3.434). This could pose formulation challenges for both, but isn't a deciding factor here.

**hERG:** Both ligands have similar hERG inhibition liabilities (0.418 and 0.583), indicating a low risk of cardiotoxicity.

**Microsomal Clearance:** Ligand A (49.693) has a higher microsomal clearance than Ligand B (28.793), suggesting lower metabolic stability. Ligand B is favored.

**In vitro Half-Life:** Ligand B (5.359) has a slightly longer in vitro half-life than Ligand A (-10.525), which is a positive.

**P-gp Efflux:** Ligand A (0.35) has lower P-gp efflux liability than Ligand B (0.157), which is a positive for CNS exposure.

**Binding Affinity:** Ligand B (-8.8 kcal/mol) has a significantly stronger binding affinity than Ligand A (-7.6 kcal/mol). This is a substantial advantage, potentially outweighing some of the other minor drawbacks.

**Overall:**

Ligand B is superior due to its significantly better BBB penetration, lower DILI risk, better metabolic stability (lower Cl_mic), longer half-life, and, most importantly, much stronger binding affinity. While Ligand A has slightly lower P-gp efflux, the other advantages of Ligand B are more critical for a CNS-targeting GPCR. The lower TPSA of Ligand B is also a significant advantage.



Output:
1
2025-04-17 05:48:08,513 - INFO - Okay, let's analyze these two ligands for their potential as DRD2 drug candidates. DRD2 is a GPCR in the CNS, so BBB penetration, logP, Pgp efflux, TPSA, and binding affinity are paramount.

**Ligand A:** [361.427, 127.74 ,   1.008,   3.   ,   5.   ,   0.605,  85.227,  34.238, -5.613,  -3.613,   0.747,  10.359, -23.372,   0.062,  -7.8  ]
**Ligand B:** [344.499,  49.41 ,   2.99 ,   1.   ,   2.   ,   0.78 ,  19.736,  71.384, -4.828,  -3.547,   0.373,  58.526, -11.915,   0.217,  -8.8  ]

**1. Molecular Weight:** Both are within the ideal range (200-500 Da). A (361.427) and B (344.499) are comparable.

**2. TPSA:** Ligand A (127.74) is higher than the ideal <90 for CNS targets, but not drastically so. Ligand B (49.41) is excellent, well below the threshold. This is a significant advantage for B.

**3. logP:** Ligand A (1.008) is at the lower end of optimal, potentially hindering permeability. Ligand B (2.99) is closer to the sweet spot of 1-3.

**4. H-Bond Donors:** Ligand A (3) is acceptable. Ligand B (1) is even better.

**5. H-Bond Acceptors:** Ligand A (5) is acceptable. Ligand B (2) is better.

**6. QED:** Both ligands have reasonable QED scores (A: 0.605, B: 0.78), indicating drug-like properties. B is slightly better.

**7. DILI Risk:** Ligand A (85.227) has a concerningly high DILI risk. Ligand B (19.736) has a very low DILI risk, a major advantage.

**8. BBB Penetration:** Ligand A (34.238) has poor predicted BBB penetration. Ligand B (71.384) is good, exceeding the >70% threshold for CNS targets. This is a critical advantage for B.

**9. Caco-2 Permeability:** Ligand A (-5.613) has poor Caco-2 permeability. Ligand B (-4.828) is also poor, but slightly better than A.

**10. Aqueous Solubility:** Both have poor solubility (-3.613 and -3.547 respectively). This could be a formulation challenge, but is less critical than BBB penetration for a CNS target.

**11. hERG Inhibition:** Both have low hERG inhibition risk (A: 0.747, B: 0.373). B is slightly better.

**12. Microsomal Clearance:** Ligand A (10.359) has lower clearance, suggesting better metabolic stability. Ligand B (58.526) has higher clearance. This favors A.

**13. In vitro Half-Life:** Ligand A (-23.372) has a longer half-life. Ligand B (-11.915) has a shorter half-life. This favors A.

**14. P-gp Efflux:** Ligand A (0.062) has lower P-gp efflux, which is good for CNS exposure. Ligand B (0.217) has higher P-gp efflux. This favors A.

**15. Binding Affinity:** Ligand B (-8.8) has a slightly better binding affinity than Ligand A (-7.8). While A is good, the 1 kcal/mol difference is significant.

**Overall Assessment:**

Despite Ligand A having better metabolic stability and half-life, Ligand B is the superior candidate. The critical advantages of Ligand B are its significantly better BBB penetration (71.384% vs 34.238%), much lower DILI risk (19.736% vs 85.227%), and lower TPSA (49.41 vs 127.74). These factors are particularly important for a CNS-targeting GPCR like DRD2. The slightly better affinity of B further reinforces this conclusion. While solubility is a concern for both, it is a formulation issue that can potentially be addressed.



1
2025-04-17 05:48:08,514 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (367.427 and 349.431 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (125.36) is slightly above the optimal <90 for CNS targets, but still reasonable. Ligand B (82.45) is excellent, well below 90.

**logP:** Ligand A (0.95) is a bit low, potentially hindering permeability. Ligand B (2.088) is within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A has 2 HBD and 6 HBA, which are acceptable. Ligand B has 1 HBD and 6 HBA, also acceptable.

**QED:** Ligand A (0.494) is just below the desirable threshold of 0.5. Ligand B (0.795) is good, exceeding 0.5.

**DILI:** Both ligands have similar DILI risk (65.491 and 64.211 percentile), indicating moderate risk. This isn't a major differentiating factor.

**BBB:** This is crucial for a CNS target like DRD2. Ligand A has a BBB percentile of 38.736, which is below the desirable >70. Ligand B has a significantly better BBB percentile of 82.086, making it much more likely to reach the target in the brain.

**Caco-2 Permeability:** Both have negative Caco-2 values (-5.231 and -4.832), which is unusual and suggests poor permeability. However, these values are on a scale where negative values are possible and don't necessarily preclude activity.

**Aqueous Solubility:** Both ligands have very poor aqueous solubility (-3.153 and -3.3). This is a concern for formulation and bioavailability.

**hERG Inhibition:** Both ligands show very low hERG inhibition risk (0.379 and 0.181), which is excellent.

**Microsomal Clearance:** Ligand A (56.785) and Ligand B (64.098) have moderate microsomal clearance, suggesting moderate metabolic stability.

**In vitro Half-Life:** Ligand A (-28.864) has a very negative half-life, which is concerning. Ligand B (-10.408) is also negative, but less so.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.071 and 0.187), which is favorable for CNS penetration.

**Binding Affinity:** Ligand B (-8.5 kcal/mol) has a slightly better binding affinity than Ligand A (-7.6 kcal/mol). While both are good, the 0.9 kcal/mol difference is noticeable.

**Overall Assessment:**

Ligand B is the stronger candidate. Its superior BBB penetration (82.086 vs. 38.736), better logP (2.088 vs. 0.95), higher QED (0.795 vs. 0.494) and slightly improved binding affinity (-8.5 vs -7.6 kcal/mol) outweigh the similar DILI and metabolic stability profiles. While both have poor solubility and Caco-2 permeability, the CNS target prioritizes BBB penetration, which Ligand B clearly excels in.

Output:
1
2025-04-17 05:48:08,514 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (359.861 and 348.487 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (71.84) is slightly higher than Ligand B (66.48). Both are below the 90 A^2 threshold desirable for CNS targets, but Ligand B is closer to the optimal range.

**3. logP:** Both ligands have good logP values (3.01 and 2.535), falling within the optimal 1-3 range.

**4. H-Bond Donors:** Ligand A (2) is slightly higher than Ligand B (1), but both are within the acceptable limit of <=5.

**5. H-Bond Acceptors:** Ligand A (4) is higher than Ligand B (3), but both are within the acceptable limit of <=10.

**6. QED:** Both ligands have similar QED values (0.806 and 0.769), indicating good drug-like properties.

**7. DILI:** Ligand A (51.377) has a higher DILI risk than Ligand B (17.449). Ligand B is significantly better in this regard, falling well below the 40 threshold.

**8. BBB:** Ligand B (75.223) has a slightly better BBB penetration percentile than Ligand A (70.997). Both are above the desirable 70% for CNS targets, but Ligand B is preferable.

**9. Caco-2 Permeability:** Ligand A (-5.009) has worse Caco-2 permeability than Ligand B (-4.815). Lower negative values are better.

**10. Aqueous Solubility:** Ligand A (-3.297) has slightly better aqueous solubility than Ligand B (-3.13).

**11. hERG Inhibition:** Both ligands have low hERG inhibition risk (0.15 and 0.244).

**12. Microsomal Clearance:** Ligand B (43.041) has significantly lower microsomal clearance than Ligand A (6.191), suggesting better metabolic stability.

**13. In vitro Half-Life:** Ligand B (-22.782) has a significantly longer in vitro half-life than Ligand A (19.912).

**14. P-gp Efflux:** Both ligands have low P-gp efflux liability (0.09 and 0.204).

**15. Binding Affinity:** Ligand A (-9.3 kcal/mol) has a slightly better binding affinity than Ligand B (-8.1 kcal/mol). This is a 1.2 kcal/mol difference, which is significant.

**Overall Assessment:**

While Ligand A has a slightly better binding affinity, Ligand B demonstrates superior ADME properties, particularly regarding DILI risk, BBB penetration, metabolic stability (lower Cl_mic and longer t1/2), and Caco-2 permeability. For a CNS target like DRD2, minimizing DILI risk and maximizing BBB penetration are critical. The 1.2 kcal/mol difference in binding affinity can potentially be overcome with further optimization of Ligand B, whereas improving the ADME profile of Ligand A would likely be more challenging.

Output:
1
2025-04-17 05:48:08,514 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (354.411 and 346.427 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (110.61) is slightly above the optimal <90 for CNS targets, while Ligand B (95.5) is within the preferred range. This gives a slight edge to Ligand B.

**3. logP:** Ligand A (-0.049) is a bit low, potentially hindering permeation. Ligand B (2.162) is within the optimal 1-3 range. Ligand B is clearly better here.

**4. H-Bond Donors:** Ligand A (2) and Ligand B (3) are both acceptable, being less than 5.

**5. H-Bond Acceptors:** Ligand A (7) and Ligand B (4) are both acceptable, being less than 10.

**6. QED:** Both ligands have good QED scores (0.633 and 0.712), indicating good drug-like properties.

**7. DILI:** Ligand A (60.566) is approaching a concerning DILI risk, while Ligand B (35.712) has a much lower, and preferable, risk. This is a significant advantage for Ligand B.

**8. BBB:** Ligand A (75.107) has a good BBB penetration percentile, while Ligand B (52.889) is lower. This favors Ligand A.

**9. Caco-2:** Both ligands have similar, poor Caco-2 permeability (-4.852 and -4.842). This is a potential issue for oral bioavailability for both.

**10. Solubility:** Both ligands have poor aqueous solubility (-0.962 and -2.963). This may necessitate formulation strategies.

**11. hERG:** Both ligands have very low hERG inhibition risk (0.056).

**12. Cl_mic:** Ligand B (2.918) has significantly lower microsomal clearance than Ligand A (21.789), indicating better metabolic stability. This is a major advantage for Ligand B.

**13. t1/2:** Ligand B (17.01) has a longer in vitro half-life than Ligand A (12.277), which is desirable.

**14. Pgp:** Both ligands have very low P-gp efflux liability (0.01 and 0.033).

**15. Binding Affinity:** Ligand A (-7.5) has a slightly better binding affinity than Ligand B (-0.0). This is a substantial advantage for Ligand A.

**Overall Assessment:**

While Ligand A has a better binding affinity and BBB penetration, Ligand B excels in several critical ADME properties. Specifically, the lower DILI risk, significantly improved metabolic stability (lower Cl_mic), and longer half-life of Ligand B are very important. The slightly lower TPSA and better logP of Ligand B also contribute to its favorability. The affinity difference, while notable, might be overcome with further optimization of Ligand B. Given the GPCR-specific priorities, and the importance of ADME properties for CNS drugs, Ligand B appears to be the more promising candidate.

Output:
1
2025-04-17 05:48:08,514 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 drug candidates, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (352.519 and 348.531 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (69.64) is slightly higher than Ligand B (41.57). For a CNS target like DRD2, a TPSA below 90 is preferred, and ideally below 60. Ligand B is significantly better in this regard.

**3. logP:** Both ligands have good logP values (2.286 and 3.351), falling within the optimal 1-3 range. Ligand B is slightly higher, which could be beneficial for membrane permeability, but isn't a major concern for either.

**4. H-Bond Donors:** Ligand A has 2 HBD, and Ligand B has 1. Both are within the acceptable limit of <=5.

**5. H-Bond Acceptors:** Both ligands have 3 HBA, well within the acceptable limit of <=10.

**6. QED:** Both ligands have good QED scores (0.704 and 0.847), indicating good drug-like properties.

**7. DILI:** Both ligands have low DILI risk (6.747 and 6.049 percentile), which is favorable.

**8. BBB:** This is a critical parameter for CNS targets. Ligand B (94.184%) has a significantly higher BBB penetration score than Ligand A (73.672%). This is a major advantage for Ligand B.

**9. Caco-2 Permeability:** Ligand A (-4.709) and Ligand B (-4.653) both have negative values, which is unusual and suggests poor permeability. However, the scale isn't specified, so it's hard to interpret.

**10. Aqueous Solubility:** Both ligands have poor aqueous solubility (-2.793 and -4.134). This could pose formulation challenges.

**11. hERG Inhibition:** Both ligands have low hERG inhibition risk (0.597 and 0.705 percentile), which is good.

**12. Microsomal Clearance:** Ligand A (30.738) has lower microsomal clearance than Ligand B (41.74), suggesting better metabolic stability.

**13. In vitro Half-Life:** Ligand B (7.31 hours) has a longer half-life than Ligand A (4.685 hours), which is preferable.

**14. P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.076 and 0.055 percentile), which is excellent for CNS penetration.

**15. Binding Affinity:** Ligand A (-7.3 kcal/mol) has a slightly better binding affinity than Ligand B (-6.7 kcal/mol). This is a 0.6 kcal/mol difference, which is significant but not overwhelming.

**Overall Assessment:**

While Ligand A has a slightly better binding affinity, Ligand B is superior overall due to its significantly better BBB penetration (94.184% vs. 73.672%), lower TPSA (41.57 vs. 69.64), and longer half-life. These factors are particularly important for a CNS-targeting GPCR like DRD2. The slightly lower affinity of Ligand B can potentially be optimized in subsequent iterations, while improving BBB penetration is often more challenging.

Output:
1
2025-04-17 05:48:08,515 - INFO - Reasoning:

Let's analyze Ligand A and Ligand B against the provided guidelines, keeping in mind DRD2 is a CNS-relevant GPCR.

**Molecular Weight:** Both ligands (342.355 and 382.913 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (95.34) is slightly above the optimal <90 for CNS targets, but still reasonable. Ligand B (58.64) is excellent, well below 90.

**logP:** Ligand A (0.509) is quite low, potentially hindering permeability. Ligand B (2.652) is within the optimal 1-3 range. This is a significant advantage for Ligand B.

**H-Bond Donors:** Both ligands have 1 HBD, which is acceptable.

**H-Bond Acceptors:** Ligand A has 7 HBAs, acceptable. Ligand B has 4 HBAs, also acceptable.

**QED:** Both ligands have similar QED values (0.87 and 0.851), indicating good drug-likeness.

**DILI:** Ligand A (86.468) has a higher DILI risk than Ligand B (33.695). This is a considerable drawback for Ligand A.

**BBB:** Ligand B (71.229) has a better BBB penetration percentile than Ligand A (61.807). Both are above 70, which is desirable for CNS targets, but B is better.

**Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and suggests a potential issue with the data or modeling. However, the values are similar.

**Aqueous Solubility:** Both ligands have negative solubility values, again suggesting a potential data issue. The values are similar.

**hERG Inhibition:** Both ligands have low hERG inhibition liability (0.214 and 0.447), which is good.

**Microsomal Clearance:** Ligand A (-22.46) has a much lower (better) microsomal clearance than Ligand B (30.615), indicating greater metabolic stability.

**In vitro Half-Life:** Ligand A (14.229 hours) has a longer half-life than Ligand B (5.86 hours).

**P-gp Efflux:** Ligand A (0.034) has significantly lower P-gp efflux liability than Ligand B (0.19), which is beneficial for CNS penetration.

**Binding Affinity:** Both ligands have similar strong binding affinities (-8.9 and -8.6 kcal/mol). The difference is less than 1.5 kcal/mol, so it's not a deciding factor.

**Overall Assessment:**

Given DRD2 is a CNS target, BBB penetration is critical. Ligand B has a significantly better BBB score (71.229 vs 61.807).  Ligand B also has a better logP, making it more likely to cross membranes. While Ligand A has better metabolic stability (lower Cl_mic, longer t1/2) and lower P-gp efflux, the poor logP and higher DILI risk are significant concerns. The slightly better BBB and lower DILI of Ligand B outweigh the metabolic advantages of Ligand A.

Output:
1
2025-04-17 05:48:08,515 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (402.288 Da and 389.708 Da) fall within the ideal 200-500 Da range. No significant difference here.

**2. TPSA:** Ligand A (55.4) is significantly better than Ligand B (75.48). For CNS targets, we want TPSA <= 90, and A is comfortably within this range, while B is approaching the upper limit. This favors A.

**3. logP:** Both ligands have a logP around 3.5, which is optimal. No clear advantage.

**4. H-Bond Donors:** Both have 1 HBD, which is within the acceptable limit of <=5. No difference.

**5. H-Bond Acceptors:** Ligand A has 3 HBAs, and Ligand B has 4. Both are below the limit of <=10. No significant difference.

**6. QED:** Ligand A (0.779) has a substantially better QED score than Ligand B (0.419). A QED > 0.5 is desirable, and A is much closer to 1. This favors A.

**7. DILI:** Ligand B (76.89) has a higher DILI risk than Ligand A (61.303). Both are above the 60 threshold, indicating a higher risk, but A is slightly better.

**8. BBB:** Both ligands have excellent BBB penetration (>70%), with Ligand A at 70.88% and Ligand B at 71.539%. No significant difference.

**9. Caco-2 Permeability:** Both have negative Caco-2 values (-4.722 and -4.704), which is unusual and suggests poor permeability. This is a concern for both.

**10. Aqueous Solubility:** Both ligands have negative solubility values (-4.236 and -4.295), indicating very poor aqueous solubility. This is a significant drawback for both.

**11. hERG Inhibition:** Ligand A (0.492) has a lower hERG inhibition liability than Ligand B (0.709). Lower is better, so this favors A.

**12. Microsomal Clearance:** Ligand A (99.114) has a much higher microsomal clearance than Ligand B (73.89). Higher clearance means faster metabolism and lower exposure, which is undesirable. This favors B.

**13. In vitro Half-Life:** Ligand B (55.839) has a slightly longer in vitro half-life than Ligand A (58.638). Longer is generally better, but the difference is small.

**14. P-gp Efflux:** Ligand A (0.358) has lower P-gp efflux liability than Ligand B (0.226). Lower is better, especially for CNS targets, so this favors A.

**15. Binding Affinity:** Ligand A (-8.6 kcal/mol) has a significantly stronger binding affinity than Ligand B (-7.9 kcal/mol). A difference of >1.5 kcal/mol is substantial and can outweigh other drawbacks. This strongly favors A.

**Overall Assessment:**

Ligand A is the better candidate. While both have issues with Caco-2 permeability and aqueous solubility, Ligand A has a significantly better QED score, lower DILI risk, lower hERG inhibition, lower P-gp efflux, and, most importantly, a much stronger binding affinity. The higher microsomal clearance for A is a concern, but the substantial affinity advantage likely outweighs this drawback. The TPSA value is also more favorable for CNS penetration.

Output:
1
2025-04-17 05:48:08,515 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (348.487 and 355.454 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (49.85) is significantly better than Ligand B (61.88). For CNS targets, we want TPSA <= 90, both are within this range, but A is more favorable.

**logP:** Ligand A (2.302) is optimal (1-3). Ligand B (1.098) is on the lower end, potentially hindering permeation.

**H-Bond Donors/Acceptors:** Ligand A (0 HBD, 3 HBA) is better than Ligand B (1 HBD, 4 HBA). Both are within acceptable limits, but fewer H-bonds generally improve permeability.

**QED:** Both ligands have good QED scores (0.633 and 0.743), indicating drug-like properties.

**DILI:** Ligand A (6.669) has a much lower DILI risk than Ligand B (12.641). This is a significant advantage.

**BBB:** Ligand A (90.849) has a superior BBB penetration percentile compared to Ligand B (71.307). This is *critical* for a CNS target like DRD2.

**Caco-2 Permeability:** Ligand A (-4.325) and Ligand B (-4.875) both have negative values, which is unusual. Lower values suggest poorer permeability. However, the difference is small.

**Aqueous Solubility:** Ligand A (-2.253) and Ligand B (-1.025) both have negative solubility values, suggesting poor solubility. B is slightly better.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.51 and 0.478).

**Microsomal Clearance:** Ligand A (52.924) has a higher microsomal clearance than Ligand B (-8.773). This suggests Ligand B is more metabolically stable, which is a positive.

**In vitro Half-Life:** Ligand A (7.579) has a slightly longer half-life than Ligand B (6.845).

**P-gp Efflux:** Ligand A (0.059) has a much lower P-gp efflux liability than Ligand B (0.022). Lower efflux is desirable for CNS exposure.

**Binding Affinity:** Ligand A (-7.6 kcal/mol) has a slightly better binding affinity than Ligand B (-8.0 kcal/mol). While both are excellent, the difference is minimal.

**Overall Assessment:**

Ligand A is the stronger candidate. It excels in crucial areas for CNS drug development: BBB penetration, lower DILI risk, and lower P-gp efflux. While Ligand B has better metabolic stability, the superior CNS penetration and safety profile of Ligand A outweigh this advantage. The slightly better affinity of A is also a plus.



Output:
1
2025-04-17 05:48:08,515 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (373.36 and 353.394 Da) fall within the ideal 200-500 Da range.

**TPSA:** Both ligands (80.12 and 78.95) are below the 90 A^2 threshold desirable for CNS targets, which is excellent.

**logP:** Ligand A (1.36) is within the optimal 1-3 range. Ligand B (-0.299) is slightly below 1, which *could* indicate permeability issues, though not drastically.

**H-Bond Donors/Acceptors:** Both ligands have acceptable HBD counts (1). Ligand A has 6 HBA, while Ligand B has 4. Both are below the 10 threshold.

**QED:** Both ligands have reasonable QED scores (0.878 and 0.739), indicating good drug-like properties.

**DILI:** Ligand A has a DILI risk of 83.404, which is high and concerning. Ligand B has a much lower DILI risk of 21.598, which is excellent.

**BBB:** Ligand A has a BBB penetration percentile of 76.309, which is good but not exceptional. Ligand B has a BBB penetration percentile of 69.407, which is acceptable, but lower than Ligand A.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.057 and -4.886). These values are unusual and suggest poor permeability. However, these values are on a log scale and may be relative to a reference compound.

**Aqueous Solubility:** Both ligands have negative solubility values (-2.668 and -1.778), also unusual and suggesting poor solubility.

**hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.115 and 0.184).

**Microsomal Clearance:** Ligand A has a clearance of 10.474 mL/min/kg, which is relatively moderate. Ligand B has a much higher clearance (-14.804 mL/min/kg), suggesting rapid metabolism and potentially lower *in vivo* exposure. The negative value is strange and may be an error.

**In vitro Half-Life:** Ligand A has a half-life of 5.968 hours, which is reasonable. Ligand B has a longer half-life of 11.219 hours, which is preferable.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.067 and 0.003), which is excellent for CNS penetration.

**Binding Affinity:** Ligand A has a significantly stronger binding affinity (-9.1 kcal/mol) compared to Ligand B (-8.1 kcal/mol). This is a substantial difference (1 kcal/mol), and is a significant advantage.

**Overall Assessment:**

Ligand A has a much stronger binding affinity, good BBB penetration, and acceptable TPSA and logP. However, its high DILI risk is a major concern. Ligand B has a much better safety profile (DILI), a longer half-life, but weaker binding affinity and slightly lower BBB penetration.

Given the GPCR target and the importance of CNS penetration, the binding affinity is paramount. While the DILI risk for Ligand A is concerning, the 1 kcal/mol difference in binding affinity is substantial. It is possible to mitigate the DILI risk through structural modifications, but improving affinity is often more challenging.

Output:
1
2025-04-17 05:48:08,515 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (345.535 and 345.491 Da) fall comfortably within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (55.63) is slightly higher than Ligand B (53.52). Both are below the 90 A^2 threshold desirable for CNS targets, which is good.

**3. logP:** Ligand A (4.309) is higher than Ligand B (2.402). Ligand A is pushing the upper limit of the optimal range (1-3) and could potentially have solubility issues. Ligand B is well within the optimal range.

**4. H-Bond Donors:** Both have 1 HBD, which is acceptable.

**5. H-Bond Acceptors:** Ligand A has 5 HBA, and Ligand B has 6. Both are within the acceptable limit of <=10.

**6. QED:** Both ligands have good QED values (0.642 and 0.73), indicating good drug-like properties.

**7. DILI:** Ligand A (27.801) has a lower DILI risk than Ligand B (33.501), which is favorable.

**8. BBB:** This is a critical parameter for a CNS target like DRD2. Ligand B (93.602) has a significantly higher BBB penetration percentile than Ligand A (78.402). This is a major advantage for Ligand B.

**9. Caco-2 Permeability:** Both have negative values (-5.155 and -4.973), which is unusual and suggests poor permeability. However, the scale is not specified, so it's difficult to interpret.

**10. Aqueous Solubility:** Both have negative values (-4.303 and -2.256), suggesting poor aqueous solubility. This is a concern, especially for Ligand A with its higher logP.

**11. hERG Inhibition:** Ligand A (0.353) has a slightly lower hERG risk than Ligand B (0.898), which is preferable.

**12. Microsomal Clearance:** Ligand A (43.723) has a higher microsomal clearance than Ligand B (32.691), indicating lower metabolic stability.

**13. In vitro Half-Life:** Ligand B (14.514) has a significantly longer in vitro half-life than Ligand A (-10.583), which is a substantial advantage.

**14. P-gp Efflux:** Ligand A (0.348) has lower P-gp efflux liability than Ligand B (0.111), which is favorable for CNS penetration.

**15. Binding Affinity:** Ligand B (-7.7 kcal/mol) has a significantly stronger binding affinity than Ligand A (-6.4 kcal/mol). This >1.5 kcal/mol difference is a major driver in the decision.

**Overall Assessment:**

While Ligand A has slightly better DILI and P-gp efflux profiles, Ligand B is superior in almost all other critical parameters for a CNS-targeting GPCR ligand. Specifically, its significantly higher BBB penetration, longer half-life, and, most importantly, much stronger binding affinity outweigh the minor drawbacks. The higher logP of Ligand A is a concern, and its lower metabolic stability is also unfavorable.

Output:
1
2025-04-17 05:48:08,516 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (346.431 and 359.352 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (93.21) is better than Ligand B (97.64). Both are below the 140 A^2 threshold for oral absorption and reasonably close to the 90 A^2 target for CNS penetration, but A is preferable.

**3. logP:** Ligand A (1.428) is within the optimal 1-3 range. Ligand B (2.534) is also acceptable, but slightly higher.

**4. H-Bond Donors:** Ligand A (2) is better than Ligand B (3). Lower HBD generally improves permeability.

**5. H-Bond Acceptors:** Ligand A (5) is better than Ligand B (3). Lower HBA generally improves permeability.

**6. QED:** Both ligands have similar QED values (0.779 and 0.708), indicating good drug-like properties.

**7. DILI:** Ligand A (35.169) has a significantly lower DILI risk than Ligand B (48.468). This is a major advantage for Ligand A.

**8. BBB:** Ligand A (65.413) has a better BBB percentile than Ligand B (53.393). While both are not ideal (>70), A is significantly better, crucial for a CNS target like DRD2.

**9. Caco-2 Permeability:** Ligand A (-4.78) has better Caco-2 permeability than Ligand B (-5.124).

**10. Aqueous Solubility:** Ligand A (-1.786) has better aqueous solubility than Ligand B (-2.944).

**11. hERG Inhibition:** Ligand A (0.071) has a lower hERG inhibition liability than Ligand B (0.579), indicating a lower risk of cardiotoxicity.

**12. Microsomal Clearance:** Ligand B (-3.59) has a significantly *lower* (better) microsomal clearance than Ligand A (15.497). This suggests better metabolic stability for Ligand B.

**13. In vitro Half-Life:** Ligand B (-20.121) has a much longer in vitro half-life than Ligand A (15.041). This is a significant advantage for Ligand B.

**14. P-gp Efflux:** Ligand A (0.004) has a much lower P-gp efflux liability than Ligand B (0.128). Lower P-gp efflux is highly desirable for CNS penetration.

**15. Binding Affinity:** Ligand A (-8.7 kcal/mol) has a stronger binding affinity than Ligand B (-7.4 kcal/mol). This is a substantial difference (1.3 kcal/mol), and generally outweighs minor ADME drawbacks.

**Overall Assessment:**

While Ligand B has superior metabolic stability and half-life, Ligand A demonstrates a more favorable profile overall, particularly for a CNS-targeting GPCR. Ligand A has a significantly better binding affinity, lower DILI risk, better BBB penetration, lower hERG inhibition, and lower P-gp efflux. The improved affinity and CNS penetration are critical for DRD2. The slightly higher clearance of Ligand A is a concern, but could potentially be addressed through structural modifications.

Output:
1
2025-04-17 05:48:08,516 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (346.431 and 345.403 Da) fall within the ideal range of 200-500 Da.

**TPSA:** Ligand A (85.77) is significantly better than Ligand B (102.05). For CNS targets, we want TPSA <= 90, and A is comfortably within that range, while B is slightly above.

**logP:** Ligand A (0.791) is a bit low, potentially hindering permeation, but still within an acceptable range. Ligand B (1.374) is better, falling nicely within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Both have 2 HBD and 5/6 HBA, which are acceptable values.

**QED:** Both ligands have good QED scores (0.845 and 0.789), indicating good drug-like properties.

**DILI:** Ligand A (47.421) has a lower DILI risk than Ligand B (56.262), which is preferable. Both are below the 60 threshold, indicating acceptable risk.

**BBB:** This is a critical parameter for CNS targets. Ligand A (24.506) has a very low BBB penetration percentile, which is a major drawback. Ligand B (55.099) is significantly better, although still not ideal (we want >70).

**Caco-2 Permeability:** Both are negative, indicating poor permeability. Ligand A (-4.815) is slightly better than Ligand B (-5.064), but both are concerning.

**Aqueous Solubility:** Both have negative solubility values, indicating poor solubility. Ligand A (-1.073) is slightly better than Ligand B (-3.028).

**hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.261 and 0.073).

**Microsomal Clearance:** Ligand A (-7.542) has a much lower (better) microsomal clearance than Ligand B (17.16). This suggests better metabolic stability for Ligand A.

**In vitro Half-Life:** Ligand A (1.351) has a lower half-life than Ligand B (7.659).

**P-gp Efflux:** Both have very low P-gp efflux liability (0.018 and 0.03).

**Binding Affinity:** Ligand B (-8.2 kcal/mol) has a significantly stronger binding affinity than Ligand A (-7.4 kcal/mol). This is a >1.5 kcal/mol advantage, which is substantial.

**Overall Assessment:**

While Ligand A has better DILI, metabolic stability (lower Cl_mic), and slightly better solubility, its extremely poor BBB penetration (24.5%) is a deal-breaker for a CNS target like DRD2. Ligand B, despite having a slightly higher DILI risk and worse metabolic stability, has a much better BBB penetration (55.1%) and, crucially, a significantly higher binding affinity (-8.2 vs -7.4 kcal/mol). The affinity difference is large enough to outweigh the ADME drawbacks.

Output:
1
2025-04-17 05:48:08,516 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (446.176 Da) is slightly higher, but acceptable. Ligand B (356.438 Da) is also good.

**TPSA:** Ligand A (57.26) is excellent for CNS penetration, well below the 90 A^2 threshold. Ligand B (78.87) is still reasonable, but less optimal than A.

**logP:** Ligand A (4.606) is a bit high, potentially leading to solubility issues and off-target effects. Ligand B (1.187) is quite low, which might hinder permeation.

**H-Bond Donors/Acceptors:** Both ligands have 2 HBD and 3-4 HBA, which are within acceptable limits.

**QED:** Both ligands have similar QED values (0.682 and 0.64), indicating reasonable drug-likeness.

**DILI:** Ligand A has a DILI risk of 63.94, which is approaching the higher risk threshold (>60). Ligand B has a very low DILI risk (13.3), a significant advantage.

**BBB:** Both ligands have good BBB penetration (74.292% and 72.354%), exceeding the desirable 70% threshold for CNS targets.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values, which is unusual and suggests a potential issue with the data or modeling. However, we'll proceed assuming these represent low permeability.

**Aqueous Solubility:** Both ligands have very poor aqueous solubility (-5.639 and -1.796). This is a concern, especially given Ligand A's higher logP.

**hERG Inhibition:** Ligand A (0.828) has a slightly higher hERG risk than Ligand B (0.279).

**Microsomal Clearance:** Ligand A (82.162) has a high microsomal clearance, indicating poor metabolic stability. Ligand B (23.301) has much better metabolic stability.

**In vitro Half-Life:** Ligand A (124.28) has a longer half-life than Ligand B (-11.294), which is a positive. However, the negative value for B is concerning.

**P-gp Efflux:** Ligand A (0.368) has lower P-gp efflux, which is favorable for CNS exposure. Ligand B (0.047) has even lower P-gp efflux, a further advantage.

**Binding Affinity:** Ligand A (-9.3 kcal/mol) has significantly stronger binding affinity than Ligand B (-7.3 kcal/mol). This is a substantial advantage, potentially outweighing some of its ADME drawbacks.

**Overall Assessment:**

Ligand A has a much stronger binding affinity, which is paramount for GPCR ligands. However, it suffers from higher logP, higher DILI risk, and poorer metabolic stability. Ligand B has a better safety profile (lower DILI, lower hERG) and better metabolic stability, but its lower affinity is a significant drawback.

Considering the GPCR-specific priorities, the strong affinity of Ligand A is a major factor. While its ADME properties are not ideal, optimization could potentially address these issues. The lower affinity of Ligand B makes it less likely to be a viable candidate, even with its better ADME profile.

Output:
1
2025-04-17 05:48:08,516 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (390.452 Da) is slightly higher than Ligand B (349.431 Da), but both are acceptable.

**TPSA:** Ligand A (51.22) is significantly better than Ligand B (86.88). For CNS targets, we want TPSA <= 90, and ideally lower. Ligand A is well within this range, while Ligand B is approaching the upper limit and less favorable.

**logP:** Ligand A (4.741) is higher than the optimal range (1-3), potentially causing solubility issues and off-target effects. Ligand B (1.237) is slightly low, which might hinder permeation. However, given the CNS target, a slightly lower logP is less concerning than a very high one.

**H-Bond Donors/Acceptors:** Both ligands have 1 HBD and 5 HBA, which are within acceptable limits.

**QED:** Both ligands have good QED scores (A: 0.742, B: 0.884), indicating good drug-like properties.

**DILI:** Ligand A (76.425) has a higher DILI risk than Ligand B (37.922). This is a significant drawback for Ligand A.

**BBB:** Ligand A (68.864) has a better BBB penetration score than Ligand B (50.872). For a CNS target like DRD2, BBB penetration is crucial.

**Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and suggests poor permeability. However, the scale isn't specified, so it's hard to interpret.

**Aqueous Solubility:** Both have negative solubility values, indicating poor aqueous solubility. This is a concern, but can be addressed with formulation strategies.

**hERG:** Both ligands have low hERG inhibition liability (A: 0.462, B: 0.285), which is good.

**Microsomal Clearance:** Ligand A (81.192) has higher microsomal clearance than Ligand B (43.628), indicating lower metabolic stability.

**In vitro Half-Life:** Ligand B (-24.296) has a longer in vitro half-life than Ligand A (-15.358).

**P-gp Efflux:** Ligand A (0.572) has slightly lower P-gp efflux liability than Ligand B (0.131), which is favorable for CNS penetration.

**Binding Affinity:** Ligand B (-8.6 kcal/mol) has a slightly better binding affinity than Ligand A (-7.9 kcal/mol). While the difference is not huge, it's enough to consider.

**Overall Assessment:**

Ligand A has better BBB penetration and P-gp efflux, but suffers from higher DILI risk, higher logP, and lower metabolic stability. Ligand B has a slightly better binding affinity, lower DILI risk, better metabolic stability, and a more reasonable logP, but its BBB penetration is lower and TPSA is higher.

Considering the GPCR-specific priorities, BBB penetration is paramount for a CNS target. While Ligand A has a better BBB score, the significantly higher DILI risk and lower metabolic stability are major concerns. Ligand B, despite its slightly lower BBB score, presents a more balanced profile with a better safety profile and metabolic stability. The slight advantage in binding affinity also tips the scale in its favor.

Output:
1
2025-04-17 05:48:08,517 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (356.463 and 367.386 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (88.1) is better than Ligand B (97.39). Both are below the 90 A^2 threshold for CNS targets, but A is closer to the ideal.

**logP:** Ligand B (2.082) is optimal (1-3), while Ligand A (0.413) is quite low, potentially hindering membrane permeability. This is a significant drawback for A.

**H-Bond Donors/Acceptors:** Both ligands have 2 HBD and 5 HBA, which are within acceptable limits.

**QED:** Both ligands have good QED scores (0.554 and 0.686, respectively), indicating drug-like properties.

**DILI:** Ligand A (10.508) has a much lower DILI risk than Ligand B (36.138), which is a positive for A.

**BBB:** Ligand B (65.258) has a significantly better BBB penetration percentile than Ligand A (53.625). While both are not ideal (>70), B is closer.

**Caco-2 Permeability:** Ligand A (-4.887) has a very poor Caco-2 permeability, while Ligand B (-5.048) is also poor, but slightly better.

**Aqueous Solubility:** Both ligands have very poor aqueous solubility (-1.401 and -1.656 respectively). This is a concern for both, but not a deciding factor.

**hERG Inhibition:** Both ligands show very low hERG inhibition risk (0.502 and 0.097 respectively).

**Microsomal Clearance:** Ligand B (21.556) has lower microsomal clearance than Ligand A (34.783), indicating better metabolic stability.

**In vitro Half-Life:** Ligand A (21.566) has a longer in vitro half-life than Ligand B (10.155).

**P-gp Efflux:** Ligand A (0.05) has lower P-gp efflux liability than Ligand B (0.022), which is beneficial for CNS exposure.

**Binding Affinity:** Ligand B (-8.3 kcal/mol) has a significantly stronger binding affinity than Ligand A (-6.8 kcal/mol). This is a substantial advantage for B, potentially outweighing some of its ADME drawbacks.

**Overall Assessment:**

Ligand A has advantages in DILI, P-gp efflux, and in vitro half-life. However, its extremely low logP and poor Caco-2 permeability are major concerns, likely hindering its ability to cross cell membranes and reach the CNS target.

Ligand B, despite a higher DILI risk and slightly worse BBB, has a much better logP, stronger binding affinity, and better metabolic stability. The significantly stronger binding affinity (-8.3 vs -6.8 kcal/mol) is a critical advantage for a GPCR ligand. The improved logP will likely translate to better permeability.

Considering the GPCR-specific priorities, the binding affinity and logP are the most important factors. Ligand B clearly outperforms Ligand A in these areas.

Output:
1
2025-04-17 05:48:08,517 - INFO - Batch 228 complete. Total preferences: 3648
2025-04-17 05:48:08,517 - INFO - Processing batch 229/512...
2025-04-17 05:48:50,043 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B based on the provided guidelines, prioritizing GPCR-specific properties (BBB, logP, Pgp, TPSA, and affinity) for DRD2.

**Molecular Weight:** Both ligands (345.4 and 343.5 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (100.55) is higher than Ligand B (71.09). For CNS targets, TPSA < 90 is preferred. Ligand B is significantly better here.

**logP:** Ligand A (0.688) is below the optimal 1-3 range, potentially hindering permeation. Ligand B (3.067) is within the optimal range. This is a significant advantage for Ligand B.

**H-Bond Donors/Acceptors:** Ligand A has 3 HBD and 5 HBA, while Ligand B has 2 HBD and 3 HBA. Both are within acceptable limits (<=5 HBD and <=10 HBA).

**QED:** Both ligands have good QED scores (0.631 and 0.807), indicating drug-like properties.

**DILI:** Both ligands have low DILI risk (43.3 and 39.7), below the 40 threshold.

**BBB:** Ligand A (57.1%) is below the desirable 70% threshold for CNS targets. Ligand B (68.4%) is closer but still below the ideal threshold. However, Ligand B is better.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.122 and -4.905), which is unusual and suggests poor permeability. This is a concern for both.

**Aqueous Solubility:** Both ligands have negative solubility values (-1.956 and -3.783), indicating very poor aqueous solubility. This is a significant drawback for both compounds.

**hERG Inhibition:** Ligand A (0.07) has a very low hERG risk, which is excellent. Ligand B (0.403) has a slightly higher, but still relatively low, hERG risk.

**Microsomal Clearance:** Ligand A (-15.553) has a negative clearance, which is not physically possible and likely indicates an error in the data. Ligand B (45.039) has a moderate clearance.

**In vitro Half-Life:** Ligand A (26.914 hours) has a reasonable half-life. Ligand B (-6.5 hours) has a negative half-life, which is not physically possible and indicates an error in the data.

**P-gp Efflux:** Ligand A (0.021) has very low P-gp efflux, which is favorable for CNS penetration. Ligand B (0.22) has slightly higher P-gp efflux.

**Binding Affinity:** Ligand A (-8.5 kcal/mol) has a significantly stronger binding affinity than Ligand B (0.0 kcal/mol). This is a major advantage for Ligand A, potentially outweighing some of its ADME drawbacks.

**Overall Assessment:**

Ligand A has a superior binding affinity and very low P-gp efflux and hERG inhibition. However, its logP is suboptimal, and its BBB penetration is below the desired threshold. The negative values for clearance and half-life are concerning and suggest data errors.

Ligand B has better TPSA and logP values, and a better BBB score than Ligand A, but its binding affinity is extremely weak. The negative half-life is also a major issue.

Despite the data inconsistencies, the substantial binding affinity advantage of Ligand A is compelling, especially for a GPCR target where potency is crucial. The poor logP of Ligand A could be addressed with further optimization, while the negative half-life and clearance values are red flags suggesting potential data quality issues.

Output:
1
2025-04-17 05:48:50,043 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (343.471 and 357.376 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (56.41) is significantly better than Ligand B (69.12). For CNS targets, we want TPSA <= 90, and A is comfortably within this range, while B is approaching the upper limit.

**3. logP:** Both ligands have good logP values (2.904 and 3.167), falling within the optimal 1-3 range.

**4. H-Bond Donors:** Both have 1 HBD, which is acceptable.

**5. H-Bond Acceptors:** Ligand A has 2 HBAs, and Ligand B has 3. Both are within the acceptable limit of <= 10.

**6. QED:** Both ligands have good QED scores (0.917 and 0.815), indicating good drug-like properties.

**7. DILI:** Ligand A (25.94) has a much lower DILI risk than Ligand B (43.66). Both are below the 40 threshold, but A is preferable.

**8. BBB:** Ligand A (85.343) has a significantly higher BBB penetration percentile than Ligand B (76.696). This is a *critical* factor for a CNS target like DRD2, and A is much more promising.

**9. Caco-2 Permeability:** Both have negative Caco-2 values (-4.898 and -4.67). These values are unusual and difficult to interpret without knowing the scale. However, the relative values are similar.

**10. Aqueous Solubility:** Both have negative solubility values (-3.612 and -3.982). Again, the scale is unknown, but the values are similar.

**11. hERG Inhibition:** Both ligands show low hERG inhibition liability (0.662 and 0.859), which is good.

**12. Microsomal Clearance:** Ligand B (32.724) has lower microsomal clearance than Ligand A (46.304), suggesting better metabolic stability.

**13. In vitro Half-Life:** Ligand A (-18.406) has a negative half-life, which is not possible. Ligand B (-3.435) also has a negative half-life, which is not possible. These values are suspect and require further investigation.

**14. P-gp Efflux:** Both ligands have low P-gp efflux liability (0.244 and 0.15), which is favorable for CNS penetration.

**15. Binding Affinity:** Ligand A (-8.6 kcal/mol) has a significantly stronger binding affinity than Ligand B (-6.9 kcal/mol). This is a substantial difference (1.7 kcal/mol), and affinity is a primary driver of potency.

**Overall Assessment:**

Ligand A is the superior candidate. While Ligand B has slightly better metabolic stability, Ligand A excels in critical areas for a CNS-targeting GPCR: TPSA, BBB penetration, and, most importantly, binding affinity. The DILI risk is also lower for Ligand A. The negative half-life values for both compounds are concerning and warrant further investigation, but the substantial affinity advantage of Ligand A outweighs the other minor drawbacks.

Output:
1
2025-04-17 05:48:50,043 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (439.14 Da) is higher, but still acceptable. Ligand B (352.41 Da) is slightly lower, which could be beneficial for permeability.

**TPSA:** Ligand A (37.61) is excellent for CNS penetration, well below the 90 A^2 threshold. Ligand B (96.25) is higher, potentially hindering BBB penetration, though still not drastically outside acceptable limits.

**logP:** Ligand A (4.888) is slightly high, potentially leading to solubility issues or off-target interactions. Ligand B (0.637) is quite low, which could impede permeation.

**H-Bond Donors/Acceptors:** Ligand A (0 HBD, 4 HBA) is favorable. Ligand B (3 HBD, 5 HBA) is also reasonable.

**QED:** Both ligands have good QED scores (A: 0.542, B: 0.671), indicating good drug-like properties.

**DILI:** Ligand A (75.378) has a higher DILI risk than Ligand B (52.695), which is preferable.

**BBB:** Ligand A (82.978) has a significantly better BBB percentile than Ligand B (63.94), a crucial factor for a CNS target like DRD2.

**Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and suggests potential issues with the data or the model's prediction. However, the magnitude of negativity is similar.

**Aqueous Solubility:** Both ligands have very poor aqueous solubility (-6.23 and -2.795 respectively). This is a major concern for both.

**hERG Inhibition:** Ligand A (0.72) has a slightly higher hERG risk than Ligand B (0.125), making B more favorable.

**Microsomal Clearance:** Ligand A (52.936) has a higher clearance than Ligand B (10.9), indicating lower metabolic stability.

**In vitro Half-Life:** Ligand A (95.303) has a much longer half-life than Ligand B (4.074), which is a significant advantage.

**P-gp Efflux:** Ligand A (0.798) has better P-gp efflux properties than Ligand B (0.044), which is favorable for CNS penetration.

**Binding Affinity:** Ligand A (-8.7 kcal/mol) has a significantly stronger binding affinity than Ligand B (-7.5 kcal/mol). This 1.2 kcal/mol difference is substantial and can outweigh some of the ADME drawbacks.

**Overall Assessment:**

Ligand A excels in binding affinity, BBB penetration, P-gp efflux, and in vitro half-life. Its logP is slightly high, and DILI risk is a concern, but the strong binding affinity and excellent CNS penetration properties are compelling. Ligand B has better hERG and DILI profiles, but suffers from poor BBB penetration, lower affinity, and poor metabolic stability.

Given the importance of CNS penetration for a DRD2 ligand, and the significant advantage in binding affinity, Ligand A is the more promising candidate despite its drawbacks. The solubility issues would need to be addressed through formulation strategies.

Output:
1
2025-04-17 05:48:50,044 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (421.689 Da) is higher, but still acceptable. Ligand B (340.467 Da) is slightly preferred.

**TPSA:** Ligand A (78.38) is higher than Ligand B (50.36). For a CNS target like DRD2, we want TPSA <= 90, both are within this range, but B is better.

**logP:** Both ligands have good logP values (A: 3.537, B: 4.489), falling within the optimal 1-3 range. Ligand B is slightly higher, which *could* indicate potential off-target effects, but isn't a major concern at this level.

**H-Bond Donors/Acceptors:** Ligand A (HBD=0, HBA=7) and Ligand B (HBD=2, HBA=2) both have reasonable H-bond characteristics. Ligand B is better here, as it has fewer H-donors.

**QED:** Both have good QED scores (A: 0.543, B: 0.842), indicating good drug-like properties. Ligand B is significantly better.

**DILI:** Ligand A (76.464) has a higher DILI risk than Ligand B (49.477). This is a significant advantage for Ligand B.

**BBB:** Both ligands have good BBB penetration (A: 77.627, B: 73.401), exceeding the 70% threshold for CNS targets. Ligand A is slightly better, but both are acceptable.

**Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and problematic. It suggests poor permeability.

**Aqueous Solubility:** Both have negative solubility values, which is also unusual and problematic. It suggests poor solubility.

**hERG Inhibition:** Both ligands show low hERG inhibition risk (A: 0.23, B: 0.804), which is good.

**Microsomal Clearance:** Both have relatively high microsomal clearance (A: 81.781, B: 83.143), indicating faster metabolism.

**In vitro Half-Life:** Ligand B (-3.02) has a *very* short half-life, which is a major drawback. Ligand A (14.154) is much better.

**P-gp Efflux:** Both have low P-gp efflux (A: 0.342, B: 0.287), which is favorable for CNS penetration.

**Binding Affinity:** Ligand B (-8.8 kcal/mol) has a significantly stronger binding affinity than Ligand A (-7.7 kcal/mol), exceeding the 1.5 kcal/mol advantage threshold.

**Overall Assessment:**

Ligand B has a superior QED, lower DILI risk, and a significantly better binding affinity. However, its extremely short in vitro half-life is a major concern. Ligand A has a better half-life, but a higher DILI risk and weaker binding. Given the importance of binding affinity for GPCRs, and the fact that the half-life issue *might* be addressable through structural modifications, Ligand B is the more promising candidate. The negative Caco-2 and solubility values are concerning for both, and would need to be addressed.

Output:
1
2025-04-17 05:48:50,044 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (341.411 Da) is slightly lower, which could be advantageous for permeability.

**TPSA:** Ligand A (65.9) is better than Ligand B (46.33). For a CNS target like DRD2, a TPSA under 90 is desirable, and Ligand A is closer to the optimal range for CNS penetration.

**logP:** Ligand A (2.219) is within the optimal range (1-3). Ligand B (4.472) is higher, potentially leading to solubility issues and off-target interactions.

**H-Bond Donors/Acceptors:** Both have acceptable HBD counts (1). Ligand A has 5 HBA, while Ligand B has 2. Both are within the acceptable limit of 10.

**QED:** Both ligands have good QED scores (A: 0.903, B: 0.824), indicating good drug-like properties.

**DILI:** Ligand A (64.986) has a higher DILI risk than Ligand B (14.541). This is a significant drawback for Ligand A.

**BBB:** Ligand B (94.261) has a much higher BBB percentile than Ligand A (49.748). This is a *critical* advantage for a CNS target like DRD2.

**Caco-2 Permeability:** Ligand A (-4.608) and Ligand B (-4.55) are both quite poor.

**Aqueous Solubility:** Ligand A (-2.383) and Ligand B (-4.103) are both quite poor.

**hERG Inhibition:** Ligand A (0.222) has a lower hERG inhibition risk than Ligand B (0.878).

**Microsomal Clearance:** Ligand B (21.664) has a higher microsomal clearance than Ligand A (1.049), indicating lower metabolic stability.

**In vitro Half-Life:** Ligand A (20.224) has a significantly longer half-life than Ligand B (10.448).

**P-gp Efflux:** Ligand A (0.082) has much lower P-gp efflux liability than Ligand B (0.471). This is crucial for CNS penetration.

**Binding Affinity:** Both ligands have very similar binding affinities (-8.8 kcal/mol and -8.7 kcal/mol). The difference is negligible.

**Overall Assessment:**

Ligand B is the stronger candidate. While Ligand A has a better TPSA and lower P-gp efflux, the significantly higher BBB penetration of Ligand B is the deciding factor for a CNS target. Ligand B also has a much lower DILI risk. The slightly higher logP of Ligand B is a concern, but the substantial advantage in BBB penetration outweighs this drawback. The longer half-life of Ligand A is a plus, but not enough to overcome the BBB and DILI issues.

Output:
1
2025-04-17 05:48:50,044 - INFO - Reasoning:

Let's analyze Ligand A and Ligand B based on the provided guidelines, prioritizing GPCR-specific properties (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (339.439 Da) is slightly lower, which is generally favorable for permeability. Ligand B (361.431 Da) is also good.

**TPSA:** Ligand A (56.15) is excellent, well below the 90 Angstrom threshold for CNS targets. Ligand B (105.9) is higher but still potentially acceptable, though less ideal.

**logP:** Ligand A (3.55) is at the upper end of the optimal range (1-3), but still acceptable. Ligand B (0.257) is significantly low, potentially hindering membrane permeability and CNS penetration.

**H-Bond Donors/Acceptors:** Both ligands have 1 HBD, which is good. Ligand A has 5 HBA, acceptable. Ligand B has 8 HBA, which is getting towards the upper limit and could impact permeability.

**QED:** Both ligands have good QED scores (A: 0.646, B: 0.74), indicating drug-like properties.

**DILI:** Both have acceptable DILI risk (A: 36.642, B: 74.409), but Ligand A is significantly better.

**BBB:** Ligand A (71.229) is very good, exceeding the 70% threshold for CNS targets. Ligand B (52.811) is considerably lower, raising concerns about brain penetration.

**Caco-2 Permeability:** Ligand A (-4.773) is poor, indicating low intestinal absorption. Ligand B (-5.647) is also poor, but slightly worse.

**Aqueous Solubility:** Ligand A (-3.933) is poor, while Ligand B (-1.303) is also poor, but better than A.

**hERG Inhibition:** Ligand A (0.696) is low risk, while Ligand B (0.009) is very low risk.

**Microsomal Clearance:** Ligand A (70.074) is moderate, indicating moderate metabolic stability. Ligand B (17.871) is low, suggesting good metabolic stability.

**In vitro Half-Life:** Ligand A (-11.425) is poor, indicating a short half-life. Ligand B (-3.072) is also poor, but better than A.

**P-gp Efflux:** Ligand A (0.607) is moderate, while Ligand B (0.065) is very low, indicating minimal P-gp efflux.

**Binding Affinity:** Ligand A (-8.4 kcal/mol) is significantly stronger than Ligand B (-7.9 kcal/mol). This 0.5 kcal/mol difference is substantial and can outweigh some ADME drawbacks.

**Overall Assessment:**

Ligand A excels in key GPCR-relevant properties: TPSA, BBB, and, most importantly, binding affinity. While its Caco-2 permeability, solubility, and half-life are poor, the strong binding affinity and good BBB penetration are crucial for a CNS-targeting drug. Ligand B has better metabolic stability and lower P-gp efflux, but its low logP and significantly lower BBB penetration are major drawbacks for a CNS drug. The better affinity of Ligand A is also a significant advantage.

Output:
1
2025-04-17 05:48:50,044 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (351.422 and 349.435 Da) fall comfortably within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (82.53) is excellent, well below the 90 A^2 threshold for CNS targets. Ligand B (109.58) is still reasonable but less optimal, being above 90 A^2.

**3. logP:** Ligand A (1.657) is within the optimal 1-3 range. Ligand B (0.009) is quite low, potentially hindering membrane permeability.

**4. H-Bond Donors:** Ligand A (2) and Ligand B (3) are both acceptable, below the 5 limit.

**5. H-Bond Acceptors:** Ligand A (4) and Ligand B (6) are both acceptable, below the 10 limit.

**6. QED:** Ligand A (0.845) has a very good drug-likeness score. Ligand B (0.64) is still acceptable, but lower.

**7. DILI:** Both ligands have low DILI risk (39.899 and 35.75 respectively), which is positive.

**8. BBB:** Ligand A (65.607) and Ligand B (71.772) both have reasonably good BBB penetration, but ligand B is slightly better. A value >70 is highly desirable for CNS targets, and both are below this, but ligand B is closer.

**9. Caco-2:** Both ligands have negative Caco-2 values (-4.643 and -5.544). This is unusual and suggests poor permeability. However, these values are on a scale where negative values are possible, and the absolute magnitude is important. Ligand B has a slightly more negative value, indicating potentially worse permeability.

**10. Solubility:** Both ligands have negative solubility values (-2.069 and -1.928). Similar to Caco-2, this is possible on the scale used, and indicates poor solubility.

**11. hERG:** Both ligands have low hERG risk (0.366 and 0.449), which is good.

**12. Cl_mic:** Ligand A (19.185) has a lower microsomal clearance than Ligand B (-23.645). This suggests better metabolic stability for Ligand A.

**13. t1/2:** Ligand A (-20.773) has a more negative in vitro half-life than Ligand B (0.13). This is unusual and suggests a very short half-life for Ligand A. Ligand B has a very short half-life as well.

**14. Pgp:** Both ligands have very low Pgp efflux liability (0.122 and 0.004), which is excellent for CNS penetration.

**15. Binding Affinity:** Ligand A (-9.1 kcal/mol) has a significantly stronger binding affinity than Ligand B (-8.2 kcal/mol). This is a substantial advantage (>1.5 kcal/mol difference).

**Overall Assessment:**

While both compounds have some drawbacks, Ligand A is the more promising candidate. Its superior binding affinity (-9.1 vs -8.2 kcal/mol) is a major advantage, and it has a better TPSA and metabolic stability (lower Cl_mic). Although the half-life is concerningly short, the strong binding could potentially compensate. Ligand B's very low logP is a significant concern, potentially hindering its ability to cross cell membranes and reach the target in the brain.

Output:
1
2025-04-17 05:48:50,044 - INFO - Reasoning:

Let's analyze Ligand A and Ligand B against the provided guidelines, prioritizing GPCR-specific properties (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (362.832 and 351.378 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (57.28) is excellent, well below the 90 A^2 threshold for CNS targets. Ligand B (91.76) is higher, but still potentially acceptable, though less ideal.

**logP:** Ligand A (4.395) is slightly high, potentially leading to solubility issues or off-target interactions. Ligand B (1.528) is quite low, potentially hindering membrane permeability.

**H-Bond Donors/Acceptors:** Ligand A (3 HBD, 3 HBA) is within the ideal range. Ligand B (2 HBD, 5 HBA) is also acceptable.

**QED:** Both ligands have good QED scores (0.609 and 0.811), indicating good drug-like properties.

**DILI:** Ligand A (53.47) has a slightly higher DILI risk than Ligand B (40.287), but both are reasonably low.

**BBB:** This is a critical parameter for a CNS target like DRD2. Ligand B (72.974) significantly outperforms Ligand A (51.997) in BBB penetration, exceeding the desirable >70% threshold.

**Caco-2 Permeability:** Ligand A (-5.266) has poor Caco-2 permeability, suggesting poor intestinal absorption. Ligand B (-4.822) is also poor, but slightly better than A.

**Aqueous Solubility:** Ligand A (-4.406) has very poor solubility. Ligand B (-2.828) is better, but still not great.

**hERG Inhibition:** Ligand A (0.911) has a slightly higher hERG risk than Ligand B (0.205).

**Microsomal Clearance:** Ligand A (43.355) has higher clearance than Ligand B (6.465), indicating lower metabolic stability.

**In vitro Half-Life:** Ligand B (-33.405) has a significantly longer half-life than Ligand A (38.031).

**P-gp Efflux:** Ligand A (0.683) has moderate P-gp efflux, while Ligand B (0.035) has very low efflux, which is highly desirable for CNS penetration.

**Binding Affinity:** Ligand B (-7.8 kcal/mol) has a considerably stronger binding affinity than Ligand A (-9.2 kcal/mol). This is a substantial advantage.

**Overall Assessment:**

While Ligand A has a slightly better affinity, Ligand B is clearly superior based on the combined ADME-Tox profile and GPCR-specific priorities. Ligand B's significantly better BBB penetration, lower P-gp efflux, longer half-life, and stronger binding affinity outweigh its slightly higher TPSA and lower logP. Ligand A's poor solubility and Caco-2 permeability are major drawbacks. The higher logP of Ligand A is also concerning.

Output:
1
2025-04-17 05:48:50,045 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (349.475 and 352.479 Da) are within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (62.83) is significantly better than Ligand B (85.25). For CNS targets, we want TPSA <= 90, and A is comfortably within this range, while B is approaching the upper limit.

**3. logP:** Both ligands have a logP around 2.0 (2.002 and 2.036), which is optimal (1-3).

**4. H-Bond Donors:** Both have 2 HBD, which is within the acceptable limit of <= 5.

**5. H-Bond Acceptors:** Ligand A has 4 HBA, and Ligand B has 5. Both are within the acceptable limit of <= 10.

**6. QED:** Ligand A (0.716) is slightly better than Ligand B (0.675), both are above the 0.5 threshold.

**7. DILI:** Ligand A (13.339) has a much lower DILI risk than Ligand B (40.054).  A score <40 is good, and A is well within this range, while B is right at the threshold.

**8. BBB:** This is a critical parameter for CNS targets. Ligand A (64.637) is considerably better than Ligand B (47.189). A value > 70 is desirable, but 64.637 is a reasonable starting point, while 47.189 is less promising.

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.873 and -4.98). This is unusual and suggests poor permeability. However, the values are very similar.

**10. Aqueous Solubility:** Both ligands have negative solubility values (-1.639 and -2.196), indicating poor solubility. Again, these are similar.

**11. hERG Inhibition:** Both ligands have very low hERG inhibition liability (0.472 and 0.167), which is excellent.

**12. Microsomal Clearance:** Ligand A (18.424) has lower microsomal clearance than Ligand B (46.16), indicating better metabolic stability.

**13. In vitro Half-Life:** Ligand A (36.051) has a longer in vitro half-life than Ligand B (26.725).

**14. P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.011 and 0.035), which is excellent for CNS penetration.

**15. Binding Affinity:** Ligand A (-7.9 kcal/mol) has a slightly better binding affinity than Ligand B (-7.4 kcal/mol). While both are good (<-7.0), the 0.5 kcal/mol difference is noticeable.

**Overall Assessment:**

Ligand A consistently outperforms Ligand B across most critical parameters, especially TPSA, BBB, DILI, and metabolic stability (Cl_mic and t1/2). While both have issues with Caco-2 and solubility, these are less critical for a CNS target where BBB penetration is paramount. The slightly better affinity of Ligand A further supports its selection.

Output:
0
2025-04-17 05:48:50,045 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 drug candidates, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (339.4 and 344.4 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (84.98) is significantly better than Ligand B (111.03). For CNS targets, we want TPSA <= 90, and Ligand A is comfortably within that range, while Ligand B exceeds it.

**3. logP:** Both ligands have good logP values (2.33 and 1.688), falling within the optimal 1-3 range.

**4. H-Bond Donors:** Both have 2 HBD, which is acceptable.

**5. H-Bond Acceptors:** Ligand A has 6 HBA, and Ligand B has 7. Both are within the acceptable limit of <=10.

**6. QED:** Both ligands have similar QED values (0.615 and 0.584), indicating reasonable drug-likeness.

**7. DILI:** Ligand A (59.6%) has a lower DILI risk than Ligand B (82.9%). Lower is better, and both are moderately risky, but A is preferable.

**8. BBB:** Both ligands have excellent BBB penetration (73.5% and 79.3%). Both are above the desirable 70% threshold for CNS targets.

**9. Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and suggests poor permeability. However, the scale is not specified, so it's difficult to interpret.

**10. Aqueous Solubility:** Both have negative solubility values, indicating poor solubility. Again, the scale is unclear.

**11. hERG Inhibition:** Ligand A (0.79) has a lower hERG inhibition liability than Ligand B (0.046). Lower is better.

**12. Microsomal Clearance:** Ligand A (59.37) has higher microsomal clearance than Ligand B (40.27). Lower clearance is preferred for metabolic stability, so Ligand B is better here.

**13. In vitro Half-Life:** Ligand B (-3.263) has a longer in vitro half-life than Ligand A (4.692). Longer is better.

**14. P-gp Efflux:** Ligand A (0.316) has lower P-gp efflux liability than Ligand B (0.102). Lower is better, especially for CNS targets, as it improves brain exposure.

**15. Binding Affinity:** Ligand B (-9.1 kcal/mol) has a slightly better binding affinity than Ligand A (-8.7 kcal/mol). A difference of 0.4 kcal/mol is significant, and could outweigh some ADME drawbacks.

**Overall Assessment:**

Ligand A excels in TPSA, DILI, hERG, and P-gp efflux, all critical for CNS GPCR targeting. Ligand B has slightly better affinity and half-life, but suffers from higher TPSA, DILI, and P-gp efflux. Given the importance of BBB penetration and minimizing off-target effects (hERG, DILI) for a CNS drug, and the fact that both have good BBB values, Ligand A appears to be the more promising candidate. The slightly weaker binding affinity of Ligand A can potentially be optimized in subsequent iterations.

Output:
1
2025-04-17 05:48:50,045 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (347.5 & 355.4 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (63.13) is slightly above the preferred <90 for CNS targets, but still reasonable. Ligand B (52.65) is well within the desired range.

**3. logP:** Both ligands have good logP values (3.175 & 2.272), falling within the optimal 1-3 range.

**4. H-Bond Donors:** Ligand A (2) and Ligand B (1) are both acceptable, being less than 5.

**5. H-Bond Acceptors:** Both ligands have 3 H-bond acceptors, well below the limit of 10.

**6. QED:** Both ligands have good QED scores (0.674 & 0.778), indicating drug-like properties.

**7. DILI:** Both ligands have low DILI risk (25.2 & 22.5 percentile), which is favorable.

**8. BBB:** Both ligands exhibit excellent BBB penetration (70.9% & 75.2%), crucial for a CNS target like DRD2. Ligand B is slightly better.

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.758 & -4.591). This is unusual and potentially problematic, suggesting poor intestinal absorption. However, for a CNS target, intestinal absorption is less critical than BBB penetration.

**10. Aqueous Solubility:** Both ligands have negative solubility values (-3.218 & -1.028), indicating poor aqueous solubility. This could pose formulation challenges.

**11. hERG Inhibition:** Both ligands show low hERG inhibition risk (0.696 & 0.659).

**12. Microsomal Clearance:** Ligand A (48.947) has higher microsomal clearance than Ligand B (18.268), suggesting lower metabolic stability.

**13. In vitro Half-Life:** Ligand B (6.758 hours) has a longer half-life than Ligand A (13.759 hours). This is a positive attribute.

**14. P-gp Efflux:** Both ligands have low P-gp efflux liability (0.394 & 0.02). Ligand B is significantly better here, which is important for CNS exposure.

**15. Binding Affinity:** Ligand B (-7.9 kcal/mol) has a slightly better binding affinity than Ligand A (-7.7 kcal/mol). While the difference is small, it's within the range where it can outweigh minor ADME drawbacks.

**Overall Assessment:**

Both ligands have promising profiles, particularly regarding BBB penetration and DILI risk. However, Ligand B is slightly superior due to its better P-gp efflux liability, longer half-life, and slightly improved binding affinity. While both have poor solubility and Caco-2 permeability, these are less critical for a CNS-targeted GPCR. The lower microsomal clearance of Ligand B is also a significant advantage.

Output:
1
2025-04-17 05:48:50,045 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B based on the provided guidelines, prioritizing GPCR properties (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (354.378) is slightly lower, which could be beneficial for permeability.

**TPSA:** Both ligands have TPSA values below the 90 A^2 threshold desirable for CNS targets. Ligand B (75.44) is lower than Ligand A (88.1), which is favorable for brain penetration.

**logP:** Ligand A (1.256) is within the optimal range (1-3), while Ligand B (3.367) is at the higher end. While still acceptable, Ligand B's higher logP could potentially lead to off-target interactions or solubility issues.

**H-Bond Donors/Acceptors:** Both ligands have acceptable HBD (2 and 1 respectively) and HBA (5) counts.

**QED:** Both ligands have similar and good QED scores (0.766 and 0.758).

**DILI:** Ligand A (34.626) has a significantly lower DILI risk than Ligand B (60.682). This is a major advantage for Ligand A.

**BBB:** Ligand A (77.705) has a much better BBB percentile than Ligand B (31.136). This is critical for a CNS target like DRD2.

**Caco-2 Permeability:** Both have negative values, indicating poor permeability. However, the scale is not defined, so it's hard to interpret.

**Aqueous Solubility:** Both have negative values, indicating poor solubility. Again, the scale is not defined.

**hERG:** Both ligands show very low hERG inhibition risk (0.084 and 0.287).

**Microsomal Clearance:** Ligand A (-20.946) has a much lower (better) microsomal clearance than Ligand B (76.395), suggesting greater metabolic stability.

**In vitro Half-Life:** Ligand A (-25.241) has a much longer in vitro half-life than Ligand B (58.569), which is desirable.

**P-gp Efflux:** Ligand A (0.004) has a significantly lower P-gp efflux liability than Ligand B (0.175), meaning it's less likely to be pumped out of the brain.

**Binding Affinity:** Ligand B (-7.3) has a slightly better binding affinity than Ligand A (-8.2). However, the difference is only 0.9 kcal/mol, and the other ADME properties of Ligand A are far superior.

**Overall Assessment:**

Ligand A is significantly better overall, especially considering the GPCR-specific priorities. Its superior BBB penetration, lower DILI risk, improved metabolic stability (lower Cl_mic, longer t1/2), and lower P-gp efflux outweigh the slightly weaker binding affinity. The slightly better logP of Ligand A is also an advantage.

Output:
0
2025-04-17 05:48:50,045 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (375.397 and 399.822 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (87.74) is better than Ligand B (78.51), both are below the 90 A^2 threshold for CNS targets.

**logP:** Both ligands (2.011 and 2.213) are within the optimal 1-3 range.

**H-Bond Donors:** Both ligands have 2 HBD, which is acceptable (<=5).

**H-Bond Acceptors:** Ligand A has 5 HBA, and Ligand B has 4. Both are within the acceptable range (<=10).

**QED:** Both ligands have similar QED values (0.774 and 0.795), indicating good drug-likeness.

**DILI:** Ligand B (61.264) has a lower DILI risk than Ligand A (77.278), which is preferable.

**BBB:** Ligand A (55.603) has a significantly better BBB penetration percentile than Ligand B (44.862). This is a *critical* advantage for a CNS target like DRD2.

**Caco-2 Permeability:** Ligand A (-4.778) has a better Caco-2 permeability than Ligand B (-5.155).

**Aqueous Solubility:** Ligand A (-3.408) has better aqueous solubility than Ligand B (-3.711).

**hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.284 and 0.471).

**Microsomal Clearance:** Ligand B (3.278) has a much lower microsomal clearance than Ligand A (27.952), indicating better metabolic stability.

**In vitro Half-Life:** Ligand A (-11.938) has a longer in vitro half-life than Ligand B (-9.67), which is desirable.

**P-gp Efflux:** Ligand A (0.049) has lower P-gp efflux than Ligand B (0.026), which is better for CNS exposure.

**Binding Affinity:** Both ligands have excellent binding affinities (-8.2 and -8.8 kcal/mol). Ligand B is slightly better (-8.8 kcal/mol), but the difference is small.

**Overall Assessment:**

Ligand A excels in BBB penetration, Caco-2 permeability, solubility, and in vitro half-life. Ligand B has better DILI and microsomal clearance. The most important factor for a CNS GPCR target is BBB penetration, and Ligand A has a substantial advantage in this area. While Ligand B's lower clearance is attractive, the difference isn't large enough to overcome Ligand A's superior BBB score. The binding affinity difference is minimal.

Output:
0
2025-04-17 05:48:50,046 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (368.5 and 349.5 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Both ligands have TPSA values (75.7 and 70.5) below 90, which is favorable for CNS penetration.

**3. logP:** Both ligands have logP values around 1.5, which is optimal.

**4. H-Bond Donors:** Both have 1 HBD, which is within the acceptable limit of 5.

**5. H-Bond Acceptors:** Both have 5 HBA, which is within the acceptable limit of 10.

**6. QED:** Both ligands have QED values above 0.6, indicating good drug-likeness.

**7. DILI:** Ligand A (37.6) has a slightly higher DILI risk than Ligand B (20.4), but both are below the 40 threshold and considered good.

**8. BBB:** Ligand A (71.7) has a better BBB percentile than Ligand B (64.0). This is a crucial factor for a CNS target like DRD2.

**9. Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and suggests poor permeability. This is a significant drawback for both compounds.

**10. Aqueous Solubility:** Both have negative solubility values, indicating very poor aqueous solubility. This is a major concern for formulation and bioavailability.

**11. hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.242 and 0.26).

**12. Microsomal Clearance:** Ligand A (93.8) has a higher microsomal clearance than Ligand B (23.1), suggesting lower metabolic stability.

**13. In vitro Half-Life:** Ligand B (12.6) has a significantly longer in vitro half-life than Ligand A (3.6).

**14. P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.09 and 0.007), which is good for CNS exposure.

**15. Binding Affinity:** Ligand B (-7.3 kcal/mol) has a slightly better binding affinity than Ligand A (-7.0 kcal/mol), although the difference is small.

**Overall Assessment:**

While both compounds have issues with Caco-2 permeability and solubility, Ligand B is slightly more favorable. It has a better binding affinity, a longer half-life, lower DILI risk, and lower P-gp efflux. The most important factor for a CNS target is BBB penetration, and Ligand A has a slightly better BBB score, but the other advantages of Ligand B outweigh this. The difference in binding affinity is not substantial enough to overcome the other ADME properties.

Output:
1
2025-04-17 05:48:50,046 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (390.452) is slightly higher than Ligand B (346.519), but both are acceptable.

**2. TPSA:** Ligand A (51.22) is better than Ligand B (59.07). For CNS targets, we want TPSA <= 90, and ideally closer to 60. Ligand A is closer to the ideal range.

**3. logP:** Both ligands have good logP values (A: 4.741, B: 4.04), falling within the optimal range of 1-3, although slightly high. This could potentially lead to off-target effects, but is not a major concern at this stage.

**4. H-Bond Donors:** Ligand A (1) is preferable to Ligand B (2). Lower HBD generally improves permeability.

**5. H-Bond Acceptors:** Both ligands have the same number of HBA (5), which is within the acceptable limit of <= 10.

**6. QED:** Both ligands have similar and good QED values (A: 0.742, B: 0.78), indicating good drug-like properties.

**7. DILI:** Ligand A (76.425) has a higher DILI risk than Ligand B (34.858). This is a significant drawback for Ligand A.

**8. BBB:** Ligand B (92.71) has a considerably better BBB penetration score than Ligand A (68.864). For a CNS target like DRD2, this is a critical advantage.

**9. Caco-2 Permeability:** Ligand A (-4.795) has better Caco-2 permeability than Ligand B (-4.611), indicating better intestinal absorption. However, given the CNS target, intestinal absorption is less crucial than BBB penetration.

**10. Aqueous Solubility:** Both ligands have poor aqueous solubility (-4.991 and -4.6 respectively). This could pose formulation challenges, but is not a deciding factor at this stage.

**11. hERG Inhibition:** Ligand A (0.462) has a lower hERG inhibition liability than Ligand B (0.867), which is favorable.

**12. Microsomal Clearance:** Ligand A (81.192) has a higher microsomal clearance than Ligand B (79.155), suggesting lower metabolic stability.

**13. In vitro Half-Life:** Ligand B (50.426) has a significantly longer in vitro half-life than Ligand A (-15.358). This is a major advantage for Ligand B.

**14. P-gp Efflux:** Ligand A (0.572) has lower P-gp efflux liability than Ligand B (0.342), which is favorable for CNS penetration.

**15. Binding Affinity:** Ligand B (-8.1) has a slightly better binding affinity than Ligand A (-7.9). While the difference is small, it's still a positive for Ligand B.

**Overall Assessment:**

Ligand B is the more promising candidate. While Ligand A has better Caco-2 permeability and lower P-gp efflux, Ligand B excels in the most critical areas for a CNS GPCR target: significantly better BBB penetration, a longer half-life, and a lower DILI risk. The slightly better binding affinity of Ligand B further strengthens its position. The higher logP of both compounds is a potential concern, but the advantages of Ligand B outweigh this drawback.

Output:
1
2025-04-17 05:48:50,046 - INFO - Reasoning:

Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (364.917 and 345.363 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (58.2) is excellent, well below the 90 A^2 threshold for CNS targets. Ligand B (136.93) is higher, but still potentially acceptable, though less ideal.

**3. logP:** Ligand A (3.864) is within the optimal 1-3 range. Ligand B (-1.596) is significantly lower, which could hinder membrane permeability and CNS penetration.

**4. H-Bond Donors:** Both ligands have acceptable HBD counts (2 and 3, respectively), below the 5 threshold.

**5. H-Bond Acceptors:** Ligand A (2) is good. Ligand B (8) is higher, but still within the acceptable limit of 10.

**6. QED:** Both ligands have similar QED values (0.619 and 0.577), indicating good drug-like properties.

**7. DILI:** Ligand A (20.24) has a much lower DILI risk than Ligand B (69.756), which is a significant advantage.

**8. BBB:** Ligand A (75.533) has a good BBB penetration percentile, exceeding the 70% target for CNS drugs. Ligand B (39.55) is considerably lower, raising concerns about reaching the target in the brain.

**9. Caco-2 Permeability:** Ligand A (-4.867) has poor Caco-2 permeability. Ligand B (-6.126) is even worse. This is a concern for both, but less critical for a CNS target where BBB penetration is paramount.

**10. Aqueous Solubility:** Ligand A (-3.865) has poor solubility. Ligand B (-2.134) is slightly better, but still low.

**11. hERG Inhibition:** Both ligands show very low hERG inhibition risk (0.646 and 0.072).

**12. Microsomal Clearance:** Ligand A (44.915) has moderate clearance. Ligand B (-5.151) has negative clearance, which is unusual and likely an artifact of the prediction method, but suggests very high metabolic stability.

**13. In vitro Half-Life:** Ligand A (40.452) has a reasonable half-life. Ligand B (-13.92) has a negative half-life, which is also likely an artifact and suggests exceptional stability.

**14. P-gp Efflux:** Ligand A (0.274) has low P-gp efflux, which is favorable for CNS penetration. Ligand B (0.004) has very low P-gp efflux, even more favorable.

**15. Binding Affinity:** Both ligands have excellent binding affinity (-8.4 and -8.5 kcal/mol), with a negligible difference.

**Overall Assessment:**

Ligand A is superior due to its significantly better BBB penetration (75.533 vs 39.55) and substantially lower DILI risk (20.24 vs 69.756). While Ligand A has poorer Caco-2 permeability and solubility, these are less critical for a CNS-targeted GPCR like DRD2, where BBB penetration is the rate-limiting step. Ligand B's negative values for clearance and half-life are suspect and raise concerns about the reliability of its ADME predictions. The slightly better P-gp efflux of Ligand B is not enough to offset the other significant drawbacks.

Output:
1
2025-04-17 05:48:50,046 - INFO - Batch 229 complete. Total preferences: 3664
2025-04-17 05:48:50,046 - INFO - Processing batch 230/512...
2025-04-17 05:49:33,502 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (359.294 and 345.447 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (29.54) is excellent, well below the 90 A^2 threshold for CNS targets. Ligand B (87.22) is higher, but still potentially acceptable, though less ideal for CNS penetration.

**3. logP:** Ligand A (3.592) is at the upper end of the optimal range (1-3), while Ligand B (1.436) is at the lower end. While both are within range, a higher logP can sometimes aid in BBB penetration for CNS targets.

**4. H-Bond Donors:** Ligand A (0) is good, minimizing potential issues with permeability. Ligand B (2) is also acceptable.

**5. H-Bond Acceptors:** Ligand A (2) is good. Ligand B (5) is also reasonable.

**6. QED:** Both ligands have good QED scores (0.603 and 0.762, respectively), indicating drug-like properties.

**7. DILI Risk:** Ligand A (60.45) has a moderate DILI risk, while Ligand B (31.601) has a low DILI risk. This favors Ligand B.

**8. BBB Penetration:** Ligand A (81.698) has excellent BBB penetration, exceeding the desirable 70% threshold. Ligand B (74.796) is also good, but slightly lower.

**9. Caco-2 Permeability:** Ligand A (-3.961) has poor Caco-2 permeability, which is a concern. Ligand B (-5.179) is even worse.

**10. Aqueous Solubility:** Ligand A (-3.8) has poor aqueous solubility, while Ligand B (-1.565) is also poor. This is a potential formulation challenge for both.

**11. hERG Inhibition:** Ligand A (0.76) has a low hERG risk. Ligand B (0.326) has a very low hERG risk, which is favorable.

**12. Microsomal Clearance:** Ligand A (81.439) has high microsomal clearance, indicating poor metabolic stability. Ligand B (12.811) has much lower clearance, suggesting better metabolic stability.

**13. In vitro Half-Life:** Ligand A (8.404) has a moderate half-life. Ligand B (5.116) has a shorter half-life.

**14. P-gp Efflux:** Ligand A (0.482) has low P-gp efflux, which is good for CNS exposure. Ligand B (0.01) has extremely low P-gp efflux, which is even better.

**15. Binding Affinity:** Ligand A (-9.0) has a significantly stronger binding affinity than Ligand B (-8.5). This 1.5 kcal/mol difference is substantial and can outweigh some ADME drawbacks.

**Overall Assessment:**

Ligand A has a superior binding affinity and excellent BBB penetration, but suffers from poor Caco-2 permeability, high microsomal clearance, and moderate DILI risk. Ligand B has better metabolic stability (lower Cl_mic), lower DILI risk, and extremely low P-gp efflux, but its binding affinity is weaker and its Caco-2 permeability is also poor.

Given the importance of affinity for GPCRs, and the relatively strong advantage of Ligand A (-9.0 vs -8.5), I believe Ligand A is the more promising candidate *despite* its ADME liabilities. The strong binding could potentially be optimized with further medicinal chemistry to address the permeability and metabolic stability issues. The excellent BBB penetration is also a significant advantage for a CNS target like DRD2.

Output:
1
2025-04-17 05:49:33,502 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (349.479 and 350.459 Da) fall within the ideal range of 200-500 Da.

**TPSA:** Ligand A (98.17) is slightly above the preferred <90 for CNS targets, while Ligand B (84.5) is well within the range. This gives a slight edge to Ligand B.

**logP:** Ligand A (3.423) is at the higher end of the optimal range (1-3), while Ligand B (1.572) is towards the lower end. While both are acceptable, a logP that's too high can lead to off-target effects, making Ligand B slightly preferable.

**H-Bond Donors/Acceptors:** Ligand A (HBD=1, HBA=3) and Ligand B (HBD=2, HBA=4) both have reasonable numbers of H-bond donors and acceptors, well within the guidelines.

**QED:** Ligand B (0.762) has a significantly better QED score than Ligand A (0.283), indicating a more drug-like profile.

**DILI:** Ligand B (20.744) has a much lower DILI risk than Ligand A (32.183), which is a significant advantage.

**BBB:** Ligand B (70.531) has a better BBB penetration percentile than Ligand A (62.97), crucial for a CNS target like DRD2.

**Caco-2 Permeability:** Ligand A (-4.706) and Ligand B (-5.037) both have negative Caco-2 values, which is unusual and indicates very poor permeability. This is a major concern for both compounds.

**Aqueous Solubility:** Ligand A (-3.116) and Ligand B (-2.204) both have poor aqueous solubility. This is a drawback, but can sometimes be overcome with formulation strategies.

**hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.38 and 0.101 respectively).

**Microsomal Clearance:** Ligand B (17.129) has a lower microsomal clearance than Ligand A (62.211), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand B (7.998) has a longer in vitro half-life than Ligand A (12.37), which is a positive attribute.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.044 and 0.027 respectively).

**Binding Affinity:** Ligand B (-7.8 kcal/mol) has a significantly stronger binding affinity than Ligand A (-6.9 kcal/mol). This 0.9 kcal/mol difference is substantial and can outweigh some of the ADME drawbacks.

**Overall Assessment:**

Ligand B is clearly the more promising candidate. It has a better QED score, lower DILI risk, better BBB penetration, lower microsomal clearance, longer half-life, and significantly stronger binding affinity. While both compounds suffer from poor Caco-2 permeability and aqueous solubility, the superior binding affinity and ADME properties of Ligand B make it the preferred choice for further development.

Output:
1
2025-04-17 05:49:33,502 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (496.196 Da) is at the higher end, while Ligand B (372.462 Da) is more favorably positioned.

**TPSA:** Ligand A (92.42) is slightly above the optimal <90 for CNS targets, but still reasonable. Ligand B (70.08) is excellent, well below 90.

**logP:** Ligand A (3.261) is within the optimal range (1-3). Ligand B (1.468) is on the lower side, potentially impacting permeability.

**H-Bond Donors/Acceptors:** Ligand A has 3 HBD and 4 HBA, which is acceptable. Ligand B has 1 HBD and 5 HBA, also acceptable.

**QED:** Both ligands have good QED scores (A: 0.549, B: 0.787), indicating good drug-like properties.

**DILI:** Ligand A (71.694) has a higher DILI risk than Ligand B (27.801). This is a significant concern for Ligand A.

**BBB:** Ligand B (85.459) has a much better BBB penetration score than Ligand A (43.893). This is *critical* for a CNS target like DRD2.

**Caco-2 Permeability:** Ligand A (-5.291) has poor Caco-2 permeability, indicating poor intestinal absorption. Ligand B (-4.566) is also poor, but slightly better.

**Aqueous Solubility:** Ligand A (-3.615) has poor aqueous solubility. Ligand B (-1.523) is also poor, but better than A.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (A: 0.819, B: 0.567).

**Microsomal Clearance:** Ligand A (37.797) has a higher microsomal clearance than Ligand B (20.868), suggesting lower metabolic stability.

**In vitro Half-Life:** Ligand B (11.685) has a significantly longer in vitro half-life than Ligand A (79.075).

**P-gp Efflux:** Ligand A (0.671) has slightly higher P-gp efflux than Ligand B (0.159), which is undesirable.

**Binding Affinity:** Ligand B (-7.4 kcal/mol) has a slightly better binding affinity than Ligand A (-8.1 kcal/mol). While A is stronger, the difference is not substantial enough to overcome the other significant drawbacks.

**Overall Assessment:**

Ligand B is the superior candidate. While both have some solubility and permeability issues, Ligand B excels in the critical areas for a CNS GPCR target: BBB penetration, lower DILI risk, better metabolic stability (lower Cl_mic, longer t1/2), lower P-gp efflux, and acceptable binding affinity. Ligand A's poor BBB, high DILI, poor permeability, and higher P-gp efflux make it a less attractive candidate despite its slightly better binding affinity.



Output:
1
2025-04-17 05:49:33,503 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (387.311 and 359.539 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (68.7) is better than Ligand B (38.13). For CNS targets, we want TPSA <= 90, both meet this, but A is closer to the upper limit, potentially indicating better hydrogen bonding for target engagement.

**3. logP:** Ligand A (2.69) is within the optimal 1-3 range. Ligand B (4.134) is slightly higher, potentially leading to solubility issues and off-target interactions.

**4. H-Bond Donors:** Ligand A (2) is acceptable, while Ligand B (0) is also good.

**5. H-Bond Acceptors:** Both ligands have 4 HBA, which is within the acceptable limit of <=10.

**6. QED:** Both ligands have similar QED values (0.78 and 0.711), indicating good drug-like properties.

**7. DILI:** Ligand A (19.969) has a significantly lower DILI risk than Ligand B (29.857), which is a major advantage.

**8. BBB:** Ligand B (78.868) has a much better BBB penetration percentile than Ligand A (47.848). This is *critical* for a CNS target like DRD2.

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.105 and -5.017), which is unusual and suggests poor permeability. This is a concern for both.

**10. Aqueous Solubility:** Both ligands have negative solubility values (-2.193 and -3.979), indicating poor aqueous solubility. This is a concern for both.

**11. hERG Inhibition:** Both ligands have low hERG inhibition risk (0.623 and 0.725).

**12. Microsomal Clearance:** Ligand A (-21.954) has a much lower (better) microsomal clearance than Ligand B (118.227), indicating better metabolic stability.

**13. In vitro Half-Life:** Ligand A (74.584) has a significantly longer in vitro half-life than Ligand B (25.454), which is desirable.

**14. P-gp Efflux:** Ligand A (0.061) has a much lower P-gp efflux liability than Ligand B (0.621), which is crucial for CNS penetration.

**15. Binding Affinity:** Ligand A (-8.4) has a significantly stronger binding affinity than Ligand B (-6.8). A difference of 1.6 kcal/mol is substantial and can outweigh some ADME drawbacks.

**Overall Assessment:**

Ligand A has superior DILI, metabolic stability (Cl_mic and t1/2), P-gp efflux, and *significantly* better binding affinity. Ligand B's main advantage is its higher BBB penetration. However, the substantial difference in binding affinity (-8.4 vs -6.8 kcal/mol) and the lower P-gp efflux of Ligand A are more important for a GPCR target. While both have poor Caco-2 and solubility, the stronger binding and better ADME profile of Ligand A make it the more promising candidate. The better BBB of Ligand B is not enough to overcome the substantial affinity difference.

Output:
0
2025-04-17 05:49:33,503 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (335.455 and 344.415 Da) are within the ideal 200-500 Da range.

**TPSA:** Ligand A (37.19) is excellent, well below the 90 A^2 threshold for CNS targets. Ligand B (94.56) is significantly higher, exceeding the desirable range for CNS penetration.

**logP:** Ligand A (3.201) is optimal (1-3). Ligand B (0.213) is quite low, potentially hindering membrane permeability and CNS entry.

**H-Bond Donors/Acceptors:** Ligand A (0 HBD, 5 HBA) and Ligand B (3 HBD, 5 HBA) both fall within acceptable limits (<=5 HBD, <=10 HBA).

**QED:** Both ligands have reasonable QED values (0.717 and 0.615), indicating good drug-like properties.

**DILI:** Ligand A (46.375) has a moderate DILI risk, while Ligand B (13.571) has a very low risk.

**BBB:** This is a crucial parameter for a CNS target like DRD2. Ligand A scores very well (92.71), indicating high predicted BBB penetration. Ligand B's BBB score (35.595) is poor, suggesting limited CNS exposure.

**Caco-2 Permeability:** Both have negative values, which is unusual and likely indicates a scaling issue. However, the magnitude of the negative value for Ligand A (-5.068) is smaller than that of Ligand B (-5.607), suggesting slightly better permeability.

**Aqueous Solubility:** Both have negative values, which is unusual. Again, the magnitude of the negative value for Ligand A (-2.699) is smaller than that of Ligand B (-1.466), suggesting slightly better solubility.

**hERG:** Ligand A (0.947) has a low hERG risk, while Ligand B (0.077) also has a very low hERG risk.

**Microsomal Clearance:** Ligand A (44.947) has moderate clearance, while Ligand B (-9.662) has negative clearance, which is impossible. This is likely an error in the data.

**In vitro Half-Life:** Ligand A (3.771) has a short half-life, while Ligand B (-0.755) has a negative half-life, which is impossible. This is likely an error in the data.

**P-gp Efflux:** Ligand A (0.786) has moderate P-gp efflux, while Ligand B (0.005) has very low P-gp efflux.

**Binding Affinity:** Both ligands have excellent binding affinities (-8.7 and -8.5 kcal/mol), with Ligand A being slightly stronger. The difference (0.2 kcal/mol) is not substantial enough to override other significant ADME differences.

**Conclusion:**

Considering the GPCR-specific priorities, Ligand A is the superior candidate. Its excellent TPSA and BBB scores are critical for CNS penetration. While Ligand B has a slightly lower DILI risk and P-gp efflux, its poor logP and BBB penetration are major drawbacks for a DRD2 ligand. The questionable negative values for clearance and half-life for Ligand B further diminish its viability. The slightly better affinity of Ligand A is a bonus, but the ADME properties are the deciding factors.

Output:
1
2025-04-17 05:49:33,503 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (349.431 Da) is slightly lower, which could be beneficial for permeability. Ligand B (375.519 Da) is also good.

**TPSA:** Ligand A (91.5) is slightly above the optimal 90 for CNS targets, but still reasonable. Ligand B (71.09) is excellent, well below 90, indicating good potential for CNS penetration.

**logP:** Ligand A (1.158) is within the optimal range (1-3). Ligand B (3.711) is at the higher end of the optimal range, potentially leading to solubility issues, but still acceptable.

**H-Bond Donors/Acceptors:** Both ligands have 2 HBDs and 4-5 HBAs, which are within the acceptable limits (<=5 HBDs, <=10 HBAs).

**QED:** Both ligands have similar QED values (0.7 and 0.782), indicating good drug-likeness.

**DILI:** Ligand A (18.302) has a significantly lower DILI risk than Ligand B (69.678). This is a major advantage for Ligand A.

**BBB:** Ligand A (61.923) has a moderate BBB penetration, while Ligand B (57.968) is lower. Neither are ideal (>70), but Ligand A is better.

**Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and suggests poor permeability. However, these values are on a scale where negative values are possible, and the absolute magnitude matters. Ligand A (-4.56) is better than Ligand B (-5.104).

**Aqueous Solubility:** Both ligands have negative solubility values, indicating poor aqueous solubility. Ligand A (-2.534) is better than Ligand B (-4.541).

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.2 and 0.425), which is good.

**Microsomal Clearance:** Ligand A (30.176) has a lower microsomal clearance than Ligand B (39.064), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand B (35.185) has a longer in vitro half-life than Ligand A (-23.25). This is a positive for Ligand B.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.017 and 0.228), which is favorable for CNS penetration.

**Binding Affinity:** Ligand B (-8.1) has a slightly better binding affinity than Ligand A (-7.8). However, the difference is only 0.3 kcal/mol, which is not substantial enough to outweigh other significant differences.

**Overall Assessment:**

Considering the GPCR-specific priorities, Ligand A is the more promising candidate. While Ligand B has a slightly better binding affinity and half-life, Ligand A has a significantly lower DILI risk, better Caco-2 permeability and solubility, and a slightly better BBB score. The lower DILI risk is a critical advantage, and the other factors contribute to a more favorable overall profile.

Output:
0
2025-04-17 05:49:33,503 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (348.367 and 355.479 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (131.06) is slightly above the optimal <90 for CNS targets, but still reasonable. Ligand B (93.11) is excellent, well within the desired range.

**3. logP:** Ligand A (-1.861) is a bit low, potentially hindering permeability. Ligand B (-0.187) is also on the lower side, but better than A. Both are below the optimal 1-3 range.

**4. H-Bond Donors:** Ligand A (2) and Ligand B (3) are both acceptable, below the limit of 5.

**5. H-Bond Acceptors:** Ligand A (9) is approaching the upper limit of 10, while Ligand B (5) is well within the acceptable range.

**6. QED:** Both ligands have similar QED values (0.6 and 0.533), indicating good drug-like properties.

**7. DILI:** Ligand A (66.654) has a higher DILI risk than Ligand B (4.769). This is a significant advantage for Ligand B.

**8. BBB:** Ligand B (43.699) has a substantially better BBB penetration percentile than Ligand A (21.946). This is *critical* for a CNS target like DRD2.

**9. Caco-2 Permeability:** Ligand A (-5.643) and Ligand B (-5.207) both have negative Caco-2 values, suggesting poor intestinal absorption. This is a concern for both.

**10. Aqueous Solubility:** Both ligands have very poor aqueous solubility (-1.064 and -1.05). This could pose formulation challenges.

**11. hERG Inhibition:** Ligand A (0.023) has a slightly better hERG profile than Ligand B (0.149), indicating lower cardiotoxicity risk.

**12. Microsomal Clearance:** Ligand A (-2.864) has a lower (better) microsomal clearance than Ligand B (-5.728), suggesting greater metabolic stability.

**13. In vitro Half-Life:** Ligand A (15.968) has a longer half-life than Ligand B (8.43).

**14. P-gp Efflux:** Ligand A (0.013) has a much lower P-gp efflux liability than Ligand B (0.008), which is favorable for CNS exposure.

**15. Binding Affinity:** Ligand A (-8.4) has a significantly stronger binding affinity than Ligand B (-7.0). This is a substantial advantage, potentially outweighing some ADME drawbacks.

**Overall Assessment:**

While Ligand A has a superior binding affinity and better metabolic stability, Ligand B excels in crucial properties for a CNS-targeting GPCR ligand: significantly better BBB penetration, much lower DILI risk, and a more favorable HBA count. The lower affinity of Ligand B is a concern, but the substantial improvement in safety (DILI) and brain exposure (BBB) makes it a more promising candidate. The slightly better P-gp efflux for ligand A is not enough to overcome the other advantages of ligand B.

Output:
1
2025-04-17 05:49:33,503 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (349.479 and 361.467 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (74.49) is slightly above the optimal <90 for CNS targets, but still reasonable. Ligand B (68.46) is excellent, well below 90.

**3. logP:** Ligand A (0.783) is a bit low, potentially hindering permeability. Ligand B (3.056) is optimal.

**4. H-Bond Donors:** Ligand A (1) is good. Ligand B (0) is also good.

**5. H-Bond Acceptors:** Both ligands (6) are within the acceptable limit of 10.

**6. QED:** Both ligands (0.751 and 0.709) have good drug-likeness scores.

**7. DILI:** Ligand A (8.569) has a very low DILI risk. Ligand B (55.642) is higher, but still within an acceptable range.

**8. BBB:** Ligand A (53.238) has a moderate BBB penetration, which is a concern for a CNS target. Ligand B (71.733) is much better, exceeding the desirable >70 threshold.

**9. Caco-2:** Ligand A (-4.862) has poor Caco-2 permeability. Ligand B (-5.185) is also poor, but slightly better than A.

**10. Solubility:** Ligand A (-0.174) has poor solubility. Ligand B (-2.878) has even poorer solubility.

**11. hERG:** Both ligands (0.141 and 0.403) have low hERG inhibition risk.

**12. Cl_mic:** Ligand A (5.321) has lower microsomal clearance, suggesting better metabolic stability. Ligand B (89.365) has high clearance, indicating rapid metabolism.

**13. t1/2:** Both ligands (17.33 and 17.717 hours) have comparable in vitro half-lives.

**14. Pgp:** Ligand A (0.037) has very low P-gp efflux, which is excellent for CNS penetration. Ligand B (0.546) has moderate P-gp efflux.

**15. Affinity:** Both ligands (-7 and -7.8 kcal/mol) have excellent binding affinity. Ligand B is slightly better.

**Overall Assessment:**

While both ligands have good affinity, Ligand B is the stronger candidate. Its superior logP, BBB penetration, and slightly better affinity outweigh its higher DILI and lower metabolic stability. Ligand A's poor logP, Caco-2 permeability, and moderate BBB penetration are significant drawbacks for a CNS-targeting drug. The lower P-gp efflux of ligand A is a positive, but the other factors are more critical for DRD2.

Output:
1
2025-04-17 05:49:33,504 - INFO - Reasoning:

Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (342.403 and 368.455 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (111.06) is slightly above the preferred <90 for CNS targets, but still reasonable. Ligand B (97.64) is excellent, well below 90.

**3. logP:** Both ligands have good logP values (2.223 and 1.193), falling within the optimal 1-3 range.

**4. H-Bond Donors:** Ligand A (1) and Ligand B (2) are both acceptable, being less than 5.

**5. H-Bond Acceptors:** Ligand A (4) and Ligand B (5) are both acceptable, being less than 10.

**6. QED:** Ligand B (0.814) has a significantly better QED score than Ligand A (0.269), indicating a more drug-like profile.

**7. DILI:** Ligand B (64.831) has a higher DILI risk than Ligand A (49.709), but both are below the concerning threshold of 60.

**8. BBB:** Ligand B (70.648) has a better BBB penetration percentile than Ligand A (55.332). Both are above 70, which is desirable for CNS targets, but Ligand B is better.

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.21 and -5.25), which is unusual and suggests poor permeability. This is a significant concern for both.

**10. Aqueous Solubility:** Both ligands have negative solubility values (-1.284 and -2.679), indicating very poor aqueous solubility. This is a major drawback for both.

**11. hERG Inhibition:** Both ligands have low hERG inhibition risk (0.394 and 0.543).

**12. Microsomal Clearance:** Ligand B (11.744) has a much higher microsomal clearance than Ligand A (5.412), suggesting lower metabolic stability.

**13. In vitro Half-Life:** Ligand B (33.289) has a much longer in vitro half-life than Ligand A (-4.353), which is a significant advantage.

**14. P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.034 and 0.092).

**15. Binding Affinity:** Both ligands have identical and excellent binding affinities (-7.9 kcal/mol).

**Overall Assessment:**

Despite both ligands having excellent binding affinity, Ligand B is the more promising candidate. Its superior BBB penetration, better QED score, and longer half-life outweigh the higher DILI risk and increased microsomal clearance. The poor Caco-2 permeability and solubility are concerning for both, but can potentially be addressed through formulation strategies. Ligand A's significantly lower QED and short half-life make it less attractive.

Output:
1
2025-04-17 05:49:33,504 - INFO - Reasoning:

Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (346.471 Da) is slightly lower, which is generally favorable for permeability.

**2. TPSA:** Ligand A (62.55) is significantly better than Ligand B (71.53). For CNS targets, TPSA < 90 is preferred, and A is closer to the optimal <60 range.

**3. logP:** Both ligands have similar logP values (3.442 and 3.448), falling within the optimal range of 1-3.

**4. H-Bond Donors:** Both ligands have 1 HBD, which is good.

**5. H-Bond Acceptors:** Ligand A has 3 HBA, while Ligand B has 6. Lower HBA is generally preferred for better permeability, making Ligand A more favorable.

**6. QED:** Ligand A (0.858) has a significantly better QED score than Ligand B (0.774), indicating a more drug-like profile.

**7. DILI:** Ligand B (83.094) has a higher DILI risk than Ligand A (47.77). Lower DILI is crucial, giving an advantage to Ligand A.

**8. BBB:** Ligand A (71.229) has a substantially better BBB penetration prediction than Ligand B (58.123). This is a *critical* factor for a CNS target like DRD2.

**9. Caco-2 Permeability:** Ligand A (-4.664) has a slightly better Caco-2 permeability than Ligand B (-5.088), although both are negative values which is unusual.

**10. Aqueous Solubility:** Ligand A (-3.843) has slightly better aqueous solubility than Ligand B (-4.226).

**11. hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.376 and 0.252).

**12. Microsomal Clearance:** Ligand B (51.366) has a slightly lower microsomal clearance than Ligand A (55.834), suggesting better metabolic stability. However, the difference is not substantial.

**13. In vitro Half-Life:** Ligand A (35.954) has a much longer in vitro half-life than Ligand B (13.589), which is a significant advantage.

**14. P-gp Efflux:** Ligand A (0.431) has a lower P-gp efflux liability than Ligand B (0.317), which is favorable for CNS exposure.

**15. Binding Affinity:** Both ligands have the same binding affinity (-7.2 kcal/mol), which is excellent.

**Overall Assessment:**

Ligand A consistently outperforms Ligand B across most critical ADME properties, particularly BBB penetration, TPSA, QED, DILI risk, and in vitro half-life. While Ligand B has slightly better metabolic stability, the other advantages of Ligand A, especially its superior CNS penetration profile, make it the more promising drug candidate for targeting DRD2. The equal binding affinity removes that as a differentiating factor.

Output:
1
2025-04-17 05:49:33,504 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (352.475 and 369.531 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (78.87) is better than Ligand B (90.27). Both are below 140, but for a CNS target like DRD2, we ideally want TPSA under 90. Ligand A is closer to this target.

**3. logP:** Both ligands have acceptable logP values (1.172 and 2.417), falling within the 1-3 range. Ligand B is slightly higher, which could potentially lead to off-target effects, but is still within the acceptable range.

**4. H-Bond Donors:** Ligand A has 2 HBD, and Ligand B has 1. Both are within the acceptable limit of <=5.

**5. H-Bond Acceptors:** Both ligands have 4 HBA, which is within the acceptable limit of <=10.

**6. QED:** Ligand A (0.752) has a better QED score than Ligand B (0.599), indicating a more drug-like profile.

**7. DILI:** Ligand B (23.226) has a significantly lower DILI risk than Ligand A (16.208), which is a substantial advantage.

**8. BBB:** Ligand B (78.79) has a considerably better BBB penetration percentile than Ligand A (52.889). This is *critical* for a CNS target like DRD2.

**9. Caco-2 Permeability:** Ligand A (-4.764) has a worse Caco-2 permeability than Ligand B (-4.978). Both are negative, indicating poor permeability, but Ligand B is slightly better.

**10. Aqueous Solubility:** Ligand A (-2.036) has slightly better solubility than Ligand B (-2.86).

**11. hERG Inhibition:** Ligand A (0.307) has a lower hERG inhibition liability than Ligand B (0.771), which is favorable.

**12. Microsomal Clearance:** Ligand B (34.707) has a lower microsomal clearance than Ligand A (40.74), suggesting better metabolic stability.

**13. In vitro Half-Life:** Ligand B (-46.446) has a significantly longer in vitro half-life than Ligand A (7.243). This is a major advantage.

**14. P-gp Efflux:** Ligand A (0.209) shows lower P-gp efflux than Ligand B (0.214), which is slightly better.

**15. Binding Affinity:** Ligand B (-7.1) has a slightly better binding affinity than Ligand A (-7.0). While the difference is small, it's still a positive.

**Overall Assessment:**

Ligand B is the stronger candidate. While Ligand A has slightly better hERG and P-gp properties, Ligand B excels in the most critical areas for a CNS GPCR target: BBB penetration, metabolic stability (lower Cl_mic, longer t1/2), and DILI risk. The slightly better binding affinity of Ligand B further supports this conclusion. The improved BBB penetration is a major factor, as it directly addresses the need for CNS exposure.

Output:
1
2025-04-17 05:49:33,504 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (359.411 and 347.409 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (102.17) is higher than the preferred <90 for CNS targets, while Ligand B (45.23) is well within the optimal range. This is a significant advantage for Ligand B.

**logP:** Both ligands (2.778 and 3.278) are within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A has 2 HBD and 7 HBA, while Ligand B has 1 HBD and 3 HBA. Both are within acceptable limits (<=5 HBD and <=10 HBA).

**QED:** Both ligands have good QED scores (0.672 and 0.923), indicating good drug-like properties.

**DILI:** Ligand A (94.843) has a concerningly high DILI risk, while Ligand B (54.789) is better, though still above the ideal <40.

**BBB:** Ligand A (71.733) is acceptable for CNS penetration, while Ligand B (89.957) is excellent, exceeding the 70% threshold. This is a major advantage for Ligand B.

**Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and suggests poor permeability. However, the scale isn't specified, so this is hard to interpret.

**Aqueous Solubility:** Both ligands have negative solubility values, which is also unusual and suggests poor solubility.

**hERG:** Both ligands have low hERG inhibition liability (0.219 and 0.817), which is favorable.

**Microsomal Clearance:** Ligand A (45.433) and Ligand B (32.669) both have relatively low microsomal clearance, suggesting reasonable metabolic stability.

**In vitro Half-Life:** Ligand A (-2.585) has a negative half-life, which is impossible. Ligand B (35.235) has a reasonable half-life.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.191 and 0.466), which is good for CNS penetration.

**Binding Affinity:** Both ligands have excellent binding affinities (-9.1 and -8.7 kcal/mol). The difference of 0.4 kcal/mol is not substantial enough to overcome other significant differences.

**Overall Assessment:**

Ligand B is significantly better due to its superior TPSA, BBB penetration, DILI risk, and in vitro half-life. While both have issues with Caco-2 and solubility, the TPSA and BBB are critical for CNS targets like DRD2. Ligand A's high DILI risk and impossible half-life are major red flags. The slightly better affinity of Ligand A is not enough to compensate for these drawbacks.

Output:
1
2025-04-17 05:49:33,504 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (348.353 and 365.459 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (97.11) is better than Ligand B (101.53). Both are under the 140 A^2 threshold for good oral absorption, and closer to the desirable <90 A^2 for CNS targets.

**3. logP:** Ligand A (1.767) is within the optimal 1-3 range. Ligand B (-0.36) is below 1, which could hinder permeation. This is a significant drawback for Ligand B.

**4. H-Bond Donors:** Ligand A (3) is acceptable, while Ligand B (1) is also good.

**5. H-Bond Acceptors:** Ligand A (4) is acceptable, while Ligand B (6) is also acceptable.

**6. QED:** Both ligands have similar, good QED values (0.741 and 0.768, respectively).

**7. DILI:** Ligand A (73.052) has a higher DILI risk than Ligand B (40.209), but both are below the concerning threshold of 60.

**8. BBB:** Ligand A (66.886) has a better BBB penetration percentile than Ligand B (37.224). This is *highly* important for a DRD2 ligand targeting CNS disorders.

**9. Caco-2 Permeability:** Both have negative values, which is unusual. However, the magnitude of the negative value is less important than the other parameters.

**10. Aqueous Solubility:** Both have negative values, which is unusual. However, the magnitude of the negative value is less important than the other parameters.

**11. hERG:** Both ligands show very low hERG inhibition liability (0.489 and 0.055), which is excellent.

**12. Microsomal Clearance:** Ligand A (33.711) has higher microsomal clearance than Ligand B (4.079), indicating lower metabolic stability.

**13. In vitro Half-Life:** Ligand A (7.933) has a longer half-life than Ligand B (-0.945), which is desirable.

**14. P-gp Efflux:** Ligand A (0.036) shows lower P-gp efflux liability than Ligand B (0.014), which is beneficial for CNS exposure.

**15. Binding Affinity:** Ligand B (-7.5 kcal/mol) has a significantly stronger binding affinity than Ligand A (-9.0 kcal/mol). This is a substantial advantage.

**Overall Assessment:**

While Ligand B has a superior binding affinity, its significantly lower logP and BBB penetration are major concerns for a CNS-targeting drug. Ligand A, despite a slightly weaker binding affinity, has a much better logP, BBB, and P-gp efflux profile, making it more likely to reach the target in the brain. The slightly higher DILI risk and clearance for Ligand A are less concerning than the permeability issues with Ligand B.

Output:
1
2025-04-17 05:49:33,505 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight (MW):** Both ligands (343.431 and 346.471 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (80.12) is better than Ligand B (58.64). Both are below the 90 A^2 threshold desirable for CNS targets, but A is closer to the upper limit.

**3. logP:** Both ligands have good logP values (1.698 and 2.577), falling within the optimal 1-3 range. Ligand B is slightly higher, which could be beneficial for membrane permeability.

**4. H-Bond Donors (HBD):** Both have 1 HBD, which is within the acceptable limit of <=5.

**5. H-Bond Acceptors (HBA):** Ligand A has 5 HBA, and Ligand B has 3. Both are within the acceptable limit of <=10.

**6. QED:** Ligand A (0.83) has a higher QED than Ligand B (0.752), indicating a more drug-like profile.

**7. DILI:** Ligand A (43.195) has a slightly higher DILI risk than Ligand B (22.334), but both are below the concerning threshold of 60.

**8. BBB:** Ligand B (67.701) has a significantly better BBB percentile than Ligand A (45.909). This is a *critical* factor for a CNS target like DRD2.

**9. Caco-2 Permeability:** Ligand A (-5.079) has worse Caco-2 permeability than Ligand B (-4.777). Both are negative, which is unusual, but B is less negative.

**10. Aqueous Solubility:** Ligand A (-1.428) has better aqueous solubility than Ligand B (-2.331).

**11. hERG Inhibition:** Both ligands have low hERG inhibition risk (0.137 and 0.325).

**12. Microsomal Clearance (Cl_mic):** Ligand A (40.338) and Ligand B (42.215) have similar microsomal clearance values.

**13. In vitro Half-Life:** Ligand A (18.653) has a longer in vitro half-life than Ligand B (-19.054). This is a positive attribute.

**14. P-gp Efflux:** Ligand A (0.018) has a much lower P-gp efflux liability than Ligand B (0.178), which is highly desirable for CNS penetration.

**15. Binding Affinity:** Ligand B (-9.2 kcal/mol) has a significantly stronger binding affinity than Ligand A (-8.0 kcal/mol). This is a substantial advantage.

**Overall Assessment:**

While Ligand A has better QED, solubility, and half-life, Ligand B excels in the most critical areas for a CNS-targeting GPCR ligand: **BBB penetration and binding affinity**. The significantly stronger binding affinity (-9.2 vs -8.0 kcal/mol) is a major advantage that can often outweigh minor ADME drawbacks. The higher BBB percentile (67.701 vs 45.909) is also crucial for CNS exposure. Lower P-gp efflux for Ligand A is good, but the difference isn't as impactful as the affinity and BBB differences.

Output:
1
2025-04-17 05:49:33,505 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (336.395 and 368.503 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (78.25) is better than Ligand B (75.63). Both are below the 90 A^2 threshold desirable for CNS targets, but A is closer to the ideal.

**3. logP:** Both ligands (2.952 and 2.263) are within the optimal 1-3 range.

**4. H-Bond Donors:** Ligand A (1) is better than Ligand B (0). While both are acceptable, having one HBD can sometimes improve solubility.

**5. H-Bond Acceptors:** Ligand B (7) is better than Ligand A (6). Both are below the 10 threshold.

**6. QED:** Ligand A (0.846) is significantly better than Ligand B (0.492), indicating a more drug-like profile.

**7. DILI:** Ligand A (75.184) has a slightly higher DILI risk than Ligand B (64.831), but both are acceptable (<80).

**8. BBB:** Ligand B (85.459) has a considerably better BBB penetration percentile than Ligand A (64.637). This is a *critical* factor for a DRD2 ligand targeting CNS disorders.

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.57 and -4.797), which is unusual and suggests poor permeability. However, these values are on a log scale and a negative value doesn't necessarily preclude development.

**10. Aqueous Solubility:** Ligand A (-5.378) has slightly better aqueous solubility than Ligand B (-2.698), though both are poor.

**11. hERG Inhibition:** Both ligands (0.756 and 0.686) show low hERG inhibition risk.

**12. Microsomal Clearance:** Ligand A (103.016) has lower microsomal clearance than Ligand B (113.805), suggesting better metabolic stability.

**13. In vitro Half-Life:** Ligand A (26.246) has a much longer in vitro half-life than Ligand B (-14.692). This is a significant advantage.

**14. P-gp Efflux:** Both ligands (0.328 and 0.501) have relatively low P-gp efflux liability.

**15. Binding Affinity:** Ligand A (-7.6) has a stronger binding affinity than Ligand B (-6.5). This is a 1.1 kcal/mol difference, which is substantial and can outweigh some ADME drawbacks.

**Overall Assessment:**

While Ligand B has a superior BBB score, Ligand A excels in most other crucial areas: QED, metabolic stability (lower Cl_mic, longer t1/2), and significantly stronger binding affinity. The difference in binding affinity is large enough to potentially overcome the slightly lower BBB score of Ligand A, especially if formulation strategies can be employed to enhance brain delivery. The poor Caco-2 values are a concern for both, but not necessarily a dealbreaker.

Output:
1
2025-04-17 05:49:33,505 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (348.451 and 361.511 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (83.36) is better than Ligand B (53.51). Both are below the 90 A^2 threshold desirable for CNS targets, but Ligand A is closer to the upper limit.

**logP:** Ligand A (0.186) is quite low, potentially hindering permeability. Ligand B (3.095) is within the optimal 1-3 range. This is a significant advantage for Ligand B.

**H-Bond Donors/Acceptors:** Ligand A has 1 HBD and 6 HBA, while Ligand B has 0 HBD and 4 HBA. Both are within acceptable limits.

**QED:** Both ligands have good QED scores (0.725 and 0.813), indicating good drug-like properties.

**DILI:** Ligand A (29.197) has a much lower DILI risk than Ligand B (45.56).

**BBB:** Both ligands have excellent BBB penetration (70.57% and 77.743%), exceeding the desirable >70% threshold for CNS targets. Ligand B is slightly better.

**Caco-2 Permeability:** Ligand A (-4.965) has poor Caco-2 permeability, while Ligand B (-4.719) is also poor, but slightly better.

**Aqueous Solubility:** Ligand A (-0.985) has poor aqueous solubility, while Ligand B (-3.086) is even worse.

**hERG Inhibition:** Ligand A (0.277) has a very low hERG risk, while Ligand B (0.525) is slightly higher.

**Microsomal Clearance:** Ligand A (20.431) has lower microsomal clearance, indicating better metabolic stability, compared to Ligand B (66.378).

**In vitro Half-Life:** Ligand A (3.475) has a shorter half-life than Ligand B (-12.121).

**P-gp Efflux:** Ligand A (0.01) has very low P-gp efflux, which is highly desirable for CNS penetration. Ligand B (0.308) has a higher, but still relatively low, P-gp efflux.

**Binding Affinity:** Ligand B (-7.8) has a slightly better binding affinity than Ligand A (-7.5), though the difference is small.

**Overall Assessment:**

Ligand B has a more favorable logP, which is crucial for GPCR ligands. While Ligand A has better DILI and P-gp efflux, the poor logP and Caco-2 permeability are significant drawbacks. The slightly better affinity of Ligand B, combined with its acceptable logP, outweighs the minor advantages of Ligand A. The metabolic stability of Ligand A is a plus, but can be addressed through structural modifications.

Output:
1
2025-04-17 05:49:33,505 - INFO - Batch 230 complete. Total preferences: 3680
2025-04-17 05:49:33,505 - INFO - Processing batch 231/512...
2025-04-17 05:50:14,815 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (356.451 and 349.475 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (83.98) is better than Ligand B (69.72) as it is closer to the <90 threshold for CNS targets.

**logP:** Both ligands have good logP values (2.415 and 1.259), falling within the optimal 1-3 range. Ligand B is slightly lower, which *could* indicate a potential permeability issue, but it's not severe.

**H-Bond Donors/Acceptors:** Ligand A has 2 HBD and 5 HBA, while Ligand B has 1 HBD and 3 HBA. Both are within acceptable limits (<=5 HBD and <=10 HBA).

**QED:** Ligand A (0.862) has a significantly better QED score than Ligand B (0.556), indicating a more drug-like profile.

**DILI:** Ligand A (70.182) has a higher DILI risk than Ligand B (34.781). This is a significant negative for Ligand A.

**BBB:** Ligand B (67.623) has a better BBB penetration percentile than Ligand A (49.011). While neither are >70, Ligand B is noticeably better. This is crucial for a CNS target like DRD2.

**Caco-2 Permeability:** Ligand A (-5.367) has a worse Caco-2 permeability than Ligand B (-4.298). Both are negative, indicating poor permeability, but B is slightly better.

**Aqueous Solubility:** Ligand A (-3.192) has worse aqueous solubility than Ligand B (-2.2).

**hERG Inhibition:** Ligand A (0.136) has a slightly better hERG profile than Ligand B (0.494), but both are low risk.

**Microsomal Clearance:** Ligand B (61.745) has a significantly higher microsomal clearance than Ligand A (-0.307). This means Ligand A is more metabolically stable.

**In vitro Half-Life:** Ligand A (25.411) has a better in vitro half-life than Ligand B (-35.287).

**P-gp Efflux:** Ligand A (0.063) has lower P-gp efflux liability than Ligand B (0.091), which is favorable for CNS penetration.

**Binding Affinity:** Ligand A (-8.5 kcal/mol) has a significantly stronger binding affinity than Ligand B (-7.4 kcal/mol). This 1.1 kcal/mol difference is substantial and can outweigh some ADME drawbacks.

**Overall Assessment:**

Ligand A has a much stronger binding affinity and better metabolic stability (lower Cl_mic, longer t1/2, lower Pgp efflux). However, it has a higher DILI risk, worse BBB penetration, and lower solubility. Ligand B has a better safety profile (lower DILI), better BBB penetration, and better solubility, but its affinity is weaker.

Given the GPCR-specific priorities and the importance of CNS penetration for a DRD2 ligand, the stronger affinity of Ligand A is a major advantage. The DILI risk is concerning, but could potentially be mitigated with structural modifications. The slightly better BBB of Ligand B is not enough to overcome the significant difference in binding affinity.

Output:
1
2025-04-17 05:50:14,815 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (370.49 and 370.925 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (78.43) is slightly higher than Ligand B (70.39). Both are below the 90 A^2 threshold desirable for CNS targets, but Ligand B is preferable.

**3. logP:** Both ligands have good logP values (2.932 and 2.371), falling within the optimal 1-3 range.

**4. H-Bond Donors:** Ligand A has 3 HBD, and Ligand B has 2. Both are acceptable (<=5).

**5. H-Bond Acceptors:** Ligand A has 4 HBA, and Ligand B has 5. Both are acceptable (<=10).

**6. QED:** Both ligands have good QED scores (0.584 and 0.737), indicating good drug-like properties.

**7. DILI:** Ligand A (37.456) has a slightly higher DILI risk than Ligand B (15.859). Ligand B is significantly better here.

**8. BBB:** Ligand A (61.38) has a better BBB percentile than Ligand B (53.276). This is a crucial factor for a CNS target like DRD2.

**9. Caco-2 Permeability:** Ligand A (-4.934) shows poorer Caco-2 permeability than Ligand B (-5.071). Both are negative, indicating poor permeability, but Ligand B is slightly better.

**10. Aqueous Solubility:** Ligand A (-3.726) has slightly better aqueous solubility than Ligand B (-2.557).

**11. hERG Inhibition:** Both ligands show low hERG inhibition risk (0.79 and 0.652).

**12. Microsomal Clearance:** Ligand A (61.695) has a higher microsomal clearance than Ligand B (43.194), indicating lower metabolic stability. Ligand B is preferable.

**13. In vitro Half-Life:** Ligand A (67.206) has a longer in vitro half-life than Ligand B (28.36). This is a positive for Ligand A.

**14. P-gp Efflux:** Ligand A (0.455) has lower P-gp efflux liability than Ligand B (0.282), which is favorable for CNS penetration.

**15. Binding Affinity:** Ligand A (-7.6 kcal/mol) has a significantly stronger binding affinity than Ligand B (-6.4 kcal/mol). This is a substantial advantage.

**Overall Assessment:**

While Ligand B has better DILI, metabolic stability, and slightly better TPSA, Ligand A's significantly stronger binding affinity (-7.6 vs -6.4 kcal/mol) and better BBB penetration (61.38 vs 53.276) are critical for a CNS GPCR target. The difference in binding affinity is substantial enough to outweigh the minor ADME drawbacks of Ligand A. The longer half-life and lower P-gp efflux also contribute to its favorability.

Output:
1
2025-04-17 05:50:14,816 - INFO - Reasoning:

Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (352.391 and 364.511 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (115.46) is slightly above the optimal <90 for CNS targets, but still reasonable. Ligand B (49.85) is excellent, well below 90.

**3. logP:** Ligand A (0.92) is a bit low, potentially hindering permeability. Ligand B (1.782) is better, falling within the 1-3 range.

**4. H-Bond Donors:** Ligand A (2) is good. Ligand B (0) is also good, potentially improving permeability.

**5. H-Bond Acceptors:** Ligand A (7) is acceptable. Ligand B (4) is also good.

**6. QED:** Ligand A (0.814) is excellent, indicating high drug-likeness. Ligand B (0.551) is acceptable, but less ideal.

**7. DILI:** Ligand A (56.068) has a moderate DILI risk. Ligand B (23.381) has a very low DILI risk, a significant advantage.

**8. BBB:** Both ligands have good BBB penetration (Ligand A: 72.237, Ligand B: 77.705), exceeding the >70 threshold for CNS targets. Ligand B is slightly better.

**9. Caco-2 Permeability:** Both have negative Caco-2 values which is unusual and suggests a potential issue with the data. However, we can still compare the relative values. Ligand A (-4.481) is slightly better than Ligand B (-4.852).

**10. Aqueous Solubility:** Both have negative solubility values, which is also unusual and suggests a potential issue with the data. Ligand A (-3.185) is slightly better than Ligand B (-2.623).

**11. hERG Inhibition:** Both ligands show very low hERG inhibition risk (Ligand A: 0.058, Ligand B: 0.366).

**12. Microsomal Clearance:** Ligand A (39.245) has lower clearance, suggesting better metabolic stability than Ligand B (52.283).

**13. In vitro Half-Life:** Both have negative half-life values which is unusual and suggests a potential issue with the data. Ligand A (-16.064) is slightly better than Ligand B (-17.038).

**14. P-gp Efflux:** Both ligands have very low P-gp efflux liability (Ligand A: 0.018, Ligand B: 0.108).

**15. Binding Affinity:** Ligand B (-7.4 kcal/mol) has a significantly stronger binding affinity than Ligand A (-8.0 kcal/mol). This is a crucial advantage, potentially outweighing some of the minor ADME drawbacks.

**Overall Assessment:**

While Ligand A has a slightly better QED and metabolic stability, Ligand B demonstrates a superior profile overall, particularly regarding DILI risk, logP, and crucially, binding affinity. The stronger binding affinity of Ligand B (-7.4 kcal/mol vs -8.0 kcal/mol) is a significant advantage for a GPCR target. The lower DILI risk is also a major positive. The TPSA of Ligand B is also much more favorable for CNS penetration. The negative values for Caco-2 and solubility are concerning, but the relative comparison still favors Ligand B.

Output:
1
2025-04-17 05:50:14,816 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (349.475 and 367.921 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (92.5) is slightly above the preferred <90 for CNS targets, but still reasonable. Ligand B (52.65) is excellent, well below the threshold.

**3. logP:** Both ligands (1.742 and 1.699) are within the optimal 1-3 range.

**4. H-Bond Donors:** Ligand A has 2 HBD, which is good. Ligand B has 1 HBD, also good.

**5. H-Bond Acceptors:** Both ligands have 3 HBA, which is acceptable.

**6. QED:** Both ligands have good QED scores (0.585 and 0.772), indicating drug-like properties. Ligand B is slightly better.

**7. DILI:** Both ligands have low DILI risk (12.059 and 10.702), both below the 40 threshold.

**8. BBB:** Ligand A (68.282) is borderline for good CNS penetration, while Ligand B (61.884) is also borderline. Both are below the desirable >70, but not drastically so.

**9. Caco-2 Permeability:** Ligand A (-5.266) and Ligand B (-5) have similar, very poor Caco-2 permeability. This is a significant concern for oral bioavailability.

**10. Aqueous Solubility:** Both ligands have poor aqueous solubility (-2.807 and -1.739). This could pose formulation challenges.

**11. hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.119 and 0.5).

**12. Microsomal Clearance:** Ligand A (12.663) has a higher microsomal clearance than Ligand B (2.469), suggesting lower metabolic stability.

**13. In vitro Half-Life:** Ligand A (-24.48) has a very short half-life, while Ligand B (14.294) is better, but still not ideal.

**14. P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.016 and 0.063), which is favorable for CNS penetration.

**15. Binding Affinity:** Ligand A (-8.0) has a significantly stronger binding affinity than Ligand B (-7.6). This is a 0.4 kcal/mol difference, which is substantial and can outweigh some ADME drawbacks.

**Overall Assessment:**

While both compounds have issues with Caco-2 permeability and solubility, Ligand A's significantly stronger binding affinity (-8.0 kcal/mol vs -7.6 kcal/mol) is a major advantage, especially for a GPCR target. The slightly higher TPSA of Ligand A is less concerning than the poorer metabolic stability and shorter half-life of Ligand B. The difference in binding affinity is likely to be more impactful than the other minor differences.

Output:
1
2025-04-17 05:50:14,816 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B based on the provided guidelines, prioritizing GPCR-specific properties (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (384.42) is slightly higher than Ligand B (347.415), but both are acceptable.

**TPSA:** Ligand A (83.55) is excellent for CNS penetration, falling well below the 90 A^2 threshold. Ligand B (100.55) is still reasonable, but less optimal.

**logP:** Both ligands have good logP values (A: 1.115, B: 0.889), falling within the 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A (HBD=1, HBA=4) is better than Ligand B (HBD=3, HBA=5) in terms of balancing solubility and permeability.

**QED:** Both ligands have acceptable QED values (A: 0.79, B: 0.68), indicating good drug-like properties.

**DILI:** Ligand A (36.681) has a lower DILI risk than Ligand B (23.924), which is preferable.

**BBB:** This is a crucial parameter for CNS targets. Ligand A (93.098) has a very high BBB percentile, indicating excellent brain penetration potential. Ligand B (49.67) is significantly lower, raising concerns about reaching the target in the brain.

**Caco-2 Permeability:** Ligand A (-4.54) shows poor permeability, while Ligand B (-5.014) is also poor. This is a potential issue for oral bioavailability, but less critical for CNS drugs where direct delivery or other routes are possible.

**Aqueous Solubility:** Ligand A (-2.541) and Ligand B (-1.708) both have poor solubility.

**hERG Inhibition:** Both ligands have very low hERG inhibition risk (A: 0.36, B: 0.065).

**Microsomal Clearance:** Ligand A (1.984) has a lower microsomal clearance, suggesting better metabolic stability than Ligand B (11.662).

**In vitro Half-Life:** Ligand A (-30.619) has a much longer in vitro half-life than Ligand B (1.556), which is a significant advantage.

**P-gp Efflux:** Ligand A (0.036) has lower P-gp efflux liability than Ligand B (0.012), which is beneficial for CNS exposure.

**Binding Affinity:** Both ligands have comparable binding affinities (A: -8.8 kcal/mol, B: -8.3 kcal/mol). The difference of 0.5 kcal/mol is not substantial enough to outweigh other significant differences.

**Overall Assessment:**

Ligand A is the stronger candidate. While both have poor solubility and Caco-2 permeability, Ligand A excels in crucial areas for CNS drug development: significantly higher BBB penetration, lower DILI risk, better metabolic stability (lower Cl_mic, longer t1/2), and lower P-gp efflux. The slightly better TPSA and H-bonding profile also contribute to its favorability. The binding affinity difference is minimal.



Output:
1
2025-04-17 05:50:14,816 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (345.355 and 346.515 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (124.69) is slightly above the preferred <90 for CNS targets, but still reasonable. Ligand B (58.2) is excellent, well below 90. This favors Ligand B.

**3. logP:** Ligand A (0.566) is quite low, potentially hindering membrane permeability. Ligand B (3.572) is optimal. This strongly favors Ligand B.

**4. H-Bond Donors:** Ligand A (4) is acceptable. Ligand B (2) is also good. No clear advantage.

**5. H-Bond Acceptors:** Ligand A (6) is acceptable. Ligand B (2) is excellent. This favors Ligand B.

**6. QED:** Both ligands (0.628 and 0.66) have good drug-likeness scores (>0.5).

**7. DILI:** Ligand A (56.727) has a moderate DILI risk. Ligand B (9.771) has a very low DILI risk. This favors Ligand B.

**8. BBB:** Ligand A (12.059) has very poor predicted BBB penetration. Ligand B (71.035) has good BBB penetration, exceeding the >70 threshold for CNS targets. This is a *critical* advantage for Ligand B.

**9. Caco-2 Permeability:** Ligand A (-5.863) has poor Caco-2 permeability. Ligand B (-4.676) is also poor, but slightly better.

**10. Aqueous Solubility:** Both ligands have very poor aqueous solubility (-2.327 and -4.094). This is a concern for both, but less critical than BBB for a CNS target.

**11. hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.095 and 0.317).

**12. Microsomal Clearance:** Ligand A (-3.496) has lower (better) microsomal clearance than Ligand B (80.792), indicating better metabolic stability. This favors Ligand A.

**13. In vitro Half-Life:** Ligand A (-13.568) has a very short half-life. Ligand B (-7.319) is better, but still not ideal.

**14. P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.011 and 0.094).

**15. Binding Affinity:** Both ligands have excellent binding affinity (-8.9 and -8.8 kcal/mol), with a negligible difference.

**Overall Assessment:**

Ligand B is significantly more promising. While Ligand A has better metabolic stability, Ligand B excels in the most crucial areas for a CNS-targeting GPCR ligand: TPSA, logP, BBB penetration, and DILI risk. The low logP and poor BBB of Ligand A are major drawbacks that outweigh its slightly better metabolic stability. The better TPSA and logP of Ligand B suggest it will have better permeability and CNS exposure.

Output:
1
2025-04-17 05:50:14,816 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (377.231 Da) is slightly higher than Ligand B (331.379 Da), but both are acceptable.

**TPSA:** Ligand A (79.26) is better than Ligand B (85.07). For CNS targets, we want TPSA <= 90, and both are under this threshold, but A is closer to the ideal.

**logP:** Both ligands have good logP values (A: 3.139, B: 2.898), falling within the optimal range of 1-3.

**H-Bond Donors/Acceptors:** Both have 2 HBDs, which is good. Ligand A has 4 HBAs, and Ligand B has 6. Both are acceptable (<=10), but A is slightly better.

**QED:** Both ligands have similar, good QED values (A: 0.736, B: 0.767), indicating good drug-like properties.

**DILI:** Both have high DILI risk (A: 79.992, B: 84.025). This is a concern, but we'll consider it later in the context of other properties.

**BBB:** Ligand A (49.864) has a significantly better BBB percentile than Ligand B (36.797). This is *critical* for a CNS target like DRD2.

**Caco-2 Permeability:** Ligand A (-4.75) has a better Caco-2 permeability than Ligand B (-5.312), indicating better intestinal absorption.

**Aqueous Solubility:** Ligand A (-5.475) has a better aqueous solubility than Ligand B (-4.624).

**hERG Inhibition:** Both ligands have low hERG inhibition risk (A: 0.316, B: 0.9). This is good.

**Microsomal Clearance:** Ligand B (54.977) has a significantly higher microsomal clearance than Ligand A (7.117), meaning A is more metabolically stable.

**In vitro Half-Life:** Ligand A (13.027) has a slightly longer half-life than Ligand B (12.602).

**P-gp Efflux:** Ligand A (0.152) has a lower P-gp efflux liability than Ligand B (0.11). Lower is better, meaning A will have better CNS exposure.

**Binding Affinity:** Both ligands have excellent binding affinities (A: -9.4 kcal/mol, B: -8.9 kcal/mol). Ligand A is slightly stronger, but the difference is relatively small.

**Overall Assessment:**

Ligand A is superior to Ligand B. The key advantages are its significantly better BBB penetration, lower P-gp efflux, lower microsomal clearance (better metabolic stability), and slightly better solubility and Caco-2 permeability. While both have high DILI risk, the improved ADME properties of Ligand A, particularly its BBB penetration, make it a more promising candidate for a CNS-targeting drug like a DRD2 ligand. The slightly better binding affinity of A is an added bonus.

Output:
1
2025-04-17 05:50:14,817 - INFO - Reasoning:

Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (349.431 and 339.487 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (78.95) is better than Ligand B (53.94). For CNS targets, we want TPSA <= 90, both are within this range, but A is closer to the upper limit.

**3. logP:** Ligand A (1.313) is optimal (1-3), while Ligand B (4.288) is slightly high. High logP can lead to solubility issues and off-target interactions.

**4. H-Bond Donors:** Both ligands have 1 HBD, which is within the acceptable limit of <=5.

**5. H-Bond Acceptors:** Ligand A has 4 HBAs, and Ligand B has 5. Both are within the acceptable limit of <=10.

**6. QED:** Ligand B (0.9) is superior to Ligand A (0.6), indicating a more drug-like profile.

**7. DILI:** Both ligands have acceptable DILI risk (Ligand A: 59.946, Ligand B: 51.377), below the 60 threshold.

**8. BBB:** Ligand B (72.896) has a significantly better BBB percentile than Ligand A (62.233).  This is *critical* for a CNS target like DRD2.

**9. Caco-2 Permeability:** Both have negative values, indicating poor permeability. Ligand A (-4.539) is slightly better than Ligand B (-4.995).

**10. Aqueous Solubility:** Ligand A (-1.573) is better than Ligand B (-4.137), indicating better solubility.

**11. hERG Inhibition:** Ligand A (0.13) has a lower hERG risk than Ligand B (0.86). This is a significant advantage.

**12. Microsomal Clearance:** Ligand B (87.414) has a much higher microsomal clearance than Ligand A (15.484), meaning it will be metabolized much faster.  Lower clearance is preferred.

**13. In vitro Half-Life:** Ligand A (-26.613) has a longer (less negative) half-life than Ligand B (21.322).

**14. P-gp Efflux:** Ligand A (0.048) shows lower P-gp efflux than Ligand B (0.351). Lower efflux is better for CNS penetration.

**15. Binding Affinity:** Ligand A (-7.1) has a slightly better binding affinity than Ligand B (-0.0). This is a substantial difference.

**Overall Assessment:**

While Ligand B has a better QED and BBB penetration, Ligand A is superior in most other critical aspects, particularly affinity, metabolic stability (lower Cl_mic, longer t1/2), hERG risk, and P-gp efflux. The significantly stronger binding affinity of Ligand A (-7.1 kcal/mol vs -0.0 kcal/mol) is a major advantage that can compensate for its slightly lower BBB score. Given the GPCR-specific priorities, the combination of strong affinity, good metabolic stability, low hERG risk, and reasonable BBB penetration makes Ligand A the more promising candidate.

Output:
1
2025-04-17 05:50:14,817 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (347.459) is slightly better positioned.

**TPSA:** Ligand A (78.51) is significantly better than Ligand B (97.83). For CNS targets, we want TPSA <= 90, and A is comfortably within that range, while B is close to the upper limit.

**logP:** Ligand A (1.365) is optimal, while Ligand B (0.269) is a bit low, potentially hindering membrane permeability.

**H-Bond Donors/Acceptors:** Ligand A (2 HBD, 3 HBA) and Ligand B (1 HBD, 6 HBA) both fall within acceptable ranges.

**QED:** Ligand A (0.737) has a higher QED score than Ligand B (0.593), indicating a more drug-like profile.

**DILI:** Ligand B (59.131) has a higher DILI risk than Ligand A (21.946). This is a significant advantage for Ligand A.

**BBB:** Ligand B (70.376) has a better BBB penetration score than Ligand A (58.007). This is a crucial factor for CNS targets. However, the difference isn't massive, and other factors need consideration.

**Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and suggests poor permeability. However, the scale is not specified, so it's difficult to interpret.

**Aqueous Solubility:** Both have negative solubility values, which is also unusual and suggests poor solubility. Again, the scale is not specified.

**hERG:** Ligand A (0.074) has a much lower hERG inhibition liability than Ligand B (0.247), making it safer from a cardiotoxicity perspective.

**Microsomal Clearance:** Ligand A (21.95) has lower microsomal clearance than Ligand B (27.759), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (20.154) has a significantly longer in vitro half-life than Ligand B (-3.406). This is a major advantage for dosing convenience.

**P-gp Efflux:** Ligand A (0.029) has a much lower P-gp efflux liability than Ligand B (0.015), which is beneficial for CNS exposure.

**Binding Affinity:** Both ligands have very similar binding affinities (-8.2 kcal/mol and -8.1 kcal/mol). The difference is negligible.

**Overall Assessment:**

Ligand A is superior in almost every ADME-Tox property. It has better TPSA, logP, QED, lower DILI risk, lower hERG inhibition, better metabolic stability (lower Cl_mic, longer t1/2), and lower P-gp efflux. While Ligand B has a slightly better BBB score, the substantial advantages of Ligand A in other critical parameters, particularly safety (DILI, hERG) and pharmacokinetic properties (Cl_mic, t1/2, Pgp), outweigh this single benefit. The similar binding affinities make the ADME profile the deciding factor.

Output:
0
2025-04-17 05:50:14,817 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B against the provided guidelines, prioritizing GPCR-specific properties (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (347.375) is slightly lower, which could be beneficial for permeability, but both are acceptable.

**TPSA:** Ligand A (113.49) is better than Ligand B (49.41) as it is closer to the ideal range for CNS targets (<=90). Ligand B is quite low, which *could* indicate poor interactions, but isn't necessarily a dealbreaker.

**logP:** Ligand B (3.843) is closer to the optimal range (1-3) than Ligand A (0.522). Ligand A's low logP is a significant concern, potentially hindering membrane permeability and CNS penetration.

**H-Bond Donors/Acceptors:** Ligand A has 2 HBD and 7 HBA, while Ligand B has 1 HBD and 2 HBA. Both are within acceptable limits.

**QED:** Both ligands have similar QED values (0.755 and 0.709), indicating good drug-like properties.

**DILI:** Ligand B (21.326) has a much lower DILI risk than Ligand A (69.756), which is a substantial advantage.

**BBB:** Ligand B (77.705) has a significantly higher BBB penetration percentile than Ligand A (62.156). This is crucial for a CNS target like DRD2.

**Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and suggests a potential issue with the data or modeling. However, the values are similar.

**Aqueous Solubility:** Both ligands have negative solubility values, which is also unusual. Again, the values are similar.

**hERG Inhibition:** Ligand A (0.071) has a slightly lower hERG risk than Ligand B (0.454), but both are relatively low.

**Microsomal Clearance:** Ligand B (50.853) has a higher microsomal clearance than Ligand A (20.729), meaning Ligand A is more metabolically stable.

**In vitro Half-Life:** Ligand A (38.117) has a longer in vitro half-life than Ligand B (3.055), which is preferable.

**P-gp Efflux:** Ligand A (0.041) exhibits lower P-gp efflux liability than Ligand B (0.386), which is a positive for CNS penetration.

**Binding Affinity:** Ligand B (-7.4 kcal/mol) has a slightly better binding affinity than Ligand A (-8.3 kcal/mol). While Ligand A has better affinity, the difference is not substantial enough to overcome the other significant drawbacks.

**Overall Assessment:**

Ligand A suffers from a very low logP, which is a major concern for CNS penetration. While it has better metabolic stability and P-gp efflux, its poor logP and higher DILI risk outweigh these benefits. Ligand B, despite slightly lower affinity, demonstrates a much more favorable profile for a CNS-targeting drug, with a good logP, significantly lower DILI risk, and excellent BBB penetration.

Output:
1
2025-04-17 05:50:14,817 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (350.419 and 345.491 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (85.69) is better than Ligand B (53.52) as it is closer to the ideal TPSA for CNS targets (<=90). Ligand B is excellent.

**3. logP:** Ligand A (0.577) is a bit low, potentially hindering permeation. Ligand B (2.154) is within the optimal 1-3 range. This favors Ligand B.

**4. H-Bond Donors:** Both have 1 HBD, which is acceptable.

**5. H-Bond Acceptors:** Both have 6 HBA, which is acceptable.

**6. QED:** Both ligands have good QED scores (0.789 and 0.883), indicating drug-like properties.

**7. DILI:** Ligand A (51.183) has a slightly higher DILI risk than Ligand B (30.748), but both are reasonably low.

**8. BBB:** Ligand B (91.508) significantly outperforms Ligand A (72.237) in BBB penetration, a crucial factor for CNS targets like DRD2.

**9. Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and suggests poor permeability. However, the scale is not specified, so it's difficult to interpret.

**10. Aqueous Solubility:** Both have negative solubility values, again, the scale is unspecified.

**11. hERG Inhibition:** Ligand A (0.21) has a lower hERG inhibition liability than Ligand B (0.937), which is preferable.

**12. Microsomal Clearance:** Ligand B (44.379) has a higher microsomal clearance than Ligand A (21.483), suggesting faster metabolism and potentially lower exposure.

**13. In vitro Half-Life:** Ligand A (36.025) has a longer half-life than Ligand B (24.385).

**14. P-gp Efflux:** Ligand A (0.018) has much lower P-gp efflux liability than Ligand B (0.126), which is highly desirable for CNS penetration.

**15. Binding Affinity:** Ligand B (-8.2 kcal/mol) has a significantly stronger binding affinity than Ligand A (0.0 kcal/mol). This is a major advantage, potentially outweighing some of the ADME drawbacks.

**Overall Assessment:**

Ligand B is the stronger candidate. While Ligand A has better hERG and P-gp efflux profiles, Ligand B's superior binding affinity (-8.2 vs 0 kcal/mol) and excellent BBB penetration (91.5%) are critical for a CNS-targeting GPCR like DRD2. The slightly higher logP of Ligand B is also beneficial. The higher clearance of Ligand B is a concern, but the strong binding affinity might compensate for that.

Output:
1
2025-04-17 05:50:14,818 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (375.837 and 379.356 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (72.48) is significantly better than Ligand B (81.7). For CNS targets, we want TPSA <= 90, and A is closer to the optimal <= 60 range. B is approaching a less desirable range.

**logP:** Both ligands have good logP values (3.786 and 2.275), falling within the 1-3 range. Ligand A is slightly higher, which *could* be a minor concern for solubility, but is still acceptable.

**H-Bond Donors/Acceptors:** Ligand A (2 HBD, 6 HBA) and Ligand B (1 HBD, 5 HBA) both have reasonable numbers of H-bond donors and acceptors, well within the guidelines.

**QED:** Both ligands have good QED scores (0.681 and 0.812), indicating good drug-like properties.

**DILI:** Ligand A (99.108) has a very high DILI risk, which is a significant concern. Ligand B (63.746) is still elevated, but considerably better than A.

**BBB:** Ligand B (71.268) has a much better BBB penetration score than Ligand A (55.603). For a CNS target like DRD2, >70 is desirable, but B is closer to that threshold than A.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.773 and -4.635). These are unusual and suggest poor permeability, but the scale is not specified, so it's hard to interpret.

**Aqueous Solubility:** Both ligands have negative solubility values (-5.863 and -4.14). Similar to Caco-2, the scale is unclear, but these suggest poor solubility.

**hERG:** Both ligands have low hERG inhibition liability (0.572 and 0.546), which is good.

**Microsomal Clearance:** Ligand B (55.164) has a slightly better (lower) microsomal clearance than Ligand A (53.8), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand B (-46.739) has a significantly longer in vitro half-life than Ligand A (43.957). This is a major advantage.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.725 and 0.108), which is good for CNS penetration. Ligand B is much better.

**Binding Affinity:** Both ligands have excellent binding affinities (-10.5 and -9.1 kcal/mol). The difference of 1.4 kcal/mol is substantial and favors Ligand A.

**Overall Assessment:**

While Ligand A has a slightly better binding affinity, its extremely high DILI risk and poor BBB penetration are major drawbacks. Ligand B, despite a slightly weaker affinity, has a much more favorable safety profile (lower DILI), better BBB penetration, and improved metabolic stability (lower Cl_mic, longer t1/2). Given the GPCR-specific priorities, the improved ADME properties of Ligand B outweigh the modest difference in binding affinity.

Output:
1
2025-04-17 05:50:14,818 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (364.379 and 346.515 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (104.68) is higher than Ligand B (58.2). For CNS targets, TPSA should be <= 90. Ligand B is significantly better here.

**logP:** Ligand A (1.929) is within the optimal 1-3 range. Ligand B (3.57) is slightly higher, but still acceptable.

**H-Bond Donors/Acceptors:** Ligand A has 0 HBD and 8 HBA, while Ligand B has 2 HBD and 2 HBA. Both are within acceptable limits (<=5 HBD and <=10 HBA).

**QED:** Both ligands have good QED scores (0.566 and 0.722), indicating good drug-like properties.

**DILI:** Ligand A (88.019) has a higher DILI risk than Ligand B (24.583). Lower is better, and Ligand B is much preferred.

**BBB:** Both ligands have good BBB penetration (70.182 and 73.245), exceeding the 70% threshold for CNS targets. Ligand B is slightly better.

**Caco-2 Permeability:** Both have negative Caco-2 values (-4.419 and -4.738), which is unusual and suggests poor permeability. This is a concern for both.

**Aqueous Solubility:** Both ligands have very poor aqueous solubility (-3.611 and -4.268). This could pose formulation challenges.

**hERG Inhibition:** Both ligands show low hERG inhibition risk (0.123 and 0.364).

**Microsomal Clearance:** Ligand A (33.847) has lower microsomal clearance than Ligand B (64.81), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand B (2.818) has a slightly longer half-life than Ligand A (5.266).

**P-gp Efflux:** Ligand A (0.048) has lower P-gp efflux than Ligand B (0.296), which is favorable for CNS penetration.

**Binding Affinity:** Ligand B (-9.8 kcal/mol) has a significantly stronger binding affinity than Ligand A (-8.8 kcal/mol). This is a substantial advantage, potentially outweighing some of the ADME drawbacks.

**Overall Assessment:**

Ligand B is the more promising candidate. While both have poor solubility and Caco-2 permeability, Ligand B has a significantly better binding affinity (-9.8 vs -8.8 kcal/mol), lower DILI risk, slightly better BBB penetration, and a longer half-life. The lower P-gp efflux of Ligand A is a benefit, but the affinity difference is more critical for a GPCR target. The TPSA of Ligand B is also much better.



Output:
1
2025-04-17 05:50:14,818 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (341.407 and 357.479 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (75.63) is slightly above the optimal <90 for CNS targets, but still reasonable. Ligand B (65.2) is excellent, well below 90.

**3. logP:** Both ligands have good logP values (2.423 and 3.161), falling within the 1-3 range. Ligand B is slightly higher, which could be beneficial for membrane permeability.

**4. H-Bond Donors:** Both have 2 HBD, which is within the acceptable limit of <=5.

**5. H-Bond Acceptors:** Ligand A has 4 HBA, and Ligand B has 3. Both are below the acceptable limit of <=10.

**6. QED:** Both ligands have good QED scores (0.791 and 0.807), indicating good drug-like properties.

**7. DILI:** Both ligands have similar DILI risk (62.233 and 61.07), which is moderately high but not alarming. Further investigation would be needed.

**8. BBB:** This is a critical parameter for CNS targets. Ligand B (73.517) has a significantly better BBB percentile than Ligand A (36.526). This is a major advantage for Ligand B.

**9. Caco-2 Permeability:** Ligand A (-4.586) has poor Caco-2 permeability, suggesting poor intestinal absorption. Ligand B (-5.344) is also poor, but slightly better than A.

**10. Aqueous Solubility:** Both ligands have very poor aqueous solubility (-4.141 and -4.3). This could pose formulation challenges.

**11. hERG Inhibition:** Both ligands have low hERG inhibition risk (0.653 and 0.549).

**12. Microsomal Clearance:** Ligand A (82.151) has higher microsomal clearance, indicating faster metabolism. Ligand B (25.794) has significantly lower clearance, suggesting better metabolic stability.

**13. In vitro Half-Life:** Ligand B (-16.03) has a longer half-life than Ligand A (-27.44), which is desirable.

**14. P-gp Efflux:** Both ligands have low P-gp efflux liability (0.379 and 0.13). Ligand B is better.

**15. Binding Affinity:** Both ligands have similar and strong binding affinities (-9.3 and -8.5 kcal/mol). The difference of 0.8 kcal/mol is not substantial enough to outweigh other factors.

**Overall Assessment:**

Ligand B is the more promising candidate. While both have similar binding affinity and acceptable physicochemical properties, Ligand B excels in crucial areas for CNS drug development: significantly better BBB penetration, lower microsomal clearance (better metabolic stability), and a longer half-life. The slightly better logP and P-gp efflux also contribute to its advantage. Although both have poor solubility and moderate DILI risk, the improved ADME properties of Ligand B make it the preferred choice.

Output:
1
2025-04-17 05:50:14,818 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (338.386 Da) is slightly lower, which could be beneficial for permeability.

**TPSA:** Ligand A (69.81) is excellent for CNS penetration, well below the 90 A^2 threshold. Ligand B (87.15) is still reasonable but less optimal.

**logP:** Ligand A (3.447) is within the optimal range (1-3). Ligand B (0.301) is significantly lower, potentially hindering membrane permeability and CNS entry.

**H-Bond Donors/Acceptors:** Ligand A (3 HBD, 2 HBA) and Ligand B (1 HBD, 5 HBA) both fall within acceptable limits.

**QED:** Both ligands have good QED scores (A: 0.682, B: 0.737), indicating generally drug-like properties.

**DILI:** Ligand A (61.884) has a moderate DILI risk, while Ligand B (14.23) has a very low risk. This favors Ligand B.

**BBB:** Ligand A (81) has excellent BBB penetration potential. Ligand B (32.765) is significantly lower, a major drawback for a CNS target.

**Caco-2 Permeability:** Both have negative values, which is unusual. However, the magnitude of the negative value is larger for Ligand A (-4.93) than for Ligand B (-4.657). This suggests slightly better permeability for Ligand A.

**Aqueous Solubility:** Both ligands have negative solubility values, which is also unusual. Ligand A (-4.315) is slightly less negative than Ligand B (-0.788), suggesting better solubility.

**hERG Inhibition:** Ligand A (0.802) has a slightly higher hERG risk than Ligand B (0.091). This favors Ligand B.

**Microsomal Clearance:** Ligand A (-3.29) has a lower (better) microsomal clearance than Ligand B (21.795), indicating better metabolic stability.

**In vitro Half-Life:** Ligand A (20.424) has a longer half-life than Ligand B (3.306).

**P-gp Efflux:** Ligand A (0.339) has lower P-gp efflux liability than Ligand B (0.04), which is favorable for CNS penetration.

**Binding Affinity:** Ligand B (-7.2 kcal/mol) has a significantly stronger binding affinity than Ligand A (-10.8 kcal/mol). This is a substantial advantage, potentially outweighing some ADME concerns.

**Overall Assessment:**

Ligand B has a significantly better binding affinity and lower DILI/hERG risk. However, its low logP and poor BBB penetration are major concerns for a CNS target like DRD2. Ligand A, while having a weaker affinity, possesses excellent BBB penetration, a favorable logP, and better metabolic stability. Given the GPCR-specific priorities, the strong BBB penetration and reasonable ADME profile of Ligand A are more important than the affinity difference, especially considering the affinity is still within a reasonable range.

Output:
1
2025-04-17 05:50:14,818 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (346.475) is slightly better, being closer to the lower end which can aid permeability.

**TPSA:** Ligand A (80.48) is significantly better than Ligand B (95.74). For CNS targets, we want TPSA <= 90, and Ligand A is comfortably within this range, while Ligand B is close to the upper limit.

**logP:** Both ligands have acceptable logP values (Ligand A: 1.204, Ligand B: 0.492), falling within the optimal 1-3 range. Ligand A is slightly preferred here.

**H-Bond Donors/Acceptors:** Ligand A (HBD=2, HBA=5) and Ligand B (HBD=1, HBA=6) both have reasonable numbers of H-bond donors and acceptors.

**QED:** Both ligands have good QED values (Ligand A: 0.775, Ligand B: 0.809), indicating good drug-like properties.

**DILI:** Ligand B (60.799) has a higher DILI risk than Ligand A (6.514). This is a significant concern, as we want DILI < 40.

**BBB:** Ligand B (68.554) has a better BBB percentile than Ligand A (55.176), but both are below the desirable >70 for CNS targets. This is a weakness for both, but less so for Ligand B.

**Caco-2 Permeability:** Ligand A (-5.273) is better than Ligand B (-4.59), indicating better intestinal absorption.

**Aqueous Solubility:** Ligand A (-0.58) is better than Ligand B (-2.666), which is important for formulation and bioavailability.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (Ligand A: 0.601, Ligand B: 0.379).

**Microsomal Clearance:** Ligand A (-50.095) shows better metabolic stability (lower clearance) than Ligand B (27.386).

**In vitro Half-Life:** Ligand A (22.962) has a longer in vitro half-life than Ligand B (-50.903), which is desirable.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (Ligand A: 0.03, Ligand B: 0.1).

**Binding Affinity:** Both ligands have very similar and strong binding affinities (Ligand A: -8.4 kcal/mol, Ligand B: -8.1 kcal/mol). The difference is less than 1.5 kcal/mol, so it's not a decisive factor.

**Overall Assessment:**

Ligand A is significantly better overall. It has a lower DILI risk, better TPSA, better solubility, better Caco-2 permeability, better metabolic stability (lower Cl_mic), and a longer half-life. While Ligand B has a slightly better BBB score, the other advantages of Ligand A outweigh this. Both ligands fall short of the ideal BBB penetration, but the superior ADME profile of Ligand A makes it the more promising candidate.

Output:
0
2025-04-17 05:50:14,819 - INFO - Batch 231 complete. Total preferences: 3696
2025-04-17 05:50:14,819 - INFO - Processing batch 232/512...
2025-04-17 05:50:56,578 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 drug candidates, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (351.447 and 346.402 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (85.61) is better than Ligand B (58.64). Both are below 90, which is favorable for CNS penetration.

**3. logP:** Both ligands have acceptable logP values (1.324 and 2.766, respectively), falling within the optimal range of 1-3.

**4. H-Bond Donors:** Ligand A (2) is slightly higher than Ligand B (1), but both are within the acceptable limit of <=5.

**5. H-Bond Acceptors:** Ligand A (6) is higher than Ligand B (3), but both are within the acceptable limit of <=10.

**6. QED:** Both ligands have similar and good QED values (0.807 and 0.806).

**7. DILI:** Ligand A (33.346) has a significantly lower DILI risk than Ligand B (44.048). Both are below 40, indicating low risk.

**8. BBB:** Ligand B (73.129) has a substantially better BBB penetration score than Ligand A (20.318). This is a crucial factor for a CNS target like DRD2.

**9. Caco-2 Permeability:** Ligand A (-5.232) has a much better Caco-2 permeability than Ligand B (-4.406). Higher values indicate better intestinal absorption.

**10. Aqueous Solubility:** Ligand A (-0.768) has better solubility than Ligand B (-3.239).

**11. hERG Inhibition:** Both ligands have similar and low hERG inhibition liability (0.309 and 0.601).

**12. Microsomal Clearance:** Ligand A (4.485) has a lower microsomal clearance than Ligand B (35.557), suggesting better metabolic stability.

**13. In vitro Half-Life:** Ligand A (27.188) has a much longer in vitro half-life than Ligand B (-15.902).

**14. P-gp Efflux:** Ligand A (0.097) has a lower P-gp efflux liability than Ligand B (0.207), which is favorable for CNS exposure.

**15. Binding Affinity:** Both ligands have the same binding affinity (-8.4 kcal/mol), which is excellent.

**Overall Assessment:**

While Ligand B has a significantly better BBB score, Ligand A excels in almost all other critical ADME properties, including Caco-2 permeability, solubility, metabolic stability (lower Cl_mic and longer t1/2), lower P-gp efflux, and lower DILI risk. Given the importance of ADME properties for *in vivo* efficacy, and the fact that both ligands have identical binding affinity, the superior ADME profile of Ligand A makes it the more promising drug candidate. The lower BBB score of Ligand A is a concern, but can potentially be addressed through formulation strategies.

Output:
1
2025-04-17 05:50:56,578 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (352.312 and 349.391 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (68.29) is excellent, well below the 90 A^2 threshold for CNS targets. Ligand B (98.58) is higher, but still potentially acceptable, though less ideal.

**logP:** Ligand A (2.767) is optimal (1-3). Ligand B (-0.786) is significantly lower, which could hinder membrane permeability and CNS penetration.

**H-Bond Donors/Acceptors:** Both have acceptable HBD counts (1). Ligand A has 4 HBA, while Ligand B has 7. Both are within the reasonable limit of 10, but Ligand A is preferable.

**QED:** Both ligands have good QED scores (0.863 and 0.693), indicating drug-like properties.

**DILI:** Ligand A (81.427) has a higher DILI risk than Ligand B (48.662). This is a negative for Ligand A.

**BBB:** Ligand A (94.455) has excellent BBB penetration, highly desirable for a CNS target. Ligand B (38.813) has poor BBB penetration, a major drawback.

**Caco-2 Permeability:** Ligand A (-4.231) and Ligand B (-5.07) both have negative Caco-2 values, which is unusual and indicates poor permeability. However, the scale is not specified, so it's difficult to interpret.

**Aqueous Solubility:** Ligand A (-4.156) and Ligand B (-1.185) both have negative solubility values, which is also unusual and indicates poor solubility.

**hERG:** Both ligands have very low hERG risk (0.582 and 0.053).

**Microsomal Clearance:** Ligand A (82.314) has higher clearance than Ligand B (-5.498). This suggests Ligand B is more metabolically stable.

**In vitro Half-Life:** Ligand B (19.699) has a significantly longer half-life than Ligand A (0.072).

**P-gp Efflux:** Ligand A (0.161) has lower P-gp efflux than Ligand B (0.006), which is favorable for CNS penetration.

**Binding Affinity:** Ligand A (-8.2 kcal/mol) has a slightly better binding affinity than Ligand B (-7.8 kcal/mol). While the difference is not huge, it is still a factor.

**Overall Assessment:**

Ligand A excels in key areas for a CNS-targeting GPCR: TPSA, logP, and especially BBB penetration. Its binding affinity is also slightly better. However, it has higher DILI risk and lower metabolic stability. Ligand B has better metabolic stability, lower DILI, and a longer half-life, but its poor logP and very low BBB penetration are significant liabilities for a CNS drug.

Given the importance of BBB penetration for DRD2 (a CNS target), Ligand A is the more promising candidate despite its drawbacks. The slightly better affinity further supports this conclusion.

Output:
1
2025-04-17 05:50:56,579 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight (MW):** Both ligands (348.443 and 344.455 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (71.78) is better than Ligand B (67.43). Both are below the 90 A^2 threshold for CNS targets, which is excellent.

**3. logP:** Both ligands have good logP values (2.552 and 1.948), falling within the optimal 1-3 range. Ligand B is slightly lower, which could marginally improve solubility but isn't a major concern.

**4. H-Bond Donors (HBD):** Ligand A (1) is better than Ligand B (2). Both are within the acceptable limit of <=5.

**5. H-Bond Acceptors (HBA):** Ligand A (4) is better than Ligand B (3). Both are within the acceptable limit of <=10.

**6. QED:** Ligand A (0.733) is better than Ligand B (0.572), indicating a more drug-like profile.

**7. DILI:** Ligand A (17.72) is significantly better than Ligand B (46.297). Ligand A is well below the 40% threshold for low risk, while Ligand B is approaching a moderate risk.

**8. BBB:** Ligand A (78.209) is substantially better than Ligand B (55.913).  For a CNS target like DRD2, a BBB percentile >70 is highly desirable. Ligand A is closer to this threshold.

**9. Caco-2 Permeability:** Ligand A (-4.607) is better than Ligand B (-4.875). Both are negative, indicating poor permeability.

**10. Aqueous Solubility:** Ligand A (-2.067) is better than Ligand B (-2.803). Both are negative, indicating poor solubility.

**11. hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.588 and 0.272).

**12. Microsomal Clearance (Cl_mic):** Ligand B (16.834) is better than Ligand A (35.316). Lower clearance indicates better metabolic stability.

**13. In vitro Half-Life:** Ligand A (11.326) is better than Ligand B (-11.774). A positive half-life is better than a negative one.

**14. P-gp Efflux:** Ligand A (0.211) is better than Ligand B (0.092). Lower P-gp efflux is preferred for CNS penetration.

**15. Binding Affinity:** Ligand B (-7.9) is slightly better than Ligand A (-7.7). However, the difference is small (0.2 kcal/mol) and may not be enough to overcome the other significant differences.

**Overall Assessment:**

Ligand A is the stronger candidate. While Ligand B has slightly better binding affinity and microsomal clearance, Ligand A excels in critical areas for a CNS-targeting GPCR: BBB penetration, DILI risk, QED, and P-gp efflux. The substantial difference in BBB (78.209 vs 55.913) and DILI (17.72 vs 46.297) are particularly important. The small affinity difference is unlikely to outweigh these advantages.

Output:
1
2025-04-17 05:50:56,579 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (357.445 and 357.451 Da) fall comfortably within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (61.44) is significantly better than Ligand B (96.97). For CNS targets, we want TPSA <= 90, and A is much closer to this threshold. B is quite high, potentially hindering BBB penetration.

**3. logP:** Both ligands have acceptable logP values (A: 2.085, B: 0.757), falling within the 1-3 range. A is slightly preferred.

**4. H-Bond Donors:** Both have 2 HBD, which is within the acceptable limit of <= 5.

**5. H-Bond Acceptors:** Ligand A has 3 HBA, and Ligand B has 6. Both are within the acceptable limit of <= 10, but A is better.

**6. QED:** Ligand A (0.621) has a better QED score than Ligand B (0.492), indicating a more drug-like profile.

**7. DILI:** Ligand A (13.61) has a much lower DILI risk than Ligand B (27.259). This is a significant advantage for A.

**8. BBB:** Ligand A (84.684) has a substantially higher BBB penetration percentile than Ligand B (58.007). This is *critical* for a CNS target like DRD2.

**9. Caco-2 Permeability:** Ligand A (-4.948) is better than Ligand B (-5.347), indicating slightly better intestinal absorption.

**10. Aqueous Solubility:** Ligand A (-2.226) is better than Ligand B (-1.363), indicating better solubility.

**11. hERG Inhibition:** Ligand A (0.576) has a lower hERG inhibition liability than Ligand B (0.279), which is preferable.

**12. Microsomal Clearance:** Ligand B (27.8) has a much higher microsomal clearance than Ligand A (3.09). This means A is more metabolically stable.

**13. In vitro Half-Life:** Ligand B (-24.871) has a longer in vitro half-life than Ligand A (-12.29). However, the metabolic stability difference (Cl_mic) is more important.

**14. P-gp Efflux:** Ligand B (0.013) has a lower P-gp efflux liability than Ligand A (0.019), which is preferable.

**15. Binding Affinity:** Ligand B (-24.871 kcal/mol) has a significantly stronger binding affinity than Ligand A (-8.0 kcal/mol). This is a substantial advantage for B.

**Overall Assessment:**

While Ligand B boasts a significantly better binding affinity, Ligand A excels in almost all ADME-Tox properties crucial for CNS penetration and safety. The substantial difference in BBB (84.7% vs 58.0%), DILI risk (13.6% vs 27.3%), and metabolic stability (Cl_mic 3.09 vs 27.8) are major factors. The higher TPSA of Ligand B is also concerning for CNS penetration. The affinity difference is large (over 6 kcal/mol), but not insurmountable. Optimization of Ligand A could potentially improve its affinity while maintaining its favorable ADME profile. Given the GPCR-specific priorities, and the importance of CNS penetration for DRD2, Ligand A is the more promising candidate.

Output:
1
2025-04-17 05:50:56,579 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (369.462 and 374.522 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (80.32) is better than Ligand B (49.85). Both are below the 90 A^2 threshold for CNS targets, but A is closer to the upper limit.

**logP:** Both ligands have good logP values (1.983 and 2.2), falling within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A has 2 HBD and 5 HBA, while Ligand B has 0 HBD and 4 HBA. Both are within acceptable limits.

**QED:** Ligand A (0.832) has a significantly higher QED score than Ligand B (0.686), indicating better overall drug-likeness.

**DILI:** Ligand A (65.762) has a higher DILI risk than Ligand B (31.563). This is a negative for Ligand A.

**BBB:** Ligand B (90.306) has a substantially higher BBB penetration percentile than Ligand A (70.027). This is a crucial advantage for a CNS target like DRD2.

**Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and difficult to interpret without knowing the scale. However, the values are similar.

**Aqueous Solubility:** Both ligands have similar, very poor aqueous solubility (-2.906 and -2.93). This could be a formulation challenge for both.

**hERG Inhibition:** Ligand A (0.32) has a lower hERG inhibition liability than Ligand B (0.701), which is favorable.

**Microsomal Clearance:** Ligand B (40.104) has a much higher microsomal clearance than Ligand A (10.659), indicating faster metabolism and potentially lower *in vivo* exposure.

**In vitro Half-Life:** Ligand A (13.607) has a longer in vitro half-life than Ligand B (-2.317). This is a positive for Ligand A.

**P-gp Efflux:** Ligand A (0.244) has lower P-gp efflux liability than Ligand B (0.144), which is favorable for CNS penetration.

**Binding Affinity:** Ligand A (-8.4 kcal/mol) has a significantly stronger binding affinity than Ligand B (-6.4 kcal/mol). This is a major advantage for Ligand A, exceeding the 1.5 kcal/mol difference threshold.

**Overall Assessment:**

While Ligand A has a higher DILI risk, its significantly superior binding affinity (-8.4 vs -6.4 kcal/mol) and better P-gp efflux, longer half-life, and higher QED outweigh this concern. Ligand B has a better BBB score and lower DILI, but the weaker binding affinity is a critical drawback, especially for a GPCR target where potency is paramount. The difference in affinity is substantial enough to overcome the slightly higher DILI risk of Ligand A.

Output:
1
2025-04-17 05:50:56,579 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (354.45 & 350.37 Da) fall comfortably within the ideal 200-500 Da range.

**TPSA:** Ligand A (77.1) is significantly better than Ligand B (87.14). For CNS targets, we want TPSA <= 90, and A is closer to the ideal <= 60 range. B is pushing the upper limit.

**logP:** Both ligands have acceptable logP values (1.23 & 2.43), falling within the 1-3 range. Ligand B is slightly higher, which could potentially lead to solubility issues, but is not a major concern.

**H-Bond Donors/Acceptors:** Ligand A (1 HBD, 5 HBA) is preferable to Ligand B (3 HBD, 5 HBA). Lower HBD counts are generally favored for better permeability.

**QED:** Both ligands have similar, good QED values (0.744 & 0.745), indicating generally drug-like properties.

**DILI:** Ligand A (25.79) has a much lower DILI risk than Ligand B (61.19). This is a significant advantage for A.

**BBB:** Both ligands have similar BBB penetration percentiles (48.66 & 48.28), which are below the desirable >70 for CNS targets. This is a weakness for both, but not a differentiating factor.

**Caco-2:** Ligand A (-4.58) has a better (more positive) Caco-2 permeability value than Ligand B (-5.20), suggesting better intestinal absorption.

**Solubility:** Ligand A (-1.17) has a better solubility score than Ligand B (-3.82).

**hERG:** Ligand A (0.19) has a much lower hERG inhibition liability than Ligand B (0.553), indicating a lower risk of cardiotoxicity.

**Microsomal Clearance:** Ligand A (29.09) has a lower microsomal clearance than Ligand B (57.71), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (-2.74) has a longer in vitro half-life than Ligand B (-21.91), which is a significant advantage.

**P-gp Efflux:** Ligand A (0.037) has a lower P-gp efflux liability than Ligand B (0.064), suggesting better CNS exposure.

**Binding Affinity:** Ligand B (-9.2 kcal/mol) has a slightly better binding affinity than Ligand A (-8.1 kcal/mol). This is a 1.1 kcal/mol difference. While affinity is crucial, the other ADME properties of A are significantly better.

**Overall Assessment:**

Ligand A is the superior candidate. While Ligand B has a slightly better binding affinity, Ligand A excels in almost all ADME properties crucial for a CNS-targeting GPCR ligand: lower DILI risk, better solubility, lower hERG inhibition, better metabolic stability, longer half-life, and lower P-gp efflux. The TPSA is also significantly better for A. The 1.1 kcal/mol difference in affinity is unlikely to outweigh the substantial ADME advantages of Ligand A.



Output:
0
2025-04-17 05:50:56,579 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (373.909 and 342.374 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (50.8) is better than Ligand B (58.87). Both are below the 90 Angstrom threshold for CNS targets, but A is closer to the optimal range.

**3. logP:** Ligand A (4.853) is higher than Ligand B (2.796). While 4.853 is approaching the upper limit, it's still within an acceptable range. Ligand B's logP is quite good.

**4. H-Bond Donors:** Both ligands have 1 HBD, which is acceptable.

**5. H-Bond Acceptors:** Ligand A has 4 HBAs, and Ligand B has 5. Both are below the 10 limit.

**6. QED:** Both ligands have good QED scores (0.601 and 0.775, respectively), indicating drug-like properties.

**7. DILI:** Both ligands have similar DILI risk (69.833 and 68.244), and both are moderately high, but not alarming.

**8. BBB:** This is a crucial parameter for a CNS target like DRD2. Ligand B (70.686) significantly outperforms Ligand A (27.259). This is a major advantage for Ligand B.

**9. Caco-2 Permeability:** Ligand A (-5.398) is worse than Ligand B (-4.539), indicating lower intestinal absorption.

**10. Aqueous Solubility:** Ligand A (-5.725) is worse than Ligand B (-3.175), indicating lower solubility.

**11. hERG Inhibition:** Ligand A (0.501) is better than Ligand B (0.868), meaning lower risk of cardiotoxicity.

**12. Microsomal Clearance:** Ligand B (34.338) has significantly lower clearance than Ligand A (63.866), suggesting better metabolic stability.

**13. In vitro Half-Life:** Ligand B (12.163 hours) has a much longer half-life than Ligand A (5.738 hours).

**14. P-gp Efflux:** Ligand A (0.77) is slightly better than Ligand B (0.348), suggesting lower P-gp efflux.

**15. Binding Affinity:** Ligand A (-9.9 kcal/mol) has a significantly stronger binding affinity than Ligand B (-8.5 kcal/mol). This is a substantial advantage for Ligand A.

**Overall Assessment:**

Ligand A has a significantly better binding affinity, and slightly better hERG and P-gp profiles. However, Ligand B excels in crucial ADME properties for a CNS drug: BBB penetration, metabolic stability (lower Cl_mic and longer t1/2), and solubility. The large difference in BBB penetration (70.69% vs 27.26%) is a decisive factor. While the affinity difference is notable, a 1.4 kcal/mol difference can be overcome with further optimization, whereas poor BBB penetration is a more difficult property to improve. The better metabolic stability and solubility of Ligand B also contribute to its overall viability.

Output:
1
2025-04-17 05:50:56,580 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B based on the provided guidelines, prioritizing GPCR-specific properties (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (348.531 and 353.419 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (58.2) is excellent, well below the 90 A^2 threshold for CNS targets. Ligand B (115.9) is higher but still potentially acceptable, though less ideal.

**logP:** Ligand A (3.938) is at the upper end of the optimal range (1-3), but still acceptable. Ligand B (0.248) is significantly low, potentially hindering permeability.

**H-Bond Donors/Acceptors:** Ligand A (2 HBD, 2 HBA) is favorable. Ligand B (3 HBD, 6 HBA) is also acceptable, but slightly higher.

**QED:** Both ligands have similar QED values (0.663 and 0.675), indicating good drug-likeness.

**DILI:** Ligand A (13.067) has a much lower DILI risk than Ligand B (39.201), a significant advantage.

**BBB:** Ligand A (77.627) has a good BBB percentile, exceeding the 70% threshold for CNS targets. Ligand B (25.785) is poor, indicating limited brain penetration. This is a critical drawback for a DRD2 ligand.

**Caco-2 Permeability:** Ligand A (-4.711) and Ligand B (-5.107) both have negative values, which is unusual and suggests very poor permeability. However, the scale isn't defined, so it's hard to interpret.

**Aqueous Solubility:** Ligand A (-4.541) and Ligand B (-0.798) both have negative values, suggesting poor solubility.

**hERG Inhibition:** Ligand A (0.596) has a lower hERG risk than Ligand B (0.254), which is preferable.

**Microsomal Clearance:** Ligand A (70.865) has higher microsomal clearance than Ligand B (13.315), suggesting lower metabolic stability.

**In vitro Half-Life:** Ligand A (1.484) has a very short half-life, while Ligand B (-20.617) is also problematic.

**P-gp Efflux:** Ligand A (0.176) has lower P-gp efflux than Ligand B (0.089), which is favorable for CNS penetration.

**Binding Affinity:** Both ligands have very similar and strong binding affinities (-8.4 and -8.3 kcal/mol). The difference is negligible.

**Conclusion:**

Considering all factors, especially the GPCR-specific priorities, **Ligand A is the more promising drug candidate.** Its significantly better BBB penetration, lower DILI risk, and lower P-gp efflux outweigh its slightly higher microsomal clearance and shorter half-life. Ligand B's very poor BBB penetration is a major drawback for a CNS target like DRD2, and its higher DILI risk is also concerning. The similar affinities make the ADME properties the deciding factor.

Output:
0
2025-04-17 05:50:56,580 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (350.459 and 356.413 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (87.66) is better than Ligand B (58.64). For CNS targets, we want TPSA <= 90, both meet this criteria, but A is closer to the upper limit.

**3. logP:** Both ligands have good logP values (1.26 and 2.122), falling within the optimal range of 1-3.

**4. H-Bond Donors:** Ligand A (3) is slightly higher than Ligand B (1), but both are within the acceptable limit of <=5.

**5. H-Bond Acceptors:** Ligand A (4) is higher than Ligand B (3), both are within the acceptable limit of <=10.

**6. QED:** Both ligands have good QED scores (0.615 and 0.843), indicating good drug-like properties. Ligand B is better here.

**7. DILI:** Ligand A (21.946) has a significantly lower DILI risk than Ligand B (33.424), which is a major advantage.

**8. BBB:** Ligand B (89.531) has a much better BBB penetration score than Ligand A (44.203). This is *critical* for a CNS target like DRD2.

**9. Caco-2 Permeability:** Ligand A (-5.375) has worse Caco-2 permeability than Ligand B (-4.485).

**10. Aqueous Solubility:** Both ligands have very poor aqueous solubility (-2.426 and -2.479). This is a concern for both, but not a deciding factor.

**11. hERG Inhibition:** Both ligands have low hERG inhibition risk (0.222 and 0.431).

**12. Microsomal Clearance:** Ligand A (4.911) has lower microsomal clearance than Ligand B (13.844), suggesting better metabolic stability.

**13. In vitro Half-Life:** Ligand A (31.323) has a longer in vitro half-life than Ligand B (-9.214).

**14. P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.058 and 0.053).

**15. Binding Affinity:** Both ligands have excellent binding affinities (-9.1 and -9.5 kcal/mol). Ligand B is slightly better.

**Overall Assessment:**

Ligand B excels in BBB penetration and binding affinity, which are paramount for a CNS GPCR target. While Ligand A has better DILI and metabolic stability, the superior BBB score of Ligand B outweighs these advantages. The slightly better QED of Ligand B is also a plus. The solubility is a concern for both, but can be addressed with formulation strategies.

Output:
1
2025-04-17 05:50:56,580 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (347.459 and 352.41 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (81.67) is better than Ligand B (90.54). For CNS targets, we want TPSA <= 90, so Ligand A is preferable.

**3. logP:** Ligand A (2.273) is optimal (1-3). Ligand B (0.019) is significantly lower, potentially hindering permeation.

**4. H-Bond Donors:** Both ligands have 3 HBD, which is acceptable (<=5).

**5. H-Bond Acceptors:** Both ligands have 3 HBA, which is acceptable (<=10).

**6. QED:** Both ligands have QED values above 0.5 (0.675 and 0.589), indicating good drug-likeness.

**7. DILI:** Ligand A (34.432) has a lower DILI risk than Ligand B (42.458), both are acceptable (<40 is good, <60 is preferred).

**8. BBB:** Ligand B (62.699) has a better BBB penetration percentile than Ligand A (53.083). However, both are below the desirable >70 for CNS targets.

**9. Caco-2 Permeability:** Ligand A (-4.953) has better Caco-2 permeability than Ligand B (-5.051), though both are poor.

**10. Aqueous Solubility:** Ligand A (-1.627) has better solubility than Ligand B (-1.89), though both are poor.

**11. hERG Inhibition:** Ligand A (0.5) has a lower hERG inhibition liability than Ligand B (0.116), which is preferable.

**12. Microsomal Clearance:** Ligand A (-13.614) has a lower (better) microsomal clearance than Ligand B (-18.494), suggesting better metabolic stability.

**13. In vitro Half-Life:** Ligand A (35.11) has a much longer in vitro half-life than Ligand B (-5.959), which is a significant advantage.

**14. P-gp Efflux:** Ligand A (0.079) has lower P-gp efflux liability than Ligand B (0.017), which is preferable for CNS exposure.

**15. Binding Affinity:** Ligand B (-8.6) has a slightly better binding affinity than Ligand A (-7.9). The difference is 0.7 kcal/mol, which is not a huge advantage, but is worth considering.

**Overall Assessment:**

While Ligand B has slightly better binding affinity and BBB penetration, Ligand A is significantly better across multiple crucial ADME properties. Specifically, Ligand A has a much better logP, metabolic stability (Cl_mic and t1/2), P-gp efflux, and hERG inhibition. The TPSA is also more favorable for CNS penetration. The slightly weaker binding affinity of Ligand A can potentially be optimized in subsequent rounds of medicinal chemistry. Given the GPCR-specific priorities, the superior ADME profile of Ligand A makes it the more promising drug candidate.

Output:
1
2025-04-17 05:50:56,580 - INFO - Reasoning:

Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (343.354 and 366.571 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (66.84) is better than Ligand B (49.41). Both are below the 90 A^2 threshold desirable for CNS targets, but Ligand A is slightly higher, potentially impacting BBB penetration.

**3. logP:** Both ligands have good logP values (2.874 and 3.021), falling within the optimal 1-3 range.

**4. H-Bond Donors:** Both have 1 HBD, which is acceptable.

**5. H-Bond Acceptors:** Ligand A has 4 HBAs, and Ligand B has 3. Both are within the acceptable limit of 10.

**6. QED:** Both ligands have reasonable QED scores (0.848 and 0.718), indicating good drug-like properties.

**7. DILI:** Ligand A (53.625) has a higher DILI risk than Ligand B (16.402). This is a significant drawback for Ligand A.

**8. BBB:** Both ligands have excellent BBB penetration (77.084 and 76.658), exceeding the desirable >70 threshold for CNS targets.

**9. Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and suggests poor permeability. However, these values are on a strange scale, so it's hard to interpret.

**10. Aqueous Solubility:** Both have negative solubility values, which is also unusual. Again, the scale is unclear.

**11. hERG Inhibition:** Both ligands show low hERG inhibition risk (0.49 and 0.677).

**12. Microsomal Clearance:** Ligand A (87.235) has higher microsomal clearance than Ligand B (75.44), indicating lower metabolic stability.

**13. In vitro Half-Life:** Ligand B (12.266) has a significantly longer in vitro half-life than Ligand A (-6.679). This is a major advantage for Ligand B.

**14. P-gp Efflux:** Both ligands have low P-gp efflux liability (0.119 and 0.141), which is good for CNS exposure.

**15. Binding Affinity:** Ligand B (-8.3 kcal/mol) has a stronger binding affinity than Ligand A (-7.7 kcal/mol). This 0.6 kcal/mol difference is substantial.

**Overall Assessment:**

Ligand B is the superior candidate. While both have good BBB penetration and logP values, Ligand B excels in several critical areas: significantly lower DILI risk, a much longer in vitro half-life, and stronger binding affinity. Ligand A's higher DILI risk and lower metabolic stability are concerning. The slightly higher TPSA of Ligand A is less of a concern given the already good BBB values. The unusual Caco-2 and solubility values are difficult to interpret, but the other factors strongly favor Ligand B.

Output:
1
2025-04-17 05:50:56,581 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (368.861 and 344.419 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (60.03) is significantly better than Ligand B (85.05). For CNS targets, we want TPSA <= 90, and A is comfortably within that range, while B is approaching the upper limit.

**logP:** Ligand A (3.78) is good, within the 1-3 optimal range. Ligand B (1.279) is on the lower side, potentially hindering permeability.

**H-Bond Donors/Acceptors:** Both have 1 HBD, which is good. Ligand A has 5 HBA, acceptable. Ligand B has 6 HBA, also acceptable, but slightly less favorable.

**QED:** Both ligands have good QED scores (0.876 and 0.905), indicating good drug-like properties.

**DILI:** Both ligands have similar DILI risk (60.489 and 60.915), placing them in a moderate risk category. This isn't a deciding factor.

**BBB:** Ligand A (91.431) has a much better BBB percentile than Ligand B (73.827). This is *crucial* for a CNS target like DRD2. A value >70 is desirable, and A exceeds that, while B is close but not as strong.

**Caco-2 Permeability:** Both have negative Caco-2 values (-4.485 and -4.814). This is unusual and suggests poor permeability. However, the absolute values are similar.

**Aqueous Solubility:** Both have negative solubility values (-4.854 and -2.598). This is also concerning, indicating poor solubility. B is slightly better than A.

**hERG:** Both ligands have low hERG inhibition liability (0.763 and 0.492), which is good.

**Microsomal Clearance:** Ligand A (43.481) has a higher microsomal clearance than Ligand B (25.456), indicating lower metabolic stability. This is a negative for A.

**In vitro Half-Life:** Ligand B (-17.788) has a negative half-life, which is highly unusual and problematic. Ligand A (24.618) has a reasonable half-life.

**P-gp Efflux:** Ligand A (0.441) has lower P-gp efflux than Ligand B (0.101), which is preferable for CNS penetration.

**Binding Affinity:** Ligand B (-7.4 kcal/mol) has a slightly better binding affinity than Ligand A (-8.0 kcal/mol). While A is stronger, the difference is not substantial enough to overcome other significant drawbacks.

**Overall Assessment:**

Ligand A excels in BBB penetration, P-gp efflux, and has a reasonable in vitro half-life. However, it has higher microsomal clearance and lower solubility. Ligand B has better solubility and lower clearance, but suffers from significantly lower BBB penetration and a highly problematic negative in vitro half-life.

Given the GPCR-specific priorities, particularly the need for good BBB penetration for a CNS target, and the severe issue with Ligand B's half-life, **Ligand A is the more promising candidate.** The slightly better affinity of Ligand B does not outweigh the critical ADME deficiencies.

Output:
1
2025-04-17 05:50:56,581 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (347.459 and 362.495 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (66.65) is better than Ligand B (69.64). Both are below the 90 A^2 threshold desirable for CNS targets, but A is closer to optimal.

**3. logP:** Both ligands have good logP values (2.902 and 2.104), falling within the 1-3 range.

**4. H-Bond Donors:** Ligand A (0) is preferable to Ligand B (2). Fewer HBDs generally improve permeability.

**5. H-Bond Acceptors:** Both ligands have 4 HBA, which is acceptable (<=10).

**6. QED:** Both ligands have good QED scores (0.711 and 0.862), indicating drug-like properties.

**7. DILI:** Ligand A (48.313) has a slightly higher DILI risk than Ligand B (24.661). This favors Ligand B.

**8. BBB:** Both ligands have excellent BBB penetration (79.76% and 72.78%), exceeding the 70% threshold for CNS targets.

**9. Caco-2 Permeability:** Ligand A (-4.515) has worse Caco-2 permeability than Ligand B (-4.888).

**10. Aqueous Solubility:** Both ligands have poor aqueous solubility (-2.072 and -2.577). This is a potential concern for both, but not a deciding factor.

**11. hERG Inhibition:** Both ligands have low hERG inhibition liability (0.262 and 0.449), which is good.

**12. Microsomal Clearance:** Ligand A (76.92) has significantly higher microsomal clearance than Ligand B (26.662), indicating lower metabolic stability. This is a significant drawback for Ligand A.

**13. In vitro Half-Life:** Ligand A (-20.072) has a much shorter in vitro half-life than Ligand B (15.268). This is another significant drawback for Ligand A.

**14. P-gp Efflux:** Ligand A (0.457) has better P-gp efflux properties than Ligand B (0.119), which is favorable for CNS penetration.

**15. Binding Affinity:** Ligand B (-8.0) has a slightly better binding affinity than Ligand A (-7.8). While the difference is small, it's still a positive for Ligand B.

**Overall Assessment:**

Ligand B is the more promising candidate. While Ligand A has slightly better P-gp efflux, Ligand B excels in key areas for a CNS-targeting GPCR ligand: lower DILI risk, significantly better metabolic stability (lower Cl_mic and longer t1/2), and slightly better binding affinity. The TPSA values are comparable and acceptable for CNS penetration. The solubility is a concern for both, but can be addressed with formulation strategies.

Output:
1
2025-04-17 05:50:56,581 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (368.865 Da) is slightly higher than Ligand B (345.443 Da), but both are acceptable.

**TPSA:** Ligand A (87.32) is borderline for CNS targets (ideally <90), while Ligand B (54.04) is well within the desired range. This is a significant advantage for Ligand B.

**logP:** Both ligands have good logP values (Ligand A: 1.763, Ligand B: 0.95), falling within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A has 2 HBD and 4 HBA, while Ligand B has 1 HBD and 5 HBA. Both are within acceptable limits.

**QED:** Both ligands have good QED scores (Ligand A: 0.847, Ligand B: 0.861), indicating good drug-like properties.

**DILI:** Ligand A (67.623) has a higher DILI risk than Ligand B (15.704). This is a clear advantage for Ligand B.

**BBB:** Ligand B (62.233) has a slightly better BBB penetration percentile than Ligand A (54.478), but both are below the desirable >70 for CNS targets.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.993 and -4.831), which is unusual and suggests poor permeability. This is a concern for both.

**Aqueous Solubility:** Both ligands have negative solubility values (-3.437 and -1.479), indicating poor solubility. This is a concern for both.

**hERG:** Ligand A (0.13) has a lower hERG risk than Ligand B (0.68). This is an advantage for Ligand A.

**Microsomal Clearance:** Ligand B (44.267) has a lower microsomal clearance than Ligand A (29.411), indicating better metabolic stability. This is an advantage for Ligand B.

**In vitro Half-Life:** Ligand B (16.285) has a slightly longer half-life than Ligand A (13.115).

**P-gp Efflux:** Ligand A (0.074) has lower P-gp efflux liability than Ligand B (0.032), which is favorable for CNS penetration.

**Binding Affinity:** Ligand A (-8.5 kcal/mol) has a significantly stronger binding affinity than Ligand B (-7.7 kcal/mol). This is a substantial advantage for Ligand A, potentially outweighing some of its ADME drawbacks. The difference of 0.8 kcal/mol is meaningful.

**Overall Assessment:**

Ligand B has better ADME properties (lower DILI, better metabolic stability, lower TPSA) but weaker binding affinity. Ligand A has a significantly stronger binding affinity, but suffers from higher DILI and slightly worse BBB penetration. Given the importance of affinity for GPCR ligands, and the 0.8 kcal/mol difference, the stronger binding of Ligand A is likely to be more critical. While the ADME properties of Ligand A are not ideal, they are not disqualifying, and further optimization could address these issues.

Output:
0
2025-04-17 05:50:56,581 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (349.391 and 346.431 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (131.54) is borderline for CNS penetration, being slightly above the preferred <90 threshold. Ligand B (78.68) is excellent, well below 90, suggesting better CNS penetration.

**logP:** Both ligands have good logP values (1.829 and 0.978), falling within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Both ligands have acceptable HBD (2 and 1 respectively) and HBA (5) counts, unlikely to cause significant issues.

**QED:** Ligand B (0.86) has a significantly better QED score than Ligand A (0.288), indicating a more drug-like profile.

**DILI:** Both ligands have low DILI risk (34.277 and 23.885 percentiles), which is favorable.

**BBB:** Ligand B (82.745) has a much higher BBB percentile than Ligand A (38.426), a critical advantage for a CNS target like DRD2.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.976 and -4.943). This is unusual and suggests potential issues with intestinal absorption, but the values are very similar.

**Aqueous Solubility:** Both ligands have negative solubility values (-1.009 and -1.449). This is also unusual and suggests poor aqueous solubility.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.172 and 0.364), which is good.

**Microsomal Clearance:** Ligand B (7.972) has a higher microsomal clearance than Ligand A (2.406), suggesting faster metabolism and potentially lower in vivo exposure.

**In vitro Half-Life:** Both ligands have similar in vitro half-lives (23.524 and 22.312 hours).

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.031 and 0.025), which is excellent for CNS penetration.

**Binding Affinity:** Ligand A (-7.8 kcal/mol) has a slightly better binding affinity than Ligand B (-7.3 kcal/mol), although the difference is less than the 1.5 kcal/mol threshold where affinity can outweigh other issues.

**Overall Assessment:**

Ligand B is the superior candidate. While Ligand A has slightly better binding affinity, Ligand B excels in crucial areas for a CNS-targeting GPCR: significantly better BBB penetration, a much higher QED score, and lower microsomal clearance. The TPSA of Ligand B is also much more favorable. The solubility and Caco-2 values are concerning for both, but the other advantages of Ligand B outweigh this concern.

Output:
1
2025-04-17 05:50:56,581 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (361.427 and 354.411 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (120.91) is slightly above the preferred <90 for CNS targets, but still reasonable. Ligand B (103.63) is better, falling comfortably below 90.

**3. logP:** Ligand A (0.832) is a bit low, potentially hindering permeability. Ligand B (-0.246) is even lower, raising concerns about membrane penetration. Both are below the optimal 1-3 range.

**4. H-Bond Donors:** Ligand A (2) and Ligand B (1) are both within the acceptable limit of <=5.

**5. H-Bond Acceptors:** Ligand A (7) and Ligand B (9) are both within the acceptable limit of <=10.

**6. QED:** Both ligands have similar QED values (0.749 and 0.715), indicating good drug-likeness.

**7. DILI:** Ligand A (67.429) has a higher DILI risk than Ligand B (47.693), but both are acceptable (<60 is good).

**8. BBB:** This is a critical parameter for CNS targets. Ligand B (74.098) has a significantly better BBB penetration percentile than Ligand A (48.003).

**9. Caco-2 Permeability:** Ligand A (-5.488) has poor Caco-2 permeability, while Ligand B (-4.894) is also poor, but slightly better.

**10. Aqueous Solubility:** Ligand A (-2.946) and Ligand B (-0.765) both have poor aqueous solubility.

**11. hERG Inhibition:** Both ligands show very low hERG inhibition risk (0.475 and 0.044).

**12. Microsomal Clearance:** Ligand A (15.127) has higher microsomal clearance than Ligand B (10.556), suggesting lower metabolic stability.

**13. In vitro Half-Life:** Ligand B (6.05) has a better in vitro half-life than Ligand A (-10.011).

**14. P-gp Efflux:** Both ligands show very low P-gp efflux liability (0.027 and 0.025).

**15. Binding Affinity:** Ligand A (-8.4 kcal/mol) has a significantly stronger binding affinity than Ligand B (-6.3 kcal/mol). This is a substantial advantage.

**Overall Assessment:**

While Ligand A has a superior binding affinity, Ligand B demonstrates a much more favorable ADME profile, particularly regarding BBB penetration (74.1% vs 48.0%), which is crucial for a CNS target like DRD2. Ligand B also has better metabolic stability (lower Cl_mic) and a longer in vitro half-life. The lower logP of both is a concern, but the stronger affinity of Ligand A might compensate. However, the significant difference in BBB penetration and the better overall ADME profile of Ligand B outweigh the affinity difference.

Output:
1
2025-04-17 05:50:56,582 - INFO - Batch 232 complete. Total preferences: 3712
2025-04-17 05:50:56,582 - INFO - Processing batch 233/512...
2025-04-17 05:51:37,313 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 drug candidates, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (346.383 and 352.45 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (95.94) is slightly higher than Ligand B (84.58). Both are below the 140 A^2 threshold for oral absorption and reasonably close to the 90 A^2 target for CNS penetration, but Ligand B is preferable here.

**3. logP:** Both ligands have good logP values (1.272 and 2.35), falling within the optimal 1-3 range. Ligand B is slightly higher, which could be beneficial for membrane permeability.

**4. H-Bond Donors:** Ligand A (2) and Ligand B (3) are both acceptable, being less than 5.

**5. H-Bond Acceptors:** Ligand A (5) and Ligand B (4) are both acceptable, being less than 10.

**6. QED:** Both ligands have similar QED values (0.756 and 0.703), indicating good drug-like properties.

**7. DILI:** Ligand A (65.374) has a higher DILI risk than Ligand B (9.926). This is a significant advantage for Ligand B.

**8. BBB:** Both ligands have good BBB penetration (56.611 and 66.344), but Ligand B is better. A value >70 is desirable for CNS targets, but both are reasonably good.

**9. Caco-2:** Both have negative Caco-2 values which is unusual and suggests poor permeability.

**10. Solubility:** Both ligands have negative solubility values which is also unusual and suggests poor solubility.

**11. hERG:** Ligand A (0.154) has a lower hERG inhibition liability than Ligand B (0.695), which is preferable.

**12. Cl_mic:** Ligand A (-11.455) has a much lower (better) microsomal clearance than Ligand B (-5.353), indicating greater metabolic stability.

**13. t1/2:** Ligand B (33.44) has a significantly longer in vitro half-life than Ligand A (11.104), which is a major advantage.

**14. Pgp:** Ligand A (0.061) has lower P-gp efflux liability than Ligand B (0.191), which is preferable for CNS exposure.

**15. Binding Affinity:** Both ligands have excellent binding affinities (-9.8 and -9.0 kcal/mol). Ligand A has a slightly better affinity, but the difference is less than 1.5 kcal/mol.

**Overall Assessment:**

While Ligand A has slightly better affinity and Pgp efflux, Ligand B is significantly better in several critical ADME properties: DILI risk, metabolic stability (Cl_mic), and in vitro half-life. The better BBB penetration of Ligand B is also favorable for a CNS target. The slightly higher logP of Ligand B could also be advantageous. Given the GPCR-specific priorities, the improved ADME profile of Ligand B outweighs the small difference in binding affinity.

Output:
1
2025-04-17 05:51:37,314 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (383.25 Da) is slightly higher than Ligand B (349.519 Da), but both are acceptable.

**TPSA:** Ligand A (49.41) is better than Ligand B (52.65) as it is closer to the ideal <90 for CNS targets.

**logP:** Both ligands have good logP values (A: 3.968, B: 2.428), falling within the optimal 1-3 range. Ligand A is slightly higher, which could potentially lead to off-target effects, but is still within an acceptable range.

**H-Bond Donors/Acceptors:** Both ligands have 1 HBD and a reasonable number of HBAs (A: 2, B: 3). This is favorable for permeability.

**QED:** Both ligands have similar QED values (A: 0.813, B: 0.776), indicating good drug-like properties.

**DILI:** Ligand A (66.421) has a significantly higher DILI risk than Ligand B (10.741). This is a major concern for Ligand A.

**BBB:** Both ligands have good BBB penetration (A: 70.841, B: 69.058), exceeding the desirable >70 threshold for CNS targets.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values, which is unusual and suggests poor permeability. However, these values are on a scale where negative values are possible, and direct comparison is difficult without knowing the scale's specifics.

**Aqueous Solubility:** Both ligands have negative solubility values, which is also unusual. Again, direct comparison is difficult without knowing the scale.

**hERG:** Both ligands have low hERG inhibition liability (A: 0.569, B: 0.523), which is good.

**Microsomal Clearance:** Ligand A (74.937) has a much higher microsomal clearance than Ligand B (16.188), indicating poorer metabolic stability.

**In vitro Half-Life:** Ligand B (-11.214) has a negative half-life, which is impossible. This is a significant red flag. Ligand A (41.018) has a reasonable half-life.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (A: 0.151, B: 0.031), which is favorable for CNS exposure.

**Binding Affinity:** Both ligands have strong binding affinities (A: -9.1 kcal/mol, B: -8.1 kcal/mol). Ligand A is 1 kcal/mol stronger, which is a substantial difference.

**Overall Assessment:**

Ligand A has a superior binding affinity and acceptable BBB penetration, TPSA, logP, and P-gp efflux. However, its significantly higher DILI risk and higher microsomal clearance are major drawbacks. The negative Caco-2 and solubility values are concerning but difficult to interpret without more information.

Ligand B has a much lower DILI risk and better metabolic stability. However, its binding affinity is weaker, and the negative half-life is a critical flaw. The negative Caco-2 and solubility values are also concerning.

Considering the GPCR-specific priorities and the overall profile, the stronger binding affinity of Ligand A is a significant advantage that *could* outweigh its drawbacks, *if* the DILI risk can be mitigated through structural modifications. However, the negative half-life of Ligand B is a showstopper.

Output:
1
2025-04-17 05:51:37,314 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (377.531 and 344.455 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (63.24) is higher than the preferred <90 for CNS targets, but still reasonable. Ligand B (47.73) is excellent, well below 90.

**3. logP:** Both ligands have good logP values (3.96 and 3.871), falling within the optimal 1-3 range.

**4. H-Bond Donors:** Ligand A has 1 HBD, which is acceptable. Ligand B has 0, also acceptable.

**5. H-Bond Acceptors:** Ligand A has 4 HBA, within the limit of 10. Ligand B has 5, also within the limit.

**6. QED:** Both ligands have good QED scores (0.829 and 0.763), indicating good drug-like properties.

**7. DILI:** Ligand A (68.205) has a higher DILI risk than Ligand B (11.71). This is a significant negative for Ligand A.

**8. BBB:** Ligand B (83.366) has a significantly better BBB penetration score than Ligand A (68.941). This is crucial for a CNS target like DRD2.

**9. Caco-2 Permeability:** Both have negative values, which is unusual and requires further investigation. However, the magnitude of negativity is similar.

**10. Aqueous Solubility:** Both ligands have negative solubility values, which is concerning.

**11. hERG Inhibition:** Ligand A (0.272) has a slightly lower hERG risk than Ligand B (0.922), which is a minor advantage.

**12. Microsomal Clearance:** Ligand B (29.622) has a lower microsomal clearance than Ligand A (42.962), indicating better metabolic stability.

**13. In vitro Half-Life:** Ligand B (1.381) has a very short half-life, which is a major drawback. Ligand A (61.152) has a much better half-life.

**14. P-gp Efflux:** Ligand A (0.471) has lower P-gp efflux than Ligand B (0.731), which is preferable for CNS penetration.

**15. Binding Affinity:** Ligand B (-8.6 kcal/mol) has a significantly stronger binding affinity than Ligand A (-7.7 kcal/mol). This >1.5 kcal/mol difference is a substantial advantage.

**Overall Assessment:**

Ligand B excels in key areas for a CNS GPCR target: BBB penetration and binding affinity. While its half-life is a major concern, the strong affinity might allow for a lower effective dose, potentially mitigating the need for a long half-life. The lower DILI risk is also a significant advantage. Ligand A has a better half-life and lower P-gp efflux, but suffers from a higher DILI risk and significantly lower BBB penetration. The affinity difference is also substantial.

Considering the GPCR-specific priorities, the superior BBB penetration and binding affinity of Ligand B outweigh its shorter half-life, making it the more promising candidate.

Output:
1
2025-04-17 05:51:37,314 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (334.335 Da and 350.503 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (107.87) is better than Ligand B (69.64). For CNS targets, we want TPSA <= 90, and Ligand B is well within this range, while Ligand A is slightly above.

**logP:** Both ligands (2.151 and 2.471) are within the optimal 1-3 range.

**H-Bond Donors:** Both have 2 HBD, which is acceptable (<=5).

**H-Bond Acceptors:** Ligand A has 5 HBA, and Ligand B has 3. Both are within the acceptable range (<=10).

**QED:** Both ligands have good QED scores (0.711 and 0.821), indicating good drug-like properties.

**DILI:** Ligand A has a significantly higher DILI risk (95.153 percentile) compared to Ligand B (5.584 percentile). This is a major concern for Ligand A.

**BBB:** Ligand B (46.84 percentile) has a better BBB penetration score than Ligand A (32.765 percentile), although both are below the desirable >70 for CNS targets.

**Caco-2 Permeability:** Ligand A (-4.948) has worse Caco-2 permeability than Ligand B (-4.739). Lower values are less desirable.

**Aqueous Solubility:** Ligand A (-5.377) has worse aqueous solubility than Ligand B (-2.534).

**hERG:** Both ligands have low hERG inhibition liability (0.534 and 0.23), which is good.

**Microsomal Clearance:** Ligand B (15.085 mL/min/kg) has a much lower microsomal clearance than Ligand A (55.958 mL/min/kg), indicating better metabolic stability.

**In vitro Half-Life:** Ligand B (4.374 hours) has a slightly longer half-life than Ligand A (24.679 hours).

**P-gp Efflux:** Ligand A (0.074) has lower P-gp efflux liability than Ligand B (0.036), which is favorable for CNS penetration.

**Binding Affinity:** Both ligands have excellent binding affinities (-9.2 kcal/mol and -8.8 kcal/mol). The difference of 0.4 kcal/mol is not substantial enough to outweigh other significant differences.

**Conclusion:**

Considering all factors, especially the GPCR-specific priorities, **Ligand B is the more promising drug candidate.** While both have good affinity and acceptable logP/TPSA, Ligand B has a significantly lower DILI risk, better BBB penetration (though still suboptimal), improved metabolic stability (lower Cl_mic), and better solubility. Ligand A's high DILI risk is a major red flag. The slightly better P-gp efflux of Ligand A is not enough to compensate for its other deficiencies.

Output:
1
2025-04-17 05:51:37,315 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (347.459 and 348.451 Da) fall comfortably within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (92.5) is better than Ligand B (97.12). Both are below the 140 threshold for oral absorption and reasonably close to the 90 target for CNS penetration, but A is preferred.

**3. logP:** Both ligands have good logP values (1.352 and 1.775), falling within the optimal 1-3 range.

**4. H-Bond Donors:** Ligand A (2) is better than Ligand B (3). Lower HBD generally improves permeability.

**5. H-Bond Acceptors:** Ligand A (3) is significantly better than Ligand B (8). High HBA can hinder permeability.

**6. QED:** Ligand A (0.71) is better than Ligand B (0.563), indicating a more drug-like profile.

**7. DILI:** Ligand A (20.822) has a much lower DILI risk than Ligand B (60.489). This is a significant advantage for Ligand A.

**8. BBB:** Ligand B (75.107) has a better BBB penetration percentile than Ligand A (65.839). This is a key factor for CNS targets like DRD2.

**9. Caco-2 Permeability:** Ligand A (-5.246) is better than Ligand B (-5.068), indicating better intestinal absorption.

**10. Aqueous Solubility:** Ligand A (-2.717) is better than Ligand B (-2.249), suggesting better solubility.

**11. hERG Inhibition:** Ligand A (0.121) has a lower hERG inhibition liability than Ligand B (0.885), reducing cardiotoxicity risk.

**12. Microsomal Clearance:** Ligand A (26.677) has lower microsomal clearance than Ligand B (43.611), suggesting better metabolic stability.

**13. In vitro Half-Life:** Ligand B (65.641) has a significantly longer in vitro half-life than Ligand A (8.835). This is a positive attribute.

**14. P-gp Efflux:** Ligand A (0.022) has much lower P-gp efflux liability than Ligand B (0.18), which is crucial for CNS exposure.

**15. Binding Affinity:** Both ligands have excellent binding affinities (-7.3 and -7.4 kcal/mol), with Ligand B being slightly better. However, the difference is small and likely not enough to outweigh the other significant advantages of Ligand A.

**Overall Assessment:**

While Ligand B has a slightly better BBB penetration and in vitro half-life, Ligand A excels in almost all other critical ADME properties. Specifically, its lower DILI risk, P-gp efflux, hERG inhibition, and better solubility, combined with a good QED score, make it a more promising drug candidate. The small difference in binding affinity is not enough to overcome the substantial advantages of Ligand A.

Output:
0
2025-04-17 05:51:37,315 - INFO - Reasoning:

Let's analyze Ligand A and Ligand B based on the provided guidelines, prioritizing GPCR-specific properties (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (343.39 and 345.40 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (100.35) is better than Ligand B (112.91). For CNS targets, we want TPSA <= 90, so both are slightly above, but A is closer.

**logP:** Ligand A (0.571) is lower than the optimal 1-3 range, potentially hindering permeability. Ligand B (1.902) is within the optimal range. This favors B.

**H-Bond Donors/Acceptors:** Ligand A (HBD=2, HBA=6) and Ligand B (HBD=3, HBA=5) both have acceptable numbers of H-bond donors and acceptors.

**QED:** Both ligands have reasonable QED values (A: 0.827, B: 0.633), indicating good drug-like properties.

**DILI:** Ligand A (34.47) has a significantly lower DILI risk than Ligand B (69.52), a major advantage.

**BBB:** Ligand A (25.09) has a very low BBB penetration, which is a critical drawback for a CNS target like DRD2. Ligand B (34.86) is also low, but slightly better. Both are far from the desirable >70.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.334 and -5.385), which is unusual and suggests poor permeability.

**Aqueous Solubility:** Both ligands have negative solubility values (-1.688 and -3.216), also unusual and indicating poor solubility.

**hERG Inhibition:** Both ligands show very low hERG inhibition risk (0.177 and 0.15).

**Microsomal Clearance:** Ligand A (-19.46) has a much lower (better) microsomal clearance than Ligand B (38.83), indicating greater metabolic stability.

**In vitro Half-Life:** Ligand A (-27.62) has a much longer (better) in vitro half-life than Ligand B (-11.69).

**P-gp Efflux:** Both ligands show very low P-gp efflux liability (0.016 and 0.037).

**Binding Affinity:** Both ligands have similar, strong binding affinities (-8.9 and -8.2 kcal/mol). The difference of 0.7 kcal/mol isn't substantial enough to outweigh other factors.

**Overall Assessment:**

Despite the similar binding affinities, Ligand A is hampered by its extremely poor BBB penetration. While Ligand B also has low BBB penetration, its logP is within the optimal range, and its DILI risk is significantly higher. The superior metabolic stability (lower Cl_mic and longer t1/2) and lower DILI risk of Ligand A are attractive. However, the extremely poor BBB penetration is a deal-breaker for a CNS target.

Given the importance of BBB penetration for a DRD2 ligand, and the fact that neither ligand performs well in this regard, and considering the slightly better logP of ligand B, I would lean towards Ligand B, but with significant reservations. Further optimization would be needed to improve BBB penetration for either compound.

Output:
1
2025-04-17 05:51:37,315 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (360.479 and 374.491 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (70.24) is better than Ligand B (67.35) as it is closer to the <90 A^2 threshold for CNS targets.

**3. logP:** Both ligands have acceptable logP values (2.893 and 3.921), falling within the 1-3 range. Ligand B is slightly higher, which could potentially lead to solubility issues, but is still within an acceptable range.

**4. H-Bond Donors:** Both ligands have 1 HBD, which is within the ideal limit of <=5.

**5. H-Bond Acceptors:** Ligand A has 3 HBA, while Ligand B has 6. Ligand A is preferred here, being closer to the ideal <=10.

**6. QED:** Ligand A (0.911) has a significantly better QED score than Ligand B (0.754), indicating a more drug-like profile.

**7. DILI:** Ligand A (61.342) has a lower DILI risk than Ligand B (93.796), making it safer.

**8. BBB:** Ligand B (81.466) has a significantly better BBB penetration percentile than Ligand A (69.407). This is a crucial factor for a CNS target like DRD2.

**9. Caco-2:** Both ligands have negative Caco-2 values (-4.684 and -4.727), which is unusual and suggests poor permeability. This is a significant drawback for both.

**10. Solubility:** Both ligands have negative solubility values (-5.574 and -4.463), indicating very poor aqueous solubility. This is a major concern.

**11. hERG:** Both ligands have low hERG inhibition risk (0.621 and 0.474).

**12. Cl_mic:** Both ligands have similar microsomal clearance values (72.654 and 71.593 mL/min/kg), indicating moderate metabolic stability.

**13. t1/2:** Ligand A (-42.591) has a much more negative in vitro half-life compared to Ligand B (37.557). This indicates a much shorter half-life for Ligand A, which is undesirable.

**14. Pgp:** Both ligands have low P-gp efflux liability (0.273 and 0.558).

**15. Binding Affinity:** Ligand B (-8.3 kcal/mol) has a slightly better binding affinity than Ligand A (-9.7 kcal/mol). While both are excellent, the difference of 1.4 kcal/mol is significant.

**Overall Assessment:**

Ligand A has better physicochemical properties (TPSA, HBA, QED, DILI) and a superior binding affinity. However, Ligand B has a significantly better BBB penetration and a more favorable in vitro half-life. Both have concerningly poor solubility and Caco-2 permeability.

Given the GPCR-specific priorities, BBB penetration is critical for CNS targets. The 1.4 kcal/mol difference in binding affinity is outweighed by the substantial improvement in BBB penetration offered by Ligand B. The longer half-life of Ligand B is also a significant advantage. While solubility and permeability are concerns for both, these can be addressed through formulation strategies.

Output:
1
2025-04-17 05:51:37,315 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (339.439 and 348.531 Da) fall comfortably within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (67.16) is slightly higher than Ligand B (58.2). Both are below the 90 A^2 threshold desirable for CNS targets, but Ligand B is preferable.

**3. logP:** Both ligands have good logP values (3.645 and 3.984) within the optimal 1-3 range.

**4. H-Bond Donors:** Both have 2 HBD, which is within the acceptable limit of <=5.

**5. H-Bond Acceptors:** Ligand A has 3 HBA, and Ligand B has 2. Both are below the acceptable limit of <=10.

**6. QED:** Ligand A (0.874) has a significantly higher QED than Ligand B (0.54), indicating a more drug-like profile.

**7. DILI:** Ligand A (36.836) has a slightly higher DILI risk than Ligand B (26.095), but both are below the 40 threshold and are considered low risk.

**8. BBB:** Ligand A (91.663) has a much higher BBB penetration percentile than Ligand B (74.758). This is a *critical* advantage for a CNS target like DRD2.

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 values which is unusual and difficult to interpret. We will disregard this metric.

**10. Aqueous Solubility:** Both ligands have negative solubility values which is unusual and difficult to interpret. We will disregard this metric.

**11. hERG:** Both ligands have low hERG inhibition liability (0.494 and 0.58), which is good.

**12. Microsomal Clearance:** Ligand A (65.907) has lower microsomal clearance than Ligand B (74.529), suggesting better metabolic stability.

**13. In vitro Half-Life:** Ligand A (45.616) has a significantly longer in vitro half-life than Ligand B (1.707). This is a substantial advantage.

**14. P-gp Efflux:** Ligand A (0.526) has slightly higher P-gp efflux than Ligand B (0.375), meaning ligand B is preferable.

**15. Binding Affinity:** Ligand A (-10.2 kcal/mol) has a *much* stronger binding affinity than Ligand B (0.0 kcal/mol). This is a decisive factor.

**Overall Assessment:**

While Ligand B has a slightly better TPSA and P-gp efflux, Ligand A overwhelmingly outperforms it in critical areas for a CNS-targeting GPCR ligand.  The significantly higher BBB penetration, substantially longer half-life, far superior binding affinity, and better QED of Ligand A make it the far more promising drug candidate. The slightly higher DILI risk is outweighed by the other benefits.

Output:
1
2025-04-17 05:51:37,315 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (366.622 and 358.429 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (49.41) is significantly better than Ligand B (58.64). For CNS targets, we want TPSA <= 90, and A is closer to the ideal.

**3. logP:** Both ligands have good logP values (3.894 and 2.344), falling within the optimal 1-3 range.

**4. H-Bond Donors:** Both have 1 HBD, which is acceptable.

**5. H-Bond Acceptors:** Ligand A has 2 HBA, and Ligand B has 3. Both are within the acceptable limit of <=10.

**6. QED:** Both ligands have similar QED values (0.75 and 0.76), indicating good drug-likeness.

**7. DILI:** Ligand A (26.755) has a slightly higher DILI risk than Ligand B (15.587), but both are below the concerning threshold of 40.

**8. BBB:** Ligand B (95.269) has a much higher BBB penetration percentile than Ligand A (81.815). This is a *critical* advantage for a CNS target like DRD2.

**9. Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and suggests poor permeability. However, the scale is not specified, so it's difficult to interpret the absolute impact.

**10. Aqueous Solubility:** Both have negative solubility values, again making interpretation difficult without knowing the scale.

**11. hERG Inhibition:** Both ligands have low hERG inhibition risk (0.458 and 0.583).

**12. Microsomal Clearance:** Ligand B (1.156) has significantly lower microsomal clearance than Ligand A (66.166), indicating better metabolic stability.

**13. In vitro Half-Life:** Ligand B (-1.095) has a slightly better (less negative) in vitro half-life than Ligand A (-11.352).

**14. P-gp Efflux:** Ligand A (0.228) has slightly lower P-gp efflux than Ligand B (0.051), which is favorable.

**15. Binding Affinity:** Ligand B (-8.5 kcal/mol) has a *significantly* stronger binding affinity than Ligand A (-0.0 kcal/mol). This is a major advantage, potentially outweighing some ADME drawbacks.

**Overall Assessment:**

While Ligand A has a slightly better TPSA and P-gp efflux, Ligand B excels in the most crucial areas for a CNS-targeting GPCR ligand: **BBB penetration** and **binding affinity**. The significantly stronger binding affinity of Ligand B (-8.5 vs -0.0 kcal/mol) is a decisive factor. The lower microsomal clearance and improved half-life also contribute to its favorability. The slightly higher DILI risk is less concerning than the poor binding of Ligand A.

Output:
1
2025-04-17 05:51:37,316 - INFO - Reasoning:

Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (363.435 and 349.391 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (76.82) is excellent, well below the 90 A^2 threshold for CNS targets. Ligand B (109.58) is higher, but still potentially acceptable, though less ideal.

**3. logP:** Ligand A (2.896) is optimal (1-3). Ligand B (-0.891) is significantly lower, which could hinder membrane permeability and CNS penetration.

**4. H-Bond Donors:** Ligand A (0) is good. Ligand B (2) is acceptable.

**5. H-Bond Acceptors:** Ligand A (6) is good. Ligand B (7) is acceptable.

**6. QED:** Both ligands have similar QED values (0.556 and 0.465), indicating reasonable drug-likeness.

**7. DILI:** Ligand A (88.949) has a higher DILI risk than Ligand B (46.956). This is a concern for Ligand A.

**8. BBB:** Ligand A (69.756) has a better BBB percentile than Ligand B (40.364). This is a crucial advantage for a CNS target like DRD2.

**9. Caco-2:** Ligand A (-4.687) is very poor, indicating poor intestinal absorption. Ligand B (-5.353) is also poor.

**10. Solubility:** Ligand A (-3.897) is poor. Ligand B (-0.733) is also poor, but slightly better than Ligand A.

**11. hERG:** Ligand A (0.563) has a lower hERG risk than Ligand B (0.067).

**12. Cl_mic:** Ligand A (76.23) has higher metabolic clearance than Ligand B (12.257), suggesting lower metabolic stability.

**13. t1/2:** Ligand A (83.628) has a longer in vitro half-life than Ligand B (9.177), which is a positive.

**14. Pgp:** Ligand A (0.47) has lower P-gp efflux liability than Ligand B (0.059), which is beneficial for CNS penetration.

**15. Affinity:** Ligand A (-8.4 kcal/mol) has a significantly stronger binding affinity than Ligand B (-7.5 kcal/mol). This 1.9 kcal/mol difference is substantial and can outweigh some ADME drawbacks.

**Overall Assessment:**

Ligand A has a significantly better binding affinity and a better BBB percentile, crucial for a CNS GPCR target. It also has lower Pgp efflux. However, it suffers from higher DILI risk, poor Caco-2 permeability, and higher metabolic clearance. Ligand B has a better safety profile (lower DILI) and slightly better solubility, but its poor logP and lower BBB penetration are significant drawbacks for a CNS target.

The strong affinity and acceptable BBB of Ligand A, combined with lower Pgp efflux, make it the more promising candidate despite its other shortcomings. Optimization efforts could focus on mitigating the DILI risk and improving metabolic stability.

Output:
1
2025-04-17 05:51:37,316 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (347.371 and 345.443 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (103.89) is higher than Ligand B (60.93). For CNS targets, TPSA should be <= 90. Ligand B is significantly better here.

**3. logP:** Both ligands have good logP values (1.456 and 1.19), falling within the optimal 1-3 range.

**4. H-Bond Donors:** Ligand A has 3 HBD, and Ligand B has 0. Both are acceptable (<=5).

**5. H-Bond Acceptors:** Ligand A has 5 HBA, and Ligand B has 3. Both are acceptable (<=10).

**6. QED:** Both ligands have good QED values (0.671 and 0.722), indicating drug-like properties.

**7. DILI:** Both ligands have acceptable DILI risk (52.074 and 47.693, both <60).

**8. BBB:** This is a critical parameter for CNS targets. Ligand B (71.462) is significantly better than Ligand A (47.577), exceeding the desirable >70 threshold.

**9. Caco-2 Permeability:** Ligand A (-5.581) and Ligand B (-4.567) both have negative values, indicating poor permeability.

**10. Aqueous Solubility:** Ligand A (-3.155) and Ligand B (-1.666) both have negative values, indicating poor solubility.

**11. hERG Inhibition:** Both ligands have low hERG inhibition risk (0.456 and 0.39).

**12. Microsomal Clearance:** Ligand A (22.552) has lower clearance than Ligand B (43.402), suggesting better metabolic stability.

**13. In vitro Half-Life:** Ligand A (-32.819) has a much longer half-life than Ligand B (-8.919).

**14. P-gp Efflux:** Ligand A (0.043) has lower P-gp efflux than Ligand B (0.128), which is favorable for CNS penetration.

**15. Binding Affinity:** Ligand B (-8.9 kcal/mol) has a slightly better binding affinity than Ligand A (-7.4 kcal/mol). The difference is 1.5 kcal/mol, which is significant enough to potentially outweigh some ADME drawbacks.

**Overall Assessment:**

Ligand B is superior due to its significantly better BBB penetration (71.462 vs 47.577) and lower TPSA (60.93 vs 103.89), both crucial for CNS GPCR targets. While Ligand A has better metabolic stability (lower Cl_mic) and a longer half-life, the improved CNS penetration of Ligand B is more important. The slightly better binding affinity of Ligand B further supports its selection.

Output:
1
2025-04-17 05:51:37,316 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (360.336 and 367.427 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (78.79) is significantly better than Ligand B (101.78). For CNS targets, we want TPSA <= 90, and A is comfortably within this range, while B is slightly above.

**logP:** Both ligands have good logP values (1.579 and 1.28), falling within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Both have 1 HBD and 6 HBA, which are acceptable.

**QED:** Ligand A (0.863) has a substantially higher QED than Ligand B (0.551), indicating a more drug-like profile.

**DILI:** Both have acceptable DILI risk (55.176 and 46.956), below the 60 threshold.

**BBB:** Ligand A (89.066) has a much better BBB percentile than Ligand B (67.584).  A value >70 is desirable for CNS targets, and A is closer to this target.

**Caco-2 Permeability:** Ligand A (-4.438) and Ligand B (-5.191) both have negative values, indicating poor permeability.

**Aqueous Solubility:** Both are very poor (-2.877 and -2.777). This is a concern, but can sometimes be overcome with formulation strategies.

**hERG:** Both ligands have very low hERG inhibition liability (0.265 and 0.148), which is excellent.

**Microsomal Clearance:** Ligand A (40.177) has a higher clearance than Ligand B (13.416). Lower clearance is preferred for metabolic stability.

**In vitro Half-Life:** Ligand B (-0.124) has a slightly better (less negative) half-life than Ligand A (-5.613).

**P-gp Efflux:** Both have very low P-gp efflux liability (0.17 and 0.063), which is good for CNS penetration.

**Binding Affinity:** Both ligands have excellent binding affinity (-8.4 and -8.0 kcal/mol). The difference of 0.4 kcal/mol is not substantial enough to outweigh other factors.

**Conclusion:**

Considering all factors, and prioritizing BBB, TPSA, and QED for a CNS GPCR target, **Ligand A is the more promising drug candidate**. While both have good affinity and low hERG/P-gp liabilities, Ligand A's superior TPSA, BBB penetration, and QED scores make it more likely to succeed as a CNS-active drug. The lower clearance of Ligand B is a plus, but the significant advantage in brain penetration and drug-likeness of Ligand A outweighs this.

Output:
0
2025-04-17 05:51:37,316 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (351.447 and 365.499 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (78.95) is excellent, well below the 90 A^2 threshold for CNS targets. Ligand B (91.32) is slightly above, but still acceptable.

**logP:** Ligand A (0.387) is quite low, potentially hindering membrane permeability. Ligand B (2.156) is much better, falling within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A (1 HBD, 4 HBA) is favorable. Ligand B (3 HBD, 5 HBA) is also acceptable, though slightly higher.

**QED:** Both ligands have reasonable QED scores (0.741 and 0.658), indicating good drug-like properties.

**DILI:** Ligand A (26.095) has a significantly lower DILI risk than Ligand B (42.109), which is a substantial advantage.

**BBB:** Ligand A (32.648) has a poor BBB percentile, making CNS penetration unlikely. Ligand B (42.575) is also low, but better than A. Both are far from the >70 desirable for CNS targets.

**Caco-2 Permeability:** Ligand A (-4.677) has very poor Caco-2 permeability, consistent with its low logP. Ligand B (-5.018) is also poor, but similar to A.

**Aqueous Solubility:** Both ligands have very poor aqueous solubility (-1.691 and -2.469). This could pose formulation challenges.

**hERG:** Both ligands show very low hERG inhibition risk (0.091 and 0.083).

**Microsomal Clearance:** Ligand A (23.716) has a slightly higher microsomal clearance than Ligand B (18.778), suggesting slightly lower metabolic stability.

**In vitro Half-Life:** Both ligands have similar in vitro half-lives (11.159 and 10.194 hours).

**P-gp Efflux:** Both ligands show very low P-gp efflux liability (0.009 and 0.11).

**Binding Affinity:** Ligand B (-8.0) has significantly stronger binding affinity than Ligand A (0.0). This is a major advantage, exceeding the 1.5 kcal/mol difference threshold.

**Overall Assessment:**

Despite the poor BBB and solubility for both, Ligand B is the stronger candidate. The significantly improved logP, coupled with the dramatically superior binding affinity (-8.0 vs 0.0 kcal/mol), outweighs the slightly higher DILI risk and similar BBB/Caco-2 values. The low logP of Ligand A is a major drawback, likely leading to poor permeability and bioavailability. While BBB is important for CNS targets, a strong binding affinity can sometimes compensate if other properties are optimized later.

Output:
1
2025-04-17 05:51:37,316 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B based on the provided guidelines, prioritizing GPCR-specific properties (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (372.403 Da) is slightly higher than Ligand B (346.387 Da), but both are acceptable.

**TPSA:** Both ligands have TPSA values below 140, suggesting good oral absorption potential. Ligand B (117.35) is better, falling closer to the preferred <90 for CNS targets than Ligand A (133.91).

**logP:** Ligand A (-1.254) is below the optimal range (1-3) and could potentially have permeability issues. Ligand B (0.444) is also on the lower side but closer to the ideal range.

**H-Bond Donors/Acceptors:** Both ligands have acceptable HBD (3) and HBA (7/6) counts.

**QED:** Both ligands have reasonable QED scores (0.434 and 0.67), indicating drug-like properties, with Ligand B being better.

**DILI:** Both ligands have DILI risk around the 60-70 percentile, which is moderately concerning. Ligand A (70.841) is slightly higher than Ligand B (60.14).

**BBB:** This is a critical parameter for CNS targets. Ligand A has a BBB penetration of 52.889%, while Ligand B has 30.981%. While neither is >70%, Ligand A is significantly better.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values, which is unusual and suggests poor permeability. This is a significant drawback for both.

**Aqueous Solubility:** Both ligands have negative solubility values, indicating poor aqueous solubility.

**hERG Inhibition:** Both ligands show low hERG inhibition risk (0.133 and 0.127).

**Microsomal Clearance:** Ligand A (-11.4 mL/min/kg) has much lower (better) microsomal clearance than Ligand B (27.63 mL/min/kg), indicating better metabolic stability.

**In vitro Half-Life:** Ligand A (2.725 hours) has a slightly longer half-life than Ligand B (-4.541 hours), which is preferable.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.023 and 0.058), which is good for CNS penetration.

**Binding Affinity:** Ligand B (-8.7 kcal/mol) has a significantly stronger binding affinity than Ligand A (-7.7 kcal/mol). This 1 kcal/mol difference is substantial and could outweigh some of the ADME drawbacks.

**Overall Assessment:**

Ligand B has a better logP, QED, and significantly stronger binding affinity. However, Ligand A has a much better BBB penetration and metabolic stability (lower Cl_mic). Given the CNS target (DRD2), BBB penetration is crucial. While Ligand B's affinity is stronger, the poor BBB penetration is a major concern. Ligand A's better BBB, combined with acceptable (though not ideal) other properties, makes it the more promising candidate. The negative Caco-2 and solubility values are concerning for both, but these can potentially be addressed through formulation strategies.

Output:
0
2025-04-17 05:51:37,317 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B against the provided guidelines, prioritizing GPCR-specific properties (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (410.268 Da) is slightly higher than Ligand B (358.419 Da), but both are acceptable.

**TPSA:** Ligand A (99.5) is closer to the ideal range for CNS targets (<=90) than Ligand B (69.68), though both are reasonably good.

**logP:** Both ligands have good logP values (A: 2.717, B: 3.712), falling within the optimal 1-3 range. Ligand B is slightly higher, which could potentially lead to off-target effects, but is still acceptable.

**H-Bond Donors/Acceptors:** Both ligands have acceptable HBD (1) and HBA (A: 5, B: 7) counts.

**QED:** Both ligands have good QED scores (A: 0.551, B: 0.678), indicating good drug-like properties. Ligand B is slightly better.

**DILI:** Ligand A (71.384) has a lower DILI risk than Ligand B (96.51). This is a significant advantage for Ligand A.

**BBB:** Both ligands have similar BBB penetration (A: 62.97, B: 63.358). While neither exceeds the desirable >70% for CNS targets, they are comparable.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values, which is unusual and suggests poor permeability. This is a concern for both.

**Aqueous Solubility:** Both ligands have negative solubility values, indicating very poor solubility. This is a significant drawback for both.

**hERG Inhibition:** Both ligands have low hERG inhibition liability (A: 0.572, B: 0.685), which is good.

**Microsomal Clearance:** Ligand A (109.574) has lower microsomal clearance than Ligand B (154.848), suggesting better metabolic stability. This is a positive for Ligand A.

**In vitro Half-Life:** Ligand A (37.431) has a longer half-life than Ligand B (2.317), which is desirable.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (A: 0.13, B: 0.257), which is good for CNS penetration.

**Binding Affinity:** Ligand B (-8.3 kcal/mol) has a significantly stronger binding affinity than Ligand A (-7.6 kcal/mol). This >1.5 kcal/mol difference is a major advantage for Ligand B, potentially outweighing some of its ADME drawbacks.

**Overall Assessment:**

Ligand B has a stronger binding affinity, which is the most important factor. While it has a higher DILI risk and slightly higher logP, the substantial improvement in binding affinity (-8.3 vs -7.6 kcal/mol) is likely to be decisive. The similar BBB values and acceptable P-gp efflux for both compounds are also positive. The poor Caco-2 and solubility are concerning for both, but can potentially be addressed through formulation strategies.

Output:
1
2025-04-17 05:51:37,317 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (346.471 and 352.389 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (62.55) is significantly better than Ligand B (87.01). For CNS targets, TPSA should be <= 90, and ideally lower. Ligand A is much closer to the optimal range for brain penetration.

**logP:** Both ligands have good logP values (3.381 and 3.277), falling within the 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A has 1 HBD and 3 HBA, while Ligand B has 0 HBD and 5 HBA. Both are within acceptable limits (<=5 HBD and <=10 HBA).

**QED:** Ligand A (0.785) has a substantially better QED score than Ligand B (0.408), indicating a more drug-like profile.

**DILI:** Ligand A (23.885) has a much lower DILI risk than Ligand B (42.536). Both are below the 40 threshold, but A is preferable.

**BBB:** Ligand B (92.323) has a significantly higher BBB percentile than Ligand A (67.933). This is a crucial factor for a CNS target like DRD2.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.377 and -4.388), which is unusual and suggests poor permeability. This is a significant concern for both.

**Aqueous Solubility:** Both ligands have negative solubility values (-3.48 and -3.682), indicating very poor aqueous solubility. This is a major drawback for both.

**hERG Inhibition:** Ligand A (0.396) has a lower hERG inhibition liability than Ligand B (0.795), which is favorable.

**Microsomal Clearance:** Ligand A (75.12) has a higher microsomal clearance than Ligand B (51.774), meaning it's metabolized faster. This is less desirable.

**In vitro Half-Life:** Ligand B (-10.726) has a negative half-life, which is not physically possible and suggests an issue with the data or the molecule's stability. Ligand A (49.711) has a reasonable half-life.

**P-gp Efflux:** Ligand A (0.249) has lower P-gp efflux liability than Ligand B (0.177), which is preferable for CNS penetration.

**Binding Affinity:** Ligand A (-8.3 kcal/mol) has a significantly stronger binding affinity than Ligand B (-6.9 kcal/mol). This is a major advantage, potentially outweighing some ADME drawbacks. The difference is >1.5 kcal/mol.

**Overall Assessment:**

Ligand A is superior despite the BBB value of Ligand B being higher. The stronger binding affinity of Ligand A (-8.3 vs -6.9 kcal/mol) is a critical advantage for a GPCR target. Furthermore, Ligand A has a better QED score, lower DILI risk, lower hERG liability, and a more reasonable in vitro half-life. While both have poor Caco-2 and solubility, the substantial affinity difference and other favorable properties of Ligand A make it the more promising candidate.

Output:
1
2025-04-17 05:51:37,317 - INFO - Batch 233 complete. Total preferences: 3728
2025-04-17 05:51:37,317 - INFO - Processing batch 234/512...
2025-04-17 05:52:20,426 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (337.339 Da) is slightly lower, which could be beneficial for permeability. Ligand B (358.404 Da) is also acceptable.

**TPSA:** Ligand A (99.0) is higher than the preferred <90 for CNS targets, but still potentially acceptable. Ligand B (64.35) is excellent, well below the 90 threshold, suggesting better CNS penetration potential.

**logP:** Ligand A (1.916) is within the optimal range (1-3). Ligand B (3.57) is at the higher end of the optimal range, potentially leading to solubility issues, but still acceptable.

**H-Bond Donors/Acceptors:** Ligand A has 1 HBD and 7 HBA, fitting well within the guidelines. Ligand B has 2 HBD and 3 HBA, also acceptable.

**QED:** Both ligands have good QED scores (A: 0.73, B: 0.846), indicating drug-like properties.

**DILI:** Ligand A has a high DILI risk (94.959), which is a significant concern. Ligand B has a very low DILI risk (18.379), a major advantage.

**BBB:** Ligand A has a BBB penetration of 40.791, which is below the desirable >70 for CNS targets. Ligand B has a much higher BBB penetration (81.815), making it more likely to reach the brain.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values, which is unusual and suggests poor permeability. However, these values are on a different scale and difficult to interpret directly without knowing the scale's specifics.

**Aqueous Solubility:** Both ligands have negative solubility values, again suggesting poor solubility. Similar to Caco-2, the scale is unknown, making direct comparison difficult.

**hERG Inhibition:** Ligand A (0.217) shows a very low risk of hERG inhibition. Ligand B (0.741) has a slightly higher, but still relatively low, risk.

**Microsomal Clearance:** Ligand A (53.141) has a moderate microsomal clearance, indicating moderate metabolic stability. Ligand B (33.261) has lower clearance, suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (8.71 hours) has a reasonable half-life. Ligand B has a negative half-life (-25.902 hours), which is nonsensical and suggests an issue with the data.

**P-gp Efflux:** Ligand A (0.086) has very low P-gp efflux, which is favorable for CNS penetration. Ligand B (0.13) also has low P-gp efflux, but slightly higher than A.

**Binding Affinity:** Ligand A (-9.0 kcal/mol) has a significantly stronger binding affinity than Ligand B (-7.7 kcal/mol). This is a substantial advantage, potentially outweighing some of its ADME drawbacks.

**Overall Assessment:**

Ligand A has a significantly better binding affinity, but suffers from a high DILI risk and poor BBB penetration. The negative values for Caco-2 and solubility are concerning but hard to interpret. Ligand B has a much better safety profile (low DILI), excellent BBB penetration, and better metabolic stability, but its binding affinity is weaker.

Given the CNS target (DRD2), BBB penetration is crucial. The significantly higher BBB value for Ligand B, combined with the lower DILI risk, makes it a more promising candidate *despite* the weaker binding affinity. The affinity difference, while substantial, might be overcome with further optimization of Ligand B. The nonsensical half-life for ligand B is a red flag, but the other properties are more favorable.

Output:
1
2025-04-17 05:52:20,427 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (346.391 and 343.475 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (134.65) is borderline, but acceptable for CNS penetration, while Ligand B (68.77) is excellent, well below the 90 A^2 threshold. This favors Ligand B.

**logP:** Ligand A (-0.687) is a bit low, potentially hindering membrane permeability. Ligand B (3.835) is nearly optimal. This strongly favors Ligand B.

**H-Bond Donors/Acceptors:** Ligand A has 3 HBD and 5 HBA, which are reasonable. Ligand B has 1 HBD and 6 HBA, also acceptable.

**QED:** Both ligands have good QED scores (0.666 and 0.738, respectively), indicating good drug-like properties.

**DILI:** Both ligands have low DILI risk (44.126 and 41.024), which is positive.

**BBB:** Ligand A (58.511) is below the desirable threshold of 70 for CNS targets. Ligand B (68.554) is also below 70, but is better than Ligand A.

**Caco-2:** Both ligands have negative Caco-2 values (-5.406 and -5.33), which is unusual and suggests poor permeability. This is a significant concern for both.

**Solubility:** Both ligands have negative solubility values (-1.838 and -4.35), indicating very low aqueous solubility. This is a major drawback for both.

**hERG:** Both ligands show low hERG inhibition liability (0.152 and 0.169), which is good.

**Microsomal Clearance:** Ligand A (-17.951) has a negative clearance, which is not possible. This is likely an error in the data. Ligand B (42.749) has a moderate clearance.

**In vitro Half-Life:** Ligand A (-11.261) has a negative half-life, which is not possible. This is likely an error in the data. Ligand B (22.304) has a reasonable half-life.

**P-gp Efflux:** Both ligands show very low P-gp efflux liability (0.002 and 0.243), which is favorable for CNS penetration.

**Binding Affinity:** Ligand B (-7.5 kcal/mol) has a significantly stronger binding affinity than Ligand A (-9.1 kcal/mol). This is a crucial advantage.

**Overall Assessment:**

Ligand B is the better candidate. While both have solubility and Caco-2 permeability issues, Ligand B has a much better logP, a significantly stronger binding affinity, and a more reasonable half-life and clearance. Ligand A has impossible values for clearance and half-life. The higher affinity of Ligand B could potentially overcome some of the ADME challenges.

Output:
1
2025-04-17 05:52:20,427 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (354.382 and 379.511 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (117.13) is slightly above the optimal <90 for CNS targets, but still reasonable. Ligand B (90.98) is excellent, falling right within the desired range.

**logP:** Both ligands (2.076 and 2.041) are within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A has 3 HBD and 4 HBA, meeting the criteria of <=5 and <=10 respectively. Ligand B has 2 HBD and 6 HBA, also meeting the criteria.

**QED:** Ligand B (0.776) has a better QED score than Ligand A (0.489), indicating a more drug-like profile.

**DILI:** Both ligands have relatively high DILI risk (65.568 and 84.102), but Ligand B is worse. This is a concern for both, but less so for A.

**BBB:** This is crucial for a CNS target. Ligand A has a BBB percentile of 79.682, which is very good (>70). Ligand B has a significantly lower BBB percentile of 21.714, which is undesirable.

**Caco-2 Permeability:** Ligand A (-4.969) and Ligand B (-5.524) both have negative values, indicating poor permeability.

**Aqueous Solubility:** Both ligands have poor aqueous solubility (-3.942 and -3.844).

**hERG:** Both ligands have low hERG inhibition liability (0.522 and 0.311), which is good.

**Microsomal Clearance:** Ligand A (16.471) has a slightly higher microsomal clearance than Ligand B (14.822), suggesting potentially lower metabolic stability.

**In vitro Half-Life:** Ligand A (16.944) has a much longer in vitro half-life than Ligand B (3.609), which is a significant advantage.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.151 and 0.164), which is favorable for CNS penetration.

**Binding Affinity:** Both ligands have very similar, strong binding affinities (-8.4 and -8.2 kcal/mol). The difference is minimal.

**Overall Assessment:**

Ligand A is significantly better due to its superior BBB penetration (79.682 vs 21.714) and longer in vitro half-life (16.944 vs 3.609). While Ligand B has a better QED score, the BBB and half-life differences are more critical for a CNS-targeting GPCR like DRD2. The slightly higher DILI risk for Ligand A is less concerning than the poor BBB penetration of Ligand B. The similar binding affinities mean that the ADME properties are the deciding factors.

Output:
0
2025-04-17 05:52:20,427 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (351.407 and 349.479 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (137.65) is borderline for CNS targets, slightly above the preferred <90, while Ligand B (102.04) is well within the optimal range. This favors Ligand B.

**3. logP:** Ligand A (0.203) is quite low, potentially hindering membrane permeability. Ligand B (1.989) is within the optimal 1-3 range. This is a significant advantage for Ligand B.

**4. H-Bond Donors:** Ligand A (4) and Ligand B (3) are both acceptable, being less than 5.

**5. H-Bond Acceptors:** Both ligands (5) are within the acceptable limit of 10.

**6. QED:** Both ligands have reasonable QED values (0.471 and 0.562), indicating decent drug-likeness. Ligand B is slightly better.

**7. DILI:** Both ligands have low DILI risk (34.587 and 39.201), both below the 40 threshold, which is good.

**8. BBB:** Ligand A (56.029) has a poor BBB percentile, making CNS penetration unlikely. Ligand B (81.272) has a much better BBB percentile, increasing the likelihood of CNS exposure. This is a critical advantage for Ligand B, given the target is DRD2.

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.64 and -5.364), which is unusual and difficult to interpret without further context. However, it suggests poor intestinal absorption for both.

**10. Aqueous Solubility:** Both ligands have negative solubility values (-1.387 and -3.25), which is also unusual. This suggests poor aqueous solubility for both.

**11. hERG Inhibition:** Ligand A (0.123) has a very low hERG risk, which is excellent. Ligand B (0.702) is slightly higher, but still relatively low.

**12. Microsomal Clearance:** Ligand A (0.158) has very low clearance, suggesting high metabolic stability. Ligand B (52.162) has significantly higher clearance, indicating faster metabolism. This favors Ligand A.

**13. In vitro Half-Life:** Ligand A (-7.74) has a negative half-life, which is not possible and indicates a data error. Ligand B (1.964) has a short half-life, but is at least a plausible value.

**14. P-gp Efflux:** Ligand A (0.009) has very low P-gp efflux, which is excellent for CNS penetration. Ligand B (0.426) has moderate P-gp efflux. This favors Ligand A.

**15. Binding Affinity:** Ligand B (-8.0) has a slightly better binding affinity than Ligand A (-7.5), a difference of 0.5 kcal/mol. While a 1.5 kcal/mol advantage is often considered significant, 0.5 kcal/mol is less impactful, especially when considering other ADME properties.

**Overall Assessment:**

Despite Ligand A's excellent metabolic stability and P-gp efflux, its poor logP, low BBB penetration, and implausible half-life are major drawbacks for a CNS-targeting drug. Ligand B, while having higher metabolic clearance and a slightly shorter half-life, exhibits a much more favorable profile with respect to TPSA, logP, and, crucially, BBB penetration. The slightly better binding affinity of Ligand B further supports its selection.

Output:
1
2025-04-17 05:52:20,427 - INFO - Reasoning:

Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (352.312 and 365.499 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (78.43) is slightly higher than Ligand B (71.53), but both are below the 90 A^2 threshold desirable for CNS targets.

**3. logP:** Both ligands have good logP values (2.281 and 1.916), falling within the optimal 1-3 range.

**4. H-Bond Donors:** Ligand A has 3 HBD, while Ligand B has 1. Both are within the acceptable limit of <=5.

**5. H-Bond Acceptors:** Ligand A has 3 HBA, while Ligand B has 5. Both are within the acceptable limit of <=10.

**6. QED:** Both ligands have reasonable QED values (0.739 and 0.679), indicating good drug-like properties.

**7. DILI:** Ligand A (69.678) has a higher DILI risk than Ligand B (27.259). This is a significant negative for Ligand A.

**8. BBB:** Ligand B (80.264) has a significantly better BBB penetration score than Ligand A (38.736). This is *crucial* for a CNS target like DRD2.

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 values, which is unusual and suggests poor permeability. However, the scale isn't specified, so it's hard to interpret.

**10. Aqueous Solubility:** Both ligands have negative solubility values, suggesting poor solubility. Again, the scale is unknown, making interpretation difficult.

**11. hERG Inhibition:** Both ligands have low hERG inhibition liability (0.519 and 0.431), which is positive.

**12. Microsomal Clearance:** Ligand B (44.006) has a higher microsomal clearance than Ligand A (11.67), indicating lower metabolic stability.

**13. In vitro Half-Life:** Ligand A (32.034) has a longer in vitro half-life than Ligand B (10.355), which is favorable.

**14. P-gp Efflux:** Ligand A (0.143) shows lower P-gp efflux liability than Ligand B (0.058), suggesting better CNS exposure.

**15. Binding Affinity:** Ligand A (-10.1 kcal/mol) has a significantly stronger binding affinity than Ligand B (-6.9 kcal/mol). This is a substantial advantage.

**Overall Assessment:**

While Ligand A boasts a much stronger binding affinity, Ligand B is clearly superior in terms of ADME properties critical for CNS penetration. The significantly better BBB score (80.264 vs 38.736) and lower DILI risk (27.259 vs 69.678) of Ligand B are decisive factors. The higher metabolic clearance and shorter half-life of Ligand B are drawbacks, but these can potentially be addressed through structural modifications. The superior affinity of Ligand A might be able to overcome some ADME issues, but the poor BBB penetration is a major hurdle for a CNS target. Given the GPCR-specific priorities, particularly BBB penetration, and the substantial difference in these properties, Ligand B is the more promising candidate.

Output:
1
2025-04-17 05:52:20,428 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (345.447 Da) is slightly lower, which could be beneficial for permeability, but both are acceptable.

**TPSA:** Ligand A (92.42) is better than Ligand B (64.8). For CNS targets, TPSA < 90 is preferred, so Ligand A is closer to the ideal range.

**logP:** Both ligands have acceptable logP values (Ligand A: 1.558, Ligand B: 2.714), falling within the optimal 1-3 range. Ligand B is slightly higher, which could potentially lead to off-target effects, but is still reasonable.

**H-Bond Donors/Acceptors:** Ligand A has 1 HBD and 5 HBA, while Ligand B has 0 HBD and 5 HBA. Both are within acceptable limits (HBD <= 5, HBA <= 10).

**QED:** Ligand A (0.809) has a significantly better QED score than Ligand B (0.664), indicating a more drug-like profile.

**DILI:** Both ligands have relatively low DILI risk (Ligand A: 34.277, Ligand B: 44.087), below the 60 threshold.

**BBB:** Ligand B (97.053) has a substantially better BBB penetration score than Ligand A (83.676). This is a critical factor for CNS targets like DRD2.

**Caco-2 Permeability:** Ligand A (-4.847) has a lower Caco-2 permeability than Ligand B (-4.429). Both are negative, indicating poor permeability, but Ligand B is slightly better.

**Aqueous Solubility:** Both ligands have poor aqueous solubility (Ligand A: -1.919, Ligand B: -3.017). This could pose formulation challenges.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (Ligand A: 0.376, Ligand B: 0.571).

**Microsomal Clearance:** Both ligands have similar microsomal clearance values (Ligand A: 42.962, Ligand B: 43.736).

**In vitro Half-Life:** Ligand A (-22.479) has a more negative in vitro half-life than Ligand B (-11.626), indicating a shorter half-life.

**P-gp Efflux:** Ligand A (0.017) has a much lower P-gp efflux liability than Ligand B (0.412). This is beneficial for CNS exposure.

**Binding Affinity:** Both ligands have very similar and strong binding affinities (Ligand A: -7.5 kcal/mol, Ligand B: -7.0 kcal/mol). The difference is less than 1.5 kcal/mol, so it's not a deciding factor.

**Overall Assessment:**

Ligand A has a better QED, TPSA, and P-gp efflux profile. However, Ligand B excels in BBB penetration, which is paramount for a DRD2 ligand targeting CNS disorders. While Ligand A has slightly better permeability, the substantial difference in BBB penetration outweighs this advantage. The similar binding affinities make the ADME properties the key differentiator.

Output:
1
2025-04-17 05:52:20,428 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (388.917 Da) is slightly higher than Ligand B (343.431 Da), but both are acceptable.

**TPSA:** Ligand A (67.87) is better than Ligand B (78.43). For CNS targets, we want TPSA <= 90, both are within this range, but A is more favorable.

**logP:** Ligand A (2.512) is optimal (1-3), while Ligand B (0.682) is a bit low, potentially hindering permeation. This is a significant advantage for A.

**H-Bond Donors/Acceptors:** Both ligands have 1 HBD and 5 HBA, which are within acceptable limits.

**QED:** Both ligands have similar QED values (0.858 and 0.851), indicating good drug-likeness.

**DILI:** Ligand A (40.054) is slightly higher than Ligand B (27.259), but both are considered good (below 40-60).

**BBB:** Ligand B (86.778) has a significantly higher BBB percentile than Ligand A (53.897). This is a crucial factor for a CNS target like DRD2, making B more promising.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.034 and -5.014), which is unusual. This suggests poor intestinal absorption. However, for a CNS target, intestinal absorption is less critical than BBB penetration.

**Aqueous Solubility:** Both ligands have negative solubility values (-2.975 and -1.381), indicating poor solubility. This could present formulation challenges.

**hERG Inhibition:** Ligand A (0.642) is slightly higher than Ligand B (0.367), indicating a slightly higher risk of cardiotoxicity, but both are relatively low.

**Microsomal Clearance:** Ligand B (17.646) has a higher microsomal clearance than Ligand A (9.588), meaning it will be metabolized faster. A is more favorable here.

**In vitro Half-Life:** Ligand B (6.937) has a longer half-life than Ligand A (-1.046), which is generally desirable.

**P-gp Efflux:** Ligand A (0.161) has lower P-gp efflux liability than Ligand B (0.01), meaning it's less likely to be pumped out of the brain, which is crucial for CNS exposure. A is more favorable.

**Binding Affinity:** Ligand B (-8.3) has a slightly better binding affinity than Ligand A (-8.1), although the difference is small.

**Overall Assessment:**

Ligand B excels in BBB penetration and has a slightly better binding affinity and longer half-life. However, Ligand A has a better logP, lower P-gp efflux, lower microsomal clearance, and a more favorable TPSA. Given the importance of BBB for CNS targets, Ligand B initially appears more promising. However, the slightly better logP and P-gp properties of Ligand A could translate to better brain exposure *in vivo*, despite the lower BBB percentile. The difference in binding affinity is minimal. Considering the balance, and prioritizing BBB for a CNS GPCR target, Ligand B is the slightly better candidate.

Output:
1
2025-04-17 05:52:20,428 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (362.373 and 348.403 Da) fall within the ideal 200-500 Da range.

**TPSA:** Both ligands have TPSA values (93.73 and 91.84) below 140, suggesting good oral absorption potential. They are also reasonably close to the <90 target for CNS penetration, but not ideal.

**logP:** Ligand A (0.622) is slightly better than Ligand B (-0.174). While both are below the optimal 1-3 range, Ligand A is closer. Ligand B's logP is quite low, potentially hindering permeation.

**H-Bond Donors/Acceptors:** Both ligands have acceptable HBD (2 and 1) and HBA (5) counts, falling within the recommended limits.

**QED:** Both ligands have QED values (0.676 and 0.545) above 0.5, indicating good drug-like properties.

**DILI:** Ligand A (49.128) has a slightly higher DILI risk than Ligand B (39.162), but both are below the concerning threshold of 60.

**BBB:** This is a critical parameter for a CNS target like DRD2. Ligand A (74.796) has a significantly better BBB percentile than Ligand B (59.093). This is a major advantage for Ligand A.

**Caco-2 Permeability:** Ligand A (-4.982) and Ligand B (-5.01) have similar, very poor Caco-2 permeability values.

**Aqueous Solubility:** Ligand A (-1.981) has slightly better solubility than Ligand B (-0.903), although both are quite poor.

**hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.236 and 0.27), which is excellent.

**Microsomal Clearance:** Ligand A (23.208) has a higher microsomal clearance than Ligand B (10.179), indicating potentially lower metabolic stability. This favors Ligand B.

**In vitro Half-Life:** Ligand B (-15.869) has a significantly longer in vitro half-life than Ligand A (3.189), which is a substantial advantage.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.021 and 0.015), which is favorable for CNS penetration.

**Binding Affinity:** Both ligands have identical binding affinities (-8.4 kcal/mol), which is excellent and removes this as a differentiating factor.

**Overall Assessment:**

While Ligand B has better metabolic stability (lower Cl_mic, longer t1/2), Ligand A is superior in several key areas for a CNS-targeting GPCR: better logP, and significantly better BBB penetration. The similar binding affinities mean the ADME properties become the deciding factor. The improved BBB penetration of Ligand A is crucial for CNS efficacy. The slightly higher DILI risk and clearance for Ligand A are less concerning given the strong affinity and the importance of CNS exposure.

Output:
1
2025-04-17 05:52:20,428 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 drug candidates, considering the provided guidelines and GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight (MW):** Both ligands are within the ideal range (200-500 Da). Ligand A (356.438 Da) is slightly lower, which could be beneficial for permeability. Ligand B (372.575 Da) is also good.

**2. TPSA:**  Both ligands have TPSA values below the 90 A^2 threshold for CNS targets. Ligand A (78.87 A^2) is better than Ligand B (67.43 A^2), suggesting potentially improved brain penetration.

**3. logP:** Ligand A (1.165) is within the optimal range (1-3), while Ligand B (3.124) is at the higher end. While still acceptable, Ligand B's higher logP could lead to solubility issues or off-target interactions.

**4. H-Bond Donors (HBD):** Both ligands have 2 HBD, which is within the acceptable limit of <=5.

**5. H-Bond Acceptors (HBA):** Both ligands have 4 HBA, which is within the acceptable limit of <=10.

**6. QED:** Ligand A (0.775) has a better QED score than Ligand B (0.652), indicating a more drug-like profile.

**7. DILI:** Ligand A (20.24%) has a significantly lower DILI risk than Ligand B (29.081%). This is a major advantage for Ligand A.

**8. BBB:** Ligand A (82.823%) has a much higher BBB penetration percentile than Ligand B (67.197%). This is crucial for a CNS target like DRD2.

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 values, which is unusual and suggests poor permeability. However, the scale is not specified, so it's difficult to interpret. Ligand A (-4.626) is slightly better than Ligand B (-4.737).

**10. Aqueous Solubility:** Both ligands have negative solubility values, indicating poor solubility. Ligand A (-1.35) is slightly better than Ligand B (-3.363).

**11. hERG Inhibition:** Both ligands have low hERG inhibition liability (0.427 and 0.391 respectively), which is good.

**12. Microsomal Clearance:** Ligand A (-6.176 mL/min/kg) has a significantly lower (better) microsomal clearance than Ligand B (70.15 mL/min/kg), indicating greater metabolic stability.

**13. In vitro Half-Life:** Ligand A (13.231 hours) has a longer half-life than Ligand B (8.609 hours), which is desirable.

**14. P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.04 and 0.079 respectively), which is good for CNS penetration.

**15. Binding Affinity:** Ligand B (-7.3 kcal/mol) has a slightly better binding affinity than Ligand A (-8.0 kcal/mol). However, the difference is not substantial enough to outweigh the significant ADME advantages of Ligand A.

**Overall Assessment:**

Ligand A consistently outperforms Ligand B in key ADME properties crucial for a CNS-targeting GPCR. Specifically, its superior BBB penetration, lower DILI risk, better metabolic stability (lower Cl_mic, longer t1/2), and higher QED score make it a much more promising drug candidate. While Ligand B has slightly better binding affinity, the ADME profile of Ligand A is significantly more favorable, and the affinity difference is not large enough to overcome these advantages.

Output:
1
2025-04-17 05:52:20,429 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (348.451 and 362.499 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (90.54) is better than Ligand B (66.4). Both are below the 90 A^2 threshold for CNS targets, but A is closer to the upper limit.

**3. logP:** Ligand B (2.924) is optimal (1-3), while Ligand A (0.664) is slightly low, potentially hindering permeation.

**4. H-Bond Donors:** Ligand A (2) is preferable to Ligand B (0). While both are acceptable, a small number of HBDs can improve permeability.

**5. H-Bond Acceptors:** Ligand A (8) is better than Ligand B (5). Both are within the acceptable range.

**6. QED:** Both ligands have similar QED values (0.724 and 0.686), indicating good drug-likeness.

**7. DILI:** Ligand A (49.399) has a significantly lower DILI risk than Ligand B (60.14), placing it in a more favorable category.

**8. BBB:** Ligand B (68.127) has a better BBB penetration score than Ligand A (58.123). This is a critical factor for CNS targets like DRD2.

**9. Caco-2 Permeability:** Ligand A (-5.232) has a much more negative Caco-2 permeability, suggesting poor intestinal absorption. Ligand B (-4.767) is better, but still not ideal.

**10. Aqueous Solubility:** Ligand A (-0.971) has slightly better solubility than Ligand B (-4.451).

**11. hERG Inhibition:** Both ligands show low hERG inhibition liability (0.892 and 0.761).

**12. Microsomal Clearance:** Ligand A (23.555) has a significantly lower microsomal clearance than Ligand B (115.414), indicating better metabolic stability.

**13. In vitro Half-Life:** Ligand A (36.793) has a longer in vitro half-life than Ligand B (8.732).

**14. P-gp Efflux:** Ligand A (0.125) has lower P-gp efflux liability than Ligand B (0.309), which is beneficial for CNS exposure.

**15. Binding Affinity:** Ligand B (-8.0) has a slightly stronger binding affinity than Ligand A (-7.1). This is a 0.9 kcal/mol difference, which is substantial.

**Overall Assessment:**

Ligand B has a better BBB score and binding affinity, which are crucial for a CNS GPCR target. However, it has a higher DILI risk, higher P-gp efflux, and significantly higher microsomal clearance, leading to a shorter half-life. Ligand A has better ADME properties (lower DILI, better metabolic stability, lower P-gp efflux) and acceptable solubility, but its lower logP and BBB penetration are concerns.

Considering the balance, the stronger binding affinity of Ligand B and its better BBB penetration outweigh the ADME drawbacks, *provided* that the DILI risk can be mitigated through further optimization. The difference in binding affinity is significant enough to prioritize Ligand B as a starting point for further development.

Output:
1
2025-04-17 05:52:20,429 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (336.395 and 342.443 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (68.52) is significantly better than Ligand B (78.09). For CNS targets, we want TPSA <= 90, and A is closer to the optimal <=60 range. B is pushing the upper limit.

**3. logP:** Both ligands have good logP values (2.722 and 2.014), falling within the 1-3 range.

**4. H-Bond Donors:** Ligand A (1) is preferable to Ligand B (2). Lower HBD generally improves permeability.

**5. H-Bond Acceptors:** Ligand A (5) is preferable to Ligand B (3). Lower HBA generally improves permeability.

**6. QED:** Ligand A (0.778) has a better QED score than Ligand B (0.635), indicating a more drug-like profile.

**7. DILI:** Ligand A (71.617) has a higher DILI risk than Ligand B (20.279). This is a significant drawback for A.

**8. BBB:** Both ligands have acceptable BBB penetration (63.358 and 65.219). However, for a CNS target like DRD2, >70 is desirable. Both are below this threshold, but comparable.

**9. Caco-2 Permeability:** Ligand A (-4.928) has worse Caco-2 permeability than Ligand B (-5.441). Lower values are less desirable.

**10. Aqueous Solubility:** Ligand A (-3.518) has worse aqueous solubility than Ligand B (-1.877). Lower values are less desirable.

**11. hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.146 and 0.158).

**12. Microsomal Clearance:** Ligand A (24.162) has lower microsomal clearance than Ligand B (-6.472). Lower clearance is better for metabolic stability.

**13. In vitro Half-Life:** Ligand A (-1.327) has a worse in vitro half-life than Ligand B (-41.741). A longer half-life is generally preferred.

**14. P-gp Efflux:** Ligand A (0.354) has lower P-gp efflux than Ligand B (0.041). Lower efflux is better for CNS exposure.

**15. Binding Affinity:** Both ligands have comparable and excellent binding affinities (-9.7 and -9.2 kcal/mol). The difference is less than 1.5 kcal/mol, so it's not a deciding factor.

**Overall Assessment:**

Ligand B is the better candidate. While Ligand A has slightly better TPSA and P-gp efflux, Ligand B significantly outperforms in DILI risk, solubility, and in vitro half-life. The slightly lower TPSA of Ligand B is not a major concern. The DILI risk associated with Ligand A is a significant red flag. The better solubility and half-life of Ligand B are important for *in vivo* performance.

Output:
1
2025-04-17 05:52:20,429 - INFO - Reasoning:

Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (344.415 and 349.431 Da) fall comfortably within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (75.94) is better than Ligand B (84.67). Both are below the 90 A^2 threshold desirable for CNS targets, but A is closer to the optimal range.

**3. logP:** Both ligands have good logP values (2.034 and 1.553), falling within the 1-3 range. Ligand A is slightly higher, which could be beneficial for membrane permeability.

**4. H-Bond Donors:** Both have 1 HBD, which is within the acceptable limit of <=5.

**5. H-Bond Acceptors:** Both have 5 HBA, also within the acceptable limit of <=10.

**6. QED:** Both have similar QED values (0.78 and 0.77), indicating good drug-like properties.

**7. DILI:** Ligand A (51.609) has a slightly higher DILI risk than Ligand B (34.626), but both are below the concerning threshold of 60.

**8. BBB:** This is a critical parameter for a CNS target like DRD2. Ligand A (74.292) has a significantly better BBB percentile than Ligand B (61.691). A value >70 is desirable, and A is closer.

**9. Caco-2 Permeability:** Ligand A (-4.834) has slightly better Caco-2 permeability than Ligand B (-4.934), though both are negative values which is unusual.

**10. Aqueous Solubility:** Ligand A (-2.658) has slightly better solubility than Ligand B (-1.139), both are negative values which is unusual.

**11. hERG Inhibition:** Both have low hERG inhibition risk (0.306 and 0.197).

**12. Microsomal Clearance:** Ligand B (37.299) has a slightly higher microsomal clearance than Ligand A (31.474), implying lower metabolic stability.

**13. In vitro Half-Life:** Ligand A (33.404) has a longer in vitro half-life than Ligand B (24.172).

**14. P-gp Efflux:** Both have low P-gp efflux liability (0.066 and 0.092).

**15. Binding Affinity:** Crucially, both ligands have the *same* binding affinity (-8.1 kcal/mol), which is excellent.

**Overall Assessment:**

Given the equal binding affinity, the decision hinges on ADME properties. Ligand A is superior in terms of BBB penetration, in vitro half-life, and has slightly better Caco-2 permeability and solubility. While Ligand A has a slightly higher DILI risk, it remains acceptable. The better BBB penetration of Ligand A is a significant advantage for a CNS-targeting drug.

Output:
1
2025-04-17 05:52:20,429 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (350.547 and 356.417 Da) fall comfortably within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (58.2) is excellent, well below the 90 target for CNS drugs. Ligand B (71.25) is still reasonable, but less optimal.

**3. logP:** Both ligands have good logP values (4.04 and 2.394), falling within the 1-3 range. Ligand B is slightly preferred here.

**4. H-Bond Donors:** Ligand A (2) and Ligand B (1) are both acceptable.

**5. H-Bond Acceptors:** Ligand A (2) and Ligand B (5) are both acceptable, though Ligand A is better.

**6. QED:** Both ligands have good QED scores (0.659 and 0.85), indicating good drug-like properties.

**7. DILI:** Ligand A (18.302) has a significantly lower DILI risk than Ligand B (34.277). This is a substantial advantage.

**8. BBB:** Both ligands have excellent BBB penetration (74.758 and 79.682), exceeding the desirable >70 threshold for CNS targets. Ligand B is slightly better.

**9. Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual. Assuming these are logP-like scales, lower values indicate poorer permeability. Ligand A (-4.589) is worse than Ligand B (-4.771).

**10. Aqueous Solubility:** Both have negative solubility values, which is also unusual. Lower values indicate poorer solubility. Ligand A (-4.802) is worse than Ligand B (-2.556).

**11. hERG:** Both ligands have low hERG inhibition risk (0.575 and 0.188). Ligand B is better.

**12. Microsomal Clearance:** Ligand A (76.63) has a higher clearance than Ligand B (1.316), suggesting lower metabolic stability. Ligand B is significantly better.

**13. In vitro Half-Life:** Ligand A (9.739) has a longer half-life than Ligand B (-7.413). Ligand A is better.

**14. P-gp Efflux:** Ligand A (0.233) has lower P-gp efflux than Ligand B (0.082), indicating better CNS exposure. Ligand A is better.

**15. Binding Affinity:** Ligand B (-8.3 kcal/mol) has a slightly better binding affinity than Ligand A (-7.5 kcal/mol). This difference of 0.8 kcal/mol is significant.

**Overall Assessment:**

While Ligand B has a slightly better binding affinity and BBB penetration, Ligand A has significantly better DILI risk, P-gp efflux, and in vitro half-life. The lower DILI risk is a major advantage. Considering the GPCR-specific priorities, the lower TPSA and P-gp efflux of Ligand A are also beneficial for CNS penetration. The slightly better affinity of Ligand B is outweighed by the other favorable properties of Ligand A.

Output:
1
2025-04-17 05:52:20,430 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (350.459 and 347.459 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (59.08) is significantly better than Ligand B (71). Both are below the 90 A^2 threshold for CNS targets, but A is closer to the optimal range.

**3. logP:** Both ligands have good logP values (1.74 and 1.941), falling within the 1-3 range.

**4. H-Bond Donors:** Ligand A (0) is preferable to Ligand B (1). Fewer HBDs generally improve permeability.

**5. H-Bond Acceptors:** Both ligands have 4 HBA, which is acceptable (<=10).

**6. QED:** Both ligands have acceptable QED values (0.685 and 0.826), indicating good drug-like properties.

**7. DILI:** Ligand A (21.326) has a much lower DILI risk than Ligand B (33.773). Both are below the 40 threshold, but A is significantly better.

**8. BBB:** This is a critical parameter for CNS targets. Ligand A (83.288) has a substantially higher BBB penetration percentile than Ligand B (63.784). A value >70 is desirable, and A is closer.

**9. Caco-2 Permeability:** Both have negative values, which is unusual. However, the magnitude is similar (-4.528 vs -4.723), so this isn't a major differentiator.

**10. Aqueous Solubility:** Ligand A (-1.548) is slightly better than Ligand B (-3.166), indicating better solubility.

**11. hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.361 and 0.188).

**12. Microsomal Clearance:** Ligand A (46.083) has higher clearance than Ligand B (19.494), suggesting lower metabolic stability. This favors Ligand B.

**13. In vitro Half-Life:** Ligand B (0.126) has a much longer half-life than Ligand A (-11.356). This is a significant advantage for Ligand B.

**14. P-gp Efflux:** Ligand A (0.095) has lower P-gp efflux liability than Ligand B (0.158), which is favorable for CNS penetration.

**15. Binding Affinity:** Ligand B (-8.6 kcal/mol) has a significantly stronger binding affinity than Ligand A (-7.2 kcal/mol). This >1.5 kcal/mol difference is substantial and can outweigh some ADME drawbacks.

**Overall Assessment:**

While Ligand A has advantages in TPSA, DILI, BBB, and P-gp efflux, the significantly stronger binding affinity of Ligand B (-8.6 vs -7.2 kcal/mol) and its longer half-life are critical advantages. The lower metabolic stability (higher Cl_mic) of Ligand A is a concern. The improved BBB of ligand A is helpful, but the affinity difference is more impactful for a GPCR target.

Output:
1
2025-04-17 05:52:20,430 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (343.39 and 385.87 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (127.74) is slightly above the optimal <90 for CNS targets, but still reasonable. Ligand B (87.74) is excellent, well below 90. This favors Ligand B.

**3. logP:** Both ligands have low logP values (0.564 and 0.424). While not ideal (optimal is 1-3), they aren't drastically outside the range. The lower values could indicate potential permeability issues, but are not disqualifying.

**4. H-Bond Donors:** Ligand A has 3 HBD, which is acceptable. Ligand B has 2, also acceptable.

**5. H-Bond Acceptors:** Both ligands have 5 HBA, which is within the acceptable limit of <=10.

**6. QED:** Both ligands have good QED scores (0.65 and 0.666), indicating drug-like properties.

**7. DILI:** Ligand A has a DILI risk of 56.5%, which is moderate. Ligand B has a lower DILI risk of 39.7%, which is preferable.

**8. BBB:** Ligand A has a BBB penetration of 48.2%, which is below the desirable >70% for CNS targets. Ligand B has a BBB penetration of 55.9%, also below 70%, but better than Ligand A.

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.123 and -5.275). This is unusual and suggests poor permeability, which is concerning, but could be an artifact of the prediction method.

**10. Aqueous Solubility:** Both ligands have negative solubility values (-3.603 and -2.625). This is also concerning and suggests poor solubility, but could be an artifact of the prediction method.

**11. hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.344 and 0.126), which is excellent.

**12. Microsomal Clearance:** Ligand A has a higher Cl_mic (16.355) than Ligand B (0.262). Lower clearance is preferred for metabolic stability, so Ligand B is favored.

**13. In vitro Half-Life:** Ligand A has a negative half-life (-15.314), which is not physically meaningful and suggests a prediction issue. Ligand B has a half-life of 12.358, which is reasonable.

**14. P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.021 and 0.031), which is excellent.

**15. Binding Affinity:** Ligand B (-9.1 kcal/mol) has a significantly stronger binding affinity than Ligand A (-8.5 kcal/mol). This 0.6 kcal/mol difference is substantial and can outweigh minor ADME drawbacks.

**Overall Assessment:**

Ligand B is the better candidate. While both have issues with predicted permeability and solubility, Ligand B has a significantly stronger binding affinity, lower DILI risk, better metabolic stability (lower Cl_mic), and a more reasonable half-life prediction. The slightly better BBB penetration of Ligand B also supports its selection as a more promising starting point for optimization. The negative Caco-2 and solubility values are concerning and would need further investigation, but the superior binding affinity of Ligand B makes it the more attractive option.

Output:
1
2025-04-17 05:52:20,430 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (350.478 and 344.459 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (49.41) is significantly better than Ligand B (65.54). For a CNS target like DRD2, TPSA should be <= 90, and ideally closer to 60. Ligand A is much closer to the ideal range.

**3. logP:** Ligand A (3.204) is within the optimal 1-3 range. Ligand B (1.991) is at the lower end, potentially hindering permeation.

**4. H-Bond Donors:** Both have 1 HBD, which is acceptable.

**5. H-Bond Acceptors:** Ligand A has 2 HBA, while Ligand B has 4. Both are within the acceptable limit of <=10, but Ligand A is preferable.

**6. QED:** Both ligands have similar QED values (0.766 and 0.783), indicating good drug-likeness.

**7. DILI:** Both have very similar, low DILI risk (19.426 and 19.504 percentile).

**8. BBB:** Ligand A (91.508) has a significantly better BBB penetration score than Ligand B (80.419). A score >70 is desirable for CNS targets, and Ligand A is much closer to this threshold.

**9. Caco-2 Permeability:** Ligand A (-4.752) has a better (more positive) Caco-2 value than Ligand B (-4.859), suggesting better intestinal absorption.

**10. Aqueous Solubility:** Ligand A (-3.847) has a better (more positive) solubility value than Ligand B (-1.343).

**11. hERG Inhibition:** Ligand A (0.802) has a lower hERG inhibition risk than Ligand B (0.374), which is preferable.

**12. Microsomal Clearance:** Ligand A (43.32) has a higher (worse) microsomal clearance than Ligand B (10.634), indicating lower metabolic stability. This is a drawback for Ligand A.

**13. In vitro Half-Life:** Ligand A (-8.842) has a much longer half-life than Ligand B (3.094). This is a significant advantage for Ligand A.

**14. P-gp Efflux:** Ligand A (0.354) has a lower P-gp efflux liability than Ligand B (0.062), which is preferable for CNS penetration.

**15. Binding Affinity:** Ligand A (-8.4 kcal/mol) has a slightly better binding affinity than Ligand B (-7.7 kcal/mol). While both are good, the 0.7 kcal/mol difference is notable.

**Overall Assessment:**

Ligand A is superior to Ligand B. It excels in critical GPCR properties like TPSA, BBB, solubility, and P-gp efflux. It also has a better binding affinity and a significantly longer half-life. The main drawback of Ligand A is its higher microsomal clearance, but the benefits outweigh this concern. Ligand B's lower logP and poorer BBB penetration are significant liabilities for a CNS target.

Output:
1
2025-04-17 05:52:20,430 - INFO - Batch 234 complete. Total preferences: 3744
2025-04-17 05:52:20,430 - INFO - Processing batch 235/512...
2025-04-17 05:53:03,618 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (350.39 Da and 364.599 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (78.87) is better than Ligand B (25.36) as it is closer to the <90 A^2 threshold for CNS targets. Ligand B is exceptionally low, which *could* be beneficial for BBB penetration, but might also indicate a lack of necessary interactions.

**logP:** Ligand A (2.085) is optimal (1-3). Ligand B (4.867) is slightly high, potentially leading to solubility issues and off-target interactions.

**H-Bond Donors:** Ligand A (2) is good. Ligand B (0) is also acceptable, but a lack of HBDs can sometimes hinder solubility.

**H-Bond Acceptors:** Both ligands have 4 HBAs, which is within the acceptable limit of <=10.

**QED:** Ligand A (0.871) is excellent, indicating strong drug-likeness. Ligand B (0.624) is still acceptable, but less favorable.

**DILI:** Ligand A (35.983) has a much lower DILI risk than Ligand B (6.863), which is a significant advantage.

**BBB:** Ligand B (83.017) has a substantially higher BBB penetration percentile than Ligand A (73.75). This is a crucial factor for a CNS target like DRD2.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.017 and -5.058). This is unusual and suggests poor permeability. However, these values are on a logarithmic scale and might not be directly comparable without knowing the scale.

**Aqueous Solubility:** Both ligands have negative solubility values (-3.952 and -4.179). This is concerning, indicating poor aqueous solubility.

**hERG Inhibition:** Ligand A (0.483) has a lower hERG inhibition liability than Ligand B (0.902), which is preferable.

**Microsomal Clearance:** Ligand B (76.364) has a significantly higher microsomal clearance than Ligand A (16.745), indicating lower metabolic stability.

**In vitro Half-Life:** Ligand B (24.105) has a longer in vitro half-life than Ligand A (10.658), which is a positive attribute.

**P-gp Efflux:** Ligand A (0.055) shows very low P-gp efflux, which is excellent for CNS penetration. Ligand B (0.506) is higher, potentially limiting CNS exposure.

**Binding Affinity:** Ligand A (-8.1 kcal/mol) has a significantly stronger binding affinity than Ligand B (-6.6 kcal/mol). This 1.5 kcal/mol difference is substantial and can outweigh some ADME drawbacks.

**Overall Assessment:**

Ligand A excels in key areas: binding affinity, DILI risk, metabolic stability (lower Cl_mic), and P-gp efflux. While its BBB penetration is lower than Ligand B, its superior binding affinity and safety profile are more critical for a DRD2 ligand. The solubility and permeability issues are concerning for both, but the stronger binding of Ligand A suggests it might overcome these hurdles. Ligand B's high logP and clearance are significant drawbacks.

Output:
0
2025-04-17 05:53:03,618 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (373.274 and 352.494 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (66.02) is slightly above the optimal <90 for CNS targets, but still reasonable. Ligand B (40.62) is excellent, well below 90.

**3. logP:** Both ligands have good logP values (2.578 and 3.544), falling within the 1-3 range. Ligand B is slightly higher, which *could* be a minor concern for solubility, but isn't a dealbreaker.

**4. H-Bond Donors:** Ligand A has 1 HBD, and Ligand B has 0. Both are within the acceptable limit of <=5.

**5. H-Bond Acceptors:** Ligand A has 5 HBA, and Ligand B has 2. Both are within the acceptable limit of <=10.

**6. QED:** Both ligands have good QED scores (0.674 and 0.776), indicating good drug-like properties.

**7. DILI:** Ligand A has a DILI risk of 59.131, which is approaching the higher risk threshold (>60). Ligand B has a much lower DILI risk (24.622), a significant advantage.

**8. BBB:** Ligand A has a BBB penetration of 76.347, which is good but not exceptional. Ligand B has a significantly higher BBB penetration (88.29), a major advantage for a CNS target like DRD2.

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.682 and -4.511). This is unusual and suggests poor permeability. However, these values are on a scale where negative values are possible, and direct comparison is difficult without knowing the scale's specifics.

**10. Aqueous Solubility:** Both ligands have very poor aqueous solubility (-3.207 and -3.342). This is a significant drawback for both.

**11. hERG Inhibition:** Both ligands have low hERG inhibition risk (0.687 and 0.632).

**12. Microsomal Clearance:** Ligand A (31.011) has lower microsomal clearance than Ligand B (58.261), suggesting better metabolic stability.

**13. In vitro Half-Life:** Ligand A has a negative half-life (-1.821), which is problematic. Ligand B has a very short half-life (0.039), also problematic.

**14. P-gp Efflux:** Both ligands have low P-gp efflux liability (0.17 and 0.563), which is favorable for CNS penetration.

**15. Binding Affinity:** Ligand A has a slightly better binding affinity (-7.2 kcal/mol) than Ligand B (-0.0 kcal/mol). This is a substantial difference, and a key consideration.

**Overall Assessment:**

Despite the poor solubility and permeability indicated by the Caco-2 and solubility values, the binding affinity of Ligand A is significantly stronger. However, Ligand B has a much better safety profile (lower DILI) and superior BBB penetration. The short half-lives of both are concerning. Considering the GPCR-specific priorities, BBB penetration is crucial for CNS targets. The substantial difference in binding affinity (-7.2 vs -0.0) is a major factor. While Ligand B has better ADME properties overall (except for half-life), the much stronger binding affinity of Ligand A is likely to outweigh the ADME drawbacks, *assuming* the binding assay is reliable.

Output:
1
2025-04-17 05:53:03,618 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (361.518 and 347.415 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (82.53) is excellent, well below the 90 A^2 threshold for CNS targets. Ligand B (95.67) is still reasonable but closer to the upper limit.

**3. logP:** Ligand A (1.706) is optimal. Ligand B (0.875) is slightly low, potentially impacting permeability.

**4. H-Bond Donors:** Both ligands have 2 HBD, which is within the acceptable limit of <=5.

**5. H-Bond Acceptors:** Ligand A has 4 HBA, and Ligand B has 5 HBA, both within the acceptable limit of <=10.

**6. QED:** Both ligands have similar QED values (0.8 and 0.796), indicating good drug-likeness.

**7. DILI:** Ligand A (47.034) has a slightly higher DILI risk than Ligand B (30.322), but both are below the concerning threshold of 60.

**8. BBB:** Ligand B (49.826) has a significantly better BBB penetration percentile than Ligand A (40.713). This is a crucial advantage for a CNS target like DRD2.

**9. Caco-2 Permeability:** Ligand A (-4.922) shows poor Caco-2 permeability. Ligand B (-5.16) is also poor, but slightly worse.

**10. Aqueous Solubility:** Ligand A (-3.021) has poor solubility. Ligand B (-1.35) is better, but still poor.

**11. hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.168 and 0.141).

**12. Microsomal Clearance:** Ligand A (38.403) has higher microsomal clearance than Ligand B (-4.176), suggesting lower metabolic stability. Ligand B is significantly more stable.

**13. In vitro Half-Life:** Ligand A (24.494) has a slightly longer half-life than Ligand B (21.4), but the difference is not substantial.

**14. P-gp Efflux:** Both ligands show very low P-gp efflux liability (0.086 and 0.043).

**15. Binding Affinity:** Ligand B (-7.8 kcal/mol) has a substantially stronger binding affinity than Ligand A (0.0 kcal/mol). This is a major advantage.

**Overall Assessment:**

Ligand B is the superior candidate. While both have acceptable MW, HBD/HBA, QED, and low hERG risk, Ligand B excels in the critical areas for a CNS GPCR target: significantly better BBB penetration, much stronger binding affinity, and improved metabolic stability (lower Cl_mic). The slightly lower logP of Ligand B is a minor concern outweighed by its other advantages. Ligand A's poor Caco-2 permeability and significantly weaker binding affinity are major drawbacks.

Output:
1
2025-04-17 05:53:03,618 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B based on the provided guidelines, prioritizing GPCR-specific properties (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (338.426 Da) is slightly lower, which can be advantageous for permeability.

**TPSA:** Ligand A (23.55) is excellent for CNS penetration, well below the 90 A^2 threshold. Ligand B (81.08) is higher, potentially hindering BBB penetration.

**logP:** Ligand A (3.598) is optimal. Ligand B (0.759) is low, potentially causing permeability issues and reduced binding.

**H-Bond Donors/Acceptors:** Ligand A (0 HBD, 2 HBA) and Ligand B (2 HBD, 4 HBA) both fall within acceptable ranges.

**QED:** Both ligands have similar QED values (0.752 and 0.71), indicating good drug-likeness.

**DILI:** Ligand A (51.881) has a lower DILI risk than Ligand B (8.802), which is preferable.

**BBB:** Ligand A (77.86) has a better BBB percentile than Ligand B (65.297), crucial for a CNS target like DRD2.

**Caco-2 Permeability:** Ligand A (-4.258) has a lower Caco-2 permeability than Ligand B (-4.822), which is less desirable.

**Aqueous Solubility:** Ligand A (-4.829) has a lower aqueous solubility than Ligand B (-2.13), which is less desirable.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.942 and 0.432).

**Microsomal Clearance:** Ligand A (69.248) has higher microsomal clearance than Ligand B (12.89), suggesting lower metabolic stability.

**In vitro Half-Life:** Ligand B (15.146) has a longer half-life than Ligand A (6.696), which is preferable.

**P-gp Efflux:** Ligand A (0.406) exhibits lower P-gp efflux than Ligand B (0.021), which is better for CNS exposure.

**Binding Affinity:** Ligand A (-8.7 kcal/mol) has a significantly stronger binding affinity than Ligand B (-7.4 kcal/mol). This 1.3 kcal/mol difference is substantial and can outweigh some ADME drawbacks.

**Conclusion:**

Despite Ligand B having better Caco-2 permeability, solubility, and half-life, Ligand A is the superior candidate. The significantly stronger binding affinity (-8.7 vs -7.4 kcal/mol) combined with the better BBB penetration (77.86 vs 65.297), lower DILI risk, and lower P-gp efflux makes Ligand A more likely to be a viable drug candidate for DRD2. The higher TPSA of Ligand B is a major concern for CNS penetration. While Ligand A's clearance is higher, the potency advantage is significant.

Output:
1
2025-04-17 05:53:03,619 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (356.463 and 358.389 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (79.31) is significantly better than Ligand B (96.25). For CNS targets, we want TPSA <= 90, so Ligand A is preferable.

**3. logP:** Both ligands have acceptable logP values (0.648 and 1.169), falling within the optimal 1-3 range. Ligand B is slightly better.

**4. H-Bond Donors:** Ligand A (1) is better than Ligand B (3). Lower HBD generally improves permeability.

**5. H-Bond Acceptors:** Both ligands have 5 HBA, which is acceptable (<=10).

**6. QED:** Ligand A (0.756) has a better QED score than Ligand B (0.617), indicating a more drug-like profile.

**7. DILI:** Ligand A (30.012) has a much lower DILI risk than Ligand B (40.364). Both are below the 40 threshold, but A is better.

**8. BBB:** Ligand B (73.245) has a slightly better BBB penetration percentile than Ligand A (68.748). Both are above 70, which is good for CNS targets.

**9. Caco-2 Permeability:** Ligand A (-4.372) has a better Caco-2 permeability than Ligand B (-5.026). Higher is better.

**10. Aqueous Solubility:** Ligand A (-0.914) has better aqueous solubility than Ligand B (-2.605). Higher is better.

**11. hERG Inhibition:** Both ligands have low hERG inhibition liability (0.23 and 0.308), which is good.

**12. Microsomal Clearance:** Ligand B (12.164) has lower microsomal clearance than Ligand A (20.545), suggesting better metabolic stability.

**13. In vitro Half-Life:** Ligand A (7.495) has a longer in vitro half-life than Ligand B (-5.668).

**14. P-gp Efflux:** Both ligands have low P-gp efflux liability (0.046 and 0.035).

**15. Binding Affinity:** Ligand B (-8.1 kcal/mol) has a slightly better binding affinity than Ligand A (-7.6 kcal/mol). This is a significant advantage.

**Overall Assessment:**

Ligand B has a slightly better binding affinity and lower microsomal clearance, and a better BBB score. However, Ligand A excels in TPSA, QED, DILI, Caco-2 permeability, solubility, and half-life. Given the GPCR-specific emphasis on BBB, logP, Pgp, TPSA, and affinity, the lower TPSA of Ligand A is a significant advantage for CNS penetration. The better QED and lower DILI risk also contribute to its favorability. While the affinity difference is notable, it's only 0.5 kcal/mol, and the other ADME properties of Ligand A are more compelling for a CNS-targeting drug.

Output:
0
2025-04-17 05:53:03,619 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (351.426 and 362.543 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (70.47) is better than Ligand B (61.88) in terms of TPSA, being closer to the <90 A^2 threshold for CNS targets.

**3. logP:** Ligand A (1.028) is within the optimal 1-3 range. Ligand B (4.848) is significantly higher, potentially leading to solubility issues and off-target interactions.

**4. H-Bond Donors:** Both ligands have 1 HBD, which is acceptable.

**5. H-Bond Acceptors:** Ligand A has 5 HBA, and Ligand B has 4. Both are within the acceptable limit of <=10.

**6. QED:** Ligand A (0.88) has a higher QED than Ligand B (0.657), indicating a more drug-like profile.

**7. DILI:** Ligand A (35.401) has a lower DILI risk than Ligand B (44.009), which is preferable.

**8. BBB:** Ligand A (82.513) has a significantly higher BBB penetration percentile than Ligand B (61.846). This is a crucial advantage for a CNS target like DRD2.

**9. Caco-2 Permeability:** Ligand A (-4.965) has better Caco-2 permeability than Ligand B (-5.249), though both are negative values which is unusual and requires further investigation.

**10. Aqueous Solubility:** Ligand A (-2.284) has better aqueous solubility than Ligand B (-4.602).

**11. hERG Inhibition:** Both ligands have relatively low hERG inhibition risk (0.436 and 0.688, respectively).

**12. Microsomal Clearance:** Ligand A (3.582) has a lower microsomal clearance than Ligand B (72.735), suggesting better metabolic stability.

**13. In vitro Half-Life:** Ligand A (18.644) has a shorter in vitro half-life than Ligand B (38.84), but this is less critical given the other advantages of Ligand A.

**14. P-gp Efflux:** Ligand A (0.019) has much lower P-gp efflux liability than Ligand B (0.621), which is highly desirable for CNS penetration.

**15. Binding Affinity:** Ligand A (-7.8 kcal/mol) has a slightly better binding affinity than Ligand B (-7.2 kcal/mol). While the difference is not huge, it contributes to the overall preference for Ligand A.

**Overall Assessment:**

Ligand A consistently outperforms Ligand B across most critical ADME properties, particularly BBB penetration, logP, P-gp efflux, and metabolic stability. The slightly better binding affinity further strengthens its position. Ligand B's high logP is a significant concern, potentially hindering solubility and increasing off-target effects.

Output:
1
2025-04-17 05:53:03,619 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (357.407 and 367.808 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (105.25) is higher than the preferred <90 for CNS targets, while Ligand B (71.53) is well within the range. This is a significant advantage for Ligand B.

**logP:** Ligand A (-0.991) is quite low, potentially hindering membrane permeability. Ligand B (2.041) is within the optimal 1-3 range. This favors Ligand B.

**H-Bond Donors/Acceptors:** Both have 1 HBD, which is acceptable. Ligand A has 6 HBA, and Ligand B has 4 HBA, both are acceptable.

**QED:** Both ligands have acceptable QED scores (0.587 and 0.83), indicating good drug-like properties.

**DILI:** Ligand A (38.736) has a lower DILI risk than Ligand B (50.989), but both are below the concerning threshold of 60.

**BBB:** Ligand B (89.57) has a significantly higher BBB penetration percentile than Ligand A (62.233). This is crucial for a CNS target like DRD2 and strongly favors Ligand B.

**Caco-2 Permeability:** Both have negative values, which is unusual and suggests poor permeability. However, the scale is not specified, so it's difficult to interpret.

**Aqueous Solubility:** Both have negative values, which is also unusual. The scale is not specified, so it's difficult to interpret.

**hERG Inhibition:** Ligand A (0.077) shows very low hERG inhibition liability, which is excellent. Ligand B (0.34) is slightly higher, but still relatively low risk.

**Microsomal Clearance:** Ligand A (33.586) has higher microsomal clearance than Ligand B (18.554), indicating lower metabolic stability. This favors Ligand B.

**In vitro Half-Life:** Ligand B (-14.995) has a significantly longer in vitro half-life than Ligand A (-5.21). This is a substantial advantage for Ligand B.

**P-gp Efflux:** Ligand A (0.006) shows very low P-gp efflux, which is excellent. Ligand B (0.018) is slightly higher, but still very low.

**Binding Affinity:** Ligand B (-8.3 kcal/mol) has a much stronger binding affinity than Ligand A (-0.0 kcal/mol). This is a decisive factor.

**Overall:**

Ligand B consistently outperforms Ligand A across several key parameters, especially those prioritized for GPCRs targeting the CNS. The superior BBB penetration, logP, metabolic stability (lower Cl_mic, longer t1/2), and significantly stronger binding affinity of Ligand B make it a much more promising drug candidate. While Ligand A has a slightly lower DILI risk and better hERG profile, these are outweighed by the other advantages of Ligand B.

Output:
1
2025-04-17 05:53:03,619 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 drug candidates, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (350.503 and 361.551 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (58.64) is significantly better than Ligand B (37.38). For CNS targets, we want TPSA <= 90, and ideally lower. Ligand A is well within this range, while Ligand B is approaching the upper limit.

**3. logP:** Ligand A (2.591) is optimal (1-3). Ligand B (4.971) is higher, potentially leading to solubility issues and off-target effects.

**4. H-Bond Donors:** Ligand A (1) is good. Ligand B (0) is also acceptable.

**5. H-Bond Acceptors:** Both ligands (3) are within the acceptable range of <= 10.

**6. QED:** Both ligands (0.801 and 0.742) are above the 0.5 threshold, indicating good drug-likeness.

**7. DILI:** Ligand A (18.379) has a lower DILI risk than Ligand B (25.475), which is preferable. Both are below the 40 threshold.

**8. BBB:** Ligand B (88.135) has a better BBB penetration percentile than Ligand A (77.782). Both are above 70, which is desirable for CNS targets.

**9. Caco-2 Permeability:** Ligand A (-4.533) and Ligand B (-4.667) are both negative, indicating poor permeability. This is a concern for both.

**10. Aqueous Solubility:** Ligand A (-3.079) is better than Ligand B (-4.833), indicating slightly better solubility.

**11. hERG Inhibition:** Both ligands (0.541 and 0.446) have low hERG inhibition liability, which is good.

**12. Microsomal Clearance:** Ligand A (31.433) has significantly lower microsomal clearance than Ligand B (111.656), suggesting better metabolic stability.

**13. In vitro Half-Life:** Ligand B (5.357) has a longer half-life than Ligand A (2.557).

**14. P-gp Efflux:** Ligand A (0.095) has lower P-gp efflux liability than Ligand B (0.84), which is beneficial for CNS exposure.

**15. Binding Affinity:** Both ligands have the same binding affinity (-8.1 kcal/mol), which is excellent.

**Overall Assessment:**

While Ligand B has better BBB penetration and in vitro half-life, Ligand A is superior in several critical areas for a CNS-targeting GPCR. Specifically, Ligand A has a significantly better TPSA, logP, lower DILI risk, lower microsomal clearance, and lower P-gp efflux. The slightly lower BBB score for Ligand A is less concerning given its other advantages. The Caco-2 permeability is poor for both, but this is less critical for a CNS target where BBB penetration is paramount. Given the GPCR-specific priorities, Ligand A is the more promising candidate.

Output:
1
2025-04-17 05:53:03,619 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 drug candidates, considering the provided guidelines and GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight (MW):** Both ligands are within the ideal range (200-500 Da). Ligand A (345.487 Da) is slightly lower, which is generally favorable for permeability.

**2. TPSA:** Both ligands have TPSA values (A: 73.2, B: 71.53) below the 90 A^2 threshold for CNS targets, which is good.

**3. logP:** Both ligands have optimal logP values (A: 3.027, B: 2.317) falling within the 1-3 range.

**4. H-Bond Donors (HBD):** Both ligands have 1 HBD, which is within the acceptable limit of <=5.

**5. H-Bond Acceptors (HBA):** Ligand A has 3 HBA, and Ligand B has 5 HBA, both are within the acceptable limit of <=10.

**6. QED:** Both ligands have good QED scores (A: 0.594, B: 0.805), indicating drug-like properties. Ligand B is slightly better.

**7. DILI:** Ligand A has a DILI risk of 8.918%, while Ligand B has 35.13%. Ligand A is significantly better regarding liver injury risk.

**8. BBB:** Both ligands have good BBB penetration (A: 75.998%, B: 70.531%), exceeding the 70% threshold for CNS targets. Ligand A is slightly better.

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.809 and -4.844). This is unusual and suggests poor permeability. However, these values are on a log scale and a negative value indicates low permeability.

**10. Aqueous Solubility:** Both ligands have negative solubility values (-2.172 and -2.017). Similar to Caco-2, these are on a log scale and indicate poor aqueous solubility.

**11. hERG Inhibition:** Both ligands have low hERG inhibition risk (A: 0.473, B: 0.408).

**12. Microsomal Clearance (Cl_mic):** Ligand A has a lower Cl_mic (12.257 mL/min/kg) than Ligand B (24.811 mL/min/kg), indicating better metabolic stability.

**13. In vitro Half-Life:** Ligand A has a negative half-life (-16.134 hours), which is not physically possible. This is a major red flag. Ligand B has a half-life of 5.645 hours.

**14. P-gp Efflux:** Both ligands have low P-gp efflux liability (A: 0.113, B: 0.118).

**15. Binding Affinity:** Ligand A has a better binding affinity (-8.6 kcal/mol) than Ligand B (-7.6 kcal/mol). This is a significant advantage (>1.5 kcal/mol difference).

**Overall Assessment:**

Ligand A has a significantly better binding affinity and lower DILI risk, and slightly better BBB penetration. However, the negative in vitro half-life is a critical issue, indicating a potential problem with the data or a highly unstable compound. Ligand B has a reasonable half-life, better QED, but a higher DILI risk and weaker binding affinity. Considering the GPCR-specific priorities, affinity and BBB are crucial. While the negative half-life for Ligand A is concerning, the substantial affinity advantage might be worth investigating further if the data can be verified or if the instability can be addressed through structural modifications. However, given the clear issues with the half-life data for Ligand A, and the overall better ADME profile of Ligand B, I would choose Ligand B.

Output:
1
2025-04-17 05:53:03,620 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (370.316 and 369.487 Da) are within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (105.56) is slightly above the preferred <90 for CNS targets, but still reasonable. Ligand B (89.95) is excellent, falling well within the desired range.

**3. logP:** Ligand A (1.361) is within the optimal 1-3 range. Ligand B (0.265) is a bit low, potentially hindering permeability.

**4. H-Bond Donors:** Both ligands have 2 HBD, which is acceptable (<=5).

**5. H-Bond Acceptors:** Ligand A has 7 HBA, and Ligand B has 6 HBA, both within the acceptable range (<=10).

**6. QED:** Both ligands have similar QED values (0.721 and 0.748), indicating good drug-like properties.

**7. DILI:** Ligand A has a DILI risk of 96.161, which is very high and a significant concern. Ligand B has a much lower DILI risk of 30.787, which is favorable.

**8. BBB:** Ligand A has a BBB penetration of 40.016, which is suboptimal for a CNS target. Ligand B has a BBB penetration of 30.593, also suboptimal, but still better than A.

**9. Caco-2 Permeability:** Both have negative Caco-2 values (-5.148 and -5.6), which is unusual and suggests poor permeability. However, these values are on a scale where negative values are possible and don't necessarily disqualify the compounds.

**10. Aqueous Solubility:** Both have negative solubility values (-3.446 and -1.156). Similar to Caco-2, these values are on a scale where negative values are possible, and don't necessarily disqualify the compounds.

**11. hERG Inhibition:** Both ligands show very low hERG inhibition risk (0.143 and 0.371).

**12. Microsomal Clearance:** Ligand A has a Cl_mic of 6.557, while Ligand B has -18.504. A negative value for Cl_mic is unusual and likely indicates very high metabolic stability. Ligand A's clearance is moderate.

**13. In vitro Half-Life:** Ligand A has a negative half-life (-31.201), which is unusual. Ligand B has a half-life of -3.14, also unusual.

**14. P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.096 and 0.008).

**15. Binding Affinity:** Both ligands have the same binding affinity (-8.7 kcal/mol), which is excellent.

**Overall Assessment:**

Despite both ligands having excellent binding affinity, Ligand B is significantly more promising. The primary driver is the dramatically lower DILI risk (30.787 vs 96.161). While both have suboptimal BBB penetration, the lower DILI risk is a critical advantage. The slightly better TPSA and potentially better metabolic stability (indicated by the negative Cl_mic value) further support choosing Ligand B. The unusual negative values for Caco-2 and half-life are concerning, but the DILI risk is the most critical factor here.

Output:
1
2025-04-17 05:53:03,620 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (347.463 and 346.439 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (77.37) is significantly better than Ligand B (109.65).  For CNS targets, we want TPSA <= 90, so Ligand A is preferable.

**3. logP:** Both ligands (1.562 and 1.335) are within the optimal 1-3 range.

**4. H-Bond Donors:** Ligand A (1) is better than Ligand B (3). Lower HBD generally improves permeability.

**5. H-Bond Acceptors:** Ligand A (5) is better than Ligand B (8). Lower HBA generally improves permeability.

**6. QED:** Ligand A (0.784) is better than Ligand B (0.628), indicating a more drug-like profile.

**7. DILI:** Ligand A (20.047) is *much* better than Ligand B (53.742).  Ligand A is well below the 40% threshold for low risk, while Ligand B is approaching a concerning level.

**8. BBB:** Ligand A (68.282) is better than Ligand B (36.797), although both are below the ideal >70% for CNS targets. This is a critical factor for DRD2.

**9. Caco-2 Permeability:** Ligand A (-4.986) is better than Ligand B (-5.419), indicating better intestinal absorption.

**10. Aqueous Solubility:** Ligand A (-1.768) is better than Ligand B (-2.094), although both are poor.

**11. hERG Inhibition:** Both ligands are very low (0.104 and 0.094), indicating minimal cardiotoxicity risk.

**12. Microsomal Clearance:** Ligand A (-2.172) is *much* better than Ligand B (42.658).  Negative clearance indicates high metabolic stability.

**13. In vitro Half-Life:** Ligand A (2.52) is significantly worse than Ligand B (21.334).

**14. P-gp Efflux:** Both ligands are very low (0.008 and 0.011), indicating minimal P-gp efflux.

**15. Binding Affinity:** Both ligands have the same binding affinity (-8 kcal/mol), which is excellent.

**Overall Assessment:**

Ligand A is clearly superior. While its in vitro half-life is shorter, it excels in almost every other critical parameter, especially those prioritized for GPCRs targeting the CNS: TPSA, DILI, BBB, and metabolic stability (Cl_mic). The lower TPSA and better BBB penetration of Ligand A are particularly important for CNS drug development. The significantly lower DILI risk is also a major advantage. The slightly better QED and H-bonding characteristics further support Ligand A.



Output:
1
2025-04-17 05:53:03,620 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (352.395 and 355.435 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (110.52) is slightly above the optimal <90 for CNS targets, while Ligand B (105.76) is closer but still slightly above. This is a minor concern for both.

**3. logP:** Ligand A (-0.641) is a bit low, potentially hindering permeability. Ligand B (0.414) is better, falling within the 1-3 range, but still on the lower end.

**4. H-Bond Donors:** Ligand A (0) is excellent. Ligand B (3) is acceptable, but higher HBD can sometimes reduce permeability.

**5. H-Bond Acceptors:** Ligand A (8) is good. Ligand B (5) is also good.

**6. QED:** Both ligands (0.474 and 0.432) are reasonably drug-like, but could be improved.

**7. DILI:** Ligand A (55.797) has a higher DILI risk than Ligand B (40.83), which is preferable.

**8. BBB:** Ligand A (76.696) has a significantly better BBB penetration percentile than Ligand B (51.221). This is *critical* for a CNS target like DRD2.

**9. Caco-2 Permeability:** Both show poor Caco-2 permeability (-4.822 and -5.224). This suggests potential absorption issues.

**10. Aqueous Solubility:** Both have poor aqueous solubility (-0.685 and -2.652). This could present formulation challenges.

**11. hERG Inhibition:** Both ligands show very low hERG inhibition risk (0.016 and 0.146).

**12. Microsomal Clearance:** Ligand A (54.387) has higher microsomal clearance than Ligand B (31.13), indicating potentially lower metabolic stability.

**13. In vitro Half-Life:** Ligand B (-2.777) has a slightly better (less negative) in vitro half-life than Ligand A (-11.553).

**14. P-gp Efflux:** Both ligands show very low P-gp efflux liability (0.044 and 0.036).

**15. Binding Affinity:** Both ligands have excellent binding affinity (-7.1 and -7.0 kcal/mol). The difference is minimal.

**Overall Assessment:**

While both ligands have good binding affinity, Ligand A is the stronger candidate due to its significantly better BBB penetration (76.7% vs 51.2%), lower DILI risk, and acceptable TPSA. Although its logP is lower and clearance is higher, the crucial BBB property outweighs these drawbacks for a CNS-targeting GPCR. The similar affinities mean the ADME properties become the deciding factor.

Output:
0
2025-04-17 05:53:03,620 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (374.47 and 347.38 Da) fall within the ideal 200-500 Da range.

**TPSA:** Both ligands (132.44 and 133.05) are slightly above the optimal <90 for CNS targets, but still reasonable.

**logP:** Both ligands (-0.594 and -0.793) are a bit low. Ideally, we want 1-3. This could potentially hinder membrane permeability, but isn't a dealbreaker if other properties are favorable.

**H-Bond Donors/Acceptors:** Ligand A (2 HBD, 7 HBA) is better than Ligand B (4 HBD, 5 HBA) in terms of balancing solubility and permeability.

**QED:** Both ligands have similar QED values (0.593 and 0.513), indicating good drug-like properties.

**DILI:** Both ligands have similar DILI risk (52.15 and 54.98), which is acceptable (below 60).

**BBB:** Ligand A (58.78%) shows significantly better BBB penetration potential than Ligand B (39.36%). This is *critical* for a CNS target like DRD2.

**Caco-2 Permeability:** Both have negative values (-5.107 and -5.76), which is unusual and suggests poor permeability. This is concerning.

**Aqueous Solubility:** Both ligands have very poor aqueous solubility (-1.831 and -2.463). This could pose formulation challenges.

**hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.08 and 0.068), which is excellent.

**Microsomal Clearance:** Ligand B (-11.658) has a much lower (better) microsomal clearance than Ligand A (27.782), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand B (9.766 hours) has a significantly longer half-life than Ligand A (-3.661 hours). This is a major advantage.

**P-gp Efflux:** Both ligands have very low P-gp efflux (0.015 and 0.008), which is good for CNS exposure.

**Binding Affinity:** Ligand B (-9.2 kcal/mol) has a stronger binding affinity than Ligand A (-7.4 kcal/mol). This difference of 1.8 kcal/mol is substantial and can outweigh some ADME drawbacks.

**Overall Assessment:**

While both ligands have issues with logP and solubility, Ligand B is the stronger candidate. Its significantly better binding affinity, lower clearance, and longer half-life are compelling. The improved BBB penetration, while not ideal, is also preferable. The Caco-2 permeability is a concern for both, but the superior potency and PK properties of Ligand B make it more likely to succeed.

Output:
1
2025-04-17 05:53:03,621 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (376.519 and 357.495 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (103.78) is slightly above the optimal <90 for CNS targets, but still reasonably acceptable. Ligand B (90.9) is better, falling comfortably under 90.

**logP:** Ligand A (0.717) is a bit low, potentially hindering permeation. Ligand B (0.515) is even lower, raising similar concerns. Both are below the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A (HBD=2, HBA=5) and Ligand B (HBD=3, HBA=5) both have acceptable numbers of H-bond donors and acceptors.

**QED:** Ligand A (0.617) has a better QED score than Ligand B (0.496), suggesting a more drug-like profile.

**DILI:** Ligand A (17.449) has a significantly lower DILI risk than Ligand B (4.188), which is a major advantage.

**BBB:** Ligand A (54.091) has a better BBB penetration percentile than Ligand B (36.371), though neither are above the desirable >70 for CNS targets.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.28 and -5.235), which is unusual and suggests poor permeability. This is a significant concern for both.

**Aqueous Solubility:** Both ligands have negative solubility values (-1.293 and -0.281), indicating very poor aqueous solubility. This will present formulation challenges.

**hERG:** Both ligands have very low hERG inhibition liability (0.255 and 0.258), which is excellent.

**Microsomal Clearance:** Ligand A (-10.091) has a much lower (better) microsomal clearance than Ligand B (-0.81). This indicates better metabolic stability.

**In vitro Half-Life:** Ligand B (10.859) has a longer in vitro half-life than Ligand A (1.379), which is a positive.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.019 and 0.016), which is favorable for CNS penetration.

**Binding Affinity:** Both ligands have the same binding affinity (-7.4 kcal/mol), which is excellent and meets the criteria.

**Overall Assessment:**

While both compounds have excellent binding affinity, Ligand A is the better candidate. Its lower DILI risk, better QED, and significantly improved metabolic stability (lower Cl_mic) are crucial advantages. Although both have poor solubility and Caco-2 permeability, the other factors tip the balance in favor of Ligand A. The slightly better BBB score for Ligand A is also a plus, given the CNS target.

Output:
1
2025-04-17 05:53:03,621 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight (MW):** Both ligands (348.334 and 350.503 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (95.34) is slightly higher than the ideal <90 for CNS targets, but still reasonable. Ligand B (69.64) is excellent, well below the threshold.

**3. logP:** Ligand A (0.661) is a bit low, potentially hindering permeability. Ligand B (2.04) is within the optimal 1-3 range.

**4. H-Bond Donors (HBD):** Both ligands are acceptable (1 and 2, respectively), staying below the 5 limit.

**5. H-Bond Acceptors (HBA):** Both ligands are acceptable (7 and 3, respectively), staying below the 10 limit.

**6. QED:** Both ligands have similar, good QED values (0.771 and 0.738), indicating good drug-like properties.

**7. DILI:** Ligand A (86.002) has a significantly higher DILI risk than Ligand B (11.09). This is a major concern for Ligand A.

**8. BBB:** Ligand A (80.962) has a good BBB penetration percentile, while Ligand B (65.839) is lower, but still acceptable.

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 values, which is unusual and suggests a potential issue with the data or modeling. However, the magnitude is similar.

**10. Aqueous Solubility:** Both ligands have negative solubility values, which is also unusual. Again, the magnitude is similar.

**11. hERG Inhibition:** Both ligands have low hERG inhibition risk (0.127 and 0.587, respectively).

**12. Microsomal Clearance:** Ligand A (46.465) has higher microsomal clearance than Ligand B (31.209), suggesting lower metabolic stability.

**13. In vitro Half-Life:** Ligand B (3.69) has a longer in vitro half-life than Ligand A (-5.477), which is a significant advantage.

**14. P-gp Efflux:** Both ligands show low P-gp efflux liability (0.14 and 0.166, respectively).

**15. Binding Affinity:** Ligand A (-8.6 kcal/mol) has a slightly better binding affinity than Ligand B (-8.1 kcal/mol), but the difference is relatively small (0.5 kcal/mol).

**Overall Assessment:**

Ligand B is the more promising candidate. While Ligand A has slightly better binding affinity, its significantly higher DILI risk, lower logP, and higher microsomal clearance are major drawbacks. Ligand B has a much better safety profile (lower DILI), better logP, and improved metabolic stability (lower Cl_mic, longer t1/2). The TPSA is also more favorable for CNS penetration. The difference in binding affinity (0.5 kcal/mol) is unlikely to outweigh these significant ADME/Tox advantages, especially for a GPCR target where CNS penetration is crucial.

Output:
1
2025-04-17 05:53:03,621 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (356.413 and 356.388 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (62.55) is better than Ligand B (49.5). Both are below the 90 A^2 threshold for CNS targets, which is excellent.

**3. logP:** Both ligands have good logP values (3.476 and 3.997), falling within the optimal 1-3 range. Ligand B is slightly higher, which could potentially lead to solubility issues, but is not a major concern.

**4. H-Bond Donors:** Both ligands have 1 HBD, which is within the acceptable limit of <=5.

**5. H-Bond Acceptors:** Ligand A has 3 HBA, and Ligand B has 4. Both are below the acceptable limit of <=10.

**6. QED:** Both ligands have good QED scores (0.776 and 0.815), indicating good drug-like properties.

**7. DILI:** Ligand A (34.277) has a slightly higher DILI risk than Ligand B (13.843). This is a significant advantage for Ligand B.

**8. BBB:** Ligand A (90.81) has a better BBB penetration percentile than Ligand B (79.411). This is a crucial factor for a CNS target like DRD2, making Ligand A more promising.

**9. Caco-2 Permeability:** Ligand A (-4.347) has a worse Caco-2 permeability than Ligand B (-4.71). Lower values indicate poorer permeability.

**10. Aqueous Solubility:** Ligand A (-3.002) has better aqueous solubility than Ligand B (-3.875).

**11. hERG Inhibition:** Ligand A (0.604) has a lower hERG inhibition risk than Ligand B (0.945). This is a significant advantage for Ligand A.

**12. Microsomal Clearance:** Ligand B (45.179) has a lower microsomal clearance than Ligand A (35.976), suggesting better metabolic stability.

**13. In vitro Half-Life:** Ligand B (41.155) has a longer in vitro half-life than Ligand A (34.273), which is generally desirable.

**14. P-gp Efflux:** Ligand A (0.27) has lower P-gp efflux liability than Ligand B (0.513), which is beneficial for CNS exposure.

**15. Binding Affinity:** Both ligands have excellent binding affinities (-8.5 and -8.0 kcal/mol). Ligand A has a slightly better affinity, but the difference is relatively small.

**Overall Assessment:**

Ligand A excels in BBB penetration, hERG inhibition, P-gp efflux, solubility, and binding affinity. Ligand B has advantages in DILI risk, metabolic stability (lower Cl_mic), and in vitro half-life. Considering the GPCR-specific priorities, BBB penetration is paramount for a CNS target. While Ligand B has a better safety profile (DILI, hERG), Ligand A's superior BBB penetration and slightly better affinity outweigh these advantages. The slightly lower metabolic stability of Ligand A can be addressed through structural modifications during lead optimization.

Output:
0
2025-04-17 05:53:03,621 - INFO - Batch 235 complete. Total preferences: 3760
2025-04-17 05:53:03,621 - INFO - Processing batch 236/512...
2025-04-17 05:53:44,529 - INFO - Reasoning:

Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (358.423 and 369.443 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (95.42) is slightly above the preferred <90 for CNS targets, while Ligand B (89.99) is closer to the ideal range.

**logP:** Ligand A (1.726) is within the optimal 1-3 range. Ligand B (0.353) is slightly low, potentially hindering permeation.

**H-Bond Donors/Acceptors:** Ligand A has 2 HBD and 6 HBA, both acceptable. Ligand B has 1 HBD and 7 HBA, also acceptable.

**QED:** Both ligands have similar QED values (0.868 and 0.806), indicating good drug-likeness.

**DILI:** Ligand A (60.217) is borderline, indicating moderate risk. Ligand B (80.729) has a significantly higher DILI risk, which is a major concern.

**BBB:** Ligand A (40.093) has a low BBB penetration percentile, which is unfavorable for a CNS target like DRD2. Ligand B (49.166) is also low, but slightly better than Ligand A.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.306 and -5.082), which is unusual and suggests poor permeability. This is a significant drawback for both.

**Aqueous Solubility:** Both ligands have very poor aqueous solubility (-4.126 and -1.714). This could pose formulation challenges.

**hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.09 and 0.044), which is excellent.

**Microsomal Clearance:** Ligand A (37.354) has moderate clearance. Ligand B (-0.775) has *very* low clearance, suggesting high metabolic stability, which is a significant advantage.

**In vitro Half-Life:** Ligand A (-26.268) has a negative half-life, which is not physically possible and indicates an issue with the data or prediction method. Ligand B (7.896) has a reasonable half-life.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.035 and 0.019), which is favorable for CNS penetration.

**Binding Affinity:** Ligand B (-7.3 kcal/mol) has a significantly stronger binding affinity than Ligand A (-8.1 kcal/mol). This 0.8 kcal/mol difference is substantial and could outweigh some of the ADME drawbacks.

**Overall Assessment:**

Ligand A suffers from poor BBB penetration, questionable half-life data, and moderate DILI risk. While its affinity is slightly better, the other issues are substantial. Ligand B, despite a slightly lower logP and a higher DILI risk, has *much* better metabolic stability (very low Cl_mic, reasonable t1/2), a significantly stronger binding affinity, and comparable P-gp efflux. The poor solubility and Caco-2 permeability are concerns for both, but the superior affinity and metabolic stability of Ligand B make it the more promising candidate.

Output:
1
2025-04-17 05:53:44,530 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (338.367 and 354.447 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Both ligands have TPSA values (89.01 and 85.89) below the 90 A^2 threshold desirable for CNS targets. This is good.

**3. logP:** Ligand A (1.227) and Ligand B (0.905) are both within the optimal 1-3 range.

**4. H-Bond Donors:** Both ligands have 2 HBD, which is acceptable (<=5).

**5. H-Bond Acceptors:** Both ligands have 5 HBA, which is acceptable (<=10).

**6. QED:** Ligand A (0.749) has a slightly better QED score than Ligand B (0.677), both being above the 0.5 threshold.

**7. DILI:** Ligand A (69.678) has a significantly higher DILI risk than Ligand B (22.838). This is a major concern for Ligand A.

**8. BBB:** Ligand B (49.438) has a better BBB penetration percentile than Ligand A (35.052). While neither is >70, Ligand B is closer and more favorable for a CNS target.

**9. Caco-2 Permeability:** Both have negative Caco-2 values (-5.538 and -5.204), which is unusual and suggests poor permeability. However, these values are on a scale where negative values are possible, and direct comparison is difficult without knowing the scale's specifics.

**10. Aqueous Solubility:** Both have negative solubility values (-2.959 and -1.442), indicating poor aqueous solubility. Again, the scale is unknown.

**11. hERG Inhibition:** Ligand A (0.48) has a lower hERG inhibition risk than Ligand B (0.129), which is preferable.

**12. Microsomal Clearance:** Ligand B (20.457) has a much higher microsomal clearance than Ligand A (-0.33). This suggests Ligand A is more metabolically stable.

**13. In vitro Half-Life:** Ligand B (26.539) has a longer in vitro half-life than Ligand A (-2.357).

**14. P-gp Efflux:** Ligand A (0.114) has lower P-gp efflux liability than Ligand B (0.036), which is favorable for CNS penetration.

**15. Binding Affinity:** Ligand B (-7.7 kcal/mol) has a significantly stronger binding affinity than Ligand A (-10.2 kcal/mol). This is a substantial advantage.

**Overall Assessment:**

Ligand B is the stronger candidate. While both have issues with Caco-2 and solubility, Ligand B's significantly better binding affinity (-7.7 vs -10.2 kcal/mol) and lower DILI risk outweigh its slightly higher P-gp efflux and lower metabolic stability. The improved BBB penetration is also a significant advantage for a CNS target like DRD2. Ligand A's high DILI risk is a major red flag.

Output:
1
2025-04-17 05:53:44,530 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (336.351) is slightly better positioned.

**TPSA:** Ligand B (53.33) is significantly better than Ligand A (107.71). For CNS targets, we want TPSA <= 90, and Ligand B comfortably meets this, while Ligand A is pushing the limit.

**logP:** Ligand A (1.419) is within the optimal range (1-3), while Ligand B (4.148) is at the upper end. While not terrible, higher logP can lead to off-target effects and solubility issues.

**H-Bond Donors/Acceptors:** Ligand A has 3 HBD and 4 HBA, while Ligand B has 0 HBD and 4 HBA. Both are within acceptable limits.

**QED:** Both ligands have good QED values (A: 0.658, B: 0.766), indicating drug-like properties.

**DILI:** Ligand B (20.667) has a much lower DILI risk than Ligand A (82.435). This is a significant advantage for Ligand B.

**BBB:** Ligand B (83.172) has a substantially higher BBB penetration score than Ligand A (26.638). This is *critical* for a CNS target like DRD2.

**Caco-2 Permeability:** Ligand A (-5.367) has a worse Caco-2 permeability than Ligand B (-4.878), indicating lower intestinal absorption.

**Aqueous Solubility:** Ligand A (-4.39) has slightly better solubility than Ligand B (-3.701).

**hERG Inhibition:** Ligand A (0.188) has a lower hERG inhibition liability than Ligand B (0.668), which is positive.

**Microsomal Clearance:** Ligand A (-13.166) has a much lower microsomal clearance, indicating better metabolic stability, than Ligand B (77.032). This is a significant advantage for Ligand A.

**In vitro Half-Life:** Ligand A (41.792) has a longer in vitro half-life than Ligand B (4.665).

**P-gp Efflux:** Ligand A (0.071) has a lower P-gp efflux liability than Ligand B (0.627). This is beneficial for CNS penetration.

**Binding Affinity:** Ligand B (-7.8) has a significantly stronger binding affinity than Ligand A (-10.5). This is a major advantage, potentially outweighing some of the ADME drawbacks.

**Overall Assessment:**

Ligand B excels in BBB penetration and binding affinity, which are paramount for a CNS GPCR target. Its lower DILI risk is also a major plus. The higher logP and P-gp efflux are concerns, but the strong affinity might compensate. Ligand A has better metabolic stability, lower hERG risk, and P-gp efflux, but its poor BBB penetration and significantly weaker binding affinity are major drawbacks. The substantial difference in binding affinity (-7.8 vs -10.5 kcal/mol) is likely to be the deciding factor.

Output:
1
2025-04-17 05:53:44,530 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 drug candidates, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (362.539 Da and 367.471 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (58.2) is excellent, well below the 90 Angstroms threshold for CNS targets. Ligand B (89.95) is higher, but still acceptable, though less optimal for brain penetration.

**3. logP:** Ligand A (4.347) is slightly high, potentially leading to solubility issues or off-target interactions. Ligand B (0.535) is quite low, which could hinder membrane permeability and brain penetration.

**4. H-Bond Donors:** Both ligands have 2 HBD, which is within the acceptable limit of 5.

**5. H-Bond Acceptors:** Ligand A has 3 HBA, and Ligand B has 5 HBA, both within the acceptable limit of 10.

**6. QED:** Both ligands have good QED scores (0.642 and 0.763), indicating good drug-like properties.

**7. DILI:** Ligand A (34.277) has a lower DILI risk than Ligand B (42.924), making it more favorable from a toxicity perspective.

**8. BBB:** This is a critical parameter for a CNS target like DRD2. Ligand A has a significantly better BBB percentile (69.523) than Ligand B (30.089).

**9. Caco-2 Permeability:** Both have negative Caco-2 values (-4.983 and -4.797), which is unusual and suggests poor permeability. However, these values are on a log scale and are likely representing very low permeability.

**10. Aqueous Solubility:** Both ligands have negative solubility values (-3.747 and -1.12), indicating poor aqueous solubility. This is a concern for both.

**11. hERG Inhibition:** Ligand A (0.411) shows a lower hERG inhibition liability than Ligand B (0.117), which is preferable.

**12. Microsomal Clearance:** Ligand A (65.091) has a higher microsomal clearance than Ligand B (9.638), indicating faster metabolism and potentially lower exposure.

**13. In vitro Half-Life:** Ligand B (-2.351) has a negative half-life, which is not physically possible and likely an error or outlier. Ligand A (24.93) has a reasonable half-life.

**14. P-gp Efflux:** Ligand A (0.303) has lower P-gp efflux liability than Ligand B (0.077), which is favorable for CNS penetration.

**15. Binding Affinity:** Ligand B (-8.9 kcal/mol) has a significantly stronger binding affinity than Ligand A (-7.6 kcal/mol). This is a substantial advantage.

**Overall Assessment:**

Ligand B has a superior binding affinity, which is a major advantage. However, it suffers from very poor BBB penetration, low logP, and a questionable half-life value. Ligand A, while having a slightly less potent binding affinity, exhibits much better BBB penetration, lower DILI risk, lower hERG risk, and a more reasonable half-life. Given the GPCR-specific priorities for CNS targets, and the importance of BBB penetration for DRD2, Ligand A is the more promising candidate despite the slightly weaker binding. The solubility and permeability issues of both compounds would need to be addressed through formulation or structural modifications.

Output:
0
2025-04-17 05:53:44,531 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (341.459 Da) is slightly lower, which could be beneficial for permeability. Ligand B (365.401 Da) is also acceptable.

**TPSA:** Ligand A (63.05) is excellent, well below the 90 A^2 threshold for CNS targets. Ligand B (46.61) is even better, indicating potentially improved BBB penetration.

**logP:** Both ligands have good logP values (Ligand A: 2.182, Ligand B: 3.208), falling within the optimal 1-3 range. Ligand B is slightly higher, which could be a minor concern for solubility but isn't a dealbreaker.

**H-Bond Donors/Acceptors:** Ligand A has 1 HBD and 5 HBA, while Ligand B has 0 HBD and 3 HBA. Both are within acceptable limits (<=5 HBD, <=10 HBA).

**QED:** Both ligands have similar QED values (Ligand A: 0.838, Ligand B: 0.821), indicating good drug-likeness.

**DILI:** Ligand A (32.299) has a significantly lower DILI risk than Ligand B (72.043). This is a substantial advantage for Ligand A.

**BBB:** Both ligands show good BBB penetration (Ligand A: 70.919, Ligand B: 76.231), exceeding the 70% threshold. Ligand B is slightly better.

**Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and suggests poor permeability. However, the scale is not defined, so it's hard to interpret.

**Aqueous Solubility:** Both have negative solubility values, again unusual and suggesting poor solubility.

**hERG:** Both ligands have low hERG inhibition liability (Ligand A: 0.158, Ligand B: 0.72), which is favorable.

**Microsomal Clearance:** Ligand A (56.535) has lower microsomal clearance than Ligand B (80.369), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (8.56 hours) has a shorter half-life than Ligand B (-3.484 hours). The negative value for Ligand B is concerning and likely an error.

**P-gp Efflux:** Ligand A (0.093) has lower P-gp efflux liability than Ligand B (0.388), which is beneficial for CNS exposure.

**Binding Affinity:** Ligand B (-10.6 kcal/mol) has a significantly stronger binding affinity than Ligand A (-8.5 kcal/mol). This is a >1.5 kcal/mol advantage, which can outweigh some ADME drawbacks.

**Conclusion:**

While Ligand A has better DILI, metabolic stability, and P-gp efflux profiles, the significantly stronger binding affinity of Ligand B (-10.6 vs -8.5 kcal/mol) is a decisive factor. For a GPCR target, strong binding is paramount. The slightly higher logP and DILI risk of Ligand B are acceptable trade-offs for the substantial improvement in potency. The negative values for Caco-2 and solubility are concerning for both, but the binding affinity difference is the dominant factor.

Output:
1
2025-04-17 05:53:44,531 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (335.415 and 354.479 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Both ligands have TPSA values (62.97 and 61.92) below the 90 A^2 threshold desirable for CNS targets, which is excellent.

**3. logP:** Ligand A (1.375) is within the optimal 1-3 range. Ligand B (3.576) is slightly higher, but still acceptable.

**4. H-Bond Donors:** Both ligands have 0 HBD, which is good, avoiding potential issues with permeability.

**5. H-Bond Acceptors:** Ligand A has 7 HBA, and Ligand B has 5 HBA. Both are below the 10 threshold.

**6. QED:** Both ligands have good QED scores (0.702 and 0.824), indicating drug-like properties.

**7. DILI:** Ligand A (42.846) has a slightly higher DILI risk than Ligand B (31.989), but both are below the concerning 60 threshold.

**8. BBB:** This is a crucial parameter for a CNS target like DRD2. Ligand B (84.413) has a significantly higher BBB penetration percentile than Ligand A (64.676). This is a major advantage for Ligand B.

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.032 and -4.931). This is unusual and suggests poor permeability. However, these values are on a log scale, so small differences can be significant.

**10. Aqueous Solubility:** Both ligands have poor aqueous solubility (-1.25 and -5.08). This could pose formulation challenges.

**11. hERG Inhibition:** Both ligands show low hERG inhibition risk (0.711 and 0.718).

**12. Microsomal Clearance:** Ligand A (11.224) has a lower microsomal clearance than Ligand B (67.223), suggesting better metabolic stability.

**13. In vitro Half-Life:** Ligand A (-39.054) has a significantly longer in vitro half-life than Ligand B (14.296). This is a strong positive for Ligand A.

**14. P-gp Efflux:** Both ligands show low P-gp efflux liability (0.029 and 0.626).

**15. Binding Affinity:** Ligand A (-9.5 kcal/mol) has a slightly better binding affinity than Ligand B (-8.1 kcal/mol). This 1.4 kcal/mol difference is substantial and could outweigh some ADME drawbacks.

**Overall Assessment:**

Ligand B excels in BBB penetration, a critical factor for CNS drug development. While Ligand A has better metabolic stability (lower Cl_mic, longer t1/2) and slightly better binding affinity, the significantly higher BBB score of Ligand B is a decisive advantage for targeting DRD2. The Caco-2 and solubility issues are concerning for both, but can potentially be addressed through formulation strategies.

Output:
1
2025-04-17 05:53:44,531 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (364.467 and 352.435 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (82.63) is significantly better than Ligand B (107.55). For CNS targets, TPSA should be <= 90. Ligand A is within this range, while Ligand B exceeds it, potentially hindering BBB penetration.

**3. logP:** Ligand A (3.065) is optimal, while Ligand B (0.936) is slightly low. A logP below 1 can impede permeation.

**4. H-Bond Donors:** Ligand A (2) and Ligand B (3) are both acceptable, being less than 5.

**5. H-Bond Acceptors:** Both ligands have 5 HBA, which is acceptable (<=10).

**6. QED:** Both ligands have similar QED values (0.74 and 0.706), indicating good drug-like properties.

**7. DILI:** Both ligands have the same DILI risk (56.146), which is moderate.

**8. BBB:** Ligand B (48.313) has a better BBB percentile than Ligand A (30.283). However, both are below the desirable >70 for CNS targets.

**9. Caco-2 Permeability:** Ligand A (-5.072) has a worse Caco-2 permeability than Ligand B (-4.809). Lower values indicate poorer permeability.

**10. Aqueous Solubility:** Ligand A (-2.762) has slightly better aqueous solubility than Ligand B (-2.529).

**11. hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.48 and 0.265).

**12. Microsomal Clearance:** Ligand B (4.813) has significantly lower microsomal clearance than Ligand A (68.171), suggesting better metabolic stability.

**13. In vitro Half-Life:** Ligand B (-39.019) has a much longer in vitro half-life than Ligand A (-10.328), which is a significant advantage.

**14. P-gp Efflux:** Ligand A (0.226) has lower P-gp efflux than Ligand B (0.051), which is more favorable for CNS exposure.

**15. Binding Affinity:** Ligand B (-7.7) has a slightly better binding affinity than Ligand A (-8.0). While both are excellent, the difference is minor.

**Overall Assessment:**

Considering the GPCR-specific priorities, Ligand A is better in terms of TPSA and P-gp efflux, which are important for CNS penetration. However, Ligand B has a significantly better metabolic stability (lower Cl_mic, longer t1/2) and a better BBB percentile, and a slightly better binding affinity. The lower logP of Ligand B is a concern, but the superior metabolic stability and slightly improved BBB penetration outweigh this drawback. The TPSA difference is also significant.

Output:
1
2025-04-17 05:53:44,531 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (330.395 Da) is slightly better, being closer to the lower end which can aid permeability.

**TPSA:** Ligand A (79.47) is significantly better than Ligand B (101.9). For CNS targets, TPSA should be <=90. Ligand A comfortably meets this, while Ligand B is pushing the limit and may have reduced brain penetration.

**logP:** Ligand A (4.559) is higher than optimal (1-3), but still potentially acceptable. Ligand B (0.004) is *very* low, which is a major concern for CNS penetration. A logP this low suggests poor membrane permeability.

**H-Bond Donors/Acceptors:** Ligand A (0 HBD, 4 HBA) is preferable to Ligand B (4 HBD, 5 HBA). Lower HBD/HBA generally improves permeability.

**QED:** Both ligands have acceptable QED values (A: 0.377, B: 0.491), indicating reasonable drug-likeness.

**DILI:** Ligand A (64.133) has a higher DILI risk than Ligand B (12.02), but both are within a tolerable range.

**BBB:** Ligand A (78.48) has a significantly better BBB percentile than Ligand B (22.606). This is a *critical* factor for a CNS target like DRD2.

**Caco-2 Permeability:** Ligand A (-4.843) has a negative Caco-2 value, which is unusual and suggests very poor permeability. Ligand B (-5.448) is also poor, but similarly.

**Aqueous Solubility:** Ligand A (-5.57) and Ligand B (-0.928) both have negative solubility values, indicating poor aqueous solubility.

**hERG Inhibition:** Ligand A (0.856) is preferable to Ligand B (0.142) as it has a lower hERG inhibition liability.

**Microsomal Clearance:** Ligand B (-14.247) has a lower (better) microsomal clearance than Ligand A (21.181), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand B (6.976) has a better in vitro half-life than Ligand A (-42.743).

**P-gp Efflux:** Ligand A (0.565) has a lower P-gp efflux liability than Ligand B (0.021), which is beneficial for CNS exposure.

**Binding Affinity:** Both ligands have similar binding affinities (-8.0 kcal/mol and -7.8 kcal/mol respectively). The difference is minimal.

**Overall Assessment:**

Despite Ligand B having better metabolic stability and a slightly better half-life, Ligand A is the stronger candidate. The critical factors driving this decision are the significantly better BBB penetration (78.48 vs 22.606) and more favorable TPSA (79.47 vs 101.9) for a CNS target. While Ligand A's logP is higher than ideal, Ligand B's extremely low logP is a major red flag for CNS penetration. The Caco-2 and solubility values are poor for both, but can potentially be addressed through formulation strategies. The lower P-gp efflux for Ligand A is also a plus.



Output:
0
2025-04-17 05:53:44,532 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (351.403 and 360.479 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (96.02) is better than Ligand B (71.34). Both are below the 90 A^2 threshold desirable for CNS targets, but A is slightly higher and could present a minor permeability issue.

**logP:** Ligand A (-0.19) is suboptimal, being below 1. This could hinder membrane permeability. Ligand B (3.252) is within the optimal 1-3 range. This is a significant advantage for Ligand B.

**H-Bond Donors/Acceptors:** Ligand A (1 HBD, 5 HBA) and Ligand B (2 HBD, 4 HBA) both have reasonable numbers of H-bonds, within the acceptable limits.

**QED:** Both ligands have good QED scores (0.669 and 0.831), indicating good drug-like properties.

**DILI:** Both ligands have similar, acceptable DILI risk (41.411 and 44.552).

**BBB:** Both ligands have good BBB penetration (62.078 and 67.041). While >70 is preferred, these are reasonably good, suggesting decent CNS exposure.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.888 and -5.046), which is unusual and suggests poor permeability. This is a concern for both.

**Aqueous Solubility:** Both ligands have negative solubility values (-1.669 and -3.067), which is also unusual and suggests poor solubility. This is a concern for both.

**hERG Inhibition:** Ligand A (0.026) has a very low hERG risk, which is excellent. Ligand B (0.328) has a slightly higher, but still acceptable, hERG risk.

**Microsomal Clearance:** Ligand A (-7.812) has a significantly *lower* (better) microsomal clearance than Ligand B (47.207), indicating greater metabolic stability.

**In vitro Half-Life:** Ligand A (-4.919) has a negative half-life, which is not physically possible and indicates a problem with the data. Ligand B (54.048) has a good in vitro half-life.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.022 and 0.169), which is favorable for CNS penetration.

**Binding Affinity:** Both ligands have the same binding affinity (-8.3 kcal/mol), which is excellent and strong.

**Overall Assessment:**

Ligand B is preferable despite the negative solubility and permeability values. The critical advantage is its logP value of 3.252, which is within the optimal range for CNS penetration and drug-like behavior, while Ligand A's logP is significantly low. Ligand A has better metabolic stability (lower Cl_mic) and a better hERG profile, but the poor logP is a major drawback. The negative half-life for Ligand A is also a red flag, suggesting a data issue. While both have issues with Caco-2 and solubility, the logP is the most critical factor for a CNS target like DRD2.

Output:
1
2025-04-17 05:53:44,532 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (366.502 and 360.523 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Both ligands have a TPSA of 49.41, which is acceptable for general oral absorption but a bit high for optimal CNS penetration (ideally <90, but lower is better).

**3. logP:** Both ligands have logP values within the optimal range (3.777 and 3.287).

**4. H-Bond Donors:** Both have 1 HBD, which is within the acceptable limit of <=5.

**5. H-Bond Acceptors:** Both have 3 HBA, which is within the acceptable limit of <=10.

**6. QED:** Both ligands have high QED scores (0.862 and 0.846), indicating good drug-like properties.

**7. DILI:** Ligand A has a DILI risk of 41.411, which is good (low risk). Ligand B has a significantly lower DILI risk of 14.889, which is excellent.

**8. BBB:** This is a critical parameter for a CNS target like DRD2. Ligand A has a BBB percentile of 95.347, which is excellent. Ligand B has a BBB percentile of 73.556, which is good, but notably lower than Ligand A.

**9. Caco-2 Permeability:** Both have negative Caco-2 values (-5.084 and -5.204), which is unusual and suggests poor permeability. This is a concern for both.

**10. Aqueous Solubility:** Both have negative solubility values (-4.028 and -2.902), indicating poor aqueous solubility. This is a concern for both.

**11. hERG Inhibition:** Both ligands have low hERG inhibition liability (0.778 and 0.425), which is positive.

**12. Microsomal Clearance:** Ligand A has a lower microsomal clearance (24.53) compared to Ligand B (47.95), suggesting better metabolic stability.

**13. In vitro Half-Life:** Ligand A has a slightly longer in vitro half-life (-1.102) than Ligand B (-9.151), which is favorable.

**14. P-gp Efflux:** Both ligands have low P-gp efflux liability (0.543 and 0.249), which is good for CNS penetration.

**15. Binding Affinity:** Ligand B has a slightly better binding affinity (-8.4 kcal/mol) than Ligand A (-7.8 kcal/mol). The difference is 0.6 kcal/mol, which is significant.

**Overall Assessment:**

While Ligand B has a better binding affinity and a much lower DILI risk, Ligand A's significantly superior BBB penetration is the deciding factor for a CNS target like DRD2. The difference in BBB penetration (95.347 vs. 73.556) is substantial. The slightly better metabolic stability and half-life of Ligand A also contribute to its favorability. The poor Caco-2 and solubility are concerns for both, but can be addressed through formulation strategies.

Output:
0
2025-04-17 05:53:44,532 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (349.385 and 349.431 Da) fall comfortably within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (62.19) is significantly better than Ligand B (86.88). For CNS targets, we want TPSA <= 90, and A is much closer to the ideal <=60 range. B is pushing the upper limit.

**3. logP:** Both ligands have good logP values (2.166 and 1.28), falling within the optimal 1-3 range.

**4. H-Bond Donors:** Ligand A (2) and Ligand B (1) are both acceptable.

**5. H-Bond Acceptors:** Ligand A (4) and Ligand B (5) are both acceptable.

**6. QED:** Both ligands have similar, good QED values (0.889 and 0.836), indicating good drug-like properties.

**7. DILI:** Ligand A (50.136) has a slightly higher DILI risk than Ligand B (29.159), but both are below the concerning threshold of 60.

**8. BBB:** This is a critical parameter for a CNS target like DRD2. Ligand A (83.908) has a much better BBB percentile than Ligand B (56.029). A value >70 is desirable, and A is closer to that.

**9. Caco-2:** Both ligands have negative Caco-2 values (-4.953 and -4.834), which is unusual and suggests poor permeability. This is a significant drawback for both.

**10. Solubility:** Both ligands have negative solubility values (-3.038 and -1.182), indicating very poor aqueous solubility. This is a major concern for bioavailability.

**11. hERG:** Both ligands have very low hERG inhibition liability (0.561 and 0.144), which is excellent.

**12. Cl_mic:** Ligand A (7.171) has a lower microsomal clearance than Ligand B (27.533), suggesting better metabolic stability.

**13. t1/2:** Ligand A (40.045) has a significantly longer in vitro half-life than Ligand B (14.31), which is desirable.

**14. Pgp:** Both ligands have very low Pgp efflux liability (0.073 and 0.071), which is excellent for CNS penetration.

**15. Binding Affinity:** Both ligands have excellent binding affinities (-10.0 and -9.0 kcal/mol). The difference of 1 kcal/mol is not large enough to outweigh other factors.

**Overall Assessment:**

Ligand A is the superior candidate. While both have poor Caco-2 and solubility, Ligand A excels in the critical areas for a CNS GPCR target: TPSA, BBB, metabolic stability (Cl_mic and t1/2). The slightly higher DILI risk is less concerning than the significantly lower BBB penetration of Ligand B. The similar affinities make these less important in the final decision.

Output:
1
2025-04-17 05:53:44,532 - INFO - Reasoning:

Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (351.407 and 345.403 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (109.58) is slightly higher than Ligand B (103.76). Both are reasonably good for CNS penetration, being below 140, but Ligand B is closer to the preferred <90 for CNS targets.

**3. logP:** Ligand A (-0.256) is quite low, potentially hindering membrane permeability. Ligand B (0.487) is better, falling within the optimal 1-3 range, though still on the lower end.

**4. H-Bond Donors:** Both ligands have 2 HBD, which is within the acceptable limit of <=5.

**5. H-Bond Acceptors:** Ligand A has 7 HBA, and Ligand B has 5. Both are within the acceptable limit of <=10.

**6. QED:** Both ligands have good QED scores (0.635 and 0.75), indicating drug-like properties.

**7. DILI:** Both ligands have similar DILI risk (58.395 and 60.14), both being acceptable (below 60 is preferred, but these are not high risk).

**8. BBB:** Ligand A (48.662) has a significantly better BBB percentile than Ligand B (36.177). This is a critical factor for a CNS target like DRD2.

**9. Caco-2 Permeability:** Both have negative Caco-2 values (-5.145 and -5.346), which is unusual and suggests poor permeability. This is a significant concern for both.

**10. Aqueous Solubility:** Both have negative solubility values (-1.231 and -2.293), which is also unusual and suggests poor solubility. This is a significant concern for both.

**11. hERG Inhibition:** Both ligands show very low hERG inhibition risk (0.153 and 0.17).

**12. Microsomal Clearance:** Ligand B (8.309) has a lower microsomal clearance than Ligand A (24.876), indicating better metabolic stability.

**13. In vitro Half-Life:** Ligand B (26.152) has a longer in vitro half-life than Ligand A (12.504), which is desirable.

**14. P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.045 and 0.02).

**15. Binding Affinity:** Ligand B (-8.7 kcal/mol) has a significantly stronger binding affinity than Ligand A (-7.5 kcal/mol). This >1.5 kcal/mol difference is substantial and can outweigh some ADME drawbacks.

**Overall Assessment:**

While both compounds have issues with Caco-2 permeability and aqueous solubility, Ligand B is the more promising candidate. Its significantly stronger binding affinity (-8.7 vs -7.5 kcal/mol) is a major advantage. It also has better logP, lower microsomal clearance, and a longer half-life. Although Ligand A has a better BBB score, the affinity difference is more important for a GPCR target, and the slightly lower BBB of Ligand B isn't a disqualifier given its other advantages.

Output:
1
2025-04-17 05:53:44,533 - INFO - Reasoning:

Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (349.431 and 351.455 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (95.41) is better than Ligand B (115.3). For CNS targets, we want TPSA <= 90, so A is closer to this threshold.

**3. logP:** Ligand A (1.927) is optimal (1-3), while Ligand B (0.908) is slightly low, potentially hindering permeation.

**4. H-Bond Donors:** Ligand A (2) and Ligand B (4) are both acceptable (<=5), but A is preferable.

**5. H-Bond Acceptors:** Ligand A (4) and Ligand B (7) are both acceptable (<=10), but A is preferable.

**6. QED:** Both ligands have reasonable QED values (A: 0.581, B: 0.489), indicating drug-like properties, but A is better.

**7. DILI:** Ligand A (56.96) has a slightly higher DILI risk than Ligand B (47.654), but both are below the concerning threshold of 60.

**8. BBB:** This is a critical parameter for CNS targets. Ligand B (67.352) significantly outperforms Ligand A (51.57). A value >70 is desirable, but B is considerably better.

**9. Caco-2 Permeability:** Ligand A (-4.953) is better than Ligand B (-5.194), but both are very poor.

**10. Aqueous Solubility:** Ligand A (-3.247) is better than Ligand B (-2.592), but both are very poor.

**11. hERG Inhibition:** Ligand A (0.228) has a lower hERG risk than Ligand B (0.559), which is preferable.

**12. Microsomal Clearance:** Ligand A (33.185) has a higher clearance than Ligand B (31.99), meaning B is more metabolically stable.

**13. In vitro Half-Life:** Ligand A (-28.084) has a longer half-life than Ligand B (20.803), which is preferable.

**14. P-gp Efflux:** Ligand A (0.131) shows lower P-gp efflux liability than Ligand B (0.011), which is preferable for CNS penetration.

**15. Binding Affinity:** Ligand B (-8.5 kcal/mol) has a significantly stronger binding affinity than Ligand A (-7.4 kcal/mol). This >1.5 kcal/mol difference is substantial and can outweigh some ADME drawbacks.

**Overall Assessment:**

While Ligand A has better TPSA, logP, H-bonding characteristics, hERG, and P-gp efflux, Ligand B's superior BBB penetration and significantly stronger binding affinity are decisive. For a CNS target like DRD2, BBB penetration is paramount. The stronger binding affinity of Ligand B also provides a greater margin for error regarding other properties. The slightly lower logP and higher DILI of Ligand B are less concerning given the strong affinity and improved BBB.

Output:
1
2025-04-17 05:53:44,533 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 drug candidates, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (345.418 and 346.471 Da) fall comfortably within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (53.51) is significantly better than Ligand B (58.64). For CNS targets, we want TPSA <= 90, and ideally closer to 60. Ligand A is much closer to this ideal.

**3. logP:** Both ligands have acceptable logP values (1.822 and 2.431), falling within the optimal 1-3 range.

**4. H-Bond Donors:** Ligand A (0) is preferable to Ligand B (1). Fewer HBDs generally improve permeability.

**5. H-Bond Acceptors:** Both ligands have 3 HBA, which is acceptable (<=10).

**6. QED:** Both ligands have similar QED values (0.818 and 0.796), indicating good drug-like properties.

**7. DILI:** Ligand A (20.861) has a much lower DILI risk than Ligand B (36.681). This is a significant advantage.

**8. BBB:** Ligand A (91.508) has a substantially higher BBB penetration percentile than Ligand B (75.107). This is *critical* for a CNS target like DRD2.

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.629 and -4.592). These values are unusual and difficult to interpret without further context, but they suggest poor permeability. However, the negative values are very similar, so this isn't a differentiating factor.

**10. Aqueous Solubility:** Ligand A (-1.842) is slightly better than Ligand B (-3.163), but both are poor. Solubility is a concern for both, but can be addressed with formulation strategies.

**11. hERG Inhibition:** Both ligands have low hERG inhibition liability (0.248 and 0.327), indicating low cardiotoxicity risk.

**12. Microsomal Clearance:** Ligand A (20.151) has lower microsomal clearance than Ligand B (27.452), suggesting better metabolic stability.

**13. In vitro Half-Life:** Ligand A (-3.776) has a longer in vitro half-life than Ligand B (2.593).

**14. P-gp Efflux:** Ligand A (0.034) has much lower P-gp efflux liability than Ligand B (0.14). Lower P-gp efflux is crucial for CNS penetration.

**15. Binding Affinity:** Both ligands have very similar and excellent binding affinities (-8.7 and -8.9 kcal/mol). The difference is negligible.

**Overall Assessment:**

Ligand A is significantly better than Ligand B. It has superior BBB penetration, lower DILI risk, lower P-gp efflux, better metabolic stability, and a longer half-life. While both have poor solubility and Caco-2 permeability, the advantages of Ligand A, especially regarding CNS penetration and safety, outweigh these drawbacks. Given the GPCR-specific priorities, particularly BBB, Ligand A is the more promising candidate.

Output:
0
2025-04-17 05:53:44,533 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (349.366 and 351.437 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (113.34) is borderline for CNS penetration, being slightly above the preferred <90, but still potentially acceptable. Ligand B (40.54) is excellent, well below 90, and highly favorable for CNS penetration.

**logP:** Ligand A (1.03) is at the low end of optimal, potentially leading to permeability issues. Ligand B (4.434) is significantly higher, exceeding the preferred range and potentially causing solubility and off-target issues.

**H-Bond Donors/Acceptors:** Ligand A has 3 HBD and 5 HBA, which are within acceptable limits. Ligand B has 1 HBD and 2 HBA, also within acceptable limits.

**QED:** Both ligands have good QED scores (0.674 and 0.852), indicating drug-like properties.

**DILI:** Ligand A (78.247) has a higher DILI risk than Ligand B (16.402), which is a significant advantage for Ligand B.

**BBB:** Ligand A (52.811) has a moderate BBB penetration score, while Ligand B (87.127) has a very high score, crucial for a CNS target like DRD2.

**Caco-2 Permeability:** Ligand A (-5.083) has poor Caco-2 permeability, which is concerning. Ligand B (-4.557) also has poor Caco-2 permeability, but slightly better than Ligand A.

**Aqueous Solubility:** Both ligands have poor aqueous solubility (-3.282 and -5.178).

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.565 and 0.829).

**Microsomal Clearance:** Ligand A (21.045) has lower microsomal clearance, suggesting better metabolic stability than Ligand B (100.126).

**In vitro Half-Life:** Ligand A (-21.547) has a very short in vitro half-life, a major drawback. Ligand B (-12.094) has a slightly better, but still short, half-life.

**P-gp Efflux:** Ligand A (0.031) has very low P-gp efflux, which is excellent for CNS penetration. Ligand B (0.308) has slightly higher P-gp efflux, but still relatively low.

**Binding Affinity:** Both ligands have excellent binding affinity (-9.2 and -8.2 kcal/mol). Ligand A is slightly better (-9.2 kcal/mol).

**Overall Assessment:**

Ligand B is the more promising candidate. While its logP is high, its exceptional BBB penetration (87.127), significantly lower DILI risk (16.402), and good QED score outweigh the drawbacks. The affinity is only slightly lower than Ligand A. Ligand A's poor Caco-2 permeability and very short half-life are major concerns, despite its slightly better affinity and lower clearance. For a CNS target, BBB penetration is paramount, and Ligand B excels in this area.

Output:
1
2025-04-17 05:53:44,533 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (345.447 Da) is slightly lower, which is generally favorable for permeability. Ligand B (370.471 Da) is also acceptable.

**TPSA:** Ligand A (80.12) is excellent, well below the 90 A^2 threshold for CNS targets. Ligand B (98.15) is still reasonable but less optimal, approaching the upper limit.

**logP:** Ligand A (1.835) is within the optimal range (1-3). Ligand B (-0.151) is below 1, which could hinder permeation. This is a significant drawback for Ligand B.

**H-Bond Donors/Acceptors:** Ligand A (HBD=1, HBA=5) is good. Ligand B (HBD=2, HBA=6) is also acceptable, but slightly higher.

**QED:** Both ligands have acceptable QED values (A: 0.765, B: 0.675), indicating good drug-like properties.

**DILI:** Ligand A (58.55) has a moderate DILI risk, but acceptable. Ligand B (32.377) has a lower DILI risk, which is favorable.

**BBB:** Ligand A (63.086) has a reasonable BBB penetration, but is less than the desirable >70% for CNS targets. Ligand B (28.848) has poor BBB penetration, a major concern for a DRD2 ligand.

**Caco-2 Permeability:** Both have negative values (-5.441 and -5.165), which is unusual and difficult to interpret without further context. However, since lower values generally indicate poorer permeability, this is a slight negative for both.

**Aqueous Solubility:** Both have negative values (-1.811 and -1.55), suggesting poor aqueous solubility. This could pose formulation challenges.

**hERG Inhibition:** Both ligands have very low hERG inhibition risk (A: 0.104, B: 0.016).

**Microsomal Clearance:** Ligand A (18.849) has lower clearance, suggesting better metabolic stability. Ligand B (23.507) has higher clearance.

**In vitro Half-Life:** Ligand A (-1.594) has a negative half-life, which is not physically possible and indicates an issue with the data. Ligand B (-2.77) also has a negative half-life. This is a significant data quality concern for both.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (A: 0.034, B: 0.013), which is favorable for CNS exposure.

**Binding Affinity:** Ligand A (-7.9 kcal/mol) has significantly stronger binding affinity than Ligand B (-6.6 kcal/mol). The 1.3 kcal/mol difference is substantial and could outweigh some ADME drawbacks.

**Overall Assessment:**

Ligand A is the better candidate despite the questionable half-life data. Its superior binding affinity, favorable TPSA, and acceptable logP and BBB penetration make it more promising. Ligand B's poor logP and BBB penetration are major drawbacks for a CNS-targeting drug. The negative half-life values for both compounds raise concerns about the data quality, but the significant affinity advantage of Ligand A makes it the more viable option.

Output:
0
2025-04-17 05:53:44,534 - INFO - Batch 236 complete. Total preferences: 3776
2025-04-17 05:53:44,534 - INFO - Processing batch 237/512...
2025-04-17 05:54:24,146 - INFO - Reasoning:

Let's analyze Ligand A and Ligand B for their potential as DRD2 drug candidates, considering the provided guidelines and GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (354.401 and 345.487 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (73.47) is slightly higher than Ligand B (71.09), but both are below the 90 A^2 threshold desirable for CNS targets.

**3. logP:** Ligand A (1.442) is within the optimal range (1-3), while Ligand B (3.313) is at the higher end, potentially raising concerns about solubility and off-target effects.

**4. H-Bond Donors:** Ligand A (3) and Ligand B (2) both satisfy the HBD <= 5 rule.

**5. H-Bond Acceptors:** Ligand A (4) and Ligand B (3) both satisfy the HBA <= 10 rule.

**6. QED:** Both ligands have similar QED values (0.7 and 0.675), indicating good drug-like properties.

**7. DILI:** Ligand A (53.509) has a higher DILI risk than Ligand B (32.067), which is preferable.

**8. BBB:** Ligand B (71.229) has a significantly better BBB penetration percentile than Ligand A (62.466). This is a *critical* advantage for a CNS target like DRD2.

**9. Caco-2 Permeability:** Ligand A (-5.081) shows poor Caco-2 permeability, while Ligand B (-4.75) is slightly better, but still not ideal.

**10. Aqueous Solubility:** Ligand A (-2.578) has slightly better aqueous solubility than Ligand B (-3.204).

**11. hERG Inhibition:** Both ligands have low hERG inhibition risk (0.652 and 0.691).

**12. Microsomal Clearance:** Ligand A (-4.962) has lower (better) microsomal clearance than Ligand B (43.914), indicating better metabolic stability.

**13. In vitro Half-Life:** Ligand A (-16.409) has a longer in vitro half-life than Ligand B (-4.515), which is desirable.

**14. P-gp Efflux:** Ligand A (0.05) has significantly lower P-gp efflux liability than Ligand B (0.32), which is crucial for CNS penetration.

**15. Binding Affinity:** Both ligands have very similar and strong binding affinities (-9.1 and -8.8 kcal/mol). The difference is less than the 1.5 kcal/mol threshold.

**Overall Assessment:**

While Ligand A has advantages in metabolic stability (Cl_mic, t1/2), solubility, and P-gp efflux, Ligand B's significantly better BBB penetration (71.229 vs 62.466) is the deciding factor for a CNS target like DRD2. The slightly higher logP of Ligand B is a minor concern, but the improved BBB outweighs this.

Output:
1
2025-04-17 05:54:24,147 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (367.515 Da and 365.88 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (93.43) is better than Ligand B (38.25). For CNS targets, we want TPSA <= 90, so Ligand A is closer to the ideal range.

**logP:** Ligand A (1.678) is optimal (1-3), while Ligand B (4.587) is slightly high, potentially leading to solubility issues and off-target interactions.

**H-Bond Donors/Acceptors:** Ligand A has 2 HBD and 5 HBA, which are reasonable. Ligand B has 0 HBD and 4 HBA, also acceptable.

**QED:** Both ligands have similar QED values (0.771 and 0.651), indicating good drug-likeness.

**DILI:** Ligand A (23.575) has a significantly lower DILI risk than Ligand B (35.983). This is a substantial advantage.

**BBB:** Ligand B (80.729) has a much higher BBB penetration percentile than Ligand A (41.218). This is *critical* for a CNS target like DRD2.

**Caco-2 Permeability:** Ligand A (-5.108) has a negative value, which is concerning. Ligand B (-4.543) is also negative, but less so. Both suggest poor intestinal absorption, but the scale is unclear.

**Aqueous Solubility:** Ligand A (-2.152) has slightly better solubility than Ligand B (-4.609).

**hERG Inhibition:** Ligand A (0.237) has a lower hERG inhibition liability than Ligand B (0.931), indicating a lower risk of cardiotoxicity.

**Microsomal Clearance:** Ligand A (-7.928) has a much lower (better) microsomal clearance than Ligand B (100.388), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (-10.13) has a longer half-life than Ligand B (31.809).

**P-gp Efflux:** Ligand A (0.012) has significantly lower P-gp efflux liability than Ligand B (0.612), which is beneficial for CNS exposure.

**Binding Affinity:** Both ligands have comparable binding affinities (-7.4 kcal/mol and -7.0 kcal/mol). The difference is less than the 1.5 kcal/mol threshold.

**Overall Assessment:**

Ligand A excels in most ADME properties (DILI, metabolic stability, P-gp efflux, hERG) and has a more favorable TPSA. Ligand B's primary advantage is its significantly higher BBB penetration. However, the substantial drawbacks of Ligand B in terms of DILI, metabolic stability, and P-gp efflux outweigh its BBB advantage. While BBB is crucial, a compound that is rapidly metabolized and has a high risk of liver injury is unlikely to be a viable drug candidate. Ligand A, despite its lower BBB score, presents a more balanced and promising profile.

Output:
0
2025-04-17 05:54:24,147 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (367.45 and 365.543 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (90.38) is slightly above the optimal <90 for CNS targets, but still reasonable. Ligand B (71.09) is well within the desired range.

**logP:** Ligand A (1.391) is within the optimal 1-3 range. Ligand B (3.787) is at the higher end of the optimal range, but still acceptable.

**H-Bond Donors/Acceptors:** Ligand A (HBD=3, HBA=7) and Ligand B (HBD=2, HBA=4) both have reasonable numbers of H-bond donors and acceptors, well below the thresholds of 5 and 10, respectively.

**QED:** Both ligands have good QED scores (A: 0.621, B: 0.805), indicating good drug-like properties.

**DILI:** Ligand A (44.668) has a lower DILI risk than Ligand B (51.997), both are acceptable, but A is preferred.

**BBB:** This is crucial for a CNS target like DRD2. Ligand B (78.209) has a significantly better BBB penetration score than Ligand A (44.591). This is a major advantage for Ligand B.

**Caco-2 Permeability:** Ligand A (-5.342) has a negative Caco-2 value, which is concerning. Ligand B (-4.749) also has a negative value, but is slightly better.

**Aqueous Solubility:** Ligand A (-1.848) has better aqueous solubility than Ligand B (-5.867).

**hERG Inhibition:** Ligand A (0.235) has a lower hERG inhibition liability than Ligand B (0.545), which is favorable.

**Microsomal Clearance:** Ligand A (11.642) has a lower microsomal clearance, indicating better metabolic stability, than Ligand B (78.878).

**In vitro Half-Life:** Ligand A (36.565) has a significantly longer in vitro half-life than Ligand B (-1.881).

**P-gp Efflux:** Ligand A (0.046) has much lower P-gp efflux liability than Ligand B (0.247), which is beneficial for CNS penetration.

**Binding Affinity:** Ligand B (-8.5 kcal/mol) has a significantly stronger binding affinity than Ligand A (-6.9 kcal/mol). This is a substantial advantage, potentially outweighing some ADME drawbacks.

**Overall Assessment:**

Ligand B excels in binding affinity and BBB penetration, the two most critical factors for a CNS-targeting GPCR. While it has some drawbacks in metabolic stability (high Cl_mic, short t1/2), P-gp efflux, and solubility, the strong binding affinity and good BBB penetration are likely to be more impactful for *in vivo* efficacy. Ligand A has better ADME properties (lower Cl_mic, longer t1/2, lower P-gp efflux, better solubility, lower DILI, lower hERG) but its significantly weaker binding affinity is a major concern. The difference in binding affinity (>1.5 kcal/mol) is substantial enough to favor Ligand B.

Output:
1
2025-04-17 05:54:24,147 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (368.478 and 358.427 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (75.19) is better than Ligand B (84.22). For CNS targets, we want TPSA <= 90, both are within this range, but A is closer to the optimal value.

**3. logP:** Ligand A (2.35) is optimal (1-3), while Ligand B (0.802) is slightly low, potentially hindering permeation.

**4. H-Bond Donors:** Ligand A (1) is preferable to Ligand B (0). Fewer HBDs generally improve permeability.

**5. H-Bond Acceptors:** Ligand A (5) is better than Ligand B (7). Lower HBA is generally preferred for CNS penetration.

**6. QED:** Both ligands have acceptable QED values (0.836 and 0.758, both > 0.5).

**7. DILI:** Ligand A (42.109) has a lower DILI risk than Ligand B (72.043), indicating a safer profile.

**8. BBB:** Ligand A (79.837) has a slightly better BBB penetration percentile than Ligand B (74.098). Both are good, but A is closer to the desirable >70 threshold.

**9. Caco-2 Permeability:** Ligand A (-4.951) is better than Ligand B (-5.16). Higher values indicate better absorption.

**10. Aqueous Solubility:** Ligand A (-3.185) is better than Ligand B (-2.353). Higher solubility is generally preferred.

**11. hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.366 and 0.144).

**12. Microsomal Clearance:** Ligand A (18.346) has a lower microsomal clearance than Ligand B (39.367), suggesting better metabolic stability.

**13. In vitro Half-Life:** Ligand A (13.556) has a longer half-life than Ligand B (-11.757).

**14. P-gp Efflux:** Ligand A (0.132) has lower P-gp efflux liability than Ligand B (0.2). Lower efflux is crucial for CNS exposure.

**15. Binding Affinity:** Both ligands have excellent binding affinities (-8.8 and -8.5 kcal/mol). The difference (0.3 kcal/mol) is not substantial enough to outweigh the ADME advantages of Ligand A.

**Overall Assessment:**

Ligand A consistently outperforms Ligand B across most ADME properties crucial for a CNS-targeting GPCR ligand. It has better TPSA, logP, HBD/HBA counts, DILI risk, BBB penetration, Caco-2 permeability, solubility, metabolic stability, half-life, and P-gp efflux. While both have strong binding affinities, Ligand A's superior ADME profile makes it the more promising drug candidate.

Output:
1
2025-04-17 05:54:24,148 - INFO - Reasoning:

Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the acceptable range (200-500 Da). Ligand A (361.397 Da) is slightly lower, which could be advantageous for permeability.

**TPSA:** Ligand A (110.45) is better than Ligand B (34.59). For CNS targets, TPSA should be <=90, so Ligand B is significantly better in this regard.

**logP:** Ligand A (0.278) is quite low, potentially hindering membrane permeability. Ligand B (4.354) is higher, approaching the upper limit, but still acceptable.

**H-Bond Donors/Acceptors:** Ligand A has 3 HBD and 9 HBA, while Ligand B has 0 HBD and 4 HBA. Both are within acceptable limits, but Ligand B's lower HBD count is often preferred for BBB penetration.

**QED:** Both ligands have reasonable QED values (A: 0.541, B: 0.468), indicating good drug-like properties.

**DILI:** Ligand A (57.658) has a higher DILI risk than Ligand B (11.71). This is a significant advantage for Ligand B.

**BBB:** Ligand B (87.476) has a much better BBB percentile than Ligand A (68.282). This is *critical* for a CNS target like DRD2.

**Caco-2 Permeability:** Ligand A (-5.288) and Ligand B (-4.867) both have negative values, which is unusual and suggests poor permeability.

**Aqueous Solubility:** Both ligands have poor aqueous solubility (-2.696 and -3.823 respectively).

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.63 and 0.854 respectively).

**Microsomal Clearance:** Ligand B (73.34) has a much higher microsomal clearance than Ligand A (10.321), indicating faster metabolism and potentially lower exposure.

**In vitro Half-Life:** Ligand A (-17.938) has a negative half-life, which is not possible and indicates a problem with the data or the molecule. Ligand B (34.181) has a reasonable half-life.

**P-gp Efflux:** Ligand A (0.002) has very low P-gp efflux, which is good for CNS penetration. Ligand B (0.632) has moderate P-gp efflux.

**Binding Affinity:** Both ligands have very similar binding affinities (-7.4 and -7.3 kcal/mol). The difference is negligible.

**Overall Assessment:**

Ligand B is the stronger candidate. While its logP is slightly higher, its significantly better BBB penetration, lower DILI risk, and more reasonable half-life outweigh the drawbacks. Ligand A's extremely low logP and impossible half-life are major concerns. The similar binding affinities make the ADME properties the deciding factors.

Output:
1
2025-04-17 05:54:24,148 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (357.401 and 348.399 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (80.32) is significantly better than Ligand B (99.85). For CNS targets, we want TPSA <= 90, and A is comfortably within that range, while B is close to the upper limit.

**logP:** Both ligands have good logP values (1.932 and 1.532), falling within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Both have 2 HBDs, which is acceptable. Ligand A has 4 HBAs, and Ligand B has 5. Both are within the acceptable limit of <=10.

**QED:** Both ligands have similar QED values (0.662 and 0.6), indicating good drug-likeness.

**DILI:** Ligand A (38.387) has a lower DILI risk than Ligand B (47.034), which is preferable. Both are below the 60 threshold, indicating acceptable risk.

**BBB:** This is a critical parameter for a CNS target like DRD2. Ligand A has a significantly higher BBB percentile (73.672) compared to Ligand B (51.803). A value >70 is desirable, and A is closer to that target.

**Caco-2 Permeability:** Both have negative Caco-2 values (-4.606 and -4.953), which is unusual and suggests poor permeability. However, these values are on a log scale and are difficult to interpret without knowing the base of the log.

**Aqueous Solubility:** Both have negative solubility values (-2.886 and -1.949), which is also unusual and suggests poor solubility. Again, the scale is unknown.

**hERG:** Both ligands have very low hERG inhibition liability (0.355 and 0.129), which is excellent.

**Microsomal Clearance:** Ligand A (43.908) has a higher microsomal clearance than Ligand B (12.269), indicating lower metabolic stability. This is a disadvantage for Ligand A.

**In vitro Half-Life:** Ligand B (-6.272) has a more negative half-life, which is unusual and suggests a very short half-life. Ligand A (37.166) is more favorable.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.106 and 0.109), which is good for CNS penetration.

**Binding Affinity:** Ligand B (-8.2 kcal/mol) has a slightly better binding affinity than Ligand A (-7.9 kcal/mol), although the difference is small (0.3 kcal/mol).

**Overall Assessment:**

Considering the GPCR-specific priorities, Ligand A is the more promising candidate. The significantly better BBB penetration (73.672 vs. 51.803) and lower TPSA (80.32 vs. 99.85) are crucial for CNS drug development. While Ligand A has a higher microsomal clearance, the superior BBB and TPSA outweigh this drawback. The slightly better affinity of Ligand B is not enough to compensate for its poorer CNS penetration properties.

Output:
1
2025-04-17 05:54:24,148 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (348.491 and 353.463 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (76.02) is significantly better than Ligand B (101.73). For CNS targets, we want TPSA <= 90, and Ligand A is comfortably within this range, while Ligand B is slightly above.

**3. logP:** Ligand A (2.549) is optimal (1-3), while Ligand B (0.954) is a bit low, potentially hindering permeation.

**4. H-Bond Donors:** Both ligands have 2 HBD, which is within the acceptable limit of <= 5.

**5. H-Bond Acceptors:** Both ligands have 4 HBA, also within the acceptable limit of <= 10.

**6. QED:** Both ligands have QED values above 0.6, indicating good drug-like properties. Ligand A (0.72) is slightly better than Ligand B (0.603).

**7. DILI:** Both ligands have very similar and low DILI risk (12.834 and 12.718 percentile), indicating minimal liver injury potential.

**8. BBB:** Ligand A (63.125) is better than Ligand B (58.24), although both are below the ideal >70 for CNS targets. However, given the other parameters, a slight advantage here is beneficial.

**9. Caco-2 Permeability:** Ligand A (-5.122) is better than Ligand B (-5.393), indicating better intestinal absorption.

**10. Aqueous Solubility:** Ligand A (-1.93) is better than Ligand B (-1.609), suggesting better solubility.

**11. hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.318 and 0.226), which is excellent.

**12. Microsomal Clearance:** Ligand B (-4.416) has a negative value, which is *better* than Ligand A (35.811) in this context, indicating lower clearance and greater metabolic stability.

**13. In vitro Half-Life:** Ligand B (-12.754) has a much longer half-life than Ligand A (-5.402), which is a significant advantage.

**14. P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.097 and 0.022). Ligand B is slightly better.

**15. Binding Affinity:** Both ligands have comparable binding affinities (-8.0 and -7.9 kcal/mol), which are both excellent and meet the criteria of < -7.0 kcal/mol. The difference is negligible.

**Overall Assessment:**

Ligand A excels in TPSA, logP, solubility, and Caco-2 permeability, all crucial for CNS penetration. Ligand B, however, demonstrates superior metabolic stability (lower Cl_mic, longer half-life) and slightly better P-gp efflux. Considering the GPCR-specific priorities, the slightly better BBB and logP of Ligand A, combined with acceptable metabolic stability, make it a more promising candidate. While the longer half-life of Ligand B is attractive, the lower logP and higher TPSA are more concerning for CNS targets.

Output:
0
2025-04-17 05:54:24,148 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (384.248 Da) is slightly higher than Ligand B (365.876 Da), but both are acceptable.

**TPSA:** Ligand A (78.87) is better than Ligand B (29.54) for CNS penetration, being closer to the <90 A^2 target. Ligand B is exceptionally low, which could be a concern for binding interactions.

**logP:** Ligand A (0.401) is below the optimal 1-3 range, potentially hindering membrane permeability. Ligand B (4.447) is above the optimal range, potentially causing solubility issues and off-target effects.

**H-Bond Donors/Acceptors:** Ligand A has 2 HBD and 4 HBA, which are reasonable. Ligand B has 0 HBD and 2 HBA, which is also acceptable.

**QED:** Both ligands have similar, good QED values (0.65 and 0.668), indicating good drug-like properties.

**DILI:** Ligand A (35.479) has a slightly higher DILI risk than Ligand B (28.655), but both are below the 40 threshold and considered low risk.

**BBB:** Ligand B (96.937) has a significantly better BBB penetration score than Ligand A (64.831). This is a critical advantage for a CNS target like DRD2.

**Caco-2 Permeability:** Ligand A (-4.987) has poor Caco-2 permeability, while Ligand B (-4.278) is slightly better, but still poor.

**Aqueous Solubility:** Ligand A (-0.986) has slightly better solubility than Ligand B (-5.416), but both are very poor.

**hERG Inhibition:** Ligand A (0.474) has a lower hERG inhibition risk than Ligand B (0.902), which is preferable.

**Microsomal Clearance:** Ligand A (-13.206) has much lower microsomal clearance (better metabolic stability) than Ligand B (104.609).

**In vitro Half-Life:** Ligand A (-20.833) has a longer in vitro half-life than Ligand B (34.401).

**P-gp Efflux:** Ligand A (0.018) has much lower P-gp efflux liability than Ligand B (0.77), which is highly desirable for CNS penetration.

**Binding Affinity:** Ligand B (-7.5 kcal/mol) has a stronger binding affinity than Ligand A (-8.5 kcal/mol). This is a significant advantage, potentially outweighing some ADME drawbacks.

**Overall Assessment:**

Ligand B excels in BBB penetration and binding affinity, which are paramount for a CNS GPCR target. However, its high logP and P-gp efflux liability are concerns. Ligand A has better metabolic stability, lower P-gp efflux, and lower hERG risk, but suffers from poor BBB penetration and a weaker binding affinity.

Despite Ligand B's drawbacks, the significantly better BBB penetration and stronger binding affinity are crucial for DRD2 targeting. The higher logP can potentially be addressed through structural modifications, but improving BBB penetration is often more challenging. The better affinity of Ligand B (-7.5 kcal/mol) is also a substantial advantage.

Output:
1
2025-04-17 05:54:24,149 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (343.402 and 364.471 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (48.72) is excellent, well below the 90 Angstroms threshold for CNS targets. Ligand B (87.58) is higher, but still acceptable, though less ideal for CNS penetration.

**3. logP:** Ligand A (3.155) is optimal. Ligand B (1.482) is on the lower side, potentially hindering membrane permeability.

**4. H-Bond Donors:** Both ligands have acceptable HBD counts (1 and 2 respectively), well within the limit of 5.

**5. H-Bond Acceptors:** Ligand A (3) is good. Ligand B (7) is higher, but still within the acceptable limit of 10.

**6. QED:** Both ligands have good QED values (0.911 and 0.807), indicating good drug-like properties.

**7. DILI:** Ligand A (51.028) has a lower DILI risk than Ligand B (63.707), which is preferable.

**8. BBB:** This is a critical parameter for a CNS target like DRD2. Ligand A (90.19) has a significantly higher BBB penetration percentile than Ligand B (62.97). This is a major advantage for Ligand A.

**9. Caco-2 Permeability:** Ligand A (-4.752) has a lower Caco-2 permeability than Ligand B (-4.91), which is less desirable.

**10. Aqueous Solubility:** Ligand A (-3.646) has better solubility than Ligand B (-1.984).

**11. hERG Inhibition:** Both ligands have low hERG inhibition risk (0.818 and 0.562).

**12. Microsomal Clearance:** Both have similar microsomal clearance rates (40.625 and 44.941).

**13. In vitro Half-Life:** Both ligands have comparable in vitro half-lives (51.337 and 53.516).

**14. P-gp Efflux:** Ligand A (0.363) has lower P-gp efflux liability than Ligand B (0.054), which is preferable for CNS exposure.

**15. Binding Affinity:** Ligand A (-10.5 kcal/mol) has a significantly stronger binding affinity than Ligand B (-8.2 kcal/mol). This is a substantial advantage, potentially outweighing minor ADME drawbacks.

**Overall Assessment:**

Ligand A is the stronger candidate. It excels in key areas for CNS GPCR targets: TPSA, BBB penetration, P-gp efflux, and, crucially, binding affinity. While Ligand B has slightly better Caco-2 permeability, the superior BBB, lower DILI, lower P-gp efflux, and significantly stronger binding affinity of Ligand A make it the more promising drug candidate. The difference in binding affinity is substantial (>1.5 kcal/mol).

Output:
1
2025-04-17 05:54:24,149 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the guidelines and GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (365.5 & 346.5 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Both ligands (71.53 & 76.02) are below the 90 A^2 threshold for CNS targets, which is good.

**3. logP:** Both ligands (2.346 & 2.565) are within the optimal 1-3 range.

**4. H-Bond Donors:** Ligand A (1) is preferable to Ligand B (2) as lower HBDs generally improve permeability.

**5. H-Bond Acceptors:** Both ligands (A: 5, B: 4) are below the 10 threshold.

**6. QED:** Ligand A (0.805) has a better QED score than Ligand B (0.675), indicating a more drug-like profile.

**7. DILI:** Both ligands have low DILI risk (33.773 & 32.493 percentile), which is favorable.

**8. BBB:** Both ligands have similar BBB penetration (64.482 & 64.444 percentile). While not exceeding the desirable >70% for CNS targets, they are reasonably good.

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.06 & -5.061), which is unusual and problematic. This suggests very poor permeability.

**10. Aqueous Solubility:** Both ligands have very poor aqueous solubility (-2.039 & -2.303). This is a significant drawback.

**11. hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.221 & 0.136).

**12. Microsomal Clearance:** Ligand A (49.022 mL/min/kg) has lower clearance than Ligand B (59.223 mL/min/kg), suggesting better metabolic stability.

**13. In vitro Half-Life:** Ligand A (1.447 hours) has a shorter half-life than Ligand B (4.289 hours). This is a negative for Ligand A.

**14. P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.154 & 0.171), which is good for CNS penetration.

**15. Binding Affinity:** Ligand B (-8.5 kcal/mol) has a slightly better binding affinity than Ligand A (-8.1 kcal/mol). This 0.4 kcal/mol difference is significant.

**Overall Assessment:**

Despite the similar BBB penetration, Ligand B is slightly favored due to its superior binding affinity (-8.5 vs -8.1 kcal/mol) and longer half-life (4.289 vs 1.447 hours). However, both ligands suffer from very poor Caco-2 permeability and aqueous solubility, which are major concerns. The slightly better affinity and half-life of Ligand B outweigh the slightly better QED and lower clearance of Ligand A.

Output:
1
2025-04-17 05:54:24,149 - INFO - Reasoning:

Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (346.475 and 357.841 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (67.23) is better than Ligand B (58.22). For CNS targets, we want TPSA <= 90, both are well within this range, but A is slightly higher.

**3. logP:** Ligand A (1.883) is optimal (1-3), while Ligand B (4.034) is pushing the upper limit. High logP can lead to solubility issues and off-target interactions.

**4. H-Bond Donors:** Both ligands have 1 HBD, which is acceptable (<=5).

**5. H-Bond Acceptors:** Ligand A has 4 HBA, and Ligand B has 3. Both are within the acceptable range (<=10).

**6. QED:** Ligand A (0.909) has a significantly better QED score than Ligand B (0.464), indicating a more drug-like profile.

**7. DILI:** Ligand A (20.9%) has a much lower DILI risk than Ligand B (69.717%). This is a significant advantage for Ligand A.

**8. BBB:** Ligand A (71.539%) has a better BBB penetration score than Ligand B (60.76%). This is *critical* for a CNS target like DRD2.

**9. Caco-2 Permeability:** Ligand A (-4.717) is better than Ligand B (-5.344). Higher values are better, so a less negative number is preferred.

**10. Aqueous Solubility:** Ligand A (-1.216) is better than Ligand B (-4.281). Higher values are better.

**11. hERG Inhibition:** Ligand A (0.228) has a lower hERG inhibition liability than Ligand B (0.809), indicating a lower risk of cardiotoxicity.

**12. Microsomal Clearance:** Ligand B (86.205) has a higher clearance than Ligand A (46.94). Lower clearance is preferred for metabolic stability.

**13. In vitro Half-Life:** Ligand B (44.911) has a longer half-life than Ligand A (-3.203). Longer half-life is generally desirable.

**14. P-gp Efflux:** Ligand A (0.064) has lower P-gp efflux than Ligand B (0.843). Lower efflux is preferred for CNS exposure.

**15. Binding Affinity:** Both ligands have very similar binding affinities (-9.1 and -8.8 kcal/mol). The difference is not substantial enough to outweigh the other significant differences.

**Overall Assessment:**

Ligand A is clearly the superior candidate. It has a better QED score, significantly lower DILI risk, better BBB penetration, better solubility, lower hERG inhibition, and lower P-gp efflux. While Ligand B has a slightly longer half-life, the other advantages of Ligand A, particularly its CNS penetration and safety profile, make it the more promising drug candidate for a CNS target like DRD2. The similar binding affinities make the ADME/Tox differences the deciding factors.

Output:
0
2025-04-17 05:54:24,150 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (350.375 and 348.487 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (113.77) is better than Ligand B (78.43). Both are below the 140 A^2 threshold for oral absorption and, importantly, below the 90 A^2 threshold desirable for CNS targets. Ligand B is significantly better here.

**3. logP:** Ligand A (-0.534) is below the optimal 1-3 range, potentially hindering permeation. Ligand B (2.439) is within the optimal range. This is a significant advantage for Ligand B.

**4. H-Bond Donors:** Ligand A (2) and Ligand B (3) are both acceptable, being less than 5.

**5. H-Bond Acceptors:** Ligand A (6) and Ligand B (3) are both acceptable, being less than 10.

**6. QED:** Both ligands have similar QED values (0.667 and 0.69), indicating good drug-like properties.

**7. DILI:** Ligand A (52.191) has a lower DILI risk than Ligand B (20.9), which is a positive attribute.

**8. BBB:** Ligand A (65.839) has a better BBB penetration percentile than Ligand B (44.979). This is a crucial factor for a CNS target like DRD2.

**9. Caco-2 Permeability:** Ligand A (-5.003) has a worse Caco-2 permeability than Ligand B (-4.717), but both are negative and therefore poor.

**10. Aqueous Solubility:** Ligand A (-1.161) has better solubility than Ligand B (-3.182).

**11. hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.076 and 0.174).

**12. Microsomal Clearance:** Ligand A (9.029) has a lower microsomal clearance than Ligand B (50.25), indicating better metabolic stability.

**13. In vitro Half-Life:** Ligand A (-36.321) has a much longer in vitro half-life than Ligand B (-9.025). This is a significant advantage.

**14. P-gp Efflux:** Both ligands have similar P-gp efflux liability (0.008 and 0.143), indicating low efflux.

**15. Binding Affinity:** Both ligands have similar binding affinity (-8.0 and -8.4 kcal/mol).

**Overall Assessment:**

While Ligand A has advantages in BBB penetration, DILI, metabolic stability, and half-life, Ligand B has a much better logP value, which is a critical factor for GPCRs. The significantly better logP of Ligand B suggests it will have better membrane permeability and target engagement. The difference in logP outweighs the advantages of Ligand A, especially considering both ligands have comparable binding affinities.

Output:
1
2025-04-17 05:54:24,150 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (341.455 and 342.443 Da) fall comfortably within the ideal 200-500 Da range.

**TPSA:** Ligand A (62.3) is slightly higher than Ligand B (58.44). Both are below the 90 A^2 threshold desirable for CNS targets, which is good.

**logP:** Ligand A (2.825) is optimal, while Ligand B (1.134) is a bit low. A logP below 1 can sometimes hinder permeation, though not always a dealbreaker.

**H-Bond Donors/Acceptors:** Ligand A has 1 HBD and 3 HBA, while Ligand B has 0 HBD and 4 HBA. Both are within acceptable limits (<=5 HBD and <=10 HBA).

**QED:** Ligand A (0.865) has a better QED score than Ligand B (0.774), indicating a more drug-like profile.

**DILI:** Ligand A (32.261) has a significantly lower DILI risk than Ligand B (50.33). This is a substantial advantage.

**BBB:** Both ligands have excellent BBB penetration (Ligand A: 70.958, Ligand B: 72.625), exceeding the >70% threshold for CNS targets.

**Caco-2 Permeability:** Both have negative Caco-2 values which is unusual and suggests a potential issue with the data. However, the negative values are close, so this isn't a major differentiator.

**Aqueous Solubility:** Both ligands have negative solubility values, which is also unusual. Again, the values are close, so it isn't a major differentiator.

**hERG:** Both ligands have very low hERG inhibition liability (Ligand A: 0.221, Ligand B: 0.242), which is excellent.

**Microsomal Clearance:** Ligand A (51.336) has a higher microsomal clearance than Ligand B (26.879), suggesting lower metabolic stability. This is a disadvantage for Ligand A.

**In vitro Half-Life:** Ligand B (-23.896) has a significantly longer in vitro half-life than Ligand A (12.893). This is a significant advantage for Ligand B.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (Ligand A: 0.027, Ligand B: 0.17), which is favorable for CNS exposure.

**Binding Affinity:** Ligand B (-8.4 kcal/mol) has a slightly better binding affinity than Ligand A (-7.8 kcal/mol). While both are excellent, the 0.6 kcal/mol difference is noteworthy.

**Overall Assessment:**

Ligand B is the stronger candidate. While Ligand A has a better QED and lower DILI risk, Ligand B's superior binding affinity, significantly better metabolic stability (lower Cl_mic, longer t1/2), and slightly better logP outweigh these advantages. For a GPCR target in the CNS, metabolic stability and affinity are critical. The similar BBB penetration and low P-gp efflux for both ligands are positive.



Output:
1
2025-04-17 05:54:24,150 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (349.41 and 344.415 Da) fall comfortably within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (91.81) is better than Ligand B (98.32). Both are below the 140 A^2 threshold for oral absorption, and reasonably close to the 90 A^2 target for CNS penetration, but A is preferable.

**3. logP:** Both ligands have good logP values (1.609 and 1.158), falling within the optimal 1-3 range.

**4. H-Bond Donors:** Both have 3 HBD, which is acceptable.

**5. H-Bond Acceptors:** Both have 4 HBA, which is acceptable.

**6. QED:** Both ligands have good QED scores (0.676 and 0.775), indicating good drug-like properties.

**7. DILI:** Both ligands have acceptable DILI risk (58.434 and 52.695), below the concerning threshold of 60.

**8. BBB:** This is a critical parameter for a CNS target like DRD2. Ligand A has a significantly better BBB penetration percentile (47.926) compared to Ligand B (20.396). This is a major advantage for Ligand A.

**9. Caco-2 Permeability:** Both have negative Caco-2 values (-5.406 and -5.186), which is unusual and suggests poor permeability. This is a concern for both, but doesn't necessarily disqualify them if other properties are strong.

**10. Aqueous Solubility:** Both have negative solubility values (-2.829 and -2.639), indicating poor aqueous solubility. This is a concern for both, but can be mitigated through formulation strategies.

**11. hERG Inhibition:** Both ligands show very low hERG inhibition risk (0.42 and 0.275), which is excellent.

**12. Microsomal Clearance:** Ligand B (1.292) has significantly lower microsomal clearance than Ligand A (13.278), suggesting better metabolic stability. This is a significant advantage for Ligand B.

**13. In vitro Half-Life:** Ligand A (6.434) has a slightly better in vitro half-life than Ligand B (-0.589), but both are relatively short.

**14. P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.05 and 0.015), which is favorable for CNS penetration.

**15. Binding Affinity:** Ligand B (-8.1 kcal/mol) has a slightly better binding affinity than Ligand A (-7.9 kcal/mol). While the difference is small (0.2 kcal/mol), it is still a positive for Ligand B.

**Overall Assessment:**

While Ligand B has better metabolic stability (lower Cl_mic) and slightly better affinity, Ligand A's significantly superior BBB penetration (47.926 vs 20.396) is the deciding factor for a CNS-targeting drug. The small affinity difference can potentially be optimized later in the drug discovery process. The poor Caco-2 and solubility are concerns for both, but are less critical than BBB penetration for a CNS target.

Output:
1
2025-04-17 05:54:24,150 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (350.503 and 348.447 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (60.85) is significantly better than Ligand B (76.46). For CNS targets, we want TPSA <= 90, and A is comfortably within this range, while B is approaching the upper limit.

**3. logP:** Both ligands have good logP values (2.425 and 1.29), falling within the optimal 1-3 range.

**4. H-Bond Donors:** Both have 1 HBD, which is acceptable.

**5. H-Bond Acceptors:** Ligand A has 3 HBAs, and Ligand B has 5. Both are below the threshold of 10.

**6. QED:** Ligand A (0.847) has a higher QED than Ligand B (0.595), indicating a more drug-like profile.

**7. DILI:** Ligand A (8.104) has a much lower DILI risk than Ligand B (36.409). This is a significant advantage.

**8. BBB:** Both ligands have excellent BBB penetration (71.733 and 71.268), exceeding the desirable threshold of 70%.

**9. Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and suggests poor permeability. However, the scale isn't specified, so it's hard to interpret.

**10. Aqueous Solubility:** Both have negative solubility values, which is also unusual and suggests poor solubility. Again, the scale is unclear.

**11. hERG Inhibition:** Both ligands show low hERG inhibition risk (0.492 and 0.381).

**12. Microsomal Clearance:** Ligand A (48.407) has higher microsomal clearance than Ligand B (26.072), indicating faster metabolism and potentially lower in vivo exposure.

**13. In vitro Half-Life:** Ligand B (0.784) has a slightly longer in vitro half-life than Ligand A (-8.522).

**14. P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.053 and 0.048), which is favorable for CNS penetration.

**15. Binding Affinity:** Ligand B (-7.6 kcal/mol) has a slightly better binding affinity than Ligand A (-8.4 kcal/mol). While A is stronger, the difference is not substantial enough to overcome other weaknesses.

**Overall Assessment:**

Ligand A is the better candidate. While Ligand B has slightly better binding affinity, Ligand A excels in crucial ADME properties: lower DILI risk, better TPSA, and a higher QED score. The faster clearance of Ligand A is a concern, but the significant improvements in safety (DILI) and drug-likeness (QED, TPSA) outweigh this drawback, especially given the already good BBB penetration for both compounds.

Output:
1
2025-04-17 05:54:24,151 - INFO - Reasoning:

Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands are within the acceptable range (200-500 Da). Ligand A (346.431 Da) is slightly preferred due to being closer to the ideal range.

**2. TPSA:** Ligand A (85.25) is excellent for CNS penetration, being well below 90. Ligand B (43.43) is also good, but less optimal.

**3. logP:** Ligand A (0.634) is a bit low, potentially hindering permeability. Ligand B (4.069) is at the upper end of the optimal range, potentially causing solubility issues, but acceptable.

**4. H-Bond Donors:** Ligand A (2) is good. Ligand B (0) is also acceptable.

**5. H-Bond Acceptors:** Ligand A (5) is good. Ligand B (6) is also acceptable.

**6. QED:** Ligand A (0.838) is excellent. Ligand B (0.625) is still acceptable, but less drug-like.

**7. DILI:** Ligand A (38.813) has a very low DILI risk. Ligand B (23.575) is also very low risk.

**8. BBB:** Ligand A (49.787) is borderline for good CNS penetration. Ligand B (76.541) is excellent for BBB penetration, a crucial factor for DRD2.

**9. Caco-2:** Both ligands have negative Caco-2 values, which is unusual and suggests potential issues with intestinal absorption prediction. However, we'll proceed with caution.

**10. Solubility:** Both ligands have negative solubility values, indicating poor aqueous solubility. This is a concern for both, but might be more problematic for Ligand B given its higher logP.

**11. hERG:** Ligand A (0.192) has a very low hERG risk. Ligand B (0.825) has a slightly elevated hERG risk, but still relatively low.

**12. Cl_mic:** Ligand A (8.528) has a lower microsomal clearance, suggesting better metabolic stability. Ligand B (61.295) has a significantly higher clearance, indicating faster metabolism.

**13. t1/2:** Ligand A (4.878) has a shorter half-life. Ligand B (50.832) has a much longer half-life, which is desirable.

**14. Pgp:** Ligand A (0.031) has very low P-gp efflux, which is excellent for CNS exposure. Ligand B (0.497) has moderate P-gp efflux.

**15. Binding Affinity:** Ligand B (-7.2 kcal/mol) has a significantly stronger binding affinity than Ligand A (-9.2 kcal/mol). This is a substantial advantage.

**Overall Assessment:**

Ligand B clearly wins on binding affinity and BBB penetration, both critical for a CNS-targeting GPCR like DRD2. The longer half-life is also a significant benefit. While Ligand B has a higher logP and slightly higher Pgp efflux, the substantial affinity advantage and excellent BBB penetration outweigh these concerns. Ligand A has better metabolic stability and lower Pgp efflux, but its weaker binding and lower BBB penetration are significant drawbacks. The negative solubility and Caco-2 values are concerning for both, but can be addressed during formulation.

Output:
1
2025-04-17 05:54:24,151 - INFO - Batch 237 complete. Total preferences: 3792
2025-04-17 05:54:24,151 - INFO - Processing batch 238/512...
2025-04-17 05:55:05,512 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 drug candidates, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (368.543 and 367.812 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (66.48) is significantly better than Ligand B (93.09). For CNS targets, TPSA should be <= 90, so Ligand A is preferable.

**3. logP:** Both ligands have acceptable logP values (3.098 and 1.768, respectively), falling within the 1-3 optimal range.

**4. H-Bond Donors:** Both have 1 HBD, which is good.

**5. H-Bond Acceptors:** Ligand A has 3 HBA, and Ligand B has 4. Both are within the acceptable limit of <=10.

**6. QED:** Both ligands have high QED scores (0.814 and 0.858), indicating good drug-like properties.

**7. DILI:** Ligand A (43.079) has a lower DILI risk than Ligand B (55.332), both are acceptable but A is better.

**8. BBB:** Ligand A (77.2) has a significantly better BBB penetration percentile than Ligand B (68.127).  A value >70 is desirable for CNS targets, and A is closer to this threshold.

**9. Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and suggests poor permeability. However, the scale is not specified, so it's difficult to interpret.

**10. Aqueous Solubility:** Both have negative solubility values, also unusual. Again, the scale is unspecified.

**11. hERG Inhibition:** Both ligands show low hERG inhibition liability (0.458 and 0.401), which is good.

**12. Microsomal Clearance:** Ligand B (-22.736) has a much lower (better) microsomal clearance than Ligand A (35.502). This indicates greater metabolic stability for Ligand B.

**13. In vitro Half-Life:** Ligand B (-8.383) has a longer in vitro half-life than Ligand A (23.562). This is a significant advantage for Ligand B.

**14. P-gp Efflux:** Both ligands have low P-gp efflux liability (0.329 and 0.048), which is favorable for CNS penetration. Ligand B is better.

**15. Binding Affinity:** Ligand A (-8.3 kcal/mol) has a slightly better binding affinity than Ligand B (-7.1 kcal/mol). A difference of >1.5 kcal/mol is considered significant, and this difference is present here.

**Overall Assessment:**

While Ligand B has superior metabolic stability (lower Cl_mic, longer t1/2) and P-gp efflux, Ligand A excels in TPSA and BBB penetration, both critical for CNS targets like DRD2. The slightly better binding affinity of Ligand A is also a plus. Considering the GPCR-specific priorities, the better TPSA and BBB of Ligand A outweigh the metabolic advantages of Ligand B.

Output:
1
2025-04-17 05:55:05,512 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (359.86 and 355.42 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (63.25) is significantly better than Ligand B (92.79). For CNS targets, TPSA should be <= 90, so Ligand A is preferable.

**logP:** Ligand A (4.27) is slightly higher than the optimal range (1-3), but still potentially acceptable. Ligand B (3.375) is within the optimal range. However, given DRD2 is a CNS target, a slightly higher logP isn't a major concern if other properties are favorable.

**H-Bond Donors/Acceptors:** Both ligands have 2 HBD and a reasonable number of HBA (4 for A, 6 for B), satisfying the guidelines.

**QED:** Both ligands have QED values above 0.7, indicating good drug-likeness.

**DILI:** Ligand A (63.63) has a moderate DILI risk, while Ligand B (92.98) has a significantly higher risk. This favors Ligand A.

**BBB:** Ligand A (71.38) has a good BBB penetration percentile, exceeding the 70% threshold for CNS targets. Ligand B (50.52) is below this threshold, which is a major drawback for a CNS-targeting drug.

**Caco-2 Permeability:** Both have negative values, which is unusual and suggests poor permeability. However, the scale is not specified, so it's hard to interpret.

**Aqueous Solubility:** Both ligands have very poor aqueous solubility (-5.13 and -4.73 respectively). This is a concern, but can potentially be addressed with formulation strategies.

**hERG Inhibition:** Ligand A (0.769) has a lower hERG risk than Ligand B (0.318), which is preferable.

**Microsomal Clearance:** Ligand A (60.66) has a higher clearance than Ligand B (40.62). Lower clearance is better, so Ligand B is slightly favored here.

**In vitro Half-Life:** Ligand A (116.13) has a much longer half-life than Ligand B (-2.39). This is a significant advantage for Ligand A.

**P-gp Efflux:** Ligand A (0.623) has a lower P-gp efflux liability than Ligand B (0.241), which is beneficial for CNS penetration.

**Binding Affinity:** Ligand A (-9.1 kcal/mol) has a significantly stronger binding affinity than Ligand B (-8.5 kcal/mol). This is a crucial advantage, potentially outweighing some of the ADME drawbacks.

**Overall Assessment:**

Ligand A is clearly the more promising candidate. It has superior BBB penetration, a much longer half-life, stronger binding affinity, lower DILI risk, and lower P-gp efflux. While its logP is slightly higher and clearance is slightly higher than Ligand B, the substantial advantages in CNS penetration and binding affinity outweigh these minor drawbacks. Both have poor solubility, but this is a formulation challenge rather than a fundamental flaw.

Output:
1
2025-04-17 05:55:05,513 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (338.426 and 344.419 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (45.05) is excellent, well below the 90 A^2 threshold for CNS targets. Ligand B (101.8) is higher, but still potentially acceptable, though less ideal.

**logP:** Ligand A (4.549) is slightly high, potentially leading to solubility issues or off-target interactions. Ligand B (0.923) is quite low, which could hinder membrane permeability and CNS penetration.

**H-Bond Donors/Acceptors:** Ligand A (1 HBD, 3 HBA) is favorable. Ligand B (2 HBD, 6 HBA) is also acceptable, though slightly higher in HBA count.

**QED:** Both ligands have similar QED values (0.84 and 0.811), indicating good drug-likeness.

**DILI:** Ligand A (28.538) has a much lower DILI risk than Ligand B (56.146), a significant advantage.

**BBB:** Ligand A (77.278) has a significantly better BBB percentile than Ligand B (32.687). This is *critical* for a CNS target like DRD2.

**Caco-2 Permeability:** Ligand A (-4.601) has poor Caco-2 permeability, while Ligand B (-5.345) is also poor.

**Aqueous Solubility:** Ligand A (-4.722) has poor aqueous solubility, while Ligand B (-2.344) is slightly better.

**hERG Inhibition:** Ligand A (0.955) has a slightly higher hERG risk than Ligand B (0.056), which is a significant advantage for B.

**Microsomal Clearance:** Ligand A (45.323) has higher microsomal clearance than Ligand B (18.394), suggesting lower metabolic stability.

**In vitro Half-Life:** Ligand A (25.156) has a longer half-life than Ligand B (15.38), which is a positive attribute.

**P-gp Efflux:** Ligand A (0.482) has lower P-gp efflux than Ligand B (0.017), which is favorable for CNS penetration.

**Binding Affinity:** Both ligands have very similar and strong binding affinities (-9.1 and -8.9 kcal/mol). The difference is not substantial enough to outweigh other factors.

**Overall Assessment:**

Ligand A excels in BBB penetration, DILI risk, P-gp efflux, and in vitro half-life. However, it suffers from high logP, poor Caco-2 permeability and aqueous solubility, and higher microsomal clearance. Ligand B has a better hERG profile and slightly better solubility, but its BBB penetration is very poor, and it has a higher DILI risk.

Given the importance of BBB penetration for a CNS target like DRD2, and the significant difference in this parameter between the two ligands, **Ligand A is the more promising candidate**, despite its other drawbacks. The high logP and poor solubility could potentially be addressed through formulation strategies or further chemical modifications. The strong binding affinity is maintained in both.



Output:
0
2025-04-17 05:55:05,513 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, considering the provided guidelines and GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (348.49 and 349.43 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (71.34) is better than Ligand B (75.01). Both are below the 90 A^2 threshold desirable for CNS targets, but A is closer to the optimal range.

**logP:** Ligand A (3.819) is within the optimal 1-3 range, while Ligand B (0.026) is significantly lower. This is a major drawback for Ligand B, as low logP can hinder membrane permeability and CNS penetration.

**H-Bond Donors/Acceptors:** Ligand A (2 HBD, 3 HBA) and Ligand B (1 HBD, 5 HBA) both fall within acceptable limits (<=5 HBD and <=10 HBA).

**QED:** Both ligands have good QED scores (0.667 and 0.814), indicating drug-like properties.

**DILI:** Ligand A (29.78) has a significantly lower DILI risk than Ligand B (17.64). Both are below the 40 threshold, but A is preferable.

**BBB:** Ligand A (69.45) has a better BBB percentile than Ligand B (51.18). While both are not optimal (>70), A is closer to the desired range for a CNS target.

**Caco-2 Permeability:** Ligand A (-4.718) has a slightly better (less negative) Caco-2 value than Ligand B (-4.615), suggesting slightly better intestinal absorption.

**Aqueous Solubility:** Ligand A (-3.882) has a slightly better solubility than Ligand B (-0.718).

**hERG:** Ligand A (0.725) has a better hERG profile than Ligand B (0.16).

**Microsomal Clearance:** Ligand A (78.37) has a higher (worse) microsomal clearance than Ligand B (4.115). This suggests Ligand B is more metabolically stable.

**In vitro Half-Life:** Ligand A (25.81) has a longer half-life than Ligand B (14.58).

**P-gp Efflux:** Ligand A (0.768) has better P-gp efflux liability than Ligand B (0.024). Lower P-gp efflux is favorable for CNS penetration.

**Binding Affinity:** Ligand A (-8.6 kcal/mol) has a significantly stronger binding affinity than Ligand B (-7.5 kcal/mol). This 1.1 kcal/mol difference is substantial and can outweigh some ADME drawbacks.

**Overall Assessment:**

Ligand A is the stronger candidate. While Ligand B has better metabolic stability (lower Cl_mic) and a slightly longer half-life, Ligand A excels in crucial areas for a CNS-targeting GPCR ligand: significantly better binding affinity, a more favorable logP, better BBB penetration, lower DILI risk, and better P-gp efflux. The slightly higher clearance of Ligand A is a concern, but the strong binding affinity and improved CNS properties are more critical for this target.

Output:
1
2025-04-17 05:55:05,513 - INFO - Reasoning:

Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight (MW):** Both ligands are within the ideal range (200-500 Da). Ligand A (339.395 Da) is slightly lower, which could be beneficial for permeability.

**2. TPSA:** Ligand A (54.78) is significantly better than Ligand B (84.14). For CNS targets, we want TPSA <= 90, and A is comfortably within this range, while B is approaching the upper limit.

**3. logP:** Both ligands have good logP values (A: 1.773, B: 2.293), falling within the optimal 1-3 range.

**4. H-Bond Donors (HBD):** Both are acceptable (A: 0, B: 1), well below the threshold of 5.

**5. H-Bond Acceptors (HBA):** Both are acceptable (A: 4, B: 7), with B being slightly higher but still under the 10 limit.

**6. QED:** Both have reasonable QED values (A: 0.856, B: 0.753), indicating good drug-like properties. A is slightly better.

**7. DILI:** Ligand A (60.682) has a higher DILI risk than Ligand B (40.403). This is a concern for A, as we prefer <40.

**8. BBB:** Ligand A (49.244) and Ligand B (46.336) are both below the desirable threshold of >70 for CNS targets. However, this is less critical if other properties are strongly favorable.

**9. Caco-2:** Both have negative values, which is unusual. Assuming these are percentile scores, lower values indicate poorer permeability. Both are poor, but A (-4.27) is slightly better than B (-5.093).

**10. Solubility:** Both have negative solubility values, again assuming percentile scores, indicating poor solubility. A (-2.789) is slightly better than B (-3.012).

**11. hERG:** Both have very low hERG inhibition liability (A: 0.352, B: 0.172), which is excellent.

**12. Cl_mic:** Ligand A (23.041) has significantly lower microsomal clearance than Ligand B (55.642), indicating better metabolic stability.

**13. t1/2:** Ligand A (-8.983) has a negative in vitro half-life, which is concerning. Ligand B (12.392) has a positive and reasonable half-life.

**14. Pgp:** Both have low Pgp efflux liability (A: 0.209, B: 0.156), which is good for CNS penetration.

**15. Binding Affinity:** Ligand A (-8.7 kcal/mol) has a significantly stronger binding affinity than Ligand B (-6.4 kcal/mol). This is a substantial advantage (>1.5 kcal/mol difference).

**Overall Assessment:**

Despite Ligand A's higher DILI risk and negative half-life, its significantly stronger binding affinity (-8.7 vs -6.4 kcal/mol) and lower TPSA, coupled with better metabolic stability (lower Cl_mic), make it the more promising candidate. The affinity difference is substantial enough to potentially overcome the DILI and half-life concerns, especially if further optimization can address those issues. The lower TPSA is also a significant advantage for CNS penetration. Ligand B's better DILI and half-life are outweighed by its weaker binding and higher TPSA.

Output:
1
2025-04-17 05:55:05,513 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B based on the provided guidelines, prioritizing GPCR-specific properties (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (347.463 and 349.475 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (80.12) is significantly better than Ligand B (91.32). For CNS targets, TPSA should be <= 90, so Ligand A is preferable.

**logP:** Both ligands have acceptable logP values (1.768 and 2.127, respectively), falling within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A (HBD=1, HBA=5) is slightly better than Ligand B (HBD=3, HBA=4) in terms of balancing solubility and permeability.

**QED:** Ligand A (0.777) has a higher QED score than Ligand B (0.637), indicating a more drug-like profile.

**DILI:** Ligand B (34.432) has a much lower DILI risk than Ligand A (53.509), which is a significant advantage.

**BBB:** Ligand A (59.403) has a better BBB penetration percentile than Ligand B (32.803). This is a *critical* factor for a CNS target like DRD2.

**Caco-2 Permeability:** Both have negative values, indicating poor permeability. However, Ligand B (-4.813) is slightly less negative than Ligand A (-5.11), suggesting marginally better permeability.

**Aqueous Solubility:** Both ligands have negative solubility values, indicating poor aqueous solubility. Ligand B (-2.54) is slightly better than Ligand A (-1.94).

**hERG Inhibition:** Both ligands have low hERG inhibition liability (0.195 and 0.373), which is good.

**Microsomal Clearance:** Ligand B (32.056) has lower microsomal clearance than Ligand A (51.636), indicating better metabolic stability.

**In vitro Half-Life:** Ligand B (24.116 hours) has a significantly longer half-life than Ligand A (-0.07 hours). This is a major advantage.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.189 and 0.115), which is good.

**Binding Affinity:** Both ligands have very similar and strong binding affinities (-8.4 and -8.1 kcal/mol). The difference is less than the 1.5 kcal/mol threshold.

**Overall Assessment:**

While Ligand B has advantages in DILI risk, metabolic stability (lower Cl_mic), and in vitro half-life, Ligand A is significantly better regarding BBB penetration and TPSA, which are crucial for CNS GPCR targets. The binding affinity is comparable. The slightly better QED of Ligand A also contributes to its favorability. The poor Caco-2 and solubility for both are concerning, but can be addressed with formulation strategies. Given the importance of CNS penetration for DRD2, Ligand A is the more promising candidate.

Output:
0
2025-04-17 05:55:05,513 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B based on the provided guidelines, prioritizing GPCR-specific properties (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Ligand A (355.429 Da) is within the ideal range (200-500 Da). Ligand B (153.181 Da) is below the preferred range, potentially impacting potency.

**TPSA:** Ligand A (52.65) is excellent for CNS penetration (<=90). Ligand B (66.48) is still reasonable, but less optimal.

**logP:** Ligand A (1.34) is within the optimal range (1-3). Ligand B (0.599) is slightly low, potentially hindering membrane permeability.

**H-Bond Donors/Acceptors:** Ligand A (HBD=1, HBA=3) is well within acceptable limits. Ligand B (HBD=3, HBA=3) is also acceptable.

**QED:** Both ligands have similar QED values (A: 0.635, B: 0.545), indicating good drug-likeness.

**DILI:** Ligand A (20.589) has a very low DILI risk. Ligand B (8.608) also has a low DILI risk.

**BBB:** Ligand A (88.445) has excellent BBB penetration potential, crucial for a CNS target. Ligand B (18.612) has very poor BBB penetration, a major drawback.

**Caco-2 Permeability:** Ligand A (-4.466) is poor, while Ligand B (-5.456) is even worse. Both are concerning, but less critical given the CNS target.

**Aqueous Solubility:** Ligand A (-1.675) is poor, while Ligand B (-0.057) is slightly better, but still not ideal.

**hERG Inhibition:** Ligand A (0.462) has a low risk of hERG inhibition. Ligand B (0.139) also has a low risk.

**Microsomal Clearance:** Ligand A (-6.673) indicates very slow clearance and high metabolic stability, which is excellent. Ligand B (-35.062) indicates very rapid clearance, a significant negative.

**In vitro Half-Life:** Ligand A (-1.07) suggests a long half-life. Ligand B (-0.194) suggests a very short half-life.

**P-gp Efflux:** Ligand A (0.025) has very low P-gp efflux, which is favorable for CNS penetration. Ligand B (0.012) also has low P-gp efflux, but slightly less than Ligand A.

**Binding Affinity:** Ligand A (-7.9 kcal/mol) has a significantly stronger binding affinity than Ligand B (-6.4 kcal/mol). This 1.5 kcal/mol difference is substantial and can outweigh some ADME drawbacks.

**Conclusion:**

Considering all factors, especially the GPCR-specific priorities, **Ligand A is the far more promising drug candidate.** Its excellent BBB penetration, strong binding affinity, low DILI risk, and favorable metabolic stability outweigh its moderate solubility and Caco-2 permeability. Ligand B's poor BBB penetration and rapid clearance are major liabilities that make it unlikely to succeed as a CNS drug, despite its acceptable safety profile and reasonable affinity.

Output:
1
2025-04-17 05:55:05,514 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (361.833 and 350.503 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (88.08) is better than Ligand B (58.64) as it is closer to the ideal <90 for CNS targets.

**logP:** Both ligands have good logP values (2.116 and 3.189), falling within the optimal 1-3 range. Ligand B is slightly higher, which could be a minor concern for solubility, but not a dealbreaker.

**H-Bond Donors/Acceptors:** Both have 1 HBD, which is good. Ligand A has 5 HBA, while Ligand B has 3. Both are within the acceptable limit of <=10.

**QED:** Both ligands have similar QED values (0.763 and 0.718), indicating good drug-likeness.

**DILI:** Ligand A (59.364) has a higher DILI risk than Ligand B (27.918). This is a significant negative for Ligand A.

**BBB:** Ligand B (71.229) has a substantially better BBB penetration percentile than Ligand A (46.84). This is *critical* for a CNS target like DRD2.

**Caco-2 Permeability:** Ligand A (-5.162) has worse Caco-2 permeability than Ligand B (-4.441), suggesting lower intestinal absorption.

**Aqueous Solubility:** Both ligands have poor aqueous solubility (-2.464 and -2.529). This is a concern, but can potentially be addressed with formulation strategies.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.488 and 0.199).

**Microsomal Clearance:** Ligand B (89.461) has a higher microsomal clearance than Ligand A (56.353), meaning it is less metabolically stable.

**In vitro Half-Life:** Ligand A (19.086) has a much longer in vitro half-life than Ligand B (0.972). This is a significant advantage for Ligand A.

**P-gp Efflux:** Ligand A (0.041) has significantly lower P-gp efflux liability than Ligand B (0.249), which is desirable for CNS penetration.

**Binding Affinity:** Ligand B (-9.0) has a significantly stronger binding affinity than Ligand A (-8.2). A 0.8 kcal/mol difference is substantial and can often outweigh minor ADME concerns.

**Overall Assessment:**

While Ligand A has a longer half-life and lower P-gp efflux, the significantly better BBB penetration (71.229 vs 46.84) and substantially stronger binding affinity (-9.0 vs -8.2) of Ligand B are decisive for a CNS-targeting GPCR. The lower DILI risk of Ligand B is also a major advantage. The higher metabolic clearance of Ligand B is a drawback, but potentially manageable.

Output:
1
2025-04-17 05:55:05,514 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 drug candidates, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (340.43 and 366.89 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (83.12) is better than Ligand B (54.71) as it is closer to the <90 A^2 threshold for CNS targets.

**logP:** Both ligands (3.033 and 3.534) are within the optimal 1-3 range. Ligand B is slightly higher, which *could* be a minor concern for solubility, but not a dealbreaker.

**H-Bond Donors/Acceptors:** Ligand A has 3 HBD and 3 HBA, while Ligand B has 1 HBD and 4 HBA. Both are within acceptable limits (<=5 HBD and <=10 HBA).

**QED:** Both ligands have good QED scores (0.724 and 0.885), indicating good drug-like properties.

**DILI:** Ligand A (55.18%) has a higher DILI risk than Ligand B (14.70%). This is a significant advantage for Ligand B.

**BBB:** Ligand B (83.64%) has a significantly better BBB penetration score than Ligand A (70.65%). This is *critical* for a CNS target like DRD2.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.854 and -4.91), which is unusual and suggests poor permeability. This is a concern for both.

**Aqueous Solubility:** Both ligands have negative solubility values (-4.11 and -3.694), indicating very poor aqueous solubility. This is a significant drawback for both.

**hERG Inhibition:** Ligand A (0.415) has a slightly higher hERG inhibition liability than Ligand B (0.677), meaning Ligand B is slightly safer from a cardiotoxicity perspective.

**Microsomal Clearance:** Ligand A (65.26) has higher microsomal clearance than Ligand B (17.92), indicating faster metabolism and potentially lower exposure. This favors Ligand B.

**In vitro Half-Life:** Ligand B (69.51) has a longer in vitro half-life than Ligand A (53.71), which is beneficial.

**P-gp Efflux:** Ligand A (0.062) has lower P-gp efflux than Ligand B (0.255), which is favorable for CNS penetration.

**Binding Affinity:** Ligand B (-7.8 kcal/mol) has a significantly stronger binding affinity than Ligand A (-9.7 kcal/mol). This is a major advantage for Ligand B, potentially outweighing some of its ADME drawbacks.

**Overall Assessment:**

While both ligands have significant solubility and permeability issues (negative Caco-2 and solubility values), Ligand B is the stronger candidate. Its superior BBB penetration, lower DILI risk, stronger binding affinity, and longer half-life outweigh the slightly higher logP and P-gp efflux. The substantial affinity difference (-7.8 vs -9.7 kcal/mol) is a key factor. Ligand A's lower P-gp efflux is a positive, but not enough to overcome the other deficiencies.

Output:
1
2025-04-17 05:55:05,514 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight (MW):** Both ligands are within the ideal range (200-500 Da). Ligand A (402.336 Da) is slightly higher than Ligand B (346.515 Da), but both are acceptable.

**2. TPSA:**  Both ligands have TPSA values below the 90 A^2 threshold for CNS targets. Ligand A (54.02 A^2) is higher than Ligand B (49.41 A^2), but both are good.

**3. logP:** Both ligands have logP values within the optimal range (1-3). Ligand A (4.592) is slightly higher than the preferred upper limit, potentially raising concerns about solubility and off-target effects. Ligand B (3.668) is better.

**4. H-Bond Donors (HBD):** Both are within the acceptable limit of <=5. Ligand A has 2, and Ligand B has 1.

**5. H-Bond Acceptors (HBA):** Both are within the acceptable limit of <=10. Both have 2.

**6. QED:** Both ligands have similar QED values (0.735 and 0.715), indicating good drug-like properties.

**7. DILI:** Ligand A (48.313) has a higher DILI risk than Ligand B (19.426). This is a significant advantage for Ligand B.

**8. BBB:** Both ligands have excellent BBB penetration (Ligand A: 74.758, Ligand B: 88.872). Ligand B is slightly better, which is crucial for a CNS target like DRD2.

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 values, which is unusual and requires further investigation. However, the values are similar (-4.983 and -4.832), so this doesn't differentiate them significantly.

**10. Aqueous Solubility:** Both ligands have negative solubility values, which is also unusual and suggests poor aqueous solubility. Again, the values are similar (-4.024 and -3.577).

**11. hERG Inhibition:** Both ligands have low hERG inhibition risk (0.66 and 0.556).

**12. Microsomal Clearance (Cl_mic):** Ligand A (58.285) has a higher clearance than Ligand B (64.851), indicating potentially lower metabolic stability.

**13. In vitro Half-Life:** Ligand B (-17.864) has a significantly *longer* in vitro half-life than Ligand A (90.895). This is a major advantage for Ligand B.

**14. P-gp Efflux:** Both ligands have low P-gp efflux liability (0.43 and 0.393).

**15. Binding Affinity:** Ligand A (-10.1 kcal/mol) has a significantly stronger binding affinity than Ligand B (-8.6 kcal/mol). This is a substantial advantage for Ligand A.

**Overall Assessment:**

While Ligand A has a superior binding affinity, Ligand B has a better safety profile (lower DILI), better BBB penetration, and significantly improved metabolic stability (longer half-life). The slightly higher logP of Ligand A is a concern. Given the GPCR-specific priorities, and the importance of CNS penetration and metabolic stability for DRD2, the advantages of Ligand B outweigh the affinity difference. A 1.5 kcal/mol difference in affinity can be overcome with optimization, but fixing a poor safety profile or low BBB penetration is much more challenging.

Output:
1
2025-04-17 05:55:05,514 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 drug candidates, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (357.881 and 366.506 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (21.7) is excellent, well below the 90 A^2 threshold for CNS targets. Ligand B (54.18) is higher but still reasonable, though less optimal for CNS penetration.

**logP:** Both ligands have good logP values (4.594 and 3.302), falling within the 1-3 range, suggesting good permeability. Ligand B is slightly better here.

**H-Bond Donors/Acceptors:** Ligand A (0 HBD, 3 HBA) and Ligand B (1 HBD, 6 HBA) both have acceptable numbers of H-bond donors and acceptors, contributing to drug-likeness.

**QED:** Both ligands have similar, good QED scores (0.781 and 0.779), indicating good overall drug-like properties.

**DILI:** Ligand A (51.493) has a slightly higher DILI risk than Ligand B (36.603), but both are below the concerning threshold of 60.

**BBB:** Both ligands exhibit excellent BBB penetration (Ligand A: 76.115, Ligand B: 82.862), which is crucial for CNS targets like DRD2. Ligand B is slightly better.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.65 and -4.697). This is unusual and suggests poor permeability, but these values are on a log scale and can be difficult to interpret without further context.

**Aqueous Solubility:** Both ligands have very poor aqueous solubility (-4.392 and -3.451). This is a significant concern for bioavailability.

**hERG Inhibition:** Both ligands show low hERG inhibition liability (0.77 and 0.607), which is favorable.

**Microsomal Clearance:** Ligand A (21.666) has a lower microsomal clearance than Ligand B (59.245), indicating better metabolic stability.

**In vitro Half-Life:** Ligand A (44.8 hours) has a much longer in vitro half-life than Ligand B (-7.103 hours). This is a significant advantage.

**P-gp Efflux:** Both ligands exhibit low P-gp efflux liability (0.724 and 0.57), which is good for CNS exposure.

**Binding Affinity:** Ligand B (-7.0 kcal/mol) has a significantly stronger binding affinity than Ligand A (-9.2 kcal/mol). This is a major advantage, potentially outweighing some of the ADME drawbacks.

**Overall Assessment:**

Ligand B has a superior binding affinity, better BBB penetration, and lower DILI risk. However, it has worse metabolic stability (higher Cl_mic) and a significantly shorter half-life. Ligand A has better metabolic stability and a longer half-life, but its binding affinity is considerably weaker. Given the importance of affinity for GPCRs, and the relatively good BBB penetration of both compounds, the stronger binding of Ligand B is the deciding factor. The poor solubility of both compounds would need to be addressed through formulation strategies.

Output:
1
2025-04-17 05:55:05,515 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B based on the provided guidelines, prioritizing GPCR-specific properties (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (378.807 Da) is slightly higher than Ligand B (354.447 Da), but both are acceptable.

**TPSA:** Ligand A (107.11) is higher than Ligand B (77.1). For CNS targets, TPSA should be <= 90. Ligand B is better here.

**logP:** Ligand A (1.486) and Ligand B (0.918) are both within the optimal range (1-3).

**H-Bond Donors:** Ligand A (4) is acceptable, while Ligand B (1) is even better.

**H-Bond Acceptors:** Ligand A (4) and Ligand B (5) are both acceptable (<=10).

**QED:** Both ligands have good QED scores (Ligand A: 0.576, Ligand B: 0.656), indicating drug-like properties.

**DILI:** Ligand A (61.691) has a higher DILI risk than Ligand B (29.934). Ligand B is significantly better.

**BBB:** Ligand B (72.237) has a significantly better BBB penetration score than Ligand A (48.972). This is a crucial factor for a CNS target like DRD2.

**Caco-2 Permeability:** Ligand A (-5.435) and Ligand B (-4.753) both have negative values, indicating poor permeability.

**Aqueous Solubility:** Both ligands have poor aqueous solubility (-2.913 and -2.25, respectively).

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.322 and 0.285, respectively).

**Microsomal Clearance:** Ligand A (-16.106) has a lower (better) microsomal clearance than Ligand B (49.046). This suggests better metabolic stability for Ligand A.

**In vitro Half-Life:** Ligand B (16.272) has a longer half-life than Ligand A (4.318).

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.035 and 0.042, respectively).

**Binding Affinity:** Ligand B (-7.3 kcal/mol) has a slightly better binding affinity than Ligand A (-8.2 kcal/mol). Although the difference is small, it's still a factor.

**Overall Assessment:**

Ligand B is the more promising candidate. While Ligand A has better metabolic stability (lower Cl_mic) and slightly better binding affinity, Ligand B excels in critical areas for a CNS-targeting GPCR: significantly better BBB penetration (72.237 vs 48.972), lower DILI risk (29.934 vs 61.691), and a more favorable TPSA (77.1 vs 107.11). The slightly longer half-life of Ligand B is also a plus. The small difference in binding affinity is outweighed by the superior ADME properties of Ligand B.

Output:
1
2025-04-17 05:55:05,515 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (358.498 and 374.522 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (49.85) is significantly better than Ligand B (69.64). For CNS targets, we want TPSA <= 90, and ideally closer to 60. Ligand A is much closer to this ideal.

**logP:** Ligand A (3.58) is slightly higher than Ligand B (2.126), both within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A (0 HBD, 3 HBA) is preferable to Ligand B (2 HBD, 4 HBA). Lower counts generally improve permeability.

**QED:** Both ligands have good QED scores (0.592 and 0.716), indicating good drug-like properties.

**DILI:** Ligand A (28.499) has a lower DILI risk than Ligand B (23.536), both are good.

**BBB:** Ligand A (96.549) has a substantially higher BBB penetration percentile than Ligand B (78.868). This is a *critical* advantage for a CNS target like DRD2.

**Caco-2 Permeability:** Ligand A (-4.481) is worse than Ligand B (-5.213). Lower values indicate lower permeability.

**Aqueous Solubility:** Ligand A (-3.236) is slightly better than Ligand B (-3.052).

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.777 and 0.556).

**Microsomal Clearance:** Ligand A (48.04) has a higher clearance than Ligand B (19.984), meaning it's less metabolically stable.

**In vitro Half-Life:** Ligand A (-3.513) has a shorter half-life than Ligand B (-0.969).

**P-gp Efflux:** Ligand A (0.366) has lower P-gp efflux liability than Ligand B (0.207), which is favorable for CNS penetration.

**Binding Affinity:** Ligand B (-7.6 kcal/mol) has a slightly better binding affinity than Ligand A (-7.0 kcal/mol). However, the difference (0.6 kcal/mol) isn't large enough to overcome the significant ADME advantages of Ligand A.

**Conclusion:**

Ligand A is the more promising candidate. While Ligand B has slightly better binding affinity and Caco-2 permeability, Ligand A excels in crucial properties for a CNS-targeting GPCR ligand: significantly better TPSA, substantially higher BBB penetration, lower P-gp efflux, and acceptable metabolic stability. The difference in binding affinity is not large enough to outweigh these advantages.

Output:
1
2025-04-17 05:55:05,515 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (356.463 and 361.833 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (96.89) is slightly higher than Ligand B (82.19). Both are below the 90 A^2 threshold desirable for CNS targets, which is good. Ligand B is preferable here.

**logP:** Ligand A (0.743) is a bit low, potentially hindering permeation. Ligand B (1.682) is better, falling within the optimal 1-3 range. Ligand B is preferable.

**H-Bond Donors:** Ligand A (3) is higher than Ligand B (1). While both are within the acceptable limit of 5, lower is generally preferred for better permeability. Ligand B is preferable.

**H-Bond Acceptors:** Ligand A (5) and Ligand B (4) are both within the acceptable limit of 10.

**QED:** Ligand B (0.898) has a significantly higher QED score than Ligand A (0.53), indicating a more drug-like profile. Ligand B is preferable.

**DILI:** Ligand A (18.573) has a much lower DILI risk than Ligand B (56.883). Ligand A is preferable.

**BBB:** Ligand B (32.765) has a slightly better BBB penetration percentile than Ligand A (28.655), although both are relatively low. This is a concern for a CNS target.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.201 and -5.068), which is unusual and suggests poor permeability. This is a significant drawback for both.

**Aqueous Solubility:** Both ligands have negative solubility values (-2.007 and -2.082), indicating very poor solubility. This is also a significant drawback for both.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.228 and 0.382).

**Microsomal Clearance:** Ligand A (30.694) has higher microsomal clearance than Ligand B (0.05), suggesting lower metabolic stability. Ligand B is preferable.

**In vitro Half-Life:** Ligand B (-22.221) has a much longer in vitro half-life than Ligand A (4.433). Ligand B is preferable.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.039 and 0.036), which is good for CNS penetration.

**Binding Affinity:** Ligand B (-7.6 kcal/mol) has a slightly better binding affinity than Ligand A (-7.3 kcal/mol). While the difference is small, it's enough to be considered.

**Overall Assessment:**

Ligand B is generally better across most key parameters, especially QED, logP, metabolic stability (Cl_mic, t1/2) and binding affinity. While Ligand A has a lower DILI risk, the other advantages of Ligand B outweigh this concern. The poor Caco-2 and solubility for both are problematic, but can potentially be addressed with formulation strategies. The BBB values are low for both, but Ligand B is slightly better. Given the GPCR-specific priorities and the overall profile, Ligand B is the more promising candidate.

Output:
1
2025-04-17 05:55:05,515 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (354.4 and 350.5 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (78.43) is higher than Ligand B (58.64). For CNS targets, we prefer TPSA <= 90, so both are acceptable, but B is better.

**3. logP:** Both ligands (2.759 and 3.045) are within the optimal 1-3 range.

**4. H-Bond Donors:** Ligand A has 3 HBD, while Ligand B has 1. Both are acceptable (<=5).

**5. H-Bond Acceptors:** Both ligands have 3 HBA, which is well within the acceptable range (<=10).

**6. QED:** Both ligands have similar QED values (0.761 and 0.732), indicating good drug-likeness.

**7. DILI:** Ligand A (31.06) has a slightly higher DILI risk than Ligand B (18.92), but both are below the 40 threshold and considered good.

**8. BBB:** Both ligands have excellent BBB penetration (74.56% and 78.52%), exceeding the desirable >70% threshold for CNS targets. Ligand B is slightly better.

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.883 and -4.508). This is unusual and suggests poor permeability. However, these values are on a scale where negative values are possible and don't necessarily preclude development.

**10. Aqueous Solubility:** Both ligands have negative solubility values (-3.566 and -2.308). Similar to Caco-2, this is not ideal but doesn't automatically disqualify them.

**11. hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.496 and 0.246).

**12. Microsomal Clearance:** Ligand A (47.39) has lower microsomal clearance than Ligand B (66.41), indicating better metabolic stability.

**13. In vitro Half-Life:** Ligand A (-27.57) has a much longer in vitro half-life than Ligand B (0.532). This is a significant advantage.

**14. P-gp Efflux:** Ligand A (0.061) has lower P-gp efflux than Ligand B (0.166), which is favorable for CNS exposure.

**15. Binding Affinity:** Ligand A (-9.0) has a significantly stronger binding affinity than Ligand B (-0.0). This is a crucial difference. A >1.5 kcal/mol advantage in binding affinity can often outweigh minor ADME drawbacks.

**Overall Assessment:**

Ligand A is the stronger candidate. While Ligand B has a slightly better TPSA and BBB, Ligand A's substantially superior binding affinity (-9.0 vs -0.0 kcal/mol) is the most important factor, especially for a GPCR target. Furthermore, Ligand A exhibits better metabolic stability (lower Cl_mic) and a longer half-life, and lower P-gp efflux. The negative Caco-2 and solubility values are concerning for both, but the strong binding affinity of Ligand A makes it more likely to be optimized to address these issues.

Output:
1
2025-04-17 05:55:05,515 - INFO - Reasoning:

Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (350.503 and 375.519 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (69.64) is slightly better than Ligand B (66.32) as both are below the 90 A^2 threshold desirable for CNS targets.

**logP:** Ligand B (3.248) is slightly higher than Ligand A (2.33), edging towards the upper limit of the optimal range (1-3). Ligand A is well within the optimal range.

**H-Bond Donors/Acceptors:** Ligand A (2 HBD, 3 HBA) is preferable to Ligand B (1 HBD, 6 HBA) as it has a lower number of HBA.

**QED:** Ligand B (0.865) has a significantly better QED score than Ligand A (0.547), indicating a more drug-like profile.

**DILI:** Ligand A (14.114) has a much lower DILI risk than Ligand B (65.568), which is a significant advantage.

**BBB:** Ligand A (45.832) has a lower BBB penetration percentile than Ligand B (49.787). While neither are above the desirable 70% threshold, B is slightly better.

**Caco-2 Permeability:** Ligand A (-4.702) has a worse Caco-2 permeability than Ligand B (-5.128). Lower values here indicate poorer permeability.

**Aqueous Solubility:** Ligand A (-2.45) has better aqueous solubility than Ligand B (-3.867).

**hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.462 and 0.396 respectively).

**Microsomal Clearance:** Ligand A (34.29) has a lower microsomal clearance than Ligand B (54.348), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (-15.637) has a longer in vitro half-life than Ligand B (-0.785).

**P-gp Efflux:** Ligand A (0.269) has lower P-gp efflux liability than Ligand B (0.207), which is favorable for CNS penetration.

**Binding Affinity:** Both ligands have the same binding affinity (-7.3 kcal/mol), which is excellent.

**Overall Assessment:**

While Ligand B has a slightly better QED and BBB penetration, Ligand A is significantly better in terms of DILI risk, metabolic stability (lower Cl_mic, longer t1/2), and P-gp efflux. The binding affinity is identical. Given the importance of minimizing toxicity (DILI) and maximizing CNS exposure (P-gp, metabolic stability) for a DRD2 ligand targeting CNS disorders, Ligand A is the more promising candidate. The slightly lower BBB penetration of A is less concerning than the higher DILI and P-gp efflux of B.



Output:
0
2025-04-17 05:55:05,516 - INFO - Batch 238 complete. Total preferences: 3808
2025-04-17 05:55:05,516 - INFO - Processing batch 239/512...
2025-04-17 05:55:45,608 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (340.467 Da) is slightly better positioned.

**TPSA:** Ligand A (50.36) is significantly better than Ligand B (83.55). For CNS targets, we want TPSA <= 90, and A is comfortably within that range, while B is approaching the upper limit.

**logP:** Ligand A (4.489) is higher than the optimal range (1-3), but still potentially acceptable. Ligand B (1.743) is at the lower end, which could hinder permeability.

**H-Bond Donors/Acceptors:** Ligand A (HBD=2, HBA=2) and Ligand B (HBD=1, HBA=4) both have reasonable numbers of H-bond donors and acceptors.

**QED:** Both ligands have acceptable QED values (A: 0.842, B: 0.703), indicating good drug-like properties.

**DILI:** Ligand A (49.477) has a slightly higher DILI risk than Ligand B (34.471), but both are below the concerning threshold of 60.

**BBB:** Ligand A (73.401) has a better BBB percentile than Ligand B (69.562). Both are reasonably good, but A is closer to the desirable >70 mark for CNS targets.

**Caco-2 Permeability:** Ligand A (-4.655) has a much worse Caco-2 permeability than Ligand B (-5.04). Lower values indicate poorer permeability.

**Aqueous Solubility:** Ligand A (-4.841) has worse aqueous solubility than Ligand B (-2.275). Lower values indicate poorer solubility.

**hERG Inhibition:** Ligand A (0.804) has a slightly higher hERG inhibition risk than Ligand B (0.247). Lower is better.

**Microsomal Clearance:** Ligand A (83.143) has a significantly higher microsomal clearance than Ligand B (12.243). Higher clearance means faster metabolism and lower exposure.

**In vitro Half-Life:** Ligand B (16.873) has a much longer in vitro half-life than Ligand A (-3.02). Longer half-life is generally preferred.

**P-gp Efflux:** Ligand A (0.287) has lower P-gp efflux liability than Ligand B (0.083). Lower efflux is better for CNS exposure.

**Binding Affinity:** Ligand B (-7.6 kcal/mol) has a better binding affinity than Ligand A (-8.8 kcal/mol). Although both are good, the 1.2 kcal/mol difference is significant.

**Overall Assessment:**

Ligand A excels in BBB penetration and P-gp efflux, but suffers from poor Caco-2 permeability, aqueous solubility, and high metabolic clearance. Ligand B has a significantly better binding affinity, longer half-life, and better solubility, but its TPSA is higher and its BBB penetration is slightly lower. Considering the GPCR-specific priorities, the binding affinity advantage of Ligand B is substantial enough to outweigh its slightly less favorable TPSA and BBB values. The longer half-life and better solubility are also significant advantages.

Output:
1
2025-04-17 05:55:45,608 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B based on the provided guidelines, prioritizing GPCR-specific properties (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (352.547 and 346.471 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (16.13) is excellent, well below the 90 A^2 threshold for CNS targets. Ligand B (69.64) is higher but still potentially acceptable, though less ideal.

**logP:** Ligand A (4.964) is slightly high, potentially leading to solubility issues or off-target effects. Ligand B (1.862) is within the optimal range of 1-3.

**H-Bond Donors/Acceptors:** Ligand A (0 HBD, 3 HBA) is favorable. Ligand B (2 HBD, 3 HBA) is also acceptable.

**QED:** Ligand A (0.776) has a good drug-like profile. Ligand B (0.495) is below the 0.5 threshold, indicating a less desirable overall drug-likeness.

**DILI:** Ligand A (24.428) has a very low DILI risk. Ligand B (6.32) also has a low DILI risk.

**BBB:** This is critical for a DRD2 ligand. Ligand A (96.433) has excellent BBB penetration potential. Ligand B (58.821) is significantly lower, which is a major concern for CNS activity.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.172 and -4.701), which is unusual and suggests poor permeability. However, these values are on a scale where negative values are possible, and their relative comparison is important.

**Aqueous Solubility:** Both ligands have negative solubility values (-3.612 and -1.972), indicating poor aqueous solubility.

**hERG Inhibition:** Both ligands have low hERG inhibition liability (0.928 and 0.211).

**Microsomal Clearance:** Both ligands have similar microsomal clearance values (21.784 and 21.541 mL/min/kg), suggesting comparable metabolic stability.

**In vitro Half-Life:** Ligand A (-19.495) has a more negative half-life, which is unusual and likely indicates a very short half-life. Ligand B (-11.198) also suggests a short half-life, but less so than Ligand A.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.719 and 0.016).

**Binding Affinity:** Both ligands have strong binding affinities (-9.8 and -8.1 kcal/mol). Ligand A is 1.7 kcal/mol more potent, which is a significant advantage.

**Overall Assessment:**

Ligand A is superior due to its excellent BBB penetration (96.433 vs 58.821), better QED score (0.776 vs 0.495), and significantly higher binding affinity (-9.8 vs -8.1 kcal/mol). While its logP is slightly high and solubility is poor, the strong affinity and BBB penetration are crucial for a CNS-targeting GPCR ligand like DRD2. The negative half-life is a concern, but could be addressed through structural modifications. Ligand B's lower BBB penetration is a major drawback, despite its more favorable logP.

Output:
1
2025-04-17 05:55:45,609 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (418.238 Da) is slightly higher than Ligand B (340.471 Da), but both are acceptable.

**2. TPSA:** Ligand A (70.67) is better than Ligand B (49.64) as it is closer to the ideal range for CNS targets (<=90).

**3. logP:** Both ligands have good logP values (A: 2.825, B: 3.022), falling within the optimal range of 1-3.

**4. H-Bond Donors:** Both ligands have acceptable HBD counts (A: 2, B: 1).

**5. H-Bond Acceptors:** Both ligands have acceptable HBA counts (A: 3, B: 4).

**6. QED:** Both ligands have high QED values (A: 0.794, B: 0.931), indicating good drug-like properties.

**7. DILI:** Ligand A (53.121) has a higher DILI risk than Ligand B (14.773). This is a significant drawback for Ligand A.

**8. BBB:** Both ligands have excellent BBB penetration (A: 84.529, B: 84.917), exceeding the desirable threshold of >70.

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 values, which is unusual and suggests poor permeability. However, these values are on a scale where negative values are possible, and a more negative value indicates lower permeability. Ligand A (-4.937) is slightly better than Ligand B (-5.054).

**10. Aqueous Solubility:** Both ligands have negative solubility values, which is also unusual. A more negative value indicates lower solubility. Ligand B (-2.684) is slightly better than Ligand A (-3.845).

**11. hERG Inhibition:** Both ligands have low hERG inhibition risk (A: 0.543, B: 0.825).

**12. Microsomal Clearance:** Ligand A (-20.294) has significantly lower (better) microsomal clearance than Ligand B (40.419), indicating greater metabolic stability.

**13. In vitro Half-Life:** Ligand A (-5.486) has a shorter in vitro half-life than Ligand B (-10.388).

**14. P-gp Efflux:** Both ligands have low P-gp efflux (A: 0.139, B: 0.272), which is favorable for CNS penetration.

**15. Binding Affinity:** Ligand A (-10.1 kcal/mol) has a significantly stronger binding affinity than Ligand B (-8.7 kcal/mol). This is a substantial advantage.

**Overall Assessment:**

While Ligand A has a higher DILI risk and a shorter half-life, its significantly stronger binding affinity (-10.1 vs -8.7 kcal/mol) and lower microsomal clearance are major advantages. The difference in binding affinity is large enough to potentially outweigh the DILI concerns, especially considering the excellent BBB penetration of both compounds. The slightly better TPSA of Ligand A also favors it.

Output:
1
2025-04-17 05:55:45,609 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (351.447 and 345.399 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (62.32) is excellent, well below the 90 A^2 threshold for CNS targets. Ligand B (107.53) is higher, but still potentially acceptable, though less ideal.

**logP:** Ligand A (-0.34) is a bit low, potentially hindering membrane permeability. Ligand B (0.728) is better, falling within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A (0 HBD, 5 HBA) is favorable. Ligand B (4 HBD, 4 HBA) is also reasonable.

**QED:** Ligand A (0.696) has a good drug-likeness score. Ligand B (0.411) is lower, indicating a less favorable overall drug-like profile.

**DILI:** Ligand A (29.391) has a very low DILI risk. Ligand B (42.342) is slightly higher, but still acceptable.

**BBB:** This is crucial for a CNS target. Ligand A (72.586) has a good BBB percentile. Ligand B (46.336) is significantly lower, raising concerns about CNS penetration.

**Caco-2 Permeability:** Ligand A (-4.515) is very poor. Ligand B (-5.042) is also poor.

**Aqueous Solubility:** Both ligands have very poor aqueous solubility (-0.189 and -2.499 respectively). This is a significant drawback.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.279 and 0.207).

**Microsomal Clearance:** Ligand A (7.943) has lower clearance, suggesting better metabolic stability. Ligand B (27.979) has much higher clearance.

**In vitro Half-Life:** Ligand A (3.987) has a short half-life. Ligand B (-4.396) has a negative half-life, which is not physically possible and likely indicates an issue with the data or model.

**P-gp Efflux:** Both ligands show very low P-gp efflux liability (0.036 and 0.043).

**Binding Affinity:** Ligand B (-7.8 kcal/mol) has significantly stronger binding affinity than Ligand A (0.0 kcal/mol). This is a major advantage.

**Overall Assessment:**

Ligand B has a significantly better binding affinity, which is the most important factor. However, its BBB penetration is considerably lower than Ligand A's, and its in vitro half-life is nonsensical. Ligand A has better BBB penetration and metabolic stability, but its binding affinity is very weak and Caco-2 permeability is poor. The poor solubility of both is a concern.

Despite the issues with Ligand B's half-life, the substantial difference in binding affinity is likely to outweigh the other drawbacks, *assuming* the half-life data is an error. The stronger binding increases the chance of achieving efficacy at lower doses, potentially mitigating some of the ADME issues. Ligand A's very weak binding makes it unlikely to be a viable candidate.

Output:
1
2025-04-17 05:55:45,609 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (353.467 and 349.435 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (98.14) is better than Ligand B (104.69). Both are below the 140 A^2 threshold for oral absorption, and closer to the <90 A^2 desired for CNS targets.

**logP:** Ligand A (2.389) is optimal (1-3). Ligand B (0.225) is quite low, potentially hindering permeation. This is a significant drawback for CNS penetration.

**H-Bond Donors/Acceptors:** Both have 2 HBD and 6 HBA, which are within acceptable limits.

**QED:** Ligand B (0.812) has a better QED score than Ligand A (0.629), indicating a more drug-like profile.

**DILI:** Ligand B (44.281) has a significantly lower DILI risk than Ligand A (63.397). This is a positive attribute for Ligand B.

**BBB:** Ligand A (71.772) has a slightly better BBB percentile than Ligand B (67.197), but both are reasonably good. A value >70 is preferable, and both are close.

**Caco-2 Permeability:** Ligand A (-4.849) shows better Caco-2 permeability than Ligand B (-5.216), suggesting better intestinal absorption.

**Aqueous Solubility:** Ligand B (-1.622) shows better aqueous solubility than Ligand A (-3.269).

**hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.136 and 0.208).

**Microsomal Clearance:** Ligand B (-9.059) has a significantly *lower* (better) microsomal clearance than Ligand A (89.697), indicating greater metabolic stability.

**In vitro Half-Life:** Ligand B (-2.023) has a longer in vitro half-life than Ligand A (-15.861).

**P-gp Efflux:** Ligand B (0.015) has a much lower P-gp efflux liability than Ligand A (0.103), which is crucial for CNS exposure.

**Binding Affinity:** Ligand B (-8.3 kcal/mol) has a slightly better binding affinity than Ligand A (-7.7 kcal/mol). While the difference is not huge, it's still a positive.

**Overall Assessment:**

Ligand B is the stronger candidate. While Ligand A has a slightly better BBB score and Caco-2 permeability, Ligand B excels in key areas: significantly lower DILI risk, substantially improved metabolic stability (lower Cl_mic, longer t1/2), lower P-gp efflux, better solubility, and slightly better binding affinity. The biggest drawback of Ligand A is its low logP, which could severely limit its ability to cross the blood-brain barrier. For a CNS target like DRD2, minimizing P-gp efflux and maximizing BBB penetration are critical, and Ligand B performs better in these areas.



Output:
1
2025-04-17 05:55:45,609 - INFO - Reasoning:

Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (350.503 and 367.881 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (67.43) is better than Ligand B (72.54). Both are below the 90 Angstrom threshold for CNS targets, but A is closer to the optimal range.

**3. logP:** Both ligands have good logP values (2.973 and 1.529), falling within the 1-3 range. Ligand A is slightly better.

**4. H-Bond Donors:** Ligand A (2) is slightly higher than Ligand B (1), but both are within the acceptable limit of 5.

**5. H-Bond Acceptors:** Ligand A (3) and Ligand B (4) are both within the acceptable limit of 10.

**6. QED:** Ligand B (0.875) has a significantly better QED score than Ligand A (0.496), indicating a more drug-like profile.

**7. DILI:** Ligand A (19.736) has a much lower DILI risk than Ligand B (30.787), which is a significant advantage.

**8. BBB:** Both ligands have reasonably good BBB penetration (64.986 and 68.67), but neither exceeds the desirable 70% threshold. Ligand B is slightly better.

**9. Caco-2 Permeability:** Ligand A (-4.871) has a worse Caco-2 permeability than Ligand B (-5.001). Lower values suggest poorer permeability.

**10. Aqueous Solubility:** Ligand A (-2.677) has slightly better aqueous solubility than Ligand B (-2.499).

**11. hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.28 and 0.286).

**12. Microsomal Clearance:** Ligand B (-5.823) has a *much* lower (better) microsomal clearance than Ligand A (46.966), suggesting greater metabolic stability.

**13. In vitro Half-Life:** Ligand B (-11.876) has a much longer in vitro half-life than Ligand A (13.021), which is a significant advantage.

**14. P-gp Efflux:** Both ligands have similar P-gp efflux liability (0.042 and 0.012).

**15. Binding Affinity:** Both ligands have excellent binding affinity (-7.8 and -7.9 kcal/mol), with Ligand B being slightly better.

**Overall Assessment:**

While Ligand B has a superior QED, metabolic stability (lower Cl_mic, longer t1/2), and slightly better affinity, Ligand A has a substantially lower DILI risk and better TPSA. Considering the GPCR-specific priorities, the slight advantage in BBB penetration for Ligand B is not enough to offset the significant DILI risk. The lower DILI risk of Ligand A is a crucial factor for a CNS drug candidate. Although Ligand B has better ADME properties overall, the DILI risk is a major concern.

Output:
0
2025-04-17 05:55:45,609 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (369.345 and 350.459 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (81.7) is slightly higher than Ligand B (78.87), but both are below the 90 A^2 threshold desirable for CNS targets.

**3. logP:** Ligand A (3.033) is optimal, while Ligand B (1.403) is on the lower side, potentially hindering permeation.

**4. H-Bond Donors:** Ligand A (1) is preferable to Ligand B (2) as fewer HBDs generally improve permeability.

**5. H-Bond Acceptors:** Ligand A (6) is preferable to Ligand B (4) as fewer HBAs generally improve permeability.

**6. QED:** Both ligands have similar, acceptable QED values (0.625 and 0.681, respectively).

**7. DILI:** Ligand A (98.759) has a very high DILI risk, which is a major concern. Ligand B (13.416) has a very low DILI risk, a significant advantage.

**8. BBB:** Ligand A (74.176) has a good BBB penetration percentile, while Ligand B (47.189) is considerably lower. This is a crucial factor for a CNS target like DRD2.

**9. Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and suggests a potential issue with the data or modeling. However, the magnitude is similar.

**10. Aqueous Solubility:** Both have negative solubility values, also unusual. Again, the magnitude is similar.

**11. hERG:** Ligand A (0.302) has a slightly higher hERG risk than Ligand B (0.099), but both are relatively low.

**12. Microsomal Clearance:** Ligand A (88.151) has a higher microsomal clearance than Ligand B (30.642), indicating lower metabolic stability.

**13. In vitro Half-Life:** Ligand A (26.822) has a longer half-life than Ligand B (1.171).

**14. P-gp Efflux:** Ligand A (0.367) has lower P-gp efflux liability than Ligand B (0.056), which is beneficial for CNS penetration.

**15. Binding Affinity:** Both ligands have very similar and strong binding affinities (-7.8 and -7.7 kcal/mol). The difference is negligible.

**Overall Assessment:**

Despite Ligand A's slightly better BBB and P-gp efflux, its extremely high DILI risk is a deal-breaker. The DILI risk for Ligand B is exceptionally low. While Ligand B's BBB penetration is lower, the significantly reduced toxicity profile outweighs this drawback. The slightly lower logP of Ligand B is a minor concern that could potentially be addressed through further optimization, but the DILI risk of Ligand A is a more fundamental issue.

Output:
1
2025-04-17 05:55:45,610 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (342.403 and 362.373 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (104.7) is slightly above the preferred <90 for CNS targets, while Ligand B (93.73) is closer to the ideal range.

**logP:** Ligand A (0.94) is a bit low, potentially hindering permeability. Ligand B (0.622) is even lower, raising similar concerns. Both are below the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A has 3 HBD and 5 HBA, which are acceptable. Ligand B has 2 HBD and 5 HBA, also acceptable.

**QED:** Both ligands have QED values (0.726 and 0.676) above 0.5, indicating good drug-like properties.

**DILI:** Ligand A (59.907) has a higher DILI risk than Ligand B (49.128), but both are reasonably acceptable.

**BBB:** This is a crucial factor for a CNS target like DRD2. Ligand B (74.796) has a significantly better BBB percentile than Ligand A (39.667). This is a major advantage for Ligand B.

**Caco-2 Permeability:** Ligand A (-5.551) and Ligand B (-4.982) both have negative Caco-2 values, which is unusual and suggests poor permeability.

**Aqueous Solubility:** Both ligands have very poor aqueous solubility (-2.763 and -1.981). This is a significant drawback.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.103 and 0.236).

**Microsomal Clearance:** Ligand A (-4.81) has a lower (better) microsomal clearance than Ligand B (23.208), indicating better metabolic stability.

**In vitro Half-Life:** Ligand A (6.873) has a longer half-life than Ligand B (3.189).

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.022 and 0.021).

**Binding Affinity:** Ligand A (-9.3 kcal/mol) has a slightly better binding affinity than Ligand B (-8.3 kcal/mol), a difference of 1 kcal/mol.

**Overall Assessment:**

While Ligand A has better affinity and metabolic stability, the significantly superior BBB penetration of Ligand B (74.8% vs 39.7%) is a decisive factor for a CNS-targeting drug. The slightly better affinity of Ligand A is unlikely to overcome the poor BBB penetration. Both have poor solubility and Caco-2 permeability, which would require formulation strategies.

Output:
1
2025-04-17 05:55:45,610 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (342.359 Da and 352.475 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (98.16) is slightly higher than Ligand B (89.87). Both are below the 140 A^2 threshold for oral absorption and reasonably close to the 90 A^2 target for CNS penetration, but Ligand B is preferable.

**3. logP:** Ligand A (0.698) is a bit low, potentially hindering permeation. Ligand B (1.194) is better, falling within the optimal 1-3 range.

**4. H-Bond Donors:** Ligand A (1) is better than Ligand B (3). Fewer HBDs generally improve permeability.

**5. H-Bond Acceptors:** Ligand A (7) is higher than Ligand B (4). Lower is better for permeability.

**6. QED:** Both ligands have similar QED values (0.749 and 0.693), indicating good drug-like properties.

**7. DILI:** Ligand A (77.317) has a significantly higher DILI risk than Ligand B (16.014). This is a major concern for Ligand A.

**8. BBB:** Ligand A (34.587) has a very poor BBB penetration percentile, making it unlikely to be effective for a CNS target like DRD2. Ligand B (22.606) is also low, but considerably better than Ligand A.

**9. Caco-2:** Both ligands have negative Caco-2 values (-4.915 and -5.065), which is unusual and suggests poor permeability. However, these values are on a scale where negative values are possible and don't necessarily disqualify a compound.

**10. Solubility:** Both ligands have negative solubility values (-2.84 and -1.77), which is also unusual. Similar to Caco-2, these values don't automatically disqualify the compounds.

**11. hERG:** Both ligands have very low hERG inhibition liability (0.248 and 0.102), which is excellent.

**12. Cl_mic:** Ligand A (2.449) has lower microsomal clearance than Ligand B (-1.741), suggesting better metabolic stability.

**13. t1/2:** Ligand B (10.281) has a significantly longer in vitro half-life than Ligand A (-3.543).

**14. Pgp:** Ligand A (0.086) has lower P-gp efflux liability than Ligand B (0.035), which is favorable for CNS exposure.

**15. Binding Affinity:** Ligand B (-8.3 kcal/mol) has a stronger binding affinity than Ligand A (-7.6 kcal/mol). This difference of 0.7 kcal/mol is substantial and can outweigh some ADME drawbacks.

**Overall Assessment:**

Ligand B is the superior candidate. While its BBB penetration is not ideal, it is significantly better than Ligand A's. Ligand B also exhibits a much lower DILI risk, a longer half-life, and a stronger binding affinity. Ligand A's poor BBB penetration and high DILI risk are major drawbacks that outweigh its slightly better metabolic stability and P-gp efflux profile. The stronger binding affinity of Ligand B is a critical advantage for a GPCR target.

Output:
1
2025-04-17 05:55:45,610 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (354.407 and 346.471 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (111.21) is borderline for CNS penetration, being slightly above the preferred <90 threshold. Ligand B (67.43) is well within the optimal range for CNS targets.

**logP:** Ligand A (-1.629) is quite low, potentially hindering membrane permeability. Ligand B (2.725) is within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A has 3 HBD and 5 HBA, acceptable values. Ligand B has 2 HBD and 3 HBA, also acceptable.

**QED:** Ligand A (0.561) has a good drug-likeness score. Ligand B (0.277) is below the 0.5 threshold, indicating a less favorable drug-like profile.

**DILI:** Both ligands have relatively low DILI risk (21.83 and 26.173, respectively), below the 40 threshold.

**BBB:** Ligand A (46.336) has a poor BBB penetration percentile. Ligand B (57.929) is better, but still not ideal (aim for >70).

**Caco-2 Permeability:** Both have negative Caco-2 values (-5.041 and -4.91), which is unusual and suggests poor permeability. This could be an artifact of the prediction method.

**Aqueous Solubility:** Both have negative solubility values (-0.446 and -3.888), also unusual and suggesting poor solubility. Again, this could be a prediction artifact.

**hERG:** Both ligands show low hERG inhibition liability (0.107 and 0.288), which is good.

**Microsomal Clearance:** Ligand A (-23.024) has a very low (and negative) microsomal clearance, suggesting high metabolic stability. Ligand B (10.527) has a moderate clearance.

**In vitro Half-Life:** Ligand A (1.054 hours) has a very short half-life. Ligand B (-2.24 hours) also has a short half-life, and the negative value is concerning.

**P-gp Efflux:** Both ligands show very low P-gp efflux liability (0.001 and 0.162), which is favorable for CNS penetration.

**Binding Affinity:** Ligand A (-7.1 kcal/mol) has a significantly stronger binding affinity than Ligand B (0.0 kcal/mol). This is a substantial advantage.

**Overall Assessment:**

Ligand A's primary drawback is its low logP and poor BBB penetration, coupled with a short half-life. However, its *much* stronger binding affinity (-7.1 kcal/mol) is a major advantage. Ligand B has a better logP and TPSA, but its QED is low, its binding affinity is very weak, and its half-life is also short.

Given the GPCR-specific priorities, and the importance of affinity for DRD2, the stronger binding of Ligand A outweighs its ADME liabilities *to a degree*. While the low logP and BBB are concerning, these could potentially be addressed through further structural modifications. The very weak binding of Ligand B makes it a less promising starting point, even with better TPSA and logP.

Output:
1
2025-04-17 05:55:45,610 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (350.459 and 354.401 Da) are within the ideal 200-500 Da range.

**TPSA:** Ligand A (67.87) is slightly higher than Ligand B (64.16), but both are below the 90 A^2 threshold desirable for CNS targets.

**logP:** Ligand A (1.622) is within the optimal 1-3 range. Ligand B (3.387) is at the higher end of optimal, but still acceptable.

**H-Bond Donors/Acceptors:** Ligand A has 1 HBD and 4 HBA, while Ligand B has 0 HBD and 5 HBA. Both are within acceptable limits (<=5 HBD and <=10 HBA).

**QED:** Both ligands have similar QED values (0.739 and 0.729), indicating good drug-likeness.

**DILI:** Ligand A (12.136) has a significantly lower DILI risk than Ligand B (43.66), which is a major advantage.

**BBB:** Ligand B (81.504) has a slightly better BBB penetration percentile than Ligand A (75.107), but both are above the desirable 70% threshold for CNS targets.

**Caco-2 Permeability:** Both have negative values (-4.722 and -4.592), which is unusual and suggests poor permeability. This is a concern for both.

**Aqueous Solubility:** Both ligands have very poor aqueous solubility (-2.046 and -4.071). This could pose formulation challenges.

**hERG Inhibition:** Ligand A (0.292) has a lower hERG inhibition liability than Ligand B (0.515), indicating a lower risk of cardiotoxicity.

**Microsomal Clearance:** Ligand B (71.714) has a higher microsomal clearance than Ligand A (32.467), suggesting lower metabolic stability.

**In vitro Half-Life:** Ligand B (15.85) has a slightly longer in vitro half-life than Ligand A (13.775).

**P-gp Efflux:** Ligand A (0.034) has significantly lower P-gp efflux liability than Ligand B (0.443), which is crucial for CNS penetration.

**Binding Affinity:** Both ligands have very similar and excellent binding affinities (-7.3 and -7.2 kcal/mol). The difference is negligible.

**Overall Assessment:**

While Ligand B has a slightly better BBB and half-life, Ligand A is significantly better in several critical areas: DILI risk, hERG inhibition, and especially P-gp efflux. The lower P-gp efflux for Ligand A is particularly important for a CNS target like DRD2. The solubility and Caco-2 permeability are poor for both, but these can potentially be addressed through formulation strategies. The lower DILI and hERG risks associated with Ligand A make it a safer candidate.

Output:
0
2025-04-17 05:55:45,610 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (354.495 and 348.407 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (81.75) is significantly better than Ligand B (120.12). For CNS targets, we want TPSA <= 90, so Ligand A is preferable.

**logP:** Ligand A (1.436) is within the optimal 1-3 range. Ligand B (-0.508) is below 1, which could hinder permeation. This favors Ligand A.

**H-Bond Donors/Acceptors:** Both have 2 HBDs, which is good. Ligand A has 3 HBAs, and Ligand B has 6. Lower HBA is generally preferred, making Ligand A slightly better.

**QED:** Both ligands have similar QED values (0.692 and 0.623), indicating good drug-likeness.

**DILI:** Ligand A (19.93) has a much lower DILI risk than Ligand B (30.942), which is a significant advantage.

**BBB:** Ligand A (69.252) has a better BBB percentile than Ligand B (38.852). While >70 is desirable, 69.252 is still reasonably good and much better than 38.852, crucial for a CNS target like DRD2.

**Caco-2 Permeability:** Ligand A (-4.761) and Ligand B (-5.455) both have negative values, which is unusual and suggests poor permeability. However, the scale isn't specified, so it's hard to interpret.

**Aqueous Solubility:** Both ligands have similar, very poor aqueous solubility (-1.642 and -1.579). This could pose formulation challenges.

**hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.424 and 0.074).

**Microsomal Clearance:** Ligand A (13.663) has a higher microsomal clearance than Ligand B (6.301), indicating faster metabolism and potentially lower *in vivo* exposure. This favors Ligand B.

**In vitro Half-Life:** Ligand B (32.844) has a much longer half-life than Ligand A (0.333), which is a significant advantage.

**P-gp Efflux:** Both ligands show very low P-gp efflux liability (0.006 and 0.007).

**Binding Affinity:** Ligand A (-7.4 kcal/mol) has a slightly better binding affinity than Ligand B (-7.2 kcal/mol). While the difference is small, it's still a positive for Ligand A.

**Overall Assessment:**

Ligand A is superior due to its significantly better TPSA, logP, DILI risk, and BBB penetration. While Ligand B has a better half-life and lower clearance, the CNS target necessitates prioritizing BBB and permeability characteristics, where Ligand A excels. The slightly better binding affinity of Ligand A further solidifies its advantage. The poor solubility of both is a concern but can be addressed with formulation strategies.



Output:
1
2025-04-17 05:55:45,611 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (344.411 and 368.821 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (71.78) is significantly better than Ligand B (93.62). For CNS targets, TPSA should be <=90, so Ligand A is preferable.

**logP:** Both ligands have acceptable logP values (1.134 and 1.623, respectively), falling within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Both have 1 HBD, which is good. Ligand B has 7 HBA, slightly higher than Ligand A's 4, but both are within the acceptable limit of <=10.

**QED:** Both ligands have similar QED values (0.786 and 0.761), indicating good drug-likeness.

**DILI:** Ligand A (29.43) has a much lower DILI risk than Ligand B (35.789), which is a significant advantage.

**BBB:** Ligand B (70.182) has a better BBB penetration percentile than Ligand A (53.936). This is a crucial factor for CNS targets like DRD2.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.645 and -4.59), which is unusual and suggests poor permeability. This is a concern for both.

**Aqueous Solubility:** Both ligands have negative solubility values (-1.208 and -2.723), indicating poor aqueous solubility. This is a concern for both.

**hERG Inhibition:** Both ligands show low hERG inhibition risk (0.161 and 0.345).

**Microsomal Clearance:** Ligand A (-7.657) has significantly lower (better) microsomal clearance than Ligand B (31.839), indicating better metabolic stability.

**In vitro Half-Life:** Ligand A (20.732 hours) has a better in vitro half-life than Ligand B (52.438 hours).

**P-gp Efflux:** Ligand A (0.042) has much lower P-gp efflux liability than Ligand B (0.195), which is beneficial for CNS penetration.

**Binding Affinity:** Ligand A (-8.4 kcal/mol) has a significantly stronger binding affinity than Ligand B (-6.3 kcal/mol). This is a major advantage, potentially outweighing some of the ADME drawbacks.

**Overall Assessment:**

Ligand A is superior due to its significantly better binding affinity, lower DILI risk, lower P-gp efflux, and better metabolic stability (lower Cl_mic). While Ligand B has a better BBB percentile, the substantial advantage in binding affinity and the other favorable ADME properties of Ligand A make it the more promising candidate. The poor Caco-2 and solubility for both are concerning, but can be addressed with formulation strategies. The strong binding affinity of Ligand A suggests it might be more potent and require lower doses, potentially mitigating some of the solubility issues.

Output:
0
2025-04-17 05:55:45,611 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (349.475 and 343.343 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (71.0) is excellent, well below the 90 A^2 threshold for CNS targets. Ligand B (104.08) is higher, but still potentially acceptable, though less ideal.

**logP:** Ligand A (2.475) is optimal (1-3). Ligand B (-1.454) is quite low, potentially hindering permeability. This is a significant drawback.

**H-Bond Donors/Acceptors:** Both ligands have 1 HBD, which is good. Ligand A has 4 HBA, and Ligand B has 6 HBA, both within the acceptable limit of 10.

**QED:** Both ligands have QED values above 0.7, indicating good drug-likeness.

**DILI:** Ligand A (16.092) has a much lower DILI risk than Ligand B (59.131). This is a substantial advantage for Ligand A.

**BBB:** Ligand A (70.26) has a good BBB percentile, exceeding the 70% threshold for CNS targets. Ligand B (23.11) has a very low BBB percentile, making CNS penetration unlikely. This is a critical disadvantage for Ligand B.

**Caco-2 Permeability:** Both have negative values, which is unusual and requires further investigation. However, the magnitude of negativity is similar.

**Aqueous Solubility:** Both have negative values, indicating poor solubility.

**hERG:** Both ligands have low hERG risk (0.129 and 0.192).

**Microsomal Clearance:** Ligand A (44.549) has higher clearance than Ligand B (-1.882), suggesting lower metabolic stability. However, the negative value for Ligand B is unusual and may indicate very high stability.

**In vitro Half-Life:** Ligand A (-12.862) has a negative half-life, which is not possible. Ligand B (25.793) has a reasonable half-life.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.086 and 0.002).

**Binding Affinity:** Both ligands have very strong binding affinities (-9.2 and -9.4 kcal/mol), with Ligand B being slightly better. However, the affinity difference is small and likely less important than the ADME differences.

**Overall Assessment:**

Ligand A is significantly better due to its superior BBB penetration, lower DILI risk, and optimal logP. While its microsomal clearance is higher and half-life is nonsensical, the CNS target profile is paramount. Ligand B's low logP and poor BBB penetration are major drawbacks for a CNS-targeting drug. The slightly better binding affinity of Ligand B is unlikely to overcome these significant ADME deficiencies.

Output:
1
2025-04-17 05:55:45,611 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (347.415 and 350.459 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (99.5) is slightly higher than Ligand B (89.87). Both are below the 140 threshold for oral absorption, and closer to the desirable <90 for CNS targets. Ligand B is preferable here.

**3. logP:** Both ligands have similar logP values (0.844 and 0.828), which are within the optimal range of 1-3.

**4. H-Bond Donors:** Ligand A has 1 HBD, while Ligand B has 3. Both are acceptable (<=5).

**5. H-Bond Acceptors:** Ligand A has 5 HBA, and Ligand B has 4. Both are within the acceptable range (<=10).

**6. QED:** Ligand A (0.718) has a higher QED than Ligand B (0.619), indicating a more drug-like profile.

**7. DILI:** Ligand A (30.71) has a significantly lower DILI risk than Ligand B (12.369), which is a substantial advantage.

**8. BBB:** This is a crucial parameter for CNS targets like DRD2. Ligand A (59.364) has a better BBB percentile than Ligand B (47.344), although neither is above the highly desirable >70.

**9. Caco-2 Permeability:** Ligand A (-4.696) has better Caco-2 permeability than Ligand B (-5.07), suggesting better intestinal absorption.

**10. Aqueous Solubility:** Ligand A (-2.148) has better aqueous solubility than Ligand B (-1.97), which is beneficial for formulation.

**11. hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.364 and 0.173), which is excellent.

**12. Microsomal Clearance:** Ligand A (29.684) has higher microsomal clearance than Ligand B (16.113), meaning it's metabolized faster. Ligand B is preferable here.

**13. In vitro Half-Life:** Ligand A (2.485) has a shorter half-life than Ligand B (-6.54), which is a disadvantage. Ligand B is preferable.

**14. P-gp Efflux:** Both ligands show low P-gp efflux liability (0.05 and 0.063).

**15. Binding Affinity:** Ligand A (-7.8 kcal/mol) has a slightly better binding affinity than Ligand B (-7.5 kcal/mol). While the difference is not huge, it's a positive for Ligand A.

**Overall Assessment:**

Ligand A has a better QED, lower DILI risk, better BBB penetration, better Caco-2 permeability, and better aqueous solubility. It also has slightly better binding affinity. Ligand B has better metabolic stability (lower Cl_mic) and a longer half-life. However, the advantages of Ligand A, especially the lower DILI and better BBB, outweigh the metabolic stability advantage of Ligand B for a CNS target. The affinity difference, while present, isn't large enough to overcome the other ADME benefits of Ligand A.

Output:
0
2025-04-17 05:55:45,611 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (347.503 and 342.483 Da) fall comfortably within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (52.65) is slightly higher than Ligand B (49.41), but both are below the 90 Angstroms threshold desirable for CNS targets.

**3. logP:** Both ligands have good logP values (2.182 and 3.03), falling within the optimal 1-3 range. Ligand B is slightly higher, which could be beneficial for membrane permeability.

**4. H-Bond Donors:** Both have 1 HBD, which is within the acceptable limit of <=5.

**5. H-Bond Acceptors:** Ligand A has 3 HBAs, and Ligand B has 2. Both are well below the 10 limit.

**6. QED:** Both ligands have similar QED values (0.829 and 0.806), indicating good drug-likeness.

**7. DILI:** Ligand A (7.445) has a significantly lower DILI risk than Ligand B (28.228). This is a major advantage for Ligand A.

**8. BBB:** Both ligands have excellent BBB penetration (71.966 and 75.107), exceeding the desirable >70 threshold for CNS targets. Ligand B is slightly better.

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.909 and -4.797). This is unusual and suggests poor permeability. However, these values are on a log scale and are likely representing very low permeability.

**10. Aqueous Solubility:** Both ligands have negative solubility values (-1.509 and -3.756), indicating very low aqueous solubility. This could pose formulation challenges.

**11. hERG Inhibition:** Both ligands show low hERG inhibition risk (0.466 and 0.39).

**12. Microsomal Clearance:** Ligand A (-6.566) has a much lower (better) microsomal clearance than Ligand B (56.859), suggesting greater metabolic stability.

**13. In vitro Half-Life:** Ligand A (-11.876) has a much longer in vitro half-life than Ligand B (-7.362), which is a significant advantage.

**14. P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.041 and 0.27), which is favorable for CNS exposure.

**15. Binding Affinity:** Ligand B (-8.1) has a slightly better binding affinity than Ligand A (-8.8). However, the difference is relatively small (0.7 kcal/mol).

**Overall Assessment:**

While Ligand B has slightly better BBB penetration and binding affinity, Ligand A is significantly better in terms of safety (DILI) and ADME properties (microsomal clearance, half-life). The small difference in binding affinity is likely outweighed by the substantial improvements in ADME/Tox for Ligand A. The poor Caco-2 and solubility for both are concerning, but these can potentially be addressed through formulation strategies. Given the CNS target and the importance of metabolic stability and minimizing off-target effects, Ligand A is the more promising candidate.

Output:
1
2025-04-17 05:55:45,612 - INFO - Batch 239 complete. Total preferences: 3824
2025-04-17 05:55:45,612 - INFO - Processing batch 240/512...
2025-04-17 05:56:27,020 - INFO - Reasoning:

Let's analyze Ligand A and Ligand B based on the provided guidelines, prioritizing GPCR-specific properties (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (346.431 and 346.515 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (95.16) is higher than the preferred <90 for CNS targets, while Ligand B (49.41) is well within the range. This is a significant advantage for Ligand B.

**logP:** Ligand A (1.321) is within the optimal 1-3 range. Ligand B (3.355) is at the higher end but still acceptable.

**H-Bond Donors/Acceptors:** Ligand A has 2 HBD and 4 HBA, both acceptable. Ligand B has 1 HBD and 2 HBA, also acceptable.

**QED:** Both ligands have similar QED scores (0.76 and 0.768), indicating good drug-likeness.

**DILI:** Ligand A (52.385) has a slightly higher DILI risk than Ligand B (23.653). Both are below the concerning threshold of 60, but lower is better.

**BBB:** This is a critical parameter for CNS targets. Ligand B (73.827) shows a significantly better BBB penetration percentile than Ligand A (57.929). This is a major advantage for Ligand B.

**Caco-2 Permeability:** Both have negative values, which is unusual. However, the magnitude is similar, and this isn't a decisive factor.

**Aqueous Solubility:** Both have negative values, which is unusual. However, the magnitude is similar, and this isn't a decisive factor.

**hERG:** Both ligands have low hERG inhibition liability (0.264 and 0.487), which is good.

**Microsomal Clearance:** Ligand A (28.056) has lower microsomal clearance than Ligand B (57.594), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (5.116) has a longer in vitro half-life than Ligand B (-2.164). This is a positive for Ligand A.

**P-gp Efflux:** Ligand A (0.052) has lower P-gp efflux than Ligand B (0.299), indicating better potential for CNS exposure.

**Binding Affinity:** Ligand B (-8.2 kcal/mol) has a slightly better binding affinity than Ligand A (-9.0 kcal/mol). While A is better, the difference is not substantial enough to outweigh the other factors.

**Overall Assessment:**

Ligand B is the more promising candidate. Its significantly better BBB penetration (73.827 vs 57.929) and lower TPSA (49.41 vs 95.16) are crucial advantages for a CNS-targeting GPCR ligand. While Ligand A has slightly better metabolic stability and P-gp efflux, the improved CNS penetration of Ligand B is more important. The binding affinity difference is relatively small.



Output:
1
2025-04-17 05:56:27,020 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (361.511 and 350.459 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (52.65) is significantly better than Ligand B (64.8). For CNS targets, we want TPSA <= 90, and ideally closer to 60. Ligand A is much closer to the ideal range.

**3. logP:** Both ligands (2.148 and 2.46) are within the optimal 1-3 range.

**4. H-Bond Donors:** Ligand A (1) is preferable to Ligand B (0). While both are acceptable, a single HBD can sometimes improve solubility without significantly impacting permeability.

**5. H-Bond Acceptors:** Ligand A (4) is preferable to Ligand B (5). Lower HBA is generally better for CNS penetration.

**6. QED:** Both ligands have reasonable QED values (0.874 and 0.721), indicating good drug-like properties.

**7. DILI:** Ligand A (19.271) has a significantly lower DILI risk than Ligand B (30.128). Lower is better, and Ligand A is well below the 40% threshold.

**8. BBB:** Ligand A (85.964) has a much better BBB penetration prediction than Ligand B (74.758).  >70 is desirable for CNS targets, and Ligand A is closer to this threshold. This is a critical factor for DRD2.

**9. Caco-2:** Ligand A (-5.255) and Ligand B (-4.742) both have negative values, which is unusual. A higher value is better, indicating better intestinal absorption. The difference isn't substantial.

**10. Solubility:** Ligand A (-2.45) is slightly better than Ligand B (-1.884), but both are poor. Solubility is a concern for both.

**11. hERG:** Both ligands have low hERG inhibition risk (0.644 and 0.416).

**12. Cl_mic:** Ligand A (34.3) has a significantly lower microsomal clearance than Ligand B (64.238). Lower clearance indicates better metabolic stability.

**13. t1/2:** Ligand A (22.714) has a slightly longer in vitro half-life than Ligand B (24.961).

**14. Pgp:** Ligand A (0.163) has lower P-gp efflux liability than Ligand B (0.312). Lower is better, especially for CNS targets, as it improves brain exposure.

**15. Binding Affinity:** Ligand B (-7.3) has a slightly better binding affinity than Ligand A (-8.2). However, the difference is only 0.9 kcal/mol. Given the superior ADME profile of Ligand A, this affinity difference is unlikely to be decisive.

**Overall Assessment:**

Ligand A consistently outperforms Ligand B across most critical ADME properties, especially those prioritized for GPCRs targeting the CNS (BBB, TPSA, Pgp). While Ligand B has slightly better binding affinity, the substantial advantages of Ligand A in terms of BBB penetration, lower DILI risk, lower Pgp efflux, and better metabolic stability make it the more promising drug candidate.

Output:
1
2025-04-17 05:56:27,020 - INFO - Reasoning:

Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (357.42 and 353.482 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (44.37) is significantly better than Ligand B (73.2). For CNS targets, we want TPSA <= 90, and ideally closer to 60. Ligand A is much closer to this ideal. Ligand B is quite high and could hinder BBB penetration.

**3. logP:** Both ligands have good logP values (3.778 and 3.199), falling within the optimal 1-3 range.

**4. H-Bond Donors:** Ligand A (2) and Ligand B (1) are both acceptable.

**5. H-Bond Acceptors:** Ligand A (2) and Ligand B (3) are both acceptable.

**6. QED:** Both ligands have reasonable QED values (0.842 and 0.728), indicating good drug-like properties.

**7. DILI:** Ligand A (41.954) is slightly higher than Ligand B (18.651), but both are below the concerning threshold of 60. Ligand B is preferable here.

**8. BBB:** Both ligands have excellent BBB penetration (88.406 and 89.919), exceeding the desirable >70 threshold for CNS targets.

**9. Caco-2:** Both ligands have negative Caco-2 values (-4.513 and -4.273). This is unusual and likely indicates a problem with the prediction method or the molecule itself. It's hard to interpret, but doesn't necessarily disqualify either.

**10. Solubility:** Both ligands have negative solubility values (-3.648 and -3.564), again suggesting issues with the prediction method. Similar to Caco-2, this is hard to interpret.

**11. hERG:** Both ligands have low hERG risk (0.797 and 0.872).

**12. Cl_mic:** Ligand A (60.111) has a lower microsomal clearance than Ligand B (68.843), suggesting better metabolic stability.

**13. t1/2:** Ligand A (12.337) has a longer in vitro half-life than Ligand B (-12.596). The negative value for Ligand B is concerning and likely an artifact of the prediction.

**14. Pgp:** Ligand A (0.19) has significantly lower P-gp efflux liability than Ligand B (0.083), which is crucial for CNS penetration.

**15. Binding Affinity:** Ligand A (-10.2 kcal/mol) has a substantially stronger binding affinity than Ligand B (-6.2 kcal/mol). This is a significant advantage, potentially outweighing minor ADME drawbacks. The difference is 4 kcal/mol, which is substantial.

**Overall Assessment:**

Considering the GPCR-specific priorities, Ligand A is the superior candidate. Its lower TPSA, lower Pgp efflux, longer half-life, and *much* stronger binding affinity are compelling advantages. While Ligand B has a slightly lower DILI risk, the difference isn't substantial enough to offset the other benefits of Ligand A. The negative values for Caco-2 and solubility are concerning for both, but the overall profile of A is far more promising.

Output:
1
2025-04-17 05:56:27,021 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (348.447 Da) is slightly preferred as it's closer to the lower end, potentially aiding permeability.

**TPSA:** Ligand A (83.56) is significantly better than Ligand B (113.33). For CNS targets, TPSA should be <= 90, and A comfortably meets this, while B is pushing the limit.

**logP:** Ligand B (1.259) is slightly better than Ligand A (0.593). Both are within the optimal range of 1-3, but A is a bit low, potentially hindering permeation.

**H-Bond Donors/Acceptors:** Ligand A has 2 HBD and 5 HBA, while Ligand B has 3 HBD and 5 HBA. Both are acceptable, falling within the recommended limits.

**QED:** Both ligands have reasonable QED values (A: 0.718, B: 0.566), indicating good drug-like properties.

**DILI:** Ligand A (14.618) has a much lower DILI risk than Ligand B (45.25). This is a significant advantage for A.

**BBB:** Ligand B (61.729) has a better BBB penetration percentile than Ligand A (52.268). While both are not ideal (>70 is desirable), B is closer.

**Caco-2 Permeability:** Ligand A (-4.996) shows better Caco-2 permeability than Ligand B (-5.454), suggesting better intestinal absorption.

**Aqueous Solubility:** Ligand A (-0.883) has better aqueous solubility than Ligand B (-2.402).

**hERG Inhibition:** Both ligands have very low hERG inhibition risk (A: 0.341, B: 0.2), which is excellent.

**Microsomal Clearance:** Ligand A (-22.994) has a much lower microsomal clearance than Ligand B (5.754), indicating better metabolic stability.

**In vitro Half-Life:** Ligand B (30.341 hours) has a significantly longer in vitro half-life than Ligand A (2.126 hours). This is a major advantage for B.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (A: 0.012, B: 0.093), which is good.

**Binding Affinity:** Both ligands have comparable binding affinities (A: -7.7 kcal/mol, B: -7.8 kcal/mol). The difference is negligible.

**Overall Assessment:**

Considering the GPCR-specific priorities, Ligand A is the better candidate. While Ligand B has a better BBB and half-life, Ligand A excels in TPSA, DILI risk, solubility, and metabolic stability (Cl_mic). The lower TPSA and DILI risk are particularly important for a CNS target like DRD2. The slightly lower logP of A is a minor concern outweighed by the other advantages. The binding affinity is essentially the same.

Output:
0
2025-04-17 05:56:27,021 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 drug candidates, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (343.304 and 347.415 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (39.19) is excellent, well below the 90 A^2 threshold for CNS targets. Ligand B (84.67) is higher, but still potentially acceptable, though less ideal.

**logP:** Ligand A (4.523) is slightly high, potentially leading to solubility issues or off-target interactions. Ligand B (1.368) is within the optimal range of 1-3.

**H-Bond Donors/Acceptors:** Ligand A (0 HBD, 3 HBA) is favorable. Ligand B (1 HBD, 5 HBA) is also acceptable.

**QED:** Both ligands have good QED scores (0.654 and 0.786, respectively), indicating drug-like properties.

**DILI:** Ligand A (88.329) has a concerningly high DILI risk. Ligand B (36.681) has a much lower, and acceptable, DILI risk.

**BBB:** Ligand A (65.452) has a moderate BBB penetration, but is below the desirable >70% for CNS targets. Ligand B (54.362) is even lower, making CNS penetration less likely.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.206 and -4.945), which is unusual and suggests poor permeability. This is a significant concern for both.

**Aqueous Solubility:** Both ligands have very poor aqueous solubility (-5.819 and -1.854). This is a major drawback, especially given Ligand A's already high logP.

**hERG Inhibition:** Ligand A (0.396) has a very low hERG risk, which is excellent. Ligand B (0.077) also has a very low hERG risk.

**Microsomal Clearance:** Ligand A (99.837) has very high microsomal clearance, indicating poor metabolic stability. Ligand B (26.292) has lower clearance, suggesting better stability.

**In vitro Half-Life:** Ligand A (-24.006) has a very short in vitro half-life, consistent with the high clearance. Ligand B (7.635) has a better, though still relatively short, half-life.

**P-gp Efflux:** Ligand A (0.229) has low P-gp efflux, which is favorable for CNS penetration. Ligand B (0.035) has even lower P-gp efflux, which is even more favorable.

**Binding Affinity:** Both ligands have very strong binding affinities (-10.7 and -9.0 kcal/mol). The difference is 1.7 kcal/mol, which is significant enough to potentially overcome some ADME issues.

**Overall Assessment:**

Despite the strong binding affinity of both compounds, Ligand A suffers from a high DILI risk, high metabolic clearance, short half-life, poor solubility, and only moderate BBB penetration. Ligand B has a much better safety profile (lower DILI), better metabolic stability, and lower P-gp efflux. While both have poor Caco-2 permeability and solubility, the other issues with Ligand A make it a less desirable candidate. The slightly better logP and lower DILI of Ligand B outweigh the slightly weaker binding affinity.

Output:
1
2025-04-17 05:56:27,021 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 drug candidates, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (347.411 and 385.917 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (73.86) is significantly better than Ligand B (82.53). For CNS targets, we want TPSA <= 90, and A is closer to the ideal <=60 range. B is pushing the upper limit.

**3. logP:** Both ligands have a logP around 2.7-2.8, which is optimal (1-3).

**4. H-Bond Donors:** Ligand A (1) is preferable to Ligand B (2). Lower HBD generally improves permeability.

**5. H-Bond Acceptors:** Both ligands have 5 HBA, which is acceptable (<=10).

**6. QED:** Ligand B (0.761) has a better QED score than Ligand A (0.549), indicating a more drug-like profile.

**7. DILI:** Ligand A (58.55) has a slightly better DILI score than Ligand B (67.313), but both are acceptable (<60 is good).

**8. BBB:** This is crucial for a CNS target like DRD2. Ligand A (71.307) has a significantly better BBB percentile than Ligand B (52.268). A score >70 is desirable, and A is closer.

**9. Caco-2 Permeability:** Ligand A (-4.168) shows better Caco-2 permeability than Ligand B (-5.141). Higher values are better.

**10. Aqueous Solubility:** Ligand A (-4.152) has slightly better aqueous solubility than Ligand B (-4.6).

**11. hERG Inhibition:** Both ligands have low hERG inhibition risk (0.207 and 0.442, respectively).

**12. Microsomal Clearance:** Ligand B (33.38) has significantly lower microsomal clearance than Ligand A (89.505), suggesting better metabolic stability.

**13. In vitro Half-Life:** Ligand A (-37.682) has a longer in vitro half-life than Ligand B (0.686).

**14. P-gp Efflux:** Ligand A (0.122) has lower P-gp efflux than Ligand B (0.21), which is favorable for CNS penetration.

**15. Binding Affinity:** Ligand B (-8.5 kcal/mol) has a stronger binding affinity than Ligand A (-7.5 kcal/mol). This is a 1 kcal/mol difference, which is significant.

**Overall Assessment:**

While Ligand B has a better QED, stronger binding affinity, and better metabolic stability, Ligand A excels in crucial properties for CNS penetration: TPSA, BBB, Caco-2 permeability, and P-gp efflux. The difference in binding affinity (1 kcal/mol) is substantial, but the improved CNS properties of Ligand A are more critical for a DRD2 target. The better BBB and lower P-gp efflux of Ligand A are likely to translate to higher brain exposure, potentially compensating for the slightly weaker binding.

Output:
0
2025-04-17 05:56:27,021 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (340.423 and 366.527 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (51.66) is significantly better than Ligand B (66.48). For CNS targets, we want TPSA <= 90, both are within this range, but A is closer to the optimal value.

**logP:** Ligand A (3.706) is slightly higher than Ligand B (2.242), both are within the optimal 1-3 range.

**H-Bond Donors:** Ligand A (0) is preferable to Ligand B (1). Fewer HBDs generally improve permeability.

**H-Bond Acceptors:** Both ligands have 4 HBA, which is acceptable (<=10).

**QED:** Both ligands have similar QED values (0.688 and 0.636), indicating good drug-likeness.

**DILI:** Ligand A (54.556) has a higher DILI risk than Ligand B (21.171). This is a significant advantage for Ligand B.

**BBB:** Ligand B (69.756) has a better BBB penetration percentile than Ligand A (58.085). While both are reasonably good, exceeding 70 is desirable for CNS targets, and B is closer.

**Caco-2 Permeability:** Ligand A (-4.434) has worse Caco-2 permeability than Ligand B (-5.378). Lower (more negative) values are less desirable.

**Aqueous Solubility:** Ligand A (-4.019) has worse aqueous solubility than Ligand B (-2.561).

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.581 and 0.247).

**Microsomal Clearance:** Ligand A (97.842) has a higher microsomal clearance than Ligand B (30.301), indicating lower metabolic stability. This is a significant advantage for Ligand B.

**In vitro Half-Life:** Ligand A (-4.228) has a shorter in vitro half-life than Ligand B (-3.323).

**P-gp Efflux:** Ligand A (0.234) has lower P-gp efflux than Ligand B (0.179), which is preferable for CNS penetration.

**Binding Affinity:** Ligand A (-8.4 kcal/mol) has a slightly better binding affinity than Ligand B (-7.7 kcal/mol). This 0.7 kcal/mol difference is meaningful, but not overwhelming.

**Overall Assessment:**

Ligand B is superior due to its significantly better ADME properties (lower DILI, better BBB, better Caco-2 permeability, better solubility, lower Cl_mic, longer t1/2), despite a slightly weaker binding affinity. The improved ADME profile, particularly the lower DILI and better BBB penetration, are crucial for a CNS-targeting drug like a DRD2 ligand. The affinity difference is not large enough to overcome the ADME deficiencies of Ligand A.

Output:
1
2025-04-17 05:56:27,022 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 drug candidates, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (348.403 and 348.447 Da) fall comfortably within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (84.74) and Ligand B (83.56) are both below the 90 A^2 threshold desirable for CNS targets, which is excellent.

**3. logP:** Both ligands have a logP around 1.68-1.69, which is within the optimal 1-3 range.

**4. H-Bond Donors:** Ligand A has 0 HBD, while Ligand B has 2. Both are acceptable (<=5).

**5. H-Bond Acceptors:** Ligand A has 6 HBA, and Ligand B has 5. Both are within the acceptable range (<=10).

**6. QED:** Both ligands have good QED scores (0.611 and 0.629, respectively), indicating drug-like properties.

**7. DILI:** Ligand A (78.945) has a higher DILI risk than Ligand B (49.283). This is a significant advantage for Ligand B.

**8. BBB:** Ligand A has a very high BBB penetration percentile (95.192), while Ligand B is lower (62.117). This is a *major* advantage for Ligand A, given DRD2 is a CNS target.

**9. Caco-2 Permeability:** Both have negative Caco-2 values (-4.274 and -4.826). This is unusual and suggests poor permeability. However, these values are on a scale where negative values are possible, and the absolute magnitude isn't directly interpretable without knowing the scale's specifics.

**10. Aqueous Solubility:** Both ligands have very poor aqueous solubility (-3.305 and -2.137). This is a concern for bioavailability.

**11. hERG Inhibition:** Ligand A (0.061) has a slightly lower hERG inhibition risk than Ligand B (0.505), which is preferable.

**12. Microsomal Clearance:** Ligand B (36.867) has lower microsomal clearance than Ligand A (64.076), indicating better metabolic stability.

**13. In vitro Half-Life:** Ligand B (40.775) has a longer in vitro half-life than Ligand A (14.38), which is desirable.

**14. P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.058 and 0.049), which is excellent for CNS penetration.

**15. Binding Affinity:** Ligand A (-7.5 kcal/mol) has a slightly better binding affinity than Ligand B (-7.1 kcal/mol). While the difference is not huge, it's a noticeable advantage.

**Overall Assessment:**

Ligand A excels in BBB penetration and binding affinity, which are critical for a CNS GPCR target like DRD2. Ligand B has advantages in DILI risk and metabolic stability (lower Cl_mic, longer t1/2). However, the superior BBB penetration of Ligand A is a decisive factor, outweighing the benefits of Ligand B's slightly improved ADME properties. The poor solubility and Caco-2 permeability are concerns for both, but can be addressed with formulation strategies.

Output:
0
2025-04-17 05:56:27,022 - INFO - Reasoning:

Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (356.463 and 363.483 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (99.1) is higher than the preferred <90 for CNS targets, while Ligand B (71.53) is well within the range. This is a significant advantage for Ligand B.

**3. logP:** Ligand A (0.146) is quite low, potentially hindering membrane permeability. Ligand B (1.694) is within the optimal 1-3 range. This favors Ligand B.

**4. H-Bond Donors:** Ligand A (3) is acceptable, while Ligand B (1) is even better, potentially improving permeability.

**5. H-Bond Acceptors:** Both ligands have 5 HBA, which is acceptable.

**6. QED:** Ligand B (0.808) has a significantly higher QED score than Ligand A (0.484), indicating a more drug-like profile.

**7. DILI:** Ligand A (11.361) has a much lower DILI risk than Ligand B (47.926). This is a positive for Ligand A.

**8. BBB:** Ligand B (55.332) has a better BBB percentile than Ligand A (36.371), though both are not ideal (>70 is preferred). However, given the other factors, this is less critical.

**9. Caco-2:** Ligand A (-4.842) and Ligand B (-5.005) both have negative Caco-2 values, which is unusual and suggests poor permeability. This is a concern for both, but doesn't differentiate them.

**10. Solubility:** Both ligands have very low aqueous solubility (-1.52 and -1.713 respectively). This is a significant drawback for both, potentially impacting bioavailability.

**11. hERG:** Both ligands have very low hERG inhibition liability (0.183 and 0.121), which is excellent.

**12. Cl_mic:** Ligand B (32.663) has lower microsomal clearance than Ligand A (39.627), suggesting better metabolic stability.

**13. t1/2:** Ligand B (18.548) has a significantly longer in vitro half-life than Ligand A (0.765). This is a major advantage for Ligand B.

**14. Pgp:** Both ligands have low P-gp efflux liability (0.08 and 0.055), which is favorable for CNS penetration.

**15. Binding Affinity:** Ligand B (-8.3 kcal/mol) has a substantially stronger binding affinity than Ligand A (-6.8 kcal/mol). This difference of 1.5 kcal/mol is significant and can outweigh some of the ADME drawbacks.

**Overall Assessment:**

Ligand B is the stronger candidate. While both have solubility issues, Ligand B excels in key areas for a CNS-targeting GPCR ligand: better logP, lower TPSA, higher QED, improved metabolic stability (lower Cl_mic, longer t1/2), and significantly stronger binding affinity. The DILI risk is higher for Ligand B, but the strong affinity and improved ADME properties make it a more promising starting point for optimization. Ligand A's low logP and weaker affinity are major drawbacks.

Output:
1
2025-04-17 05:56:27,022 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (405.38) is slightly higher, but acceptable. Ligand B (346.383) is also good.

**2. TPSA:** Ligand A (32.34) is excellent, well below the 90 Angstroms threshold for CNS targets. Ligand B (96.89) is higher, but still potentially acceptable, though less ideal for CNS penetration.

**3. logP:** Ligand A (4.323) is a bit high, potentially leading to solubility issues or off-target interactions. Ligand B (0.589) is quite low, which could hinder membrane permeability and brain penetration.

**4. H-Bond Donors:** Ligand A (1) is good. Ligand B (3) is acceptable, but approaching the upper limit.

**5. H-Bond Acceptors:** Ligand A (2) is good. Ligand B (5) is acceptable.

**6. QED:** Ligand A (0.791) is excellent, indicating good drug-like properties. Ligand B (0.599) is acceptable, but less optimal.

**7. DILI Risk:** Ligand A (14.618) has a very low DILI risk. Ligand B (48.817) is moderate, but still within an acceptable range.

**8. BBB Penetration:** Ligand A (89.492) has excellent BBB penetration potential. Ligand B (54.634) is significantly lower, a major concern for a CNS target like DRD2.

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.195 and -5.264), which is unusual and suggests poor permeability. This is a red flag for both, but the negative values are hard to interpret directly.

**10. Aqueous Solubility:** Both ligands have negative solubility values (-3.678 and -2.079), indicating very poor aqueous solubility. This is a significant issue for both.

**11. hERG Inhibition:** Ligand A (0.918) has a low risk of hERG inhibition. Ligand B (0.123) has a very low risk.

**12. Microsomal Clearance:** Ligand A (10.413) has moderate clearance. Ligand B (-1.515) has negative clearance, which is not physically possible and indicates a data error or unusual behavior.

**13. In vitro Half-Life:** Ligand A (13.823) has a reasonable half-life. Ligand B (-5.993) has a negative half-life, which is not possible and suggests a data error.

**14. P-gp Efflux:** Ligand A (0.411) has low P-gp efflux liability, which is good for CNS penetration. Ligand B (0.049) also has very low P-gp efflux liability.

**15. Binding Affinity:** Ligand A (-10.2 kcal/mol) has significantly stronger binding affinity than Ligand B (-8.7 kcal/mol). This is a substantial difference.

**Overall Assessment:**

Ligand A is the stronger candidate. While its logP is slightly high and solubility is poor, its superior BBB penetration, much stronger binding affinity, lower DILI risk, and better QED outweigh these drawbacks, especially considering the GPCR-specific priorities. The negative values for Caco-2, solubility, and half-life for Ligand B are highly concerning and likely indicate data issues. The significantly weaker binding affinity of Ligand B further diminishes its potential.

Output:
1
2025-04-17 05:56:27,022 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (364.804 and 361.873 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (68.29) is slightly higher than Ligand B (62.3). Both are below the 90 A^2 threshold for CNS targets, which is good.

**3. logP:** Both ligands have good logP values (3.227 and 3.633), falling within the optimal 1-3 range. Ligand B is slightly higher, which *could* be a minor concern for solubility, but is not a major issue.

**4. H-Bond Donors:** Both have 1 HBD, which is within the acceptable limit of <=5.

**5. H-Bond Acceptors:** Ligand A has 4 HBA, and Ligand B has 3. Both are below the acceptable limit of <=10.

**6. QED:** Both ligands have good QED scores (0.605 and 0.814), indicating good drug-like properties. Ligand B is better here.

**7. DILI:** Ligand A has a DILI risk of 72.043, which is approaching the higher risk threshold (>60). Ligand B has a much lower DILI risk of 48.623, a significant advantage.

**8. BBB:** Ligand A has a BBB penetration of 70.531, which is acceptable, but Ligand B has a significantly higher BBB penetration of 80.031. This is a crucial advantage for a CNS target like DRD2.

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.612 and -4.994). These values are unusual and likely indicate poor permeability *in vitro*. However, the scale isn't clearly defined, so it's difficult to interpret the absolute impact.

**10. Aqueous Solubility:** Both ligands have negative solubility values (-3.71 and -4.15), suggesting poor aqueous solubility. This is a concern, but can be addressed with formulation strategies.

**11. hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.281 and 0.59). This is excellent.

**12. Microsomal Clearance:** Ligand A has a higher microsomal clearance (92.061) than Ligand B (43.409), indicating faster metabolism and potentially lower *in vivo* exposure. This favors Ligand B.

**13. In vitro Half-Life:** Ligand B has a significantly longer in vitro half-life (35.767 hours) than Ligand A (8.081 hours). This is a substantial advantage.

**14. P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.103 and 0.126), which is good for CNS penetration.

**15. Binding Affinity:** Ligand B (-7.7 kcal/mol) has a stronger binding affinity than Ligand A (-9.0 kcal/mol). While both are good, the 1.3 kcal/mol difference is substantial and can outweigh some ADME drawbacks.

**Overall Assessment:**

Ligand B is the superior candidate. It has a better BBB score, lower DILI risk, significantly improved metabolic stability (lower Cl_mic, longer t1/2), and a stronger binding affinity. While both have poor solubility and permeability, the other advantages of Ligand B make it more likely to succeed as a DRD2 drug candidate.

Output:
1
2025-04-17 05:56:27,022 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (345.443 and 350.427 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (86.34) is excellent for CNS penetration, being well below 90. Ligand B (130.32) is higher, but still potentially acceptable, though less ideal.

**logP:** Ligand A (2.885) is optimal (1-3). Ligand B (-0.723) is quite low, potentially hindering membrane permeability and CNS penetration despite a good BBB score.

**H-Bond Donors/Acceptors:** Ligand A (HBD=1, HBA=4) is favorable. Ligand B (HBD=4, HBA=9) is getting toward the upper limits, potentially impacting permeability.

**QED:** Both ligands have reasonable QED scores (0.859 and 0.525), indicating drug-like properties. Ligand A is superior.

**DILI:** Both ligands have low DILI risk (41.411 and 37.611), which is good.

**BBB:** Ligand B (72.392) has a better BBB score than Ligand A (65.025), which is a significant advantage for a CNS target.

**Caco-2 Permeability:** Ligand A (-4.611) has poor Caco-2 permeability, a major concern. Ligand B (-5.753) is also poor, but slightly better than A.

**Aqueous Solubility:** Both have very poor aqueous solubility (-3.191 and -1.912). This could present formulation challenges.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.659 and 0.228).

**Microsomal Clearance:** Ligand B (7.025) has significantly lower microsomal clearance than Ligand A (28.775), indicating better metabolic stability.

**In vitro Half-Life:** Ligand B (1.857) has a slightly better in vitro half-life than Ligand A (19.249), but both are relatively low.

**P-gp Efflux:** Ligand A (0.326) has lower P-gp efflux than Ligand B (0.001), which is desirable for CNS penetration.

**Binding Affinity:** Ligand B (-7.7 kcal/mol) has a significantly stronger binding affinity than Ligand A (-8.1 kcal/mol). This is a substantial advantage, potentially outweighing some of its ADME drawbacks.

**Overall Assessment:**

While Ligand A has better TPSA, QED, and P-gp efflux, Ligand B excels in the most critical areas for a CNS GPCR target: significantly stronger binding affinity, better BBB penetration, and improved metabolic stability (lower Cl_mic). The low logP of Ligand B is a concern, but the strong binding affinity might compensate. The poor solubility and Caco-2 permeability are drawbacks for both, but are less critical for a CNS target where direct oral bioavailability isn't always essential.

Output:
1
2025-04-17 05:56:27,023 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the acceptable range (200-500 Da). Ligand A (443.706 Da) is higher, but still reasonable. Ligand B (339.483 Da) is preferable.

**TPSA:** Ligand A (81.28) is higher than the ideal <90 for CNS targets, but still potentially acceptable. Ligand B (37.27) is excellent, well below the threshold.

**logP:** Both ligands have logP values around 4.0 (A: 4.269, B: 4.005), which is at the upper limit of the optimal range. This could lead to solubility issues, but is not a dealbreaker given the importance of CNS penetration for DRD2.

**H-Bond Donors/Acceptors:** Both have 1 HBD, which is good. Ligand A has 5 HBA, while Ligand B has 2. Both are within the acceptable limits.

**QED:** Ligand B (0.901) has a significantly better QED score than Ligand A (0.596), indicating better overall drug-likeness.

**DILI:** Ligand A (94.959) has a very high DILI risk, which is a major concern. Ligand B (32.842) has a low DILI risk, a significant advantage.

**BBB:** Ligand B (97.053) has excellent BBB penetration, exceeding the desirable >70% threshold. Ligand A (25.165) has poor BBB penetration, a critical drawback for a CNS target like DRD2.

**Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and suggests poor permeability. However, these values are on a different scale and difficult to directly compare.

**Aqueous Solubility:** Both have negative solubility values, indicating poor solubility.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (A: 0.53, B: 0.921).

**Microsomal Clearance:** Ligand B (51.73) has a higher microsomal clearance than Ligand A (20.055), suggesting faster metabolism and potentially lower in vivo exposure.

**In vitro Half-Life:** Ligand A (38.981) has a slightly longer half-life than Ligand B (35.575).

**P-gp Efflux:** Both ligands have low P-gp efflux liability (A: 0.545, B: 0.565).

**Binding Affinity:** Ligand B (-9.9 kcal/mol) has a slightly better binding affinity than Ligand A (-9.2 kcal/mol). While the difference is not huge, it's still a positive factor.

**Overall Assessment:**

Ligand B is significantly more promising. Its superior BBB penetration, much lower DILI risk, better QED score, and slightly better binding affinity outweigh the slightly higher microsomal clearance and similar logP values. Ligand A's poor BBB penetration and high DILI risk are major red flags. While both have solubility concerns, the other factors heavily favor Ligand B.

Output:
1
2025-04-17 05:56:27,023 - INFO - Reasoning:

Let's analyze Ligand A and Ligand B for their potential as DRD2 drug candidates, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (369.447 Da) is slightly higher than Ligand B (337.379 Da), but both are acceptable.

**2. TPSA:** Ligand A (119.67) is closer to the upper limit for good oral absorption but still within range, and acceptable for a CNS target. Ligand B (91.32) is excellent, well below the 90 A^2 threshold for CNS targets.

**3. logP:** Ligand A (-0.25) is a bit low, potentially hindering permeation. Ligand B (2.622) is optimal. This is a significant advantage for Ligand B.

**4. H-Bond Donors:** Ligand A (2) and Ligand B (3) are both acceptable, below the threshold of 5.

**5. H-Bond Acceptors:** Ligand A (8) and Ligand B (4) are both acceptable, below the threshold of 10.

**6. QED:** Both ligands have reasonable QED scores (Ligand A: 0.709, Ligand B: 0.578), indicating good drug-like properties.

**7. DILI:** Ligand A (63.823) has a higher DILI risk than Ligand B (51.842), but both are below the concerning threshold of 60.

**8. BBB:** Ligand A (83.792) has a significantly better BBB penetration score than Ligand B (54.478). This is a crucial factor for a CNS target like DRD2.

**9. Caco-2 Permeability:** Both have negative values, which is unusual. Assuming these are percentile scores, both are very poor.

**10. Aqueous Solubility:** Both have negative values, indicating poor solubility.

**11. hERG Inhibition:** Both ligands have very low hERG inhibition risk (Ligand A: 0.211, Ligand B: 0.202).

**12. Microsomal Clearance:** Ligand A (10.658) has a lower (better) microsomal clearance than Ligand B (31.72). This suggests better metabolic stability for Ligand A.

**13. In vitro Half-Life:** Ligand A (-13.565) has a very poor in vitro half-life, while Ligand B (-21.984) is even worse. Both are problematic.

**14. P-gp Efflux:** Both ligands have very low P-gp efflux liability (Ligand A: 0.035, Ligand B: 0.044).

**15. Binding Affinity:** Ligand B (-9.8 kcal/mol) has a significantly stronger binding affinity than Ligand A (-7.4 kcal/mol). This >1.5 kcal/mol difference is a major advantage for Ligand B, potentially outweighing some of its ADME drawbacks.

**Overall Assessment:**

Ligand B is the stronger candidate. While Ligand A has better BBB penetration and metabolic stability, Ligand B's superior binding affinity (-9.8 vs -7.4 kcal/mol) is a critical advantage for a GPCR target. The optimal logP of Ligand B also supports better permeation. The poor Caco-2 and solubility for both are concerning, but can be addressed with formulation strategies. The lower BBB for Ligand B is a drawback, but the affinity difference is substantial.

Output:
1
2025-04-17 05:56:27,023 - INFO - Reasoning:

Let's analyze Ligand A and Ligand B against the provided guidelines, prioritizing GPCR-specific properties (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (345.443 and 382.473 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (84.66) is better than Ligand B (75.71), both are below the 90 A^2 threshold for CNS targets.

**logP:** Both ligands have good logP values (2.37 and 1.471), falling within the optimal 1-3 range. Ligand A is slightly higher, which could be beneficial for membrane permeability.

**H-Bond Donors/Acceptors:** Ligand A (HBD=2, HBA=3) and Ligand B (HBD=1, HBA=4) both have acceptable numbers of H-bond donors and acceptors.

**QED:** Ligand A (0.859) has a significantly better QED score than Ligand B (0.645), indicating a more drug-like profile.

**DILI:** Ligand A (28.616) has a much lower DILI risk than Ligand B (40.403), making it safer from a liver toxicity perspective. Both are below the 40 threshold.

**BBB:** Both ligands have excellent BBB penetration (Ligand A: 90.151, Ligand B: 89.298), exceeding the desirable >70 percentile for CNS targets.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.866 and -4.924), which is unusual and suggests poor permeability. This is a significant drawback for both.

**Aqueous Solubility:** Both ligands have very poor aqueous solubility (-2.74 and -2.718). This is a major concern for formulation and bioavailability.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.451 and 0.623).

**Microsomal Clearance:** Ligand A (7.689) has a significantly lower microsomal clearance than Ligand B (54.551), indicating better metabolic stability.

**In vitro Half-Life:** Ligand A (-14.531) has a significantly longer in vitro half-life than Ligand B (-30.928).

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.066 and 0.105), which is favorable for CNS penetration.

**Binding Affinity:** Both ligands have very similar and strong binding affinities (-8.9 and -8.5 kcal/mol). The difference of 0.4 kcal/mol is not substantial enough to outweigh other factors.

**Conclusion:**

Considering all factors, **Ligand A** is the more promising drug candidate. It has a better QED score, significantly lower DILI risk, lower microsomal clearance (better metabolic stability), a longer half-life, and slightly better logP and TPSA values. While both have poor solubility and Caco-2 permeability, the other advantages of Ligand A make it the preferred choice. The similar binding affinities mean that the ADME/Tox profile is the deciding factor here.

Output:
1
2025-04-17 05:56:27,023 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (371.415 and 350.547 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (105.25) is higher than the preferred <90 for CNS targets, while Ligand B (49.41) is excellent. This is a significant advantage for Ligand B.

**logP:** Ligand A (-0.653) is quite low, potentially hindering membrane permeability. Ligand B (3.848) is within the optimal 1-3 range. This favors Ligand B.

**H-Bond Donors/Acceptors:** Both have 1 HBD, which is good. Ligand A has 6 HBA, acceptable. Ligand B has 2 HBA, which is also good.

**QED:** Both ligands have good QED scores (0.639 and 0.723), indicating drug-likeness.

**DILI:** Ligand A (63.668) has a moderate DILI risk, while Ligand B (11.128) has a very low risk. This is a strong advantage for Ligand B.

**BBB:** Ligand A (71.268) is acceptable for CNS penetration, but Ligand B (92.943) is excellent, exceeding the >70 desirable threshold. This is a major advantage for Ligand B.

**Caco-2 Permeability:** Both have negative values, which is unusual and suggests poor permeability. However, the scale is not specified, making direct comparison difficult.

**Aqueous Solubility:** Both have negative values, also unusual. Again, the scale is unspecified.

**hERG:** Ligand A (0.348) has a slightly higher hERG risk than Ligand B (0.779).

**Microsomal Clearance:** Both have similar microsomal clearance values (65.159 and 67.221), suggesting comparable metabolic stability.

**In vitro Half-Life:** Ligand A (7.256) has a longer half-life than Ligand B (3.265), which is generally preferred.

**P-gp Efflux:** Ligand A (0.091) has lower P-gp efflux, which is better for CNS exposure. Ligand B (0.157) is slightly higher.

**Binding Affinity:** Ligand B (-7.6 kcal/mol) has significantly stronger binding affinity than Ligand A (-0.0 kcal/mol). This is a crucial advantage, as a >1.5 kcal/mol difference can outweigh other drawbacks.

**Overall:**

Ligand B clearly outperforms Ligand A. It has superior TPSA, logP, DILI risk, BBB penetration, and, most importantly, binding affinity. While Ligand A has a slightly longer half-life and lower P-gp efflux, the advantages of Ligand B are far more significant, especially considering the CNS target and GPCR class priorities. The strong binding affinity of Ligand B is a key factor.

Output:
1
2025-04-17 05:56:27,024 - INFO - Batch 240 complete. Total preferences: 3840
2025-04-17 05:56:27,024 - INFO - Processing batch 241/512...
2025-04-17 05:57:10,427 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (360.479 and 376.551 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (58.64) is better than Ligand B (51.02). Both are below the 90 A^2 threshold for CNS targets, which is excellent.

**3. logP:** Both ligands have good logP values (2.962 and 3.74), falling within the optimal 1-3 range. Ligand B is slightly higher, potentially increasing permeability but also slightly increasing the risk of off-target effects.

**4. H-Bond Donors:** Ligand A has 1 HBD, and Ligand B has 0. Both are within the acceptable limit of <=5.

**5. H-Bond Acceptors:** Ligand A has 5 HBA, and Ligand B has 6. Both are within the acceptable limit of <=10.

**6. QED:** Both ligands have reasonable QED scores (0.852 and 0.771), indicating good drug-like properties.

**7. DILI:** Both ligands have acceptable DILI risk (50.64 and 46.336), well below the concerning threshold of 60.

**8. BBB:** Ligand A (78.945) has a slightly better BBB percentile than Ligand B (70.027). Both are good, but >70 is desirable for CNS targets.

**9. Caco-2 Permeability:** Ligand A (-4.641) has a worse Caco-2 permeability than Ligand B (-5.212). Lower values are worse.

**10. Aqueous Solubility:** Ligand A (-3.943) has a worse aqueous solubility than Ligand B (-3.315). Lower values are worse.

**11. hERG Inhibition:** Both ligands have low hERG inhibition liability (0.522 and 0.663), which is good.

**12. Microsomal Clearance:** Ligand A (73.764) has higher microsomal clearance than Ligand B (52.182). Lower clearance is preferred.

**13. In vitro Half-Life:** Ligand B (-27.882) has a significantly longer in vitro half-life than Ligand A (29.936). This is a major advantage.

**14. P-gp Efflux:** Both ligands have low P-gp efflux liability (0.26 and 0.53).

**15. Binding Affinity:** Ligand B (-7.0 kcal/mol) has a significantly better binding affinity than Ligand A (-6.4 kcal/mol). This 0.6 kcal/mol difference is substantial and can outweigh minor ADME drawbacks.

**Overall Assessment:**

While Ligand A has a slightly better TPSA and BBB, Ligand B excels in several crucial areas. The most significant advantages of Ligand B are its superior binding affinity (-7.0 vs -6.4 kcal/mol) and significantly longer in vitro half-life. The slightly higher logP of Ligand B is not a major concern. Considering the GPCR-specific priorities, the stronger binding and improved metabolic stability of Ligand B make it the more promising drug candidate.

Output:
1
2025-04-17 05:57:10,427 - INFO - Okay, let's analyze these two ligands for their potential as DRD2 drug candidates. DRD2 is a GPCR in the CNS, so BBB penetration, logP, Pgp efflux, TPSA, and binding affinity are paramount.

**Ligand A:** [351.447, 89.95, 0.289, 2, 4, 0.615, 8.763, 54.246, -4.954, -1.259, 0.124, 13.702, -19.566, 0.008, -7]
**Ligand B:** [363.464, 29.54, 4.451, 0, 2, 0.596, 21.365, 96.161, -4.412, -4.192, 0.888, 70.697, 20.356, 0.644, -7.9]

**Step-by-step comparison:**

1. **MW:** Both are within the ideal range (200-500 Da). A (351.447) is slightly preferred.
2. **TPSA:** A (89.95) is better than B (29.54) for CNS penetration, being closer to the <90 target. B is excellent.
3. **logP:** A (0.289) is quite low, potentially hindering permeability. B (4.451) is high, potentially causing solubility and off-target issues.
4. **HBD:** A (2) is good. B (0) is also good.
5. **HBA:** A (4) is good. B (2) is good.
6. **QED:** Both are acceptable (A: 0.615, B: 0.596).
7. **DILI:** A (8.763) is significantly better than B (21.365), indicating a much lower risk of liver injury.
8. **BBB:** B (96.161) is *excellent* and far superior to A (54.246). This is a critical advantage for a CNS target.
9. **Caco-2:** A (-4.954) is poor. B (-4.412) is also poor.
10. **Solubility:** A (-1.259) is poor. B (-4.192) is very poor.
11. **hERG:** A (0.124) is very low risk. B (0.888) is moderate risk.
12. **Cl_mic:** A (13.702) is better (lower clearance) than B (70.697), suggesting better metabolic stability.
13. **t1/2:** B (20.356) has a much longer half-life than A (-19.566).
14. **Pgp:** A (0.008) is very low efflux, which is good. B (0.644) is moderate efflux.
15. **Affinity:** B (-7.9) is slightly better than A (-7.0), but the difference is not huge.

**Overall Assessment:**

Ligand B has a *significant* advantage in BBB penetration, which is the most important factor for a CNS GPCR target like DRD2. It also has a longer half-life. However, it suffers from a higher logP, higher DILI risk, and lower metabolic stability. Ligand A has better DILI, metabolic stability, and Pgp efflux, but its BBB penetration is a major concern. The low logP of A is also problematic.

Despite the slightly better affinity of B, the poor solubility of both compounds is a concern. However, the BBB penetration of B is so strong that it likely outweighs the other drawbacks, assuming formulation strategies can be developed to address the solubility issue.

Output:
1
2025-04-17 05:57:10,428 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B based on the provided guidelines, prioritizing GPCR-specific properties (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (368.861 and 359.354 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (60.03) is excellent, well below the 90 A^2 threshold for CNS targets. Ligand B (119.24) is higher, but still potentially acceptable, though less optimal.

**logP:** Ligand A (3.78) is within the optimal 1-3 range. Ligand B (-1.551) is significantly lower, which is a concern for membrane permeability and CNS penetration.

**H-Bond Donors/Acceptors:** Both ligands have acceptable HBD (1) and HBA (5/6) counts.

**QED:** Ligand A (0.876) has a very good drug-likeness score, while Ligand B (0.453) is below the desirable 0.5 threshold.

**DILI:** Ligand A (60.489) is moderately risky, while Ligand B (44.552) is better.

**BBB:** Ligand A (91.431) has excellent BBB penetration potential, exceeding the 70% threshold. Ligand B (79.062) is lower, but still reasonably good.

**Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and suggests a potential issue with the data or modeling. However, we can still compare them relatively. Ligand A (-4.485) is better than Ligand B (-4.985).

**Aqueous Solubility:** Both have negative solubility values, which is also unusual. Ligand A (-4.854) is slightly better than Ligand B (-1.527).

**hERG Inhibition:** Ligand A (0.763) has a slightly higher hERG risk than Ligand B (0.171), but both are relatively low.

**Microsomal Clearance:** Ligand A (43.481) has a higher clearance than Ligand B (2.993), indicating lower metabolic stability.

**In vitro Half-Life:** Ligand A (24.618) has a longer half-life than Ligand B (-34.976), which is a positive.

**P-gp Efflux:** Ligand A (0.441) has lower P-gp efflux liability than Ligand B (0.026), which is favorable for CNS penetration.

**Binding Affinity:** Both ligands have strong binding affinities (-8.0 and -7.7 kcal/mol), with Ligand A being slightly better. The difference of 0.3 kcal/mol is not substantial enough to outweigh other significant differences.

**Overall Assessment:**

Ligand A is significantly better due to its superior logP, TPSA, QED, and BBB penetration. While its DILI score is higher and clearance is lower than Ligand B, the critical CNS-related properties are much more favorable. Ligand B's low logP is a major drawback for a CNS-targeting drug, potentially hindering its ability to cross the blood-brain barrier.



Output:
1
2025-04-17 05:57:10,428 - INFO - Reasoning:

Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (357.479 and 379.488 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (73.2) is higher than the preferred <90 for CNS targets, but still reasonable. Ligand B (37.38) is excellent, well below 90. This favors Ligand B.

**3. logP:** Ligand A (2.941) is within the optimal 1-3 range. Ligand B (4.099) is slightly above, potentially raising concerns about solubility and off-target effects, but not drastically.

**4. H-Bond Donors:** Ligand A (1) is good. Ligand B (0) is also acceptable.

**5. H-Bond Acceptors:** Ligand A (4) is good. Ligand B (3) is also good.

**6. QED:** Both ligands have reasonable QED scores (0.842 and 0.637), indicating good drug-like properties.

**7. DILI:** Ligand A (60.682) is approaching a concerning level, while Ligand B (27.801) is excellent, indicating low liver injury risk. This is a significant advantage for Ligand B.

**8. BBB:** Ligand A (60.993) is below the desirable >70 for CNS targets. Ligand B (95.502) is *excellent*, strongly suggesting good brain penetration. This is a critical advantage for a DRD2 ligand.

**9. Caco-2 Permeability:** Both have negative values, which is unusual. Assuming these are logP values, they are very poor.

**10. Aqueous Solubility:** Both have negative values, which is unusual. Assuming these are logS values, they are very poor.

**11. hERG Inhibition:** Both ligands have low hERG risk (0.584 and 0.47).

**12. Microsomal Clearance:** Ligand A (37.561) has lower clearance, suggesting better metabolic stability than Ligand B (66.043).

**13. In vitro Half-Life:** Ligand B (-9.041) has a significantly longer half-life than Ligand A (-4.346).

**14. P-gp Efflux:** Ligand A (0.43) has lower P-gp efflux, which is favorable for CNS exposure. Ligand B (0.375) is also good, but slightly higher.

**15. Binding Affinity:** Ligand A (-8.1) has a slightly better binding affinity than Ligand B (-7.5). However, the difference is less than 1.5 kcal/mol, so it's not a decisive factor.

**Overall Assessment:**

While Ligand A has slightly better binding affinity and metabolic stability, Ligand B overwhelmingly wins due to its *excellent* BBB penetration (95.502), significantly lower DILI risk (27.801), and longer half-life. For a CNS target like DRD2, BBB penetration is paramount, and Ligand B excels in this area. The lower DILI risk is also a major advantage. The slightly higher logP of Ligand B is a minor concern that could potentially be addressed with further optimization.

Output:
1
2025-04-17 05:57:10,428 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (346.515 and 350.511 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (49.41) is significantly better than Ligand B (59.31). For CNS targets, we want TPSA <= 90, and ideally closer to 60. Ligand A is much closer to this ideal.

**logP:** Ligand A (3.648) is optimal (1-3). Ligand B (1.92) is on the lower side, potentially hindering permeability.

**H-Bond Donors/Acceptors:** Ligand A (HBD=1, HBA=2) is preferable to Ligand B (HBD=0, HBA=7). While both are within acceptable limits, more H-bond acceptors can sometimes lead to reduced permeability.

**QED:** Both ligands have good QED scores (0.512 and 0.749), indicating drug-like properties.

**DILI:** Ligand A (8.259) has a much lower DILI risk than Ligand B (15.2). This is a significant advantage.

**BBB:** Both ligands have excellent BBB penetration (89.337 and 87.553), exceeding the desirable >70 threshold for CNS targets.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.768 and -4.761), which is unusual and suggests a potential issue with in vitro permeability assessment. However, the values are very similar.

**Aqueous Solubility:** Both ligands have negative solubility values (-3.796 and -1.58), also unusual and suggesting poor aqueous solubility. Ligand B is slightly better.

**hERG:** Both ligands have low hERG inhibition liability (0.703 and 0.546), which is good.

**Microsomal Clearance:** Ligand A (43.7 mL/min/kg) has higher clearance than Ligand B (25.838 mL/min/kg), suggesting lower metabolic stability.

**In vitro Half-Life:** Ligand B (7.331 hours) has a significantly longer half-life than Ligand A (3.498 hours).

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.309 and 0.073), which is favorable for CNS penetration. Ligand B is slightly better.

**Binding Affinity:** Ligand A (-7.7 kcal/mol) has a significantly stronger binding affinity than Ligand B (-5.9 kcal/mol). This >1.5 kcal/mol difference is a major advantage, potentially outweighing some ADME drawbacks.

**Overall Assessment:**

Ligand A is the stronger candidate. While it has slightly higher microsomal clearance and a shorter half-life, its superior binding affinity (-7.7 vs -5.9 kcal/mol), lower DILI risk, and more favorable TPSA outweigh these concerns. The similar BBB penetration and P-gp efflux profiles are positive for both, but the lower logP of Ligand B is a concern. The unusual negative values for Caco-2 and solubility warrant further investigation, but the overall profile of Ligand A is more promising for CNS drug development targeting DRD2.

Output:
1
2025-04-17 05:57:10,428 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (350.463 and 344.459 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (90.54) is slightly above the preferred <90 for CNS targets, but still reasonable. Ligand B (67.23) is well within the ideal range.

**logP:** Ligand A (0.172) is quite low, potentially hindering membrane permeability. Ligand B (1.816) is within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A has 3 HBD and 4 HBA, acceptable values. Ligand B has 1 HBD and 4 HBA, also acceptable.

**QED:** Both ligands have good QED scores (0.545 and 0.856), indicating drug-like properties.

**DILI:** Ligand A (12.641) has a very low DILI risk, significantly better than Ligand B (24.467).

**BBB:** This is a crucial parameter for a CNS target like DRD2. Ligand A (28.034) has a poor BBB percentile, while Ligand B (70.492) is excellent, exceeding the desirable >70 threshold.

**Caco-2 Permeability:** Ligand A (-5.484) has poor Caco-2 permeability, consistent with its low logP. Ligand B (-4.884) also has poor Caco-2 permeability.

**Aqueous Solubility:** Both ligands have poor aqueous solubility (-1.269 and -1.77 respectively).

**hERG Inhibition:** Ligand A (0.084) shows very low hERG inhibition risk, much better than Ligand B (0.371).

**Microsomal Clearance:** Ligand A (-14.336) has very low microsomal clearance (high metabolic stability), which is favorable. Ligand B (48.936) has a high clearance, suggesting rapid metabolism.

**In vitro Half-Life:** Ligand A (16.377) has a moderate half-life. Ligand B (-21.865) has a very short half-life.

**P-gp Efflux:** Ligand A (0.002) shows very low P-gp efflux, which is excellent for CNS penetration. Ligand B (0.163) has slightly higher P-gp efflux.

**Binding Affinity:** Ligand B (-8.4 kcal/mol) has a slightly better binding affinity than Ligand A (-7.9 kcal/mol), but the difference is not substantial enough to overcome the other significant drawbacks of Ligand B.

**Overall Assessment:**

Ligand A has a superior safety profile (DILI, hERG) and metabolic stability (Cl_mic, t1/2) and P-gp efflux. However, its low logP and poor BBB penetration are major concerns for a CNS target. Ligand B has a much better BBB penetration, but suffers from higher DILI risk, hERG liability, rapid metabolism, and shorter half-life.

Considering the GPCR-specific priorities, BBB penetration is paramount for DRD2. While Ligand B's BBB is good, its other liabilities are substantial. Ligand A's poor BBB is a significant issue, but could potentially be addressed through prodrug strategies or formulation approaches. The significantly better safety and metabolic stability of Ligand A make it a more promising starting point for optimization.

Output:
0
2025-04-17 05:57:10,429 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (351.363 and 367.881 Da) fall within the ideal range of 200-500 Da.

**TPSA:** Ligand A (115.65) is above the optimal <90 for CNS targets, but not drastically so. Ligand B (72.54) is well within the desired range. This favors Ligand B.

**logP:** Ligand A (-0.582) is quite low, potentially hindering membrane permeability. Ligand B (1.529) is within the optimal 1-3 range. This is a significant advantage for Ligand B.

**H-Bond Donors/Acceptors:** Both have acceptable HBD counts (1). Ligand A has more HBAs (8) than Ligand B (4), but both are below the limit of 10.

**QED:** Both ligands have good QED values (0.557 and 0.875), indicating drug-like properties. Ligand B is better here.

**DILI:** Ligand A (76.037) has a higher DILI risk than Ligand B (30.787). This favors Ligand B.

**BBB:** Ligand A (58.085) has a suboptimal BBB penetration percentile. Ligand B (68.67) is better, but still not ideal (we want >70 for CNS targets).

**Caco-2 Permeability:** Both have negative Caco-2 values (-5.204 and -5.001), which is unusual and suggests poor permeability. This is a concern for both, but doesn't differentiate them.

**Aqueous Solubility:** Both have negative solubility values (-2.061 and -2.499), also unusual and indicating poor solubility. Again, this is a concern for both but doesn't differentiate them.

**hERG:** Ligand A (0.054) has a slightly lower hERG risk than Ligand B (0.286), which is a minor advantage.

**Microsomal Clearance:** Ligand A (38.486) has higher clearance than Ligand B (-5.823), indicating lower metabolic stability. This favors Ligand B.

**In vitro Half-Life:** Ligand A (9.282) has a shorter half-life than Ligand B (-11.876), suggesting faster metabolism. This favors Ligand B.

**P-gp Efflux:** Ligand A (0.038) has lower P-gp efflux liability than Ligand B (0.012), which is a slight advantage for CNS penetration.

**Binding Affinity:** Ligand B (-7.9 kcal/mol) has a significantly stronger binding affinity than Ligand A (-6.8 kcal/mol). This >1.5 kcal/mol difference is a major factor.

**Overall Assessment:**

Ligand B consistently outperforms Ligand A across most critical parameters, especially logP, DILI, metabolic stability (Cl_mic and t1/2), and binding affinity. While both have issues with Caco-2 and solubility, Ligand B's superior affinity and ADME profile make it a more promising drug candidate for DRD2. The slightly lower BBB score for Ligand B is a concern, but the stronger binding and better overall properties outweigh this drawback.

Output:
1
2025-04-17 05:57:10,429 - INFO - Reasoning:

Let's analyze Ligand A and Ligand B for their potential as DRD2 drug candidates, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (390.398 and 358.36 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (102.87) is slightly above the optimal <90 for CNS targets, but still reasonable. Ligand B (75.27) is excellent, well below 90.

**logP:** Ligand A (2.686) is within the optimal 1-3 range. Ligand B (1.585) is on the lower end but still acceptable.

**H-Bond Donors/Acceptors:** Ligand A has 0 HBD and 8 HBA, which is good. Ligand B has 2 HBD and 3 HBA, also good. Both are within acceptable limits.

**QED:** Both ligands have good QED scores (0.401 and 0.679), indicating reasonable drug-likeness. Ligand B is better.

**DILI:** Ligand A (62.156) has a moderate DILI risk. Ligand B (35.944) has a lower, more favorable DILI risk.

**BBB:** Both ligands have good BBB penetration (70.105 and 77.162), exceeding the >70 threshold for CNS targets. Ligand B is slightly better.

**Caco-2 Permeability:** Both have negative Caco-2 values (-4.596 and -4.915), which is unusual and suggests poor permeability. This is a significant concern for both.

**Aqueous Solubility:** Both have negative solubility values (-2.587 and -2.72), which is also concerning and suggests poor solubility.

**hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.106 and 0.058). This is excellent.

**Microsomal Clearance:** Ligand A (109.965) has higher microsomal clearance, indicating faster metabolism. Ligand B (6.848) has much lower clearance, suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (-18.984) has a negative half-life, which is not physically possible and indicates a problem with the data or prediction. Ligand B (-13.351) also has a negative half-life, also problematic.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.225 and 0.035), which is favorable for CNS penetration. Ligand B is better.

**Binding Affinity:** Ligand B (-8.4 kcal/mol) has significantly stronger binding affinity than Ligand A (-6.1 kcal/mol). This is a >1.5 kcal/mol advantage, which can outweigh other drawbacks.

**Overall Assessment:**

While both ligands have issues with Caco-2 and solubility, Ligand B is superior. It has a better logP, lower DILI risk, better metabolic stability (lower Cl_mic), lower P-gp efflux, and, most importantly, much stronger binding affinity. The negative half-life values are concerning for both, but the substantial affinity difference favors Ligand B. Given the GPCR-specific priorities, the strong binding affinity and good BBB penetration of Ligand B make it the more promising candidate, despite the permeability and solubility concerns.

Output:
1
2025-04-17 05:57:10,430 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (346.43 and 367.92 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (73.99) is better than Ligand B (47.36). For CNS targets, we want TPSA <= 90, both are within this range, but A is closer to the upper limit.

**logP:** Ligand A (1.82) is optimal (1-3), while Ligand B (3.798) is approaching the higher end of optimal, but still acceptable.

**H-Bond Donors:** Ligand A (1) is good, while Ligand B (0) is also good.

**H-Bond Acceptors:** Both ligands have 4 HBA, which is acceptable (<=10).

**QED:** Ligand A (0.902) is excellent, indicating high drug-likeness. Ligand B (0.702) is still good, but lower.

**DILI:** Ligand A (28.344) has a lower DILI risk than Ligand B (16.092), both are good (<40).

**BBB:** Ligand B (87.631) has a significantly better BBB penetration score than Ligand A (64.482). This is a *critical* factor for a CNS target like DRD2.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.516 and -4.662), which is unusual and suggests poor permeability. This is a significant concern for both.

**Aqueous Solubility:** Both ligands have negative solubility values (-2.454 and -2.874), which is also concerning.

**hERG Inhibition:** Ligand A (0.288) has a lower hERG risk than Ligand B (0.661).

**Microsomal Clearance:** Ligand A (47.778) has lower microsomal clearance than Ligand B (77.685), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (45.338) has a longer half-life than Ligand B (16.213).

**P-gp Efflux:** Ligand A (0.106) has lower P-gp efflux than Ligand B (0.685), which is favorable for CNS penetration.

**Binding Affinity:** Ligand B (-7.0) has a slightly better binding affinity than Ligand A (-6.8). While a 1.5 kcal/mol difference can be significant, the other ADME properties are more concerning.

**Overall Assessment:**

Ligand B excels in BBB penetration and binding affinity. However, Ligand A demonstrates better drug-likeness (QED), lower DILI risk, better metabolic stability (lower Cl_mic, longer t1/2), and lower P-gp efflux. Both have concerning Caco-2 and solubility values. Given the importance of BBB penetration for a CNS target, and the slightly better affinity of Ligand B, it is the more promising candidate *despite* the lower QED and higher P-gp efflux. The poor Caco-2 and solubility would need to be addressed through formulation or structural modification, but the CNS penetration is a significant advantage.

Output:
1
2025-04-17 05:57:10,430 - INFO - Reasoning:

Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (412.219 Da) is slightly higher than Ligand B (348.487 Da), but both are acceptable.

**2. TPSA:** Ligand A (106.1) is higher than the preferred <90 for CNS targets, while Ligand B (66.48) is well within the range. This is a significant advantage for Ligand B.

**3. logP:** Both ligands have good logP values (A: 1.949, B: 2.535), falling within the optimal 1-3 range.

**4. H-Bond Donors:** Both are acceptable (A: 2, B: 1).

**5. H-Bond Acceptors:** Both are acceptable (A: 6, B: 3).

**6. QED:** Both have good QED scores (A: 0.555, B: 0.769), indicating drug-like properties. Ligand B is better here.

**7. DILI:** Ligand A (81.776) has a higher DILI risk than Ligand B (17.449). This is a significant concern for Ligand A.

**8. BBB:** Ligand A (69.678) and Ligand B (75.223) both have good BBB penetration, exceeding the 70% threshold for CNS targets. Ligand B is slightly better.

**9. Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and suggests poor permeability. However, the scale isn't specified, so it's hard to interpret.

**10. Aqueous Solubility:** Both have negative solubility values, also unusual. Again, the scale is unknown.

**11. hERG Inhibition:** Both ligands show low hERG inhibition risk (A: 0.095, B: 0.244).

**12. Microsomal Clearance:** Ligand A (82.006) has a higher microsomal clearance than Ligand B (43.041), suggesting lower metabolic stability.

**13. In vitro Half-Life:** Ligand B (-22.782) has a negative half-life, which is not possible. This is a major red flag for Ligand B. Ligand A (26.51) is acceptable.

**14. P-gp Efflux:** Both ligands have low P-gp efflux liability (A: 0.022, B: 0.204).

**15. Binding Affinity:** Both ligands have very good binding affinities (A: -8.8 kcal/mol, B: -8.1 kcal/mol). Ligand A has a slightly better affinity.

**Overall Assessment:**

Ligand A has a slightly better binding affinity and half-life, but suffers from higher DILI risk, higher microsomal clearance, and a TPSA value that is less ideal for CNS penetration. Ligand B has a better TPSA, DILI, and Pgp efflux. However, the negative half-life for Ligand B is a critical flaw.

Given the importance of BBB penetration and minimizing toxicity (DILI) for CNS targets, and the fact that the affinity difference is relatively small (0.7 kcal/mol), and considering the negative half-life value for Ligand B, **Ligand A is the more promising candidate despite its drawbacks.** The negative half-life for Ligand B is a showstopper.

Output:
0
2025-04-17 05:57:10,430 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (464.117 Da) is higher, but still acceptable. Ligand B (346.431 Da) is lower, potentially aiding permeability.

**TPSA:** Ligand A (71.42) is better than Ligand B (86.63) as it is closer to the optimal value for CNS targets (<90). Ligand B is still within a reasonable range, but less favorable.

**logP:** Ligand A (4.602) is significantly higher than the optimal range (1-3). This could lead to solubility issues and off-target interactions. Ligand B (0.722) is quite low, potentially hindering permeation.

**H-Bond Donors/Acceptors:** Ligand A (HBD=2, HBA=4) and Ligand B (HBD=1, HBA=5) both fall within acceptable ranges.

**QED:** Both ligands have good QED scores (Ligand A: 0.466, Ligand B: 0.872). Ligand B is considerably better, indicating a more drug-like profile.

**DILI:** Both have relatively low DILI risk, with Ligand B (47.034) being slightly better than Ligand A (96.82).

**BBB:** Ligand A (48.119) has a concerningly low BBB penetration percentile. Ligand B (50.95) is also low, but slightly better. Neither is ideal for a CNS target (>70).

**Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and suggests a potential issue with the modeling or data quality. However, we can interpret these as very low permeability.

**Aqueous Solubility:** Both have negative solubility values, which is also unusual and suggests very low solubility.

**hERG Inhibition:** Ligand A (0.898) has a slightly higher hERG risk than Ligand B (0.256).

**Microsomal Clearance:** Ligand B (22.363) has significantly lower microsomal clearance than Ligand A (45.254), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand B (-9.477) has a negative half-life, which is not physically possible and indicates a data issue. Ligand A (63.127) has a reasonable half-life.

**P-gp Efflux:** Ligand A (0.867) has a higher P-gp efflux liability than Ligand B (0.09), which is unfavorable for CNS penetration.

**Binding Affinity:** Both ligands have excellent binding affinities (Ligand A: -9.3 kcal/mol, Ligand B: -8.6 kcal/mol). Ligand A has a 0.7 kcal/mol advantage.

**Overall Assessment:**

Ligand A has a superior binding affinity, but suffers from high logP, low BBB, and high P-gp efflux. These factors are particularly detrimental for a CNS-targeting GPCR like DRD2. The negative solubility and Caco-2 values are also concerning.

Ligand B, while having slightly weaker affinity, has a better QED score, lower DILI risk, lower P-gp efflux, and lower microsomal clearance. Its logP is low, which is a drawback, but less severe than Ligand A's high logP. The negative solubility and Caco-2 values are also concerning.

Considering the GPCR-specific priorities, the lower logP, P-gp efflux, and better metabolic stability of Ligand B make it the more promising candidate, *despite* the slightly weaker affinity and questionable solubility/permeability data. The affinity difference is not large enough to overcome the significant ADME liabilities of Ligand A.

Output:
1
2025-04-17 05:57:10,431 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (349.479 and 341.415 Da) fall within the ideal 200-500 Da range.

**TPSA:** Both ligands have TPSA values (87.36 and 84.83) below the 90 A^2 threshold desirable for CNS targets, which is excellent.

**logP:** Ligand A (1.231) is within the optimal 1-3 range, while Ligand B (2.343) is also acceptable, leaning towards the higher end.

**H-Bond Donors/Acceptors:** Both ligands have 2 HBD and 6/5 HBA, respectively, which are within acceptable limits (<=5 HBD and <=10 HBA).

**QED:** Ligand A (0.835) has a significantly better QED score than Ligand B (0.691), indicating a more drug-like profile.

**DILI:** Ligand A (28.461) has a much lower DILI risk (better) than Ligand B (74.68). This is a significant advantage.

**BBB:** Ligand A (72.896) has a better BBB penetration percentile than Ligand B (61.535). While both are not extremely high, Ligand A is closer to the desirable >70 for CNS targets.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.117 and -5.438), which is unusual and suggests poor permeability. However, these values are on a log scale, so the absolute difference is important.

**Aqueous Solubility:** Both ligands have negative solubility values (-2.981 and -3.016), indicating poor aqueous solubility.

**hERG Inhibition:** Both ligands have low hERG inhibition liability (0.872 and 0.473), which is good.

**Microsomal Clearance:** Ligand A (-22.443) has significantly lower (better) microsomal clearance than Ligand B (42.91). This suggests better metabolic stability.

**In vitro Half-Life:** Ligand B (28.183) has a longer in vitro half-life than Ligand A (-16.866). This is a positive for Ligand B.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.095 and 0.325), which is favorable for CNS penetration.

**Binding Affinity:** Ligand B (-8.9 kcal/mol) has a slightly better binding affinity than Ligand A (-8.4 kcal/mol), but the difference is not substantial enough to outweigh other factors.

**Overall Assessment:**

Considering the GPCR-specific priorities, Ligand A is the more promising candidate. While Ligand B has slightly better affinity and half-life, Ligand A excels in crucial areas like DILI risk, BBB penetration, QED, and metabolic stability (lower Cl_mic). The lower DILI risk and better BBB are particularly important for a CNS target like DRD2. The slightly weaker affinity of Ligand A can potentially be optimized in subsequent iterations.

Output:
0
2025-04-17 05:57:10,431 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B based on the provided guidelines, prioritizing GPCR-specific properties (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (343.427 Da) is slightly lower, which could be beneficial for permeability.

**TPSA:** Ligand A (62.62) is significantly better than Ligand B (84.42). For CNS targets, TPSA should be <= 90, and A is comfortably within this range, while B is approaching the upper limit.

**logP:** Both ligands have acceptable logP values (A: 1.318, B: 1.989), falling within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A (HBD=0, HBA=4) is preferable to Ligand B (HBD=1, HBA=7). Lower HBD/HBA generally improves permeability.

**QED:** Both have reasonable QED scores (A: 0.445, B: 0.671), but B is better.

**DILI:** Ligand A (37.03) has a much lower DILI risk than Ligand B (67.197). This is a significant advantage for A.

**BBB:** Ligand A (65.413) has a better BBB percentile than Ligand B (53.005). While >70 is desirable, A is closer to that threshold and more favorable for a CNS target like DRD2.

**Caco-2 Permeability:** Ligand A (-4.407) has worse Caco-2 permeability than Ligand B (-5.117). Both are very poor, but B is slightly better.

**Aqueous Solubility:** Ligand A (-2.453) has slightly better solubility than Ligand B (-1.614).

**hERG Inhibition:** Both ligands have low hERG inhibition risk (A: 0.225, B: 0.429).

**Microsomal Clearance:** Ligand A (41.376) has lower microsomal clearance than Ligand B (55.091), indicating better metabolic stability.

**In vitro Half-Life:** Ligand A (-24.348) has a significantly longer in vitro half-life than Ligand B (28.492). This is a major advantage for A.

**P-gp Efflux:** Ligand A (0.173) has lower P-gp efflux than Ligand B (0.232), which is beneficial for CNS penetration.

**Binding Affinity:** Both ligands have very similar and strong binding affinities (A: -7.7 kcal/mol, B: -7.0 kcal/mol). A is slightly better, but the difference is relatively small.

**Overall Assessment:**

Ligand A is the stronger candidate. While Ligand B has a slightly better QED and Caco-2 permeability, Ligand A excels in crucial areas for a CNS-targeting GPCR ligand: lower TPSA, lower DILI risk, better BBB penetration, better metabolic stability (lower Cl_mic and longer t1/2), lower P-gp efflux, and slightly better binding affinity. The significantly lower DILI and improved BBB are particularly important.

Output:
0
2025-04-17 05:57:10,431 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (411.256 Da) is slightly higher, but still acceptable. Ligand B (360.889 Da) is preferable.

**TPSA:** Ligand A (95.79) is borderline for CNS targets (ideally <90), while Ligand B (61.02) is well within the desired range. This favors Ligand B.

**logP:** Ligand A (1.991) is optimal. Ligand B (4.173) is a bit high, potentially leading to solubility issues and off-target interactions, but not drastically so. Ligand A is slightly favored.

**H-Bond Donors/Acceptors:** Ligand A (HBD=1, HBA=5) and Ligand B (HBD=2, HBA=3) both have reasonable numbers of H-bond donors and acceptors, falling within the acceptable limits.

**QED:** Both ligands have good QED scores (Ligand A: 0.456, Ligand B: 0.841). Ligand B is significantly better, indicating a more drug-like profile.

**DILI:** Ligand A (65.568) has a higher DILI risk than Ligand B (32.299). This is a significant advantage for Ligand B.

**BBB:** Both ligands have excellent BBB penetration (Ligand A: 83.172, Ligand B: 81.194). This is crucial for a CNS target like DRD2, and the difference is negligible.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values, which is unusual and suggests a potential issue with the experimental setup or data quality. However, we'll proceed assuming these represent low permeability.

**Aqueous Solubility:** Both ligands have very poor aqueous solubility (-3.96 and -4.155). This is a concern, but can sometimes be mitigated with formulation strategies.

**hERG Inhibition:** Both ligands show low hERG inhibition liability (Ligand A: 0.677, Ligand B: 0.943). This is good.

**Microsomal Clearance:** Ligand A (1.018) has a much lower microsomal clearance than Ligand B (33.115), suggesting better metabolic stability. This is a strong advantage for Ligand A.

**In vitro Half-Life:** Ligand A (19.541) has a shorter half-life than Ligand B (-8.902). The negative value for Ligand B is suspect and suggests a very rapid degradation. Ligand A is favored.

**P-gp Efflux:** Ligand A (0.165) has much lower P-gp efflux liability than Ligand B (0.643), which is beneficial for CNS exposure. This favors Ligand A.

**Binding Affinity:** Ligand A (-7.9 kcal/mol) has slightly better binding affinity than Ligand B (-8.0 kcal/mol). While the difference is small, it is still a positive for Ligand A.

**Overall Assessment:**

Ligand B has advantages in QED and DILI risk. However, Ligand A excels in metabolic stability (Cl_mic), P-gp efflux, and has a slightly better binding affinity. Critically, Ligand B's negative in vitro half-life is a major red flag. The TPSA of Ligand A is slightly higher, but still within an acceptable range, and the logP is optimal. Considering the GPCR-specific priorities (BBB is good for both, logP is acceptable for A, Pgp is better for A, TPSA is better for B, and affinity is slightly better for A), and the significant concerns with Ligand B's half-life and DILI, **Ligand A is the more promising drug candidate.**

Output:
0
2025-04-17 05:57:10,432 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (339.4) is slightly preferred due to being closer to the lower end, potentially aiding permeability.

**TPSA:** Ligand A (79.26) is excellent for CNS penetration, well below the 90 threshold. Ligand B (114.19) is higher, but still potentially acceptable, although less ideal.

**logP:** Both ligands have good logP values (A: 2.388, B: 1.791) within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Both have acceptable HBD counts (2). Ligand B has a higher HBA count (7 vs 4), which *could* slightly hinder permeability, but isn't a major concern.

**QED:** Ligand A (0.898) has a significantly better QED score than Ligand B (0.648), indicating a more drug-like profile.

**DILI:** Ligand B (92.672) has a higher DILI risk than Ligand A (77.278), making A more favorable.

**BBB:** Ligand A (79.294) has a very good BBB penetration percentile, exceeding the desirable >70 threshold. Ligand B (38.775) is significantly lower, a major drawback for a CNS target.

**Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and suggests a potential issue with the data or prediction method. However, the magnitude of the negative value is larger for Ligand B (-5.754 vs -4.926), suggesting potentially lower permeability.

**Aqueous Solubility:** Both have negative solubility values, also unusual. Ligand A (-3.81) is slightly better than Ligand B (-2.748).

**hERG:** Both ligands have low hERG inhibition liability (A: 0.375, B: 0.265), which is good.

**Microsomal Clearance:** Ligand B (0.174) has a much lower microsomal clearance than Ligand A (5.037), suggesting greater metabolic stability.

**In vitro Half-Life:** Ligand B (42.258) has a longer in vitro half-life than Ligand A (35.071), which is favorable.

**P-gp Efflux:** Ligand A (0.082) has lower P-gp efflux liability than Ligand B (0.065), which is good for CNS exposure.

**Binding Affinity:** Ligand B (-8.3 kcal/mol) has a significantly stronger binding affinity than Ligand A (-10.2 kcal/mol). This is a substantial advantage.

**Overall Assessment:**

While Ligand B has a superior binding affinity and better metabolic stability/half-life, the significantly lower BBB penetration (38.775) is a critical disadvantage for a CNS target like DRD2. Ligand A, despite its slightly weaker binding affinity, has a much better BBB score (79.294), a higher QED, and a lower DILI risk. The combination of these factors, particularly the BBB score, makes Ligand A the more promising candidate. The unusual negative Caco-2 and solubility values are concerning for both, but the other advantages of Ligand A outweigh these concerns.

Output:
0
2025-04-17 05:57:10,432 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (340.427 and 346.435 Da) fall within the ideal range of 200-500 Da.

**TPSA:** Ligand A (77.0) is significantly better than Ligand B (106.14). For CNS targets, we want TPSA <= 90, and A is comfortably within that range, while B is pushing the limit.

**logP:** Ligand A (3.788) is optimal (1-3), while Ligand B (0.856) is a bit low, potentially hindering permeation.

**H-Bond Donors/Acceptors:** Ligand A (1 HBD, 5 HBA) and Ligand B (2 HBD, 6 HBA) are both acceptable, well below the thresholds of 5 and 10 respectively.

**QED:** Ligand A (0.866) is excellent, indicating high drug-likeness. Ligand B (0.645) is still acceptable, but less favorable.

**DILI:** Ligand A (70.686) has a moderate DILI risk, while Ligand B (34.277) has a very low risk. This is a point in favor of Ligand B.

**BBB:** Both ligands have good BBB penetration (Ligand A: 75.107, Ligand B: 72.586), exceeding the 70% threshold for CNS targets.

**Caco-2 Permeability:** Ligand A (-4.635) and Ligand B (-5.612) both have negative values, indicating poor permeability. However, these values are on a scale where lower values are worse, and B is slightly worse than A.

**Aqueous Solubility:** Ligand A (-4.652) and Ligand B (-2.239) both have negative solubility values, indicating poor solubility. B is slightly better than A.

**hERG Inhibition:** Both ligands show very low hERG inhibition risk (Ligand A: 0.282, Ligand B: 0.101), which is excellent.

**Microsomal Clearance:** Ligand A (83.775) has higher clearance than Ligand B (19.69), suggesting lower metabolic stability. This favors Ligand B.

**In vitro Half-Life:** Both ligands have negative half-lives (-13.158 and -13.484). These values are likely on a log scale, and indicate relatively short half-lives. Ligand B is slightly worse.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (Ligand A: 0.118, Ligand B: 0.014), which is favorable for CNS penetration. Ligand B is significantly better.

**Binding Affinity:** Ligand A (-9.1 kcal/mol) has a significantly stronger binding affinity than Ligand B (-7.9 kcal/mol). This is a substantial advantage, potentially outweighing some of the ADME drawbacks. A difference of >1.5 kcal/mol is considered significant.

**Overall Assessment:**

Ligand A excels in binding affinity and TPSA, and has good BBB penetration and QED. However, it has moderate DILI risk, higher clearance, and lower solubility. Ligand B has better DILI, clearance, solubility, and P-gp efflux, but weaker binding affinity and a higher TPSA. Given the importance of strong binding for GPCR ligands, and the acceptable BBB penetration for both, the superior affinity of Ligand A is the deciding factor.

Output:
1
2025-04-17 05:57:10,432 - INFO - Batch 241 complete. Total preferences: 3856
2025-04-17 05:57:10,432 - INFO - Processing batch 242/512...
2025-04-17 05:57:53,593 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (364.27 and 361.27 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (59.5) is significantly better than Ligand B (74.25). For a CNS target like DRD2, TPSA should be <= 90, and A is comfortably within this range, while B is approaching the upper limit.

**3. logP:** Both ligands have good logP values (2.681 and 3.084), falling within the optimal 1-3 range.

**4. H-Bond Donors:** Ligand A (0) is preferable to Ligand B (3). Fewer HBDs generally improve permeability.

**5. H-Bond Acceptors:** Ligand A (4) is better than Ligand B (3). Both are within the acceptable range of <=10.

**6. QED:** Both ligands have good QED scores (0.611 and 0.733), indicating good drug-like properties.

**7. DILI:** Ligand A (66.344) has a slightly higher DILI risk than Ligand B (54.75), but both are acceptable (<60 is good).

**8. BBB:** This is a critical parameter for CNS targets. Ligand A (83.986) has a significantly higher BBB penetration percentile than Ligand B (50.368). This is a major advantage for A.

**9. Caco-2 Permeability:** Ligand A (-4.337) is worse than Ligand B (-5.137), indicating lower intestinal absorption. However, for a CNS target, intestinal absorption is less critical than BBB penetration.

**10. Aqueous Solubility:** Both ligands have poor aqueous solubility (-3.315 and -3.613). This could pose formulation challenges, but is less critical than CNS penetration for a CNS target.

**11. hERG Inhibition:** Both ligands have low hERG inhibition liability (0.447 and 0.597), which is good.

**12. Microsomal Clearance:** Ligand B (36.497) has a significantly lower microsomal clearance than Ligand A (70.171), suggesting better metabolic stability.

**13. In vitro Half-Life:** Ligand B (12.463) has a longer in vitro half-life than Ligand A (-4.767), which is desirable.

**14. P-gp Efflux:** Ligand A (0.17) has lower P-gp efflux than Ligand B (0.126), which is favorable for CNS exposure.

**15. Binding Affinity:** Ligand B (-9.8 kcal/mol) has a slightly better binding affinity than Ligand A (-8.8 kcal/mol). This is a 1 kcal/mol difference, which is significant, but may be outweighed by other factors.

**Overall Assessment:**

Ligand A is superior due to its significantly better BBB penetration (83.986 vs 50.368) and lower TPSA (59.5 vs 74.25), both crucial for a CNS-targeting GPCR. While Ligand B has better metabolic stability and slightly better affinity, the improved CNS penetration of Ligand A is more important for DRD2. The slightly lower affinity of A can potentially be optimized in subsequent iterations.

Output:
1
2025-04-17 05:57:53,594 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (362.495 Da) is slightly higher than Ligand B (347.419 Da), but both are acceptable.

**TPSA:** Ligand A (75.36) is much better than Ligand B (100.35). For CNS targets, we want TPSA <= 90, so Ligand A is preferable.

**logP:** Ligand A (3.758) is optimal (1-3), while Ligand B (0.344) is quite low, potentially hindering permeability. This is a significant advantage for Ligand A.

**H-Bond Donors/Acceptors:** Both have 2 HBDs, which is good. Ligand A has 5 HBAs, and Ligand B has 6. Both are acceptable, being under the 10 HBA limit.

**QED:** Both ligands have similar QED values (0.734 and 0.693), indicating good drug-like properties.

**DILI:** Both have acceptable DILI risk (Ligand A: 55.293, Ligand B: 50.136), below the 60 threshold.

**BBB:** Ligand A (82.513) has a significantly better BBB percentile than Ligand B (53.703). This is crucial for a CNS target like DRD2.

**Caco-2 Permeability:** Both have negative Caco-2 values (-5.065 and -5.095), which is unusual and suggests poor permeability. However, these values are on a log scale, and the absolute difference isn't huge.

**Aqueous Solubility:** Both have negative solubility values (-4.341 and -2.219), indicating poor aqueous solubility. This could be a formulation challenge, but is not a dealbreaker at this stage.

**hERG:** Ligand A (0.563) has a slightly higher hERG risk than Ligand B (0.038), but both are relatively low.

**Microsomal Clearance:** Ligand A (88.637) has a higher microsomal clearance than Ligand B (15.15). This means Ligand B is more metabolically stable, which is desirable.

**In vitro Half-Life:** Ligand A (10.54) has a longer half-life than Ligand B (-1.277), which is a positive.

**P-gp Efflux:** Ligand A (0.616) has a lower P-gp efflux liability than Ligand B (0.048). Lower P-gp efflux is better for CNS exposure.

**Binding Affinity:** Ligand A (-9.5 kcal/mol) has a significantly stronger binding affinity than Ligand B (-7.6 kcal/mol). This difference of 1.9 kcal/mol is substantial and can outweigh some of the ADME drawbacks.

**Overall Assessment:**

Ligand A is the superior candidate. While it has slightly higher DILI and hERG risk and higher clearance, its significantly better BBB penetration, optimal logP, and *much* stronger binding affinity outweigh these concerns. The lower TPSA is also a significant advantage for CNS penetration. Ligand B's low logP is a major drawback, and its weaker affinity is difficult to overcome.

Output:
1
2025-04-17 05:57:53,594 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (347.415 and 346.471 Da) fall comfortably within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (92.45) is higher than Ligand B (58.64). For CNS targets, we prefer TPSA <= 90, so Ligand B is significantly better here.

**3. logP:** Both ligands have a logP around 2.2 (2.216 and 2.292), which is optimal (1-3).

**4. H-Bond Donors:** Ligand A has 3 HBD, while Ligand B has 1. Both are within the acceptable limit of <=5.

**5. H-Bond Acceptors:** Ligand A has 4 HBA, and Ligand B has 3. Both are within the acceptable limit of <=10.

**6. QED:** Ligand A (0.716) has a much better QED score than Ligand B (0.286), indicating a more drug-like profile.

**7. DILI:** Ligand A (65.607) has a higher DILI risk than Ligand B (13.571). Lower is better, so Ligand B is preferable.

**8. BBB:** Ligand B (70.764) has a better BBB penetration percentile than Ligand A (67.352), though both are reasonably good (>70 is desirable).

**9. Caco-2 Permeability:** Ligand A (-4.904) has worse Caco-2 permeability than Ligand B (-4.711). Higher is better, so Ligand B is preferable.

**10. Aqueous Solubility:** Ligand A (-3.516) has worse aqueous solubility than Ligand B (-2.071). Higher is better, so Ligand B is preferable.

**11. hERG Inhibition:** Ligand A (0.54) has a slightly higher hERG inhibition risk than Ligand B (0.313). Lower is better, so Ligand B is preferable.

**12. Microsomal Clearance:** Ligand A (52.681) has higher microsomal clearance than Ligand B (5). Lower clearance is better for metabolic stability, so Ligand B is preferable.

**13. In vitro Half-Life:** Ligand A (-17.277) has a negative half-life, which is unusual and suggests rapid degradation. Ligand B (-1.414) is better.

**14. P-gp Efflux:** Ligand A (0.142) has higher P-gp efflux than Ligand B (0.1). Lower efflux is better for CNS exposure, so Ligand B is preferable.

**15. Binding Affinity:** Ligand A (-8.2 kcal/mol) has a significantly better binding affinity than Ligand B (-7.4 kcal/mol). A >1.5 kcal/mol advantage in affinity can outweigh some ADME drawbacks.

**Overall Assessment:**

While Ligand A has a significantly better binding affinity and QED, Ligand B excels in almost all ADME properties crucial for CNS penetration and safety (TPSA, DILI, BBB, Caco-2, Solubility, hERG, Cl_mic, Pgp, t1/2). The substantial difference in binding affinity (-0.8 kcal/mol) is important, but the ADME profile of Ligand B is far superior, especially considering this is a CNS target. The poor half-life and high clearance of Ligand A are major concerns.

Output:
1
2025-04-17 05:57:53,594 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (352.435 and 362.436 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (113.76) is better than Ligand B (58.2). For CNS targets, TPSA should be <= 90, and both meet this criterion, but A is closer to the upper limit.

**logP:** Ligand B (3.414) is better than Ligand A (-0.031). The optimal range is 1-3, and B falls within it, while A is significantly below 1, potentially hindering permeation.

**H-Bond Donors/Acceptors:** Ligand A (HBD=3, HBA=4) is slightly higher in both counts than Ligand B (HBD=2, HBA=2). Both are within acceptable limits (<=5 HBD and <=10 HBA).

**QED:** Both ligands have good QED scores (A=0.558, B=0.682), indicating drug-like properties.

**DILI:** Ligand B (40.054) has a much lower DILI risk than Ligand A (16.13). This is a significant advantage for B.

**BBB:** Ligand A (80.07) has a substantially better BBB penetration score than Ligand B (57.852). This is a critical factor for a CNS target like DRD2.

**Caco-2 Permeability:** Ligand A (-5.333) has a lower Caco-2 permeability than Ligand B (-4.696). Both are negative, indicating poor permeability, but B is slightly better.

**Aqueous Solubility:** Ligand A (-1.248) has slightly better aqueous solubility than Ligand B (-4.296).

**hERG Inhibition:** Both ligands have low hERG inhibition risk (A=0.2, B=0.461).

**Microsomal Clearance:** Ligand A (-16.991) has significantly lower microsomal clearance than Ligand B (53.858), indicating better metabolic stability.

**In vitro Half-Life:** Ligand A (-8.009) has a longer in vitro half-life than Ligand B (3.083).

**P-gp Efflux:** Ligand A (0.01) has a much lower P-gp efflux liability than Ligand B (0.082). Lower efflux is desirable for CNS exposure.

**Binding Affinity:** Ligand B (-7.3 kcal/mol) has a slightly better binding affinity than Ligand A (-8.4 kcal/mol). While A is better, the difference is not substantial enough to outweigh other factors.

**Overall Assessment:**

Ligand A excels in BBB penetration, metabolic stability, half-life, and P-gp efflux. However, its poor logP and lower DILI score are concerning. Ligand B has a better logP, lower DILI, and slightly better affinity, but suffers from lower BBB penetration and higher P-gp efflux.

Given the GPCR-specific priorities, particularly BBB for a CNS target, and the relatively small difference in binding affinity, Ligand A is the more promising candidate. The improved BBB penetration and reduced P-gp efflux are crucial for CNS exposure. The logP issue could potentially be addressed through further optimization.

Output:
0
2025-04-17 05:57:53,595 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (362.459 Da and 357.523 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (95.12) is higher than the preferred <90 for CNS targets, while Ligand B (59.22) is well within the range. This is a significant advantage for Ligand B.

**logP:** Ligand A (0.45) is quite low, potentially hindering permeability. Ligand B (4.647) is slightly high, but still within an acceptable range, and could be optimized.

**H-Bond Donors/Acceptors:** Ligand A has 0 HBD and 7 HBA, which is reasonable. Ligand B has 1 HBD and 4 HBA, also acceptable.

**QED:** Both ligands have good QED scores (0.772 and 0.819), indicating good drug-like properties.

**DILI:** Ligand A (63.086) has a higher DILI risk than Ligand B (31.989), which is preferable.

**BBB:** Ligand B (85.072) has a significantly better BBB penetration percentile than Ligand A (50.795). This is *critical* for a CNS target like DRD2.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.979 and -4.964), which is unusual and suggests poor permeability. However, these values are on a log scale and are likely indicative of very low permeability.

**Aqueous Solubility:** Both ligands have negative solubility values (-3.524 and -4.222), indicating poor aqueous solubility. This is a concern for both compounds.

**hERG Inhibition:** Ligand A (0.128) has a slightly lower hERG risk than Ligand B (0.846), but both are relatively low.

**Microsomal Clearance:** Ligand B (66.224) has a higher microsomal clearance than Ligand A (39.186), meaning it's metabolized faster. Ligand A has better metabolic stability.

**In vitro Half-Life:** Ligand A (-8.552) has a negative half-life, which is not physically possible and indicates a problem with the data. Ligand B (26.368) has a reasonable half-life.

**P-gp Efflux:** Ligand A (0.121) has lower P-gp efflux liability than Ligand B (0.544), which is beneficial for CNS penetration.

**Binding Affinity:** Ligand B (-7.8) has a slightly better binding affinity than Ligand A (-7.0). While both are good, the 0.8 kcal/mol difference is noteworthy.

**Overall Assessment:**

Ligand B is the stronger candidate. Its superior BBB penetration (85.072 vs 50.795) is a major advantage for a CNS target. While its logP is slightly higher and clearance is higher, these can be addressed through further optimization. The significantly lower DILI risk is also a positive. The questionable half-life value for Ligand A is a red flag. The slightly better affinity of Ligand B further supports its selection.

Output:
1
2025-04-17 05:57:53,595 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (349.308 and 352.475 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Both ligands have TPSA values around 59-60 A<sup>2</sup>, which is excellent for CNS penetration, well below the 90 A<sup>2</sup> threshold.

**3. logP:** Ligand A (4.045) is slightly higher than optimal (1-3), potentially leading to solubility issues. Ligand B (1.679) is within the optimal range.

**4. H-Bond Donors:** Both have 0 HBD, which is acceptable.

**5. H-Bond Acceptors:** Both have 4 HBA, which is acceptable.

**6. QED:** Both ligands have good QED scores (0.583 and 0.775), indicating drug-likeness.

**7. DILI:** Ligand A (67.546) has a moderate DILI risk, while Ligand B (30.903) has a low DILI risk. This favors Ligand B.

**8. BBB:** Ligand B (84.8%) has significantly better predicted BBB penetration than Ligand A (70.531%). This is a critical factor for a CNS target like DRD2.

**9. Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and difficult to interpret without further context. However, the values are similar.

**10. Aqueous Solubility:** Both have negative solubility values, which is also unusual. Ligand B is slightly better (-1.532 vs -5.87).

**11. hERG Inhibition:** Both ligands show low hERG inhibition liability (0.844 and 0.343), which is favorable.

**12. Microsomal Clearance:** Ligand A (98.633) has a higher microsomal clearance than Ligand B (30.592), suggesting lower metabolic stability. Ligand B is preferred.

**13. In vitro Half-Life:** Ligand B (-11.713) has a significantly longer predicted half-life than Ligand A (-6.713). This is a strong advantage for Ligand B.

**14. P-gp Efflux:** Ligand A (0.38) has lower P-gp efflux liability than Ligand B (0.085), which is favorable for CNS exposure.

**15. Binding Affinity:** Ligand B (-7.7 kcal/mol) has a slightly better binding affinity than Ligand A (-9.0 kcal/mol). While A is more negative, the difference is not substantial enough to outweigh the other factors.

**Overall Assessment:**

Ligand B is the more promising candidate. It has better BBB penetration, lower DILI risk, better metabolic stability (lower Cl_mic, longer half-life), and comparable binding affinity. While Ligand A has slightly lower P-gp efflux, the other advantages of Ligand B, especially the superior BBB penetration and metabolic stability, are more crucial for a CNS-targeting GPCR like DRD2.

Output:
1
2025-04-17 05:57:53,595 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (342.443 and 362.367 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (66.4) is better than Ligand B (49.41). Both are below the 90 A^2 threshold for CNS targets, which is excellent.

**logP:** Ligand A (2.06) is within the optimal 1-3 range. Ligand B (3.443) is slightly higher, but still acceptable.

**H-Bond Donors/Acceptors:** Ligand A (0 HBD, 4 HBA) and Ligand B (1 HBD, 2 HBA) both have favorable counts, well below the limits of 5 and 10 respectively.

**QED:** Both ligands have similar QED values (0.768 and 0.756), indicating good drug-likeness.

**DILI:** Ligand A (24.583) has a significantly lower DILI risk than Ligand B (46.297). This is a major advantage for Ligand A.

**BBB:** Both ligands exhibit excellent BBB penetration (Ligand A: 84.684, Ligand B: 88.096), exceeding the desirable >70% threshold for CNS targets. Ligand B is slightly better.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.715 and -4.468). This is unusual and suggests poor permeability. However, these values are on a log scale, and the negative values may not be directly comparable.

**Aqueous Solubility:** Ligand A (-1.393) is better than Ligand B (-3.156). Higher solubility is generally preferred.

**hERG Inhibition:** Ligand A (0.221) has a lower hERG inhibition liability than Ligand B (0.694), indicating a lower risk of cardiotoxicity.

**Microsomal Clearance:** Ligand A (16.405) has a considerably lower microsomal clearance than Ligand B (52.177), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (-4.168) has a longer in vitro half-life than Ligand B (14.075).

**P-gp Efflux:** Ligand A (0.034) has a much lower P-gp efflux liability than Ligand B (0.145), which is crucial for CNS penetration.

**Binding Affinity:** Ligand B (-8.2) has a slightly better binding affinity than Ligand A (-7.9). However, the difference is only 0.3 kcal/mol, which is not substantial enough to outweigh the other significant advantages of Ligand A.

**Overall Assessment:**

Ligand A consistently outperforms Ligand B in crucial ADME properties (DILI, metabolic stability, P-gp efflux, solubility) and hERG risk, while maintaining comparable BBB penetration and only slightly weaker binding affinity. The lower DILI risk and better metabolic stability are particularly important for a CNS drug candidate. The slightly better affinity of Ligand B is not enough to compensate for the superior ADME profile of Ligand A.

Output:
1
2025-04-17 05:57:53,595 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (380.413 Da) is slightly higher than Ligand B (348.443 Da), but both are acceptable.

**TPSA:** Ligand A (104.73) is higher than the preferred <90 for CNS targets, while Ligand B (67.87) is well within the range. This is a significant advantage for Ligand B.

**logP:** Ligand A (0.228) is quite low, potentially hindering membrane permeability. Ligand B (1.539) is within the optimal 1-3 range. This favors Ligand B.

**H-Bond Donors/Acceptors:** Ligand A has 3 HBD and 6 HBA, acceptable values. Ligand B has 1 HBD and 4 HBA, also acceptable and slightly more favorable due to the lower counts.

**QED:** Both ligands have reasonable QED values (Ligand A: 0.37, Ligand B: 0.74). Ligand B's value is significantly higher, indicating better overall drug-likeness.

**DILI:** Both ligands have low DILI risk (Ligand A: 35.285, Ligand B: 34.432), which is good.

**BBB:** Ligand A (59.364) has a moderate BBB penetration, below the desirable >70 for CNS targets. Ligand B (74.176) is much better, exceeding the 70% threshold. This is a crucial advantage for Ligand B.

**Caco-2 Permeability:** Both have negative Caco-2 values (-5.384 and -5.003), which is unusual and likely indicates poor permeability *in vitro*. However, the values are similar.

**Aqueous Solubility:** Both have negative solubility values (-1.71 and -2.2), also unusual. Solubility is likely low for both.

**hERG Inhibition:** Both ligands show very low hERG inhibition risk (0.108 and 0.111), which is excellent.

**Microsomal Clearance:** Ligand A (31.616) and Ligand B (29.495) have similar, relatively low, microsomal clearance values, suggesting reasonable metabolic stability.

**In vitro Half-Life:** Ligand A (-31.826) has a negative half-life, which is nonsensical. Ligand B (54.277) has a reasonable half-life. This is a major issue for Ligand A.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.022 and 0.028), which is favorable for CNS penetration.

**Binding Affinity:** Ligand B (-8.2 kcal/mol) has a significantly stronger binding affinity than Ligand A (-6.2 kcal/mol). This >1.5 kcal/mol difference is substantial and can outweigh minor ADME drawbacks.

**Overall Assessment:**

Ligand B is clearly superior. It has better TPSA, logP, QED, and, critically, BBB penetration and binding affinity. Ligand A's low logP, questionable half-life, and lower BBB penetration are significant drawbacks. The stronger binding affinity of Ligand B further solidifies its advantage.

Output:
1
2025-04-17 05:57:53,596 - INFO - Reasoning:

Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (351.407 Da) is slightly lower, which could be advantageous for permeability.

**2. TPSA:** Ligand A (134.58) is better than Ligand B (105.98) as it is closer to the 140 A^2 threshold for oral absorption, and more importantly, still reasonably low for CNS penetration. Ligand B is very low, which *could* indicate a lack of necessary interactions.

**3. logP:** Ligand A (0.315) is suboptimal, being below the preferred 1-3 range. Ligand B (0.622) is also low, but better than A. Both may struggle with membrane permeability.

**4. H-Bond Donors:** Ligand A (3) is acceptable. Ligand B (2) is also acceptable.

**5. H-Bond Acceptors:** Both ligands (A: 7, B: 7) are within the acceptable limit of 10.

**6. QED:** Both ligands have similar, acceptable QED values (A: 0.695, B: 0.641).

**7. DILI:** Ligand A (43.622) has a lower DILI risk than Ligand B (66.615), which is a significant advantage.

**8. BBB:** Ligand A (80.031) has a substantially better BBB penetration percentile than Ligand B (37.844). This is *critical* for a CNS target like DRD2.

**9. Caco-2 Permeability:** Both have negative values, which is unusual and suggests poor permeability. Ligand A (-5.261) is slightly better than Ligand B (-5.688).

**10. Aqueous Solubility:** Both have negative values, indicating poor solubility. Ligand A (-2.355) is slightly better than Ligand B (-2.402).

**11. hERG Inhibition:** Both ligands have low hERG inhibition risk (A: 0.402, B: 0.057). Ligand B is slightly better.

**12. Microsomal Clearance:** Ligand A (-2.74) has a lower (better) microsomal clearance than Ligand B (48.769), suggesting better metabolic stability.

**13. In vitro Half-Life:** Ligand A (-21.69) has a negative half-life, which is not possible. This is a red flag. Ligand B (-41.076) also has a negative half-life, also a red flag.

**14. P-gp Efflux:** Ligand A (0.016) has very low P-gp efflux, which is excellent for CNS penetration. Ligand B (0.058) is also low, but higher than A.

**15. Binding Affinity:** Ligand B (-6.4 kcal/mol) has a significantly stronger binding affinity than Ligand A (0.0 kcal/mol). This is a major advantage, potentially outweighing some of the ADME concerns.

**Overall Assessment:**

Despite Ligand B's superior binding affinity, the significantly better BBB penetration, lower DILI risk, and better metabolic stability of Ligand A make it the more promising candidate. The negative half-life values for both are concerning and need to be investigated, but the other factors strongly favor Ligand A. Ligand B's strong affinity is attractive, but its poor BBB penetration and higher DILI risk are significant drawbacks for a CNS-targeted drug.

Output:
0
2025-04-17 05:57:53,596 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (364.471 and 348.403 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (84.3) is excellent, well below the 90 A^2 threshold for CNS targets. Ligand B (102.44) is still reasonable, but less optimal.

**3. logP:** Both ligands have good logP values (1.565 and 1.255), falling within the 1-3 range.

**4. H-Bond Donors:** Ligand A (1) is preferred over Ligand B (2). Lower HBD generally improves permeability.

**5. H-Bond Acceptors:** Ligand A (5) is better than Ligand B (6).

**6. QED:** Ligand A (0.835) has a significantly better QED score than Ligand B (0.396), indicating a more drug-like profile.

**7. DILI:** Ligand A (49.477) has a lower DILI risk than Ligand B (56.262), both are acceptable, but A is better.

**8. BBB:** Ligand A (85.343) has a much higher BBB percentile than Ligand B (62.156). This is *critical* for a CNS target like DRD2.

**9. Caco-2:** Both have negative Caco-2 values which is unusual and makes comparison difficult.

**10. Solubility:** Both have negative solubility values which is unusual and makes comparison difficult.

**11. hERG:** Ligand A (0.539) has a much lower hERG risk than Ligand B (0.116).

**12. Cl_mic:** Ligand B (13.308) has a lower microsomal clearance than Ligand A (21.561), suggesting better metabolic stability.

**13. t1/2:** Ligand B (-23.747) has a negative in vitro half-life, which is concerning and likely an error. Ligand A (22.121) is a reasonable value.

**14. Pgp:** Ligand A (0.169) has a lower P-gp efflux liability than Ligand B (0.01), which is desirable for CNS penetration.

**15. Binding Affinity:** Ligand B (-8.2 kcal/mol) has a significantly stronger binding affinity than Ligand A (0.0 kcal/mol). This is a substantial advantage.

**Overall Assessment:**

Despite Ligand B's superior binding affinity, Ligand A is the more promising drug candidate. The combination of excellent TPSA, high BBB penetration, good QED, lower DILI and hERG risk, and reasonable metabolic stability outweighs the affinity difference. Ligand B's poor BBB penetration, low QED, negative half-life, and higher Pgp efflux liability are significant drawbacks for a CNS-targeting drug. The negative values for Caco-2 and solubility are concerning for both compounds and would require further investigation.



Output:
0
2025-04-17 05:57:53,596 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (358.32 and 346.471 Da) fall comfortably within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (74.65) is slightly higher than Ligand B (69.64), but both are below the 90 A^2 threshold desirable for CNS targets.

**3. logP:** Both ligands have good logP values (1.243 and 1.835), falling within the optimal 1-3 range.

**4. H-Bond Donors:** Ligand A (1) is better than Ligand B (2) as lower HBDs are generally preferred.

**5. H-Bond Acceptors:** Ligand A (4) is better than Ligand B (3) as lower HBAs are generally preferred.

**6. QED:** Both ligands have acceptable QED values (0.821 and 0.771), indicating good drug-like properties.

**7. DILI:** Ligand A (70.531) has a higher DILI risk than Ligand B (7.445). This is a significant drawback for Ligand A.

**8. BBB:** Both ligands have excellent BBB penetration (78.596 and 71.927), exceeding the 70% threshold for CNS targets.

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.75 and -4.888), which is unusual and suggests poor permeability. However, these values are on a log scale, so small differences can be meaningful.

**10. Aqueous Solubility:** Both ligands have negative solubility values (-2.798 and -2.606), indicating poor aqueous solubility.

**11. hERG Inhibition:** Both ligands show low hERG inhibition risk (0.401 and 0.318).

**12. Microsomal Clearance:** Ligand A (1.627) has significantly lower microsomal clearance than Ligand B (5.966), suggesting better metabolic stability.

**13. In vitro Half-Life:** Ligand A (18.363) has a longer in vitro half-life than Ligand B (-0.217).

**14. P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.035 and 0.054), which is favorable for CNS penetration.

**15. Binding Affinity:** Both ligands have excellent binding affinities (-9.2 and -8.5 kcal/mol). Ligand A is slightly better (-9.2 kcal/mol).

**Overall Assessment:**

While Ligand A has a slightly better affinity and metabolic stability, the significantly higher DILI risk is a major concern. Ligand B, despite slightly lower affinity and higher clearance, presents a much more favorable safety profile (DILI). Given the importance of safety in drug development, and the acceptable affinity and BBB penetration of Ligand B, it is the more promising candidate.

Output:
1
2025-04-17 05:57:53,597 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (342.37 and 341.455 Da) fall comfortably within the ideal 200-500 Da range.

**2. TPSA:** Both ligands have TPSA values (59.5 and 58.37) below the 90 A^2 threshold desirable for CNS targets, which is excellent.

**3. logP:** Ligand A (2.563) is within the optimal 1-3 range. Ligand B (3.92) is slightly higher, approaching the upper limit, but still acceptable.

**4. H-Bond Donors:** Ligand A (0) is ideal. Ligand B (1) is also acceptable.

**5. H-Bond Acceptors:** Both ligands (4) are well below the 10 threshold.

**6. QED:** Both ligands have good QED scores (0.787 and 0.916), indicating good drug-like properties. Ligand B is slightly better.

**7. DILI:** Ligand A (56.611) has a slightly higher DILI risk than Ligand B (44.513), but both are below the concerning 60 threshold.

**8. BBB:** Both ligands exhibit excellent BBB penetration (98.216 and 95.967), exceeding the 70% threshold for CNS targets.

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.158 and -4.582). This is unusual and suggests poor permeability, but the scale is not specified, so it's difficult to interpret.

**10. Aqueous Solubility:** Both ligands have negative solubility values (-3.061 and -4.745). Similar to Caco-2, this is concerning and the scale is unknown.

**11. hERG:** Both ligands have low hERG inhibition liability (0.825 and 0.821), which is favorable.

**12. Microsomal Clearance:** Ligand A (68.543) has lower microsomal clearance than Ligand B (100.565), suggesting better metabolic stability.

**13. In vitro Half-Life:** Ligand A (-14.411) has a negative half-life, which is impossible. Ligand B (65.356) has a reasonable half-life. This is a major red flag for Ligand A.

**14. P-gp Efflux:** Both ligands have low P-gp efflux liability (0.209 and 0.622), which is good for CNS exposure.

**15. Binding Affinity:** Both ligands have very similar and strong binding affinities (-8.9 and -8.8 kcal/mol). The difference is negligible.

**Overall Assessment:**

Ligand B is significantly better due to its more reasonable *in vitro* half-life. The negative half-life for Ligand A is a critical flaw. While both have excellent BBB penetration and affinity, the metabolic stability issue with Ligand A is a deal-breaker. The slightly better QED and lower DILI risk of Ligand B are additional advantages. The negative Caco-2 and solubility values are concerning for both, but the half-life issue is more critical.

Output:
1
2025-04-17 05:57:53,597 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (371.853 and 388.599 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (80.66) is slightly higher than Ligand B (66.48). Both are below the 90 A^2 threshold for CNS targets, which is good.

**logP:** Ligand A (3.561) is slightly higher than Ligand B (2.028). Both are within the optimal 1-3 range, but Ligand B is closer to the lower bound.

**H-Bond Donors/Acceptors:** Both ligands have 1 HBD and a reasonable number of HBAs (6 and 4 respectively). This is acceptable.

**QED:** Both ligands have good QED scores (0.69 and 0.783), indicating drug-like properties.

**DILI:** Ligand A (88.6) has a higher DILI risk than Ligand B (31.563). This is a significant negative for Ligand A.

**BBB:** Ligand A (62.97) has a better BBB penetration score than Ligand B (45.909), but both are below the desirable >70 for CNS targets.

**Caco-2 Permeability:** Ligand A (-5.285) has worse Caco-2 permeability than Ligand B (-4.963), suggesting lower intestinal absorption.

**Aqueous Solubility:** Ligand A (-3.661) has worse aqueous solubility than Ligand B (-2.57).

**hERG:** Both ligands have very low hERG inhibition liability (0.145 and 0.148), which is excellent.

**Microsomal Clearance:** Ligand A (52.878) has higher microsomal clearance than Ligand B (37.383), meaning faster metabolism.

**In vitro Half-Life:** Ligand B (-3.373) has a significantly longer in vitro half-life than Ligand A (27.166).

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.12 and 0.052), which is good for CNS penetration.

**Binding Affinity:** Ligand A (-9.4 kcal/mol) has a significantly stronger binding affinity than Ligand B (-8.0 kcal/mol). This is a substantial advantage.

**Overall Assessment:**

Ligand A has a much stronger binding affinity, which is a major plus. However, it suffers from higher DILI risk, lower solubility, worse Caco-2 permeability, and faster metabolism. Ligand B has a better safety profile (lower DILI), better solubility, better permeability, and longer half-life, but its binding affinity is weaker.

Given the GPCR-specific priorities, the strong affinity of Ligand A is compelling, potentially outweighing some of its ADME drawbacks. The difference in affinity (>1.5 kcal/mol) is substantial. While the BBB values are both suboptimal, the stronger binding of Ligand A might still translate to sufficient target engagement *in vivo*. The DILI risk is a concern, but could be mitigated with further structural modifications.

Output:
1
2025-04-17 05:57:53,597 - INFO - Okay, let's analyze these two ligands for their potential as DRD2 drug candidates. DRD2 is a GPCR in the CNS, so BBB penetration, logP, Pgp efflux, TPSA, and binding affinity are key.

**Ligand A:** [367.852, 55.81, 1.632, 2, 4, 0.852, 39.977, 67.08, -4.949, -2.491, 0.708, 0.681, -0.777, 0.149, -8.6]
**Ligand B:** [390.531, 111.63, -0.061, 3, 7, 0.573, 37.844, 27.801, -5.857, -1.207, 0.232, -12.279, -3.019, 0.038, -8.2]

Here's a breakdown, comparing each property:

1. **MW:** Both are within the ideal range (200-500 Da). A (367.852) is slightly preferred due to being lower.
2. **TPSA:** A (55.81) is excellent for CNS penetration (<90). B (111.63) is higher, potentially hindering BBB penetration.
3. **logP:** A (1.632) is optimal (1-3). B (-0.061) is slightly low, potentially impacting permeability.
4. **HBD:** Both are acceptable (A: 2, B: 3), within the <5 guideline.
5. **HBA:** Both are acceptable (A: 4, B: 7), within the <10 guideline.
6. **QED:** A (0.852) is better than B (0.573), indicating a more drug-like profile.
7. **DILI:** Both are good (<40), with A (39.977) being slightly better than B (37.844).
8. **BBB:** A (67.08) is decent, but B (27.801) is significantly lower, a major concern for a CNS target.
9. **Caco-2:** A (-4.949) and B (-5.857) are both negative, indicating poor permeability. This is a weakness for both.
10. **Solubility:** A (-2.491) and B (-1.207) are both negative, indicating poor solubility. This is a weakness for both.
11. **hERG:** Both are low (A: 0.708, B: 0.232), suggesting low cardiotoxicity risk.
12. **Cl_mic:** A (0.681) is much better (lower is better) than B (-12.279), indicating better metabolic stability.
13. **t1/2:** A (-0.777) is better than B (-3.019), suggesting a longer half-life.
14. **Pgp:** A (0.149) is much better (lower is better) than B (0.038), indicating less P-gp efflux and better CNS exposure.
15. **Affinity:** A (-8.6) is slightly better than B (-8.2), though both are excellent.

**Overall Assessment:**

Ligand A is significantly better than Ligand B. While both have issues with Caco-2 and solubility, Ligand A excels in crucial areas for a CNS GPCR target: TPSA, logP, BBB, metabolic stability (Cl_mic), half-life, and P-gp efflux. The slightly better affinity of A is a bonus. Ligand B's poor BBB penetration is a major drawback, making it less likely to reach the target in the brain.

Output:
1
2025-04-17 05:57:53,597 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (361.511 and 340.467 Da) fall within the ideal range of 200-500 Da.

**TPSA:** Ligand A (71.09) is better than Ligand B (44.12), both are below the 90 A^2 threshold for CNS targets, which is excellent.

**logP:** Ligand A (2.96) is within the optimal range (1-3), while Ligand B (4.475) is slightly above, potentially leading to solubility issues.

**H-Bond Donors:** Ligand A (2) is better than the guideline of <=5, while Ligand B (0) is also good.

**H-Bond Acceptors:** Both ligands (A: 4, B: 4) are well within the acceptable limit of <=10.

**QED:** Both ligands have reasonable QED values (A: 0.847, B: 0.754), indicating good drug-like properties.

**DILI:** Ligand A (43.66) has a slightly higher DILI risk than Ligand B (35.595), but both are below the concerning threshold of 60.

**BBB:** This is a critical parameter for a CNS target like DRD2. Ligand B (75.998) significantly outperforms Ligand A (46.336) in BBB penetration, making it more likely to reach the target in the brain.

**Caco-2 Permeability:** Ligand A (-5.077) and Ligand B (-4.499) both have negative values, which is unusual and suggests poor permeability. However, the scale is not specified, so it's difficult to interpret.

**Aqueous Solubility:** Ligand A (-2.755) has better solubility than Ligand B (-6.217), which is a positive.

**hERG Inhibition:** Both ligands show low hERG inhibition risk (A: 0.112, B: 0.4), which is favorable.

**Microsomal Clearance:** Ligand B (100.471) has a much higher microsomal clearance than Ligand A (20.789), suggesting faster metabolism and potentially lower exposure.

**In vitro Half-Life:** Ligand A (9.213) has a better in vitro half-life than Ligand B (-9.609).

**P-gp Efflux:** Both ligands show low P-gp efflux liability (A: 0.164, B: 0.294), which is good.

**Binding Affinity:** Both ligands have similar and excellent binding affinities (-8.3 and -8.4 kcal/mol). The difference is negligible.

**Conclusion:**

While Ligand A has better solubility and metabolic stability, Ligand B's significantly higher BBB penetration (75.998 vs 46.336) is a decisive advantage for a CNS-targeting drug. The slightly higher logP of Ligand B is a minor concern, but the substantial improvement in BBB penetration outweighs this drawback. The better half-life of Ligand A is also a positive, but the difference isn't enough to overcome the BBB advantage of Ligand B.

Output:
1
2025-04-17 05:57:53,598 - INFO - Reasoning:

Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (346.402 and 347.419 Da) fall comfortably within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (70.59) is significantly better than Ligand B (87.54). For CNS targets, we want TPSA <= 90, and A is closer to the ideal <= 60 for optimal brain penetration. B is pushing the upper limit and may have reduced CNS penetration.

**3. logP:** Ligand A (3.562) is optimal (1-3), while Ligand B (0.246) is quite low. Low logP can hinder membrane permeability, including BBB penetration. This is a significant disadvantage for B.

**4. H-Bond Donors:** Ligand A (3) is acceptable, while Ligand B (1) is also good.

**5. H-Bond Acceptors:** Ligand A (3) is acceptable, and Ligand B (5) is also within the reasonable limit of 10.

**6. QED:** Both ligands have good QED scores (A: 0.749, B: 0.827), indicating generally drug-like properties.

**7. DILI:** Both ligands have similar DILI risk (A: 59.442, B: 58.085), and are both acceptable (<60).

**8. BBB:** Ligand A (61.962) is better than Ligand B (53.974), but both are below the desirable >70 for CNS targets. However, given the other factors, A's slightly better BBB is a plus.

**9. Caco-2:** Both ligands have negative Caco-2 values (-4.486 and -4.937), which is unusual and suggests poor permeability. This is a concern for both.

**10. Solubility:** Both ligands have negative solubility values (-4.038 and -1.553), also unusual and indicating poor aqueous solubility. This is a concern for both.

**11. hERG:** Ligand A (0.674) is better than Ligand B (0.136), indicating lower hERG inhibition risk.

**12. Cl_mic:** Ligand A (72.783) has a higher microsomal clearance than Ligand B (21.205), suggesting faster metabolism and potentially lower *in vivo* exposure. This is a negative for A.

**13. t1/2:** Ligand B (19.176) has a significantly longer in vitro half-life than Ligand A (4.971). This is a major advantage for B.

**14. Pgp:** Ligand A (0.361) has lower P-gp efflux liability than Ligand B (0.014), which is favorable for CNS penetration.

**15. Binding Affinity:** Ligand B (-7.8 kcal/mol) has a significantly stronger binding affinity than Ligand A (-9.4 kcal/mol). This is a substantial advantage for B, potentially outweighing some of its ADME drawbacks.

**Overall Assessment:**

While Ligand B has a lower logP and Caco-2/Solubility issues, its significantly stronger binding affinity (-7.8 vs -9.4 kcal/mol) and longer half-life are compelling advantages, especially for a GPCR target where potency is crucial. Ligand A has better TPSA and Pgp efflux, but the weaker binding and faster metabolism are significant drawbacks. Given the GPCR-specific priorities, the strong affinity of Ligand B is the most important factor.

Output:
1
2025-04-17 05:57:53,598 - INFO - Batch 242 complete. Total preferences: 3872
2025-04-17 05:57:53,598 - INFO - Processing batch 243/512...
2025-04-17 05:58:33,189 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands fall within the ideal range (200-500 Da). Ligand A (456.215 Da) is higher, but still acceptable. Ligand B (349.395 Da) is slightly lower, which could be beneficial for permeability.

**TPSA:** Ligand A (93.04) is excellent, falling well below the 90 A^2 threshold for CNS targets. Ligand B (126.96) is higher, but still within a reasonable range, though less optimal for CNS penetration.

**logP:** Ligand A (2.959) is optimal. Ligand B (-0.935) is significantly lower, which is a major concern. Low logP can lead to poor membrane permeability and reduced brain exposure.

**H-Bond Donors/Acceptors:** Ligand A (HBD=2, HBA=5) is good. Ligand B (HBD=3, HBA=8) is also acceptable, but slightly higher HBA could potentially impact permeability.

**QED:** Both ligands have similar, good QED values (A: 0.557, B: 0.565), indicating generally drug-like properties.

**DILI:** Ligand A (88.639) has a higher DILI risk than Ligand B (44.048). This is a negative for Ligand A.

**BBB:** Ligand A (58.278) has a moderate BBB penetration, while Ligand B (14.153) has very poor predicted BBB penetration. This is a critical difference, given DRD2 is a CNS target.

**Caco-2 Permeability:** Both have negative values, which is unusual. However, the magnitude is different. Ligand A (-5.383) is less negative than Ligand B (-5.942), suggesting slightly better permeability.

**Aqueous Solubility:** Both have negative values, which is also unusual. Ligand A (-4.388) is slightly better than Ligand B (-1.134).

**hERG Inhibition:** Ligand A (0.535) has a slightly higher hERG risk than Ligand B (0.009), but both are relatively low.

**Microsomal Clearance:** Ligand A (52.715) has moderate clearance, while Ligand B (-1.952) has very low clearance, suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (8.855 hours) has a reasonable half-life. Ligand B (18.394 hours) has a significantly longer half-life, which is advantageous.

**P-gp Efflux:** Ligand A (0.466) has lower P-gp efflux liability than Ligand B (0.004), meaning it is less likely to be pumped out of the brain.

**Binding Affinity:** Ligand A (-10.2 kcal/mol) has significantly stronger binding affinity than Ligand B (-8.2 kcal/mol). This is a substantial advantage, potentially outweighing some of the ADME drawbacks.

**Overall Assessment:**

Despite Ligand A's higher DILI risk, its superior binding affinity, better logP, and significantly better BBB penetration make it the more promising candidate. The strong binding affinity is a major driver, and the acceptable (though not ideal) ADME properties, combined with better CNS penetration, outweigh the concerns. Ligand B's very low logP and poor BBB penetration are major liabilities for a CNS-targeting drug.

Output:
1
2025-04-17 05:58:33,190 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (346.402 and 351.397 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (58.64) is slightly above the optimal <90 for CNS targets, but still reasonable. Ligand B (53.51) is excellent, well below 90.

**3. logP:** Both ligands have good logP values (2.9 and 2.362), falling within the 1-3 range.

**4. H-Bond Donors:** Ligand A has 1 HBD, which is good. Ligand B has 0, also good.

**5. H-Bond Acceptors:** Both ligands have 3 HBAs, which is within the acceptable limit of <=10.

**6. QED:** Both ligands have good QED scores (0.636 and 0.837), indicating drug-like properties.

**7. DILI:** Ligand A (57.658) has a moderate DILI risk, but is still acceptable. Ligand B (21.481) has a very low DILI risk, which is a significant advantage.

**8. BBB:** Ligand A (81.776) has a good BBB penetration percentile. Ligand B (95.192) is *excellent*, exceeding 90%, a critical factor for CNS targets like DRD2.

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.525 and -4.184) which is unusual and suggests poor permeability. This is a concern for both.

**10. Aqueous Solubility:** Both ligands have very poor aqueous solubility (-3.211 and -2.325). This is a significant drawback.

**11. hERG Inhibition:** Both ligands have low hERG inhibition liability (0.8 and 0.279), which is favorable.

**12. Microsomal Clearance:** Ligand A (65.803) has higher microsomal clearance than Ligand B (21.36), indicating lower metabolic stability.

**13. In vitro Half-Life:** Ligand B (-11.314) has a very negative half-life, which is problematic. Ligand A (2.138) is better, but still not ideal.

**14. P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.438 and 0.063), which is good for CNS penetration.

**15. Binding Affinity:** Ligand A (-8.9 kcal/mol) has a slightly better binding affinity than Ligand B (-8.3 kcal/mol). The difference is 0.6 kcal/mol, which is not substantial enough to overcome other significant drawbacks.

**Overall Assessment:**

Despite Ligand A's slightly better affinity, Ligand B is the more promising candidate. The key advantages of Ligand B are its significantly lower DILI risk, *much* better BBB penetration (95.192 vs 81.776), and lower microsomal clearance. While both have poor solubility and Caco-2 permeability, the CNS target profile of DRD2 prioritizes BBB penetration and minimizing off-target effects (DILI). The better BBB and lower DILI of Ligand B outweigh the small difference in binding affinity.

Output:
1
2025-04-17 05:58:33,190 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (344.375 and 342.403 Da) fall comfortably within the ideal 200-500 Da range.

**TPSA:** Ligand A (122.03) is slightly above the preferred <90 for CNS targets, but still reasonable. Ligand B (95.08) is excellent, falling well within the desired range.

**logP:** Ligand A (0.24) is quite low, potentially hindering membrane permeability. Ligand B (0.639) is also on the lower side but better than A. Both are below the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A has 3 HBD and 7 HBA, acceptable values. Ligand B has 1 HBD and 5 HBA, which is even more favorable.

**QED:** Both ligands have similar QED values (0.69 and 0.64), indicating good drug-likeness.

**DILI:** Ligand A (68.825) has a higher DILI risk than Ligand B (52.617), though both are not alarming.

**BBB:** This is crucial for a CNS target. Ligand A has a BBB percentile of 35.052, which is quite low and concerning. Ligand B has a significantly better BBB percentile of 65.374, which is good, though ideally >70.

**Caco-2 Permeability:** Both have negative Caco-2 values (-5.154 and -5.5), which is unusual and suggests poor permeability. This could be an artifact of the prediction method or indicate issues with the molecule's structure.

**Aqueous Solubility:** Both have negative solubility values (-2.511 and -1.397), also unusual and potentially problematic.

**hERG Inhibition:** Both ligands show very low hERG inhibition risk (0.059 and 0.043).

**Microsomal Clearance:** Ligand A (9.455) has lower microsomal clearance than Ligand B (16.8), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand B (-17.774) has a significantly longer predicted half-life than Ligand A (-3.268).

**P-gp Efflux:** Both have very low P-gp efflux liability (0.005 and 0.068), which is favorable for CNS penetration.

**Binding Affinity:** Ligand B (-9.0 kcal/mol) has a significantly stronger binding affinity than Ligand A (-7.5 kcal/mol). This is a substantial advantage (1.5 kcal/mol difference).

**Overall Assessment:**

Ligand B is the stronger candidate. While both have issues with predicted permeability and solubility, Ligand B's superior BBB penetration, significantly better binding affinity, and longer half-life outweigh the slightly higher metabolic clearance. The lower logP of Ligand B is also less problematic than that of Ligand A. The affinity difference is substantial enough to overcome the other ADME concerns, especially for a GPCR target where potency is key.

Output:
1
2025-04-17 05:58:33,190 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (350.39 and 373.425 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (98.66) is higher than Ligand B (71.53). For CNS targets, TPSA should be <= 90, so Ligand B is preferable.

**logP:** Ligand A (0.645) is quite low, potentially hindering permeability. Ligand B (1.812) is better, falling within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A has 4 HBD and 4 HBA, while Ligand B has 1 HBD and 5 HBA. Both are within acceptable limits (<=5 HBD and <=10 HBA).

**QED:** Both ligands have good QED scores (0.605 and 0.826, respectively), indicating drug-like properties. Ligand B is slightly better.

**DILI:** Both ligands have acceptable DILI risk (36.758 and 43.622, both <40).

**BBB:** Ligand B (85.498) has a significantly higher BBB percentile than Ligand A (61.923). This is a crucial advantage for a CNS target like DRD2.

**Caco-2 Permeability:** Both have negative Caco-2 values (-4.946 and -4.8), which is unusual and suggests poor permeability. However, these values are on a scale where negative values are possible and don't necessarily preclude development.

**Aqueous Solubility:** Both have negative solubility values (-1.971 and -2.322), also unusual, and suggest poor aqueous solubility.

**hERG Inhibition:** Both ligands show low hERG inhibition liability (0.329 and 0.165), which is favorable.

**Microsomal Clearance:** Ligand A (-4.474) has a more negative (lower) value, indicating potentially better metabolic stability than Ligand B (-3.967).

**In vitro Half-Life:** Ligand A (13.975) has a longer half-life than Ligand B (-1.731). This is a positive attribute.

**P-gp Efflux:** Both ligands show low P-gp efflux liability (0.049 and 0.042), which is good for CNS penetration.

**Binding Affinity:** Both ligands have excellent binding affinities (-8.9 and -9.1 kcal/mol). Ligand B is slightly better.

**Overall Assessment:**

Considering the GPCR-specific priorities, Ligand B is the more promising candidate. Its superior BBB penetration (85.498 vs 61.923) and better logP (1.812 vs 0.645) are critical for CNS drug development. While Ligand A has slightly better metabolic stability and half-life, the substantial advantage in BBB penetration and logP for Ligand B outweighs these factors. The similar binding affinities mean potency is not a differentiating factor. The negative Caco-2 and solubility values are concerning for both, but not necessarily disqualifying at this stage.

Output:
1
2025-04-17 05:58:33,190 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (373.45 and 361.471 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (105.23) is slightly above the optimal <90 for CNS targets, but still reasonable. Ligand B (96.01) is better, falling comfortably under 90.

**logP:** Ligand A (0.973) is a bit low, potentially hindering permeation. Ligand B (1.514) is better, within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A (2 HBD, 5 HBA) and Ligand B (3 HBD, 6 HBA) both have acceptable numbers of hydrogen bond donors and acceptors, well within the recommended limits.

**QED:** Both ligands have acceptable QED scores (0.693 and 0.558 respectively), indicating good drug-like properties.

**DILI:** Ligand A (66.344) has a higher DILI risk than Ligand B (51.57), though both are moderately risky.

**BBB:** Ligand B (64.482) has a significantly better BBB penetration percentile than Ligand A (55.215). This is a crucial advantage for a CNS target like DRD2.

**Caco-2 Permeability:** Ligand A (-4.894) has poor Caco-2 permeability, which is concerning. Ligand B (-5.696) is also poor, but slightly better.

**Aqueous Solubility:** Ligand A (-2.648) has poor aqueous solubility, while Ligand B (-1.797) is slightly better.

**hERG:** Both ligands have low hERG inhibition liability (0.271 and 0.44 respectively), which is positive.

**Microsomal Clearance:** Ligand A (10.906) has lower microsomal clearance than Ligand B (58.135), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (54.938) has a significantly longer in vitro half-life than Ligand B (9.64), which is a major advantage.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.083 and 0.038 respectively), which is favorable for CNS penetration.

**Binding Affinity:** Both ligands have excellent binding affinity (-7.8 and -7.9 kcal/mol), with Ligand B being slightly more potent. The difference is minimal, and both are well below the -7.0 kcal/mol threshold.

**Overall Assessment:**

Ligand B is the better candidate. While Ligand A has better metabolic stability and half-life, Ligand B excels in crucial GPCR-specific properties: significantly better BBB penetration and slightly better logP. The improved BBB is paramount for a CNS target, and the slightly better logP aids in permeation. The small difference in binding affinity is less important given the already excellent affinity of both compounds. The slightly lower DILI risk for Ligand B is also a positive.



Output:
1
2025-04-17 05:58:33,190 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (347.346 and 346.402 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (89.95) is better than Ligand B (58.64). Both are below the 90 A^2 threshold for CNS targets, but A is closer to the upper limit.

**3. logP:** Ligand A (0.867) is slightly lower than optimal (1-3), potentially impacting permeability. Ligand B (2.202) is within the optimal range.

**4. H-Bond Donors:** Ligand A (2) and Ligand B (1) are both acceptable (<=5).

**5. H-Bond Acceptors:** Ligand A (4) and Ligand B (3) are both acceptable (<=10).

**6. QED:** Both ligands have reasonable QED values (0.777 and 0.635, both >= 0.5).

**7. DILI:** Ligand A (62.893) has a higher DILI risk than Ligand B (37.96). This is a significant drawback for Ligand A.

**8. BBB:** Ligand B (84.529) has a significantly better BBB penetration percentile than Ligand A (64.676). This is *critical* for a CNS target like DRD2.

**9. Caco-2 Permeability:** Both have negative Caco-2 values (-4.658 and -4.646), which is unusual and suggests poor permeability. This is a concern for both.

**10. Aqueous Solubility:** Both have negative solubility values (-2.88 and -2.486), indicating poor solubility. This is a concern for both.

**11. hERG Inhibition:** Both ligands show very low hERG inhibition risk (0.146 and 0.769).

**12. Microsomal Clearance:** Ligand A (-14.488) has a much lower (better) microsomal clearance than Ligand B (31.456), indicating greater metabolic stability.

**13. In vitro Half-Life:** Ligand A (38.027) has a longer half-life than Ligand B (-0.624).

**14. P-gp Efflux:** Both ligands show very low P-gp efflux liability (0.012 and 0.299).

**15. Binding Affinity:** Both ligands have similar and strong binding affinities (-9.6 and -9.4 kcal/mol). The difference is negligible.

**Overall Assessment:**

Ligand B is the more promising candidate. While both have issues with Caco-2 and solubility, Ligand B's superior BBB penetration is a decisive advantage for a CNS target. The lower DILI risk and better logP also contribute to its favorability. Although Ligand A has better metabolic stability (lower Cl_mic) and a slightly longer half-life, the BBB and DILI concerns are more critical for a DRD2 ligand.

Output:
1
2025-04-17 05:58:33,191 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (341.386 and 343.471 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (53.51) is significantly better than Ligand B (71.09). For CNS targets, we want TPSA <= 90, and ideally closer to 60. Ligand A is much closer to this ideal.

**3. logP:** Both ligands have good logP values (2.736 and 3.146), falling within the optimal 1-3 range.

**4. H-Bond Donors:** Ligand A (0) is preferable to Ligand B (2). Fewer HBDs generally improve permeability.

**5. H-Bond Acceptors:** Both have 3 HBA, which is acceptable.

**6. QED:** Both ligands have reasonable QED values (0.863 and 0.747), indicating good drug-like properties.

**7. DILI:** Ligand A (51.493) has a slightly higher DILI risk than Ligand B (27.336), but both are below the concerning threshold of 60.

**8. BBB:** This is crucial for a CNS target. Ligand A (94.184) has a *much* higher BBB penetration percentile than Ligand B (59.287). This is a major advantage for Ligand A.

**9. Caco-2 Permeability:** Ligand A (-4.524) and Ligand B (-4.938) both have negative values, indicating poor permeability. However, the scale isn't specified, so it's difficult to interpret the absolute difference.

**10. Aqueous Solubility:** Both have negative solubility values (-3.093 and -2.261), indicating poor solubility.

**11. hERG Inhibition:** Both ligands have low hERG inhibition risk (0.717 and 0.237).

**12. Microsomal Clearance:** Both ligands have similar microsomal clearance (25.547 and 24.471 mL/min/kg), suggesting comparable metabolic stability.

**13. In vitro Half-Life:** Ligand A (-17.532) has a negative half-life, which is concerning. Ligand B (11.87) has a positive half-life, indicating better stability.

**14. P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.172 and 0.055), which is good for CNS penetration.

**15. Binding Affinity:** Both ligands have excellent binding affinities (-9.5 and -8.0 kcal/mol). Ligand A is slightly better, but the difference is less than the 1.5 kcal/mol threshold.

**Overall Assessment:**

Ligand A is the stronger candidate. While Ligand B has a better in vitro half-life and lower DILI risk, Ligand A's significantly superior BBB penetration (94.184 vs 59.287) and lower TPSA (53.51 vs 71.09) are critical for a CNS-targeting GPCR like DRD2. The slightly better affinity of Ligand A is a bonus. The negative half-life of Ligand A is a concern, but could potentially be addressed with structural modifications.



Output:
0
2025-04-17 05:58:33,191 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (348.45 & 350.51 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (78.67) is higher than Ligand B (52.41). For CNS targets, we prefer TPSA <= 90, so both are acceptable, but B is better.

**logP:** Ligand A (0.976) is a bit low, potentially hindering permeability. Ligand B (2.732) is within the optimal 1-3 range. This favors B.

**H-Bond Donors:** Ligand A (1) and Ligand B (0) are both acceptable (<=5).

**H-Bond Acceptors:** Ligand A (5) and Ligand B (6) are both acceptable (<=10).

**QED:** Both ligands have reasonable QED scores (0.745 and 0.685, both >= 0.5).

**DILI:** Ligand A (19.93) has a significantly lower DILI risk than Ligand B (10.90). This is a substantial advantage for A.

**BBB:** Ligand B (82.05) has a much higher BBB penetration percentile than Ligand A (42.19). This is *critical* for a CNS target like DRD2, and strongly favors B.

**Caco-2 Permeability:** Both have negative values, indicating poor permeability. Ligand A (-4.59) is slightly better than Ligand B (-4.892).

**Aqueous Solubility:** Both have negative values, suggesting poor solubility. Ligand A (-0.648) is slightly better than Ligand B (-2.399).

**hERG Inhibition:** Ligand A (0.271) has a lower hERG risk than Ligand B (0.702), which is preferable.

**Microsomal Clearance:** Ligand B (43.71) has higher clearance than Ligand A (25.78), indicating lower metabolic stability. A favors lower clearance.

**In vitro Half-Life:** Ligand B (12.99) has a longer half-life than Ligand A (-20.36). This is a significant advantage for B.

**P-gp Efflux:** Both have low P-gp efflux liability (0.082 and 0.447).

**Binding Affinity:** Ligand B (-6.5 kcal/mol) has a slightly better binding affinity than Ligand A (-8.0 kcal/mol). While A is stronger, the difference isn't huge enough to overcome other issues.

**Overall Assessment:**

Ligand B is clearly superior due to its excellent BBB penetration (82%) and acceptable logP. While Ligand A has a lower DILI risk and slightly better solubility, the BBB penetration is paramount for a CNS-targeting drug. The slightly better affinity of A is outweighed by B's superior CNS penetration and half-life.

Output:
1
2025-04-17 05:58:33,191 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (342.483 and 360.801 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (40.62) is significantly better than Ligand B (97.55). For CNS targets, we want TPSA <= 90, and A is comfortably within that, while B is considerably above. This is a major advantage for A.

**logP:** Both ligands have acceptable logP values (3.26 and 2.317), falling within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A (0 HBD, 3 HBA) is preferable to Ligand B (2 HBD, 5 HBA) as lower counts generally improve permeability.

**QED:** Both ligands have good QED scores (0.825 and 0.872), indicating good drug-like properties.

**DILI:** Ligand B (85.653) has a higher DILI risk than Ligand A (8.414). This is a significant concern for B.

**BBB:** Ligand A (82.862) has a much better BBB penetration percentile than Ligand B (62.389). For a CNS target like DRD2, >70 is desirable, and A is closer to this threshold.

**Caco-2 Permeability:** Ligand A (-4.793) has a worse Caco-2 permeability than Ligand B (-5.017). However, Caco-2 is less critical than BBB for CNS targets.

**Aqueous Solubility:** Both have poor aqueous solubility (-2.187 and -3.888). This is a potential formulation challenge for both, but not a deciding factor.

**hERG Inhibition:** Ligand A (0.806) has a slightly higher hERG inhibition risk than Ligand B (0.298). This is a minor concern for A.

**Microsomal Clearance:** Ligand B (-3.207) has a lower (better) microsomal clearance than Ligand A (14.502). This suggests B is more metabolically stable.

**In vitro Half-Life:** Ligand B (-2.887) has a longer in vitro half-life than Ligand A (-25.211). This is a significant advantage for B.

**P-gp Efflux:** Ligand A (0.371) has lower P-gp efflux liability than Ligand B (0.056), which is favorable for CNS penetration.

**Binding Affinity:** Ligand B (-9.6 kcal/mol) has a significantly stronger binding affinity than Ligand A (-8.9 kcal/mol). This is a substantial advantage for B, potentially outweighing some of its ADME drawbacks. The difference is >1.5 kcal/mol.

**Overall Assessment:**

While Ligand B has superior binding affinity and metabolic stability, Ligand A shines in terms of TPSA, BBB penetration, and lower DILI risk. Given the CNS target (DRD2), BBB penetration and low toxicity are paramount. The significant difference in TPSA and BBB, combined with the lower DILI risk, makes Ligand A the more promising candidate despite the slightly weaker binding affinity. The 0.7 kcal/mol difference in binding affinity can potentially be optimized in later stages of drug development.

Output:
0
2025-04-17 05:58:33,191 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (352.494 and 342.374 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (49.41) is excellent, well below the 90 A^2 threshold for CNS targets. Ligand B (83.98) is higher but still potentially acceptable, though less ideal.

**logP:** Ligand A (3.616) is optimal. Ligand B (1.544) is a bit low, potentially hindering membrane permeability.

**H-Bond Donors/Acceptors:** Ligand A (HBD=1, HBA=2) is good. Ligand B (HBD=2, HBA=4) is also acceptable.

**QED:** Both ligands have good QED scores (0.761 and 0.834, respectively), indicating drug-like properties.

**DILI:** Ligand A (29.43) has a much lower DILI risk than Ligand B (65.723), which is a significant advantage.

**BBB:** Ligand A (96.045) shows excellent BBB penetration, crucial for a CNS target. Ligand B (77.588) is reasonable, but significantly lower than Ligand A.

**Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and requires further investigation. However, the magnitude of the negative value is similar, so this isn't a major differentiator.

**Aqueous Solubility:** Both have negative solubility values, also unusual. Again, the values are similar, so this isn't a major differentiator.

**hERG:** Ligand A (0.85) has a slightly higher hERG risk than Ligand B (0.143), but both are relatively low.

**Microsomal Clearance:** Ligand A (56.426) has higher clearance than Ligand B (22.746), suggesting lower metabolic stability.

**In vitro Half-Life:** Ligand B (-25.58) has a longer half-life than Ligand A (-19.105).

**P-gp Efflux:** Ligand A (0.545) has lower P-gp efflux liability than Ligand B (0.046), which is favorable for CNS penetration.

**Binding Affinity:** Ligand B (-9.7 kcal/mol) has a stronger binding affinity than Ligand A (-8.6 kcal/mol) by 1.1 kcal/mol. This is a substantial difference.

**Overall Assessment:**

Ligand B has a significantly better binding affinity. However, Ligand A excels in several key areas for a CNS-targeting GPCR: superior BBB penetration, much lower DILI risk, and lower P-gp efflux. While Ligand A has higher clearance and a slightly higher hERG risk, the benefits of its CNS-related properties and safety profile outweigh these drawbacks, *especially* given the strong, though not overwhelmingly superior, affinity of Ligand B. The lower logP of Ligand B is also a concern.

Output:
1
2025-04-17 05:58:33,191 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (478.225 Da) is towards the upper end, while Ligand B (369.531 Da) is more favorably positioned.

**TPSA:** Ligand A (42.96) is excellent for CNS penetration, well below the 90 A^2 threshold. Ligand B (87.3) is higher, but still potentially acceptable, though less optimal.

**logP:** Both ligands have good logP values (A: 3.002, B: 1.588) within the 1-3 range. Ligand A is slightly better.

**H-Bond Donors/Acceptors:** Ligand A (HBD=1, HBA=5) and Ligand B (HBD=3, HBA=4) both have reasonable numbers of H-bond donors and acceptors.

**QED:** Both ligands have good QED scores (A: 0.554, B: 0.663), indicating drug-like properties.

**DILI:** Both ligands have acceptable DILI risk (A: 23.226, B: 30.438), below the 40 threshold.

**BBB:** This is critical for a CNS target. Ligand A has a significantly better BBB percentile (77.2) than Ligand B (45.677). This is a major advantage for Ligand A.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values, which is unusual and potentially indicates an issue with the prediction method or the molecule itself. However, we'll proceed with caution.

**Aqueous Solubility:** Both ligands have negative solubility values, which is also unusual.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (A: 0.848, B: 0.129).

**Microsomal Clearance:** Ligand A (38.037) has higher microsomal clearance than Ligand B (20.77), suggesting lower metabolic stability.

**In vitro Half-Life:** Ligand B (15.71 hours) has a significantly longer in vitro half-life than Ligand A (5.465 hours).

**P-gp Efflux:** Ligand A (0.459) has higher P-gp efflux than Ligand B (0.033), which is unfavorable for CNS penetration.

**Binding Affinity:** Ligand B (-7.6 kcal/mol) has a slightly better binding affinity than Ligand A (-8.0 kcal/mol). While the difference is small, it's still a factor.

**Overall Assessment:**

Ligand A excels in TPSA and BBB penetration, crucial for a CNS GPCR target. However, it suffers from higher microsomal clearance and P-gp efflux, potentially limiting its exposure in the brain. Ligand B has better metabolic stability (longer half-life) and lower P-gp efflux, but its BBB penetration is significantly worse. The binding affinity difference is small. Given the importance of CNS penetration for DRD2, Ligand A's superior BBB score outweighs its drawbacks, despite the slightly worse metabolic stability and P-gp efflux.

Output:
1
2025-04-17 05:58:33,191 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B based on the provided guidelines, prioritizing GPCR-specific properties (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (338.327 Da) is slightly preferred due to being closer to the lower end, potentially aiding permeability.

**TPSA:** Ligand A (106.14) is better than Ligand B (68.46) as it is closer to the desirable threshold of <=90 for CNS targets.

**logP:** Ligand B (3.112) is optimal (1-3), while Ligand A (0.859) is a bit low, potentially hindering permeation.

**H-Bond Donors/Acceptors:** Ligand A (1 HBD, 7 HBA) is preferable to Ligand B (0 HBD, 5 HBA) as it strikes a better balance for permeability and solubility.

**QED:** Both ligands have acceptable QED values (A: 0.756, B: 0.69), indicating good drug-like properties.

**DILI:** Ligand A (92.284) has a higher DILI risk than Ligand B (44.824). This is a significant drawback for Ligand A.

**BBB:** Ligand B (83.831) has a significantly better BBB penetration percentile than Ligand A (25.126). This is *critical* for a CNS target like DRD2.

**Caco-2 Permeability:** Ligand A (-5.132) has a worse Caco-2 permeability than Ligand B (-4.453).

**Aqueous Solubility:** Ligand A (-2.443) has a worse aqueous solubility than Ligand B (-4.189).

**hERG Inhibition:** Ligand A (0.011) has a much lower hERG inhibition risk than Ligand B (0.78). This is a strong advantage for Ligand A.

**Microsomal Clearance:** Ligand A (-7.852) has a much lower microsomal clearance than Ligand B (77.297), indicating better metabolic stability.

**In vitro Half-Life:** Ligand B (26.264) has a longer in vitro half-life than Ligand A (-3.038).

**P-gp Efflux:** Ligand A (0.017) has a much lower P-gp efflux liability than Ligand B (0.426), which is beneficial for CNS exposure.

**Binding Affinity:** Ligand A (-8.4 kcal/mol) has a slightly better binding affinity than Ligand B (-7.2 kcal/mol). The 1.2 kcal/mol difference is substantial enough to potentially overcome some ADME drawbacks.

**Overall Assessment:**

While Ligand A has better affinity, metabolic stability, lower hERG risk, and P-gp efflux, Ligand B excels in BBB penetration and has a lower DILI risk. For a CNS target like DRD2, BBB penetration is paramount. The significantly higher BBB value of Ligand B (83.831 vs 25.126) outweighs the slightly better affinity of Ligand A. The lower DILI risk of Ligand B is also a significant advantage.

Output:
1
2025-04-17 05:58:33,191 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (349.431 and 346.471 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (101.9) is higher than Ligand B (60.85). For CNS targets, TPSA should be <= 90. Ligand B is significantly better here.

**logP:** Ligand A (1.169) is within the optimal range (1-3), while Ligand B (2.262) is also acceptable.

**H-Bond Donors/Acceptors:** Ligand A has 4 HBD and 5 HBA, while Ligand B has 1 HBD and 3 HBA. Both are within acceptable limits (<=5 HBD and <=10 HBA).

**QED:** Both ligands have good QED scores (0.592 and 0.719, respectively), indicating drug-like properties.

**DILI:** Ligand A (42.769) has a slightly higher DILI risk than Ligand B (10.896), but both are below the concerning threshold of 60.

**BBB:** This is crucial for a CNS target like DRD2. Ligand B (73.711) has a much better BBB percentile than Ligand A (12.292). This is a major advantage for Ligand B.

**Caco-2 Permeability:** Ligand A (-5.511) and Ligand B (-4.548) both have negative values, which is unusual. It's difficult to interpret without knowing the scale, but lower values generally indicate poorer permeability.

**Aqueous Solubility:** Both ligands have negative solubility values (-2.189 and -1.889), suggesting poor aqueous solubility. This could be a formulation challenge.

**hERG:** Both ligands have low hERG inhibition liability (0.356 and 0.155), which is good.

**Microsomal Clearance:** Ligand A (-1.941) has a lower (better) microsomal clearance than Ligand B (26.256), indicating better metabolic stability.

**In vitro Half-Life:** Ligand A (-0.065) has a slightly longer half-life than Ligand B (-4.905), but both are negative values and difficult to interpret without knowing the scale.

**P-gp Efflux:** Ligand A (0.021) has lower P-gp efflux liability than Ligand B (0.064), which is favorable for CNS penetration.

**Binding Affinity:** Ligand B (-7.6 kcal/mol) has a slightly better binding affinity than Ligand A (-8.3 kcal/mol). While the difference is small, it's still a positive for Ligand B.

**Overall Assessment:**

Ligand B is the more promising candidate. Its significantly higher BBB penetration (73.711 vs. 12.292) is the most important factor for a CNS-targeting drug. It also has a lower TPSA, lower DILI risk, and a slightly better binding affinity. While Ligand A has better metabolic stability (lower Cl_mic) and P-gp efflux, the BBB advantage of Ligand B outweighs these benefits for DRD2.

Output:
1
2025-04-17 05:58:33,191 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (355.29 and 351.49 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (38.77) is excellent, well below the 90 A^2 threshold for CNS targets. Ligand B (72.88) is higher but still reasonable, though less optimal.

**logP:** Ligand A (3.914) is at the upper end of the optimal range (1-3), potentially raising solubility concerns. Ligand B (1.297) is a bit low, potentially hindering membrane permeability.

**H-Bond Donors/Acceptors:** Ligand A (0 HBD, 3 HBA) is favorable. Ligand B (2 HBD, 4 HBA) is also acceptable.

**QED:** Both ligands have similar QED values (0.784 and 0.678), indicating good drug-likeness.

**DILI:** Ligand A (81.82%) has a significantly higher DILI risk than Ligand B (8.03%). This is a major concern for Ligand A.

**BBB:** Ligand A (91.59%) has excellent BBB penetration, crucial for a CNS target like DRD2. Ligand B (57.19%) is considerably lower, which is a significant drawback.

**Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and difficult to interpret without further context. However, the magnitude suggests Ligand A (-4.139) might have slightly better permeability than Ligand B (-4.831).

**Aqueous Solubility:** Both ligands have poor aqueous solubility (-5.34 and -0.643). This could pose formulation challenges.

**hERG Inhibition:** Ligand A (0.851) has a slightly higher hERG risk than Ligand B (0.105).

**Microsomal Clearance:** Ligand A (60.39 mL/min/kg) has higher clearance than Ligand B (8.51 mL/min/kg), indicating lower metabolic stability.

**In vitro Half-Life:** Ligand B (-16.08 hours) has a negative half-life, which is impossible and indicates a data error or unusual experimental result. Ligand A (33.28 hours) is reasonable.

**P-gp Efflux:** Ligand A (0.623) has moderate P-gp efflux, while Ligand B (0.012) has very low efflux, which is highly desirable for CNS penetration.

**Binding Affinity:** Ligand A (-8.8 kcal/mol) has a significantly stronger binding affinity than Ligand B (-7.3 kcal/mol). This is a substantial advantage.

**Overall Assessment:**

Ligand A excels in BBB penetration and binding affinity, which are critical for a CNS GPCR target. However, its high DILI risk and higher metabolic clearance are major concerns. Ligand B has a much better safety profile (DILI, hERG) and lower P-gp efflux, but its BBB penetration is significantly lower, and its binding affinity is weaker. The negative half-life for Ligand B is a red flag and suggests potential data quality issues.

Despite the higher DILI risk, the superior binding affinity and excellent BBB penetration of Ligand A outweigh the drawbacks, *assuming the DILI risk can be mitigated through structural modifications*. The difference in binding affinity is substantial (1.5 kcal/mol), and for a GPCR, this can be a deciding factor.

Output:
1
2025-04-17 05:58:33,192 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (345.355 and 342.443 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (88.18) is better than Ligand B (76.02), both are below the 90 A^2 threshold for CNS targets.

**logP:** Ligand B (1.945) is optimal (1-3), while Ligand A (-0.472) is below 1, potentially hindering permeation. This is a significant drawback for Ligand A.

**H-Bond Donors/Acceptors:** Ligand A (1 HBD, 5 HBA) and Ligand B (2 HBD, 4 HBA) both fall within acceptable ranges.

**QED:** Ligand A (0.783) has a better QED score than Ligand B (0.587), indicating better overall drug-likeness.

**DILI:** Ligand B (30.516) has a significantly lower DILI risk than Ligand A (52.966), making it safer.

**BBB:** Ligand A (73.478) has a better BBB penetration percentile than Ligand B (63.629), which is crucial for a CNS target like DRD2.

**Caco-2 Permeability:** Ligand B (-5.129) has a better Caco-2 permeability than Ligand A (-4.511), indicating better intestinal absorption.

**Aqueous Solubility:** Ligand B (-1.663) has better aqueous solubility than Ligand A (-2.702).

**hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.071 and 0.26, respectively).

**Microsomal Clearance:** Ligand A (-12.778) has a lower (better) microsomal clearance than Ligand B (33.197), suggesting greater metabolic stability.

**In vitro Half-Life:** Ligand A (-22.395) has a longer in vitro half-life than Ligand B (-17.808).

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.013 and 0.142, respectively).

**Binding Affinity:** Both ligands have similar binding affinities (-8.9 and -8.5 kcal/mol). The difference is less than the 1.5 kcal/mol threshold.

**Overall Assessment:**

While Ligand A has a better QED, BBB, and metabolic stability, its significantly negative logP is a major concern. Poor logP can lead to poor permeability and bioavailability, even with good BBB penetration. Ligand B, while having a slightly lower BBB score, presents a much more balanced profile with an optimal logP, lower DILI risk, and better solubility and Caco-2 permeability. The similar binding affinities make the ADME properties the deciding factor. For a CNS GPCR target, a balanced profile with good permeability and safety is paramount.

Output:
1
2025-04-17 05:58:33,192 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (348.45 & 364.51 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (81.75) is better than Ligand B (53.76). For CNS targets, we want TPSA <= 90, both are within this range, but A is closer to the upper limit.

**3. logP:** Ligand A (-0.425) is suboptimal, being below the preferred 1-3 range. Ligand B (3.501) is excellent, falling squarely within the optimal range. This is a significant advantage for B.

**4. H-Bond Donors:** Ligand A (2) is acceptable, while Ligand B (0) is also good.

**5. H-Bond Acceptors:** Both ligands have 4 HBA, which is acceptable.

**6. QED:** Both ligands have good QED values (0.612 and 0.751, respectively), indicating drug-like properties.

**7. DILI:** Ligand A (24.12) has a much lower DILI risk than Ligand B (48.62). This is a clear advantage for A.

**8. BBB:** Ligand B (77.05) has a significantly better BBB penetration percentile than Ligand A (41.22). This is crucial for a CNS target like DRD2, and a major advantage for B.

**9. Caco-2 Permeability:** Both have negative values, indicating poor permeability. However, the scale is not provided, so it's difficult to interpret the absolute values.

**10. Aqueous Solubility:** Both have negative values, indicating poor solubility. Again, the scale is not provided.

**11. hERG Inhibition:** Ligand A (0.089) has a very low hERG inhibition risk, while Ligand B (0.578) is higher. A is preferable here.

**12. Microsomal Clearance:** Ligand A (2.98) has a lower clearance, suggesting better metabolic stability than Ligand B (75.97). This is a significant advantage for A.

**13. In vitro Half-Life:** Ligand A (-18.154) has a negative half-life, which is not possible. This is a red flag. Ligand B (12.783) has a reasonable half-life.

**14. P-gp Efflux:** Ligand A (0.008) has very low P-gp efflux liability, which is excellent for CNS penetration. Ligand B (0.644) has moderate P-gp efflux. A is preferable.

**15. Binding Affinity:** Ligand B (-8.3) has a slightly better binding affinity than Ligand A (-7.9). While the difference is not huge, it is still a positive for B.

**Overall Assessment:**

Ligand A has advantages in DILI, hERG, P-gp efflux, and metabolic stability. However, the negative in vitro half-life is a critical flaw. Ligand B excels in BBB penetration and logP, both crucial for CNS GPCR targets. The better binding affinity of B is also a positive. Despite the higher DILI and P-gp efflux, the superior CNS penetration profile of Ligand B, combined with its acceptable logP, outweighs the drawbacks.

Output:
1
2025-04-17 05:58:33,192 - INFO - Batch 243 complete. Total preferences: 3888
2025-04-17 05:58:33,192 - INFO - Processing batch 244/512...
2025-04-17 05:59:25,908 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B based on the provided guidelines, prioritizing GPCR-specific properties (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (335.407 Da) is slightly lower, which could be beneficial for permeability.

**TPSA:** Ligand A (63.13) is better than Ligand B (86.64). For CNS targets, TPSA should be <= 90, both are within this range, but A is preferable.

**logP:** Both ligands have good logP values (A: 1.818, B: 1.119) falling within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Both have 2 HBD, which is good. Ligand A has 3 HBA, while Ligand B has 9 HBA. Lower HBA is generally preferred for better permeability, making Ligand A slightly better.

**QED:** Both ligands have acceptable QED scores (A: 0.837, B: 0.756), indicating good drug-like properties.

**DILI:** Ligand B (75.339) has a higher DILI risk than Ligand A (63.823), suggesting A is safer.

**BBB:** Ligand A (66.576) has a better BBB percentile than Ligand B (58.317). While both are below the desirable >70 for CNS targets, A is closer.

**Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and suggests poor permeability. This is a significant concern for both.

**Aqueous Solubility:** Both have negative solubility values, indicating poor solubility. This is also a significant concern for both.

**hERG Inhibition:** Ligand A (0.247) has a lower hERG inhibition liability than Ligand B (0.483), indicating a lower risk of cardiotoxicity.

**Microsomal Clearance:** Ligand B (61.534) has a higher microsomal clearance than Ligand A (17.058), meaning A is more metabolically stable.

**In vitro Half-Life:** Both ligands have similar in vitro half-lives (A: 25.253, B: 25.032).

**P-gp Efflux:** Ligand A (0.171) has a lower P-gp efflux liability than Ligand B (0.045), which is beneficial for CNS exposure.

**Binding Affinity:** Ligand A (-9.3 kcal/mol) has a significantly stronger binding affinity than Ligand B (-7.1 kcal/mol). This is a crucial advantage, potentially outweighing some of the ADME drawbacks. The difference is >1.5 kcal/mol.

**Overall Assessment:**

Ligand A is superior due to its significantly better binding affinity, lower DILI risk, better BBB penetration, lower P-gp efflux, lower hERG inhibition, and more favorable TPSA and HBA values. While both ligands suffer from poor Caco-2 permeability and solubility, the strong binding affinity of Ligand A makes it a more promising candidate, especially considering the potential for optimization of these solubility/permeability issues.

Output:
1
2025-04-17 05:59:25,908 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (352.391 and 351.407 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (102.88) is better than Ligand B (109.58). Both are reasonably good for CNS penetration, being below the 140 A^2 threshold, and ligand A is closer to the preferred <90 A^2 for CNS targets.

**logP:** Ligand A (0.468) is slightly better than Ligand B (-0.256). Both are a bit low, potentially hindering membrane permeability, but not drastically.

**H-Bond Donors/Acceptors:** Ligand A (1 HBD, 7 HBA) is slightly better than Ligand B (2 HBD, 7 HBA). Both are within acceptable limits.

**QED:** Both ligands have similar QED values (0.611 and 0.635), indicating good drug-likeness.

**DILI:** Ligand A (64.056) has a slightly higher DILI risk than Ligand B (58.395), but both are acceptable (<60 is good).

**BBB:** Ligand A (70.88) has a significantly better BBB penetration percentile than Ligand B (48.662). This is a crucial advantage for a CNS target like DRD2.

**Caco-2 Permeability:** Ligand A (-4.964) has a worse Caco-2 permeability than Ligand B (-5.145). Both are poor, but similar.

**Aqueous Solubility:** Ligand A (-1.579) has slightly better solubility than Ligand B (-1.231). Both are poor.

**hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.19 and 0.153, respectively).

**Microsomal Clearance:** Ligand A (10.476) has significantly lower microsomal clearance than Ligand B (24.876), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (-17.268) has a much longer in vitro half-life than Ligand B (12.504), which is a significant advantage.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.008 and 0.045, respectively).

**Binding Affinity:** Ligand B (-7.5 kcal/mol) has a stronger binding affinity than Ligand A (-6.5 kcal/mol). This is a 1.0 kcal/mol difference, which is substantial and could outweigh some ADME drawbacks.

**Overall Assessment:**

While Ligand B has a better binding affinity, Ligand A demonstrates a superior ADME profile, particularly regarding BBB penetration (70.88 vs 48.662), metabolic stability (lower Cl_mic), and longer half-life. For a CNS target like DRD2, BBB penetration is paramount. The 1.0 kcal/mol difference in binding affinity is significant, but the improved pharmacokinetic properties of Ligand A, especially its BBB score, make it the more promising candidate.

Output:
1
2025-04-17 05:59:25,909 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 drug candidates, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (343.431 and 343.475 Da) fall comfortably within the ideal 200-500 Da range.

**TPSA:** Ligand A (78.43) is better than Ligand B (55.21). Both are below the 90 A^2 threshold desirable for CNS targets.

**logP:** Ligand B (3.334) is higher than Ligand A (0.848). While both are within the 1-3 range, Ligand B is closer to the upper limit, which could raise solubility concerns, but is generally acceptable for GPCRs. Ligand A is quite low, potentially hindering permeation.

**H-Bond Donors:** Both have 1 HBD, which is within the acceptable limit of 5.

**H-Bond Acceptors:** Ligand A has 5 HBA, and Ligand B has 6. Both are below the 10 limit.

**QED:** Both ligands have similar QED values (0.877 and 0.836), indicating good drug-likeness.

**DILI:** Ligand B (38.813) has a significantly lower DILI risk than Ligand A (53.083). This is a clear advantage for Ligand B.

**BBB:** Ligand B (78.868) has a substantially better BBB penetration percentile than Ligand A (67.546). This is *critical* for a CNS target like DRD2.

**Caco-2 Permeability:** Both have negative values (-5.08 and -4.8), which is unusual. This suggests poor permeability.

**Aqueous Solubility:** Both have negative solubility values (-1.186 and -3.859), indicating poor aqueous solubility.

**hERG Inhibition:** Ligand A (0.36) shows slightly lower hERG inhibition liability than Ligand B (0.934), which is preferable.

**Microsomal Clearance:** Ligand B (90.39) has a much higher microsomal clearance than Ligand A (11.947), suggesting faster metabolism and lower metabolic stability.

**In vitro Half-Life:** Ligand A (9.769) has a shorter half-life than Ligand B (43.289).

**P-gp Efflux:** Ligand A (0.036) has significantly lower P-gp efflux liability than Ligand B (0.315), which is beneficial for CNS penetration.

**Binding Affinity:** Both ligands have very similar binding affinities (-8.5 and -8.3 kcal/mol), and both are excellent. The difference is not substantial enough to outweigh other factors.

**Overall Assessment:**

Ligand B excels in BBB penetration and DILI risk, which are crucial for a CNS GPCR target. While it has higher P-gp efflux and faster clearance, the significant advantage in BBB outweighs these drawbacks. Ligand A has better P-gp efflux and clearance, but its significantly lower BBB penetration is a major concern. The solubility and Caco-2 permeability are poor for both, but these can be addressed with formulation strategies.

Output:
1
2025-04-17 05:59:25,909 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (345.407 and 338.411 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (138.68) is close to the upper limit for good oral absorption and acceptable for CNS targets, while Ligand B (83.98) is excellent for CNS penetration. This favors Ligand B.

**3. logP:** Ligand A (0.65) is a bit low, potentially hindering permeation. Ligand B (1.605) is within the optimal range (1-3). This favors Ligand B.

**4. H-Bond Donors:** Ligand A (4) is acceptable, while Ligand B (2) is even better.

**5. H-Bond Acceptors:** Both ligands (A: 6, B: 4) are within the acceptable limit of 10.

**6. QED:** Both ligands have similar QED values (A: 0.581, B: 0.584), indicating good drug-likeness.

**7. DILI:** Ligand A (63.746) has a higher DILI risk than Ligand B (52.617), though both are within a reasonable range.

**8. BBB:** Ligand A (35.246) has poor BBB penetration, which is a major drawback for a CNS target like DRD2. Ligand B (53.276) shows moderate BBB penetration, significantly better than Ligand A. This is a critical advantage for Ligand B.

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 values, which is unusual. However, the magnitude of negativity is similar, so this doesn't strongly differentiate them.

**10. Aqueous Solubility:** Both ligands have negative solubility values, which is also unusual. Again, the magnitude is similar.

**11. hERG Inhibition:** Both ligands have very low hERG inhibition risk (A: 0.198, B: 0.079), which is excellent.

**12. Microsomal Clearance:** Ligand A (0.479) has significantly lower microsomal clearance than Ligand B (15.5), suggesting better metabolic stability. This favors Ligand A.

**13. In vitro Half-Life:** Ligand A (-12.944) has a very negative half-life, which is problematic. Ligand B (-13.303) is also negative, but slightly worse.

**14. P-gp Efflux:** Both ligands have very low P-gp efflux liability (A: 0.008, B: 0.023), which is favorable for CNS penetration.

**15. Binding Affinity:** Both ligands have strong binding affinities (A: -8.8 kcal/mol, B: -8.1 kcal/mol). Ligand A has a slightly better affinity, but the difference (0.7 kcal/mol) is not substantial enough to overcome its other weaknesses.

**Overall Assessment:**

Ligand B is significantly more promising due to its superior BBB penetration, better logP, and lower DILI risk. While Ligand A has slightly better affinity and metabolic stability, the poor BBB penetration is a critical flaw for a CNS-targeted drug. The GPCR-specific priorities heavily favor Ligand B.

Output:
1
2025-04-17 05:59:25,909 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (345.443 and 363.458 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (78.51) is better than Ligand B (69.22). Both are below the 90 A^2 threshold desirable for CNS targets, but A is closer to the ideal range.

**logP:** Ligand A (0.987) is slightly below the optimal 1-3 range, while Ligand B (3.267) is within the optimal range. This favors B.

**H-Bond Donors:** Both ligands have 2 HBD, which is acceptable.

**H-Bond Acceptors:** Ligand A has 3 HBA, and Ligand B has 4. Both are below the 10 threshold.

**QED:** Both ligands have good QED scores (0.746 and 0.855), indicating drug-like properties.

**DILI:** Ligand A (20.396) has a significantly lower DILI risk than Ligand B (49.981). This is a substantial advantage for A.

**BBB:** Both ligands have similar BBB penetration (67.352 and 68.205). While neither exceeds the desirable >70 percentile, they are reasonably close.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.132 and -5.084), which is unusual and suggests poor permeability. This is a concern for both.

**Aqueous Solubility:** Both ligands have negative solubility values (-2.293 and -4.548), indicating very poor aqueous solubility. This is a significant drawback for both.

**hERG Inhibition:** Ligand A (0.121) has a much lower hERG inhibition liability than Ligand B (0.84). This is a major advantage for A.

**Microsomal Clearance:** Ligand A (16.246) has lower microsomal clearance than Ligand B (63.586), suggesting better metabolic stability. This favors A.

**In vitro Half-Life:** Ligand A (2.556) has a shorter half-life than Ligand B (-27.642). The negative value for B is suspect and likely indicates a very rapid clearance. This favors A.

**P-gp Efflux:** Ligand A (0.016) has significantly lower P-gp efflux liability than Ligand B (0.499). This is a crucial advantage for A, especially for CNS penetration.

**Binding Affinity:** Ligand B (-7.9 kcal/mol) has a slightly better binding affinity than Ligand A (-8.4 kcal/mol). While the difference is small, it's a factor to consider.

**Overall Assessment:**

Ligand A is significantly better overall. While Ligand B has slightly better binding affinity and logP, Ligand A excels in safety (DILI, hERG), metabolic stability (Cl_mic, t1/2), and efflux (Pgp). The poor solubility and Caco-2 permeability are concerns for both, but the superior ADME profile of Ligand A, particularly its lower toxicity and better CNS penetration potential, makes it the more promising drug candidate. The small affinity difference is outweighed by the other factors.

Output:
0
2025-04-17 05:59:25,909 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 drug candidates, considering the provided guidelines and GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight (MW):**
* Ligand A: 436.703 Da - Within the ideal range (200-500 Da).
* Ligand B: 344.455 Da - Also within the ideal range.
* *Advantage: Neither is significantly outside the preferred range.*

**2. Topological Polar Surface Area (TPSA):**
* Ligand A: 28.16  - Excellent, well below the 90 A^2 threshold for CNS targets.
* Ligand B: 54.82 - Still reasonable, but higher than Ligand A and approaching the upper limit for CNS penetration.
* *Advantage: Ligand A*

**3. Lipophilicity (logP):**
* Ligand A: 4.765 - Slightly high, potentially leading to solubility issues or off-target interactions.
* Ligand B: 3.444 - Optimal, within the 1-3 range.
* *Advantage: Ligand B*

**4. H-Bond Donors (HBD):**
* Ligand A: 1 - Good.
* Ligand B: 1 - Good.
* *Advantage: None*

**5. H-Bond Acceptors (HBA):**
* Ligand A: 3 - Good.
* Ligand B: 5 - Acceptable, but higher.
* *Advantage: Ligand A*

**6. QED:**
* Ligand A: 0.751 - Excellent, indicating strong drug-like properties.
* Ligand B: 0.87 - Excellent, slightly better than Ligand A.
* *Advantage: Ligand B*

**7. DILI Risk:**
* Ligand A: 42.73 - Good, low risk.
* Ligand B: 24.622 - Very good, even lower risk.
* *Advantage: Ligand B*

**8. BBB Penetration:**
* Ligand A: 95.153 - Excellent, very high probability of crossing the BBB.
* Ligand B: 78.945 - Good, but lower than Ligand A.
* *Advantage: Ligand A*

**9. Caco-2 Permeability:**
* Ligand A: -4.82 - Negative values are unusual, suggesting poor permeability.
* Ligand B: -4.699 - Also negative, but slightly less negative than Ligand A.
* *Advantage: Ligand B*

**10. Aqueous Solubility:**
* Ligand A: -5.033 - Very poor solubility. This is a significant concern.
* Ligand B: -3.511 - Poor solubility, but better than Ligand A.
* *Advantage: Ligand B*

**11. hERG Inhibition:**
* Ligand A: 0.948 - Acceptable risk.
* Ligand B: 0.917 - Acceptable risk.
* *Advantage: None*

**12. Microsomal Clearance:**
* Ligand A: -3.074 - Negative clearance is unusual and likely an error or indicates very high stability.
* Ligand B: 64.911 - Moderate clearance, suggesting moderate metabolic stability.
* *Advantage: Ligand A (with caution regarding the negative value)*

**13. In vitro Half-Life:**
* Ligand A: 70.297 - Excellent, long half-life.
* Ligand B: 6.257 - Short half-life, potentially requiring frequent dosing.
* *Advantage: Ligand A*

**14. P-gp Efflux:**
* Ligand A: 0.62 - Moderate efflux.
* Ligand B: 0.257 - Low efflux, which is favorable for CNS exposure.
* *Advantage: Ligand B*

**15. Binding Affinity:**
* Ligand A: -9.3 kcal/mol - Excellent, very strong binding.
* Ligand B: -8.7 kcal/mol - Very good, but slightly weaker than Ligand A.
* *Advantage: Ligand A*

**Overall Assessment:**

Ligand A has a significantly higher binding affinity and excellent BBB penetration and in vitro half-life. However, it suffers from very poor solubility and questionable Caco-2 permeability. The negative microsomal clearance is also concerning. Ligand B has a more balanced profile with better solubility, permeability, lower DILI risk, and lower P-gp efflux. While its affinity is slightly lower, it's still very good.

Considering the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity), and the critical need for reasonable solubility and permeability for *in vivo* efficacy, **Ligand B is the more promising drug candidate.** The slightly weaker affinity can potentially be optimized in later stages of drug development, while addressing the solubility issues of Ligand A would be a much more significant hurdle.

Output:
1
2025-04-17 05:59:25,910 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B based on the provided guidelines, prioritizing GPCR-specific properties (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (354.491 and 344.419 Da) fall within the ideal range of 200-500 Da.

**TPSA:** Ligand A (78.87) is better than Ligand B (85.05). Both are below the 90 A^2 threshold desirable for CNS targets, but A is closer to the optimal range.

**logP:** Ligand A (1.706) is better than Ligand B (0.506). Both are within the 1-3 range, but B is quite low, potentially hindering permeation.

**H-Bond Donors/Acceptors:** Ligand A (2 HBD, 4 HBA) is slightly better than Ligand B (1 HBD, 6 HBA). Both are within acceptable limits.

**QED:** Ligand B (0.875) is better than Ligand A (0.695), indicating a more drug-like profile.

**DILI:** Ligand A (32.92) has a lower DILI risk than Ligand B (43.234), which is preferable. Both are below the 60 threshold.

**BBB:** Ligand A (54.75) has a significantly better BBB penetration percentile than Ligand B (43.311). This is *critical* for a CNS target like DRD2.

**Caco-2 Permeability:** Ligand A (-4.566) has a worse Caco-2 permeability than Ligand B (-5.314). Both are negative, indicating poor permeability.

**Aqueous Solubility:** Ligand A (-2.431) has better aqueous solubility than Ligand B (-1.298).

**hERG:** Both ligands (0.241 and 0.245) have similar and low hERG inhibition liability, which is good.

**Microsomal Clearance:** Ligand B (-15.494) has a lower (better) microsomal clearance than Ligand A (44.882), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand B (3.23) has a better in vitro half-life than Ligand A (-17.807).

**P-gp Efflux:** Both ligands (0.12 and 0.01) have very low P-gp efflux liability, which is excellent.

**Binding Affinity:** Ligand B (-8.1 kcal/mol) has a significantly stronger binding affinity than Ligand A (-7.3 kcal/mol). This is a substantial advantage (1.8 kcal/mol difference).

**Overall Assessment:**

While Ligand B has a better QED, metabolic stability (lower Cl_mic, higher t1/2), and significantly stronger binding affinity, Ligand A excels in BBB penetration and has a lower DILI risk. For a CNS target like DRD2, BBB penetration is paramount. The 1.8 kcal/mol difference in binding affinity is substantial, but can potentially be overcome with further optimization. The poor Caco-2 permeability of both compounds is a concern, but less critical for a CNS-focused drug. Considering the GPCR-specific priorities, the superior BBB score of Ligand A outweighs the benefits of Ligand B's stronger affinity and better metabolic properties.

Output:
0
2025-04-17 05:59:25,910 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (378.441 and 399.292 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (92.34) is better than Ligand B (61.92). For CNS targets, TPSA should be <=90, so Ligand A is borderline, while Ligand B is well within the desired range.

**logP:** Ligand A (1.176) is within the optimal 1-3 range, while Ligand B (3.471) is at the higher end, potentially causing solubility issues.

**H-Bond Donors/Acceptors:** Ligand A has 2 HBD and 4 HBA, which are acceptable. Ligand B has 0 HBD and 4 HBA, also acceptable.

**QED:** Both ligands have similar QED values (0.703 and 0.699), indicating good drug-likeness.

**DILI:** Ligand A (45.25) has a lower DILI risk than Ligand B (55.797), which is preferable.

**BBB:** Ligand A (82.9) has significantly better BBB penetration (82.9%) than Ligand B (54.595%). This is a *critical* factor for a CNS target like DRD2.

**Caco-2 Permeability:** Ligand A (-5.118) shows poor permeability, while Ligand B (-4.803) is slightly better, but both are negative values, indicating poor permeability.

**Aqueous Solubility:** Ligand A (-2.25) has slightly better solubility than Ligand B (-3.888), but both are poor.

**hERG Inhibition:** Ligand A (0.151) has a lower hERG inhibition risk than Ligand B (0.909), which is a significant advantage.

**Microsomal Clearance:** Ligand A (-12.342) has a much lower (better) microsomal clearance than Ligand B (73.793), indicating better metabolic stability.

**In vitro Half-Life:** Ligand A (14.559) has a longer half-life than Ligand B (10.987).

**P-gp Efflux:** Ligand A (0.085) has lower P-gp efflux than Ligand B (0.551), which is favorable for CNS penetration.

**Binding Affinity:** Ligand A (-8.5 kcal/mol) has a significantly stronger binding affinity than Ligand B (-7.0 kcal/mol). This is a substantial advantage.

**Overall Assessment:**

Ligand A is superior to Ligand B. While Ligand B has a better TPSA and slightly better Caco-2 permeability, Ligand A excels in the most critical parameters for a CNS-targeting GPCR: BBB penetration, binding affinity, metabolic stability (lower Cl_mic), lower P-gp efflux, and lower hERG risk. The stronger binding affinity of Ligand A (-8.5 kcal/mol vs -7.0 kcal/mol) is a significant advantage that can compensate for its slightly higher TPSA and poorer permeability.



Output:
1
2025-04-17 05:59:25,910 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B based on the provided guidelines, prioritizing GPCR-specific properties (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (337.423 and 345.443 Da) fall within the ideal range of 200-500 Da.

**TPSA:** Ligand A (54.46) is significantly better than Ligand B (73.74). For CNS targets, TPSA should be <=90, both are within this range, but A is closer to the optimal range.

**logP:** Ligand A (3.18) is optimal, while Ligand B (1.553) is slightly low, potentially hindering permeation.

**H-Bond Donors/Acceptors:** Both ligands have 1 HBD and 4 HBA, which are within acceptable limits.

**QED:** Both ligands have high QED scores (0.931 and 0.899), indicating good drug-likeness.

**DILI:** Ligand A (52.268) has a moderately higher DILI risk than Ligand B (11.322). This is a negative for Ligand A.

**BBB:** Both ligands have good BBB penetration (Ligand A: 76.658, Ligand B: 70.027), exceeding the 70% threshold for CNS targets. Ligand A is slightly better.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values, which is unusual and difficult to interpret without knowing the scale. However, we can assume they are both low.

**Aqueous Solubility:** Both ligands have negative solubility values, which is also unusual and difficult to interpret.

**hERG:** Both ligands have low hERG inhibition liability (0.742 and 0.44), which is favorable.

**Microsomal Clearance:** Ligand A (15.684) has a higher microsomal clearance than Ligand B (0.864), suggesting lower metabolic stability. This is a negative for Ligand A.

**In vitro Half-Life:** Ligand B (-10.24) has a much longer in vitro half-life than Ligand A (3.833). This is a significant advantage for Ligand B.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.179 and 0.029), which is excellent for CNS penetration. Ligand B is slightly better.

**Binding Affinity:** Both ligands have excellent binding affinity (-9.4 and -9.0 kcal/mol). The difference is 0.4 kcal/mol, which is not substantial enough to override other ADME differences.

**Overall Assessment:**

Ligand A has better TPSA and BBB penetration, but suffers from higher DILI risk, higher microsomal clearance (lower metabolic stability), and a shorter half-life. Ligand B has a more favorable ADME profile overall, with lower DILI, better metabolic stability (lower Cl_mic, longer t1/2), and slightly better P-gp efflux. While Ligand A's logP is slightly better, the differences in ADME properties are more critical for a CNS-targeting GPCR ligand.

Output:
1
2025-04-17 05:59:25,910 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (371.449 and 358.429 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (54.45) is better than Ligand B (58.64). Both are below the 90 A^2 threshold desirable for CNS targets, but A is closer to optimal.

**logP:** Both ligands have good logP values (2.856 and 1.998), falling within the 1-3 range. Ligand A is slightly better.

**H-Bond Donors/Acceptors:** Ligand A (0 HBD, 3 HBA) and Ligand B (1 HBD, 3 HBA) both have acceptable numbers of H-bond donors and acceptors.

**QED:** Both ligands have reasonable QED scores (0.8 and 0.642), indicating good drug-like properties.

**DILI:** Ligand A (40.83) has a slightly higher DILI risk than Ligand B (18.728), but both are below the concerning threshold of 60.

**BBB:** This is a crucial parameter for a CNS target like DRD2. Ligand A (95.89) has a significantly higher BBB penetration percentile than Ligand B (81.776). This is a major advantage for Ligand A.

**Caco-2 Permeability:** Both have negative Caco-2 values which is unusual and likely indicates an issue with the prediction method, but we can assume they are similar.

**Aqueous Solubility:** Both have negative solubility values, which is also unusual and likely indicates an issue with the prediction method.

**hERG:** Ligand A (0.681) has a slightly higher hERG risk than Ligand B (0.453), but both are relatively low.

**Microsomal Clearance:** Ligand B (10.79) has a significantly lower microsomal clearance than Ligand A (41.86), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand B (-11.551) has a much longer in vitro half-life than Ligand A (-0.011). This is a significant advantage for Ligand B.

**P-gp Efflux:** Ligand A (0.657) has lower P-gp efflux than Ligand B (0.075), which is favorable for CNS penetration.

**Binding Affinity:** Ligand B (-7.9 kcal/mol) has a substantially stronger binding affinity than Ligand A (-10.2 kcal/mol). This is a very important factor.

**Overall Assessment:**

Ligand B has a significantly better binding affinity and metabolic stability (lower Cl_mic and longer t1/2). However, Ligand A has superior BBB penetration and lower P-gp efflux. The difference in binding affinity (-7.9 vs -10.2 kcal/mol) is substantial (a 2.3 kcal/mol difference), and this difference is likely to outweigh the benefits of Ligand A's slightly better BBB and P-gp properties. The better metabolic stability of Ligand B is also a significant advantage.

Output:
1
2025-04-17 05:59:25,910 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (350.459 and 366.487 Da) fall within the ideal 200-500 Da range.

**TPSA:** Both ligands have TPSA values (89.87 and 85.77) below the 90 A^2 threshold for CNS targets, which is excellent.

**logP:** Both ligands have logP values (0.521 and 0.662) which are quite low. While not immediately disqualifying, values between 1-3 are preferred for better membrane permeability.

**H-Bond Donors/Acceptors:** Ligand A (3 HBD, 4 HBA) is slightly better than Ligand B (2 HBD, 6 HBA) in terms of balancing solubility and permeability, but both are acceptable.

**QED:** Both ligands have good QED scores (0.645 and 0.773), indicating drug-like properties.

**DILI:** Ligand A (14.385) has a significantly lower DILI risk than Ligand B (46.258). This is a substantial advantage.

**BBB:** Ligand A (29.74) has a slightly better BBB percentile than Ligand B (25.475), but both are relatively low and concerning for a CNS target.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.835 and -5.033) which is not ideal.

**Aqueous Solubility:** Both ligands have negative solubility values (-2.028 and -1.086) which is not ideal.

**hERG:** Both ligands have very low hERG inhibition liability (0.123 and 0.176), which is excellent.

**Microsomal Clearance:** Ligand A (3.965) has a higher microsomal clearance than Ligand B (1.591), meaning it's likely to be metabolized faster. This is a negative for Ligand A.

**In vitro Half-Life:** Ligand A (-14.136) has a significantly shorter in vitro half-life than Ligand B (-7.146). This is a major drawback for Ligand A.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.013 and 0.034), which is good.

**Binding Affinity:** Both ligands have the same binding affinity (-8.0 kcal/mol), which is excellent and a strong point for both.

**Overall Assessment:**

While both ligands have excellent binding affinity and acceptable TPSA, Ligand B is the more promising candidate. The key factors driving this decision are:

*   **DILI:** Ligand B has a much lower DILI risk.
*   **Metabolic Stability:** Ligand B has significantly lower microsomal clearance and a longer in vitro half-life.
*   **BBB:** While both are low, Ligand A has a slightly lower BBB penetration.

The lower logP values for both are a concern, but the superior ADME properties of Ligand B outweigh this drawback.

Output:
1
2025-04-17 05:59:25,911 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (357.451 and 349.475 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (82.55) is better than Ligand B (69.72). Both are below the 90 A^2 threshold for CNS targets, which is excellent.

**logP:** Ligand B (0.905) is slightly better than Ligand A (-0.633). Both are within the 1-3 range, but A is a bit low, potentially hindering permeability.

**H-Bond Donors:** Both ligands have 1 HBD, which is acceptable.

**H-Bond Acceptors:** Ligand A has 6 HBAs, while Ligand B has 4. Both are below the 10 threshold.

**QED:** Both ligands have good QED scores (0.66 and 0.774), indicating good drug-like properties.

**DILI:** Ligand A (14.424) has a significantly lower DILI risk than Ligand B (18.922), which is a major advantage.

**BBB:** Ligand B (61.342) has a much better BBB penetration percentile than Ligand A (43.893). This is critical for a CNS target like DRD2.

**Caco-2 Permeability:** Ligand A (-4.361) and Ligand B (-4.91) both have negative values, which is unusual and suggests very poor permeability. This is a significant concern for both.

**Aqueous Solubility:** Ligand A (-0.444) is slightly better than Ligand B (-1.084), but both are poor.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.163 and 0.095).

**Microsomal Clearance:** Ligand A (8.247) has a lower microsomal clearance than Ligand B (13.281), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (-9.963) has a much longer in vitro half-life than Ligand B (0.944).

**P-gp Efflux:** Ligand A (0.01) has significantly lower P-gp efflux liability than Ligand B (0.032), which is favorable for CNS penetration.

**Binding Affinity:** Ligand B (-8.0 kcal/mol) has a slightly better binding affinity than Ligand A (-6.9 kcal/mol). This 1.1 kcal/mol difference is substantial and could outweigh some ADME drawbacks.

**Overall Assessment:**

Ligand B has a significantly better BBB score and binding affinity, which are the most important factors for a CNS GPCR target. However, Ligand A has better DILI risk, metabolic stability, P-gp efflux, and half-life. Both have poor Caco-2 permeability and solubility. The improved binding affinity of Ligand B, coupled with its better BBB penetration, is likely to be more impactful for *in vivo* efficacy at the DRD2 receptor.

Output:
1
2025-04-17 05:59:25,911 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (351.359 Da and 342.443 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (118.06) is slightly above the optimal <90 for CNS targets, but still reasonable. Ligand B (76.44) is excellent, well below 90.

**logP:** Ligand A (0.294) is quite low, potentially hindering permeation. Ligand B (1.539) is within the optimal 1-3 range. This is a significant advantage for Ligand B.

**H-Bond Donors/Acceptors:** Ligand A has 2 HBD and 6 HBA, which are acceptable. Ligand B has 1 HBD and 4 HBA, also acceptable.

**QED:** Both ligands have good QED scores (0.756 and 0.904), indicating drug-likeness.

**DILI:** Both ligands have relatively low DILI risk (77.976 and 41.179), with Ligand B being slightly better.

**BBB:** Ligand A's BBB penetration (39.977) is concerningly low for a CNS target. Ligand B shows a much better BBB penetration (43.815), though still not ideal (>70).

**Caco-2 Permeability:** Ligand A has a very negative Caco-2 value (-5.358), indicating poor permeability. Ligand B (-4.932) is also poor, but slightly better.

**Aqueous Solubility:** Both ligands have negative solubility values (-1.751 and -1.455), suggesting poor solubility.

**hERG Inhibition:** Both ligands show very low hERG inhibition risk (0.017 and 0.564).

**Microsomal Clearance:** Ligand A has a very low (negative) microsomal clearance (-28.473), suggesting high metabolic stability. Ligand B has a slightly less favorable, but still reasonable, clearance (-4.566).

**In vitro Half-Life:** Ligand A has a negative half-life (-12.909), which is not physically meaningful. Ligand B has a positive half-life (29.583), which is good.

**P-gp Efflux:** Both ligands have negligible P-gp efflux (0.006 and 0.049).

**Binding Affinity:** Ligand A has a binding affinity of 0 kcal/mol, which is not good. Ligand B has a binding affinity of 0 kcal/mol, which is also not good.

**Overall Assessment:**

Ligand B is the better candidate. While both have poor solubility and Caco-2 permeability, Ligand B has a much more favorable logP, a better BBB score (though still not optimal), and a reasonable microsomal clearance and half-life. Ligand A's extremely low logP and BBB penetration, coupled with a poor binding affinity, make it a less promising candidate. The negative values for half-life and clearance for ligand A are also concerning.

Output:
1
2025-04-17 05:59:25,911 - INFO - Reasoning:

Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (418.213 Da) is slightly higher than Ligand B (347.415 Da), but both are acceptable.

**2. TPSA:** Ligand A (74.85) is better than Ligand B (101.34). For CNS targets, we want TPSA <= 90. Ligand A is closer to this threshold, suggesting better CNS penetration potential.

**3. logP:** Ligand A (3.928) is optimal, while Ligand B (1.575) is on the lower side. A logP between 1-3 is preferred. Ligand B's lower logP might hinder its ability to cross cell membranes.

**4. H-Bond Donors:** Both ligands have 2 HBD, which is within the acceptable limit of <=5.

**5. H-Bond Acceptors:** Ligand A has 3 HBA, and Ligand B has 4. Both are within the acceptable limit of <=10.

**6. QED:** Ligand A (0.791) has a significantly better QED score than Ligand B (0.415). A QED >= 0.5 is desirable, and Ligand A clearly meets this criterion, indicating a more drug-like profile.

**7. DILI:** Ligand A (79.449) has a higher DILI risk than Ligand B (35.285). While both are below 60 (moderate risk), Ligand B is preferable.

**8. BBB:** Ligand A (72.896) has a better BBB percentile than Ligand B (50.679). For a CNS target like DRD2, >70 is desirable, but Ligand A is closer.

**9. Caco-2 Permeability:** Both have negative Caco-2 values (-5.098 and -5.103). This is unusual and suggests poor permeability. However, these values are on a similar scale, so don't strongly differentiate the ligands.

**10. Aqueous Solubility:** Both have negative solubility values (-5.286 and -2.661). This suggests poor aqueous solubility for both compounds, which could be a formulation challenge. Ligand B is slightly better.

**11. hERG Inhibition:** Ligand A (0.711) has a slightly higher hERG inhibition risk than Ligand B (0.076). Lower is better, so Ligand B is preferable.

**12. Microsomal Clearance:** Both ligands have similar microsomal clearance values (21.109 and 21.401 mL/min/kg), indicating comparable metabolic stability.

**13. In vitro Half-Life:** Ligand A (56.678) has a significantly longer in vitro half-life than Ligand B (6.449). This is a major advantage for Ligand A, potentially allowing for less frequent dosing.

**14. P-gp Efflux:** Ligand A (0.634) has lower P-gp efflux than Ligand B (0.094). Lower P-gp efflux is desirable for CNS exposure.

**15. Binding Affinity:** Both ligands have very similar binding affinities (-8.4 kcal/mol and -8.1 kcal/mol). The difference of 0.3 kcal/mol is not substantial enough to be the deciding factor.

**Overall Assessment:**

Ligand A is superior despite the slightly elevated DILI risk. It has a better QED score, TPSA, logP, BBB penetration, and significantly longer half-life. While Ligand B has lower DILI and hERG risk, the advantages of Ligand A in terms of CNS penetration (TPSA, BBB, Pgp) and drug-like properties (QED) are more critical for a DRD2 ligand. The similar binding affinities make the ADME properties the deciding factor.

Output:
1
2025-04-17 05:59:25,911 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (349.435 and 342.439 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (104.29) is higher than Ligand B (67.43). For a CNS target like DRD2, TPSA should be <= 90. Ligand B is much closer to this threshold, making it more favorable.

**3. logP:** Ligand A (0.492) is quite low, potentially hindering membrane permeability. Ligand B (1.843) is within the optimal 1-3 range. This is a significant advantage for Ligand B.

**4. H-Bond Donors:** Both ligands have 2 HBD, which is acceptable.

**5. H-Bond Acceptors:** Ligand A has 5 HBA, and Ligand B has 3. Both are within the acceptable limit of <= 10.

**6. QED:** Both ligands have reasonable QED values (0.675 and 0.592), indicating good drug-like properties.

**7. DILI:** Ligand A (35.169) has a lower DILI risk than Ligand B (46.026), which is favorable.

**8. BBB:** Both ligands have similar BBB penetration (53.974% and 53.083%). While neither is >70%, they are comparable.

**9. Caco-2:** Both have negative Caco-2 values, which is unusual and suggests poor permeability. However, the scale is not specified, so it's difficult to interpret.

**10. Solubility:** Both ligands have negative solubility values, which is also unusual and suggests poor solubility. Again, the scale is not specified.

**11. hERG:** Both ligands have very low hERG inhibition liability (0.053 and 0.186), which is excellent.

**12. Cl_mic:** Ligand A (13.906) has lower microsomal clearance than Ligand B (31.537), indicating better metabolic stability.

**13. t1/2:** Ligand A (17.779) has a longer in vitro half-life than Ligand B (-12.507). This is a significant advantage for Ligand A.

**14. Pgp:** Ligand A (0.002) has much lower P-gp efflux liability than Ligand B (0.19). This is crucial for CNS penetration and is a strong point for Ligand A.

**15. Binding Affinity:** Ligand B (-8.7 kcal/mol) has a slightly better binding affinity than Ligand A (-7.7 kcal/mol). This difference of 1 kcal/mol is substantial and could potentially outweigh some of the ADME drawbacks of Ligand B.

**Overall Assessment:**

Ligand B has a significantly better logP and TPSA, which are critical for GPCRs, especially those in the CNS. Its superior binding affinity is also a major plus. While Ligand A has better metabolic stability (lower Cl_mic, longer t1/2) and lower P-gp efflux, the poor logP and higher TPSA are concerning. The slightly lower DILI risk for Ligand A is a minor advantage. Given the importance of CNS penetration and receptor engagement for DRD2, Ligand B appears to be the more promising candidate.

Output:
1
2025-04-17 05:59:25,912 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (340.427 Da) is slightly better positioned.

**TPSA:** Ligand A (77.49) is significantly better than Ligand B (109.08). For CNS targets, TPSA should be <=90, and A is comfortably within this range, while B is pushing the limit.

**logP:** Ligand A (2.212) is optimal (1-3), while Ligand B (0.334) is quite low, potentially hindering membrane permeability.

**H-Bond Donors/Acceptors:** Ligand A (HBD=3, HBA=4) and Ligand B (HBD=2, HBA=7) both fall within acceptable ranges.

**QED:** Both ligands have similar QED values (A: 0.78, B: 0.631), indicating good drug-likeness.

**DILI:** Ligand A (52.23) has a slightly higher DILI risk than Ligand B (32.261), but both are reasonably low.

**BBB:** Ligand A (60.411) has a better BBB percentile than Ligand B (54.246), but both are below the desirable >70 for CNS targets. This is a concern for both, but less so for A.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.23 and -5.132), which is unusual and suggests poor permeability. This is a significant drawback for both.

**Aqueous Solubility:** Both ligands have negative solubility values (-3.138 and -1.21), indicating very poor aqueous solubility. This is a major issue for both.

**hERG Inhibition:** Ligand A (0.663) has a slightly higher hERG risk than Ligand B (0.344), but both are relatively low.

**Microsomal Clearance:** Ligand A (66.057) has higher microsomal clearance than Ligand B (4.252), indicating lower metabolic stability. This is a negative for A.

**In vitro Half-Life:** Ligand B (30.666) has a longer half-life than Ligand A (12.157), which is preferable.

**P-gp Efflux:** Ligand A (0.146) has lower P-gp efflux than Ligand B (0.033), suggesting better CNS exposure.

**Binding Affinity:** Ligand A (-10.1 kcal/mol) has significantly stronger binding affinity than Ligand B (-6.9 kcal/mol). This is a substantial advantage for A. The difference of 3.2 kcal/mol is very significant and can outweigh many other drawbacks.

**Overall Assessment:**

Despite the poor Caco-2 and solubility for both, Ligand A is the better candidate. Its superior binding affinity (-10.1 vs -6.9 kcal/mol) is a major advantage, especially for a GPCR target. It also has better TPSA and P-gp efflux, and a more optimal logP. While its BBB is still suboptimal, it's better than Ligand B's. The higher clearance is a concern, but the strong binding may compensate. Ligand B's low logP and weaker binding are significant drawbacks.

Output:
0
2025-04-17 05:59:25,912 - INFO - Batch 244 complete. Total preferences: 3904
2025-04-17 05:59:25,912 - INFO - Processing batch 245/512...
2025-04-17 06:00:08,906 - INFO - Reasoning:

Let's analyze Ligand A and Ligand B based on the provided guidelines, prioritizing GPCR-specific properties (BBB, logP, Pgp, TPSA, and affinity).

**Ligand A:**

*   **MW:** 341.415 Da - Good (within 200-500 range)
*   **TPSA:** 71.33 - Excellent (well below 90 for CNS targets)
*   **logP:** 0.963 - Acceptable, but on the lower side. Could potentially limit permeability.
*   **HBD:** 0 - Good (low, favors permeability)
*   **HBA:** 5 - Good (within the limit)
*   **QED:** 0.571 - Good (above 0.5)
*   **DILI:** 46.995 - Excellent (low risk)
*   **BBB:** 63.94 - Moderate. Below the desirable >70 for CNS targets, but not terrible.
*   **Caco-2:** -4.418 - Poor. Indicates very low permeability.
*   **Solubility:** -2.477 - Poor. Indicates low solubility.
*   **hERG:** 0.042 - Excellent (very low risk)
*   **Cl_mic:** 20.949 - Moderate. Not ideal, but not extremely high.
*   **t1/2:** -16.779 - Very poor. Indicates a very short half-life.
*   **Pgp:** 0.04 - Excellent (low efflux)
*   **Affinity:** -7.5 kcal/mol - Excellent (strong binding)

**Ligand B:**

*   **MW:** 353.419 Da - Good (within 200-500 range)
*   **TPSA:** 115.9 - Moderate. Higher than ideal for CNS targets (above 90), but not a complete deal-breaker.
*   **logP:** 0.248 - Poor. Very low, likely to cause permeability issues.
*   **HBD:** 3 - Good (within the limit)
*   **HBA:** 6 - Good (within the limit)
*   **QED:** 0.675 - Good (above 0.5)
*   **DILI:** 39.201 - Excellent (low risk)
*   **BBB:** 25.785 - Poor. Very low, suggesting poor CNS penetration.
*   **Caco-2:** -5.107 - Poor. Indicates very low permeability.
*   **Solubility:** -0.798 - Poor. Indicates low solubility.
*   **hERG:** 0.254 - Good (low risk)
*   **Cl_mic:** 13.315 - Good. Relatively low clearance.
*   **t1/2:** -20.617 - Very poor. Indicates a very short half-life.
*   **Pgp:** 0.089 - Good (low efflux)
*   **Affinity:** -8.3 kcal/mol - Excellent (very strong binding, 0.8 kcal/mol better than Ligand A)

**Comparison and Decision:**

Both compounds have significant issues with permeability (Caco-2) and solubility. Both also have poor *in vitro* half-lives. However, Ligand B has a significantly better binding affinity (-8.3 vs -7.5 kcal/mol). While Ligand A has a better BBB score, the difference isn't large enough to overcome the substantial affinity advantage of Ligand B. Given the GPCR target and the importance of binding affinity, the stronger binding of Ligand B is a critical factor. The TPSA of Ligand B is higher, but still within a range that could be acceptable with further optimization. The low logP of Ligand B is a concern, but could potentially be addressed through medicinal chemistry efforts.

Therefore, despite the drawbacks, Ligand B is the more promising candidate due to its superior binding affinity.

Output:
1
2025-04-17 06:00:08,907 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (366.53 and 341.46 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (61.8) is slightly higher than Ligand B (53.51). For CNS targets, we ideally want TPSA <= 90, so both are acceptable, but B is better.

**logP:** Both ligands have good logP values (3.37 and 2.667), falling within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A has 2 HBD and 4 HBA, while Ligand B has 0 HBD and 3 HBA. Both are within acceptable limits (<=5 HBD and <=10 HBA).

**QED:** Both ligands have good QED scores (0.727 and 0.831), indicating good drug-like properties.

**DILI:** Ligand A (35.87) has a lower DILI risk than Ligand B (47.42), suggesting a more favorable safety profile.

**BBB:** This is a crucial parameter for CNS targets. Ligand B (73.71) has a significantly better BBB penetration percentile than Ligand A (60.37). This is a major advantage for B.

**Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and suggests poor permeability. However, the scale isn't specified, so it's hard to interpret.

**Aqueous Solubility:** Both have negative solubility values, which is also unusual. This could be a potential issue for formulation.

**hERG:** Both ligands have low hERG inhibition liability (0.756 and 0.425), which is good.

**Microsomal Clearance:** Ligand A (61.73) has a higher microsomal clearance than Ligand B (55.04), indicating lower metabolic stability.

**In vitro Half-Life:** Ligand B (-7.76) has a significantly longer in vitro half-life than Ligand A (9.59). This is a significant advantage for B.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.55 and 0.289), which is favorable for CNS penetration.

**Binding Affinity:** Ligand A (0 kcal/mol) has the same binding affinity as Ligand B (0 kcal/mol).

**Overall Assessment:**

Ligand B is the stronger candidate. While Ligand A has a slightly lower DILI risk, Ligand B excels in the critical areas for CNS GPCR targets: significantly better BBB penetration (73.71 vs 60.37) and a longer in vitro half-life (-7.76 vs 9.59). The similar binding affinity means these differences in ADME properties are decisive. The negative Caco-2 and solubility values are concerning for both, but the superior CNS properties of B outweigh this concern.

Output:
1
2025-04-17 06:00:08,907 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (352.475 & 351.466 Da) fall comfortably within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (84.5) is slightly higher than Ligand B (75.43). Both are below the 90 A^2 threshold desirable for CNS targets, but B is better.

**3. logP:** Ligand A (2.165) and Ligand B (3.119) are both within the optimal 1-3 range. Ligand B is closer to the upper end, which could be slightly problematic, but not a major concern.

**4. H-Bond Donors:** Both ligands have 2 HBD, which is within the acceptable limit of <=5.

**5. H-Bond Acceptors:** Ligand A has 4 HBA, and Ligand B has 3. Both are below the limit of <=10.

**6. QED:** Both ligands have good QED scores (0.623 and 0.707, respectively), indicating good drug-like properties.

**7. DILI:** Both ligands have similar DILI risk (52.346 and 51.881 percentile), and are both considered low risk (<60).

**8. BBB:** This is a crucial parameter for a CNS target like DRD2. Ligand B (80.69%) has a significantly higher BBB penetration score than Ligand A (64.637%). This is a major advantage for Ligand B.

**9. Caco-2 Permeability:** Ligand A (-4.874) has a more negative Caco-2 value, indicating *better* permeability than Ligand B (-4.618). However, both are negative, which is unusual and requires further investigation, but the difference isn't huge.

**10. Aqueous Solubility:** Both ligands have very poor aqueous solubility (-3.631 and -3.436). This is a significant drawback for both, potentially impacting bioavailability.

**11. hERG Inhibition:** Both ligands have low hERG inhibition risk (0.101 and 0.848), which is favorable.

**12. Microsomal Clearance:** Ligand B (62.359) has higher microsomal clearance than Ligand A (44.237), meaning it's cleared more quickly and has lower metabolic stability. Ligand A is preferable here.

**13. In vitro Half-Life:** Ligand A (-10.94) has a more negative in vitro half-life, which means a shorter half-life. Ligand B (38.394) has a much longer half-life, which is preferable.

**14. P-gp Efflux:** Both ligands have low P-gp efflux liability (0.222 and 0.317), which is good for CNS penetration.

**15. Binding Affinity:** Ligand B (-8.9 kcal/mol) has a slightly better binding affinity than Ligand A (-8.4 kcal/mol). While the difference is not huge, it is over 0.5 kcal/mol, which is enough to potentially outweigh some ADME drawbacks.

**Overall Assessment:**

Ligand B is the stronger candidate. The significantly improved BBB penetration (80.69% vs 64.637%) is a critical advantage for a CNS-targeting drug. While Ligand A has better metabolic stability (lower Cl_mic) and Caco-2 permeability, the superior BBB score and slightly better affinity of Ligand B outweigh these factors. The poor solubility is a concern for both, but can be addressed with formulation strategies.

Output:
1
2025-04-17 06:00:08,907 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, considering the provided guidelines and GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (351.491 and 344.375 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (61.88) is significantly better than Ligand B (111.03). For CNS targets, TPSA should be <= 90, and A is comfortably within this range, while B exceeds it. This is a major advantage for A.

**logP:** Both ligands have acceptable logP values (1.418 and 1.688), falling within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A (HBD=1, HBA=4) is preferable to Ligand B (HBD=2, HBA=7) as it has fewer hydrogen bond donors and acceptors, potentially improving permeability.

**QED:** Ligand A (0.705) has a higher QED score than Ligand B (0.584), indicating a more drug-like profile.

**DILI:** Both ligands have relatively low DILI risk (8.918 and 82.862), but Ligand A is significantly better. A DILI score under 40 is good, and A is much closer to this than B.

**BBB:** Ligand B (79.333) has a significantly higher BBB penetration percentile than Ligand A (53.897). This is a critical factor for CNS targets like DRD2.

**Caco-2 Permeability:** Both have negative Caco-2 values (-4.911 and -4.849), which is unusual and suggests poor permeability. However, the scale isn't defined, so it's hard to interpret.

**Aqueous Solubility:** Both have negative solubility values (-0.725 and -3.193), also unusual and suggesting poor solubility.

**hERG:** Ligand A (0.364) has a much lower hERG inhibition liability than Ligand B (0.046), making it safer from a cardiotoxicity perspective.

**Microsomal Clearance:** Ligand A (2.979) has a significantly lower microsomal clearance than Ligand B (40.273), indicating better metabolic stability.

**In vitro Half-Life:** Ligand A (-0.034) has a slightly better (less negative) in vitro half-life than Ligand B (-3.263).

**P-gp Efflux:** Ligand A (0.029) shows lower P-gp efflux liability than Ligand B (0.102), which is beneficial for CNS exposure.

**Binding Affinity:** Ligand B (-9.1 kcal/mol) has a substantially stronger binding affinity than Ligand A (-7.8 kcal/mol). This is a significant advantage for B, potentially outweighing some ADME drawbacks. The difference is >1.5 kcal/mol.

**Overall Assessment:**

Ligand B has a superior binding affinity and better BBB penetration, which are crucial for a CNS GPCR target. However, it suffers from higher TPSA, higher DILI risk, higher P-gp efflux, and significantly worse metabolic stability (higher Cl_mic, lower t1/2). Ligand A has a much better ADME profile (TPSA, DILI, Cl_mic, Pgp, hERG) and a good QED score. The affinity difference is substantial. Given the importance of affinity for GPCRs, and the >1.5 kcal/mol advantage of B, I believe **Ligand B** is the more promising candidate, despite its ADME liabilities. Further optimization could focus on improving its metabolic stability and reducing its DILI risk.

Output:
1
2025-04-17 06:00:08,907 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (348.451 and 359.535 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (93.01) is better than Ligand B (40.54). For CNS targets, TPSA should be <= 90, so Ligand A is closer to the ideal range.

**logP:** Ligand A (0.975) is within the optimal 1-3 range, while Ligand B (4.527) is slightly high. High logP can lead to solubility issues and off-target effects.

**H-Bond Donors/Acceptors:** Both have acceptable HBD counts (1). Ligand A has 6 HBAs, and Ligand B has 3. Both are within the acceptable range of <=10.

**QED:** Both ligands have similar QED scores (0.707 and 0.694), indicating good drug-likeness.

**DILI:** Ligand A (42.536) has a slightly higher DILI risk than Ligand B (14.696), but both are below the concerning threshold of 60.

**BBB:** Ligand A (58.085) and Ligand B (62.97) both have acceptable BBB penetration, but are below the desirable 70% for CNS targets. However, Ligand B is slightly better.

**Caco-2 Permeability:** Ligand A (-5.142) has poor Caco-2 permeability, while Ligand B (-4.977) is also poor, but slightly better.

**Aqueous Solubility:** Ligand A (-1.474) has slightly better solubility than Ligand B (-5.335).

**hERG Inhibition:** Ligand A (0.055) has a very low hERG risk, significantly lower than Ligand B (0.575). This is a major advantage for Ligand A.

**Microsomal Clearance:** Ligand A (26.205) has lower clearance than Ligand B (141.72), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (-4.739) has a longer in vitro half-life than Ligand B (-17.225).

**P-gp Efflux:** Ligand A (0.037) has much lower P-gp efflux than Ligand B (0.603), which is crucial for CNS penetration.

**Binding Affinity:** Ligand A (-7.7) has a slightly better binding affinity than Ligand B (-7.5). While both are good, the 1.5 kcal/mol difference can be significant.

**Overall Assessment:**

Considering the GPCR-specific priorities, Ligand A is the more promising candidate. It has a better TPSA, lower logP, significantly lower hERG risk, better metabolic stability (lower Cl_mic and longer t1/2), lower P-gp efflux, and slightly better binding affinity. While Ligand B has a slightly better BBB penetration and lower DILI risk, the advantages of Ligand A in terms of safety (hERG, P-gp) and pharmacokinetic properties (Cl_mic, t1/2) outweigh these minor differences.

Output:
1
2025-04-17 06:00:08,908 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 drug candidates, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (348.487 Da) is slightly lower, which is generally favorable for permeability.

**2. TPSA:** Ligand A (69.64) is significantly better than Ligand B (42.68). For CNS targets, TPSA < 90 is desirable, and Ligand A is much closer to the ideal range.

**3. logP:** Ligand A (2.413) is optimal (1-3). Ligand B (4.616) is higher, potentially leading to solubility issues and off-target interactions.

**4. H-Bond Donors:** Both have acceptable HBD counts (Ligand A: 2, Ligand B: 0).

**5. H-Bond Acceptors:** Both have acceptable HBA counts (Ligand A: 3, Ligand B: 3).

**6. QED:** Both have good QED values (Ligand A: 0.523, Ligand B: 0.63), indicating drug-like properties.

**7. DILI:** Ligand A (19.814) has a much lower DILI risk than Ligand B (9.228), which is a significant advantage.

**8. BBB:** Ligand B (96.743) has a substantially higher BBB penetration percentile than Ligand A (57.193). This is a *critical* factor for a CNS target like DRD2.

**9. Caco-2 Permeability:** Ligand A (-4.725) and Ligand B (-4.306) both have negative values, which is unusual. A higher value is preferred, but the difference isn't dramatic.

**10. Aqueous Solubility:** Ligand A (-2.822) and Ligand B (-4.889) both have negative values, indicating poor solubility. Ligand B is slightly worse.

**11. hERG Inhibition:** Ligand A (0.188) has a lower hERG inhibition liability than Ligand B (0.884), which is preferable.

**12. Microsomal Clearance:** Ligand B (81.84) has a higher microsomal clearance than Ligand A (55.754), indicating lower metabolic stability.

**13. In vitro Half-Life:** Ligand A (-10.976) has a lower in vitro half-life than Ligand B (40.019), which is less desirable.

**14. P-gp Efflux:** Ligand A (0.161) has lower P-gp efflux liability than Ligand B (0.52), which is favorable for CNS penetration.

**15. Binding Affinity:** Ligand B (-7.1) has a slightly better binding affinity than Ligand A (-7.6). However, the difference is only 0.5 kcal/mol, which isn't large enough to overcome the significant ADME deficiencies of Ligand B.

**Overall Assessment:**

Ligand B excels in BBB penetration and binding affinity, but suffers from higher logP, higher DILI risk, higher hERG inhibition, and higher P-gp efflux. Ligand A has a more balanced profile with better TPSA, logP, DILI, hERG, and P-gp properties, despite a lower BBB score and slightly weaker binding affinity. Given the GPCR-specific priorities, the superior ADME profile of Ligand A outweighs the small difference in binding affinity. The better TPSA and lower logP will likely translate to better CNS exposure despite the lower predicted BBB.

Output:
0
2025-04-17 06:00:08,908 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B based on the provided guidelines, prioritizing GPCR-specific properties (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (340.39) is slightly lower, which could be beneficial for permeability, but both are acceptable.

**TPSA:** Ligand A (96.77) is better than Ligand B (49.41) as it is closer to the ideal range for CNS targets (<=90). Ligand B is very low, which might suggest potential off-target interactions.

**logP:** Ligand B (3.475) is optimal (1-3), while Ligand A (0.598) is quite low, potentially hindering membrane permeability. This is a significant drawback for Ligand A.

**H-Bond Donors/Acceptors:** Both ligands have acceptable HBD (1) and HBA (6 for A, 3 for B) counts.

**QED:** Both ligands have reasonable QED values (0.83 for A, 0.702 for B), indicating good drug-like properties.

**DILI:** Ligand B (8.492) has a much lower DILI risk than Ligand A (53.936), which is a substantial advantage.

**BBB:** Ligand B (76.89) has a significantly better BBB penetration percentile than Ligand A (47.577). This is crucial for a CNS target like DRD2.

**Caco-2 Permeability:** Ligand A (-5.186) has a worse Caco-2 permeability score than Ligand B (-4.705), but both are negative and thus indicate poor permeability.

**Aqueous Solubility:** Ligand A (-2.255) has slightly better solubility than Ligand B (-3.876).

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.061 for A, 0.607 for B).

**Microsomal Clearance:** Ligand A (9.17) has lower microsomal clearance, indicating better metabolic stability than Ligand B (89.673).

**In vitro Half-Life:** Ligand A (-24.56) has a negative half-life, which is not possible. This is a major red flag. Ligand B (4.256) has a short half-life but is at least a realistic value.

**P-gp Efflux:** Ligand A (0.083) has lower P-gp efflux, which is favorable for CNS penetration, compared to Ligand B (0.057).

**Binding Affinity:** Ligand B (-7.9) has a slightly better binding affinity than Ligand A (-8.9). While both are excellent, the difference is not substantial enough to overcome other weaknesses.

**Overall Assessment:**

Ligand A has a problematic negative in vitro half-life, which immediately disqualifies it. It also has a poor logP and lower BBB penetration. While it has better metabolic stability and P-gp efflux, these are overshadowed by its significant drawbacks. Ligand B, despite having a shorter half-life and slightly lower P-gp, presents a much more favorable profile overall, particularly regarding BBB penetration, DILI risk, and logP.



Output:
1
2025-04-17 06:00:08,908 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (348.334 and 350.503 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (124.18) is borderline for CNS penetration, slightly above the preferred <90, while Ligand B (69.64) is well within the ideal range. This is a significant advantage for Ligand B.

**logP:** Ligand A (0.439) is quite low, potentially hindering membrane permeability. Ligand B (2.491) is within the optimal 1-3 range. This favors Ligand B.

**H-Bond Donors/Acceptors:** Ligand A has 4 HBD and 5 HBA, acceptable values. Ligand B has 2 HBD and 3 HBA, also acceptable and potentially better for permeability.

**QED:** Both ligands have good QED scores (0.603 and 0.693), indicating drug-like properties.

**DILI:** Ligand A has a DILI risk of 64.288, which is concerning (high risk). Ligand B has a much lower DILI risk of 13.3, which is excellent. This is a major advantage for Ligand B.

**BBB:** Ligand A has a BBB penetration of 33.036, which is poor for a CNS target. Ligand B has a BBB penetration of 67.546, which is better, though still not optimal (>70 is preferred).

**Caco-2 Permeability:** Ligand A (-5.529) has very poor Caco-2 permeability, suggesting poor absorption. Ligand B (-4.914) is also poor, but slightly better than A.

**Aqueous Solubility:** Both ligands have poor aqueous solubility (-3.072 and -2.81). This might pose formulation challenges but isn't a dealbreaker.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.304 and 0.225).

**Microsomal Clearance:** Ligand A has a lower Cl_mic (22.771) than Ligand B (39.267), suggesting better metabolic stability. This favors Ligand A, but the difference isn't huge.

**In vitro Half-Life:** Ligand A has a negative half-life (-35.578), which is nonsensical and likely an error or outlier. Ligand B has a very short half-life (0.851), which is not ideal.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.021 and 0.075), which is good for CNS penetration.

**Binding Affinity:** Ligand B (-7.9 kcal/mol) has a significantly stronger binding affinity than Ligand A (-8.4 kcal/mol). While both are good, the difference of 0.5 kcal/mol is meaningful.

**Overall Assessment:**

Ligand B is the superior candidate. While both have solubility issues, Ligand B excels in key areas for a CNS GPCR target: TPSA, logP, BBB penetration, and crucially, DILI risk. The significantly better binding affinity further strengthens its case. Ligand A's low logP, poor Caco-2 permeability, high DILI risk, and poor BBB penetration are major drawbacks. The questionable half-life further diminishes its viability.



Output:
1
2025-04-17 06:00:08,908 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (337.379 and 348.487 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (83.22) is better than Ligand B (67.43) as it is closer to the ideal range for CNS targets (<=90).

**3. logP:** Both ligands have good logP values (2.95 and 2.701), falling within the optimal range of 1-3.

**4. H-Bond Donors:** Ligand A (3) is slightly higher than Ligand B (2), but both are acceptable (<=5).

**5. H-Bond Acceptors:** Both ligands have the same number of H-bond acceptors (3), which is well within the acceptable limit of <=10.

**6. QED:** Both ligands have similar QED values (0.64 and 0.63), indicating good drug-likeness.

**7. DILI:** Ligand A (95.58) has a significantly higher DILI risk than Ligand B (28.189). This is a major concern for Ligand A.

**8. BBB:** Ligand B (62.737) has a much better BBB penetration percentile than Ligand A (32.222). This is crucial for a CNS target like DRD2.

**9. Caco-2 Permeability:** Ligand A (-4.934) has a worse Caco-2 permeability than Ligand B (-4.876).

**10. Aqueous Solubility:** Ligand A (-5.092) has worse aqueous solubility than Ligand B (-3.163).

**11. hERG Inhibition:** Both ligands have low hERG inhibition liability (0.483 and 0.264), which is good.

**12. Microsomal Clearance:** Ligand B (45.017) has a higher microsomal clearance than Ligand A (32.011), meaning Ligand A is more metabolically stable.

**13. In vitro Half-Life:** Ligand A (25.23) has a longer in vitro half-life than Ligand B (10.263).

**14. P-gp Efflux:** Ligand A (0.309) has lower P-gp efflux than Ligand B (0.285), which is favorable for CNS penetration.

**15. Binding Affinity:** Ligand B (-7.9 kcal/mol) has a significantly stronger binding affinity than Ligand A (-9.4 kcal/mol). This is a substantial advantage.

**Overall Assessment:**

While Ligand A has slightly better metabolic stability and P-gp efflux, the significantly higher DILI risk, lower BBB penetration, and weaker binding affinity make it a less desirable candidate. Ligand B excels in the critical areas for a CNS GPCR target: strong binding affinity, good BBB penetration, and low DILI risk. The slightly higher metabolic clearance is a manageable drawback compared to the advantages of Ligand B.

Output:
1
2025-04-17 06:00:08,908 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (341.411 and 346.515 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (86.03) is excellent, well below the 90 A^2 threshold for CNS targets. Ligand B (49.41) is even better.

**logP:** Ligand A (1.846) is within the optimal 1-3 range. Ligand B (3.666) is slightly higher, but still acceptable.

**H-Bond Donors/Acceptors:** Ligand A has 2 HBD and 3 HBA, which is good. Ligand B has 1 HBD and 2 HBA, also good. Both are within the recommended limits.

**QED:** Ligand A (0.89) has a very strong drug-like profile. Ligand B (0.538) is acceptable, but less optimal.

**DILI:** Ligand A (72.78) has a moderate DILI risk. Ligand B (10.198) has a very low DILI risk, a significant advantage.

**BBB:** Ligand A (76.735) has good BBB penetration. Ligand B (93.757) is *excellent* and highly desirable for a CNS target like DRD2.

**Caco-2 Permeability:** Both have negative values, which is unusual and suggests a problem with the data. However, the magnitude suggests Ligand A (-4.766) is slightly better than Ligand B (-4.883).

**Aqueous Solubility:** Both have negative values, which is also unusual. Ligand A (-4.816) is slightly better than Ligand B (-3.95).

**hERG:** Both ligands have low hERG inhibition liability (0.568 and 0.689), which is good.

**Microsomal Clearance:** Ligand A (30.066) has lower clearance, indicating better metabolic stability than Ligand B (54.556).

**In vitro Half-Life:** Ligand A (16.012) has a longer half-life than Ligand B (-3.649), which is a positive.

**P-gp Efflux:** Ligand A (0.307) has lower P-gp efflux, which is favorable for CNS penetration. Ligand B (0.173) is even better.

**Binding Affinity:** Ligand A (-9.5 kcal/mol) has significantly stronger binding affinity than Ligand B (-8.0 kcal/mol). This is a substantial advantage, potentially outweighing some ADME drawbacks.

**Overall Assessment:**

Ligand B excels in BBB penetration, DILI risk, and P-gp efflux. However, Ligand A has a significantly stronger binding affinity, better metabolic stability (lower Cl_mic, longer t1/2), and a higher QED score. The superior binding affinity of Ligand A is a critical factor for a GPCR target, and the differences in ADME properties are not so substantial as to negate this advantage. The negative values for Caco-2 and Solubility are concerning for both, but we'll assume these are data artifacts.

Output:
1
2025-04-17 06:00:08,909 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B based on the provided guidelines, prioritizing GPCR properties (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (345.487 Da) is slightly lower, which could be beneficial for permeability.

**TPSA:** Ligand A (52.65) is significantly better than Ligand B (58.64) as it is closer to the ideal range for CNS targets (<=90).

**logP:** Both ligands have acceptable logP values (A: 1.624, B: 2.041), falling within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Both ligands have reasonable HBD (1) and HBA (A: 3, B: 4) counts, likely not causing major issues.

**QED:** Both ligands have similar and acceptable QED scores (A: 0.796, B: 0.722), indicating good drug-likeness.

**DILI:** Ligand A (5.273) has a much lower DILI risk than Ligand B (37.263), a significant advantage.

**BBB:** Ligand B (90.772) has a substantially higher BBB percentile than Ligand A (71.888), which is a critical factor for a CNS target like DRD2.

**Caco-2 Permeability:** Ligand A (-5.027) has a more negative Caco-2 value, indicating poorer permeability than Ligand B (-4.879).

**Aqueous Solubility:** Ligand A (-1.765) has slightly better aqueous solubility than Ligand B (-3.534).

**hERG:** Both ligands have low hERG inhibition liability (A: 0.529, B: 0.495).

**Microsomal Clearance:** Ligand A (-7.854) has a much lower (better) microsomal clearance than Ligand B (35.595), suggesting greater metabolic stability.

**In vitro Half-Life:** Ligand A (5.364) has a slightly longer in vitro half-life than Ligand B (-7.573).

**P-gp Efflux:** Ligand A (0.017) has a significantly lower P-gp efflux liability than Ligand B (0.096), which is crucial for CNS penetration.

**Binding Affinity:** Both ligands have excellent binding affinities (A: -8.7 kcal/mol, B: -8.5 kcal/mol), with Ligand A being slightly stronger. The difference of 0.2 kcal/mol is not substantial enough to override other significant differences.

**Overall Assessment:**

Ligand A excels in several key areas: lower DILI risk, better metabolic stability (lower Cl_mic), longer half-life, and significantly lower P-gp efflux. While Ligand B has a better BBB score, the combination of superior ADME properties in Ligand A, coupled with slightly better binding affinity, makes it the more promising candidate. The lower P-gp efflux and better metabolic stability of Ligand A are particularly important for CNS drug development.

Output:
1
2025-04-17 06:00:08,909 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (366.53 and 343.43 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (67.43) is significantly better than Ligand B (80.12). For CNS targets, we want TPSA <= 90, and ideally closer to 60. Ligand A is much closer to this ideal.

**logP:** Ligand A (3.27) is optimal (1-3), while Ligand B (1.22) is on the lower end, potentially hindering membrane permeability.

**H-Bond Donors/Acceptors:** Ligand A (2 HBD, 4 HBA) and Ligand B (1 HBD, 5 HBA) both have acceptable numbers of hydrogen bond donors and acceptors.

**QED:** Both ligands have good QED scores (0.778 and 0.82), indicating good drug-like properties.

**DILI:** Both ligands have low DILI risk (31.02 and 31.25), which is positive.

**BBB:** Ligand A (56.30) is better than Ligand B (44.59), though both are below the desirable >70 for CNS targets. However, given the other factors, a higher BBB is more critical.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.023 and -5.138), which is unusual and suggests poor permeability. This is a significant concern.

**Aqueous Solubility:** Both ligands have negative solubility values (-3.053 and -0.927), also unusual and concerning.

**hERG:** Both ligands have very low hERG risk (0.269 and 0.121), which is excellent.

**Microsomal Clearance:** Ligand A (54.69) has higher clearance than Ligand B (24.99), indicating lower metabolic stability.

**In vitro Half-Life:** Ligand B (-2.96) has a negative half-life, which is not physically possible and likely an error in the data. Ligand A (24.00) is reasonable.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.078 and 0.017), which is favorable for CNS penetration.

**Binding Affinity:** Ligand A (-8.1 kcal/mol) has a slightly better binding affinity than Ligand B (-7.9 kcal/mol). While the difference is small, it's still a factor.

**Overall Assessment:**

Ligand A is the better candidate. While both have issues with Caco-2 and solubility, Ligand A has a more favorable logP, TPSA, and binding affinity. The negative half-life for Ligand B is a major red flag. The slightly better BBB and affinity of Ligand A, combined with its more optimal physicochemical properties, make it more likely to succeed. The poor Caco-2 and solubility would need to be addressed through formulation or further chemical modification, but these are less fundamental issues than a negative half-life.

Output:
1
2025-04-17 06:00:08,909 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (345.418 and 350.467 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (62.71) is significantly better than Ligand B (92.62). For CNS targets, we want TPSA <= 90, so Ligand A is preferable.

**3. logP:** Both ligands have good logP values (2.023 and 1.726), falling within the optimal 1-3 range.

**4. H-Bond Donors:** Ligand A has 1 HBD, while Ligand B has 0. Both are acceptable (<=5).

**5. H-Bond Acceptors:** Both ligands have 4 HBAs, which is well within the acceptable limit of <=10.

**6. QED:** Ligand A (0.87) has a much better QED score than Ligand B (0.379), indicating a more drug-like profile.

**7. DILI:** Ligand A (16.479) has a significantly lower DILI risk than Ligand B (26.444). Both are below 40, which is good.

**8. BBB:** Both ligands have excellent BBB penetration (78.868 and 77.627), exceeding the desirable threshold of >70 for CNS targets.

**9. Caco-2 Permeability:** Ligand A (-5.124) has a worse Caco-2 permeability than Ligand B (-4.721), but both are negative, indicating poor permeability.

**10. Aqueous Solubility:** Ligand A (-1.227) has slightly worse solubility than Ligand B (-0.581), but both are negative, indicating poor solubility.

**11. hERG Inhibition:** Ligand A (0.95) has a slightly higher hERG inhibition risk than Ligand B (0.361), but both are relatively low.

**12. Microsomal Clearance:** Ligand B (56.287) has a much lower microsomal clearance than Ligand A (9.886), suggesting better metabolic stability.

**13. In vitro Half-Life:** Ligand A (10.372) has a better in vitro half-life than Ligand B (-25.633).

**14. P-gp Efflux:** Ligand A (0.148) has a much lower P-gp efflux liability than Ligand B (0.03), which is crucial for CNS penetration.

**15. Binding Affinity:** Ligand B (-7.2) has a slightly better binding affinity than Ligand A (-9.0). However, the difference is not substantial enough to outweigh other factors.

**Overall Assessment:**

Ligand A is the more promising candidate. While Ligand B has slightly better affinity and metabolic stability, Ligand A excels in crucial areas for CNS drug development: TPSA, QED, DILI risk, and *especially* P-gp efflux. The lower P-gp efflux for Ligand A will likely translate to significantly better brain exposure. The better half-life of Ligand A is also a plus. The slightly worse Caco-2 and solubility of Ligand A are less critical given the CNS target.

Output:
1
2025-04-17 06:00:08,909 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (345.4 and 360.4 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (73.66) is excellent, well below the 90 A^2 threshold for CNS targets. Ligand B (88.44) is still acceptable but less optimal.

**logP:** Both ligands have good logP values (1.152 and 1.954), falling within the 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A (0 HBD, 6 HBA) and Ligand B (1 HBD, 7 HBA) both have reasonable numbers of H-bond donors and acceptors, well within the guidelines.

**QED:** Both ligands have good QED scores (0.777 and 0.847), indicating good drug-like properties.

**DILI:** Both ligands have acceptable DILI risk (51.69 and 66.89), below the 60 threshold.

**BBB:** This is a critical parameter for a CNS target like DRD2. Ligand A has a very high BBB penetration percentile (91.2), which is excellent. Ligand B's BBB penetration (55.6) is significantly lower and less desirable.

**Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and suggests a potential issue with intestinal absorption modeling. However, the absolute values are similar.

**Aqueous Solubility:** Both ligands have negative solubility values, which is also unusual.

**hERG Inhibition:** Both ligands show low hERG inhibition risk (0.327 and 0.306).

**Microsomal Clearance:** Ligand A (68.94) has higher microsomal clearance than Ligand B (36.41), suggesting lower metabolic stability.

**In vitro Half-Life:** Ligand B (-5.911) has a longer in vitro half-life than Ligand A (-3.583).

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.199 and 0.102).

**Binding Affinity:** Ligand A (-7.5 kcal/mol) has a slightly better binding affinity than Ligand B (-7.2 kcal/mol), although the difference is relatively small.

**Overall Assessment:**

The most significant difference between the two ligands is the BBB penetration. Ligand A's excellent BBB score (91.2) is a major advantage for a CNS-targeting drug. While Ligand B has a slightly better half-life and lower clearance, the poor BBB score outweighs these benefits. The slightly better affinity of Ligand A is a bonus.

Output:
1
2025-04-17 06:00:08,910 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (352.415 Da) is slightly lower, which could be advantageous for permeability.

**TPSA:** Ligand A (68.29) is significantly better than Ligand B (93.87). For CNS targets, we want TPSA <= 90, so Ligand A is preferable.

**logP:** Ligand A (4.274) is higher than the optimal range (1-3), but still potentially manageable. Ligand B (0.381) is *too* low, potentially hindering membrane permeability and CNS penetration.

**H-Bond Donors/Acceptors:** Both have 1 HBD and 5 HBA, which are within acceptable limits.

**QED:** Both ligands have reasonable QED scores (A: 0.696, B: 0.74), indicating good drug-like properties.

**DILI:** Ligand A (98.759) has a very high DILI risk, which is a major concern. Ligand B (26.677) has a much lower, and acceptable, DILI risk.

**BBB:** Ligand A (45.677) has a moderate BBB penetration, while Ligand B (57.929) is also moderate, but slightly better. Both are below the desirable >70 for CNS targets, but the difference isn't huge.

**Caco-2 Permeability:** Both are negative, indicating poor permeability.

**Aqueous Solubility:** Both are negative, indicating poor solubility.

**hERG Inhibition:** Both have low hERG inhibition risk (A: 0.42, B: 0.501).

**Microsomal Clearance:** Ligand A (66.57) has a higher clearance than Ligand B (-8.018). Negative values for Cl_mic are unusual and likely indicate very high metabolic stability. Ligand B is significantly more metabolically stable.

**In vitro Half-Life:** Ligand A (-3.201) has a negative half-life, which is unusual and likely indicates high stability. Ligand B (-19.347) is even more stable.

**P-gp Efflux:** Ligand A (0.74) has a higher P-gp efflux liability than Ligand B (0.031). Lower P-gp efflux is preferred for CNS penetration.

**Binding Affinity:** Ligand A (-9.4 kcal/mol) has a significantly stronger binding affinity than Ligand B (-6.3 kcal/mol). This is a substantial advantage, potentially outweighing some ADME concerns.

**Overall Assessment:**

Ligand A has a much better binding affinity, but suffers from a very high DILI risk and moderate BBB penetration. Ligand B has a lower affinity but exhibits a significantly better safety profile (DILI) and improved metabolic stability (Cl_mic, t1/2) and lower P-gp efflux. Given the CNS target and the importance of safety, the high DILI risk of Ligand A is a major drawback. While the affinity difference is significant, the other properties of Ligand B make it a more promising starting point for optimization.

Output:
1
2025-04-17 06:00:08,910 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Ligand A (453.692 Da) is within the ideal range, while Ligand B (359.495 Da) is also acceptable, though closer to the lower bound.

**TPSA:** Ligand A (67.43) is better than Ligand B (73.2) as it is closer to the ideal <90 for CNS targets.

**logP:** Ligand A (4.581) is slightly high, potentially leading to solubility issues or off-target interactions. Ligand B (3.026) is within the optimal range.

**H-Bond Donors:** Both ligands are acceptable (Ligand A: 2, Ligand B: 1).

**H-Bond Acceptors:** Both ligands are acceptable (Ligand A: 4, Ligand B: 4).

**QED:** Both ligands have good QED scores (Ligand A: 0.651, Ligand B: 0.901), indicating drug-like properties. Ligand B is better.

**DILI:** Ligand A (82.28) has a higher DILI risk than Ligand B (50.136). This is a significant concern for Ligand A.

**BBB:** Both ligands have good BBB penetration (Ligand A: 68.36, Ligand B: 60.682), but Ligand A is slightly better. However, both are below the desirable >70 for CNS targets.

**Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and suggests poor permeability.

**Aqueous Solubility:** Both have negative solubility values, which is also unusual and suggests poor solubility.

**hERG Inhibition:** Both ligands have low hERG inhibition liability (Ligand A: 0.483, Ligand B: 0.604).

**Microsomal Clearance:** Ligand B (21.015 mL/min/kg) has significantly lower clearance than Ligand A (60.502 mL/min/kg), indicating better metabolic stability.

**In vitro Half-Life:** Ligand A (66.892 hours) has a much longer half-life than Ligand B (1.511 hours).

**P-gp Efflux:** Ligand A (0.507) has lower P-gp efflux than Ligand B (0.297), which is favorable for CNS penetration.

**Binding Affinity:** Ligand B (-8.8 kcal/mol) has a slightly better binding affinity than Ligand A (-8.2 kcal/mol). While the difference is not huge, it's still a factor.

**Overall Assessment:**

Ligand B is the better candidate. While Ligand A has a slightly better BBB score and longer half-life, Ligand B excels in several critical areas: lower DILI risk, significantly better metabolic stability (lower Cl_mic, longer t1/2), a slightly better binding affinity, and a more optimal logP. The higher DILI risk associated with Ligand A is a major concern. The negative Caco-2 and solubility values are concerning for both, but can be addressed with formulation strategies. Given the GPCR-specific priorities, the balance of properties favors Ligand B.

Output:
1
2025-04-17 06:00:08,910 - INFO - Batch 245 complete. Total preferences: 3920
2025-04-17 06:00:08,910 - INFO - Processing batch 246/512...
2025-04-17 06:00:54,053 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (369.864 and 361.873 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (55.4) is significantly better than Ligand B (62.3). For CNS targets, we want TPSA <= 90, and ideally lower. Ligand A is closer to the ideal range.

**3. logP:** Ligand A (4.04) is slightly higher than the optimal 1-3 range, but still acceptable. Ligand B (2.778) is within the optimal range. However, for a GPCR, a slightly higher logP can be tolerated if other properties are favorable.

**4. H-Bond Donors:** Both ligands have 1 HBD, which is within the acceptable limit of <=5.

**5. H-Bond Acceptors:** Both ligands have 3 HBA, also within the acceptable limit of <=10.

**6. QED:** Both ligands have good QED scores (0.797 and 0.896), indicating drug-like properties.

**7. DILI:** Ligand B (31.989) has a much lower DILI risk than Ligand A (46.258). This is a significant advantage for Ligand B.

**8. BBB:** Ligand A (83.172) has a better BBB penetration percentile than Ligand B (77.976). This is crucial for a CNS target like DRD2.

**9. Caco-2 Permeability:** Ligand A (-4.267) has a worse Caco-2 permeability than Ligand B (-5.047). Lower values indicate poorer permeability.

**10. Aqueous Solubility:** Ligand A (-4.935) has a worse aqueous solubility than Ligand B (-3.918). Lower values indicate poorer solubility.

**11. hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.46 and 0.259).

**12. Microsomal Clearance:** Ligand B (49.543) has a lower microsomal clearance than Ligand A (114.945), suggesting better metabolic stability.

**13. In vitro Half-Life:** Ligand B (-2.436) has a much better in vitro half-life than Ligand A (15.632).

**14. P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.467 and 0.048).

**15. Binding Affinity:** Ligand B (-8.2 kcal/mol) has a significantly stronger binding affinity than Ligand A (-0.0 kcal/mol). This is a major advantage, potentially outweighing some ADME drawbacks.

**Overall Assessment:**

While Ligand A has a better BBB score and slightly better logP, Ligand B excels in almost all other critical areas. It has a significantly lower DILI risk, better metabolic stability (lower Cl_mic, longer t1/2), better solubility, and *much* stronger binding affinity. The stronger affinity of Ligand B is a decisive factor, especially for a GPCR target where potent binding is essential. The slightly lower BBB of Ligand B is less concerning given its superior overall profile.

Output:
1
2025-04-17 06:00:54,054 - INFO - Reasoning:

Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (363.845 and 351.535 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (83.71) is slightly above the optimal <90 for CNS targets, but still reasonable. Ligand B (50.38) is excellent, well below 90.

**3. logP:** Ligand A (1.443) is within the optimal 1-3 range. Ligand B (3.794) is at the higher end of the optimal range, but still acceptable.

**4. H-Bond Donors:** Both ligands have 1 HBD, which is within the acceptable limit of <=5.

**5. H-Bond Acceptors:** Ligand A has 3 HBAs, and Ligand B has 4 HBAs, both within the acceptable limit of <=10.

**6. QED:** Ligand A (0.882) has a very good QED score, indicating high drug-likeness. Ligand B (0.735) is also good, but slightly lower.

**7. DILI:** Ligand A (51.725) has a moderate DILI risk, but is still acceptable (<60 is good). Ligand B (4.265) has a very low DILI risk, which is highly favorable.

**8. BBB:** Ligand A (70.803) has a good BBB percentile, meeting the >70 threshold for CNS targets. Ligand B (83.249) has an excellent BBB percentile, significantly better than Ligand A.

**9. Caco-2:** Both ligands have negative Caco-2 values (-4.972 and -4.663), which is unusual and suggests poor permeability. This is a significant concern for both.

**10. Solubility:** Both ligands have negative solubility values (-2.712 and -2.361), indicating very poor aqueous solubility. This is a major drawback for both.

**11. hERG:** Ligand A (0.195) has a very low hERG risk, which is excellent. Ligand B (0.885) has a slightly elevated hERG risk, but still relatively low.

**12. Cl_mic:** Ligand A (0.426) has very low microsomal clearance, suggesting good metabolic stability. Ligand B (37.449) has much higher clearance, indicating faster metabolism and potentially lower *in vivo* exposure.

**13. t1/2:** Ligand A (-19.727) has a negative in vitro half-life, which is impossible and indicates a data error or a very rapidly metabolized compound. Ligand B (16.518) has a reasonable in vitro half-life.

**14. Pgp:** Ligand A (0.07) has very low P-gp efflux, which is favorable for CNS penetration. Ligand B (0.301) has slightly higher P-gp efflux, but still relatively low.

**15. Binding Affinity:** Ligand A (-8.7 kcal/mol) has a significantly stronger binding affinity than Ligand B (-6.8 kcal/mol). This is a substantial advantage.

**Overall Assessment:**

Despite the poor Caco-2 and solubility for both compounds, Ligand A's significantly stronger binding affinity (-8.7 vs -6.8 kcal/mol) and superior metabolic stability (low Cl_mic) are compelling advantages. The BBB penetration is also acceptable. However, the negative half-life for Ligand A is a major red flag. Ligand B has better TPSA, DILI, and BBB, but its weaker affinity and higher metabolic clearance are significant drawbacks.

Considering the GPCR-specific priorities, the strong affinity of Ligand A is the most important factor. While the negative half-life is concerning, it could be an experimental error. The other properties, while not ideal, are less critical than potency for a starting point in a drug discovery program.

Output:
1
2025-04-17 06:00:54,054 - INFO - Okay, let's analyze these two ligands for their potential as DRD2 drug candidates. DRD2 is a GPCR in the CNS, so BBB penetration, logP, Pgp efflux, TPSA, and binding affinity are paramount.

**Ligand A: [358.427, 94.82, 1.837, 1, 8, 0.618, 89.259, 58.007, -5.419, -2.723, 0.262, 48.016, -17.189, 0.358, -9.1]**
**Ligand B: [345.399, 82.45, 1.783, 1, 6, 0.524, 52.152, 70.531, -4.886, -2.227, 0.528, 100.188, -34.497, 0.357, -7.8]**

Here's a breakdown comparing each property:

1. **MW:** Both are within the ideal range (200-500 Da). A (358.43) is slightly higher than B (345.40), but both are acceptable.
2. **TPSA:** A (94.82) is higher than B (82.45). For CNS targets, we want TPSA < 90. Ligand B is better here.
3. **logP:** Both are excellent (around 1.8), falling within the optimal 1-3 range.
4. **HBD:** Both have 1 HBD, which is good.
5. **HBA:** A has 8, B has 6. Both are acceptable (<=10).
6. **QED:** A (0.618) is better than B (0.524), indicating a slightly more drug-like profile.
7. **DILI:** A (89.26%) is significantly *higher* than B (52.15%). This is a major concern for Ligand A.
8. **BBB:** B (70.53%) is much better than A (58.01%).  >70% is desirable for CNS targets, making B significantly more promising.
9. **Caco-2:** A (-5.419) is worse than B (-4.886). Lower values indicate poorer permeability.
10. **Solubility:** A (-2.723) is worse than B (-2.227). Lower values indicate poorer solubility.
11. **hERG:** Both are low risk (0.262 and 0.528).
12. **Cl_mic:** A (48.02) is *much* better than B (100.19). Lower clearance is preferred for metabolic stability.
13. **t1/2:** A (-17.19) is worse than B (-34.50). Lower values indicate shorter half-life.
14. **Pgp:** Both are low risk (0.358 and 0.357).
15. **Binding Affinity:** A (-9.1) is *significantly* better than B (-7.8). This is a substantial advantage.

**Overall Assessment:**

Ligand A has a much stronger binding affinity and better metabolic stability (lower Cl_mic). However, its significantly higher DILI risk and poorer BBB penetration are major drawbacks for a CNS target. Ligand B has a more favorable safety profile (lower DILI) and better BBB penetration, along with acceptable TPSA and logP values. While its binding affinity is weaker, the difference isn't so large that it can't potentially be overcome with further optimization.

Considering the GPCR-specific priorities (BBB, logP, Pgp, TPSA, affinity) and the importance of safety for CNS drugs, **Ligand B is the more promising candidate.** The superior BBB penetration and lower DILI risk outweigh the weaker binding affinity, which can be addressed in subsequent rounds of optimization.

Output:
1
2025-04-17 06:00:54,054 - INFO - Reasoning:

Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (350.463 Da) is slightly preferred as it's closer to the lower end, potentially aiding permeability.

**2. TPSA:** Ligand A (100.27) is excellent, falling well below the 90 A^2 threshold for CNS targets. Ligand B (137.92) is still reasonable but less optimal.

**3. logP:** Ligand A (1.039) is within the optimal range (1-3). Ligand B (-1.925) is below 1, which could hinder permeation. This is a significant drawback for Ligand B.

**4. H-Bond Donors:** Both ligands have acceptable HBD counts (Ligand A: 3, Ligand B: 2), well below the limit of 5.

**5. H-Bond Acceptors:** Both ligands have acceptable HBA counts (Ligand A: 6, Ligand B: 7), below the limit of 10.

**6. QED:** Both ligands have similar and acceptable QED values (Ligand A: 0.585, Ligand B: 0.552), indicating good drug-like properties.

**7. DILI:** Ligand A (19.504) has a much lower DILI risk than Ligand B (35.905). This is a substantial advantage for Ligand A.

**8. BBB:** Ligand A (49.787) has a moderate BBB penetration, while Ligand B (13.377) has very poor predicted BBB penetration.  This is a critical factor for a CNS target like DRD2.

**9. Caco-2 Permeability:** Ligand A (-4.987) and Ligand B (-5.704) both have negative Caco-2 values, which is unusual and suggests poor permeability. However, the scale isn't specified, so it's hard to interpret.

**10. Aqueous Solubility:** Both ligands have poor aqueous solubility (-1.92 and -1.178 respectively). This could pose formulation challenges.

**11. hERG Inhibition:** Both ligands have very low hERG inhibition risk (Ligand A: 0.083, Ligand B: 0.035).

**12. Microsomal Clearance:** Ligand A (-7.353) has a lower (better) microsomal clearance than Ligand B (-15.667), indicating greater metabolic stability.

**13. In vitro Half-Life:** Ligand A (23.154) has a longer half-life than Ligand B (14.079).

**14. P-gp Efflux:** Both ligands have very low P-gp efflux liability (Ligand A: 0.024, Ligand B: 0.01).

**15. Binding Affinity:** Ligand B (-7.9 kcal/mol) has a slightly better binding affinity than Ligand A (-7.5 kcal/mol). While a 0.4 kcal/mol difference is noticeable, it's unlikely to overcome the significant ADME deficiencies of Ligand B.

**Overall Assessment:**

Ligand A is the superior candidate. While Ligand B has slightly better binding affinity, Ligand A demonstrates significantly better predicted BBB penetration, lower DILI risk, better metabolic stability, and a more favorable logP value. These factors are particularly crucial for a CNS-targeting GPCR like DRD2. The poor solubility of both compounds is a concern, but can potentially be addressed through formulation strategies.

Output:
0
2025-04-17 06:00:54,054 - INFO - Reasoning:

Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (346.475 Da) is slightly lower, which could be beneficial for permeability.

**2. TPSA:** Ligand A (76.02) is excellent, well below the 90 A^2 threshold for CNS targets. Ligand B (84.74) is still reasonable but less optimal.

**3. logP:** Ligand A (3.192) is within the optimal range (1-3). Ligand B (0.397) is quite low, potentially hindering membrane permeability and CNS penetration.

**4. H-Bond Donors:** Ligand A (2) is good. Ligand B (0) is also acceptable.

**5. H-Bond Acceptors:** Ligand A (4) is good. Ligand B (7) is slightly higher, but still within the acceptable limit of 10.

**6. QED:** Both ligands have good QED scores (A: 0.532, B: 0.767), indicating drug-like properties. Ligand B is slightly better.

**7. DILI:** Both ligands have acceptable DILI risk (A: 48.313, B: 68.786), with Ligand A showing a lower risk.

**8. BBB:** This is critical for a CNS target. Ligand A has a very good BBB percentile (78.596). Ligand B's BBB percentile (58.085) is considerably lower and less desirable.

**9. Caco-2 Permeability:** Both have negative values which is unusual and indicates low permeability.

**10. Aqueous Solubility:** Both have negative values which is unusual and indicates low solubility.

**11. hERG Inhibition:** Both ligands show low hERG inhibition liability (A: 0.406, B: 0.452).

**12. Microsomal Clearance:** Ligand A (68.305) has a higher clearance than Ligand B (20.604), suggesting Ligand B is more metabolically stable.

**13. In vitro Half-Life:** Ligand A (20.338) has a longer half-life than Ligand B (3.239).

**14. P-gp Efflux:** Both ligands show low P-gp efflux liability (A: 0.465, B: 0.082). Ligand B is slightly better.

**15. Binding Affinity:** Both ligands have excellent binding affinities (A: -8.1 kcal/mol, B: -8.3 kcal/mol). Ligand B is slightly stronger, but the difference is likely not substantial enough to overcome its other weaknesses.

**Overall Assessment:**

Considering the GPCR-specific priorities, Ligand A is the more promising candidate. While Ligand B has slightly better binding affinity and P-gp efflux, Ligand A excels in crucial areas for CNS penetration: TPSA, logP, and especially BBB. The lower logP and BBB of Ligand B are significant drawbacks for a DRD2 ligand. Ligand A's better DILI score and longer half-life also contribute to its favorability.

Output:
1
2025-04-17 06:00:54,054 - INFO - Reasoning:

Let's analyze Ligand A and Ligand B based on the provided guidelines, prioritizing GPCR-specific properties (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (349.45 and 352.431 Da) fall within the ideal range of 200-500 Da.

**TPSA:** Ligand A (43.86) is significantly better than Ligand B (84.94). For CNS targets, TPSA should be <= 90, and ideally lower. Ligand A is well within this range, while Ligand B is approaching the upper limit and less favorable.

**logP:** Ligand A (1.654) is optimal, while Ligand B (0.743) is slightly low, potentially impacting permeability.

**H-Bond Donors/Acceptors:** Ligand A (0 HBD, 3 HBA) is preferable to Ligand B (1 HBD, 5 HBA). Both are within acceptable limits, but fewer H-bonds generally improve permeability.

**QED:** Both ligands have similar and acceptable QED values (0.519 and 0.54).

**DILI:** Ligand A (14.541) has a much lower DILI risk than Ligand B (20.512), indicating a safer profile.

**BBB:** Ligand A (86.545) has a significantly better BBB penetration percentile than Ligand B (65.839). This is crucial for a CNS target like DRD2; >70 is desirable, and Ligand A is closer to that threshold.

**Caco-2 Permeability:** Ligand A (-4.301) is better than Ligand B (-4.554), indicating slightly better intestinal absorption.

**Aqueous Solubility:** Both ligands have similar and poor aqueous solubility (-1.459 and -1.609). This could pose formulation challenges, but is less critical than CNS penetration for a CNS target.

**hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.42 and 0.121).

**Microsomal Clearance:** Ligand A (10.02) has a much lower microsomal clearance than Ligand B (60.864), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (-14.031) has a longer in vitro half-life than Ligand B (-16.323).

**P-gp Efflux:** Ligand A (0.058) has lower P-gp efflux liability than Ligand B (0.005), which is favorable for CNS exposure.

**Binding Affinity:** Ligand B (-7.7) has a slightly better binding affinity than Ligand A (-7.4), but the difference is relatively small (0.3 kcal/mol). Given the other significant advantages of Ligand A, this difference is unlikely to be decisive.

**Overall Assessment:**

Ligand A is significantly better across multiple critical ADME properties, especially those prioritized for GPCRs targeting the CNS (BBB, TPSA, Pgp). Its lower DILI risk and improved metabolic stability are also highly desirable. While Ligand B has slightly better binding affinity, the other advantages of Ligand A outweigh this minor difference.

Output:
1
2025-04-17 06:00:54,054 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (367.921 and 351.378 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (54.34) is significantly better than Ligand B (96.62). For CNS targets, TPSA should be <= 90, so Ligand A is much more favorable.

**3. logP:** Both ligands have acceptable logP values (3.098 and 1.837, respectively), falling within the optimal 1-3 range.

**4. H-Bond Donors:** Ligand A (1) is preferable to Ligand B (3) as fewer HBDs generally improve permeability.

**5. H-Bond Acceptors:** Ligand A (3) is preferable to Ligand B (6) for similar reasons as HBDs.

**6. QED:** Both ligands have reasonable QED scores (0.753 and 0.597), indicating good drug-like properties. Ligand A is slightly better.

**7. DILI:** Both ligands have high DILI risk (22.257 and 69.717), but Ligand A is considerably lower, suggesting a better safety profile.

**8. BBB:** Ligand A (69.562) and Ligand B (76.774) both have good BBB penetration, being above the 70 percentile threshold for CNS targets. Ligand B is slightly better here.

**9. Caco-2 Permeability:** Both have negative Caco-2 values (-4.46 and -4.814), which is unusual and suggests poor permeability. This is a significant concern for both.

**10. Aqueous Solubility:** Both have negative solubility values (-3.503 and -3.202), indicating poor aqueous solubility. This is a drawback for both.

**11. hERG Inhibition:** Both ligands show low hERG inhibition liability (0.311 and 0.69), which is good.

**12. Microsomal Clearance:** Ligand A (61.687) has lower microsomal clearance than Ligand B (70), suggesting better metabolic stability.

**13. In vitro Half-Life:** Ligand B (58.949) has a longer in vitro half-life than Ligand A (37.516), which is generally desirable.

**14. P-gp Efflux:** Both ligands exhibit low P-gp efflux liability (0.128 and 0.306), which is favorable for CNS penetration.

**15. Binding Affinity:** Both ligands have excellent binding affinities (-7.6 and -7.7 kcal/mol), which is a major positive. Ligand B is slightly better.

**Overall Assessment:**

Considering the GPCR-specific priorities, Ligand A is the better candidate. While Ligand B has a slightly better BBB and binding affinity, Ligand A excels in TPSA, DILI risk, HBD/HBA counts, and metabolic stability. The lower TPSA of Ligand A is critical for CNS penetration, and the lower DILI risk is a significant safety advantage. The negative Caco-2 and solubility values are concerning for both, but can potentially be addressed through formulation strategies.

Output:
0
2025-04-17 06:00:54,055 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (387.487 Da) is slightly higher than Ligand B (359.455 Da), but both are acceptable.

**TPSA:** Ligand A (122.31) is borderline for CNS penetration, being slightly above the preferred <90 threshold. Ligand B (87.22) is well within the desired range. This favors Ligand B.

**logP:** Ligand A (0.174) is quite low, potentially hindering membrane permeability. Ligand B (1.46) is within the optimal range (1-3). This is a significant advantage for Ligand B.

**H-Bond Donors/Acceptors:** Ligand A has 3 HBD and 8 HBA, while Ligand B has 2 HBD and 6 HBA. Both are within acceptable limits, though Ligand B has a slightly more favorable profile.

**QED:** Both ligands have good QED scores (A: 0.531, B: 0.774), indicating good drug-like properties. Ligand B is better.

**DILI:** Both ligands have relatively high DILI risk (A: 79.798, B: 71.539), but are still within a range that isn't immediately disqualifying.

**BBB:** Ligand A (61.691) has a moderate BBB penetration score, while Ligand B (70.143) is better, approaching the desirable >70 threshold for CNS targets. This favors Ligand B.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.621 and -5.414), which is unusual and suggests poor permeability. This is a concern for both.

**Aqueous Solubility:** Both ligands have negative solubility values (-2.554 and -3.408), which is also unusual and suggests poor solubility. This is a concern for both.

**hERG Inhibition:** Both ligands have very low hERG inhibition risk (A: 0.343, B: 0.168), which is excellent.

**Microsomal Clearance:** Ligand A (54.187) has a higher microsomal clearance than Ligand B (39.709), suggesting lower metabolic stability. This favors Ligand B.

**In vitro Half-Life:** Ligand B (8.198) has a slightly longer in vitro half-life than Ligand A (6.018).

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (A: 0.023, B: 0.04), which is favorable for CNS penetration.

**Binding Affinity:** Ligand B (-8.7 kcal/mol) has a significantly stronger binding affinity than Ligand A (-7.2 kcal/mol). This is a substantial advantage, exceeding the 1.5 kcal/mol difference threshold.

**Overall Assessment:**

Ligand B consistently outperforms Ligand A across most critical parameters for a CNS-targeting GPCR ligand. It has a better logP, TPSA, BBB penetration, metabolic stability, half-life, and, crucially, a significantly higher binding affinity. While both have concerning Caco-2 and solubility values, the superior binding affinity and ADME profile of Ligand B outweigh these drawbacks.

Output:
1
2025-04-17 06:00:54,055 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (426.713 Da) is slightly higher, but still acceptable. Ligand B (371.438 Da) is also good.

**TPSA:** Ligand A (38.33) is excellent, well below the 90 A^2 threshold for CNS targets. Ligand B (111.21) is higher, but still potentially acceptable, though less ideal for CNS penetration.

**logP:** Ligand A (4.713) is a bit high, potentially leading to solubility issues or off-target interactions. Ligand B (-0.006) is very low, which could hinder membrane permeability and CNS penetration.

**H-Bond Donors/Acceptors:** Ligand A (HBD=1, HBA=2) is favorable. Ligand B (HBD=3, HBA=6) is also acceptable, but slightly higher counts could affect permeability.

**QED:** Both ligands have similar QED values (A: 0.726, B: 0.649), indicating good drug-like properties.

**DILI:** Ligand A (49.283) has a slightly better DILI score than Ligand B (54.168), suggesting a lower risk of liver injury. Both are acceptable.

**BBB:** Ligand A (84.684) has a significantly better BBB percentile than Ligand B (37.65). This is a *critical* advantage for a CNS target like DRD2.

**Caco-2 Permeability:** Ligand A (-4.541) has a negative value, which is unusual and suggests poor permeability. Ligand B (-5.867) is also negative and similarly poor.

**Aqueous Solubility:** Ligand A (-5.729) has poor solubility, consistent with its high logP. Ligand B (-2.215) is also poor, but slightly better than A.

**hERG Inhibition:** Ligand A (0.784) has a slightly higher hERG risk than Ligand B (0.032), but both are relatively low.

**Microsomal Clearance:** Ligand A (86.474) has high microsomal clearance, indicating rapid metabolism. Ligand B (-31.012) has negative clearance, which is not physically possible and likely an error in the data. This is a significant red flag.

**In vitro Half-Life:** Ligand A (28.815) has a moderate half-life. Ligand B (-7.587) has a negative half-life, which is not physically possible and further reinforces the data quality issue.

**P-gp Efflux:** Ligand A (0.57) has moderate P-gp efflux, which is acceptable. Ligand B (0.007) has very low P-gp efflux, which is favorable.

**Binding Affinity:** Ligand A (-8.9 kcal/mol) has a significantly stronger binding affinity than Ligand B (-7.1 kcal/mol). This 1.8 kcal/mol difference is substantial and could outweigh some of the ADME drawbacks.

**Overall Assessment:**

Ligand A has a superior BBB score and a much stronger binding affinity, which are crucial for a CNS GPCR target. However, it suffers from high logP, poor solubility, and high metabolic clearance. Ligand B has a very poor BBB score and its negative clearance and half-life values are highly suspect, indicating a data quality issue. Despite its lower logP, the questionable ADME properties make it a less attractive candidate. The strong affinity of Ligand A, combined with the importance of CNS penetration for DRD2, makes it the more promising candidate, even with its drawbacks. Further optimization could address the solubility and metabolic stability issues.

Output:
1
2025-04-17 06:00:54,055 - INFO - Reasoning:

Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (350.478 and 381.468 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (41.57) is significantly better than Ligand B (55.21). For CNS targets, we want TPSA <= 90, and ideally closer to 60. Ligand A is much closer to this ideal.

**3. logP:** Both ligands have acceptable logP values (4.058 and 2.122), falling within the 1-3 range. Ligand B is slightly better here.

**4. H-Bond Donors:** Both have 1 HBD, which is good.

**5. H-Bond Acceptors:** Ligand A has 3 HBA, Ligand B has 7. Ligand A is preferable.

**6. QED:** Both ligands have similar QED values (0.683 and 0.627), indicating good drug-likeness.

**7. DILI:** Ligand A (9.151) has a much lower DILI risk than Ligand B (19.426). This is a significant advantage.

**8. BBB:** Both ligands have excellent BBB penetration (85.111 and 83.986), exceeding the desirable >70 threshold.

**9. Caco-2 Permeability:** Ligand A (-4.668) is slightly better than Ligand B (-5.222), indicating better intestinal absorption.

**10. Aqueous Solubility:** Both ligands have poor aqueous solubility (-2.201 and -2.065). This is a potential issue, but not a deal-breaker, especially for CNS drugs where BBB penetration is prioritized.

**11. hERG Inhibition:** Both ligands have low hERG inhibition liability (0.95 and 0.712), which is good.

**12. Microsomal Clearance:** Ligand B (-15.789) has significantly lower (better) microsomal clearance than Ligand A (16.384), suggesting better metabolic stability.

**13. In vitro Half-Life:** Ligand B (-0.902) has a slightly longer half-life than Ligand A (6.215).

**14. P-gp Efflux:** Ligand A (0.444) has lower P-gp efflux than Ligand B (0.068), which is desirable for CNS exposure.

**15. Binding Affinity:** Ligand A (-8.6 kcal/mol) has a significantly stronger binding affinity than Ligand B (-6.7 kcal/mol). This is a crucial advantage, exceeding the 1.5 kcal/mol difference threshold.

**Overall Assessment:**

Ligand A is the superior candidate. While Ligand B has slightly better metabolic stability and half-life, Ligand A excels in the most critical areas for a CNS-targeting GPCR ligand: TPSA, DILI risk, P-gp efflux, and, most importantly, binding affinity. The significantly stronger binding affinity of Ligand A (-8.6 vs -6.7 kcal/mol) outweighs the minor drawbacks in metabolic stability. The lower TPSA and DILI risk are also strong positives.

Output:
1
2025-04-17 06:00:54,055 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 drug candidates, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (348.353 and 344.467 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (78.09) is significantly better than Ligand B (97.78). For CNS targets, we want TPSA <= 90, and A is comfortably within that range, while B is approaching the upper limit.

**3. logP:** Both ligands have good logP values (2.538 and 2.325), falling within the optimal 1-3 range.

**4. H-Bond Donors:** Both have 2 HBD, which is acceptable.

**5. H-Bond Acceptors:** Ligand A has 3 HBA, and Ligand B has 8. While both are under the 10 limit, Ligand A is preferable.

**6. QED:** Ligand A (0.872) has a substantially higher QED than Ligand B (0.532), indicating a more drug-like profile.

**7. DILI:** Ligand A (69.097) has a slightly higher DILI risk than Ligand B (52.036), but both are below the concerning threshold of 60.

**8. BBB:** Ligand A (80.031) has a significantly better BBB penetration percentile than Ligand B (71.074). This is *critical* for a CNS target like DRD2.

**9. Caco-2 Permeability:** Ligand A (-4.92) has a worse Caco-2 permeability than Ligand B (-5.519), but both are negative, indicating poor permeability.

**10. Aqueous Solubility:** Ligand A (-4.591) has worse aqueous solubility than Ligand B (-2.277).

**11. hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.652 and 0.642).

**12. Microsomal Clearance:** Ligand A (9.89) has much lower microsomal clearance than Ligand B (40.24), suggesting better metabolic stability.

**13. In vitro Half-Life:** Ligand A (13.79) has a shorter half-life than Ligand B (17.465).

**14. P-gp Efflux:** Ligand A (0.058) has much lower P-gp efflux than Ligand B (0.163), which is highly desirable for CNS penetration.

**15. Binding Affinity:** Ligand A (-8.8 kcal/mol) has a significantly stronger binding affinity than Ligand B (-7.4 kcal/mol). This >1.5 kcal/mol difference is a major advantage.

**Overall Assessment:**

Ligand A is the superior candidate. While Ligand B has slightly better solubility and half-life, Ligand A excels in the most important parameters for a CNS-targeting GPCR: **BBB penetration, binding affinity, metabolic stability (low Cl_mic), and P-gp efflux**. The lower TPSA and higher QED of Ligand A also contribute to its better overall profile. The stronger binding affinity is a significant advantage that can potentially offset any minor drawbacks in other properties.

Output:
1
2025-04-17 06:00:54,055 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (341.411 and 352.475 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (94.31) is slightly above the optimal <90 for CNS targets, but still reasonable. Ligand B (78.87) is well within the desired range.

**logP:** Ligand A (2.519) is within the optimal 1-3 range. Ligand B (1.173) is at the lower end, potentially impacting permeability.

**H-Bond Donors/Acceptors:** Both ligands have 2 HBD and 5/4 HBA, respectively, which are acceptable.

**QED:** Both ligands have similar QED scores (0.755 and 0.752), indicating good drug-likeness.

**DILI:** Ligand A has a DILI risk of 69.019, which is approaching the higher risk threshold (>60). Ligand B has a much lower DILI risk (12.059), a significant advantage.

**BBB:** Ligand A has a BBB penetration of 73.401, which is good for a CNS target. Ligand B's BBB penetration (55.215) is lower and less desirable.

**Caco-2 Permeability:** Both have negative Caco-2 values (-4.884 and -4.927), which is unusual and suggests poor permeability. This is a concern for both.

**Aqueous Solubility:** Both ligands have negative solubility values (-4.041 and -1.663), again indicating poor solubility. This is a significant drawback for both.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.593 and 0.253).

**Microsomal Clearance:** Ligand A (68.558) has a higher microsomal clearance than Ligand B (36.691), suggesting lower metabolic stability.

**In vitro Half-Life:** Ligand B has a longer in vitro half-life (14.577 hours) than Ligand A (-15.523 hours - negative value is concerning).

**P-gp Efflux:** Ligand A (0.166) has lower P-gp efflux than Ligand B (0.034), which is favorable for CNS penetration.

**Binding Affinity:** Ligand B (-7.8 kcal/mol) has a slightly better binding affinity than Ligand A (-8.9 kcal/mol). While both are excellent, the difference is not substantial enough to overcome other issues.

**Overall Assessment:**

Ligand A has better BBB penetration and P-gp efflux, which are critical for CNS targets. However, its DILI risk is higher, and its metabolic stability is lower. Ligand B has a significantly lower DILI risk, a better half-life, and slightly better binding affinity. The poor Caco-2 and solubility for both are concerning, but can potentially be addressed with formulation strategies. Given the importance of minimizing toxicity (DILI) and maximizing metabolic stability for a CNS drug, and the relatively small difference in binding affinity, Ligand B appears to be the more promising candidate.

Output:
1
2025-04-17 06:00:54,055 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (350.503 and 354.491 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (67.43) is slightly above the optimal <90 for CNS targets, but still reasonable. Ligand B (59.08) is well within the desired range.

**3. logP:** Both ligands have good logP values (2.951 and 2.09), falling within the 1-3 optimal range.

**4. H-Bond Donors:** Ligand A has 2 HBD, which is acceptable. Ligand B has 0, also acceptable.

**5. H-Bond Acceptors:** Ligand A has 3 HBA, and Ligand B has 4. Both are within the acceptable limit of <=10.

**6. QED:** Both ligands have QED values (0.694 and 0.564) above the 0.5 threshold, indicating good drug-like properties.

**7. DILI:** Ligand A (28.887) has a slightly higher DILI risk than Ligand B (17.914), but both are below the concerning threshold of 60.

**8. BBB:** Ligand B (89.802) has a significantly better BBB penetration percentile than Ligand A (73.517). This is a crucial advantage for a CNS target like DRD2.

**9. Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and suggests a potential issue with the data or modeling. However, the magnitude is similar, so it doesn't strongly differentiate the two.

**10. Aqueous Solubility:** Both ligands have negative solubility values, again suggesting a potential data issue. The values are similar, so this isn't a major differentiator.

**11. hERG Inhibition:** Both ligands have low hERG inhibition risk (0.286 and 0.46).

**12. Microsomal Clearance:** Ligand A (67.772) has higher microsomal clearance than Ligand B (29.064), indicating lower metabolic stability.

**13. In vitro Half-Life:** Ligand B (3.745) has a longer in vitro half-life than Ligand A (-0.619). This is a significant advantage.

**14. P-gp Efflux:** Both ligands have low P-gp efflux liability (0.12 and 0.241).

**15. Binding Affinity:** Ligand A (-9.0) has a significantly stronger binding affinity than Ligand B (-6.8). This is a substantial advantage, potentially outweighing some of the ADME drawbacks.

**Overall Assessment:**

While Ligand A boasts a superior binding affinity, Ligand B demonstrates a more favorable ADME profile, particularly regarding BBB penetration (89.802 vs 73.517) and metabolic stability (lower Cl_mic and longer t1/2). For a CNS target like DRD2, good brain penetration is paramount. The difference in binding affinity (-9.0 vs -6.8) is substantial, but a difference of 2.2 kcal/mol can sometimes be overcome with optimization. Given the importance of BBB penetration for CNS drugs, and the acceptable, though not ideal, affinity of Ligand B, I would prioritize Ligand B.

Output:
1
2025-04-17 06:00:54,055 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (359.451 and 366.893 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Both ligands have TPSA values (95.13 and 93.01) that are acceptable for oral absorption (<140), but slightly higher than optimal for CNS penetration (<90).

**3. logP:** Both ligands have logP values (3.24 and 2.912) within the optimal 1-3 range.

**4. H-Bond Donors:** Both ligands have 2 HBD, which is within the acceptable limit of <=5.

**5. H-Bond Acceptors:** Ligand A has 5 HBA, and Ligand B has 4 HBA, both within the acceptable limit of <=10.

**6. QED:** Both ligands have QED values (0.742 and 0.702) indicating good drug-like properties (>=0.5).

**7. DILI:** Ligand A has a DILI risk of 63.668, which is moderately high. Ligand B has a much lower DILI risk of 16.44, which is excellent. This is a significant advantage for Ligand B.

**8. BBB:** Ligand A has a BBB penetration of 26.638, which is quite low and concerning for a CNS target. Ligand B has a much better BBB penetration of 48.662, though still not ideal (>70).

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.089 and -4.901), which is unusual and suggests poor permeability. However, these values are on a log scale and can be interpreted as very low permeability.

**10. Aqueous Solubility:** Both ligands have negative solubility values (-4.282 and -3.997), suggesting very poor aqueous solubility. This could pose formulation challenges.

**11. hERG Inhibition:** Both ligands have low hERG inhibition risk (0.693 and 0.49).

**12. Microsomal Clearance:** Ligand A has a Cl_mic of 48.304, and Ligand B has 51.556. Both are moderate, suggesting moderate metabolic stability.

**13. In vitro Half-Life:** Ligand A has a half-life of 63.942, while Ligand B has a negative half-life (-9.155). A negative half-life is not physically meaningful and indicates a very rapid degradation or other issue.

**14. P-gp Efflux:** Both ligands have low P-gp efflux liability (0.419 and 0.16). Lower is better, so Ligand B is slightly better here.

**15. Binding Affinity:** Ligand A has a binding affinity of -8.1 kcal/mol, which is excellent. Ligand B has a binding affinity of -6.5 kcal/mol, which is good, but significantly weaker than Ligand A. The difference of 1.6 kcal/mol is substantial.

**Overall Assessment:**

Ligand A has a significantly better binding affinity, which is a major advantage. However, its low BBB penetration and moderately high DILI risk are concerning. Ligand B has a better safety profile (lower DILI), better Pgp efflux, and a better BBB score, but its binding affinity is considerably weaker, and its in vitro half-life is nonsensical.

Given the GPCR-specific priorities, BBB penetration is crucial for CNS targets. While Ligand B's BBB is not ideal, it's significantly better than Ligand A's. The substantial difference in binding affinity (-1.6 kcal/mol) is a significant factor. For a GPCR, a strong binding affinity can sometimes overcome other ADME deficiencies, especially if the compound can still reach the target (even if limited).

Therefore, despite the issues with Ligand B's half-life, the superior binding affinity of Ligand A makes it the more promising candidate, assuming the low BBB penetration can be addressed through further optimization.

Output:
0
2025-04-17 06:00:54,055 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (379.869 Da) is slightly higher than Ligand B (352.366 Da), but both are acceptable.

**TPSA:** Ligand A (70.58) is excellent for CNS penetration, well below the 90 A^2 threshold. Ligand B (100.6) is still reasonable, but less optimal.

**logP:** Ligand A (2.057) is within the optimal range (1-3). Ligand B (0.237) is quite low, potentially hindering membrane permeability and CNS entry.

**H-Bond Donors/Acceptors:** Ligand A (0 HBD, 4 HBA) is favorable. Ligand B (2 HBD, 6 HBA) is also acceptable, though slightly higher.

**QED:** Both ligands have similar QED values (Ligand A: 0.8, Ligand B: 0.673), indicating good drug-likeness.

**DILI:** Ligand A (79.798) has a higher DILI risk than Ligand B (54.556), which is better.

**BBB:** Ligand A (81.621) shows excellent BBB penetration potential. Ligand B (30.361) is significantly lower, a major drawback for a CNS target.

**Caco-2 Permeability:** Ligand A (-4.724) and Ligand B (-5.211) both have negative values, indicating poor permeability. However, these values are on a scale where negative values are possible and don't necessarily disqualify a compound.

**Aqueous Solubility:** Ligand A (-4.049) and Ligand B (-1.25) both have negative solubility values, indicating poor solubility.

**hERG:** Ligand A (0.609) has a slightly higher hERG risk than Ligand B (0.253), but both are relatively low.

**Microsomal Clearance:** Ligand A (67.73) has higher clearance than Ligand B (13.472), meaning Ligand B is more metabolically stable.

**In vitro Half-Life:** Ligand B (34.235) has a longer half-life than Ligand A (-30.01), which is a positive attribute.

**P-gp Efflux:** Ligand A (0.214) has lower P-gp efflux liability than Ligand B (0.031), which is preferable for CNS penetration.

**Binding Affinity:** Ligand B (-7.5 kcal/mol) has a significantly stronger binding affinity than Ligand A (-9.4 kcal/mol). This is a substantial advantage.

**Overall Assessment:**

While Ligand B has a superior binding affinity and better metabolic stability (lower Cl_mic, longer t1/2), Ligand A is markedly better in terms of BBB penetration (81.621 vs 30.361) and has a more favorable logP value (2.057 vs 0.237). For a CNS target like DRD2, BBB penetration is critical. The lower logP of Ligand B is a significant concern, potentially limiting its ability to cross the blood-brain barrier despite the P-gp efflux data. The affinity difference is substantial, but the other ADME properties of Ligand A are more aligned with CNS drug development.

Output:
0
2025-04-17 06:00:54,055 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (346.515 and 348.399 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (40.62) is excellent, well below the 90 A^2 threshold for CNS targets. Ligand B (81.01) is higher, but still potentially acceptable, though less favorable.

**logP:** Ligand A (3.618) is optimal. Ligand B (1.282) is a bit low, potentially hindering membrane permeability.

**H-Bond Donors/Acceptors:** Ligand A (0 HBD, 2 HBA) is very favorable. Ligand B (1 HBD, 5 HBA) is also acceptable, but slightly less so than A.

**QED:** Both ligands have good QED scores (0.661 and 0.867), indicating good drug-like properties.

**DILI:** Ligand A (11.361) has a much lower DILI risk than Ligand B (43.273). This is a significant advantage for A.

**BBB:** Ligand A (84.025) has excellent BBB penetration, exceeding the 70% threshold. Ligand B (49.748) is considerably lower, raising concerns about CNS exposure.

**Caco-2 Permeability:** Both have negative values (-4.698 and -4.589), which is unusual and difficult to interpret without further context. However, we can assume lower (more negative) values indicate lower permeability.

**Aqueous Solubility:** Both have negative values (-3.133 and -1.937), which is also unusual. Lower values suggest poor solubility.

**hERG Inhibition:** Both ligands show low hERG inhibition liability (0.495 and 0.239), which is good.

**Microsomal Clearance:** Ligand A (52.625) has higher clearance than Ligand B (23.902), suggesting lower metabolic stability.

**In vitro Half-Life:** Ligand B (30.024) has a longer half-life than Ligand A (-17.787), which is preferable.

**P-gp Efflux:** Ligand A (0.315) shows lower P-gp efflux than Ligand B (0.035), which is a significant advantage for CNS penetration.

**Binding Affinity:** Ligand A (-8.6 kcal/mol) has significantly stronger binding affinity than Ligand B (0.0 kcal/mol). This is a crucial factor.

**Overall Assessment:**

Ligand A is clearly superior. Its strong binding affinity, excellent BBB penetration, low DILI risk, and favorable TPSA and logP values outweigh its slightly higher microsomal clearance. Ligand B's lower logP, significantly higher DILI risk, and poor BBB penetration are major drawbacks, despite its longer half-life. The substantial difference in binding affinity (-8.6 vs 0.0 kcal/mol) is a decisive factor.



Output:
1
2025-04-17 06:00:54,056 - INFO - Batch 246 complete. Total preferences: 3936
2025-04-17 06:00:54,056 - INFO - Processing batch 247/512...
2025-04-17 06:01:36,891 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B based on the provided guidelines, prioritizing GPCR-specific properties (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (346.43) is slightly better, being closer to the lower end which can aid permeability.

**TPSA:** Ligand A (59.08) is excellent, well below the 90 A^2 threshold for CNS targets. Ligand B (105.98) is higher, but still potentially acceptable, though less ideal.

**logP:** Both ligands have good logP values (A: 2.371, B: 1.639), falling within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A (0 HBD, 4 HBA) is better than Ligand B (2 HBD, 8 HBA) in terms of balancing solubility and permeability. Fewer H-bonds generally favor CNS penetration.

**QED:** Both ligands have similar QED values (A: 0.733, B: 0.668), indicating good drug-like properties.

**DILI:** Ligand B (94.882) has a significantly higher DILI risk than Ligand A (53.858). This is a major concern.

**BBB:** Ligand A (87.127) has a much better BBB penetration percentile than Ligand B (54.285). This is *critical* for a CNS target like DRD2.

**Caco-2 Permeability:** Ligand A (-4.094) has a more negative Caco-2 value, which is unusual and suggests poor permeability. Ligand B (-5.6) is even worse. However, these values are on a scale where lower is worse, and the absolute values aren't directly comparable without knowing the scale's specifics.

**Aqueous Solubility:** Both ligands have negative solubility values (-2.294 and -3.117), indicating poor solubility. This is a concern, but can sometimes be mitigated with formulation strategies.

**hERG Inhibition:** Both ligands have very low hERG inhibition risk (A: 0.418, B: 0.121).

**Microsomal Clearance:** Ligand A (88.434) has a higher microsomal clearance than Ligand B (13.779), meaning it's metabolized faster. Ligand B is significantly more metabolically stable.

**In vitro Half-Life:** Ligand B (55.268) has a significantly longer in vitro half-life than Ligand A (-9.014).

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (A: 0.153, B: 0.163).

**Binding Affinity:** Ligand B (-7.9 kcal/mol) has a slightly better binding affinity than Ligand A (-7.6 kcal/mol), though the difference is relatively small.

**Overall Assessment:**

Ligand A excels in TPSA, BBB, and DILI risk. Its lower metabolic stability and shorter half-life are drawbacks, but the strong BBB penetration is a significant advantage for a CNS target. Ligand B has better metabolic stability and half-life, and slightly better affinity, but suffers from a high DILI risk and poor BBB penetration. Given the importance of BBB penetration for DRD2, and the significant concern with Ligand B's DILI risk, Ligand A is the more promising candidate. The poor Caco-2 values for both are a concern, but can potentially be addressed.



Output:
0
2025-04-17 06:01:36,891 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (362.832 and 348.403 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (41.57) is excellent, well below the 90 A^2 threshold for CNS targets. Ligand B (95) is significantly higher, potentially hindering BBB penetration.

**logP:** Ligand A (3.169) is optimal (1-3). Ligand B (0.499) is quite low, which could limit its ability to cross cell membranes, including the BBB.

**H-Bond Donors/Acceptors:** Ligand A (HBD=1, HBA=3) is within acceptable limits. Ligand B (HBD=2, HBA=6) is also acceptable, but higher HBA could slightly impact permeability.

**QED:** Both ligands have similar and good QED values (0.888 and 0.823, respectively), indicating drug-like properties.

**DILI:** Ligand A (52.423) has a lower DILI risk than Ligand B (61.962), making it preferable from a safety perspective. Both are acceptable, but A is better.

**BBB:** Ligand A (87.515) has a very good BBB percentile, crucial for a CNS target like DRD2. Ligand B (60.295) is substantially lower, raising concerns about brain exposure.

**Caco-2 Permeability:** Ligand A (-4.743) and Ligand B (-5.25) both have negative values, indicating poor permeability. This is a concern for both, but less so for Ligand A given its other favorable properties.

**Aqueous Solubility:** Ligand A (-3.965) and Ligand B (-1.503) both have negative values, indicating poor solubility. This is a concern for both.

**hERG:** Both ligands have low hERG inhibition risk (0.799 and 0.228, respectively).

**Microsomal Clearance:** Ligand B (-10.071) has a significantly lower (better) microsomal clearance than Ligand A (43.597), suggesting greater metabolic stability.

**In vitro Half-Life:** Ligand B (-1.578) has a very short half-life, while Ligand A (11.428) is better, though still not ideal.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.229 and 0.008, respectively), which is good for CNS penetration.

**Binding Affinity:** Both ligands have identical binding affinities (-8.4 kcal/mol), which is excellent.

**Conclusion:**

Considering all factors, especially the GPCR-specific priorities, **Ligand A is the more promising drug candidate.** While both have good binding affinity, Ligand A's superior BBB penetration (87.5% vs 60.3%), better TPSA (41.6 vs 95), and acceptable DILI risk outweigh Ligand B's better metabolic stability. The lower logP of Ligand B is a significant drawback for a CNS target. The poor Caco-2 and solubility are concerns for both, but can be addressed with formulation strategies.

Output:
1
2025-04-17 06:01:36,891 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 drug candidates, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (358.454 and 354.491 Da) fall comfortably within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (78.87) is slightly higher than Ligand B (67.87). Both are below the 90 A^2 threshold desirable for CNS targets, but Ligand B is preferable.

**3. logP:** Both ligands have acceptable logP values (1.267 and 2.116), falling within the optimal 1-3 range. Ligand B is slightly higher, which could be beneficial for membrane permeability.

**4. H-Bond Donors:** Ligand A (2) and Ligand B (1) are both within the acceptable limit of <=5. Ligand B is slightly better.

**5. H-Bond Acceptors:** Both ligands have 4 H-bond acceptors, well within the acceptable limit of <=10.

**6. QED:** Both ligands have similar QED values (0.641 and 0.61), indicating good drug-likeness.

**7. DILI:** Ligand A (5.777) has a significantly lower DILI risk than Ligand B (17.138). This is a substantial advantage for Ligand A.

**8. BBB:** Both ligands show excellent BBB penetration (88.872 and 88.29), exceeding the desirable >70 threshold for CNS targets. This is a positive for both.

**9. Caco-2 Permeability:** Ligand A (-4.716) has slightly better Caco-2 permeability than Ligand B (-4.569), indicating better intestinal absorption.

**10. Aqueous Solubility:** Both ligands have poor aqueous solubility (-1.151 and -1.578). This is a potential issue for both, requiring formulation strategies.

**11. hERG Inhibition:** Both ligands have low hERG inhibition risk (0.608 and 0.479), which is good.

**12. Microsomal Clearance:** Ligand A (-2.541) has significantly lower (better) microsomal clearance than Ligand B (58.358), suggesting better metabolic stability.

**13. In vitro Half-Life:** Ligand A (-5.908) has a significantly longer in vitro half-life than Ligand B (12.155), which is a major advantage.

**14. P-gp Efflux:** Ligand A (0.143) has lower P-gp efflux than Ligand B (0.065), which is preferable for CNS exposure.

**15. Binding Affinity:** Both ligands have very similar and excellent binding affinities (-7.4 and -7.3 kcal/mol). The difference is negligible.

**Overall Assessment:**

While both ligands have good binding affinity and BBB penetration, Ligand A is significantly better overall. It has a much lower DILI risk, better metabolic stability (lower Cl_mic, longer t1/2), lower P-gp efflux, and slightly better Caco-2 permeability. Ligand B has a slightly more favorable logP and TPSA, but these are minor differences compared to the substantial advantages of Ligand A in terms of safety (DILI) and pharmacokinetics (Cl_mic, t1/2).

Output:
0
2025-04-17 06:01:36,891 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (352.431 and 362.514 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (104.73) is better than Ligand B (36.36). For CNS targets, we want TPSA <= 90, and A is closer to that threshold.

**logP:** Ligand A (0.359) is quite low, potentially hindering permeability. Ligand B (4.556) is high, potentially causing solubility and off-target issues. This is a significant drawback for B.

**H-Bond Donors/Acceptors:** Ligand A has 3 HBD and 5 HBA, which are acceptable. Ligand B has 1 HBD and 4 HBA, also acceptable.

**QED:** Both ligands have good QED scores (0.574 and 0.748), indicating good drug-like properties.

**DILI:** Ligand A (13.339) has a much lower DILI risk than Ligand B (15.2). This is a clear advantage for A.

**BBB:** Ligand B (84.839) has a significantly higher BBB penetration percentile than Ligand A (31.214). This is a *major* advantage for B, given DRD2 is a CNS target.

**Caco-2 Permeability:** Both have negative values, which is unusual. However, the magnitude of the negative value is smaller for Ligand B (-4.988) than for Ligand A (-5.095), suggesting slightly better permeability for B.

**Aqueous Solubility:** Both have negative values, which is also unusual. Ligand A (-1.59) is slightly better than Ligand B (-4.322).

**hERG Inhibition:** Ligand A (0.095) has a very low hERG risk, while Ligand B (0.968) has a moderate risk. This is a strong advantage for A.

**Microsomal Clearance:** Ligand A (26.036) has lower microsomal clearance than Ligand B (41.664), indicating better metabolic stability.

**In vitro Half-Life:** Ligand B (29.614) has a significantly longer in vitro half-life than Ligand A (-0.879).

**P-gp Efflux:** Ligand A (0.009) has very low P-gp efflux, while Ligand B (0.903) has moderate efflux. This is a significant advantage for A.

**Binding Affinity:** Ligand B (-8.3 kcal/mol) has a slightly better binding affinity than Ligand A (-7.6 kcal/mol). The difference is 0.7 kcal/mol, which is substantial.

**Overall Assessment:**

Ligand B excels in BBB penetration and binding affinity, which are crucial for a CNS GPCR target. However, its high logP, moderate P-gp efflux, and moderate hERG risk are concerning. Ligand A has better ADME properties (lower DILI, hERG, P-gp, and better metabolic stability), but its BBB penetration is poor and logP is too low.

The difference in binding affinity (0.7 kcal/mol) is significant, and the superior BBB penetration of Ligand B is a major factor for a CNS target. While Ligand B's logP is high, it might be optimized. The poor BBB penetration of Ligand A is a more difficult property to improve.

Output:
1
2025-04-17 06:01:36,892 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands are within the acceptable range (200-500 Da). Ligand A (429.292 Da) is higher, but not excessively so. Ligand B (349.435 Da) is slightly better.

**2. TPSA:**  For CNS targets, we want TPSA <= 90. Ligand A (98.54) is slightly above this, while Ligand B (101.65) is also above. Both are suboptimal, but not dramatically so.

**3. logP:** Optimal range is 1-3. Ligand A (3.277) is good. Ligand B (0.794) is quite low, potentially hindering membrane permeability.

**4. H-Bond Donors:** Both have 1 HBD, which is within the acceptable limit of <=5.

**5. H-Bond Acceptors:** Ligand A has 5 HBA, and Ligand B has 6 HBA, both are within the acceptable limit of <=10.

**6. QED:** Ligand B (0.866) has a significantly better QED score than Ligand A (0.395), indicating a more drug-like profile.

**7. DILI:** Ligand A (85.653) has a higher DILI risk than Ligand B (54.362). Lower is better, so Ligand B is preferable.

**8. BBB:** This is crucial for a CNS target. Ligand B (77.549) has a much better BBB percentile than Ligand A (53.897). This is a significant advantage for Ligand B.

**9. Caco-2 Permeability:** Ligand A (-5.085) has a negative value, which is unusual and suggests very poor permeability. Ligand B (-4.834) is also poor, but slightly better.

**10. Aqueous Solubility:** Both have negative values, indicating poor solubility. Ligand A (-4.885) is slightly worse than Ligand B (-2.38).

**11. hERG Inhibition:** Ligand A (0.819) has a higher hERG risk than Ligand B (0.416). Lower is better, so Ligand B is preferable.

**12. Microsomal Clearance:** Ligand A (79.89) has a higher clearance than Ligand B (20.687), suggesting lower metabolic stability. Ligand B is much better.

**13. In vitro Half-Life:** Ligand B (9.158) has a better half-life than Ligand A (-22.005).

**14. P-gp Efflux:** Ligand A (0.737) has a higher P-gp efflux liability than Ligand B (0.021). Lower is better, so Ligand B is preferable.

**15. Binding Affinity:** Ligand A (-8.5 kcal/mol) has a significantly better binding affinity than Ligand B (-0.0 kcal/mol). This is a major advantage for Ligand A. A difference of >1.5 kcal/mol can outweigh other drawbacks.

**Overall Assessment:**

Despite Ligand B having better ADME properties (BBB, DILI, hERG, Cl_mic, Pgp, QED), Ligand A's *much* stronger binding affinity (-8.5 vs -0.0 kcal/mol) is a decisive factor. The affinity difference is so large that it is likely to overcome the ADME liabilities of Ligand A. While the TPSA is slightly high, and solubility is poor, these can be addressed through further optimization. The poor Caco-2 permeability is a concern, but the strong binding and potential for CNS penetration (BBB of 53.897 is not terrible) make Ligand A the more promising candidate.

Output:
1
2025-04-17 06:01:36,892 - INFO - Reasoning:

Let's analyze Ligand A and Ligand B based on the provided guidelines, prioritizing GPCR-specific properties (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (345.359 Da) is slightly lower, which could be beneficial for permeability, but both are acceptable.

**TPSA:** Ligand A (124.44) is better than Ligand B (75.62). For CNS targets, TPSA should be <= 90, both are within this range, but Ligand B is significantly better.

**logP:** Ligand A (1.162) is within the optimal range (1-3), while Ligand B (3.63) is at the higher end. While still acceptable, Ligand B's higher logP could potentially lead to solubility issues or off-target interactions.

**H-Bond Donors/Acceptors:** Ligand A (HBD=1, HBA=8) and Ligand B (HBD=2, HBA=7) both have reasonable numbers of H-bond donors and acceptors, falling within the suggested limits.

**QED:** Ligand A (0.822) has a significantly better QED score than Ligand B (0.499), indicating a more drug-like profile.

**DILI:** Ligand B (69.639) has a lower DILI risk than Ligand A (81.466), which is a positive attribute.

**BBB:** Ligand A (90.772) has a significantly higher BBB penetration percentile than Ligand B (74.021). This is *critical* for a CNS target like DRD2.

**Caco-2 Permeability:** Ligand A (-4.734) and Ligand B (-5.43) both have negative values, which is unusual and suggests poor permeability. However, the scale is not defined, so it's hard to interpret.

**Aqueous Solubility:** Ligand A (-2.731) and Ligand B (-3.414) both have negative values, suggesting poor solubility.

**hERG Inhibition:** Both ligands have relatively low hERG inhibition risk (Ligand A: 0.325, Ligand B: 0.627).

**Microsomal Clearance:** Ligand B (74.782) has a higher microsomal clearance than Ligand A (48.557), suggesting lower metabolic stability.

**In vitro Half-Life:** Ligand A (-34.614) has a much longer in vitro half-life than Ligand B (50.948).

**P-gp Efflux:** Ligand A (0.02) has a much lower P-gp efflux liability than Ligand B (0.474), which is favorable for CNS penetration.

**Binding Affinity:** Both ligands have excellent binding affinity (-7.8 kcal/mol and -7.7 kcal/mol, respectively). The difference is negligible.

**Overall Assessment:**

Considering the GPCR-specific priorities, Ligand A is the better candidate. Its superior BBB penetration, lower P-gp efflux, better QED, and longer half-life outweigh the slightly higher DILI risk and potentially lower solubility. While both have poor Caco-2 and solubility, the CNS target makes BBB and P-gp more critical. The similar binding affinities mean that ADME properties become the deciding factors.

Output:
0
2025-04-17 06:01:36,892 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (355.404 and 345.451 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (35.58) is excellent, well below the 90 A^2 threshold for CNS targets. Ligand B (82.68) is higher, but still potentially acceptable, though less ideal.

**logP:** Ligand A (2.251) is optimal (1-3). Ligand B (1.354) is at the lower end of optimal, potentially impacting permeability.

**H-Bond Donors:** Both ligands have 1 HBD, which is good.

**H-Bond Acceptors:** Ligand A has 3 HBA, and Ligand B has 8 HBA. Both are within the acceptable range of <=10, but Ligand A is preferred.

**QED:** Ligand A (0.842) has a strong drug-like profile, while Ligand B (0.655) is still reasonable, but less favorable.

**DILI:** Ligand A (23.653) has a very low DILI risk. Ligand B (34.393) is also low risk, but slightly higher.

**BBB:** This is crucial for a CNS target. Ligand A (90.074) has excellent BBB penetration. Ligand B (70.919) is acceptable, but significantly lower than Ligand A.

**Caco-2 Permeability:** Ligand A (-4.418) has poor Caco-2 permeability, which is concerning. Ligand B (-5.547) is even worse.

**Aqueous Solubility:** Both ligands have poor aqueous solubility (-1.647 and -1.233 respectively). This could pose formulation challenges.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.943 and 0.201 respectively).

**Microsomal Clearance:** Ligand A (-31.537) has very low microsomal clearance, indicating high metabolic stability. Ligand B (17.61) has moderate clearance.

**In vitro Half-Life:** Ligand A (-4.895) has a very long half-life, which is desirable. Ligand B (2.892) has a shorter half-life.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.173 and 0.17 respectively).

**Binding Affinity:** Ligand A (-9.6 kcal/mol) has significantly stronger binding affinity than Ligand B (-7.1 kcal/mol). This is a substantial difference (2.5 kcal/mol), which can outweigh some ADME drawbacks.

**Overall Assessment:**

Ligand A is superior despite the poor Caco-2 permeability. The exceptionally strong binding affinity (-9.6 kcal/mol), excellent BBB penetration (90.074), low DILI risk, high metabolic stability (low Cl_mic), and long half-life are highly favorable for a CNS-targeting GPCR ligand. While the poor Caco-2 permeability and solubility are drawbacks, they might be mitigated through formulation strategies. Ligand B, while having acceptable properties, is significantly weaker in binding affinity and has lower BBB penetration.

Output:
1
2025-04-17 06:01:36,892 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (351.447 and 347.507 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (89.02) is excellent, falling below the 90 A^2 threshold for CNS targets. Ligand B (53.4) is even better.

**logP:** Both ligands (1.678 and 1.805) are within the optimal 1-3 range.

**H-Bond Donors:** Ligand A has 2 HBD, which is acceptable. Ligand B has 1 HBD, also acceptable.

**H-Bond Acceptors:** Both ligands have 5 HBA, which is within the acceptable limit of <=10.

**QED:** Both ligands have good QED scores (0.619 and 0.817), indicating drug-like properties. Ligand B is slightly better.

**DILI:** Ligand A (29.314) has a lower DILI risk than Ligand B (12.059), indicating a safer profile.

**BBB:** This is crucial for a CNS target like DRD2. Ligand B (77.2) is significantly better than Ligand A (41.644), exceeding the desirable >70 percentile.

**Caco-2 Permeability:** Both have negative values, indicating poor permeability. Ligand A (-5.208) is slightly worse than Ligand B (-4.967).

**Aqueous Solubility:** Both have negative values, indicating poor solubility. Ligand A (-1.599) is slightly worse than Ligand B (-1.16).

**hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.088 and 0.528).

**Microsomal Clearance:** Ligand A (11.486) has lower clearance than Ligand B (37.067), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand B (18.786) has a slightly longer half-life than Ligand A (15.098).

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.029 and 0.056).

**Binding Affinity:** Ligand A (-7.4) has a slightly better binding affinity than Ligand B (-7.2). However, the difference is only 0.2 kcal/mol, which is not substantial enough to outweigh other factors.

**Overall Assessment:**

Ligand B is superior due to its significantly better BBB penetration (77.2 vs. 41.644). While Ligand A has a slightly better binding affinity and lower DILI, the BBB is paramount for a CNS-targeting drug. Ligand B also has a better QED score and longer half-life. The slightly worse metabolic stability of Ligand B is a minor concern compared to the poor BBB penetration of Ligand A.

Output:
1
2025-04-17 06:01:36,892 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (423.292 Da) is slightly higher than Ligand B (365.463 Da), but both are acceptable.

**TPSA:** Ligand A (77.75) is better than Ligand B (123.95). For CNS targets, we want TPSA <= 90. Ligand A is well within this range, while Ligand B is approaching the upper limit.

**logP:** Both ligands have good logP values (A: 3.483, B: 2.231), falling within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Both ligands have acceptable HBD (1) and HBA (A: 7, B: 6) counts, well below the thresholds of 5 and 10, respectively.

**QED:** Ligand A (0.634) has a better QED score than Ligand B (0.431), indicating a more drug-like profile. A QED > 0.5 is desirable.

**DILI:** Ligand A (98.139) has a significantly higher DILI risk than Ligand B (60.45). This is a major concern for Ligand A.

**BBB:** Both ligands have similar BBB penetration (A: 55.021, B: 57.619). Neither is ideal (>70), but acceptable given the other properties.

**Caco-2 Permeability:** Ligand A (-4.767) has worse Caco-2 permeability than Ligand B (-5.268), suggesting lower intestinal absorption. Lower (more negative) values are worse.

**Aqueous Solubility:** Ligand A (-4.874) has worse aqueous solubility than Ligand B (-2.741).

**hERG Inhibition:** Both ligands have low hERG inhibition risk (A: 0.571, B: 0.453).

**Microsomal Clearance:** Ligand B (30.859) has significantly lower microsomal clearance than Ligand A (75.158), indicating better metabolic stability.

**In vitro Half-Life:** Ligand B (11.165) has a longer in vitro half-life than Ligand A (45.413).

**P-gp Efflux:** Ligand A (0.639) has slightly higher P-gp efflux than Ligand B (0.11), which is unfavorable for CNS penetration.

**Binding Affinity:** Ligand A (-8.6 kcal/mol) has a significantly stronger binding affinity than Ligand B (-7.3 kcal/mol). This is a substantial advantage. The difference of 1.3 kcal/mol is significant and could outweigh some ADME drawbacks.

**Overall Assessment:**

Ligand A has a much stronger binding affinity, which is a critical factor for GPCRs. However, it suffers from high DILI risk, poor solubility, and higher P-gp efflux. Ligand B has better ADME properties (lower DILI, better solubility, lower clearance, longer half-life, lower P-gp efflux), but its binding affinity is weaker.

Given the importance of CNS penetration for DRD2, and the relatively modest BBB values for both, minimizing efflux (P-gp) and maximizing solubility are important. The significantly stronger binding affinity of Ligand A is compelling, but the high DILI risk is a major concern. While the affinity difference is substantial, the DILI risk is a significant red flag that would likely require substantial medicinal chemistry effort to mitigate. Ligand B, while weaker in affinity, presents a more balanced profile with fewer liabilities.

Output:
1
2025-04-17 06:01:36,892 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (358.454 and 348.403 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (76.66) is excellent, well below the 90 A^2 threshold for CNS targets. Ligand B (118.53) is still reasonable but less optimal, exceeding the preferred 90 A^2.

**logP:** Ligand A (2.276) is within the optimal 1-3 range. Ligand B (0.605) is a bit low, potentially hindering membrane permeability.

**H-Bond Donors/Acceptors:** Both ligands have 2 HBDs, which is good. Ligand A has 4 HBAs, and Ligand B has 5 HBAs, both acceptable.

**QED:** Ligand B (0.826) has a significantly better QED score than Ligand A (0.464), suggesting a more drug-like profile overall.

**DILI:** Ligand A (14.036) has a much lower DILI risk than Ligand B (43.932), indicating better predicted liver safety.

**BBB:** Ligand A (81.582) has a very good BBB penetration percentile, exceeding the 70% threshold for CNS targets. Ligand B (65.529) is lower, which is concerning for a CNS target like DRD2.

**Caco-2 Permeability:** Ligand A (-4.932) has poor Caco-2 permeability, which is a negative. Ligand B (-5.33) is similarly poor.

**Aqueous Solubility:** Both ligands have negative solubility values, indicating poor aqueous solubility. This could be a formulation challenge.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.525 and 0.096), which is positive.

**Microsomal Clearance:** Ligand A (19.013) has higher microsomal clearance than Ligand B (2.411), suggesting faster metabolism and potentially lower in vivo exposure.

**In vitro Half-Life:** Ligand B (-20.871) has a negative half-life, which is not possible and likely indicates an issue with the data or prediction method. Ligand A (16.826) has a reasonable half-life.

**P-gp Efflux:** Ligand A (0.077) has very low P-gp efflux, which is favorable for CNS penetration. Ligand B (0.017) also has low P-gp efflux, but slightly less than Ligand A.

**Binding Affinity:** Both ligands have similar binding affinities (-8.0 and -7.9 kcal/mol), which are both excellent and meet the > -7.0 kcal/mol threshold. The difference is negligible.

**Overall Assessment:**

Ligand A excels in BBB penetration, DILI risk, and P-gp efflux, all crucial for a CNS GPCR target. While its Caco-2 permeability is poor and solubility is low, the strong BBB penetration and low P-gp efflux could mitigate the solubility issue. Ligand B has a better QED score, but suffers from lower BBB penetration, higher DILI risk, and a problematic (negative) in vitro half-life. The similar binding affinities make the ADME properties the deciding factor.

Output:
1
2025-04-17 06:01:36,893 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (348.491 and 348.359 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (74.33) is significantly better than Ligand B (125.57). For CNS targets, we want TPSA <= 90, and A is comfortably within that, while B is pushing the limit.

**3. logP:** Ligand A (2.053) is optimal (1-3), while Ligand B (-0.467) is below 1, which might hinder permeation.

**4. H-Bond Donors:** Both have acceptable HBD counts (2 and 4, respectively), below the threshold of 5.

**5. H-Bond Acceptors:** Both have acceptable HBA counts (4 and 6, respectively), below the threshold of 10.

**6. QED:** Both ligands have reasonable QED values (0.716 and 0.536), indicating good drug-like properties.

**7. DILI:** Ligand A (21.908) has a much lower DILI risk than Ligand B (76.503). This is a significant advantage for A.

**8. BBB:** Ligand A (52.036) has a better BBB percentile than Ligand B (38.775), although both are not ideal (>70 is desirable). However, given the other factors, A's BBB is less of a concern.

**9. Caco-2:** Both have negative Caco-2 values (-5.107 and -5.929) which is unusual and difficult to interpret without further context. It suggests poor permeability.

**10. Solubility:** Both have negative solubility values (-1.346 and -2.545), also unusual and suggesting poor aqueous solubility.

**11. hERG:** Both ligands have very low hERG inhibition liability (0.47 and 0.218), which is excellent.

**12. Cl_mic:** Ligand B (-5.446) has a *negative* microsomal clearance, which is not physically possible. This is likely an error in the data. Ligand A (19.449) has a reasonable clearance.

**13. t1/2:** Ligand A (59.219) has a longer in vitro half-life than Ligand B (35.902), which is preferable.

**14. Pgp:** Both ligands have very low Pgp efflux liability (0.017 and 0.013), which is good.

**15. Binding Affinity:** Ligand B (-8.8 kcal/mol) has a slightly better binding affinity than Ligand A (-8.1 kcal/mol). However, the difference is only 0.7 kcal/mol, which is not substantial enough to override the significant ADME advantages of Ligand A.

**Overall Assessment:**

Ligand A is the superior candidate. While Ligand B has slightly better binding affinity, Ligand A excels in critical ADME properties for a CNS-targeting GPCR: TPSA, logP, DILI risk, BBB penetration, and in vitro half-life. The negative values for Caco-2 and solubility are concerning for both, but the other advantages of Ligand A outweigh this issue. The erroneous negative Cl_mic value for Ligand B is also a major red flag.

Output:
0
2025-04-17 06:01:36,893 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B based on the provided guidelines, prioritizing GPCR-specific properties (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (364.47) is slightly higher than Ligand B (345.40), but both are acceptable.

**TPSA:** Ligand A (66.92) is excellent for CNS penetration, well below the 90 A^2 threshold. Ligand B (102.76) is higher, but still potentially acceptable, though less ideal.

**logP:** Ligand A (1.01) is within the optimal range (1-3). Ligand B (0.516) is a bit low, potentially hindering permeability.

**H-Bond Donors/Acceptors:** Ligand A (0 HBD, 4 HBA) is favorable. Ligand B (3 HBD, 5 HBA) is also acceptable, though slightly higher.

**QED:** Both ligands have good QED scores (A: 0.782, B: 0.675), indicating drug-like properties.

**DILI:** Ligand A (43.12) has a slightly higher DILI risk than Ligand B (25.09), but both are below the concerning threshold of 60.

**BBB:** This is a crucial parameter for a CNS target like DRD2. Ligand A (89.10) shows excellent BBB penetration, exceeding the 70% threshold. Ligand B (22.96) is very poor, making it less likely to reach the target in the brain.

**Caco-2 Permeability:** Ligand A (-4.676) is unfavorable. Ligand B (-5.446) is also unfavorable, but slightly worse.

**Aqueous Solubility:** Both ligands have negative solubility values, indicating poor solubility. Ligand B (-1.695) is slightly better than Ligand A (-3.273), but both are problematic.

**hERG Inhibition:** Ligand A (0.579) has a lower hERG risk than Ligand B (0.028), which is a significant advantage.

**Microsomal Clearance:** Ligand A (58.71) has a higher clearance than Ligand B (-9.41), meaning Ligand B is more metabolically stable.

**In vitro Half-Life:** Ligand B (-20.95) has a longer half-life than Ligand A (-34.65), which is favorable.

**P-gp Efflux:** Ligand A (0.204) has lower P-gp efflux liability than Ligand B (0.008), which is preferable for CNS penetration.

**Binding Affinity:** Both ligands have excellent binding affinities (A: -7.4 kcal/mol, B: -8.6 kcal/mol). Ligand B is slightly stronger, but the difference is likely not enough to overcome its poor BBB penetration.

**Conclusion:**

Considering the GPCR-specific priorities, Ligand A is the more promising candidate. While Ligand B has a slightly better binding affinity and metabolic stability, Ligand A's significantly superior BBB penetration (89.10% vs 22.96%), combined with its acceptable logP, lower hERG risk, and good QED, outweigh the minor advantages of Ligand B. The poor Caco-2 and solubility of both are concerns that would need to be addressed in further optimization, but are less critical than CNS penetration for this target.

Output:
0
2025-04-17 06:01:36,893 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (349.39 and 350.38 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (116.76) is slightly higher than Ligand B (104.45). For CNS targets, we prefer TPSA <= 90, so both are somewhat suboptimal, but Ligand B is closer to the ideal range.

**3. logP:** Ligand A (-0.188) is quite low, potentially hindering membrane permeability. Ligand B (0.351) is better, falling within the 1-3 optimal range, though still on the lower end.

**4. H-Bond Donors:** Ligand A (4) is higher than Ligand B (1). Lower HBD is generally preferred for better permeability.

**5. H-Bond Acceptors:** Ligand A (5) and Ligand B (6) are both acceptable, being less than 10.

**6. QED:** Both ligands have good QED values (0.509 and 0.609), indicating drug-like properties.

**7. DILI:** Both ligands have acceptable DILI risk (44.55 and 48.74), below the 60% threshold.

**8. BBB:** Ligand A (52.27%) has a better BBB percentile than Ligand B (37.46%). This is a crucial factor for CNS targets like DRD2.

**9. Caco-2:** Both have negative Caco-2 values (-5.347 and -4.883) which is unusual and suggests poor permeability.

**10. Solubility:** Both ligands have poor aqueous solubility (-1.335 and -1.403).

**11. hERG:** Both ligands have very low hERG inhibition risk (0.128 and 0.081).

**12. Cl_mic:** Ligand A (14.29) has a significantly lower microsomal clearance than Ligand B (31.14), indicating better metabolic stability.

**13. t1/2:** Ligand B (57.58) has a much longer in vitro half-life than Ligand A (10.77).

**14. Pgp:** Both ligands have very low P-gp efflux liability (0.011 and 0.039).

**15. Binding Affinity:** Ligand B (-7.9 kcal/mol) has a slightly better binding affinity than Ligand A (-8.4 kcal/mol). While both are excellent, the difference of 0.5 kcal/mol is meaningful.

**Overall Assessment:**

Ligand A has a better BBB score and lower Cl_mic, which are both important for CNS targets. However, its logP is quite low, potentially limiting permeability, and its in vitro half-life is short. Ligand B has a better logP, longer half-life, and slightly better affinity. While its BBB is lower, the improved pharmacokinetic properties and binding outweigh this drawback. The Caco-2 values for both are concerning, but the better overall profile of Ligand B makes it the more promising candidate.

Output:
1
2025-04-17 06:01:36,893 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (350.507 and 367.53 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (85.23) is better than Ligand B (29.54). For CNS targets, we want TPSA <= 90, both are within this range, but A is closer to the upper limit. B is significantly lower, which is very favorable for BBB penetration.

**logP:** Ligand A (2.202) is within the optimal 1-3 range. Ligand B (4.798) is higher, potentially causing solubility issues and off-target interactions.

**H-Bond Donors/Acceptors:** Ligand A has 2 HBD and 4 HBA, while Ligand B has 0 HBD and 3 HBA. Both are within acceptable limits (<=5 HBD and <=10 HBA).

**QED:** Both ligands have similar QED values (0.632 and 0.627), indicating good drug-like properties.

**DILI:** Ligand A (9.151) has a much lower DILI risk than Ligand B (18.302), which is a significant advantage.

**BBB:** Ligand B (96.743) has a substantially higher BBB penetration percentile than Ligand A (62.233). This is a critical factor for a CNS target like DRD2.

**Caco-2 Permeability:** Ligand A (-4.899) and Ligand B (-4.504) both have negative values, which is unusual. It's difficult to interpret without knowing the scale, but generally, higher values are better.

**Aqueous Solubility:** Ligand A (-1.911) and Ligand B (-4.664) both have negative values, indicating poor solubility. B is worse.

**hERG Inhibition:** Ligand A (0.335) has a lower hERG inhibition liability than Ligand B (0.825), which is preferable.

**Microsomal Clearance:** Ligand A (29.937) has a lower microsomal clearance than Ligand B (113.112), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand B (26.529) has a longer in vitro half-life than Ligand A (13.095), which is generally desirable.

**P-gp Efflux:** Ligand A (0.005) has much lower P-gp efflux liability than Ligand B (0.818), which is crucial for CNS penetration.

**Binding Affinity:** Ligand B (-7.7 kcal/mol) has a slightly better binding affinity than Ligand A (-7.2 kcal/mol). The difference is 0.5 kcal/mol, which is significant but not overwhelming.

**Overall Assessment:**

Ligand B excels in BBB penetration and binding affinity, and has a longer half-life. However, it suffers from higher logP, higher DILI risk, higher P-gp efflux, and lower metabolic stability. Ligand A has better ADME properties (lower DILI, better metabolic stability, lower P-gp efflux, better hERG) and a reasonable binding affinity.

Given the GPCR-specific priorities, BBB penetration is paramount for a CNS target. While Ligand B has a much better BBB score, the other ADME liabilities, particularly the high logP and P-gp efflux, are concerning. Ligand A, while not as potent or BBB-permeable, presents a more balanced profile with better ADME characteristics. The slightly better affinity of Ligand B might be overcome with further optimization of Ligand A.

Output:
0
2025-04-17 06:01:36,893 - INFO - Reasoning:

Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (368.5 and 350.4 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (76.66) is significantly better than Ligand B (98.82). For CNS targets, we want TPSA <= 90, so Ligand A is preferable.

**3. logP:** Ligand A (2.337) is optimal (1-3). Ligand B (0.085) is quite low, potentially hindering membrane permeability and CNS penetration.

**4. H-Bond Donors:** Both ligands have 2 HBD, which is within the acceptable limit of <=5.

**5. H-Bond Acceptors:** Ligand A has 5 HBA, and Ligand B has 4. Both are within the acceptable limit of <=10.

**6. QED:** Ligand A (0.622) is better than Ligand B (0.455), indicating a more drug-like profile.

**7. DILI:** Both ligands have acceptable DILI risk (Ligand A: 38.5%, Ligand B: 40.98%), both below the 40% threshold.

**8. BBB:** Ligand A (70.65%) is significantly better than Ligand B (65.45%).  For CNS targets, >70% is desirable. Ligand A is closer to this threshold.

**9. Caco-2 Permeability:** Both have negative values, indicating poor permeability. However, the scale is not specified, making direct comparison difficult.

**10. Aqueous Solubility:** Both have negative values, indicating poor solubility. Again, the scale is not specified.

**11. hERG Inhibition:** Both ligands have very low hERG inhibition risk (Ligand A: 0.594, Ligand B: 0.062).

**12. Microsomal Clearance:** Ligand A (32.3) is higher than Ligand B (-7.233). Lower clearance is preferred for metabolic stability, so Ligand B is better here.

**13. In vitro Half-Life:** Ligand A (15.024 hours) is much better than Ligand B (-8.623 hours). Longer half-life is desirable.

**14. P-gp Efflux:** Ligand A (0.185) is better than Ligand B (0.006). Lower P-gp efflux is crucial for CNS penetration.

**15. Binding Affinity:** Both ligands have very similar and excellent binding affinities (-7.5 and -7.3 kcal/mol). The difference is less than the 1.5 kcal/mol threshold.

**Overall Assessment:**

Ligand A is significantly better overall, especially considering the GPCR-specific priorities. It has a more favorable TPSA, logP, BBB, QED, and P-gp efflux profile. While Ligand B has better microsomal clearance, the other advantages of Ligand A outweigh this single benefit. The similar binding affinities make the ADME properties the deciding factor.

Output:
1
2025-04-17 06:01:36,894 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (358.36 and 351.36 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (58.64) is excellent, well below the 90 A^2 threshold for CNS targets. Ligand B (110.97) is higher, but still potentially acceptable, though less ideal.

**logP:** Ligand A (2.535) is optimal (1-3). Ligand B (-0.041) is quite low, potentially hindering permeability and CNS penetration.

**H-Bond Donors/Acceptors:** Both have 1 HBD, which is good. Ligand A has 4 HBA, acceptable. Ligand B has 7 HBA, which is higher but still within the reasonable limit of 10.

**QED:** Both ligands have good QED scores (0.761 and 0.565), indicating drug-like properties.

**DILI:** Ligand A (38.66) has a lower DILI risk than Ligand B (64.79), which is a significant advantage.

**BBB:** Ligand A (83.99) has a significantly better BBB penetration percentile than Ligand B (65.45). This is crucial for a CNS target like DRD2.

**Caco-2 Permeability:** Both have negative Caco-2 values (-4.468 and -4.825), which is unusual and suggests poor permeability. However, these values are on a logarithmic scale, and the negative values are not directly comparable without knowing the base of the logarithm. We'll need to consider other permeability indicators.

**Aqueous Solubility:** Both have negative solubility values (-2.886 and -2.755), also on a logarithmic scale. Similar to Caco-2, these aren't directly comparable and suggest low solubility.

**hERG:** Both ligands have low hERG risk (0.533 and 0.093).

**Microsomal Clearance:** Ligand A (52.86) has a higher microsomal clearance than Ligand B (41.84), suggesting potentially lower metabolic stability.

**In vitro Half-Life:** Ligand B (11.08) has a longer in vitro half-life than Ligand A (-13.29), which is a positive.

**P-gp Efflux:** Both have low P-gp efflux liability (0.06 and 0.03), which is good for CNS penetration.

**Binding Affinity:** Ligand A (-7.5 kcal/mol) has a slightly better binding affinity than Ligand B (-6.9 kcal/mol). While the difference is less than the 1.5 kcal/mol threshold, it's still a factor.

**Overall Assessment:**

Ligand A is significantly better due to its superior BBB penetration, lower DILI risk, and optimal logP. While its microsomal clearance is higher and half-life lower than Ligand B, the CNS-specific requirements for DRD2 (BBB, logP) and safety (DILI) are more critical. The slightly better binding affinity of Ligand A further supports its selection. The negative Caco-2 and solubility values are concerning for both, but the other advantages of Ligand A outweigh this concern.

Output:
1
2025-04-17 06:01:36,894 - INFO - Batch 247 complete. Total preferences: 3952
2025-04-17 06:01:36,894 - INFO - Processing batch 248/512...
2025-04-17 06:02:21,528 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (352.345 and 347.419 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (112.7) is slightly above the optimal <90 for CNS targets, but still reasonable. Ligand B (91.46) is better, falling comfortably under 90.

**logP:** Ligand A (0.183) is quite low, potentially hindering membrane permeability. Ligand B (0.781) is better, but still on the lower side of the optimal 1-3 range.

**H-Bond Donors:** Ligand A (2) is acceptable. Ligand B (0) is also good, potentially improving permeability.

**H-Bond Acceptors:** Both ligands (6) are within the acceptable limit of 10.

**QED:** Both ligands have good QED scores (0.693 and 0.785), indicating drug-like properties.

**DILI:** Ligand A (55.68) has a slightly higher DILI risk than Ligand B (46.917), but both are below the concerning threshold of 60.

**BBB:** Ligand A (70.066) is at the threshold for good CNS penetration, while Ligand B (66.305) is slightly below. This is a critical factor for DRD2, and A has a slight edge.

**Caco-2 Permeability:** Ligand A (-5.152) has poor Caco-2 permeability, which is concerning. Ligand B (-4.461) is also poor, but slightly better than A.

**Aqueous Solubility:** Both ligands have very poor aqueous solubility (-2.661 and -1.658). This could pose formulation challenges.

**hERG Inhibition:** Ligand A (0.126) has a very low hERG risk, which is excellent. Ligand B (0.637) is higher, but still relatively low.

**Microsomal Clearance:** Ligand A (0.425) has very low microsomal clearance, suggesting good metabolic stability. Ligand B (21.731) has significantly higher clearance, indicating faster metabolism.

**In vitro Half-Life:** Ligand A (-16.137) has a very long in vitro half-life, which is a strong positive. Ligand B (8.251) has a shorter half-life.

**P-gp Efflux:** Both ligands have very low P-gp efflux (0.011 and 0.209), which is favorable for CNS penetration.

**Binding Affinity:** Ligand A (-7.6) has a significantly stronger binding affinity than Ligand B (-0.0). This is a major advantage.

**Overall Assessment:**

Ligand A has a significantly better binding affinity and metabolic stability (lower Cl_mic, longer t1/2) and lower hERG risk. While its logP and Caco-2 permeability are concerning, the strong affinity (-7.6 kcal/mol) can often compensate for minor ADME deficiencies, especially given the low P-gp efflux and acceptable BBB penetration. Ligand B, while having better TPSA and a slightly lower DILI risk, suffers from significantly weaker binding affinity and poorer metabolic stability.

Given the GPCR-specific priorities and the substantial difference in binding affinity, Ligand A is the more promising candidate.

Output:
1
2025-04-17 06:02:21,528 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B based on the provided guidelines, prioritizing GPCR-specific properties (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (343.343 and 352.431 Da) fall within the ideal range of 200-500 Da.

**TPSA:** Ligand B (93.73) is significantly better than Ligand A (110.49). For CNS targets, TPSA should be <= 90, so Ligand B is closer to this ideal.

**logP:** Both ligands have good logP values (1.782 and 1.074), falling within the optimal range of 1-3.

**H-Bond Donors/Acceptors:** Ligand A has 1 HBD and 7 HBA, while Ligand B has 2 HBD and 5 HBA. Both are within acceptable limits (<=5 HBD and <=10 HBA).

**QED:** Both ligands have reasonable QED scores (0.665 and 0.503), indicating good drug-like properties.

**DILI:** Ligand A has a concerningly high DILI risk (95.774%), while Ligand B has a much lower risk (35.983%). This is a significant advantage for Ligand B.

**BBB:** Ligand A has a better BBB penetration (61.342%) than Ligand B (56.766%), but both are below the desirable threshold of >70% for CNS targets.

**Caco-2 Permeability:** Ligand A (-4.706) has better Caco-2 permeability than Ligand B (-5.179), suggesting better intestinal absorption. However, both are negative values, so interpretation is difficult without knowing the scale.

**Aqueous Solubility:** Ligand A (-3.537) has better aqueous solubility than Ligand B (-1.879).

**hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.324 and 0.082).

**Microsomal Clearance:** Both ligands have similar microsomal clearance values (33.417 and 34.574 mL/min/kg), suggesting similar metabolic stability.

**In vitro Half-Life:** Ligand B has a significantly longer in vitro half-life (-11.779 hours) than Ligand A (-4.917 hours). This is a major advantage for Ligand B.

**P-gp Efflux:** Ligand A (0.058) has lower P-gp efflux liability than Ligand B (0.028), which is favorable for CNS exposure.

**Binding Affinity:** Ligand A (-9.5 kcal/mol) has a significantly stronger binding affinity than Ligand B (-7.9 kcal/mol). This is a substantial advantage for Ligand A.

**Overall Assessment:**

While Ligand A has a much better binding affinity and slightly better BBB and P-gp efflux, its extremely high DILI risk is a major red flag. Ligand B, despite having weaker affinity, presents a much more favorable safety profile (low DILI), better TPSA, and a longer half-life. For a CNS target like DRD2, a balance of properties is crucial. The significantly lower DILI risk and improved TPSA of Ligand B outweigh the affinity difference, especially considering the affinity of Ligand B is still quite good (-7.9 kcal/mol).

Output:
1
2025-04-17 06:02:21,528 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (348.49 and 349.43 Da) fall comfortably within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (49.85) is significantly better than Ligand B (84.67). For CNS targets, we want TPSA <= 90, and ideally closer to 60. Ligand A is much closer to this ideal.

**3. logP:** Both ligands have acceptable logP values (2.587 and 1.722), falling within the 1-3 range. Ligand A is slightly better.

**4. H-Bond Donors:** Both have low HBD counts (0 and 1), which is good for permeability.

**5. H-Bond Acceptors:** Both have reasonable HBA counts (4 and 5), within the acceptable limit of 10.

**6. QED:** Both ligands have similar and good QED values (0.736 and 0.734), indicating good drug-like properties.

**7. DILI:** Ligand A (19.97) has a much lower DILI risk than Ligand B (28.38). Lower is better, and Ligand A is well below the 40% threshold.

**8. BBB:** Ligand B (77.16) has a significantly better BBB penetration percentile than Ligand A (53.47). For a CNS target like DRD2, >70% is desirable, and Ligand B is closer to this.

**9. Caco-2 Permeability:** Both have negative Caco-2 values (-4.682 and -4.681), which is unusual and suggests poor permeability. This is a significant concern for both.

**10. Aqueous Solubility:** Both have negative solubility values (-2.181 and -2.318), indicating very poor aqueous solubility. This is a major drawback for both.

**11. hERG Inhibition:** Both ligands have low hERG inhibition risk (0.574 and 0.155). Ligand B is slightly better.

**12. Microsomal Clearance:** Both have similar microsomal clearance values (54.74 and 53.36 mL/min/kg). These are relatively high, suggesting moderate metabolic instability.

**13. In vitro Half-Life:** Ligand A (-13.362) has a much better (longer) in vitro half-life than Ligand B (5.315).

**14. P-gp Efflux:** Ligand A (0.258) has a lower P-gp efflux liability than Ligand B (0.119), which is favorable for CNS penetration.

**15. Binding Affinity:** Ligand B (-7.9 kcal/mol) has a slightly better binding affinity than Ligand A (-8.7 kcal/mol). This is a small difference, but potentially important.

**Overall Assessment:**

Considering the GPCR-specific priorities, Ligand B has a clear advantage in BBB penetration and a slightly better binding affinity. However, Ligand A excels in TPSA, DILI risk, and in vitro half-life, and has lower P-gp efflux. Both have poor Caco-2 permeability and aqueous solubility, which are significant liabilities.

The better BBB penetration of Ligand B is crucial for a CNS target. While Ligand A has a better safety profile (DILI), the slightly stronger affinity and better BBB of Ligand B outweigh these benefits. The poor solubility and permeability are concerns for both, but can potentially be addressed through formulation strategies.

Output:
1
2025-04-17 06:02:21,528 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (348.359 Da) is slightly lower, which could be beneficial for permeability. Ligand B (379.595 Da) is also good.

**TPSA:** Ligand A (128.53) is better than Ligand B (38.13) for CNS penetration, being closer to the <90 threshold. Ligand B is quite high and may hinder BBB penetration.

**logP:** Ligand A (-0.191) is a concern. It's below the optimal 1-3 range and may have permeability issues. Ligand B (4.872) is high, potentially leading to solubility and off-target issues, but is within a range sometimes tolerated.

**H-Bond Donors/Acceptors:** Ligand A has 3 HBD and 6 HBA, which are acceptable. Ligand B has 0 HBD and 5 HBA, also acceptable.

**QED:** Both ligands have similar QED values (0.664 and 0.624), indicating good drug-likeness.

**DILI:** Ligand A (69.756) has a higher DILI risk than Ligand B (53.509), but both are reasonably acceptable.

**BBB:** Ligand B (75.107) has a significantly better BBB percentile than Ligand A (8.181). This is a critical factor for a CNS target like DRD2.

**Caco-2 Permeability:** Both have negative values, indicating poor permeability. However, the scale is not specified, making direct comparison difficult.

**Aqueous Solubility:** Both have negative values, indicating poor solubility. Again, scale is not specified.

**hERG Inhibition:** Ligand A (0.135) has a slightly lower hERG risk than Ligand B (0.723), which is preferable.

**Microsomal Clearance:** Ligand B (122.524) has a significantly higher microsomal clearance than Ligand A (16.49), indicating lower metabolic stability.

**In vitro Half-Life:** Ligand B (61.418) has a longer half-life than Ligand A (11.153), which is desirable.

**P-gp Efflux:** Ligand A (0.019) shows very low P-gp efflux, which is excellent for CNS penetration. Ligand B (0.753) has moderate P-gp efflux, which is less favorable.

**Binding Affinity:** Ligand A (-7.9 kcal/mol) has a slightly better binding affinity than Ligand B (-6.9 kcal/mol). This 1 kcal/mol difference is significant and could outweigh some ADME drawbacks.

**Overall Assessment:**

While Ligand B has better BBB penetration and a longer half-life, Ligand A has a superior binding affinity, lower P-gp efflux, and a better TPSA. The biggest concern with Ligand A is its low logP, which could limit permeability. However, the strong binding affinity and low P-gp efflux are significant advantages for a CNS target. Ligand B's high logP and high clearance are concerning. Given the GPCR-specific priorities, the strong affinity and low efflux of Ligand A are more compelling, despite the logP issue.

Output:
1
2025-04-17 06:02:21,529 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight (MW):** Both ligands (352.475 & 355.435 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (89.87) is excellent, below the 90 threshold for CNS targets. Ligand B (99.18) is still reasonable but less optimal.

**3. logP:** Ligand A (1.363) is within the optimal 1-3 range. Ligand B (-0.498) is slightly below 1, potentially hindering permeation.

**4. H-Bond Donors (HBD):** Both ligands (A: 3, B: 2) are within the acceptable limit of <=5.

**5. H-Bond Acceptors (HBA):** Both ligands (A: 4, B: 6) are within the acceptable limit of <=10.

**6. QED:** Both ligands (A: 0.652, B: 0.598) are above 0.5, indicating good drug-like properties.

**7. DILI:** Both ligands have low DILI risk (A: 10.896, B: 10.237), both under the 40 threshold.

**8. BBB:** Both ligands have similar BBB penetration (A: 52.036, B: 51.377). While not exceeding the desirable >70, they are not drastically low either.

**9. Caco-2 Permeability:** Ligand A (-4.85) is significantly better than Ligand B (-5.087), indicating better intestinal absorption.

**10. Aqueous Solubility:** Ligand A (-1.887) is better than Ligand B (0.202), suggesting better formulation potential.

**11. hERG Inhibition:** Both ligands show very low hERG inhibition risk (A: 0.162, B: 0.117).

**12. Microsomal Clearance (Cl_mic):** Ligand A (7.827) has a lower clearance than Ligand B (1.367), indicating better metabolic stability.

**13. In vitro Half-Life:** Ligand B (-13.199) has a slightly longer half-life than Ligand A (-12.432), but both are negative values, which is unusual and may indicate a problem with the data.

**14. P-gp Efflux:** Both ligands show very low P-gp efflux (A: 0.024, B: 0.013).

**15. Binding Affinity:** Ligand A (-8.9 kcal/mol) has a *significantly* stronger binding affinity than Ligand B (-0.0 kcal/mol). This is a crucial difference.

**Overall Assessment:**

Ligand A is superior to Ligand B. While both have acceptable drug-like properties and low toxicity risk, Ligand A excels in key areas: TPSA, logP, Caco-2 permeability, solubility, metabolic stability (Cl_mic), and *most importantly*, binding affinity. The substantial difference in binding affinity (-8.9 vs -0.0 kcal/mol) is likely to outweigh any minor drawbacks. The slightly better TPSA and logP values of Ligand A also contribute to its favorability as a CNS-targeting GPCR ligand.

Output:
1
2025-04-17 06:02:21,529 - INFO - Reasoning:

Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (379.964 Da) is slightly higher than Ligand B (352.475 Da), but both are acceptable.

**2. TPSA:** Ligand A (64.11) is significantly better than Ligand B (87.66). For CNS targets, we want TPSA <= 90, and ideally closer to 60. Ligand A is much closer to this ideal.

**3. logP:** Ligand A (4.744) is high, potentially causing solubility issues and off-target effects. Ligand B (1.674) is within the optimal range (1-3). This is a significant advantage for Ligand B.

**4. H-Bond Donors:** Ligand A (1) is good. Ligand B (3) is acceptable, but higher HBD can sometimes reduce permeability.

**5. H-Bond Acceptors:** Ligand A (5) is good. Ligand B (4) is also good.

**6. QED:** Both ligands have similar QED values (0.6 for A, 0.635 for B), indicating reasonable drug-likeness.

**7. DILI:** Ligand A (70.299) has a higher DILI risk than Ligand B (18.922). Ligand B is well below the 40% threshold for low risk.

**8. BBB:** Ligand A (60.295) is borderline for CNS penetration, while Ligand B (38.542) is quite low. While >70 is desirable, a value above 50 is often considered acceptable. Ligand A is better here.

**9. Caco-2 Permeability:** Both have negative Caco-2 values (-4.658 and -4.854), which is unusual. This suggests poor permeability. However, these values are on a log scale and the negative values are not directly comparable.

**10. Aqueous Solubility:** Ligand A (-5.877) has very poor predicted solubility, likely due to its high logP. Ligand B (-1.76) is better, but still suggests low solubility.

**11. hERG Inhibition:** Ligand A (0.602) has a slightly higher hERG risk than Ligand B (0.159).

**12. Microsomal Clearance:** Ligand A (120.578) has higher clearance than Ligand B (20.021), indicating lower metabolic stability.

**13. In vitro Half-Life:** Ligand A (93.236) has a much longer half-life than Ligand B (8.864). This is a significant advantage for Ligand A.

**14. P-gp Efflux:** Ligand A (0.382) has lower P-gp efflux than Ligand B (0.085), which is favorable for CNS penetration.

**15. Binding Affinity:** Ligand B (-9.3 kcal/mol) has a significantly stronger binding affinity than Ligand A (0.0 kcal/mol). This is a major advantage, potentially outweighing some of the ADME drawbacks.

**Overall Assessment:**

Ligand B has a much better binding affinity, lower DILI risk, and a more favorable logP. However, its BBB penetration is low, and its in vitro half-life is short. Ligand A has better BBB penetration and a longer half-life, but suffers from a high logP, poor solubility, higher DILI risk, and significantly weaker binding affinity.

Given the GPCR-specific priorities, *binding affinity is paramount*. The substantial difference in binding affinity (-9.3 vs 0.0 kcal/mol) makes Ligand B the more promising candidate, despite its lower BBB and shorter half-life. These ADME properties can be potentially addressed through further optimization. The poor BBB can be improved with structural modifications, and the short half-life can be extended through prodrug strategies or modifications to reduce metabolic clearance.

Output:
1
2025-04-17 06:02:21,529 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B based on the provided guidelines, prioritizing GPCR-specific properties (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (350.419 Da) is slightly lower than Ligand B (378.929 Da), which isn't a significant difference.

**TPSA:** Ligand A (105.48) is higher than Ligand B (53.66). For CNS targets, TPSA should be <=90. Ligand A is marginally above this, while Ligand B is well within the range. This favors Ligand B.

**logP:** Ligand A (0.619) is below the optimal range (1-3) and could potentially hinder permeation. Ligand B (3.853) is very close to the upper limit but still within the optimal range. This strongly favors Ligand B.

**H-Bond Donors:** Ligand A (3) is acceptable, while Ligand B (1) is even better, minimizing potential issues with permeability.

**H-Bond Acceptors:** Both ligands have 6 HBA, which is within the acceptable limit of <=10.

**QED:** Both ligands have reasonable QED values (A: 0.471, B: 0.646), but Ligand B is better, indicating a more drug-like profile.

**DILI:** Ligand A (59.248) and Ligand B (42.613) both have acceptable DILI risk, but Ligand B is lower, indicating a lower risk of liver injury.

**BBB:** This is crucial for CNS targets. Ligand A (54.634) is below the desirable threshold of >70, while Ligand B (49.321) is also below the threshold. However, the difference is not significant.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.224 and -5.18), which is unusual and suggests poor permeability. This is a significant drawback for both.

**Aqueous Solubility:** Both ligands have negative solubility values (-2.115 and -3.048), indicating very poor solubility. This is a major concern for both.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (A: 0.371, B: 0.912).

**Microsomal Clearance:** Ligand A (37.959) has higher clearance than Ligand B (29.155), suggesting lower metabolic stability. This favors Ligand B.

**In vitro Half-Life:** Ligand A (-23.651) has a negative half-life, which is not physically possible and indicates a problem with the data or the molecule. Ligand B (54.601) has a reasonable half-life. This is a major advantage for Ligand B.

**P-gp Efflux:** Ligand A (0.103) has lower P-gp efflux than Ligand B (0.675), which is favorable for CNS penetration.

**Binding Affinity:** Ligand B (-7.3) has a significantly stronger binding affinity than Ligand A (-8.1). A >1.5 kcal/mol advantage in binding can outweigh minor ADME drawbacks.

**Overall Assessment:**

Despite both ligands having significant issues with solubility and Caco-2 permeability, Ligand B is the better candidate. It has a more favorable logP, lower TPSA, better QED, lower DILI risk, better metabolic stability (lower Cl_mic, longer t1/2), and, most importantly, a significantly stronger binding affinity. The negative half-life for Ligand A is a critical flaw. While both have poor BBB penetration, the other advantages of Ligand B make it the more promising starting point for optimization.

Output:
1
2025-04-17 06:02:21,529 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (350.415 and 353.507 Da) fall within the ideal range of 200-500 Da.

**TPSA:** Ligand A (107.89) is slightly above the optimal <90 for CNS targets, but still reasonable. Ligand B (78.59) is excellent, well below 90.

**logP:** Ligand A (0.518) is quite low, potentially hindering membrane permeability. Ligand B (2.345) is within the optimal 1-3 range. This is a significant advantage for Ligand B.

**H-Bond Donors/Acceptors:** Ligand A has 4 HBD and 5 HBA, which are acceptable. Ligand B has 2 HBD and 5 HBA, also acceptable.

**QED:** Both ligands have good QED scores (0.619 and 0.677), indicating good drug-like properties.

**DILI:** Ligand A (35.712) has a slightly higher DILI risk than Ligand B (5.312), though both are below the concerning threshold of 60.

**BBB:** Ligand A (65.839) has a moderate BBB penetration, while Ligand B (51.803) is lower. While both are not ideal (>70), Ligand A is better in this regard.

**Caco-2 Permeability:** Both have negative Caco-2 values (-4.974 and -4.791), which is unusual and suggests poor permeability. This is a significant concern for both.

**Aqueous Solubility:** Both have negative solubility values (-1.683 and -1.292), also unusual and concerning.

**hERG:** Both ligands show low hERG inhibition liability (0.449 and 0.6), which is favorable.

**Microsomal Clearance:** Ligand A (34.877) has lower microsomal clearance than Ligand B (48.362), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (-2.137) has a negative half-life, which is not possible and indicates a problem with the data. Ligand B (11.482) has a reasonable half-life.

**P-gp Efflux:** Both have very low P-gp efflux liability (0.081 and 0.078), which is good for CNS penetration.

**Binding Affinity:** Ligand A (-9.5 kcal/mol) has significantly stronger binding affinity than Ligand B (-5.8 kcal/mol). This is a substantial advantage for Ligand A.

**Overall Assessment:**

Despite Ligand A's superior binding affinity, the negative and unrealistic values for Caco-2 permeability and in vitro half-life are major red flags. The low logP is also a concern. Ligand B, while having a weaker affinity, presents more reasonable ADME properties, particularly the logP value, and a positive half-life. The TPSA is also excellent. While the BBB penetration is not ideal, it's not as problematic as the issues with Ligand A. The significant difference in binding affinity (-3.7 kcal/mol) might be overcome with further optimization of Ligand B, but the data issues with Ligand A are too severe.

Output:
1
2025-04-17 06:02:21,529 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B based on the provided guidelines, prioritizing GPCR-specific properties (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (372.531 and 344.415 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (86.71) is excellent, falling well below the 90 A^2 threshold for CNS targets. Ligand B (96.26) is still reasonable but less optimal.

**logP:** Ligand A (0.907) is a bit low, potentially hindering permeability. Ligand B (1.756) is better, falling within the 1-3 optimal range.

**H-Bond Donors/Acceptors:** Ligand A (HBD=2, HBA=4) and Ligand B (HBD=3, HBA=5) both have acceptable numbers of hydrogen bond donors and acceptors.

**QED:** Both ligands have good QED scores (A: 0.597, B: 0.678), indicating drug-like properties.

**DILI:** Ligand A (10.702) has a significantly lower DILI risk than Ligand B (55.37), which is a substantial advantage.

**BBB:** Ligand B (67.235) has a better BBB penetration percentile than Ligand A (50.523), which is crucial for a CNS target like DRD2.

**Caco-2 Permeability:** Ligand A (-4.951) shows poor Caco-2 permeability, while Ligand B (-5.275) is also poor, but slightly better.

**Aqueous Solubility:** Both ligands have poor aqueous solubility (-1.481 and -2.908, respectively).

**hERG Inhibition:** Ligand A (0.123) has a much lower hERG inhibition liability than Ligand B (0.336), which is a significant safety advantage.

**Microsomal Clearance:** Ligand A (41.29) has slightly lower microsomal clearance than Ligand B (46.152), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand B (25.327) has a longer in vitro half-life than Ligand A (14.63), which is generally desirable.

**P-gp Efflux:** Ligand A (0.019) has a much lower P-gp efflux liability than Ligand B (0.074), which is a major advantage for CNS penetration.

**Binding Affinity:** Ligand B (-9.3 kcal/mol) has a substantially stronger binding affinity than Ligand A (-6.9 kcal/mol). This >1.5 kcal/mol difference is a significant driver.

**Overall Assessment:**

Ligand B has a better BBB score and significantly stronger binding affinity, which are key for a CNS GPCR target. However, it has higher DILI risk, hERG inhibition, and P-gp efflux. Ligand A has a much better safety profile (lower DILI and hERG) and P-gp efflux, but weaker affinity and lower BBB. The affinity difference is substantial. Given the importance of potency for GPCRs, and the fact that some ADME issues can be mitigated with formulation strategies, the stronger binding of Ligand B is likely to outweigh its drawbacks.

Output:
1
2025-04-17 06:02:21,529 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (362.813 Da and 347.415 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (81.43) is better than Ligand B (84.67), both are below the 90 A^2 threshold desirable for CNS targets.

**logP:** Ligand A (3.542) is good, while Ligand B (1.588) is a bit low, potentially hindering membrane permeability.

**H-Bond Donors/Acceptors:** Both have 1 HBD and 5 HBA, which are within acceptable limits.

**QED:** Both ligands have good QED scores (0.601 and 0.733, respectively), indicating drug-like properties.

**DILI:** Ligand A (80.496) has a higher DILI risk than Ligand B (38.309). This is a significant negative for Ligand A.

**BBB:** Ligand B (74.254) has a substantially better BBB penetration score than Ligand A (56.65). This is critical for a CNS target like DRD2.

**Caco-2 Permeability:** Ligand A (-4.787) has worse Caco-2 permeability than Ligand B (-4.51).

**Aqueous Solubility:** Ligand A (-3.578) has worse aqueous solubility than Ligand B (-2.705).

**hERG:** Both ligands have low hERG inhibition liability (0.224 and 0.177, respectively).

**Microsomal Clearance:** Ligand A (110.965) has higher microsomal clearance than Ligand B (40.371), suggesting lower metabolic stability.

**In vitro Half-Life:** Ligand B (8.494) has a longer in vitro half-life than Ligand A (13.975).

**P-gp Efflux:** Ligand A (0.234) has slightly higher P-gp efflux liability than Ligand B (0.057). Lower P-gp efflux is preferred for CNS penetration.

**Binding Affinity:** Ligand A (-7.9 kcal/mol) has a slightly better binding affinity than Ligand B (-7.5 kcal/mol). However, the difference is not substantial enough to overcome the ADME deficiencies of Ligand A.

**Overall Assessment:**

Ligand B is the more promising candidate. While Ligand A has slightly better binding affinity, Ligand B excels in crucial ADME properties for a CNS-targeting GPCR, particularly BBB penetration, lower DILI risk, better metabolic stability (lower Cl_mic, longer t1/2), and lower P-gp efflux. The logP of Ligand B is a minor concern, but the overall profile is significantly more favorable.



Output:
1
2025-04-17 06:02:21,529 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (341.451 and 345.403 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (47.56) is excellent, well below the 90 A^2 threshold for CNS targets. Ligand B (89.35) is higher, but still reasonable, though less optimal for CNS penetration.

**logP:** Ligand A (4.013) is at the upper end of the optimal range (1-3), potentially raising solubility concerns. Ligand B (0.368) is quite low, which could hinder membrane permeability and potentially reduce binding affinity.

**H-Bond Donors/Acceptors:** Both have 1 HBD, which is good. Ligand A has 3 HBA, and Ligand B has 6 HBA. Both are within the acceptable limit of 10, but Ligand B is closer to the upper bound.

**QED:** Ligand A (0.823) has a strong drug-like profile. Ligand B (0.438) is below the 0.5 threshold, indicating a less favorable drug-like profile.

**DILI:** Ligand A (37.728) has a low DILI risk. Ligand B (49.903) is slightly higher, but still acceptable.

**BBB:** Ligand A (81.039) has excellent BBB penetration potential. Ligand B (65.529) is lower, which is a significant drawback for a CNS target like DRD2.

**Caco-2 Permeability:** Both have negative values which is unusual. Assuming these are logP values, Ligand A (-4.855) is very poor, and Ligand B (-5.39) is even worse. This is concerning for oral absorption.

**Aqueous Solubility:** Both have negative values which is unusual.

**hERG:** Ligand A (0.702) has a low hERG risk. Ligand B (0.19) also has a low hERG risk.

**Microsomal Clearance:** Ligand A (83.041) has a high microsomal clearance, suggesting rapid metabolism. Ligand B (-10.166) has a negative value which is unusual.

**In vitro Half-Life:** Ligand A (10.803) has a moderate half-life. Ligand B (1.99) has a very short half-life, indicating rapid degradation.

**P-gp Efflux:** Both ligands have a value of 0.729 and 0.022 respectively, which is unusual.

**Binding Affinity:** Ligand A (-10.0) has significantly stronger binding affinity than Ligand B (-8.4). This is a substantial advantage.

**Overall Assessment:**

Ligand A is clearly superior. While its logP is slightly high and clearance is high, its excellent TPSA, strong BBB penetration, high QED, strong binding affinity, and low DILI risk outweigh these drawbacks. Ligand B suffers from a low logP, poor BBB penetration, low QED, and a very short half-life, making it a less promising candidate. The substantial difference in binding affinity (-1.6 kcal/mol) further solidifies Ligand A as the better choice.

Output:
1
2025-04-17 06:02:21,529 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (347.459 Da) is slightly lower, which could be beneficial for permeability. Ligand B (369.422 Da) is also acceptable.

**TPSA:** Ligand A (80.32) is excellent, well below the 90 A^2 threshold for CNS targets. Ligand B (126.21) is higher, but still potentially acceptable, though less ideal.

**logP:** Ligand A (2.366) is optimal. Ligand B (-0.176) is significantly lower, which is a major concern for CNS penetration. A logP below 1 can severely hinder brain exposure.

**H-Bond Donors/Acceptors:** Ligand A (2 HBD, 4 HBA) and Ligand B (4 HBD, 6 HBA) both fall within acceptable ranges.

**QED:** Both ligands have reasonable QED scores (A: 0.672, B: 0.554), indicating good drug-like properties.

**DILI:** Ligand A (37.65) has a much lower DILI risk than Ligand B (69.329), which is a significant advantage.

**BBB:** Ligand A (59.131) has a moderate BBB penetration, while Ligand B (68.399) is also moderate. Both are below the desirable >70 for CNS targets, but Ligand A is better.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.077 and -5.837), which is unusual and suggests poor permeability. This is a concern for both.

**Aqueous Solubility:** Both ligands have negative solubility values (-2.126 and -2.178), also unusual and indicating poor solubility.

**hERG:** Both ligands have very low hERG risk (0.46 and 0.183).

**Microsomal Clearance:** Ligand A (30.135) has higher clearance than Ligand B (-11.823), meaning Ligand B is more metabolically stable.

**In vitro Half-Life:** Ligand B (-5.04) has a negative half-life, which is not possible. This is a major red flag for Ligand B. Ligand A (9.747) has a reasonable half-life.

**P-gp Efflux:** Both ligands have very low P-gp efflux (0.153 and 0.021).

**Binding Affinity:** Both ligands have similar and strong binding affinities (-8.3 kcal/mol and -8.2 kcal/mol). The difference is negligible.

**Overall Assessment:**

Ligand A is significantly more promising. While both have issues with Caco-2 and solubility, Ligand A has a much better logP, lower DILI risk, and a reasonable half-life. Ligand B's extremely low logP is a major drawback for CNS penetration, and its negative half-life is a critical flaw. The slightly better BBB of Ligand A, combined with its superior ADME properties, makes it the better candidate.

Output:
0
2025-04-17 06:02:21,529 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (348.487 and 347.415 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (53.01) is significantly better than Ligand B (84.67). For CNS targets, we want TPSA <= 90, and A is comfortably within that range, while B is approaching the upper limit.

**3. logP:** Both ligands have good logP values (2.388 and 1.305), falling within the optimal 1-3 range.

**4. H-Bond Donors:** Both have 1 HBD, which is acceptable.

**5. H-Bond Acceptors:** Ligand A has 4 HBAs, and Ligand B has 5. Both are within the acceptable limit of <=10.

**6. QED:** Ligand A (0.858) has a higher QED than Ligand B (0.784), indicating better overall drug-likeness.

**7. DILI:** Ligand A (11.322) has a much lower DILI risk than Ligand B (48.662). This is a significant advantage for A.

**8. BBB:** Ligand A (63.784) has a better BBB penetration percentile than Ligand B (55.176). While both are not ideal (>70 is desirable), A is closer. This is crucial for a CNS target like DRD2.

**9. Caco-2 Permeability:** Ligand A (-4.256) has a higher (less negative) Caco-2 value than Ligand B (-4.996), suggesting better intestinal absorption.

**10. Aqueous Solubility:** Ligand A (-1.458) has better aqueous solubility than Ligand B (-2.104).

**11. hERG Inhibition:** Ligand A (0.838) has a slightly higher hERG inhibition risk than Ligand B (0.086). This is a negative for A, but B's value is very low and favorable.

**12. Microsomal Clearance:** Ligand A (39.418) has a higher microsomal clearance than Ligand B (34.049), meaning it's metabolized faster. This is a negative for A.

**13. In vitro Half-Life:** Ligand A (16.224) has a longer half-life than Ligand B (-18.681). The negative value for B is concerning and suggests very rapid degradation.

**14. P-gp Efflux:** Ligand A (0.27) has lower P-gp efflux than Ligand B (0.065), meaning it's less likely to be pumped out of the brain. This is a positive for A.

**15. Binding Affinity:** Ligand A (-8.4 kcal/mol) has a significantly stronger binding affinity than Ligand B (-7.0 kcal/mol). This 1.4 kcal/mol difference is substantial and can outweigh some of the ADME drawbacks.

**Overall Assessment:**

Despite Ligand A having a slightly higher hERG risk and clearance, its superior BBB penetration, lower DILI risk, better solubility, longer half-life, lower P-gp efflux, and *significantly* stronger binding affinity make it the more promising candidate. The strong affinity is a major driver, and the better ADME properties related to CNS penetration (BBB, Pgp) are crucial for a DRD2 ligand.

Output:
1
2025-04-17 06:02:21,530 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the acceptable range (200-500 Da). Ligand A (341.459 Da) is slightly better, being closer to the lower end which can aid permeability.

**TPSA:** Ligand A (76.18) is significantly better than Ligand B (106.61). For CNS targets, TPSA should be <= 90, and A is comfortably within this range, while B is approaching the upper limit.

**logP:** Both ligands have good logP values (A: 2.223, B: 2.643), falling within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A (HBD=2, HBA=5) is slightly better than Ligand B (HBD=1, HBA=7) in terms of balancing solubility and permeability. Both are acceptable.

**QED:** Ligand A (0.894) has a significantly better QED score than Ligand B (0.654), indicating a more drug-like profile.

**DILI:** Ligand A (52.734) has a much lower DILI risk than Ligand B (98.449). This is a significant advantage for A.

**BBB:** Both ligands have similar BBB penetration (A: 61.535, B: 61.923). While both are above 60%, they are below the desirable >70 for CNS targets. This is not a major differentiating factor here.

**Caco-2 Permeability:** Both have negative Caco-2 values (-5.109 and -5.032). This is unusual and suggests poor permeability, but the scale is not clearly defined. We'll consider this a neutral point.

**Aqueous Solubility:** Both have negative solubility values (-2.224 and -3.464), again unusual. This suggests poor solubility, but the scale is not clearly defined. We'll consider this a neutral point.

**hERG Inhibition:** Ligand A (0.806) has a slightly higher hERG risk than Ligand B (0.363), which is preferable.

**Microsomal Clearance:** Ligand A (-24.288) has significantly lower (better) microsomal clearance than Ligand B (27.231), indicating greater metabolic stability.

**In vitro Half-Life:** Ligand B (95.428) has a much longer in vitro half-life than Ligand A (22.506), which is a positive attribute.

**P-gp Efflux:** Ligand A (0.099) has lower P-gp efflux than Ligand B (0.531), which is beneficial for CNS exposure.

**Binding Affinity:** Ligand B (-7.3) has a significantly stronger binding affinity than Ligand A (-9.1). This is a substantial advantage. A >1.5 kcal/mol difference can outweigh other issues.

**Overall Assessment:**

Ligand A has advantages in terms of TPSA, QED, DILI risk, metabolic stability (Cl_mic), and P-gp efflux. However, Ligand B's significantly stronger binding affinity (-7.3 vs -9.1 kcal/mol) is a major factor. The difference in affinity is substantial enough to potentially overcome the drawbacks of higher DILI risk and slightly worse ADME properties. Considering the GPCR-specific priorities, the strong binding affinity is paramount.

Output:
1
2025-04-17 06:02:21,530 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (343.427 and 361.555 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (66.65) is significantly better than Ligand B (38.13). For a CNS target like DRD2, a TPSA <= 90 is preferred, and Ligand A is much closer to this threshold.

**3. logP:** Both ligands have acceptable logP values (2.207 and 3.88), falling within the optimal 1-3 range. Ligand B is slightly higher, which *could* indicate potential off-target effects, but isn't a major concern.

**4. H-Bond Donors:** Both have 0 HBD, which is acceptable.

**5. H-Bond Acceptors:** Both have 4 HBA, which is acceptable.

**6. QED:** Ligand A (0.841) has a better QED score than Ligand B (0.74), indicating a more drug-like profile.

**7. DILI:** Ligand A (38.348) has a slightly higher DILI risk than Ligand B (25.94), but both are below the concerning threshold of 60.

**8. BBB:** Both ligands exhibit excellent BBB penetration (Ligand A: 79.992, Ligand B: 84.839). Ligand B is slightly better, but both are above the desirable 70% threshold for CNS targets.

**9. Caco-2 Permeability:** Ligand A (-4.809) has a worse Caco-2 permeability than Ligand B (-5.049). Lower values are less desirable.

**10. Aqueous Solubility:** Ligand A (-1.709) has better aqueous solubility than Ligand B (-4.271).

**11. hERG Inhibition:** Both ligands have low hERG inhibition risk (Ligand A: 0.241, Ligand B: 0.516).

**12. Microsomal Clearance:** Ligand A (52.258) has significantly lower microsomal clearance than Ligand B (111.822), suggesting better metabolic stability.

**13. In vitro Half-Life:** Ligand A (1.783) has a shorter in vitro half-life than Ligand B (8.216).

**14. P-gp Efflux:** Ligand A (0.215) has lower P-gp efflux liability than Ligand B (0.667), which is favorable for CNS penetration.

**15. Binding Affinity:** Ligand A (-7.7 kcal/mol) has a slightly better binding affinity than Ligand B (-6.9 kcal/mol). This ~0.8 kcal/mol difference is significant and can outweigh minor ADME drawbacks.

**Overall Assessment:**

Ligand A is the stronger candidate. While Ligand B has slightly better BBB penetration and in vitro half-life, Ligand A excels in crucial areas: TPSA, QED, metabolic stability (lower Cl_mic), P-gp efflux, and, importantly, binding affinity. The lower TPSA and P-gp efflux are particularly important for CNS penetration, and the better affinity is a significant advantage. The slightly higher DILI risk for Ligand A is not a major concern given the overall profile.

Output:
1
2025-04-17 06:02:21,531 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (335.411 Da) is slightly lower, which could be beneficial for permeability. Ligand B (366.433 Da) is also good.

**TPSA:** Ligand A (63.91) is better than Ligand B (53.43) as it is closer to the ideal range for CNS targets (<=90).

**logP:** Ligand A (2.562) is within the optimal range (1-3). Ligand B (4.078) is a bit high, potentially leading to solubility issues and off-target interactions.

**H-Bond Donors/Acceptors:** Ligand A (0 HBD, 5 HBA) and Ligand B (1 HBD, 4 HBA) both have acceptable numbers of HBD and HBA.

**QED:** Both ligands have good QED scores (Ligand A: 0.594, Ligand B: 0.838), indicating good drug-like properties. Ligand B is slightly better.

**DILI:** Ligand A (59.364) has a higher DILI risk than Ligand B (27.336). This is a significant advantage for Ligand B.

**BBB:** Both ligands have good BBB penetration (Ligand A: 74.913, Ligand B: 86.972). Ligand B is superior here, which is crucial for a CNS target like DRD2.

**Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual. However, the magnitude is similar and doesn't strongly favor either.

**Aqueous Solubility:** Both have negative solubility values, indicating poor aqueous solubility. Ligand A (-2.367) is slightly better than Ligand B (-4.771).

**hERG Inhibition:** Both ligands show low hERG inhibition risk (Ligand A: 0.559, Ligand B: 0.711).

**Microsomal Clearance:** Both have relatively high microsomal clearance (Ligand A: 80.715, Ligand B: 85.566), indicating faster metabolism.

**In vitro Half-Life:** Both have negative half-life values, which is unusual. Ligand B (-13.734) is slightly better than Ligand A (-22.373).

**P-gp Efflux:** Both ligands have low P-gp efflux (Ligand A: 0.264, Ligand B: 0.317), which is favorable for CNS penetration.

**Binding Affinity:** Ligand B (-7.1 kcal/mol) has a significantly better binding affinity than Ligand A (-9.3 kcal/mol). This is a substantial advantage.

**Overall Assessment:**

Ligand B is the more promising candidate. While Ligand A has slightly better TPSA and solubility, Ligand B excels in critical areas for a CNS GPCR target: significantly better binding affinity, lower DILI risk, and higher BBB penetration. The slightly higher logP of Ligand B is a minor concern that could potentially be addressed with further optimization, but the stronger binding and improved safety profile outweigh this drawback.

Output:
1
2025-04-17 06:02:21,531 - INFO - Batch 248 complete. Total preferences: 3968
2025-04-17 06:02:21,531 - INFO - Processing batch 249/512...
2025-04-17 06:03:02,633 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (352.341 and 384.933 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (69.48) is better than Ligand B (60.25). Both are below the 90 A^2 threshold desirable for CNS targets, which is excellent.

**3. logP:** Ligand B (3.436) is slightly higher than Ligand A (2.027). While both are within the optimal 1-3 range, Ligand B is approaching the upper limit, potentially raising solubility concerns.

**4. H-Bond Donors:** Both ligands have 0 HBD, which is acceptable.

**5. H-Bond Acceptors:** Both ligands have 6 HBA, which is acceptable.

**6. QED:** Ligand A (0.824) has a significantly better QED score than Ligand B (0.664), indicating a more drug-like profile.

**7. DILI:** Both ligands have acceptable DILI risk (59.325 and 55.448, respectively), below the 60 threshold.

**8. BBB:** Ligand A (89.841) has a substantially better BBB percentile than Ligand B (73.362). This is a *critical* advantage for a CNS target like DRD2.

**9. Caco-2 Permeability:** Ligand A (-4.322) has a worse Caco-2 permeability than Ligand B (-4.87). Lower values indicate lower permeability.

**10. Aqueous Solubility:** Ligand A (-1.942) has better aqueous solubility than Ligand B (-3.395).

**11. hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.111 and 0.43, respectively).

**12. Microsomal Clearance:** Ligand B (74.576) has a higher microsomal clearance than Ligand A (37.122), suggesting lower metabolic stability.

**13. In vitro Half-Life:** Ligand B (60.669) has a much longer in vitro half-life than Ligand A (-19.787). This is a significant advantage.

**14. P-gp Efflux:** Ligand A (0.229) has lower P-gp efflux liability than Ligand B (0.747), which is favorable for CNS penetration.

**15. Binding Affinity:** Ligand A (-8.5 kcal/mol) has a significantly stronger binding affinity than Ligand B (-6.3 kcal/mol). This is a substantial advantage, exceeding the 1.5 kcal/mol difference threshold.

**Overall Assessment:**

Ligand A is the better candidate. The superior BBB penetration, significantly stronger binding affinity, better QED, and lower P-gp efflux outweigh the slightly worse Caco-2 permeability and shorter half-life. For a CNS target like DRD2, BBB penetration and affinity are paramount. The better solubility of Ligand A is also a plus. While Ligand B has a longer half-life, the other advantages of Ligand A are more critical for this specific target.

Output:
1
2025-04-17 06:03:02,633 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (353.853 and 396.171 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (48.99) is better than Ligand B (45.23). Both are below the 90 A^2 threshold desirable for CNS targets, which is excellent.

**3. logP:** Both ligands have similar logP values (4.41 and 4.621), slightly above the optimal 1-3 range, but not excessively high. This could potentially lead to some solubility issues, but is not a major concern.

**4. H-Bond Donors:** Both have 1 HBD, which is within the acceptable limit of <=5.

**5. H-Bond Acceptors:** Ligand A has 2 HBA, and Ligand B has 3. Both are within the acceptable limit of <=10.

**6. QED:** Ligand A (0.758) has a better QED score than Ligand B (0.606), indicating a more drug-like profile.

**7. DILI:** Ligand B (79.333) has a higher DILI risk than Ligand A (63.862).  Ligand A is preferable here.

**8. BBB:** Both ligands have good BBB penetration (Ligand A: 72.005, Ligand B: 75.649), exceeding the >70% threshold for CNS targets. Ligand B is slightly better.

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.825 and -4.613). This is unusual and suggests poor permeability. However, these values are on a scale where negative values are possible, and direct comparison is difficult without knowing the scale's specifics.

**10. Aqueous Solubility:** Both ligands have very poor aqueous solubility (-5.385 and -5.406). This is a significant drawback.

**11. hERG Inhibition:** Both ligands show low hERG inhibition risk (0.885 and 0.575).

**12. Microsomal Clearance:** Ligand B (60.522) has lower microsomal clearance than Ligand A (66.568), suggesting better metabolic stability.

**13. In vitro Half-Life:** Ligand B (77.539) has a significantly longer in vitro half-life than Ligand A (31.02). This is a major advantage.

**14. P-gp Efflux:** Ligand A (0.654) has lower P-gp efflux than Ligand B (0.412), which is desirable for CNS penetration.

**15. Binding Affinity:** Ligand B (-9.4 kcal/mol) has a stronger binding affinity than Ligand A (-10.7 kcal/mol). This is a substantial advantage and can often outweigh minor ADME concerns.

**Overall Assessment:**

Ligand B has a significantly better binding affinity and a longer half-life, which are crucial for a GPCR ligand. While it has a slightly higher DILI risk, the superior affinity and half-life are likely to be more impactful. The poor solubility and Caco-2 permeability are concerns for both, but can potentially be addressed through formulation strategies. The lower P-gp efflux for Ligand A is a plus, but the affinity difference is substantial.

Output:
1
2025-04-17 06:03:02,633 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (384.523 and 371.503 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (85.36) is slightly above the preferred <90 for CNS targets, but still reasonable. Ligand B (78.95) is excellent, well below 90.

**3. logP:** Both ligands have good logP values (2.178 and 1.468), falling within the optimal 1-3 range.

**4. H-Bond Donors:** Both have 1 HBD, which is acceptable.

**5. H-Bond Acceptors:** Ligand A has 6 HBAs, and Ligand B has 5. Both are within the acceptable limit of 10.

**6. QED:** Both ligands have QED values (0.812 and 0.765) above 0.5, indicating good drug-likeness.

**7. DILI:** Ligand A (68.282) has a higher DILI risk than Ligand B (36.797). Ligand B is well below the 40 threshold, indicating low risk.

**8. BBB:** Ligand A (72.082) has a good BBB percentile, while Ligand B (66.925) is slightly lower. Both are acceptable, but A is preferable.

**9. Caco-2 Permeability:** Both have negative Caco-2 values (-5.23 and -4.792). This is unusual and suggests poor permeability. However, the scale is not specified, so it's hard to interpret.

**10. Aqueous Solubility:** Both have negative solubility values (-2.824 and -1.813), indicating poor aqueous solubility. This is a concern for bioavailability.

**11. hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.055 and 0.137).

**12. Microsomal Clearance:** Ligand A (4.46) has significantly lower microsomal clearance than Ligand B (46.123), suggesting better metabolic stability.

**13. In vitro Half-Life:** Ligand A (8.046) has a better in vitro half-life than Ligand B (-35.791). The negative value for B is concerning and likely indicates rapid degradation.

**14. P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.281 and 0.033).

**15. Binding Affinity:** Ligand A (-7.5 kcal/mol) has a slightly better binding affinity than Ligand B (-6.4 kcal/mol). The difference is 1.1 kcal/mol, which is significant.

**Overall Assessment:**

Considering the GPCR-specific priorities, Ligand A is the better candidate. While both have issues with solubility and Caco-2 permeability, Ligand A's superior binding affinity, lower DILI risk, better BBB penetration, and significantly improved metabolic stability (lower Cl_mic and longer t1/2) outweigh the slightly higher TPSA. The difference in binding affinity is also substantial enough to be a key deciding factor.

Output:
1
2025-04-17 06:03:02,633 - INFO - Reasoning:

Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight (MW):** Both ligands (342.443 and 344.415 Da) fall comfortably within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (74.33) is significantly better than Ligand B (95.32). For CNS targets, we want TPSA <= 90, and A is closer to this threshold.

**3. logP:** Both ligands have acceptable logP values (0.972 and 1.233), falling within the 1-3 optimal range.

**4. H-Bond Donors (HBD):** Both are acceptable (2 and 1 respectively), well below the limit of 5.

**5. H-Bond Acceptors (HBA):** Both are acceptable (4 and 5 respectively), below the limit of 10.

**6. QED:** Both ligands have good QED scores (0.545 and 0.727), indicating good drug-like properties.

**7. DILI:** Both have low DILI risk (38.736 and 32.803), both well below the 40 threshold.

**8. BBB:** Ligand A (65.452) and Ligand B (63.629) are both reasonably good, but fall short of the >70 desirable for CNS targets. However, given the other parameters, this isn't a disqualifier.

**9. Caco-2 Permeability:** Both have negative Caco-2 values (-4.567 and -4.527). This is unusual and suggests poor permeability. However, these values are on a scale where negative values are possible, and the absolute value is similar for both.

**10. Aqueous Solubility:** Both have negative solubility values (-2.767 and -2.475). Again, this is unusual, but similar for both.

**11. hERG Inhibition:** Both have very low hERG risk (0.263 and 0.229).

**12. Microsomal Clearance (Cl_mic):** Ligand B (24.856) has a lower Cl_mic than Ligand A (33.284), indicating better metabolic stability.

**13. In vitro Half-Life:** Ligand A (7.861) has a slightly longer half-life than Ligand B (5.708).

**14. P-gp Efflux:** Both have very low P-gp efflux liability (0.027 and 0.022).

**15. Binding Affinity:** Ligand A (-8.4 kcal/mol) has a significantly stronger binding affinity than Ligand B (-7.2 kcal/mol). This is a difference of 1.2 kcal/mol, which is substantial and can outweigh minor ADME drawbacks.

**Conclusion:**

Despite similar profiles in several areas, Ligand A is the better candidate. The most important factor is the significantly stronger binding affinity (-8.4 vs -7.2 kcal/mol). Additionally, Ligand A has a lower TPSA, which is beneficial for CNS penetration. While both have suboptimal Caco-2 and solubility values, the affinity difference makes Ligand A more promising.

Output:
1
2025-04-17 06:03:02,633 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (345.483 and 344.415 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (47.56) is excellent, well below the 90 A^2 threshold for CNS targets. Ligand B (84.42) is higher, but still potentially acceptable, though less ideal.

**3. logP:** Ligand A (3.858) is optimal. Ligand B (1.706) is on the lower side, potentially hindering permeability.

**4. H-Bond Donors:** Both ligands have 1 HBD, which is within the acceptable limit of <=5.

**5. H-Bond Acceptors:** Ligand A has 3 HBAs, and Ligand B has 5. Both are within the acceptable limit of <=10.

**6. QED:** Both ligands have good QED scores (0.603 and 0.899), indicating good drug-like properties.

**7. DILI:** Ligand A (18.922) has a significantly lower DILI risk than Ligand B (63.125). This is a major advantage for Ligand A.

**8. BBB:** Ligand A (83.288) has a much better BBB penetration percentile than Ligand B (67.895). This is *critical* for a CNS target like DRD2.

**9. Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and suggests potential issues with the calculation or data. However, the magnitude is similar.

**10. Aqueous Solubility:** Both have negative solubility values, which is also unusual. Again, the magnitude is similar.

**11. hERG Inhibition:** Both ligands have low hERG inhibition risk (0.605 and 0.196).

**12. Microsomal Clearance:** Ligand A (68.27) has a higher (worse) microsomal clearance than Ligand B (32.254), suggesting faster metabolism.

**13. In vitro Half-Life:** Ligand B (-19.331) has a negative half-life, which is impossible and indicates a data issue. Ligand A (5.651) has a reasonable half-life.

**14. P-gp Efflux:** Ligand A (0.193) has lower P-gp efflux liability than Ligand B (0.13), which is favorable for CNS penetration.

**15. Binding Affinity:** Ligand B (-9.0) has a slightly better binding affinity than Ligand A (-8.6), but the difference is less than 1.5 kcal/mol.

**Overall Assessment:**

Ligand A is significantly more promising. While Ligand B has slightly better binding affinity, Ligand A excels in crucial areas for a CNS-targeting GPCR ligand: TPSA, logP, BBB penetration, and DILI risk. The problematic data for Caco-2 and Solubility for both ligands are concerning, but the other differences are more impactful. The negative half-life for Ligand B is a showstopper. Ligand A's better BBB and lower DILI risk outweigh the small difference in binding affinity.

Output:
1
2025-04-17 06:03:02,634 - INFO - Reasoning:

Let's analyze Ligand A and Ligand B against the provided guidelines, prioritizing GPCR-specific properties (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (338.447 and 341.342 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (35.53) is excellent, well below the 90 A^2 threshold for CNS targets. Ligand B (91.22) is significantly higher, exceeding the preferred threshold for CNS penetration.

**logP:** Both ligands have acceptable logP values (4.373 and 3.23), falling within the 1-3 range, though Ligand A is slightly higher.

**H-Bond Donors/Acceptors:** Ligand A (0 HBD, 3 HBA) and Ligand B (2 HBD, 4 HBA) both meet the criteria of <=5 HBD and <=10 HBA.

**QED:** Both ligands have good QED scores (0.637 and 0.817), indicating drug-like properties.

**DILI:** Ligand A (15.083) has a much lower DILI risk than Ligand B (88.561), which is a significant advantage.

**BBB:** Ligand A (68.127) has a better BBB percentile than Ligand B (54.207), though ideally, both would be higher for a CNS target like DRD2.

**Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and suggests poor permeability. However, the absolute values are similar.

**Aqueous Solubility:** Both ligands have negative solubility values, suggesting poor aqueous solubility.

**hERG:** Both ligands have low hERG inhibition liability (0.854 and 0.399), which is favorable.

**Microsomal Clearance:** Ligand A (110.003) has higher microsomal clearance than Ligand B (45.765), indicating lower metabolic stability.

**In vitro Half-Life:** Ligand B (45.787 hours) has a significantly longer half-life than Ligand A (-8.945 hours), which is a substantial advantage.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.42 and 0.207), which is good.

**Binding Affinity:** Both ligands have excellent binding affinities (-9.0 and -9.4 kcal/mol), with Ligand B being slightly more potent. The difference is less than 1.5 kcal/mol, so it's not a decisive factor on its own.

**Overall Assessment:**

Considering the GPCR-specific priorities, Ligand A is superior. Its significantly lower TPSA, much lower DILI risk, and better BBB penetration outweigh the slightly higher logP and lower in vitro half-life compared to Ligand B. While Ligand B has a slightly better binding affinity and half-life, the TPSA and DILI risks are major concerns for CNS drug development. The negative solubility and Caco-2 values are problematic for both, but can be addressed with formulation strategies.

Output:
0
2025-04-17 06:03:02,634 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (348.4 and 344.5 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (93.73) is slightly higher than the preferred <90 for CNS targets, but still reasonably close. Ligand B (75.19) is well within the optimal range.

**logP:** Ligand A (0.491) is quite low, potentially hindering membrane permeability. Ligand B (2.046) is much better, falling within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A has 2 HBD and 5 HBA, which are acceptable. Ligand B has 1 HBD and 4 HBA, also acceptable.

**QED:** Both ligands have good QED scores (0.527 and 0.857, respectively), indicating drug-like properties.

**DILI:** Ligand A (49.632) has a higher DILI risk than Ligand B (29.042), though both are below the concerning threshold of 60.

**BBB:** This is crucial for a CNS target. Ligand A (29.779) has a poor BBB penetration percentile. Ligand B (75.301) is much more promising, exceeding the desirable >70 threshold.

**Caco-2 Permeability:** Both have negative values, which is unusual. Assuming these are logP-scale values, they suggest poor permeability. However, the absolute values are similar and don't strongly differentiate the two.

**Aqueous Solubility:** Both ligands have very low solubility (-1.579 and -1.571). This is a concern, but formulation strategies could potentially address it.

**hERG Inhibition:** Both ligands show very low hERG inhibition risk (0.137 and 0.286).

**Microsomal Clearance:** Ligand A (17.94) has lower clearance than Ligand B (22.837), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand B (-11.131) has a significantly longer half-life than Ligand A (-4.298).

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.037 and 0.034), which is favorable for CNS penetration.

**Binding Affinity:** Both ligands have identical binding affinities (-8.9 kcal/mol), which is excellent.

**Conclusion:**

Despite similar binding affinities, Ligand B is the superior candidate. Its significantly better BBB penetration (75.3 vs. 29.8), more favorable logP (2.05 vs. 0.49), and longer half-life outweigh the slightly higher microsomal clearance and DILI risk compared to Ligand A. The low logP of Ligand A is a major drawback for CNS penetration, even with low P-gp efflux.

Output:
1
2025-04-17 06:03:02,634 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (387.615 and 362.451 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (52.65) is significantly better than Ligand B (91.57). For CNS targets, we want TPSA <= 90, and A is comfortably within this range, while B is approaching the upper limit.

**logP:** Both ligands have acceptable logP values (2.122 and 3.634), falling within the optimal 1-3 range. Ligand B is slightly higher, which *could* indicate potential off-target issues, but is not a major concern.

**H-Bond Donors/Acceptors:** Ligand A (HBD=1, HBA=5) is preferable to Ligand B (HBD=3, HBA=5). Lower HBD is generally better for BBB penetration.

**QED:** Both ligands have reasonable QED values (0.757 and 0.624), indicating good drug-like properties.

**DILI:** Both ligands have relatively high DILI risk (28.112 and 65.064), but Ligand A is significantly lower, suggesting a better safety profile.

**BBB:** Ligand A (64.482) is *much* better than Ligand B (36.526) in terms of BBB penetration. For a CNS target like DRD2, BBB penetration >70 is highly desirable. Ligand A is approaching this, while Ligand B is quite low.

**Caco-2 Permeability:** Both have negative Caco-2 values (-5.103 and -5.612). This is unusual and likely indicates a problem with the prediction method, or these compounds are not well absorbed. However, we can't rely on this data point heavily.

**Aqueous Solubility:** Both have negative solubility values (-3.533 and -4.793). Similar to Caco-2, this is concerning but may be a prediction artifact.

**hERG Inhibition:** Both ligands show low hERG inhibition risk (0.359 and 0.608), which is good.

**Microsomal Clearance:** Ligand B (54.582) has lower microsomal clearance than Ligand A (74.383), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand B (30.642 hours) has a significantly longer half-life than Ligand A (3.153 hours). This is a major advantage for Ligand B.

**P-gp Efflux:** Ligand A (0.072) has much lower P-gp efflux than Ligand B (0.288), which is favorable for CNS exposure.

**Binding Affinity:** Ligand B (-8.5 kcal/mol) has a significantly stronger binding affinity than Ligand A (-6.2 kcal/mol). This is a substantial advantage (a >2 kcal/mol difference).

**Overall Assessment:**

While Ligand B has a superior binding affinity and better metabolic stability (lower Cl_mic, longer t1/2), Ligand A is significantly better in terms of BBB penetration, TPSA, DILI risk, and P-gp efflux. For a CNS target like DRD2, BBB penetration is critical. The strong affinity of Ligand B is tempting, but the poor BBB penetration is a major drawback. The lower TPSA and DILI risk of Ligand A also contribute to its favorability.

Considering the GPCR-specific priorities, Ligand A is the more promising candidate. The affinity difference, while significant, might be overcome with further optimization, while improving BBB penetration is often a much more challenging task.

Output:
0
2025-04-17 06:03:02,634 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (372.441 and 348.403 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (83.98) is excellent for CNS penetration, being well below 90. Ligand B (98.82) is still reasonable but less optimal.

**logP:** Ligand A (2.214) is within the optimal 1-3 range. Ligand B (-1.146) is significantly lower, potentially hindering membrane permeability and CNS entry.

**H-Bond Donors/Acceptors:** Ligand A has 3 HBD and 5 HBA, which are acceptable. Ligand B has 2 HBD and 4 HBA, also acceptable.

**QED:** Ligand A (0.641) has a good drug-likeness score. Ligand B (0.484) is lower, indicating a less favorable overall drug-like profile.

**DILI:** Ligand A (70.958) has a moderate DILI risk, but still acceptable. Ligand B (30.903) has a very low DILI risk, which is excellent.

**BBB:** Ligand A (72.354) has good BBB penetration. Ligand B (33.85) has poor BBB penetration, a major drawback for a CNS target.

**Caco-2 Permeability:** Ligand A (-4.873) has poor Caco-2 permeability. Ligand B (-5.132) also has poor Caco-2 permeability.

**Aqueous Solubility:** Ligand A (-3.676) has poor aqueous solubility. Ligand B (-1.83) has slightly better solubility, but still poor.

**hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.279 and 0.026, respectively).

**Microsomal Clearance:** Ligand A (18.262) has moderate clearance. Ligand B (-3.42) has negative clearance, which is not physically possible and suggests an issue with the data or modeling.

**In vitro Half-Life:** Ligand A (7.383 hours) has a reasonable half-life. Ligand B (-20.712 hours) has a negative half-life, indicating a data issue.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.049 and 0.004, respectively).

**Binding Affinity:** Both ligands have excellent binding affinity (-7.9 and -7.6 kcal/mol). The difference of 0.3 kcal/mol is not substantial enough to override other significant differences.

**Conclusion:**

Despite Ligand B's lower DILI risk, Ligand A is the more promising candidate. The primary reason is its significantly better BBB penetration (72.354 vs 33.85). Given that DRD2 is a CNS target, this is a critical factor. While Ligand A has poorer Caco-2 permeability and solubility, these can be addressed through formulation strategies. The negative values for clearance and half-life for Ligand B are concerning and suggest unreliable data. The slightly better logP of Ligand A also supports its potential for CNS entry.

Output:
1
2025-04-17 06:03:02,634 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (338.371 and 347.361 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (93.96) is better than Ligand B (69.56). Both are below the 90 A^2 threshold for CNS targets, but A is closer to the upper limit.

**logP:** Ligand A (1.721) is optimal, while Ligand B (4.035) is approaching the upper limit of the preferred range (1-3). This is a significant drawback for B.

**H-Bond Donors/Acceptors:** Ligand A (HBD=2, HBA=6) and Ligand B (HBD=3, HBA=3) both have acceptable numbers of H-bond donors and acceptors.

**QED:** Both ligands have similar QED values (0.755 and 0.73), indicating good drug-likeness.

**DILI:** Ligand A (82.668) has a higher DILI risk than Ligand B (69.252), but both are still reasonably acceptable.

**BBB:** Ligand A (73.013) has a significantly better BBB penetration percentile than Ligand B (32.92). This is *critical* for a CNS target like DRD2.

**Caco-2 Permeability:** Ligand A (-5.421) has a worse Caco-2 permeability than Ligand B (-5.204), but both are negative, indicating poor permeability.

**Aqueous Solubility:** Both ligands have poor aqueous solubility (-2.59 and -3.573).

**hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.106 and 0.235).

**Microsomal Clearance:** Ligand A (2.412) has a lower microsomal clearance than Ligand B (9.999), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (56.379) has a better in vitro half-life than Ligand B (45.64).

**P-gp Efflux:** Ligand A (0.04) has significantly lower P-gp efflux liability than Ligand B (0.277), which is crucial for CNS penetration.

**Binding Affinity:** Ligand A (-10.2 kcal/mol) has a *much* stronger binding affinity than Ligand B (0.0 kcal/mol). This is the most important factor, and the difference is substantial.

**Overall Assessment:**

Ligand A is clearly superior. While both have poor solubility and Caco-2 permeability, Ligand A's dramatically better BBB penetration, lower P-gp efflux, significantly stronger binding affinity, and improved metabolic stability outweigh its slightly higher DILI risk and worse Caco-2 permeability. Ligand B's high logP and very weak binding affinity are major drawbacks.

Output:
1
2025-04-17 06:03:02,634 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (348.447 and 351.535 Da) fall within the ideal range of 200-500 Da.

**TPSA:** Ligand A (76.46) is better than Ligand B (43.86), being closer to the <90 threshold for CNS targets. Ligand B is excellent.

**logP:** Both ligands have acceptable logP values (1.034 and 2.77), falling within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A has 1 HBD and 5 HBA, while Ligand B has 0 HBD and 3 HBA. Both are within acceptable limits (<=5 HBD and <=10 HBA).

**QED:** Ligand A (0.761) has a better QED score than Ligand B (0.569), indicating a more drug-like profile.

**DILI:** Ligand A (18.728) has a slightly higher DILI risk than Ligand B (11.632), but both are below the concerning threshold of 60.

**BBB:** Ligand B (75.727) has a better BBB penetration percentile than Ligand A (68.864). While both are reasonably good, exceeding 70 is preferred for CNS targets.

**Caco-2 Permeability:** Ligand A (-4.923) has slightly better Caco-2 permeability than Ligand B (-4.607). Both are negative, which is unusual and requires further investigation, but the difference isn't substantial.

**Aqueous Solubility:** Both ligands have poor aqueous solubility (-1.361 and -1.397). This could be a formulation challenge.

**hERG Inhibition:** Ligand A (0.172) has a lower hERG inhibition liability than Ligand B (0.765), which is preferable.

**Microsomal Clearance:** Ligand B (48.438) has a significantly lower microsomal clearance than Ligand A (14.325), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand B (20.593 hours) has a longer in vitro half-life than Ligand A (10.976 hours).

**P-gp Efflux:** Ligand A (0.016) has significantly lower P-gp efflux liability than Ligand B (0.274), which is crucial for CNS penetration.

**Binding Affinity:** Ligand A (-7.7 kcal/mol) has a stronger binding affinity than Ligand B (-6.8 kcal/mol). This is a substantial difference (0.9 kcal/mol), which can outweigh some ADME drawbacks.

**Overall Assessment:**

Ligand A has a better binding affinity, QED, hERG profile, and P-gp efflux. However, Ligand B has a better BBB, metabolic stability (lower Cl_mic, longer t1/2), and slightly lower DILI risk. Given the importance of CNS penetration for a DRD2 ligand, the stronger affinity of Ligand A, coupled with its lower P-gp efflux, makes it the more promising candidate despite the slightly less favorable metabolic stability. The difference in affinity is significant.

Output:
1
2025-04-17 06:03:02,634 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (358.473 and 385.465 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (41.57) is excellent, well below the 90 A^2 threshold for CNS targets. Ligand B (71.96) is higher but still acceptable, though less optimal.

**3. logP:** Both ligands have a logP around 4.0 (4.049 and 4.082). This is at the upper end of the optimal range (1-3) and could potentially lead to solubility issues or off-target interactions, but is not a dealbreaker.

**4. H-Bond Donors:** Ligand A (1) is ideal. Ligand B (2) is acceptable.

**5. H-Bond Acceptors:** Ligand A (3) is good. Ligand B (8) is higher, potentially impacting permeability.

**6. QED:** Ligand A (0.824) is excellent, indicating high drug-likeness. Ligand B (0.609) is still reasonable, but less favorable.

**7. DILI:** Ligand A (6.592) has a very low DILI risk, which is excellent. Ligand B (84.8) has a significantly higher DILI risk, a major concern.

**8. BBB:** Ligand A (91.586) has excellent BBB penetration, crucial for a CNS target like DRD2. Ligand B (63.784) has moderate BBB penetration, significantly lower than Ligand A.

**9. Caco-2:** Both have negative Caco-2 values (-4.425 and -4.891), which is unusual and suggests poor permeability. This is a potential issue for both.

**10. Solubility:** Both have negative solubility values (-3.222 and -4.563) which is also unusual and suggests poor solubility. This is a potential issue for both.

**11. hERG:** Both ligands have low hERG inhibition liability (0.848 and 0.836), which is good.

**12. Cl_mic:** Ligand A (27.805) has lower microsomal clearance, indicating better metabolic stability. Ligand B (92.657) has much higher clearance, suggesting faster metabolism.

**13. t1/2:** Ligand A (5.529) has a shorter in vitro half-life than Ligand B (16.829). Longer half-life is generally preferred.

**14. Pgp:** Both ligands have low P-gp efflux liability (0.114 and 0.486), which is favorable for CNS exposure.

**15. Binding Affinity:** Ligand A (-8.8 kcal/mol) has a significantly stronger binding affinity than Ligand B (-7.8 kcal/mol). This 1.0 kcal/mol difference is substantial and can outweigh some ADME drawbacks.

**Overall Assessment:**

Ligand A is the superior candidate. While both have issues with Caco-2 and solubility, Ligand A excels in critical areas for a CNS GPCR target: excellent BBB penetration, much lower DILI risk, better metabolic stability (lower Cl_mic), and significantly stronger binding affinity. The stronger affinity is a major advantage. Ligand B's higher DILI risk and lower BBB penetration are significant drawbacks.

Output:
0
2025-04-17 06:03:02,634 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (347.5 and 362.9 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (52.65) is significantly better than Ligand B (84.73). For CNS targets, we want TPSA <= 90, and A is comfortably within that range, while B is approaching the upper limit.

**3. logP:** Both ligands have good logP values (2.33 and 2.00), falling within the optimal 1-3 range.

**4. H-Bond Donors:** Both ligands have acceptable HBD counts (1 and 2 respectively), well below the threshold of 5.

**5. H-Bond Acceptors:** Ligand A (3) is better than Ligand B (6), both are below the 10 threshold.

**6. QED:** Both ligands have similar QED values (0.802 and 0.768), indicating good drug-likeness.

**7. DILI:** Ligand A (7.794) has a much lower DILI risk than Ligand B (61.38). This is a significant advantage for A.

**8. BBB:** Both ligands have excellent BBB penetration (87.941 and 80.574), exceeding the desirable >70 threshold for CNS targets.

**9. Caco-2 Permeability:** Ligand A (-4.714) is better than Ligand B (-5.31), higher values indicate better intestinal absorption.

**10. Aqueous Solubility:** Ligand A (-2.033) is better than Ligand B (-2.72), higher values indicate better solubility.

**11. hERG Inhibition:** Both ligands have low hERG inhibition risk (0.37 and 0.521).

**12. Microsomal Clearance:** Ligand A (35.963) has a higher (worse) microsomal clearance than Ligand B (19.977). This suggests Ligand B is more metabolically stable.

**13. In vitro Half-Life:** Ligand B (36.238) has a much longer in vitro half-life than Ligand A (-7.101). This is a significant advantage for B.

**14. P-gp Efflux:** Both ligands have low P-gp efflux liability (0.047 and 0.11).

**15. Binding Affinity:** Both ligands have very similar and excellent binding affinities (-8.5 and -8.6 kcal/mol). The difference is negligible.

**Overall Assessment:**

Ligand A excels in TPSA, DILI risk, Caco-2 permeability, and solubility. Ligand B has better metabolic stability (lower Cl_mic) and a longer half-life. Given the GPCR-specific priorities, the lower TPSA and DILI risk of Ligand A are particularly important. While metabolic stability is important, the strong binding affinity of both ligands mitigates some concern about Ligand A's slightly higher clearance. The slightly better solubility and permeability of A also contribute to a more favorable profile.

Output:
1
2025-04-17 06:03:02,634 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (351.403 and 348.443 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (96.97) is better than Ligand B (59.08) as it is closer to the optimal range for CNS targets (<=90). Ligand B is excellent.

**logP:** Ligand B (1.375) is within the optimal range (1-3), while Ligand A (-0.307) is slightly below, potentially hindering permeation.

**H-Bond Donors/Acceptors:** Ligand A has 2 HBD and 5 HBA, while Ligand B has 0 HBD and 4 HBA. Both are within acceptable limits.

**QED:** Both ligands have good QED scores (0.614 and 0.72), indicating good drug-like properties.

**DILI:** Both ligands have low DILI risk (35.789 and 33.812 percentile), which is favorable.

**BBB:** Ligand B (60.644%) has a significantly better BBB penetration score than Ligand A (48.895%). This is a crucial advantage for a CNS target like DRD2.

**Caco-2 Permeability:** Ligand A (-5.323) and Ligand B (-4.397) both have negative values, which is unusual. It's difficult to interpret without knowing the scale, but lower (more negative) values generally indicate lower permeability.

**Aqueous Solubility:** Both ligands have poor aqueous solubility (-1.413 and -1.522). This could pose formulation challenges.

**hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.096 and 0.173), which is excellent.

**Microsomal Clearance:** Ligand A (-5.143) has a lower (better) microsomal clearance than Ligand B (31.681), suggesting greater metabolic stability.

**In vitro Half-Life:** Both have short half-lives (-12.63 and -11.729).

**P-gp Efflux:** Both ligands show very low P-gp efflux liability (0.022 and 0.028), which is good for CNS penetration.

**Binding Affinity:** Ligand A (-9.3 kcal/mol) has a significantly stronger binding affinity than Ligand B (-8.1 kcal/mol). This is a substantial advantage, potentially outweighing some of the ADME drawbacks.

**Overall Assessment:**

While Ligand B has better BBB penetration and logP, Ligand A's significantly stronger binding affinity (-9.3 vs -8.1 kcal/mol) is a major advantage, especially for a GPCR target. The difference in affinity is >1.5 kcal/mol, which, as per the guidelines, can outweigh minor ADME drawbacks. Ligand A also has better metabolic stability. The solubility and Caco-2 permeability are concerns for both, but the affinity advantage of Ligand A is compelling.

Output:
1
2025-04-17 06:03:02,635 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (359.403 and 349.431 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Both ligands have TPSA values (78.63 and 79.9) that are above the optimal <90 for CNS targets, but not drastically so. This is a minor concern.

**3. logP:** Ligand A (3.486) is optimal, while Ligand B (2.096) is slightly low, potentially impacting membrane permeability.

**4. H-Bond Donors:** Ligand A (0) is excellent, while Ligand B (2) is acceptable.

**5. H-Bond Acceptors:** Ligand A (7) is good, while Ligand B (4) is also good.

**6. QED:** Both ligands have good QED scores (0.495 and 0.79), indicating reasonable drug-likeness. Ligand B is better.

**7. DILI:** Ligand A (94.3) has a significantly higher DILI risk than Ligand B (47.77). This is a major concern for Ligand A.

**8. BBB:** Ligand B (71.384) has a better BBB penetration score than Ligand A (60.45), which is crucial for a CNS target like DRD2.

**9. Caco-2 Permeability:** Ligand A (-4.617) has worse Caco-2 permeability than Ligand B (-4.781). Both are negative, indicating poor permeability.

**10. Aqueous Solubility:** Ligand A (-4.156) has worse solubility than Ligand B (-2.063).

**11. hERG Inhibition:** Both ligands have low hERG inhibition risk (0.153 and 0.34).

**12. Microsomal Clearance:** Ligand B (4.354) has significantly lower microsomal clearance than Ligand A (46.601), suggesting better metabolic stability.

**13. In vitro Half-Life:** Ligand B (39.91) has a much longer in vitro half-life than Ligand A (0.87).

**14. P-gp Efflux:** Ligand A (0.765) has higher P-gp efflux than Ligand B (0.009), which is undesirable for CNS penetration.

**15. Binding Affinity:** Ligand A (-8.5 kcal/mol) has a slightly better binding affinity than Ligand B (-7.6 kcal/mol). However, the difference is less than 1.5 kcal/mol, and can be outweighed by other factors.

**Overall Assessment:**

Ligand B is significantly better overall. While Ligand A has a slightly better binding affinity, Ligand B excels in crucial ADME properties for a CNS-targeting GPCR: lower DILI risk, better BBB penetration, improved metabolic stability (lower Cl_mic, longer t1/2), lower P-gp efflux, and better solubility. The slightly lower logP of Ligand B is a minor concern compared to the significant advantages it holds in other areas.

Output:
1
2025-04-17 06:03:02,635 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (389.807 and 374.522 Da) fall within the ideal range of 200-500 Da.

**TPSA:** Ligand A (72.47) is excellent, well below the 90 A^2 threshold for CNS targets. Ligand B (78.43) is still reasonable but less optimal.

**logP:** Ligand A (3.42) is at the upper end of the optimal range (1-3), while Ligand B (2.172) is closer to the lower end. Both are acceptable, but a slightly higher logP can be beneficial for CNS penetration.

**H-Bond Donors/Acceptors:** Ligand A has 1 HBD and 5 HBA, while Ligand B has 3 HBD and 4 HBA. Both are within acceptable limits (<=5 HBD and <=10 HBA).

**QED:** Ligand A (0.793) has a better QED score than Ligand B (0.541), indicating a more drug-like profile.

**DILI:** Ligand A (93.292) has a significantly higher DILI risk than Ligand B (21.171). This is a major concern for Ligand A.

**BBB:** Both ligands have similar BBB penetration (Ligand A: 68.282, Ligand B: 67.158). Neither exceeds the desirable >70 percentile, but they are comparable.

**Caco-2 Permeability:** Ligand A (-4.303) shows poor Caco-2 permeability, suggesting poor intestinal absorption. Ligand B (-5.258) is also poor, but slightly worse.

**Aqueous Solubility:** Ligand A (-5.377) has very poor aqueous solubility, which could hinder formulation and bioavailability. Ligand B (-2.804) is better, but still not ideal.

**hERG Inhibition:** Both ligands show low hERG inhibition risk (Ligand A: 0.503, Ligand B: 0.56).

**Microsomal Clearance:** Ligand A (64.521) has a higher microsomal clearance than Ligand B (11.425), suggesting faster metabolism and potentially lower *in vivo* exposure.

**In vitro Half-Life:** Ligand A (110.724) has a longer half-life than Ligand B (5.086).

**P-gp Efflux:** Both ligands show low P-gp efflux liability (Ligand A: 0.513, Ligand B: 0.286).

**Binding Affinity:** Ligand A (-8.8 kcal/mol) has a significantly stronger binding affinity than Ligand B (-7.8 kcal/mol). This is a substantial advantage.

**Overall Assessment:**

Ligand A has a much stronger binding affinity and a better QED score and longer half-life. However, its high DILI risk, poor solubility, and poor Caco-2 permeability are significant liabilities. Ligand B has a lower DILI risk, better solubility, and a slightly better P-gp efflux profile. However, its binding affinity is weaker, and its half-life is very short.

Given the GPCR-specific priorities, the strong binding affinity of Ligand A is a major advantage that could potentially outweigh some of its ADME drawbacks *if* those can be addressed through further optimization. The DILI risk is the biggest concern. While both have suboptimal BBB penetration, the higher affinity of A might still translate to sufficient target engagement.

Output:
1
2025-04-17 06:03:02,635 - INFO - Batch 249 complete. Total preferences: 3984
2025-04-17 06:03:02,635 - INFO - Processing batch 250/512...
2025-04-17 06:03:43,233 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (346.45 & 356.46 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (58.2) is higher than Ligand B (40.62). For a CNS target like DRD2, TPSA < 90 is preferred, both are within this range, but B is better.

**3. logP:** Both ligands have a logP around 3.3 (3.393 & 3.309), which is optimal (1-3).

**4. H-Bond Donors:** Ligand A has 2 HBD, while Ligand B has 0. Both are acceptable (<=5).

**5. H-Bond Acceptors:** Both ligands have 2 HBA, which is well within the acceptable range (<=10).

**6. QED:** Both ligands have a QED > 0.7, indicating good drug-likeness.

**7. DILI:** Both ligands have low DILI risk (23.89 & 23.19 percentile), which is favorable.

**8. BBB:** Ligand B (97.21%) significantly outperforms Ligand A (81.70%) in BBB penetration. This is *crucial* for a CNS target like DRD2.

**9. Caco-2 Permeability:** Ligand A (-4.565) and Ligand B (-4.416) have similar, and poor, Caco-2 permeability. This is a potential concern for oral bioavailability.

**10. Aqueous Solubility:** Ligand A (-3.852) and Ligand B (-3.066) have similar, and poor, aqueous solubility. This could pose formulation challenges.

**11. hERG Inhibition:** Both ligands show low hERG inhibition liability (0.635 & 0.637), which is good.

**12. Microsomal Clearance:** Ligand B (30.42) has significantly lower microsomal clearance than Ligand A (77.97), indicating better metabolic stability.

**13. In vitro Half-Life:** Ligand A (17.42) has a positive half-life, while Ligand B (-17.99) has a negative half-life, which is not realistic. This is a major red flag for Ligand B.

**14. P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.254 & 0.251), which is favorable for CNS penetration.

**15. Binding Affinity:** Ligand A (-9.2 kcal/mol) has a *much* stronger binding affinity than Ligand B (0.0 kcal/mol). This is a substantial advantage.

**Overall Assessment:**

While Ligand B has better BBB penetration and metabolic stability, the extremely poor binding affinity (0.0 kcal/mol) is a deal-breaker. A binding affinity of 0 kcal/mol suggests no significant interaction with the target. Ligand A, despite slightly lower BBB and higher clearance, has a very strong binding affinity (-9.2 kcal/mol), which is the most important factor for initial hit selection. The negative half-life for Ligand B is also a major concern, indicating a potential issue with the data or the molecule itself.

Output:
1
2025-04-17 06:03:43,233 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (340.47 and 347.42 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (40.62) is significantly better than Ligand B (97.61). For CNS targets, TPSA should be <=90, so Ligand A is much more favorable.

**logP:** Ligand A (2.892) is optimal (1-3), while Ligand B (0.936) is a bit low, potentially hindering permeability.

**H-Bond Donors/Acceptors:** Ligand A (0 HBD, 2 HBA) is preferable to Ligand B (2 HBD, 6 HBA). Lower values generally improve permeability.

**QED:** Both ligands have good QED scores (0.773 and 0.8), indicating good drug-like properties.

**DILI:** Ligand A (17.371) has a much lower DILI risk than Ligand B (38.348).

**BBB:** Ligand A (80.419) has a significantly better BBB penetration score than Ligand B (45.638). This is *critical* for a CNS target like DRD2.

**Caco-2 Permeability:** Ligand A (-4.609) is better than Ligand B (-5.22), indicating better intestinal absorption.

**Aqueous Solubility:** Ligand A (-2.656) is better than Ligand B (-1.455).

**hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.621 and 0.138).

**Microsomal Clearance:** Ligand A (50.521) has higher clearance than Ligand B (-9.072), suggesting lower metabolic stability. However, the negative value for B is unusual and might indicate a very stable compound.

**In vitro Half-Life:** Ligand A (-24.207) has a negative half-life, which is not physically possible and suggests a problem with the data. Ligand B (17.806) has a reasonable half-life.

**P-gp Efflux:** Ligand A (0.404) has lower P-gp efflux liability than Ligand B (0.03), which is favorable for CNS penetration.

**Binding Affinity:** Both ligands have similar, strong binding affinities (-9.1 and -8.4 kcal/mol). The difference of 0.7 kcal/mol is not substantial enough to outweigh the other significant differences.

**Overall Assessment:**

Ligand A is significantly better overall, primarily due to its superior TPSA, logP, BBB penetration, DILI risk, and P-gp efflux. While its microsomal clearance is a concern, the other advantages, particularly the excellent BBB score, make it a much more promising candidate for a CNS-targeting drug like a DRD2 ligand. The negative half-life for ligand A is a red flag, but the other properties are so much better that it still appears to be the better candidate.

Output:
1
2025-04-17 06:03:43,234 - INFO - Reasoning:

Let's analyze Ligand A and Ligand B based on the provided guidelines, prioritizing GPCR-specific properties (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (349.39 and 345.44 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (116.76) is higher than Ligand B (69.72). For a CNS target like DRD2, TPSA should be <= 90. Ligand B is significantly better here.

**logP:** Ligand A (-0.188) is quite low, potentially hindering membrane permeability. Ligand B (0.764) is within the optimal 1-3 range. Ligand B is superior.

**H-Bond Donors/Acceptors:** Ligand A has 4 HBD and 5 HBA, while Ligand B has 1 HBD and 3 HBA. Both are acceptable, but Ligand B is slightly more favorable due to fewer hydrogen bonding groups, potentially improving permeability.

**QED:** Both ligands have good QED scores (0.509 and 0.607), indicating drug-like properties.

**DILI:** Ligand A (44.552) has a higher DILI risk than Ligand B (13.532). Lower is better, so Ligand B is preferred.

**BBB:** Ligand A (52.268) and Ligand B (61.38) both have moderate BBB penetration. However, for a CNS target, >70 is desirable. Ligand B is slightly better, but both are suboptimal.

**Caco-2 Permeability:** Ligand A (-5.347) has poor Caco-2 permeability, while Ligand B (-4.824) is also poor, but slightly better.

**Aqueous Solubility:** Both ligands have very poor aqueous solubility (-1.335 and -2.724). This could pose formulation challenges.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.128 and 0.119).

**Microsomal Clearance:** Both ligands have similar microsomal clearance (14.292 and 14.076), suggesting comparable metabolic stability.

**In vitro Half-Life:** Ligand A (10.774) has a slightly longer half-life than Ligand B (-2.317).

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.011 and 0.01).

**Binding Affinity:** Ligand A (-8.4 kcal/mol) has a significantly stronger binding affinity than Ligand B (-7.3 kcal/mol). This is a substantial advantage, exceeding the 1.5 kcal/mol threshold.

**Overall Assessment:**

While Ligand A has a superior binding affinity, its poor logP and TPSA values are significant drawbacks for a CNS-targeting GPCR. Ligand B, despite having a weaker binding affinity, possesses a much more favorable profile regarding TPSA, logP, and DILI risk. The better logP and TPSA of Ligand B suggest it will have better brain penetration and overall pharmacokinetic properties. The difference in binding affinity (-1.1 kcal/mol) is substantial, but the ADME properties of Ligand B are more promising for *in vivo* efficacy.

Output:
1
2025-04-17 06:03:43,234 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (366.527 and 346.471 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Both ligands have a TPSA of 67.43, which is above the optimal <90 for CNS targets, but not drastically so.

**3. logP:** Ligand A (3.273) is slightly higher than Ligand B (2.725), both within the optimal 1-3 range.

**4. H-Bond Donors:** Both have 2 HBD, which is acceptable.

**5. H-Bond Acceptors:** Ligand A has 4 HBA, and Ligand B has 3. Both are within the acceptable limit of <=10.

**6. QED:** Ligand A (0.778) has a significantly better QED score than Ligand B (0.277), indicating better overall drug-likeness.

**7. DILI:** Ligand A (31.02) has a slightly higher DILI risk than Ligand B (26.173), but both are well below the concerning threshold of 60.

**8. BBB:** Both ligands have good BBB penetration (Ligand A: 56.301, Ligand B: 57.929), but neither exceeds 70, which would be highly desirable for a CNS target.

**9. Caco-2 Permeability:** Both have negative Caco-2 values (-5.023 and -4.91), which is unusual and suggests poor permeability.

**10. Aqueous Solubility:** Both have negative solubility values (-3.053 and -3.888), indicating very poor aqueous solubility. This is a significant concern.

**11. hERG Inhibition:** Both have very low hERG inhibition risk (0.269 and 0.288).

**12. Microsomal Clearance:** Ligand A (54.687) has a significantly higher microsomal clearance than Ligand B (10.527), suggesting lower metabolic stability.

**13. In vitro Half-Life:** Ligand B (-2.24) has a negative half-life, which is not possible and suggests an issue with the data. Ligand A (23.997) has a reasonable half-life.

**14. P-gp Efflux:** Both have very low P-gp efflux liability (0.078 and 0.162).

**15. Binding Affinity:** Ligand A (-8.1 kcal/mol) has a substantially stronger binding affinity than Ligand B (0.0 kcal/mol). This is a crucial difference.

**Overall Assessment:**

Ligand A is clearly superior due to its significantly stronger binding affinity (-8.1 vs 0.0 kcal/mol). While both have issues with solubility and Caco-2 permeability, a strong binding affinity can sometimes compensate for these drawbacks, especially if formulation strategies can be employed to address solubility. Ligand A also has a better QED score and a more reasonable in vitro half-life. Ligand B's negative half-life is a major red flag. The higher metabolic clearance of Ligand A is a concern, but less critical than the lack of binding affinity in Ligand B.

Output:
1
2025-04-17 06:03:43,234 - INFO - Reasoning:

Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (343.39 and 348.49 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (109.14) is higher than the preferred <90 for CNS targets, while Ligand B (58.64) is well within the desired range. This is a significant advantage for Ligand B.

**3. logP:** Both ligands have acceptable logP values (1.22 and 2.51), falling within the 1-3 range. Ligand B is slightly better.

**4. H-Bond Donors:** Ligand A has 3 HBD, acceptable. Ligand B has 1 HBD, also acceptable.

**5. H-Bond Acceptors:** Ligand A has 6 HBA, acceptable. Ligand B has 3 HBA, also acceptable.

**6. QED:** Both ligands have similar and good QED values (0.756 and 0.777), indicating good drug-like properties.

**7. DILI:** Ligand A (50.10) has a slightly higher DILI risk than Ligand B (11.13), but both are below the concerning threshold of 60.

**8. BBB:** This is a crucial parameter for a CNS target like DRD2. Ligand A has a BBB percentile of 36.45, which is below the desirable >70. Ligand B has a significantly better BBB percentile of 79.53, making it much more likely to reach the target in the brain.

**9. Caco-2 Permeability:** Ligand A (-5.117) and Ligand B (-4.553) both have negative values, which is unusual and suggests poor permeability. However, the scale isn't specified, so it's hard to interpret.

**10. Aqueous Solubility:** Both ligands have negative solubility values (-3.079 and -2.448), indicating poor aqueous solubility. This could be a formulation challenge, but not a deal-breaker if other properties are favorable.

**11. hERG Inhibition:** Both ligands have low hERG inhibition risk (0.132 and 0.282).

**12. Microsomal Clearance:** Ligand A (9.93) has lower microsomal clearance than Ligand B (33.95), suggesting better metabolic stability.

**13. In vitro Half-Life:** Ligand A (-27.04) has a more negative half-life, which is unusual. Ligand B (-3.28) is more reasonable.

**14. P-gp Efflux:** Both ligands have low P-gp efflux liability (0.004 and 0.062), which is good for CNS penetration.

**15. Binding Affinity:** Ligand B (-8.4 kcal/mol) has a slightly better binding affinity than Ligand A (-7.6 kcal/mol). While both are good, the 0.8 kcal/mol difference is significant and could outweigh some of the ADME drawbacks of Ligand A.

**Overall Assessment:**

Ligand B is the more promising candidate. Its superior BBB penetration, lower TPSA, and slightly better binding affinity are critical advantages for a CNS-targeting GPCR like DRD2. While Ligand A has better metabolic stability, the poor BBB penetration is a major drawback. The slightly better affinity of Ligand B further strengthens its position.

Output:
1
2025-04-17 06:03:43,234 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (351.451 and 334.419 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (82.86) is excellent for CNS penetration, well below the 90 A^2 threshold. Ligand B (44.95) is also very good.

**logP:** Ligand A (-0.635) is a bit low, potentially hindering membrane permeability. Ligand B (3.412) is almost ideal.

**H-Bond Donors/Acceptors:** Ligand A (2 HBD, 7 HBA) and Ligand B (1 HBD, 3 HBA) both have reasonable numbers of H-bond donors and acceptors.

**QED:** Both ligands have acceptable QED values (0.751 and 0.673, respectively), indicating good drug-like properties.

**DILI:** Both ligands have low DILI risk (23.497 and 22.993 percentile), which is favorable.

**BBB:** This is a critical parameter for a CNS target. Ligand B (77.627) has a significantly better BBB percentile than Ligand A (31.02).

**Caco-2 Permeability:** Ligand A (-5.213) has poor Caco-2 permeability, while Ligand B (-4.744) is also low, but comparatively better.

**Aqueous Solubility:** Ligand A (0.264) has very poor aqueous solubility. Ligand B (-3.314) also has poor solubility, but is slightly better than A.

**hERG:** Both ligands have low hERG inhibition liability (0.201 and 0.819), which is good.

**Microsomal Clearance:** Ligand A (-44.356) has a much lower (better) microsomal clearance than Ligand B (44.082), indicating greater metabolic stability.

**In vitro Half-Life:** Ligand A (23.212 hours) has a significantly longer half-life than Ligand B (6.161 hours).

**P-gp Efflux:** Ligand A (0.007) has very low P-gp efflux, which is excellent for CNS penetration. Ligand B (0.377) has slightly higher efflux.

**Binding Affinity:** Ligand B (-9.0 kcal/mol) has a substantially stronger binding affinity than Ligand A (-7.1 kcal/mol). This is a >1.9 kcal/mol difference, which is very significant and can outweigh some ADME drawbacks.

**Overall Assessment:**

Ligand B is the stronger candidate. While both have issues with solubility and Caco-2 permeability, Ligand B's superior BBB penetration and significantly higher binding affinity are decisive. The better logP value also contributes to its favorability. Although Ligand A has better metabolic stability and lower P-gp efflux, the binding affinity difference is too large to ignore, especially for a GPCR target where potency is paramount.

Output:
1
2025-04-17 06:03:43,234 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B against the provided guidelines, prioritizing GPCR-specific properties (BBB, logP, Pgp, TPSA, and affinity) for DRD2.

**Molecular Weight:** Both ligands (344.419 and 352.454 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (93.84) is slightly above the optimal <90 for CNS targets, but still reasonable. Ligand B (78.09) is well within the desired range.

**logP:** Both ligands have acceptable logP values (1.016 and 2.55), falling within the 1-3 range.

**H-Bond Donors/Acceptors:** Both have 2 HBD and acceptable HBA counts (6 and 3 respectively), satisfying the <5 HBD and <10 HBA criteria.

**QED:** Both ligands have QED values above 0.5 (0.733 and 0.635), indicating good drug-likeness.

**DILI:** Both ligands have similar DILI risk (59.442 and 54.944), both falling under the acceptable <60 threshold.

**BBB:** This is a crucial parameter for DRD2. Ligand B (77.627) has a significantly higher BBB percentile than Ligand A (47.111). This is a major advantage for Ligand B.

**Caco-2 Permeability:** Both have negative Caco-2 values (-5.167 and -4.881). These values are unusual and suggest poor permeability. However, the scale isn't clearly defined, so it's hard to interpret these values.

**Aqueous Solubility:** Both ligands have negative solubility values (-2.468 and -2.846), which is also unusual. It suggests poor solubility.

**hERG:** Both ligands have low hERG inhibition liability (0.033 and 0.604), which is favorable.

**Microsomal Clearance:** Ligand A (34.267) has lower microsomal clearance than Ligand B (42.359), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand B (21.282) has a longer in vitro half-life than Ligand A (14.618).

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.052 and 0.169), which is good for CNS penetration.

**Binding Affinity:** Both ligands have the same binding affinity (-8.0 kcal/mol), which is excellent.

**Conclusion:**

While Ligand A has slightly better metabolic stability (lower Cl_mic), Ligand B is significantly better in terms of BBB penetration (77.627 vs 47.111). Given that DRD2 is a CNS target, BBB penetration is paramount. The similar binding affinities make the BBB difference the deciding factor.

Output:
1
2025-04-17 06:03:43,235 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 drug candidates, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (338.371 Da) is slightly lower, which could be beneficial for permeability, but both are acceptable.

**TPSA:** Ligand A (99.93) is higher than Ligand B (58.64). For CNS targets, we ideally want TPSA <= 90. Ligand A is marginally above this, while Ligand B is well within the desired range. This favors Ligand B.

**logP:** Both ligands have good logP values (Ligand A: 1.287, Ligand B: 2.052), falling within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A has 2 HBD and 6 HBA, while Ligand B has 1 HBD and 4 HBA. Both are within acceptable limits (<=5 HBD and <=10 HBA).

**QED:** Both ligands have good QED scores (Ligand A: 0.705, Ligand B: 0.782), indicating good drug-like properties.

**DILI:** Ligand A has a higher DILI risk (82.396%) than Ligand B (35.091%). This is a significant advantage for Ligand B.

**BBB:** Ligand B (71.888%) has a significantly better BBB penetration score than Ligand A (26.638%). This is *critical* for a CNS target like DRD2 and strongly favors Ligand B.

**Caco-2 Permeability:** Ligand A (-5.471) has a worse Caco-2 permeability than Ligand B (-4.95). Both are negative, but B is better.

**Aqueous Solubility:** Both have poor aqueous solubility (-3.23 and -3.596). This is a concern for both, but not a deciding factor.

**hERG Inhibition:** Both ligands show low hERG inhibition risk (Ligand A: 0.242, Ligand B: 0.456).

**Microsomal Clearance:** Ligand A (-3.52) has a lower (better) microsomal clearance than Ligand B (41.696). This suggests better metabolic stability for Ligand A.

**In vitro Half-Life:** Ligand B (14.534 hours) has a significantly longer in vitro half-life than Ligand A (2.39 hours). This is a major advantage for Ligand B.

**P-gp Efflux:** Ligand A (0.028) has a lower P-gp efflux liability than Ligand B (0.193). Lower is better, favoring Ligand A.

**Binding Affinity:** Ligand B (-7.1 kcal/mol) has a slightly better binding affinity than Ligand A (-8.2 kcal/mol). While A is slightly better, the difference is not substantial enough to outweigh other factors.

**Overall Assessment:**

Ligand B is the stronger candidate. While Ligand A has slightly better affinity and lower P-gp efflux, Ligand B excels in crucial areas for a CNS GPCR target: significantly better BBB penetration, lower DILI risk, and a longer in vitro half-life. Its TPSA is also much more favorable. The improved BBB is the most important factor, as it directly addresses the need for CNS exposure.

Output:
1
2025-04-17 06:03:43,235 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (343.431 and 349.435 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (86.36) is better than Ligand B (80.56), both are below the 90 A^2 threshold desirable for CNS targets.

**3. logP:** Ligand B (1.192) is better than Ligand A (0.209). Ligand A is quite low, potentially hindering membrane permeability. Ligand B is within the optimal 1-3 range.

**4. H-Bond Donors:** Ligand A (3) is higher than Ligand B (0). Lower is generally preferred, but both are acceptable.

**5. H-Bond Acceptors:** Ligand A (5) and Ligand B (6) are both acceptable, below the 10 threshold.

**6. QED:** Both ligands have good QED scores (0.73 and 0.798), indicating drug-like properties.

**7. DILI:** Ligand A (27.142) has a significantly lower DILI risk than Ligand B (42.924). This is a substantial advantage for Ligand A.

**8. BBB:** Ligand B (70.88) has a much better BBB penetration score than Ligand A (49.826). This is a critical factor for a CNS target like DRD2.

**9. Caco-2 Permeability:** Ligand A (-5.546) is significantly worse than Ligand B (-4.737). Lower values suggest poor permeability.

**10. Aqueous Solubility:** Both ligands have very poor aqueous solubility (-1.611 and -1.585). This could pose formulation challenges.

**11. hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.388 and 0.089).

**12. Microsomal Clearance:** Ligand A (-37.208) has a much lower (better) microsomal clearance than Ligand B (20.37). This suggests greater metabolic stability for Ligand A.

**13. In vitro Half-Life:** Ligand A (19.551) has a longer half-life than Ligand B (1.019).

**14. P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.003 and 0.045).

**15. Binding Affinity:** Both ligands have identical binding affinities (-8.6 kcal/mol), which is excellent.

**Overall Assessment:**

While Ligand B has a significantly better BBB score and logP, Ligand A demonstrates superior safety (DILI), metabolic stability (Cl_mic), and half-life. The binding affinity is the same for both. The poor logP of Ligand A is a concern, but the strong affinity might compensate. Given the importance of CNS penetration for DRD2, Ligand B initially appears more promising. However, the significantly lower DILI risk and better metabolic profile of Ligand A are crucial factors. Considering the balance, and the potential to mitigate the logP issue through further optimization, Ligand A is slightly favored.

Output:
1
2025-04-17 06:03:43,235 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 drug candidates, considering the provided guidelines and GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (354.401 and 348.531 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (58.44) is better than Ligand B (49.41). Both are below the 90 A^2 threshold desirable for CNS targets, which is excellent.

**3. logP:** Ligand A (1.694) is within the optimal 1-3 range. Ligand B (3.914) is pushing the upper limit but still acceptable.

**4. H-Bond Donors:** Ligand A (0) is preferable to Ligand B (1). Fewer HBDs generally improve permeability.

**5. H-Bond Acceptors:** Ligand A (4) is slightly higher than Ligand B (2), but both are within the acceptable limit of 10.

**6. QED:** Ligand A (0.827) is significantly better than Ligand B (0.609), indicating a more drug-like profile.

**7. DILI:** Ligand A (34.432) has a much lower DILI risk than Ligand B (11.206), which is a significant advantage.

**8. BBB:** Ligand A (92.943) has a substantially higher BBB penetration percentile than Ligand B (80.962). This is *critical* for a CNS target like DRD2.

**9. Caco-2 Permeability:** Ligand A (-4.531) and Ligand B (-4.412) are both very poor. This is a concern, but can be mitigated if the compound shows good BBB penetration.

**10. Aqueous Solubility:** Ligand A (-1.77) is better than Ligand B (-4.352).

**11. hERG Inhibition:** Both ligands show low hERG inhibition risk (0.516 and 0.553, respectively).

**12. Microsomal Clearance:** Ligand A (29.086) has a lower (better) microsomal clearance than Ligand B (106.491), indicating greater metabolic stability.

**13. In vitro Half-Life:** Ligand A (-26.67) has a much longer in vitro half-life than Ligand B (7.654).

**14. P-gp Efflux:** Ligand A (0.052) has a much lower P-gp efflux liability than Ligand B (0.283), which is crucial for CNS penetration.

**15. Binding Affinity:** Ligand B (-7.9 kcal/mol) has a slightly better binding affinity than Ligand A (-8.7 kcal/mol). However, the difference is not substantial enough to outweigh the numerous advantages of Ligand A.

**Overall Assessment:**

Ligand A consistently outperforms Ligand B across most critical ADME properties, especially those important for CNS GPCR targets (BBB, Pgp, TPSA). While Ligand B has slightly better binding affinity, the superior BBB penetration, lower DILI risk, better metabolic stability, and lower P-gp efflux of Ligand A make it a much more promising drug candidate. The poor Caco-2 permeability is a concern for both, but the strong BBB penetration of Ligand A suggests it can still achieve sufficient CNS exposure.

Output:
1
2025-04-17 06:03:43,235 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 drug candidates, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (350.344 and 344.419 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (70.71) is excellent, well below the 90 A^2 threshold for CNS targets. Ligand B (121.34) is higher, but still within acceptable limits for some CNS penetration, though less ideal.

**logP:** Ligand A (2.905) is optimal (1-3). Ligand B (-0.086) is quite low, potentially hindering membrane permeability and brain penetration.

**H-Bond Donors/Acceptors:** Ligand A (HBD=1, HBA=4) is favorable. Ligand B (HBD=3, HBA=5) is also acceptable, though slightly higher.

**QED:** Both ligands have good QED scores (0.922 and 0.7), indicating drug-like properties.

**DILI:** Both ligands have similar, acceptable DILI risk (42.691 and 44.707).

**BBB:** Ligand A (76.464) shows good BBB penetration, exceeding the 70% threshold. Ligand B (32.183) has poor predicted BBB penetration, a significant drawback for a CNS target.

**Caco-2 Permeability:** Ligand A (-4.532) is negative, indicating poor permeability. Ligand B (-5.804) is also negative and worse.

**Aqueous Solubility:** Ligand A (-3.816) is poor. Ligand B (-1.154) is also poor.

**hERG Inhibition:** Both ligands show low hERG inhibition risk (0.358 and 0.593).

**Microsomal Clearance:** Ligand A (41.103) is moderate. Ligand B (-23.254) is negative, indicating potentially very low clearance and high metabolic stability.

**In vitro Half-Life:** Ligand A (-13.729) is negative, indicating a very long half-life. Ligand B (-2.185) is also negative, indicating a long half-life.

**P-gp Efflux:** Both ligands show low P-gp efflux (0.144 and 0.006), which is favorable for CNS exposure.

**Binding Affinity:** Both ligands have similar, strong binding affinities (-9.4 and -8.7 kcal/mol). The difference is less than 1.5 kcal/mol, so it's not a deciding factor.

**Conclusion:**

Considering the GPCR-specific priorities, Ligand A is the more promising candidate. Its significantly better BBB penetration (76.5% vs 32.2%) and optimal logP value (2.9 vs -0.1) are crucial for CNS drug development. While both have poor Caco-2 permeability and solubility, the CNS target mitigates the importance of Caco-2. The similar affinities and acceptable safety profiles (DILI, hERG) don't differentiate them significantly.

Output:
0
2025-04-17 06:03:43,236 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (352.391 and 358.507 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (110.72) is borderline for CNS penetration, being slightly above the preferred <90 threshold. Ligand B (42.43) is excellent, well below 90.

**logP:** Ligand A (0.022) is very low, potentially hindering membrane permeability and CNS penetration. Ligand B (3.85) is within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A has 1 HBD and 7 HBA, which are acceptable. Ligand B has 0 HBD and 5 HBA, also acceptable.

**QED:** Both ligands have good QED scores (0.624 and 0.671), indicating drug-like properties.

**DILI:** Ligand A has a DILI risk of 63.358, which is moderately high. Ligand B has a much lower DILI risk of 37.263, which is preferable.

**BBB:** Ligand A has a BBB penetration of 59.868, which is below the desirable >70 for CNS targets. Ligand B has a BBB penetration of 68.709, which is better but still not optimal.

**Caco-2 Permeability:** Both have negative Caco-2 values (-4.77 and -4.892), which is unusual and suggests poor permeability. This is a red flag for both.

**Aqueous Solubility:** Both have negative solubility values (-0.919 and -4.654), also unusual and indicating poor solubility. This is another red flag for both.

**hERG Inhibition:** Ligand A (0.058) has very low hERG inhibition risk. Ligand B (0.901) has a moderate hERG risk.

**Microsomal Clearance:** Ligand A (67.396) has moderate clearance, while Ligand B (146.69) has high clearance, suggesting lower metabolic stability.

**In vitro Half-Life:** Ligand A (-20.516) has a very short half-life, while Ligand B (12.806) has a more reasonable half-life.

**P-gp Efflux:** Ligand A (0.011) has very low P-gp efflux, which is good for CNS penetration. Ligand B (0.404) has moderate P-gp efflux.

**Binding Affinity:** Ligand B (-7.7 kcal/mol) has significantly stronger binding affinity than Ligand A (-6.5 kcal/mol). This 1.2 kcal/mol difference is substantial and can outweigh some ADME drawbacks.

**Overall Assessment:**

Ligand B is the better candidate. While both have issues with Caco-2 and solubility, Ligand B's superior logP, significantly stronger binding affinity, lower DILI risk, and better (though still not ideal) BBB penetration outweigh its higher clearance and moderate P-gp efflux. Ligand A's very low logP and poor BBB penetration are major drawbacks for a CNS target. The stronger binding affinity of Ligand B is a critical advantage for a GPCR ligand.

Output:
1
2025-04-17 06:03:43,236 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 drug candidates, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (344.43 and 367.515 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (49.41) is excellent, well below the 90 A^2 threshold for CNS targets. Ligand B (71.53) is still reasonable, but less optimal, being above 60 A^2.

**logP:** Both ligands have logP values (2.901 and 2.481) within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Both ligands have acceptable HBD counts (1 each). Ligand B has a higher HBA count (5) compared to Ligand A (2), but both are within the acceptable limit of 10.

**QED:** Ligand A (0.893) has a significantly better QED score than Ligand B (0.728), indicating a more drug-like profile.

**DILI:** Ligand A (24.351) has a much lower DILI risk than Ligand B (32.067), suggesting better hepatotoxicity potential. Both are below the 40 threshold.

**BBB:** This is a crucial parameter for CNS targets. Ligand A (94.494) has an excellent BBB penetration percentile, exceeding the desirable >70 threshold. Ligand B (62.233) is considerably lower and less favorable for CNS penetration.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.647 and -4.814), which is unusual and suggests poor permeability. However, these values are on a log scale and are difficult to interpret without further context.

**Aqueous Solubility:** Both ligands have negative solubility values (-3.669 and -2.021), again suggesting poor solubility.

**hERG:** Both ligands have low hERG inhibition liability (0.847 and 0.548), which is good.

**Microsomal Clearance:** Ligand B (27.37) has a slightly lower microsomal clearance than Ligand A (22.006), suggesting slightly better metabolic stability.

**In vitro Half-Life:** Ligand A (-9.021) has a significantly longer in vitro half-life than Ligand B (6.036).

**P-gp Efflux:** Ligand A (0.221) has a much lower P-gp efflux liability than Ligand B (0.181), indicating better potential for CNS exposure.

**Binding Affinity:** Ligand B (-7.3 kcal/mol) has a slightly better binding affinity than Ligand A (-9.4 kcal/mol). However, the difference is not substantial enough to outweigh the significant ADME advantages of Ligand A.

**Overall Assessment:**

Ligand A is the superior candidate. While Ligand B has slightly better binding affinity, Ligand A excels in critical ADME properties for a CNS-targeting GPCR drug. Specifically, its significantly higher BBB penetration, lower DILI risk, better QED, lower P-gp efflux, and longer half-life are all highly favorable. The negative Caco-2 and solubility values are concerning for both, but the other advantages of Ligand A are more impactful.



Output:
0
2025-04-17 06:03:43,236 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (350.39 and 336.395 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (78.87) is better than Ligand B (64.59). Both are below the 90 A^2 threshold desirable for CNS targets, but A is closer to the upper limit.

**logP:** Ligand A (2.376) is within the optimal 1-3 range. Ligand B (4.28) is higher, potentially leading to solubility issues and off-target interactions.

**H-Bond Donors/Acceptors:** Ligand A (2 HBD, 4 HBA) and Ligand B (1 HBD, 6 HBA) both have acceptable numbers of H-bond donors and acceptors.

**QED:** Ligand A (0.855) has a significantly higher QED score than Ligand B (0.602), indicating a more drug-like profile.

**DILI:** Ligand A (36.603) has a much lower DILI risk than Ligand B (93.059). This is a major advantage for Ligand A.

**BBB:** Ligand A (74.796) has a good BBB penetration score, exceeding the 70% threshold for CNS targets. Ligand B (52.811) is significantly lower, raising concerns about CNS exposure.

**Caco-2 Permeability:** Ligand A (-5.106) and Ligand B (-4.644) both have negative values, which is unusual. It's difficult to interpret without knowing the scale. However, the values are similar.

**Aqueous Solubility:** Ligand A (-3.024) and Ligand B (-5.723) both have negative values, indicating poor solubility. Ligand B is worse.

**hERG Inhibition:** Ligand A (0.545) has a lower hERG inhibition risk than Ligand B (0.938).

**Microsomal Clearance:** Ligand A (15.357) has a lower microsomal clearance than Ligand B (45.905), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (-11.099) has a negative half-life, which is not possible. This is a red flag. Ligand B (79.677) has a long half-life, which is desirable.

**P-gp Efflux:** Ligand A (0.035) has very low P-gp efflux, which is excellent for CNS penetration. Ligand B (0.68) has moderate P-gp efflux.

**Binding Affinity:** Ligand B (-8.0) has a significantly stronger binding affinity than Ligand A (0.0). This is a substantial advantage for Ligand B, potentially outweighing some of its ADME drawbacks.

**Overall Assessment:**

Despite the negative half-life for Ligand A, its superior BBB penetration, lower DILI risk, lower logP, better QED, and lower P-gp efflux make it a more promising candidate. However, the very strong binding affinity of Ligand B is a significant factor. The negative half-life of Ligand A is a serious concern and needs further investigation. Given the importance of affinity for GPCRs, and the substantial difference in binding (-8.0 vs 0.0), Ligand B is the better candidate, *assuming the negative half-life of Ligand A is an error*.

Output:
1
2025-04-17 06:03:43,236 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (369.575 and 343.347 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (61.44) is significantly better than Ligand B (120.85). For CNS targets, we want TPSA <= 90, and A is comfortably within that, while B exceeds it.

**logP:** Both ligands have acceptable logP values (2.404 and 0.86), falling within the 1-3 range. However, Ligand B is on the lower side, potentially impacting permeability.

**H-Bond Donors/Acceptors:** Ligand A (HBD=2, HBA=4) and Ligand B (HBD=1, HBA=9) both meet the general guidelines (<=5 HBD, <=10 HBA).

**QED:** Both ligands have similar QED values (0.69 and 0.67), indicating good drug-likeness.

**DILI:** Ligand A (10.237) has a much lower DILI risk than Ligand B (88.639). This is a significant advantage for A.

**BBB:** Ligand A (59.946) has a better BBB percentile than Ligand B (50.33), though both are below the desirable >70 for CNS targets.

**Caco-2 Permeability:** Ligand A (-5.502) has a more negative Caco-2 value, indicating lower permeability. Ligand B (-4.951) is slightly better.

**Aqueous Solubility:** Both ligands have poor aqueous solubility (-1.537 and -2.2). This could pose formulation challenges.

**hERG Inhibition:** Both ligands show low hERG inhibition liability (0.293 and 0.163), which is good.

**Microsomal Clearance:** Ligand A (14.869) has significantly lower microsomal clearance than Ligand B (33.055), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (23.39) has a longer half-life than Ligand B (14.696).

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.014 and 0.023).

**Binding Affinity:** Ligand B (-8.0 kcal/mol) has a slightly better binding affinity than Ligand A (-7.5 kcal/mol), but the difference is less than 1.5 kcal/mol.

**Overall Assessment:**

Considering the GPCR-specific priorities, Ligand A is the more promising candidate. While Ligand B has slightly better binding affinity and Caco-2 permeability, Ligand A excels in crucial areas for CNS drug development: significantly lower DILI risk, better BBB penetration, lower microsomal clearance (better metabolic stability), and a more favorable TPSA. The difference in binding affinity is not substantial enough to outweigh these advantages. The lower TPSA of Ligand A is particularly important for CNS penetration.

Output:
1
2025-04-17 06:03:43,236 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (344.415 and 351.531 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (87.32) is excellent for CNS penetration, being below the 90 A^2 threshold. Ligand B (38.77) is even better, significantly below the threshold.

**3. logP:** Ligand A (1.568) is within the optimal 1-3 range. Ligand B (4.539) is slightly above the optimal range, potentially leading to solubility issues or off-target interactions, but not drastically so.

**4. H-Bond Donors:** Ligand A (2) is good. Ligand B (0) is also acceptable.

**5. H-Bond Acceptors:** Ligand A (4) is good. Ligand B (3) is also acceptable.

**6. QED:** Both ligands have reasonable QED values (0.806 and 0.632), indicating good drug-like properties.

**7. DILI:** Ligand A (49.128) has a moderate DILI risk, while Ligand B (20.783) has a very low DILI risk, which is a significant advantage.

**8. BBB:** Ligand A (52.268) has moderate BBB penetration. Ligand B (90.461) has *excellent* BBB penetration, exceeding the desirable >70% threshold. This is a crucial factor for a CNS target like DRD2.

**9. Caco-2:** Both ligands have negative Caco-2 values (-5.035 and -4.575), which is unusual and suggests poor permeability. However, these values are on a scale where negative values can occur, and their absolute interpretation is difficult without knowing the scale's specifics.

**10. Solubility:** Both ligands have negative solubility values (-2.249 and -5.033), indicating poor aqueous solubility. This is a concern, but can be addressed through formulation strategies.

**11. hERG:** Both ligands have low hERG inhibition risk (0.615 and 0.738).

**12. Cl_mic:** Ligand A (4.315) has a lower microsomal clearance, suggesting better metabolic stability. Ligand B (104.523) has a high clearance, indicating rapid metabolism.

**13. t1/2:** Ligand A (-8.579) has a negative in vitro half-life, which is not physically possible and likely indicates an issue with the data or scale. Ligand B (2.335) has a short half-life.

**14. Pgp:** Both ligands have low P-gp efflux liability (0.018 and 0.72).

**15. Binding Affinity:** Ligand B (-7.6 kcal/mol) has a significantly stronger binding affinity than Ligand A (-0.0 kcal/mol). This is a major advantage, potentially outweighing some of the ADME drawbacks.

**Overall Assessment:**

Ligand B is the more promising candidate. While it has a higher logP and a higher Cl_mic, its *exceptional* BBB penetration and *significantly* stronger binding affinity are critical for a CNS GPCR target. The lower DILI risk is also a substantial benefit. The poor solubility and short half-life of Ligand B are addressable through formulation and structural modifications, respectively. Ligand A's negative half-life is a red flag, and its weak binding affinity is a major drawback.

Output:
1
2025-04-17 06:03:43,237 - INFO - Batch 250 complete. Total preferences: 4000
2025-04-17 06:03:43,237 - INFO - Processing batch 251/512...
2025-04-17 06:04:25,360 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (347.379 and 352.475 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (137.87) is marginally above the preferred <90 for CNS targets, but still reasonable. Ligand B (75.71) is excellent, well below 90.

**logP:** Both ligands (2.145 and 2.428) are within the optimal 1-3 range.

**H-Bond Donors:** Ligand A (4) is acceptable, while Ligand B (1) is even better, minimizing potential permeability issues.

**H-Bond Acceptors:** Both ligands (6 and 4) are below the 10 threshold.

**QED:** Both ligands have reasonable QED scores (0.483 and 0.609), with Ligand B being slightly more drug-like.

**DILI:** Ligand A (86.39) has a higher DILI risk than Ligand B (29.236), which is a significant concern.

**BBB:** Ligand A (48.236) has a lower BBB penetration percentile than Ligand B (51.725). While neither are exceptionally high, Ligand B is better.

**Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and suggests poor permeability. However, these values are on a different scale and may not be directly comparable.

**Aqueous Solubility:** Both have negative solubility values, which is also unusual.

**hERG Inhibition:** Both ligands show very low hERG inhibition liability (0.18 and 0.153), which is excellent.

**Microsomal Clearance:** Ligand B (83.602) has a considerably higher microsomal clearance than Ligand A (17.951), indicating lower metabolic stability.

**In vitro Half-Life:** Ligand A (22.957) has a longer in vitro half-life than Ligand B (-13.563), which is a positive attribute.

**P-gp Efflux:** Both ligands show very low P-gp efflux liability (0.032).

**Binding Affinity:** Ligand A (-9.1 kcal/mol) has a significantly stronger binding affinity than Ligand B (-6.8 kcal/mol). This is a substantial advantage.

**Overall Assessment:**

The most critical factor for a CNS GPCR target like DRD2 is BBB penetration and affinity. While neither ligand has outstanding BBB penetration, Ligand A's substantially higher binding affinity (-9.1 vs -6.8 kcal/mol) is a major advantage that could outweigh its slightly higher TPSA and DILI risk. The longer half-life of Ligand A is also beneficial. Ligand B has better DILI and TPSA, but the weaker binding affinity is a significant drawback. Given the importance of potency for GPCRs, the stronger binding of Ligand A makes it the more promising candidate.

Output:
1
2025-04-17 06:04:25,361 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (365.5 & 372.5 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (78.51) is slightly higher than Ligand B (75.27). Both are below the 90 A^2 threshold desirable for CNS targets, but Ligand B is preferable.

**3. logP:** Ligand A (1.94) is within the optimal 1-3 range. Ligand B (3.617) is at the higher end of the optimal range, but still acceptable.

**4. H-Bond Donors:** Both ligands have 2 HBD, which is within the acceptable limit of <=5.

**5. H-Bond Acceptors:** Ligand A has 4 HBA, and Ligand B has 3. Both are below the acceptable limit of <=10.

**6. QED:** Ligand A (0.691) has a better QED score than Ligand B (0.575), indicating a more drug-like profile.

**7. DILI:** Ligand A (33.5) has a slightly higher DILI risk than Ligand B (20.24), but both are well below the concerning threshold of 60.

**8. BBB:** Ligand B (71.811) has a significantly better BBB penetration percentile than Ligand A (62.97). This is a crucial factor for a CNS target like DRD2.

**9. Caco-2 Permeability:** Ligand A (-5.179) shows poor Caco-2 permeability, whereas Ligand B (-4.749) is slightly better, but still poor.

**10. Aqueous Solubility:** Ligand A (-2.178) has slightly better aqueous solubility than Ligand B (-3.438).

**11. hERG Inhibition:** Both ligands (0.391 and 0.35) show very low hERG inhibition risk.

**12. Microsomal Clearance:** Ligand B (83.521) has a higher microsomal clearance than Ligand A (36.809), suggesting faster metabolism and potentially lower exposure.

**13. In vitro Half-Life:** Ligand A (15.574) has a considerably longer in vitro half-life than Ligand B (-2.93).

**14. P-gp Efflux:** Both ligands (0.149 and 0.183) have low P-gp efflux liability.

**15. Binding Affinity:** Both ligands have the same binding affinity (-7.4 kcal/mol), which is excellent.

**Overall Assessment:**

While Ligand A has a better QED and longer half-life, Ligand B is superior due to its significantly better BBB penetration (71.8 vs 62.97) and lower DILI risk. The slightly higher logP of Ligand B is acceptable, and the difference in Caco-2 permeability is not as critical given the focus on CNS penetration. The longer half-life of Ligand A is a plus, but the improved CNS exposure potential of Ligand B outweighs this benefit.

Output:
1
2025-04-17 06:04:25,361 - INFO - Reasoning:

Let's analyze Ligand A and Ligand B for their potential as DRD2 drug candidates, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (352.431 and 348.531 Da) fall comfortably within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (77.1) is better than Ligand B (58.2). For CNS targets, we want TPSA <= 90, both are within this range, but A is closer to the upper limit.

**3. logP:** Ligand A (1.308) is optimal (1-3), while Ligand B (3.962) is approaching the upper limit. Higher logP can lead to off-target effects and solubility issues.

**4. H-Bond Donors:** Ligand A (1) is preferable to Ligand B (2). Fewer HBDs generally improve permeability.

**5. H-Bond Acceptors:** Ligand A (5) is preferable to Ligand B (2). Fewer HBAs generally improve permeability.

**6. QED:** Ligand A (0.811) is significantly better than Ligand B (0.464), indicating a more drug-like profile.

**7. DILI:** Both ligands have similar, relatively low DILI risk (25.979 and 27.181, respectively).

**8. BBB:** Ligand A (80.031) has a much better BBB penetration score than Ligand B (55.099). This is *critical* for a CNS target like DRD2.

**9. Caco-2 Permeability:** Ligand A (-4.39) is better than Ligand B (-4.748). Higher values are better.

**10. Aqueous Solubility:** Ligand A (-1.899) is better than Ligand B (-4.454). Higher values are better.

**11. hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.138 and 0.46, respectively).

**12. Microsomal Clearance:** Ligand A (23.854) has significantly lower microsomal clearance than Ligand B (64.305), suggesting better metabolic stability.

**13. In vitro Half-Life:** Ligand A (8.137) has a lower in vitro half-life than Ligand B (26.216).

**14. P-gp Efflux:** Ligand A (0.01) has a much lower P-gp efflux liability than Ligand B (0.206), which is highly desirable for CNS penetration.

**15. Binding Affinity:** Both ligands have excellent binding affinity (-7.3 and -7.4 kcal/mol), with Ligand B being slightly better. However, the difference is small and likely less important than the ADME advantages of Ligand A.

**Overall Assessment:**

Ligand A is clearly the superior candidate. While Ligand B has slightly better binding affinity, Ligand A excels in almost all ADME properties crucial for a CNS-targeting GPCR. Specifically, its significantly better BBB penetration, lower P-gp efflux, lower microsomal clearance, and higher QED make it much more likely to reach the target in the brain and exhibit favorable pharmacokinetic properties. The slightly lower half-life of Ligand A is a minor concern that could potentially be addressed through structural modifications.

Output:
1
2025-04-17 06:04:25,361 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (345.4 and 343.4 Da) fall comfortably within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (107.35) is better than Ligand B (117.42). For CNS targets, we want TPSA <= 90, so both are above this ideal, but A is closer.

**3. logP:** Ligand B (-0.302) is slightly lower than Ligand A (0.51). Both are a bit low, potentially hindering permeation, but A is preferable.

**4. H-Bond Donors:** Both have acceptable HBD counts (4 and 3 respectively), well below the limit of 5.

**5. H-Bond Acceptors:** Both have acceptable HBA counts (5 and 4 respectively), well below the limit of 10.

**6. QED:** Both ligands have similar and good QED values (0.612 and 0.615).

**7. DILI:** Ligand B (48.934) has a significantly lower DILI risk than Ligand A (65.491). This is a substantial advantage for Ligand B.

**8. BBB:** Ligand B (54.362) has a much better BBB penetration percentile than Ligand A (32.726). This is *critical* for a CNS target like DRD2, making Ligand B very attractive.

**9. Caco-2 Permeability:** Both have negative Caco-2 values (-5.092 and -5.009), which is unusual and suggests poor permeability. This is a concern for both.

**10. Aqueous Solubility:** Both have negative solubility values (-2.581 and -2.445), also unusual and suggesting poor solubility. This is a concern for both.

**11. hERG Inhibition:** Both have very low hERG inhibition risk (0.256 and 0.07).

**12. Microsomal Clearance:** Ligand A (-19.225) has significantly lower (better) microsomal clearance than Ligand B (-23.936), indicating better metabolic stability.

**13. In vitro Half-Life:** Ligand A (-8.417) has a longer in vitro half-life than Ligand B (-2.891).

**14. P-gp Efflux:** Both have very low P-gp efflux liability (0.051 and 0.005).

**15. Binding Affinity:** Ligand A (-9.6 kcal/mol) has a slightly better binding affinity than Ligand B (-8.3 kcal/mol). This is a 1.3 kcal/mol difference, which is significant.

**Overall Assessment:**

While Ligand A has better affinity and metabolic stability, Ligand B is superior in crucial areas for a CNS-targeting GPCR: BBB penetration and DILI risk. The difference in BBB is substantial. The slightly weaker affinity of Ligand B could potentially be optimized through further medicinal chemistry efforts, but improving BBB is much more challenging. The poor Caco-2 and solubility are concerning for both, but can be addressed with formulation strategies.

Output:
1
2025-04-17 06:04:25,361 - INFO - Reasoning:

Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (404.308 Da) is slightly higher than Ligand B (351.382 Da), but both are acceptable.

**2. TPSA:** Ligand A (74.25) is better than Ligand B (96.33). For CNS targets, we want TPSA <= 90. Ligand A is closer to this threshold, suggesting better CNS penetration potential.

**3. logP:** Ligand A (4.06) is at the higher end of the optimal range (1-3), while Ligand B (-0.246) is significantly below.  A very low logP like that of Ligand B can hinder membrane permeability. Ligand A is favored here.

**4. H-Bond Donors:** Both ligands have acceptable HBD counts (Ligand A: 3, Ligand B: 2), well within the limit of 5.

**5. H-Bond Acceptors:** Both ligands have acceptable HBA counts (Ligand A: 3, Ligand B: 6), within the limit of 10.

**6. QED:** Both ligands have good QED scores (Ligand A: 0.722, Ligand B: 0.763), indicating good drug-like properties.

**7. DILI:** Ligand B (72.741) has a higher DILI risk than Ligand A (55.487), although both are reasonably acceptable. Lower is better.

**8. BBB:** Both ligands have excellent BBB penetration (Ligand A: 73.711, Ligand B: 75.262), exceeding the desirable threshold of >70.

**9. Caco-2 Permeability:** Ligand A (-4.762) has a negative value, which is unusual and suggests very poor permeability. Ligand B (-5.055) is also poor, but similar.

**10. Aqueous Solubility:** Ligand A (-5.036) and Ligand B (-2.944) both have poor aqueous solubility.

**11. hERG Inhibition:** Both ligands have low hERG inhibition risk (Ligand A: 0.689, Ligand B: 0.349).

**12. Microsomal Clearance:** Ligand B (-1.532) has a negative clearance, which is not physically possible. This is a red flag and suggests an issue with the data or prediction method. Ligand A (41.758) has a reasonable clearance.

**13. In vitro Half-Life:** Ligand A (93.912) has a much longer half-life than Ligand B (6.95). This is a significant advantage.

**14. P-gp Efflux:** Ligand A (0.416) has lower P-gp efflux than Ligand B (0.032), which is favorable for CNS exposure.

**15. Binding Affinity:** Ligand A (-10.8 kcal/mol) has a significantly stronger binding affinity than Ligand B (-9.0 kcal/mol). This is a crucial advantage, exceeding the 1.5 kcal/mol difference threshold.

**Overall Assessment:**

Ligand A is the superior candidate. While both have poor solubility and Caco-2 permeability, Ligand A excels in key areas: significantly stronger binding affinity, better logP, lower DILI risk, a longer half-life, and lower P-gp efflux. The negative clearance value for Ligand B is a major concern and casts doubt on its overall profile. Despite the TPSA being slightly higher for Ligand A, the overall balance of properties, particularly the strong affinity and favorable CNS penetration parameters, makes it the more promising drug candidate.

Output:
1
2025-04-17 06:04:25,362 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (359.348 and 349.475 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (71.53) is better than Ligand B (69.72), both are below the 90 A^2 threshold for CNS targets.

**logP:** Ligand A (1.959) is optimal, while Ligand B (0.905) is slightly low, potentially hindering permeation.

**H-Bond Donors/Acceptors:** Both have 1 HBD and 4 HBA, which are within acceptable limits.

**QED:** Both ligands have good QED scores (0.808 and 0.774, respectively), indicating good drug-like properties.

**DILI:** Ligand A (52.772) has a lower DILI risk than Ligand B (18.922), which is preferable.

**BBB:** Ligand A (85.964) has a significantly higher BBB penetration percentile than Ligand B (61.342). This is *critical* for a CNS target like DRD2.

**Caco-2 Permeability:** Ligand A (-4.548) is better than Ligand B (-4.91), indicating better intestinal absorption.

**Aqueous Solubility:** Ligand A (-2.686) is better than Ligand B (-1.084), indicating better solubility.

**hERG:** Both ligands have very low hERG inhibition liability (0.472 and 0.095), which is excellent.

**Microsomal Clearance:** Ligand A (17.816) has a higher microsomal clearance than Ligand B (13.281), meaning it's less metabolically stable.

**In vitro Half-Life:** Ligand B (0.944) has a slightly longer in vitro half-life than Ligand A (-16.82), which is preferable.

**P-gp Efflux:** Ligand A (0.036) has lower P-gp efflux than Ligand B (0.032), meaning it is less likely to be pumped out of the brain.

**Binding Affinity:** Both ligands have excellent binding affinity (-8.5 and -8.0 kcal/mol). The difference is 0.5kcal/mol, which is not enough to overcome the other differences.

**Overall:**

Ligand A is superior due to its significantly better BBB penetration, lower DILI risk, better solubility, and better Caco-2 permeability. While Ligand B has a slightly longer half-life, the CNS target demands high BBB penetration, which Ligand A delivers. The slight difference in metabolic stability is less concerning than the significant difference in brain exposure.

Output:
1
2025-04-17 06:04:25,362 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (336.4) is slightly better, being closer to the lower end which can aid permeability.

**TPSA:** Ligand A (84.73) is excellent, falling well below the 90 Angstroms threshold for CNS targets. Ligand B (40.54) is also good, but less optimal than A.

**logP:** Ligand A (1.814) is within the optimal range (1-3). Ligand B (4.252) is a bit high, potentially leading to solubility issues and off-target interactions.

**H-Bond Donors/Acceptors:** Ligand A (2 HBD, 5 HBA) and Ligand B (1 HBD, 2 HBA) both have acceptable numbers of H-bond donors and acceptors.

**QED:** Ligand A (0.744) has a significantly better QED score than Ligand B (0.428), indicating a more drug-like profile.

**DILI:** Ligand A (65.723) has a higher DILI risk than Ligand B (16.479). This is a negative for Ligand A.

**BBB:** Ligand A (74.874) has a better BBB penetration percentile than Ligand B (66.188), which is crucial for a CNS target like DRD2. Both are above 70, which is desirable.

**Caco-2 Permeability:** Ligand A (-5.537) has a worse Caco-2 permeability than Ligand B (-4.686).

**Aqueous Solubility:** Ligand A (-2.135) has a worse aqueous solubility than Ligand B (-4.257).

**hERG Inhibition:** Ligand A (0.086) has a lower hERG inhibition liability than Ligand B (0.915), which is a positive.

**Microsomal Clearance:** Ligand B (65.014) has a lower microsomal clearance than Ligand A (26.094), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (30.496) has a longer in vitro half-life than Ligand B (13.564).

**P-gp Efflux:** Ligand A (0.101) has lower P-gp efflux liability than Ligand B (0.415), which is favorable for CNS penetration.

**Binding Affinity:** Ligand A (-10.1 kcal/mol) has a significantly stronger binding affinity than Ligand B (-7.5 kcal/mol). This is a substantial advantage, potentially outweighing some of the ADME drawbacks. The difference is >1.5 kcal/mol.

**Overall Assessment:**

Ligand A excels in key areas for a CNS-targeting GPCR ligand: TPSA, BBB, P-gp efflux, and *especially* binding affinity. While its DILI risk is higher and solubility/permeability are lower than Ligand B, the significantly stronger binding affinity and favorable BBB penetration make it the more promising candidate. The higher affinity suggests it might be effective at lower doses, potentially mitigating some of the DILI concerns.

Output:
1
2025-04-17 06:04:25,362 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (353.296 and 363.805 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (76.23) is significantly better than Ligand B (88.61). For CNS targets, we want TPSA <= 90, and A is closer to the ideal <= 60. B is pushing the upper limit.

**logP:** Both ligands have good logP values (2.594 and 2.289), falling within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A (HBD=1, HBA=4) is better than Ligand B (HBD=2, HBA=6) in terms of balancing solubility and permeability.

**QED:** Both ligands have good QED scores (0.81 and 0.847), indicating good drug-like properties.

**DILI:** Ligand A (76.076) has a lower DILI risk than Ligand B (90.733). Both are acceptable, but A is preferable.

**BBB:** Both ligands have similar, good BBB penetration (75.649 and 76.541), exceeding the 70% threshold for CNS targets.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values, which is unusual and suggests a potential issue with the data or modeling. However, the values are similar (-4.566 and -4.767) so this is unlikely to be a deciding factor.

**Aqueous Solubility:** Both ligands have negative solubility values, which is also unusual. Again, the values are similar (-4.026 and -4.571).

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.394 and 0.479).

**Microsomal Clearance:** Ligand A (55.527) has a lower microsomal clearance than Ligand B (60.037), indicating better metabolic stability.

**In vitro Half-Life:** Ligand A (-29.913) has a longer in vitro half-life than Ligand B (45.65). This is a significant advantage.

**P-gp Efflux:** Ligand A (0.38) has lower P-gp efflux than Ligand B (0.087), which is better for CNS exposure.

**Binding Affinity:** Both ligands have excellent binding affinities (-9.5 and -8.6 kcal/mol). Ligand A is 0.9 kcal/mol stronger, which is a substantial difference and can outweigh minor ADME drawbacks.

**Overall:** Ligand A is superior to Ligand B. It has a lower TPSA, lower DILI risk, better metabolic stability (lower Cl_mic, longer t1/2), lower P-gp efflux, and a significantly stronger binding affinity. While both have acceptable BBB penetration and logP values, the combined advantages of Ligand A make it the more promising drug candidate.

Output:
1
2025-04-17 06:04:25,362 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 drug candidates, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (353.507 Da) is slightly lower, which could be advantageous for permeability. Ligand B (382.873 Da) is also acceptable.

**TPSA:** Ligand A (70.67) is excellent, well below the 90 A^2 threshold for CNS targets. Ligand B (91.48) is still reasonable, but less optimal, being closer to the 140 A^2 threshold for oral absorption.

**logP:** Both ligands have a logP around 1.5, which is optimal.

**H-Bond Donors/Acceptors:** Both have 2 HBDs, which is good. Ligand A has 4 HBAs, and Ligand B has 7 HBAs. Both are within acceptable limits (<=10), but Ligand A is slightly preferred.

**QED:** Both ligands have good QED values (A: 0.681, B: 0.836), indicating good drug-like properties.

**DILI:** Ligand A (16.712) has a significantly lower DILI risk than Ligand B (62.776), which is a major advantage.

**BBB:** Ligand A (68.282) has a much better BBB penetration percentile than Ligand B (36.371). This is *critical* for a CNS target like DRD2.

**Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and suggests poor permeability. However, the scale is not specified, so it's difficult to interpret.

**Aqueous Solubility:** Both have negative solubility values, which is also unusual and suggests poor solubility.

**hERG:** Both ligands have very low hERG risk (A: 0.31, B: 0.105), which is excellent.

**Microsomal Clearance:** Ligand B (-7.67) has a negative clearance, which is not physically possible. This is likely an error in the data. Ligand A (26.93) has a higher clearance, indicating faster metabolism.

**In vitro Half-Life:** Ligand B (9.314) has a longer half-life than Ligand A (-13.18), but the negative value for A is suspect.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (A: 0.041, B: 0.086), which is favorable for CNS penetration.

**Binding Affinity:** Both ligands have very similar and strong binding affinities (-8.1 kcal/mol and -7.9 kcal/mol). The difference is minor.

**Overall Assessment:**

Ligand A is significantly better due to its superior BBB penetration (68.282 vs 36.371), lower DILI risk (16.712 vs 62.776), and more favorable TPSA (70.67 vs 91.48). While Ligand B has a slightly better QED and in vitro half-life, the issues with its BBB penetration and DILI risk are substantial drawbacks for a CNS drug candidate. The negative values for Caco-2, solubility, and half-life for Ligand A are concerning, but the other factors strongly favor Ligand A. The negative clearance for Ligand B is a data error and further diminishes its viability.

Output:
1
2025-04-17 06:04:25,362 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (347.459 Da) is slightly lower, which could be beneficial for permeability. Ligand B (378.46 Da) is also good.

**TPSA:** Ligand A (75.44) is higher than Ligand B (49.41). For CNS targets, TPSA < 90 is preferred, both meet this, but Ligand B is significantly better.

**logP:** Both ligands have good logP values (Ligand A: 2.541, Ligand B: 3.483), falling within the optimal 1-3 range. Ligand B is slightly higher, which could potentially lead to off-target effects, but is still acceptable.

**H-Bond Donors/Acceptors:** Both have 1 HBD and a reasonable number of HBAs (Ligand A: 4 HBA, Ligand B: 3 HBA), satisfying the criteria of <=5 HBD and <=10 HBA.

**QED:** Both have acceptable QED values (Ligand A: 0.822, Ligand B: 0.72), indicating good drug-like properties.

**DILI:** Both have low DILI risk (Ligand A: 35.789, Ligand B: 34.471), both are well below the 40% threshold.

**BBB:** This is critical for a CNS target like DRD2. Ligand B (90.074%) has a significantly higher BBB penetration percentile than Ligand A (76.696%). This is a major advantage for Ligand B.

**Caco-2 Permeability:** Both have negative Caco-2 values (-4.986 and -4.871). This is unusual and suggests poor permeability. However, the scale isn't specified, so it's hard to interpret.

**Aqueous Solubility:** Both have negative solubility values (-2.699 and -4.184). Similar to Caco-2, the scale is unknown, making interpretation difficult.

**hERG Inhibition:** Both have low hERG inhibition risk (Ligand A: 0.314, Ligand B: 0.526).

**Microsomal Clearance:** Ligand A (58.275) has higher clearance than Ligand B (39.846). Lower clearance is preferred for metabolic stability, favoring Ligand B.

**In vitro Half-Life:** Ligand B (-32.492) has a much longer in vitro half-life than Ligand A (-3.595). This is a significant advantage for Ligand B.

**P-gp Efflux:** Ligand A (0.321) has a slightly higher P-gp efflux liability than Ligand B (0.199), meaning Ligand B is less likely to be pumped out of the brain.

**Binding Affinity:** Ligand B (-9.2 kcal/mol) has a *much* stronger binding affinity than Ligand A (-0.0 kcal/mol). This is the most important factor, and the substantial difference in affinity outweighs any minor drawbacks.

**Conclusion:**

Considering all factors, especially the critical GPCR-specific priorities (BBB, logP, Pgp, TPSA) and the overwhelmingly superior binding affinity, **Ligand B is the much more promising drug candidate.** The higher BBB penetration, lower clearance, longer half-life, lower P-gp efflux, and dramatically improved binding affinity make it a clear winner despite slightly higher logP. The negative values for Caco-2 and solubility are concerning but could be addressed with formulation strategies.



Output:
1
2025-04-17 06:04:25,363 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (350.503 and 356.551 Da) fall comfortably within the ideal 200-500 Da range.

**2. TPSA:** Both ligands have a TPSA of 58.64, which is excellent for CNS penetration, being well below the 90 A^2 threshold.

**3. logP:** Ligand A (2.593) is optimal, while Ligand B (3.616) is slightly higher but still within the acceptable 1-3 range.

**4. H-Bond Donors:** Both have 1 HBD, which is good.

**5. H-Bond Acceptors:** Ligand A has 3 HBA, and Ligand B has 4 HBA, both are acceptable.

**6. QED:** Ligand A (0.829) has a better QED score than Ligand B (0.608), indicating a more drug-like profile.

**7. DILI:** Ligand A (10.392) has a significantly lower DILI risk than Ligand B (17.604). This is a substantial advantage.

**8. BBB:** Ligand A (69.407) has a better BBB penetration percentile than Ligand B (57.619). While both are not ideal (>70), A is closer and more favorable.

**9. Caco-2 Permeability:** Both have negative Caco-2 values (-4.616 and -4.556), which is unusual and suggests poor permeability. This is a concern for both, but doesn't differentiate them.

**10. Aqueous Solubility:** Both have negative solubility values (-2.83 and -3.854), indicating poor solubility. This is a concern for both, but doesn't differentiate them.

**11. hERG Inhibition:** Both have low hERG inhibition risk (0.434 and 0.627).

**12. Microsomal Clearance:** Ligand A (46.509) has a lower microsomal clearance than Ligand B (114.137), indicating better metabolic stability.

**13. In vitro Half-Life:** Ligand A (10.898) has a shorter half-life than Ligand B (17.084), but both are reasonable.

**14. P-gp Efflux:** Both have very low P-gp efflux liability (0.044 and 0.079), which is good for CNS penetration.

**15. Binding Affinity:** Ligand A (-8.4 kcal/mol) has a significantly stronger binding affinity than Ligand B (-5.3 kcal/mol). This is a >3 kcal/mol difference, which is a major advantage and can outweigh some ADME drawbacks.

**Overall Assessment:**

Ligand A is the superior candidate. It has a better QED score, significantly lower DILI risk, better BBB penetration, lower microsomal clearance (better metabolic stability), and *much* stronger binding affinity. While both compounds have issues with Caco-2 permeability and solubility, the substantial improvement in binding affinity and safety profile of Ligand A makes it the more promising drug candidate for DRD2.

Output:
1
2025-04-17 06:04:25,363 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (376.469 and 364.515 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (67.43) is better than Ligand B (71.11). Both are below the 90 A^2 threshold for CNS targets, but A is closer to the optimal range.

**3. logP:** Ligand A (2.097) is within the optimal range (1-3). Ligand B (3.546) is slightly higher, but still acceptable.

**4. H-Bond Donors:** Ligand A (2) and Ligand B (1) both satisfy the <=5 rule.

**5. H-Bond Acceptors:** Ligand A (4) and Ligand B (5) both satisfy the <=10 rule.

**6. QED:** Both ligands have good QED scores (0.613 and 0.7), indicating drug-like properties.

**7. DILI:** Ligand A (26.483) has a significantly lower DILI risk than Ligand B (37.999). Both are below the 40 threshold, but A is preferable.

**8. BBB:** Ligand A (78.247) has a much better BBB penetration score than Ligand B (63.164). This is *critical* for a CNS target like DRD2. A score >70 is desirable, and A is closer.

**9. Caco-2 Permeability:** Both have negative values, indicating poor permeability. However, the scale isn't specified, so it's hard to interpret.

**10. Aqueous Solubility:** Both have negative values, indicating poor solubility. Again, the scale is unspecified.

**11. hERG Inhibition:** Both ligands have low hERG inhibition risk (0.389 and 0.636).

**12. Microsomal Clearance:** Ligand A (25.288) has a lower microsomal clearance than Ligand B (66.555), suggesting better metabolic stability.

**13. In vitro Half-Life:** Ligand B (33.575) has a longer half-life than Ligand A (2.578). This is a positive for B.

**14. P-gp Efflux:** Ligand A (0.095) has a much lower P-gp efflux liability than Ligand B (0.481), which is beneficial for CNS penetration.

**15. Binding Affinity:** Ligand A (-7.6 kcal/mol) has a slightly better binding affinity than Ligand B (-6.7 kcal/mol). While both are good, the 0.9 kcal/mol difference is significant.

**Overall Assessment:**

Ligand A is significantly better overall, especially considering the GPCR-specific priorities. Its superior BBB penetration, lower DILI risk, lower P-gp efflux, and slightly better binding affinity outweigh Ligand B's longer half-life. The TPSA and logP values are also more favorable for A. While both have poor solubility and permeability, the CNS target makes BBB penetration and efflux the most critical factors.

Output:
1
2025-04-17 06:04:25,363 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (384.173 and 358.498 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (82.7) is slightly higher than Ligand B (78.43). Both are below the 90 A^2 threshold desirable for CNS targets, which is good.

**3. logP:** Ligand A (4.701) is significantly higher than Ligand B (2.855). Ligand A is pushing the upper limit, potentially leading to solubility issues and off-target effects. Ligand B is within the optimal 1-3 range.

**4. H-Bond Donors:** Both ligands have 3 HBD, which is acceptable.

**5. H-Bond Acceptors:** Both ligands have 3 HBA, which is acceptable.

**6. QED:** Both ligands have similar QED values (0.573 and 0.593), indicating good drug-like properties.

**7. DILI:** Ligand A (99.341) has a very high DILI risk, a major red flag. Ligand B (23.769) has a low DILI risk, which is excellent.

**8. BBB:** Ligand B (82.125) has a much better BBB penetration percentile than Ligand A (53.974). This is critical for a CNS target like DRD2.

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 values, which is unusual and suggests poor permeability. However, the scale isn't specified, making direct comparison difficult.

**10. Aqueous Solubility:** Both ligands have negative solubility values, indicating poor aqueous solubility.

**11. hERG Inhibition:** Ligand A (0.401) has a slightly lower hERG inhibition risk than Ligand B (0.628), but both are relatively low.

**12. Microsomal Clearance:** Ligand B (49.589) has a lower microsomal clearance than Ligand A (25.237), indicating better metabolic stability.

**13. In vitro Half-Life:** Ligand B (1.638) has a slightly longer in vitro half-life than Ligand A (102.667), although the units are inconsistent.

**14. P-gp Efflux:** Ligand A (0.168) has lower P-gp efflux liability than Ligand B (0.14), which is favorable for CNS penetration.

**15. Binding Affinity:** Ligand B (-7.9 kcal/mol) has a significantly stronger binding affinity than Ligand A (-11.3 kcal/mol). This is a substantial advantage, potentially outweighing minor ADME drawbacks.

**Overall Assessment:**

Ligand B is the superior candidate. While both have issues with solubility and Caco-2 permeability, Ligand B exhibits a much more favorable safety profile (significantly lower DILI risk), better BBB penetration, improved metabolic stability, and, crucially, a substantially stronger binding affinity. The higher logP of Ligand A is concerning, and its very high DILI risk is a deal-breaker. The affinity difference between Ligand B (-7.9 kcal/mol) and Ligand A (-11.3 kcal/mol) is significant.

Output:
1
2025-04-17 06:04:25,363 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (345.4 and 343.3 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (91.76) is slightly above the optimal <90 for CNS targets, but still reasonable. Ligand B (59.32) is well within the desired range.

**logP:** Ligand A (0.933) is a bit low, potentially hindering permeability. Ligand B (3.834) is near the upper end of the optimal 1-3 range, but acceptable.

**H-Bond Donors/Acceptors:** Ligand A has 2 HBD and 5 HBA, which are within acceptable limits. Ligand B has 0 HBD and 4 HBA, also acceptable.

**QED:** Both ligands have good QED scores (0.85 and 0.792), indicating good drug-like properties.

**DILI:** Ligand A (41.88) has a lower DILI risk than Ligand B (65.53), which is a significant advantage.

**BBB:** Ligand B (84.37) has a much higher BBB penetration percentile than Ligand A (54.63). This is a *critical* advantage for a CNS target like DRD2.

**Caco-2 Permeability:** Ligand A (-4.875) shows poor Caco-2 permeability, which is concerning. Ligand B (-3.846) is better, but still not great.

**Aqueous Solubility:** Ligand A (-2.579) has better solubility than Ligand B (-5.293).

**hERG Inhibition:** Ligand A (0.131) has a lower hERG inhibition liability than Ligand B (0.71), which is preferred.

**Microsomal Clearance:** Ligand B (83.58) has a significantly higher microsomal clearance than Ligand A (7.48), indicating lower metabolic stability.

**In vitro Half-Life:** Ligand A (-14.25) has a negative half-life, which is likely an error in the data, or indicates very rapid degradation. Ligand B (12.76) has a reasonable half-life.

**P-gp Efflux:** Ligand A (0.019) has very low P-gp efflux, which is a significant advantage for CNS penetration. Ligand B (0.321) has moderate P-gp efflux.

**Binding Affinity:** Ligand B (-9.4 kcal/mol) has a stronger binding affinity than Ligand A (-7.5 kcal/mol). This difference of 1.9 kcal/mol is substantial and can outweigh some ADME drawbacks.

**Overall Assessment:**

Ligand B is the stronger binder and has significantly better BBB penetration, which is paramount for a CNS target. However, it has higher DILI risk, higher microsomal clearance, and moderate P-gp efflux. Ligand A has better solubility, lower DILI, lower hERG, and very low P-gp efflux, but suffers from poor Caco-2 permeability and a questionable half-life. The superior binding affinity and BBB penetration of Ligand B are compelling, and can be addressed through further optimization. The poor permeability and potential instability of Ligand A are more difficult to overcome.

Output:
1
2025-04-17 06:04:25,363 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (337.4) is slightly better being closer to the middle of the range.

**TPSA:** Ligand A (78.91) is excellent for CNS penetration, well below the 90 A^2 threshold. Ligand B (111.21) is still reasonable, but less optimal.

**logP:** Ligand A (2.892) is within the optimal range (1-3). Ligand B (-1.831) is significantly lower, which could hinder membrane permeability and CNS penetration.

**H-Bond Donors/Acceptors:** Ligand A (HBD=2, HBA=3) and Ligand B (HBD=3, HBA=6) both fall within acceptable limits.

**QED:** Ligand A (0.88) has a very good drug-likeness score. Ligand B (0.447) is below the 0.5 threshold, indicating a less favorable drug-like profile.

**DILI:** Ligand A (39.899) has a low DILI risk. Ligand B (24.234) also has a low DILI risk.

**BBB:** Ligand A (70.686) has a good BBB percentile, exceeding the 70% threshold for CNS targets. Ligand B (41.799) is significantly lower, raising concerns about CNS exposure.

**Caco-2 Permeability:** Both have negative values, which is unusual. Assuming these are logP-like scales, lower values indicate poorer permeability. Ligand A (-5.051) is slightly better than Ligand B (-5.173).

**Aqueous Solubility:** Both ligands have negative values, indicating poor solubility. Ligand B (-0.511) is slightly better than Ligand A (-3.324).

**hERG Inhibition:** Ligand A (0.865) has a lower hERG risk than Ligand B (0.082).

**Microsomal Clearance:** Ligand A (5.937) has lower clearance, suggesting better metabolic stability. Ligand B (13.738) has higher clearance.

**In vitro Half-Life:** Ligand A (22.61) has a longer half-life than Ligand B (-10.695).

**P-gp Efflux:** Ligand A (0.454) has lower P-gp efflux, which is favorable for CNS penetration. Ligand B (0.004) has very low P-gp efflux.

**Binding Affinity:** Ligand A (-9.6 kcal/mol) has a significantly stronger binding affinity than Ligand B (-6.3 kcal/mol). This is a substantial advantage.

**Overall Assessment:**

Ligand A is clearly superior. It excels in key GPCR properties like TPSA, BBB, and binding affinity. Its logP is optimal, and it has a good QED score and low DILI risk. While its solubility is poor, the strong binding affinity and favorable CNS properties outweigh this drawback. Ligand B suffers from a poor logP, lower BBB penetration, a lower QED score, and significantly weaker binding affinity. The slightly better solubility and P-gp efflux are not enough to compensate for these deficiencies.

Output:
1
2025-04-17 06:04:25,364 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (346.515 and 358.511 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (58.2) is significantly better than Ligand B (66.91). For CNS targets, we want TPSA <= 90, and A is much closer to the ideal <=60 range.

**logP:** Both ligands (3.406 and 3.523) are within the optimal 1-3 range.

**H-Bond Donors:** Both have 2 HBD, which is acceptable (<=5).

**H-Bond Acceptors:** Ligand A has 2 HBA, while Ligand B has 5.  Ligand A is preferable here (<=10).

**QED:** Both ligands have good QED scores (0.662 and 0.718), indicating good drug-like properties.

**DILI:** Ligand A (35.867) has a lower DILI risk than Ligand B (60.721). Both are acceptable, but A is better.

**BBB:** Ligand A (70.764) has a significantly better BBB penetration score than Ligand B (64.637).  >70 is desirable for CNS targets, and A meets this, while B is close but misses.

**Caco-2 Permeability:** Ligand A (-4.601) has better Caco-2 permeability than Ligand B (-5.389). Higher values are better.

**Aqueous Solubility:** Ligand A (-4.319) has better aqueous solubility than Ligand B (-4.076). Higher values are better.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.489 and 0.658).

**Microsomal Clearance:** Ligand A (56.136) has lower microsomal clearance than Ligand B (102.615), indicating better metabolic stability.

**In vitro Half-Life:** Ligand A (-11.143) has a longer in vitro half-life than Ligand B (66.195).

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.269 and 0.239).

**Binding Affinity:** Both ligands have excellent binding affinity (-8.3 and -8.7 kcal/mol). The difference is minimal.

**Overall Assessment:**

Ligand A consistently outperforms Ligand B across most ADME properties crucial for CNS penetration and drug-likeness. Specifically, its superior TPSA, BBB, solubility, metabolic stability, and lower DILI risk are significant advantages. While both have good affinity, the ADME profile of Ligand A makes it a more promising drug candidate for targeting DRD2.

Output:
1
2025-04-17 06:04:25,364 - INFO - Batch 251 complete. Total preferences: 4016
2025-04-17 06:04:25,364 - INFO - Processing batch 252/512...
2025-04-17 06:05:06,335 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (341.411 and 359.499 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (66.24) is significantly better than Ligand B (70.15). For CNS targets, we want TPSA <= 90, and ideally closer to 60. Ligand A is closer to the ideal range.

**3. logP:** Both ligands have good logP values (2.968 and 2.478), falling within the optimal 1-3 range.

**4. H-Bond Donors:** Ligand A (0) is preferable to Ligand B (2). Fewer HBDs generally improve permeability.

**5. H-Bond Acceptors:** Both ligands have 6 HBAs, which is acceptable (<=10).

**6. QED:** Ligand B (0.855) has a significantly better QED score than Ligand A (0.419), indicating a more drug-like profile overall.

**7. DILI:** Ligand B (54.75) has a lower DILI risk than Ligand A (64.637), which is favorable.

**8. BBB:** Both ligands have good BBB penetration (70.648 and 68.437), exceeding the 70% threshold for CNS targets. Ligand A is slightly better.

**9. Caco-2 Permeability:** Ligand A (-4.515) has a *much* worse Caco-2 permeability than Ligand B (-5.135). Lower values indicate poor permeability.

**10. Aqueous Solubility:** Both ligands have poor aqueous solubility (-3.699 and -3.422). This is a concern, but can sometimes be mitigated with formulation strategies.

**11. hERG Inhibition:** Ligand A (0.105) has a lower hERG inhibition risk than Ligand B (0.8), which is preferable.

**12. Microsomal Clearance:** Ligand B (48.046) has a lower microsomal clearance than Ligand A (56.164), suggesting better metabolic stability.

**13. In vitro Half-Life:** Ligand B (32.235) has a significantly longer in vitro half-life than Ligand A (-14.602), which is a major advantage.

**14. P-gp Efflux:** Ligand A (0.482) has lower P-gp efflux than Ligand B (0.177), which is favorable for CNS exposure.

**15. Binding Affinity:** Ligand A (-7.7) has a significantly better binding affinity than Ligand B (0.0). This is a substantial advantage.

**Overall Assessment:**

While Ligand B has better QED, DILI, metabolic stability, and half-life, Ligand A's superior binding affinity (-7.7 vs 0.0 kcal/mol) and lower P-gp efflux are critical for a CNS GPCR target. The difference in affinity is substantial, and can often outweigh minor ADME drawbacks. The slightly better TPSA and BBB of Ligand A are also beneficial. The poor Caco-2 permeability of Ligand A is a concern, but not insurmountable.

Output:
1
2025-04-17 06:05:06,335 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (367.515 and 358.427 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (69.72) is significantly better than Ligand B (104.03). For CNS targets, we want TPSA <= 90. Ligand A is within this range, while Ligand B exceeds it, potentially hindering BBB penetration.

**3. logP:** Both ligands have good logP values (1.245 and 1.077), falling within the optimal 1-3 range.

**4. H-Bond Donors:** Both have 1 HBD, which is acceptable.

**5. H-Bond Acceptors:** Ligand A has 4 HBAs, while Ligand B has 8. Both are within the acceptable limit of <=10, but Ligand A is preferable.

**6. QED:** Both ligands have good QED scores (0.743 and 0.872), indicating good drug-like properties.

**7. DILI:** Ligand A (55.448) has a lower DILI risk than Ligand B (81.776). Lower is better, and Ligand A is comfortably below the 60 threshold.

**8. BBB:** Both ligands have similar BBB penetration percentiles (52.811 and 53.083). Neither is outstanding (>70), but they are comparable.

**9. Caco-2 Permeability:** Both have negative Caco-2 values (-4.833 and -5.221), which is unusual and suggests poor permeability.

**10. Aqueous Solubility:** Both have negative solubility values (-2.877 and -3.318), indicating very poor aqueous solubility. This is a significant concern.

**11. hERG Inhibition:** Ligand A (0.148) has a much lower hERG inhibition liability than Ligand B (0.364). This is a crucial advantage for Ligand A.

**12. Microsomal Clearance:** Ligand A (48.712) has higher microsomal clearance than Ligand B (24.362), meaning it's less metabolically stable. This favors Ligand B.

**13. In vitro Half-Life:** Ligand B (9.499) has a significantly longer in vitro half-life than Ligand A (-20.441). This is a major advantage for Ligand B.

**14. P-gp Efflux:** Ligand A (0.056) has lower P-gp efflux liability than Ligand B (0.121), which is beneficial for CNS penetration.

**15. Binding Affinity:** Ligand A (-7.4 kcal/mol) has a significantly stronger binding affinity than Ligand B (0.0 kcal/mol). This is a substantial advantage, potentially outweighing some of the ADME drawbacks.

**Overall Assessment:**

Ligand A is the better candidate despite some ADME concerns. The significantly stronger binding affinity (-7.4 vs 0.0 kcal/mol) is a major advantage for a GPCR target. While both have poor solubility and Caco-2 permeability, Ligand A has a much better TPSA, lower DILI risk, lower hERG inhibition, and lower P-gp efflux. Ligand B's advantage in metabolic stability (lower Cl_mic, longer t1/2) is not enough to overcome the significantly weaker binding affinity. The poor solubility of both compounds would need to be addressed through formulation strategies.

Output:
0
2025-04-17 06:05:06,335 - INFO - Reasoning:

Let's analyze Ligand A and Ligand B for their potential as DRD2 drug candidates, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (354.347 and 379.379 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (33.29) is significantly better than Ligand B (62.3). For CNS targets, we want TPSA <= 90, and ideally closer to 60. Ligand A is excellent, while Ligand B is pushing the upper limit and could face permeability issues.

**3. logP:** Ligand A (4.282) is slightly higher than optimal (1-3), but still potentially acceptable. Ligand B (2.463) is well within the optimal range. However, for a GPCR, a slightly higher logP can sometimes be tolerated if other properties are favorable.

**4. H-Bond Donors:** Ligand A (2) and Ligand B (1) are both acceptable, well below the limit of 5.

**5. H-Bond Acceptors:** Ligand A (3) and Ligand B (4) are both acceptable, below the limit of 10.

**6. QED:** Both ligands have good QED scores (0.787 and 0.821), indicating good drug-like properties.

**7. DILI:** Both ligands have similar DILI risk (65.839 and 60.682), both are acceptable but could be improved.

**8. BBB:** Both ligands have excellent BBB penetration (85.576 and 83.404), exceeding the desirable >70 threshold for CNS targets.

**9. Caco-2 Permeability:** Ligand A (-5.038) has poor Caco-2 permeability, while Ligand B (-4.57) is also poor, but slightly better. Both are negative values, which is concerning.

**10. Aqueous Solubility:** Both ligands have very poor aqueous solubility (-4.372 and -4.173). This is a significant drawback.

**11. hERG Inhibition:** Ligand A (0.958) has a slightly higher hERG risk than Ligand B (0.262). Lower is better here.

**12. Microsomal Clearance:** Ligand A (24.311) has lower microsomal clearance than Ligand B (30.751), suggesting better metabolic stability.

**13. In vitro Half-Life:** Ligand B (-8.709) has a longer in vitro half-life than Ligand A (5.635). This is a positive for Ligand B.

**14. P-gp Efflux:** Ligand A (0.603) has lower P-gp efflux than Ligand B (0.032), which is favorable for CNS penetration.

**15. Binding Affinity:** Ligand A (-9.8 kcal/mol) has a significantly stronger binding affinity than Ligand B (-8.1 kcal/mol). This is a substantial advantage (1.7 kcal/mol difference).

**Overall Assessment:**

Ligand A has a superior binding affinity and better TPSA, and P-gp efflux, which are crucial for a CNS-targeting GPCR. However, it suffers from poor Caco-2 permeability and slightly higher hERG risk. Ligand B has better logP, half-life, and lower hERG risk, but significantly weaker binding affinity and a higher TPSA.

The strong binding affinity of Ligand A is a major advantage that could potentially outweigh its drawbacks. The poor solubility and permeability are concerning, but formulation strategies might mitigate these issues. The difference in binding affinity is substantial enough to prioritize Ligand A.

Output:
1
2025-04-17 06:05:06,336 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B against the provided guidelines, keeping in mind DRD2 is a CNS-relevant GPCR.

**Molecular Weight:** Both ligands (338.367 and 342.458 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (94.05) is slightly above the optimal <90 for CNS targets, but still reasonable. Ligand B (23.55) is excellent, well below the threshold. This favors Ligand B.

**logP:** Both ligands (3.232 and 3.788) are within the optimal 1-3 range.

**H-Bond Donors:** Ligand A has 1 HBD, and Ligand B has 0. Both are acceptable (<=5).

**H-Bond Acceptors:** Ligand A has 6 HBA, and Ligand B has 1. Both are acceptable (<=10).

**QED:** Both ligands have good QED scores (0.785 and 0.802), indicating drug-like properties.

**DILI:** Ligand A (82.784) has a higher DILI risk than Ligand B (18.185). This is a significant advantage for Ligand B.

**BBB:** Both ligands have excellent BBB penetration (58.782 and 82.435), with Ligand B being slightly better. This is crucial for a CNS target like DRD2.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.868 and -4.504). This is unusual and suggests poor permeability. However, these values are on a scale where negative values are possible, and direct comparison is difficult without knowing the scale's specifics.

**Aqueous Solubility:** Both ligands have negative solubility values (-3.926 and -4.445). Similar to Caco-2, this is unusual and requires caution.

**hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.164 and 0.808).

**Microsomal Clearance:** Both ligands have similar microsomal clearance values (47.738 and 46.696), suggesting comparable metabolic stability.

**In vitro Half-Life:** Ligand B (17.628) has a significantly longer in vitro half-life than Ligand A (-33.726). This is a major advantage for Ligand B.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.128 and 0.344).

**Binding Affinity:** Ligand B (-9.8 kcal/mol) has a slightly better binding affinity than Ligand A (-9.0 kcal/mol). While both are excellent, the difference is notable.

**Overall Assessment:**

Considering the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity), Ligand B is the stronger candidate. It has a significantly lower DILI risk, a longer half-life, and slightly better BBB penetration and binding affinity. While both have unusual Caco-2 and solubility values, the other advantages of Ligand B outweigh these concerns. The lower TPSA of Ligand B is also beneficial for CNS penetration.

Output:
1
2025-04-17 06:05:06,336 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (359.344 and 352.391 Da) are within the ideal 200-500 Da range.

**TPSA:** Ligand A (59.0) is excellent for CNS penetration, well below the 90 A^2 threshold. Ligand B (116.92) is higher, but still potentially acceptable, though less ideal.

**logP:** Ligand A (1.876) is within the optimal 1-3 range. Ligand B (-0.872) is slightly below 1, which could hinder permeability.

**H-Bond Donors/Acceptors:** Ligand A (1 HBD, 4 HBA) and Ligand B (3 HBD, 7 HBA) both have reasonable numbers of H-bond donors and acceptors, unlikely to cause significant issues.

**QED:** Both ligands have acceptable QED values (0.895 and 0.613, respectively), indicating good drug-like properties.

**DILI:** Ligand A (38.077) has a lower DILI risk than Ligand B (60.566), which is approaching a higher risk category.

**BBB:** This is a critical parameter for a CNS target like DRD2. Ligand A (81.698) has a good BBB percentile, exceeding the 70% threshold. Ligand B (12.408) has a very poor BBB percentile, suggesting limited CNS exposure.

**Caco-2 Permeability:** Ligand A (-4.504) and Ligand B (-5.166) both have negative values, which is unusual and suggests poor permeability. However, these values are on a scale where negative values are possible and don't necessarily preclude activity.

**Aqueous Solubility:** Ligand A (-2.697) and Ligand B (-1.632) both have negative solubility values, suggesting poor solubility.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.766 and 0.168, respectively).

**Microsomal Clearance:** Ligand A (14.661) has a higher microsomal clearance than Ligand B (6.055), indicating potentially lower metabolic stability.

**In vitro Half-Life:** Ligand A (-7.455) has a longer in vitro half-life than Ligand B (-3.182).

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.325 and 0.016, respectively), which is favorable for CNS penetration.

**Binding Affinity:** Both ligands have the same binding affinity (-8.6 kcal/mol), which is excellent.

**Conclusion:**

Considering all factors, especially the GPCR-specific priorities, **Ligand A is the more promising drug candidate**. While both have excellent binding affinity, Ligand A significantly outperforms Ligand B in BBB penetration (81.7% vs 12.4%), has a lower DILI risk, and a longer half-life. The slightly higher microsomal clearance of Ligand A is a minor drawback compared to the substantial advantage in CNS exposure. The negative solubility and Caco-2 values are concerning for both, but can be addressed through formulation strategies.

Output:
1
2025-04-17 06:05:06,336 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B based on the provided guidelines, prioritizing GPCR-specific properties (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (364.808 and 361.515 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (82.26) is higher than Ligand B (56.07). For CNS targets, TPSA should be <=90, so both are acceptable, but B is better.

**logP:** Both ligands have good logP values (3.366 and 3.278), falling within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A has 4 HBD and 2 HBA, while Ligand B has 0 HBD and 7 HBA. Both are within acceptable limits (<=5 HBD and <=10 HBA).

**QED:** Both ligands have good QED scores (0.627 and 0.836), indicating good drug-likeness.

**DILI:** Ligand A (88.329) has a higher DILI risk than Ligand B (49.128). This is a significant drawback for Ligand A.

**BBB:** Both ligands have excellent BBB penetration (68.127 and 88.329 percentile). Ligand B is significantly better.

**Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and suggests potential issues with the data or modeling. However, we can still compare them. Ligand A (-4.69) is slightly better than Ligand B (-5.087).

**Aqueous Solubility:** Ligand A (-5.874) has worse solubility than Ligand B (-3.48).

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.481 and 0.283).

**Microsomal Clearance:** Ligand A (41.722) has lower microsomal clearance, indicating better metabolic stability, than Ligand B (55.591).

**In vitro Half-Life:** Ligand A (87.727) has a significantly longer in vitro half-life than Ligand B (-13.582). This is a major advantage for Ligand A.

**P-gp Efflux:** Ligand A (0.136) has lower P-gp efflux, which is favorable for CNS penetration, than Ligand B (0.539).

**Binding Affinity:** Ligand A (-10.5 kcal/mol) has a significantly stronger binding affinity than Ligand B (-6.7 kcal/mol). This is a substantial advantage, potentially outweighing some of the ADME drawbacks.

**Overall Assessment:**

Ligand A has a much stronger binding affinity and better metabolic stability (lower Cl_mic, longer t1/2) and P-gp efflux. However, it has a higher DILI risk and lower solubility. Ligand B has better TPSA, lower DILI, and better solubility, but significantly weaker binding affinity.

Given the target is a CNS GPCR (DRD2), BBB penetration is critical, and both ligands perform well. However, the substantial difference in binding affinity (-10.5 vs -6.7 kcal/mol) is a major factor. This difference is large enough to potentially overcome the slightly higher DILI risk and lower solubility of Ligand A, especially considering optimization can address these issues. The longer half-life and lower P-gp efflux of Ligand A are also beneficial for CNS exposure.

Output:
1
2025-04-17 06:05:06,336 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (342.483 and 364.471 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (49.41) is significantly better than Ligand B (85.37). For CNS targets, we want TPSA <= 90, and A is comfortably within this range, while B is approaching the upper limit.

**3. logP:** Both ligands have good logP values (3.204 and 2.075), falling within the optimal 1-3 range.

**4. H-Bond Donors:** Both have acceptable HBD counts (1 and 2, respectively), well below the threshold of 5.

**5. H-Bond Acceptors:** Ligand A (2) is better than Ligand B (7), which is getting closer to the upper limit of 10.

**6. QED:** Ligand A (0.893) has a much better QED score than Ligand B (0.624), indicating a more drug-like profile.

**7. DILI:** Ligand A (26.095) has a significantly lower DILI risk than Ligand B (60.915). This is a major advantage for A.

**8. BBB:** Ligand A (77.2) has a much better BBB percentile than Ligand B (57.736). This is critical for a CNS target like DRD2.

**9. Caco-2:** Both have negative Caco-2 values (-4.762 and -4.837), which is unusual and suggests poor permeability. This is a drawback for both, but doesn't differentiate them.

**10. Solubility:** Both have negative solubility values (-3.334 and -3.279), also unusual and indicating poor solubility. Again, a drawback for both, not a differentiator.

**11. hERG:** Both ligands have low hERG inhibition liability (0.549 and 0.846), which is good.

**12. Cl_mic:** Ligand B (51.014) has lower microsomal clearance than Ligand A (63.719), suggesting better metabolic stability.

**13. t1/2:** Ligand B (-19.053) has a slightly longer in vitro half-life than Ligand A (-18.312), but both are negative, which is unusual.

**14. Pgp:** Ligand A (0.344) has significantly lower P-gp efflux liability than Ligand B (0.145), which is favorable for CNS penetration.

**15. Binding Affinity:** Ligand B (-7.6) has a significantly better binding affinity than Ligand A (-10). This is a substantial advantage for B, potentially outweighing some of its ADME drawbacks.

**Overall Assessment:**

While Ligand B has a superior binding affinity, Ligand A is significantly better across multiple crucial ADME properties, especially those prioritized for GPCRs targeting the CNS: TPSA, BBB, DILI, and Pgp efflux. The substantial difference in BBB penetration (77.2 vs 57.736) and DILI risk (26.095 vs 60.915) are particularly important. The better QED score of A also contributes to its overall drug-likeness. The affinity difference is significant, but a 2.4 kcal/mol difference can sometimes be overcome with further optimization, whereas fixing poor ADME properties is often more challenging.

Output:
0
2025-04-17 06:05:06,337 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (345.443 and 378.441 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (66.65) is better than Ligand B (78.87). For CNS targets, we want TPSA <= 90, both are within this range, but A is closer to the optimal value.

**3. logP:** Ligand A (2.512) is within the optimal 1-3 range. Ligand B (0.489) is slightly low, potentially hindering permeation.

**4. H-Bond Donors:** Ligand A (0) is preferable to Ligand B (2). Fewer HBDs generally improve permeability.

**5. H-Bond Acceptors:** Ligand A (4) is preferable to Ligand B (5).

**6. QED:** Both ligands have similar QED values (0.787 and 0.703), indicating good drug-likeness.

**7. DILI:** Both ligands have low DILI risk (32.803 and 35.285), which is good.

**8. BBB:** Both ligands exhibit excellent BBB penetration (81.776 and 82.862), exceeding the desirable >70 threshold.

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.572 and -4.98). These values are unusual and suggest potential issues with the assay or the compounds themselves. However, the negative values are similar, so this doesn't strongly differentiate them.

**10. Aqueous Solubility:** Both ligands have negative solubility values (-3.799 and -2.873). Similar to Caco-2, this is concerning and suggests poor solubility.

**11. hERG Inhibition:** Both ligands show low hERG inhibition risk (0.375 and 0.323).

**12. Microsomal Clearance:** Ligand A (66.249) has a higher microsomal clearance than Ligand B (14.973). This suggests Ligand B is more metabolically stable.

**13. In vitro Half-Life:** Ligand B (-14.348) has a significantly longer in vitro half-life than Ligand A (-4.986). This is a major advantage for Ligand B.

**14. P-gp Efflux:** Ligand A (0.486) has lower P-gp efflux than Ligand B (0.03). Lower efflux is better for CNS exposure.

**15. Binding Affinity:** Ligand A (-7.8) has a slightly better binding affinity than Ligand B (-7.3). A difference of 0.5 kcal/mol is significant.

**Overall Assessment:**

Ligand A has a better logP, fewer H-bonds, and a slightly better binding affinity. However, Ligand B has significantly improved metabolic stability (lower Cl_mic, longer t1/2) and lower P-gp efflux. Considering the GPCR-specific priorities, BBB is excellent for both. The slightly better affinity of Ligand A is appealing, but the improved metabolic stability and longer half-life of Ligand B are crucial for *in vivo* efficacy, especially for a CNS target. The negative solubility and Caco-2 values are a concern for both, but can be addressed with formulation strategies.

Output:
1
2025-04-17 06:05:06,337 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (344.5 & 346.4 Da) fall comfortably within the ideal 200-500 Da range.

**TPSA:** Ligand A (49.41) is excellent, well below the 90 A^2 threshold for CNS targets. Ligand B (71.78) is higher, but still reasonably acceptable, though less ideal.

**logP:** Ligand A (3.276) is optimal (1-3). Ligand B (1.743) is on the lower side, potentially impacting permeability.

**H-Bond Donors/Acceptors:** Both ligands have 1 HBD, which is good. Ligand A has 2 HBA, and Ligand B has 4 HBA. Both are within the acceptable range of <=10.

**QED:** Both ligands have good QED scores (0.804 and 0.882), indicating good drug-like properties.

**DILI:** Ligand A (16.712) has a lower DILI risk than Ligand B (29.314), which is favorable.

**BBB:** This is crucial for a CNS target. Ligand A has a significantly better BBB penetration percentile (78.209) than Ligand B (58.938).

**Caco-2 Permeability:** Both have negative values, indicating poor permeability. However, the scale is not specified, so it's difficult to interpret these values directly.

**Aqueous Solubility:** Both have negative values, indicating poor solubility. Again, the scale is not specified, making interpretation difficult.

**hERG:** Both ligands have low hERG inhibition liability (0.404 and 0.17), which is good.

**Microsomal Clearance:** Ligand A (87.038) has a higher microsomal clearance, suggesting faster metabolism. Ligand B (-0.955) has a *very* favorable, low clearance, indicating high metabolic stability.

**In vitro Half-Life:** Ligand B (50.661) has a significantly longer in vitro half-life than Ligand A (33.946), which is a major advantage.

**P-gp Efflux:** Ligand A (0.342) has lower P-gp efflux liability than Ligand B (0.029), which is better for CNS exposure.

**Binding Affinity:** Ligand B (-8.9 kcal/mol) has a slightly better binding affinity than Ligand A (-8.3 kcal/mol). While the difference is not huge, it's still a positive for Ligand B.

**Overall Assessment:**

Ligand B has several advantages: significantly better metabolic stability (lower Cl_mic, longer t1/2), and slightly better binding affinity. However, Ligand A has a much better BBB score and lower P-gp efflux, which are critical for CNS penetration. Ligand A also has a lower DILI risk. The lower logP of Ligand B is a concern, potentially hindering permeability.

Given the importance of CNS penetration for a DRD2 ligand (targeting CNS disorders), and the fact that the affinity difference isn't overwhelming, the better BBB score and lower P-gp efflux of Ligand A outweigh the metabolic advantages of Ligand B.

Output:
0
2025-04-17 06:05:06,337 - INFO - Reasoning:

Let's analyze Ligand A and Ligand B based on the provided guidelines, prioritizing GPCR-specific properties (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (345.443 and 349.439 Da) fall comfortably within the ideal 200-500 Da range.

**TPSA:** Ligand A (71.53) is significantly better than Ligand B (110.76). For CNS targets, we want TPSA <= 90, and A is much closer to this threshold. B is considerably higher, potentially hindering BBB penetration.

**logP:** Both ligands have acceptable logP values (2.094 and 1.102), falling within the 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A (HBD=1, HBA=4) is preferable to Ligand B (HBD=2, HBA=8) as it has fewer hydrogen bond acceptors. While both are within acceptable limits, lower HBA generally improves permeability.

**QED:** Both ligands have reasonable QED scores (0.802 and 0.734), indicating good drug-like properties.

**DILI:** Ligand A (42.846) has a lower DILI risk than Ligand B (59.131), which is desirable. Both are below the concerning 60 threshold, but A is better.

**BBB:** This is a critical parameter for CNS targets like DRD2. Ligand A (73.013) has a significantly higher BBB percentile than Ligand B (47.964). A score >70 is desirable, and A is close, while B is considerably lower.

**Caco-2 Permeability:** Ligand A (-4.5) is better than Ligand B (-5.334). Higher values indicate better intestinal absorption.

**Aqueous Solubility:** Ligand A (-2.388) is better than Ligand B (-1.882). Higher values indicate better solubility.

**hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.452 and 0.041).

**Microsomal Clearance:** Ligand A (59.828) has a slightly higher (worse) microsomal clearance than Ligand B (50.088). Lower clearance is preferred.

**In vitro Half-Life:** Ligand B (22.651) has a significantly longer half-life than Ligand A (-9.083). This is a positive for B.

**P-gp Efflux:** Ligand A (0.061) has lower P-gp efflux liability than Ligand B (0.047), which is desirable for CNS penetration.

**Binding Affinity:** Ligand A (-8.6 kcal/mol) has a stronger binding affinity than Ligand B (-6.4 kcal/mol). This is a substantial difference (2.2 kcal/mol), and a strong affinity can often outweigh minor ADME drawbacks.

**Overall Assessment:**

Ligand A is the stronger candidate. Its superior TPSA, BBB penetration, lower DILI risk, better solubility, and significantly higher binding affinity outweigh the slightly higher microsomal clearance and shorter half-life compared to Ligand B. The strong affinity of Ligand A is a major advantage for a GPCR target.



Output:
1
2025-04-17 06:05:06,337 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B based on the provided guidelines, prioritizing GPCR-specific properties (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (348.443 and 362.499 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (70.08) is significantly better than Ligand B (75.02). For CNS targets, we want TPSA <= 90, and A is closer to the optimal <= 60 range.

**logP:** Ligand A (0.825) is suboptimal, being slightly below the 1-3 range. Ligand B (3.399) is within the optimal range. This favors B.

**H-Bond Donors:** Both ligands have 1 HBD, which is acceptable (<=5).

**H-Bond Acceptors:** Ligand A has 4 HBA, and Ligand B has 5. Both are acceptable (<=10).

**QED:** Both ligands have good QED values (0.722 and 0.852, both >= 0.5).

**DILI:** Ligand B (68.476) has a higher DILI risk than Ligand A (18.302). This is a significant advantage for A.

**BBB:** Ligand A (68.515) is better than Ligand B (53.587), but ideally, we want >70 for CNS targets. A is closer.

**Caco-2:** Ligand A (-4.473) and Ligand B (-5.431) both have negative Caco-2 values, which is unusual and suggests poor permeability.

**Solubility:** Ligand A (-1.744) is better than Ligand B (-4.069). Higher solubility is generally preferred.

**hERG:** Both ligands have low hERG inhibition liability (0.309 and 0.435), which is good.

**Microsomal Clearance:** Ligand A (43.283) has significantly lower microsomal clearance than Ligand B (105.282), indicating better metabolic stability.

**In vitro Half-Life:** Ligand A (2.65) has a shorter half-life than Ligand B (-31.985 - this is a very negative value, likely indicating very rapid degradation). This is a strong advantage for B, *assuming* the negative value isn't an error.

**P-gp Efflux:** Ligand A (0.072) has much lower P-gp efflux than Ligand B (0.218), which is crucial for CNS penetration.

**Binding Affinity:** Ligand B (-7.6) has a slightly better binding affinity than Ligand A (-8.0). While A is better, the difference is small.

**Overall Assessment:**

Considering the GPCR-specific priorities, Ligand A is preferable. It has a significantly better BBB score, lower DILI risk, lower P-gp efflux, and better metabolic stability (lower Cl_mic). While Ligand B has a slightly better binding affinity and logP, the advantages of A in terms of CNS penetration and safety outweigh these. The negative half-life for B is concerning.

Output:
0
2025-04-17 06:05:06,337 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B based on the provided guidelines, prioritizing GPCR-specific properties (BBB, logP, Pgp, TPSA, and affinity) for DRD2.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (365.455 Da) is slightly lower than Ligand B (404.348 Da), which is generally favorable for permeability.

**TPSA:** Ligand A (119.29) is closer to the desirable threshold of 90 for CNS targets than Ligand B (30.49). This suggests better potential for brain penetration for Ligand A.

**logP:** Ligand A (1.106) is within the optimal range (1-3), while Ligand B (4.927) is significantly higher. High logP can lead to poor solubility and off-target effects, making Ligand A preferable.

**H-Bond Donors/Acceptors:** Ligand A has 3 HBD and 5 HBA, while Ligand B has 1 HBD and 3 HBA. Both are within acceptable limits, but Ligand A's higher HBD count might slightly improve solubility.

**QED:** Both ligands have similar QED values (0.722 and 0.677), indicating good drug-likeness.

**DILI:** Ligand A (38.581) has a slightly higher DILI risk than Ligand B (18.728), but both are below the concerning threshold of 60.

**BBB:** Ligand B (78.596) has a substantially better BBB percentile than Ligand A (22.955). This is a critical factor for a CNS target like DRD2.

**Caco-2 Permeability:** Ligand A (-5.252) shows poor Caco-2 permeability, while Ligand B (-4.878) is also poor, but slightly better.

**Aqueous Solubility:** Ligand A (-2.382) has slightly better aqueous solubility than Ligand B (-4.323).

**hERG:** Both ligands have low hERG inhibition liability (0.286 and 0.931), indicating a low risk of cardiotoxicity.

**Microsomal Clearance:** Ligand A (-26.023) has a much lower (better) microsomal clearance than Ligand B (64.626), suggesting greater metabolic stability.

**In vitro Half-Life:** Ligand A (65.781) has a longer in vitro half-life than Ligand B (21.207), which is desirable.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.011 and 0.714).

**Binding Affinity:** Ligand B (-9.7 kcal/mol) has a significantly stronger binding affinity than Ligand A (-9.0 kcal/mol). This is a substantial advantage.

**Overall Assessment:**

Despite Ligand A's better TPSA, logP, solubility, metabolic stability, and half-life, Ligand B's superior BBB penetration and significantly stronger binding affinity are decisive. For a CNS target like DRD2, achieving brain exposure and potent target engagement are paramount. The higher logP of Ligand B, while a potential concern, might be mitigated by its strong binding affinity and good BBB penetration. The difference in binding affinity (-9.7 vs -9.0 kcal/mol) is substantial and likely outweighs the drawbacks of the higher logP.

Output:
1
2025-04-17 06:05:06,338 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (355.435 and 359.388 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (107.97) is better than Ligand B (46.61). For CNS targets, we want TPSA <= 90, so Ligand B is significantly better.

**logP:** Ligand A (-0.594) is suboptimal, potentially hindering permeation. Ligand B (3.645) is within the optimal 1-3 range. This is a significant advantage for Ligand B.

**H-Bond Donors:** Ligand A (3) is acceptable, while Ligand B (0) is also good.

**H-Bond Acceptors:** Ligand A (5) is acceptable, and Ligand B (3) is also good.

**QED:** Both ligands have good QED scores (0.512 and 0.633, respectively), suggesting drug-like properties.

**DILI:** Both have low DILI risk (24.118 and 27.026), which is positive.

**BBB:** Ligand A (43.117) is poor for a CNS target. Ligand B (91.508) is excellent, exceeding the >70% threshold. This is a critical advantage for Ligand B.

**Caco-2 Permeability:** Ligand A (-5.089) is very poor, indicating poor intestinal absorption. Ligand B (-4.087) is also poor, but slightly better.

**Aqueous Solubility:** Ligand A (-1.137) is poor, while Ligand B (-3.713) is even worse. Solubility is a concern for both.

**hERG Inhibition:** Ligand A (0.082) has very low hERG risk, which is excellent. Ligand B (0.884) has a slightly elevated risk, but still relatively low.

**Microsomal Clearance:** Ligand A (12.187) is better than Ligand B (103.036) - lower clearance means better metabolic stability.

**In vitro Half-Life:** Ligand A (-0.905) is poor, while Ligand B (4.015) is better.

**P-gp Efflux:** Ligand A (0.023) has very low P-gp efflux, which is highly desirable for CNS penetration. Ligand B (0.236) is better than many compounds, but not as good as Ligand A.

**Binding Affinity:** Ligand A (-7.3) has a slightly better binding affinity than Ligand B (-6.9), but the difference is less than 1.5 kcal/mol.

**Overall Assessment:**

Ligand B is the superior candidate. While Ligand A has slightly better affinity and P-gp efflux, Ligand B excels in crucial areas for a CNS-targeting GPCR ligand: TPSA, logP, and, most importantly, BBB penetration. The significantly better BBB score of Ligand B outweighs the minor affinity difference. The lower metabolic stability and solubility of Ligand B are concerns, but could be addressed through further optimization. Ligand A's poor logP and BBB make it a less promising candidate despite its slightly better affinity.

Output:
1
2025-04-17 06:05:06,338 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (347.419 and 367.471 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (111.27) is slightly above the preferred <90 for CNS targets, while Ligand B (98.66) is comfortably below. This gives a slight edge to Ligand B.

**logP:** Ligand A (0.194) is quite low, potentially hindering membrane permeability. Ligand B (1.724) is within the optimal 1-3 range. This is a significant advantage for Ligand B.

**H-Bond Donors/Acceptors:** Ligand A has 3 HBD and 6 HBA, which are acceptable. Ligand B has 1 HBD and 6 HBA, also acceptable.

**QED:** Both ligands have similar QED values (0.68 and 0.632), indicating good drug-likeness.

**DILI:** Ligand A (48.662) has a slightly higher DILI risk than Ligand B (37.65), but both are below the concerning threshold of 60.

**BBB:** Ligand B (83.172) has a substantially better BBB penetration percentile than Ligand A (71.035). This is a critical factor for a CNS target like DRD2.

**Caco-2 Permeability:** Both have negative Caco-2 values (-5.377 and -5.216), which is unusual and suggests poor permeability. However, these values are on a different scale and may not be directly comparable.

**Aqueous Solubility:** Both ligands have very poor aqueous solubility (-3.19 and -2.52). This could pose formulation challenges.

**hERG Inhibition:** Both ligands show very low hERG inhibition risk (0.185 and 0.165).

**Microsomal Clearance:** Ligand A (4.068) has significantly lower microsomal clearance than Ligand B (60.791), suggesting better metabolic stability. This is a positive for Ligand A.

**In vitro Half-Life:** Ligand A (20.417) has a longer in vitro half-life than Ligand B (0.867), further supporting its better metabolic stability.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.019 and 0.208), which is favorable for CNS penetration.

**Binding Affinity:** Ligand A (-7.9 kcal/mol) has a significantly stronger binding affinity than Ligand B (-6.8 kcal/mol). This is a substantial advantage for Ligand A, potentially outweighing some of its ADME drawbacks.

**Overall Assessment:**

While Ligand A has superior binding affinity and metabolic stability, Ligand B excels in BBB penetration and has a more favorable logP value. The low logP of Ligand A is a significant concern for CNS penetration, despite its strong binding. The substantial difference in binding affinity (-1.1 kcal/mol) is noteworthy, but the CNS target necessitates good brain exposure. Ligand B's better TPSA and logP, coupled with excellent BBB penetration, make it a more promising candidate, even with slightly weaker binding.

Output:
1
2025-04-17 06:05:06,338 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (401.264 Da) is slightly higher, but still acceptable. Ligand B (355.454 Da) is a bit lower, potentially favoring permeability.

**TPSA:** Ligand A (80.04) is borderline for CNS targets (ideally <90), while Ligand B (61.88) is well within the desired range. This favors Ligand B.

**logP:** Ligand A (3.326) is optimal. Ligand B (1.67) is on the lower side, potentially hindering membrane permeability. This favors Ligand A.

**H-Bond Donors/Acceptors:** Ligand A has 2 HBD and 5 HBA, which are within acceptable limits. Ligand B has 1 HBD and 4 HBA, also within limits. No clear advantage here.

**QED:** Both ligands have reasonable QED values (A: 0.663, B: 0.531), indicating drug-like properties. Ligand A is slightly better.

**DILI:** Ligand A (84.18) has a higher DILI risk than Ligand B (28.189). This is a significant advantage for Ligand B.

**BBB:** Ligand B (86.545) has a much higher BBB penetration percentile than Ligand A (21.753). This is a *critical* advantage for a CNS target like DRD2.

**Caco-2 Permeability:** Ligand A (-5.202) shows poor Caco-2 permeability, while Ligand B (-4.94) is slightly better, but still not great.

**Aqueous Solubility:** Ligand A (-3.545) has poor aqueous solubility, while Ligand B (-1.892) is better. This favors Ligand B.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (A: 0.059, B: 0.485), which is good. No clear advantage.

**Microsomal Clearance:** Ligand B (4.931) has a much lower microsomal clearance than Ligand A (18.446), indicating better metabolic stability. This favors Ligand B.

**In vitro Half-Life:** Ligand B (-2.922) has a slightly longer in vitro half-life than Ligand A (-16.782). This favors Ligand B.

**P-gp Efflux:** Ligand A (0.039) has lower P-gp efflux liability than Ligand B (0.078), which is favorable for CNS penetration. This favors Ligand A.

**Binding Affinity:** Ligand A (-9.3 kcal/mol) has a slightly stronger binding affinity than Ligand B (-8.2 kcal/mol). This is a notable advantage for Ligand A, and could potentially outweigh some of its ADME drawbacks.

**Overall Assessment:**

While Ligand A has a slightly better binding affinity and lower P-gp efflux, Ligand B overwhelmingly wins on ADME properties crucial for a CNS-targeting GPCR. Specifically, its significantly better BBB penetration, lower DILI risk, improved solubility, and better metabolic stability are highly desirable. The affinity difference, while present, is not substantial enough to overcome these ADME advantages, especially given the importance of CNS exposure for DRD2.

Output:
1
2025-04-17 06:05:06,338 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B against the provided guidelines, prioritizing GPCR-specific properties (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (349.475 Da) is slightly preferred due to being closer to the lower end, potentially aiding permeability.

**TPSA:** Ligand A (61.88) is significantly better than Ligand B (51.45) as it is closer to the optimal range for CNS targets (<=90).

**logP:** Ligand A (0.716) is within the optimal range (1-3), while Ligand B (4.948) is high, potentially leading to solubility issues and off-target interactions.

**H-Bond Donors/Acceptors:** Both ligands have acceptable HBD (1) and HBA (4 & 5) counts.

**QED:** Ligand A (0.794) has a better QED score than Ligand B (0.588), indicating a more drug-like profile.

**DILI:** Ligand A (7.445) has a much lower DILI risk than Ligand B (85.498), which is a significant concern.

**BBB:** Ligand A (75.107) has a good BBB penetration percentile, while Ligand B (67.584) is lower. While both are not ideal (>70), A is better.

**Caco-2 Permeability:** Both have negative values, which is unusual. However, the magnitude of the negative value for Ligand A (-4.686) is less than that of Ligand B (-4.415), suggesting slightly better permeability.

**Aqueous Solubility:** Ligand A (-1.476) has better solubility than Ligand B (-5.302).

**hERG Inhibition:** Ligand A (0.333) has a lower hERG inhibition liability than Ligand B (0.878), reducing cardiotoxicity risk.

**Microsomal Clearance:** Ligand A (4.052) has a lower microsomal clearance than Ligand B (72.886), indicating better metabolic stability.

**In vitro Half-Life:** Ligand A (-7.212) has a much better in vitro half-life than Ligand B (56.92).

**P-gp Efflux:** Ligand A (0.017) has significantly lower P-gp efflux liability than Ligand B (0.887), which is crucial for CNS penetration.

**Binding Affinity:** Ligand B (-7.7) has a slightly better binding affinity than Ligand A (-8.2). However, the difference (0.5 kcal/mol) is not substantial enough to outweigh the numerous ADME advantages of Ligand A.

**Overall:** Ligand A demonstrates a significantly more favorable ADME profile, with better BBB penetration, lower DILI risk, better solubility, lower hERG inhibition, improved metabolic stability, and lower P-gp efflux. While Ligand B has slightly better binding affinity, the overall profile of Ligand A is far superior for development as a CNS-targeting drug.

Output:
0
2025-04-17 06:05:06,339 - INFO - Batch 252 complete. Total preferences: 4032
2025-04-17 06:05:06,339 - INFO - Processing batch 253/512...
2025-04-17 06:05:48,018 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (350.277 and 369.506 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (72.22) is better than Ligand B (64.41), both are below the 90 A^2 threshold for CNS targets.

**logP:** Both ligands (2.566 and 2.611) are within the optimal 1-3 range.

**H-Bond Donors:** Both have 0 HBD, which is acceptable.

**H-Bond Acceptors:** Ligand A has 5, and Ligand B has 4, both are below the 10 threshold.

**QED:** Both ligands have good QED scores (0.793 and 0.722, respectively), indicating drug-likeness.

**DILI:** Ligand A (87.282) has a higher DILI risk than Ligand B (23.73). This is a significant drawback for Ligand A.

**BBB:** Both ligands have excellent BBB penetration (94.184 and 92.672), which is crucial for a CNS target like DRD2.

**Caco-2 Permeability:** Both have negative values, which is unusual and suggests poor permeability. However, the scale is not specified, so it's hard to interpret.

**Aqueous Solubility:** Both have negative values, indicating low solubility. This is a concern for both compounds.

**hERG Inhibition:** Ligand A (0.344) has a lower hERG inhibition liability than Ligand B (0.659), which is preferable.

**Microsomal Clearance:** Ligand A (31.996) has a lower microsomal clearance than Ligand B (52.713), indicating better metabolic stability.

**In vitro Half-Life:** Ligand A (31.971) has a longer in vitro half-life than Ligand B (-16.561), which is a significant advantage.

**P-gp Efflux:** Ligand A (0.194) has lower P-gp efflux liability than Ligand B (0.091), which is beneficial for CNS exposure.

**Binding Affinity:** Ligand A (-9.8 kcal/mol) has significantly stronger binding affinity than Ligand B (-6.5 kcal/mol). This is a substantial advantage, potentially outweighing some of the ADME drawbacks. The difference is >1.5 kcal/mol.

**Overall Assessment:**

Ligand A has a much stronger binding affinity, better metabolic stability, longer half-life, and lower P-gp efflux. However, it has a significantly higher DILI risk. Ligand B has a lower DILI risk but weaker binding affinity and poorer metabolic properties.

Given the strong binding affinity of Ligand A, and the importance of potency for GPCRs, I believe Ligand A is the more promising candidate *despite* the higher DILI risk. DILI risk can potentially be mitigated through structural modifications during lead optimization. The large affinity difference is a major driver.

Output:
1
2025-04-17 06:05:48,019 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (343.402 and 350.419 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (63.25) is significantly better than Ligand B (104.39). For CNS targets, TPSA should be <= 90, and A is comfortably within this range, while B is pushing the limit.

**logP:** Ligand A (3.015) is optimal (1-3), while Ligand B (1.171) is a bit low, potentially hindering permeability.

**H-Bond Donors/Acceptors:** Both have acceptable HBD counts (2). Ligand B has a slightly higher HBA count (5 vs 3), but both are within the acceptable range of <=10.

**QED:** Both ligands have reasonable QED values (0.812 and 0.75), indicating good drug-like properties.

**DILI:** Ligand A (40.403) has a lower DILI risk than Ligand B (65.064). Both are reasonably good, but A is preferable.

**BBB:** Ligand A (83.831) has significantly better BBB penetration potential than Ligand B (51.803). This is a *critical* factor for a CNS target like DRD2.

**Caco-2 Permeability:** Both have negative Caco-2 values (-4.427 and -4.651), which is unusual and suggests poor permeability. This is a concern for both, but doesn't strongly differentiate them.

**Aqueous Solubility:** Both have negative solubility values (-3.698 and -2.827), indicating poor aqueous solubility. This is a drawback for both, but doesn't strongly differentiate them.

**hERG:** Both ligands have low hERG inhibition liability (0.441 and 0.09), which is good.

**Microsomal Clearance:** Ligand A (38.004) has lower microsomal clearance than Ligand B (72.377), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (26.433) has a longer in vitro half-life than Ligand B (-24.659).

**P-gp Efflux:** Ligand A (0.085) has lower P-gp efflux liability than Ligand B (0.023), which is favorable for CNS exposure.

**Binding Affinity:** Ligand A (-9.6 kcal/mol) has a significantly stronger binding affinity than Ligand B (-7.3 kcal/mol). This is a substantial difference (>1.5 kcal/mol) and can outweigh minor ADME drawbacks.

**Conclusion:**

Ligand A is clearly the superior candidate. It excels in key areas for a CNS-targeting GPCR ligand: TPSA, BBB penetration, metabolic stability, P-gp efflux, and, most importantly, binding affinity. While both have solubility and permeability concerns, the stronger affinity and better CNS properties of Ligand A make it much more likely to be a viable drug candidate.

Output:
1
2025-04-17 06:05:48,019 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (351.447 and 355.454 Da) fall comfortably within the ideal 200-500 Da range.

**TPSA:** Ligand A (87.74) is better than Ligand B (69.72). Both are below the 90 A^2 threshold desirable for CNS targets, but A is closer to the upper limit.

**logP:** Ligand A (0.577) is lower than the optimal 1-3 range, potentially hindering permeability. Ligand B (1.349) is within the optimal range. This is a significant advantage for B.

**H-Bond Donors/Acceptors:** Ligand A (2 HBD, 4 HBA) and Ligand B (1 HBD, 3 HBA) both have acceptable numbers of H-bond donors and acceptors.

**QED:** Both ligands have good QED values (0.685 and 0.731), indicating drug-like properties.

**DILI:** Ligand A (14.541) has a much lower DILI risk than Ligand B (18.728), which is a positive for A.

**BBB:** Ligand B (88.6) has a significantly higher BBB penetration percentile than Ligand A (67.197). This is a critical advantage for a CNS target like DRD2.

**Caco-2 Permeability:** Ligand A (-5.144) has a worse Caco-2 permeability than Ligand B (-4.759), indicating lower intestinal absorption.

**Aqueous Solubility:** Ligand A (-1.154) has slightly better solubility than Ligand B (-1.941).

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.184 and 0.43).

**Microsomal Clearance:** Ligand A (-1.324) has a lower (better) microsomal clearance than Ligand B (22.899), suggesting greater metabolic stability.

**In vitro Half-Life:** Ligand A (-0.924) has a better in vitro half-life than Ligand B (-11.774).

**P-gp Efflux:** Ligand A (0.016) has a much lower P-gp efflux liability than Ligand B (0.029), which is favorable for CNS penetration.

**Binding Affinity:** Ligand B (-8.5 kcal/mol) has a slightly better binding affinity than Ligand A (-7.9 kcal/mol). While the difference is not huge, it's still a positive for B.

**Overall Assessment:**

Ligand B excels in BBB penetration and has a more optimal logP value. These are crucial for CNS GPCR targets. It also has a slightly better binding affinity. Ligand A has advantages in DILI risk, metabolic stability, half-life, and P-gp efflux, but the BBB and logP advantages of Ligand B are more important for DRD2. The slight affinity difference further tips the scale.

Output:
1
2025-04-17 06:05:48,019 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B based on the provided guidelines, prioritizing GPCR-specific properties (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (379.806 and 381.929 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (55.4) is significantly better than Ligand B (66.64). For CNS targets, we want TPSA <= 90, and ideally closer to 60. Ligand A is much closer to this ideal.

**logP:** Ligand A (4.414) is slightly higher than the optimal 1-3 range, but still potentially acceptable. Ligand B (2.882) is within the optimal range. However, for a GPCR, a slightly higher logP can be tolerated if other properties are favorable.

**H-Bond Donors/Acceptors:** Both ligands have 1 HBD and a reasonable number of HBAs (3 and 4 respectively), satisfying the <5 HBD and <10 HBA guidelines.

**QED:** Both ligands have QED values (0.745 and 0.629) above the 0.5 threshold, indicating good drug-likeness.

**DILI:** Both ligands have acceptable DILI risk (55.68 and 51.493 percentile), below the concerning 60 threshold.

**BBB:** This is a crucial parameter for CNS targets. Ligand B (92.943) is *much* better than Ligand A (60.295). A value >70 is desirable, and Ligand B is closer to this.

**Caco-2 Permeability:** Ligand A (-4.469) and Ligand B (-5.057) both have negative Caco-2 values, indicating poor permeability. This is a concern for both.

**Aqueous Solubility:** Both ligands have poor aqueous solubility (-4.805 and -3.805). This could pose formulation challenges.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.493 and 0.871).

**Microsomal Clearance:** Ligand A (100.604) has higher microsomal clearance than Ligand B (44.533), suggesting lower metabolic stability.

**In vitro Half-Life:** Ligand B (-21.61) has a negative half-life, which is not physically possible and indicates a significant issue. Ligand A (35.907) has a reasonable half-life.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.129 and 0.262).

**Binding Affinity:** Ligand B (-7.9 kcal/mol) has significantly stronger binding affinity than Ligand A (-9.0 kcal/mol). A >1.5 kcal/mol advantage is considered significant.

**Overall Assessment:**

Ligand B has a much better BBB score and significantly stronger binding affinity. However, its negative in vitro half-life is a critical flaw. Ligand A has a more reasonable half-life, better TPSA, and acceptable (though not ideal) logP. While Ligand A's BBB is lower, the combination of its other properties, particularly the reasonable half-life and TPSA, makes it a more viable starting point for optimization. The negative half-life of Ligand B is a showstopper.

Output:
0
2025-04-17 06:05:48,019 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (354.347 and 346.406 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (46.33) is excellent, well below the 90 A^2 threshold for CNS targets. Ligand B (67.23) is higher, but still potentially acceptable, though less desirable.

**3. logP:** Ligand A (3.019) is optimal. Ligand B (1.77) is on the lower side, potentially hindering membrane permeability.

**4. H-Bond Donors:** Both ligands have 1 HBD, which is within the acceptable limit of <=5.

**5. H-Bond Acceptors:** Ligand A has 2 HBAs, and Ligand B has 4 HBAs. Both are within the acceptable limit of <=10.

**6. QED:** Both ligands have good QED scores (0.64 and 0.792), indicating good drug-like properties.

**7. DILI:** Ligand A (34.432) has a lower DILI risk than Ligand B (43.234), both are acceptable.

**8. BBB:** Ligand A (84.025) has a significantly better BBB penetration percentile than Ligand B (74.758). This is a crucial factor for a CNS target like DRD2.

**9. Caco-2 Permeability:** Both have negative Caco-2 values (-4.644 and -4.826), which is unusual and suggests poor permeability. However, these values are on a scale where lower is worse, and the difference is minimal.

**10. Aqueous Solubility:** Both have negative solubility values (-3.121 and -2.023) which is also unusual and suggests poor solubility. The difference is minimal.

**11. hERG Inhibition:** Ligand A (0.944) has a slightly higher hERG risk than Ligand B (0.561), but both are relatively low.

**12. Microsomal Clearance:** Ligand B (38.549) has a higher microsomal clearance than Ligand A (26.344), suggesting lower metabolic stability.

**13. In vitro Half-Life:** Both have similar in vitro half-lives (23.462 and 22.434 hours).

**14. P-gp Efflux:** Ligand A (0.516) has lower P-gp efflux liability than Ligand B (0.1), meaning it's less likely to be pumped out of the brain, which is favorable for CNS penetration.

**15. Binding Affinity:** Ligand B (-8.6 kcal/mol) has a slightly better binding affinity than Ligand A (-9.3 kcal/mol). While a difference of 0.7 kcal/mol is notable, the other ADME properties are more concerning for Ligand B.

**Overall Assessment:**

Ligand A is the more promising candidate. It has a superior BBB score, better logP, lower P-gp efflux, and lower microsomal clearance, all critical for CNS drug development. While Ligand B has slightly better binding affinity, the differences in ADME properties, particularly BBB and logP, outweigh this advantage. The negative Caco-2 and solubility values are concerning for both, but the other properties of Ligand A make it the better choice.

Output:
1
2025-04-17 06:05:48,020 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B based on the provided guidelines, prioritizing GPCR-specific properties (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (364.511 and 349.475 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (67.43) is better than Ligand B (71). Both are reasonably good for CNS penetration, being below 90, but A is closer to the ideal.

**logP:** Both ligands have good logP values (3.222 and 2.354), falling within the 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A has 2 HBD and 4 HBA, while Ligand B has 1 HBD and 4 HBA. Both are acceptable.

**QED:** Both ligands have good QED scores (0.66 and 0.717), indicating good drug-likeness.

**DILI:** Ligand A (53.47) has a higher DILI risk than Ligand B (23.769). This is a significant drawback for Ligand A.

**BBB:** Ligand B (68.786) has a better BBB penetration percentile than Ligand A (52.423). This is crucial for a CNS target like DRD2.

**Caco-2 Permeability:** Ligand A (-5.134) has worse Caco-2 permeability than Ligand B (-4.695), indicating lower intestinal absorption.

**Aqueous Solubility:** Ligand A (-3.946) has worse aqueous solubility than Ligand B (-2.584).

**hERG Inhibition:** Ligand A (0.182) has slightly better hERG inhibition profile than Ligand B (0.456).

**Microsomal Clearance:** Ligand B (19.084) has lower microsomal clearance than Ligand A (44.862), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand B (2.736) has a better in vitro half-life than Ligand A (-13.734).

**P-gp Efflux:** Ligand A (0.042) has lower P-gp efflux liability than Ligand B (0.2), which is favorable for CNS penetration.

**Binding Affinity:** Ligand B (-8.7 kcal/mol) has a slightly better binding affinity than Ligand A (-7.9 kcal/mol). While the difference is not huge, it's still a positive for Ligand B.

**Overall Assessment:**

Ligand B is the more promising candidate. While Ligand A has a slightly better hERG profile and P-gp efflux, Ligand B excels in critical areas for a CNS-targeting GPCR: significantly lower DILI risk, better BBB penetration, better metabolic stability (lower Cl_mic, longer t1/2), improved Caco-2 permeability and solubility, and slightly better binding affinity. The lower DILI risk is a major advantage.

Output:
1
2025-04-17 06:05:48,020 - INFO - Reasoning:

Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (362.459 Da and 356.427 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (103.91) is better than Ligand B (139.66). For CNS targets, we want TPSA <= 90, so Ligand A is closer to this threshold, suggesting better CNS penetration potential. Ligand B is approaching a TPSA that could hinder brain entry.

**3. logP:** Ligand A (0.488) is slightly better than Ligand B (-0.222). Both are a bit low, potentially impacting permeability. However, Ligand A is closer to the optimal 1-3 range.

**4. H-Bond Donors:** Ligand A (1) is preferable to Ligand B (3). Fewer HBDs generally improve permeability.

**5. H-Bond Acceptors:** Ligand A (7) is better than Ligand B (6). Both are within the acceptable range (<=10).

**6. QED:** Ligand A (0.739) is significantly better than Ligand B (0.313). A higher QED indicates a more drug-like profile.

**7. DILI:** Ligand A (51.028) is better than Ligand B (8.647). Both are relatively low risk, but Ligand B is even more favorable.

**8. BBB:** Ligand A (49.787) is significantly better than Ligand B (17.798). This is *critical* for a CNS target like DRD2. Ligand A has a moderate BBB penetration, while Ligand B is quite poor.

**9. Caco-2:** Both ligands have negative Caco-2 values (-5.43 and -5.293), which is unusual and suggests poor permeability. This is a significant concern for both.

**10. Solubility:** Ligand A (-2.753) is better than Ligand B (0.077). Both are poor, but Ligand A is less poor. Solubility is a concern for both.

**11. hERG:** Ligand A (0.099) is better than Ligand B (0.039). Both are very low risk for hERG inhibition.

**12. Cl_mic:** Ligand A (10.983) is better than Ligand B (11.576). Lower is better, indicating greater metabolic stability.

**13. t1/2:** Ligand A (7.164) is significantly better than Ligand B (-2.252). A longer half-life is generally desirable.

**14. Pgp:** Ligand A (0.068) is significantly better than Ligand B (0.002). Lower P-gp efflux is crucial for CNS exposure.

**15. Affinity:** Ligand A (-7.3) is slightly better than Ligand B (-6.9). While both have good affinity, the difference is not substantial enough to overcome the other significant differences.

**Overall Assessment:**

Ligand A is the superior candidate. While both have issues with Caco-2 permeability and solubility, Ligand A has a significantly better BBB score, QED, half-life, Pgp efflux profile, and slightly better affinity. These factors are particularly important for a CNS GPCR target like DRD2. Ligand B's poor BBB penetration is a major drawback.

Output:
1
2025-04-17 06:05:48,020 - INFO - Reasoning:

Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (352.291 and 344.459 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (77.81) is slightly higher than Ligand B (74.33). Both are below the 90 A^2 threshold desirable for CNS targets, which is good.

**3. logP:** Ligand A (3.994) is at the upper end of the optimal range (1-3), while Ligand B (2.143) is well within it. Ligand A's higher logP could potentially lead to off-target effects or solubility issues, but it's not drastically high.

**4. H-Bond Donors:** Both ligands have 2 HBD, which is within the acceptable limit of <=5.

**5. H-Bond Acceptors:** Ligand A has 3 HBA and Ligand B has 4 HBA, both within the acceptable limit of <=10.

**6. QED:** Ligand A (0.82) has a significantly better QED score than Ligand B (0.532), indicating a more drug-like profile.

**7. DILI:** Ligand A (73.323) has a higher DILI risk than Ligand B (33.23). This is a significant drawback for Ligand A.

**8. BBB:** Both ligands have good BBB penetration (Ligand A: 69.678, Ligand B: 71.074), exceeding the 70 percentile threshold for CNS targets.

**9. Caco-2 Permeability:** Ligand A (-4.631) has poor Caco-2 permeability, while Ligand B (-5.021) is also poor. This is a concern for oral bioavailability for both, but Ligand A is slightly better.

**10. Aqueous Solubility:** Ligand A (-4.935) has very poor aqueous solubility, while Ligand B (-2.794) is also poor, but better than Ligand A.

**11. hERG Inhibition:** Both ligands have low hERG inhibition risk (Ligand A: 0.628, Ligand B: 0.65).

**12. Microsomal Clearance:** Ligand B (50.012) has lower microsomal clearance than Ligand A (21.995), suggesting better metabolic stability.

**13. In vitro Half-Life:** Ligand B (58.995) has a longer in vitro half-life than Ligand A (53.108), which is desirable.

**14. P-gp Efflux:** Both ligands have low P-gp efflux liability (Ligand A: 0.173, Ligand B: 0.06), which is good for CNS exposure.

**15. Binding Affinity:** Ligand B (-7.9 kcal/mol) has a significantly stronger binding affinity than Ligand A (-9.8 kcal/mol). This is a crucial advantage, as a >1.5 kcal/mol difference can outweigh other drawbacks.

**Overall Assessment:**

While Ligand A has a better QED score, its significantly higher DILI risk, poor solubility, and weaker binding affinity are major concerns. Ligand B, despite a lower QED, exhibits a much more favorable safety profile (lower DILI), better metabolic stability (lower Cl_mic, longer t1/2), and, most importantly, a substantially stronger binding affinity. The slightly better logP of Ligand B is also preferable. Given the GPCR-specific priorities, the strong binding affinity and improved safety/ADME properties of Ligand B make it the more promising drug candidate.

Output:
1
2025-04-17 06:05:48,020 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (352.45 and 346.475 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (49.85) is excellent, well below the 90 A^2 threshold for CNS targets. Ligand B (78.09) is still reasonable but less optimal, approaching the 90 A^2 limit.

**3. logP:** Both ligands have good logP values (2.143 and 2.074), falling within the optimal 1-3 range.

**4. H-Bond Donors:** Ligand A (0) is preferable to Ligand B (2). Fewer HBDs generally improve permeability.

**5. H-Bond Acceptors:** Both ligands have 3 HBA, which is acceptable.

**6. QED:** Both ligands have similar QED values (0.762 and 0.742), indicating good drug-likeness.

**7. DILI:** Ligand A (19.271) has a significantly lower DILI risk than Ligand B (23.769), both are good, but A is better.

**8. BBB:** This is a crucial parameter for a CNS target like DRD2. Ligand A has a very high BBB penetration percentile (97.751), while Ligand B is much lower (42.226). This is a major advantage for Ligand A.

**9. Caco-2 Permeability:** Ligand A (-4.34) is worse than Ligand B (-5.333). Lower values are worse.

**10. Aqueous Solubility:** Ligand A (-2.969) is worse than Ligand B (-1.644). Lower values are worse.

**11. hERG Inhibition:** Both ligands have low hERG inhibition liability (0.576 and 0.387), which is good.

**12. Microsomal Clearance:** Ligand A (16.27) is higher than Ligand B (12.705), meaning Ligand A has faster clearance and lower metabolic stability.

**13. In vitro Half-Life:** Ligand B (-25.513) has a much longer half-life than Ligand A (16.462), which is a significant advantage.

**14. P-gp Efflux:** Ligand A (0.087) has lower P-gp efflux liability than Ligand B (0.156), which is preferable for CNS exposure.

**15. Binding Affinity:** Ligand B (-7.9 kcal/mol) has a slightly better binding affinity than Ligand A (-6.9 kcal/mol). While a 1 kcal/mol difference is notable, the other factors are more important.

**Overall Assessment:**

Ligand A is the stronger candidate. Its excellent BBB penetration (97.751) and low DILI risk are critical advantages for a CNS-targeted drug. The slightly weaker affinity is outweighed by these factors, especially considering the importance of getting the drug into the brain. While Ligand B has a longer half-life, the poor BBB penetration is a major drawback.

Output:
1
2025-04-17 06:05:48,020 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (388.333 and 365.763 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (49.41) is significantly better than Ligand B (57.61). For CNS targets, we want TPSA <= 90, and ideally closer to 60. Ligand A is much closer to this ideal.

**3. logP:** Both ligands have good logP values (3.439 and 3.631), falling within the optimal 1-3 range.

**4. H-Bond Donors:** Both have 1 HBD, which is acceptable.

**5. H-Bond Acceptors:** Ligand A has 3 HBAs, while Ligand B has 2. Both are within the acceptable limit of <= 10.

**6. QED:** Both ligands have good QED scores (0.79 and 0.9), indicating good drug-like properties.

**7. DILI:** Ligand A (46.491) has a lower DILI risk than Ligand B (78.054). Both are below 60, but A is preferable.

**8. BBB:** This is critical for a CNS target like DRD2. Ligand A has a much higher BBB penetration percentile (89.066) compared to Ligand B (41.218). This is a major advantage for Ligand A.

**9. Caco-2 Permeability:** Ligand A (-4.873) and Ligand B (-4.589) both have negative values, which is unusual and suggests poor permeability. However, the scale isn't defined, so it's hard to interpret.

**10. Aqueous Solubility:** Both ligands have similar, very poor aqueous solubility (-3.593 and -3.571). This is a potential issue for both, but not a deciding factor.

**11. hERG Inhibition:** Ligand A (0.514) has a slightly higher hERG risk than Ligand B (0.189). This is a minor drawback for Ligand A.

**12. Microsomal Clearance:** Ligand A (9.965) has a higher microsomal clearance than Ligand B (3.179), indicating lower metabolic stability. This is a drawback for Ligand A.

**13. In vitro Half-Life:** Ligand B (1.167) has a slightly longer half-life than Ligand A (-2.04). The negative value for A is concerning.

**14. P-gp Efflux:** Ligand A (0.16) has lower P-gp efflux than Ligand B (0.096), which is beneficial for CNS penetration.

**15. Binding Affinity:** Both ligands have excellent binding affinities (-9.5 and -10.4 kcal/mol). Ligand B is slightly better, but the difference is relatively small.

**Overall Assessment:**

Ligand A excels in BBB penetration and has a lower DILI risk, and lower P-gp efflux. Ligand B has a slightly better binding affinity and half-life, but its significantly lower BBB penetration is a major concern for a CNS target. Given the GPCR-specific priorities, particularly the importance of BBB penetration for CNS targets, **Ligand A is the more promising candidate**. While its metabolic stability and solubility are concerns, these can be addressed through further optimization. The substantial difference in BBB penetration outweighs the slight advantage of Ligand B in binding affinity and half-life.

Output:
1
2025-04-17 06:05:48,021 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (410.587 Da) is slightly higher than Ligand B (352.435 Da), but both are acceptable.

**2. TPSA:** Both ligands have TPSA values below 140, which is good for oral absorption, and reasonably close to the 90 threshold for CNS targets. Ligand A (112.81) is slightly higher than Ligand B (107.61), but both are favorable.

**3. logP:** Both ligands have logP values around -0.5, which is a bit low. Ideally, we want 1-3. This could potentially hinder permeation, but isn't a dealbreaker if other properties are strong.

**4. H-Bond Donors:** Ligand A (2) is preferable to Ligand B (3). Keeping HBDs low is generally beneficial for permeability.

**5. H-Bond Acceptors:** Ligand A (7) is slightly higher than Ligand B (4), but both are within the acceptable limit of 10.

**6. QED:** Both ligands have similar QED values (A: 0.567, B: 0.522), indicating good drug-like properties.

**7. DILI:** Ligand A (58.705) has a significantly higher DILI risk than Ligand B (20.551). This is a major concern for Ligand A.

**8. BBB:** Both ligands have very similar BBB penetration (A: 48.779, B: 47.15). These are both below the desirable >70 for CNS targets, but not drastically so.

**9. Caco-2:** Both ligands have negative Caco-2 values, which is unusual and suggests poor permeability. This is a significant negative for both.

**10. Solubility:** Both ligands have negative solubility values, indicating poor aqueous solubility. This is also a concern for both.

**11. hERG:** Both ligands have low hERG inhibition liability (A: 0.686, B: 0.041). Ligand B is slightly better here.

**12. Cl_mic:** Ligand B (-7.603) has a much lower (and therefore better) microsomal clearance than Ligand A (4.447). This suggests better metabolic stability for Ligand B.

**13. t1/2:** Ligand B (-5.355) has a slightly longer in vitro half-life than Ligand A (-4.877), indicating better stability.

**14. Pgp:** Both ligands have very low Pgp efflux liability (A: 0.024, B: 0.005). This is good for CNS exposure.

**15. Binding Affinity:** Both ligands have excellent binding affinity (-7.0 and -7.5 kcal/mol, respectively). Ligand B is slightly better, but the difference is small.

**Overall Assessment:**

While both ligands have good binding affinity, Ligand B is significantly better overall. The major advantage of Ligand B is its much lower DILI risk and better metabolic stability (lower Cl_mic and longer t1/2). Although both have suboptimal logP, Caco-2, and solubility, the DILI risk associated with Ligand A is a major red flag. Given the GPCR-specific priority of minimizing off-target effects, and the fact that both ligands have comparable affinity and BBB penetration, Ligand B is the more promising candidate.

Output:
1
2025-04-17 06:05:48,021 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (356.373 and 355.435 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (76.46) is excellent, well below the 90 A^2 threshold for CNS targets. Ligand B (107.97) is higher, but still potentially acceptable, though less ideal.

**logP:** Ligand A (2.618) is optimal (1-3). Ligand B (-0.571) is below 1, which could hinder permeation. This is a significant drawback.

**H-Bond Donors/Acceptors:** Ligand A (HBD=1, HBA=5) and Ligand B (HBD=3, HBA=5) both have reasonable H-bond characteristics, within the guidelines.

**QED:** Ligand A (0.884) has a very strong drug-like profile. Ligand B (0.505) is acceptable, but less favorable.

**DILI:** Ligand A (64.754) has a moderate DILI risk, while Ligand B (21.055) has a very low risk. This favors Ligand B.

**BBB:** Ligand A (87.747) has excellent BBB penetration potential, exceeding the 70% threshold. Ligand B (31.214) has poor BBB penetration. This is a critical difference for a CNS target like DRD2 and strongly favors Ligand A.

**Caco-2 Permeability:** Ligand A (-4.251) and Ligand B (-5.374) both have negative Caco-2 values, which is unusual and suggests poor permeability. This is a concern for both, but the scale is not clearly defined.

**Aqueous Solubility:** Ligand A (-4.373) and Ligand B (-1.268) both have negative solubility values, which is also unusual and suggests poor solubility. This is a concern for both, but the scale is not clearly defined.

**hERG:** Both ligands have very low hERG inhibition risk (0.264 and 0.116).

**Microsomal Clearance:** Ligand A (64.48) has a moderate clearance. Ligand B (34.767) has a lower clearance, suggesting better metabolic stability. This favors Ligand B.

**In vitro Half-Life:** Ligand A (-10.97) and Ligand B (-4.697) both have negative half-life values, which is unusual.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.056 and 0.012).

**Binding Affinity:** Ligand A (-8.2 kcal/mol) has a significantly stronger binding affinity than Ligand B (-7.4 kcal/mol). This 0.8 kcal/mol difference is substantial and can outweigh some ADME drawbacks.

**Overall Assessment:**

Ligand A excels in key areas for a CNS GPCR target: TPSA, logP, BBB penetration, and, crucially, binding affinity. While its DILI risk is higher and its Caco-2/Solubility values are concerning, the strong affinity and excellent BBB penetration are highly predictive of *in vivo* activity. Ligand B has a better DILI and clearance profile, but its poor logP and extremely low BBB penetration make it unlikely to achieve sufficient CNS exposure to be effective. The affinity difference is also significant.

Output:
1
2025-04-17 06:05:48,021 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (409.259 Da) is slightly higher than Ligand B (353.507 Da), but both are acceptable.

**TPSA:** Ligand A (58.56) is excellent for CNS penetration, well below the 90 A^2 threshold. Ligand B (72.88) is still reasonable, but less optimal.

**logP:** Both ligands have good logP values (A: 2.408, B: 1.234) falling within the 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A (HBD=0, HBA=5) and Ligand B (HBD=2, HBA=4) both have acceptable numbers of H-bond donors and acceptors.

**QED:** Both ligands have reasonable QED scores (A: 0.777, B: 0.62), indicating good drug-like properties.

**DILI:** Ligand A (78.402) has a higher DILI risk than Ligand B (3.335). This is a significant drawback for Ligand A.

**BBB:** Ligand A (94.455) has excellent BBB penetration, exceeding the 70% threshold. Ligand B (47.15) is significantly lower and less desirable for a CNS target.

**Caco-2 Permeability:** Ligand A (-4.477) and Ligand B (-4.84) both have negative Caco-2 values, indicating poor permeability.

**Aqueous Solubility:** Ligand A (-3.531) and Ligand B (-0.984) both have negative solubility values, indicating poor solubility.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (A: 0.593, B: 0.188).

**Microsomal Clearance:** Ligand A (95.74) has high microsomal clearance, suggesting poor metabolic stability. Ligand B (16.14) has much lower clearance, indicating better metabolic stability.

**In vitro Half-Life:** Ligand A (-17.462) has a negative in vitro half-life, which is concerning. Ligand B (-6.721) is also negative, but less so.

**P-gp Efflux:** Ligand A (0.356) has lower P-gp efflux liability than Ligand B (0.023), which is favorable for CNS penetration.

**Binding Affinity:** Ligand A (-9.1 kcal/mol) has a significantly stronger binding affinity than Ligand B (-7.1 kcal/mol). This is a substantial advantage.

**Overall Assessment:**

Ligand A has a much stronger binding affinity and excellent BBB penetration, which are critical for a CNS GPCR target. However, it suffers from high DILI risk, poor metabolic stability (high Cl_mic), and a concerning in vitro half-life. Ligand B has a better safety profile (lower DILI) and metabolic stability, but its BBB penetration is significantly lower and its binding affinity is weaker.

The difference in binding affinity (-2 kcal/mol) is substantial enough to potentially overcome Ligand A's ADME liabilities *if* those liabilities can be addressed through further optimization. The poor metabolic stability and DILI risk are the biggest concerns. However, given the importance of affinity for GPCRs and the excellent BBB penetration, Ligand A is the more promising starting point for further development.

Output:
1
2025-04-17 06:05:48,021 - INFO - Reasoning:

Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (337.379 and 346.471 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (86.45) is better than Ligand B (58.64). Both are below the 90 A^2 threshold for CNS targets, but A is closer to the ideal.

**3. logP:** Both ligands have good logP values (2.59 and 1.977), falling within the optimal 1-3 range.

**4. H-Bond Donors:** Both have 1 HBD, which is acceptable.

**5. H-Bond Acceptors:** Ligand A has 5 HBA, and Ligand B has 3. Both are below the 10 threshold.

**6. QED:** Both ligands have good QED scores (0.926 and 0.775), indicating drug-like properties.

**7. DILI:** Ligand A (50.33) has a higher DILI risk than Ligand B (17.449). This is a significant drawback for Ligand A.

**8. BBB:** Ligand B (64.482) has a significantly better BBB penetration percentile than Ligand A (46.84). This is *critical* for a CNS target like DRD2.

**9. Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and suggests poor permeability. However, the values are close enough that this isn't a major differentiator.

**10. Aqueous Solubility:** Both have negative solubility values, which is also unusual. Again, the values are similar.

**11. hERG Inhibition:** Ligand A (0.718) has a slightly higher hERG risk than Ligand B (0.217), but both are relatively low.

**12. Microsomal Clearance:** Ligand A (-5.222) has much lower (better) microsomal clearance than Ligand B (25.476), indicating greater metabolic stability.

**13. In vitro Half-Life:** Ligand B (5.521) has a longer half-life than Ligand A (3.005).

**14. P-gp Efflux:** Ligand A (0.165) has lower P-gp efflux than Ligand B (0.078), which is desirable for CNS penetration.

**15. Binding Affinity:** Both ligands have very similar and excellent binding affinities (-8.9 and -8.8 kcal/mol). The difference is negligible.

**Overall Assessment:**

While Ligand A has better metabolic stability (lower Cl_mic) and slightly lower P-gp efflux, the significantly higher DILI risk and *much* lower BBB penetration make it a less favorable candidate. Ligand B's superior BBB penetration is the deciding factor for a CNS-targeting drug. The slightly shorter half-life and higher P-gp efflux are less concerning than the DILI and BBB issues with Ligand A.

Output:
1
2025-04-17 06:05:48,022 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (346.471 Da) is slightly lower, which can be advantageous for permeability.

**2. TPSA:** Ligand A (60.85) is significantly better than Ligand B (115.98). For CNS targets, TPSA < 90 is preferred, and Ligand A is well within this range, while Ligand B is approaching the upper limit.

**3. logP:** Both ligands have good logP values (A: 1.816, B: 1.138), falling within the optimal 1-3 range.

**4. H-Bond Donors:** Ligand A (1) is better than Ligand B (4). Fewer HBDs generally improve membrane permeability.

**5. H-Bond Acceptors:** Ligand A (3) is better than Ligand B (5). Fewer HBAs also generally improve permeability.

**6. QED:** Both ligands have similar and acceptable QED values (A: 0.565, B: 0.575), indicating good drug-like properties.

**7. DILI:** Both ligands have similar and acceptable DILI risk (A: 6.01, B: 65.568).

**8. BBB:** Both ligands have similar and acceptable BBB penetration (A: 65.374, B: 65.839).

**9. Caco-2 Permeability:** Ligand A (-4.398) is better than Ligand B (-5.469). Higher values indicate better intestinal absorption.

**10. Aqueous Solubility:** Ligand A (-1.747) is better than Ligand B (-3.655). Higher values indicate better solubility.

**11. hERG Inhibition:** Ligand A (0.205) is significantly better than Ligand B (0.573). Lower hERG inhibition is crucial for avoiding cardiotoxicity.

**12. Microsomal Clearance:** Ligand A (24.052) is better than Ligand B (34.89). Lower clearance suggests better metabolic stability.

**13. In vitro Half-Life:** Ligand A (-4.71) is significantly better than Ligand B (-17.078). Longer half-life is generally desirable.

**14. P-gp Efflux:** Ligand A (0.031) is significantly better than Ligand B (0.061). Lower P-gp efflux is crucial for CNS exposure.

**15. Binding Affinity:** Ligand B (-8.8 kcal/mol) has a slightly better binding affinity than Ligand A (-7.9 kcal/mol). However, the difference is less than 1.5 kcal/mol, and can be outweighed by other factors.

**Overall Assessment:**

Ligand A consistently outperforms Ligand B across most ADME properties, including TPSA, HBD, HBA, Caco-2 permeability, solubility, hERG inhibition, microsomal clearance, half-life, and P-gp efflux. While Ligand B has slightly better binding affinity, the superior ADME profile of Ligand A, particularly its lower TPSA and better predicted CNS penetration (P-gp, BBB), makes it the more promising drug candidate for a CNS target like DRD2.

Output:
0
2025-04-17 06:05:48,022 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (349.333 Da) is slightly better, being closer to the lower end which can aid permeability.

**TPSA:** Ligand A (66.84) is significantly better than Ligand B (127.59). For CNS targets, TPSA should be <=90, and Ligand A comfortably meets this, while Ligand B is pushing the limit and may have reduced brain penetration.

**logP:** Ligand A (3.694) is optimal (1-3), while Ligand B (-0.341) is quite low. Low logP can hinder membrane permeability and reduce CNS exposure. This is a substantial negative for Ligand B.

**H-Bond Donors/Acceptors:** Ligand A (HBD=1, HBA=3) and Ligand B (HBD=3, HBA=5) are both acceptable, falling within the recommended ranges.

**QED:** Ligand A (0.828) has a better QED score than Ligand B (0.502), indicating a more drug-like profile.

**DILI:** Ligand B (42.458) has a much lower DILI risk than Ligand A (78.402), which is a positive for Ligand B.

**BBB:** Ligand A (56.65) has a slightly better BBB percentile than Ligand B (47.15), but both are below the desirable >70 for CNS targets.

**Caco-2 Permeability:** Ligand A (-4.478) has a worse Caco-2 permeability compared to Ligand B (-5.919). Lower values indicate lower permeability.

**Aqueous Solubility:** Ligand A (-3.451) has a better aqueous solubility than Ligand B (-1.68).

**hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.234 and 0.085 respectively).

**Microsomal Clearance:** Ligand B (4.571) has a lower microsomal clearance than Ligand A (12.726), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand B (-13.614) has a longer in vitro half-life than Ligand A (-9.293).

**P-gp Efflux:** Ligand A (0.107) has lower P-gp efflux liability than Ligand B (0.016), which is favorable for CNS penetration.

**Binding Affinity:** Both ligands have very similar binding affinities (-8.8 kcal/mol and -8.5 kcal/mol). The difference is not substantial enough to override the other ADME differences.

**Overall Assessment:**

Ligand A has a better TPSA, QED, solubility, and P-gp efflux profile, and a slightly better BBB. However, Ligand B has a much better logP, lower DILI risk, lower microsomal clearance, and longer half-life. The low logP of Ligand B is a significant concern for CNS penetration. Considering the GPCR-specific priorities, the TPSA and logP are critical. While Ligand A's BBB isn't ideal, it's still better than Ligand B's, and its TPSA is much more favorable. The better logP and metabolic stability of Ligand B are attractive, but are outweighed by the poor TPSA and logP values.

Output:
0
2025-04-17 06:05:48,022 - INFO - Batch 253 complete. Total preferences: 4048
2025-04-17 06:05:48,022 - INFO - Processing batch 254/512...
2025-04-17 06:06:29,518 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (346.471 Da) is slightly lower, which is generally favorable for permeability.

**TPSA:** Ligand A (49.85) is excellent for CNS penetration, well below the 90 A^2 threshold. Ligand B (93.21) is higher, but still potentially acceptable, though less ideal.

**logP:** Ligand A (3.338) is optimal. Ligand B (2.416) is a bit lower, potentially impacting permeability, but still within a reasonable range.

**H-Bond Donors/Acceptors:** Ligand A (0 HBD, 4 HBA) is favorable. Ligand B (2 HBD, 6 HBA) is also acceptable, though slightly higher counts could potentially affect permeability.

**QED:** Ligand A (0.741) has a better drug-likeness score than Ligand B (0.464).

**DILI:** Ligand B (85.576) has a significantly higher DILI risk than Ligand A (49.011). This is a major concern for Ligand B.

**BBB:** Ligand A (89.027) has excellent BBB penetration potential, exceeding the 70% threshold. Ligand B (62.156) is lower and less desirable for a CNS target.

**Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and suggests a potential issue with the experimental data or the compounds themselves. However, the values are similar and don't strongly differentiate the two.

**Aqueous Solubility:** Both have negative solubility values, also unusual. Again, similar values don't provide a clear advantage for either.

**hERG:** Ligand A (0.844) shows lower hERG inhibition liability than Ligand B (0.115), which is preferable.

**Microsomal Clearance:** Ligand A (67.072) has lower microsomal clearance than Ligand B (74.593), indicating better metabolic stability.

**In vitro Half-Life:** Ligand B (25.413) has a significantly longer half-life than Ligand A (8.05). This is a positive for Ligand B.

**P-gp Efflux:** Ligand A (0.344) has lower P-gp efflux liability than Ligand B (0.046), which is highly desirable for CNS penetration.

**Binding Affinity:** Ligand B (-9.0 kcal/mol) has a significantly stronger binding affinity than Ligand A (-8.4 kcal/mol). This is a substantial advantage for Ligand B, potentially outweighing some of its ADME drawbacks.

**Overall Assessment:**

Ligand A has a superior ADME profile, with better QED, lower DILI risk, better BBB penetration, lower hERG risk, and lower P-gp efflux. However, Ligand B boasts a considerably stronger binding affinity (-9.0 vs -8.4 kcal/mol). For a GPCR, strong affinity is crucial. While Ligand B's DILI risk and BBB penetration are concerns, the substantial affinity advantage, coupled with a longer half-life, makes it the more promising candidate *provided* the DILI risk can be mitigated through structural modifications. The lower P-gp efflux is also beneficial.

Output:
1
2025-04-17 06:06:29,518 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (370.837 Da) is slightly higher than Ligand B (346.475 Da), but both are acceptable.

**TPSA:** Ligand A (85.69) is closer to the ideal range for CNS targets (<=90), while Ligand B (67.23) is even better. Both are good.

**logP:** Ligand A (1.054) is at the lower end of the optimal range (1-3), while Ligand B (2.306) is well within it. This gives a slight edge to Ligand B regarding permeability.

**H-Bond Donors/Acceptors:** Both ligands have 1 HBD and a reasonable number of HBAs (6 for A, 4 for B), satisfying the criteria.

**QED:** Both ligands have acceptable QED values (0.859 and 0.785, both > 0.5).

**DILI:** Ligand A (77.394) has a higher DILI risk than Ligand B (21.753). This is a significant advantage for Ligand B.

**BBB:** Both ligands have good BBB penetration (70.88% and 79.217%), exceeding the 70% threshold for CNS targets. Ligand B is slightly better.

**Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and suggests a potential issue with the data or modeling. However, we can still compare them relatively.

**Aqueous Solubility:** Both have negative solubility values, which is also unusual.

**hERG Inhibition:** Ligand A (0.118) shows very low hERG inhibition risk, while Ligand B (0.612) is slightly higher. This favors Ligand A.

**Microsomal Clearance:** Ligand A (12.784) has lower clearance than Ligand B (50.806), indicating better metabolic stability.

**In vitro Half-Life:** Ligand A (23.769) has a positive half-life, while Ligand B (-23.876) has a negative half-life, which is unusual. This favors Ligand A.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.083 and 0.262).

**Binding Affinity:** Ligand B (-7.8 kcal/mol) has a significantly stronger binding affinity than Ligand A (0.0 kcal/mol). This is a substantial advantage, potentially outweighing some ADME drawbacks.

**Overall Assessment:**

Ligand B has a significantly better binding affinity, lower DILI risk, and slightly better BBB penetration and logP. The negative values for Caco-2 and solubility are concerning but may be artifacts of the modeling. Ligand A has better hERG and metabolic stability, but the substantially weaker binding affinity is a major drawback. For a GPCR target like DRD2, strong binding affinity is paramount.

Output:
1
2025-04-17 06:06:29,519 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (356.451 and 345.418 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (66.4) is slightly higher than Ligand B (62.3). Both are below the 90 A^2 threshold desirable for CNS targets, which is good.

**3. logP:** Both ligands have excellent logP values (2.218 and 2.157), falling within the optimal 1-3 range.

**4. H-Bond Donors:** Ligand A has 0 HBD, while Ligand B has 1. Both are within the acceptable limit of <=5.

**5. H-Bond Acceptors:** Ligand A has 6 HBA, and Ligand B has 3. Both are below the acceptable limit of <=10.

**6. QED:** Ligand A (0.783) has a better QED score than Ligand B (0.657), indicating a more drug-like profile.

**7. DILI:** Ligand A (72.043) has a higher DILI risk than Ligand B (27.608). This is a significant negative for Ligand A.

**8. BBB:** Ligand B (82.474) has a substantially better BBB penetration percentile than Ligand A (76.154). This is crucial for a CNS target like DRD2.

**9. Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and suggests potential issues with permeability prediction. However, the values are similar (-4.82 and -4.424).

**10. Aqueous Solubility:** Both have negative solubility values, again indicating potential issues with prediction. Similar values (-2.203 and -2.454).

**11. hERG Inhibition:** Both ligands show low hERG inhibition liability (0.441 and 0.579), which is favorable.

**12. Microsomal Clearance:** Ligand A (31.517) has higher microsomal clearance than Ligand B (25.966), suggesting lower metabolic stability.

**13. In vitro Half-Life:** Ligand B (-32.255) has a significantly longer in vitro half-life than Ligand A (-3.326). This is a major advantage for Ligand B.

**14. P-gp Efflux:** Both ligands have low P-gp efflux liability (0.505 and 0.125), which is good for CNS penetration. Ligand B is better.

**15. Binding Affinity:** Both ligands have very similar and strong binding affinities (-8.7 and -8.3 kcal/mol). The difference is less than the 1.5 kcal/mol threshold.

**Overall Assessment:**

Ligand B is the better candidate. While both have good potency and logP, Ligand B excels in critical ADME properties for a CNS drug: significantly better BBB penetration, lower DILI risk, and a much longer in vitro half-life. The slightly lower QED is outweighed by these advantages. Ligand A's higher DILI risk and lower BBB penetration are concerning.

Output:
1
2025-04-17 06:06:29,519 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (342.355 and 359.543 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (120.25) is borderline for CNS penetration, being slightly above the preferred <90. Ligand B (55.63) is excellent, well below 90, suggesting better CNS penetration.

**logP:** Ligand A (0.985) is a bit low, potentially hindering permeability. Ligand B (4.625) is high, potentially causing solubility issues and off-target effects, but acceptable.

**H-Bond Donors/Acceptors:** Ligand A (4 HBD, 5 HBA) is within acceptable limits. Ligand B (1 HBD, 6 HBA) is also within limits.

**QED:** Both ligands have good QED scores (0.532 and 0.629), indicating drug-like properties.

**DILI:** Ligand A (74.603) has a higher DILI risk than Ligand B (62.389), though both are reasonably acceptable.

**BBB:** Ligand B (70.88) has a significantly better BBB percentile than Ligand A (11.206). This is a *critical* advantage for a CNS target like DRD2.

**Caco-2 Permeability:** Both have negative Caco-2 values (-5.789 and -5.632), which is unusual and difficult to interpret without more context. However, it suggests poor permeability.

**Aqueous Solubility:** Both have negative solubility values (-3.153 and -3.707), which is also unusual and suggests poor solubility.

**hERG Inhibition:** Both ligands show low hERG inhibition risk (0.389 and 0.453).

**Microsomal Clearance:** Ligand A (-2.949) has a lower (better) microsomal clearance than Ligand B (78.273), indicating better metabolic stability.

**In vitro Half-Life:** Ligand A (72.072) has a much longer half-life than Ligand B (21.892).

**P-gp Efflux:** Ligand A (0.045) has a much lower P-gp efflux liability than Ligand B (0.676), which is favorable for CNS penetration.

**Binding Affinity:** Ligand A (-8.8 kcal/mol) has a significantly stronger binding affinity than Ligand B (-7.0 kcal/mol). This is a substantial advantage.

**Overall Assessment:**

While Ligand A has better metabolic stability, half-life, P-gp efflux, and *significantly* better binding affinity, Ligand B excels in BBB penetration and has a lower DILI risk. Given the CNS target (DRD2), BBB penetration is paramount. The 1.8 kcal/mol difference in binding affinity is substantial, but can potentially be overcome with further optimization. The poor solubility and permeability values for both are concerning and would need to be addressed in further development. However, the superior BBB score of Ligand B, combined with acceptable other parameters, makes it the more promising candidate.

Output:
1
2025-04-17 06:06:29,519 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (366.527 and 363.527 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (78.43) is higher than Ligand B (62.3). For a CNS target like DRD2, TPSA should ideally be <=90. Both are acceptable, but B is better.

**3. logP:** Ligand A (2.685) and Ligand B (3.47) are both within the optimal 1-3 range.

**4. H-Bond Donors:** Ligand A (3) is higher than Ligand B (1). Both are acceptable (<=5).

**5. H-Bond Acceptors:** Both ligands have 4 H-bond acceptors, which is within the acceptable range of <=10.

**6. QED:** Ligand B (0.871) has a significantly higher QED score than Ligand A (0.588), indicating a more drug-like profile.

**7. DILI:** Ligand A (23.575) has a much lower DILI risk than Ligand B (44.397), suggesting better liver safety.

**8. BBB:** Ligand B (77.278) has a significantly higher BBB penetration percentile than Ligand A (50.446). This is *critical* for a CNS target like DRD2.

**9. Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and suggests poor permeability. However, the scale is not specified, so it's difficult to interpret.

**10. Aqueous Solubility:** Both have negative solubility values, again, difficult to interpret without knowing the scale.

**11. hERG Inhibition:** Ligand A (0.383) shows lower hERG inhibition liability than Ligand B (0.527), which is favorable.

**12. Microsomal Clearance:** Ligand A (72.952) has higher microsomal clearance than Ligand B (56.309), indicating lower metabolic stability.

**13. In vitro Half-Life:** Ligand B (-4.965) has a negative half-life, which is not physically possible and suggests an issue with the data. Ligand A (21.214) has a reasonable half-life.

**14. P-gp Efflux:** Ligand A (0.16) has lower P-gp efflux liability than Ligand B (0.295), which is beneficial for CNS penetration.

**15. Binding Affinity:** Ligand B (-8.8 kcal/mol) has a significantly stronger binding affinity than Ligand A (-7.5 kcal/mol). This is a substantial advantage (>1.5 kcal/mol difference).

**Overall Assessment:**

While Ligand A has better DILI, hERG, and P-gp efflux profiles, Ligand B excels in the most crucial areas for a CNS GPCR target: **BBB penetration and binding affinity.** The significantly stronger binding affinity of Ligand B (-8.8 vs -7.5) is a major advantage that can potentially offset some of the less favorable ADME properties. The higher BBB value (77.278) is also very important. The negative half-life for Ligand B is concerning and suggests a data error, but the affinity difference is so large it still warrants consideration.

Output:
1
2025-04-17 06:06:29,519 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (340.423 and 351.531 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (59.59) is significantly better than Ligand B (38.77). For a CNS target like DRD2, a TPSA below 90 is preferred, and A is much closer to this threshold.

**3. logP:** Both ligands have a logP around 3.7 (3.773 and 3.741), which is within the optimal range of 1-3.

**4. H-Bond Donors:** Ligand A has 2 HBD, while Ligand B has 0. Both are acceptable (<=5).

**5. H-Bond Acceptors:** Both ligands have 3 HBA, which is well within the acceptable range (<=10).

**6. QED:** Ligand A (0.891) has a substantially higher QED than Ligand B (0.669), indicating better overall drug-likeness.

**7. DILI:** Ligand A (70.531) has a higher DILI risk than Ligand B (6.708). This is a significant drawback for Ligand A.

**8. BBB:** Both ligands show excellent BBB penetration (Ligand A: 85.072, Ligand B: 88.251). Both are above the desirable 70% threshold for CNS targets. Ligand B is slightly better.

**9. Caco-2 Permeability:** Both have negative Caco-2 values (-4.596 and -4.537). This is unusual and suggests poor permeability. However, the values are very close.

**10. Aqueous Solubility:** Both ligands have negative solubility values (-4.948 and -3.686), indicating very poor aqueous solubility. This is a significant concern for both.

**11. hERG Inhibition:** Both ligands have low hERG inhibition risk (Ligand A: 0.808, Ligand B: 0.795).

**12. Microsomal Clearance:** Ligand B (101.616) has a higher microsomal clearance than Ligand A (83.85), indicating faster metabolism and potentially lower *in vivo* exposure.

**13. In vitro Half-Life:** Ligand A (20.594) has a longer half-life than Ligand B (13.813), which is generally desirable.

**14. P-gp Efflux:** Both ligands have low P-gp efflux liability (Ligand A: 0.504, Ligand B: 0.427).

**15. Binding Affinity:** Ligand A (-9.9 kcal/mol) has a significantly stronger binding affinity than Ligand B (-6.7 kcal/mol). This is a >3 kcal/mol difference, which is a substantial advantage and can outweigh some ADME concerns.

**Overall Assessment:**

Ligand A has a much stronger binding affinity and better QED and half-life. However, it has a significantly higher DILI risk and worse TPSA. Ligand B has a much lower DILI risk, slightly better BBB penetration, and a better TPSA, but its binding affinity is considerably weaker.

Given the GPCR-specific priorities, the strong binding affinity of Ligand A is a major advantage. While the DILI risk is concerning, it might be mitigated through structural modifications during lead optimization. The poor solubility of both compounds is a shared concern, but can also be addressed during optimization. The slightly better TPSA of Ligand B is not enough to offset the large difference in binding affinity.

Output:
1
2025-04-17 06:06:29,520 - INFO - Reasoning:

Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (399.288 and 362.495 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (53.33) is significantly better than Ligand B (79.03). For CNS targets, we want TPSA <= 90, and A is comfortably within this range, while B is approaching the upper limit.

**logP:** Ligand A (4.352) is a bit high, potentially leading to solubility issues and off-target effects. Ligand B (2.657) is within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A (0 HBD, 3 HBA) and Ligand B (2 HBD, 3 HBA) both have reasonable numbers of H-bonds, well within the guidelines.

**QED:** Both ligands have good QED scores (0.651 and 0.878), indicating good drug-like properties.

**DILI:** Both ligands have acceptable DILI risk (49.515 and 56.96), below the 60 threshold.

**BBB:** Ligand A (58.86) is suboptimal for a CNS target, falling below the desirable >70 threshold. Ligand B (72.237) is much better, exceeding the 70% threshold. This is a critical advantage for CNS penetration.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.739 and -5.362). This is unusual and suggests poor permeability. However, these values are on a log scale, so the negative values indicate very low permeability.

**Aqueous Solubility:** Both ligands have negative solubility values (-5.366 and -3.311). Similar to Caco-2, this suggests very poor aqueous solubility.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.922 and 0.618).

**Microsomal Clearance:** Ligand A (98.414) has a very high microsomal clearance, indicating rapid metabolism and potentially low bioavailability. Ligand B (55.466) has a moderate clearance, which is preferable.

**In vitro Half-Life:** Ligand A (32.715 hours) has a reasonable half-life. Ligand B (-3.516 hours) has a negative half-life, which is not physically possible and indicates a significant issue with the data or the molecule's stability.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.619 and 0.404), which is good for CNS exposure.

**Binding Affinity:** Ligand B (-9.7 kcal/mol) has a significantly stronger binding affinity than Ligand A (-8.7 kcal/mol). This 1 kcal/mol difference is substantial and can outweigh some ADME drawbacks.

**Overall Assessment:**

While Ligand A has a better TPSA, its high logP, very high clearance, and suboptimal BBB penetration are significant drawbacks for a CNS-targeting drug. Ligand B, despite a slightly higher TPSA, has a much better BBB score, a more favorable logP, lower clearance, and *significantly* stronger binding affinity. The negative half-life for Ligand B is a major concern and suggests the data is flawed or the molecule is unstable. However, the affinity difference is so large that it warrants further investigation into the half-life issue.

Output:
1
2025-04-17 06:06:29,520 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (384.259 Da) and Ligand B (362.495 Da) are both acceptable.

**TPSA:** Both ligands have TPSA values below 90, which is good for CNS penetration. Ligand A (78.79) is slightly higher than Ligand B (66.57), but both are favorable.

**logP:** Both ligands have logP values around 3.6, which is within the optimal range (1-3).

**H-Bond Donors/Acceptors:** Ligand A has 3 HBD and 4 HBA, while Ligand B has 1 HBD and 5 HBA. Both are within acceptable limits (<=5 HBD and <=10 HBA).

**QED:** Both ligands have good QED scores (A: 0.711, B: 0.851), indicating good drug-like properties.

**DILI:** Ligand A has a DILI risk of 59.636%, which is approaching the higher risk threshold. Ligand B has a significantly lower DILI risk of 22.838%, which is a substantial advantage.

**BBB:** Ligand B has a much better BBB penetration percentile (52.23%) compared to Ligand A (29.275%). This is a critical factor for a CNS target like DRD2.

**Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and suggests poor permeability. However, the scale is not specified, so it's hard to interpret.

**Aqueous Solubility:** Both have negative solubility values, also unusual. Again, the scale is unspecified, making interpretation difficult.

**hERG Inhibition:** Both ligands show low hERG inhibition liability (A: 0.667, B: 0.362), which is favorable.

**Microsomal Clearance:** Ligand B has a much higher microsomal clearance (40.522 mL/min/kg) than Ligand A (9.982 mL/min/kg). Lower clearance is preferred for better metabolic stability.

**In vitro Half-Life:** Ligand B has a longer in vitro half-life (46.344 hours) than Ligand A (25.206 hours). This is a positive attribute.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (A: 0.491, B: 0.341), which is good for CNS exposure.

**Binding Affinity:** Ligand A has a better binding affinity (-8.9 kcal/mol) than Ligand B (-7.6 kcal/mol). This is a significant advantage, exceeding the 1.5 kcal/mol threshold.

**Overall Assessment:**

While Ligand A boasts a superior binding affinity, Ligand B has a much more favorable ADME profile, particularly regarding BBB penetration (critical for a CNS target), lower DILI risk, and better metabolic stability (lower Cl_mic and longer t1/2). The difference in binding affinity (1.3 kcal/mol) is substantial, but the improved ADME properties of Ligand B, especially the BBB score, outweigh this difference for a DRD2 ligand.

Output:
1
2025-04-17 06:06:29,520 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (349.519 and 361.511 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (52.65) is significantly better than Ligand B (57.84). For CNS targets, we want TPSA <= 90, both are well within this range, but A is preferable.

**logP:** Both ligands have good logP values (2.428 and 3.322), falling within the optimal 1-3 range. Ligand B is slightly higher, which could potentially lead to some off-target effects, but is not a major concern.

**H-Bond Donors/Acceptors:** Both have 1 HBD, which is good. Ligand A has 3 HBA, and Ligand B has 5. Both are acceptable (<=10), but A is slightly better.

**QED:** Both ligands have good QED scores (0.776 and 0.889), indicating good drug-like properties.

**DILI:** Ligand A (10.741) has a much lower DILI risk than Ligand B (29.159). This is a significant advantage for Ligand A.

**BBB:** Ligand A (69.058) and Ligand B (76.464) both have good BBB penetration, exceeding the desirable >70 threshold for CNS targets. Ligand B is slightly better.

**Caco-2 Permeability:** Both have negative Caco-2 values (-4.749 and -4.687), which is unusual and suggests poor permeability. This is a significant drawback for both.

**Aqueous Solubility:** Both have negative solubility values (-2.447 and -3.601), indicating very poor aqueous solubility. This is a major concern for both compounds.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.523 and 0.628), which is good.

**Microsomal Clearance:** Ligand A (16.188) has a lower microsomal clearance than Ligand B (65.88), indicating better metabolic stability.

**In vitro Half-Life:** Ligand A (-11.214) has a negative half-life, which is not physically possible. Ligand B (-13.191) also has a negative half-life. Both are problematic.

**P-gp Efflux:** Both have very low P-gp efflux liability (0.031 and 0.504), which is good for CNS penetration.

**Binding Affinity:** Ligand A (-8.1 kcal/mol) has a slightly better binding affinity than Ligand B (-7.0 kcal/mol). This 1.1 kcal/mol difference is substantial and can outweigh some ADME drawbacks.

**Overall Assessment:**

Ligand A is the better candidate. While both have poor solubility and permeability, Ligand A has a significantly lower DILI risk, better metabolic stability (lower Cl_mic), and a superior binding affinity. The slightly better BBB penetration of Ligand B is not enough to compensate for these advantages. The negative half-life values are concerning for both, but this could be an artifact of the prediction method.

Output:
0
2025-04-17 06:06:29,520 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (341.382 and 352.36 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (38.77) is significantly better than Ligand B (61.02). For CNS targets, we want TPSA <= 90, and ideally much lower. Ligand A is well within this range, while Ligand B is pushing the upper limit and less favorable.

**logP:** Both ligands have good logP values (3.671 and 4.278), falling within the optimal 1-3 range. Ligand B is slightly higher, which *could* indicate potential off-target effects, but isn't a major concern.

**H-Bond Donors/Acceptors:** Ligand A has 0 HBD and 3 HBA, while Ligand B has 2 HBD and 2 HBA. Both are acceptable, well below the thresholds of 5 and 10, respectively.

**QED:** Both ligands have similar and good QED values (0.837 and 0.863), indicating good drug-like properties.

**DILI:** Ligand A (66.615) has a higher DILI risk than Ligand B (52.579). This is a negative for Ligand A.

**BBB:** Both ligands have excellent BBB penetration (87.088 and 85.576), exceeding the desirable >70 threshold for CNS targets.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.146 and -4.707). This is unusual and requires further investigation, but doesn't immediately disqualify either.

**Aqueous Solubility:** Both ligands have negative solubility values (-4.383 and -5.124), also unusual and requiring further investigation.

**hERG Inhibition:** Ligand A (0.856) has a slightly higher hERG risk than Ligand B (0.611), but both are reasonably low.

**Microsomal Clearance:** Ligand A (86.796) has higher microsomal clearance than Ligand B (36.725). This suggests Ligand B is more metabolically stable, which is desirable.

**In vitro Half-Life:** Ligand B (-14.354) has a negative half-life, which is impossible and indicates a data error or a very rapidly metabolized compound. This is a significant negative for Ligand B. Ligand A (32.365) has a reasonable half-life.

**P-gp Efflux:** Ligand A (0.8) has lower P-gp efflux than Ligand B (0.279), which is favorable for CNS penetration.

**Binding Affinity:** Both ligands have excellent binding affinity (-9.2 and -8.8 kcal/mol). The difference of 0.4 kcal/mol is not substantial enough to outweigh other factors.

**Overall Assessment:**

Ligand A excels in TPSA, P-gp efflux, and has a reasonable half-life. While its DILI risk is higher, the other favorable properties, particularly the low TPSA and P-gp efflux, are crucial for CNS penetration. Ligand B has a lower DILI risk and better metabolic stability, but its significantly higher TPSA and the nonsensical negative half-life are major drawbacks. The negative half-life is a critical issue.

Output:
0
2025-04-17 06:06:29,520 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 drug candidates, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (350.547 and 342.439 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Both ligands have TPSA values (50.36 and 49.85) below the 90 A^2 threshold for CNS targets, which is excellent.

**3. logP:** Ligand A (4.345) is slightly above the optimal range (1-3) but still potentially acceptable. Ligand B (2.155) is within the optimal range.

**4. H-Bond Donors:** Ligand A (2) is within the acceptable limit of <=5. Ligand B (0) is also good.

**5. H-Bond Acceptors:** Ligand A (2) is within the acceptable limit of <=10. Ligand B (3) is also good.

**6. QED:** Both ligands have good QED values (0.748 and 0.827), indicating drug-like properties.

**7. DILI:** Ligand A (23.846) has a significantly lower DILI risk than Ligand B (49.283), which is a major advantage.

**8. BBB:** Ligand A (85.459) has a better BBB penetration percentile than Ligand B (73.943), which is crucial for a CNS target like DRD2.

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.667 and -4.373), which is unusual and suggests poor permeability. However, these values are on a log scale and a negative value doesn't necessarily preclude development, but warrants further investigation.

**10. Aqueous Solubility:** Both ligands have negative solubility values (-4.363 and -2.08), which is concerning. Poor solubility can hinder bioavailability.

**11. hERG Inhibition:** Both ligands have low hERG inhibition liability (0.67 and 0.514), which is positive.

**12. Microsomal Clearance:** Ligand A (62.285) has a higher microsomal clearance than Ligand B (44.136), meaning it's metabolized faster. This is a disadvantage.

**13. In vitro Half-Life:** Ligand B (5.113) has a slightly longer in vitro half-life than Ligand A (24.77), which is preferable.

**14. P-gp Efflux:** Both ligands have low P-gp efflux liability (0.195 and 0.298), which is good for CNS penetration.

**15. Binding Affinity:** Both ligands have very similar and strong binding affinities (-8.9 and -8.8 kcal/mol). The difference is negligible.

**Overall Assessment:**

Considering the GPCR-specific priorities, Ligand A is slightly favored. While it has a higher microsomal clearance, its significantly lower DILI risk and better BBB penetration are critical advantages for a CNS drug candidate. Both ligands have poor solubility and permeability, which are major drawbacks that would need to be addressed through formulation or structural modifications. However, the improved safety profile and CNS exposure potential of Ligand A make it the more promising candidate.

Output:
0
2025-04-17 06:06:29,521 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (359.491 and 350.375 Da) are within the ideal 200-500 Da range.

**TPSA:** Ligand A (55.4) is significantly better than Ligand B (119.51). For CNS targets, TPSA should be <= 90, and A comfortably meets this, while B is above.

**logP:** Ligand A (3.801) is optimal (1-3), while Ligand B (0.063) is quite low, potentially hindering membrane permeability.

**H-Bond Donors/Acceptors:** Ligand A (HBD=1, HBA=3) and Ligand B (HBD=2, HBA=7) both fall within acceptable ranges.

**QED:** Both ligands have reasonable QED values (A: 0.853, B: 0.636), indicating good drug-like properties.

**DILI:** Ligand A (55.68) is slightly higher than Ligand B (72.819), suggesting a slightly increased risk of liver injury for A, but both are reasonably acceptable.

**BBB:** Ligand A (60.45) is lower than Ligand B (54.478). While both are below the desirable >70 for CNS targets, B is lower.

**Caco-2 Permeability:** Both have negative values (-4.591 and -4.83), which is unusual and suggests poor permeability.

**Aqueous Solubility:** Both have negative values (-5.175 and -2.965). This is also unusual and suggests poor solubility.

**hERG Inhibition:** Ligand A (0.575) has a much lower hERG risk than Ligand B (0.029).

**Microsomal Clearance:** Ligand A (90.275) has higher clearance than Ligand B (55.993), indicating lower metabolic stability.

**In vitro Half-Life:** Ligand A (-18.137) has a shorter half-life than Ligand B (-21.245).

**P-gp Efflux:** Ligand A (0.314) has lower P-gp efflux liability than Ligand B (0.029), which is favorable for CNS penetration.

**Binding Affinity:** Ligand A (-9.1 kcal/mol) has a significantly stronger binding affinity than Ligand B (-7.2 kcal/mol). This is a substantial difference (>1.5 kcal/mol) and can often outweigh minor ADME drawbacks.

**Overall Assessment:**

Given the GPCR-specific priorities, the most important factors are BBB, logP, TPSA, Pgp, and affinity. Ligand A excels in TPSA, logP, Pgp, and *especially* affinity. While its BBB is not ideal, its significantly superior binding affinity and better logP and TPSA make it a more promising candidate. Ligand B's low logP is a major concern, and its lower affinity further diminishes its potential. The negative Caco-2 and solubility values for both are concerning, but the affinity difference is substantial enough to favor A.

Output:
1
2025-04-17 06:06:29,521 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (347.371 and 346.475 Da) fall comfortably within the ideal 200-500 Da range.

**TPSA:** Ligand A (108.81) is higher than Ligand B (58.44). For CNS targets, TPSA should be <= 90. Ligand B is significantly better in this regard.

**logP:** Ligand A (0.971) is a bit low, potentially hindering membrane permeability. Ligand B (2.488) is within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A has 2 HBD and 6 HBA, while Ligand B has 0 HBD and 4 HBA. Both are within acceptable limits.

**QED:** Ligand A (0.806) has a better QED score than Ligand B (0.68), suggesting a more drug-like profile overall.

**DILI:** Ligand B (23.032) has a much lower DILI risk than Ligand A (53.005), indicating better predicted liver safety.

**BBB:** Ligand B (75.921) has a significantly higher BBB penetration score than Ligand A (27.646). This is *critical* for a CNS target like DRD2.

**Caco-2 Permeability:** Ligand A (-5.078) has a worse Caco-2 permeability score than Ligand B (-4.423), suggesting lower intestinal absorption.

**Aqueous Solubility:** Both ligands have similar, poor aqueous solubility scores (-1.993 and -1.887). This could pose formulation challenges, but is less critical than BBB for a CNS drug.

**hERG Inhibition:** Ligand A (0.152) has a slightly lower hERG inhibition risk than Ligand B (0.391), which is favorable.

**Microsomal Clearance:** Ligand B (55.374) has a lower microsomal clearance than Ligand A (19.564), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand B (2.165) has a longer in vitro half-life than Ligand A (-2.816).

**P-gp Efflux:** Ligand A (0.034) has a lower P-gp efflux liability than Ligand B (0.072), which is desirable for CNS penetration.

**Binding Affinity:** Ligand B (-7.8 kcal/mol) has a slightly better binding affinity than Ligand A (-8.1 kcal/mol). While the difference is small, it's still a positive.

**Overall Assessment:**

Ligand B is the stronger candidate. While Ligand A has a slightly better QED and lower P-gp efflux, Ligand B excels in the most crucial areas for a CNS-targeting GPCR: **BBB penetration (75.921 vs 27.646), TPSA (58.44 vs 108.81), and metabolic stability (lower Cl_mic and longer t1/2).** The lower DILI risk for Ligand B is also a significant advantage. The slightly better affinity of Ligand B further supports its selection. The lower logP of Ligand A is a concern, and the higher TPSA is problematic for CNS entry.

Output:
1
2025-04-17 06:06:29,521 - INFO - Reasoning:

Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (343.475 and 349.431 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (63.05) is excellent, well below the 90 A^2 threshold for CNS targets. Ligand B (101.9) is higher but still potentially acceptable, though less ideal.

**3. logP:** Ligand A (2.441) is within the optimal range of 1-3. Ligand B (0.012) is very low, which could significantly hinder membrane permeability and CNS penetration.

**4. H-Bond Donors:** Ligand A (1) is good. Ligand B (4) is at the higher end of the acceptable range.

**5. H-Bond Acceptors:** Ligand A (4) is good. Ligand B (5) is acceptable.

**6. QED:** Ligand A (0.854) is excellent, indicating strong drug-like properties. Ligand B (0.503) is acceptable, but lower than Ligand A.

**7. DILI:** Ligand A (32.028) has a low DILI risk. Ligand B (4.382) has a very low DILI risk, which is positive.

**8. BBB:** Ligand A (79.488) has a good BBB percentile. Ligand B (17.836) has a very poor BBB percentile, a major concern for a CNS target.

**9. Caco-2 Permeability:** Ligand A (-4.71) is concerningly low, suggesting poor intestinal absorption. Ligand B (-6.024) is even worse.

**10. Aqueous Solubility:** Ligand A (-2.7) is poor. Ligand B (-1.484) is also poor.

**11. hERG Inhibition:** Both ligands show very low hERG inhibition risk (0.119 and 0.067, respectively).

**12. Microsomal Clearance:** Ligand A (15.074) is moderate. Ligand B (-1.676) is excellent, indicating high metabolic stability.

**13. In vitro Half-Life:** Ligand A (25.213) is reasonable. Ligand B (-22.096) is exceptionally high, suggesting very slow metabolism.

**14. P-gp Efflux:** Both ligands show low P-gp efflux liability (0.123 and 0.004, respectively).

**15. Binding Affinity:** Both ligands have very strong binding affinities (-9 and -8.4 kcal/mol), with Ligand A being slightly better. The affinity difference is not large enough to overcome the significant ADME deficiencies of Ligand B.

**Overall Assessment:**

Ligand A is the better candidate despite its poor Caco-2 permeability and solubility. Its superior BBB penetration, good TPSA and logP values, and excellent QED score make it more likely to reach the target in the CNS. Ligand B, despite its excellent metabolic stability and low DILI, suffers from extremely poor BBB penetration and a very low logP, which will severely limit its ability to cross the blood-brain barrier. The strong binding affinity of Ligand B is overshadowed by its poor pharmacokinetic properties.

Output:
1
2025-04-17 06:06:29,521 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (349.341 and 355.507 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (79.26) is better than Ligand B (59.22). Both are below the 90 A^2 threshold desirable for CNS targets, but A is closer to the upper limit.

**logP:** Ligand A (1.337) is within the optimal 1-3 range. Ligand B (3.765) is at the higher end of the optimal range, potentially increasing off-target effects.

**H-Bond Donors/Acceptors:** Ligand A has 2 HBD and 5 HBA, while Ligand B has 1 HBD and 4 HBA. Both are within acceptable limits.

**QED:** Both ligands have similar QED values (0.854 and 0.858), indicating good drug-likeness.

**DILI:** Ligand A (84.374) has a significantly higher DILI risk than Ligand B (38.348). This is a major concern for Ligand A.

**BBB:** Ligand B (92.555) has a much higher BBB penetration percentile than Ligand A (64.017). This is crucial for a CNS target like DRD2.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.056 and -5.009). This is unusual and suggests poor permeability. However, these values are on a log scale and should be interpreted cautiously.

**Aqueous Solubility:** Both ligands have negative solubility values (-3.594 and -3.884), indicating poor aqueous solubility.

**hERG Inhibition:** Ligand A (0.469) has a slightly lower hERG inhibition risk than Ligand B (0.871).

**Microsomal Clearance:** Ligand B (76.594) has a significantly higher microsomal clearance than Ligand A (3.827), suggesting lower metabolic stability.

**In vitro Half-Life:** Ligand A (-9.079) has a much longer in vitro half-life than Ligand B (0.524). This is a positive attribute for Ligand A.

**P-gp Efflux:** Ligand A (0.112) has a lower P-gp efflux liability than Ligand B (0.706), which is beneficial for CNS penetration.

**Binding Affinity:** Ligand B (-8.3 kcal/mol) has a stronger binding affinity than Ligand A (-9.1 kcal/mol). While A has a slightly better affinity, the difference is not substantial enough to outweigh other factors.

**Overall Assessment:**

Ligand B is the more promising candidate. While it has a higher logP and P-gp efflux, its significantly better BBB penetration, lower DILI risk, and stronger binding affinity are critical advantages for a CNS-targeting GPCR. Ligand A's high DILI risk is a major red flag. The longer half-life and lower P-gp efflux of Ligand A are positive, but do not compensate for the DILI and BBB issues.

Output:
1
2025-04-17 06:06:29,522 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (344.371 and 351.403 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (87.76) is excellent, falling well below the 90 A^2 threshold for CNS targets. Ligand B (113.69) is still reasonable, but less optimal, being above 100.

**3. logP:** Ligand A (-0.378) is a bit low, potentially hindering permeation. Ligand B (0.945) is better, falling within the optimal 1-3 range.

**4. H-Bond Donors:** Ligand A (1) is good. Ligand B (3) is acceptable, but higher.

**5. H-Bond Acceptors:** Ligand A (5) is good. Ligand B (6) is acceptable.

**6. QED:** Both ligands have acceptable QED values (0.756 and 0.601), indicating good drug-like properties.

**7. DILI:** Ligand A (62.97) has a slightly higher DILI risk than Ligand B (54.207), but both are within acceptable limits (<60 is good).

**8. BBB:** This is crucial for a CNS target. Ligand A (28.887) has a very low BBB penetration percentile, which is a major drawback. Ligand B (41.218) is better, but still not ideal (we want >70).

**9. Caco-2 Permeability:** Both have negative values (-4.805 and -5.236), which is unusual. Assuming these are logP-like scales, lower values indicate poorer permeability. Ligand A is slightly better.

**10. Aqueous Solubility:** Both ligands have very poor aqueous solubility (-2.636 and -2.187). This could pose formulation challenges.

**11. hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.182 and 0.134).

**12. Microsomal Clearance:** Ligand A (-10.579) has significantly lower (better) microsomal clearance than Ligand B (5.669), suggesting greater metabolic stability.

**13. In vitro Half-Life:** Ligand A (6.503) has a shorter half-life than Ligand B (45.437), which is less desirable.

**14. P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.016 and 0.169).

**15. Binding Affinity:** Ligand B (-8.4 kcal/mol) has a slightly better binding affinity than Ligand A (-7.9 kcal/mol). While the difference is not huge, it's a positive.

**Overall Assessment:**

Ligand A has a better TPSA and clearance, but suffers from very poor BBB penetration and a shorter half-life. Its logP is also suboptimal. Ligand B has a better logP, BBB penetration, half-life, and binding affinity, but a slightly higher TPSA and clearance.

Given the GPCR-specific priorities, **BBB penetration is paramount for a CNS target like DRD2.** While Ligand B's BBB value isn't ideal, it's significantly better than Ligand A's. The slightly better binding affinity of Ligand B, combined with its more favorable logP and half-life, outweighs its slightly higher TPSA and clearance.

Output:
1
2025-04-17 06:06:29,522 - INFO - Batch 254 complete. Total preferences: 4064
2025-04-17 06:06:29,522 - INFO - Processing batch 255/512...
2025-04-17 06:07:10,318 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B based on the provided guidelines, prioritizing GPCR-specific properties (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (340.383 and 350.419 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (77.75) is significantly better than Ligand B (102.44). For CNS targets, we want TPSA <= 90, and A is comfortably within that range, while B is slightly above.

**logP:** Ligand A (2.075) is optimal (1-3), while Ligand B (0.379) is quite low, potentially hindering permeation.

**H-Bond Donors/Acceptors:** Ligand A (HBD=1, HBA=7) and Ligand B (HBD=2, HBA=6) both have reasonable values, well within the guidelines.

**QED:** Both ligands have good QED values (A=0.5, B=0.703), indicating good drug-like properties.

**DILI:** Ligand A (70.725) has a higher DILI risk than Ligand B (41.838), but both are acceptable.

**BBB:** Ligand B (63.009) has a slightly better BBB penetration than Ligand A (59.442), but both are below the desirable >70 for CNS targets. This is a weakness for both, but less so for B.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.921 and -4.886), which is unusual and suggests poor permeability. This is a significant concern for both.

**Aqueous Solubility:** Both ligands have negative solubility values (-2.593 and -1.297), which is also unusual and suggests poor solubility. This is a significant concern for both.

**hERG Inhibition:** Ligand A (0.796) has a slightly higher hERG risk than Ligand B (0.171), but both are relatively low.

**Microsomal Clearance:** Ligand A (88.809) has a much higher microsomal clearance than Ligand B (17.045), indicating poorer metabolic stability.

**In vitro Half-Life:** Ligand B (20.451) has a significantly longer in vitro half-life than Ligand A (-5.236), which is a major advantage.

**P-gp Efflux:** Ligand A (0.228) has lower P-gp efflux than Ligand B (0.003), which is favorable for CNS penetration.

**Binding Affinity:** Ligand A (-7.7 kcal/mol) has a slightly better binding affinity than Ligand B (-7.5 kcal/mol), although the difference is small.

**Overall Assessment:**

Considering the GPCR-specific priorities, Ligand A is better despite the slightly higher DILI and lower BBB. The key advantages of Ligand A are its significantly better TPSA and logP, and lower P-gp efflux. These properties are more critical for CNS penetration than the slight advantage of Ligand B in BBB. The superior binding affinity of A is also a factor. The poor Caco-2 and solubility are concerning for both, but can potentially be addressed with formulation strategies. The metabolic stability of Ligand B is a significant advantage, but the poor logP and higher P-gp efflux are major drawbacks for a CNS target.

Output:
1
2025-04-17 06:07:10,318 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (363.571 and 349.326 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (53.16) is excellent, well below the 90 A^2 threshold for CNS targets. Ligand B (125.87) is higher, but still potentially acceptable, though less desirable.

**3. logP:** Ligand A (3.429) is within the optimal 1-3 range. Ligand B (-1.22) is significantly lower, which could hinder membrane permeability and CNS penetration.

**4. H-Bond Donors:** Both ligands have acceptable HBD counts (3 and 2 respectively), below the 5 threshold.

**5. H-Bond Acceptors:** Ligand A (4) is good, below the 10 threshold. Ligand B (7) is also acceptable, but closer to the upper limit.

**6. QED:** Both ligands have similar and good QED values (0.695 and 0.697), indicating good drug-like properties.

**7. DILI:** Ligand A (18.418) has a much lower DILI risk than Ligand B (78.713). This is a significant advantage for Ligand A.

**8. BBB:** Ligand A (77.898) has a good BBB percentile, exceeding the 70% threshold for CNS targets. Ligand B (44.668) is considerably lower, suggesting poor brain penetration.

**9. Caco-2 Permeability:** Both have negative values, which is unusual. Assuming these are logP-scale values, they indicate poor permeability.

**10. Aqueous Solubility:** Both have negative values, indicating poor solubility.

**11. hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.742 and 0.09).

**12. Microsomal Clearance:** Ligand A (29.175) has a moderate clearance, while Ligand B (0.989) has very low clearance, suggesting high metabolic stability.

**13. In vitro Half-Life:** Ligand A (44.099) has a reasonable half-life. Ligand B (-22.908) has a negative half-life, which is not possible and indicates a problem with the data.

**14. P-gp Efflux:** Ligand A (0.139) has low P-gp efflux, which is favorable for CNS penetration. Ligand B (0.01) also has low P-gp efflux.

**15. Binding Affinity:** Ligand B (-9.2 kcal/mol) has a significantly stronger binding affinity than Ligand A (-7.7 kcal/mol), exceeding the 1.5 kcal/mol advantage threshold.

**Overall Assessment:**

Despite the superior binding affinity of Ligand B, several critical factors favor Ligand A. Ligand B's low logP raises concerns about permeability and BBB penetration, which are crucial for a CNS target like DRD2. Its high DILI risk is also a major drawback. The negative half-life is a data quality issue. Ligand A, while having a slightly weaker binding affinity, exhibits a much better balance of properties, including good BBB penetration, lower DILI risk, and acceptable metabolic stability. The TPSA is also significantly better for Ligand A. Given the GPCR-specific priorities, the better overall profile of Ligand A makes it the more promising drug candidate.

Output:
1
2025-04-17 06:07:10,318 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (332.403 Da) is slightly lower than Ligand B (346.515 Da), but both are acceptable.

**TPSA:** Ligand A (52.08) is higher than Ligand B (40.62). For CNS targets, we want TPSA <= 90, both are well within this range. Ligand B is preferable here.

**logP:** Ligand A (4.299) is slightly higher than the optimal range (1-3), potentially leading to solubility issues. Ligand B (3.739) is closer to the optimal range. Ligand B is preferable.

**H-Bond Donors:** Both ligands have 0 HBD, which is good.

**H-Bond Acceptors:** Ligand A has 4 HBA, while Ligand B has 2. Lower is generally better for permeability, so Ligand B is preferable.

**QED:** Both ligands have good QED scores (A: 0.654, B: 0.704), indicating drug-like properties. Ligand B is slightly better.

**DILI:** Ligand A (64.831) has a higher DILI risk than Ligand B (15.083). This is a significant advantage for Ligand B.

**BBB:** Ligand A (49.864) has a lower BBB penetration score than Ligand B (91.392). This is a *critical* difference, as DRD2 is a CNS target. Ligand B is strongly preferred.

**Caco-2 Permeability:** Both have negative values, which is unusual and suggests poor permeability. However, the scale isn't specified, so it's difficult to interpret.

**Aqueous Solubility:** Both have negative values, indicating poor solubility.

**hERG:** Both have low hERG inhibition liability (A: 0.441, B: 0.575), which is good.

**Microsomal Clearance:** Ligand A (103.101) has higher microsomal clearance than Ligand B (80.527), indicating lower metabolic stability. Ligand B is preferable.

**In vitro Half-Life:** Ligand A (-27.535) has a negative half-life, which is not possible. Ligand B (1.205) has a short half-life, but it's at least a positive value. This is a significant advantage for Ligand B.

**P-gp Efflux:** Ligand A (0.288) has lower P-gp efflux than Ligand B (0.333), which is preferable for CNS penetration.

**Binding Affinity:** Ligand B (-8.5 kcal/mol) has a significantly stronger binding affinity than Ligand A (-10.2 kcal/mol). This is a substantial advantage for Ligand B, potentially outweighing some minor ADME drawbacks.

**Overall:**

Ligand B consistently outperforms Ligand A across most crucial parameters for a CNS-targeting GPCR ligand. The most important factors are the significantly better BBB penetration (91.392 vs 49.864) and the much stronger binding affinity (-8.5 vs -10.2 kcal/mol). While both have solubility concerns, Ligand B's superior ADME profile and potency make it the more promising candidate. Ligand A's negative in vitro half-life is also a major red flag.

Output:
1
2025-04-17 06:07:10,319 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 drug candidates, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (334.354 Da and 363.418 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (70.67) is significantly better than Ligand B (83.29). For CNS targets, we want TPSA <= 90, and A is closer to the optimal range for brain penetration.

**3. logP:** Ligand A (3.74) is slightly higher than the optimal 1-3 range, but still acceptable. Ligand B (1.115) is a bit low, potentially hindering membrane permeability.

**4. H-Bond Donors:** Both ligands have 2 HBD, which is within the acceptable limit of <=5.

**5. H-Bond Acceptors:** Ligand A has 3 HBA, and Ligand B has 5. Both are within the acceptable limit of <=10.

**6. QED:** Both ligands have good QED scores (0.599 and 0.713), indicating good drug-like properties.

**7. DILI:** Ligand A (88.251) has a higher DILI risk than Ligand B (73.245), but both are still reasonably acceptable.

**8. BBB:** Ligand B (74.719) has a significantly better BBB percentile than Ligand A (61.38). This is a crucial factor for a CNS target like DRD2.

**9. Caco-2 Permeability:** Both have negative values, indicating poor permeability. Ligand A (-5.379) is slightly worse than Ligand B (-5.188).

**10. Aqueous Solubility:** Both have negative values, indicating poor solubility. Ligand A (-3.783) is slightly worse than Ligand B (-2.791).

**11. hERG Inhibition:** Both ligands have low hERG inhibition risk (0.805 and 0.604).

**12. Microsomal Clearance:** Ligand B (34.334) has lower microsomal clearance than Ligand A (44.15), suggesting better metabolic stability.

**13. In vitro Half-Life:** Ligand A (44.807) has a longer half-life than Ligand B (12.711).

**14. P-gp Efflux:** Both have low P-gp efflux liability (0.3 and 0.232).

**15. Binding Affinity:** Both ligands have excellent binding affinities (-9.7 and -9.1 kcal/mol). The difference of 0.6 kcal/mol is not substantial enough to outweigh other ADME considerations.

**Overall Assessment:**

While Ligand A has a longer half-life, Ligand B clearly wins out due to its superior BBB penetration (74.719 vs 61.38), better metabolic stability (lower Cl_mic), and slightly better logP. The TPSA is also more favorable for Ligand B. For a CNS target like DRD2, BBB penetration is paramount, and Ligand B's higher score makes it the more promising candidate.

Output:
1
2025-04-17 06:07:10,319 - INFO - Reasoning:

Let's analyze Ligand A and Ligand B based on the provided guidelines and GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (349.308 and 357.382 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (46.61) is excellent, well below the 90 A^2 threshold for CNS targets. Ligand B (102.69) is higher, but still potentially acceptable, though less ideal.

**3. logP:** Ligand A (2.891) is optimal (1-3). Ligand B (1.135) is a bit low, potentially impacting permeability.

**4. H-Bond Donors:** Ligand A (0) is good. Ligand B (2) is also acceptable.

**5. H-Bond Acceptors:** Ligand A (4) is good. Ligand B (6) is also acceptable.

**6. QED:** Both ligands (0.629 and 0.609) have good drug-likeness scores (>0.5).

**7. DILI:** Ligand A (76.464) has a higher DILI risk than Ligand B (47.77). Ligand B is preferable here.

**8. BBB:** Both ligands have excellent BBB penetration (86.39 and 87.902), exceeding the >70% threshold for CNS targets.

**9. Caco-2:** Both have negative values, which is unusual. Assuming these are log values, both are poor.

**10. Solubility:** Both have negative values, indicating poor solubility.

**11. hERG:** Both ligands have low hERG inhibition risk (0.492 and 0.421).

**12. Cl_mic:** Ligand A (90.416) has a higher microsomal clearance, indicating lower metabolic stability, compared to Ligand B (29.387). Ligand B is preferable.

**13. t1/2:** Ligand A (22.885) has a longer in vitro half-life than Ligand B (-26.528). This is a strong advantage for Ligand A.

**14. Pgp:** Both ligands have low P-gp efflux liability (0.646 and 0.107). Ligand B is preferable.

**15. Binding Affinity:** Ligand A (-8.5 kcal/mol) has a significantly stronger binding affinity than Ligand B (-7.5 kcal/mol). This is a substantial advantage.

**Overall Assessment:**

Ligand A excels in binding affinity and in vitro half-life, and has a favorable TPSA and logP. However, it has a higher DILI risk and higher microsomal clearance. Ligand B has a better DILI score and lower clearance, but weaker binding affinity and a less optimal logP.

Given the GPCR-specific priorities, *binding affinity is paramount*. The 1.0 kcal/mol difference in binding affinity is significant and likely outweighs the drawbacks of Ligand A's slightly higher DILI and clearance. The BBB penetration is excellent for both, and TPSA is good for Ligand A. The poor Caco-2 and solubility are concerning for both, but can be addressed with formulation strategies.

Output:
1
2025-04-17 06:07:10,319 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (342.414 Da) is slightly lower, which is generally favorable for permeability.

**2. TPSA:** Ligand A (43.78) is significantly better than Ligand B (65.54). For CNS targets, we want TPSA <= 90, and ideally closer to 60. Ligand A is much closer to this ideal.

**3. logP:** Both ligands have acceptable logP values (A: 2.934, B: 1.913), falling within the 1-3 range.

**4. H-Bond Donors:** Both have 1 HBD, which is good.

**5. H-Bond Acceptors:** Ligand A has 3 HBA, while Ligand B has 5. Both are acceptable (<=10), but A is slightly preferred.

**6. QED:** Ligand A (0.933) has a much higher QED score than Ligand B (0.687), indicating a more drug-like profile.

**7. DILI:** Ligand A (47.654) has a slightly higher DILI risk than Ligand B (16.44), but both are below the concerning threshold of 60.

**8. BBB:** Both ligands show good BBB penetration (A: 71.462, B: 75.882), exceeding the 70% threshold for CNS targets. Ligand B is slightly better.

**9. Caco-2 Permeability:** Ligand A (-4.381) has a worse Caco-2 permeability than Ligand B (-5.022). Lower values are less desirable.

**10. Aqueous Solubility:** Both ligands have similar and poor aqueous solubility (-1.726). This could be a formulation challenge for both.

**11. hERG Inhibition:** Ligand A (0.897) has a slightly higher hERG risk than Ligand B (0.284), but both are relatively low.

**12. Microsomal Clearance:** Ligand A (-12.725) has a much lower (better) microsomal clearance than Ligand B (60.036), indicating greater metabolic stability.

**13. In vitro Half-Life:** Ligand A (11.247) has a significantly longer half-life than Ligand B (4.989).

**14. P-gp Efflux:** Ligand A (0.454) has a lower P-gp efflux liability than Ligand B (0.036), which is favorable for CNS exposure.

**15. Binding Affinity:** Ligand A (-9.8 kcal/mol) has a significantly stronger binding affinity than Ligand B (-6.4 kcal/mol). This is a substantial advantage (>1.5 kcal/mol difference).

**Overall Assessment:**

Ligand A is clearly the better candidate. While Ligand B has slightly better BBB penetration, Ligand A excels in most critical areas: TPSA, QED, metabolic stability (Cl_mic, t1/2), P-gp efflux, and, most importantly, binding affinity. The significantly stronger binding affinity of Ligand A (-9.8 vs -6.4 kcal/mol) can compensate for its slightly higher DILI risk and poorer Caco-2 permeability. The lower TPSA and better QED also contribute to its overall superior drug-like properties.

Output:
1
2025-04-17 06:07:10,319 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (336.355 Da) is slightly lower, which could be advantageous for permeability.

**TPSA:** Ligand B (71.53) is significantly better than Ligand A (101.8). For CNS targets, we want TPSA <= 90, so Ligand B is preferable.

**logP:** Both ligands have good logP values (A: 2.088, B: 1.768), falling within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A has 2 HBD and 6 HBA, while Ligand B has 1 HBD and 5 HBA. Both are within acceptable limits (<=5 HBD and <=10 HBA).

**QED:** Ligand A (0.759) has a better QED score than Ligand B (0.435), indicating a more drug-like profile.

**DILI:** Ligand A (90.733) has a higher DILI risk than Ligand B (47.421). Lower is better, so Ligand B is preferable.

**BBB:** Ligand B (52.074) has a significantly better BBB percentile than Ligand A (40.403). For a CNS target like DRD2, BBB penetration is crucial, making Ligand B more attractive.

**Caco-2 Permeability:** Ligand A (-5.205) has a more negative Caco-2 value, indicating poorer permeability than Ligand B (-4.843).

**Aqueous Solubility:** Ligand A (-3.401) has a more negative solubility value, indicating poorer solubility than Ligand B (-2.095).

**hERG Inhibition:** Both ligands have low hERG inhibition risk (A: 0.349, B: 0.289).

**Microsomal Clearance:** Ligand A (16.743) has lower microsomal clearance than Ligand B (35.799), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (32.863) has a longer in vitro half-life than Ligand B (-11.336). A longer half-life is generally desirable.

**P-gp Efflux:** Ligand A (0.062) has lower P-gp efflux liability than Ligand B (0.191). Lower P-gp efflux is preferred, especially for CNS targets.

**Binding Affinity:** Both ligands have excellent binding affinities (A: -9 kcal/mol, B: -6.9 kcal/mol). Ligand A is significantly more potent, with a 2.1 kcal/mol advantage. This is a substantial difference and can outweigh some ADME drawbacks.

**Overall Assessment:**

Ligand B excels in properties critical for CNS penetration (BBB, TPSA, Pgp) and has a lower DILI risk. However, Ligand A boasts a significantly higher binding affinity and better metabolic stability (lower Cl_mic, longer t1/2) and lower P-gp efflux. The substantial binding affinity advantage of Ligand A (-9 vs -6.9 kcal/mol) is a major factor. While Ligand B has better ADME properties regarding CNS penetration, the potency difference is likely to be more impactful in achieving therapeutic efficacy, and the ADME properties of A are still reasonable.

Output:
1
2025-04-17 06:07:10,320 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (345.4 and 343.5 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (92.55) is slightly above the optimal <90 for CNS targets, but still reasonable. Ligand B (71.09) is excellent, well below 90.

**logP:** Ligand A (0.974) is a bit low, potentially hindering permeability. Ligand B (2.985) is closer to the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A has 1 HBD and 4 HBA, within acceptable limits. Ligand B has 2 HBD and 3 HBA, also good.

**QED:** Ligand B (0.799) has a significantly better QED score than Ligand A (0.356), indicating a more drug-like profile.

**DILI:** Ligand A (17.45) has a much lower DILI risk than Ligand B (25.94), which is a significant advantage.

**BBB:** Ligand B (76.15) has a much better BBB penetration score than Ligand A (56.65). This is *critical* for a CNS target like DRD2.

**Caco-2 Permeability:** Ligand A (-5.054) shows poor permeability, while Ligand B (-4.704) is slightly better, but still low.

**Aqueous Solubility:** Both ligands have very poor aqueous solubility (-2.413 and -3.184 respectively). This is a concern for both, but might be mitigated by formulation strategies.

**hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.069 and 0.404).

**Microsomal Clearance:** Ligand A (-18.347) has much better metabolic stability (lower clearance) than Ligand B (42.216).

**In vitro Half-Life:** Ligand A (-13.171) has a longer predicted half-life than Ligand B (3.86).

**P-gp Efflux:** Both ligands show low P-gp efflux (0.026 and 0.081).

**Binding Affinity:** Both ligands have very similar and excellent binding affinities (-8.4 and -8.6 kcal/mol). The difference is negligible.

**Overall Assessment:**

Ligand B excels in BBB penetration and QED, which are crucial for a CNS GPCR target. However, it has a higher DILI risk and poorer metabolic stability (higher Cl_mic) and shorter half-life compared to Ligand A. Ligand A has better metabolic stability, lower DILI, and a longer half-life, but suffers from poor BBB penetration and a lower QED score.

Given the importance of BBB penetration for a CNS target, and the similar binding affinities, Ligand B is the more promising candidate *despite* its slightly higher DILI and lower metabolic stability. The poor solubility of both is a concern, but can potentially be addressed through formulation. The difference in binding affinity is minimal and doesn't outweigh the BBB advantage.

Output:
1
2025-04-17 06:07:10,320 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (346.471 and 356.419 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (58.64) is excellent, well below the 90 A^2 threshold for CNS targets. Ligand B (116.17) is higher, but still potentially acceptable, though less ideal.

**3. logP:** Ligand A (2.289) is optimal (1-3). Ligand B (-0.574) is below 1, which could hinder permeation.

**4. H-Bond Donors:** Ligand A (1) is good. Ligand B (3) is acceptable, but edging towards the higher end of the preferred range.

**5. H-Bond Acceptors:** Ligand A (3) is good. Ligand B (6) is also acceptable.

**6. QED:** Both ligands have similar QED values (0.437 and 0.415), indicating moderate drug-likeness.

**7. DILI:** Both ligands have low DILI risk (23.459 and 22.8), which is positive.

**8. BBB:** Ligand A (75.107) has a good BBB percentile, desirable for a CNS target. Ligand B (24.738) is significantly lower, raising concerns about CNS penetration.

**9. Caco-2:** Both have negative values (-5.058 and -5.01), which is unusual and difficult to interpret without knowing the scale. However, this is less critical than other parameters for a CNS target.

**10. Solubility:** Both have negative values (-1.973 and -1.091), also unusual. Solubility isn't the biggest concern for CNS drugs, as long as it's sufficient for formulation.

**11. hERG:** Both ligands have very low hERG inhibition risk (0.36 and 0.084).

**12. Cl_mic:** Ligand A (39.88) has a higher microsomal clearance than Ligand B (20.897), suggesting lower metabolic stability.

**13. t1/2:** Ligand A (0.974) has a very short in vitro half-life, which is a significant drawback. Ligand B (-20.477) is also very short, and the negative value is concerning.

**14. Pgp:** Ligand A (0.139) has low P-gp efflux, which is good for CNS penetration. Ligand B (0.012) has even lower P-gp efflux, which is excellent.

**15. Binding Affinity:** Ligand A (-8.1 kcal/mol) has significantly stronger binding affinity than Ligand B (-6.7 kcal/mol). This is a substantial advantage.

**Overall Assessment:**

Ligand A excels in binding affinity and BBB penetration, and has acceptable TPSA and logP. Its main weaknesses are its short half-life and higher metabolic clearance. Ligand B has a better P-gp profile and lower metabolic clearance, but suffers from poor logP and significantly lower BBB penetration.

Given the GPCR-specific priorities, particularly for a CNS target like DRD2, **binding affinity and BBB penetration are paramount**. Ligand A's superior affinity and BBB score outweigh its metabolic liabilities, especially considering optimization could potentially address those issues. The poor logP of Ligand B is a major concern, and its low BBB score is a deal-breaker for CNS drug development.

Output:
1
2025-04-17 06:07:10,320 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (346.39 and 351.41 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (111.63) is better than Ligand B (120.58). For CNS targets, we want TPSA <= 90, so both are slightly above the ideal, but A is closer.

**logP:** Ligand A (0.095) is quite low, potentially hindering permeability. Ligand B (-0.533) is also low, but slightly better. Both are below the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Both have 3 HBDs (good) and acceptable HBA counts (5 and 7 respectively, both <=10).

**QED:** Both ligands have good QED scores (0.672 and 0.607, both >= 0.5).

**DILI:** Ligand A (58.40) has a higher DILI risk than Ligand B (46.22), but both are reasonably acceptable (<60).

**BBB:** Ligand A (29.78) and Ligand B (31.21) both have low BBB penetration, which is a significant drawback for a CNS target like DRD2. However, B is slightly better.

**Caco-2 Permeability:** Both have negative Caco-2 values (-4.962 and -5.276), which is unusual and suggests poor permeability.

**Aqueous Solubility:** Both have negative solubility values (-2.374 and -1.505), also unusual and suggesting poor solubility.

**hERG:** Both have very low hERG inhibition liability (0.035 and 0.048), which is excellent.

**Microsomal Clearance:** Ligand B (-9.832) has significantly *lower* (better) microsomal clearance than Ligand A (8.088), indicating greater metabolic stability.

**In vitro Half-Life:** Ligand B (4.522) has a slightly longer half-life than Ligand A (-45.004), but both are quite poor.

**P-gp Efflux:** Both have very low P-gp efflux liability (0.004 and 0.02), which is favorable for CNS penetration.

**Binding Affinity:** Both ligands have the same binding affinity (-8.2 kcal/mol), which is excellent and well below the -7.0 kcal/mol threshold.

**Conclusion:**

Despite the similar binding affinities, Ligand B is the better candidate. Its slightly better logP, lower DILI risk, lower microsomal clearance (higher metabolic stability), and slightly longer half-life outweigh the slightly higher TPSA. The biggest issue for both is the poor predicted BBB penetration and permeability. However, given that we *must* choose one, the improved ADME profile of Ligand B makes it the more promising starting point for optimization.

Output:
1
2025-04-17 06:07:10,320 - INFO - Reasoning:

Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (349.391 and 354.447 Da) fall within the ideal range of 200-500 Da.

**TPSA:** Ligand A (115.21) is higher than the preferred <90 for CNS targets, while Ligand B (79.31) is well within the range. This is a significant advantage for Ligand B.

**logP:** Ligand A (-0.556) is below the optimal 1-3 range and could hinder permeation. Ligand B (1.097) is within the optimal range.

**H-Bond Donors/Acceptors:** Ligand A has 2 HBD and 7 HBA, which are acceptable. Ligand B has 1 HBD and 5 HBA, also acceptable.

**QED:** Both ligands have good QED scores (0.556 and 0.8), indicating good drug-like properties.

**DILI:** Ligand A (52.307) has a moderate DILI risk, while Ligand B (22.218) has a lower risk.

**BBB:** Ligand A (50.523) has a moderate BBB penetration, while Ligand B (59.364) is better, though still not ideal (>70 is preferred).

**Caco-2 Permeability:** Both have negative values (-5.073 and -4.88), which is unusual and suggests poor permeability. However, these values are on a scale where negative values are possible and don't necessarily mean zero permeability.

**Aqueous Solubility:** Both ligands have negative solubility values (-1.594 and -1.317), which is also unusual and suggests poor solubility.

**hERG Inhibition:** Ligand A (0.014) has a very low hERG risk, which is excellent. Ligand B (0.299) has a slightly higher, but still acceptable, risk.

**Microsomal Clearance:** Ligand A (16.76) has a higher clearance than Ligand B (-0.149), suggesting lower metabolic stability. Ligand B's negative value suggests very slow clearance.

**In vitro Half-Life:** Ligand A (13.71) has a moderate half-life, while Ligand B (-3.847) suggests a very long half-life.

**P-gp Efflux:** Ligand A (0.022) has very low P-gp efflux, which is good for CNS penetration. Ligand B (0.084) also has low P-gp efflux.

**Binding Affinity:** Ligand B (-7.7 kcal/mol) has a slightly better binding affinity than Ligand A (-8.3 kcal/mol). While both are good, the difference is not substantial enough to outweigh other factors.

**Overall Assessment:**

Ligand B is the more promising candidate. It has a much better TPSA, logP, DILI risk, and microsomal clearance. While its BBB is not ideal, it's better than Ligand A's. The superior logP and TPSA are critical for CNS penetration, and the lower DILI risk is a significant advantage. The slightly better affinity and dramatically improved metabolic stability further support choosing Ligand B.



Output:
1
2025-04-17 06:07:10,320 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (357.451 and 352.356 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (82.55) is better than Ligand B (58.2). Both are below the 90 A^2 threshold desirable for CNS targets, but Ligand B is closer to optimal.

**logP:** Ligand A (-0.633) is suboptimal, being below the preferred 1-3 range. Ligand B (2.298) is within the optimal range. This is a significant advantage for Ligand B.

**H-Bond Donors/Acceptors:** Ligand A (HBD=1, HBA=6) and Ligand B (HBD=2, HBA=2) both have reasonable numbers of H-bond donors and acceptors, well within the guidelines.

**QED:** Both ligands have good QED scores (0.66 and 0.772), indicating good drug-like properties.

**DILI:** Ligand A (14.424) has a much lower DILI risk than Ligand B (47.77). This is a positive for Ligand A.

**BBB:** Ligand B (89.957) has a significantly better BBB penetration score than Ligand A (43.893). This is a crucial advantage for a CNS target like DRD2.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.361 and -4.62), which is unusual and suggests poor permeability. This is a concern for both.

**Aqueous Solubility:** Both ligands have negative solubility values (-0.444 and -4.006), indicating poor aqueous solubility. This is also a concern for both.

**hERG Inhibition:** Ligand A (0.163) has a lower hERG inhibition liability than Ligand B (0.584), which is favorable.

**Microsomal Clearance:** Ligand A (8.247) has lower microsomal clearance than Ligand B (13.114), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (-9.963) has a more negative in vitro half-life, which is not good. Ligand B (6.466) is better.

**P-gp Efflux:** Ligand A (0.01) has a much lower P-gp efflux liability than Ligand B (0.086), which is highly desirable for CNS penetration.

**Binding Affinity:** Ligand B (-9.3 kcal/mol) has a slightly better binding affinity than Ligand A (-6.9 kcal/mol). The difference of 2.4 kcal/mol is substantial and can outweigh some ADME drawbacks.

**Overall Assessment:**

Ligand B is the stronger candidate. While Ligand A has better DILI, hERG, and P-gp efflux profiles, Ligand B excels in the most critical areas for a CNS-targeting GPCR ligand: logP, BBB penetration, and binding affinity. The 2.4 kcal/mol difference in binding affinity is significant. The slightly worse ADME properties of Ligand B can potentially be addressed through further optimization, but a strong starting affinity is paramount.

Output:
1
2025-04-17 06:07:10,321 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (364.8) is slightly higher than Ligand B (346.4).

**TPSA:** Ligand A (82.26) is better than Ligand B (67.67) for CNS penetration, being closer to the <90 target.

**logP:** Ligand A (3.366) is optimal, while Ligand B (1.484) is a bit low, potentially hindering membrane permeability.

**H-Bond Donors/Acceptors:** Ligand A (4 HBD, 2 HBA) and Ligand B (0 HBD, 5 HBA) both have reasonable counts.

**QED:** Both ligands have good QED scores (A: 0.627, B: 0.758), indicating drug-likeness.

**DILI:** Ligand B (38.116) has a significantly lower DILI risk than Ligand A (88.329), a major advantage.

**BBB:** Both ligands have acceptable BBB penetration (A: 68.127, B: 66.615), but neither is above the desirable 70% threshold.

**Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and suggests poor permeability.

**Aqueous Solubility:** Both have negative solubility values, which is also unusual and suggests poor solubility.

**hERG Inhibition:** Ligand A (0.481) has a slightly higher hERG risk than Ligand B (0.252), but both are relatively low.

**Microsomal Clearance:** Ligand B (17.859) has significantly lower microsomal clearance than Ligand A (41.722), indicating better metabolic stability.

**In vitro Half-Life:** Ligand A (87.727) has a much longer in vitro half-life than Ligand B (9.751), which is desirable.

**P-gp Efflux:** Ligand A (0.136) has lower P-gp efflux than Ligand B (0.041), which is favorable for CNS penetration.

**Binding Affinity:** Ligand A (-10.5 kcal/mol) has a significantly stronger binding affinity than Ligand B (-8.2 kcal/mol). This is a substantial advantage, potentially outweighing some of the ADME drawbacks.

**Overall Assessment:**

Ligand A has a significantly better binding affinity and a longer half-life, and lower P-gp efflux. However, it has a higher DILI risk, higher TPSA, and higher microsomal clearance. Ligand B has a much better safety profile (lower DILI, lower clearance), but weaker binding affinity and shorter half-life.

Given the GPCR target and the importance of CNS penetration, the strong binding affinity of Ligand A is a critical factor. While the DILI risk is a concern, it might be mitigated through structural modifications during lead optimization. The slightly higher TPSA is also less of a concern given the strong binding. The better metabolic stability of Ligand B is attractive, but the weaker binding affinity is a significant drawback.

Output:
1
2025-04-17 06:07:10,321 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (378.372 and 361.467 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Both ligands have TPSA values (72.64 and 70.67) below the 90 A^2 threshold desirable for CNS targets, which is excellent.

**3. logP:** Both ligands have logP values (2.73 and 3.24) within the optimal 1-3 range. Ligand B is slightly higher, potentially aiding membrane permeability.

**4. H-Bond Donors:** Ligand A has 0 HBD, while Ligand B has 2. Both are acceptable (<=5).

**5. H-Bond Acceptors:** Ligand A has 5 HBA, and Ligand B has 4. Both are within the acceptable range (<=10).

**6. QED:** Both ligands have good QED scores (0.671 and 0.882), indicating drug-like properties. Ligand B is better here.

**7. DILI:** Ligand A has a DILI risk of 69.407, while Ligand B has 56.921. Both are acceptable (<60 is good), but Ligand B is preferable.

**8. BBB:** Both ligands exhibit excellent BBB penetration (88.833 and 91.702 percentile). This is crucial for a CNS target like DRD2. Ligand B is slightly better.

**9. Caco-2 Permeability:** Both have negative Caco-2 values (-4.513 and -4.89). These values are unusual and likely represent a scaling issue or an error in the data. We cannot reliably compare based on this metric.

**10. Aqueous Solubility:** Both have negative solubility values (-4.056 and -3.578). Similar to Caco-2, these values are problematic and cannot be used for comparison.

**11. hERG Inhibition:** Both ligands have low hERG inhibition risk (0.843 and 0.716 percentile).

**12. Microsomal Clearance:** Ligand A has a higher Cl_mic (79.563) compared to Ligand B (51.013). This suggests Ligand B is more metabolically stable.

**13. In vitro Half-Life:** Ligand A has a negative half-life (-33.771), which is impossible. Ligand B has a short half-life (11.191), but it's a valid value. This is a significant drawback for Ligand A.

**14. P-gp Efflux:** Both ligands have low P-gp efflux liability (0.398 and 0.297). Ligand B is slightly better.

**15. Binding Affinity:** Ligand B has a significantly stronger binding affinity (-9.7 kcal/mol) compared to Ligand A (-7.5 kcal/mol). This >1.5 kcal/mol difference is a major advantage for Ligand B, potentially outweighing minor ADME drawbacks.

**Overall Assessment:**

Ligand B is the superior candidate. It has a better QED score, lower DILI risk, slightly better BBB penetration, significantly better metabolic stability (lower Cl_mic), a valid half-life, slightly lower P-gp efflux, and, most importantly, a much stronger binding affinity for DRD2. The problematic solubility and Caco-2 values for both compounds are concerning but do not outweigh the other advantages of Ligand B. The negative half-life for Ligand A is a dealbreaker.

Output:
1
2025-04-17 06:07:10,321 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (338.451 and 350.394 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (75.35) is better than Ligand B (78.67), both are below the 90 A^2 threshold for CNS targets, which is good.

**3. logP:** Ligand A (2.74) is optimal (1-3), while Ligand B (0.532) is a bit low, potentially hindering permeability.

**4. H-Bond Donors:** Ligand A (3) and Ligand B (1) are both acceptable (<=5).

**5. H-Bond Acceptors:** Ligand A (3) and Ligand B (5) are both acceptable (<=10).

**6. QED:** Both ligands have good QED scores (0.758 and 0.786, both >=0.5).

**7. DILI:** Ligand A (15.626) has a significantly lower DILI risk than Ligand B (29.081), indicating better potential for liver safety.

**8. BBB:** Ligand A (49.67) has a slightly better BBB penetration percentile than Ligand B (43.583), but both are below the desirable >70% for CNS targets.

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.936 and -4.839), which is unusual and suggests poor permeability. This is a significant concern for both.

**10. Aqueous Solubility:** Both ligands have negative solubility values (-2.647 and -0.571), which is also unusual and suggests poor solubility.

**11. hERG Inhibition:** Both ligands have low hERG inhibition risk (0.731 and 0.334).

**12. Microsomal Clearance:** Ligand A (3.31) has a higher (worse) microsomal clearance than Ligand B (1.474), indicating lower metabolic stability.

**13. In vitro Half-Life:** Ligand B (-16.51) has a much longer in vitro half-life than Ligand A (8.932), which is a significant advantage.

**14. P-gp Efflux:** Ligand A (0.307) has lower P-gp efflux liability than Ligand B (0.042), which is better for CNS exposure.

**15. Binding Affinity:** Ligand A (-9.5 kcal/mol) has a significantly stronger binding affinity than Ligand B (-7.7 kcal/mol). This is a substantial advantage, potentially outweighing some of the ADME drawbacks.

**Overall Assessment:**

Despite the unusual negative values for Caco-2 and solubility, the stronger binding affinity of Ligand A (-9.5 kcal/mol vs -7.7 kcal/mol) is a major advantage, especially for a GPCR target. Ligand A also shows a lower DILI risk and lower P-gp efflux. While Ligand B has a better half-life and slightly better metabolic stability, the difference in binding affinity is substantial. Given the GPCR-specific focus on affinity, and the fact that both have issues with permeability/solubility, the stronger binder is the better candidate, assuming these solubility/permeability issues can be addressed through formulation or further chemical modifications.

Output:
1
2025-04-17 06:07:10,321 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (382.356 and 376.953 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (89.9) is excellent, falling below the 90 A^2 threshold for CNS targets. Ligand B (25.36) is also very good, well below the threshold.

**logP:** Ligand A (1.695) is optimal (1-3). Ligand B (4.842) is slightly high, potentially leading to solubility issues or off-target interactions, but not drastically so.

**H-Bond Donors/Acceptors:** Ligand A (1 HBD, 6 HBA) and Ligand B (0 HBD, 4 HBA) both meet the criteria of <=5 HBD and <=10 HBA.

**QED:** Both ligands have similar QED values (0.78 and 0.721), indicating good drug-like properties.

**DILI:** Ligand A (39.511) has a slightly higher DILI risk than Ligand B (14.618), but both are below the concerning threshold of 60.

**BBB:** Ligand A (86.002) has good BBB penetration, but Ligand B (93.292) is *excellent*, exceeding 90%. This is a significant advantage for a CNS target like DRD2.

**Caco-2 Permeability:** Ligand A (-4.589) and Ligand B (-5.241) both have negative Caco-2 values, which is unusual and suggests poor permeability. This is a concern for both.

**Aqueous Solubility:** Both ligands have very poor aqueous solubility (-2.712 and -3.946). This is a major drawback.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.693 and 0.824).

**Microsomal Clearance:** Ligand A (22.274) has lower microsomal clearance, indicating better metabolic stability than Ligand B (52.504).

**In vitro Half-Life:** Ligand B (-4.789) has a longer in vitro half-life than Ligand A (-2.56), which is desirable.

**P-gp Efflux:** Both ligands show low P-gp efflux liability (0.262 and 0.582).

**Binding Affinity:** Both ligands have very similar and strong binding affinities (-8.1 and -8.2 kcal/mol). The difference is negligible.

**Conclusion:**

While Ligand A has better metabolic stability (lower Cl_mic) and slightly lower DILI risk, Ligand B's significantly higher BBB penetration (93.292 vs 86.002) is the deciding factor for a CNS target. The similar binding affinities mean this difference in BBB is the most important. The poor solubility and Caco-2 permeability are concerns for both, but can potentially be addressed with formulation strategies.

Output:
1
2025-04-17 06:07:10,322 - INFO - Batch 255 complete. Total preferences: 4080
2025-04-17 06:07:10,322 - INFO - Processing batch 256/512...
2025-04-17 06:07:54,183 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (354.5 and 353.5 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (65.12) is significantly better than Ligand B (70.67). For CNS targets, we want TPSA <= 90, and A is closer to the ideal <= 60 range. B is approaching the upper limit and may have reduced brain penetration.

**3. logP:** Ligand B (1.4) is better than Ligand A (0.158). The optimal range is 1-3, and B falls within this. A is quite low, potentially hindering membrane permeability.

**4. H-Bond Donors:** Ligand A (1) is preferable to Ligand B (2). Fewer HBDs generally improve permeability.

**5. H-Bond Acceptors:** Ligand A (5) is preferable to Ligand B (4). Fewer HBAs generally improve permeability.

**6. QED:** Both ligands have good QED scores (0.598 and 0.726), indicating good drug-like properties.

**7. DILI:** Ligand A (3.8) has a much lower DILI risk than Ligand B (7.484). This is a significant advantage for A.

**8. BBB:** Ligand B (60.682) is better than Ligand A (53.354), but both are below the desirable >70 for CNS targets. However, the combination of TPSA and Pgp will be critical.

**9. Caco-2 Permeability:** Both ligands have very poor Caco-2 permeability (-5.029 and -5.02). This suggests poor intestinal absorption for both.

**10. Aqueous Solubility:** Both ligands have very poor solubility (-0.007 and -2.05).

**11. hERG Inhibition:** Ligand A (0.596) has a lower hERG risk than Ligand B (0.455), which is preferable.

**12. Microsomal Clearance:** Ligand A (-7.021) has a much lower (better) microsomal clearance than Ligand B (-0.098), indicating greater metabolic stability.

**13. In vitro Half-Life:** Ligand A (-20.566) has a much longer half-life than Ligand B (4.497), which is a significant advantage.

**14. P-gp Efflux:** Ligand A (0.006) has much lower P-gp efflux than Ligand B (0.037), which is critical for CNS penetration.

**15. Binding Affinity:** Ligand B (-7.3) has slightly better binding affinity than Ligand A (-7.2), but the difference is small (0.1 kcal/mol).

**Overall Assessment:**

While Ligand B has slightly better affinity and logP, Ligand A is significantly better across multiple crucial ADME properties, especially for a CNS target. Ligand A has lower DILI risk, better metabolic stability (lower Cl_mic, longer t1/2), lower P-gp efflux, lower hERG risk, and a more favorable TPSA. The lower logP of Ligand A is a concern, but the other advantages, particularly the P-gp efflux and TPSA, are more critical for brain penetration. The slightly better affinity of Ligand B is unlikely to overcome the substantial ADME deficiencies.

Output:
0
2025-04-17 06:07:54,183 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (341.415 and 372.893 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (82.19) is better than Ligand B (67.87). Both are below the 90 A^2 threshold desirable for CNS targets.

**logP:** Both ligands have good logP values (1.713 and 2.069), within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Both have 1 HBD and 4 HBA, which are acceptable.

**QED:** Both ligands have acceptable QED scores (0.777 and 0.708), indicating good drug-likeness.

**DILI:** Ligand B (18.961) has a significantly lower DILI risk than Ligand A (54.789). This is a major advantage for Ligand B.

**BBB:** Ligand B (83.443) has a much higher BBB penetration percentile than Ligand A (49.515). This is *critical* for a CNS target like DRD2.

**Caco-2 Permeability:** Ligand A (-5.372) has better Caco-2 permeability than Ligand B (-4.539), but both are negative values, which is unusual and requires further investigation.

**Aqueous Solubility:** Ligand A (-1.617) has better aqueous solubility than Ligand B (-2.533), though both are negative, indicating poor solubility.

**hERG:** Ligand A (0.144) has a lower hERG inhibition liability than Ligand B (0.553), which is preferable.

**Microsomal Clearance:** Ligand B (33.841) has a slightly lower microsomal clearance than Ligand A (28.982), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand B (-2.445) has a longer in vitro half-life than Ligand A (-1.62).

**P-gp Efflux:** Ligand A (0.017) has a much lower P-gp efflux liability than Ligand B (0.175). This is a significant advantage for CNS penetration.

**Binding Affinity:** Both ligands have the same binding affinity (-7.5 kcal/mol), which is excellent.

**Overall Assessment:**

While Ligand A has better Caco-2 permeability, P-gp efflux, and hERG inhibition, Ligand B is significantly better in terms of BBB penetration and DILI risk. For a CNS target like DRD2, BBB penetration is paramount. The lower DILI risk is also a substantial benefit. The slightly better metabolic stability and half-life of Ligand B further support its selection. The solubility is poor for both, but can be addressed with formulation strategies.

Output:
1
2025-04-17 06:07:54,183 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (350.394 Da and 368.503 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (74.77) is excellent, well below the 90 A^2 threshold for CNS targets. Ligand B (104.21) is still reasonable, but less optimal, being above 90 A^2.

**logP:** Ligand A (0.329) is quite low, potentially hindering membrane permeability. Ligand B (1.673) is better, falling within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A has 1 HBD and 5 HBA, which is good. Ligand B has 3 HBD and 7 HBA, also acceptable, but slightly higher.

**QED:** Ligand A (0.847) has a very strong drug-like profile. Ligand B (0.672) is still acceptable, but less so.

**DILI:** Ligand A (44.591) has a low DILI risk. Ligand B (62.699) is higher, indicating a moderate risk.

**BBB:** Ligand A (68.554) has a reasonable BBB penetration, but is below the desirable >70% for CNS targets. Ligand B (48.391) is significantly lower, making CNS penetration less likely.

**Caco-2 Permeability:** Ligand A (-4.451) has poor Caco-2 permeability. Ligand B (-5.366) is even worse. Both are problematic.

**Aqueous Solubility:** Ligand A (-1.207) has poor aqueous solubility. Ligand B (-2.93) is even lower. Both are problematic.

**hERG Inhibition:** Ligand A (0.076) has very low hERG inhibition risk. Ligand B (0.548) has a slightly higher, but still acceptable, risk.

**Microsomal Clearance:** Ligand A (-21.128) has very low microsomal clearance, indicating good metabolic stability. Ligand B (2.449) has a positive value, suggesting faster clearance and lower metabolic stability.

**In vitro Half-Life:** Ligand A (-7.765) has a long in vitro half-life. Ligand B (32.006) has a shorter half-life.

**P-gp Efflux:** Ligand A (0.008) has very low P-gp efflux liability, which is excellent for CNS penetration. Ligand B (0.054) is slightly higher, but still good.

**Binding Affinity:** Ligand B (-8.9 kcal/mol) has a significantly stronger binding affinity than Ligand A (-7.6 kcal/mol). This is a >1.3 kcal/mol difference, which is substantial.

**Overall Assessment:**

Ligand B's superior binding affinity is a major advantage. While it has some drawbacks (higher TPSA, lower BBB, poorer solubility/permeability, faster clearance), the strong binding could potentially overcome these issues. Ligand A has better TPSA, DILI, metabolic stability, and P-gp efflux, but its low logP, poor solubility/permeability, and weaker binding affinity are significant concerns. For a CNS target like DRD2, the binding affinity is critical, and the difference between -7.6 and -8.9 kcal/mol is substantial. The slightly higher TPSA and lower BBB of Ligand B are less concerning than the poor binding of Ligand A.

Output:
1
2025-04-17 06:07:54,184 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (354.387) is slightly better positioned.

**TPSA:** Ligand A (88.35) is excellent for CNS penetration, being well below 90. Ligand B (132.46) is higher, potentially hindering BBB penetration, but still within a reasonable range.

**logP:** Ligand A (4.255) is a bit high, potentially leading to solubility issues or off-target effects. Ligand B (-0.802) is too low, which could impede membrane permeability and reduce CNS exposure.

**H-Bond Donors/Acceptors:** Both ligands have acceptable HBD (2 & 3) and HBA (6 & 6) counts.

**QED:** Both ligands have good QED scores (0.535 & 0.575), indicating drug-likeness.

**DILI:** Ligand A (93.602) has a significantly higher DILI risk than Ligand B (78.325). This is a major concern for Ligand A.

**BBB:** Ligand A (30.748) has a very low BBB percentile, making CNS penetration unlikely. Ligand B (27.763) is also low, but slightly better than A. Neither is ideal (>70).

**Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and suggests poor permeability.

**Aqueous Solubility:** Both have negative solubility values, which is also unusual and suggests poor solubility.

**hERG:** Both ligands have very low hERG inhibition liability (0.553 & 0.062), which is good.

**Microsomal Clearance:** Ligand A (107.514) has higher microsomal clearance, indicating faster metabolism and potentially lower exposure. Ligand B (-12.316) has negative clearance, which is not physically possible and likely an error in the data.

**In vitro Half-Life:** Ligand A (-35.631) has a negative half-life, which is impossible. Ligand B (14.083) has a reasonable half-life.

**P-gp Efflux:** Both ligands show good P-gp efflux profiles (0.571 & 0.012).

**Binding Affinity:** Ligand B (-7.3 kcal/mol) has a significantly stronger binding affinity than Ligand A (-10.0 kcal/mol). This is a substantial advantage.

**Overall Assessment:**

Ligand A has a very high DILI risk, poor BBB penetration, and impossible values for half-life and clearance. While its logP is higher, the other liabilities outweigh this benefit. Ligand B, despite having a low logP and BBB penetration, has a much stronger binding affinity and better ADME properties (lower DILI, reasonable half-life, and P-gp efflux). The negative values for Caco-2 and solubility are concerning, but the binding affinity advantage is significant.

Given the GPCR-specific priorities and the substantial difference in binding affinity, Ligand B is the more promising candidate, assuming the negative values for Caco-2 and solubility can be addressed through structural modifications.

Output:
1
2025-04-17 06:07:54,184 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (350.419 and 362.905 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (104.54) is slightly above the preferred <90 for CNS targets, but still reasonable. Ligand B (51.14) is excellent, well below 90.

**logP:** Ligand A (0.608) is a bit low, potentially hindering permeation. Ligand B (4.28) is high, potentially causing solubility/off-target issues, but within the acceptable range.

**H-Bond Donors/Acceptors:** Ligand A has 2 HBD and 5 HBA, which is acceptable. Ligand B has 0 HBD and 5 HBA, also acceptable.

**QED:** Both ligands have similar QED values (0.715 and 0.688), indicating good drug-likeness.

**DILI:** Both ligands have low DILI risk (32.377 and 29.546), which is good.

**BBB:** Ligand B (74.758) has a significantly better BBB percentile than Ligand A (61.535). This is a crucial advantage for a CNS target like DRD2.

**Caco-2 Permeability:** Ligand A (-5.38) has poor Caco-2 permeability, while Ligand B (-4.766) is slightly better, but still not great.

**Aqueous Solubility:** Ligand A (-0.355) has slightly better solubility than Ligand B (-4.126).

**hERG Inhibition:** Ligand A (0.034) has very low hERG inhibition risk, a significant advantage. Ligand B (0.786) has a moderate risk.

**Microsomal Clearance:** Ligand A (14.424) has lower microsomal clearance, indicating better metabolic stability than Ligand B (73.896).

**In vitro Half-Life:** Ligand A (-14.451) has a negative half-life, which is not possible and likely represents an outlier or error in the data. Ligand B (21.682) has a reasonable half-life.

**P-gp Efflux:** Ligand A (0.011) shows very low P-gp efflux, which is excellent for CNS penetration. Ligand B (0.312) has moderate P-gp efflux.

**Binding Affinity:** Ligand A (-8.2) has a significantly stronger binding affinity than Ligand B (-6.6). This is a substantial advantage, potentially outweighing some ADME drawbacks.

**Overall Assessment:**

Ligand A has a superior binding affinity and better P-gp efflux, lower hERG risk, and better metabolic stability. However, its low logP and poor Caco-2 permeability are concerning. The negative half-life is a major red flag and suggests a data error.

Ligand B has a better BBB score, TPSA, and a reasonable half-life, but its logP is high, and hERG risk is moderate.

Considering the importance of BBB penetration for a CNS target like DRD2, and the substantial binding affinity advantage of Ligand A, I would lean towards Ligand A *if* the half-life data is corrected. The strong binding could overcome the permeability issues. However, the negative half-life is a serious concern. Assuming the half-life is an error, and prioritizing affinity and P-gp efflux for CNS targets, Ligand A is the better candidate.

Output:
1
2025-04-17 06:07:54,184 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (352.479 and 371.909 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (83.03) is better than Ligand B (70.67). Both are below the 90 A^2 threshold desirable for CNS targets.

**3. logP:** Both ligands have good logP values (1.286 and 1.785), falling within the optimal 1-3 range. Ligand B is slightly higher, which could be beneficial for membrane permeability.

**4. H-Bond Donors:** Both have 2 HBD, which is acceptable (<=5).

**5. H-Bond Acceptors:** Ligand A has 5 HBA, while Ligand B has 4. Both are within the acceptable range (<=10).

**6. QED:** Both ligands have good QED scores (0.509 and 0.638), indicating good drug-like properties. Ligand B is slightly better.

**7. DILI:** Ligand A (12.098) has a significantly lower DILI risk than Ligand B (20.473). This is a substantial advantage for Ligand A.

**8. BBB:** Both ligands have good BBB penetration (65.801 and 68.127), but neither exceeds the desirable >70% threshold. Ligand B is slightly better.

**9. Caco-2 Permeability:** Both have negative Caco-2 values (-5.186 and -5.156). This is unusual and suggests poor permeability. However, these values are on a log scale, and the absolute difference is small.

**10. Aqueous Solubility:** Both ligands have negative solubility values (-1.864 and -2.08). This is also concerning, indicating poor solubility. Ligand A is slightly better.

**11. hERG Inhibition:** Both ligands have low hERG inhibition risk (0.454 and 0.641).

**12. Microsomal Clearance:** Ligand A (-0.409) has lower (better) microsomal clearance than Ligand B (1.833), indicating better metabolic stability.

**13. In vitro Half-Life:** Ligand A (10.112) has a better in vitro half-life than Ligand B (18.642).

**14. P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.03 and 0.027).

**15. Binding Affinity:** Ligand B (-7.9 kcal/mol) has a slightly better binding affinity than Ligand A (-8.0 kcal/mol). While the difference is small, it is still a positive for Ligand B.

**Overall Assessment:**

Ligand A excels in DILI risk, metabolic stability (Cl_mic), and in vitro half-life. Ligand B has a slightly better binding affinity and BBB penetration, and QED. However, the significantly lower DILI risk of Ligand A is a major advantage, as liver toxicity is a common issue in drug development. The small difference in binding affinity can likely be optimized during lead optimization. The solubility and permeability concerns are present in both, but are not disqualifying at this stage.

Output:
0
2025-04-17 06:07:54,184 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (356.373 and 344.419 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (75.72) is significantly better than Ligand B (103.87). For CNS targets, we want TPSA <= 90, so Ligand A is preferable.

**3. logP:** Both ligands have good logP values (2.058 and 1.41), falling within the optimal 1-3 range.

**4. H-Bond Donors:** Both have 2 HBD, which is within the acceptable limit of <=5.

**5. H-Bond Acceptors:** Both have 5 HBA, also within the acceptable limit of <=10.

**6. QED:** Both ligands have reasonable QED values (0.864 and 0.79), indicating good drug-like properties.

**7. DILI:** Ligand A (42.575) has a lower DILI risk than Ligand B (57.425). Both are below 60, so the risk is moderate, but A is better.

**8. BBB:** This is a crucial parameter for a CNS target like DRD2. Ligand A has a much higher BBB penetration percentile (81.582) compared to Ligand B (44.591). A value >70 is desirable, and Ligand A meets this criterion, while B does not.

**9. Caco-2 Permeability:** Ligand A (-4.929) is better than Ligand B (-5.583). Higher values are better, but these are both negative, indicating poor permeability.

**10. Aqueous Solubility:** Ligand A (-2.476) is better than Ligand B (-1.683). Higher values are better, but both are negative, indicating poor solubility.

**11. hERG Inhibition:** Both ligands have very low hERG inhibition liability (0.443 and 0.133), which is excellent.

**12. Microsomal Clearance:** Ligand A (-28.677) has significantly lower (better) microsomal clearance than Ligand B (21.145). Lower clearance indicates greater metabolic stability.

**13. In vitro Half-Life:** Ligand A (18.565) has a longer in vitro half-life than Ligand B (-14.737).

**14. P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.022 and 0.025), which is good.

**15. Binding Affinity:** Both ligands have similar, strong binding affinities (-8.9 and -8.5 kcal/mol). The difference of 0.4 kcal/mol is not substantial enough to override the other ADME differences.

**Overall Assessment:**

Ligand A is significantly better than Ligand B. The key advantages of Ligand A are its superior TPSA, much higher BBB penetration, lower DILI risk, lower microsomal clearance, and longer half-life. While both have good logP, QED, hERG, and P-gp profiles, and comparable binding affinity, the ADME properties of Ligand A make it a much more promising drug candidate for a CNS target like DRD2.

Output:
1
2025-04-17 06:07:54,185 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (352.475 and 352.435 Da) fall comfortably within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (67.87) is significantly better than Ligand B (96.95). For CNS targets, we want TPSA <= 90, so Ligand A is preferable.

**3. logP:** Ligand A (1.868) is within the optimal 1-3 range. Ligand B (0.165) is quite low, potentially hindering permeation.

**4. H-Bond Donors:** Both have acceptable HBD counts (1 and 2, respectively), well below the threshold of 5.

**5. H-Bond Acceptors:** Both have the same HBA count (4), which is acceptable (<=10).

**6. QED:** Both ligands have similar, good QED values (0.724 and 0.662), indicating drug-like properties.

**7. DILI:** Ligand A (11.865) has a much lower DILI risk than Ligand B (25.087). This is a significant advantage.

**8. BBB:** Ligand A (76.231) has a much better BBB penetration percentile than Ligand B (24.738). This is *critical* for a CNS target like DRD2.

**9. Caco-2 Permeability:** Ligand A (-4.833) is better than Ligand B (-5.241), indicating slightly better intestinal absorption.

**10. Aqueous Solubility:** Ligand A (-1.349) is better than Ligand B (-0.639), suggesting better solubility.

**11. hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.304 and 0.137), which is excellent.

**12. Microsomal Clearance:** Ligand A (25.308) has higher clearance than Ligand B (7.243), indicating lower metabolic stability. This is a drawback for Ligand A.

**13. In vitro Half-Life:** Ligand B (-10.524) has a longer half-life than Ligand A (17.003), which is preferable.

**14. P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.02 and 0.018), which is good.

**15. Binding Affinity:** Ligand B (-7.3) has a slightly better binding affinity than Ligand A (-8.0). However, the difference is relatively small (0.7 kcal/mol).

**Overall Assessment:**

Ligand A is significantly better overall, despite the slightly higher clearance and shorter half-life. The key advantages of Ligand A are its much better TPSA, logP, BBB penetration, and lower DILI risk. These factors are particularly important for a CNS GPCR target like DRD2. While Ligand B has a slightly better binding affinity and half-life, the poor logP and BBB penetration are major drawbacks that likely outweigh the small affinity advantage.

Output:
1
2025-04-17 06:07:54,185 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (358.391 and 367.471 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (125.4) is slightly above the optimal <90 for CNS targets, but still reasonable. Ligand B (84.67) is excellent, well below 90.

**logP:** Ligand A (-0.891) is a bit low, potentially hindering permeability. Ligand B (1.472) is within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A (3 HBD, 7 HBA) is good. Ligand B (1 HBD, 6 HBA) is also good. Both are within acceptable limits.

**QED:** Ligand B (0.871) has a significantly better QED score than Ligand A (0.43), indicating a more drug-like profile.

**DILI:** Ligand A (42.536) has a lower DILI risk than Ligand B (67.429). This is a positive for Ligand A.

**BBB:** Ligand B (58.123) has a much better BBB penetration percentile than Ligand A (25.475). This is a crucial advantage for a CNS target like DRD2.

**Caco-2 Permeability:** Both have negative values, indicating poor permeability. However, the scale is not specified, making direct comparison difficult.

**Aqueous Solubility:** Both have negative values, indicating poor solubility. Again, the scale is not specified.

**hERG:** Both ligands have very low hERG inhibition liability (0.065 and 0.176), which is excellent.

**Microsomal Clearance:** Ligand A (-8.686) has a much lower (better) microsomal clearance than Ligand B (69.68). This suggests better metabolic stability for Ligand A.

**In vitro Half-Life:** Ligand A (2.363) has a shorter half-life than Ligand B (-10.987). The negative value for Ligand B is unusual and may indicate a very long half-life or an error in the data.

**P-gp Efflux:** Ligand A (0.012) has significantly lower P-gp efflux liability than Ligand B (0.098). Lower P-gp efflux is desirable for CNS penetration.

**Binding Affinity:** Ligand A (-7.4) has a slightly better binding affinity than Ligand B (0.0).

**Overall Assessment:**

Ligand B excels in BBB penetration, logP, and QED, which are critical for a CNS-targeting GPCR. However, its higher DILI risk, higher P-gp efflux, and potentially problematic clearance are drawbacks. Ligand A has better metabolic stability (lower Cl_mic), lower DILI, and lower P-gp efflux, but suffers from poor logP and lower BBB penetration.

Considering the importance of CNS penetration for DRD2, and the relatively small difference in binding affinity, Ligand B is the more promising candidate *despite* its drawbacks. The better BBB and logP are likely to outweigh the higher DILI and P-gp efflux, especially with further optimization.

Output:
1
2025-04-17 06:07:54,185 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (345.359 Da) is slightly lower, which could be beneficial for permeability. Ligand B (367.471 Da) is also good.

**TPSA:** Ligand A (136.47) is borderline for CNS penetration, slightly above the ideal <90, but still potentially acceptable. Ligand B (82.97) is excellent, well below 90 and favorable for CNS penetration.

**logP:** Ligand A (0.262) is quite low, potentially hindering membrane permeability and brain penetration. Ligand B (0.532) is better, but still on the lower side of the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A has 5 HBD and 7 HBA. Ligand B has 1 HBD and 6 HBA. Both are within acceptable limits, but Ligand B is better with fewer H-bond donors, potentially improving permeability.

**QED:** Both ligands have good QED scores (Ligand A: 0.506, Ligand B: 0.793), indicating drug-like properties. Ligand B is superior here.

**DILI:** Ligand A has a DILI risk of 67.778, which is moderately high. Ligand B has a much lower DILI risk of 33.773, which is excellent.

**BBB:** Ligand A has a BBB penetration of 11.671, which is very poor. Ligand B has a BBB penetration of 27.491, which is still not ideal but significantly better than Ligand A.

**Caco-2 Permeability:** Both have negative values (-5.798 and -4.726), which is unusual and difficult to interpret without further context. However, a more negative value generally suggests lower permeability.

**Aqueous Solubility:** Both have negative values (-3.37 and -0.445), also unusual. Lower values suggest lower solubility.

**hERG Inhibition:** Both ligands show low hERG inhibition risk (Ligand A: 0.335, Ligand B: 0.202).

**Microsomal Clearance:** Ligand A (14.579) and Ligand B (16.171) have similar microsomal clearance values, suggesting comparable metabolic stability.

**In vitro Half-Life:** Ligand B (4.094 hours) has a better in vitro half-life than Ligand A (-0.257 hours).

**P-gp Efflux:** Both have very low P-gp efflux liability (Ligand A: 0.029, Ligand B: 0.083), which is favorable for CNS penetration.

**Binding Affinity:** Ligand A (-8.4 kcal/mol) has a significantly stronger binding affinity than Ligand B (-6.8 kcal/mol). This is a substantial advantage.

**Overall Assessment:**

Despite Ligand A's superior binding affinity, its extremely poor BBB penetration (11.671) and moderate DILI risk (67.778) are major drawbacks for a CNS-targeting drug. The low logP also raises concerns about permeability. Ligand B, while having a weaker binding affinity, exhibits a much better safety profile (lower DILI), better BBB penetration (27.491), and a more favorable logP. Given the GPCR-specific priorities, particularly BBB penetration for CNS targets, Ligand B is the more promising candidate. The difference in binding affinity (-1.6 kcal/mol) while significant, can potentially be overcome with further optimization, whereas improving BBB penetration is often more challenging.

Output:
1
2025-04-17 06:07:54,185 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (346.471 and 351.535 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (58.64) is higher than Ligand B (44.81). For a CNS target like DRD2, we ideally want TPSA <= 90. Both are within this range, but B is better.

**3. logP:** Both ligands have good logP values (2.29 and 1.97), falling within the optimal 1-3 range.

**4. H-Bond Donors:** Both have 1 HBD, which is acceptable.

**5. H-Bond Acceptors:** Ligand A has 3 HBAs, and Ligand B has 4. Both are within the acceptable limit of <=10.

**6. QED:** Both ligands have good QED scores (0.614 and 0.726), indicating good drug-like properties.

**7. DILI:** Ligand A (23.614) has a slightly higher DILI risk than Ligand B (3.994), but both are well below the concerning threshold of 60.

**8. BBB:** This is crucial for a CNS target. Ligand B (86.894) has a significantly higher BBB percentile than Ligand A (69.794). This is a major advantage for B.

**9. Caco-2 Permeability:** Both have negative values (-4.9 and -4.864). This is unusual and suggests poor permeability. However, the scale isn't specified, so it's difficult to interpret.

**10. Aqueous Solubility:** Both have negative values (-2.162 and -1.141). Again, the scale is unclear, but suggests poor solubility.

**11. hERG Inhibition:** Ligand A (0.156) has a slightly higher hERG inhibition risk than Ligand B (0.714), but both are low.

**12. Microsomal Clearance:** Ligand A (48.933) has a higher microsomal clearance than Ligand B (15.928), meaning it's less metabolically stable.

**13. In vitro Half-Life:** Ligand B (2.014) has a longer in vitro half-life than Ligand A (-16.531). This is a significant advantage for B.

**14. P-gp Efflux:** Ligand A (0.102) has a slightly higher P-gp efflux liability than Ligand B (0.04). Lower is better for CNS penetration.

**15. Binding Affinity:** Ligand B (-6.2 kcal/mol) has a significantly stronger binding affinity than Ligand A (0.0 kcal/mol). This is a decisive advantage.

**Overall Assessment:**

Ligand B is the superior candidate. It has a significantly better BBB score, a stronger binding affinity, a longer half-life, lower P-gp efflux, and lower microsomal clearance. While both have issues with Caco-2 and solubility, the superior CNS penetration and potency of Ligand B outweigh these concerns. The lower DILI risk is also a plus.

Output:
1
2025-04-17 06:07:54,185 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (358.825 and 354.447 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (67.43) is excellent, well below the 90 A^2 threshold for CNS targets. Ligand B (93.73) is higher, but still potentially acceptable, though less ideal.

**3. logP:** Ligand A (3.724) is at the upper end of the optimal range (1-3), but still acceptable. Ligand B (0.869) is quite low, potentially hindering membrane permeability and CNS penetration.

**4. H-Bond Donors:** Both ligands have 2 HBD, which is within the acceptable limit of <=5.

**5. H-Bond Acceptors:** Ligand A has 3 HBA, and Ligand B has 5 HBA, both within the acceptable limit of <=10.

**6. QED:** Both ligands have reasonable QED values (0.821 and 0.599), indicating good drug-like properties.

**7. DILI:** Ligand A has a high DILI risk (80.729), which is a significant concern. Ligand B has a much lower DILI risk (29.314), a major advantage.

**8. BBB:** Ligand A shows excellent BBB penetration (77.162), crucial for a CNS target. Ligand B's BBB penetration (63.358) is lower, though not terrible, it's less desirable than Ligand A.

**9. Caco-2:** Ligand A has a negative Caco-2 value (-4.559), which is unusual and suggests poor permeability. Ligand B also has a negative Caco-2 value (-5), indicating poor permeability.

**10. Solubility:** Ligand A has a very poor aqueous solubility (-5.733). Ligand B has slightly better solubility (-1.931), but still poor.

**11. hERG:** Ligand A has a low hERG risk (0.552). Ligand B has a very low hERG risk (0.169), which is excellent.

**12. Cl_mic:** Ligand A has a high microsomal clearance (89.959), indicating poor metabolic stability. Ligand B has a lower clearance (53.697), suggesting better metabolic stability.

**13. t1/2:** Ligand A has a moderate in vitro half-life (56.704). Ligand B has a very short half-life (-5.857), which is a major drawback.

**14. Pgp:** Ligand A has a low P-gp efflux liability (0.211), which is good for CNS penetration. Ligand B has a very low P-gp efflux liability (0.012), even better.

**15. Affinity:** Ligand A has a significantly better binding affinity (-10.1 kcal/mol) than Ligand B (-7.8 kcal/mol). This is a substantial difference and could outweigh some of the ADME concerns.

**Overall Assessment:**

Ligand A has a much stronger binding affinity and good BBB penetration, but suffers from high DILI risk, poor solubility, high metabolic clearance, and poor Caco-2 permeability. Ligand B has a lower affinity, but exhibits a much better safety profile (lower DILI, lower hERG), better metabolic stability, and lower P-gp efflux.

Given the GPCR-specific priorities, and the significant difference in binding affinity, I would lean towards **Ligand A** *despite* its ADME liabilities. The strong binding affinity is a critical factor, and optimization efforts could potentially address the solubility and metabolic stability issues. The high DILI risk is concerning, but might be mitigated with structural modifications. The poor Caco-2 is less critical for a CNS target where direct absorption isn't the primary route of entry.

Output:
1
2025-04-17 06:07:54,186 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (349.39 and 364.92 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (93.9) is slightly above the optimal <90 for CNS targets, but still reasonable. Ligand B (58.2) is excellent, well below 90.

**logP:** Ligand A (0.759) is a bit low, potentially hindering permeability. Ligand B (3.864) is near the upper limit of the optimal range (1-3) but still acceptable.

**H-Bond Donors/Acceptors:** Ligand A (1 HBD, 6 HBA) is good. Ligand B (2 HBD, 2 HBA) is also excellent. Both are within the recommended limits.

**QED:** Ligand A (0.862) is very good, indicating high drug-likeness. Ligand B (0.619) is acceptable, but lower than Ligand A.

**DILI:** Ligand A (67.43) has a moderate risk of DILI. Ligand B (20.24) has a very low risk, a significant advantage.

**BBB:** Ligand A (63.09) is below the desirable >70 for CNS targets. Ligand B (75.53) is excellent, exceeding the 70% threshold. This is a major advantage for CNS penetration.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.919 and -4.867), which is unusual and suggests poor permeability. However, these values are on a log scale and may not be directly comparable.

**Aqueous Solubility:** Both ligands have negative solubility values (-1.341 and -3.865), also unusual and suggesting poor solubility.

**hERG Inhibition:** Ligand A (0.204) shows very low hERG inhibition risk. Ligand B (0.646) has a slightly higher, but still relatively low, risk.

**Microsomal Clearance:** Ligand A (37.96) has a moderate clearance, while Ligand B (44.92) has a slightly higher clearance. Lower is better for metabolic stability.

**In vitro Half-Life:** Ligand A (-4.535) has a very short half-life, a significant drawback. Ligand B (40.45) has a much longer and more desirable half-life.

**P-gp Efflux:** Ligand A (0.045) shows very low P-gp efflux, which is good for CNS exposure. Ligand B (0.274) has slightly higher P-gp efflux, but is still reasonable.

**Binding Affinity:** Ligand B (-8.4 kcal/mol) has a significantly stronger binding affinity than Ligand A (-0.0 kcal/mol). This is a crucial advantage, as a >1.5 kcal/mol difference can outweigh other drawbacks.

**Overall Assessment:**

Ligand B is significantly better. While Ligand A has a slightly better QED and lower P-gp efflux, Ligand B excels in the most critical areas for a CNS-targeting GPCR ligand: BBB penetration, binding affinity, DILI risk, and in vitro half-life. The superior binding affinity of Ligand B is a major factor, and its excellent BBB penetration will likely overcome the slightly higher P-gp efflux. The lower DILI risk and longer half-life further strengthen its profile. The negative Caco-2 and solubility values are concerning for both, but the strong affinity and BBB penetration of Ligand B suggest it might still be a viable candidate with appropriate formulation strategies.

Output:
1
2025-04-17 06:07:54,186 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (359.447 and 352.391 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (72.47) is excellent, well below the 90 A^2 threshold for CNS targets. Ligand B (114.63) is higher, but still potentially acceptable, though less ideal.

**logP:** Ligand A (3.38) is optimal. Ligand B (0.083) is very low, which is a significant concern for membrane permeability and CNS penetration.

**H-Bond Donors/Acceptors:** Both have 1 HBD, which is good. Ligand A has 4 HBA, and Ligand B has 7 HBA. Both are within the acceptable range of <=10.

**QED:** Both ligands have reasonable QED scores (0.85 and 0.659), indicating good drug-like properties.

**DILI:** Ligand A (89.957) has a higher DILI risk than Ligand B (47.46), which is a negative for Ligand A.

**BBB:** Both ligands have good BBB penetration (Ligand A: 71.035, Ligand B: 74.758), exceeding the desirable >70% threshold for CNS targets.

**Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and suggests potential issues with the calculation or data quality. However, the magnitude is similar.

**Aqueous Solubility:** Both have negative solubility values, also unusual. Again, the magnitude is similar.

**hERG:** Ligand A (0.528) has a slightly higher hERG risk than Ligand B (0.038), but both are relatively low.

**Microsomal Clearance:** Ligand A (69.704) has higher clearance than Ligand B (36.995), suggesting lower metabolic stability.

**In vitro Half-Life:** Ligand A (35.964) has a longer half-life than Ligand B (2.506), which is favorable.

**P-gp Efflux:** Ligand A (0.328) has lower P-gp efflux than Ligand B (0.026), which is good for CNS exposure.

**Binding Affinity:** Ligand B (-7.8 kcal/mol) has a significantly stronger binding affinity than Ligand A (-9.1 kcal/mol). This is a substantial advantage.

**Overall Assessment:**

Ligand B's significantly stronger binding affinity (-7.8 vs -9.1 kcal/mol) is a major advantage that could potentially overcome some of its drawbacks. However, its very low logP (0.083) is a serious concern. This suggests poor membrane permeability and potentially very limited CNS exposure despite the good BBB prediction. Ligand A has a better logP, but its DILI risk is higher and its affinity is weaker.

Considering the GPCR-specific priorities, strong binding affinity and good CNS penetration are crucial. While Ligand B has the better affinity and acceptable BBB, the extremely low logP is a major red flag. Ligand A, despite its weaker affinity, has a more reasonable logP and lower P-gp efflux, which could translate to better overall CNS exposure. The higher DILI risk for Ligand A is a concern, but could be addressed with further structural modifications.

Given the importance of affinity and the significant difference between the two ligands, I will choose Ligand B, but with a strong caveat that the low logP needs to be addressed in further optimization.

Output:
1
2025-04-17 06:07:54,186 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (345.311 and 340.383 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (123.71) is slightly above the optimal <90 for CNS targets, but still reasonable. Ligand B (71.58) is excellent, well below 90.

**logP:** Both ligands (1.282 and 1.463) are within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A has 2 HBD and 6 HBA, both acceptable. Ligand B has 0 HBD and 5 HBA, also acceptable.

**QED:** Ligand B (0.848) has a significantly better QED score than Ligand A (0.462), indicating a more drug-like profile.

**DILI:** Ligand B (61.691) has a slightly higher DILI risk than Ligand A (83.172), but both are acceptable.

**BBB:** Ligand B (69.794) has a substantially better BBB penetration score than Ligand A (45.715). This is a *critical* advantage for a CNS target like DRD2.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.91 and -4.717), which is unusual and suggests poor permeability. However, these values are on a scale where negative values are possible, and the absolute magnitude isn't necessarily directly comparable.

**Aqueous Solubility:** Both ligands have negative solubility values (-4.124 and -1.824), indicating poor solubility.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.511 and 0.302).

**Microsomal Clearance:** Ligand B (65.015) has a higher microsomal clearance than Ligand A (16.359), meaning it's likely to be metabolized more quickly. This is a disadvantage.

**In vitro Half-Life:** Ligand A (46.784) has a longer in vitro half-life than Ligand B (29.14), which is preferable.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.386 and 0.259), which is good for CNS penetration.

**Binding Affinity:** Both ligands have excellent binding affinity (-9.0 and -9.2 kcal/mol), with Ligand B being slightly better. The affinity difference is small enough that it's unlikely to overcome other significant ADME differences.

**Overall Assessment:**

Ligand B is the stronger candidate. The *significant* improvement in BBB penetration (69.794 vs 45.715) is the deciding factor for a CNS target. While Ligand B has a higher clearance and lower half-life, the superior BBB penetration is more crucial. The better QED score also supports Ligand B. The solubility and permeability concerns are shared by both compounds and would need to be addressed in further optimization, but don't currently disqualify either.

Output:
1
2025-04-17 06:07:54,186 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (348.443 and 348.487 Da) fall comfortably within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (71.78) is better than Ligand B (78.43). Both are below the 90 A^2 threshold desirable for CNS targets, but A is closer to optimal.

**3. logP:** Both ligands have a logP of 2.32, which is within the optimal 1-3 range.

**4. H-Bond Donors:** Ligand A (1) is better than Ligand B (3). Lower HBD generally favors permeability.

**5. H-Bond Acceptors:** Ligand A (4) is slightly better than Ligand B (3), both are well within the acceptable limit of 10.

**6. QED:** Ligand A (0.856) has a significantly higher QED score than Ligand B (0.53), indicating a more drug-like profile.

**7. DILI:** Ligand A (22.102) has a much lower DILI risk than Ligand B (9.616), suggesting better hepatotoxicity potential.

**8. BBB:** Ligand A (73.633) has a better BBB penetration percentile than Ligand B (66.227). While both are reasonably good, A is closer to the >70% target for CNS drugs.

**9. Caco-2 Permeability:** Ligand A (-4.645) has slightly better Caco-2 permeability than Ligand B (-4.704).

**10. Aqueous Solubility:** Ligand A (-1.7) has better aqueous solubility than Ligand B (-2.646).

**11. hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.316 and 0.243 respectively).

**12. Microsomal Clearance:** Ligand A (39.201) has lower microsomal clearance than Ligand B (53.418), suggesting better metabolic stability.

**13. In vitro Half-Life:** Ligand A (28.164) has a longer in vitro half-life than Ligand B (17.209).

**14. P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.04 and 0.081 respectively).

**15. Binding Affinity:** Ligand A (-8.7 kcal/mol) has a slightly better binding affinity than Ligand B (-8.2 kcal/mol). While both are excellent, the 0.5 kcal/mol difference is noticeable.

**Overall Assessment:**

Ligand A consistently outperforms Ligand B across most critical ADME-Tox properties, especially QED, DILI, BBB, metabolic stability (Cl_mic and t1/2), and solubility. While the binding affinity difference is relatively small, it adds to the overall advantage of Ligand A. Given the GPCR target and the need for CNS penetration, the better BBB score and overall drug-like properties of Ligand A make it the more promising candidate.

Output:
1
2025-04-17 06:07:54,187 - INFO - Batch 256 complete. Total preferences: 4096
2025-04-17 06:07:54,187 - INFO - Processing batch 257/512...
2025-04-17 06:08:36,193 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (338.499 and 346.387 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (33.09) is excellent, well below the 90 A^2 threshold for CNS targets. Ligand B (94.74) is significantly higher, exceeding the preferred range and potentially hindering BBB penetration.

**logP:** Ligand A (3.119) is optimal (1-3). Ligand B (0.573) is low, potentially causing permeability issues.

**H-Bond Donors/Acceptors:** Ligand A (HBD=1, HBA=4) and Ligand B (HBD=2, HBA=4) both have acceptable numbers of H-bond donors and acceptors.

**QED:** Both ligands have good QED scores (0.909 and 0.819), indicating drug-like properties.

**DILI:** Ligand A (7.135) has a very favorable DILI score. Ligand B (60.915) is higher, indicating a moderate risk of liver injury.

**BBB:** Ligand A (88.6) has a very good BBB percentile, exceeding the 70% threshold for CNS targets. Ligand B (35.285) is poor, suggesting limited brain penetration.

**Caco-2 Permeability:** Ligand A (-5.316) and Ligand B (-4.893) have negative values, which is unusual. Without knowing the scale, it's difficult to interpret, but generally lower numbers suggest lower permeability.

**Aqueous Solubility:** Both ligands have very poor aqueous solubility (-1.996 and -2.711). This could pose formulation challenges.

**hERG Inhibition:** Ligand A (0.91) has a low hERG risk. Ligand B (0.131) also has a low hERG risk.

**Microsomal Clearance:** Ligand A (-0.094) suggests good metabolic stability (lower is better). Ligand B (-25.976) indicates rapid clearance, which is undesirable.

**In vitro Half-Life:** Ligand A (7.594) has a reasonable half-life. Ligand B (-17.167) has a very short half-life, suggesting it will be rapidly metabolized.

**P-gp Efflux:** Ligand A (0.234) has low P-gp efflux, which is favorable for CNS penetration. Ligand B (0.01) also has very low P-gp efflux.

**Binding Affinity:** Ligand A (-10.6 kcal/mol) has significantly stronger binding affinity than Ligand B (-7.6 kcal/mol). The difference of 3 kcal/mol is substantial and can outweigh minor ADME drawbacks.

**Conclusion:**

Considering all factors, especially the GPCR-specific priorities, **Ligand A is the more promising drug candidate.** It has superior BBB penetration, a better logP value, a significantly stronger binding affinity, and a lower DILI risk. While both have poor aqueous solubility, the other advantages of Ligand A outweigh this drawback. The rapid clearance and poor BBB penetration of Ligand B are major concerns for a CNS-targeting drug.

Output:
1
2025-04-17 06:08:36,193 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (362.539 Da and 365.455 Da) are within the ideal 200-500 Da range.

**TPSA:** Ligand A (43.78) is significantly better than Ligand B (116.82). For CNS targets, we want TPSA <= 90, and A is comfortably within that range, while B is considerably above.

**logP:** Ligand A (4.412) is higher than the optimal 1-3 range, but still potentially manageable. Ligand B (0.227) is *very* low, which could severely hamper permeability.

**H-Bond Donors/Acceptors:** Ligand A (1 HBD, 3 HBA) is better than Ligand B (4 HBD, 7 HBA). Both are within acceptable limits, but A is more favorable.

**QED:** Ligand A (0.865) has a much better QED score than Ligand B (0.593), indicating a more drug-like profile.

**DILI:** Ligand A (10.585) has a significantly lower DILI risk than Ligand B (37.65).

**BBB:** Ligand A (85.731) has excellent BBB penetration potential, exceeding the desirable >70 threshold. Ligand B (53.974) is much lower and less promising for a CNS target.

**Caco-2 Permeability:** Ligand A (-4.703) and Ligand B (-5.322) both have negative values, which is unusual and requires further investigation. However, the values are similar.

**Aqueous Solubility:** Ligand A (-3.335) and Ligand B (-2.6) both have negative solubility values, which is also unusual and could be problematic for formulation.

**hERG:** Both ligands have low hERG inhibition liability (0.743 and 0.688, respectively).

**Microsomal Clearance:** Ligand A (35.014) has higher microsomal clearance than Ligand B (-9.101). A negative value for B suggests very high metabolic stability, which is a positive.

**In vitro Half-Life:** Ligand A (8.514) has a reasonable half-life, while Ligand B (34.392) has a much longer half-life.

**P-gp Efflux:** Ligand A (0.471) has lower P-gp efflux than Ligand B (0.072), which is favorable for CNS penetration.

**Binding Affinity:** Both ligands have similar binding affinities (-9.0 kcal/mol and -8.0 kcal/mol). Ligand A is slightly better.

**Overall Assessment:**

Ligand A is significantly better overall, especially considering the GPCR-specific priorities. Its superior TPSA, BBB penetration, QED, and lower DILI risk outweigh the slightly higher logP and clearance. Ligand B's very low logP is a major concern, likely leading to poor permeability. While B has a longer half-life and better metabolic stability, these are less critical than CNS penetration for a DRD2 target.



Output:
0
2025-04-17 06:08:36,194 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (342.399 and 349.381 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (90.54) is better than Ligand B (62.3). Both are below the 90 A^2 threshold for CNS targets, which is excellent.

**logP:** Ligand A (1.175) is slightly lower than Ligand B (2.679), but both are within the optimal 1-3 range.

**H-Bond Donors:** Ligand A (3) is higher than Ligand B (1), but both are acceptable (<=5).

**H-Bond Acceptors:** Both ligands have 3 H-bond acceptors, which is well within the acceptable limit of <=10.

**QED:** Both ligands have good QED scores (0.754 and 0.85), indicating good drug-like properties.

**DILI:** Ligand A (39.977) has a lower DILI risk than Ligand B (52.152), both are below the 60 threshold, indicating acceptable liver safety.

**BBB:** Both ligands have good BBB penetration (65.529 and 68.166), but Ligand B is slightly better. A value >70 is desirable, but both are reasonably good for a CNS target.

**Caco-2:** Ligand A (-5.281) has a worse Caco-2 permeability than Ligand B (-4.31). Higher values are preferred.

**Solubility:** Both ligands have similar, poor aqueous solubility (-2.886 and -2.869). This could be a formulation challenge.

**hERG:** Both ligands have very low hERG inhibition liability (0.148 and 0.383), which is excellent.

**Microsomal Clearance:** Ligand A (-36.237) has significantly lower (better) microsomal clearance than Ligand B (37.8). Lower clearance indicates better metabolic stability.

**In vitro Half-Life:** Ligand A (21.422) has a longer half-life than Ligand B (5.2). Longer half-life is generally preferred.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.008 and 0.083), which is excellent for CNS penetration.

**Binding Affinity:** Both ligands have similar, strong binding affinities (-9.0 and -8.8 kcal/mol). This is a critical parameter, and the difference is not substantial enough to be decisive.

**Overall Assessment:**

Ligand A is slightly better overall. It has a lower DILI risk, significantly better metabolic stability (lower Cl_mic, longer t1/2), and comparable binding affinity. While Ligand B has slightly better BBB penetration and Caco-2 permeability, the improvements in metabolic stability and safety profile of Ligand A are more important for a CNS-targeting drug. The TPSA is also better for Ligand A.

Output:
1
2025-04-17 06:08:36,194 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (338.411 and 357.445 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (68.44) is significantly better than Ligand B (43.86), being closer to the optimal <90 for CNS targets. Ligand B is excellent.

**3. logP:** Both ligands (1.327 and 1.965) are within the optimal 1-3 range.

**4. H-Bond Donors:** Ligand A has 2 HBD, while Ligand B has 0. Both are acceptable (<=5).

**5. H-Bond Acceptors:** Both ligands have 3 HBA, well within the acceptable limit of <=10.

**6. QED:** Ligand A (0.868) has a slightly better QED than Ligand B (0.73), indicating a more drug-like profile.

**7. DILI:** Ligand A (44.048) has a slightly higher DILI risk than Ligand B (23.575), but both are below the concerning threshold of 60.

**8. BBB:** Ligand B (89.802) has a substantially better BBB penetration percentile than Ligand A (73.827). This is a *critical* advantage for a CNS target like DRD2.

**9. Caco-2 Permeability:** Ligand A (-4.901) has a more negative Caco-2 value, indicating poorer permeability than Ligand B (-4.369).

**10. Aqueous Solubility:** Ligand A (-3.141) has slightly worse solubility than Ligand B (-2.043).

**11. hERG Inhibition:** Both ligands have low hERG inhibition risk (0.757 and 0.806, respectively).

**12. Microsomal Clearance:** Ligand A (14.8 mL/min/kg) has a lower microsomal clearance than Ligand B (38.67 mL/min/kg), suggesting better metabolic stability.

**13. In vitro Half-Life:** Ligand A (-24.866) has a more negative in vitro half-life, suggesting a shorter half-life than Ligand B (-10.425).

**14. P-gp Efflux:** Ligand A (0.074) has lower P-gp efflux than Ligand B (0.097), which is beneficial for CNS exposure.

**15. Binding Affinity:** Ligand A (-10.2 kcal/mol) has a significantly stronger binding affinity than Ligand B (-8.8 kcal/mol). This is a substantial advantage.

**Overall Assessment:**

While Ligand A has better metabolic stability (lower Cl_mic) and a stronger binding affinity, Ligand B excels in crucial properties for a CNS-targeting GPCR ligand: significantly better BBB penetration and acceptable Caco-2 permeability. The difference in binding affinity (-1.4 kcal/mol) is considerable, but the superior BBB penetration of Ligand B is a major advantage that likely outweighs the affinity difference. The lower P-gp efflux of Ligand A is also a plus, but the difference isn't as dramatic as the BBB difference.

Output:
1
2025-04-17 06:08:36,194 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (376.737 Da) is slightly higher than Ligand B (357.495 Da), but both are acceptable.

**2. TPSA:** Ligand A (75.35) is better than Ligand B (87.74). For CNS targets, we want TPSA <= 90, both are within this range, but A is preferable.

**3. logP:** Ligand A (3.633) is optimal, while Ligand B (2.156) is a bit low, potentially hindering membrane permeability.

**4. H-Bond Donors:** Both ligands have acceptable HBD counts (A: 3, B: 2).

**5. H-Bond Acceptors:** Both ligands have acceptable HBA counts (A: 3, B: 4).

**6. QED:** Both ligands have similar and good QED values (A: 0.713, B: 0.731).

**7. DILI:** Ligand B (20.318) has a significantly lower DILI risk than Ligand A (41.218), which is a strong advantage for B.

**8. BBB:** Ligand B (71.811) has a much better BBB penetration percentile than Ligand A (43.273). This is *critical* for a CNS target like DRD2.

**9. Caco-2 Permeability:** Ligand A (-5.182) has worse Caco-2 permeability than Ligand B (-4.701), indicating lower intestinal absorption.

**10. Aqueous Solubility:** Ligand A (-3.649) has worse aqueous solubility than Ligand B (-2.426).

**11. hERG Inhibition:** Both ligands have low hERG inhibition risk (A: 0.782, B: 0.485), which is good.

**12. Microsomal Clearance:** Ligand B (71.68) has a much higher microsomal clearance than Ligand A (12.761), suggesting lower metabolic stability. This is a drawback for B.

**13. In vitro Half-Life:** Ligand A (12.142) has a better in vitro half-life than Ligand B (-15.81). This is a drawback for B.

**14. P-gp Efflux:** Ligand A (0.236) has lower P-gp efflux than Ligand B (0.014), which is favorable for CNS exposure.

**15. Binding Affinity:** Ligand A (-8.5 kcal/mol) has a significantly stronger binding affinity than Ligand B (-7.3 kcal/mol). This is a substantial advantage for A.

**Overall Assessment:**

While Ligand B has a much better safety profile (lower DILI) and BBB penetration, Ligand A boasts a significantly stronger binding affinity. The affinity difference is substantial (>1.2 kcal/mol), and this can often outweigh minor ADME drawbacks. The lower P-gp efflux of Ligand A is also beneficial for CNS penetration. The metabolic stability and half-life of Ligand A are also better. Although Ligand B has better solubility and Caco-2 permeability, the affinity and CNS-related properties of Ligand A are more crucial for a DRD2 ligand.

Output:
1
2025-04-17 06:08:36,194 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (341.411 and 341.503 Da) fall comfortably within the ideal 200-500 Da range.

**TPSA:** Ligand A (84.23) is better than Ligand B (53.08) as it is closer to the <90 A^2 threshold for CNS targets.

**logP:** Both ligands have good logP values (2.751 and 3.216), falling within the optimal 1-3 range. Ligand B is slightly higher, which could potentially lead to some off-target effects, but is still acceptable.

**H-Bond Donors/Acceptors:** Both have 2 HBD and a reasonable number of HBA (4 and 5 respectively), satisfying the <5 HBD and <10 HBA guidelines.

**QED:** Both ligands have good QED scores (0.811 and 0.832), indicating good drug-like properties.

**DILI:** Ligand A (52.966) has a slightly higher DILI risk than Ligand B (32.842), but both are below the concerning threshold of 60.

**BBB:** This is a critical parameter for a CNS target like DRD2. Ligand B (94.029) significantly outperforms Ligand A (65.839) in BBB penetration, exceeding the desirable >70 percentile.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.875 and -5.193). This is unusual and suggests poor intestinal absorption. However, for a CNS target, intestinal absorption is less critical than BBB penetration.

**Aqueous Solubility:** Both ligands have very poor aqueous solubility (-3.522 and -3.115). This could pose formulation challenges.

**hERG Inhibition:** Ligand A (0.311) has a slightly lower hERG inhibition risk than Ligand B (0.928), which is preferable.

**Microsomal Clearance:** Ligand B (39.101) has a slightly higher microsomal clearance than Ligand A (30.646), suggesting slightly lower metabolic stability.

**In vitro Half-Life:** Ligand B (27.546) has a slightly longer half-life than Ligand A (22.526), which is desirable.

**P-gp Efflux:** Ligand A (0.243) has lower P-gp efflux liability than Ligand B (0.081), which is beneficial for CNS exposure.

**Binding Affinity:** Both ligands have excellent binding affinities (-9.3 and -8.4 kcal/mol). Ligand A has a 0.9 kcal/mol advantage, which is significant.

**Overall Assessment:**

While Ligand A has a better binding affinity and lower P-gp efflux, the significantly superior BBB penetration of Ligand B (94.029 vs 65.839) is the deciding factor for a CNS-targeting drug. The difference in BBB is substantial and outweighs the slight advantages of Ligand A. The slightly higher DILI and hERG risk of Ligand B are less concerning than the poor BBB penetration of Ligand A.

Output:
1
2025-04-17 06:08:36,194 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (344.46 and 346.47 Da) fall comfortably within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (67.23) is better than Ligand B (69.64). Both are below the 90 A^2 threshold for CNS targets, which is good.

**3. logP:** Both ligands have logP values around 2 (1.965 and 2.003), which is optimal for permeability and solubility.

**4. H-Bond Donors:** Ligand A has 1 HBD, while Ligand B has 2. Both are within the acceptable limit of <=5.

**5. H-Bond Acceptors:** Ligand A has 4 HBA, and Ligand B has 3. Both are below the acceptable limit of <=10.

**6. QED:** Ligand A (0.831) has a higher QED than Ligand B (0.723), indicating better overall drug-likeness.

**7. DILI:** Ligand A (15.2%) has a significantly lower DILI risk than Ligand B (6.979%). This is a substantial advantage.

**8. BBB:** Ligand A (66.886%) is slightly better than Ligand B (63.629%) in terms of BBB penetration, but both are below the desirable 70% threshold for CNS targets.

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.834 and -4.895), which is unusual and suggests poor permeability. This is a significant concern for both.

**10. Aqueous Solubility:** Both ligands have negative solubility values (-1.092 and -2.366), which is also concerning. Poor solubility can hinder bioavailability.

**11. hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.17 and 0.278).

**12. Microsomal Clearance:** Both ligands have similar microsomal clearance values (22.265 and 22.334 mL/min/kg), suggesting comparable metabolic stability.

**13. In vitro Half-Life:** Ligand A has a negative half-life (-18.017 hours), which is not physically possible and indicates a problem with the data. Ligand B has a half-life of 8.794 hours, which is reasonable.

**14. P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.042 and 0.056), which is favorable for CNS penetration.

**15. Binding Affinity:** Both ligands have very similar and strong binding affinities (-8.7 and -8.4 kcal/mol). The difference is less than 0.5 kcal/mol, so it's not a major deciding factor.

**Overall Assessment:**

Ligand A is preferable despite the negative Caco-2 and solubility values. Its significantly lower DILI risk, higher QED, and slightly better BBB penetration outweigh the concerns about the impossible half-life value (which suggests a data error). The binding affinities are comparable. The negative Caco-2 and solubility values are red flags for both, but can be addressed through prodrug strategies or formulation techniques. Ligand B's positive half-life is good, but the higher DILI risk is a significant drawback.

Output:
0
2025-04-17 06:08:36,194 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B based on the provided guidelines, prioritizing GPCR-specific properties (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (357.401 and 369.487 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (80.32) is better than Ligand B (89.55). Both are below the 90 A^2 threshold desirable for CNS targets, but A is closer to the optimal range.

**logP:** Both ligands have good logP values (1.932 and 1.761) within the 1-3 range.

**H-Bond Donors:** Both have 2 HBD, which is acceptable.

**H-Bond Acceptors:** Ligand A has 4 HBA, while Ligand B has 6. Ligand A is preferable here, staying further from the upper limit of 10.

**QED:** Both ligands have similar QED values (0.662 and 0.614), indicating good drug-likeness.

**DILI:** Ligand A (38.387) has a significantly lower DILI risk than Ligand B (54.75). This is a substantial advantage.

**BBB:** Ligand A (73.672) has a much better BBB penetration percentile than Ligand B (53.819). This is *critical* for a CNS target like DRD2.

**Caco-2 Permeability:** Ligand A (-4.606) has a worse Caco-2 permeability than Ligand B (-5.332). While both are negative, B is slightly better.

**Aqueous Solubility:** Ligand A (-2.886) has slightly better solubility than Ligand B (-1.48).

**hERG:** Both ligands have low hERG inhibition liability (0.355 and 0.225), which is good.

**Microsomal Clearance:** Ligand A (43.908) has higher microsomal clearance than Ligand B (15.812), indicating lower metabolic stability. This favors Ligand B.

**In vitro Half-Life:** Ligand A (37.166) has a longer half-life than Ligand B (29.737), which is preferable.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.106 and 0.051), which is good, with B being slightly better.

**Binding Affinity:** Ligand A (-7.9 kcal/mol) has a slightly better binding affinity than Ligand B (-7.4 kcal/mol). While the difference is less than the 1.5 kcal/mol threshold to outweigh other issues, it is still a positive factor.

**Overall Assessment:**

Ligand A is significantly better due to its superior BBB penetration, lower DILI risk, and better TPSA and HBA values. The slightly worse microsomal clearance is a concern, but the strong advantages in CNS penetration and safety outweigh this drawback. The affinity difference is a bonus. Ligand B's better Caco-2 permeability and slightly lower P-gp efflux are not enough to compensate for its poor BBB and higher DILI risk.

Output:
1
2025-04-17 06:08:36,194 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (350.419 and 346.475 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (130.39) is borderline for CNS targets (ideally <90), but acceptable. Ligand B (60.25) is excellent, well below the 90 threshold, suggesting better CNS penetration potential.

**3. logP:** Ligand A (0.186) is quite low, potentially hindering membrane permeability. Ligand B (2.527) is within the optimal 1-3 range. This is a significant advantage for Ligand B.

**4. H-Bond Donors:** Ligand A (4) is acceptable. Ligand B (0) is also good, potentially improving permeability.

**5. H-Bond Acceptors:** Both ligands (A: 4, B: 5) are within the acceptable limit of 10.

**6. QED:** Both ligands have good QED scores (A: 0.522, B: 0.822), indicating drug-like properties. Ligand B is better.

**7. DILI:** Both ligands have low DILI risk (A: 41.024, B: 32.571), below the 40 threshold. Ligand B is slightly better.

**8. BBB:** Both ligands have high BBB penetration (A: 87.398, B: 83.831), exceeding the desirable >70 threshold for CNS targets. Ligand A is slightly better.

**9. Caco-2:** Both ligands have negative Caco-2 values, which is unusual and problematic. It suggests poor intestinal absorption.

**10. Solubility:** Both ligands have negative solubility values, which is also problematic and suggests poor aqueous solubility.

**11. hERG:** Both ligands have very low hERG risk (A: 0.06, B: 0.242).

**12. Cl_mic:** Ligand A (41.189) has lower microsomal clearance than Ligand B (67.887), suggesting better metabolic stability.

**13. t1/2:** Both ligands have negative in vitro half-life values, which is unusual and problematic.

**14. Pgp:** Both ligands have very low P-gp efflux liability (A: 0.023, B: 0.336), which is favorable for CNS exposure. Ligand A is better.

**15. Binding Affinity:** Both ligands have excellent binding affinities (A: -9.0 kcal/mol, B: -8.4 kcal/mol). Ligand A is slightly better.

**Overall Assessment:**

While Ligand A has a slightly better binding affinity, BBB penetration, and lower Cl_mic, Ligand B has a significantly better logP and TPSA, which are crucial for CNS penetration and GPCR targeting. The negative Caco-2 and solubility values are concerning for both, but the low logP of Ligand A is a more significant drawback. Considering the GPCR-specific priorities, Ligand B's superior logP and TPSA outweigh the slight advantage of Ligand A in other parameters.

Output:
1
2025-04-17 06:08:36,194 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (368.5 and 351.4 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (76.66) is better than Ligand B (84.46). Both are below the 90 A^2 threshold desirable for CNS targets, but A is closer to the optimal range.

**logP:** Both ligands have good logP values (2.337 and 1.203), falling within the 1-3 range. Ligand A is slightly more lipophilic, which could aid in membrane permeability.

**H-Bond Donors & Acceptors:** Ligand A has 2 HBD and 5 HBA, while Ligand B has 1 HBD and 5 HBA. Both are within acceptable limits (<=5 HBD and <=10 HBA).

**QED:** Both ligands have good QED scores (0.622 and 0.835), indicating good drug-like properties. Ligand B is slightly better here.

**DILI:** Ligand A (38.5) has a lower DILI risk than Ligand B (45.6), suggesting a better safety profile.

**BBB:** Ligand B (88.06) has a significantly better BBB penetration score than Ligand A (70.65). This is a crucial factor for a CNS target like DRD2.

**Caco-2 Permeability:** Both have negative values, indicating poor permeability. Ligand A (-5.149) is slightly better than Ligand B (-4.949), but both are concerning.

**Aqueous Solubility:** Both have very poor aqueous solubility (-2.223 and -2.58). This is a significant drawback for both compounds.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.594 and 0.549).

**Microsomal Clearance:** Ligand B (20.568) has lower microsomal clearance than Ligand A (32.298), indicating better metabolic stability.

**In vitro Half-Life:** Ligand B (-14.901) has a negative half-life, which is problematic. Ligand A (15.024) has a reasonable half-life.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.185 and 0.092), which is favorable for CNS penetration. Ligand B is slightly better.

**Binding Affinity:** Both ligands have excellent binding affinity (-7.5 and -7.6 kcal/mol). The difference is negligible.

**Overall Assessment:**

Ligand B excels in BBB penetration and metabolic stability, which are critical for CNS GPCR targets. However, it has a negative in vitro half-life, which is a major concern. Ligand A has a more reasonable half-life and lower DILI risk, but its BBB penetration is significantly worse. The solubility is poor for both. Given the importance of BBB penetration for a CNS target and the slight advantage of B in P-gp efflux, I would lean towards Ligand B *if* the half-life issue could be addressed through structural modification. However, the negative half-life is a substantial red flag. Considering all factors, and prioritizing a reasonable half-life, I would select Ligand A.

Output:
1
2025-04-17 06:08:36,194 - INFO - Reasoning:

Let's analyze Ligand A and Ligand B based on the provided guidelines, prioritizing GPCR-specific properties (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (342.414 and 356.463 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (62.22) is excellent for CNS penetration, well below the 90 A^2 threshold. Ligand B (79.31) is still reasonable but less optimal.

**logP:** Ligand A (3.231) is within the optimal 1-3 range. Ligand B (0.652) is quite low, potentially hindering membrane permeability and CNS entry despite a good BBB score.

**H-Bond Donors/Acceptors:** Ligand A (2 HBD, 3 HBA) and Ligand B (1 HBD, 5 HBA) both have acceptable numbers of hydrogen bond donors and acceptors.

**QED:** Ligand A (0.877) has a significantly better QED score than Ligand B (0.614), indicating a more drug-like profile.

**DILI:** Ligand A (35.324) has a slightly higher DILI risk than Ligand B (4.731), but both are below the concerning threshold of 60.

**BBB:** Both ligands have good BBB penetration (Ligand A: 73.129, Ligand B: 70.105), exceeding the 70% threshold for CNS targets.

**Caco-2 Permeability:** Ligand A (-4.605) and Ligand B (-4.467) both have negative Caco-2 values, indicating poor permeability. This is concerning, but can be offset by other favorable properties.

**Aqueous Solubility:** Both ligands have poor aqueous solubility (-3.675 and -0.548 respectively).

**hERG:** Both ligands have low hERG inhibition risk (0.426 and 0.31 respectively).

**Microsomal Clearance:** Ligand A (44.151) has a higher microsomal clearance than Ligand B (21.336), suggesting lower metabolic stability.

**In vitro Half-Life:** Ligand B (11.843 hours) has a significantly longer half-life than Ligand A (-3.469 hours).

**P-gp Efflux:** Ligand A (0.206) exhibits lower P-gp efflux than Ligand B (0.018), which is favorable for CNS penetration.

**Binding Affinity:** Ligand B (-7.1 kcal/mol) has a significantly stronger binding affinity than Ligand A (-9.2 kcal/mol). This is a substantial advantage.

**Overall Assessment:**

While Ligand A has better QED, TPSA, and P-gp efflux, Ligand B's significantly stronger binding affinity (-7.1 vs -9.2 kcal/mol) and longer half-life are crucial advantages, especially for a GPCR target like DRD2. The lower logP of Ligand B is a concern, but the strong binding affinity may compensate for this. The lower DILI risk of Ligand B is also a positive. The poor Caco-2 values for both ligands are a drawback, but not decisive given the CNS target.

Output:
1
2025-04-17 06:08:36,195 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (348.403) is slightly preferred as it's closer to the lower end, potentially aiding permeability.

**TPSA:** Ligand A (123.41) is excellent for CNS penetration, being below the 90 A^2 threshold. Ligand B (62.66) is also very good.

**logP:** Ligand A (0.117) is quite low, potentially hindering membrane permeability. Ligand B (3.416) is within the optimal range (1-3). This is a significant advantage for Ligand B.

**H-Bond Donors/Acceptors:** Ligand A (3 HBD, 5 HBA) and Ligand B (1 HBD, 6 HBA) both fall within acceptable limits.

**QED:** Both ligands have good QED scores (A: 0.585, B: 0.809), indicating drug-like properties. Ligand B is better.

**DILI:** Both have acceptable DILI risk (A: 39.201, B: 58.589), with Ligand A being slightly preferred.

**BBB:** Ligand B (79.217) has a significantly better BBB percentile than Ligand A (64.754). This is a critical advantage for a CNS target like DRD2.

**Caco-2 Permeability:** Ligand A (-5.456) has poor Caco-2 permeability, while Ligand B (-4.89) is slightly better, but still not great.

**Aqueous Solubility:** Both have poor aqueous solubility (A: -2.451, B: -4.111). This could pose formulation challenges, but is less critical than BBB and permeability for CNS drugs.

**hERG Inhibition:** Ligand A (0.039) has very low hERG risk, which is excellent. Ligand B (0.392) is also low, but higher than A.

**Microsomal Clearance:** Ligand A (-3.037) has a negative value, indicating very low clearance and excellent metabolic stability. Ligand B (38.8) has a high clearance, suggesting faster metabolism. This is a major advantage for Ligand A.

**In vitro Half-Life:** Ligand A (5.113) has a shorter half-life than Ligand B (16.53), but the negative clearance of A suggests the *in vivo* half-life could be longer.

**P-gp Efflux:** Ligand A (0.01) has very low P-gp efflux, which is ideal for CNS penetration. Ligand B (0.516) has moderate P-gp efflux.

**Binding Affinity:** Ligand A (-7.8) has a slightly better binding affinity than Ligand B (-7.4). While both are good (<-7.0), the 0.4 kcal/mol difference is notable.

**Overall Assessment:**

Ligand A has advantages in binding affinity, metabolic stability (low Cl_mic, low P-gp efflux), and hERG risk. However, its low logP and poor Caco-2 permeability are significant drawbacks. Ligand B excels in BBB penetration and has a better logP, but suffers from higher metabolic clearance and P-gp efflux.

Considering the GPCR-specific priorities for DRD2, BBB penetration is crucial. Ligand B's significantly higher BBB percentile (79.217 vs 64.754) is a major factor. While Ligand A's affinity is slightly better, the difference is not large enough to overcome the permeability and BBB issues. The better logP of Ligand B also contributes to better potential for crossing the blood-brain barrier.

Output:
1
2025-04-17 06:08:36,195 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (406.328 Da) is slightly higher than Ligand B (348.495 Da), but both are acceptable.

**2. TPSA:** Ligand A (62.53) is better than Ligand B (73.39). For CNS targets, we want TPSA <= 90, both are within this range, but A is preferable.

**3. logP:** Ligand A (3.157) is optimal (1-3), while Ligand B (1.536) is on the lower side. Lower logP can hinder permeation. Ligand A is better here.

**4. H-Bond Donors:** Ligand A (1) and Ligand B (2) are both acceptable (<=5).

**5. H-Bond Acceptors:** Ligand A (5) and Ligand B (6) are both acceptable (<=10).

**6. QED:** Both ligands have similar QED values (A: 0.848, B: 0.742), both are good (>0.5).

**7. DILI:** Ligand A (58.395) has a higher DILI risk than Ligand B (27.685). This favors Ligand B.

**8. BBB:** Ligand A (89.608) has a significantly better BBB penetration percentile than Ligand B (76.231). This is a critical factor for a CNS target like DRD2, strongly favoring Ligand A.

**9. Caco-2 Permeability:** Both have negative values, indicating a scale rather than percentile. Without knowing the scale, it's hard to interpret, but the values are similar.

**10. Aqueous Solubility:** Both have negative values, indicating a scale rather than percentile. Again, hard to interpret, but values are similar.

**11. hERG Inhibition:** Ligand A (0.799) has a slightly higher hERG inhibition risk than Ligand B (0.528). This favors Ligand B.

**12. Microsomal Clearance:** Ligand A (72.631) has higher clearance than Ligand B (7.502), indicating lower metabolic stability. This favors Ligand B.

**13. In vitro Half-Life:** Ligand A (17.545) has a shorter half-life than Ligand B (24.638). This favors Ligand B.

**14. P-gp Efflux:** Ligand A (0.601) has lower P-gp efflux liability than Ligand B (0.012). Lower P-gp efflux is desirable for CNS exposure, favoring Ligand A.

**15. Binding Affinity:** Ligand A (-8.4 kcal/mol) has a slightly better binding affinity than Ligand B (-7.6 kcal/mol).  A 0.8 kcal/mol difference is significant and can outweigh some ADME drawbacks.

**Overall Assessment:**

Ligand A excels in BBB penetration and binding affinity, which are paramount for a CNS GPCR target. While it has a higher DILI risk and lower metabolic stability, the strong affinity and excellent BBB penetration are likely to be more impactful. Ligand B has better ADME properties (DILI, clearance, half-life, P-gp efflux), but its lower affinity and BBB penetration are significant drawbacks for a CNS target. The affinity difference is substantial enough to overcome the ADME concerns with Ligand A.

Output:
1
2025-04-17 06:08:36,195 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B based on the provided guidelines, prioritizing GPCR-specific properties (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (350.394 and 355.494 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (67.67) is significantly higher than Ligand B (46.61). For a CNS target like DRD2, TPSA should be <=90, so both are acceptable, but B is better.

**logP:** Ligand A (0.317) is quite low, potentially hindering permeability. Ligand B (3.835) is within the optimal 1-3 range. This is a significant advantage for B.

**H-Bond Donors/Acceptors:** Ligand A has 0 HBD and 5 HBA, while Ligand B has 0 HBD and 3 HBA. Both are within acceptable limits.

**QED:** Ligand A (0.734) has a better QED score than Ligand B (0.56), suggesting slightly better overall drug-likeness.

**DILI:** Ligand A (32.028) has a lower DILI risk than Ligand B (15.665), indicating a safer profile.

**BBB:** Ligand B (95.308) has a much higher BBB penetration percentile than Ligand A (84.684). This is *critical* for a CNS target and a major advantage for B.

**Caco-2 Permeability:** Ligand A (-4.47) has a worse Caco-2 permeability than Ligand B (-3.973), indicating lower intestinal absorption.

**Aqueous Solubility:** Ligand A (-1.143) has better solubility than Ligand B (-4.798).

**hERG Inhibition:** Ligand A (0.263) has a lower hERG inhibition risk than Ligand B (0.849).

**Microsomal Clearance:** Ligand B (123.486) has a significantly higher microsomal clearance than Ligand A (18.993), meaning it will be metabolized faster. This is a disadvantage for B.

**In vitro Half-Life:** Ligand A (-28.795) has a longer in vitro half-life than Ligand B (-6.738). This is a significant advantage for A.

**P-gp Efflux:** Ligand A (0.03) has lower P-gp efflux than Ligand B (0.348), which is favorable for CNS penetration.

**Binding Affinity:** Both ligands have comparable binding affinities (-7.8 and -6.8 kcal/mol). The difference of 1.0 kcal/mol is not substantial enough to outweigh other factors.

**Overall Assessment:**

Ligand B excels in BBB penetration and logP, which are crucial for CNS GPCR targets. While it has a higher DILI risk and faster clearance, the superior BBB penetration is a major advantage. Ligand A has better solubility, lower DILI, and better metabolic stability, but its low logP and lower BBB penetration are significant drawbacks. Given the target (DRD2 in the CNS), the improved brain penetration of Ligand B is the deciding factor.

Output:
1
2025-04-17 06:08:36,195 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B based on the provided guidelines, prioritizing GPCR-specific properties (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (346.475 and 354.495 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (76.02) is significantly better than Ligand B (104.53). For CNS targets, TPSA should be <= 90, and A is comfortably within this range, while B is approaching the upper limit.

**logP:** Both ligands have good logP values (1.966 and 1.614), falling within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A (HBD=2, HBA=4) is slightly better than Ligand B (HBD=3, HBA=3) in terms of balancing solubility and permeability. Both are acceptable.

**QED:** Both ligands have similar QED values (0.671 and 0.605), indicating good drug-likeness.

**DILI:** Ligand A (25.126) has a slightly higher DILI risk than Ligand B (19.387), but both are well below the concerning threshold of 60.

**BBB:** Ligand B (81.698) has a substantially better BBB penetration percentile than Ligand A (61.109). This is a *critical* advantage for a CNS target like DRD2.

**Caco-2 Permeability:** Ligand A (-4.852) has better Caco-2 permeability than Ligand B (-5.036), but both are negative, indicating poor permeability.

**Aqueous Solubility:** Both have very poor aqueous solubility (-2.134 and -2.421). This is a significant drawback for both.

**hERG:** Both ligands have low hERG inhibition liability (0.112 and 0.359), which is good.

**Microsomal Clearance:** Ligand B (24.33) has lower microsomal clearance than Ligand A (39.744), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand B (-9.71) has a significantly longer in vitro half-life than Ligand A (-2.88).

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.021 and 0.011), which is beneficial for CNS penetration.

**Binding Affinity:** Ligand A (-7.9) has a slightly better binding affinity than Ligand B (-7.2). While both are excellent, the 0.7 kcal/mol difference is noteworthy.

**Overall Assessment:**

While Ligand A has a slightly better binding affinity and Caco-2 permeability, Ligand B is superior overall, particularly due to its significantly better BBB penetration (81.7% vs 61.1%), longer half-life, and lower microsomal clearance. For a CNS target like DRD2, BBB penetration is paramount. The slightly weaker affinity of Ligand B can potentially be optimized in subsequent iterations, but improving BBB penetration is often more challenging. The lower clearance and longer half-life of Ligand B also contribute to a more favorable pharmacokinetic profile.

Output:
1
2025-04-17 06:08:36,195 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (353.379 and 341.415 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (107.81) is higher than Ligand B (72.58). For CNS targets, we prefer TPSA <= 90, so Ligand B is significantly better here.

**logP:** Ligand A (0.424) is slightly better than Ligand B (0.275) as both are a bit low, but ideally we want 1-3. The low logP of both could hinder membrane permeability.

**H-Bond Donors/Acceptors:** Ligand A has 1 HBD and 8 HBA, while Ligand B has 0 HBD and 5 HBA. Both are within acceptable limits (<=5 HBD and <=10 HBA).

**QED:** Both ligands have good QED scores (0.765 and 0.791), indicating good drug-like properties.

**DILI:** Ligand A (69.794) has a higher DILI risk than Ligand B (30.787). Lower is better, so Ligand B is preferred.

**BBB:** Ligand A (79.488) has a better BBB penetration percentile than Ligand B (49.826). This is a critical factor for CNS targets like DRD2, making Ligand A more favorable.

**Caco-2 Permeability:** Both have negative Caco-2 values (-4.609 and -4.784), which is unusual and suggests poor permeability.

**Aqueous Solubility:** Both have negative solubility values (-2.689 and -1.817), which is also unusual and suggests poor solubility.

**hERG:** Ligand A (0.058) has a slightly lower hERG risk than Ligand B (0.473), which is preferred.

**Microsomal Clearance:** Ligand A (48.057) has a higher microsomal clearance than Ligand B (21.7). Lower clearance is better for metabolic stability, favoring Ligand B.

**In vitro Half-Life:** Ligand B (17.902) has a significantly longer half-life than Ligand A (-2.918). This is a major advantage for Ligand B.

**P-gp Efflux:** Ligand A (0.013) has a lower P-gp efflux liability than Ligand B (0.01). Both are very low, indicating minimal efflux.

**Binding Affinity:** Ligand B (-8.2 kcal/mol) has a slightly better binding affinity than Ligand A (-7.5 kcal/mol). A difference of 0.7 kcal/mol is significant and can outweigh some ADME drawbacks.

**Overall Assessment:**

Ligand A excels in BBB penetration and has a slightly lower hERG risk. However, Ligand B demonstrates superior properties in terms of DILI risk, metabolic stability (lower Cl_mic, longer t1/2), and binding affinity. The TPSA of Ligand B is also much more favorable for CNS penetration. While both have issues with solubility and permeability, the stronger binding affinity and better ADME profile of Ligand B make it the more promising candidate.

Output:
1
2025-04-17 06:08:36,195 - INFO - Batch 257 complete. Total preferences: 4112
2025-04-17 06:08:36,195 - INFO - Processing batch 258/512...
2025-04-17 06:09:18,538 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (369.418 and 363.437 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (98.66) is higher than the preferred <90 for CNS targets, but still reasonable. Ligand B (45.46) is excellent, well below the 90 threshold.

**3. logP:** Ligand A (1.453) is within the optimal 1-3 range. Ligand B (4.043) is slightly above, potentially raising concerns about solubility and off-target effects, but not drastically.

**4. H-Bond Donors:** Both ligands have 1 HBD, which is acceptable.

**5. H-Bond Acceptors:** Both ligands have 6 HBA, which is acceptable.

**6. QED:** Both ligands have similar QED values (0.793 and 0.743), indicating good drug-likeness.

**7. DILI:** Ligand A (54.207) has a lower DILI risk than Ligand B (85.072), which is a significant advantage.

**8. BBB:** Ligand A (70.764) and Ligand B (68.631) are both reasonably good, but slightly below the >70 desirable for CNS targets.

**9. Caco-2 Permeability:** Ligand A (-5.243) has worse Caco-2 permeability than Ligand B (-4.696).

**10. Aqueous Solubility:** Ligand A (-2.129) has better aqueous solubility than Ligand B (-4.466).

**11. hERG Inhibition:** Ligand A (0.492) shows lower hERG inhibition liability than Ligand B (0.855), which is a positive.

**12. Microsomal Clearance:** Ligand A (14.258) has a lower microsomal clearance, suggesting better metabolic stability, than Ligand B (44.814).

**13. In vitro Half-Life:** Ligand A (-2.843) has a longer in vitro half-life than Ligand B (-3.919).

**14. P-gp Efflux:** Ligand A (0.171) has lower P-gp efflux liability than Ligand B (0.672), which is beneficial for CNS penetration.

**15. Binding Affinity:** Ligand B (-8.1) has a slightly better binding affinity than Ligand A (-7.7), a difference of 0.4 kcal/mol.

**Overall Assessment:**

While Ligand B has a slightly better binding affinity, Ligand A demonstrates a significantly more favorable ADMET profile. Specifically, Ligand A has a much lower DILI risk, better metabolic stability (lower Cl_mic and longer t1/2), lower P-gp efflux, and lower hERG inhibition. Considering DRD2 is a CNS target, the lower P-gp efflux and better metabolic stability of Ligand A are particularly important for achieving sufficient brain exposure. The TPSA of Ligand A is a slight concern, but the benefits outweigh this drawback. The solubility of ligand A is also better.

Output:
0
2025-04-17 06:09:18,539 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (363.288 Da and 362.459 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (90.93) is excellent, falling below the 90 threshold for CNS targets. Ligand B (103.87) is still reasonable but less optimal, exceeding the preferred TPSA for CNS penetration.

**3. logP:** Ligand A (1.924) is within the optimal range of 1-3. Ligand B (0.964) is slightly below 1, which *could* indicate permeability issues, though not drastically.

**4. H-Bond Donors:** Ligand A (1) and Ligand B (2) are both acceptable, being less than 5.

**5. H-Bond Acceptors:** Both ligands (6) are within the acceptable limit of 10.

**6. QED:** Both ligands have good QED scores (0.561 and 0.797), indicating good drug-like properties.

**7. DILI:** Ligand A (75.456) has a slightly higher DILI risk than Ligand B (60.915), but both are within acceptable limits (<60 is good, <40 is better).

**8. BBB:** This is a critical parameter for a CNS target like DRD2. Ligand A scores very well (89.104), exceeding the desirable >70 threshold. Ligand B is significantly lower (33.501), raising concerns about CNS penetration.

**9. Caco-2 Permeability:** Ligand A (-4.942) and Ligand B (-5.585) are both negative values, which is unusual. It's difficult to interpret without knowing the scale, but lower (more negative) values generally indicate lower permeability.

**10. Aqueous Solubility:** Both ligands have negative solubility values (-3.96 and -2.681). Again, the scale is unknown, but lower values suggest poorer solubility.

**11. hERG Inhibition:** Both ligands have low hERG inhibition liability (0.67 and 0.417), which is favorable.

**12. Microsomal Clearance:** Ligand A (58.136) has a higher microsomal clearance than Ligand B (11.749), suggesting lower metabolic stability.

**13. In vitro Half-Life:** Ligand B (-12.903) has a significantly longer in vitro half-life than Ligand A (-2.173). This is a substantial advantage.

**14. P-gp Efflux:** Ligand A (0.26) has lower P-gp efflux liability than Ligand B (0.071), which is better for CNS exposure.

**15. Binding Affinity:** Ligand A (-7.8 kcal/mol) has a slightly better binding affinity than Ligand B (-8.5 kcal/mol). While both are excellent, the difference is relatively small.

**Overall Assessment:**

Ligand A excels in BBB penetration, TPSA, and P-gp efflux, all critical for CNS GPCR targets. Ligand B has a significantly better in vitro half-life and lower microsomal clearance, indicating improved metabolic stability. While Ligand A has a slightly better binding affinity, the difference is small. The poor BBB score of Ligand B is a major drawback for a DRD2 ligand. Considering the GPCR-specific priorities, the superior BBB penetration of Ligand A outweighs the metabolic advantages of Ligand B.

Output:
1
2025-04-17 06:09:18,539 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (354.491 and 346.515 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (67.87) is higher than Ligand B (40.62). For a CNS target like DRD2, TPSA < 90 is preferred, so both are acceptable, but B is significantly better.

**3. logP:** Ligand A (2.114) and Ligand B (3.916) are both within the optimal 1-3 range, though B is approaching the upper limit.

**4. H-Bond Donors:** Ligand A (1) is better than Ligand B (0). Fewer HBDs generally improve permeability.

**5. H-Bond Acceptors:** Ligand A (4) is higher than Ligand B (2). Lower is better for permeability.

**6. QED:** Ligand A (0.76) has a better QED score than Ligand B (0.444), indicating a more drug-like profile.

**7. DILI:** Ligand A (20.9) has a much lower DILI risk than Ligand B (16.983), indicating a safer profile.

**8. BBB:** Ligand B (90.074) has a significantly higher BBB penetration percentile than Ligand A (73.943). This is *critical* for a CNS target like DRD2.

**9. Caco-2 Permeability:** Ligand A (-4.205) and Ligand B (-4.721) are both negative, indicating poor permeability.

**10. Aqueous Solubility:** Ligand A (-1.781) and Ligand B (-3.76) are both negative, indicating poor solubility.

**11. hERG Inhibition:** Ligand A (0.29) has a lower hERG inhibition liability than Ligand B (0.674), which is preferable.

**12. Microsomal Clearance:** Ligand B (69.854) has higher microsomal clearance than Ligand A (43.502), meaning it's metabolized faster. Lower clearance is better.

**13. In vitro Half-Life:** Ligand A (-18.679) has a longer in vitro half-life than Ligand B (4.666).

**14. P-gp Efflux:** Ligand A (0.023) has much lower P-gp efflux liability than Ligand B (0.778). Lower efflux is crucial for CNS exposure.

**15. Binding Affinity:** Ligand A (-7.8) has a slightly better binding affinity than Ligand B (-7.3). While both are good, the 0.5 kcal/mol difference is notable.

**Overall Assessment:**

Ligand B excels in BBB penetration, which is paramount for a DRD2 ligand. However, it suffers from higher P-gp efflux, higher DILI risk, and faster metabolic clearance. Ligand A, while having a lower BBB score, has a significantly better safety profile (lower DILI, hERG, and P-gp efflux), better metabolic stability, and comparable affinity. The slightly better affinity of Ligand A combined with its superior ADME properties, particularly the lower P-gp efflux and DILI, makes it the more promising candidate.

Output:
0
2025-04-17 06:09:18,539 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (353.423 and 342.355 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (116.56) is better than Ligand B (120.25) as it is closer to the <90 A^2 threshold for CNS targets.

**logP:** Ligand B (0.985) is slightly better than Ligand A (-1.013). While both are a bit outside the optimal 1-3 range, Ligand B is closer to 1, which is preferable. Ligand A's negative logP is a concern for permeability.

**H-Bond Donors/Acceptors:** Ligand A (HBD=3, HBA=6) is slightly better than Ligand B (HBD=4, HBA=5) in terms of balancing solubility and permeability.

**QED:** Both ligands have similar QED values (0.466 and 0.532), indicating moderate drug-likeness.

**DILI:** Ligand B (74.603) has a significantly higher DILI risk than Ligand A (17.255). This is a major drawback for Ligand B.

**BBB:** Ligand A (24.389) has a much better BBB penetration percentile than Ligand B (11.206). This is *critical* for a CNS target like DRD2.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.651 and -5.789), which is unusual and suggests poor permeability.

**Aqueous Solubility:** Both ligands have negative solubility values (-0.71 and -3.153), indicating very poor aqueous solubility.

**hERG Inhibition:** Ligand A (0.058) has a lower hERG inhibition liability than Ligand B (0.389), which is preferable.

**Microsomal Clearance:** Ligand B (-2.949) has a negative clearance, which is not physically possible and suggests an issue with the data. Ligand A (15.373) has a reasonable, though not ideal, clearance value.

**In vitro Half-Life:** Ligand B (72.072) has a much longer in vitro half-life than Ligand A (13.518), which is a positive attribute.

**P-gp Efflux:** Ligand A (0.006) has a much lower P-gp efflux liability than Ligand B (0.045), which is beneficial for CNS penetration.

**Binding Affinity:** Ligand B (-8.8 kcal/mol) has a significantly stronger binding affinity than Ligand A (-7.0 kcal/mol). This is a substantial advantage.

**Overall Assessment:**

Despite Ligand B's superior binding affinity and half-life, its significantly higher DILI risk, poor BBB penetration, and questionable clearance data are major concerns. Ligand A, while having a weaker affinity and shorter half-life, has a much better safety profile (lower DILI, lower hERG), better BBB penetration, and lower P-gp efflux. For a CNS target, BBB penetration is paramount, and the lower DILI risk is also crucial. The affinity difference, while significant (1.8 kcal/mol), might be overcome with further optimization of Ligand A.

Output:
0
2025-04-17 06:09:18,539 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (349.431 and 365.474 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (93.46) is better than Ligand B (63.25). For CNS targets, we want TPSA <= 90, so A is closer to the threshold, while B is well within.

**3. logP:** Ligand A (1.294) is optimal, while Ligand B (3.643) is approaching the upper limit of the optimal range (1-3).

**4. H-Bond Donors:** Both ligands have 2 HBD, which is within the acceptable limit of <=5.

**5. H-Bond Acceptors:** Both ligands have 5 HBA, also within the acceptable limit of <=10.

**6. QED:** Both ligands have good QED scores (0.621 and 0.701), indicating drug-like properties.

**7. DILI:** Ligand A (14.541) has a significantly lower DILI risk than Ligand B (69.911). This is a major advantage for A.

**8. BBB:** Ligand B (77.821) has a much better BBB penetration percentile than Ligand A (51.609).  This is critical for a CNS target like DRD2.

**9. Caco-2 Permeability:** Both have negative values, which is unusual. Assuming these are logP-like scales, lower values indicate poorer permeability. Ligand A (-4.796) is worse than Ligand B (-4.821), but both are poor.

**10. Aqueous Solubility:** Ligand A (-1.983) is better than Ligand B (-3.842), indicating better solubility.

**11. hERG Inhibition:** Ligand A (0.071) has a lower hERG inhibition risk than Ligand B (0.761).

**12. Microsomal Clearance:** Ligand A (27.208) has significantly lower microsomal clearance than Ligand B (114.159), suggesting better metabolic stability.

**13. In vitro Half-Life:** Ligand B (114.358) has a much longer in vitro half-life than Ligand A (-3.052).

**14. P-gp Efflux:** Ligand A (0.007) has a much lower P-gp efflux liability than Ligand B (0.772), which is very important for CNS penetration.

**15. Binding Affinity:** Ligand B (-8.1) has a stronger binding affinity than Ligand A (-7.3). This is a 1.5 kcal/mol difference, which is significant.

**Overall Assessment:**

Ligand B has a substantially better binding affinity and BBB penetration, and a longer half-life. However, it suffers from higher DILI risk, higher P-gp efflux, and higher metabolic clearance. Ligand A has better safety profiles (DILI, hERG), better metabolic stability, and lower P-gp efflux, but weaker binding affinity and lower BBB.

Given the GPCR-specific priorities, BBB penetration is crucial. The 1.5 kcal/mol difference in binding affinity can be potentially overcome with further optimization, but poor BBB penetration is a more difficult property to improve. The lower DILI and P-gp efflux of Ligand A are also beneficial, but the affinity difference is significant. Considering the balance, the stronger affinity and better BBB penetration of Ligand B outweigh its drawbacks, especially given that these drawbacks are potentially addressable through further medicinal chemistry efforts.

Output:
1
2025-04-17 06:09:18,539 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (377.491 Da) and Ligand B (348.495 Da) are both acceptable.

**TPSA:** Ligand A (91.22) is slightly above the optimal 90 for CNS targets, but still reasonable. Ligand B (77.15) is well within the desired range.

**logP:** Both ligands have good logP values (A: 2.935, B: 1.631) falling within the 1-3 range.

**H-Bond Donors/Acceptors:** Both have 2 HBD and 5-6 HBA, which are acceptable.

**QED:** Both ligands have similar and good QED values (A: 0.81, B: 0.817), indicating good drug-likeness.

**DILI:** Ligand A has a significantly higher DILI risk (79.682) than Ligand B (8.414). This is a major concern for Ligand A.

**BBB:** Ligand B has a much better BBB penetration percentile (58.278) than Ligand A (16.053). This is critical for a CNS target like DRD2.

**Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and suggests poor permeability. However, the scale is not defined, so it's difficult to interpret.

**Aqueous Solubility:** Both have negative solubility values, indicating poor solubility. Again, the scale is undefined.

**hERG:** Both ligands have low hERG inhibition liability (A: 0.558, B: 0.33), which is good.

**Microsomal Clearance:** Ligand B has negative clearance (-8.728), which is unusual and potentially indicates very high metabolic stability. Ligand A has a clearance of 47.387, which is reasonable.

**In vitro Half-Life:** Ligand B has a negative half-life (-0.487), which is also unusual. Ligand A has a half-life of 56.83, which is good.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (A: 0.443, B: 0.02). Ligand B is slightly better.

**Binding Affinity:** Both ligands have very similar and strong binding affinities (A: -8.2 kcal/mol, B: -8.3 kcal/mol). The difference is negligible.

**Conclusion:**

Considering all factors, especially the GPCR-specific priorities for CNS targets, **Ligand B is the more promising candidate**. While both have similar affinity, Ligand B has a significantly better BBB penetration (58.278 vs 16.053), a much lower DILI risk (8.414 vs 79.682), and slightly better P-gp efflux liability. The unusual negative values for Caco-2 and half-life for Ligand B are concerning, but the significantly improved safety profile and CNS penetration outweigh these issues. Ligand A's high DILI risk is a major red flag.

Output:
1
2025-04-17 06:09:18,539 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (367.519 and 360.38 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (87.22) is slightly higher than Ligand B (81.34), but both are below the 90 A^2 threshold desirable for CNS targets.

**3. logP:** Ligand A (1.354) is within the optimal range (1-3), while Ligand B (3.092) is at the higher end of the optimal range.

**4. H-Bond Donors:** Ligand A (2) and Ligand B (1) both meet the criteria of <=5.

**5. H-Bond Acceptors:** Ligand A (6) and Ligand B (5) both meet the criteria of <=10.

**6. QED:** Both ligands have similar QED values (0.76 and 0.77), indicating good drug-like properties.

**7. DILI:** Ligand A (13.649) has a significantly lower DILI risk than Ligand B (52.734). This is a substantial advantage for Ligand A.

**8. BBB:** Ligand B (87.941) has a much higher BBB penetration percentile than Ligand A (51.997). This is a critical advantage for a CNS target like DRD2.

**9. Caco-2 Permeability:** Ligand A (-5.603) has worse Caco-2 permeability than Ligand B (-4.507), indicating potentially lower intestinal absorption.

**10. Aqueous Solubility:** Ligand A (-1.432) has better aqueous solubility than Ligand B (-3.683).

**11. hERG Inhibition:** Ligand A (0.078) has a lower hERG inhibition liability than Ligand B (0.676), which is a safety advantage.

**12. Microsomal Clearance:** Ligand A (-25.058) has a much lower (better) microsomal clearance than Ligand B (53.737), suggesting greater metabolic stability.

**13. In vitro Half-Life:** Ligand A (6.585) has a shorter half-life than Ligand B (-10.9), which is a disadvantage.

**14. P-gp Efflux:** Ligand A (0.01) has significantly lower P-gp efflux liability than Ligand B (0.267), which is beneficial for CNS exposure.

**15. Binding Affinity:** Both ligands have very similar binding affinities (-8.0 and -6.9 kcal/mol). Ligand A is slightly better, but the difference is not huge.

**Overall Assessment:**

Ligand A has advantages in DILI risk, hERG inhibition, microsomal clearance, and P-gp efflux. Ligand B has a substantial advantage in BBB penetration and slightly better Caco-2 permeability. Given the CNS target (DRD2), BBB penetration is a crucial factor. However, the significantly lower DILI and P-gp efflux of Ligand A, coupled with its better hERG profile and metabolic stability, are compelling. The slight difference in binding affinity is less important than these ADME properties.

Output:
1
2025-04-17 06:09:18,540 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 drug candidates, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (351.491 and 347.463 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (53.09) is significantly better than Ligand B (88.17). For CNS targets, we want TPSA <= 90, and A is comfortably within that, while B is approaching the upper limit.

**3. logP:** Both ligands have acceptable logP values (1.225 and 2.093, respectively) falling within the optimal 1-3 range.

**4. H-Bond Donors:** Ligand A (0) is preferable to Ligand B (3). Fewer HBDs generally improve permeability.

**5. H-Bond Acceptors:** Ligand A (4) is better than Ligand B (6). Lower HBA is generally preferred.

**6. QED:** Both ligands have similar QED values (0.699 and 0.667), indicating good drug-likeness.

**7. DILI:** Ligand A (15.587) has a much lower DILI risk than Ligand B (39.201). This is a significant advantage for A.

**8. BBB:** Ligand A (82.047) has a better BBB percentile than Ligand B (74.641). While both are reasonably good, A is closer to the desirable >70 threshold for CNS targets.

**9. Caco-2 Permeability:** Ligand A (-4.223) has worse Caco-2 permeability than Ligand B (-5.241). Lower (more negative) values indicate lower permeability.

**10. Aqueous Solubility:** Ligand A (-1.148) has slightly better aqueous solubility than Ligand B (-2.026).

**11. hERG Inhibition:** Both ligands show low hERG inhibition liability (0.457 and 0.344), which is good.

**12. Microsomal Clearance:** Ligand A (21.85) has lower microsomal clearance than Ligand B (31.215), suggesting better metabolic stability.

**13. In vitro Half-Life:** Ligand A (-26.547) has a much longer in vitro half-life than Ligand B (25.845). This is a significant advantage for A.

**14. P-gp Efflux:** Ligand A (0.14) has lower P-gp efflux liability than Ligand B (0.019). Lower efflux is preferred for CNS exposure.

**15. Binding Affinity:** Ligand B (-8.5) has a stronger binding affinity than Ligand A (-7.2). This is a 1.3 kcal/mol difference, which is substantial and could potentially outweigh some of the ADME drawbacks.

**Overall Assessment:**

Ligand A has a significantly better ADME profile across multiple parameters (TPSA, DILI, BBB, Cl_mic, t1/2, Pgp) and a more favorable balance of physicochemical properties. While Ligand B has a stronger binding affinity, the substantial improvements in ADME properties for Ligand A, particularly its better BBB penetration, lower DILI risk, and improved metabolic stability, make it the more promising drug candidate for a CNS target like DRD2. The difference in affinity, while notable, is likely surmountable with further optimization of Ligand A.

Output:
0
2025-04-17 06:09:18,540 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (349.289 Da and 366.491 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (78.63) is better than Ligand B (81.67). Both are below the 90 A^2 threshold desirable for CNS targets, but A is closer to the optimal value.

**logP:** Ligand A (2.533) is within the optimal 1-3 range. Ligand B (-0.249) is significantly lower, which could hinder permeability.

**H-Bond Donors/Acceptors:** Ligand A (0 HBD, 6 HBA) is preferable to Ligand B (1 HBD, 7 HBA). Both are within acceptable limits, but fewer H-bonds generally improve permeability.

**QED:** Both ligands have good QED scores (0.623 and 0.795, respectively), indicating drug-like properties.

**DILI:** Ligand A (84.762) has a higher DILI risk than Ligand B (37.767). This is a significant drawback for Ligand A.

**BBB:** Ligand A (85.731) has a much better BBB penetration percentile than Ligand B (67.623). This is crucial for a CNS target like DRD2.

**Caco-2 Permeability:** Ligand A (-3.871) has poor Caco-2 permeability, while Ligand B (-5.075) is even worse. Both are problematic, but A is slightly better.

**Aqueous Solubility:** Ligand A (-4.29) has slightly better solubility than Ligand B (-1.554), but both are very poor.

**hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.275 and 0.273).

**Microsomal Clearance:** Ligand A (118.049) has higher microsomal clearance than Ligand B (-4.01).  B is much better, indicating greater metabolic stability.

**In vitro Half-Life:** Ligand A (-34.453) has a negative half-life, which is not possible. This is a major red flag. Ligand B (3.456) has a short, but positive half-life.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.426 and 0.067). Ligand B is better.

**Binding Affinity:** Ligand B (-7.1 kcal/mol) has a slightly better binding affinity than Ligand A (-8.2 kcal/mol). While A is better, the difference is not substantial enough to overcome other issues.

**Overall Assessment:**

Ligand A has a better BBB score and slightly better TPSA and Caco-2 permeability, but suffers from a very high DILI risk, a nonsensical half-life, and poorer metabolic stability. Ligand B, despite a lower logP and BBB, has a significantly lower DILI risk, better metabolic stability, and a reasonable binding affinity. Given the importance of metabolic stability and safety (DILI) for a CNS drug, and the relatively small difference in binding affinity, Ligand B is the more promising candidate. The poor logP of Ligand B could potentially be addressed through further optimization.

Output:
1
2025-04-17 06:09:18,540 - INFO - Reasoning:

Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (350.463 and 367.471 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (96.11) is better than Ligand B (101.3). Both are below the 140 A^2 threshold for oral absorption, and closer to the <90 A^2 desired for CNS targets, but A is preferable.

**3. logP:** Both ligands have good logP values (2.02 and 1.858), falling within the optimal 1-3 range.

**4. H-Bond Donors:** Ligand A (3) is slightly higher than Ligand B (2), but both are within the acceptable limit of <=5.

**5. H-Bond Acceptors:** Ligand A (4) is lower than Ligand B (5), and both are within the acceptable limit of <=10.

**6. QED:** Ligand A (0.668) has a better QED score than Ligand B (0.485), indicating a more drug-like profile.

**7. DILI:** Ligand A (31.485) has a significantly lower DILI risk than Ligand B (52.423). This is a major advantage for Ligand A.

**8. BBB:** Ligand A (72.741) has a much better BBB penetration percentile than Ligand B (55.642). This is *critical* for a CNS target like DRD2.

**9. Caco-2 Permeability:** Ligand A (-4.711) has a slightly better Caco-2 permeability than Ligand B (-5.26), but both are negative values which is unusual and suggests poor permeability.

**10. Aqueous Solubility:** Ligand A (-2.526) has slightly better aqueous solubility than Ligand B (-2.814), but both are negative, indicating poor solubility.

**11. hERG:** Both ligands have low hERG inhibition liability (0.479 and 0.153), which is good.

**12. Microsomal Clearance:** Ligand A (21.462) has a lower microsomal clearance than Ligand B (69.366), indicating better metabolic stability.

**13. In vitro Half-Life:** Ligand A (-17.419) has a significantly longer in vitro half-life than Ligand B (-39.347).

**14. P-gp Efflux:** Ligand A (0.112) has lower P-gp efflux liability than Ligand B (0.078), which is desirable for CNS penetration.

**15. Binding Affinity:** Both ligands have very similar binding affinities (-7.7 and -7.6 kcal/mol). The difference is negligible.

**Overall Assessment:**

Ligand A is clearly superior. It has a better QED score, significantly lower DILI risk, substantially better BBB penetration, lower microsomal clearance (better metabolic stability), and a longer in vitro half-life. While both have similar affinities, the improved ADME properties of Ligand A make it a much more promising drug candidate for a CNS target like DRD2. The slightly better TPSA and solubility also contribute to its favorability.

Output:
1
2025-04-17 06:09:18,540 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (345.414 and 357.841 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (47.56) is significantly better than Ligand B (55.32). For CNS targets, we want TPSA <= 90, and A is closer to the optimal <=60 range. B is still acceptable, but A is preferable.

**3. logP:** Both ligands have good logP values (4.121 and 3.507), falling within the 1-3 range. Ligand A is slightly higher, which could be a minor concern for solubility, but not a dealbreaker.

**4. H-Bond Donors:** Ligand A has 1 HBD, and Ligand B has 0. Both are within the acceptable limit of <=5.

**5. H-Bond Acceptors:** Ligand A has 3 HBA, and Ligand B has 4. Both are within the acceptable limit of <=10.

**6. QED:** Both ligands have similar QED values (0.857 and 0.821), indicating good drug-like properties.

**7. DILI:** Ligand A has a DILI risk of 62.001, which is moderately high. Ligand B has a much lower DILI risk of 38.581, which is preferable.

**8. BBB:** Ligand B (83.288) has a significantly better BBB penetration percentile than Ligand A (65.258). For a CNS target like DRD2, >70 is desirable, and B is much closer to this threshold.

**9. Caco-2 Permeability:** Both have negative Caco-2 values (-4.275 and -4.465), which is unusual and suggests poor permeability. This is a significant drawback for both.

**10. Aqueous Solubility:** Both ligands have very poor aqueous solubility (-4.894 and -4.307). This is a major concern for both.

**11. hERG Inhibition:** Ligand A (0.779) has a slightly higher hERG inhibition risk than Ligand B (0.553), but both are relatively low.

**12. Microsomal Clearance:** Ligand B (92.968) has a higher microsomal clearance than Ligand A (70.126), indicating faster metabolism and lower metabolic stability. A is preferable here.

**13. In vitro Half-Life:** Ligand A (12.71 hours) has a much longer in vitro half-life than Ligand B (-23.733 hours). The negative value for B is concerning and likely an error, but even if interpreted as very short, A is significantly better.

**14. P-gp Efflux:** Ligand A (0.352) has lower P-gp efflux liability than Ligand B (0.103), which is beneficial for CNS exposure.

**15. Binding Affinity:** Ligand B (-7.9 kcal/mol) has a slightly better binding affinity than Ligand A (-8.3 kcal/mol). While both are excellent, the 0.4 kcal/mol difference is not huge.

**Overall Assessment:**

Despite the poor Caco-2 and solubility for both, Ligand B is the more promising candidate. Its significantly better BBB penetration (83.288 vs 65.258) and lower DILI risk (38.581 vs 62.001) are crucial advantages for a CNS target. The slightly better binding affinity of B is a bonus. While Ligand A has better metabolic stability and P-gp efflux, the BBB and safety profiles of B outweigh these benefits.

Output:
1
2025-04-17 06:09:18,540 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (349.475 and 347.419 Da) fall comfortably within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (72.88) is significantly better than Ligand B (113.08). For CNS targets, we want TPSA <= 90, so Ligand A is preferable.

**3. logP:** Ligand A (0.908) is slightly better than Ligand B (0.417), both are a bit low, but acceptable.

**4. H-Bond Donors:** Ligand A (2) is better than Ligand B (3). Lower is generally preferred.

**5. H-Bond Acceptors:** Ligand A (4) is better than Ligand B (5). Lower is generally preferred.

**6. QED:** Ligand A (0.74) is better than Ligand B (0.56), indicating a more drug-like profile.

**7. DILI:** Ligand A (5.235) is *much* better than Ligand B (39.55). This is a significant advantage for Ligand A.

**8. BBB:** Ligand A (57.425) is slightly better than Ligand B (55.138), but both are below the desirable >70 for CNS targets.

**9. Caco-2 Permeability:** Ligand A (-4.957) is better than Ligand B (-5.597). Higher values are better.

**10. Aqueous Solubility:** Ligand A (-1.367) is better than Ligand B (-1.417). Higher values are better.

**11. hERG Inhibition:** Both ligands are very low (0.155 and 0.051), indicating minimal cardiotoxicity risk.

**12. Microsomal Clearance:** Ligand A (-6.515) is *much* better than Ligand B (17.608). Lower clearance indicates greater metabolic stability.

**13. In vitro Half-Life:** Ligand A (-12.002) is better than Ligand B (9.723). Longer half-life is generally preferred.

**14. P-gp Efflux:** Both ligands are very low (0.008), indicating minimal P-gp efflux.

**15. Binding Affinity:** Ligand B (-7.7) is slightly better than Ligand A (-8.4). While a 1.5 kcal/mol advantage is significant, the other ADME properties of Ligand A are far superior.

**Overall Assessment:**

Ligand A is significantly better overall. While Ligand B has a slightly better binding affinity, Ligand A excels in crucial ADME properties, especially DILI risk and metabolic stability (Cl_mic). Given the CNS target (DRD2), the lower TPSA of Ligand A is also a major advantage. The slightly lower BBB penetration for both is a concern, but the superior overall profile of Ligand A makes it the more promising candidate.

Output:
1
2025-04-17 06:09:18,540 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (350.321 and 352.454 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (92.47) is slightly higher than the preferred <90 for CNS targets, but still reasonable. Ligand B (65.54) is excellent, well below 90.

**3. logP:** Both ligands (2.308 and 2.254) are within the optimal range of 1-3.

**4. H-Bond Donors:** Ligand A (2) and Ligand B (1) are both acceptable, below the threshold of 5.

**5. H-Bond Acceptors:** Both ligands (4) are below the threshold of 10.

**6. QED:** Both ligands (0.592 and 0.656) have good drug-like properties, exceeding the 0.5 threshold.

**7. DILI:** Ligand A (54.556) is slightly higher than Ligand B (41.838), but both are below the concerning threshold of 60, indicating acceptable liver injury risk.

**8. BBB:** This is a critical parameter for a CNS target like DRD2. Ligand B (83.908) is significantly better than Ligand A (52.579), exceeding the desirable >70 threshold, while A is only moderately acceptable.

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.738 and -4.736), which is unusual and suggests very poor permeability. This is a significant concern for both.

**10. Aqueous Solubility:** Both ligands have negative solubility values (-3.398 and -2.42), which is also unusual and suggests very poor solubility. This is a significant concern for both.

**11. hERG Inhibition:** Both ligands (0.662 and 0.845) have low hERG inhibition risk, which is favorable.

**12. Microsomal Clearance:** Ligand A (37.009) has lower clearance than Ligand B (67.457), suggesting better metabolic stability.

**13. In vitro Half-Life:** Ligand B (26.406) has a longer half-life than Ligand A (18.56), which is generally desirable.

**14. P-gp Efflux:** Ligand A (0.297) has lower P-gp efflux than Ligand B (0.137), which is beneficial for CNS penetration.

**15. Binding Affinity:** Ligand B (-7.6 kcal/mol) has a significantly stronger binding affinity than Ligand A (-9.6 kcal/mol). This is a substantial advantage, potentially outweighing some ADME drawbacks.

**Overall Assessment:**

While both ligands have concerning Caco-2 and solubility values, Ligand B is the more promising candidate. Its superior BBB penetration (83.908 vs 52.579), significantly stronger binding affinity (-7.6 vs -9.6 kcal/mol), and longer half-life outweigh the slightly higher P-gp efflux and microsomal clearance. The lower TPSA of Ligand B is also beneficial. The negative Caco-2 and solubility values would need to be addressed through formulation or structural modification, but the stronger affinity and better CNS penetration make Ligand B the better starting point.

Output:
1
2025-04-17 06:09:18,540 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (347.411 and 347.434 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (76.07) is slightly above the preferred <90 for CNS targets, but still reasonable. Ligand B (62.3) is well within the ideal range.

**3. logP:** Ligand A (1.26) is within the optimal range of 1-3. Ligand B (2.936) is also within the optimal range, closer to the upper limit.

**4. H-Bond Donors:** Both ligands have 1 HBD, which is acceptable (<=5).

**5. H-Bond Acceptors:** Ligand A has 5 HBA, and Ligand B has 3 HBA, both within the acceptable range (<=10).

**6. QED:** Both ligands have similar QED values (0.83 and 0.805), indicating good drug-likeness.

**7. DILI:** Both ligands have low DILI risk (30.516 and 35.091 percentiles), which is favorable.

**8. BBB:** This is a critical parameter for CNS targets. Ligand B (84.374) has a significantly higher BBB penetration percentile than Ligand A (53.819). This is a major advantage for Ligand B.

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.528), which is unusual and suggests poor permeability. This is a concern for both.

**10. Aqueous Solubility:** Both ligands have negative solubility values (-1.16 and -2.541), indicating poor aqueous solubility. This is a significant drawback for both.

**11. hERG Inhibition:** Ligand A (0.263) has a lower hERG inhibition risk than Ligand B (0.638), which is preferable.

**12. Microsomal Clearance:** Ligand A (43.354) has a higher microsomal clearance than Ligand B (28.884), suggesting lower metabolic stability.

**13. In vitro Half-Life:** Ligand B (-6.226) has a negative half-life, which is not physically possible and indicates a potential issue with the data. Ligand A (12.188) has a reasonable half-life.

**14. P-gp Efflux:** Ligand A (0.213) has lower P-gp efflux liability than Ligand B (0.194), which is favorable for CNS penetration.

**15. Binding Affinity:** Ligand B (0.0) has a significantly better binding affinity than Ligand A (-6.9 kcal/mol). This is a substantial advantage that can outweigh some of the ADME drawbacks.

**Overall Assessment:**

While both ligands have issues with Caco-2 permeability and aqueous solubility, Ligand B stands out due to its significantly better BBB penetration and binding affinity. The negative half-life for Ligand B is a red flag, but the superior affinity might still make it a better starting point for optimization, assuming the half-life data is an error. Ligand A has better hERG and P-gp profiles, but the lower affinity and BBB penetration are significant drawbacks for a CNS target like DRD2.

Output:
1
2025-04-17 06:09:18,540 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (361.389 Da) is slightly higher than Ligand B (346.431 Da), but both are acceptable.

**TPSA:** Ligand A (107.53) is higher than Ligand B (76.72). For CNS targets, we want TPSA <= 90. Ligand B is much better here.

**logP:** Ligand A (-0.352) is below the optimal range (1-3) and could indicate poor membrane permeability. Ligand B (0.722) is closer to the ideal range, but still a bit low.

**H-Bond Donors/Acceptors:** Ligand A has 4 HBD and 4 HBA, which is acceptable. Ligand B has 1 HBD and 3 HBA, which is also acceptable.

**QED:** Both ligands have reasonable QED values (Ligand A: 0.35, Ligand B: 0.857). Ligand B is significantly better, indicating a more drug-like profile.

**DILI:** Both ligands have similar DILI risk (Ligand A: 33.773, Ligand B: 42.264), and both are below the concerning threshold of 60.

**BBB:** Ligand A (40.326) has a low BBB percentile, which is a major drawback for a CNS target like DRD2. Ligand B (49.128) is better, but still not ideal (we want >70).

**Caco-2 Permeability:** Both have negative Caco-2 values (-4.966 and -4.708), which is unusual and suggests poor permeability. These values are difficult to interpret without further context, but are likely indicating very low permeability.

**Aqueous Solubility:** Both have negative solubility values (-2.069 and -1.514), also unusual. This suggests very poor solubility.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (Ligand A: 0.587, Ligand B: 0.253).

**Microsomal Clearance:** Ligand A (13.18) has a higher microsomal clearance than Ligand B (-6.158), indicating lower metabolic stability.

**In vitro Half-Life:** Ligand A (-16.12) has a negative half-life, which is not physically meaningful. Ligand B (-22.095) is also negative. These values are problematic.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (Ligand A: 0.034, Ligand B: 0.027). This is good, as it suggests better CNS exposure.

**Binding Affinity:** Ligand B (-7.9 kcal/mol) has a slightly better binding affinity than Ligand A (-7.4 kcal/mol), although both are good (<-7.0 kcal/mol). The difference is less than 1.5 kcal/mol, so it's not a decisive factor on its own.

**Overall Assessment:**

Ligand B is the more promising candidate. While neither ligand is perfect, Ligand B has a significantly better TPSA, QED, and a slightly better binding affinity. The biggest concern for Ligand A is its very low BBB penetration. The negative Caco-2 and solubility values for both are concerning and require further investigation, but the BBB issue for Ligand A is a critical disadvantage for a CNS target.

Output:
1
2025-04-17 06:09:18,541 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (329.403 Da) is slightly lower, which is generally favorable for permeability.

**2. TPSA:** Both ligands have TPSA values below 90, which is good for CNS penetration. Ligand A (47.04) is better than Ligand B (44.81).

**3. logP:** Both ligands have logP values between 4-5, which is slightly high. This could potentially lead to solubility issues or off-target interactions. Ligand A (4.845) is slightly higher than Ligand B (4.416).

**4. H-Bond Donors:** Both have 1 HBD, which is within the acceptable limit of 5.

**5. H-Bond Acceptors:** Ligand A has 4 HBAs, and Ligand B has 3. Both are within the acceptable limit of 10.

**6. QED:** Both ligands have similar QED scores (0.727 and 0.709), indicating good drug-likeness.

**7. DILI:** Ligand A has a significantly higher DILI risk (84.684%) compared to Ligand B (44.746%). This is a major concern for Ligand A.

**8. BBB:** Ligand A (74.06%) has a better BBB penetration score than Ligand B (66.344%), which is crucial for a CNS target like DRD2.

**9. Caco-2 Permeability:** Ligand A (-4.938) has worse Caco-2 permeability than Ligand B (-5.213). Lower values indicate poorer permeability.

**10. Aqueous Solubility:** Ligand A (-5.857) has worse aqueous solubility than Ligand B (-3.959).

**11. hERG Inhibition:** Ligand A (0.751) has a slightly higher hERG inhibition risk than Ligand B (0.911). Lower is better here.

**12. Microsomal Clearance:** Ligand A (79.597) has higher microsomal clearance than Ligand B (53.463), indicating faster metabolism and potentially lower exposure.

**13. In vitro Half-Life:** Ligand B (39.037) has a much longer in vitro half-life than Ligand A (-13.213). This is a significant advantage for Ligand B.

**14. P-gp Efflux:** Ligand A (0.447) has lower P-gp efflux than Ligand B (0.45), which is slightly better.

**15. Binding Affinity:** Ligand B (-8.5 kcal/mol) has a significantly stronger binding affinity than Ligand A (-10.8 kcal/mol). This is a substantial advantage.

**Overall Assessment:**

While Ligand A has a slightly better BBB score and lower P-gp efflux, its significantly higher DILI risk, poorer solubility, faster metabolism, and weaker binding affinity make it a less desirable candidate. Ligand B, despite a slightly lower BBB score, exhibits a much more favorable ADME-Tox profile (lower DILI, better solubility, longer half-life, lower clearance) and, crucially, a significantly stronger binding affinity. The stronger binding affinity of Ligand B can potentially compensate for the slightly lower BBB score. Considering the GPCR-specific priorities, the combination of strong affinity and improved ADME properties makes Ligand B the more promising drug candidate.

Output:
1
2025-04-17 06:09:18,541 - INFO - Batch 258 complete. Total preferences: 4128
2025-04-17 06:09:18,541 - INFO - Processing batch 259/512...
2025-04-17 06:10:00,111 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, considering the provided guidelines and GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (370.515 Da and 371.438 Da) fall within the ideal range of 200-500 Da.

**TPSA:** Ligand A (70.08) is significantly better than Ligand B (96.33). For CNS targets, TPSA should be <=90, and A is comfortably within this range, while B is approaching the upper limit.

**logP:** Ligand A (0.978) is borderline, potentially slightly low for optimal permeation. Ligand B (0.117) is quite low, raising concerns about membrane permeability.

**H-Bond Donors/Acceptors:** Ligand A (HBD=1, HBA=5) and Ligand B (HBD=2, HBA=6) both have acceptable numbers of H-bond donors and acceptors.

**QED:** Both ligands have similar QED values (0.781 and 0.71), indicating good drug-likeness.

**DILI:** Ligand A (23.149) has a much lower DILI risk than Ligand B (63.862). This is a significant advantage for A.

**BBB:** Ligand A (40.558) is lower than Ligand B (49.205), but both are below the desirable threshold of >70 for CNS targets. However, given the other factors, this is less critical.

**Caco-2 Permeability:** Ligand A (-4.911) has better Caco-2 permeability than Ligand B (-5.314), though both are negative and suggest limited permeability.

**Aqueous Solubility:** Ligand A (-1.733) shows better solubility than Ligand B (-2.495).

**hERG:** Both ligands have very low hERG inhibition risk (0.268 and 0.07).

**Microsomal Clearance:** Ligand A (16.764) has higher microsomal clearance than Ligand B (10.261), suggesting lower metabolic stability.

**In vitro Half-Life:** Ligand B (24.539) has a significantly longer in vitro half-life than Ligand A (-5.372), which is a major advantage.

**P-gp Efflux:** Ligand A (0.081) has lower P-gp efflux liability than Ligand B (0.018), which is beneficial for CNS penetration.

**Binding Affinity:** Ligand B (-7.3) has a slightly better binding affinity than Ligand A (-7.8). While a 0.5 kcal/mol difference is not huge, it is noticeable.

**Overall Assessment:**

Considering the GPCR-specific priorities, Ligand A is the better candidate. While Ligand B has a slightly better binding affinity and half-life, Ligand A excels in TPSA, DILI risk, solubility, and P-gp efflux. The lower TPSA and DILI risk are particularly important. The logP for ligand A is borderline, but the other advantages outweigh this concern. The BBB values are suboptimal for both, but the combination of properties in Ligand A makes it more likely to achieve sufficient CNS exposure.

Output:
0
2025-04-17 06:10:00,111 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (365.43 and 354.441 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (69.85) is higher than Ligand B (36.69). For a CNS target like DRD2, we ideally want TPSA <= 90. Ligand B is significantly better here.

**3. logP:** Both ligands have good logP values (2.959 and 3.788), falling within the optimal 1-3 range. Ligand B is slightly higher, which could be a minor concern for solubility, but not a dealbreaker.

**4. H-Bond Donors:** Ligand A has 1 HBD, while Ligand B has 0. Both are within the acceptable limit of <=5.

**5. H-Bond Acceptors:** Ligand A has 6 HBA, and Ligand B has 3. Both are within the acceptable limit of <=10.

**6. QED:** Both ligands have good QED scores (0.652 and 0.829), indicating good drug-like properties. Ligand B is slightly better.

**7. DILI:** Ligand A has a DILI risk of 56.727, while Ligand B has 15.82. Both are below 60, indicating acceptable risk, but Ligand B is *much* better.

**8. BBB:** Ligand A has a BBB penetration of 82.784%, and Ligand B has 91.043%. Both are good (>70%), but Ligand B is superior for a CNS target.

**9. Caco-2 Permeability:** Both have negative Caco-2 values (-4.903 and -4.571) which is unusual and suggests poor permeability. This is a significant concern for both.

**10. Aqueous Solubility:** Both have negative solubility values (-3.673 and -2.264), indicating very poor aqueous solubility. This is a major drawback for both compounds.

**11. hERG Inhibition:** Both ligands have low hERG inhibition risk (0.958 and 0.943).

**12. Microsomal Clearance:** Ligand A has a Cl_mic of 37.798, while Ligand B has -6.327. A negative value for Cl_mic is not physically possible and likely indicates an error or an *extremely* stable compound. This is a significant advantage for Ligand B.

**13. In vitro Half-Life:** Ligand A has a t1/2 of 17.191 hours, while Ligand B has 59.846 hours. Ligand B has a much longer half-life, which is desirable.

**14. P-gp Efflux:** Both ligands have low P-gp efflux liability (0.774 and 0.499), which is good for CNS penetration. Ligand B is slightly better.

**15. Binding Affinity:** Ligand B (-8.7 kcal/mol) has a slightly better binding affinity than Ligand A (-8.1 kcal/mol). While the difference is not huge, it's enough to be considered.

**Overall Assessment:**

Ligand B consistently outperforms Ligand A across most crucial parameters, especially for a CNS target. It has better BBB penetration, lower DILI risk, a significantly longer half-life, and slightly better binding affinity. The negative Caco-2 and solubility values are concerning for both, but the superior ADME profile of Ligand B, particularly its predicted metabolic stability (Cl_mic) and CNS penetration, makes it the more promising candidate.

Output:
1
2025-04-17 06:10:00,111 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (342.439 and 358.429 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (58.64) is significantly better than Ligand B (67.43). For CNS targets, we want TPSA <= 90, and lower is preferable. Ligand A is much closer to the optimal range.

**3. logP:** Both ligands have acceptable logP values (1.86 and 2.763), falling within the 1-3 range. Ligand B is slightly higher, which *could* indicate potential off-target effects, but isn't a major concern.

**4. H-Bond Donors:** Ligand A (1) is preferable to Ligand B (2). Lower HBD generally improves permeability.

**5. H-Bond Acceptors:** Both ligands have 3 HBA, which is within the acceptable limit of <=10.

**6. QED:** Ligand A (0.912) has a much higher QED score than Ligand B (0.767), indicating a more drug-like profile.

**7. DILI:** Both ligands have similar, low DILI risk (31.601 and 31.989 percentile).

**8. BBB:** Both ligands show excellent BBB penetration (77.007 and 77.2 percentile), which is crucial for a CNS target like DRD2.

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.795 and -4.684), which is unusual and suggests poor permeability. However, these values are on a scale where negative values are possible, and the absolute difference is small.

**10. Aqueous Solubility:** Both ligands have negative solubility values (-2.498 and -2.613), indicating poor aqueous solubility. This could be a formulation challenge, but not a deal-breaker if other properties are favorable.

**11. hERG Inhibition:** Both ligands show very low hERG inhibition risk (0.299 and 0.342 percentile).

**12. Microsomal Clearance:** Ligand A (40.596 mL/min/kg) has lower microsomal clearance than Ligand B (47.938 mL/min/kg), suggesting better metabolic stability.

**13. In vitro Half-Life:** Ligand A (2.996 hours) has a shorter half-life than Ligand B (-15.13 hours). The negative value for Ligand B is concerning and likely an error or outlier.

**14. P-gp Efflux:** Both ligands show very low P-gp efflux (0.17 and 0.091 percentile), which is excellent for CNS penetration.

**15. Binding Affinity:** Ligand B (-9.3 kcal/mol) has significantly stronger binding affinity than Ligand A (0 kcal/mol). This is a substantial difference. A >1.5 kcal/mol advantage often outweighs minor ADME drawbacks.

**Overall Assessment:**

While Ligand A has better physicochemical properties (TPSA, QED, metabolic stability) and a more reasonable half-life, the significantly stronger binding affinity of Ligand B (-9.3 kcal/mol vs 0 kcal/mol) is a decisive factor. The binding affinity difference is large enough to potentially overcome the slightly less favorable ADME profile of Ligand B. The negative half-life for Ligand B is a red flag, but the binding affinity is so much better that it's worth investigating further to determine if that value is an error.

Output:
1
2025-04-17 06:10:00,112 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 drug candidates, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (371.363 and 352.45 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (55.63) is slightly higher than Ligand B (49.85), but both are below the 90 A^2 threshold desirable for CNS targets.

**logP:** Ligand A (4.017) is at the upper end of the optimal range (1-3), while Ligand B (2.143) is well within it. Ligand A's higher logP *could* lead to solubility issues or off-target interactions, but isn't immediately disqualifying.

**H-Bond Donors/Acceptors:** Ligand A (HBD=1, HBA=6) and Ligand B (HBD=0, HBA=3) both have acceptable numbers of H-bond donors and acceptors.

**QED:** Both ligands have good QED values (0.704 and 0.762, respectively), indicating generally drug-like properties.

**DILI:** Ligand A (81.543) has a significantly higher DILI risk than Ligand B (19.271). This is a major concern for Ligand A.

**BBB:** Ligand B (97.751) has excellent BBB penetration, exceeding the desirable >70% threshold. Ligand A (75.611) is still reasonably good, but significantly lower. This is a critical advantage for Ligand B given the CNS target.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.888 and -4.34). These values are unusual and likely represent a scaling issue or error in the data. We can't reliably interpret these values.

**Aqueous Solubility:** Both ligands have negative solubility values (-4.888 and -2.969). Similar to Caco-2, these are likely scaling issues and cannot be reliably interpreted.

**hERG:** Both ligands have low hERG inhibition risk (0.453 and 0.576).

**Microsomal Clearance:** Ligand B (16.27 mL/min/kg) has a lower microsomal clearance than Ligand A (52.517 mL/min/kg), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand B (16.462 hours) has a much longer in vitro half-life than Ligand A (3.388 hours), which is a significant advantage.

**P-gp Efflux:** Ligand A (0.61) has slightly higher P-gp efflux liability than Ligand B (0.087), meaning Ligand B is less likely to be pumped out of the brain.

**Binding Affinity:** Ligand A (-9.6 kcal/mol) has a stronger binding affinity than Ligand B (-6.9 kcal/mol). This is a substantial difference (2.7 kcal/mol), and is a major point in favor of Ligand A.

**Overall Assessment:**

While Ligand A boasts a significantly better binding affinity, its higher DILI risk, lower BBB penetration, higher P-gp efflux, and shorter half-life are substantial drawbacks. Ligand B, despite its weaker binding affinity, presents a much more favorable ADME-Tox profile, particularly its excellent BBB penetration, low DILI risk, and improved metabolic stability. For a CNS target like DRD2, achieving sufficient brain exposure is paramount. The affinity difference, while significant, *might* be overcome with further optimization of Ligand B. The poor ADME profile of Ligand A makes it a less viable starting point.

Output:
1
2025-04-17 06:10:00,112 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (365.503 and 364.515 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (69.64) is excellent, well below the 90 A^2 threshold for CNS targets. Ligand B (86.88) is still reasonable but less optimal.

**logP:** Ligand A (1.395) is within the optimal 1-3 range. Ligand B (2.445) is also acceptable, though slightly higher.

**H-Bond Donors/Acceptors:** Ligand A (0 HBD, 6 HBA) is favorable. Ligand B (3 HBD, 4 HBA) is also acceptable, but the higher HBD count could potentially affect permeability.

**QED:** Ligand A (0.81) has a very strong drug-like profile. Ligand B (0.595) is still acceptable, but less ideal.

**DILI:** Ligand A (34.393) has a low DILI risk. Ligand B (29.624) is even lower, indicating a very favorable safety profile regarding liver toxicity.

**BBB:** Ligand A (76.696) has good BBB penetration, exceeding the 70% threshold. Ligand B (53.781) is significantly lower and less desirable for a CNS target.

**Caco-2 Permeability:** Ligand A (-4.801) has poor Caco-2 permeability. Ligand B (-5.555) is also poor.

**Aqueous Solubility:** Ligand A (-1.113) has poor aqueous solubility. Ligand B (-3.25) is even worse.

**hERG Inhibition:** Both ligands (0.359 and 0.33) show low hERG inhibition risk, which is excellent.

**Microsomal Clearance:** Ligand A (11.812) has lower microsomal clearance, suggesting better metabolic stability. Ligand B (24.474) has higher clearance.

**In vitro Half-Life:** Ligand A (16.038 hours) has a reasonable half-life. Ligand B (2.696 hours) has a very short half-life, potentially requiring frequent dosing.

**P-gp Efflux:** Both ligands (0.266 and 0.064) have low P-gp efflux, which is positive for CNS exposure.

**Binding Affinity:** Ligand B (-7.6 kcal/mol) has significantly stronger binding affinity than Ligand A (-0.0 kcal/mol). This is a substantial advantage.

**Overall Assessment:**

While Ligand A has better TPSA, QED, and metabolic stability, the significantly stronger binding affinity of Ligand B (-7.6 vs -0.0 kcal/mol) is a major advantage that can potentially overcome its slightly less favorable ADME properties. The lower BBB penetration and solubility of Ligand B are concerning, but the strong affinity suggests that it might still achieve sufficient CNS exposure. The short half-life is also a drawback, but could be addressed through formulation strategies. Ligand A, despite its better ADME profile, has essentially no binding affinity and is therefore unlikely to be a viable drug candidate.

Output:
1
2025-04-17 06:10:00,112 - INFO - Reasoning:

Let's analyze Ligand A and Ligand B for their potential as DRD2 drug candidates, considering the provided guidelines and GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (379.222 and 347.467 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (59.81) is excellent, well below the 90 Angstroms threshold for CNS targets. Ligand B (82.68) is still reasonable, but less optimal, being closer to the 90 Angstroms limit.

**3. logP:** Ligand A (4.333) is slightly high, potentially leading to solubility issues or off-target interactions. Ligand B (1.655) is within the optimal 1-3 range.

**4. H-Bond Donors:** Both ligands have 1 HBD, which is acceptable.

**5. H-Bond Acceptors:** Ligand A has 4 HBAs, within the limit. Ligand B has 8 HBAs, approaching the upper limit of 10.

**6. QED:** Both ligands have acceptable QED values (0.734 and 0.658), indicating good drug-like properties.

**7. DILI:** Ligand A has a DILI risk of 88.019, which is high and concerning. Ligand B has a much lower DILI risk of 42.536, which is preferable.

**8. BBB:** Both ligands have very similar and good BBB penetration (73.827 and 73.401), exceeding the 70% threshold for CNS targets.

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.652 and -5.519). This is unusual and suggests poor permeability. However, these values are on a log scale, and negative values are not uncommon for compounds with very low permeability.

**10. Aqueous Solubility:** Both ligands have negative solubility values (-5.99 and -1.519) indicating poor solubility. This is a concern, especially for Ligand A with its higher logP.

**11. hERG Inhibition:** Ligand A (0.523) has a slightly higher hERG risk than Ligand B (0.15), though both are relatively low.

**12. Microsomal Clearance:** Ligand A (72.129) has a higher microsomal clearance than Ligand B (25.355), indicating lower metabolic stability.

**13. In vitro Half-Life:** Ligand A (31.671) has a longer half-life than Ligand B (3.361).

**14. P-gp Efflux:** Ligand A (0.495) has lower P-gp efflux than Ligand B (0.181), which is favorable for CNS penetration.

**15. Binding Affinity:** Ligand A (-10.1 kcal/mol) has significantly stronger binding affinity than Ligand B (-6.2 kcal/mol). This is a substantial advantage.

**Overall Assessment:**

Ligand A has a much stronger binding affinity, better P-gp efflux, and a longer half-life. However, it suffers from a high DILI risk, high logP, and higher microsomal clearance. Ligand B has a lower DILI risk, better logP, and lower clearance, but significantly weaker binding affinity.

Given the GPCR-specific priorities, strong affinity is crucial. The 3.9 kcal/mol difference in binding affinity is a significant advantage for Ligand A. While the DILI risk is concerning, it might be mitigated through structural modifications during lead optimization. The solubility and permeability issues are also addressable. The higher logP is less concerning than the DILI risk.

Output:
1
2025-04-17 06:10:00,112 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (351.451 and 354.357 Da) fall comfortably within the ideal 200-500 Da range.

**TPSA:** Ligand A (98.98) is slightly higher than Ligand B (84.42). Both are below the 90 A^2 threshold desirable for CNS targets, but B is closer.

**logP:** Ligand A (-0.554) is below the optimal 1-3 range, potentially hindering permeability. Ligand B (0.645) is also a bit low, but closer to the desired range.

**H-Bond Donors/Acceptors:** Ligand A has 2 HBD and 4 HBA, while Ligand B has 1 HBD and 5 HBA. Both are within acceptable limits (<=5 HBD and <=10 HBA).

**QED:** Both ligands have good QED scores (0.712 and 0.811), indicating good drug-like properties.

**DILI:** Ligand A (13.067) has a significantly lower DILI risk than Ligand B (38.038), which is a major advantage.

**BBB:** Ligand B (87.864) has a much higher BBB penetration percentile than Ligand A (53.974). This is *critical* for a CNS target like DRD2.

**Caco-2 Permeability:** Both have negative values (-5.34 and -4.636), which is unusual and suggests poor permeability. However, the scale isn't specified, so it's hard to interpret.

**Aqueous Solubility:** Both ligands have negative solubility values (-1.178 and -2.09), also unusual. Again, the scale is unknown.

**hERG:** Both ligands have very low hERG inhibition risk (0.142 and 0.192).

**Microsomal Clearance:** Ligand A (-32.261) has a much lower (better) microsomal clearance than Ligand B (7.866), indicating greater metabolic stability.

**In vitro Half-Life:** Ligand A (-11.797) has a negative half-life, which is not possible. Ligand B (-7.321) also has a negative half-life, indicating an issue with the data.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.002 and 0.004), which is favorable for CNS penetration.

**Binding Affinity:** Both ligands have similar and strong binding affinities (-8.7 and -8.6 kcal/mol). The difference is negligible.

**Overall Assessment:**

Ligand B is strongly favored due to its significantly higher BBB penetration (87.864 vs 53.974). While Ligand A has a better DILI score and lower microsomal clearance, BBB penetration is paramount for a CNS GPCR target. The negative solubility and half-life values are concerning for both, but the affinity is strong for both. The slightly better logP of ligand B also contributes to its favorability.

Output:
1
2025-04-17 06:10:00,112 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (345.447 and 348.491 Da) fall comfortably within the ideal 200-500 Da range.

**2. TPSA:** Both ligands have TPSA values (79.26 and 78.09) below the 90 A^2 threshold for CNS targets, which is excellent.

**3. logP:** Both ligands have logP values (2.206 and 2.871) within the optimal 1-3 range. Ligand B is slightly higher, potentially offering better membrane permeability.

**4. H-Bond Donors:** Both ligands have 2 HBD, which is acceptable.

**5. H-Bond Acceptors:** Ligand A has 4 HBA, and Ligand B has 3. Both are below the 10 threshold.

**6. QED:** Ligand A (0.859) has a significantly better QED score than Ligand B (0.758), indicating a more drug-like profile.

**7. DILI:** Ligand A (22.722) has a lower DILI risk than Ligand B (16.092), suggesting better hepatotoxicity potential. Lower is better.

**8. BBB:** This is a crucial parameter for a CNS target like DRD2. Ligand A has a BBB percentile of 83.831, which is very good (>70). Ligand B's BBB percentile is 63.746, which is below the desirable threshold.

**9. Caco-2 Permeability:** Both have negative values (-4.975 and -5.077). These values are unusual and likely represent a scaling issue or indicate very poor permeability. However, since both are similarly poor, it doesn't differentiate them.

**10. Aqueous Solubility:** Both have negative values (-2.979 and -2.291), indicating poor solubility. Again, similar for both, so not a differentiating factor.

**11. hERG Inhibition:** Both ligands have low hERG inhibition liability (0.339 and 0.511).

**12. Microsomal Clearance:** Ligand A (-2.989) has a lower (better) microsomal clearance than Ligand B (22.237), indicating greater metabolic stability.

**13. In vitro Half-Life:** Ligand A (-1.655) has a better in vitro half-life than Ligand B (-29.59).

**14. P-gp Efflux:** Ligand A (0.058) has lower P-gp efflux liability than Ligand B (0.095), which is favorable for CNS penetration.

**15. Binding Affinity:** Both ligands have excellent binding affinities (-8.9 and -8.5 kcal/mol). The difference of 0.4 kcal/mol is not substantial enough to outweigh the other ADME differences.

**Overall Assessment:**

Ligand A is significantly better overall. It has a superior QED score, lower DILI risk, much better BBB penetration, improved metabolic stability (lower Cl_mic, better t1/2), and lower P-gp efflux. While both have similar logP and hERG values, and comparable (excellent) binding affinity, the ADME properties of Ligand A make it a far more promising drug candidate for a CNS target like DRD2.

Output:
0
2025-04-17 06:10:00,112 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (341.371 and 351.422 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (88.4) is better than Ligand B (81.67) as it is closer to the ideal <90 for CNS targets.

**logP:** Ligand B (1.528) is better than Ligand A (0.49). A logP between 1-3 is optimal, and A is quite low, potentially hindering permeation.

**H-Bond Donors/Acceptors:** Ligand A (0 HBD, 6 HBA) is preferable to Ligand B (3 HBD, 4 HBA). While both are within acceptable limits, fewer H-bonds generally improve permeability.

**QED:** Both ligands have reasonable QED scores (0.758 and 0.589), indicating good drug-like properties.

**DILI:** Ligand B (18.069) is significantly better than Ligand A (67.429). A DILI percentile <40 is desirable, and B is well within this range, while A is approaching a higher-risk level.

**BBB:** Ligand A (79.566) is significantly better than Ligand B (55.603). For a CNS target like DRD2, a BBB percentile >70 is ideal, and A is closer to this threshold.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.194 and -5.366), which is unusual and suggests poor permeability. This is a significant drawback for both.

**Aqueous Solubility:** Both ligands have very poor aqueous solubility (-2.394 and -2.127). This is a major concern for bioavailability.

**hERG Inhibition:** Ligand A (0.038) is better than Ligand B (0.585) indicating lower cardiotoxicity risk.

**Microsomal Clearance:** Ligand A (28.841) is worse than Ligand B (8.389) indicating lower metabolic stability.

**In vitro Half-Life:** Ligand B (10.579) is better than Ligand A (-28.309) indicating a longer half-life.

**P-gp Efflux:** Ligand A (0.037) is better than Ligand B (0.046) indicating lower P-gp efflux.

**Binding Affinity:** Ligand A (-9.6 kcal/mol) is significantly better than Ligand B (-8.1 kcal/mol). This is a substantial difference in potency, and a >1.5 kcal/mol advantage can often outweigh other drawbacks.

**Overall Assessment:**

Despite the poor solubility and Caco-2 permeability for both compounds, Ligand A is the more promising candidate. The significantly stronger binding affinity (-9.6 vs -8.1 kcal/mol) is a major advantage, especially for a GPCR target. It also has a better BBB score (79.6 vs 55.6), lower hERG risk, and lower P-gp efflux. While Ligand B has a better DILI score and metabolic stability, the potency and CNS penetration advantages of Ligand A are more critical for DRD2 targeting. The poor solubility and permeability would need to be addressed through formulation or further structural modifications, but the core binding and CNS properties of Ligand A are superior.

Output:
0
2025-04-17 06:10:00,112 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 drug candidates, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (355.337 and 336.443 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (65.07) is better than Ligand B (69.73). Both are below the 90 A^2 threshold desirable for CNS targets, but A is closer to optimal.

**3. logP:** Both ligands have good logP values (2.119 and 3.023), falling within the 1-3 range. Ligand B is slightly higher, potentially increasing off-target interactions, but not drastically.

**4. H-Bond Donors:** Ligand A (0) is preferable to Ligand B (2). Fewer HBDs generally improve permeability.

**5. H-Bond Acceptors:** Both ligands have 5 HBA, which is acceptable (<=10).

**6. QED:** Both ligands have similar QED values (0.761 and 0.749), indicating good drug-likeness.

**7. DILI:** Both ligands have acceptable DILI risk (68.592 and 64.754), below the concerning threshold of 60.

**8. BBB:** Ligand A (83.133) has a significantly better BBB penetration percentile than Ligand B (62.97). This is *critical* for a CNS target like DRD2.

**9. Caco-2 Permeability:** Ligand A (-3.848) is better than Ligand B (-5.478). Higher values indicate better intestinal absorption.

**10. Aqueous Solubility:** Ligand A (-2.926) is better than Ligand B (-3.244). Higher values are preferred.

**11. hERG Inhibition:** Ligand A (0.319) has a lower hERG inhibition liability than Ligand B (0.897), making it safer from a cardiotoxicity perspective.

**12. Microsomal Clearance:** Ligand B (52.209) has a lower microsomal clearance than Ligand A (67.076), suggesting better metabolic stability.

**13. In vitro Half-Life:** Ligand B (24.316) has a significantly longer in vitro half-life than Ligand A (5.595). This is a major advantage.

**14. P-gp Efflux:** Ligand A (0.052) has a lower P-gp efflux liability than Ligand B (0.251), which is beneficial for CNS exposure.

**15. Binding Affinity:** Ligand A (-8.2 kcal/mol) has a much stronger binding affinity than Ligand B (-0.0 kcal/mol). This is the most important factor, and the difference is substantial.

**Overall Assessment:**

While Ligand B has better metabolic stability (lower Cl_mic, longer t1/2), Ligand A is superior in almost every other critical parameter, especially for a CNS target. The significantly better BBB penetration, much stronger binding affinity, lower hERG risk, and lower P-gp efflux of Ligand A outweigh the slightly higher clearance. The TPSA and logP values are also favorable for both compounds. The substantial difference in binding affinity (-8.2 vs -0.0 kcal/mol) is a decisive factor.

Output:
1
2025-04-17 06:10:00,112 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (355.364 and 363.483 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (82.7) is better than Ligand B (91.32). Both are below the 90 A^2 threshold for CNS targets, but A is closer to the ideal.

**logP:** Ligand A (3.12) is optimal, while Ligand B (1.251) is a bit low, potentially hindering permeation.

**H-Bond Donors:** Both have 3 HBD, which is acceptable.

**H-Bond Acceptors:** Ligand A has 3 HBA, while Ligand B has 5. Ligand A is preferable as it is closer to the ideal of <=10.

**QED:** Ligand A (0.771) has a significantly better QED score than Ligand B (0.546), indicating better overall drug-likeness.

**DILI:** Ligand B (33.346) has a much lower DILI risk than Ligand A (65.452), which is a significant advantage.

**BBB:** Ligand A (44.009) has a slightly better BBB percentile than Ligand B (35.091), but both are below the desirable >70% for CNS targets.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values, which is unusual and suggests poor permeability. However, the scale is not specified, so it's hard to interpret.

**Aqueous Solubility:** Both have negative solubility values, which is also unusual and suggests poor solubility.

**hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.208 and 0.098).

**Microsomal Clearance:** Ligand B (12.577) has a lower microsomal clearance than Ligand A (19.958), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand B (-9.025) has a significantly longer in vitro half-life than Ligand A (-4.121).

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.075 and 0.119).

**Binding Affinity:** Ligand A (-9.9 kcal/mol) has a significantly stronger binding affinity than Ligand B (-8.0 kcal/mol). This is a crucial advantage, exceeding the 1.5 kcal/mol difference threshold.

**Overall Assessment:**

While Ligand B has better DILI and metabolic stability, the significantly stronger binding affinity of Ligand A (-9.9 vs -8.0 kcal/mol) is the deciding factor. The affinity difference is large enough to potentially overcome the slightly higher DILI risk and lower BBB penetration. The better QED and TPSA of Ligand A also contribute to its favorability. The poor solubility and permeability of both are concerning, but can be addressed through formulation strategies. Given the importance of affinity for GPCR ligands, and the substantial difference here, Ligand A is the more promising candidate.

Output:
1
2025-04-17 06:10:00,112 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (336.439 and 338.407 Da) fall comfortably within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (58.12) is slightly higher than Ligand B (53.76). Both are below the 90 A^2 threshold desirable for CNS targets, which is good.

**3. logP:** Both ligands have excellent logP values (2.466 and 2.27), falling within the optimal 1-3 range.

**4. H-Bond Donors:** Ligand A has 1 HBD, while Ligand B has 0. Both are within the acceptable limit of <=5.

**5. H-Bond Acceptors:** Ligand A has 4 HBA, and Ligand B has 3. Both are below the acceptable limit of <=10.

**6. QED:** Both ligands have good QED scores (0.935 and 0.792), indicating good drug-like properties.

**7. DILI:** Ligand A (45.173) has a slightly higher DILI risk than Ligand B (31.252), but both are below the concerning threshold of 60.

**8. BBB:** Ligand A (91.663) has a significantly better BBB penetration percentile than Ligand B (85.498). This is a crucial factor for a CNS target like DRD2.

**9. Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and suggests poor permeability. However, the scale isn't specified, so it's hard to interpret.

**10. Aqueous Solubility:** Both ligands have negative solubility values, which is also unusual and suggests poor solubility.

**11. hERG Inhibition:** Both ligands show low hERG inhibition risk (0.761 and 0.313), which is favorable.

**12. Microsomal Clearance:** Ligand A (75.858) has a higher microsomal clearance than Ligand B (13.299), indicating lower metabolic stability. This is a significant drawback for Ligand A.

**13. In vitro Half-Life:** Ligand B (14.306) has a much longer in vitro half-life than Ligand A (-1.244), suggesting better stability.

**14. P-gp Efflux:** Ligand A (0.305) has lower P-gp efflux liability than Ligand B (0.092), which is beneficial for CNS penetration.

**15. Binding Affinity:** Ligand A (-8.9 kcal/mol) has a slightly better binding affinity than Ligand B (-7.8 kcal/mol). This 1.1 kcal/mol difference is substantial and could potentially outweigh some of the ADME drawbacks of Ligand A.

**Overall Assessment:**

While Ligand A has a slightly better binding affinity and P-gp efflux profile, Ligand B is significantly better in terms of metabolic stability (lower Cl_mic, longer t1/2) and has a lower DILI risk. The BBB penetration is good for both, but Ligand A is slightly better. Considering the importance of metabolic stability and minimizing potential toxicity for a CNS drug, and the relatively small advantage in binding affinity for Ligand A, Ligand B appears to be the more promising candidate. The negative values for Caco-2 and solubility are concerning for both, but can be addressed with formulation strategies.

Output:
1
2025-04-17 06:10:00,113 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the acceptable range (200-500 Da). Ligand A (345.418 Da) is slightly preferred as it's closer to the ideal range.

**TPSA:** Both ligands have TPSA values below 90, which is favorable for CNS penetration. Ligand A (71.09) is slightly higher than Ligand B (69.21), but both are good.

**logP:** Both ligands have logP values between 2.5 and 3.1, which is optimal. No significant difference here.

**H-Bond Donors/Acceptors:** Ligand A has 2 HBD and 3 HBA, while Ligand B has 0 HBD and 8 HBA. Ligand A is slightly better balanced.

**QED:** Ligand A (0.746) has a better QED score than Ligand B (0.55), indicating a more drug-like profile.

**DILI:** Ligand A (27.685) has a significantly lower DILI risk than Ligand B (74.719), which is a major advantage.

**BBB:** Ligand A (81.233) has a better BBB penetration percentile than Ligand B (74.486). This is crucial for a CNS target like DRD2.

**Caco-2 Permeability:** Ligand A (-4.692) has a worse Caco-2 permeability than Ligand B (-5.294), indicating lower intestinal absorption.

**Aqueous Solubility:** Both ligands have poor aqueous solubility (-3.437 and -3.985 respectively).

**hERG:** Both ligands have similar, low hERG inhibition liability (0.458 and 0.406).

**Microsomal Clearance:** Ligand A (34.022) has a lower microsomal clearance than Ligand B (49.122), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand B (39.696) has a significantly longer in vitro half-life than Ligand A (-0.263), which is a positive attribute.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.035 and 0.464).

**Binding Affinity:** Ligand A (-9.1 kcal/mol) has a significantly stronger binding affinity than Ligand B (-6.3 kcal/mol). This is a substantial advantage, and can often outweigh minor ADME deficiencies.

**Overall Assessment:**

Ligand A is the stronger candidate. While Ligand B has a better half-life and Caco-2 permeability, Ligand A excels in the most critical areas for a CNS-targeting GPCR ligand: binding affinity, BBB penetration, and DILI risk. The significantly stronger binding affinity of Ligand A (-9.1 vs -6.3 kcal/mol) is a major driver, and the lower DILI risk is a critical safety factor. The slightly lower metabolic stability of Ligand A is a manageable concern compared to the benefits.

Output:
1
2025-04-17 06:10:00,113 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (360.401 and 346.431 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (67.87) is significantly better than Ligand B (107.11). For CNS targets, TPSA should be <= 90. Ligand A meets this criterion, while Ligand B exceeds it, potentially hindering BBB penetration.

**3. logP:** Both ligands have good logP values (1.36 and 1.253), falling within the optimal 1-3 range.

**4. H-Bond Donors:** Ligand A (1) is preferable to Ligand B (4). Fewer HBDs generally improve permeability.

**5. H-Bond Acceptors:** Both ligands have 4 HBA, which is acceptable (<=10).

**6. QED:** Ligand A (0.696) has a much better QED score than Ligand B (0.339), indicating a more drug-like profile.

**7. DILI:** Ligand A (32.842) has a lower DILI risk than Ligand B (50.136), which is favorable. Both are below the concerning threshold of 60.

**8. BBB:** This is a critical parameter for CNS targets. Ligand A (90.694) has a significantly higher BBB percentile than Ligand B (22.412). This is a major advantage for Ligand A.

**9. Caco-2 Permeability:** Ligand A (-4.818) and Ligand B (-5.244) both have negative values, which is unusual. Without knowing the scale, it's hard to interpret, but they are similarly poor.

**10. Aqueous Solubility:** Ligand A (-1.803) and Ligand B (-2.98) both have negative values, suggesting poor solubility. Ligand B is slightly worse.

**11. hERG Inhibition:** Both ligands show low hERG inhibition risk (0.447 and 0.247), which is good.

**12. Microsomal Clearance:** Ligand A (-13.28) has a lower (better) microsomal clearance than Ligand B (-8.229), indicating greater metabolic stability.

**13. In vitro Half-Life:** Ligand A (-2.955) has a longer in vitro half-life than Ligand B (-9.525), which is desirable.

**14. P-gp Efflux:** Ligand A (0.025) has a lower P-gp efflux liability than Ligand B (0.084), which is beneficial for CNS exposure.

**15. Binding Affinity:** Ligand B (0.0) has a better binding affinity than Ligand A (-8.2). This is a substantial difference. However, the other ADME properties of Ligand A are far superior.

**Overall Assessment:**

While Ligand B has a better binding affinity, Ligand A is a much more promising drug candidate due to its superior ADME properties, particularly its significantly better BBB penetration (90.694 vs 22.412), TPSA (67.87 vs 107.11), QED (0.696 vs 0.339), metabolic stability, and lower P-gp efflux. For a CNS target like DRD2, these factors are crucial for achieving adequate brain exposure and efficacy. The difference in affinity, while significant, can potentially be overcome with further optimization, whereas poor ADME properties are often harder to fix.

Output:
0
2025-04-17 06:10:00,113 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B based on the provided guidelines, prioritizing GPCR-specific properties (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (357.376 and 349.431 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (44.81) is significantly better than Ligand B (91.5). For CNS targets, TPSA should be <= 90, so Ligand A is well within this range, while Ligand B is close to the upper limit and less desirable.

**logP:** Ligand A (3.047) is optimal (1-3), while Ligand B (1.158) is a bit low, potentially hindering membrane permeability.

**H-Bond Donors/Acceptors:** Ligand A (HBD=1, HBA=3) and Ligand B (HBD=2, HBA=4) both have acceptable numbers of H-bond donors and acceptors.

**QED:** Both ligands have similar QED values (0.728 and 0.7), indicating good drug-likeness.

**DILI:** Ligand A (42.924) has a slightly higher DILI risk than Ligand B (18.302), but both are below the concerning threshold of 60.

**BBB:** Ligand A (78.054) has a significantly better BBB penetration percentile than Ligand B (61.923). A value >70 is desirable for CNS targets, and Ligand A is closer to this threshold.

**Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and difficult to interpret without knowing the scale. However, we can assume lower values are less favorable.

**Aqueous Solubility:** Both ligands have negative solubility values, again making direct comparison difficult.

**hERG:** Ligand A (0.857) has a slightly higher hERG inhibition liability than Ligand B (0.2), but both are relatively low risk.

**Microsomal Clearance:** Ligand A (35.309) and Ligand B (30.176) have comparable microsomal clearance values, suggesting similar metabolic stability.

**In vitro Half-Life:** Ligand A (4.183) has a shorter half-life than Ligand B (-23.25). A negative value for half-life is unusual and suggests a very rapid clearance.

**P-gp Efflux:** Ligand A (0.092) has much lower P-gp efflux liability than Ligand B (0.017), which is crucial for CNS penetration.

**Binding Affinity:** Ligand B (-7.8) has a slightly better binding affinity than Ligand A (-7.5), but the difference is small (0.3 kcal/mol). Given the other ADME properties, this difference is unlikely to be decisive.

**Conclusion:**

Considering the GPCR-specific priorities, Ligand A is the more promising candidate. Its superior TPSA, logP, and BBB penetration, coupled with lower P-gp efflux, outweigh the slightly weaker binding affinity and higher DILI risk. Ligand B's low logP and poorer BBB penetration are significant drawbacks for a CNS-targeting drug.

Output:
1
2025-04-17 06:10:00,113 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (351.407 and 360.527 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (123.58) is better than Ligand B (66.91). Both are below the 90 A^2 threshold for CNS targets, but A is closer to the upper limit.

**3. logP:** Ligand A (0.293) is quite low, potentially hindering permeability. Ligand B (4.332) is high, potentially causing solubility and off-target issues. This is a significant drawback for both, but B's is more concerning.

**4. H-Bond Donors:** Both ligands have 2 HBD, which is within the acceptable limit of <=5.

**5. H-Bond Acceptors:** Ligand A has 7 HBA, while Ligand B has 5. Both are within the acceptable limit of <=10.

**6. QED:** Both ligands have QED values above 0.6, indicating good drug-like properties. Ligand A (0.706) is slightly better than Ligand B (0.619).

**7. DILI:** Both ligands have acceptable DILI risk (Ligand A: 57.348, Ligand B: 51.028), both below the 60 threshold.

**8. BBB:** Ligand A (85.149) has a significantly better BBB penetration percentile than Ligand B (73.672). This is crucial for a CNS target like DRD2.

**9. Caco-2 Permeability:** Ligand A (-4.874) has very poor Caco-2 permeability, indicating poor intestinal absorption. Ligand B (-5.319) is also poor, but slightly better than A.

**10. Aqueous Solubility:** Both have poor aqueous solubility (Ligand A: -2.836, Ligand B: -3.971).

**11. hERG Inhibition:** Both ligands have low hERG inhibition risk (Ligand A: 0.719, Ligand B: 0.792).

**12. Microsomal Clearance:** Ligand A (27.159) has much lower microsomal clearance than Ligand B (83.343), suggesting better metabolic stability.

**13. In vitro Half-Life:** Ligand A (-7.032) has a much longer in vitro half-life than Ligand B (64.312).

**14. P-gp Efflux:** Both ligands have low P-gp efflux liability (Ligand A: 0.027, Ligand B: 0.742). Ligand A is significantly better.

**15. Binding Affinity:** Both ligands have excellent binding affinity (Ligand A: -8.5 kcal/mol, Ligand B: -8.2 kcal/mol). Ligand A is slightly better.

**Overall Assessment:**

Ligand A is the better candidate. While its logP is low and Caco-2 permeability is poor, its significantly better BBB penetration, lower microsomal clearance, longer half-life, lower P-gp efflux, and slightly better affinity outweigh these drawbacks, especially considering the CNS target. Ligand B's high logP is a major concern, and its poorer ADME profile (BBB, Cl_mic, t1/2, Pgp) makes it less desirable. The affinity difference is small enough that the ADME advantages of A are more important.

Output:
0
2025-04-17 06:10:00,113 - INFO - Batch 259 complete. Total preferences: 4144
2025-04-17 06:10:00,113 - INFO - Processing batch 260/512...
2025-04-17 06:10:41,920 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (372.853 and 346.427 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (98.76) is slightly higher than Ligand B (91.57), but both are below the 140 A^2 threshold for good oral absorption and reasonably close to the 90 A^2 target for CNS penetration.

**logP:** Both ligands have good logP values (1.679 and 1.975), falling within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A has 2 HBD and 5 HBA, while Ligand B has 3 HBD and 4 HBA. Both are within acceptable limits (<=5 HBD and <=10 HBA).

**QED:** Both ligands have acceptable QED scores (0.822 and 0.704), indicating good drug-like properties.

**DILI:** Ligand A (70.841) has a higher DILI risk than Ligand B (39.434). This is a significant negative for Ligand A.

**BBB:** Ligand B (29.895) has a significantly better BBB penetration score than Ligand A (19.698). This is crucial for a CNS target like DRD2.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.786 and -4.96), which is unusual and suggests poor permeability. However, these values are on a scale where negative values are possible and don't necessarily disqualify the compounds.

**Aqueous Solubility:** Both ligands have negative solubility values (-2.565 and -3.316), indicating poor aqueous solubility. This could pose formulation challenges.

**hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.287 and 0.117).

**Microsomal Clearance:** Ligand B (10.492) has a much lower microsomal clearance than Ligand A (34.001), indicating better metabolic stability.

**In vitro Half-Life:** Ligand B (57.959) has a significantly longer in vitro half-life than Ligand A (-17.353). This is a major advantage for Ligand B.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.156 and 0.17).

**Binding Affinity:** Ligand B (-8.1 kcal/mol) has a significantly stronger binding affinity than Ligand A (0.0 kcal/mol). This is a substantial advantage.

**Conclusion:**

Considering all factors, especially the GPCR-specific priorities, **Ligand B is the more promising drug candidate.** It exhibits significantly better BBB penetration, metabolic stability (lower Cl_mic, longer t1/2), and binding affinity. While both have poor solubility and Caco-2 permeability, the superior binding affinity and CNS penetration of Ligand B outweigh these drawbacks. The lower DILI risk for Ligand B is also a significant advantage.

Output:
1
2025-04-17 06:10:41,921 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 drug candidates, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (353.495 and 360.531 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (62.73) is significantly better than Ligand B (68.87). For CNS targets, we want TPSA <= 90, and lower is preferable. Ligand A is closer to the optimal range.

**3. logP:** Ligand A (4.751) is slightly higher than the optimal 1-3 range, but still potentially acceptable. Ligand B (3.018) is within the optimal range. However, for a GPCR, a slightly higher logP can be tolerated if other properties are favorable.

**4. H-Bond Donors:** Ligand A (2) and Ligand B (3) are both acceptable (<=5).

**5. H-Bond Acceptors:** Both ligands (6) are within the acceptable limit of <=10.

**6. QED:** Both ligands have similar QED values (0.693 and 0.672), indicating good drug-like properties.

**7. DILI:** Ligand A (77.549) has a higher DILI risk than Ligand B (66.15). Lower is better, and B is preferable here.

**8. BBB:** Ligand B (82.9) has a significantly better BBB penetration percentile than Ligand A (73.866). This is *critical* for a CNS target like DRD2.

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.255 and -5.622). These values are unusual and suggest poor permeability. However, these values are on a log scale, and the negative values are not directly comparable without knowing the scale.

**10. Aqueous Solubility:** Both ligands have negative solubility values (-4.742 and -3.353). Similar to Caco-2, these values are unusual and suggest poor solubility.

**11. hERG Inhibition:** Ligand A (0.633) has a slightly lower hERG risk than Ligand B (0.909), which is preferable.

**12. Microsomal Clearance:** Ligand B (44.085) has significantly lower microsomal clearance than Ligand A (90.875), indicating better metabolic stability.

**13. In vitro Half-Life:** Ligand B (39.601) has a longer in vitro half-life than Ligand A (59.643).

**14. P-gp Efflux:** Ligand A (0.46) has lower P-gp efflux than Ligand B (0.186), which is desirable for CNS penetration.

**15. Binding Affinity:** Ligand A (-8.8 kcal/mol) has a significantly stronger binding affinity than Ligand B (-7.8 kcal/mol). This is a substantial advantage (1.0 kcal/mol difference).

**Overall Assessment:**

While Ligand A has a superior binding affinity, Ligand B has a much more favorable profile regarding CNS penetration (BBB, P-gp efflux) and metabolic stability (Cl_mic, t1/2). The higher DILI risk for Ligand A is also a concern. For a CNS GPCR target, the ability to cross the blood-brain barrier and remain stable in the body are paramount. The 1.0 kcal/mol difference in binding affinity, while significant, can potentially be optimized in later stages of drug development. The poor solubility and permeability of both compounds are concerning, but might be addressed with formulation strategies.

Output:
1
2025-04-17 06:10:41,921 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (357.445 and 367.471 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (52.65) is excellent, well below the 90 A^2 threshold for CNS targets. Ligand B (95.58) is higher, but still potentially acceptable, though less ideal.

**logP:** Ligand A (1.725) is optimal. Ligand B (0.598) is a bit low, potentially hindering membrane permeability.

**H-Bond Donors/Acceptors:** Ligand A (HBD=1, HBA=3) is good. Ligand B (HBD=2, HBA=5) is also acceptable.

**QED:** Ligand A (0.788) is strong, indicating good drug-likeness. Ligand B (0.39) is significantly lower, suggesting potential issues.

**DILI:** Ligand A (11.516) has a very low DILI risk. Ligand B (43.971) is higher, but still within an acceptable range.

**BBB:** Ligand A (85.072) has excellent BBB penetration potential. Ligand B (73.75) is good, but less favorable than Ligand A.

**Caco-2 Permeability:** Ligand A (-4.843) has poor Caco-2 permeability. Ligand B (-5.751) also has poor Caco-2 permeability.

**Aqueous Solubility:** Ligand A (-1.328) has poor aqueous solubility. Ligand B (-3.0) has even worse aqueous solubility.

**hERG:** Both ligands have very low hERG inhibition risk (0.514 and 0.075, respectively).

**Microsomal Clearance:** Ligand A (-12.993) has very low microsomal clearance, indicating high metabolic stability. Ligand B (9.163) has a higher clearance, suggesting faster metabolism.

**In vitro Half-Life:** Ligand A (-0.134) has a very long in vitro half-life. Ligand B (-0.54) has a slightly shorter half-life.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.028 and 0.027, respectively).

**Binding Affinity:** Ligand A (-8.5 kcal/mol) has a significantly stronger binding affinity than Ligand B (-7.1 kcal/mol). This 1.4 kcal/mol difference is substantial.

**Overall Assessment:**

Ligand A is superior. While both have poor Caco-2 permeability and solubility, Ligand A possesses a significantly better binding affinity, excellent BBB penetration, a higher QED score, and better metabolic stability (lower Cl_mic, longer t1/2). The stronger binding affinity is a major advantage for a GPCR ligand, and can potentially compensate for the solubility/permeability issues. Ligand B's lower logP and QED are concerning.

Output:
1
2025-04-17 06:10:41,921 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (351.403 and 348.447 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (107.97) is slightly above the optimal <90 for CNS targets, but still reasonable. Ligand B (89.27) is excellent, well within the desired range.

**logP:** Ligand A (-0.247) is quite low, potentially hindering permeation. Ligand B (1.575) is within the optimal 1-3 range. This is a significant advantage for Ligand B.

**H-Bond Donors/Acceptors:** Ligand A has 3 HBD and 5 HBA, acceptable. Ligand B has 2 HBD and 6 HBA, also acceptable.

**QED:** Both ligands have good QED scores (0.647 and 0.781), indicating drug-like properties.

**DILI:** Ligand A (36.177) has a slightly higher DILI risk than Ligand B (26.134), but both are below the concerning threshold of 60.

**BBB:** Both ligands have similar BBB penetration (30.128 and 31.834), which is not ideal (>70 is desirable for CNS targets), but not a major differentiating factor here.

**Caco-2 Permeability:** Both have very poor Caco-2 permeability (-5.203 and -5.197). This is a concern for oral bioavailability, but less critical for a CNS target where direct delivery or other routes might be considered.

**Aqueous Solubility:** Both ligands have poor aqueous solubility (-1.141 and -2.324). This could pose formulation challenges.

**hERG Inhibition:** Both ligands show very low hERG inhibition risk (0.062 and 0.08), which is excellent.

**Microsomal Clearance:** Ligand A (-52.282) has significantly lower (better) microsomal clearance than Ligand B (8.799), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand B (9.223) has a much longer half-life than Ligand A (0.703), which is a considerable advantage.

**P-gp Efflux:** Both ligands show minimal P-gp efflux liability (0.005 and 0.044).

**Binding Affinity:** Ligand B (-8.6 kcal/mol) has a slightly better binding affinity than Ligand A (-8.0 kcal/mol). While both are good, the 0.6 kcal/mol difference is notable.

**Overall Assessment:**

Ligand B is the stronger candidate. While both have poor solubility and Caco-2 permeability, Ligand B excels in key areas for a CNS GPCR target: a more favorable logP, a longer half-life, and slightly better binding affinity. The lower logP of Ligand A is a significant drawback, potentially limiting its ability to cross cell membranes and reach the target in the brain. The better metabolic stability of Ligand A is a plus, but the other advantages of Ligand B outweigh this benefit.

Output:
1
2025-04-17 06:10:41,922 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the acceptable range (200-500 Da). Ligand A (357.435 Da) is slightly preferred as it's closer to the lower end, potentially aiding permeability.

**TPSA:** Both ligands have TPSA values (72.7 and 74.85) that are acceptable for oral absorption (<140) but borderline for CNS penetration (<90). Neither is ideal, but this is less critical given the other parameters.

**logP:** Ligand A (2.351) is within the optimal range (1-3). Ligand B (3.928) is pushing the upper limit, potentially leading to solubility issues or off-target interactions. Ligand A is favored here.

**H-Bond Donors/Acceptors:** Ligand A (HBD=1, HBA=6) and Ligand B (HBD=2, HBA=3) both have reasonable numbers of H-bond donors and acceptors, well within the guidelines.

**QED:** Both ligands have similar QED values (0.776 and 0.791), indicating good drug-like properties.

**DILI:** Ligand A (61.962) has a lower DILI risk than Ligand B (79.449), which is a significant advantage.

**BBB:** Ligand B (72.896) has a significantly better BBB percentile than Ligand A (49.244). This is a *major* advantage for a CNS target like DRD2.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.057 and -5.098), which is unusual and suggests poor permeability. This is a concern for both.

**Aqueous Solubility:** Both ligands exhibit poor aqueous solubility (-2.814 and -5.286). This could pose formulation challenges.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.579 and 0.711).

**Microsomal Clearance:** Ligand B (21.109) has lower microsomal clearance than Ligand A (24.878), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand B (56.678 hours) has a significantly longer half-life than Ligand A (22.731 hours), which is desirable.

**P-gp Efflux:** Ligand A (0.278) has lower P-gp efflux than Ligand B (0.634), which is a positive for CNS exposure.

**Binding Affinity:** Ligand B (-8.4 kcal/mol) has a slightly better binding affinity than Ligand A (-9.2 kcal/mol). While the difference is not huge, it's still a positive for Ligand B.

**Overall Assessment:**

Ligand B excels in BBB penetration, metabolic stability (lower Cl_mic, longer t1/2), and binding affinity. These are crucial for a CNS GPCR target. While its logP is slightly higher and DILI risk is greater than Ligand A, the significant advantage in BBB and affinity outweigh these drawbacks. Ligand A has better P-gp efflux and DILI, but the lower BBB is a critical disadvantage. The poor Caco-2 and solubility are concerns for both, but can potentially be addressed through formulation strategies.

Output:
1
2025-04-17 06:10:41,922 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (352.431 and 357.479 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (84.94) is significantly better than Ligand B (54.79), both being below the 90 A^2 threshold desirable for CNS targets.

**logP:** Ligand A (1.004) is within the optimal 1-3 range. Ligand B (3.746) is approaching the upper limit, potentially raising concerns about solubility and off-target effects.

**H-Bond Donors:** Ligand A has 1 HBD, while Ligand B has 0. Both are acceptable (<=5).

**H-Bond Acceptors:** Both ligands have 5 HBAs, which is within the acceptable limit of <=10.

**QED:** Both ligands have good QED scores (0.691 and 0.791, respectively), indicating good drug-like properties.

**DILI:** Ligand A (21.791) has a much lower DILI risk than Ligand B (54.323). This is a significant advantage for Ligand A.

**BBB:** Ligand A (55.099) has a lower BBB penetration percentile than Ligand B (61.419). While both are not ideal (>70), Ligand B is slightly better.

**Caco-2 Permeability:** Ligand A (-4.858) has poorer Caco-2 permeability than Ligand B (-4.598).

**Aqueous Solubility:** Ligand A (-1.304) has better aqueous solubility than Ligand B (-3.547).

**hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.104 and 0.264, respectively).

**Microsomal Clearance:** Ligand A (16.913) has significantly lower microsomal clearance than Ligand B (53.792), indicating better metabolic stability.

**In vitro Half-Life:** Ligand B (27.131) has a longer in vitro half-life than Ligand A (4.68).

**P-gp Efflux:** Ligand A (0.031) has much lower P-gp efflux liability than Ligand B (0.358), which is crucial for CNS penetration.

**Binding Affinity:** Ligand B (-7.9) has slightly better binding affinity than Ligand A (-7.7), but the difference is relatively small (0.2 kcal/mol).

**Overall Assessment:**

Considering the GPCR-specific priorities, Ligand A is the more promising candidate. While Ligand B has slightly better BBB penetration and binding affinity, Ligand A excels in critical areas like DILI risk, P-gp efflux, and metabolic stability (microsomal clearance). The lower P-gp efflux of Ligand A is particularly important for CNS targets like DRD2. The better solubility of ligand A is also a positive. The small difference in binding affinity (0.2 kcal/mol) is unlikely to outweigh the significant advantages of Ligand A in ADME properties.

Output:
0
2025-04-17 06:10:41,922 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 drug candidates, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (478.225 Da) is at the higher end, while Ligand B (348.531 Da) is comfortably within the range.

**2. TPSA:** Both ligands have TPSA values (42.96 and 41.57) below the 90 A^2 threshold for CNS targets, which is excellent.

**3. logP:** Both ligands have logP values (3.002 and 3.373) within the optimal range of 1-3.

**4. H-Bond Donors:** Both ligands have 1 HBD, which is acceptable.

**5. H-Bond Acceptors:** Ligand A has 5 HBA, and Ligand B has 3 HBA. Both are below the 10 threshold.

**6. QED:** Both ligands have good QED scores (0.554 and 0.717), indicating good drug-like properties. Ligand B is slightly better.

**7. DILI:** Ligand A (23.226) has a lower DILI risk than Ligand B (16.285), which is favorable.

**8. BBB:** Both ligands exhibit good BBB penetration (77.2% and 81.815%), exceeding the desirable threshold of 70% for CNS targets. Ligand B is slightly better.

**9. Caco-2 Permeability:** Both have negative Caco-2 values (-5.127 and -4.802), which is unusual and suggests poor permeability. This is a significant concern for both.

**10. Aqueous Solubility:** Both ligands have negative solubility values (-2.767 and -3.171), indicating very poor aqueous solubility. This is a major drawback for both.

**11. hERG Inhibition:** Both ligands show low hERG inhibition risk (0.848 and 0.518), which is good.

**12. Microsomal Clearance:** Ligand A (38.037 mL/min/kg) has lower microsomal clearance than Ligand B (47.45 mL/min/kg), suggesting better metabolic stability.

**13. In vitro Half-Life:** Ligand B (44.612 hours) has a significantly longer in vitro half-life than Ligand A (5.465 hours). This is a substantial advantage.

**14. P-gp Efflux:** Both ligands have low P-gp efflux liability (0.459 and 0.387), which is beneficial for CNS exposure.

**15. Binding Affinity:** Ligand B (-7.3 kcal/mol) has a stronger binding affinity than Ligand A (-8.0 kcal/mol). While A is slightly better, the difference is not huge.

**Overall Assessment:**

Both ligands have significant drawbacks (poor solubility and permeability). However, considering the GPCR-specific priorities, Ligand B is slightly more promising. It has a better BBB penetration, a significantly longer half-life, and a slightly better QED score, and a better binding affinity. The lower DILI risk of Ligand A is a plus, but the substantial difference in half-life and the slightly better affinity of Ligand B outweigh this benefit. The poor solubility and permeability would need to be addressed through formulation or structural modifications for either compound.

Output:
1
2025-04-17 06:10:41,922 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (342.4 and 359.9 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (82.7) is better than Ligand B (55.32). Both are below the 90 A^2 threshold for CNS targets, but A is closer to the upper limit.

**3. logP:** Ligand A (1.362) is within the optimal 1-3 range. Ligand B (3.416) is at the higher end of the optimal range, potentially raising concerns about solubility and off-target effects, but still acceptable.

**4. H-Bond Donors:** Ligand A (1) is preferable to Ligand B (0). While both are low, having one donor can sometimes improve solubility.

**5. H-Bond Acceptors:** Ligand A (6) is slightly higher than Ligand B (5), but both are within the acceptable limit of 10.

**6. QED:** Ligand A (0.903) has a significantly better QED score than Ligand B (0.618), indicating a more drug-like profile.

**7. DILI:** Ligand B (52.385) has a lower DILI risk than Ligand A (67.623), making it slightly safer from a liver toxicity perspective.

**8. BBB:** Ligand B (77.782) has a substantially higher BBB penetration percentile than Ligand A (56.999). This is *critical* for a CNS target like DRD2.

**9. Caco-2 Permeability:** Ligand A (-4.632) has better Caco-2 permeability than Ligand B (-4.901), suggesting better intestinal absorption. However, both are negative values, which is unusual and requires further investigation.

**10. Aqueous Solubility:** Ligand A (-1.764) has better aqueous solubility than Ligand B (-3.488).

**11. hERG Inhibition:** Ligand A (0.424) has a lower hERG inhibition liability than Ligand B (0.777), indicating a lower risk of cardiotoxicity.

**12. Microsomal Clearance:** Ligand B (55.671) has a lower microsomal clearance than Ligand A (9.906), suggesting better metabolic stability.

**13. In vitro Half-Life:** Ligand B (14.998) has a longer in vitro half-life than Ligand A (10.847), which is generally desirable.

**14. P-gp Efflux:** Ligand A (0.058) has significantly lower P-gp efflux liability than Ligand B (0.645). Lower P-gp efflux is crucial for CNS penetration.

**15. Binding Affinity:** Both ligands have very similar and excellent binding affinities (-8.4 and -8.1 kcal/mol). The difference is less than 1.5 kcal/mol, so it's not a deciding factor.

**Overall Assessment:**

While Ligand A has better QED, solubility, Caco-2 permeability, and lower hERG risk, Ligand B *significantly* outperforms it in BBB penetration and has better metabolic stability (lower Cl_mic, longer t1/2). Given that DRD2 is a CNS target, BBB penetration is paramount. The lower P-gp efflux of Ligand A is a positive, but the substantial difference in BBB is more important. The slightly higher DILI risk of Ligand A is also a concern.

Output:
1
2025-04-17 06:10:41,922 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (360.361 and 351.359 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (110.56) is better than Ligand B (117.16). Both are reasonably close to the 90 A^2 threshold for CNS targets, but A is preferable.

**3. logP:** Ligand B (0.944) is slightly better than Ligand A (-0.671). Both are a bit low, potentially hindering permeability, but B is closer to the optimal 1-3 range.

**4. H-Bond Donors:** Ligand A (2) is slightly worse than Ligand B (1). Both are within the acceptable limit of <=5.

**5. H-Bond Acceptors:** Ligand A (8) is slightly worse than Ligand B (7). Both are within the acceptable limit of <=10.

**6. QED:** Both ligands have similar QED values (0.689 and 0.636), indicating good drug-like properties.

**7. DILI:** Ligand B (71.539) has a better DILI score than Ligand A (55.68), indicating a lower risk of liver injury.

**8. BBB:** Ligand A (78.364) has a significantly better BBB penetration score than Ligand B (62.117). This is *critical* for a CNS target like DRD2.

**9. Caco-2 Permeability:** Ligand A (-4.942) is better than Ligand B (-4.507), indicating better intestinal absorption.

**10. Aqueous Solubility:** Ligand A (-1.865) is better than Ligand B (-2.718), indicating better solubility.

**11. hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.45 and 0.313).

**12. Microsomal Clearance:** Ligand A (-7.839) has significantly lower (better) microsomal clearance than Ligand B (4.274), suggesting better metabolic stability.

**13. In vitro Half-Life:** Ligand A (-28.204) has a significantly longer in vitro half-life than Ligand B (-19.684).

**14. P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.128 and 0.164).

**15. Binding Affinity:** Both ligands have the same binding affinity (-7.6 kcal/mol), which is excellent.

**Overall Assessment:**

While Ligand B has a slightly better logP and DILI score, Ligand A is significantly better in terms of BBB penetration, metabolic stability (Cl_mic), and in vitro half-life. Given that DRD2 is a CNS target, BBB penetration is paramount. The superior metabolic stability of Ligand A also makes it more likely to achieve adequate exposure *in vivo*. The slightly lower logP of Ligand A is a minor drawback compared to the substantial advantage in CNS penetration and metabolic stability.

Output:
0
2025-04-17 06:10:41,923 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (353.423 Da) is slightly lower, which could be beneficial for permeability, while Ligand B (384.611 Da) is still well within the range.

**TPSA:** Ligand A (125.35) is closer to the upper limit for good oral absorption (<=140) and is significantly better than Ligand B (40.62) for CNS penetration (<=90 is preferred). This is a major advantage for Ligand A.

**logP:** Ligand A (-0.902) is a bit low, potentially hindering membrane permeability. Ligand B (3.255) is within the optimal range (1-3).

**H-Bond Donors/Acceptors:** Ligand A has 4 HBD and 6 HBA, which are acceptable. Ligand B has 0 HBD and 4 HBA, also acceptable.

**QED:** Both ligands have reasonable QED values (A: 0.458, B: 0.659), indicating drug-like properties, with B being slightly better.

**DILI:** Both ligands have low DILI risk (A: 37.224, B: 29.391), which is good.

**BBB:** Ligand B has a significantly higher BBB percentile (76.735) compared to Ligand A (20.822). This is a crucial advantage for a CNS target like DRD2.

**Caco-2 Permeability:** Both have negative Caco-2 values (-5.552 and -5.076), which is unusual and suggests poor permeability. However, these values are on a scale where negative values are possible, and their relative comparison is less informative without knowing the scale's specifics.

**Aqueous Solubility:** Both have negative solubility values (-1.219 and -3.739), indicating poor solubility. Again, the scale is important, but B appears slightly worse.

**hERG Inhibition:** Both have low hERG inhibition liability (A: 0.107, B: 0.678), which is favorable.

**Microsomal Clearance:** Ligand A (12.115) has a lower microsomal clearance than Ligand B (84.704), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (23.39) has a longer half-life than Ligand B (0.104), which is desirable.

**P-gp Efflux:** Ligand A (0.01) has very low P-gp efflux, a significant advantage for CNS penetration. Ligand B (0.521) has moderate P-gp efflux.

**Binding Affinity:** Ligand A (-7.7 kcal/mol) has a slightly better binding affinity than Ligand B (-7.2 kcal/mol). While both are good, the 0.5 kcal/mol difference is noticeable.

**Overall Assessment:**

Ligand A excels in metabolic stability (Cl_mic, t1/2), P-gp efflux, and binding affinity. Its TPSA is also much more favorable for CNS penetration. However, its logP is low, and BBB penetration is poor.

Ligand B has a good logP and excellent BBB penetration, but suffers from high metabolic clearance, short half-life, and moderate P-gp efflux.

Considering the GPCR-specific priorities for DRD2, BBB penetration is critical. While Ligand A has a better binding affinity and ADME profile in most other aspects, the significantly better BBB value of Ligand B is a strong advantage. The slightly better affinity of Ligand A might be overcome with further optimization, but the BBB value is harder to improve.

Output:
1
2025-04-17 06:10:41,923 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (356.451 and 363.868 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (83.98) is better than Ligand B (55.63), both are below the 90 A^2 threshold for CNS targets.

**logP:** Ligand A (2.415) is within the optimal 1-3 range. Ligand B (3.588) is slightly higher, but still acceptable.

**H-Bond Donors:** Ligand A (2) and Ligand B (1) are both acceptable, being less than 5.

**H-Bond Acceptors:** Both ligands (A: 5, B: 5) are within the acceptable limit of 10.

**QED:** Both ligands have good QED scores (A: 0.862, B: 0.901), indicating good drug-like properties.

**DILI:** Ligand A (70.182) is higher than Ligand B (47.305), indicating a slightly higher potential for liver injury. Ligand B is preferable here.

**BBB:** Ligand B (88.445) is significantly better than Ligand A (49.011). This is a *critical* factor for a CNS target like DRD2.

**Caco-2 Permeability:** Both are negative values, which is unusual. However, the magnitude is similar, and this is less critical than BBB for CNS penetration.

**Aqueous Solubility:** Both are negative values, which is unusual. However, the magnitude is similar, and this is less critical than BBB for CNS penetration.

**hERG Inhibition:** Ligand A (0.136) has a lower hERG inhibition risk than Ligand B (0.337), which is favorable.

**Microsomal Clearance:** Ligand A (-0.307) has a lower (better) microsomal clearance than Ligand B (33.779), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (25.411) has a shorter half-life than Ligand B (22.859), which is less desirable.

**P-gp Efflux:** Ligand A (0.063) has lower P-gp efflux liability than Ligand B (0.557), which is preferable for CNS exposure.

**Binding Affinity:** Both ligands have the same binding affinity (-8.4 kcal/mol), which is excellent.

**Overall Assessment:**

While Ligand A has advantages in hERG, microsomal clearance, and P-gp efflux, the *significant* advantage of Ligand B in BBB penetration outweighs these factors for a CNS-targeting drug. The slightly higher DILI risk for Ligand A is also a concern, though not as critical as the BBB score. The similar binding affinities mean that the primary differentiator is ADME properties, and specifically CNS penetration.

Output:
1
2025-04-17 06:10:41,923 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (345.334 and 350.434 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (101.38) is better than Ligand B (59.59). For CNS targets, TPSA < 90 is preferred, so Ligand B is significantly better in this regard.

**logP:** Ligand A (1.201) is within the optimal 1-3 range. Ligand B (3.541) is at the higher end of the optimal range, potentially leading to solubility issues but acceptable.

**H-Bond Donors/Acceptors:** Both have 2 HBDs, which is good. Ligand A has 6 HBAs, while Ligand B has 3. Both are acceptable (<=10), but Ligand B is preferable.

**QED:** Both ligands have good QED scores (0.724 and 0.873), indicating drug-like properties.

**DILI:** Ligand A (90.617) has a significantly higher DILI risk than Ligand B (31.873). This is a major concern for Ligand A.

**BBB:** Ligand B (84.529) has a much better BBB penetration score than Ligand A (57.464). This is crucial for a CNS target like DRD2.

**Caco-2 Permeability:** Ligand A (-4.846) has worse Caco-2 permeability than Ligand B (-4.406), indicating lower intestinal absorption.

**Aqueous Solubility:** Both have very poor aqueous solubility (-3.134 and -3.379). This could be a formulation challenge for both.

**hERG Inhibition:** Both have low hERG inhibition risk (0.199 and 0.438).

**Microsomal Clearance:** Ligand A (18.273) has lower microsomal clearance than Ligand B (28.888), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (-22.712) has a much shorter in vitro half-life than Ligand B (22.565). This is a significant drawback for Ligand A.

**P-gp Efflux:** Both have low P-gp efflux liability (0.083 and 0.125).

**Binding Affinity:** Both have excellent binding affinities (-9.3 and -8.5 kcal/mol). Ligand A is slightly better (-9.3 kcal/mol), but the difference is not substantial enough to overcome its other weaknesses.

**Overall Assessment:**

Ligand B is the superior candidate. While both have poor solubility, Ligand B excels in crucial areas for a CNS-targeting GPCR: significantly better BBB penetration, lower DILI risk, and a longer half-life. Although Ligand A has slightly better binding affinity, the ADME properties of Ligand B are far more favorable. The TPSA is also much better for Ligand B.

Output:
1
2025-04-17 06:10:41,923 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (352.435 Da and 349.431 Da) fall comfortably within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (91.31) is better than Ligand B (104.46). For CNS targets, we want TPSA <= 90, so Ligand A is closer to this threshold.

**3. logP:** Ligand B (1.155) is slightly better than Ligand A (0.374). Both are within the optimal 1-3 range, but A is quite low and might struggle with membrane permeability.

**4. H-Bond Donors:** Ligand A (1) is preferable to Ligand B (3). Lower HBD generally improves permeability.

**5. H-Bond Acceptors:** Both ligands have 5 HBA, which is acceptable (<=10).

**6. QED:** Both ligands have good QED scores (0.615 and 0.685, respectively), indicating drug-like properties.

**7. DILI:** Ligand A (27.104) has a significantly lower DILI risk than Ligand B (34.238). This is a major advantage for Ligand A.

**8. BBB:** Ligand A (68.864) has a better BBB penetration percentile than Ligand B (58.821). While both are below the desirable >70 for CNS targets, A is closer.

**9. Caco-2 Permeability:** Ligand A (-4.789) has a worse Caco-2 permeability than Ligand B (-5.157). Lower values are worse.

**10. Aqueous Solubility:** Ligand A (-1.603) has better aqueous solubility than Ligand B (-2.075).

**11. hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.199 and 0.044, respectively).

**12. Microsomal Clearance:** Ligand A (26.214) has lower microsomal clearance than Ligand B (41.904), indicating better metabolic stability.

**13. In vitro Half-Life:** Ligand A (-14.922) has a longer in vitro half-life than Ligand B (-22.882).

**14. P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.015 and 0.052, respectively).

**15. Binding Affinity:** Ligand B (-7.9 kcal/mol) has a stronger binding affinity than Ligand A (-6.8 kcal/mol). This is a 1.1 kcal/mol difference, which is significant and can outweigh some ADME drawbacks.

**Overall Assessment:**

Ligand B has a significantly better binding affinity, which is crucial for GPCR targets. However, Ligand A demonstrates superior ADME properties, particularly in terms of DILI risk, BBB penetration, and metabolic stability. Given the CNS target (DRD2), the lower DILI and better BBB of Ligand A are highly valuable. The difference in binding affinity, while substantial, might be overcome with further optimization of Ligand A. The lower logP of Ligand A is a concern, but not insurmountable.

Output:
1
2025-04-17 06:10:41,923 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (345.345 Da) is slightly lower, which could be beneficial for permeability, while Ligand B (376.523 Da) is also well within range.

**TPSA:** Ligand A (46.61) is excellent, well below the 90 Angstroms threshold for CNS targets. Ligand B (121.6) is higher, but still potentially acceptable, though less optimal for brain penetration.

**logP:** Ligand A (3.214) is within the optimal range (1-3). Ligand B (0.371) is quite low, potentially hindering membrane permeability and CNS penetration.

**H-Bond Donors/Acceptors:** Ligand A (0 HBD, 3 HBA) is favorable. Ligand B (3 HBD, 4 HBA) is also acceptable, though slightly higher.

**QED:** Both ligands have reasonable QED scores (A: 0.597, B: 0.477), indicating decent drug-likeness. Ligand A is better.

**DILI:** Ligand A (88.523) has a higher DILI risk than Ligand B (33.695). This is a concern for Ligand A.

**BBB:** Ligand A (77.898) has a significantly better BBB penetration prediction than Ligand B (43.815). This is a critical advantage for a CNS target like DRD2.

**Caco-2 Permeability:** Ligand A (-4.009) has poor predicted Caco-2 permeability. Ligand B (-5.38) is even worse. Both are very negative, indicating very low permeability.

**Aqueous Solubility:** Ligand A (-4.419) has poor predicted solubility. Ligand B (-1.785) is better, but still not ideal.

**hERG Inhibition:** Ligand A (0.603) has a slightly higher hERG risk than Ligand B (0.219), but both are relatively low.

**Microsomal Clearance:** Ligand A (96.545) has a high predicted clearance, suggesting poor metabolic stability. Ligand B (40.419) is much better, indicating better metabolic stability.

**In vitro Half-Life:** Ligand A (-1.404) has a very short predicted half-life. Ligand B (-7.543) also has a short half-life, but is better than Ligand A.

**P-gp Efflux:** Ligand A (0.335) has lower P-gp efflux liability than Ligand B (0.006). This is favorable for CNS exposure.

**Binding Affinity:** Ligand A (-8.5 kcal/mol) has a significantly stronger binding affinity than Ligand B (-7.1 kcal/mol). This is a substantial advantage.

**Overall Assessment:**

Ligand A excels in BBB penetration and binding affinity, crucial for a CNS GPCR target. However, it has concerning DILI risk, poor Caco-2 permeability, poor solubility, and high clearance/short half-life. Ligand B has better metabolic stability and lower DILI risk, but suffers from poor logP, lower BBB penetration, and weaker binding affinity.

The strong binding affinity and good BBB of Ligand A are compelling, and could potentially be optimized with further medicinal chemistry to address its ADME liabilities. The weak binding affinity of Ligand B makes it a less attractive starting point, even with its better ADME profile.

Output:
1
2025-04-17 06:10:41,924 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight (MW):** Both ligands (350.346 and 346.387 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (81.75) is significantly better than Ligand B (114.5). For CNS targets, we want TPSA <= 90, so Ligand A is preferable.

**3. logP:** Ligand A (1.515) is within the optimal 1-3 range. Ligand B (-0.464) is below 1, which might hinder permeation. This favors Ligand A.

**4. H-Bond Donors (HBD):** Both ligands are acceptable (0 and 2, respectively), well below the threshold of 5.

**5. H-Bond Acceptors (HBA):** Both ligands are acceptable (6 and 5, respectively), well below the threshold of 10.

**6. QED:** Both ligands have similar, good QED scores (0.784 and 0.718), indicating good drug-like properties.

**7. DILI:** Ligand A (59.907) has a higher DILI risk than Ligand B (42.924). Ligand B is preferable here.

**8. BBB:** Ligand A (96.161) has a much higher BBB penetration percentile than Ligand B (61.962). This is a *critical* advantage for a CNS target like DRD2.

**9. Caco-2 Permeability:** Ligand A (-4.165) has a lower Caco-2 value than Ligand B (-5.37). Lower values suggest poorer permeability, but this is less critical than BBB for CNS targets.

**10. Aqueous Solubility:** Ligand A (-2.902) has a lower solubility than Ligand B (-2.374). Solubility is important, but can be addressed with formulation.

**11. hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.317 and 0.102).

**12. Microsomal Clearance:** Ligand B (-22.346) has significantly lower (better) microsomal clearance than Ligand A (59.404), indicating better metabolic stability.

**13. In vitro Half-Life:** Ligand B (-4.922) has a longer half-life than Ligand A (-15.882).

**14. P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.235 and 0.019).

**15. Binding Affinity:** Both ligands have similar, strong binding affinities (-8.7 and -8.3 kcal/mol). The difference is not substantial enough to outweigh other factors.

**Overall Assessment:**

Ligand A excels in BBB penetration and has a more favorable logP and TPSA. These are crucial for CNS GPCR targeting. While Ligand B has better DILI, metabolic stability and half-life, the superior BBB penetration of Ligand A is paramount for DRD2, a CNS target. The slightly lower solubility of Ligand A is a manageable concern.

Output:
1
2025-04-17 06:10:41,924 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B against the provided guidelines, prioritizing GPCR-specific properties (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (351.403 and 362.503 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (104.9) is slightly above the optimal <90 for CNS targets, but still reasonable. Ligand B (91.83) is better, falling comfortably under 90.

**logP:** Ligand A (0.408) is quite low, potentially hindering permeability. Ligand B (2.907) is much better, falling within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A (HBD=2, HBA=6) and Ligand B (HBD=3, HBA=7) both have acceptable numbers of H-bond donors and acceptors.

**QED:** Both ligands have similar QED values (0.657 and 0.626), indicating good drug-likeness.

**DILI:** Ligand A (32.842) has a lower DILI risk than Ligand B (46.219), which is preferable.

**BBB:** Ligand A (45.366) has a slightly better BBB percentile than Ligand B (42.924), but both are below the desirable >70 for CNS targets.

**Caco-2 Permeability:** Ligand A (-5.137) has a worse Caco-2 permeability than Ligand B (-5.461).

**Aqueous Solubility:** Both ligands have very poor aqueous solubility (-1.194 and -2.042). This is a significant concern.

**hERG Inhibition:** Ligand A (0.055) has a lower hERG inhibition liability than Ligand B (0.455), which is better.

**Microsomal Clearance:** Ligand B (42.791) has a significantly higher microsomal clearance than Ligand A (4.474), indicating lower metabolic stability.

**In vitro Half-Life:** Ligand B (43.633) has a longer in vitro half-life than Ligand A (23.703), which is preferable.

**P-gp Efflux:** Ligand A (0.037) has a lower P-gp efflux liability than Ligand B (0.05), which is better for CNS penetration.

**Binding Affinity:** Ligand B (-8.4 kcal/mol) has a significantly stronger binding affinity than Ligand A (-7.4 kcal/mol). This >1.5 kcal/mol difference is substantial and can outweigh some ADME drawbacks.

**Overall Assessment:**

While Ligand A has advantages in DILI, hERG, and P-gp efflux, Ligand B's superior logP, binding affinity, and in vitro half-life are more critical for a CNS-targeting GPCR ligand. The stronger binding affinity is a major advantage. The lower logP of Ligand A is a significant concern for brain penetration. Although both have poor solubility, the overall profile of Ligand B is more promising, especially considering the importance of potency for GPCRs.

Output:
1
2025-04-17 06:10:41,924 - INFO - Batch 260 complete. Total preferences: 4160
2025-04-17 06:10:41,924 - INFO - Processing batch 261/512...
2025-04-17 06:11:22,555 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (348.418 and 344.415 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (71.34) is significantly better than Ligand B (87.32). For CNS targets, we want TPSA <= 90, and A is closer to the optimal <= 60 range. B is pushing the upper limit.

**3. logP:** Both ligands have acceptable logP values (2.918 and 1.566), falling within the 1-3 range. Ligand A is slightly preferred.

**4. H-Bond Donors:** Both have 2 HBD, which is good.

**5. H-Bond Acceptors:** Ligand A has 3 HBA, and Ligand B has 4. Both are acceptable (<=10).

**6. QED:** Both ligands have high QED scores (0.83 and 0.862), indicating good drug-like properties.

**7. DILI:** Ligand A (37.767) has a lower DILI risk than Ligand B (52.695), which is favorable. Both are below the 60 threshold.

**8. BBB:** This is crucial for a CNS target. Ligand A has a significantly higher BBB penetration percentile (76.541) compared to Ligand B (52.889). A score >70 is desirable, and A is closer.

**9. Caco-2 Permeability:** Ligand A (-4.654) has a worse Caco-2 permeability than Ligand B (-5.024). Lower values are less desirable.

**10. Aqueous Solubility:** Ligand A (-3.59) has better solubility than Ligand B (-2.675).

**11. hERG Inhibition:** Ligand A (0.324) has a lower hERG inhibition liability than Ligand B (0.512), which is preferable.

**12. Microsomal Clearance:** Ligand A (14.817) has higher microsomal clearance than Ligand B (7.541), indicating lower metabolic stability. This favors Ligand B.

**13. In vitro Half-Life:** Ligand A (31.657) has a longer half-life than Ligand B (10.442), which is desirable.

**14. P-gp Efflux:** Ligand A (0.123) has lower P-gp efflux liability than Ligand B (0.036), which is better for CNS exposure.

**15. Binding Affinity:** Ligand A (-8.8 kcal/mol) has a significantly stronger binding affinity than Ligand B (-7.3 kcal/mol). This is a substantial advantage (>1.5 kcal/mol difference).

**Overall Assessment:**

Ligand A is clearly superior. While Ligand B has better metabolic stability (lower Cl_mic) and slightly better Caco-2 permeability, Ligand A excels in the most critical areas for a CNS-targeting GPCR ligand: **BBB penetration, binding affinity, TPSA, DILI risk, and P-gp efflux.** The strong binding affinity of Ligand A (-8.8 kcal/mol) is a major advantage that outweighs the slightly higher clearance. The better TPSA and BBB scores are also critical for CNS penetration.



Output:
1
2025-04-17 06:11:22,555 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 drug candidates, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (360.43 and 349.48 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (90.31) is slightly above the optimal <90 for CNS targets, but still reasonable. Ligand B (81.67) is well within the desired range.

**logP:** Ligand A (-0.055) is a bit low, potentially hindering permeability. Ligand B (0.809) is closer to the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A (HBD=2, HBA=5) and Ligand B (HBD=3, HBA=4) both have acceptable numbers of H-bond donors and acceptors.

**QED:** Both ligands have similar and good QED values (0.592 and 0.594).

**DILI:** Ligand A (12.52) has a significantly better DILI score than Ligand B (9.97), indicating a lower risk of liver injury.

**BBB:** This is a crucial parameter for CNS targets. Ligand A has a very good BBB percentile (73.94), while Ligand B is considerably lower (34.35).

**Caco-2 Permeability:** Ligand A (-4.711) and Ligand B (-5.237) both have negative Caco-2 values, which is unusual and suggests poor permeability. However, these values are on a scale where negative values are possible and don't necessarily disqualify a compound.

**Aqueous Solubility:** Both ligands have very poor aqueous solubility (-0.016 and -1.799). This could pose formulation challenges.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.348 and 0.109).

**Microsomal Clearance:** Ligand A (3.812) has a lower (better) microsomal clearance than Ligand B (9.601), suggesting greater metabolic stability.

**In vitro Half-Life:** Ligand A (4.007) has a slightly better in vitro half-life than Ligand B (-1.585).

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.039 and 0.047), which is favorable for CNS penetration.

**Binding Affinity:** Ligand B (-8.2 kcal/mol) has a significantly stronger binding affinity than Ligand A (-7.2 kcal/mol). This 1.0 kcal/mol difference is substantial and can outweigh some ADME drawbacks.

**Overall Assessment:**

Ligand B has a superior binding affinity, which is paramount for GPCR targets. While its BBB penetration is lower than Ligand A, the difference in affinity is significant. Ligand A has better DILI and metabolic stability, but the stronger binding of Ligand B is likely to be more impactful. The poor solubility of both compounds is a concern, but can potentially be addressed through formulation strategies. The slightly better logP of Ligand B also favors its permeability.

Output:
1
2025-04-17 06:11:22,556 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (351.793 and 345.487 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (62.3) is excellent, well below the 90 A^2 threshold for CNS targets. Ligand B (67.15) is still reasonable but less optimal.

**logP:** Both ligands (3.369 and 3.591) are within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A (1 HBD, 3 HBA) and Ligand B (2 HBD, 4 HBA) both meet the criteria of <=5 HBD and <=10 HBA.

**QED:** Both ligands have good QED scores (0.684 and 0.856), indicating good drug-like properties.

**DILI:** Ligand A has a concerning DILI risk (87.631 percentile), suggesting potential liver toxicity. Ligand B has a much lower and acceptable DILI risk (23.769 percentile).

**BBB:** Ligand A has a very good BBB penetration score (76.735 percentile), crucial for a CNS target. Ligand B's BBB penetration (38.542 percentile) is significantly lower and less desirable.

**Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and likely indicates a data error or a very poor permeability. However, since we are comparing them, the relative difference is important. Ligand A (-4.682) is better than Ligand B (-5.327).

**Aqueous Solubility:** Ligand A (-5.489) is lower than Ligand B (-2.721), suggesting Ligand B might have better solubility.

**hERG:** Both ligands have very low hERG inhibition liability (0.49 and 0.118), which is excellent.

**Microsomal Clearance:** Ligand A (45.29 mL/min/kg) is better than Ligand B (-18.601 mL/min/kg) indicating better metabolic stability. Note the negative value for Ligand B is unusual and might indicate an error.

**In vitro Half-Life:** Ligand A (54.125 hours) has a significantly longer half-life than Ligand B (15.879 hours), which is a major advantage.

**P-gp Efflux:** Ligand A (0.319) has lower P-gp efflux than Ligand B (0.057), which is favorable for CNS penetration.

**Binding Affinity:** Both ligands have excellent binding affinities (-10.9 kcal/mol and -9.0 kcal/mol). Ligand A is slightly better, but the difference is not massive.

**Overall Assessment:**

Ligand A excels in BBB penetration, metabolic stability, half-life, and P-gp efflux, all critical for a CNS GPCR target. However, its high DILI risk is a major concern. Ligand B has a better solubility profile and a much lower DILI risk, but suffers from poorer BBB penetration, lower metabolic stability, and a shorter half-life.

Given the importance of CNS penetration for DRD2 and the significant difference in DILI risk, I would prioritize mitigating the DILI risk of Ligand A through structural modifications. The superior BBB, half-life, and P-gp properties of Ligand A are more easily optimized than fundamentally improving Ligand B's CNS penetration.

Output:
0
2025-04-17 06:11:22,556 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (347.459 and 344.463 Da) fall comfortably within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (69.72) and Ligand B (68.1) are both below the 90 A^2 threshold for CNS targets, which is excellent.

**3. logP:** Ligand A (1.174) is within the optimal 1-3 range. Ligand B (2.433) is also within the optimal range, but slightly higher.

**4. H-Bond Donors:** Both ligands have 1 HBD, which is acceptable.

**5. H-Bond Acceptors:** Ligand A has 3 HBA, and Ligand B has 7 HBA. Both are below the 10 threshold, but Ligand A is preferable.

**6. QED:** Both ligands have similar QED values (0.779 and 0.793), indicating good drug-likeness.

**7. DILI:** Ligand A (21.442) has a significantly lower DILI risk than Ligand B (36.332). This is a substantial advantage.

**8. BBB:** Ligand B (74.176) has a better BBB penetration percentile than Ligand A (63.629). This is a key factor for CNS targets.

**9. Caco-2 Permeability:** Ligand A (-4.974) has a worse Caco-2 permeability than Ligand B (-5.165). Both are negative, indicating poor permeability.

**10. Aqueous Solubility:** Ligand A (-1.828) has better aqueous solubility than Ligand B (-2.532).

**11. hERG Inhibition:** Both ligands have low hERG inhibition risk (0.1 and 0.467 respectively).

**12. Microsomal Clearance:** Ligand B (30.159) has lower microsomal clearance than Ligand A (33.043), suggesting better metabolic stability.

**13. In vitro Half-Life:** Ligand B (25.399) has a significantly longer in vitro half-life than Ligand A (7.678). This is a significant advantage.

**14. P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.039 and 0.129 respectively).

**15. Binding Affinity:** Ligand B (-7.5 kcal/mol) has a substantially stronger binding affinity than Ligand A (-0.0 kcal/mol). This is a *major* advantage, potentially outweighing some ADME concerns.

**Overall Assessment:**

While Ligand A has a lower DILI risk and better solubility, Ligand B's significantly stronger binding affinity (-7.5 vs -0.0 kcal/mol) and better BBB penetration (74.176 vs 63.629) are critical for a CNS GPCR target like DRD2. The longer half-life of Ligand B is also a plus. The slightly higher logP and DILI risk of Ligand B are acceptable given the substantial improvement in binding and BBB. The Caco-2 permeability is similar for both.

Output:
1
2025-04-17 06:11:22,556 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B based on the provided guidelines, prioritizing GPCR-specific properties (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (342.399 Da) is slightly lower, which could be beneficial for permeability, but both are acceptable.

**TPSA:** Ligand A (83.87) is excellent for CNS penetration, well below the 90 A^2 threshold. Ligand B (58.2) is even better.

**logP:** Both ligands have good logP values (A: 2.95, B: 3.769), falling within the optimal 1-3 range. Ligand B is slightly higher, which might slightly increase off-target interactions, but is still acceptable.

**H-Bond Donors/Acceptors:** Ligand A (HBD=1, HBA=6) and Ligand B (HBD=2, HBA=4) both have reasonable H-bond counts, well within the guidelines.

**QED:** Both ligands have acceptable QED values (A: 0.767, B: 0.673), indicating good drug-like properties.

**DILI:** Both ligands have similar and acceptable DILI risk (A: 51.028, B: 47.266), below the 60 threshold.

**BBB:** This is a crucial parameter for a CNS target like DRD2. Ligand B (71.811) has a significantly better BBB percentile than Ligand A (46.026). This is a major advantage for Ligand B.

**Caco-2 Permeability:** Both have negative values, which is unusual. Assuming these are logP-scale values, lower values indicate poorer permeability. Ligand A (-4.976) is slightly better than Ligand B (-5.044), but both are poor.

**Aqueous Solubility:** Both have negative values, which is unusual. Assuming these are logS values, lower values indicate poorer solubility. Ligand A (-2.984) is slightly better than Ligand B (-4.791).

**hERG Inhibition:** Both ligands show low hERG inhibition risk (A: 0.214, B: 0.683).

**Microsomal Clearance:** Ligand A (48.348) has lower clearance than Ligand B (89.83), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (1.037 hours) has a shorter half-life than Ligand B (37.619 hours). This is a significant advantage for Ligand B.

**P-gp Efflux:** Ligand A (0.033) has much lower P-gp efflux liability than Ligand B (0.395), which is favorable for CNS exposure.

**Binding Affinity:** Ligand B (-7.9 kcal/mol) has a slightly better binding affinity than Ligand A (-8.5 kcal/mol). While the difference is small, it's still a positive for Ligand B.

**Overall Assessment:**

Ligand B clearly emerges as the more promising candidate. Its significantly better BBB penetration (71.811 vs 46.026) and substantially longer half-life (37.619 vs 1.037) are critical advantages for a CNS-targeting drug. While Ligand A has slightly better P-gp efflux and microsomal clearance, the benefits of improved CNS exposure and duration of action with Ligand B outweigh these minor drawbacks. The slight affinity difference also favors Ligand B.



Output:
1
2025-04-17 06:11:22,556 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (343.43 & 353.46 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (70.67) is significantly better than Ligand B (87.74). For CNS targets, we want TPSA <= 90, and A is closer to the ideal <= 60 range. B is pushing the upper limit.

**3. logP:** Both ligands have acceptable logP values (1.93 & 0.83), falling within the 1-3 range. Ligand A is slightly better.

**4. H-Bond Donors:** Both have 2 HBD, which is within the acceptable limit of <= 5.

**5. H-Bond Acceptors:** Ligand A has 3 HBA, and Ligand B has 4. Both are within the acceptable limit of <= 10.

**6. QED:** Both ligands have reasonable QED scores (0.776 & 0.643), indicating good drug-like properties.

**7. DILI:** Ligand A (43.62) has a slightly higher DILI risk than Ligand B (16.67), but both are below the concerning threshold of 60.

**8. BBB:** Both ligands have good BBB penetration (67.51% & 69.68%), exceeding the desirable 70% for CNS targets. B is slightly better.

**9. Caco-2:** Both have negative Caco-2 values (-4.56 & -4.82), which is unusual and difficult to interpret. It suggests poor permeability.

**10. Solubility:** Both have negative solubility values (-1.88 & -1.31), indicating very poor aqueous solubility. This is a significant concern.

**11. hERG:** Both ligands have very low hERG inhibition risk (0.33 & 0.12).

**12. Cl_mic:** Ligand A (-3.33) has much lower (better) microsomal clearance than Ligand B (34.67). This indicates better metabolic stability for Ligand A.

**13. t1/2:** Ligand A (9.38 hours) has a significantly longer half-life than Ligand B (2.38 hours).

**14. Pgp:** Both ligands have very low Pgp efflux liability (0.07 & 0.01).

**15. Binding Affinity:** Ligand A (-7.5 kcal/mol) has a slightly better binding affinity than Ligand B (-7.3 kcal/mol). While the difference is small, it's within the range where it could outweigh some ADME drawbacks.

**Overall Assessment:**

Ligand A is the more promising candidate. While both have poor solubility and Caco-2 permeability, Ligand A excels in key areas: lower TPSA, better metabolic stability (lower Cl_mic, longer t1/2), and slightly better binding affinity. The slightly higher DILI risk is less concerning than the metabolic liabilities of Ligand B. Given the GPCR target and the need for CNS penetration, the better TPSA and metabolic profile of Ligand A are crucial.

Output:
1
2025-04-17 06:11:22,557 - INFO - Reasoning:

Let's analyze Ligand A and Ligand B for their potential as DRD2 drug candidates, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (349.475 & 342.443 Da) fall comfortably within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (74.57) is significantly better than Ligand B (97.11). For CNS targets, we want TPSA <= 90, so Ligand A is preferable.

**3. logP:** Both ligands (2.026 & 2.118) are within the optimal 1-3 range.

**4. H-Bond Donors:** Ligand A (2) and Ligand B (3) are both acceptable, being <= 5.

**5. H-Bond Acceptors:** Both ligands (4) are well below the 10 threshold.

**6. QED:** Ligand A (0.791) is better than Ligand B (0.661), indicating a more drug-like profile.

**7. DILI:** Ligand A (36.642) has a lower DILI risk than Ligand B (46.297), both are good, but A is better.

**8. BBB:** This is *critical* for a CNS target like DRD2. Ligand B (73.905) is significantly better than Ligand A (35.052), exceeding the desirable >70 threshold.

**9. Caco-2 Permeability:** Ligand A (-4.747) and Ligand B (-5.248) are both negative, indicating poor permeability. This is a concern for both, but the values are similar.

**10. Aqueous Solubility:** Both ligands (-2.569 & -2.772) have poor aqueous solubility. This could pose formulation challenges.

**11. hERG Inhibition:** Both ligands (0.398 & 0.144) have low hERG inhibition risk, which is good.

**12. Microsomal Clearance:** Ligand B (15.6) has significantly lower microsomal clearance than Ligand A (42.384), suggesting better metabolic stability.

**13. In vitro Half-Life:** Ligand B (-11.919) has a negative half-life, which is concerning. Ligand A (19.493) is much better.

**14. P-gp Efflux:** Ligand A (0.206) has lower P-gp efflux than Ligand B (0.031), which is preferable for CNS penetration.

**15. Binding Affinity:** Both ligands have strong binding affinities (-8.1 & -8.4 kcal/mol). The difference is minimal.

**Overall Assessment:**

Ligand B excels in BBB penetration and metabolic stability (lower Cl_mic). However, it has a concerning negative in vitro half-life. Ligand A has a better TPSA, QED, DILI, P-gp efflux, and a reasonable half-life. While both have poor solubility and Caco-2 permeability, the superior BBB penetration of Ligand B is a major advantage for a CNS target. Given the importance of CNS penetration for DRD2, and the relatively minor difference in affinity, Ligand B is the more promising candidate despite its metabolic liability.

Output:
1
2025-04-17 06:11:22,557 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (350.503 and 349.431 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (69.64) is better than Ligand B (75.88). Both are below the 90 A^2 threshold for CNS targets, but A is closer to the ideal range.

**3. logP:** Both ligands have good logP values (2.33 and 1.582), falling within the optimal 1-3 range. Ligand A is slightly higher, which could be beneficial for membrane permeability.

**4. H-Bond Donors:** Ligand A (2) is reasonable, while Ligand B (0) is also acceptable.

**5. H-Bond Acceptors:** Ligand A (3) is good, and Ligand B (5) is also within the acceptable limit of 10.

**6. QED:** Ligand B (0.828) has a significantly better QED score than Ligand A (0.547), indicating a more drug-like profile.

**7. DILI:** Ligand B (42.885) has a lower DILI risk than Ligand A (14.114), which is a significant advantage.

**8. BBB:** Ligand B (75.688) has a much higher BBB penetration percentile than Ligand A (45.832). This is *critical* for a CNS target like DRD2.

**9. Caco-2 Permeability:** Ligand A (-4.702) has better Caco-2 permeability than Ligand B (-4.416), although both are negative values and need further investigation.

**10. Aqueous Solubility:** Ligand A (-2.45) has slightly better solubility than Ligand B (-1.06), but both are low and could pose formulation challenges.

**11. hERG Inhibition:** Both ligands have low hERG inhibition risk (0.462 and 0.316).

**12. Microsomal Clearance:** Ligand B (31.845) has lower microsomal clearance than Ligand A (34.29), suggesting better metabolic stability.

**13. In vitro Half-Life:** Ligand B (-25.059) has a significantly longer in vitro half-life than Ligand A (-15.637).

**14. P-gp Efflux:** Ligand A (0.269) has lower P-gp efflux than Ligand B (0.141), which is favorable for CNS exposure.

**15. Binding Affinity:** Ligand B (-8.3 kcal/mol) has a stronger binding affinity than Ligand A (-7.3 kcal/mol). This 1 kcal/mol difference is substantial and can outweigh minor ADME drawbacks.

**Overall Assessment:**

While Ligand A has slightly better Caco-2 permeability and P-gp efflux, Ligand B is superior in almost every other crucial parameter for a CNS-targeting GPCR ligand. Specifically, its significantly better BBB penetration, lower DILI risk, longer half-life, stronger binding affinity, and higher QED score make it the more promising candidate. The improved metabolic stability (lower Cl_mic) is also a significant benefit.

Output:
1
2025-04-17 06:11:22,557 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands fall within the ideal range (200-500 Da). Ligand A (383.809 Da) is slightly higher than Ligand B (338.338 Da), but both are acceptable.

**TPSA:** Ligand A (109.77) is higher than the preferred <90 for CNS targets, while Ligand B (62.55) is well within the range. This is a significant advantage for Ligand B.

**logP:** Both ligands have good logP values (A: 2.555, B: 3.686), falling within the optimal 1-3 range. Ligand B is slightly higher, which could potentially be a minor concern for solubility, but is still acceptable.

**H-Bond Donors/Acceptors:** Ligand A has 2 HBD and 5 HBA, while Ligand B has 1 HBD and 3 HBA. Both are within acceptable limits (<=5 HBD and <=10 HBA).

**QED:** Both ligands have similar and good QED values (A: 0.742, B: 0.775), indicating good drug-like properties.

**DILI:** Both ligands have high DILI scores (A: 98.953, B: 90.151), indicating potential liver toxicity risk. This is a concern for both, but Ligand B is slightly better.

**BBB:** Ligand B (87.088) has a significantly better BBB penetration percentile than Ligand A (15.083). This is *critical* for a CNS target like DRD2.

**Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and suggests poor permeability. Ligand A (-5.248) is slightly better than Ligand B (-4.518).

**Aqueous Solubility:** Both ligands have very poor aqueous solubility (-3.954 and -4.731 respectively). This is a significant drawback for both.

**hERG Inhibition:** Ligand A (0.037) shows very low hERG inhibition risk, which is excellent. Ligand B (0.786) has a higher, though still relatively low, hERG risk.

**Microsomal Clearance:** Ligand A (2.734) has a lower (better) microsomal clearance than Ligand B (52.284), indicating better metabolic stability.

**In vitro Half-Life:** Ligand B (81.517) has a much longer in vitro half-life than Ligand A (28.114). This is a significant advantage for Ligand B.

**P-gp Efflux:** Ligand A (0.057) has very low P-gp efflux liability, which is favorable for CNS penetration. Ligand B (0.562) has a higher, but still acceptable, P-gp efflux.

**Binding Affinity:** Ligand B (-10.3 kcal/mol) has a significantly stronger binding affinity than Ligand A (-8.2 kcal/mol). This is a substantial advantage, potentially outweighing some of the ADME drawbacks.

**Overall:**

While both ligands have issues with solubility and DILI risk, Ligand B is the stronger candidate. Its superior BBB penetration, significantly better binding affinity, and longer half-life are crucial advantages for a CNS GPCR target. The slightly higher logP and P-gp efflux are manageable, and the better BBB penetration will likely offset these. Ligand A's low P-gp efflux and hERG risk are good, but its poor BBB penetration and weaker affinity are major drawbacks.

Output:
1
2025-04-17 06:11:22,557 - INFO - Reasoning:

Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (351.387 and 346.471 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (95.13) is higher than the preferred <90 for CNS targets, while Ligand B (58.64) is well within the range. This favors Ligand B.

**logP:** Ligand A (4.026) is at the upper end of the optimal range (1-3), potentially leading to solubility issues. Ligand B (2.265) is well within the optimal range. This favors Ligand B.

**H-Bond Donors/Acceptors:** Ligand A has 2 HBD and 5 HBA, which are acceptable. Ligand B has 1 HBD and 3 HBA, also acceptable. No clear advantage here.

**QED:** Both ligands have good QED scores (0.742 and 0.777), indicating good drug-like properties.

**DILI:** Ligand A has a high DILI risk (93.951 percentile), which is a significant concern. Ligand B has a very low DILI risk (14.308 percentile), a major advantage.

**BBB:** Ligand A has a low BBB penetration (27.724 percentile), which is problematic for a CNS target. Ligand B has a much better BBB penetration (62.854 percentile). This strongly favors Ligand B.

**Caco-2 Permeability:** Both have negative Caco-2 values (-4.987 and -4.761). These values are unusual and difficult to interpret without further context, but they suggest poor permeability.

**Aqueous Solubility:** Both ligands have very poor aqueous solubility (-5.961 and -2.601). This is a concern, but potentially manageable with formulation strategies.

**hERG Inhibition:** Ligand A (0.613) has a slightly higher hERG risk than Ligand B (0.145), favoring Ligand B.

**Microsomal Clearance:** Both have similar microsomal clearance values (37.87 and 38.899 mL/min/kg), indicating comparable metabolic stability.

**In vitro Half-Life:** Ligand A has a longer half-life (132.066 hours) than Ligand B (9.298 hours). This is a potential advantage for Ligand A, but less important than the other factors.

**P-gp Efflux:** Ligand A (0.423) has lower P-gp efflux than Ligand B (0.031), which is better for CNS exposure. This favors Ligand A.

**Binding Affinity:** Ligand B (-9.4 kcal/mol) has a significantly stronger binding affinity than Ligand A (-8.7 kcal/mol). This is a substantial advantage, potentially outweighing some of the ADME drawbacks.

**Overall Assessment:**

Ligand B is significantly better overall. It has a much lower DILI risk, better BBB penetration, a more favorable logP, lower hERG risk, and significantly stronger binding affinity. While both have poor solubility and Caco-2 permeability, the advantages of Ligand B outweigh the benefits of Ligand A's longer half-life and lower P-gp efflux. The strong binding affinity of Ligand B is a key factor.

Output:
1
2025-04-17 06:11:22,557 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (345.49 & 351.54 Da) fall comfortably within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (43.86) is significantly better than Ligand B (61.44). For CNS targets, we want TPSA <= 90, and ideally closer to 60. Ligand A is much closer to this ideal.

**3. logP:** Both ligands have acceptable logP values (1.58 & 2.84), falling within the 1-3 range. Ligand B is slightly higher, which could potentially lead to some solubility issues, but is still within an acceptable range.

**4. H-Bond Donors:** Ligand A (0) is preferable to Ligand B (2). Fewer HBDs generally improve permeability.

**5. H-Bond Acceptors:** Both ligands have 3 HBA, which is acceptable.

**6. QED:** Both ligands have similar QED values (0.763 & 0.741), indicating good drug-like properties.

**7. DILI:** Ligand A (6.28) has a much lower DILI risk than Ligand B (9.15), which is a significant advantage.

**8. BBB:** Ligand A (72.74) has a better BBB percentile than Ligand B (66.89). While both are above 60, exceeding 70 is desirable for CNS targets, and A is closer.

**9. Caco-2:** Ligand A (-4.692) has a slightly better (less negative) Caco-2 permeability than Ligand B (-5.03), suggesting slightly better absorption.

**10. Solubility:** Ligand A (-2.579) has better solubility than Ligand B (-2.265).

**11. hERG:** Both ligands have very low hERG inhibition liability (0.477 & 0.48).

**12. Cl_mic:** Ligand B (3.58) has a significantly lower (better) microsomal clearance than Ligand A (33.84). This suggests better metabolic stability for Ligand B.

**13. t1/2:** Ligand A (14.90) has a longer in vitro half-life than Ligand B (-10.01). This is a positive attribute.

**14. Pgp:** Both ligands have very low P-gp efflux liability (0.013 & 0.065).

**15. Binding Affinity:** Ligand A (-7.5) has a slightly better binding affinity than Ligand B (-8.2). While both are excellent, the difference is not substantial enough to outweigh other factors.

**Overall Assessment:**

Ligand A is the better candidate. It excels in key properties for CNS penetration (lower TPSA, better BBB, better solubility) and has a significantly lower DILI risk. While Ligand B has better metabolic stability (lower Cl_mic), the advantages of Ligand A in terms of CNS penetration and safety are more critical for a DRD2 ligand targeting CNS disorders. The slightly better half-life of Ligand A is also a plus.

Output:
1
2025-04-17 06:11:22,558 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (343.383 and 361.467 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (84.67) is better than Ligand B (87.3). Both are below the 90 A^2 threshold for CNS targets, which is good.

**3. logP:** Both ligands have similar logP values (1.77 and 1.696), falling within the optimal 1-3 range.

**4. H-Bond Donors:** Ligand A (1) is preferable to Ligand B (3). Fewer HBDs generally improve permeability.

**5. H-Bond Acceptors:** Ligand A (5) is preferable to Ligand B (4). Fewer HBAs generally improve permeability.

**6. QED:** Ligand A (0.894) has a significantly better QED score than Ligand B (0.646), indicating a more drug-like profile.

**7. DILI:** Ligand A (44.126) has a lower DILI risk than Ligand B (56.495), both are acceptable but A is better.

**8. BBB:** Ligand B (57.193) has a slightly better BBB penetration percentile than Ligand A (41.528). However, both are below the desirable >70% for CNS targets.

**9. Caco-2 Permeability:** Ligand A (-4.574) has better Caco-2 permeability than Ligand B (-5.564).

**10. Aqueous Solubility:** Ligand A (-2.705) has better aqueous solubility than Ligand B (-3.001).

**11. hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.234 and 0.101).

**12. Microsomal Clearance:** Ligand A (16.8) has lower microsomal clearance than Ligand B (24.138), suggesting better metabolic stability.

**13. In vitro Half-Life:** Ligand A (3.503) has a longer in vitro half-life than Ligand B (-3.238).

**14. P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.029 and 0.059).

**15. Binding Affinity:** Both ligands have very similar binding affinities (-8.5 and -8.3 kcal/mol). The difference is negligible.

**Overall Assessment:**

Ligand A is superior to Ligand B based on a more favorable balance of properties. It has a better QED score, lower DILI risk, better Caco-2 permeability, better aqueous solubility, lower microsomal clearance, and a longer in vitro half-life. While Ligand B has slightly better BBB penetration, the overall profile of Ligand A is more promising for development as a CNS-active drug targeting DRD2.

Output:
1
2025-04-17 06:11:22,558 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (356.813 and 352.356 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (64.16) is slightly higher than Ligand B (51.22). For a CNS target like DRD2, we ideally want TPSA <= 90, both are within this range, but B is better.

**3. logP:** Both ligands have good logP values (3.452 and 3.887), falling within the optimal 1-3 range. Ligand B is slightly higher, which *could* be a minor negative if it impacts solubility, but is generally acceptable.

**4. H-Bond Donors:** Ligand A (0) has fewer HBDs than Ligand B (1). Lower is generally preferred for BBB penetration.

**5. H-Bond Acceptors:** Ligand A (5) has more HBAs than Ligand B (4). Both are within the acceptable limit of <=10, but B is slightly better.

**6. QED:** Both ligands have good QED scores (0.721 and 0.802) indicating good drug-like properties. Ligand B is slightly better.

**7. DILI:** Ligand A (84.219) has a higher DILI risk than Ligand B (52.772). This is a significant negative for Ligand A.

**8. BBB:** Ligand B (73.672) has a better BBB percentile than Ligand A (68.166). Both are reasonably good, but B is preferable for a CNS target.

**9. Caco-2:** Both have negative Caco-2 values, which is unusual and suggests a potential issue with permeability prediction. However, the values are close enough to not be a major differentiator.

**10. Solubility:** Both have negative solubility values, which is also unusual. Again, the values are close and not a major differentiator.

**11. hERG:** Both ligands have low hERG inhibition liability (0.33 and 0.689), which is good.

**12. Cl_mic:** Ligand A (46.255) has lower microsomal clearance than Ligand B (84.995), suggesting better metabolic stability. This is a positive for Ligand A.

**13. t1/2:** Ligand B (10.939) has a longer in vitro half-life than Ligand A (7.509), which is generally desirable.

**14. Pgp:** Both ligands have very low Pgp efflux liability (0.277 and 0.244), which is excellent for CNS penetration.

**15. Binding Affinity:** Both ligands have excellent binding affinities (-9.7 and -9.2 kcal/mol). Ligand A has a slightly better affinity.

**Overall Assessment:**

While Ligand A has a slightly better binding affinity and metabolic stability, Ligand B is superior in several key areas for a CNS-targeting GPCR: lower DILI risk, better BBB penetration, slightly better QED, and a longer half-life. The differences in TPSA and H-bonds also favor Ligand B. The slightly better affinity of Ligand A is unlikely to overcome the more significant advantages of Ligand B regarding safety (DILI) and CNS penetration (BBB).

Output:
1
2025-04-17 06:11:22,558 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (366.53 and 369.55 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (58.64) is slightly higher than the ideal <90 for CNS targets, but still reasonable. Ligand B (40.54) is excellent, well below 90.

**3. logP:** Ligand A (2.22) is within the optimal 1-3 range. Ligand B (4.63) is a bit high, potentially leading to solubility issues and off-target interactions, but not drastically so.

**4. H-Bond Donors:** Both ligands have 1 HBD, which is acceptable (<=5).

**5. H-Bond Acceptors:** Ligand A has 4 HBAs, and Ligand B has 3, both within the acceptable limit of <=10.

**6. QED:** Ligand A (0.783) has a better QED score than Ligand B (0.689), indicating a more drug-like profile.

**7. DILI:** Ligand A (32.18) has a slightly higher DILI risk than Ligand B (21.83), but both are below the 40 threshold and considered good.

**8. BBB:** Ligand B (91.39) has a significantly better BBB penetration percentile than Ligand A (74.25). This is a crucial advantage for a CNS target like DRD2.

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 values, which is unusual and suggests poor permeability. However, the scale is not specified, so it's difficult to interpret.

**10. Aqueous Solubility:** Both ligands have negative solubility values, indicating poor aqueous solubility. This is a concern, but can be addressed with formulation strategies.

**11. hERG Inhibition:** Ligand A (0.465) has a lower hERG inhibition liability than Ligand B (0.847), which is preferable.

**12. Microsomal Clearance:** Ligand B (70.50) has a higher microsomal clearance than Ligand A (51.81), suggesting lower metabolic stability.

**13. In vitro Half-Life:** Ligand A (4.73) has a shorter half-life than Ligand B (33.51), which is less desirable.

**14. P-gp Efflux:** Ligand A (0.137) has a lower P-gp efflux liability than Ligand B (0.903), which is better for CNS exposure.

**15. Binding Affinity:** Ligand A (-7.9 kcal/mol) has a slightly better binding affinity than Ligand B (-7.1 kcal/mol). This is a significant advantage.

**Overall Assessment:**

While Ligand A has better affinity, QED, hERG, and P-gp properties, Ligand B's superior BBB penetration is a critical factor for a CNS target like DRD2. The higher half-life of Ligand B is also a benefit. The slightly higher logP of Ligand B is a concern, but the difference isn't extreme. Considering the GPCR-specific priorities, the improved BBB penetration of Ligand B outweighs the slightly better affinity of Ligand A.

Output:
1
2025-04-17 06:11:22,558 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (351.407 and 364.555 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (120.58) is better than Ligand B (49.41). For CNS targets, we want TPSA <= 90, so Ligand B is significantly better.

**logP:** Ligand A (-1.072) is a bit low, potentially hindering permeability. Ligand B (3.228) is within the optimal 1-3 range. This favors Ligand B.

**H-Bond Donors/Acceptors:** Ligand A has 3 HBD and 7 HBA, while Ligand B has 1 HBD and 3 HBA. Both are within acceptable limits (<=5 HBD and <=10 HBA).

**QED:** Both ligands have good QED scores (0.575 and 0.736), indicating good drug-like properties.

**DILI:** Ligand A (33.812) has a slightly higher DILI risk than Ligand B (19.465), but both are below the concerning threshold of 60.

**BBB:** Ligand B (71.966) has a significantly better BBB penetration score than Ligand A (51.803). For a CNS target like DRD2, >70 is desirable, and Ligand B is closer to that target.

**Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and difficult to interpret without knowing the scale. However, the values are similar.

**Aqueous Solubility:** Both have negative solubility values, which is also unusual. Again, the values are similar.

**hERG:** Both ligands have very low hERG inhibition liability (0.122 and 0.385), which is excellent.

**Microsomal Clearance:** Ligand A (0.321) has much lower microsomal clearance than Ligand B (72.271), suggesting better metabolic stability. This is a significant advantage for Ligand A.

**In vitro Half-Life:** Ligand A (-7.491) has a much longer in vitro half-life than Ligand B (-15.615). This is a strong positive for Ligand A.

**P-gp Efflux:** Ligand A (0.006) has much lower P-gp efflux liability than Ligand B (0.177), which is beneficial for CNS penetration.

**Binding Affinity:** Both ligands have excellent binding affinity (-7.9 kcal/mol). The difference is negligible.

**Overall Assessment:**

Ligand B excels in TPSA and BBB penetration, crucial for CNS GPCR targets. However, Ligand A demonstrates superior metabolic stability (lower Cl_mic), longer half-life, and lower P-gp efflux, all of which are highly desirable for CNS drug candidates. The slightly lower logP of Ligand A is a concern, but the other ADME properties and comparable affinity outweigh this drawback. Given the importance of CNS penetration and metabolic stability for DRD2 targeting, Ligand A is the more promising candidate.

Output:
0
2025-04-17 06:11:22,558 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (339.395 and 348.334 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (66.24) is excellent, well below the 90 A^2 threshold for CNS targets. Ligand B (124.18) is higher, but still potentially acceptable, though less ideal.

**3. logP:** Ligand A (3.034) is optimal. Ligand B (0.439) is quite low, potentially hindering membrane permeability and CNS penetration.

**4. H-Bond Donors:** Ligand A (0) is good. Ligand B (4) is acceptable.

**5. H-Bond Acceptors:** Ligand A (6) is good. Ligand B (5) is good.

**6. QED:** Both ligands (0.646 and 0.603) have good drug-likeness scores.

**7. DILI:** Both ligands have acceptable DILI risk (72.043 and 64.288).

**8. BBB:** This is critical for a CNS target. Ligand A (68.67) is reasonably good, while Ligand B (33.036) is poor, suggesting limited brain penetration.

**9. Caco-2 Permeability:** Ligand A (-4.641) is concerningly low, indicating poor intestinal absorption. Ligand B (-5.529) is also low, but slightly worse.

**10. Aqueous Solubility:** Both are very poor (-3.786 and -3.072). This could pose formulation challenges.

**11. hERG Inhibition:** Both ligands have low hERG risk (0.402 and 0.304).

**12. Microsomal Clearance:** Ligand A (101.895) is moderate, while Ligand B (22.771) is low, indicating better metabolic stability.

**13. In vitro Half-Life:** Ligand A (8.093) is reasonable, but Ligand B (-35.578) is extremely poor, suggesting rapid metabolism.

**14. P-gp Efflux:** Both have low P-gp efflux (0.676 and 0.021), which is favorable for CNS penetration.

**15. Binding Affinity:** Both ligands have very similar and excellent binding affinities (-8.6 and -8.4 kcal/mol). The difference is not substantial enough to override other factors.

**Overall Assessment:**

Ligand A is preferable despite the poor Caco-2 permeability. Its superior logP and BBB penetration are crucial for a CNS-targeting GPCR like DRD2. While solubility is a concern for both, the better predicted brain exposure with Ligand A outweighs the slightly better metabolic stability of Ligand B. The very poor half-life of Ligand B is a significant drawback.

Output:
1
2025-04-17 06:11:22,559 - INFO - Batch 261 complete. Total preferences: 4176
2025-04-17 06:11:22,559 - INFO - Processing batch 262/512...
2025-04-17 06:12:05,637 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (352.431 and 348.531 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (88.1) is excellent for CNS penetration, being well below 90. Ligand B (40.62) is also very good.

**logP:** Ligand A (0.085) is quite low, potentially hindering membrane permeability. Ligand B (3.987) is closer to the optimal 1-3 range.

**H-Bond Donors:** Ligand A (2) is acceptable. Ligand B (0) is also acceptable.

**H-Bond Acceptors:** Ligand A (5) is acceptable. Ligand B (2) is also acceptable.

**QED:** Both ligands have good QED scores (0.634 and 0.754, respectively), indicating drug-like properties.

**DILI:** Ligand A (15.743) has a much lower DILI risk than Ligand B (31.563), which is a significant advantage.

**BBB:** Ligand B (90.733) has a significantly higher BBB penetration percentile than Ligand A (68.282). This is a crucial factor for a CNS target like DRD2.

**Caco-2 Permeability:** Ligand A (-4.819) has poor Caco-2 permeability, likely due to its low logP. Ligand B (-4.588) is also poor, but slightly better than A.

**Aqueous Solubility:** Ligand A (-1.275) and Ligand B (-3.5) both have poor solubility.

**hERG Inhibition:** Ligand A (0.213) has a lower hERG inhibition risk than Ligand B (0.733).

**Microsomal Clearance:** Ligand B (89.977) has a much higher microsomal clearance than Ligand A (26.154), indicating lower metabolic stability.

**In vitro Half-Life:** Ligand A (-1.37) has a slightly better (less negative) in vitro half-life than Ligand B (-19.952).

**P-gp Efflux:** Ligand A (0.021) has very low P-gp efflux, which is favorable for CNS penetration. Ligand B (0.554) has moderate P-gp efflux.

**Binding Affinity:** Both ligands have the same binding affinity (-7.8 kcal/mol), which is excellent.

**Overall Assessment:**

Ligand B excels in BBB penetration, a critical factor for DRD2. However, it suffers from higher DILI risk, higher microsomal clearance (lower metabolic stability), and moderate P-gp efflux. Ligand A has a much better safety profile (lower DILI, lower hERG), better metabolic stability, and lower P-gp efflux, but its low logP and poor Caco-2 permeability are concerning.

Given the equal binding affinity, the balance tips towards Ligand A due to its superior safety and pharmacokinetic properties, especially the lower DILI and P-gp efflux. While the low logP is a drawback, it might be addressable through structural modifications without significantly impacting binding. The improved metabolic stability is also a significant advantage.

Output:
1
2025-04-17 06:12:05,637 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (351.378 Da and 359.535 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (86.79) is excellent, being below the 90 A^2 threshold for CNS targets. Ligand B (29.54) is even better, indicating potentially improved brain penetration.

**logP:** Ligand A (-0.213) is a bit low, potentially hindering membrane permeability. Ligand B (4.284) is high, potentially leading to solubility issues and off-target interactions.

**H-Bond Donors/Acceptors:** Ligand A (1 HBD, 4 HBA) is good. Ligand B (0 HBD, 3 HBA) is also favorable.

**QED:** Both ligands have acceptable QED values (0.746 and 0.681, respectively), suggesting reasonable drug-likeness.

**DILI:** Both ligands have low DILI risk (38.348 and 26.638 percentiles), which is positive.

**BBB:** Ligand A (68.282) is borderline for good CNS penetration. Ligand B (83.831) is excellent, exceeding the 70% threshold. This is a significant advantage for a DRD2 ligand.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.769 and -5.172), which is unusual and problematic. These values likely indicate poor permeability.

**Aqueous Solubility:** Both ligands have negative solubility values (-2.447 and -4.863), indicating very poor aqueous solubility. This is a major concern.

**hERG Inhibition:** Both ligands have low hERG risk (0.064 and 0.767), which is good.

**Microsomal Clearance:** Ligand A (13.226 mL/min/kg) has lower clearance, suggesting better metabolic stability than Ligand B (125.288 mL/min/kg).

**In vitro Half-Life:** Ligand A (-35.252 hours) has a negative half-life, which is not possible. This is a data error. Ligand B (4.025 hours) is a reasonable half-life, but could be improved.

**P-gp Efflux:** Ligand A (0.006) has very low P-gp efflux, which is excellent. Ligand B (0.736) has moderate P-gp efflux, which could limit CNS exposure.

**Binding Affinity:** Ligand B (-8.2 kcal/mol) has a slightly better binding affinity than Ligand A (-7.8 kcal/mol), but the difference is not substantial.

**Overall Assessment:**

Ligand B has a significantly better BBB score and a slightly better binding affinity. However, it has a high logP and very high microsomal clearance. Ligand A has a better logP and lower clearance, but its BBB score is marginal and its half-life is reported as a negative value, which is impossible. The poor solubility and permeability of both compounds are major drawbacks.

Despite the issues with both compounds, Ligand B's superior BBB penetration is crucial for a CNS target like DRD2. The higher logP and clearance are concerns, but might be addressable through further optimization. The negative half-life for Ligand A is a fatal flaw.

Output:
1
2025-04-17 06:12:05,637 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (349.435 and 348.491 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (100.21) is slightly above the optimal <90 for CNS targets, but still reasonable. Ligand B (68.3) is excellent, well below 90.

**logP:** Ligand A (1.321) is within the optimal 1-3 range. Ligand B (3.241) is at the higher end of optimal, but still acceptable.

**H-Bond Donors/Acceptors:** Both ligands have 2 HBD and 5-6 HBA, which are within acceptable limits.

**QED:** Both ligands have QED values above 0.6, indicating good drug-likeness.

**DILI:** Ligand A (44.513) has a slightly higher DILI risk than Ligand B (34.665), but both are below the concerning threshold of 60.

**BBB:** This is a critical parameter for CNS targets. Ligand A (47.615) has a moderate BBB penetration, while Ligand B (90.306) has *excellent* BBB penetration. This is a significant advantage for Ligand B.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values, which is unusual and suggests poor permeability. However, these values are on a different scale and may not be directly comparable.

**Aqueous Solubility:** Both ligands have negative solubility values, suggesting poor aqueous solubility.

**hERG Inhibition:** Ligand A (0.016) has very low hERG inhibition risk, which is excellent. Ligand B (0.879) has a higher, though not alarming, hERG risk.

**Microsomal Clearance:** Ligand A (-4.541) has a negative clearance, suggesting very high metabolic stability. Ligand B (75.675) has a high clearance, indicating rapid metabolism.

**In vitro Half-Life:** Ligand A (-3.882) has a negative half-life, suggesting extremely long duration of action. Ligand B (30.048) has a moderate half-life.

**P-gp Efflux:** Ligand A (0.018) has very low P-gp efflux, which is favorable for CNS penetration. Ligand B (0.306) has a slightly higher, but still acceptable, P-gp efflux.

**Binding Affinity:** Ligand B (-8.5 kcal/mol) has a significantly stronger binding affinity than Ligand A (-7.2 kcal/mol). The difference of 1.3 kcal/mol is substantial and can outweigh some ADME drawbacks.

**Overall Assessment:**

Ligand B is the superior candidate. While Ligand A has better metabolic stability and lower hERG risk, Ligand B's significantly stronger binding affinity and *excellent* BBB penetration are critical advantages for a CNS-targeting GPCR ligand. The higher logP and clearance of Ligand B are less concerning given the strong affinity and BBB penetration. The poor solubility and Caco-2 permeability are concerns for both, but can be addressed with formulation strategies.

Output:
1
2025-04-17 06:12:05,638 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (347.415 and 353.413 Da) fall within the ideal range of 200-500 Da.

**TPSA:** Ligand A (93.46) is slightly above the optimal <90 for CNS targets, but still reasonable. Ligand B (51.27) is excellent, well below 90.

**logP:** Ligand A (2.269) is within the optimal 1-3 range. Ligand B (3.718) is slightly higher, but still acceptable.

**H-Bond Donors/Acceptors:** Ligand A has 2 HBD and 5 HBA, which are acceptable. Ligand B has 0 HBD and 4 HBA, also acceptable.

**QED:** Both ligands have similar QED values (0.679 and 0.646), indicating good drug-like properties.

**DILI:** Ligand A (50.601) has a moderate DILI risk, but is still acceptable. Ligand B (26.018) has a very low DILI risk, which is a significant advantage.

**BBB:** Ligand A (73.556) has a good BBB penetration percentile. Ligand B (87.864) is even better, exceeding 80% and highly desirable for a CNS target like DRD2.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.05 and -4.639). This is unusual and suggests poor permeability. However, these values are on a log scale, and a negative value doesn't necessarily preclude development, especially if other properties are favorable.

**Aqueous Solubility:** Both ligands have negative solubility values (-2.834 and -2.556), indicating poor aqueous solubility. This could pose formulation challenges.

**hERG:** Both ligands have low hERG inhibition liability (0.543 and 0.742), which is positive.

**Microsomal Clearance:** Ligand A (37.338) has lower microsomal clearance than Ligand B (66.216), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (51.564) has a longer in vitro half-life than Ligand B (-15.124). The negative value for Ligand B is concerning and indicates very rapid metabolism.

**P-gp Efflux:** Ligand A (0.168) has lower P-gp efflux than Ligand B (0.524), which is favorable for CNS penetration.

**Binding Affinity:** Both ligands have similar binding affinities (-8.0 and -7.0 kcal/mol), both of which are excellent.

**Overall Assessment:**

Ligand B has several advantages: significantly lower DILI risk, much better BBB penetration, and lower P-gp efflux. While Ligand A has better metabolic stability (lower Cl_mic and longer t1/2), the superior CNS properties of Ligand B are more critical for a DRD2 target. The negative Caco-2 and solubility values are concerning for both, but can potentially be addressed with formulation strategies. The slightly higher logP of Ligand B is acceptable. The superior BBB penetration and lower efflux of Ligand B outweigh the slightly worse metabolic stability.

Output:
1
2025-04-17 06:12:05,638 - INFO - Reasoning:

Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (389.905 and 383.455 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (78.95) is significantly better than Ligand B (117.75). For CNS targets, we want TPSA <= 90, and A is comfortably within this range, while B exceeds it. This is a substantial advantage for A.

**3. logP:** Both ligands have acceptable logP values (1.414 and 0.961), falling within the optimal 1-3 range.

**4. H-Bond Donors:** Both have 1 HBD, which is good.

**5. H-Bond Acceptors:** Ligand A has 4 HBA, while Ligand B has 8.  While both are under the 10 limit, A is preferable.

**6. QED:** Ligand A (0.797) has a much better QED score than Ligand B (0.362), indicating a more drug-like profile.

**7. DILI:** Ligand B (88.057) has a higher DILI risk than Ligand A (58.627). Lower is better, and B is approaching a concerning level.

**8. BBB:** Ligand A (59.093) has a better BBB percentile than Ligand B (42.769). While neither is *excellent* (>70), A is significantly better, and crucial for a CNS target like DRD2.

**9. Caco-2:** Both have negative Caco-2 values which is unusual and suggests poor permeability.

**10. Solubility:** Both have negative solubility values which is unusual and suggests poor solubility.

**11. hERG:** Both ligands have very low hERG inhibition liability (0.529 and 0.059), which is excellent.

**12. Cl_mic:** Ligand B (8.595) has a lower microsomal clearance than Ligand A (25.187), suggesting better metabolic stability. This is a point in favor of B.

**13. t1/2:** Ligand B (17.902) has a longer in vitro half-life than Ligand A (-5.507). This is a significant advantage for B.

**14. Pgp:** Both have very low Pgp efflux liability (0.088 and 0.091).

**15. Binding Affinity:** Both ligands have very similar and excellent binding affinities (-7.6 and -7.7 kcal/mol). The difference is negligible.

**Overall Assessment:**

Ligand A is superior due to its significantly better TPSA, QED, and BBB penetration, and lower DILI risk. While Ligand B has better metabolic stability (lower Cl_mic) and a slightly longer half-life, the CNS penetration and overall drug-likeness of Ligand A are more critical for a DRD2 ligand. The similar binding affinities mean that the ADME properties become the deciding factor.

Output:
1
2025-04-17 06:12:05,638 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (351.359 and 379.869 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (114.04) is slightly above the preferred <90 for CNS targets, but still reasonable. Ligand B (92.18) is within the preferred range.

**logP:** Ligand A (-0.23) is quite low, potentially hindering permeability. Ligand B (2.81) is within the optimal 1-3 range. This is a significant advantage for Ligand B.

**H-Bond Donors/Acceptors:** Both ligands have 2 HBD and 5-6 HBA, which are acceptable.

**QED:** Both ligands have similar QED values (0.541 and 0.514), indicating good drug-likeness.

**DILI:** Both ligands have elevated DILI risk (68.011 and 71.539), but are not excessively high.

**BBB:** Ligand A (47.926) has a moderate BBB penetration, while Ligand B (32.765) is lower. This is a clear advantage for Ligand A, though both are below the desirable >70 for CNS targets.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.119 and -5.849), which is unusual and suggests poor permeability.

**Aqueous Solubility:** Both ligands have negative solubility values (-1.878 and -3.0), which is also unusual and suggests poor solubility.

**hERG Inhibition:** Both ligands show very low hERG inhibition risk (0.133 and 0.074).

**Microsomal Clearance:** Ligand A (49.385) has higher clearance than Ligand B (16.139), suggesting lower metabolic stability. Ligand B is preferable here.

**In vitro Half-Life:** Ligand A (-18.425) has a very short half-life, while Ligand B (-1.961) is slightly better.

**P-gp Efflux:** Both ligands show very low P-gp efflux (0.031 and 0.054), which is good for CNS penetration.

**Binding Affinity:** Ligand B (-8.1 kcal/mol) has a significantly stronger binding affinity than Ligand A (-7.0 kcal/mol), exceeding the 1.5 kcal/mol advantage threshold.

**Overall Assessment:**

Ligand B is the more promising candidate. While both have issues with Caco-2 and solubility, Ligand B has a much better logP, significantly stronger binding affinity, and lower microsomal clearance. The superior affinity and logP are particularly important for a GPCR target like DRD2. Although Ligand A has a slightly better BBB score, the other factors heavily favor Ligand B.

Output:
1
2025-04-17 06:12:05,638 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (367.471 and 346.427 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (71.97) is excellent, well below the 90 A^2 threshold for CNS targets. Ligand B (78.87) is still reasonable but less optimal.

**logP:** Ligand A (2.025) is within the optimal 1-3 range. Ligand B (0.461) is a bit low, potentially hindering membrane permeability.

**H-Bond Donors/Acceptors:** Ligand A (0 HBD, 6 HBA) is good. Ligand B (2 HBD, 4 HBA) is also acceptable.

**QED:** Both ligands have reasonable QED scores (0.814 and 0.573), indicating good drug-like properties.

**DILI:** Ligand A (57.697) has a higher DILI risk than Ligand B (29.857), but both are below the concerning threshold of 60.

**BBB:** Ligand A (71.501) has a significantly better BBB penetration percentile than Ligand B (47.809). This is a *critical* advantage for a CNS target like DRD2.

**Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and suggests a potential issue with the data or modeling. However, we'll proceed assuming these are percentile scores and higher is better.

**Aqueous Solubility:** Both have negative solubility values, again unusual.

**hERG:** Both ligands have very low hERG inhibition liability (0.401 and 0.103), which is excellent.

**Microsomal Clearance:** Ligand A (36.683) has a higher microsomal clearance than Ligand B (0.185), meaning it's likely to be metabolized more quickly. Ligand B exhibits much better metabolic stability.

**In vitro Half-Life:** Ligand B (8.679) has a much longer in vitro half-life than Ligand A (-5.036).

**P-gp Efflux:** Ligand A (0.326) has lower P-gp efflux liability than Ligand B (0.033), which is favorable for CNS penetration.

**Binding Affinity:** Ligand B (-7.6 kcal/mol) has a slightly better binding affinity than Ligand A (-7.3 kcal/mol). While the difference is small, it's still a positive.

**Overall Assessment:**

Ligand A excels in TPSA, BBB, and P-gp efflux, which are crucial for CNS GPCR targets. However, it has a higher DILI risk, faster clearance, and shorter half-life. Ligand B has better metabolic stability (lower Cl_mic, longer t1/2), lower DILI, and slightly better affinity. The biggest drawback for Ligand B is its lower BBB penetration and logP.

Considering the importance of BBB penetration for a CNS target, and the relatively small affinity difference, Ligand A is the more promising candidate. The slightly higher DILI risk and faster clearance can potentially be addressed through further optimization, but poor BBB penetration is much harder to fix.

Output:
1
2025-04-17 06:12:05,638 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (341.411 and 356.394 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (80.32) is excellent, well below the 90 target for CNS penetration. Ligand B (95.94) is still reasonable, but closer to the upper limit.

**logP:** Ligand A (1.575) is optimal. Ligand B (-0.192) is a concern; it's below 1, potentially hindering permeation.

**H-Bond Donors/Acceptors:** Both have 2 HBD and are within the acceptable range. Ligand A has 4 HBA, and Ligand B has 5 HBA, both are acceptable.

**QED:** Both ligands have QED values above 0.6, indicating good drug-likeness.

**DILI:** Ligand A (49.399) has a slightly higher DILI risk than Ligand B (31.252), but both are below the concerning threshold of 60.

**BBB:** Both ligands have very similar BBB penetration (57.154 and 57.115). While not exceeding the desirable >70, they are reasonable for a starting point.

**Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and suggests poor permeability. This is a significant concern for both.

**Aqueous Solubility:** Both ligands have very poor aqueous solubility (-2.665 and -1.091). This is a major drawback for both compounds.

**hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.48 and 0.101).

**Microsomal Clearance:** Ligand B (-8.119) has a significantly *lower* (better) microsomal clearance than Ligand A (32.017), indicating better metabolic stability.

**In vitro Half-Life:** Both have very short in vitro half-lives (11.21 and 0.061 hours), which is undesirable.

**P-gp Efflux:** Both have low P-gp efflux liability (0.066 and 0.024), which is good for CNS exposure.

**Binding Affinity:** Both ligands have excellent binding affinity (-8.6 and -8.2 kcal/mol). The difference of 0.4 kcal/mol is not substantial enough to outweigh other factors.

**Overall Assessment:**

Ligand A has a better logP and TPSA, but Ligand B has significantly better metabolic stability (lower Cl_mic) and lower DILI risk. The poor solubility and Caco-2 permeability are major concerns for both. However, the negative logP of Ligand B is a significant disadvantage for CNS penetration, despite the acceptable BBB values. Given the GPCR-specific priorities, the slightly better logP and TPSA of Ligand A, combined with acceptable DILI, make it marginally more promising, *assuming* the solubility and permeability issues can be addressed through formulation or structural modification.

Output:
0
2025-04-17 06:12:05,639 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (343.387 and 353.369 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (110.01) is slightly above the optimal <90 for CNS targets, but still reasonable. Ligand B (91.06) is better, falling comfortably under 90.

**3. logP:** Both ligands have good logP values (2.388 and 1.519), within the 1-3 range. Ligand B is slightly lower, which could potentially affect permeability, but it's not a major concern.

**4. H-Bond Donors:** Ligand A (2) and Ligand B (3) are both acceptable, being less than 5.

**5. H-Bond Acceptors:** Ligand A (6) and Ligand B (3) are both acceptable, being less than 10.

**6. QED:** Both ligands have reasonable QED values (0.779 and 0.677), indicating good drug-like properties.

**7. DILI:** Ligand A (72.47) has a higher DILI risk than Ligand B (49.477). This is a significant advantage for Ligand B.

**8. BBB:** Ligand B (69.252) has a considerably better BBB penetration score than Ligand A (52.811). This is *critical* for a CNS target like DRD2.

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.086 and -5.124), which is unusual and suggests poor permeability. This is a potential red flag for both, but the scale isn't clearly defined, so it's hard to interpret.

**10. Aqueous Solubility:** Both ligands have negative solubility values (-2.683 and -2.96), which is also unusual and suggests poor solubility. Again, the scale is unclear, making interpretation difficult.

**11. hERG Inhibition:** Both ligands have low hERG inhibition risk (0.131 and 0.438).

**12. Microsomal Clearance:** Ligand B (-1.982) has significantly lower (better) microsomal clearance than Ligand A (65.742), indicating greater metabolic stability.

**13. In vitro Half-Life:** Ligand B (-25.504) has a longer in vitro half-life than Ligand A (-22.29), which is desirable.

**14. P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.03 and 0.067), which is good for CNS penetration.

**15. Binding Affinity:** Ligand B (-9.1 kcal/mol) has a slightly better binding affinity than Ligand A (-8.4 kcal/mol). While the difference is not huge, it's still a positive factor.

**Overall Assessment:**

Ligand B is the superior candidate. Its significantly better BBB penetration, lower DILI risk, lower microsomal clearance (better metabolic stability), longer half-life, and slightly improved binding affinity outweigh the slightly lower logP and the shared issues with Caco-2 and solubility. Given the CNS target, BBB is paramount, and Ligand B excels in this area.

Output:
1
2025-04-17 06:12:05,639 - INFO - Reasoning:

Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (376.283 Da) is slightly higher than Ligand B (333.435 Da), but both are acceptable.

**2. TPSA:** Ligand A (52.49) is better than Ligand B (56.13). For CNS targets, we want TPSA <= 90, both are well within this limit.

**3. logP:** Ligand A (4.462) is slightly higher than the optimal range (1-3), while Ligand B (3.55) is within the optimal range. Higher logP can sometimes lead to off-target effects, but is less concerning than a very low logP.

**4. H-Bond Donors:** Ligand A (3) is higher than Ligand B (1). Both are acceptable, but lower is generally preferred for better permeability.

**5. H-Bond Acceptors:** Both ligands have 3 H-bond acceptors, which is within the acceptable range.

**6. QED:** Ligand B (0.843) has a higher QED score than Ligand A (0.595), suggesting a more drug-like profile.

**7. DILI:** Ligand B (34.161) has a significantly lower DILI risk than Ligand A (48.623). This is a major advantage for Ligand B.

**8. BBB:** Ligand B (83.521) has a much higher BBB penetration percentile than Ligand A (37.34). This is *critical* for a CNS target like DRD2.

**9. Caco-2 Permeability:** Ligand A (-5.168) has a much higher Caco-2 permeability than Ligand B (-4.612). This suggests better intestinal absorption for Ligand A.

**10. Aqueous Solubility:** Both ligands have very poor aqueous solubility (-4.205 and -4.326 respectively). This is a concern for both, but can be addressed with formulation strategies.

**11. hERG Inhibition:** Both ligands have similar hERG inhibition risk (0.92 and 0.892 respectively), and are relatively low.

**12. Microsomal Clearance:** Ligand A (12.141) has a lower microsomal clearance than Ligand B (34.367), indicating better metabolic stability.

**13. In vitro Half-Life:** Ligand A (140.185) has a significantly longer in vitro half-life than Ligand B (38.796). This is a substantial advantage for Ligand A.

**14. P-gp Efflux:** Ligand A (0.673) has lower P-gp efflux than Ligand B (0.226), suggesting better CNS exposure.

**15. Binding Affinity:** Both ligands have very similar and strong binding affinities (-9.1 and -9.2 kcal/mol). The difference is negligible.

**Overall Assessment:**

While Ligand A has advantages in Caco-2 permeability, metabolic stability, and in vitro half-life, Ligand B overwhelmingly wins due to its significantly better BBB penetration (83.521 vs 37.34) and lower DILI risk (34.161 vs 48.623). For a CNS target like DRD2, BBB penetration is paramount. The lower DILI risk is also a significant safety advantage. The slightly higher logP of Ligand A is a minor concern compared to the substantial benefits of Ligand B's CNS properties.

Output:
1
2025-04-17 06:12:05,639 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B against the provided guidelines, prioritizing GPCR-specific properties (BBB, logP, Pgp, TPSA, and affinity) for DRD2.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (355.479 Da) is slightly lower, which could be favorable for permeability, but both are acceptable.

**TPSA:** Ligand A (82.11) is better than Ligand B (29.54). For CNS targets, TPSA should be <=90, both are well within this range. Ligand B is significantly better, suggesting potentially improved brain penetration.

**logP:** Ligand A (0.225) is quite low, potentially hindering membrane permeability. Ligand B (4.447) is higher, but also outside the optimal 1-3 range, potentially leading to off-target effects or solubility issues.

**H-Bond Donors/Acceptors:** Ligand A has 2 HBD and 5 HBA, which are acceptable. Ligand B has 0 HBD and 2 HBA, also acceptable.

**QED:** Both ligands have good QED scores (A: 0.548, B: 0.668), indicating drug-like properties.

**DILI:** Ligand A (6.747) has a much lower DILI risk than Ligand B (28.655), a significant advantage.

**BBB:** Ligand A (35.673) has a very poor BBB percentile, making CNS penetration unlikely. Ligand B (96.937) has an excellent BBB percentile, crucial for a DRD2 targeting drug.

**Caco-2 Permeability:** Ligand A (-4.815) has poor Caco-2 permeability, consistent with its low logP. Ligand B (-4.278) is also poor, but slightly better than A.

**Aqueous Solubility:** Ligand A (-0.117) has poor solubility, likely due to its low logP. Ligand B (-5.416) also has poor solubility.

**hERG Inhibition:** Ligand A (0.462) has a slightly elevated hERG risk, but still relatively low. Ligand B (0.902) has a higher hERG risk.

**Microsomal Clearance:** Ligand A (19.555) has lower microsomal clearance, suggesting better metabolic stability than Ligand B (104.609).

**In vitro Half-Life:** Ligand B (34.401) has a significantly longer in vitro half-life than Ligand A (3.577), which is a major advantage.

**P-gp Efflux:** Ligand A (0.036) has very low P-gp efflux, which is favorable for CNS penetration. Ligand B (0.77) has moderate P-gp efflux.

**Binding Affinity:** Ligand B (-7.5 kcal/mol) has a significantly stronger binding affinity than Ligand A (-6.2 kcal/mol). This 1.3 kcal/mol difference is substantial and can outweigh many ADME drawbacks.

**Overall Assessment:**

Ligand B is the stronger candidate despite some drawbacks. The *critical* advantage is its excellent BBB penetration (96.937) and significantly higher binding affinity (-7.5 kcal/mol). While its logP is high and solubility is poor, the strong affinity and ability to cross the BBB are paramount for a CNS-targeting drug like a DRD2 modulator. Ligand A's poor BBB penetration is a deal-breaker, even with its better DILI profile and lower clearance. The longer half-life of Ligand B is also a significant benefit.

Output:
1
2025-04-17 06:12:05,639 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (346.402) is slightly lower, which could be beneficial for permeability. Ligand B (355.391) is also good.

**TPSA:** Ligand A (70.59) is excellent, well below the 90 A^2 threshold for CNS targets. Ligand B (124.22) is higher, but still potentially acceptable, though less ideal for CNS penetration.

**logP:** Ligand A (3.237) is optimal. Ligand B (-0.766) is significantly lower, which is a major concern. Low logP can hinder membrane permeability and reduce brain exposure.

**H-Bond Donors/Acceptors:** Ligand A (HBD=3, HBA=3) is well within the acceptable ranges. Ligand B (HBD=2, HBA=6) is also acceptable, though the higher HBA count might slightly impact permeability.

**QED:** Both ligands have reasonable QED values (Ligand A: 0.752, Ligand B: 0.504), suggesting drug-like properties.

**DILI:** Ligand A (44.087) has a moderate DILI risk, but acceptable. Ligand B (18.069) has a very low DILI risk, which is excellent.

**BBB:** Both ligands have similar BBB penetration (Ligand A: 43.815, Ligand B: 42.497), and are below the desirable >70 percentile for CNS targets. This is a weakness for both, but not a decisive factor between them.

**Caco-2 Permeability:** Ligand A (-4.626) has poor Caco-2 permeability, while Ligand B (-5.179) is also poor.

**Aqueous Solubility:** Ligand A (-3.135) and Ligand B (-0.984) both have poor aqueous solubility. This could pose formulation challenges.

**hERG Inhibition:** Ligand A (0.712) has a slightly higher hERG risk than Ligand B (0.081), which is a significant advantage for Ligand B.

**Microsomal Clearance:** Ligand A (55.556) has moderate clearance, while Ligand B (-24.14) has negative clearance (highly stable). This is a major advantage for Ligand B.

**In vitro Half-Life:** Ligand A (1.078) has a short half-life, while Ligand B (8.648) has a longer half-life. This is a significant advantage for Ligand B.

**P-gp Efflux:** Ligand A (0.403) has lower P-gp efflux than Ligand B (0.007), which is a positive for CNS exposure.

**Binding Affinity:** Ligand A (-9.3) has a significantly stronger binding affinity than Ligand B (-8.8). This is a substantial advantage for Ligand A. The difference of 0.5 kcal/mol is meaningful.

**Overall Assessment:**

While Ligand A has a superior binding affinity, Ligand B has a much better ADME profile. The low logP of Ligand B is a major drawback, potentially limiting its ability to cross the blood-brain barrier despite its reasonable BBB percentile. Ligand B's excellent metabolic stability (negative Cl_mic), longer half-life, and lower hERG risk are compelling advantages. Ligand A's poor Caco-2 permeability and shorter half-life are concerning. Given the GPCR-specific priorities, and the importance of BBB penetration and metabolic stability for CNS drugs, Ligand B is the more promising candidate, despite the weaker binding affinity. The affinity difference, while significant, might be overcome with further optimization, whereas fixing the logP issue in Ligand B would be more challenging.

Output:
1
2025-04-17 06:12:05,640 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (349.333 and 341.455 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (78.62) is higher than Ligand B (53.51). For CNS targets, we prefer TPSA <= 90, so both are acceptable, but B is better.

**logP:** Both ligands have good logP values (3.01 and 2.719), falling within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A has 1 HBD and 5 HBA, while Ligand B has 0 HBD and 3 HBA. Both are within acceptable limits (<=5 HBD and <=10 HBA).

**QED:** Both ligands have similar QED values (0.641 and 0.649), indicating good drug-likeness.

**DILI:** Ligand A has a DILI risk of 77.162, which is concerning (approaching the high-risk threshold of >60). Ligand B has a much lower DILI risk of 18.224, a significant advantage.

**BBB:** Ligand A has a BBB penetration of 73.129, which is good, but Ligand B is better at 83.366. Both are above the desirable 70% threshold for CNS targets.

**Caco-2 Permeability:** Both have negative Caco-2 values (-4.466 and -4.34), which is unusual and suggests poor permeability. This is a significant drawback for both.

**Aqueous Solubility:** Both have negative solubility values (-5.728 and -1.775), which is also concerning. Poor solubility can hinder bioavailability.

**hERG Inhibition:** Ligand A (0.789) has a slightly higher hERG inhibition risk than Ligand B (0.175). Lower is better here.

**Microsomal Clearance:** Ligand A (85.597) has higher microsomal clearance than Ligand B (79.543), indicating faster metabolism and potentially lower exposure.

**In vitro Half-Life:** Ligand B (-13.455) has a negative half-life, which is not physically possible and indicates a problem with the data or the molecule itself. Ligand A has a half-life of 17.594, which is reasonable.

**P-gp Efflux:** Ligand A (0.398) has lower P-gp efflux than Ligand B (0.075), which is favorable for CNS penetration.

**Binding Affinity:** Ligand A (-9.1 kcal/mol) has a significantly stronger binding affinity than Ligand B (-7.7 kcal/mol). This is a substantial advantage, potentially outweighing some ADME concerns.

**Overall Assessment:**

Ligand A has a much stronger binding affinity, which is a key factor for GPCR ligands. However, it has a higher DILI risk and higher metabolic clearance. Ligand B has a better safety profile (lower DILI, lower hERG), better BBB penetration, and lower P-gp efflux, but its binding affinity is weaker. The negative Caco-2 and solubility values are concerning for both. Considering the importance of affinity for GPCRs, and the fact that the difference in affinity is substantial (1.4 kcal/mol), Ligand A is the more promising candidate *despite* its drawbacks, assuming the DILI risk can be mitigated through further optimization. The negative half-life for ligand B is a showstopper.

Output:
1
2025-04-17 06:12:05,640 - INFO - Reasoning:

Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (385.781 and 342.439 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (112.81) is higher than the preferred <90 for CNS targets, while Ligand B (62.55) is well within the optimal range. This is a significant advantage for Ligand B.

**3. logP:** Both ligands have good logP values (2.944 and 2.364), falling within the 1-3 range.

**4. H-Bond Donors:** Ligand A has 0 HBD, which is good. Ligand B has 1 HBD, also acceptable.

**5. H-Bond Acceptors:** Ligand A has 7 HBA, acceptable. Ligand B has 3 HBA, also good.

**6. QED:** Both ligands have reasonable QED values (0.325 and 0.863). Ligand B's QED is significantly better, indicating a more drug-like profile.

**7. DILI:** Ligand A has a high DILI risk (97.867%), which is concerning. Ligand B has a much lower DILI risk (20.396%), a major advantage.

**8. BBB:** Ligand A has a BBB penetration of 46.219%, which is below the desirable >70% for CNS targets. Ligand B has a significantly better BBB penetration of 57.193%, though still not optimal.

**9. Caco-2 Permeability:** Ligand A has a negative Caco-2 value (-4.449), which is unusual and suggests poor permeability. Ligand B has a negative value as well (-5.184), indicating poor permeability.

**10. Aqueous Solubility:** Ligand A has a very poor aqueous solubility (-5.032). Ligand B has a slightly better, but still poor, solubility (-2.903).

**11. hERG Inhibition:** Both ligands have low hERG inhibition risk (0.34 and 0.266).

**12. Microsomal Clearance:** Ligand A has a higher microsomal clearance (64.776) compared to Ligand B (34.674), suggesting lower metabolic stability.

**13. In vitro Half-Life:** Both ligands have similar in vitro half-lives (30.305 and 31.134 hours).

**14. P-gp Efflux:** Both ligands have low P-gp efflux liability (0.245 and 0.154).

**15. Binding Affinity:** Both ligands have the same binding affinity (-8.5 kcal/mol), which is excellent.

**Overall Assessment:**

While both ligands exhibit excellent binding affinity, Ligand B is the superior candidate. It has a much lower DILI risk, a better QED score, a significantly lower TPSA, and a better (though still suboptimal) BBB penetration. Ligand A's high DILI risk and poor TPSA are major drawbacks. The poor Caco-2 and solubility for both are concerning, but could potentially be addressed with formulation strategies. Given the importance of BBB penetration for a CNS target like DRD2, and the significant safety advantage of lower DILI risk, Ligand B is the more promising candidate.

Output:
1
2025-04-17 06:12:05,640 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (341.386 and 362.539 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (62.3) is better than Ligand B (49.41). Both are below the 90 A^2 threshold for CNS targets, which is excellent.

**3. logP:** Both ligands have a logP around 2.6, which is optimal (1-3).

**4. H-Bond Donors:** Both have 1 HBD, which is within the acceptable limit of <=5.

**5. H-Bond Acceptors:** Both have 3 HBA, which is within the acceptable limit of <=10.

**6. QED:** Ligand A (0.93) has a slightly better QED score than Ligand B (0.836), indicating a more drug-like profile. Both are above the 0.5 threshold.

**7. DILI:** Ligand A (53.354) has a higher DILI risk than Ligand B (17.216). This is a significant drawback for Ligand A. Ligand B is well below the 40 threshold.

**8. BBB:** Ligand A (81.698) has a better BBB penetration percentile than Ligand B (75.843). Both are good, but A is preferable for a CNS target.

**9. Caco-2 Permeability:** Ligand A (-4.767) has worse Caco-2 permeability than Ligand B (-5.106). Lower values are less desirable.

**10. Aqueous Solubility:** Ligand A (-3.263) has better aqueous solubility than Ligand B (-3.709).

**11. hERG Inhibition:** Both ligands have low hERG inhibition risk (0.334 and 0.458, respectively).

**12. Microsomal Clearance:** Ligand A (20.587) has significantly lower microsomal clearance than Ligand B (67.236), indicating better metabolic stability.

**13. In vitro Half-Life:** Ligand A (-7.17) has a much longer in vitro half-life than Ligand B (3.977). This is a major advantage.

**14. P-gp Efflux:** Ligand A (0.137) has lower P-gp efflux liability than Ligand B (0.083), which is favorable for CNS penetration.

**15. Binding Affinity:** Ligand B (-8.8 kcal/mol) has a significantly stronger binding affinity than Ligand A (-10.3 kcal/mol). This is a substantial advantage.

**Overall Assessment:**

While Ligand A has better BBB penetration, metabolic stability, half-life, and P-gp efflux, the significantly higher DILI risk and weaker binding affinity are major concerns. Ligand B, despite slightly lower BBB and higher P-gp efflux, has a much better safety profile (DILI) and substantially stronger binding affinity. For a GPCR target like DRD2, strong binding affinity is paramount, and a favorable safety profile is critical. The 1.5 kcal/mol advantage in binding affinity for Ligand B outweighs the minor ADME drawbacks.

Output:
1
2025-04-17 06:12:05,640 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (373.465 Da) is slightly higher than Ligand B (344.371 Da), but both are acceptable.

**TPSA:** Ligand A (46.61) is excellent for CNS penetration, well below the 90 A^2 threshold. Ligand B (95.6) is higher, potentially hindering BBB penetration, though not drastically.

**logP:** Ligand A (3.602) is optimal. Ligand B (0.383) is quite low, which could lead to poor membrane permeability and bioavailability.

**H-Bond Donors/Acceptors:** Ligand A (0 HBD, 3 HBA) is good. Ligand B (1 HBD, 5 HBA) is also acceptable, but slightly higher counts could impact permeability.

**QED:** Both ligands have similar QED values (A: 0.699, B: 0.632), indicating good drug-like properties.

**DILI:** Ligand A (37.456) has a much lower DILI risk than Ligand B (74.603). This is a significant advantage for Ligand A.

**BBB:** Ligand A (93.37) has excellent predicted BBB penetration. Ligand B (43.117) is considerably lower, raising concerns about reaching the target in the CNS.

**Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and suggests potential issues with the prediction method or the compounds themselves. However, the magnitude of negativity is similar.

**Aqueous Solubility:** Both have negative solubility values, again suggesting potential issues with prediction. The values are similar in magnitude.

**hERG Inhibition:** Ligand A (0.821) has a slightly higher hERG risk than Ligand B (0.064), but both are relatively low.

**Microsomal Clearance:** Ligand A (71.668) has higher clearance than Ligand B (12.595), meaning it's likely to be metabolized more quickly. This is a drawback for Ligand A.

**In vitro Half-Life:** Both have negative half-life values, which is not physically meaningful.

**P-gp Efflux:** Ligand A (0.498) has lower P-gp efflux liability than Ligand B (0.037), which is beneficial for CNS penetration.

**Binding Affinity:** Ligand A (-8.0 kcal/mol) has a significantly stronger binding affinity than Ligand B (-7.5 kcal/mol). This 1.5 kcal/mol difference is substantial and can outweigh some ADME drawbacks.

**Overall Assessment:**

Ligand A is the stronger candidate. While its microsomal clearance is higher, its superior BBB penetration, lower DILI risk, and significantly better binding affinity outweigh this drawback. Ligand B's low logP and poor BBB penetration are major concerns for a CNS-targeting drug. The affinity difference is also critical.

Output:
1
2025-04-17 06:12:05,641 - INFO - Batch 262 complete. Total preferences: 4192
2025-04-17 06:12:05,641 - INFO - Processing batch 263/512...
2025-04-17 06:12:48,156 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (344.459 and 372.531 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (75.19) is better than Ligand B (83.55). Both are below the 90 A^2 threshold desirable for CNS targets, but A is closer to the optimal range.

**3. logP:** Both ligands have good logP values (2.046 and 1.745), falling within the optimal 1-3 range.

**4. H-Bond Donors:** Both have 1 HBD, which is acceptable.

**5. H-Bond Acceptors:** Both have 4 HBA, which is acceptable.

**6. QED:** Ligand A (0.857) has a significantly better QED score than Ligand B (0.703), indicating a more drug-like profile.

**7. DILI:** Ligand A (29.042) has a much lower DILI risk than Ligand B (37.379), which is a significant advantage. Both are below the 40 threshold.

**8. BBB:** Ligand A (75.301) has a better BBB percentile than Ligand B (68.631). While both are reasonably good, A is closer to the desirable >70 for CNS targets.

**9. Caco-2:** Both have negative Caco-2 values (-5.021 and -5.037). This is unusual and suggests poor permeability.

**10. Solubility:** Both have negative solubility values (-1.571 and -2.458), indicating very poor aqueous solubility.

**11. hERG:** Both have very low hERG inhibition risk (0.286 and 0.285).

**12. Cl_mic:** Ligand A (22.837) has a slightly higher microsomal clearance than Ligand B (21.772), meaning it might be metabolized slightly faster.

**13. t1/2:** Ligand B (1.714) has a longer in vitro half-life than Ligand A (-11.131). This is a significant advantage for dosing frequency, but the negative value for A is concerning.

**14. Pgp:** Both have very low P-gp efflux liability (0.034 and 0.227).

**15. Binding Affinity:** Ligand A (-8.9 kcal/mol) has a significantly stronger binding affinity than Ligand B (0.0 kcal/mol). This is a crucial advantage, potentially outweighing some of the ADME drawbacks.

**Overall Assessment:**

Despite both compounds having poor solubility and Caco-2 permeability, Ligand A is the more promising candidate. Its significantly stronger binding affinity (-8.9 vs 0.0 kcal/mol) is a major advantage for a GPCR target. Additionally, it has a better QED score, lower DILI risk, and better BBB penetration. While Ligand B has a longer half-life, the negative half-life value for Ligand A is highly suspect and needs further investigation. However, the potency difference is so large that it likely outweighs this concern.

Output:
1
2025-04-17 06:12:48,157 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (364.423 and 348.487 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (94.99) is slightly above the optimal <90 for CNS targets, but still reasonable. Ligand B (58.64) is well within the desired range. This favors Ligand B.

**3. logP:** Both ligands have good logP values (1.529 and 2.489), falling within the 1-3 range.

**4. H-Bond Donors:** Both have 1 HBD, which is acceptable.

**5. H-Bond Acceptors:** Ligand A has 4 HBAs, and Ligand B has 3. Both are within the acceptable limit of <=10.

**6. QED:** Both ligands have similar QED values (0.878 and 0.83), indicating good drug-likeness.

**7. DILI:** Ligand A (72.664) has a higher DILI risk than Ligand B (8.492). This is a significant advantage for Ligand B.

**8. BBB:** Both ligands have good BBB penetration (59.946 and 72.237). Ligand B is slightly better, exceeding 70%, which is desirable for CNS targets.

**9. Caco-2 Permeability:** Ligand A (-5.033) has poor Caco-2 permeability, while Ligand B (-4.638) is also poor, but slightly better.

**10. Aqueous Solubility:** Both have very poor aqueous solubility (-2.6 and -2.378). This is a concern for both, but not a deciding factor given the CNS target.

**11. hERG Inhibition:** Ligand A (0.032) has a slightly lower hERG risk than Ligand B (0.316), which is favorable.

**12. Microsomal Clearance:** Ligand A (26.043) has lower microsomal clearance than Ligand B (33.951), suggesting better metabolic stability.

**13. In vitro Half-Life:** Ligand A (-12.943) has a significantly longer in vitro half-life than Ligand B (0.601). This is a substantial advantage for Ligand A.

**14. P-gp Efflux:** Ligand A (0.021) has much lower P-gp efflux liability than Ligand B (0.031), which is crucial for CNS penetration.

**15. Binding Affinity:** Ligand B (-9.0) has a significantly stronger binding affinity than Ligand A (-8.1). This is a major advantage for Ligand B, potentially outweighing some ADME drawbacks.

**Overall Assessment:**

Ligand B has a superior binding affinity and lower DILI risk, and better BBB penetration. While Ligand A has better metabolic stability and lower P-gp efflux, the substantial affinity difference of Ligand B is a key factor for GPCR targets. The slightly better BBB and significantly lower DILI risk of Ligand B are also important. The poor solubility and Caco-2 permeability are less critical given the CNS target.

Output:
1
2025-04-17 06:12:48,157 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (345.351 and 348.487 Da) fall comfortably within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (89.21) is excellent, being below the 90 A^2 threshold for CNS targets. Ligand B (49.85) is also very good, well below the threshold.

**3. logP:** Both ligands have a logP around 2.45-2.46, which is optimal (1-3).

**4. H-Bond Donors:** Ligand A has 1 HBD, within the acceptable limit of <=5. Ligand B has 0, also good.

**5. H-Bond Acceptors:** Ligand A has 6 HBA, within the acceptable limit of <=10. Ligand B has 3, also good.

**6. QED:** Both ligands have QED values above 0.5 (0.639 and 0.525), indicating good drug-like properties.

**7. DILI:** Ligand A has a DILI risk of 64.831, which is moderately high. Ligand B has a significantly lower DILI risk of 13.106, which is excellent.

**8. BBB:** This is a crucial parameter for a CNS target like DRD2. Ligand A has a BBB penetration of 48.391%, which is below the desirable >70% threshold. Ligand B has a BBB penetration of 84.025%, which is excellent.

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.899 and -4.583). This is unusual and suggests poor permeability, but the scale isn't defined, so it's hard to interpret.

**10. Aqueous Solubility:** Both ligands have negative solubility values (-3.448 and -1.965). Similar to Caco-2, the scale is undefined, making interpretation difficult.

**11. hERG Inhibition:** Both ligands show low hERG inhibition liability (0.485 and 0.403), which is good.

**12. Microsomal Clearance:** Ligand A has a higher microsomal clearance (89.784) than Ligand B (44.385), indicating lower metabolic stability.

**13. In vitro Half-Life:** Ligand A has a negative half-life (-7.809), which is problematic. Ligand B has a positive half-life (7.157), which is much better.

**14. P-gp Efflux:** Both ligands have low P-gp efflux liability (0.371 and 0.307), which is favorable for CNS penetration.

**15. Binding Affinity:** Ligand B (-7.6 kcal/mol) has slightly better binding affinity than Ligand A (-7.8 kcal/mol), though the difference is small.

**Overall Assessment:**

Ligand B is significantly better. While both ligands have acceptable MW, logP, H-bonds, QED, and hERG, Ligand B excels in the critical areas for a CNS-targeting GPCR: significantly lower DILI risk, much higher BBB penetration, better metabolic stability (lower Cl_mic, higher t1/2), and slightly better binding affinity. The negative values for Caco-2 and solubility are concerning for both, but the other advantages of Ligand B outweigh these issues.

Output:
1
2025-04-17 06:12:48,158 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the acceptable range (200-500 Da). Ligand A (369.447 Da) is slightly higher than Ligand B (345.487 Da), but this isn't a major concern.

**TPSA:** Ligand A (120.5) is borderline for CNS penetration, being above the ideal <90, while Ligand B (52.65) is excellent for CNS penetration. This is a significant advantage for Ligand B.

**logP:** Ligand A (0.609) is quite low, potentially hindering membrane permeability. Ligand B (2.228) is within the optimal range (1-3). This favors Ligand B.

**H-Bond Donors/Acceptors:** Ligand A has 3 HBD and 5 HBA, which are acceptable. Ligand B has 1 HBD and 3 HBA, also acceptable.

**QED:** Both ligands have good QED values (A: 0.672, B: 0.824), indicating drug-like properties. Ligand B is slightly better.

**DILI:** Ligand A (77.782) has a higher DILI risk than Ligand B (24.467), which is a significant concern.

**BBB:** Ligand A (64.017) has a moderate BBB penetration, while Ligand B (70.88) is better, though still not exceptional. For a CNS target like DRD2, maximizing BBB penetration is crucial.

**Caco-2 Permeability:** Both have negative values, which is unusual and suggests poor permeability. However, the scale is not specified, so it's hard to interpret.

**Aqueous Solubility:** Both have negative values, suggesting poor solubility. Again, the scale is not specified.

**hERG Inhibition:** Ligand A (0.037) has a very low hERG risk, which is excellent. Ligand B (0.525) has a slightly higher, but still acceptable, hERG risk.

**Microsomal Clearance:** Ligand A (7.735) has a lower clearance than Ligand B (39.974), indicating better metabolic stability.

**In vitro Half-Life:** Ligand A (-13.75) has a negative half-life, which is not possible. This is a red flag. Ligand B (17.11) has a reasonable half-life.

**P-gp Efflux:** Ligand A (0.029) has very low P-gp efflux, which is favorable for CNS penetration. Ligand B (0.1) is also low, but slightly higher.

**Binding Affinity:** Ligand B (-8.4) has a significantly stronger binding affinity than Ligand A (-9.3). A 1.5 kcal/mol advantage is substantial and can often outweigh minor ADME drawbacks.

**Overall Assessment:**

Ligand B is the stronger candidate. While Ligand A has a slightly better P-gp efflux and hERG profile, its low logP, questionable half-life, higher DILI risk, and weaker binding affinity are significant drawbacks. Ligand B excels in TPSA, logP, BBB, binding affinity, and DILI risk, all of which are critical for a CNS-targeting GPCR ligand. The negative values for Caco-2 and solubility are concerning for both, but the other advantages of Ligand B make it the more promising candidate.

Output:
1
2025-04-17 06:12:48,158 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (367.354 and 348.487 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (109.77) is higher than the preferred <90 for CNS targets, but not drastically so. Ligand B (60.85) is excellent, well below the 90 threshold.

**logP:** Both ligands have a logP around 2.0 (2.04 and 2.057), which is optimal.

**H-Bond Donors/Acceptors:** Ligand A has 2 HBD and 5 HBA, which are acceptable. Ligand B has 1 HBD and 3 HBA, also acceptable.

**QED:** Both ligands have reasonable QED scores (0.756 and 0.683), indicating good drug-like properties.

**DILI:** Ligand A has a very high DILI risk (98.294), which is a major concern. Ligand B has a low DILI risk (6.747), a significant advantage.

**BBB:** Ligand A has a very poor BBB penetration (19.698). Ligand B has excellent BBB penetration (61.419), which is crucial for a CNS target like DRD2.

**Caco-2 Permeability:** Ligand A shows poor Caco-2 permeability (-5.227). Ligand B shows poor Caco-2 permeability (-4.726). Both are not ideal.

**Aqueous Solubility:** Ligand A shows poor aqueous solubility (-3.404). Ligand B shows poor aqueous solubility (-1.513). Both are not ideal.

**hERG Inhibition:** Ligand A has very low hERG inhibition liability (0.053), which is good. Ligand B has a slightly higher hERG inhibition liability (0.445), but still relatively low.

**Microsomal Clearance:** Ligand A has a lower microsomal clearance (15.609) than Ligand B (54.714), indicating better metabolic stability.

**In vitro Half-Life:** Ligand A has a moderate half-life (11.411 hours). Ligand B has a negative half-life (-21.746 hours), which is problematic and likely an error or indicates very rapid degradation.

**P-gp Efflux:** Ligand A has very low P-gp efflux liability (0.066), which is favorable for CNS penetration. Ligand B has moderate P-gp efflux liability (0.323).

**Binding Affinity:** Ligand B (-7.5 kcal/mol) has a slightly better binding affinity than Ligand A (-9.0 kcal/mol), although both are excellent.

**Overall Assessment:**

Ligand A is hampered by its extremely high DILI risk and poor BBB penetration, despite its good affinity and low P-gp efflux. Ligand B has excellent BBB penetration, low DILI risk, and good affinity, making it a much more promising candidate. The negative in vitro half-life for Ligand B is concerning and requires further investigation, but the other factors strongly favor it.

Output:
1
2025-04-17 06:12:48,158 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (368.587 and 347.463 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (58.2) is significantly better than Ligand B (77.57). For CNS targets, we want TPSA <= 90, and A is comfortably within that range, while B is approaching the upper limit.

**3. logP:** Ligand A (3.603) is optimal (1-3). Ligand B (0.724) is a bit low, potentially hindering permeation.

**4. H-Bond Donors:** Both have 2 HBD, which is within the acceptable limit of <= 5.

**5. H-Bond Acceptors:** Ligand A has 3 HBA, and Ligand B has 5. Both are within the acceptable limit of <= 10.

**6. QED:** Both ligands have similar QED values (0.675 and 0.688), indicating good drug-likeness.

**7. DILI:** Ligand A (17.371) has a much lower DILI risk than Ligand B (43.932). This is a significant advantage for A.

**8. BBB:** Both ligands have excellent BBB penetration (Ligand A: 70.997, Ligand B: 73.129), exceeding the desirable threshold of >70.

**9. Caco-2 Permeability:** Both have negative Caco-2 values (-4.941 and -4.996), which is unusual and difficult to interpret without further context. However, the values are similar.

**10. Aqueous Solubility:** Both have negative solubility values (-4.042 and -1.127). This is also unusual, and suggests poor aqueous solubility. Ligand B is slightly better.

**11. hERG Inhibition:** Both have low hERG inhibition liability (0.594 and 0.494), which is good.

**12. Microsomal Clearance:** Ligand A (76.779) has higher microsomal clearance than Ligand B (23.248), suggesting lower metabolic stability. This is a drawback for A.

**13. In vitro Half-Life:** Ligand B (29.749) has a longer in vitro half-life than Ligand A (15.548), which is preferable.

**14. P-gp Efflux:** Ligand A (0.145) has lower P-gp efflux than Ligand B (0.01), which is better for CNS exposure.

**15. Binding Affinity:** Ligand B (-7.8 kcal/mol) has a slightly better binding affinity than Ligand A (-8.4 kcal/mol). While A is better, the difference is not substantial enough to overcome other issues.

**Overall Assessment:**

Considering the GPCR-specific priorities, Ligand A is the better candidate. It has a significantly lower DILI risk, a much more favorable TPSA, and better logP. While Ligand B has a slightly better binding affinity and half-life, the advantages of Ligand A in terms of safety (DILI) and CNS penetration (TPSA, logP, Pgp) are more critical for a DRD2 ligand targeting CNS disorders. The higher clearance of Ligand A is a concern, but could potentially be addressed through structural modifications.

Output:
1
2025-04-17 06:12:48,158 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (350.507 and 348.531 Da) fall comfortably within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (47.1) is better than Ligand B (49.41). Both are below the 90 A^2 threshold for CNS targets, but closer to the ideal.

**3. logP:** Ligand A (1.016) is within the optimal range (1-3), while Ligand B (3.746) is approaching the upper limit. This favors Ligand A.

**4. H-Bond Donors:** Ligand A (0) is preferable to Ligand B (1). Fewer HBDs generally improve permeability.

**5. H-Bond Acceptors:** Ligand A (4) is better than Ligand B (2). Both are within the acceptable range, but fewer is generally better.

**6. QED:** Ligand A (0.759) is better than Ligand B (0.654), indicating a more drug-like profile.

**7. DILI:** Ligand A (8.647%) has a significantly lower DILI risk than Ligand B (14.23%). This is a major advantage for Ligand A.

**8. BBB:** Ligand B (85.459%) has a much higher BBB penetration percentile than Ligand A (64.482%). This is a critical advantage for a CNS target like DRD2.

**9. Caco-2 Permeability:** Ligand A (-4.956) and Ligand B (-4.625) both have negative values, which is unusual and suggests poor permeability.

**10. Aqueous Solubility:** Ligand A (-0.234) is better than Ligand B (-3.9). Solubility is a concern for both, but less so for A.

**11. hERG Inhibition:** Both ligands show low hERG inhibition liability (0.592 and 0.618, respectively).

**12. Microsomal Clearance:** Ligand A (1.692) has a much lower microsomal clearance than Ligand B (89.69), indicating better metabolic stability.

**13. In vitro Half-Life:** Ligand A (-1.088) has a longer in vitro half-life than Ligand B (-1.857).

**14. P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.026 and 0.384).

**15. Binding Affinity:** Ligand B (-7.7 kcal/mol) has a significantly stronger binding affinity than Ligand A (-0.0 kcal/mol). This is a substantial advantage that could outweigh some ADME drawbacks.

**Overall Assessment:**

Ligand B excels in BBB penetration and binding affinity, which are paramount for a CNS GPCR target. However, it suffers from higher DILI risk, higher microsomal clearance, and a less favorable logP. Ligand A has better ADME properties (DILI, clearance, logP, solubility), but its binding affinity is very weak.

The strong binding affinity of Ligand B (-7.7 kcal/mol) is a significant advantage. A difference of >1.5 kcal/mol can often justify optimizing around some ADME liabilities. While the higher DILI and clearance are concerns, they might be addressable through further structural modifications. The superior BBB penetration is also crucial.

Output:
1
2025-04-17 06:12:48,158 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (352.391 and 349.475 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (106.79) is better than Ligand B (69.72). Both are below the 90 A^2 threshold for CNS targets, but A is slightly higher and could potentially impact BBB penetration less favorably.

**logP:** Ligand B (1.398) is within the optimal 1-3 range, while Ligand A (0.037) is quite low, potentially hindering membrane permeability. This is a significant drawback for A.

**H-Bond Donors/Acceptors:** Both ligands have 1 HBD, which is good. Ligand A has 7 HBA, while Ligand B has 3. Both are within the acceptable limits, but B is preferable.

**QED:** Both ligands have good QED scores (0.738 and 0.834), indicating drug-like properties.

**DILI:** Ligand A (61.07) has a higher DILI risk than Ligand B (11.632). This is a negative for Ligand A.

**BBB:** Both ligands have excellent BBB penetration (79.566 and 76.347), exceeding the 70% threshold for CNS targets.

**Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual. However, the magnitude is similar, so this isn't a major differentiator.

**Aqueous Solubility:** Both have negative solubility values, which is also unusual. Again, the magnitudes are similar.

**hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.065 and 0.268), which is excellent.

**Microsomal Clearance:** Both have similar microsomal clearance values (11.32 and 11.784), suggesting similar metabolic stability.

**In vitro Half-Life:** Ligand B (-11.669) has a *negative* half-life, which is impossible and indicates a data error. Ligand A (10.276) has a reasonable half-life. This is a major issue for B.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.014 and 0.013), which is favorable for CNS penetration.

**Binding Affinity:** Ligand B (-8.6 kcal/mol) has a significantly stronger binding affinity than Ligand A (-7.7 kcal/mol). This 0.9 kcal/mol difference is substantial and can outweigh some ADME drawbacks.

**Overall Assessment:**

Ligand B is the better candidate. While Ligand A has a slightly better TPSA, Ligand B excels in several critical areas: logP (within optimal range vs. very low for A), DILI risk (much lower), and, most importantly, binding affinity (significantly stronger). The negative half-life for Ligand B is a clear data quality issue, but even ignoring that, the affinity difference is crucial. Ligand A's low logP is a significant concern for permeability and overall drug-likeness.



Output:
1
2025-04-17 06:12:48,158 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (386.21 Da) is slightly higher than Ligand B (350.507 Da), but both are acceptable.

**TPSA:** Ligand A (75.44) is higher than Ligand B (47.1). For CNS targets, we want TPSA <= 90, so both are within range, but Ligand B is significantly better.

**logP:** Ligand A (2.966) is optimal (1-3), while Ligand B (0.872) is a bit low, potentially hindering permeation. This favors Ligand A.

**H-Bond Donors:** Ligand A (1) and Ligand B (0) are both acceptable (<=5).

**H-Bond Acceptors:** Both ligands have 4 H-bond acceptors, well within the acceptable limit of 10.

**QED:** Both ligands have reasonable QED values (Ligand A: 0.877, Ligand B: 0.713), indicating good drug-like properties.

**DILI:** Ligand A (76.464) has a higher DILI risk than Ligand B (5.584). This is a significant advantage for Ligand B.

**BBB:** Ligand A (82.125) has better BBB penetration than Ligand B (61.535). Since DRD2 is a CNS target, this is a crucial factor favoring Ligand A. A value >70 is desirable, and Ligand A is closer.

**Caco-2 Permeability:** Both have negative values, which is unusual. Assuming these are percentile scores, Ligand A (-4.663) is *worse* than Ligand B (-4.808), indicating lower intestinal absorption.

**Aqueous Solubility:** Both ligands have very poor aqueous solubility (-4.557 and -0.13, respectively). This is a concern for both, but Ligand B is slightly better.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.408 and 0.421, respectively).

**Microsomal Clearance:** Ligand A (19.062) has higher clearance than Ligand B (-5.448). Lower clearance is preferred for metabolic stability, favoring Ligand B.

**In vitro Half-Life:** Ligand A (0.342) has a very short half-life, while Ligand B (3.028) is better. This favors Ligand B.

**P-gp Efflux:** Ligand A (0.257) has lower P-gp efflux than Ligand B (0.017). Lower efflux is better, especially for CNS penetration, favoring Ligand A.

**Binding Affinity:** Both ligands have the same binding affinity (-7.8 kcal/mol), which is excellent.

**Overall Assessment:**

Ligand A excels in BBB penetration and P-gp efflux, which are crucial for CNS GPCR targets. However, it has a higher DILI risk, higher clearance, and a shorter half-life. Ligand B has a much lower DILI risk, better metabolic stability (lower Cl_mic), and a longer half-life, but suffers from lower logP and BBB penetration.

Given the importance of CNS penetration for a DRD2 ligand, and the excellent binding affinity shared by both, the better BBB score of Ligand A is the deciding factor, despite its other drawbacks. The lower DILI risk of Ligand B is attractive, but can be addressed in later optimization stages.

Output:
1
2025-04-17 06:12:48,158 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (348.407) is slightly better, being closer to the lower end which can aid permeability.

**TPSA:** Ligand A (114.94) is better than Ligand B (75.62). Both are below the 90 A^2 threshold for CNS targets, but Ligand A is closer to the optimal range.

**logP:** Ligand A (0.852) is suboptimal, being slightly below the 1-3 range. Ligand B (3.964) is within the optimal range. This favors Ligand B.

**H-Bond Donors:** Both ligands have 2 HBD, which is within the acceptable limit of <=5.

**H-Bond Acceptors:** Ligand A has 7 HBA, and Ligand B has 8 HBA. Both are within the acceptable limit of <=10.

**QED:** Both ligands have similar QED values (0.694 and 0.711), indicating good drug-likeness.

**DILI:** Ligand A (59.752) has a lower DILI risk than Ligand B (80.613). This favors Ligand A.

**BBB:** Ligand B (77.588) has a significantly better BBB penetration score than Ligand A (46.413). This is a crucial factor for a CNS target like DRD2, heavily favoring Ligand B.

**Caco-2 Permeability:** Both have negative Caco-2 permeability values, which is unusual. However, the magnitude is similar.

**Aqueous Solubility:** Both have negative solubility values, which is also unusual. The magnitude is similar.

**hERG Inhibition:** Ligand A (0.067) has a much lower hERG inhibition liability than Ligand B (0.43). This is a significant advantage for Ligand A.

**Microsomal Clearance:** Ligand A (10.244) has a lower microsomal clearance than Ligand B (63.184), indicating better metabolic stability. This favors Ligand A.

**In vitro Half-Life:** Ligand A (23.59) has a longer half-life than Ligand B (12.333). This favors Ligand A.

**P-gp Efflux:** Ligand A (0.043) has a much lower P-gp efflux liability than Ligand B (0.218). This is crucial for CNS penetration and favors Ligand A.

**Binding Affinity:** Ligand B (-8.5) has a slightly better binding affinity than Ligand A (-8.2). While a 1.5 kcal/mol advantage is significant, the other ADME properties are more critical in this case.

**Overall Assessment:**

Ligand B excels in BBB penetration and binding affinity, which are important for a CNS GPCR target. However, it suffers from higher DILI risk, higher P-gp efflux, higher hERG inhibition, and faster clearance. Ligand A, while having slightly weaker binding affinity and lower logP, demonstrates a much more favorable ADME profile, particularly regarding CNS penetration (lower P-gp efflux, better BBB), safety (lower DILI, lower hERG), and metabolic stability. Given the importance of BBB penetration and manageable ADME properties for a CNS target, Ligand A is the more promising candidate.

Output:
0
2025-04-17 06:12:48,159 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (371.796 Da) is slightly lower, which is generally favorable for permeability. Ligand B (425.689 Da) is still acceptable.

**TPSA:** Ligand A (91.76) is better than Ligand B (51.45). For CNS targets, TPSA should be <= 90, so Ligand A is borderline, while Ligand B is well within the desired range.

**logP:** Ligand A (1.825) is optimal, falling within the 1-3 range. Ligand B (4.948) is high, potentially leading to solubility issues and off-target interactions.

**H-Bond Donors:** Both ligands have acceptable HBD counts (2 and 1, respectively), well below the threshold of 5.

**H-Bond Acceptors:** Both ligands have acceptable HBA counts (5), well below the threshold of 10.

**QED:** Ligand A (0.744) has a better QED score than Ligand B (0.588), indicating a more drug-like profile.

**DILI:** Ligand A (57.115) has a lower DILI risk than Ligand B (85.498), which is a significant advantage.

**BBB:** Both ligands have similar BBB penetration percentiles (68.941 and 67.584, respectively), both are acceptable, but not outstanding.

**Caco-2 Permeability:** Ligand A (-5.013) has a more negative Caco-2 value, suggesting *lower* permeability compared to Ligand B (-4.415).

**Aqueous Solubility:** Ligand A (-2.777) has a more negative solubility value, indicating *lower* solubility compared to Ligand B (-5.302).

**hERG Inhibition:** Ligand A (0.192) has a lower hERG inhibition liability than Ligand B (0.878), which is a significant safety advantage.

**Microsomal Clearance:** Ligand A (-1.662) has a lower (better) microsomal clearance than Ligand B (72.886), indicating greater metabolic stability.

**In vitro Half-Life:** Ligand A (-28.565) has a more negative half-life, suggesting a *shorter* half-life than Ligand B (56.92).

**P-gp Efflux:** Ligand A (0.038) has a lower P-gp efflux liability than Ligand B (0.887), which is crucial for CNS penetration.

**Binding Affinity:** Both ligands have excellent binding affinities (-7.9 and -7.7 kcal/mol, respectively). The difference of 0.2 kcal/mol is not substantial enough to outweigh other factors.

**Overall Assessment:**

Ligand A is superior due to its better TPSA, logP, QED, DILI risk, hERG inhibition, P-gp efflux, and microsomal clearance. While Ligand B has slightly better Caco-2 permeability and solubility, the other advantages of Ligand A are more critical for a CNS-targeting GPCR ligand. The lower P-gp efflux and DILI risk are particularly important.



Output:
0
2025-04-17 06:12:48,159 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (373.861 Da) is slightly higher than Ligand B (339.439 Da), but both are acceptable.

**TPSA:** Ligand A (48.3) is excellent, well below the 90 A^2 threshold for CNS targets. Ligand B (67.16) is still reasonable, but less optimal.

**logP:** Ligand A (4.35) is slightly high, potentially leading to solubility issues or off-target interactions. Ligand B (3.645) is within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A has 0 HBD and 5 HBA, which is good. Ligand B has 2 HBD and 3 HBA, also acceptable.

**QED:** Ligand B (0.874) has a significantly better QED score than Ligand A (0.366), indicating a more drug-like profile.

**DILI:** Ligand B (36.836) has a much lower DILI risk than Ligand A (76.464). This is a significant advantage.

**BBB:** Ligand B (91.663) has excellent BBB penetration, exceeding the 70% threshold. Ligand A (71.772) is acceptable, but less desirable.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.843 and -4.762) which is unusual and suggests poor permeability. This is a concern for both.

**Aqueous Solubility:** Both ligands have negative solubility values (-4.589 and -4.166), which is also concerning and indicates very poor solubility.

**hERG:** Both ligands have low hERG inhibition liability (0.246 and 0.494), which is good.

**Microsomal Clearance:** Ligand B (65.907) has lower microsomal clearance than Ligand A (119.837), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand B (45.616) has a slightly longer in vitro half-life than Ligand A (40.739).

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.789 and 0.526), which is good for CNS penetration.

**Binding Affinity:** Ligand B (-10.2 kcal/mol) has a significantly stronger binding affinity than Ligand A (-9.1 kcal/mol). This is a crucial advantage, exceeding the 1.5 kcal/mol difference threshold.

**Overall Assessment:**

Ligand B is clearly the superior candidate. While both have issues with Caco-2 and solubility, Ligand B excels in key areas for a CNS-targeting GPCR ligand: BBB penetration, DILI risk, metabolic stability, QED, and, most importantly, binding affinity. The stronger binding affinity of Ligand B can potentially offset the permeability and solubility concerns, as a higher potency may allow for a lower dose.

Output:
1
2025-04-17 06:12:48,159 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (346.471 and 344.375 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (49.85) is excellent, well below the 90 A^2 threshold for CNS targets. Ligand B (104.19) is higher, but still potentially acceptable, though less ideal.

**logP:** Ligand A (2.377) is optimal (1-3). Ligand B (-0.121) is quite low, which could hinder membrane permeability and CNS penetration.

**H-Bond Donors/Acceptors:** Ligand A (0 HBD, 3 HBA) is favorable. Ligand B (1 HBD, 6 HBA) is also reasonable, but slightly higher.

**QED:** Both ligands have good QED scores (0.366 and 0.818), with Ligand B being significantly better.

**DILI:** Ligand A (26.444) has a much lower DILI risk than Ligand B (71.229), which is a significant advantage.

**BBB:** Ligand A (63.784) has a moderate BBB penetration, while Ligand B (27.026) is poor. This is a critical difference for a CNS target like DRD2.

**Caco-2 Permeability:** Ligand A (-4.241) shows poor permeability, while Ligand B (-5.119) is even worse.

**Aqueous Solubility:** Ligand A (-1.707) and Ligand B (-2.64) both have poor solubility.

**hERG:** Both ligands have low hERG inhibition risk (0.517 and 0.273).

**Microsomal Clearance:** Ligand A (49.12) has moderate clearance, while Ligand B (9.969) has low clearance, suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (-13.555) has a very short half-life, while Ligand B (-4.173) is slightly better, but still short.

**P-gp Efflux:** Both ligands have low P-gp efflux (0.202 and 0.044), which is good for CNS penetration.

**Binding Affinity:** Ligand B (-8.6 kcal/mol) has a significantly stronger binding affinity than Ligand A (-6.9 kcal/mol). This is a substantial advantage.

**Overall Assessment:**

Ligand B has a much better binding affinity and metabolic stability. However, its low logP and poor BBB penetration are major drawbacks for a CNS target. Ligand A has a better logP and a reasonable BBB score, but its weak binding affinity and short half-life are concerning. The DILI score is also much better for Ligand A.

Considering the GPCR-specific priorities, the BBB is crucial. While Ligand B's affinity is excellent, its inability to cross the BBB effectively makes it less likely to be a viable drug candidate. Ligand A, despite its weaker affinity, has a more favorable profile for CNS penetration and lower toxicity. The affinity difference, while significant (1.7 kcal/mol), might be overcome with further optimization of Ligand A, whereas improving the BBB penetration of Ligand B would be a more substantial challenge.

Output:
0
2025-04-17 06:12:48,159 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (383.239 Da) is slightly higher than Ligand B (348.487 Da), but both are acceptable.

**2. TPSA:** Ligand A (93.01) is borderline for CNS targets (ideally <90), while Ligand B (49.85) is well within the desired range. This favors Ligand B.

**3. logP:** Both ligands have good logP values (Ligand A: 1.497, Ligand B: 2.324), falling within the optimal 1-3 range.

**4. H-Bond Donors:** Ligand A has 1 HBD, and Ligand B has 0. Both are within the acceptable limit of <=5.

**5. H-Bond Acceptors:** Ligand A has 6 HBA, and Ligand B has 3. Both are within the acceptable limit of <=10.

**6. QED:** Ligand A (0.641) has a better QED score than Ligand B (0.475), indicating a more drug-like profile.

**7. DILI:** Ligand A (79.643) has a higher DILI risk than Ligand B (15.2). This strongly favors Ligand B.

**8. BBB:** Ligand A (38.426) has a poor BBB penetration percentile, while Ligand B (68.67) is better, though still not ideal (>70 is preferred). This favors Ligand B.

**9. Caco-2:** Ligand A (-5.362) has a very poor Caco-2 permeability, suggesting poor absorption. Ligand B (-4.096) is also poor, but slightly better than A.

**10. Solubility:** Both ligands have poor aqueous solubility (-2.648 and -2.006 respectively). This is a concern for both, but not a deciding factor.

**11. hERG:** Both ligands have very low hERG inhibition risk (0.019 and 0.306 respectively), which is excellent.

**12. Cl_mic:** Ligand A (3.898) has significantly lower microsomal clearance than Ligand B (43.616), indicating better metabolic stability. This favors Ligand A.

**13. t1/2:** Ligand A (3.333) has a shorter in vitro half-life than Ligand B (11.719). This favors Ligand B.

**14. Pgp:** Ligand A (0.056) has lower P-gp efflux liability than Ligand B (0.086), which is favorable for CNS penetration.

**15. Binding Affinity:** Ligand A (-8.5 kcal/mol) has a significantly stronger binding affinity than Ligand B (-7.0 kcal/mol). This is a substantial advantage for Ligand A.

**Overall Assessment:**

While Ligand A has superior binding affinity and metabolic stability, its poor BBB penetration, high DILI risk, and very poor Caco-2 permeability are major drawbacks. Ligand B, despite its weaker affinity, exhibits a significantly better safety profile (lower DILI), better BBB penetration, and a longer half-life. For a CNS target like DRD2, BBB penetration and safety are paramount. The 1.5 kcal/mol affinity difference can potentially be overcome with further optimization, while fixing the ADME issues of Ligand A would likely require more substantial structural changes.

Output:
1
2025-04-17 06:12:48,159 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (337.427 Da) is slightly lower, which could be advantageous for permeability. Ligand B (394.871 Da) is still acceptable.

**TPSA:** Ligand A (90.75) is excellent for CNS penetration, being below the 90 A^2 threshold. Ligand B (58.64) is even better, indicating potentially improved brain penetration.

**logP:** Both ligands have good logP values (A: 4.39, B: 3.386), falling within the optimal range of 1-3, although A is a bit high.

**H-Bond Donors/Acceptors:** Both have 1 HBD and a reasonable number of HBAs (A: 3, B: 4), satisfying the <5 HBD and <10 HBA guidelines.

**QED:** Both ligands have acceptable QED values (A: 0.498, B: 0.771), with Ligand B being considerably more drug-like.

**DILI:** Both ligands have similar and acceptable DILI risk (A: 58.434, B: 55.68), both below the 60 threshold.

**BBB:** Both ligands show good BBB penetration (A: 74.254, B: 82.862), exceeding the 70% threshold for CNS targets. Ligand B is superior.

**Caco-2 Permeability:** Both have negative Caco-2 values (-4.954 and -4.775). This is unusual and suggests poor permeability. However, these values are on a log scale, and negative values are common for compounds with very low permeability.

**Aqueous Solubility:** Both have negative solubility values (-4.801 and -4.122), indicating very poor aqueous solubility. This is a significant concern for bioavailability.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (A: 0.841, B: 0.612), which is favorable.

**Microsomal Clearance:** Ligand A has a higher microsomal clearance (62.934) than Ligand B (22.621), suggesting faster metabolism and potentially lower in vivo exposure.

**In vitro Half-Life:** Ligand B has a slightly longer in vitro half-life (-0.423) than Ligand A (12.356), which is desirable.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (A: 0.462, B: 0.285), which is good for CNS exposure.

**Binding Affinity:** Ligand B (-8.4 kcal/mol) has a significantly stronger binding affinity than Ligand A (-9.9 kcal/mol). This >1.5 kcal/mol difference is a major advantage.

**Conclusion:**

While both compounds have some drawbacks (poor solubility and Caco-2 permeability), Ligand B is the more promising candidate. It exhibits:

*   Stronger binding affinity (-8.4 vs -9.9 kcal/mol)
*   Better QED score (0.771 vs 0.498)
*   Lower microsomal clearance (22.621 vs 62.934)
*   Longer in vitro half-life (-0.423 vs 12.356)
*   Superior BBB penetration (82.862 vs 74.254)
*   Lower P-gp efflux (0.285 vs 0.462)

The improved ADME properties and significantly stronger binding affinity of Ligand B outweigh the similar DILI and hERG risks and the shared solubility/permeability issues.

Output:
1
2025-04-17 06:12:48,160 - INFO - Reasoning:

Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight (MW):** Both ligands (370.431 and 343.431 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (115.89) is slightly above the optimal <90 for CNS targets, but still reasonable. Ligand B (80.12) is well within the desired range. This favors Ligand B.

**3. logP:** Ligand A (-0.385) is a bit low, potentially hindering membrane permeability. Ligand B (1.698) is within the optimal 1-3 range. This strongly favors Ligand B.

**4. H-Bond Donors (HBD):** Both ligands have acceptable HBD counts (2 and 1, respectively), well below the threshold of 5.

**5. H-Bond Acceptors (HBA):** Both ligands have acceptable HBA counts (5 each), below the threshold of 10.

**6. QED:** Both ligands have good QED scores (0.662 and 0.83), indicating good drug-like properties.

**7. DILI:** Ligand A (65.491) has a higher DILI risk than Ligand B (43.195), though both are not alarmingly high. This favors Ligand B.

**8. BBB:** Both ligands have similar BBB penetration (46.762 and 45.909). Neither is exceptional (>70), but acceptable given the affinity.

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.314 and -5.079), which is unusual and suggests poor permeability. This is a concern for both.

**10. Aqueous Solubility:** Both ligands have negative solubility values (-2.091 and -1.428), which is also unusual and suggests poor solubility. This is a concern for both.

**11. hERG Inhibition:** Both ligands have very low hERG risk (0.113 and 0.137).

**12. Microsomal Clearance (Cl_mic):** Ligand A (-2.881) has a negative clearance, which is not physically possible and suggests an issue with the data. Ligand B (40.338) has a relatively high clearance, indicating faster metabolism. This favors Ligand A, *assuming the negative value is an error*.

**13. In vitro Half-Life:** Ligand A (-6.641) has a negative half-life, which is not physically possible and suggests an issue with the data. Ligand B (18.653) has a reasonable half-life.

**14. P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.015 and 0.018).

**15. Binding Affinity:** Ligand B (-8.0 kcal/mol) has a slightly better binding affinity than Ligand A (-7.7 kcal/mol). While the difference is not huge, it's still a factor.

**Overall Assessment:**

Ligand B is significantly better overall. It has a more favorable logP, TPSA, and DILI profile. While both have issues with Caco-2 and solubility, the negative values for clearance and half-life for Ligand A are highly suspect and indicate a data quality issue. The slightly better affinity of Ligand B further strengthens its position. The BBB values are not ideal for either, but the stronger binding and better ADME properties of Ligand B make it the more promising candidate.

Output:
1
2025-04-17 06:12:48,160 - INFO - Batch 263 complete. Total preferences: 4208
2025-04-17 06:12:48,160 - INFO - Processing batch 264/512...
2025-04-17 06:13:34,927 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (356.813 and 349.431 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (70.99) is significantly better than Ligand B (84.67). For CNS targets, we want TPSA <= 90, and A is closer to the ideal <= 60 range. B is pushing the upper limit.

**logP:** Both ligands have good logP values (2.651 and 2.153), falling within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Both have 1 HBD, which is good. Ligand A has 4 HBA, while Ligand B has 5. Both are acceptable (<=10).

**QED:** Both ligands have good QED scores (0.728 and 0.763), indicating good drug-like properties.

**DILI:** Ligand A (74.952) has a higher DILI risk than Ligand B (47.034). This is a negative for A.

**BBB:** Ligand B (65.064) has a significantly better BBB penetration percentile than Ligand A (54.866). For a CNS target like DRD2, >70 is desirable, but 65 is better than 54.

**Caco-2 Permeability:** Ligand A (-5.21) has worse Caco-2 permeability than Ligand B (-4.621). Lower values indicate poorer permeability.

**Aqueous Solubility:** Ligand A (-3.871) has worse aqueous solubility than Ligand B (-2.704).

**hERG Inhibition:** Ligand A (0.614) has a slightly higher hERG inhibition risk than Ligand B (0.228). Lower is better.

**Microsomal Clearance:** Ligand B (48.832) has a significantly higher microsomal clearance than Ligand A (18.395). Lower clearance is preferred for better metabolic stability.

**In vitro Half-Life:** Ligand B (-11.382) has a worse in vitro half-life than Ligand A (-2.647). More negative values indicate shorter half-life.

**P-gp Efflux:** Ligand A (0.414) has a lower P-gp efflux liability than Ligand B (0.241). Lower efflux is better for CNS exposure.

**Binding Affinity:** Ligand B (-7.3) has a significantly stronger binding affinity than Ligand A (-10.2). This is a crucial advantage, as a >1.5 kcal/mol difference can outweigh other drawbacks.

**Overall Assessment:**

While Ligand A has better TPSA and P-gp efflux, Ligand B excels in the most critical areas for a CNS GPCR target: **Binding Affinity** and **BBB penetration**. The significantly stronger binding affinity of Ligand B (-7.3 vs -10.2 kcal/mol) is a major advantage. Although Ligand A has better metabolic stability (lower Cl_mic), the superior BBB and affinity of Ligand B outweigh this benefit. The DILI risk for Ligand B is also lower.

Output:
1
2025-04-17 06:13:34,927 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 drug candidates, considering the provided guidelines and GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (348.378 Da) is slightly lower, which is generally favorable for permeability. Ligand B (365.499 Da) is also good.

**2. TPSA:** Ligand A (95.37) is slightly above the preferred <90 for CNS targets, but still reasonable. Ligand B (71.53) is excellent, well below the 90 threshold. This favors Ligand B.

**3. logP:** Ligand A (3.961) is at the upper end of the optimal range (1-3), potentially raising concerns about solubility and off-target effects. Ligand B (1.953) is ideal. This strongly favors Ligand B.

**4. H-Bond Donors:** Ligand A (0) is good. Ligand B (1) is also acceptable.

**5. H-Bond Acceptors:** Ligand A (4) is good. Ligand B (5) is also acceptable.

**6. QED:** Both ligands have acceptable QED values (Ligand A: 0.358, Ligand B: 0.748). Ligand B's value is significantly better, indicating a more drug-like profile.

**7. DILI:** Ligand A (52.772) has a moderate DILI risk. Ligand B (37.34) has a lower, and more desirable, DILI risk.

**8. BBB:** Ligand A (83.908) has good BBB penetration, exceeding the 70% threshold. Ligand B (51.997) is below this threshold, a significant drawback for a CNS target. This favors Ligand A.

**9. Caco-2 Permeability:** Both have negative values, which is unusual. Assuming these are logP values, lower values indicate lower permeability. Ligand B (-4.913) is worse than Ligand A (-4.274).

**10. Aqueous Solubility:** Both have negative values, which is unusual. Assuming these are logS values, lower values indicate lower solubility. Ligand B (-1.995) is worse than Ligand A (-3.828).

**11. hERG Inhibition:** Both ligands have low hERG inhibition liability (Ligand A: 0.613, Ligand B: 0.274). Ligand B is slightly better.

**12. Microsomal Clearance:** Ligand A (34.462) has moderate clearance. Ligand B (25.995) has lower clearance, indicating better metabolic stability, which is favorable.

**13. In vitro Half-Life:** Ligand A (12.393) has a reasonable half-life. Ligand B (-1.165) has a very short half-life, which is a significant concern. This favors Ligand A.

**14. P-gp Efflux:** Ligand A (0.231) has low P-gp efflux, which is good for CNS exposure. Ligand B (0.098) has even lower efflux, which is excellent. This favors Ligand B.

**15. Binding Affinity:** Ligand A (-8.4) has significantly stronger binding affinity than Ligand B (0.0). This is a major advantage for Ligand A, potentially outweighing some of its ADME drawbacks.

**Overall Assessment:**

Ligand B has better physicochemical properties (logP, TPSA, QED, DILI, P-gp efflux, Cl_mic) and hERG liability. However, it suffers from poor BBB penetration and a very short half-life. Ligand A has a significantly stronger binding affinity and acceptable BBB penetration, despite a less ideal logP and moderate DILI risk.

Given the GPCR-specific priorities for a CNS target (DRD2), strong binding affinity and BBB penetration are crucial. The substantial difference in binding affinity (-8.4 vs 0.0 kcal/mol) is a decisive factor. While Ligand B has better ADME properties overall, its lack of BBB penetration and very short half-life are major liabilities that are unlikely to be overcome. Ligand A's strong affinity suggests it's more likely to achieve efficacy, and its BBB penetration is acceptable.

Output:
1
2025-04-17 06:13:34,928 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (411.3) is slightly higher than Ligand B (361.364), but both are acceptable.

**2. TPSA:**  Ligand A (78.53) is borderline for CNS targets (ideally <90), while Ligand B (69.72) is well within the desired range. This gives a slight edge to Ligand B.

**3. logP:** Ligand A (2.788) is optimal. Ligand B (0.77) is a bit low, potentially hindering membrane permeability.

**4. H-Bond Donors:** Both ligands have 1 HBD, which is good.

**5. H-Bond Acceptors:** Ligand A has 4 HBAs, and Ligand B has 3. Both are within the acceptable limit of 10.

**6. QED:** Both ligands have similar QED values (0.771 and 0.739), indicating good drug-likeness.

**7. DILI:** Ligand A (54.168) has a moderate DILI risk, while Ligand B (29.43) has a low risk. This is a significant advantage for Ligand B.

**8. BBB:** Ligand A (53.276) has a moderate BBB penetration, while Ligand B (82.435) has excellent BBB penetration. This is a crucial factor for a CNS target like DRD2, strongly favoring Ligand B.

**9. Caco-2 Permeability:** Both have negative values, indicating poor permeability. This is concerning for both, but the scale is unclear.

**10. Aqueous Solubility:** Both have negative values, indicating poor solubility. This is concerning for both, but the scale is unclear.

**11. hERG Inhibition:** Both ligands show low hERG inhibition risk (0.422 and 0.361).

**12. Microsomal Clearance:** Ligand A (66.538) has higher clearance than Ligand B (1.935), suggesting lower metabolic stability. This favors Ligand B.

**13. In vitro Half-Life:** Ligand B (-3.144) has a more negative value, indicating a longer half-life than Ligand A (-18.736). This is a significant advantage for Ligand B.

**14. P-gp Efflux:** Ligand A (0.216) has moderate P-gp efflux, while Ligand B (0.017) has very low efflux. Lower efflux is preferred for CNS penetration, favoring Ligand B.

**15. Binding Affinity:** Ligand A (-8.1) has a significantly stronger binding affinity than Ligand B (0.0). This is a substantial advantage for Ligand A.

**Overall Assessment:**

While Ligand A boasts a much stronger binding affinity, Ligand B demonstrates superior ADME properties, particularly regarding BBB penetration, DILI risk, metabolic stability, P-gp efflux, and half-life. For a CNS GPCR target like DRD2, these ADME properties are paramount. The substantial difference in binding affinity *could* be overcome with optimization, but the poor ADME profile of Ligand A makes it a less promising starting point. Ligand B's better balance of properties makes it the more viable drug candidate.

Output:
1
2025-04-17 06:13:34,928 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands fall within the ideal range (200-500 Da). Ligand A (348.531 Da) is slightly lower, which could be beneficial for permeability. Ligand B (402.651 Da) is still well within range.

**TPSA:** Ligand A (58.2) is better than Ligand B (50.27) as it is closer to the ideal TPSA for CNS targets (<90). Both are good.

**logP:** Both ligands have good logP values (A: 3.96, B: 3.646), falling within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A (HBD=2, HBA=2) is better than Ligand B (HBD=0, HBA=6). While both are acceptable, a moderate number of H-bonds can aid solubility without drastically hindering permeability.

**QED:** Both ligands have acceptable QED values (A: 0.54, B: 0.631), indicating reasonable drug-likeness.

**DILI:** Ligand A (33.889) has a significantly lower DILI risk than Ligand B (50.136), which is a major advantage.

**BBB:** Ligand B (71.966) has a slightly better BBB penetration percentile than Ligand A (61.497), but both are above the 70% threshold for CNS targets.

**Caco-2 Permeability:** Ligand A (-4.751) has a worse Caco-2 permeability than Ligand B (-5.489).

**Aqueous Solubility:** Ligand A (-4.268) has a worse Aqueous Solubility than Ligand B (-3.785).

**hERG:** Both ligands have low hERG inhibition liability (A: 0.418, B: 0.66), which is good.

**Microsomal Clearance:** Ligand A (71.061) has higher microsomal clearance than Ligand B (35.322), indicating lower metabolic stability.

**In vitro Half-Life:** Ligand B (7.254) has a longer in vitro half-life than Ligand A (-2.281), which is desirable.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (A: 0.452, B: 0.399), which is excellent for CNS penetration.

**Binding Affinity:** Ligand B (-6.4 kcal/mol) has a significantly stronger binding affinity than Ligand A (-0.0 kcal/mol). This is a crucial factor, as a >1.5 kcal/mol advantage can often outweigh minor ADME drawbacks.

**Overall Assessment:**

Ligand B is the stronger candidate. While Ligand A has a lower DILI risk and slightly better TPSA, the significantly stronger binding affinity of Ligand B (-6.4 kcal/mol vs -0.0 kcal/mol) is the deciding factor. The improved BBB, half-life, and acceptable ADME properties of Ligand B further support its selection. The difference in binding affinity is substantial enough to overcome the slightly higher DILI risk.

Output:
1
2025-04-17 06:13:34,928 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (348.334 Da) is slightly preferred as it's closer to the lower end, potentially aiding permeability.

**TPSA:** Ligand B (67.23) is significantly better than Ligand A (124.18). For CNS targets, a TPSA <= 90 is desirable, and Ligand B comfortably meets this, while Ligand A is pushing the limit.

**logP:** Ligand B (1.9) is optimal, while Ligand A (0.439) is quite low. A logP < 1 can hinder permeation. This is a significant advantage for Ligand B.

**H-Bond Donors/Acceptors:** Ligand A has 4 HBD and 5 HBA, while Ligand B has 1 HBD and 4 HBA. Both are acceptable, but Ligand B's lower HBD count is slightly preferable for permeability.

**QED:** Both ligands have good QED scores (A: 0.603, B: 0.78), indicating drug-like properties. Ligand B is slightly better.

**DILI:** Both have acceptable DILI risk (A: 64.288, B: 37.728), with Ligand B being preferable due to the lower percentile.

**BBB:** Ligand B (78.558) is much better than Ligand A (33.036) in terms of BBB penetration. This is *critical* for a CNS target like DRD2.

**Caco-2 Permeability:** Ligand A (-5.529) and Ligand B (-4.739) are both very poor. This is a concern for both, but less critical than BBB for a CNS target.

**Aqueous Solubility:** Both have poor aqueous solubility (-3.072 and -3.171). This could pose formulation challenges, but is less critical than BBB penetration for CNS drugs.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (A: 0.304, B: 0.286).

**Microsomal Clearance:** Ligand A (22.771) has lower clearance than Ligand B (50.576), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (-35.578) has a longer half-life than Ligand B (-39.652), which is desirable.

**P-gp Efflux:** Both have very low P-gp efflux liability (A: 0.021, B: 0.029).

**Binding Affinity:** Both have excellent binding affinity (-8.4 and -8.5 kcal/mol). The difference is negligible.

**Overall Assessment:**

Ligand B is significantly better due to its superior BBB penetration (78.558 vs 33.036) and logP (1.9 vs 0.439). While Ligand A has better metabolic stability (lower Cl_mic) and half-life, the BBB and logP are far more important for a CNS GPCR target. The TPSA of Ligand B is also significantly better. The slight advantage in DILI for Ligand B is a bonus.

Output:
1
2025-04-17 06:13:34,928 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (378.42 and 353.419 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (97.11) is better than Ligand B (104.9), both are below the 140 threshold for oral absorption, but closer to the 90 desired for CNS targets. Ligand A is preferable.

**3. logP:** Ligand A (2.956) is optimal (1-3), while Ligand B (0.521) is quite low, potentially hindering permeation. This is a significant advantage for Ligand A.

**4. H-Bond Donors:** Ligand A (3) and Ligand B (2) are both acceptable (<=5).

**5. H-Bond Acceptors:** Ligand A (4) and Ligand B (6) are both acceptable (<=10).

**6. QED:** Both ligands have similar QED values (0.735 and 0.706), indicating good drug-likeness.

**7. DILI:** Ligand A (59.829) has a slightly higher DILI risk than Ligand B (46.142), but both are below the concerning 60 threshold.

**8. BBB:** Ligand A (81.698) has a significantly better BBB penetration percentile than Ligand B (53.587). This is crucial for a CNS target like DRD2.

**9. Caco-2:** Both ligands have negative Caco-2 values (-4.97 and -4.883), which is unusual and suggests poor permeability. However, the values are very similar.

**10. Solubility:** Ligand A (-3.835) has slightly better solubility than Ligand B (-1.555), though both are poor.

**11. hERG:** Ligand A (0.087) has a lower hERG inhibition liability than Ligand B (0.224), indicating a lower risk of cardiotoxicity.

**12. Cl_mic:** Ligand A (25.96) has a lower microsomal clearance than Ligand B (38.974), suggesting better metabolic stability.

**13. t1/2:** Ligand B (17.704) has a longer in vitro half-life than Ligand A (-5.619). This is a positive for Ligand B, but the negative value for A is concerning.

**14. Pgp:** Ligand A (0.084) has lower P-gp efflux liability than Ligand B (0.094). Lower P-gp efflux is desirable for CNS exposure.

**15. Binding Affinity:** Ligand B (-7.6 kcal/mol) has a slightly better binding affinity than Ligand A (-8.0 kcal/mol). While a difference of 0.4 kcal/mol is not huge, it is a factor.

**Overall Assessment:**

Despite the slightly better affinity of Ligand B, Ligand A is the more promising candidate. The key advantages of Ligand A are its better logP, significantly improved BBB penetration, lower hERG risk, and lower microsomal clearance. These factors are particularly important for a CNS GPCR target like DRD2. The longer half-life of Ligand B is a plus, but the poor logP and lower BBB penetration are significant drawbacks. The negative Caco-2 values for both are concerning and would require further investigation, but the other ADME properties of Ligand A are more favorable overall.

Output:
1
2025-04-17 06:13:34,928 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the acceptable range (200-500 Da). Ligand A (348.4) is slightly preferred due to being closer to the ideal range.

**TPSA:** Ligand A (85.89) is excellent for CNS penetration, being well below 90. Ligand B (62.22) is also good, but slightly higher.

**logP:** Ligand A (1.331) is optimal. Ligand B (4.764) is high, potentially leading to solubility issues and off-target interactions.

**H-Bond Donors/Acceptors:** Both ligands have 2 HBD and 5/4 HBA, respectively, which are within acceptable limits.

**QED:** Ligand A (0.758) has a better QED score than Ligand B (0.643), indicating better overall drug-likeness.

**DILI:** Ligand A (65.917) has a higher DILI risk than Ligand B (52.152), but both are reasonably acceptable.

**BBB:** Ligand A (67.468) has a significantly better BBB percentile than Ligand B (37.146). This is *critical* for a CNS target like DRD2.

**Caco-2 Permeability:** Ligand A (-4.619) and Ligand B (-5.135) both have negative Caco-2 values, indicating poor permeability. This is a concern for both, but less critical than BBB for CNS targets.

**Aqueous Solubility:** Ligand A (-2.329) has slightly better solubility than Ligand B (-5.137).

**hERG Inhibition:** Ligand A (0.101) has a much lower hERG inhibition liability than Ligand B (0.345), making it safer from a cardiotoxicity perspective.

**Microsomal Clearance:** Ligand A (-2.476) has a lower (better) microsomal clearance than Ligand B (91.58). This suggests better metabolic stability for Ligand A.

**In vitro Half-Life:** Ligand A (19.802) has a longer half-life than Ligand B (5.387).

**P-gp Efflux:** Ligand A (0.037) has significantly lower P-gp efflux liability than Ligand B (0.415), which is crucial for CNS penetration.

**Binding Affinity:** Both ligands have very similar binding affinities (-8.6 and -8.4 kcal/mol). The difference is not substantial enough to outweigh the other significant differences.

**Overall Assessment:**

Ligand A is clearly superior. It has a better BBB score, lower logP, better QED, lower hERG risk, better metabolic stability (lower Cl_mic and longer t1/2), and lower P-gp efflux. While both have poor Caco-2 permeability, the CNS target prioritizes BBB penetration, where Ligand A excels. The similar binding affinities make the ADME/Tox advantages of Ligand A decisive.

Output:
0
2025-04-17 06:13:34,929 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 drug candidates, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (346.431 and 368.543 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (85.25) is better than Ligand B (60.85). Both are below the 90 A^2 threshold desirable for CNS targets, but A is slightly higher and could potentially impact BBB penetration.

**3. logP:** Both ligands have good logP values (1.442 and 2.334), falling within the optimal 1-3 range.

**4. H-Bond Donors:** Ligand A (2) is slightly higher than Ligand B (1), but both are acceptable (<=5).

**5. H-Bond Acceptors:** Ligand A (5) is slightly higher than Ligand B (4), but both are acceptable (<=10).

**6. QED:** Both ligands have good QED scores (0.708 and 0.782), indicating good drug-like properties.

**7. DILI:** Ligand A (23.614) has a significantly lower DILI risk than Ligand B (16.44). This is a substantial advantage.

**8. BBB:** Ligand B (68.554) has a considerably better BBB penetration percentile than Ligand A (54.013). This is a critical factor for a CNS target like DRD2.

**9. Caco-2 Permeability:** Ligand A (-5.309) has a worse Caco-2 permeability than Ligand B (-4.859). Both are negative, indicating poor permeability.

**10. Aqueous Solubility:** Ligand A (-1.611) has slightly better aqueous solubility than Ligand B (-2.895), but both are poor.

**11. hERG Inhibition:** Ligand A (0.077) has a much lower hERG inhibition liability than Ligand B (0.472), which is a significant safety advantage.

**12. Microsomal Clearance:** Ligand B (60.311) has a much higher microsomal clearance than Ligand A (10.191), indicating lower metabolic stability.

**13. In vitro Half-Life:** Ligand A (12.638) has a longer in vitro half-life than Ligand B (7.83), which is favorable.

**14. P-gp Efflux:** Ligand A (0.023) has a much lower P-gp efflux liability than Ligand B (0.2), suggesting better CNS exposure.

**15. Binding Affinity:** Ligand A (-7.8 kcal/mol) has a slightly better binding affinity than Ligand B (-7.1 kcal/mol). While the difference is less than the 1.5 kcal/mol threshold, it's still a positive factor.

**Overall Assessment:**

Ligand A excels in safety (DILI, hERG) and metabolic stability (Cl_mic, t1/2), and P-gp efflux. Ligand B has a better BBB penetration, but this is offset by its higher DILI risk, hERG liability, and poorer metabolic stability. Considering the GPCR-specific priorities, BBB is important, but not at the expense of significant safety concerns. The slightly better affinity of Ligand A, coupled with its superior safety and metabolic profile, makes it the more promising candidate.

Output:
0
2025-04-17 06:13:34,929 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (342.395 Da) is slightly lower, which could be beneficial for permeability.

**TPSA:** Ligand A (77.52) is better than Ligand B (49.41) as it is closer to the ideal range for CNS targets (<=90). Ligand B is quite low, potentially indicating reduced hydrogen bonding and possibly lower aqueous solubility.

**logP:** Both ligands have good logP values (A: 2.006, B: 3.206), falling within the optimal 1-3 range. Ligand B is slightly higher, which could lead to some off-target interactions or solubility issues, but is still acceptable.

**H-Bond Donors/Acceptors:** Both have 1 HBD, which is good. Ligand A has 5 HBA, while Ligand B has 3. Both are within the acceptable limits (<=10).

**QED:** Both ligands have similar QED values (A: 0.841, B: 0.815), indicating good drug-like properties.

**DILI:** Ligand A (67.39) has a higher DILI risk than Ligand B (22.993). This is a significant drawback for Ligand A.

**BBB:** Ligand B (75.301) has a significantly better BBB penetration percentile than Ligand A (68.399). This is crucial for a CNS target like DRD2.

**Caco-2 Permeability:** Ligand A (-4.876) has a worse Caco-2 permeability than Ligand B (-5.025). Both are negative, indicating poor permeability, but Ligand A is slightly better.

**Aqueous Solubility:** Ligand A (-2.323) has a better aqueous solubility than Ligand B (-4.313).

**hERG:** Both ligands have low hERG inhibition liability (A: 0.225, B: 0.314), which is good.

**Microsomal Clearance:** Ligand B (62.673) has lower microsomal clearance than Ligand A (67.335), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand B (-4.062) has a longer in vitro half-life than Ligand A (18.521). This is a significant advantage.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (A: 0.107, B: 0.185).

**Binding Affinity:** Ligand A (-8.4 kcal/mol) has a significantly stronger binding affinity than Ligand B (-7.0 kcal/mol). This is a substantial advantage.

**Overall Assessment:**

While Ligand A boasts a superior binding affinity, Ligand B demonstrates a much more favorable ADME profile, particularly regarding BBB penetration, DILI risk, and metabolic stability. The stronger binding of Ligand A might overcome some ADME issues, *but* the higher DILI risk and lower BBB are concerning. For a CNS target like DRD2, good brain penetration and low toxicity are paramount. The 1.4 kcal/mol difference in binding affinity is substantial, but not insurmountable with further optimization.

Output:
1
2025-04-17 06:13:34,929 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (346.431 Da) is slightly lower, which could be beneficial for permeability.

**TPSA:** Ligand A (94.48) is better than Ligand B (114.94). For CNS targets, TPSA should be <=90, and A is closer to this threshold.

**logP:** Ligand A (1.754) is optimal, while Ligand B (0.588) is a bit low, potentially hindering membrane permeability.

**H-Bond Donors/Acceptors:** Ligand A (HBD=1, HBA=6) is preferable to Ligand B (HBD=2, HBA=8) as it has fewer hydrogen bond forming groups, which generally improves permeability. Both are within acceptable limits.

**QED:** Both ligands have acceptable QED values (A: 0.896, B: 0.702), indicating good drug-like properties.

**DILI:** Both ligands have relatively high DILI risk (A: 52.036, B: 74.719), but Ligand A is better.

**BBB:** Ligand A (75.262) has a significantly better BBB penetration percentile than Ligand B (47.421). This is a *critical* factor for a CNS target like DRD2.

**Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and suggests poor permeability. However, the scale isn't defined, so it's difficult to interpret.

**Aqueous Solubility:** Both ligands have very poor aqueous solubility (-1.911 and -1.925). This is a concern for bioavailability.

**hERG Inhibition:** Both ligands have very low hERG inhibition risk (A: 0.26, B: 0.035).

**Microsomal Clearance:** Ligand A (-4.627) has much lower (better) microsomal clearance than Ligand B (33.017), indicating better metabolic stability.

**In vitro Half-Life:** Ligand A (9.333 hours) has a better in vitro half-life than Ligand B (-0.162 hours).

**P-gp Efflux:** Ligand A (0.072) has lower P-gp efflux than Ligand B (0.017), which is favorable for CNS penetration.

**Binding Affinity:** Ligand A (-8.8 kcal/mol) has a significantly stronger binding affinity than Ligand B (-7.5 kcal/mol). This is a substantial difference and a major advantage.

**Overall Assessment:**

Ligand A is clearly superior. It has better TPSA, logP, BBB penetration, metabolic stability (Cl_mic, t1/2), P-gp efflux, and significantly stronger binding affinity. While both have poor solubility and moderate DILI risk, the advantages of Ligand A, particularly its superior BBB and binding affinity, outweigh these drawbacks. The affinity difference of 1.3 kcal/mol is significant.

Output:
1
2025-04-17 06:13:34,929 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B against the provided guidelines, prioritizing GPCR-specific properties (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (366.286 Da) is slightly higher than Ligand B (347.415 Da), but both are acceptable.

**TPSA:** Ligand A (58.64) is excellent for CNS penetration, well below the 90 A^2 threshold. Ligand B (105.66) is higher, but still potentially acceptable, though less ideal.

**logP:** Ligand A (2.257) is optimal. Ligand B (-0.202) is significantly lower, potentially hindering membrane permeability and CNS penetration.

**H-Bond Donors/Acceptors:** Ligand A (HBD=1, HBA=3) is favorable. Ligand B (HBD=4, HBA=4) is slightly higher in both, but still within reasonable limits.

**QED:** Both ligands have acceptable QED values (A: 0.835, B: 0.592), indicating good drug-like properties.

**DILI:** Ligand A (54.517) has a moderate DILI risk, while Ligand B (11.981) has a very low risk.

**BBB:** Ligand A (85.847) shows excellent BBB penetration potential, exceeding the 70% threshold. Ligand B (18.534) has very poor predicted BBB penetration. This is a critical difference given the target is DRD2, a CNS receptor.

**Caco-2 Permeability:** Ligand A (-4.393) is poor, while Ligand B (-5.481) is also poor. This is less critical than BBB for a CNS target.

**Aqueous Solubility:** Ligand A (-2.602) and Ligand B (-1.799) are both poor.

**hERG:** Both ligands have low hERG risk (A: 0.641, B: 0.136).

**Microsomal Clearance:** Ligand A (1.124) has lower clearance than Ligand B (-10.259), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (-21.425) has a negative half-life, which is unusual and suggests rapid metabolism. Ligand B (-12.7) is also negative, but less so.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (A: 0.082, B: 0.004).

**Binding Affinity:** Both ligands have similar binding affinity (-8 kcal/mol and -8.5 kcal/mol respectively). The difference is negligible.

**Conclusion:**

Considering the GPCR-specific priorities, Ligand A is the more promising candidate. Its superior BBB penetration (85.8% vs. 18.5%), optimal logP (2.257 vs -0.202), and better metabolic stability (lower Cl_mic) outweigh its slightly higher DILI risk and poor Caco-2 permeability. While both have poor solubility and negative half-lives, the CNS target makes BBB and logP the most critical factors.

Output:
1
2025-04-17 06:13:34,930 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (352.41 and 340.471 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (94.56) is better than Ligand B (51.02). For CNS targets, we want TPSA <= 90, so Ligand A is closer to the threshold, but both are acceptable.

**logP:** Ligand A (-0.302) is suboptimal, being below the preferred 1-3 range. Ligand B (3.735) is excellent. This is a significant advantage for Ligand B.

**H-Bond Donors/Acceptors:** Ligand A has 3 HBD and 5 HBA, which is acceptable. Ligand B has 0 HBD and 4 HBA, also acceptable.

**QED:** Both ligands have good QED scores (0.586 and 0.833), indicating drug-likeness.

**DILI:** Ligand A (20.279) has a lower DILI risk than Ligand B (31.912), which is preferable.

**BBB:** Ligand B (74.564) has a significantly better BBB penetration score than Ligand A (37.573). This is *critical* for a CNS target like DRD2.

**Caco-2 Permeability:** Both have negative values (-5.263 and -4.737), which is unusual and suggests poor permeability. However, the scale is not specified, so it's hard to interpret.

**Aqueous Solubility:** Both have negative values (-1.135 and -4.14), suggesting poor solubility.

**hERG:** Both have low hERG inhibition risk (0.136 and 0.358).

**Microsomal Clearance:** Ligand A (-16.365) has much lower (better) microsomal clearance than Ligand B (77.589), indicating greater metabolic stability.

**In vitro Half-Life:** Ligand A (-6.777) has a shorter half-life than Ligand B (-10.769), which is less desirable.

**P-gp Efflux:** Ligand A (0.005) has a much lower P-gp efflux liability than Ligand B (0.331), which is a significant advantage for CNS penetration.

**Binding Affinity:** Ligand B (-9.6 kcal/mol) has a stronger binding affinity than Ligand A (-7.7 kcal/mol). This is a substantial advantage, exceeding the 1.5 kcal/mol threshold.

**Overall Assessment:**

Ligand B excels in key areas for a CNS GPCR target: logP, BBB penetration, and binding affinity. While Ligand A has better DILI and P-gp efflux, the superior BBB and affinity of Ligand B outweigh these benefits. The lower logP of Ligand A is a significant concern, potentially hindering its ability to cross the blood-brain barrier. The better metabolic stability of Ligand A is a plus, but can be addressed through structural modifications.

Output:
1
2025-04-17 06:13:34,930 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (358.463) is slightly higher than Ligand B (337.423), but both are acceptable.

**TPSA:** Ligand A (75.27) is higher than Ligand B (45.67). For CNS targets, we prefer TPSA <= 90, so both are within range, but Ligand B is significantly better.

**logP:** Both ligands have good logP values (A: 2.473, B: 2.809), falling within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A has 2 HBD and 3 HBA, while Ligand B has 0 HBD and 4 HBA. Both are within acceptable limits (<=5 HBD and <=10 HBA).

**QED:** Both ligands have good QED scores (A: 0.747, B: 0.842), indicating good drug-like properties.

**DILI:** Both ligands have moderate DILI risk (A: 60.799, B: 55.719). Ligand B is slightly better here.

**BBB:** This is a crucial parameter for CNS targets. Ligand B (83.249) has a significantly higher BBB penetration percentile than Ligand A (52.772). This is a major advantage for Ligand B.

**Caco-2 Permeability:** Both have negative Caco-2 values (-4.747 and -4.636). This is unusual and suggests poor permeability. However, these values are on a scale where negative values are possible, and direct comparison is difficult without knowing the scale's specifics.

**Aqueous Solubility:** Both have negative solubility values (-3.778 and -2.626), indicating poor aqueous solubility. This could be a formulation challenge.

**hERG Inhibition:** Ligand A (0.294) has a slightly lower hERG inhibition risk than Ligand B (0.877), which is preferable.

**Microsomal Clearance:** Ligand A (32.648) has a higher microsomal clearance than Ligand B (22.331), meaning it's less metabolically stable.

**In vitro Half-Life:** Ligand B (10.819) has a significantly longer in vitro half-life than Ligand A (-20.474). This is a significant advantage for Ligand B.

**P-gp Efflux:** Ligand A (0.105) has lower P-gp efflux liability than Ligand B (0.562), which is preferable for CNS exposure.

**Binding Affinity:** Both ligands have very similar and strong binding affinities (A: -10.1 kcal/mol, B: -9.9 kcal/mol). The difference is minor.

**Overall Assessment:**

Ligand B is the more promising candidate. Its superior BBB penetration (83.249 vs 52.772), longer half-life (10.819 vs -20.474), and lower microsomal clearance (22.331 vs 32.648) outweigh the slightly higher hERG risk and P-gp efflux. The lower TPSA of Ligand B is also beneficial. While both have poor solubility and Caco-2 permeability, the CNS target prioritizes BBB penetration, which Ligand B excels in. The binding affinities are comparable, so the ADME properties are the deciding factors.

Output:
1
2025-04-17 06:13:34,930 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (367.39 and 345.44 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (136.23) is borderline for CNS penetration, slightly above the preferred <90, but acceptable. Ligand B (71.53) is excellent, well below 90.

**logP:** Ligand A (0.276) is quite low, potentially hindering membrane permeability. Ligand B (2.175) is within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A has 2 HBD and 7 HBA, which are reasonable. Ligand B has 1 HBD and 4 HBA, also acceptable.

**QED:** Ligand A (0.371) is below the desirable 0.5 threshold, indicating a less drug-like profile. Ligand B (0.55) is above 0.5, suggesting better drug-likeness.

**DILI:** Ligand A (72.703) has a moderate DILI risk. Ligand B (29.081) has a very low DILI risk, a significant advantage.

**BBB:** Ligand A (51.299) has a low BBB penetration percentile, which is a major concern for a CNS target like DRD2. Ligand B (73.982) has a good BBB penetration percentile, a critical advantage.

**Caco-2 Permeability:** Ligand A (-5.447) has poor Caco-2 permeability. Ligand B (-4.89) also has poor Caco-2 permeability, but is slightly better than Ligand A.

**Aqueous Solubility:** Both ligands have very poor aqueous solubility (-2.93 and -2.095). This could pose formulation challenges.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.212 and 0.555).

**Microsomal Clearance:** Ligand A (27.189) has moderate clearance. Ligand B (7.633) has low clearance, indicating better metabolic stability.

**In vitro Half-Life:** Ligand A (-24.901) has a very short half-life. Ligand B (10.896) has a longer, though still not ideal, half-life.

**P-gp Efflux:** Ligand A (0.071) has low P-gp efflux, which is good. Ligand B (0.104) also has low P-gp efflux.

**Binding Affinity:** Ligand A (-8.6 kcal/mol) has slightly better binding affinity than Ligand B (-7.7 kcal/mol). However, the difference is not substantial enough to overcome the significant ADME deficiencies of Ligand A.

**Overall Assessment:**

Ligand B is the more promising candidate. While both have solubility issues, Ligand B excels in key areas for a CNS GPCR target: better logP, significantly better BBB penetration, lower DILI risk, and improved metabolic stability. The slightly weaker binding affinity of Ligand B is outweighed by its superior ADME properties, especially for a CNS target where brain exposure is paramount. Ligand A's poor logP and low BBB penetration are major drawbacks.

Output:
1
2025-04-17 06:13:34,930 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (450.244 Da) is higher, but still acceptable. Ligand B (345.443 Da) is lower, potentially aiding permeability.

**TPSA:** Both ligands have TPSA values below the 140 A^2 threshold for oral absorption. Importantly, both are *above* the 90 A^2 target for CNS penetration, but Ligand B (91.32 A^2) is closer to the desired value than Ligand A (104.62 A^2).

**logP:** Both ligands have logP values within the optimal range (1-3). Ligand A (1.639) and Ligand B (2.404) are both good.

**H-Bond Donors/Acceptors:** Ligand A has 2 HBD and 6 HBA, while Ligand B has 3 HBD and 4 HBA. Both are within acceptable limits (<=5 HBD and <=10 HBA).

**QED:** Both ligands have QED values above 0.5 (Ligand A: 0.591, Ligand B: 0.568), indicating good drug-like properties.

**DILI:** Ligand A has a higher DILI risk (84.994%) compared to Ligand B (32.92%). This is a significant negative for Ligand A.

**BBB:** Ligand B has a significantly better BBB penetration score (57.852%) than Ligand A (43.117%). For a CNS target like DRD2, this is a crucial advantage.

**Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and suggests a potential issue with the data or the model. However, the values are similar.

**Aqueous Solubility:** Both ligands have negative solubility values, which is also unusual. Again, the values are similar.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (Ligand A: 0.347, Ligand B: 0.254).

**Microsomal Clearance:** Ligand A has a lower microsomal clearance (31.978 mL/min/kg) than Ligand B (46.462 mL/min/kg), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand B has a significantly longer in vitro half-life (-19.926 hours) than Ligand A (-1.787 hours). This is a substantial advantage for Ligand B.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (Ligand A: 0.037, Ligand B: 0.078).

**Binding Affinity:** Ligand A has a better binding affinity (-9.5 kcal/mol) than Ligand B (-7.6 kcal/mol). This is a 1.9 kcal/mol difference, which is substantial and could potentially outweigh some ADME drawbacks.

**Overall Assessment:**

Despite Ligand A's superior binding affinity, Ligand B is the more promising candidate. The significantly better BBB penetration (57.852% vs 43.117%), lower DILI risk (32.92% vs 84.994%), and longer half-life (-19.926 vs -1.787) are critical advantages for a CNS-targeting GPCR. The 1.9 kcal/mol difference in binding affinity, while significant, can potentially be optimized in subsequent iterations of drug design. The unusual negative solubility and Caco-2 values are concerning and would require further investigation, but are similar for both compounds.

Output:
1
2025-04-17 06:13:34,930 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (364.408 and 363.845 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (58.64) is excellent, well below the 90 A^2 threshold for CNS targets. Ligand B (75.44) is still reasonable, but less optimal.

**logP:** Both ligands have good logP values (2.089 and 3.194), falling within the 1-3 range. Ligand B is slightly higher, potentially increasing off-target interactions, but not drastically.

**H-Bond Donors/Acceptors:** Both have 1 HBD and a reasonable number of HBAs (3 and 4 respectively), satisfying the <5 HBD and <10 HBA guidelines.

**QED:** Both ligands have good QED scores (0.604 and 0.766), indicating drug-like properties.

**DILI:** Ligand A (28.383) has a significantly lower DILI risk than Ligand B (56.34), which is a substantial advantage.

**BBB:** This is a critical parameter for a CNS target like DRD2. Ligand A (93.563) has excellent BBB penetration, exceeding the 70% threshold. Ligand B (37.146) is poor, indicating limited CNS exposure.

**Caco-2 Permeability:** Both have negative values, which is unusual. Assuming these are logP values, they indicate poor permeability.

**Aqueous Solubility:** Both ligands have negative solubility values, indicating poor solubility.

**hERG Inhibition:** Both ligands have low hERG inhibition liability (0.651 and 0.211), which is good.

**Microsomal Clearance:** Ligand B (79.839) has a higher microsomal clearance than Ligand A (35.77), suggesting faster metabolism and potentially lower exposure.

**In vitro Half-Life:** Ligand B (49.031) has a longer half-life than Ligand A (-4.503), which is a positive.

**P-gp Efflux:** Ligand A (0.205) has lower P-gp efflux liability than Ligand B (0.066), meaning it's less likely to be pumped out of the brain, improving CNS exposure.

**Binding Affinity:** Ligand B (-8.8 kcal/mol) has a significantly stronger binding affinity than Ligand A (-7.8 kcal/mol). This 1.0 kcal/mol difference is substantial and could outweigh some of the ADME drawbacks.

**Overall Assessment:**

While Ligand B boasts a superior binding affinity, Ligand A is the more promising candidate due to its significantly better BBB penetration (93.6% vs. 37.1%), lower DILI risk (28.4% vs. 56.3%), and lower P-gp efflux. These factors are crucial for a CNS-targeting drug, as they directly impact brain exposure and safety. The difference in binding affinity, while significant, might be overcome with further optimization of Ligand A. The poor solubility and permeability of both compounds are concerning and would need to be addressed during lead optimization.

Output:
0
2025-04-17 06:13:34,931 - INFO - Batch 264 complete. Total preferences: 4224
2025-04-17 06:13:34,931 - INFO - Processing batch 265/512...
2025-04-17 06:14:15,437 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (346.431 and 343.329 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (95.16) is higher than Ligand B (59.32). For CNS targets, TPSA < 90 is preferred. Ligand B is significantly better here.

**3. logP:** Ligand A (1.188) is within the optimal 1-3 range. Ligand B (3.834) is at the higher end, potentially leading to solubility issues but acceptable.

**4. H-Bond Donors:** Ligand A (2) and Ligand B (0) are both acceptable (<=5).

**5. H-Bond Acceptors:** Both ligands (A: 4, B: 4) are within the acceptable range (<=10).

**6. QED:** Both ligands have similar QED values (A: 0.775, B: 0.792), indicating good drug-likeness.

**7. DILI:** Ligand A (33.656) has a much lower DILI risk than Ligand B (65.529). This is a significant advantage for Ligand A.

**8. BBB:** Ligand B (84.374) has a substantially higher BBB penetration percentile than Ligand A (54.905). This is a critical factor for a CNS target like DRD2.

**9. Caco-2 Permeability:** Ligand A (-5.188) has a worse Caco-2 permeability than Ligand B (-3.846). However, both are negative, indicating poor permeability.

**10. Aqueous Solubility:** Ligand A (-2.067) has better aqueous solubility than Ligand B (-5.293).

**11. hERG Inhibition:** Ligand A (0.076) has a lower hERG inhibition liability than Ligand B (0.71). This is favorable for Ligand A.

**12. Microsomal Clearance:** Ligand B (83.581) has a much higher microsomal clearance than Ligand A (21.098), indicating lower metabolic stability. Ligand A is preferred.

**13. In vitro Half-Life:** Ligand A (-20.463) has a longer in vitro half-life than Ligand B (12.758). This is a significant advantage for Ligand A.

**14. P-gp Efflux:** Both ligands have similar P-gp efflux liability (A: 0.033, B: 0.321), but both are low, which is good.

**15. Binding Affinity:** Ligand B (-9.4) has a stronger binding affinity than Ligand A (-8). This is a significant advantage for Ligand B.

**Overall Assessment:**

Ligand B excels in BBB penetration and binding affinity, which are crucial for a CNS GPCR target. However, it suffers from higher DILI risk, higher microsomal clearance (lower metabolic stability), and lower solubility. Ligand A has a better safety profile (lower DILI, hERG), better metabolic stability, and better solubility. While its BBB penetration is lower, the affinity difference isn't large enough to completely outweigh the ADME/Tox advantages of Ligand A. The stronger binding of Ligand B could potentially be optimized later, but correcting the ADME liabilities is often more challenging.

Output:
1
2025-04-17 06:14:15,437 - INFO - Reasoning:

Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (348.403 and 363.567 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (113.18) is better than Ligand B (29.54). For CNS targets, we want TPSA <= 90, and Ligand B is significantly better in this regard.

**3. logP:** Ligand A (0.82) is suboptimal, being below the preferred 1-3 range. Ligand B (4.912) is high, potentially causing solubility issues and off-target effects.

**4. H-Bond Donors:** Ligand A (3) is acceptable, while Ligand B (0) is also good.

**5. H-Bond Acceptors:** Ligand A (5) is acceptable, while Ligand B (3) is also good.

**6. QED:** Both ligands have similar QED values (0.602 and 0.624), indicating good drug-like properties.

**7. DILI:** Ligand A (53.858) has a higher DILI risk than Ligand B (33.307), but both are reasonably low.

**8. BBB:** This is crucial for a CNS target like DRD2. Ligand B (71.229) is significantly better than Ligand A (48.313), exceeding the desirable >70 percentile.

**9. Caco-2 Permeability:** Ligand A (-5.308) has poor Caco-2 permeability, while Ligand B (-4.965) is also poor, but slightly better.

**10. Aqueous Solubility:** Ligand A (-2.04) has poor solubility, while Ligand B (-5.259) is even worse.

**11. hERG Inhibition:** Ligand A (0.095) has a very low hERG risk, which is excellent. Ligand B (0.834) is slightly higher, but still relatively low.

**12. Microsomal Clearance:** Ligand A (33.102) has a lower clearance than Ligand B (145.814), suggesting better metabolic stability.

**13. In vitro Half-Life:** Ligand A (-22.019) has a negative half-life, which is not possible. This is likely an error in the data. Ligand B (3.379) has a short half-life.

**14. P-gp Efflux:** Ligand A (0.017) has very low P-gp efflux, which is highly desirable for CNS penetration. Ligand B (0.839) has moderate P-gp efflux.

**15. Binding Affinity:** Ligand B (-7.7 kcal/mol) has a significantly better binding affinity than Ligand A (-8.1 kcal/mol). A 0.4 kcal/mol difference is substantial.

**Overall Assessment:**

Ligand B is the better candidate despite its higher logP and lower solubility. The significantly improved BBB penetration (71.229 vs 48.313) and substantially stronger binding affinity (-7.7 vs -8.1 kcal/mol) outweigh the drawbacks. The higher logP could be addressed with further medicinal chemistry optimization. Ligand A's poor Caco-2 permeability and negative half-life are major concerns.

Output:
1
2025-04-17 06:14:15,438 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (343.402 and 349.519 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (53.82) and Ligand B (52.65) are both below the 90 A^2 threshold for CNS targets, which is excellent.

**3. logP:** Both ligands have a logP around 2.4, which is optimal (1-3).

**4. H-Bond Donors:** Both have 1 HBD, well within the acceptable limit of <=5.

**5. H-Bond Acceptors:** Both have 3 HBA, also within the acceptable limit of <=10.

**6. QED:** Ligand A (0.906) has a significantly better QED score than Ligand B (0.718), indicating better overall drug-likeness.

**7. DILI:** Ligand A (53.276) has a slightly higher DILI risk than Ligand B (8.414), but both are below the concerning threshold of 60.

**8. BBB:** This is a crucial parameter for a CNS target like DRD2. Ligand A (85.537) has a substantially better BBB percentile than Ligand B (62.233). A value >70 is desirable, and Ligand A is closer to this target.

**9. Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and suggests poor permeability. However, the scale is not defined, so it's difficult to interpret.

**10. Aqueous Solubility:** Both have negative solubility values, again unusual and suggesting poor solubility. The scale is not defined, so it's difficult to interpret.

**11. hERG Inhibition:** Both ligands show very low hERG inhibition risk (0.508 and 0.314), which is excellent.

**12. Microsomal Clearance:** Ligand A (-2.887) has a *negative* microsomal clearance, which is not physically possible and likely indicates an error or unusual behavior in the prediction. Ligand B (34.918) has a moderate clearance. Lower is better, so Ligand A appears more metabolically stable, but the negative value is concerning.

**13. In vitro Half-Life:** Ligand A (-8.7) has a negative half-life, which is impossible. Ligand B (4.01) has a short half-life, which is not ideal.

**14. P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.093 and 0.05), which is favorable for CNS penetration.

**15. Binding Affinity:** Ligand A (-8.1 kcal/mol) has a slightly better binding affinity than Ligand B (-7.7 kcal/mol), although both are good (<-7.0 kcal/mol). The difference is 0.4 kcal/mol, which is not huge, but still a factor.

**Overall Assessment:**

Despite the unusual negative values for clearance and half-life for Ligand A, its superior BBB penetration (85.537 vs 62.233), higher QED (0.906 vs 0.718), and slightly better binding affinity (-8.1 vs -7.7) make it the more promising candidate. The negative values for clearance and half-life are red flags that would require further investigation, but the other properties are more favorable. Ligand B's moderate clearance and shorter half-life are less desirable.

Output:
1
2025-04-17 06:14:15,438 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B based on the provided guidelines, prioritizing GPCR-specific properties (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (351.451 and 365.499 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (79.58) is better than Ligand B (71.53) as it is closer to the ideal <90 for CNS targets.

**logP:** Ligand B (2.317) is optimal (1-3), while Ligand A (-0.358) is below 1, potentially hindering permeation. This is a significant drawback for Ligand A.

**H-Bond Donors/Acceptors:** Both have acceptable HBD (1) and HBA (6/5) counts.

**QED:** Both ligands have good QED scores (0.759 and 0.805), indicating drug-likeness.

**DILI:** Ligand A (21.908) has a much lower DILI risk than Ligand B (35.13), which is a positive attribute.

**BBB:** Ligand B (70.531) has a significantly better BBB penetration percentile than Ligand A (47.654). This is crucial for a CNS target like DRD2.

**Caco-2 Permeability:** Both have similar, very poor Caco-2 permeability (-4.864 and -4.844).

**Aqueous Solubility:** Both have poor aqueous solubility (-0.133 and -2.017).

**hERG:** Both have low hERG inhibition risk (0.258 and 0.408).

**Microsomal Clearance:** Ligand A (-4.867) has significantly better metabolic stability (lower clearance) than Ligand B (24.811).

**In vitro Half-Life:** Both have similar in vitro half-lives (5.236 and 5.645).

**P-gp Efflux:** Both have low P-gp efflux liability (0.013 and 0.118).

**Binding Affinity:** Ligand B (-7.6) has slightly better binding affinity than Ligand A (-7.4), but the difference is small (0.2 kcal/mol), and may not be enough to overcome other deficiencies.

**Overall Assessment:**

Ligand B excels in BBB penetration, which is paramount for a DRD2 ligand. It also has a better logP value. However, it has a higher DILI risk and worse metabolic stability. Ligand A has a much better safety profile (DILI, metabolic stability) but suffers from a poor logP and lower BBB penetration.

Considering the GPCR-specific priorities, the better BBB penetration of Ligand B is a significant advantage, even with the slightly higher DILI risk. The small difference in binding affinity isn't enough to outweigh the logP and BBB issues of Ligand A.

Output:
1
2025-04-17 06:14:15,438 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B based on the provided guidelines, prioritizing GPCR-specific properties (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (360.332 and 365.543 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (89.87) is better than Ligand B (61.44), both being below the 90 A^2 threshold for CNS targets.

**logP:** Ligand B (2.728) is optimal (1-3), while Ligand A (0.375) is quite low, potentially hindering permeation. This is a significant drawback for Ligand A.

**H-Bond Donors:** Ligand A (3) and Ligand B (2) are both acceptable, being less than 5.

**H-Bond Acceptors:** Both ligands (4) are within the acceptable limit of 10.

**QED:** Both ligands have good QED scores (0.724 and 0.745, respectively), indicating drug-like properties.

**DILI:** Both ligands have low DILI risk (37.03 and 34.393 percentiles), which is favorable.

**BBB:** Ligand B (64.948) is significantly better than Ligand A (49.515) regarding BBB penetration, crucial for a CNS target like DRD2. While >70 is desirable, 64.948 is a substantial improvement over 49.515.

**Caco-2 Permeability:** Ligand A (-4.926) is worse than Ligand B (-5.297). Lower values indicate poorer permeability.

**Aqueous Solubility:** Both ligands have poor aqueous solubility (-1.9 and -2.193). This could pose formulation challenges, but is less critical than CNS penetration for a CNS target.

**hERG Inhibition:** Both ligands have low hERG inhibition liability (0.455 and 0.664), which is good.

**Microsomal Clearance:** Ligand A (-21.017) has much lower (better) microsomal clearance than Ligand B (21.558). This suggests better metabolic stability for Ligand A.

**In vitro Half-Life:** Ligand B (26.038) has a longer half-life than Ligand A (-12.43). Longer half-life is generally preferred.

**P-gp Efflux:** Ligand A (0.038) has much lower P-gp efflux than Ligand B (0.183). Lower efflux is better for CNS exposure.

**Binding Affinity:** Ligand B (-7.8) has a slightly better binding affinity than Ligand A (-8.1). While both are excellent, the difference is relatively small.

**Overall Assessment:**

Ligand B is the stronger candidate. While Ligand A has better metabolic stability (lower Cl_mic) and P-gp efflux, the significantly lower logP and BBB penetration of Ligand A are major drawbacks for a CNS-targeting drug. Ligand B's logP is optimal, and its BBB penetration is considerably better, outweighing the slightly worse metabolic stability and P-gp efflux. The small difference in binding affinity is not enough to compensate for the ADME deficiencies of Ligand A.

Output:
1
2025-04-17 06:14:15,438 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (336.405 and 349.475 Da) fall within the ideal range of 200-500 Da.

**TPSA:** Ligand A (38.77) is excellent, well below the 90 A^2 threshold for CNS targets. Ligand B (67.6) is higher, but still potentially acceptable, though less ideal.

**logP:** Ligand A (4.764) is slightly high, potentially leading to solubility issues or off-target interactions. Ligand B (2.9) is within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A (0 HBD, 3 HBA) is favorable. Ligand B (1 HBD, 5 HBA) is also acceptable.

**QED:** Both ligands have good QED scores (0.651 and 0.781), indicating drug-like properties.

**DILI:** Ligand A (77.511) has a higher DILI risk than Ligand B (8.841). This is a significant drawback for Ligand A.

**BBB:** Ligand B (91.508) has excellent BBB penetration, exceeding the desirable >70% threshold. Ligand A (72.237) is also good, but not as high.

**Caco-2 Permeability:** Both have negative Caco-2 values which is unusual and suggests issues with the modeling or data. We'll proceed cautiously.

**Aqueous Solubility:** Both ligands have negative solubility values, which is also unusual and suggests issues with the modeling or data. We'll proceed cautiously.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.852 and 0.583).

**Microsomal Clearance:** Ligand A (30.058) has lower microsomal clearance, suggesting better metabolic stability than Ligand B (51.625).

**In vitro Half-Life:** Ligand A (-36.219) has a negative half-life, which is not possible. Ligand B (4.767) has a short half-life, which is a concern.

**P-gp Efflux:** Ligand A (0.498) has lower P-gp efflux, which is favorable for CNS penetration. Ligand B (0.111) has very low P-gp efflux, even more favorable.

**Binding Affinity:** Ligand B (-7.3 kcal/mol) has a significantly stronger binding affinity than Ligand A (-9.5 kcal/mol). This is a substantial advantage.

**Overall Assessment:**

Ligand B is the stronger candidate. While Ligand A has better metabolic stability, Ligand B excels in the most critical areas for a CNS-targeting GPCR ligand: BBB penetration, binding affinity, and lower DILI risk. The higher logP of Ligand A is a concern, and the negative values for solubility and Caco-2 permeability are red flags. The significantly stronger binding affinity of Ligand B (-7.3 vs -9.5 kcal/mol) is likely to outweigh the slightly higher metabolic clearance. The negative half-life for Ligand A is a showstopper.

Output:
1
2025-04-17 06:14:15,438 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (346.471 and 339.439 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (61.8) is slightly higher than Ligand B (54.34). Both are below the 90 A^2 threshold desirable for CNS targets, but Ligand B is closer to the optimal range.

**logP:** Ligand A (2.583) is within the optimal 1-3 range. Ligand B (4.423) is a bit high, potentially leading to solubility issues and off-target interactions.

**H-Bond Donors/Acceptors:** Ligand A has 2 HBD and 4 HBA, while Ligand B has 1 HBD and 3 HBA. Both are within acceptable limits.

**QED:** Both ligands have similar QED values (0.831 and 0.842), indicating good drug-likeness.

**DILI:** Both ligands have relatively high DILI risk (19.155 and 63.125), but Ligand A is significantly lower. This is a substantial advantage for Ligand A.

**BBB:** Ligand B (87.864) has a much higher BBB percentile than Ligand A (63.901). This is a critical advantage for a CNS target like DRD2.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.557 and -4.638), which is unusual and indicates very poor permeability. This is a major concern for both.

**Aqueous Solubility:** Both ligands have negative solubility values (-2.68 and -5.145), indicating very poor aqueous solubility. This is also a significant concern.

**hERG Inhibition:** Both ligands have low hERG inhibition liability (0.723 and 0.608), which is good.

**Microsomal Clearance:** Ligand B (69.531) has a higher microsomal clearance than Ligand A (28.778), suggesting lower metabolic stability.

**In vitro Half-Life:** Ligand B (48.422) has a significantly longer in vitro half-life than Ligand A (-4.354). This is a positive for Ligand B.

**P-gp Efflux:** Both ligands have similar low P-gp efflux liability (0.437 and 0.757), which is favorable for CNS penetration.

**Binding Affinity:** Both ligands have very similar and strong binding affinities (-8.9 and -8.8 kcal/mol). The difference is negligible.

**Overall Assessment:**

Ligand B excels in BBB penetration and in vitro half-life. However, its high logP, higher DILI risk, and higher microsomal clearance are concerning. Ligand A has a much lower DILI risk, which is a significant advantage. Both have poor Caco-2 permeability and solubility, which are major drawbacks. Given the importance of BBB for a CNS target, and the similar binding affinities, Ligand B appears slightly more promising *despite* the higher DILI and clearance. However, the poor permeability and solubility of both compounds are substantial hurdles.

Output:
1
2025-04-17 06:14:15,439 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (353.507 and 368.499 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (70.67) is significantly better than Ligand B (86.71). For CNS targets, we want TPSA <= 90, and A is closer to the ideal <= 60 range. B is pushing the upper limit.

**logP:** Ligand A (1.543) is optimal, while Ligand B (0.575) is a bit low, potentially hindering membrane permeability.

**H-Bond Donors/Acceptors:** Both have 2 HBD and 4 HBA, which are within acceptable limits.

**QED:** Both ligands have similar QED values (0.625 and 0.695), indicating good drug-likeness.

**DILI:** Ligand A (10.702) has a much lower DILI risk than Ligand B (55.952). This is a significant advantage for A.

**BBB:** Ligand A (65.452) has a considerably better BBB penetration score than Ligand B (45.366). While >70 is desirable, 65.452 is a reasonable starting point, whereas 45.366 is concerning for a CNS target.

**Caco-2 Permeability:** Both have negative Caco-2 values (-4.712 and -4.812), which is unusual and suggests poor permeability. However, these values are on a log scale and are difficult to interpret without knowing the base.

**Aqueous Solubility:** Ligand A (-1.543) is better than Ligand B (-3.11), indicating better solubility.

**hERG Inhibition:** Both have low hERG inhibition risk (0.218 and 0.338).

**Microsomal Clearance:** Ligand A (38.824) has higher clearance than Ligand B (35.167), meaning B is more metabolically stable.

**In vitro Half-Life:** Ligand B (-43.697) has a much longer in vitro half-life than Ligand A (0.925). This is a significant advantage for B.

**P-gp Efflux:** Both have low P-gp efflux liability (0.02 and 0.121).

**Binding Affinity:** Ligand B (-7.9) has a slightly stronger binding affinity than Ligand A (-7.0), a 0.9 kcal/mol difference.

**Overall Assessment:**

Considering the GPCR-specific priorities, Ligand A is more promising. Its superior TPSA, logP, DILI risk, and BBB penetration are crucial for a CNS-targeting drug. While Ligand B has a slightly better binding affinity and a much better half-life, the differences in affinity are not substantial enough to outweigh the ADME advantages of Ligand A, especially for a CNS target where BBB penetration is critical. The negative Caco-2 values are a concern for both, but the other properties of A are more favorable.

Output:
0
2025-04-17 06:14:15,439 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (346.274 Da) is slightly lower, which could be beneficial for permeability. Ligand B (386.279 Da) is also good.

**TPSA:** Ligand A (123.46) is closer to the ideal range for CNS targets (<=90), but still slightly above. Ligand B (80.32) is excellent, well within the desired range. This favors Ligand B.

**logP:** Ligand A (1.354) is within the optimal range (1-3). Ligand B (3.311) is at the higher end of optimal, but still acceptable.

**H-Bond Donors/Acceptors:** Both ligands have 2 HBD and a reasonable number of HBA (7 for A, 4 for B). This is acceptable for both.

**QED:** Both ligands have acceptable QED values (0.486 and 0.581), indicating reasonable drug-likeness. Ligand B is slightly better.

**DILI:** Ligand A has a very high DILI risk (99.147), which is a significant concern. Ligand B has a much lower DILI risk (54.401), making it more favorable.

**BBB:** Ligand A has a moderate BBB penetration (63.474), which isn't ideal for a CNS target. Ligand B has a slightly lower BBB penetration (57.464), but still not great. However, given the other factors, this isn't a dealbreaker.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values, which is unusual and suggests poor permeability. This is a concern for both.

**Aqueous Solubility:** Both ligands have negative solubility values, indicating very poor solubility. This is a significant drawback for both.

**hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.207 and 0.208), which is excellent.

**Microsomal Clearance:** Ligand A has a lower microsomal clearance (9.355) than Ligand B (47.107), indicating better metabolic stability. This favors Ligand A.

**In vitro Half-Life:** Ligand A has a longer half-life (32.58 hours) than Ligand B (23.34 hours), which is preferable. This favors Ligand A.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.149 and 0.038), which is excellent for CNS penetration. Ligand B is slightly better.

**Binding Affinity:** Ligand A (-10.3 kcal/mol) has significantly stronger binding affinity than Ligand B (-8.2 kcal/mol). This is a major advantage for Ligand A, potentially outweighing some of its ADME drawbacks.

**Overall Assessment:**

Ligand A has a much stronger binding affinity and better metabolic stability and half-life. However, it has a very high DILI risk. Ligand B has a lower DILI risk, better TPSA, and slightly better P-gp efflux, but significantly weaker binding affinity.

Given the importance of potency for GPCR ligands, and the substantial difference in binding affinity (-10.3 vs -8.2 kcal/mol), the stronger binding of Ligand A is likely to be more important than its higher DILI risk, *provided* that the DILI risk can be mitigated through structural modifications. The poor solubility and permeability are concerns for both, but can also be addressed through formulation or prodrug strategies.

Output:
0
2025-04-17 06:14:15,439 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (365.905 and 351.451 Da) fall within the ideal range of 200-500 Da.

**TPSA:** Ligand A (71.09) is excellent, well below the 90 A^2 threshold for CNS targets. Ligand B (130.23) is higher, but still potentially acceptable, though less ideal.

**logP:** Ligand A (4.237) is slightly high, potentially leading to solubility issues or off-target interactions. Ligand B (1.013) is a bit low, which could hinder permeation.

**H-Bond Donors/Acceptors:** Ligand A (HBD=2, HBA=3) is within acceptable limits. Ligand B (HBD=4, HBA=6) is also acceptable, but approaching the upper limits.

**QED:** Both ligands have reasonable QED values (0.677 and 0.525), suggesting decent drug-like properties.

**DILI:** Ligand A (37.224) has a lower DILI risk than Ligand B (52.036), which is preferable.

**BBB:** Ligand A (78.713) has a significantly better BBB penetration percentile than Ligand B (65.374). This is a *critical* advantage for a CNS target like DRD2.

**Caco-2 Permeability:** Ligand A (-4.958) shows poor Caco-2 permeability, which is concerning. Ligand B (-5.613) is also poor, but slightly worse.

**Aqueous Solubility:** Ligand A (-3.764) has poor aqueous solubility, consistent with its high logP. Ligand B (-2.147) is better, but still not ideal.

**hERG Inhibition:** Both ligands show low hERG inhibition risk (0.441 and 0.302).

**Microsomal Clearance:** Ligand A (56.163) has higher microsomal clearance, suggesting lower metabolic stability. Ligand B (17.331) has much lower clearance, indicating better metabolic stability.

**In vitro Half-Life:** Ligand A (52.47) has a better in vitro half-life than Ligand B (-8.228).

**P-gp Efflux:** Ligand A (0.214) has lower P-gp efflux, which is beneficial for CNS penetration. Ligand B (0.023) has even lower efflux, which is even more favorable.

**Binding Affinity:** Ligand A (-8.7 kcal/mol) has a significantly stronger binding affinity than Ligand B (-7.1 kcal/mol). This 1.6 kcal/mol difference is substantial and can outweigh some ADME drawbacks.

**Overall Assessment:**

Ligand A's primary strengths are its excellent TPSA, strong binding affinity, good BBB penetration, and low DILI risk. Its weaknesses are its high logP, poor Caco-2 permeability, and moderate metabolic stability.

Ligand B has better metabolic stability and P-gp efflux, but its lower affinity and BBB penetration are significant drawbacks for a CNS target. Its TPSA is also less ideal.

Given the importance of BBB penetration and binding affinity for a CNS GPCR target, the stronger affinity and better BBB score of Ligand A outweigh its ADME liabilities. While the solubility and permeability are concerns, these can potentially be addressed through formulation strategies.

Output:
1
2025-04-17 06:14:15,439 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 drug candidates, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (348.443 and 354.42 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (101.65) is better than Ligand B (44.81). For CNS targets, TPSA should be <= 90. Ligand A is slightly above this, but Ligand B is well below, which could indicate poor binding.

**3. logP:** Ligand A (1.299) is optimal (1-3), while Ligand B (4.519) is high. High logP can lead to solubility issues and off-target effects.

**4. H-Bond Donors:** Ligand A (3) is acceptable, while Ligand B (1) is also good.

**5. H-Bond Acceptors:** Ligand A (5) is acceptable, while Ligand B (3) is also good.

**6. QED:** Both ligands have good QED scores (0.645 and 0.758, respectively), indicating drug-like properties.

**7. DILI:** Ligand A (9.112) has a much lower DILI risk than Ligand B (34.471), which is a significant advantage.

**8. BBB:** Ligand B (80.031) has a significantly better BBB penetration score than Ligand A (55.913). This is a critical factor for CNS targets like DRD2.

**9. Caco-2 Permeability:** Both have negative values, indicating poor permeability. Ligand A (-4.81) is slightly better than Ligand B (-4.932).

**10. Aqueous Solubility:** Both have negative values, indicating poor solubility. Ligand A (-1.468) is slightly better than Ligand B (-4.189).

**11. hERG Inhibition:** Ligand A (0.243) has a lower hERG inhibition risk than Ligand B (0.948), which is preferable.

**12. Microsomal Clearance:** Ligand B (25.453) has lower microsomal clearance than Ligand A (32.83), suggesting better metabolic stability.

**13. In vitro Half-Life:** Ligand B (12.777) has a longer in vitro half-life than Ligand A (-11.923), which is desirable.

**14. P-gp Efflux:** Ligand A (0.081) has lower P-gp efflux than Ligand B (0.319), which is better for CNS exposure.

**15. Binding Affinity:** Ligand B (-7.3) has a slightly better binding affinity than Ligand A (-8.2). However, the difference is not substantial enough to outweigh the other significant drawbacks of Ligand B.

**Overall Assessment:**

Ligand A is the better candidate. While Ligand B has a better BBB score and affinity, its high logP, higher DILI risk, and higher P-gp efflux are significant concerns. Ligand A has a more balanced profile, with acceptable logP, lower DILI, lower hERG, and lower P-gp efflux. The slightly lower BBB score of Ligand A can potentially be addressed through further optimization, but the issues with Ligand B are more difficult to resolve.

Output:
0
2025-04-17 06:14:15,439 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (352.519 and 364.471 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (78.43) is better than Ligand B (84.42). Both are below the 90 A^2 threshold desirable for CNS targets, but A is closer to the optimal range.

**logP:** Ligand A (2.787) is within the optimal 1-3 range. Ligand B (1.632) is at the lower end, potentially impacting permeability.

**H-Bond Donors/Acceptors:** Ligand A has 3 HBD and 3 HBA, which is good. Ligand B has 1 HBD and 6 HBA. Both are within acceptable limits, but A is slightly more balanced.

**QED:** Ligand B (0.821) has a better QED score than Ligand A (0.588), suggesting a more drug-like profile overall.

**DILI:** Ligand A (24.506) has a significantly lower DILI risk than Ligand B (68.282). This is a major advantage for Ligand A.

**BBB:** Ligand B (64.211) has a better BBB penetration score than Ligand A (53.858), but neither is above the desirable 70% threshold for CNS targets.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.68 and -4.882), which is unusual and suggests poor permeability. This is a significant concern for both.

**Aqueous Solubility:** Both ligands have negative solubility values (-3.365 and -2.71), indicating poor aqueous solubility. This is a concern for both.

**hERG Inhibition:** Both ligands have low hERG inhibition liability (0.415 and 0.168), which is good.

**Microsomal Clearance:** Ligand B (46.415) has a lower microsomal clearance than Ligand A (57.453), indicating better metabolic stability.

**In vitro Half-Life:** Ligand A (17.374) has a longer in vitro half-life than Ligand B (-16.226). The negative value for B is concerning and likely an error or indicates very rapid degradation.

**P-gp Efflux:** Ligand A (0.256) has lower P-gp efflux liability than Ligand B (0.152), which is better for CNS exposure.

**Binding Affinity:** Ligand B (-8.8 kcal/mol) has a significantly stronger binding affinity than Ligand A (-7.2 kcal/mol). This is a substantial advantage for Ligand B, potentially outweighing some of its ADME drawbacks.

**Overall Assessment:**

Ligand B has a significantly better binding affinity and a better QED score. However, it has a higher DILI risk, lower metabolic stability, and a concerning negative in vitro half-life. Ligand A has a lower DILI risk, better P-gp efflux, and a longer half-life. Both have poor Caco-2 permeability and solubility.

Given the importance of binding affinity for GPCRs, and the substantial difference (-8.8 vs -7.2 kcal/mol), Ligand B is more likely to be a viable drug candidate *despite* its ADME liabilities. The stronger binding could allow for lower dosing, potentially mitigating some of the ADME issues. The negative half-life for B is a red flag, but could be an experimental artifact.

Output:
1
2025-04-17 06:14:15,440 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B based on the provided guidelines, prioritizing GPCR-specific properties (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (356.35 and 358.435 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (101.24) is slightly above the optimal <90 for CNS targets, while Ligand B (86.33) is comfortably within the range. This favors Ligand B.

**logP:** Ligand A (-0.012) is quite low, potentially hindering permeation. Ligand B (1.918) is within the optimal 1-3 range. This is a significant advantage for Ligand B.

**H-Bond Donors/Acceptors:** Ligand A has 2 HBD and 6 HBA, while Ligand B has 1 HBD and 6 HBA. Both are within acceptable limits.

**QED:** Both ligands have good QED scores (0.743 and 0.808), indicating good drug-like properties.

**DILI:** Ligand A (54.091) has a higher DILI risk than Ligand B (29.701). This favors Ligand B.

**BBB:** Ligand B (80.07) has a significantly higher BBB percentile than Ligand A (57.736). This is a crucial advantage for a CNS target like DRD2.

**Caco-2 Permeability:** Both have negative values, which is unusual. Assuming these are percentile scores, Ligand A (-4.988) appears to have worse permeability than Ligand B (-4.351), though both are poor.

**Aqueous Solubility:** Both ligands have negative solubility values, which is also unusual. Assuming these are percentile scores, Ligand A (-1.586) appears to have slightly better solubility than Ligand B (-2.069).

**hERG:** Both ligands have low hERG inhibition liability (0.315 and 0.274), which is good.

**Microsomal Clearance:** Ligand A (-9.983) has a much lower (better) microsomal clearance than Ligand B (41.222), indicating greater metabolic stability. This favors Ligand A.

**In vitro Half-Life:** Ligand A (27.096) has a longer half-life than Ligand B (-0.618). This is a significant advantage for Ligand A.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.02 and 0.011), which is good.

**Binding Affinity:** Both ligands have strong binding affinities (-8 and -6.8 kcal/mol). Ligand A is 1.2 kcal/mol stronger, which is a substantial advantage and can outweigh some ADME drawbacks.

**Overall Assessment:**

Ligand B excels in key GPCR properties like TPSA and BBB penetration, and has a lower DILI risk. However, Ligand A has a significantly stronger binding affinity and better metabolic stability (lower Cl_mic and longer t1/2). The stronger binding affinity of Ligand A is a major advantage, and the improved metabolic stability could be crucial for maintaining therapeutic concentrations *in vivo*. While Ligand B's better BBB is desirable, the difference in affinity is substantial enough to potentially overcome this. The low logP of Ligand A is a concern, but formulation strategies could potentially mitigate this.

Output:
1
2025-04-17 06:14:15,440 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands fall within the ideal range (200-500 Da). Ligand A (347.39 Da) is slightly lower, which is generally favorable for permeability.

**2. TPSA:** Ligand A (73.48) is significantly better than Ligand B (58.22). For a CNS target like DRD2, a TPSA <= 90 is desired, and A is closer to the optimal range for brain penetration.

**3. logP:** Ligand A (1.108) is within the optimal range (1-3). Ligand B (4.391) is higher, potentially leading to solubility issues and off-target interactions.

**4. H-Bond Donors:** Both ligands have 1 HBD, which is acceptable.

**5. H-Bond Acceptors:** Ligand A has 3 HBAs, and Ligand B has 5. Both are within the acceptable limit of <=10, but A is preferable.

**6. QED:** Ligand A (0.811) has a better QED score than Ligand B (0.666), indicating a more drug-like profile.

**7. DILI:** Ligand A (42.536) has a much lower DILI risk than Ligand B (75.998). This is a significant advantage for A.

**8. BBB:** Ligand A (65.529) has a better BBB percentile than Ligand B (44.785). While >70 is highly desirable for CNS targets, A is still better positioned for brain penetration.

**9. Caco-2 Permeability:** Ligand A (-4.51) is better than Ligand B (-5.309). Higher values indicate better intestinal absorption.

**10. Aqueous Solubility:** Ligand A (-2.394) is better than Ligand B (-4.482). Higher values indicate better solubility.

**11. hERG Inhibition:** Ligand A (0.37) has a lower hERG inhibition liability than Ligand B (0.568), reducing the risk of cardiotoxicity.

**12. Microsomal Clearance:** Ligand A (-6.76) has a lower (better) microsomal clearance than Ligand B (113.255), suggesting greater metabolic stability.

**13. In vitro Half-Life:** Ligand A (-31.261) has a better in vitro half-life than Ligand B (-15.561).

**14. P-gp Efflux:** Ligand A (0.061) has a lower P-gp efflux liability than Ligand B (0.488), which is crucial for CNS exposure.

**15. Binding Affinity:** Ligand B (-7.7) has a slightly better binding affinity than Ligand A (-8.2). However, the difference is relatively small (0.5 kcal/mol), and the significant advantages of Ligand A in ADME properties outweigh this slight difference in binding.

**Overall:**

Ligand A consistently outperforms Ligand B across most critical ADME properties, especially those prioritized for GPCRs targeting the CNS (BBB, logP, Pgp, TPSA). While Ligand B has a slightly better binding affinity, Ligand A's superior drug-like properties, lower toxicity risk, and better potential for brain penetration make it the more promising drug candidate.

Output:
0
2025-04-17 06:14:15,440 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (359.442 Da) is slightly lower, which could be beneficial for permeability, but both are acceptable.

**TPSA:** Ligand A (101.73) is better than Ligand B (69.64) as it is closer to the optimal range for CNS targets (<=90). Ligand B is quite low, which might suggest a lack of necessary interactions.

**logP:** Both ligands have acceptable logP values (A: 0.757, B: 2.309), falling within the 1-3 range. Ligand B is slightly better.

**H-Bond Donors/Acceptors:** Both have 2 HBDs, which is good. Ligand A has 4 HBAs, and Ligand B has 5 HBAs, both acceptable.

**QED:** Both ligands have good QED scores (A: 0.7, B: 0.792), indicating good drug-like properties.

**DILI:** Both ligands have low DILI risk (A: 34.393, B: 31.601), which is favorable.

**BBB:** Ligand A (78.829) has a significantly better BBB percentile than Ligand B (66.615). This is a critical advantage for a CNS target like DRD2.

**Caco-2 Permeability:** Ligand A (-5.006) has a better Caco-2 permeability than Ligand B (-5.281).

**Aqueous Solubility:** Ligand A (-2.762) has better aqueous solubility than Ligand B (-3.78).

**hERG:** Both ligands have very low hERG risk (A: 0.365, B: 0.239).

**Microsomal Clearance:** Ligand A (18.589) has a higher microsomal clearance than Ligand B (5.67), suggesting lower metabolic stability. This is a negative for Ligand A.

**In vitro Half-Life:** Ligand A (-10.746) has a shorter half-life than Ligand B (-6.498). This is a negative for Ligand A.

**P-gp Efflux:** Ligand A (0.065) has lower P-gp efflux than Ligand B (0.175), which is favorable for CNS penetration.

**Binding Affinity:** Ligand B (-8.4 kcal/mol) has a significantly stronger binding affinity than Ligand A (-6.5 kcal/mol). This is a major advantage for Ligand B, potentially outweighing some of its ADME drawbacks. The difference of 1.9 kcal/mol is substantial.

**Overall Assessment:**

Ligand B has a significantly stronger binding affinity, which is paramount for GPCR targets. While Ligand A has a better BBB score and lower P-gp efflux, the difference in affinity is substantial enough to overcome the slightly lower BBB and higher P-gp efflux of Ligand B. The metabolic stability and half-life are better for Ligand B as well.

Output:
1
2025-04-17 06:14:15,440 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B against the provided guidelines, prioritizing GPCR-specific properties (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (346.431 and 354.447 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (83.56) is better than Ligand B (88.1), both are below the 90 A^2 threshold for CNS targets.

**logP:** Ligand A (2.036) is optimal (1-3), while Ligand B (0.306) is quite low, potentially hindering permeability.

**H-Bond Donors/Acceptors:** Both have 2 HBD and 5 HBA, which are within acceptable limits.

**QED:** Both ligands have good QED scores (0.875 and 0.687, respectively), indicating drug-like properties.

**DILI:** Ligand A (49.632) has a moderate DILI risk, while Ligand B (14.851) is very low risk.

**BBB:** Ligand A (70.841) is good for CNS penetration, while Ligand B (38.813) is considerably lower, suggesting poor brain exposure. This is a critical difference given the target (DRD2).

**Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and difficult to interpret without knowing the scale. However, the values are similar.

**Aqueous Solubility:** Both have negative solubility values, which is also unusual and difficult to interpret. Ligand B (-1.343) is slightly better than Ligand A (-3.535).

**hERG:** Both ligands have low hERG inhibition liability (0.666 and 0.151), which is favorable.

**Microsomal Clearance:** Ligand A (34.54) has a higher clearance than Ligand B (5.259), indicating lower metabolic stability.

**In vitro Half-Life:** Ligand B (14.689) has a longer half-life than Ligand A (7.565).

**P-gp Efflux:** Ligand A (0.043) has lower P-gp efflux liability than Ligand B (0.012), which is beneficial for CNS penetration.

**Binding Affinity:** Ligand A (-8.4 kcal/mol) has a significantly stronger binding affinity than Ligand B (-7.5 kcal/mol). The 0.9 kcal/mol difference is substantial and can outweigh some ADME drawbacks.

**Conclusion:**

Despite Ligand B having a better DILI score and half-life, Ligand A is the stronger candidate. The superior binding affinity (-8.4 vs -7.5 kcal/mol) is a major advantage. Critically, Ligand A's BBB penetration (70.841) is much better than Ligand B's (38.813), which is essential for a CNS target like DRD2. While Ligand A has slightly higher DILI risk and lower metabolic stability, the improved affinity and BBB penetration are more important for this specific target class. The logP value of Ligand A is also more favorable.

Output:
1
2025-04-17 06:14:15,440 - INFO - Batch 265 complete. Total preferences: 4240
2025-04-17 06:14:15,441 - INFO - Processing batch 266/512...
2025-04-17 06:14:55,837 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (340.427 Da) is slightly better, being closer to the lower end which can aid permeability.

**TPSA:** Ligand B (49.41) is significantly better than Ligand A (70.44). For CNS targets, we want TPSA <= 90, and lower is preferable. Ligand B is well within this range, while Ligand A is approaching the upper limit.

**logP:** Both ligands have good logP values (A: 3.35, B: 2.912), falling within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A has 2 HBD and 5 HBA, while Ligand B has 1 HBD and 2 HBA. Both are within acceptable limits (<=5 HBD and <=10 HBA).

**QED:** Both ligands have good QED scores (A: 0.623, B: 0.731), indicating good drug-like properties.

**DILI:** Ligand B (25.165) has a much lower DILI risk than Ligand A (69.135). This is a significant advantage for Ligand B.

**BBB:** Ligand B (93.68) has a substantially higher BBB penetration score than Ligand A (70.997).  This is *critical* for a CNS target like DRD2.

**Caco-2 Permeability:** Ligand A (-5.18) has better Caco-2 permeability than Ligand B (-4.589), but both are negative values which is unusual and requires further investigation.

**Aqueous Solubility:** Ligand A (-3.561) has slightly better aqueous solubility than Ligand B (-3.04), but both are negative values which is unusual and requires further investigation.

**hERG:** Both ligands have low hERG inhibition liability (A: 0.904, B: 0.735).

**Microsomal Clearance:** Ligand A (5.015) has lower microsomal clearance than Ligand B (9.859), indicating better metabolic stability.

**In vitro Half-Life:** Ligand B (-24.972) has a significantly longer in vitro half-life than Ligand A (18.044).

**P-gp Efflux:** Ligand A (0.358) has lower P-gp efflux than Ligand B (0.063), which is preferable for CNS penetration.

**Binding Affinity:** Both ligands have very similar and excellent binding affinities (A: -8.9 kcal/mol, B: -8.8 kcal/mol). The difference is negligible.

**Overall Assessment:**

Ligand B is the stronger candidate. While Ligand A has slightly better Caco-2 permeability, solubility, and P-gp efflux, Ligand B's superior BBB penetration, significantly lower DILI risk, and longer half-life outweigh these minor drawbacks. The binding affinities are nearly identical, so the ADME properties become the deciding factors. For a CNS target, maximizing BBB penetration and minimizing toxicity (DILI) are paramount.

Output:
1
2025-04-17 06:14:55,838 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (366.483 Da) is slightly lower, which can be beneficial for permeability.

**TPSA:** Ligand A (77.52) is better than Ligand B (49.64) as it is closer to the ideal range for CNS targets (<=90). Ligand B is quite low, which might indicate a lack of necessary interactions.

**logP:** Both ligands have good logP values (A: 2.57, B: 2.988), falling within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Both have acceptable HBD counts (1). Ligand A has 6 HBAs, while Ligand B has 4. Both are within the acceptable range of <=10.

**QED:** Both ligands have reasonable QED values (A: 0.829, B: 0.785), indicating good drug-like properties.

**DILI:** Ligand A (65.452) has a higher DILI risk than Ligand B (47.77), which is preferable.

**BBB:** Ligand B (76.037) has a significantly better BBB penetration percentile than Ligand A (65.064). This is a crucial factor for a CNS target like DRD2.

**Caco-2 Permeability:** Ligand A (-4.869) has a negative Caco-2 value, which is concerning. Ligand B (-5.308) is also negative, but slightly worse. Both are poor.

**Aqueous Solubility:** Ligand A (-3.389) has slightly better solubility than Ligand B (-1.714), but both are poor.

**hERG Inhibition:** Ligand A (0.143) has a lower hERG inhibition liability than Ligand B (0.814), which is desirable.

**Microsomal Clearance:** Ligand B (28.021) has a much lower microsomal clearance than Ligand A (88.536), indicating better metabolic stability.

**In vitro Half-Life:** Ligand B (9.739) has a significantly longer in vitro half-life than Ligand A (-1.878), which is a major advantage.

**P-gp Efflux:** Ligand A (0.171) has lower P-gp efflux liability than Ligand B (0.519), which is better for CNS exposure.

**Binding Affinity:** Ligand B (-9.4 kcal/mol) has a significantly stronger binding affinity than Ligand A (-7.3 kcal/mol). This is a substantial advantage, potentially outweighing some of the ADME drawbacks.

**Overall Assessment:**

Ligand B clearly wins out due to its significantly superior binding affinity and better BBB penetration, coupled with improved metabolic stability (lower Cl_mic) and longer half-life. While Ligand A has a slightly better DILI and P-gp profile, the substantial difference in affinity and BBB penetration of Ligand B are more important for a CNS-targeting GPCR. The negative Caco-2 values for both are a concern, but can be addressed through formulation strategies.



Output:
1
2025-04-17 06:14:55,838 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (346.431 and 353.419 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (86.63) is excellent, well below the 90 A^2 threshold for CNS targets. Ligand B (107.11) is still reasonable but less optimal, exceeding the preferred threshold.

**logP:** Ligand A (0.786) is slightly below the optimal 1-3 range but acceptable. Ligand B (-0.036) is quite low, potentially hindering membrane permeability.

**H-Bond Donors/Acceptors:** Ligand A (HBD=1, HBA=5) is good. Ligand B (HBD=2, HBA=6) is also acceptable.

**QED:** Both ligands have reasonable QED values (0.852 and 0.743), indicating good drug-like properties.

**DILI:** Ligand A (28.926) has a significantly lower DILI risk than Ligand B (22.955), which is preferable.

**BBB:** Ligand A (70.764) has a good BBB percentile, exceeding the desirable >70% threshold for CNS targets. Ligand B (31.214) is considerably lower, raising concerns about CNS penetration. This is a critical difference given the target.

**Caco-2 Permeability:** Ligand A (-4.706) has poor Caco-2 permeability. Ligand B (-5.125) is also poor.

**Aqueous Solubility:** Both ligands have very poor aqueous solubility (-0.303 and -0.467). This could pose formulation challenges.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.239 and 0.132).

**Microsomal Clearance:** Ligand A (3.358) has higher microsomal clearance than Ligand B (-1.761), suggesting lower metabolic stability.

**In vitro Half-Life:** Ligand A (10.877) has a longer in vitro half-life than Ligand B (-2.918).

**P-gp Efflux:** Both ligands show very low P-gp efflux liability (0.022 and 0.041).

**Binding Affinity:** Both ligands have excellent binding affinity (-8.4 and -8.0 kcal/mol). The difference is 0.4 kcal/mol, which is not substantial enough to override other significant differences.

**Conclusion:**

Considering the GPCR-specific priorities, Ligand A is the more promising candidate. Its superior BBB penetration (70.764% vs 31.214%), lower DILI risk, and acceptable TPSA outweigh the slightly higher microsomal clearance and poor Caco-2 permeability. While both have poor solubility, the CNS target makes BBB a crucial factor. The affinity difference is minimal.

Output:
1
2025-04-17 06:14:55,838 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (356.46 and 361.88 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (40.62) is significantly better than Ligand B (47.59). For CNS targets, we want TPSA <= 90, and ideally lower. Ligand A is much closer to the ideal range.

**logP:** Both ligands have good logP values (3.47 and 3.07), falling within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A (0 HBD, 2 HBA) is preferable to Ligand B (0 HBD, 6 HBA). While both are reasonable, fewer H-bonds generally improve permeability.

**QED:** Both ligands have similar QED scores (0.68 and 0.58), indicating reasonable drug-likeness.

**DILI:** Ligand A (20.74) has a much lower DILI risk than Ligand B (37.73), which is a significant advantage.

**BBB:** Ligand A (95.81) has excellent BBB penetration, while Ligand B (78.21) is still good, but less desirable. This is *critical* for a CNS target like DRD2.

**Caco-2 Permeability:** Ligand A (-4.33) is significantly better than Ligand B (-5.16), indicating better intestinal absorption.

**Aqueous Solubility:** Ligand A (-2.87) is better than Ligand B (-1.85), though both are quite poor.

**hERG Inhibition:** Ligand A (0.56) has a lower hERG risk than Ligand B (0.93), which is preferable.

**Microsomal Clearance:** Ligand B (58.43) has a higher clearance than Ligand A (41.99), indicating lower metabolic stability.

**In vitro Half-Life:** Ligand B (50.84) has a better half-life than Ligand A (-31.41). This is a point in favor of Ligand B, but the negative value for Ligand A is concerning.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.15 and 0.53), which is good.

**Binding Affinity:** Ligand B (-7.1 kcal/mol) has a significantly stronger binding affinity than Ligand A (-0.0 kcal/mol). This is a *major* advantage, and could potentially outweigh some of the ADME drawbacks.

**Overall Assessment:**

While Ligand B boasts a much stronger binding affinity, Ligand A has superior ADME properties, particularly BBB penetration, DILI risk, and TPSA. The significantly better BBB penetration of Ligand A is crucial for a CNS target. The affinity difference is substantial, but not insurmountable. Optimization of Ligand A could potentially improve its affinity without sacrificing its favorable ADME profile. The negative half-life for Ligand A is a significant red flag.

Output:
0
2025-04-17 06:14:55,838 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (352.439 Da and 361.559 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (92.59) is slightly above the optimal <90 for CNS targets, but still reasonable. Ligand B (46.84) is excellent, well below 90.

**logP:** Ligand A (1.319) is within the optimal 1-3 range. Ligand B (3.388) is also within range, but approaching the upper limit.

**H-Bond Donors:** Ligand A (1) is good. Ligand B (0) is also good.

**H-Bond Acceptors:** Both ligands (6) are within the acceptable limit of <=10.

**QED:** Ligand A (0.825) is very good, indicating high drug-likeness. Ligand B (0.745) is also good, but slightly lower.

**DILI:** Ligand A (51.648) has a moderate DILI risk, but is acceptable. Ligand B (29.197) is excellent, indicating low DILI risk.

**BBB:** Ligand A (62.97) is below the desirable >70 for CNS targets. Ligand B (92.633) is excellent, exceeding the 70% threshold. This is a significant advantage for Ligand B.

**Caco-2 Permeability:** Ligand A (-4.571) is poor, indicating low intestinal absorption. Ligand B (-5.55) is similarly poor.

**Aqueous Solubility:** Ligand A (-1.624) is poor. Ligand B (-4.147) is even worse.

**hERG Inhibition:** Ligand A (0.191) is very low risk. Ligand B (0.603) is slightly higher, but still relatively low.

**Microsomal Clearance:** Ligand A (40.673) is moderate. Ligand B (55.725) is higher, suggesting faster metabolism.

**In vitro Half-Life:** Ligand A (-2.926) is good. Ligand B (-13.018) is poor.

**P-gp Efflux:** Ligand A (0.027) is very low, indicating minimal P-gp efflux. Ligand B (0.533) is higher, suggesting more P-gp efflux.

**Binding Affinity:** Both ligands (-7.4) have the same excellent binding affinity.

**Overall Assessment:**

Ligand B clearly stands out due to its superior BBB penetration (92.633%) and lower DILI risk (29.197%). While its solubility and Caco-2 permeability are poor, the strong BBB penetration is critical for a CNS target like DRD2, and can potentially overcome some of these issues. Ligand A has a better QED and lower P-gp efflux, but its significantly lower BBB penetration is a major drawback. The equal binding affinity makes the ADME properties the deciding factor.

Output:
1
2025-04-17 06:14:55,838 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B based on the provided guidelines, prioritizing GPCR-specific properties (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (363.845 and 343.387 Da) fall within the ideal range of 200-500 Da.

**TPSA:** Ligand A (77.25) is significantly better than Ligand B (91.42). For CNS targets, we want TPSA <= 90, so Ligand A is preferable.

**logP:** Ligand A (4.236) is higher than the optimal range (1-3), but still potentially manageable. Ligand B (0.667) is *below* the optimal range and could indicate poor membrane permeability. This is a significant disadvantage for a CNS drug.

**H-Bond Donors/Acceptors:** Both have 1 HBD and 5 HBA, which are within acceptable limits.

**QED:** Both ligands have good QED scores (0.859 and 0.881), indicating good drug-like properties.

**DILI:** Ligand A (70.066) has a higher DILI risk than Ligand B (60.217), but both are acceptable (below 60 is good, and both are below 70).

**BBB:** Ligand A (82.745) has a much better BBB percentile than Ligand B (45.638). This is *critical* for a CNS target like DRD2.

**Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual. Assuming these are logP-like scales, lower values indicate poorer permeability. Both are poor, but the difference isn't huge.

**Aqueous Solubility:** Both have negative solubility values, again unusual. Lower values indicate poorer solubility.

**hERG:** Both ligands have low hERG inhibition liability (0.207 and 0.264), which is good.

**Microsomal Clearance:** Ligand A (70.377) has higher microsomal clearance than Ligand B (6.916), suggesting faster metabolism and potentially lower *in vivo* exposure. This is a negative for Ligand A.

**In vitro Half-Life:** Ligand B (8.653) has a slightly longer half-life than Ligand A (11.414), which is a minor advantage.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.082 and 0.025), which is favorable for CNS penetration.

**Binding Affinity:** Ligand A (-9.5 kcal/mol) has a slightly better binding affinity than Ligand B (-8.6 kcal/mol). While both are excellent, the 0.9 kcal/mol difference is notable.

**Overall Assessment:**

Ligand A excels in TPSA, BBB, and binding affinity. However, it has higher logP and higher microsomal clearance. Ligand B has a better DILI profile and lower clearance, but suffers from a significantly lower BBB penetration and a less favorable logP.

Given the CNS target (DRD2), BBB penetration is paramount. The substantial difference in BBB percentile (82.745 vs. 45.638) heavily favors Ligand A. The slightly better affinity of Ligand A further strengthens its position. While the higher logP and clearance of Ligand A are concerns, they are potentially addressable through further optimization, whereas improving BBB penetration is often more challenging.

Output:
1
2025-04-17 06:14:55,839 - INFO - Reasoning:

Let's analyze Ligand A and Ligand B against the provided guidelines, prioritizing GPCR-specific properties (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (351.403 and 356.463 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (107.11) is slightly above the optimal <90 for CNS targets, but still reasonable. Ligand B (87.15) is excellent, well below 90.

**logP:** Ligand A (-0.203) is a concern, being below 1, potentially hindering permeation. Ligand B (0.901) is closer to the optimal range of 1-3, though still on the lower side.

**H-Bond Donors/Acceptors:** Ligand A (2 HBD, 6 HBA) and Ligand B (1 HBD, 5 HBA) both have acceptable numbers of hydrogen bond donors and acceptors.

**QED:** Ligand A (0.704) has a better QED score than Ligand B (0.588), indicating a more drug-like profile.

**DILI:** Ligand A (21.171) has a significantly lower DILI risk than Ligand B (14.541), which is a major advantage.

**BBB:** Ligand B (64.715) has a better BBB penetration percentile than Ligand A (58.86), though both are below the desirable >70 for CNS targets.

**Caco-2 Permeability:** Ligand A (-4.977) shows poor Caco-2 permeability, while Ligand B (-4.161) is slightly better, but still unfavorable.

**Aqueous Solubility:** Both ligands have very poor aqueous solubility (-2.013 and -1.256 respectively). This is a concern for formulation.

**hERG Inhibition:** Ligand A (0.058) has a very low hERG risk, while Ligand B (0.289) is slightly higher, but still relatively low.

**Microsomal Clearance:** Ligand A (11.627) has a lower microsomal clearance than Ligand B (94.213), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (-8.183) has a negative half-life, which is not possible. This is an error in the data. Ligand B (-36.403) also has a negative half-life, indicating a data issue.

**P-gp Efflux:** Ligand A (0.013) has very low P-gp efflux, which is highly desirable for CNS penetration. Ligand B (0.07) is slightly higher, but still low.

**Binding Affinity:** Ligand B (-7.0) has a slightly better binding affinity than Ligand A (-6.6), but the difference is not substantial enough to overcome other significant drawbacks.

**Overall Assessment:**

Ligand A has a better safety profile (lower DILI, lower hERG, lower P-gp efflux) and metabolic stability (lower Cl_mic). While its logP is suboptimal and Caco-2 permeability is poor, its superior safety profile and P-gp efflux are crucial for a CNS-targeting drug. Ligand B has better TPSA and BBB, but suffers from a higher DILI risk and significantly worse metabolic stability. The negative half-life values for both compounds are concerning and suggest data errors. However, even ignoring this, the other factors favor Ligand A.

Output:
0
2025-04-17 06:14:55,839 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (346.431 and 347.419 Da) fall comfortably within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (101.05) is slightly higher than Ligand B (88.61). For a CNS target like DRD2, we ideally want TPSA <= 90. Ligand B is better here.

**3. logP:** Ligand A (1.906) is within the optimal 1-3 range. Ligand B (0.409) is a bit low, potentially hindering membrane permeability. Ligand A is better.

**4. H-Bond Donors:** Both have 2 HBD, which is acceptable.

**5. H-Bond Acceptors:** Ligand A has 5 HBA, and Ligand B has 7. Both are within the acceptable limit of <=10, but Ligand A is slightly preferred.

**6. QED:** Ligand B (0.819) has a significantly higher QED than Ligand A (0.498), indicating a more drug-like profile overall.

**7. DILI:** Both ligands have similar DILI risk (60.295 and 61.109), placing them in a moderate risk category. This isn't a major differentiator.

**8. BBB:** Ligand A (59.674) has a slightly better BBB percentile than Ligand B (57.736). While both are below the desirable >70 for CNS targets, A is closer.

**9. Caco-2:** Both have negative Caco-2 values (-5.06 and -5.198) which is unusual and suggests poor permeability. This is a significant concern for both.

**10. Solubility:** Ligand A (-3.351) has better solubility than Ligand B (-1.767).

**11. hERG:** Both ligands have very low hERG inhibition liability (0.21 and 0.242), which is excellent.

**12. Cl_mic:** Ligand B (7.745) has a much lower microsomal clearance than Ligand A (40.184), suggesting better metabolic stability. This is a significant advantage for Ligand B.

**13. t1/2:** Ligand B (40.39) has a much longer in vitro half-life than Ligand A (3.022), further supporting its better metabolic stability.

**14. Pgp:** Ligand A (0.215) has lower P-gp efflux liability than Ligand B (0.003), which is favorable for CNS penetration.

**15. Binding Affinity:** Ligand A (-8.7 kcal/mol) has a significantly stronger binding affinity than Ligand B (-0.0 kcal/mol). This is a crucial advantage, potentially outweighing some of the ADME drawbacks.

**Overall Assessment:**

Ligand A has a much stronger binding affinity, better solubility, and lower P-gp efflux. However, Ligand B exhibits superior QED, metabolic stability (lower Cl_mic and longer t1/2), and a slightly better TPSA. The low Caco-2 values are concerning for both. Given the importance of binding affinity for GPCRs, and the fact that the affinity difference is substantial (8.7 vs 0.0), I would prioritize Ligand A. The better BBB and Pgp values also support this choice for a CNS target. The lower metabolic stability of A could be addressed with further optimization.

Output:
1
2025-04-17 06:14:55,839 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (350.547 and 349.431 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (58.2) is significantly better than Ligand B (87.74). For CNS targets, we want TPSA <= 90, and A is comfortably within that range, while B is approaching the upper limit.

**3. logP:** Ligand A (4.206) is higher than the optimal 1-3 range, but still potentially acceptable. Ligand B (1.03) is *below* the optimal range and could have permeability issues.

**4. H-Bond Donors:** Both ligands have 2 HBD, which is within the acceptable limit of <= 5.

**5. H-Bond Acceptors:** Ligand A has 2 HBA, while Ligand B has 4. Both are within the acceptable limit of <= 10.

**6. QED:** Both ligands have good QED scores (0.676 and 0.75), indicating good drug-like properties.

**7. DILI:** Ligand A (15.238) has a much lower DILI risk than Ligand B (18.651), both are good.

**8. BBB:** Both ligands have good BBB penetration (76.231 and 75.145), exceeding the 70% threshold for CNS targets.

**9. Caco-2 Permeability:** Ligand A (-4.432) has a negative Caco-2 value, which is unusual and suggests very poor permeability. Ligand B (-4.889) is also poor, but slightly worse.

**10. Aqueous Solubility:** Ligand A (-4.811) and Ligand B (-2.821) both have poor aqueous solubility.

**11. hERG Inhibition:** Ligand A (0.537) has a very low hERG risk, while Ligand B (0.207) is even lower. Both are excellent.

**12. Microsomal Clearance:** Ligand A (86.114) has a high microsomal clearance, indicating rapid metabolism. Ligand B (2.98) has very low clearance, suggesting excellent metabolic stability.

**13. In vitro Half-Life:** Ligand A (23.032) has a moderate half-life. Ligand B (-16.167) has a negative half-life, which is not physically possible. This is a major red flag and indicates a problem with the data or the molecule's stability.

**14. P-gp Efflux:** Both ligands have very low P-gp efflux (0.048 and 0.027), which is favorable for CNS penetration.

**15. Binding Affinity:** Ligand B (-8.4 kcal/mol) has a significantly stronger binding affinity than Ligand A (0.0 kcal/mol). This is a *substantial* advantage.

**Overall Assessment:**

Despite Ligand A's better TPSA and lower DILI, the significantly stronger binding affinity of Ligand B (-8.4 vs 0.0 kcal/mol) is a decisive factor. The negative half-life for Ligand B is concerning, but the large difference in binding affinity is likely to outweigh this issue during optimization. The poor Caco-2 and solubility for both are problematic, but can be addressed through formulation or further structural modifications. Ligand A's high microsomal clearance is also a significant drawback. The logP of Ligand A is also less ideal.

Output:
1
2025-04-17 06:14:55,839 - INFO - Reasoning:

Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (376.425 and 362.459 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (82.78) is significantly better than Ligand B (96.29). For CNS targets, we want TPSA <= 90, and A is comfortably within this range, while B is slightly above.

**3. logP:** Both ligands have good logP values (2.086 and 1.226), falling within the optimal 1-3 range.

**4. H-Bond Donors:** Both have 2 HBD, which is acceptable.

**5. H-Bond Acceptors:** Ligand A has 5 HBA, while Ligand B has 9.  Lower is generally preferred, making A slightly better.

**6. QED:** Both ligands have similar QED values (0.761 and 0.759), indicating good drug-likeness.

**7. DILI:** Ligand A (32.067) has a much lower DILI risk than Ligand B (57.348). Both are below 60, but A is significantly safer.

**8. BBB:** Ligand A (59.093) has a slightly better BBB percentile than Ligand B (57.464). While neither is >70 (desirable for CNS targets), A is closer.

**9. Caco-2:** Both have negative Caco-2 values (-5.204 and -5.428), which is unusual and suggests poor permeability. This is a significant drawback for both.

**10. Solubility:** Both have negative solubility values (-3.399 and -2.348), indicating very poor aqueous solubility. This is a major concern for both compounds.

**11. hERG:** Both ligands have low hERG risk (0.464 and 0.475).

**12. Cl_mic:** Ligand A (-1.435) has a *much* lower (better) microsomal clearance than Ligand B (42.231). This indicates significantly better metabolic stability for Ligand A.

**13. t1/2:** Ligand A (15.516 hours) has a better in vitro half-life than Ligand B (20.468 hours).

**14. Pgp:** Both have very low Pgp efflux liability (0.074 and 0.014), which is good for CNS penetration.

**15. Binding Affinity:** Ligand B (-8.3 kcal/mol) has a slightly better binding affinity than Ligand A (-7.9 kcal/mol). This is a 0.4 kcal/mol difference, which is noticeable but not overwhelmingly large.

**Overall Assessment:**

While Ligand B has a slightly better binding affinity, Ligand A is significantly superior in almost all other critical ADME properties, particularly DILI risk, metabolic stability (Cl_mic), and TPSA. The poor Caco-2 and solubility are concerning for both, but the other advantages of Ligand A, especially its lower DILI and better metabolic stability, make it the more promising candidate. Given the GPCR-specific emphasis on BBB, logP, Pgp, TPSA, and affinity, Ligand A strikes a better balance, despite the slightly weaker binding.

Output:
0
2025-04-17 06:14:55,840 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B against the provided guidelines, prioritizing GPCR-specific properties (BBB, logP, Pgp, TPSA, and affinity) for DRD2.

**Molecular Weight:** Both ligands (350.423 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (121.03) is slightly above the optimal <90 for CNS targets, but still reasonable. Ligand B (92.59) is well within the desired range. This favors Ligand B.

**logP:** Ligand A (0.957) is at the lower end of optimal, potentially hindering permeation. Ligand B (-0.341) is even lower, raising concerns about permeability. Both are suboptimal, but Ligand A is slightly better.

**H-Bond Donors/Acceptors:** Ligand A (4 HBD, 5 HBA) is acceptable. Ligand B (1 HBD, 7 HBA) is also acceptable. No strong preference here.

**QED:** Both ligands have good QED scores (A: 0.603, B: 0.689), indicating good drug-like properties. Ligand B is slightly better.

**DILI:** Ligand A (60.915) has a moderate DILI risk, while Ligand B (28.306) has a low DILI risk. This strongly favors Ligand B.

**BBB:** Both ligands have good BBB penetration (A: 69.794, B: 65.452), but Ligand A is slightly better. However, both are below the desirable >70 threshold.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.282 and -5.783). This is unusual and suggests poor permeability.

**Aqueous Solubility:** Both ligands have negative solubility values (-2.252 and -0.871), indicating very poor aqueous solubility.

**hERG:** Both ligands have very low hERG inhibition risk (A: 0.038, B: 0.075).

**Microsomal Clearance:** Ligand A (-19.666) has a lower (better) microsomal clearance than Ligand B (-17.549), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand B (19.304 hours) has a significantly longer half-life than Ligand A (8.666 hours). This is a substantial advantage for Ligand B.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (A: 0.005, B: 0.003), which is favorable for CNS penetration.

**Binding Affinity:** Ligand B (-7.2 kcal/mol) has a stronger binding affinity than Ligand A (-9.0 kcal/mol). This is a significant advantage for Ligand B.

**Overall Assessment:**

Ligand B is the more promising candidate. While both have issues with logP and solubility, Ligand B demonstrates superior DILI risk, binding affinity, and *in vitro* half-life. The slightly better TPSA and QED scores also contribute to its favorability. The difference in binding affinity (-7.2 vs -9.0) is substantial enough to outweigh the slightly lower BBB penetration and higher clearance.

Output:
1
2025-04-17 06:14:55,840 - INFO - Reasoning:

Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (357.284 and 386.945 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (88.02) is better than Ligand B (66.48) as it is closer to the ideal range for CNS targets (<=90).

**3. logP:** Both ligands have good logP values (2.462 and 3.211), falling within the optimal 1-3 range.

**4. H-Bond Donors:** Ligand A (3) is slightly higher than Ligand B (1), but both are within the acceptable limit of <=5.

**5. H-Bond Acceptors:** Ligand A (5) is slightly higher than Ligand B (4), but both are within the acceptable limit of <=10.

**6. QED:** Both ligands have similar, good QED values (0.765 and 0.744), indicating good drug-like properties.

**7. DILI:** Ligand A (70.686) has a higher DILI risk than Ligand B (38.852). This is a significant drawback for Ligand A.

**8. BBB:** Both ligands have excellent BBB penetration (35.091 and 70.609). Ligand B is slightly better.

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.853 and -4.775), which is unusual and suggests poor permeability. However, these values are on a scale where negative values are possible, and a direct comparison is difficult without knowing the scale's specifics.

**10. Aqueous Solubility:** Both ligands have very poor aqueous solubility (-3.173 and -3.264). This is a concern for both.

**11. hERG Inhibition:** Both ligands have low hERG inhibition risk (0.603 and 0.611).

**12. Microsomal Clearance:** Ligand B (35.611) has slightly better metabolic stability (lower clearance) than Ligand A (31.454).

**13. In vitro Half-Life:** Ligand B (45.088) has a significantly longer in vitro half-life than Ligand A (-12.738). This is a major advantage for Ligand B.

**14. P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.117 and 0.248), which is good for CNS exposure.

**15. Binding Affinity:** Ligand B (-7.8 kcal/mol) has a significantly stronger binding affinity than Ligand A (-9.0 kcal/mol). This is a substantial advantage.

**Overall Assessment:**

While Ligand A has a slightly better TPSA, Ligand B clearly outperforms it in most critical parameters. Ligand B has a much lower DILI risk, better metabolic stability (lower Cl_mic, longer t1/2), and, most importantly, a significantly stronger binding affinity. The similar BBB values are good for both, but the superior ADME profile and potency of Ligand B make it the more promising drug candidate. The poor solubility and Caco-2 permeability are concerns for both, but can be addressed through formulation strategies.

Output:
1
2025-04-17 06:14:55,840 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (347.375 and 348.443 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (97.11) is slightly above the optimal <90 for CNS targets, but still reasonable. Ligand B (77.52) is well within the desired range.

**logP:** Ligand A (0.213) is quite low, potentially hindering permeability. Ligand B (3.593) is excellent, falling right within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A has 0 HBD and 7 HBA, which is acceptable. Ligand B has 1 HBD and 5 HBA, also acceptable.

**QED:** Both ligands have good QED scores (0.664 and 0.841), indicating good drug-like properties.

**DILI:** Ligand A (66.421) has a higher DILI risk than Ligand B (46.413), though both are below the concerning >60 threshold.

**BBB:** Ligand A (71.772) has a good BBB penetration score, but Ligand B (82.939) is even better, exceeding 80%. This is a crucial factor for a CNS target like DRD2.

**Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and suggests a potential issue with the data or modeling. However, the magnitude of negativity is similar.

**Aqueous Solubility:** Ligand A (-0.996) has poor aqueous solubility, which is a significant drawback. Ligand B (-4.767) is even worse, posing formulation challenges.

**hERG Inhibition:** Both ligands show very low hERG inhibition risk (0.143 and 0.186).

**Microsomal Clearance:** Ligand A (85.834) has lower microsomal clearance, indicating better metabolic stability than Ligand B (119.696).

**In vitro Half-Life:** Ligand A (11.359) has a longer half-life than Ligand B (-4.732), which is a positive attribute.

**P-gp Efflux:** Both ligands show very low P-gp efflux liability (0.041 and 0.033).

**Binding Affinity:** Ligand B (-8.5 kcal/mol) has a significantly stronger binding affinity than Ligand A (-7.7 kcal/mol). The 0.8 kcal/mol difference is substantial and can often outweigh minor ADME deficiencies.

**Overall Assessment:**

Ligand B is the stronger candidate. While its solubility is poor, its superior logP, BBB penetration, and, crucially, binding affinity make it more promising. The better BBB penetration is particularly important for a CNS target like DRD2. Ligand A's lower logP and weaker affinity are significant drawbacks. The slightly better metabolic stability and half-life of Ligand A are not enough to compensate for these deficiencies.

Output:
1
2025-04-17 06:14:55,840 - INFO - Reasoning:

Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (348.403 and 353.463 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (104.53) is higher than Ligand B (80.23). For CNS targets, TPSA should be <= 90. Both are acceptable, but B is better.

**logP:** Ligand A (-0.463) is below the optimal 1-3 range and could indicate poor membrane permeability. Ligand B (1.854) is within the optimal range. This is a significant advantage for B.

**H-Bond Donors/Acceptors:** Ligand A has 2 HBD and 6 HBA, while Ligand B has 1 HBD and 5 HBA. Both are within acceptable limits.

**QED:** Both ligands have similar QED values (0.694 and 0.676), indicating good drug-likeness.

**DILI:** Ligand A (35.634) has a slightly higher DILI risk than Ligand B (8.104), though both are reasonably low.

**BBB:** This is crucial for a CNS target like DRD2. Ligand B (65.258) has a significantly higher BBB penetration percentile than Ligand A (31.214). This is a major advantage for B.

**Caco-2 Permeability:** Both have negative values (-5.257 and -4.931), which is unusual and suggests poor permeability. However, these values are on a scale where negative values are possible and don't necessarily disqualify a compound.

**Aqueous Solubility:** Both ligands have very poor aqueous solubility (-1.138 and -1.064). This could pose formulation challenges.

**hERG Inhibition:** Ligand A (0.037) has a slightly lower hERG inhibition risk than Ligand B (0.289), which is preferable.

**Microsomal Clearance:** Ligand B (-13.873) has a much lower (better) microsomal clearance than Ligand A (21.802), indicating greater metabolic stability.

**In vitro Half-Life:** Ligand B (-1.178) has a slightly longer half-life than Ligand A (-7.207), which is desirable.

**P-gp Efflux:** Ligand A (0.009) has a lower P-gp efflux liability than Ligand B (0.033), which is better for CNS exposure.

**Binding Affinity:** Both ligands have very similar and strong binding affinities (-8.1 and -7.3 kcal/mol). The difference of 0.8 kcal/mol is not substantial enough to outweigh other significant differences.

**Overall Assessment:**

Ligand B is the better candidate. While both have similar affinities, Ligand B excels in critical areas for a CNS-targeting GPCR: significantly better BBB penetration, a more favorable logP, and improved metabolic stability (lower Cl_mic). Ligand A has a slightly lower hERG risk and P-gp efflux, but these are less critical given the substantial advantages of Ligand B in BBB and logP. The poor solubility of both ligands is a concern that would need to be addressed during formulation development.

Output:
1
2025-04-17 06:14:55,840 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (344.411 and 378.313 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (68.82) is slightly above the optimal <90 for CNS targets, but still reasonable. Ligand B (60.85) is excellent, well below 90.

**3. logP:** Both ligands have good logP values (1.022 and 2.092), falling within the 1-3 range.

**4. H-Bond Donors:** Ligand A has 2 HBD, and Ligand B has 1. Both are acceptable (<=5).

**5. H-Bond Acceptors:** Ligand A has 5 HBA, and Ligand B has 3. Both are acceptable (<=10).

**6. QED:** Both ligands have similar QED values (0.781 and 0.763), indicating good drug-likeness.

**7. DILI:** Both ligands have low DILI risk (38.503 and 36.526), below the 40 threshold.

**8. BBB:** This is a critical parameter for a CNS target like DRD2. Ligand B (73.556) is significantly better than Ligand A (48.352), exceeding the desirable >70 threshold.

**9. Caco-2 Permeability:** Both have negative values, which is unusual. However, the magnitude of negativity is similar, and this metric is less critical than BBB for CNS penetration.

**10. Aqueous Solubility:** Both have negative values, which is also unusual. Again, the values are similar.

**11. hERG Inhibition:** Ligand A (0.244) has a slightly better hERG profile than Ligand B (0.567), indicating lower cardiotoxicity risk.

**12. Microsomal Clearance:** Ligand B (4.322) has significantly lower microsomal clearance than Ligand A (15.304), suggesting better metabolic stability.

**13. In vitro Half-Life:** Ligand B (5.034) has a longer half-life than Ligand A (12.935).

**14. P-gp Efflux:** Ligand B (0.105) has much lower P-gp efflux than Ligand A (0.038), which is crucial for CNS exposure.

**15. Binding Affinity:** Ligand A (-8.0) has a significantly stronger binding affinity than Ligand B (-0.0). This is a substantial advantage.

**Overall Assessment:**

While Ligand A boasts a superior binding affinity, Ligand B demonstrates a much more favorable ADME profile, particularly regarding BBB penetration (73.556 vs 48.352), P-gp efflux (0.105 vs 0.038), and metabolic stability (lower Cl_mic and longer t1/2). For a CNS target like DRD2, achieving sufficient brain exposure is paramount. The large difference in affinity *could* potentially be overcome with optimization of Ligand B, whereas improving the ADME properties of Ligand A to achieve sufficient brain penetration would likely be more challenging. The significantly better BBB and P-gp profile of Ligand B outweigh the affinity difference.

Output:
1
2025-04-17 06:14:55,841 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (379.404 and 364.515 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (101.29) is slightly above the preferred <90 for CNS targets, but still reasonable. Ligand B (76.02) is excellent, well below 90.

**logP:** Both ligands have good logP values (1.271 and 2.129), falling within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A has 3 HBD and 4 HBA, which are acceptable. Ligand B has 2 HBD and 5 HBA, also acceptable.

**QED:** Both ligands have QED values above 0.5 (0.693 and 0.741), indicating good drug-like properties.

**DILI:** Both ligands have similar, acceptable DILI risk (41.877 and 41.838, both <40).

**BBB:** Ligand A has a significantly better BBB penetration percentile (61.38) compared to Ligand B (45.56). While >70 is desirable, 61.38 is a reasonable starting point. Ligand B is lower and less favorable.

**Caco-2 Permeability:** Both have negative Caco-2 values (-5.433 and -5.616), which is unusual and suggests poor permeability. This is a significant concern for both.

**Aqueous Solubility:** Both have negative solubility values (-2.882 and -1.884), indicating poor aqueous solubility. This is also a concern, but can be addressed with formulation strategies.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.455 and 0.251).

**Microsomal Clearance:** Ligand A has a lower (better) microsomal clearance (3.783) than Ligand B (11.373), indicating better metabolic stability.

**In vitro Half-Life:** Ligand A has a significantly longer in vitro half-life (-27.696) than Ligand B (-7.947), which is highly desirable.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.047 and 0.065), which is excellent for CNS penetration.

**Binding Affinity:** Both ligands have strong binding affinities (-9.0 and -7.8 kcal/mol). Ligand A is significantly more potent, with a 1.2 kcal/mol advantage. This difference is substantial enough to potentially outweigh some of the ADME drawbacks.

**Overall Assessment:**

Ligand A is the better candidate. While both have issues with Caco-2 permeability and aqueous solubility, Ligand A has a significantly better binding affinity, longer half-life, lower clearance, and better BBB penetration. The 1.2 kcal/mol difference in binding affinity is a major advantage for a GPCR target. The slightly higher TPSA of Ligand A is less concerning than the lower BBB and affinity of Ligand B.

Output:
1
2025-04-17 06:14:55,841 - INFO - Batch 266 complete. Total preferences: 4256
2025-04-17 06:14:55,841 - INFO - Processing batch 267/512...
2025-04-17 06:15:36,848 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B based on the provided guidelines, prioritizing GPCR-specific properties (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (360.53 and 366.57 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (57.26) is slightly higher than Ligand B (49.41). Both are below the 90 A^2 threshold desirable for CNS targets, but B is closer to optimal.

**logP:** Ligand A (4.157) is slightly higher than the optimal range (1-3), potentially causing solubility issues. Ligand B (3.453) is within the optimal range.

**H-Bond Donors/Acceptors:** Ligand A has 2 HBD and 4 HBA, while Ligand B has 1 HBD and 3 HBA. Both are within acceptable limits.

**QED:** Both ligands have similar QED values (0.842 and 0.811), indicating good drug-likeness.

**DILI:** Ligand A (55.021) has a higher DILI risk than Ligand B (23.032). This is a significant advantage for Ligand B.

**BBB:** Ligand A (93.757) has a better BBB penetration percentile than Ligand B (79.488), which is a critical factor for CNS targets like DRD2.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.778 and -4.972). This is unusual and suggests poor permeability, but the values are very close.

**Aqueous Solubility:** Both ligands have negative solubility values (-3.778 and -3.924), indicating poor aqueous solubility. This is a concern, but can sometimes be overcome with formulation strategies.

**hERG Inhibition:** Ligand A (0.955) has a slightly higher hERG inhibition risk than Ligand B (0.551), making B more favorable from a safety perspective.

**Microsomal Clearance:** Ligand B (72.381) has a significantly higher microsomal clearance than Ligand A (29.098), indicating faster metabolism and potentially lower *in vivo* exposure.

**In vitro Half-Life:** Ligand A (76.204) has a much longer half-life than Ligand B (-4.057), which is a significant advantage.

**P-gp Efflux:** Ligand A (0.694) has lower P-gp efflux than Ligand B (0.3), meaning A is less likely to be pumped out of the brain, improving CNS exposure.

**Binding Affinity:** Ligand A (-8.9 kcal/mol) has a significantly stronger binding affinity than Ligand B (-7.5 kcal/mol). This 1.4 kcal/mol difference is substantial and can outweigh some of the ADME drawbacks.

**Overall Assessment:**

Ligand A has a superior binding affinity and better BBB penetration and P-gp efflux, which are crucial for a CNS-targeting GPCR. It also has a longer half-life. However, it has a higher logP, DILI risk, and hERG inhibition. Ligand B has better ADME properties (lower DILI, hERG, and clearance), but its affinity is weaker and BBB penetration is lower.

Given the importance of potency and CNS penetration for DRD2, the stronger binding affinity and better BBB of Ligand A are more critical. While the ADME properties of A are not ideal, they may be addressable through further optimization. The significant affinity advantage of A outweighs the ADME concerns.

Output:
1
2025-04-17 06:15:36,849 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (364.486 and 366.418 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (58.2) is excellent, well below the 90 Angstroms threshold for CNS targets. Ligand B (111.95) is higher but still potentially acceptable, though less ideal.

**3. logP:** Ligand A (3.804) is optimal. Ligand B (0.942) is a bit low, potentially hindering membrane permeability.

**4. H-Bond Donors:** Both ligands have 2 HBD, which is within the acceptable limit of 5.

**5. H-Bond Acceptors:** Ligand A has 3 HBA, and Ligand B has 5 HBA, both within the acceptable limit of 10.

**6. QED:** Both ligands have good QED scores (0.689 and 0.778), indicating drug-like properties.

**7. DILI:** Ligand A (34.781) has a much lower DILI risk than Ligand B (64.599). This is a significant advantage for Ligand A.

**8. BBB:** Ligand A (83.676) has a significantly better BBB penetration percentile than Ligand B (60.644). This is crucial for a CNS target like DRD2.

**9. Caco-2:** Both have negative Caco-2 values which is unusual. Assuming these are percentile scores, both are very poor.

**10. Solubility:** Both ligands have negative solubility values, which is also unusual. Assuming these are percentile scores, both are very poor.

**11. hERG:** Both ligands have very low hERG inhibition liability (0.277 and 0.272), which is excellent.

**12. Cl_mic:** Ligand A (55.674) has a higher microsomal clearance than Ligand B (2.585), suggesting lower metabolic stability. This is a drawback for Ligand A.

**13. t1/2:** Ligand A (29.194) has a longer in vitro half-life than Ligand B (0.759). This is a positive for Ligand A.

**14. Pgp:** Ligand A (0.249) has lower P-gp efflux liability than Ligand B (0.038), which is beneficial for CNS penetration.

**15. Binding Affinity:** Ligand B (-8.7 kcal/mol) has a significantly stronger binding affinity than Ligand A (-7.5 kcal/mol). This is a substantial advantage for Ligand B, potentially outweighing some of its ADME drawbacks.

**Overall Assessment:**

Ligand A excels in TPSA, logP, BBB, DILI, and Pgp efflux, all critical for CNS GPCR targeting. However, its metabolic stability (Cl_mic) is a concern. Ligand B has a much stronger binding affinity, which is paramount, but suffers from lower BBB penetration, higher DILI risk, and a lower logP.

Given the strong preference for binding affinity in GPCR drug discovery, and the fact that the difference in affinity (-8.7 vs -7.5) is substantial (1.2 kcal/mol), I believe Ligand B is the more promising candidate *despite* its ADME liabilities. The higher affinity provides a larger window for optimization of the ADME properties.

Output:
1
2025-04-17 06:15:36,849 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (349.431 and 352.41 Da) fall within the ideal range of 200-500 Da.

**TPSA:** Ligand A (84.67) is better than Ligand B (67.67) as it is closer to the optimal range for CNS targets (<=90).

**logP:** Ligand A (2.229) is optimal, while Ligand B (0.539) is a bit low, potentially hindering permeability.

**H-Bond Donors:** Ligand A (1) is better than Ligand B (0), as a single donor can aid solubility without significantly impacting permeability.

**H-Bond Acceptors:** Both ligands have 5 HBA, which is acceptable.

**QED:** Ligand A (0.816) is superior to Ligand B (0.749), indicating a more drug-like profile.

**DILI:** Ligand B (33.23) has a significantly lower DILI risk than Ligand A (44.126), which is a substantial advantage.

**BBB:** Ligand B (91.702) has a much higher BBB penetration percentile than Ligand A (52.268). This is *critical* for a CNS target like DRD2.

**Caco-2 Permeability:** Ligand A (-4.904) has slightly better Caco-2 permeability than Ligand B (-4.573).

**Aqueous Solubility:** Ligand A (-1.408) has slightly better aqueous solubility than Ligand B (-0.848).

**hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.24 and 0.135 respectively).

**Microsomal Clearance:** Ligand B (4.893) has a much lower microsomal clearance than Ligand A (60.574), indicating better metabolic stability.

**In vitro Half-Life:** Ligand A (7.877) has a better in vitro half-life than Ligand B (-0.803).

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.1 and 0.038 respectively).

**Binding Affinity:** Ligand A (-8.1 kcal/mol) has a significantly stronger binding affinity than Ligand B (-6.8 kcal/mol). This is a 1.3 kcal/mol difference, which is a substantial advantage.

**Overall Assessment:**

While Ligand B excels in DILI, BBB, and metabolic stability, Ligand A's significantly stronger binding affinity (-8.1 vs -6.8 kcal/mol) is a major deciding factor, especially for a GPCR target. The difference in affinity is large enough to potentially overcome the slightly higher DILI risk and lower BBB penetration of Ligand A. The TPSA of Ligand A is also more favorable for CNS penetration.

Output:
1
2025-04-17 06:15:36,849 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (340.43 and 344.46 Da) fall comfortably within the ideal 200-500 Da range.

**TPSA:** Ligand A (77.0) and Ligand B (75.19) are both below the 90 A^2 threshold desirable for CNS targets, which is excellent.

**logP:** Ligand A (3.788) is at the higher end of the optimal range (1-3), while Ligand B (2.476) is well within it. Ligand A's higher logP *could* lead to off-target effects, but isn't immediately disqualifying.

**H-Bond Donors/Acceptors:** Both ligands have 1 HBD and 5/4 HBA respectively, meeting the <5 HBD and <10 HBA criteria.

**QED:** Both ligands have good QED scores (0.866 and 0.91), indicating good drug-like properties.

**DILI:** Ligand A (70.69) has a higher DILI risk than Ligand B (37.73), which is a significant negative.

**BBB:** Both ligands have good BBB penetration (75.11 and 77.98 percentile), exceeding the >70% threshold for CNS targets.

**Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and suggests a potential issue with the data or prediction method. However, given the context of comparing two ligands, we can treat these as relative indicators.

**Aqueous Solubility:** Both have negative solubility values, which is also unusual. Again, we'll treat these as relative indicators.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.282 and 0.321).

**Microsomal Clearance:** Ligand A (83.78) has significantly higher microsomal clearance than Ligand B (32.17), indicating lower metabolic stability.

**In vitro Half-Life:** Ligand B (-7.13) has a much longer in vitro half-life than Ligand A (-13.16).

**P-gp Efflux:** Ligand A (0.118) has slightly higher P-gp efflux than Ligand B (0.058), but both are relatively low.

**Binding Affinity:** Ligand A (-9.1 kcal/mol) has a substantially stronger binding affinity than Ligand B (-0.0 kcal/mol). This is a *major* advantage. A difference of >1.5 kcal/mol can often outweigh other drawbacks.

**Overall Assessment:**

Ligand A has a significantly better binding affinity, which is the most important factor. However, it has a higher DILI risk and lower metabolic stability (higher Cl_mic, shorter half-life). Ligand B has better ADME properties (lower DILI, better metabolic stability), but its binding affinity is very weak.

Given the importance of affinity for GPCR ligands, and the fact that both ligands meet the BBB criteria, I believe Ligand A is the more promising candidate *despite* its ADME liabilities. The strong binding affinity provides a larger window for optimization of the ADME properties. The DILI risk and metabolic stability can be addressed through structural modifications.

Output:
1
2025-04-17 06:15:36,849 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 drug candidates, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (352.475 Da and 347.415 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (66.92) is significantly better than Ligand B (93.46). For CNS targets, we want TPSA <= 90, so Ligand A is preferable.

**logP:** Both ligands have acceptable logP values (1.868 and 2.271, respectively), falling within the 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A (0 HBD, 4 HBA) is slightly better than Ligand B (2 HBD, 5 HBA) in terms of balancing solubility and permeability. Both are within acceptable limits.

**QED:** Both ligands have reasonable QED scores (0.656 and 0.583), indicating good drug-like properties.

**DILI:** Ligand A (29.624) has a much lower DILI risk than Ligand B (64.521). This is a significant advantage for Ligand A.

**BBB:** Both ligands have good BBB penetration (68.786 and 70.648), both being >70, which is desirable for CNS targets. Ligand B is slightly better.

**Caco-2 Permeability:** Ligand A (-4.137) and Ligand B (-5.046) both have negative values, indicating poor permeability. This is a concern for both, but Ligand A is slightly better.

**Aqueous Solubility:** Ligand A (-2.071) is better than Ligand B (-3.46) in terms of solubility, although both are poor.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.314 and 0.139).

**Microsomal Clearance:** Ligand A (53.269) has higher microsomal clearance than Ligand B (39.935), indicating lower metabolic stability. Ligand B is preferable here.

**In vitro Half-Life:** Ligand B (-16.699) has a longer in vitro half-life than Ligand A (-12.074), which is a positive attribute.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.07 and 0.17), which is good for CNS exposure.

**Binding Affinity:** Ligand B (-8.4 kcal/mol) has a significantly stronger binding affinity than Ligand A (-7.6 kcal/mol). This is a substantial advantage, potentially outweighing some of the ADME drawbacks. The difference is >1.5 kcal/mol.

**Overall Assessment:**

While Ligand A has advantages in TPSA, DILI, solubility, and H-bonding, Ligand B's significantly stronger binding affinity (-8.4 vs -7.6 kcal/mol) is the most crucial factor for a GPCR target. The slightly better BBB penetration and longer half-life of Ligand B also contribute to its favorability. The higher DILI risk and slightly worse TPSA are less concerning given the potency advantage.

Output:
1
2025-04-17 06:15:36,850 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (437.344 Da) is higher, but still acceptable. Ligand B (366.399 Da) is slightly better.

**TPSA:**  For CNS targets, we want TPSA <= 90. Ligand A (94.88) is slightly above, while Ligand B (103.62) is further above. This is a negative for both, but more so for Ligand B.

**logP:** Optimal is 1-3. Ligand A (4.163) is a bit high, potentially leading to solubility issues and off-target effects. Ligand B (0.586) is quite low, which could hinder membrane permeability.

**H-Bond Donors/Acceptors:** Ligand A (2 HBD, 6 HBA) is better balanced. Ligand B (0 HBD, 8 HBA) has no donors, which isn't ideal, and a higher number of acceptors.

**QED:** Both ligands have good QED scores (A: 0.625, B: 0.729), indicating good drug-like properties.

**DILI:** Ligand A (97.518) has a very high DILI risk, which is a major concern. Ligand B (87.127) is better, but still relatively high.

**BBB:** This is critical for a CNS target. Ligand A (37.611) has poor BBB penetration, making it unlikely to reach the target in the brain. Ligand B (61.962) is better, but still not ideal (we want >70).

**Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and suggests poor permeability.

**Aqueous Solubility:** Both have negative solubility values, indicating poor solubility.

**hERG:** Ligand A (0.739) has a slightly higher hERG risk than Ligand B (0.116).

**Microsomal Clearance:** Ligand A (14.17 mL/min/kg) is better than Ligand B (119.635 mL/min/kg), indicating better metabolic stability.

**In vitro Half-Life:** Ligand A (136.869 hours) has a significantly longer half-life than Ligand B (-50.561 hours).

**P-gp Efflux:** Ligand A (0.299) has lower P-gp efflux, which is favorable for CNS penetration. Ligand B (0.094) has even lower efflux, which is good.

**Binding Affinity:** Ligand A (-8.6 kcal/mol) has a significantly stronger binding affinity than Ligand B (-7.7 kcal/mol). This is a substantial advantage.

**Overall Assessment:**

Ligand A has a major drawback in its very high DILI risk and poor BBB penetration. However, it boasts a much stronger binding affinity and better metabolic stability. Ligand B has better P-gp efflux and lower hERG risk, but suffers from a weaker binding affinity, poor metabolic stability, and only moderately improved BBB penetration.

Given the importance of binding affinity for GPCRs, and the fact that the difference in affinity (-8.6 vs -7.7) is substantial (over 1 kcal/mol), Ligand A is more likely to be a viable drug candidate *if* the DILI risk can be mitigated through structural modifications. The poor BBB penetration is also a concern, but could potentially be addressed with prodrug strategies. Ligand B's weak affinity makes it less promising, even with its slightly better ADME properties.

Output:
1
2025-04-17 06:15:36,850 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (333.347 and 350.503 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (76.98) is slightly higher than the ideal <90 for CNS targets, but still reasonable. Ligand B (49.85) is excellent, well below 90.

**3. logP:** Both ligands (2.772 and 2.974) are within the optimal 1-3 range.

**4. H-Bond Donors:** Ligand A has 1 HBD, which is good. Ligand B has 0, also good.

**5. H-Bond Acceptors:** Ligand A has 5 HBA, acceptable. Ligand B has 3 HBA, also acceptable.

**6. QED:** Both ligands have good QED scores (0.585 and 0.632), indicating drug-like properties.

**7. DILI:** Ligand A has a DILI risk of 85.459, which is high and concerning. Ligand B has a much lower DILI risk of 17.759, which is excellent.

**8. BBB:** Ligand A has a BBB penetration of 59.636, which is below the desirable >70 for CNS targets. Ligand B has a BBB penetration of 75.107, which is good and meets the threshold.

**9. Caco-2 Permeability:** Ligand A (-5.208) and Ligand B (-4.619) both have negative values, indicating poor permeability. This is a concern for both.

**10. Aqueous Solubility:** Both ligands have poor aqueous solubility (-3.8 and -2.352). This could pose formulation challenges.

**11. hERG Inhibition:** Both ligands have low hERG inhibition risk (0.471 and 0.591), which is good.

**12. Microsomal Clearance:** Ligand A (76.585) has higher microsomal clearance than Ligand B (61.382), suggesting lower metabolic stability.

**13. In vitro Half-Life:** Ligand A (10.297) has a longer half-life than Ligand B (-8.673). This is a positive for Ligand A, but the negative value for B is concerning.

**14. P-gp Efflux:** Both ligands have low P-gp efflux liability (0.605 and 0.489), which is favorable for CNS penetration.

**15. Binding Affinity:** Ligand A (-9.2 kcal/mol) has a significantly stronger binding affinity than Ligand B (-7.4 kcal/mol). This is a substantial advantage.

**Overall Assessment:**

While Ligand A boasts a superior binding affinity, its high DILI risk and suboptimal BBB penetration are major drawbacks. Ligand B, despite a slightly weaker affinity, presents a much more favorable safety profile (low DILI) and better BBB penetration, which are critical for a CNS-targeting drug. The Caco-2 permeability and solubility are concerns for both, but the safety and CNS penetration advantages of Ligand B outweigh the affinity difference.

Output:
1
2025-04-17 06:15:36,850 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (369.487 and 354.411 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (78.95) is significantly better than Ligand B (103.63). For CNS targets, TPSA should be <= 90, and A is comfortably within this range, while B is pushing the limit.

**logP:** Ligand A (1.077) is within the optimal 1-3 range. Ligand B (-0.246) is slightly below 1, which *could* indicate permeability issues, though not drastically.

**H-Bond Donors/Acceptors:** Both have 1 HBD, which is good. Ligand A has 5 HBA, acceptable. Ligand B has 9 HBA, which is higher, potentially impacting permeability.

**QED:** Both ligands have similar QED values (0.726 and 0.715), indicating good drug-like properties.

**DILI:** Both have acceptable DILI risk (42.536 and 47.693 percentile).

**BBB:** Ligand B (74.098) has a significantly better BBB penetration score than Ligand A (63.125). This is a crucial factor for a CNS target like DRD2.

**Caco-2 Permeability:** Both have negative Caco-2 values (-4.993 and -4.894), which is unusual and suggests poor permeability. However, these values are on a log scale and require careful interpretation.

**Aqueous Solubility:** Both have negative solubility values (-2.318 and -0.765), also unusual. Again, these are on a log scale and indicate poor aqueous solubility.

**hERG Inhibition:** Both ligands show very low hERG inhibition risk (0.143 and 0.044 percentile).

**Microsomal Clearance:** Ligand A (12.605 mL/min/kg) has slightly higher clearance than Ligand B (10.556 mL/min/kg), indicating potentially lower metabolic stability.

**In vitro Half-Life:** Ligand B (6.05 hours) has a significantly longer half-life than Ligand A (1.208 hours).

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.026 and 0.025 percentile), which is favorable for CNS penetration.

**Binding Affinity:** Ligand A (-7.7 kcal/mol) has a substantially stronger binding affinity than Ligand B (-6.3 kcal/mol). This is a 1.4 kcal/mol difference, which is significant and can outweigh some ADME drawbacks.

**Overall Assessment:**

Ligand A has a superior binding affinity and a more favorable TPSA. However, Ligand B exhibits significantly better BBB penetration and a longer half-life. The negative Caco-2 and solubility values are concerning for both, but the affinity difference for Ligand A is substantial. Given the importance of BBB penetration for a CNS target, and the relatively strong affinity of Ligand A, I believe the better candidate is Ligand A, *assuming* the solubility and permeability issues can be addressed through formulation or further chemical modifications. The strong binding affinity is a major advantage.

Output:
0
2025-04-17 06:15:36,850 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (376.519 and 370.465 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (96.89) is slightly above the optimal <90 for CNS targets, but still reasonable. Ligand B (50.27) is excellent, well below the 90 threshold.

**logP:** Ligand A (1.104) is within the optimal 1-3 range. Ligand B (4.057) is at the upper end of acceptable, potentially raising concerns about solubility and off-target effects.

**H-Bond Donors/Acceptors:** Ligand A has 3 HBD and 6 HBA, both within acceptable limits. Ligand B has 0 HBD and 4 HBA, also acceptable.

**QED:** Both ligands have reasonable QED values (0.494 and 0.693), indicating decent drug-likeness. Ligand B is better.

**DILI:** Ligand A (23.459) has a lower DILI risk than Ligand B (32.454), which is preferable.

**BBB:** This is a critical parameter for a CNS target. Ligand A (34.626) has a poor BBB percentile, while Ligand B (92.516) is excellent, exceeding the desirable >70 threshold. This is a major advantage for Ligand B.

**Caco-2 Permeability:** Ligand A (-5.448) has poor Caco-2 permeability. Ligand B (-4.454) is also poor, but slightly better.

**Aqueous Solubility:** Both ligands have very poor aqueous solubility (-2.33 and -3.647). This is a significant concern for both.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.173 and 0.345).

**Microsomal Clearance:** Ligand A (22.728) has lower microsomal clearance than Ligand B (44.113), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (-7.27) has a longer in vitro half-life than Ligand B (-4.31), which is favorable.

**P-gp Efflux:** Both have very low P-gp efflux liability (0.031 and 0.328).

**Binding Affinity:** Ligand B (-7.1) has a slightly better binding affinity than Ligand A (-6.9), although the difference is small.

**Overall Assessment:**

Ligand B is significantly better regarding BBB penetration, a crucial factor for CNS targets like DRD2. While its logP is higher and solubility is lower than ideal, the excellent BBB score and slightly better affinity outweigh these concerns. Ligand A has better metabolic stability and DILI risk, but its poor BBB penetration is a major drawback. Given the GPCR-specific priorities, Ligand B is the more promising candidate.

Output:
1
2025-04-17 06:15:36,850 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (362.539 Da and 342.527 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (58.2) is significantly higher than Ligand B (32.34). For a CNS target like DRD2, TPSA should be <=90, both are within this range, but B is better.

**logP:** Both ligands have logP values (4.121 and 4.567) slightly above the optimal 1-3 range. This could potentially lead to solubility issues or off-target effects, but is not a dealbreaker. Ligand B is slightly higher.

**H-Bond Donors/Acceptors:** Ligand A has 2 HBD and 3 HBA, while Ligand B has 1 HBD and 2 HBA. Both are within acceptable limits (<=5 HBD and <=10 HBA).

**QED:** Both ligands have similar QED values (0.717 and 0.702), indicating good drug-likeness.

**DILI:** Ligand A (30.748) has a higher DILI risk than Ligand B (12.641). This is a significant advantage for Ligand B.

**BBB:** Ligand B (85.459) has a much higher BBB penetration percentile than Ligand A (63.746). This is *crucial* for a CNS target like DRD2, making Ligand B far more promising.

**Caco-2 Permeability:** Both have negative values, which is unusual. Assuming these are logP values, they are similar and suggest poor permeability.

**Aqueous Solubility:** Both ligands have very poor aqueous solubility (-3.41 and -4.471). This is a concern, but can potentially be addressed with formulation strategies.

**hERG Inhibition:** Ligand A (0.401) has a slightly higher hERG inhibition risk than Ligand B (0.893). Lower is better here, so Ligand B is preferred.

**Microsomal Clearance:** Both ligands have similar microsomal clearance values (61.361 and 63.336), suggesting comparable metabolic stability.

**In vitro Half-Life:** Ligand B (0.003) has a very short in vitro half-life, while Ligand A (23.289) has a much longer one. This is a significant advantage for Ligand A.

**P-gp Efflux:** Ligand A (0.257) has lower P-gp efflux liability than Ligand B (0.512), which is desirable for CNS penetration.

**Binding Affinity:** Ligand B (-8.6 kcal/mol) has a slightly better binding affinity than Ligand A (-9.2 kcal/mol). While the difference is small, it's still a positive for Ligand B.

**Overall Assessment:**

Considering the GPCR-specific priorities, Ligand B is the better candidate. The significantly higher BBB penetration (85.459 vs 63.746) and lower DILI risk (12.641 vs 30.748) are major advantages for a CNS drug. While Ligand A has a longer half-life and lower P-gp efflux, the BBB and safety profiles of Ligand B outweigh these benefits. The slightly better affinity of Ligand B also contributes to its favorability.

Output:
1
2025-04-17 06:15:36,851 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B against the provided guidelines, prioritizing GPCR-specific properties (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (345.49 & 351.45 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (62.3) is excellent for CNS penetration (<90), while Ligand B (93.78) is pushing the upper limit, potentially hindering BBB penetration.

**logP:** Ligand A (3.246) is optimal (1-3). Ligand B (-1.477) is significantly lower, which could lead to poor membrane permeability and bioavailability.

**H-Bond Donors/Acceptors:** Ligand A (HBD=1, HBA=3) is well within acceptable limits. Ligand B (HBD=3, HBA=5) is also acceptable, but slightly higher.

**QED:** Ligand A (0.787) has a strong drug-like profile, while Ligand B (0.464) is lower, indicating a less favorable overall profile.

**DILI:** Ligand A (21.99) has a very low DILI risk. Ligand B (12.06) also has a low DILI risk, but is higher than A.

**BBB:** Ligand A (77.63) shows good BBB penetration, desirable for a CNS target. Ligand B (28.69) is poor, a major drawback for DRD2 targeting.

**Caco-2 Permeability:** Ligand A (-4.304) is concerningly low, suggesting poor intestinal absorption. Ligand B (-5.919) is even worse.

**Aqueous Solubility:** Ligand A (-3.286) is poor, while Ligand B (-0.667) is also poor.

**hERG:** Both ligands have low hERG inhibition liability (0.545 and 0.124 respectively).

**Microsomal Clearance:** Ligand A (72.40) is moderate. Ligand B (-25.07) is excellent, indicating high metabolic stability.

**In vitro Half-Life:** Ligand A (29.97 hours) is good. Ligand B (7.04 hours) is relatively short.

**P-gp Efflux:** Ligand A (0.096) shows low P-gp efflux, which is beneficial for CNS exposure. Ligand B (0.001) shows even lower efflux, which is also good.

**Binding Affinity:** Ligand A (-8.1 kcal/mol) has a slightly better binding affinity than Ligand B (-7.8 kcal/mol), although both are strong binders. The 0.3 kcal/mol difference is not substantial enough to outweigh the significant ADME deficiencies of Ligand B.

**Overall Assessment:**

Ligand A is significantly more promising. While its Caco-2 permeability and aqueous solubility are concerns, its excellent BBB penetration, optimal logP, good QED, and strong binding affinity outweigh these drawbacks, especially considering the target is a CNS GPCR. Ligand B's poor logP and extremely low BBB penetration are major liabilities that are unlikely to be overcome. The better metabolic stability of Ligand B is not enough to compensate for these critical deficiencies.

Output:
1
2025-04-17 06:15:36,851 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (408.296 Da) is slightly higher than Ligand B (354.422 Da), but both are acceptable.

**TPSA:** Both ligands have TPSA values (65.79 and 67.87) that are above the optimal <90 for CNS targets, but not drastically so. This is a minor concern.

**logP:** Both ligands have good logP values (2.284 and 1.039), falling within the 1-3 range. Ligand A is slightly better.

**H-Bond Donors/Acceptors:** Both have 1 HBD and 4 HBA, which are within acceptable limits.

**QED:** Both ligands have acceptable QED scores (0.792 and 0.694), indicating good drug-like properties.

**DILI:** Ligand A (62.893) has a higher DILI risk than Ligand B (30.903). This is a significant negative for Ligand A.

**BBB:** Both ligands have excellent BBB penetration (71.035 and 73.129), exceeding the desirable >70 threshold for CNS targets.

**Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and suggests poor permeability. However, the scale is not specified, so it is difficult to interpret.

**Aqueous Solubility:** Both have negative solubility values, indicating poor solubility. This is a concern for both.

**hERG Inhibition:** Both ligands have low hERG inhibition liability (0.755 and 0.283), which is good.

**Microsomal Clearance:** Ligand B (16.693 mL/min/kg) has significantly lower microsomal clearance than Ligand A (32.881 mL/min/kg), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand B (-11.384 hours) has a negative half-life, which is problematic. Ligand A (105.15 hours) has a very long half-life, which is a positive.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.271 and 0.051), which is favorable for CNS penetration.

**Binding Affinity:** Ligand A (-9.4 kcal/mol) has a significantly stronger binding affinity than Ligand B (-8.0 kcal/mol). This is a substantial advantage.

**Overall Assessment:**

Ligand A has a much stronger binding affinity and a very long half-life, which are major positives. However, it has a higher DILI risk and higher microsomal clearance. Ligand B has a lower DILI risk and better metabolic stability, but its binding affinity is weaker and its half-life is problematic.

Given the importance of binding affinity for GPCRs, and the acceptable BBB penetration of both, the stronger affinity of Ligand A outweighs its drawbacks, *assuming* the DILI risk can be mitigated through structural modifications. The negative half-life of Ligand B is a significant issue.

Output:
1
2025-04-17 06:15:36,851 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (348.407 and 344.415 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (118.01) is borderline for CNS targets, slightly above the preferred <90, but acceptable. Ligand B (84.42) is excellent, well below 90, favoring CNS penetration.

**3. logP:** Ligand A (-0.65) is a bit low, potentially hindering permeation. Ligand B (1.243) is within the optimal 1-3 range.

**4. H-Bond Donors:** Ligand A (3) is acceptable. Ligand B (1) is also good.

**5. H-Bond Acceptors:** Ligand A (6) is acceptable. Ligand B (5) is also good.

**6. QED:** Both ligands have good QED scores (0.548 and 0.785, respectively), indicating drug-like properties. Ligand B is slightly better.

**7. DILI:** Both ligands have acceptable DILI risk (40.403 and 47.034), below the concerning threshold of 60.

**8. BBB:** This is a critical parameter for a CNS target like DRD2. Ligand A (35.983) has a poor BBB percentile, suggesting limited brain penetration. Ligand B (70.648) is very good, exceeding the desirable >70 threshold.

**9. Caco-2 Permeability:** Both have negative values, which is unusual. Assuming these are logP-like scales where lower is worse, Ligand B (-4.716) is worse than Ligand A (-5.989).

**10. Aqueous Solubility:** Both have negative values, again assuming a logS-like scale where lower is worse. Ligand A (-1.298) is better than Ligand B (-2.264).

**11. hERG Inhibition:** Both ligands show very low hERG inhibition risk (0.034 and 0.207), which is excellent.

**12. Microsomal Clearance:** Ligand A (-6.135) has a lower (better) clearance than Ligand B (38.883), indicating greater metabolic stability.

**13. In vitro Half-Life:** Ligand A (30.08) has a reasonable half-life. Ligand B (-2.776) has a negative half-life, which is impossible, and likely indicates a data error or a very short half-life.

**14. P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.004 and 0.032), which is favorable for CNS penetration.

**15. Binding Affinity:** Ligand B (-9.3 kcal/mol) has a significantly stronger binding affinity than Ligand A (-7.9 kcal/mol). This >1.5 kcal/mol difference is substantial and can outweigh some ADME drawbacks.

**Overall Assessment:**

While Ligand A has better metabolic stability and solubility, Ligand B is superior due to its significantly higher binding affinity and, crucially, its much better BBB penetration. The lower logP of Ligand A is a concern, and its poor BBB score is a major drawback for a CNS target. Ligand B's slightly worse Caco-2 and solubility are less concerning given the strong affinity and BBB penetration. The negative half-life for Ligand B is concerning and should be investigated, but the overall profile is still more promising.

Output:
1
2025-04-17 06:15:36,851 - INFO - Reasoning:

Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight (MW):** Both ligands are within the ideal range (200-500 Da). Ligand A (401.272 Da) is slightly higher than Ligand B (363.439 Da), but both are acceptable.

**2. TPSA:** Ligand A (107.85) is better than Ligand B (113.66) as it is closer to the <90 threshold for CNS targets.

**3. logP:** Ligand A (1.687) is within the optimal range (1-3), while Ligand B (0.216) is quite low, potentially hindering membrane permeability. This is a significant disadvantage for Ligand B.

**4. H-Bond Donors (HBD):** Both ligands are within the acceptable limit of <=5. Ligand A has 1 HBD, and Ligand B has 3.

**5. H-Bond Acceptors (HBA):** Both ligands are within the acceptable limit of <=10. Ligand A has 8 HBA, and Ligand B has 6.

**6. QED:** Both ligands have similar QED values (0.775 and 0.692), indicating good drug-like properties.

**7. DILI:** Ligand A (84.18) has a higher DILI risk than Ligand B (45.328), which is preferable.

**8. BBB:** Ligand A (71.268) has a significantly better BBB penetration percentile than Ligand B (38.465). This is *critical* for a CNS target like DRD2.

**9. Caco-2 Permeability:** Both have negative values, indicating poor permeability. Ligand A (-5.139) is slightly better than Ligand B (-5.452).

**10. Aqueous Solubility:** Both have negative values, indicating poor solubility. Ligand A (-4.089) is slightly better than Ligand B (-2.44).

**11. hERG Inhibition:** Both ligands have low hERG inhibition risk (0.65 and 0.319).

**12. Microsomal Clearance (Cl_mic):** Ligand B (-27.508) has a lower (better) Cl_mic than Ligand A (34.246), suggesting greater metabolic stability.

**13. In vitro Half-Life:** Ligand B (14.509) has a longer half-life than Ligand A (-11.225).

**14. P-gp Efflux:** Both have very low P-gp efflux liability (0.03 and 0.071).

**15. Binding Affinity:** Both ligands have very similar and strong binding affinities (-8.2 and -8.4 kcal/mol). The difference is negligible.

**Overall Assessment:**

While Ligand B has better metabolic stability and half-life, Ligand A is significantly better in terms of BBB penetration and logP. Given that DRD2 is a CNS target, BBB penetration is paramount. The low logP of Ligand B is a major concern, as it suggests poor membrane permeability and reduced CNS exposure. Ligand A's slightly higher DILI risk is less concerning than the permeability issues of Ligand B.

Output:
1
2025-04-17 06:15:36,852 - INFO - Reasoning:

Let's analyze Ligand A and Ligand B based on the provided guidelines, prioritizing GPCR-specific properties (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (348.431 Da) is slightly lower, which could be beneficial for permeability.

**TPSA:** Ligand A (59.81) is significantly better than Ligand B (37.49). For a CNS target like DRD2, a TPSA below 90 is preferred, and A is comfortably within this range, while B is also good.

**logP:** Both ligands have logP values (3.972 and 4.434) within the optimal range of 1-3, although approaching the upper limit. Ligand B is slightly higher, which *could* indicate potential off-target effects or solubility issues, but isn't a major concern.

**H-Bond Donors/Acceptors:** Both ligands have acceptable HBD (1) and HBA (5 for A, 3 for B) counts, well below the thresholds of 5 and 10, respectively.

**QED:** Both ligands have good QED scores (0.607 and 0.838), indicating good drug-like properties. Ligand B is slightly better here.

**DILI:** Ligand A has a higher DILI risk (87.747%) than Ligand B (47.732%). This is a significant drawback for Ligand A.

**BBB:** Ligand B (90.035%) has a substantially better BBB penetration score than Ligand A (70.919%). This is a critical factor for a CNS target like DRD2.

**Caco-2 Permeability:** Both have negative Caco-2 values which is unusual and suggests a potential issue with the data. However, we can still compare the values. Ligand A (-5.267) is slightly better than Ligand B (-4.631).

**Aqueous Solubility:** Both ligands have poor aqueous solubility (-4.364 and -4.765). This could pose formulation challenges, but is not a deal-breaker.

**hERG Inhibition:** Both ligands have low hERG inhibition liability (0.619 and 0.939), which is good.

**Microsomal Clearance:** Ligand B (29.759 mL/min/kg) has significantly lower microsomal clearance than Ligand A (108.322 mL/min/kg), indicating better metabolic stability.

**In vitro Half-Life:** Ligand B (-6.38 hours) has a longer half-life than Ligand A (13.794 hours). This is a positive for Ligand B.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.653 and 0.754), which is good for CNS penetration.

**Binding Affinity:** Ligand B (-8.4 kcal/mol) has a significantly stronger binding affinity than Ligand A (-10.1 kcal/mol). This is a substantial advantage, potentially outweighing minor ADME concerns.

**Overall Assessment:**

Ligand B is the stronger candidate. While both have some weaknesses (solubility), Ligand B excels in the most critical areas for a CNS GPCR target: BBB penetration, metabolic stability (lower Cl_mic, longer t1/2), and significantly stronger binding affinity. The lower DILI risk for Ligand B is also a major advantage. The slightly higher logP of Ligand B is less concerning than the higher DILI and lower BBB of Ligand A.

Output:
1
2025-04-17 06:15:36,852 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (368.587 Da) is slightly higher than Ligand B (350.415 Da), but both are acceptable.

**TPSA:** Ligand A (58.2) is excellent for CNS penetration, well below the 90 A^2 threshold. Ligand B (90.31) is at the upper limit for CNS targets, potentially hindering BBB penetration.

**logP:** Ligand A (4.056) is at the higher end of the optimal range, potentially leading to solubility issues, but still acceptable. Ligand B (-0.31) is significantly below the optimal range, which could impede permeation.

**H-Bond Donors/Acceptors:** Both ligands have 2 HBDs, which is good. Ligand A has 3 HBAs, and Ligand B has 5 HBAs. Both are within the acceptable range (<=10).

**QED:** Both ligands have good QED scores (A: 0.452, B: 0.507), indicating reasonable drug-likeness.

**DILI:** Ligand A (33.773) has a much lower DILI risk than Ligand B (25.94). Both are good, but A is preferable.

**BBB:** Ligand A (64.637) has a significantly better BBB percentile than Ligand B (47.111). This is a crucial factor for a CNS target like DRD2.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.986 and -4.848), which is unusual and suggests poor permeability. This is a concern for both.

**Aqueous Solubility:** Both ligands have negative solubility values (-4.521 and -1.242), indicating poor aqueous solubility. This is a concern for both.

**hERG Inhibition:** Ligand A (0.48) has a slightly higher hERG risk than Ligand B (0.255), but both are relatively low.

**Microsomal Clearance:** Ligand A (98.301) has a very high microsomal clearance, suggesting rapid metabolism. Ligand B (4.273) has a much lower clearance, indicating better metabolic stability.

**In vitro Half-Life:** Ligand A (29.942) has a shorter half-life than Ligand B (9.716), consistent with the higher clearance.

**P-gp Efflux:** Ligand A (0.458) has lower P-gp efflux liability than Ligand B (0.026), which is beneficial for CNS exposure.

**Binding Affinity:** Ligand B (-7.8 kcal/mol) has a slightly better binding affinity than Ligand A (-7.0 kcal/mol). However, the difference is less than 1.5 kcal/mol, so it doesn't necessarily outweigh other ADME drawbacks.

**Overall Assessment:**

Ligand A is superior due to its significantly better BBB penetration, lower DILI risk, and lower P-gp efflux. While it has a higher logP and clearance, the crucial BBB property for a CNS target like DRD2 makes it the more promising candidate. Ligand B's low logP and poor BBB penetration are significant drawbacks. The slightly better affinity of Ligand B is not enough to compensate for these issues.

Output:
1
2025-04-17 06:15:36,852 - INFO - Batch 267 complete. Total preferences: 4272
2025-04-17 06:15:36,852 - INFO - Processing batch 268/512...
2025-04-17 06:16:22,051 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (351.447 and 347.459 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (87.74) is better than Ligand B (75.44). Both are below the 90 A^2 threshold desirable for CNS targets.

**3. logP:** Ligand B (2.858) is optimal (1-3), while Ligand A (0.292) is quite low, potentially hindering permeation. This is a significant drawback for Ligand A.

**4. H-Bond Donors:** Ligand A (2) is slightly higher than Ligand B (1), but both are within the acceptable limit of 5.

**5. H-Bond Acceptors:** Both ligands have 4 HBA, well within the acceptable limit of 10.

**6. QED:** Ligand B (0.912) has a much better QED score than Ligand A (0.674), indicating a more drug-like profile.

**7. DILI:** Ligand B (32.377) has a significantly lower DILI risk than Ligand A (16.557), suggesting better hepatotoxicity potential.

**8. BBB:** Ligand B (76.309) has a better BBB penetration percentile than Ligand A (59.287). Both are reasonably good, but Ligand B is preferable for a CNS target like DRD2.

**9. Caco-2 Permeability:** Ligand A (-5.115) has a worse Caco-2 permeability than Ligand B (-4.873).

**10. Aqueous Solubility:** Ligand A (-2.12) has a worse aqueous solubility than Ligand B (-3.16).

**11. hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.131 and 0.26, respectively).

**12. Microsomal Clearance:** Ligand B (50.191) has a lower microsomal clearance than Ligand A (12.815), indicating better metabolic stability.

**13. In vitro Half-Life:** Ligand B (-26.834) has a significantly longer in vitro half-life than Ligand A (12.4).

**14. P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.006 and 0.064, respectively).

**15. Binding Affinity:** Both ligands have excellent binding affinities (-8.3 and -8.9 kcal/mol). Ligand B is slightly better.

**Overall Assessment:**

Ligand B consistently outperforms Ligand A across most crucial ADME properties, especially logP, QED, DILI, BBB, metabolic stability (Cl_mic and t1/2), and solubility. While both have good binding affinity and low hERG/Pgp liabilities, the superior ADME profile of Ligand B makes it a much more promising drug candidate for targeting DRD2. The low logP of Ligand A is a major concern for CNS penetration.

Output:
1
2025-04-17 06:16:22,051 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (363.849 Da and 387.311 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (102.04) is higher than the preferred <90 for CNS targets, while Ligand B (58.44) is well within the desired range. This is a significant advantage for Ligand B.

**3. logP:** Both ligands have good logP values (3.597 and 2.26), falling within the optimal 1-3 range.

**4. H-Bond Donors:** Ligand A has 3 HBD, which is acceptable. Ligand B has 0, which is also acceptable.

**5. H-Bond Acceptors:** Both ligands have 4 HBA, which is within the acceptable limit of <=10.

**6. QED:** Both ligands have similar QED values (0.773 and 0.729), indicating good drug-likeness.

**7. DILI:** Ligand A (78.247) has a higher DILI risk than Ligand B (30.71). This is a clear advantage for Ligand B.

**8. BBB:** Both ligands have good BBB penetration (64.095 and 77.821), but Ligand B is better. A value >70 is desirable, and Ligand B is closer to that threshold.

**9. Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and suggests poor permeability. However, the scale isn't defined, so it's hard to interpret.

**10. Aqueous Solubility:** Both have negative solubility values, which is also unusual. Again, the scale is undefined.

**11. hERG Inhibition:** Both ligands have low hERG inhibition risk (0.341 and 0.313).

**12. Microsomal Clearance:** Ligand A (56.676) has higher microsomal clearance than Ligand B (20.789), indicating lower metabolic stability. Ligand B is preferable.

**13. In vitro Half-Life:** Ligand A (85.904) has a longer half-life than Ligand B (-0.925). This is a positive for Ligand A, *but* the negative value for B is concerning and could indicate rapid degradation.

**14. P-gp Efflux:** Both ligands have low P-gp efflux liability (0.218 and 0.087), which is good for CNS penetration.

**15. Binding Affinity:** Both ligands have very similar and excellent binding affinities (-8.4 kcal/mol and -8.2 kcal/mol). The difference is less than 1.5 kcal/mol, so it's not a deciding factor.

**Overall Assessment:**

Considering the GPCR-specific priorities, Ligand B is the more promising candidate. It has a significantly lower TPSA, lower DILI risk, better BBB penetration, and better metabolic stability (lower Cl_mic). While Ligand A has a slightly longer in vitro half-life, the negative value for Ligand B is a red flag. The similar binding affinities make the ADME properties the deciding factor.

Output:
1
2025-04-17 06:16:22,051 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (357.39 and 345.403 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (57.61) is excellent, well below the 90 A^2 threshold for CNS targets. Ligand B (100.21) is higher but still potentially acceptable, though less ideal.

**logP:** Ligand A (3.328) is optimal (1-3). Ligand B (0.039) is very low, which is a significant concern for permeability and CNS penetration.

**H-Bond Donors/Acceptors:** Ligand A (HBD=1, HBA=3) is good. Ligand B (HBD=2, HBA=5) is also acceptable.

**QED:** Both ligands have similar QED values (0.858 and 0.802), indicating good drug-likeness.

**DILI:** Ligand A (56.262) has a slightly higher DILI risk than Ligand B (41.024), but both are below the concerning 60 threshold.

**BBB:** Ligand A (61.225) has a moderate BBB penetration, while Ligand B (45.095) is significantly lower. This is a critical factor for a CNS target like DRD2.

**Caco-2 Permeability:** Ligand A (-4.54) has poor Caco-2 permeability, while Ligand B (-5.192) is even worse. Both are concerning.

**Aqueous Solubility:** Ligand A (-3.354) has poor solubility, while Ligand B (-2.55) is slightly better.

**hERG:** Both ligands have very low hERG inhibition risk (0.785 and 0.048, respectively).

**Microsomal Clearance:** Ligand A (42.123) has moderate clearance, while Ligand B (19.178) has lower clearance, suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (92.466) has a long half-life, which is desirable. Ligand B (-1.916) has a very short half-life, a significant drawback.

**P-gp Efflux:** Ligand A (0.772) has moderate P-gp efflux, while Ligand B (0.007) has very low P-gp efflux, which is favorable for CNS penetration.

**Binding Affinity:** Ligand A (-9.6 kcal/mol) has significantly stronger binding affinity than Ligand B (-7.7 kcal/mol). This is a substantial advantage.

**Overall Assessment:**

Ligand A's strong binding affinity and acceptable TPSA are major positives. However, its poor Caco-2 permeability and moderate BBB penetration are concerns. Ligand B suffers from a very low logP, poor BBB penetration, and a very short half-life, despite its lower P-gp efflux and slightly better metabolic stability.

Given the GPCR-specific priorities, particularly BBB penetration and logP, and the substantial difference in binding affinity, Ligand A is the more promising candidate. The strong binding affinity could potentially outweigh the permeability and BBB issues, and further optimization could address these shortcomings. The low logP of Ligand B is a major obstacle.

Output:
1
2025-04-17 06:16:22,051 - INFO - Reasoning:

Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (363.889 Da and 349.439 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (47.36) is excellent, well below the 90 Angstroms threshold for CNS targets. Ligand B (119.03) is higher, but still potentially acceptable, though less ideal.

**3. logP:** Ligand A (4.725) is slightly high, potentially leading to solubility issues or off-target interactions. Ligand B (0.355) is quite low, which could hinder membrane permeability and CNS penetration.

**4. H-Bond Donors:** Ligand A (0) is optimal. Ligand B (2) is acceptable.

**5. H-Bond Acceptors:** Ligand A (4) is good. Ligand B (7) is also acceptable, but higher.

**6. QED:** Both ligands (0.725 and 0.741) have good drug-likeness scores.

**7. DILI:** Ligand A (51.26) has a moderate DILI risk, but is acceptable. Ligand B (60.217) has a slightly higher DILI risk, but still within a manageable range.

**8. BBB:** Ligand A (76.774) has a good BBB penetration score. Ligand B (81.698) is even better, exceeding 80%. This is a critical factor for a CNS target like DRD2.

**9. Caco-2 Permeability:** Ligand A (-4.558) is poor. Ligand B (-5.378) is also poor. Both are unfavorable.

**10. Aqueous Solubility:** Ligand A (-4.931) is poor. Ligand B (-2.428) is also poor, but slightly better than Ligand A.

**11. hERG Inhibition:** Ligand A (0.512) has low hERG inhibition risk. Ligand B (0.167) is even lower, indicating a very low risk of cardiotoxicity.

**12. Microsomal Clearance:** Ligand A (74.325) has moderate clearance. Ligand B (7.601) has very low clearance, suggesting good metabolic stability.

**13. In vitro Half-Life:** Ligand A (31.275) has a moderate half-life. Ligand B (-3.932) has a very short half-life, which is undesirable.

**14. P-gp Efflux:** Ligand A (0.317) shows low P-gp efflux, which is favorable for CNS penetration. Ligand B (0.061) shows very low P-gp efflux, even more favorable.

**15. Binding Affinity:** Ligand B (-8.0 kcal/mol) has a significantly stronger binding affinity than Ligand A (-7.4 kcal/mol). This 1.6 kcal/mol difference is substantial and can outweigh some ADME drawbacks.

**Overall Assessment:**

Ligand B is the stronger candidate. While it has a lower logP and poor Caco-2 permeability/solubility, its significantly superior binding affinity (-8.0 vs -7.4 kcal/mol) and excellent BBB penetration (81.698%) are crucial for a CNS-targeting GPCR like DRD2. The very low P-gp efflux and hERG risk are also highly favorable. The low microsomal clearance and short half-life are concerns, but could potentially be addressed through structural modifications. Ligand A's higher logP and poor Caco-2 permeability are less easily addressed.

Output:
1
2025-04-17 06:16:22,052 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (347.415 and 356.491 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (73.32) is higher than Ligand B (40.62). For a CNS target like DRD2, TPSA should be <= 90, so both are acceptable, but B is significantly better.

**logP:** Ligand A (0.641) is a bit low, potentially hindering permeation. Ligand B (2.892) is within the optimal 1-3 range. This favors B.

**H-Bond Donors/Acceptors:** Ligand A has 1 HBD and 6 HBA, which are reasonable. Ligand B has 0 HBD and 3 HBA, also acceptable.

**QED:** Both ligands have similar QED values (0.809 and 0.782), indicating good drug-likeness.

**DILI:** Ligand A (22.722) has a much lower DILI risk than Ligand B (42.846), which is a significant advantage.

**BBB:** Ligand B (83.249) has a much higher BBB penetration percentile than Ligand A (64.327). This is *critical* for a CNS target like DRD2, making B strongly favored.

**Caco-2 Permeability:** Both have negative values (-4.877 and -4.742), which is unusual and suggests poor permeability. However, these values are on a scale where negative values are possible, and direct comparison is difficult without knowing the scale's specifics.

**Aqueous Solubility:** Both have negative values (-1.474 and -3.994), indicating poor solubility. This is a concern, but potentially manageable with formulation strategies.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.586 and 0.373).

**Microsomal Clearance:** Ligand B (98.744) has a much higher microsomal clearance than Ligand A (11.705), indicating faster metabolism and lower metabolic stability. This is a significant drawback for B.

**In vitro Half-Life:** Ligand A (2.7 hours) has a shorter half-life than Ligand B (-17.867 hours). The negative value for B is suspect and likely indicates a very long half-life, or an error in the data.

**P-gp Efflux:** Both ligands show very low P-gp efflux liability (0.016 and 0.367), which is good.

**Binding Affinity:** Both ligands have excellent binding affinity (-8.2 and -8.0 kcal/mol). The difference is relatively small and unlikely to be decisive.

**Overall Assessment:**

While Ligand A has a better safety profile (lower DILI) and metabolic stability (lower Cl_mic), Ligand B excels in BBB penetration, which is paramount for a CNS drug targeting DRD2. The slightly better logP of Ligand B also contributes to its favorability. The negative half-life for Ligand B is suspicious. Despite the solubility concerns for both, the superior BBB penetration of Ligand B outweighs the other drawbacks, especially given the strong binding affinity.

Output:
1
2025-04-17 06:16:22,052 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (348.491 and 348.487 Da) fall comfortably within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (59.39) and Ligand B (58.64) are both below the 90 A^2 threshold for CNS targets, which is excellent.

**3. logP:** Both ligands have logP values (2.476 and 2.509) within the optimal 1-3 range.

**4. H-Bond Donors:** Both ligands have 1 HBD, which is within the acceptable limit of <=5.

**5. H-Bond Acceptors:** Ligand A has 6 HBAs, and Ligand B has 3 HBAs, both are within the acceptable limit of <=10.

**6. QED:** Ligand A (0.801) has a significantly better QED score than Ligand B (0.686), indicating a more drug-like profile.

**7. DILI:** Ligand A (9.035 percentile) has a much lower DILI risk than Ligand B (17.255 percentile). This is a significant advantage.

**8. BBB:** Both ligands have excellent BBB penetration (Ligand A: 74.564%, Ligand B: 75.805%). Both exceed the desirable >70% threshold for CNS targets.

**9. Caco-2 Permeability:** Ligand A (-5.224) and Ligand B (-4.899) have negative values, which is unusual and suggests poor permeability. However, the scale isn't specified, so it's hard to interpret.

**10. Aqueous Solubility:** Ligand A (-1.038) and Ligand B (-3.035) have negative solubility values, indicating poor solubility. Ligand B is worse.

**11. hERG Inhibition:** Ligand A (0.849) has a lower hERG inhibition risk than Ligand B (0.261), which is preferable.

**12. Microsomal Clearance:** Ligand A (-6.738) has a much lower (better) microsomal clearance than Ligand B (58.096). This suggests greater metabolic stability for Ligand A.

**13. In vitro Half-Life:** Ligand A (5.033) has a better in vitro half-life than Ligand B (-11.814).

**14. P-gp Efflux:** Ligand A (0.133) has lower P-gp efflux than Ligand B (0.085), which is favorable for CNS exposure.

**15. Binding Affinity:** Ligand B (-7.6 kcal/mol) has a significantly stronger binding affinity than Ligand A (0.0 kcal/mol). This is a substantial advantage, potentially outweighing some of the ADME drawbacks.

**Overall Assessment:**

Ligand B has a much better binding affinity, which is crucial for GPCR targets. However, Ligand A demonstrates superior ADME properties across the board: better QED, significantly lower DILI risk, better metabolic stability (lower Cl_mic and better t1/2), and lower P-gp efflux. While both have poor solubility and Caco-2 permeability, the ADME profile of Ligand A is far more favorable. Given the importance of ADME properties for *in vivo* efficacy and safety, and the relatively small difference in BBB penetration, Ligand A is the more promising candidate, *assuming* the binding affinity can be improved through further optimization.

Output:
0
2025-04-17 06:16:22,052 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (340.442 Da) is slightly better positioned.

**TPSA:** Ligand A (33.29) is excellent for CNS penetration, well below 90. Ligand B (119.03) is higher, but still potentially acceptable, though less ideal.

**logP:** Ligand A (4.349) is a bit high, potentially leading to solubility issues or off-target effects. Ligand B (0.399) is quite low, which could hinder membrane permeability and CNS penetration.

**H-Bond Donors/Acceptors:** Both have 2 HBDs, which is good. Ligand A has 3 HBAs, and Ligand B has 7. Ligand A is preferable here.

**QED:** Both ligands have similar QED values (0.82 and 0.811), indicating good drug-likeness.

**DILI:** Ligand A (39.86) has a lower DILI risk than Ligand B (80.031), which is a significant advantage.

**BBB:** Ligand A (78.247) has a much better BBB percentile than Ligand B (60.256). This is crucial for a CNS target like DRD2.

**Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and suggests poor permeability. However, the scale is not specified, so it's difficult to interpret.

**Aqueous Solubility:** Both have negative solubility values, indicating poor solubility.

**hERG Inhibition:** Ligand A (0.946) has a slightly lower hERG risk than Ligand B (0.424), which is preferable.

**Microsomal Clearance:** Ligand B (-7.949) has a *negative* microsomal clearance, which is impossible and likely an error in the data. Ligand A (35.423) is reasonable. This is a major red flag for Ligand B.

**In vitro Half-Life:** Ligand A (16.149 hours) has a much longer half-life than Ligand B (5.061 hours).

**P-gp Efflux:** Ligand A (0.687) shows lower P-gp efflux than Ligand B (0.016), which is better for CNS exposure.

**Binding Affinity:** Both ligands have excellent binding affinities (-9.7 kcal/mol and -8.3 kcal/mol). Ligand A is slightly better, but the difference is not huge.

**Overall Assessment:**

Ligand A is significantly better due to its superior BBB penetration, lower DILI risk, more reasonable microsomal clearance, longer half-life, and lower P-gp efflux. While its logP is slightly high, the benefits in ADME and CNS penetration outweigh this concern. Ligand B has a problematic negative microsomal clearance and poor BBB penetration, making it a less viable candidate despite its good affinity.

Output:
0
2025-04-17 06:16:22,052 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (348.403 and 348.399 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (110.26) is higher than the preferred <90 for CNS targets, while Ligand B (88.85) is closer to the ideal range. This favors Ligand B.

**3. logP:** Both ligands have good logP values (2.382 and 1.282), falling within the optimal 1-3 range. Ligand B is slightly lower, which could be beneficial for solubility, but both are acceptable.

**4. H-Bond Donors:** Both ligands have acceptable HBD counts (2 and 1, respectively), well below the limit of 5.

**5. H-Bond Acceptors:** Both ligands have acceptable HBA counts (6 and 5, respectively), below the limit of 10.

**6. QED:** Both ligands have good QED scores (0.758 and 0.81), indicating good drug-like properties.

**7. DILI:** Ligand A (70.686) has a higher DILI risk than Ligand B (44.164). This favors Ligand B.

**8. BBB:** Ligand B (85.459) has a significantly higher BBB penetration percentile than Ligand A (54.517). This is a critical advantage for a CNS target like DRD2.

**9. Caco-2 Permeability:** Ligand A (-5.049) has worse Caco-2 permeability than Ligand B (-4.428), though both are negative values and suggest poor permeability.

**10. Aqueous Solubility:** Both ligands have poor aqueous solubility (-2.9 and -3.253, respectively). This is a concern, but can sometimes be mitigated with formulation strategies.

**11. hERG Inhibition:** Both ligands have low hERG inhibition risk (0.203 and 0.409, respectively).

**12. Microsomal Clearance:** Ligand B (51.527) has lower microsomal clearance than Ligand A (66.417), suggesting better metabolic stability. This favors Ligand B.

**13. In vitro Half-Life:** Ligand B (-8.524) has a longer in vitro half-life than Ligand A (-22.619), which is desirable.

**14. P-gp Efflux:** Both ligands have low P-gp efflux liability (0.14 and 0.133, respectively).

**15. Binding Affinity:** Ligand A (-7.8 kcal/mol) has slightly better binding affinity than Ligand B (-8.1 kcal/mol). While this difference is small, it's a positive for Ligand A.

**Overall Assessment:**

Ligand B is the more promising candidate. While Ligand A has slightly better binding affinity, Ligand B excels in crucial ADME properties for a CNS-targeting GPCR, particularly BBB penetration (85.459 vs 54.517), lower DILI risk (44.164 vs 70.686), and better metabolic stability (lower Cl_mic and longer t1/2). The TPSA value for Ligand B is also more favorable for CNS penetration. The small difference in binding affinity is likely outweighed by the significant improvements in ADME properties.



Output:
1
2025-04-17 06:16:22,052 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (386.627 and 381.567 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (58.2) is slightly higher than Ligand B (53.51). Both are below the 90 Angstroms threshold desirable for CNS targets, which is good.

**3. logP:** Ligand A (3.451) is slightly higher than Ligand B (2.873), both falling within the optimal 1-3 range.

**4. H-Bond Donors:** Ligand A has 2 HBD, while Ligand B has 0. Both are within the acceptable limit of <=5.

**5. H-Bond Acceptors:** Ligand A has 4 HBA, and Ligand B has 5. Both are below the limit of <=10.

**6. QED:** Both ligands have good QED values (0.604 and 0.787 respectively), indicating good drug-like properties.

**7. DILI:** Ligand A (31.485) has a slightly higher DILI risk than Ligand B (20.861), but both are below the 40 threshold, indicating low risk.

**8. BBB:** Both ligands have excellent BBB penetration (71.656 and 76.851 percentile), exceeding the >70 desirable threshold for CNS targets.

**9. Caco-2 Permeability:** Ligand A (-5.344) has worse Caco-2 permeability than Ligand B (-4.987), but both are negative values which is not ideal.

**10. Aqueous Solubility:** Ligand A (-3.992) has worse aqueous solubility than Ligand B (-2.797), but both are negative values which is not ideal.

**11. hERG Inhibition:** Both ligands have similar and low hERG inhibition risk (0.609 and 0.613).

**12. Microsomal Clearance:** Ligand A (77.267) has higher microsomal clearance than Ligand B (67.396), suggesting lower metabolic stability.

**13. In vitro Half-Life:** Ligand B (-10.991) has a significantly *longer* in vitro half-life than Ligand A (18.562). This is a major advantage.

**14. P-gp Efflux:** Both ligands have similar P-gp efflux liability (0.114 and 0.262).

**15. Binding Affinity:** Ligand A (-7.3 kcal/mol) has a slightly better binding affinity than Ligand B (-7.1 kcal/mol). While the difference is small (0.2 kcal/mol), it's within the range where it could be significant.

**Overall Assessment:**

While Ligand A has slightly better binding affinity, Ligand B has a significantly better in vitro half-life, lower DILI risk, and slightly better Caco-2 permeability and solubility. Given the importance of metabolic stability and reduced toxicity for CNS drugs, and the relatively small difference in binding affinity, Ligand B appears to be the more promising candidate. The BBB penetration is excellent for both.

Output:
1
2025-04-17 06:16:22,053 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (344.415 Da) is slightly lower, which could be advantageous for permeability, but both are acceptable.

**TPSA:** Ligand A (98.22) is better than Ligand B (41.57) as it is closer to the ideal range for CNS targets (<=90). Ligand B is quite low, which might indicate a lack of necessary interactions.

**logP:** Both ligands have acceptable logP values (Ligand A: 1.444, Ligand B: 3.699). Ligand B is closer to the upper limit of the optimal range, which could potentially lead to solubility issues, but is still within acceptable limits.

**H-Bond Donors/Acceptors:** Ligand A has 2 HBD and 4 HBA, while Ligand B has 1 HBD and 3 HBA. Both are within the desirable ranges (<=5 HBD, <=10 HBA).

**QED:** Both ligands have reasonable QED scores (Ligand A: 0.763, Ligand B: 0.676), indicating good drug-like properties.

**DILI:** Both ligands have low DILI risk (Ligand A: 43.66, Ligand B: 34.238), which is excellent.

**BBB:** Ligand B (78.015) has a significantly better BBB penetration score than Ligand A (56.029). This is a crucial advantage for a CNS target like DRD2.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.781 and -4.96), which is unusual and suggests poor permeability. This is a significant concern for both.

**Aqueous Solubility:** Both ligands have negative solubility values (-3.907 and -3.708), also unusual and concerning.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (Ligand A: 0.333, Ligand B: 0.804).

**Microsomal Clearance:** Ligand A (-11.523) has a much lower (better) microsomal clearance than Ligand B (65.859), indicating better metabolic stability.

**In vitro Half-Life:** Ligand B (71.081) has a significantly longer in vitro half-life than Ligand A (12.912). This is a positive attribute for dosing convenience.

**P-gp Efflux:** Ligand A (0.102) has lower P-gp efflux liability than Ligand B (0.417), which is favorable for CNS exposure.

**Binding Affinity:** Ligand B (-7.2 kcal/mol) has a slightly better binding affinity than Ligand A (-7.9 kcal/mol). While the difference is not huge, it's still a positive for Ligand B.

**Overall Assessment:**

Ligand B is the better candidate despite some drawbacks. The superior BBB penetration (78.015 vs 56.029) is a major advantage for a CNS target. The slightly better binding affinity and longer half-life also contribute. While Ligand A has better metabolic stability and P-gp efflux, the BBB score of Ligand B outweighs these benefits. The negative Caco-2 and solubility values are concerning for both, and would need to be addressed through further optimization.

Output:
1
2025-04-17 06:16:22,053 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (367.519 and 386.411 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (87.22) is better than Ligand B (66.48) as it is closer to the ideal range for CNS targets (<=90).

**3. logP:** Both ligands have good logP values (1.354 and 1.843), falling within the optimal 1-3 range.

**4. H-Bond Donors:** Ligand A (2) is slightly higher than Ligand B (1), but both are acceptable (<=5).

**5. H-Bond Acceptors:** Ligand A (6) is higher than Ligand B (3), but both are within the acceptable range (<=10).

**6. QED:** Both ligands have reasonable QED values (0.76 and 0.648), indicating good drug-like properties.

**7. DILI:** Ligand A (13.649) has a significantly lower DILI risk than Ligand B (50.291), which is a major advantage.

**8. BBB:** Ligand B (86.506) has a much better BBB penetration percentile than Ligand A (51.997). This is a critical factor for CNS targets like DRD2.

**9. Caco-2 Permeability:** Both have negative values, which is unusual. Assuming these are logP values, Ligand A (-5.603) is worse than Ligand B (-5.131).

**10. Aqueous Solubility:** Both have negative values, which is unusual. Assuming these are logS values, Ligand A (-1.432) is better than Ligand B (-3.51).

**11. hERG Inhibition:** Ligand A (0.078) has a lower hERG inhibition liability than Ligand B (0.73), which is preferable.

**12. Microsomal Clearance:** Ligand A (-25.058) has significantly lower (better) microsomal clearance than Ligand B (30.509), indicating greater metabolic stability.

**13. In vitro Half-Life:** Ligand A (6.585) has a shorter half-life than Ligand B (-20.576).

**14. P-gp Efflux:** Ligand A (0.01) has much lower P-gp efflux liability than Ligand B (0.133), which is beneficial for CNS exposure.

**15. Binding Affinity:** Ligand B (-8.6) has a slightly better binding affinity than Ligand A (-8.0), but the difference is not substantial enough to outweigh other factors.

**Overall Assessment:**

Ligand A exhibits a superior safety profile (lower DILI, hERG, and P-gp efflux) and better metabolic stability (lower Cl_mic). While Ligand B has a better BBB score, the other advantages of Ligand A, particularly its lower toxicity liabilities, make it the more promising candidate. The slight difference in binding affinity is not enough to overcome the significant ADME/Tox advantages of Ligand A.

Output:
0
2025-04-17 06:16:22,053 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (335.5) is slightly lower, which is generally favorable for permeability.

**2. TPSA:** Ligand A (27.3) is excellent, well below the 90 A^2 threshold for CNS targets. Ligand B (58.64) is higher, but still acceptable, though less ideal for CNS penetration.

**3. logP:** Both ligands have good logP values (A: 3.799, B: 2.602) falling within the 1-3 range.

**4. H-Bond Donors:** Ligand A has 2 HBD, and Ligand B has 1. Both are within the acceptable limit of <=5.

**5. H-Bond Acceptors:** Both ligands have 3 HBA, well within the limit of <=10.

**6. QED:** Both ligands have reasonable QED scores (A: 0.806, B: 0.754), indicating good drug-like properties.

**7. DILI:** Ligand A (11.594) has a significantly lower DILI risk than Ligand B (27.685). This is a substantial advantage.

**8. BBB:** Ligand A (97.945) has a much higher predicted BBB penetration than Ligand B (86.39). This is *critical* for a CNS target like DRD2.

**9. Caco-2 Permeability:** Ligand A (-4.918) shows poor Caco-2 permeability, while Ligand B (-4.548) is slightly better, though still poor.

**10. Aqueous Solubility:** Both ligands have very poor aqueous solubility (-3.039 and -2.676 respectively). This could pose formulation challenges, but is less critical than BBB penetration for a CNS target.

**11. hERG Inhibition:** Both ligands have low hERG inhibition risk (A: 0.981, B: 0.577).

**12. Microsomal Clearance:** Ligand A (23.766) has lower microsomal clearance than Ligand B (44.885), suggesting better metabolic stability.

**13. In vitro Half-Life:** Ligand A (54.755) has a much longer in vitro half-life than Ligand B (-0.156). This is a significant advantage.

**14. P-gp Efflux:** Ligand A (0.217) has lower P-gp efflux liability than Ligand B (0.05), which is favorable for CNS exposure.

**15. Binding Affinity:** Ligand B (-7.4) has a significantly stronger binding affinity than Ligand A (-9.1). This is a substantial advantage, potentially outweighing some ADME drawbacks.

**Overall Assessment:**

While Ligand B has a better binding affinity, Ligand A is the more promising candidate due to its superior ADME properties, *particularly* its high BBB penetration (97.945) and low DILI risk. For a CNS target like DRD2, getting the drug into the brain is paramount. The better metabolic stability (lower Cl_mic, longer t1/2) and lower P-gp efflux of Ligand A also contribute to its potential for improved CNS exposure. The poor Caco-2 permeability is a concern for both, but less critical for a CNS-focused drug. The affinity difference, while significant, might be overcome with further optimization of Ligand A.

Output:
0
2025-04-17 06:16:22,053 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (456.215 Da) is higher, but still acceptable. Ligand B (350.467 Da) is slightly preferred.

**2. TPSA:** Both ligands have TPSA values around 93, which is slightly above the ideal <90 for CNS targets, but not disqualifying.

**3. logP:** Ligand A (2.959) is optimal. Ligand B (1.726) is a bit low, potentially hindering membrane permeability.

**4. H-Bond Donors:** Ligand A (2) is good. Ligand B (0) is also acceptable.

**5. H-Bond Acceptors:** Ligand A (5) is good. Ligand B (4) is also good.

**6. QED:** Ligand A (0.557) is good, indicating drug-like properties. Ligand B (0.379) is lower, suggesting a less favorable drug-like profile.

**7. DILI:** Ligand A (88.639) has a higher DILI risk, which is concerning. Ligand B (26.444) has a much lower DILI risk, a significant advantage.

**8. BBB:** Ligand B (77.627) has a significantly better BBB penetration percentile than Ligand A (58.278). This is crucial for a CNS target like DRD2.

**9. Caco-2 Permeability:** Ligand A (-5.383) has poor Caco-2 permeability, indicating poor absorption. Ligand B (-4.721) is also poor, but slightly better.

**10. Aqueous Solubility:** Ligand A (-4.388) and Ligand B (-0.581) both have poor aqueous solubility.

**11. hERG Inhibition:** Ligand A (0.535) has a slightly higher hERG inhibition risk than Ligand B (0.361), but both are relatively low.

**12. Microsomal Clearance:** Ligand A (52.715) and Ligand B (56.287) have similar microsomal clearance values, indicating comparable metabolic stability.

**13. In vitro Half-Life:** Ligand B (-25.633) has a negative half-life, which is not possible. This is a data error, and makes it difficult to assess. Ligand A (8.855) has a reasonable half-life.

**14. P-gp Efflux:** Ligand A (0.466) has lower P-gp efflux, which is favorable for CNS penetration. Ligand B (0.03) has very low P-gp efflux, which is even better.

**15. Binding Affinity:** Ligand A (-10.2 kcal/mol) has a significantly stronger binding affinity than Ligand B (-7.2 kcal/mol). This is a substantial advantage.

**Overall Assessment:**

Despite Ligand A's superior binding affinity, several factors favor Ligand B. Ligand B has a much better BBB score, significantly lower DILI risk, and lower P-gp efflux. While its logP is slightly lower, the substantial improvement in safety (DILI) and CNS penetration (BBB) outweigh this drawback. The negative half-life for Ligand B is a data quality issue, but even ignoring that, the affinity difference is large enough that the other properties of Ligand B are more favorable.

Output:
1
2025-04-17 06:16:22,054 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (347.5 and 353.4 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (81.99) is significantly better than Ligand B (102.66). For CNS targets, we want TPSA <= 90, so Ligand A is preferable.

**3. logP:** Ligand A (3.298) is optimal (1-3), while Ligand B (0.65) is quite low, potentially hindering membrane permeability. This is a significant advantage for Ligand A.

**4. H-Bond Donors:** Both have 2 HBD, which is within the acceptable limit of <= 5.

**5. H-Bond Acceptors:** Ligand A has 3 HBA, and Ligand B has 5. Both are within the acceptable limit of <=10.

**6. QED:** Both ligands have good QED scores (0.595 and 0.73), indicating good drug-like properties.

**7. DILI:** Both ligands have low DILI risk (31.06 and 31.60), which is positive.

**8. BBB:** Ligand A (73.28%) has a better BBB penetration score than Ligand B (58.01%). While >70 is desirable, Ligand A is closer and more promising for a CNS target like DRD2.

**9. Caco-2:** Both have negative Caco-2 values, which is unusual. However, the magnitude of the negative value for Ligand A (-4.705) is less than that of Ligand B (-4.839), suggesting slightly better permeability.

**10. Solubility:** Ligand A (-4.325) has a slightly better solubility score than Ligand B (-1.111).

**11. hERG:** Both ligands have low hERG inhibition risk (0.671 and 0.395).

**12. Cl_mic:** Ligand A (77.37) has a higher microsomal clearance than Ligand B (1.887), indicating faster metabolism and potentially lower *in vivo* exposure. This is a disadvantage for Ligand A.

**13. t1/2:** Ligand B (11.855) has a significantly longer *in vitro* half-life than Ligand A (-5.897), which is a major advantage.

**14. Pgp:** Ligand A (0.288) has lower P-gp efflux liability than Ligand B (0.028), which is beneficial for CNS penetration.

**15. Binding Affinity:** Ligand B (-8.2 kcal/mol) has a stronger binding affinity than Ligand A (-7.4 kcal/mol). This is a substantial advantage for Ligand B, potentially outweighing some of its ADME drawbacks. A difference of 0.8 kcal/mol is significant.

**Overall Assessment:**

While Ligand A excels in TPSA, logP, and BBB penetration, Ligand B boasts a significantly better binding affinity and a much longer half-life. The lower logP and higher Cl_mic of Ligand A are concerning. For a GPCR target in the CNS, strong binding affinity is paramount. The improved half-life of Ligand B also suggests better potential for *in vivo* efficacy. The slightly lower BBB score of Ligand B is less critical given the strong affinity.

Output:
1
2025-04-17 06:16:22,054 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (353.379 and 348.407 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (125.79) is slightly above the optimal <90 for CNS targets, but still reasonable. Ligand B (113.93) is better, falling comfortably below 90.

**logP:** Ligand A (-2.268) is quite low, potentially hindering membrane permeability. Ligand B (0.474) is better, within the optimal 1-3 range, but on the lower end.

**H-Bond Donors/Acceptors:** Both ligands have 3 HBD and a reasonable number of HBA (7 and 6 respectively), satisfying the <5 HBD and <10 HBA guidelines.

**QED:** Both ligands have acceptable QED scores (0.484 and 0.642), indicating reasonable drug-likeness. Ligand B is slightly better.

**DILI:** Ligand A (41.024) has a lower DILI risk than Ligand B (61.807), which is approaching a higher risk level.

**BBB:** Ligand A (21.985) has a very poor BBB penetration percentile. Ligand B (36.758) is better, but still not ideal for a CNS target (below the desired >70).

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.284 and -5.439), which is unusual and suggests poor permeability. This is a significant concern for both.

**Aqueous Solubility:** Both ligands have negative solubility values (-0.519 and -2.888), indicating very poor aqueous solubility. This is a major drawback for both.

**hERG Inhibition:** Both ligands show low hERG inhibition risk (0.104 and 0.184).

**Microsomal Clearance:** Ligand A (-13.012) has a much lower (better) microsomal clearance than Ligand B (16.001), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand B (26.087 hours) has a significantly longer half-life than Ligand A (7.32 hours).

**P-gp Efflux:** Both ligands show very low P-gp efflux liability (0.004 and 0.05).

**Binding Affinity:** Ligand B (-8.0 kcal/mol) has a considerably stronger binding affinity than Ligand A (-6.9 kcal/mol) - a difference of 1.1 kcal/mol. This is a substantial advantage.

**Overall Assessment:**

While neither ligand is ideal, Ligand B is the more promising candidate. Its significantly stronger binding affinity (-8.0 vs -6.9 kcal/mol) is a major advantage, and it has a longer half-life. Although its BBB penetration is still suboptimal, it's better than Ligand A's. Ligand A's low logP and poor BBB penetration are significant liabilities. The poor Caco-2 and solubility for both are concerning and would require significant medicinal chemistry efforts to address, but the affinity advantage of Ligand B makes it the better starting point.

Output:
1
2025-04-17 06:16:22,054 - INFO - Okay, let's analyze these two ligands for their potential as DRD2 drug candidates. DRD2 is a GPCR in the CNS, so BBB penetration, logP, Pgp efflux, TPSA, and binding affinity are paramount.

**Ligand A:** [336.391, 59.59, 3.516, 2, 3, 0.822, 67.429, 63.746, -4.645, -4.569, 0.711, 37.666, 22.954, 0.316, -8.8]
**Ligand B:** [348.487, 69.64, 2.534, 2, 3, 0.695, 12.524, 68.554, -4.823, -2.478, 0.298, 21.737, 22.698, 0.112, -8]

**1. Molecular Weight:** Both ligands are within the ideal range (200-500 Da). A (336.391) is slightly preferred.

**2. TPSA:** A (59.59) is excellent, well below the 90 threshold for CNS targets. B (69.64) is still reasonable, but less optimal.

**3. logP:** A (3.516) is optimal. B (2.534) is also good, but slightly lower.

**4. H-Bond Donors:** Both have 2 HBD, which is acceptable.

**5. H-Bond Acceptors:** Both have 3 HBA, which is acceptable.

**6. QED:** A (0.822) is very good, indicating high drug-likeness. B (0.695) is still acceptable, but lower.

**7. DILI:** A (67.429) is moderately high, indicating some potential liver toxicity risk. B (12.524) is *very* good, indicating low risk. This is a significant advantage for B.

**8. BBB:** Both have good BBB penetration (A: 63.746, B: 68.554). B is slightly better, exceeding 68%.

**9. Caco-2:** Both have negative Caco-2 values, which is unusual and potentially problematic. It suggests poor permeability. However, these values can be unreliable and may indicate issues with the prediction method.

**10. Solubility:** Both have negative solubility values, which is also unusual and potentially problematic. Similar to Caco-2, these values might be unreliable.

**11. hERG:** A (0.711) is better than B (0.298), indicating lower cardiotoxicity risk.

**12. Cl_mic:** A (37.666) is higher than B (21.737), meaning A has faster metabolic clearance and potentially lower *in vivo* exposure. B is preferred.

**13. t1/2:** Both are similar (A: 22.954, B: 22.698).

**14. Pgp:** A (0.316) is better than B (0.112), indicating lower P-gp efflux and potentially better CNS exposure.

**15. Binding Affinity:** A (-8.8) is slightly better than B (-8.0), a difference of 0.8 kcal/mol. This is a meaningful difference, potentially outweighing some ADME concerns.

**Overall Assessment:**

While Ligand A has a slightly better binding affinity and Pgp efflux, Ligand B demonstrates a significantly better safety profile (DILI) and metabolic stability (Cl_mic). The BBB penetration is comparable. The negative Caco-2 and solubility values are concerning for both, but may be prediction artifacts. Given the CNS target and the importance of minimizing off-target effects, the lower DILI risk of Ligand B is a crucial advantage. The 0.8 kcal/mol difference in binding affinity is not substantial enough to overcome the safety concerns associated with Ligand A.

Therefore, I recommend proceeding with **Ligand B**.

1
2025-04-17 06:16:22,054 - INFO - Batch 268 complete. Total preferences: 4288
2025-04-17 06:16:22,054 - INFO - Processing batch 269/512...
2025-04-17 06:17:03,279 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (378.425 and 362.506 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (42.43) is excellent, well below the 90 A^2 threshold for CNS targets. Ligand B (96.97) is higher, approaching the upper limit for oral absorption (140) but less ideal for CNS penetration.

**logP:** Ligand A (4.407) is slightly above the optimal range (1-3), potentially leading to solubility issues or off-target interactions. Ligand B (2.736) is within the optimal range.

**H-Bond Donors/Acceptors:** Ligand A (0 HBD, 5 HBA) and Ligand B (2 HBD, 5 HBA) both have acceptable numbers of H-bond donors and acceptors.

**QED:** Both ligands have similar QED values (0.634 and 0.63), indicating good drug-likeness.

**DILI:** Ligand A (94.533) has a high DILI risk, which is a significant concern. Ligand B (76.425) has a moderate DILI risk, but is considerably better than Ligand A.

**BBB:** Ligand A (83.443) has a very good BBB penetration percentile, crucial for a CNS target like DRD2. Ligand B (28.189) has poor BBB penetration.

**Caco-2 Permeability:** Ligand A (-4.47) has poor Caco-2 permeability. Ligand B (-5.055) also has poor Caco-2 permeability.

**Aqueous Solubility:** Both ligands have poor aqueous solubility (-5.853 and -4.453).

**hERG Inhibition:** Ligand A (0.6) has a slightly elevated hERG risk, while Ligand B (0.286) has a very low risk.

**Microsomal Clearance:** Ligand A (105.342) has a relatively high microsomal clearance, suggesting faster metabolism. Ligand B (79.72) has lower clearance, indicating better metabolic stability.

**In vitro Half-Life:** Ligand B (25.48) has a longer half-life than Ligand A (16.716).

**P-gp Efflux:** Ligand A (0.736) has moderate P-gp efflux, while Ligand B (0.085) has very low P-gp efflux, which is favorable for CNS penetration.

**Binding Affinity:** Ligand A (-9.6 kcal/mol) has significantly stronger binding affinity than Ligand B (-0.0 kcal/mol). This is a substantial advantage.

**Overall Assessment:**

Ligand A has a much stronger binding affinity and good BBB penetration, but suffers from high DILI risk, poor Caco-2 permeability, and relatively high metabolic clearance. Ligand B has better ADME properties (lower DILI, better metabolic stability, lower P-gp efflux, lower hERG risk) but extremely weak binding affinity and poor BBB penetration.

Given the importance of binding affinity for GPCRs, and the CNS target, the strong affinity of Ligand A is a major advantage. While the DILI risk is concerning, it might be mitigated through structural modifications. The poor permeability and clearance are also modifiable. Ligand B's weak affinity makes it unlikely to be a viable candidate, even with better ADME properties.

Output:
1
2025-04-17 06:17:03,280 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (345.407) is slightly lower, which could be beneficial for permeability, but both are acceptable.

**TPSA:** Ligand A (90.96) is right at the threshold for CNS targets (<=90), while Ligand B (53.51) is well below, which is excellent for brain penetration.

**logP:** Ligand A (0.458) is quite low, potentially hindering membrane permeability. Ligand B (3.095) is optimal. This is a significant advantage for Ligand B.

**H-Bond Donors/Acceptors:** Ligand A has 0 HBD and 8 HBA, which is reasonable. Ligand B has 0 HBD and 4 HBA, also reasonable.

**QED:** Both ligands have good QED scores (A: 0.677, B: 0.813), indicating drug-like properties.

**DILI:** Ligand A (73.09) has a higher DILI risk than Ligand B (45.56), though both are acceptable.

**BBB:** Ligand B (77.743) has a significantly better BBB percentile than Ligand A (62.97). This is crucial for a CNS target like DRD2.

**Caco-2 Permeability:** Ligand A (-5.011) shows poor Caco-2 permeability, which is a concern. Ligand B (-4.719) is also poor, but slightly better.

**Aqueous Solubility:** Both ligands have very poor aqueous solubility (-1.145 and -3.086 respectively). This could pose formulation challenges.

**hERG Inhibition:** Ligand A (0.062) has a very low hERG risk, which is excellent. Ligand B (0.525) is slightly higher, but still relatively low.

**Microsomal Clearance:** Ligand A (19.67) has lower microsomal clearance, suggesting better metabolic stability than Ligand B (66.378).

**In vitro Half-Life:** Ligand A (29.464) has a better in vitro half-life than Ligand B (-12.121).

**P-gp Efflux:** Ligand A (0.018) has very low P-gp efflux, which is favorable for CNS penetration. Ligand B (0.308) is higher, but still relatively low.

**Binding Affinity:** Ligand B (-7.8 kcal/mol) has a slightly better binding affinity than Ligand A (-7.2 kcal/mol). While the difference is not huge, it's enough to consider given the other factors.

**Overall Assessment:**

Ligand B is the stronger candidate. While both have poor solubility, Ligand B excels in key areas for a CNS GPCR target: significantly better BBB penetration, optimal logP, and slightly better binding affinity. Ligand A has better metabolic stability and lower hERG risk, but the poor logP and lower BBB penetration are major drawbacks. The difference in binding affinity, combined with the superior ADME properties related to brain penetration, makes Ligand B the more promising drug candidate.

Output:
1
2025-04-17 06:17:03,280 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (347.375 and 347.463 Da) fall within the ideal range of 200-500 Da.

**TPSA:** Ligand A (133.14) is close to the upper limit for good oral absorption and acceptable for CNS targets, but not ideal. Ligand B (72.28) is excellent, well below the 90 A^2 threshold for CNS penetration.

**logP:** Ligand A (0.32) is quite low, potentially hindering membrane permeability. Ligand B (1.294) is within the optimal range of 1-3.

**H-Bond Donors/Acceptors:** Ligand A has 4 HBD and 6 HBA, acceptable values. Ligand B has 1 HBD and 6 HBA, also acceptable.

**QED:** Both ligands have good QED scores (0.615 and 0.84), indicating drug-like properties.

**DILI:** Ligand A (69.019) has a higher DILI risk than Ligand B (18.224), which is a significant concern.

**BBB:** Ligand B (71.229) has a much better BBB penetration percentile than Ligand A (21.714). This is crucial for a CNS target like DRD2.

**Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and suggests a potential issue with the data or the compounds themselves. However, the magnitude is worse for Ligand A (-5.53 vs -5.058).

**Aqueous Solubility:** Both have negative solubility values, which is also concerning. The values are similar, so this isn't a major differentiator.

**hERG:** Both ligands have very low hERG inhibition liability (0.132 and 0.19), which is positive.

**Microsomal Clearance:** Ligand A (-4.033) has a negative clearance, which is not physically possible. This is a major data quality issue. Ligand B (13.475) has a reasonable, though not ideal, clearance.

**In vitro Half-Life:** Ligand A (-26.525) has a negative half-life, another data quality issue. Ligand B (10.894) has a reasonable half-life.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.046 and 0.04), which is favorable for CNS penetration.

**Binding Affinity:** Both ligands have strong binding affinities (-7.9 and -7.6 kcal/mol), and the difference of 0.3 kcal/mol is not substantial enough to overcome other significant differences.

**Conclusion:**

Ligand B is significantly more promising. It has a much better BBB score, lower DILI risk, more favorable logP, and more reasonable ADME properties (clearance and half-life). The data for Ligand A contains physically impossible values for clearance and half-life, making it immediately suspect. While both have good affinity, the superior ADME profile of Ligand B makes it the more viable drug candidate.

Output:
1
2025-04-17 06:17:03,280 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (341.386 and 360.361 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (62.3) is significantly better than Ligand B (96.69). For CNS targets, we want TPSA <= 90, and A is comfortably within this range, while B is approaching the upper limit.

**3. logP:** Both ligands have good logP values (2.316 and 1.387), falling within the optimal 1-3 range.

**4. H-Bond Donors:** Ligand A (1) and Ligand B (2) are both acceptable, being <= 5.

**5. H-Bond Acceptors:** Ligand A (3) and Ligand B (6) are both acceptable, being <= 10.

**6. QED:** Both ligands have reasonable QED scores (0.877 and 0.791), indicating good drug-like properties.

**7. DILI:** Both ligands have similar, acceptable DILI risk (56.689 and 53.858), both below the 60 threshold.

**8. BBB:** Ligand A (79.566) has a better BBB percentile than Ligand B (85.925), but both are above the 70% threshold desirable for CNS targets.

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.882 and -4.598). This is unusual and suggests poor permeability. However, these values are on a scale where negative values are possible, and the absolute magnitude isn't directly interpretable without knowing the scale's specifics.

**10. Aqueous Solubility:** Both ligands have negative solubility values (-2.552 and -2.408). Similar to Caco-2, this is unusual and requires knowing the scale. Negative values suggest poor solubility.

**11. hERG Inhibition:** Both ligands have low hERG inhibition risk (0.551 and 0.498).

**12. Microsomal Clearance:** Ligand A (15.775) has a significantly lower microsomal clearance than Ligand B (24.498), indicating better metabolic stability.

**13. In vitro Half-Life:** Ligand A (-7.035) has a better in vitro half-life than Ligand B (-2.819).

**14. P-gp Efflux:** Ligand A (0.099) has a lower P-gp efflux liability than Ligand B (0.066), which is favorable for CNS penetration.

**15. Binding Affinity:** Ligand B (-7.2) has a slightly better binding affinity than Ligand A (-9.1). However, the difference is relatively small, and A already has excellent affinity.

**Overall Assessment:**

Considering the GPCR-specific priorities, Ligand A is the more promising candidate. While Ligand B has a slightly better binding affinity, Ligand A excels in TPSA, BBB, metabolic stability (Cl_mic and t1/2), and P-gp efflux. The lower TPSA and P-gp efflux of Ligand A are particularly important for CNS penetration. The better metabolic stability will likely translate to a longer duration of action. The negative Caco-2 and solubility values are concerning for both, but the other advantages of Ligand A outweigh this drawback, especially given the focus on CNS targets where direct oral bioavailability might be less critical than brain penetration.

Output:
1
2025-04-17 06:17:03,280 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (342.399 Da) is slightly lower, which could be beneficial for permeability, but both are acceptable.

**TPSA:** Ligand A (78.67) is significantly better than Ligand B (49.85) for CNS penetration, falling well below the 90 A^2 threshold. Ligand B is still reasonable, but A is preferred.

**logP:** Ligand A (-0.36) is a bit low, potentially hindering membrane permeability. Ligand B (2.003) is within the optimal range (1-3). This is a significant advantage for Ligand B.

**H-Bond Donors/Acceptors:** Ligand A has 1 HBD and 5 HBA, while Ligand B has 0 HBD and 4 HBA. Both are within acceptable limits.

**QED:** Both ligands have similar QED values (0.761 and 0.756), indicating good drug-like properties.

**DILI:** Ligand A (20.202) has a much lower DILI risk than Ligand B (35.595). This is a substantial advantage for Ligand A.

**BBB:** Ligand B (90.772) has a significantly higher BBB penetration percentile than Ligand A (43.932). This is a critical advantage for a CNS target like DRD2.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values, which is unusual and suggests poor permeability. However, the scale is not specified, so we can't interpret these values definitively.

**Aqueous Solubility:** Both ligands have negative solubility values, indicating poor solubility. Again, the scale is undefined.

**hERG Inhibition:** Both ligands have low hERG inhibition liability (0.137 and 0.449), which is good.

**Microsomal Clearance:** Ligand A (-19.125) has a much lower (better) microsomal clearance than Ligand B (18.526), indicating greater metabolic stability.

**In vitro Half-Life:** Ligand A (-14.801) has a much longer in vitro half-life than Ligand B (-25.399). This is a significant advantage for Ligand A.

**P-gp Efflux:** Ligand A (0.017) has a much lower P-gp efflux liability than Ligand B (0.116), which is crucial for CNS penetration.

**Binding Affinity:** Ligand B (-7.1) has a slightly better binding affinity than Ligand A (-8.4). While a 1.3 kcal/mol difference is noticeable, the other ADME properties are more concerning.

**Overall Assessment:**

Ligand A excels in metabolic stability (Cl_mic, t1/2), DILI risk, and P-gp efflux. It also has a better TPSA. However, its logP is suboptimal, and BBB penetration is low. Ligand B has a much better logP and significantly higher BBB penetration, but suffers from higher DILI risk, worse metabolic stability, and higher P-gp efflux.

For a CNS target like DRD2, BBB penetration is paramount. While Ligand A has other favorable properties, Ligand B's superior BBB score outweighs its drawbacks, especially considering the relatively small difference in binding affinity. The lower logP of Ligand A is a concern, but could potentially be addressed with further optimization.

Output:
1
2025-04-17 06:17:03,281 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (344.5 and 353.5 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (49.41) is excellent, well below the 90 Angstroms threshold for CNS targets. Ligand B (62.32) is still reasonable, but less optimal.

**logP:** Ligand A (2.824) is within the optimal 1-3 range. Ligand B (0.051) is significantly low, potentially hindering membrane permeability and CNS penetration.

**H-Bond Donors/Acceptors:** Ligand A (1 HBD, 2 HBA) is favorable. Ligand B (0 HBD, 5 HBA) is also acceptable, though slightly higher HBA count.

**QED:** Both ligands have similar QED values (0.772 and 0.699), indicating good drug-like properties.

**DILI:** Ligand A (8.03) has a very low DILI risk. Ligand B (13.11) is still relatively low, but higher than Ligand A.

**BBB:** Ligand A (85.96) shows excellent BBB penetration potential. Ligand B (62.74) is considerably lower, raising concerns about reaching the CNS target.

**Caco-2 Permeability:** Both have negative values, indicating poor permeability. This is unusual and requires further investigation. However, the values are similar.

**Aqueous Solubility:** Both ligands have negative solubility values, which is also unusual and suggests poor solubility. Again, the values are comparable.

**hERG Inhibition:** Ligand A (0.717) has a low hERG risk. Ligand B (0.283) is even lower, indicating very low cardiotoxicity potential.

**Microsomal Clearance:** Ligand A (42.05) has moderate clearance, while Ligand B (9.66) has very low clearance, suggesting better metabolic stability.

**In vitro Half-Life:** Ligand B (13.33) has a significantly longer half-life than Ligand A (2.19), which is a positive attribute.

**P-gp Efflux:** Ligand A (0.085) has very low P-gp efflux, which is excellent for CNS penetration. Ligand B (0.021) is even lower, but the difference isn't substantial.

**Binding Affinity:** Ligand A (-8.2 kcal/mol) has a significantly stronger binding affinity than Ligand B (-7.2 kcal/mol). This 1.0 kcal/mol difference is substantial and can outweigh some ADME drawbacks.

**Overall Assessment:**

Given the GPCR-specific priorities, Ligand A is the more promising candidate. Its superior BBB penetration, optimal logP, and significantly stronger binding affinity are crucial for a CNS-targeting drug. While Ligand B has better metabolic stability and a longer half-life, its poor logP and lower BBB penetration are major drawbacks. The comparable Caco-2 and solubility values are concerning for both, but the affinity and CNS penetration advantages of Ligand A are more critical.

Output:
1
2025-04-17 06:17:03,281 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (343.515 and 344.39 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (58.36) is significantly better than Ligand B (67.23). For CNS targets, we want TPSA <= 90, and ideally closer to 60. Ligand A is much closer to this ideal.

**logP:** Both ligands have good logP values (2.674 and 1.804), falling within the optimal 1-3 range. Ligand A is slightly higher, which might be beneficial for membrane permeability.

**H-Bond Donors/Acceptors:** Ligand A (HBD=2, HBA=3) and Ligand B (HBD=1, HBA=4) both have acceptable numbers of H-bond donors and acceptors, well below the thresholds of 5 and 10 respectively.

**QED:** Both ligands have the same QED score (0.864), indicating good drug-likeness.

**DILI:** Ligand A (2.21) has a much lower DILI risk than Ligand B (59.131). This is a significant advantage for Ligand A.

**BBB:** Ligand A (82.202) has a substantially better BBB penetration score than Ligand B (76.58).  Both are above 70, which is desirable for CNS targets, but Ligand A is better.

**Caco-2 Permeability:** Ligand A (-5.248) has a worse Caco-2 permeability than Ligand B (-4.71). However, Caco-2 values are often difficult to interpret and less reliable than other parameters.

**Aqueous Solubility:** Ligand A (-1.271) has slightly better aqueous solubility than Ligand B (-2.95).

**hERG:** Ligand A (0.804) has a lower hERG inhibition liability than Ligand B (0.263), indicating a lower risk of cardiotoxicity.

**Microsomal Clearance:** Ligand A (-32.655) has a much lower (better) microsomal clearance than Ligand B (46.643), suggesting greater metabolic stability.

**In vitro Half-Life:** Ligand A (-9.56) has a worse in vitro half-life than Ligand B (6.432). This is a drawback for Ligand A.

**P-gp Efflux:** Ligand A (0.044) has a significantly lower P-gp efflux liability than Ligand B (0.179), which is crucial for CNS penetration.

**Binding Affinity:** Ligand B (-9.7) has a slightly better binding affinity than Ligand A (-8.8). This is a 1.9 kcal/mol difference, which is substantial and could potentially outweigh some ADME drawbacks.

**Overall Assessment:**

Ligand A consistently outperforms Ligand B in most critical ADME properties, especially DILI, BBB, P-gp efflux, and microsomal clearance. While Ligand B has a slightly better binding affinity, the superior ADME profile of Ligand A, particularly its improved CNS penetration potential (BBB, P-gp), and reduced toxicity (DILI, hERG), makes it the more promising drug candidate for a CNS target like DRD2. The difference in binding affinity, while notable, is likely surmountable with further optimization, whereas fixing poor ADME properties is often more challenging.

Output:
1
2025-04-17 06:17:03,281 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (354.38 and 351.407 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (58.87) is excellent, well below the 90 A^2 threshold for CNS targets. Ligand B (115.21) is higher but still potentially acceptable, though less optimal.

**3. logP:** Ligand A (2.847) is within the optimal 1-3 range. Ligand B (-0.338) is significantly lower, which could hinder membrane permeability and CNS penetration.

**4. H-Bond Donors:** Both ligands have acceptable HBD counts (1 and 2, respectively), below the threshold of 5.

**5. H-Bond Acceptors:** Both ligands have acceptable HBA counts (6 and 7, respectively), below the threshold of 10.

**6. QED:** Ligand A (0.895) has a very good drug-likeness score. Ligand B (0.465) is below the 0.5 threshold, indicating a less favorable drug-like profile.

**7. DILI:** Both ligands have low DILI risk (41.915 and 38.232, respectively), below the 40% threshold.

**8. BBB:** Ligand A (93.447) has excellent predicted BBB penetration, exceeding the desirable >70% threshold. Ligand B (52.423) is considerably lower, raising concerns about CNS exposure.

**9. Caco-2 Permeability:** Ligand A (-4.966) and Ligand B (-5.073) both have negative Caco-2 values, which is unusual and suggests poor permeability. However, these values are on a scale where negative values are possible and don't necessarily disqualify a compound.

**10. Aqueous Solubility:** Ligand A (-3.446) and Ligand B (-1.134) both have negative solubility values, which is also unusual. This suggests poor aqueous solubility.

**11. hERG Inhibition:** Both ligands have very low hERG risk (0.886 and 0.038, respectively).

**12. Microsomal Clearance:** Ligand A (-3.869) has a negative clearance, suggesting high metabolic stability. Ligand B (43.046) has a high clearance, indicating rapid metabolism.

**13. In vitro Half-Life:** Ligand A (0.173) has a very short half-life. Ligand B (-11.318) also has a very short half-life.

**14. P-gp Efflux:** Both ligands have very low P-gp efflux (0.105 and 0.023, respectively).

**15. Binding Affinity:** Ligand A (-8.5 kcal/mol) has a slightly better binding affinity than Ligand B (-7.9 kcal/mol), although both are strong binders. The difference of 0.6 kcal/mol is not huge, but it's a factor.

**Overall Assessment:**

Ligand A is significantly more promising. It excels in TPSA, logP, BBB penetration, QED, and has better metabolic stability (lower clearance). While both have poor solubility and short half-lives, the superior CNS penetration and drug-likeness of Ligand A outweigh the slightly better affinity of Ligand B. The negative Caco-2 and solubility values are concerning for both, but can be addressed in later optimization stages. Given the CNS target, BBB is paramount, and Ligand A's high BBB score is a major advantage.

Output:
1
2025-04-17 06:17:03,281 - INFO - Reasoning:

Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (377.586 Da) and Ligand B (353.482 Da) are both acceptable.

**2. TPSA:** Ligand A (73.2) is slightly above the ideal <90 for CNS targets, but still reasonable. Ligand B (47.36) is excellent, well below 90.

**3. logP:** Both ligands have good logP values (A: 3.246, B: 3.545), falling within the optimal 1-3 range.

**4. H-Bond Donors:** Ligand A has 1 HBD, which is good. Ligand B has 0, also good.

**5. H-Bond Acceptors:** Both ligands have 4 HBAs, which is acceptable (<=10).

**6. QED:** Both ligands have reasonable QED scores (A: 0.801, B: 0.735), indicating good drug-like properties.

**7. DILI:** Ligand A (40.364) is slightly higher than Ligand B (12.098), but both are below the concerning threshold of 60. Ligand B is significantly better here.

**8. BBB:** This is a critical parameter for CNS targets. Ligand A (70.376) is acceptable, but Ligand B (95.657) is *excellent*, suggesting much better brain penetration.

**9. Caco-2:** Both have negative values, which is unusual. Assuming these are logP values, they suggest poor permeability.

**10. Solubility:** Both have negative values, which is unusual. Assuming these are logS values, they suggest poor solubility.

**11. hERG:** Both ligands have very low hERG risk (0.698 and 0.625), which is excellent.

**12. Cl_mic:** Ligand A (41.807) has lower microsomal clearance than Ligand B (75.708), indicating better metabolic stability.

**13. t1/2:** Ligand A (21.924) has a longer in vitro half-life than Ligand B (-2.854). This is a significant advantage.

**14. Pgp:** Both ligands have low P-gp efflux liability (0.258 and 0.306), which is good.

**15. Binding Affinity:** Ligand A (0 kcal/mol) has equal binding affinity to Ligand B (0 kcal/mol).

**Overall Assessment:**

Ligand B is superior due to its significantly better BBB penetration (95.657 vs 70.376), lower DILI risk (12.098 vs 40.364), and better TPSA (47.36 vs 73.2). While Ligand A has better metabolic stability (lower Cl_mic) and a longer half-life, the CNS-specific priorities of BBB and low toxicity outweigh these advantages. The binding affinity is the same for both, so this doesn't factor into the decision.

Output:
1
2025-04-17 06:17:03,281 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (340.339 and 343.431 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (109.73) is higher than the preferred <90 for CNS targets, while Ligand B (80.12) is within the desired range. This is a significant advantage for Ligand B.

**3. logP:** Both ligands have good logP values (2.002 and 1.546), falling within the optimal 1-3 range.

**4. H-Bond Donors:** Ligand A has 2 HBD, and Ligand B has 1. Both are acceptable (<=5).

**5. H-Bond Acceptors:** Ligand A has 6 HBA, and Ligand B has 5. Both are acceptable (<=10).

**6. QED:** Both ligands have acceptable QED values (0.735 and 0.69), indicating good drug-like properties.

**7. DILI:** Ligand A has a very high DILI risk (95.502%), which is a major concern. Ligand B has a much lower DILI risk (39.899%), which is preferable.

**8. BBB:** Ligand A has a very low BBB penetration (17.449%), making it less likely to reach the target in the CNS. Ligand B has significantly better BBB penetration (69.407%), which is good, though ideally above 70.

**9. Caco-2:** Both ligands have negative Caco-2 values (-5.318 and -4.883), which is unusual and suggests poor permeability. However, these values are on a scale where negative values are possible and don't necessarily disqualify the compounds.

**10. Solubility:** Both ligands have negative solubility values (-3.294 and -3.305), which is also unusual, but doesn't necessarily disqualify the compounds.

**11. hERG:** Both ligands have very low hERG inhibition risk (0.004 and 0.123), which is excellent.

**12. Cl_mic:** Ligand A has a much lower (better) microsomal clearance (-11.561) than Ligand B (45.417), suggesting greater metabolic stability.

**13. t1/2:** Ligand A has a longer in vitro half-life (19.201 hours) than Ligand B (-10.454 hours).

**14. Pgp:** Ligand A has a very low Pgp efflux liability (0.011), which is excellent. Ligand B has a slightly higher Pgp efflux liability (0.102), but still relatively low.

**15. Binding Affinity:** Ligand A has a slightly better binding affinity (-8.5 kcal/mol) than Ligand B (-7.4 kcal/mol). This is a 1.1 kcal/mol difference, which is significant.

**Overall Assessment:**

While Ligand A has slightly better affinity and metabolic stability, its extremely high DILI risk and poor BBB penetration are major drawbacks for a CNS target like DRD2. Ligand B, despite slightly weaker affinity, has a much better safety profile (lower DILI), better BBB penetration, and a more favorable TPSA. The difference in affinity (1.1 kcal/mol) can potentially be overcome with further optimization, while mitigating the severe liabilities of Ligand A would be much more challenging. Given the GPCR-specific priorities, Ligand B is the more promising candidate.

Output:
1
2025-04-17 06:17:03,282 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (345.443 and 354.451 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (66.65) is excellent, well below the 90 A^2 threshold for CNS targets. Ligand B (90.98) is at the upper limit, but still acceptable.

**logP:** Ligand A (2.517) is optimal (1-3). Ligand B (0.733) is a bit low, potentially hindering permeability.

**H-Bond Donors/Acceptors:** Both ligands have reasonable HBD (0/2) and HBA (4/4) counts, well within the guidelines.

**QED:** Both ligands have good QED scores (0.844 and 0.521), indicating drug-likeness.

**DILI:** Both ligands have acceptable DILI risk (36.681 and 41.411), below the 40-60 threshold.

**BBB:** Ligand A (93.253) shows excellent BBB penetration, a crucial factor for a CNS target like DRD2. Ligand B (55.254) has poor predicted BBB penetration.

**Caco-2 Permeability:** Ligand A (-4.612) has poor Caco-2 permeability, which is concerning. Ligand B (-5.032) is also poor.

**Aqueous Solubility:** Both have poor aqueous solubility (-3.349 and -1.759). This could present formulation challenges.

**hERG:** Both ligands show low hERG inhibition liability (0.431 and 0.311), which is positive.

**Microsomal Clearance:** Ligand A (59.978) has moderate clearance, while Ligand B (-5.427) has negative clearance, which is not possible and likely an error in the data. Assuming this is an outlier, we should consider this a potential issue with Ligand B.

**In vitro Half-Life:** Ligand A (-6.531) has a negative half-life, which is not possible and indicates a data issue. Ligand B (9.787) has a reasonable half-life.

**P-gp Efflux:** Both ligands show low P-gp efflux liability (0.285 and 0.023), which is favorable for CNS penetration.

**Binding Affinity:** Ligand A (-9.8 kcal/mol) has significantly stronger binding affinity than Ligand B (-7.4 kcal/mol). This is a substantial difference (2.4 kcal/mol), which can outweigh some ADME drawbacks.

**Overall Assessment:**

Despite the issues with Caco-2 permeability and half-life for Ligand A, its superior binding affinity (-9.8 kcal/mol) and excellent BBB penetration (93.253) make it the more promising candidate. The strong binding affinity suggests it could be effective at lower doses, potentially mitigating some solubility issues. Ligand B has poor BBB penetration, and questionable clearance and half-life values.

Output:
1
2025-04-17 06:17:03,282 - INFO - Reasoning:

Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (340.427 and 371.88 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (77.0) is better than Ligand B (60.77). Both are below the 90 A^2 threshold for CNS targets, which is excellent.

**3. logP:** Both ligands have good logP values (3.788 and 4.047), falling within the optimal 1-3 range, although edging towards the higher end.

**4. H-Bond Donors:** Ligand A (1) is preferable to Ligand B (2). Lower HBD generally improves permeability.

**5. H-Bond Acceptors:** Ligand A (5) is better than Ligand B (3). Lower HBA generally improves permeability.

**6. QED:** Ligand A (0.866) is significantly better than Ligand B (0.652), indicating a more drug-like profile.

**7. DILI:** Ligand A (70.686) has a higher DILI risk than Ligand B (10.237). This is a significant drawback for Ligand A.

**8. BBB:** Ligand A (75.107) has a better BBB penetration prediction than Ligand B (56.34). This is crucial for a CNS target like DRD2.

**9. Caco-2 Permeability:** Ligand A (-4.635) has worse Caco-2 permeability than Ligand B (-4.823). Lower values are less desirable.

**10. Aqueous Solubility:** Ligand A (-4.652) has worse aqueous solubility than Ligand B (-3.611).

**11. hERG Inhibition:** Ligand A (0.282) has a lower hERG inhibition risk than Ligand B (0.867). This is a positive for Ligand A.

**12. Microsomal Clearance:** Both ligands have similar microsomal clearance values (83.775 and 84.008), suggesting comparable metabolic stability.

**13. In vitro Half-Life:** Ligand B (44.684) has a much longer in vitro half-life than Ligand A (-13.158). This is a significant advantage for Ligand B.

**14. P-gp Efflux:** Ligand A (0.118) has a much lower P-gp efflux liability than Ligand B (0.472). This is a positive for Ligand A, as it suggests better CNS exposure.

**15. Binding Affinity:** Ligand A (-9.1 kcal/mol) has a significantly stronger binding affinity than Ligand B (-6.8 kcal/mol). This is a substantial advantage for Ligand A, potentially outweighing some of its ADME drawbacks.

**Overall Assessment:**

Ligand A excels in binding affinity, TPSA, BBB, P-gp efflux, and hERG. However, it suffers from higher DILI risk, worse solubility, and a shorter half-life. Ligand B has a better safety profile (lower DILI), better half-life, and slightly better solubility, but its affinity is considerably weaker, and its BBB penetration is lower.

Given the importance of affinity for GPCRs, and the substantial difference (-2.3 kcal/mol), Ligand A's stronger binding is a major advantage. The lower P-gp efflux also contributes to better CNS exposure. While the DILI risk is a concern, it might be mitigated through structural modifications during lead optimization. The lower solubility and half-life are also addressable.

Output:
1
2025-04-17 06:17:03,282 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (371.419 and 376.519 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (135.7) is slightly above the optimal <90 for CNS targets, but still reasonable. Ligand B (112.57) is better, falling comfortably under 140 and closer to the CNS target threshold.

**logP:** Ligand A (-0.917) is a bit low, potentially hindering membrane permeability. Ligand B (0.619) is within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Both have 3 HBDs (good) and acceptable HBA counts (6 and 5 respectively).

**QED:** Both ligands have identical QED scores (0.564), indicating similar drug-likeness.

**DILI:** Ligand A (65.568) has a higher DILI risk than Ligand B (31.291). This is a significant negative for Ligand A.

**BBB:** Ligand B (39.511) has a substantially better BBB penetration score than Ligand A (12.602). This is crucial for a CNS target like DRD2.

**Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and suggests poor permeability. However, the scale is not specified, so it's difficult to interpret.

**Aqueous Solubility:** Both have negative solubility values, again, difficult to interpret without knowing the scale.

**hERG:** Both ligands have very low hERG inhibition risk (0.023 and 0.208), which is excellent.

**Microsomal Clearance:** Ligand A (-8.763) has a much lower (better) microsomal clearance than Ligand B (25.553), indicating greater metabolic stability.

**In vitro Half-Life:** Ligand A (-18.61) has a negative half-life, which is not possible. This is a red flag. Ligand B (1.54) has a very short half-life, which is not ideal.

**P-gp Efflux:** Both have low P-gp efflux liability (0.004 and 0.034), which is good.

**Binding Affinity:** Ligand B (-7.3) has a slightly better binding affinity than Ligand A (-7.1), although the difference is small.

**Overall Assessment:**

Ligand B is the stronger candidate. While its half-life is short, its significantly better BBB penetration, lower DILI risk, and acceptable logP outweigh the slightly better metabolic stability of Ligand A. The negative half-life for Ligand A is a major concern, and its poor BBB penetration is a significant drawback for a CNS target. The small difference in binding affinity is not enough to overcome the other deficiencies of Ligand A.

Output:
1
2025-04-17 06:17:03,282 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (349.435 and 361.32 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (81.77) is slightly above the optimal <90 for CNS targets, while Ligand B (71.44) is well within the range. This favors Ligand B.

**logP:** Ligand A (-0.14) is quite low, potentially hindering membrane permeability. Ligand B (0.255) is better, though still on the lower side of the 1-3 optimal range.

**H-Bond Donors/Acceptors:** Ligand A has 1 HBD and 5 HBA, which are acceptable. Ligand B has 0 HBD and 5 HBA, also acceptable.

**QED:** Both ligands have reasonable QED values (0.818 and 0.723), indicating good drug-like properties.

**DILI:** Both have low DILI risk (33.23 and 44.552), which is good.

**BBB:** This is crucial for a CNS target. Ligand A has a BBB percentile of 43.932, which is below the desirable >70. Ligand B excels with a BBB percentile of 96.782, a significant advantage.

**Caco-2 Permeability:** Both have negative Caco-2 values (-4.966 and -4.281), which is unusual and suggests poor permeability. However, these values are on a scale where negative values are possible and don't necessarily disqualify a compound.

**Aqueous Solubility:** Both ligands have negative solubility values (-1.285 and -2.491), indicating poor aqueous solubility. This could be a formulation challenge.

**hERG Inhibition:** Both ligands show very low hERG inhibition risk (0.123 and 0.233).

**Microsomal Clearance:** Ligand A has a moderate Cl_mic (8.643), while Ligand B shows a significantly *lower* (better) Cl_mic (-2.281). This suggests better metabolic stability for Ligand B.

**In vitro Half-Life:** Ligand A has a half-life of 6.158 hours, while Ligand B has a very long half-life of -19.759 hours (negative values are possible and indicate a very long half-life).

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.005 and 0.082), which is favorable for CNS penetration.

**Binding Affinity:** Ligand B (-8.8 kcal/mol) has a substantially stronger binding affinity than Ligand A (-6.7 kcal/mol). This difference of 2.1 kcal/mol is significant and can outweigh some of the ADME drawbacks.

**Overall:**

Ligand B is the stronger candidate. Its superior BBB penetration, significantly better binding affinity, and improved metabolic stability (lower Cl_mic, longer half-life) outweigh the slightly lower logP and solubility concerns. While both have poor Caco-2 and solubility, the strong affinity and CNS penetration profile of Ligand B make it more likely to succeed as a DRD2-targeting drug.

Output:
1
2025-04-17 06:17:03,283 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (352.519 and 360.845 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (78.43) is better than Ligand B (67.23) as it is closer to the ideal <90 A^2 for CNS targets.

**logP:** Both ligands have excellent logP values (2.765 and 2.498), falling within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A has 3 HBD and 3 HBA, while Ligand B has 1 HBD and 4 HBA. Both are within acceptable limits (<=5 HBD, <=10 HBA).

**QED:** Ligand B (0.91) has a significantly better QED score than Ligand A (0.628), indicating a more drug-like profile.

**DILI:** Ligand A (20.706) has a much lower DILI risk than Ligand B (59.287). This is a significant advantage for Ligand A.

**BBB:** Ligand B (68.166) has a slightly better BBB penetration score than Ligand A (62.466), but both are below the desirable >70 threshold for CNS targets.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.637 and -4.954), which is unusual and suggests poor permeability. This is a concern for both.

**Aqueous Solubility:** Both ligands have negative solubility values (-3.292 and -3.494), indicating very poor aqueous solubility. This is a major drawback for both.

**hERG Inhibition:** Both ligands have similar, low hERG inhibition liability (0.32 and 0.329).

**Microsomal Clearance:** Ligand A (52.073) has a higher microsomal clearance than Ligand B (14.556), suggesting lower metabolic stability. Ligand B is significantly better here.

**In vitro Half-Life:** Ligand B (24.538 hours) has a much longer in vitro half-life than Ligand A (-2 hours). This is a substantial advantage for Ligand B.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.247 and 0.179), which is good for CNS exposure.

**Binding Affinity:** Ligand B (-8.7 kcal/mol) has a significantly stronger binding affinity than Ligand A (-7.3 kcal/mol). This is a crucial advantage, exceeding the 1.5 kcal/mol difference threshold.

**Overall Assessment:**

While Ligand A has a lower DILI risk, Ligand B excels in the most critical areas for a CNS-targeting GPCR ligand: binding affinity and metabolic stability (lower Cl_mic, longer t1/2). The significantly stronger binding affinity of Ligand B (-8.7 vs -7.3 kcal/mol) outweighs the slightly lower BBB and higher DILI risk. The poor solubility and permeability are concerns for both, but can potentially be addressed with formulation strategies.

Output:
1
2025-04-17 06:17:03,283 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (337.402 Da) is slightly lower, which could be advantageous for permeability.

**TPSA:** Ligand A (54.8) is significantly better than Ligand B (84.23). For a CNS target like DRD2, a TPSA under 90 is preferred, and Ligand A is well within this range, while Ligand B is approaching the upper limit.

**logP:** Both ligands have good logP values (3.322 and 3.265), falling within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A (0 HBD, 5 HBA) has a more favorable profile than Ligand B (2 HBD, 4 HBA). Lower HBD counts generally improve BBB penetration.

**QED:** Both ligands have acceptable QED values (0.715 and 0.677), indicating good drug-likeness.

**DILI:** Ligand A (55.448) has a higher DILI risk than Ligand B (35.867). This is a drawback for Ligand A.

**BBB:** Ligand A (86.933) has a significantly better BBB percentile than Ligand B (64.676). This is a crucial advantage for a CNS target.

**Caco-2 Permeability:** Both have negative Caco-2 values which is unusual and suggests a problem with the data. We will disregard this parameter.

**Aqueous Solubility:** Both have negative solubility values which is unusual and suggests a problem with the data. We will disregard this parameter.

**hERG:** Ligand A (0.709) has a lower hERG risk than Ligand B (0.289), which is preferable.

**Microsomal Clearance:** Ligand B (70.312) has higher microsomal clearance than Ligand A (38.281), indicating lower metabolic stability.

**In vitro Half-Life:** Ligand A (-17.524) has a negative half-life, which is not possible. Ligand B (8.027) has a short half-life, but is at least a plausible value.

**P-gp Efflux:** Ligand A (0.674) has lower P-gp efflux liability than Ligand B (0.218), which is beneficial for CNS penetration.

**Binding Affinity:** Ligand B (-7.9 kcal/mol) has a significantly stronger binding affinity than Ligand A (-10.3 kcal/mol). This is a substantial advantage that could outweigh some ADME drawbacks.

**Overall Assessment:**

Ligand A excels in TPSA, BBB, P-gp efflux, and hERG. However, it has a higher DILI risk and a nonsensical half-life. Ligand B has a much stronger binding affinity, lower DILI, and a plausible half-life, but suffers from higher TPSA, higher P-gp efflux, and a less favorable BBB score.

Given the importance of binding affinity for GPCR ligands, and the relatively good (though not ideal) ADME profile of Ligand B, it is the more promising candidate. The stronger binding affinity of Ligand B (-7.9 kcal/mol vs -10.3 kcal/mol) is a significant advantage that can be addressed through further optimization. The issues with Ligand A's half-life and DILI are more concerning.

Output:
1
2025-04-17 06:17:03,283 - INFO - Batch 269 complete. Total preferences: 4304
2025-04-17 06:17:03,283 - INFO - Processing batch 270/512...
2025-04-17 06:17:43,446 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B based on the provided guidelines, prioritizing GPCR-specific properties (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (339.443 Da) is slightly lower, which could be beneficial for permeability, while Ligand B (380.447 Da) is still well within the acceptable range.

**TPSA:** Ligand A (56.9) is excellent, falling well below the 90 A^2 threshold for CNS targets. Ligand B (101.57) is higher, but still potentially acceptable, though less ideal for brain penetration.

**logP:** Both ligands have good logP values (A: 2.566, B: 1.385), falling within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A (HBD=1, HBA=6) and Ligand B (HBD=2, HBA=5) both have reasonable numbers of H-bond donors and acceptors, suggesting a balance between solubility and permeability.

**QED:** Both ligands have similar and acceptable QED values (A: 0.717, B: 0.738), indicating good drug-like properties.

**DILI:** Ligand A (39.667) has a much lower DILI risk than Ligand B (89.104), which is a significant advantage.

**BBB:** This is a critical parameter for CNS targets like DRD2. Ligand A has a very good BBB percentile (75.572), while Ligand B's BBB percentile is very low (15.316). This is a major drawback for Ligand B.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.311 and -5.163), which is unusual and difficult to interpret without knowing the scale. However, the values are similar.

**Aqueous Solubility:** Both ligands have negative solubility values (-2.694 and -3.44), again unusual and difficult to interpret. The values are similar.

**hERG Inhibition:** Ligand A (0.894) has a slightly higher hERG risk than Ligand B (0.207), but both are relatively low.

**Microsomal Clearance:** Ligand A (69.372) has a higher microsomal clearance than Ligand B (-3.222). This suggests Ligand B is more metabolically stable, which is a positive.

**In vitro Half-Life:** Ligand A (31.867) has a longer in vitro half-life than Ligand B (19.4), which is preferable.

**P-gp Efflux:** Ligand A (0.38) has lower P-gp efflux liability than Ligand B (0.133), which is beneficial for CNS penetration.

**Binding Affinity:** Ligand B (-8.5 kcal/mol) has a slightly stronger binding affinity than Ligand A (-7.8 kcal/mol). This 0.7 kcal/mol difference is notable, but might not be enough to overcome the significant ADME deficiencies of Ligand B.

**Overall Assessment:**

Ligand A is the more promising candidate. While Ligand B has slightly better binding affinity, Ligand A excels in crucial ADME properties for a CNS-targeting drug, particularly its significantly better BBB penetration, lower DILI risk, and lower P-gp efflux. The higher metabolic stability of Ligand B is a plus, but the poor BBB penetration is a major hurdle. The similar solubility and Caco-2 values don't strongly favor either compound.

Output:
0
2025-04-17 06:17:43,447 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (357.451 Da) and Ligand B (337.427 Da) are both acceptable.

**TPSA:** Ligand A (102.34) is borderline for CNS penetration, being above the preferred <90, but not drastically so. Ligand B (54.69) is excellent for CNS penetration.

**logP:** Ligand A (-1.198) is a bit low, potentially hindering membrane permeability. Ligand B (3.055) is optimal.

**H-Bond Donors:** Ligand A (3) is acceptable. Ligand B (1) is also good.

**H-Bond Acceptors:** Both ligands (A: 6, B: 6) are within the acceptable range of <=10.

**QED:** Both ligands have good QED scores (A: 0.529, B: 0.701), indicating drug-like properties.

**DILI:** Ligand A (10.818) has a very low DILI risk, which is excellent. Ligand B (76.192) has a significantly higher DILI risk, which is a concern.

**BBB:** Ligand A (28.306) has poor BBB penetration, making it less suitable for a CNS target. Ligand B (86.39) has excellent BBB penetration, a major advantage.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.109 and -4.741), which is unusual and suggests poor permeability. However, the scale isn't specified, so it's hard to interpret.

**Aqueous Solubility:** Both ligands have negative solubility values (-0.324 and -3.862), which is also unusual and suggests poor solubility. Again, the scale isn't specified.

**hERG Inhibition:** Ligand A (0.095) has very low hERG inhibition risk, which is excellent. Ligand B (0.968) has a moderate hERG risk.

**Microsomal Clearance:** Ligand A (-15.042) has very low microsomal clearance, indicating high metabolic stability. Ligand B (56.668) has higher clearance, meaning faster metabolism.

**In vitro Half-Life:** Ligand A (-0.257) has a very short half-life, which is undesirable. Ligand B (-3.694) also has a short half-life, but is slightly better than Ligand A.

**P-gp Efflux:** Ligand A (0.004) has very low P-gp efflux, which is excellent for CNS penetration. Ligand B (0.839) has moderate P-gp efflux.

**Binding Affinity:** Ligand B (-7.7 kcal/mol) has a significantly stronger binding affinity than Ligand A (-6.7 kcal/mol). This 1.0 kcal/mol difference is substantial and can outweigh some ADME drawbacks.

**Overall Assessment:**

Ligand B is the stronger candidate despite some ADME concerns. Its superior binding affinity, excellent BBB penetration, and optimal logP are crucial for a CNS-targeting GPCR. While the DILI risk is higher and the half-life is short, these issues can potentially be addressed through further optimization. Ligand A's poor BBB penetration and low logP are significant drawbacks that are harder to overcome. The negative solubility and Caco-2 values for both are concerning, but could be scale-dependent artifacts.

Output:
1
2025-04-17 06:17:43,447 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B based on the provided guidelines, prioritizing GPCR-specific parameters (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (356.392 Da) is slightly higher than Ligand B (343.431 Da), but this difference isn't significant.

**TPSA:** Ligand A (48.47) is excellent for CNS penetration, well below the 90 A^2 threshold. Ligand B (71.33) is still reasonable but less optimal, being further from the ideal range.

**logP:** Both ligands have good logP values (A: 2.895, B: 1.523) within the 1-3 range. Ligand A is slightly more lipophilic, which could be beneficial for membrane permeability.

**H-Bond Donors/Acceptors:** Ligand A (HBD=1, HBA=4) and Ligand B (HBD=0, HBA=5) both fall within acceptable ranges.

**QED:** Both ligands have reasonable QED scores (A: 0.905, B: 0.764), indicating good drug-like properties.

**DILI:** Ligand A (32.803) has a significantly lower DILI risk than Ligand B (55.758), which is a substantial advantage.

**BBB:** Ligand A (86.39) has a much higher BBB penetration percentile than Ligand B (71.811). This is *critical* for a CNS target like DRD2.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.714 and -4.756). This is unusual and suggests poor permeability, but the values are very close.

**Aqueous Solubility:** Both ligands have negative solubility values (-3.537 and -1.975). This is also unusual and suggests poor solubility, but again, the values are close.

**hERG Inhibition:** Ligand A (0.82) has a slightly higher hERG risk than Ligand B (0.154), but both are relatively low.

**Microsomal Clearance:** Ligand B (56.088) has a much higher microsomal clearance than Ligand A (10.333), indicating lower metabolic stability.

**In vitro Half-Life:** Ligand A (-9.896) has a longer in vitro half-life than Ligand B (-13.8), which is favorable.

**P-gp Efflux:** Ligand A (0.111) has a lower P-gp efflux liability than Ligand B (0.152), which is beneficial for CNS exposure.

**Binding Affinity:** Ligand B (-8.5 kcal/mol) has a slightly better binding affinity than Ligand A (-7.8 kcal/mol). However, the difference is only 0.7 kcal/mol, and other factors are more important.

**Overall Assessment:**

Ligand A is the superior candidate. While Ligand B has slightly better binding affinity, Ligand A excels in critical ADME properties for a CNS-targeting GPCR: significantly better BBB penetration, lower DILI risk, lower microsomal clearance (better metabolic stability), longer half-life, and lower P-gp efflux. The TPSA is also more favorable. The slight difference in binding affinity is outweighed by these substantial ADME advantages.

Output:
1
2025-04-17 06:17:43,447 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 drug candidates, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (381.391 Da) is slightly higher than Ligand B (354.292 Da), but both are acceptable.

**TPSA:** Ligand A (46.61) is excellent for CNS penetration, well below the 90 A^2 threshold. Ligand B (99.94) is higher, but still potentially acceptable, though less ideal.

**logP:** Ligand A (3.34) is optimal. Ligand B (2.306) is also good, falling within the 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A (0 HBD, 3 HBA) is favorable. Ligand B (2 HBD, 5 HBA) is also reasonable.

**QED:** Both ligands have similar QED values (A: 0.752, B: 0.749), indicating good drug-likeness.

**DILI:** Ligand A (46.995) has a lower DILI risk than Ligand B (85.498). This is a significant advantage.

**BBB:** Ligand A (96.355) has excellent BBB penetration, exceeding the desirable 70% threshold. Ligand B (74.486) is still good, but less favorable.

**Caco-2 Permeability:** Ligand A (-4.51) is very poor, indicating very low intestinal absorption. Ligand B (-5.137) is also poor, but slightly better than A.

**Aqueous Solubility:** Both ligands have poor aqueous solubility (A: -4.567, B: -3.401).

**hERG Inhibition:** Both ligands have low hERG inhibition risk (A: 0.786, B: 0.302).

**Microsomal Clearance:** Ligand A (50.127) has higher microsomal clearance than Ligand B (39.655), suggesting lower metabolic stability.

**In vitro Half-Life:** Ligand A (-39.088) has a very short half-life, while Ligand B (-4.596) is better.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (A: 0.257, B: 0.044).

**Binding Affinity:** Ligand A (-9.0 kcal/mol) has a significantly stronger binding affinity than Ligand B (-9.7 kcal/mol). This is a substantial advantage.

**Overall Assessment:**

Ligand A excels in key areas for a CNS-targeting GPCR ligand: TPSA, logP, BBB, and *especially* binding affinity. The strong affinity could potentially offset some of its ADME liabilities. However, its poor Caco-2 permeability and short half-life are concerning. Ligand B has a better DILI profile and half-life, but its TPSA is higher, BBB penetration is lower, and its binding affinity is weaker.

Given the importance of CNS penetration and strong binding for DRD2, and the fact that the affinity difference is substantial, I believe **Ligand A** is the more promising candidate, despite its ADME drawbacks. Further optimization could focus on improving its solubility, permeability, and metabolic stability.

Output:
1
2025-04-17 06:17:43,447 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (349.519 and 364.475 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (52.65) is significantly better than Ligand B (86.03). For CNS targets, we want TPSA <= 90, and A is comfortably within that, while B is approaching the upper limit. This favors A.

**3. logP:** Both ligands have good logP values (2.262 and 1.834), falling within the optimal 1-3 range.

**4. H-Bond Donors:** Both have 1 HBD, which is acceptable.

**5. H-Bond Acceptors:** Ligand A has 3 HBA, and Ligand B has 8.  While both are within the general limit of 10, Ligand A is preferable.

**6. QED:** Ligand A (0.847) has a much better QED score than Ligand B (0.568), indicating a more drug-like profile.

**7. DILI:** Ligand B (65.491) has a higher DILI risk than Ligand A (6.049). This is a significant advantage for A.

**8. BBB:** Ligand A (89.027) has a substantially higher BBB penetration percentile than Ligand B (60.101). This is *critical* for a CNS target like DRD2, making A much more promising.

**9. Caco-2 Permeability:** Ligand A (-4.699) and Ligand B (-5.058) both have negative Caco-2 values, which is unusual and suggests poor permeability. However, the scale isn't specified, so we can't definitively say which is worse.

**10. Aqueous Solubility:** Both have negative solubility values (-2.151 and -1.958), indicating poor solubility. This is a concern for both, but not a deciding factor.

**11. hERG Inhibition:** Ligand A (0.607) has a slightly better hERG profile than Ligand B (0.156), meaning lower risk of cardiotoxicity.

**12. Microsomal Clearance:** Ligand B (35.794) has a higher microsomal clearance than Ligand A (27.904), indicating faster metabolism and potentially lower in vivo exposure.

**13. In vitro Half-Life:** Ligand A (-14.136) has a worse in vitro half-life than Ligand B (23.033). This is a negative for A.

**14. P-gp Efflux:** Ligand A (0.038) has a much lower P-gp efflux liability than Ligand B (0.176). Lower P-gp efflux is highly desirable for CNS penetration.

**15. Binding Affinity:** Ligand A (-7.6 kcal/mol) has a slightly better binding affinity than Ligand B (-6.8 kcal/mol). While both are good, the 0.8 kcal/mol difference is significant.

**Overall Assessment:**

Ligand A is significantly better overall, especially considering the GPCR-specific priorities. Its superior BBB penetration, lower DILI risk, lower P-gp efflux, and slightly better binding affinity outweigh its slightly worse half-life. Ligand B's higher DILI and lower BBB are major drawbacks for a CNS drug. The TPSA and QED values also favor Ligand A.

Output:
1
2025-04-17 06:17:43,448 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (343.358 and 358.423 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (76.24) is significantly better than Ligand B (95.42). For CNS targets, we want TPSA <= 90, so Ligand A is preferable.

**logP:** Both ligands have acceptable logP values (2.544 and 1.726), falling within the 1-3 range. Ligand A is slightly higher, which could be beneficial for membrane permeability.

**H-Bond Donors/Acceptors:** Both have 2 HBD, which is good. Ligand A has 4 HBA, and Ligand B has 6. Both are acceptable (<=10), but Ligand A is slightly better.

**QED:** Both ligands have good QED scores (0.691 and 0.868), indicating good drug-like properties.

**DILI:** Ligand A (76.192) has a higher DILI risk than Ligand B (60.217), though both are reasonably acceptable.

**BBB:** Ligand A (53.974) has a significantly better BBB penetration percentile than Ligand B (40.093). This is *critical* for a CNS target like DRD2.

**Caco-2 Permeability:** Ligand A (-4.777) has a worse Caco-2 permeability than Ligand B (-5.306). Lower values indicate lower permeability.

**Aqueous Solubility:** Both have very poor aqueous solubility (-3.983 and -4.126). This is a concern for both, but not a deciding factor.

**hERG:** Ligand A (0.834) has a slightly higher hERG risk than Ligand B (0.09). Lower is better, so Ligand B is preferable.

**Microsomal Clearance:** Ligand A (43.452) has a higher microsomal clearance than Ligand B (37.354), indicating faster metabolism and lower metabolic stability. Ligand B is preferable.

**In vitro Half-Life:** Ligand B (-26.268) has a significantly longer in vitro half-life than Ligand A (-10.421). This is a significant advantage for Ligand B.

**P-gp Efflux:** Ligand A (0.414) has lower P-gp efflux than Ligand B (0.035), which is preferable for CNS penetration.

**Binding Affinity:** Both ligands have excellent binding affinities (-8.9 and -8.1 kcal/mol). Ligand A is slightly better (-8.9 kcal/mol), but the difference is relatively small.

**Overall Assessment:**

Ligand A excels in TPSA, logP, P-gp efflux, and binding affinity. However, its BBB penetration is significantly better than Ligand B, and this is paramount for a CNS target. Ligand B has better metabolic stability (lower Cl_mic, longer t1/2) and lower hERG risk. The difference in binding affinity is not substantial enough to outweigh the significant advantage of Ligand A's BBB penetration.

Output:
0
2025-04-17 06:17:43,448 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (346.39 and 362.50 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (95.34) is slightly above the optimal <90 for CNS targets, but still reasonable. Ligand B (66.4) is excellent, well below 90.

**logP:** Both ligands (2.41 and 2.35) are within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A has 1 HBD and 7 HBA, which are acceptable. Ligand B has 0 HBD and 5 HBA, also acceptable.

**QED:** Ligand A (0.81) has a very good drug-likeness score, significantly better than Ligand B (0.58).

**DILI:** Ligand A (69.72) has a moderate DILI risk, while Ligand B (31.02) has a low DILI risk, which is a significant advantage.

**BBB:** Ligand A (60.64) has a moderate BBB penetration, while Ligand B (74.18) has good BBB penetration, exceeding the desirable >70 threshold. This is a crucial factor for a CNS target like DRD2.

**Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and suggests poor permeability. However, the scale is not specified, so it's difficult to interpret.

**Aqueous Solubility:** Both ligands have negative solubility values, indicating poor solubility. This is a concern for bioavailability.

**hERG:** Both ligands have low hERG inhibition liability (0.21 and 0.42), which is positive.

**Microsomal Clearance:** Ligand A (79.55) has higher clearance than Ligand B (33.81), indicating lower metabolic stability.

**In vitro Half-Life:** Ligand B (-9.24) has a negative half-life, which is not possible and suggests an issue with the data. Ligand A (9.79) has a reasonable half-life.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.05 and 0.47), which is good for CNS penetration.

**Binding Affinity:** Both ligands have excellent binding affinities (-7.9 and -7.7 kcal/mol), with Ligand A being slightly better. The difference is less than 1.5 kcal/mol, so it's not a decisive factor on its own.

**Overall Assessment:**

Ligand B is the better candidate. While Ligand A has a slightly better binding affinity and QED, Ligand B excels in critical areas for a CNS GPCR target: significantly lower DILI risk, better BBB penetration, and lower microsomal clearance. The negative half-life for Ligand B is a data quality issue, but the other advantages outweigh this concern. The lower TPSA of Ligand B is also beneficial.

Output:
1
2025-04-17 06:17:43,448 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (342.414 Da) is slightly better, being closer to the lower end which can aid permeability.

**TPSA:** Ligand A (43.78) is significantly better than Ligand B (127.55). For CNS targets, TPSA should be <= 90, and A is well within this range, while B is considerably above.

**logP:** Ligand A (2.934) is optimal (1-3). Ligand B (-0.821) is below 1, which may impede permeation.

**H-Bond Donors/Acceptors:** Ligand A (HBD=1, HBA=3) is preferable to Ligand B (HBD=2, HBA=8). Both are within acceptable limits, but B has a higher HBA count, potentially impacting permeability.

**QED:** Both ligands have acceptable QED values (A: 0.933, B: 0.679), indicating good drug-like properties. A is superior.

**DILI:** Both have relatively low DILI risk (A: 47.654, B: 39.511), with B being slightly better.

**BBB:** Ligand A (71.462) is significantly better than Ligand B (23.73). A is above the desirable threshold of 70 for CNS targets, while B is quite low. This is a major advantage for A.

**Caco-2 Permeability:** Ligand A (-4.381) and Ligand B (-5.826) both have negative values. Lower values indicate poorer permeability. B is slightly worse.

**Aqueous Solubility:** Both have negative solubility values, indicating poor solubility. Ligand A (-1.726) is slightly better than Ligand B (-1.428).

**hERG Inhibition:** Ligand A (0.897) is better than Ligand B (0.027), indicating lower cardiotoxicity risk.

**Microsomal Clearance:** Ligand A (-12.725) has a lower (better) clearance than Ligand B (-22.437), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (11.247 hours) has a better half-life than Ligand B (33.447 hours).

**P-gp Efflux:** Ligand A (0.454) is better than Ligand B (0.007), indicating lower efflux and improved CNS exposure.

**Binding Affinity:** Ligand B (-7.1 kcal/mol) has a slightly better binding affinity than Ligand A (-9.8 kcal/mol). However, the difference is not substantial enough to outweigh the significant ADME advantages of Ligand A.

**Overall:** Considering the GPCR-specific priorities, Ligand A is the superior candidate. Its significantly better TPSA, logP, BBB, P-gp efflux, and metabolic stability outweigh the slightly weaker binding affinity compared to Ligand B. The poor solubility of both is a concern, but can be addressed with formulation strategies.



Output:
0
2025-04-17 06:17:43,448 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (344.363 and 347.459 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (74.97) is significantly better than Ligand B (84.64). For CNS targets, we want TPSA <= 90, and A is comfortably within that range, while B is approaching the upper limit.

**3. logP:** Both ligands have acceptable logP values (2.784 and 1.538), falling within the 1-3 range. Ligand A is slightly better.

**4. H-Bond Donors:** Ligand A (0) is preferable to Ligand B (1). Fewer HBDs generally improve permeability.

**5. H-Bond Acceptors:** Ligand A (6) is higher than Ligand B (4), but both are within the acceptable limit of <= 10.

**6. QED:** Both ligands have similar and good QED values (0.777 and 0.79), indicating good drug-like properties.

**7. DILI:** Ligand A (63.086) has a higher DILI risk than Ligand B (7.135). This is a significant advantage for Ligand B.

**8. BBB:** Ligand A (80.419) has a better BBB penetration percentile than Ligand B (68.67). This is critical for a CNS target like DRD2.

**9. Caco-2 Permeability:** Ligand A (-4.445) has better Caco-2 permeability than Ligand B (-4.767), suggesting better intestinal absorption.

**10. Aqueous Solubility:** Ligand A (-4.278) has slightly better aqueous solubility than Ligand B (-1.303).

**11. hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.389 and 0.474).

**12. Microsomal Clearance:** Ligand B (-11.659) has a lower (better) microsomal clearance than Ligand A (77.787), indicating greater metabolic stability.

**13. In vitro Half-Life:** Ligand B (2.889) has a longer in vitro half-life than Ligand A (-14.481).

**14. P-gp Efflux:** Ligand A (0.579) has lower P-gp efflux than Ligand B (0.02), which is desirable for CNS penetration.

**15. Binding Affinity:** Ligand B (-7.8) has a significantly stronger binding affinity than Ligand A (-9). A difference of >1.5 kcal/mol is very impactful.

**Overall Assessment:**

While Ligand A has better BBB penetration and Caco-2 permeability, Ligand B shines in several crucial areas. It has a much lower DILI risk, significantly better metabolic stability (lower Cl_mic, longer t1/2), and, most importantly, a substantially stronger binding affinity. The stronger affinity of Ligand B is likely to outweigh the slightly higher TPSA and lower BBB compared to Ligand A. Considering the GPCR-specific priorities, the strong binding affinity and improved safety profile of Ligand B make it the more promising candidate.

Output:
1
2025-04-17 06:17:43,448 - INFO - Reasoning:

Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (343.43 and 370.56 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (71.41) is slightly above the optimal <90 for CNS targets, but still reasonable. Ligand B (66.48) is excellent, well below 90.

**3. logP:** Ligand A (1.154) is at the lower end of the optimal 1-3 range, potentially impacting permeability. Ligand B (2.769) is well within the optimal range.

**4. H-Bond Donors:** Both ligands have 1 HBD, which is acceptable.

**5. H-Bond Acceptors:** Ligand A has 4 HBA, and Ligand B has 3. Both are within the acceptable limit of 10.

**6. QED:** Both ligands have similar QED values (0.788 and 0.714), indicating good drug-like properties.

**7. DILI:** Ligand A (23.50) has a significantly lower DILI risk than Ligand B (40.05). This is a substantial advantage for Ligand A.

**8. BBB:** Both ligands have good BBB penetration (75.11 and 72.24), exceeding the >70 threshold for CNS targets.

**9. Caco-2 Permeability:** Ligand A (-4.79) has poor Caco-2 permeability, while Ligand B (-5.05) is also poor, but slightly worse.

**10. Aqueous Solubility:** Both ligands have very poor aqueous solubility (-2.121 and -3.905). This is a concern for both.

**11. hERG Inhibition:** Both ligands have low hERG inhibition risk (0.388 and 0.611).

**12. Microsomal Clearance:** Ligand A (40.47) has a lower microsomal clearance than Ligand B (86.20), indicating better metabolic stability.

**13. In vitro Half-Life:** Ligand A (-9.133) has a much longer in vitro half-life than Ligand B (-40.592), which is a significant advantage.

**14. P-gp Efflux:** Both ligands have very low P-gp efflux (0.082 and 0.308), which is favorable for CNS penetration.

**15. Binding Affinity:** Both ligands have excellent binding affinities (-8.6 and -8.1 kcal/mol). Ligand A is slightly better, but the difference is less than 1.5 kcal/mol.

**Overall Assessment:**

Ligand A has a better safety profile (lower DILI), better metabolic stability (lower Cl_mic, longer t1/2), and slightly better binding affinity. While its logP is a bit low and Caco-2 permeability is poor, these are less critical given the strong CNS target and the excellent BBB penetration. Ligand B has a better logP and TPSA, but suffers from higher DILI risk, poorer metabolic stability, and a shorter half-life.

Considering the GPCR-specific priorities, the improved safety and pharmacokinetic properties of Ligand A outweigh the slightly less optimal logP and Caco-2 permeability.

Output:
1
2025-04-17 06:17:43,449 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (350.369 and 345.447 Da) fall comfortably within the ideal 200-500 Da range.

**TPSA:** Ligand A (82.62) is better than Ligand B (87.22). Both are below the 90 A^2 threshold desirable for CNS targets, but A is closer to the optimal range.

**logP:** Ligand A (2.699) is better than Ligand B (1.058). Both are within the 1-3 range, but B is on the lower end, potentially hindering permeability.

**H-Bond Donors/Acceptors:** Ligand A (1 HBD, 5 HBA) is slightly better than Ligand B (2 HBD, 5 HBA). Both are within acceptable limits.

**QED:** Ligand B (0.722) has a better QED score than Ligand A (0.325), suggesting a more drug-like profile overall.

**DILI:** Ligand B (20.279) has a significantly lower DILI risk than Ligand A (58.511). This is a substantial advantage for Ligand B.

**BBB:** Ligand A (77.705) has a better BBB penetration score than Ligand B (64.87). This is a critical factor for a CNS target like DRD2.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values, which is unusual and suggests poor permeability. However, the scale is not specified, so it's hard to interpret.

**Aqueous Solubility:** Both ligands have negative solubility values, which is also unusual. Again, the scale is not specified.

**hERG Inhibition:** Ligand B (0.137) has a much lower hERG inhibition liability than Ligand A (0.866). This is a significant safety advantage for Ligand B.

**Microsomal Clearance:** Ligand B (-6.133) has a negative clearance, which is not possible. This is likely an error in the data. Ligand A (45.936) has a moderate clearance.

**In vitro Half-Life:** Ligand B (2.99) has a very short half-life, while Ligand A (-18.489) has a negative half-life, which is impossible.

**P-gp Efflux:** Ligand B (0.003) has extremely low P-gp efflux, a huge advantage for CNS penetration. Ligand A (0.886) has moderate P-gp efflux.

**Binding Affinity:** Ligand A (-8.5 kcal/mol) has a slightly better binding affinity than Ligand B (-7.4 kcal/mol). This 1.1 kcal/mol difference is significant.

**Overall Assessment:**

Despite the slightly better affinity of Ligand A, Ligand B is the more promising candidate. The significantly lower DILI and hERG risk, coupled with extremely low P-gp efflux, outweigh the slightly weaker binding. The better QED score also contributes to its drug-likeness. The BBB score for Ligand A is better, but the other ADME properties of Ligand B are far superior and more critical for a CNS-targeting drug. The negative values for Caco-2, solubility, and half-life are concerning and should be investigated, but the overall profile of Ligand B is more favorable.

Output:
1
2025-04-17 06:17:43,449 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (349.479 and 338.411 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (102.04) is slightly above the optimal <90 for CNS targets, but still reasonable. Ligand B (75.19) is excellent, well below 90.

**logP:** Both ligands have good logP values (1.989 and 2.128), falling within the 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A has 3 HBD and 5 HBA, which are acceptable. Ligand B has 1 HBD and 4 HBA, also acceptable and slightly more favorable.

**QED:** Both ligands have good QED scores (0.562 and 0.927), indicating drug-like properties. Ligand B is significantly better.

**DILI:** Both ligands have acceptable DILI risk (39.201 and 49.399), below the 60 threshold.

**BBB:** This is crucial for a CNS target. Ligand A has a BBB percentile of 81.272, which is very good (>70). Ligand B has a BBB percentile of 57.774, which is less desirable.

**Caco-2 Permeability:** Ligand A (-5.364) and Ligand B (-4.892) have negative values, which is unusual and suggests poor permeability. However, these are scale values and not percentiles, so direct comparison is difficult.

**Aqueous Solubility:** Both ligands have poor aqueous solubility (-3.25 and -2.684). This could be a formulation challenge.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.702 and 0.357).

**Microsomal Clearance:** Ligand A (52.162) has a moderate clearance, while Ligand B (15.426) has a much lower clearance, suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (1.964) has a short half-life, while Ligand B (6.942) has a significantly longer half-life.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.426 and 0.03). Ligand B is better.

**Binding Affinity:** Both ligands have excellent binding affinity (-8.0 and -8.2 kcal/mol). Ligand B is slightly better.

**Overall Assessment:**

Ligand B has several advantages: a better QED score, lower microsomal clearance, longer half-life, lower P-gp efflux, and slightly better binding affinity. However, the critical factor is the BBB penetration. Ligand A has a significantly higher BBB percentile (81.272) compared to Ligand B (57.774). Given DRD2 is a CNS target, BBB penetration is paramount. While Ligand B has other favorable properties, the lower BBB score is a major drawback.

Output:
1
2025-04-17 06:17:43,449 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (361.47 and 348.49 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (91.32) is slightly above the optimal <90 for CNS targets, but still reasonable. Ligand B (49.85) is excellent, well below 90.

**logP:** Both ligands (2.33 and 2.61) are within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A has 3 HBD and 5 HBA, which are acceptable. Ligand B has 0 HBD and 3 HBA, also acceptable.

**QED:** Both ligands have similar QED values (0.71 and 0.69), indicating good drug-likeness.

**DILI:** Ligand A has a DILI risk of 52.77, which is acceptable (below 60). Ligand B has a very low DILI risk of 7.79, which is excellent.

**BBB:** This is a critical parameter for a CNS target like DRD2. Ligand A has a BBB penetration of 26.21, which is low and concerning. Ligand B has a BBB penetration of 85.73, which is excellent and highly desirable.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.45 and -4.54), which is unusual and suggests poor permeability. However, these values are on a log scale and can be misleading. We'll need to consider other factors.

**Aqueous Solubility:** Both ligands have negative solubility values (-2.85 and -2.06), indicating poor aqueous solubility. This could be a formulation challenge.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.23 and 0.33).

**Microsomal Clearance:** Ligand A (28.29) has lower microsomal clearance than Ligand B (40.14), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (-3.66) has a negative half-life, which is unusual and likely indicates rapid metabolism. Ligand B (2.92) has a positive half-life, suggesting better stability.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.07 and 0.054), which is favorable for CNS penetration.

**Binding Affinity:** Ligand A (-8.5 kcal/mol) has a significantly stronger binding affinity than Ligand B (-7.3 kcal/mol). This is a substantial advantage (1.2 kcal/mol difference).

**Overall Assessment:**

While Ligand A has a superior binding affinity, its poor BBB penetration (26.21) is a major drawback for a CNS drug targeting DRD2. The negative half-life and lower solubility are also concerning. Ligand B, despite having a slightly weaker binding affinity, exhibits excellent BBB penetration (85.73), a very low DILI risk, and a better half-life. The slightly higher metabolic clearance is less concerning given the strong BBB penetration. For a CNS GPCR target, BBB penetration is paramount. The affinity difference, while significant, might be overcome with further optimization of Ligand B.

Output:
1
2025-04-17 06:17:43,449 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (345.403) is slightly lower, which is generally favorable for permeability.

**TPSA:** Ligand A (108.88) is better than Ligand B (51.02) as it is closer to the desired threshold of <90 for CNS targets. Ligand B is quite low, which could indicate poor interactions with the receptor.

**logP:** Ligand A (0.595) is low, potentially hindering membrane permeability. Ligand B (4.062) is higher, potentially causing solubility issues or off-target interactions, but within acceptable limits.

**H-Bond Donors/Acceptors:** Ligand A has 3 HBD and 5 HBA, which are reasonable. Ligand B has 0 HBD and 6 HBA, also acceptable.

**QED:** Both ligands have similar QED values (0.651 and 0.626), indicating good drug-like properties.

**DILI:** Both ligands have similar DILI risk (60.295 and 61.225), indicating moderate risk.

**BBB:** Ligand B (52.191) has a significantly better BBB percentile than Ligand A (32.765). This is a crucial advantage for a CNS target like DRD2.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values, which is unusual and suggests poor permeability. However, these values can be unreliable and are less critical than other parameters.

**Aqueous Solubility:** Both ligands have negative solubility values, indicating poor solubility. This is a concern for both.

**hERG Inhibition:** Ligand A (0.152) has a lower hERG inhibition liability than Ligand B (0.343), which is preferable.

**Microsomal Clearance:** Ligand B (68.15) has a higher microsomal clearance than Ligand A (10.905), indicating faster metabolism and potentially lower *in vivo* exposure.

**In vitro Half-Life:** Ligand A (-19.397) has a negative half-life, which is not possible. This is a significant red flag. Ligand B (21.328) has a reasonable half-life.

**P-gp Efflux:** Ligand A (0.025) has much lower P-gp efflux liability than Ligand B (0.264), which is beneficial for CNS penetration.

**Binding Affinity:** Ligand A (-8.2 kcal/mol) has a significantly stronger binding affinity than Ligand B (-6.7 kcal/mol). This is a major advantage, potentially outweighing some of its ADME drawbacks.

**Overall Assessment:**

Ligand A has a much better binding affinity and lower P-gp efflux, but suffers from a very low logP, a negative half-life, and poor BBB penetration. Ligand B has better BBB penetration and a reasonable half-life, but weaker binding affinity and higher P-gp efflux. The negative half-life for Ligand A is a critical flaw. While the affinity of Ligand A is significantly better, the poor predicted pharmacokinetics, particularly the BBB penetration and half-life, are major concerns. The better BBB penetration of Ligand B is crucial for a CNS target.

Output:
1
2025-04-17 06:17:43,449 - INFO - Reasoning:

Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (353.463 and 347.354 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (87.74) is excellent, falling well below the 90 A^2 threshold for CNS targets. Ligand B (107.97) is still acceptable but less optimal, being closer to the 140 A^2 threshold for oral absorption.

**3. logP:** Ligand A (0.681) is a bit low, potentially hindering permeation. Ligand B (0.13) is even lower, raising concerns about membrane permeability.

**4. H-Bond Donors:** Ligand A (2) and Ligand B (1) are both within the acceptable limit of <=5.

**5. H-Bond Acceptors:** Ligand A (5) and Ligand B (6) are both within the acceptable limit of <=10.

**6. QED:** Ligand B (0.824) has a significantly better QED score than Ligand A (0.564), indicating a more drug-like profile.

**7. DILI:** Ligand A (18.069) has a much lower DILI risk than Ligand B (76.386), which is a significant advantage.

**8. BBB:** Ligand B (68.67) has a better BBB percentile than Ligand A (38.387), but both are below the desirable >70 for CNS targets.

**9. Caco-2:** Ligand A (-5.337) and Ligand B (-4.937) both have negative Caco-2 values, which is unusual and suggests poor permeability.

**10. Solubility:** Ligand A (-0.834) and Ligand B (-1.601) both have negative solubility values, indicating very poor aqueous solubility.

**11. hERG:** Both ligands (0.057 and 0.059) have very low hERG inhibition liability, which is good.

**12. Cl_mic:** Ligand A (-5.932) has a much lower (better) microsomal clearance than Ligand B (4.808), suggesting better metabolic stability.

**13. t1/2:** Ligand B (-8.125) has a longer in vitro half-life than Ligand A (-7.253), which is preferable.

**14. Pgp:** Both ligands (0.006 and 0.035) have very low P-gp efflux liability, which is good for CNS penetration.

**15. Binding Affinity:** Both ligands have very similar and strong binding affinities (-7.9 and -8.3 kcal/mol). The difference is minimal.

**Overall Assessment:**

Despite Ligand B's better QED and half-life, Ligand A is the more promising candidate. The primary reasons are its significantly lower DILI risk and better metabolic stability (lower Cl_mic). While both have poor logP and BBB values, the lower DILI risk is a critical advantage, especially early in drug development. The similar binding affinities mean that the ADME properties become the deciding factor. The poor solubility and Caco-2 values are concerning for both, but can be addressed with formulation strategies.

Output:
0
2025-04-17 06:17:43,450 - INFO - Reasoning:

Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (364.486 and 358.37 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (40.62) is excellent, well below the 90 A^2 threshold for CNS targets. Ligand B (108.05) is higher, but still potentially acceptable, though less ideal.

**3. logP:** Ligand A (3.338) is within the optimal 1-3 range. Ligand B (-1.122) is significantly lower, which could hinder membrane permeability and CNS penetration.

**4. H-Bond Donors:** Ligand A (0) is favorable. Ligand B (2) is acceptable.

**5. H-Bond Acceptors:** Ligand A (3) is favorable. Ligand B (5) is acceptable.

**6. QED:** Both ligands have reasonable QED values (0.825 and 0.561), indicating good drug-like properties.

**7. DILI:** Both ligands have similar DILI risk (49.128 and 51.842), both being reasonably low.

**8. BBB:** Ligand A (96.006) has a very high BBB penetration percentile, extremely desirable for a CNS target like DRD2. Ligand B (81.233) is lower, which is a significant drawback.

**9. Caco-2:** Ligand A (-4.727) and Ligand B (-5.188) both have negative Caco-2 values, which is unusual. It's difficult to interpret without knowing the scale, but generally, a higher value is preferred.

**10. Solubility:** Ligand A (-4.079) and Ligand B (-1.798) both have negative solubility values, which is also unusual. Again, a higher value is preferred.

**11. hERG:** Both ligands have low hERG inhibition liability (0.622 and 0.101), which is good.

**12. Cl_mic:** Ligand A (51.396) has a higher microsomal clearance than Ligand B (-11.98), indicating potentially lower metabolic stability.

**13. t1/2:** Ligand A (22.78) has a longer in vitro half-life than Ligand B (-4.448).

**14. Pgp:** Ligand A (0.597) has lower P-gp efflux liability than Ligand B (0.004), which is beneficial for CNS penetration.

**15. Binding Affinity:** Both ligands have comparable binding affinities (-9.4 and -8.2 kcal/mol), both being strong binders. The difference of 1.2 kcal/mol is not substantial enough to outweigh other factors.

**Overall Assessment:**

Ligand A is significantly more promising due to its superior BBB penetration (96% vs. 81%), better logP (3.338 vs -1.122), and lower P-gp efflux (0.597 vs 0.004). While Ligand A has a higher Cl_mic, the strong BBB penetration and favorable logP are critical for CNS drug development and outweigh this concern. The negative values for Caco-2 and solubility are concerning for both, but the overall profile of A is much more favorable.

Output:
1
2025-04-17 06:17:43,450 - INFO - Batch 270 complete. Total preferences: 4320
2025-04-17 06:17:43,450 - INFO - Processing batch 271/512...
2025-04-17 06:18:24,885 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B based on the provided guidelines, prioritizing GPCR-specific properties (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (351.475 and 351.491 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (64.92) is slightly above the optimal <90 for CNS targets, but still reasonable. Ligand B (53.09) is well within the desired range.

**logP:** Ligand A (4.81) is high, potentially causing solubility issues and off-target effects. Ligand B (1.369) is within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A has 2 HBD and 3 HBA, which are acceptable. Ligand B has 0 HBD and 4 HBA, also acceptable.

**QED:** Both ligands have QED values (0.734 and 0.62) above the 0.5 threshold, indicating good drug-like properties.

**DILI:** Ligand A (58.976) has a moderate DILI risk, while Ligand B (13.339) has a very low risk.

**BBB:** Ligand A (82.513) has a good BBB penetration percentile, desirable for a CNS target. Ligand B (70.997) also has good BBB penetration, but slightly lower than A.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.777 and -4.434), which is unusual and suggests poor permeability. This is a significant concern for both.

**Aqueous Solubility:** Both ligands have very poor aqueous solubility (-6.1 and -0.37). This is a major drawback.

**hERG Inhibition:** Ligand A (0.747) has a slightly higher hERG risk than Ligand B (0.341), but both are relatively low.

**Microsomal Clearance:** Ligand A (100.622) has higher microsomal clearance, indicating lower metabolic stability, compared to Ligand B (39.018).

**In vitro Half-Life:** Ligand A (27.787) has a longer half-life than Ligand B (3.057).

**P-gp Efflux:** Ligand A (0.405) has lower P-gp efflux liability than Ligand B (0.029), which is beneficial for CNS penetration.

**Binding Affinity:** Ligand A (-7.7 kcal/mol) has a significantly stronger binding affinity than Ligand B (-6.3 kcal/mol). This 1.4 kcal/mol difference is substantial and could outweigh some of the ADME drawbacks.

**Overall Assessment:**

Ligand A has a superior binding affinity and better BBB penetration and P-gp efflux, but suffers from a high logP, moderate DILI risk, and higher metabolic clearance. Ligand B has better ADME properties (lower logP, DILI, and clearance), but a weaker binding affinity.

Given the importance of affinity for GPCRs, and the significant 1.4 kcal/mol advantage of Ligand A, I would prioritize Ligand A despite its ADME liabilities. The strong binding could potentially be optimized through further structural modifications to improve solubility and reduce logP while retaining potency. The poor Caco-2 permeability is concerning for both, and would need to be addressed.

Output:
1
2025-04-17 06:18:24,885 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (380.417 and 350.438 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (94.39) is slightly above the preferred <90 for CNS targets, but still reasonable. Ligand B (76.02) is well within the desired range.

**3. logP:** Ligand A (0.343) is quite low, potentially hindering membrane permeability. Ligand B (1.84) is within the optimal 1-3 range. This is a significant advantage for Ligand B.

**4. H-Bond Donors:** Ligand A (0) is good. Ligand B (2) is also acceptable.

**5. H-Bond Acceptors:** Ligand A (7) is good. Ligand B (4) is also good.

**6. QED:** Both ligands have good QED scores (0.646 and 0.703), indicating drug-like properties.

**7. DILI:** Ligand A (54.517) has a moderate DILI risk, while Ligand B (32.687) has a lower risk.

**8. BBB:** Ligand A (91.431) shows excellent BBB penetration, a crucial factor for CNS targets. Ligand B (76.696) is reasonable, but not as high as Ligand A.

**9. Caco-2:** Both ligands have negative Caco-2 values (-4.934 and -4.951), which is unusual and suggests poor permeability. This is a concern for both.

**10. Solubility:** Both ligands have negative solubility values (-2.029 and -1.986), indicating poor aqueous solubility. This is a significant drawback for both.

**11. hERG:** Both ligands show very low hERG inhibition risk (0.248 and 0.229).

**12. Cl_mic:** Ligand A (-11.204) has a negative microsomal clearance, which is unusual and suggests very high metabolic stability. Ligand B (20.768) has a moderate clearance.

**13. t1/2:** Both ligands have negative in vitro half-lives (-6.722 and -11.339), which is also unusual and suggests very rapid metabolism.

**14. Pgp:** Both ligands have very low P-gp efflux liability (0.102 and 0.086).

**15. Binding Affinity:** Both ligands have strong binding affinities (-8.0 and -8.1 kcal/mol). The difference is negligible.

**Overall Assessment:**

Despite the unusual negative values for Caco-2 and t1/2, the key differentiating factors are logP and BBB. Ligand B has a much more favorable logP (1.84 vs 0.343), which is critical for permeability and CNS penetration. While Ligand A has a higher BBB percentile, the poor logP significantly hinders its ability to reach the target in the brain. Ligand A's negative Cl_mic is also concerning. Both have poor solubility which would need to be addressed. Given the GPCR-specific priorities, and the importance of logP for CNS targets, Ligand B is the more promising candidate.

Output:
1
2025-04-17 06:18:24,885 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (352.475 and 350.503 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (78.87) is better than Ligand B (55.57). Both are below the 90 A^2 threshold desirable for CNS targets, but A is closer to the upper limit.

**logP:** Ligand A (2.155) is optimal, while Ligand B (4.578) is pushing the upper limit. High logP can lead to off-target effects and solubility issues.

**H-Bond Donors:** Ligand A (2) is acceptable, while Ligand B (0) is also good.

**H-Bond Acceptors:** Both ligands have 4 H-bond acceptors, which is within the acceptable range.

**QED:** Ligand A (0.743) has a better QED score than Ligand B (0.58), indicating better overall drug-likeness.

**DILI:** Ligand A (23.497) has a significantly lower DILI risk than Ligand B (8.53). This is a major advantage for Ligand A.

**BBB:** Ligand B (83.908) has a much higher BBB penetration percentile than Ligand A (40.83). This is a critical factor for a CNS target like DRD2.

**Caco-2 Permeability:** Ligand A (-5.138) has poor Caco-2 permeability, while Ligand B (-4.37) is slightly better, but both are quite poor.

**Aqueous Solubility:** Ligand A (-2.344) has better solubility than Ligand B (-4.818).

**hERG Inhibition:** Ligand A (0.167) shows lower hERG inhibition liability than Ligand B (0.661), which is preferable.

**Microsomal Clearance:** Ligand B (92.047) has significantly higher microsomal clearance than Ligand A (3.235), indicating poorer metabolic stability.

**In vitro Half-Life:** Ligand B (39.152) has a much longer in vitro half-life than Ligand A (-12.194).

**P-gp Efflux:** Ligand A (0.093) has lower P-gp efflux than Ligand B (0.246), which is beneficial for CNS penetration.

**Binding Affinity:** Ligand A (-8.6 kcal/mol) has a significantly stronger binding affinity than Ligand B (-6.0 kcal/mol). This is a substantial advantage.

**Overall Assessment:**

Ligand A excels in binding affinity, DILI risk, hERG inhibition, metabolic stability, solubility, and P-gp efflux. However, its BBB penetration and Caco-2 permeability are concerning. Ligand B has excellent BBB penetration and a longer half-life, but suffers from higher logP, higher DILI risk, poorer metabolic stability, and weaker binding affinity.

Given the GPCR-specific priorities, BBB is crucial. However, the significantly stronger binding affinity of Ligand A (-8.6 vs -6.0 kcal/mol) is a major advantage that can potentially outweigh its lower BBB. Furthermore, the lower DILI and hERG risks for Ligand A are important safety considerations. While the poor Caco-2 permeability is a concern, it's less critical for a CNS target where direct brain exposure is the goal. The better metabolic stability of Ligand A is also a significant plus.

Output:
1
2025-04-17 06:18:24,885 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (347.419 and 344.499 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (110.44) is higher than Ligand B (58.2). For CNS targets, TPSA should be <= 90. Ligand B is significantly better here.

**logP:** Ligand A (0.596) is quite low, potentially hindering permeation. Ligand B (2.728) is within the optimal 1-3 range. This is a significant advantage for Ligand B.

**H-Bond Donors:** Both have 2 HBD, which is acceptable.

**H-Bond Acceptors:** Ligand A has 6 HBA, acceptable. Ligand B has 2 HBA, also acceptable.

**QED:** Both ligands have good QED scores (0.807 and 0.698), indicating good drug-like properties.

**DILI:** Ligand A (35.479) has a slightly higher DILI risk than Ligand B (15.859), but both are below the concerning threshold of 60.

**BBB:** Ligand A (89.066) has a much better BBB penetration percentile than Ligand B (54.246). This is a critical factor for a CNS target like DRD2.

**Caco-2 Permeability:** Ligand A (-5.26) has poor Caco-2 permeability, while Ligand B (-4.652) is slightly better, but still not great.

**Aqueous Solubility:** Both ligands have very poor aqueous solubility (-2.253 and -4.868). This could pose formulation challenges.

**hERG Inhibition:** Ligand A (0.359) has a lower hERG inhibition liability than Ligand B (0.123), which is preferable.

**Microsomal Clearance:** Ligand A (-11.268) has significantly lower microsomal clearance than Ligand B (12.629), indicating better metabolic stability.

**In vitro Half-Life:** Ligand A (-0.908) has a slightly shorter in vitro half-life than Ligand B (6.83).

**P-gp Efflux:** Ligand A (0.005) has very low P-gp efflux, which is desirable for CNS penetration. Ligand B (0.066) is slightly higher but still low.

**Binding Affinity:** Ligand B (-7.7 kcal/mol) has a slightly better binding affinity than Ligand A (-8.0 kcal/mol). While the difference is small, it's still a positive for Ligand B.

**Overall Assessment:**

Ligand B excels in key GPCR-relevant properties: logP, TPSA, and binding affinity. While Ligand A has a better BBB score and lower P-gp efflux, its poor logP and higher TPSA are significant drawbacks. The slightly better metabolic stability of Ligand A is not enough to offset these issues. The better binding affinity of Ligand B, combined with its more favorable physicochemical properties, makes it the more promising candidate.

Output:
1
2025-04-17 06:18:24,886 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (347.419 and 355.391 Da) fall within the ideal range of 200-500 Da.

**TPSA:** Ligand A (98.14) is better than Ligand B (111.92). For CNS targets, we want TPSA <= 90, so A is closer to this ideal.

**logP:** Ligand A (0.461) is quite low, potentially hindering permeability. Ligand B (0.109) is even lower. Both are below the optimal 1-3 range, and could cause issues with membrane permeation.

**H-Bond Donors:** Both ligands have 2 HBD, which is within the acceptable limit of <=5.

**H-Bond Acceptors:** Ligand A has 6 HBA, and Ligand B has 7. Both are within the acceptable limit of <=10.

**QED:** Both ligands have good QED scores (0.5 and 0.612, respectively), indicating drug-like properties.

**DILI:** Ligand A (39.356) has a better DILI score than Ligand B (51.221). Both are below the concerning threshold of 60, but A is preferable.

**BBB:** Both ligands have similar BBB penetration (61.923% and 60.566%). These are below the desirable >70% for CNS targets, but not drastically so.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.909 and -5.116), which is unusual and suggests poor permeability. This is a significant concern.

**Aqueous Solubility:** Both ligands have negative solubility values (-2.15 and -1.544), which is also unusual and suggests poor solubility. This is a significant concern.

**hERG Inhibition:** Ligand A (0.024) has a much lower hERG inhibition risk than Ligand B (0.177), which is a significant advantage.

**Microsomal Clearance:** Ligand A (18.79) has a lower microsomal clearance than Ligand B (8.248), indicating better metabolic stability.

**In vitro Half-Life:** Ligand A (-5.129) has a shorter in vitro half-life than Ligand B (25.752), which is less desirable.

**P-gp Efflux:** Ligand A (0.05) has a lower P-gp efflux liability than Ligand B (0.012), which is beneficial for CNS penetration.

**Binding Affinity:** Ligand B (-7.7 kcal/mol) has a slightly better binding affinity than Ligand A (-8.2 kcal/mol). This is a 0.5 kcal/mol difference, which is significant.

**Overall Assessment:**

Despite the slightly better affinity of Ligand B, Ligand A is the more promising candidate. The key factors driving this decision are: significantly lower hERG risk, lower DILI risk, and better metabolic stability (lower Cl_mic). While both have poor logP, Caco-2, and solubility, the safety profile of Ligand A is more favorable. The affinity difference is not large enough to overcome these ADME/Tox advantages.

Output:
0
2025-04-17 06:18:24,886 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B based on the provided guidelines, prioritizing GPCR-specific properties (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (347.419 Da) is slightly lower, which could be beneficial for permeability.

**TPSA:** Both are below the 140 A^2 threshold for oral absorption, but for a CNS target like DRD2, we want <90 A^2. Ligand A (80.56 A^2) is better than Ligand B (87.3 A^2).

**logP:** Ligand A (0.303) is a bit low, potentially hindering permeation. Ligand B (1.366) is within the optimal 1-3 range. This is a significant advantage for Ligand B.

**H-Bond Donors/Acceptors:** Ligand A (0 HBD, 6 HBA) is better than Ligand B (3 HBD, 4 HBA) in terms of balancing solubility and permeability.

**QED:** Both ligands have reasonable QED scores (A: 0.765, B: 0.593), indicating acceptable drug-likeness.

**DILI:** Ligand A (49.826) has a moderate DILI risk, while Ligand B (18.845) has a very low risk. This is a strong advantage for Ligand B.

**BBB:** Ligand A (74.564) has a good BBB penetration percentile, exceeding the 70% threshold for CNS targets. Ligand B (52.423) is below this threshold, which is a significant drawback.

**Caco-2 Permeability:** Ligand A (-4.637) has poor Caco-2 permeability, while Ligand B (-5.462) is also poor.

**Aqueous Solubility:** Both ligands have very poor aqueous solubility (-1.79 and -2.456 respectively).

**hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.105 and 0.075 respectively).

**Microsomal Clearance:** Both have similar microsomal clearance (A: 33.341, B: 38.756), indicating similar metabolic stability.

**In vitro Half-Life:** Both have negative in vitro half-lives (-6.015 and -6.815 respectively). This is unusual and suggests rapid metabolism or instability, but the values are relatively close.

**P-gp Efflux:** Both have low P-gp efflux liability (0.182 and 0.039 respectively).

**Binding Affinity:** Both ligands have the same binding affinity (-7.8 kcal/mol), which is excellent.

**Overall Assessment:**

Ligand A excels in TPSA and BBB penetration, which are crucial for CNS targets. However, its low logP and poor Caco-2 permeability are concerning. Ligand B has a better logP, significantly lower DILI risk, and acceptable P-gp efflux. While its BBB penetration is lower, the superior logP and DILI profile outweigh this disadvantage, especially given the equal binding affinity. The solubility is poor for both, which would require formulation strategies.

Output:
1
2025-04-17 06:18:24,886 - INFO - Reasoning:

Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (371.463 and 353.423 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (96.77) is better than Ligand B (107.37). Both are below the 140 A^2 threshold for oral absorption, and Ligand A is closer to the preferred <90 A^2 for CNS targets.

**3. logP:** Ligand A (0.251) is slightly better than Ligand B (-0.125), but both are quite low. A logP between 1-3 is optimal, and values <1 can hinder permeation. This is a potential concern for both.

**4. H-Bond Donors:** Ligand A (1) is preferable to Ligand B (2). Lower HBDs generally improve permeability.

**5. H-Bond Acceptors:** Ligand A (6) is preferable to Ligand B (7). Lower HBAs generally improve permeability.

**6. QED:** Ligand A (0.818) has a significantly better QED score than Ligand B (0.599), indicating a more drug-like profile.

**7. DILI:** Ligand B (55.176) has a lower DILI risk than Ligand A (65.568), which is favorable.

**8. BBB:** Ligand A (75.921) has a significantly higher BBB penetration percentile than Ligand B (51.299). This is *critical* for a CNS target like DRD2.

**9. Caco-2 Permeability:** Ligand A (-4.74) has a better Caco-2 permeability than Ligand B (-5.409).

**10. Aqueous Solubility:** Ligand B (-1.091) has better aqueous solubility than Ligand A (-2.081). Solubility is important for formulation.

**11. hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.127 and 0.069, respectively), which is excellent.

**12. Microsomal Clearance:** Ligand B (-3.026) has a *much* lower (better) microsomal clearance than Ligand A (10.893), suggesting greater metabolic stability.

**13. In vitro Half-Life:** Ligand B (22.03) has a significantly longer in vitro half-life than Ligand A (-38.65). This is a major advantage.

**14. P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.014 and 0.018, respectively).

**15. Binding Affinity:** Ligand B (-7.1) has a slightly better binding affinity than Ligand A (-8.7). While both are excellent, a >1.5 kcal/mol advantage can be significant.

**Overall Assessment:**

While Ligand B has a better binding affinity and significantly improved metabolic stability (lower Cl_mic, longer t1/2), Ligand A's superior BBB penetration is a decisive factor for a CNS target like DRD2. The slightly lower logP of Ligand A is a concern, but the higher BBB score and better QED outweigh this. The difference in binding affinity is not large enough to overcome the BBB difference.

Output:
1
2025-04-17 06:18:24,886 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (399.299 and 368.865 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (54.71) is significantly better than Ligand B (87.32). For CNS targets, we want TPSA <= 90, and A is comfortably within that, while B is approaching the upper limit.

**logP:** Ligand A (3.983) is at the higher end of the optimal range (1-3), while Ligand B (1.763) is at the lower end. While both are within range, higher logP can sometimes be tolerated for CNS drugs to aid in BBB penetration, but needs to be balanced with solubility.

**H-Bond Donors/Acceptors:** Ligand A (HBD=1, HBA=4) and Ligand B (HBD=2, HBA=4) are both reasonable.

**QED:** Both ligands have good QED scores (A: 0.775, B: 0.847), indicating good drug-like properties.

**DILI:** Ligand A (81.892) has a higher DILI risk than Ligand B (67.623), which is less desirable.

**BBB:** Ligand A (57.076) and Ligand B (54.478) are similar, but both are below the desirable >70 percentile for CNS targets. This is a concern for both, but not a differentiating factor.

**Caco-2 Permeability:** Both have negative Caco-2 values (-4.751 and -4.993), which is unusual and suggests poor permeability. This is a significant drawback for both.

**Aqueous Solubility:** Both have negative solubility values (-5.201 and -3.437) which is also unusual and suggests poor solubility.

**hERG:** Ligand A (0.542) has a slightly higher hERG risk than Ligand B (0.13), which is less desirable.

**Microsomal Clearance:** Ligand B (29.411) has a lower (better) microsomal clearance than Ligand A (19.273), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand B (13.115) has a longer half-life than Ligand A (70.882), which is a significant advantage.

**P-gp Efflux:** Ligand A (0.718) has higher P-gp efflux than Ligand B (0.074), meaning B will have better CNS exposure. This is a crucial advantage for a CNS target.

**Binding Affinity:** Ligand B (-8.5 kcal/mol) has a significantly stronger binding affinity than Ligand A (-7.7 kcal/mol). This >1.5 kcal/mol difference is substantial and can outweigh some ADME drawbacks.

**Overall Assessment:**

While Ligand A has a slightly better TPSA, Ligand B excels in several critical areas: significantly stronger binding affinity, lower P-gp efflux (better CNS penetration), longer half-life, and lower DILI risk. The negative Caco-2 and solubility values are concerning for both, but the superior binding affinity and P-gp profile of Ligand B are more impactful for a CNS GPCR target like DRD2.

Output:
1
2025-04-17 06:18:24,886 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (372.531 and 348.447 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Both ligands have TPSA values (78.87 and 78.68) that are acceptable for oral absorption (<140) but slightly high for optimal CNS penetration (<90). This is a minor drawback, but not disqualifying.

**3. logP:** Both ligands have logP values (1.558 and 1.434) within the optimal 1-3 range, suggesting good permeability and reasonable solubility.

**4. H-Bond Donors:** Ligand A (2) and Ligand B (1) both have acceptable HBD counts, well below the threshold of 5. Ligand B is slightly better here.

**5. H-Bond Acceptors:** Both ligands (5) have acceptable HBA counts, below the threshold of 10.

**6. QED:** Both ligands have good QED scores (0.569 and 0.841), indicating drug-like properties. Ligand B is significantly better here.

**7. DILI Risk:** Ligand A (14.541) has a slightly higher DILI risk than Ligand B (23.769), but both are below the concerning threshold of 60.

**8. BBB Penetration:** This is crucial for a CNS target like DRD2. Ligand B (76.58) has a significantly better BBB percentile than Ligand A (53.47). This is a major advantage for Ligand B.

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 permeability values, which is unusual and suggests a potential issue with the data. However, the values are close enough that this isn't a major differentiator.

**10. Aqueous Solubility:** Both ligands have negative solubility values, also unusual. Again, the values are similar.

**11. hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.384 and 0.387), which is excellent.

**12. Microsomal Clearance:** Ligand A (35.87) has a slightly higher microsomal clearance than Ligand B (31.548), indicating potentially lower metabolic stability.

**13. In vitro Half-Life:** Ligand B (9.158) has a significantly longer in vitro half-life than Ligand A (18.771), which is desirable.

**14. P-gp Efflux:** Both ligands have low P-gp efflux liability (0.11 and 0.076), which is good for CNS exposure.

**15. Binding Affinity:** Ligand B (-7.8 kcal/mol) has a slightly better binding affinity than Ligand A (-7.2 kcal/mol). While the difference is relatively small, it's enough to be considered, especially given the other advantages of Ligand B.

**Overall Assessment:**

Ligand B consistently outperforms Ligand A in the most important parameters for a CNS-targeting GPCR ligand: BBB penetration, QED, in vitro half-life, and binding affinity. While both have acceptable profiles, Ligand B's superior BBB penetration and longer half-life make it the more promising candidate.

Output:
1
2025-04-17 06:18:24,886 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 drug candidates, considering the provided guidelines and GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (365.455 Da and 360.483 Da) fall within the ideal range of 200-500 Da.

**TPSA:** Ligand A (78.0) is better than Ligand B (75.19). Both are reasonably good, and below the 90 A^2 threshold for CNS targets, but lower is preferable.

**logP:** Ligand B (2.587) is within the optimal range (1-3), while Ligand A (0.774) is slightly below, potentially hindering permeation. This is a significant advantage for Ligand B.

**H-Bond Donors/Acceptors:** Ligand A (0 HBD, 4 HBA) and Ligand B (1 HBD, 5 HBA) are both within acceptable limits.

**QED:** Both ligands have similar QED values (0.793 and 0.746), indicating good drug-like properties.

**DILI:** Ligand B (42.458) has a considerably lower DILI risk than Ligand A (71.539). This is a substantial advantage for Ligand B.

**BBB:** Ligand A (56.572) is better than Ligand B (42.342) in terms of BBB penetration, but neither are above the desirable 70% threshold for CNS targets.

**Caco-2 Permeability:** Ligand A (-4.551) is better than Ligand B (-5.137), indicating better intestinal absorption.

**Aqueous Solubility:** Ligand A (-2.241) is better than Ligand B (-1.42), indicating better solubility.

**hERG:** Both ligands have very low hERG inhibition liability (0.232 and 0.115), posing minimal cardiotoxicity risk.

**Microsomal Clearance:** Both ligands have similar microsomal clearance values (32.504 and 32.421 mL/min/kg), suggesting comparable metabolic stability.

**In vitro Half-Life:** Ligand A (-10.852) has a longer in vitro half-life than Ligand B (43.919), which is a positive attribute.

**P-gp Efflux:** Ligand A (0.091) has lower P-gp efflux liability than Ligand B (0.041), which is favorable for CNS exposure.

**Binding Affinity:** Ligand B (-7.9 kcal/mol) has a slightly better binding affinity than Ligand A (-8.0 kcal/mol). While the difference is small, it's still a positive for Ligand B.

**Overall Assessment:**

Considering the GPCR-specific priorities, Ligand B is the more promising candidate. While Ligand A has better BBB penetration and P-gp efflux, Ligand B excels in crucial areas like logP (better for permeation), DILI risk (significantly lower), and has comparable binding affinity. The slightly lower BBB of Ligand B is a concern, but the superior logP and DILI profile outweigh this drawback. The better solubility and Caco-2 permeability of Ligand A are also positives, but not as impactful as the other factors.

Output:
1
2025-04-17 06:18:24,886 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (350.28 and 352.43 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (72.22) is excellent, well below the 90 A^2 threshold for CNS targets. Ligand B (88.1) is still acceptable, but less optimal.

**logP:** Ligand A (2.566) is within the optimal 1-3 range. Ligand B (0.228) is quite low, potentially hindering membrane permeability and CNS penetration.

**H-Bond Donors/Acceptors:** Both have acceptable HBD (0/2) and HBA (5/5) counts, well within the guidelines.

**QED:** Both ligands have reasonable QED scores (0.793 and 0.641), indicating good drug-like properties.

**DILI:** Ligand A (87.282) has a higher DILI risk than Ligand B (17.642), which is a significant concern.

**BBB:** Ligand A (94.184) has excellent BBB penetration, highly desirable for a CNS target. Ligand B (45.638) is significantly lower, which is a major drawback.

**Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and suggests a potential issue with the data or modeling. However, we can still compare them relatively. Ligand A (-4.229) is better than Ligand B (-4.966).

**Aqueous Solubility:** Both have negative solubility values, which is also unusual. Ligand A (-4.842) is slightly better than Ligand B (-0.931).

**hERG:** Both ligands have low hERG inhibition risk (0.344 and 0.141).

**Microsomal Clearance:** Ligand A (31.996) has higher clearance than Ligand B (10.388), indicating lower metabolic stability.

**In vitro Half-Life:** Ligand A (31.971) has a longer half-life than Ligand B (9.051).

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.194 and 0.055).

**Binding Affinity:** Ligand A (-9.8 kcal/mol) has a significantly stronger binding affinity than Ligand B (-7.9 kcal/mol). This >1.5 kcal/mol difference is substantial and can outweigh some ADME drawbacks.

**Overall Assessment:**

Ligand A excels in key areas for a CNS-targeting GPCR ligand: TPSA, BBB, and, most importantly, binding affinity. While its DILI risk is higher and clearance is faster than Ligand B, the significantly stronger binding affinity and excellent BBB penetration are critical advantages. Ligand B's low logP and poor BBB penetration are major liabilities. The unusual negative Caco-2 and solubility values are concerning, but the relative comparison still favors A.

Output:
1
2025-04-17 06:18:24,886 - INFO - Reasoning:

Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight (MW):** Both ligands are within the ideal range (200-500 Da). Ligand A (364.431 Da) and Ligand B (350.503 Da) are comparable.

**2. TPSA:** Ligand A (109.22) is higher than the preferred <90 for CNS targets, while Ligand B (49.85) is well within the range. This is a significant advantage for Ligand B.

**3. logP:** Both ligands have good logP values (Ligand A: 1.008, Ligand B: 2.974), falling within the optimal 1-3 range. Ligand B is closer to the ideal range.

**4. H-Bond Donors (HBD):** Both ligands are acceptable (Ligand A: 2, Ligand B: 0), being less than or equal to 5.

**5. H-Bond Acceptors (HBA):** Both ligands are acceptable (Ligand A: 7, Ligand B: 3), being less than or equal to 10.

**6. QED:** Both ligands have reasonable QED scores (Ligand A: 0.819, Ligand B: 0.766), indicating good drug-like properties.

**7. DILI:** Ligand A (82.241) has a considerably higher DILI risk than Ligand B (19.038). This is a major drawback for Ligand A.

**8. BBB:** Ligand B (71.074) has a much better BBB penetration prediction than Ligand A (53.781). This is crucial for a CNS target like DRD2.

**9. Caco-2 Permeability:** Ligand A (-5.078) has poor Caco-2 permeability, while Ligand B (-4.535) is slightly better, but still not ideal.

**10. Aqueous Solubility:** Both have poor solubility (Ligand A: -3.114, Ligand B: -2.427). This is a concern, but can potentially be addressed with formulation strategies.

**11. hERG Inhibition:** Both ligands have low hERG inhibition risk (Ligand A: 0.165, Ligand B: 0.519).

**12. Microsomal Clearance:** Ligand A (0.063) has significantly lower microsomal clearance, suggesting better metabolic stability than Ligand B (40.535).

**13. In vitro Half-Life:** Ligand B (13.623) has a longer in vitro half-life than Ligand A (55.124). This is a positive for Ligand B.

**14. P-gp Efflux:** Ligand A (0.018) has very low P-gp efflux, which is excellent for CNS penetration. Ligand B (0.177) has slightly higher efflux, but still acceptable.

**15. Binding Affinity:** Both ligands have comparable and strong binding affinities (Ligand A: -8.6 kcal/mol, Ligand B: -8.3 kcal/mol). The difference of 0.3 kcal/mol is not substantial enough to override other significant differences.

**Overall Assessment:**

Ligand B is the more promising candidate. While both have good affinity, Ligand B excels in crucial areas for CNS drug development: significantly lower DILI risk, much better BBB penetration, and a longer half-life. Ligand A's higher TPSA and poor Caco-2 permeability are also concerns. The improved metabolic stability of Ligand A is a positive, but it's outweighed by the other factors.

Output:
1
2025-04-17 06:18:24,887 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (344.365 Da) is slightly lower, which is generally favorable for permeability.

**TPSA:** Ligand A (51.85) is significantly better than Ligand B (100.35). For CNS targets, TPSA should be <=90, so Ligand A is much more promising.

**logP:** Ligand A (4.018) is at the upper end of the optimal range (1-3), potentially leading to solubility issues. Ligand B (0.6) is too low, which could hinder membrane permeability.

**H-Bond Donors/Acceptors:** Ligand A (1 HBD, 4 HBA) is better than Ligand B (2 HBD, 7 HBA). Both are within acceptable limits, but lower counts are generally preferred.

**QED:** Both ligands have good QED scores (A: 0.777, B: 0.812), indicating good drug-like properties.

**DILI:** Ligand A (78.441) has a higher DILI risk than Ligand B (62.389), but both are below the concerning threshold of 60.

**BBB:** Ligand A (84.451) has a significantly higher BBB penetration percentile than Ligand B (21.791). This is *critical* for a CNS target like DRD2.

**Caco-2 Permeability:** Ligand A (-4.813) and Ligand B (-5.094) both have negative Caco-2 values, which is unusual and suggests poor permeability. However, the scale isn't specified, so it's hard to interpret.

**Aqueous Solubility:** Ligand A (-3.914) and Ligand B (-2.464) both have negative solubility values, which is also unusual and suggests poor solubility.

**hERG Inhibition:** Ligand A (0.798) has a lower hERG risk than Ligand B (0.127), which is preferable.

**Microsomal Clearance:** Ligand A (34.297) has a higher microsomal clearance than Ligand B (4.56), meaning it's less metabolically stable.

**In vitro Half-Life:** Ligand A (27.059) has a longer half-life than Ligand B (-7.126), which is desirable.

**P-gp Efflux:** Ligand A (0.519) has lower P-gp efflux liability than Ligand B (0.027), which is better for CNS penetration.

**Binding Affinity:** Ligand B (-7.6 kcal/mol) has a significantly stronger binding affinity than Ligand A (-10.2 kcal/mol). This is a substantial advantage.

**Overall Assessment:**

Despite the stronger binding affinity of Ligand B, Ligand A is the more promising candidate. The critical factor is BBB penetration. Ligand A's 84.451 percentile BBB score is far superior to Ligand B's 21.791, which is essential for a CNS drug. Ligand A also has a better TPSA, lower P-gp efflux, and a longer half-life. While Ligand A has a higher logP and DILI risk, and a higher clearance, these can potentially be addressed through further optimization. The substantial affinity difference is a concern, but can be overcome with further medicinal chemistry.

Output:
0
2025-04-17 06:18:24,887 - INFO - Reasoning:

Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (367.471 and 352.395 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (97.39) is better than Ligand B (118.45). For CNS targets, we want TPSA <= 90, so Ligand A is closer to this threshold.

**3. logP:** Ligand A (2.044) is optimal (1-3). Ligand B (-0.309) is below 1, which could hinder permeation.

**4. H-Bond Donors:** Both have 2 HBD, which is within the acceptable limit of <= 5.

**5. H-Bond Acceptors:** Ligand A has 5 HBA, and Ligand B has 7. Both are within the acceptable limit of <= 10.

**6. QED:** Ligand A (0.849) is better than Ligand B (0.695), indicating a more drug-like profile.

**7. DILI:** Ligand B (64.133) has a slightly higher DILI risk than Ligand A (56.921), but both are acceptable (<60 is good).

**8. BBB:** Ligand A (71.035) is significantly better than Ligand B (40.558).  For CNS targets, >70 is desirable, and Ligand A is much closer. This is a critical factor for DRD2.

**9. Caco-2 Permeability:** Ligand A (-4.817) and Ligand B (-5.362) both have negative values, which is unusual and suggests poor permeability. This is a concern for both.

**10. Aqueous Solubility:** Ligand A (-2.943) and Ligand B (-1.629) both have negative values, suggesting low solubility. This is a concern for both.

**11. hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.216 and 0.028).

**12. Microsomal Clearance:** Ligand B (-11.558) has a significantly lower (better) microsomal clearance than Ligand A (54.041), suggesting greater metabolic stability.

**13. In vitro Half-Life:** Ligand B (-6.255) has a longer in vitro half-life than Ligand A (-39.207), which is desirable.

**14. P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.043 and 0.004).

**15. Binding Affinity:** Ligand A (-8.4 kcal/mol) has a slightly better binding affinity than Ligand B (-7.8 kcal/mol). While both are good, the 0.6 kcal/mol difference is noteworthy.

**Overall Assessment:**

Ligand A is superior due to its better BBB penetration, more optimal logP, higher QED, and slightly better binding affinity. While Ligand B has better metabolic stability and half-life, the BBB penetration is a critical factor for a CNS target like DRD2, and Ligand A significantly outperforms Ligand B in this regard. The slightly better affinity of Ligand A also contributes to its favorability. The poor Caco-2 and solubility for both are concerns that would need to be addressed during optimization, but the CNS penetration advantage of Ligand A is decisive.

Output:
1
2025-04-17 06:18:24,887 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (362.308 Da and 343.423 Da) fall within the ideal range of 200-500 Da.

**TPSA:** Ligand A (104.65) is slightly above the optimal <90 for CNS targets, but still reasonable. Ligand B (64.63) is well within the desired range.

**logP:** Ligand A (0.504) is a bit low, potentially hindering membrane permeability. Ligand B (3.275) is excellent, falling right within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A has 2 HBD and 6 HBA, which are acceptable. Ligand B has 1 HBD and 4 HBA, also acceptable.

**QED:** Both ligands have similar QED values (0.791 and 0.673), indicating good drug-likeness.

**DILI:** Ligand A (62.737) has a higher DILI risk than Ligand B (46.297), though both are moderately risky.

**BBB:** Ligand B (78.558) has a significantly better BBB penetration percentile than Ligand A (63.901). This is a crucial advantage for a CNS target like DRD2.

**Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and suggests poor permeability. However, the scale isn't specified, so it's hard to interpret.

**Aqueous Solubility:** Both have negative solubility values, also unusual and suggesting poor solubility.

**hERG:** Ligand A (0.135) has a slightly better hERG profile (lower risk) than Ligand B (0.414).

**Microsomal Clearance:** Ligand A (-2.638) has a much lower (better) microsomal clearance than Ligand B (89.029), indicating greater metabolic stability.

**In vitro Half-Life:** Ligand A (-23.314) has a much longer in vitro half-life than Ligand B (-7.028).

**P-gp Efflux:** Ligand A (0.012) has a much lower P-gp efflux liability than Ligand B (0.174), which is highly desirable for CNS penetration.

**Binding Affinity:** Ligand B (-8.2 kcal/mol) has a significantly stronger binding affinity than Ligand A (-6.8 kcal/mol). This is a substantial advantage that can outweigh some ADME drawbacks.

**Overall Assessment:**

Ligand B excels in BBB penetration and binding affinity, both critical for a DRD2 ligand. While its DILI and P-gp efflux are slightly higher and metabolic stability is lower than Ligand A, the stronger binding and better BBB penetration are more important for CNS drug development. Ligand A has better metabolic stability and P-gp efflux, but its lower affinity and BBB penetration are significant drawbacks. The lower logP of Ligand A is also concerning.

Output:
1
2025-04-17 06:18:24,887 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (346.431 Da) is slightly lower, which could be beneficial for permeability.

**TPSA:** Both ligands have TPSA values below 140, suggesting reasonable oral absorption. Ligand A (82.18) is better than Ligand B (87.76), and closer to the preferred <90 for CNS targets.

**logP:** Ligand A (3.483) is optimal (1-3), while Ligand B (0.361) is quite low, potentially hindering permeation. This is a significant drawback for Ligand B.

**H-Bond Donors/Acceptors:** Both ligands have acceptable HBD (1) and HBA (7/6) counts.

**QED:** Both ligands have acceptable QED scores (0.806 and 0.667), indicating good drug-like properties.

**DILI:** Both ligands have relatively low DILI risk (54.634 and 51.26), which is positive.

**BBB:** Ligand A (81.97) has a significantly better BBB penetration score than Ligand B (64.87). This is *critical* for a CNS target like DRD2.

**Caco-2 Permeability:** Ligand A (-4.654) and Ligand B (-5.176) both have negative Caco-2 values, which is unusual and suggests poor permeability. However, the scale is not defined, so it's hard to interpret.

**Aqueous Solubility:** Both ligands have poor aqueous solubility (-4.964 and -2.862). This could pose formulation challenges.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.177 and 0.375).

**Microsomal Clearance:** Ligand A (97.828) has high microsomal clearance, indicating rapid metabolism and potentially low bioavailability. Ligand B (18.888) has much lower clearance, suggesting better metabolic stability.

**In vitro Half-Life:** Ligand B (-21.852) has a very negative half-life, which is concerning. Ligand A (12.842) is better, but still not ideal.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.286 and 0.022), which is favorable for CNS penetration.

**Binding Affinity:** Ligand A (-8.4 kcal/mol) has a slightly better binding affinity than Ligand B (-7.1 kcal/mol), although both are good. The 1.3 kcal/mol difference can be significant.

**Overall Assessment:**

Ligand A is the stronger candidate. While it has higher metabolic clearance, its superior BBB penetration, optimal logP, and slightly better binding affinity outweigh this drawback. Ligand B's very low logP is a major concern, as it will likely limit its ability to cross cell membranes and reach the CNS. The negative half-life is also a significant issue. The better metabolic stability of Ligand B is not enough to compensate for these significant ADME liabilities.

Output:
1
2025-04-17 06:18:24,888 - INFO - Batch 271 complete. Total preferences: 4336
2025-04-17 06:18:24,888 - INFO - Processing batch 272/512...
2025-04-17 06:19:08,070 - INFO - Reasoning:

Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight (MW):** Both ligands are within the ideal range (200-500 Da). Ligand A (340.467 Da) is slightly lower, which is generally favorable for permeability.

**2. TPSA:** Ligand A (50.36) is significantly better than Ligand B (91.32). For CNS targets, TPSA should be <= 90, and A is comfortably within this range, while B is close to the upper limit. This favors A.

**3. logP:** Ligand A (4.647) is higher than the optimal range (1-3), but still potentially acceptable. Ligand B (2.056) is within the optimal range. However, for a CNS target, a slightly higher logP can be beneficial for BBB penetration, so A isn't severely penalized.

**4. H-Bond Donors (HBD):** Both ligands are within the acceptable limit of <=5 (A: 2, B: 3).

**5. H-Bond Acceptors (HBA):** Both ligands are within the acceptable limit of <=10 (A: 3, B: 4).

**6. QED:** Both ligands have similar QED values (A: 0.722, B: 0.698), indicating good drug-like properties.

**7. DILI:** Ligand A (69.872) has a higher DILI risk than Ligand B (45.25). This is a negative for A, but not a deal-breaker at this stage.

**8. BBB:** Ligand B (68.554) has a slightly better BBB percentile than Ligand A (53.548). However, both are below the desirable >70 for CNS targets.

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.748 and -4.818), which is unusual and suggests poor permeability. This is a significant concern for both.

**10. Aqueous Solubility:** Both ligands have negative solubility values (-5.398 and -2.491). This is also a concern, indicating poor aqueous solubility.

**11. hERG Inhibition:** Ligand A (0.756) has a slightly higher hERG inhibition risk than Ligand B (0.306). Lower is better, so B is preferable here.

**12. Microsomal Clearance:** Ligand A (88.193) has a higher microsomal clearance than Ligand B (14.553), indicating lower metabolic stability. This is a negative for A.

**13. In vitro Half-Life:** Ligand B (-13.84) has a negative half-life, which is not physically possible and indicates a data error or a very rapidly metabolized compound. Ligand A (31.506) has a reasonable half-life.

**14. P-gp Efflux:** Ligand A (0.548) has lower P-gp efflux than Ligand B (0.038), which is preferable for CNS exposure.

**15. Binding Affinity:** Ligand A (-10.2 kcal/mol) has significantly stronger binding affinity than Ligand B (-9.0 kcal/mol). This is a substantial advantage for A. A difference of >1.5 kcal/mol can often outweigh other drawbacks.

**Overall Assessment:**

Despite some drawbacks (higher DILI, slightly lower BBB), Ligand A is the more promising candidate. Its significantly stronger binding affinity (-10.2 vs -9.0 kcal/mol) is a major advantage. Its TPSA is much better, and it has acceptable logP. The negative Caco-2 and solubility values are concerning for both, but the superior affinity of A makes it more likely to be optimized to overcome these issues. Ligand B has a problematic negative half-life, which is a major red flag.

Output:
1
2025-04-17 06:19:08,070 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (403.324 Da) is slightly higher than Ligand B (353.463 Da), but both are acceptable.

**TPSA:** Ligand A (52.39) is significantly better than Ligand B (71.11). For CNS targets, we want TPSA <= 90, and ideally lower. Ligand A is well within this range, while Ligand B is approaching the upper limit.

**logP:** Both ligands have acceptable logP values (Ligand A: 3.045, Ligand B: 1.079), falling within the optimal 1-3 range. Ligand A is slightly more lipophilic, which could aid in membrane permeability.

**H-Bond Donors/Acceptors:** Both ligands have reasonable HBD/HBA counts (A: 0/5, B: 1/5). These are within the acceptable limits for good permeability.

**QED:** Both ligands have similar and good QED values (A: 0.712, B: 0.724), indicating good drug-like properties.

**DILI:** Ligand A (42.846) has a slightly higher DILI risk than Ligand B (16.596), but both are below the concerning threshold of 60.

**BBB:** Ligand A (91.121) has a significantly better BBB penetration prediction than Ligand B (61.846). This is a *critical* factor for a CNS target like DRD2.

**Caco-2 Permeability:** Ligand A (-4.691) has a more negative Caco-2 value, which is less desirable. Ligand B (-5.268) is also negative, but slightly worse. This suggests both may have limited intestinal absorption, but the difference is minor.

**Aqueous Solubility:** Ligand A (-2.47) has slightly better aqueous solubility than Ligand B (-0.876), although both are negative.

**hERG Inhibition:** Ligand A (0.965) has a slightly higher hERG risk than Ligand B (0.217). This is a potential concern for Ligand A, but the value is not critically high.

**Microsomal Clearance:** Ligand A (47.116) has a higher microsomal clearance than Ligand B (-6.128). This suggests Ligand B is more metabolically stable, which is desirable.

**In vitro Half-Life:** Ligand A (56.37) has a longer in vitro half-life than Ligand B (24.851), which is a positive attribute.

**P-gp Efflux:** Ligand A (0.355) has lower P-gp efflux liability than Ligand B (0.005), which is beneficial for CNS exposure.

**Binding Affinity:** Ligand B (-7.6 kcal/mol) has a slightly better binding affinity than Ligand A (-7.2 kcal/mol). While both are excellent, the 0.4 kcal/mol difference is noteworthy.

**Overall Assessment:**

Ligand A excels in BBB penetration, P-gp efflux, and in vitro half-life. Its TPSA is also significantly better than Ligand B. While its DILI risk and hERG inhibition are slightly higher, and its Caco-2 permeability is less favorable, the strong CNS-related properties are paramount for a DRD2 ligand. Ligand B has better metabolic stability and slightly better binding affinity, but its significantly lower BBB prediction is a major drawback.

Given the GPCR-specific priorities for CNS targets, **Ligand A is the more promising candidate.** The superior BBB penetration and lower P-gp efflux outweigh the minor drawbacks in metabolic stability and binding affinity.

Output:
1
2025-04-17 06:19:08,070 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (364.475 and 363.567 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (85.91) is better than Ligand B (40.54). For CNS targets, TPSA should be <= 90, both meet this criteria, but A is closer to the upper limit and may have some permeability issues.

**3. logP:** Ligand B (4.763) is higher than Ligand A (0.666). While both are within the acceptable range (1-3 is optimal), Ligand B is pushing the upper limit and could potentially have solubility issues or off-target effects. Ligand A is quite low, which could hinder permeation.

**4. H-Bond Donors:** Ligand A (0) is better than Ligand B (1). Lower HBDs generally improve permeability.

**5. H-Bond Acceptors:** Ligand A (8) is higher than Ligand B (3). Both are within the acceptable range of <=10.

**6. QED:** Both ligands have similar QED values (0.718 and 0.758), indicating good drug-like properties.

**7. DILI:** Ligand B (13.377) has a significantly lower DILI risk than Ligand A (62.893), making it safer from a liver toxicity perspective.

**8. BBB:** Ligand B (88.29) has a much better BBB penetration percentile than Ligand A (66.382). This is *critical* for a CNS target like DRD2.

**9. Caco-2 Permeability:** Ligand A (-5.057) has a negative value which is unusual and indicates very poor permeability. Ligand B (-4.634) is also poor, but less so than A.

**10. Aqueous Solubility:** Ligand A (-1.553) has very poor solubility, while Ligand B (-4.871) is also poor.

**11. hERG Inhibition:** Ligand A (0.152) has a slightly lower hERG inhibition risk than Ligand B (0.758), but both are relatively low.

**12. Microsomal Clearance:** Ligand B (111.585) has significantly higher microsomal clearance than Ligand A (33.608), meaning it's metabolized more quickly. This is a drawback for Ligand B.

**13. In vitro Half-Life:** Ligand A (22.617) has a much longer in vitro half-life than Ligand B (2.906). This is a significant advantage for Ligand A.

**14. P-gp Efflux:** Ligand A (0.158) has lower P-gp efflux liability than Ligand B (0.733), which is beneficial for CNS penetration.

**15. Binding Affinity:** Both ligands have very similar and strong binding affinities (-7.7 and -7.6 kcal/mol). The difference is negligible.

**Overall Assessment:**

While Ligand B has a better BBB score and lower DILI risk, Ligand A has superior metabolic stability (lower Cl_mic, longer t1/2), lower P-gp efflux, and better Caco-2 permeability. The poor solubility and logP of both are concerning, but the metabolic advantages of Ligand A, coupled with its better P-gp profile, make it a more promising candidate, especially considering the importance of CNS penetration for DRD2. The slightly better BBB of B is outweighed by the other factors.

Output:
0
2025-04-17 06:19:08,070 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (350.463 and 352.431 Da) are within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (96.11) is slightly above the preferred <90 for CNS targets, but still reasonable. Ligand B (88.1) is better, falling comfortably below 90.

**3. logP:** Ligand A (2.02) is optimal (1-3). Ligand B (0.203) is quite low, potentially hindering membrane permeability.

**4. H-Bond Donors:** Both ligands have acceptable HBD counts (3 and 2, respectively), well below the limit of 5.

**5. H-Bond Acceptors:** Both ligands have acceptable HBA counts (4 and 5, respectively), well below the limit of 10.

**6. QED:** Both ligands have good QED scores (0.668 and 0.755), indicating drug-like properties.

**7. DILI:** Both ligands have low DILI risk (31.485 and 28.306), which is favorable.

**8. BBB:** Ligand A has a significantly better BBB penetration percentile (72.741) than Ligand B (61.38). This is a crucial factor for a CNS target like DRD2.

**9. Caco-2 Permeability:** Ligand A (-4.711) has worse Caco-2 permeability than Ligand B (-4.75).

**10. Aqueous Solubility:** Ligand A (-2.526) has better aqueous solubility than Ligand B (-1.68).

**11. hERG Inhibition:** Both ligands have very low hERG inhibition liability (0.479 and 0.191), which is excellent.

**12. Microsomal Clearance:** Ligand A (21.462) has higher microsomal clearance than Ligand B (1.737), suggesting lower metabolic stability.

**13. In vitro Half-Life:** Ligand A (-17.419) has a lower in vitro half-life than Ligand B (18.639).

**14. P-gp Efflux:** Ligand A (0.112) has lower P-gp efflux than Ligand B (0.074), which is beneficial for CNS exposure.

**15. Binding Affinity:** Ligand B (-8.3) has a slightly stronger binding affinity than Ligand A (-7.7). The difference is 0.6 kcal/mol, which is significant but not overwhelming.

**Overall Assessment:**

Ligand A excels in BBB penetration, P-gp efflux, and solubility, all critical for CNS drug development. While its TPSA is slightly higher and its metabolic stability (Cl_mic and t1/2) are poorer than Ligand B, the superior BBB penetration and P-gp efflux are more important for DRD2 targeting. Ligand B has a slightly better binding affinity and logP, but the low logP is a significant concern for permeability. The difference in binding affinity (0.6 kcal/mol) is unlikely to overcome the permeability issues of Ligand B.

Output:
1
2025-04-17 06:19:08,070 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 drug candidates, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (385.961 Da) is slightly higher than Ligand B (354.475 Da), but both are acceptable.

**TPSA:** Both ligands have TPSA values above the optimal 90 A^2 for CNS targets. Ligand A (52.65 A^2) is significantly better than Ligand B (58.2 A^2). This is a positive for Ligand A.

**logP:** Both ligands have logP values within the optimal range (1-3). Ligand A (3.243) and Ligand B (3.493) are comparable.

**H-Bond Donors/Acceptors:** Ligand A (HBD=1, HBA=4) is slightly better than Ligand B (HBD=2, HBA=3) in terms of balancing solubility and permeability, although both are within acceptable limits.

**QED:** Ligand A (0.783) has a better QED score than Ligand B (0.591), indicating a more drug-like profile.

**DILI:** Ligand A (19.969) has a significantly lower DILI risk than Ligand B (65.723), a major advantage.

**BBB:** Both ligands have good BBB penetration (Ligand A: 74.758, Ligand B: 75.107). They are both above the 70% threshold, so this is not a major differentiating factor.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values, which is unusual and suggests poor permeability. However, these values are on a scale where negative values are possible, and direct comparison is difficult without knowing the scale's specifics.

**Aqueous Solubility:** Both ligands have negative solubility values, again suggesting poor solubility. Similar to Caco-2, the scale is unclear.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.644), which is good.

**Microsomal Clearance:** Ligand A (8.218 mL/min/kg) has a much lower microsomal clearance than Ligand B (89.706 mL/min/kg), indicating better metabolic stability.

**In vitro Half-Life:** Ligand A (34.374 hours) has a significantly longer in vitro half-life than Ligand B (8.589 hours).

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.107 and 0.56, respectively), which is favorable for CNS penetration. Ligand A is slightly better.

**Binding Affinity:** Ligand B (-9.6 kcal/mol) has a significantly stronger binding affinity than Ligand A (-7.3 kcal/mol). This is a substantial advantage for Ligand B.

**Overall Assessment:**

While Ligand B boasts a superior binding affinity, Ligand A presents a much more favorable ADME-Tox profile. Specifically, its lower DILI risk, significantly better metabolic stability (lower Cl_mic, longer t1/2), and better QED score are compelling. The slightly better TPSA and P-gp efflux also contribute. The difference in binding affinity (-9.6 vs -7.3 kcal/mol) is substantial (2.3 kcal/mol), however, the ADME profile of Ligand B is concerning. Given the CNS target and the importance of avoiding toxicity and ensuring adequate exposure, Ligand A appears to be the more promising candidate, despite the weaker binding. Further optimization of Ligand A to improve its affinity could yield an excellent drug candidate.

Output:
0
2025-04-17 06:19:08,071 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (348.45 & 354.44 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (87.51) is better than Ligand B (75.19) as it's closer to the <90 target for CNS penetration. Both are acceptable.

**logP:** Ligand A (3.596) is optimal, while Ligand B (1.401) is on the lower side. Lower logP can hinder permeation, especially across the BBB.

**H-Bond Donors/Acceptors:** Ligand A (HBD=2, HBA=4) and Ligand B (HBD=1, HBA=5) both meet the criteria of <=5 HBD and <=10 HBA.

**QED:** Both ligands have good QED scores (A: 0.645, B: 0.842), indicating drug-like properties.

**DILI:** Ligand A (39.32) has a lower DILI risk than Ligand B (52.89), which is preferable. Both are below the concerning threshold of 60.

**BBB:** Ligand A (81.47) has significantly better BBB penetration potential than Ligand B (49.79). This is a crucial factor for a CNS target like DRD2.

**Caco-2 & Solubility:** Both ligands have negative values for Caco-2 and Solubility, suggesting poor permeability and solubility. This is a concern for both, but the negative values are similar.

**hERG:** Both ligands have very low hERG inhibition liability (A: 0.776, B: 0.12), which is excellent.

**Microsomal Clearance:** Ligand A (-9.229) has a *much* lower (better) microsomal clearance than Ligand B (20.449). This suggests greater metabolic stability for Ligand A.

**In vitro Half-Life:** Ligand A (15.523 hours) has a better in vitro half-life than Ligand B (-16.142 hours).

**P-gp Efflux:** Ligand A (0.062) has lower P-gp efflux liability than Ligand B (0.132), which is favorable for CNS exposure.

**Binding Affinity:** Ligand A (-8.8 kcal/mol) has a slightly better binding affinity than Ligand B (-7.8 kcal/mol). While both are good, the 1 kcal/mol difference is meaningful.

**Overall Assessment:**

Ligand A is significantly better than Ligand B. While both have acceptable MW, QED, and hERG profiles, Ligand A excels in crucial areas for a CNS-targeting GPCR ligand: BBB penetration, metabolic stability (lower Cl_mic), P-gp efflux, and binding affinity. Ligand B's lower logP and poorer BBB penetration are significant drawbacks.

Output:
1
2025-04-17 06:19:08,071 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (349.391 and 353.507 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (111.28) is slightly above the optimal <90 for CNS targets, but still reasonable. Ligand B (61.88) is excellent, well below 90.

**logP:** Ligand A (0.704) is a bit low, potentially hindering permeation. Ligand B (1.639) is better, falling within the 1-3 optimal range.

**H-Bond Donors/Acceptors:** Ligand A has 2 HBD and 7 HBA, which are acceptable. Ligand B has 1 HBD and 4 HBA, also acceptable.

**QED:** Both ligands have good QED scores (0.611 and 0.721), indicating drug-like properties.

**DILI:** Ligand A has a DILI risk of 62.001, which is moderately high. Ligand B has a very low DILI risk of 4.653, a significant advantage.

**BBB:** Ligand A has a BBB penetration of 52.85%, below the desirable >70% for CNS targets. Ligand B has a much better BBB penetration of 72.237%, exceeding the threshold.

**Caco-2 Permeability:** Ligand A (-5.313) shows poor permeability. Ligand B (-4.626) is slightly better, but still not great.

**Aqueous Solubility:** Both ligands have negative solubility values (-2.035 and -0.969), indicating very poor aqueous solubility, which is a concern for bioavailability.

**hERG Inhibition:** Both ligands show low hERG inhibition liability (0.343 and 0.344), which is positive.

**Microsomal Clearance:** Ligand A has a higher microsomal clearance (48.368) than Ligand B (24.678), suggesting lower metabolic stability.

**In vitro Half-Life:** Ligand A has a longer half-life (4.738 hours) than Ligand B (-12.898 hours - this is a negative value, likely an error or indicating very rapid degradation).

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.118 and 0.021), which is favorable for CNS penetration.

**Binding Affinity:** Both ligands have very similar and strong binding affinities (-7.8 and -7.7 kcal/mol). The difference is negligible.

**Conclusion:**

Considering the GPCR-specific priorities, Ligand B is the more promising candidate. While both have good affinity, Ligand B significantly outperforms Ligand A in crucial areas: lower DILI risk, much better BBB penetration, and lower microsomal clearance. Although both have poor solubility and Caco-2 permeability, the improved safety and CNS penetration of Ligand B outweigh these drawbacks. The negative half-life for Ligand B is concerning and would need further investigation, but the other factors strongly favor it.

Output:
1
2025-04-17 06:19:08,071 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands fall within the ideal range (200-500 Da). Ligand A (345.443) is slightly lower than Ligand B (370.515), which is acceptable.

**TPSA:** Both ligands have TPSA values below the 90 A^2 threshold desirable for CNS targets. Ligand A (82.53) is slightly higher than Ligand B (74.76), but both are good.

**logP:** Both ligands have logP values within the optimal range (1-3). Ligand A (1.582) and Ligand B (1.761) are both well within the range.

**H-Bond Donors:** Ligand A has 2 HBD, which is acceptable. Ligand B has 0 HBD, which is also acceptable.

**H-Bond Acceptors:** Both ligands have 4 HBA, which is within the acceptable limit of <=10.

**QED:** Ligand A (0.631) has a better QED score than Ligand B (0.482), indicating a more drug-like profile.

**DILI:** Ligand B (35.13) has a significantly lower DILI risk than Ligand A (48.197), making it safer from a liver toxicity perspective.

**BBB:** Ligand B (71.733) has a much better BBB penetration percentile than Ligand A (28.848). This is *critical* for a CNS target like DRD2.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values, indicating poor permeability. Ligand A (-4.539) is slightly worse than Ligand B (-4.825).

**Aqueous Solubility:** Both ligands have negative solubility values, indicating poor solubility. Ligand A (-3.468) is slightly better than Ligand B (-1.744).

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.461 and 0.311, respectively).

**Microsomal Clearance:** Ligand B (15.336) has significantly lower microsomal clearance than Ligand A (55.066), indicating better metabolic stability.

**In vitro Half-Life:** Ligand B (13.969 hours) has a much longer in vitro half-life than Ligand A (3.51 hours).

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.191 and 0.221, respectively).

**Binding Affinity:** Ligand A (-7.2 kcal/mol) has a slightly better binding affinity than Ligand B (-6.9 kcal/mol), but the difference is relatively small (0.3 kcal/mol).

**Overall Assessment:**

While Ligand A has slightly better binding affinity and solubility, Ligand B is significantly superior in terms of ADME properties crucial for CNS drug development. Specifically, the much higher BBB penetration (71.733 vs 28.848), lower DILI risk, lower microsomal clearance, and longer half-life of Ligand B outweigh the minor affinity difference. The poor Caco-2 permeability is a concern for both, but less critical for a CNS target where direct brain exposure is prioritized.

Output:
1
2025-04-17 06:19:08,071 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (374.409 Da) is slightly higher than Ligand B (349.431 Da), but both are acceptable.

**TPSA:** Ligand A (84.5) is better than Ligand B (93.46). For CNS targets, we want TPSA <= 90, so Ligand A is preferable.

**logP:** Both ligands have good logP values (A: 2.113, B: 1.867) falling within the optimal range of 1-3.

**H-Bond Donors/Acceptors:** Both have 2 HBD and 5 HBA, which are within acceptable limits.

**QED:** Both ligands have good QED scores (A: 0.539, B: 0.747), indicating good drug-like properties. Ligand B is slightly better here.

**DILI:** Ligand A (61.574) has a higher DILI risk than Ligand B (41.411). This favors Ligand B.

**BBB:** Ligand A (66.925) has a better BBB penetration score than Ligand B (55.874). Given this is a CNS target, this is a significant advantage for Ligand A. A score >70 is desirable, but 66.925 is still reasonably good.

**Caco-2 Permeability:** Ligand A (-4.849) is better than Ligand B (-5.342). Higher values indicate better absorption.

**Aqueous Solubility:** Ligand A (-3.526) is better than Ligand B (-1.174). Higher values are better.

**hERG:** Both ligands have very low hERG inhibition liability (A: 0.463, B: 0.139), which is excellent. Ligand B is slightly better.

**Microsomal Clearance:** Ligand A (64.633) has higher clearance than Ligand B (50.219), meaning it's less metabolically stable. Ligand B is preferable.

**In vitro Half-Life:** Ligand A (23.741) has a shorter half-life than Ligand B (-22.219). A negative value for half-life is unusual and suggests a very long half-life, which is favorable. Ligand B is significantly better here.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (A: 0.115, B: 0.137), which is excellent.

**Binding Affinity:** Both ligands have excellent binding affinities (A: -8.4 kcal/mol, B: -8.6 kcal/mol). Ligand B is slightly better, but the difference is small.

**Overall Assessment:**

Ligand B has advantages in DILI, half-life, and slightly better affinity and hERG. However, Ligand A has a significantly better BBB score and TPSA, which are crucial for CNS penetration. Considering the target is DRD2 (a CNS GPCR), the BBB score and TPSA are more important. While Ligand B has a slightly better half-life, the difference isn't substantial enough to outweigh the BBB advantage of Ligand A.

Output:
1
2025-04-17 06:19:08,071 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B based on the provided guidelines, prioritizing GPCR-specific properties (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (364.471 Da) is slightly higher than Ligand B (337.362 Da), but both are acceptable.

**TPSA:** Both ligands have TPSA values below 90, which is favorable for CNS penetration. Ligand B (86.92) is slightly better than Ligand A (91.4).

**logP:** Ligand A (0.946) is a bit low, potentially hindering permeation. Ligand B (2.822) is closer to the optimal range of 1-3. This favors Ligand B.

**H-Bond Donors/Acceptors:** Ligand A has 2 HBD and 5 HBA, while Ligand B has 1 HBD and 7 HBA. Both are within acceptable limits.

**QED:** Both ligands have reasonable QED values (A: 0.761, B: 0.621), indicating good drug-like properties.

**DILI:** Ligand A (49.011) has a much lower DILI risk than Ligand B (89.841). This is a significant advantage for Ligand A.

**BBB:** Ligand B (64.482) has a better BBB percentile than Ligand A (41.722). This is crucial for a CNS target like DRD2, and favors Ligand B.

**Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and difficult to interpret without knowing the scale. However, they are similarly poor.

**Aqueous Solubility:** Both have negative solubility values, again making comparison difficult. They are similarly poor.

**hERG Inhibition:** Ligand A (0.296) has a much lower hERG inhibition liability than Ligand B (0.617), indicating a lower risk of cardiotoxicity. This favors Ligand A.

**Microsomal Clearance:** Ligand A (13.485) has significantly lower microsomal clearance than Ligand B (28.005), suggesting better metabolic stability. This favors Ligand A.

**In vitro Half-Life:** Ligand A (18.067) has a longer in vitro half-life than Ligand B (-6.117). This is a strong advantage for Ligand A.

**P-gp Efflux:** Ligand A (0.051) has much lower P-gp efflux liability than Ligand B (0.43), which is beneficial for CNS exposure. This favors Ligand A.

**Binding Affinity:** Ligand B (-9.4 kcal/mol) has a significantly stronger binding affinity than Ligand A (-7.9 kcal/mol). This is a substantial advantage for Ligand B, and could potentially outweigh some of the ADME drawbacks.

**Overall Assessment:**

Ligand B has a superior binding affinity and better BBB penetration, which are critical for a CNS GPCR target. However, it suffers from higher DILI risk, higher hERG inhibition, higher P-gp efflux, and faster metabolic clearance. Ligand A has a more favorable ADME profile overall (lower DILI, hERG, P-gp, Cl_mic, and longer t1/2), but its binding affinity is weaker and BBB penetration is lower.

The difference in binding affinity (1.5 kcal/mol) is significant. While Ligand A has a better safety profile and drug-like properties, the stronger binding of Ligand B to DRD2 is likely to be more important for efficacy. The BBB value of 64.482 for Ligand B is reasonably good, and could be improved with further optimization.

Output:
1
2025-04-17 06:19:08,071 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (347.419 and 356.442 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (100.21) is slightly higher than Ligand B (96.25), but both are below the 140 A^2 threshold for good oral absorption and reasonably close to the 90 A^2 target for CNS penetration.

**3. logP:** Ligand A (0.074) is quite low, potentially hindering membrane permeability. Ligand B (1.335) is much better, falling within the optimal 1-3 range. This is a significant advantage for Ligand B.

**4. H-Bond Donors:** Ligand A (2) and Ligand B (3) are both acceptable, being less than 5.

**5. H-Bond Acceptors:** Both ligands (A: 5, B: 5) are within the acceptable limit of 10.

**6. QED:** Both ligands have similar QED values (A: 0.649, B: 0.655), indicating good drug-like properties.

**7. DILI:** Ligand A (57.387) has a higher DILI risk than Ligand B (38.348), although both are below the concerning 60 percentile.

**8. BBB:** Both ligands have similar and good BBB penetration (A: 65.839, B: 64.831), but ideally, we'd like to see values >70 for a CNS target.

**9. Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and suggests poor permeability. However, the scale isn't specified, so it's hard to interpret.

**10. Aqueous Solubility:** Both have negative solubility values, indicating poor solubility. Again, the scale is unknown.

**11. hERG Inhibition:** Ligand A (0.07) has a lower hERG risk than Ligand B (0.324), which is favorable.

**12. Microsomal Clearance:** Ligand A (7.459) has significantly lower microsomal clearance than Ligand B (33.686), indicating better metabolic stability.

**13. In vitro Half-Life:** Ligand A (-7.994) has a much longer in vitro half-life than Ligand B (-1.174). This is a substantial advantage for Ligand A.

**14. P-gp Efflux:** Ligand A (0.023) has very low P-gp efflux liability, while Ligand B (0.046) is slightly higher. Lower is better for CNS exposure.

**15. Binding Affinity:** Ligand B (-8.0) has a slightly better binding affinity than Ligand A (-7.1), a difference of 0.9 kcal/mol. This is a significant advantage, potentially outweighing some ADME drawbacks.

**Overall Assessment:**

Ligand B has a better logP and binding affinity, which are crucial for GPCR targets. However, Ligand A exhibits superior metabolic stability (lower Cl_mic, longer t1/2), lower P-gp efflux, and lower hERG risk. The low logP of Ligand A is a concern, but the stronger affinity of Ligand B is a significant advantage. Considering the balance, the slightly better binding affinity of Ligand B, coupled with its more favorable logP, makes it the more promising candidate despite the slightly higher DILI and P-gp efflux.

Output:
1
2025-04-17 06:19:08,071 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (342.355 and 349.431 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (117.52) is slightly above the optimal <90 for CNS targets, but still reasonable. Ligand B (89.43) is excellent, well within the desired range.

**3. logP:** Both ligands (1.294 and 1.383) are within the optimal 1-3 range.

**4. H-Bond Donors:** Ligand A has 3 HBD, which is acceptable. Ligand B has 2 HBD, also acceptable.

**5. H-Bond Acceptors:** Ligand A has 4 HBA, within the limit of 10. Ligand B has 5 HBA, also within the limit.

**6. QED:** Both ligands have good QED scores (0.713 and 0.728), indicating drug-like properties.

**7. DILI:** Ligand A has a DILI risk of 87.01, which is high and concerning. Ligand B has a much lower DILI risk of 59.442, which is still moderately high but significantly better.

**8. BBB:** Ligand A shows a BBB penetration of 67.584%, which is good but could be better for a CNS target. Ligand B has a lower BBB penetration of 45.444%, which is less favorable.

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.114 and -5.073), which is unusual and suggests poor permeability. This is a significant drawback for both.

**10. Aqueous Solubility:** Both ligands have very poor aqueous solubility (-4.375 and -2.002). This is a major concern for formulation and bioavailability.

**11. hERG Inhibition:** Both ligands show low hERG inhibition risk (0.422 and 0.121), which is positive.

**12. Microsomal Clearance:** Ligand A has a very low (good) microsomal clearance (-17.801), indicating high metabolic stability. Ligand B has a higher clearance (13.931), suggesting faster metabolism.

**13. In vitro Half-Life:** Ligand A has a very short in vitro half-life (-12.252), which is undesirable. Ligand B has a longer half-life (12.325), which is better.

**14. P-gp Efflux:** Ligand A has very low P-gp efflux (0.017), which is excellent for CNS penetration. Ligand B has slightly higher P-gp efflux (0.083), but still relatively low.

**15. Binding Affinity:** Ligand A has a significantly stronger binding affinity (-9.6 kcal/mol) than Ligand B (-0.0 kcal/mol). This is a substantial advantage.

**Overall Assessment:**

Ligand A has a much stronger binding affinity and better metabolic stability (lower Cl_mic) and P-gp efflux. However, its high DILI risk and poor in vitro half-life are major drawbacks. Ligand B has a lower DILI risk, better half-life, and a more favorable TPSA, but its binding affinity is extremely weak.

Given the importance of affinity for GPCRs, and the fact that a >1.5 kcal/mol advantage can outweigh other drawbacks, Ligand A is the more promising candidate *despite* its liabilities. The high DILI risk would need to be addressed through structural modifications, but the strong binding is a crucial starting point. The poor solubility and permeability are also concerns, but these can be tackled with formulation strategies or further chemical modifications.

Output:
0
2025-04-17 06:19:08,071 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (354.535 and 367.515 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (58.64) is significantly better than Ligand B (61.88). Both are below the 90 A^2 threshold for CNS targets, but A is closer to optimal.

**3. logP:** Ligand A (3.227) is within the optimal 1-3 range. Ligand B (1.954) is slightly lower, potentially impacting permeability.

**4. H-Bond Donors:** Both ligands have 1 HBD, which is acceptable.

**5. H-Bond Acceptors:** Ligand A has 3 HBA, and Ligand B has 5. Both are below the 10 threshold, but A is preferable.

**6. QED:** Both ligands have good QED scores (0.613 and 0.864), indicating drug-like properties.

**7. DILI:** Ligand A (7.794) has a slightly higher DILI risk than Ligand B (30.826), but both are below the concerning 60 threshold.

**8. BBB:** This is a critical parameter for CNS targets. Ligand A (81.039) has a significantly better BBB penetration percentile than Ligand B (55.642). This is a major advantage for A.

**9. Caco-2 Permeability:** Ligand A (-4.126) has a worse Caco-2 permeability than Ligand B (-4.799). However, Caco-2 values are often difficult to interpret and can be less reliable than other parameters.

**10. Aqueous Solubility:** Ligand A (-2.756) has a worse solubility than Ligand B (-1.044).

**11. hERG Inhibition:** Ligand A (0.638) has a slightly higher hERG inhibition risk than Ligand B (0.194), but both are relatively low.

**12. Microsomal Clearance:** Ligand A (65.438) has a higher microsomal clearance than Ligand B (12.524), indicating lower metabolic stability. This is a disadvantage for A.

**13. In vitro Half-Life:** Ligand B (18.398) has a much longer in vitro half-life than Ligand A (5.347). This is a significant advantage for B.

**14. P-gp Efflux:** Ligand A (0.205) has lower P-gp efflux liability than Ligand B (0.02), which is favorable for CNS penetration.

**15. Binding Affinity:** Ligand B (-8.1 kcal/mol) has a stronger binding affinity than Ligand A (-7.4 kcal/mol). The difference of 0.7 kcal/mol is substantial and can outweigh some ADME drawbacks.

**Overall Assessment:**

While Ligand A has better TPSA and P-gp efflux, Ligand B excels in several crucial areas for a CNS-targeting GPCR ligand. The significantly stronger binding affinity (-8.1 vs -7.4 kcal/mol), much better BBB penetration (55.642 vs 81.039), and longer half-life (18.398 vs 5.347) are compelling advantages. The slightly lower logP of B is a minor concern, but the superior affinity and BBB penetration are likely to compensate. The lower DILI risk for B is also a positive.

Output:
1
2025-04-17 06:19:08,072 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (343.343 and 351.422 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (113.86) is slightly above the optimal <90 for CNS targets, but still reasonable. Ligand B (93.45) is well within the desired range.

**logP:** Both ligands have good logP values (1.451 and 1.705), falling within the 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A (1 HBD, 9 HBA) and Ligand B (3 HBD, 4 HBA) both have acceptable numbers of H-bond donors and acceptors.

**QED:** Ligand A (0.547) has a better QED score than Ligand B (0.466), indicating a more drug-like profile.

**DILI:** Ligand A (97.906) has a significantly higher DILI risk than Ligand B (39.977). This is a major concern for Ligand A.

**BBB:** Ligand B (83.986) has a much better BBB penetration percentile than Ligand A (68.282). This is crucial for a CNS target like DRD2.

**Caco-2 Permeability:** Ligand A (-4.831) has poor Caco-2 permeability, while Ligand B (-5.005) is also poor, but slightly better.

**Aqueous Solubility:** Ligand A (-3.433) has slightly better solubility than Ligand B (-2.774).

**hERG:** Ligand A (0.335) has a lower hERG inhibition liability than Ligand B (0.687), which is favorable.

**Microsomal Clearance:** Ligand B (22.687) has significantly lower microsomal clearance than Ligand A (66.964), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand B (9.827) has a longer in vitro half-life than Ligand A (-22.172), indicating better stability.

**P-gp Efflux:** Ligand A (0.074) has lower P-gp efflux than Ligand B (0.094), which is favorable for CNS penetration.

**Binding Affinity:** Ligand B (-8.0) has a slightly better binding affinity than Ligand A (-7.5). While the difference is less than 1.5 kcal/mol, it's still a positive factor.

**Overall Assessment:**

Ligand B is the stronger candidate. While Ligand A has a slightly better QED and lower P-gp efflux, its significantly higher DILI risk and lower BBB penetration are major drawbacks for a CNS-targeted drug. Ligand B exhibits a much more favorable safety profile (lower DILI), better BBB penetration, and improved metabolic stability (lower Cl_mic, longer t1/2). The slightly better affinity of Ligand B further supports its selection.

Output:
1
2025-04-17 06:19:08,072 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (354.382 and 346.471 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (85.69) is better than Ligand B (58.64). Both are below the 90 A^2 threshold desirable for CNS targets, but ligand B is closer to optimal.

**logP:** Ligand A (-0.109) is suboptimal, being below 1, which could hinder permeation. Ligand B (2.924) is within the optimal 1-3 range. This is a significant advantage for Ligand B.

**H-Bond Donors/Acceptors:** Both ligands have 1 HBD and a reasonable number of HBAs (6 and 3 respectively), satisfying the <5 HBD and <10 HBA guidelines.

**QED:** Both ligands have similar QED values (0.704 and 0.721), indicating good drug-likeness.

**DILI:** Both ligands have acceptable DILI risk (48.313 and 41.411 percentile), below the 60% threshold.

**BBB:** Ligand A (83.831%) has a significantly better BBB penetration prediction than Ligand B (65.103%). This is a crucial factor for a CNS target like DRD2.

**Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and suggests potential issues with the prediction method or the molecules themselves. It's difficult to draw firm conclusions from these values.

**Aqueous Solubility:** Both ligands have very poor predicted aqueous solubility (-1.76 and -3.21). This is a concern for both, but more so for Ligand B.

**hERG Inhibition:** Both ligands have low hERG inhibition liability (0.151 and 0.271), which is good.

**Microsomal Clearance:** Ligand A (3.259 mL/min/kg) has a much lower microsomal clearance than Ligand B (93.491 mL/min/kg), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (-19.638 hours) has a negative half-life, which is not physically possible and indicates a problem with the prediction. Ligand B (-17.625 hours) also has a negative half-life. These values are unreliable.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.031 and 0.412), which is favorable for CNS penetration.

**Binding Affinity:** Both ligands have similar, strong binding affinities (-8.3 and -8.6 kcal/mol). The difference is minimal.

**Overall Assessment:**

Ligand A excels in BBB penetration and metabolic stability (lower Cl_mic). However, its logP is significantly suboptimal, and its predicted half-life is nonsensical. Ligand B has a better logP and TPSA, but suffers from higher metabolic clearance and a lower BBB prediction. The binding affinities are comparable.

Given the importance of BBB penetration for a CNS target like DRD2, Ligand A initially appears more promising. However, the negative and unreliable half-life prediction for Ligand A is a major red flag. The poor logP of Ligand A is also a significant concern. While Ligand B has a lower BBB score, its logP is within the optimal range, and it may be more amenable to optimization.

Considering the unreliable data and prioritizing a reasonable logP for CNS penetration, I would lean towards Ligand B as the more viable starting point for further optimization.

Output:
1
2025-04-17 06:19:08,072 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (348.487 Da) is slightly lower, which could be advantageous for permeability.

**TPSA:** Ligand A (58.64) is significantly better than Ligand B (48.99) as it is closer to the desired value of <90 for CNS targets.

**logP:** Both ligands have acceptable logP values (A: 2.798, B: 4.093). Ligand B is pushing the upper limit, potentially leading to solubility issues or off-target interactions.

**H-Bond Donors/Acceptors:** Both ligands have a reasonable number of HBD (1) and HBA (A: 3, B: 4).

**QED:** Ligand A (0.777) has a better QED score than Ligand B (0.53), indicating a more drug-like profile.

**DILI:** Both ligands have low DILI risk (A: 33.773, B: 39.667), which is good.

**BBB:** Ligand A (85.537) has a significantly better BBB percentile than Ligand B (39.822). This is a critical advantage for a CNS target like DRD2.

**Caco-2 Permeability:** Ligand A (-4.363) has a worse Caco-2 permeability than Ligand B (-5.32).

**Aqueous Solubility:** Both ligands have poor aqueous solubility (-3.589 and -3.495 respectively).

**hERG Inhibition:** Both ligands have low hERG inhibition risk (A: 0.256, B: 0.834).

**Microsomal Clearance:** Ligand A (47.552) has a lower microsomal clearance than Ligand B (89.125), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (-14.784) has a worse in vitro half-life than Ligand B (-0.024).

**P-gp Efflux:** Ligand A (0.182) has lower P-gp efflux than Ligand B (0.469), which is favorable for CNS penetration.

**Binding Affinity:** Ligand B (-7.7) has a slightly better binding affinity than Ligand A (-8.1). However, the difference is relatively small (0.4 kcal/mol) and can be outweighed by other factors.

**Overall Assessment:**

Considering the GPCR-specific priorities, Ligand A is the more promising candidate. Its superior BBB penetration, lower TPSA, better QED, lower P-gp efflux, and better metabolic stability outweigh the slightly weaker binding affinity and worse Caco-2 permeability. The solubility of both compounds is poor, but this can be addressed with formulation strategies. The small advantage in binding affinity of Ligand B is not enough to overcome the significant disadvantages in CNS penetration and metabolic stability.

Output:
0
2025-04-17 06:19:08,072 - INFO - Batch 272 complete. Total preferences: 4352
2025-04-17 06:19:08,072 - INFO - Processing batch 273/512...
2025-04-17 06:19:50,797 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (348.349 and 361.833 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (65.22) is significantly better than Ligand B (104.11). For CNS targets, we want TPSA <= 90, and A is comfortably within this, while B exceeds it.

**logP:** Ligand A (3.746) is good, within the optimal 1-3 range. Ligand B (1.987) is a bit low, potentially hindering permeation.

**H-Bond Donors/Acceptors:** Ligand A (0 HBD, 5 HBA) is preferable to Ligand B (3 HBD, 4 HBA). Both are within acceptable limits, but fewer H-bonds generally improve permeability.

**QED:** Both ligands have similar QED values (0.744 and 0.724), indicating good drug-likeness.

**DILI:** Both ligands have similar DILI risk (63.823 and 63.978), placing them in a moderate risk category. This isn't a major differentiator.

**BBB:** Ligand A (96.937) has a *much* better BBB percentile than Ligand B (65.452). This is a critical factor for a CNS target like DRD2.

**Caco-2 Permeability:** Ligand A (-4.379) is better than Ligand B (-5.345), indicating better intestinal absorption.

**Aqueous Solubility:** Ligand A (-4.63) is better than Ligand B (-3.384), suggesting better solubility.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.207 and 0.483).

**Microsomal Clearance:** Ligand B (13.453) has significantly lower microsomal clearance than Ligand A (75.804), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand B (-27.388) has a longer in vitro half-life than Ligand A (-20.698).

**P-gp Efflux:** Ligand A (0.301) has lower P-gp efflux than Ligand B (0.046), which is favorable for CNS penetration.

**Binding Affinity:** Both ligands have similar binding affinities (-9.3 and -8.5 kcal/mol). While A is slightly better, the difference isn't substantial enough to outweigh other factors.

**Overall Assessment:**

Ligand A excels in key properties for a CNS-targeting GPCR ligand: TPSA, BBB, Caco-2 permeability, solubility, and P-gp efflux. While Ligand B has better metabolic stability and half-life, the superior BBB penetration and TPSA of Ligand A are more critical for DRD2 engagement. The slightly better affinity of A is a bonus.

Output:
1
2025-04-17 06:19:50,797 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B based on the provided guidelines, prioritizing GPCR-specific properties (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (347.34 Da) is slightly lower, which could be beneficial for permeability.

**TPSA:** Ligand A (39.08) is excellent for CNS penetration, well below the 90 A^2 threshold. Ligand B (66.4) is higher, but still reasonable, though less optimal for CNS targets.

**logP:** Ligand A (4.843) is a bit high, potentially leading to solubility issues or off-target effects. Ligand B (1.783) is within the optimal range (1-3).

**H-Bond Donors/Acceptors:** Ligand A (1 HBD, 4 HBA) and Ligand B (0 HBD, 5 HBA) both have acceptable counts.

**QED:** Both ligands have similar QED values (0.718 and 0.66), indicating good drug-likeness.

**DILI:** Ligand A (64.172) has a higher DILI risk than Ligand B (38.891). This is a significant negative for Ligand A.

**BBB:** Ligand B (76.813) has a substantially better BBB percentile than Ligand A (62.233). This is crucial for a CNS target like DRD2.

**Caco-2 Permeability:** Ligand A (-4.701) has a very poor Caco-2 permeability score, suggesting poor intestinal absorption. Ligand B (-5.249) is also poor, but slightly better.

**Aqueous Solubility:** Ligand A (-4.914) has very poor solubility. Ligand B (-1.625) is better, but still not ideal.

**hERG Inhibition:** Ligand A (0.951) has a slightly higher hERG risk than Ligand B (0.239).

**Microsomal Clearance:** Ligand B (36.826) has a higher microsomal clearance than Ligand A (24.021), indicating faster metabolism and potentially lower exposure.

**In vitro Half-Life:** Ligand A (-22.844) has a very short in vitro half-life. Ligand B (-1.914) is better, but still relatively short.

**P-gp Efflux:** Ligand A (0.839) has higher P-gp efflux liability than Ligand B (0.032). Lower P-gp efflux is preferred for CNS penetration.

**Binding Affinity:** Ligand A (-9.4 kcal/mol) has a significantly stronger binding affinity than Ligand B (-6.6 kcal/mol). This is a substantial advantage for Ligand A.

**Overall Assessment:**

Despite the superior binding affinity of Ligand A, its poor ADME properties (BBB, solubility, Caco-2 permeability, DILI, Pgp efflux, and half-life) are major drawbacks. Ligand B, while having a weaker affinity, presents a much more favorable ADME profile, particularly its significantly better BBB penetration and lower DILI risk. For a CNS target like DRD2, good brain penetration is paramount. The affinity difference, while substantial, might be overcome with further optimization of Ligand B. The high logP of Ligand A is also concerning.

Output:
1
2025-04-17 06:19:50,798 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (349.435 and 343.402 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (110.93) is higher than the preferred <90 for CNS targets, while Ligand B (71.09) is well within the range. This favors Ligand B.

**logP:** Ligand A (0.952) is a bit low, potentially hindering permeability. Ligand B (3.312) is optimal. This strongly favors Ligand B.

**H-Bond Donors/Acceptors:** Ligand A has 4 HBD and 4 HBA, which is acceptable. Ligand B has 2 HBD and 3 HBA, also acceptable.

**QED:** Both ligands have good QED scores (0.634 and 0.845), indicating drug-like properties.

**DILI:** Ligand A (16.867) has a much lower DILI risk than Ligand B (61.303). This favors Ligand A.

**BBB:** Ligand A (63.862) is below the desirable >70 for CNS targets, but Ligand B (73.517) exceeds it. This is a significant advantage for Ligand B.

**Caco-2 Permeability:** Ligand A (-5.662) has poor Caco-2 permeability, while Ligand B (-4.713) is slightly better, but still not great.

**Aqueous Solubility:** Ligand A (-1.084) and Ligand B (-3.364) both have poor aqueous solubility.

**hERG Inhibition:** Ligand A (0.363) has a lower hERG risk than Ligand B (0.771), which is preferable. This favors Ligand A.

**Microsomal Clearance:** Ligand A (-4.654) has a negative clearance, indicating very good metabolic stability. Ligand B (40.166) has a high clearance, suggesting rapid metabolism. This is a strong advantage for Ligand A.

**In vitro Half-Life:** Ligand A (9.209 hours) has a shorter half-life than Ligand B (33.482 hours). This favors Ligand B.

**P-gp Efflux:** Ligand A (0.017) has very low P-gp efflux, which is excellent for CNS penetration. Ligand B (0.353) has moderate P-gp efflux. This strongly favors Ligand A.

**Binding Affinity:** Ligand B (-8.7 kcal/mol) has a slightly better binding affinity than Ligand A (-8.2 kcal/mol), but the difference is not substantial enough to overcome the other significant ADME differences.

**Overall Assessment:**

Ligand B excels in BBB penetration and binding affinity, and has a longer half-life. However, it suffers from higher DILI risk, higher logP, higher P-gp efflux, and a significantly higher microsomal clearance. Ligand A has better metabolic stability (Cl_mic), lower DILI, lower P-gp efflux, and a lower hERG risk, which are all crucial for a CNS drug. While Ligand A's TPSA is slightly high and logP is a bit low, its superior ADME properties, particularly the low P-gp efflux and metabolic stability, outweigh these drawbacks, especially given the modest affinity difference.

Output:
1
2025-04-17 06:19:50,798 - INFO - Reasoning:

Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (345.443 and 352.475 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (71.53) is slightly higher than Ligand B (67.87), but both are below the 90 A^2 threshold desirable for CNS targets.

**3. logP:** Both ligands have excellent logP values (1.928 and 1.869), falling within the optimal 1-3 range.

**4. H-Bond Donors:** Both have 1 HBD, which is within the acceptable limit of <=5.

**5. H-Bond Acceptors:** Both have 4 HBA, which is within the acceptable limit of <=10.

**6. QED:** Ligand A (0.855) has a better QED score than Ligand B (0.759), indicating a more drug-like profile.

**7. DILI:** Both ligands have low DILI risk (23.032 and 20.085 percentiles), which is favorable.

**8. BBB:** Ligand B (71.501) has a slightly better BBB penetration percentile than Ligand A (64.211), but both are reasonably good for a CNS target.

**9. Caco-2 Permeability:** Ligand A (-4.701) and Ligand B (-4.704) have similar, very poor Caco-2 permeability. This is a significant concern.

**10. Aqueous Solubility:** Both ligands have very poor aqueous solubility (-2.002 and -1.943). This is also a significant concern.

**11. hERG Inhibition:** Both ligands have very low hERG inhibition liability (0.312 and 0.237), which is excellent.

**12. Microsomal Clearance:** Ligand A (28.89) has a lower microsomal clearance than Ligand B (42.31), suggesting better metabolic stability.

**13. In vitro Half-Life:** Ligand B (-17.21) has a significantly longer in vitro half-life than Ligand A (-4.119), which is a major advantage.

**14. P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.038 and 0.085), which is favorable for CNS penetration.

**15. Binding Affinity:** Both ligands have very similar and excellent binding affinities (-8.3 and -8.4 kcal/mol). The difference is negligible.

**Overall Assessment:**

While both ligands have good potency and acceptable safety profiles (DILI, hERG), their poor Caco-2 permeability and aqueous solubility are major drawbacks. Ligand B has a significant advantage in terms of *in vitro* half-life, which is crucial for maintaining therapeutic concentrations. The slightly better BBB score for Ligand B is also a plus, though both are already reasonably good. Ligand A has a slightly better QED and lower Cl_mic, but these are outweighed by the longer half-life of Ligand B.

Output:
1
2025-04-17 06:19:50,798 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (356.369 and 342.395 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (60.03) is significantly better than Ligand B (83.68). For CNS targets, we want TPSA <= 90, and A is comfortably within that, while B is approaching the upper limit.

**logP:** Both ligands have good logP values (2.744 and 3.155), falling within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Both have 1 HBD and 4 HBA, which are acceptable.

**QED:** Both have good QED scores (0.901 and 0.559), indicating drug-likeness. Ligand A is superior.

**DILI:** Ligand A (64.948) has a higher DILI risk than Ligand B (47.732). This favors B.

**BBB:** Ligand A (82.513) has a substantially better BBB penetration percentile than Ligand B (54.052). This is a *critical* advantage for a CNS target like DRD2.

**Caco-2 Permeability:** Both have negative Caco-2 values (-4.425 and -4.913), which is unusual and suggests poor permeability. However, these values are on a different scale and difficult to directly compare.

**Aqueous Solubility:** Both have negative solubility values (-2.43 and -3.112), suggesting poor solubility.

**hERG:** Both ligands have low hERG inhibition liability (0.497 and 0.521), which is good.

**Microsomal Clearance:** Ligand A (-5.252) has much lower (better) microsomal clearance than Ligand B (13.184), indicating greater metabolic stability.

**In vitro Half-Life:** Ligand A (-22.703) has a more negative (better) in vitro half-life than Ligand B (-18.962).

**P-gp Efflux:** Both have very low P-gp efflux liability (0.039 and 0.049), which is excellent for CNS penetration.

**Binding Affinity:** Both ligands have strong binding affinities (-9.0 and -8.2 kcal/mol). Ligand A is 0.8 kcal/mol more potent, which is a significant advantage.

**Overall Assessment:**

Considering the GPCR-specific priorities, Ligand A is the better candidate. Its superior BBB penetration (82.5 vs 54.0), significantly better metabolic stability (lower Cl_mic), longer half-life, and stronger binding affinity outweigh its slightly higher DILI risk. The TPSA is also much more favorable for CNS penetration. While both have poor solubility and permeability, the affinity and CNS-related properties of A are more compelling for a DRD2 target.

Output:
1
2025-04-17 06:19:50,798 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 drug candidates, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (367.471 and 361.511 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (102.76) is higher than the preferred <90 for CNS targets, while Ligand B (73.2) is well within the range. This is a significant advantage for Ligand B.

**3. logP:** Ligand A (0.583) is quite low, potentially hindering membrane permeability. Ligand B (2.653) is within the optimal 1-3 range. This favors Ligand B.

**4. H-Bond Donors:** Ligand A (3) is acceptable, while Ligand B (1) is even better, potentially improving permeability.

**5. H-Bond Acceptors:** Ligand A (6) is acceptable, and Ligand B (4) is also good.

**6. QED:** Both ligands have good QED scores (0.612 and 0.738, respectively), indicating drug-like properties.

**7. DILI:** Both have low DILI risk (34.858 and 30.593), which is positive.

**8. BBB:** Ligand A (33.23) has a very poor BBB penetration score, making it unlikely to reach the target in the CNS. Ligand B (62.117) is much better, though still not ideal (>70 is preferred). This is a major advantage for Ligand B.

**9. Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and potentially problematic. However, the scale is not specified, so it's hard to interpret.

**10. Aqueous Solubility:** Both have negative solubility values, which is also unusual.

**11. hERG Inhibition:** Both ligands show low hERG inhibition risk (0.171 and 0.478), which is good.

**12. Microsomal Clearance:** Ligand A (4.678) has lower clearance than Ligand B (55.838), suggesting better metabolic stability.

**13. In vitro Half-Life:** Ligand A (-7.908) has a much longer half-life than Ligand B (2.327), which is a significant advantage.

**14. P-gp Efflux:** Ligand A (0.03) has very low P-gp efflux, which is excellent for CNS penetration. Ligand B (0.063) is also low, but slightly higher.

**15. Binding Affinity:** Both ligands have very similar and strong binding affinities (-7.2 and -7.1 kcal/mol). The difference is negligible.

**Overall Assessment:**

Ligand B clearly outperforms Ligand A due to its significantly better TPSA, logP, and BBB penetration. While Ligand A has better metabolic stability (lower Cl_mic and longer half-life) and slightly lower P-gp efflux, these advantages are outweighed by the poor CNS penetration properties. For a CNS target like DRD2, BBB penetration is paramount, and Ligand B is far superior in this regard. The similar affinities mean that the ADME properties will be the deciding factor.

Output:
1
2025-04-17 06:19:50,798 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (349.431 Da) is slightly lower, which could be beneficial for permeability.

**TPSA:** Ligand A (91.65) is better than Ligand B (137.08). For CNS targets, TPSA should be <=90, so Ligand A is closer to this threshold. Ligand B is significantly higher, potentially hindering BBB penetration.

**logP:** Both ligands have acceptable logP values (A: 1.534, B: 1.699), falling within the optimal range of 1-3.

**H-Bond Donors/Acceptors:** Both have 2 HBD, which is good. Ligand A has 4 HBA, while Ligand B has 6. Both are acceptable (<=10), but Ligand A is slightly preferable.

**QED:** Ligand A (0.696) has a better QED score than Ligand B (0.467), indicating a more drug-like profile.

**DILI:** Ligand A (38.852) has a much lower DILI risk than Ligand B (68.437). This is a significant advantage for Ligand A.

**BBB:** Ligand A (58.24) has a lower BBB penetration percentile than Ligand B (67.623). While both are not ideal (>70 desirable), Ligand B is better in this regard.

**Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and difficult to interpret without knowing the scale. However, the magnitude of the negative value for Ligand A (-5.008) is less than that of Ligand B (-5.343), suggesting potentially slightly better permeability.

**Aqueous Solubility:** Both have negative solubility values, again unusual. Ligand A (-1.567) is slightly better than Ligand B (-3.424).

**hERG:** Both have low hERG inhibition liability (A: 0.421, B: 0.394), which is good.

**Microsomal Clearance:** Ligand A (-6.219) has a significantly lower (better) microsomal clearance than Ligand B (9.975), indicating better metabolic stability.

**In vitro Half-Life:** Ligand A (21.058) has a longer half-life than Ligand B (-8.257). This is a substantial advantage.

**P-gp Efflux:** Ligand A (0.173) has a lower P-gp efflux liability than Ligand B (0.054), which is preferable for CNS exposure.

**Binding Affinity:** Ligand A (-8.2 kcal/mol) has a slightly better binding affinity than Ligand B (-6.9 kcal/mol). This difference of 1.3 kcal/mol is significant and can outweigh some ADME drawbacks.

**Overall Assessment:**

Ligand A is superior to Ligand B. While Ligand B has a slightly better BBB score, Ligand A excels in most other crucial parameters, particularly DILI risk, metabolic stability (Cl_mic and t1/2), QED, and binding affinity. The lower TPSA and P-gp efflux of Ligand A are also beneficial for CNS penetration. The slightly better affinity of Ligand A further solidifies its position as the more promising candidate.

Output:
1
2025-04-17 06:19:50,798 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B based on the provided guidelines, prioritizing GPCR-specific properties (BBB, logP, Pgp, TPSA, and affinity).

**Ligand A:**

*   **MW:** 360.523 Da - Good (within 200-500 range)
*   **TPSA:** 41.9 A<sup>2</sup> - Excellent (well below 90 A<sup>2</sup> for CNS targets)
*   **logP:** 4.462 - Slightly high, potential for off-target effects or solubility issues.
*   **HBD:** 0 - Low, could impact solubility.
*   **HBA:** 4 - Good (<=10)
*   **QED:** 0.782 - Excellent (>=0.5)
*   **DILI:** 49.128 - Good (low risk)
*   **BBB:** 91.508 - Excellent (very high, ideal for CNS target)
*   **Caco-2:** -4.96 - Very poor permeability.
*   **Solubility:** -4.384 - Very poor solubility.
*   **hERG:** 0.787 - Low risk.
*   **Cl_mic:** 102.64 mL/min/kg - Moderate clearance, could be better.
*   **t1/2:** -12.213 hours - Very short half-life.
*   **Pgp:** 0.906 - Moderate efflux, could limit CNS exposure.
*   **Affinity:** -8.1 kcal/mol - Excellent.

**Ligand B:**

*   **MW:** 386.543 Da - Good (within 200-500 range)
*   **TPSA:** 86.63 A<sup>2</sup> - Acceptable, but approaching the upper limit for CNS targets.
*   **logP:** 1.3 - Good (within optimal range)
*   **HBD:** 1 - Good (<=5)
*   **HBA:** 7 - Good (<=10)
*   **QED:** 0.678 - Good (>=0.5)
*   **DILI:** 47.034 - Good (low risk)
*   **BBB:** 43.311 - Poor (below 70, not ideal for CNS)
*   **Caco-2:** -5.437 - Very poor permeability.
*   **Solubility:** -1.515 - Poor solubility.
*   **hERG:** 0.147 - Very low risk.
*   **Cl_mic:** 28.614 mL/min/kg - Low clearance, good metabolic stability.
*   **t1/2:** -3.062 hours - Short half-life, but better than Ligand A.
*   **Pgp:** 0.176 - Low efflux, favorable for CNS exposure.
*   **Affinity:** -6.4 kcal/mol - Good, but significantly weaker than Ligand A.

**Comparison & Decision:**

Ligand A has a significantly stronger binding affinity (-8.1 kcal/mol vs -6.4 kcal/mol) and excellent BBB penetration (91.5% vs 43.3%). These are the most critical factors for a CNS-targeting GPCR like DRD2. However, Ligand A suffers from very poor Caco-2 permeability, solubility, and a short half-life. Ligand B has better solubility and lower Pgp efflux, but its affinity and BBB penetration are considerably worse.

The large affinity difference between Ligand A and B is a major advantage for A. While the ADME properties of A are concerning, the potency advantage is substantial (over 1.5 kcal/mol). Optimization efforts could focus on improving the solubility, permeability, and metabolic stability of Ligand A. Ligand B, with its weaker affinity, would likely require more extensive structural modifications to achieve a viable drug candidate.

Output:
1
2025-04-17 06:19:50,798 - INFO - Reasoning:

Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (412.292 Da) is slightly higher than Ligand B (348.491 Da), but both are acceptable.

**2. TPSA:** This is crucial for CNS penetration. Ligand A (117.71) is higher than the preferred <90 for CNS targets, while Ligand B (76.02) is well within the optimal range. This is a significant advantage for Ligand B.

**3. logP:** Both ligands have good logP values (A: 2.211, B: 2.858), falling within the 1-3 range. Ligand B is slightly higher, which could be beneficial for membrane permeability.

**4. H-Bond Donors:** Both are acceptable (A: 3, B: 2).

**5. H-Bond Acceptors:** Both are acceptable (A: 6, B: 4).

**6. QED:** Both ligands have similar, good QED values (A: 0.642, B: 0.674), indicating a generally drug-like profile.

**7. DILI:** Ligand A (78.131) has a considerably higher DILI risk than Ligand B (25.281). This is a major concern for Ligand A.

**8. BBB:** Ligand B (74.176) has a much better BBB percentile than Ligand A (35.207). This is a critical factor for a CNS target like DRD2.

**9. Caco-2:** Both have negative values, which is unusual. Assuming these are percentile scores, Ligand A (-5.319) appears to have *worse* Caco-2 permeability than Ligand B (-4.853), though both are poor.

**10. Solubility:** Both have negative solubility values, indicating poor aqueous solubility. Ligand A (-2.927) is slightly worse than Ligand B (-2.655).

**11. hERG:** Both ligands have low hERG risk (A: 0.085, B: 0.716).

**12. Cl_mic:** Ligand A (22.376) has a lower microsomal clearance than Ligand B (44.952), suggesting better metabolic stability.

**13. t1/2:** Ligand A (-11.29) has a negative in vitro half-life, which is problematic. Ligand B (-2.78) is also negative, but less so. Both are concerning.

**14. Pgp:** Ligand A (0.024) has a much lower P-gp efflux liability than Ligand B (0.398). This is a positive for Ligand A, suggesting better CNS exposure.

**15. Binding Affinity:** Both ligands have similar, strong binding affinities (A: -8.8 kcal/mol, B: -8.1 kcal/mol). The difference of 0.7 kcal/mol is not substantial enough to outweigh other significant differences.

**Overall Assessment:**

Ligand B is the stronger candidate. While both have issues with solubility and in vitro half-life, Ligand B excels in the critical areas for a CNS GPCR target: TPSA, BBB penetration, and DILI risk. The slightly better logP also contributes. Ligand A's higher DILI risk and significantly lower BBB penetration are major drawbacks. Although Ligand A has better metabolic stability and lower P-gp efflux, these are less critical than the CNS-related properties in this context.

Output:
1
2025-04-17 06:19:50,798 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight (MW):** Both ligands (344.455 and 354.51 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Both ligands have TPSA values (49.85 and 49.41) below the 90 A^2 threshold for CNS targets, which is excellent.

**3. logP:** Ligand A (2.136) is within the optimal 1-3 range. Ligand B (4.065) is slightly higher, approaching the upper limit, which could potentially cause solubility issues.

**4. H-Bond Donors (HBD):** Both ligands are within the acceptable limit of <=5 (Ligand A: 0, Ligand B: 1).

**5. H-Bond Acceptors (HBA):** Both ligands are within the acceptable limit of <=10 (Ligand A: 3, Ligand B: 2).

**6. QED:** Both ligands have good QED scores (0.737 and 0.757), indicating good drug-like properties.

**7. DILI:** Ligand A (22.722) has a significantly lower DILI risk than Ligand B (41.024), which is a major advantage.

**8. BBB:** Both ligands have excellent BBB penetration (Ligand A: 85.731, Ligand B: 90.074), exceeding the desirable >70 threshold for CNS targets. Ligand B is slightly better.

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.328 and -4.326). These values are unusual and suggest poor permeability. However, since these are negative values, it's difficult to interpret directly.

**10. Aqueous Solubility:** Both ligands have very poor aqueous solubility (-2.001 and -4.315). This is a significant concern for bioavailability.

**11. hERG Inhibition:** Both ligands show low hERG inhibition risk (0.319 and 0.686).

**12. Microsomal Clearance (Cl_mic):** Ligand A (32.356) has a lower microsomal clearance than Ligand B (63.777), indicating better metabolic stability.

**13. In vitro Half-Life:** Ligand A (-11.731) has a negative half-life, which is not physically possible. Ligand B (1.81) has a very short half-life. Both are concerning.

**14. P-gp Efflux:** Both ligands have low P-gp efflux liability (0.142 and 0.356), which is favorable for CNS exposure.

**15. Binding Affinity:** Both ligands have comparable and strong binding affinities (-8.9 and -8.0 kcal/mol). Ligand A is slightly better.

**Overall Assessment:**

While both ligands have good binding affinity and BBB penetration, Ligand A is the more promising candidate. It has a significantly lower DILI risk, better metabolic stability (lower Cl_mic), and slightly better binding affinity. The negative half-life for Ligand A is a major concern, but the other advantages outweigh this issue. The poor solubility and Caco-2 permeability are shared concerns that would need to be addressed through formulation or structural modifications. Ligand B's higher logP and DILI risk make it less attractive.

Output:
0
2025-04-17 06:19:50,799 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, considering the provided guidelines and GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (365.459 and 348.447 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (98.14) is slightly higher than Ligand B (83.56). Both are below the 140 A^2 threshold for oral absorption, and closer to the desirable <90 A^2 for CNS targets. Ligand B is preferable here.

**3. logP:** Ligand A (0.978) is a bit low, potentially hindering permeation. Ligand B (1.681) is better, falling within the optimal 1-3 range. Ligand B is preferable.

**4. H-Bond Donors:** Both ligands have 2 HBD, which is within the acceptable limit of <=5.

**5. H-Bond Acceptors:** Ligand A has 7 HBA, while Ligand B has 5. Both are below the limit of <=10. Ligand B is preferable.

**6. QED:** Both ligands have similar QED values (0.68 and 0.629), both above the 0.5 threshold, indicating good drug-likeness.

**7. DILI:** Ligand A (63.397) has a higher DILI risk than Ligand B (49.283). Both are acceptable (<60 is good), but Ligand B is preferable.

**8. BBB:** Ligand B (62.117) has a significantly better BBB penetration percentile than Ligand A (49.942). This is *critical* for a CNS target like DRD2.

**9. Caco-2 Permeability:** Ligand A (-5.39) has worse Caco-2 permeability than Ligand B (-4.826). Lower (more negative) values indicate lower permeability. Ligand B is preferable.

**10. Aqueous Solubility:** Ligand A (-1.824) has slightly better solubility than Ligand B (-2.137).

**11. hERG Inhibition:** Both ligands have low hERG inhibition risk (0.537 and 0.505).

**12. Microsomal Clearance:** Ligand B (36.867) has a slightly lower microsomal clearance than Ligand A (28.832), indicating better metabolic stability.

**13. In vitro Half-Life:** Ligand B (40.775) has a slightly longer in vitro half-life than Ligand A (37.425).

**14. P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.184 and 0.049). Ligand B is preferable.

**15. Binding Affinity:** Ligand B (-7.1 kcal/mol) has a slightly better binding affinity than Ligand A (-7.9 kcal/mol). While both are excellent, the difference is not substantial enough to outweigh other factors.

**Overall Assessment:**

Ligand B consistently outperforms Ligand A across most critical parameters for a CNS-targeting GPCR. The most significant advantage is the much better BBB penetration (62.117 vs 49.942). It also has better logP, TPSA, DILI, Caco-2 permeability, metabolic stability, and P-gp efflux. While Ligand A has slightly better solubility, the other advantages of Ligand B are more important for CNS drug development.



Output:
1
2025-04-17 06:19:50,799 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (349.431 and 342.403 Da) are within the ideal 200-500 Da range.

**TPSA:** Ligand A (75.88) is excellent, well below the 90 A^2 threshold for CNS targets. Ligand B (101.8) is still reasonable but less optimal, exceeding the preferred threshold.

**logP:** Ligand A (1.854) is within the optimal 1-3 range. Ligand B (0.733) is a bit low, potentially hindering permeability.

**H-Bond Donors/Acceptors:** Ligand A (0 HBD, 5 HBA) is good. Ligand B (2 HBD, 6 HBA) is also acceptable.

**QED:** Both ligands have good QED scores (0.502 and 0.834), indicating drug-like properties.

**DILI:** Ligand A (17.255) has a much lower DILI risk than Ligand B (52.772), a significant advantage.

**BBB:** Ligand A (81.233) has a very good BBB penetration percentile, exceeding the desirable >70% threshold for CNS targets. Ligand B (47.15) is considerably lower and less favorable for CNS penetration.

**Caco-2 Permeability:** Ligand A (-4.901) and Ligand B (-5.247) both have negative Caco-2 values, which is unusual and suggests poor permeability. However, these values are on a scale where negative values are possible, and the absolute difference isn't huge.

**Aqueous Solubility:** Ligand A (-0.307) and Ligand B (-2.189) both have negative solubility values, indicating poor solubility. Ligand B is worse.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.278 and 0.087).

**Microsomal Clearance:** Ligand A (31.404) has a higher microsomal clearance than Ligand B (5.929), indicating lower metabolic stability.

**In vitro Half-Life:** Ligand A (-19.42) has a negative half-life, which is problematic. Ligand B (-3.218) is also negative, but less so. These values are likely on a scale where negative values are possible and indicate rapid degradation.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.047 and 0.01), which is excellent for CNS exposure.

**Binding Affinity:** Ligand B (-8.4 kcal/mol) has a significantly stronger binding affinity than Ligand A (-6.8 kcal/mol). This is a substantial difference (1.6 kcal/mol) and a major factor.

**Overall Assessment:**

While Ligand B has a superior binding affinity, Ligand A is a more promising drug candidate due to its significantly better BBB penetration, lower DILI risk, and more favorable TPSA. The lower affinity of Ligand A could potentially be optimized during lead optimization, but improving BBB penetration and reducing toxicity are often more challenging. The negative solubility and half-life values are concerning for both, but these are properties that can be addressed through formulation or structural modifications. Given the GPCR target and the importance of CNS penetration, Ligand A is the better choice.

Output:
1
2025-04-17 06:19:50,799 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (409.284 Da) is slightly higher than Ligand B (357.479 Da), but both are acceptable.

**TPSA:** Ligand A (102.3) is above the preferred <90 for CNS targets, while Ligand B (55.32) is well within the range. This is a significant advantage for Ligand B.

**logP:** Both ligands have acceptable logP values (Ligand A: 1.878, Ligand B: 3.535), falling within the optimal 1-3 range. Ligand B is slightly higher, which could potentially lead to solubility issues, but isn't a major concern.

**H-Bond Donors/Acceptors:** Ligand A has 2 HBD and 4 HBA, while Ligand B has 0 HBD and 5 HBA. Both are within acceptable limits (<=5 HBD and <=10 HBA).

**QED:** Both ligands have good QED scores (Ligand A: 0.725, Ligand B: 0.84), indicating good drug-like properties.

**DILI:** Ligand A (64.676) has a slightly higher DILI risk than Ligand B (61.07), but both are reasonably low.

**BBB:** Ligand B (78.519) has a significantly better BBB percentile than Ligand A (51.066). This is a *critical* advantage for a CNS target like DRD2.

**Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and suggests potential issues with intestinal absorption. However, the scale is not specified, so it's hard to interpret.

**Aqueous Solubility:** Both ligands have negative solubility values, which is also unusual and suggests poor solubility.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (Ligand A: 0.511, Ligand B: 0.428).

**Microsomal Clearance:** Ligand A (42.751) has lower microsomal clearance than Ligand B (85.163), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (57.175) has a longer in vitro half-life than Ligand B (-41.276). The negative value for Ligand B is concerning and suggests rapid degradation.

**P-gp Efflux:** Ligand A (0.088) has lower P-gp efflux liability than Ligand B (0.401), which is favorable for CNS penetration.

**Binding Affinity:** Ligand B (-9.0 kcal/mol) has a significantly stronger binding affinity than Ligand A (-7.9 kcal/mol). This difference of 1.1 kcal/mol is substantial and can outweigh some ADME drawbacks.

**Overall Assessment:**

Ligand B is the stronger candidate. While Ligand A has better metabolic stability and P-gp efflux, Ligand B's superior BBB penetration (78.5 vs 51.1) and significantly higher binding affinity (-9.0 vs -7.9 kcal/mol) are decisive advantages for a CNS-targeting GPCR like DRD2. The lower TPSA of Ligand B is also beneficial. The negative values for Caco-2 and Solubility are concerning for both, but the affinity and BBB advantages of Ligand B are more important in this context.

Output:
1
2025-04-17 06:19:50,799 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (368.455 and 342.483 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (104.73) is higher than the optimal <90 for CNS targets, but still potentially acceptable. Ligand B (58.2) is excellent, well below 90.

**logP:** Ligand A (1.45) is within the optimal 1-3 range. Ligand B (3.507) is at the higher end of the optimal range, but still acceptable.

**H-Bond Donors/Acceptors:** Ligand A has 3 HBD and 6 HBA, both within acceptable limits. Ligand B has 2 HBD and 2 HBA, also good.

**QED:** Both ligands have good QED scores (0.632 and 0.745), indicating good drug-like properties.

**DILI:** Both ligands have similar, acceptable DILI risk (48.43 and 48.468).

**BBB:** Ligand B (76.541) has a significantly better BBB percentile than Ligand A (65.219). This is a crucial advantage for a CNS target like DRD2.

**Caco-2 Permeability:** Ligand A (-4.945) shows poor Caco-2 permeability, while Ligand B (-4.79) is slightly better, but still not great.

**Aqueous Solubility:** Ligand A (-2.575) has slightly better aqueous solubility than Ligand B (-4.09).

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.123 and 0.616).

**Microsomal Clearance:** Ligand B (46.625) has lower microsomal clearance than Ligand A (56.252), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand B (15.827) has a significantly longer in vitro half-life than Ligand A (-11.204). This is a major advantage.

**P-gp Efflux:** Ligand A (0.07) has lower P-gp efflux liability than Ligand B (0.535), which is favorable for CNS penetration.

**Binding Affinity:** Ligand B (-9.0) has a significantly stronger binding affinity than Ligand A (-7.2). This >1.5 kcal/mol difference is a substantial advantage and can outweigh some ADME drawbacks.

**Overall Assessment:**

Ligand B is the stronger candidate. While Ligand A has slightly better solubility and P-gp efflux, Ligand B excels in the most critical areas for a CNS-targeting GPCR: BBB penetration, metabolic stability (lower Cl_mic, longer t1/2), and, most importantly, binding affinity. The superior affinity of Ligand B is a decisive factor. The TPSA of Ligand B is also much more favorable for CNS penetration.

Output:
1
2025-04-17 06:19:50,799 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (349.431 Da) is slightly lower, which could be beneficial for permeability. Ligand B (365.459 Da) is also good.

**TPSA:** Both ligands have TPSA values around 98-99, which is slightly above the optimal <90 for CNS targets, but still potentially acceptable.

**logP:** Ligand A (2.829) is within the optimal range (1-3). Ligand B (0.978) is at the lower end, potentially hindering permeability.

**H-Bond Donors/Acceptors:** Ligand A (HBD=1, HBA=6) and Ligand B (HBD=2, HBA=7) both have reasonable numbers of H-bond donors and acceptors, falling within acceptable limits.

**QED:** Both ligands have good QED scores (Ligand A: 0.51, Ligand B: 0.68), indicating drug-like properties.

**DILI:** Ligand A (45.56) has a better DILI score than Ligand B (63.397), indicating lower potential for liver injury.

**BBB:** This is a critical parameter for CNS targets. Ligand A (76.231) has a significantly better BBB percentile than Ligand B (49.942).

**Caco-2 Permeability:** Ligand A (-4.941) has a better Caco-2 permeability score than Ligand B (-5.39), suggesting better intestinal absorption.

**Aqueous Solubility:** Ligand A (-4.166) has a better aqueous solubility score than Ligand B (-1.824).

**hERG Inhibition:** Both ligands have low hERG inhibition liability (Ligand A: 0.917, Ligand B: 0.537), which is favorable.

**Microsomal Clearance:** Ligand A (43.467) has a higher microsomal clearance than Ligand B (28.832), meaning it is less metabolically stable.

**In vitro Half-Life:** Ligand B (37.425) has a significantly longer in vitro half-life than Ligand A (-4.441), which is a major advantage.

**P-gp Efflux:** Ligand A (0.362) has lower P-gp efflux liability than Ligand B (0.184), which is beneficial for CNS exposure.

**Binding Affinity:** Ligand B (-7.9 kcal/mol) has a slightly better binding affinity than Ligand A (-7.2 kcal/mol), which is a 0.7 kcal/mol difference.

**Overall Assessment:**

Ligand B has a better binding affinity and a significantly longer half-life. However, Ligand A has superior BBB penetration, lower DILI risk, better solubility, and lower P-gp efflux. Given the CNS target (DRD2), BBB penetration is paramount. The 0.7 kcal/mol difference in binding affinity, while noticeable, can potentially be optimized during lead optimization, whereas improving BBB penetration is often more challenging. The lower metabolic stability of Ligand A is a concern, but could be addressed with structural modifications. The better solubility and lower DILI risk of Ligand A are also beneficial.

Output:
1
2025-04-17 06:19:50,799 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (340.427 and 341.415 Da) fall comfortably within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (67.23) is significantly better than Ligand B (88.39). For CNS targets, we want TPSA <= 90, and A is closer to the optimal <=60 range. B is approaching a less desirable range.

**3. logP:** Both ligands have acceptable logP values (1.334 and 1.853), falling within the 1-3 range.

**4. H-Bond Donors:** Ligand A (1) is preferable to Ligand B (2). Lower HBD generally improves permeability.

**5. H-Bond Acceptors:** Ligand A (4) is preferable to Ligand B (5). Lower HBA generally improves permeability.

**6. QED:** Both ligands have similar and good QED values (0.826 and 0.831), indicating good drug-like properties.

**7. DILI:** Ligand B (74.603) has a considerably higher DILI risk than Ligand A (54.556). While both are above the ideal <40, A is much closer.

**8. BBB:** Ligand A (62.35) has a slightly better BBB penetration percentile than Ligand B (53.819). While neither is >70, A is better positioned. This is crucial for a CNS target like DRD2.

**9. Caco-2 Permeability:** Ligand A (-4.844) has slightly better Caco-2 permeability than Ligand B (-5.055), but both are poor.

**10. Aqueous Solubility:** Both have very poor aqueous solubility (-3.084 and -3.077). This is a concern for both, but not a deciding factor.

**11. hERG Inhibition:** Both ligands show very low hERG inhibition risk (0.258 and 0.238).

**12. Microsomal Clearance:** Ligand A (24.702) has a significantly lower microsomal clearance than Ligand B (36.393), suggesting better metabolic stability.

**13. In vitro Half-Life:** Ligand A (-4.32) has a much better in vitro half-life than Ligand B (17.266).

**14. P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.127 and 0.069).

**15. Binding Affinity:** Both ligands have identical binding affinities (-8.1 kcal/mol), which is excellent.

**Overall Assessment:**

Ligand A is superior to Ligand B. While both have excellent binding affinity, Ligand A demonstrates better ADME properties, particularly regarding TPSA, DILI risk, BBB penetration, microsomal clearance, and in vitro half-life. These factors are especially important for a CNS-targeting GPCR like DRD2. The lower TPSA and better BBB prediction for Ligand A are significant advantages. The lower DILI risk and improved metabolic stability further support its selection.

Output:
0
2025-04-17 06:19:50,799 - INFO - Batch 273 complete. Total preferences: 4368
2025-04-17 06:19:50,800 - INFO - Processing batch 274/512...
2025-04-17 06:20:31,976 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (346.431 and 349.439 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (76.46) is significantly better than Ligand B (95.39). For CNS targets, we want TPSA <= 90, so Ligand A is preferable.

**logP:** Ligand A (0.829) is slightly lower than optimal (1-3), but still acceptable. Ligand B (-1.054) is below 1, which could hinder permeation. Ligand A is better here.

**H-Bond Donors/Acceptors:** Ligand A (HBD=1, HBA=5) is better than Ligand B (HBD=2, HBA=7) in terms of balancing solubility and permeability. Both are within acceptable limits, but fewer H-bonds are generally preferred.

**QED:** Ligand A (0.774) has a higher QED score than Ligand B (0.552), indicating a more drug-like profile.

**DILI:** Both ligands have low DILI risk (Ligand A: 39.201, Ligand B: 34.161), which is good. Ligand B is slightly better.

**BBB:** Ligand A (55.642) and Ligand B (52.889) are both below the desirable threshold of >70 for CNS targets. However, this isn't a complete dealbreaker, as other factors can compensate.

**Caco-2 Permeability:** Both have negative Caco-2 values (-5.105 and -5.464), which is unusual and suggests poor permeability. This is a significant concern for both.

**Aqueous Solubility:** Both have negative solubility values (-1.086 and -0.946), also unusual and problematic.

**hERG Inhibition:** Both ligands have very low hERG inhibition risk (Ligand A: 0.095, Ligand B: 0.148).

**Microsomal Clearance:** Ligand A (12.632) has lower clearance than Ligand B (18.443), suggesting better metabolic stability.

**In Vitro Half-Life:** Ligand A (19.037 hours) has a longer half-life than Ligand B (11.965 hours), which is desirable.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (Ligand A: 0.022, Ligand B: 0.006).

**Binding Affinity:** Ligand B (-7.1 kcal/mol) has a slightly better binding affinity than Ligand A (-8.0 kcal/mol). While Ligand A has a better affinity, the difference is not substantial enough to outweigh the other factors.

**Overall Assessment:**

Ligand A is superior overall. While both ligands exhibit poor Caco-2 permeability and solubility, Ligand A has a significantly better TPSA, logP, QED, metabolic stability (lower Cl_mic, longer t1/2), and a slightly better BBB score. The slightly better affinity of Ligand B is not enough to compensate for these drawbacks, especially considering the importance of TPSA and logP for CNS penetration.

Output:
1
2025-04-17 06:20:31,977 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (348.487 and 342.395 Da) fall comfortably within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (49.85) is excellent, well below the 90 A^2 threshold for CNS targets. Ligand B (73.44) is still reasonable but less optimal, nearing the 140 A^2 limit for oral absorption and further from the ideal for CNS penetration.

**3. logP:** Ligand A (2.629) is within the optimal 1-3 range. Ligand B (3.931) is slightly higher, potentially increasing off-target interactions and decreasing solubility, but still acceptable.

**4. H-Bond Donors:** Both ligands have acceptable HBD counts (0 for A, 1 for B), well below the 5 threshold.

**5. H-Bond Acceptors:** Ligand A (3) and Ligand B (5) are both below the 10 threshold.

**6. QED:** Both ligands have good QED scores (0.665 and 0.852), indicating good drug-like properties.

**7. DILI:** Ligand A (34.781) has a lower DILI risk than Ligand B (68.399), which is approaching the higher risk threshold.

**8. BBB:** Both ligands have good BBB penetration (79.721% and 74.952%), exceeding the 70% target for CNS drugs. Ligand A is slightly better.

**9. Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and suggests a potential issue with the data or modeling. However, we'll proceed assuming this indicates poor permeability.

**10. Aqueous Solubility:** Both ligands have negative solubility values, which is also unusual and suggests poor solubility.

**11. hERG Inhibition:** Both ligands have low hERG inhibition risk (0.513 and 0.548).

**12. Microsomal Clearance:** Both ligands have similar microsomal clearance values (86.241 and 83.719), indicating moderate metabolic stability.

**13. In vitro Half-Life:** Ligand A (16.065 hours) has a significantly longer half-life than Ligand B (5.273 hours), which is a major advantage.

**14. P-gp Efflux:** Both ligands have low P-gp efflux liability (0.285 and 0.553), which is good for CNS exposure.

**15. Binding Affinity:** Ligand B (-9.2 kcal/mol) has a significantly stronger binding affinity than Ligand A (-7.1 kcal/mol) - a difference of 2.1 kcal/mol. This is a substantial advantage.

**Overall Assessment:**

While Ligand A has better TPSA, DILI risk, BBB, and half-life, the significantly stronger binding affinity of Ligand B (-9.2 vs -7.1 kcal/mol) is a decisive factor, especially for a GPCR target. The 2.1 kcal/mol difference is large enough to potentially overcome the slightly higher DILI risk and shorter half-life of Ligand B. The poor Caco-2 and solubility values are concerning for both, but can be addressed through formulation strategies. Given the CNS target, the good BBB penetration of both compounds is also positive.

Output:
1
2025-04-17 06:20:31,977 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (345.443 and 362.499 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (75.44) is higher than Ligand B (56.75). For CNS targets, we prefer TPSA <= 90, so both are acceptable, but B is better.

**logP:** Both ligands have good logP values (2.847 and 2.072), falling within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A has 1 HBD and 4 HBA, while Ligand B has 0 HBD and 5 HBA. Both are within acceptable limits (<=5 HBD and <=10 HBA).

**QED:** Both ligands have similar QED values (0.852 and 0.826), indicating good drug-likeness.

**DILI:** Both ligands have similar DILI risk (60.295 and 57.348), which is acceptable (below 60 is preferred, but these are not high risk).

**BBB:** Ligand B (85.731) has a significantly higher BBB percentile than Ligand A (74.254). This is a *critical* advantage for a CNS target like DRD2.

**Caco-2 Permeability:** Both have negative values (-4.835 and -4.625), which is unusual and suggests poor permeability. However, these values are on a scale where negative values are possible, and direct comparison is difficult without knowing the scale's specifics.

**Aqueous Solubility:** Both ligands have negative values (-3.142 and -2.879), suggesting poor aqueous solubility.

**hERG Inhibition:** Ligand A (0.154) has a slightly lower hERG inhibition liability than Ligand B (0.568), which is preferable.

**Microsomal Clearance:** Ligand B (59.507) has a slightly lower microsomal clearance than Ligand A (64.782), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand B (-0.72) has a slightly longer in vitro half-life than Ligand A (-27.179).

**P-gp Efflux:** Ligand A (0.367) has a lower P-gp efflux liability than Ligand B (0.245), which is better for CNS exposure.

**Binding Affinity:** Ligand B (-7.9 kcal/mol) has a *significantly* stronger binding affinity than Ligand A (-0.0 kcal/mol). This is the most important factor, and a difference of >1.5 kcal/mol can outweigh other drawbacks.

**Conclusion:**

While Ligand A has a slightly better hERG profile and P-gp efflux, Ligand B is the superior candidate. The dramatically stronger binding affinity (-7.9 vs -0.0 kcal/mol) is the most important factor. Furthermore, Ligand B has a significantly better BBB penetration (85.731 vs 74.254) and slightly better metabolic stability and half-life. The TPSA is also more favorable for CNS penetration. The solubility and Caco-2 permeability are poor for both, but the binding affinity and BBB of Ligand B are compelling enough to prioritize it.

Output:
1
2025-04-17 06:20:31,977 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (351.447 and 344.375 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (92.45) is better than Ligand B (95.14). Both are below the 90 A^2 threshold desirable for CNS targets, but A is closer.

**3. logP:** Ligand A (1.475) is slightly better than Ligand B (0.783), both are within the optimal 1-3 range.

**4. H-Bond Donors:** Ligand A (3) is better than Ligand B (0). While 0 is acceptable, a small number of HBDs can contribute to solubility.

**5. H-Bond Acceptors:** Ligand B (8) is better than Ligand A (4). Both are within the acceptable limit of 10.

**6. QED:** Ligand B (0.744) is better than Ligand A (0.557). A higher QED suggests better overall drug-likeness.

**7. DILI:** Ligand A (47.421) is significantly better than Ligand B (73.517). Lower DILI risk is crucial.

**8. BBB:** Ligand B (67.197) is better than Ligand A (53.121). Both are reasonably good, but B is closer to the >70% threshold for CNS targets.

**9. Caco-2:** Ligand A (-5.159) is better than Ligand B (-4.625). Higher Caco-2 permeability is preferred.

**10. Solubility:** Ligand A (-2.445) is better than Ligand B (-2.299).

**11. hERG:** Both ligands have very low hERG inhibition risk (0.48 and 0.052, respectively), which is excellent.

**12. Cl_mic:** Ligand B (40.018) is better than Ligand A (43.93). Lower microsomal clearance is preferred for metabolic stability.

**13. t1/2:** Ligand B (-7.467) is better than Ligand A (-3.348). A longer in vitro half-life is desirable.

**14. Pgp:** Both ligands have very low P-gp efflux liability (0.048 and 0.041, respectively), which is excellent for CNS penetration.

**15. Binding Affinity:** Ligand B (-8.7 kcal/mol) is significantly better than Ligand A (-7.4 kcal/mol). This 1.3 kcal/mol difference in binding affinity is substantial and can outweigh some ADME drawbacks.

**Overall Assessment:**

Ligand B has a significantly better binding affinity and a better BBB score, which are critical for a CNS GPCR target like DRD2. It also has a better QED, lower Cl_mic, and longer t1/2. While Ligand A has a slightly better TPSA and solubility, the advantages of Ligand B in affinity, BBB, and metabolic stability are more important. The DILI risk is higher for Ligand B, but still within an acceptable range.



Output:
1
2025-04-17 06:20:31,977 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (340.47 and 380.50 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (40.62) is significantly better than Ligand B (105.31). For CNS targets, TPSA should be <=90, and A is well within this range, while B is above. This is a substantial advantage for A.

**logP:** Both ligands have acceptable logP values (2.758 and 1.516, respectively), falling within the 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A (0 HBD, 2 HBA) is more favorable than Ligand B (1 HBD, 8 HBA). Lower HBD/HBA generally improves permeability.

**QED:** Both ligands have good QED scores (0.725 and 0.862), indicating good drug-like properties.

**DILI:** Ligand A (17.84) has a much lower DILI risk than Ligand B (63.67). This is a significant advantage for A.

**BBB:** Both ligands show good BBB penetration (87.48% and 82.98%), exceeding the 70% threshold for CNS targets.

**Caco-2 Permeability:** Ligand A (-4.793) and Ligand B (-5.24) both have negative values, which is unusual. Without knowing the scale, it's hard to interpret directly, but lower values generally suggest poorer permeability.

**Aqueous Solubility:** Both ligands have negative solubility values (-3.276 and -3.541), suggesting poor solubility. This could be a formulation challenge.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.368 and 0.474).

**Microsomal Clearance:** Ligand A (53.72) has higher microsomal clearance than Ligand B (17.05), indicating lower metabolic stability. This is a disadvantage for A.

**In vitro Half-Life:** Ligand B (6.842) has a longer in vitro half-life than Ligand A (-6.997). This is a significant advantage for B.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.328 and 0.198).

**Binding Affinity:** Ligand B (-7.4 kcal/mol) has a slightly better binding affinity than Ligand A (-8.8 kcal/mol). While A is stronger, the difference is not substantial enough to overcome other significant drawbacks.

**Overall Assessment:**

Ligand A excels in TPSA, DILI, and has a slightly better binding affinity. However, it suffers from higher microsomal clearance and a negative in vitro half-life. Ligand B, while having a higher TPSA, has a significantly better DILI profile, a longer half-life, and a reasonably good binding affinity. Considering the GPCR-specific priorities, the lower TPSA and DILI risk of Ligand A are attractive, but the metabolic liabilities are concerning. The slightly weaker binding of Ligand B is outweighed by its improved ADME properties, particularly the longer half-life and lower DILI risk.

Output:
1
2025-04-17 06:20:31,977 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (352.475 and 347.459 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (59.08) is significantly better than Ligand B (72.36). For CNS targets, we want TPSA <= 90, and ideally closer to 60. Ligand A is much closer to the ideal range.

**3. logP:** Both ligands have similar logP values (1.82 and 1.919), falling within the optimal 1-3 range.

**4. H-Bond Donors:** Ligand A (0) is better than Ligand B (2). Fewer H-bond donors generally improve permeability.

**5. H-Bond Acceptors:** Both ligands have the same number of H-bond acceptors (4).

**6. QED:** Both ligands have similar QED values (0.701 and 0.671), indicating good drug-likeness.

**7. DILI:** Ligand A (8.647) has a much lower DILI risk than Ligand B (21.753). This is a significant advantage.

**8. BBB:** Ligand A (83.908) has a better BBB penetration percentile than Ligand B (70.066). Both are reasonably good, but Ligand A is preferable for a CNS target like DRD2.

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.483 and -4.686), which is unusual and suggests poor permeability. However, these values are on a scale where negative values are possible.

**10. Aqueous Solubility:** Both ligands have negative solubility values (-0.912 and -1.902), suggesting poor aqueous solubility.

**11. hERG Inhibition:** Both ligands have low hERG inhibition liability (0.324 and 0.431).

**12. Microsomal Clearance:** Ligand A (28.218) has lower microsomal clearance than Ligand B (34.129), indicating better metabolic stability.

**13. In vitro Half-Life:** Ligand B (34.816) has a much longer in vitro half-life than Ligand A (-0.069). This is a significant advantage for Ligand B.

**14. P-gp Efflux:** Both ligands have low P-gp efflux liability (0.084 and 0.087).

**15. Binding Affinity:** Ligand A (-7.8) has a slightly better binding affinity than Ligand B (-7.5). While the difference is not huge, it's still a positive for Ligand A.

**Overall Assessment:**

Considering the GPCR-specific priorities, Ligand A is the better candidate. It has a significantly lower DILI risk, better TPSA, better BBB penetration, and better metabolic stability. The slightly better binding affinity also contributes. While Ligand B has a longer in vitro half-life, the other advantages of Ligand A outweigh this benefit, especially given the poor Caco-2 and solubility for both.

Output:
0
2025-04-17 06:20:31,977 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (345.403) is slightly lower, which could be beneficial for permeability. Ligand B (364.555) is also good.

**TPSA:** Ligand A (79.7) is better than Ligand B (42.43). For CNS targets, we want TPSA <= 90, both are within this range, but A is closer to the upper limit. B is excellent.

**logP:** Ligand A (-0.337) is quite low, potentially hindering membrane permeability. Ligand B (4.167) is high, potentially causing solubility issues and off-target effects. This is a significant drawback for B.

**H-Bond Donors:** Both ligands have 1 HBD, which is within the acceptable limit of <=5.

**H-Bond Acceptors:** Ligand A has 6 HBA, and Ligand B has 4. Both are within the acceptable limit of <=10.

**QED:** Both ligands have QED values above 0.7, indicating good drug-likeness.

**DILI:** Both ligands have low DILI risk (Ligand A: 39.977, Ligand B: 37.611), which is favorable.

**BBB:** Ligand A (67.623) and Ligand B (65.18) are both reasonably good, but below the desirable >70 for CNS targets.

**Caco-2 Permeability:** Ligand A (-5.08) is very poor, indicating extremely low intestinal absorption. Ligand B (-4.711) is also poor, but slightly better than A.

**Aqueous Solubility:** Both ligands have negative solubility values (-2.451 and -4.527), suggesting poor aqueous solubility.

**hERG Inhibition:** Ligand A (0.341) has a slightly lower hERG risk than Ligand B (0.822), which is preferable.

**Microsomal Clearance:** Ligand A (26.605) has a lower clearance than Ligand B (71.946), indicating better metabolic stability.

**In vitro Half-Life:** Ligand A (7.524) has a shorter half-life than Ligand B (31.426).

**P-gp Efflux:** Ligand A (0.014) has very low P-gp efflux liability, which is excellent for CNS penetration. Ligand B (0.573) is higher, but still relatively low.

**Binding Affinity:** Both ligands have very similar and excellent binding affinities (-7.2 and -7.3 kcal/mol). The difference is negligible.

**Overall Assessment:**

Ligand A has a better TPSA, lower clearance, and significantly lower P-gp efflux, which are all beneficial for CNS penetration. However, its logP is very low and Caco-2 permeability is extremely poor. Ligand B has a higher logP, which is a concern, but better Caco-2 permeability. Considering the GPCR-specific priorities, BBB penetration is crucial. While both are below the ideal threshold, Ligand A's lower P-gp efflux could potentially compensate for its lower BBB score, allowing for better brain exposure. The very poor Caco-2 permeability of A is a major concern for oral bioavailability, but for a CNS target, this is less critical than BBB penetration. The high logP of B is a significant drawback.

Output:
0
2025-04-17 06:20:31,977 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (352.391 Da) is slightly lower, which could be beneficial for permeability.

**TPSA:** Ligand A (132.81) is closer to the desirable threshold of 90 for CNS targets than Ligand B (61.44). Ligand B is significantly lower, which is generally good for BBB penetration, but *too* low can sometimes reduce binding affinity.

**logP:** Ligand A (-1.131) is a bit low, potentially hindering permeation. Ligand B (2.108) is within the optimal range (1-3). This is a significant advantage for Ligand B.

**H-Bond Donors/Acceptors:** Ligand A has 5 HBD and 7 HBA, while Ligand B has 2 HBD and 5 HBA. Both are within acceptable limits.

**QED:** Both ligands have reasonable QED values (A: 0.419, B: 0.679), with Ligand B being better.

**DILI:** Ligand A (62.466) has a higher DILI risk than Ligand B (44.591), though both are reasonably acceptable.

**BBB:** Ligand B (68.825) has a substantially better BBB percentile than Ligand A (35.595). This is a critical advantage for a CNS target like DRD2.

**Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and suggests poor permeability, but the scale is not defined. We'll have to rely on other parameters for permeability assessment.

**Aqueous Solubility:** Both have negative solubility values, also unusual.

**hERG:** Both ligands have low hERG inhibition liability, which is good.

**Microsomal Clearance:** Ligand A (-13.906) has *much* lower microsomal clearance than Ligand B (54.236), indicating better metabolic stability. This is a significant advantage for Ligand A.

**In vitro Half-Life:** Ligand B (16.86) has a longer half-life than Ligand A (7.88).

**P-gp Efflux:** Ligand A (0.004) has very low P-gp efflux liability, which is excellent for CNS penetration. Ligand B (0.177) is also low, but higher than A.

**Binding Affinity:** Ligand B (-8.4 kcal/mol) has a stronger binding affinity than Ligand A (-7.4 kcal/mol). The difference of 1 kcal/mol is substantial and can often outweigh minor ADME drawbacks.

**Overall Assessment:**

Ligand B excels in BBB penetration and binding affinity, both crucial for a DRD2 ligand. Its logP is also optimal. While its metabolic stability is worse than Ligand A, the significantly stronger binding affinity is a major advantage. Ligand A has better metabolic stability and P-gp efflux, but its lower BBB penetration and weaker binding affinity are significant drawbacks. Given the GPCR-specific priorities, the stronger affinity and better BBB of Ligand B are more important.

Output:
1
2025-04-17 06:20:31,978 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 drug candidates, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (358.435 and 350.503 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (119.33) is borderline for CNS penetration, being slightly above the preferred <90, but acceptable. Ligand B (78.43) is excellent for CNS penetration.

**logP:** Ligand A (-0.987) is a bit low, potentially hindering membrane permeability. Ligand B (2.661) is within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A has 4 HBD and 6 HBA, which are reasonable. Ligand B has 3 HBD and 3 HBA, also good.

**QED:** Both ligands have good QED scores (0.501 and 0.667), indicating drug-like properties.

**DILI:** Ligand A (14.114) has a very low DILI risk, which is excellent. Ligand B (30.361) is still relatively low, but higher than Ligand A.

**BBB:** Ligand A (19.581) has poor BBB penetration, a major drawback for a CNS target like DRD2. Ligand B (30.748) is also not ideal, but significantly better than Ligand A.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.254 and -5.034), which is unusual and suggests poor permeability. This is concerning for both.

**Aqueous Solubility:** Both ligands have negative solubility values (-0.738 and -3.312), indicating poor aqueous solubility. This could pose formulation challenges.

**hERG Inhibition:** Both ligands have low hERG risk (0.14 and 0.328).

**Microsomal Clearance:** Ligand A (-20.099) has a very low (negative) microsomal clearance, suggesting high metabolic stability. Ligand B (13.091) has a moderate clearance.

**In vitro Half-Life:** Ligand A (-15.166) has a negative half-life, which is not realistic. Ligand B (8.764) has a reasonable half-life.

**P-gp Efflux:** Ligand A (0.012) has very low P-gp efflux, which is favorable for CNS penetration. Ligand B (0.392) has slightly higher efflux, but still relatively low.

**Binding Affinity:** Ligand A (-8.0) has significantly better binding affinity than Ligand B (0.0). This is a substantial advantage.

**Overall Assessment:**

Despite Ligand A's superior binding affinity, its extremely poor BBB penetration and unrealistic half-life are major concerns. While its low DILI and P-gp efflux are positives, they are outweighed by the permeability and CNS penetration issues. Ligand B, while having weaker affinity, has a more favorable profile regarding TPSA, logP, and a more reasonable half-life. The Caco-2 and solubility are concerning for both, but can potentially be addressed with formulation strategies. Given the CNS target, BBB penetration is critical, and Ligand B is clearly better in this regard. The large affinity difference is significant, but not insurmountable in optimization.

Output:
1
2025-04-17 06:20:31,978 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (347.5 and 341.5 Da) fall comfortably within the ideal 200-500 Da range.

**TPSA:** Ligand A (55.4) is significantly better than Ligand B (68.02). For CNS targets, we want TPSA <= 90, and ideally lower. Ligand A is much closer to the ideal range.

**logP:** Both ligands have good logP values (3.833 and 3.778), falling within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Both have 1 HBD, which is good. Ligand A has 3 HBA, and Ligand B has 4. Both are acceptable, being under the 10 limit.

**QED:** Both ligands have good QED scores (0.769 and 0.898), indicating good drug-like properties.

**DILI:** Ligand A (15.781) has a much lower DILI risk than Ligand B (35.828). This is a significant advantage.

**BBB:** Ligand B (84.451) has a substantially better BBB penetration score than Ligand A (55.293). This is a critical factor for a CNS target like DRD2.

**Caco-2 Permeability:** Both have negative Caco-2 values (-4.528 and -4.773), which is unusual and suggests poor permeability. However, these values are on a scale where negative values are possible, and direct comparison is difficult without knowing the scale's specifics.

**Aqueous Solubility:** Both ligands have very poor aqueous solubility (-4.415 and -4.416). This could be a formulation challenge.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.58 and 0.2).

**Microsomal Clearance:** Ligand A (101.984) has higher microsomal clearance than Ligand B (66.784), indicating faster metabolism and potentially lower *in vivo* exposure.

**In vitro Half-Life:** Ligand B (-6.644) has a longer in vitro half-life than Ligand A (-12.632).

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.268 and 0.315).

**Binding Affinity:** Ligand B (-9.8 kcal/mol) has a significantly stronger binding affinity than Ligand A (-8.7 kcal/mol). This is a 1.1 kcal/mol difference, which is substantial and can outweigh some ADME drawbacks.

**Overall Assessment:**

The key trade-offs are: Ligand B has superior BBB penetration and binding affinity, while Ligand A has a lower DILI risk and better TPSA. Given that this is a CNS target (DRD2), BBB penetration is paramount. The significantly stronger binding affinity of Ligand B is also a major advantage. While Ligand A's lower DILI is desirable, the difference isn't large enough to overcome the benefits of Ligand B's BBB and affinity. The poor solubility and Caco-2 permeability are concerns for both, but can potentially be addressed through formulation strategies.

Output:
1
2025-04-17 06:20:31,978 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 drug candidates, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (340.427 and 350.503 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (83.98) is better than Ligand B (63.45) as it is closer to the 90 A^2 threshold for CNS targets. Ligand B is excellent.

**3. logP:** Ligand A (1.523) is within the optimal range (1-3). Ligand B (4.421) is a bit high, potentially leading to solubility issues and off-target interactions.

**4. H-Bond Donors:** Ligand A (2) and Ligand B (0) are both acceptable, below the threshold of 5.

**5. H-Bond Acceptors:** Ligand A (4) and Ligand B (3) are both acceptable, below the threshold of 10.

**6. QED:** Ligand A (0.769) is significantly better than Ligand B (0.481), indicating a more drug-like profile.

**7. DILI:** Ligand A (44.552) has a lower DILI risk than Ligand B (16.44), both are good.

**8. BBB:** Ligand B (77.2) has a much better BBB penetration percentile than Ligand A (48.662). This is a critical factor for a CNS target like DRD2.

**9. Caco-2 Permeability:** Both are negative, indicating poor permeability.

**10. Aqueous Solubility:** Both are negative, indicating poor solubility.

**11. hERG Inhibition:** Ligand A (0.155) has a lower hERG inhibition liability than Ligand B (0.784), which is preferable.

**12. Microsomal Clearance:** Ligand A (15.243) has a lower microsomal clearance than Ligand B (88.164), suggesting better metabolic stability.

**13. In vitro Half-Life:** Ligand A (-18.296) has a negative half-life, which is not possible. Ligand B (6.297) has a reasonable half-life. This is a major red flag for Ligand A.

**14. P-gp Efflux:** Ligand A (0.024) has a much lower P-gp efflux liability than Ligand B (0.791), which is favorable for CNS penetration.

**15. Binding Affinity:** Ligand A (-8.1) has a significantly stronger binding affinity than Ligand B (0.0). This is a substantial advantage.

**Overall Assessment:**

Ligand A has a superior binding affinity, better QED, lower DILI, lower hERG, lower P-gp efflux, and lower microsomal clearance. However, the negative in vitro half-life is a critical flaw. Ligand B excels in BBB penetration, but suffers from a higher logP, lower QED, and weaker binding affinity.

Despite the strong affinity of Ligand A, the negative half-life is a showstopper. A negative half-life is not physically possible and indicates a problem with the data or the molecule's stability. Ligand B, while not ideal, has a reasonable profile and a good BBB score, making it the more viable candidate *given the provided data*.

Output:
1
2025-04-17 06:20:31,978 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (355.366 and 349.391 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (100.89) and Ligand B (96.77) are both below the 140 A^2 threshold for good oral absorption and, crucially, below the 90 A^2 threshold desirable for CNS targets.

**logP:** Ligand A (0.084) is slightly below the optimal 1-3 range, potentially hindering permeation. Ligand B (-1.002) is also below the optimal range, and even lower, posing a more significant concern for permeability.

**H-Bond Donors/Acceptors:** Both ligands have 1 HBD and 6 HBA, which are within acceptable limits (<=5 and <=10 respectively).

**QED:** Both ligands have similar QED values (0.701 and 0.703), indicating good drug-like properties.

**DILI:** Both ligands have DILI risk around the 55-57 percentile, which is acceptable (below 60).

**BBB:** Ligand A (76.541) has a significantly better BBB penetration percentile than Ligand B (53.432). This is a *critical* factor for a CNS target like DRD2.

**Caco-2 Permeability:** Ligand A (-4.985) and Ligand B (-4.753) have negative Caco-2 values, which is unusual and suggests poor permeability. However, these values are on a scale where negative values are possible, and direct comparison is difficult without knowing the scale's specifics.

**Aqueous Solubility:** Both ligands have very poor aqueous solubility (-2.173 and -1.39). This is a concern for formulation and bioavailability.

**hERG Inhibition:** Both ligands show very low hERG inhibition risk (0.39 and 0.042).

**Microsomal Clearance:** Ligand A (-25.925) has a higher (worse) microsomal clearance than Ligand B (-9.767), indicating lower metabolic stability.

**In vitro Half-Life:** Ligand B (-3.92) has a shorter in vitro half-life than Ligand A (6.942).

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.034 and 0.012), which is favorable for CNS penetration.

**Binding Affinity:** Both ligands have excellent binding affinities (-7.7 and -7.5 kcal/mol), which are well below the -7.0 kcal/mol threshold. The difference of 0.2 kcal/mol is not substantial enough to outweigh other factors.

**Conclusion:**

Considering all factors, especially the GPCR-specific priorities, **Ligand A is the more promising candidate.** While both have poor solubility and Caco-2 permeability, Ligand A's significantly better BBB penetration (76.541 vs 53.432) is a decisive advantage for a CNS-targeting drug. Although Ligand A has a higher microsomal clearance, the difference isn't large enough to offset the substantial benefit of improved BBB penetration.

Output:
1
2025-04-17 06:20:31,978 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 drug candidates, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight (MW):** Both ligands (372.575 and 359.501 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (78.43) is higher than the preferred <90 for CNS targets, but still reasonable. Ligand B (29.54) is excellent, well below the threshold.

**3. logP:** Ligand A (2.716) is within the optimal 1-3 range. Ligand B (4.604) is slightly above, potentially raising concerns about solubility and off-target effects, but not drastically.

**4. H-Bond Donors (HBD):** Ligand A (3) is good. Ligand B (0) is also acceptable, though very low HBD can sometimes hinder solubility.

**5. H-Bond Acceptors (HBA):** Ligand A (4) is good. Ligand B (2) is also acceptable.

**6. QED:** Both ligands (0.581 and 0.57) have good drug-likeness scores, exceeding the 0.5 threshold.

**7. DILI:** Ligand A (29.081) has a lower DILI risk than Ligand B (18.651), which is preferable.

**8. BBB:** This is a critical parameter for CNS targets. Ligand A (44.397) is moderate, while Ligand B (96.123) is *excellent*, exceeding the desirable >70 threshold. This is a major advantage for Ligand B.

**9. Caco-2 Permeability:** Ligand A (-5.292) is poor, indicating low intestinal absorption. Ligand B (-4.131) is also poor, but slightly better than A.

**10. Aqueous Solubility:** Both ligands have very poor aqueous solubility (-3.015 and -4.83 respectively). This is a significant concern for both.

**11. hERG Inhibition:** Ligand A (0.341) has a lower hERG risk than Ligand B (0.898), which is preferable.

**12. Microsomal Clearance:** Ligand A (45.498) has lower clearance, suggesting better metabolic stability than Ligand B (81.855).

**13. In vitro Half-Life:** Ligand B (28.122) has a longer half-life than Ligand A (16.095), which is beneficial.

**14. P-gp Efflux:** Ligand A (0.1) has lower P-gp efflux, which is good for CNS penetration. Ligand B (0.641) has higher efflux, potentially limiting CNS exposure.

**15. Binding Affinity:** Both ligands have excellent binding affinities (-7.2 and -7.3 kcal/mol). Ligand B is slightly better, but the difference is small.

**Overall Assessment:**

Ligand B excels in BBB penetration (96.123), a critical factor for a CNS target like DRD2. It also has a longer half-life. However, it has a higher logP, higher DILI risk, and higher P-gp efflux. Ligand A has better metabolic stability, lower DILI and hERG risk, and lower P-gp efflux, but its BBB penetration is significantly lower and Caco-2 permeability is worse.

Given the importance of BBB penetration for CNS drug development, and the relatively small difference in binding affinity, Ligand B is the more promising candidate *despite* its drawbacks. The solubility issues of both compounds would need to be addressed through formulation strategies.

Output:
1
2025-04-17 06:20:31,978 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (360.523 and 397.85 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (72.19) is better than Ligand B (53.51) as it is closer to the ideal <90 for CNS targets.

**3. logP:** Both ligands have similar logP values (3.471 and 3.448), falling within the optimal 1-3 range.

**4. H-Bond Donors:** Ligand A has 2 HBD, and Ligand B has 0. Both are acceptable (<=5).

**5. H-Bond Acceptors:** Ligand A has 3 HBA, and Ligand B has 4. Both are acceptable (<=10).

**6. QED:** Both ligands have similar QED values (0.794 and 0.785), indicating good drug-likeness.

**7. DILI:** Ligand A (43.66) has a lower DILI risk than Ligand B (61.691). This is a significant advantage.

**8. BBB:** Ligand B (89.104) has a substantially higher BBB penetration percentile than Ligand A (46.375). This is a *major* advantage for a CNS target like DRD2.

**9. Caco-2 Permeability:** Ligand A (-5.158) has a worse Caco-2 permeability than Ligand B (-4.583), but both are negative, indicating poor permeability.

**10. Aqueous Solubility:** Ligand A (-3.946) has slightly worse solubility than Ligand B (-4.253), but both are poor.

**11. hERG Inhibition:** Ligand A (0.838) has a slightly higher hERG risk than Ligand B (0.461). Lower is better.

**12. Microsomal Clearance:** Ligand B (40.168) has lower microsomal clearance than Ligand A (55.504), suggesting better metabolic stability.

**13. In vitro Half-Life:** Ligand B (-4.469) has a longer in vitro half-life than Ligand A (-6.818).

**14. P-gp Efflux:** Ligand B (0.402) has lower P-gp efflux than Ligand A (0.28), indicating better potential for CNS exposure.

**15. Binding Affinity:** Ligand A (-8.2 kcal/mol) has a significantly stronger binding affinity than Ligand B (-0.0 kcal/mol). This is a *critical* advantage, potentially outweighing some ADME drawbacks.

**Overall Assessment:**

While Ligand B excels in BBB penetration, P-gp efflux, metabolic stability, and half-life, the *massive* difference in binding affinity (-8.2 vs 0.0 kcal/mol) makes Ligand A the far more promising candidate. A strong binding affinity is paramount for GPCR targets, and the 8.2 kcal/mol difference is substantial. The slightly higher DILI and lower BBB of Ligand A are concerns, but these could potentially be addressed through further optimization without sacrificing the crucial binding affinity. The poor Caco-2 and solubility are also concerns, but less critical for a CNS target where BBB penetration is prioritized.

Output:
1
2025-04-17 06:20:31,979 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (343.471 and 350.459 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (62.3) is excellent, well below the 90 A^2 threshold for CNS targets. Ligand B (87.66) is higher but still reasonable, though less favorable.

**logP:** Ligand A (2.996) is optimal (1-3). Ligand B (1.114) is at the lower end, potentially hindering permeability.

**H-Bond Donors/Acceptors:** Ligand A (HBD=1, HBA=3) is good. Ligand B (HBD=3, HBA=4) is also acceptable, but slightly higher.

**QED:** Both ligands have acceptable QED values (0.738 and 0.67), indicating good drug-like properties.

**DILI:** Ligand A (11.361) has a much lower DILI risk than Ligand B (23.769), which is a significant advantage.

**BBB:** Ligand A (76.347) has a good BBB penetration score, exceeding the 70% threshold for CNS targets. Ligand B (35.673) is considerably lower, suggesting poor brain exposure. This is a critical disadvantage for a DRD2 ligand.

**Caco-2 Permeability:** Ligand A (-4.8) and Ligand B (-5.401) both have negative values, which is unusual. However, the scale is not specified, so it's difficult to interpret.

**Aqueous Solubility:** Both ligands have negative solubility values (-1.705 and -1.453), which is also unusual and suggests poor solubility.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.359 and 0.14).

**Microsomal Clearance:** Ligand A (49.379) has a moderate clearance, while Ligand B (-15.738) has a negative clearance, which is impossible and likely an error in the data.

**In vitro Half-Life:** Ligand A (-14.813) has a negative half-life, which is impossible and likely an error in the data. Ligand B (30.379) has a reasonable half-life.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.138 and 0.041), which is favorable for CNS penetration.

**Binding Affinity:** Both ligands have strong binding affinities (-8.7 and -9.0 kcal/mol). Ligand B is slightly better, but the difference is small.

**Overall Assessment:**

Ligand A is superior due to its significantly better BBB penetration (76.35% vs 35.67%), lower DILI risk (11.36% vs 23.77%), and more favorable TPSA (62.3 vs 87.66). While both have issues with solubility and potentially Caco-2 permeability, the CNS target necessitates prioritizing BBB. The negative values for clearance and half-life for Ligand A are concerning and suggest data errors. However, even ignoring those, the BBB advantage of Ligand A is decisive.

Output:
1
2025-04-17 06:20:31,979 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (361.423 and 368.905 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (99.5) is higher than Ligand B (69.64). For CNS targets, we prefer TPSA <= 90. Ligand B is better in this regard.

**3. logP:** Both ligands have good logP values (1.316 and 2.568), falling within the optimal range of 1-3. Ligand B is slightly higher, potentially offering better membrane permeability.

**4. H-Bond Donors:** Ligand A (1) and Ligand B (2) are both acceptable, being less than 5.

**5. H-Bond Acceptors:** Ligand A (6) and Ligand B (3) are both acceptable, being less than 10.

**6. QED:** Both ligands have good QED values (0.608 and 0.783), indicating good drug-like properties. Ligand B is slightly better.

**7. DILI:** Ligand A (61.807) has a higher DILI risk than Ligand B (24.157). This is a significant advantage for Ligand B.

**8. BBB:** Both ligands have reasonable BBB penetration (56.65 and 60.527). While neither exceeds the desirable >70, Ligand B is slightly better.

**9. Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and suggests poor permeability. This is a concern for both.

**10. Aqueous Solubility:** Both have negative solubility values, which is also unusual and suggests poor solubility. This is a concern for both.

**11. hERG Inhibition:** Both ligands show low hERG inhibition liability (0.44 and 0.338), which is good.

**12. Microsomal Clearance:** Ligand A (42.299) has higher microsomal clearance than Ligand B (38.467), indicating lower metabolic stability. Ligand B is preferable.

**13. In vitro Half-Life:** Ligand A (20.832) has a longer half-life than Ligand B (2.357). This is a positive for Ligand A.

**14. P-gp Efflux:** Both ligands have low P-gp efflux liability (0.169 and 0.226), which is good for CNS penetration.

**15. Binding Affinity:** Ligand B (-8.3 kcal/mol) has a slightly better binding affinity than Ligand A (-8.0 kcal/mol). While the difference is small, it's still a positive for Ligand B.

**Overall Assessment:**

Considering the GPCR-specific priorities, Ligand B is the more promising candidate. It has a lower TPSA, lower DILI risk, better logP, better metabolic stability (lower Cl_mic), and slightly better binding affinity. Although both have issues with Caco-2 and solubility, the ADME profile of Ligand B is generally superior, especially regarding safety (DILI) and CNS penetration potential. The longer half-life of Ligand A is a benefit, but the other advantages of Ligand B outweigh this.

Output:
1
2025-04-17 06:20:31,979 - INFO - Batch 274 complete. Total preferences: 4384
2025-04-17 06:20:31,979 - INFO - Processing batch 275/512...
2025-04-17 06:21:22,048 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (346.387 and 352.41 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (111.63) is slightly above the optimal <90 for CNS targets, while Ligand B (83.56) is well within the desired range. This favors Ligand B.

**logP:** Ligand A (0.095) is quite low, potentially hindering membrane permeability. Ligand B (1.677) is within the optimal 1-3 range. This is a significant advantage for Ligand B.

**H-Bond Donors/Acceptors:** Ligand A has 3 HBD and 5 HBA, acceptable values. Ligand B has 2 HBD and 4 HBA, also acceptable. No clear advantage here.

**QED:** Both ligands have similar QED values (0.672 and 0.662), indicating good drug-likeness.

**DILI:** Ligand A (58.395) has a higher DILI risk than Ligand B (41.915), although both are reasonably low.

**BBB:** This is crucial for a CNS target. Ligand B (85.072) has a significantly higher BBB penetration percentile than Ligand A (29.779). This is a major advantage for Ligand B.

**Caco-2 Permeability:** Ligand A (-4.962) and Ligand B (-4.347) both have negative values, which is unusual and suggests poor permeability. However, the scale isn't fully defined, so it's hard to draw strong conclusions.

**Aqueous Solubility:** Both ligands have similar, very poor aqueous solubility (-2.374 and -2.273). This could pose formulation challenges.

**hERG Inhibition:** Ligand A (0.035) shows a very low hERG inhibition risk, slightly better than Ligand B (0.291).

**Microsomal Clearance:** Ligand A (8.088) has a lower (better) microsomal clearance than Ligand B (51.601), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (-45.004) has a much shorter in vitro half-life than Ligand B (-14.961). This is a disadvantage for Ligand A.

**P-gp Efflux:** Ligand A (0.004) has very low P-gp efflux liability, which is excellent. Ligand B (0.035) is also low, but higher than Ligand A.

**Binding Affinity:** Ligand B (-7.3) has a slightly better binding affinity than Ligand A (-8.3). While A is better, the difference is not huge.

**Overall Assessment:**

Ligand B clearly outperforms Ligand A, especially regarding critical GPCR/CNS properties. Its superior BBB penetration, more favorable logP, and acceptable metabolic stability outweigh the slightly higher hERG risk and poorer solubility. Ligand A's low logP and poor BBB penetration are significant drawbacks. While Ligand A has better metabolic stability and P-gp efflux, the CNS target necessitates prioritizing BBB and logP.

Output:
1
2025-04-17 06:21:22,048 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (365.861 Da) is slightly lower, which could be beneficial for permeability.

**TPSA:** Both ligands have TPSA values below 90, which is good for CNS penetration. Ligand A (61.88) is slightly higher than Ligand B (58.87), but both are acceptable.

**logP:** Both ligands have logP values around 3.2, which is optimal.

**H-Bond Donors/Acceptors:** Both have 1 HBD, which is good. Ligand A has 4 HBA, and Ligand B has 6 HBA. Both are within the acceptable limit of 10.

**QED:** Both ligands have high QED scores (0.874 and 0.853), indicating good drug-like properties.

**DILI:** Ligand A (36.952) has a significantly lower DILI risk than Ligand B (47.383). This is a major advantage.

**BBB:** Both ligands have excellent BBB penetration (85.459 and 83.017), exceeding the desirable threshold of 70.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values, which is unusual and suggests poor permeability. However, the scale is not specified, so it's hard to interpret.

**Aqueous Solubility:** Both ligands have negative solubility values, which is also unusual and suggests poor solubility.

**hERG:** Both ligands have low hERG inhibition liability (0.763 and 0.64).

**Microsomal Clearance:** Ligand A (-12.178) has a much lower (better) microsomal clearance than Ligand B (27.401), indicating greater metabolic stability.

**In vitro Half-Life:** Ligand B (37.767) has a significantly longer in vitro half-life than Ligand A (9.239).

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.097 and 0.397), which is favorable for CNS exposure.

**Binding Affinity:** Ligand B (-9.1 kcal/mol) has a slightly better binding affinity than Ligand A (-8.0 kcal/mol). The difference is 1.1 kcal/mol, which is not a huge advantage, but still noticeable.

**Overall Assessment:**

Ligand A has significant advantages in terms of DILI risk and metabolic stability (lower Cl_mic). While Ligand B has a slightly better binding affinity and longer half-life, the lower DILI and Cl_mic of Ligand A are more critical for a CNS-targeting drug, given the potential for liver toxicity and the need for sustained exposure. The solubility and permeability issues are concerning for both, but can be addressed through formulation strategies. Given the GPCR-specific priorities, and the importance of minimizing toxicity for CNS drugs, Ligand A is the more promising candidate.

Output:
0
2025-04-17 06:21:22,049 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (346.475 and 374.888 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (78.09) is slightly higher than Ligand B (59.39). Both are below the 90 A^2 threshold desirable for CNS targets, but Ligand B is better.

**logP:** Both ligands have a logP around 2.3, which is optimal (1-3).

**H-Bond Donors/Acceptors:** Ligand A has 2 HBD and 3 HBA, while Ligand B has 1 HBD and 5 HBA. Both are within acceptable limits (<=5 HBD and <=10 HBA).

**QED:** Both ligands have similar QED values (0.795 and 0.744), indicating good drug-likeness.

**DILI:** Ligand A (13.687) has a lower DILI risk than Ligand B (16.557), which is preferable.

**BBB:** This is a crucial parameter for a CNS target like DRD2. Ligand B (90.074) has a significantly higher BBB penetration percentile than Ligand A (55.332). This is a major advantage for Ligand B.

**Caco-2 Permeability:** Ligand A (-5.056) has worse Caco-2 permeability than Ligand B (-4.618).

**Aqueous Solubility:** Ligand A (-1.837) has slightly better solubility than Ligand B (-2.71).

**hERG Inhibition:** Ligand A (0.37) has a lower hERG inhibition risk than Ligand B (0.662), which is preferable.

**Microsomal Clearance:** Ligand A (18.241) has a higher microsomal clearance than Ligand B (16.341), meaning it is less metabolically stable.

**In vitro Half-Life:** Ligand B (8.162) has a longer in vitro half-life than Ligand A (-18.015), which is desirable.

**P-gp Efflux:** Ligand A (0.031) has lower P-gp efflux liability than Ligand B (0.087), which is preferable for CNS penetration.

**Binding Affinity:** Ligand A (-8.0) has a slightly better binding affinity than Ligand B (-6.7). However, the difference is less than 1.5 kcal/mol, and can be offset by other factors.

**Overall Assessment:**

Ligand B is the more promising candidate. While Ligand A has slightly better affinity and lower hERG/Pgp, Ligand B's significantly higher BBB penetration (90.074 vs 55.332) and longer half-life are critical advantages for a CNS-targeting drug. The slightly higher DILI risk and P-gp efflux of Ligand B are less concerning compared to the poor BBB penetration of Ligand A. The TPSA is also better for Ligand B.

Output:
1
2025-04-17 06:21:22,049 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (360.885 and 374.535 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (64.35) is better than Ligand B (61.92). Both are below the 90 A^2 threshold desirable for CNS targets, but A is closer to the ideal.

**3. logP:** Ligand A (4.765) is slightly higher than Ligand B (3.788). Ligand A is approaching the upper limit of the optimal range (1-3), while Ligand B is well within it.

**4. H-Bond Donors:** Ligand A (2) is better than Ligand B (0). While both are acceptable, a small number of HBDs can aid solubility.

**5. H-Bond Acceptors:** Ligand B (6) is better than Ligand A (3). Both are within the acceptable limit of 10.

**6. QED:** Ligand A (0.677) is significantly better than Ligand B (0.469), indicating a more drug-like profile.

**7. DILI:** Ligand A (47.732) is better than Ligand B (57.193), indicating lower potential for drug-induced liver injury. Both are below the 60 threshold.

**8. BBB:** Ligand A (69.523) is better than Ligand B (61.729). While both are not ideal (>70), A is closer to the desired threshold for CNS penetration.

**9. Caco-2:** Both ligands have negative Caco-2 values (-5.056 and -5.232), which is unusual and suggests poor permeability. This is a significant drawback for both.

**10. Solubility:** Both ligands have negative solubility values (-4.701 and -4.21). This is also a significant drawback, suggesting poor aqueous solubility.

**11. hERG:** Both ligands have very low hERG inhibition liability (0.797 and 0.791), which is excellent.

**12. Cl_mic:** Ligand A (59.053) is significantly better than Ligand B (106.78), indicating better metabolic stability.

**13. t1/2:** Ligand A (76.9) is significantly better than Ligand B (36.012), indicating a longer in vitro half-life.

**14. Pgp:** Both ligands have low P-gp efflux liability (0.565 and 0.755), which is good for CNS exposure.

**15. Binding Affinity:** Ligand A (-8.9 kcal/mol) is significantly better than Ligand B (-6.8 kcal/mol). This is a substantial difference in potency.

**Overall Assessment:**

Ligand A is the superior candidate. While both compounds share problematic Caco-2 and solubility values, Ligand A demonstrates advantages in almost every other critical parameter, particularly binding affinity, metabolic stability (Cl_mic & t1/2), QED, BBB penetration, and DILI risk. The significantly stronger binding affinity of Ligand A (-8.9 vs -6.8 kcal/mol) is a major advantage that can potentially compensate for the permeability and solubility issues, especially given that we are targeting a GPCR in the CNS where good penetration is crucial.

Output:
1
2025-04-17 06:21:22,049 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B based on the provided guidelines, prioritizing GPCR-specific properties (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (338.386 Da) is slightly lower, which could be beneficial for permeability. Ligand B (352.435 Da) is also good.

**TPSA:** Ligand A (47.09) is excellent for CNS penetration, well below the 90 A^2 threshold. Ligand B (96.69) is higher, but still potentially acceptable, though less ideal.

**logP:** Ligand A (3.504) is within the optimal range (1-3). Ligand B (-0.082) is significantly lower than ideal, potentially hindering permeation.

**H-Bond Donors/Acceptors:** Ligand A (0 HBD, 5 HBA) is favorable. Ligand B (2 HBD, 6 HBA) is also reasonable.

**QED:** Both ligands have similar QED values (A: 0.73, B: 0.682), indicating good drug-like properties.

**DILI:** Ligand A (56.96) has a moderate DILI risk, while Ligand B (24.234) has a very low DILI risk, a significant advantage.

**BBB:** Ligand A (86.08) has excellent BBB penetration potential, exceeding the 70% threshold. Ligand B (23.11) has very poor BBB penetration, a major drawback for a CNS target like DRD2.

**Caco-2 Permeability:** Ligand A (-4.947) has poor Caco-2 permeability. Ligand B (-5.229) is also poor.

**Aqueous Solubility:** Ligand A (-2.696) and Ligand B (-0.647) both have poor aqueous solubility.

**hERG Inhibition:** Ligand A (0.921) has a low hERG risk. Ligand B (0.132) has a very low hERG risk, another advantage.

**Microsomal Clearance:** Ligand A (76.42) has a relatively high microsomal clearance, suggesting lower metabolic stability. Ligand B (6.744) has very low clearance, indicating good metabolic stability.

**In vitro Half-Life:** Ligand A (-49.268) has a very short half-life. Ligand B (3.008) has a short half-life, but better than Ligand A.

**P-gp Efflux:** Ligand A (0.758) has moderate P-gp efflux. Ligand B (0.02) has very low P-gp efflux, a significant advantage for CNS penetration.

**Binding Affinity:** Ligand B (-7.4 kcal/mol) has a significantly stronger binding affinity than Ligand A (-9.5 kcal/mol). This is a substantial advantage, potentially outweighing some ADME drawbacks.

**Overall Assessment:**

Ligand B demonstrates a much stronger binding affinity and favorable metabolic stability (low Cl_mic), low DILI risk, and low P-gp efflux. While its logP is suboptimal and BBB penetration is poor, the strong binding affinity and other favorable properties make it a more promising candidate. Ligand A has good BBB penetration, but suffers from poor Caco-2 permeability, high microsomal clearance, short half-life, and weaker binding affinity. The poor solubility of both compounds is a concern, but can be addressed through formulation strategies. Given the importance of affinity and CNS penetration for a DRD2 ligand, Ligand B is the better choice.

Output:
1
2025-04-17 06:21:22,049 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (354.422 and 354.466 Da) fall comfortably within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (75.71) is higher than Ligand B (49.85). For CNS targets, TPSA < 90 is preferred. Both are under this threshold, but Ligand B is significantly better.

**3. logP:** Both ligands have good logP values (1.429 and 2.104), falling within the optimal 1-3 range. Ligand B is slightly higher, which could be beneficial for membrane permeability.

**4. H-Bond Donors:** Ligand A has 1 HBD, and Ligand B has 0. Both are acceptable (<=5).

**5. H-Bond Acceptors:** Ligand A has 4 HBA, and Ligand B has 3. Both are within the acceptable range (<=10).

**6. QED:** Both ligands have good QED scores (0.702 and 0.76), indicating good drug-like properties.

**7. DILI:** Ligand A (23.149) has a lower DILI risk than Ligand B (10.392), suggesting it's less likely to cause liver injury. This is a significant advantage for Ligand A.

**8. BBB:** Ligand B (97.635) has a much higher BBB penetration percentile than Ligand A (86.817). This is *critical* for a CNS target like DRD2, making Ligand B more promising.

**9. Caco-2 Permeability:** Both have negative values (-4.418 and -4.438), which is unusual and suggests poor permeability. This is a concern for both.

**10. Aqueous Solubility:** Both have negative values (-2.421 and -2.319), indicating poor solubility. This is a concern for both.

**11. hERG Inhibition:** Ligand A (0.292) has a lower hERG inhibition risk than Ligand B (0.73), indicating a lower risk of cardiotoxicity. This favors Ligand A.

**12. Microsomal Clearance:** Both have similar microsomal clearance values (51.497 and 49.466), suggesting comparable metabolic stability.

**13. In vitro Half-Life:** Ligand B (-11.901) has a slightly longer in vitro half-life than Ligand A (-14.353), which is a minor advantage.

**14. P-gp Efflux:** Ligand A (0.054) has a lower P-gp efflux liability than Ligand B (0.144), meaning it's less likely to be pumped out of the brain, improving CNS exposure. This is a significant advantage for Ligand A.

**15. Binding Affinity:** Ligand B (-8.7 kcal/mol) has a stronger binding affinity than Ligand A (-7.7 kcal/mol). This is a substantial advantage (1.0 kcal/mol difference), and often outweighs minor ADME drawbacks.

**Overall Assessment:**

While Ligand A has advantages in DILI risk, hERG inhibition, and P-gp efflux, Ligand B's significantly higher BBB penetration and stronger binding affinity are decisive for a CNS GPCR target like DRD2. The affinity difference is substantial. The poor Caco-2 and solubility for both are concerning, but can potentially be addressed with formulation strategies.

Output:
1
2025-04-17 06:21:22,050 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (356.413 and 364.427 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (75.27) is significantly better than Ligand B (101.91). For CNS targets, we want TPSA <= 90, and A is comfortably within that range, while B is pushing the limit.

**logP:** Both ligands have good logP values (1.559 and 1.228), falling within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Both have 2 HBDs, which is acceptable. Ligand B has 7 HBAs, slightly higher than A's 3, but both are within the acceptable limit of <=10.

**QED:** Both ligands have good QED scores (0.624 and 0.818), indicating good drug-like properties.

**DILI:** Ligand A (15.626) has a much lower DILI risk than Ligand B (67.119). This is a significant advantage for A.

**BBB:** Ligand A (87.476) has a substantially higher BBB penetration percentile than Ligand B (45.56). This is *critical* for a CNS target like DRD2.

**Caco-2 Permeability:** Ligand A (-5.047) has worse Caco-2 permeability than Ligand B (-4.738), but both are negative, indicating poor permeability.

**Aqueous Solubility:** Both ligands have very poor aqueous solubility (-2.528 and -2.623). This is a concern, but can sometimes be mitigated through formulation.

**hERG:** Both ligands have very low hERG inhibition risk (0.183 and 0.141).

**Microsomal Clearance:** Ligand A (8.162) has a slightly higher microsomal clearance than Ligand B (5.723), meaning it might be metabolized faster.

**In vitro Half-Life:** Both have similar in vitro half-lives (26.766 and 28.168 hours).

**P-gp Efflux:** Both ligands show very low P-gp efflux (0.014 and 0.092).

**Binding Affinity:** Crucially, both ligands have the *same* binding affinity (-8.4 kcal/mol), which is excellent.

**Conclusion:**

Given the GPCR-specific priorities, Ligand A is the superior candidate. The significantly better TPSA, lower DILI risk, and *much* higher BBB penetration outweigh the slightly worse Caco-2 permeability and slightly higher microsomal clearance. The identical binding affinity removes that as a differentiating factor. For a CNS target, getting the drug into the brain is paramount, and Ligand A is far more likely to achieve that.

Output:
0
2025-04-17 06:21:22,050 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight (MW):**
* Ligand A: 343.479 Da - Within the ideal range (200-500 Da).
* Ligand B: 409.368 Da - Also within the ideal range.
* *No clear advantage here.*

**2. Topological Polar Surface Area (TPSA):**
* Ligand A: 70.9  - Excellent, well below the 90 A^2 threshold for CNS targets.
* Ligand B: 45.59 - Excellent, even better than Ligand A, well below the 90 A^2 threshold.
* *Ligand B has a slight advantage.*

**3. Lipophilicity (logP):**
* Ligand A: 2.351 - Optimal (1-3).
* Ligand B: 3.48 - Optimal (1-3), but approaching the upper limit.
* *Ligand A is slightly preferred due to lower logP.*

**4. H-Bond Donors (HBD):**
* Ligand A: 2 - Meets the criteria (<=5).
* Ligand B: 1 - Meets the criteria (<=5).
* *No clear advantage.*

**5. H-Bond Acceptors (HBA):**
* Ligand A: 7 - Meets the criteria (<=10).
* Ligand B: 4 - Meets the criteria (<=10).
* *Ligand B is slightly preferred.*

**6. QED:**
* Ligand A: 0.717 - Excellent, above 0.5.
* Ligand B: 0.749 - Excellent, above 0.5, slightly better than A.
* *Ligand B has a slight advantage.*

**7. DILI:**
* Ligand A: 54.827 - Good, below 60.
* Ligand B: 10.314 - Excellent, very low risk.
* *Ligand B is significantly preferred.*

**8. BBB:**
* Ligand A: 85.072 - Very good, above 70.
* Ligand B: 89.027 - Excellent, even better than A.
* *Ligand B has a slight advantage.*

**9. Caco-2 Permeability:**
* Ligand A: -5.295 - Negative values are unusual and suggest poor permeability.
* Ligand B: -5.0 - Also negative, but slightly less negative than A.
* *Ligand B is slightly preferred.*

**10. Aqueous Solubility:**
* Ligand A: -3.198 - Negative values are unusual and suggest poor solubility.
* Ligand B: -3.099 - Also negative, but slightly less negative than A.
* *Ligand B is slightly preferred.*

**11. hERG Inhibition:**
* Ligand A: 0.955 - Low risk.
* Ligand B: 0.895 - Low risk.
* *No clear advantage.*

**12. Microsomal Clearance:**
* Ligand A: 60.109 - Moderate clearance.
* Ligand B: 41.0 - Lower clearance, indicating better metabolic stability.
* *Ligand B is preferred.*

**13. In vitro Half-Life:**
* Ligand A: 48.595 - Moderate half-life.
* Ligand B: 30.151 - Shorter half-life.
* *Ligand A is preferred.*

**14. P-gp Efflux:**
* Ligand A: 0.35 - Low efflux, good.
* Ligand B: 0.658 - Higher efflux, less desirable.
* *Ligand A is preferred.*

**15. Binding Affinity:**
* Ligand A: -7.8 kcal/mol - Excellent.
* Ligand B: -8.1 kcal/mol - Slightly better than A.
* *Ligand B has a slight advantage.*

**Overall Assessment:**

Ligand B consistently outperforms Ligand A in most key ADME properties relevant to CNS drug development (DILI, BBB, metabolic stability, TPSA). While Ligand A has a better P-gp efflux profile and in vitro half-life, the stronger binding affinity of Ligand B (-8.1 vs -7.8 kcal/mol) and superior ADME properties outweigh these minor drawbacks. The negative Caco-2 and solubility values are concerning for both, but Ligand B is slightly less problematic in these areas. Given the GPCR target and the need for CNS penetration, Ligand B is the more promising candidate.

Output:
1
2025-04-17 06:21:22,050 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 drug candidates, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (366.439 and 382.507 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (96.8) is slightly above the ideal <90 for CNS targets, but still reasonable. Ligand B (67.87) is well within the desired range. This favors Ligand B.

**3. logP:** Both ligands have excellent logP values (1.813 and 1.75), falling within the optimal 1-3 range.

**4. H-Bond Donors:** Both have 1 HBD, which is good.

**5. H-Bond Acceptors:** Both have 6 HBA, also good.

**6. QED:** Both ligands have good QED scores (0.735 and 0.84), indicating drug-like properties.

**7. DILI:** Ligand A (64.521) has a slightly higher DILI risk than Ligand B (74.176), though both are acceptable.

**8. BBB:** Ligand B (56.34) has a better BBB penetration percentile than Ligand A (48.74), which is crucial for a CNS target like DRD2.

**9. Caco-2 Permeability:** Ligand A (-5.319) has slightly better Caco-2 permeability than Ligand B (-5.257), but the difference is minimal.

**10. Aqueous Solubility:** Ligand A (-2.613) has slightly better aqueous solubility than Ligand B (-3.803).

**11. hERG Inhibition:** Ligand A (0.045) shows a slightly lower hERG inhibition liability than Ligand B (0.342), which is favorable.

**12. Microsomal Clearance:** Ligand B (40.644) has significantly lower microsomal clearance than Ligand A (6.593), indicating better metabolic stability.

**13. In vitro Half-Life:** Ligand B (36.282) has a much longer in vitro half-life than Ligand A (-12.214), a significant advantage.

**14. P-gp Efflux:** Ligand A (0.018) has lower P-gp efflux liability than Ligand B (0.184), which is good for CNS penetration.

**15. Binding Affinity:** Ligand A (-7.9) has a slightly better binding affinity than Ligand B (-7.1). This is a 0.8 kcal/mol difference, which is significant.

**Overall Assessment:**

While Ligand A has a slightly better binding affinity and lower P-gp efflux, Ligand B excels in several key areas crucial for a CNS-targeting GPCR drug. Specifically, it has a lower TPSA, better BBB penetration, significantly improved metabolic stability (lower Cl_mic and longer t1/2), and a slightly better DILI profile. The difference in binding affinity (0.8 kcal/mol) is outweighed by the superior ADME properties of Ligand B, particularly its BBB penetration and metabolic stability.

Output:
1
2025-04-17 06:21:22,050 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 drug candidates, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (346.391 Da) is slightly lower, which can be beneficial for permeability.

**TPSA:** Ligand A (102.12) is better than Ligand B (78.09) as it is closer to the ideal range for CNS targets (<=90).

**logP:** Ligand B (2.088) is optimal (1-3), while Ligand A (0.177) is quite low, potentially hindering permeation. This is a significant drawback for Ligand A.

**H-Bond Donors/Acceptors:** Ligand A has 1 HBD and 7 HBA, while Ligand B has 2 HBD and 4 HBA. Both are within acceptable limits.

**QED:** Both ligands have good QED scores (A: 0.804, B: 0.878), indicating good drug-like properties.

**DILI:** Both have acceptable DILI risk (A: 67.429, B: 58.434), though A is slightly higher.

**BBB:** Ligand A (70.919) has a better BBB percentile than Ligand B (50.523). This is crucial for a CNS target like DRD2.

**Caco-2 Permeability:** Ligand A (-4.962) is significantly worse than Ligand B (-5.306), indicating poor intestinal absorption.

**Aqueous Solubility:** Both have poor aqueous solubility (-2.096 and -3.228 respectively). This is not ideal but can be addressed with formulation strategies.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (A: 0.207, B: 0.322).

**Microsomal Clearance:** Ligand B (14.153) has a lower (better) microsomal clearance than Ligand A (29.632), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (41.295) has a better in vitro half-life than Ligand B (-19.872).

**P-gp Efflux:** Both ligands have low P-gp efflux liability (A: 0.099, B: 0.102).

**Binding Affinity:** Both ligands have the same binding affinity (-8.4 kcal/mol), which is excellent.

**Overall Assessment:**

Ligand A has a better BBB penetration and in vitro half-life, but suffers from a very low logP and poor Caco-2 permeability. Ligand B has a better logP, lower microsomal clearance, and a slightly lower DILI risk. Given the importance of logP and BBB for CNS GPCR targets, and the equal binding affinity, Ligand B is the more promising candidate. The low logP of Ligand A is a major concern, likely hindering its ability to cross cell membranes and reach the brain.

Output:
1
2025-04-17 06:21:22,050 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (347.361 and 357.401 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (66.4) is significantly better than Ligand B (80.32). For CNS targets, we want TPSA <= 90, and A is comfortably within that range, while B is approaching the upper limit.

**logP:** Both ligands have good logP values (4.034 and 2.396), falling within the optimal 1-3 range. Ligand A is slightly higher, which *could* be a minor concern for solubility, but is still acceptable.

**H-Bond Donors/Acceptors:** Both have 2 HBDs, which is good. Ligand A has 2 HBAs, while Ligand B has 4. Lower HBA counts are generally preferred for better permeability, giving a slight edge to A.

**QED:** Both have reasonable QED scores (0.829 and 0.711), indicating good drug-like properties.

**DILI:** Ligand A (78.247) has a higher DILI risk than Ligand B (48.468). This is a significant negative for Ligand A.

**BBB:** Ligand B (70.531) has a substantially better BBB penetration score than Ligand A (41.218). This is *critical* for a CNS target like DRD2, giving a major advantage to B.

**Caco-2 Permeability:** Both have negative Caco-2 values (-4.748 and -4.609), which is unusual and suggests poor permeability. However, these values are on a log scale, and the absolute difference is small.

**Aqueous Solubility:** Both have negative solubility values (-3.398 and -2.989), indicating poor aqueous solubility. This is a concern for both, but the difference is minor.

**hERG Inhibition:** Ligand A (0.208) has a slightly lower hERG risk than Ligand B (0.585), which is preferable.

**Microsomal Clearance:** Ligand B (43.218) has a higher microsomal clearance than Ligand A (20.829), meaning A is more metabolically stable.

**In vitro Half-Life:** Ligand A (5.945) has a better in vitro half-life than Ligand B (-17.681). The negative value for B is concerning and suggests rapid degradation.

**P-gp Efflux:** Ligand A (0.074) has a much lower P-gp efflux liability than Ligand B (0.093), which is beneficial for CNS penetration.

**Binding Affinity:** Both ligands have excellent binding affinities (-9.0 and -8.1 kcal/mol). Ligand A is slightly better (-9.0 kcal/mol), but the difference is less than 1.5 kcal/mol, so it doesn't fully compensate for other weaknesses.

**Overall Assessment:**

Ligand B is the stronger candidate. While Ligand A has a slightly better affinity and metabolic stability, Ligand B's significantly improved BBB penetration (70.531 vs 41.218) and lower DILI risk (48.468 vs 78.247) are crucial for a CNS-targeting drug. The slightly higher P-gp efflux of B is less concerning than A's poor BBB score. The similar permeability and solubility issues are drawbacks for both, but can potentially be addressed through formulation strategies.



Output:
1
2025-04-17 06:21:22,051 - INFO - Reasoning:

Let's analyze Ligand A and Ligand B based on the provided guidelines, prioritizing GPCR-specific properties (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (383.813 Da) is slightly lower, which is generally favorable for permeability.

**TPSA:** Ligand B (74.25) is significantly better than Ligand A (107.36). For CNS targets, TPSA should be <= 90, and Ligand B comfortably meets this, while Ligand A is close to the upper limit.

**logP:** Ligand A (1.194) is optimal, falling within the 1-3 range. Ligand B (4.06) is higher, potentially leading to solubility issues and off-target effects.

**H-Bond Donors/Acceptors:** Ligand A (1 HBD, 7 HBA) is better than Ligand B (3 HBD, 3 HBA) in terms of maintaining a balance between solubility and permeability.

**QED:** Both ligands have similar QED values (0.795 and 0.722), indicating good drug-likeness.

**DILI:** Ligand B (55.487) has a lower DILI risk than Ligand A (96.976), which is a significant advantage.

**BBB:** Ligand B (73.711) has a much better BBB percentile than Ligand A (51.377). For a CNS target like DRD2, >70 is desirable, and Ligand B is closer to this threshold.

**Caco-2 Permeability:** Both have negative values, which is unusual. Assuming these are logP-scale values, the values are similar and suggest poor permeability.

**Aqueous Solubility:** Both have negative values, suggesting poor solubility.

**hERG Inhibition:** Ligand A (0.263) has a lower hERG inhibition liability than Ligand B (0.689), which is preferable.

**Microsomal Clearance:** Ligand A (-1.637) has a lower (better) microsomal clearance than Ligand B (41.758), indicating greater metabolic stability.

**In vitro Half-Life:** Ligand B (93.912) has a much longer in vitro half-life than Ligand A (-9.945), which is a significant advantage.

**P-gp Efflux:** Ligand A (0.079) has lower P-gp efflux liability than Ligand B (0.416), which is beneficial for CNS exposure.

**Binding Affinity:** Ligand B (-10.8 kcal/mol) has a significantly stronger binding affinity than Ligand A (-7.7 kcal/mol). This >1.5 kcal/mol difference is substantial and can outweigh some ADME drawbacks.

**Overall Assessment:**

While Ligand A has advantages in terms of logP, metabolic stability, and P-gp efflux, Ligand B excels in crucial areas for a CNS GPCR target: BBB penetration, binding affinity, and DILI risk. The significantly stronger binding affinity of Ligand B is a major factor. The improved BBB and lower DILI are also very important. Although Ligand B has a higher logP and P-gp efflux, the strong binding affinity and better CNS properties likely compensate for these.

Output:
1
2025-04-17 06:21:22,051 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (347.459 Da) is slightly lower, which could be advantageous for permeability, but both are acceptable.

**TPSA:** Ligand A (69.72) is excellent for CNS penetration, well below the 90 A^2 threshold. Ligand B (92.08) is still reasonable, but less optimal.

**logP:** Ligand A (1.149) is within the optimal range, while Ligand B (2.741) is approaching the upper limit. Both are acceptable, but A is slightly preferred.

**H-Bond Donors/Acceptors:** Ligand A (HBD=1, HBA=3) and Ligand B (HBD=2, HBA=3) both have favorable counts, well within the guidelines.

**QED:** Ligand A (0.811) has a higher QED score than Ligand B (0.569), indicating a more drug-like profile.

**DILI:** Ligand A (17.759) has a significantly lower DILI risk than Ligand B (47.926), which is a substantial advantage.

**BBB:** Both ligands have good BBB penetration (Ligand A: 71.539, Ligand B: 73.75). Both exceed the 70% threshold, making them viable for CNS targets. Ligand B is marginally better.

**Caco-2 Permeability:** Ligand A (-4.896) and Ligand B (-5.509) both have negative Caco-2 values. Lower values indicate lower permeability, but the scale isn't specified, so it's hard to interpret.

**Aqueous Solubility:** Both ligands have very poor aqueous solubility (-2.635 and -3.275 respectively). This is a significant drawback for both compounds.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (Ligand A: 0.134, Ligand B: 0.492).

**Microsomal Clearance:** Ligand A (10.657) has lower microsomal clearance than Ligand B (16.132), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (3.792) has a shorter half-life than Ligand B (-5.237). The negative value for B is unusual and potentially indicates a very long half-life, but the scale is unclear.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (Ligand A: 0.053, Ligand B: 0.046).

**Binding Affinity:** Both ligands have very similar and strong binding affinities (-7.5 kcal/mol and -7.4 kcal/mol). The difference is negligible.

**Overall Assessment:**

Ligand A is superior due to its better TPSA, QED, significantly lower DILI risk, and lower microsomal clearance. While both have poor solubility, the other advantages of Ligand A outweigh this drawback. The slightly better BBB penetration of Ligand B isn't enough to compensate for the other factors.

Output:
0
2025-04-17 06:21:22,051 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (355.45 and 352.494 Da) fall comfortably within the ideal 200-500 Da range.

**TPSA:** Ligand A (55.84) is better than Ligand B (49.41). Both are below the 90 A^2 threshold desirable for CNS targets, which is excellent.

**logP:** Both ligands have good logP values (4.015 and 3.614), falling within the optimal 1-3 range, though slightly on the higher end. This could potentially lead to off-target effects, but is not a major concern at this stage.

**H-Bond Donors/Acceptors:** Ligand A (0 HBD, 4 HBA) is slightly better than Ligand B (1 HBD, 2 HBA) in terms of balancing solubility and permeability. Both are within acceptable limits.

**QED:** Both ligands have good QED scores (0.41 and 0.611), indicating reasonable drug-likeness. Ligand B is better.

**DILI:** Ligand A (28.655) has a significantly lower DILI risk than Ligand B (12.214). This is a substantial advantage for Ligand A.

**BBB:** Ligand A (94.184) has a much higher BBB penetration percentile than Ligand B (85.964). This is *critical* for a CNS target like DRD2.

**Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and suggests a potential issue with in vitro permeability. However, these values are on a strange scale and may not be directly comparable.

**Aqueous Solubility:** Both ligands have negative solubility values, which is also unusual and suggests poor aqueous solubility. This could be a formulation challenge.

**hERG:** Both ligands have low hERG inhibition liability (0.697 and 0.593), which is positive.

**Microsomal Clearance:** Ligand A (99.737) has a very high microsomal clearance, indicating poor metabolic stability. Ligand B (36.792) has a much lower clearance, which is a significant advantage.

**In vitro Half-Life:** Ligand A (-3.102) has a negative half-life, which is not physically meaningful and suggests a problem with the data. Ligand B (3.242) has a reasonable half-life.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.278 and 0.181), which is good for CNS exposure.

**Binding Affinity:** Ligand B (-8.0 kcal/mol) has a slightly better binding affinity than Ligand A (-7.7 kcal/mol), but the difference is relatively small (0.3 kcal/mol).

**Overall Assessment:**

Ligand A excels in BBB penetration and DILI risk, which are crucial for CNS drug development. However, it suffers from very high metabolic clearance and a nonsensical half-life value, raising serious concerns about its in vivo stability.

Ligand B has better metabolic stability (lower Cl_mic, positive t1/2), a slightly better binding affinity, and a good QED score. While its BBB penetration is lower than Ligand A, it's still reasonably high. The DILI risk is higher than Ligand A, but not alarmingly so.

Given the importance of metabolic stability and a reasonable half-life for in vivo efficacy, and the relatively small difference in binding affinity, **Ligand B is the more promising candidate.** The issues with solubility and Caco-2 permeability can be addressed through formulation strategies.



Output:
1
2025-04-17 06:21:22,051 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (346.362 and 366.527 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (87.46) is better than Ligand B (51.66) as it is closer to the optimal range for CNS targets (<=90). Ligand B is excellent.

**3. logP:** Ligand A (1.672) is within the optimal range (1-3). Ligand B (3.268) is also within the optimal range, but closer to the upper limit.

**4. H-Bond Donors:** Ligand A (2) is good. Ligand B (0) is also good.

**5. H-Bond Acceptors:** Both ligands (A: 5, B: 5) are within the acceptable limit of <=10.

**6. QED:** Ligand A (0.885) is better than Ligand B (0.743), indicating higher drug-likeness.

**7. DILI:** Ligand A (47.77) has a slightly higher DILI risk than Ligand B (29.042), but both are below the concerning threshold of 60.

**8. BBB:** Ligand B (88.057) significantly outperforms Ligand A (50.523) in BBB penetration, which is crucial for a CNS target like DRD2.

**9. Caco-2 Permeability:** Ligand A (-5.025) and Ligand B (-4.72) are both negative, suggesting poor permeability. This is a concern for both.

**10. Aqueous Solubility:** Ligand A (-3.083) and Ligand B (-2.203) are both negative, suggesting poor solubility. This is a concern for both.

**11. hERG Inhibition:** Both ligands show low hERG inhibition risk (A: 0.48, B: 0.44).

**12. Microsomal Clearance:** Ligand B (70.301) has a much higher microsomal clearance than Ligand A (5.789), indicating faster metabolism and lower metabolic stability.

**13. In vitro Half-Life:** Ligand A (-31.967) has a much longer in vitro half-life than Ligand B (-1.19), indicating better stability.

**14. P-gp Efflux:** Both ligands show low P-gp efflux liability (A: 0.04, B: 0.336).

**15. Binding Affinity:** Ligand A (-8.1) has a slightly better binding affinity than Ligand B (-7.4). However, the difference is less than 1.5 kcal/mol.

**Overall Assessment:**

While Ligand A has a slightly better binding affinity and QED, Ligand B is significantly better regarding BBB penetration and has a lower DILI risk. The longer half-life of Ligand A is a plus, but the dramatic difference in BBB penetration is a major factor favoring Ligand B for a CNS target. The higher metabolic clearance of Ligand B is a concern, but could potentially be addressed through structural modifications. The poor Caco-2 permeability and solubility are concerns for both, but are less critical for a CNS target where direct oral bioavailability isn't always essential.

Output:
1
2025-04-17 06:21:22,052 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (378.904 Da) is slightly higher than Ligand B (349.391 Da), but both are acceptable.

**TPSA:** Ligand A (53.6) is excellent for CNS penetration, well below the 90 A^2 threshold. Ligand B (138.51) is higher, approaching the 140 A^2 limit for oral absorption, and less ideal for CNS targets.

**logP:** Ligand A (4.967) is slightly high, potentially leading to solubility issues or off-target interactions, but still within a manageable range. Ligand B (-1.092) is significantly low, which could hinder membrane permeability and reduce CNS exposure.

**H-Bond Donors/Acceptors:** Ligand A (2 HBD, 4 HBA) is well within the acceptable limits. Ligand B (3 HBD, 6 HBA) is also acceptable, but slightly higher.

**QED:** Both ligands have similar QED values (A: 0.659, B: 0.535), indicating reasonable drug-likeness.

**DILI:** Ligand A (70.221) has a higher DILI risk than Ligand B (43.66), which is preferable.

**BBB:** Ligand A (43.001) has a slightly better BBB percentile than Ligand B (41.14), but both are not ideal for a CNS target.

**Caco-2 Permeability:** Ligand A (-4.914) has poor Caco-2 permeability, while Ligand B (-5.504) is also poor.

**Aqueous Solubility:** Ligand A (-5.183) has poor aqueous solubility, while Ligand B (-1.719) is also poor.

**hERG Inhibition:** Ligand A (0.658) has a lower hERG inhibition risk than Ligand B (0.041), which is preferable.

**Microsomal Clearance:** Ligand A (36.812) has a higher microsomal clearance than Ligand B (4.311), indicating lower metabolic stability.

**In vitro Half-Life:** Ligand A (39.47) has a longer in vitro half-life than Ligand B (-2.676), which is preferable.

**P-gp Efflux:** Ligand A (0.483) has lower P-gp efflux liability than Ligand B (0.005), which is preferable for CNS penetration.

**Binding Affinity:** Ligand A (-9.2 kcal/mol) has a significantly stronger binding affinity than Ligand B (-8.2 kcal/mol). This 1.0 kcal/mol difference is substantial and can outweigh some of the ADME drawbacks.

**Overall Assessment:**

Considering the GPCR-specific priorities, Ligand A is the better candidate. While its logP is a bit high and DILI risk is elevated, its significantly stronger binding affinity (-9.2 vs -8.2 kcal/mol) and better TPSA (53.6 vs 138.51) are crucial for a CNS-targeting GPCR ligand. The lower P-gp efflux and better hERG profile also contribute to its favorability. Ligand B's very low logP is a major concern, likely hindering its ability to cross the BBB despite its lower DILI risk.

Output:
1
2025-04-17 06:21:22,052 - INFO - Batch 275 complete. Total preferences: 4400
2025-04-17 06:21:22,052 - INFO - Processing batch 276/512...
2025-04-17 06:22:17,186 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (350.415 and 347.375 Da) fall within the ideal range of 200-500 Da.

**TPSA:** Ligand A (88.1) is excellent for CNS penetration, being well below 90. Ligand B (116.42) is higher, but still potentially acceptable, though less ideal.

**logP:** Ligand A (1.674) is within the optimal range of 1-3. Ligand B (-0.207) is slightly below 1, which *could* indicate permeability issues, but isn't a hard disqualifier.

**H-Bond Donors/Acceptors:** Both have reasonable HBD (2 and 3 respectively) and HBA (5 each) counts, falling within the guidelines.

**QED:** Both ligands have good QED scores (0.697 and 0.7), indicating drug-like properties.

**DILI:** Ligand A (35.014) has a lower DILI risk than Ligand B (54.75), which is preferable. Both are below the concerning threshold of 60.

**BBB:** Both ligands have similar BBB penetration (55.37% and 55.874%). While not exceptional (>70%), they are not terrible, and the other parameters will be more decisive.

**Caco-2 Permeability:** Ligand A (-4.652) has a more negative Caco-2 permeability value, suggesting *lower* intestinal absorption. Ligand B (-5.033) is similar. These values are on a scale where higher is better, and both are quite poor.

**Aqueous Solubility:** Both ligands have very poor aqueous solubility (-2.907 and -2.63). This could be a significant formulation challenge.

**hERG Inhibition:** Both ligands show low hERG inhibition liability (0.115 and 0.257), which is good.

**Microsomal Clearance:** Ligand B (-37.481) has significantly lower microsomal clearance than Ligand A (82.014), indicating better metabolic stability. This is a major advantage.

**In vitro Half-Life:** Ligand B (-36.196) has a longer in vitro half-life than Ligand A (-24.848), further supporting its better metabolic stability.

**P-gp Efflux:** Both ligands show minimal P-gp efflux liability (0.032 and 0.012), which is positive for CNS exposure.

**Binding Affinity:** Ligand B (-9.2 kcal/mol) has a substantially stronger binding affinity than Ligand A (-7.7 kcal/mol). This difference of 1.5 kcal/mol is significant and can outweigh some ADME drawbacks.

**Conclusion:**

While both ligands have issues with solubility and Caco-2 permeability, Ligand B is the superior candidate. Its significantly stronger binding affinity, coupled with its improved metabolic stability (lower Cl_mic and longer t1/2), outweigh the slightly lower logP and higher DILI risk compared to Ligand A. The TPSA values are comparable, and both have acceptable hERG and P-gp profiles. For a GPCR target like DRD2, strong binding is paramount, and Ligand B delivers on that front.

Output:
1
2025-04-17 06:22:17,186 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (350.394 and 366.502 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (78.67) is better than Ligand B (40.62). For CNS targets, we want TPSA <= 90, both are within this range, but A is closer to the upper limit.

**logP:** Ligand A (0.532) is quite low, potentially hindering permeability. Ligand B (3.863) is much better, falling within the optimal 1-3 range. This is a significant advantage for B.

**H-Bond Donors/Acceptors:** Ligand A has 1 HBD and 5 HBA, while Ligand B has 0 HBD and 3 HBA. Both are within acceptable limits.

**QED:** Both ligands have good QED scores (0.786 and 0.812), indicating drug-like properties.

**DILI:** Ligand A (29.081) has a significantly lower DILI risk than Ligand B (45.095). This is a positive for A.

**BBB:** Ligand B (89.88) has a much higher BBB penetration percentile than Ligand A (43.583). This is *critical* for a CNS target like DRD2, making B highly preferable.

**Caco-2 Permeability:** Ligand A (-4.839) has poor Caco-2 permeability. Ligand B (-4.312) is slightly better, but both are quite low.

**Aqueous Solubility:** Ligand A (-0.571) has slightly better solubility than Ligand B (-3.813), but both are quite poor.

**hERG Inhibition:** Ligand A (0.334) has a lower hERG inhibition liability than Ligand B (0.805), which is favorable.

**Microsomal Clearance:** Ligand A (1.474) has much lower microsomal clearance than Ligand B (79.077), suggesting better metabolic stability. This is a significant advantage for A.

**In vitro Half-Life:** Ligand B (69.942) has a much longer in vitro half-life than Ligand A (-16.51). This is a positive for B.

**P-gp Efflux:** Ligand A (0.042) has much lower P-gp efflux liability than Ligand B (0.818). This is a significant advantage for A, especially for CNS penetration.

**Binding Affinity:** Ligand B (-8.1) has a slightly better binding affinity than Ligand A (-7.7). While a 1.5 kcal/mol difference is usually significant, the other ADME properties are more concerning for A.

**Overall Assessment:**

Ligand B excels in BBB penetration and binding affinity, which are paramount for a CNS GPCR target. Its logP is also within the optimal range. While its DILI and P-gp efflux are higher than Ligand A, the strong BBB penetration and affinity likely outweigh these concerns. Ligand A has better metabolic stability (lower Cl_mic) and lower P-gp efflux, but its extremely low logP and poor Caco-2 permeability are major drawbacks that would likely hinder its ability to reach the brain. The poor solubility is also a concern.

Output:
1
2025-04-17 06:22:17,187 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (352.475 and 347.503 Da) fall within the ideal range of 200-500 Da.

**TPSA:** Ligand A (59.08) is slightly higher than Ligand B (52.65), but both are well below the 90 A^2 threshold for CNS targets, indicating good potential for brain penetration.

**logP:** Ligand A (1.533) and Ligand B (2.337) are both within the optimal 1-3 range. Ligand B is slightly more lipophilic, which *could* be beneficial for membrane permeability, but isn't a major difference.

**H-Bond Donors/Acceptors:** Ligand A has 0 HBD and 4 HBA, while Ligand B has 1 HBD and 3 HBA. Both are within acceptable limits (<=5 HBD and <=10 HBA).

**QED:** Both ligands have similar QED values (0.697 and 0.686), indicating good drug-likeness.

**DILI:** Ligand A (9.771) has a slightly higher DILI risk than Ligand B (6.282), but both are below the concerning threshold of 40, suggesting low hepatotoxicity risk.

**BBB:** Ligand A (89.066) has a higher BBB percentile than Ligand B (71.539). This is a significant advantage for a CNS target like DRD2.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.37 and -4.917), which is unusual and suggests poor permeability. However, these values are on a log scale, and the negative values indicate very low permeability.

**Aqueous Solubility:** Both ligands have negative solubility values (-1.294 and -1.883), suggesting poor aqueous solubility. This could be a formulation challenge.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.34 and 0.523).

**Microsomal Clearance:** Ligand A (41.132) has a higher microsomal clearance than Ligand B (11.202), indicating lower metabolic stability. This is a disadvantage for Ligand A.

**In vitro Half-Life:** Ligand B (-7.23) has a longer in vitro half-life than Ligand A (-3.119), which is a positive attribute.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.052 and 0.044), which is favorable for CNS penetration.

**Binding Affinity:** Ligand A (-7.5 kcal/mol) has a slightly better binding affinity than Ligand B (-7.0 kcal/mol). This 0.5 kcal/mol difference is significant, and can outweigh minor ADME drawbacks.

**Overall Assessment:**

Ligand A has a superior binding affinity and better BBB penetration. However, it has higher DILI risk, higher microsomal clearance (lower metabolic stability), and a shorter half-life. Ligand B has better metabolic stability and a slightly lower DILI risk, but its binding affinity and BBB penetration are inferior.

Given the importance of BBB penetration for a CNS target like DRD2, and the relatively small difference in DILI risk, the stronger binding affinity of Ligand A, coupled with its better BBB score, makes it the more promising candidate *despite* its slightly worse metabolic profile. The affinity difference is substantial enough to potentially overcome the metabolic concerns through structural modifications later in the optimization process.

Output:
1
2025-04-17 06:22:17,187 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (369.575 and 345.487 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (61.44) is slightly above the optimal <90 for CNS targets, but still reasonable. Ligand B (52.65) is well within the desired range.

**logP:** Both ligands have good logP values (2.404 and 1.815), falling within the 1-3 optimal range.

**H-Bond Donors/Acceptors:** Ligand A has 2 HBD and 4 HBA, while Ligand B has 1 HBD and 3 HBA. Both are within acceptable limits.

**QED:** Both ligands have good QED scores (0.69 and 0.747), indicating good drug-likeness.

**DILI:** Ligand A (10.237) has a slightly higher DILI risk than Ligand B (6.747), but both are below the concerning threshold of 40.

**BBB:** This is a critical parameter for CNS targets. Ligand B (87.67) has a significantly higher BBB penetration percentile than Ligand A (59.946). This is a major advantage for Ligand B.

**Caco-2 Permeability:** Ligand A (-5.502) and Ligand B (-4.837) both have negative values, which is unusual. It's difficult to interpret without knowing the scale, but lower values likely indicate poorer permeability.

**Aqueous Solubility:** Both ligands have poor aqueous solubility (-1.537 and -1.579). This could pose formulation challenges.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.293 and 0.438).

**Microsomal Clearance:** Ligand B (7.983) has a lower microsomal clearance than Ligand A (14.869), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand B (2.944 hours) has a significantly lower in vitro half-life than Ligand A (23.39 hours). This is a disadvantage for Ligand B.

**P-gp Efflux:** Both ligands show low P-gp efflux liability (0.014 and 0.029).

**Binding Affinity:** Ligand B (-8.4 kcal/mol) has a slightly better binding affinity than Ligand A (-7.5 kcal/mol). While both are good, the 0.9 kcal/mol difference is significant.

**Overall Assessment:**

Ligand B is the more promising candidate. The significantly higher BBB penetration (87.67 vs 59.946) and better binding affinity (-8.4 vs -7.5 kcal/mol) outweigh the disadvantage of the lower in vitro half-life. The lower DILI risk and microsomal clearance are also beneficial. While both have poor solubility, this is a formulation challenge that can be addressed. The slightly higher TPSA of Ligand A is less concerning than the lower BBB.

Output:
1
2025-04-17 06:22:17,187 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (346.43 and 348.45 Da) fall within the ideal range of 200-500 Da.

**TPSA:** Ligand A (70.83) is significantly better than Ligand B (94.46). For CNS targets, we want TPSA <= 90, so Ligand A is preferable.

**logP:** Ligand A (2.266) is optimal (1-3), while Ligand B (0.125) is quite low, potentially hindering permeability. This favors Ligand A.

**H-Bond Donors/Acceptors:** Ligand A (0 HBD, 4 HBA) is better than Ligand B (2 HBD, 5 HBA) in terms of balancing solubility and permeability. Both are within acceptable ranges.

**QED:** Ligand A (0.842) has a higher QED score than Ligand B (0.682), indicating better overall drug-likeness.

**DILI:** Ligand A (34.43) has a slightly higher DILI risk than Ligand B (19.43), but both are below the concerning threshold of 60.

**BBB:** Ligand A (70.57) has a significantly better BBB penetration percentile than Ligand B (42.38). This is *critical* for a CNS target like DRD2, giving a strong advantage to Ligand A.

**Caco-2 Permeability:** Ligand A (-4.461) has a worse Caco-2 permeability than Ligand B (-5.166), but both are negative values and thus indicate poor permeability.

**Aqueous Solubility:** Ligand A (-1.974) has slightly better aqueous solubility than Ligand B (-1.43), but both are poor.

**hERG:** Ligand A (0.086) has a much lower hERG inhibition liability than Ligand B (0.38), which is a significant safety advantage.

**Microsomal Clearance:** Ligand A (40.314) has higher microsomal clearance than Ligand B (-7.352), meaning Ligand B is more metabolically stable.

**In vitro Half-Life:** Ligand A (20.65) has a longer in vitro half-life than Ligand B (14.699), which is preferable.

**P-gp Efflux:** Ligand A (0.157) has lower P-gp efflux liability than Ligand B (0.006), which is better for CNS exposure.

**Binding Affinity:** Ligand B (-7.9 kcal/mol) has a slightly better binding affinity than Ligand A (-8.5 kcal/mol). While affinity is important, the difference here is not substantial enough to outweigh the significant ADME advantages of Ligand A.

**Overall:** Ligand A is the stronger candidate. It excels in key properties for CNS penetration (BBB, TPSA, logP, Pgp) and has a better safety profile (hERG). While Ligand B has slightly better affinity and metabolic stability, the ADME/Tox profile of Ligand A is far more favorable for development as a DRD2-targeting drug.

Output:
1
2025-04-17 06:22:17,187 - INFO - Here's a step-by-step comparison of Ligand A and Ligand B, followed by my final decision:

**1. Molecular Weight (MW):**
*   Ligand A: 389.861 Da - Within the ideal range (200-500 Da).
*   Ligand B: 349.475 Da - Within the ideal range (200-500 Da).
*   *Both are acceptable.*

**2. Topological Polar Surface Area (TPSA):**
*   Ligand A: 118.41  - Slightly above the preferred <90 for CNS targets, but not drastically so.
*   Ligand B: 74.57 - Excellent, well below the 90 threshold for CNS targets.
*   *Ligand B is better.*

**3. Lipophilicity (logP):**
*   Ligand A: 2.138 - Optimal (1-3).
*   Ligand B: 1.699 - Optimal (1-3).
*   *Both are acceptable.*

**4. H-Bond Donors (HBD):**
*   Ligand A: 2 - Acceptable (<=5).
*   Ligand B: 2 - Acceptable (<=5).
*   *Both are acceptable.*

**5. H-Bond Acceptors (HBA):**
*   Ligand A: 5 - Acceptable (<=10).
*   Ligand B: 4 - Acceptable (<=10).
*   *Both are acceptable.*

**6. Quantitative Estimate of Drug-likeness (QED):**
*   Ligand A: 0.604 - Good, above the threshold of 0.5.
*   Ligand B: 0.85 - Excellent, well above the threshold of 0.5.
*   *Ligand B is better.*

**7. DILI Risk (DILI):**
*   Ligand A: 89.57 - High risk (>60).
*   Ligand B: 16.092 - Low risk (<40).
*   *Ligand B is significantly better.*

**8. Blood-Brain Barrier Penetration (BBB):**
*   Ligand A: 45.715 - Below the desirable threshold of 70 for CNS targets.
*   Ligand B: 53.974 - Below the desirable threshold of 70 for CNS targets.
*   *Both are suboptimal, but Ligand B is slightly better.*

**9. Caco-2 Permeability:**
*   Ligand A: -5.12 - Not interpretable without units. Assuming a negative value indicates poor permeability.
*   Ligand B: -4.875 - Not interpretable without units. Assuming a negative value indicates poor permeability.
*   *Difficult to compare without units, but likely similar.*

**10. Aqueous Solubility:**
*   Ligand A: -4.102 - Not interpretable without units. Assuming a negative value indicates poor solubility.
*   Ligand B: -2.176 - Not interpretable without units. Assuming a negative value indicates poor solubility.
*   *Difficult to compare without units, but likely similar.*

**11. hERG Inhibition:**
*   Ligand A: 0.21 - Low risk.
*   Ligand B: 0.168 - Low risk.
*   *Both are acceptable.*

**12. Microsomal Clearance (Cl_mic):**
*   Ligand A: 34.507 mL/min/kg - Moderate clearance.
*   Ligand B: 11.481 mL/min/kg - Low clearance, suggesting better metabolic stability.
*   *Ligand B is better.*

**13. In vitro Half-Life (t1/2):**
*   Ligand A: -2.445 hours - Negative half-life is not possible. This is likely an error or an unusual scale.
*   Ligand B: -12.658 hours - Negative half-life is not possible. This is likely an error or an unusual scale.
*   *Difficult to compare due to the negative values.*

**14. P-gp Efflux:**
*   Ligand A: 0.217 - Low efflux, good for CNS exposure.
*   Ligand B: 0.056 - Very low efflux, excellent for CNS exposure.
*   *Ligand B is better.*

**15. Binding Affinity:**
*   Ligand A: -8.4 kcal/mol - Excellent.
*   Ligand B: -8.3 kcal/mol - Excellent.
*   *Both are very good, with Ligand A having a slight advantage.*

**Overall Assessment:**

Given the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity), Ligand B is the more promising candidate. While both have good affinity, Ligand B demonstrates superior drug-like properties: a lower DILI risk, better QED, lower P-gp efflux, and a more favorable TPSA. Although both have suboptimal BBB penetration, Ligand B is slightly better. The issues with the half-life data are concerning for both, but the other advantages of Ligand B outweigh this uncertainty. The slight affinity advantage of Ligand A is not enough to overcome the significant ADME/Tox benefits of Ligand B.

1
2025-04-17 06:22:17,188 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (355.36 and 345.403 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (58.36) is excellent, well below the 90 A^2 threshold for CNS targets. Ligand B (102.05) is higher, but still acceptable, though less ideal.

**3. logP:** Ligand A (3.536) is at the upper end of the optimal range (1-3), while Ligand B (1.322) is at the lower end. For a CNS target, a slightly higher logP is often preferred to aid membrane permeability, but both are within acceptable limits.

**4. H-Bond Donors:** Ligand A (1) and Ligand B (2) are both within the acceptable limit of <=5.

**5. H-Bond Acceptors:** Ligand A (4) and Ligand B (6) are both within the acceptable limit of <=10.

**6. QED:** Both ligands have good QED scores (0.893 and 0.851), indicating good drug-like properties.

**7. DILI:** Ligand A (32.222) has a lower DILI risk than Ligand B (49.826), which is favorable.

**8. BBB:** Ligand A (66.072) has a significantly better BBB penetration percentile than Ligand B (54.44). This is a crucial factor for a CNS target like DRD2.

**9. Caco-2 Permeability:** Ligand A (-4.66) has a negative value, which is unusual and suggests poor permeability. Ligand B (-5.215) is also negative, but slightly worse. This is a concern for both, but the negative values are on a scale that is hard to interpret without knowing the scale's bounds.

**10. Aqueous Solubility:** Ligand A (-3.626) and Ligand B (-1.992) both have negative solubility values, indicating poor solubility. This is a potential issue for both, but less so for Ligand B.

**11. hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.596 and 0.173), which is excellent.

**12. Microsomal Clearance:** Ligand A (68.316) has a higher microsomal clearance than Ligand B (2.278), suggesting faster metabolism and potentially lower *in vivo* exposure. This favors Ligand B.

**13. In vitro Half-Life:** Ligand A (-8.001) has a negative half-life, which is not physically possible and indicates an issue with the data or scale. Ligand B (1.494) has a short half-life, but it is a reasonable value.

**14. P-gp Efflux:** Ligand A (0.209) has lower P-gp efflux liability than Ligand B (0.035), which is favorable for CNS penetration.

**15. Binding Affinity:** Both ligands have very similar and strong binding affinities (-8.2 and -8.3 kcal/mol). The difference is negligible.

**Overall Assessment:**

Ligand A has a better TPSA, DILI, BBB, and P-gp efflux profile. However, it suffers from a negative Caco-2 permeability and a nonsensical negative in vitro half-life. Ligand B has better metabolic stability (lower Cl_mic) and a more reasonable half-life. The solubility is better for Ligand B, and while the BBB is lower, it is not drastically so.

Given the importance of BBB penetration for a CNS target, and the problematic values for Ligand A's permeability and half-life, I would favor **Ligand A** despite its slightly higher DILI and lower solubility. The significantly better BBB and P-gp efflux outweigh these concerns, assuming the negative permeability and half-life values are data errors.

Output:
0
2025-04-17 06:22:17,188 - INFO - Reasoning:

Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (399.705 Da) is slightly higher than Ligand B (349.519 Da), but both are acceptable.

**2. TPSA:** Ligand A (43.78) is better than Ligand B (52.65). For CNS targets, we want TPSA <= 90, and ideally closer to 60. Both are within the acceptable range, but A is preferable.

**3. logP:** Ligand A (4.31) is higher than Ligand B (2.428). While both are within the 1-3 optimal range, A is pushing the upper limit and could potentially have solubility issues. B is closer to the ideal.

**4. H-Bond Donors:** Both ligands have 1 HBD, which is within the acceptable limit of <=5.

**5. H-Bond Acceptors:** Both ligands have 3 HBA, which is within the acceptable limit of <=10.

**6. QED:** Both ligands have similar QED values (A: 0.782, B: 0.776), indicating good drug-like properties.

**7. DILI:** Ligand B (10.741) has a significantly lower DILI risk than Ligand A (54.634). This is a major advantage for Ligand B.

**8. BBB:** Ligand B (69.058) has a better BBB penetration percentile than Ligand A (62.815). While both are reasonably good, B is closer to the desirable >70 threshold for CNS targets.

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 values, indicating poor permeability. This is a concern for both, but the value for A (-4.961) is slightly less negative than B (-4.749).

**10. Aqueous Solubility:** Both ligands have negative solubility values, indicating poor solubility. A (-4.632) is slightly better than B (-2.447).

**11. hERG Inhibition:** Both ligands have low hERG inhibition liability (A: 0.94, B: 0.523), which is good. B is slightly better.

**12. Microsomal Clearance:** Ligand B (16.188) has a much lower microsomal clearance than Ligand A (49.04). Lower clearance indicates better metabolic stability, a significant advantage for B.

**13. In vitro Half-Life:** Ligand B (-11.214) has a longer in vitro half-life than Ligand A (-10.484), which is preferable.

**14. P-gp Efflux:** Both ligands have very low P-gp efflux liability (A: 0.597, B: 0.031). B is significantly better, which is crucial for CNS penetration.

**15. Binding Affinity:** Both ligands have similar binding affinities (A: -8.4 kcal/mol, B: -8.1 kcal/mol). The difference is less than 1.5 kcal/mol, so this isn't a deciding factor.

**Overall Assessment:**

While Ligand A has a slightly better TPSA and Caco-2 permeability, Ligand B is superior in almost every other critical parameter, especially those prioritized for GPCRs targeting the CNS. Ligand B exhibits lower DILI risk, better BBB penetration, significantly improved metabolic stability (lower Cl_mic and longer t1/2), and lower P-gp efflux. The slightly lower logP of Ligand B is also beneficial. The similar binding affinities make the ADME/Tox advantages of Ligand B decisive.

Output:
1
2025-04-17 06:22:17,188 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (340.423 and 356.491 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (58.64) is better than Ligand B (53.43). Both are below the 90 A^2 threshold for CNS targets, which is excellent.

**3. logP:** Both ligands have good logP values (2.899 and 3.733), falling within the optimal 1-3 range. Ligand B is slightly higher, which *could* be a minor concern for solubility, but isn't critical.

**4. H-Bond Donors:** Both have 1 HBD, which is within the acceptable limit of <=5.

**5. H-Bond Acceptors:** Ligand A has 3 HBAs, and Ligand B has 4. Both are below the acceptable limit of <=10.

**6. QED:** Ligand A (0.92) has a significantly higher QED than Ligand B (0.769), indicating better overall drug-likeness.

**7. DILI:** Ligand A (60.915) has a higher DILI risk than Ligand B (36.952). This is a significant drawback for Ligand A.

**8. BBB:** Ligand A (79.643) has a slightly better BBB penetration percentile than Ligand B (70.027). Both are good, exceeding the 70% threshold for CNS targets, but A is preferable.

**9. Caco-2 Permeability:** Both have negative Caco-2 values (-5.051 and -4.881). This is unusual and suggests poor permeability. However, these values are on a log scale, and the absolute values are similar, so this isn't a major differentiating factor.

**10. Aqueous Solubility:** Both have negative solubility values (-3.333 and -3.394). Similar to Caco-2, these are unusual and indicate poor solubility.

**11. hERG Inhibition:** Both have low hERG inhibition risk (0.39 and 0.68).

**12. Microsomal Clearance:** Ligand B (75.864) has a higher microsomal clearance than Ligand A (24.347). This means Ligand A is more metabolically stable, which is desirable.

**13. In vitro Half-Life:** Ligand B (42.988) has a longer in vitro half-life than Ligand A (21.386). This is a positive for Ligand B.

**14. P-gp Efflux:** Both have low P-gp efflux liability (0.168 and 0.719). Ligand A is better here.

**15. Binding Affinity:** Ligand B (-7.5 kcal/mol) has a significantly stronger binding affinity than Ligand A (-9.7 kcal/mol). This is a crucial advantage, as a 1.5 kcal/mol difference can outweigh other drawbacks.

**Overall Assessment:**

Ligand B has a significantly stronger binding affinity, a longer half-life, and a lower DILI risk. While Ligand A has a slightly better BBB and P-gp efflux, the superior affinity of Ligand B is the most important factor for a GPCR target. The DILI risk associated with Ligand A is a major concern. The similar poor solubility and permeability profiles are less critical given the potency advantage of Ligand B.

Output:
1
2025-04-17 06:22:17,188 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 drug candidates, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (408.292 Da) is slightly higher than Ligand B (371.547 Da), but both are acceptable.

**TPSA:** Ligand A (70.0) is significantly better than Ligand B (92.5). For CNS targets, we want TPSA <= 90, and A is comfortably within that range, while B is close to the upper limit.

**logP:** Both ligands have good logP values (A: 2.733, B: 1.775), falling within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Both ligands have 2 HBDs and 5/4 HBAs, respectively, which are within acceptable limits.

**QED:** Both ligands have similar QED values (A: 0.658, B: 0.573), indicating good drug-likeness.

**DILI:** Both ligands have low DILI risk (A: 13.843, B: 12.214), which is favorable.

**BBB:** This is a critical parameter for a CNS target like DRD2. Ligand B (65.374) has a significantly higher BBB percentile than Ligand A (23.536). This is a major advantage for B.

**Caco-2 Permeability:** Both have negative Caco-2 values (-5.353 and -5.486), which is unusual and suggests poor permeability. However, these values are on a scale where negative values are possible and don't necessarily disqualify a compound.

**Aqueous Solubility:** Both have negative solubility values (-3.176 and -2.645), indicating poor aqueous solubility. This could be a formulation challenge.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (A: 0.835, B: 0.344), which is excellent.

**Microsomal Clearance:** Ligand B (30.433) has lower microsomal clearance than Ligand A (51.684), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand B (-18.099) has a *negative* half-life, which is impossible. This is a significant data quality issue and raises serious concerns about the reliability of the data for Ligand B. Ligand A has a reasonable half-life (32.271).

**P-gp Efflux:** Ligand A (0.539) has lower P-gp efflux than Ligand B (0.042), which is beneficial for CNS penetration.

**Binding Affinity:** Ligand A (-8.5 kcal/mol) has a significantly stronger binding affinity than Ligand B (-6.8 kcal/mol). This is a substantial advantage for A, potentially outweighing some ADME drawbacks. The difference is >1.5 kcal/mol.

**Overall Assessment:**

While Ligand B has a better BBB score and lower microsomal clearance, the negative in vitro half-life is a critical flaw, suggesting a data error or a highly unstable compound. Ligand A, despite a lower BBB score, has a much stronger binding affinity, acceptable ADME properties (with the exception of solubility), and a plausible half-life. The strong affinity is a key advantage for a GPCR target. Given the importance of potency and the questionable data for Ligand B, Ligand A is the more promising candidate.

Output:
1
2025-04-17 06:22:17,189 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (361.433 Da) is slightly higher than Ligand B (337.335 Da), but both are acceptable.

**2. TPSA:** Ligand A (87.3) is excellent, falling well below the 90 A^2 threshold for CNS targets. Ligand B (104.46) is still reasonable but less optimal, being above 90 A^2.

**3. logP:** Both ligands have good logP values (Ligand A: 1.739, Ligand B: 1.196), falling within the optimal 1-3 range.

**4. H-Bond Donors:** Both have 3 HBD, which is within the acceptable limit of <=5.

**5. H-Bond Acceptors:** Ligand A has 3 HBA, while Ligand B has 5. Both are within the acceptable limit of <=10.

**6. QED:** Both ligands have good QED scores (Ligand A: 0.554, Ligand B: 0.727), indicating good drug-like properties.

**7. DILI:** Ligand A (23.924) has a significantly lower DILI risk than Ligand B (64.521). This is a major advantage for Ligand A.

**8. BBB:** Ligand A (80.613) has a much higher BBB penetration percentile than Ligand B (24.855). This is crucial for a CNS target like DRD2.

**9. Caco-2 Permeability:** Ligand A (-4.893) and Ligand B (-5.126) both have negative Caco-2 values, indicating poor permeability. This is a concern for both.

**10. Aqueous Solubility:** Both have negative solubility values (Ligand A: -2.207, Ligand B: -3.958), indicating poor solubility. This is a concern for both.

**11. hERG Inhibition:** Both ligands have very low hERG inhibition risk (Ligand A: 0.224, Ligand B: 0.144).

**12. Microsomal Clearance:** Ligand A (16.591) has a lower (better) microsomal clearance than Ligand B (-28.535). This suggests better metabolic stability for Ligand A.

**13. In vitro Half-Life:** Ligand B (28.545) has a significantly longer in vitro half-life than Ligand A (-5.534). This is a positive for Ligand B.

**14. P-gp Efflux:** Both ligands have very low P-gp efflux liability (Ligand A: 0.015, Ligand B: 0.024).

**15. Binding Affinity:** Both ligands have excellent binding affinities (Ligand A: -8.0 kcal/mol, Ligand B: -8.1 kcal/mol). The difference is minimal.

**Overall Assessment:**

Ligand A is the stronger candidate. While both ligands have similar binding affinities, Ligand A significantly outperforms Ligand B in several critical ADME properties, especially DILI risk and BBB penetration. The lower DILI risk and higher BBB are crucial for CNS drug development. Although both have poor Caco-2 and solubility, the other advantages of Ligand A outweigh this. The longer half-life of Ligand B is a plus, but the superior safety and CNS penetration profile of Ligand A make it the more promising candidate.

Output:
1
2025-04-17 06:22:17,189 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (371.503 and 352.523 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (87.74) is better than Ligand B (55.89) as it is closer to the ideal range of <90 for CNS targets. Ligand B is very good as well.

**3. logP:** Both ligands have similar logP values (1.082 and 1.023), falling within the optimal 1-3 range.

**4. H-Bond Donors:** Ligand A (2) is slightly higher than Ligand B (1), but both are within the acceptable limit of <=5.

**5. H-Bond Acceptors:** Ligand A (6) is higher than Ligand B (4), but both are within the acceptable limit of <=10.

**6. QED:** Both ligands have good QED scores (0.621 and 0.709), indicating good drug-like properties.

**7. DILI:** Ligand A (56.844) has a higher DILI risk than Ligand B (2.559). This is a significant advantage for Ligand B.

**8. BBB:** Ligand B (58.744) has a slightly better BBB penetration percentile than Ligand A (47.15). Both are not ideal, but Ligand B is better.

**9. Caco-2 Permeability:** Ligand A (-5.26) has a worse Caco-2 permeability than Ligand B (-5.066).

**10. Aqueous Solubility:** Ligand A (-3.261) has worse aqueous solubility than Ligand B (-0.581).

**11. hERG Inhibition:** Ligand A (0.194) has a slightly higher hERG inhibition liability than Ligand B (0.477), meaning Ligand B is safer.

**12. Microsomal Clearance:** Ligand A (43.55) has a higher microsomal clearance than Ligand B (-5.211), indicating lower metabolic stability. Ligand B is better.

**13. In vitro Half-Life:** Ligand B (-7.505) has a longer in vitro half-life than Ligand A (-6.404).

**14. P-gp Efflux:** Ligand A (0.035) has a lower P-gp efflux liability than Ligand B (0.004), meaning it is less likely to be pumped out of the brain.

**15. Binding Affinity:** Ligand B (-7.5 kcal/mol) has a slightly better binding affinity than Ligand A (-6.8 kcal/mol). This difference of 0.7 kcal/mol is significant.

**Overall Assessment:**

Ligand B is the superior candidate. It has a significantly lower DILI risk, better BBB penetration, better metabolic stability (lower Cl_mic, longer t1/2), better solubility, and a slightly improved binding affinity. While Ligand A has a lower P-gp efflux liability, the other advantages of Ligand B outweigh this. Given the GPCR target and the need for CNS penetration, the improved ADME properties of Ligand B are crucial.

Output:
1
2025-04-17 06:22:17,189 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (364.408 and 359.47 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (67.43) is better than Ligand B (42.16), as it is closer to the optimal range for CNS targets (<=90). Ligand B is quite low, which *could* indicate reduced hydrogen bonding and potentially lower specificity.

**3. logP:** Ligand A (2.688) is optimal (1-3). Ligand B (4.706) is slightly high, potentially leading to solubility issues and off-target interactions.

**4. H-Bond Donors:** Ligand A (2) is within the acceptable limit of <=5. Ligand B (0) is also good.

**5. H-Bond Acceptors:** Ligand A (3) is within the acceptable limit of <=10. Ligand B (5) is also good.

**6. QED:** Both ligands have similar QED values (0.73 and 0.639), indicating good drug-like properties.

**7. DILI:** Ligand A (29.43) has a significantly lower DILI risk than Ligand B (49.399), suggesting better hepatotoxicity potential.

**8. BBB:** Ligand A (83.792) has a better BBB penetration percentile than Ligand B (79.217), which is crucial for a CNS target like DRD2.

**9. Caco-2 Permeability:** Ligand A (-4.618) is significantly better than Ligand B (-5.031). Higher values indicate better absorption.

**10. Aqueous Solubility:** Ligand A (-3.616) is better than Ligand B (-4.247).

**11. hERG Inhibition:** Ligand A (0.366) has a lower hERG inhibition liability than Ligand B (0.838), indicating a lower risk of cardiotoxicity.

**12. Microsomal Clearance:** Ligand A (45.009) has lower microsomal clearance than Ligand B (52.301), suggesting better metabolic stability.

**13. In vitro Half-Life:** Ligand A (-7.375) has a significantly better in vitro half-life than Ligand B (16.306).

**14. P-gp Efflux:** Ligand A (0.083) has lower P-gp efflux liability than Ligand B (0.72), which is favorable for CNS exposure.

**15. Binding Affinity:** Ligand B (-7.9 kcal/mol) has a slightly better binding affinity than Ligand A (-9.1 kcal/mol). While affinity is important, the difference of 1.2 kcal/mol is not substantial enough to outweigh the numerous advantages of Ligand A.

**Overall Assessment:**

Ligand A consistently outperforms Ligand B across most critical ADME-Tox properties, including DILI, BBB, solubility, hERG, metabolic stability, and P-gp efflux. While Ligand B has slightly better binding affinity, the substantial advantages of Ligand A in terms of safety, permeability, and CNS penetration make it the more promising drug candidate.

Output:
1
2025-04-17 06:22:17,189 - INFO - Reasoning:

Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (371.547 and 376.551 Da) fall comfortably within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (60.93) is better than Ligand B (58.12) as it is closer to the ideal <90 for CNS targets. Both are acceptable.

**3. logP:** Ligand A (0.936) is slightly lower than optimal (1-3), potentially impacting permeability, but still within a reasonable range. Ligand B (3.648) is closer to the ideal range.

**4. H-Bond Donors:** Ligand A (0) is preferable to Ligand B (1). Fewer HBDs generally improve permeability.

**5. H-Bond Acceptors:** Ligand A (4) is better than Ligand B (6). Lower HBA counts are generally favored for CNS penetration.

**6. QED:** Both ligands have good QED scores (0.668 and 0.807, respectively), indicating drug-like properties. Ligand B is slightly better.

**7. DILI:** Both ligands have relatively low DILI risk (11.516 and 71.384), suggesting minimal liver injury potential. Ligand B is slightly higher, but still acceptable.

**8. BBB:** Both ligands show good BBB penetration (71.966 and 75.107), which is crucial for a CNS target like DRD2. Ligand B is slightly better.

**9. Caco-2 Permeability:** Ligand A (-4.731) is significantly worse than Ligand B (-5.186). Lower values indicate lower permeability.

**10. Aqueous Solubility:** Ligand A (-1.055) is better than Ligand B (-4.059). Higher solubility is generally preferred.

**11. hERG Inhibition:** Both ligands have low hERG inhibition risk (0.456 and 0.747), which is good.

**12. Microsomal Clearance:** Ligand A (10.861) has lower clearance, indicating better metabolic stability, than Ligand B (67.769).

**13. In vitro Half-Life:** Ligand A (-5.685) has a longer half-life than Ligand B (15.958).

**14. P-gp Efflux:** Ligand A (0.058) has significantly lower P-gp efflux liability than Ligand B (0.254), which is very important for CNS exposure.

**15. Binding Affinity:** Ligand B (-7.7) has a slightly better binding affinity than Ligand A (-7.4). While both are excellent, the 0.3 kcal/mol difference is noteworthy.

**Overall Assessment:**

Ligand A has several advantages: better TPSA, fewer HBDs/HBAs, better metabolic stability (lower Cl_mic, longer half-life), lower P-gp efflux, and better solubility. These factors are particularly important for CNS penetration. Ligand B has a slightly better logP and binding affinity, and BBB, but these are outweighed by the ADME advantages of Ligand A. Given the GPCR-specific priorities, the improved CNS penetration profile of Ligand A makes it the more promising candidate.

Output:
0
2025-04-17 06:22:17,190 - INFO - Reasoning:

Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight (MW):** Both ligands (349.519 and 378.485 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (43.86) is better than Ligand B (49.85). Both are below the 90 A^2 threshold for CNS targets, which is good.

**3. logP:** Both ligands have good logP values (2.524 and 2.107), falling within the optimal 1-3 range.

**4. H-Bond Donors (HBD):** Both have 0 HBD, which is acceptable.

**5. H-Bond Acceptors (HBA):** Ligand A has 3 HBA, and Ligand B has 4 HBA. Both are below the 10 threshold.

**6. QED:** Both ligands have similar QED values (0.633 and 0.71), indicating good drug-like properties.

**7. DILI:** Ligand A (6.979) has a significantly lower DILI risk than Ligand B (31.485). This is a major advantage for Ligand A.

**8. BBB:** Both ligands have excellent BBB penetration (83.831 and 85.731), exceeding the desirable >70 threshold for CNS targets.

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.903 and -4.464). This is unusual and suggests poor permeability, but the scale is not specified, so it's difficult to interpret.

**10. Aqueous Solubility:** Both ligands have negative solubility values (-1.377 and -2.906). Again, the scale is unclear, but suggests poor solubility.

**11. hERG Inhibition:** Both ligands show low hERG inhibition liability (0.735 and 0.643).

**12. Microsomal Clearance (Cl_mic):** Ligand B (39.309) has slightly lower microsomal clearance than Ligand A (45.185), suggesting better metabolic stability, but the difference is not huge.

**13. In vitro Half-Life:** Ligand B (-6.872) has a longer in vitro half-life than Ligand A (-1.891). This is a positive for Ligand B.

**14. P-gp Efflux:** Both ligands have low P-gp efflux liability (0.105 and 0.191).

**15. Binding Affinity:** Both ligands have identical binding affinities (-7.0 kcal/mol), which is excellent.

**Overall Assessment:**

While both ligands have excellent binding affinity and BBB penetration, Ligand A is superior due to its significantly lower DILI risk. The slight advantage of Ligand B in half-life is outweighed by the higher potential for liver toxicity. The negative Caco-2 and solubility values are concerning for both, but the strong affinity and BBB penetration are crucial for CNS targets. Given the GPCR-specific priorities, and the importance of safety (DILI) for drug development, Ligand A is the more promising candidate.

Output:
1
2025-04-17 06:22:17,190 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 drug candidates, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (354.447 and 358.551 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (99.1) is higher than the preferred <90 for CNS targets, while Ligand B (23.55) is excellent. This is a significant advantage for B.

**3. logP:** Ligand A (0.21) is quite low, potentially hindering membrane permeability. Ligand B (4.76) is slightly high, but still within an acceptable range, and could be optimized.

**4. H-Bond Donors:** Ligand A (3) is acceptable. Ligand B (0) is also good, potentially improving permeability.

**5. H-Bond Acceptors:** Both ligands (A: 5, B: 3) are within the acceptable limit of 10.

**6. QED:** Both ligands have good QED scores (A: 0.541, B: 0.712), indicating drug-like properties.

**7. DILI:** Both ligands have low DILI risk (A: 20.279, B: 15.2), which is favorable.

**8. BBB:** This is a critical parameter for CNS targets. Ligand A (38.852) has a poor BBB percentile, while Ligand B (96.355) is excellent, exceeding the >70 desirable threshold. This is a major advantage for B.

**9. Caco-2 Permeability:** Ligand A (-5.218) has very poor Caco-2 permeability. Ligand B (-4.512) is also poor, but slightly better than A.

**10. Aqueous Solubility:** Ligand A (-1.395) and B (-4.073) both have poor solubility.

**11. hERG Inhibition:** Ligand A (0.176) and B (0.809) both have acceptable hERG inhibition liability.

**12. Microsomal Clearance:** Ligand A (18.489) has lower clearance than Ligand B (83.543), suggesting better metabolic stability.

**13. In vitro Half-Life:** Ligand B (43.384) has a significantly longer half-life than Ligand A (5.557), which is desirable.

**14. P-gp Efflux:** Ligand A (0.048) has very low P-gp efflux, which is good. Ligand B (0.439) is slightly higher, but still reasonable.

**15. Binding Affinity:** Both ligands have the same excellent binding affinity (-7.3 kcal/mol).

**Overall Assessment:**

While Ligand A has better metabolic stability and P-gp efflux, its extremely low logP, poor BBB penetration, and poor Caco-2 permeability are major drawbacks for a CNS-targeting drug. Ligand B excels in the critical areas for a CNS GPCR target: excellent BBB penetration, a reasonable logP, and a good half-life. The slightly higher metabolic clearance and slightly higher P-gp efflux can be addressed through further optimization. The TPSA is also significantly better for Ligand B. The similar binding affinity means the ADME properties will be the deciding factor.

Output:
1
2025-04-17 06:22:17,190 - INFO - Batch 276 complete. Total preferences: 4416
2025-04-17 06:22:17,190 - INFO - Processing batch 277/512...
2025-04-17 06:23:02,941 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (354.447 Da) is slightly lower, which could be beneficial for permeability.

**TPSA:** Both ligands have TPSA values below 90 (A: 84.94, B: 86.8), which is good for CNS penetration.

**logP:** Ligand A (1.252) is closer to the optimal range (1-3) than Ligand B (2.827). While 2.827 isn't terrible, 1.252 suggests better solubility.

**H-Bond Donors/Acceptors:** Ligand A (HBD=1, HBA=5) is better than Ligand B (HBD=2, HBA=7) in terms of adhering to the <5 HBD and <10 HBA rule.

**QED:** Both ligands have acceptable QED values (A: 0.663, B: 0.714), indicating good drug-like properties.

**DILI:** Ligand A (26.173) has a significantly lower DILI risk than Ligand B (70.88). This is a major advantage for Ligand A.

**BBB:** Both ligands have similar BBB penetration (A: 42.303, B: 42.264), and are not ideal (aim for >70). However, this is less critical if other properties are favorable.

**Caco-2 Permeability:** Ligand A (-4.996) has a more negative Caco-2 value, suggesting *lower* permeability than Ligand B (-5.456). This is a negative for Ligand A.

**Aqueous Solubility:** Ligand A (-1.265) has better solubility than Ligand B (-3.239).

**hERG Inhibition:** Ligand A (0.18) has a much lower hERG inhibition risk than Ligand B (0.642). This is a significant advantage for Ligand A.

**Microsomal Clearance:** Ligand B (57.447) has lower microsomal clearance than Ligand A (11.746), indicating better metabolic stability.

**In vitro Half-Life:** Ligand B (24.21) has a significantly longer half-life than Ligand A (-0.042). This is a major advantage for Ligand B.

**P-gp Efflux:** Ligand A (0.024) has lower P-gp efflux than Ligand B (0.179), which is favorable for CNS penetration.

**Binding Affinity:** Ligand B (-8.2 kcal/mol) has a slightly better binding affinity than Ligand A (-7.7 kcal/mol). This difference is 0.5 kcal/mol, which is a moderate advantage.

**Overall Assessment:**

Ligand A excels in safety (DILI, hERG) and solubility, and has lower P-gp efflux. Ligand B has better metabolic stability (lower Cl_mic, longer t1/2) and a slightly better binding affinity. The BBB values are similar and suboptimal for both. However, the significantly lower DILI and hERG risks for Ligand A, combined with its better solubility and P-gp profile, outweigh the modest affinity advantage of Ligand B, especially given the importance of safety for CNS drugs. The Caco-2 permeability is a concern for Ligand A, but can potentially be addressed with formulation strategies.

Output:
0
2025-04-17 06:23:02,941 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (349.439 and 347.419 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (106.25) is slightly higher than Ligand B (96.41). Both are below the 140 threshold for oral absorption, but closer to the 90 target for CNS penetration. Ligand B is preferable here.

**logP:** Ligand A (0.286) is quite low, potentially hindering membrane permeability. Ligand B (0.946) is better, falling within the optimal 1-3 range. This is a significant advantage for Ligand B.

**H-Bond Donors/Acceptors:** Ligand A has 3 HBD and 5 HBA, while Ligand B has 2 HBD and 7 HBA. Both are within acceptable limits.

**QED:** Both ligands have good QED scores (0.708 and 0.862), indicating drug-likeness.

**DILI:** Ligand A (43.622) has a slightly better DILI score than Ligand B (52.772), but both are below the concerning threshold of 60.

**BBB:** This is critical for a CNS target. Ligand A has a BBB percentile of 61.613, which is reasonable but not outstanding. Ligand B has a significantly lower BBB percentile of 24.351, which is a major drawback.

**Caco-2 Permeability:** Both have negative Caco-2 values (-5.373 and -4.974), which is unusual and suggests poor permeability.

**Aqueous Solubility:** Both ligands have very poor aqueous solubility (-1.715 and -1.647). This is a concern for formulation.

**hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.249 and 0.096).

**Microsomal Clearance:** Ligand A (-26.459) has a much lower (better) microsomal clearance than Ligand B (6.185), indicating greater metabolic stability.

**In vitro Half-Life:** Ligand B (17.763 hours) has a significantly longer half-life than Ligand A (1.436 hours), which is a major advantage.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.004 and 0.062).

**Binding Affinity:** Both ligands have similar and excellent binding affinities (-8.6 and -8.5 kcal/mol). The difference is negligible.

**Overall Assessment:**

Ligand B has advantages in logP and in vitro half-life, which are important for a GPCR targeting the CNS. However, its significantly lower BBB penetration is a major concern. Ligand A has a better BBB score and better metabolic stability (lower Cl_mic). While Ligand A's logP is suboptimal, the better BBB and metabolic stability outweigh this, especially considering the similar binding affinities. The poor solubility and Caco-2 values are concerns for both, but can be addressed with formulation strategies.

Output:
0
2025-04-17 06:23:02,941 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 drug candidates, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (365.539 and 351.491 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (55.4) is excellent, well below the 90 A^2 threshold for CNS targets. Ligand B (101.29) is higher, but still potentially acceptable, though less ideal.

**3. logP:** Ligand A (3.668) is within the optimal 1-3 range. Ligand B (1.868) is at the lower end of the optimal range, potentially impacting permeability.

**4. H-Bond Donors:** Ligand A (1) is good. Ligand B (3) is acceptable, but higher.

**5. H-Bond Acceptors:** Both ligands have 3 HBA, which is within the acceptable limit of 10.

**6. QED:** Ligand A (0.802) is excellent, indicating high drug-likeness. Ligand B (0.622) is still good, but lower than Ligand A.

**7. DILI:** Ligand A (36.06) has a slightly higher DILI risk than Ligand B (26.095), but both are below the concerning threshold of 60.

**8. BBB:** Ligand A (81) has a significantly better BBB penetration percentile than Ligand B (65.723). This is a *critical* advantage for a CNS target like DRD2.

**9. Caco-2 Permeability:** Ligand A (-4.969) has better Caco-2 permeability than Ligand B (-5.241).

**10. Aqueous Solubility:** Ligand A (-4.463) has better aqueous solubility than Ligand B (-3.552).

**11. hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.779 and 0.138, respectively).

**12. Microsomal Clearance:** Ligand A (67.794) has higher microsomal clearance than Ligand B (58.284), suggesting lower metabolic stability.

**13. In vitro Half-Life:** Ligand B (-17.542) has a longer in vitro half-life than Ligand A (-31.296).

**14. P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.516 and 0.06, respectively).

**15. Binding Affinity:** Both ligands have identical binding affinities (-8.1 kcal/mol), which is excellent.

**Overall Assessment:**

While Ligand B has a slightly better half-life and lower DILI risk, Ligand A is superior due to its significantly better BBB penetration (81 vs 65.723), better TPSA (55.4 vs 101.29), and better solubility.  For a CNS GPCR target, BBB penetration is paramount. The slightly higher clearance of Ligand A is a manageable concern, especially given its excellent binding affinity. The better QED score also favors Ligand A.

Output:
1
2025-04-17 06:23:02,941 - INFO - Reasoning:

Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (388.917 and 352.414 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (67.87) is better than Ligand B (78.07). For CNS targets, we want TPSA <= 90, both are within this range, but A is closer to the optimal value.

**3. logP:** Both ligands have good logP values (2.512 and 1.452), falling within the optimal 1-3 range.

**4. H-Bond Donors:** Ligand A (1) is preferable to Ligand B (0), as having some HBD can improve solubility.

**5. H-Bond Acceptors:** Ligand B (7) is preferable to Ligand A (5).

**6. QED:** Both ligands have acceptable QED values (0.858 and 0.719), indicating good drug-like properties.

**7. DILI:** Both ligands have similar, acceptable DILI risk (40.054 and 41.411 percentile).

**8. BBB:** Ligand B (74.564) is significantly better than Ligand A (53.897) in terms of BBB penetration. This is a *critical* factor for a CNS target like DRD2.

**9. Caco-2 Permeability:** Ligand A (-5.034) is better than Ligand B (-4.533), indicating better intestinal absorption.

**10. Aqueous Solubility:** Ligand A (-2.975) is better than Ligand B (-0.91), indicating better solubility.

**11. hERG Inhibition:** Both ligands have low hERG inhibition risk (0.642 and 0.228).

**12. Microsomal Clearance:** Ligand A (9.588) has lower clearance than Ligand B (48.389), suggesting better metabolic stability.

**13. In vitro Half-Life:** Ligand A (-1.046) has a longer half-life than Ligand B (5.27).

**14. P-gp Efflux:** Ligand A (0.161) has lower P-gp efflux than Ligand B (0.133), indicating better CNS exposure.

**15. Binding Affinity:** Ligand B (-7.2 kcal/mol) has a slightly better binding affinity than Ligand A (-8.1 kcal/mol). While A is better, the difference is not substantial enough to outweigh the other factors.

**Overall Assessment:**

Ligand A has advantages in TPSA, solubility, metabolic stability, half-life, and P-gp efflux. However, Ligand B *significantly* outperforms Ligand A in BBB penetration, which is paramount for a DRD2 ligand. The slightly better affinity of Ligand B is a bonus. While Ligand A has a slightly better binding affinity, the substantial improvement in BBB penetration with Ligand B makes it the more promising candidate.

Output:
1
2025-04-17 06:23:02,942 - INFO - Okay, let's analyze these two ligands for their potential as DRD2 drug candidates. DRD2 is a GPCR in the CNS, so BBB penetration, logP, Pgp efflux, TPSA, and binding affinity are paramount.

**Ligand A:** [341.411, 73.1, 2.397, 1, 5, 0.928, 64.754, 75.572, -4.509, -3.369, 0.443, 10.426, 11.631, 0.193, -8.9]
**Ligand B:** [348.531, 40.62, 3.842, 0, 2, 0.757, 16.906, 92.827, -4.567, -3.526, 0.683, 72.515, -3.673, 0.351, -8.1]

Here's a breakdown comparing each property:

1. **MW:** Both are within the ideal range (200-500 Da).
2. **TPSA:** Ligand A (73.1) is higher than Ligand B (40.62).  For CNS targets, we want TPSA < 90, so both are acceptable, but B is significantly better.
3. **logP:** Both are good (between 1-3), but Ligand B (3.842) is closer to the upper limit and might have solubility issues, while A (2.397) is optimal.
4. **HBD:** Ligand A (1) is slightly better than Ligand B (0). Fewer HBDs generally improve permeability.
5. **HBA:** Ligand A (5) is higher than Ligand B (2). Lower HBA is preferred for permeability.
6. **QED:** Ligand A (0.928) has a much better QED score than Ligand B (0.757), indicating a more drug-like profile.
7. **DILI:** Ligand A (64.754) has a higher DILI risk than Ligand B (16.906). B is significantly better here.
8. **BBB:** Ligand B (92.827) has a *much* better BBB percentile than Ligand A (75.572). This is a critical advantage for a CNS target.
9. **Caco-2:** Both have negative Caco-2 values, which is unusual and suggests poor permeability. This is a concern for both.
10. **Solubility:** Both have negative solubility values, which is also unusual and suggests poor solubility. This is a concern for both.
11. **hERG:** Both have low hERG risk.
12. **Cl_mic:** Ligand B (72.515) has a lower microsomal clearance than Ligand A (10.426), suggesting better metabolic stability.
13. **t1/2:** Ligand A (11.631) has a longer in vitro half-life than Ligand B (-3.673). This is a positive for A.
14. **Pgp:** Ligand B (0.351) has lower P-gp efflux liability than Ligand A (0.193), meaning better CNS exposure.
15. **Binding Affinity:** Ligand A (-8.9 kcal/mol) has a slightly better binding affinity than Ligand B (-8.1 kcal/mol). This difference is significant (0.8 kcal/mol).

**Overall Assessment:**

While Ligand A has a slightly better binding affinity and in vitro half-life, Ligand B is superior in almost all other critical ADME properties for a CNS-targeting GPCR. Specifically, the significantly better BBB penetration (92.8% vs 75.6%), lower DILI risk, lower Pgp efflux, and lower TPSA make Ligand B a much more promising candidate. The lower microsomal clearance is also a plus. The QED score is lower for B, but the other benefits outweigh this. The negative Caco-2 and solubility values are concerning for both, but can be addressed through formulation strategies.

Therefore, I recommend prioritizing **Ligand B**.

1
2025-04-17 06:23:02,942 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (352.475 and 338.375 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (75.71) is excellent, well below the 90 A^2 threshold for CNS targets. Ligand B (134.5) is higher, but still potentially acceptable, though less ideal.

**logP:** Both ligands have good logP values (1.975 and 1.479), falling within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A (1 HBD, 4 HBA) is better than Ligand B (4 HBD, 7 HBA) in terms of balancing solubility and permeability.

**QED:** Both ligands have acceptable QED scores (0.678 and 0.512), indicating reasonable drug-likeness.

**DILI:** Ligand A (21.442) has a significantly lower DILI risk than Ligand B (68.282). This is a major advantage.

**BBB:** Ligand A (75.805) has a much higher BBB penetration score than Ligand B (30.748). This is *critical* for a CNS target like DRD2.

**Caco-2 Permeability:** Ligand A (-4.464) has a worse Caco-2 permeability score than Ligand B (-6.081). However, given the CNS target, intestinal absorption is less crucial than BBB penetration.

**Aqueous Solubility:** Both ligands have similar, poor aqueous solubility scores (-2.34 and -2.76). This could pose formulation challenges, but isn't a dealbreaker.

**hERG Inhibition:** Both ligands have low hERG inhibition liability (0.26 and 0.517), which is good.

**Microsomal Clearance:** Ligand A (75.069) has higher microsomal clearance than Ligand B (-4.781), suggesting lower metabolic stability. This is a drawback for Ligand A.

**In vitro Half-Life:** Ligand B (3.344) has a slightly better in vitro half-life than Ligand A (-20.315).

**P-gp Efflux:** Ligand A (0.1) shows very low P-gp efflux, which is excellent for CNS penetration. Ligand B (0.01) is even lower, which is also excellent.

**Binding Affinity:** Ligand B (-8.6 kcal/mol) has a slightly better binding affinity than Ligand A (-7.7 kcal/mol). While a 1.5 kcal/mol difference is significant, the other factors are more important in this case.

**Overall Assessment:**

Ligand A is significantly better overall. The superior BBB penetration (75.805 vs 30.748), much lower DILI risk (21.442 vs 68.282), and low P-gp efflux outweigh the slightly lower binding affinity and higher microsomal clearance. For a CNS GPCR target, BBB penetration is paramount, and Ligand A excels in this area. The difference in binding affinity, while present, is not substantial enough to overcome the significant advantages of Ligand A in terms of safety and CNS exposure.

Output:
1
2025-04-17 06:23:02,942 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (368.455 and 377.432 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (95.94) is higher than the preferred <90 for CNS targets, while Ligand B (45.55) is excellent. This is a significant advantage for Ligand B.

**logP:** Ligand A (0.223) is quite low, potentially hindering membrane permeability. Ligand B (1.919) is within the optimal 1-3 range. This favors Ligand B.

**H-Bond Donors/Acceptors:** Ligand A has 2 HBD and 6 HBA, acceptable values. Ligand B has 0 HBD and 5 HBA, also acceptable.

**QED:** Both ligands have good QED scores (0.674 and 0.76), indicating good drug-like properties.

**DILI:** Ligand A (53.625) has a moderate DILI risk, while Ligand B (22.218) has a low DILI risk. This favors Ligand B.

**BBB:** Ligand A (54.478) has a poor BBB penetration percentile. Ligand B (87.088) has excellent BBB penetration, a critical factor for a CNS target like DRD2. This is a major advantage for Ligand B.

**Caco-2 Permeability:** Ligand A (-5.207) has poor Caco-2 permeability, consistent with its low logP. Ligand B (-4.766) is also not great, but slightly better than A.

**Aqueous Solubility:** Both ligands have poor aqueous solubility (-2.793 and -1.851). This could present formulation challenges, but is less critical than BBB penetration for a CNS drug.

**hERG Inhibition:** Ligand A (0.103) has very low hERG inhibition risk, while Ligand B (0.67) has a slightly higher, but still acceptable, risk.

**Microsomal Clearance:** Ligand A (46.964) has moderate clearance, while Ligand B (7.901) has very low clearance, indicating better metabolic stability. This favors Ligand B.

**In vitro Half-Life:** Ligand A (-12.976) has a very short half-life, while Ligand B (-26.107) has a longer half-life. This favors Ligand B.

**P-gp Efflux:** Ligand A (0.078) has low P-gp efflux, which is good. Ligand B (0.095) also has low P-gp efflux.

**Binding Affinity:** Both ligands have similar and strong binding affinities (-7.5 and -7.0 kcal/mol). The difference of 0.5 kcal/mol is not enough to override the significant ADME advantages of Ligand B.

**Conclusion:**

Ligand B is significantly more promising. It excels in key properties for a CNS-targeting GPCR ligand: excellent BBB penetration, favorable logP, low DILI risk, improved metabolic stability (low Cl_mic and longer t1/2), and acceptable TPSA. While both ligands have similar binding affinities and solubility concerns, the ADME profile of Ligand B is far superior, making it the more viable drug candidate.

Output:
1
2025-04-17 06:23:02,942 - INFO - Reasoning:

Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (332.491 and 348.418 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (6.48) is excellent, well below the 90 A^2 threshold for CNS targets. Ligand B (69.64) is higher, but still potentially acceptable, though less ideal.

**3. logP:** Ligand A (4.48) is slightly above the optimal 1-3 range, potentially leading to solubility issues. Ligand B (2.688) is within the optimal range.

**4. H-Bond Donors:** Both ligands have acceptable HBD counts (0 for A, 2 for B), well below the 5 threshold.

**5. H-Bond Acceptors:** Both ligands have acceptable HBA counts (2 for A, 3 for B), well below the 10 threshold.

**6. QED:** Both ligands have good QED scores (0.814 and 0.83), indicating good drug-like properties.

**7. DILI:** Ligand A (22.024) has a very low DILI risk, significantly better than Ligand B (31.175).

**8. BBB:** This is crucial for a CNS target. Ligand A (97.131) has excellent BBB penetration, while Ligand B (70.88) is good, but less favorable.

**9. Caco-2 Permeability:** Ligand A (-4.904) and Ligand B (-4.752) both have negative values, indicating poor permeability. This is a concern for both.

**10. Aqueous Solubility:** Ligand A (-5.013) and Ligand B (-3.638) both have negative values, indicating poor solubility. This is a concern for both.

**11. hERG Inhibition:** Both ligands show low hERG inhibition risk (0.981 and 0.469).

**12. Microsomal Clearance:** Ligand A (51.051) has a higher microsomal clearance than Ligand B (42.085), suggesting lower metabolic stability.

**13. In vitro Half-Life:** Ligand A (-12.896) has a shorter half-life than Ligand B (-4.605).

**14. P-gp Efflux:** Ligand A (0.672) has lower P-gp efflux than Ligand B (0.063), which is favorable for CNS penetration.

**15. Binding Affinity:** Ligand B (-7.8) has a significantly stronger binding affinity than Ligand A (-9.5). This is a substantial advantage.

**Overall Assessment:**

Ligand B has a superior binding affinity and a better logP value. However, Ligand A has a much better BBB score, lower DILI risk, and lower P-gp efflux. The strong affinity of Ligand B is a significant advantage, potentially outweighing the slightly less favorable BBB and higher DILI risk. The poor Caco-2 and solubility for both are concerning, but can be addressed with formulation strategies. Given the importance of binding affinity for GPCRs, and the reasonably acceptable BBB and safety profiles of Ligand B, it appears to be the more promising candidate.

Output:
1
2025-04-17 06:23:02,943 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (353.5 and 356.5 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (61.88) is excellent, well below the 90 threshold for CNS targets. Ligand B (84.91) is still reasonable but less optimal.

**logP:** Ligand A (1.785) is within the optimal 1-3 range. Ligand B (0.064) is quite low, potentially hindering permeability.

**H-Bond Donors/Acceptors:** Ligand A (1 HBD, 4 HBA) is favorable. Ligand B (3 HBD, 5 HBA) is acceptable, though slightly higher.

**QED:** Ligand A (0.642) is good, indicating strong drug-likeness. Ligand B (0.482) is lower, suggesting a less ideal drug-like profile.

**DILI:** Ligand A (10.275) has a very low DILI risk. Ligand B (4.033) also has a low DILI risk, but slightly higher than A.

**BBB:** Ligand A (70.143) has excellent BBB penetration, meeting the >70% threshold for CNS targets. Ligand B (32.532) is significantly lower, raising concerns about CNS exposure.

**Caco-2 Permeability:** Ligand A (-4.775) has poor Caco-2 permeability. Ligand B (-5.462) is also poor.

**Aqueous Solubility:** Ligand A (-0.977) has poor solubility. Ligand B (-0.495) is also poor.

**hERG:** Both ligands have very low hERG inhibition risk (0.482 and 0.213 respectively).

**Microsomal Clearance:** Ligand A (26.358) has moderate clearance, while Ligand B (20.165) has lower clearance, indicating better metabolic stability.

**In vitro Half-Life:** Ligand A (5.297 hours) has a moderate half-life. Ligand B (-5.804 hours) has a negative half-life, which is not possible and likely represents an outlier or error in the data.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.114 and 0.002 respectively).

**Binding Affinity:** Ligand B (-6.7 kcal/mol) has a significantly stronger binding affinity than Ligand A (-0.0 kcal/mol). This is a crucial advantage.

**Overall Assessment:**

Despite the poor Caco-2 and solubility for both, Ligand B's significantly stronger binding affinity (-6.7 vs -0.0 kcal/mol) is a major advantage that likely outweighs the lower BBB and logP. The negative half-life for ligand B is a red flag and suggests a data error. However, even without considering that, the affinity difference is substantial. For a GPCR target like DRD2, strong binding is paramount, and the other parameters can potentially be optimized in later stages of drug development. Ligand A's excellent BBB is negated by its extremely weak binding.

Output:
1
2025-04-17 06:23:02,943 - INFO - Reasoning:

Let's analyze Ligand A and Ligand B against the provided guidelines, prioritizing GPCR-specific properties (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (346.515 and 348.418 Da) fall comfortably within the ideal 200-500 Da range.

**TPSA:** Ligand A (49.41) is excellent, well below the 90 A^2 threshold for CNS targets. Ligand B (67.43) is still reasonable, but less optimal.

**logP:** Ligand A (3.666) is at the higher end of the optimal range (1-3), but still acceptable. Ligand B (2.48) is well within the optimal range.

**H-Bond Donors/Acceptors:** Ligand A (HBD=1, HBA=2) and Ligand B (HBD=2, HBA=3) both have acceptable numbers of H-bond donors and acceptors.

**QED:** Both ligands have good QED scores (A: 0.565, B: 0.795), indicating good drug-like properties. Ligand B is slightly better.

**DILI:** Ligand A (23.226) has a significantly lower DILI risk than Ligand B (40.83), making it safer from a liver toxicity perspective.

**BBB:** This is a critical parameter for a CNS target like DRD2. Ligand A (64.676) is decent, but Ligand B (89.841) is *very* good, exceeding the >70 percentile threshold.

**Caco-2 Permeability:** Both show poor Caco-2 permeability (-5.085 and -4.523). This suggests potential absorption issues.

**Aqueous Solubility:** Both ligands have very poor aqueous solubility (-4.006 and -3.925). This could present formulation challenges.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.549 and 0.538).

**Microsomal Clearance:** Ligand A (66.464) has a higher microsomal clearance than Ligand B (17.358), indicating faster metabolism and potentially lower *in vivo* exposure.

**In vitro Half-Life:** Ligand B (22.38) has a significantly longer half-life than Ligand A (2.453), which is a major advantage.

**P-gp Efflux:** Both ligands show negligible P-gp efflux (0.639 and 0.178).

**Binding Affinity:** Ligand B (-8.7 kcal/mol) has a *much* stronger binding affinity than Ligand A (-0.0 kcal/mol). This is a decisive advantage, potentially outweighing some of the ADME drawbacks.

**Overall Assessment:**

While Ligand A has a better safety profile (lower DILI) and TPSA, Ligand B excels in the most critical areas for a CNS GPCR target: **BBB penetration and binding affinity**. The significantly stronger binding affinity of Ligand B (-8.7 vs -0.0 kcal/mol) is a substantial advantage. The longer half-life of Ligand B is also a significant benefit. The poor solubility and Caco-2 permeability are concerns for both, but can potentially be addressed through formulation strategies. The higher DILI risk for Ligand B is a concern, but the strong affinity may allow for lower dosing, mitigating this risk.

Output:
1
2025-04-17 06:23:02,943 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (349.475 and 373.9 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (74.57) is better than Ligand B (47.36) as it is closer to the optimal range for CNS targets (<=90). Ligand B is excellent.

**3. logP:** Ligand A (1.944) is within the optimal range (1-3). Ligand B (3.744) is at the higher end but still acceptable.

**4. H-Bond Donors:** Ligand A (2) is good. Ligand B (0) is also good.

**5. H-Bond Acceptors:** Both ligands (4) are within the acceptable limit of <=10.

**6. QED:** Both ligands (0.753 and 0.763) have excellent drug-likeness scores.

**7. DILI:** Both ligands have low DILI risk (24.467 and 22.993), which is favorable.

**8. BBB:** This is a crucial parameter for CNS targets. Ligand B (95.076) significantly outperforms Ligand A (47.732). This is a major advantage for Ligand B.

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.737 and -4.27), which is unusual and suggests poor permeability. This is a concern for both.

**10. Aqueous Solubility:** Both ligands have negative solubility values (-1.715 and -3.562), indicating poor aqueous solubility. This is a concern for both.

**11. hERG Inhibition:** Both ligands have low hERG inhibition risk (0.343 and 0.611), which is good.

**12. Microsomal Clearance:** Ligand A (23.067) has lower clearance than Ligand B (43.527), suggesting better metabolic stability.

**13. In vitro Half-Life:** Ligand B (6.174) has a slightly longer half-life than Ligand A (4.414).

**14. P-gp Efflux:** Both ligands have low P-gp efflux liability (0.164 and 0.179), which is favorable for CNS penetration.

**15. Binding Affinity:** Ligand A (-8.2 kcal/mol) has a significantly stronger binding affinity than Ligand B (-7.1 kcal/mol). This is a substantial advantage for Ligand A (a 1.1 kcal/mol difference).

**Overall Assessment:**

While Ligand A has superior binding affinity and metabolic stability, Ligand B's significantly higher BBB penetration (95.076 vs 47.732) is a critical advantage for a CNS target like DRD2. The difference in binding affinity, while substantial, might be outweighed by the drastically improved brain exposure offered by Ligand B. The poor Caco-2 and solubility for both are concerning, but can potentially be addressed with formulation strategies. Given the GPCR-specific priority of BBB penetration, Ligand B is the more promising candidate.

Output:
1
2025-04-17 06:23:02,943 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (345.311 and 355.435 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (123.71) is slightly above the optimal <90 for CNS targets, but still reasonable. Ligand B (107.97) is better, falling comfortably below 90.

**logP:** Ligand A (1.282) is within the optimal 1-3 range. Ligand B (-0.593) is below 1, which could hinder permeation.

**H-Bond Donors/Acceptors:** Ligand A (HBD=2, HBA=6) and Ligand B (HBD=3, HBA=5) both have acceptable numbers of H-bond donors and acceptors.

**QED:** Both ligands have good QED scores (A: 0.462, B: 0.566), indicating reasonable drug-likeness.

**DILI:** Ligand A (83.172) has a higher DILI risk than Ligand B (11.322). This is a significant negative for Ligand A.

**BBB:** Ligand A (45.715) has a low BBB penetration percentile, which is a major drawback for a CNS target like DRD2. Ligand B (36.06) is also low, but slightly better.

**Caco-2 Permeability:** Ligand A (-4.91) has poor Caco-2 permeability, suggesting poor intestinal absorption. Ligand B (-5.256) is also poor, but comparable.

**Aqueous Solubility:** Ligand A (-4.124) has poor aqueous solubility. Ligand B (-0.574) is also poor, but better than A.

**hERG Inhibition:** Both ligands have very low hERG inhibition risk (A: 0.511, B: 0.053).

**Microsomal Clearance:** Ligand A (16.359) has a moderate microsomal clearance. Ligand B (-18.662) has a *negative* clearance, which is unusual and likely an artifact of the prediction method, but suggests very high metabolic stability.

**In vitro Half-Life:** Ligand A (46.784) has a reasonable half-life. Ligand B (15.872) has a shorter half-life.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (A: 0.386, B: 0.002), which is good for CNS penetration.

**Binding Affinity:** Ligand B (-7.3 kcal/mol) has a significantly stronger binding affinity than Ligand A (-9.0 kcal/mol). This is a substantial advantage.

**Overall Assessment:**

Ligand B is the superior candidate. While both have issues with Caco-2 permeability and solubility, Ligand B's significantly better binding affinity, much lower DILI risk, and slightly better BBB penetration outweigh the drawbacks. Ligand A's high DILI risk and poor BBB penetration are major concerns for a CNS-targeting drug. The negative clearance for Ligand B is a flag, but the overall profile is still more promising.

Output:
1
2025-04-17 06:23:02,943 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (348.349 and 356.463 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (60.45) is excellent, well below the 90 A^2 threshold for CNS targets. Ligand B (99.1) is higher, but still potentially acceptable, though less ideal.

**logP:** Ligand A (2.595) is optimal (1-3). Ligand B (0.288) is quite low, which could hinder membrane permeability and CNS penetration.

**H-Bond Donors/Acceptors:** Ligand A (1 HBD, 4 HBA) is good. Ligand B (3 HBD, 5 HBA) is also acceptable.

**QED:** Ligand A (0.836) is very good, indicating high drug-likeness. Ligand B (0.675) is also good, but lower than A.

**DILI:** Ligand A (59.946) has a moderate DILI risk, but is acceptable. Ligand B (30.322) has a very low DILI risk, which is excellent.

**BBB:** This is crucial for a CNS target. Ligand A (92.129) has excellent BBB penetration potential. Ligand B (35.401) has very poor predicted BBB penetration.

**Caco-2 Permeability:** Ligand A (-3.968) is poor. Ligand B (-4.987) is also poor.

**Aqueous Solubility:** Ligand A (-4.041) is poor. Ligand B (-1.091) is also poor.

**hERG:** Both ligands have very low hERG inhibition risk (0.456 and 0.134, respectively).

**Microsomal Clearance:** Ligand A (80.726) has moderate clearance. Ligand B (16.803) has low clearance, indicating better metabolic stability.

**In vitro Half-Life:** Ligand A (-32.209) has a long half-life which is good. Ligand B (8.815) has a short half-life, which is less desirable.

**P-gp Efflux:** Ligand A (0.108) has low P-gp efflux, which is good for CNS penetration. Ligand B (0.018) also has very low P-gp efflux.

**Binding Affinity:** Ligand A (-8.9 kcal/mol) has significantly stronger binding affinity than Ligand B (0.0 kcal/mol). This is a major advantage.

**Overall Assessment:**

Ligand A is clearly superior. While Ligand B has a better DILI score and metabolic stability, the critical factors for a CNS-targeting GPCR like DRD2 are high BBB penetration and strong binding affinity. Ligand A excels in both of these areas, with a very high BBB percentile and a much more negative binding energy. The lower logP of Ligand B is a significant concern, as it will likely limit its ability to cross the blood-brain barrier, even with low P-gp efflux. The poor Caco-2 and solubility of both ligands are drawbacks, but can potentially be addressed with formulation strategies. The strong binding affinity of Ligand A can potentially compensate for these issues.

Output:
1
2025-04-17 06:23:02,944 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (342.443 and 362.47 Da) fall comfortably within the ideal 200-500 Da range.

**TPSA:** Ligand A (67.23) is slightly higher than Ligand B (53.43). Both are below the 90 A^2 threshold desirable for CNS targets, but B is better.

**logP:** Ligand A (2.049) is within the optimal 1-3 range. Ligand B (4.011) is at the upper end, potentially raising concerns about solubility and off-target effects, but still acceptable.

**H-Bond Donors/Acceptors:** Both have 1 HBD and 4 HBA, which are within acceptable limits.

**QED:** Both ligands have similar QED values (0.833 and 0.81), indicating good drug-likeness.

**DILI:** Ligand A (35.983) has a lower DILI risk than Ligand B (31.989), which is preferable.

**BBB:** Both ligands exhibit excellent BBB penetration (Ligand A: 83.443, Ligand B: 86.274), exceeding the 70% threshold for CNS targets. Ligand B is slightly better.

**Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and suggests poor permeability. However, these values are on a strange scale, and may not be directly comparable.

**Aqueous Solubility:** Both have negative solubility values, which is also unusual. Again, these values are on a strange scale, and may not be directly comparable.

**hERG Inhibition:** Ligand A (0.175) shows a much lower hERG inhibition liability than Ligand B (0.692), a significant advantage.

**Microsomal Clearance:** Ligand A (31.164 mL/min/kg) has lower microsomal clearance than Ligand B (92.483 mL/min/kg), indicating better metabolic stability.

**In vitro Half-Life:** Ligand A (24.6 hours) has a significantly longer half-life than Ligand B (-9.386 hours). This is a major advantage.

**P-gp Efflux:** Ligand A (0.114) has lower P-gp efflux liability than Ligand B (0.447), which is beneficial for CNS exposure.

**Binding Affinity:** Ligand A (-7.7 kcal/mol) has a slightly better binding affinity than Ligand B (-7.3 kcal/mol). While the difference is not huge, it's enough to be considered.

**Overall Assessment:**

Ligand A is the stronger candidate. It has a better safety profile (lower DILI, lower hERG), better metabolic stability (lower Cl_mic, longer t1/2), lower P-gp efflux, and slightly better binding affinity. While Ligand B has slightly better BBB penetration and a lower TPSA, the ADME/Tox advantages of Ligand A are more critical, especially for a CNS target. The negative solubility and Caco-2 values are concerning for both, but the other factors strongly favor Ligand A.

Output:
0
2025-04-17 06:23:02,944 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (349.406 and 362.821 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (71.53) is significantly better than Ligand B (97.98). For CNS targets, we want TPSA <= 90, so Ligand A is preferable.

**logP:** Both ligands have good logP values (1.807 and 1.398), falling within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Both have acceptable HBD (1 & 2) and HBA (4 & 4) counts, well below the thresholds of 5 and 10, respectively.

**QED:** Both have high QED scores (0.85 and 0.862), indicating good drug-like properties.

**DILI:** Ligand A (38.387) has a much lower DILI risk than Ligand B (66.072).  Below 40 is good, so Ligand A is significantly better here.

**BBB:** Ligand A (88.561) has a much higher BBB penetration percentile than Ligand B (31.291).  For a CNS target like DRD2, >70 is desirable, and Ligand A is closer to this target.

**Caco-2 Permeability:** Ligand A (-4.366) has better Caco-2 permeability than Ligand B (-5.302). Higher is better.

**Aqueous Solubility:** Ligand A (-2.814) has better aqueous solubility than Ligand B (-3.479). Higher is better.

**hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.544 and 0.226).

**Microsomal Clearance:** Ligand A (24.619) has higher microsomal clearance than Ligand B (9.66). Lower is better, so Ligand B is preferable.

**In vitro Half-Life:** Ligand A (-39.122) has a much longer in vitro half-life than Ligand B (-1.997). Longer is better.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.05 and 0.069).

**Binding Affinity:** Both ligands have the same binding affinity (-9 kcal/mol), which is excellent.

**Overall Assessment:**

Ligand A is clearly superior. While Ligand B has slightly better metabolic stability (lower Cl_mic), Ligand A excels in almost every other critical parameter, particularly those prioritized for GPCRs targeting the CNS: TPSA, BBB penetration, DILI risk, solubility, and half-life. The difference in BBB is substantial, making Ligand A much more likely to reach the target in the brain. The similar binding affinity removes that as a differentiating factor.

Output:
1
2025-04-17 06:23:02,944 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (347.419 and 348.443 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (111.21) is higher than the preferred <90 for CNS targets, while Ligand B (59.08) is well within the range. This is a significant advantage for Ligand B.

**3. logP:** Ligand A (0.421) is slightly low, potentially hindering permeation. Ligand B (0.919) is better, falling within the optimal 1-3 range.

**4. H-Bond Donors:** Ligand A has 3 HBD, which is acceptable. Ligand B has 0, also acceptable.

**5. H-Bond Acceptors:** Ligand A has 5 HBA, acceptable. Ligand B has 4, also acceptable.

**6. QED:** Both ligands have similar QED values (0.715 and 0.709), indicating good drug-likeness.

**7. DILI:** Ligand A (38.503) has a slightly higher DILI risk than Ligand B (23.149), but both are below the concerning threshold of 60.

**8. BBB:** Ligand B (68.166) has a significantly better BBB percentile than Ligand A (52.579). This is crucial for a CNS target like DRD2.

**9. Caco-2 Permeability:** Ligand A (-5.396) has poor Caco-2 permeability, while Ligand B (-4.636) is slightly better, but still not ideal.

**10. Aqueous Solubility:** Both ligands have poor aqueous solubility (-1.875 and -1.425 respectively). This could pose formulation challenges.

**11. hERG Inhibition:** Both ligands have low hERG inhibition risk (0.18 and 0.389).

**12. Microsomal Clearance:** Ligand A (-33.48) has a lower (better) microsomal clearance than Ligand B (33.596), suggesting greater metabolic stability.

**13. In vitro Half-Life:** Ligand B (5.931) has a longer half-life than Ligand A (3.666).

**14. P-gp Efflux:** Ligand A (0.022) has very low P-gp efflux, which is excellent. Ligand B (0.098) is also low, but higher than A.

**15. Binding Affinity:** Ligand B (-8.6 kcal/mol) has a stronger binding affinity than Ligand A (-7.8 kcal/mol). This difference of 0.8 kcal/mol is significant, and can outweigh some of the ADME drawbacks.

**Overall Assessment:**

Ligand B is the more promising candidate. While both have solubility issues, Ligand B excels in key areas for a CNS GPCR target: significantly better BBB penetration, a lower TPSA, and stronger binding affinity. The slightly better metabolic stability of Ligand A is offset by the other advantages of Ligand B.

Output:
1
2025-04-17 06:23:02,944 - INFO - Batch 277 complete. Total preferences: 4432
2025-04-17 06:23:02,944 - INFO - Processing batch 278/512...
2025-04-17 06:23:45,336 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (369.441 and 367.475 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (79.8) is better than Ligand B (89.35). Both are below the 140 threshold for oral absorption, but for a CNS target like DRD2, we ideally want <90. Ligand A is closer to this target.

**3. logP:** Ligand A (3.135) is within the optimal 1-3 range. Ligand B (1.411) is on the lower side, potentially hindering permeation.

**4. H-Bond Donors:** Ligand A (2) and Ligand B (1) are both acceptable, being less than 5.

**5. H-Bond Acceptors:** Ligand A (6) and Ligand B (7) are both acceptable, being less than 10.

**6. QED:** Both ligands have the same QED score (0.784), indicating good drug-likeness.

**7. DILI:** Ligand A (70.26) has a lower DILI risk than Ligand B (63.513), which is preferable.

**8. BBB:** This is a critical parameter for CNS targets. Ligand A (84.451) has a significantly better BBB penetration percentile than Ligand B (45.677). This is a major advantage for Ligand A.

**9. Caco-2 Permeability:** Ligand A (-4.986) and Ligand B (-5.237) both have negative values, indicating poor permeability. This is a concern for both.

**10. Aqueous Solubility:** Ligand A (-3.519) and Ligand B (-2.738) both have negative values, indicating poor solubility. This is a concern for both.

**11. hERG Inhibition:** Ligand A (0.642) has a slightly higher hERG inhibition risk than Ligand B (0.068). Ligand B is much better here.

**12. Microsomal Clearance:** Ligand A (27.334) has a lower microsomal clearance than Ligand B (40.213), suggesting better metabolic stability.

**13. In vitro Half-Life:** Ligand A (22.939) has a longer in vitro half-life than Ligand B (-12.192), which is desirable.

**14. P-gp Efflux:** Ligand A (0.23) has a lower P-gp efflux liability than Ligand B (0.062), meaning it's less likely to be pumped out of the brain, improving CNS exposure.

**15. Binding Affinity:** Ligand A (-8.8 kcal/mol) has a significantly stronger binding affinity than Ligand B (-6.6 kcal/mol). This difference of 2.2 kcal/mol is substantial and can outweigh some of the ADME drawbacks.

**Overall Assessment:**

Ligand A is the stronger candidate. While both have issues with Caco-2 permeability and aqueous solubility, Ligand A excels in the critical areas for a CNS GPCR target: BBB penetration, binding affinity, metabolic stability, and P-gp efflux. The significantly better BBB and binding affinity of Ligand A are particularly compelling. Although Ligand B has a better hERG profile, the other advantages of Ligand A outweigh this concern.

Output:
1
2025-04-17 06:23:45,336 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (337.339 Da) is slightly preferred as it's closer to the lower end, potentially aiding permeability.

**TPSA:** Ligand A (99.0) is better than Ligand B (133.91). For CNS targets, we want TPSA <= 90, so Ligand A is closer to this threshold.

**logP:** Ligand A (1.916) is within the optimal range (1-3). Ligand B (-1.899) is below 1, which could hinder permeation. This is a significant advantage for Ligand A.

**H-Bond Donors/Acceptors:** Ligand A (1 HBD, 7 HBA) is better than Ligand B (3 HBD, 6 HBA) in terms of balancing solubility and permeability.

**QED:** Ligand A (0.73) has a much better QED score than Ligand B (0.366), indicating a more drug-like profile.

**DILI:** Ligand B (47.926) has a lower DILI risk than Ligand A (94.959), which is good.

**BBB:** Ligand B (44.707) and Ligand A (40.791) both have low BBB penetration, which is a major concern for a CNS target like DRD2. However, the difference is minimal.

**Caco-2 Permeability:** Ligand A (-4.685) has better Caco-2 permeability than Ligand B (-5.632).

**Aqueous Solubility:** Ligand A (-3.382) has better solubility than Ligand B (-1.896).

**hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.217 and 0.049 respectively).

**Microsomal Clearance:** Ligand B (-1.266) has a significantly lower (better) microsomal clearance than Ligand A (53.141), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand B (-30.289) has a much longer half-life than Ligand A (8.71).

**P-gp Efflux:** Ligand A (0.086) has lower P-gp efflux than Ligand B (0.004), which is beneficial for CNS exposure.

**Binding Affinity:** Ligand B (-7.7) has a significantly stronger binding affinity than Ligand A (-9.0). A 1.3 kcal/mol difference is substantial and can outweigh some ADME drawbacks.

**Overall Assessment:**

While Ligand A has better physicochemical properties (logP, TPSA, QED, solubility, Caco-2) and P-gp efflux, Ligand B has a much stronger binding affinity and better metabolic stability (lower Cl_mic, longer t1/2). The low BBB penetration for both is a concern, but the significantly improved binding affinity of Ligand B is a major advantage for a GPCR target. The stronger binding could potentially be optimized to improve selectivity and efficacy, and further modifications could be explored to improve BBB penetration.

Output:
1
2025-04-17 06:23:45,336 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B based on the provided guidelines, prioritizing GPCR-specific properties (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (338.407 Da) is slightly better, being closer to the lower end which can aid permeability.

**TPSA:** Ligand A (59.59) is excellent for CNS penetration, well below the 90 A^2 threshold. Ligand B (102.76) is higher, but still potentially acceptable, though less ideal.

**logP:** Ligand A (4.374) is a bit high, potentially leading to solubility issues or off-target effects. Ligand B (0.96) is quite low, which could hinder permeation.

**H-Bond Donors/Acceptors:** Ligand A (HBD=2, HBA=3) and Ligand B (HBD=3, HBA=7) both fall within acceptable ranges.

**QED:** Both ligands have reasonable QED scores (A: 0.87, B: 0.698), indicating good drug-like properties.

**DILI:** Ligand A (80.923) has a higher DILI risk than Ligand B (52.772), which is a concern.

**BBB:** This is a critical parameter for a CNS target like DRD2. Ligand A (73.866) has a good BBB percentile, exceeding the 70% threshold. Ligand B (12.175) is very poor, suggesting limited CNS exposure.

**Caco-2 Permeability:** Ligand A (-4.777) and Ligand B (-5.651) both show poor Caco-2 permeability, suggesting limited intestinal absorption.

**Aqueous Solubility:** Both ligands have very poor aqueous solubility (A: -5.091, B: -3.131).

**hERG Inhibition:** Ligand A (0.791) has a slightly higher hERG risk than Ligand B (0.066), but both are relatively low.

**Microsomal Clearance:** Ligand A (71.72) has higher microsomal clearance than Ligand B (7.286), indicating lower metabolic stability.

**In vitro Half-Life:** Ligand B (-1.573) has a negative half-life, which is not physically possible and likely an outlier or error in the data. Ligand A (46.845) has a reasonable half-life.

**P-gp Efflux:** Ligand A (0.497) has lower P-gp efflux than Ligand B (0.053), which is favorable for CNS penetration.

**Binding Affinity:** Ligand A (-9.5 kcal/mol) has significantly stronger binding affinity than Ligand B (-7.5 kcal/mol). This is a substantial advantage, potentially outweighing some of the ADME drawbacks.

**Overall Assessment:**

Despite Ligand A's higher DILI risk and poor solubility, its superior BBB penetration, significantly stronger binding affinity, lower P-gp efflux, and reasonable half-life make it the more promising candidate. Ligand B's extremely poor BBB penetration is a major drawback for a CNS-targeted drug. The negative half-life reported for Ligand B is also a red flag. While Ligand A's logP is a bit high, the strong affinity could compensate.



Output:
1
2025-04-17 06:23:45,336 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (356.323 and 353.507 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (83.8) is better than Ligand B (61.88). Both are below the 90 A^2 threshold for CNS targets, but Ligand B is closer to optimal.

**3. logP:** Ligand A (3.051) is within the optimal range (1-3). Ligand B (1.354) is at the lower end, potentially impacting permeability.

**4. H-Bond Donors:** Ligand A (3) is acceptable. Ligand B (1) is also good.

**5. H-Bond Acceptors:** Ligand A (3) is acceptable. Ligand B (4) is also good.

**6. QED:** Both ligands have similar, good QED values (0.739 and 0.751, respectively).

**7. DILI:** Ligand A (65.103) has a higher DILI risk than Ligand B (4.731). This is a significant drawback for Ligand A.

**8. BBB:** Ligand A (87.67) has a significantly better BBB penetration percentile than Ligand B (72.082). This is crucial for a CNS target like DRD2.

**9. Caco-2 Permeability:** Ligand A (-5.363) has poor Caco-2 permeability. Ligand B (-4.714) is also poor, but slightly better.

**10. Aqueous Solubility:** Ligand A (-4.113) has poor aqueous solubility. Ligand B (-1.015) has better solubility.

**11. hERG Inhibition:** Ligand A (0.861) has a higher hERG inhibition risk than Ligand B (0.384).

**12. Microsomal Clearance:** Ligand A (-2.904) has lower (better) microsomal clearance than Ligand B (1.135).

**13. In vitro Half-Life:** Ligand A (24.774) has a longer half-life than Ligand B (6.798).

**14. P-gp Efflux:** Ligand A (0.304) has lower P-gp efflux than Ligand B (0.019). Lower P-gp efflux is favorable for CNS penetration.

**15. Binding Affinity:** Ligand B (-7.7 kcal/mol) has a significantly stronger binding affinity than Ligand A (-10 kcal/mol). This is a substantial advantage.

**Overall Assessment:**

Ligand A has a better BBB and P-gp profile, and a longer half-life. However, it suffers from poor Caco-2 permeability, solubility, higher DILI risk, and higher hERG inhibition. Ligand B has a much stronger binding affinity, lower DILI and hERG risks, better solubility, and slightly better Caco-2 permeability. The superior binding affinity of Ligand B (-7.7 kcal/mol vs -10 kcal/mol) is a major advantage that can potentially outweigh some of its slightly less favorable ADME properties. Given the GPCR-specific priorities, the strong affinity and improved safety profile of Ligand B make it the more promising candidate.

Output:
1
2025-04-17 06:23:45,336 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 drug candidates, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (374.547 Da) is slightly lower, which could be advantageous for permeability. Ligand B (424.73 Da) is also acceptable.

**TPSA:** Both ligands have TPSA values below the 90 A^2 threshold for CNS targets. Ligand A (84.5 A^2) is slightly higher than Ligand B (75.35 A^2), making Ligand B more favorable for brain penetration.

**logP:** Both ligands have logP values within the optimal range (1-3). Ligand A (2.591) and Ligand B (3.134) are both good, but Ligand B is approaching the upper limit, potentially raising concerns about solubility and off-target effects.

**H-Bond Donors/Acceptors:** Ligand A (2 HBD, 4 HBA) and Ligand B (1 HBD, 5 HBA) both fall within acceptable limits.

**QED:** Both ligands have good QED scores (Ligand A: 0.684, Ligand B: 0.75), indicating drug-like properties.

**DILI:** Ligand A (18.534) has a significantly lower DILI risk than Ligand B (78.48). This is a major advantage for Ligand A.

**BBB:** Ligand A (81.582) has a better BBB penetration percentile than Ligand B (76.231), though both are reasonably good for a CNS target.

**Caco-2 Permeability:** Ligand A (-4.369) has a worse Caco-2 permeability than Ligand B (-5.015). Lower values indicate poorer permeability.

**Aqueous Solubility:** Ligand A (-3.155) has slightly better aqueous solubility than Ligand B (-3.676).

**hERG Inhibition:** Both ligands have low hERG inhibition risk (Ligand A: 0.477, Ligand B: 0.76).

**Microsomal Clearance:** Ligand A (82.02) has a higher microsomal clearance than Ligand B (45.291), indicating lower metabolic stability. This is a disadvantage for Ligand A.

**In vitro Half-Life:** Ligand A (-27.972) has a much lower in vitro half-life than Ligand B (-4.425), suggesting faster metabolism. This is a significant drawback for Ligand A.

**P-gp Efflux:** Ligand A (0.048) has a lower P-gp efflux liability than Ligand B (0.267), which is favorable for CNS exposure.

**Binding Affinity:** Ligand B (-8.6 kcal/mol) has a significantly stronger binding affinity than Ligand A (-7.2 kcal/mol). This is a crucial advantage, as a 1.4 kcal/mol difference is substantial and can outweigh some ADME concerns.

**Overall Assessment:**

Ligand B has a superior binding affinity and better metabolic stability (lower Cl_mic, longer t1/2). While its DILI risk is higher and TPSA slightly less favorable, the strong affinity is a major driver for CNS GPCR drug candidates. Ligand A has better BBB penetration and lower DILI, but its weaker affinity and poor metabolic stability are significant drawbacks. The difference in binding affinity is substantial enough to overcome the slightly higher DILI risk of Ligand B.

Output:
1
2025-04-17 06:23:45,337 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (373.475 Da) is slightly higher than Ligand B (347.503 Da), but both are acceptable.

**TPSA:** Ligand A (129.8) is borderline for CNS penetration, being slightly above the preferred <90. Ligand B (63.13) is excellent, well below the threshold.

**logP:** Ligand A (-0.678) is a bit low, potentially hindering membrane permeability. Ligand B (2.968) is optimal.

**H-Bond Donors/Acceptors:** Ligand A has 3 HBD and 5 HBA, which are acceptable. Ligand B has 2 HBD and 3 HBA, also acceptable.

**QED:** Both ligands have good QED scores (A: 0.588, B: 0.71), indicating drug-likeness.

**DILI:** Ligand A (19.504) has a low DILI risk, which is favorable. Ligand B (12.059) also has a low DILI risk.

**BBB:** This is a crucial parameter for a CNS target. Ligand A (15.743) has a very poor BBB percentile, making it unlikely to reach the target in the brain. Ligand B (70.027) has a good BBB percentile, significantly increasing its potential.

**Caco-2 Permeability:** Ligand A (-5.646) has poor Caco-2 permeability. Ligand B (-4.724) is also not great, but slightly better.

**Aqueous Solubility:** Both ligands have poor aqueous solubility (-1.713 and -2.601 respectively). This could pose formulation challenges, but isn't a dealbreaker if other properties are favorable.

**hERG Inhibition:** Both ligands show very low hERG inhibition risk (0.075 and 0.408 respectively).

**Microsomal Clearance:** Ligand A (1.682) has much lower microsomal clearance than Ligand B (61.226), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (-22.475) has a very short half-life, which is a significant drawback. Ligand B (8.223) has a better, though still not ideal, half-life.

**P-gp Efflux:** Both ligands exhibit low P-gp efflux liability (0.005 and 0.192 respectively).

**Binding Affinity:** Both ligands have similar, strong binding affinities (-8.7 kcal/mol). The difference is negligible.

**Overall Assessment:**

Ligand B is significantly more promising due to its excellent BBB penetration (70.027) and optimal logP (2.968). While its Caco-2 permeability and half-life aren't ideal, the strong BBB penetration outweighs these concerns for a CNS target like DRD2. Ligand A's extremely poor BBB penetration (15.743) is a major disqualifier, despite its better metabolic stability and slightly better half-life. The similar binding affinities make the ADME properties the deciding factor.

Output:
1
2025-04-17 06:23:45,337 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (353.463 and 339.399 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (71.11) is excellent, falling well below the 90 A^2 threshold for CNS targets. Ligand B (88.08) is still reasonable but less optimal.

**logP:** Ligand A (0.382) is a bit low, potentially hindering permeability. Ligand B (1.523) is better, falling within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Both have 1 HBD and 5 HBA, which are acceptable.

**QED:** Both ligands have good QED scores (0.774 and 0.892), indicating drug-like properties.

**DILI:** Ligand A (15.781) has a significantly lower DILI risk than Ligand B (47.15). This is a substantial advantage.

**BBB:** Ligand A (61.729) is moderate, while Ligand B (56.146) is lower. Both are below the desirable >70 for CNS targets, but A is better.

**Caco-2 Permeability:** Both have negative Caco-2 values (-4.849 and -4.903), which is unusual and suggests poor permeability. This is a significant concern for both.

**Aqueous Solubility:** Both have negative solubility values (-0.627 and -1.567), also concerning.

**hERG:** Both ligands have very low hERG inhibition risk (0.162 and 0.141).

**Microsomal Clearance:** Ligand A (0.32) has much lower microsomal clearance than Ligand B (6.269), indicating better metabolic stability.

**In vitro Half-Life:** Ligand A (13.334) has a longer half-life than Ligand B (11.873), which is preferable.

**P-gp Efflux:** Both have very low P-gp efflux liability (0.008 and 0.004), which is good for CNS penetration.

**Binding Affinity:** Ligand B (-8.8 kcal/mol) has a stronger binding affinity than Ligand A (-7.8 kcal/mol), with a difference of 1.0 kcal/mol. This is a significant advantage.

**Overall Assessment:**

Ligand B has a better binding affinity and a more favorable logP. However, Ligand A has significantly lower DILI risk, better metabolic stability (lower Cl_mic and longer t1/2), and slightly better BBB penetration. The negative Caco-2 and solubility values are concerning for both, suggesting potential formulation challenges. The affinity difference is substantial, but the ADME profile of Ligand A is more promising, particularly the lower DILI and better metabolic stability. Given the CNS target, a lower DILI risk is crucial.

Output:
0
2025-04-17 06:23:45,337 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (354.491 and 363.483 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (70.08) is significantly better than Ligand B (79.46). For CNS targets, we want TPSA <= 90, and A is comfortably within this range, while B is approaching the upper limit.

**3. logP:** Ligand A (1.517) is optimal (1-3), while Ligand B (3.746) is higher, potentially leading to solubility issues and off-target interactions, though still within the acceptable range.

**4. H-Bond Donors:** Both have 1 HBD, which is good.

**5. H-Bond Acceptors:** Ligand A has 4 HBA, and Ligand B has 6. Both are acceptable (<=10), but A is preferable.

**6. QED:** Ligand A (0.717) is better than Ligand B (0.514), indicating a more drug-like profile.

**7. DILI:** Ligand A (7.794) has a much lower DILI risk than Ligand B (60.14). B is considered high risk.

**8. BBB:** Ligand A (53.936) has a slightly better BBB percentile than Ligand B (51.415), but both are below the desirable >70 for CNS targets. This is a weakness for both, but less so for A.

**9. Caco-2 Permeability:** Ligand A (-4.492) has a worse Caco-2 permeability than Ligand B (-5.009). Lower values indicate lower permeability.

**10. Aqueous Solubility:** Ligand A (-0.813) has better aqueous solubility than Ligand B (-3.327).

**11. hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.359 and 0.441).

**12. Microsomal Clearance:** Ligand A (32.231) has lower microsomal clearance, suggesting better metabolic stability, compared to Ligand B (88.861).

**13. In vitro Half-Life:** Ligand A (17.42) has a longer in vitro half-life than Ligand B (-5.1).

**14. P-gp Efflux:** Ligand A (0.088) shows lower P-gp efflux liability than Ligand B (0.853), which is crucial for CNS penetration.

**15. Binding Affinity:** Ligand A (-7.1) has a slightly better binding affinity than Ligand B (-6.8). While both are good, the difference is not huge.

**Overall Assessment:**

Ligand A is significantly better overall. It has a lower DILI risk, better QED, better metabolic stability (lower Cl_mic, longer t1/2), lower P-gp efflux, better solubility, and a slightly better binding affinity. While both have suboptimal BBB penetration, Ligand A's other properties make it a more promising candidate. Ligand B's high DILI risk and higher P-gp efflux are major drawbacks. The slightly worse Caco-2 permeability of A is less concerning than the issues with B.

Output:
0
2025-04-17 06:23:45,337 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (349.381 and 349.519 Da) fall comfortably within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (58.36) is significantly better than Ligand B (61.44). For CNS targets, we want TPSA <= 90, and lower is preferable. Ligand A is closer to the ideal range for CNS penetration.

**3. logP:** Both ligands have good logP values (3.088 and 2.474), falling within the optimal 1-3 range. Ligand A is slightly higher, which could be beneficial for membrane permeability.

**4. H-Bond Donors:** Ligand A (1) is better than Ligand B (2). Lower HBD generally improves permeability.

**5. H-Bond Acceptors:** Ligand A (4) is better than Ligand B (3). Lower HBA generally improves permeability.

**6. QED:** Ligand A (0.836) has a significantly better QED score than Ligand B (0.596), indicating a more drug-like profile.

**7. DILI:** Ligand A (49.438) has a higher DILI risk than Ligand B (10.585). This is a significant advantage for Ligand B.

**8. BBB:** Ligand A (90.074) has a much better BBB percentile than Ligand B (65.801). This is *critical* for a CNS target like DRD2, and strongly favors Ligand A.

**9. Caco-2 Permeability:** Ligand A (-4.203) is worse than Ligand B (-5.083). Lower values indicate poorer permeability.

**10. Aqueous Solubility:** Ligand A (-3.613) is worse than Ligand B (-1.95). Lower values indicate poorer solubility.

**11. hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.613 and 0.399).

**12. Microsomal Clearance:** Ligand A (45.117) has higher microsomal clearance than Ligand B (17.085), meaning it is less metabolically stable. This favors Ligand B.

**13. In vitro Half-Life:** Ligand A (14.94) has a longer half-life than Ligand B (7.551). This favors Ligand A.

**14. P-gp Efflux:** Ligand A (0.442) has lower P-gp efflux than Ligand B (0.029). Lower efflux is better for CNS exposure, favoring Ligand A.

**15. Binding Affinity:** Ligand A (-7.6) has a slightly better binding affinity than Ligand B (-7.2). While both are excellent, the 0.4 kcal/mol difference is meaningful.

**Overall Assessment:**

Ligand A excels in key areas for a CNS GPCR target: BBB penetration, TPSA, QED, P-gp efflux, and binding affinity. While it has some drawbacks in solubility, permeability, and metabolic stability, the strong BBB penetration and affinity are paramount. Ligand B has a better safety profile (lower DILI) and metabolic stability, but its lower BBB penetration is a major concern for a CNS target. The difference in affinity, while not huge, also favors Ligand A.

Output:
1
2025-04-17 06:23:45,337 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B based on the provided guidelines, prioritizing GPCR-specific properties (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (425.352 Da) is higher, but still acceptable. Ligand B (348.487 Da) is slightly preferred.

**TPSA:** Ligand A (88.32) is close to the upper limit for CNS targets (90), while Ligand B (58.64) is well below. This favors Ligand B.

**logP:** Both ligands have good logP values (A: 2.881, B: 2.348), falling within the optimal range of 1-3. No significant difference here.

**H-Bond Donors/Acceptors:** Ligand A has 2 HBD and 5 HBA, while Ligand B has 1 HBD and 3 HBA. Both are within acceptable limits.

**QED:** Both ligands have reasonable QED values (A: 0.787, B: 0.541), indicating good drug-like properties. Ligand A is slightly better.

**DILI:** Ligand A (76.968) has a higher DILI risk than Ligand B (10.896). This is a significant advantage for Ligand B.

**BBB:** Ligand B (70.609) has a much better BBB percentile than Ligand A (52.889). This is crucial for a CNS target like DRD2, making Ligand B strongly favored.

**Caco-2 Permeability:** Ligand A (-5.419) has worse Caco-2 permeability than Ligand B (-4.414). This favors Ligand B.

**Aqueous Solubility:** Both ligands have similar, very poor aqueous solubility (-2.956 and -2.9). This is a concern for both, but not a deciding factor.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (A: 0.611, B: 0.403). No significant difference.

**Microsomal Clearance:** Ligand A (27.121) has lower microsomal clearance than Ligand B (36.514), suggesting better metabolic stability. This favors Ligand A.

**In vitro Half-Life:** Ligand A (24.642) has a longer in vitro half-life than Ligand B (-15.402). This is a significant advantage for Ligand A.

**P-gp Efflux:** Ligand A (0.207) has lower P-gp efflux than Ligand B (0.063), indicating better potential for CNS exposure. This favors Ligand A.

**Binding Affinity:** Both ligands have excellent binding affinity (A: -7.7 kcal/mol, B: -7.5 kcal/mol). The difference of 0.2 kcal/mol is not substantial enough to outweigh other factors.

**Overall Assessment:**

Ligand B excels in key GPCR-specific properties: TPSA and BBB. It also has a significantly lower DILI risk and better Caco-2 permeability. While Ligand A has advantages in metabolic stability, half-life, and P-gp efflux, the importance of BBB penetration for a CNS target like DRD2, combined with the lower DILI risk, makes Ligand B the more promising candidate.

Output:
1
2025-04-17 06:23:45,337 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (348.4 and 341.4 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (92.01) is slightly above the optimal <90 for CNS targets, but still reasonable. Ligand B (80.32) is well within the desired range.

**logP:** Ligand A (0.564) is quite low, potentially hindering membrane permeability. Ligand B (1.517) is better, falling within the 1-3 optimal range.

**H-Bond Donors/Acceptors:** Both have 2 HBD and are within acceptable limits. Ligand A has 5 HBA, while Ligand B has 4. Both are acceptable.

**QED:** Both ligands have good QED scores (0.733 and 0.769), indicating drug-likeness.

**DILI:** Both have low DILI risk (35.17 and 32.84), which is positive.

**BBB:** This is a critical parameter for a CNS target. Ligand A has a BBB percentile of 24.66, which is poor. Ligand B has a significantly better BBB percentile of 50.52, making it much more likely to reach the target in the brain.

**Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and suggests a potential issue with the data or modeling. However, the magnitude is similar.

**Aqueous Solubility:** Both have negative solubility values, which is also unusual. Again, the magnitude is similar.

**hERG Inhibition:** Both ligands show very low hERG inhibition risk (0.24 and 0.114).

**Microsomal Clearance:** Ligand A has a negative Cl_mic (-14.666), which is not physically meaningful and suggests a data issue. Ligand B has a Cl_mic of 20.194, indicating moderate metabolic clearance.

**In vitro Half-Life:** Ligand A has a short half-life (2.044 hours). Ligand B has a very long half-life (-29.225 hours), which is also not physically meaningful and suggests a data issue.

**P-gp Efflux:** Both have very low P-gp efflux liability (0.16 and 0.012), which is favorable for CNS penetration.

**Binding Affinity:** Both ligands have the same binding affinity (-7.9 kcal/mol), which is excellent.

**Overall Assessment:**

Despite the questionable values for Caco-2, solubility, Cl_mic, and t1/2, the most significant difference lies in the BBB penetration. Ligand B has a much higher BBB percentile (50.52) compared to Ligand A (24.66). Given that DRD2 is a CNS target, this is a crucial advantage. Ligand A's low logP is also a concern. While both have excellent binding affinity, the improved BBB and logP of Ligand B make it the more promising candidate. The negative values for Cl_mic and t1/2 for Ligand B are concerning, but the BBB difference is substantial enough to favor Ligand B.

Output:
1
2025-04-17 06:23:45,337 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B against the provided guidelines, prioritizing GPCR-specific properties (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (352.36 and 351.447 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (49.42) is excellent, well below the 90 A^2 threshold for CNS targets. Ligand B (70.16) is still reasonable but less optimal, exceeding 60 A^2.

**logP:** Ligand A (2.529) is within the optimal 1-3 range. Ligand B (0.339) is quite low, potentially hindering membrane permeability.

**H-Bond Donors/Acceptors:** Ligand A has 2 HBD and 5 HBA, which are acceptable. Ligand B has 0 HBD and 5 HBA, also acceptable.

**QED:** Both ligands have reasonable QED scores (0.81 and 0.683), indicating good drug-like properties.

**DILI:** Ligand A (71.384) has a higher DILI risk than Ligand B (25.436). This is a negative for Ligand A.

**BBB:** Ligand A (71.656) has a good BBB percentile, exceeding the 70% threshold for CNS targets. Ligand B (55.099) is lower, which is a significant drawback for a CNS-targeting drug.

**Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and suggests a potential issue with the data or modeling. However, we'll proceed assuming these represent low permeability.

**Aqueous Solubility:** Both have negative solubility values, also unusual. We'll assume this indicates poor solubility.

**hERG:** Both ligands have low hERG inhibition liability (0.838 and 0.125), which is positive.

**Microsomal Clearance:** Ligand B (18.222) has slightly higher microsomal clearance than Ligand A (16.53), suggesting potentially lower metabolic stability.

**In vitro Half-Life:** Ligand A (-0.528) has a slightly longer in vitro half-life than Ligand B (-2.377).

**P-gp Efflux:** Ligand A (0.119) has lower P-gp efflux liability than Ligand B (0.023), which is favorable for CNS penetration.

**Binding Affinity:** Ligand A (-8.8 kcal/mol) has a significantly stronger binding affinity than Ligand B (-7.9 kcal/mol). This 0.9 kcal/mol difference is substantial and can outweigh some ADME concerns.

**Overall Assessment:**

Ligand A is superior due to its significantly better binding affinity and excellent BBB penetration, both crucial for a CNS-targeting GPCR. While its DILI risk is higher, the strong binding and good CNS penetration are likely to be more impactful for efficacy. Ligand B suffers from a low logP and a significantly lower BBB percentile, making it less likely to reach the target in the brain. The slightly better DILI profile of Ligand B is not enough to compensate for these critical deficiencies.

Output:
1
2025-04-17 06:23:45,338 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (355.479 and 343.427 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (101.9) is slightly above the optimal <90 for CNS targets, but still reasonable. Ligand B (86.34) is excellent, well below 90.

**logP:** Ligand A (0.004) is very low, potentially hindering membrane permeability. Ligand B (2.36) is within the optimal 1-3 range. This is a significant advantage for Ligand B.

**H-Bond Donors/Acceptors:** Ligand A has 4 HBD and 5 HBA, acceptable. Ligand B has 1 HBD and 4 HBA, also acceptable.

**QED:** Ligand B (0.889) has a much better QED score than Ligand A (0.491), indicating a more drug-like profile.

**DILI:** Ligand A (12.02) has a very low DILI risk, better than Ligand B (21.869), but both are acceptable.

**BBB:** Ligand B (71.501) has a good BBB penetration percentile, exceeding the desirable >70 threshold for CNS targets. Ligand A (22.606) is significantly lower and concerning for CNS activity.

**Caco-2 Permeability:** Ligand A (-5.448) has poor Caco-2 permeability. Ligand B (-4.835) is also poor, but slightly better.

**Aqueous Solubility:** Ligand A (-0.928) has poor aqueous solubility. Ligand B (-2.89) is even worse. This could pose formulation challenges for both, but is less critical than permeability for CNS targets.

**hERG:** Ligand A (0.142) has a low hERG risk, better than Ligand B (0.559).

**Microsomal Clearance:** Ligand A (-14.247) has very low microsomal clearance, suggesting high metabolic stability. Ligand B (20.517) has higher clearance, indicating faster metabolism.

**In vitro Half-Life:** Ligand B (18.343 hours) has a significantly longer half-life than Ligand A (6.976 hours).

**P-gp Efflux:** Ligand A (0.021) has very low P-gp efflux, which is excellent for CNS penetration. Ligand B (0.08) also has low P-gp efflux, but higher than Ligand A.

**Binding Affinity:** Ligand B (-8.8 kcal/mol) has a stronger binding affinity than Ligand A (-7.8 kcal/mol), by a margin of 1 kcal/mol, which is significant.

**Overall Assessment:**

Ligand B is the stronger candidate. While both have solubility issues, Ligand B excels in key areas for CNS GPCR targets: logP, BBB penetration, binding affinity, QED, and *in vitro* half-life. Ligand A's low logP and poor BBB penetration are major drawbacks. Although Ligand A has better metabolic stability and lower hERG risk, the superior CNS-relevant properties of Ligand B outweigh these advantages.

Output:
1
2025-04-17 06:23:45,338 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (374.5 and 344.4 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (113.32) is slightly above the optimal <90 for CNS targets, but still reasonable. Ligand B (91.23) is better, falling comfortably under 90.

**3. logP:** Ligand A (0.994) is a bit low, potentially hindering permeability. Ligand B (1.592) is better, falling within the 1-3 optimal range.

**4. H-Bond Donors:** Ligand A (3) and Ligand B (2) are both acceptable, below the threshold of 5.

**5. H-Bond Acceptors:** Ligand A (6) and Ligand B (4) are both acceptable, below the threshold of 10.

**6. QED:** Both ligands have good QED scores (0.529 and 0.832), indicating drug-like properties.

**7. DILI:** Both ligands have acceptable DILI risk (26.95 and 36.10), well below the 60 threshold.

**8. BBB:** Ligand A (38.54) has a poor BBB percentile, which is a significant drawback for a CNS target like DRD2. Ligand B (50.06) is better, but still not ideal (aim for >70).

**9. Caco-2:** Both have negative Caco-2 values, which is unusual. Assuming these are percentile scores, lower is worse.

**10. Solubility:** Both have negative solubility values, which is also unusual. Assuming these are percentile scores, lower is worse.

**11. hERG:** Both ligands have very low hERG inhibition risk (0.334 and 0.041).

**12. Cl_mic:** Ligand A (0.324) has a very low microsomal clearance, suggesting good metabolic stability. Ligand B (11.923) has a significantly higher clearance, indicating faster metabolism.

**13. t1/2:** Ligand A (26.43) has a longer in vitro half-life than Ligand B (-20.63). The negative value for ligand B is concerning and likely an error.

**14. Pgp:** Ligand A (0.088) has lower P-gp efflux liability than Ligand B (0.035), which is favorable for CNS penetration.

**15. Binding Affinity:** Ligand B (-8.4 kcal/mol) has a stronger binding affinity than Ligand A (-7.2 kcal/mol). The difference of 1.2 kcal/mol is substantial and could outweigh some of the ADME drawbacks.

**Overall Assessment:**

Ligand B has a significantly better binding affinity and a more favorable logP value. While its BBB penetration is not ideal, it's better than Ligand A's. Ligand A's main advantage is its metabolic stability (low Cl_mic) and longer half-life, but its poor BBB penetration is a major concern for a CNS target. The negative values for Caco-2 and solubility are concerning for both, but the affinity difference is substantial. Given the GPCR-specific priorities, and the significant affinity advantage of Ligand B, it is the more promising candidate.

Output:
1
2025-04-17 06:23:45,338 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (360.351 and 352.435 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (58.2) is significantly better than Ligand B (96.69). For CNS targets, we want TPSA <= 90, and A is comfortably within this range, while B is pushing the limit.

**logP:** Both ligands have acceptable logP values (3.135 and 1.85, respectively), falling within the 1-3 optimal range.

**H-Bond Donors & Acceptors:** Both have 2 HBD, which is good. Ligand A has 2 HBA, while Ligand B has 6. While both are under the 10 limit, the lower HBA count of Ligand A is preferable for permeability.

**QED:** Both ligands have similar and good QED values (0.793 and 0.806).

**DILI:** Ligand A (57.348) has a slightly higher DILI risk than Ligand B (47.77), but both are below the concerning threshold of 60.

**BBB:** Both ligands have excellent BBB penetration (79.682 and 76.735), exceeding the desirable >70 threshold for CNS targets.

**Caco-2 Permeability:** Ligand A (-5.007) has a worse Caco-2 permeability score than Ligand B (-4.581). Higher values are better.

**Aqueous Solubility:** Ligand A (-3.483) has a worse aqueous solubility score than Ligand B (-3.2). Higher values are better.

**hERG:** Both ligands have low hERG inhibition liability (0.535 and 0.279).

**Microsomal Clearance:** Ligand B (45.668) has a significantly lower microsomal clearance than Ligand A (22.594), indicating better metabolic stability.

**In vitro Half-Life:** Ligand B (7.891) has a significantly longer half-life than Ligand A (-0.195).

**P-gp Efflux:** Ligand A (0.258) has a lower P-gp efflux liability than Ligand B (0.139), which is beneficial for CNS exposure.

**Binding Affinity:** Ligand A (-8.9 kcal/mol) has a significantly stronger binding affinity than Ligand B (-7.4 kcal/mol). This is a substantial advantage (>1.5 kcal/mol difference).

**Overall Assessment:**

Ligand A excels in TPSA, P-gp efflux, and crucially, binding affinity. The significantly stronger binding affinity of Ligand A (-8.9 vs -7.4 kcal/mol) is a major advantage that can offset some of its drawbacks. Ligand B has better metabolic stability (lower Cl_mic, longer t1/2), Caco-2 permeability, and solubility, but these are less critical for a CNS target like DRD2 compared to BBB penetration (which both have) and strong binding affinity. The higher TPSA of Ligand B is a concern for CNS penetration, even though its BBB percentile is good.

Output:
1
2025-04-17 06:23:45,338 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (338.411 Da) is slightly lower, which could be beneficial for permeability. Ligand B (352.312 Da) is also acceptable.

**TPSA:** Ligand A (83.2) is better than Ligand B (59.59). Both are below the 90 A^2 threshold desirable for CNS targets, but Ligand A is closer to the optimal range for brain penetration.

**logP:** Both ligands have good logP values (Ligand A: 2.671, Ligand B: 3.842), falling within the 1-3 range. Ligand B is slightly higher, potentially leading to some solubility issues, but still acceptable.

**H-Bond Donors/Acceptors:** Ligand A has 3 HBD and 6 HBA, while Ligand B has 2 HBD and 3 HBA. Both are within acceptable limits (<=5 HBD and <=10 HBA).

**QED:** Both have good QED scores (Ligand A: 0.644, Ligand B: 0.879), indicating good drug-like properties. Ligand B is slightly better.

**DILI:** Ligand A (53.742) has a lower DILI risk than Ligand B (73.982), which is a significant advantage.

**BBB:** Ligand B (79.217) has a significantly better BBB penetration score than Ligand A (52.423). This is a critical factor for a CNS target like DRD2.

**Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and suggests poor permeability. Ligand A (-5.12) is slightly better than Ligand B (-4.786), but both are concerning.

**Aqueous Solubility:** Both have negative solubility values, indicating poor aqueous solubility. Ligand A (-3.064) is slightly better than Ligand B (-4.638).

**hERG Inhibition:** Both have low hERG inhibition liability (Ligand A: 0.683, Ligand B: 0.816), which is good.

**Microsomal Clearance:** Ligand A (2.531) has a lower microsomal clearance than Ligand B (43.351), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (35.093) has a longer in vitro half-life than Ligand B (-13.52), which is a significant advantage.

**P-gp Efflux:** Ligand A (0.229) has lower P-gp efflux liability than Ligand B (0.448), which is favorable for CNS penetration.

**Binding Affinity:** Ligand B (-10.1 kcal/mol) has a significantly stronger binding affinity than Ligand A (-8.4 kcal/mol). This is a substantial advantage, potentially outweighing some of the ADME drawbacks.

**Overall Assessment:**

Ligand B excels in binding affinity and BBB penetration, which are crucial for a CNS GPCR target. However, it has higher DILI risk, higher P-gp efflux, and poorer metabolic stability. Ligand A has better ADME properties (lower DILI, better metabolic stability, lower P-gp efflux) but weaker binding affinity and lower BBB penetration.

The difference in binding affinity (-1.7 kcal/mol) is significant. For a GPCR, strong binding is paramount, and the improved BBB penetration of Ligand B is also a major plus. While Ligand B's ADME profile isn't ideal, it's potentially optimizable. Ligand A's weaker binding affinity makes it less likely to be a successful drug candidate, even with its better ADME properties.

Output:
1
2025-04-17 06:23:45,338 - INFO - Batch 278 complete. Total preferences: 4448
2025-04-17 06:23:45,338 - INFO - Processing batch 279/512...
2025-04-17 06:24:27,751 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (379.222 Da) and Ligand B (365.499 Da) are comparable.

**2. TPSA:**  For CNS targets, we want TPSA <= 90. Ligand A (80.04) is excellent, while Ligand B (92.5) is slightly above the preferred threshold, but not dramatically so.

**3. logP:** Optimal is 1-3. Ligand A (4.585) is quite high, potentially leading to solubility issues and off-target interactions. Ligand B (1.051) is at the lower end of the optimal range, but still acceptable.

**4. H-Bond Donors:**  <= 5 is preferred. Both ligands are within this range: Ligand A (3) and Ligand B (2).

**5. H-Bond Acceptors:** <= 10 is preferred. Both ligands are within this range: Ligand A (3) and Ligand B (5).

**6. QED:** >= 0.5 is good. Both ligands exceed this threshold: Ligand A (0.583) and Ligand B (0.814).

**7. DILI:** Lower is better. Ligand A (92.168) has a significantly higher DILI risk than Ligand B (17.255). This is a major concern for Ligand A.

**8. BBB:** > 70 is desirable for CNS targets. Both ligands are good: Ligand A (72.78) and Ligand B (74.486).

**9. Caco-2 Permeability:** Higher is better. Ligand A (-4.875) is very poor, indicating poor intestinal absorption. Ligand B (-6.156) is also poor, but slightly better than Ligand A.

**10. Aqueous Solubility:** Higher is better. Ligand A (-5.835) is very poor, consistent with its high logP. Ligand B (-1.772) is better, but still relatively low.

**11. hERG Inhibition:** Lower is better. Both ligands have similar, low hERG risk: Ligand A (0.661) and Ligand B (0.601).

**12. Microsomal Clearance:** Lower is better. Ligand B (-14.624) has much lower (better) microsomal clearance than Ligand A (40.808), indicating greater metabolic stability.

**13. In vitro Half-Life:** Longer is better. Ligand B (37.944) has a longer half-life than Ligand A (109.409). This is a positive for Ligand B.

**14. P-gp Efflux:** Lower is better. Both ligands have very low P-gp efflux: Ligand A (0.215) and Ligand B (0.022).

**15. Binding Affinity:** More negative is better. Both ligands have excellent binding affinity: Ligand A (-8.8 kcal/mol) and Ligand B (-8.6 kcal/mol). The difference is small (0.2 kcal/mol), and likely not enough to overcome other significant differences.

**Overall Assessment:**

Ligand B is the superior candidate. While its Caco-2 and solubility are not ideal, they are better than Ligand A's. Critically, Ligand B has a much lower DILI risk and better metabolic stability (lower Cl_mic, longer t1/2). Ligand A's high logP, poor solubility, poor Caco-2 permeability, and high DILI risk are significant drawbacks. The slightly better affinity of Ligand A is not enough to compensate for these issues.

Output:
1
2025-04-17 06:24:27,752 - INFO - Reasoning:

Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight (MW):** Both ligands (357.401 and 351.422 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (78.51) is slightly higher than Ligand B (71.53). Both are below the 90 A^2 threshold desirable for CNS targets, which is good.

**3. logP:** Ligand A (1.196) is within the optimal 1-3 range. Ligand B (2.065) is also within the optimal range, but closer to the upper limit.

**4. H-Bond Donors (HBD):** Both ligands have acceptable HBD counts (2 and 1, respectively), well below the 5 threshold.

**5. H-Bond Acceptors (HBA):** Both ligands have acceptable HBA counts (3 and 4, respectively), below the 10 threshold.

**6. QED:** Both ligands have good QED scores (0.75 and 0.778), indicating drug-like properties.

**7. DILI:** Ligand A (27.608) has a lower DILI risk than Ligand B (32.842), which is favorable.

**8. BBB:** Ligand B (91.819) has a significantly higher BBB penetration percentile than Ligand A (83.366). This is a crucial advantage for a CNS target like DRD2.

**9. Caco-2 Permeability:** Ligand A (-4.863) has worse Caco-2 permeability than Ligand B (-3.889).

**10. Aqueous Solubility:** Both ligands have very poor aqueous solubility (-2.23 and -2.258). This is a concern, but can sometimes be mitigated with formulation strategies.

**11. hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.154 and 0.304).

**12. Microsomal Clearance:** Ligand A (1.054) has significantly lower microsomal clearance than Ligand B (65.134), suggesting better metabolic stability.

**13. In vitro Half-Life:** Ligand A (-1.634) has a longer in vitro half-life than Ligand B (-23.167). This is a significant advantage.

**14. P-gp Efflux:** Both ligands have low P-gp efflux liability (0.01 and 0.055).

**15. Binding Affinity:** Ligand B (-7.4 kcal/mol) has a slightly better binding affinity than Ligand A (-8.2 kcal/mol). While the difference is relatively small, it's still a positive for Ligand B.

**Overall Assessment:**

Ligand B excels in BBB penetration, a critical factor for CNS targets. It also has slightly better affinity and Caco-2 permeability. However, Ligand A has significantly better metabolic stability (lower Cl_mic, longer half-life) and lower DILI risk. The difference in binding affinity is small enough that the superior ADME profile of Ligand A, particularly the BBB and metabolic stability, makes it the more promising candidate.

Output:
1
2025-04-17 06:24:27,752 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B based on the provided guidelines, prioritizing GPCR-specific properties (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (335.411 Da) is slightly lower, which could be beneficial for permeability, but both are acceptable.

**TPSA:** Both ligands have TPSA values below the 90 A^2 threshold for CNS targets. Ligand B (71.09 A^2) is better than Ligand A (89.89 A^2), suggesting potentially better CNS penetration.

**logP:** Both ligands have logP values within the optimal range (1-3). Ligand B (3.537) is slightly higher than Ligand A (4.303), but both are acceptable.

**H-Bond Donors/Acceptors:** Both ligands have 2 HBDs, which is good. Ligand A has 2 HBAs, while Ligand B has 4. Both are within the acceptable limits (<=10).

**QED:** Both ligands have acceptable QED values (>0.5), with Ligand B (0.776) being slightly better than Ligand A (0.476).

**DILI:** Ligand B (45.095) has a significantly lower DILI risk than Ligand A (56.572), making it more favorable from a safety perspective.

**BBB:** Ligand A (70.803) has a better BBB percentile than Ligand B (63.629). This is a crucial factor for CNS targets like DRD2.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values which is unusual and suggests poor permeability.

**Aqueous Solubility:** Both ligands have negative solubility values which is also unusual and suggests poor solubility.

**hERG Inhibition:** Both ligands have low hERG inhibition liability, which is good. Ligand B (0.317) is slightly better than Ligand A (0.535).

**Microsomal Clearance:** Ligand B (57.996) has a higher microsomal clearance than Ligand A (20.615), indicating lower metabolic stability. This is a drawback for Ligand B.

**In vitro Half-Life:** Ligand B (30.793) has a significantly longer in vitro half-life than Ligand A (-1.455), which is a major advantage.

**P-gp Efflux:** Both ligands have low P-gp efflux liability, which is good. Ligand A (0.198) is slightly better than Ligand B (0.229).

**Binding Affinity:** Ligand A (-9.7 kcal/mol) has a significantly stronger binding affinity than Ligand B (-8.0 kcal/mol). This is a substantial advantage that can outweigh some ADME drawbacks.

**Overall Assessment:**

The key trade-offs are: Ligand A has superior binding affinity and BBB penetration, while Ligand B has better DILI risk, QED, and in vitro half-life. Given that DRD2 is a CNS target, BBB penetration is critical. The significantly stronger binding affinity of Ligand A is also a major advantage. Although Ligand B has a better safety profile (DILI), the difference isn't drastic enough to overcome the substantial benefits of Ligand A in terms of potency and CNS penetration. The negative values for Caco-2 and solubility are concerning for both, but can potentially be addressed through formulation strategies.

Output:
0
2025-04-17 06:24:27,752 - INFO - Reasoning:

Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (352.435 and 352.494 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (113.76) is better than Ligand B (49.41). For CNS targets, we want TPSA <= 90, so Ligand A is closer to this threshold, suggesting better CNS penetration potential.

**3. logP:** Ligand B (3.616) is within the optimal 1-3 range, while Ligand A (-0.031) is slightly below 1, which *could* hinder permeation.

**4. H-Bond Donors:** Ligand A (3) is higher than Ligand B (1), but both are within the acceptable limit of <=5.

**5. H-Bond Acceptors:** Ligand A (4) is higher than Ligand B (2), but both are within the acceptable limit of <=10.

**6. QED:** Both ligands have good QED scores (0.558 and 0.761), indicating good drug-like properties.

**7. DILI:** Ligand A (16.13) has a significantly lower DILI risk than Ligand B (29.43), which is a substantial advantage.

**8. BBB:** Ligand B (96.045) has a much higher BBB penetration percentile than Ligand A (80.07). This is a critical factor for a CNS target like DRD2.

**9. Caco-2 Permeability:** Ligand A (-5.333) has a negative value, indicating poor permeability. Ligand B (-4.458) is also poor, but slightly better.

**10. Aqueous Solubility:** Ligand A (-1.248) has poor solubility, while Ligand B (-3.898) is even worse.

**11. hERG Inhibition:** Both ligands have low hERG inhibition risk (0.2 and 0.85, respectively).

**12. Microsomal Clearance:** Ligand A (-16.991) has a much lower (better) microsomal clearance than Ligand B (56.426), indicating greater metabolic stability.

**13. In vitro Half-Life:** Ligand A (-8.009) has a negative value, indicating a very short half-life. Ligand B (-19.105) is even worse.

**14. P-gp Efflux:** Ligand A (0.01) has very low P-gp efflux, which is excellent for CNS penetration. Ligand B (0.545) is higher, indicating more efflux.

**15. Binding Affinity:** Both ligands have very similar and strong binding affinities (-8.4 and -8.6 kcal/mol). The difference is negligible.

**Overall Assessment:**

Ligand B excels in BBB penetration, which is paramount for a CNS GPCR target. However, Ligand A demonstrates better metabolic stability (lower Cl_mic), lower DILI risk, and lower P-gp efflux. The poor solubility and permeability of both are concerning, but can potentially be addressed with formulation strategies. Given the importance of CNS penetration for DRD2, and the relatively small difference in binding affinity, Ligand B is the more promising candidate.

Output:
1
2025-04-17 06:24:27,752 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (355.41 and 345.443 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (98.74) is better than Ligand B (104.45) as it's closer to the <90 A^2 threshold for CNS targets. Ligand B is still acceptable, but A is preferred.

**logP:** Ligand A (-0.271) is a bit low, potentially hindering permeability. Ligand B (1.224) is within the optimal 1-3 range. This is a significant advantage for Ligand B.

**H-Bond Donors/Acceptors:** Both have 3 HBDs and 4 HBAs, which are acceptable values.

**QED:** Ligand A (0.571) has a better QED score than Ligand B (0.339), indicating a more drug-like profile.

**DILI:** Both ligands have low DILI risk (29.042 and 31.524, respectively), which is good.

**BBB:** Ligand A (46.607) has a lower BBB penetration percentile than Ligand B (54.091). While both are below the desirable >70 for CNS targets, Ligand B is better.

**Caco-2 Permeability:** Both have negative Caco-2 values (-5.349 and -5.19), which is unusual and suggests poor permeability.

**Aqueous Solubility:** Both have negative solubility values (-1.585 and -2.438), indicating very poor aqueous solubility. This is a major concern for both.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.191 and 0.829).

**Microsomal Clearance:** Ligand A (-24.994) has significantly lower (better) microsomal clearance than Ligand B (28.012), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (9.083) has a slightly better in vitro half-life than Ligand B (-11.27).

**P-gp Efflux:** Ligand A (0.022) has a much lower P-gp efflux liability than Ligand B (0.182), which is crucial for CNS penetration.

**Binding Affinity:** Ligand A (-8.4 kcal/mol) has a significantly stronger binding affinity than Ligand B (-7.7 kcal/mol). This is a substantial advantage for Ligand A. The 0.7 kcal/mol difference is large enough to potentially overcome some ADME deficiencies.

**Overall Assessment:**

Ligand A has a superior binding affinity, better QED, lower P-gp efflux, and better metabolic stability. However, it suffers from a low logP and lower BBB penetration. Ligand B has a better logP and slightly better BBB penetration, but weaker binding affinity, lower QED, and higher P-gp efflux.

Given the GPCR-specific priorities, the strong binding affinity of Ligand A is a significant factor. While the logP and BBB are not ideal, the improved metabolic stability and reduced efflux could compensate, especially if further optimization can address these issues. The difference in binding affinity is substantial enough to prioritize Ligand A.

Output:
0
2025-04-17 06:24:27,752 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (353.413 and 347.419 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (53.6) is excellent, well below the 90 A^2 threshold for CNS targets. Ligand B (87.54) is higher, but still potentially acceptable, though less ideal.

**logP:** Ligand A (3.483) is optimal (1-3). Ligand B (0.025) is very low, which is a significant concern for permeability and CNS penetration.

**H-Bond Donors/Acceptors:** Ligand A (HBD=2, HBA=3) is well within the acceptable ranges. Ligand B (HBD=1, HBA=5) is also acceptable.

**QED:** Both ligands have reasonable QED scores (A: 0.823, B: 0.705), indicating good drug-like properties.

**DILI:** Ligand A (30.826) has a very low DILI risk. Ligand B (42.575) is slightly higher, but still within an acceptable range.

**BBB:** This is critical for a CNS target like DRD2. Ligand A scores very highly (91.431), suggesting excellent brain penetration. Ligand B scores poorly (46.917), raising serious doubts about its ability to reach the target.

**Caco-2 Permeability:** Ligand A (-4.905) is negative, indicating poor permeability. Ligand B (-5.368) is also negative, indicating poor permeability.

**Aqueous Solubility:** Ligand A (-3.038) is negative, indicating poor solubility. Ligand B (-0.827) is also negative, indicating poor solubility.

**hERG Inhibition:** Ligand A (0.879) has a low hERG risk. Ligand B (0.03) has a very low hERG risk.

**Microsomal Clearance:** Ligand A (0.389) has a very low clearance, indicating good metabolic stability. Ligand B (21.486) has a higher clearance, suggesting faster metabolism.

**In vitro Half-Life:** Ligand A (5.644) has a reasonable half-life. Ligand B (8.007) has a longer half-life, which is a positive.

**P-gp Efflux:** Ligand A (0.161) has low P-gp efflux, which is favorable for CNS penetration. Ligand B (0.02) has very low P-gp efflux, which is also favorable.

**Binding Affinity:** Ligand A (-8.9 kcal/mol) has significantly stronger binding affinity than Ligand B (-7.7 kcal/mol). The 1.2 kcal/mol difference is substantial and can outweigh some ADME drawbacks.

**Overall Assessment:**

Ligand A is the stronger candidate. While both have poor Caco-2 permeability and solubility, Ligand A's superior BBB penetration, significantly higher binding affinity, and low DILI risk outweigh its slightly higher clearance. Ligand B's extremely low logP is a major red flag, severely limiting its potential for CNS penetration despite its longer half-life and low P-gp efflux. The strong binding affinity of Ligand A is a critical advantage for a GPCR target.

Output:
1
2025-04-17 06:24:27,752 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B based on the provided guidelines, prioritizing GPCR-specific properties (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (353.423 and 364.515 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (113.53) is better than Ligand B (64.68). Both are below the 90 A^2 threshold desirable for CNS targets, but A is closer to the upper limit.

**logP:** Both ligands have good logP values (1.386 and 1.212), falling within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Both have 2 HBDs, which is good. Ligand A has 7 HBAs, while Ligand B has 5. Both are acceptable (<=10).

**QED:** Both ligands have good QED scores (0.539 and 0.796), indicating drug-like properties. Ligand B is better here.

**DILI:** Ligand A has a DILI risk of 54.401, which is acceptable (below 60). Ligand B has a much lower DILI risk of 13.339, which is excellent.

**BBB:** Ligand B (74.292) significantly outperforms Ligand A (56.029) in BBB penetration, exceeding the desirable >70% threshold. This is a *critical* advantage for a CNS target like DRD2.

**Caco-2 Permeability:** Both have negative values, indicating poor permeability. Ligand A (-5.127) is slightly better than Ligand B (-5.448), but both are problematic.

**Aqueous Solubility:** Both have negative solubility values, indicating poor solubility. Ligand A (-2.545) is slightly better than Ligand B (-2.052).

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.587 and 0.498).

**Microsomal Clearance:** Ligand B (13.153) has a much lower microsomal clearance than Ligand A (45.353), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand B (9.013) has a significantly longer in vitro half-life than Ligand A (-5.132).

**P-gp Efflux:** Ligand A (0.278) has lower P-gp efflux than Ligand B (0.017), which is favorable for CNS penetration.

**Binding Affinity:** Ligand A (-7.0) has a slightly better binding affinity than Ligand B (-6.6). However, the difference is less than 1.5 kcal/mol, so it's not a decisive factor.

**Overall Assessment:**

While Ligand A has slightly better binding affinity and P-gp efflux, Ligand B is superior in almost all other crucial ADME properties, especially BBB penetration (74.292 vs 56.029), DILI risk (13.339 vs 54.401), microsomal clearance (13.153 vs 45.353), and in vitro half-life (9.013 vs -5.132). Given the CNS target (DRD2), BBB penetration is paramount, and Ligand B excels in this area. The lower DILI and better metabolic stability of Ligand B also contribute to its higher potential as a drug candidate.

Output:
1
2025-04-17 06:24:27,752 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (350.369 and 354.426 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (67.23) is significantly better than Ligand B (87.46). For CNS targets, we want TPSA <= 90, and A is comfortably within that, while B is approaching the upper limit.

**3. logP:** Both ligands (2.28 and 2.364) are within the optimal 1-3 range.

**4. H-Bond Donors:** Ligand A (1) is preferable to Ligand B (2). Lower HBD generally improves permeability.

**5. H-Bond Acceptors:** Ligand A (4) is preferable to Ligand B (5). Lower HBA generally improves permeability.

**6. QED:** Ligand A (0.9) is significantly better than Ligand B (0.736), indicating a more drug-like profile.

**7. DILI:** Ligand A (61.07) has a slightly higher DILI risk than Ligand B (47.732), but both are acceptable (<60 is good).

**8. BBB:** Both ligands have excellent BBB penetration (83.482 and 82.474, both >70), which is crucial for a CNS target like DRD2.

**9. Caco-2:** Both ligands have negative Caco-2 values, which is unusual and suggests a potential issue with the data or modeling. However, the values are similar (-4.442 and -4.847).

**10. Solubility:** Both ligands have negative solubility values, which is also unusual. Again, the values are similar (-2.812 and -3.474).

**11. hERG:** Both ligands have low hERG inhibition liability (0.587 and 0.452), which is good.

**12. Cl_mic:** Ligand B (21.96) has a significantly lower microsomal clearance than Ligand A (40.1), suggesting better metabolic stability.

**13. t1/2:** Ligand B (-22.72) has a much longer in vitro half-life than Ligand A (37.623). This is a major advantage. Note the negative value for ligand B is unusual, but indicates a very long half-life.

**14. Pgp:** Ligand A (0.149) has lower P-gp efflux liability than Ligand B (0.419), which is desirable for CNS exposure.

**15. Binding Affinity:** Ligand A (-8.5 kcal/mol) has a slightly stronger binding affinity than Ligand B (-7.8 kcal/mol). A 0.7 kcal/mol difference is significant.

**Overall Assessment:**

Ligand A excels in TPSA, QED, Pgp efflux, and binding affinity. Ligand B has a better metabolic profile (lower Cl_mic, longer t1/2) and slightly lower DILI risk. The affinity difference is important, and the lower TPSA of A is highly favorable for CNS penetration. While B has better metabolic stability, the superior binding affinity and drug-like properties of A, combined with acceptable metabolic parameters, make it the more promising candidate.

Output:
1
2025-04-17 06:24:27,752 - INFO - Reasoning:

Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (358.829 Da and 352.475 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (80.05) is better than Ligand B (70.08). Both are below the 90 A^2 threshold desirable for CNS targets, but A is slightly higher.

**3. logP:** Ligand A (3.481) is within the optimal 1-3 range. Ligand B (1.273) is at the lower end, potentially hindering permeation.

**4. H-Bond Donors:** Ligand A (2) and Ligand B (1) are both acceptable (<=5).

**5. H-Bond Acceptors:** Both ligands (A: 4, B: 4) are within the acceptable range (<=10).

**6. QED:** Both ligands have reasonable QED values (A: 0.707, B: 0.635), indicating good drug-like properties.

**7. DILI:** Ligand A (79.449) has a significantly higher DILI risk than Ligand B (18.651). This is a major concern for Ligand A.

**8. BBB:** Ligand A (69.639) has a better BBB percentile than Ligand B (48.003). However, ideally, we want >70 for CNS targets.

**9. Caco-2:** Ligand A (-5.035) and Ligand B (-4.179) both have negative values, which is unusual. Lower (more negative) values suggest poor permeability.

**10. Solubility:** Ligand A (-3.887) and Ligand B (-1.836) both have negative values, indicating poor aqueous solubility.

**11. hERG:** Both ligands have low hERG risk (A: 0.392, B: 0.464).

**12. Cl_mic:** Ligand A (67.538) has a higher microsomal clearance than Ligand B (28.327), indicating lower metabolic stability.

**13. t1/2:** Ligand A (102.241) has a much longer in vitro half-life than Ligand B (-1.486).

**14. Pgp:** Ligand A (0.262) has lower P-gp efflux liability than Ligand B (0.164), which is favorable for CNS penetration.

**15. Binding Affinity:** Ligand A (-9.9 kcal/mol) has a significantly stronger binding affinity than Ligand B (-5.9 kcal/mol). This is a substantial advantage.

**Overall Assessment:**

Ligand A has a much stronger binding affinity and better BBB penetration and Pgp efflux properties. However, its high DILI risk and higher metabolic clearance are significant drawbacks. Ligand B has a much lower DILI risk and better metabolic stability, but its weaker binding affinity and lower BBB penetration are concerning.

Given the GPCR-specific priorities, and the importance of CNS penetration for a DRD2 target, the strong binding affinity of Ligand A is a major advantage that *could* outweigh its other weaknesses, *if* the DILI risk can be mitigated through structural modifications. The difference in binding affinity (-9.9 vs -5.9) is substantial (4 kcal/mol), and this is a large enough advantage to prioritize further investigation of Ligand A.

Output:
1
2025-04-17 06:24:27,752 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (348.451 and 348.403 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (83.36) is significantly better than Ligand B (109.39). For CNS targets, we want TPSA <= 90, which Ligand A meets, while Ligand B exceeds it.

**3. logP:** Ligand B (1.318) is better than Ligand A (0.325). The optimal range is 1-3, and Ligand B falls within this, while Ligand A is below 1, potentially hindering permeation.

**4. H-Bond Donors:** Ligand A (1) is preferable to Ligand B (3). Lower HBD generally improves permeability.

**5. H-Bond Acceptors:** Both ligands have 6 HBA, which is acceptable (<=10).

**6. QED:** Ligand A (0.829) has a better QED score than Ligand B (0.561), indicating a more drug-like profile.

**7. DILI:** Ligand A (21.908) has a much lower DILI risk than Ligand B (52.617), which is a significant advantage.

**8. BBB:** Ligand A (34.122) has a much better BBB penetration percentile than Ligand B (13.377). This is *critical* for a CNS target like DRD2.

**9. Caco-2 Permeability:** Ligand A (-5.405) has a slightly better (less negative) Caco-2 value than Ligand B (-5.519), suggesting better intestinal absorption.

**10. Aqueous Solubility:** Ligand A (-0.2) is slightly better than Ligand B (-2.114).

**11. hERG Inhibition:** Ligand A (0.048) has a much lower hERG inhibition liability than Ligand B (0.353), reducing cardiotoxicity risk.

**12. Microsomal Clearance:** Ligand A (-17.44) has a much lower (better) microsomal clearance than Ligand B (14.769), indicating greater metabolic stability.

**13. In vitro Half-Life:** Ligand B (81.496) has a significantly longer in vitro half-life than Ligand A (17.307). This is a positive attribute.

**14. P-gp Efflux:** Ligand A (0.01) has a much lower P-gp efflux liability than Ligand B (0.181), which is crucial for CNS penetration.

**15. Binding Affinity:** Both ligands have very similar binding affinities (-7.6 and -7.7 kcal/mol), which are both excellent. The difference is negligible.

**Overall Assessment:**

Ligand A is significantly better overall, especially considering the GPCR-specific priorities for a CNS target. While Ligand B has a better half-life, Ligand A excels in TPSA, BBB, DILI, hERG, P-gp efflux, and microsomal clearance, all of which are vital for CNS drug development. The slightly lower logP of Ligand A is a minor drawback outweighed by its superior ADME properties and safety profile.

Output:
0
2025-04-17 06:24:27,753 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (352.439 and 366.487 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (126.37) is slightly above the optimal <90 for CNS targets, but still reasonable. Ligand B (67.67) is excellent, well below the threshold.

**logP:** Ligand A (-0.234) is a bit low, potentially hindering membrane permeability. Ligand B (1.119) is within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A has 3 HBD and 7 HBA, both acceptable. Ligand B has 0 HBD and 6 HBA, also acceptable.

**QED:** Both ligands have good QED scores (0.555 and 0.799), indicating good drug-like properties.

**DILI:** Ligand A (32.067) has a lower DILI risk than Ligand B (44.591), both are acceptable.

**BBB:** Ligand B (63.94) has a significantly better BBB penetration percentile than Ligand A (52.074). This is a crucial advantage for a CNS target like DRD2.

**Caco-2 Permeability:** Ligand A (-5.59) has poor Caco-2 permeability, while Ligand B (-4.895) is slightly better, but still not great.

**Aqueous Solubility:** Both ligands have poor aqueous solubility (-1.141 and -2.256 respectively).

**hERG:** Both ligands have very low hERG inhibition risk (0.192 and 0.122).

**Microsomal Clearance:** Ligand A (0.009) has extremely low microsomal clearance, suggesting high metabolic stability. Ligand B (35.263) has significantly higher clearance, indicating faster metabolism.

**In vitro Half-Life:** Ligand A (-13.768) has a very long in vitro half-life, consistent with its low clearance. Ligand B (2.12) has a short half-life.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.016 and 0.046).

**Binding Affinity:** Ligand A (-7.5 kcal/mol) has a slightly better binding affinity than Ligand B (-6.7 kcal/mol). However, the difference is less than the 1.5 kcal/mol threshold that would strongly favor A despite other drawbacks.

**Overall Assessment:**

Ligand B is the better candidate. While Ligand A has slightly better affinity and metabolic stability, Ligand B's superior BBB penetration, better logP, and acceptable overall profile make it more likely to reach the target in the CNS. The poor Caco-2 permeability of both is a concern, but less critical for a CNS-focused drug. The lower TPSA of Ligand B is also beneficial.



Output:
1
2025-04-17 06:24:27,753 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (353.423 and 349.356 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (117.33) is better than Ligand B (38.56) as it is closer to the <90 threshold for CNS targets. Ligand B is quite low, which could indicate poor interactions with the receptor.

**logP:** Ligand A (-0.936) is suboptimal, being slightly below the 1-3 range. Ligand B (4.894) is too high, potentially leading to solubility issues and off-target effects.

**H-Bond Donors/Acceptors:** Ligand A (2 HBD, 6 HBA) is better than Ligand B (1 HBD, 4 HBA) as it is within the ideal range.

**QED:** Both ligands have good QED scores (0.584 and 0.712), indicating drug-like properties.

**DILI:** Ligand A (17.759) has a significantly lower DILI risk than Ligand B (66.576), which is a major advantage.

**BBB:** Both ligands have acceptable BBB penetration (69.097 and 67.817), but neither exceeds the desirable >70 threshold.

**Caco-2 Permeability:** Ligand A (-5.733) has poor Caco-2 permeability, while Ligand B (-4.61) is also poor, but better than A.

**Aqueous Solubility:** Ligand A (-0.969) has poor solubility, while Ligand B (-5.674) is even worse.

**hERG Inhibition:** Ligand A (0.049) has very low hERG inhibition risk, a significant advantage. Ligand B (0.905) has a moderate risk.

**Microsomal Clearance:** Ligand A (3.324) has lower microsomal clearance than Ligand B (45.377), indicating better metabolic stability.

**In vitro Half-Life:** Ligand A (-3.85) has a very short half-life, while Ligand B (-19.409) is even shorter. Both are poor.

**P-gp Efflux:** Ligand A (0.005) has very low P-gp efflux, which is highly desirable for CNS penetration. Ligand B (0.808) has moderate P-gp efflux.

**Binding Affinity:** Ligand B (-8.5 kcal/mol) has a significantly stronger binding affinity than Ligand A (-7.2 kcal/mol). This is a substantial advantage, potentially outweighing some of its ADME drawbacks.

**Overall Assessment:**

While Ligand B has a superior binding affinity, its high logP, poor solubility, higher DILI risk, and moderate P-gp efflux are significant concerns. Ligand A, despite its weaker affinity and poor Caco-2 permeability, has a much better safety profile (low DILI, low hERG), better metabolic stability, and very low P-gp efflux. Given the CNS target and the importance of minimizing off-target effects and maximizing brain exposure, Ligand A is the more promising candidate, assuming the affinity can be improved through further optimization. The affinity difference of 1.3 kcal/mol is substantial, but the ADME profile of Ligand A is far more favorable.

Output:
0
2025-04-17 06:24:27,753 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (344.415 and 349.406 Da) fall comfortably within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (91.4) is slightly higher than Ligand B (74.43). For CNS targets, we prefer TPSA <= 90, so Ligand B is better here.

**3. logP:** Both ligands have good logP values (1.693 and 1.857), falling within the optimal 1-3 range.

**4. H-Bond Donors:** Both have 2 HBD, which is acceptable.

**5. H-Bond Acceptors:** Ligand A has 6 HBA, and Ligand B has 3. Both are within the acceptable limit of <=10.

**6. QED:** Both ligands have similar QED scores (0.832 and 0.823), indicating good drug-likeness.

**7. DILI:** Both ligands have similar DILI risk (43.971 and 45.715), and are both below the 60 threshold, indicating low risk.

**8. BBB:** Both ligands have excellent BBB penetration (72.005 and 74.486), exceeding the desirable >70 threshold for CNS targets.

**9. Caco-2 Permeability:** Ligand A (-4.712) has worse Caco-2 permeability than Ligand B (-4.543). Higher values are better.

**10. Aqueous Solubility:** Both ligands have very poor aqueous solubility (-2.778 and -2.857). This is a concern, but can sometimes be mitigated with formulation strategies.

**11. hERG Inhibition:** Both ligands have low hERG inhibition risk (0.31 and 0.577).

**12. Microsomal Clearance:** Ligand B (21.822) has significantly lower microsomal clearance than Ligand A (39.178), suggesting better metabolic stability.

**13. In vitro Half-Life:** Ligand B (-11.445) has a much longer in vitro half-life than Ligand A (-2.855), which is highly desirable.

**14. P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.028 and 0.082), which is good for CNS exposure.

**15. Binding Affinity:** Both ligands have excellent binding affinity (-8.9 and -9.3 kcal/mol). Ligand B is slightly better, but the difference is small.

**Overall Assessment:**

While both ligands are promising, Ligand B is superior. It has a lower TPSA, better Caco-2 permeability, significantly lower microsomal clearance, and a longer in vitro half-life. The slightly better binding affinity of Ligand B is a bonus. The poor aqueous solubility is a concern for both, but the other advantages of Ligand B make it the more viable candidate.

Output:
1
2025-04-17 06:24:27,753 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (351.491 and 347.415 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (53.09) is significantly better than Ligand B (93.46). For CNS targets, TPSA should be <= 90, and A is comfortably within that range, while B is nearing the upper limit.

**logP:** Both ligands have acceptable logP values (1.347 and 1.639), falling within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A (0 HBD, 4 HBA) is preferable to Ligand B (2 HBD, 5 HBA). Lower HBD/HBA generally improves permeability.

**QED:** Both ligands have reasonable QED scores (0.662 and 0.551), indicating good drug-like properties.

**DILI:** Ligand A (6.979) has a much lower DILI risk than Ligand B (47.693). This is a significant advantage.

**BBB:** Both ligands have good BBB penetration (72.16 and 71.811), exceeding the desirable threshold of >70 for CNS targets.

**Caco-2 Permeability:** Both have negative Caco-2 values (-4.691 and -4.461). This is unusual and suggests poor permeability. However, the scale isn't specified, so it's hard to interpret.

**Aqueous Solubility:** Both have negative solubility values (-0.036 and -3.143). This is also unusual and suggests poor solubility.

**hERG:** Both ligands have low hERG inhibition liability (0.497 and 0.339), which is good.

**Microsomal Clearance:** Ligand A (16.299) has a lower microsomal clearance than Ligand B (35.07), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (11.856) has a longer in vitro half-life than Ligand B (-11.927). A negative half-life is not possible, so this is likely an error in the data. However, even ignoring this, A is better.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.019 and 0.242), which is favorable for CNS penetration.

**Binding Affinity:** Ligand B (-7.5) has a slightly better binding affinity than Ligand A (-7.0), but the difference is less than the 1.5 kcal/mol threshold where affinity outweighs other factors.

**Overall Assessment:**

Ligand A is significantly better overall. It has a much lower DILI risk, better TPSA, lower microsomal clearance, and a longer half-life. While Ligand B has slightly better binding affinity, the other ADME properties of Ligand A are far more favorable, especially for a CNS target like DRD2. The negative solubility and Caco-2 values are concerning for both, but the other advantages of A outweigh this.

Output:
1
2025-04-17 06:24:27,753 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (351.382 and 352.45 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (107.19) is better than Ligand B (78.43). Both are below the 140 A^2 threshold for oral absorption, and Ligand B is closer to the desirable <90 A^2 for CNS targets.

**logP:** Ligand B (2.557) is optimal (1-3), while Ligand A (-0.439) is too low, potentially hindering permeation. This is a significant advantage for Ligand B.

**H-Bond Donors/Acceptors:** Both have 3 HBD and 3-4 HBA, which are within acceptable limits.

**QED:** Both ligands have similar QED values (0.668 and 0.639), indicating good drug-likeness.

**DILI:** Ligand B (31.059) has a much lower DILI risk than Ligand A (59.131), making it safer.

**BBB:** Ligand A (76.541) has a better BBB percentile than Ligand B (62.544), which is important for a CNS target like DRD2.

**Caco-2 Permeability:** Ligand A (-5.185) has worse Caco-2 permeability than Ligand B (-4.639), indicating lower intestinal absorption.

**Aqueous Solubility:** Ligand A (-2.307) has slightly better solubility than Ligand B (-3.125), but both are poor.

**hERG Inhibition:** Ligand B (0.774) shows a slightly higher hERG inhibition risk than Ligand A (0.227), but both are relatively low.

**Microsomal Clearance:** Ligand A (-7.141) has a much lower (better) microsomal clearance than Ligand B (42.922), indicating greater metabolic stability.

**In vitro Half-Life:** Ligand B (36.458) has a significantly longer half-life than Ligand A (-12.04), which is desirable.

**P-gp Efflux:** Ligand A (0.038) has much lower P-gp efflux than Ligand B (0.358), which is favorable for CNS penetration.

**Binding Affinity:** Ligand B (-7.9) has a slightly better (more negative) binding affinity than Ligand A (-9.1). However, the difference is not substantial enough to outweigh other factors.

**Overall Assessment:**

Ligand B is the better candidate. While Ligand A has a better BBB score and lower P-gp efflux, Ligand B excels in critical areas: logP (optimal), DILI (much lower risk), metabolic stability (longer half-life), and a good binding affinity. The lower logP of Ligand A is a significant drawback for a GPCR target, potentially hindering its ability to cross cell membranes. The improved metabolic stability and reduced toxicity of Ligand B are also crucial advantages. The slightly lower BBB of Ligand B is a concern, but the other benefits outweigh this.

Output:
1
2025-04-17 06:24:27,753 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B based on the provided guidelines, prioritizing GPCR-specific properties (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (391.274 Da) is slightly higher than Ligand B (344.499 Da), but both are acceptable.

**TPSA:** Ligand A (67.23) is higher than Ligand B (49.41). For CNS targets, TPSA should be <= 90. Both are well within this range, but Ligand B is preferable.

**logP:** Ligand A (1.9) and Ligand B (3.276) are both within the optimal range (1-3). Ligand B is slightly more lipophilic, which could be beneficial for membrane permeability, but not excessively so.

**H-Bond Donors/Acceptors:** Both ligands have 1 HBD, which is good. Ligand A has 4 HBA, and Ligand B has 2 HBA. Both are acceptable (<=10). Ligand B is slightly better here.

**QED:** Both ligands have QED values above 0.5 (Ligand A: 0.78, Ligand B: 0.687), indicating good drug-like properties.

**DILI:** Ligand A (37.728) has a slightly higher DILI risk than Ligand B (14.889). Ligand B is significantly better in terms of predicted liver toxicity.

**BBB:** Both ligands have good BBB penetration (Ligand A: 78.558, Ligand B: 73.401), exceeding the 70% threshold for CNS targets. Ligand A is slightly better.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values, which is unusual and potentially problematic. It's difficult to interpret these values without knowing the scale. However, we can assume lower values indicate poorer permeability.

**Aqueous Solubility:** Both ligands have negative solubility values, which is also unusual. Again, interpretation is difficult without knowing the scale, but lower values suggest poorer solubility.

**hERG Inhibition:** Both ligands have very low hERG inhibition risk (Ligand A: 0.286, Ligand B: 0.46).

**Microsomal Clearance:** Ligand A (50.576) has lower microsomal clearance than Ligand B (69.006), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (-39.652) has a significantly longer in vitro half-life than Ligand B (0.883). This is a major advantage.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (Ligand A: 0.029, Ligand B: 0.318). Ligand A is better.

**Binding Affinity:** Both ligands have similar binding affinities (Ligand A: -8.5 kcal/mol, Ligand B: -8.2 kcal/mol). Ligand A has a slightly better affinity, but the difference is small.

**Overall Assessment:**

Considering all parameters and the GPCR-specific priorities, **Ligand A is the more promising candidate.** While Ligand B has slightly better TPSA and DILI, Ligand A excels in BBB penetration, metabolic stability (lower Cl_mic, longer t1/2), P-gp efflux, and has a slightly better binding affinity. The negative solubility and Caco-2 values are concerning for both, but the other advantages of Ligand A outweigh these drawbacks. The longer half-life and better CNS penetration are particularly valuable for a CNS-targeting drug.

Output:
1
2025-04-17 06:24:27,753 - INFO - Batch 279 complete. Total preferences: 4464
2025-04-17 06:24:27,753 - INFO - Processing batch 280/512...
2025-04-17 06:25:07,633 - INFO - Reasoning:

Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (363.483 and 353.482 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (79.46) is higher than Ligand B (61.44). For a CNS target like DRD2, TPSA should be <= 90, so both are acceptable, but B is better.

**3. logP:** Ligand A (3.54) is slightly higher than Ligand B (2.383), both within the optimal 1-3 range.

**4. H-Bond Donors:** Ligand A (1) is better than Ligand B (2). Lower HBDs generally improve permeability.

**5. H-Bond Acceptors:** Ligand A (7) is higher than Ligand B (3). Lower HBAs are preferred for CNS penetration.

**6. QED:** Both ligands have similar QED values (0.683 and 0.691), indicating good drug-likeness.

**7. DILI:** Ligand A (43.971) has a higher DILI risk than Ligand B (13.532). B is significantly better here.

**8. BBB:** Ligand B (86.041) has a much higher BBB penetration percentile than Ligand A (38.813). This is *critical* for a CNS target like DRD2.

**9. Caco-2 Permeability:** Ligand A (-5.497) and Ligand B (-4.899) both have negative values, which is unusual. This suggests poor permeability.

**10. Aqueous Solubility:** Ligand A (-3.505) and Ligand B (-1.636) both have negative values, suggesting poor solubility.

**11. hERG Inhibition:** Ligand A (0.275) has a slightly lower hERG risk than Ligand B (0.607).

**12. Microsomal Clearance:** Ligand B (-8.323) has a *much* lower (better) microsomal clearance than Ligand A (86.496). This indicates better metabolic stability for Ligand B.

**13. In vitro Half-Life:** Ligand B (-5.671) has a better in vitro half-life than Ligand A (-7.706).

**14. P-gp Efflux:** Ligand A (0.345) has lower P-gp efflux liability than Ligand B (0.085). Lower efflux is better for CNS exposure.

**15. Binding Affinity:** Both ligands have excellent binding affinities (-8.3 and -8.0 kcal/mol). The difference is minimal.

**Overall Assessment:**

Ligand B is significantly more promising. While both have good affinity, Ligand B excels in critical areas for a CNS-targeting GPCR: BBB penetration, lower DILI risk, and significantly improved metabolic stability (lower Cl_mic and better half-life). Although Ligand A has slightly lower P-gp efflux, the benefits of B in the other key areas outweigh this. The solubility and permeability are poor for both, but can be addressed with formulation strategies.

Output:
1
2025-04-17 06:25:07,633 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight (MW):** Both ligands (364.477 and 345.487 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (58.64) is slightly above the optimal <90 for CNS targets, but still reasonable. Ligand B (52.65) is excellent, well below 90.

**3. logP:** Both ligands have good logP values (3.084 and 2.758), falling within the 1-3 optimal range.

**4. H-Bond Donors (HBD):** Both have 1 HBD, which is within the acceptable limit of <=5.

**5. H-Bond Acceptors (HBA):** Both have 3 HBA, also within the acceptable limit of <=10.

**6. QED:** Both ligands have good QED scores (0.648 and 0.893), indicating drug-like properties. Ligand B is slightly better.

**7. DILI:** Ligand A (30.399) has a slightly higher DILI risk than Ligand B (11.594), but both are below the concerning threshold of 60.

**8. BBB:** Both ligands have excellent BBB penetration (85.537 and 86.623), exceeding the desirable >70 for CNS targets.

**9. Caco-2 Permeability:** Both have negative Caco-2 values (-4.31 and -4.643), which is unusual and suggests poor permeability. This is a significant concern for both.

**10. Aqueous Solubility:** Both have negative solubility values (-3.308 and -2.035), indicating very poor aqueous solubility. This is a major drawback for both.

**11. hERG Inhibition:** Both ligands have low hERG inhibition risk (0.825 and 0.804).

**12. Microsomal Clearance:** Ligand A (76.881) has a higher microsomal clearance than Ligand B (-3.549), indicating lower metabolic stability. Ligand B is significantly better here.

**13. In vitro Half-Life:** Ligand A (17.688) has a shorter half-life than Ligand B (7.423).

**14. P-gp Efflux:** Both ligands have low P-gp efflux liability (0.22 and 0.127), which is favorable for CNS penetration. Ligand B is slightly better.

**15. Binding Affinity:** Ligand B (-8.5 kcal/mol) has a significantly stronger binding affinity than Ligand A (-6.5 kcal/mol). This is a >2 kcal/mol difference, which is substantial and can outweigh some ADME drawbacks.

**Overall Assessment:**

While both ligands have issues with Caco-2 permeability and aqueous solubility, Ligand B is superior. It has a significantly better binding affinity, lower microsomal clearance (better metabolic stability), slightly better P-gp efflux, and a lower DILI risk. The stronger binding affinity is a critical advantage for a GPCR ligand. The solubility and permeability issues would need to be addressed through formulation or structural modifications, but the improved potency and ADME profile of Ligand B make it the more promising candidate.

Output:
1
2025-04-17 06:25:07,633 - INFO - Reasoning:

Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (383.857 Da) is slightly higher than Ligand B (347.419 Da), but both are acceptable.

**2. TPSA:**  Ligand A (90.41) is better than Ligand B (100.35). For CNS targets, we want TPSA <= 90, so Ligand A is closer to the ideal.

**3. logP:** Ligand A (1.891) is within the optimal range (1-3), while Ligand B (-0.064) is slightly below 1.  This is a significant advantage for Ligand A, as low logP can hinder permeation.

**4. H-Bond Donors:** Ligand A (1) is better than Ligand B (2). Fewer HBDs generally improve permeability.

**5. H-Bond Acceptors:** Ligand A (7) is better than Ligand B (6).

**6. QED:** Both ligands have similar, good QED values (0.7 and 0.777 respectively).

**7. DILI:** Ligand A (78.402) has a higher DILI risk than Ligand B (43.389). This is a negative for Ligand A, but not a dealbreaker at this stage.

**8. BBB:** Ligand A (52.772) has a considerably better BBB penetration percentile than Ligand B (34.083). This is *crucial* for a CNS target like DRD2.

**9. Caco-2 Permeability:** Ligand A (-4.738) is significantly better than Ligand B (-5.52). Higher values are better.

**10. Aqueous Solubility:** Ligand A (-3.713) is better than Ligand B (-1.529).

**11. hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.103 and 0.065 respectively), which is excellent.

**12. Microsomal Clearance:** Ligand B (-11.987) has a lower (better) microsomal clearance than Ligand A (72.17). This suggests better metabolic stability for Ligand B.

**13. In vitro Half-Life:** Ligand B (13.748) has a longer half-life than Ligand A (-12.392). This is a positive for Ligand B.

**14. P-gp Efflux:** Ligand A (0.109) has lower P-gp efflux than Ligand B (0.005), which is favorable for CNS penetration.

**15. Binding Affinity:** Both ligands have excellent binding affinities (-8.2 and -8.5 kcal/mol). Ligand B is slightly better, but the difference is small.

**Overall Assessment:**

While Ligand B has better metabolic stability (Cl_mic, t1/2) and a lower DILI risk, Ligand A significantly outperforms it in key properties for a CNS-targeting GPCR: TPSA, logP, and *especially* BBB penetration. The slightly higher DILI risk for Ligand A is less concerning than the poor BBB penetration of Ligand B. The better Caco-2 and solubility also favor Ligand A. The P-gp efflux is also better for Ligand A. Given the importance of CNS penetration for DRD2, Ligand A is the more promising candidate.

Output:
1
2025-04-17 06:25:07,633 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (348.531 and 374.503 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (49.41) is excellent, well below the 90 A^2 threshold for CNS targets. Ligand B (84.94) is still reasonable but higher, potentially impacting BBB penetration.

**logP:** Ligand A (4.033) is at the upper end of the optimal range (1-3), potentially leading to solubility issues. Ligand B (0.893) is below the optimal range and could have permeability issues.

**H-Bond Donors/Acceptors:** Both ligands have acceptable HBD (1) and HBA (2 for A, 5 for B) counts, staying within the recommended limits.

**QED:** Both ligands have good QED scores (0.684 and 0.715), indicating good drug-like properties.

**DILI:** Ligand A (12.214) has a much lower DILI risk than Ligand B (47.77). This is a significant advantage for Ligand A.

**BBB:** Ligand A (90.772) has a significantly higher BBB penetration percentile than Ligand B (70.648). This is crucial for a CNS target like DRD2.

**Caco-2 Permeability:** Ligand A (-4.86) and Ligand B (-5.134) both have negative values, which is unusual and needs clarification on the scale used. Assuming lower values indicate poorer permeability, both are concerning, but similar.

**Aqueous Solubility:** Both ligands have poor aqueous solubility (-3.893 and -2.704). This is a potential issue, especially for Ligand A with its higher logP.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.667 and 0.42).

**Microsomal Clearance:** Both ligands have similar microsomal clearance values (51.662 and 55.094), suggesting comparable metabolic stability.

**In vitro Half-Life:** Both ligands have negative in vitro half-life values (-16.875 and -15.921), which is also unusual and requires clarification on the scale. Assuming lower values indicate shorter half-life, both are concerning, but similar.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.384 and 0.118), which is favorable for CNS penetration.

**Binding Affinity:** Ligand A (-7.9 kcal/mol) has a slightly better binding affinity than Ligand B (-7.5 kcal/mol). While the difference is not huge (1.5 kcal/mol), it's enough to consider, especially given the other favorable properties of Ligand A.

**Overall Assessment:**

Ligand A is the more promising candidate. It has a superior BBB score, lower DILI risk, and slightly better binding affinity. While its logP is higher and solubility is lower than ideal, the strong BBB penetration and low toxicity risk outweigh these concerns for a CNS-targeting GPCR. Ligand B's lower logP is good, but its significantly higher DILI risk and lower BBB penetration make it less attractive.

Output:
0
2025-04-17 06:25:07,633 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (368.371 and 352.391 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (49.85) is excellent, well below the 90 A^2 threshold for CNS targets. Ligand B (127.84) is higher, but still potentially acceptable, though less optimal.

**logP:** Ligand A (2.153) is within the optimal 1-3 range. Ligand B (-1.093) is below 1, which could hinder permeation.

**H-Bond Donors/Acceptors:** Ligand A (0 HBD, 3 HBA) is favorable. Ligand B (4 HBD, 5 HBA) is also reasonable, but slightly higher counts could affect permeability.

**QED:** Ligand A (0.715) is excellent, indicating good drug-likeness. Ligand B (0.181) is poor, suggesting potential issues.

**DILI:** Ligand A (25.553) has a low DILI risk. Ligand B (33.385) is also relatively low, but higher than A.

**BBB:** Ligand A (87.864) has excellent BBB penetration potential, exceeding the desirable >70% threshold. Ligand B (37.573) is significantly lower, raising concerns about CNS exposure.

**Caco-2 Permeability:** Ligand A (-4.252) has poor Caco-2 permeability. Ligand B (-5.634) is even worse.

**Aqueous Solubility:** Ligand A (-2.248) has poor aqueous solubility. Ligand B (-1.6) is also poor.

**hERG Inhibition:** Both ligands (0.625 and 0.044) have low hERG inhibition risk, which is good.

**Microsomal Clearance:** Ligand A (25.93) has moderate clearance. Ligand B (-26.687) has negative clearance, which is not physically possible and indicates an error in the data or a very stable compound.

**In vitro Half-Life:** Ligand A (-15.162) has a negative half-life, which is not physically possible and indicates an error in the data. Ligand B (-4.543) also has a negative half-life.

**P-gp Efflux:** Both ligands (0.027 and 0.006) have low P-gp efflux, which is favorable for CNS penetration.

**Binding Affinity:** Ligand A (-8.1 kcal/mol) has a significantly stronger binding affinity than Ligand B (-7.5 kcal/mol). The 0.6 kcal/mol difference is substantial and could outweigh some ADME drawbacks.

**Overall Assessment:**

Ligand A is clearly superior. While both ligands have issues with solubility and Caco-2 permeability, Ligand A has a much better BBB score, a higher QED, better DILI risk, and a significantly stronger binding affinity. The negative values for clearance and half-life for both compounds are concerning and likely indicate data errors, but the large difference in binding affinity is still a major factor. The lower logP of Ligand B is also a significant drawback. Given the GPCR-specific emphasis on BBB and affinity, Ligand A is the more promising candidate.

Output:
1
2025-04-17 06:25:07,634 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (342.399 and 346.471 Da) fall comfortably within the ideal 200-500 Da range.

**TPSA:** Ligand A (95.42) is higher than Ligand B (58.64). For CNS targets, we prefer TPSA <= 90, so Ligand B is significantly better here.

**logP:** Both ligands have good logP values (1.767 and 2.267), falling within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A has 2 HBD and 5 HBA, while Ligand B has 1 HBD and 3 HBA. Both are within acceptable limits (<=5 HBD and <=10 HBA).

**QED:** Both have reasonable QED scores (0.834 and 0.72), indicating good drug-like properties.

**DILI:** Ligand A (67.507) has a higher DILI risk than Ligand B (25.126). Lower DILI is preferred.

**BBB:** This is crucial for a CNS target like DRD2. Ligand B (70.415) has a significantly better BBB percentile than Ligand A (31.873). This is a major advantage for Ligand B.

**Caco-2 Permeability:** Both have negative Caco-2 values (-4.921 and -4.882), which is unusual and suggests poor permeability. However, these values are on a scale where negative values are possible, and the absolute value is what matters. They are similar and not a strong differentiator.

**Aqueous Solubility:** Both ligands have negative solubility values (-2.893 and -3.03), indicating poor solubility. This is a concern, but not a primary differentiator given the other factors.

**hERG:** Both ligands have low hERG inhibition liability (0.205 and 0.381), which is good.

**Microsomal Clearance:** Ligand B (65.432) has higher microsomal clearance than Ligand A (42.957), meaning it's metabolized faster. Lower clearance is preferable.

**In vitro Half-Life:** Ligand A (36.424) has a longer half-life than Ligand B (0.783). Longer half-life is generally desirable.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.08 and 0.107), which is good for CNS penetration.

**Binding Affinity:** Both ligands have excellent binding affinity (-8.0 and -8.1 kcal/mol). The difference is minimal.

**Overall Assessment:**

Ligand B is the stronger candidate. While Ligand A has a slightly longer half-life, Ligand B excels in the most critical areas for a CNS-targeting GPCR ligand: significantly better BBB penetration, lower DILI risk, and a lower TPSA. The slightly higher clearance of Ligand B is a minor drawback compared to these advantages. The binding affinities are comparable.

Output:
1
2025-04-17 06:25:07,634 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (355.454 and 343.387 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (72.88) is significantly better than Ligand B (91.42). For CNS targets, TPSA should be <= 90, so Ligand A is preferable.

**3. logP:** Both ligands have acceptable logP values (0.543 and 0.667), falling within the 1-3 range.

**4. H-Bond Donors:** Both ligands are acceptable (2 and 1, respectively), well below the threshold of 5.

**5. H-Bond Acceptors:** Both ligands are acceptable (4 and 5, respectively), below the threshold of 10.

**6. QED:** Both ligands have good QED scores (0.772 and 0.881), indicating good drug-like properties.

**7. DILI:** Both ligands have similar, acceptable DILI risk (6.863 and 60.217 percentile).

**8. BBB:** Ligand A (60.915%) is significantly better than Ligand B (45.638%). A BBB percentile >70 is desirable for CNS targets, but Ligand A is closer to that target.

**9. Caco-2 Permeability:** Ligand A (-5.131) is better than Ligand B (-4.819), indicating better intestinal absorption.

**10. Aqueous Solubility:** Ligand A (-1.203) is better than Ligand B (-2.437), suggesting better solubility.

**11. hERG Inhibition:** Both ligands have low hERG inhibition risk (0.305 and 0.264 percentile).

**12. Microsomal Clearance:** Ligand A (-27.249) is *much* better than Ligand B (6.916). Lower clearance indicates greater metabolic stability, a crucial factor.

**13. In vitro Half-Life:** Ligand A (-16.154) is better than Ligand B (8.653), indicating a longer half-life.

**14. P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.019 and 0.025 percentile).

**15. Binding Affinity:** Ligand B (-8.6 kcal/mol) has a slightly better binding affinity than Ligand A (-7.5 kcal/mol). However, the difference is only 1.1 kcal/mol, and the ADME properties of Ligand A are significantly superior.

**Overall Assessment:**

Ligand A clearly outperforms Ligand B in almost all ADME properties crucial for a CNS-targeting GPCR ligand. The most significant advantages are its substantially better BBB penetration, lower microsomal clearance, and longer half-life. While Ligand B has a slightly better binding affinity, the ADME profile of Ligand A is far more favorable, suggesting it is more likely to achieve adequate brain exposure and maintain therapeutic concentrations.

Output:
1
2025-04-17 06:25:07,634 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (378.881 Da) is slightly higher than Ligand B (345.487 Da), but both are acceptable.

**TPSA:** Both ligands have TPSA values below 90 (Ligand A: 68.29, Ligand B: 64.41), which is favorable for CNS penetration.

**logP:** Both ligands have logP values around 2.8-2.9, falling within the optimal range of 1-3.

**H-Bond Donors/Acceptors:** Ligand A has 1 HBD and 5 HBA, while Ligand B has 0 HBD and 3 HBA. Both are within acceptable limits (<=5 HBD and <=10 HBA).

**QED:** Both ligands have QED values above 0.6 (Ligand A: 0.715, Ligand B: 0.635), indicating good drug-like properties.

**DILI:** Ligand A has a DILI risk of 70.221, which is approaching the higher risk threshold (>60). Ligand B has a significantly lower DILI risk of 11.361, which is excellent.

**BBB:** Ligand B (72.237) has a better BBB percentile than Ligand A (42.924). This is a crucial factor for CNS targets like DRD2.

**Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and suggests poor permeability. However, the scale is not specified, so it's difficult to interpret.

**Aqueous Solubility:** Both ligands have negative solubility values, which is also unusual and suggests poor solubility. Again, the scale is unclear.

**hERG Inhibition:** Ligand A (0.373) has a slightly lower hERG inhibition risk than Ligand B (0.697), which is preferable.

**Microsomal Clearance:** Ligand B (31.973) has significantly lower microsomal clearance than Ligand A (91.309), indicating better metabolic stability.

**In vitro Half-Life:** Ligand B (-7.335) has a longer in vitro half-life than Ligand A (-0.803).

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.135), which is good.

**Binding Affinity:** Ligand A (-8.1 kcal/mol) has a slightly better binding affinity than Ligand B (-7.3 kcal/mol). This is a 1.8 kcal/mol difference, which is significant.

**Overall Assessment:**

While Ligand A has a slightly better binding affinity, Ligand B is superior in almost all other critical ADME properties, especially for a CNS target. Ligand B's significantly better BBB penetration, lower DILI risk, lower microsomal clearance, and longer half-life outweigh the small difference in binding affinity. The poor solubility and permeability values are concerning for both, but the other advantages of Ligand B make it a more promising candidate.

Output:
1
2025-04-17 06:25:07,634 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (345.443 Da) is slightly better, being closer to the lower end which can aid permeability.

**TPSA:** Ligand A (76.38) is significantly better than Ligand B (46.84). For CNS targets, we want TPSA <= 90, and ideally lower. Ligand A is well within this range, while Ligand B is approaching a less desirable value.

**logP:** Both ligands have logP values (3.236 and 4.529) within the optimal range (1-3), but Ligand B is pushing the upper limit. Higher logP can lead to solubility issues and off-target interactions.

**H-Bond Donors/Acceptors:** Ligand A (2 HBD, 6 HBA) and Ligand B (0 HBD, 6 HBA) are both acceptable.

**QED:** Both ligands have similar QED values (0.754 and 0.613), indicating good drug-like properties.

**DILI:** Both ligands have low DILI risk (32.377 and 36.138), which is positive.

**BBB:** This is a crucial parameter for a CNS target like DRD2. Ligand B (90.074) has a significantly higher BBB percentile than Ligand A (57.619). This is a major advantage for Ligand B.

**Caco-2 Permeability:** Ligand A (-4.846) has a more negative Caco-2 value, indicating lower permeability. Ligand B (-5.199) is also low, but slightly better.

**Aqueous Solubility:** Both ligands have very poor aqueous solubility (-2.991 and -4.41). This is a concern for both, but more so for Ligand B.

**hERG Inhibition:** Both ligands have low hERG inhibition liability (0.65 and 0.454), which is good.

**Microsomal Clearance:** Ligand A (41.113) has lower microsomal clearance than Ligand B (50.203), indicating better metabolic stability.

**In vitro Half-Life:** Ligand A (56.311) has a longer in vitro half-life than Ligand B (24.959), which is desirable.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.165 and 0.375), which is good.

**Binding Affinity:** Ligand A (-7.7 kcal/mol) has a significantly stronger binding affinity than Ligand B (-6.1 kcal/mol). This 1.6 kcal/mol difference is substantial and can outweigh some ADME drawbacks.

**Overall Assessment:**

Ligand B has a much better BBB score, which is critical for CNS penetration. However, Ligand A boasts a significantly stronger binding affinity, better metabolic stability (lower Cl_mic, longer t1/2), and a lower TPSA. The solubility is poor for both, but the affinity difference is substantial. Considering the GPCR-specific priorities, the stronger affinity of Ligand A, combined with acceptable TPSA and metabolic stability, makes it the more promising candidate, despite the lower BBB score. The higher affinity could potentially overcome the lower BBB penetration, especially with further optimization.

Output:
0
2025-04-17 06:25:07,634 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (346.471 and 349.387 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (58.64) is excellent, well below the 90 A^2 threshold for CNS targets. Ligand B (92.95) is higher, but still acceptable, though less optimal for CNS penetration.

**logP:** Ligand A (2.5) is within the optimal 1-3 range. Ligand B (0.742) is a bit low, potentially hindering membrane permeability.

**H-Bond Donors/Acceptors:** Ligand A (1 HBD, 4 HBA) is good. Ligand B (0 HBD, 6 HBA) is also acceptable.

**QED:** Both ligands have similar QED values (0.735 and 0.703), indicating good drug-like properties.

**DILI:** Ligand A (12.834) has a much lower DILI risk than Ligand B (38.62). This is a significant advantage for Ligand A.

**BBB:** Both ligands have very good BBB penetration (77.162 and 76.813). This is crucial for a CNS target like DRD2.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.777 and -4.25). This is unusual and suggests poor permeability. However, these values are on a log scale, so the absolute difference is important.

**Aqueous Solubility:** Both ligands have negative solubility values (-2.845 and -1.254). This is also concerning, indicating poor aqueous solubility.

**hERG Inhibition:** Ligand A (0.837) has a slightly higher hERG risk than Ligand B (0.028). Ligand B is much better here.

**Microsomal Clearance:** Ligand A (36.109) has significantly lower microsomal clearance than Ligand B (66.044), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (-5.511) has a more negative half-life, which is unusual and likely indicates a very short half-life. Ligand B (-17.227) is even worse.

**P-gp Efflux:** Ligand A (0.216) has lower P-gp efflux than Ligand B (0.023), indicating better potential for CNS exposure.

**Binding Affinity:** Ligand A (-8.7 kcal/mol) has a significantly stronger binding affinity than Ligand B (-6.5 kcal/mol). This >1.5 kcal/mol difference is a major advantage for Ligand A, potentially outweighing some of its ADME drawbacks.

**Conclusion:**

Despite the concerning Caco-2 and solubility values for both, Ligand A is the more promising candidate. Its superior binding affinity, lower DILI risk, better metabolic stability (lower Cl_mic), and lower P-gp efflux outweigh the slightly higher hERG risk and the potentially problematic half-life. The TPSA is also much more favorable for CNS penetration. The strong binding affinity suggests that even with some permeability challenges, sufficient drug concentrations at the target site might be achievable.

Output:
0
2025-04-17 06:25:07,634 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (343.339 and 349.366 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (109.75) is slightly above the preferred <90 for CNS targets, while Ligand B (93.11) is closer to the ideal range. This gives a slight edge to Ligand B.

**logP:** Both ligands have good logP values (2.515 and 1.189), falling within the optimal 1-3 range. Ligand A is slightly higher, which could be beneficial for membrane permeability but might increase off-target interactions.

**H-Bond Donors/Acceptors:** Both have 1 HBD and 6 HBA, which are within acceptable limits.

**QED:** Both ligands have good QED scores (0.66 and 0.837), indicating good drug-like properties. Ligand B is slightly better here.

**DILI:** Ligand A (52.191) has a lower DILI risk than Ligand B (59.713), which is preferable.

**BBB:** Ligand B (81.194) has a significantly better BBB penetration percentile than Ligand A (69.678). This is a *critical* advantage for a CNS target like DRD2.

**Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and suggests poor permeability. However, the scale is not specified, so it's difficult to interpret.

**Aqueous Solubility:** Both have negative solubility values, which is also unusual and suggests poor solubility. Again, the scale is not specified.

**hERG Inhibition:** Ligand A (0.837) has a slightly higher hERG inhibition liability than Ligand B (0.104). Ligand B is much better here, reducing cardiotoxicity concerns.

**Microsomal Clearance:** Ligand A (22.768) has lower microsomal clearance than Ligand B (39.28), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand B (-34.968) has a significantly longer in vitro half-life than Ligand A (-16.242). This is a major advantage for dosing convenience.

**P-gp Efflux:** Ligand A (0.455) has lower P-gp efflux liability than Ligand B (0.046), meaning it is less likely to be pumped out of the brain, increasing CNS exposure.

**Binding Affinity:** Both ligands have excellent binding affinities (-9.3 and -8.3 kcal/mol). Ligand A has a 1 kcal/mol advantage, which is substantial and could outweigh some of its other drawbacks.

**Overall Assessment:**

While Ligand A has a slightly better binding affinity and lower DILI risk, Ligand B excels in crucial areas for a CNS-targeting GPCR ligand. Specifically, its significantly better BBB penetration, longer half-life, and lower hERG inhibition are highly desirable. The slightly lower affinity of Ligand B is likely acceptable given its superior ADME properties. The negative Caco-2 and solubility values are concerning for both, but the other advantages of Ligand B are more impactful for this specific target.

Output:
1
2025-04-17 06:25:07,634 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (358.435 and 349.475 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (85.38) is slightly above the optimal <90 for CNS targets, but still reasonable. Ligand B (76.82) is well within the desired range.

**logP:** Ligand A (1.075) is at the lower end of optimal, potentially impacting permeability. Ligand B (3.068) is excellent, falling squarely within the 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A (0 HBD, 7 HBA) is favorable. Ligand B (2 HBD, 4 HBA) is also good, staying within the recommended limits.

**QED:** Both ligands have good QED scores (0.657 and 0.742), indicating drug-like properties.

**DILI:** Ligand A (41.024) has a slightly higher DILI risk than Ligand B (12.33), but both are below the concerning threshold of 60.

**BBB:** Both ligands exhibit excellent BBB penetration (79.992 and 84.606), which is crucial for a CNS target like DRD2.

**Caco-2 Permeability:** Ligand A (-3.951) shows poor Caco-2 permeability, a significant drawback. Ligand B (-4.682) also shows poor Caco-2 permeability, but is slightly better than Ligand A.

**Aqueous Solubility:** Both ligands have poor aqueous solubility (-1.811 and -1.623). This could pose formulation challenges.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.319 and 0.79).

**Microsomal Clearance:** Ligand A (84.934) has a higher microsomal clearance, indicating faster metabolism. Ligand B (-9.828) exhibits negative clearance, which is unusual and suggests very high metabolic stability.

**In vitro Half-Life:** Ligand A (-32.778) has a negative half-life, which is not possible and indicates a potential data error or a very rapidly metabolized compound. Ligand B (-2.289) has a very short half-life.

**P-gp Efflux:** Both ligands show low P-gp efflux liability (0.117 and 0.173), which is favorable for CNS penetration.

**Binding Affinity:** Ligand B (-8.0 kcal/mol) has a significantly stronger binding affinity than Ligand A (-6.1 kcal/mol). This >1.5 kcal/mol difference is substantial and can often outweigh minor ADME drawbacks.

**Conclusion:**

Despite both ligands having good BBB penetration and acceptable safety profiles (DILI, hERG), Ligand B is the superior candidate. Its stronger binding affinity, better logP, and significantly improved metabolic stability (negative Cl_mic) outweigh the slightly worse solubility and Caco-2 permeability compared to Ligand A. The negative half-life for Ligand A is a major red flag.

Output:
1
2025-04-17 06:25:07,634 - INFO - Reasoning:

Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight (MW):** Both ligands are within the ideal range (200-500 Da). Ligand A (338.367 Da) is slightly lower, which could be favorable for permeability.

**2. TPSA:** Ligand A (100.02) is better than Ligand B (49.85) as it is closer to the desired value of <=90 for CNS targets.

**3. logP:** Both ligands have good logP values (A: 2.792, B: 2.067) falling within the optimal range of 1-3.

**4. H-Bond Donors (HBD):** Both ligands are acceptable. Ligand A has 3 HBD, and Ligand B has 0.

**5. H-Bond Acceptors (HBA):** Both ligands are acceptable. Ligand A has 4 HBA, and Ligand B has 4 HBA.

**6. QED:** Both ligands have good QED scores (A: 0.666, B: 0.704), indicating good drug-like properties.

**7. DILI:** Ligand A (79.643) has a higher DILI risk than Ligand B (44.436). This is a significant drawback for Ligand A.

**8. BBB:** Ligand B (79.837) has a significantly better BBB percentile than Ligand A (49.515). This is *critical* for a CNS target like DRD2.

**9. Caco-2 Permeability:** Both have negative values, which is unusual. However, the magnitude of the negative value for Ligand A (-5.329) is worse than that of Ligand B (-5.103).

**10. Aqueous Solubility:** Both have negative values, which is unusual. The magnitude of the negative value for Ligand A (-4.267) is worse than that of Ligand B (-3.032).

**11. hERG Inhibition:** Both ligands have low hERG inhibition risk (A: 0.526, B: 0.362).

**12. Microsomal Clearance (Cl_mic):** Ligand B (57.174) has a higher microsomal clearance than Ligand A (16.775), suggesting lower metabolic stability.

**13. In vitro Half-Life:** Ligand A (35.097) has a longer half-life than Ligand B (-5.527).

**14. P-gp Efflux:** Ligand B (0.314) has lower P-gp efflux than Ligand A (0.094), which is favorable for CNS penetration.

**15. Binding Affinity:** Ligand A (-9.5 kcal/mol) has a significantly stronger binding affinity than Ligand B (0.0 kcal/mol). This is a *major* advantage for Ligand A.

**Overall Assessment:**

Despite Ligand A's superior binding affinity, the significantly better BBB penetration, lower DILI risk, and lower P-gp efflux of Ligand B make it the more promising candidate. The strong binding affinity of Ligand A is appealing, but the poor BBB penetration and higher DILI risk are major concerns for a CNS drug. The difference in affinity, while substantial, may be overcome with further optimization of Ligand B.

Output:
1
2025-04-17 06:25:07,635 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (425.308 Da) is higher, but still acceptable. Ligand B (345.447 Da) is slightly better.

**TPSA:** Both ligands have TPSA values below the 90 A^2 threshold desirable for CNS targets. Ligand B (70.47 A^2) is significantly better than Ligand A (90.88 A^2).

**logP:** Ligand A (3.271) is within the optimal range (1-3). Ligand B (0.454) is below 1, which could hinder permeation. This is a significant drawback for Ligand B.

**H-Bond Donors/Acceptors:** Ligand A (0 HBD, 7 HBA) and Ligand B (1 HBD, 5 HBA) both fall within acceptable limits (<=5 HBD, <=10 HBA).

**QED:** Both ligands have good QED scores (Ligand A: 0.623, Ligand B: 0.787), indicating drug-like properties. Ligand B is slightly better.

**DILI:** Ligand A (92.323 percentile) has a higher DILI risk than Ligand B (31.563 percentile). This is a significant negative for Ligand A.

**BBB:** Ligand A (64.831 percentile) has a better BBB penetration prediction than Ligand B (51.221 percentile). This is a positive for Ligand A, crucial for a CNS target.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values, which is unusual and suggests a potential issue with the prediction method or the compounds themselves. However, we can still compare them relatively.

**Aqueous Solubility:** Both ligands have negative solubility values, again suggesting potential issues with the prediction.

**hERG Inhibition:** Both ligands show low hERG inhibition liability (Ligand A: 0.265, Ligand B: 0.131).

**Microsomal Clearance:** Ligand A (22.399 mL/min/kg) has a higher clearance than Ligand B (11.376 mL/min/kg), indicating lower metabolic stability.

**In vitro Half-Life:** Ligand A (23.722 hours) has a longer half-life than Ligand B (3.441 hours).

**P-gp Efflux:** Ligand A (0.371) shows lower P-gp efflux than Ligand B (0.017), which is favorable for CNS penetration.

**Binding Affinity:** Both ligands have excellent binding affinities (Ligand A: -8.9 kcal/mol, Ligand B: -8.0 kcal/mol). Ligand A is slightly better.

**Overall Assessment:**

Ligand A has a better binding affinity, BBB penetration, P-gp efflux, and half-life. However, it has a significantly higher DILI risk and higher microsomal clearance. Ligand B has better TPSA, QED, DILI risk, and P-gp efflux, but suffers from a low logP and lower BBB penetration.

Given the GPCR-specific priorities, BBB penetration and logP are critical. While Ligand B's logP is concerning, the substantial difference in DILI risk and the slightly better BBB score for Ligand A are outweighed by the very low logP of Ligand B. The affinity difference is not large enough to overcome the ADME liabilities of Ligand A.

Output:
1
2025-04-17 06:25:07,635 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (443.084 Da) is at the higher end, while Ligand B (368.499 Da) is more favorably positioned.

**TPSA:** Both ligands have TPSA values below 90, which is good for CNS penetration. Ligand B (75.71) is slightly better than Ligand A (83.7).

**logP:** Ligand A (4.032) is slightly above the optimal range (1-3), potentially leading to solubility issues. Ligand B (1.578) is within the optimal range.

**H-Bond Donors/Acceptors:** Ligand A has 2 HBD and 4 HBA, which are acceptable. Ligand B has 1 HBD and 5 HBA, also acceptable.

**QED:** Both ligands have good QED scores (A: 0.638, B: 0.746), indicating drug-like properties.

**DILI:** Ligand A has a high DILI risk (90.151), which is a significant concern. Ligand B has a much lower DILI risk (37.611), a major advantage.

**BBB:** Ligand B has a significantly better BBB penetration percentile (71.733) compared to Ligand A (21.52). This is crucial for a CNS target like DRD2.

**Caco-2 Permeability:** Both have negative values, which is unusual. Assuming these are logP-like scales, lower values indicate poorer permeability. Ligand A (-5.158) is worse than Ligand B (-4.802).

**Aqueous Solubility:** Both have negative values, indicating poor solubility. Ligand A (-4.176) is slightly worse than Ligand B (-3.555).

**hERG Inhibition:** Ligand A (0.073) has a slightly lower hERG risk than Ligand B (0.242), but both are relatively low.

**Microsomal Clearance:** Ligand B (93.823) has a much higher microsomal clearance than Ligand A (7.203), indicating faster metabolism and potentially lower *in vivo* exposure.

**In vitro Half-Life:** Ligand A (24.192 hours) has a significantly longer half-life than Ligand B (3.565 hours).

**P-gp Efflux:** Ligand A (0.085) has lower P-gp efflux liability than Ligand B (0.09), which is favorable for CNS penetration.

**Binding Affinity:** Ligand A (-9.2 kcal/mol) has a significantly stronger binding affinity than Ligand B (-7.0 kcal/mol). This is a substantial advantage, potentially outweighing some of the ADME drawbacks.

**Overall Assessment:**

While Ligand A boasts a superior binding affinity, its high DILI risk, poor BBB penetration, and relatively poor solubility are major drawbacks. Ligand B, although with a weaker binding affinity, presents a much more favorable ADME profile, particularly its significantly lower DILI risk and much better BBB penetration, which are critical for a CNS-targeting drug. The difference in binding affinity (2.2 kcal/mol) is substantial, but the ADME liabilities of Ligand A are too significant to ignore.

Output:
1
2025-04-17 06:25:07,635 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (354.491 and 364.471 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (78.87) is significantly better than Ligand B (84.3).  For CNS targets, we want TPSA <= 90, and A is closer to the ideal <= 60.

**logP:** Ligand A (1.851) is optimal, while Ligand B (0.641) is a bit low, potentially hindering membrane permeability.

**H-Bond Donors/Acceptors:** Ligand A (HBD=2, HBA=4) is preferable to Ligand B (HBD=1, HBA=6). Both are within acceptable limits, but A strikes a better balance.

**QED:** Both ligands have good QED scores (A: 0.731, B: 0.829), indicating drug-like properties.

**DILI:** Ligand B (59.984) has a higher DILI risk than Ligand A (20.706), which is a significant concern.

**BBB:** Ligand A (56.65) has a better BBB penetration percentile than Ligand B (51.881), although both are below the desirable >70 for CNS targets.

**Caco-2 Permeability:** Ligand A (-4.586) has better Caco-2 permeability than Ligand B (-5.287).

**Aqueous Solubility:** Ligand A (-1.569) has better solubility than Ligand B (-2.256).

**hERG:** Both ligands have very low hERG inhibition liability (A: 0.268, B: 0.146).

**Microsomal Clearance:** Ligand A (46.376) has higher microsomal clearance than Ligand B (24.216), meaning B is more metabolically stable.

**In vitro Half-Life:** Ligand B (4.944) has a longer in vitro half-life than Ligand A (-1.757).

**P-gp Efflux:** Both ligands have low P-gp efflux liability (A: 0.055, B: 0.046).

**Binding Affinity:** Ligand B (-8.0 kcal/mol) has a slightly better binding affinity than Ligand A (-7.7 kcal/mol). However, the difference is less than 1.5 kcal/mol, so it doesn't automatically outweigh other factors.

**Overall Assessment:**

Considering the GPCR-specific priorities, Ligand A is the better candidate. While Ligand B has slightly better affinity and metabolic stability, Ligand A excels in TPSA, logP, solubility, and crucially, has a much lower DILI risk. The BBB penetration is similar for both, but the combination of better ADME properties and lower toxicity makes Ligand A more promising. The slightly lower affinity of Ligand A can likely be optimized in subsequent iterations, while mitigating a high DILI risk is often more challenging.

Output:
0
2025-04-17 06:25:07,635 - INFO - Batch 280 complete. Total preferences: 4480
2025-04-17 06:25:07,635 - INFO - Processing batch 281/512...
2025-04-17 06:25:49,198 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (364.475 Da) is slightly higher than Ligand B (343.471 Da), but both are acceptable.

**TPSA:** Ligand A (93.01) is borderline for CNS penetration, being slightly above the preferred <90 cutoff. Ligand B (65.2) is well within the ideal range for CNS targets. This is a significant advantage for Ligand B.

**logP:** Ligand A (1.283) is within the optimal range. Ligand B (3.179) is also within the optimal range, but closer to the upper limit.

**H-Bond Donors/Acceptors:** Ligand A has 1 HBD and 7 HBA, which are reasonable. Ligand B has 2 HBD and 2 HBA, also reasonable.

**QED:** Both ligands have good QED scores (Ligand A: 0.641, Ligand B: 0.833), indicating good drug-like properties. Ligand B is slightly better.

**DILI:** Both ligands have acceptable DILI risk (Ligand A: 49.67, Ligand B: 53.587), below the 60% threshold.

**BBB:** This is a crucial parameter for CNS targets. Ligand A has a BBB percentile of 41.218, which is below the desirable >70% threshold. Ligand B has a much better BBB percentile of 65.452, making it significantly more likely to reach the target in the brain.

**Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and suggests poor permeability. This is a concern for both.

**Aqueous Solubility:** Both ligands have very poor aqueous solubility (Ligand A: -0.464, Ligand B: -3.967). This could pose formulation challenges. Ligand B is worse.

**hERG Inhibition:** Both ligands show low hERG inhibition risk (Ligand A: 0.254, Ligand B: 0.67).

**Microsomal Clearance:** Ligand A (24.75 mL/min/kg) has a lower clearance than Ligand B (56.601 mL/min/kg), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (10.029 hours) has a better half-life than Ligand B (14.142 hours), although both are acceptable.

**P-gp Efflux:** Ligand A (0.064) shows very low P-gp efflux, which is excellent. Ligand B (0.455) shows moderate P-gp efflux, which is less desirable.

**Binding Affinity:** Ligand B (-8.3 kcal/mol) has a significantly stronger binding affinity than Ligand A (-7.0 kcal/mol). This 1.3 kcal/mol difference is substantial and can outweigh some of the ADME drawbacks.

**Overall Assessment:**

Ligand B has a significantly better binding affinity and a much improved BBB penetration compared to Ligand A. While its solubility is worse and clearance is higher, the superior affinity and BBB are critical for a CNS-targeting GPCR like DRD2. The lower P-gp efflux of Ligand A is a plus, but the affinity difference is substantial. The TPSA of Ligand A is also borderline for CNS penetration.

Output:
1
2025-04-17 06:25:49,198 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (431.352 Da) is slightly higher, but acceptable. Ligand B (378.426 Da) is also good.

**TPSA:** Ligand A (86.71) is excellent for CNS penetration, being well below 90. Ligand B (138.67) is approaching the upper limit for good oral absorption (140) and is less ideal for CNS targets.

**logP:** Ligand A (2.848) is within the optimal range (1-3). Ligand B (-1.323) is significantly below 1, which could hinder permeability.

**H-Bond Donors/Acceptors:** Ligand A (HBD=2, HBA=3) and Ligand B (HBD=3, HBA=5) both have reasonable numbers of H-bond donors and acceptors.

**QED:** Ligand A (0.718) has a better QED score than Ligand B (0.526), indicating a more drug-like profile.

**DILI:** Ligand A (64.327) has a higher DILI risk than Ligand B (39.434), but both are reasonably acceptable.

**BBB:** Ligand A (59.984) has a lower BBB percentile than Ligand B (54.013). While neither is ideal (>70), Ligand B is slightly better.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values, which is unusual and potentially problematic. It suggests poor permeability. However, the scale is not specified, so it's hard to interpret.

**Aqueous Solubility:** Both ligands have negative solubility values, indicating low solubility. This is a concern for bioavailability.

**hERG Inhibition:** Ligand A (0.261) shows very low hERG inhibition risk, which is excellent. Ligand B (0.087) also shows very low hERG inhibition risk.

**Microsomal Clearance:** Ligand A (8.251) has a lower (better) microsomal clearance than Ligand B (-27.934). This suggests better metabolic stability for Ligand A.

**In vitro Half-Life:** Ligand A (30.773) has a longer half-life than Ligand B (21.851), which is preferable.

**P-gp Efflux:** Ligand A (0.114) has lower P-gp efflux liability than Ligand B (0.016), which is favorable for CNS penetration.

**Binding Affinity:** Ligand B (-7.9 kcal/mol) has a significantly stronger binding affinity than Ligand A (0.0 kcal/mol). This is a substantial advantage, potentially outweighing some of the ADME drawbacks.

**Overall Assessment:**

Ligand B has a much stronger binding affinity, which is the most critical factor for GPCR ligands. While it has a less optimal logP and TPSA, the strong binding could compensate. Ligand A has better ADME properties overall (better QED, lower DILI, better metabolic stability, longer half-life, lower P-gp efflux), but its binding affinity is very weak. Given the importance of affinity for GPCRs, and the relatively modest ADME concerns with Ligand B, I would choose Ligand B.

Output:
1
2025-04-17 06:25:49,199 - INFO - Reasoning:

Let's analyze Ligand A and Ligand B for their potential as DRD2 drug candidates, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (371.547 and 354.435 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (81.67) is slightly higher than Ligand B (75.19). Both are below the 90 A^2 threshold desirable for CNS targets, which is good.

**3. logP:** Both ligands have optimal logP values (1.535 and 1.401), falling within the 1-3 range.

**4. H-Bond Donors:** Ligand A has 3 HBD, while Ligand B has 1. Both are acceptable (<=5).

**5. H-Bond Acceptors:** Both ligands have 5 HBA, which is within the acceptable range (<=10).

**6. QED:** Ligand B (0.842) has a better QED score than Ligand A (0.632), suggesting a more drug-like profile.

**7. DILI:** Both ligands have similar DILI risk (52.423 and 52.889), and are within an acceptable range (<60).

**8. BBB:** This is a crucial parameter for a CNS target like DRD2. Ligand B (49.787) has a significantly higher BBB percentile than Ligand A (17.449). This is a major advantage for Ligand B.

**9. Caco-2 Permeability:** Both have negative values, which is unusual. However, the magnitude is similar.

**10. Aqueous Solubility:** Both have negative values, which is also unusual. The magnitude is similar.

**11. hERG Inhibition:** Both ligands show very low hERG inhibition liability (0.273 and 0.12), which is excellent.

**12. Microsomal Clearance:** Ligand B (20.449) has a lower microsomal clearance than Ligand A (25.922), indicating better metabolic stability.

**13. In vitro Half-Life:** Ligand B (-16.142) has a *negative* half-life, which is impossible. This is a major red flag. Ligand A (2.194) has a reasonable half-life.

**14. P-gp Efflux:** Both ligands show very low P-gp efflux liability (0.036 and 0.132).

**15. Binding Affinity:** Both ligands have excellent binding affinities (-8.0 and -7.8 kcal/mol). The difference of 0.2 kcal/mol is not substantial enough to outweigh other factors.

**Overall Assessment:**

Ligand B initially appears more promising due to its superior BBB penetration, better QED, and lower microsomal clearance. However, the *negative* in vitro half-life is a critical flaw. This suggests a major issue with the compound's stability or assay conditions, rendering it unlikely to be a viable drug candidate. Ligand A, while having a lower BBB score, has a reasonable half-life and acceptable overall properties.

Output:
1
2025-04-17 06:25:49,199 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (383.832 and 366.527 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (80.32) is slightly above the preferred <90 for CNS targets, but still reasonable. Ligand B (67.43) is excellent, well below 90.

**3. logP:** Ligand A (3.718) is at the higher end of the optimal range (1-3), but acceptable. Ligand B (2.552) is well within the optimal range.

**4. H-Bond Donors:** Both ligands have 2 HBD, which is within the acceptable limit of <=5.

**5. H-Bond Acceptors:** Ligand A has 5 HBA, and Ligand B has 4. Both are within the acceptable limit of <=10.

**6. QED:** Both ligands have good QED scores (0.625 and 0.785, respectively), indicating drug-like properties.

**7. DILI:** Ligand A has a significantly higher DILI risk (93.757 percentile) compared to Ligand B (47.15 percentile). This is a major concern for Ligand A.

**8. BBB:** Ligand A (77.123 percentile) has a good BBB penetration score, while Ligand B (68.748 percentile) is lower, but still potentially acceptable.

**9. Caco-2 Permeability:** Ligand A (-4.379) has poor Caco-2 permeability, suggesting poor intestinal absorption. Ligand B (-5.169) is also poor, but slightly better than Ligand A.

**10. Aqueous Solubility:** Ligand A (-5.178) has very poor aqueous solubility. Ligand B (-3.638) is also poor, but better than Ligand A.

**11. hERG Inhibition:** Ligand A (0.44) has a slightly elevated hERG risk, while Ligand B (0.178) has a very low risk.

**12. Microsomal Clearance:** Ligand A (81.837) has higher microsomal clearance, indicating lower metabolic stability. Ligand B (63.3) has better metabolic stability.

**13. In vitro Half-Life:** Ligand A (74.999) has a good in vitro half-life. Ligand B (22.052) has a very short half-life, which is a significant drawback.

**14. P-gp Efflux:** Ligand A (0.583) has moderate P-gp efflux, while Ligand B (0.107) has very low P-gp efflux, which is favorable for CNS penetration.

**15. Binding Affinity:** Ligand A (-9.5 kcal/mol) has a significantly stronger binding affinity than Ligand B (-8.3 kcal/mol). This is a substantial advantage for Ligand A.

**Overall Assessment:**

While Ligand A boasts a superior binding affinity, its significant drawbacks in DILI risk, Caco-2 permeability, aqueous solubility, and metabolic stability are major concerns. Ligand B, despite a slightly weaker affinity, presents a much more favorable ADME-Tox profile, particularly its low DILI risk and P-gp efflux. For a CNS target like DRD2, a balance between affinity and brain penetration is crucial. Ligand B's better BBB score, lower P-gp efflux, and improved metabolic stability, combined with acceptable logP and TPSA, make it a more promising candidate. The affinity difference, while notable, may be overcome with further optimization of Ligand B.

Output:
1
2025-04-17 06:25:49,199 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (370.312 and 364.433 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (107.97) is higher than the preferred <90 for CNS targets, but not drastically so. Ligand B (78.87) is well within the desired range. This favors Ligand B.

**3. logP:** Both ligands have good logP values (1.994 and 1.42), falling within the optimal 1-3 range.

**4. H-Bond Donors:** Ligand A (3) and Ligand B (2) are both acceptable, being less than 5.

**5. H-Bond Acceptors:** Ligand A (5) and Ligand B (4) are both acceptable, being less than 10.

**6. QED:** Both ligands have good QED scores (0.596 and 0.683), indicating good drug-like properties.

**7. DILI:** Ligand A has a very high DILI risk (99.341), which is a significant concern. Ligand B has a much lower DILI risk (14.773), making it substantially more favorable.

**8. BBB:** Ligand A has a BBB penetration percentile of 37.301, which is below the desirable >70 for CNS targets. Ligand B has a significantly better BBB penetration (72.896), exceeding the threshold. This is a major advantage for Ligand B.

**9. Caco-2 Permeability:** Ligand A (-5.655) and Ligand B (-4.627) both have negative Caco-2 values which is unusual and suggests poor permeability.

**10. Aqueous Solubility:** Ligand A (-2.86) and Ligand B (-1.317) both have negative solubility values which is unusual and suggests poor solubility.

**11. hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.042 and 0.446), which is excellent.

**12. Microsomal Clearance:** Ligand A (-14.658) has a much lower (better) microsomal clearance than Ligand B (-1.545), indicating greater metabolic stability.

**13. In vitro Half-Life:** Ligand A (-6.993) has a lower half-life than Ligand B (-28.51), which is less desirable.

**14. P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.034 and 0.027), which is favorable for CNS penetration.

**15. Binding Affinity:** Ligand A (-9.5 kcal/mol) has a slightly better binding affinity than Ligand B (-7.5 kcal/mol). However, the difference is not large enough to overcome the significant ADME liabilities of Ligand A.

**Overall Assessment:**

While Ligand A has a slightly better binding affinity, its extremely high DILI risk and suboptimal BBB penetration are major drawbacks. Ligand B, despite a slightly weaker binding affinity, presents a much more favorable ADME profile, with lower DILI risk, better BBB penetration, and acceptable values for other key parameters. Given the GPCR-specific priorities for CNS targets, Ligand B is the more promising candidate.

Output:
1
2025-04-17 06:25:49,199 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (341.455 Da) is slightly better than Ligand B (380.495 Da) as it's closer to the lower end, potentially aiding permeability.

**TPSA:** Ligand A (81.99) is significantly better than Ligand B (94.56). For CNS targets, we want TPSA <= 90, which Ligand A meets, while Ligand B is close to exceeding it.

**logP:** Both ligands have acceptable logP values (Ligand A: 3.017, Ligand B: 1.027), falling within the 1-3 range. Ligand A is slightly preferred as it's closer to the optimal range. Ligand B's lower logP might hinder permeation.

**H-Bond Donors/Acceptors:** Ligand A (HBD=2, HBA=3) is better than Ligand B (HBD=3, HBA=7). Lower values are generally preferred for better permeability.

**QED:** Both ligands have similar QED values (Ligand A: 0.762, Ligand B: 0.664), both above the 0.5 threshold, indicating good drug-like properties.

**DILI:** Ligand A (41.76) has a much lower DILI risk than Ligand B (73.982). This is a significant advantage for Ligand A.

**BBB:** Ligand A (55.06) has a better BBB penetration percentile than Ligand B (39.24). While both are below the ideal >70, Ligand A is closer. This is crucial for a CNS target like DRD2.

**Caco-2 Permeability:** Ligand A (-4.61) shows better Caco-2 permeability than Ligand B (-5.499), indicating better intestinal absorption.

**Aqueous Solubility:** Ligand A (-4.189) has better aqueous solubility than Ligand B (-2.933).

**hERG Inhibition:** Ligand A (0.511) has a slightly better hERG profile than Ligand B (0.367), indicating lower cardiotoxicity risk.

**Microsomal Clearance:** Ligand A (26.85) has a significantly lower microsomal clearance than Ligand B (64.112), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand B (27.981) has a longer in vitro half-life than Ligand A (6.12). This is a positive for Ligand B, but the other advantages of Ligand A likely outweigh this.

**P-gp Efflux:** Ligand A (0.092) has lower P-gp efflux liability than Ligand B (0.273), which is favorable for CNS exposure.

**Binding Affinity:** Both ligands have very similar and strong binding affinities (Ligand A: -8.8 kcal/mol, Ligand B: -8.5 kcal/mol). The difference is less than 1.5 kcal/mol, so it's not a decisive factor.

**Overall:** Considering all factors, especially the GPCR-specific priorities, Ligand A is the more promising candidate. It has better TPSA, DILI, BBB, Caco-2 permeability, aqueous solubility, microsomal clearance, and P-gp efflux, all critical for CNS penetration and safety. While Ligand B has a slightly longer half-life, the other advantages of Ligand A are more significant.

Output:
0
2025-04-17 06:25:49,199 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (349.391 and 367.368 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (123.66) is slightly above the optimal <90 for CNS targets, but still reasonable. Ligand B (93.11) is well within the desired range. This favors Ligand B.

**logP:** Ligand A (-0.014) is a bit low, potentially hindering permeability. Ligand B (-0.528) is also on the lower side, but slightly better than A. Both are below the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A has 4 HBD and 6 HBA, while Ligand B has 3 HBD and 5 HBA. Both are within acceptable limits (<=5 HBD and <=10 HBA).

**QED:** Both ligands have reasonable QED values (0.405 and 0.563), with Ligand B being slightly more drug-like.

**DILI:** Ligand A (59.17) has a moderate DILI risk, while Ligand B (18.573) has a very low risk. This is a significant advantage for Ligand B.

**BBB:** Ligand A (53.276) has a moderate BBB penetration, while Ligand B (39.899) is lower. While both are not ideal (>70), A is better.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.436 and -5.186), which is unusual and suggests poor permeability. This is a concern for both.

**Aqueous Solubility:** Both ligands have negative solubility values (-2.267 and -0.673), which is also concerning and suggests poor solubility. This is a concern for both.

**hERG Inhibition:** Ligand A (0.066) has a very low hERG risk, while Ligand B (0.473) has a slightly higher, but still acceptable, risk.

**Microsomal Clearance:** Ligand A (2.749) has a relatively low clearance, suggesting better metabolic stability. Ligand B (-17.624) has a very high (negative) clearance, indicating rapid metabolism. This is a major advantage for Ligand A.

**In vitro Half-Life:** Ligand A (10.583) has a reasonable half-life, while Ligand B (-9.449) has a negative half-life, which is not possible and indicates a very short half-life or instability. This is a significant advantage for Ligand A.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.004 and 0.008), which is favorable for CNS penetration.

**Binding Affinity:** Ligand B (-8.1 kcal/mol) has a significantly stronger binding affinity than Ligand A (-7.0 kcal/mol). This is a substantial advantage for Ligand B, potentially outweighing some of its ADME liabilities.

**Overall Assessment:**

Ligand B has a superior binding affinity and a lower DILI risk, and better TPSA. However, it suffers from significantly worse metabolic stability (high clearance, negative half-life) and lower BBB penetration. Ligand A has better metabolic stability, a slightly better BBB score, and a lower hERG risk. The significantly stronger binding affinity of Ligand B is a major factor. While the ADME properties of B are concerning, the potency advantage is substantial. Given the focus on affinity for GPCRs, and the possibility of addressing ADME issues through further optimization, Ligand B is the more promising candidate.

Output:
1
2025-04-17 06:25:49,200 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B based on the provided guidelines, prioritizing GPCR-specific properties (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (356.438 and 343.391 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (67.87) is significantly better than Ligand B (137.08). For CNS targets, TPSA should be <= 90, and A is comfortably within this range, while B exceeds it. This is a substantial advantage for A.

**logP:** Both ligands have acceptable logP values (2.267 and 1.333), falling within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A (HBD=1, HBA=4) is preferable to Ligand B (HBD=2, HBA=5) as lower values generally improve permeability.

**QED:** Ligand A (0.644) has a significantly better QED score than Ligand B (0.334), indicating a more drug-like profile.

**DILI:** Ligand A (22.838) has a much lower DILI risk than Ligand B (39.977), indicating better safety.

**BBB:** Ligand A (90.074) has a considerably higher BBB penetration percentile than Ligand B (77.472). This is a critical advantage for a CNS target like DRD2.

**Caco-2 Permeability:** Both have negative values, which is unusual. However, the magnitude is less important than other factors here.

**Aqueous Solubility:** Both have negative values, indicating poor solubility.

**hERG Inhibition:** Both ligands show low hERG inhibition liability (0.364 and 0.549), which is good.

**Microsomal Clearance:** Ligand A (2.619) has a much lower microsomal clearance than Ligand B (-13.184). This suggests better metabolic stability for Ligand A.

**In vitro Half-Life:** Ligand A (19.79) has a longer in vitro half-life than Ligand B (-29.583), which is desirable.

**P-gp Efflux:** Ligand A (0.07) has a much lower P-gp efflux liability than Ligand B (0.008), which is a significant advantage for CNS penetration.

**Binding Affinity:** Ligand A (-8.3 kcal/mol) has a slightly better binding affinity than Ligand B (-7.8 kcal/mol), though the difference is relatively small.

**Overall Assessment:**

Ligand A is significantly superior to Ligand B across most critical ADME-Tox properties, especially those prioritized for GPCRs targeting the CNS. It has better TPSA, BBB, QED, DILI, metabolic stability (lower Cl_mic, longer t1/2), lower P-gp efflux, and slightly better binding affinity. While both have poor solubility, the other advantages of Ligand A outweigh this drawback.

Output:
1
2025-04-17 06:25:49,200 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B based on the provided guidelines and GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (425.666 Da) is slightly higher, but acceptable. Ligand B (356.419 Da) is also good.

**TPSA:**  Ligand A (84.5) is excellent for CNS penetration, well below the 90 A^2 threshold. Ligand B (102.96) is still reasonable, but less optimal than A.

**logP:** Ligand A (3.144) is within the optimal range (1-3). Ligand B (1.355) is at the lower end, potentially impacting permeability.

**H-Bond Donors/Acceptors:** Both ligands have 2 HBDs, which is good. Ligand A has 4 HBAs, and Ligand B has 6 HBAs. Both are acceptable (<=10), but A is slightly better.

**QED:** Both ligands have QED values below 0.6, indicating moderate drug-likeness. Ligand A (0.582) is slightly better than Ligand B (0.452).

**DILI:** Ligand A (87.786) has a higher DILI risk than Ligand B (59.403). This is a negative for Ligand A.

**BBB:** Ligand A (59.597) has a better BBB percentile than Ligand B (49.515), but both are below the desirable >70 for CNS targets.

**Caco-2 Permeability:** Ligand A (-4.705) has a more negative Caco-2 value, suggesting poorer permeability. Ligand B (-5.222) is even worse.

**Aqueous Solubility:** Both ligands have very poor aqueous solubility (-5.458 and -1.826 respectively). This is a significant drawback for both.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.491 and 0.212 respectively).

**Microsomal Clearance:** Ligand A (74.222) has a higher microsomal clearance than Ligand B (56.375), indicating lower metabolic stability.

**In vitro Half-Life:** Ligand B (-8.747) has a negative half-life, which is concerning and likely indicates very rapid metabolism. Ligand A (42.072) is much better.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.269 and 0.129 respectively), which is positive for CNS penetration.

**Binding Affinity:** Ligand A (-9.3 kcal/mol) has significantly stronger binding affinity than Ligand B (-7.1 kcal/mol). This is a substantial advantage for Ligand A, potentially outweighing some of its ADME drawbacks.

**Overall Assessment:**

Considering the GPCR-specific priorities, Ligand A is the better candidate. While its DILI risk is higher, its superior binding affinity (-9.3 vs -7.1 kcal/mol), better TPSA, and more reasonable half-life are crucial for a CNS-targeting drug. The lower BBB penetration for both is a concern, but the stronger binding of A increases the likelihood of achieving sufficient target engagement *in vivo*. The solubility issues are a concern for both, but can be addressed with formulation strategies. Ligand B's extremely short half-life is a major red flag.

Output:
1
2025-04-17 06:25:49,200 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (351.407 and 343.391 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (120.58) is slightly above the optimal <90 for CNS targets, but still reasonable. Ligand B (105.9) is better, falling comfortably under 90.

**3. logP:** Ligand A (-0.533) is a bit low, potentially hindering permeation. Ligand B (0.186) is closer to the optimal 1-3 range, making it preferable.

**4. H-Bond Donors:** Ligand A (3) is acceptable. Ligand B (1) is even better, potentially improving permeability.

**5. H-Bond Acceptors:** Both ligands (A: 7, B: 7) are within the acceptable limit of 10.

**6. QED:** Both ligands have good QED scores (A: 0.607, B: 0.83), indicating drug-like properties. Ligand B is superior.

**7. DILI:** Ligand A (46.219) has a lower DILI risk than Ligand B (80.07), which is a positive for A.

**8. BBB:** Ligand A (31.214) has a poor BBB percentile, a significant drawback for a CNS target. Ligand B (41.024) is better, but still not ideal (we want >70).

**9. Caco-2:** Both have negative Caco-2 values (-5.276 and -5.502) which is unusual and likely indicates poor permeability.

**10. Solubility:** Both ligands have very poor aqueous solubility (-1.505 and -1.509). This is a major concern for both.

**11. hERG:** Both ligands have very low hERG inhibition risk (0.048 and 0.101).

**12. Cl_mic:** Ligand A (-9.832) has a much lower (better) microsomal clearance than Ligand B (3.343), suggesting better metabolic stability.

**13. t1/2:** Both have similar in vitro half-lives (A: 4.522, B: 4.695).

**14. Pgp:** Both ligands have very low P-gp efflux liability (0.02 and 0.009).

**15. Binding Affinity:** Both ligands have identical binding affinities (-8.2 kcal/mol), which is excellent.

**Overall Assessment:**

Despite Ligand A's lower DILI and better metabolic stability, Ligand B is the more promising candidate. The primary reason is the slightly better logP and TPSA values, which are critical for CNS penetration. While both have poor solubility and Caco-2 permeability, the better BBB percentile of Ligand B, combined with its slightly improved drug-like properties (higher QED) and logP, make it the more favorable choice. The identical binding affinity removes that as a differentiating factor. The poor solubility and permeability would need to be addressed in further optimization, but the starting point is better with Ligand B.

Output:
1
2025-04-17 06:25:49,200 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (360.445 and 348.403 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (58.64) is excellent, well below the 90 A^2 threshold for CNS targets. Ligand B (115.65) is higher, but still potentially acceptable, though less ideal.

**logP:** Ligand A (2.448) is optimal (1-3). Ligand B (-0.246) is significantly lower, which could hinder permeability and potentially reduce binding affinity.

**H-Bond Donors/Acceptors:** Ligand A (HBD=1, HBA=3) is within the desirable ranges. Ligand B (HBD=3, HBA=6) is also acceptable, but slightly higher.

**QED:** Both ligands have reasonable QED values (0.643 and 0.53), indicating good drug-like properties.

**DILI:** Ligand A (20.861) has a much lower DILI risk than Ligand B (46.297), which is a significant advantage.

**BBB:** Ligand A (94.106) has excellent BBB penetration potential, exceeding the 70% threshold. Ligand B (38.426) is considerably lower, raising concerns about CNS exposure.

**Caco-2 Permeability:** Ligand A (-4.696) shows poor Caco-2 permeability. Ligand B (-5.433) is also poor, but slightly worse.

**Aqueous Solubility:** Ligand A (-2.8) and Ligand B (-0.441) both have poor solubility.

**hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.69 and 0.059).

**Microsomal Clearance:** Ligand A (62.083) has a higher microsomal clearance than Ligand B (11.694), suggesting lower metabolic stability.

**In vitro Half-Life:** Ligand B (12.385) has a significantly longer in vitro half-life than Ligand A (-1.116).

**P-gp Efflux:** Both ligands exhibit low P-gp efflux liability (0.091 and 0.014).

**Binding Affinity:** Ligand A (-8.1 kcal/mol) has a better binding affinity than Ligand B (-7.1 kcal/mol). This 1.0 kcal/mol difference is substantial and can outweigh some ADME drawbacks.

**Overall Assessment:**

Ligand A is the stronger candidate. While it has poor Caco-2 permeability and moderate microsomal clearance, its superior BBB penetration, lower DILI risk, and significantly higher binding affinity are critical advantages for a CNS-targeted GPCR like DRD2. The logP value is optimal, and TPSA is excellent. Ligand B suffers from a poor logP, lower BBB penetration, and a higher DILI risk, despite a longer half-life. The affinity difference is also significant.

Output:
1
2025-04-17 06:25:49,201 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B based on the provided guidelines, prioritizing GPCR-specific properties (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (337.423 Da) is slightly better than Ligand B (363.361 Da) as it's closer to the lower end, potentially aiding permeability.

**TPSA:** Ligand A (62.3) is excellent, well below the 90 A^2 threshold for CNS targets. Ligand B (107.97) is higher, but still potentially acceptable, though less optimal.

**logP:** Ligand A (2.264) is within the optimal range (1-3). Ligand B (-1.269) is significantly lower, which could hinder membrane permeability and CNS penetration.

**H-Bond Donors/Acceptors:** Ligand A (HBD=1, HBA=3) is better than Ligand B (HBD=3, HBA=5) in terms of balancing solubility and permeability.

**QED:** Both ligands have acceptable QED values (A: 0.623, B: 0.523), indicating reasonable drug-likeness.

**DILI:** Ligand A (42.769) has a slightly higher DILI risk than Ligand B (28.461), but both are below the concerning threshold of 60.

**BBB:** Ligand A (67.197) has a significantly better BBB percentile than Ligand B (53.858). This is a *critical* advantage for a CNS target like DRD2.

**Caco-2 Permeability:** Ligand A (-4.729) has a lower Caco-2 permeability than Ligand B (-5.166), which is not ideal for either, but the difference is minor.

**Aqueous Solubility:** Ligand A (-2.898) has slightly better solubility than Ligand B (-1.417), which is a positive attribute.

**hERG Inhibition:** Both ligands have very low hERG inhibition risk (A: 0.296, B: 0.165).

**Microsomal Clearance:** Ligand B (-19.059) has significantly lower microsomal clearance than Ligand A (70.3), suggesting better metabolic stability. This is a substantial advantage.

**In vitro Half-Life:** Ligand B (4.367) has a longer in vitro half-life than Ligand A (-10.732), which is a positive.

**P-gp Efflux:** Ligand A (0.135) has lower P-gp efflux liability than Ligand B (0.004), which is beneficial for CNS penetration.

**Binding Affinity:** Ligand A (-9.2 kcal/mol) has a significantly stronger binding affinity than Ligand B (-7.8 kcal/mol). This is a major advantage, potentially outweighing some ADME drawbacks. The difference is >1.5 kcal/mol.

**Overall Assessment:**

Ligand A excels in key areas for a CNS-targeting GPCR: TPSA, BBB, and especially binding affinity. While Ligand B has better metabolic stability and half-life, the significantly weaker affinity and poorer BBB penetration are major drawbacks. The stronger binding affinity of Ligand A is likely to be more impactful than the metabolic advantages of Ligand B, especially in the early stages of drug development.

Output:
1
2025-04-17 06:25:49,201 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 drug candidates, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (347.459 Da) is slightly preferred as it's closer to the lower end, potentially aiding permeability.

**TPSA:** Ligand A (91.22) is better than Ligand B (41.29). For CNS targets, TPSA should be <=90, so Ligand A is acceptable, while Ligand B is excellent.

**logP:** Ligand A (1.896) is optimal (1-3), while Ligand B (4.16) is slightly high.  Higher logP can lead to off-target effects and solubility issues. Ligand A is preferred.

**H-Bond Donors/Acceptors:** Ligand A (HBD=2, HBA=4) and Ligand B (HBD=1, HBA=5) both fall within acceptable ranges.

**QED:** Both ligands have similar QED values (0.794 and 0.77), indicating good drug-likeness.

**DILI:** Ligand A (33.695) has a significantly lower DILI risk than Ligand B (34.626), which is a clear advantage.

**BBB:** Ligand B (82.784) has a better BBB penetration percentile than Ligand A (67.584). This is a crucial factor for CNS targets like DRD2, making Ligand B more attractive.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values, which is unusual and suggests poor permeability. However, the scale isn't specified, so it's hard to interpret.

**Aqueous Solubility:** Both ligands have negative solubility values, which is also unusual.

**hERG Inhibition:** Ligand A (0.253) shows a lower hERG inhibition liability than Ligand B (0.882), indicating a lower risk of cardiotoxicity.

**Microsomal Clearance:** Ligand A (31.5 mL/min/kg) has a lower microsomal clearance than Ligand B (57.707 mL/min/kg), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (17.428 hours) has a slightly longer half-life than Ligand B (16.187 hours).

**P-gp Efflux:** Ligand A (0.031) has a much lower P-gp efflux liability than Ligand B (0.665), which is highly desirable for CNS penetration.

**Binding Affinity:** Ligand B (-7.5 kcal/mol) has a slightly better binding affinity than Ligand A (-8.3 kcal/mol). While a 1.5 kcal/mol advantage is significant, the other ADME properties need to be considered.

**Overall Assessment:**

Ligand A excels in several key areas: lower DILI risk, lower hERG inhibition, better metabolic stability (lower Cl_mic), longer half-life, and significantly lower P-gp efflux. Ligand B's primary advantage is its better BBB penetration and slightly improved binding affinity. However, the higher logP, P-gp efflux, and DILI risk of Ligand B are concerning. Given the importance of BBB penetration for a CNS target, the difference isn't substantial enough to outweigh the other advantages of Ligand A.

Output:
0
2025-04-17 06:25:49,201 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (351.447 and 360.889 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (78.95) is better than Ligand B (61.02). Both are below the 90 A^2 threshold desirable for CNS targets.

**logP:** Ligand A (1.511) is optimal, while Ligand B (4.173) is approaching the upper limit and could potentially cause solubility issues or off-target interactions.

**H-Bond Donors/Acceptors:** Ligand A has 1 HBD and 4 HBA, while Ligand B has 2 HBD and 3 HBA. Both are within acceptable ranges.

**QED:** Both ligands have similar and good QED values (0.836 and 0.841).

**DILI:** Both ligands have low DILI risk (33.307 and 32.299 percentile), which is favorable.

**BBB:** Ligand B (81.194) has a significantly better BBB penetration score than Ligand A (68.127). This is a crucial advantage for a CNS target like DRD2.

**Caco-2 Permeability:** Ligand A (-4.544) has a worse Caco-2 permeability than Ligand B (-5.006). Both are negative, indicating poor permeability.

**Aqueous Solubility:** Ligand A (-2.585) has better aqueous solubility than Ligand B (-4.155).

**hERG:** Both ligands have low hERG inhibition liability (0.211 and 0.943), which is good.

**Microsomal Clearance:** Ligand A (40.969) has higher microsomal clearance than Ligand B (33.115), indicating lower metabolic stability.

**In vitro Half-Life:** Ligand B (-8.902) has a longer in vitro half-life than Ligand A (-7.657).

**P-gp Efflux:** Both ligands have similar P-gp efflux liability (0.029 and 0.643).

**Binding Affinity:** Both ligands have excellent binding affinities (-7.0 and -8.0 kcal/mol). Ligand B is slightly better.

**Overall Assessment:**

Ligand B is the more promising candidate. While Ligand A has slightly better TPSA and solubility, Ligand B excels in BBB penetration, in vitro half-life, and binding affinity. The higher logP of Ligand B is a minor concern, but the significantly improved BBB penetration outweighs this drawback for a CNS target. The better binding affinity of Ligand B also contributes to its higher potential.

Output:
1
2025-04-17 06:25:49,201 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (360.885 and 349.435 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (64.33) is excellent, well below the 90 A^2 threshold for CNS targets. Ligand B (90.03) is right at the upper limit, which is less ideal, but still acceptable.

**logP:** Ligand A (3.594) is within the optimal 1-3 range. Ligand B (0.382) is quite low, potentially hindering membrane permeability and CNS penetration.

**H-Bond Donors/Acceptors:** Ligand A (1 HBD, 3 HBA) and Ligand B (2 HBD, 5 HBA) both have reasonable numbers of H-bond donors and acceptors, well within the guidelines.

**QED:** Ligand A (0.892) has a very good QED score, indicating high drug-likeness. Ligand B (0.574) is acceptable, but lower than Ligand A.

**DILI:** Ligand A (9.965) has a very low DILI risk. Ligand B (25.902) has a moderate DILI risk, but is still acceptable.

**BBB:** This is critical for a CNS target. Ligand A (73.672) has a good BBB percentile. Ligand B (40.713) is significantly lower, raising concerns about CNS exposure.

**Caco-2 Permeability:** Ligand A (-4.617) and Ligand B (-5.167) both have negative values, which is unusual and suggests poor permeability. However, the scale is not specified, so it's difficult to interpret.

**Aqueous Solubility:** Both ligands have negative solubility values (-4.207 and -1.388 respectively), suggesting poor solubility. This could be a formulation challenge.

**hERG Inhibition:** Ligand A (0.774) has a low hERG risk. Ligand B (0.33) also has a low hERG risk.

**Microsomal Clearance:** Ligand A (21.128) has a moderate clearance. Ligand B (-17.931) has a negative clearance, which is impossible and likely indicates an error in the data.

**In vitro Half-Life:** Ligand A (2.27) has a short half-life, which might require frequent dosing. Ligand B (9.699) has a much longer half-life, which is more desirable.

**P-gp Efflux:** Ligand A (0.204) has low P-gp efflux, which is good for CNS penetration. Ligand B (0.063) has very low P-gp efflux, which is even better.

**Binding Affinity:** Ligand A (-8.6 kcal/mol) has a significantly stronger binding affinity than Ligand B (-7.0 kcal/mol). This is a substantial difference.

**Overall Assessment:**

Ligand A is superior due to its significantly better binding affinity, excellent TPSA, good BBB penetration, and low DILI risk. While its solubility and half-life are not ideal, the strong binding affinity could potentially compensate for these drawbacks. Ligand B suffers from a low logP, poor BBB penetration, and a nonsensical negative microsomal clearance value, making it a less attractive candidate. The longer half-life of Ligand B is a positive, but is outweighed by the other issues.

Output:
1
2025-04-17 06:25:49,201 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (354.288 Da and 344.499 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (94.05) is higher than Ligand B (40.62). For CNS targets, we prefer TPSA <= 90, so Ligand B is significantly better here.

**3. logP:** Both ligands have a logP around 3.2, which is optimal.

**4. H-Bond Donors:** Ligand A has 1 HBD, while Ligand B has 0. Both are acceptable (<=5).

**5. H-Bond Acceptors:** Ligand A has 6 HBA, and Ligand B has 2. Both are within the acceptable range (<=10).

**6. QED:** Ligand A (0.773) has a better QED score than Ligand B (0.446), indicating a more drug-like profile.

**7. DILI:** Ligand A (92.012) has a significantly higher DILI risk than Ligand B (13.339). This is a major concern for Ligand A.

**8. BBB:** Ligand B (77.627) has a better BBB penetration percentile than Ligand A (69.523). Both are reasonably good, but Ligand B is preferable for a CNS target.

**9. Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual. However, the magnitude is similar, so it doesn't strongly differentiate them.

**10. Aqueous Solubility:** Both have negative solubility values, which is also unusual. Again, the magnitudes are similar.

**11. hERG Inhibition:** Ligand A (0.263) has a slightly lower hERG inhibition risk than Ligand B (0.692), which is favorable.

**12. Microsomal Clearance:** Ligand A (67.584) has a higher microsomal clearance than Ligand B (49.342), suggesting lower metabolic stability.

**13. In vitro Half-Life:** Ligand B (18.043 hours) has a significantly longer half-life than Ligand A (-5.345 hours - which is problematic).

**14. P-gp Efflux:** Ligand A (0.156) has lower P-gp efflux than Ligand B (0.322), which is better for CNS penetration.

**15. Binding Affinity:** Ligand A (-9.4 kcal/mol) has a *much* stronger binding affinity than Ligand B (-0.0 kcal/mol). This is a substantial advantage.

**Overall Assessment:**

Ligand A has a significantly better binding affinity, lower P-gp efflux, and slightly lower hERG risk. However, it suffers from a very high DILI risk, higher microsomal clearance (lower stability), and a negative in vitro half-life. Ligand B has a much better safety profile (DILI), better BBB penetration, a longer half-life, and a lower TPSA, which are all important for a CNS-targeting GPCR ligand. The large difference in binding affinity is the biggest factor. While the DILI risk for Ligand A is concerning, the substantial binding affinity advantage *could* outweigh this risk, especially if further modifications can mitigate the DILI liability.

Output:
1
2025-04-17 06:25:49,202 - INFO - Batch 281 complete. Total preferences: 4496
2025-04-17 06:25:49,202 - INFO - Processing batch 282/512...
2025-04-17 06:26:43,106 - INFO - Reasoning:

Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight (MW):** Both ligands (350.375 and 340.406 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (127.8) is borderline for CNS targets, slightly above the preferred <90, but acceptable. Ligand B (69.73) is excellent, well below 90, suggesting better CNS penetration potential.

**3. logP:** Ligand A (0.812) is a bit low, potentially hindering membrane permeability. Ligand B (3.464) is optimal, within the 1-3 range.

**4. H-Bond Donors (HBD):** Both ligands have 2 HBD, which is within the acceptable limit of <=5.

**5. H-Bond Acceptors (HBA):** Both ligands have 5 HBA, also within the acceptable limit of <=10.

**6. QED:** Both ligands have good QED scores (0.555 and 0.761), indicating drug-like properties. Ligand B is slightly better.

**7. DILI:** Ligand A (57.58) has a moderate DILI risk. Ligand B (71.113) has a higher, but still manageable, DILI risk.

**8. BBB:** Both ligands have the same BBB penetration percentile (76.735), which is good and meets the >70 requirement for CNS targets.

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.214 and -5.165), which is unusual and suggests poor permeability. This is a significant concern for both.

**10. Aqueous Solubility:** Both ligands have negative solubility values (-2.378 and -4.223), indicating very poor aqueous solubility. This is a major drawback for both.

**11. hERG Inhibition:** Ligand A (0.163) has a very low hERG risk, which is excellent. Ligand B (0.918) has a slightly higher, but still acceptable, hERG risk.

**12. Microsomal Clearance (Cl_mic):** Ligand A (13.311) has lower clearance, indicating better metabolic stability. Ligand B (46.817) has significantly higher clearance, suggesting faster metabolism.

**13. In vitro Half-Life:** Ligand A (15.401) has a longer half-life than Ligand B (35.769), which is desirable.

**14. P-gp Efflux:** Ligand A (0.033) has very low P-gp efflux, which is excellent for CNS exposure. Ligand B (0.236) has slightly higher P-gp efflux, but still relatively low.

**15. Binding Affinity:** Ligand B (-9.1 kcal/mol) has a significantly stronger binding affinity than Ligand A (-8.5 kcal/mol). This >1.5 kcal/mol difference is substantial and can outweigh some ADME drawbacks.

**Overall Assessment:**

Despite both ligands having issues with Caco-2 permeability and aqueous solubility, Ligand B is the more promising candidate. Its superior logP, significantly stronger binding affinity, and slightly better QED outweigh the higher DILI risk and faster clearance. The similar BBB penetration is a positive for both, but the affinity difference is crucial for a GPCR target. The lower hERG risk of Ligand A is a plus, but the potency of Ligand B is more important.

Output:
1
2025-04-17 06:26:43,106 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (343.471 and 348.443 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (60.18) is significantly better than Ligand B (75.71). For CNS targets, we want TPSA <= 90, and A is comfortably within that range, while B is approaching the upper limit.

**3. logP:** Ligand A (3.95) is within the optimal 1-3 range, though on the higher side. Ligand B (0.99) is a bit low, potentially hindering membrane permeability.

**4. H-Bond Donors:** Both ligands have 1 HBD, which is acceptable.

**5. H-Bond Acceptors:** Ligand A has 5 HBA, and Ligand B has 4, both within the acceptable limit of <= 10.

**6. QED:** Ligand A (0.825) has a better QED score than Ligand B (0.744), indicating a more drug-like profile.

**7. DILI:** Ligand A (44.552) has a slightly higher DILI risk than Ligand B (20.589), but both are below the concerning threshold of 60.

**8. BBB:** Ligand A (74.176) has a better BBB percentile than Ligand B (66.731). Both are reasonably good, but A is closer to the desirable >70 for CNS targets.

**9. Caco-2 Permeability:** Ligand A (-4.949) and Ligand B (-4.742) both have negative values, which is unusual and suggests poor permeability. However, the scale is not clearly defined, so it's hard to interpret.

**10. Aqueous Solubility:** Ligand A (-3.194) and Ligand B (-1.922) both have negative values, suggesting low solubility.

**11. hERG Inhibition:** Ligand A (0.82) has a slightly higher hERG risk than Ligand B (0.095). B is much preferred here.

**12. Microsomal Clearance:** Ligand A (32.417) has a higher microsomal clearance than Ligand B (16.992), suggesting lower metabolic stability.

**13. In vitro Half-Life:** Ligand A (10.386) has a longer half-life than Ligand B (-1.574). This is a significant advantage for A.

**14. P-gp Efflux:** Ligand A (0.516) has lower P-gp efflux than Ligand B (0.045), which is desirable for CNS penetration.

**15. Binding Affinity:** Ligand B (-8.1) has a slightly better binding affinity than Ligand A (-8.8). While A is already very good, B has a 0.7 kcal/mol advantage.

**Overall Assessment:**

Considering the GPCR-specific priorities, Ligand A is slightly more promising. While Ligand B has a slightly better binding affinity and lower hERG risk, Ligand A excels in TPSA, BBB penetration, P-gp efflux, and *in vitro* half-life. The slightly higher logP of Ligand A is acceptable, and the differences in DILI are not substantial. The better BBB and P-gp properties of A are crucial for CNS drug development, outweighing the small affinity difference.

Output:
1
2025-04-17 06:26:43,107 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (391.295 Da) is slightly lower, which could be advantageous for permeability. Ligand B (450.28 Da) is still acceptable.

**TPSA:** Both ligands have TPSA values below 90 (A: 71.78, B: 69.38), which is good for CNS penetration.

**logP:** Both ligands have logP values within the optimal range (1-3), with A at 2.978 and B at 3.583. B is slightly higher, potentially leading to slight solubility issues but still acceptable.

**H-Bond Donors/Acceptors:** Ligand A (HBD=1, HBA=4) is better than Ligand B (HBD=0, HBA=6) in terms of H-bonding potential, being closer to the ideal ranges.

**QED:** Ligand A (0.519) has a slightly better QED score than Ligand B (0.439), indicating a more drug-like profile.

**DILI:** Ligand A (29.391) has a significantly lower DILI risk than Ligand B (74.254). This is a major advantage for Ligand A.

**BBB:** Ligand A (82.629) has a much better BBB penetration percentile than Ligand B (67.895). This is crucial for a CNS target like DRD2.

**Caco-2 Permeability:** Ligand A (-4.588) and Ligand B (-5.3) both have negative Caco-2 values, indicating poor permeability. This is a concern for both, but the value for A is slightly better.

**Aqueous Solubility:** Both ligands have poor aqueous solubility (-3.717 and -4.418 respectively). This could pose formulation challenges.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.591 and 0.366 respectively).

**Microsomal Clearance:** Ligand B (75.064) has a higher microsomal clearance than Ligand A (48.122), suggesting lower metabolic stability.

**In vitro Half-Life:** Both ligands have similar in vitro half-lives (A: 42.959, B: 46.795).

**P-gp Efflux:** Ligand A (0.184) has a lower P-gp efflux liability than Ligand B (0.682), which is favorable for CNS exposure.

**Binding Affinity:** Ligand B (-9.5 kcal/mol) has a significantly stronger binding affinity than Ligand A (-7.3 kcal/mol). This is a substantial advantage, potentially outweighing some of the ADME drawbacks. A difference of 2.2 kcal/mol is significant.

**Overall Assessment:**

While Ligand B boasts a superior binding affinity, Ligand A demonstrates a significantly better safety profile (lower DILI) and improved CNS penetration (higher BBB, lower P-gp efflux). The slightly better QED and H-bonding characteristics also favor Ligand A. The affinity difference is substantial, but the ADME/Tox profile of Ligand A is much more promising for development. Given the importance of CNS penetration and safety for a DRD2 ligand, I believe Ligand A is the more viable candidate, despite the lower affinity. Further optimization of Ligand A could potentially improve its binding affinity while maintaining its favorable ADME/Tox properties.

Output:
0
2025-04-17 06:26:43,107 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (354.447 and 352.519 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (85.89) is slightly higher than Ligand B (69.64). Both are below the 90 A^2 threshold desirable for CNS targets, but Ligand B is better.

**3. logP:** Both ligands have good logP values (1.746 and 2.574), falling within the optimal 1-3 range.

**4. H-Bond Donors:** Both have 2 HBD, which is within the acceptable limit of <=5.

**5. H-Bond Acceptors:** Ligand A has 5 HBA, and Ligand B has 3. Both are below the 10 limit.

**6. QED:** Both ligands have similar QED values (0.68 and 0.67), indicating good drug-likeness.

**7. DILI:** Ligand A (28.577) has a higher DILI risk than Ligand B (10.237). Ligand B is significantly better here.

**8. BBB:** Ligand A (85.343) has a better BBB percentile than Ligand B (70.26), which is good for a CNS target. However, both are above the 70% threshold.

**9. Caco-2 Permeability:** Ligand A (-4.663) shows poorer Caco-2 permeability than Ligand B (-4.476). Higher values are better.

**10. Aqueous Solubility:** Ligand A (-2.07) has slightly better solubility than Ligand B (-2.847).

**11. hERG Inhibition:** Ligand A (0.267) has a lower hERG inhibition liability than Ligand B (0.621), which is preferable.

**12. Microsomal Clearance:** Ligand B (77.884) has a higher microsomal clearance than Ligand A (38.651), indicating lower metabolic stability.

**13. In vitro Half-Life:** Ligand B (10.769) has a longer in vitro half-life than Ligand A (6.384), which is desirable.

**14. P-gp Efflux:** Ligand A (0.011) has significantly lower P-gp efflux liability than Ligand B (0.28). This is a major advantage for CNS penetration.

**15. Binding Affinity:** Both ligands have the same binding affinity (-7.4 kcal/mol), which is excellent.

**Overall Assessment:**

While Ligand A has better BBB penetration and lower P-gp efflux, Ligand B excels in several critical areas: lower DILI risk, better Caco-2 permeability, and a longer half-life. The lower DILI risk is particularly important. Considering the GPCR-specific priorities, the lower P-gp efflux of Ligand A is valuable, but the superior safety profile (DILI) and absorption (Caco-2) of Ligand B are more compelling. The difference in BBB is not substantial enough to outweigh the other advantages of Ligand B.

Output:
1
2025-04-17 06:26:43,107 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (354.539 and 372.531 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (55.89) is significantly better than Ligand B (92.34). For CNS targets, TPSA should be <= 90, so Ligand A is preferable.

**3. logP:** Both ligands (1.554 and 1.648) are within the optimal 1-3 range.

**4. H-Bond Donors:** Ligand A (1) is better than Ligand B (2). Lower HBD generally improves permeability.

**5. H-Bond Acceptors:** Both ligands have the same HBA count (4), which is acceptable (<=10).

**6. QED:** Both ligands have similar QED values (0.647 and 0.61), indicating good drug-likeness.

**7. DILI:** Ligand A (3.18) has a much lower DILI risk than Ligand B (34.626). This is a significant advantage for Ligand A.

**8. BBB:** Ligand A (57.115) has a lower BBB penetration than Ligand B (63.28). While both are not ideal (>70 is desirable), Ligand B is better in this regard.

**9. Caco-2 Permeability:** Ligand A (-5.246) has a worse Caco-2 permeability than Ligand B (-5.123). Both are poor, but B is slightly better.

**10. Aqueous Solubility:** Ligand A (0.17) has significantly worse aqueous solubility than Ligand B (-2.209). This is a drawback for Ligand A.

**11. hERG Inhibition:** Ligand A (0.436) has a lower hERG inhibition liability than Ligand B (0.319), which is preferable.

**12. Microsomal Clearance:** Ligand A (-20.611) has a much lower microsomal clearance than Ligand B (37.39), indicating better metabolic stability.

**13. In vitro Half-Life:** Ligand A (-2.036) has a worse in vitro half-life than Ligand B (5.234).

**14. P-gp Efflux:** Ligand A (0.003) has significantly lower P-gp efflux liability than Ligand B (0.147). This is a major advantage for CNS penetration.

**15. Binding Affinity:** Ligand B (-8.0) has a slightly better binding affinity than Ligand A (-7.4). However, the difference is less than 1.5 kcal/mol, so it's not a decisive factor.

**Overall Assessment:**

Considering the GPCR-specific priorities, Ligand A is the more promising candidate. Its significantly lower TPSA, DILI risk, and P-gp efflux liability are crucial advantages for a CNS-targeting drug. While Ligand B has better BBB penetration and solubility, these are outweighed by Ligand A's superior safety profile and permeability characteristics. The slightly better affinity of Ligand B isn't enough to compensate for the other drawbacks.

Output:
0
2025-04-17 06:26:43,107 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (371.38 and 362.499 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (42.68) is significantly better than Ligand B (69.3). For CNS targets, we want TPSA <= 90, and ideally closer to 60. Ligand A is much closer to this ideal.

**logP:** Ligand A (4.957) is higher than the optimal 1-3 range, potentially causing solubility issues. Ligand B (1.999) is within the optimal range. However, for a GPCR, a slightly higher logP can be tolerated if other properties are favorable.

**H-Bond Donors/Acceptors:** Ligand A (0 HBD, 4 HBA) and Ligand B (1 HBD, 4 HBA) both have acceptable numbers of H-bond donors and acceptors.

**QED:** Both ligands have good QED scores (0.674 and 0.832), indicating good drug-like properties.

**DILI:** Ligand A (59.054) has a slightly higher DILI risk than Ligand B (48.662), but both are below the concerning threshold of 60.

**BBB:** Ligand A (89.57) has a significantly better BBB penetration percentile than Ligand B (60.566). This is *critical* for a CNS target like DRD2.

**Caco-2 Permeability:** Ligand A (-4.281) and Ligand B (-5.341) both have negative values, indicating poor permeability. This is a concern for both.

**Aqueous Solubility:** Ligand A (-6.261) and Ligand B (-2.832) both have poor aqueous solubility.

**hERG Inhibition:** Ligand A (0.706) has a slightly higher hERG risk than Ligand B (0.356), but both are relatively low.

**Microsomal Clearance:** Ligand A (57.035) has a higher microsomal clearance than Ligand B (47.358), suggesting faster metabolism.

**In vitro Half-Life:** Ligand B (-19.604) has a negative half-life, which is not possible and likely indicates an issue with the data or experimental setup. Ligand A (31.092) has a reasonable half-life.

**P-gp Efflux:** Ligand A (0.464) has a lower P-gp efflux liability than Ligand B (0.16), which is favorable for CNS penetration.

**Binding Affinity:** Ligand A (-8.4 kcal/mol) has a *much* stronger binding affinity than Ligand B (-0.0 kcal/mol). This is a decisive advantage. A difference of >1.5 kcal/mol can outweigh other drawbacks.

**Overall Assessment:**

While Ligand A has a higher logP and slightly higher DILI risk, its significantly superior BBB penetration, much stronger binding affinity, and better P-gp efflux profile make it the more promising candidate. The negative half-life reported for Ligand B is a major red flag. The strong binding affinity of Ligand A is the most important factor, as it can potentially compensate for some of the less ideal ADME properties.

Output:
1
2025-04-17 06:26:43,108 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (352.435 and 345.443 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (96.69) is slightly above the optimal <90 for CNS targets, but still reasonable. Ligand B (71.53) is excellent, well below 90.

**3. logP:** Both ligands have good logP values (1.068 and 2.096), falling within the optimal 1-3 range.

**4. H-Bond Donors:** Ligand A (2) and Ligand B (1) are both within the acceptable limit of <=5.

**5. H-Bond Acceptors:** Ligand A (6) and Ligand B (4) are both within the acceptable limit of <=10.

**6. QED:** Both ligands have good QED scores (0.747 and 0.802), indicating good drug-like properties.

**7. DILI:** Both ligands have low DILI risk (39.434 and 29.779), both below the 40 threshold.

**8. BBB:** Ligand A (50.097) is borderline for good CNS penetration. Ligand B (59.442) is also borderline, but slightly better. Both are below the desirable >70, but not drastically so.

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.155 and -4.663). This is unusual and suggests poor permeability. However, these values are on a log scale, and negative values are not uncommon, indicating low permeability.

**10. Aqueous Solubility:** Both ligands have poor aqueous solubility (-1.45 and -1.989). This is a concern for bioavailability.

**11. hERG Inhibition:** Both ligands have low hERG inhibition risk (0.512 and 0.131).

**12. Microsomal Clearance:** Both ligands have similar microsomal clearance values (25.609 and 30.815), suggesting moderate metabolic stability.

**13. In vitro Half-Life:** Both ligands have similar and relatively short in vitro half-lives (-4.269 and -8.769 hours). This could necessitate frequent dosing.

**14. P-gp Efflux:** Ligand A (0.083) has lower P-gp efflux liability than Ligand B (0.029), which is favorable for CNS penetration.

**15. Binding Affinity:** Ligand A (-8.0) has a significantly better binding affinity than Ligand B (-0.0). This is a crucial difference. A difference of >1.5 kcal/mol can outweigh other drawbacks.

**Overall Assessment:**

While both ligands have some weaknesses (poor solubility, borderline BBB, and low Caco-2 permeability), Ligand A's substantially superior binding affinity (-8.0 kcal/mol vs -0.0 kcal/mol) is the deciding factor. The stronger binding is likely to overcome some of the ADME deficiencies, especially given the GPCR target class where potency is paramount. The lower P-gp efflux for Ligand A is also a plus for CNS exposure.

Output:
1
2025-04-17 06:26:43,108 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (341.342 and 352.475 Da) fall within the ideal range of 200-500 Da.

**TPSA:** Both ligands have TPSA values (86.34 and 87.66) below the 90 A^2 threshold desirable for CNS targets. This is good.

**logP:** Ligand A (2.325) is within the optimal range (1-3). Ligand B (1.506) is at the lower end, potentially impacting permeability.

**H-Bond Donors/Acceptors:** Ligand A (1 HBD, 4 HBA) and Ligand B (3 HBD, 4 HBA) both have reasonable numbers of H-bond donors and acceptors, well within the guidelines.

**QED:** Ligand A (0.928) has a higher QED score than Ligand B (0.648), indicating a more drug-like profile.

**DILI:** Ligand A (72.974) has a higher DILI risk than Ligand B (16.44), which is a significant negative.

**BBB:** Ligand A (46.762) has a much better BBB percentile than Ligand B (25.94). This is *critical* for a CNS target like DRD2.

**Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and suggests potential issues with the data or modeling. However, the values are similar.

**Aqueous Solubility:** Both have negative solubility values, which is also unusual. Again, the values are similar.

**hERG:** Both ligands have low hERG inhibition liability (0.502 and 0.151), which is positive.

**Microsomal Clearance:** Ligand A (-7.226) has a much lower (better) microsomal clearance than Ligand B (10.518), suggesting greater metabolic stability.

**In vitro Half-Life:** Ligand A (33.168 hours) has a significantly longer half-life than Ligand B (11.617 hours).

**P-gp Efflux:** Ligand A (0.106) has lower P-gp efflux liability than Ligand B (0.024), which is favorable for CNS penetration.

**Binding Affinity:** Both ligands have excellent binding affinities (-8.3 and -8.0 kcal/mol), with Ligand A being slightly better. The affinity difference is less than 1.5 kcal/mol, so it's not a deciding factor on its own.

**Overall Assessment:**

Ligand A is superior despite the higher DILI risk. The significantly better BBB penetration, lower P-gp efflux, lower microsomal clearance, and longer half-life outweigh the DILI concern. The higher QED score also supports its drug-like properties. Ligand B's low BBB penetration is a major drawback for a CNS target.

Output:
1
2025-04-17 06:26:43,108 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (345.359 and 348.447 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (99.44) is better than Ligand B (107.11). For CNS targets, we want TPSA <= 90, so both are slightly above, but A is closer.

**3. logP:** Ligand B (1.148) is better than Ligand A (0.124). The optimal range is 1-3, and A is significantly below 1, which could hinder permeation.

**4. H-Bond Donors:** Ligand A (0) is better than Ligand B (4). Lower HBDs generally improve permeability.

**5. H-Bond Acceptors:** Ligand A (8) is better than Ligand B (4). Both are within the acceptable range of <=10.

**6. QED:** Ligand A (0.71) is slightly better than Ligand B (0.593), indicating a more drug-like profile. Both are above the 0.5 threshold.

**7. DILI:** Ligand B (33.579) is significantly better than Ligand A (73.284). Lower DILI is crucial.

**8. BBB:** Ligand A (63.629) is better than Ligand B (54.052). For a CNS target like DRD2, a BBB percentile > 70 is desirable, but A is closer.

**9. Caco-2 Permeability:** Ligand A (-4.563) is better than Ligand B (-5.16). Higher values are better, indicating better intestinal absorption.

**10. Aqueous Solubility:** Ligand A (-1.76) is better than Ligand B (-2.141). Higher solubility is generally preferred.

**11. hERG Inhibition:** Ligand A (0.03) is significantly better than Ligand B (0.267). Lower hERG inhibition is vital to avoid cardiotoxicity.

**12. Microsomal Clearance:** Ligand B (5.09) is much better than Ligand A (35.46). Lower clearance indicates better metabolic stability.

**13. In vitro Half-Life:** Ligand B (-27.041) is significantly better than Ligand A (-8.093). Longer half-life is generally desirable.

**14. P-gp Efflux:** Ligand A (0.037) is better than Ligand B (0.042). Lower P-gp efflux is preferred for CNS exposure.

**15. Binding Affinity:** Ligand B (-8.6) is significantly better than Ligand A (-7.4). A difference of >1.5 kcal/mol is substantial and can outweigh other drawbacks.

**Overall Assessment:**

Ligand B has a significantly stronger binding affinity (-8.6 vs -7.4 kcal/mol). While Ligand A has some advantages in BBB and TPSA, Ligand B's superior affinity, lower DILI, and better metabolic stability (lower Cl_mic and higher t1/2) are critical. The lower logP of Ligand B is a concern, but the substantial affinity advantage likely compensates for this. The better DILI and metabolic stability profile of Ligand B also make it a more promising candidate.

Output:
1
2025-04-17 06:26:43,108 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (367.896 and 346.362 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (26.79) is excellent, well below the 90 A^2 threshold for CNS targets. Ligand B (95.42) is significantly higher, potentially hindering BBB penetration.

**logP:** Ligand A (3.174) is optimal (1-3). Ligand B (2.155) is acceptable but closer to the lower limit, potentially impacting permeability.

**H-Bond Donors/Acceptors:** Ligand A (0 HBD, 3 HBA) is favorable. Ligand B (2 HBD, 5 HBA) is also acceptable, but slightly higher counts could affect permeability.

**QED:** Both ligands have good QED scores (0.817 and 0.865), indicating drug-like properties.

**DILI:** Ligand A (46.297) has a lower DILI risk than Ligand B (69.678), which is approaching a concerning level.

**BBB:** This is a critical parameter for a CNS target. Ligand A scores very highly (97.208), suggesting excellent brain penetration. Ligand B's BBB score (30.477) is poor, a major drawback.

**Caco-2 Permeability:** Ligand A (-4.495) is poor, while Ligand B (-5.029) is even worse. Both are very low, which is concerning.

**Aqueous Solubility:** Both ligands have poor aqueous solubility (-3.034 and -2.838 respectively). This could pose formulation challenges.

**hERG:** Ligand A (0.964) has a lower hERG risk than Ligand B (0.139), which is a significant concern.

**Microsomal Clearance:** Ligand A (33.1 mL/min/kg) is better than Ligand B (51.81 mL/min/kg), indicating better metabolic stability.

**In vitro Half-Life:** Ligand A (24.224 hours) has a much longer half-life than Ligand B (-17.005 hours), which is a significant advantage.

**P-gp Efflux:** Ligand A (0.336) shows lower P-gp efflux than Ligand B (0.019), which is favorable for CNS exposure.

**Binding Affinity:** Both ligands have excellent binding affinities (-8.9 kcal/mol and -9.0 kcal/mol), with Ligand B being slightly better. However, the affinity difference is small and likely outweighed by other factors.

**Conclusion:**

Considering the GPCR-specific priorities and the overall profile, **Ligand A is the more promising drug candidate.** While both have poor Caco-2 and solubility, Ligand A's significantly better BBB penetration, lower DILI risk, lower hERG risk, better metabolic stability, longer half-life, and lower P-gp efflux outweigh the slightly better binding affinity of Ligand B. The poor BBB penetration of Ligand B is a critical flaw for a CNS-targeting drug.

Output:
0
2025-04-17 06:26:43,108 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 drug candidates, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (348.487 and 344.415 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Both ligands (67.43 and 67.67) are slightly above the optimal <90 for CNS targets, but still reasonable.

**3. logP:** Ligand A (2.54) is within the optimal 1-3 range. Ligand B (1.068) is at the lower end, potentially impacting permeability.

**4. H-Bond Donors:** Ligand A (2) is good. Ligand B (0) is also acceptable.

**5. H-Bond Acceptors:** Ligand A (3) is good. Ligand B (5) is also acceptable.

**6. QED:** Both ligands have good QED scores (0.549 and 0.766), indicating drug-like properties.

**7. DILI:** Ligand A (34.277) has a lower DILI risk than Ligand B (42.071), which is preferable. Both are below the 60 threshold.

**8. BBB:** Both ligands have good BBB penetration (71.268 and 75.301), exceeding the 70% threshold for CNS targets. Ligand B is slightly better.

**9. Caco-2:** Both have negative Caco-2 values, which is unusual and suggests a problem with the data. We'll proceed cautiously.

**10. Solubility:** Both have negative solubility values, which is also unusual.

**11. hERG:** Both ligands have low hERG inhibition liability (0.59 and 0.121), which is excellent.

**12. Cl_mic:** Ligand A (36.487) has a lower microsomal clearance than Ligand B (63.492), indicating better metabolic stability.

**13. t1/2:** Ligand A (6.503) has a longer in vitro half-life than Ligand B (-23.594). The negative value for Ligand B is concerning and likely indicates a very short half-life.

**14. Pgp:** Ligand A (0.173) has lower P-gp efflux liability than Ligand B (0.134), which is favorable for CNS exposure.

**15. Binding Affinity:** Ligand B (-8.4 kcal/mol) has a slightly better binding affinity than Ligand A (-7.8 kcal/mol). This is a 0.6 kcal/mol difference, which is significant, but not overwhelming.

**Overall Assessment:**

Ligand A is the better candidate. While Ligand B has slightly better BBB penetration and binding affinity, Ligand A demonstrates superior ADME properties, particularly in metabolic stability (lower Cl_mic, longer t1/2) and lower DILI risk. The negative values for Caco-2 and solubility are concerning for both, but the more favorable ADME profile of Ligand A, coupled with its reasonable affinity, makes it the more promising drug candidate. The negative half-life for Ligand B is a significant red flag.

Output:
1
2025-04-17 06:26:43,109 - INFO - Okay, let's analyze these two ligands for their potential as DRD2 drug candidates. DRD2 is a GPCR in the CNS, so BBB penetration, logP, Pgp efflux, TPSA, and binding affinity are key.

**Ligand A: [385.917, 80.32, 2.65, 2, 5, 0.674, 65.568, 50.679, -5.203, -3.702, 0.316, 37.898, 39.647, 0.232, -8.2]**

*   **MW:** 385.917 Da - Good, within the ideal range.
*   **TPSA:** 80.32  - Good, below the 90 threshold for CNS targets.
*   **logP:** 2.65 - Excellent, within the optimal 1-3 range.
*   **HBD:** 2 - Good, within the acceptable limit of 5.
*   **HBA:** 5 - Good, within the acceptable limit of 10.
*   **QED:** 0.674 - Good, above the 0.5 threshold.
*   **DILI:** 65.568 - Concerning, above the 60 threshold, indicating higher liver injury risk.
*   **BBB:** 50.679 - Moderate. Below the desirable >70 for CNS targets, but not terrible.
*   **Caco-2:** -5.203 - Very poor permeability.
*   **Solubility:** -3.702 - Very poor solubility.
*   **hERG:** 0.316 - Low risk, good.
*   **Cl_mic:** 37.898 - Moderate clearance. Not ideal, but not extremely high.
*   **t1/2:** 39.647 - Moderate half-life.
*   **Pgp:** 0.232 - Low efflux, good.
*   **Affinity:** -8.2 kcal/mol - Excellent, very strong binding.

**Ligand B: [344.455, 78.43, 2.73, 3, 3, 0.742, 15.781, 38.038, -4.995, -4.342, 0.215, 64.062, -23.371, 0.052, -9.2]**

*   **MW:** 344.455 Da - Good, within the ideal range.
*   **TPSA:** 78.43 - Good, below the 90 threshold for CNS targets.
*   **logP:** 2.73 - Excellent, within the optimal 1-3 range.
*   **HBD:** 3 - Good, within the acceptable limit of 5.
*   **HBA:** 3 - Good, within the acceptable limit of 10.
*   **QED:** 0.742 - Good, above the 0.5 threshold.
*   **DILI:** 15.781 - Excellent, very low liver injury risk.
*   **BBB:** 38.038 - Poor. Significantly below the desirable >70 for CNS targets.
*   **Caco-2:** -4.995 - Very poor permeability.
*   **Solubility:** -4.342 - Very poor solubility.
*   **hERG:** 0.215 - Low risk, good.
*   **Cl_mic:** 64.062 - High clearance, indicating poor metabolic stability.
*   **t1/2:** -23.371 - Very short half-life, problematic.
*   **Pgp:** 0.052 - Low efflux, good.
*   **Affinity:** -9.2 kcal/mol - Excellent, even stronger binding than Ligand A.

**Comparison and Decision:**

Both ligands have very poor Caco-2 permeability and aqueous solubility, which would present significant formulation challenges. However, the binding affinity of Ligand B (-9.2 kcal/mol) is substantially better than Ligand A (-8.2 kcal/mol). This 1 kcal/mol difference is significant, and could potentially outweigh some of the ADME liabilities.

However, Ligand A has a much lower DILI risk (65.57 vs 15.78) and a more reasonable metabolic clearance. Ligand B has a very high clearance and a very short half-life, making it unlikely to be viable. While Ligand A's BBB penetration is not ideal, it is considerably better than Ligand B's.

Considering the GPCR-specific priorities (BBB, logP, Pgp, TPSA, affinity) and the overall balance of properties, **Ligand A is the more promising candidate**, despite the DILI risk. The stronger binding affinity of Ligand B is tempting, but the poor metabolic stability and short half-life are major drawbacks for a CNS drug. The DILI risk of Ligand A can be investigated further and potentially mitigated through structural modifications.

1
2025-04-17 06:26:43,109 - INFO - Reasoning:

Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (358.829 and 346.427 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (90.9) is excellent, falling below the 90 threshold for CNS targets. Ligand B (105.56) is still reasonable but less optimal, exceeding the preferred threshold.

**3. logP:** Both ligands have good logP values (3.099 and 2.085), within the optimal 1-3 range.

**4. H-Bond Donors:** Both have 3 HBD, which is within the acceptable limit of <=5.

**5. H-Bond Acceptors:** Ligand A has 4 HBA, and Ligand B has 5 HBA, both within the acceptable limit of <=10.

**6. QED:** Both ligands have similar QED values (0.653 and 0.695), indicating good drug-like properties.

**7. DILI:** Ligand A (69.678) has a higher DILI risk than Ligand B (29.042). This is a significant drawback for Ligand A.

**8. BBB:** This is crucial for a CNS target like DRD2. Ligand A (23.381) has a very low BBB penetration, making it unlikely to reach the target in the brain. Ligand B (42.924) has a significantly better, though still not ideal, BBB percentile.

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.482 and -5.672), which is unusual and suggests poor permeability. However, these values are on a log scale, and the negative values suggest very low permeability.

**10. Aqueous Solubility:** Both ligands have negative solubility values (-3.95 and -2.689), indicating poor aqueous solubility. This could pose formulation challenges.

**11. hERG Inhibition:** Both ligands have low hERG inhibition liability (0.667 and 0.658), which is good.

**12. Microsomal Clearance:** Ligand A (-3.839) has a lower (better) microsomal clearance than Ligand B (42.427), suggesting better metabolic stability.

**13. In vitro Half-Life:** Ligand A (27.346) has a significantly longer half-life than Ligand B (4.049).

**14. P-gp Efflux:** Ligand A (0.242) has lower P-gp efflux liability than Ligand B (0.124), which is favorable for CNS penetration.

**15. Binding Affinity:** Both ligands have excellent binding affinities (-8.5 and -8.9 kcal/mol). The difference is minimal.

**Overall Assessment:**

Despite Ligand A's better metabolic stability (lower Cl_mic, longer t1/2) and lower P-gp efflux, its extremely poor BBB penetration (23.381) is a deal-breaker for a CNS target. The higher DILI risk is also concerning. Ligand B, while having a higher Cl_mic and shorter half-life, has a significantly better (though still not great) BBB penetration (42.924). Given the GPCR-specific priority of BBB penetration for CNS targets, Ligand B is the more promising candidate, despite its drawbacks.

Output:
1
2025-04-17 06:26:43,109 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (344.5 and 351.5 Da) fall comfortably within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (49.41) is better than Ligand B (52.65). Both are below the 90 A^2 threshold for CNS targets, which is good.

**3. logP:** Both ligands have good logP values (2.966 and 2.364), falling within the optimal 1-3 range.

**4. H-Bond Donors:** Both have 1 HBD, which is acceptable.

**5. H-Bond Acceptors:** Ligand A has 2 HBA, and Ligand B has 3. Both are within the acceptable limit of 10.

**6. QED:** Both ligands have QED values above 0.7, indicating good drug-likeness.

**7. DILI:** Ligand A (22.14) has a significantly lower DILI risk than Ligand B (5.118), which is a major advantage.

**8. BBB:** Ligand B (81.97) has a slightly better BBB penetration percentile than Ligand A (78.054), but both are above the desirable 70% threshold for CNS targets.

**9. Caco-2 Permeability:** Ligand A (-4.866) has slightly better Caco-2 permeability than Ligand B (-4.682).

**10. Aqueous Solubility:** Ligand A (-3.956) has better aqueous solubility than Ligand B (-2.064).

**11. hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.514 and 0.526).

**12. Microsomal Clearance:** Ligand A (26.651) has a lower microsomal clearance than Ligand B (39.041), suggesting better metabolic stability.

**13. In vitro Half-Life:** Ligand A (5.145) has a better in vitro half-life than Ligand B (-10.475).

**14. P-gp Efflux:** Both ligands show low P-gp efflux liability (0.161 and 0.087).

**15. Binding Affinity:** Both ligands have excellent binding affinity (-8.6 and -8.0 kcal/mol).  Ligand A is slightly better.

**Overall Assessment:**

While both ligands are promising, Ligand A is the superior candidate. It has a significantly lower DILI risk, better solubility, better metabolic stability (lower Cl_mic and longer t1/2), and slightly better Caco-2 permeability. The binding affinity difference is small, and both are well within the desired range. Given the GPCR-specific priorities, the improved ADME properties of Ligand A outweigh the slight advantage of Ligand B in BBB penetration.

Output:
1
2025-04-17 06:26:43,109 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (380.798 and 372.491 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (76.02) is excellent, well below the 90 A^2 threshold for CNS targets. Ligand B (115.97) is higher, but still potentially acceptable, though less ideal.

**logP:** Ligand A (2.287) is within the optimal 1-3 range. Ligand B (-1.233) is significantly lower, which could hinder membrane permeability and CNS penetration.

**H-Bond Donors/Acceptors:** Ligand A (2 HBD, 4 HBA) is well within acceptable limits. Ligand B (3 HBD, 6 HBA) is also acceptable, but slightly higher.

**QED:** Ligand A (0.762) is very good, indicating strong drug-likeness. Ligand B (0.515) is acceptable, but lower than Ligand A.

**DILI:** Ligand A (59.403) has a moderate DILI risk, but is acceptable. Ligand B (11.283) has a very low DILI risk, which is excellent.

**BBB:** Ligand A (83.831) has excellent BBB penetration potential, exceeding the 70% threshold. Ligand B (14.541) has very poor BBB penetration, a major drawback for a CNS target.

**Caco-2 Permeability:** Ligand A (-4.827) has poor Caco-2 permeability. Ligand B (-5.978) also has poor Caco-2 permeability.

**Aqueous Solubility:** Ligand A (-3.911) has poor aqueous solubility. Ligand B (-0.806) has slightly better aqueous solubility.

**hERG:** Both ligands have very low hERG inhibition risk (0.22 and 0.07, respectively).

**Microsomal Clearance:** Ligand A (28.428 mL/min/kg) has moderate clearance. Ligand B (-11.696 mL/min/kg) has negative clearance, which is not possible, and likely indicates an error or outlier in the data. However, even if we consider it as very low clearance, it is still favorable.

**In vitro Half-Life:** Ligand A (0.655 hours) has a very short half-life. Ligand B (-7.902 hours) also has a negative half-life, which is not possible.

**P-gp Efflux:** Ligand A (0.135) has low P-gp efflux, which is good. Ligand B (0.007) has very low P-gp efflux, which is excellent.

**Binding Affinity:** Ligand A (-8.4 kcal/mol) has significantly stronger binding affinity than Ligand B (0.0 kcal/mol). This is a crucial advantage.

**Overall Assessment:**

Ligand A excels in TPSA, BBB penetration, and, most importantly, binding affinity. Its main drawbacks are the poor Caco-2 permeability and short half-life. Ligand B has a better DILI profile and P-gp efflux, but suffers from poor logP, very poor BBB penetration, and extremely weak binding affinity. The strong affinity of Ligand A outweighs its ADME liabilities, especially given the GPCR target and the importance of CNS penetration. The negative values for clearance and half-life of Ligand B are concerning and suggest potential data quality issues.

Output:
1
2025-04-17 06:26:43,110 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (346.402 and 339.399 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (71.45) is significantly better than Ligand B (84.98). For CNS targets, we want TPSA <= 90, and A is closer to the ideal <= 60-70 range. B is pushing the upper limit.

**3. logP:** Both ligands have good logP values (2.443 and 2.33), falling within the optimal 1-3 range.

**4. H-Bond Donors:** Both have 2 HBD, which is acceptable (<=5).

**5. H-Bond Acceptors:** Ligand A has 4 HBA, and Ligand B has 6. Both are within the acceptable limit of <=10, but A is preferable.

**6. QED:** Both have reasonable QED values (0.72 and 0.615), indicating good drug-like properties.

**7. DILI:** Ligand A (37.728) has a lower DILI risk than Ligand B (59.636). Both are below 60, so the risk is moderate, but A is better.

**8. BBB:** Ligand B (73.517) has a significantly better BBB penetration percentile than Ligand A (50.523). This is a *critical* factor for a CNS target like DRD2.

**9. Caco-2:** Ligand A (-4.611) and Ligand B (-5.45) both have negative Caco-2 values, which is unusual and suggests poor permeability. This is a significant drawback for both.

**10. Solubility:** Both have very poor aqueous solubility (-2.991 and -2.39). This is a major concern for bioavailability.

**11. hERG:** Both ligands have low hERG inhibition liability (0.523 and 0.79).

**12. Cl_mic:** Ligand B (59.372) has slightly lower microsomal clearance than Ligand A (63.573), suggesting better metabolic stability, which is favorable.

**13. t1/2:** Ligand B (4.692) has a longer in vitro half-life than Ligand A (-2.547). This is a significant advantage.

**14. Pgp:** Both ligands have low P-gp efflux liability (0.2 and 0.316), which is good for CNS penetration.

**15. Binding Affinity:** Both ligands have very similar and excellent binding affinities (-8.9 and -8.7 kcal/mol). The difference is negligible.

**Overall Assessment:**

Ligand B is superior in terms of BBB penetration and in vitro half-life, which are crucial for CNS drug development. While Ligand A has a slightly better TPSA and DILI score, the BBB advantage of Ligand B outweighs these minor benefits. The poor Caco-2 and solubility are concerning for both, but can be addressed with formulation strategies. The similar binding affinities mean that the ADME properties become the deciding factor.

Output:
1
2025-04-17 06:26:43,110 - INFO - Batch 282 complete. Total preferences: 4512
2025-04-17 06:26:43,110 - INFO - Processing batch 283/512...
2025-04-17 06:27:25,372 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (346.471 Da) is slightly better, being closer to the middle of the range.

**TPSA:** Ligand A (49.85) is excellent, well below the 90 A^2 threshold for CNS targets. Ligand B (121.8) is higher, but still potentially acceptable, though less desirable.

**logP:** Ligand A (2.377) is optimal (1-3). Ligand B (-0.478) is below 1, which could impede permeation. This is a significant drawback for Ligand B.

**H-Bond Donors/Acceptors:** Ligand A (0 HBD, 3 HBA) is favorable. Ligand B (3 HBD, 6 HBA) is also acceptable, but slightly higher counts could affect permeability.

**QED:** Both ligands have good QED scores (A: 0.366, B: 0.486), indicating reasonable drug-likeness.

**DILI:** Ligand A (26.444) has a much lower DILI risk than Ligand B (53.47). This is a significant advantage for Ligand A.

**BBB:** Ligand A (63.784) has a better BBB percentile than Ligand B (43.699). While both are not ideal (>70), A is closer. Given DRD2 is a CNS target, this is important.

**Caco-2 Permeability:** Ligand A (-4.241) and Ligand B (-5.508) both have negative Caco-2 values which is unusual and suggests poor permeability. However, the scale is not specified, so it's hard to interpret.

**Aqueous Solubility:** Both ligands have very poor aqueous solubility (-1.707 and -1.802 respectively). This will be a formulation challenge for both.

**hERG Inhibition:** Both ligands show low hERG inhibition risk (A: 0.517, B: 0.162).

**Microsomal Clearance:** Ligand A (49.12) has a moderate clearance, while Ligand B (-5.262) has a negative clearance, which is not physically possible and indicates an issue with the data or model.

**In vitro Half-Life:** Ligand A (-13.555) has a negative half-life, which is not physically possible. Ligand B (-36.262) also has a negative half-life. This indicates issues with the data/model.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (A: 0.202, B: 0.022).

**Binding Affinity:** Ligand B (-7.8 kcal/mol) has a significantly better binding affinity than Ligand A (-6.9 kcal/mol). This is a substantial advantage for Ligand B.

**Overall Assessment:**

Despite the superior binding affinity of Ligand B, several factors favor Ligand A. Ligand B has a problematic logP value, indicating poor permeability. It also has a higher DILI risk and a lower BBB percentile. Furthermore, the negative values for clearance and half-life for both compounds are concerning and suggest data quality issues. However, the affinity difference is substantial.

Given the GPCR-specific priorities and the importance of CNS penetration for a DRD2 ligand, and acknowledging the data quality concerns, the better logP and BBB of Ligand A, combined with its lower DILI risk, make it the more promising candidate *despite* the weaker binding affinity. The negative clearance and half-life values are red flags that would require further investigation.

Output:
0
2025-04-17 06:27:25,373 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (344.455 and 342.443 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (75.27) is slightly above the preferred <90 for CNS targets, but acceptable. Ligand B (69.3) is excellent, well below 90.

**3. logP:** Both ligands have good logP values (2.113 and 2.293), falling within the optimal 1-3 range.

**4. H-Bond Donors:** Ligand A has 2 HBD, and Ligand B has 1. Both are within the acceptable limit of <=5.

**5. H-Bond Acceptors:** Both ligands have 3 HBA, well within the acceptable limit of <=10.

**6. QED:** Both ligands have good QED scores (0.802 and 0.913), indicating good drug-like properties.

**7. DILI:** Both ligands have low DILI risk (25.785 and 29.081), both well below the 40 threshold.

**8. BBB:** This is a crucial parameter for a CNS target like DRD2. Ligand B (74.06) is significantly better than Ligand A (55.176), exceeding the desirable >70 threshold.

**9. Caco-2 Permeability:** Ligand A (-4.864) and Ligand B (-5.009) both have negative Caco-2 values, which is unusual and suggests poor permeability. However, these values are on a strange scale, so it's hard to interpret.

**10. Aqueous Solubility:** Both ligands have very poor aqueous solubility (-2.718 and -2.905). This is a significant concern.

**11. hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.076 and 0.622).

**12. Microsomal Clearance:** Ligand A (23.512) has a lower microsomal clearance than Ligand B (45.669), suggesting better metabolic stability.

**13. In vitro Half-Life:** Ligand B (-36.665) has a significantly longer in vitro half-life than Ligand A (-2.797). This is a major advantage.

**14. P-gp Efflux:** Both ligands have low P-gp efflux liability (0.06 and 0.069).

**15. Binding Affinity:** Ligand A (-9.5 kcal/mol) has a slightly better binding affinity than Ligand B (-8.3 kcal/mol). This is a 1.2 kcal/mol difference, which is significant.

**Overall Assessment:**

While Ligand A has slightly better binding affinity and metabolic stability, Ligand B is superior due to its significantly better BBB penetration (74.06 vs 55.176) and longer in vitro half-life. The poor solubility of both compounds is a concern, but the improved CNS exposure profile of Ligand B outweighs the slight advantage in affinity and clearance of Ligand A. Given the GPCR-specific priorities, particularly BBB penetration for a CNS target, Ligand B is the more promising candidate.

Output:
1
2025-04-17 06:27:25,373 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (344.273) is slightly lower, which could be advantageous for permeability.

**TPSA:** Ligand A (89.38) is excellent for CNS penetration, being well below 90. Ligand B (49.41) is also very good.

**logP:** Ligand A (2.653) is optimal. Ligand B (4.246) is pushing the upper limit, potentially leading to solubility issues or off-target interactions, but still within an acceptable range.

**H-Bond Donors/Acceptors:** Both ligands have a reasonable number of HBDs (1) and HBAs (6 for A, 3 for B), suggesting a good balance between solubility and permeability.

**QED:** Both ligands have good QED scores (0.578 and 0.712), indicating drug-like properties.

**DILI:** Ligand A has a very high DILI risk (98.992), which is a significant concern. Ligand B has a much lower DILI risk (34.781), making it more favorable.

**BBB:** Ligand A (65.607) has moderate BBB penetration, while Ligand B (73.711) is better, exceeding the 70% threshold desirable for CNS targets.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values, which is unusual and suggests poor permeability. However, these values are on a log scale, so the more negative value (Ligand A at -4.277) indicates *worse* permeability than Ligand B (-4.782).

**Aqueous Solubility:** Both ligands have very poor aqueous solubility (-4.193 and -4.003). This is a concern, but can sometimes be mitigated with formulation strategies.

**hERG Inhibition:** Ligand A (0.191) has a slightly higher hERG risk than Ligand B (0.676), though both are relatively low.

**Microsomal Clearance:** Ligand A (102.531) has higher microsomal clearance, indicating faster metabolism and lower metabolic stability. Ligand B (78.338) has better metabolic stability.

**In vitro Half-Life:** Ligand B (50.168) has a significantly longer in vitro half-life than Ligand A (-28.9), which is a substantial advantage.

**P-gp Efflux:** Ligand A (0.309) has lower P-gp efflux, which is good for CNS exposure. Ligand B (0.468) has slightly higher efflux.

**Binding Affinity:** Ligand B (-7.4) has a significantly stronger binding affinity than Ligand A (-10.7). This is a crucial advantage, as a >1.5 kcal/mol difference can outweigh other drawbacks.

**Overall Assessment:**

Ligand B is the superior candidate. While both have solubility issues and negative Caco-2 permeability, Ligand B's significantly stronger binding affinity, lower DILI risk, better BBB penetration, and improved metabolic stability (lower Cl_mic, longer t1/2) outweigh the slightly higher logP and P-gp efflux. The extremely high DILI risk associated with Ligand A is a major red flag.

Output:
1
2025-04-17 06:27:25,373 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (342.46 & 362.46 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (23.55) is excellent, well below the 90 A^2 threshold for CNS targets. Ligand B (74.77) is higher, but still potentially acceptable, though less ideal.

**logP:** Ligand A (3.79) is at the upper end of the optimal range (1-3), while Ligand B (1.31) is at the lower end. For a CNS target, a slightly higher logP is often preferred for BBB penetration, giving a slight edge to Ligand A.

**H-Bond Donors/Acceptors:** Ligand A (0 HBD, 1 HBA) is very favorable. Ligand B (1 HBD, 6 HBA) is also acceptable, but the higher HBA count could slightly hinder permeability.

**QED:** Both ligands have good QED scores (0.802 and 0.874), indicating good drug-like properties.

**DILI:** Ligand A (18.19) has a significantly lower DILI risk than Ligand B (67.39), which is a substantial advantage.

**BBB:** Ligand A (82.44) has a much better BBB percentile than Ligand B (63.40). This is *critical* for a CNS target like DRD2.

**Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and suggests potential issues with permeability prediction. However, the magnitude is similar.

**Aqueous Solubility:** Both have negative solubility values, which is also unusual.

**hERG:** Ligand A (0.81) shows lower hERG inhibition liability than Ligand B (0.13), which is a positive.

**Microsomal Clearance:** Ligand A (46.70) has higher clearance than Ligand B (19.11), suggesting lower metabolic stability.

**In vitro Half-Life:** Ligand B (30.90) has a longer half-life than Ligand A (17.63), which is a benefit.

**P-gp Efflux:** Ligand A (0.34) has lower P-gp efflux liability than Ligand B (0.03), which is favorable for CNS penetration.

**Binding Affinity:** Ligand B (-7.8 kcal/mol) has a significantly stronger binding affinity than Ligand A (-9.8 kcal/mol). This is a substantial advantage and could potentially outweigh some of the ADME drawbacks.

**Overall Assessment:**

Ligand A excels in properties crucial for CNS penetration (BBB, TPSA, Pgp, logP) and has a much better safety profile (DILI, hERG). However, Ligand B has a significantly stronger binding affinity and a longer half-life. The difference in binding affinity (-7.8 vs -9.8 kcal/mol) is a 2 kcal/mol advantage, which is substantial. Given the importance of potency for GPCRs, and the fact that the other ADME properties of Ligand B are not dramatically worse than Ligand A, the stronger binding affinity of Ligand B tips the balance.

Output:
1
2025-04-17 06:27:25,373 - INFO - Reasoning:

Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (416.316 Da) is slightly higher than Ligand B (346.471 Da), but both are acceptable.

**2. TPSA:** Ligand A (100.55) is borderline for CNS targets (ideally <90), while Ligand B (69.64) is well within the desired range. This favors Ligand B.

**3. logP:** Both ligands have good logP values (Ligand A: 2.167, Ligand B: 1.86), falling within the optimal 1-3 range.

**4. H-Bond Donors:** Both ligands have acceptable HBD counts (Ligand A: 3, Ligand B: 2), well below the threshold of 5.

**5. H-Bond Acceptors:** Both ligands have acceptable HBA counts (Ligand A: 5, Ligand B: 3), below the threshold of 10.

**6. QED:** Both ligands have good QED scores (Ligand A: 0.618, Ligand B: 0.747), indicating good drug-like properties. Ligand B is slightly better.

**7. DILI:** Ligand A (46.297) has a moderate DILI risk, while Ligand B (16.906) has a very low risk. This strongly favors Ligand B.

**8. BBB:** Both ligands have the same BBB penetration (55.603 percentile), which is acceptable but not ideal for a CNS target (ideally >70).

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.951 and -4.624), which is unusual and suggests poor permeability. This is a concern for both.

**10. Aqueous Solubility:** Both ligands have negative solubility values (-2.907 and -2.592), indicating very poor aqueous solubility. This is a significant drawback for both.

**11. hERG Inhibition:** Both ligands have low hERG inhibition risk (Ligand A: 0.171, Ligand B: 0.246).

**12. Microsomal Clearance:** Ligand A (65.326) has higher microsomal clearance than Ligand B (11.367), indicating lower metabolic stability. Ligand B is significantly better.

**13. In vitro Half-Life:** Ligand B (-19.289) has a negative half-life, which is not possible and suggests an issue with the data or prediction method. Ligand A (3.451) has a short half-life, which is less than ideal.

**14. P-gp Efflux:** Both ligands have low P-gp efflux liability (Ligand A: 0.046, Ligand B: 0.103).

**15. Binding Affinity:** Ligand B (-8.2 kcal/mol) has a slightly better binding affinity than Ligand A (-7.8 kcal/mol). While the difference is not huge, it is still a positive factor for Ligand B.

**Overall Assessment:**

Considering all factors, and prioritizing GPCR-specific properties (BBB, logP, Pgp, TPSA, and affinity), **Ligand B is the more promising candidate**. While both have issues with solubility and Caco-2 permeability, Ligand B exhibits significantly lower DILI risk, better metabolic stability (lower Cl_mic), and slightly better binding affinity. The TPSA value is also more favorable for CNS penetration. The negative half-life for Ligand B is concerning and would need further investigation, but the other advantages outweigh this issue for initial ranking.

Output:
1
2025-04-17 06:27:25,374 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 drug candidates, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (352.475 Da and 342.483 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (59.08) is better than Ligand B (40.62), both are well below the 90 A^2 threshold for CNS targets.

**logP:** Ligand A (1.681) is within the optimal 1-3 range. Ligand B (3.378) is at the higher end of the optimal range, but still acceptable.

**H-Bond Donors/Acceptors:** Ligand A has 0 HBD and 4 HBA, while Ligand B has 0 HBD and 2 HBA. Both are within acceptable limits.

**QED:** Ligand B (0.744) has a better QED score than Ligand A (0.443), indicating a more drug-like profile.

**DILI:** Ligand A (12.641) has a significantly lower DILI risk than Ligand B (18.922), which is a substantial advantage.

**BBB:** Ligand B (85.459) has a better BBB penetration percentile than Ligand A (79.488), both are above the 70% threshold, but B is better.

**Caco-2 Permeability:** Both have negative Caco-2 values (-4.275 and -4.301), which is unusual and suggests poor permeability. This is a significant concern for both.

**Aqueous Solubility:** Both have negative solubility values (-1.049 and -2.647), indicating very poor aqueous solubility, which is a major drawback.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.526 and 0.64), which is good.

**Microsomal Clearance:** Ligand B (96.507) has a much higher microsomal clearance than Ligand A (13.027), suggesting lower metabolic stability. This is a significant disadvantage for Ligand B.

**In vitro Half-Life:** Ligand A (-7.592) has a more favorable in vitro half-life than Ligand B (27.667).

**P-gp Efflux:** Ligand A (0.071) has a lower P-gp efflux liability than Ligand B (0.487), which is preferable for CNS penetration.

**Binding Affinity:** Ligand B (-8.6 kcal/mol) has a significantly stronger binding affinity than Ligand A (-6.6 kcal/mol). This is a substantial advantage that could potentially outweigh some of the ADME drawbacks.

**Overall Assessment:**

Ligand B has a superior binding affinity and BBB penetration, but suffers from higher DILI risk, significantly higher microsomal clearance, and higher P-gp efflux. Ligand A has better metabolic stability (lower Cl_mic), lower DILI risk, and lower P-gp efflux, but weaker binding affinity. The poor Caco-2 and solubility for both are concerning. However, given the importance of binding affinity for GPCRs, and the relatively modest differences in other parameters, the stronger binding of Ligand B is the deciding factor.

Output:
1
2025-04-17 06:27:25,374 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (349.435 and 347.379 Da) fall comfortably within the ideal 200-500 Da range.

**TPSA:** Ligand A (98.4) is excellent, falling well below the 90 threshold for CNS targets. Ligand B (129.03) is higher, but still potentially acceptable, though less ideal.

**logP:** Ligand A (0.666) is a bit low, potentially hindering permeability. Ligand B (0.129) is even lower and concerning for permeability.

**H-Bond Donors/Acceptors:** Ligand A (2 HBD, 4 HBA) is well within acceptable limits. Ligand B (3 HBD, 7 HBA) is also acceptable, but slightly higher.

**QED:** Both ligands have similar, good QED values (0.674 and 0.681), suggesting generally drug-like properties.

**DILI:** Ligand A (25.204) has a very favorable DILI score, indicating low liver injury risk. Ligand B (71.268) has a significantly higher DILI score, raising a concern.

**BBB:** Ligand A (51.842) has a moderate BBB penetration score. Ligand B (18.147) has a very low BBB score, which is a major drawback for a CNS target like DRD2.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.566 and -5.512), which is unusual and suggests poor permeability. However, these values are on a log scale and may not be directly comparable.

**Aqueous Solubility:** Both ligands have negative solubility values (-1.455 and -2.867), indicating poor aqueous solubility.

**hERG:** Both ligands have very low hERG inhibition liability (0.093 and 0.064), which is excellent.

**Microsomal Clearance:** Ligand A (4.703) has a lower (better) microsomal clearance than Ligand B (-5.27). This suggests better metabolic stability for Ligand A.

**In vitro Half-Life:** Ligand A (-11.706) has a longer (better) in vitro half-life than Ligand B (-27.52).

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.008 and 0.012), which is positive for CNS penetration.

**Binding Affinity:** Ligand B (-8.6 kcal/mol) has a slightly better binding affinity than Ligand A (-7.5 kcal/mol). However, the difference is less than the 1.5 kcal/mol threshold that might outweigh other drawbacks.

**Overall Assessment:**

Ligand A is significantly better overall. While its logP is a bit low, its superior BBB penetration, much lower DILI risk, better metabolic stability (lower Cl_mic, longer t1/2), and acceptable TPSA make it a much more promising candidate for a CNS-targeting drug like a DRD2 ligand. Ligand B's extremely low BBB score is a critical flaw, and its higher DILI risk is also concerning. The slightly better affinity of Ligand B is not enough to compensate for these significant liabilities.

Output:
0
2025-04-17 06:27:25,374 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (340.43 and 350.46 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (90.01) is slightly higher than Ligand B (80.48), but both are below the 90-140 threshold for good absorption and acceptable for CNS targets. Ligand B is preferable here.

**logP:** Ligand A (2.201) and Ligand B (1.57) are both within the optimal 1-3 range. Ligand A is slightly better.

**H-Bond Donors:** Ligand A (2) and Ligand B (1) are both acceptable (<=5). Ligand B is preferable.

**H-Bond Acceptors:** Ligand A (4) and Ligand B (6) are both acceptable (<=10). Ligand A is preferable.

**QED:** Both ligands have similar QED values (0.845 and 0.807), indicating good drug-likeness.

**DILI:** Ligand A (50.33) has a slightly higher DILI risk than Ligand B (38.813), but both are below the concerning threshold of 60. Ligand B is preferable.

**BBB:** Ligand A (92.4) has significantly better predicted BBB penetration than Ligand B (64.211). This is a *critical* advantage for a CNS target like DRD2.

**Caco-2 Permeability:** Ligand A (-5.289) and Ligand B (-4.848) have negative values which are difficult to interpret without knowing the scale. However, they are similar.

**Aqueous Solubility:** Ligand A (-3.824) and Ligand B (-1.891) have negative values which are difficult to interpret without knowing the scale. However, Ligand B is preferable.

**hERG Inhibition:** Ligand A (0.5) has a lower hERG inhibition liability than Ligand B (0.128), which is better.

**Microsomal Clearance:** Ligand A (58.172) has a higher microsomal clearance than Ligand B (27.521), indicating lower metabolic stability. Ligand B is preferable.

**In vitro Half-Life:** Ligand A (10.959) has a longer half-life than Ligand B (-9.55), which is preferable.

**P-gp Efflux:** Ligand A (0.526) has lower P-gp efflux liability than Ligand B (0.154), which is preferable.

**Binding Affinity:** Both ligands have very strong binding affinities (-10.0 and -8.1 kcal/mol). Ligand A has a 1.9 kcal/mol advantage, which is substantial and can outweigh some ADME drawbacks.

**Overall Assessment:**

Ligand A excels in binding affinity and BBB penetration, which are paramount for a CNS GPCR target. While Ligand B has slightly better scores in some ADME properties (DILI, Cl_mic), the significantly better BBB and binding affinity of Ligand A are more important. The difference in binding affinity is large enough to overcome the slightly higher DILI and clearance of Ligand A.

Output:
1
2025-04-17 06:27:25,375 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (340.43 and 354.47 Da) fall within the ideal 200-500 Da range.

**TPSA:** Both ligands (70.39 and 69.64) are below the 90 A^2 threshold desirable for CNS targets, which is good.

**logP:** Both ligands have logP values (3.01 and 2.195) within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Both have 2 HBDs, which is acceptable. Ligand A has 4 HBAs, and Ligand B has 3, both are within the acceptable limit of <=10.

**QED:** Both ligands have QED values (0.902 and 0.719) above 0.5, indicating good drug-likeness.

**DILI:** Ligand A has a DILI risk of 63.2%, which is moderately high. Ligand B has a significantly lower DILI risk of 24.3%, which is a major advantage.

**BBB:** Ligand B (81.7%) has a much better BBB penetration percentile than Ligand A (68.3%). This is crucial for a CNS target like DRD2.

**Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and suggests poor permeability. However, the scale is not specified, so it's hard to interpret.

**Aqueous Solubility:** Both have negative solubility values, also unusual and suggesting poor solubility. Again, the scale is not specified.

**hERG:** Both have low hERG inhibition liability (0.633 and 0.397), which is good.

**Microsomal Clearance:** Ligand A (46.223) has lower microsomal clearance than Ligand B (61.485), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand B (-18.156) has a negative half-life, which is impossible and indicates a data error or an unusual scale. Ligand A (36.462) has a reasonable half-life.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.196 and 0.216), which is favorable for CNS penetration.

**Binding Affinity:** Both ligands have very similar and excellent binding affinities (-8.1 and -8.2 kcal/mol). The difference is negligible.

**Conclusion:**

While both ligands have good potency and acceptable physicochemical properties, Ligand B is the superior candidate due to its significantly better BBB penetration (81.7% vs 68.3%) and much lower DILI risk (24.3% vs 63.2%). The questionable half-life value for Ligand B is concerning, but the other advantages outweigh this issue. The similar affinities mean that the improved ADME properties of Ligand B are the deciding factor.

Output:
1
2025-04-17 06:27:25,375 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (345.447 and 350.419 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (80.12) is significantly better than Ligand B (105.48). For CNS targets, we want TPSA <= 90, and A is comfortably within that range, while B is pushing the limit.

**logP:** Ligand A (1.067) is within the optimal 1-3 range. Ligand B (0.302) is a bit low, potentially hindering permeability.

**H-Bond Donors/Acceptors:** Ligand A (HBD=1, HBA=5) and Ligand B (HBD=3, HBA=6) both have reasonable numbers of H-bond donors and acceptors, staying within the guidelines.

**QED:** Both ligands have acceptable QED values (0.75 and 0.656), indicating good drug-like properties.

**DILI:** Ligand A (23.575) has a much lower DILI risk than Ligand B (49.205), which is a significant advantage.

**BBB:** Ligand A (85.731) has a much better BBB penetration score than Ligand B (53.509). This is *critical* for a CNS target like DRD2.

**Caco-2 Permeability:** Both are negative, indicating poor permeability. This is a concern, but less so than BBB for a CNS target.

**Aqueous Solubility:** Both are negative, indicating poor solubility. This is a concern for formulation.

**hERG:** Both ligands show very low hERG inhibition risk (0.061 and 0.098).

**Microsomal Clearance:** Ligand A (26.152) has a lower (better) microsomal clearance than Ligand B (0.745).

**In vitro Half-Life:** Ligand A (-9.467) has a much longer in vitro half-life than Ligand B (33.013).

**P-gp Efflux:** Both ligands show very low P-gp efflux liability (0.022 and 0.029).

**Binding Affinity:** Ligand B (-7.9) has slightly better binding affinity than Ligand A (-7.7), but the difference is small (0.2 kcal/mol). This difference is unlikely to outweigh the substantial ADME advantages of Ligand A.

**Overall:**

Ligand A is significantly better overall, particularly regarding CNS penetration (BBB), DILI risk, metabolic stability (Cl_mic, t1/2), and TPSA. While Ligand B has a slightly better binding affinity, the ADME profile of Ligand A is far superior, making it a more promising drug candidate for a CNS target like DRD2.

Output:
1
2025-04-17 06:27:25,375 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight (MW):** Both ligands (364.364 and 370.827 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (87.66) is better than Ligand B (49.41), both are below the 90 A^2 threshold for CNS targets.

**3. logP:** Ligand B (2.178) is optimal (1-3), while Ligand A (0.595) is slightly low, potentially hindering permeation.

**4. H-Bond Donors (HBD):** Both ligands are acceptable (Ligand A: 3, Ligand B: 1), staying under the 5 limit.

**5. H-Bond Acceptors (HBA):** Both ligands are acceptable (Ligand A: 4, Ligand B: 2), staying under the 10 limit.

**6. QED:** Both ligands have similar good QED values (Ligand A: 0.624, Ligand B: 0.609), indicating drug-likeness.

**7. DILI:** Both ligands have similar low DILI risk (Ligand A: 35.789, Ligand B: 35.75), both well below the 40 threshold.

**8. BBB:** Ligand B (83.56) significantly outperforms Ligand A (47.499) in BBB penetration, which is crucial for a CNS target like DRD2. This is a major advantage for Ligand B.

**9. Caco-2 Permeability:** Ligand A (-5.061) is significantly better than Ligand B (-4.919).

**10. Aqueous Solubility:** Ligand A (-1.967) is better than Ligand B (-3.606).

**11. hERG Inhibition:** Both ligands show low hERG inhibition liability (Ligand A: 0.281, Ligand B: 0.381).

**12. Microsomal Clearance:** Ligand B (10.833) has a higher clearance than Ligand A (1.716), indicating lower metabolic stability.

**13. In vitro Half-Life:** Ligand B (1.883) has a shorter half-life than Ligand A (-16.384).

**14. P-gp Efflux:** Both ligands have low P-gp efflux (Ligand A: 0.03, Ligand B: 0.056).

**15. Binding Affinity:** Ligand B (-8.5 kcal/mol) has a significantly stronger binding affinity than Ligand A (-6.9 kcal/mol). This >1.5 kcal/mol difference is substantial and can outweigh some ADME drawbacks.

**Overall Assessment:**

While Ligand A has better solubility, Caco-2 permeability, metabolic stability, and half-life, Ligand B excels in the most critical areas for a CNS-targeting GPCR ligand: **BBB penetration and binding affinity**. The significantly stronger binding affinity of Ligand B (-8.5 vs -6.9 kcal/mol) is a major advantage. The higher BBB value (83.56%) is also critical. The slightly lower logP of Ligand A is a concern, and the higher clearance/shorter half-life of Ligand B are drawbacks, but the superior affinity and BBB penetration make Ligand B the more promising candidate.

Output:
1
2025-04-17 06:27:25,375 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (357.479 and 356.394 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (46.84) is excellent, well below the 90 A^2 threshold for CNS targets. Ligand B (103.01) is higher, but still potentially acceptable, though less ideal.

**logP:** Ligand A (3.747) is within the optimal 1-3 range. Ligand B (0.707) is quite low, potentially hindering permeability.

**H-Bond Donors/Acceptors:** Ligand A has 0 HBD and 5 HBA, which is good. Ligand B has 3 HBD and 5 HBA, also acceptable.

**QED:** Both ligands have similar QED values (0.699 and 0.668), indicating good drug-likeness.

**DILI:** Ligand A has a DILI risk of 60.062, which is borderline high. Ligand B has a much lower DILI risk of 21.636, which is excellent.

**BBB:** Ligand A has a BBB penetration of 66.925%, which is reasonably good, but not outstanding. Ligand B has a lower BBB penetration of 53.587%, which is less desirable for a CNS target.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.564 and -4.856), which is unusual and suggests poor permeability. This is a significant concern for both.

**Aqueous Solubility:** Both ligands have negative solubility values (-3.496 and -2.464), indicating very poor aqueous solubility, a major formulation challenge.

**hERG Inhibition:** Ligand A (0.712) has a slightly higher hERG risk than Ligand B (0.368), but both are relatively low.

**Microsomal Clearance:** Ligand A (79.356) has a higher microsomal clearance, suggesting faster metabolism. Ligand B (-2.567) has a negative clearance, which is not physically possible and likely indicates an issue with the prediction or data. We will assume this means very low clearance and high metabolic stability.

**In vitro Half-Life:** Ligand A has a short half-life (2.72 hours). Ligand B has a very long half-life (17.2 hours).

**P-gp Efflux:** Ligand A (0.83) has moderate P-gp efflux. Ligand B (0.031) has very low P-gp efflux, which is highly desirable for CNS penetration.

**Binding Affinity:** Both ligands have excellent binding affinities (-8.9 and -8.0 kcal/mol). Ligand A has a slightly better affinity, but the difference is less than 1.5 kcal/mol.

**Overall Assessment:**

Ligand A has a better affinity and BBB penetration, but suffers from higher DILI risk, faster metabolism, and moderate P-gp efflux. Ligand B has a significantly lower DILI risk, much better metabolic stability, and very low P-gp efflux, which are crucial for CNS drug development. However, its logP is quite low, and its BBB penetration is lower than Ligand A. The negative Caco-2 and solubility values are concerning for both.

Given the GPCR-specific priorities, the low logP of Ligand B is a significant drawback. However, the combination of low DILI, excellent metabolic stability (indicated by negative clearance), and very low P-gp efflux for Ligand B outweighs the slightly lower BBB and affinity, especially considering the negative Caco-2 and solubility values for both. Improving the logP of Ligand B through medicinal chemistry is more feasible than addressing the other issues with Ligand A.

Output:
1
2025-04-17 06:27:25,376 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (349.519 and 353.413 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (52.65) is better than Ligand B (54.34) as it's closer to the <90 target for CNS penetration. Both are acceptable, but A is slightly favored.

**3. logP:** Both ligands (2.119 and 2.52) are within the optimal 1-3 range.

**4. H-Bond Donors:** Both have 1 HBD, which is good.

**5. H-Bond Acceptors:** Both have 3 HBA, which is good.

**6. QED:** Both ligands have good QED scores (0.766 and 0.854), indicating drug-like properties.

**7. DILI:** Ligand A (6.824) has a significantly lower DILI risk than Ligand B (34.82). This is a substantial advantage for Ligand A.

**8. BBB:** Ligand B (93.059) has a much higher BBB penetration percentile than Ligand A (77.705). This is a significant advantage for Ligand B, given DRD2 is a CNS target.

**9. Caco-2 Permeability:** Ligand A (-4.871) has slightly better Caco-2 permeability than Ligand B (-4.612), but both are negative values which is not ideal.

**10. Aqueous Solubility:** Ligand A (-1.655) has better aqueous solubility than Ligand B (-2.87).

**11. hERG Inhibition:** Both ligands have similar, low hERG inhibition liability (0.536 and 0.559).

**12. Microsomal Clearance:** Ligand B (17.81) has lower microsomal clearance than Ligand A (32.835), indicating better metabolic stability.

**13. In vitro Half-Life:** Ligand B (-8.8) has a slightly longer in vitro half-life than Ligand A (-0.026).

**14. P-gp Efflux:** Both ligands have similar P-gp efflux liability (0.035 and 0.093).

**15. Binding Affinity:** Both ligands have very similar binding affinities (-8.0 and -7.8 kcal/mol). The difference is negligible.

**Overall Assessment:**

Ligand B excels in BBB penetration and metabolic stability, which are crucial for a CNS target like DRD2. However, Ligand A has a much lower DILI risk and better solubility. The binding affinity is almost identical. Considering the GPCR-specific priorities, the superior BBB penetration of Ligand B outweighs the slightly better DILI and solubility of Ligand A. While DILI is important, achieving sufficient CNS exposure is paramount for a DRD2-targeted drug.

Output:
1
2025-04-17 06:27:25,376 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (358.41 and 392.497 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (77.1) is better than Ligand B (66.4). Both are below the 90 A^2 threshold desirable for CNS targets.

**logP:** Ligand B (1.917) is better than Ligand A (0.415). Ligand A is a bit low, potentially hindering permeation. Ligand B is within the optimal 1-3 range.

**H-Bond Donors:** Ligand A (1) is better than Ligand B (0). Both are acceptable.

**H-Bond Acceptors:** Ligand B (6) is slightly better than Ligand A (5). Both are below the 10 threshold.

**QED:** Both ligands have similar QED values (0.788 and 0.74), indicating good drug-likeness.

**DILI:** Ligand A (49.011) is significantly better than Ligand B (64.831), indicating a lower risk of drug-induced liver injury.

**BBB:** Ligand A (83.404) is better than Ligand B (78.402). Both are reasonably good, but Ligand A is closer to the desirable >70 percentile for CNS targets.

**Caco-2 Permeability:** Ligand A (-4.489) is better than Ligand B (-4.925). Higher values indicate better intestinal absorption.

**Aqueous Solubility:** Ligand A (-1.633) is better than Ligand B (-2.531). Higher values are better.

**hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.249 and 0.165).

**Microsomal Clearance:** Ligand A (2.057) is significantly better than Ligand B (51.584), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand B (2.007) is better than Ligand A (0.469). A longer half-life is generally preferred.

**P-gp Efflux:** Ligand B (0.126) is better than Ligand A (0.056). Lower efflux is preferred for CNS exposure.

**Binding Affinity:** Ligand A (-7.9) is significantly better than Ligand B (0.0). This is a crucial difference, as a stronger binding affinity can outweigh minor ADME drawbacks.

**Overall Assessment:**

Ligand A excels in binding affinity, BBB penetration, DILI risk, metabolic stability, solubility, and Caco-2 permeability. While its logP is a bit low, the strong binding affinity (-7.9 kcal/mol) is a significant advantage, especially for a GPCR target like DRD2. Ligand B has a better logP and P-gp efflux, but its significantly weaker binding affinity and higher DILI risk are major drawbacks.

Output:
1
2025-04-17 06:27:25,376 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (348.491 and 363.439 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (78.09) is significantly better than Ligand B (93.46). For CNS targets, we want TPSA <= 90, so Ligand A is preferable.

**3. logP:** Both ligands have good logP values (2.666 and 2.088), falling within the optimal 1-3 range.

**4. H-Bond Donors:** Both have 2 HBD, which is acceptable.

**5. H-Bond Acceptors:** Ligand A has 3 HBA, while Ligand B has 6. Lower is generally better, and Ligand A is preferable.

**6. QED:** Both ligands have acceptable QED values (0.709 and 0.666), indicating good drug-like properties.

**7. DILI:** Ligand A (25.09) has a much lower DILI risk than Ligand B (67.00). This is a significant advantage for Ligand A.

**8. BBB:** Ligand A (69.213) has a better BBB percentile than Ligand B (58.007). While >70 is desirable, Ligand A is closer to that threshold. This is crucial for a CNS target like DRD2.

**9. Caco-2:** Both have negative Caco-2 values, indicating poor permeability. This is a concern for both, but the values are similar.

**10. Solubility:** Both have negative solubility values, indicating poor solubility. This is a concern for both, but the values are similar.

**11. hERG:** Both ligands have low hERG inhibition liability (0.401 and 0.276), which is good.

**12. Cl_mic:** Ligand A (33.962) has lower microsomal clearance than Ligand B (70.556), suggesting better metabolic stability.

**13. t1/2:** Ligand A (-11.066) has a more negative in vitro half-life, which is not good. Ligand B (-5.348) is also not ideal, but better than A.

**14. Pgp:** Ligand A (0.182) has lower P-gp efflux liability than Ligand B (0.283), which is favorable for CNS penetration.

**15. Binding Affinity:** Ligand A (-8.1) has a significantly stronger binding affinity than Ligand B (-7.6). A >1.5 kcal/mol advantage is considered substantial and can outweigh minor ADME drawbacks.

**Overall Assessment:**

Ligand A is superior to Ligand B. It has a better TPSA, lower DILI risk, better BBB penetration, lower microsomal clearance, lower P-gp efflux, and significantly stronger binding affinity. While both have poor Caco-2 and solubility, the superior binding affinity and CNS-relevant properties of Ligand A make it the more promising drug candidate. The negative in vitro half-life for Ligand A is a concern, but can be addressed through structural modifications.

Output:
1
2025-04-17 06:27:25,376 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (351.403 and 366.527 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (109.67) is higher than the ideal <90 for CNS targets, while Ligand B (58.64) is well within the desired range. This is a significant advantage for Ligand B.

**logP:** Ligand A (0.647) is a bit low, potentially hindering permeability. Ligand B (2.566) is within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A has 3 HBD and 5 HBA, which are acceptable. Ligand B has 1 HBD and 4 HBA, also acceptable.

**QED:** Both ligands have good QED scores (0.566 and 0.812), indicating drug-like properties.

**DILI:** Both ligands have low DILI risk (36.758 and 33.773), below the 40 threshold.

**BBB:** Ligand A (39.007) has a poor BBB percentile, which is a major drawback for a CNS target. Ligand B (60.411) is better, but ideally, we want >70.

**Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and suggests a potential issue with the data or modeling. However, comparing the absolute values, Ligand A (-5.618) is worse than Ligand B (-5.144).

**Aqueous Solubility:** Both have negative solubility values, again indicating a potential issue with the data. Ligand A (-1.41) is slightly better than Ligand B (-2.976).

**hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.044 and 0.31).

**Microsomal Clearance:** Ligand B (37.212) has a higher microsomal clearance than Ligand A (1.319), suggesting Ligand A is more metabolically stable.

**In vitro Half-Life:** Ligand A (23.446 hours) has a longer half-life than Ligand B (3.418 hours).

**P-gp Efflux:** Ligand A (0.01) has very low P-gp efflux, which is excellent for CNS penetration. Ligand B (0.108) is slightly higher, but still relatively low.

**Binding Affinity:** Ligand B (-8.1 kcal/mol) has a significantly stronger binding affinity than Ligand A (-7.0 kcal/mol). This >1.5 kcal/mol difference is substantial and can outweigh some ADME drawbacks.

**Overall Assessment:**

Ligand B is the stronger candidate despite some weaknesses. Its superior TPSA, logP, and, most importantly, binding affinity outweigh the slightly higher P-gp efflux and lower BBB penetration compared to Ligand A. Ligand A's poor BBB penetration is a critical flaw for a CNS target, and its lower affinity is a significant disadvantage. While Ligand B's BBB isn't ideal, it's considerably better than Ligand A's, and the strong binding affinity will likely drive efficacy. The longer half-life and better metabolic stability of Ligand A are positives, but not enough to overcome the other issues.

Output:
1
2025-04-17 06:27:25,377 - INFO - Batch 283 complete. Total preferences: 4528
2025-04-17 06:27:25,377 - INFO - Processing batch 284/512...
2025-04-17 06:28:06,812 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (349.435 Da) is slightly lower, which could be advantageous for permeability.

**2. TPSA:** Both are below the 140 A^2 threshold for oral absorption. However, for a CNS target like DRD2, we want <90 A^2. Ligand A (79.7 A^2) is better than Ligand B (83.78 A^2).

**3. logP:** Ligand A (-0.601) is a bit low, potentially hindering membrane permeability. Ligand B (2.128) is within the optimal 1-3 range. This is a significant advantage for Ligand B.

**4. H-Bond Donors:** Both have 1 HBD, which is acceptable.

**5. H-Bond Acceptors:** Both have 6 HBA, also acceptable.

**6. QED:** Both have good QED scores (>0.5), indicating drug-likeness. Ligand B (0.803) is slightly better.

**7. DILI:** Ligand A (35.479) has a much lower DILI risk than Ligand B (59.907). This is a substantial advantage for Ligand A.

**8. BBB:** Ligand B (49.477) has a better BBB penetration percentile than Ligand A (25.475). This is a critical factor for a CNS target.

**9. Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and suggests poor permeability. Ligand A (-4.921) is slightly better than Ligand B (-5.108).

**10. Aqueous Solubility:** Both have negative solubility values, which is also unusual and suggests poor solubility. Ligand A (-0.109) is slightly better than Ligand B (-2.046).

**11. hERG Inhibition:** Both have very low hERG inhibition risk.

**12. Microsomal Clearance:** Ligand A (-24.598) has significantly lower (better) microsomal clearance than Ligand B (17.043), indicating greater metabolic stability.

**13. In vitro Half-Life:** Ligand B (13.494 hours) has a longer half-life than Ligand A (7.995 hours).

**14. P-gp Efflux:** Both have very low P-gp efflux liability.

**15. Binding Affinity:** Both have the same binding affinity (-7.6 kcal/mol), which is excellent.

**Overall Assessment:**

Ligand B has advantages in BBB penetration, logP, QED, and in vitro half-life. However, Ligand A excels in DILI risk and microsomal clearance. The low logP and solubility of Ligand A are concerning, but the superior DILI profile and metabolic stability are valuable. The BBB penetration of Ligand B is a significant plus for a CNS target. Given the equal binding affinity, the better BBB penetration of Ligand B outweighs the slightly better ADME profile of Ligand A.

Output:
1
2025-04-17 06:28:06,812 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (337.467 Da) is slightly lower, which could be beneficial for permeability.

**2. TPSA:** Ligand A (45.23) is significantly better than Ligand B (62.99). For a CNS target like DRD2, TPSA < 90 is preferred, and A is comfortably within this range, while B is approaching the upper limit.

**3. logP:** Ligand A (4.325) is higher than the optimal range (1-3), potentially leading to solubility issues or off-target interactions. Ligand B (1.935) is within the optimal range.

**4. H-Bond Donors:** Ligand A (1) is good. Ligand B (0) is also acceptable.

**5. H-Bond Acceptors:** Ligand A (2) is good. Ligand B (4) is acceptable, but higher.

**6. QED:** Both ligands have good QED values (A: 0.903, B: 0.836), indicating generally drug-like properties.

**7. DILI:** Ligand A (39.705) has a slightly higher DILI risk than Ligand B (28.616), but both are below the concerning threshold of 60.

**8. BBB:** Both ligands have excellent BBB penetration (A: 81.466, B: 88.057), which is crucial for a CNS target. Ligand B is slightly better.

**9. Caco-2 Permeability:** Both have negative Caco-2 values which is unusual and likely indicates a problem with the prediction method. We can't rely on this data.

**10. Aqueous Solubility:** Both have negative solubility values, again indicating a problem with the prediction method. We can't rely on this data.

**11. hERG:** Ligand A (0.712) has a slightly higher hERG risk than Ligand B (0.545), but both are relatively low.

**12. Microsomal Clearance:** Ligand B (73.098) has a higher microsomal clearance than Ligand A (56.359), suggesting faster metabolism and potentially lower *in vivo* exposure.

**13. In vitro Half-Life:** Ligand B (21.108) has a significantly longer half-life than Ligand A (3.781), which is a major advantage.

**14. P-gp Efflux:** Ligand A (0.207) has lower P-gp efflux than Ligand B (0.288), which is favorable for CNS penetration.

**15. Binding Affinity:** Ligand B (-8.6 kcal/mol) has a slightly better binding affinity than Ligand A (-9.3 kcal/mol). While A has a slightly better affinity, the difference is small and other factors are more important.

**Overall Assessment:**

Considering the GPCR-specific priorities, Ligand B is the more promising candidate. While Ligand A has a slightly better binding affinity, Ligand B excels in key areas: better logP, lower microsomal clearance (longer half-life), and slightly better BBB penetration. The TPSA of Ligand A is also a concern. The slightly better P-gp efflux of Ligand A is outweighed by the other advantages of Ligand B.



Output:
1
2025-04-17 06:28:06,813 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (366.933 and 353.507 Da) fall within the ideal range of 200-500 Da.

**TPSA:** Ligand A (41.57) is excellent, well below the 90 A^2 threshold for CNS targets. Ligand B (72.88) is higher but still acceptable, though less optimal.

**logP:** Ligand A (4.509) is slightly high, potentially leading to solubility issues or off-target interactions. Ligand B (1.518) is quite low, potentially hindering membrane permeability.

**H-Bond Donors/Acceptors:** Ligand A (HBD=1, HBA=2) is favorable. Ligand B (HBD=2, HBA=4) is also reasonable.

**QED:** Both ligands have similar QED values (0.771 and 0.759), indicating good drug-like properties.

**DILI:** Ligand A (13.377) has a significantly lower DILI risk than Ligand B (8.104). This is a major advantage for Ligand A.

**BBB:** Ligand A (90.074) has excellent BBB penetration, exceeding the desirable >70 percentile. Ligand B (27.801) has very poor predicted BBB penetration, a critical drawback for a CNS target.

**Caco-2 Permeability:** Ligand A (-4.414) has poor Caco-2 permeability. Ligand B (-5.115) is even worse.

**Aqueous Solubility:** Ligand A (-4.791) has poor aqueous solubility, consistent with its high logP. Ligand B (-0.754) has slightly better solubility.

**hERG Inhibition:** Ligand A (0.89) has a moderate hERG risk, while Ligand B (0.318) has a very low risk.

**Microsomal Clearance:** Ligand A (58.59) has a higher microsomal clearance, suggesting faster metabolism. Ligand B (-5.844) has a negative clearance, which is unusual and likely indicates very high metabolic stability.

**In vitro Half-Life:** Ligand A (26.648) has a moderate half-life. Ligand B (20.74) is also moderate.

**P-gp Efflux:** Ligand A (0.489) has moderate P-gp efflux. Ligand B (0.021) has very low P-gp efflux, which is beneficial for CNS penetration.

**Binding Affinity:** Ligand A (-7.8) has a significantly stronger binding affinity than Ligand B (0.0). This is a substantial advantage, potentially outweighing some of its ADME drawbacks.

**Overall Assessment:**

Ligand A excels in binding affinity and BBB penetration, which are crucial for a CNS-targeting GPCR. While its logP is a bit high and solubility is low, the strong binding could compensate. Its DILI risk is also low. Ligand B has a better safety profile (hERG, DILI, Pgp) and slightly better solubility, but its extremely poor BBB penetration and very weak binding affinity make it a much less promising candidate. The difference in binding affinity is particularly significant.

Output:
1
2025-04-17 06:28:06,813 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (368.503 and 364.511 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (83.56) is better than Ligand B (58.64). For CNS targets, we want TPSA <= 90, both are within this range, but A is closer to the upper limit.

**logP:** Ligand B (2.138) is optimal (1-3), while Ligand A (0.665) is slightly low, potentially hindering permeation.

**H-Bond Donors/Acceptors:** Ligand A (2 HBD, 6 HBA) and Ligand B (1 HBD, 4 HBA) both have acceptable numbers of H-bond donors and acceptors.

**QED:** Both ligands have good QED scores (0.669 and 0.777, respectively), indicating drug-likeness.

**DILI:** Ligand A (29.236) has a slightly higher DILI risk than Ligand B (21.598), but both are below the concerning threshold of 60.

**BBB:** Ligand B (61.807) has a significantly better BBB penetration percentile than Ligand A (36.642). This is a *critical* factor for a CNS target like DRD2.

**Caco-2 Permeability:** Ligand A (-5.296) has a worse Caco-2 permeability than Ligand B (-4.923), indicating lower intestinal absorption.

**Aqueous Solubility:** Ligand A (-0.819) has worse aqueous solubility than Ligand B (-3.281).

**hERG Inhibition:** Both ligands show very low hERG inhibition liability (0.221 and 0.194).

**Microsomal Clearance:** Ligand A (-0.704) has a lower (better) microsomal clearance than Ligand B (29.181), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (7.009) has a longer half-life than Ligand B (0.429).

**P-gp Efflux:** Ligand A (0.013) has a much lower P-gp efflux liability than Ligand B (0.06), meaning it's less likely to be pumped out of the brain.

**Binding Affinity:** Ligand A (-7.7 kcal/mol) has a slightly better binding affinity than Ligand B (-7.3 kcal/mol). While both are excellent, the 0.4 kcal/mol difference is noteworthy.

**Overall Assessment:**

Ligand A has better affinity, metabolic stability (lower Cl_mic), longer half-life, and lower P-gp efflux. However, Ligand B excels in BBB penetration, logP, and has slightly better solubility. For a CNS target like DRD2, BBB penetration is paramount. While Ligand A's affinity is marginally better, the significant difference in BBB penetration and the acceptable logP of Ligand B outweigh this advantage. The lower P-gp efflux of A is a plus, but the BBB difference is more important.

Output:
1
2025-04-17 06:28:06,813 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (340.423 Da) is slightly lower than Ligand B (371.432 Da), which isn't a significant difference.

**TPSA:** Both ligands have TPSA values below the 90 A^2 threshold for CNS targets. Ligand A (69.64 A^2) is slightly higher than Ligand B (62.73 A^2), favoring B.

**logP:** Ligand A (2.274) is within the optimal range (1-3), while Ligand B (4.555) is higher. While higher logP can sometimes be tolerated, exceeding 4 increases the risk of off-target effects and solubility issues. This favors A.

**H-Bond Donors/Acceptors:** Both have acceptable HBD counts (2). Ligand B has a higher HBA count (6) compared to Ligand A (3), but both are within the acceptable limit of 10.

**QED:** Both ligands have QED values above 0.5 (A: 0.826, B: 0.78), indicating good drug-like properties.

**DILI:** Both ligands have relatively low DILI risk, but Ligand A (17.449%) is significantly lower than Ligand B (72.819%), which is a substantial advantage.

**BBB:** Both ligands have good BBB penetration (A: 71.074%, B: 77.937%), exceeding the 70% threshold for CNS targets. Ligand B is slightly better.

**Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and suggests poor permeability. This is a concern for both, but the values are similar.

**Aqueous Solubility:** Both have negative solubility values, which is also unusual and suggests poor solubility. Again, similar for both.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (A: 0.269, B: 0.486), which is good.

**Microsomal Clearance:** Ligand A (55.477 mL/min/kg) has lower clearance than Ligand B (68.199 mL/min/kg), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (-12.106 hours) has a negative half-life, which is impossible. This is a major red flag. Ligand B (31.288 hours) has a reasonable half-life.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (A: 0.063, B: 0.137), which is favorable for CNS penetration.

**Binding Affinity:** Ligand A (-9.0 kcal/mol) has significantly stronger binding affinity than Ligand B (-8.4 kcal/mol). This is a substantial advantage, potentially outweighing some ADME drawbacks.

**Overall Assessment:**

Despite Ligand A's superior binding affinity and lower DILI risk, the *negative* in vitro half-life is a critical flaw. A negative half-life is physically impossible and indicates a severe issue with the data or the molecule's stability. While Ligand B has a higher logP and DILI risk, its positive half-life and generally acceptable profile make it the more viable candidate.

Output:
1
2025-04-17 06:28:06,813 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (380.275) is slightly higher than Ligand B (353.463), but both are acceptable.

**TPSA:** Ligand A (61.44) is much better than Ligand B (98.74). For CNS targets, we want TPSA <= 90. Ligand A is well within this range, while Ligand B is close to the upper limit and less desirable.

**logP:** Ligand A (4.379) is a bit high, potentially leading to solubility issues or off-target interactions. Ligand B (0.417) is quite low, potentially hindering permeability. An optimal range is 1-3.

**H-Bond Donors/Acceptors:** Ligand A (HBD=2, HBA=3) is better than Ligand B (HBD=3, HBA=4). Both are within acceptable limits, but fewer H-bonds generally improve permeability.

**QED:** Ligand A (0.809) has a significantly better QED score than Ligand B (0.551), indicating a more drug-like profile.

**DILI:** Ligand A (73.401) has a higher DILI risk than Ligand B (8.647). This is a concern for Ligand A.

**BBB:** Ligand A (67.352) has a much better BBB penetration percentile than Ligand B (35.324). This is a critical factor for a CNS target like DRD2.

**Caco-2 Permeability:** Ligand A (-4.647) has a negative Caco-2 value, which is unusual and suggests poor permeability. Ligand B (-5.144) is also negative and similarly poor.

**Aqueous Solubility:** Ligand A (-5.48) has very poor solubility, consistent with its high logP. Ligand B (-1.309) also has poor solubility, but slightly better than Ligand A.

**hERG:** Ligand A (0.746) has a slightly higher hERG risk than Ligand B (0.205). Lower is better.

**Microsomal Clearance:** Ligand A (30.982) has a higher microsomal clearance than Ligand B (15.801), indicating faster metabolism and potentially lower *in vivo* exposure.

**In vitro Half-Life:** Ligand A (100.592) has a significantly longer half-life than Ligand B (-18.375). This is a major advantage for Ligand A.

**P-gp Efflux:** Ligand A (0.318) has lower P-gp efflux liability than Ligand B (0.035), which is favorable for CNS penetration.

**Binding Affinity:** Ligand A (-8.5 kcal/mol) has a significantly stronger binding affinity than Ligand B (-7.3 kcal/mol). This is a substantial advantage, potentially outweighing some of the ADME concerns.

**Overall Assessment:**

Ligand A has a much stronger binding affinity and better BBB penetration, which are critical for a CNS GPCR target. It also has a better QED and longer half-life. However, it suffers from higher DILI risk, poor solubility, and potentially problematic logP. Ligand B has better DILI and hERG profiles, but its weak affinity, poor BBB penetration, and lower QED make it a less attractive candidate. The substantial affinity difference (-1.2 kcal/mol) and the BBB advantage of Ligand A are likely to be decisive. While the DILI risk is a concern, it could be addressed through structural modifications.

Output:
1
2025-04-17 06:28:06,813 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (352.435 and 345.443 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (87.91) is better than Ligand B (69.72) as it is closer to the ideal range of <90 for CNS targets.

**logP:** Both ligands have good logP values (1.935 and 0.944), falling within the optimal 1-3 range. Ligand A is slightly better.

**H-Bond Donors/Acceptors:** Both have 1 HBD, which is good. Ligand A has 6 HBA, while Ligand B has 3. Both are acceptable (<=10).

**QED:** Ligand A (0.833) is significantly better than Ligand B (0.384), indicating a more drug-like profile.

**DILI:** Ligand A (52.423) has a slightly higher DILI risk than Ligand B (29.081), but both are below the concerning threshold of 60.

**BBB:** Ligand A (76.464) has a significantly better BBB penetration percentile than Ligand B (54.944). This is a crucial factor for a CNS target like DRD2.

**Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and suggests poor permeability. However, the scale is not specified, so it's difficult to interpret.

**Aqueous Solubility:** Both have negative solubility values, indicating poor solubility.

**hERG Inhibition:** Both ligands show very low hERG inhibition risk (0.343 and 0.098).

**Microsomal Clearance:** Ligand A (78.851) has a higher microsomal clearance than Ligand B (27.597), suggesting lower metabolic stability.

**In vitro Half-Life:** Ligand B (-29.763) has a much longer in vitro half-life than Ligand A (-12.297).

**P-gp Efflux:** Both have very low P-gp efflux liability (0.036 and 0.014).

**Binding Affinity:** Ligand A (-7.9 kcal/mol) has a slightly better binding affinity than Ligand B (-7.4 kcal/mol), but the difference is relatively small.

**Overall Assessment:**

Considering the GPCR-specific priorities, Ligand A is the better candidate. Its superior BBB penetration (76.464 vs 54.944) and QED score (0.833 vs 0.384) are significant advantages for a CNS-targeting drug. While Ligand A has a higher DILI risk and lower metabolic stability, the difference in binding affinity is small, and the BBB and QED advantages outweigh these drawbacks.

Output:
1
2025-04-17 06:28:06,814 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (349.391 and 350.369 Da) fall comfortably within the ideal 200-500 Da range.

**TPSA:** Ligand A (118.37) is higher than Ligand B (86.88). For CNS targets, TPSA should be <= 90, so Ligand B is preferable.

**logP:** Ligand A (0.583) is quite low, potentially hindering membrane permeability. Ligand B (2.067) is within the optimal 1-3 range. This is a significant advantage for Ligand B.

**H-Bond Donors/Acceptors:** Both have 3 HBDs, which is acceptable. Ligand A has 7 HBAs, while Ligand B has 3. Lower HBA counts generally improve permeability, favoring Ligand B.

**QED:** Both ligands have acceptable QED values (0.687 and 0.745), indicating good drug-like properties.

**DILI:** Both ligands have relatively high DILI risk (65.917 and 70.803), but are still within a range that isn't immediately disqualifying.

**BBB:** Ligand A (63.862) and Ligand B (59.093) are both below the desirable >70 percentile for CNS targets. However, this is less critical if other properties are favorable.

**Caco-2 Permeability:** Both have negative Caco-2 values (-4.877 and -5.123), which is unusual and suggests poor permeability. This is a concern for both, but the values are similar.

**Aqueous Solubility:** Both have negative solubility values (-2.789 and -3.193), which is also unusual. This suggests poor solubility, potentially hindering bioavailability.

**hERG:** Both ligands show very low hERG inhibition risk (0.098 and 0.432), which is excellent.

**Microsomal Clearance:** Ligand A (42.656) has higher clearance than Ligand B (32.016), indicating lower metabolic stability. Ligand B is preferred.

**In vitro Half-Life:** Ligand B (-11.497) has a negative half-life, which is impossible and indicates a data error or unusual behavior. Ligand A (21.546) has a reasonable half-life.

**P-gp Efflux:** Ligand A (0.033) has very low P-gp efflux, which is excellent for CNS penetration. Ligand B (0.091) also has low P-gp efflux, but slightly higher.

**Binding Affinity:** Ligand B (-8.8 kcal/mol) has a significantly stronger binding affinity than Ligand A (-7.5 kcal/mol). This >1.5 kcal/mol difference is a major advantage, potentially outweighing some ADME drawbacks.

**Overall Assessment:**

Despite both ligands having issues with Caco-2 and solubility, Ligand B is significantly better. It has a more favorable logP, lower TPSA, lower microsomal clearance, and, crucially, a much stronger binding affinity. The negative half-life for Ligand B is a major red flag, but the substantial affinity advantage makes it worth further investigation to determine if the half-life value is an error. Ligand A's low logP is a significant drawback for a CNS target.



Output:
1
2025-04-17 06:28:06,814 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (339.439 Da) is slightly lower, which could be beneficial for permeability, while Ligand B (350.463 Da) is also good.

**TPSA:** Ligand A (47.36) is excellent, well below the 90 Angstroms threshold for CNS targets. Ligand B (85.77) is higher but still potentially acceptable, though less ideal.

**logP:** Ligand A (3.291) is optimal. Ligand B (0.533) is quite low, which raises concerns about membrane permeability and potentially bioavailability.

**H-Bond Donors/Acceptors:** Ligand A (0 HBD, 4 HBA) is favorable. Ligand B (2 HBD, 5 HBA) is also within acceptable limits.

**QED:** Both ligands have reasonable QED values (A: 0.862, B: 0.679), indicating good drug-like properties.

**DILI:** Ligand A (53.742) has a moderate DILI risk, while Ligand B (19.659) has a very low risk.

**BBB:** Ligand A (83.443) has a very good BBB penetration score, highly desirable for a CNS target. Ligand B (33.501) has a poor BBB score, a significant drawback.

**Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and suggests potential issues with the prediction method or the compounds themselves. However, the magnitude of negativity is similar.

**Aqueous Solubility:** Both have negative solubility values, again unusual and potentially problematic. The values are similar in magnitude.

**hERG:** Both ligands have low hERG inhibition liability (A: 0.273, B: 0.264).

**Microsomal Clearance:** Ligand A (45.693) and Ligand B (40.879) have similar and relatively moderate microsomal clearance values.

**In vitro Half-Life:** Ligand A (10.122 hours) has a better in vitro half-life than Ligand B (24.858 hours).

**P-gp Efflux:** Both ligands have low P-gp efflux liability (A: 0.514, B: 0.032). Ligand B is slightly better.

**Binding Affinity:** Ligand A (-9.5 kcal/mol) has a significantly stronger binding affinity than Ligand B (-7.0 kcal/mol). This is a substantial advantage.

**Overall Assessment:**

Ligand A is the stronger candidate. Its superior BBB penetration, optimal logP, and significantly higher binding affinity outweigh its slightly higher DILI risk. The lower TPSA is also beneficial for CNS penetration. While both have unusual solubility and Caco-2 values, the difference in affinity and BBB is decisive. Ligand B's low logP and poor BBB penetration are major liabilities for a CNS-targeting drug.

Output:
1
2025-04-17 06:28:06,814 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (396.843 and 378.519 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (84.5) is better than Ligand B (66.48). Both are below the 90 A^2 threshold for CNS targets, which is excellent.

**logP:** Both ligands have good logP values (2.735 and 3.241), falling within the optimal 1-3 range. Ligand B is slightly higher, potentially increasing permeability but also slightly increasing the risk of off-target effects.

**H-Bond Donors/Acceptors:** Ligand A has 2 HBD and 4 HBA, while Ligand B has 1 HBD and 4 HBA. Both are within acceptable limits (<=5 HBD and <=10 HBA).

**QED:** Both ligands have high QED scores (0.801 and 0.888), indicating good drug-like properties.

**DILI:** Ligand A (69.523) has a slightly higher DILI risk than Ligand B (60.062), but both are reasonably acceptable.

**BBB:** Ligand B (89.531) has a significantly better BBB penetration score than Ligand A (70.648). This is a critical advantage for a CNS target like DRD2.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.947 and -5.032), which is unusual and suggests poor permeability. However, these values are on a log scale, and the negative values indicate very low permeability.

**Aqueous Solubility:** Both ligands have very poor aqueous solubility (-3.94 and -3.826). This is a significant drawback.

**hERG Inhibition:** Ligand A (0.27) has a lower hERG inhibition liability than Ligand B (0.635), which is preferable.

**Microsomal Clearance:** Both ligands have similar microsomal clearance rates (-4.03 and -26.241).

**In vitro Half-Life:** Ligand B (32.716) has a longer in vitro half-life than Ligand A (26.488), which is a positive attribute.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.174 and 0.513).

**Binding Affinity:** Ligand B (-9.3 kcal/mol) has a stronger binding affinity than Ligand A (-8.8 kcal/mol). This difference of 0.5 kcal/mol is substantial and can outweigh some of the other drawbacks.

**Overall Assessment:**

While both ligands have issues with solubility and Caco-2 permeability, Ligand B is the more promising candidate. Its significantly better BBB penetration (89.531 vs 70.648) and stronger binding affinity (-9.3 vs -8.8 kcal/mol) are crucial advantages for a CNS-targeting GPCR. The slightly better half-life and lower DILI risk also contribute to its favorability. The slightly higher hERG risk is a concern, but potentially manageable.

Output:
1
2025-04-17 06:28:06,814 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (348.45 & 366.50 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (93.21) is slightly above the preferred <90 for CNS targets, but still reasonable. Ligand B (49.41) is excellent, well below 90.

**logP:** Ligand A (1.61) is within the optimal 1-3 range. Ligand B (3.78) is at the higher end of optimal, but still acceptable.

**H-Bond Donors/Acceptors:** Ligand A has 2 HBD and 5 HBA, both acceptable. Ligand B has 1 HBD and 3 HBA, also acceptable.

**QED:** Both ligands have good QED scores (0.815 and 0.862), indicating good drug-like properties.

**DILI:** Both ligands have low DILI risk (52.42 & 41.41), well below the 60 threshold.

**BBB:** This is a crucial parameter for CNS targets. Ligand A has a BBB percentile of 41.22, which is below the desirable >70. Ligand B has a significantly better BBB percentile of 95.35, making it much more likely to reach the target in the brain.

**Caco-2 Permeability:** Both have negative Caco-2 values (-5.234 and -5.084), which is unusual and suggests poor permeability. This is a significant concern for both.

**Aqueous Solubility:** Both ligands have poor aqueous solubility (-2.28 and -4.028). This could pose formulation challenges.

**hERG Inhibition:** Ligand A (0.068) has very low hERG risk. Ligand B (0.778) has slightly higher, but still relatively low, hERG risk.

**Microsomal Clearance:** Ligand A (28.30) and Ligand B (24.53) both have relatively low microsomal clearance, suggesting reasonable metabolic stability.

**In vitro Half-Life:** Ligand A (3.093) has a short half-life. Ligand B (-1.102) has a negative half-life, which is not physically meaningful and suggests a potential issue with the data or model.

**P-gp Efflux:** Ligand A (0.01) has very low P-gp efflux, which is excellent. Ligand B (0.543) has moderate P-gp efflux.

**Binding Affinity:** Ligand B (-7.8 kcal/mol) has a slightly better binding affinity than Ligand A (-8.1 kcal/mol). While the difference is small, it's still a positive factor.

**Overall Assessment:**

Ligand B is the more promising candidate. Its significantly higher BBB penetration (95.35 vs 41.22) is the most important factor given the CNS target. While both have issues with Caco-2 permeability and solubility, the better BBB and slightly improved affinity of Ligand B outweigh the minor drawbacks. The negative half-life for Ligand B is concerning and would need further investigation, but the other factors strongly favor it.

Output:
1
2025-04-17 06:28:06,815 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (342.443 and 345.443 Da) fall comfortably within the ideal 200-500 Da range.

**TPSA:** Ligand A (71.26) is significantly better than Ligand B (88.16). For CNS targets, we want TPSA <= 90, and A is closer to the optimal <= 60 range. B is pushing the upper limit.

**logP:** Both ligands have good logP values (3.036 and 2.476), falling within the 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A (1 HBD, 5 HBA) is slightly better than Ligand B (2 HBD, 4 HBA) in terms of balancing solubility and permeability. Both are within acceptable limits.

**QED:** Both ligands have reasonable QED scores (0.874 and 0.775), indicating good drug-like properties.

**DILI:** Ligand A (31.059) has a much lower DILI risk than Ligand B (48.623). Both are below the 60 threshold, but A is preferred.

**BBB:** Both ligands have good BBB penetration (78.17% and 73.943%), exceeding the 70% threshold for CNS targets. Ligand A is slightly better.

**Caco-2 Permeability:** Ligand A (-4.844) has slightly better Caco-2 permeability than Ligand B (-4.464). Higher values are better.

**Aqueous Solubility:** Ligand A (-2.866) has slightly better solubility than Ligand B (-3.488). Higher values are better.

**hERG Inhibition:** Ligand A (0.444) has a lower hERG inhibition liability than Ligand B (0.161), indicating a lower risk of cardiotoxicity. Lower values are better.

**Microsomal Clearance:** Ligand A (25.213) has significantly lower microsomal clearance than Ligand B (54.915), suggesting better metabolic stability. Lower values are better.

**In vitro Half-Life:** Ligand A (-1.308) has a better in vitro half-life than Ligand B (-16.051). Higher values are better.

**P-gp Efflux:** Ligand A (0.12) has lower P-gp efflux liability than Ligand B (0.038). Lower values are better, especially for CNS targets.

**Binding Affinity:** Both ligands have very similar and excellent binding affinities (-8.5 kcal/mol and -8.3 kcal/mol). The difference is less than 1.5 kcal/mol, so this isn't a deciding factor.

**Overall Assessment:**

Ligand A consistently outperforms Ligand B across most ADME-Tox properties. It has a lower DILI risk, better metabolic stability (lower Cl_mic, better t1/2), lower P-gp efflux, and slightly better BBB penetration, solubility, and Caco-2 permeability. While both have good affinities and acceptable logP/TPSA values, the superior ADME profile of Ligand A makes it the more promising drug candidate.

Output:
0
2025-04-17 06:28:06,815 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (348.447 and 352.41 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (85.25) is significantly better than Ligand B (104.21). For CNS targets, we want TPSA <= 90, so Ligand A is preferable.

**3. logP:** Both ligands have good logP values (1.425 and 1.794), falling within the optimal range of 1-3.

**4. H-Bond Donors:** Ligand A (2) is better than Ligand B (3). Lower is generally preferred.

**5. H-Bond Acceptors:** Ligand A (6) is better than Ligand B (5). Both are acceptable, but lower is slightly favored.

**6. QED:** Both ligands have acceptable QED values (0.76 and 0.677), indicating good drug-like properties.

**7. DILI:** Ligand A (34.626) has a significantly lower DILI risk than Ligand B (51.648). Both are below 60, but A is much safer.

**8. BBB:** Ligand A (68.786) has a better BBB penetration percentile than Ligand B (51.725). While both are below the ideal >70, A is closer. This is a crucial factor for a CNS target like DRD2.

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.835 and -4.795). This is unusual and suggests poor permeability. However, the values are very similar.

**10. Aqueous Solubility:** Ligand A (-1.623) is better than Ligand B (-3.043). Higher solubility is preferred.

**11. hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.114 and 0.117).

**12. Microsomal Clearance:** Ligand A (65.299) has higher microsomal clearance than Ligand B (39.04). Lower clearance is better for metabolic stability, favoring Ligand B.

**13. In vitro Half-Life:** Ligand B (-28.775) has a much longer in vitro half-life than Ligand A (11.863). This is a significant advantage for Ligand B.

**14. P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.031 and 0.01).

**15. Binding Affinity:** Ligand A (-7.9) has a slightly better binding affinity than Ligand B (-7.4). A difference of 0.5 kcal/mol is meaningful.

**Overall Assessment:**

Ligand A excels in TPSA, DILI, BBB, solubility, and binding affinity. Ligand B has better metabolic stability (lower Cl_mic) and a longer half-life. Considering the GPCR-specific priorities, BBB penetration is critical for CNS targets. Ligand A's better BBB score, combined with its superior binding affinity and lower DILI risk, outweigh the benefits of Ligand B's improved metabolic stability. The similar Caco-2 values are concerning for both, but the stronger binding and CNS penetration potential of A are more important.

Output:
1
2025-04-17 06:28:06,815 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (345.447 and 346.515 Da) fall comfortably within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (88.91) is excellent, falling well below the 90 A^2 threshold for CNS targets. Ligand B (49.41) is also very good, well below the threshold.

**3. logP:** Ligand A (1.467) is within the optimal 1-3 range. Ligand B (3.665) is at the higher end of optimal, but still acceptable.

**4. H-Bond Donors:** Ligand A (2) and Ligand B (1) are both within the acceptable limit of <=5.

**5. H-Bond Acceptors:** Ligand A (5) and Ligand B (2) are both within the acceptable limit of <=10.

**6. QED:** Ligand A (0.817) has a very strong drug-like profile. Ligand B (0.538) is acceptable, but less ideal.

**7. DILI:** Both ligands have low DILI risk (Ligand A: 32.067, Ligand B: 28.577), both well below the 40 threshold.

**8. BBB:** Both ligands show good BBB penetration (Ligand A: 50.097, Ligand B: 55.176). While >70 is desirable, these are reasonable starting points, and further optimization could improve this.

**9. Caco-2 Permeability:** Ligand A (-5.396) has poor Caco-2 permeability. Ligand B (-4.72) also has poor Caco-2 permeability.

**10. Aqueous Solubility:** Both ligands have very poor aqueous solubility (Ligand A: -2.012, Ligand B: -4.278). This is a significant concern.

**11. hERG Inhibition:** Both ligands show very low hERG inhibition risk (Ligand A: 0.078, Ligand B: 0.224).

**12. Microsomal Clearance:** Ligand A (11.63) has lower microsomal clearance, suggesting better metabolic stability than Ligand B (63.35).

**13. In vitro Half-Life:** Ligand A (12.312) has a better in vitro half-life than Ligand B (15.849).

**14. P-gp Efflux:** Both ligands have very low P-gp efflux liability (Ligand A: 0.011, Ligand B: 0.534).

**15. Binding Affinity:** Ligand A (-8.4 kcal/mol) has significantly stronger binding affinity than Ligand B (-0.0 kcal/mol). This is a major advantage.

**Overall Assessment:**

Ligand A is the superior candidate. While both have poor solubility and Caco-2 permeability, Ligand A's dramatically stronger binding affinity (-8.4 vs -0.0 kcal/mol) outweighs these drawbacks. The better metabolic stability (lower Cl_mic, longer t1/2), higher QED, and acceptable BBB penetration further support this conclusion. The poor solubility and permeability would need to be addressed in further optimization, but the strong affinity provides a solid foundation. Ligand B's affinity is simply too weak to be a viable starting point, even with slightly better permeability.

Output:
1
2025-04-17 06:28:06,815 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (355.523 and 340.446 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (64.09) is better than Ligand B (49.84) as it is closer to the ideal range for CNS targets (<=90).

**logP:** Ligand A (1.429) is optimal (1-3), while Ligand B (4.432) is high, potentially leading to solubility issues and off-target interactions.

**H-Bond Donors/Acceptors:** Both ligands have acceptable HBD (1 & 2) and HBA (4 & 4) counts.

**QED:** Both ligands have identical QED scores (0.783), indicating good drug-likeness.

**DILI:** Ligand A (15.161) has a significantly lower DILI risk than Ligand B (40.093), which is already approaching a moderate risk.

**BBB:** Ligand B (80.07) has a much better BBB penetration percentile than Ligand A (48.391). This is a critical factor for a CNS target like DRD2.

**Caco-2 Permeability:** Ligand A (-4.559) and Ligand B (-4.921) both have negative values, indicating poor permeability.

**Aqueous Solubility:** Ligand A (-0.593) is better than Ligand B (-4.812) in terms of solubility.

**hERG Inhibition:** Ligand A (0.425) has a lower hERG inhibition liability than Ligand B (0.904), which is preferable.

**Microsomal Clearance:** Ligand A (20.782) has a lower microsomal clearance than Ligand B (55.466), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand B (60.161) has a significantly longer in vitro half-life than Ligand A (3.823).

**P-gp Efflux:** Ligand A (0.06) has much lower P-gp efflux liability than Ligand B (0.593), which is beneficial for CNS exposure.

**Binding Affinity:** Ligand B (-9.8 kcal/mol) has a significantly stronger binding affinity than Ligand A (-6.7 kcal/mol). This is a substantial advantage.

**Overall Assessment:**

Ligand B excels in BBB penetration and binding affinity, which are crucial for a CNS GPCR target. However, it suffers from a high logP, moderate DILI risk, and higher P-gp efflux. Ligand A has better ADME properties (lower logP, DILI, P-gp, better solubility, lower clearance) but significantly weaker binding affinity and poorer BBB penetration.

The difference in binding affinity (-9.8 vs -6.7 kcal/mol) is substantial (a difference of 3.1 kcal/mol). This is likely to outweigh the ADME drawbacks of Ligand B, especially considering that ADME properties can be further optimized. The strong binding affinity suggests a higher probability of achieving efficacy at a reasonable dose.

Output:
1
2025-04-17 06:28:06,815 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (344.434 Da) is slightly lower, which is generally favorable for permeability. Ligand B (362.455 Da) is also good.

**TPSA:** Ligand A (58.95) is excellent, well below the 90 A^2 threshold for CNS targets. Ligand B (76.46) is still reasonable but less optimal.

**logP:** Ligand A (2.337) is within the optimal range (1-3). Ligand B (0.186) is quite low, potentially hindering permeation and CNS entry.

**H-Bond Donors/Acceptors:** Ligand A (HBD=2, HBA=4) and Ligand B (HBD=1, HBA=6) both have acceptable numbers of H-bond donors and acceptors.

**QED:** Both ligands have similar and good QED values (A: 0.846, B: 0.827), indicating good drug-like properties.

**DILI:** Both ligands have acceptable DILI risk (A: 43.389, B: 49.593), below the 60 threshold.

**BBB:** This is a critical parameter for a CNS target like DRD2. Ligand A has a significantly better BBB percentile (79.217) compared to Ligand B (56.495).

**Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and suggests a problem with the prediction method or the molecules themselves. However, we can still compare them. Ligand A (-5.334) is slightly better than Ligand B (-5.183).

**Aqueous Solubility:** Both have negative solubility values, again suggesting a problem with the prediction. Ligand A (-2.352) is slightly better than Ligand B (-2.277).

**hERG Inhibition:** Ligand A (0.899) has a slightly higher hERG risk than Ligand B (0.036), but both are relatively low.

**Microsomal Clearance:** Ligand A (-1.17) has a lower (better) microsomal clearance than Ligand B (26.499), indicating better metabolic stability.

**In vitro Half-Life:** Ligand A (23.901) has a significantly longer in vitro half-life than Ligand B (16.382).

**P-gp Efflux:** Ligand A (0.497) has a lower P-gp efflux liability than Ligand B (0.015), which is favorable for CNS penetration.

**Binding Affinity:** Ligand B (-7.1) has a substantially stronger binding affinity than Ligand A (-0.0). This is a major advantage.

**Overall Assessment:**

Ligand B has a significantly better binding affinity, which is a huge plus. However, its low logP and poor BBB penetration are major concerns for a CNS target. Ligand A, while having a weaker binding affinity, exhibits much better physicochemical properties for CNS penetration (TPSA, logP, BBB, P-gp efflux) and metabolic stability. The difference in binding affinity (7.1 vs 0.0) is substantial, but the ADME properties of Ligand A are far more favorable for a CNS-active drug. Given the GPCR-specific priorities, and the importance of BBB penetration for DRD2, I believe Ligand A is the more viable candidate, despite its weaker binding. Further optimization of Ligand A to improve its binding affinity would be a promising strategy.

Output:
0
2025-04-17 06:28:06,816 - INFO - Batch 284 complete. Total preferences: 4544
2025-04-17 06:28:06,816 - INFO - Processing batch 285/512...
2025-04-17 06:28:48,705 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (418.253 Da) is slightly higher, but acceptable. Ligand B (343.45 Da) is also good.

**2. TPSA:**  Ligand A (32.7) is excellent, well below the 90 A^2 threshold for CNS targets. Ligand B (55.63) is still reasonable, but less optimal, being closer to the 140 A^2 threshold for oral absorption.

**3. logP:** Both ligands have a logP around 4.2, which is slightly above the optimal range of 1-3. This could potentially lead to solubility issues or off-target interactions, but is not a dealbreaker.

**4. H-Bond Donors:** Both have 1 HBD, which is within the acceptable limit of <=5.

**5. H-Bond Acceptors:** Ligand A has 3 HBAs, and Ligand B has 5 HBAs, both within the acceptable limit of <=10.

**6. QED:** Both ligands have good QED scores (A: 0.728, B: 0.903), indicating good drug-like properties.

**7. DILI:** Ligand A (35.905) has a lower DILI risk than Ligand B (49.283), which is preferable. Both are below the concerning threshold of 60.

**8. BBB:** Ligand B (88.174) has a significantly better BBB penetration percentile than Ligand A (71.811). This is a *critical* advantage for a CNS target like DRD2.

**9. Caco-2 Permeability:** Both have negative Caco-2 values, indicating poor permeability. This is a concern for both, but the negative value for Ligand A (-4.425) is worse than Ligand B (-4.907).

**10. Aqueous Solubility:** Both ligands have negative solubility values, indicating poor solubility. The value for Ligand A (-3.775) is slightly better than Ligand B (-4.618).

**11. hERG Inhibition:** Both ligands have low hERG inhibition risk (A: 0.965, B: 0.491), which is positive. Ligand B is slightly better.

**12. Microsomal Clearance:** Ligand A (41.155) has slightly lower microsomal clearance than Ligand B (46.825), suggesting better metabolic stability.

**13. In vitro Half-Life:** Ligand A (51.212) has a longer in vitro half-life than Ligand B (34.267), which is desirable.

**14. P-gp Efflux:** Ligand A (0.867) has lower P-gp efflux than Ligand B (0.604), which is beneficial for CNS exposure.

**15. Binding Affinity:** Both ligands have very similar and strong binding affinities (A: -8.5 kcal/mol, B: -8.2 kcal/mol). The difference of 0.3 kcal/mol is unlikely to be decisive.

**Overall Assessment:**

While Ligand A has some advantages in terms of metabolic stability (lower Cl_mic, longer t1/2) and DILI risk, Ligand B's *significantly* higher BBB penetration (88.174 vs 71.811) is the deciding factor for a CNS target like DRD2. The slightly better hERG profile of Ligand B is also a minor positive. The poor Caco-2 and solubility are concerns for both, but can be addressed through formulation strategies.

Output:
1
2025-04-17 06:28:48,705 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 drug candidates, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (353.438 and 357.479 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (64.09) is significantly better than Ligand B (71.09). For CNS targets, TPSA should be <= 90, both are within this range, but A is closer to the optimal range.

**3. logP:** Ligand A (0.249) is quite low, potentially hindering permeability. Ligand B (3.056) is within the optimal 1-3 range. This is a significant advantage for B.

**4. H-Bond Donors:** Ligand A (1) is good. Ligand B (2) is acceptable.

**5. H-Bond Acceptors:** Both ligands (A: 4, B: 4) are within the acceptable limit of <= 10.

**6. QED:** Both ligands have similar and good QED values (A: 0.787, B: 0.799), indicating drug-likeness.

**7. DILI:** Ligand A (8.143) has a much lower DILI risk than Ligand B (59.287). This is a substantial advantage for A.

**8. BBB:** Both ligands have comparable BBB penetration (A: 68.36, B: 68.554). Neither exceeds the desirable >70 threshold, but they are reasonably close.

**9. Caco-2 Permeability:** Both have negative Caco-2 values (-4.819 and -4.968), which is unusual and suggests poor permeability. This is a concern for both.

**10. Aqueous Solubility:** Both ligands have negative solubility values (-0.823 and -4.585), indicating poor solubility. This is a significant drawback for both.

**11. hERG Inhibition:** Both ligands have low hERG inhibition risk (A: 0.521, B: 0.626).

**12. Microsomal Clearance:** Ligand A (7.647) has lower clearance than Ligand B (65.218), suggesting better metabolic stability.

**13. In vitro Half-Life:** Ligand B (4.817) has a slightly longer half-life than Ligand A (3.542).

**14. P-gp Efflux:** Ligand A (0.031) has significantly lower P-gp efflux liability than Ligand B (0.251), which is crucial for CNS penetration.

**15. Binding Affinity:** Ligand B (-9.5 kcal/mol) has a significantly stronger binding affinity than Ligand A (-7.8 kcal/mol). This is a >1.5 kcal/mol difference, which is a major advantage for B and can potentially outweigh some ADME drawbacks.

**Overall Assessment:**

Ligand B has a superior binding affinity and a more favorable logP value. However, Ligand A has a much lower DILI risk, lower P-gp efflux, and better metabolic stability. Both have poor solubility and permeability. Considering the GPCR-specific priorities, the strong binding affinity of Ligand B is a critical factor. While the lower logP of Ligand A is concerning, the significant difference in binding affinity (-9.5 vs -7.8 kcal/mol) is likely to be more impactful, especially given the relatively similar BBB values. The lower DILI and P-gp efflux of Ligand A are beneficial, but the potency advantage of B is substantial.

Output:
1
2025-04-17 06:28:48,705 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (350.547 and 350.419 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (50.36) is significantly better than Ligand B (87.91). For CNS targets, TPSA < 90 is preferred, and A is comfortably within that, while B is approaching the upper limit.

**logP:** Ligand A (4.345) is higher than the optimal 1-3 range, but still potentially acceptable. Ligand B (0.461) is *below* 1, which is concerning for membrane permeability and CNS penetration.

**H-Bond Donors/Acceptors:** Ligand A (2 HBD, 2 HBA) is well within acceptable limits. Ligand B (1 HBD, 6 HBA) is also acceptable, but the higher HBA count could slightly hinder permeability.

**QED:** Both ligands have good QED scores (0.748 and 0.83), indicating good drug-like properties.

**DILI:** Ligand A (23.846) has a much lower DILI risk than Ligand B (38.736), which is a significant advantage. Both are below the concerning threshold of 60.

**BBB:** Ligand A (85.459) has excellent BBB penetration, exceeding the desirable >70% threshold for CNS targets. Ligand B (55.138) is considerably lower, raising concerns about reaching the target in the brain.

**Caco-2 Permeability:** Both have negative Caco-2 values (-4.667 and -4.776), which is unusual and suggests poor permeability. However, these values are on a log scale and can be difficult to interpret directly.

**Aqueous Solubility:** Both ligands have very poor aqueous solubility (-4.363 and -1.322). This could pose formulation challenges.

**hERG Inhibition:** Both ligands show low hERG inhibition risk (0.67 and 0.265).

**Microsomal Clearance:** Ligand A (62.285) has a higher clearance than Ligand B (0.43), suggesting lower metabolic stability. However, the units for Ligand A are mL/min/kg, while for Ligand B it is a percentile, making direct comparison difficult.

**In vitro Half-Life:** Ligand A (24.77 hours) has a better in vitro half-life than Ligand B (12.193 hours).

**P-gp Efflux:** Ligand A (0.195) has lower P-gp efflux liability than Ligand B (0.026), which is favorable for CNS penetration.

**Binding Affinity:** Both ligands have excellent binding affinities (-8.9 and -8.2 kcal/mol), well below the -7.0 kcal/mol threshold. Ligand A is slightly better (-8.9 vs -8.2).

**Overall Assessment:**

Considering the GPCR-specific priorities, Ligand A is significantly more promising. Its superior BBB penetration, lower DILI risk, and lower P-gp efflux are crucial for a CNS-targeting drug. While its logP is slightly high and clearance is higher, the substantial advantage in BBB penetration and safety outweighs these concerns. Ligand B's low logP and poor BBB penetration are major drawbacks. The binding affinity difference is relatively small and doesn't compensate for the ADME deficiencies of Ligand B.

Output:
0
2025-04-17 06:28:48,705 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (386.901 and 386.543 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (86.71) is better than Ligand B (91.4). Both are below the 90 A^2 threshold desirable for CNS targets.

**logP:** Ligand A (1.391) is better than Ligand B (0.596). Both are within the optimal 1-3 range, but Ligand B is closer to the lower limit, potentially hindering permeation.

**H-Bond Donors:** Both ligands have 2 HBD, which is within the acceptable limit of <=5.

**H-Bond Acceptors:** Ligand A has 4 HBA, while Ligand B has 6. Both are below the 10 threshold, but Ligand A is preferable.

**QED:** Ligand A (0.749) is better than Ligand B (0.575). Ligand A is significantly more drug-like.

**DILI:** Ligand B (35.052) has a lower DILI risk than Ligand A (43.66), which is favorable.

**BBB:** Ligand B (52.268) has a slightly better BBB penetration percentile than Ligand A (48.972). Both are below the desirable >70 for CNS targets, but B is closer.

**Caco-2 Permeability:** Ligand A (-5.191) has better Caco-2 permeability than Ligand B (-5.716). Higher values are better.

**Aqueous Solubility:** Ligand A (-3.427) has better aqueous solubility than Ligand B (-1.595). Higher values are better.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.495 and 0.37, respectively).

**Microsomal Clearance:** Ligand B (3.619) has significantly lower microsomal clearance than Ligand A (42.27), indicating better metabolic stability.

**In vitro Half-Life:** Ligand B (-19.725) has a significantly longer in vitro half-life than Ligand A (-37.088).

**P-gp Efflux:** Ligand A (0.283) has lower P-gp efflux than Ligand B (0.023), which is favorable for CNS exposure.

**Binding Affinity:** Ligand A (-8.5 kcal/mol) has a significantly stronger binding affinity than Ligand B (-7.2 kcal/mol). This is a substantial advantage, exceeding the 1.5 kcal/mol threshold.

**Overall Assessment:**

Ligand A excels in binding affinity, solubility, Caco-2 permeability, TPSA, HBA, and QED. However, Ligand B demonstrates advantages in DILI risk, BBB penetration, metabolic stability (lower Cl_mic and longer t1/2), and P-gp efflux. The difference in binding affinity is substantial (-8.5 vs -7.2 kcal/mol), and in the context of a GPCR target, this difference is likely to outweigh the slightly less favorable BBB and metabolic properties of Ligand A. The better solubility and permeability of Ligand A also contribute to its potential for good oral bioavailability.

Output:
1
2025-04-17 06:28:48,705 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (367.877 and 348.462 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (81.67) is higher than Ligand B (49.41). For a CNS target like DRD2, TPSA should ideally be <=90. Ligand B is significantly better here.

**3. logP:** Both ligands have similar logP values (2.717 and 2.812), falling within the optimal 1-3 range.

**4. H-Bond Donors:** Ligand A has 3 HBD, and Ligand B has 1. Both are acceptable (<=5).

**5. H-Bond Acceptors:** Ligand A has 3 HBA, and Ligand B has 2. Both are acceptable (<=10).

**6. QED:** Both ligands have good QED scores (0.748 and 0.853), indicating good drug-like properties.

**7. DILI:** Ligand A (34.471) has a slightly higher DILI risk than Ligand B (28.383), but both are below the concerning threshold of 60.

**8. BBB:** Ligand B (79.062) has a significantly better BBB penetration score than Ligand A (60.915). This is a critical factor for CNS targets.

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.78 and -4.743). This is unusual and suggests poor permeability. However, these values are on a log scale, and the absolute difference is small.

**10. Aqueous Solubility:** Both ligands have negative solubility values (-3.663 and -4.232), indicating poor aqueous solubility. This could be a formulation challenge.

**11. hERG Inhibition:** Both ligands have similar, low hERG inhibition liability (0.452 and 0.59).

**12. Microsomal Clearance:** Ligand A (-11.91) has a lower (better) microsomal clearance than Ligand B (24.589), suggesting better metabolic stability.

**13. In vitro Half-Life:** Ligand B (6.954) has a longer half-life than Ligand A (32.85), but the units are inconsistent (hours vs percentile). Assuming 32.85 is a percentile, it suggests a long half-life. However, the percentile scale makes direct comparison difficult.

**14. P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.059 and 0.205), which is favorable for CNS penetration.

**15. Binding Affinity:** Both ligands have the same binding affinity (-8.6 kcal/mol), which is excellent.

**Overall Assessment:**

While Ligand A has better metabolic stability (lower Cl_mic), Ligand B is superior in several key areas for a CNS-targeting GPCR: significantly lower TPSA, and much better BBB penetration. The similar binding affinity makes these differences decisive. The poor Caco-2 and solubility are concerns for both, but can potentially be addressed with formulation strategies.

Output:
1
2025-04-17 06:28:48,706 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B based on the provided guidelines, prioritizing GPCR-specific properties (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (340.379 Da) is slightly lower than Ligand B (378.441 Da), which is not a significant difference.

**TPSA:** Both ligands are below the 140 A^2 threshold for oral absorption, but more importantly, both are reasonably close to the 90 A^2 target for CNS penetration. Ligand A (75.8) is better than Ligand B (78.87).

**logP:** Ligand A (2.392) is optimal (1-3). Ligand B (0.489) is a bit low, potentially hindering permeation.

**H-Bond Donors/Acceptors:** Both ligands have acceptable HBD (1 & 2) and HBA (5) counts.

**QED:** Both ligands have good QED scores (0.925 and 0.703), indicating drug-like properties.

**DILI:** Ligand A (65.568) has a higher DILI risk than Ligand B (35.285). This is a negative for Ligand A.

**BBB:** Ligand B (82.862) has a significantly better BBB penetration percentile than Ligand A (63.203). This is a crucial advantage for a CNS target like DRD2.

**Caco-2 Permeability:** Both have negative values, which is unusual. Assuming these are logP values, both are poor.

**Aqueous Solubility:** Both are very poor.

**hERG Inhibition:** Both ligands show low hERG inhibition liability (0.474 and 0.323), which is positive.

**Microsomal Clearance:** Ligand A (54.031) has a moderate clearance, while Ligand B (14.973) has a very low clearance, suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (4.363) has a reasonable half-life, while Ligand B (-14.348) is concerningly low (negative value suggests instability or rapid degradation).

**P-gp Efflux:** Ligand A (0.598) has slightly higher P-gp efflux liability than Ligand B (0.03), which is unfavorable.

**Binding Affinity:** Ligand A (-8.5 kcal/mol) has a stronger binding affinity than Ligand B (-7.3 kcal/mol). This is a substantial advantage.

**Overall Assessment:**

Despite the stronger binding affinity of Ligand A, Ligand B is the more promising candidate. The significantly better BBB penetration (82.862 vs 63.203), much lower microsomal clearance (14.973 vs 54.031), and lower P-gp efflux (0.03 vs 0.598) outweigh the affinity difference. The lower DILI risk for Ligand B is also a benefit. The negative in vitro half-life for Ligand B is a concern, but could be addressed with structural modifications. The lower logP for Ligand B is a drawback, but not insurmountable. Given the GPCR target and the need for CNS penetration, the ADME properties of Ligand B are far superior.

Output:
1
2025-04-17 06:28:48,706 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (353.463 and 369.795 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (89.95) is excellent, falling well below the 90 A^2 threshold for CNS targets. Ligand B (49.77) is also very good.

**logP:** Ligand A (0.227) is quite low, potentially hindering membrane permeability. Ligand B (4.238) is higher, approaching the upper limit, but still acceptable.

**H-Bond Donors/Acceptors:** Ligand A has 2 HBD and 4 HBA, which are reasonable. Ligand B has 1 HBD and 3 HBA, also reasonable.

**QED:** Both ligands have good QED scores (0.669 and 0.828), indicating drug-like properties.

**DILI:** Ligand A (18.185) has a much lower DILI risk than Ligand B (37.611), which is a significant advantage.

**BBB:** Ligand B (46.879) has a better BBB penetration percentile than Ligand A (38.465), but both are below the desirable >70% for CNS targets.

**Caco-2 Permeability:** Ligand A (-5.154) has poor Caco-2 permeability, which is concerning. Ligand B (-4.613) is also poor, but slightly better.

**Aqueous Solubility:** Ligand A (-0.953) has poor aqueous solubility. Ligand B (-4.544) also has poor aqueous solubility.

**hERG Inhibition:** Ligand A (0.152) has a very low hERG risk, a major advantage. Ligand B (0.885) has a higher, but still relatively low, hERG risk.

**Microsomal Clearance:** Ligand A (4.092) has a lower microsomal clearance, suggesting better metabolic stability. Ligand B (79.66) has a high clearance, indicating rapid metabolism.

**In vitro Half-Life:** Ligand A (-4.348) has a negative half-life, which is unusual and likely indicates very rapid degradation. Ligand B (22.893) has a more reasonable half-life.

**P-gp Efflux:** Ligand A (0.022) has very low P-gp efflux, which is highly desirable for CNS penetration. Ligand B (0.339) has slightly higher P-gp efflux.

**Binding Affinity:** Ligand B (-7.7 kcal/mol) has a significantly better binding affinity than Ligand A (-8.1 kcal/mol). This is a substantial advantage, potentially outweighing some ADME concerns.

**Overall Assessment:**

While Ligand B has a superior binding affinity and better BBB penetration, Ligand A exhibits a much more favorable safety profile (lower DILI and hERG risk) and better metabolic stability. However, the extremely poor Caco-2 permeability and very short half-life of Ligand A are major drawbacks. The low logP of Ligand A is also a concern. Ligand B's high metabolic clearance is also a concern. Considering the GPCR-specific priorities, the binding affinity is crucial. The difference in affinity (-7.7 vs -8.1) is substantial. The slightly better BBB of B, combined with the significantly improved binding, outweighs the higher DILI and clearance.

Output:
1
2025-04-17 06:28:48,706 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (367.446 and 348.418 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (72.48) is better than Ligand B (69.64), both are below the 90 A^2 threshold for CNS targets.

**logP:** Ligand A (3.729) is slightly higher than Ligand B (2.371), both are within the optimal 1-3 range, but A is approaching the upper limit.

**H-Bond Donors:** Both ligands have 2 HBD, which is acceptable.

**H-Bond Acceptors:** Ligand A has 5 HBA, while Ligand B has 3. Both are below the 10 threshold.

**QED:** Both ligands have high QED scores (0.816 and 0.829), indicating good drug-like properties.

**DILI:** Ligand A (68.166) has a higher DILI risk than Ligand B (16.712). This is a significant drawback for Ligand A.

**BBB:** Ligand B (80.419) has a substantially better BBB penetration score than Ligand A (49.864). This is a critical advantage for a CNS target like DRD2.

**Caco-2 Permeability:** Ligand A (-4.528) has worse Caco-2 permeability than Ligand B (-4.913). Both are negative, indicating poor permeability.

**Aqueous Solubility:** Both ligands have similar poor aqueous solubility (-3.252 and -3.2).

**hERG Inhibition:** Ligand A (0.137) has a slightly lower hERG risk than Ligand B (0.328), but both are relatively low.

**Microsomal Clearance:** Ligand B (32.069) has significantly lower microsomal clearance than Ligand A (49.026), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (10.538) has a longer half-life than Ligand B (-10.106). However, the negative value for ligand B is concerning and likely indicates rapid degradation.

**P-gp Efflux:** Ligand A (0.183) has lower P-gp efflux than Ligand B (0.077), which is favorable for CNS penetration.

**Binding Affinity:** Ligand B (-9.0) has a slightly better binding affinity than Ligand A (-7.9). While both are good, the 1.1 kcal/mol difference is substantial and can outweigh some ADME drawbacks.

**Conclusion:**

Considering all factors, especially the GPCR-specific priorities, **Ligand B is the more promising drug candidate.** While Ligand A has slightly better P-gp efflux and in vitro half-life, Ligand B excels in crucial areas for CNS drug development: significantly better BBB penetration, lower DILI risk, and better metabolic stability (lower Cl_mic). The slightly stronger binding affinity of Ligand B further strengthens its position. The poor Caco-2 and solubility are concerns for both, but less critical for a CNS-targeted drug where BBB penetration is paramount.

Output:
1
2025-04-17 06:28:48,706 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B based on the provided guidelines, prioritizing GPCR-specific properties (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (354.801 and 352.431 Da) fall within the ideal range of 200-500 Da.

**TPSA:** Ligand A (85.59) is excellent, well below the 90 A^2 threshold for CNS targets. Ligand B (101.57) is still reasonable but less optimal.

**logP:** Ligand A (2.842) is within the optimal range (1-3). Ligand B (0.956) is slightly below 1, which could potentially hinder permeation.

**H-Bond Donors/Acceptors:** Ligand A (HBD=1, HBA=6) and Ligand B (HBD=2, HBA=5) both have acceptable numbers of H-bond donors and acceptors.

**QED:** Both ligands have similar QED values (0.731 and 0.634), indicating good drug-likeness.

**DILI:** Ligand A (95.502) has a very high DILI risk, which is a significant concern. Ligand B (35.479) has a low DILI risk, a major advantage.

**BBB:** Ligand A (77.007) has a good BBB percentile, exceeding the 70% threshold for CNS targets. Ligand B (46.491) is significantly lower, indicating poor BBB penetration.

**Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and suggests potential issues with the data or the compounds themselves. However, we'll proceed assuming these represent low permeability.

**Aqueous Solubility:** Both have negative solubility values, also unusual. Assuming these represent low solubility, this is a drawback for both.

**hERG Inhibition:** Ligand A (0.304) has a very low hERG risk. Ligand B (0.045) has an even lower hERG risk, which is excellent.

**Microsomal Clearance:** Ligand A (64.697) has moderate clearance, while Ligand B (39.719) has lower clearance, suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (31.676) has a moderate half-life. Ligand B (-22.589) has a negative half-life, which is impossible and indicates a data issue.

**P-gp Efflux:** Ligand A (0.341) has low P-gp efflux, which is favorable for CNS penetration. Ligand B (0.033) has very low P-gp efflux, even more favorable.

**Binding Affinity:** Ligand A (-10.3 kcal/mol) has significantly stronger binding affinity than Ligand B (-7.8 kcal/mol). This is a substantial advantage, potentially outweighing some ADME drawbacks.

**Overall Assessment:**

Ligand A has a superior binding affinity and good BBB penetration and P-gp efflux. However, its extremely high DILI risk is a major red flag. Ligand B has a much better safety profile (low DILI, low hERG) and better metabolic stability, but its lower affinity and poor BBB penetration are significant drawbacks for a CNS target. The negative half-life for Ligand B is a data quality concern.

Despite the superior affinity of Ligand A, the high DILI risk makes it a less viable candidate. While the negative values for Caco-2 and solubility are concerning for both, the DILI risk is a more immediate and serious issue.

Output:
1
2025-04-17 06:28:48,706 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (368.905 and 358.467 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (58.64) is significantly better than Ligand B (83.98). For CNS targets, we want TPSA <= 90, and A is comfortably within this range, while B is approaching the upper limit.

**3. logP:** Both ligands have similar and optimal logP values (2.462 and 2.37), falling within the 1-3 range.

**4. H-Bond Donors:** Ligand A (1) is preferable to Ligand B (2). Lower HBD generally improves permeability.

**5. H-Bond Acceptors:** Ligand A (3) is preferable to Ligand B (5) for similar reasons as HBD.

**6. QED:** Both ligands have good QED values (0.733 and 0.859), indicating good drug-like properties.

**7. DILI:** Ligand A (20.318) has a much lower DILI risk than Ligand B (60.14). This is a significant advantage for Ligand A.

**8. BBB:** Ligand A (63.94) and Ligand B (61.691) are both reasonably good, but below the ideal >70 for CNS targets. However, given the other factors, this isn't a dealbreaker.

**9. Caco-2 Permeability:** Ligand A (-4.892) is worse than Ligand B (-5.422). Lower values indicate lower permeability.

**10. Aqueous Solubility:** Ligand A (-3.705) is better than Ligand B (-3.016).

**11. hERG Inhibition:** Ligand A (0.501) has a lower hERG risk than Ligand B (0.144), which is a positive.

**12. Microsomal Clearance:** Ligand A (49.42) has higher clearance than Ligand B (18.191), suggesting lower metabolic stability. This favors Ligand B.

**13. In vitro Half-Life:** Ligand B (14.066) has a significantly longer half-life than Ligand A (0.338), which is a major advantage.

**14. P-gp Efflux:** Ligand A (0.218) has lower P-gp efflux than Ligand B (0.075), which is preferable for CNS penetration.

**15. Binding Affinity:** Both ligands have excellent binding affinities (-8.5 and -8.7 kcal/mol). The difference is negligible.

**Overall Assessment:**

Ligand A excels in TPSA, DILI, hERG, solubility, and P-gp efflux. Its lower TPSA and DILI risk are particularly important. While its Caco-2 permeability and metabolic stability (higher clearance, shorter half-life) are less favorable, the strong binding affinity and better safety profile outweigh these drawbacks. Ligand B has a better half-life and lower clearance, but suffers from higher TPSA and DILI risk.

Given the GPCR-specific priorities, the lower TPSA and significantly lower DILI risk of Ligand A make it the more promising candidate, despite the slightly less favorable pharmacokinetic properties.

Output:
0
2025-04-17 06:28:48,706 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (367.43 and 364.49 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (101.78) is slightly above the preferred <90 for CNS targets, but still reasonable. Ligand B (51.02) is excellent, well below 90.

**logP:** Ligand A (1.28) is within the optimal 1-3 range. Ligand B (3.696) is at the higher end of optimal, but still acceptable.

**H-Bond Donors/Acceptors:** Ligand A has 1 HBD and 6 HBA, both within acceptable limits. Ligand B has 0 HBD and 5 HBA, also good.

**QED:** Both ligands have good QED scores (0.551 and 0.753), indicating drug-like properties.

**DILI:** Both ligands have low DILI risk (46.96 and 38.50), which is favorable.

**BBB:** Ligand B (93.02) has a significantly better BBB penetration score than Ligand A (67.58). This is a critical advantage for a CNS target like DRD2.

**Caco-2 Permeability:** Ligand A (-5.191) and Ligand B (-4.761) both have negative values, indicating poor permeability. This is a concern for both compounds.

**Aqueous Solubility:** Both ligands have poor aqueous solubility (-2.777 and -3.943). This could pose formulation challenges.

**hERG Inhibition:** Ligand A (0.148) has a very low hERG risk, which is excellent. Ligand B (0.599) is slightly higher, but still relatively low.

**Microsomal Clearance:** Ligand B (48.924) has a lower microsomal clearance than Ligand A (13.416), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand B (36.124) has a significantly longer in vitro half-life than Ligand A (-0.124), which is a major advantage.

**P-gp Efflux:** Ligand A (0.063) has a very low P-gp efflux liability, which is excellent. Ligand B (0.454) is higher, but still reasonable.

**Binding Affinity:** Ligand B (-7.7) has a slightly better binding affinity than Ligand A (-8.0). While both are excellent, the difference is minor.

**Overall Assessment:**

Ligand B is the more promising candidate. While both have poor Caco-2 permeability and solubility, Ligand B excels in the critical areas for CNS GPCR targets: significantly better BBB penetration (93.02 vs 67.58), improved metabolic stability (lower Cl_mic), and a longer half-life. The slightly better affinity of Ligand A is outweighed by the superior ADME properties of Ligand B, especially its BBB score.

Output:
1
2025-04-17 06:28:48,706 - INFO - Reasoning:

Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (385.917 and 370.837 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (71.53) is significantly better than Ligand B (113.44). For CNS targets, we want TPSA <= 90, so Ligand A is much closer to this threshold. Ligand B is above the preferred range.

**3. logP:** Ligand A (2.89) is optimal (1-3). Ligand B (0.54) is quite low, potentially hindering membrane permeability and CNS penetration.

**4. H-Bond Donors:** Ligand A (1) is good. Ligand B (3) is acceptable but less ideal.

**5. H-Bond Acceptors:** Ligand A (5) is good. Ligand B (6) is acceptable.

**6. QED:** Both ligands have similar QED values (0.764 and 0.645), indicating good drug-like properties.

**7. DILI:** Ligand A (74.021) has a slightly higher DILI risk than Ligand B (57.503), but both are below the concerning threshold of 60.

**8. BBB:** Ligand A (57.736) has a better BBB percentile than Ligand B (42.807). While both are below the ideal >70 for CNS targets, Ligand A is closer.

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.746 and -4.925). These values are unusual and suggest poor permeability. However, the magnitude is similar.

**10. Aqueous Solubility:** Both ligands have negative solubility values (-3.288 and -2.061), indicating poor aqueous solubility.

**11. hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.195 and 0.086).

**12. Microsomal Clearance:** Ligand A (48.922) has higher microsomal clearance than Ligand B (13.529), suggesting lower metabolic stability.

**13. In vitro Half-Life:** Ligand B (3.616) has a slightly longer half-life than Ligand A (21.269). However, these values are reversed and likely an error in the data provided.

**14. P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.265 and 0.008).

**15. Binding Affinity:** Ligand A (-7.9 kcal/mol) has a significantly stronger binding affinity than Ligand B (-6.9 kcal/mol). This 1.0 kcal/mol difference is substantial and can outweigh some ADME drawbacks.

**Overall Assessment:**

Considering the GPCR-specific priorities, Ligand A is the superior candidate. Its lower TPSA, optimal logP, and significantly higher binding affinity are crucial advantages. While its BBB is not ideal, it's better than Ligand B's. The slightly higher DILI and clearance are less concerning given the strong affinity. Ligand B's low logP is a significant drawback for CNS penetration. The reversed half-life values are suspect and don't heavily influence the decision.

Output:
1
2025-04-17 06:28:48,706 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (364.47 & 349.48 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (67.87) is significantly better than Ligand B (81.33). For CNS targets, we want TPSA <= 90, and A is closer to the ideal <=60. B is pushing the upper limit.

**3. logP:** Both ligands have acceptable logP values (0.943 and 1.334, respectively), falling within the 1-3 range.

**4. H-Bond Donors:** Ligand A has 1 HBD, and Ligand B has 2. Both are acceptable (<=5).

**5. H-Bond Acceptors:** Ligand A has 5 HBA, and Ligand B has 4. Both are within the acceptable range (<=10).

**6. QED:** Both ligands have good QED scores (0.814 and 0.84), indicating good drug-like properties.

**7. DILI:** Ligand A (41.062) has a slightly higher DILI risk than Ligand B (17.72), but both are below the concerning threshold of 60.

**8. BBB:** This is critical for a CNS target. Ligand B (68.67) is significantly better than Ligand A (39.279). A value > 70 is desirable, but 68.67 is a good starting point.

**9. Caco-2:** Both have negative values which is unusual. Assuming these are logP-scale values, lower values indicate poorer permeability. Ligand A (-4.942) is worse than Ligand B (-5.05).

**10. Solubility:** Both have negative values, which is also unusual. Assuming these are logS values, lower values indicate poorer solubility. Ligand A (-3.015) is better than Ligand B (-1.754).

**11. hERG:** Both ligands have low hERG inhibition liability (0.252 and 0.42), which is good.

**12. Cl_mic:** Ligand B (-7.439) has a *lower* (better) microsomal clearance than Ligand A (30.369), suggesting greater metabolic stability.

**13. t1/2:** Ligand B (-6.519) has a longer in vitro half-life than Ligand A (-6.143).

**14. Pgp:** Both ligands have very low P-gp efflux liability (0.051 and 0.037), which is excellent for CNS penetration.

**15. Binding Affinity:** Both ligands have very similar, strong binding affinities (-7.5 and -7.7 kcal/mol). The difference is negligible.

**Overall Assessment:**

Ligand B is the better candidate. While Ligand A has a slightly better solubility, Ligand B excels in the critical areas for a CNS-targeting GPCR: significantly better BBB penetration, lower microsomal clearance (better metabolic stability), and a longer half-life. The TPSA is also more favorable for Ligand A, but the difference is not substantial enough to outweigh the advantages of Ligand B regarding CNS penetration and metabolic stability.

Output:
1
2025-04-17 06:28:48,707 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B based on the provided guidelines, prioritizing GPCR-specific properties (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (345.403 and 356.419 Da) fall within the ideal range of 200-500 Da.

**TPSA:** Ligand A (81.39) is significantly better than Ligand B (110.8). For CNS targets, TPSA should be <= 90, which Ligand A meets, while Ligand B exceeds it.

**logP:** Ligand A (1.525) is within the optimal range (1-3), while Ligand B (0.682) is slightly below, potentially hindering permeation.

**H-Bond Donors/Acceptors:** Ligand A (HBD=1, HBA=6) and Ligand B (HBD=2, HBA=6) both have acceptable numbers of H-bond donors and acceptors.

**QED:** Ligand A (0.852) has a much better QED score than Ligand B (0.464), indicating higher drug-likeness.

**DILI:** Ligand A (37.03) has a lower DILI risk than Ligand B (46.219), both are acceptable but A is preferable.

**BBB:** Ligand A (71.888) has a significantly better BBB percentile than Ligand B (27.491).  A BBB > 70 is desirable for CNS targets, and Ligand A is closer to this threshold. This is a crucial factor for DRD2.

**Caco-2 Permeability:** Ligand A (-4.694) and Ligand B (-5.191) both have negative values, indicating poor permeability. However, the scale is not explicitly defined, making direct comparison difficult.

**Aqueous Solubility:** Both ligands have similar, very poor aqueous solubility (-1.782 and -1.921). This could pose formulation challenges.

**hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.386 and 0.071).

**Microsomal Clearance:** Ligand A (65.016) has higher microsomal clearance than Ligand B (18.581), suggesting lower metabolic stability.

**In vitro Half-Life:** Ligand A (-7.986) has a significantly longer in vitro half-life than Ligand B (-2.51), which is a positive attribute.

**P-gp Efflux:** Ligand A (0.065) has lower P-gp efflux liability than Ligand B (0.035), which is favorable for CNS penetration.

**Binding Affinity:** Ligand A (-8.2 kcal/mol) has a slightly better binding affinity than Ligand B (-7.3 kcal/mol). While both are good, the 0.9 kcal/mol difference is significant and can outweigh some ADME drawbacks.

**Overall Assessment:**

Ligand A is clearly superior. It has better TPSA, logP, QED, BBB penetration, P-gp efflux, and binding affinity. While its microsomal clearance is higher, its significantly longer half-life and superior CNS penetration (BBB) make it a more promising candidate for a DRD2 target. Ligand B's poor BBB and lower QED are major drawbacks.

Output:
1
2025-04-17 06:28:48,707 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (346.515 and 344.503 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (40.62) is significantly better than Ligand B (59.81). For CNS targets, we want TPSA <= 90, and ideally lower. Ligand A is much closer to the ideal range.

**3. logP:** Both ligands have good logP values (3.171 and 3.607), falling within the optimal 1-3 range.

**4. H-Bond Donors:** Ligand A (0) is preferable to Ligand B (1). Fewer HBDs generally improve permeability.

**5. H-Bond Acceptors:** Ligand A (2) is preferable to Ligand B (4). Fewer HBAs generally improve permeability.

**6. QED:** Both ligands have good QED scores (0.57 and 0.733), indicating drug-like properties.

**7. DILI:** Ligand A (12.02) has a much lower DILI risk than Ligand B (27.22). This is a significant advantage for Ligand A.

**8. BBB:** Both ligands have good BBB penetration (70.997 and 69.833). Both are above the 70% threshold desirable for CNS targets.

**9. Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and suggests a potential issue with the data or a very poor permeability. However, the values are similar (-4.279 vs -4.912).

**10. Aqueous Solubility:** Both have negative solubility values, which is also unusual and suggests a potential issue with the data. The values are similar (-3.909 vs -4.259).

**11. hERG Inhibition:** Ligand A (0.74) has a slightly better hERG profile than Ligand B (0.224), indicating lower cardiotoxicity risk.

**12. Microsomal Clearance:** Ligand A (77.828) has a higher microsomal clearance than Ligand B (71.711), suggesting lower metabolic stability. This is a slight disadvantage for Ligand A.

**13. In vitro Half-Life:** Ligand B (-6.551) has a longer half-life than Ligand A (14.994), which is a significant advantage.

**14. P-gp Efflux:** Ligand A (0.136) shows lower P-gp efflux than Ligand B (0.388). Lower P-gp efflux is preferred for CNS penetration.

**15. Binding Affinity:** Ligand B (-8.8 kcal/mol) has a significantly stronger binding affinity than Ligand A (-6.4 kcal/mol). This is a substantial advantage, potentially outweighing some of the ADME drawbacks.

**Overall Assessment:**

While Ligand B has a superior binding affinity, Ligand A demonstrates a more favorable ADME profile, particularly regarding TPSA, DILI risk, and P-gp efflux. The difference in binding affinity is 2.4 kcal/mol, which is significant. However, the lower TPSA and DILI risk of Ligand A are crucial for a CNS-targeting drug. The negative solubility and Caco-2 values are concerning for both, but the other properties of Ligand A are more promising. Considering the GPCR-specific priorities, the better TPSA, lower DILI, and lower P-gp efflux of Ligand A, combined with acceptable BBB penetration, make it a slightly more viable candidate despite the weaker binding affinity.

Output:
0
2025-04-17 06:28:48,707 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (349.391 Da) is slightly lower, which could be beneficial for permeability, while Ligand B (377.378 Da) is also well within the range.

**TPSA:** Ligand A (118.37) is closer to the desirable threshold of 90 for CNS targets, while Ligand B (21.26) is *much* better, well below 90. This is a significant advantage for B.

**logP:** Ligand A (0.583) is quite low, potentially hindering membrane permeability. Ligand B (4.788) is high, potentially causing solubility and off-target issues, but closer to the optimal range of 1-3.

**H-Bond Donors/Acceptors:** Ligand A has 3 HBD and 7 HBA, both acceptable. Ligand B has 1 HBD and 3 HBA, also acceptable.

**QED:** Ligand A (0.687) has a better QED score than Ligand B (0.406), indicating a more drug-like profile.

**DILI:** Ligand A (65.917) has a higher DILI risk than Ligand B (51.028), but both are reasonably acceptable.

**BBB:** Ligand B (73.672) has a significantly better BBB penetration percentile than Ligand A (63.862). This is a crucial factor for a CNS target like DRD2.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.877 and -4.829), which is unusual and suggests poor permeability. This is a concern for both, but doesn't differentiate them.

**Aqueous Solubility:** Both ligands have negative solubility values (-2.789 and -4.951), also unusual and suggesting poor solubility. This is a concern for both, but doesn't differentiate them.

**hERG Inhibition:** Ligand A (0.098) has a very low hERG risk, much better than Ligand B (0.961). This is a significant advantage for A.

**Microsomal Clearance:** Ligand A (42.656) has lower microsomal clearance than Ligand B (49.99), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand B (28.232) has a longer in vitro half-life than Ligand A (21.546).

**P-gp Efflux:** Ligand A (0.033) has much lower P-gp efflux liability than Ligand B (0.738), which is very favorable for CNS penetration.

**Binding Affinity:** Ligand B (-8.8 kcal/mol) has a significantly stronger binding affinity than Ligand A (-7.5 kcal/mol). This is a substantial advantage, potentially outweighing some of the ADME drawbacks.

**Overall Assessment:**

Ligand B excels in BBB penetration and binding affinity, which are critical for a CNS GPCR target. While its logP is high and P-gp efflux is moderate, the strong affinity could compensate. Ligand A has better QED, lower hERG risk, lower P-gp efflux, and lower clearance, but suffers from poor logP and lower BBB penetration.

Given the importance of BBB penetration and binding affinity for DRD2, and the substantial difference in affinity (-8.8 vs -7.5 kcal/mol), Ligand B is the more promising candidate despite its higher logP and P-gp efflux.

Output:
1
2025-04-17 06:28:48,707 - INFO - Batch 285 complete. Total preferences: 4560
2025-04-17 06:28:48,707 - INFO - Processing batch 286/512...
2025-04-17 06:29:28,978 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 drug candidates, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (360.483 and 345.487 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (75.19) is better than Ligand B (81.99). Both are below the 90 A^2 threshold desirable for CNS targets, but A is closer to the optimal range.

**logP:** Both ligands (2.587 and 2.641) are within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A (HBD=1, HBA=5) is slightly better than Ligand B (HBD=2, HBA=3) in terms of balancing solubility and permeability.

**QED:** Both ligands have acceptable QED scores (0.746 and 0.696), indicating good drug-like properties.

**DILI:** Ligand A (42.458) has a slightly higher DILI risk than Ligand B (29.973), but both are below the concerning threshold of 60.

**BBB:** Ligand B (58.899) has a significantly better BBB penetration percentile than Ligand A (42.342). This is a *critical* advantage for a CNS target like DRD2.

**Caco-2 Permeability:** Ligand A (-5.137) has a worse Caco-2 permeability score than Ligand B (-4.63).

**Aqueous Solubility:** Ligand A (-1.42) has a slightly better solubility score than Ligand B (-3.91).

**hERG:** Ligand A (0.115) has a much lower hERG inhibition liability than Ligand B (0.372), which is a significant safety advantage.

**Microsomal Clearance:** Ligand B (53.814) has a higher microsomal clearance than Ligand A (32.421), indicating faster metabolism and potentially lower *in vivo* exposure.

**In vitro Half-Life:** Ligand A (43.919) has a longer half-life than Ligand B (-11.395), which is preferable.

**P-gp Efflux:** Ligand A (0.041) has a much lower P-gp efflux liability than Ligand B (0.167), which is favorable for CNS penetration.

**Binding Affinity:** Ligand B (-8.1) has a slightly stronger binding affinity than Ligand A (-7.9). While a 1.5 kcal/mol difference is generally significant, the other ADME properties are more critical in this case.

**Overall Assessment:**

Ligand B has a superior BBB score and slightly better binding affinity, which are important for a CNS GPCR target. However, it suffers from higher P-gp efflux, higher hERG inhibition, and faster metabolic clearance. Ligand A, while having a slightly weaker binding affinity, exhibits a much more favorable ADME profile, particularly regarding BBB penetration (though still not ideal), P-gp efflux, hERG inhibition, and metabolic stability. The better ADME profile of Ligand A, particularly the lower hERG and P-gp efflux, makes it the more promising candidate despite the slightly weaker binding.

Output:
0
2025-04-17 06:29:28,978 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B against the provided guidelines, prioritizing GPCR-specific properties (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (345.4 and 359.4 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (91.76) is better than Ligand B (97.64). Both are below the 140 threshold for oral absorption, and closer to the <90 desired for CNS targets, but A is preferable.

**logP:** Ligand B (2.534) is within the optimal 1-3 range. Ligand A (0.347) is *below* 1, which is a concern for membrane permeability. This is a significant drawback for A.

**H-Bond Donors/Acceptors:** Ligand A (2 HBD, 5 HBA) and Ligand B (3 HBD, 3 HBA) both fall within acceptable ranges.

**QED:** Ligand A (0.821) has a better QED score than Ligand B (0.708), indicating better overall drug-likeness.

**DILI:** Both ligands have similar DILI risk (46.142 and 48.468), both being reasonably low.

**BBB:** Ligand B (53.393) has a significantly better BBB penetration percentile than Ligand A (25.824). This is *critical* for a CNS target like DRD2.

**Caco-2 Permeability:** Ligand A (-4.807) has worse Caco-2 permeability than Ligand B (-5.124), but both are quite poor.

**Aqueous Solubility:** Ligand A (-1.559) has better solubility than Ligand B (-2.944).

**hERG:** Ligand A (0.198) has a lower hERG risk than Ligand B (0.579), which is favorable.

**Microsomal Clearance:** Ligand B (-3.59) has a much lower (better) microsomal clearance than Ligand A (9.568), indicating greater metabolic stability.

**In vitro Half-Life:** Ligand B (-20.121) has a significantly longer in vitro half-life than Ligand A (-2.682).

**P-gp Efflux:** Ligand A (0.017) has a much lower P-gp efflux liability than Ligand B (0.128), which is beneficial for CNS penetration.

**Binding Affinity:** Ligand B (-7.4) has a slightly better binding affinity than Ligand A (-9.0). While A is stronger, the difference is not large enough to overcome the other deficiencies.

**Overall Assessment:**

Ligand B is the stronger candidate despite having a slightly weaker binding affinity. Its superior BBB penetration, metabolic stability (lower Cl_mic, longer t1/2), and acceptable logP outweigh the benefits of Ligand A's better QED, lower hERG, and P-gp efflux. Ligand A's very low logP is a major concern, hindering its ability to cross cell membranes, including the BBB.



Output:
1
2025-04-17 06:29:28,979 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (373.381 and 340.379 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (89.77) is better than Ligand B (62.99) as it is closer to the optimal range for CNS targets (<=90). Ligand B is excellent.

**logP:** Both ligands have good logP values (1.853 and 2.037), falling within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A has 1 HBD and 7 HBA, while Ligand B has 0 HBD and 4 HBA. Both are within acceptable limits (<=5 HBD and <=10 HBA).

**QED:** Both ligands have good QED scores (0.748 and 0.858), indicating good drug-like properties.

**DILI:** Ligand A (81.815) has a higher DILI risk than Ligand B (60.682). Ligand B is preferable here.

**BBB:** Ligand B (81.737) has a significantly better BBB penetration percentile than Ligand A (74.06). This is a crucial advantage for a CNS target like DRD2.

**Caco-2 Permeability:** Ligand A (-4.584) has poorer Caco-2 permeability than Ligand B (-4.185).

**Aqueous Solubility:** Ligand A (-3.264) has poorer aqueous solubility than Ligand B (-2.647).

**hERG:** Both ligands have very low hERG inhibition liability (0.283 and 0.167), which is excellent.

**Microsomal Clearance:** Ligand B (39.454) has a lower microsomal clearance than Ligand A (69.554), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand B (83.968) has a significantly longer in vitro half-life than Ligand A (12.68).

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.173 and 0.089), which is good.

**Binding Affinity:** Ligand B (-8.5 kcal/mol) has a slightly better binding affinity than Ligand A (-7.9 kcal/mol). While the difference is not huge, it's a positive factor.

**Overall Assessment:**

Ligand B consistently outperforms Ligand A in several key areas crucial for a CNS-targeting GPCR ligand. Specifically, it has better BBB penetration, lower DILI risk, better metabolic stability (lower Cl_mic and longer t1/2), slightly better affinity, and better solubility. While Ligand A has a slightly better TPSA, the other advantages of Ligand B outweigh this minor difference.

Output:
1
2025-04-17 06:29:28,979 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (358.463 and 370.515 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (58.64) is excellent, well below the 90 A^2 threshold for CNS targets. Ligand B (76.66) is still reasonable but less optimal.

**3. logP:** Ligand A (4.095) is at the upper end of the optimal range (1-3) and could potentially cause solubility issues. Ligand B (1.192) is a bit low, potentially hindering permeation.

**4. H-Bond Donors:** Ligand A (1) and Ligand B (2) are both acceptable (<=5).

**5. H-Bond Acceptors:** Ligand A (4) and Ligand B (5) are both acceptable (<=10).

**6. QED:** Both ligands have similar, good QED values (0.646 and 0.671, both >=0.5).

**7. DILI:** Ligand A (78.635) has a higher DILI risk than Ligand B (39.55), which is a significant concern.

**8. BBB:** Ligand A (59.054) is borderline for good CNS penetration, while Ligand B (69.446) is better, though still not ideal (>70 is preferred).

**9. Caco-2:** Both ligands have negative Caco-2 values (-4.556 and -5.302), which is unusual and suggests poor permeability. This is a major red flag for both.

**10. Solubility:** Both ligands have negative solubility values (-5.514 and -2.667), indicating very poor aqueous solubility. This is a significant issue.

**11. hERG:** Both ligands have very low hERG risk (0.294 and 0.281).

**12. Cl_mic:** Ligand A (137.698) has a higher microsomal clearance than Ligand B (31.015), indicating lower metabolic stability.

**13. t1/2:** Both have similar in vitro half-lives (12.614 and 11.124 hours).

**14. Pgp:** Both ligands have low P-gp efflux liability (0.194 and 0.112).

**15. Binding Affinity:** Ligand A (-8.9 kcal/mol) has a significantly stronger binding affinity than Ligand B (-7.7 kcal/mol). This is a substantial advantage (1.2 kcal/mol difference).

**Overall Assessment:**

Despite the strong affinity of Ligand A, its high DILI risk and poor solubility are major drawbacks. The Caco-2 values for both are concerning. Ligand B has better DILI and BBB, but a weaker affinity and lower logP. Given the GPCR-specific priorities, the affinity is crucial, but not at the expense of safety (DILI) and permeability. The poor solubility and permeability of both are problematic. However, the significantly better affinity of Ligand A *might* be optimizable to overcome the other issues, while improving the affinity of Ligand B might be more difficult.

Output:
1
2025-04-17 06:29:28,979 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (346.431 and 338.327 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (81.27) is excellent, well below the 90 A^2 threshold for CNS targets. Ligand B (135.86) is higher, but still potentially acceptable, though less ideal.

**logP:** Ligand A (3.315) is optimal. Ligand B (1.761) is on the lower side, potentially impacting permeability.

**H-Bond Donors/Acceptors:** Ligand A (0 HBD, 5 HBA) is favorable. Ligand B (3 HBD, 7 HBA) is also acceptable, though slightly higher.

**QED:** Both ligands have reasonable QED scores (0.621 and 0.472), indicating good drug-like properties. Ligand A is slightly better.

**DILI:** Ligand A (22.8) has a very low DILI risk. Ligand B (96.549) has a very high DILI risk, a significant concern.

**BBB:** Ligand A (83.055) has excellent BBB penetration, highly desirable for a CNS target like DRD2. Ligand B (31.214) has poor BBB penetration, a major drawback.

**Caco-2 Permeability:** Ligand A (-4.778) has poor Caco-2 permeability. Ligand B (-5.65) also has poor Caco-2 permeability.

**Aqueous Solubility:** Both ligands have poor aqueous solubility (-3.47 and -3.929). This might require formulation strategies.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.434 and 0.86).

**Microsomal Clearance:** Ligand A (23.244) has higher microsomal clearance than Ligand B (13.291), indicating lower metabolic stability.

**In vitro Half-Life:** Ligand B (0.495) has a very short half-life. Ligand A (6.959) is better, but still not ideal.

**P-gp Efflux:** Ligand A (0.142) shows low P-gp efflux, which is good for CNS penetration. Ligand B (0.089) also shows low P-gp efflux.

**Binding Affinity:** Both ligands have very similar and strong binding affinities (-9.7 and -9.0 kcal/mol). The difference is less than 1.5 kcal/mol, so this isn't a deciding factor.

**Overall Assessment:**

Ligand A is significantly better due to its excellent BBB penetration (83.055) and very low DILI risk (22.8). While its Caco-2 permeability and microsomal clearance are not ideal, the strong affinity and favorable CNS properties outweigh these drawbacks. Ligand B's high DILI risk and poor BBB penetration are major liabilities that make it a less viable candidate, despite its slightly better metabolic stability.

Output:
0
2025-04-17 06:29:28,979 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (351.451 and 346.471 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (97.28) is slightly above the preferred <90 for CNS targets, but still reasonable. Ligand B (58.64) is excellent, well below 90.

**logP:** Ligand A (1.246) is within the optimal 1-3 range. Ligand B (2.127) is also good, within the optimal range.

**H-Bond Donors/Acceptors:** Ligand A has 3 HBD and 5 HBA, which are acceptable. Ligand B has 1 HBD and 3 HBA, also acceptable.

**QED:** Ligand A (0.672) has a good drug-likeness score. Ligand B (0.395) is below the 0.5 threshold, indicating a less drug-like profile.

**DILI:** Ligand A (40.83) has a low DILI risk. Ligand B (8.375) has a very low DILI risk, which is excellent.

**BBB:** Ligand A (71.268) is good, exceeding the 70% threshold for CNS targets. Ligand B (80.341) is even better, indicating excellent potential for brain penetration.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.826 and -4.689), which is unusual and suggests poor permeability. However, these values are on a log scale, and the negative values don't necessarily preclude activity.

**Aqueous Solubility:** Both ligands have negative solubility values (-1.782 and -2.273), which is also unusual and suggests poor aqueous solubility.

**hERG Inhibition:** Ligand A (0.044) has very low hERG inhibition risk. Ligand B (0.355) also has low hERG inhibition risk.

**Microsomal Clearance:** Ligand A (27.812) and Ligand B (23.256) have relatively low microsomal clearance, suggesting reasonable metabolic stability.

**In vitro Half-Life:** Ligand A (37.695) has a moderate half-life. Ligand B (-1.137) has a very short half-life, which is a significant drawback.

**P-gp Efflux:** Ligand A (0.018) has very low P-gp efflux liability, which is favorable for CNS penetration. Ligand B (0.122) also has low P-gp efflux liability.

**Binding Affinity:** Ligand B (-7.3 kcal/mol) has significantly stronger binding affinity than Ligand A (-0.0 kcal/mol). This is a substantial advantage.

**Overall Assessment:**

Ligand B has a significantly better binding affinity, excellent BBB penetration, very low DILI risk, and low P-gp efflux. While its QED is lower and in vitro half-life is very short, the strong affinity and favorable CNS properties are compelling. Ligand A has a better QED and reasonable BBB penetration, but its binding affinity is extremely weak, making it unlikely to be a viable candidate. The poor solubility and permeability for both are concerning, but can potentially be addressed with formulation strategies. The superior affinity of Ligand B outweighs its other drawbacks, especially for a CNS target like DRD2.

Output:
1
2025-04-17 06:29:28,979 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (345.33 and 350.365 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (88.43) is better than Ligand B (69.64) as it is closer to the ideal range of <90 for CNS targets.

**logP:** Both ligands have good logP values (2.662 and 1.692), falling within the optimal 1-3 range. Ligand B is slightly lower, which might slightly hinder permeability, but is still acceptable.

**H-Bond Donors/Acceptors:** Ligand A has 1 HBD and 5 HBA, while Ligand B has 2 HBD and 3 HBA. Both are within acceptable limits (<=5 HBD and <=10 HBA).

**QED:** Both ligands have good QED scores (0.735 and 0.852), indicating good drug-like properties.

**DILI:** Ligand A (91.314) has a significantly higher DILI risk than Ligand B (47.732). This is a major concern for Ligand A.

**BBB:** Ligand B (77.084) has a better BBB penetration score than Ligand A (63.862). While both are reasonably good, exceeding 70 is preferred for CNS targets, and Ligand B is closer.

**Caco-2 Permeability:** Ligand A (-4.476) has worse Caco-2 permeability than Ligand B (-4.975). Lower values are less desirable.

**Aqueous Solubility:** Ligand A (-4.139) has worse aqueous solubility than Ligand B (-2.523).

**hERG:** Ligand A (0.652) has a higher hERG risk than Ligand B (0.127). Lower is better.

**Microsomal Clearance:** Ligand B (-6.16) has a much lower (better) microsomal clearance than Ligand A (80.12). This suggests better metabolic stability for Ligand B.

**In vitro Half-Life:** Ligand B (-8.801) has a much longer in vitro half-life than Ligand A (59.296).

**P-gp Efflux:** Ligand A (0.178) has a higher P-gp efflux liability than Ligand B (0.018). Lower is better for CNS exposure.

**Binding Affinity:** Both ligands have excellent binding affinities (-8.5 and -8.9 kcal/mol), with Ligand B being slightly better. The difference is small, but could be meaningful.

**Overall Assessment:**

Ligand B is clearly superior. While both have good potency and acceptable physicochemical properties, Ligand B demonstrates significantly better ADME-Tox properties, particularly regarding DILI risk, BBB penetration, metabolic stability (lower Cl_mic, longer t1/2), P-gp efflux, and hERG inhibition. The slightly better binding affinity of Ligand B further supports its selection. Ligand A's high DILI risk and poorer ADME profile make it a less desirable candidate.

Output:
1
2025-04-17 06:29:28,980 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (356.438 and 360.483 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (59.08) is better than Ligand B (60.25). Both are below the 90 A^2 threshold for CNS targets, which is good.

**logP:** Ligand A (1.379) is within the optimal 1-3 range. Ligand B (2.397) is also acceptable, though trending higher.

**H-Bond Donors:** Both ligands have 0 HBD, which is acceptable.

**H-Bond Acceptors:** Ligand A (4) and Ligand B (6) are both within the acceptable limit of 10.

**QED:** Both ligands have good QED scores (0.767 and 0.819, respectively), indicating drug-like properties.

**DILI:** Ligand A (30.748) has a significantly lower DILI risk than Ligand B (65.491). This is a major advantage for Ligand A.

**BBB:** Ligand A (89.531) has a much better BBB penetration percentile than Ligand B (59.248). This is crucial for a CNS target like DRD2.

**Caco-2 Permeability:** Both have negative values (-4.348 and -4.864), which is unusual and suggests poor permeability. However, these values are on a scale where negative numbers are possible and don't necessarily disqualify the compounds.

**Aqueous Solubility:** Both have negative values (-1.162 and -3.423), indicating poor solubility. This could be a formulation challenge.

**hERG Inhibition:** Both ligands have low hERG risk (0.314 and 0.228).

**Microsomal Clearance:** Ligand A (14.747) has a lower microsomal clearance than Ligand B (58.464), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand B (13.369) has a longer half-life than Ligand A (2.38).

**P-gp Efflux:** Ligand A (0.043) has lower P-gp efflux than Ligand B (0.124), which is favorable for CNS penetration.

**Binding Affinity:** Ligand B (-9.0) has a significantly stronger binding affinity than Ligand A (0.0). This is a substantial advantage.

**Overall Assessment:**

Ligand B has a much stronger binding affinity, which is a primary driver for GPCR drug candidates. However, Ligand A has significantly better ADME properties, particularly regarding DILI risk, BBB penetration, and metabolic stability. The superior BBB penetration of Ligand A is extremely important for a CNS target. While the affinity difference is large, the poor ADME profile of Ligand B, especially the high DILI risk and lower BBB, are concerning. The difference in binding affinity might be overcome with further optimization of Ligand A.

Output:
0
2025-04-17 06:29:28,980 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (351.535 and 346.515 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (52.65) is better than Ligand B (49.41) as it is closer to the <90 threshold for CNS targets. Both are well below the 140 threshold for oral absorption.

**3. logP:** Both ligands have good logP values (2.364 and 3.665) within the optimal 1-3 range. Ligand B is slightly higher, which could potentially lead to some off-target effects, but is not a major concern.

**4. H-Bond Donors:** Both ligands have 1 HBD, which is within the acceptable limit of <=5.

**5. H-Bond Acceptors:** Ligand A has 3 HBAs, and Ligand B has 2. Both are well below the <=10 limit.

**6. QED:** Ligand A (0.766) has a significantly better QED score than Ligand B (0.538), indicating a more drug-like profile.

**7. DILI:** Ligand A (5.118%) has a much lower DILI risk than Ligand B (28.577%). This is a significant advantage for Ligand A.

**8. BBB:** Ligand A (81.97%) has a substantially higher BBB penetration score than Ligand B (55.176%). This is *critical* for a CNS target like DRD2.

**9. Caco-2 Permeability:** Ligand A (-4.682) and Ligand B (-4.72) have similar, and poor, Caco-2 permeability.

**10. Aqueous Solubility:** Ligand A (-2.064) has better aqueous solubility than Ligand B (-4.278).

**11. hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.526 and 0.224, respectively).

**12. Microsomal Clearance:** Ligand A (39.041) has lower microsomal clearance than Ligand B (63.35), suggesting better metabolic stability.

**13. In vitro Half-Life:** Ligand A (-10.475) has a significantly longer in vitro half-life than Ligand B (15.849).

**14. P-gp Efflux:** Ligand A (0.087) has lower P-gp efflux liability than Ligand B (0.534), which is favorable for CNS penetration.

**15. Binding Affinity:** Ligand B (-0.0 kcal/mol) has a better binding affinity than Ligand A (-8.0 kcal/mol). However, the difference in affinity is not large enough to overcome the substantial ADME advantages of Ligand A.

**Overall Assessment:**

Ligand A is clearly the superior candidate. While Ligand B has a slightly better binding affinity, Ligand A excels in almost all other crucial ADME properties, particularly BBB penetration, DILI risk, metabolic stability, and QED. For a CNS target like DRD2, high BBB penetration is paramount, and Ligand A's 81.97% score is highly desirable. The lower DILI risk and better metabolic stability further strengthen its profile. The difference in binding affinity is not substantial enough to outweigh these significant advantages.

Output:
1
2025-04-17 06:29:28,980 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (365.543 and 351.447 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (61.44) is significantly better than Ligand B (87.74). For CNS targets, we want TPSA <= 90, and A is comfortably within this range, while B is approaching the upper limit.

**logP:** Ligand A (3.564) is optimal (1-3), while Ligand B (0.433) is quite low, potentially hindering membrane permeability.

**H-Bond Donors/Acceptors:** Both have 2 HBDs, which is good. Ligand A has 4 HBAs, and Ligand B has 5. Both are acceptable, being under the 10 HBA threshold.

**QED:** Both ligands have similar QED values (0.81 and 0.702), indicating good drug-likeness.

**DILI:** Ligand A (37.224) has a slightly higher DILI risk than Ligand B (28.15), but both are below the 40 threshold and considered low risk.

**BBB:** Ligand A (82.823) has a significantly better BBB penetration percentile than Ligand B (56.34).  For a CNS target like DRD2, >70 is desirable, so A is much closer to this goal.

**Caco-2 Permeability:** Both have negative Caco-2 values (-4.65 and -4.773), which is unusual and suggests poor permeability. However, these values are on a log scale and the absolute difference isn't huge.

**Aqueous Solubility:** Both have negative solubility values (-3.173 and -1.502), which is also unusual. Solubility is a concern for both, but B is slightly better.

**hERG:** Ligand A (0.694) has a slightly higher hERG risk than Ligand B (0.11), but both are relatively low.

**Microsomal Clearance:** Ligand A (47.008) has a higher microsomal clearance than Ligand B (42.4), suggesting faster metabolism and potentially lower *in vivo* exposure.

**In vitro Half-Life:** Ligand A (87.137) has a much longer half-life than Ligand B (-15.784). This is a significant advantage for dosing considerations.

**P-gp Efflux:** Ligand A (0.231) has lower P-gp efflux liability than Ligand B (0.015), meaning A is less likely to be pumped out of the brain, improving CNS exposure.

**Binding Affinity:** Both ligands have the same binding affinity (-7.4 kcal/mol), which is excellent.

**Overall Assessment:**

Considering the GPCR-specific priorities, Ligand A is the superior candidate. Its significantly better TPSA, logP, and BBB penetration are crucial for CNS drug development. While Ligand B has a slightly better DILI score and solubility, the benefits of A in terms of permeability and brain exposure outweigh these minor advantages. The longer half-life and lower P-gp efflux of A are also significant positives.



Output:
1
2025-04-17 06:29:28,980 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (348.447 Da) is slightly lower, which could be beneficial for permeability, while Ligand B (386.436 Da) is still well within the acceptable range.

**TPSA:** Both ligands have TPSA values below 90 (Ligand A: 86.63, Ligand B: 75.71), which is excellent for CNS penetration. Ligand B is slightly better here.

**logP:** Both ligands have optimal logP values (around 1.0), suggesting good permeability and reasonable solubility. Ligand A (1.081) and Ligand B (1.032) are very similar.

**H-Bond Donors/Acceptors:** Both ligands have acceptable HBD (1) and HBA (Ligand A: 5, Ligand B: 4) counts, balancing solubility and permeability.

**QED:** Ligand A (0.797) has a better QED score than Ligand B (0.601), indicating a more drug-like profile.

**DILI:** Ligand A (19.504) has a significantly lower DILI risk than Ligand B (29.43). This is a major advantage for Ligand A.

**BBB:** Ligand B (88.872) has a much higher BBB percentile than Ligand A (55.293). This is a critical factor for a CNS target like DRD2.

**Caco-2 Permeability:** Both have negative Caco-2 values which is unusual and likely indicates a problem with the modeling or data.

**Aqueous Solubility:** Ligand A (-0.279) has slightly better solubility than Ligand B (-2.165), though both are quite poor.

**hERG Inhibition:** Ligand A (0.14) has a lower hERG inhibition liability than Ligand B (0.596), which is preferable.

**Microsomal Clearance:** Ligand A (13.714 mL/min/kg) has a lower microsomal clearance than Ligand B (22.059 mL/min/kg), indicating better metabolic stability.

**In vitro Half-Life:** Ligand B (-25.607 hours) has a negative half-life, which is impossible. This is a major red flag. Ligand A (3.844 hours) is reasonable.

**P-gp Efflux:** Ligand A (0.007) has much lower P-gp efflux liability than Ligand B (0.041), which will improve CNS exposure.

**Binding Affinity:** Both ligands have excellent binding affinities (Ligand A: -7.7 kcal/mol, Ligand B: -7.5 kcal/mol). Ligand A is slightly better, but the difference is small.

**Overall Assessment:**

Ligand A is superior due to its better QED, significantly lower DILI risk, lower hERG inhibition, lower microsomal clearance, lower P-gp efflux, and a slightly better (though very close) binding affinity. The biggest advantage for Ligand B is its higher BBB penetration, but the negative half-life is a dealbreaker. The slightly lower BBB of Ligand A can potentially be mitigated through formulation strategies. The poor solubility of both compounds is a concern, but not as critical as the other issues with Ligand B.

Output:
0
2025-04-17 06:29:28,980 - INFO - Reasoning:

Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (353.849 and 346.391 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (42.24) is excellent, well below the 90 A^2 threshold for CNS targets. Ligand B (97.36) is higher, but still potentially acceptable, though less ideal.

**3. logP:** Ligand A (4.995) is slightly high, potentially leading to solubility issues or off-target interactions. Ligand B (0.328) is quite low, which could hinder membrane permeability and CNS penetration.

**4. H-Bond Donors:** Ligand A (1) is good. Ligand B (0) is also acceptable.

**5. H-Bond Acceptors:** Ligand A (2) is good. Ligand B (7) is higher, but still within the acceptable range of <=10.

**6. QED:** Both ligands (0.717 and 0.774) have good drug-likeness scores.

**7. DILI:** Both ligands have acceptable DILI risk (59.907 and 56.146).

**8. BBB:** Ligand A (62.854) is moderately good for BBB penetration, but could be better. Ligand B (54.634) is lower, raising concerns for CNS exposure.

**9. Caco-2:** Both have negative Caco-2 values which is unusual and suggests a problem with the data. We will proceed assuming these are percentile values and higher is better.

**10. Solubility:** Ligand A (-4.327) has poor aqueous solubility, consistent with its high logP. Ligand B (-0.876) is also poor, but less so than A.

**11. hERG:** Ligand A (0.691) has a low hERG risk. Ligand B (0.076) has very low hERG risk.

**12. Cl_mic:** Ligand A (62.41) has moderate microsomal clearance. Ligand B (39.604) has lower clearance, suggesting better metabolic stability.

**13. t1/2:** Ligand A (185.663) has a good in vitro half-life. Ligand B (-23.601) has a negative half-life, which is not physically possible and indicates a data error.

**14. Pgp:** Ligand A (0.757) has moderate P-gp efflux. Ligand B (0.017) has very low P-gp efflux, which is highly desirable for CNS penetration.

**15. Binding Affinity:** Ligand A (-10.2 kcal/mol) has significantly stronger binding affinity than Ligand B (-7.7 kcal/mol). This is a substantial advantage.

**Overall Assessment:**

Despite Ligand A's high logP and poor solubility, its *much* stronger binding affinity (-10.2 vs -7.7 kcal/mol) and acceptable BBB penetration outweigh these drawbacks, especially for a GPCR target. The difference in affinity is >1.5 kcal/mol, making it a significant factor. Ligand B has better ADME properties (lower logP, lower Pgp efflux, better metabolic stability), but its significantly weaker binding affinity is a major concern. The negative half-life for ligand B is also a red flag, indicating a data quality issue.

Output:
1
2025-04-17 06:29:28,981 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (343.39 and 344.46 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (119.23) is borderline for CNS penetration, being slightly above the preferred <90, but acceptable. Ligand B (65.54) is excellent, well below 90. This favors Ligand B.

**3. logP:** Both ligands have good logP values (1.615 and 2.201), falling within the optimal 1-3 range.

**4. H-Bond Donors:** Ligand A has 3 HBD, which is acceptable. Ligand B has 1, also acceptable.

**5. H-Bond Acceptors:** Ligand A has 5 HBA, acceptable. Ligand B has 4, also acceptable.

**6. QED:** Both ligands have good QED scores (0.673 and 0.889), indicating good drug-like properties. Ligand B is slightly better.

**7. DILI:** Ligand A has a DILI risk of 64.33, which is moderately high. Ligand B has a much lower DILI risk of 42.54, which is preferable.

**8. BBB:** This is critical for a CNS target. Ligand A has a BBB penetration of 62.97%, which is below the desirable >70%. Ligand B has a BBB penetration of 81.97%, which is excellent. This is a significant advantage for Ligand B.

**9. Caco-2:** Both ligands have negative Caco-2 values, which is unusual and difficult to interpret without knowing the scale. However, this is less critical than BBB for a CNS target.

**10. Solubility:** Both ligands have negative solubility values, which is also unusual and difficult to interpret.

**11. hERG:** Both ligands have low hERG inhibition liability (0.135 and 0.454), which is good.

**12. Cl_mic:** Ligand A has a lower microsomal clearance (14.713) than Ligand B (31.428), suggesting better metabolic stability. This favors Ligand A.

**13. t1/2:** Ligand B has a longer in vitro half-life (16.779 hours) than Ligand A (1.812 hours). This is a significant advantage for Ligand B.

**14. Pgp:** Both ligands have very low P-gp efflux liability (0.024 and 0.03), which is excellent for CNS penetration.

**15. Binding Affinity:** Ligand A has a slightly better binding affinity (-8.2 kcal/mol) than Ligand B (-7.6 kcal/mol). This is a 0.6 kcal/mol difference, which is notable but may not be decisive given the other factors.

**Overall Assessment:**

Ligand B is the stronger candidate. While Ligand A has a slightly better binding affinity and lower Cl_mic, Ligand B excels in crucial areas for a CNS-targeting GPCR ligand: significantly better BBB penetration (81.97% vs 62.97%), lower DILI risk, and a longer half-life. The lower TPSA of Ligand B is also beneficial. The 0.6 kcal/mol difference in binding affinity can likely be optimized in later stages of drug development.

Output:
1
2025-04-17 06:29:28,981 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B based on the provided guidelines, prioritizing GPCR-specific properties (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (370.381 Da) is slightly higher than Ligand B (343.431 Da), but both are acceptable.

**TPSA:** Both ligands have TPSA values below 140, suggesting good oral absorption potential. Ligand A (96.37) is slightly higher than Ligand B (83.28), but both are below the 90 threshold desirable for CNS targets.

**logP:** Ligand A (3.388) is within the optimal range (1-3), while Ligand B (1.75) is towards the lower end. A slightly higher logP is generally preferred for CNS penetration, making Ligand A favorable here.

**H-Bond Donors/Acceptors:** Ligand A has 3 HBD and 6 HBA, while Ligand B has 2 HBD and 5 HBA. Both are within acceptable limits (<=5 HBD and <=10 HBA).

**QED:** Both ligands have good QED scores (Ligand A: 0.533, Ligand B: 0.783). Ligand B has a slightly better QED, suggesting a more drug-like profile overall.

**DILI:** Ligand A (85.266) has a higher DILI risk than Ligand B (50.136). This is a significant drawback for Ligand A.

**BBB:** Both ligands have good BBB penetration (Ligand A: 71.578, Ligand B: 69.562), exceeding the 70% threshold for CNS targets. Ligand A is slightly better.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values, which is unusual and requires further investigation. However, we can compare the magnitudes; Ligand A (-5.203) is slightly less negative than Ligand B (-5.058).

**Aqueous Solubility:** Both ligands have negative solubility values, also unusual. Ligand B (-1.632) is slightly less negative than Ligand A (-4.828), suggesting slightly better solubility.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (Ligand A: 0.22, Ligand B: 0.188).

**Microsomal Clearance:** Ligand A (60.933) has higher microsomal clearance than Ligand B (-2.476), indicating lower metabolic stability. This is a negative for Ligand A.

**In vitro Half-Life:** Ligand B (17.207 hours) has a significantly longer half-life than Ligand A (9.044 hours), which is a major advantage.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (Ligand A: 0.105, Ligand B: 0.053).

**Binding Affinity:** Both ligands have very similar and strong binding affinities (Ligand A: -8.8 kcal/mol, Ligand B: -8.6 kcal/mol). The difference of 0.2 kcal/mol is not substantial enough to be decisive.

**Overall Assessment:**

Ligand B is the more promising candidate. While Ligand A has a slightly better logP and BBB, Ligand B excels in crucial areas: lower DILI risk, significantly longer half-life, and a slightly better QED score. The slightly better solubility of Ligand B is also a plus. The similar binding affinities mean that the ADME/Tox advantages of Ligand B outweigh the minor differences in other properties.

Output:
1
2025-04-17 06:29:28,981 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (339.435 and 342.443 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (58.56) is significantly better than Ligand B (97.78). For CNS targets, we want TPSA <= 90, and A is comfortably within this range, while B is close to the upper limit and less desirable.

**3. logP:** Both ligands have good logP values (2.649 and 2.337), falling within the optimal 1-3 range.

**4. H-Bond Donors:** Both have acceptable HBD counts (2 and 3, respectively), well below the threshold of 5.

**5. H-Bond Acceptors:** Both have acceptable HBA counts (3), well below the threshold of 10.

**6. QED:** Both have reasonable QED scores (0.88 and 0.709), indicating good drug-like properties.

**7. DILI:** Ligand A (30.865) has a much lower DILI risk than Ligand B (47.383). Both are below 60, but A is significantly preferred.

**8. BBB:** Ligand A (40.946) has a lower BBB penetration percentile than Ligand B (56.301). While both are not ideal (>70 is desirable), B is better for CNS penetration.

**9. Caco-2 Permeability:** Ligand A (-4.74) has worse Caco-2 permeability than Ligand B (-5.029). Lower values are less desirable.

**10. Aqueous Solubility:** Ligand A (-2.871) has better aqueous solubility than Ligand B (-4.177). Higher values are better.

**11. hERG Inhibition:** Both ligands have low hERG inhibition risk (0.3 and 0.555, respectively).

**12. Microsomal Clearance:** Ligand B (15.61) has lower microsomal clearance than Ligand A (20.846), suggesting better metabolic stability.

**13. In vitro Half-Life:** Ligand A (44.591) has a longer in vitro half-life than Ligand B (-6.341).

**14. P-gp Efflux:** Ligand A (0.111) has lower P-gp efflux than Ligand B (0.174), which is favorable for CNS exposure.

**15. Binding Affinity:** Both ligands have very similar and excellent binding affinities (-8.6 and -8.1 kcal/mol). The difference is less than 1.5 kcal/mol, so it doesn't significantly sway the decision.

**Overall Assessment:**

Considering the GPCR-specific priorities, Ligand A is slightly preferred. While Ligand B has better BBB penetration and metabolic stability, Ligand A has a significantly lower DILI risk, better TPSA, better solubility, and lower P-gp efflux. The binding affinity difference is minimal. The lower TPSA and DILI risk of Ligand A are more important for a CNS-targeting drug.

Output:
0
2025-04-17 06:29:28,981 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (361.833 and 364.339 Da) fall comfortably within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (70.59) is higher than Ligand B (58.64). For CNS targets, we prefer TPSA <= 90, so both are acceptable, but B is better.

**3. logP:** Ligand A (2.801) and Ligand B (1.826) are both within the optimal 1-3 range.

**4. H-Bond Donors:** Both have 1 HBD, which is good.

**5. H-Bond Acceptors:** Ligand A has 5 HBA, Ligand B has 3. Both are below the threshold of 10.

**6. QED:** Both ligands have QED values above 0.7, indicating good drug-likeness.

**7. DILI:** Ligand A (86.623) has a significantly higher DILI risk than Ligand B (41.179). This is a major concern for Ligand A.

**8. BBB:** Ligand B (87.476) has a much better BBB penetration percentile than Ligand A (61.923). This is crucial for a CNS target like DRD2.

**9. Caco-2:** Both have negative Caco-2 values, which is unusual and suggests poor permeability. However, the scale isn't specified, so it's hard to interpret.

**10. Solubility:** Both have negative solubility values, again making interpretation difficult.

**11. hERG:** Both ligands have low hERG inhibition liability (0.417 and 0.42).

**12. Cl_mic:** Ligand B (35.102) has a lower microsomal clearance than Ligand A (61.681), indicating better metabolic stability.

**13. t1/2:** Ligand B (-10.01) has a negative half-life, which is not physically possible. Ligand A (-0.808) also has a negative half-life, which is also not physically possible.

**14. Pgp:** Both ligands have very low Pgp efflux liability (0.076 and 0.12).

**15. Binding Affinity:** Ligand A (-8.6 kcal/mol) has a slightly better binding affinity than Ligand B (-7.9 kcal/mol). However, the difference is less than 1.5 kcal/mol, so it doesn't necessarily outweigh other factors.

**Overall Assessment:**

Ligand B is significantly better due to its much lower DILI risk and substantially improved BBB penetration. While Ligand A has slightly better binding affinity, the superior ADME properties of Ligand B, particularly the lower DILI and higher BBB, make it the more promising drug candidate for a CNS target like DRD2. The negative half-life values for both compounds are concerning and require further investigation, but the other factors strongly favor Ligand B.

Output:
1
2025-04-17 06:29:28,982 - INFO - Batch 286 complete. Total preferences: 4576
2025-04-17 06:29:28,982 - INFO - Processing batch 287/512...
2025-04-17 06:30:12,310 - INFO - Reasoning:

Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (352.387 Da and 361.385 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (102.96) is slightly above the optimal <90 for CNS targets, but still reasonable. Ligand B (65.07) is excellent, well below 90. This favors Ligand B.

**3. logP:** Both ligands have good logP values (1.032 and 1.619), falling within the 1-3 range.

**4. H-Bond Donors:** Ligand A has 2 HBD, which is acceptable. Ligand B has 0, which is also good.

**5. H-Bond Acceptors:** Ligand A has 6 HBA, acceptable. Ligand B has 5, also acceptable.

**6. QED:** Both ligands have good QED scores (0.508 and 0.673), indicating good drug-like properties. Ligand B is slightly better.

**7. DILI:** Ligand A (67.739) has a higher DILI risk than Ligand B (44.591). This favors Ligand B.

**8. BBB:** Ligand B (87.088) has a significantly better BBB penetration score than Ligand A (76.309). This is a crucial advantage for a CNS target like DRD2.

**9. Caco-2 Permeability:** Ligand A (-5.029) has poor Caco-2 permeability, while Ligand B (-4.491) is slightly better, but still poor.

**10. Aqueous Solubility:** Both ligands have poor aqueous solubility (-2.344 and -2.122). This could pose formulation challenges, but isn't a dealbreaker if other properties are strong.

**11. hERG Inhibition:** Both ligands have low hERG inhibition risk (0.25 and 0.389).

**12. Microsomal Clearance:** Ligand B (13.915) has a lower microsomal clearance than Ligand A (48.789), indicating better metabolic stability. This favors Ligand B.

**13. In vitro Half-Life:** Ligand A (-33.399) has a negative half-life, which is problematic. Ligand B (13.373) has a reasonable half-life. This is a significant advantage for Ligand B.

**14. P-gp Efflux:** Both ligands have low P-gp efflux liability (0.152 and 0.067). Ligand B is slightly better.

**15. Binding Affinity:** Ligand A (-7.7) has a slightly better binding affinity than Ligand B (-7.3). However, the difference is less than 1.5 kcal/mol, so it's not enough to outweigh the other significant advantages of Ligand B.

**Overall:**

Ligand B consistently outperforms Ligand A in several crucial ADME properties, particularly BBB penetration, DILI risk, metabolic stability (Cl_mic), and in vitro half-life. While Ligand A has slightly better binding affinity, the other factors make Ligand B a more promising drug candidate for a CNS target like DRD2. The poor Caco-2 and solubility are concerns for both, but can be addressed with formulation strategies.

Output:
1
2025-04-17 06:30:12,311 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (348.359 and 347.463 Da) fall within the ideal range of 200-500 Da.

**TPSA:** Ligand A (134.85) is slightly above the optimal <90 for CNS targets, but still reasonable. Ligand B (106.96) is excellent, well below 90.

**logP:** Ligand A (-1.453) is a bit low, potentially hindering permeability. Ligand B (3.367) is near the upper end of the optimal range (1-3), which is good.

**H-Bond Donors/Acceptors:** Ligand A (3 HBD, 6 HBA) is good. Ligand B (2 HBD, 3 HBA) is also excellent.

**QED:** Ligand A (0.575) is good, indicating drug-likeness. Ligand B (0.319) is below the 0.5 threshold, suggesting a less favorable drug-like profile.

**DILI:** Ligand A (54.75) has a moderate DILI risk. Ligand B (35.75) has a lower, more favorable DILI risk.

**BBB:** Ligand A (39.511) has a poor BBB penetration percentile. Ligand B (55.293) is better, but still below the desirable >70 for CNS targets.

**Caco-2 Permeability:** Ligand A (-5.593) is very poor, suggesting poor intestinal absorption. Ligand B (-4.758) is also poor, but slightly better than A.

**Aqueous Solubility:** Both ligands have very poor aqueous solubility (-2.04 and -3.206 respectively).

**hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.025 and 0.215 respectively).

**Microsomal Clearance:** Ligand A (-20.118) has a very low (good) microsomal clearance, indicating high metabolic stability. Ligand B (51.602) has a high clearance, suggesting rapid metabolism.

**In vitro Half-Life:** Ligand A (7.158 hours) is a reasonable half-life. Ligand B (-3.486 hours) is very short, which is undesirable.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.004 and 0.118 respectively).

**Binding Affinity:** Both ligands have comparable and strong binding affinities (-8.0 and -8.1 kcal/mol).

**Overall Assessment:**

While both ligands exhibit strong binding affinity, Ligand B has several advantages for CNS penetration despite its lower QED. It has a better logP, lower DILI risk, and a more favorable TPSA. However, the biggest drawback for Ligand B is its poor in vitro half-life and high microsomal clearance. Ligand A has a better half-life and clearance, but its low logP and very poor BBB penetration are significant liabilities for a CNS target. Given the importance of BBB penetration for DRD2, and the relatively small difference in affinity, Ligand B is slightly more promising, *if* its metabolic instability can be addressed through structural modifications. However, the poor solubility of both compounds is a concern.

Output:
1
2025-04-17 06:30:12,311 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (375.921 and 342.399 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (46.17) is excellent, well below the 90 A^2 threshold for CNS targets. Ligand B (85.25) is higher but still potentially acceptable, though less ideal.

**3. logP:** Ligand A (4.37) is slightly high, potentially leading to solubility issues or off-target interactions. Ligand B (0.987) is quite low, which could hinder membrane permeability and CNS penetration.

**4. H-Bond Donors:** Both ligands have acceptable HBD counts (1 and 2, respectively), well below the limit of 5.

**5. H-Bond Acceptors:** Both ligands have acceptable HBA counts (2 and 5, respectively), within the limit of 10.

**6. QED:** Both ligands have good QED scores (0.862 and 0.868), indicating drug-likeness.

**7. DILI:** Ligand A (54.983) has a moderate DILI risk, while Ligand B (76.192) has a higher DILI risk.

**8. BBB:** This is crucial for a CNS target like DRD2. Ligand A (86.817) shows excellent BBB penetration potential. Ligand B (43.699) is significantly lower, suggesting poor CNS exposure.

**9. Caco-2 Permeability:** Ligand A (-4.502) has poor Caco-2 permeability, which is concerning. Ligand B (-5.264) is also poor, but slightly worse than A.

**10. Aqueous Solubility:** Both ligands have very poor aqueous solubility (-5.432 and -2.002, respectively). This is a significant drawback.

**11. hERG Inhibition:** Ligand A (0.859) has a slightly higher hERG risk than Ligand B (0.29).

**12. Microsomal Clearance:** Ligand A (60.179) has higher clearance, indicating lower metabolic stability. Ligand B (3.868) has very low clearance, suggesting good metabolic stability.

**13. In vitro Half-Life:** Ligand A (80.3) has a good half-life. Ligand B (23.503) has a shorter half-life.

**14. P-gp Efflux:** Ligand A (0.692) has moderate P-gp efflux, while Ligand B (0.012) has very low P-gp efflux, which is highly desirable for CNS penetration.

**15. Binding Affinity:** Both ligands have excellent binding affinity (-9.5 and -8.9 kcal/mol, respectively). The difference of 0.6 kcal/mol is not substantial enough to override other significant differences.

**Overall Assessment:**

Ligand A excels in BBB penetration and has a good in vitro half-life and binding affinity. However, it suffers from a high logP, poor Caco-2 permeability, moderate DILI risk, and higher metabolic clearance. Ligand B has better metabolic stability and lower P-gp efflux, but its low logP and poor BBB penetration are major drawbacks for a CNS target.

Considering the GPCR-specific priorities, *BBB penetration is paramount*. Ligand A's significantly higher BBB percentile (86.817 vs. 43.699) makes it the more promising candidate, despite its other weaknesses. The poor solubility and permeability could potentially be addressed with formulation strategies.

Output:
0
2025-04-17 06:30:12,311 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (366.49 and 351.49 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (72.64) is slightly higher than Ligand B (70.67), but both are below the 90 A^2 threshold desirable for CNS targets.

**3. logP:** Both ligands have optimal logP values (2.047 and 1.609), falling within the 1-3 range.

**4. H-Bond Donors:** Ligand A (1) is better than Ligand B (2), both are within the acceptable limit of 5.

**5. H-Bond Acceptors:** Ligand A (8) is higher than Ligand B (4), but both are within the acceptable limit of 10.

**6. QED:** Both ligands have good QED scores (0.771 and 0.731), indicating good drug-like properties.

**7. DILI:** Ligand A (33.114) has a significantly lower DILI risk than Ligand B (13.843). This is a major advantage for Ligand A.

**8. BBB:** Ligand A (63.048) has a better BBB penetration percentile than Ligand B (54.595). While both are below the ideal >70, A is closer. This is critical for a CNS target like DRD2.

**9. Caco-2 Permeability:** Both have negative values (-5.574 and -5.012), suggesting poor permeability. This is a concern for both.

**10. Aqueous Solubility:** Both have negative values (-1.497 and -0.87), indicating poor aqueous solubility. This could pose formulation challenges.

**11. hERG Inhibition:** Both ligands have low hERG inhibition risk (0.333 and 0.153).

**12. Microsomal Clearance:** Ligand A (9.815) has lower microsomal clearance than Ligand B (12.931), suggesting better metabolic stability.

**13. In vitro Half-Life:** Ligand A (51.652) has a significantly longer in vitro half-life than Ligand B (6.694). This is a significant advantage.

**14. P-gp Efflux:** Ligand A (0.078) has lower P-gp efflux liability than Ligand B (0.016), meaning it's less likely to be pumped out of the brain, improving CNS exposure.

**15. Binding Affinity:** Ligand A (-7.7 kcal/mol) has a significantly stronger binding affinity than Ligand B (0.0 kcal/mol). This is the most crucial factor.

**Overall Assessment:**

Ligand A is clearly superior. While both have issues with Caco-2 permeability and solubility, Ligand A excels in the most critical areas for a CNS-targeting GPCR: binding affinity, BBB penetration, metabolic stability (lower Cl_mic, longer t1/2), lower DILI risk, and lower P-gp efflux. The substantial difference in binding affinity (-7.7 vs 0.0) is a decisive factor, and can potentially overcome the permeability/solubility issues.

Output:
1
2025-04-17 06:30:12,311 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (345.403 Da) is slightly lower, which is generally favorable for permeability.

**2. TPSA:** Ligand A (106.07) is better than Ligand B (77.92). Both are below the 140 threshold for oral absorption and, importantly, below the 90 threshold preferred for CNS targets.

**3. logP:** Both ligands have similar logP values (A: 0.894, B: 0.913), falling within the optimal 1-3 range.

**4. H-Bond Donors:** Ligand A has 2 HBD, while Ligand B has 1. Both are acceptable (<=5).

**5. H-Bond Acceptors:** Ligand A has 7 HBA, and Ligand B has 4. Both are within the acceptable range (<=10).

**6. QED:** Both ligands have similar QED values (A: 0.805, B: 0.769), indicating good drug-like properties.

**7. DILI:** Ligand A (44.94) has a slightly higher DILI risk than Ligand B (27.453), but both are below the concerning threshold of 60.

**8. BBB:** This is a crucial parameter for a CNS target like DRD2. Ligand B (80.264) significantly outperforms Ligand A (24.389). This is a major advantage for Ligand B.

**9. Caco-2 Permeability:** Ligand A (-5.273) has a negative Caco-2 value, which is unusual and suggests very poor permeability. Ligand B (-4.798) also has a negative value, but is slightly better. Both are concerning.

**10. Aqueous Solubility:** Ligand A (-1.66) has slightly better solubility than Ligand B (-2.403), but both are poor.

**11. hERG Inhibition:** Both ligands have very low hERG inhibition risk (A: 0.028, B: 0.604).

**12. Microsomal Clearance:** Ligand A (-16.928) has a lower (better) microsomal clearance than Ligand B (15.311), indicating greater metabolic stability.

**13. In vitro Half-Life:** Ligand B (-33.364) has a significantly longer in vitro half-life than Ligand A (25.951).

**14. P-gp Efflux:** Both ligands have very low P-gp efflux liability (A: 0.015, B: 0.033).

**15. Binding Affinity:** Both ligands have very similar binding affinities (A: -8.9 kcal/mol, B: -8.2 kcal/mol). The difference is less than 1.5 kcal/mol, so it's not a decisive factor.

**Overall Assessment:**

While Ligand A has slightly better metabolic stability and solubility, Ligand B is significantly better in terms of BBB penetration (80.264 vs 24.389) and has a longer half-life. The poor Caco-2 permeability of both is a concern, but the superior BBB penetration of Ligand B is critical for a CNS-targeting drug. Given the GPCR-specific priorities, the substantial advantage in BBB outweighs the minor benefits of Ligand A.

Output:
1
2025-04-17 06:30:12,311 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B based on the provided guidelines, prioritizing GPCR-specific properties (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (360.523 and 346.431 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (49.41) is significantly better than Ligand B (76.46). For CNS targets, TPSA should be <=90, and A is comfortably within this range, while B is approaching the upper limit.

**logP:** Ligand A (3.815) is optimal (1-3), while Ligand B (0.904) is slightly low, potentially hindering permeation.

**H-Bond Donors/Acceptors:** Both have acceptable HBD (1) and Ligand A has 3 HBA, and Ligand B has 5 HBA, both within the recommended limits.

**QED:** Both ligands have reasonable QED values (0.838 and 0.588), indicating good drug-like properties.

**DILI:** Both ligands have low DILI risk (36.06 and 33.695), below the 40 threshold.

**BBB:** Both ligands exhibit excellent BBB penetration (80.419 and 83.443), exceeding the desirable >70 threshold for CNS targets.

**Caco-2 Permeability:** Both have negative Caco-2 values (-5.013 and -4.973), which is unusual and likely indicates a problem with the prediction method or the molecule's structure. However, the values are similar.

**Aqueous Solubility:** Both have negative solubility values (-4.114 and -2.057). Again, this is unusual and problematic, suggesting poor solubility. Ligand B is slightly better.

**hERG:** Both ligands have low hERG risk (0.511 and 0.319).

**Microsomal Clearance:** Ligand A (43.184) has higher clearance than Ligand B (26.154). Lower clearance is preferred, so Ligand B is better here.

**In vitro Half-Life:** Ligand B (3.55) has a longer half-life than Ligand A (2.015). Longer half-life is generally preferred.

**P-gp Efflux:** Both ligands have low P-gp efflux (0.341 and 0.076), which is good for CNS exposure. Ligand B is better.

**Binding Affinity:** Ligand B (-8.2 kcal/mol) has a significantly stronger binding affinity than Ligand A (-7.2 kcal/mol). This >1.5 kcal/mol difference is substantial and can outweigh some ADME drawbacks.

**Overall Assessment:**

Ligand B has a superior binding affinity, better metabolic stability (lower Cl_mic, longer t1/2), and lower P-gp efflux. While its logP is slightly lower and solubility is worse, the strong affinity and favorable CNS properties (BBB, Pgp) are crucial for a CNS-targeting GPCR. Ligand A has better TPSA, but the affinity difference is significant. The negative solubility and Caco-2 values are concerning for both, but the binding affinity advantage of Ligand B is compelling.

Output:
1
2025-04-17 06:30:12,312 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (346.381 and 362.461 Da) fall within the ideal 200-500 Da range.

**TPSA:** Both ligands (57.26 and 58.64) are below the 90 A^2 threshold desirable for CNS targets, which is good.

**logP:** Ligand A (3.642) is slightly higher than Ligand B (2.838), both within the optimal 1-3 range.

**H-Bond Donors:** Ligand A (2) is slightly higher than Ligand B (1), both are within the acceptable limit of 5.

**H-Bond Acceptors:** Both ligands have 3 H-bond acceptors, well within the limit of 10.

**QED:** Both ligands have QED values above 0.7, indicating good drug-likeness.

**DILI:** Ligand A (60.062) has a higher DILI risk than Ligand B (18.922). This is a significant drawback for Ligand A.

**BBB:** Ligand B (88.6) has a substantially higher BBB penetration percentile than Ligand A (77.2). This is a critical advantage for a CNS target like DRD2.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values, which is unusual and suggests poor permeability. However, the values are similar.

**Aqueous Solubility:** Both ligands have negative solubility values, which is also unusual and suggests poor solubility. However, the values are similar.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.811 and 0.672).

**Microsomal Clearance:** Ligand A (-2.146) has a more negative clearance value, indicating *lower* clearance and thus better metabolic stability than Ligand B (16.153).

**In vitro Half-Life:** Ligand A (15.187 hours) has a longer half-life than Ligand B (-2.248 hours).

**P-gp Efflux:** Ligand A (0.119) has lower P-gp efflux liability than Ligand B (0.075), which is favorable for CNS penetration.

**Binding Affinity:** Ligand B (-7.6 kcal/mol) has a significantly stronger binding affinity than Ligand A (-10.0 kcal/mol). This is a substantial advantage.

**Overall Assessment:**

Ligand B is the stronger candidate. While Ligand A has better metabolic stability and P-gp efflux, the significantly better binding affinity, much lower DILI risk, and higher BBB penetration of Ligand B outweigh these advantages. The negative Caco-2 and solubility values are concerning for both, but can be addressed in further optimization. For a CNS target, BBB penetration is paramount, and Ligand B excels in this area.

Output:
1
2025-04-17 06:30:12,312 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (422.055 Da) is slightly higher than Ligand B (344.459 Da), but both are acceptable.

**2. TPSA:** Ligand A (93.21) is borderline for CNS targets (ideally <90), while Ligand B (67.23) is well within the desired range. This is a significant advantage for Ligand B.

**3. logP:** Both ligands have good logP values (A: 3.567, B: 2.194), falling within the optimal 1-3 range.

**4. H-Bond Donors:** Both ligands have acceptable HBD counts (A: 2, B: 1).

**5. H-Bond Acceptors:** Both ligands have acceptable HBA counts (A: 6, B: 4).

**6. QED:** Both ligands have good QED scores (A: 0.736, B: 0.833), indicating good drug-like properties.

**7. DILI:** Ligand A has a very high DILI risk (99.457%), which is a major red flag. Ligand B has a much lower DILI risk (34.587%), which is favorable.

**8. BBB:** Ligand A has a moderate BBB penetration (53.703%), which is not ideal for a CNS target. Ligand B has a significantly better BBB penetration (67.701%), though still not optimal (>70 is preferred).

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.766 and -4.764), which is unusual and suggests poor permeability. However, these values are on the same scale, so don't differentiate the ligands.

**10. Aqueous Solubility:** Both ligands have very poor aqueous solubility (-5.538 and -2.983). This is a concern for both, but less so if the compounds are designed for direct CNS administration.

**11. hERG Inhibition:** Both ligands have low hERG inhibition risk (A: 0.241, B: 0.113).

**12. Microsomal Clearance:** Ligand A has lower microsomal clearance (14.323) than Ligand B (24.823), suggesting better metabolic stability.

**13. In vitro Half-Life:** Ligand A has a longer in vitro half-life (19.861) than Ligand B (13.664).

**14. P-gp Efflux:** Ligand A has higher P-gp efflux (0.479) than Ligand B (0.049), meaning Ligand B is less likely to be pumped out of the brain, improving CNS exposure.

**15. Binding Affinity:** Ligand B has a significantly stronger binding affinity (-7.5 kcal/mol) compared to Ligand A (-10.1 kcal/mol). This is a substantial advantage.

**Overall Assessment:**

While Ligand A has better metabolic stability and half-life, its extremely high DILI risk, moderate BBB penetration, and higher P-gp efflux make it a less desirable candidate. Ligand B, despite slightly worse metabolic properties, has a much lower DILI risk, better BBB penetration, lower P-gp efflux, and significantly stronger binding affinity. The strong affinity of Ligand B can potentially compensate for the slightly less favorable metabolic properties. Given the GPCR-specific priorities, especially BBB and affinity, Ligand B is the more promising candidate.

Output:
1
2025-04-17 06:30:12,312 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (357.439 and 342.439 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (99.81) is higher than Ligand B (53.35). For CNS targets, TPSA should be <=90, so Ligand B is significantly better here.

**logP:** Ligand A (1.856) is within the optimal 1-3 range. Ligand B (3.862) is at the higher end, potentially leading to solubility issues, but still acceptable.

**H-Bond Donors:** Ligand A (2) and Ligand B (0) are both acceptable (<=5).

**H-Bond Acceptors:** Ligand A (6) and Ligand B (5) are both acceptable (<=10).

**QED:** Both ligands have similar QED values (0.79 and 0.717), indicating good drug-likeness.

**DILI:** Ligand A (52.772) has a slightly higher DILI risk than Ligand B (38.193), but both are below the concerning threshold of 60.

**BBB:** This is a critical parameter for a CNS target like DRD2. Ligand B (69.756) is much better than Ligand A (43.777), being closer to the desirable >70 percentile.

**Caco-2 Permeability:** Ligand A (-5.416) and Ligand B (-4.38) both have negative values, indicating poor permeability.

**Aqueous Solubility:** Ligand A (-2.795) and Ligand B (-4.113) both have negative values, indicating poor solubility.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.535 and 0.554).

**Microsomal Clearance:** Ligand A (-0.882) has a lower (better) microsomal clearance than Ligand B (86.1). This suggests better metabolic stability for Ligand A.

**In vitro Half-Life:** Ligand A (10.473) has a longer half-life than Ligand B (-0.204).

**P-gp Efflux:** Ligand A (0.019) has a much lower P-gp efflux liability than Ligand B (0.429), which is crucial for CNS penetration.

**Binding Affinity:** Both ligands have excellent binding affinities (-8.1 and -8.3 kcal/mol). The difference is minimal.

**Overall Assessment:**

Ligand B clearly wins on the most important criteria for a CNS-targeting GPCR ligand: BBB penetration and P-gp efflux. While Ligand A has better metabolic stability (lower Cl_mic and longer half-life), the superior CNS penetration profile of Ligand B outweighs this advantage. The TPSA of Ligand B is also significantly better. The slight difference in binding affinity is negligible.

Output:
1
2025-04-17 06:30:12,312 - INFO - Reasoning:

Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (333.435 and 345.447 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (56.13) is excellent, well below the 90 A^2 threshold for CNS targets. Ligand B (81.33) is still reasonable, but higher and less favorable.

**3. logP:** Ligand A (3.55) is optimal. Ligand B (1.005) is a bit low, potentially hindering membrane permeability.

**4. H-Bond Donors:** Ligand A (1) and Ligand B (2) are both within the acceptable limit of <=5.

**5. H-Bond Acceptors:** Ligand A (3) and Ligand B (4) are both within the acceptable limit of <=10.

**6. QED:** Both ligands have good QED scores (0.843 and 0.856), indicating good drug-like properties.

**7. DILI:** Ligand A (34.161) has a slightly higher DILI risk than Ligand B (24.118), but both are below the concerning threshold of 60.

**8. BBB:** This is crucial for a CNS target. Ligand A (83.521) has a significantly better BBB percentile than Ligand B (67.003).  Ligand A is much closer to the desirable >70.

**9. Caco-2:** Ligand A (-4.612) and Ligand B (-5.254) both have negative values, which is unusual and suggests very poor permeability. This is a significant concern for both.

**10. Solubility:** Ligand A (-4.326) and Ligand B (-2.389) both have negative values, suggesting poor aqueous solubility. This is a concern for both.

**11. hERG:** Both ligands have low hERG risk (0.892 and 0.395).

**12. Cl_mic:** Ligand B (-5.144) has a *much* lower (better) microsomal clearance than Ligand A (34.367), indicating greater metabolic stability.

**13. t1/2:** Ligand A (38.796) has a better in vitro half-life than Ligand B (-13.554).

**14. Pgp:** Ligand A (0.226) has lower P-gp efflux liability than Ligand B (0.018), which is favorable for CNS penetration.

**15. Binding Affinity:** Ligand A (-9.2 kcal/mol) has a significantly stronger binding affinity than Ligand B (-7.7 kcal/mol). This is a substantial advantage.

**Overall Assessment:**

Despite both compounds having issues with Caco-2 and solubility, Ligand A is the stronger candidate. The significantly better BBB penetration, substantially stronger binding affinity, and lower P-gp efflux outweigh the slightly higher DILI risk and worse metabolic stability (Cl_mic). The affinity difference is large enough to potentially overcome the ADME liabilities with appropriate formulation strategies. Ligand B's low logP is a major drawback, and its poor metabolic stability is also concerning.

Output:
1
2025-04-17 06:30:12,312 - INFO - Reasoning:

Let's analyze Ligand A and Ligand B for their potential as DRD2 drug candidates, considering the provided guidelines and GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (349.821 Da) is slightly lower, which could be beneficial for permeability.

**2. TPSA:** Ligand A (46.92) is excellent for CNS penetration, well below the 90 A^2 threshold. Ligand B (82.68) is higher but still potentially acceptable, though less ideal.

**3. logP:** Ligand A (4.352) is a bit high, potentially leading to solubility issues or off-target effects. Ligand B (1.359) is within the optimal range.

**4. H-Bond Donors:** Both ligands have 1 HBD, which is within the acceptable limit of 5.

**5. H-Bond Acceptors:** Ligand A has 4 HBAs, and Ligand B has 9 HBAs, both within the acceptable limit of 10.

**6. QED:** Both ligands have good QED values (A: 0.598, B: 0.756), indicating drug-like properties.

**7. DILI:** Ligand A (87.243) has a higher DILI risk than Ligand B (59.829). This is a significant concern.

**8. BBB:** Ligand A (64.482) has a moderate BBB penetration, while Ligand B (54.711) is lower. Both are below the ideal >70 for CNS targets, but A is better.

**9. Caco-2 Permeability:** Ligand A (-4.854) has poor Caco-2 permeability, suggesting poor intestinal absorption. Ligand B (-5.819) is also poor, but slightly better than A.

**10. Aqueous Solubility:** Ligand A (-4.964) has very poor aqueous solubility, consistent with its high logP. Ligand B (-1.783) has better solubility.

**11. hERG Inhibition:** Ligand A (0.707) has a slightly elevated hERG risk, while Ligand B (0.084) has very low risk.

**12. Microsomal Clearance:** Ligand A (46.524) has moderate clearance, while Ligand B (20.555) has low clearance, indicating better metabolic stability.

**13. In vitro Half-Life:** Ligand A (96.511) has a long half-life, which is desirable. Ligand B (22.518) has a shorter half-life.

**14. P-gp Efflux:** Ligand A (0.749) has moderate P-gp efflux, while Ligand B (0.106) has very low efflux, which is beneficial for CNS exposure.

**15. Binding Affinity:** Ligand A (-10.3 kcal/mol) has significantly stronger binding affinity than Ligand B (-6.3 kcal/mol). This is a substantial advantage.

**Overall Assessment:**

Ligand A has a much stronger binding affinity, a longer half-life, and better BBB penetration than Ligand B. However, it suffers from poor solubility, poor Caco-2 permeability, a higher DILI risk, and moderate P-gp efflux. Ligand B has better ADME properties (solubility, metabolic stability, P-gp efflux, hERG) but significantly weaker binding affinity.

Given the GPCR-specific priorities, and the substantial affinity difference, I believe **Ligand A** is the more promising candidate *despite* its ADME liabilities. The strong binding affinity (-10.3 kcal/mol) is a major advantage that could potentially be mitigated through further medicinal chemistry optimization to improve solubility and reduce DILI risk. The poor permeability and solubility are addressable through prodrug strategies or structural modifications. The weaker affinity of Ligand B is a more difficult hurdle to overcome.

Output:
1
2025-04-17 06:30:12,313 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B against the provided guidelines, prioritizing GPCR-specific properties (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (348.575) is slightly lower, which is generally favorable for permeability.

**TPSA:** Both ligands have TPSA values below 140, but Ligand B (29.54) is closer to the ideal <90 for CNS targets than Ligand A (32.34).

**logP:** Both ligands have logP values within the optimal range (1-3), with Ligand A (4.9) being slightly higher than Ligand B (4.004). While still acceptable, Ligand A's higher logP could potentially lead to off-target effects or solubility issues.

**H-Bond Donors/Acceptors:** Ligand A has 1 HBD and 2 HBA, while Ligand B has 0 HBD and 2 HBA. Both are within acceptable limits.

**QED:** Ligand A (0.74) has a better QED score than Ligand B (0.552), indicating a more drug-like profile.

**DILI:** Ligand B (37.999) has a significantly lower DILI risk than Ligand A (13.532), which is a substantial advantage.

**BBB:** Both ligands exhibit excellent BBB penetration, with Ligand B (88.406) being slightly better than Ligand A (79.992). This is crucial for a CNS target like DRD2.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values, which is unusual. Assuming these are logP-like scales, lower values indicate poorer permeability. Ligand A (-4.883) is worse than Ligand B (-4.324).

**Aqueous Solubility:** Both ligands have negative solubility values, again unusual. Lower values indicate poorer solubility. Ligand A (-4.344) is slightly worse than Ligand B (-4.61).

**hERG Inhibition:** Both ligands show low hERG inhibition risk. Ligand A (0.895) is slightly higher than Ligand B (0.653).

**Microsomal Clearance:** Ligand B (88.615) has a significantly higher microsomal clearance than Ligand A (62.387), meaning it's metabolized faster and has lower metabolic stability.

**In vitro Half-Life:** Ligand A (8.915) has a longer in vitro half-life than Ligand B (-25.752). The negative value for Ligand B is concerning and suggests very rapid degradation.

**P-gp Efflux:** Both ligands show minimal P-gp efflux liability.

**Binding Affinity:** Ligand B (-7.8 kcal/mol) has a significantly stronger binding affinity than Ligand A (-0.0 kcal/mol). This is a major advantage, potentially outweighing some ADME drawbacks.

**Overall Assessment:**

Ligand B is the stronger candidate. The significantly improved binding affinity (-7.8 vs -0.0 kcal/mol) is a decisive factor for a GPCR target. While Ligand B has higher microsomal clearance and a concerning negative half-life, its superior BBB penetration, lower DILI risk, and better TPSA make it more promising. Ligand A's better QED and half-life are overshadowed by its weaker binding and higher DILI risk. The negative Caco-2 and solubility values for both are concerning and would require further investigation, but the potency advantage of Ligand B is substantial.

Output:
1
2025-04-17 06:30:12,313 - INFO - Reasoning:

Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (351.491 and 369.443 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (83.71) is excellent, well below the 90 A^2 threshold for CNS targets. Ligand B (116.67) is still reasonable but higher, potentially impacting BBB penetration.

**3. logP:** Ligand A (1.774) is optimal. Ligand B (0.184) is quite low, which could hinder membrane permeability and potentially reduce binding affinity.

**4. H-Bond Donors:** Both ligands have acceptable HBD counts (1 and 2 respectively), well within the limit of 5.

**5. H-Bond Acceptors:** Ligand A (3) and Ligand B (6) are both within the acceptable limit of 10.

**6. QED:** Both ligands have similar and good QED values (0.759 and 0.765), indicating good drug-like properties.

**7. DILI:** Ligand A (7.251) has a very favorable DILI score, indicating low liver injury risk. Ligand B (50.136) is higher, suggesting a moderate risk.

**8. BBB:** This is crucial for a CNS target. Ligand A (87.398) has a very good BBB percentile, exceeding the desirable >70 threshold. Ligand B (57.697) is significantly lower, raising concerns about CNS exposure.

**9. Caco-2 Permeability:** Ligand A (-5.066) and Ligand B (-5.36) both have negative values, which is unusual and suggests poor permeability. However, the scale is not specified, so we can't interpret this definitively.

**10. Aqueous Solubility:** Both ligands have negative solubility values (-2.196 and -1.774), which is also unusual and suggests poor solubility. Again, the scale is unspecified.

**11. hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.341 and 0.105).

**12. Microsomal Clearance:** Ligand A (32.834) has moderate clearance. Ligand B (-39.667) has negative clearance, which is not physically possible and likely an error in the data. This is a major red flag.

**13. In vitro Half-Life:** Ligand A (-24.583) has a negative half-life, which is impossible. Ligand B (20.486) has a reasonable half-life.

**14. P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.021).

**15. Binding Affinity:** Both ligands have excellent binding affinities (-7.8 and -7.7 kcal/mol), which are very close and both well below the -7.0 kcal/mol threshold. The difference of 0.1 kcal/mol is unlikely to be decisive.

**Overall Assessment:**

Ligand A is significantly more promising despite the unusual negative values for Caco-2 and solubility. It has a much better BBB score, a lower DILI risk, and a more favorable logP. The negative values for half-life and Caco-2 for Ligand A are concerning, but the negative clearance for Ligand B is a fatal flaw. The slightly better BBB and DILI profile of Ligand A outweigh the small difference in binding affinity.

Output:
0
2025-04-17 06:30:12,313 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (342.395 Da) is slightly lower, which could be beneficial for permeability. Ligand B (365.499 Da) is also good.

**TPSA:** Ligand A (91.68) is borderline for CNS targets (<=90 is preferred) but acceptable. Ligand B (69.72) is excellent, well below the 90 threshold, suggesting better CNS penetration potential.

**logP:** Both ligands have good logP values (Ligand A: 2.113, Ligand B: 1.025), falling within the optimal 1-3 range. Ligand A is slightly higher, which could be a minor concern for off-target effects, but still reasonable.

**H-Bond Donors/Acceptors:** Ligand A has 3 HBD and 5 HBA, while Ligand B has 1 HBD and 4 HBA. Both are within acceptable limits (<=5 HBD and <=10 HBA).

**QED:** Both ligands have good QED scores (Ligand A: 0.774, Ligand B: 0.811), indicating good drug-like properties.

**DILI:** Ligand A (33.695) has a lower DILI risk than Ligand B (44.164), which is a positive. Both are below the 60 threshold, indicating acceptable risk.

**BBB:** Ligand A (40.403) has a lower BBB percentile than Ligand B (47.15). While neither is *high* (>70), Ligand B is slightly better for CNS penetration.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.145 and -5.26), which is unusual and suggests poor intestinal absorption. This is a significant drawback for both.

**Aqueous Solubility:** Both ligands have negative solubility values (-3.127 and -2.266), indicating very poor aqueous solubility. This is a major concern for formulation and bioavailability.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (Ligand A: 0.124, Ligand B: 0.249).

**Microsomal Clearance:** Ligand A (10.992) has significantly lower microsomal clearance than Ligand B (23.503), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (-3.079) has a negative half-life, which is not physically possible and indicates a problem with the data or the molecule itself. Ligand B (17.229) has a reasonable half-life.

**P-gp Efflux:** Ligand A (0.077) has lower P-gp efflux than Ligand B (0.055), indicating better potential for CNS exposure.

**Binding Affinity:** Ligand A (-9.3 kcal/mol) has a *much* stronger binding affinity than Ligand B (-0.0 kcal/mol). This is a huge advantage, potentially outweighing some of the ADME drawbacks.

**Overall Assessment:**

Ligand A's significantly stronger binding affinity (-9.3 kcal/mol vs -0.0 kcal/mol) is the most important factor. While it has a slightly less favorable TPSA and BBB, the binding affinity difference is substantial. The negative half-life for Ligand A is a major red flag, but assuming that is a data error, the rest of the profile is reasonable. Ligand B has better TPSA and BBB, but its extremely weak binding affinity makes it unlikely to be a viable candidate. The poor Caco-2 and solubility for both are concerning, but can sometimes be addressed with formulation strategies.

Output:
1
2025-04-17 06:30:12,313 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (346.471 and 361.511 Da) fall within the ideal 200-500 Da range.

**TPSA:** Both ligands have TPSA values (57.69 and 56.67) below the 90 A^2 threshold desirable for CNS targets, which is excellent.

**logP:** Both ligands have logP values (2.551 and 3.253) within the optimal 1-3 range. Ligand B is slightly higher, potentially improving membrane permeability.

**H-Bond Donors/Acceptors:** Ligand A (0 HBD, 3 HBA) and Ligand B (1 HBD, 5 HBA) both have reasonable H-bond characteristics, well within the guidelines.

**QED:** Both ligands have good QED scores (0.581 and 0.858), indicating drug-like properties. Ligand B is better here.

**DILI:** Ligand A (44.009) is slightly higher than Ligand B (23.769), indicating a potentially higher risk of drug-induced liver injury. Ligand B is preferable.

**BBB:** Ligand A (81.776) has a significantly better BBB percentile than Ligand B (59.093). This is a *critical* factor for a CNS target like DRD2.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.385 and -4.797), which is unusual and suggests poor permeability. However, these values are on a log scale and can be difficult to interpret without further context.

**Aqueous Solubility:** Both ligands have negative solubility values (-3.253 and -2.641), indicating poor aqueous solubility. This could pose formulation challenges.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.305 and 0.448).

**Microsomal Clearance:** Ligand A (53.092) has lower microsomal clearance than Ligand B (78.103), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (-14.829) has a negative half-life, which is not possible, and suggests an issue with the data. Ligand B (12.936) has a reasonable in vitro half-life.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.329 and 0.071), which is good for CNS penetration. Ligand B is better here.

**Binding Affinity:** Both ligands have excellent binding affinity (-7.1 and -7.2 kcal/mol), with Ligand B being slightly stronger. The difference is small, but could be meaningful.

**Overall Assessment:**

Ligand A has a significantly better BBB score and lower microsomal clearance, which are both important for CNS drug development. However, Ligand B has better QED, lower DILI risk, a slightly better binding affinity, and a more reasonable in vitro half-life. The negative half-life for Ligand A is a major red flag. While the Caco-2 and solubility values are poor for both, the BBB score is paramount for a CNS target. However, the questionable half-life of ligand A makes it less favorable.

Output:
1
2025-04-17 06:30:12,314 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (341.342 and 347.459 Da) fall comfortably within the ideal 200-500 Da range.

**2. TPSA:** Both ligands have a TPSA of 75.44, which is above the optimal <90 for CNS targets but not drastically so.

**3. logP:** Ligand A (1.967) is within the optimal 1-3 range. Ligand B (3.206) is at the higher end of the optimal range, but still acceptable.

**4. H-Bond Donors:** Both ligands have 1 HBD, which is well within the acceptable limit of <=5.

**5. H-Bond Acceptors:** Both ligands have 4 HBA, also within the acceptable limit of <=10.

**6. QED:** Both ligands have QED values >0.8, indicating good drug-like properties.

**7. DILI:** Ligand A (69.678) has a higher DILI risk than Ligand B (33.346). This is a significant negative for Ligand A.

**8. BBB:** Both ligands have good BBB penetration (67.39% and 70.609%), exceeding the 70% threshold for CNS targets. Ligand B is slightly better.

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 values, which is unusual and suggests poor permeability. This is a concern for both.

**10. Aqueous Solubility:** Both ligands have negative solubility values, indicating poor aqueous solubility. This is a concern for both.

**11. hERG Inhibition:** Both ligands show very low hERG inhibition liability (0.199 and 0.056), which is excellent.

**12. Microsomal Clearance:** Ligand A (1.177 mL/min/kg) has significantly lower microsomal clearance than Ligand B (68.963 mL/min/kg), suggesting better metabolic stability.

**13. In vitro Half-Life:** Ligand A (3.762 hours) has a shorter half-life than Ligand B (9.55 hours).

**14. P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.091 and 0.076), which is favorable for CNS penetration.

**15. Binding Affinity:** Ligand A (-8.6 kcal/mol) has a slightly better binding affinity than Ligand B (-8.1 kcal/mol). The difference is 0.5 kcal/mol, which is significant.

**Overall Assessment:**

While Ligand A has a slightly better binding affinity and metabolic stability, Ligand B is clearly superior due to its significantly lower DILI risk. The DILI risk for Ligand A is quite high (69.678), making it a less desirable candidate. Both compounds have issues with Caco-2 permeability and aqueous solubility, but these can potentially be addressed through formulation strategies. The small advantage in binding affinity of Ligand A is outweighed by the substantial risk associated with its DILI score.

Output:
1
2025-04-17 06:30:12,314 - INFO - Batch 287 complete. Total preferences: 4592
2025-04-17 06:30:12,314 - INFO - Processing batch 288/512...
2025-04-17 06:30:55,326 - INFO - Reasoning:

Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (352.41 and 350.503 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (96.25) is better than Ligand B (67.43). Both are below the 90 A^2 threshold for CNS targets, but A is slightly higher.

**3. logP:** Ligand B (2.949) is optimal (1-3), while Ligand A (0.637) is below 1, which could impede permeation. This is a significant drawback for Ligand A.

**4. H-Bond Donors:** Ligand A (3) and Ligand B (2) are both acceptable (<=5).

**5. H-Bond Acceptors:** Ligand A (5) and Ligand B (3) are both acceptable (<=10).

**6. QED:** Both ligands have reasonable QED values (0.671 and 0.595), indicating good drug-like properties.

**7. DILI:** Ligand B (8.026) has a much lower DILI risk than Ligand A (52.695). This is a major advantage for Ligand B.

**8. BBB:** Both ligands have reasonable BBB penetration (63.94% and 61.807%). While ideally >70%, these are acceptable, and fairly similar.

**9. Caco-2 Permeability:** Ligand A (-4.995) has slightly better Caco-2 permeability than Ligand B (-4.535), but both are negative values which are not ideal.

**10. Aqueous Solubility:** Ligand A (-2.795) has slightly better solubility than Ligand B (-3.066), but both are negative values which are not ideal.

**11. hERG Inhibition:** Ligand A (0.125) has a lower hERG inhibition risk than Ligand B (0.307), which is preferable.

**12. Microsomal Clearance:** Ligand B (65.755) has significantly higher microsomal clearance than Ligand A (10.9). This suggests Ligand A is more metabolically stable.

**13. In vitro Half-Life:** Ligand B (-8.59) has a much longer in vitro half-life than Ligand A (4.074). This is a significant advantage for Ligand B.

**14. P-gp Efflux:** Ligand A (0.044) has lower P-gp efflux than Ligand B (0.083), which is preferable for CNS penetration.

**15. Binding Affinity:** Ligand A (-7.5) has slightly better binding affinity than Ligand B (-8.1). However, the difference is relatively small.

**Overall Assessment:**

While Ligand A has slightly better affinity and P-gp efflux, its significantly lower logP and higher DILI risk are major concerns. The low logP suggests poor membrane permeability, hindering its ability to reach the CNS target. Ligand B, despite slightly weaker affinity, has a much more favorable profile with optimal logP, lower DILI risk, and a longer half-life. Given the GPCR-specific priorities, particularly BBB penetration, logP, and safety (DILI), Ligand B is the more promising candidate.

Output:
1
2025-04-17 06:30:55,326 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (353.375 and 355.463 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (122.08) is better than Ligand B (57.01). For CNS targets, we want TPSA <= 90, and Ligand B is well within this range, while A is slightly above.

**logP:** Ligand A (-0.025) is suboptimal, being close to 0 and potentially hindering permeation. Ligand B (4.472) is too high, potentially causing solubility and off-target issues.

**H-Bond Donors & Acceptors:** Ligand A (2 HBD, 8 HBA) is better balanced than Ligand B (0 HBD, 6 HBA). Both are within acceptable limits.

**QED:** Both ligands have reasonable QED values (0.684 and 0.587), indicating good drug-like properties.

**DILI:** Ligand A (44.009) has a much lower DILI risk than Ligand B (81.311). This is a significant advantage for Ligand A.

**BBB:** Ligand A (40.403) has a low BBB penetration, which is a major drawback for a CNS target like DRD2. Ligand B (50.679) is also low, but better than A.

**Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and suggests poor permeability.

**Aqueous Solubility:** Both have negative solubility values, which is also unusual and suggests poor solubility.

**hERG Inhibition:** Both ligands show low hERG inhibition risk (0.137 and 0.358).

**Microsomal Clearance:** Ligand A (70.464) has lower microsomal clearance, indicating better metabolic stability than Ligand B (110.419).

**In vitro Half-Life:** Ligand A (-34.473) has a very negative half-life which is not possible. Ligand B (4.804) has a short half-life.

**P-gp Efflux:** Ligand A (0.019) has very low P-gp efflux, which is excellent for CNS penetration. Ligand B (0.446) has moderate P-gp efflux.

**Binding Affinity:** Ligand B (-8.6 kcal/mol) has significantly stronger binding affinity than Ligand A (-6.2 kcal/mol). This is a substantial advantage, potentially outweighing some ADME concerns.

**Overall Assessment:**

Ligand B has a significantly better binding affinity, which is the most crucial factor. While its logP is high and BBB penetration is low, the strong binding could compensate for these issues. Ligand A has better metabolic stability and lower DILI risk, but its poor BBB penetration is a critical flaw for a CNS target. The negative values for Caco-2 and solubility are concerning for both, but the affinity difference is significant.

Output:
1
2025-04-17 06:30:55,327 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 drug candidates, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (342.399 Da) is slightly lower, which could be advantageous for permeability, but both are acceptable.

**TPSA:** Ligand A (85.37) is better than Ligand B (49.41) as it is closer to the ideal range for CNS targets (<=90). Ligand B is excellent.

**logP:** Both ligands have good logP values (A: 3.207, B: 2.44), falling within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A has 2 HBD and 5 HBA, while Ligand B has 1 HBD and 4 HBA. Both are within acceptable limits (<=5 HBD, <=10 HBA).

**QED:** Both ligands have similar and good QED values (A: 0.769, B: 0.775), indicating good drug-like properties.

**DILI:** Ligand A (53.974) has a slightly higher DILI risk than Ligand B (35.052), but both are below the concerning threshold of 60.

**BBB:** Ligand B (88.29) has a significantly better BBB penetration percentile than Ligand A (74.486). This is a crucial advantage for a CNS target like DRD2.

**Caco-2 Permeability:** Ligand A (-4.529) has poor Caco-2 permeability, while Ligand B (-5.266) is also poor.

**Aqueous Solubility:** Both ligands have poor aqueous solubility (-3.764 and -3.156 respectively).

**hERG Inhibition:** Both ligands have low hERG inhibition risk (A: 0.47, B: 0.768).

**Microsomal Clearance:** Ligand B (91.281) has a higher microsomal clearance than Ligand A (26.581), suggesting lower metabolic stability. This is a drawback for Ligand B.

**In vitro Half-Life:** Ligand A (8.651) has a shorter in vitro half-life than Ligand B (-7.049). This is a drawback for Ligand A.

**P-gp Efflux:** Ligand A (0.017) has significantly lower P-gp efflux liability than Ligand B (0.402), which is a positive for CNS penetration.

**Binding Affinity:** Ligand B (-7.9 kcal/mol) has a slightly better binding affinity than Ligand A (-8.2 kcal/mol). While both are excellent, the difference is small.

**Overall Assessment:**

Considering the GPCR-specific priorities, Ligand B is the more promising candidate. Its superior BBB penetration (88.29 vs 74.486) is a major advantage for a CNS drug. While Ligand A has better P-gp efflux and metabolic stability, the difference in binding affinity is minimal, and the BBB advantage of Ligand B outweighs these factors. The poor solubility and Caco-2 permeability are concerns for both, but can be addressed with formulation strategies.

Output:
1
2025-04-17 06:30:55,327 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (355.5 & 368.5 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (54.02) is significantly better than Ligand B (75.19). For a CNS target like DRD2, TPSA should be <=90, and lower is preferred. Ligand A is well within this range, while Ligand B is approaching the upper limit.

**3. logP:** Both ligands have good logP values (4.09 and 2.35), falling within the optimal 1-3 range. Ligand A is slightly higher, which *could* be a minor concern for solubility, but isn't a dealbreaker.

**4. H-Bond Donors:** Ligand A has 2 HBD, and Ligand B has 1. Both are acceptable (<=5).

**5. H-Bond Acceptors:** Ligand A has 4 HBA, and Ligand B has 5. Both are acceptable (<=10).

**6. QED:** Both ligands have good QED scores (0.786 and 0.836), indicating good drug-like properties.

**7. DILI:** Both ligands have acceptable DILI risk (49.79 and 42.11), both well below the 60 threshold.

**8. BBB:** Both ligands have excellent BBB penetration (80.42 and 79.84), exceeding the desirable >70 threshold for CNS targets.

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.004 and -4.951). This is unusual and suggests poor permeability. However, these values are on a log scale and are likely representing very low permeability.

**10. Aqueous Solubility:** Both ligands have poor aqueous solubility (-4.017 and -3.185). This is a concern, but can sometimes be mitigated with formulation strategies.

**11. hERG Inhibition:** Both ligands have low hERG inhibition risk (0.666 and 0.366).

**12. Microsomal Clearance:** Ligand A (79.38) has significantly higher microsomal clearance than Ligand B (18.35). This suggests Ligand A will be metabolized more quickly, leading to a shorter half-life.

**13. In vitro Half-Life:** Ligand A (46.75) has a longer half-life than Ligand B (13.56). This seems contradictory to the microsomal clearance data, but the units are different (mL/min/kg vs. hours).

**14. P-gp Efflux:** Ligand A (0.741) has higher P-gp efflux than Ligand B (0.132). Lower P-gp efflux is preferred, especially for CNS targets, as it improves brain exposure. Ligand B is significantly better here.

**15. Binding Affinity:** Both ligands have very similar and excellent binding affinities (-8.9 and -8.8 kcal/mol). The difference is negligible.

**Overall Assessment:**

Ligand B is the more promising candidate. While both have good affinity and BBB penetration, Ligand B has a significantly lower P-gp efflux liability and lower microsomal clearance, suggesting better CNS exposure and potentially longer duration of action. Although Ligand A has a slightly lower TPSA, the benefits of Ligand B's improved ADME properties outweigh this minor difference. The poor Caco-2 and solubility are concerns for both, but are secondary to the CNS-specific considerations.

Output:
1
2025-04-17 06:30:55,327 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (363.571 and 344.499 Da) fall within the ideal range of 200-500 Da.

**TPSA:** Ligand A (53.16) is slightly higher than Ligand B (49.41). Both are below the 90 A^2 threshold for CNS targets, which is good.

**logP:** Both ligands have excellent logP values (3.429 and 3.276), falling within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A has 3 HBD and 4 HBA, while Ligand B has 1 HBD and 2 HBA. Both are within acceptable limits (<=5 HBD and <=10 HBA). Ligand B is slightly more favorable here, potentially leading to better permeability.

**QED:** Both ligands have good QED scores (0.695 and 0.804), indicating drug-like properties. Ligand B is slightly better.

**DILI:** Ligand A (18.418) has a slightly higher DILI risk than Ligand B (16.712), but both are below the 40 threshold, indicating low risk.

**BBB:** Both ligands have excellent BBB penetration (77.898 and 78.209 percentile), exceeding the desirable >70% threshold for CNS targets. This is a crucial positive for both.

**Caco-2 Permeability:** Ligand A (-5.343) and Ligand B (-4.582) both have negative Caco-2 values, which is unusual and suggests poor permeability. This is a significant concern for both.

**Aqueous Solubility:** Both ligands have very poor aqueous solubility (-2.485 and -3.987). This is a major drawback for both, potentially hindering formulation and bioavailability.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.742 and 0.404), which is favorable. Ligand B is better.

**Microsomal Clearance:** Ligand B (87.038) has significantly higher microsomal clearance than Ligand A (29.175), suggesting lower metabolic stability. Ligand A is much better here.

**In vitro Half-Life:** Ligand A (44.099) has a longer in vitro half-life than Ligand B (33.946), which is desirable.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.139 and 0.342), which is good for CNS exposure. Ligand A is slightly better.

**Binding Affinity:** Ligand B (-8.3 kcal/mol) has a slightly better binding affinity than Ligand A (-7.7 kcal/mol). This difference of 0.6 kcal/mol is significant, and could outweigh some of the ADME drawbacks.

**Overall Assessment:**

Both ligands have significant drawbacks in terms of solubility and Caco-2 permeability. However, Ligand B has a better binding affinity, a slightly better QED, lower hERG risk, and fewer H-bonds. Ligand A has better metabolic stability (lower Cl_mic) and a longer half-life, and slightly better P-gp efflux. Given the importance of binding affinity for GPCRs, and the relatively small difference in other parameters, Ligand B is the more promising candidate. The slightly better affinity could be optimized further, while addressing the solubility issues.

Output:
1
2025-04-17 06:30:55,327 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (362.495 and 351.447 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (58.64) is excellent, well below the 90 A^2 threshold for CNS targets. Ligand B (70.16) is still reasonable but less optimal.

**logP:** Ligand A (3.37) is within the optimal 1-3 range. Ligand B (0.341) is quite low, potentially hindering membrane permeability and CNS penetration.

**H-Bond Donors/Acceptors:** Ligand A has 1 HBD and 4 HBA, which are acceptable. Ligand B has 0 HBD and 4 HBA, also acceptable.

**QED:** Ligand A (0.893) has a very strong drug-like profile. Ligand B (0.735) is also good, but not as high as Ligand A.

**DILI:** Ligand A (51.687) has a moderate DILI risk, but acceptable. Ligand B (43.622) has a lower DILI risk, which is favorable.

**BBB:** Ligand A (86.545) has excellent BBB penetration potential, exceeding the 70% threshold. Ligand B (73.362) is still good, but less favorable than Ligand A.

**Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and suggests a potential issue with the data or modeling. However, we'll proceed assuming these are percentile scores and interpret them accordingly. Ligand A (-4.935) is worse than Ligand B (-4.395).

**Aqueous Solubility:** Both have negative solubility values, which is also unusual. Ligand A (-3.836) is slightly worse than Ligand B (-0.88).

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.47 and 0.21, respectively).

**Microsomal Clearance:** Ligand A (18.2 mL/min/kg) is significantly lower than Ligand B (28.581 mL/min/kg), indicating better metabolic stability.

**In vitro Half-Life:** Ligand A (8.404 hours) is significantly longer than Ligand B (-19.679 hours). The negative value for Ligand B is concerning and likely an artifact of the modeling.

**P-gp Efflux:** Ligand A (0.204) has lower P-gp efflux liability than Ligand B (0.078), which is beneficial for CNS exposure.

**Binding Affinity:** Ligand A (-8.6 kcal/mol) has a significantly stronger binding affinity than Ligand B (0.0 kcal/mol). This is a crucial advantage.

**Overall Assessment:**

Ligand A clearly outperforms Ligand B. While Ligand B has a slightly lower DILI risk, Ligand A excels in critical areas for a CNS-targeting GPCR ligand: TPSA, logP, BBB penetration, metabolic stability (Cl_mic and t1/2), P-gp efflux, and, most importantly, binding affinity. The significantly stronger binding affinity of Ligand A (-8.6 kcal/mol vs 0.0 kcal/mol) is a decisive factor, as it can compensate for minor ADME drawbacks. The negative values for Caco-2 and solubility are concerning for both, but the overall profile of Ligand A is far superior.

Output:
1
2025-04-17 06:30:55,328 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (343.431 and 348.451 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (80.12) is excellent, well below the 90 A^2 threshold for CNS targets. Ligand B (110.2) is still reasonable, but less optimal, being above 100.

**3. logP:** Both ligands have good logP values (1.025 and 1.428), falling within the optimal 1-3 range.

**4. H-Bond Donors:** Ligand A (1) is good. Ligand B (2) is acceptable.

**5. H-Bond Acceptors:** Ligand A (5) is good. Ligand B (4) is good.

**6. QED:** Ligand A (0.81) is excellent, indicating high drug-likeness. Ligand B (0.412) is below the 0.5 threshold, suggesting a less favorable drug-like profile.

**7. DILI:** Ligand A (41.373) has a low DILI risk. Ligand B (15.355) also has a low DILI risk.

**8. BBB:** Ligand A (64.831) is borderline for good CNS penetration, but not ideal. Ligand B (59.131) is even lower, making CNS penetration a concern.

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.031 and -5.51), which is unusual and suggests poor permeability. This is a significant drawback for both.

**10. Aqueous Solubility:** Both ligands have negative solubility values (-2.404 and -1.617), indicating very poor aqueous solubility. This is a major issue for formulation and bioavailability.

**11. hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.028 and 0.259).

**12. Microsomal Clearance:** Ligand A (44.829) has moderate clearance. Ligand B (5.852) has very low clearance, indicating better metabolic stability.

**13. In vitro Half-Life:** Ligand A (-13.177) has a negative half-life, which is not physically possible and indicates a problem with the data or the molecule. Ligand B (16.134) has a reasonable half-life.

**14. P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.089 and 0.008).

**15. Binding Affinity:** Ligand A (-8.0) has a significantly stronger binding affinity than Ligand B (-7.8). This 0.2 kcal/mol difference is substantial.

**Overall Assessment:**

Despite both ligands having issues with Caco-2 permeability and aqueous solubility, Ligand A is the more promising candidate. It has a much better QED score, a significantly stronger binding affinity, and a lower DILI risk. The negative half-life for Ligand A is a red flag, but the superior affinity and drug-likeness outweigh the other drawbacks. Ligand B's lower QED, weaker affinity, and lower BBB penetration make it less attractive. The very low clearance of Ligand B is a positive, but not enough to overcome its other weaknesses.

Output:
1
2025-04-17 06:30:55,328 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (342.399 and 343.387 Da) fall comfortably within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (87.32) is excellent, being below the 90 A^2 threshold for CNS targets. Ligand B (98.14) is still reasonable but less optimal, slightly above the preferred range.

**3. logP:** Ligand A (1.512) is within the optimal 1-3 range. Ligand B (0.739) is a bit low, potentially hindering permeability.

**4. H-Bond Donors:** Both ligands have 2 HBDs, which is within the acceptable limit of <=5.

**5. H-Bond Acceptors:** Ligand A has 4 HBAs, and Ligand B has 6. Both are within the acceptable limit of <=10.

**6. QED:** Both ligands have a QED of 0.833/0.834, indicating good drug-like properties.

**7. DILI:** Ligand A (63.978) has a slightly higher DILI risk than Ligand B (70.182), but both are acceptable (below 60 is good, these are both above).

**8. BBB:** This is crucial for a CNS target like DRD2. Ligand A (43.273) has a significantly better BBB percentile than Ligand B (36.371).

**9. Caco-2 Permeability:** Both have negative values, indicating poor permeability. Ligand A (-4.953) is slightly better than Ligand B (-5.197).

**10. Aqueous Solubility:** Both have negative values, indicating poor solubility. Ligand A (-3.648) is slightly better than Ligand B (-2.042).

**11. hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.236 and 0.048).

**12. Microsomal Clearance:** Ligand A (25.148) has a higher clearance than Ligand B (-2.631), indicating lower metabolic stability. Ligand B is much more metabolically stable.

**13. In vitro Half-Life:** Ligand A (-24.151) has a negative half-life, which is concerning, while Ligand B (4.021) has a positive half-life, indicating better stability.

**14. P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.094 and 0.034).

**15. Binding Affinity:** Ligand A (-8.5 kcal/mol) has a *much* stronger binding affinity than Ligand B (0.0 kcal/mol). This is a decisive advantage.

**Overall Assessment:**

Ligand A excels in binding affinity and TPSA, and has a better BBB score. However, it has poorer metabolic stability (higher Cl_mic, negative half-life) and lower solubility. Ligand B has better metabolic stability and solubility, but significantly weaker binding affinity and a lower BBB score.

Given the strong emphasis on affinity for GPCRs, and the importance of BBB penetration for CNS targets, the significantly stronger binding affinity of Ligand A (-8.5 kcal/mol vs 0.0 kcal/mol) outweighs its drawbacks. While metabolic stability is a concern, it might be addressable through structural modifications. The poor solubility could also be improved. The much better BBB score of Ligand A is also a significant advantage.

Output:
1
2025-04-17 06:30:55,328 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (346.471 and 355.341 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (69.64) is significantly better than Ligand B (102.76). For CNS targets, we want TPSA <= 90, so Ligand A is preferable.

**3. logP:** Ligand A (2.313) is within the optimal 1-3 range. Ligand B (0.442) is a bit low, potentially hindering membrane permeability.

**4. H-Bond Donors:** Both have acceptable HBD counts (2 and 3 respectively), well below the threshold of 5.

**5. H-Bond Acceptors:** Both have acceptable HBA counts (3 and 5 respectively), well below the threshold of 10.

**6. QED:** Both ligands have good QED scores (0.593 and 0.727), indicating good drug-like properties.

**7. DILI:** Both ligands have relatively high DILI risk (26.095 and 52.191), but are still below the concerning threshold of 60.

**8. BBB:** Both ligands have similar BBB penetration (52.268 and 52.772). While not ideal (>70), they aren't drastically low.

**9. Caco-2:** Both ligands have negative Caco-2 values (-4.918 and -5.017), which is unusual and suggests poor permeability. This is concerning.

**10. Solubility:** Both ligands have negative solubility values (-2.614 and -2.388), which is also unusual and suggests poor solubility. This is concerning.

**11. hERG:** Both ligands have low hERG inhibition liability (0.263 and 0.168), which is good.

**12. Cl_mic:** Ligand B (-21.156) has a much lower (better) microsomal clearance than Ligand A (47.722), indicating greater metabolic stability.

**13. t1/2:** Ligand B (-30.698) has a much longer in vitro half-life than Ligand A (-4.376), which is a significant advantage.

**14. Pgp:** Both ligands have very low Pgp efflux liability (0.346 and 0.006), which is excellent for CNS penetration.

**15. Binding Affinity:** Ligand A (-8.8 kcal/mol) has a slightly better binding affinity than Ligand B (-7.9 kcal/mol). This difference of 0.9 kcal/mol is significant.

**Overall Assessment:**

While Ligand B has superior metabolic stability and half-life, Ligand A has a better TPSA and binding affinity. The negative Caco-2 and solubility values for both are concerning and would require further investigation (potentially indicating issues with the prediction method or unusual chemical features). However, considering the GPCR-specific priorities, the slightly better TPSA and significantly better binding affinity of Ligand A, combined with acceptable BBB, make it the more promising candidate. The affinity advantage could outweigh the metabolic concerns, which can be addressed through structural modifications.

Output:
1
2025-04-17 06:30:55,328 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (351.363 and 348.487 Da) fall within the ideal range of 200-500 Da.

**TPSA:** Ligand A (115.65) is higher than the ideal <90 for CNS targets, while Ligand B (58.64) is well within the desired range. This is a significant advantage for Ligand B.

**logP:** Ligand A (-0.725) is a bit low, potentially hindering membrane permeability. Ligand B (2.511) is within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Both have 1 HBD, which is good. Ligand A has 8 HBA, which is acceptable (<=10). Ligand B has 3 HBA, which is also acceptable.

**QED:** Both ligands have good QED scores (0.711 and 0.751), indicating good drug-like properties.

**DILI:** Ligand A (76.425) has a higher DILI risk than Ligand B (24.738). This is a clear advantage for Ligand B.

**BBB:** Both ligands have excellent BBB penetration (70.415 and 76.076 percentile), fulfilling the requirement for CNS targets.

**Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and suggests potential issues with the modeling or data quality. However, we can still compare them.

**Aqueous Solubility:** Both have negative solubility values, which is also unusual.

**hERG Inhibition:** Ligand A (0.042) has a very low hERG risk, while Ligand B (0.216) is slightly higher but still acceptable.

**Microsomal Clearance:** Ligand A (25.226) has lower clearance, indicating better metabolic stability than Ligand B (53.368).

**In vitro Half-Life:** Ligand A (-10.609) has a negative half-life, which is unrealistic. Ligand B (4.565) has a reasonable half-life.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.045 and 0.078), which is favorable for CNS penetration.

**Binding Affinity:** Ligand B (-8.7 kcal/mol) has a significantly stronger binding affinity than Ligand A (-7.0 kcal/mol). This >1.5 kcal/mol difference is substantial and can outweigh minor ADME drawbacks.

**Overall Assessment:**

Ligand B is the superior candidate. It has a much better TPSA, logP, DILI risk, and significantly stronger binding affinity. While Ligand A has better metabolic stability, the other advantages of Ligand B, particularly its superior TPSA, logP, and binding affinity, are more critical for a CNS-targeting GPCR ligand. The negative values for Caco-2 and Solubility are concerning for both, but the overall profile of Ligand B is more promising.

Output:
1
2025-04-17 06:30:55,328 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (340.354 and 343.387 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (62.56) is significantly better than Ligand B (99). For CNS targets, TPSA < 90 is preferred, and A is comfortably within this range, while B is slightly above.

**3. logP:** Ligand A (3.373) is optimal (1-3), while Ligand B (1.851) is at the lower end of the acceptable range. Lower logP can sometimes hinder BBB penetration.

**4. H-Bond Donors:** Ligand A (0) is preferable to Ligand B (1). Fewer HBDs generally improve membrane permeability.

**5. H-Bond Acceptors:** Ligand A (4) is better than Ligand B (7). Lower HBA counts are generally preferred for CNS penetration.

**6. QED:** Both ligands have acceptable QED values (0.859 and 0.674, both > 0.5).

**7. DILI:** Ligand A (67.429) has a slightly higher DILI risk than Ligand B (83.792), but both are reasonably acceptable.

**8. BBB:** Ligand A (76.541) has a better BBB percentile than Ligand B (67.701). While both are above 60, a higher BBB is crucial for CNS targets like DRD2.

**9. Caco-2:** Both ligands have negative Caco-2 values, which is unusual and suggests poor permeability. However, the scale is not specified, so it's difficult to interpret.

**10. Solubility:** Both ligands have negative solubility values, which is also unusual.

**11. hERG:** Ligand A (0.708) has a lower hERG risk than Ligand B (0.034). Lower hERG is always preferred.

**12. Cl_mic:** Ligand A (10.231) has a significantly lower microsomal clearance than Ligand B (42.609), indicating better metabolic stability.

**13. t1/2:** Ligand A (-17.866) has a negative half-life, which is impossible. Ligand B (2.554) has a short half-life.

**14. Pgp:** Ligand A (0.314) has a lower P-gp efflux liability than Ligand B (0.193), which is favorable for CNS exposure.

**15. Binding Affinity:** Ligand A (-9.8 kcal/mol) has a *much* stronger binding affinity than Ligand B (-0.0 kcal/mol). This is a decisive advantage.

**Overall Assessment:**

Ligand A is significantly better than Ligand B. It has a superior binding affinity, better TPSA, logP, BBB, Pgp efflux, and metabolic stability. While Ligand A has a slightly higher DILI risk, the substantial difference in binding affinity and favorable ADME properties outweigh this concern. The negative values for Caco-2 and solubility are concerning, but the strong affinity of Ligand A makes it a more promising starting point for optimization.

Output:
1
2025-04-17 06:30:55,329 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (363.527 and 366.527 Da) fall comfortably within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (62.3) is slightly above the optimal <90 for CNS targets, but still reasonable. Ligand B (51.66) is excellent, well below 90.

**3. logP:** Both ligands have good logP values (3.315 and 3.268), falling within the 1-3 range.

**4. H-Bond Donors:** Ligand A has 1 HBD, which is good. Ligand B has 0, also good.

**5. H-Bond Acceptors:** Ligand A has 4 HBA, and Ligand B has 5. Both are acceptable (<=10).

**6. QED:** Both ligands have reasonable QED scores (0.808 and 0.743), indicating good drug-like properties.

**7. DILI:** Ligand A (44.63) has a slightly higher DILI risk than Ligand B (29.042), but both are below the concerning threshold of 60.

**8. BBB:** This is a critical parameter for a CNS target like DRD2. Ligand B (88.057) has a significantly higher BBB penetration percentile than Ligand A (72.237). This is a major advantage for Ligand B.

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.052 and -4.72). These values are unusual and suggest poor permeability, however, these values are on a log scale and thus are likely representing very low permeability.

**10. Aqueous Solubility:** Both ligands have negative solubility values (-2.986 and -2.203), indicating poor aqueous solubility.

**11. hERG Inhibition:** Both ligands show low hERG inhibition liability (0.443 and 0.44), which is favorable.

**12. Microsomal Clearance:** Ligand A (48.278) has lower microsomal clearance than Ligand B (70.301), suggesting better metabolic stability.

**13. In vitro Half-Life:** Ligand B (-1.19) has a negative half-life, which is not possible. This is likely an error in the data. Ligand A (6.276) has a reasonable half-life.

**14. P-gp Efflux:** Both ligands have low P-gp efflux liability (0.464 and 0.336), which is good for CNS penetration.

**15. Binding Affinity:** Ligand A (-8.7 kcal/mol) has a significantly stronger binding affinity than Ligand B (-7.4 kcal/mol). This is a substantial difference (1.3 kcal/mol), which can outweigh some ADME drawbacks.

**Overall Assessment:**

While Ligand A has superior binding affinity and metabolic stability, Ligand B excels in BBB penetration and has a lower DILI risk. Given the CNS target (DRD2), BBB penetration is paramount. The 1.3 kcal/mol difference in binding affinity, while significant, might be overcome with further optimization of Ligand B. The negative half-life for Ligand B is a major red flag, and suggests a data error.

Output:
1
2025-04-17 06:30:55,329 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (349.431 and 348.462 Da) fall comfortably within the ideal 200-500 Da range.

**TPSA:** Ligand A (84.67) is excellent for CNS penetration, being well below the 90 A^2 threshold. Ligand B (41.57) is even better.

**logP:** Ligand A (1.945) is within the optimal 1-3 range. Ligand B (3.226) is slightly higher but still acceptable.

**H-Bond Donors/Acceptors:** Both ligands have 1 HBD and a reasonable number of HBAs (5 and 3 respectively), satisfying the <5 HBD and <10 HBA guidelines.

**QED:** Both ligands have QED values above 0.7, indicating good drug-likeness.

**DILI:** Ligand A (51.648) has a moderate DILI risk, but is acceptable. Ligand B (11.09) has a very low DILI risk, which is a significant advantage.

**BBB:** Ligand A (78.79) is good, but Ligand B (93.331) is excellent, exceeding the desirable >70 threshold for CNS targets. This is a major point in favor of Ligand B.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values, which is unusual and suggests a potential issue with permeability prediction. However, we can still compare them relatively.

**Aqueous Solubility:** Both ligands have negative solubility values, which is also unusual.

**hERG Inhibition:** Ligand A (0.2) has a very low hERG risk. Ligand B (0.911) has a slightly higher, but still acceptable, hERG risk.

**Microsomal Clearance:** Ligand A (48.733) has a moderate clearance, while Ligand B (34.626) has a lower clearance, indicating better metabolic stability.

**In vitro Half-Life:** Ligand A (-31.671) has a negative half-life, which is not possible. Ligand B (5.014) has a short half-life, but it's a plausible value.

**P-gp Efflux:** Ligand A (0.067) has very low P-gp efflux, which is excellent for CNS penetration. Ligand B (0.426) has a slightly higher efflux, but it's still relatively low.

**Binding Affinity:** Ligand B (-8.0 kcal/mol) has a significantly stronger binding affinity than Ligand A (-7.5 kcal/mol). This 0.5 kcal/mol difference is substantial and can outweigh minor ADME drawbacks.

**Overall Assessment:**

Ligand B is superior due to its excellent BBB penetration, lower DILI risk, better metabolic stability (lower Cl_mic), and significantly stronger binding affinity. While Ligand A has very low P-gp efflux and a low hERG risk, the advantages of Ligand B in terms of CNS penetration and potency are more critical for a DRD2 target. The negative values for Caco-2 and solubility are concerning for both, but the overall profile of Ligand B is more promising.

Output:
1
2025-04-17 06:30:55,329 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (366.33) is slightly higher than Ligand B (349.475), but both are acceptable.

**TPSA:** Ligand A (41.57) is excellent for CNS penetration, well below the 90 A^2 threshold. Ligand B (70.67) is higher, but still potentially acceptable, though less ideal.

**logP:** Ligand A (3.664) is within the optimal range (1-3). Ligand B (0.908) is a bit low, potentially hindering membrane permeability.

**H-Bond Donors/Acceptors:** Ligand A (HBD=1, HBA=2) and Ligand B (HBD=2, HBA=4) both have reasonable numbers of H-bond donors and acceptors, well within the guidelines.

**QED:** Both ligands have acceptable QED values (Ligand A: 0.808, Ligand B: 0.683), indicating good drug-like properties.

**DILI:** Ligand A (42.148) has a higher DILI risk than Ligand B (6.863). This is a significant negative for Ligand A.

**BBB:** Ligand A (85.033) has a significantly better BBB penetration percentile than Ligand B (76.192), which is already good but not as strong. This is a crucial factor for a CNS target like DRD2.

**Caco-2 Permeability:** Ligand A (-4.512) has poor Caco-2 permeability, which is concerning. Ligand B (-5.085) is also poor, but slightly worse.

**Aqueous Solubility:** Both ligands have very poor aqueous solubility (-3.5 and -1.805 respectively). This could pose formulation challenges.

**hERG Inhibition:** Ligand A (0.749) has a slightly higher hERG inhibition risk than Ligand B (0.391), but both are relatively low.

**Microsomal Clearance:** Ligand A (37.568) has higher microsomal clearance than Ligand B (7.394), indicating faster metabolism and potentially lower in vivo exposure.

**In vitro Half-Life:** Ligand A (-25.273) has a very short in vitro half-life, a major drawback. Ligand B (6.637) has a much better half-life.

**P-gp Efflux:** Ligand A (0.169) has lower P-gp efflux than Ligand B (0.012), which is favorable for CNS penetration.

**Binding Affinity:** Ligand A (-9.1 kcal/mol) has a significantly stronger binding affinity than Ligand B (-7.5 kcal/mol). This is a substantial advantage.

**Overall Assessment:**

Ligand A has a much stronger binding affinity and better BBB penetration, and lower P-gp efflux, which are all highly desirable for a CNS-targeting GPCR. However, it suffers from poor Caco-2 permeability, high DILI risk, high metabolic clearance, and a very short half-life.

Ligand B has a lower affinity, but better DILI risk, metabolic stability (lower Cl_mic, longer t1/2), and slightly better hERG profile. Its BBB penetration is good, but not as high as Ligand A.

The strong affinity of Ligand A is a significant advantage that might outweigh some of its ADME liabilities, *if* those liabilities can be addressed through further optimization. However, the combination of poor permeability, high DILI, and short half-life makes it a riskier candidate. Ligand B is a more balanced molecule with fewer red flags, even though its affinity is lower.

Given the GPCR-specific priorities, the strong affinity and BBB penetration of Ligand A are compelling.

Output:
1
2025-04-17 06:30:55,329 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (349.362 and 359.535 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (99.6) is slightly above the preferred <90 for CNS targets, but still reasonable. Ligand B (40.54) is excellent, well below the threshold.

**logP:** Ligand A (0.822) is a bit low, potentially hindering permeation. Ligand B (4.34) is high, potentially causing solubility and off-target issues, but within an acceptable range.

**H-Bond Donors/Acceptors:** Ligand A (HBD=2, HBA=5) and Ligand B (HBD=1, HBA=3) both have acceptable numbers of H-bond donors and acceptors.

**QED:** Both ligands have a QED of 0.82, indicating good drug-like properties.

**DILI:** Ligand A (49.283) has a moderate DILI risk, while Ligand B (12.098) has a very low risk. This favors Ligand B.

**BBB:** Ligand A (65.801) has a moderate BBB penetration, while Ligand B (84.684) has excellent BBB penetration, exceeding the desirable >70 threshold. This is a significant advantage for Ligand B, given the CNS target.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.987 and -4.957), which is unusual and suggests poor permeability. This is a concern for both.

**Aqueous Solubility:** Both ligands have negative solubility values (-2.239 and -4.488), indicating very poor aqueous solubility. This is a major drawback for both.

**hERG Inhibition:** Ligand A (0.051) has a very low hERG risk, while Ligand B (0.77) has a slightly elevated, but still acceptable, risk.

**Microsomal Clearance:** Ligand A (-6.088) has a negative clearance, which is not physically possible and likely indicates a very stable compound. Ligand B (86.34) has a high clearance, suggesting rapid metabolism. This strongly favors Ligand A.

**In vitro Half-Life:** Ligand A (-0.814) has a negative half-life, which is not physically possible. Ligand B (9.955) has a reasonable half-life.

**P-gp Efflux:** Ligand A (0.009) has very low P-gp efflux, which is favorable for CNS penetration. Ligand B (0.698) has moderate P-gp efflux.

**Binding Affinity:** Ligand A (-8.0) has a slightly better binding affinity than Ligand B (-7.6). However, the difference is less than 1.5 kcal/mol.

**Overall Assessment:**

Ligand B excels in BBB penetration, DILI risk, and has a reasonable half-life. While its logP is high and solubility is poor, the strong BBB penetration is crucial for a CNS target like DRD2. Ligand A has a better affinity and very low P-gp efflux, but its negative clearance and half-life are concerning and physically impossible. The negative values for clearance and half-life suggest data errors or a highly unusual compound behavior. The poor solubility of both compounds is a significant issue, but formulation strategies might mitigate this.

Considering the GPCR-specific priorities and the more realistic ADME profile, Ligand B is the more promising candidate.

Output:
1
2025-04-17 06:30:55,330 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (349.431 and 362.47 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (91.23) is slightly above the optimal <90 for CNS targets, but still reasonable. Ligand B (40.62) is excellent, well below 90.

**logP:** Ligand A (0.667) is a bit low, potentially hindering permeation. Ligand B (3.0) is within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A has 2 HBD and 5 HBA, which are acceptable. Ligand B has 0 HBD and 3 HBA, also acceptable.

**QED:** Both ligands have similar QED scores (0.763 and 0.773), indicating good drug-likeness.

**DILI:** Ligand A (13.571) has a significantly lower DILI risk than Ligand B (36.293), which is a substantial advantage.

**BBB:** Ligand B (84.451) has a much higher BBB penetration score than Ligand A (38.813). This is crucial for a CNS target like DRD2.

**Caco-2 Permeability:** Ligand A (-5.039) has poor Caco-2 permeability, while Ligand B (-4.579) is slightly better, but still not great.

**Aqueous Solubility:** Ligand A (-1.219) has slightly better solubility than Ligand B (-4.18).

**hERG:** Ligand A (0.081) has a very low hERG risk, while Ligand B (0.719) is somewhat higher, though still relatively low.

**Microsomal Clearance:** Ligand B (34.941) has a higher microsomal clearance than Ligand A (8.291), indicating faster metabolism and potentially lower *in vivo* exposure.

**In vitro Half-Life:** Ligand A (22.805) has a longer half-life than Ligand B (6.359).

**P-gp Efflux:** Ligand A (0.015) has very low P-gp efflux, which is beneficial for CNS penetration. Ligand B (0.586) has moderate P-gp efflux.

**Binding Affinity:** Ligand B (-9.1 kcal/mol) has a stronger binding affinity than Ligand A (-8.5 kcal/mol). This 1.6 kcal/mol difference is significant and can outweigh some ADME drawbacks.

**Overall Assessment:**

Ligand B excels in BBB penetration and binding affinity, which are paramount for a CNS GPCR target. While its DILI risk is higher and its metabolic clearance is faster, the strong affinity and good BBB penetration are compelling. Ligand A has a better safety profile (DILI, hERG, Pgp) and metabolic stability, but its poor BBB penetration and weaker affinity are significant drawbacks for a CNS target. The difference in binding affinity is substantial.

Output:
1
2025-04-17 06:30:55,330 - INFO - Batch 288 complete. Total preferences: 4608
2025-04-17 06:30:55,330 - INFO - Processing batch 289/512...
2025-04-17 06:31:47,851 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (347.46 and 348.39 Da) fall comfortably within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (54.04) is higher than Ligand B (40.62). For a CNS target like DRD2, we ideally want TPSA <= 90, both are within this range, but B is preferable.

**3. logP:** Ligand A (2.01) and Ligand B (3.07) are both within the optimal 1-3 range. B is slightly better.

**4. H-Bond Donors:** Ligand A has 1 HBD, Ligand B has 0. Both are acceptable (<=5).

**5. H-Bond Acceptors:** Ligand A has 4 HBA, Ligand B has 2. Both are acceptable (<=10).

**6. QED:** Both ligands have similar QED values (0.885 and 0.824), indicating good drug-likeness.

**7. DILI:** Ligand A (21.75) has a lower DILI risk than Ligand B (36.06), which is favorable.

**8. BBB:** Both ligands show excellent BBB penetration (83.25% and 84.68%), exceeding the desirable >70% threshold for CNS targets. This is a key positive for both.

**9. Caco-2 Permeability:** Both have negative values (-4.545 and -4.318). This is unusual and suggests poor permeability. However, the scale is not specified, so it's hard to interpret.

**10. Aqueous Solubility:** Both have negative values (-0.972 and -2.656). Again, the scale is not specified, so it's hard to interpret.

**11. hERG Inhibition:** Both ligands have similar, low hERG inhibition risk (0.68 and 0.687).

**12. Microsomal Clearance:** Ligand A (14.64) has lower microsomal clearance than Ligand B (26.46), indicating better metabolic stability.

**13. In vitro Half-Life:** Ligand A (33.83) has a longer half-life than Ligand B (-2.49), which is desirable.

**14. P-gp Efflux:** Both have similar P-gp efflux liability (0.066 and 0.27).

**15. Binding Affinity:** Ligand B (-9.6 kcal/mol) has a significantly stronger binding affinity than Ligand A (-8.2 kcal/mol). This >1.5 kcal/mol difference is substantial and can outweigh minor ADME drawbacks.

**Overall Assessment:**

While Ligand A has better DILI, metabolic stability, and half-life, the significantly stronger binding affinity of Ligand B (-9.6 vs -8.2 kcal/mol) is the most important factor, especially for a GPCR target. The BBB penetration is excellent for both. The negative Caco-2 and solubility values are concerning, but the strong affinity of B suggests it might overcome these issues.

Output:
1
2025-04-17 06:31:47,852 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B based on the provided guidelines, prioritizing GPCR-specific properties (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (382.404 Da) is slightly higher than Ligand B (340.471 Da), but both are acceptable.

**TPSA:** Ligand A (98.49) is closer to the upper limit for CNS targets (<=90), while Ligand B (50.16) is well within the desired range. This favors Ligand B.

**logP:** Both ligands have good logP values (A: 1.949, B: 2.761), falling within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Both ligands have acceptable HBD (A: 2, B: 1) and HBA (A: 4, B: 4) counts, well below the limits of 5 and 10, respectively.

**QED:** Both ligands have good QED scores (A: 0.638, B: 0.88), indicating good drug-like properties. Ligand B is slightly better.

**DILI:** Ligand A (45.677) has a moderate DILI risk, while Ligand B (15.2) has a very low DILI risk. This strongly favors Ligand B.

**BBB:** Ligand A (69.794) is close to the desired threshold (>70) for CNS targets, but Ligand B (87.67) is significantly better, exceeding it comfortably. This is a critical advantage for a DRD2 ligand.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.012 and -5.052). This is unusual and suggests poor permeability. However, the values are very similar.

**Aqueous Solubility:** Both ligands have negative solubility values (-2.658 and -2.362), indicating poor aqueous solubility. Again, the values are similar.

**hERG Inhibition:** Both ligands have low hERG inhibition liability (A: 0.568, B: 0.929), which is favorable.

**Microsomal Clearance:** Ligand A (27.994) has a higher microsomal clearance than Ligand B (4.68), indicating lower metabolic stability. This favors Ligand B.

**In vitro Half-Life:** Ligand A (-28.756) has a negative half-life, which is not physically possible and suggests a problem with the data or the molecule. Ligand B (13.065) has a reasonable half-life. This is a major advantage for Ligand B.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (A: 0.144, B: 0.398), which is good for CNS penetration.

**Binding Affinity:** Ligand B (-9.3 kcal/mol) has a significantly stronger binding affinity than Ligand A (-8.2 kcal/mol). The difference of 1.1 kcal/mol is substantial and can outweigh minor ADME drawbacks.

**Overall Assessment:**

Ligand B consistently outperforms Ligand A across most critical parameters, especially BBB penetration, DILI risk, metabolic stability, and binding affinity. While both have issues with Caco-2 permeability and aqueous solubility, the superior binding affinity and CNS penetration profile of Ligand B make it a much more promising drug candidate for targeting DRD2. The negative half-life for Ligand A is a significant red flag.

Output:
1
2025-04-17 06:31:47,852 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (348.443 and 354.411 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (75.71) is significantly better than Ligand B (103.63). For CNS targets, we want TPSA <= 90, so Ligand A is preferable.

**3. logP:** Ligand A (1.564) is within the optimal 1-3 range. Ligand B (-0.246) is below 1, which could hinder permeation. This favors Ligand A.

**4. H-Bond Donors:** Both have 1 HBD, which is acceptable (<=5).

**5. H-Bond Acceptors:** Ligand A has 4 HBAs, and Ligand B has 9. Ligand A is better, as we want <=10.

**6. QED:** Both are reasonably good (0.79 and 0.715), exceeding the 0.5 threshold.

**7. DILI:** Ligand A (29.042) has a much lower DILI risk than Ligand B (47.693). Both are below 60, but A is significantly better.

**8. BBB:** Both have good BBB penetration (72.625% and 74.098%), exceeding the 70% target for CNS drugs. Ligand B is slightly better, but the difference is minor.

**9. Caco-2:** Both have negative Caco-2 values, which is unusual and difficult to interpret without knowing the scale. However, we can assume lower values are less favorable.

**10. Solubility:** Both have negative solubility values, again, making comparison difficult.

**11. hERG:** Both have very low hERG inhibition risk (0.14 and 0.044).

**12. Cl_mic:** Ligand A (17.687) has a higher microsomal clearance than Ligand B (10.556), indicating lower metabolic stability. This favors Ligand B.

**13. t1/2:** Both have similar in vitro half-lives (6.18 and 6.05 hours).

**14. Pgp:** Both have very low P-gp efflux liability (0.047 and 0.025).

**15. Binding Affinity:** Ligand A (-8.0 kcal/mol) has a significantly stronger binding affinity than Ligand B (-6.3 kcal/mol). This is a substantial advantage (>1.5 kcal/mol difference).

**Overall Assessment:**

Ligand A is superior due to its better TPSA, logP, HBA count, and significantly stronger binding affinity. While Ligand B has slightly better BBB penetration and lower Cl_mic, the advantages of Ligand A in key GPCR properties (especially affinity and TPSA) outweigh these drawbacks. The lower DILI risk for Ligand A is also a significant benefit.

Output:
1
2025-04-17 06:31:47,852 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (344.419 and 367.559 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (84.22) is significantly better than Ligand B (65.2). Both are below the 90 A^2 threshold for CNS targets, but A is closer to the optimal range.

**3. logP:** Ligand B (3.52) is better than Ligand A (0.2). A's logP is quite low, potentially hindering membrane permeability. B is within the optimal 1-3 range.

**4. H-Bond Donors:** Ligand A (0) is preferable to Ligand B (2). Fewer HBDs generally improve permeability.

**5. H-Bond Acceptors:** Ligand A (6) is slightly higher than Ligand B (3), but both are within acceptable limits (<=10).

**6. QED:** Both ligands have similar QED values (0.689 and 0.691), indicating good drug-likeness.

**7. DILI:** Both ligands have acceptable DILI risk (31.059 and 37.263), well below the 60 threshold.

**8. BBB:** Ligand A (76.309) has a considerably higher BBB penetration percentile than Ligand B (60.062). This is a critical advantage for a CNS target like DRD2.

**9. Caco-2 Permeability:** Ligand A (-4.918) has a worse Caco-2 permeability compared to Ligand B (-5.313). However, both are negative values, which is unusual and requires further investigation.

**10. Aqueous Solubility:** Ligand A (-1.225) has better aqueous solubility than Ligand B (-3.73).

**11. hERG Inhibition:** Ligand A (0.045) has a much lower hERG inhibition risk than Ligand B (0.701). This is a significant safety advantage.

**12. Microsomal Clearance:** Ligand B (85.125) has a much higher microsomal clearance than Ligand A (1.89). This suggests Ligand A is more metabolically stable.

**13. In vitro Half-Life:** Ligand B (33.511) has a longer in vitro half-life than Ligand A (-1.227).

**14. P-gp Efflux:** Ligand A (0.02) has a much lower P-gp efflux liability than Ligand B (0.218). Lower P-gp efflux is crucial for CNS penetration.

**15. Binding Affinity:** Ligand A (-7.7) has a slightly better binding affinity than Ligand B (-7.5). While the difference is small, it's still a positive factor.

**Overall Assessment:**

Ligand A is the more promising candidate. While Ligand B has a better logP and half-life, Ligand A excels in crucial areas for a CNS-targeting GPCR ligand: significantly better BBB penetration, lower P-gp efflux, lower hERG inhibition, and improved metabolic stability (lower Cl_mic). The slightly better binding affinity of A further supports this conclusion. The low logP of A is a concern, but the other advantages outweigh this drawback.

Output:
0
2025-04-17 06:31:47,852 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (357.4 and 370.5 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (106.2) is slightly above the optimal <90 for CNS targets, but still reasonable. Ligand B (84.5) is excellent, well below 90.

**logP:** Ligand A (-1.484) is quite low, potentially hindering membrane permeability. Ligand B (1.416) is within the optimal 1-3 range. This is a significant advantage for Ligand B.

**H-Bond Donors/Acceptors:** Both have 2 HBD and are within acceptable limits. Ligand A has 6 HBA, while Ligand B has 4. Both are below the 10 threshold.

**QED:** Both ligands have good QED scores (0.575 and 0.71), indicating drug-like properties.

**DILI:** Ligand A (35.673) has a better DILI score than Ligand B (47.266), indicating lower potential for liver injury.

**BBB:** Ligand B (68.941) has a significantly better BBB penetration score than Ligand A (35.401). This is a crucial factor for a CNS target like DRD2.

**Caco-2 Permeability:** Both have negative Caco-2 values (-5.192 and -5.22), which is unusual and suggests poor permeability. However, these values are on a log scale and should be interpreted cautiously.

**Aqueous Solubility:** Both have negative solubility values (-0.978 and -3.766), also on a log scale, suggesting poor solubility.

**hERG Inhibition:** Ligand A (0.034) shows very low hERG inhibition risk, a significant advantage. Ligand B (0.432) has a slightly higher, but still relatively low, risk.

**Microsomal Clearance:** Ligand A (-4.439) has a more negative value, suggesting lower clearance and better metabolic stability than Ligand B (53.465).

**In vitro Half-Life:** Ligand B (5.36) has a longer half-life than Ligand A (2.299).

**P-gp Efflux:** Ligand A (0.007) has very low P-gp efflux, which is excellent for CNS penetration. Ligand B (0.067) also has low P-gp efflux, but higher than Ligand A.

**Binding Affinity:** Ligand B (-8.4 kcal/mol) has a significantly stronger binding affinity than Ligand A (-6.6 kcal/mol). This >1.5 kcal/mol difference is substantial and can outweigh some ADME drawbacks.

**Overall Assessment:**

Ligand B is the stronger candidate. While Ligand A has advantages in DILI, hERG, and P-gp efflux, Ligand B's superior BBB penetration, significantly stronger binding affinity, and acceptable logP outweigh these concerns. The lower TPSA of Ligand B is also beneficial. The poor Caco-2 and solubility values are concerning for both, but can potentially be addressed through formulation strategies. For a CNS target, strong binding and BBB penetration are paramount, making Ligand B the more promising candidate.

Output:
1
2025-04-17 06:31:47,852 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands fall within the ideal range (200-500 Da). Ligand A (456.284 Da) is higher, but still acceptable. Ligand B (355.385 Da) is slightly better.

**TPSA:** Both ligands have TPSA values below 140, which is good for oral absorption, and reasonably close to the 90 threshold for CNS targets. Ligand B (87.3) is slightly better than Ligand A (99.24).

**logP:** Ligand A (2.505) is within the optimal range (1-3). Ligand B (0.279) is quite low, potentially hindering membrane permeability. This is a significant disadvantage for Ligand B.

**H-Bond Donors/Acceptors:** Ligand A (HBD=2, HBA=5) and Ligand B (HBD=3, HBA=3) both have reasonable numbers of H-bond donors and acceptors, staying within the guidelines.

**QED:** Both ligands have QED values above 0.5, indicating good drug-like properties. Ligand A (0.626) is slightly higher.

**DILI:** Ligand A (65.917) has a higher DILI risk than Ligand B (36.758). Ligand B is preferable here.

**BBB:** Both ligands have good BBB penetration (Ligand A: 67.468, Ligand B: 67.197). They are slightly below the >70 desirable mark, but acceptable.

**Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and suggests poor permeability. However, the scale isn't specified, so it's difficult to interpret.

**Aqueous Solubility:** Both ligands have negative solubility values, also unusual and suggesting poor solubility. Again, the scale is unclear.

**hERG Inhibition:** Ligand A (0.453) has a slightly higher hERG risk than Ligand B (0.189). Ligand B is preferable.

**Microsomal Clearance:** Ligand B (-3.979) has a negative clearance, which is not physically possible. This is a major red flag and suggests an issue with the data or the model. Ligand A (52.252) has a reasonable clearance.

**In vitro Half-Life:** Ligand A (24.14) has a better half-life than Ligand B (-0.898). The negative value for Ligand B is another data quality concern.

**P-gp Efflux:** Ligand A (0.207) has lower P-gp efflux than Ligand B (0.027), which is favorable for CNS penetration.

**Binding Affinity:** Ligand B (-8.8 kcal/mol) has a significantly stronger binding affinity than Ligand A (-7.9 kcal/mol). This is a substantial advantage, potentially outweighing some of the ADME concerns.

**Overall Assessment:**

Ligand B has a significantly better binding affinity, lower DILI risk, and lower hERG risk. However, its low logP is a major concern, potentially hindering its ability to cross cell membranes. Furthermore, the negative values for Caco-2 permeability, solubility, microsomal clearance, and half-life raise serious questions about the reliability of the data for Ligand B. Ligand A, while not perfect, has more reasonable ADME properties and a good binding affinity. Given the questionable data for Ligand B, and the importance of reasonable ADME properties for a GPCR targeting the CNS, Ligand A is the more viable candidate.

Output:
1
2025-04-17 06:31:47,853 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (348.45 & 365.46 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (94.56) is better than Ligand B (104.29). Both are below the 140 A^2 threshold for oral absorption, and importantly, below the 90 A^2 target for CNS penetration.

**3. logP:** Ligand A (0.681) is slightly better than Ligand B (0.245). Both are a bit low, potentially hindering permeation, but Ligand A is closer to the optimal 1-3 range.

**4. H-Bond Donors:** Ligand A (3) is slightly higher than Ligand B (2), but both are within the acceptable limit of <=5.

**5. H-Bond Acceptors:** Ligand A (5) is slightly lower than Ligand B (6), and both are within the acceptable limit of <=10.

**6. QED:** Both ligands have good QED values (A: 0.642, B: 0.752), indicating drug-like properties. Ligand B is slightly better.

**7. DILI:** Ligand A (19.232) has a significantly lower DILI risk than Ligand B (36.487). This is a major advantage for Ligand A.

**8. BBB:** Both ligands have reasonable BBB penetration (A: 48.895, B: 50.407), but neither reaches the highly desirable >70 percentile for CNS targets. However, for a GPCR, some CNS penetration is still valuable.

**9. Caco-2:** Both have negative Caco-2 values (-5.141 and -5.69), which is unusual and suggests poor permeability. This is a significant drawback for both.

**10. Solubility:** Both have negative solubility values (-1.117 and -1.667), indicating poor aqueous solubility. This is a concern for bioavailability.

**11. hERG:** Both ligands have very low hERG inhibition risk (A: 0.079, B: 0.017), which is excellent.

**12. Cl_mic:** Ligand A (2.523) has a much lower microsomal clearance than Ligand B (-12.945), suggesting better metabolic stability. This is a significant advantage for Ligand A.

**13. t1/2:** Ligand A (1.328) has a slightly shorter in vitro half-life than Ligand B (2.03), but both are relatively short.

**14. Pgp:** Both ligands have very low P-gp efflux liability (A: 0.006, B: 0.015), which is favorable for CNS exposure.

**15. Binding Affinity:** Both ligands have excellent binding affinity (-7.4 and -7.5 kcal/mol). The difference is negligible.

**Overall Assessment:**

Ligand A is the better candidate. While both have issues with Caco-2 and solubility, Ligand A has a significantly lower DILI risk and better metabolic stability (lower Cl_mic). Its logP is also slightly more favorable. The binding affinity is comparable. Given the GPCR target and the need for CNS penetration, the improved safety profile and metabolic stability of Ligand A outweigh the slightly lower BBB value and solubility.

Output:
0
2025-04-17 06:31:47,853 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B based on the provided guidelines, prioritizing GPCR-specific properties (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (338.371) is slightly lower, which could be beneficial for permeability.

**TPSA:** Ligand A (84.53) is excellent for CNS penetration, well below 90. Ligand B (62.55) is also very good.

**logP:** Ligand A (0.712) is a bit low, potentially hindering permeation. Ligand B (3.799) is closer to the optimal range of 1-3.

**H-Bond Donors/Acceptors:** Both have acceptable HBD (1) and HBA (6 for A, 3 for B) counts.

**QED:** Both ligands have good QED scores (0.762 and 0.737), indicating good drug-likeness.

**DILI:** Ligand A (64.754) has a higher DILI risk than Ligand B (31.214). This is a significant drawback for Ligand A.

**BBB:** Ligand B (54.75) has a much better BBB percentile than Ligand A (32.144). This is crucial for a CNS target like DRD2.

**Caco-2 Permeability:** Ligand A (-5.14) has poor Caco-2 permeability, while Ligand B (-4.462) is slightly better, but still not great.

**Aqueous Solubility:** Both have very poor aqueous solubility (-2.086 and -2.928). This could pose formulation challenges.

**hERG:** Both ligands have low hERG inhibition liability (0.379 and 0.664).

**Microsomal Clearance:** Ligand A (8.201) has lower microsomal clearance, suggesting better metabolic stability than Ligand B (73.519).

**In vitro Half-Life:** Ligand B (113.08) has a significantly longer in vitro half-life than Ligand A (11.417), which is a major advantage.

**P-gp Efflux:** Ligand A (0.023) has very low P-gp efflux, which is favorable for CNS penetration. Ligand B (0.333) has slightly higher efflux.

**Binding Affinity:** Ligand A (-8.6 kcal/mol) has a significantly stronger binding affinity than Ligand B (-6.5 kcal/mol). This is a substantial advantage, potentially outweighing some ADME concerns.

**Overall Assessment:**

While Ligand A boasts a superior binding affinity, its poor BBB penetration, higher DILI risk, and poor Caco-2 permeability are major concerns. Ligand B, despite a weaker affinity, has a much better BBB score, lower DILI risk, and a significantly longer half-life. Given the CNS target (DRD2), BBB penetration is paramount. The affinity difference, while substantial, might be overcome with further optimization of Ligand B. The improved ADME profile of Ligand B makes it a more promising starting point for drug development.

Output:
1
2025-04-17 06:31:47,853 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (353.403 and 361.511 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (84.12) is better than Ligand B (51.39) as it is closer to the ideal range for CNS targets (<=90). Ligand B is excellent.

**logP:** Both ligands have good logP values (3.295 and 3.857), falling within the optimal 1-3 range.

**H-Bond Donors:** Ligand A has 1 HBD, which is acceptable. Ligand B has 0, also acceptable.

**H-Bond Acceptors:** Both ligands have 6 HBAs, which is within the acceptable limit of <=10.

**QED:** Both ligands have good QED scores (0.73 and 0.782), indicating good drug-like properties.

**DILI:** Ligand A has a high DILI risk (95.386), which is a significant concern. Ligand B has a much lower DILI risk (21.442), a major advantage.

**BBB:** Ligand B has a better BBB penetration percentile (80.264) than Ligand A (63.746). Both are acceptable, but Ligand B is preferable for a CNS target.

**Caco-2 Permeability:** Ligand A (-4.869) has poor Caco-2 permeability, while Ligand B (-5.078) is also poor.

**Aqueous Solubility:** Ligand A (-5.503) has poor aqueous solubility, and Ligand B (-3.654) is also poor.

**hERG Inhibition:** Ligand A (0.544) has a slightly lower hERG inhibition risk than Ligand B (0.794), but both are acceptable.

**Microsomal Clearance:** Ligand A (90.33) has higher microsomal clearance than Ligand B (64.083), indicating lower metabolic stability.

**In vitro Half-Life:** Ligand B (12.912 hours) has a significantly longer half-life than Ligand A (58.693 hours).

**P-gp Efflux:** Ligand A (0.545) has lower P-gp efflux than Ligand B (0.438), which is favorable for CNS penetration.

**Binding Affinity:** Ligand B (-7.6 kcal/mol) has a slightly better binding affinity than Ligand A (-8.5 kcal/mol). Although the difference is small, it is still a benefit.

**Overall Assessment:**

Ligand B is the superior candidate. While Ligand A has slightly better binding affinity and P-gp efflux, Ligand B excels in critical areas: significantly lower DILI risk, better BBB penetration, and a longer half-life. The poor solubility and Caco-2 permeability are concerns for both, but can potentially be addressed through formulation strategies. The high DILI risk associated with Ligand A is a major red flag that outweighs its minor advantages.

Output:
1
2025-04-17 06:31:47,853 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (358.435 and 354.411 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (108.33) is slightly higher than Ligand B (103.63). Both are below the 140 A^2 threshold for oral absorption, but closer to the 90 A^2 target for CNS penetration. Ligand B is slightly better here.

**3. logP:** Both ligands have similar logP values (-0.169 and -0.246), which are a bit low. While not ideal, they aren't excessively low.

**4. H-Bond Donors:** Ligand A has 3 HBD, and Ligand B has 1. Both are within the acceptable limit of <=5. Ligand B is preferable.

**5. H-Bond Acceptors:** Ligand A has 6 HBA, and Ligand B has 9. Both are within the acceptable limit of <=10, but Ligand A is better.

**6. QED:** Ligand B (0.715) has a significantly better QED score than Ligand A (0.411), indicating a more drug-like profile.

**7. DILI:** Ligand A (21.287%) has a much lower DILI risk than Ligand B (47.693%). This is a substantial advantage for Ligand A.

**8. BBB:** Ligand B (74.098%) has a significantly higher BBB penetration percentile than Ligand A (29.818%). This is a *critical* advantage for a CNS target like DRD2.

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.156 and -4.894), which is unusual and suggests poor permeability.

**10. Aqueous Solubility:** Both ligands have negative solubility values (-0.827 and -0.765), also unusual and suggesting poor solubility.

**11. hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.234 and 0.044).

**12. Microsomal Clearance:** Ligand A (-12.554) has a much lower (better) microsomal clearance than Ligand B (10.556). This suggests better metabolic stability for Ligand A.

**13. In vitro Half-Life:** Ligand A (8.524 hours) has a slightly longer half-life than Ligand B (6.05 hours).

**14. P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.02 and 0.025).

**15. Binding Affinity:** Ligand A (-7.3 kcal/mol) has a slightly better binding affinity than Ligand B (-6.3 kcal/mol). This is a 1.0 kcal/mol difference, which is significant.

**Overall Assessment:**

The key trade-offs are BBB penetration (strongly favors Ligand B) versus DILI risk and metabolic stability (favor Ligand A). Given that this is a CNS target (DRD2), BBB penetration is paramount. While Ligand A has better metabolic stability and lower DILI, the substantial difference in BBB penetration (74.1% vs 29.8%) makes Ligand B the more promising candidate. The slightly better affinity of Ligand A is outweighed by the critical need for CNS exposure.

Output:
1
2025-04-17 06:31:47,853 - INFO - Reasoning:

Let's analyze Ligand A and Ligand B based on the provided guidelines, prioritizing GPCR-specific properties (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (359.344 and 367.555 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (66.84) is significantly better than Ligand B (38.77). For CNS targets, we want TPSA <= 90, and ideally lower. Ligand A is well within this range, while Ligand B is also acceptable but less optimal.

**logP:** Ligand A (2.967) is within the optimal 1-3 range. Ligand B (4.755) is slightly higher, potentially increasing off-target effects and decreasing solubility, but still within a reasonable range.

**H-Bond Donors/Acceptors:** Ligand A has 1 HBD and 3 HBA, while Ligand B has 0 HBD and 4 HBA. Both are within acceptable limits (<=5 HBD and <=10 HBA).

**QED:** Ligand A (0.898) has a better QED score than Ligand B (0.599), indicating a more drug-like profile.

**DILI:** Ligand A (39.085) has a slightly higher DILI risk than Ligand B (22.024), but both are below the concerning threshold of 60.

**BBB:** Both ligands have excellent BBB penetration (Ligand A: 83.56, Ligand B: 89.957), exceeding the desirable >70 threshold for CNS targets. Ligand B is slightly better here.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values, which is unusual and suggests a potential issue with the data or modeling. However, we'll proceed assuming these represent low permeability.

**Aqueous Solubility:** Both ligands have negative solubility values, again unusual. This suggests poor solubility, which could be a significant issue.

**hERG Inhibition:** Ligand A (0.338) shows a lower hERG inhibition liability than Ligand B (0.821), which is preferable.

**Microsomal Clearance:** Ligand A (-1.473) has a *negative* clearance, which is not physically possible and indicates a problem with the data. Ligand B (104.662) has a high clearance, suggesting rapid metabolism.

**In vitro Half-Life:** Ligand A (-20.505) has a negative half-life, which is impossible and indicates a data issue. Ligand B (35.305) has a reasonable half-life.

**P-gp Efflux:** Ligand A (0.091) has lower P-gp efflux liability than Ligand B (0.888), which is beneficial for CNS exposure.

**Binding Affinity:** Ligand B (-7.1) has a significantly stronger binding affinity than Ligand A (-8.7). A >1.5 kcal/mol advantage in affinity can often outweigh other drawbacks.

**Overall Assessment:**

Despite the questionable solubility and permeability data, the most significant difference lies in binding affinity and metabolic stability. Ligand B has a much stronger binding affinity (-7.1 vs -8.7 kcal/mol), which is crucial for a GPCR target. While Ligand B has higher microsomal clearance, the superior affinity is likely to be more impactful. Ligand A has a negative clearance and half-life, which are clear red flags indicating data issues. Ligand B also has a better Pgp efflux profile and slightly better BBB penetration. The slightly higher logP of Ligand B is a minor concern, but the strong affinity and better BBB penetration outweigh this.



Output:
1
2025-04-17 06:31:47,853 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B based on the provided guidelines, prioritizing GPCR-specific properties (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (350.46 and 351.54 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (87.66) is better than Ligand B (52.65). For CNS targets, TPSA should be <=90, both meet this, but lower is preferred. Ligand B is significantly lower, which is a positive.

**logP:** Both ligands have acceptable logP values (1.26 and 2.65), falling within the optimal 1-3 range. Ligand B is slightly better.

**H-Bond Donors/Acceptors:** Ligand A has 3 HBD and 4 HBA, while Ligand B has 1 HBD and 3 HBA. Both are within acceptable limits (<=5 HBD and <=10 HBA).

**QED:** Both ligands have good QED scores (0.697 and 0.8), indicating good drug-like properties.

**DILI:** Ligand A has a DILI risk of 28.62%, while Ligand B has 11.09%. Both are below the 40% threshold, but Ligand B is significantly better.

**BBB:** This is a crucial parameter for CNS targets. Ligand A has a BBB penetration of 28.81%, which is suboptimal. Ligand B has a much higher BBB penetration of 68.59%, exceeding the desirable >70% threshold. This is a major advantage for Ligand B.

**Caco-2 Permeability:** Both have negative values (-5.095 and -4.621). These are unusual and suggest poor permeability. However, the scale is not specified, so it's difficult to interpret.

**Aqueous Solubility:** Both have negative values (-2.783 and -2.202), again suggesting poor solubility. The scale is not specified, so it's difficult to interpret.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.136 and 0.364).

**Microsomal Clearance:** Ligand A has a lower Cl_mic (28.402) than Ligand B (43.532), indicating better metabolic stability.

**In vitro Half-Life:** Ligand A has a longer half-life (15.624 hours) than Ligand B (4.964 hours).

**P-gp Efflux:** Ligand A has very low P-gp efflux (0.046), which is excellent. Ligand B has slightly higher efflux (0.09), but still relatively low.

**Binding Affinity:** Ligand A has a stronger binding affinity (-8.6 kcal/mol) than Ligand B (-7.5 kcal/mol). This is a significant advantage for Ligand A (1.1 kcal/mol difference).

**Overall Assessment:**

Ligand A has a stronger binding affinity and better metabolic stability (lower Cl_mic and longer half-life) and lower P-gp efflux. However, Ligand B excels in BBB penetration and has a lower DILI risk. Given that this is a CNS target (DRD2), BBB penetration is paramount. The 1.1 kcal/mol difference in binding affinity, while substantial, can potentially be overcome with further optimization, whereas improving BBB penetration is often more challenging. The lower DILI risk of Ligand B is also a significant benefit.

Output:
1
2025-04-17 06:31:47,854 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (382.404 and 348.447 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (75.71) is better than Ligand B (78.53) as it is closer to the <90 A^2 threshold for CNS targets.

**3. logP:** Both ligands have good logP values (2.019 and 1.598), falling within the optimal 1-3 range.

**4. H-Bond Donors:** Both have 1 HBD, which is acceptable.

**5. H-Bond Acceptors:** Ligand A has 5 HBA, and Ligand B has 4. Both are below the acceptable threshold of 10.

**6. QED:** Both ligands have good QED scores (0.745 and 0.877), indicating good drug-like properties.

**7. DILI:** Ligand A (56.65) has a higher DILI risk than Ligand B (31.834). This favors Ligand B.

**8. BBB:** Ligand A (82.784) has a slightly better BBB penetration percentile than Ligand B (78.48), but both are reasonably good for a CNS target.

**9. Caco-2:** Ligand A (-4.887) has a worse Caco-2 permeability than Ligand B (-4.45), indicating lower intestinal absorption.

**10. Solubility:** Ligand A (-2.472) has worse solubility than Ligand B (-2.054).

**11. hERG:** Both ligands have low hERG inhibition liability (0.747 and 0.351), which is good.

**12. Cl_mic:** Ligand B (11.385) has significantly lower microsomal clearance than Ligand A (38.837), suggesting better metabolic stability.

**13. t1/2:** Ligand B (5.13) has a longer in vitro half-life than Ligand A (2.897), which is desirable.

**14. Pgp:** Ligand A (0.147) has slightly lower P-gp efflux liability than Ligand B (0.111), which is favorable for CNS penetration.

**15. Binding Affinity:** Ligand B (-7.6) has slightly better binding affinity than Ligand A (-7.5). While the difference is small, it's still a positive.

**Overall Assessment:**

Ligand B is the better candidate. While Ligand A has a slightly better BBB score and Pgp efflux, Ligand B excels in crucial areas: lower DILI risk, significantly better metabolic stability (lower Cl_mic and longer t1/2), better Caco-2 permeability, and slightly better binding affinity. The small advantage in binding affinity, combined with the improved ADME properties, outweighs the minor differences in BBB and Pgp.

Output:
1
2025-04-17 06:31:47,854 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight (MW):** Both ligands (345.443 and 348.487 Da) fall comfortably within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (74.43) is slightly higher than Ligand B (58.64). Both are below the 90 A^2 threshold for CNS targets, which is good. Ligand B is preferable here.

**3. logP:** Both ligands have good logP values (1.574 and 2.37), falling within the optimal 1-3 range. Ligand B is slightly better.

**4. H-Bond Donors (HBD):** Both ligands are acceptable (2 and 1 respectively), being less than 5. Ligand B is slightly preferable.

**5. H-Bond Acceptors (HBA):** Both ligands are acceptable (3 each), being less than 10.

**6. QED:** Both ligands have acceptable QED values (0.851 and 0.514), with Ligand A being significantly better.

**7. DILI:** Ligand B (23.885) has a much lower DILI risk than Ligand A (35.285), making it more favorable.

**8. BBB:** Ligand A (72.586) has a significantly better BBB penetration percentile than Ligand B (52.927). This is a *critical* factor for a CNS target like DRD2.

**9. Caco-2 Permeability:** Ligand A (-4.781) has slightly better Caco-2 permeability than Ligand B (-4.42), though both are negative and therefore difficult to interpret without knowing the scale.

**10. Aqueous Solubility:** Ligand A (-3.119) has slightly better aqueous solubility than Ligand B (-2.722), though both are negative and therefore difficult to interpret without knowing the scale.

**11. hERG Inhibition:** Both ligands have low hERG inhibition risk (0.488 and 0.271). Ligand B is slightly better.

**12. Microsomal Clearance:** Ligand B (41.649) has slightly higher microsomal clearance than Ligand A (39.423), meaning Ligand A is slightly more metabolically stable.

**13. In vitro Half-Life:** Ligand A (-13.755) has a significantly longer in vitro half-life than Ligand B (-7.492). This is a positive for Ligand A.

**14. P-gp Efflux:** Both ligands have low P-gp efflux liability (0.185 and 0.081). Ligand B is slightly preferable.

**15. Binding Affinity:** Both ligands have excellent binding affinities (-8.3 and -7.6 kcal/mol). Ligand A has a 0.7 kcal/mol advantage, which is substantial and can outweigh some ADME drawbacks.

**Overall Assessment:**

While Ligand B has advantages in DILI, logP, Pgp efflux, and hERG, Ligand A's significantly better BBB penetration (72.59% vs 52.93%), longer half-life, and slightly better binding affinity are crucial for a CNS-targeting GPCR like DRD2. The 0.7 kcal/mol difference in binding affinity is also a significant advantage. The slightly higher TPSA and DILI risk of Ligand A are acceptable given its superior CNS properties and potency.

Output:
0
2025-04-17 06:31:47,854 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 drug candidates, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (352.312 and 369.897 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (68.29) is excellent, well below the 90 A^2 threshold for CNS targets. Ligand B (96.01) is still reasonable, but closer to the 140 A^2 limit for oral absorption and less ideal for CNS penetration.

**3. logP:** Both ligands have good logP values (2.767 and 2.233), falling within the optimal 1-3 range.

**4. H-Bond Donors:** Ligand A (1) is preferable to Ligand B (3). Fewer HBDs generally improve permeability.

**5. H-Bond Acceptors:** Ligand A (4) is preferable to Ligand B (5) for similar reasons as HBDs.

**6. QED:** Both ligands have acceptable QED values (0.863 and 0.62), indicating good drug-like properties.

**7. DILI:** Ligand A (81.427) has a higher DILI risk than Ligand B (58.434), but both are within acceptable limits (<60 is good).

**8. BBB:** This is a critical parameter for a CNS target like DRD2. Ligand A (94.455) has a significantly higher BBB penetration percentile than Ligand B (58.123). This is a major advantage for Ligand A.

**9. Caco-2 Permeability:** Ligand A (-4.231) has a very poor Caco-2 permeability score, which is concerning. Ligand B (-5.18) is also poor, but slightly better.

**10. Aqueous Solubility:** Ligand A (-4.156) has poor solubility, while Ligand B (-3.27) is slightly better.

**11. hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.582 and 0.356).

**12. Microsomal Clearance:** Ligand A (82.314) has higher microsomal clearance than Ligand B (50.886), suggesting lower metabolic stability.

**13. In vitro Half-Life:** Ligand B (45.527) has a much longer in vitro half-life than Ligand A (0.072). This is a significant advantage for Ligand B.

**14. P-gp Efflux:** Both ligands have low P-gp efflux liability (0.161 and 0.085), which is favorable for CNS exposure.

**15. Binding Affinity:** Both ligands have excellent binding affinities (-8.2 and -8.3 kcal/mol), which are comparable. The difference is negligible.

**Overall Assessment:**

Ligand A excels in TPSA and BBB penetration, which are crucial for CNS GPCR targets. However, it suffers from poor Caco-2 permeability, poor solubility, and higher microsomal clearance. Ligand B, while having a slightly higher TPSA, demonstrates better solubility, a longer half-life, and lower clearance. The substantial difference in BBB penetration heavily favors Ligand A. Given the importance of CNS penetration for DRD2, and the comparable binding affinities, Ligand A is the more promising candidate despite its other drawbacks. The poor Caco-2 and solubility could potentially be addressed with formulation strategies.

Output:
0
2025-04-17 06:31:47,854 - INFO - Okay, let's analyze these two ligands for their potential as DRD2 drug candidates. DRD2 is a GPCR in the CNS, so BBB penetration, logP, Pgp efflux, TPSA, and binding affinity are paramount.

**Ligand A: [360.292, 110.25 ,   1.099,   2.   ,   7.   ,   0.773,  67.39 ,  62.97 , -4.804,  -1.869,   0.076,  41.317, -40.233,   0.083,  -8.2  ]**

*   **MW:** 360.292 Da - Good, within the ideal range.
*   **TPSA:** 110.25 - Acceptable, but pushing the limit for CNS targets (ideally <90).
*   **logP:** 1.099 - Good, within the optimal range.
*   **HBD:** 2 - Good.
*   **HBA:** 7 - Good.
*   **QED:** 0.773 - Excellent, highly drug-like.
*   **DILI:** 67.39 - Moderate risk, but manageable.
*   **BBB:** 62.97 - Below the desirable threshold of >70 for CNS targets. This is a significant drawback.
*   **Caco-2:** -4.804 - Not interpretable without units. Assuming this is a log scale, this is poor permeability.
*   **Solubility:** -1.869 - Not interpretable without units. Assuming this is a log scale, this is poor solubility.
*   **hERG:** 0.076 - Very low risk, excellent.
*   **Cl_mic:** 41.317 mL/min/kg - Moderate clearance, could be better for metabolic stability.
*   **t1/2:** -40.233 hours - Not interpretable without units. Assuming this is a log scale, this is very short half-life.
*   **Pgp:** 0.083 - Low efflux, good.
*   **Affinity:** -8.2 kcal/mol - Excellent, very strong binding.

**Ligand B: [354.426,  87.46 ,   2.364,   2.   ,   5.   ,   0.736,  47.732,  82.474, -4.847,  -3.474,   0.452,  21.96 , -22.72 ,   0.419,  -7.8  ]**

*   **MW:** 354.426 Da - Good, within the ideal range.
*   **TPSA:** 87.46 - Good, within the ideal range for CNS targets.
*   **logP:** 2.364 - Good, within the optimal range.
*   **HBD:** 2 - Good.
*   **HBA:** 5 - Good.
*   **QED:** 0.736 - Excellent, highly drug-like.
*   **DILI:** 47.732 - Low risk, excellent.
*   **BBB:** 82.474 - Excellent, very good CNS penetration predicted.
*   **Caco-2:** -4.847 - Not interpretable without units. Assuming this is a log scale, this is poor permeability.
*   **Solubility:** -3.474 - Not interpretable without units. Assuming this is a log scale, this is poor solubility.
*   **hERG:** 0.452 - Low risk, good.
*   **Cl_mic:** 21.96 mL/min/kg - Low clearance, excellent metabolic stability.
*   **t1/2:** -22.72 hours - Not interpretable without units. Assuming this is a log scale, this is a long half-life.
*   **Pgp:** 0.419 - Moderate efflux, acceptable.
*   **Affinity:** -7.8 kcal/mol - Very good, strong binding.

**Comparison and Decision:**

While Ligand A has a slightly better binding affinity (-8.2 vs -7.8 kcal/mol), Ligand B is significantly better overall, especially considering the CNS target. The key advantages of Ligand B are its superior BBB penetration (82.474 vs 62.97), lower DILI risk (47.732 vs 67.39), and better metabolic stability (lower Cl_mic and longer t1/2). Both have poor Caco-2 and solubility, but these can be addressed with formulation strategies. The 0.4 kcal/mol difference in binding affinity is unlikely to outweigh the substantial improvements in ADME properties, particularly BBB penetration, for a CNS-targeted drug.

Therefore, I recommend **Ligand B** as the more viable drug candidate.

1
2025-04-17 06:31:47,854 - INFO - Batch 289 complete. Total preferences: 4624
2025-04-17 06:31:47,854 - INFO - Processing batch 290/512...
2025-04-17 06:32:30,584 - INFO - Reasoning:

Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (366.53 and 339.44 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (69.64) is significantly better than Ligand B (82.7). For CNS targets, we want TPSA <= 90, and A is closer to the optimal <=60 range. B is pushing the upper limit.

**3. logP:** Both ligands have a logP of approximately 3.03, which is optimal.

**4. H-Bond Donors:** Ligand A (2) is preferable to Ligand B (3). Lower HBD generally improves permeability.

**5. H-Bond Acceptors:** Ligand A (4) is preferable to Ligand B (5) for similar reasons.

**6. QED:** Both ligands have similar QED values (0.669 and 0.676), indicating good drug-likeness.

**7. DILI:** Ligand A (29.39) has a much lower DILI risk than Ligand B (54.52). This is a significant advantage.

**8. BBB:** Both ligands have similar BBB penetration (67.16% and 66.89%). While not exceeding the desirable >70%, they are reasonably good.

**9. Caco-2 Permeability:** Ligand A (-4.689) is better than Ligand B (-5.477), indicating better intestinal absorption.

**10. Aqueous Solubility:** Both ligands have similar, very poor aqueous solubility (-3.582 and -3.416). This could be a formulation challenge.

**11. hERG Inhibition:** Ligand A (0.627) has a slightly lower hERG risk than Ligand B (0.739), which is preferable.

**12. Microsomal Clearance:** Ligand A (83.695) has higher clearance than Ligand B (40.838), suggesting lower metabolic stability. This is a drawback for A.

**13. In vitro Half-Life:** Ligand B (48.413) has a significantly longer half-life than Ligand A (15.448). This is a major advantage for B.

**14. P-gp Efflux:** Ligand A (0.422) shows lower P-gp efflux than Ligand B (0.308), which is beneficial for CNS penetration.

**15. Binding Affinity:** Ligand B (-8.4 kcal/mol) has a stronger binding affinity than Ligand A (-7.6 kcal/mol). The 0.8 kcal/mol difference is substantial and can outweigh some ADME drawbacks.

**Overall Assessment:**

Ligand B has a significantly better binding affinity and a longer half-life, which are crucial for a GPCR ligand. While Ligand A has better TPSA and lower DILI risk, the stronger binding and improved metabolic stability of Ligand B are more important. The slightly higher P-gp efflux of B is less concerning than the higher clearance of A. The similar BBB values and logP values don't differentiate the two.

Output:
1
2025-04-17 06:32:30,585 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 drug candidates, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (347.415 and 357.376 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (93.46) is slightly above the optimal <90 for CNS targets, but still reasonable. Ligand B (55.32) is excellent, well below 90.

**logP:** Ligand A (1.804) is within the optimal 1-3 range. Ligand B (3.206) is at the higher end of the optimal range, but still acceptable.

**H-Bond Donors/Acceptors:** Ligand A has 2 HBD and 5 HBA, both within acceptable limits. Ligand B has 0 HBD and 4 HBA, also good.

**QED:** Both ligands have similar QED values (0.734 and 0.703), indicating good drug-likeness.

**DILI:** Ligand A (54.052) has a slightly higher DILI risk than Ligand B (47.732), but both are below the concerning threshold of 60.

**BBB:** This is crucial for a CNS target. Ligand A has 75.223, which is good, but Ligand B has a significantly higher BBB penetration score of 85.111, making it more favorable.

**Caco-2 Permeability:** Both have negative values (-4.931 and -4.201), which is unusual and suggests poor permeability. However, these values are on a scale where negative values are possible, and the absolute magnitude is important. They are relatively close, so this isn't a major differentiator.

**Aqueous Solubility:** Both ligands have very poor aqueous solubility (-3.19 and -3.393). This is a significant concern for both, potentially hindering bioavailability.

**hERG Inhibition:** Ligand A (0.175) shows very low hERG inhibition risk, which is excellent. Ligand B (0.645) is slightly higher, but still relatively low.

**Microsomal Clearance:** Ligand A (39.966) has lower microsomal clearance than Ligand B (65.447), indicating better metabolic stability.

**In vitro Half-Life:** Ligand A (-1.475) has a negative half-life, which is not physically possible and indicates a problem with the data or prediction method. Ligand B (-28.159) also has a negative half-life, indicating a similar issue.

**P-gp Efflux:** Ligand A (0.089) has very low P-gp efflux, which is favorable for CNS penetration. Ligand B (0.28) is slightly higher, but still reasonably low.

**Binding Affinity:** Ligand A (-8.1 kcal/mol) has a significantly stronger binding affinity than Ligand B (-6.3 kcal/mol). This is a substantial advantage, potentially outweighing some of the ADME drawbacks.

**Overall Assessment:**

Ligand A has a much stronger binding affinity and better metabolic stability (lower Cl_mic) and lower P-gp efflux. However, Ligand B has superior BBB penetration and a slightly lower DILI risk. The negative half-life values for both are concerning and suggest issues with the data. Despite the poor solubility and permeability predictions, the strong affinity of Ligand A, coupled with its favorable P-gp efflux, makes it the more promising candidate, *assuming the half-life issue can be resolved with further investigation or is a data artifact*. The difference in binding affinity (1.8 kcal/mol) is significant.

Output:
0
2025-04-17 06:32:30,585 - INFO - Reasoning:

Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (368.5) is slightly higher than Ligand B (346.4), but both are acceptable.

**2. TPSA:** Ligand A (66.92) is significantly better than Ligand B (110.28). For CNS targets, we want TPSA <= 90, so Ligand A is much more favorable. Ligand B is above this threshold and could have reduced brain penetration.

**3. logP:** Both ligands have similar logP values (A: 0.653, B: 0.718), falling within the optimal range of 1-3.

**4. H-Bond Donors:** Ligand A (0) is preferable to Ligand B (2). Fewer H-bond donors generally improve permeability.

**5. H-Bond Acceptors:** Ligand A (4) is better than Ligand B (6). Fewer H-bond acceptors also contribute to better permeability.

**6. QED:** Both ligands have similar and good QED values (A: 0.669, B: 0.704), indicating good drug-like properties.

**7. DILI:** Ligand A (30.71) has a much lower DILI risk than Ligand B (64.366). This is a significant advantage for Ligand A.

**8. BBB:** Ligand A (60.84) is better than Ligand B (56.61), although neither is above the highly desirable >70 percentile. However, given the CNS target, Ligand A's higher BBB score is important.

**9. Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and suggests poor permeability. However, the absolute value for Ligand A (-1.694) is less negative than Ligand B (-2.232), indicating slightly better potential permeability.

**10. Aqueous Solubility:** Both have negative solubility values, indicating poor solubility. Again, Ligand A (-4.311) is slightly better than Ligand B (-4.886).

**11. hERG Inhibition:** Both ligands have very low hERG inhibition risk (A: 0.146, B: 0.031).

**12. Microsomal Clearance:** Ligand B (27.02) has a lower microsomal clearance than Ligand A (46.83), suggesting better metabolic stability.

**13. In vitro Half-Life:** Ligand B (8.232) has a significantly longer in vitro half-life than Ligand A (-16.13). This is a substantial advantage for Ligand B.

**14. P-gp Efflux:** Both ligands have very low P-gp efflux liability (A: 0.048, B: 0.005).

**15. Binding Affinity:** Ligand B (-8.4) has a slightly better binding affinity than Ligand A (-7.8). While a 0.6 kcal/mol difference is not huge, it's noticeable.

**Overall Assessment:**

Ligand A excels in properties crucial for CNS penetration (TPSA, BBB) and safety (DILI). Ligand B has better metabolic stability (Cl_mic, t1/2) and slightly better affinity. However, the higher TPSA and DILI risk of Ligand B are significant drawbacks for a CNS-targeting drug. The slightly better affinity of Ligand B is unlikely to outweigh the advantages of Ligand A regarding brain penetration and safety.

Output:
0
2025-04-17 06:32:30,585 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (349.5 and 354.4 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (52.65) is significantly better than Ligand B (68.31). For CNS targets, we want TPSA <= 90, and A is much closer to the optimal <=60 range. B is pushing the upper limit.

**logP:** Ligand A (2.26) is optimal (1-3). Ligand B (0.832) is a bit low, potentially hindering membrane permeability.

**H-Bond Donors/Acceptors:** Ligand A (1 HBD, 3 HBA) and Ligand B (0 HBD, 5 HBA) both have reasonable numbers.

**QED:** Both ligands have similar QED values (0.695 and 0.604), indicating good drug-likeness.

**DILI:** Ligand A (7.794) has a much lower DILI risk than Ligand B (23.342). This is a significant advantage.

**BBB:** Ligand A (78.054) and Ligand B (83.56) both have good BBB penetration, exceeding the 70% threshold for CNS targets. B is slightly better.

**Caco-2 Permeability:** Both are negative, indicating poor permeability.

**Aqueous Solubility:** Both ligands have negative solubility values, which is concerning.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.477 and 0.172).

**Microsomal Clearance:** Ligand A (53.12) has higher clearance than Ligand B (19.745), meaning B is more metabolically stable.

**In vitro Half-Life:** Ligand B (5.121) has a longer half-life than Ligand A (-5.899).

**P-gp Efflux:** Both have low P-gp efflux (0.066 and 0.056), which is good for CNS penetration.

**Binding Affinity:** Ligand A (-7.9 kcal/mol) has a slightly better binding affinity than Ligand B (-7.3 kcal/mol). While both are good, the 0.6 kcal/mol difference is noticeable.

**Overall Assessment:**

Considering the GPCR-specific priorities, Ligand A is the better candidate. Its significantly lower TPSA and DILI risk are major advantages. While Ligand B has slightly better BBB penetration and metabolic stability, the TPSA and DILI concerns for B outweigh these benefits. The slightly better affinity of A also contributes to its favorability. The negative solubility and Caco-2 permeability are concerns for both, but can be addressed in later optimization stages.

Output:
1
2025-04-17 06:32:30,585 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (345.447 and 361.471 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (98.17) is slightly higher than the preferred <90 for CNS targets, but still reasonable. Ligand B (71.33) is well within the ideal range. This favors Ligand B.

**3. logP:** Both ligands have good logP values (2.929 and 2.045), falling within the optimal 1-3 range.

**4. H-Bond Donors:** Ligand A has 1 HBD, which is acceptable. Ligand B has 0, also acceptable.

**5. H-Bond Acceptors:** Ligand A has 3 HBA, and Ligand B has 6. Both are within the acceptable limit of <=10, but Ligand A is slightly better.

**6. QED:** Both ligands have reasonable QED values (0.481 and 0.817). Ligand B's QED is significantly higher, indicating a more drug-like profile.

**7. DILI:** Ligand A (39.007) has a lower DILI risk than Ligand B (58.511), which is favorable.

**8. BBB:** Both ligands have good BBB penetration (69.678 and 71.307), exceeding the 70% threshold for CNS targets. Ligand B is slightly better.

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.752 and -4.836). This is unusual and suggests poor permeability. However, these values are on a scale where negative values are possible and don't necessarily disqualify the compounds.

**10. Aqueous Solubility:** Both ligands have negative solubility values (-3.056 and -2.291), indicating poor aqueous solubility. This is a concern for bioavailability.

**11. hERG Inhibition:** Both ligands have low hERG inhibition risk (0.186 and 0.238).

**12. Microsomal Clearance:** Both ligands have similar microsomal clearance values (41.655 and 42.61), indicating similar metabolic stability.

**13. In vitro Half-Life:** Ligand B (23.242 hours) has a significantly longer half-life than Ligand A (4.263 hours), which is a significant advantage.

**14. P-gp Efflux:** Both ligands have low P-gp efflux liability (0.045 and 0.195).

**15. Binding Affinity:** Both ligands have excellent binding affinities (-8.2 and -8.3 kcal/mol). The difference is minimal.

**Overall Assessment:**

Ligand B is slightly favored. While Ligand A has a lower DILI risk, Ligand B has a significantly better QED score, better TPSA, and a much longer in vitro half-life. The BBB penetration is comparable for both. The negative Caco-2 and solubility values are concerns for both, but the superior overall profile of Ligand B makes it the more promising candidate.

Output:
1
2025-04-17 06:32:30,585 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (339.307 Da) is slightly lower, which could be advantageous for permeability. Ligand B (366.418 Da) is also good.

**TPSA:** Both ligands have TPSA values (A: 115.19, B: 111.95) that are above the optimal <90 for CNS targets, but not drastically so. This is a moderate concern for both.

**logP:** Ligand A (2.44) is within the optimal range (1-3). Ligand B (0.942) is slightly below 1, which *could* indicate permeability issues, but isn't a hard disqualifier.

**H-Bond Donors/Acceptors:** Ligand A (HBD=1, HBA=6) and Ligand B (HBD=2, HBA=5) both have reasonable numbers of H-bond donors and acceptors, well within the guidelines.

**QED:** Both ligands have acceptable QED values (A: 0.319, B: 0.778). Ligand B's QED is significantly better, suggesting a more drug-like profile overall.

**DILI:** Ligand A (98.72) has a very high DILI risk, which is a major red flag. Ligand B (64.599) has a moderate DILI risk, which is much more acceptable.

**BBB:** Both ligands have reasonably good BBB penetration (A: 65.839, B: 60.644), but neither exceeds the desirable >70 threshold.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.119 and -5.025), which is unusual and likely indicates poor permeability. This is a significant concern for both.

**Aqueous Solubility:** Both ligands have negative solubility values (-4.705 and -3.709), indicating very poor aqueous solubility. This is a major issue for both.

**hERG Inhibition:** Both ligands have very low hERG inhibition risk (A: 0.29, B: 0.272), which is excellent.

**Microsomal Clearance:** Ligand A (102.734) has a higher microsomal clearance than Ligand B (2.585), meaning it is likely to be metabolized more quickly. This is unfavorable.

**In vitro Half-Life:** Ligand A (-22.703) has a negative half-life, which is not physically possible and indicates a problem with the data or the molecule. Ligand B (0.759) has a very short half-life, which is not ideal.

**P-gp Efflux:** Both ligands have low P-gp efflux (A: 0.446, B: 0.038), which is favorable for CNS penetration. Ligand B is better in this regard.

**Binding Affinity:** Ligand B (-8.7 kcal/mol) has a significantly stronger binding affinity than Ligand A (-9.5 kcal/mol). This is a substantial advantage.

**Overall Assessment:**

Ligand A is severely hampered by its extremely high DILI risk and nonsensical half-life. While its MW and logP are acceptable, the DILI risk alone is enough to disqualify it.

Ligand B, while not perfect, is significantly better. It has a much lower DILI risk, a better QED score, lower microsomal clearance, better P-gp efflux, and, crucially, a stronger binding affinity. The poor Caco-2 and solubility are concerns, but the strong affinity might compensate for these issues, especially considering the CNS target.

Output:
1
2025-04-17 06:32:30,585 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (361.518 and 342.483 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (82.53) is better than Ligand B (58.2). Both are below the 90 A^2 threshold for CNS targets, but Ligand B is significantly lower, which is favorable.

**logP:** Ligand A (1.706) is within the optimal 1-3 range. Ligand B (3.697) is at the higher end, potentially increasing off-target effects and decreasing solubility, but still acceptable.

**H-Bond Donors/Acceptors:** Both ligands have 2 HBDs and a reasonable number of HBAs (4 for A, 2 for B), satisfying the <5 HBD and <10 HBA guidelines.

**QED:** Ligand A (0.8) has a better QED score than Ligand B (0.571), indicating a more drug-like profile.

**DILI:** Ligand A (47.034) has a slightly higher DILI risk than Ligand B (36.875), but both are below the concerning threshold of 60.

**BBB:** Ligand B (70.143) has a significantly better BBB penetration percentile than Ligand A (40.713). This is *critical* for a CNS target like DRD2.

**Caco-2 Permeability:** Both ligands have negative Caco-2 permeability values (-4.922 and -4.943), which is unusual and suggests poor intestinal absorption. This is a significant drawback for both.

**Aqueous Solubility:** Both ligands have very poor aqueous solubility (-3.021 and -3.938). This will likely pose formulation challenges.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.168 and 0.204).

**Microsomal Clearance:** Ligand A (38.403) has lower microsomal clearance than Ligand B (60.947), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (24.494 hours) has a longer half-life than Ligand B (13.61 hours), which is desirable.

**P-gp Efflux:** Ligand A (0.086) has lower P-gp efflux than Ligand B (0.343), which is beneficial for CNS exposure.

**Binding Affinity:** Ligand B (-9.0 kcal/mol) has a *much* stronger binding affinity than Ligand A (-0.0 kcal/mol). This is a decisive advantage, potentially outweighing some of the ADME concerns.

**Overall Assessment:**

While Ligand A has better QED, metabolic stability, half-life, and P-gp efflux, Ligand B's significantly superior binding affinity (-9.0 vs -0.0 kcal/mol) and much better BBB penetration (70.143 vs 40.713) are crucial for a CNS GPCR target. The poor Caco-2 and solubility are concerning for both, but can potentially be addressed with formulation strategies. The higher logP of Ligand B is a minor concern compared to the large affinity difference.

Output:
1
2025-04-17 06:32:30,585 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (366.46 and 350.46 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (66.48) is significantly better than Ligand B (76.66). For CNS targets, we want TPSA <= 90, and A is closer to the optimal <=60 range. B is pushing the upper limit.

**3. logP:** Both ligands have good logP values (1.96 and 1.53), falling within the 1-3 range.

**4. H-Bond Donors:** Ligand A (1) is preferable to Ligand B (2). Lower HBD generally improves permeability.

**5. H-Bond Acceptors:** Ligand A (3) is preferable to Ligand B (4). Lower HBA generally improves permeability.

**6. QED:** Ligand A (0.866) has a higher QED score than Ligand B (0.696), indicating better overall drug-likeness.

**7. DILI:** Ligand A (31.06) has a much lower DILI risk than Ligand B (15.24), suggesting a safer profile.

**8. BBB:** Ligand A (76.15) has a significantly better BBB penetration score than Ligand B (66.81). This is *critical* for a CNS target like DRD2.

**9. Caco-2 Permeability:** Ligand A (-4.664) is better than Ligand B (-4.937), indicating better intestinal absorption.

**10. Aqueous Solubility:** Ligand A (-3.82) is better than Ligand B (-2.311), indicating better solubility.

**11. hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.369 and 0.392).

**12. Microsomal Clearance:** Ligand B (27.04) has slightly higher microsomal clearance than Ligand A (24.82), suggesting faster metabolism and potentially lower exposure.

**13. In vitro Half-Life:** Ligand B (23.124) has a better in vitro half-life than Ligand A (-25.61). This is a positive for B, but the difference is substantial enough to be concerning.

**14. P-gp Efflux:** Ligand A (0.107) has lower P-gp efflux liability than Ligand B (0.014), which is favorable for CNS penetration.

**15. Binding Affinity:** Ligand B (-7.9) has a slightly better binding affinity than Ligand A (-8.8). While affinity is important, the difference of 0.9 kcal/mol is not large enough to overcome the significant ADME advantages of Ligand A.

**Overall:**

Ligand A is the stronger candidate. It excels in properties crucial for CNS penetration (BBB, TPSA, Pgp), has a better safety profile (DILI), and superior drug-likeness (QED). While Ligand B has a slightly better binding affinity and half-life, the ADME advantages of Ligand A, particularly its BBB score, are more important for a DRD2 ligand.

Output:
1
2025-04-17 06:32:30,586 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (342.483 and 348.447 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (40.62) is significantly better than Ligand B (96.25). For CNS targets, we want TPSA <= 90, so Ligand A is much more favorable.

**logP:** Ligand A (2.984) is optimal (1-3), while Ligand B (0.906) is a bit low, potentially hindering permeability.

**H-Bond Donors/Acceptors:** Ligand A (0 HBD, 2 HBA) is preferable to Ligand B (3 HBD, 5 HBA) as lower values generally improve permeability. Both are within acceptable limits.

**QED:** Both ligands have similar QED values (0.74 and 0.712), indicating good drug-likeness.

**DILI:** Ligand A (17.72) has a lower DILI risk than Ligand B (20.977), both are good.

**BBB:** Ligand A (71.656) has a significantly higher BBB penetration percentile than Ligand B (52.423). This is *critical* for a CNS target like DRD2. A value >70 is desirable, and Ligand A is closer to that threshold.

**Caco-2 Permeability:** Ligand A (-4.74) has a worse Caco-2 permeability than Ligand B (-5.001). Both are very poor, but this is less critical given the BBB focus.

**Aqueous Solubility:** Ligand A (-3.289) has better solubility than Ligand B (-1.373).

**hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.335 and 0.261).

**Microsomal Clearance:** Ligand A (63.316) has higher microsomal clearance than Ligand B (7.321), meaning it's less metabolically stable. This is a negative for Ligand A.

**In vitro Half-Life:** Ligand B (2.085) has a longer in vitro half-life than Ligand A (-9.169), which is a positive for Ligand B.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.158 and 0.008).

**Binding Affinity:** Ligand B (-8.5) has a slightly better binding affinity than Ligand A (-8.2), but the difference is relatively small (0.3 kcal/mol).

**Overall Assessment:**

Ligand A excels in TPSA and BBB penetration, which are crucial for CNS GPCR targets. It also has better solubility and a lower DILI risk. However, it suffers from higher microsomal clearance and a shorter half-life. Ligand B has slightly better affinity and half-life, but its significantly higher TPSA and lower BBB penetration are major drawbacks for a CNS drug. The small affinity difference is likely outweighed by the substantial ADME advantages of Ligand A, particularly its BBB score.

Output:
1
2025-04-17 06:32:30,586 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (353.5 and 354.5 Da) fall comfortably within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (53.09) is significantly better than Ligand B (69.64). For CNS targets, we want TPSA <= 90, and A is much closer to the ideal <=60 range. B is pushing the upper limit.

**3. logP:** Both ligands have acceptable logP values (1.593 and 2.195), falling within the optimal 1-3 range.

**4. H-Bond Donors:** Ligand A has 0 HBD, while Ligand B has 2. Both are within the acceptable limit of <=5.

**5. H-Bond Acceptors:** Ligand A has 4 HBA, and Ligand B has 3. Both are within the acceptable limit of <=10.

**6. QED:** Both ligands have similar QED values (0.728 and 0.719), indicating good drug-likeness.

**7. DILI:** Ligand A (11.2) has a significantly lower DILI risk than Ligand B (24.3). This is a major advantage for A.

**8. BBB:** Both ligands have excellent BBB penetration (81.6% and 81.7%), exceeding the desirable >70% threshold for CNS targets.

**9. Caco-2:** Both ligands have negative Caco-2 values (-4.326 and -4.688), which is unusual and suggests poor permeability. However, these values are on a scale where negative values are possible and don't necessarily preclude further investigation.

**10. Solubility:** Ligand A (-0.683) has slightly better solubility than Ligand B (-2.931), though both are quite poor.

**11. hERG:** Both ligands have low hERG inhibition liability (0.414 and 0.397), which is good.

**12. Cl_mic:** Ligand A (33.5) has a lower microsomal clearance than Ligand B (61.5), indicating better metabolic stability.

**13. t1/2:** Both have negative in vitro half-lives (-17.99 and -18.156), which is also unusual and likely indicates rapid metabolism.

**14. Pgp:** Both ligands have very low P-gp efflux liability (0.052 and 0.216), which is favorable for CNS penetration.

**15. Binding Affinity:** Ligand B (-8.2 kcal/mol) has a slightly better binding affinity than Ligand A (-7.5 kcal/mol). While a 0.7 kcal/mol difference is noticeable, it's not a huge advantage, especially considering the other factors.

**Overall Assessment:**

Ligand A is the stronger candidate. While Ligand B has slightly better binding affinity, Ligand A excels in crucial ADME properties, particularly TPSA and DILI risk. The lower TPSA of A is beneficial for CNS penetration, and the significantly lower DILI risk is a major advantage for safety. The better metabolic stability (lower Cl_mic) also favors A. The solubility is poor for both, but A is slightly better. The unusual Caco-2 and t1/2 values are concerning for both, but the overall profile of A is more promising.

Output:
0
2025-04-17 06:32:30,586 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (353.419 and 341.415 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (113.17) is slightly above the optimal <90 for CNS targets, but still reasonable. Ligand B (91.81) is within the preferred range.

**logP:** Ligand A (-0.735) is a bit low, potentially hindering membrane permeability. Ligand B (1.426) is within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A (2 HBD, 5 HBA) and Ligand B (3 HBD, 4 HBA) both have acceptable numbers of H-bond donors and acceptors.

**QED:** Both ligands have QED values above 0.5 (0.632 and 0.501), indicating good drug-likeness.

**DILI:** Ligand A (22.451) has a significantly lower DILI risk than Ligand B (49.632), indicating a safer profile.

**BBB:** Ligand A (63.474) has a better BBB penetration percentile than Ligand B (43.699). While both are below the desirable >70 for CNS targets, A is closer.

**Caco-2 Permeability:** Ligand A (-4.897) has poor Caco-2 permeability, while Ligand B (-5.729) is also poor.

**Aqueous Solubility:** Both ligands have poor aqueous solubility (-1.176 and -2.39).

**hERG:** Both ligands have low hERG inhibition risk (0.178 and 0.47).

**Microsomal Clearance:** Ligand A (-0.583) has lower (better) microsomal clearance than Ligand B (25.589), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (-25.607) has a very long in vitro half-life, while Ligand B (-3.805) is shorter.

**P-gp Efflux:** Ligand A (0.029) has very low P-gp efflux liability, which is favorable for CNS penetration. Ligand B (0.152) is also low, but higher than A.

**Binding Affinity:** Both ligands have the same binding affinity (-7.9 kcal/mol), which is excellent.

**Overall Assessment:**

Given the GPCR-specific priorities, Ligand A is the more promising candidate. While its logP is slightly low and Caco-2 permeability is poor, its superior BBB penetration, significantly lower DILI risk, better metabolic stability (lower Cl_mic, longer t1/2), and very low P-gp efflux outweigh these drawbacks. The equal binding affinity is a tiebreaker in its favor due to the other ADME properties. Ligand B's higher DILI and lower BBB are significant concerns for a CNS-targeting drug.

Output:
0
2025-04-17 06:32:30,586 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (344.415 and 361.507 Da) fall within the ideal range of 200-500 Da.

**TPSA:** Ligand A (84.42) is excellent, well below the 90 A^2 threshold for CNS targets. Ligand B (46.61) is even better.

**logP:** Ligand A (1.212) is within the optimal range (1-3). Ligand B (3.345) is at the higher end, but still acceptable.

**H-Bond Donors/Acceptors:** Ligand A has 1 HBD and 5 HBA, which is reasonable. Ligand B has 0 HBD and 4 HBA, also reasonable.

**QED:** Both ligands have similar QED values (0.887 and 0.808), indicating good drug-likeness.

**DILI:** Ligand A (60.682) has a moderate DILI risk, while Ligand B (28.616) has a low DILI risk. This favors Ligand B.

**BBB:** Ligand A (60.954) has a moderate BBB penetration, which is not ideal for a CNS target. Ligand B (85.847) has excellent BBB penetration, exceeding the >70% threshold. This is a significant advantage for Ligand B.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.064 and -4.822), which is unusual and suggests poor permeability. However, these values are on a log scale, so they are likely representing very low permeability.

**Aqueous Solubility:** Both ligands have negative solubility values (-2.004 and -3.244), indicating poor aqueous solubility. This could be a formulation challenge.

**hERG Inhibition:** Ligand A (0.091) has very low hERG inhibition risk, which is excellent. Ligand B (0.375) has a slightly higher, but still acceptable, hERG risk.

**Microsomal Clearance:** Ligand A (16.469) has lower microsomal clearance, suggesting better metabolic stability. Ligand B (67.734) has higher clearance, indicating faster metabolism. This favors Ligand A.

**In vitro Half-Life:** Ligand A (11.073) has a longer half-life than Ligand B (6.948).

**P-gp Efflux:** Ligand A (0.007) has very low P-gp efflux, which is excellent for CNS penetration. Ligand B (0.598) has moderate P-gp efflux. This strongly favors Ligand A.

**Binding Affinity:** Ligand B (-7.7 kcal/mol) has a slightly better binding affinity than Ligand A (-8.5 kcal/mol). While a 1.5 kcal/mol difference is significant, the other ADME properties are more concerning.

**Overall Assessment:**

Ligand B excels in BBB penetration and has a lower DILI risk and better binding affinity. However, it has higher P-gp efflux and faster metabolic clearance. Ligand A has superior metabolic stability, lower P-gp efflux, and a very low hERG risk. While Ligand A has slightly weaker binding affinity, the combination of its favorable ADME properties, particularly BBB and P-gp, makes it a more promising candidate for a CNS-targeting drug like a DRD2 ligand. The poor Caco-2 and solubility for both are concerning, but can potentially be addressed through formulation strategies.

Output:
0
2025-04-17 06:32:30,586 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (379.266 Da) is slightly higher than Ligand B (348.531 Da), but both are acceptable.

**TPSA:** Ligand A (33.95) is excellent, well below the 90 A^2 threshold for CNS targets. Ligand B (52.57) is still reasonable, but less optimal, being above 50 A^2.

**logP:** Ligand A (4.906) is a bit high, potentially leading to solubility issues and off-target interactions. Ligand B (2.658) is within the optimal range (1-3).

**H-Bond Donors/Acceptors:** Ligand A (0 HBD, 4 HBA) and Ligand B (2 HBD, 3 HBA) both have acceptable numbers of H-bond donors and acceptors.

**QED:** Both ligands have good QED values (A: 0.632, B: 0.744), indicating drug-like properties.

**DILI:** Both ligands have low DILI risk (A: 56.611, B: 5.312), with Ligand B being significantly better.

**BBB:** Both ligands exhibit good BBB penetration (A: 73.866, B: 81.388), with Ligand B being slightly better. This is crucial for a CNS target like DRD2.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.628 and -4.898), which is unusual and suggests poor permeability. This is a significant concern for both.

**Aqueous Solubility:** Both ligands have poor aqueous solubility (-5.348 and -3.148). This is a concern, particularly for Ligand A given its higher logP.

**hERG Inhibition:** Both ligands have low hERG inhibition liability (A: 0.824, B: 0.805), which is positive.

**Microsomal Clearance:** Ligand A (42.715 mL/min/kg) has better metabolic stability than Ligand B (52.559 mL/min/kg).

**In vitro Half-Life:** Ligand B (14.838 hours) has a significantly longer half-life than Ligand A (1.476 hours). This is a major advantage for Ligand B.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (A: 0.639, B: 0.262), with Ligand B being better.

**Binding Affinity:** Ligand A (-9.7 kcal/mol) has a significantly stronger binding affinity than Ligand B (-7.7 kcal/mol). This is a substantial advantage for Ligand A, potentially outweighing some of its ADME drawbacks.

**Overall Assessment:**

While Ligand A has a superior binding affinity, its high logP, poor solubility, and very short half-life are major concerns. Ligand B, despite a weaker affinity, has a more balanced profile with better solubility, lower DILI risk, better P-gp efflux, and a significantly longer half-life. The slightly better BBB penetration of Ligand B is also beneficial. Given the GPCR-specific priorities, and the substantial difference in half-life, Ligand B is the more promising candidate. The affinity difference, while significant, might be overcome with further optimization of Ligand B.

Output:
1
2025-04-17 06:32:30,586 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (346.431 and 345.403 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (82.18) is significantly better than Ligand B (110.01). For CNS targets, we want TPSA <= 90, so Ligand A is preferable.

**3. logP:** Ligand A (3.483) is within the optimal range (1-3), while Ligand B (1.581) is on the lower end, potentially hindering permeation.

**4. H-Bond Donors:** Ligand A (1) and Ligand B (2) are both acceptable, being <=5.

**5. H-Bond Acceptors:** Ligand A (7) and Ligand B (6) are both acceptable, being <=10.

**6. QED:** Both ligands have similar, good QED values (0.806 and 0.822).

**7. DILI:** Ligand A (54.634) has a lower DILI risk than Ligand B (65.995), making it more favorable. Both are below the concerning threshold of 60.

**8. BBB:** Ligand A (81.97) has a much higher BBB penetration percentile than Ligand B (49.67). This is *critical* for a CNS target like DRD2.

**9. Caco-2 Permeability:** Ligand A (-4.654) and Ligand B (-5.18) both have negative values, indicating poor permeability. However, the scale isn't defined, so it's hard to interpret the absolute difference.

**10. Aqueous Solubility:** Ligand A (-4.964) and Ligand B (-2.335) both have negative values, indicating poor solubility. Again, the scale is undefined.

**11. hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.177 and 0.169).

**12. Microsomal Clearance:** Ligand A (97.828) has higher microsomal clearance than Ligand B (42.55), suggesting lower metabolic stability. This is a negative for Ligand A.

**13. In vitro Half-Life:** Ligand B (-11.821) has a longer in vitro half-life than Ligand A (12.842), which is desirable.

**14. P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.286 and 0.023).

**15. Binding Affinity:** Both ligands have identical and excellent binding affinities (-8.3 kcal/mol).

**Overall Assessment:**

Ligand A is significantly better due to its superior TPSA and BBB penetration, both crucial for CNS GPCR targets. While Ligand A has higher clearance and shorter half-life, the strong affinity and favorable CNS penetration outweigh these drawbacks. Ligand B's lower logP and significantly lower BBB penetration are major concerns.

Output:
1
2025-04-17 06:32:30,586 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (371.478 Da) is slightly better, being closer to the lower end which can aid permeability.

**TPSA:** Ligand A (78.51) is significantly better than Ligand B (54.46). For CNS targets, we want TPSA <= 90, and A is comfortably within this range while B is approaching the upper limit.

**logP:** Both ligands have logP values within the optimal range (1-3), with Ligand A (2.308) being slightly more favorable than Ligand B (4.686). B is approaching the upper limit where solubility issues can arise.

**H-Bond Donors/Acceptors:** Ligand A (HBD=2, HBA=3) and Ligand B (HBD=1, HBA=4) both have reasonable numbers of H-bond donors and acceptors, falling within the guidelines.

**QED:** Both ligands have similar QED values (A: 0.805, B: 0.681), indicating good drug-likeness.

**DILI:** Ligand B (68.592) has a higher DILI risk than Ligand A (55.68), although both are acceptable.

**BBB:** Both ligands show good BBB penetration (A: 70.066, B: 71.462), exceeding the desirable threshold of >70. This is crucial for a CNS target like DRD2.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values, which is unusual and suggests potential issues with intestinal absorption. However, these values are on a different scale and hard to interpret directly.

**Aqueous Solubility:** Both ligands have negative solubility values, which is also unusual.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (A: 0.621, B: 0.463).

**Microsomal Clearance:** Both ligands have similar microsomal clearance values (A: 38.238, B: 39.831), suggesting comparable metabolic stability.

**In vitro Half-Life:** Ligand A (-16.734) has a negative half-life, which is not physically possible. Ligand B (21.785) has a more reasonable half-life.

**P-gp Efflux:** Ligand A (0.09) has significantly lower P-gp efflux liability than Ligand B (0.541). Lower P-gp efflux is highly desirable for CNS penetration.

**Binding Affinity:** Both ligands have very similar and strong binding affinities (A: -8.6 kcal/mol, B: -8.4 kcal/mol). The difference is less than 1.5 kcal/mol, so this is not a major differentiating factor.

**Overall Assessment:**

Ligand A is superior due to its lower TPSA, lower logP, lower DILI risk, and significantly lower P-gp efflux. While the negative half-life is a concern, the other favorable properties outweigh this issue. Ligand B has a more reasonable half-life, but its higher logP and P-gp efflux are less desirable for CNS penetration. The similar binding affinities make the ADME properties the deciding factors.

Output:
0
2025-04-17 06:32:30,587 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (348.403 and 335.367 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (123.41) is slightly above the optimal <90 for CNS targets, but still reasonable. Ligand B (88.39) is excellent, well below 90.

**3. logP:** Ligand A (0.117) is quite low, potentially hindering membrane permeability. Ligand B (2.805) is near optimal (1-3).

**4. H-Bond Donors:** Ligand A (3) is acceptable. Ligand B (2) is also good.

**5. H-Bond Acceptors:** Both ligands (A: 5, B: 5) are within the acceptable limit of 10.

**6. QED:** Both ligands have good QED scores (A: 0.585, B: 0.718), indicating drug-like properties.

**7. DILI:** Ligand A (39.201) has a low DILI risk, which is favorable. Ligand B (95.929) has a significantly higher DILI risk, which is a concern.

**8. BBB:** Ligand A (64.754) has a moderate BBB penetration, while Ligand B (51.066) is lower. While both are below the ideal >70, A is better.

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.456 and -5.273), which is unusual and suggests poor permeability. This is a significant drawback for both.

**10. Aqueous Solubility:** Both have negative solubility values (-2.451 and -4.465), indicating poor solubility.

**11. hERG Inhibition:** Ligand A (0.039) has very low hERG inhibition risk, excellent. Ligand B (0.459) has a slightly higher, but still relatively low, risk.

**12. Microsomal Clearance:** Ligand A (-3.037) has negative clearance, which is not physically possible and likely indicates an issue with the prediction. Ligand B (68.029) has high clearance, suggesting rapid metabolism.

**13. In vitro Half-Life:** Ligand A (5.113) has a short half-life. Ligand B (53.945) has a much longer half-life, which is preferable.

**14. P-gp Efflux:** Ligand A (0.01) has very low P-gp efflux, which is excellent for CNS penetration. Ligand B (0.259) has slightly higher efflux.

**15. Binding Affinity:** Ligand B (-9.4 kcal/mol) has a significantly stronger binding affinity than Ligand A (-7.8 kcal/mol). This is a substantial advantage, potentially outweighing some ADME concerns.

**Overall Assessment:**

Ligand B has a much stronger binding affinity, a longer half-life, and a more optimal logP. However, it suffers from a high DILI risk and high metabolic clearance. Ligand A has a better safety profile (DILI, hERG, Pgp) and a slightly better BBB prediction, but its low logP and weaker affinity are significant drawbacks. The negative Caco-2 and solubility values for both are concerning.

Given the GPCR-specific priorities, and the substantial affinity difference, I would lean towards **Ligand B** despite its drawbacks. The stronger binding is likely to be more impactful for efficacy, and the DILI risk could potentially be mitigated through structural modifications. The high clearance is a concern, but could also be addressed through medicinal chemistry. The poor permeability and solubility are shared issues that would require attention for both compounds.

Output:
1
2025-04-17 06:32:30,587 - INFO - Batch 290 complete. Total preferences: 4640
2025-04-17 06:32:30,587 - INFO - Processing batch 291/512...
2025-04-17 06:33:11,827 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B based on the provided guidelines, prioritizing GPCR-specific properties (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (340.423 and 364.511 Da) are within the ideal range of 200-500 Da.

**TPSA:** Ligand A (50.8) is significantly better than Ligand B (57.69). For CNS targets, we want TPSA <= 90, both are well within this range, but A is closer to the optimal value.

**logP:** Ligand A (3.641) is optimal (1-3), while Ligand B (1.25) is on the lower side. Lower logP can hinder permeation, which is a concern for CNS penetration.

**H-Bond Donors/Acceptors:** Ligand A has 1 HBD and 4 HBA, while Ligand B has 0 HBD and 3 HBA. Both are within acceptable limits.

**QED:** Ligand A (0.923) is excellent, indicating high drug-likeness. Ligand B (0.757) is still reasonable, but lower.

**DILI:** Ligand B (35.634) has a much lower DILI risk than Ligand A (56.146), making it safer from a liver toxicity perspective.

**BBB:** Ligand A (76.464) has a better BBB percentile than Ligand B (57.736). This is a critical factor for CNS targets like DRD2.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.414 and -4.648), which is unusual and suggests poor permeability. This is a significant drawback for both.

**Aqueous Solubility:** Both ligands have negative solubility values (-4.449 and -2.541), indicating very poor aqueous solubility. This is a major concern for formulation and bioavailability.

**hERG Inhibition:** Ligand A (0.925) has a slightly higher hERG inhibition risk than Ligand B (0.217). Lower is better here.

**Microsomal Clearance:** Ligand A (71.705) has higher microsomal clearance than Ligand B (49.571), suggesting faster metabolism and potentially lower exposure.

**In vitro Half-Life:** Ligand B (-2.587) has a negative half-life, which is not physically meaningful. Ligand A (33.399) has a reasonable half-life.

**P-gp Efflux:** Ligand A (0.387) has lower P-gp efflux liability than Ligand B (0.193), which is favorable for CNS penetration.

**Binding Affinity:** Ligand B (-7.6 kcal/mol) has a slightly better binding affinity than Ligand A (-8.2 kcal/mol). While both are excellent, the difference is relatively small.

**Overall Assessment:**

Ligand A excels in BBB penetration, P-gp efflux, and has a reasonable half-life and good QED. However, it has a higher DILI risk, higher microsomal clearance, and a slightly higher hERG risk. Ligand B has a much lower DILI risk and better hERG profile, and a slightly better binding affinity. Both have poor solubility and permeability.

Considering the GPCR-specific priorities, BBB is paramount for CNS targets. Ligand A's significantly higher BBB percentile (76.464 vs 57.736) is a major advantage. The slightly better affinity of Ligand B is not enough to overcome this difference, particularly given the similar permeability and solubility issues. The lower DILI risk of B is also a positive, but the BBB is the deciding factor.

Output:
0
2025-04-17 06:33:11,827 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (353.423 and 367.555 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (118.37) is better than Ligand B (38.77) as it is closer to the ideal <90 for CNS targets. Ligand B is quite low, which might indicate poor interactions with the receptor.

**logP:** Ligand A (-0.496) is suboptimal, being slightly below the preferred 1-3 range. Ligand B (4.755) is too high, potentially leading to solubility issues and off-target effects.

**H-Bond Donors/Acceptors:** Ligand A (3 HBD, 7 HBA) is more balanced and within the acceptable ranges. Ligand B (0 HBD, 4 HBA) is also acceptable, but may have reduced aqueous solubility.

**QED:** Both ligands have good QED scores (0.515 and 0.599), indicating good drug-like properties.

**DILI:** Ligand A (48.468) has a slightly higher DILI risk than Ligand B (22.024), but both are below the concerning threshold of 60.

**BBB:** Ligand B (89.957) has a significantly better BBB penetration score than Ligand A (58.085). This is a crucial advantage for a CNS target like DRD2.

**Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual. Assuming these are percentile scores, Ligand B (-4.924) is slightly worse than Ligand A (-5.319).

**Aqueous Solubility:** Ligand B (-4) has very poor aqueous solubility, which is a major concern. Ligand A (-1.033) is also poor, but better than B.

**hERG Inhibition:** Ligand A (0.048) has a very low hERG risk, which is excellent. Ligand B (0.821) has a moderate risk, which is less desirable.

**Microsomal Clearance:** Ligand B (104.662) has a much higher microsomal clearance than Ligand A (18.911), indicating faster metabolism and potentially lower *in vivo* exposure.

**In vitro Half-Life:** Ligand B (35.305) has a longer half-life than Ligand A (3.385), which is generally preferred.

**P-gp Efflux:** Ligand A (0.01) shows very low P-gp efflux, which is favorable for CNS penetration. Ligand B (0.888) has moderate P-gp efflux, which could limit brain exposure.

**Binding Affinity:** Ligand A (-7.5 kcal/mol) has a slightly better binding affinity than Ligand B (-7.1 kcal/mol). While the difference is not huge, it's enough to potentially outweigh some of the ADME drawbacks.

**Overall Assessment:**

Ligand B excels in BBB penetration and has a longer half-life. However, it suffers from very poor aqueous solubility, high logP, and higher P-gp efflux. Ligand A has a better TPSA, lower hERG risk, lower P-gp efflux, and better metabolic stability (lower Cl_mic). While its logP and solubility are suboptimal, its slightly better binding affinity and more favorable ADME profile, particularly the low P-gp efflux and hERG risk, make it the more promising candidate. The BBB score for Ligand A is still reasonable.

Output:
0
2025-04-17 06:33:11,828 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (346.4 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (67.23) is significantly better than Ligand B (98.32). For CNS targets, TPSA should be <=90, so Ligand A is preferable.

**logP:** Ligand A (1.77) is optimal, while Ligand B (0.61) is a bit low, potentially hindering permeation.

**H-Bond Donors/Acceptors:** Ligand A (1 HBD, 4 HBA) and Ligand B (3 HBD, 4 HBA) both fall within acceptable ranges.

**QED:** Both ligands have reasonable QED scores (A: 0.792, B: 0.674), indicating good drug-like properties.

**DILI:** Ligand A (43.234) has a slightly higher DILI risk than Ligand B (15.122), but both are below the concerning threshold of 60.

**BBB:** Ligand A (74.758) has a much better BBB percentile than Ligand B (29.701). This is *critical* for a CNS target like DRD2.

**Caco-2 Permeability:** Ligand A (-4.826) is worse than Ligand B (-5.467), but both are negative, indicating poor permeability.

**Aqueous Solubility:** Ligand A (-2.023) is slightly better than Ligand B (-1.592), but both are poor.

**hERG:** Both ligands have very low hERG risk (A: 0.561, B: 0.144).

**Microsomal Clearance:** Ligand B (-9.633) has a significantly *lower* (better) microsomal clearance than Ligand A (38.549), suggesting greater metabolic stability.

**In vitro Half-Life:** Ligand B (-21.02) has a longer half-life than Ligand A (22.434), which is favorable.

**P-gp Efflux:** Ligand A (0.1) has a lower P-gp efflux liability than Ligand B (0.013), which is better for CNS exposure.

**Binding Affinity:** Both ligands have excellent binding affinities (A: -8.6 kcal/mol, B: -8.3 kcal/mol). The difference of 0.3 kcal/mol is not substantial enough to outweigh other factors.

**Overall:**

Ligand A excels in TPSA and BBB penetration, both crucial for CNS GPCR targets. While its Caco-2 permeability and microsomal clearance are less favorable, the strong BBB score and acceptable TPSA make it a better candidate. Ligand B has better metabolic stability and half-life, but its poor BBB penetration is a major drawback for a CNS-targeting drug. The slightly better affinity of Ligand A is a minor advantage.

Output:
0
2025-04-17 06:33:11,828 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (351.475 and 346.427 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (64.92) is excellent, well below the 90 A^2 threshold for CNS targets. Ligand B (73.99) is still reasonable but less optimal.

**logP:** Ligand A (4.81) is slightly high, potentially leading to solubility issues or off-target interactions. Ligand B (2.046) is within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A (2 HBD, 3 HBA) and Ligand B (1 HBD, 4 HBA) both have acceptable numbers of H-bond donors and acceptors.

**QED:** Both ligands have good QED scores (0.734 and 0.847), indicating good drug-like properties.

**DILI:** Ligand A (58.976) has a moderate DILI risk, while Ligand B (29.779) has a very low risk, which is a significant advantage.

**BBB:** Ligand A (82.513) has a good BBB penetration percentile, exceeding the desirable >70% for CNS targets. Ligand B (66.188) is lower, which is a concern for CNS penetration.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.777 and -4.701), which is unusual and suggests poor permeability. This is a significant drawback for both.

**Aqueous Solubility:** Both ligands have very poor aqueous solubility (-6.1 and -1.648). This is a major concern for bioavailability.

**hERG Inhibition:** Ligand A (0.747) has a slightly higher hERG risk than Ligand B (0.136), which is preferable.

**Microsomal Clearance:** Ligand A (100.622) has higher microsomal clearance, indicating faster metabolism. Ligand B (15.139) has much lower clearance and better metabolic stability.

**In vitro Half-Life:** Both ligands have similar in vitro half-lives (27.787 and 26.415 hours).

**P-gp Efflux:** Ligand A (0.405) has lower P-gp efflux, which is beneficial for CNS exposure. Ligand B (0.168) has even lower efflux, a further advantage.

**Binding Affinity:** Ligand A (-7.7 kcal/mol) has a slightly better binding affinity than Ligand B (-7.2 kcal/mol). This 0.5 kcal/mol difference is noteworthy.

**Overall Assessment:**

Ligand A has a better binding affinity and BBB penetration, but suffers from higher logP, higher DILI risk, and faster metabolism. Ligand B has better ADME properties (lower logP, lower DILI, lower clearance, lower P-gp efflux), but slightly weaker binding affinity and lower BBB.

Given the GPCR-specific priorities, BBB penetration is crucial. While Ligand A has better BBB, the combination of Ligand B's superior ADME profile (especially the significantly lower DILI and P-gp efflux) and acceptable BBB makes it the more promising candidate. The affinity difference is not large enough to overcome Ligand A's ADME liabilities. The poor Caco-2 and solubility for both are concerning and would need to be addressed in further optimization, but are less critical than the other factors.

Output:
1
2025-04-17 06:33:11,828 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (350.503 and 361.877 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (78.43) is higher than Ligand B (52.57). For a CNS target like DRD2, TPSA should ideally be <=90. Both are within this range, but B is significantly better.

**logP:** Ligand A (2.376) is within the optimal 1-3 range. Ligand B (1.509) is also within range, but closer to the lower bound.

**H-Bond Donors/Acceptors:** Ligand A has 3 HBD and 3 HBA, which is acceptable. Ligand B has 0 HBD and 5 HBA, also acceptable.

**QED:** Both ligands have good QED scores (0.66 and 0.816, respectively), indicating good drug-like properties.

**DILI:** Ligand A (11.632) has a much lower DILI risk than Ligand B (38.387). This is a significant advantage for A.

**BBB:** Ligand B (93.253) has a significantly higher BBB penetration percentile than Ligand A (32.61). This is a *critical* advantage for a CNS target like DRD2.

**Caco-2 Permeability:** Both have negative values (-4.785 and -4.911), which is unusual and suggests poor permeability. This is a concern for both.

**Aqueous Solubility:** Both have negative values (-3.316 and -2.433), indicating poor aqueous solubility. This is a concern for both.

**hERG Inhibition:** Ligand A (0.289) has a lower hERG inhibition liability than Ligand B (0.803), suggesting a lower risk of cardiotoxicity.

**Microsomal Clearance:** Both ligands have similar microsomal clearance values (44.482 and 43.492 mL/min/kg), indicating similar metabolic stability.

**In vitro Half-Life:** Ligand B (-1.076) has a slightly better (less negative) in vitro half-life than Ligand A (-4.076).

**P-gp Efflux:** Ligand A (0.107) has a lower P-gp efflux liability than Ligand B (0.069), which is favorable for CNS penetration.

**Binding Affinity:** Ligand B (-7.3 kcal/mol) has a significantly stronger binding affinity than Ligand A (-9.0 kcal/mol). This is a substantial advantage, potentially outweighing some of the ADME drawbacks.

**Overall Assessment:**

Ligand B excels in BBB penetration and binding affinity, which are paramount for a CNS GPCR target. While it has a higher DILI risk and slightly worse P-gp efflux, the strong affinity and excellent BBB penetration are likely to be more impactful. Ligand A has better DILI and hERG profiles, but its significantly lower BBB penetration is a major drawback. The Caco-2 and solubility issues are concerns for both, but can potentially be addressed through formulation strategies.

Output:
1
2025-04-17 06:33:11,828 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (359.388 and 358.291 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (49.77) is significantly better than Ligand B (70.59). For CNS targets, we want TPSA <= 90, and A is comfortably within this range, while B is approaching the upper limit.

**3. logP:** Both ligands have good logP values (3.437 and 3.075), falling within the optimal 1-3 range.

**4. H-Bond Donors:** Ligand A (1) is better than Ligand B (3). Lower HBD generally improves permeability.

**5. H-Bond Acceptors:** Ligand A (3) is better than Ligand B (4).

**6. QED:** Ligand A (0.899) is significantly better than Ligand B (0.568), indicating a more drug-like profile.

**7. DILI:** Ligand A (29.469) has a much lower DILI risk than Ligand B (68.592). Both are below 60, but A is preferred.

**8. BBB:** Ligand A (79.333) has a better BBB penetration percentile than Ligand B (66.421). Both are reasonably good, but A is better, and >70 is desirable for CNS targets.

**9. Caco-2 Permeability:** Ligand A (-4.279) is better than Ligand B (-4.551). Higher values are better, indicating better intestinal absorption.

**10. Aqueous Solubility:** Ligand A (-3.679) is better than Ligand B (-4.27). Higher values are better.

**11. hERG Inhibition:** Both ligands have similar, low hERG inhibition risk (0.835 and 0.716).

**12. Microsomal Clearance:** Ligand A (28.506) has lower microsomal clearance than Ligand B (31.593), suggesting better metabolic stability.

**13. In vitro Half-Life:** Ligand A (-17.355) has a better (longer) in vitro half-life than Ligand B (-23.504).

**14. P-gp Efflux:** Ligand A (0.515) has lower P-gp efflux liability than Ligand B (0.168). Lower efflux is crucial for CNS exposure.

**15. Binding Affinity:** Ligand B (-9.9) has a slightly better binding affinity than Ligand A (-8.6). This is a 1.3 kcal/mol difference, which is significant but needs to be weighed against the other ADME properties.

**Overall Assessment:**

While Ligand B has a slightly better binding affinity, Ligand A is superior across almost all other critical ADME properties, especially those prioritized for GPCRs targeting the CNS (BBB, TPSA, Pgp). Ligand A has a better QED score, lower DILI risk, better BBB penetration, lower P-gp efflux, better solubility, and better metabolic stability. The 1.3 kcal/mol difference in binding affinity is likely outweighed by the significantly improved ADME profile of Ligand A.

Output:
1
2025-04-17 06:33:11,828 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (346.446 Da) is slightly lower, which can be advantageous for permeability.

**2. TPSA:** Ligand A (40.62) is excellent, well below the 90 A^2 threshold for CNS targets. Ligand B (75.63) is still reasonable but less optimal, potentially hindering BBB penetration.

**3. logP:** Both ligands have good logP values (A: 3.323, B: 2.263), falling within the 1-3 range.

**4. H-Bond Donors:** Both have 0 HBD, which is acceptable.

**5. H-Bond Acceptors:** Ligand A has 2 HBA, and Ligand B has 7. Ligand A is preferable here, as excessive HBA can sometimes reduce permeability.

**6. QED:** Ligand A (0.821) has a significantly better QED score than Ligand B (0.492), indicating a more drug-like profile.

**7. DILI:** Ligand A (31.601) has a much lower DILI risk than Ligand B (64.831), which is a significant advantage.

**8. BBB:** Ligand A (94.378) has a very high BBB penetration percentile, making it highly suitable for a CNS target like DRD2. Ligand B (85.459) is still good, but not as promising.

**9. Caco-2:** Both have negative Caco-2 values, which is unusual and requires further investigation. However, the magnitude of negativity is similar.

**10. Solubility:** Both have negative solubility values. Again, unusual and requires further investigation. The values are similar in magnitude.

**11. hERG:** Both have low hERG inhibition liability, which is good.

**12. Cl_mic:** Ligand A (57.667) has a lower microsomal clearance than Ligand B (113.805), suggesting better metabolic stability.

**13. t1/2:** Ligand A (6.021) has a positive in vitro half-life, while Ligand B (-14.692) has a negative one, which is problematic.

**14. Pgp:** Ligand A (0.254) has lower P-gp efflux liability than Ligand B (0.501), which is favorable for CNS penetration.

**15. Binding Affinity:** Ligand A (-8.0) has a slightly better binding affinity than Ligand B (-6.5). While both are good, the 1.5 kcal/mol difference is significant.

**Overall Assessment:**

Ligand A consistently outperforms Ligand B across most critical parameters, especially those prioritized for GPCRs targeting the CNS. It has a superior BBB score, lower DILI risk, better QED, lower Cl_mic, better Pgp efflux, and slightly better binding affinity. The negative Caco-2 and solubility values are concerning for both, but the overall profile of Ligand A is much more promising.

Output:
1
2025-04-17 06:33:11,829 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (341.415 Da) is slightly lower, which could be beneficial for permeability.

**TPSA:** Both ligands have TPSA values below the 90 A^2 threshold desirable for CNS targets. Ligand B (71.09 A^2) is lower than Ligand A (88.47 A^2), which is favorable for brain penetration.

**logP:** Ligand A (0.311) is significantly below the optimal 1-3 range, potentially hindering membrane permeability. Ligand B (4.071) is slightly above the optimal range, but still acceptable.

**H-Bond Donors/Acceptors:** Both ligands have 2 HBDs and 4-5 HBAs, which are within acceptable limits.

**QED:** Both ligands have QED values above 0.7, indicating good drug-like properties.

**DILI:** Ligand A (37.999) has a much lower DILI risk than Ligand B (77.782), which is a significant advantage.

**BBB:** Both ligands have similar BBB penetration percentiles (Ligand A: 54.13, Ligand B: 52.656), and are below the desirable >70% for CNS targets, but not dramatically so.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values, which is unusual and suggests poor permeability.

**Aqueous Solubility:** Both ligands have very poor aqueous solubility (-2.278 and -5.149). This is a major concern for bioavailability.

**hERG Inhibition:** Both ligands show low hERG inhibition liability, which is good.

**Microsomal Clearance:** Ligand A (-47.418) has a much lower (better) microsomal clearance than Ligand B (74.676), indicating greater metabolic stability.

**In vitro Half-Life:** Ligand B (46.382 hours) has a significantly longer half-life than Ligand A (13.349 hours), which is desirable.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability, which is good for CNS penetration.

**Binding Affinity:** Both ligands have similar strong binding affinities (-9.1 and -8.9 kcal/mol), which are excellent. The difference is less than 1.5 kcal/mol, so it's not a deciding factor.

**Overall Assessment:**

Ligand A has a better safety profile (lower DILI) and metabolic stability (lower Cl_mic), but suffers from very low logP and poor solubility. Ligand B has better solubility and a longer half-life, but has a higher DILI risk and faster metabolism. Given the CNS target and the importance of BBB penetration, the lower TPSA of Ligand B is slightly advantageous. However, the significantly lower DILI risk and better metabolic stability of Ligand A are more critical factors, especially considering the similar binding affinities. The poor solubility of both is a significant hurdle, but can be addressed with formulation strategies. The low logP of A is more concerning for permeability.

Output:
1
2025-04-17 06:33:11,829 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (342.37 and 349.475 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (49.85) is excellent, well below the 90 A^2 threshold for CNS targets. Ligand B (69.72) is still reasonable but less optimal.

**logP:** Ligand A (2.922) is within the optimal 1-3 range. Ligand B (1.256) is a bit low, potentially hindering permeability.

**H-Bond Donors/Acceptors:** Both have acceptable HBD (0/1) and HBA (3/3) counts, well within the guidelines.

**QED:** Both ligands have good QED scores (0.858 and 0.777), indicating good drug-like properties.

**DILI:** Ligand A (77.123) has a higher DILI risk than Ligand B (12.718), which is a significant concern.

**BBB:** Ligand A (89.492) has excellent BBB penetration, exceeding the desirable >70% threshold. Ligand B (58.511) is considerably lower, which is a major drawback for a CNS target.

**Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and suggests potential issues with the experimental setup or prediction method. However, the values are similar.

**Aqueous Solubility:** Both ligands have negative solubility values, which is also unusual. Again, the values are similar.

**hERG:** Both ligands have low hERG inhibition risk (0.708 and 0.328).

**Microsomal Clearance:** Ligand A (33.385) has higher microsomal clearance than Ligand B (14.242), suggesting lower metabolic stability.

**In vitro Half-Life:** Ligand A (-23.973) has a very negative half-life, which is concerning. Ligand B (-6.951) is also negative, but less so.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.369 and 0.038), which is favorable for CNS penetration.

**Binding Affinity:** Both ligands have similar and excellent binding affinities (-8.8 and -8.3 kcal/mol). The difference is less than 1.5 kcal/mol, so it's not a deciding factor.

**Overall Assessment:**

Ligand A excels in TPSA and BBB penetration, crucial for a CNS-targeting GPCR. However, its higher DILI risk and poor predicted metabolic stability (higher Cl_mic, negative t1/2) are significant liabilities. Ligand B has a lower DILI risk and better metabolic stability, but its lower logP and significantly worse BBB penetration are major drawbacks.

Given the importance of BBB penetration for a CNS target like DRD2, and the relatively small difference in binding affinity, Ligand A is the more promising candidate *despite* its DILI and metabolic concerns. These issues could potentially be addressed through further structural modifications, whereas improving BBB penetration is often more challenging.

Output:
1
2025-04-17 06:33:11,829 - INFO - Reasoning:

Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (380.861 Da) is slightly higher than Ligand B (349.475 Da), but both are acceptable.

**2. TPSA:** Both ligands have TPSA values below 140, suggesting good oral absorption potential. Ligand A (114.07) is slightly higher than Ligand B (101.29), but both are below the 90 threshold desirable for CNS targets.

**3. logP:** Ligand A (0.682) is a bit low, potentially hindering permeation. Ligand B (1.644) is better, falling within the optimal 1-3 range.

**4. H-Bond Donors:** Both ligands have acceptable HBD counts (Ligand A: 4, Ligand B: 3), well below the limit of 5.

**5. H-Bond Acceptors:** Both ligands have acceptable HBA counts (Ligand A: 5, Ligand B: 3), well below the limit of 10.

**6. QED:** Both ligands have reasonable QED values (Ligand A: 0.448, Ligand B: 0.581). Ligand B is better, exceeding the 0.5 threshold.

**7. DILI:** Ligand A (85.459) has a significantly higher DILI risk than Ligand B (18.728). This is a major concern for Ligand A.

**8. BBB:** Ligand B (65.839) has a much better BBB penetration percentile than Ligand A (54.556). For a CNS target like DRD2, a BBB percentile >70 is highly desirable, but Ligand B is a better starting point.

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.28 and -5.265), which is unusual and suggests poor permeability. This is a significant drawback for both.

**10. Aqueous Solubility:** Both ligands have negative solubility values (-3.391 and -2.42). This is also a concern, indicating poor solubility.

**11. hERG Inhibition:** Both ligands show very low hERG inhibition risk (Ligand A: 0.093, Ligand B: 0.117).

**12. Microsomal Clearance:** Both ligands have similar microsomal clearance values (Ligand A: 32.865, Ligand B: 31.207). These values are not ideal, suggesting moderate metabolic liability.

**13. In vitro Half-Life:** Ligand B (-7.868) has a longer in vitro half-life than Ligand A (-0.414).

**14. P-gp Efflux:** Both ligands have low P-gp efflux liability (Ligand A: 0.085, Ligand B: 0.023). Ligand B is slightly better.

**15. Binding Affinity:** Ligand B (-9.1 kcal/mol) has a significantly stronger binding affinity than Ligand A (-7.9 kcal/mol). This is a substantial advantage, exceeding the 1.5 kcal/mol threshold.

**Overall Assessment:**

Ligand B is the superior candidate. While both have issues with Caco-2 permeability and solubility, Ligand B demonstrates significantly better BBB penetration, lower DILI risk, stronger binding affinity, and a longer in vitro half-life. The better logP and QED values also contribute to its improved profile. The affinity difference is large enough to potentially overcome the permeability/solubility concerns with further optimization.

Output:
1
2025-04-17 06:33:11,829 - INFO - Reasoning:

Let's analyze Ligand A and Ligand B against the provided guidelines, prioritizing GPCR-specific properties (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (370.837 and 370.519 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (113.44) is slightly above the optimal <90 for CNS targets, but still reasonable. Ligand B (84.3) is excellent, well within the desired range.

**logP:** Ligand A (0.54) is quite low, potentially hindering permeability. Ligand B (1.682) is better, falling within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A has 3 HBD and 6 HBA, acceptable. Ligand B has 1 HBD and 6 HBA, also acceptable.

**QED:** Both ligands have good QED scores (0.645 and 0.824), indicating drug-like properties.

**DILI:** Ligand A (57.503) has a moderate DILI risk. Ligand B (35.479) has a lower, more favorable DILI risk.

**BBB:** This is critical for a DRD2 ligand. Ligand A (42.807) has a poor BBB percentile. Ligand B (75.107) is very good, exceeding the desirable >70 threshold.

**Caco-2 Permeability:** Both have negative Caco-2 values which is unusual, but we'll assume this means low permeability.

**Aqueous Solubility:** Both ligands have very low solubility (-2.061 and -2.045). This could pose formulation challenges.

**hERG:** Both ligands have very low hERG inhibition risk (0.086 and 0.395).

**Microsomal Clearance:** Ligand A (13.529) has moderate clearance. Ligand B (1.163) has very low clearance, suggesting better metabolic stability.

**In vitro Half-Life:** Ligand B (22.937) has a significantly longer half-life than Ligand A (3.616).

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.008 and 0.088), which is good for CNS penetration.

**Binding Affinity:** Ligand B (-8.6 kcal/mol) has a substantially stronger binding affinity than Ligand A (-6.9 kcal/mol). This is a >1.5 kcal/mol difference, which can outweigh some ADME drawbacks.

**Overall Assessment:**

Ligand B is the superior candidate. While both have solubility concerns, Ligand B excels in the critical areas for a CNS-targeting GPCR ligand: significantly better BBB penetration, much stronger binding affinity, and improved metabolic stability (lower Cl_mic, longer t1/2). The slightly better logP and lower DILI risk further support choosing Ligand B. The TPSA is also more favorable.



Output:
1
2025-04-17 06:33:11,830 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (364.515 and 354.491 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (79.18) is slightly higher than Ligand B (67.87). Both are below the 90 A^2 threshold desirable for CNS targets, but Ligand B is preferable.

**3. logP:** Ligand A (1.708) and Ligand B (2.69) are both within the optimal 1-3 range. Ligand B is slightly better.

**4. H-Bond Donors:** Ligand A (3) is higher than Ligand B (1). Ligand B is preferable.

**5. H-Bond Acceptors:** Ligand A (5) is higher than Ligand B (4). Ligand B is preferable.

**6. QED:** Ligand A (0.743) has a better QED score than Ligand B (0.413), suggesting better overall drug-likeness.

**7. DILI:** Ligand A (33.385) has a slightly higher DILI risk than Ligand B (26.406), but both are below the 40 threshold and are considered good.

**8. BBB:** Ligand B (80.07) has a significantly better BBB penetration percentile than Ligand A (61.962). This is a *critical* advantage for a CNS target like DRD2.

**9. Caco-2 Permeability:** Ligand A (-5.296) has worse Caco-2 permeability than Ligand B (-4.914).

**10. Aqueous Solubility:** Both ligands have very poor aqueous solubility (-2.514 and -2.742 respectively). This is a concern for both, but not a deciding factor.

**11. hERG Inhibition:** Ligand A (0.144) has a lower hERG inhibition liability than Ligand B (0.587), making it safer from a cardiotoxicity perspective.

**12. Microsomal Clearance:** Ligand A (0.742) has lower microsomal clearance than Ligand B (23.39), indicating better metabolic stability.

**13. In vitro Half-Life:** Ligand A (39.201) has a significantly longer in vitro half-life than Ligand B (-1.868).

**14. P-gp Efflux:** Ligand A (0.043) has a much lower P-gp efflux liability than Ligand B (0.063), which is favorable for CNS penetration.

**15. Binding Affinity:** Ligand A (-8.5 kcal/mol) has a stronger binding affinity than Ligand B (-6.9 kcal/mol). This is a substantial difference (1.6 kcal/mol), and a significant advantage.

**Overall Assessment:**

While Ligand A has better QED, metabolic stability, half-life, and P-gp efflux, the *critical* advantage of Ligand B is its significantly higher BBB penetration (80.07 vs 61.962). Given that DRD2 is a CNS target, BBB penetration is paramount. The stronger binding affinity of Ligand A is also a significant plus, and could potentially overcome the lower BBB score, but the difference in BBB is substantial. The slightly better logP and TPSA of Ligand B also contribute to its favorability.

Output:
1
2025-04-17 06:33:11,830 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (351.435 and 362.495 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (71.01) is slightly above the optimal <90 for CNS targets, but still reasonable. Ligand B (57.69) is excellent, well below 90.

**logP:** Ligand A (2.597) is within the optimal 1-3 range. Ligand B (1.615) is also within range, but closer to the lower bound.

**H-Bond Donors/Acceptors:** Ligand A has 1 HBD and 6 HBA, both acceptable. Ligand B has 0 HBD and 3 HBA, also acceptable.

**QED:** Both ligands have good QED scores (0.782 and 0.818), indicating good drug-like properties.

**DILI:** Ligand A has a DILI risk of 71.229, which is concerning as it's above the 60 threshold. Ligand B has a much lower DILI risk of 39.473, which is favorable.

**BBB:** Ligand A has a BBB penetration of 69.407, which is below the desirable >70 for CNS targets. Ligand B has a significantly better BBB penetration of 82.164, a major advantage.

**Caco-2 Permeability:** Ligand A (-5.204) has poor Caco-2 permeability. Ligand B (-4.43) also has poor Caco-2 permeability.

**Aqueous Solubility:** Ligand A (-2.815) has poor aqueous solubility. Ligand B (-1.782) also has poor aqueous solubility.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.412 and 0.3), which is good.

**Microsomal Clearance:** Ligand A (72.301) has moderate microsomal clearance. Ligand B (53.92) has lower clearance, suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (-8.365) has a very short in vitro half-life, which is a significant drawback. Ligand B (24.138) has a much better half-life.

**P-gp Efflux:** Ligand A (0.112) has low P-gp efflux, which is good for CNS penetration. Ligand B (0.267) also has low P-gp efflux.

**Binding Affinity:** Both ligands have very strong binding affinities (-9.7 and -8.0 kcal/mol). Ligand A is slightly better (-9.7 kcal/mol). However, the 1.7 kcal/mol difference in affinity is likely outweighed by the other ADME properties.

**Overall Assessment:**

Ligand B is the more promising candidate. While Ligand A has slightly better binding affinity, Ligand B excels in crucial ADME properties for a CNS-targeting GPCR ligand: significantly lower DILI risk, much better BBB penetration, and a substantially longer in vitro half-life. The TPSA of Ligand B is also more favorable. Although both have poor Caco-2 permeability and aqueous solubility, these can potentially be addressed through formulation strategies. The DILI and BBB properties of Ligand A are major concerns.

Output:
1
2025-04-17 06:33:11,830 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (345.403 and 352.479 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (101.16) is higher than the preferred <90 for CNS targets, while Ligand B (76.46) is well within the desired range. This is a significant advantage for Ligand B.

**3. logP:** Ligand A (0.154) is quite low, potentially hindering membrane permeability. Ligand B (2.622) is within the optimal 1-3 range. This favors Ligand B.

**4. H-Bond Donors:** Ligand A (3) is acceptable, while Ligand B (1) is even better, potentially improving permeability.

**5. H-Bond Acceptors:** Ligand A (6) and Ligand B (5) are both within the acceptable limit of <=10.

**6. QED:** Both ligands have similar QED values (0.729 and 0.693), indicating good drug-likeness.

**7. DILI:** Ligand A (43.66) has a slightly higher DILI risk than Ligand B (25.436), but both are below the concerning threshold of 60.

**8. BBB:** Ligand B (77.433) has a significantly higher BBB penetration percentile than Ligand A (31.834). This is a crucial advantage for a CNS target like DRD2.

**9. Caco-2 Permeability:** Ligand A (-5.697) has poor Caco-2 permeability, while Ligand B (-4.513) is slightly better, but still not ideal.

**10. Aqueous Solubility:** Both ligands have poor aqueous solubility (-1.579 and -1.908). This could present formulation challenges, but is less critical than permeability for CNS targets.

**11. hERG Inhibition:** Both ligands have low hERG inhibition risk (0.145 and 0.489).

**12. Microsomal Clearance:** Ligand A (-25.255) has a lower (better) microsomal clearance than Ligand B (59.187), suggesting better metabolic stability.

**13. In vitro Half-Life:** Both ligands have similar in vitro half-lives (29.14 and 28.086 hours).

**14. P-gp Efflux:** Ligand A (0.006) has very low P-gp efflux, which is excellent. Ligand B (0.033) is also low, but slightly higher.

**15. Binding Affinity:** Ligand B (-7.2 kcal/mol) has a significantly stronger binding affinity than Ligand A (-9.9 kcal/mol). This is a substantial advantage, potentially outweighing some of the ADME drawbacks.

**Overall Assessment:**

Ligand B is the stronger candidate. While both have solubility issues, Ligand B excels in key areas for a CNS GPCR target: significantly better BBB penetration, a more favorable logP, and a much stronger binding affinity. The slightly higher metabolic clearance of Ligand B is a concern, but the superior affinity and BBB penetration are likely to be more impactful for *in vivo* efficacy. Ligand A's low logP and poor Caco-2 permeability are major drawbacks.

Output:
1
2025-04-17 06:33:11,830 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (349.36 and 365.46 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (57.94) is excellent, well below the 90 A^2 threshold for CNS targets. Ligand B (92.63) is higher, but still potentially acceptable, though less desirable.

**logP:** Ligand A (4.466) is at the higher end of the optimal range (1-3), potentially leading to solubility issues. Ligand B (1.627) is good, falling comfortably within the optimal range.

**H-Bond Donors/Acceptors:** Ligand A (1 HBD, 4 HBA) is favorable. Ligand B (2 HBD, 9 HBA) is also acceptable, but the higher HBA count could slightly impact permeability.

**QED:** Both ligands have reasonable QED values (0.865 and 0.765), indicating good drug-like properties.

**DILI:** Both ligands have relatively high DILI risk (52.97 and 75.18), which is a concern. However, this can be addressed in later optimization stages.

**BBB:** Ligand A (61.54) is moderately good, but not ideal for a CNS target. Ligand B (44.55) is significantly lower, making CNS penetration less likely. This is a major drawback for Ligand B.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.472 and -4.911), which is unusual and suggests poor permeability. This is a significant concern for both.

**Aqueous Solubility:** Both ligands have very poor aqueous solubility (-6.039 and -3.377). This is a significant issue, especially given Ligand A's already high logP.

**hERG Inhibition:** Both ligands show low hERG inhibition risk (0.87 and 0.754), which is positive.

**Microsomal Clearance:** Ligand A (74.83) has higher clearance than Ligand B (59.25), suggesting lower metabolic stability.

**In vitro Half-Life:** Ligand B (6.35) has a very short half-life, which is undesirable. Ligand A (23.59) is better, but still not optimal.

**P-gp Efflux:** Both ligands show low P-gp efflux liability (0.602 and 0.059), which is favorable for CNS penetration.

**Binding Affinity:** Ligand B (-7.4 kcal/mol) has a significantly stronger binding affinity than Ligand A (-9.2 kcal/mol). This is a substantial advantage, potentially outweighing some of its ADME drawbacks.

**Overall Assessment:**

While Ligand B has a superior binding affinity, its significantly lower BBB penetration is a major concern for a CNS target like DRD2. Ligand A has better BBB penetration, but suffers from a higher logP, poor solubility, and higher clearance. The poor Caco-2 permeability for both is concerning. However, the binding affinity difference is substantial. Given the GPCR-specific priorities, and the fact that affinity can sometimes outweigh ADME issues (especially with optimization), Ligand B is the more promising starting point, *provided* efforts can be made to improve its BBB penetration.

Output:
1
2025-04-17 06:33:11,831 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (355.523 and 366.575 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (61.88) is slightly above the optimal <90 for CNS targets, but still reasonable. Ligand B (52.23) is excellent, well below 90.

**logP:** Ligand A (1.743) is within the optimal 1-3 range. Ligand B (3.176) is at the higher end of optimal, but still acceptable.

**H-Bond Donors/Acceptors:** Both ligands have 1 HBD and 4 HBA, which are within the acceptable limits (<=5 and <=10 respectively).

**QED:** Both ligands have similar QED values (0.72 and 0.691), indicating good drug-likeness.

**DILI:** Ligand A (11.09) has a significantly lower DILI risk than Ligand B (15.355), which is a substantial advantage.

**BBB:** Both ligands have comparable BBB penetration (57.425% and 56.921%), which is acceptable but not ideal (>70 is preferred for CNS targets).

**Caco-2 Permeability:** Ligand A (-4.834) has poor Caco-2 permeability, while Ligand B (-5.66) is also poor, but slightly better.

**Aqueous Solubility:** Ligand A (-0.884) has slightly better solubility than Ligand B (-2.308).

**hERG Inhibition:** Ligand A (0.452) shows lower hERG inhibition risk than Ligand B (0.836), which is preferable.

**Microsomal Clearance:** Ligand B (72.755) has significantly higher microsomal clearance than Ligand A (24.383), indicating lower metabolic stability.

**In vitro Half-Life:** Ligand B (12.465) has a longer half-life than Ligand A (8.442), which is a positive attribute.

**P-gp Efflux:** Both ligands show minimal P-gp efflux (0.038 and 0.223), which is good for CNS penetration.

**Binding Affinity:** Ligand B (-6.8 kcal/mol) has a significantly stronger binding affinity than Ligand A (-0.0 kcal/mol). This is a major advantage, potentially outweighing some of the ADME drawbacks.

**Overall Assessment:**

Ligand B has a much stronger binding affinity, which is paramount for a GPCR ligand. While it has some ADME liabilities (higher DILI, higher Cl_mic, lower solubility), the substantial affinity advantage is likely to be decisive. Ligand A has better safety profiles (DILI, hERG) and solubility, but its extremely weak binding affinity makes it unlikely to be effective. The slightly better BBB penetration of both is not enough to compensate for the affinity difference.

Output:
1
2025-04-17 06:33:11,831 - INFO - Batch 291 complete. Total preferences: 4656
2025-04-17 06:33:11,831 - INFO - Processing batch 292/512...
2025-04-17 06:33:53,071 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (349.391 and 348.422 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (132.88) is slightly above the optimal <90 for CNS targets, but still reasonable. Ligand B (66.4) is excellent, well below the 90 threshold.

**logP:** Ligand A (-0.967) is a bit low, potentially hindering permeability. Ligand B (1.927) is within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A (3 HBD, 7 HBA) is good. Ligand B (0 HBD, 4 HBA) is also favorable, with fewer hydrogen bond donors potentially aiding permeability.

**QED:** Both ligands have good QED scores (0.602 and 0.815), indicating drug-like properties.

**DILI:** Ligand A (54.556) has a slightly higher DILI risk than Ligand B (45.25), but both are below the concerning 60 threshold.

**BBB:** Ligand B (90.461) has a significantly better BBB penetration score than Ligand A (56.185). This is a *critical* advantage for a CNS target like DRD2.

**Caco-2 Permeability:** Ligand A (-5.404) and Ligand B (-4.553) both have negative values, which is unusual and suggests low permeability. However, the scale isn't specified, so it's difficult to interpret.

**Aqueous Solubility:** Both ligands have poor aqueous solubility (-1.002 and -1.857). This could pose formulation challenges.

**hERG Inhibition:** Ligand A (0.158) has a slightly lower hERG risk than Ligand B (0.564), which is preferable.

**Microsomal Clearance:** Ligand A (-3.137) has a much lower (better) microsomal clearance than Ligand B (26.669), indicating greater metabolic stability.

**In vitro Half-Life:** Ligand A (-0.329) has a slightly better in vitro half-life than Ligand B (-13.425).

**P-gp Efflux:** Ligand A (0.023) has a much lower P-gp efflux liability than Ligand B (0.177), which is a significant advantage for CNS penetration.

**Binding Affinity:** Ligand A (-7.7) has a slightly better binding affinity than Ligand B (0.0).

**Overall Assessment:**

Ligand B excels in BBB penetration and has a good logP, making it more likely to reach the target in the CNS. However, Ligand A has superior metabolic stability (lower Cl_mic), lower P-gp efflux, and slightly better binding affinity. The difference in binding affinity is not large enough to overcome the significant advantages of Ligand B in terms of CNS penetration. The poor solubility of both compounds is a concern but can be addressed with formulation strategies.

Output:
1
2025-04-17 06:33:53,071 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (346.387 and 358.467 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (95.86) is slightly above the optimal <90 for CNS targets, but still reasonable. Ligand B (71.69) is well within the desired range.

**logP:** Ligand A (-0.606) is a bit low, potentially hindering permeation. Ligand B (1.957) is within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Both ligands have 1 HBD and 6 HBA, which are acceptable values.

**QED:** Ligand A (0.731) has a better QED score than Ligand B (0.503), indicating better overall drug-likeness.

**DILI:** Ligand A (60.721) is at the upper limit of acceptable DILI risk, while Ligand B (70.686) is higher and concerning.

**BBB:** This is a critical parameter for a CNS target. Ligand A (41.295) has a poor BBB penetration score. Ligand B (75.998) is excellent, exceeding the desirable >70 threshold.

**Caco-2 Permeability:** Both ligands have similar, very poor Caco-2 permeability scores (-4.881 and -4.942). This is a significant drawback for both.

**Aqueous Solubility:** Both ligands have poor aqueous solubility (-0.63 and -2.13).

**hERG Inhibition:** Ligand A (0.052) shows very low hERG inhibition risk, which is excellent. Ligand B (0.745) has a higher, though not critically high, hERG risk.

**Microsomal Clearance:** Ligand A (-0.095) indicates very low clearance and thus good metabolic stability. Ligand B (28.908) has a much higher clearance, suggesting faster metabolism.

**In vitro Half-Life:** Ligand A (0.052) has a very short half-life, while Ligand B (4.738) has a more reasonable half-life.

**P-gp Efflux:** Ligand A (0.006) has very low P-gp efflux, which is favorable for CNS penetration. Ligand B (0.248) has slightly higher efflux.

**Binding Affinity:** Ligand A (-7.5) has a slightly better binding affinity than Ligand B (0.0).

**Overall Assessment:**

Ligand B is the stronger candidate despite some drawbacks. The *critical* advantage of Ligand B is its excellent BBB penetration (75.998), which is essential for a CNS-targeting drug. While its DILI risk is higher and metabolic stability lower than Ligand A, these can potentially be addressed through further optimization. Ligand A's extremely poor BBB penetration is a major hurdle that is difficult to overcome. The slightly better affinity of Ligand A is outweighed by the BBB issue. The poor Caco-2 and solubility for both are concerning, but less critical for a CNS drug where direct oral absorption is less important than brain exposure.

Output:
1
2025-04-17 06:33:53,071 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (349.362) is slightly preferred as it's closer to the lower end, potentially aiding permeability.

**TPSA:** Ligand A (93.31) is excellent for CNS penetration, being well below 90. Ligand B (38.13) is also very good.

**logP:** Ligand A (1.792) is optimal. Ligand B (4.417) is a bit high, potentially leading to solubility issues or off-target interactions, though still within an acceptable range.

**H-Bond Donors/Acceptors:** Ligand A (HBD=2, HBA=5) and Ligand B (HBD=0, HBA=4) both have reasonable values, well within the guidelines.

**QED:** Ligand A (0.803) has a significantly better QED score than Ligand B (0.497), indicating a more drug-like profile.

**DILI:** Ligand A (73.09) has a higher DILI risk than Ligand B (51.338), but both are below the concerning threshold of 60.

**BBB:** Ligand A (75.572) has a better BBB percentile than Ligand B (65.374), which is crucial for a CNS target like DRD2.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values which is unusual and likely indicates a problem with the prediction method. We will disregard this metric.

**Aqueous Solubility:** Both ligands have negative solubility values which is also unusual and likely indicates a problem with the prediction method. We will disregard this metric.

**hERG:** Both ligands have low hERG inhibition liability (Ligand A: 0.691, Ligand B: 0.894).

**Microsomal Clearance:** Ligand A (30.801) has lower microsomal clearance than Ligand B (83.557), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (26.044) has a longer half-life than Ligand B (-4.029).

**P-gp Efflux:** Ligand A (0.064) has much lower P-gp efflux liability than Ligand B (0.443), which is very important for CNS penetration.

**Binding Affinity:** Both ligands have very similar and excellent binding affinities (-7.5 kcal/mol and -7.4 kcal/mol, respectively). The difference is negligible.

**Overall Assessment:**

Ligand A is superior due to its better QED score, lower P-gp efflux, lower microsomal clearance, longer half-life, and better BBB penetration. While Ligand B has a slightly lower DILI risk, the other advantages of Ligand A are more critical for a CNS-targeting GPCR ligand. The slight increase in DILI risk for Ligand A is outweighed by the improved ADME properties and CNS penetration.

Output:
1
2025-04-17 06:33:53,071 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (355.385 and 349.475 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Both ligands have TPSA values (61.88 and 63.57) that are acceptable for oral absorption (<140) but slightly higher than optimal for CNS penetration (<90).

**3. logP:** Both ligands have logP values (1.679 and 1.975) within the optimal range of 1-3, suggesting good permeability and reasonable solubility.

**4. H-Bond Donors:** Both ligands have 1 HBD, which is within the acceptable limit of <=5.

**5. H-Bond Acceptors:** Both ligands have 4 HBA, which is within the acceptable limit of <=10.

**6. QED:** Both ligands have high QED scores (0.808 and 0.884), indicating good drug-like properties.

**7. DILI:** Both ligands have low DILI risk (30.593 and 34.238), which is favorable.

**8. BBB:** This is a critical parameter for a CNS target like DRD2. Ligand A has a significantly higher BBB percentile (87.088) compared to Ligand B (65.413). This is a major advantage for Ligand A.

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.634 and -4.538). This is unusual and suggests poor permeability. However, these values are on a log scale and should be interpreted cautiously.

**10. Aqueous Solubility:** Both ligands have very low aqueous solubility (-1.841 and -1.899). This is a concern for bioavailability, but can sometimes be overcome with formulation strategies.

**11. hERG Inhibition:** Both ligands have low hERG inhibition liability (0.634 and 0.371), which is good.

**12. Microsomal Clearance:** Ligand A has a lower (better) microsomal clearance (10.804) than Ligand B (59.942), indicating greater metabolic stability.

**13. In vitro Half-Life:** Ligand A has a negative in vitro half-life (-15.905), which is problematic. Ligand B has a positive half-life (18.137), which is much better.

**14. P-gp Efflux:** Ligand A has a very low P-gp efflux liability (0.05) compared to Ligand B (0.156), which is favorable for CNS exposure.

**15. Binding Affinity:** Ligand A has a significantly stronger binding affinity (-8.5 kcal/mol) than Ligand B (-0.0 kcal/mol). This is a substantial advantage, potentially outweighing some of the ADME drawbacks.

**Overall Assessment:**

Ligand A excels in BBB penetration, binding affinity, P-gp efflux, and metabolic stability. While its solubility and half-life are concerning, its superior affinity and BBB penetration are crucial for a CNS-targeting GPCR. Ligand B has a better half-life, but its significantly weaker binding affinity and lower BBB penetration make it a less promising candidate. The negative Caco-2 values for both are concerning, but the strong affinity of Ligand A makes it more likely to be optimized to overcome this issue.

Output:
1
2025-04-17 06:33:53,072 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 drug candidates, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight (MW):** Both ligands are within the ideal range (200-500 Da). Ligand A (344.5) and Ligand B (338.4) are comparable.

**2. TPSA:** Ligand A (58.2) is significantly better than Ligand B (78.96). For CNS targets, we want TPSA <= 90, and A is comfortably within that, while B is approaching the upper limit.

**3. logP:** Both ligands have good logP values (A: 3.762, B: 2.58), falling within the optimal range of 1-3.

**4. H-Bond Donors (HBD):** Both ligands have 2 HBD, which is acceptable (<=5).

**5. H-Bond Acceptors (HBA):** Ligand A (2) is better than Ligand B (6). Keeping HBA low is generally preferred for better permeability.

**6. QED:** Both ligands have similar QED values (A: 0.754, B: 0.744), indicating good drug-likeness.

**7. DILI:** Ligand A (33.23) has a much lower DILI risk than Ligand B (81.504). This is a significant advantage for A.

**8. BBB:** Ligand A (73.517) has a considerably higher BBB penetration percentile than Ligand B (59.364). This is *critical* for a CNS target like DRD2. A value >70 is desirable, and A is closer to that threshold.

**9. Caco-2 Permeability:** Ligand A (-4.561) shows better Caco-2 permeability than Ligand B (-5.051).

**10. Aqueous Solubility:** Ligand A (-4.6) is slightly better than Ligand B (-3.891).

**11. hERG Inhibition:** Both ligands have similar hERG inhibition liability (A: 0.625, B: 0.882).

**12. Microsomal Clearance (Cl_mic):** Ligand B (54.228) has lower microsomal clearance than Ligand A (88.554), suggesting better metabolic stability.

**13. In vitro Half-Life:** Ligand B (18.244) has a longer in vitro half-life than Ligand A (9.155). This is a positive for B.

**14. P-gp Efflux:** Ligand A (0.582) has lower P-gp efflux than Ligand B (0.066), which is favorable for CNS penetration.

**15. Binding Affinity:** Both ligands have excellent binding affinity (A: -9.5 kcal/mol, B: -9.7 kcal/mol). The difference is minimal.

**Overall Assessment:**

Ligand A is the stronger candidate. While Ligand B has better metabolic stability and half-life, Ligand A excels in crucial areas for a CNS-targeting GPCR: lower TPSA, significantly lower DILI risk, substantially better BBB penetration, and lower P-gp efflux. The binding affinity is comparable between the two. The benefits of improved CNS penetration and reduced toxicity outweigh the slightly less favorable metabolic profile of Ligand A.

Output:
1
2025-04-17 06:33:53,072 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B based on the provided guidelines, prioritizing GPCR-specific properties (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (353.463 and 353.507 Da) fall within the ideal range of 200-500 Da.

**TPSA:** Ligand A (81.16) is slightly higher than Ligand B (61.88). For CNS targets, TPSA should be <= 90, so both are acceptable, but B is better.

**logP:** Ligand A (0.467) is quite low, potentially hindering permeation. Ligand B (1.354) is within the optimal 1-3 range. This is a significant advantage for B.

**H-Bond Donors & Acceptors:** Both have 1 HBD and 4 HBA, which are within acceptable limits.

**QED:** Both ligands have good QED scores (0.611 and 0.751), indicating drug-like properties.

**DILI:** Ligand A (8.918) has a slightly higher DILI risk than Ligand B (4.731), but both are relatively low and acceptable.

**BBB:** Ligand B (72.082) has a substantially better BBB penetration score than Ligand A (44.979). This is *critical* for a CNS target like DRD2.

**Caco-2 Permeability:** Both have negative Caco-2 values (-4.861 and -4.714), which is unusual and suggests poor permeability. This is a concern for both.

**Aqueous Solubility:** Both have negative solubility values (-0.202 and -1.015), indicating poor aqueous solubility. This is a concern for both.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.39 and 0.384).

**Microsomal Clearance:** Ligand A (14.215) has a higher microsomal clearance than Ligand B (1.135), indicating faster metabolism and potentially lower exposure.

**In vitro Half-Life:** Ligand B (6.798) has a much longer in vitro half-life than Ligand A (-0.307). This is a significant advantage for B.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.03 and 0.019).

**Binding Affinity:** Ligand B (-7.7 kcal/mol) has a slightly better binding affinity than Ligand A (-7.0 kcal/mol), although both are good. The 0.7 kcal/mol difference is meaningful.

**Overall Assessment:**

Ligand B is the superior candidate. While both have issues with Caco-2 permeability and aqueous solubility, Ligand B excels in the most critical areas for a CNS-targeting GPCR: BBB penetration, logP, in vitro half-life, and binding affinity. The better logP and BBB scores of Ligand B are particularly important for CNS drug development. The slightly better affinity further strengthens its position.

Output:
1
2025-04-17 06:33:53,072 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (340.47 & 361.40 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (40.62) is better than Ligand B (34.84), both are below the 90 A^2 threshold for CNS targets.

**3. logP:** Both ligands have good logP values (3.21 & 3.99), falling within the optimal 1-3 range. Ligand B is slightly higher, which could be a minor concern for solubility, but not a deal-breaker.

**4. H-Bond Donors:** Both have 0 HBD, which is good.

**5. H-Bond Acceptors:** Ligand A has 2 HBA, Ligand B has 4. Both are acceptable (<=10).

**6. QED:** Both ligands have similar QED values (0.572 and 0.59), indicating good drug-likeness.

**7. DILI:** Ligand A (26.29%) has a significantly lower DILI risk than Ligand B (20.40%). This is a substantial advantage.

**8. BBB:** Ligand B (96.05%) has a much higher predicted BBB penetration than Ligand A (75.57%). This is a *critical* advantage for a CNS target like DRD2.

**9. Caco-2 Permeability:** Both have negative Caco-2 values (-4.72 and -4.63). This is unusual and suggests poor permeability. However, these values are on a strange scale and may not be directly comparable.

**10. Aqueous Solubility:** Both have negative solubility values (-2.895 and -3.209). Similar to Caco-2, these values are concerning and suggest poor solubility.

**11. hERG Inhibition:** Ligand A (0.336) has a lower hERG inhibition liability than Ligand B (0.983), which is favorable.

**12. Microsomal Clearance:** Ligand A (61.75) has a higher microsomal clearance than Ligand B (20.20), indicating lower metabolic stability. This is a disadvantage for Ligand A.

**13. In vitro Half-Life:** Ligand B (66.01) has a much longer in vitro half-life than Ligand A (-15.96), indicating better metabolic stability.

**14. P-gp Efflux:** Ligand A (0.293) has lower P-gp efflux liability than Ligand B (0.549), which is beneficial for CNS penetration.

**15. Binding Affinity:** Ligand B (-7.3 kcal/mol) has a significantly stronger binding affinity than Ligand A (-9.3 kcal/mol). This is a major advantage, potentially outweighing some of the ADME drawbacks.

**Overall Assessment:**

Ligand B is the stronger candidate. While Ligand A has a lower DILI risk and P-gp efflux, Ligand B's *significantly* better BBB penetration and binding affinity are decisive for a CNS GPCR target like DRD2. The longer half-life and lower clearance also contribute to its favorability. The slightly higher logP and hERG risk of Ligand B are less concerning given the substantial benefit of its affinity and BBB penetration. The unusual Caco-2 and solubility values are a concern for both, but the binding affinity and BBB are more critical for CNS targets.

Output:
1
2025-04-17 06:33:53,072 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 drug candidates, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (406.232 Da) is slightly higher than Ligand B (362.455 Da), but both are acceptable.

**TPSA:** Both ligands have TPSA values below the 90 A^2 threshold desirable for CNS targets. Ligand A (88.78 A^2) is closer to the limit, while Ligand B (76.46 A^2) is better.

**logP:** Both ligands have optimal logP values (1-3). Ligand A (3.187) is at the higher end, while Ligand B (1.164) is at the lower end.

**H-Bond Donors/Acceptors:** Both ligands have 1 HBD and 6 HBA, which are within acceptable limits.

**QED:** Both ligands have good QED scores (>0.5), indicating drug-like properties. Ligand B (0.837) is slightly better than Ligand A (0.742).

**DILI:** Ligand A (69.252) has a higher DILI risk than Ligand B (54.944), but both are below the concerning threshold of 60.

**BBB:** This is a crucial parameter for CNS targets. Ligand B (64.715) has a significantly better BBB penetration percentile than Ligand A (35.246). This is a major advantage for Ligand B.

**Caco-2 Permeability:** Ligand A (-4.586) shows poor Caco-2 permeability, while Ligand B (-5.126) is also poor, but slightly better.

**Aqueous Solubility:** Ligand A (-5.294) has very poor aqueous solubility, while Ligand B (-1.627) is also poor, but better than Ligand A.

**hERG Inhibition:** Ligand A (0.705) has a slightly higher hERG inhibition risk than Ligand B (0.399), but both are relatively low.

**Microsomal Clearance:** Ligand B (32.086 mL/min/kg) has a lower microsomal clearance than Ligand A (94.99 mL/min/kg), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand B (-7.152 hours) has a negative half-life, which is concerning. Ligand A (26.659 hours) has a reasonable half-life. However, negative values are often artifacts of the prediction method.

**P-gp Efflux:** Ligand A (0.665) has a lower P-gp efflux liability than Ligand B (0.07), which is favorable for CNS exposure.

**Binding Affinity:** Ligand B (-8.1 kcal/mol) has a significantly stronger binding affinity than Ligand A (-7.6 kcal/mol). This difference of 0.5 kcal/mol is substantial and can outweigh some ADME drawbacks.

**Overall Assessment:**

Ligand B is the more promising candidate. While it has a concerning negative in vitro half-life, its superior BBB penetration, stronger binding affinity, lower DILI risk, and better metabolic stability outweigh the slightly higher P-gp efflux. Ligand A's poor solubility and Caco-2 permeability are significant drawbacks. The affinity difference is also a key factor, as it's a GPCR target.



Output:
1
2025-04-17 06:33:53,073 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (374.459 Da and 359.543 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (102.01) is higher than the preferred <90 for CNS targets, but not drastically so. Ligand B (46.84) is excellent, well below 90.

**logP:** Ligand A (-0.463) is a bit low, potentially hindering permeation. Ligand B (3.308) is within the optimal 1-3 range.

**H-Bond Donors:** Ligand A (1) is good. Ligand B (0) is also good.

**H-Bond Acceptors:** Both ligands (6) are within the acceptable limit of <=10.

**QED:** Both ligands (0.671 and 0.526) are above the 0.5 threshold, indicating good drug-likeness.

**DILI:** Ligand A (41.76) has a slightly higher DILI risk than Ligand B (22.761), but both are below the concerning 60 percentile.

**BBB:** Ligand B (96.937) has a significantly higher BBB penetration score than Ligand A (70.454). This is a crucial advantage for a CNS target like DRD2.

**Caco-2 Permeability:** Ligand A (-4.865) has poor Caco-2 permeability, which is concerning. Ligand B (-5.668) is also poor, but slightly better.

**Aqueous Solubility:** Ligand A (-1.153) and Ligand B (-3.482) both have poor solubility.

**hERG Inhibition:** Ligand A (0.082) has a very low hERG risk, which is excellent. Ligand B (0.743) is slightly higher, but still relatively low.

**Microsomal Clearance:** Ligand A (-0.569) shows better metabolic stability (lower clearance) than Ligand B (62.434).

**In vitro Half-Life:** Ligand B (-8.505) has a longer in vitro half-life than Ligand A (31.195).

**P-gp Efflux:** Both ligands show low P-gp efflux liability (0.017 and 0.679 respectively), which is favorable for CNS penetration.

**Binding Affinity:** Ligand B (-7.7) has a significantly stronger binding affinity than Ligand A (-9). This is a substantial advantage.

**Overall Assessment:**

While Ligand A has a better hERG profile and slightly better metabolic stability, Ligand B excels in the most critical areas for a CNS-targeting GPCR ligand: BBB penetration and binding affinity. The significantly higher BBB score and stronger binding affinity of Ligand B outweigh the minor drawbacks in metabolic stability and solubility. The logP value is also more favorable for Ligand B. The TPSA is also much better for Ligand B.

Output:
1
2025-04-17 06:33:53,073 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (347.459 and 350.375 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (75.44) is excellent, well below the 90 A^2 threshold for CNS targets. Ligand B (115.97) is higher, but still potentially acceptable, though less ideal.

**logP:** Ligand A (2.928) is optimal (1-3). Ligand B (-1.803) is significantly lower, which could hinder membrane permeability and CNS penetration.

**H-Bond Donors/Acceptors:** Ligand A (HBD=1, HBA=4) and Ligand B (HBD=2, HBA=7) both fall within acceptable ranges.

**QED:** Both ligands have reasonable QED scores (A: 0.823, B: 0.662), indicating good drug-like properties.

**DILI:** Ligand A (21.791) has a much lower DILI risk than Ligand B (49.399), which is a significant advantage.

**BBB:** Ligand A (91.392) has excellent BBB penetration, exceeding the desirable >70% threshold. Ligand B (25.863) is very poor for CNS penetration. This is a critical difference given DRD2's role in CNS disorders.

**Caco-2 Permeability:** Ligand A (-4.899) and Ligand B (-5.025) both have negative Caco-2 values, indicating poor permeability. This is a concern, but less critical than BBB for a CNS target.

**Aqueous Solubility:** Ligand A (-2.59) and Ligand B (-0.965) both have negative solubility values. Solubility is a concern for both, but can be addressed with formulation strategies.

**hERG:** Both ligands have very low hERG inhibition risk (A: 0.416, B: 0.104).

**Microsomal Clearance:** Ligand A (54.47) has higher clearance than Ligand B (-11.228), suggesting lower metabolic stability.

**In vitro Half-Life:** Ligand B (21.205) has a longer half-life than Ligand A (-29.12), which is favorable.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (A: 0.159, B: 0.026).

**Binding Affinity:** Both ligands have the same binding affinity (-7.7 kcal/mol), which is excellent.

**Overall Assessment:**

Ligand A is significantly better due to its superior BBB penetration (91.392 vs 25.863) and lower DILI risk (21.791 vs 49.399). While Ligand B has a slightly better half-life and slightly lower P-gp efflux, these are less critical for a CNS-targeted GPCR like DRD2. The poor logP of Ligand B is also a major drawback. The similar binding affinity means the ADME properties will be the deciding factor.

Output:
1
2025-04-17 06:33:53,073 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (346.515 Da) is slightly lower, which could be beneficial for permeability, but both are acceptable.

**TPSA:** Ligand A (49.41) is significantly better than Ligand B (29.54). For a CNS target like DRD2, a TPSA below 90 is preferred, and Ligand A is much closer to that ideal. Ligand B's low TPSA is good, but might come at the cost of solubility.

**logP:** Both ligands have logP values within the optimal range (1-3), but Ligand B (4.912) is pushing the upper limit. This could lead to solubility issues and increased off-target interactions. Ligand A (3.502) is more favorable.

**H-Bond Donors/Acceptors:** Ligand A (HBD=1, HBA=2) and Ligand B (HBD=0, HBA=3) both have reasonable numbers of H-bond donors and acceptors, falling within the guidelines.

**QED:** Both ligands have acceptable QED values (A: 0.717, B: 0.624), indicating good drug-like properties.

**DILI:** Both ligands have low DILI risk (A: 37.611, B: 33.307), which is positive.

**BBB:** Both ligands exhibit good BBB penetration (A: 73.362, B: 71.229), exceeding the 70% threshold for CNS targets. This is a critical factor for DRD2.

**Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and potentially problematic. However, the scale is not specified, so it's difficult to interpret.

**Aqueous Solubility:** Both ligands have very poor aqueous solubility (A: -3.937, B: -5.259). This is a significant concern, potentially hindering bioavailability.

**hERG Inhibition:** Both ligands show low hERG inhibition risk (A: 0.507, B: 0.834), which is good.

**Microsomal Clearance:** Ligand A (63.828) has a lower microsomal clearance than Ligand B (145.814), suggesting better metabolic stability. This is a major advantage.

**In vitro Half-Life:** Ligand A (-9.436) has a much longer in vitro half-life than Ligand B (3.379), which is highly desirable.

**P-gp Efflux:** Both ligands have relatively low P-gp efflux liability (A: 0.446, B: 0.839), which is favorable for CNS penetration.

**Binding Affinity:** Both ligands have very similar and strong binding affinities (A: -7.8 kcal/mol, B: -7.7 kcal/mol). The difference is negligible.

**Overall Assessment:**

While both ligands have good binding affinity and BBB penetration, Ligand A is superior due to its lower logP, significantly better TPSA, lower microsomal clearance, and longer half-life. The poor solubility is a concern for both, but the other ADME properties of Ligand A are more favorable, especially considering the GPCR-specific priorities. Ligand B's higher logP and significantly higher clearance are drawbacks.

Output:
0
2025-04-17 06:33:53,073 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight (MW):** Both ligands (351.372 and 367.852 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (48.13) is significantly better than Ligand B (62.3). For CNS targets, we want TPSA <= 90, and ideally closer to 60. Ligand A is much closer to this ideal.

**3. logP:** Both ligands have good logP values (3.334 and 2.728), falling within the optimal 1-3 range.

**4. H-Bond Donors (HBD):** Both ligands have acceptable HBD counts (2 and 1, respectively), well below the threshold of 5.

**5. H-Bond Acceptors (HBA):** Both ligands have acceptable HBA counts (2 and 3, respectively), well below the threshold of 10.

**6. QED:** Both ligands have good QED scores (0.774 and 0.832), indicating good drug-like properties.

**7. DILI:** Ligand A (53.044) has a slightly higher DILI risk than Ligand B (33.501), but both are below the concerning threshold of 60.

**8. BBB:** Both ligands have excellent BBB penetration (88.29% and 86.041%), which is crucial for a CNS target like DRD2.

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.748 and -5.135). These values are unusual and likely indicate poor permeability. However, given the focus on BBB penetration for a CNS target, this is less critical than it would be for a peripherally acting drug.

**10. Aqueous Solubility:** Both ligands have negative solubility values (-3.487 and -3.297). This is a concern, but can potentially be addressed through formulation strategies. Again, less critical for CNS drugs due to BBB.

**11. hERG Inhibition:** Both ligands show low hERG inhibition liability (0.913 and 0.316), which is favorable.

**12. Microsomal Clearance (Cl_mic):** Ligand A has a significantly lower (better) Cl_mic (-15.836) than Ligand B (8.243). This suggests better metabolic stability for Ligand A.

**13. In vitro Half-Life:** Ligand A has a longer half-life (13.285 hours) than Ligand B (-4.321 hours). This is desirable for less frequent dosing.

**14. P-gp Efflux:** Ligand A (0.252) has lower P-gp efflux liability than Ligand B (0.074), which is beneficial for CNS exposure.

**15. Binding Affinity:** Ligand A (-10.5 kcal/mol) has a significantly stronger binding affinity than Ligand B (-8.4 kcal/mol). This is a substantial advantage, exceeding the 1.5 kcal/mol threshold.

**Overall Assessment:**

Ligand A is the superior candidate. While both ligands have good BBB penetration and acceptable logP values, Ligand A excels in several key areas: significantly better TPSA, much better metabolic stability (lower Cl_mic, longer half-life), lower P-gp efflux, and, most importantly, a substantially stronger binding affinity. The slightly higher DILI risk for Ligand A is less concerning given the strong affinity and other favorable properties. The negative Caco-2 and solubility values are drawbacks for both, but less critical for a CNS-targeting drug.

Output:
1
2025-04-17 06:33:53,073 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (357.401 and 374.35 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (69.72) is slightly higher than Ligand B (58.64). Both are below the 90 A^2 threshold desirable for CNS targets, but Ligand B is preferable.

**3. logP:** Ligand A (0.802) is a bit low, potentially hindering permeability. Ligand B (2.846) is within the optimal 1-3 range. This is a significant advantage for Ligand B.

**4. H-Bond Donors:** Both have 1 HBD, which is acceptable.

**5. H-Bond Acceptors:** Both have 3 HBA, which is acceptable.

**6. QED:** Ligand A (0.812) has a better QED score than Ligand B (0.525), indicating a more drug-like profile overall.

**7. DILI:** Ligand A (44.087) has a slightly higher DILI risk than Ligand B (35.285), but both are below the concerning threshold of 60.

**8. BBB:** Ligand B (90.772) has a significantly better BBB penetration percentile than Ligand A (81.233). This is crucial for a CNS target like DRD2.

**9. Caco-2 Permeability:** Both have negative Caco-2 values (-4.605 and -4.569), which is unusual and suggests poor permeability. However, these values are on a log scale and are difficult to interpret without further context.

**10. Aqueous Solubility:** Both have negative solubility values (-2.449 and -2.778), also unusual and suggesting poor solubility.

**11. hERG Inhibition:** Ligand A (0.346) shows slightly lower hERG inhibition liability than Ligand B (0.756), which is favorable.

**12. Microsomal Clearance:** Ligand A (4.914) has a lower microsomal clearance than Ligand B (23.579), indicating better metabolic stability.

**13. In vitro Half-Life:** Ligand A (-11.189) has a negative half-life, which is impossible. This is likely an error in the data. Ligand B (6.166) has a reasonable half-life.

**14. P-gp Efflux:** Ligand A (0.135) has lower P-gp efflux liability than Ligand B (0.295), which is better for CNS exposure.

**15. Binding Affinity:** Both ligands have very similar binding affinities (-8.9 and -8.6 kcal/mol), which are both excellent. The difference of 0.3 kcal/mol is not substantial enough to be a deciding factor.

**Overall Assessment:**

Ligand B is the more promising candidate. While Ligand A has a better QED and lower P-gp efflux, Ligand B excels in critical areas for a CNS-targeting GPCR: significantly better BBB penetration, a more optimal logP, and a reasonable in vitro half-life. The anomalous negative values for Caco-2 and solubility are concerning for both, but the superior BBB and logP of Ligand B outweigh the slightly better metabolic stability of Ligand A. The negative half-life for Ligand A is a major red flag.

Output:
1
2025-04-17 06:33:53,074 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 drug candidates, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (347.459 and 366.487 Da) fall within the ideal 200-500 Da range.

**TPSA:** Both ligands (78.51 and 79.74) are below the 90 A^2 threshold desirable for CNS targets, which is excellent.

**logP:** Both ligands (1.078 and 1.402) fall within the optimal 1-3 range.

**H-Bond Donors:** Both ligands have 2 HBD, which is within the acceptable limit of <=5.

**H-Bond Acceptors:** Ligand A has 3 HBA, and Ligand B has 8 HBA. While both are under the 10 limit, Ligand A is preferable.

**QED:** Both ligands have good QED scores (0.706 and 0.81), indicating good drug-like properties.

**DILI:** Ligand A (16.053) has a significantly lower DILI risk than Ligand B (60.217). This is a major advantage for Ligand A.

**BBB:** Ligand B (69.678) has a slightly better BBB percentile than Ligand A (63.358), but both are reasonably good, and above the 60% threshold.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.16 and -5.095), which is unusual and suggests poor permeability. This is a concern for both.

**Aqueous Solubility:** Both ligands have negative solubility values (-1.858 and -2.719), indicating very poor aqueous solubility. This is a significant drawback for both.

**hERG Inhibition:** Ligand A (0.104) has a much lower hERG inhibition liability than Ligand B (0.598), indicating a lower risk of cardiotoxicity.

**Microsomal Clearance:** Ligand A (5.584) has a lower microsomal clearance than Ligand B (47.701), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand B (43.011) has a much longer in vitro half-life than Ligand A (-1.555). This is a significant advantage for Ligand B.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.032 and 0.045), which is favorable for CNS penetration.

**Binding Affinity:** Ligand A (-8.8 kcal/mol) has a slightly better binding affinity than Ligand B (-7.8 kcal/mol). The difference is 1 kcal/mol, which is a meaningful advantage.

**Overall Assessment:**

Ligand A is the better candidate. While both have poor solubility and Caco-2 permeability, Ligand A excels in crucial areas: significantly lower DILI risk, lower hERG inhibition, better metabolic stability (lower Cl_mic), and slightly better binding affinity. The slightly lower BBB for Ligand A is less concerning than the higher DILI and hERG risks of Ligand B. The longer half-life of Ligand B is a plus, but the other ADME/Tox properties of Ligand A are more favorable.

Output:
0
2025-04-17 06:33:53,074 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (368.405 and 348.451 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (71.45) is significantly better than Ligand B (83.36). For CNS targets, we want TPSA <= 90, and A is closer to the optimal <= 60 range. B is pushing the upper limit.

**logP:** Ligand A (4.142) is higher than optimal (1-3), potentially leading to solubility issues, but is still within a reasonable range. Ligand B (0.431) is quite low, which could hinder membrane permeability and CNS penetration.

**H-Bond Donors/Acceptors:** Ligand A (2 HBD, 5 HBA) and Ligand B (1 HBD, 6 HBA) both have acceptable numbers of H-bond donors and acceptors.

**QED:** Both ligands have similar QED values (0.83 and 0.737), indicating good drug-likeness.

**DILI:** Ligand A (93.37) has a significantly higher DILI risk than Ligand B (29.779). This is a major concern for A.

**BBB:** Ligand A (50.64) and Ligand B (54.595) both have moderate BBB penetration, but neither are particularly high. However, given the other factors, BBB is less critical here.

**Caco-2:** Ligand A (-4.897) and Ligand B (-5.752) both have very poor Caco-2 permeability.

**Solubility:** Ligand A (-5.052) and Ligand B (-0.803) both have poor solubility.

**hERG:** Both ligands have low hERG inhibition risk (0.112 and 0.13).

**Microsomal Clearance:** Ligand B (-9.483) has a significantly *lower* (better) microsomal clearance than Ligand A (6.079), indicating greater metabolic stability.

**In vitro Half-Life:** Ligand B (4.421) has a shorter half-life than Ligand A (28.108).

**P-gp Efflux:** Ligand A (0.09) has lower P-gp efflux than Ligand B (0.008), which is favorable for CNS penetration.

**Binding Affinity:** Ligand A (-9.6 kcal/mol) has a substantially stronger binding affinity than Ligand B (-7.8 kcal/mol). This is a significant advantage, potentially outweighing some of the ADME drawbacks.

**Overall Assessment:**

Ligand A has a much better binding affinity, lower P-gp efflux, and longer half-life. However, it has a very high DILI risk and a logP that is on the higher side. Ligand B has a better safety profile (lower DILI) and better metabolic stability, but its low logP and weaker binding affinity are significant drawbacks.

Considering the GPCR-specific priorities, the strong binding affinity of Ligand A is a major advantage. While the DILI risk is concerning, it might be mitigated through structural modifications. The poor permeability of both compounds is a concern, but the affinity difference is substantial.

Output:
1
2025-04-17 06:33:53,074 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (341.455 and 346.406 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (45.55) is significantly better than Ligand B (65.54). For CNS targets, we want TPSA <= 90, both are within this range, but A is much closer to the ideal.

**logP:** Both ligands have acceptable logP values (2.741 and 1.74), falling within the 1-3 range. Ligand A is slightly better.

**H-Bond Donors/Acceptors:** Ligand A (0 HBD, 3 HBA) and Ligand B (1 HBD, 4 HBA) both have reasonable numbers of H-bond donors and acceptors, well below the thresholds of 5 and 10 respectively.

**QED:** Both ligands have good QED scores (0.794 and 0.844), indicating good drug-like properties.

**DILI:** Ligand A (43.234) is better than Ligand B (60.915) regarding DILI risk, both are acceptable but A is preferable.

**BBB:** Ligand B (80.031) has a significantly higher BBB percentile than Ligand A (71.229). This is a crucial factor for a CNS target like DRD2.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.796 and -4.578). This is unusual and suggests poor permeability. However, these values are on a scale where negative values are possible, and the absolute magnitude isn't directly comparable without knowing the scale's specifics.

**Aqueous Solubility:** Both ligands have negative solubility values (-2.986 and -2.835). Similar to Caco-2, this is unusual and requires context.

**hERG:** Both ligands have low hERG inhibition liability (0.392 and 0.431), which is good.

**Microsomal Clearance:** Ligand B (34.223) has significantly lower microsomal clearance than Ligand A (71.535), indicating better metabolic stability.

**In vitro Half-Life:** Ligand B (12.196 hours) has a much longer half-life than Ligand A (38.533 hours). This is a significant advantage.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.413 and 0.027), which is excellent.

**Binding Affinity:** Ligand B (-8.3 kcal/mol) has a slightly better binding affinity than Ligand A (-8.0 kcal/mol), although the difference is small.

**Overall Assessment:**

Ligand B excels in BBB penetration and metabolic stability (lower Cl_mic, longer t1/2). Ligand A is better in TPSA and DILI. The difference in binding affinity is minor. Given the importance of BBB penetration for a CNS target like DRD2, and the acceptable metabolic stability of Ligand B, it is the more promising candidate. The slightly better TPSA of A is outweighed by the superior BBB value of B.

Output:
1
2025-04-17 06:33:53,074 - INFO - Batch 292 complete. Total preferences: 4672
2025-04-17 06:33:53,075 - INFO - Processing batch 293/512...
2025-04-17 06:34:32,307 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (368.861 and 356.256 Da) fall within the ideal range of 200-500 Da.

**TPSA:** Ligand A (68.73) is significantly better than Ligand B (98.61).  For CNS targets, we want TPSA <= 90, and A is comfortably within this range, while B is approaching the upper limit and less desirable.

**logP:** Both ligands have acceptable logP values (3.331 and 2.473), falling within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A (0 HBD, 5 HBA) is slightly better than Ligand B (1 HBD, 6 HBA) in terms of balancing solubility and permeability. Both are within acceptable limits.

**QED:** Both ligands have good QED scores (0.762 and 0.794), indicating good drug-like properties.

**DILI:** Ligand A (46.297) has a much lower DILI risk than Ligand B (95.347). This is a significant advantage for A.

**BBB:** Ligand A (73.672) has a better BBB penetration percentile than Ligand B (64.211). While both are reasonable, A is closer to the desirable >70 threshold for CNS targets.

**Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and suggests a potential issue with the data or modeling. However, the values are similar (-4.438 and -4.591).

**Aqueous Solubility:** Both ligands have similar, poor aqueous solubility (-3.553 and -3.498). This could be a formulation challenge.

**hERG Inhibition:** Ligand A (0.418) has a lower hERG inhibition liability than Ligand B (0.087), which is a positive attribute.

**Microsomal Clearance:** Ligand A (66.133) has a higher microsomal clearance than Ligand B (47.919), indicating potentially lower metabolic stability. This is a drawback for A.

**In vitro Half-Life:** Ligand B (-17.659) has a significantly *longer* in vitro half-life than Ligand A (6.431). This is a major advantage for B.

**P-gp Efflux:** Ligand A (0.149) has lower P-gp efflux liability than Ligand B (0.129), which is favorable for CNS penetration.

**Binding Affinity:** Ligand B (-8.2 kcal/mol) has a slightly stronger binding affinity than Ligand A (-7.9 kcal/mol). While the difference is small, it is still a factor.

**Overall Assessment:**

Considering the GPCR-specific priorities, Ligand A is more promising. Its superior TPSA, lower DILI risk, and better BBB penetration are crucial for a CNS-targeting drug. While Ligand B has a better half-life and slightly better affinity, the higher DILI risk and worse TPSA are significant drawbacks. The P-gp and hERG values are also better for Ligand A. The difference in affinity is small enough that it's outweighed by the other factors.

Output:
0
2025-04-17 06:34:32,307 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (375.443 and 357.376 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (83.53) is better than Ligand B (56.41). For CNS targets, we want TPSA <= 90, both are within this range, but A is closer to the upper limit.

**3. logP:** Ligand A (0.996) is slightly lower than optimal (1-3), but acceptable. Ligand B (2.795) is well within the optimal range.

**4. H-Bond Donors:** Ligand A (0) is ideal. Ligand B (1) is also acceptable.

**5. H-Bond Acceptors:** Ligand A (7) is good. Ligand B (2) is excellent.

**6. QED:** Both ligands have good QED scores (0.703 and 0.885, respectively), indicating drug-likeness.

**7. DILI:** Ligand A (72.819) has a higher DILI risk than Ligand B (39.395). This is a significant drawback for Ligand A.

**8. BBB:** Ligand B (87.01) has a significantly better BBB penetration score than Ligand A (70.531). This is *critical* for a CNS target like DRD2.

**9. Caco-2:** Both have negative Caco-2 values which is odd. Assuming these are percentile scores, both are poor.

**10. Solubility:** Both have negative solubility values which is odd. Assuming these are percentile scores, both are poor.

**11. hERG:** Both ligands have low hERG inhibition liability (0.542 and 0.59), which is good.

**12. Cl_mic:** Ligand B (5.998) has a much lower microsomal clearance than Ligand A (35.113), indicating better metabolic stability.

**13. t1/2:** Ligand B (-22.163) has a slightly better in vitro half-life than Ligand A (-24.392).

**14. Pgp:** Both ligands have very low P-gp efflux liability (0.19 and 0.07), which is excellent for CNS penetration.

**15. Binding Affinity:** Ligand B (-7.4) has a *much* stronger binding affinity than Ligand A (0). A difference of >1.5 kcal/mol is considered significant.

**Overall Assessment:**

Ligand B is clearly superior. While Ligand A has a slightly better TPSA, Ligand B excels in almost every other critical parameter, especially BBB penetration, metabolic stability (Cl_mic), and binding affinity. The significantly lower DILI risk for Ligand B is also a major advantage. The strong binding affinity of Ligand B can potentially compensate for the poor Caco-2 and solubility scores. Given the GPCR-specific priorities, the superior BBB penetration and binding affinity of Ligand B make it the far more promising drug candidate.

Output:
1
2025-04-17 06:34:32,307 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (345.443 and 350.503 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (62.74) is significantly better than Ligand B (67.43). For CNS targets, we want TPSA <= 90, both are within this range, but A is preferable.

**logP:** Both ligands have good logP values (1.947 and 2.351), falling within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A (0 HBD, 4 HBA) is slightly better than Ligand B (2 HBD, 3 HBA) in terms of balancing solubility and permeability.

**QED:** Both ligands have acceptable QED scores (0.584 and 0.66), indicating good drug-like properties.

**DILI:** Ligand A (21.946) has a much lower DILI risk than Ligand B (14.036). This is a significant advantage.

**BBB:** Ligand B (76.735) has a better BBB penetration percentile than Ligand A (63.784). This is a crucial factor for a CNS target like DRD2.

**Caco-2 Permeability:** Ligand A (-3.916) has a worse Caco-2 permeability than Ligand B (-4.465).

**Aqueous Solubility:** Ligand A (-1.885) has a slightly better aqueous solubility than Ligand B (-3.032).

**hERG Inhibition:** Ligand A (0.192) has a lower hERG inhibition liability than Ligand B (0.422), indicating a lower risk of cardiotoxicity.

**Microsomal Clearance:** Ligand B (37.817) has a lower microsomal clearance than Ligand A (74.57), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand B (4.437) has a longer in vitro half-life than Ligand A (-15.945).

**P-gp Efflux:** Ligand A (0.024) has much lower P-gp efflux liability than Ligand B (0.161). Lower P-gp efflux is highly desirable for CNS penetration.

**Binding Affinity:** Ligand B (-7.8 kcal/mol) has a significantly stronger binding affinity than Ligand A (-6.8 kcal/mol). This is a substantial advantage, potentially outweighing some ADME drawbacks.

**Overall Assessment:**

The key trade-offs are BBB penetration and binding affinity. Ligand B has superior BBB penetration and a significantly stronger binding affinity. However, Ligand A has a much better safety profile (lower DILI and hERG) and lower P-gp efflux. Considering the importance of potency for GPCR ligands, the 1 kcal/mol difference in binding affinity is substantial. The better BBB of Ligand B is also a strong positive. The lower DILI and P-gp efflux of Ligand A are valuable, but the potency and BBB advantages of Ligand B are more critical for a CNS-targeting drug.

Output:
1
2025-04-17 06:34:32,307 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (346.45 & 349.43 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (49.41) is excellent for CNS penetration, well below the 90 A^2 threshold. Ligand B (83.81) is higher, but still potentially acceptable, though less ideal.

**logP:** Ligand A (3.345) is within the optimal 1-3 range. Ligand B (1.312) is at the lower end, which *could* hinder permeability, but isn't a dealbreaker.

**H-Bond Donors/Acceptors:** Ligand A (1 HBD, 2 HBA) is favorable. Ligand B (2 HBD, 5 HBA) is also acceptable, but slightly higher.

**QED:** Ligand A (0.803) has a very strong drug-like profile. Ligand B (0.519) is acceptable, but less optimal.

**DILI:** Ligand A (25.824) has a very low DILI risk. Ligand B (22.8) is also very low risk.

**BBB:** Ligand A (83.404) has excellent BBB penetration, exceeding the 70% threshold. Ligand B (61.923) is significantly lower, which is a major concern for a CNS target like DRD2.

**Caco-2:** Ligand A (-4.735) has poor Caco-2 permeability. Ligand B (-5) has similarly poor Caco-2 permeability.

**Solubility:** Ligand A (-2.955) has poor aqueous solubility. Ligand B (-1.599) has slightly better, but still poor aqueous solubility.

**hERG:** Both ligands (0.671 & 0.371) have low hERG inhibition risk.

**Cl_mic:** Ligand A (38.505) has moderate metabolic clearance. Ligand B (-9.218) has negative clearance, which is not possible and likely a data error, but suggests very high metabolic stability.

**t1/2:** Ligand A (-0.503) has a very short in vitro half-life. Ligand B (5.711) has a good in vitro half-life.

**Pgp:** Both ligands (0.344 & 0.029) have low P-gp efflux, which is good for CNS penetration.

**Binding Affinity:** Ligand B (-7.6 kcal/mol) has a significantly stronger binding affinity than Ligand A (0 kcal/mol). This is a substantial advantage.

**Overall Assessment:**

Ligand B is the stronger candidate despite its higher TPSA and lower logP. The dramatically superior binding affinity (-7.6 vs 0 kcal/mol) is a major advantage that can potentially overcome the slightly less favorable ADME properties. The better half-life and potentially very high metabolic stability are also significant positives. The biggest drawback for Ligand B is the lower BBB penetration (61.923%), but it's not disqualifying, especially given the strong affinity. Ligand A's poor affinity and short half-life are significant drawbacks. The poor Caco-2 and solubility for both are concerning and would need to be addressed in further optimization, but are less critical than potency and CNS penetration for a CNS target.

Output:
1
2025-04-17 06:34:32,307 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (345.309 Da) is slightly lower, which is generally favorable for permeability. Ligand B (371.855 Da) is also good.

**TPSA:** Ligand A (81.81) is better than Ligand B (29.54) for CNS penetration, falling well below the 90 A^2 threshold. Ligand B is excellent, suggesting good BBB penetration.

**logP:** Ligand A (2.385) is within the optimal range (1-3). Ligand B (4.643) is slightly higher, potentially leading to solubility issues or off-target interactions, but still acceptable.

**H-Bond Donors/Acceptors:** Ligand A has 1 HBD and 6 HBA, which are reasonable. Ligand B has 0 HBD and 2 HBA, which is also good.

**QED:** Both ligands have acceptable QED values (Ligand A: 0.787, Ligand B: 0.666), indicating good drug-like properties.

**DILI:** Ligand A has a high DILI risk (98.449), which is a major concern. Ligand B has a much lower DILI risk (31.524), making it significantly safer.

**BBB:** Ligand A has a good BBB penetration (74.06), but Ligand B is even better (90.074). This is crucial for a CNS target like DRD2.

**Caco-2 Permeability:** Both have negative values, which is unusual and likely indicates a scaling issue. However, the magnitude suggests Ligand A (-4.586) has slightly better permeability than Ligand B (-4.183).

**Aqueous Solubility:** Both ligands have poor aqueous solubility (-4.122 and -5.162 respectively).

**hERG Inhibition:** Ligand A has a low hERG risk (0.448), while Ligand B has a moderate risk (0.907).

**Microsomal Clearance:** Ligand A has lower clearance (35.416) than Ligand B (80.736), indicating better metabolic stability.

**In vitro Half-Life:** Ligand B has a significantly longer half-life (43.607 hours) than Ligand A (15.87 hours).

**P-gp Efflux:** Ligand A has very low P-gp efflux (0.114), which is excellent for CNS exposure. Ligand B has moderate P-gp efflux (0.574).

**Binding Affinity:** Ligand B (-7.3 kcal/mol) has a substantially stronger binding affinity than Ligand A (-10.1 kcal/mol). This difference in affinity is significant and can outweigh some of the ADME drawbacks.

**Overall Assessment:**

While Ligand A has better P-gp efflux and metabolic stability, its extremely high DILI risk is a deal-breaker. Ligand B, despite slightly higher logP and P-gp efflux, exhibits a much more favorable safety profile (DILI), superior BBB penetration, and, critically, significantly stronger binding affinity to DRD2. The improved half-life is also a plus. Given the GPCR-specific priorities, the combination of strong affinity, good BBB penetration, and low DILI risk makes Ligand B the more promising drug candidate.

Output:
1
2025-04-17 06:34:32,308 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 drug candidates, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (366.849 and 372.824 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (87.32) is slightly above the ideal <90 for CNS targets, but acceptable. Ligand B (75.71) is well within the desired range.

**logP:** Both ligands have good logP values (2.486 and 1.672), falling within the optimal 1-3 range.

**H-Bond Donors:** Ligand A has 2 HBD, and Ligand B has 1. Both are within the acceptable limit of <=5.

**H-Bond Acceptors:** Both ligands have 4 HBA, well below the limit of <=10.

**QED:** Both ligands have good QED scores (0.42 and 0.762), with Ligand B being significantly better, indicating a more drug-like profile.

**DILI:** Ligand A (59.519) has a higher DILI risk than Ligand B (42.846), though both are reasonably acceptable.

**BBB:** This is a critical parameter for a CNS target like DRD2. Ligand B (76.309) is significantly better than Ligand A (44.668), exceeding the desirable >70 threshold.

**Caco-2 Permeability:** Ligand A (-5.338) has poor Caco-2 permeability, suggesting poor intestinal absorption. Ligand B (-4.769) is also poor, but slightly better than A.

**Aqueous Solubility:** Both ligands have very poor aqueous solubility (-3.191 and -2.906 respectively). This could pose formulation challenges.

**hERG Inhibition:** Both ligands show low hERG inhibition liability (0.415 and 0.279), which is favorable.

**Microsomal Clearance:** Ligand A (7.159) has higher microsomal clearance than Ligand B (4.182), indicating lower metabolic stability.

**In vitro Half-Life:** Ligand B (-11.663) has a slightly better (less negative) in vitro half-life than Ligand A (-16.682).

**P-gp Efflux:** Both ligands show low P-gp efflux liability (0.092 and 0.075), which is good for CNS penetration.

**Binding Affinity:** Ligand B (-8.8 kcal/mol) has a slightly better binding affinity than Ligand A (-7.9 kcal/mol). While both are good, the difference is significant enough to be considered.

**Overall Assessment:**

Ligand B is the superior candidate. It has a better BBB score, a higher QED, lower DILI risk, better metabolic stability, a slightly better half-life, and a slightly stronger binding affinity. While both have poor solubility and Caco-2 permeability, the CNS target prioritizes BBB penetration, where Ligand B excels. The affinity difference, though not huge, adds to the advantage.

Output:
1
2025-04-17 06:34:32,308 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (360.479 and 365.419 Da) are within the ideal range of 200-500 Da.

**TPSA:** Ligand A (62.55) is excellent, well below the 90 A^2 threshold for CNS targets. Ligand B (127.94) is higher, but still potentially acceptable, though less ideal.

**logP:** Ligand A (3.34) is optimal (1-3). Ligand B (-0.165) is significantly lower than ideal, potentially hindering membrane permeability and CNS penetration.

**H-Bond Donors/Acceptors:** Ligand A (HBD=1, HBA=4) is well within acceptable limits. Ligand B (HBD=2, HBA=6) is also acceptable, but slightly higher.

**QED:** Both ligands have reasonable QED values (0.889 and 0.774), indicating good drug-like properties.

**DILI:** Ligand A (40.752) has a low DILI risk. Ligand B (87.476) has a significantly higher DILI risk, which is a major concern.

**BBB:** Ligand A (67.313) has a moderate BBB penetration, which could be improved but isn't terrible. Ligand B (25.126) has very poor predicted BBB penetration, a critical drawback for a CNS target like DRD2.

**Caco-2 Permeability:** Both have negative values (-5.049 and -5.312), which is unusual and suggests issues with the prediction method or the compounds themselves. However, the values are similar.

**Aqueous Solubility:** Both have negative values (-3.279 and -2.574) which is unusual.

**hERG:** Both ligands have low hERG inhibition risk (0.695 and 0.148).

**Microsomal Clearance:** Ligand A (33.468) has moderate clearance. Ligand B (-4.2) has a negative clearance, which is not physically possible and indicates a problem with the prediction.

**In vitro Half-Life:** Ligand A (38.467) has a reasonable half-life. Ligand B (-24.865) has a negative half-life, which is not physically possible and indicates a problem with the prediction.

**P-gp Efflux:** Ligand A (0.49) has low P-gp efflux, which is good. Ligand B (0.017) also has very low P-gp efflux, which is good.

**Binding Affinity:** Both ligands have excellent binding affinities (-8.8 and -9.4 kcal/mol), with Ligand B being slightly better. However, this advantage is likely outweighed by its other significant drawbacks.

**Overall Assessment:**

Ligand A is significantly more promising. It has a better logP, a much lower DILI risk, and a more reasonable (though still not ideal) BBB prediction. While Ligand B has slightly better binding affinity, its poor logP, high DILI risk, and extremely poor BBB penetration make it a much less viable candidate. The negative values for clearance and half-life for Ligand B are also red flags.

Output:
0
2025-04-17 06:34:32,308 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (370.833 and 343.471 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (99.88) is slightly higher than the preferred <90 for CNS targets, but still reasonable. Ligand B (53.51) is excellent, well below 90.

**logP:** Ligand A (1.615) is optimal. Ligand B (3.063) is also within the optimal range, but closer to the upper limit.

**H-Bond Donors/Acceptors:** Ligand A has 2 HBD and 5 HBA, which are acceptable. Ligand B has 0 HBD and 3 HBA, also acceptable.

**QED:** Both ligands have good QED scores (0.688 and 0.715), indicating good drug-like properties.

**DILI:** Ligand A (51.221) has a slightly higher DILI risk than Ligand B (35.556), but both are below the concerning threshold of 60.

**BBB:** Ligand A (81.388) has a good BBB penetration score, while Ligand B (77.007) is slightly lower, but still acceptable. Both are above 70, which is desirable for CNS targets.

**Caco-2 Permeability:** Ligand A (-4.884) has poor Caco-2 permeability, which is a concern. Ligand B (-4.475) is also poor, but slightly better than A.

**Aqueous Solubility:** Both ligands have poor aqueous solubility (-3.463 and -2.012 respectively). This could present formulation challenges.

**hERG Inhibition:** Both ligands show low hERG inhibition risk (0.153 and 0.337).

**Microsomal Clearance:** Ligand A (31.896) has significantly lower microsomal clearance than Ligand B (72.316), indicating better metabolic stability.

**In vitro Half-Life:** Ligand A (-17.797) has a negative half-life, which is not physically possible and suggests an issue with the data or model. Ligand B (11.58) has a reasonable half-life.

**P-gp Efflux:** Both ligands show low P-gp efflux liability (0.139 and 0.253).

**Binding Affinity:** Both ligands have the same binding affinity (-7.8 kcal/mol), which is excellent.

**Overall Assessment:**

Despite the equal binding affinity, Ligand A has a significant issue with its reported negative in vitro half-life, making it immediately less viable. Ignoring that data error, Ligand A has better metabolic stability (lower Cl_mic) and a slightly better BBB score. However, Ligand B has a much better TPSA and Caco-2 permeability, and a more reasonable half-life. Given the importance of BBB penetration, logP, and metabolic stability for CNS GPCR targets, and the questionable half-life of Ligand A, Ligand B is the more promising candidate.

Output:
1
2025-04-17 06:34:32,308 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (417.288 Da) is slightly higher, but acceptable. Ligand B (357.382 Da) is also good.

**TPSA:** Ligand A (77.0) is excellent for CNS penetration, well below the 90 A^2 threshold. Ligand B (107.97) is higher, but still reasonably good, though less ideal for CNS targets.

**logP:** Ligand A (4.046) is at the upper end of the optimal range (1-3), potentially leading to solubility issues. Ligand B (-0.299) is too low, which could hinder membrane permeability and potentially reduce binding affinity.

**H-Bond Donors/Acceptors:** Ligand A (HBD=1, HBA=6) is within acceptable limits. Ligand B (HBD=3, HBA=5) is also within acceptable limits.

**QED:** Both ligands have similar QED values (A: 0.632, B: 0.626), indicating good drug-like properties.

**DILI:** Ligand A (88.29) has a higher DILI risk than Ligand B (35.828), which is a significant concern.

**BBB:** Ligand A (51.997) has a moderate BBB penetration, while Ligand B (44.397) is also moderate. Both are below the desirable >70 percentile for CNS targets, but Ligand A is slightly better.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.107 and -5.061), which is unusual and suggests poor permeability. This is a red flag for both.

**Aqueous Solubility:** Both ligands have negative solubility values (-4.734 and -1.499), indicating very poor aqueous solubility. This is a major drawback for both.

**hERG Inhibition:** Both ligands have low hERG inhibition liability (A: 0.477, B: 0.184), which is positive.

**Microsomal Clearance:** Ligand A (60.36) has moderate clearance, while Ligand B (-43.723) has negative clearance, which is unrealistic and indicates a potential issue with the data or modeling.

**In vitro Half-Life:** Ligand A (10.751) has a reasonable half-life. Ligand B (-12.507) has a negative half-life, which is unrealistic.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (A: 0.364, B: 0.018), which is favorable for CNS penetration.

**Binding Affinity:** Both ligands have very similar and strong binding affinities (-8.8 kcal/mol and -8.6 kcal/mol). The difference of 0.2 kcal/mol is not substantial enough to outweigh other factors.

**Overall Assessment:**

Ligand A is better despite the higher DILI risk. Ligand B has several problematic values (negative clearance and half-life) that are unrealistic and raise serious concerns about the data quality or the molecule's inherent properties. While both have poor solubility and permeability, Ligand A's slightly better BBB penetration, more realistic ADME properties, and comparable affinity make it the more promising candidate. The DILI risk is a concern that would need to be addressed through structural modifications.

Output:
0
2025-04-17 06:34:32,308 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (364.56 and 355.48 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (32.78) is excellent, well below the 90 A^2 threshold for CNS targets. Ligand B (93.78) is significantly higher, exceeding the optimal range and potentially hindering BBB penetration.

**logP:** Ligand A (3.653) is within the optimal 1-3 range. Ligand B (-0.985) is below 1, which could impede permeation.

**H-Bond Donors/Acceptors:** Ligand A (0 HBD, 4 HBA) is favorable. Ligand B (3 HBD, 5 HBA) is acceptable but less ideal.

**QED:** Both ligands have similar QED values (0.593 and 0.494), indicating reasonable drug-likeness.

**DILI:** Ligand A (36.14) has a slightly higher DILI risk than Ligand B (18.46), but both are below the concerning threshold of 60.

**BBB:** Ligand A (73.71) has a good BBB percentile, exceeding the 70% target for CNS drugs. Ligand B (35.21) is significantly lower, raising concerns about CNS exposure.

**Caco-2 Permeability:** Ligand A (-4.971) has poor Caco-2 permeability. Ligand B (-5.422) is also poor, but slightly worse.

**Aqueous Solubility:** Ligand A (-3.699) has poor solubility. Ligand B (-0.785) is also poor, but slightly better.

**hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.958 and 0.1).

**Microsomal Clearance:** Ligand A (109.96) has higher clearance than Ligand B (10.17), suggesting lower metabolic stability.

**In vitro Half-Life:** Ligand A (-28.33) has a negative half-life, which is unusual and suggests rapid degradation. Ligand B (-11.84) is also negative, but less so.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.799 and 0.001), which is favorable for CNS penetration.

**Binding Affinity:** Ligand A (-7.8 kcal/mol) has a slightly better binding affinity than Ligand B (-6.9 kcal/mol). The difference is 0.9 kcal/mol, which is significant.

**Overall Assessment:**

Considering the GPCR-specific priorities, Ligand A is the more promising candidate. Its superior TPSA, logP, and BBB penetration, coupled with a slightly better binding affinity, outweigh its slightly higher DILI risk and poorer Caco-2 permeability. Ligand B's poor TPSA and logP are significant drawbacks for a CNS-targeting drug, despite its lower DILI. The negative half-life values for both are concerning and would require further investigation, but the differences in other key parameters favor Ligand A.

Output:
1
2025-04-17 06:34:32,308 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (339.395 and 345.443 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (87.99) is slightly higher than Ligand B (80.32), but both are below the 90 A^2 threshold desirable for CNS targets.

**3. logP:** Both ligands have good logP values (2.881 and 2.38), falling within the optimal 1-3 range.

**4. H-Bond Donors:** Both ligands have 2 HBD, which is within the acceptable limit of <=5.

**5. H-Bond Acceptors:** Both ligands have 4 HBA, also within the acceptable limit of <=10.

**6. QED:** Both ligands have good QED scores (0.748 and 0.776), indicating good drug-like properties.

**7. DILI:** Ligand A (62.854) has a higher DILI risk than Ligand B (41.411). This is a negative for Ligand A.

**8. BBB:** Ligand B (65.801) has a significantly better BBB penetration percentile than Ligand A (49.515). This is a *critical* advantage for a CNS target like DRD2.

**9. Caco-2 Permeability:** Ligand A (-5.283) shows poorer Caco-2 permeability than Ligand B (-4.474). Both are negative values, indicating poor permeability, but Ligand B is better.

**10. Aqueous Solubility:** Ligand A (-3.933) has slightly worse solubility than Ligand B (-3.267). Both are poor, but B is better.

**11. hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.522 and 0.254).

**12. Microsomal Clearance:** Ligand A (27.706) has lower microsomal clearance than Ligand B (76.911), suggesting better metabolic stability. This is a positive for Ligand A.

**13. In vitro Half-Life:** Ligand A (18.737) has a shorter in vitro half-life than Ligand B (-42.067). The negative value for B is unusual and could indicate very high stability, but needs further investigation.

**14. P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.19 and 0.188).

**15. Binding Affinity:** Ligand B (-8.1 kcal/mol) has a slightly better binding affinity than Ligand A (-10.3 kcal/mol). While A has a better affinity, the difference is not substantial enough to outweigh the other factors.

**Overall Assessment:**

Ligand B is the more promising candidate. The significantly better BBB penetration (65.801 vs 49.515) is a major advantage for a CNS target. It also has a lower DILI risk and better Caco-2 permeability and solubility. While Ligand A has better metabolic stability and a slightly better binding affinity, the BBB penetration is paramount for DRD2, and Ligand B excels in this area.

Output:
1
2025-04-17 06:34:32,309 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (353.379 and 347.459 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (107.81) is higher than Ligand B (78.51). For CNS targets, TPSA should be <= 90. Ligand B is better here.

**logP:** Ligand A (0.424) is quite low, potentially hindering permeation. Ligand B (1.235) is within the optimal 1-3 range. Ligand B is significantly better.

**H-Bond Donors:** Ligand A (1) and Ligand B (2) are both acceptable, being <= 5.

**H-Bond Acceptors:** Ligand A (8) and Ligand B (3) are both acceptable, being <= 10.

**QED:** Both ligands have similar QED values (0.765 and 0.71), indicating good drug-likeness.

**DILI:** Ligand A (69.794) has a higher DILI risk than Ligand B (16.053). Lower is better, so Ligand B is favored.

**BBB:** Ligand A (79.488) has a better BBB percentile than Ligand B (59.597). For a CNS target like DRD2, >70 is desirable, so Ligand A is better here, but both are not optimal.

**Caco-2 Permeability:** Ligand A (-4.609) has worse Caco-2 permeability than Ligand B (-5.088). Higher is better. Ligand B is slightly better.

**Aqueous Solubility:** Ligand A (-2.689) has worse aqueous solubility than Ligand B (-1.753). Higher is better. Ligand B is slightly better.

**hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.058 and 0.13).

**Microsomal Clearance:** Ligand A (48.057) has a higher microsomal clearance than Ligand B (-9.146). Lower is better for metabolic stability, so Ligand B is favored.

**In vitro Half-Life:** Ligand A (-2.918) has a shorter in vitro half-life than Ligand B (-6.736). Longer is better, so Ligand B is favored.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.013 and 0.021).

**Binding Affinity:** Ligand B (-8.8 kcal/mol) has a slightly better binding affinity than Ligand A (-7.5 kcal/mol). A difference of >1.5 kcal/mol can be significant.

**Overall Assessment:**

Ligand B consistently outperforms Ligand A in several key ADME properties (logP, DILI, Cl_mic, t1/2) and has a slightly better binding affinity. While Ligand A has a better BBB score, the overall profile of Ligand B is more favorable for a CNS-targeting drug candidate. The low logP of Ligand A is a major concern, potentially hindering its ability to cross cell membranes and reach the brain.

Output:
1
2025-04-17 06:34:32,309 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (349.479 Da) is slightly better, being closer to the lower end which can aid permeability.

**TPSA:** Both ligands have TPSA values below 90, which is good for CNS penetration. Ligand A (79.26) is preferable to Ligand B (88.4) as lower TPSA generally correlates with better BBB penetration.

**logP:** Both ligands have optimal logP values (between 1 and 3). Ligand A (1.432) is slightly higher than Ligand B (0.975), which is a marginal advantage.

**H-Bond Donors/Acceptors:** Ligand A (2 HBD, 5 HBA) is slightly better than Ligand B (0 HBD, 7 HBA) in terms of balancing solubility and permeability.

**QED:** Both ligands have acceptable QED values (>0.5), indicating good drug-like properties.

**DILI:** Ligand A (16.053) has a significantly lower DILI risk than Ligand B (55.021). This is a major advantage.

**BBB:** Ligand A (57.736) has a lower BBB percentile than Ligand B (68.554). While both are not ideal (>70), Ligand B is better in this regard.

**Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and suggests poor permeability. However, the scale is not defined, so it is difficult to interpret.

**Aqueous Solubility:** Both ligands have negative solubility values, indicating low solubility. This is a significant drawback for both.

**hERG Inhibition:** Both ligands show very low hERG inhibition risk.

**Microsomal Clearance:** Ligand A (6.006) has a much lower microsomal clearance than Ligand B (37.663), indicating better metabolic stability.

**In vitro Half-Life:** Ligand A (1.598) has a shorter half-life than Ligand B (-57.593). The negative value for Ligand B is suspect and likely an error.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability.

**Binding Affinity:** Ligand A (-7.6 kcal/mol) has a slightly better binding affinity than Ligand B (-7.3 kcal/mol), although the difference is small.

**Overall Assessment:**

Considering the GPCR-specific priorities, Ligand A is the more promising candidate. It has a lower DILI risk, better metabolic stability (lower Cl_mic), and slightly better binding affinity. While Ligand B has a slightly better BBB score, the lower DILI and Cl_mic of Ligand A outweigh this advantage. The solubility issues are concerning for both, but can potentially be addressed through formulation strategies.

Output:
0
2025-04-17 06:34:32,309 - INFO - Reasoning:

Let's analyze Ligand A and Ligand B based on the provided guidelines, prioritizing GPCR-specific properties (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (366.889 and 378.447 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (78.43) is excellent, well below the 90 A^2 threshold for CNS targets. Ligand B (133.24) is higher, but still potentially acceptable, though less ideal.

**logP:** Ligand A (3.361) is optimal (1-3). Ligand B (-1.408) is significantly below this range, which could hinder permeability and potentially reduce binding affinity.

**H-Bond Donors/Acceptors:** Both ligands have 3 HBD, which is good. Ligand A has 3 HBA, while Ligand B has 7 HBA. Both are within the acceptable range, but Ligand A is slightly better.

**QED:** Both ligands have reasonable QED scores (0.722 and 0.535), indicating drug-like properties.

**DILI:** Both ligands have acceptable DILI risk (35.828 and 41.062), below the 60 threshold.

**BBB:** Ligand A (67.623) is better than Ligand B (33.967) for CNS penetration, though ideally >70 is preferred. Ligand B's BBB score is a significant concern.

**Caco-2 Permeability:** Ligand A (-4.762) is poor, indicating low intestinal absorption. Ligand B (-5.973) is even worse.

**Aqueous Solubility:** Ligand A (-4.052) is poor, while Ligand B (-1.23) is also poor. Both are problematic for formulation.

**hERG Inhibition:** Both ligands have very low hERG risk (0.35 and 0.111).

**Microsomal Clearance:** Ligand A (32.911) has moderate clearance, while Ligand B (-21.918) has negative clearance, which is not realistic. This suggests a potential issue with the data for Ligand B, or a very high metabolic stability.

**In vitro Half-Life:** Ligand A (44.435 hours) has a good half-life. Ligand B (23.703 hours) is also acceptable, but less favorable.

**P-gp Efflux:** Both ligands have very low P-gp efflux (0.092 and 0.018), which is favorable for CNS exposure.

**Binding Affinity:** Ligand A (-9.0 kcal/mol) has a significantly stronger binding affinity than Ligand B (-7.7 kcal/mol). This >1.5 kcal/mol difference is substantial and can outweigh some ADME liabilities.

**Overall Assessment:**

Ligand A is the stronger candidate. While its Caco-2 permeability and solubility are poor, its superior BBB penetration, optimal logP, and *much* stronger binding affinity outweigh these drawbacks, especially considering the target is a CNS GPCR. Ligand B's very low logP and poor BBB penetration are major concerns. The negative microsomal clearance for Ligand B is also suspect. The significant difference in binding affinity further solidifies Ligand A as the better choice.

Output:
1
2025-04-17 06:34:32,309 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (356.419 Da) is slightly lower, which could be beneficial for permeability.

**TPSA:** Ligand A (94.17) is better than Ligand B (107.97). For CNS targets, TPSA should be <= 90, so Ligand A is closer to this threshold.

**logP:** Ligand A (0.242) is quite low, potentially hindering membrane permeability. Ligand B (-1.03) is also low, but slightly better than A. Both are below the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A has 1 HBD and 6 HBA, while Ligand B has 3 HBD and 6 HBA. Both are within acceptable limits.

**QED:** Both ligands have reasonable QED values (Ligand A: 0.657, Ligand B: 0.527), indicating good drug-like properties.

**DILI:** Ligand A (41.373) has a slightly higher DILI risk than Ligand B (29.236), but both are below the concerning threshold of 60.

**BBB:** This is a critical parameter for CNS targets. Ligand A (68.282) is significantly better than Ligand B (27.026), exceeding the desirable >70% threshold.

**Caco-2 Permeability:** Ligand A (-4.769) is significantly worse than Ligand B (-5.686). Both are poor, but B is slightly better.

**Aqueous Solubility:** Ligand A (-0.916) is better than Ligand B (-1.443), but both are very poor.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (Ligand A: 0.069, Ligand B: 0.089).

**Microsomal Clearance:** Ligand B (-14.878) has a much lower (better) microsomal clearance than Ligand A (53.747), indicating greater metabolic stability.

**In vitro Half-Life:** Ligand B (-6.861) has a much longer half-life than Ligand A (-0.227).

**P-gp Efflux:** Both ligands show very low P-gp efflux liability (Ligand A: 0.018, Ligand B: 0.005).

**Binding Affinity:** Ligand B (-7.1) has a significantly stronger binding affinity than Ligand A (0.0). This is a substantial advantage.

**Overall Assessment:**

Ligand B has a significantly better binding affinity and metabolic stability (lower Cl_mic, longer t1/2). While its logP and BBB are less favorable than Ligand A, the substantial affinity advantage (-7.1 vs 0.0 kcal/mol) outweighs these drawbacks, especially for a GPCR target where potency is paramount. Ligand A's better BBB is a positive, but not enough to compensate for the weak binding. The poor solubility of both is a concern, but can be addressed with formulation strategies.

Output:
1
2025-04-17 06:34:32,309 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (354.397 and 349.431 Da) are within the ideal 200-500 Da range.

**TPSA:** Ligand A (58.64) is excellent, well below the 90 A^2 threshold for CNS targets. Ligand B (80.23) is still reasonable, but less optimal.

**logP:** Both ligands have good logP values (2.497 and 1.099), falling within the 1-3 range. Ligand A is slightly preferred.

**H-Bond Donors:** Both have 1 HBD, which is acceptable.

**H-Bond Acceptors:** Ligand A has 3 HBA, and Ligand B has 5. Both are within the acceptable limit of 10, but A is slightly better.

**QED:** Both ligands have good QED scores (0.73 and 0.754), indicating good drug-like properties.

**DILI:** Ligand A (46.297) has a moderate DILI risk, but is acceptable. Ligand B (19.736) has a very low DILI risk, a significant advantage.

**BBB:** Ligand A (90.694) has excellent BBB penetration, exceeding the desirable >70 percentile. Ligand B (55.487) is considerably lower, which is a major drawback for a CNS target like DRD2.

**Caco-2 Permeability:** Both have negative Caco-2 values (-4.469 and -4.827), which is unusual and suggests poor permeability. This is a concern for both, but the values are similar.

**Aqueous Solubility:** Both have negative solubility values (-2.722 and -1.54), indicating poor aqueous solubility. This is a concern for both, but B is slightly better.

**hERG:** Both ligands have low hERG inhibition risk (0.703 and 0.109). Ligand B is significantly better here.

**Microsomal Clearance:** Ligand A (44.348) has moderate clearance, while Ligand B (-9.208) has *negative* clearance, suggesting very high metabolic stability. This is a substantial advantage for Ligand B.

**In vitro Half-Life:** Ligand A (37.967) has a reasonable half-life. Ligand B (-0.864) has a negative half-life, which is unrealistic but indicates exceptional stability.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.26 and 0.009), which is favorable for CNS penetration.

**Binding Affinity:** Both ligands have the same excellent binding affinity (-8.7 kcal/mol).

**Overall Assessment:**

Ligand B excels in several critical areas for a CNS-targeting GPCR: very low DILI risk, exceptional metabolic stability (negative clearance/half-life), very low P-gp efflux, and low hERG risk. While its BBB penetration is lower than Ligand A, the other advantages, particularly the metabolic stability, are compelling. Ligand A's primary advantage is its excellent BBB penetration, but this is offset by the higher DILI risk and moderate metabolic clearance. The similar Caco-2 and solubility values are concerns for both, but can be addressed with formulation strategies.

Output:
1
2025-04-17 06:34:32,310 - INFO - Batch 293 complete. Total preferences: 4688
2025-04-17 06:34:32,310 - INFO - Processing batch 294/512...
2025-04-17 06:35:19,427 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (346.431 and 364.515 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (95.42) is slightly above the optimal <90 for CNS targets, but still reasonable. Ligand B (71.11) is well within the desired range.

**logP:** Ligand A (0.994) is a bit low, potentially hindering permeability. Ligand B (3.546) is excellent, falling right in the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A has 2 HBD and 5 HBA, which are acceptable. Ligand B has 1 HBD and 5 HBA, also acceptable.

**QED:** Both ligands have reasonable QED scores (0.829 and 0.7), indicating good drug-like properties.

**DILI:** Both ligands have low DILI risk (39.667 and 37.999 percentile), which is positive.

**BBB:** Both ligands have good BBB penetration (61.846 and 63.164 percentile), but ideally, we'd want >70 for a CNS target. Ligand B is slightly better.

**Caco-2 Permeability:** Both have negative Caco-2 values (-5.039 and -5.621), which is unusual and suggests poor permeability. This is a significant concern for both.

**Aqueous Solubility:** Both have negative solubility values (-2.014 and -2.856), which is also concerning and suggests poor solubility.

**hERG Inhibition:** Both ligands show low hERG inhibition risk (0.383 and 0.636), which is good.

**Microsomal Clearance:** Ligand A has a lower Cl_mic (9.158) than Ligand B (66.555), indicating better metabolic stability.

**In vitro Half-Life:** Ligand A has a negative half-life (-10.934), which is not physically possible and suggests an issue with the data or the model. Ligand B has a half-life of 33.575 hours, which is good.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.093 and 0.481), which is favorable for CNS penetration.

**Binding Affinity:** Ligand A (-9.2 kcal/mol) has a significantly stronger binding affinity than Ligand B (-6.7 kcal/mol). This is a substantial advantage.

**Overall Assessment:**

Despite the negative Caco-2 and solubility values for both, the significantly stronger binding affinity of Ligand A (-9.2 vs -6.7 kcal/mol) is a major advantage. This difference in affinity could potentially overcome some of the ADME liabilities. Ligand B has better logP and half-life, but the affinity difference is too significant to ignore. The negative half-life for Ligand A is a data quality concern, but the binding affinity is still the deciding factor.

Output:
1
2025-04-17 06:35:19,427 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (368.905 Da) is slightly higher than Ligand B (345.403 Da), but both are acceptable.

**TPSA:** Ligand A (69.64) is excellent for CNS penetration, well below the 90 A^2 threshold. Ligand B (110.32) is higher, but still potentially acceptable, though less ideal.

**logP:** Ligand A (3.704) is at the upper end of the optimal range (1-3), but still reasonable. Ligand B (-0.184) is significantly below the optimal range, which could hinder permeability.

**H-Bond Donors/Acceptors:** Both have acceptable HBD counts (2). Ligand B has a higher HBA count (5) compared to Ligand A (3), but both remain within the acceptable limit of 10.

**QED:** Both ligands have good QED scores (A: 0.653, B: 0.74), indicating good drug-like properties.

**DILI:** Ligand A (21.714) has a much lower DILI risk than Ligand B (34.393), which is a significant advantage.

**BBB:** Ligand A (62.854) has a better BBB penetration percentile than Ligand B (59.054), though both are below the desirable >70% for CNS targets.

**Caco-2 Permeability:** Ligand A (-4.581) has poor Caco-2 permeability, which is a concern. Ligand B (-5.151) is also poor, but slightly worse.

**Aqueous Solubility:** Ligand A (-3.438) has poor aqueous solubility, while Ligand B (-2.519) is slightly better, but still poor.

**hERG:** Both ligands have low hERG inhibition liability (A: 0.776, B: 0.208), which is good.

**Microsomal Clearance:** Ligand A (41.223) has higher microsomal clearance than Ligand B (4.299), indicating lower metabolic stability. Ligand B is much more metabolically stable.

**In vitro Half-Life:** Ligand B (10.046) has a significantly longer in vitro half-life than Ligand A (71.509), which is a major advantage.

**P-gp Efflux:** Ligand A (0.331) has lower P-gp efflux than Ligand B (0.018), which is favorable for CNS exposure.

**Binding Affinity:** Ligand B (-8.2 kcal/mol) has a significantly stronger binding affinity than Ligand A (-7.0 kcal/mol). This >1.5 kcal/mol difference is substantial and can outweigh some ADME drawbacks.

**Overall Assessment:**

Ligand B has a significantly stronger binding affinity, better metabolic stability (lower Cl_mic, longer t1/2), and lower DILI risk. However, it has a lower logP and BBB penetration. Ligand A has better P-gp efflux and TPSA, but suffers from poor Caco-2 permeability, solubility, and metabolic stability.

Considering the GPCR-specific priorities, the strong binding affinity of Ligand B is crucial. While its logP and BBB are not ideal, the difference in binding affinity is substantial enough to potentially overcome these issues with further optimization. The improved metabolic stability and reduced DILI risk also make Ligand B a more promising starting point.

Output:
1
2025-04-17 06:35:19,428 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (353.5 & 361.5 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Both ligands (61.88 & 62.3) are below the 90 A^2 threshold desirable for CNS targets, which is excellent.

**3. logP:** Ligand A (1.497) is optimal, while Ligand B (3.163) is at the higher end of the optimal range.

**4. H-Bond Donors:** Both ligands have 1 HBD, which is well within the acceptable limit of <=5.

**5. H-Bond Acceptors:** Both ligands have 4 HBA, also within the acceptable limit of <=10.

**6. QED:** Both ligands have good QED scores (0.753 and 0.82), indicating good drug-like properties.

**7. DILI:** Both ligands have low DILI risk (5.312 and 64.754 percentile), with Ligand A being slightly preferable.

**8. BBB:** Ligand B (70.415%) has a significantly better BBB penetration score than Ligand A (56.029%). This is a crucial advantage for a CNS target like DRD2.

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.848 & -4.947), which is unusual and suggests poor permeability. However, these values are on a log scale and are likely representing very low permeability.

**10. Aqueous Solubility:** Both ligands have negative solubility values (-1.078 & -3.781), indicating very poor aqueous solubility. This is a significant drawback.

**11. hERG Inhibition:** Both ligands show low hERG inhibition liability (0.505 & 0.339).

**12. Microsomal Clearance:** Ligand B (64.859) has a much higher microsomal clearance than Ligand A (0.907), suggesting faster metabolism and potentially lower *in vivo* exposure.

**13. In vitro Half-Life:** Ligand A (6.805) has a longer in vitro half-life than Ligand B (-7.479).

**14. P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.012 & 0.458).

**15. Binding Affinity:** Ligand B (-8.6 kcal/mol) has a slightly better binding affinity than Ligand A (-8.0 kcal/mol). This difference of 0.6 kcal/mol is significant, but needs to be weighed against other factors.

**Overall Assessment:**

While Ligand A has slightly better DILI and metabolic stability (lower Cl_mic, longer t1/2), Ligand B excels in BBB penetration (70.4% vs 56.0%), which is paramount for a CNS target. The slightly better binding affinity of Ligand B (-8.6 vs -8.0 kcal/mol) further strengthens its case. The poor solubility and permeability are concerning for both, but the superior CNS penetration of Ligand B is likely to outweigh these drawbacks, assuming formulation strategies can be employed to address them.

Output:
1
2025-04-17 06:35:19,428 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (366.49 and 344.50 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (72.96) is higher than Ligand B (40.62). For CNS targets, we ideally want TPSA <= 90, so both are acceptable, but B is significantly better.

**logP:** Ligand A (0.927) is slightly below the optimal 1-3 range, potentially hindering permeability. Ligand B (3.062) is within the optimal range.

**H-Bond Donors/Acceptors:** Ligand A has 1 HBD and 4 HBA, while Ligand B has 0 HBD and 2 HBA. Both are within acceptable limits (<=5 HBD and <=10 HBA).

**QED:** Both ligands have reasonable QED scores (0.841 and 0.743), suggesting good drug-like properties.

**DILI:** Ligand A (25.79%) has a much lower DILI risk than Ligand B (11.71%). This is a significant advantage for A.

**BBB:** Ligand B (89.80%) has a significantly higher BBB penetration score than Ligand A (65.49%). This is *critical* for a CNS target like DRD2.

**Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and suggests poor permeability. However, the scale is not specified, so it's hard to interpret.

**Aqueous Solubility:** Both ligands have negative solubility values, which is also unusual.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.497 and 0.666).

**Microsomal Clearance:** Ligand A (9.30) has lower microsomal clearance than Ligand B (57.89), indicating better metabolic stability.

**In vitro Half-Life:** Ligand A (-44.91) has a much longer in vitro half-life than Ligand B (1.74).

**P-gp Efflux:** Ligand A (0.011) has much lower P-gp efflux liability than Ligand B (0.254), which is favorable for CNS penetration.

**Binding Affinity:** Ligand B (-8.8 kcal/mol) has a slightly better binding affinity than Ligand A (-7.9 kcal/mol), a difference of 0.9 kcal/mol.

**Overall Assessment:**

Ligand B excels in BBB penetration and binding affinity, both crucial for a CNS GPCR target. However, it suffers from higher DILI risk, higher P-gp efflux, and faster clearance. Ligand A has a better safety profile (DILI), better metabolic stability (clearance, half-life), and lower P-gp efflux. The difference in binding affinity (0.9 kcal/mol) is not substantial enough to outweigh the significant ADME advantages of Ligand A, especially considering the importance of CNS penetration and safety for a DRD2 ligand.

Output:
1
2025-04-17 06:35:19,428 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (385.917 Da) is slightly higher than Ligand B (352.475 Da), but both are acceptable.

**TPSA:** Both ligands have TPSA values below the 90 A^2 threshold desirable for CNS targets. Ligand A (80.32 A^2) is slightly higher than Ligand B (67.87 A^2), making Ligand B more favorable for brain penetration.

**logP:** Both ligands have logP values within the optimal range (1-3). Ligand A (2.792) is slightly higher than Ligand B (1.891), but both are acceptable.

**H-Bond Donors/Acceptors:** Ligand A has 2 HBD and 5 HBA, while Ligand B has 1 HBD and 4 HBA. Both are within the acceptable limits (<=5 HBD and <=10 HBA).

**QED:** Both ligands have QED values above 0.5, indicating good drug-like properties. Ligand B (0.767) is slightly better than Ligand A (0.64).

**DILI:** Ligand A (43.622) has a slightly higher DILI risk than Ligand B (31.989), but both are below the concerning threshold of 60.

**BBB:** Both ligands have good BBB penetration (Ligand A: 68.864, Ligand B: 68.786). While ideally >70, these are reasonably good and similar.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values, which is unusual and suggests poor permeability. However, the scale is not specified, so it's difficult to interpret.

**Aqueous Solubility:** Both ligands have negative solubility values, which is also unusual and suggests poor solubility. Again, the scale is not specified.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (Ligand A: 0.249, Ligand B: 0.192).

**Microsomal Clearance:** Ligand B (31.256 mL/min/kg) has a lower microsomal clearance than Ligand A (48.457 mL/min/kg), indicating better metabolic stability.

**In vitro Half-Life:** Ligand B (12.691 hours) has a longer in vitro half-life than Ligand A (20.467 hours). This is unexpected, as lower clearance should correlate with longer half-life.

**P-gp Efflux:** Ligand B (0.036) has significantly lower P-gp efflux liability than Ligand A (0.116), which is a major advantage for CNS penetration.

**Binding Affinity:** Ligand A (-7.7 kcal/mol) has a significantly stronger binding affinity than Ligand B (-0.0 kcal/mol). This is a crucial factor, and the 7.7 kcal/mol advantage is substantial.

**Overall Assessment:**

Despite Ligand B having slightly better ADME properties (lower TPSA, lower DILI, lower P-gp efflux, lower Cl_mic, longer t1/2), the significantly stronger binding affinity of Ligand A (-7.7 vs -0.0 kcal/mol) outweighs these minor differences. A strong binding affinity is paramount for GPCR ligands, and a 7.7 kcal/mol difference is a large advantage. The unusual negative values for Caco-2 and Solubility are concerning for both, but the potency difference is so large that it's likely these can be addressed through further optimization.

Output:
1
2025-04-17 06:35:19,428 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (343.431 and 391.295 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Both ligands have TPSA values (76.18 and 75.71) below the 90 A^2 threshold desirable for CNS targets, which is excellent.

**3. logP:** Both ligands have logP values (2.378 and 2.019) within the optimal 1-3 range.

**4. H-Bond Donors:** Both ligands have 1 HBD, which is well within the acceptable limit of <=5.

**5. H-Bond Acceptors:** Ligand A has 6 HBAs, and Ligand B has 4 HBAs, both are within the acceptable limit of <=10.

**6. QED:** Ligand A (0.922) has a significantly higher QED than Ligand B (0.588), suggesting a more drug-like profile.

**7. DILI:** Both ligands have low DILI risk (35.595 and 31.563 percentiles), which is favorable.

**8. BBB:** Ligand B (65.801 percentile) has a considerably better BBB penetration score than Ligand A (50.523 percentile). This is a critical factor for a CNS target like DRD2.

**9. Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and suggests a potential issue with the data or modeling. However, we will proceed assuming these represent low permeability.

**10. Aqueous Solubility:** Both ligands have negative solubility values, which is also unusual. This suggests poor aqueous solubility.

**11. hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.148 and 0.261 percentiles), which is excellent.

**12. Microsomal Clearance:** Ligand A (-6.197 mL/min/kg) has a much lower (better) microsomal clearance than Ligand B (20.659 mL/min/kg), indicating greater metabolic stability.

**13. In vitro Half-Life:** Ligand A (15.805 hours) has a longer half-life than Ligand B (-11.934 hours). The negative value for Ligand B is concerning and likely indicates a modeling artifact.

**14. P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.025 and 0.056 percentiles), which is favorable for CNS penetration.

**15. Binding Affinity:** Both ligands have excellent binding affinities (-8.0 and -8.4 kcal/mol). Ligand B is slightly better (-8.4 kcal/mol).

**Overall Assessment:**

While Ligand B has a better BBB score and slightly better binding affinity, Ligand A is superior in most other crucial ADME properties. Specifically, Ligand A has a much higher QED, significantly better metabolic stability (lower Cl_mic, longer t1/2), and more reasonable solubility/permeability values (even if both are negative). The negative values for solubility and Caco-2 are concerning for both, but the other advantages of Ligand A outweigh the slight benefit of Ligand B's BBB penetration. Given the GPCR-specific emphasis on BBB, logP, Pgp, TPSA, and affinity, and considering the overall balance of properties, Ligand A is the more promising candidate.

Output:
1
2025-04-17 06:35:19,429 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B based on the provided guidelines, prioritizing GPCR-specific properties (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (354.466 and 367.534 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (58.64) is significantly better than Ligand B (38.13). For CNS targets, we want TPSA <= 90, both are well within this range, but A is closer to the optimal value.

**logP:** Both ligands have good logP values (2.749 and 3.761), falling within the 1-3 range. Ligand B is slightly higher, which *could* indicate potential off-target effects, but isn't a major concern.

**H-Bond Donors/Acceptors:** Ligand A has 1 HBD and 3 HBA, while Ligand B has 0 HBD and 4 HBA. Both are within acceptable limits (<=5 HBD and <=10 HBA).

**QED:** Both ligands have good QED scores (0.565 and 0.736), indicating good drug-like properties. Ligand B is slightly better.

**DILI:** Both ligands have low DILI risk (22.024 and 28.499), well below the 40 threshold.

**BBB:** Both ligands exhibit excellent BBB penetration (88.135 and 92.323), exceeding the desirable >70 threshold for CNS targets. Ligand B is slightly better.

**Caco-2 Permeability:** Both have negative Caco-2 values (-4.622 and -5.017). This is unusual and suggests poor permeability. However, these values are on a scale where negative values are possible, and the absolute magnitude is important. They are relatively similar.

**Aqueous Solubility:** Both ligands have very poor aqueous solubility (-2.273 and -3.808). This is a significant drawback for both.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.383 and 0.696).

**Microsomal Clearance:** Ligand A (45.043) has lower microsomal clearance than Ligand B (86.683), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (-3.827) has a shorter in vitro half-life than Ligand B (-13.48). This is a negative for Ligand A.

**P-gp Efflux:** Ligand A (0.218) has lower P-gp efflux than Ligand B (0.606), which is favorable for CNS exposure.

**Binding Affinity:** Ligand B (-7.2 kcal/mol) has significantly stronger binding affinity than Ligand A (-0.0 kcal/mol). This is a crucial advantage, potentially outweighing some of the ADME drawbacks.

**Overall Assessment:**

Ligand B is the stronger candidate. The significantly improved binding affinity (-7.2 vs -0.0 kcal/mol) is the most important factor. While Ligand A has better metabolic stability (lower Cl_mic) and P-gp efflux, the large difference in affinity is decisive. Both ligands have poor solubility and Caco-2 permeability, which would need to be addressed during optimization. The slightly better BBB and QED of Ligand B are also beneficial.

Output:
1
2025-04-17 06:35:19,429 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 drug candidates, considering the provided guidelines and GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (362.455 Da) is slightly lower, which could be advantageous for permeability. Ligand B (412.284 Da) is still acceptable.

**TPSA:** Both ligands have TPSA values below the 140 A^2 threshold for oral absorption, but are above the stricter 90 A^2 for CNS targets. Ligand A (87.58 A^2) is better than Ligand B (91.76 A^2) in this regard, suggesting potentially better CNS penetration.

**logP:** Both ligands have optimal logP values (between 1 and 3). Ligand A (1.781) is slightly higher than Ligand B (1.077), but both are within the desired range.

**H-Bond Donors/Acceptors:** Both ligands have acceptable HBD (2) and HBA (6/5) counts, falling within the guidelines.

**QED:** Both ligands have QED values above 0.5, indicating good drug-like properties. Ligand A (0.784) is slightly better than Ligand B (0.654).

**DILI:** Ligand A (67.546) has a higher DILI risk than Ligand B (35.905). This is a significant drawback for Ligand A.

**BBB:** Both ligands have reasonable BBB penetration, but Ligand A (49.321) is slightly better than Ligand B (42.769). However, both are below the desirable >70 percentile for CNS targets.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values, which is unusual and suggests poor permeability. Ligand A (-5.01) is slightly better than Ligand B (-4.959).

**Aqueous Solubility:** Both ligands have negative solubility values, indicating poor aqueous solubility. This is a concern for both. Ligand A (-2.395) is slightly better than Ligand B (-2.325).

**hERG Inhibition:** Both ligands have low hERG inhibition risk, which is good. Ligand A (0.165) is slightly better than Ligand B (0.359).

**Microsomal Clearance:** Ligand A (11.41 mL/min/kg) has lower microsomal clearance than Ligand B (8.766 mL/min/kg), indicating better metabolic stability.

**In vitro Half-Life:** Ligand B (28.631 hours) has a significantly longer in vitro half-life than Ligand A (9.759 hours), which is a major advantage.

**P-gp Efflux:** Both ligands have low P-gp efflux liability, which is good. Ligand A (0.212) is slightly better than Ligand B (0.048).

**Binding Affinity:** Ligand A (-8.6 kcal/mol) has a significantly stronger binding affinity than Ligand B (-7.5 kcal/mol). This is a substantial advantage, potentially outweighing some of the ADME drawbacks. The difference is >1.5 kcal/mol.

**Overall Assessment:**

While Ligand A has a better binding affinity, lower TPSA, better metabolic stability, and slightly better BBB penetration and P-gp efflux, its significantly higher DILI risk is a major concern. Ligand B, despite its weaker affinity, exhibits a much lower DILI risk and a substantially longer half-life. For a CNS target like DRD2, a balance of properties is crucial. The stronger affinity of Ligand A is attractive, but the DILI risk is too high. The longer half-life of Ligand B is also a significant advantage for CNS drugs, reducing the dosing frequency.

Output:
1
2025-04-17 06:35:19,429 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (348.403 Da) is slightly lower, which is generally favorable for permeability.

**TPSA:** Ligand B (88.93) is better than Ligand A (102.31). Both are below 140, but for a CNS target like DRD2, we ideally want <90. Ligand B is closer to this target.

**logP:** Ligand B (1.678) is within the optimal range (1-3), while Ligand A (-0.668) is slightly below 1. This could hinder permeation for Ligand A.

**H-Bond Donors/Acceptors:** Ligand A has 2 HBD and 5 HBA, while Ligand B has 1 HBD and 7 HBA. Both are within acceptable limits, though Ligand A has a slightly more favorable profile.

**QED:** Both ligands have similar QED values (0.706 and 0.688), indicating good drug-likeness.

**DILI:** Ligand B (54.556) has a higher DILI risk than Ligand A (40.636), but both are below the concerning threshold of 60.

**BBB:** Ligand A (45.444) and Ligand B (52.074) are both below the desirable >70 for CNS targets. This is a significant drawback for both, but Ligand B is slightly better.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.187 and -5.246). This is unusual and suggests poor permeability.

**Aqueous Solubility:** Both ligands have negative solubility values (-1.833 and -3.031), suggesting poor aqueous solubility.

**hERG Inhibition:** Both ligands have low hERG inhibition liability (0.245 and 0.424).

**Microsomal Clearance:** Ligand A (-16.636) has a much lower (better) microsomal clearance than Ligand B (63.613), indicating greater metabolic stability.

**In vitro Half-Life:** Ligand A (16.686 hours) has a significantly longer half-life than Ligand B (9.989 hours).

**P-gp Efflux:** Ligand A (0.005) has much lower P-gp efflux liability than Ligand B (0.143), which is highly desirable for CNS penetration.

**Binding Affinity:** Ligand A (-8.2 kcal/mol) has a significantly stronger binding affinity than Ligand B (-6.6 kcal/mol). This is a substantial advantage.

**Overall Assessment:**

Despite both ligands having issues with BBB penetration, solubility, and Caco-2 permeability, Ligand A is the more promising candidate. Its significantly stronger binding affinity (-8.2 vs -6.6 kcal/mol) is a major advantage, and can potentially overcome some of the ADME deficiencies. Furthermore, Ligand A exhibits much better metabolic stability (lower Cl_mic), longer half-life, and lower P-gp efflux, all crucial for CNS drug development. While Ligand B has a slightly better TPSA, the other factors heavily favor Ligand A.

Output:
0
2025-04-17 06:35:19,429 - INFO - Okay, let's analyze these two ligands for their potential as DRD2 drug candidates. DRD2 is a GPCR in the CNS, so BBB penetration, logP, Pgp efflux, TPSA, and binding affinity are crucial.

**Ligand A:** [353.403, 92.18, 3.151, 2, 5, 0.71, 94.804, 22.993, -5.485, -3.171, 0.028, -3.565, -1.605, 0.023, -9.4]
**Ligand B:** [379.511, 90.98, 1.758, 2, 6, 0.682, 63.513, 35.324, -5.674, -2.116, 0.211, 15.973, -26.801, 0.05, -7.2]

**Step-by-step comparison:**

1. **MW:** Both are within the ideal range (200-500 Da). A (353.4) is slightly better.
2. **TPSA:** Both are reasonably good for CNS penetration (below 90 A<sup>2</sup>). B (90.98) is marginally better.
3. **logP:** A (3.151) is optimal, while B (1.758) is on the lower side, potentially impacting permeability.
4. **HBD:** Both have 2 HBD, which is acceptable.
5. **HBA:** A has 5 HBA, B has 6. Both are acceptable, but A is slightly preferred.
6. **QED:** Both are above 0.5, indicating good drug-likeness, but A (0.71) is better than B (0.682).
7. **DILI:** A (94.8%) has a very high DILI risk, which is a major concern. B (63.5%) is still elevated but significantly lower.
8. **BBB:** A (22.993%) has very poor predicted BBB penetration. B (35.324%) is better, but still not ideal (target >70%).
9. **Caco-2:** Both have negative Caco-2 values, which is unusual and suggests potential issues with the prediction method or the molecules themselves. This is difficult to interpret without further information.
10. **Solubility:** Both have negative solubility values, also unusual. Again, difficult to interpret.
11. **hERG:** A (0.028) has very low hERG risk. B (0.211) has a slightly higher, but still low, hERG risk.
12. **Cl_mic:** A (-3.565) has a negative clearance, which is not physically possible and indicates a problem with the prediction. B (15.973) is reasonable.
13. **t1/2:** A (-1.605) has a negative half-life, again indicating a prediction issue. B (-26.801) is also negative.
14. **Pgp:** A (0.023) has very low Pgp efflux, which is good for CNS penetration. B (0.05) is slightly higher.
15. **Affinity:** A (-9.4 kcal/mol) has significantly stronger binding affinity than B (-7.2 kcal/mol). This is a substantial advantage.

**Overall Assessment:**

Ligand A has a much better binding affinity and lower Pgp efflux, but suffers from a very high DILI risk, poor BBB penetration, and impossible predicted clearance and half-life values. Ligand B has a better safety profile (lower DILI), better predicted metabolic stability, and a more reasonable (though still not ideal) BBB prediction, but its binding affinity is considerably weaker and logP is lower.

The negative values for Caco-2, solubility, clearance, and half-life for both compounds raise significant concerns about the reliability of the predictions. However, given the importance of binding affinity for DRD2, and the fact that A's affinity is *much* stronger, I would still lean towards **Ligand A** *if* the DILI and ADME issues could be addressed through structural modifications. The large affinity difference could outweigh some ADME drawbacks. However, the DILI risk is a major red flag.

1
2025-04-17 06:35:19,430 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (351.447 and 343.387 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (101.73) is better than Ligand B (120) as it's closer to the <90 desired for CNS targets. Ligand B is still acceptable, but A has an advantage.

**logP:** Ligand A (1.259) is within the optimal 1-3 range. Ligand B (0.511) is slightly below 1, which *could* indicate potential permeability issues, though not critically.

**H-Bond Donors/Acceptors:** Ligand A (HBD=2, HBA=4) and Ligand B (HBD=4, HBA=5) are both within acceptable limits (<=5 HBD and <=10 HBA).

**QED:** Both ligands have reasonable QED values (0.674 and 0.584), indicating good drug-like properties.

**DILI:** Ligand A (32.61) has a significantly lower DILI risk than Ligand B (66.421). This is a substantial advantage for Ligand A.

**BBB:** This is critical for a CNS target like DRD2. Ligand A (58.356) is better than Ligand B (24.738), though both are below the desirable >70. However, A is considerably better.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.558 and -5.487), which is unusual and suggests poor permeability. This is a concern for both, but doesn't necessarily disqualify them if other properties are strong.

**Aqueous Solubility:** Both ligands have negative solubility values (-2.767 and -3.094), indicating poor aqueous solubility. This is a potential formulation challenge for both.

**hERG Inhibition:** Both ligands have very low hERG risk (0.211 and 0.167), which is excellent.

**Microsomal Clearance:** Ligand A (10.182) has a higher (worse) microsomal clearance than Ligand B (2.323). This suggests Ligand B is more metabolically stable.

**In vitro Half-Life:** Ligand B (-15.804) has a *very* negative half-life, which is concerning and likely indicates rapid degradation. Ligand A (-0.697) is much better.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.037 and 0.019), which is favorable for CNS penetration.

**Binding Affinity:** Both ligands have similar, strong binding affinities (-8.0 and -8.3 kcal/mol). The difference is negligible.

**Overall Assessment:**

Ligand A is the stronger candidate. While both have issues with Caco-2 and solubility, Ligand A excels in critical areas for a CNS GPCR target: significantly lower DILI risk, much better BBB penetration, and a more reasonable in vitro half-life. Ligand B's very poor half-life is a major drawback, and its lower BBB penetration is also concerning. The slightly better metabolic stability of Ligand B is outweighed by these factors.

Output:
0
2025-04-17 06:35:19,430 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (379.869 and 353.419 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (92.18) is better than Ligand B (105.76). For CNS targets, we want TPSA <= 90, so Ligand A is closer to this threshold.

**logP:** Ligand A (2.81) is optimal (1-3), while Ligand B (-0.528) is significantly lower, potentially hindering permeation. This is a major strike against Ligand B.

**H-Bond Donors/Acceptors:** Ligand A (HBD=2, HBA=5) and Ligand B (HBD=3, HBA=5) are both acceptable.

**QED:** Both ligands have good QED scores (0.514 and 0.595, respectively), indicating drug-like properties.

**DILI:** Ligand A (71.539) has a higher DILI risk than Ligand B (47.266), but both are below the concerning threshold of 60.

**BBB:** Ligand B (46.762) has a better BBB penetration percentile than Ligand A (32.765). However, both are below the desirable >70 for CNS targets.

**Caco-2 Permeability:** Both have negative Caco-2 values (-5.849 and -5.539), which is unusual and suggests poor permeability. This is a concern for both.

**Aqueous Solubility:** Both ligands have negative solubility values (-3 and -1.652), indicating very poor aqueous solubility. This is a significant drawback for both.

**hERG:** Both ligands have very low hERG inhibition liability (0.074 and 0.075).

**Microsomal Clearance:** Ligand B (-9.495) has a negative clearance, which is not physically possible. This is a red flag and suggests an issue with the data or the prediction method. Ligand A (16.139) is more reasonable.

**In vitro Half-Life:** Ligand B (19.498) has a longer half-life than Ligand A (-1.961).

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.054 and 0.009).

**Binding Affinity:** Both ligands have excellent binding affinity (-8.1 and -8.0 kcal/mol), with Ligand A being slightly better. The affinity difference is small and likely not decisive.

**Overall Assessment:**

Ligand B has a better BBB and in vitro half-life, but its significantly negative logP and the nonsensical negative microsomal clearance are major concerns. The poor logP will severely limit its ability to cross cell membranes. The negative clearance is a data quality issue. Ligand A, while not perfect, has a more reasonable profile overall. Its logP is within the optimal range, and its clearance is positive. The TPSA is slightly high, but the affinity is very good. The poor solubility and Caco-2 permeability are drawbacks for both, but the logP issue with Ligand B is more critical for a CNS target.

Output:
1
2025-04-17 06:35:19,430 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (384.479) is slightly higher than Ligand B (362.499), but both are acceptable.

**TPSA:** Ligand A (100.62) is borderline for CNS penetration, being above the preferred 90. Ligand B (71.25) is well within the ideal range for CNS targets. This is a significant advantage for Ligand B.

**logP:** Ligand A (0.314) is quite low, potentially hindering membrane permeability. Ligand B (2.536) is within the optimal range (1-3). This is a clear advantage for Ligand B.

**H-Bond Donors/Acceptors:** Both ligands have 1 HBD and a reasonable number of HBAs (5 and 6 respectively). No major concerns here for either.

**QED:** Both ligands have good QED scores (0.791 and 0.822), indicating good drug-like properties.

**DILI:** Ligand A (78.325) has a higher DILI risk than Ligand B (39.201). This is a concern for Ligand A.

**BBB:** Both ligands have similar BBB penetration (53.936 and 54.362), which is acceptable but not ideal (>70 is preferred).

**Caco-2 Permeability:** Both ligands have negative Caco-2 values, which is unusual and suggests poor permeability. However, the scale is not specified, so it's hard to interpret.

**Aqueous Solubility:** Both ligands have negative solubility values, which is also unusual and suggests poor solubility. Again, the scale is not specified.

**hERG Inhibition:** Both ligands show low hERG inhibition liability (0.165 and 0.233), which is good.

**Microsomal Clearance:** Ligand A (16.792) has lower microsomal clearance than Ligand B (34.953), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (56.417) has a longer in vitro half-life than Ligand B (8.554), which is desirable.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.084 and 0.128), which is good for CNS penetration.

**Binding Affinity:** Ligand A (-9.5 kcal/mol) has a significantly stronger binding affinity than Ligand B (-7.8 kcal/mol). This is a substantial advantage for Ligand A, potentially outweighing some of its ADME drawbacks.

**Overall Assessment:**

Ligand B has better physicochemical properties (logP, TPSA) for CNS penetration and a lower DILI risk. However, Ligand A boasts a significantly stronger binding affinity. Given that this is a GPCR target in the CNS, the binding affinity is paramount. While Ligand A's low logP is a concern, the strong binding could compensate. The similar BBB values suggest that the lower logP might not completely negate CNS exposure. The longer half-life and lower clearance of Ligand A are also beneficial.

Output:
1
2025-04-17 06:35:19,430 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (350.459 and 354.466 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (87.66) is better than Ligand B (49.85) as it is closer to the ideal range for CNS targets (<=90). Ligand B is quite low, which *could* indicate reduced hydrogen bonding and potentially lower specificity.

**3. logP:** Both ligands have acceptable logP values (1.118 and 2.557), falling within the optimal 1-3 range. Ligand B is slightly higher, potentially leading to some solubility concerns, but still within acceptable limits.

**4. H-Bond Donors:** Ligand A has 3 HBD, which is acceptable. Ligand B has 0, which is also acceptable but might impact target interactions.

**5. H-Bond Acceptors:** Ligand A has 4 HBA, acceptable. Ligand B has 3, also acceptable.

**6. QED:** Ligand A (0.642) has a better QED score than Ligand B (0.497), indicating a more drug-like profile.

**7. DILI:** Ligand A (11.361) has a significantly lower DILI risk than Ligand B (8.298), which is a major advantage.

**8. BBB:** Ligand B (91.508) has a *much* higher BBB penetration percentile than Ligand A (34.238). This is a critical factor for a CNS target like DRD2.

**9. Caco-2 Permeability:** Ligand A (-5.235) has poor Caco-2 permeability, which is a concern. Ligand B (-4.47) is also poor, but slightly better.

**10. Aqueous Solubility:** Both ligands have very poor aqueous solubility (-1.66 and -2.15 respectively). This is a significant drawback for both, but might be manageable with formulation strategies.

**11. hERG Inhibition:** Ligand A (0.194) has a lower hERG inhibition risk than Ligand B (0.618), which is favorable.

**12. Microsomal Clearance:** Ligand B (26.994) has lower microsomal clearance than Ligand A (2.398), suggesting better metabolic stability.

**13. In vitro Half-Life:** Ligand B (3.237) has a slightly longer in vitro half-life than Ligand A (32.277). This is a positive attribute.

**14. P-gp Efflux:** Ligand A (0.02) has a much lower P-gp efflux liability than Ligand B (0.128), which is beneficial for CNS penetration.

**15. Binding Affinity:** Ligand A (-8.4 kcal/mol) has a significantly stronger binding affinity than Ligand B (-7.3 kcal/mol). This is a substantial advantage, potentially outweighing some of the ADME drawbacks.

**Overall Assessment:**

Ligand A has superior binding affinity, lower DILI risk, lower hERG risk, and lower P-gp efflux. However, Ligand B has a much better BBB penetration and slightly better metabolic stability. The strong binding affinity of Ligand A is a significant advantage for GPCR targets. While its BBB penetration is lower, the strong binding *could* compensate for that, and the lower P-gp efflux will help. The poor solubility and Caco-2 permeability are concerns for both, but formulation strategies could be explored. Given the importance of potency for GPCRs, and the significant difference in binding affinity, Ligand A is the more promising candidate.

Output:
0
2025-04-17 06:35:19,430 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (352.385 and 352.331 Da) fall comfortably within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (101.13) is higher than the preferred <90 for CNS targets, but not drastically so. Ligand B (32.34) is excellent, well below 90, suggesting better potential for brain penetration.

**3. logP:** Both ligands have good logP values (A: 1.995, B: 3.247), falling within the optimal 1-3 range.

**4. H-Bond Donors:** Ligand A (3) is acceptable, while Ligand B (1) is even better, minimizing potential permeability issues.

**5. H-Bond Acceptors:** Ligand A (5) is acceptable, Ligand B (2) is even better.

**6. QED:** Both ligands have reasonable QED values (A: 0.772, B: 0.677), indicating good drug-like properties.

**7. DILI:** Ligand A (61.962) has a higher DILI risk than Ligand B (49.011), though both are acceptable.

**8. BBB:** Ligand B (89.608) has a significantly higher BBB percentile than Ligand A (74.641), a crucial advantage for a CNS target like DRD2.

**9. Caco-2:** Both ligands have negative Caco-2 values, which is unusual and suggests a potential issue with the data or modeling. However, the values are close enough that this is unlikely to be a deciding factor.

**10. Solubility:** Both ligands have negative solubility values, which is unusual and suggests a potential issue with the data or modeling. However, the values are close enough that this is unlikely to be a deciding factor.

**11. hERG:** Ligand A (0.416) has a slightly lower hERG risk than Ligand B (0.939), which is preferable.

**12. Cl_mic:** Ligand A (-4.812) has a lower (better) microsomal clearance than Ligand B (-5.201), indicating better metabolic stability.

**13. t1/2:** Ligand A (10.88) has a longer half-life than Ligand B (3.303), which is generally desirable.

**14. Pgp:** Ligand A (0.03) has a much lower P-gp efflux liability than Ligand B (0.5), meaning it's less likely to be pumped out of the brain, enhancing CNS exposure.

**15. Binding Affinity:** Ligand B (-10.1 kcal/mol) has a significantly stronger binding affinity than Ligand A (-8.9 kcal/mol). This >1.5 kcal/mol difference is a substantial advantage, potentially outweighing some of the ADME drawbacks of Ligand B.

**Overall Assessment:**

While Ligand A has better metabolic stability (Cl_mic, t1/2) and lower Pgp efflux, Ligand B excels in key areas for a CNS-targeting GPCR: significantly higher BBB penetration, lower TPSA, and, most importantly, a much stronger binding affinity. The stronger binding affinity of Ligand B is a critical factor. The slightly higher hERG risk and lower metabolic stability are less concerning given the potency advantage and improved brain penetration.

Output:
1
2025-04-17 06:35:19,431 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (351.451 and 383.279 Da) fall within the ideal 200-500 Da range.

**TPSA:** Both ligands (91.56 and 92.08) are close to the 90 A^2 threshold for CNS targets, which is acceptable.

**logP:** Ligand A (0.94) is slightly below the optimal 1-3 range, potentially hindering permeability. Ligand B (2.741) is well within the optimal range.

**H-Bond Donors/Acceptors:** Ligand A has 1 HBD and 6 HBA, while Ligand B has 2 HBD and 3 HBA. Both are within acceptable limits (<=5 HBD and <=10 HBA).

**QED:** Ligand A (0.823) has a better QED score than Ligand B (0.569), indicating a more drug-like profile.

**DILI:** Ligand A (55.991) has a slightly higher DILI risk than Ligand B (47.926), but both are below the concerning threshold of 60.

**BBB:** Ligand B (73.75) has a significantly better BBB penetration percentile than Ligand A (41.218). This is a crucial advantage for a CNS target like DRD2.

**Caco-2 Permeability:** Ligand A (-4.715) has a worse Caco-2 permeability than Ligand B (-5.509).

**Aqueous Solubility:** Both ligands have very poor aqueous solubility (-2.171 and -3.275 respectively). This is a concern for both, but might be mitigated with formulation strategies.

**hERG Inhibition:** Both ligands show low hERG inhibition risk (0.273 and 0.492).

**Microsomal Clearance:** Ligand B (16.132) has a significantly lower microsomal clearance than Ligand A (45.118), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (-13.353) has a worse in vitro half-life than Ligand B (-5.237).

**P-gp Efflux:** Ligand A (0.134) has a lower P-gp efflux liability than Ligand B (0.046), which is favorable for CNS penetration.

**Binding Affinity:** Ligand B (-7.4 kcal/mol) has a slightly better binding affinity than Ligand A (-7.8 kcal/mol). While the difference is small, it's still a positive for Ligand B.

**Overall Assessment:**

Ligand B is the more promising candidate. While Ligand A has a better QED and slightly lower P-gp efflux, Ligand B excels in the critical areas for a CNS-targeting GPCR ligand: significantly better BBB penetration, lower microsomal clearance (better metabolic stability), and a slightly better binding affinity. The logP value for Ligand B is also more optimal. The solubility is a concern for both, but the other advantages of Ligand B outweigh this drawback.

Output:
1
2025-04-17 06:35:19,431 - INFO - Batch 294 complete. Total preferences: 4704
2025-04-17 06:35:19,431 - INFO - Processing batch 295/512...
2025-04-17 06:36:04,536 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (346.35 and 357.49 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (123.22) is slightly above the preferred <90 for CNS targets, but still reasonable. Ligand B (90.55) is excellent, falling right within the desired range.

**logP:** Ligand A (-1.105) is a bit low, potentially hindering membrane permeability. Ligand B (2.682) is within the optimal 1-3 range. This is a significant advantage for Ligand B.

**H-Bond Donors/Acceptors:** Ligand A (1 HBD, 8 HBA) is favorable. Ligand B (4 HBD, 7 HBA) is also acceptable, although slightly higher in HBD count.

**QED:** Both ligands have reasonable QED scores (0.704 and 0.561), indicating good drug-like properties.

**DILI:** Both ligands have elevated DILI risk (64.79 and 77.39), but are still below the concerning >60 threshold.

**BBB:** Ligand A (38.23) has a poor BBB percentile, making CNS penetration unlikely. Ligand B (54.91) is better, but still not ideal (aim for >70).

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.462 and -5.828), which is unusual and suggests poor permeability. These values are likely errors or indicate very poor absorption.

**Aqueous Solubility:** Both ligands have negative solubility values (-0.913 and -2.67), which is also unusual and suggests very poor solubility. These values are likely errors or indicate very poor solubility.

**hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.018 and 0.789).

**Microsomal Clearance:** Ligand A (-15.33) suggests very low clearance and high metabolic stability, a significant advantage. Ligand B (14.84) indicates faster clearance.

**In vitro Half-Life:** Ligand A (3.02) has a short half-life. Ligand B (-2.66) has a negative half-life, which is not possible.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.007 and 0.049), which is favorable for CNS penetration.

**Binding Affinity:** Both ligands have the same binding affinity (-8.5 kcal/mol), which is excellent.

**Overall Assessment:**

Despite the equal binding affinity, Ligand B is the more promising candidate. Its logP is optimal, TPSA is excellent for CNS penetration, and P-gp efflux is low. Ligand A suffers from a low logP and, critically, a very poor BBB percentile. The negative Caco-2 and solubility values for both are concerning, but the other properties of Ligand B make it preferable. The negative half-life for Ligand B is a clear error.

Output:
1
2025-04-17 06:36:04,537 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (383.583 Da) is slightly higher than Ligand B (347.459 Da), but both are acceptable.

**TPSA:** Ligand A (62.3) is better than Ligand B (69.72). For CNS targets, we want TPSA <= 90, both are well within this range, but lower is preferable.

**logP:** Ligand A (2.962) is optimal (1-3). Ligand B (1.174) is on the lower end, potentially hindering permeability.

**H-Bond Donors/Acceptors:** Both ligands have 1 HBD, which is good. Ligand A has 5 HBA, and Ligand B has 3 HBA. Both are within acceptable limits (<=10).

**QED:** Both ligands have good QED scores (A: 0.701, B: 0.779), indicating good drug-like properties.

**DILI:** Ligand A (33.424) has a slightly higher DILI risk than Ligand B (21.442), but both are below the 40 threshold and considered good.

**BBB:** Both ligands have good BBB penetration (A: 61.729, B: 63.629), but ideally, we want >70 for CNS targets. Ligand B is marginally better.

**Caco-2 Permeability:** Both have negative values, which is unusual and suggests poor permeability. Ligand A (-5.37) is worse than Ligand B (-4.974).

**Aqueous Solubility:** Both have negative values, indicating poor solubility. Ligand A (-2.418) is worse than Ligand B (-1.828).

**hERG Inhibition:** Both have very low hERG inhibition risk (A: 0.578, B: 0.1), which is excellent.

**Microsomal Clearance:** Ligand A (51.729) has higher clearance than Ligand B (33.043), meaning it's less metabolically stable.

**In vitro Half-Life:** Ligand B (7.678 hours) has a significantly longer half-life than Ligand A (-0.673 hours). This is a major advantage for Ligand B.

**P-gp Efflux:** Ligand A (0.169) has higher P-gp efflux than Ligand B (0.039), meaning less CNS exposure.

**Binding Affinity:** Ligand A (-7.1 kcal/mol) has a slightly better binding affinity than Ligand B (-0.0 kcal/mol). This is a significant advantage, as a >1.5 kcal/mol difference can outweigh other drawbacks.

**Overall Assessment:**

Ligand A has a better binding affinity, but suffers from worse Caco-2 permeability, solubility, metabolic stability, P-gp efflux, and a shorter half-life. Ligand B has better ADME properties (BBB, solubility, metabolic stability, half-life, P-gp efflux), but weaker binding affinity. Given the importance of CNS penetration for a DRD2 ligand, and the substantial difference in half-life and P-gp efflux, Ligand B appears to be the more promising candidate. The affinity difference, while present, is not large enough to overcome the significant ADME advantages of Ligand B.

Output:
1
2025-04-17 06:36:04,537 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (348.45 & 368.50 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Both ligands (87.46 & 89.87) are below the 90 A^2 threshold for CNS targets, which is excellent.

**3. logP:** Ligand A (0.873) is a bit low, potentially hindering permeability. Ligand B (1.484) is better, falling within the optimal 1-3 range.

**4. H-Bond Donors:** Ligand A (2) and Ligand B (3) are both acceptable, below the 5 limit.

**5. H-Bond Acceptors:** Both ligands (5) are within the acceptable limit of 10.

**6. QED:** Both ligands have similar QED values (0.683 and 0.68), indicating good drug-likeness.

**7. DILI:** Ligand A (18.73) has a significantly lower DILI risk than Ligand B (31.25). This is a substantial advantage.

**8. BBB:** Ligand B (49.83) has a better BBB penetration percentile than Ligand A (39.71), though neither is above the highly desirable 70. This is a key consideration for a CNS target.

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.034 and -5.361). This is unusual and suggests poor permeability. However, these values are on a log scale and the negative values may not be directly comparable.

**10. Aqueous Solubility:** Both ligands have negative solubility values (-1.544 and -2.322), suggesting poor aqueous solubility.

**11. hERG Inhibition:** Both ligands have low hERG inhibition risk (0.31 and 0.409).

**12. Microsomal Clearance:** Ligand A (0.589) has significantly lower microsomal clearance than Ligand B (0.853), indicating better metabolic stability.

**13. In vitro Half-Life:** Ligand A (-10.032) has a much longer in vitro half-life than Ligand B (9.094).

**14. P-gp Efflux:** Both ligands have low P-gp efflux liability (0.066 and 0.106).

**15. Binding Affinity:** Ligand B (-7.9 kcal/mol) has a slightly better binding affinity than Ligand A (-8.4 kcal/mol). While the difference is small, it's within the range where it could outweigh some ADME drawbacks.

**Overall Assessment:**

Ligand A excels in metabolic stability (lower Cl_mic, longer t1/2), DILI risk, and has a slightly better binding affinity. However, Ligand B shows better BBB penetration and a slightly better logP. The negative Caco-2 and solubility values are concerning for both. Given the CNS target (DRD2), BBB is critical. While Ligand B's BBB is not ideal, it's significantly better than Ligand A's. The slightly stronger binding affinity of Ligand B, combined with its better BBB, makes it the more promising candidate, despite the higher DILI risk. The DILI risk could potentially be addressed through further structural modifications.

Output:
1
2025-04-17 06:36:04,537 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (354.33 and 367.49 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (51.66) is significantly better than Ligand B (69.22). For CNS targets, we want TPSA <= 90, and A is much closer to the ideal <=60. B is pushing the upper limit.

**logP:** Both ligands have good logP values (3.40 and 3.23), falling within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A (0 HBD, 4 HBA) is slightly better than Ligand B (2 HBD, 4 HBA). Both are within acceptable limits.

**QED:** Both ligands have similar QED scores (0.746 and 0.715), indicating good drug-likeness.

**DILI:** Ligand A (63.09) has a higher DILI risk than Ligand B (26.33). This is a significant drawback for A.

**BBB:** Ligand A (83.25) has a substantially better BBB penetration score than Ligand B (54.79). This is a critical advantage for a CNS target like DRD2.

**Caco-2 Permeability:** Ligand A (-4.424) shows poor Caco-2 permeability, while Ligand B (-5.296) is also poor, but slightly better than A.

**Aqueous Solubility:** Ligand A (-3.653) has slightly better aqueous solubility than Ligand B (-2.332), though both are quite poor.

**hERG:** Both ligands have similar, low hERG inhibition liability (0.783 and 0.782).

**Microsomal Clearance:** Ligand A (54.09) has higher microsomal clearance than Ligand B (33.36), suggesting lower metabolic stability for A.

**In vitro Half-Life:** Ligand B (-2.772) has a negative half-life, which is not possible. This is a major red flag and suggests an issue with the data or the compound itself. Ligand A (5.781) has a reasonable half-life.

**P-gp Efflux:** Both ligands have similar P-gp efflux liability (0.408 and 0.576).

**Binding Affinity:** Ligand A (-7.9 kcal/mol) has a slightly better binding affinity than Ligand B (-7.0 kcal/mol). This 0.9 kcal/mol difference is significant, potentially outweighing some ADME drawbacks.

**Overall Assessment:**

Ligand A excels in BBB penetration and binding affinity, which are crucial for a CNS GPCR target. However, it has concerning DILI risk, poor Caco-2 permeability, and higher metabolic clearance. Ligand B has a much lower DILI risk, slightly better Caco-2 permeability, and lower clearance, but suffers from significantly worse BBB penetration and a lower binding affinity. The negative in vitro half-life for Ligand B is a critical flaw.

Given the importance of CNS penetration for DRD2, and the substantial difference in BBB scores, Ligand A is the more promising candidate *despite* its drawbacks. The slightly better affinity further supports this. The DILI risk and permeability could potentially be addressed through further optimization. The negative half-life of B makes it a non-starter.

Output:
0
2025-04-17 06:36:04,538 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (348.487 and 346.475 Da) fall comfortably within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (58.64) is significantly better than Ligand B (67.23). For CNS targets, we want TPSA <= 90, and ideally closer to 60. Ligand A is much closer to the ideal range.

**3. logP:** Both ligands have good logP values (2.654 and 2.306), falling within the optimal 1-3 range.

**4. H-Bond Donors:** Both have 1 HBD, which is acceptable.

**5. H-Bond Acceptors:** Ligand A has 3 HBAs, and Ligand B has 4. Both are within the acceptable limit of <= 10.

**6. QED:** Both ligands have good QED scores (0.686 and 0.785), indicating good drug-like properties.

**7. DILI:** Ligand A (16.906) has a much lower DILI risk than Ligand B (21.753). Both are reasonably low, but A is preferable.

**8. BBB:** Ligand B (79.217) has a significantly higher BBB penetration percentile than Ligand A (64.482). This is a *critical* factor for a CNS target like DRD2. A value >70 is desirable, and B is closer to this threshold.

**9. Caco-2 Permeability:** Both have negative Caco-2 values (-4.888 and -4.972), which is unusual and suggests poor permeability. This is a concern for both.

**10. Aqueous Solubility:** Both have negative solubility values (-2.958 and -2.288), indicating very poor aqueous solubility. This is a significant drawback for both.

**11. hERG Inhibition:** Both have low hERG inhibition risk (0.366 and 0.612).

**12. Microsomal Clearance:** Ligand A (42.468) has a lower microsomal clearance than Ligand B (50.806), suggesting better metabolic stability.

**13. In vitro Half-Life:** Ligand B (-23.876) has a much longer in vitro half-life than Ligand A (6.926). This is a significant advantage for B.

**14. P-gp Efflux:** Both have low P-gp efflux liability (0.147 and 0.262).

**15. Binding Affinity:** Ligand A (-8.3 kcal/mol) has a slightly better binding affinity than Ligand B (-7.8 kcal/mol). While the difference is not huge, it's a positive for A.

**Overall Assessment:**

The key trade-offs are BBB penetration (B is better) vs. TPSA and DILI (A is better). Given that this is a CNS target (DRD2), BBB penetration is paramount. While Ligand A has a slightly better affinity and lower DILI, the significantly higher BBB score for Ligand B outweighs these advantages. The poor Caco-2 and solubility are concerning for both, but can potentially be addressed with formulation strategies. The longer half-life of Ligand B is also a significant benefit.

Output:
1
2025-04-17 06:36:04,538 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight (MW):** Both ligands (347.5 & 362.4 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (56.15) is excellent, well below the 90 A^2 threshold for CNS targets. Ligand B (108.6) is higher, but still potentially acceptable, though less ideal.

**3. logP:** Both ligands have good logP values (3.235 & 2.499), falling within the optimal 1-3 range.

**4. H-Bond Donors (HBD):** Both ligands are within the acceptable limit of <=5 (1 & 2 respectively).

**5. H-Bond Acceptors (HBA):** Both ligands are within the acceptable limit of <=10 (4 & 7 respectively).

**6. QED:** Both ligands have similar and acceptable QED values (0.661 & 0.625), indicating good drug-like properties.

**7. DILI:** Ligand A (15.394) has a significantly lower DILI risk than Ligand B (87.515), which is a major concern.

**8. BBB:** Ligand A (76.347) has a much better BBB penetration percentile than Ligand B (40.675). This is *critical* for a CNS target like DRD2.

**9. Caco-2 Permeability:** Ligand A (-4.836) and Ligand B (-5.267) have similar, negative Caco-2 values, suggesting poor intestinal absorption. This isn't a primary concern for CNS drugs, as BBB penetration is more important.

**10. Aqueous Solubility:** Both ligands have poor aqueous solubility (-2.488 & -4.819). This could pose formulation challenges, but is less critical than BBB penetration for a CNS drug.

**11. hERG Inhibition:** Both ligands show low hERG inhibition risk (0.551 & 0.36).

**12. Microsomal Clearance:** Ligand A (60.747) has lower microsomal clearance than Ligand B (73.502), suggesting better metabolic stability.

**13. In vitro Half-Life:** Ligand A (8.13) has a shorter half-life than Ligand B (-35.192). However, the negative value for B is suspect and likely indicates a very long half-life, but the data is questionable.

**14. P-gp Efflux:** Ligand A (0.58) has lower P-gp efflux liability than Ligand B (0.186), which is favorable for CNS penetration.

**15. Binding Affinity:** Ligand B (-9.1 kcal/mol) has a slightly better binding affinity than Ligand A (-8.4 kcal/mol). While a 0.7 kcal/mol difference is noticeable, it's not a huge advantage, and can be overcome by superior ADME properties.

**Overall Assessment:**

Ligand A is significantly better overall. Its superior BBB penetration, lower DILI risk, lower P-gp efflux, and better metabolic stability outweigh the slightly weaker binding affinity compared to Ligand B. The high DILI risk and poor BBB penetration of Ligand B are major red flags for CNS drug development.

Output:
0
2025-04-17 06:36:04,538 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (356.438 and 356.394 Da) fall comfortably within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (78.87) is significantly better than Ligand B (92.01). For CNS targets, we want TPSA <= 90, so Ligand A is preferable.

**3. logP:** Both ligands have acceptable logP values (1.187 and 0.665), falling within the 1-3 range. Ligand A is slightly better.

**4. H-Bond Donors:** Both have 2 HBD, which is good.

**5. H-Bond Acceptors:** Ligand A has 4 HBA, and Ligand B has 5. Both are acceptable (<=10).

**6. QED:** Both ligands have good QED scores (0.701 and 0.749), indicating drug-like properties.

**7. DILI:** Ligand A (20.202) has a much lower DILI risk than Ligand B (35.595). This is a significant advantage for Ligand A.

**8. BBB:** Both ligands have reasonably good BBB penetration (66.499% and 64.831%), but are below the desirable >70% threshold for CNS targets. The difference is minimal.

**9. Caco-2 Permeability:** Both have negative Caco-2 values (-4.739 and -4.895). This is unusual and suggests poor permeability. However, these values are on a scale where negative values are possible, and the absolute difference is small.

**10. Aqueous Solubility:** Both have negative solubility values (-1.548 and -1.384), which is also unusual. Again, the difference is minimal.

**11. hERG:** Both ligands have very low hERG inhibition risk (0.258 and 0.24), which is excellent.

**12. Microsomal Clearance:** Ligand A (1.432) has significantly lower microsomal clearance than Ligand B (5.048), indicating better metabolic stability.

**13. In vitro Half-Life:** Ligand A (0.775) has a slightly better in vitro half-life than Ligand B (2.1).

**14. P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.037 and 0.027), which is favorable for CNS penetration.

**15. Binding Affinity:** Ligand B (-7.2 kcal/mol) has a slightly better binding affinity than Ligand A (-8.0 kcal/mol). However, the difference is relatively small (0.8 kcal/mol).

**Overall Assessment:**

Considering the GPCR-specific priorities, Ligand A is the better candidate. While Ligand B has slightly better binding affinity, Ligand A excels in crucial ADME properties: lower TPSA, significantly lower DILI risk, and lower microsomal clearance. These factors are particularly important for a CNS-targeting drug like a DRD2 ligand. The slightly better BBB penetration of Ligand A, combined with its superior safety profile and metabolic stability, outweigh the small difference in binding affinity.

Output:
1
2025-04-17 06:36:04,538 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (378.885 Da) is slightly higher than Ligand B (335.407 Da), but both are acceptable.

**2. TPSA:** Ligand A (83.98) is better than Ligand B (55.32). For CNS targets, TPSA should be <=90. Both are below this threshold, but A is closer to the upper limit.

**3. logP:** Both ligands have good logP values (A: 2.537, B: 3.527), falling within the optimal range of 1-3. Ligand B is slightly higher, which *could* indicate potential off-target effects, but isn't a major concern.

**4. H-Bond Donors:** Ligand A (2) is slightly higher than Ligand B (0), but both are within the acceptable limit of <=5.

**5. H-Bond Acceptors:** Ligand A (5) is higher than Ligand B (4), but both are within the acceptable limit of <=10.

**6. QED:** Both ligands have reasonable QED values (A: 0.474, B: 0.732). Ligand B is significantly better, indicating a more drug-like profile.

**7. DILI:** Both ligands have acceptable DILI risk (A: 75.107, B: 60.527), below the concerning threshold of 60. Ligand B is preferable.

**8. BBB:** This is crucial for a CNS target like DRD2. Ligand B (72.819) is significantly better than Ligand A (52.191), exceeding the desirable threshold of >70.

**9. Caco-2 Permeability:** Ligand A (-5.41) is worse than Ligand B (-4.52). Lower values here indicate poorer permeability.

**10. Aqueous Solubility:** Both ligands have poor aqueous solubility (-3.614 and -3.669). This is a potential issue for formulation, but not a deal-breaker if other properties are favorable.

**11. hERG Inhibition:** Both ligands have very low hERG inhibition risk (A: 0.096, B: 0.747), which is excellent.

**12. Microsomal Clearance:** Ligand A (46.049) has significantly lower clearance than Ligand B (106.239), indicating better metabolic stability.

**13. In vitro Half-Life:** Ligand A (15.262) has a positive half-life, while Ligand B (-10.022) has a negative half-life. This is a major advantage for Ligand A.

**14. P-gp Efflux:** Ligand A (0.114) has lower P-gp efflux than Ligand B (0.405), suggesting better CNS exposure.

**15. Binding Affinity:** Both ligands have excellent binding affinity (A: -9.1 kcal/mol, B: -9.4 kcal/mol). Ligand B is slightly better, but the difference is small.

**Overall Assessment:**

Ligand B is superior in terms of QED, DILI, BBB penetration, and binding affinity. However, Ligand A has significantly better metabolic stability (lower Cl_mic, positive half-life) and lower P-gp efflux, which are crucial for CNS drug development. The BBB score for Ligand B is the most compelling advantage. While Ligand A's BBB is not ideal, the combination of better metabolic stability and lower P-gp efflux could potentially overcome this limitation. Given the importance of CNS penetration for DRD2, and the significant advantage of Ligand B in that regard, it is the better candidate.

Output:
1
2025-04-17 06:36:04,538 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 drug candidates, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (363.797 and 375.535 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (66.88) is excellent, well below the 90 A^2 threshold for CNS targets. Ligand B (89.95) is approaching the upper limit but still acceptable.

**logP:** Ligand A (3.504) is optimal. Ligand B (0.398) is quite low, potentially hindering membrane permeability and CNS penetration.

**H-Bond Donors/Acceptors:** Ligand A (0 HBD, 6 HBA) is good. Ligand B (2 HBD, 5 HBA) is also acceptable.

**QED:** Both ligands have reasonable QED values (0.732 and 0.609), indicating good drug-like properties.

**DILI:** Ligand A (82.319) has a higher DILI risk than Ligand B (13.843), which is a significant concern.

**BBB:** Ligand A (62.233) has a moderate BBB penetration, while Ligand B (49.36) is lower. Both are below the desirable >70% for CNS targets, but Ligand A is better.

**Caco-2 Permeability:** Ligand A (-4.108) has poor Caco-2 permeability, while Ligand B (-5.232) is even worse.

**Aqueous Solubility:** Ligand A (-4.654) and Ligand B (-1.296) both have poor aqueous solubility.

**hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.243 and 0.376).

**Microsomal Clearance:** Ligand A (95.702) has high microsomal clearance, indicating rapid metabolism. Ligand B (35.116) has lower clearance, suggesting better metabolic stability.

**In vitro Half-Life:** Ligand B (-44.815) has a significantly longer in vitro half-life than Ligand A (-15.449).

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.081 and 0.021).

**Binding Affinity:** Both ligands have the same binding affinity (-7.3 kcal/mol), which is excellent.

**Conclusion:**

Despite Ligand A's better logP and TPSA, the significantly higher DILI risk and poor Caco-2 permeability are major drawbacks. Ligand B, while having a suboptimal logP, exhibits a much lower DILI risk and a longer half-life, which are crucial for a CNS drug candidate. The similar binding affinity makes the ADME properties the deciding factor. While both have poor solubility and BBB penetration, Ligand B's superior metabolic stability and safety profile make it the more promising candidate.

Output:
1
2025-04-17 06:36:04,539 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (358.36 and 366.799 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (61.8) is slightly higher than Ligand B (50.16). Both are below the 90 A^2 threshold desirable for CNS targets, but B is better.

**logP:** Both ligands have good logP values (3.456 and 3.961), falling within the optimal 1-3 range. Ligand B is slightly higher, which could potentially lead to some solubility issues, but is still acceptable.

**H-Bond Donors/Acceptors:** Ligand A has 2 HBD and 3 HBA, while Ligand B has 1 HBD and 3 HBA. Both are within the acceptable limits.

**QED:** Both ligands have high QED scores (0.87 and 0.893), indicating good drug-like properties.

**DILI:** Ligand A (48.313) has a significantly lower DILI risk than Ligand B (66.072). This is a substantial advantage for Ligand A.

**BBB:** Both ligands exhibit excellent BBB penetration (86.739 and 89.957), exceeding the desirable >70% threshold for CNS targets. Ligand B is slightly better.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.89 and -4.407). These values are difficult to interpret without knowing the scale, but negative values are not ideal.

**Aqueous Solubility:** Both ligands have very poor aqueous solubility (-3.297 and -5.509). This is a significant drawback for both, potentially hindering bioavailability.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.816 and 0.562).

**Microsomal Clearance:** Ligand A (10.583) has a much lower microsomal clearance than Ligand B (27.864), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (18.614) has a longer in vitro half-life than Ligand B (-19.279). The negative value for Ligand B is concerning and suggests very rapid degradation.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.171 and 0.087), which is favorable for CNS penetration.

**Binding Affinity:** Both ligands have excellent binding affinities (-8.7 and -8.8 kcal/mol). The difference is minimal.

**Overall Assessment:**

Ligand A is superior due to its significantly lower DILI risk, better metabolic stability (lower Cl_mic, longer t1/2), and better overall ADME profile despite slightly higher TPSA. While both have poor solubility, the other advantages of Ligand A outweigh this drawback. The negative Caco-2 values are concerning for both, but the other properties of A are more favorable.



Output:
0
2025-04-17 06:36:04,539 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (338.447 and 344.499 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (35.53) is significantly better than Ligand B (61.36). For CNS targets, TPSA should be <=90, and A is comfortably within this range, while B is approaching the upper limit.

**3. logP:** Both ligands have good logP values (4.373 and 3.42), falling within the optimal 1-3 range. Ligand B is slightly better.

**4. H-Bond Donors:** Ligand A (0) is preferable to Ligand B (3). Fewer HBDs generally improve permeability.

**5. H-Bond Acceptors:** Ligand A (3) is slightly higher than Ligand B (2), but both are acceptable.

**6. QED:** Both ligands have good QED scores (0.637 and 0.733), indicating good drug-like properties.

**7. DILI:** Ligand A (15.083) has a much lower DILI risk than Ligand B (28.693), which is a significant advantage.

**8. BBB:** Ligand B (81.233) has a better BBB penetration percentile than Ligand A (68.127), which is crucial for a CNS target like DRD2.

**9. Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and difficult to interpret without knowing the scale. However, the values are similar.

**10. Aqueous Solubility:** Both have negative solubility values, again unusual and hard to interpret.

**11. hERG Inhibition:** Both ligands have low hERG inhibition risk (0.854 and 0.581).

**12. Microsomal Clearance:** Ligand A (110.003) has a higher microsomal clearance than Ligand B (41.62), indicating lower metabolic stability. This is a disadvantage for Ligand A.

**13. In vitro Half-Life:** Ligand B (22.941) has a significantly longer in vitro half-life than Ligand A (-8.945), which is a major advantage.

**14. P-gp Efflux:** Ligand A (0.42) has lower P-gp efflux than Ligand B (0.435), which is slightly favorable for CNS penetration.

**15. Binding Affinity:** Ligand A (-9.0) has a much stronger binding affinity than Ligand B (-0.0). This is a substantial advantage, potentially outweighing some ADME drawbacks.

**Overall Assessment:**

Ligand A has a significantly better binding affinity and lower DILI risk. However, Ligand B has better BBB penetration, metabolic stability (lower Cl_mic, longer t1/2) and a slightly better logP. The strong affinity of Ligand A is a major driver, and the lower TPSA is also beneficial for CNS penetration. While Ligand B's BBB is better, the affinity difference is substantial. The lower metabolic stability of Ligand A can be addressed with structural modifications during optimization.

Output:
1
2025-04-17 06:36:04,539 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 drug candidates, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (370.299 Da and 347.419 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (90.31) is excellent, falling below the 90 A^2 threshold for CNS targets. Ligand B (97.61) is still reasonable but slightly higher.

**logP:** Ligand A (-0.93) is a bit low, potentially hindering permeation. Ligand B (0.936) is better, falling within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Both have 2 HBDs and 5/6 HBAs, which are acceptable and balance solubility and permeability.

**QED:** Both ligands have good QED scores (0.627 and 0.8), indicating drug-like properties.

**DILI:** Both have low DILI risk (35.944 and 38.348), which is positive.

**BBB:** Both ligands have acceptable BBB penetration (43.699% and 45.638%), although ideally, we'd want >70% for a CNS target. This isn't a major differentiating factor here.

**Caco-2 Permeability:** Both have negative Caco-2 values (-4.88 and -5.22), which is unusual and suggests poor permeability. This is a significant concern for both.

**Aqueous Solubility:** Both have very poor aqueous solubility (-1.242 and -1.455), which could lead to formulation challenges.

**hERG:** Both ligands have low hERG inhibition liability (0.336 and 0.138), which is favorable.

**Microsomal Clearance:** Ligand A (-6.792) has significantly lower (better) microsomal clearance than Ligand B (-9.072), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (-4.791) has a shorter half-life than Ligand B (17.806), which is less desirable.

**P-gp Efflux:** Both have very low P-gp efflux liability (0.013 and 0.03), which is good for CNS penetration.

**Binding Affinity:** Both ligands have excellent binding affinity (-8.3 and -8.4 kcal/mol), very similar and strong.

**Overall Assessment:**

The key differences lie in logP, microsomal clearance, and in vitro half-life. Ligand B has a better logP, which is crucial for GPCRs. However, Ligand A has superior metabolic stability (lower Cl_mic) and a more favorable TPSA. The Caco-2 permeability and solubility are poor for both, representing significant hurdles. Given the similar affinities, the better logP and half-life of Ligand B slightly outweigh the better TPSA and clearance of Ligand A. However, the poor permeability and solubility are major concerns for both.

Output:
1
2025-04-17 06:36:04,539 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (347.423 and 349.519 Da) fall comfortably within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (117.59) is borderline for CNS targets, being slightly above the preferred <90. Ligand B (43.86) is excellent, well below 90. This is a significant advantage for Ligand B.

**3. logP:** Both ligands have good logP values (1.045 and 2.07), falling within the optimal 1-3 range.

**4. H-Bond Donors:** Ligand A has 3 HBD, acceptable. Ligand B has 0, also acceptable.

**5. H-Bond Acceptors:** Ligand A has 6 HBA, acceptable. Ligand B has 3, also acceptable.

**6. QED:** Both ligands have good QED scores (0.626 and 0.737), indicating good drug-like properties.

**7. DILI:** Ligand A has a DILI risk of 60.411, which is approaching the higher risk threshold. Ligand B has a much lower DILI risk of 5.816, a clear advantage.

**8. BBB:** This is crucial for a CNS target. Ligand A has a BBB penetration of 30.206%, which is quite low. Ligand B has a significantly higher BBB penetration of 81.311%, a major advantage.

**9. Caco-2 Permeability:** Ligand A has a negative Caco-2 value (-5.825), which is unusual and suggests poor permeability. Ligand B has a negative value as well (-4.514), but it's less negative. Both are concerning, but A is worse.

**10. Aqueous Solubility:** Both ligands have negative solubility values (-1.915 and -0.953), indicating poor aqueous solubility. This is a drawback for both, but less severe for Ligand B.

**11. hERG Inhibition:** Both ligands show very low hERG inhibition risk (0.122 and 0.519).

**12. Microsomal Clearance:** Ligand A has a lower Cl_mic (4.323) than Ligand B (32.623), suggesting better metabolic stability. This is an advantage for Ligand A.

**13. In vitro Half-Life:** Ligand A has a longer half-life (15.668 hours) than Ligand B (7.722 hours), which is preferable. Another advantage for Ligand A.

**14. P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.04 and 0.041), which is good.

**15. Binding Affinity:** Ligand A has a slightly better binding affinity (-7.8 kcal/mol) than Ligand B (-7.3 kcal/mol). This 0.5 kcal/mol difference is significant, but needs to be weighed against other factors.

**Overall Assessment:**

Ligand B is the stronger candidate. While Ligand A has slightly better affinity, longer half-life, and lower clearance, Ligand B excels in critical areas for a CNS-targeting GPCR: significantly lower TPSA, much higher BBB penetration, and a substantially lower DILI risk. The poor Caco-2 permeability of both is a concern, but the superior CNS penetration profile of Ligand B outweighs the slightly better affinity and metabolic stability of Ligand A.

Output:
1
2025-04-17 06:36:04,540 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 drug candidates, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (361.785 Da and 370.431 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (94.75) is better than Ligand B (101.81). Both are below the 140 A^2 threshold for oral absorption, and importantly, below the 90 A^2 threshold preferred for CNS targets.

**logP:** Ligand A (1.981) is within the optimal 1-3 range. Ligand B (-0.711) is slightly below 1, which *could* indicate permeability issues, although not severely.

**H-Bond Donors/Acceptors:** Ligand A (HBD=1, HBA=5) is preferable to Ligand B (HBD=0, HBA=7). Both are within acceptable limits, but having some hydrogen bond donors can aid solubility.

**QED:** Ligand A (0.84) has a significantly better QED score than Ligand B (0.678), indicating a more drug-like profile.

**DILI:** Ligand B (63.552) has a lower DILI risk than Ligand A (85.847), which is a positive for Ligand B.

**BBB:** Ligand A (69.833) has a better BBB penetration percentile than Ligand B (59.829). While both are not ideal (>70), Ligand A is closer to the desired threshold for a CNS target.

**Caco-2 Permeability:** Ligand A (-4.614) is better than Ligand B (-4.434), indicating better intestinal absorption.

**Aqueous Solubility:** Ligand A (-4.146) is better than Ligand B (-1.798), which is important for formulation.

**hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.281 and 0.108, respectively), which is excellent.

**Microsomal Clearance:** Ligand A (36.187) has a lower microsomal clearance than Ligand B (8.637), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (23.845 hours) has a significantly longer half-life than Ligand B (-2.947 hours). This is a major advantage for Ligand A.

**P-gp Efflux:** Ligand A (0.224) has lower P-gp efflux liability than Ligand B (0.072), which is favorable for CNS exposure.

**Binding Affinity:** Ligand B (-7.7 kcal/mol) has a slightly better binding affinity than Ligand A (-8.3 kcal/mol). This is a significant advantage, but needs to be weighed against other factors.

**Overall Assessment:**

Ligand A has a more favorable ADME profile overall. It has better QED, BBB penetration, Caco-2 permeability, solubility, metabolic stability (lower Cl_mic and longer t1/2), and lower P-gp efflux. While Ligand B has a slightly better binding affinity and lower DILI risk, the ADME advantages of Ligand A, particularly its BBB penetration and metabolic stability, are crucial for a CNS-targeting GPCR like DRD2. The difference in binding affinity (0.6 kcal/mol) is unlikely to outweigh the substantial ADME benefits of Ligand A.

Output:
1
2025-04-17 06:36:04,540 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (349.475 Da) is slightly lower, which could be beneficial for permeability. Ligand B (354.451 Da) is also good.

**TPSA:** Ligand A (80.32) is excellent, well below the 90 A^2 threshold for CNS targets. Ligand B (105.48) is still reasonable, but less optimal, being above 90 A^2.

**logP:** Ligand A (3.336) is within the optimal range (1-3). Ligand B (0.236) is significantly lower, which is a major concern for CNS penetration as it may struggle to cross cell membranes.

**H-Bond Donors/Acceptors:** Ligand A (HBD=2, HBA=4) and Ligand B (HBD=3, HBA=6) both fall within acceptable limits (<=5 HBD, <=10 HBA).

**QED:** Ligand A (0.854) has a very good drug-likeness score. Ligand B (0.589) is acceptable, but less favorable.

**DILI:** Ligand A (44.552) has a moderate DILI risk, but is acceptable. Ligand B (27.026) has a very low DILI risk, which is excellent.

**BBB:** Ligand A (68.554) has a good BBB percentile, indicating reasonable CNS penetration. Ligand B (29.12) has a very low BBB percentile, severely hindering its potential for CNS activity.

**Caco-2 Permeability:** Ligand A (-4.549) shows poor Caco-2 permeability. Ligand B (-5.194) shows even poorer Caco-2 permeability.

**Aqueous Solubility:** Ligand A (-3.863) has poor aqueous solubility. Ligand B (-1.714) has slightly better solubility, but still not ideal.

**hERG Inhibition:** Both ligands (A: 0.228, B: 0.082) have low hERG inhibition risk, which is positive.

**Microsomal Clearance:** Ligand A (82.903) has a higher microsomal clearance, suggesting faster metabolism. Ligand B (36.056) has a lower clearance, indicating better metabolic stability.

**In vitro Half-Life:** Ligand A (1.234 hours) has a short half-life. Ligand B (7.181 hours) has a much longer half-life, which is a significant advantage.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (A: 0.033, B: 0.029), which is favorable for CNS penetration.

**Binding Affinity:** Ligand A (-7.7 kcal/mol) has a significantly stronger binding affinity than Ligand B (-6.4 kcal/mol). This 1.3 kcal/mol difference is substantial and can outweigh some ADME drawbacks.

**Overall Assessment:**

Ligand A excels in binding affinity and TPSA, with acceptable BBB and DILI. Its main weaknesses are poor Caco-2 permeability, aqueous solubility, and a relatively short half-life.

Ligand B has better metabolic stability (lower Cl_mic, longer t1/2) and a lower DILI risk, but suffers from a very poor logP, resulting in extremely low BBB penetration and poor Caco-2 permeability. The weaker binding affinity is also a major drawback.

Given the GPCR-specific priorities, particularly BBB penetration for a CNS target like DRD2, and the significant advantage in binding affinity, **Ligand A is the more promising candidate despite its ADME liabilities**. The strong binding affinity suggests that even with less-than-ideal permeability, sufficient drug concentration at the target site might be achievable. The ADME properties of Ligand A could potentially be improved through further optimization, whereas the low logP of Ligand B is a more fundamental issue that would be harder to address without drastically altering the core structure and potentially losing binding affinity.

Output:
0
2025-04-17 06:36:04,540 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the acceptable range (200-500 Da). Ligand A (415.154 Da) is slightly higher than Ligand B (376.523 Da), but this isn't a major concern.

**TPSA:** Both ligands have TPSA values above the ideal <90 A^2 for CNS targets. Ligand A (114.41 A^2) is higher than Ligand B (121.6 A^2), which is unfavorable.

**logP:** Ligand A (1.963) is within the optimal range (1-3), while Ligand B (0.371) is slightly below, potentially hindering permeation.

**H-Bond Donors/Acceptors:** Ligand A (2 HBD, 7 HBA) and Ligand B (3 HBD, 4 HBA) both fall within acceptable limits.

**QED:** Both ligands have QED values above 0.5, indicating good drug-likeness, but Ligand A (0.659) is higher than Ligand B (0.477).

**DILI:** Ligand A (99.225) has a very high DILI risk, which is a significant red flag. Ligand B (33.695) has a much lower, and acceptable, DILI risk.

**BBB:** Both ligands have moderate BBB penetration, but Ligand A (46.724) is slightly better than Ligand B (43.815). However, both are below the desirable >70 for CNS targets.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values, which is unusual and suggests poor permeability. Ligand A (-5.681) is slightly better than Ligand B (-5.38).

**Aqueous Solubility:** Both ligands have negative solubility values, indicating poor aqueous solubility. Ligand A (-3.118) is slightly better than Ligand B (-1.785).

**hERG Inhibition:** Both ligands have very low hERG inhibition risk, which is good. Ligand A (0.042) is slightly better than Ligand B (0.219).

**Microsomal Clearance:** Ligand A (-0.491) has a negative clearance, indicating high metabolic stability, which is favorable. Ligand B (40.419) has high clearance, suggesting rapid metabolism.

**In vitro Half-Life:** Ligand A (26.883 hours) has a longer half-life than Ligand B (-7.543 hours).

**P-gp Efflux:** Both ligands have very low P-gp efflux liability, which is good. Ligand A (0.02) is slightly better than Ligand B (0.006).

**Binding Affinity:** Ligand A (-8.3 kcal/mol) has a significantly stronger binding affinity than Ligand B (-7.1 kcal/mol). The 1.2 kcal/mol difference is substantial and can outweigh some ADME drawbacks.

**Overall Assessment:**

Ligand A has a significantly better binding affinity and metabolic stability, but suffers from a very high DILI risk and higher TPSA. Ligand B has a lower DILI risk, but weaker binding affinity, poorer metabolic stability, and a lower logP.

Given the GPCR-specific priorities, and the importance of binding affinity for CNS targets, the stronger affinity of Ligand A is a major advantage. However, the extremely high DILI risk is a critical concern. While optimization could potentially reduce the DILI risk, it's a significant hurdle. Ligand B is safer, but its weaker binding affinity makes it less likely to be effective.

Considering the balance, the stronger affinity of Ligand A is compelling, and the DILI risk might be mitigated with further structural modifications.

Output:
1
2025-04-17 06:36:04,540 - INFO - Batch 295 complete. Total preferences: 4720
2025-04-17 06:36:04,540 - INFO - Processing batch 296/512...
2025-04-17 06:36:49,160 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 drug candidates, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (350.434 and 366.527 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (58.64) is significantly better than Ligand B (67.43). For a CNS target like DRD2, TPSA should be <= 90, and ideally lower. Ligand A is much closer to the ideal range.

**3. logP:** Both ligands have acceptable logP values (2.609 and 3.14), falling within the 1-3 optimal range.

**4. H-Bond Donors:** Ligand A (1) is preferable to Ligand B (2). Lower HBD generally improves permeability.

**5. H-Bond Acceptors:** Ligand A (3) is preferable to Ligand B (4). Lower HBA generally improves permeability.

**6. QED:** Ligand A (0.803) has a significantly better QED score than Ligand B (0.66), indicating a more drug-like profile.

**7. DILI:** Ligand A (21.055) has a much lower DILI risk than Ligand B (49.011). This is a significant advantage.

**8. BBB:** Ligand A (89.531) has a substantially higher BBB penetration percentile than Ligand B (61.38). This is *critical* for a CNS target like DRD2.

**9. Caco-2 Permeability:** Ligand A (-4.391) is better than Ligand B (-5.284), indicating slightly better intestinal absorption.

**10. Aqueous Solubility:** Ligand A (-2.368) is better than Ligand B (-2.958), indicating slightly better solubility.

**11. hERG Inhibition:** Both ligands have similar, low hERG inhibition liabilities (0.741 and 0.699).

**12. Microsomal Clearance:** Ligand A (-2.594) has a lower (better) microsomal clearance than Ligand B (47.337), indicating greater metabolic stability.

**13. In vitro Half-Life:** Ligand A (5.363) has a lower half-life than Ligand B (39.966), but this is less critical than other factors.

**14. P-gp Efflux:** Ligand A (0.092) has a much lower P-gp efflux liability than Ligand B (0.495). This is important for CNS exposure.

**15. Binding Affinity:** Ligand B (-7.6) has a slightly better binding affinity than Ligand A (-8.1). However, the difference is relatively small (0.5 kcal/mol) and is outweighed by the superior ADME properties of Ligand A.

**Overall Assessment:**

Ligand A consistently outperforms Ligand B across most crucial ADME properties, particularly BBB penetration, DILI risk, P-gp efflux, and metabolic stability. While Ligand B has a slightly better binding affinity, the difference isn't substantial enough to overcome Ligand A's superior overall profile, especially considering the CNS target.

Output:
0
2025-04-17 06:36:49,160 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (353.423 and 370.523 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (133.63) is better than Ligand B (94.48), both are below the 140 threshold for oral absorption and, importantly, below the 90 threshold desirable for CNS targets.

**logP:** Ligand A (-0.766) is slightly low, potentially hindering permeation, while Ligand B (0.117) is within the optimal 1-3 range. This favors Ligand B.

**H-Bond Donors/Acceptors:** Ligand A has 4 HBD and 4 HBA, which is acceptable. Ligand B has 2 HBD and 8 HBA, also acceptable, but slightly higher HBA could potentially impact permeability.

**QED:** Ligand B (0.633) has a better QED score than Ligand A (0.32), indicating a more drug-like profile.

**DILI:** Ligand A (23.885) has a significantly lower DILI risk than Ligand B (50.291), which is a strong advantage for Ligand A.

**BBB:** Ligand A (71.888) has a much better BBB penetration percentile than Ligand B (52.617). This is *critical* for a CNS target like DRD2, and heavily favors Ligand A.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.736 and -5.178), which is unusual and suggests poor permeability. However, the scale isn't specified, so it's hard to interpret.

**Aqueous Solubility:** Both ligands have negative solubility values (-1.289 and -1.606), also unusual and suggesting poor solubility.

**hERG:** Ligand A (0.058) has a lower hERG inhibition liability than Ligand B (0.758), indicating a lower risk of cardiotoxicity.

**Microsomal Clearance:** Ligand A (-8.685) has a much lower (better) microsomal clearance than Ligand B (33.73), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (-4.175) has a longer in vitro half-life than Ligand B (5.183), which is desirable.

**Pgp Efflux:** Ligand A (0.003) has a significantly lower Pgp efflux liability than Ligand B (0.083), improving CNS exposure.

**Binding Affinity:** Both ligands have very similar binding affinities (-7.6 and -7.4 kcal/mol). The difference is less than the 1.5 kcal/mol threshold.

**Overall Assessment:**

Ligand A excels in key areas for a CNS-targeting GPCR: BBB penetration, DILI risk, metabolic stability (Cl_mic and t1/2), Pgp efflux, and hERG inhibition. While its logP is slightly low, the substantial benefits in CNS penetration and safety outweigh this drawback. Ligand B has a better QED and logP, but suffers from higher DILI, lower BBB, and poorer metabolic stability. Given the importance of CNS penetration for DRD2, Ligand A is the more promising candidate.

Output:
0
2025-04-17 06:36:49,160 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (345.4 and 356.5 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (87.74) is excellent for CNS penetration, being well below 90. Ligand B (49.41) is even better.

**logP:** Ligand A (0.695) is a bit low, potentially hindering permeation. Ligand B (3.939) is closer to the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A (2 HBD, 4 HBA) and Ligand B (1 HBD, 2 HBA) both have reasonable numbers, well within the guidelines.

**QED:** Both ligands have similar QED values (0.789 and 0.716), indicating good drug-likeness.

**DILI:** Ligand A (53.3) has a slightly higher DILI risk than Ligand B (30.9), but both are acceptable (<60).

**BBB:** Ligand A (78.2%) is good, but Ligand B (93.5%) is *excellent* for CNS penetration, a critical factor for DRD2 targeting.

**Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and suggests poor permeability. However, the scale isn't specified, so it's hard to interpret.

**Aqueous Solubility:** Both have negative solubility values, which is also unusual and suggests poor solubility.

**hERG:** Ligand A (0.109) has a very low hERG risk. Ligand B (0.692) is slightly higher but still relatively low.

**Microsomal Clearance:** Ligand A (-5.936) has a negative clearance, which is impossible. This is likely an error in the data. Ligand B (81.244) has a high clearance, indicating rapid metabolism, which is unfavorable.

**In vitro Half-Life:** Ligand A (-4.65) has a negative half-life, which is impossible. This is likely an error in the data. Ligand B (-11.913) also has a negative half-life, also likely an error.

**P-gp Efflux:** Ligand A (0.012) shows very low P-gp efflux, which is highly desirable for CNS penetration. Ligand B (0.452) has moderate P-gp efflux.

**Binding Affinity:** Ligand A (-8.6 kcal/mol) has a significantly stronger binding affinity than Ligand B (-7.8 kcal/mol). The difference of 0.8 kcal/mol is substantial and can outweigh some ADME drawbacks.

**Overall Assessment:**

Despite the questionable solubility, permeability, half-life and clearance data, Ligand A stands out due to its superior binding affinity and very low P-gp efflux. The slightly lower logP is a concern, but the strong binding could compensate. Ligand B has excellent BBB penetration, but its weaker affinity and high clearance are significant drawbacks. The negative values for clearance and half-life are concerning and suggest data errors.

Output:
1
2025-04-17 06:36:49,160 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (364.324 Da) is slightly higher than Ligand B (338.367 Da), but both are acceptable.

**TPSA:** Both ligands have TPSA values below the 90 A^2 threshold desirable for CNS targets. Ligand A (96.69 A^2) is slightly higher than Ligand B (79.54 A^2), making Ligand B more favorable for brain penetration.

**logP:** Ligand A (-0.468) is below the optimal 1-3 range and could hinder permeability. Ligand B (1.299) is within the optimal range. This is a significant advantage for Ligand B.

**H-Bond Donors/Acceptors:** Ligand A has 2 HBD and 6 HBA, while Ligand B has 0 HBD and 5 HBA. Both are within acceptable limits (<=5 HBD and <=10 HBA).

**QED:** Both ligands have good QED scores (A: 0.712, B: 0.825), indicating good drug-like properties.

**DILI:** Both ligands have acceptable DILI risk (A: 52.307, B: 59.442), below the concerning threshold of 60.

**BBB:** Both ligands have reasonable BBB penetration (A: 65.529, B: 61.768), but are below the 70% target.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.843 and -4.971), which is unusual and suggests poor permeability. This is a concern for both.

**Aqueous Solubility:** Both ligands have negative solubility values (-1.2 and -2.59), indicating very poor aqueous solubility. This is a major drawback for both.

**hERG Inhibition:** Both ligands show low hERG inhibition risk (A: 0.353, B: 0.149), which is good.

**Microsomal Clearance:** Ligand A has a negative clearance (-2.569), which is not physically meaningful. Ligand B has a relatively high clearance (27.718 mL/min/kg), suggesting faster metabolism.

**In vitro Half-Life:** Ligand A has a very short half-life (-16.653 hours), which is not physically meaningful. Ligand B has a longer half-life (36.148 hours), which is preferable.

**P-gp Efflux:** Both ligands show low P-gp efflux liability (A: 0.077, B: 0.134), which is favorable for CNS penetration.

**Binding Affinity:** Ligand B (-9.8 kcal/mol) has a significantly stronger binding affinity than Ligand A (-7.0 kcal/mol). This difference of 2.8 kcal/mol is substantial and can outweigh some of the ADME drawbacks.

**Overall Assessment:**

Ligand B is the better candidate. While both have poor solubility and permeability, Ligand B has a more favorable logP, better metabolic stability (longer half-life), and *significantly* stronger binding affinity. The stronger affinity is a crucial advantage for a GPCR ligand, and the logP value is within the optimal range, while Ligand A's is not. The negative values for clearance and half-life for Ligand A are concerning and likely indicate issues with the data or model.



Output:
1
2025-04-17 06:36:49,161 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B based on the provided guidelines, prioritizing GPCR-specific properties (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (344.375 and 365.817 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (100.38) is slightly higher than Ligand B (93.46), but both are below the 140 A^2 threshold for oral absorption and reasonably close to the 90 A^2 target for CNS penetration. Ligand B is slightly better here.

**logP:** Ligand A (0.829) is a bit low, potentially hindering permeability. Ligand B (1.525) is better, falling within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A has 1 HBD and 7 HBA, while Ligand B has 2 HBD and 5 HBA. Both are within acceptable limits.

**QED:** Both ligands have reasonable QED scores (0.88 and 0.792), indicating good drug-likeness.

**DILI:** Both ligands have high DILI risk (74.99 and 75.766), which is a concern, but comparable between the two.

**BBB:** This is a critical parameter for a CNS target like DRD2. Ligand A has a BBB percentile of 71.85, which is good (above the 70% threshold). Ligand B has a significantly lower BBB percentile of 52.617, which is a major drawback.

**Caco-2 Permeability:** Both have negative values (-5.007 and -4.994) which is unusual and suggests poor permeability. This is a potential issue for both.

**Aqueous Solubility:** Both have negative values (-2.376 and -3.484) which is also unusual and suggests poor solubility. This is a potential issue for both.

**hERG:** Both ligands have low hERG inhibition liability (0.191 and 0.201), which is favorable.

**Microsomal Clearance:** Ligand A (26.416) has a higher microsomal clearance than Ligand B (-1.508), indicating lower metabolic stability. Ligand B is much better here.

**In vitro Half-Life:** Ligand A (21.409) has a longer half-life than Ligand B (7.769), which is desirable.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.054 and 0.197), which is good for CNS penetration.

**Binding Affinity:** Ligand A (-8.8 kcal/mol) has a significantly stronger binding affinity than Ligand B (-7.2 kcal/mol). This is a substantial advantage (over 1.5 kcal/mol difference).

**Overall Assessment:**

Ligand A has a significantly better binding affinity and a good BBB percentile, which are crucial for a CNS-targeting GPCR. While its TPSA is slightly higher and logP a bit low, the strong affinity and acceptable BBB outweigh these drawbacks. Ligand B has better metabolic stability (lower Cl_mic) and a slightly better TPSA, but its significantly lower BBB penetration is a major concern for a CNS drug. The poor Caco-2 and solubility values are concerning for both, but the affinity advantage of A is substantial.

Output:
1
2025-04-17 06:36:49,161 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B based on the provided guidelines, prioritizing GPCR-specific properties (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (346.39) is slightly preferred due to being closer to the lower end, potentially aiding permeability.

**TPSA:** Ligand A (105.34) is better than Ligand B (41.57) as it is closer to the 90 A^2 threshold for CNS targets. Ligand B is very low, which might indicate poor interactions with the receptor.

**logP:** Ligand A (1.562) is optimal (1-3). Ligand B (4.496) is higher, potentially leading to solubility issues and off-target effects.

**H-Bond Donors/Acceptors:** Ligand A (HBD=3, HBA=6) and Ligand B (HBD=1, HBA=3) both fall within acceptable ranges.

**QED:** Both ligands have good QED scores (A: 0.627, B: 0.787), indicating drug-likeness.

**DILI:** Ligand A (78.402) has a higher DILI risk than Ligand B (57.038), but both are acceptable.

**BBB:** Ligand B (81.621) has a significantly better BBB penetration score than Ligand A (65.801). This is a critical factor for a CNS target like DRD2.

**Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and problematic. However, the values are close enough that it doesn't heavily influence the decision.

**Aqueous Solubility:** Both ligands have negative solubility values, which is also problematic. Ligand A (-3.807) is slightly better than Ligand B (-5.209).

**hERG Inhibition:** Ligand A (0.414) has a lower hERG inhibition risk than Ligand B (0.92).

**Microsomal Clearance:** Ligand B (81.452) has a higher microsomal clearance than Ligand A (35.55), indicating lower metabolic stability.

**In vitro Half-Life:** Ligand B (51.433) has a longer in vitro half-life than Ligand A (-37.46), which is desirable.

**P-gp Efflux:** Ligand A (0.098) has lower P-gp efflux liability than Ligand B (0.758), which is beneficial for CNS penetration.

**Binding Affinity:** Both ligands have strong binding affinities (A: -8.8 kcal/mol, B: -9.1 kcal/mol). Ligand B is slightly better, but the difference is relatively small.

**Overall Assessment:**

Ligand B excels in BBB penetration and in vitro half-life, which are crucial for CNS drug development. However, its higher logP, P-gp efflux, and microsomal clearance are concerning. Ligand A has a better balance of properties, with a more favorable logP, lower P-gp efflux, and lower clearance, despite having a slightly lower BBB score. The slightly better affinity of ligand B is not enough to overcome the ADME liabilities.

Output:
0
2025-04-17 06:36:49,161 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (379.913 and 377.495 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (62.3) is significantly better than Ligand B (92.93). For CNS targets, a TPSA <= 90 is preferred, and A is comfortably within this range, while B is close to the upper limit and less desirable.

**3. logP:** Both ligands have acceptable logP values (2.957 and 2.164), falling within the 1-3 range.

**4. H-Bond Donors:** Ligand A (1) is preferable to Ligand B (2). Lower HBD generally improves permeability.

**5. H-Bond Acceptors:** Ligand A (4) is preferable to Ligand B (8). Lower HBA generally improves permeability.

**6. QED:** Both ligands have reasonable QED values (0.773 and 0.613), indicating good drug-like properties.

**7. DILI:** Ligand A (47.15) has a much lower DILI risk than Ligand B (84.064). This is a significant advantage for A.

**8. BBB:** Ligand A (66.886) has a substantially better BBB penetration percentile than Ligand B (19.698). This is *critical* for a CNS target like DRD2.

**9. Caco-2 Permeability:** Ligand A (-5.014) has better Caco-2 permeability than Ligand B (-5.545), although both are negative values which is unusual.

**10. Aqueous Solubility:** Ligand A (-3.817) has better aqueous solubility than Ligand B (-2.93), though both are negative values which is unusual.

**11. hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.342 and 0.183).

**12. Microsomal Clearance:** Ligand A (4.502) has lower microsomal clearance than Ligand B (43.685), indicating better metabolic stability.

**13. In vitro Half-Life:** Ligand B (43.472) has a longer in vitro half-life than Ligand A (3.064).

**14. P-gp Efflux:** Ligand A (0.373) has lower P-gp efflux liability than Ligand B (0.308). Lower efflux is better for CNS exposure.

**15. Binding Affinity:** Both ligands have very similar and excellent binding affinities (-8.7 and -8.3 kcal/mol). The difference is less than 0.5 kcal/mol, so it's not a deciding factor.

**Overall Assessment:**

Ligand A is significantly superior to Ligand B. While both have good binding affinity, Ligand A excels in critical ADME properties for a CNS-targeting GPCR: TPSA, BBB, DILI, and microsomal clearance. The lower TPSA and higher BBB are particularly important for DRD2. Although Ligand B has a longer half-life, the other advantages of Ligand A outweigh this benefit.

Output:
1
2025-04-17 06:36:49,161 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (352.431 and 351.447 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Both ligands have TPSA values (100.8 and 104.46) slightly above the optimal <90 for CNS targets, but still reasonable.

**3. logP:** Both ligands have similar logP values (1.602 and 1.659), falling within the optimal range of 1-3.

**4. H-Bond Donors:** Both ligands have 3 HBD, which is within the acceptable limit of <=5.

**5. H-Bond Acceptors:** Both ligands have 5 HBA, which is within the acceptable limit of <=10.

**6. QED:** Both ligands have similar QED values (0.627 and 0.628), indicating good drug-like properties.

**7. DILI:** Ligand A (29.081) has a significantly lower DILI risk than Ligand B (44.591). This is a substantial advantage.

**8. BBB:** Both ligands have similar BBB penetration (57.115 and 56.999). While not exceeding the desirable >70, they are comparable.

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.828 and -4.9), which is unusual and suggests poor permeability. This is a significant drawback for both.

**10. Aqueous Solubility:** Both ligands have negative solubility values (-1.467 and -1.569), indicating very poor aqueous solubility. This is a major concern for both.

**11. hERG Inhibition:** Both ligands have very low hERG inhibition liability (0.25 and 0.177), which is excellent.

**12. Microsomal Clearance:** Ligand A (-9.622) has a much lower (better) microsomal clearance than Ligand B (35.308), indicating greater metabolic stability.

**13. In vitro Half-Life:** Ligand A (55.561) has a significantly longer in vitro half-life than Ligand B (-29.538). This is a major advantage.

**14. P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.096 and 0.164), which is favorable for CNS penetration.

**15. Binding Affinity:** Ligand A (-8.2 kcal/mol) has a slightly better binding affinity than Ligand B (-7.8 kcal/mol). While the difference is not huge (1.5 kcal/mol), it's enough to be considered.

**Overall Assessment:**

Ligand A is the superior candidate. While both ligands suffer from poor Caco-2 permeability and solubility, Ligand A demonstrates significantly better metabolic stability (lower Cl_mic, longer t1/2), lower DILI risk, and slightly improved binding affinity. These factors, particularly the improved safety profile (DILI) and pharmacokinetic properties (Cl_mic, t1/2), outweigh the comparable BBB penetration and slightly higher affinity of Ligand B.

Output:
0
2025-04-17 06:36:49,162 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (369.491 and 359.539 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (91.42) is slightly above the optimal <90 for CNS targets, but still reasonable. Ligand B (28.6) is excellent, well below 90, suggesting good BBB penetration potential.

**logP:** Ligand A (1.017) is at the lower end of the optimal 1-3 range, potentially hindering permeability. Ligand B (3.945) is closer to the upper end, which is good for permeability but could raise solubility concerns.

**H-Bond Donors/Acceptors:** Ligand A has 1 HBD and 6 HBA, which are acceptable. Ligand B has 0 HBD and 5 HBA, also acceptable.

**QED:** Both ligands have similar QED values (0.722 and 0.678), indicating good drug-like properties.

**DILI:** Ligand A (67.235) has a higher DILI risk than Ligand B (23.808), which is a significant negative.

**BBB:** Ligand A (42.342) has a poor BBB percentile, making CNS penetration unlikely. Ligand B (93.331) has an excellent BBB percentile, a crucial advantage for a DRD2 ligand.

**Caco-2 Permeability:** Ligand A (-5.378) has poor Caco-2 permeability, consistent with its lower logP. Ligand B (-4.565) is also not great, but better than ligand A.

**Aqueous Solubility:** Ligand A (-2.336) has poor solubility. Ligand B (-4.339) also has poor solubility.

**hERG:** Ligand A (0.233) has a very low hERG risk, which is excellent. Ligand B (0.934) has a slightly higher, but still acceptable, hERG risk.

**Microsomal Clearance:** Ligand A (45.079) has moderate clearance. Ligand B (84.577) has high clearance, indicating lower metabolic stability.

**In vitro Half-Life:** Ligand A (-20.345) has a very short half-life. Ligand B (19.624) has a reasonable half-life.

**P-gp Efflux:** Ligand A (0.087) has low P-gp efflux, which is favorable for CNS penetration. Ligand B (0.835) has higher P-gp efflux, which is less desirable.

**Binding Affinity:** Ligand B (-7.2 kcal/mol) has a significantly stronger binding affinity than Ligand A (-6.9 kcal/mol). This 1.5 kcal/mol difference is substantial and can outweigh some ADME drawbacks.

**Overall Assessment:**

Ligand B is the superior candidate. While its solubility and metabolic stability are concerns, its excellent BBB penetration, strong binding affinity, and low DILI risk outweigh these drawbacks. Ligand A suffers from poor BBB penetration, poor solubility, short half-life, and a higher DILI risk, making it a less promising candidate despite its low hERG risk. The strong affinity of Ligand B, coupled with its favorable BBB profile, makes it much more likely to be a viable drug candidate for a CNS target like DRD2.

Output:
1
2025-04-17 06:36:49,162 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (380.275 Da) is slightly higher than Ligand B (350.503 Da), but both are acceptable.

**2. TPSA:** Ligand A (61.44) is much better than Ligand B (78.43). For CNS targets, we want TPSA <= 90, and ideally closer to 60. Ligand A is comfortably within the desirable range, while Ligand B is approaching the upper limit and less favorable.

**3. logP:** Ligand A (4.379) is a bit high, potentially leading to solubility issues and off-target interactions. Ligand B (2.378) is within the optimal range (1-3).

**4. H-Bond Donors:** Both have acceptable HBD counts (Ligand A: 2, Ligand B: 3), well below the threshold of 5.

**5. H-Bond Acceptors:** Both have acceptable HBA counts (Ligand A: 3, Ligand B: 3), well below the threshold of 10.

**6. QED:** Ligand A (0.809) has a significantly better QED score than Ligand B (0.529), indicating a more drug-like profile.

**7. DILI:** Ligand A (73.401) has a higher DILI risk than Ligand B (10.857). This is a significant drawback for Ligand A.

**8. BBB:** Ligand A (67.352) has a better BBB penetration percentile than Ligand B (48.313). For a CNS target like DRD2, >70 is desirable, so both are suboptimal, but Ligand A is closer.

**9. Caco-2 Permeability:** Both have negative Caco-2 values (-4.647 and -4.689), which is unusual and suggests poor permeability. This is a concern for both.

**10. Aqueous Solubility:** Both have negative solubility values (-5.48 and -3.089), indicating very poor aqueous solubility. This is a major issue for both compounds.

**11. hERG Inhibition:** Ligand A (0.746) has a slightly higher hERG inhibition risk than Ligand B (0.225), but both are relatively low.

**12. Microsomal Clearance:** Ligand A (30.982) has lower microsomal clearance than Ligand B (40.912), suggesting better metabolic stability.

**13. In vitro Half-Life:** Ligand A (100.592) has a much longer in vitro half-life than Ligand B (-15.623). This is a significant advantage for Ligand A.

**14. P-gp Efflux:** Ligand A (0.318) has lower P-gp efflux liability than Ligand B (0.145), which is favorable for CNS penetration.

**15. Binding Affinity:** Ligand A (-8.5 kcal/mol) has a significantly stronger binding affinity than Ligand B (-7.6 kcal/mol). This is a crucial advantage, potentially outweighing some of the ADME drawbacks.

**Overall Assessment:**

Ligand A has a superior binding affinity, better TPSA, QED, BBB, metabolic stability, half-life, and P-gp efflux. However, it has a higher DILI risk and a less optimal logP. Ligand B has a better logP and lower DILI risk, but suffers from weaker binding affinity, higher TPSA, and poorer ADME properties overall.

Given the importance of affinity for GPCRs, and the relatively large difference in binding energy (-8.5 vs -7.6 kcal/mol), Ligand A is the more promising candidate *despite* its higher DILI risk and logP. The DILI risk could potentially be mitigated through structural modifications, but improving the affinity of Ligand B to a similar level as Ligand A would be more challenging.

Output:
1
2025-04-17 06:36:49,162 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (355.395 and 347.503 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (118.81) is slightly above the optimal <90 for CNS targets, but still reasonable. Ligand B (81.99) is excellent, well below 90.

**logP:** Ligand A (0.384) is quite low, potentially hindering membrane permeability. Ligand B (3.298) is within the optimal 1-3 range. This is a significant advantage for Ligand B.

**H-Bond Donors/Acceptors:** Both have 2 HBDs, which is good. Ligand A has 8 HBAs, while Ligand B has 3. Both are within acceptable limits (<=10), but Ligand B is preferable.

**QED:** Both ligands have good QED scores (0.804 and 0.595, respectively), indicating drug-like properties.

**DILI:** Ligand A (67.39) has a higher DILI risk than Ligand B (31.059).

**BBB:** Ligand B (73.284) has a significantly better BBB penetration score than Ligand A (48.197). This is crucial for a CNS target like DRD2.

**Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and suggests poor permeability. However, the scale is not specified, so it's hard to interpret.

**Aqueous Solubility:** Both have negative solubility values, which is also unusual and suggests poor solubility. The scale is not specified, so it's hard to interpret.

**hERG Inhibition:** Ligand A (0.078) has a very low hERG risk, which is excellent. Ligand B (0.671) is higher, representing a moderate risk.

**Microsomal Clearance:** Ligand A (20.612) has lower clearance, suggesting better metabolic stability than Ligand B (77.37).

**In vitro Half-Life:** Ligand A (-25.742) has a negative half-life, which is impossible. Ligand B (-5.897) also has a negative half-life, which is impossible. These values are likely errors or on a different scale.

**P-gp Efflux:** Ligand A (0.045) has very low P-gp efflux, which is favorable for CNS penetration. Ligand B (0.288) has moderate P-gp efflux.

**Binding Affinity:** Ligand B (-7.4 kcal/mol) has a slightly better binding affinity than Ligand A (-6.8 kcal/mol). While both are good, the 0.6 kcal/mol difference is notable.

**Overall Assessment:**

Considering the GPCR-specific priorities, Ligand B is the more promising candidate. Its superior logP, BBB penetration, and binding affinity outweigh the slightly higher hERG risk and higher metabolic clearance. The lower TPSA is also a benefit. The questionable Caco-2 and solubility values, and the impossible half-life values, are concerning for both, but the other factors push Ligand B ahead.

Output:
1
2025-04-17 06:36:49,162 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (350.463 and 338.459 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (84.42) is better than Ligand B (79.42). Both are below the 90 A^2 threshold for CNS targets, which is excellent.

**3. logP:** Ligand A (1.353) is within the optimal range (1-3). Ligand B (3.351) is at the higher end of the optimal range, but still acceptable.

**4. H-Bond Donors:** Both ligands have 1 HBD, which is within the acceptable limit of <=5.

**5. H-Bond Acceptors:** Ligand A has 5 HBAs, and Ligand B has 6. Both are below the acceptable limit of <=10.

**6. QED:** Both ligands have good QED scores (0.727 and 0.837, respectively), indicating good drug-like properties.

**7. DILI:** Ligand A (23.769) has a significantly lower DILI risk than Ligand B (37.999). This is a substantial advantage.

**8. BBB:** Ligand B (82.125) has a better BBB penetration percentile than Ligand A (68.554). This is a critical factor for a CNS target like DRD2.

**9. Caco-2 Permeability:** Ligand A (-4.791) is significantly better than Ligand B (-5.094). Higher values indicate better intestinal absorption.

**10. Aqueous Solubility:** Ligand A (-0.629) is better than Ligand B (-3.977). Higher values indicate better solubility.

**11. hERG Inhibition:** Ligand A (0.173) has a lower hERG inhibition liability than Ligand B (0.433), indicating a lower risk of cardiotoxicity.

**12. Microsomal Clearance:** Ligand B (34.87) has a lower microsomal clearance than Ligand A (44.216), suggesting better metabolic stability.

**13. In vitro Half-Life:** Ligand A (4.31) has a longer half-life than Ligand B (-5.133).

**14. P-gp Efflux:** Ligand A (0.012) has significantly lower P-gp efflux liability than Ligand B (0.399). Lower efflux is crucial for CNS exposure.

**15. Binding Affinity:** Ligand A (-7.5 kcal/mol) has a slightly better binding affinity than Ligand B (-6.9 kcal/mol). While both are good, the 0.6 kcal/mol difference is noteworthy.

**Overall Assessment:**

Ligand A excels in several key areas: DILI risk, solubility, hERG inhibition, P-gp efflux, and binding affinity. While Ligand B has a better BBB score and metabolic stability, the advantages of Ligand A in safety (DILI, hERG) and CNS penetration (P-gp) are more important for a DRD2 ligand. The slightly better affinity of Ligand A further strengthens its position.

Output:
1
2025-04-17 06:36:49,162 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B based on the provided guidelines, prioritizing GPCR-specific properties (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (349.391 Da) is slightly lower, which could be beneficial for permeability, but both are acceptable.

**TPSA:** Ligand A (96.77) is closer to the ideal range for CNS targets (<=90), while Ligand B (79.37) is even better. This favors Ligand B.

**logP:** Ligand A (-1.002) is a bit low, potentially hindering permeation. Ligand B (1.714) is within the optimal range (1-3). This is a significant advantage for Ligand B.

**H-Bond Donors/Acceptors:** Both ligands have acceptable HBD (1) and HBA (6/4) counts.

**QED:** Both ligands have good QED scores (0.703 and 0.781), indicating good drug-like properties.

**DILI:** Both ligands have similar and acceptable DILI risk (57.076 and 56.844, both <60).

**BBB:** Ligand B (67.158) has a considerably higher BBB percentile than Ligand A (53.432). This is a crucial advantage for a CNS target like DRD2.

**Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and suggests poor permeability. However, the scale is not defined, so we can't interpret these values definitively.

**Aqueous Solubility:** Both ligands have negative solubility values, which is also unusual. Again, the scale is undefined.

**hERG Inhibition:** Both ligands have very low hERG inhibition liability (0.042 and 0.627), indicating a low risk of cardiotoxicity.

**Microsomal Clearance:** Ligand A (-9.767) has a *lower* (better) microsomal clearance than Ligand B (-22.204). This suggests better metabolic stability for Ligand A.

**In vitro Half-Life:** Ligand B (-30.813) has a significantly longer in vitro half-life than Ligand A (-3.92). This is a major advantage for Ligand B.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.012 and 0.034), which is favorable for CNS penetration.

**Binding Affinity:** Ligand B (-7.9 kcal/mol) has a slightly better binding affinity than Ligand A (-7.5 kcal/mol). While the difference is not huge, it's still a positive for Ligand B.

**Overall Assessment:**

Considering the GPCR-specific priorities, Ligand B is the more promising candidate. It has a better logP, significantly higher BBB penetration, and a longer half-life. While Ligand A has better metabolic stability (lower Cl_mic), the advantages of Ligand B in terms of CNS penetration and drug-like properties outweigh this drawback. The slightly better binding affinity of Ligand B is also a plus.

Output:
1
2025-04-17 06:36:49,163 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (352.519 and 354.407 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (67.43) is significantly better than Ligand B (116.84).  For CNS targets, we want TPSA <= 90, and A is comfortably within that, while B exceeds it. This is a substantial advantage for A.

**logP:** Ligand A (3.195) is optimal (1-3). Ligand B (-0.47) is quite low, potentially hindering membrane permeability and CNS penetration. This is a significant drawback for B.

**H-Bond Donors/Acceptors:** Ligand A (HBD=2, HBA=3) and Ligand B (HBD=3, HBA=5) are both acceptable, falling within the recommended limits.

**QED:** Ligand A (0.692) is good, indicating drug-likeness. Ligand B (0.362) is below the 0.5 threshold, suggesting a less favorable drug-like profile.

**DILI:** Ligand A (29.391) has a lower DILI risk than Ligand B (42.807), which is preferable.

**BBB:** Ligand A (60.876) is moderately good, but Ligand B (78.79) is significantly better, exceeding the desirable >70 threshold for CNS targets. This is a key advantage for B.

**Caco-2 Permeability:** Ligand A (-4.794) has poor Caco-2 permeability, while Ligand B (-5.308) is also poor. Both are unfavorable.

**Aqueous Solubility:** Ligand A (-3.268) and Ligand B (-1.595) both have poor aqueous solubility.

**hERG:** Both ligands have very low hERG inhibition risk (0.362 and 0.054 respectively), which is excellent.

**Microsomal Clearance:** Ligand A (63.361) has higher clearance than Ligand B (16.009), indicating lower metabolic stability. This favors B.

**In vitro Half-Life:** Ligand A (15.512) has a longer half-life than Ligand B (2.063), which is preferable.

**P-gp Efflux:** Ligand A (0.08) has slightly higher P-gp efflux than Ligand B (0.006), which is unfavorable for CNS penetration. This favors B.

**Binding Affinity:** Ligand A (-7.9 kcal/mol) has a slightly better binding affinity than Ligand B (-7.5 kcal/mol), although both are excellent. The 0.4 kcal/mol difference is potentially significant.

**Overall Assessment:**

Ligand B excels in BBB penetration and has better metabolic stability (lower Cl_mic) and lower P-gp efflux, which are crucial for CNS GPCR targets. However, its low logP and TPSA are concerning. Ligand A has a better TPSA, QED, DILI, and half-life, and a slightly better binding affinity, but suffers from poor BBB penetration and higher clearance.

Given the emphasis on CNS penetration for a DRD2 ligand, and the substantial difference in BBB scores, Ligand B is initially favored. However, the very low logP of B is a significant concern. The slightly better affinity of A, combined with its more favorable TPSA and QED, and the fact that the difference in binding affinity isn't enormous, makes it a reasonable candidate. The poor Caco-2 permeability of both is a concern, but can potentially be addressed with formulation strategies.

Considering all factors, the slightly better binding affinity and more favorable physicochemical properties (TPSA, QED, DILI) of Ligand A, despite its lower BBB, make it a more promising starting point for optimization. The BBB issue could be addressed through structural modifications.

Output:
0
2025-04-17 06:36:49,163 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (346.391 and 353.419 Da) fall within the ideal range of 200-500 Da.

**TPSA:** Ligand A (106.15) is slightly above the optimal <90 for CNS targets, but still reasonable. Ligand B (96.97) is excellent, well within the desired range.

**logP:** Ligand A (0.595) is a bit low, potentially hindering permeation. Ligand B (0.266) is even lower and concerning for permeability.

**H-Bond Donors/Acceptors:** Ligand A (1 HBD, 7 HBA) is good. Ligand B (2 HBD, 5 HBA) is also acceptable.

**QED:** Both ligands have reasonable QED scores (0.849 and 0.714), indicating good drug-like properties.

**DILI:** Ligand A (67.429) has a higher DILI risk than Ligand B (28.577), which is a significant advantage for B.

**BBB:** Ligand B (73.284) has a substantially better BBB penetration score than Ligand A (66.499). This is crucial for a CNS target like DRD2.

**Caco-2 Permeability:** Ligand A (-5.148) and Ligand B (-4.775) both have negative Caco-2 values, which is unusual and suggests poor permeability. However, the scale isn't specified, so it's hard to interpret.

**Aqueous Solubility:** Both ligands have poor aqueous solubility (-2.454 and -1.526).

**hERG:** Both ligands have very low hERG inhibition liability (0.104 and 0.188), which is excellent.

**Microsomal Clearance:** Ligand A (16.139) has a higher microsomal clearance than Ligand B (8.567), suggesting lower metabolic stability.

**In vitro Half-Life:** Ligand B (-14.592) has a significantly *shorter* in vitro half-life than Ligand A (0.433), which is a major drawback.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.032 and 0.007), which is favorable for CNS penetration.

**Binding Affinity:** Both ligands have very similar and excellent binding affinities (-8.4 and -8.2 kcal/mol). The difference is less than 1.5 kcal/mol, so it's not a deciding factor.

**Conclusion:**

Despite the similar binding affinities, Ligand B is the more promising candidate. Its significantly better BBB penetration (73.284 vs 66.499), much lower DILI risk (28.577 vs 67.429), and lower P-gp efflux are crucial advantages for a CNS-targeting GPCR. The shorter half-life of Ligand B is a concern, but potentially addressable through structural modifications. The lower logP values for both are a concern, but the other benefits of Ligand B outweigh this.

Output:
1
2025-04-17 06:36:49,163 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 drug candidates, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (346.471 and 366.55 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (73.58) is significantly higher than the preferred <90 for CNS targets, while Ligand B (33.95) is excellent. This is a substantial advantage for Ligand B.

**3. logP:** Ligand A (2.419) is within the optimal 1-3 range. Ligand B (4.692) is slightly higher, potentially leading to solubility issues or off-target interactions, but not drastically so.

**4. H-Bond Donors:** Ligand A (2) and Ligand B (0) both meet the <=5 criteria.

**5. H-Bond Acceptors:** Both ligands (A: 5, B: 5) are within the acceptable limit of <=10.

**6. QED:** Both ligands have reasonable QED values (A: 0.742, B: 0.611), indicating good drug-like properties.

**7. DILI:** Ligand A (7.445) has a very low DILI risk, significantly better than Ligand B (23.769).

**8. BBB:** Ligand B (80.419) has a much higher BBB penetration percentile than Ligand A (59.519). This is a critical advantage for a CNS target like DRD2.

**9. Caco-2 Permeability:** Both have negative values, which is unusual. However, the magnitude is similar (-4.861 vs -4.951), so this doesn't strongly favor either.

**10. Aqueous Solubility:** Both have negative values, indicating poor solubility. Ligand A (-2.088) is slightly better than Ligand B (-4.155), but both are problematic.

**11. hERG Inhibition:** Ligand A (0.68) is a lower risk than Ligand B (0.939).

**12. Microsomal Clearance:** Ligand A (29.161) has lower clearance, suggesting better metabolic stability than Ligand B (50.844).

**13. In vitro Half-Life:** Ligand B (39.223) has a significantly longer half-life than Ligand A (-12.257). This is a major advantage.

**14. P-gp Efflux:** Ligand A (0.068) has lower P-gp efflux, which is desirable for CNS penetration, compared to Ligand B (0.623).

**15. Binding Affinity:** Ligand A (-8.3 kcal/mol) has a stronger binding affinity than Ligand B (-6.9 kcal/mol). This is a substantial advantage, potentially outweighing some ADME drawbacks.

**Overall Assessment:**

Ligand B excels in BBB penetration and has a longer half-life, both crucial for CNS drug development. However, Ligand A has a significantly better binding affinity, lower DILI risk, lower hERG risk, better metabolic stability, and lower P-gp efflux. The TPSA of Ligand A is a concern, but the superior binding affinity and more favorable safety profile are compelling. Given the importance of potency for GPCRs, and the substantial difference in affinity (-8.3 vs -6.9 kcal/mol), I believe Ligand A is the more promising candidate, despite its higher TPSA and lower BBB. Further optimization could address the TPSA issue.

Output:
0
2025-04-17 06:36:49,163 - INFO - Batch 296 complete. Total preferences: 4736
2025-04-17 06:36:49,163 - INFO - Processing batch 297/512...
2025-04-17 06:37:31,295 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (344.459 and 383.945 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (67.23) is slightly above the optimal <90 for CNS targets, but still reasonable. Ligand B (53.51) is excellent, well below 90.

**3. logP:** Both ligands have good logP values (3.058 and 3.686), falling within the 1-3 range.

**4. H-Bond Donors:** Ligand A has 1 HBD, which is good. Ligand B has 0, also good.

**5. H-Bond Acceptors:** Both ligands have 4 HBA, which is acceptable (<=10).

**6. QED:** Both ligands have QED values (0.854 and 0.782) above 0.5, indicating good drug-like properties.

**7. DILI:** Ligand A (37.301) has a lower DILI risk than Ligand B (58.395), which is preferable.

**8. BBB:** This is a critical parameter for a CNS target like DRD2. Ligand A has a significantly higher BBB percentile (91.896) compared to Ligand B (72.005). This is a major advantage for Ligand A.

**9. Caco-2 Permeability:** Both have negative Caco-2 values (-4.805 and -4.871), which is unusual and suggests poor permeability. This is a concern for both, but doesn't necessarily disqualify either.

**10. Aqueous Solubility:** Both have negative solubility values (-3.548 and -4.269), indicating very poor aqueous solubility. This is a significant drawback for both.

**11. hERG Inhibition:** Ligand A (0.294) has a much lower hERG inhibition risk than Ligand B (0.633). This is a significant advantage for Ligand A.

**12. Microsomal Clearance:** Ligand B (56.591) has a higher microsomal clearance than Ligand A (38.937), meaning it's likely to be metabolized faster. Lower clearance is preferred.

**13. In vitro Half-Life:** Ligand A (10.009) has a longer in vitro half-life than Ligand B (-5.038). This is a positive for Ligand A.

**14. P-gp Efflux:** Ligand A (0.254) shows lower P-gp efflux liability than Ligand B (0.797), which is desirable for CNS penetration.

**15. Binding Affinity:** Ligand A (-8.3 kcal/mol) has a substantially stronger binding affinity than Ligand B (-0.0 kcal/mol). This is a decisive advantage for Ligand A.

**Overall Assessment:**

Ligand A is clearly superior. It has a significantly better binding affinity, higher BBB penetration, lower DILI risk, lower hERG inhibition, longer half-life, and lower P-gp efflux. While both have poor solubility and permeability, the substantial advantages of Ligand A in terms of target engagement and CNS penetration outweigh these drawbacks. The large difference in binding affinity is particularly important.

Output:
1
2025-04-17 06:37:31,295 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (366.845 and 347.459 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (70.08) is better than Ligand B (73.74). Both are reasonably good for CNS penetration, being below 90, but A is closer to the ideal.

**3. logP:** Both ligands (2.035 and 2.216) are within the optimal 1-3 range.

**4. H-Bond Donors:** Both have 1 HBD, which is acceptable.

**5. H-Bond Acceptors:** Both have 4 HBA, which is acceptable.

**6. QED:** Both ligands have good QED scores (0.883 and 0.821), indicating good drug-like properties.

**7. DILI:** Ligand A (55.68) has a slightly higher DILI risk than Ligand B (35.479), but both are below the concerning threshold of 60.

**8. BBB:** Ligand B (51.221) has a significantly better BBB penetration percentile than Ligand A (43.699). This is a crucial factor for a CNS target like DRD2.

**9. Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and suggests poor permeability. However, the values are similar (-4.918 vs -4.743).

**10. Aqueous Solubility:** Both have negative solubility values, which is also unusual. Again, the values are similar (-2.288 vs -1.884).

**11. hERG Inhibition:** Ligand A (0.048) has a lower hERG inhibition liability than Ligand B (0.374), making it safer from a cardiotoxicity perspective.

**12. Microsomal Clearance:** Ligand B (47.327) has a much higher microsomal clearance than Ligand A (0.243), indicating lower metabolic stability. This is a significant drawback.

**13. In vitro Half-Life:** Ligand B (8.817) has a longer in vitro half-life than Ligand A (-2.155), which is generally desirable. However, the negative value for A is concerning.

**14. P-gp Efflux:** Ligand A (0.012) has a much lower P-gp efflux liability than Ligand B (0.09), which is favorable for CNS penetration.

**15. Binding Affinity:** Ligand B (-7.9 kcal/mol) has a slightly better binding affinity than Ligand A (-8.8 kcal/mol). While the difference is small, it's still a positive for Ligand B.

**Overall Assessment:**

Ligand B has a better BBB score and binding affinity, which are key for a CNS GPCR target. However, it suffers from significantly higher microsomal clearance and P-gp efflux, and a higher hERG risk. Ligand A has better metabolic stability (lower Cl_mic and Pgp), lower hERG risk, and a slightly better TPSA. The negative solubility and Caco-2 values are concerning for both, but the differences in metabolic stability and efflux are more critical. The slightly better affinity of Ligand B is likely outweighed by the ADME concerns.

Output:
0
2025-04-17 06:37:31,295 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (383.704 and 380.63 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (67.01) is higher than Ligand B (40.62). For CNS targets, we prefer TPSA <= 90, so both are acceptable, but B is significantly better.

**3. logP:** Ligand A (3.835) is slightly higher than Ligand B (2.775). Both fall within the optimal 1-3 range.

**4. H-Bond Donors:** Ligand A has 2 HBD, while Ligand B has 0. Both are within the acceptable limit of <=5.

**5. H-Bond Acceptors:** Both ligands have 3 HBA, which is well within the limit of <=10.

**6. QED:** Both ligands have good QED scores (0.609 and 0.689, respectively), indicating drug-like properties.

**7. DILI:** Ligand A (66.15) has a higher DILI risk than Ligand B (25.087). This is a significant advantage for Ligand B.

**8. BBB:** Ligand B (74.292) has a much better BBB penetration percentile than Ligand A (65.529). This is crucial for a CNS target like DRD2.

**9. Caco-2 Permeability:** Ligand A (-4.932) has worse Caco-2 permeability than Ligand B (-5.057). Both are negative, indicating poor permeability, but A is slightly better.

**10. Aqueous Solubility:** Ligand A (-4.575) has worse aqueous solubility than Ligand B (-3.919). Both are negative, indicating poor solubility, but B is slightly better.

**11. hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.566 and 0.52, respectively).

**12. Microsomal Clearance:** Ligand B (67.754) has a higher microsomal clearance than Ligand A (24.841), meaning A is more metabolically stable.

**13. In vitro Half-Life:** Ligand B (-18.359) has a much longer in vitro half-life than Ligand A (-7.354). This is a significant advantage for B.

**14. P-gp Efflux:** Ligand B (0.217) has lower P-gp efflux than Ligand A (0.386). Lower efflux is preferred for CNS penetration.

**15. Binding Affinity:** Ligand A (-8.9 kcal/mol) has a significantly stronger binding affinity than Ligand B (-0.0 kcal/mol). This is a major advantage for A.

**Overall Assessment:**

While Ligand A has a substantially better binding affinity, Ligand B excels in ADME properties critical for CNS drug development. Specifically, its superior BBB penetration, lower DILI risk, longer half-life, and lower P-gp efflux are highly favorable. The difference in binding affinity is substantial, but a difference of 8.9 kcal/mol can potentially be overcome with further optimization. The poor ADME profile of Ligand A, particularly the lower BBB and higher DILI, makes it less likely to succeed as a drug candidate.

Output:
1
2025-04-17 06:37:31,296 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (350.419 and 352.523 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (115.39) is higher than the preferred <90 for CNS targets, while Ligand B (55.89) is well within the desired range. This is a significant advantage for Ligand B.

**3. logP:** Ligand A (0.291) is quite low, potentially hindering membrane permeability. Ligand B (1.025) is better, falling within the optimal 1-3 range.

**4. H-Bond Donors:** Ligand A has 3 HBD, acceptable. Ligand B has 1 HBD, also acceptable.

**5. H-Bond Acceptors:** Ligand A has 5 HBA, acceptable. Ligand B has 4 HBA, also acceptable.

**6. QED:** Both ligands have good QED scores (0.623 and 0.743, respectively), indicating drug-like properties.

**7. DILI:** Ligand A (26.095) has a lower DILI risk than Ligand B (6.049), which is favorable.

**8. BBB:** Ligand B (67.468) has a considerably higher BBB penetration percentile than Ligand A (43.583). This is crucial for a CNS target like DRD2.

**9. Caco-2 Permeability:** Ligand A (-5.326) has poor Caco-2 permeability. Ligand B (-4.809) is also poor, but slightly better.

**10. Aqueous Solubility:** Ligand A (-1.705) and Ligand B (-0.79) both have poor aqueous solubility, but Ligand B is slightly better.

**11. hERG Inhibition:** Both ligands have low hERG inhibition risk (0.253 and 0.495, respectively).

**12. Microsomal Clearance:** Ligand A (6.844) has lower microsomal clearance, suggesting better metabolic stability, than Ligand B (12.106).

**13. In vitro Half-Life:** Both ligands have negative in vitro half-life values (-12.125 and -12.336). This is unusual and suggests rapid metabolism or instability, but the values are similar.

**14. P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.014 and 0.006, respectively), which is excellent for CNS penetration.

**15. Binding Affinity:** Ligand B (-7.4 kcal/mol) has a slightly better binding affinity than Ligand A (-7.9 kcal/mol). While the difference is small, it's still a positive for Ligand B.

**Overall Assessment:**

Ligand B is the more promising candidate. While Ligand A has a slightly lower DILI risk and better metabolic stability, Ligand B excels in the key GPCR-specific properties: significantly better TPSA, a substantially higher BBB percentile, and a slightly improved binding affinity. The logP value of Ligand B is also more favorable. The poor Caco-2 and solubility of both are concerns, but can be addressed through formulation strategies. The BBB penetration is the most critical factor here, given the CNS target.

Output:
1
2025-04-17 06:37:31,296 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B based on the provided guidelines, prioritizing GPCR-specific properties (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (356.897 Da) is slightly lower, which can be favorable for permeability.

**TPSA:** Ligand A (32.34) is significantly better than Ligand B (64.16). For CNS targets, TPSA should be <= 90, and ideally lower. Ligand A is well within this range, while Ligand B is approaching the upper limit and less desirable.

**logP:** Both ligands have acceptable logP values (A: 4.564, B: 3.59), falling within the 1-3 optimal range, though A is a bit high.

**H-Bond Donors/Acceptors:** Ligand A (HBD=1, HBA=1) is better than Ligand B (HBD=0, HBA=6). Lower HBD/HBA generally improves permeability.

**QED:** Both ligands have reasonable QED values (A: 0.808, B: 0.658), indicating good drug-like properties.

**DILI:** Ligand A (35.556) has a slightly better DILI score than Ligand B (45.522), indicating a lower risk of liver injury. Both are below the 60 threshold.

**BBB:** Ligand B (96.084) has a significantly higher BBB percentile than Ligand A (86.545). This is a crucial factor for CNS targets like DRD2, making Ligand B initially more attractive.

**Caco-2 Permeability:** Ligand A (-4.477) has a worse Caco-2 permeability than Ligand B (-5.121), meaning B is more permeable.

**Aqueous Solubility:** Ligand A (-5.243) has a worse solubility than Ligand B (-2.272).

**hERG:** Both ligands have low hERG inhibition liability (A: 0.839, B: 0.962).

**Microsomal Clearance:** Ligand B (14.693) has a significantly lower microsomal clearance than Ligand A (82.727), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (54.282) has a better in vitro half-life than Ligand B (11.19).

**P-gp Efflux:** Ligand A (0.387) has a lower P-gp efflux liability than Ligand B (0.91), which is favorable for CNS penetration.

**Binding Affinity:** Ligand B (-11.0) has a slightly better binding affinity than Ligand A (-10.3). While both are excellent, the difference is not huge.

**Overall Assessment:**

Ligand B excels in BBB penetration and metabolic stability, which are critical for a CNS GPCR target. While Ligand A has better P-gp efflux, the superior BBB value of Ligand B outweighs this advantage. Ligand B's slightly better binding affinity also contributes. The TPSA of Ligand A is better, but the difference is not enough to overcome the advantages of Ligand B regarding BBB and metabolic stability.

Output:
1
2025-04-17 06:37:31,296 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (364.398 and 364.471 Da) fall comfortably within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (106.33) is slightly above the optimal <90 for CNS targets, but still reasonable. Ligand B (87.46) is excellent, well below 90. This favors Ligand B.

**3. logP:** Both ligands have a logP of approximately 1.46, which is within the optimal 1-3 range. No significant difference here.

**4. H-Bond Donors:** Both have 2 HBD, which is acceptable (<=5).

**5. H-Bond Acceptors:** Ligand A has 4 HBA, and Ligand B has 6 HBA. Both are within the acceptable range (<=10).

**6. QED:** Ligand A (0.757) has a better QED than Ligand B (0.66), suggesting a more drug-like profile.

**7. DILI:** Ligand A (77.549) has a higher DILI risk than Ligand B (27.142). This is a significant advantage for Ligand B.

**8. BBB:** This is crucial for a CNS target like DRD2. Ligand A has a BBB penetration of 63.94%, which is okay but not great. Ligand B has a very low BBB penetration of 29.857%. This is a major drawback for Ligand B.

**9. Caco-2 Permeability:** Ligand A (-5.023) shows poor Caco-2 permeability, while Ligand B (-5.808) is even worse. Both are undesirable.

**10. Aqueous Solubility:** Ligand A (-3.299) and Ligand B (-0.64) both have poor solubility. Ligand B is slightly better.

**11. hERG Inhibition:** Both ligands have low hERG inhibition risk (0.33 and 0.329 respectively).

**12. Microsomal Clearance:** Ligand A (0.959) has much lower microsomal clearance than Ligand B (21.351), indicating better metabolic stability. This is a significant advantage for Ligand A.

**13. In vitro Half-Life:** Ligand A (-0.253) has a slightly better (less negative) in vitro half-life than Ligand B (18.286).

**14. P-gp Efflux:** Ligand A (0.24) has lower P-gp efflux than Ligand B (0.063), which is favorable for CNS penetration.

**15. Binding Affinity:** Ligand B (-7.6 kcal/mol) has a slightly better binding affinity than Ligand A (-8.2 kcal/mol). While a difference of 0.6 kcal/mol isn't huge, it's noticeable.

**Overall Assessment:**

Ligand B has better affinity and lower DILI risk. However, its significantly lower BBB penetration is a major concern for a CNS target. Ligand A, while having slightly lower affinity, demonstrates better BBB penetration, lower DILI, better metabolic stability (lower Cl_mic), and lower P-gp efflux. The combination of these factors, particularly the BBB penetration and metabolic stability, makes Ligand A the more promising candidate despite the slightly weaker binding affinity. The affinity difference is not large enough to overcome the ADME deficiencies of Ligand B.

Output:
0
2025-04-17 06:37:31,297 - INFO - Reasoning:

Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (351.491 and 347.419 Da) fall comfortably within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (78.51) is significantly better than Ligand B (110.32). For CNS targets, we want TPSA <= 90, so Ligand A is preferable.

**3. logP:** Ligand A (1.55) is within the optimal 1-3 range. Ligand B (0.041) is quite low, potentially hindering permeation. This favors Ligand A.

**4. H-Bond Donors:** Both have 2 HBD, which is acceptable (<=5).

**5. H-Bond Acceptors:** Ligand A has 3 HBA, and Ligand B has 5. Both are within the acceptable limit of <=10, but Ligand A is slightly better.

**6. QED:** Both ligands have good QED scores (0.651 and 0.783), indicating drug-like properties.

**7. DILI:** Ligand A (13.067%) has a much lower DILI risk than Ligand B (43.66%). This is a significant advantage for Ligand A.

**8. BBB:** Ligand A (70.803%) has a good BBB penetration score, exceeding the desirable threshold of >70%. Ligand B (55.138%) is below this threshold, making it less likely to reach the target in the CNS. This is a critical advantage for Ligand A.

**9. Caco-2:** Both have negative Caco-2 values (-5.105 and -5.487), which is unusual and difficult to interpret without further context. However, it doesn't strongly sway the decision as other factors are more decisive.

**10. Solubility:** Both have negative solubility values (-1.761 and -2.339), also unusual. Similar to Caco-2, this doesn't strongly sway the decision.

**11. hERG:** Both ligands have very low hERG inhibition risk (0.322 and 0.132).

**12. Cl_mic:** Ligand A (37.168) has a higher microsomal clearance than Ligand B (-1.19). Lower clearance is preferred, giving a slight edge to Ligand B, but the difference isn't huge.

**13. t1/2:** Ligand A (-13.19) has a negative half-life, which is not physically meaningful. Ligand B (15.254) has a positive half-life, which is preferable.

**14. Pgp:** Both have very low Pgp efflux liability (0.015 and 0.012).

**15. Binding Affinity:** Ligand B (-8.7 kcal/mol) has a stronger binding affinity than Ligand A (-7.3 kcal/mol). This is a 1.4 kcal/mol difference, which is substantial and could potentially outweigh some of the ADME drawbacks of Ligand B *if* the ADME properties were comparable.

**Overall Assessment:**

Despite Ligand B's superior binding affinity, Ligand A is the more promising candidate. The critical factors for a CNS GPCR target are BBB penetration and TPSA, where Ligand A significantly outperforms Ligand B. Ligand A also has a much lower DILI risk. While Ligand B has better metabolic stability (lower Cl_mic and a positive half-life), the differences aren't large enough to overcome the substantial advantages of Ligand A in terms of CNS penetration and safety. The negative half-life for Ligand A is concerning and needs investigation, but the other factors strongly favor it.

Output:
1
2025-04-17 06:37:31,297 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (347.463 and 350.394 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (100.35) is slightly above the optimal <90 for CNS targets, while Ligand B (93.21) is closer to the ideal range. This gives a slight edge to Ligand B.

**3. logP:** Both ligands have good logP values (1.285 and 1.057), falling within the 1-3 range.

**4. H-Bond Donors:** Ligand A has 3 HBD, which is acceptable. Ligand B has 2 HBD, also acceptable.

**5. H-Bond Acceptors:** Ligand A has 4 HBA, and Ligand B has 5 HBA, both within the acceptable limit of <=10.

**6. QED:** Both ligands have good QED scores (0.764 and 0.8), indicating good drug-like properties.

**7. DILI:** Both ligands have similar DILI risk (21.946 and 64.754 percentile). Ligand A is preferable here.

**8. BBB:** This is critical for a CNS target. Ligand B has a significantly higher BBB penetration (84.529%) compared to Ligand A (64.831%). This is a major advantage for Ligand B.

**9. Caco-2 Permeability:** Both have negative Caco-2 values (-5.14 and -4.822). This is unusual and suggests poor permeability. However, these values are on a different scale and hard to directly compare.

**10. Aqueous Solubility:** Both have negative solubility values (-1.882 and -2.023), indicating poor solubility.

**11. hERG Inhibition:** Both ligands show low hERG inhibition risk (0.395 and 0.227).

**12. Microsomal Clearance:** Ligand A has a much lower (better) microsomal clearance (-45.048) compared to Ligand B (6.76). This suggests Ligand A is more metabolically stable.

**13. In vitro Half-Life:** Ligand A has a slightly longer half-life (21.628 hours) than Ligand B (18.278 hours).

**14. P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.007 and 0.014).

**15. Binding Affinity:** Both ligands have similar, strong binding affinities (-8.7 and -8.3 kcal/mol). The difference is less than the 1.5 kcal/mol threshold.

**Overall Assessment:**

While Ligand A has better metabolic stability (lower Cl_mic, longer t1/2) and a slightly lower DILI risk, Ligand B significantly outperforms it in BBB penetration, which is paramount for a CNS-targeting drug like a DRD2 ligand. The TPSA is also slightly better for Ligand B. The binding affinities are comparable. Considering the GPCR-specific priorities, the improved BBB penetration of Ligand B outweighs the advantages of Ligand A.

Output:
1
2025-04-17 06:37:31,297 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 drug candidates, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (357.416 and 348.462 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (29.54) is excellent, well below the 90 A^2 threshold for CNS targets. Ligand B (49.41) is still reasonable, but higher, potentially impacting BBB penetration.

**3. logP:** Ligand A (4.42) is slightly high, potentially leading to solubility issues or off-target interactions. Ligand B (2.838) is within the optimal 1-3 range.

**4. H-Bond Donors:** Both ligands have acceptable HBD counts (0 for A, 1 for B), well below the 5 threshold.

**5. H-Bond Acceptors:** Both ligands have acceptable HBA counts (3 for A, 2 for B), below the 10 threshold.

**6. QED:** Both ligands have similar and acceptable QED values (0.677 and 0.627, both > 0.5).

**7. DILI:** Ligand A (8.298) has a very low DILI risk, significantly better than Ligand B (29.701).

**8. BBB:** This is crucial for a CNS target. Ligand A (95.541) has excellent BBB penetration, exceeding the desirable >70 threshold. Ligand B (74.913) is good, but not as favorable.

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.546 and -4.607), which is unusual and suggests poor permeability. However, these values are on a log scale and negative values are not uncommon.

**10. Aqueous Solubility:** Both ligands have negative solubility values (-4.433 and -3.824), indicating poor aqueous solubility. This is a concern, especially given Ligand A's higher logP.

**11. hERG Inhibition:** Ligand A (0.979) has a slightly higher hERG risk than Ligand B (0.355), but both are reasonably low.

**12. Microsomal Clearance:** Ligand A (48.934) has higher microsomal clearance than Ligand B (32.526), indicating faster metabolism and potentially lower in vivo exposure.

**13. In vitro Half-Life:** Ligand B (-22.32) has a negative half-life, which is not possible. This is likely an error in the data. Ligand A (5.876) has a reasonable half-life.

**14. P-gp Efflux:** Ligand A (0.562) has lower P-gp efflux liability than Ligand B (0.23), which is favorable for CNS penetration.

**15. Binding Affinity:** Ligand A (-8.7 kcal/mol) has significantly stronger binding affinity than Ligand B (-7.3 kcal/mol). The difference of 1.4 kcal/mol is substantial and can outweigh some of the ADME drawbacks.

**Overall Assessment:**

Ligand A is the stronger candidate despite some ADME concerns. Its significantly superior binding affinity (-8.7 vs -7.3 kcal/mol) and excellent BBB penetration (95.541) are major advantages for a CNS-targeting GPCR. While its logP is a bit high and solubility is low, the strong binding and high BBB penetration are likely to be more critical for efficacy. The lower DILI risk is also a significant plus. Ligand B's negative half-life is a red flag, and its lower BBB penetration and weaker affinity make it less attractive.



Output:
1
2025-04-17 06:37:31,297 - INFO - Reasoning:

Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (383.239 and 342.443 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (93.01) is slightly above the preferred <90 for CNS targets, but still reasonably close. Ligand B (75.5) is well within the desired range.

**3. logP:** Both ligands have good logP values (1.497 and 2.397), falling within the optimal 1-3 range.

**4. H-Bond Donors:** Ligand A (1) and Ligand B (2) are both acceptable, well below the limit of 5.

**5. H-Bond Acceptors:** Ligand A (6) and Ligand B (4) are both below the limit of 10.

**6. QED:** Both ligands have good QED scores (0.641 and 0.773), indicating good drug-like properties.

**7. DILI:** Ligand A (79.643) has a higher DILI risk than Ligand B (43.195). Ligand B is preferable here.

**8. BBB:** This is critical for a CNS target like DRD2. Ligand A (38.426) has a poor BBB percentile, while Ligand B (79.062) is quite good, exceeding the >70 desirable threshold. This is a major advantage for Ligand B.

**9. Caco-2 Permeability:** Both have negative values, which is unusual. However, the magnitude is similar, and this is less critical than BBB for CNS penetration.

**10. Aqueous Solubility:** Both have negative values, indicating poor solubility. This is a drawback for both, but can be addressed with formulation strategies.

**11. hERG Inhibition:** Ligand A (0.019) has a very low hERG risk, slightly better than Ligand B (0.646).

**12. Microsomal Clearance:** Ligand B (53.535) has a significantly higher microsomal clearance than Ligand A (3.898), suggesting faster metabolism and potentially lower *in vivo* exposure.

**13. In vitro Half-Life:** Ligand A (3.333) has a shorter half-life than Ligand B (20.508), further supporting the faster metabolism of Ligand A.

**14. P-gp Efflux:** Both ligands have low P-gp efflux liability (0.056 and 0.067), which is favorable for CNS penetration.

**15. Binding Affinity:** Ligand B (-8.7 kcal/mol) has a slightly better binding affinity than Ligand A (-8.5 kcal/mol), although the difference is small.

**Overall Assessment:**

Ligand B is the stronger candidate. While Ligand A has a slightly better hERG profile, Ligand B excels in the most critical areas for a CNS-targeting GPCR ligand: significantly better BBB penetration, lower DILI risk, and improved metabolic stability (lower Cl_mic, longer t1/2). The slightly better affinity of Ligand B is a bonus. The solubility issues are a concern for both, but are addressable.



Output:
1
2025-04-17 06:37:31,297 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (349.406 and 350.507 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (70.67) is higher than Ligand B (50.6). For CNS targets, TPSA < 90 is preferred, both are within range, but B is better.

**logP:** Ligand A (0.487) is slightly low, potentially hindering permeation. Ligand B (2.249) is within the optimal 1-3 range. This favors B.

**H-Bond Donors:** Ligand A (2) and Ligand B (0) are both acceptable (<=5).

**H-Bond Acceptors:** Ligand A (4) and Ligand B (5) are both acceptable (<=10).

**QED:** Both ligands have good QED scores (0.637 and 0.757, respectively), indicating good drug-like properties.

**DILI:** Ligand A (21.869) has a slightly higher DILI risk than Ligand B (12.796), but both are below the concerning threshold of 40.

**BBB:** Ligand B (80.884) has a significantly better BBB penetration score than Ligand A (74.176). This is a critical advantage for a CNS target like DRD2.

**Caco-2 Permeability:** Ligand A (-4.848) has worse Caco-2 permeability than Ligand B (-4.664). Lower values are less desirable.

**Aqueous Solubility:** Ligand A (-2.122) has worse aqueous solubility than Ligand B (-0.637).

**hERG Inhibition:** Both ligands have similar, low hERG inhibition liability (0.487 and 0.57).

**Microsomal Clearance:** Ligand A (39.849) has lower microsomal clearance than Ligand B (42.095), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand B (11.737) has a significantly longer in vitro half-life than Ligand A (-7.57).

**P-gp Efflux:** Both ligands have similar P-gp efflux liability (0.03 and 0.067).

**Binding Affinity:** Ligand A (-8.4 kcal/mol) has a considerably stronger binding affinity than Ligand B (-6.7 kcal/mol). This is a substantial advantage.

**Overall Assessment:**

Ligand A has a better binding affinity, which is a major plus. However, Ligand B excels in several crucial ADME properties for a CNS-targeting GPCR: significantly better BBB penetration, better logP, better solubility, and a longer half-life. The difference in binding affinity (-1.7 kcal/mol) is substantial, but the ADME advantages of Ligand B, particularly the BBB score, are compelling. Given the importance of CNS penetration for DRD2, and the relatively good affinity of Ligand B, it is the more promising candidate.

Output:
1
2025-04-17 06:37:31,298 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (351.447 and 352.45 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (78.95) is better than Ligand B (58.64), both are below the 90 A^2 threshold for CNS targets.

**logP:** Ligand B (2.357) is optimal (1-3), while Ligand A (0.387) is quite low, potentially hindering membrane permeability.

**H-Bond Donors:** Both have 1 HBD, which is within the acceptable limit of <=5.

**H-Bond Acceptors:** Ligand A has 4 HBA, and Ligand B has 3. Both are below the acceptable limit of <=10.

**QED:** Both ligands have good QED scores (0.795 and 0.848, respectively), indicating drug-like properties.

**DILI:** Ligand A (19.426) has a significantly lower DILI risk than Ligand B (38.891). This is a substantial advantage.

**BBB:** Ligand B (89.221) has a much higher BBB penetration percentile than Ligand A (57.852). This is a critical factor for a CNS target like DRD2.

**Caco-2 Permeability:** Both have negative Caco-2 values (-4.867 and -4.736), which is unusual and suggests poor permeability. However, these values are on a log scale and may not be directly comparable without further context.

**Aqueous Solubility:** Both have negative solubility values (-1.409 and -2.52), also unusual and suggesting poor solubility.

**hERG:** Both ligands have low hERG inhibition liability (0.119 and 0.427).

**Microsomal Clearance:** Ligand A (-3.143) has much lower (better) microsomal clearance than Ligand B (28.221), indicating better metabolic stability.

**In vitro Half-Life:** Ligand A (-2.019) has a better in vitro half-life than Ligand B (11.621).

**P-gp Efflux:** Ligand A (0.015) has significantly lower P-gp efflux liability than Ligand B (0.109), which is favorable for CNS penetration.

**Binding Affinity:** Ligand B (-8.5 kcal/mol) has a stronger binding affinity than Ligand A (-7.2 kcal/mol). The difference is 1.3 kcal/mol, which is a significant advantage.

**Overall Assessment:**

Ligand B excels in BBB penetration and binding affinity, two crucial factors for a CNS GPCR target. However, it has higher DILI risk, higher P-gp efflux, and worse metabolic stability (higher Cl_mic and lower t1/2) compared to Ligand A. Ligand A has a better safety profile (lower DILI), better metabolic stability, and lower P-gp efflux. The lower logP of Ligand A is a concern, but the significantly better affinity of Ligand B might compensate for this.

Considering the balance, the stronger binding affinity of Ligand B, coupled with its excellent BBB penetration, outweighs the slightly higher DILI and P-gp efflux. The metabolic stability is a concern, but can be addressed with structural modifications.

Output:
1
2025-04-17 06:37:31,298 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (338.331 Da) is slightly lower, which could be beneficial for permeability.

**TPSA:** Ligand A (129.65) is closer to the desirable threshold of 90 for CNS targets than Ligand B (52.65). Ligand B is exceptionally low, which might be *too* low and potentially impact binding affinity.

**logP:** Ligand A (-0.674) is a bit low, potentially hindering membrane permeability. Ligand B (2.818) is within the optimal range (1-3). This is a significant advantage for Ligand B.

**H-Bond Donors/Acceptors:** Ligand A has 2 HBD and 7 HBA, while Ligand B has 1 HBD and 3 HBA. Both are within acceptable limits.

**QED:** Both ligands have good QED scores (A: 0.645, B: 0.718), indicating drug-like properties.

**DILI:** Ligand A (85.576) has a considerably higher DILI risk than Ligand B (6.437). This is a major concern for Ligand A.

**BBB:** Ligand B (79.256) has a much better BBB penetration score than Ligand A (23.071). This is crucial for a CNS target like DRD2.

**Caco-2 Permeability:** Ligand A (-5.767) has poor Caco-2 permeability, while Ligand B (-4.627) is also poor, but slightly better.

**Aqueous Solubility:** Both ligands have poor aqueous solubility (-2.59 and -1.894 respectively). This could pose formulation challenges.

**hERG Inhibition:** Ligand A (0.134) shows a slightly higher risk of hERG inhibition than Ligand B (0.614).

**Microsomal Clearance:** Ligand A (-6.287) has significantly lower (better) microsomal clearance than Ligand B (23.924), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (-1.56) has a shorter half-life than Ligand B (-10.998).

**P-gp Efflux:** Ligand A (0.003) has very low P-gp efflux, which is excellent for CNS penetration. Ligand B (0.034) also has low P-gp efflux, but slightly higher.

**Binding Affinity:** Ligand A (-8.8 kcal/mol) has a significantly stronger binding affinity than Ligand B (-7.2 kcal/mol). This is a substantial advantage for Ligand A.

**Overall Assessment:**

Ligand A has a superior binding affinity and better metabolic stability (lower Cl_mic) and P-gp efflux. However, it suffers from poor BBB penetration, higher DILI risk, and lower Caco-2 permeability. Ligand B has a better logP, significantly better BBB penetration, and a much lower DILI risk. The difference in binding affinity (1.6 kcal/mol) is substantial, but the poor ADME properties of Ligand A, especially the low BBB and high DILI, are major drawbacks for CNS drug development. The better BBB penetration and lower toxicity profile of Ligand B outweigh the slightly weaker binding affinity.

Output:
1
2025-04-17 06:37:31,298 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (353.348 and 368.499 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (77.04) is significantly better than Ligand B (84.5). For CNS targets, we want TPSA <= 90, and A is closer to the ideal <= 60 range.

**3. logP:** Both ligands have good logP values (2.009 and 1.421), falling within the optimal 1-3 range.

**4. H-Bond Donors:** Ligand A (1) is better than Ligand B (2). Lower is generally preferred.

**5. H-Bond Acceptors:** Both ligands have 5 H-bond acceptors, which is acceptable (<=10).

**6. QED:** Ligand A (0.916) has a significantly higher QED than Ligand B (0.71), indicating a more drug-like profile.

**7. DILI:** Ligand A (56.572) has a lower DILI risk than Ligand B (40.054), though both are acceptable (<60).

**8. BBB:** Ligand A (87.088) has a much better BBB penetration percentile than Ligand B (54.44). For a CNS target like DRD2, >70 is desirable, and A is closer to that threshold.

**9. Caco-2 Permeability:** Ligand A (-4.888) has worse Caco-2 permeability than Ligand B (-5.453), but both are poor.

**10. Aqueous Solubility:** Both ligands have similar and poor aqueous solubility (-2.695 and -2.617).

**11. hERG Inhibition:** Ligand A (0.638) has a slightly higher hERG risk than Ligand B (0.064), which is a significant advantage for B.

**12. Microsomal Clearance:** Ligand A (-33.474) has much lower (better) microsomal clearance than Ligand B (30.239), indicating greater metabolic stability.

**13. In vitro Half-Life:** Ligand B (-9.98) has a longer in vitro half-life than Ligand A (2.713), which is a positive.

**14. P-gp Efflux:** Ligand A (0.093) has lower P-gp efflux than Ligand B (0.103), which is favorable for CNS penetration.

**15. Binding Affinity:** Ligand A (-9.0) has a significantly stronger binding affinity than Ligand B (-7.9). A >1.5 kcal/mol advantage in binding is substantial and can outweigh minor ADME drawbacks.

**Overall Assessment:**

Ligand A excels in key areas for a CNS GPCR target: TPSA, BBB penetration, QED, metabolic stability (Cl_mic), and, most importantly, binding affinity. While its Caco-2 permeability and solubility are poor, the strong binding affinity and good BBB penetration are likely to compensate. Ligand B has better hERG and half-life, but its poorer TPSA, lower BBB, and significantly weaker binding affinity make it less promising. The substantial difference in binding affinity (-9.0 vs -7.9 kcal/mol) is a decisive factor.

Output:
1
2025-04-17 06:37:31,298 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (351.407 Da) is slightly lower, which could be beneficial for permeability, but both are acceptable.

**TPSA:** Both ligands have TPSA values below 140, suggesting good oral absorption potential. Ligand B (99.68) is slightly better than Ligand A (109.58), edging closer to the preferred <90 for CNS targets.

**logP:** Ligand A (-0.523) is a bit low, potentially hindering permeation. Ligand B (0.093) is better, falling within the optimal 1-3 range, though still on the lower side.

**H-Bond Donors/Acceptors:** Ligand A (2 HBD, 7 HBA) and Ligand B (1 HBD, 6 HBA) both fall within acceptable limits (<=5 HBD and <=10 HBA).

**QED:** Both ligands have similar QED values (0.713 and 0.709), indicating good drug-like properties.

**DILI:** Both ligands have relatively high DILI risk (61.497 and 65.103), which is a concern. However, this can be addressed during lead optimization.

**BBB:** Ligand B (56.921) has a significantly better BBB percentile than Ligand A (39.395). This is a *critical* advantage for a CNS target like DRD2.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values which is unusual and suggests poor permeability.

**Aqueous Solubility:** Both ligands have negative solubility values, indicating poor solubility.

**hERG Inhibition:** Both ligands show low hERG inhibition risk (0.106 and 0.19), which is positive.

**Microsomal Clearance:** Ligand B (-6.322) has a *much* lower (better) microsomal clearance than Ligand A (25.544), suggesting greater metabolic stability.

**In vitro Half-Life:** Ligand B (-18.982) has a significantly longer in vitro half-life than Ligand A (-8.872), which is desirable.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.019 and 0.033), which is favorable for CNS penetration.

**Binding Affinity:** Ligand A (-7.5 kcal/mol) has a slightly better binding affinity than Ligand B (-6.7 kcal/mol). However, the difference (0.8 kcal/mol) is not substantial enough to outweigh the significant ADME advantages of Ligand B.

**Overall Assessment:**

Ligand B is the more promising candidate. While Ligand A has slightly better binding affinity, Ligand B demonstrates superior BBB penetration, metabolic stability (lower Cl_mic), and a longer half-life. These factors are particularly important for a CNS-targeting GPCR like DRD2. The slightly lower logP of Ligand B is less concerning than the poor BBB penetration of Ligand A. Both have concerning DILI scores, but this is a secondary consideration at this stage.



Output:
1
2025-04-17 06:37:31,298 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (404.26 Da) is slightly higher than Ligand B (345.443 Da), but both are acceptable.

**2. TPSA:** Ligand A (59.0) is better than Ligand B (73.74). For CNS targets, we want TPSA <= 90, both are within this range, but A is closer to the optimal <60 for CNS penetration.

**3. logP:** Both ligands have good logP values (A: 3.053, B: 1.553), falling within the optimal 1-3 range.

**4. H-Bond Donors:** Both have 1 HBD, which is good.

**5. H-Bond Acceptors:** Both have 4 HBA, which is good.

**6. QED:** Both ligands have high QED values (A: 0.836, B: 0.899), indicating good drug-likeness.

**7. DILI:** Ligand A (55.293) has a higher DILI risk than Ligand B (11.322). This is a significant drawback for Ligand A.

**8. BBB:** Ligand A (66.305) and Ligand B (70.027) both have reasonably good BBB penetration, but Ligand B is slightly better. A value >70 is desirable for CNS targets, and B is closer.

**9. Caco-2 Permeability:** Ligand A (-5.1) has poor Caco-2 permeability, while Ligand B (-4.507) is slightly better, but still not great.

**10. Aqueous Solubility:** Ligand A (-4.053) has poor solubility, while Ligand B (-1.015) is better, but still not ideal.

**11. hERG Inhibition:** Ligand A (0.773) has a slightly higher hERG risk than Ligand B (0.44).

**12. Microsomal Clearance:** Ligand A (81.022) has higher microsomal clearance than Ligand B (0.864), indicating lower metabolic stability.

**13. In vitro Half-Life:** Ligand A (40.65) has a longer half-life than Ligand B (-10.24).

**14. P-gp Efflux:** Ligand A (0.702) has better P-gp efflux properties than Ligand B (0.029). Lower P-gp efflux is preferred for CNS exposure.

**15. Binding Affinity:** Ligand B (-9.0) has *significantly* stronger binding affinity than Ligand A (0.0). This is a crucial factor. A difference of >1.5 kcal/mol often outweighs other drawbacks.

**Overall Assessment:**

While Ligand A has some favorable properties (good logP, QED, P-gp efflux, and half-life), its poor solubility, Caco-2 permeability, higher DILI risk, and *very weak* binding affinity are major concerns. Ligand B, despite slightly less favorable TPSA and solubility, has a much stronger binding affinity, lower DILI risk, and better BBB penetration. The substantial difference in binding affinity is the deciding factor.

Output:
1
2025-04-17 06:37:31,299 - INFO - Batch 297 complete. Total preferences: 4752
2025-04-17 06:37:31,299 - INFO - Processing batch 298/512...
2025-04-17 06:38:21,743 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (346.471 and 343.471 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (62.55) is significantly better than Ligand B (73.99). For CNS targets, we want TPSA <= 90, and A is comfortably within this range, while B is closer to the upper limit.

**3. logP:** Both ligands have good logP values (3.676 and 2.972), falling within the optimal 1-3 range.

**4. H-Bond Donors:** Ligand A (1) is better than Ligand B (3). Lower HBD generally improves permeability.

**5. H-Bond Acceptors:** Ligand A (3) is slightly better than Ligand B (2), both are within the acceptable limit of 10.

**6. QED:** Ligand A (0.827) has a significantly higher QED score than Ligand B (0.571), indicating better overall drug-likeness.

**7. DILI:** Ligand A (47.421) has a higher DILI risk than Ligand B (27.026), but both are below the concerning threshold of 60.

**8. BBB:** Both ligands have good BBB penetration (70.609 and 69.484), exceeding the desirable 70% for CNS targets.

**9. Caco-2:** Both ligands have negative Caco-2 values (-4.41 and -4.824), which is unusual and suggests poor permeability. This is a significant concern for both.

**10. Solubility:** Both ligands have negative solubility values (-3.436 and -3.844), indicating very poor aqueous solubility. This is a major drawback.

**11. hERG:** Both ligands have low hERG inhibition risk (0.258 and 0.415).

**12. Cl_mic:** Ligand B (54.021) has lower microsomal clearance than Ligand A (78.574), suggesting better metabolic stability.

**13. t1/2:** Ligand A (69.988) has a much longer in vitro half-life than Ligand B (-13.24). A negative half-life is not physically possible and indicates a problem with the data or the molecule's stability.

**14. Pgp:** Ligand A (0.58) has lower P-gp efflux liability than Ligand B (0.096), which is favorable for CNS exposure.

**15. Binding Affinity:** Ligand B (-8.0) has a significantly stronger binding affinity than Ligand A (0.0). This is a substantial advantage.

**Overall Assessment:**

Ligand B has a significantly better binding affinity (-8.0 kcal/mol vs. 0.0 kcal/mol), which is a critical factor for GPCR ligands. It also has better metabolic stability (lower Cl_mic) and lower DILI risk. However, the negative Caco-2 and solubility values are concerning for both. The negative half-life for ligand B is a showstopper. Ligand A has a better QED and Pgp profile, but the affinity is very weak and the half-life is also questionable.

Despite the poor solubility and permeability predictions for both, the dramatically superior binding affinity of Ligand B outweighs the other drawbacks, *assuming the negative half-life is a data error*. If the half life is correct, then ligand B is not viable.

Output:
1
2025-04-17 06:38:21,743 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B against the provided guidelines, keeping in mind DRD2 is a CNS-relevant GPCR.

**Molecular Weight:** Both ligands (366.439 and 349.475 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (101.57) is slightly above the optimal <90 for CNS targets, but still reasonable. Ligand B (82.53) is well within the desired range.

**logP:** Both ligands (1.967 and 2.224) are within the optimal 1-3 range.

**H-Bond Donors:** Both ligands have 2 HBD, which is acceptable (<=5).

**H-Bond Acceptors:** Ligand A has 5 HBA, and Ligand B has 4 HBA, both within the acceptable limit of <=10.

**QED:** Both ligands have good QED scores (0.541 and 0.754, respectively), indicating drug-likeness. Ligand B is slightly better.

**DILI:** Ligand A (74.603) has a higher DILI risk than Ligand B (32.377). This is a significant drawback for Ligand A.

**BBB:** Ligand A (60.682) has a moderate BBB penetration, while Ligand B (50.679) is lower. Both are below the desirable >70 for CNS targets, but Ligand A is better.

**Caco-2 Permeability:** Ligand A (-5.239) and Ligand B (-4.622) both have negative Caco-2 values, indicating poor permeability. This is concerning.

**Aqueous Solubility:** Both ligands have poor aqueous solubility (-3.772 and -2.56, respectively).

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.327 and 0.663, respectively).

**Microsomal Clearance:** Both ligands have similar microsomal clearance values (77.55 and 79.297 mL/min/kg).

**In vitro Half-Life:** Ligand B (17.666 hours) has a significantly longer half-life than Ligand A (-1.624 hours). This is a major advantage for Ligand B.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.179 and 0.097, respectively).

**Binding Affinity:** Ligand A (-8.7 kcal/mol) has a significantly stronger binding affinity than Ligand B (-7.0 kcal/mol). This is a substantial advantage for Ligand A.

**Overall Assessment:**

For a CNS GPCR target like DRD2, BBB penetration, logP, Pgp efflux, TPSA, and affinity are key. While Ligand A has a superior binding affinity, its higher DILI risk and significantly shorter half-life are major concerns. Ligand B, despite the weaker affinity, has a much better safety profile (lower DILI) and a longer half-life. Both have poor solubility and Caco-2 permeability, which would need to be addressed in further optimization. However, the combination of better safety and longer duration of action for Ligand B outweighs the affinity advantage of Ligand A.

Output:
1
2025-04-17 06:38:21,744 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (365.248 and 344.371 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (29.1) is excellent for CNS penetration, well below the 90 A^2 threshold. Ligand B (119.73) is higher, but still potentially acceptable, though less ideal.

**logP:** Ligand A (4.751) is slightly high, potentially leading to solubility issues or off-target effects. Ligand B (-0.829) is too low, which could hinder membrane permeability and brain penetration.

**H-Bond Donors/Acceptors:** Ligand A (1 HBD, 1 HBA) is optimal. Ligand B (3 HBD, 4 HBA) is acceptable, but slightly higher, potentially impacting permeability.

**QED:** Both ligands have reasonable QED values (0.782 and 0.618), indicating good drug-like properties.

**DILI:** Ligand A (68.476) has a higher DILI risk than Ligand B (43.35), but both are within acceptable ranges (<60 is good).

**BBB:** This is a critical parameter for a CNS target. Ligand A (79.953) shows excellent BBB penetration, exceeding the desirable >70 percentile. Ligand B (14.114) has very poor predicted BBB penetration.

**Caco-2 Permeability:** Ligand A (-4.47) shows poor Caco-2 permeability. Ligand B (-5.33) is also poor.

**Aqueous Solubility:** Ligand A (-5.816) has very poor solubility, which is concerning given its already high logP. Ligand B (-2.492) is also poor, but slightly better than Ligand A.

**hERG Inhibition:** Ligand A (0.816) has a low risk of hERG inhibition. Ligand B (0.104) also has a very low risk.

**Microsomal Clearance:** Ligand A (42.471) has moderate clearance. Ligand B (-31.626) has negative clearance, which is not physically possible and indicates a potential issue with the prediction method or the molecule itself.

**In vitro Half-Life:** Ligand A (36.242) has a reasonable half-life. Ligand B (-9.656) has a negative half-life, which is not physically possible and indicates a potential issue with the prediction method or the molecule itself.

**P-gp Efflux:** Ligand A (0.363) has low P-gp efflux, which is favorable for CNS penetration. Ligand B (0.008) has very low P-gp efflux, which is also favorable.

**Binding Affinity:** Ligand A (-10.3 kcal/mol) has significantly stronger binding affinity than Ligand B (-8.2 kcal/mol). This >1.5 kcal/mol difference is a major advantage.

**Overall Assessment:**

Ligand A excels in BBB penetration and binding affinity, which are crucial for a CNS-targeting GPCR. While its logP and solubility are concerning, the strong affinity might overcome these issues with appropriate formulation strategies. Ligand B has a better DILI score, but suffers from extremely poor BBB penetration, a negative clearance and half-life, and a significantly weaker binding affinity. The negative values for clearance and half-life are red flags, suggesting issues with the prediction or the molecule itself.

Output:
1
2025-04-17 06:38:21,744 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (346.475 Da) is slightly lower, which could be advantageous for permeability.

**2. TPSA:** Ligand A (86.88) is excellent for CNS penetration, well below the 90 A^2 threshold. Ligand B (37.61) is also very good.

**3. logP:** Ligand A (2.796) is optimal. Ligand B (4.354) is a bit high, potentially leading to solubility issues or off-target interactions, but still within an acceptable range.

**4. H-Bond Donors:** Ligand A (3) is good. Ligand B (0) is also acceptable.

**5. H-Bond Acceptors:** Both ligands are acceptable (Ligand A: 3, Ligand B: 5).

**6. QED:** Both ligands have similar QED values (Ligand A: 0.633, Ligand B: 0.551), indicating reasonable drug-likeness.

**7. DILI:** Both ligands have the same DILI risk (50.136), which is moderate but not alarming.

**8. BBB:** This is a critical parameter for a CNS target like DRD2. Ligand B (77.821) has a significantly higher BBB percentile than Ligand A (46.84). This is a major advantage for Ligand B.

**9. Caco-2 Permeability:** Ligand A (-5.204) has better Caco-2 permeability than Ligand B (-5.547), suggesting better intestinal absorption.

**10. Aqueous Solubility:** Both ligands have poor aqueous solubility (-3.488 and -3.532 respectively). This might require formulation strategies.

**11. hERG Inhibition:** Ligand A (0.6) has a lower hERG inhibition risk than Ligand B (0.954), which is preferable.

**12. Microsomal Clearance:** Ligand A (57.161) has lower microsomal clearance, indicating better metabolic stability than Ligand B (125.936).

**13. In vitro Half-Life:** Ligand B (49.677) has a much longer in vitro half-life than Ligand A (-11.598). This is a significant advantage for Ligand B.

**14. P-gp Efflux:** Ligand A (0.228) has lower P-gp efflux, which is beneficial for CNS exposure. Ligand B (0.917) has higher P-gp efflux.

**15. Binding Affinity:** Ligand B (-7.0 kcal/mol) has a slightly better binding affinity than Ligand A (-8.2 kcal/mol). While Ligand A has a better affinity, the difference is not substantial enough to overcome the other significant advantages of Ligand B.

**Overall Assessment:**

Ligand B is the more promising candidate. While Ligand A has better Caco-2 permeability, hERG inhibition, and metabolic stability, Ligand B's significantly higher BBB penetration, longer half-life, and slightly better binding affinity outweigh these drawbacks, especially for a CNS target like DRD2. The slightly higher logP of Ligand B is a minor concern that could be addressed through structural modifications if necessary.

Output:
1
2025-04-17 06:38:21,744 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (342.458 Da) is slightly lower, which is generally favorable for permeability.

**TPSA:** Ligand A (33.29) is excellent for CNS penetration, well below the 90 A^2 threshold. Ligand B (93.87) is higher, potentially hindering BBB penetration, although still not drastically outside acceptable ranges.

**logP:** Ligand A (4.308) is a bit high, potentially causing solubility issues or off-target interactions. Ligand B (0.381) is quite low, which could impede permeation.

**H-Bond Donors/Acceptors:** Ligand A (2 HBD, 3 HBA) and Ligand B (1 HBD, 5 HBA) both fall within acceptable limits.

**QED:** Both ligands have good QED scores (A: 0.702, B: 0.74), indicating drug-like properties.

**DILI:** Ligand A (27.104) has a much lower DILI risk than Ligand B (26.677), which is a significant advantage.

**BBB:** Ligand A (78.48) has a significantly better BBB percentile than Ligand B (57.929). This is crucial for a CNS target like DRD2.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.758 and -4.698), which is unusual and suggests poor permeability. This is a concern for both.

**Aqueous Solubility:** Both ligands have negative solubility values (-3.484 and -0.904), indicating very poor aqueous solubility. This is a major drawback for both.

**hERG Inhibition:** Ligand A (0.979) has a slightly higher hERG inhibition risk than Ligand B (0.501), but both are relatively low.

**Microsomal Clearance:** Ligand B (-8.018) has a negative microsomal clearance, which is not physically possible and likely indicates a very stable compound. Ligand A (52.126) has a moderate clearance.

**In vitro Half-Life:** Ligand B (-19.347) has a negative half-life, which is also not physically possible. Ligand A (16.665) has a reasonable half-life.

**P-gp Efflux:** Ligand A (0.773) has a lower P-gp efflux liability than Ligand B (0.031), which is favorable for CNS exposure.

**Binding Affinity:** Ligand A (-9.3 kcal/mol) has a significantly stronger binding affinity than Ligand B (-6.3 kcal/mol). This is a major advantage, potentially outweighing some of the ADME concerns.

**Overall Assessment:**

Ligand A is the more promising candidate. While its logP is slightly high and solubility is poor, its significantly better BBB penetration, lower DILI risk, stronger binding affinity, and more reasonable ADME properties (half-life, clearance, P-gp) make it a superior choice for targeting DRD2. Ligand B has several problematic values (negative clearance and half-life) and a much lower BBB percentile, making it less likely to be a viable drug candidate. The substantial affinity difference also heavily favors Ligand A.

Output:
1
2025-04-17 06:38:21,744 - INFO - Reasoning:

Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (417.304 Da) is slightly higher, but still acceptable. Ligand B (344.411 Da) is a bit lower, which could be beneficial for permeability.

**2. TPSA:** Both ligands have TPSA values below the 90 A^2 threshold for CNS targets. Ligand A (94.48 A^2) is slightly higher than Ligand B (84.5 A^2), making Ligand B more favorable for brain penetration.

**3. logP:** Both ligands have optimal logP values (between 1 and 3). Ligand A (2.823) and Ligand B (2.492) are both good.

**4. H-Bond Donors:** Both have 2 HBD, which is within the acceptable limit of 5.

**5. H-Bond Acceptors:** Ligand A has 6 HBA, and Ligand B has 4 HBA, both within the acceptable limit of 10.

**6. QED:** Both ligands have good QED scores (>0.5), indicating drug-like properties. Ligand A (0.769) is slightly better than Ligand B (0.804).

**7. DILI:** Both ligands have relatively high DILI risk, but are still acceptable. Ligand A (71.384) and Ligand B (76.503) are both below the concerning threshold of 60.

**8. BBB:** Both ligands show good BBB penetration, but Ligand B (88.794) is significantly better than Ligand A (77.472). This is a critical factor for a CNS target like DRD2.

**9. Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and suggests poor permeability. However, the scale is not specified, so it's difficult to interpret.

**10. Aqueous Solubility:** Both have negative solubility values, which is also unusual. Again, the scale is not specified, making interpretation difficult.

**11. hERG Inhibition:** Both ligands have very low hERG inhibition liability, which is excellent. Ligand A (0.185) and Ligand B (0.098) are both very safe.

**12. Microsomal Clearance:** Ligand B (39.022 mL/min/kg) has significantly lower microsomal clearance than Ligand A (96.963 mL/min/kg), indicating better metabolic stability.

**13. In vitro Half-Life:** Ligand B (1.687 hours) has a slightly longer half-life than Ligand A (-12.76 hours), although the negative value for A is concerning and likely an error.

**14. P-gp Efflux:** Both ligands have low P-gp efflux liability, which is favorable. Ligand A (0.159) and Ligand B (0.102) are both good.

**15. Binding Affinity:** Ligand B (-9.7 kcal/mol) has a significantly stronger binding affinity than Ligand A (-7.8 kcal/mol). This is a substantial advantage, potentially outweighing minor ADME drawbacks.

**Overall Assessment:**

Ligand B is the more promising candidate. While both ligands have acceptable properties, Ligand B excels in key areas for a CNS-targeting GPCR: significantly better BBB penetration, much lower microsomal clearance (better metabolic stability), and a substantially stronger binding affinity. The negative values for Caco-2 and Solubility are concerning for both, but the large affinity difference and improved CNS properties of Ligand B make it the better choice.

Output:
1
2025-04-17 06:38:21,745 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B based on the provided guidelines, prioritizing GPCR-specific properties (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (350.394 and 372.506 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (68.62) is better than Ligand B (51.66). Both are below the 90 A^2 threshold desirable for CNS targets, but A is closer to the ideal.

**logP:** Ligand A (1.926) is within the optimal 1-3 range. Ligand B (3.708) is at the higher end of the optimal range, potentially raising concerns about solubility and off-target effects, but still acceptable.

**H-Bond Donors/Acceptors:** Ligand A has 1 HBD and 5 HBA, while Ligand B has 0 HBD and 5 HBA. Both are within acceptable limits.

**QED:** Ligand A (0.79) has a better QED score than Ligand B (0.62), indicating a more drug-like profile.

**DILI:** Ligand A (47.848) has a slightly higher DILI risk than Ligand B (20.202), but both are below the 40 threshold, indicating low risk.

**BBB:** Ligand B (97.751) significantly outperforms Ligand A (82.086) in BBB penetration, which is crucial for a CNS target like DRD2.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.308 and -4.397), which is unusual and suggests poor permeability. This is a significant concern for both.

**Aqueous Solubility:** Both ligands have negative solubility values (-2.237 and -4.234), indicating very poor aqueous solubility, a major drawback.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.492 and 0.425).

**Microsomal Clearance:** Ligand B (99.4) has a much higher microsomal clearance than Ligand A (78.303), suggesting faster metabolism and potentially lower *in vivo* exposure.

**In vitro Half-Life:** Ligand B (13.542) has a longer half-life than Ligand A (-2.479). The negative value for A is concerning.

**P-gp Efflux:** Ligand A (0.069) has lower P-gp efflux than Ligand B (0.285), which is favorable for CNS penetration.

**Binding Affinity:** Ligand A (-7.7 kcal/mol) has a slightly better binding affinity than Ligand B (-6.0 kcal/mol). This is a substantial difference (1.7 kcal/mol), which can outweigh some ADME drawbacks.

**Overall Assessment:**

Despite the poor Caco-2 and solubility for both, Ligand A is favored due to its superior binding affinity, better TPSA, lower P-gp efflux, and better QED. While Ligand B has a better BBB score, the strong binding affinity of Ligand A is a significant advantage for a GPCR target, and the lower P-gp efflux could help overcome some BBB challenges. The significantly better half-life of Ligand B is a positive, but the poor metabolic stability (high Cl_mic) may negate this benefit.



Output:
0
2025-04-17 06:38:21,745 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B based on the provided guidelines, prioritizing GPCR-specific properties (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (359.348 and 346.431 Da) fall within the ideal range of 200-500 Da.

**TPSA:** Ligand A (73.64) is significantly better than Ligand B (107.01). For CNS targets, TPSA should be <=90, and A is comfortably within this range, while B exceeds it.

**logP:** Both ligands have acceptable logP values (1.135 and 1.802), falling within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A (0 HBD, 4 HBA) is slightly better than Ligand B (3 HBD, 4 HBA) regarding the number of hydrogen bond donors. Both are within acceptable limits.

**QED:** Both ligands have reasonable QED scores (0.667 and 0.593), indicating good drug-like properties.

**DILI:** Ligand A (39.55) has a lower DILI risk than Ligand B (56.689), which is preferable. Both are below the concerning threshold of 60.

**BBB:** This is a critical parameter for CNS targets. Ligand A has a significantly higher BBB penetration percentile (79.721) compared to Ligand B (38.581). This is a major advantage for A.

**Caco-2 Permeability:** Both have negative Caco-2 values which is unusual and potentially problematic, but we'll proceed assuming these are percentile scores where lower is worse. Ligand A (-4.441) is better than Ligand B (-4.956).

**Aqueous Solubility:** Ligand A (-1.377) is better than Ligand B (-3.862). Higher solubility is generally preferred.

**hERG:** Both ligands have low hERG inhibition liability (0.46 and 0.674), indicating a low risk of cardiotoxicity.

**Microsomal Clearance:** Ligand A (2.875) has a much lower microsomal clearance than Ligand B (56.434), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (-13.641) has a significantly longer in vitro half-life than Ligand B (13.154).

**P-gp Efflux:** Ligand A (0.038) has much lower P-gp efflux liability than Ligand B (0.148), which is beneficial for CNS exposure.

**Binding Affinity:** Ligand B (-7.5 kcal/mol) has a slightly better binding affinity than Ligand A (-6.9 kcal/mol). While a 1.5 kcal/mol advantage is significant, the other ADME properties of A are much more favorable.

**Overall Assessment:**

Ligand A is clearly superior. While Ligand B has slightly better binding affinity, Ligand A excels in almost every other critical parameter, especially those prioritized for GPCRs targeting the CNS: TPSA, BBB, P-gp efflux, and metabolic stability (Cl_mic and t1/2). The significantly better BBB penetration and lower P-gp efflux of Ligand A are crucial for CNS drug development. The lower DILI risk and better solubility also contribute to its improved profile.



Output:
0
2025-04-17 06:38:21,745 - INFO - Reasoning:

Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (418.312) is slightly higher, but still acceptable. Ligand B (346.471) is also good.

**2. TPSA:** Ligand A (63.24) is higher than Ligand B (49.85). For a CNS target like DRD2, we ideally want TPSA <= 90, so both are within range, but Ligand B is preferable.

**3. logP:** Ligand A (3.933) is at the upper end of the optimal range (1-3), while Ligand B (2.358) is well within.  Ligand B is better here.

**4. H-Bond Donors:** Ligand A (1) and Ligand B (0) are both acceptable (<=5).

**5. H-Bond Acceptors:** Both ligands have 3 H-bond acceptors, which is well within the acceptable limit of <=10.

**6. QED:** Both ligands have similar QED values (0.804 and 0.734), both indicating good drug-likeness (>0.5).

**7. DILI:** Ligand A (82.823) has a significantly higher DILI risk than Ligand B (28.306). This is a major concern for Ligand A.

**8. BBB:** Both ligands have excellent BBB penetration (Ligand A: 75.223, Ligand B: 82.474), exceeding the >70 threshold for CNS targets. Ligand B is slightly better.

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 values, which is unusual and suggests poor permeability. However, the scale isn't specified, so it's hard to interpret.

**10. Aqueous Solubility:** Both ligands have negative solubility values, which is also unusual and suggests poor solubility. Again, the scale isn't specified.

**11. hERG Inhibition:** Ligand A (0.659) has a slightly higher hERG risk than Ligand B (0.257), but both are relatively low.

**12. Microsomal Clearance:** Ligand A (23.381) has lower microsomal clearance than Ligand B (46.24), indicating better metabolic stability. This is a positive for Ligand A.

**13. In vitro Half-Life:** Ligand A (139.059) has a much longer in vitro half-life than Ligand B (-18.723). This is a significant advantage for Ligand A.

**14. P-gp Efflux:** Ligand A (0.708) has lower P-gp efflux than Ligand B (0.217), which is favorable for CNS penetration.

**15. Binding Affinity:** Ligand A (-10.8 kcal/mol) has a significantly stronger binding affinity than Ligand B (-8.5 kcal/mol). This is a substantial advantage for Ligand A, potentially outweighing some of its ADME drawbacks.

**Overall Assessment:**

While Ligand A has a higher DILI risk and a slightly higher logP, its significantly stronger binding affinity (-10.8 vs -8.5 kcal/mol), lower P-gp efflux, and longer half-life are compelling advantages, particularly for a CNS target. The better BBB penetration of Ligand B is somewhat offset by its weaker binding. The negative solubility and Caco-2 values are concerning for both, but the affinity difference is substantial. Given the importance of affinity for GPCRs, and the acceptable BBB penetration of Ligand A, it appears to be the more promising candidate.

Output:
1
2025-04-17 06:38:21,745 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (348.443 and 344.455 Da) fall comfortably within the ideal 200-500 Da range.

**TPSA:** Ligand A (78.87) is higher than Ligand B (58.64). For a CNS target like DRD2, TPSA should be <=90, so both are acceptable, but B is preferable.

**logP:** Both ligands have good logP values (2.777 and 2.668), falling within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A has 2 HBD and 4 HBA, while Ligand B has 1 HBD and 3 HBA. Both are within acceptable limits (<=5 HBD and <=10 HBA).

**QED:** Both ligands have reasonable QED scores (0.792 and 0.664), indicating good drug-like properties.

**DILI:** Ligand A (60.682) has a higher DILI risk than Ligand B (24.312). Lower DILI is preferred.

**BBB:** This is a crucial parameter for CNS targets. Ligand B (77.705) has a significantly better BBB penetration percentile than Ligand A (36.177). This is a major advantage for Ligand B.

**Caco-2 Permeability:** Ligand A (-5.022) and Ligand B (-4.668) both have negative values, which is unusual. Lower values suggest poor permeability.

**Aqueous Solubility:** Both ligands have poor aqueous solubility (-2.038 and -2.559). This could pose formulation challenges.

**hERG Inhibition:** Ligand A (0.088) has a slightly lower hERG inhibition liability than Ligand B (0.594), which is preferable.

**Microsomal Clearance:** Ligand B (82.324) has a much higher microsomal clearance than Ligand A (18.842). This suggests lower metabolic stability for Ligand B.

**In vitro Half-Life:** Ligand B (10.199 hours) has a longer half-life than Ligand A (-6.861 hours). This is a positive attribute.

**P-gp Efflux:** Ligand A (0.016) has a much lower P-gp efflux liability than Ligand B (0.188), which is desirable for CNS penetration.

**Binding Affinity:** Ligand B (-8.0 kcal/mol) has a slightly better binding affinity than Ligand A (-7.5 kcal/mol). While both are good, the difference is significant enough to consider.

**Overall Assessment:**

Ligand B excels in BBB penetration and binding affinity, both critical for a CNS GPCR target. While it has higher P-gp efflux and microsomal clearance, the superior BBB and affinity outweigh these drawbacks. Ligand A has better DILI and P-gp efflux, but its significantly lower BBB penetration is a major disadvantage. The better affinity of Ligand B is also a key factor.

Output:
1
2025-04-17 06:38:21,745 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (358.364 and 340.343 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (72.09) is excellent, well below the 90 A^2 threshold for CNS targets. Ligand B (125.8) is higher, but still potentially acceptable, though less ideal.

**3. logP:** Ligand A (2.908) is optimal. Ligand B (1.212) is a bit low, potentially hindering membrane permeability.

**4. H-Bond Donors:** Ligand A (2) and Ligand B (3) both are within the acceptable limit of <=5.

**5. H-Bond Acceptors:** Ligand A (4) and Ligand B (6) both are within the acceptable limit of <=10.

**6. QED:** Both ligands have similar QED values (0.799 and 0.619), indicating good drug-like properties.

**7. DILI:** Ligand A (39.046) has a much lower DILI risk than Ligand B (84.917), which is a significant advantage.

**8. BBB:** Ligand A (67.701) has a better BBB penetration percentile than Ligand B (46.568). While both are below the ideal >70, A is closer. This is crucial for a CNS target like DRD2.

**9. Caco-2 Permeability:** Ligand A (-4.909) has a worse Caco-2 permeability than Ligand B (-5.801). However, Caco-2 values are often difficult to interpret and can be less reliable than other parameters.

**10. Aqueous Solubility:** Ligand A (-2.79) has slightly better solubility than Ligand B (-3.86).

**11. hERG Inhibition:** Ligand A (0.628) has a slightly higher hERG risk than Ligand B (0.453), but both are relatively low.

**12. Microsomal Clearance:** Ligand A (20.698) has a lower microsomal clearance than Ligand B (25.107), indicating better metabolic stability.

**13. In vitro Half-Life:** Ligand A (30.089) has a longer in vitro half-life than Ligand B (15.921), which is preferable.

**14. P-gp Efflux:** Ligand A (0.213) has significantly lower P-gp efflux liability than Ligand B (0.028), which is a major advantage for CNS penetration.

**15. Binding Affinity:** Ligand B (-9.6 kcal/mol) has a slightly better binding affinity than Ligand A (-8.4 kcal/mol). This is a 1.2 kcal/mol difference, which is significant, but needs to be weighed against the other ADME properties.

**Overall Assessment:**

Ligand A is the more promising candidate. While Ligand B has slightly better binding affinity, Ligand A excels in crucial ADME properties for a CNS-targeting GPCR. Specifically, its lower DILI risk, better BBB penetration, lower P-gp efflux, and improved metabolic stability outweigh the small difference in binding affinity. The TPSA and logP values for Ligand A are also more favorable.



Output:
1
2025-04-17 06:38:21,746 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B based on the provided guidelines, prioritizing GPCR-specific properties (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (345.439 and 352.479 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (55.84) is excellent, well below the 90 A^2 threshold for CNS targets. Ligand B (95.74) is higher, but still potentially acceptable, though less ideal.

**logP:** Ligand A (2.58) is optimal (1-3). Ligand B (0.191) is quite low, potentially hindering permeability and CNS penetration.

**H-Bond Donors/Acceptors:** Ligand A (0 HBD, 4 HBA) and Ligand B (2 HBD, 4 HBA) both have reasonable numbers of H-bond donors and acceptors, well within the guidelines.

**QED:** Both ligands have acceptable QED values (0.744 and 0.684, both > 0.5).

**DILI:** Ligand A (35.285) has a low DILI risk. Ligand B (10.314) has a very low DILI risk, which is good.

**BBB:** This is critical for a CNS target. Ligand A has a very high BBB penetration (90.035%), which is excellent. Ligand B's BBB penetration (53.47%) is significantly lower and concerning for CNS activity.

**Caco-2 Permeability:** Ligand A (-4.216) has poor Caco-2 permeability. Ligand B (-5.517) also has poor Caco-2 permeability.

**Aqueous Solubility:** Ligand A (-3.56) and Ligand B (-1.526) both have poor aqueous solubility.

**hERG:** Ligand A (0.396) has a low hERG risk. Ligand B (0.139) has a very low hERG risk.

**Microsomal Clearance:** Ligand A (76.867) has moderate microsomal clearance. Ligand B (15.565) has low microsomal clearance, indicating better metabolic stability.

**In vitro Half-Life:** Ligand A (1.147 hours) has a short half-life. Ligand B (-7.884 hours) has a negative half-life, which is not physically possible and likely indicates an error in the data.

**P-gp Efflux:** Ligand A (0.26) has low P-gp efflux, which is favorable. Ligand B (0.003) has very low P-gp efflux, which is also favorable.

**Binding Affinity:** Both ligands have strong binding affinities (-8.7 and -7.0 kcal/mol), with Ligand A being slightly better. The 1.7 kcal/mol difference is significant.

**Overall Assessment:**

Ligand A is superior due to its excellent BBB penetration, optimal logP, and slightly better binding affinity. While its Caco-2 permeability and aqueous solubility are poor, the strong BBB penetration is a major advantage for a CNS-targeting drug. Ligand B's low logP and significantly lower BBB penetration are major drawbacks, outweighing its better metabolic stability and very low P-gp efflux. The negative half-life for Ligand B is also a red flag.

Output:
0
2025-04-17 06:38:21,746 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (345.443) is slightly lower, which is generally favorable for permeability.

**TPSA:** Ligand A (71.53) is significantly better than Ligand B (114.34). For CNS targets, TPSA should be <= 90, so Ligand A is much closer to this threshold.

**logP:** Ligand A (1.952) is optimal (1-3). Ligand B (-0.7) is below 1, which could hinder permeation.

**H-Bond Donors/Acceptors:** Ligand A (HBD=1, HBA=4) is better than Ligand B (HBD=2, HBA=6) in terms of balancing solubility and permeability. Both are within acceptable limits, but A is more favorable.

**QED:** Both ligands have similar QED values (A: 0.695, B: 0.65), indicating good drug-likeness.

**DILI:** Ligand A (15.355) has a much lower DILI risk than Ligand B (58.434). This is a significant advantage.

**BBB:** Both ligands have reasonably good BBB penetration (A: 67.895, B: 68.864), but neither exceeds the desirable >70% threshold.

**Caco-2 Permeability:** Ligand A (-4.236) has a more negative Caco-2 value, which is unusual and suggests poor permeability. Ligand B (-5.192) is similarly poor. This is a concern for both, but potentially less so for a CNS target where BBB penetration is also important.

**Aqueous Solubility:** Both ligands have poor aqueous solubility (A: -1.948, B: -2.229).

**hERG Inhibition:** Ligand A (0.097) has a much lower hERG inhibition liability than Ligand B (0.333), indicating a lower risk of cardiotoxicity.

**Microsomal Clearance:** Ligand B (-7.842) has a negative clearance, which is not physically possible and likely indicates a very stable compound. Ligand A (53.793) has a moderate clearance.

**In vitro Half-Life:** Ligand A (-27.241) has a negative half-life, which is not physically possible. Ligand B (43.177) has a reasonable half-life.

**P-gp Efflux:** Ligand A (0.013) has very low P-gp efflux, which is excellent for CNS penetration. Ligand B (0.068) is also low, but higher than A.

**Binding Affinity:** Ligand B (-8.2) has a slightly better binding affinity than Ligand A (-7.3), a difference of 0.9 kcal/mol. While a 1.5 kcal/mol advantage is often decisive, 0.9 kcal/mol is less compelling.

**Overall Assessment:**

Despite the slightly better affinity of Ligand B, Ligand A is the more promising candidate. It has a significantly better TPSA, logP, DILI risk, and P-gp efflux. While both have poor solubility and Caco-2 permeability, the BBB penetration is reasonable enough to potentially offset these issues for a CNS target. The negative values for half-life and Caco-2 for Ligand A are concerning, but the overall profile is superior. The negative clearance and half-life for Ligand B are also problematic.

Output:
1
2025-04-17 06:38:21,746 - INFO - Reasoning:

Let's analyze Ligand A and Ligand B for their potential as DRD2 drug candidates, considering the provided guidelines and GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight (MW):**
* Ligand A: 415.255 Da - Within the ideal range (200-500 Da).
* Ligand B: 346.471 Da - Also within the ideal range.
* *No clear advantage here.*

**2. Topological Polar Surface Area (TPSA):**
* Ligand A: 64.99  - Excellent, well below the 90 A^2 threshold for CNS targets.
* Ligand B: 60.85 - Also excellent, below the 90 A^2 threshold.
* *No clear advantage here.*

**3. Lipophilicity (logP):**
* Ligand A: 3.658 - Good, within the optimal 1-3 range.
* Ligand B: 1.929 - Also good, within the optimal 1-3 range.
* *No clear advantage here.*

**4. H-Bond Donors (HBD):**
* Ligand A: 1 - Meets the <=5 guideline.
* Ligand B: 1 - Meets the <=5 guideline.
* *No clear advantage here.*

**5. H-Bond Acceptors (HBA):**
* Ligand A: 5 - Meets the <=10 guideline.
* Ligand B: 3 - Meets the <=10 guideline.
* *No clear advantage here.*

**6. QED:**
* Ligand A: 0.527 - Good, above the 0.5 threshold.
* Ligand B: 0.849 - Excellent, well above the 0.5 threshold.
* *Ligand B has a better drug-like profile.*

**7. DILI:**
* Ligand A: 60.682 - Moderate risk.
* Ligand B: 6.359 - Very low risk.
* *Ligand B is significantly better regarding DILI.*

**8. BBB:**
* Ligand A: 79.062 - Good, above the 70% threshold for CNS targets.
* Ligand B: 77.549 - Good, above the 70% threshold for CNS targets.
* *Similar BBB penetration.*

**9. Caco-2 Permeability:**
* Ligand A: -4.579 - Negative value is unusual, indicating poor permeability.
* Ligand B: -4.614 - Also negative, indicating poor permeability.
* *Both have poor Caco-2 permeability.*

**10. Aqueous Solubility:**
* Ligand A: -4.255 - Poor solubility.
* Ligand B: -2.246 - Better solubility than A, but still poor.
* *Ligand B is slightly better.*

**11. hERG Inhibition:**
* Ligand A: 0.821 - Low risk.
* Ligand B: 0.251 - Very low risk.
* *Ligand B has lower hERG risk.*

**12. Microsomal Clearance (Cl_mic):**
* Ligand A: 100.061 - High clearance, indicating poor metabolic stability.
* Ligand B: 13.281 - Low clearance, indicating good metabolic stability.
* *Ligand B is significantly better regarding metabolic stability.*

**13. In vitro Half-Life (t1/2):**
* Ligand A: 93.673 - Long half-life.
* Ligand B: 0.236 - Very short half-life.
* *Ligand A has a much better half-life.*

**14. P-gp Efflux:**
* Ligand A: 0.783 - Moderate efflux.
* Ligand B: 0.053 - Very low efflux.
* *Ligand B is significantly better regarding P-gp efflux.*

**15. Binding Affinity:**
* Ligand A: -8.1 kcal/mol
* Ligand B: -8.3 kcal/mol
* *Ligand B has a slightly better affinity.*

**Overall Assessment:**

While Ligand A has a better half-life, Ligand B demonstrates superiority in several critical ADME properties, particularly DILI risk, metabolic stability (Cl_mic), P-gp efflux, and hERG inhibition.  It also has a slightly better QED score and binding affinity. The poor Caco-2 permeability is a concern for both, but the other advantages of Ligand B, especially its safety profile and potential for better CNS exposure due to lower P-gp efflux, make it the more promising candidate. The slight affinity difference is less important than the ADME advantages.

Output:
1
2025-04-17 06:38:21,746 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (343.391 and 362.499 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (129.89) is slightly above the optimal <90 for CNS targets, but still reasonable. Ligand B (72.21) is excellent, well below 90.

**logP:** Ligand A (0.513) is quite low, potentially hindering permeability. Ligand B (3.955) is much better, nearing the upper end of the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A has 3 HBD and 6 HBA, which are acceptable. Ligand B has 2 HBD and 7 HBA, also acceptable.

**QED:** Both ligands have similar QED values (0.744 and 0.736), indicating good drug-likeness.

**DILI:** Ligand A (68.282) has a slightly higher DILI risk than Ligand B (59.442), but both are below the concerning threshold of 60.

**BBB:** Ligand B (64.87) has a better BBB percentile than Ligand A (55.913). While neither are >70, Ligand B is closer and more favorable for a CNS target.

**Caco-2 Permeability:** Ligand A (-5.661) has poor Caco-2 permeability. Ligand B (-5.23) is also poor, but slightly better.

**Aqueous Solubility:** Both ligands have very poor aqueous solubility (-3.435 and -4.426). This is a significant drawback.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.356 and 0.517).

**Microsomal Clearance:** Ligand A (-19.467) has much lower (better) microsomal clearance than Ligand B (74.694), suggesting greater metabolic stability.

**In vitro Half-Life:** Ligand B (85.205) has a significantly longer in vitro half-life than Ligand A (-17.245).

**P-gp Efflux:** Both ligands show very low P-gp efflux liability (0.025 and 0.094).

**Binding Affinity:** Both ligands have excellent binding affinity (-8.2 and -8.5 kcal/mol), with Ligand B being slightly stronger. The affinity difference is not substantial enough to override other significant differences.

**Overall Assessment:**

Ligand B is the more promising candidate. While both have poor solubility, Ligand B excels in crucial areas for a CNS-targeting GPCR: better logP, better BBB penetration, and a longer half-life. Ligand A's very low logP and poor Caco-2 permeability are major concerns. Although Ligand A has better metabolic stability (lower Cl_mic), the other advantages of Ligand B outweigh this benefit.

Output:
1
2025-04-17 06:38:21,747 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (337.423 Da) is slightly lower, which could be beneficial for permeability. Ligand B (355.435 Da) is also good.

**TPSA:** Ligand A (55.2) is excellent, well below the 90 A^2 threshold for CNS targets. Ligand B (118.8) is higher, but still potentially acceptable, though less ideal.

**logP:** Ligand A (3.11) is optimal. Ligand B (0.339) is quite low, potentially hindering membrane permeability and CNS penetration.

**H-Bond Donors/Acceptors:** Ligand A (0 HBD, 4 HBA) is favorable. Ligand B (2 HBD, 5 HBA) is also acceptable.

**QED:** Both ligands have reasonable QED values (A: 0.865, B: 0.609), indicating good drug-like properties.

**DILI:** Ligand A (34.432) has a lower DILI risk than Ligand B (15.82), which is preferable.

**BBB:** Ligand A (80.264) has a significantly better BBB penetration score than Ligand B (67.623). This is a critical advantage for a CNS target like DRD2.

**Caco-2 Permeability:** Ligand A (-4.676) has a negative Caco-2 value, which is unusual and suggests poor permeability. Ligand B (-5.403) is also poor.

**Aqueous Solubility:** Ligand A (-3.38) and Ligand B (-1.779) both have negative solubility values, which is concerning.

**hERG Inhibition:** Both ligands have very low hERG inhibition risk (A: 0.434, B: 0.102).

**Microsomal Clearance:** Ligand A (28.973) has a moderate clearance, while Ligand B (21.198) has a lower clearance, indicating better metabolic stability.

**In vitro Half-Life:** Ligand A (6.424 hours) has a short half-life, while Ligand B (-21.876 hours) has a negative half-life, which is not possible.

**P-gp Efflux:** Ligand A (0.226) has lower P-gp efflux liability than Ligand B (0.005), which is good.

**Binding Affinity:** Ligand A (-8.2 kcal/mol) has a significantly stronger binding affinity than Ligand B (-7.7 kcal/mol). This 0.5 kcal/mol difference is substantial and can outweigh some ADME drawbacks.

**Overall Assessment:**

Ligand A is the more promising candidate. While it has a negative Caco-2 and solubility, its superior BBB penetration, lower DILI risk, significantly stronger binding affinity, and lower P-gp efflux outweigh these concerns. Ligand B's low logP is a major drawback for CNS penetration, and its negative half-life is impossible. The affinity difference is also significant.

Output:
1
2025-04-17 06:38:21,747 - INFO - Batch 298 complete. Total preferences: 4768
2025-04-17 06:38:21,747 - INFO - Processing batch 299/512...
2025-04-17 06:39:03,659 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B based on the provided guidelines, prioritizing GPCR-specific properties (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (397.871 Da) is slightly higher than Ligand B (362.455 Da), but both are acceptable.

**TPSA:** Ligand A (64.63) is significantly better than Ligand B (97.12). For CNS targets, we want TPSA <= 90, so Ligand A is much more favorable.

**logP:** Both ligands have good logP values (A: 3.389, B: 2.358), falling within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A (HBD=1, HBA=4) is better than Ligand B (HBD=2, HBA=6) in terms of balancing solubility and permeability.

**QED:** Both ligands have similar and good QED values (A: 0.73, B: 0.748), indicating good drug-like properties.

**DILI:** Both ligands have similar DILI risk (A: 55.836, B: 58.976), both being acceptable (below 60).

**BBB:** Ligand A (77.705) has a significantly better BBB percentile than Ligand B (57.774). This is *critical* for a CNS target like DRD2.

**Caco-2 Permeability:** Ligand A (-4.64) is better than Ligand B (-5.383), indicating better intestinal absorption.

**Aqueous Solubility:** Ligand A (-4.234) is better than Ligand B (-3.057), indicating better solubility.

**hERG:** Both ligands have low hERG inhibition liability (A: 0.598, B: 0.235), which is good.

**Microsomal Clearance:** Ligand B (65.74) has slightly better microsomal clearance than Ligand A (60.758), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand B (26.21) has a better half-life than Ligand A (-31.235).

**P-gp Efflux:** Ligand A (0.226) has a lower P-gp efflux liability than Ligand B (0.138), which is favorable for CNS penetration.

**Binding Affinity:** Ligand B (-8.9 kcal/mol) has a significantly stronger binding affinity than Ligand A (-7.6 kcal/mol). This is a substantial advantage (1.3 kcal/mol difference).

**Overall Assessment:**

While Ligand B has a better binding affinity and *in vitro* half-life, Ligand A is superior in almost all other critical ADME properties, especially those crucial for CNS penetration (TPSA, BBB, P-gp efflux, solubility). The difference in binding affinity, while significant, can potentially be overcome with further optimization, whereas improving BBB penetration is often much more challenging. Given the target is a CNS GPCR (DRD2), maximizing brain exposure is paramount.

Output:
0
2025-04-17 06:39:03,659 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 drug candidates, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (347.415 and 357.841 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (95.67) is better than Ligand B (58.22). For CNS targets, TPSA should be <=90, so Ligand A is closer to the ideal, but both are acceptable.

**logP:** Ligand A (0.875) is suboptimal, being slightly below the 1-3 range. Ligand B (4.034) is higher, potentially causing solubility issues, but within the acceptable range.

**H-Bond Donors/Acceptors:** Ligand A has 2 HBD and 5 HBA, while Ligand B has 1 HBD and 3 HBA. Both are within the acceptable limits of <=5 HBD and <=10 HBA.

**QED:** Ligand A (0.796) has a better QED score than Ligand B (0.464), indicating a more drug-like profile.

**DILI:** Ligand A (30.322) has a significantly lower DILI risk than Ligand B (69.717). This is a major advantage for Ligand A.

**BBB:** Ligand A (49.826) has a lower BBB penetration percentile than Ligand B (60.76). While both are not ideal (>70 is desirable for CNS targets), Ligand B is better.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.16 and -5.344), which is unusual and suggests poor permeability. This is a significant concern for both.

**Aqueous Solubility:** Both ligands have negative solubility values (-1.35 and -4.281), indicating very poor aqueous solubility. This is a major drawback for both.

**hERG Inhibition:** Ligand A (0.141) has a lower hERG inhibition liability than Ligand B (0.809), which is preferable.

**Microsomal Clearance:** Ligand A (-4.176) has a lower (better) microsomal clearance than Ligand B (86.205), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (21.4) has a shorter half-life than Ligand B (44.911), but both are reasonable.

**P-gp Efflux:** Ligand A (0.043) has significantly lower P-gp efflux liability than Ligand B (0.843), which is crucial for CNS penetration.

**Binding Affinity:** Ligand B (-8.8 kcal/mol) has a slightly better binding affinity than Ligand A (-7.8 kcal/mol). However, the difference is less than 1.5 kcal/mol, so it doesn't automatically outweigh other factors.

**Overall Assessment:**

Ligand A is the more promising candidate. While its logP and BBB are not ideal, it significantly outperforms Ligand B in crucial areas like DILI risk, P-gp efflux, microsomal clearance, and hERG inhibition. The better QED score also supports its drug-likeness. The slightly weaker binding affinity of Ligand A can potentially be optimized during lead optimization. The poor Caco-2 and solubility are concerning for both, but these properties are often improved through formulation strategies.

Output:
0
2025-04-17 06:39:03,659 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (352.347 and 348.443 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (131.04) is borderline for CNS penetration, slightly above the preferred <90, but acceptable. Ligand B (70.08) is excellent, well below 90.

**3. logP:** Ligand A (-0.347) is a bit low, potentially hindering membrane permeability. Ligand B (0.825) is within the optimal 1-3 range.

**4. H-Bond Donors:** Ligand A (4) is acceptable. Ligand B (1) is also good.

**5. H-Bond Acceptors:** Ligand A (7) is acceptable. Ligand B (4) is also good.

**6. QED:** Both ligands have good QED scores (0.545 and 0.722), indicating drug-like properties.

**7. DILI:** Ligand A (79.682) has a higher DILI risk than Ligand B (18.302), which is a significant concern.

**8. BBB:** Both have reasonably good BBB penetration (65.839 and 68.515), but neither exceeds the desirable >70 threshold.

**9. Caco-2:** Both have negative Caco-2 values, which is unusual and suggests poor permeability. However, the scale isn't specified, so it's hard to interpret.

**10. Solubility:** Both have negative solubility values, also unusual and suggesting poor solubility. Again, the scale isn't specified.

**11. hERG:** Both ligands have very low hERG risk (0.027 and 0.309).

**12. Cl_mic:** Ligand A (-28.252) has a *negative* microsomal clearance, which is not physically possible and likely indicates an error in the data. Ligand B (43.283) is moderate, suggesting reasonable metabolic stability.

**13. t1/2:** Ligand A (16.714) has a longer half-life than Ligand B (2.65).

**14. Pgp:** Both have low Pgp efflux liability (0.004 and 0.072).

**15. Binding Affinity:** Both have excellent binding affinity (-8.6 and -8.0 kcal/mol). The difference is 0.6 kcal/mol, which is not substantial enough to overcome other deficiencies.

**Overall Assessment:**

Ligand A has a major red flag: the negative microsomal clearance. This is a data error and makes it immediately less viable. While its half-life is longer, the DILI risk is significantly higher, and the logP is suboptimal. Ligand B, despite slightly lower affinity, has a much better safety profile (DILI), a more favorable logP, and a plausible (though moderate) metabolic clearance. The TPSA is also significantly better for CNS penetration.

Output:
1
2025-04-17 06:39:03,660 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (354.491 and 352.523 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (59.08) is better than Ligand B (50.6). Both are below the 90 A^2 threshold desirable for CNS targets.

**3. logP:** Both ligands have good logP values (2.09 and 2.758), falling within the optimal 1-3 range. Ligand B is slightly higher, which could be a minor concern for solubility.

**4. H-Bond Donors:** Both ligands have 0 HBD, which is acceptable.

**5. H-Bond Acceptors:** Ligand A has 4 HBA, and Ligand B has 5. Both are within the acceptable limit of 10.

**6. QED:** Both ligands have good QED scores (0.564 and 0.686), indicating drug-like properties. Ligand B is slightly better.

**7. DILI:** Ligand A (17.914) has a higher DILI risk than Ligand B (12.253), but both are below the concerning threshold of 40.

**8. BBB:** Ligand A (89.802) has a better BBB penetration percentile than Ligand B (81.194). This is a crucial factor for a CNS target like DRD2.

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.208 and -4.451). This is unusual and suggests poor permeability. However, these values are on a scale where negative values are possible and don't necessarily preclude development.

**10. Aqueous Solubility:** Both ligands have very poor aqueous solubility (-1.627 and -1.99). This is a significant drawback.

**11. hERG Inhibition:** Both ligands have low hERG inhibition risk (0.46 and 0.748).

**12. Microsomal Clearance:** Ligand B (87.721) has a significantly higher microsomal clearance than Ligand A (29.064), suggesting lower metabolic stability.

**13. In vitro Half-Life:** Ligand A (3.745) has a shorter in vitro half-life than Ligand B (26.791). This is consistent with the higher clearance of Ligand B.

**14. P-gp Efflux:** Both ligands have low P-gp efflux liability (0.241 and 0.097).

**15. Binding Affinity:** Both ligands have the same binding affinity (-6.8 kcal/mol), which is excellent.

**Overall Assessment:**

While both ligands have good binding affinity, Ligand A is more favorable due to its better BBB penetration, lower DILI risk, significantly lower microsomal clearance (implying better metabolic stability), and longer in vitro half-life. The solubility is a concern for both, but the ADME properties of Ligand A are superior, making it a more promising starting point for optimization. The Caco-2 values are concerning for both, and would need further investigation.

Output:
0
2025-04-17 06:39:03,660 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (349.402 and 350.415 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (75.63) is better than Ligand B (81.01). Both are below the 90 A^2 threshold desirable for CNS targets, but A is closer to the optimal range.

**3. logP:** Both ligands have good logP values (2.066 and 1.703), falling within the 1-3 range.

**4. H-Bond Donors:** Ligand A (2) is slightly higher than Ligand B (1), but both are within the acceptable limit of 5.

**5. H-Bond Acceptors:** Ligand A (4) is lower than Ligand B (5), both are within the acceptable limit of 10.

**6. QED:** Both ligands have good QED scores (0.816 and 0.845), indicating good drug-like properties.

**7. DILI:** Ligand A (27.142) has a significantly lower DILI risk than Ligand B (37.728). Both are below the 40 threshold, but A is preferable.

**8. BBB:** Ligand A (66.305) and Ligand B (63.94) are both reasonably good, but below the >70 percentile desired for CNS targets. Ligand A is slightly better.

**9. Caco-2:** Both have negative Caco-2 values (-4.401 and -4.672) which is unusual and suggests poor permeability.

**10. Solubility:** Both have negative solubility values (-2.615 and -2.304) which is also unusual and suggests poor solubility.

**11. hERG:** Both ligands have very low hERG inhibition risk (0.34 and 0.238).

**12. Cl_mic:** Ligand A (23.792) has a lower microsomal clearance than Ligand B (42.224), suggesting better metabolic stability.

**13. t1/2:** Ligand B (63.909) has a significantly longer in vitro half-life than Ligand A (6.495). This is a substantial advantage for Ligand B.

**14. Pgp:** Both ligands have very low P-gp efflux liability (0.074 and 0.071).

**15. Binding Affinity:** Ligand B (-7.7 kcal/mol) has a significantly stronger binding affinity than Ligand A (-9.0 kcal/mol). This is a crucial advantage, as a >1.5 kcal/mol difference can outweigh other drawbacks.

**Overall Assessment:**

While Ligand A has advantages in TPSA, DILI, and Cl_mic, the significantly stronger binding affinity of Ligand B (-7.7 vs -9.0 kcal/mol) and longer half-life (63.909 vs 6.495) are decisive. The slightly higher DILI risk and TPSA of Ligand B are less concerning given the potency advantage. The negative Caco-2 and solubility values are a concern for both, but can potentially be addressed through formulation strategies.

Output:
1
2025-04-17 06:39:03,660 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (336.391 and 346.475 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (62.55) is excellent, well below the 90 A^2 threshold for CNS targets. Ligand B (78.09) is still reasonable but less optimal.

**logP:** Both ligands (2.426 and 2.798) are within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A has 1 HBD and 3 HBA, which is good. Ligand B has 2 HBD and 3 HBA, also acceptable.

**QED:** Both ligands have similar QED values (0.79 and 0.745), indicating good drug-likeness.

**DILI:** Ligand A (55.913) has a slightly higher DILI risk than Ligand B (31.563), but both are acceptable (<60).

**BBB:** Ligand B (67.662) has a significantly better BBB penetration percentile than Ligand A (53.548). This is a crucial factor for a CNS target like DRD2.

**Caco-2 Permeability:** Ligand A (-4.656) has poor Caco-2 permeability, while Ligand B (-5.228) is also poor, but slightly better.

**Aqueous Solubility:** Both ligands have poor aqueous solubility (-3.683 and -3.06). This could pose formulation challenges.

**hERG:** Both ligands have low hERG inhibition risk (0.651 and 0.808).

**Microsomal Clearance:** Both ligands have similar microsomal clearance values (45.541 and 44.501), suggesting comparable metabolic stability.

**In vitro Half-Life:** Ligand B (-30.285) has a significantly longer in vitro half-life than Ligand A (52.181). This is a positive attribute.

**P-gp Efflux:** Ligand A (0.191) has lower P-gp efflux than Ligand B (0.36), which is favorable for CNS penetration.

**Binding Affinity:** Ligand B (-7.5 kcal/mol) has a slightly better binding affinity than Ligand A (-8.1 kcal/mol). While both are excellent, the difference is small.

**Overall Assessment:**

Ligand B is the more promising candidate. Its superior BBB penetration (67.662 vs 53.548), longer half-life, and slightly better binding affinity outweigh the slightly higher P-gp efflux and DILI risk compared to Ligand A. The TPSA for both is acceptable, and both have good logP and QED scores. While both have poor solubility, this is a formulation challenge that can be addressed. The improved CNS penetration profile of Ligand B is critical for a DRD2 ligand.

Output:
1
2025-04-17 06:39:03,660 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B based on the provided guidelines, prioritizing GPCR-specific properties (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (344.46 and 343.43 Da) fall comfortably within the ideal 200-500 Da range.

**TPSA:** Ligand A (67.23) is excellent, well below the 90 A^2 threshold for CNS targets. Ligand B (104.11) is higher, but still potentially acceptable, though less optimal.

**logP:** Ligand A (3.058) is optimal. Ligand B (1.835) is at the lower end of the optimal range, potentially impacting permeability.

**H-Bond Donors/Acceptors:** Ligand A (1 HBD, 4 HBA) and Ligand B (3 HBD, 4 HBA) both have reasonable numbers of H-bond donors and acceptors, well within the guidelines.

**QED:** Ligand A (0.854) has a better QED score than Ligand B (0.713), indicating a more drug-like profile.

**DILI:** Ligand A (37.301) has a lower DILI risk than Ligand B (55.68), which is preferable.

**BBB:** This is a critical parameter for a CNS target like DRD2. Ligand A (91.896) has a significantly higher BBB penetration percentile than Ligand B (48.895). This is a major advantage for Ligand A.

**Caco-2 Permeability:** Ligand A (-4.805) and Ligand B (-5.608) both have negative Caco-2 values, indicating poor permeability. However, the scale is not defined, so this is hard to interpret.

**Aqueous Solubility:** Ligand A (-3.548) and Ligand B (-2.747) both have negative solubility values, suggesting poor solubility. Again, the scale is not defined, so this is hard to interpret.

**hERG:** Both ligands have low hERG inhibition liability (0.294 and 0.636, respectively), which is good.

**Microsomal Clearance:** Ligand A (38.937) has a higher microsomal clearance than Ligand B (22.849), suggesting lower metabolic stability.

**In vitro Half-Life:** Ligand B (24.444 hours) has a longer in vitro half-life than Ligand A (10.009 hours), which is advantageous.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.254 and 0.051, respectively), which is good.

**Binding Affinity:** Both ligands have the same binding affinity (-8.3 kcal/mol), which is excellent and strong.

**Overall Assessment:**

Ligand A is superior due to its significantly better BBB penetration (91.9% vs 48.9%), lower DILI risk, and higher QED score. While Ligand A has a higher microsomal clearance and shorter half-life, the superior CNS penetration and safety profile outweigh these drawbacks, especially for a CNS-targeting GPCR like DRD2. The similar binding affinities mean potency isn't a differentiating factor.

Output:
1
2025-04-17 06:39:03,661 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (344.415 and 344.459 Da) fall comfortably within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (80.49) is better than Ligand B (83.98). Both are below the 90 A^2 threshold desirable for CNS targets, but A is closer to optimal.

**3. logP:** Ligand A (2.834) is within the optimal 1-3 range. Ligand B (1.776) is on the lower end, potentially hindering permeability.

**4. H-Bond Donors:** Ligand A (1) is preferable to Ligand B (2). Lower HBD generally improves permeability.

**5. H-Bond Acceptors:** Ligand A (6) is better than Ligand B (4). Both are within the acceptable range of <=10.

**6. QED:** Ligand A (0.918) is significantly better than Ligand B (0.79), indicating a more drug-like profile.

**7. DILI:** Ligand A (65.413) has a higher DILI risk than Ligand B (21.714). This is a significant drawback for Ligand A.

**8. BBB:** Ligand A (80.264) has a much better BBB penetration score than Ligand B (57.076). This is crucial for a CNS target like DRD2.

**9. Caco-2:** Ligand A (-4.562) is better than Ligand B (-5.283), indicating better intestinal absorption.

**10. Solubility:** Ligand A (-3.577) is better than Ligand B (-1.337).

**11. hERG:** Ligand A (0.513) is better than Ligand B (0.092), indicating lower cardiotoxicity risk.

**12. Cl_mic:** Ligand A (30.74) has a higher (worse) microsomal clearance than Ligand B (1.632), suggesting lower metabolic stability.

**13. t1/2:** Ligand A (-7.233) has a much longer in vitro half-life than Ligand B (14.39).

**14. Pgp:** Ligand A (0.183) has a lower Pgp efflux liability than Ligand B (0.012), which is favorable for CNS exposure.

**15. Affinity:** Ligand B (-7.5 kcal/mol) has a slightly better binding affinity than Ligand A (-8.9 kcal/mol). While A is better, the difference is not substantial enough to overcome other issues.

**Overall Assessment:**

Ligand A excels in BBB penetration, solubility, hERG, Pgp efflux, and in vitro half-life. Its QED is also much higher. However, it has a concerningly high DILI risk and higher microsomal clearance. Ligand B has a better DILI profile, better metabolic stability, and slightly better affinity, but suffers from lower BBB penetration, lower QED, and higher Pgp efflux.

Given the CNS target (DRD2), BBB penetration is paramount. While the DILI risk for Ligand A is a concern, it might be mitigated through structural modifications. The lower BBB score of Ligand B is a more difficult property to improve. The slightly better affinity of ligand B is not enough to overcome the poor BBB score.

Output:
1
2025-04-17 06:39:03,661 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (378.219 Da) is slightly higher than Ligand B (358.479 Da), but both are acceptable.

**TPSA:** Both ligands have TPSA values around 90-100, which is a bit high for optimal CNS penetration, but not disqualifying. Ligand A (92.41) is slightly better than Ligand B (99.1).

**logP:** Ligand A (2.813) is within the optimal range (1-3). Ligand B (0.678) is below 1, which is a concern for membrane permeability and CNS penetration.

**H-Bond Donors/Acceptors:** Ligand A (HBD=2, HBA=6) and Ligand B (HBD=3, HBA=5) both have reasonable numbers of H-bond donors and acceptors, falling within acceptable limits.

**QED:** Both ligands have acceptable QED values (Ligand A: 0.731, Ligand B: 0.533), indicating good drug-like properties.

**DILI:** Ligand A (94.106) has a significantly higher DILI risk than Ligand B (23.575). This is a major concern for Ligand A.

**BBB:** Ligand A (33.036) has a very low BBB penetration percentile, making it unlikely to effectively reach the target in the CNS. Ligand B (29.779) is also low, but slightly better.

**Caco-2 Permeability:** Both ligands have negative Caco-2 permeability values, indicating poor intestinal absorption. This is unusual and could indicate issues with the prediction method or the compounds themselves.

**Aqueous Solubility:** Both ligands have negative solubility values, which is also unusual and suggests poor aqueous solubility.

**hERG Inhibition:** Both ligands show very low hERG inhibition risk (Ligand A: 0.291, Ligand B: 0.23).

**Microsomal Clearance:** Ligand A (26.973 mL/min/kg) has a higher microsomal clearance than Ligand B (15.807 mL/min/kg), suggesting faster metabolism and potentially lower in vivo exposure.

**In vitro Half-Life:** Ligand A (12.893 hours) has a longer half-life than Ligand B (3.818 hours), which is a positive attribute.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (Ligand A: 0.106, Ligand B: 0.035), which is favorable for CNS penetration.

**Binding Affinity:** Ligand A (-10.1 kcal/mol) has a significantly stronger binding affinity than Ligand B (-7.3 kcal/mol). This is a substantial advantage.

**Overall Assessment:**

Despite the strong binding affinity of Ligand A, its very poor BBB penetration (33%), high DILI risk (94%), and higher metabolic clearance make it a less desirable candidate. Ligand B, while having weaker affinity, has a lower DILI risk (24%), slightly better (though still poor) BBB penetration (30%), and lower clearance. Given the GPCR-specific emphasis on BBB penetration, and the need to avoid toxicity, Ligand B is the more promising candidate, even with the weaker binding. The negative solubility and Caco-2 values are concerning for both, and would require further investigation, but can be addressed with formulation strategies. The affinity difference, while significant, might be overcome with further optimization of Ligand B.

Output:
1
2025-04-17 06:39:03,661 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (345.403 and 348.495 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (110.32) is higher than the preferred <90 for CNS targets, but not drastically so. Ligand B (57.5) is excellent, well below the threshold.

**logP:** Ligand A (-0.184) is quite low, potentially hindering permeability. Ligand B (0.859) is better, falling within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A has 2 HBD and 5 HBA, which are acceptable. Ligand B has 0 HBD and 6 HBA, also acceptable.

**QED:** Both ligands have similar QED values (0.74 and 0.697), indicating good drug-likeness.

**DILI:** Ligand A (34.393) has a lower DILI risk than Ligand B (10.198), which is favorable.

**BBB:** Ligand A (59.054) has a moderate BBB penetration, while Ligand B (64.056) is slightly better. Both are below the desirable >70 for CNS targets, but Ligand B is closer.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.151 and -5.161), which is unusual and suggests poor permeability. This is a significant concern for both.

**Aqueous Solubility:** Both ligands have negative solubility values (-2.519 and -0.071), indicating poor aqueous solubility, which could hinder formulation and bioavailability.

**hERG Inhibition:** Both ligands show low hERG inhibition risk (0.208 and 0.277).

**Microsomal Clearance:** Ligand A has a higher microsomal clearance (4.299 mL/min/kg) than Ligand B (-10.298 mL/min/kg). This means Ligand B is predicted to be more metabolically stable.

**In vitro Half-Life:** Ligand A (10.046 hours) has a longer half-life than Ligand B (0.072 hours), which is preferable.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.018 and 0.02), which is good for CNS exposure.

**Binding Affinity:** Ligand A (-8.2 kcal/mol) has a significantly stronger binding affinity than Ligand B (-7.9 kcal/mol). This 0.3 kcal/mol difference is substantial and can outweigh some ADME drawbacks.

**Overall Assessment:**

Ligand A has a superior binding affinity and lower DILI risk, but suffers from a low logP and moderate BBB penetration. Ligand B has a better logP, TPSA, and metabolic stability (lower Cl_mic), but its binding affinity is weaker. The poor Caco-2 and solubility for both are concerning. However, the strong affinity of Ligand A is a major advantage for a GPCR target. Given the GPCR-specific emphasis on affinity, and the relatively small difference in other parameters, the stronger binding of Ligand A makes it the more promising candidate, despite its lower logP. Further optimization could focus on improving the logP of Ligand A while maintaining its high affinity.

Output:
0
2025-04-17 06:39:03,661 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (364.555 and 342.403 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (49.41) is excellent, well below the 90 A^2 threshold for CNS targets. Ligand B (104.7) is higher, but still potentially acceptable, though less ideal.

**logP:** Ligand A (3.375) is optimal. Ligand B (0.94) is a concern; it's quite low and may hinder membrane permeability.

**H-Bond Donors/Acceptors:** Ligand A (HBD=1, HBA=3) is good. Ligand B (HBD=3, HBA=5) is also acceptable, but slightly higher.

**QED:** Both ligands have good QED scores (A: 0.556, B: 0.726), indicating drug-like properties.

**DILI:** Ligand A (16.053) has a very favorable DILI score. Ligand B (59.907) is higher, suggesting a moderate risk of liver injury.

**BBB:** This is critical for a CNS target. Ligand A (81.776) has a good BBB percentile. Ligand B (39.667) is significantly lower, indicating poor predicted brain penetration.

**Caco-2 Permeability:** Both have negative values (-5.04 and -5.551) which is unusual and requires further investigation. However, these values are on a scale where higher is better, so both are poor.

**Aqueous Solubility:** Both have negative values (-3.621 and -2.763) which is unusual and requires further investigation. However, these values are on a scale where higher is better, so both are poor.

**hERG:** Ligand A (0.736) has a low hERG risk. Ligand B (0.103) is even lower, indicating very low cardiotoxicity risk.

**Microsomal Clearance:** Ligand A (93.888) has high microsomal clearance, suggesting rapid metabolism and potentially low bioavailability. Ligand B (-4.81) has negative clearance, which is not physically possible and suggests an issue with the data.

**In vitro Half-Life:** Ligand A (-2.238) has a negative half-life, which is not physically possible and suggests an issue with the data. Ligand B (6.873) has a reasonable half-life.

**P-gp Efflux:** Ligand A (0.299) has low P-gp efflux, which is good for CNS penetration. Ligand B (0.022) has very low P-gp efflux, which is even better.

**Binding Affinity:** Ligand B (-9.3 kcal/mol) has a significantly stronger binding affinity than Ligand A (-7.4 kcal/mol). This is a substantial advantage (1.9 kcal/mol difference).

**Overall Assessment:**

Ligand B has a superior binding affinity, lower P-gp efflux, and lower hERG risk. However, it suffers from a low logP, poor BBB penetration, and questionable microsomal clearance and half-life data. Ligand A has a better logP and BBB, but weaker affinity and higher clearance.

Despite the questionable data for Ligand B, the significantly stronger binding affinity is a major advantage for a GPCR ligand. The low logP and BBB can potentially be addressed through structural modifications, whereas improving affinity is often more challenging. The negative values for clearance and half-life are concerning and would need to be investigated further.

Output:
1
2025-04-17 06:39:03,662 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (356.369 and 366.571 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (67.87) is better than Ligand B (49.41). Both are below the 90 A^2 threshold for CNS targets, which is excellent.

**logP:** Ligand A (1.581) is within the optimal 1-3 range. Ligand B (3.596) is at the higher end of the optimal range, potentially increasing off-target interactions.

**H-Bond Donors/Acceptors:** Both ligands have 1 HBD and a reasonable number of HBAs (4 for A, 3 for B), satisfying the criteria.

**QED:** Ligand A (0.806) has a significantly better QED score than Ligand B (0.678), indicating a more drug-like profile.

**DILI:** Ligand A (41.838) has a lower DILI risk than Ligand B (13.339), which is a significant advantage.

**BBB:** Ligand A (88.096) has a much higher BBB penetration percentile than Ligand B (76.154). This is *critical* for a CNS target like DRD2.

**Caco-2 Permeability:** Ligand A (-4.644) has a worse Caco-2 permeability than Ligand B (-5.27). However, this is less important than BBB for CNS targets.

**Aqueous Solubility:** Ligand A (-1.924) has better solubility than Ligand B (-3.414).

**hERG:** Both ligands have low hERG inhibition liability (0.437 and 0.555).

**Microsomal Clearance:** Ligand B (75.288) has a higher microsomal clearance than Ligand A (29.887), suggesting lower metabolic stability.

**In vitro Half-Life:** Ligand A (19.937) has a longer half-life than Ligand B (7.968).

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.061 and 0.231).

**Binding Affinity:** Ligand A (-8.9 kcal/mol) has a significantly stronger binding affinity than Ligand B (-7.4 kcal/mol). This >1.5 kcal/mol difference is substantial and can outweigh minor ADME drawbacks.

**Overall Assessment:**

Ligand A is superior to Ligand B. The key advantages of Ligand A are its significantly higher BBB penetration, stronger binding affinity, better QED score, lower DILI risk, and improved metabolic stability (lower Cl_mic and longer t1/2). While Ligand B has slightly better Caco-2 permeability, this is less important for a CNS target. The superior affinity of Ligand A is a major factor, and the favorable ADME properties further support its selection.

Output:
1
2025-04-17 06:39:03,662 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (348.334 Da) is slightly lower, which could be beneficial for permeability. Ligand B (371.591 Da) is also good.

**TPSA:** Ligand A (95.34) is borderline for CNS targets (ideally <90), but acceptable. Ligand B (43.86) is excellent, well below the 90 threshold. This is a significant advantage for B.

**logP:** Ligand A (0.661) is a bit low, potentially hindering membrane permeability. Ligand B (2.699) is within the optimal range (1-3). This favors B.

**H-Bond Donors/Acceptors:** Ligand A has 1 HBD and 7 HBA, which are reasonable. Ligand B has 0 HBD and 4 HBA, also acceptable.

**QED:** Both ligands have reasonable QED values (A: 0.771, B: 0.592), indicating good drug-like properties.

**DILI:** Ligand A has a higher DILI risk (86.002 percentile) than Ligand B (11.09 percentile). This is a major concern for A.

**BBB:** Both ligands have good BBB penetration (A: 80.962, B: 83.56), exceeding the 70% threshold for CNS targets. B is slightly better.

**Caco-2 Permeability:** Both have negative Caco-2 values (-4.821 and -4.895). These values are unusual and likely indicate issues with the prediction model or the compounds themselves. We can't rely on this metric.

**Aqueous Solubility:** Both have negative solubility values (-3.072 and -1.588). Similar to Caco-2, these are problematic and unreliable.

**hERG Inhibition:** Ligand A (0.127) has a very low hERG risk, which is excellent. Ligand B (0.563) is slightly higher, but still relatively low.

**Microsomal Clearance:** Both have similar microsomal clearance values (A: 46.465, B: 42.961), suggesting comparable metabolic stability.

**In vitro Half-Life:** Ligand A (-5.477) has a negative half-life, which is impossible and indicates a problem with the prediction. Ligand B (12.993) has a reasonable half-life.

**P-gp Efflux:** Ligand A (0.14) has low P-gp efflux, which is favorable for CNS penetration. Ligand B (0.082) has even lower P-gp efflux, which is even better.

**Binding Affinity:** Ligand A (-8.6 kcal/mol) has a significantly stronger binding affinity than Ligand B (-7.2 kcal/mol). This is a substantial advantage for A, potentially outweighing some of its ADME drawbacks.

**Overall Assessment:**

Ligand A has a much better binding affinity, but suffers from a high DILI risk and an impossible in vitro half-life prediction. Ligand B has superior ADME properties (lower DILI, better TPSA, logP, and P-gp efflux) and a reasonable half-life, but its binding affinity is weaker.

Given the importance of ADME properties for CNS drugs, and the problematic predictions for Ligand A (DILI, half-life), I believe Ligand B is the more viable drug candidate, despite the weaker binding affinity. The difference in affinity (1.4 kcal/mol) *might* be overcome with further optimization, while fixing the severe ADME liabilities of Ligand A would likely require a more substantial redesign.

Output:
1
2025-04-17 06:39:03,662 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (339.41 Da) is slightly lower, which is generally favorable for permeability. Ligand B (376.513 Da) is also good.

**TPSA:** Ligand A (38.33) is excellent, well below the 90 A^2 threshold for CNS targets. Ligand B (49.41) is still reasonable, but less optimal.

**logP:** Both ligands have good logP values (A: 4.017, B: 3.166), falling within the 1-3 range. Ligand B is slightly more optimal.

**H-Bond Donors/Acceptors:** Both ligands have acceptable HBD (1) and HBA (A: 2, B: 3) counts.

**QED:** Both ligands have good QED scores (A: 0.917, B: 0.742), indicating drug-like properties.

**DILI:** Ligand A (71.966) has a higher DILI risk than Ligand B (22.838), which is a significant concern.

**BBB:** Ligand B (96.355) has a much better BBB penetration score than Ligand A (87.088). This is *critical* for a CNS target like DRD2.

**Caco-2 Permeability:** Both have negative Caco-2 values which is unusual, but we will assume they are percentile scores and that lower is worse. Ligand A (-4.503) is worse than Ligand B (-4.875).

**Aqueous Solubility:** Both ligands have negative solubility values, again assuming percentile scores, and are therefore poor. Ligand A (-5.034) is slightly worse than Ligand B (-3.611).

**hERG:** Both ligands have low hERG inhibition risk (A: 0.792, B: 0.772).

**Microsomal Clearance:** Ligand A (28.729) has lower microsomal clearance than Ligand B (42.801), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand B (-5.165) has a negative half-life which is unusual, and suggests it is very unstable. Ligand A (24.148) is much better.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (A: 0.49, B: 0.162). Ligand B is slightly better.

**Binding Affinity:** Ligand B (-8.2 kcal/mol) has a significantly stronger binding affinity than Ligand A (-10.6 kcal/mol). This is a substantial advantage.

**Overall Assessment:**

Ligand B has a much better BBB score and a significantly improved binding affinity. While Ligand A has better metabolic stability, the superior CNS penetration and binding of Ligand B outweigh this advantage. The lower DILI risk of Ligand B is also a major positive. The negative solubility and Caco-2 values are concerning for both, but can be addressed with formulation strategies. The negative half-life of Ligand B is a significant concern.

Output:
1
2025-04-17 06:39:03,663 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (350.463 and 371.547 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (89.27) is slightly above the optimal <90 for CNS targets, but still reasonable. Ligand B (78.51) is excellent, well below 90.

**logP:** Both ligands have good logP values (1.766 and 1.029), falling within the 1-3 range. Ligand B is slightly better, closer to 1.

**H-Bond Donors/Acceptors:** Both have 2 HBD, which is good. Ligand A has 6 HBA, while Ligand B has 4. Both are acceptable (<=10), but Ligand B is slightly more favorable.

**QED:** Both ligands have QED values above 0.7, indicating good drug-likeness.

**DILI:** Ligand A (36.293) has a moderate DILI risk, but is acceptable. Ligand B (14.967) has a significantly lower DILI risk, which is a major advantage.

**BBB:** Both ligands have reasonable BBB penetration (64.87% and 66.576%). While ideally >70% for CNS targets, these are not dramatically different.

**Caco-2 Permeability:** Ligand A (-4.741) and Ligand B (-5.089) both have negative Caco-2 values, which is unusual and suggests poor permeability. This is a concern for both.

**Aqueous Solubility:** Both ligands have poor aqueous solubility (-3.307 and -1.986). This could pose formulation challenges.

**hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.247 and 0.22). This is excellent.

**Microsomal Clearance:** Ligand A (38.889) has higher microsomal clearance than Ligand B (-6.076). Ligand B's negative value suggests very good metabolic stability.

**In vitro Half-Life:** Ligand A (25.256) has a moderate half-life, while Ligand B (-3.059) has a very long predicted half-life.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.103 and 0.023). This is favorable for CNS penetration.

**Binding Affinity:** Ligand A (-8.4 kcal/mol) has a slightly better binding affinity than Ligand B (-7.2 kcal/mol). This is a 1.2 kcal/mol difference, which is significant.

**Overall Assessment:**

While Ligand A has a slightly better binding affinity, Ligand B has significantly better ADME properties, particularly lower DILI risk, better metabolic stability (lower Cl_mic, longer t1/2), and slightly better logP and HBA. The Caco-2 permeability is poor for both, but the other advantages of Ligand B outweigh the small affinity difference. For a CNS target like DRD2, metabolic stability and minimizing toxicity (DILI) are crucial.

Output:
1
2025-04-17 06:39:03,663 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 drug candidates, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (343.467 and 348.359 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (38.77) is excellent, well below the 90 A^2 threshold for CNS targets. Ligand B (123.46) is higher, but still reasonable, though less favorable.

**logP:** Ligand A (3.746) is optimal (1-3). Ligand B (1.416) is on the lower side, potentially hindering permeability.

**H-Bond Donors/Acceptors:** Ligand A (0 HBD, 3 HBA) is very favorable. Ligand B (2 HBD, 6 HBA) is acceptable, but slightly higher counts could impact permeability.

**QED:** Ligand A (0.765) is excellent, indicating strong drug-likeness. Ligand B (0.436) is below the 0.5 threshold, suggesting a less ideal drug-like profile.

**DILI:** Ligand A (25.087) has a very low DILI risk. Ligand B (63.978) has a moderate DILI risk, but is still within acceptable limits.

**BBB:** Ligand A (80.574) has excellent BBB penetration potential. Ligand B (68.282) is lower, which is a significant drawback for a CNS target like DRD2.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.612 and -4.976), which is unusual and suggests potential issues with the assay or the compounds themselves. However, we'll assume these are relative values and focus on the other parameters.

**Aqueous Solubility:** Both ligands have negative solubility values (-3.041 and -3.268), indicating poor aqueous solubility, which could pose formulation challenges.

**hERG Inhibition:** Ligand A (0.684) has a low hERG risk. Ligand B (0.199) also has a low hERG risk.

**Microsomal Clearance:** Ligand A (74.856) has moderate clearance. Ligand B (29.019) has low clearance, suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (12.845) has a moderate half-life. Ligand B (10.285) has a shorter half-life.

**P-gp Efflux:** Ligand A (0.671) has moderate P-gp efflux. Ligand B (0.073) has very low P-gp efflux, which is highly desirable for CNS penetration.

**Binding Affinity:** Ligand B (-8.0) has significantly stronger binding affinity than Ligand A (-0.0). This is a substantial advantage.

**Overall Assessment:**

Ligand B's significantly higher binding affinity (-8.0 kcal/mol vs -0.0 kcal/mol) is a major advantage that could outweigh some of its less favorable properties. The lower P-gp efflux is also a significant plus for CNS penetration. However, its lower logP, lower QED, and lower BBB penetration are concerns. Ligand A has better overall ADME properties (BBB, QED, logP) but its binding affinity is extremely weak.

Given the GPCR-specific priorities, and the importance of affinity, I would choose Ligand B, despite its ADME drawbacks. The strong binding affinity provides a good starting point for optimization, and the lower P-gp efflux is a significant benefit for CNS targets. The other ADME properties can be addressed through medicinal chemistry efforts.

Output:
1
2025-04-17 06:39:03,663 - INFO - Batch 299 complete. Total preferences: 4784
2025-04-17 06:39:03,663 - INFO - Processing batch 300/512...
2025-04-17 06:39:44,468 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (362.392 and 354.466 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Both ligands have a TPSA of 58.64, which is excellent for CNS penetration (well below the 90 A^2 threshold).

**3. logP:** Ligand A (1.758) is within the optimal range (1-3). Ligand B (2.749) is also within the optimal range.

**4. H-Bond Donors:** Both ligands have 1 HBD, which is acceptable.

**5. H-Bond Acceptors:** Both ligands have 3 HBA, which is acceptable.

**6. QED:** Ligand A (0.751) has a better QED score than Ligand B (0.565), indicating a more drug-like profile.

**7. DILI:** Ligand A (29.042) has a slightly higher DILI risk than Ligand B (22.024), but both are well below the concerning threshold of 60.

**8. BBB:** Both ligands exhibit excellent BBB penetration (Ligand A: 90.074%, Ligand B: 88.135%), exceeding the desirable 70% threshold for CNS targets.

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.57 and -4.622). This is unusual and could indicate issues with the prediction method or inherent properties leading to poor permeability. However, given the strong BBB scores, this is less concerning.

**10. Aqueous Solubility:** Both ligands have negative solubility values (-2.659 and -2.273). Similar to Caco-2, this is a potential issue, but the strong BBB scores suggest reasonable *in vivo* exposure.

**11. hERG Inhibition:** Ligand A (0.584) has a slightly higher hERG risk than Ligand B (0.383), but both are relatively low.

**12. Microsomal Clearance:** Ligand B (45.043) has a lower microsomal clearance than Ligand A (32.164), suggesting better metabolic stability.

**13. In vitro Half-Life:** Ligand B (-3.827) has a negative half-life, which is nonsensical. Ligand A (10.931) has a reasonable half-life. This is a significant red flag for Ligand B.

**14. P-gp Efflux:** Ligand A (0.04) has a very low P-gp efflux liability, which is favorable for CNS penetration. Ligand B (0.218) also has low P-gp efflux, but higher than Ligand A.

**15. Binding Affinity:** Ligand A (-6.7 kcal/mol) has a slightly better binding affinity than Ligand B (-0.0 kcal/mol). The difference is substantial (6.7 kcal/mol), and this is a critical factor.

**Overall Assessment:**

Ligand A is clearly the superior candidate. It has a better QED score, a more reasonable in vitro half-life, and significantly stronger binding affinity. While both ligands have similar TPSA, logP, BBB, and DILI scores, the combination of improved drug-likeness, metabolic stability (implied by the half-life), and substantially increased binding affinity makes Ligand A the more promising drug candidate. The negative Caco-2 and solubility values are concerning but potentially mitigated by the excellent BBB penetration. The negative half-life of Ligand B is a dealbreaker.

Output:
1
2025-04-17 06:39:44,469 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (354.447 Da) is slightly lower, which *could* be beneficial for permeability, but both are acceptable.

**TPSA:** Ligand A (84.94) is excellent for CNS penetration, well below the 90 A^2 threshold. Ligand B (48.3) is even better.

**logP:** Ligand A (1.111) is within the optimal range. Ligand B (2.856) is also good, leaning towards the higher end but still acceptable.

**H-Bond Donors/Acceptors:** Both ligands have 1 HBD and 5-6 HBA, which are within acceptable limits.

**QED:** Both ligands have good QED scores (A: 0.66, B: 0.805), indicating drug-like properties.

**DILI:** Ligand A (19.659) has a significantly lower DILI risk than Ligand B (35.13). This is a substantial advantage for Ligand A.

**BBB:** Ligand B (89.57) has a much higher BBB penetration percentile than Ligand A (62.117). This is a *major* advantage for Ligand B, given DRD2 is a CNS target.

**Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and suggests poor permeability. However, the scale is not specified, so it's hard to interpret.

**Aqueous Solubility:** Both ligands have negative solubility values, which is also unusual and suggests poor solubility. Again, the scale is not specified.

**hERG:** Ligand A (0.313) has a lower hERG risk than Ligand B (0.989). This is a positive for Ligand A.

**Microsomal Clearance:** Both have similar microsomal clearance rates (A: 45.492, B: 42.576), suggesting comparable metabolic stability.

**In vitro Half-Life:** Ligand B (-10.889) has a significantly longer half-life than Ligand A (-7.969). This is a benefit for Ligand B.

**P-gp Efflux:** Ligand A (0.041) has a much lower P-gp efflux liability than Ligand B (0.917). This is a significant advantage for Ligand A, as it would improve CNS exposure.

**Binding Affinity:** Ligand B (-10.889 kcal/mol) has a substantially stronger binding affinity than Ligand A (-7.3 kcal/mol). This is a *very* significant advantage for Ligand B, potentially outweighing some of the ADME drawbacks. A difference of >1.5 kcal/mol is considered substantial.

**Overall Assessment:**

Ligand B excels in BBB penetration and binding affinity, which are critical for a CNS GPCR target like DRD2. While it has a higher DILI risk and P-gp efflux, the strong affinity and BBB penetration are likely to be more impactful. Ligand A has a better safety profile (lower DILI, hERG, P-gp) but significantly weaker binding affinity and lower BBB penetration. The difference in binding affinity is large enough to likely overcome the ADME liabilities of Ligand B.

Output:
1
2025-04-17 06:39:44,469 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B based on the provided guidelines, prioritizing GPCR-specific properties (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (339.41 and 312.442 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (41.49) is slightly higher than Ligand B (30.87). Both are below the 90 A^2 threshold desirable for CNS targets, but Ligand B is significantly better.

**logP:** Both ligands (3.674 and 3.439) are within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A has 2 HBD and 3 HBA, while Ligand B has 1 HBD and 5 HBA. Both are within acceptable limits.

**QED:** Both ligands have good QED scores (0.789 and 0.808), indicating drug-like properties.

**DILI:** Ligand A (40.287) has a lower DILI risk than Ligand B (66.305). This is a significant advantage for Ligand A.

**BBB:** Ligand B (94.572) has a much higher BBB penetration score than Ligand A (70.027). This is a critical advantage for a CNS target like DRD2.

**Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and suggests poor permeability. Ligand A (-4.528) is slightly worse than Ligand B (-4.707).

**Aqueous Solubility:** Both have negative solubility values, indicating poor solubility. Ligand A (-4.314) is slightly better than Ligand B (-3.765).

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.931 and 0.966).

**Microsomal Clearance:** Ligand B (35.87) has lower microsomal clearance than Ligand A (38.156), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand B (-18.94) has a significantly longer in vitro half-life than Ligand A (50.054). This is a major advantage for Ligand B.

**P-gp Efflux:** Ligand A (0.876) has slightly lower P-gp efflux than Ligand B (0.633), which is favorable for CNS penetration.

**Binding Affinity:** Ligand A (-9.4 kcal/mol) has a stronger binding affinity than Ligand B (-8.2 kcal/mol). This is a substantial advantage for Ligand A (1.2 kcal/mol difference).

**Overall Assessment:**

While Ligand A has a better binding affinity and lower DILI risk, Ligand B excels in crucial GPCR-specific properties for CNS targets: significantly higher BBB penetration and a much longer half-life. The improved BBB penetration is particularly important for DRD2, and the longer half-life could translate to less frequent dosing. The lower P-gp efflux also supports better CNS exposure. The difference in binding affinity, while substantial, might be overcome with further optimization, whereas improving BBB and half-life are generally more challenging.

Output:
1
2025-04-17 06:39:44,469 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B based on the provided guidelines, prioritizing GPCR-specific properties (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (347.415 Da) is slightly lower, which could be beneficial for permeability, but both are acceptable.

**TPSA:** Ligand A (88.6) is excellent for CNS penetration, being well below the 90 A^2 threshold. Ligand B (99.67) is still reasonable, but less optimal.

**logP:** Both ligands have good logP values (A: 1.881, B: 1.49), falling within the 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A (HBD=1, HBA=5) and Ligand B (HBD=2, HBA=6) both have acceptable numbers of H-bond donors and acceptors.

**QED:** Both ligands have similar QED values (A: 0.761, B: 0.702), indicating good drug-likeness.

**DILI:** Ligand A (64.444) has a higher DILI risk than Ligand B (35.867). This is a significant drawback for Ligand A.

**BBB:** Ligand A (59.093) has a better BBB percentile than Ligand B (33.54). This is a critical advantage for a CNS target like DRD2.

**Caco-2 Permeability:** Ligand A (-4.448) has worse Caco-2 permeability than Ligand B (-5.562). Both are negative, indicating poor permeability, but B is slightly worse.

**Aqueous Solubility:** Both ligands have very poor aqueous solubility (-3.382 and -3.115 respectively). This could pose formulation challenges.

**hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.236 and 0.222 respectively).

**Microsomal Clearance:** Ligand A (44.758) has a higher microsomal clearance than Ligand B (8.934), suggesting lower metabolic stability. This is a negative for Ligand A.

**In vitro Half-Life:** Ligand A (-30.892) has a much longer in vitro half-life than Ligand B (0.7). This is a significant advantage for Ligand A.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.095 and 0.062 respectively).

**Binding Affinity:** Ligand A (-7.3 kcal/mol) has a significantly stronger binding affinity than Ligand B (-6.2 kcal/mol). This 1.1 kcal/mol difference is substantial and can outweigh some ADME drawbacks.

**Overall Assessment:**

Ligand A excels in BBB penetration, binding affinity, and in vitro half-life. However, it has a higher DILI risk and lower metabolic stability. Ligand B has a lower DILI risk and better metabolic stability, but significantly weaker binding affinity and poorer BBB penetration.

Given the CNS target (DRD2), BBB penetration and binding affinity are paramount. The 1.1 kcal/mol difference in binding affinity, coupled with the better BBB score of Ligand A, outweighs its higher DILI risk and lower metabolic stability. The poor solubility of both compounds is a concern that would need to be addressed in formulation.

Output:
1
2025-04-17 06:39:44,470 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B against the provided guidelines, prioritizing GPCR-specific properties (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (342.399 Da) is slightly lower, which *could* be beneficial for permeability, but both are acceptable.

**TPSA:** Ligand A (96.6) is better than Ligand B (58.64). For CNS targets, we want TPSA <= 90, so Ligand A is closer to the ideal.

**logP:** Ligand B (2.216) is optimal (1-3), while Ligand A (0.277) is quite low, potentially hindering membrane permeability. This is a significant drawback for Ligand A.

**H-Bond Donors/Acceptors:** Both have acceptable numbers of HBD (1) and HBA (Ligand A: 4, Ligand B: 3).

**QED:** Ligand A (0.777) has a better QED score than Ligand B (0.484), indicating a more drug-like profile.

**DILI:** Ligand A (32.067) has a much lower DILI risk than Ligand B (10.237), which is a significant advantage.

**BBB:** Ligand B (88.406) has a substantially better BBB penetration percentile than Ligand A (71.268). For a CNS target like DRD2, this is *critical*.

**Caco-2 Permeability:** Ligand A (-5.153) has poor Caco-2 permeability, while Ligand B (-4.741) is also poor, but slightly better.

**Aqueous Solubility:** Both have negative solubility values, which is unusual and indicates very poor solubility. Ligand A (-1.251) is slightly better than Ligand B (-2.12).

**hERG:** Both ligands have very low hERG inhibition liability (Ligand A: 0.044, Ligand B: 0.578), which is excellent.

**Microsomal Clearance:** Ligand A (-7.485) has significantly lower (better) microsomal clearance than Ligand B (50.179), suggesting greater metabolic stability.

**In vitro Half-Life:** Ligand A (-21.227) has a longer in vitro half-life than Ligand B (-13.811), which is desirable.

**P-gp Efflux:** Ligand A (0.008) has much lower P-gp efflux liability than Ligand B (0.207), meaning it's less likely to be pumped out of the brain, improving CNS exposure.

**Binding Affinity:** Both ligands have excellent binding affinities (Ligand A: -8.2 kcal/mol, Ligand B: -7.9 kcal/mol). Ligand A is slightly better, but the difference is relatively small.

**Overall Assessment:**

Ligand A excels in QED, DILI, metabolic stability (Cl_mic, t1/2), P-gp efflux, and binding affinity. However, its very low logP and poor Caco-2 permeability are major concerns. Ligand B has a significantly better BBB penetration, which is paramount for a CNS target, and a more favorable logP. While its DILI and metabolic stability are worse, the strong BBB penetration and acceptable logP outweigh these drawbacks. The slightly better affinity of Ligand A isn't enough to compensate for its permeability issues.

Output:
1
2025-04-17 06:39:44,470 - INFO - Reasoning:

Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (355.507 and 347.459 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (45.23) is excellent, well below the 90 Angstroms threshold for CNS targets. Ligand B (76.64) is higher, but still reasonable, though less favorable for CNS penetration.

**3. logP:** Ligand A (3.338) is optimal. Ligand B (1.795) is a bit low, potentially hindering membrane permeability, but not drastically.

**4. H-Bond Donors:** Ligand A (1) is good. Ligand B (2) is also acceptable.

**5. H-Bond Acceptors:** Ligand A (4) is good. Ligand B (3) is also acceptable.

**6. QED:** Both ligands have good QED scores (0.918 and 0.853), indicating drug-like properties.

**7. DILI:** Both ligands have low DILI risk (44.475 and 32.261), which is favorable.

**8. BBB:** Ligand A (77.937) has a good BBB percentile, exceeding the 70% threshold for CNS targets. Ligand B (29.508) is significantly lower, suggesting poor brain penetration. This is a critical disadvantage for a DRD2 ligand.

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.081 and -4.86), which is unusual and suggests poor permeability. However, these values are on a log scale and can be difficult to interpret without knowing the experimental setup.

**10. Aqueous Solubility:** Both ligands have negative solubility values (-2.905 and -2.105), suggesting poor aqueous solubility. This could pose formulation challenges.

**11. hERG Inhibition:** Both ligands have low hERG inhibition risk (0.78 and 0.521), which is good.

**12. Microsomal Clearance:** Ligand A (29.054) has higher clearance than Ligand B (20.316), indicating potentially lower metabolic stability.

**13. In vitro Half-Life:** Ligand B (-10.335) has a negative half-life, which is not physically possible and indicates an issue with the data. Ligand A (21.536) has a reasonable half-life.

**14. P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.488 and 0.171), which is favorable for CNS exposure.

**15. Binding Affinity:** Ligand B (-6.7 kcal/mol) has a significantly stronger binding affinity than Ligand A (0.0 kcal/mol). This is a substantial advantage.

**Overall Assessment:**

Despite Ligand B's superior binding affinity, its very poor BBB penetration (29.508) is a major drawback for a DRD2 ligand targeting CNS disorders. The negative half-life is also concerning, suggesting a data error. Ligand A, while having weaker affinity, exhibits a much better BBB score (77.937), acceptable TPSA, and a reasonable half-life. The slightly higher clearance of Ligand A is less concerning than the poor CNS penetration of Ligand B. Given the GPCR-specific priorities and the target (DRD2 in the CNS), Ligand A is the more promising candidate.

Output:
1
2025-04-17 06:39:44,470 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (379.869 Da) is slightly higher than Ligand B (343.475 Da), but both are acceptable.

**TPSA:** Ligand A (80.32) is borderline for CNS penetration, being above the preferred <90. Ligand B (55.47) is excellent for CNS penetration.

**logP:** Ligand A (3.613) is at the higher end of the optimal range, while Ligand B (1.169) is a bit low, potentially hindering membrane permeability.

**H-Bond Donors/Acceptors:** Ligand A (HBD=2, HBA=6) and Ligand B (HBD=1, HBA=4) are both within acceptable limits.

**QED:** Both ligands have good QED scores (Ligand A: 0.567, Ligand B: 0.895), indicating drug-like properties. Ligand B is better.

**DILI:** Ligand A (83.598) has a higher DILI risk than Ligand B (10.779), which is a significant concern.

**BBB:** Ligand B (89.027) has a much better BBB penetration score than Ligand A (61.225). This is crucial for a CNS target like DRD2.

**Caco-2 Permeability:** Both have negative Caco-2 values, indicating poor permeability. However, the scale is not specified, so it's hard to interpret.

**Aqueous Solubility:** Both have negative solubility values, indicating poor solubility. Again, the scale is not specified.

**hERG Inhibition:** Both ligands show low hERG inhibition risk (Ligand A: 0.525, Ligand B: 0.804).

**Microsomal Clearance:** Ligand B (-6.906) has a negative clearance, which is unusual and likely indicates very high metabolic stability. Ligand A (31.589) has a moderate clearance.

**In vitro Half-Life:** Ligand B (-3.884) has a negative half-life, which is also unusual and likely indicates very high stability. Ligand A (9.538) has a moderate half-life.

**P-gp Efflux:** Ligand A (0.488) has lower P-gp efflux than Ligand B (0.051), which is favorable for CNS penetration.

**Binding Affinity:** Both ligands have excellent binding affinity (-8.8 and -8.9 kcal/mol), with Ligand B being slightly better. The difference is small enough that other factors become more important.

**Overall Assessment:**

Ligand B is significantly better due to its superior BBB penetration (89.027 vs 61.225), much lower DILI risk (10.779 vs 83.598), and potentially excellent metabolic stability (negative clearance and half-life). While Ligand A has slightly better P-gp efflux, the other advantages of Ligand B outweigh this. The slightly lower logP of Ligand B is a minor concern, but the strong affinity and excellent CNS properties make it the more promising candidate.

Output:
1
2025-04-17 06:39:44,470 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B based on the provided guidelines, prioritizing GPCR-specific properties (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (353.507 Da) is slightly lower, potentially aiding permeability, while Ligand B (371.825 Da) is also acceptable.

**TPSA:** Ligand A (81.67) is excellent for CNS penetration, being well below 90. Ligand B (96.77) is still reasonable but less optimal, potentially hindering BBB penetration.

**logP:** Ligand A (1.446) is within the optimal range (1-3). Ligand B (0.236) is quite low, potentially causing permeability issues.

**H-Bond Donors/Acceptors:** Ligand A (HBD=3, HBA=4) is well within the acceptable limits. Ligand B (HBD=1, HBA=6) is also acceptable.

**QED:** Both ligands have good QED scores (A: 0.519, B: 0.66), indicating drug-like properties.

**DILI:** Both have low DILI risk (A: 5.312, B: 56.572), but Ligand A is significantly better.

**BBB:** Ligand B (81.388) has a much better BBB percentile than Ligand A (50.523). This is a crucial factor for a CNS target like DRD2.

**Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and suggests potential issues with the calculation or data quality. However, the magnitude of the negative value for Ligand A (-5.153) is larger than for Ligand B (-4.801), suggesting potentially lower permeability.

**Aqueous Solubility:** Both have negative solubility values, again suggesting potential issues with the data. Ligand A (-1.57) is slightly better than Ligand B (-2.261).

**hERG Inhibition:** Both have very low hERG inhibition risk (A: 0.472, B: 0.06).

**Microsomal Clearance:** Ligand A (2.08) has significantly lower clearance than Ligand B (10.843), indicating better metabolic stability.

**In vitro Half-Life:** Ligand A (2.814) has a slightly longer half-life than Ligand B (-2.825).

**P-gp Efflux:** Ligand A (0.032) has much lower P-gp efflux liability than Ligand B (0.013), which is beneficial for CNS penetration.

**Binding Affinity:** Ligand A (-7.8 kcal/mol) has a significantly stronger binding affinity than Ligand B (-6.7 kcal/mol). This 1.1 kcal/mol difference is substantial and can outweigh some ADME drawbacks.

**Overall Assessment:**

While Ligand B has a superior BBB score, Ligand A excels in most other crucial parameters, particularly binding affinity, metabolic stability (lower Cl_mic), P-gp efflux, and DILI risk. The stronger binding affinity of Ligand A is a significant advantage for a GPCR target. The lower logP of Ligand B is concerning, potentially hindering its ability to cross cell membranes. The better BBB of ligand B is important, but the strong affinity of ligand A combined with its better ADME profile makes it the more promising candidate.

Output:
1
2025-04-17 06:39:44,470 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (387.511 Da) is slightly higher than Ligand B (341.43 Da), but both are acceptable.

**TPSA:** Ligand A (61.44) is higher than Ligand B (45.23). For CNS targets, we want TPSA <= 90, both are well within this range. Ligand B is preferable here.

**logP:** Both ligands have good logP values (A: 3.675, B: 3.305), falling within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A has 2 HBD and 5 HBA, while Ligand B has 1 HBD and 3 HBA. Both are within acceptable limits (<=5 HBD and <=10 HBA).

**QED:** Both ligands have good QED scores (A: 0.72, B: 0.911), indicating good drug-like properties. Ligand B is slightly better.

**DILI:** Ligand A (85.964) has a higher DILI risk than Ligand B (52.695). This is a significant concern, as we prefer DILI < 40. Ligand B is much better.

**BBB:** Ligand B (78.402) has a better BBB penetration percentile than Ligand A (69.407). Both are reasonably good, but >70 is desirable for CNS targets, and B is closer.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.976 and -4.705). These values are unusual and difficult to interpret without further context. However, they suggest poor permeability.

**Aqueous Solubility:** Both ligands have negative solubility values (-5.125 and -2.816). Similar to Caco-2, these are problematic and suggest poor solubility.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (A: 0.551, B: 0.862).

**Microsomal Clearance:** Ligand B (29.494) has significantly lower microsomal clearance than Ligand A (55.451), indicating better metabolic stability.

**In vitro Half-Life:** Ligand B (-1.131) has a negative half-life, which is not physically possible. This is a major red flag. Ligand A (52.25) is reasonable.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (A: 0.396, B: 0.408).

**Binding Affinity:** Both ligands have the same binding affinity (-9.5 kcal/mol), which is excellent.

**Overall Assessment:**

Ligand B appears better overall, despite the nonsensical negative half-life. It has a significantly lower DILI risk, better BBB penetration, and lower microsomal clearance. The slightly better QED and lower TPSA also contribute to its favorability. However, the negative half-life is a critical issue that needs investigation. Ligand A has a reasonable half-life, but the higher DILI risk is a major drawback. Given the equal binding affinity, the ADME properties of Ligand B (excluding the half-life issue) make it the more promising candidate *if* the half-life can be clarified or corrected.

Output:
1
2025-04-17 06:39:44,471 - INFO - Reasoning:

Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (360.361 and 350.463 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (130.39) is slightly above the optimal <90 for CNS targets, but still reasonable. Ligand B (80.48) is excellent, well below 90.

**logP:** Ligand A (-0.969) is a bit low, potentially hindering permeability. Ligand B (1.604) is within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A (4 HBD, 4 HBA) is good. Ligand B (1 HBD, 6 HBA) is also acceptable.

**QED:** Both ligands have good QED scores (0.465 and 0.808), suggesting drug-like properties. Ligand B is significantly better.

**DILI:** Both have acceptable DILI risk (37.728 and 26.328), below the 40 threshold. Ligand B is slightly better.

**BBB:** Both ligands exhibit good BBB penetration (70.027 and 73.129), exceeding the desirable >70 threshold for CNS targets. Ligand B is slightly better.

**Caco-2 Permeability:** Both have negative Caco-2 values (-5.934 and -4.93). This is unusual and suggests poor permeability *in vitro*. However, these values are on a logarithmic scale and should be interpreted cautiously.

**Aqueous Solubility:** Both have negative solubility values (-1.86 and -1.352), indicating poor aqueous solubility. This is a concern for bioavailability.

**hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.088 and 0.239).

**Microsomal Clearance:** Ligand A (-4.007) has a negative clearance, which is not physically possible. This is likely an error in the data. Ligand B (40.041) has a high clearance, suggesting rapid metabolism.

**In vitro Half-Life:** Ligand A (-16.43) has a negative half-life, which is not physically possible. This is likely an error in the data. Ligand B (-4.582) has a short half-life, which is not ideal.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.012 and 0.039), which is favorable for CNS penetration.

**Binding Affinity:** Both ligands have comparable binding affinities (-8.3 and -6.2 kcal/mol). Ligand A has a significantly stronger binding affinity, exceeding the -7.0 threshold. The 2.1 kcal/mol difference is substantial.

**Overall Assessment:**

Despite the unusual negative values for Caco-2, solubility, clearance and half-life, the most important factor for a CNS GPCR target is binding affinity and BBB penetration. Ligand A has a much stronger binding affinity (-8.3 kcal/mol vs -6.2 kcal/mol) and comparable BBB penetration. While Ligand B has better TPSA and logP, the substantial difference in binding affinity outweighs these advantages. The negative values for some parameters in Ligand A are concerning and require further investigation, but the strong binding affinity makes it the more promising candidate *given the available data*.

Output:
1
2025-04-17 06:39:44,471 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (352.431 and 362.367 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (101.57) is borderline for CNS penetration, being slightly above the preferred <90. Ligand B (42.43) is excellent, well below 90, suggesting better CNS penetration.

**logP:** Ligand A (0.956) is a bit low, potentially hindering permeability. Ligand B (3.52) is optimal.

**H-Bond Donors/Acceptors:** Ligand A has 2 HBD and 5 HBA, which are acceptable. Ligand B has 0 HBD and 3 HBA, also acceptable.

**QED:** Both ligands have reasonable QED scores (0.634 and 0.525), indicating good drug-like properties.

**DILI:** Both have low DILI risk (35.479 and 30.399), which is positive.

**BBB:** Ligand B (97.053) shows excellent BBB penetration, a crucial factor for a CNS target like DRD2. Ligand A (46.491) is significantly lower and less desirable.

**Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and requires further investigation. However, we can still compare them relatively. Ligand A (-4.94) is slightly better than Ligand B (-4.06).

**Aqueous Solubility:** Both have negative solubility values, which is also unusual. Ligand A (-1.633) is slightly better than Ligand B (-3.626).

**hERG:** Ligand A (0.045) has a very low hERG risk, which is excellent. Ligand B (0.867) has a moderate hERG risk, which is less ideal.

**Microsomal Clearance:** Ligand A (39.719) has lower clearance, suggesting better metabolic stability than Ligand B (59.723).

**In vitro Half-Life:** Ligand B (23.318) has a longer half-life than Ligand A (-22.589), which is generally preferred.

**P-gp Efflux:** Ligand A (0.033) has very low P-gp efflux, which is excellent for CNS penetration. Ligand B (0.612) has moderate P-gp efflux.

**Binding Affinity:** Ligand B (-7.1) has a slightly better binding affinity than Ligand A (-7.8), although both are very good.

**Overall Assessment:**

Considering the GPCR-specific priorities, Ligand B is the stronger candidate. Its excellent BBB penetration (97.053), optimal logP (3.52), and good binding affinity (-7.1) outweigh the slightly higher P-gp efflux and moderate hERG risk. While Ligand A has a better hERG profile and lower P-gp efflux, its significantly lower BBB penetration is a major drawback for a CNS target. The negative Caco-2 and solubility values are concerning for both, but the other factors favor Ligand B.

Output:
1
2025-04-17 06:39:44,471 - INFO - Reasoning:

Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (359.312 and 360.479 Da) fall comfortably within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (106.85) is slightly above the optimal <90 for CNS targets, but still reasonable. Ligand B (57.69) is excellent, well below 90, indicating good potential for brain penetration.

**3. logP:** Both ligands have good logP values (A: 1.3, B: 2.457), falling within the 1-3 range. Ligand B is slightly better, leaning towards the higher end of optimal.

**4. H-Bond Donors:** Ligand A (2) is acceptable, while Ligand B (0) is also good.

**5. H-Bond Acceptors:** Ligand A (7) is acceptable, while Ligand B (4) is also good.

**6. QED:** Both ligands have good QED scores (A: 0.722, B: 0.81), indicating drug-like properties.

**7. DILI:** Ligand A (72.043) has a higher DILI risk than Ligand B (27.336), which is a significant concern.

**8. BBB:** Ligand A (83.715) has a good BBB percentile, exceeding the 70% threshold for CNS targets. Ligand B (78.79) is also good, but slightly lower.

**9. Caco-2:** Both have negative Caco-2 values which is unusual and suggests a potential issue with the data or modeling. However, we will proceed assuming these are percentile scores and higher is better.

**10. Solubility:** Both ligands have very poor aqueous solubility (-2.19 and -2.088). This is a major drawback for both, potentially hindering bioavailability.

**11. hERG:** Both ligands have very low hERG inhibition liability (A: 0.115, B: 0.076), which is excellent.

**12. Cl_mic:** Ligand A (26.632) has lower microsomal clearance than Ligand B (32.128), suggesting better metabolic stability.

**13. t1/2:** Ligand A (-10.423) has a negative in vitro half-life, which is concerning. Ligand B (-8.765) is also negative, but less so. These negative values are unusual and likely indicate issues with the modeling.

**14. Pgp:** Both ligands have low P-gp efflux liability (A: 0.124, B: 0.112), which is favorable for CNS penetration.

**15. Binding Affinity:** Both ligands have excellent binding affinities (A: -8.2 kcal/mol, B: -8.5 kcal/mol). Ligand B has a slightly better affinity, but the difference is relatively small.

**Overall Assessment:**

While both ligands show promising binding affinity, Ligand B is the more favorable candidate. It has a significantly lower DILI risk, a better logP, and a lower TPSA, all of which are important for a CNS-targeting GPCR ligand. The slightly better BBB and affinity of Ligand B further support this conclusion. The poor solubility and negative half-life values are concerning for both, but the DILI risk associated with Ligand A is a major red flag.

Output:
1
2025-04-17 06:39:44,471 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (376.36 and 356.419 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (103.35) is slightly higher than Ligand B (97.33), but both are below the 140 A^2 threshold for oral absorption and reasonably close to the <90 A^2 target for CNS penetration.

**logP:** Ligand A (2.69) is within the optimal 1-3 range. Ligand B (-0.705) is below 1, which could impede permeation. This is a significant negative for Ligand B.

**H-Bond Donors/Acceptors:** Ligand A has 4 HBD and 5 HBA, while Ligand B has 2 HBD and 6 HBA. Both are within acceptable limits.

**QED:** Both ligands have similar QED values (0.644 and 0.597), indicating reasonable drug-likeness.

**DILI:** Ligand A (87.049) has a higher DILI risk than Ligand B (16.014). This is a concern for Ligand A.

**BBB:** Ligand A (58.86) has a better BBB penetration percentile than Ligand B (33.967), but neither are above the desirable >70 threshold for CNS targets.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.164 and -5.032), which is unusual and suggests poor permeability.

**Aqueous Solubility:** Both ligands have negative solubility values (-3.506 and -0.468), indicating very poor aqueous solubility.

**hERG Inhibition:** Both ligands have low hERG inhibition liability (0.478 and 0.127).

**Microsomal Clearance:** Ligand B (-4.586) has a negative clearance, which is not physically possible and suggests an issue with the data. Ligand A (27.398) has a reasonable clearance.

**In vitro Half-Life:** Ligand A (70.26) has a longer half-life than Ligand B (22.44).

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.131 and 0.008).

**Binding Affinity:** Ligand A (-8.5 kcal/mol) has a significantly stronger binding affinity than Ligand B (-7.0 kcal/mol). This is a >1.5 kcal/mol advantage, which can outweigh other drawbacks.

**Overall Assessment:**

Ligand A has a superior binding affinity and better BBB penetration and half-life. However, it has a higher DILI risk. Ligand B has a much lower DILI risk, but suffers from a significantly lower logP (potentially impacting permeability), a questionable negative clearance value, and weaker binding affinity. Given the importance of affinity for GPCRs, and the fact that the difference in affinity is substantial, Ligand A is the more promising candidate *despite* the higher DILI risk. Further optimization could address the DILI concern. The negative clearance for Ligand B is a major red flag.

Output:
1
2025-04-17 06:39:44,472 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (352.391 and 345.487 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (132.81) is better than Ligand B (43.86). For CNS targets, we want TPSA <= 90, and A is closer to that threshold. B is quite high, potentially hindering BBB penetration despite other favorable factors.

**logP:** Ligand A (-1.131) is a bit low, potentially impacting permeability. Ligand B (1.742) is within the optimal 1-3 range. This is a significant advantage for B.

**H-Bond Donors/Acceptors:** Ligand A has 5 HBD and 7 HBA, acceptable. Ligand B has 0 HBD and 3 HBA, also acceptable and potentially better for permeability.

**QED:** Both ligands have good QED scores (0.419 and 0.732, respectively), indicating drug-like properties. Ligand B is better.

**DILI:** Both have relatively low DILI risk (62.466 and 7.212), with Ligand B being significantly better.

**BBB:** Ligand B (91.043) is excellent, exceeding the desirable >70 threshold for CNS targets. Ligand A (35.595) is poor, a major drawback.

**Caco-2 Permeability:** Both have negative values (-5.544 and -4.711), which is unusual and difficult to interpret without knowing the scale. However, assuming lower values indicate poorer permeability, both are concerning.

**Aqueous Solubility:** Both have negative values (-1.181 and -1.795), which is also unusual. Again, assuming lower values indicate poorer solubility, both are concerning.

**hERG:** Both have low hERG risk (0.154 and 0.518).

**Microsomal Clearance:** Ligand A (-13.906) has much lower (better) microsomal clearance than Ligand B (28.229), suggesting better metabolic stability.

**In vitro Half-Life:** Both have similar in vitro half-lives (7.88 and 7.529 hours).

**P-gp Efflux:** Ligand A (0.004) has extremely low P-gp efflux, a significant advantage for CNS penetration. Ligand B (0.096) is also low, but not as favorable as A.

**Binding Affinity:** Both ligands have very similar and excellent binding affinities (-7.4 and -7.5 kcal/mol).

**Overall Assessment:**

Ligand B is significantly better regarding BBB penetration and logP, two critical factors for CNS GPCR targets. Its DILI risk is also much lower. While Ligand A has better P-gp efflux and metabolic stability, the poor BBB penetration is a major hurdle. Given the target is DRD2 (a CNS target), the superior BBB penetration of Ligand B outweighs the advantages of Ligand A.

Output:
1
2025-04-17 06:39:44,472 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (364.389 and 356.373 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (99.1) is higher than the preferred <90 for CNS targets, while Ligand B (73.39) is comfortably below. This favors Ligand B.

**logP:** Ligand A (0.45) is quite low, potentially hindering membrane permeability. Ligand B (2.128) is within the optimal 1-3 range. This is a significant advantage for Ligand B.

**H-Bond Donors/Acceptors:** Ligand A has 3 HBD and 5 HBA, acceptable. Ligand B has 0 HBD and 6 HBA, also acceptable.

**QED:** Both ligands have reasonable QED values (0.45 and 0.61), indicating drug-like properties. Ligand B is slightly better.

**DILI:** Ligand A (28.228) has a lower DILI risk than Ligand B (44.552), which is favorable.

**BBB:** Ligand B (95.347) has a significantly higher BBB percentile than Ligand A (65.607). This is *crucial* for a CNS target like DRD2 and strongly favors Ligand B.

**Caco-2 Permeability:** Ligand A (-5.105) has poor Caco-2 permeability, while Ligand B (-4.445) is also poor but slightly better.

**Aqueous Solubility:** Both ligands have very poor aqueous solubility (-2.147 and -2.343). This is a concern for both, but can be addressed with formulation strategies.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.565 and 0.639).

**Microsomal Clearance:** Ligand A (-17.434) exhibits much lower microsomal clearance (better metabolic stability) than Ligand B (57.259). This is a substantial advantage for Ligand A.

**In vitro Half-Life:** Ligand A (-20.407) has a longer in vitro half-life than Ligand B (18.073), further supporting its better metabolic stability.

**P-gp Efflux:** Ligand A (0.051) has lower P-gp efflux than Ligand B (0.467), which is favorable for CNS penetration.

**Binding Affinity:** Ligand B (-6.1 kcal/mol) has a slightly better binding affinity than Ligand A (-8.2 kcal/mol). This is a significant advantage for Ligand B.

**Overall Assessment:**

While Ligand A has better metabolic stability (lower Cl_mic, longer t1/2), lower P-gp efflux, and a slightly better binding affinity, Ligand B excels in key properties for a CNS-targeting GPCR ligand: significantly better BBB penetration, a more optimal logP, and a lower TPSA. The superior BBB penetration and logP of Ligand B outweigh the metabolic advantages of Ligand A, especially considering formulation strategies can potentially mitigate solubility issues. The affinity difference, while present, is not large enough to overcome the ADME advantages of Ligand B.

Output:
1
2025-04-17 06:39:44,472 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 drug candidates, considering the provided guidelines and GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (344.375 and 347.463 Da) fall comfortably within the ideal 200-500 Da range.

**TPSA:** Ligand A (122.03) is slightly above the optimal <90 for CNS targets, but still reasonable. Ligand B (88.17) is excellent, well below 90, favoring CNS penetration.

**logP:** Ligand A (-0.049) is a bit low, potentially hindering membrane permeability. Ligand B (2.093) is within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Both have 3 HBD and are within the acceptable limits. Ligand A has 7 HBA, while Ligand B has 6. Both are acceptable.

**QED:** Both ligands have good QED scores (0.606 and 0.667), indicating drug-like properties.

**DILI:** Ligand A (60.217) has a higher DILI risk than Ligand B (39.201). Ligand B is preferred here.

**BBB:** This is crucial for a CNS target like DRD2. Ligand B (74.641) is significantly better than Ligand A (24.622).

**Caco-2 Permeability:** Both are negative (-5.555 and -5.241), which is unusual and potentially problematic. However, the scale isn't specified, so it's hard to interpret.

**Aqueous Solubility:** Both are also negative (-2.056 and -2.026) which is also unusual.

**hERG Inhibition:** Both ligands show low hERG inhibition risk (0.1 and 0.344).

**Microsomal Clearance:** Ligand A (15.07) has a lower (better) microsomal clearance than Ligand B (31.215), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand B (25.845) has a significantly longer half-life than Ligand A (3.479).

**P-gp Efflux:** Both ligands show low P-gp efflux liability (0.02 and 0.019).

**Binding Affinity:** Both ligands have very similar and strong binding affinities (-8.6 and -8.5 kcal/mol). The difference is negligible.

**Overall Assessment:**

Ligand B is the stronger candidate. While Ligand A has better metabolic stability (lower Cl_mic), Ligand B excels in the critical areas for a CNS-targeting GPCR: TPSA, logP, and especially BBB penetration. The lower DILI risk for Ligand B is also a significant advantage. The similar binding affinities mean that the ADME/PK advantages of Ligand B outweigh the slightly better metabolic stability of Ligand A. The negative values for Caco-2 and solubility are concerning for both, but the other factors strongly favor Ligand B.

Output:
1
2025-04-17 06:39:44,472 - INFO - Batch 300 complete. Total preferences: 4800
2025-04-17 06:39:44,472 - INFO - Processing batch 301/512...
2025-04-17 06:40:25,794 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (345.447) is slightly lower, which could be beneficial for permeability.

**TPSA:** Ligand A (70.47) is significantly better than Ligand B (129.89). For CNS targets, TPSA should be <= 90, and A is comfortably within this range, while B is approaching the upper limit.

**logP:** Ligand A (0.162) is quite low, potentially hindering membrane permeability. Ligand B (0.786) is better, falling within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A (HBD=1, HBA=5) is more favorable than Ligand B (HBD=3, HBA=7). Both are within acceptable limits, but lower counts generally improve permeability.

**QED:** Ligand A (0.844) has a much higher QED score than Ligand B (0.467), indicating a more drug-like profile.

**DILI:** Ligand B (61.419) has a higher DILI risk than Ligand A (14.618). A lower DILI risk is always preferred.

**BBB:** Ligand A (62.854) has a slightly better BBB penetration percentile than Ligand B (59.248), but both are below the desirable >70% for CNS targets.

**Caco-2 Permeability:** Ligand A (-5.191) has a significantly worse Caco-2 permeability than Ligand B (-6.154). Lower values suggest poorer intestinal absorption.

**Aqueous Solubility:** Ligand A (-1.099) has slightly better aqueous solubility than Ligand B (-2.985).

**hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.127 and 0.691 respectively).

**Microsomal Clearance:** Ligand A (-11.527) has a much lower (better) microsomal clearance than Ligand B (33.935), suggesting greater metabolic stability.

**In vitro Half-Life:** Ligand A (16.42) has a better in vitro half-life than Ligand B (-13.892).

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.011 and 0.075 respectively).

**Binding Affinity:** Both ligands have the same binding affinity (-7.5 kcal/mol), which is excellent.

**Overall Assessment:**

Despite Ligand B having a better logP and slightly better Caco-2 permeability, Ligand A is the superior candidate. The significantly better TPSA, QED, DILI, microsomal clearance, and in vitro half-life outweigh the slightly lower logP and BBB. The equal binding affinity means potency isn't a differentiating factor. The lower TPSA of Ligand A is particularly important for a CNS target like DRD2, and the improved metabolic stability (lower Cl_mic and higher t1/2) are crucial for *in vivo* efficacy. While both BBB values are suboptimal, Ligand A's other advantages make it more likely to succeed.

Output:
0
2025-04-17 06:40:25,795 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (341.382 and 365.909 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (47.56) is significantly better than Ligand B (59.11). For CNS targets, we want TPSA <= 90, and ideally lower. Ligand A is much closer to the ideal range.

**3. logP:** Both ligands have good logP values (3.332 and 2.813), falling within the optimal 1-3 range.

**4. H-Bond Donors:** Both have 1 HBD, which is acceptable.

**5. H-Bond Acceptors:** Ligand A has 3 HBAs, Ligand B has 6. Both are within the acceptable limit of <=10, but Ligand A is preferable.

**6. QED:** Both ligands have good QED scores (0.931 and 0.855), indicating good drug-like properties.

**7. DILI:** Ligand A (53.276) has a higher DILI risk than Ligand B (20.396). This is a significant advantage for Ligand B.

**8. BBB:** Both ligands have excellent BBB penetration (78.209 and 72.082), exceeding the desirable >70 threshold for CNS targets.

**9. Caco-2 Permeability:** Both have negative Caco-2 values (-4.684 and -4.909). This is unusual and suggests poor permeability. However, these values are on a scale where negative values are possible, and direct comparison is difficult without knowing the scale's specifics.

**10. Aqueous Solubility:** Both have negative solubility values (-4.072 and -3.116), indicating poor aqueous solubility. Similar to Caco-2, interpretation is limited by the scale.

**11. hERG Inhibition:** Both ligands show low hERG inhibition risk (0.739 and 0.562).

**12. Microsomal Clearance:** Ligand A (65.907) has higher microsomal clearance than Ligand B (32.489), indicating lower metabolic stability. Ligand B is preferable.

**13. In vitro Half-Life:** Both ligands have similar in vitro half-lives (21.352 and 21.921 hours).

**14. P-gp Efflux:** Ligand A (0.617) has lower P-gp efflux than Ligand B (0.37), which is favorable for CNS penetration.

**15. Binding Affinity:** Ligand B (-7.4 kcal/mol) has significantly stronger binding affinity than Ligand A (-10.2 kcal/mol). This is a substantial advantage, potentially outweighing some ADME drawbacks.

**Overall Assessment:**

Ligand B has a significantly better binding affinity and lower DILI risk and microsomal clearance. While Ligand A has a slightly better TPSA and P-gp efflux, the superior affinity of Ligand B is a critical factor for a GPCR target. The negative Caco-2 and solubility values are concerning for both, but the strong binding of Ligand B suggests it might overcome these issues.

Output:
1
2025-04-17 06:40:25,795 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (364.47 and 351.45 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (82.63) is better than Ligand B (78.95) as both are below the 90 A^2 threshold for CNS targets.

**logP:** Ligand A (3.065) is optimal, while Ligand B (0.53) is quite low, potentially hindering membrane permeability. This is a significant drawback for a CNS target.

**H-Bond Donors & Acceptors:** Ligand A (2 HBD, 5 HBA) and Ligand B (1 HBD, 4 HBA) both meet the criteria of <=5 HBD and <=10 HBA.

**QED:** Both ligands have good QED scores (0.74 and 0.801), indicating good drug-like properties.

**DILI:** Ligand B (16.25) has a much lower DILI risk than Ligand A (56.15), which is a positive attribute.

**BBB:** Ligand B (74.49) has a significantly better BBB penetration score than Ligand A (30.28). This is *critical* for a CNS target like DRD2.

**Caco-2 Permeability:** Ligand A (-5.072) and Ligand B (-4.522) both have negative values, which is unusual. However, the scale is not specified, so it's difficult to interpret.

**Aqueous Solubility:** Both ligands have negative solubility values (-2.762 and -1.389). This is concerning, but solubility can often be improved with formulation strategies.

**hERG Inhibition:** Ligand A (0.48) has a slightly higher hERG risk than Ligand B (0.136), but both are relatively low.

**Microsomal Clearance:** Ligand B (-0.838) exhibits lower microsomal clearance, suggesting better metabolic stability, compared to Ligand A (68.171).

**In vitro Half-Life:** Ligand B (-12.294) has a longer in vitro half-life than Ligand A (-10.328).

**P-gp Efflux:** Ligand A (0.226) has lower P-gp efflux liability than Ligand B (0.016), which is favorable for CNS penetration.

**Binding Affinity:** Both ligands have comparable binding affinities (-8.0 and -7.8 kcal/mol), which are both excellent. The difference is less than the 1.5 kcal/mol threshold.

**Conclusion:**

While Ligand A has slightly better P-gp efflux, Ligand B is significantly superior overall, particularly regarding BBB penetration (74.5% vs 30.3%), logP (0.53 vs 3.065), and metabolic stability (lower Cl_mic). The better BBB and logP are crucial for CNS targets. The lower DILI risk and longer half-life of Ligand B are also beneficial. The similar binding affinities make these ADME properties the deciding factors.

Output:
1
2025-04-17 06:40:25,795 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (448.726 Da) is higher, but still acceptable. Ligand B (348.407 Da) is slightly better.

**TPSA:** Both ligands have TPSA values around 109, which is above the optimal <90 for CNS targets, but not drastically so. This is a moderate concern for both.

**logP:** Ligand A (2.22) is within the optimal 1-3 range. Ligand B (-0.13) is significantly below this, which could hinder membrane permeability and potentially reduce brain exposure.

**H-Bond Donors/Acceptors:** Ligand A (HBD=3, HBA=5) and Ligand B (HBD=2, HBA=8) both fall within acceptable limits.

**QED:** Both ligands have good QED scores (A: 0.587, B: 0.797), indicating good drug-like properties. Ligand B is slightly better.

**DILI:** Ligand A (82.319) has a higher DILI risk than Ligand B (50.485), which is preferable.

**BBB:** Ligand A (21.714) has a very low BBB penetration percentile, which is a major drawback for a CNS target like DRD2. Ligand B (24.544) is also low, but slightly better.

**Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and suggests poor permeability.

**Aqueous Solubility:** Both ligands have negative solubility values, which is also unusual and suggests poor solubility.

**hERG Inhibition:** Both ligands have very low hERG inhibition risk (A: 0.401, B: 0.089), which is excellent.

**Microsomal Clearance:** Ligand A (53.92) has a higher microsomal clearance than Ligand B (-14.411), indicating lower metabolic stability. Ligand B is significantly better.

**In vitro Half-Life:** Ligand A (-18.48) has a negative half-life, which is not possible. Ligand B (24.08) is a reasonable value.

**P-gp Efflux:** Ligand A (0.264) has moderate P-gp efflux liability, while Ligand B (0.019) has very low efflux, which is highly desirable for CNS penetration.

**Binding Affinity:** Ligand A (-9.0 kcal/mol) has significantly stronger binding affinity than Ligand B (-0.0 kcal/mol). This is a substantial advantage.

**Overall Assessment:**

Despite the strong binding affinity of Ligand A, its extremely poor BBB penetration (21.714%) and higher DILI risk are major concerns. The negative values for Caco-2 and solubility are also problematic. Ligand B, while having a much weaker binding affinity, has a better safety profile (lower DILI, lower P-gp efflux), better metabolic stability (lower Cl_mic, higher t1/2), and a slightly better (though still poor) BBB percentile.

Given the GPCR-specific priorities, particularly BBB penetration for a CNS target, and the substantial difference in binding affinity, the stronger binding of Ligand A *could* potentially overcome its other deficiencies with further optimization. However, the extremely low BBB value is a significant hurdle. Considering the current data, Ligand B is the more promising starting point for further development, as improving its affinity is more tractable than dramatically improving the BBB penetration of Ligand A.

Output:
1
2025-04-17 06:40:25,795 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (349.289 Da) is slightly better positioned.

**TPSA:** Ligand A (78.63) is excellent for CNS penetration, well below the 90 A^2 threshold. Ligand B (126.13) is higher, but still potentially acceptable, though less ideal.

**logP:** Ligand A (2.533) is optimal. Ligand B (-0.698) is significantly lower, which could hinder membrane permeability and CNS penetration.

**H-Bond Donors/Acceptors:** Ligand A (0 HBD, 6 HBA) is favorable. Ligand B (2 HBD, 9 HBA) is also acceptable, but slightly higher counts could impact permeability.

**QED:** Both ligands have good QED scores (A: 0.623, B: 0.693), indicating drug-like properties.

**DILI:** Ligand A (84.762) has a higher DILI risk than Ligand B (76.425), but both are reasonably low.

**BBB:** This is crucial for a CNS target. Ligand A (85.731) has excellent BBB penetration potential. Ligand B (23.071) is very poor, a major drawback.

**Caco-2 Permeability:** Ligand A (-3.871) is poor. Ligand B (-5.755) is even worse, suggesting significant absorption issues.

**Aqueous Solubility:** Ligand A (-4.29) is poor, but Ligand B (-1.461) is better.

**hERG Inhibition:** Both ligands have very low hERG inhibition risk (A: 0.275, B: 0.049).

**Microsomal Clearance:** Ligand A (118.049) has moderate clearance, while Ligand B (3.67) has very low clearance, indicating better metabolic stability.

**In vitro Half-Life:** Ligand A (-34.453) has a very short half-life. Ligand B (1.046) has a short half-life, but is better than ligand A.

**P-gp Efflux:** Ligand A (0.426) has moderate P-gp efflux. Ligand B (0.034) has very low P-gp efflux, which is highly desirable for CNS penetration.

**Binding Affinity:** Ligand B (-7.4 kcal/mol) has a significantly stronger binding affinity than Ligand A (-8.2 kcal/mol). While A is already good, B's affinity is substantially better.

**Overall Assessment:**

Ligand B has a superior binding affinity and better metabolic stability (lower Cl_mic) and P-gp efflux. However, its major weaknesses are the poor logP and very low BBB penetration. Ligand A has a better logP and excellent BBB penetration, but its affinity is weaker, and its half-life is very short.

Given the GPCR-specific priorities, BBB penetration is critical for a CNS target like DRD2. While Ligand B's affinity is attractive, its inability to cross the BBB is a deal-breaker. Ligand A, despite its weaker affinity, has a much higher chance of reaching the target in the brain. The poor Caco-2 and solubility of both are concerns, but can be addressed with formulation strategies. The short half-life of Ligand A is also a concern, but could be addressed through structural modifications.

Output:
1
2025-04-17 06:40:25,795 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (350.503 and 338.455 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (69.64) is slightly above the optimal <90 for CNS targets, but still reasonable. Ligand B (50.16) is excellent, well below 90.

**logP:** Both ligands have good logP values (2.639 and 3.142), falling within the 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A has 2 HBD and 3 HBA, while Ligand B has 1 HBD and 4 HBA. Both are within acceptable limits (<=5 HBD and <=10 HBA).

**QED:** Both ligands have good QED scores (0.724 and 0.88), indicating good drug-like properties.

**DILI:** Ligand A (8.375) has a very low DILI risk, significantly better than Ligand B (30.516).

**BBB:** This is a critical parameter for CNS targets. Ligand B (89.104) has a much higher BBB penetration percentile than Ligand A (60.644). This is a substantial advantage for Ligand B.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.678 and -4.898), which is unusual and suggests poor permeability. However, these values are on a scale where negative values are possible, and direct comparison is difficult without knowing the scale's specifics.

**Aqueous Solubility:** Both ligands have negative solubility values (-2.033 and -3.058), also unusual. Similar to Caco-2, interpretation is limited without knowing the scale.

**hERG Inhibition:** Ligand A (0.287) has a lower hERG inhibition risk than Ligand B (0.875), which is favorable.

**Microsomal Clearance:** Ligand B (69.731) has a higher microsomal clearance than Ligand A (37.969), suggesting faster metabolism and potentially lower in vivo exposure.

**In vitro Half-Life:** Ligand B (6.653) has a longer half-life than Ligand A (-5.65). This is a positive attribute.

**P-gp Efflux:** Ligand A (0.056) has significantly lower P-gp efflux liability than Ligand B (0.639), which is crucial for CNS penetration.

**Binding Affinity:** Both ligands have very similar and strong binding affinities (-8.4 and -8.2 kcal/mol). The difference of 0.2 kcal/mol is unlikely to be decisive.

**Overall Assessment:**

Ligand B excels in BBB penetration and in vitro half-life. However, it has a higher DILI risk, higher P-gp efflux, and higher microsomal clearance. Ligand A has a significantly better safety profile (lower DILI, lower hERG, lower P-gp efflux) and better metabolic stability. While Ligand B's BBB is superior, Ligand A's lower efflux liability could compensate for the slightly lower BBB value. The similar binding affinities make the ADME properties the deciding factors. Given the importance of minimizing off-target effects and maximizing CNS exposure, Ligand A appears to be the more promising candidate.

Output:
0
2025-04-17 06:40:25,796 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (346.475 and 362.499 Da) fall within the ideal range of 200-500 Da.

**TPSA:** Ligand A (75.19) is significantly better than Ligand B (86.88). For CNS targets, we want TPSA <= 90, and A is closer to the ideal <= 60. B is pushing the upper limit.

**logP:** Both ligands have good logP values (2.517 and 1.581), falling within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A (HBD=1, HBA=4) is preferable to Ligand B (HBD=3, HBA=4). While both are acceptable, fewer HBDs generally improve permeability.

**QED:** Ligand A (0.859) has a significantly higher QED score than Ligand B (0.582), indicating a more drug-like profile.

**DILI:** Both ligands have acceptable DILI risk (35.556 and 38.581, both < 40).

**BBB:** This is crucial for a CNS target like DRD2. Ligand A (68.282) is better than Ligand B (51.764), although ideally, we'd like to see >70.

**Caco-2 Permeability:** Ligand A (-4.718) is better than Ligand B (-5.859). Higher values indicate better intestinal absorption.

**Aqueous Solubility:** Ligand A (-3.689) is better than Ligand B (-2.427). Higher values are preferred.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.519 and 0.187).

**Microsomal Clearance:** Ligand A (66.19) has a higher clearance than Ligand B (20.652), meaning B is more metabolically stable.

**In vitro Half-Life:** Both ligands have similar negative half-lives (-1.481 and -4.361).

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.052).

**Binding Affinity:** Ligand B (-8.0 kcal/mol) has a slightly better binding affinity than Ligand A (-7.2 kcal/mol). This is a significant advantage.

**Overall Assessment:**

Ligand A excels in most ADME properties (TPSA, QED, BBB, solubility, Caco-2 permeability) and has a good logP. However, its binding affinity is weaker. Ligand B has a superior binding affinity, which is a high priority for GPCRs, and better metabolic stability. While its TPSA is less ideal, the affinity difference is substantial. The slightly lower BBB for B is a concern, but the affinity advantage likely outweighs this drawback, especially considering the other reasonably favorable ADME properties.

Output:
1
2025-04-17 06:40:25,796 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (348.422 and 345.491 Da) fall well within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (67.23) is better than Ligand B (70.15). Both are below the 90 A^2 threshold for CNS targets, but A is closer to the optimal range.

**3. logP:** Both ligands have acceptable logP values (1.568 and 2.882), falling within the 1-3 range. Ligand B is slightly higher, which *could* be a minor concern for solubility, but not a dealbreaker.

**4. H-Bond Donors:** Ligand A (1) is preferable to Ligand B (2). Lower HBD generally improves permeability.

**5. H-Bond Acceptors:** Ligand A (4) is preferable to Ligand B (5). Lower HBA generally improves permeability.

**6. QED:** Both ligands have good QED values (0.822 and 0.859), indicating good drug-like properties.

**7. DILI:** Ligand B (35.867) has a significantly lower DILI risk than Ligand A (51.648). This is a substantial advantage for Ligand B.

**8. BBB:** Both ligands show excellent BBB penetration (82.435 and 85.072), exceeding the desirable >70% threshold for CNS targets. Ligand B is slightly better.

**9. Caco-2 Permeability:** Ligand A (-4.761) is better than Ligand B (-5.084). Higher (less negative) values indicate better permeability.

**10. Aqueous Solubility:** Ligand A (-2.581) is better than Ligand B (-3.237). Higher values indicate better solubility.

**11. hERG Inhibition:** Both ligands show low hERG inhibition liability (0.41 and 0.601), which is good.

**12. Microsomal Clearance:** Ligand A (22.258) has a significantly lower microsomal clearance than Ligand B (62.356), suggesting better metabolic stability. This is a significant advantage for Ligand A.

**13. In vitro Half-Life:** Ligand A (-7.667) has a much longer in vitro half-life than Ligand B (4.853). This is a major advantage for Ligand A.

**14. P-gp Efflux:** Ligand A (0.128) has lower P-gp efflux than Ligand B (0.08). Lower efflux is better for CNS exposure.

**15. Binding Affinity:** Ligand B (-9.0) has a significantly stronger binding affinity than Ligand A (-7.7). This is a substantial advantage for Ligand B, potentially outweighing some ADME concerns.

**Overall Assessment:**

Ligand B has a superior binding affinity and slightly better BBB penetration and DILI risk. However, Ligand A has better metabolic stability (lower Cl_mic, longer t1/2), lower P-gp efflux, and better solubility. The difference in affinity is significant (1.3 kcal/mol), and for a GPCR target, strong binding is paramount. While Ligand A has better ADME properties, the potency advantage of Ligand B is likely to be more impactful in driving efficacy.

Output:
1
2025-04-17 06:40:25,796 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (366.571 and 352.391 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (63.4) is excellent, well below the 90 A^2 threshold for CNS targets. Ligand B (117.17) is higher, but still potentially acceptable, though less desirable.

**logP:** Ligand A (3.535) is optimal (1-3). Ligand B (-0.585) is significantly outside the optimal range and is concerningly low, potentially hindering membrane permeability.

**H-Bond Donors/Acceptors:** Ligand A (1 HBD, 3 HBA) is good. Ligand B (2 HBD, 6 HBA) is also acceptable, but higher HBA could slightly impact permeability.

**QED:** Both ligands have reasonable QED values (0.89 and 0.62), indicating good drug-like properties.

**DILI:** Ligand A (29.546) has a much lower DILI risk than Ligand B (55.68). This is a significant advantage for Ligand A.

**BBB:** Ligand A (80.264) has a good BBB percentile, exceeding the 70% threshold for CNS targets. Ligand B (55.138) is considerably lower and less favorable for CNS penetration.

**Caco-2 Permeability:** Ligand A (-4.79) and Ligand B (-5.107) both have negative values, which is unusual and requires further investigation. However, the scale is not specified, so we can't draw definitive conclusions.

**Aqueous Solubility:** Ligand A (-4.218) and Ligand B (-2.306) both have negative solubility values, which is also unusual and requires further investigation.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.86 and 0.111).

**Microsomal Clearance:** Ligand A (56.363) has higher microsomal clearance than Ligand B (23.548), suggesting lower metabolic stability.

**In vitro Half-Life:** Ligand B (-7.518) has a more negative half-life, which is unusual, and suggests a very short half-life. Ligand A (-27.951) is also negative, but less so.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.333 and 0.012), which is favorable for CNS exposure.

**Binding Affinity:** Both ligands have very similar and strong binding affinities (-8.2 and -8.0 kcal/mol). The difference is not substantial enough to outweigh other factors.

**Overall Assessment:**

Ligand A is significantly better due to its superior logP, BBB penetration, and lower DILI risk. While its microsomal clearance is higher, the substantial advantages in CNS penetration and safety profile outweigh this drawback. Ligand B's low logP is a major concern, likely hindering its ability to cross the blood-brain barrier despite the low P-gp efflux. The unusual negative values for Caco-2 and Solubility also raise concerns.

Output:
1
2025-04-17 06:40:25,796 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (350.459 Da and 360.47 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (78.87) is significantly better than Ligand B (98.66). For CNS targets, TPSA should be <= 90, and A is comfortably within this range, while B is close to the upper limit.

**3. logP:** Both ligands have acceptable logP values (0.79 and 1.461), falling within the optimal 1-3 range.

**4. H-Bond Donors:** Both have 2 and 4 HBDs, respectively, which are acceptable (<=5).

**5. H-Bond Acceptors:** Both ligands have 4 HBAs, which is also acceptable (<=10).

**6. QED:** Ligand A (0.635) has a better QED score than Ligand B (0.37), indicating a more drug-like profile.

**7. DILI:** Ligand A (12.369) has a much lower DILI risk than Ligand B (19.387), which is a significant advantage.

**8. BBB:** Ligand B (60.566) has a better BBB penetration percentile than Ligand A (46.84). While >70 is desirable, 60.566 is still reasonably good, but A is considerably lower.

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.783 and -4.938), which is unusual and suggests poor permeability. However, these values are on a scale where negative values are possible, and direct comparison is difficult without knowing the scale's specifics.

**10. Aqueous Solubility:** Both ligands have negative solubility values (-1.397 and -2.382), indicating poor aqueous solubility. Again, the scale is unclear, but B is worse than A.

**11. hERG Inhibition:** Ligand A (0.205) has a lower hERG inhibition liability than Ligand B (0.627), which is a positive.

**12. Microsomal Clearance:** Ligand A (14.475) has a lower microsomal clearance than Ligand B (31.455), suggesting better metabolic stability.

**13. In vitro Half-Life:** Ligand A (12.562) has a longer in vitro half-life than Ligand B (-31.848). The negative value for B is concerning and suggests very rapid degradation.

**14. P-gp Efflux:** Ligand A (0.017) has significantly lower P-gp efflux liability than Ligand B (0.109), which is crucial for CNS penetration.

**15. Binding Affinity:** Both ligands have very similar and excellent binding affinities (-7.7 and -7.8 kcal/mol). The difference is negligible.

**Overall Assessment:**

Considering the GPCR-specific priorities, Ligand A is the more promising candidate. While Ligand B has a slightly better BBB score, Ligand A excels in almost all other critical areas: TPSA, QED, DILI risk, hERG inhibition, metabolic stability (Cl_mic and t1/2), and P-gp efflux. The lower TPSA and P-gp efflux of Ligand A are particularly important for CNS penetration, outweighing the modest difference in BBB. The significantly better DILI and metabolic stability profiles of A also make it a safer and more viable option. The negative Caco-2 and solubility values are concerning for both, but the other advantages of A make it the better choice.

Output:
0
2025-04-17 06:40:25,797 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 drug candidates, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (385.873) is slightly higher than Ligand B (354.426), but both are acceptable.

**TPSA:** Both ligands have TPSA values below the 90 A^2 threshold desirable for CNS targets. Ligand A (81.62) is slightly higher than Ligand B (76.46), but both are good.

**logP:** Ligand A (2.577) is within the optimal range (1-3). Ligand B (0.785) is a bit low, potentially hindering permeation. This is a strike against Ligand B.

**H-Bond Donors/Acceptors:** Ligand A (0 HBD, 7 HBA) and Ligand B (1 HBD, 5 HBA) both fall within acceptable limits (<=5 HBD, <=10 HBA).

**QED:** Both ligands have good QED scores (Ligand A: 0.535, Ligand B: 0.785), indicating good drug-like properties.

**DILI:** Ligand A (83.133) has a higher DILI risk than Ligand B (37.069). This is a significant negative for Ligand A.

**BBB:** Both ligands have good BBB penetration (Ligand A: 76.386, Ligand B: 70.415), exceeding the 70% threshold.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values which is unusual. However, the magnitude of the negative value is similar, suggesting similar absorption potential.

**Aqueous Solubility:** Both ligands have negative solubility values, which is also unusual. Again, the magnitudes are similar.

**hERG:** Both ligands have low hERG inhibition liability (Ligand A: 0.288, Ligand B: 0.224).

**Microsomal Clearance:** Ligand A (57.17) has a higher microsomal clearance than Ligand B (29.87), indicating lower metabolic stability. This favors Ligand B.

**In vitro Half-Life:** Ligand B (-10.714) has a significantly longer in vitro half-life than Ligand A (1.713). This is a strong advantage for Ligand B.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (Ligand A: 0.226, Ligand B: 0.015), which is excellent for CNS penetration.

**Binding Affinity:** Both ligands have very similar and strong binding affinities (Ligand A: -7.7 kcal/mol, Ligand B: -7.6 kcal/mol). The difference is negligible.

**Overall Assessment:**

Ligand B is the better candidate. While both have good affinity and BBB penetration, Ligand B has a lower DILI risk, better metabolic stability (lower Cl_mic, longer t1/2), and a more favorable logP. Ligand A's higher DILI risk and lower metabolic stability are significant drawbacks. The slightly lower logP of Ligand B is a minor concern, but the other advantages outweigh this.

Output:
1
2025-04-17 06:40:25,797 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B based on the provided guidelines, prioritizing GPCR-specific properties (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (381.259 Da) is slightly higher than Ligand B (359.853 Da), but both are acceptable.

**TPSA:** Both ligands have TPSA values below 90, which is good for CNS targets. Ligand A (68.29) is slightly higher than Ligand B (58.56), but both are favorable.

**logP:** Both ligands have logP values around 4, which is at the upper limit of the optimal range (1-3). This could potentially lead to solubility issues or off-target effects, but is not a disqualifier on its own. Ligand A (4.583) is slightly higher than Ligand B (4.08).

**H-Bond Donors/Acceptors:** Ligand A (HBD=1, HBA=4) and Ligand B (HBD=2, HBA=3) both fall within acceptable ranges.

**QED:** Both ligands have good QED scores (A: 0.744, B: 0.783), indicating a generally drug-like profile.

**DILI:** Ligand A has a higher DILI risk (78.17%) than Ligand B (50.136%). This is a significant concern, as a lower DILI risk is preferred.

**BBB:** Ligand A has a much better BBB penetration score (69.058%) compared to Ligand B (43.273%). This is a critical factor for a CNS target like DRD2.

**Caco-2 Permeability:** Both ligands have negative Caco-2 permeability values, which is unusual and suggests poor intestinal absorption. However, for a CNS target, intestinal absorption is less critical than BBB penetration.

**Aqueous Solubility:** Both ligands have very poor aqueous solubility (-5.519 and -4.707 respectively). This is a potential issue for formulation and bioavailability, but can sometimes be overcome.

**hERG Inhibition:** Both ligands show low hERG inhibition risk (0.489 and 0.473 respectively).

**Microsomal Clearance:** Ligand A has a very high microsomal clearance (99.727), indicating rapid metabolism and potentially low bioavailability. Ligand B has a lower clearance (33.982), which is more favorable.

**In vitro Half-Life:** Ligand A has a shorter in vitro half-life (34.153 hours) compared to Ligand B (56.35 hours).

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.247 and 0.416 respectively).

**Binding Affinity:** Both ligands have excellent binding affinity (-8.0 and -8.5 kcal/mol respectively). Ligand B is slightly more potent.

**Overall Assessment:**

While Ligand B has slightly better potency and a lower DILI risk and clearance, Ligand A's significantly better BBB penetration is the deciding factor for a CNS-targeting drug. The high DILI risk and clearance of Ligand A are concerning, but could potentially be addressed through further optimization. The poor solubility of both is a concern, but less critical than CNS penetration for this target. Given the importance of BBB penetration for DRD2, Ligand A is the more promising candidate.

Output:
0
2025-04-17 06:40:25,797 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (359.392 and 353.467 Da) fall within the ideal range of 200-500 Da.

**TPSA:** Ligand A (61.44) is significantly better than Ligand B (107.4). For CNS targets, we want TPSA <= 90, and A is comfortably within that range, while B is above. This is a substantial advantage for A.

**logP:** Both ligands have acceptable logP values (1.231 and 2.634, respectively), falling within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A (HBD=2, HBA=3) and Ligand B (HBD=1, HBA=4) both have reasonable H-bond characteristics, well within the guidelines.

**QED:** Ligand A (0.702) has a much better QED score than Ligand B (0.391). A QED > 0.5 is desirable, and A easily meets this criterion, suggesting a more drug-like profile.

**DILI:** Ligand A (31.136) has a lower DILI risk than Ligand B (19.659). Both are good, but A is slightly preferable.

**BBB:** Both ligands have good BBB penetration (74.254 and 70.609, respectively), exceeding the 70% threshold for CNS targets. This is a positive for both.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.753 and -4.578). These values are difficult to interpret without knowing the scale, but the negative values suggest poor permeability.

**Aqueous Solubility:** Both ligands have negative solubility values (-2.455 and -1.846). Again, the scale is unknown, but negative values suggest poor solubility.

**hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.152 and 0.209, respectively). This is excellent.

**Microsomal Clearance:** Ligand A (5.765) has significantly lower microsomal clearance than Ligand B (42.355). Lower clearance indicates better metabolic stability, a major advantage for A.

**In vitro Half-Life:** Ligand A (-15.834) has a negative half-life, which is concerning. Ligand B (-0.081) is also negative, but closer to zero. This suggests both compounds are rapidly metabolized, but B is slightly better.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.005 and 0.007, respectively). This is good, as it should improve CNS exposure.

**Binding Affinity:** Both ligands have very similar and excellent binding affinities (-6.9 and -6.8 kcal/mol). The difference is minimal.

**Overall Assessment:**

Ligand A is clearly superior. It has a much better TPSA, QED, and microsomal clearance. While both have poor solubility and permeability, the other advantages of A, particularly the TPSA and QED, outweigh the slightly better half-life of B. The similar binding affinities mean that the ADME properties are the deciding factors. Given the importance of BBB penetration and favorable ADME properties for CNS GPCR targets, Ligand A is the more promising candidate.

Output:
1
2025-04-17 06:40:25,797 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (367.293 and 349.431 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (39.08) is excellent, well below the 90 A^2 threshold for CNS targets. Ligand B (103.94) is higher, but still potentially acceptable, though less ideal.

**logP:** Ligand A (4.475) is slightly high, potentially leading to solubility issues or off-target interactions. Ligand B (-0.283) is quite low, which could hinder membrane permeability and CNS penetration.

**H-Bond Donors/Acceptors:** Ligand A (1 HBD, 4 HBA) and Ligand B (2 HBD, 4 HBA) both have reasonable numbers of H-bond donors and acceptors, within the guidelines.

**QED:** Both ligands have similar QED values (0.766 and 0.712), indicating good drug-like properties.

**DILI:** Ligand A (45.095) has a moderate DILI risk, while Ligand B (10.857) has a very low DILI risk, a significant advantage.

**BBB:** Ligand A (76.464) has a good BBB percentile, desirable for a CNS target. Ligand B (45.366) is lower, which is a concern for CNS penetration.

**Caco-2 Permeability:** Ligand A (-4.734) has poor Caco-2 permeability, suggesting poor intestinal absorption. Ligand B (-5.261) is also poor, but slightly worse.

**Aqueous Solubility:** Ligand A (-4.943) has poor aqueous solubility. Ligand B (-2.104) is also poor, but slightly better.

**hERG Inhibition:** Ligand A (0.895) has a low hERG inhibition risk. Ligand B (0.061) has a very low hERG inhibition risk, another advantage.

**Microsomal Clearance:** Ligand A (46.292) has moderate microsomal clearance, suggesting moderate metabolic stability. Ligand B (-11.917) has negative clearance, which is not physically possible and likely indicates an error or unusual behavior in the prediction model. This is a major red flag.

**In vitro Half-Life:** Both ligands have similar in vitro half-lives (1.542 and 1.527 hours), which are relatively short.

**P-gp Efflux:** Ligand A (0.85) has moderate P-gp efflux liability. Ligand B (0.007) has very low P-gp efflux liability, which is highly desirable for CNS penetration.

**Binding Affinity:** Ligand A (-9.1 kcal/mol) has significantly stronger binding affinity than Ligand B (-6.8 kcal/mol). This is a substantial advantage, potentially outweighing some of the ADME drawbacks.

**Overall Assessment:**

Ligand A has a much better binding affinity and acceptable BBB penetration, but suffers from poor solubility, permeability, and moderate DILI risk. Ligand B has better ADME properties (lower DILI, hERG, P-gp efflux) but significantly weaker binding affinity.

Given the GPCR-specific priorities, affinity is paramount. The 2.3 kcal/mol difference in binding affinity is substantial. While Ligand A's ADME profile isn't ideal, it's potentially optimizable. The negative clearance for Ligand B is a showstopper.

Output:
1
2025-04-17 06:40:25,798 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (362.304 Da and 343.427 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (104.73) is slightly above the optimal <90 for CNS targets, while Ligand B (87.3) is comfortably below. This favors Ligand B.

**logP:** Both ligands have acceptable logP values (1.337 and 0.636), falling within the 1-3 range. Ligand A is slightly better.

**H-Bond Donors/Acceptors:** Both have 3 HBD and a reasonable number of HBA (4 for A, 3 for B), satisfying the <5 HBD and <10 HBA guidelines.

**QED:** Ligand A (0.606) has a better QED score than Ligand B (0.376), indicating a more drug-like profile.

**DILI:** Both ligands have the same DILI risk (61.303 percentile), which is moderately high, but not disqualifying.

**BBB:** Ligand B (30.128%) has a slightly better BBB penetration prediction than Ligand A (27.608%), but both are below the desirable >70% for CNS targets. This is a weakness for both.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.316 and -5.037), which is unusual and suggests poor permeability. This is a significant concern for both.

**Aqueous Solubility:** Both ligands have very poor aqueous solubility (-2.024 and -2.972). This is a major drawback for both.

**hERG Inhibition:** Both ligands show very low hERG inhibition liability (0.083 and 0.031), which is excellent.

**Microsomal Clearance:** Ligand B (22.291 mL/min/kg) has a lower microsomal clearance than Ligand A (14.439 mL/min/kg), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand B (-17.036 hours) has a longer in vitro half-life than Ligand A (-34.161 hours). Note that negative values here likely indicate a faster degradation rate, so a less negative number is preferable. Thus, Ligand B is better here.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.011 and 0.03), which is favorable for CNS penetration.

**Binding Affinity:** Both ligands have very similar and strong binding affinities (-8.3 and -8.2 kcal/mol). The difference is negligible.

**Overall Assessment:**

Considering the GPCR-specific priorities, Ligand B emerges as the slightly more promising candidate. While both have poor solubility and permeability, Ligand B has a lower TPSA, better metabolic stability (lower Cl_mic, longer t1/2), and a slightly better BBB prediction. The binding affinity is comparable. Ligand A has a better QED score, but the other ADME properties of Ligand B are more favorable for CNS penetration and duration of action.

Output:
1
2025-04-17 06:40:25,798 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (333.351 Da) is slightly lower, which could be beneficial for permeability, but both are acceptable.

**TPSA:** Ligand A (78.86) is better than Ligand B (58.2). For CNS targets, we want TPSA <= 90, both are within this range, but A is closer to the ideal.

**logP:** Both ligands have good logP values (A: 3.111, B: 3.993), falling within the optimal 1-3 range. Ligand B is slightly higher, which *could* indicate potential off-target effects, but it's not a major concern.

**H-Bond Donors/Acceptors:** Ligand A (0 HBD, 7 HBA) is better than Ligand B (2 HBD, 3 HBA). Lower HBD/HBA generally improves permeability.

**QED:** Both ligands have good QED values (A: 0.558, B: 0.611), indicating good drug-like properties.

**DILI:** Ligand A (83.676) has a significantly higher DILI risk than Ligand B (7.251). This is a major red flag for Ligand A.

**BBB:** Ligand B (79.837) has a much better BBB penetration percentile than Ligand A (32.881). This is critical for a CNS target like DRD2.

**Caco-2 Permeability:** Ligand A (-5.059) has poor Caco-2 permeability, while Ligand B (-4.898) is slightly better, but still poor.

**Aqueous Solubility:** Both ligands have poor aqueous solubility (A: -3.676, B: -4.217). This could pose formulation challenges.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (A: 0.819, B: 0.622).

**Microsomal Clearance:** Ligand B (84.907) has a higher microsomal clearance than Ligand A (22.382), suggesting lower metabolic stability.

**In vitro Half-Life:** Ligand A (-41.397) has a very short in vitro half-life compared to Ligand B (17.67).

**P-gp Efflux:** Ligand A (0.508) has lower P-gp efflux than Ligand B (0.019), which is favorable for CNS penetration.

**Binding Affinity:** Ligand B (-7.2 kcal/mol) has a significantly stronger binding affinity than Ligand A (-9.5 kcal/mol). This is a substantial advantage.

**Overall Assessment:**

Ligand B is the clear winner. While it has some drawbacks (higher logP, higher Cl_mic, poor solubility), its superior BBB penetration, significantly stronger binding affinity, and drastically lower DILI risk outweigh these concerns. Ligand A's high DILI risk and poor BBB penetration make it a less viable candidate despite its slightly lower MW and better P-gp efflux. The affinity difference is also substantial.

Output:
1
2025-04-17 06:40:25,798 - INFO - Batch 301 complete. Total preferences: 4816
2025-04-17 06:40:25,798 - INFO - Processing batch 302/512...
2025-04-17 06:41:06,127 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (361.433 and 352.387 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (70.67) is significantly better than Ligand B (106.87). For CNS targets, we want TPSA <= 90, and A is comfortably within that range, while B is pushing the limit.

**logP:** Both ligands have acceptable logP values (0.806 and 0.973), falling within the 1-3 range.

**H-Bond Donors/Acceptors:** Both have 2 HBDs, which is good. Ligand A has 4 HBAs, while Ligand B has 6. Both are acceptable (<=10), but A is slightly preferred.

**QED:** Both ligands have similar QED values (0.671 and 0.675), indicating good drug-likeness.

**DILI:** Ligand A (11.632) has a much lower DILI risk than Ligand B (58.976). This is a significant advantage for A.

**BBB:** Ligand A (81.466) has a substantially higher BBB penetration percentile than Ligand B (69.446).  This is *critical* for a CNS target like DRD2, and gives A a major advantage. >70 is desirable, and A is closer to that threshold.

**Caco-2 Permeability:** Ligand A (-5.022) has a worse Caco-2 permeability than Ligand B (-4.574), but both are negative and therefore indicate poor permeability. This is a drawback for both.

**Aqueous Solubility:** Ligand A (-1.466) has slightly better aqueous solubility than Ligand B (-2.865), but both are poor.

**hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.271 and 0.24), which is excellent.

**Microsomal Clearance:** Ligand A (1.883) has a much lower microsomal clearance than Ligand B (68.834), indicating better metabolic stability. This is a significant advantage for A.

**In vitro Half-Life:** Ligand A (-2.562) has a longer in vitro half-life than Ligand B (1.935), which is desirable.

**P-gp Efflux:** Ligand A (0.008) has significantly lower P-gp efflux liability than Ligand B (0.068), which is crucial for CNS penetration.

**Binding Affinity:** Ligand A (-7.5) has slightly better binding affinity than Ligand B (-7.3), although the difference is relatively small (0.2 kcal/mol).

**Overall Assessment:**

Ligand A is clearly superior. It excels in the most important parameters for a CNS-targeting GPCR ligand: BBB penetration, low DILI risk, low P-gp efflux, and metabolic stability (low Cl_mic and longer t1/2). While both have acceptable logP and MW, A's TPSA is also more favorable. The slightly better affinity of A further solidifies its advantage. The poorer Caco-2 and solubility of A are less concerning given the CNS target.



Output:
1
2025-04-17 06:41:06,127 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (345.443 and 346.427 Da) fall comfortably within the ideal 200-500 Da range.

**2. TPSA:** Both ligands have TPSA values (80.2 and 82.78) below the 90 A^2 threshold for CNS targets, which is good.

**3. logP:** Both ligands have logP values (1.755 and 1.585) within the optimal 1-3 range.

**4. H-Bond Donors:** Both have 2 HBD, which is acceptable.

**5. H-Bond Acceptors:** Both have 4 HBA, also acceptable.

**6. QED:** Both ligands have QED values (0.705 and 0.7) above 0.5, indicating good drug-likeness.

**7. DILI:** Ligand A (35.091) has a slightly higher DILI risk than Ligand B (19.504), but both are below the concerning threshold of 40, suggesting low liver injury risk.

**8. BBB:** This is a critical parameter for a CNS target like DRD2. Ligand A has a BBB percentile of 55.176, while Ligand B has 46.762. While neither are *excellent* (>70), Ligand A is better.

**9. Caco-2 Permeability:** Both have negative Caco-2 values (-4.92 and -4.484) which is unusual and suggests poor permeability. This is a concern for both.

**10. Aqueous Solubility:** Both have negative solubility values (-2.199 and -2.463), which is also concerning and suggests poor solubility.

**11. hERG Inhibition:** Both ligands have low hERG inhibition liability (0.161 and 0.237), which is good.

**12. Microsomal Clearance:** Ligand A (4.285) has significantly lower microsomal clearance than Ligand B (37.918), suggesting better metabolic stability.

**13. In vitro Half-Life:** Ligand A (-9.257) has a more negative (longer) in vitro half-life than Ligand B (-4.95), indicating better stability.

**14. P-gp Efflux:** Both have low P-gp efflux liability (0.088 and 0.096), which is favorable for CNS penetration.

**15. Binding Affinity:** Ligand A (-8.2 kcal/mol) has a slightly better binding affinity than Ligand B (-7.3 kcal/mol). This 0.9 kcal/mol difference is significant and could outweigh some of the ADME drawbacks.

**Overall Assessment:**

Ligand A is the more promising candidate. While both have issues with Caco-2 permeability and aqueous solubility, Ligand A demonstrates superior BBB penetration, significantly better metabolic stability (lower Cl_mic and longer t1/2), and slightly stronger binding affinity. The lower DILI risk is a minor advantage. Given the GPCR target and the need for CNS penetration, the improved BBB and metabolic stability of Ligand A are crucial advantages.

Output:
1
2025-04-17 06:41:06,128 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the acceptable range (200-500 Da). Ligand A (429.292 Da) is higher, but not excessively so. Ligand B (351.447 Da) is slightly preferred.

**TPSA:** Both ligands have TPSA values below 140, which is good for oral absorption. However, for a CNS target like DRD2, we ideally want <90. Ligand B (83.8) is significantly better than Ligand A (98.54) in this regard.

**logP:** Ligand A (3.277) is within the optimal range (1-3). Ligand B (0.629) is quite low, potentially hindering membrane permeability. This is a significant drawback for CNS penetration.

**H-Bond Donors/Acceptors:** Ligand A has 1 HBD and 5 HBA, while Ligand B has 2 HBD and 5 HBA. Both are acceptable within the guidelines.

**QED:** Ligand B (0.719) has a better QED score than Ligand A (0.395), indicating a more drug-like profile.

**DILI:** Ligand B (20.24) has a much lower DILI risk than Ligand A (85.653). This is a major advantage for Ligand B.

**BBB:** Ligand A (53.897) has a better BBB percentile than Ligand B (48.119), but both are below the desirable >70 for CNS targets.

**Caco-2 Permeability:** Ligand A (-5.085) shows poor Caco-2 permeability, while Ligand B (-4.614) is also poor, but slightly better.

**Aqueous Solubility:** Both ligands have poor aqueous solubility (-4.885 and -1.436 respectively).

**hERG Inhibition:** Ligand B (0.091) has a much lower hERG inhibition risk than Ligand A (0.819). This is a significant safety advantage.

**Microsomal Clearance:** Ligand A (79.89) has higher microsomal clearance than Ligand B (13.12), meaning it's metabolized faster. Ligand B is preferred for metabolic stability.

**In vitro Half-Life:** Ligand B (8.766 hours) has a longer half-life than Ligand A (-22.005 hours - negative value is concerning).

**P-gp Efflux:** Ligand A (0.737) has lower P-gp efflux than Ligand B (0.061), which is favorable for CNS exposure.

**Binding Affinity:** Ligand B (-7.4 kcal/mol) has a slightly better binding affinity than Ligand A (-8.5 kcal/mol). While A is better, the difference is not substantial enough to overcome the other issues.

**Overall Assessment:**

Ligand B is the stronger candidate. While its logP is low, its superior DILI profile, lower hERG risk, better metabolic stability (lower Cl_mic, longer t1/2), better QED, and slightly better binding affinity outweigh the lower BBB and logP values. The lower TPSA of Ligand B is also a significant advantage for CNS penetration. Ligand A's high DILI risk and poor metabolic stability are major concerns.

Output:
1
2025-04-17 06:41:06,128 - INFO - Reasoning:

Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight (MW):** Both ligands (343.43 & 350.46 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (65.79) is significantly better than Ligand B (87.46). For CNS targets, we want TPSA <= 90, and A is comfortably within this, while B is approaching the upper limit.

**3. logP:** Both ligands have acceptable logP values (1.768 and 0.867), falling within the optimal 1-3 range.

**4. H-Bond Donors (HBD):** Both are low (1 and 2 respectively), which is good.

**5. H-Bond Acceptors (HBA):** Both are reasonable (4 and 5 respectively), below the 10 threshold.

**6. QED:** Ligand A (0.868) has a better QED score than Ligand B (0.692), indicating a more drug-like profile.

**7. DILI:** Ligand A (32.03) has a slightly higher DILI risk than Ligand B (21.71), but both are well below the concerning threshold of 60.

**8. BBB:** This is a critical parameter for CNS targets. Ligand A (62.93) is better than Ligand B (50.10), though ideally, we'd want >70. However, the difference is significant.

**9. Caco-2:** Both are very poor (-5.014 and -5.015). This is a concern for oral bioavailability, but less critical for a CNS target where direct delivery or other routes might be considered.

**10. Solubility:** Both are very poor (-1.17 and -0.685). This is a significant drawback, but can sometimes be overcome with formulation strategies.

**11. hERG:** Both ligands show very low hERG inhibition risk (0.423 and 0.089).

**12. Cl_mic:** Ligand A (2.763) has a much lower microsomal clearance than Ligand B (5.802), suggesting better metabolic stability.

**13. t1/2:** Ligand A (58.93) has a much longer in vitro half-life than Ligand B (5.404). This is a major advantage.

**14. Pgp:** Both have very low P-gp efflux liability (0.041 and 0.033).

**15. Binding Affinity:** Ligand A (-8.7 kcal/mol) has a slightly better binding affinity than Ligand B (-8.1 kcal/mol). While both are excellent, the 0.6 kcal/mol difference is noticeable.

**Overall Assessment:**

Ligand A consistently outperforms Ligand B across most critical parameters for a CNS-targeting GPCR ligand. It has a better TPSA, QED, BBB penetration, metabolic stability (lower Cl_mic, longer t1/2), and slightly stronger binding affinity. While both have poor solubility and Caco-2 permeability, the superior CNS penetration and metabolic properties of Ligand A make it the more promising candidate.

Output:
1
2025-04-17 06:41:06,128 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (340.47 and 357.38 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (52.57) is significantly better than Ligand B (84.31). For CNS targets, we want TPSA <= 90, and A is comfortably within that, while B is approaching the upper limit.

**logP:** Both ligands have good logP values (2.705 and 2.153), falling within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Both have 2 HBDs, which is good. Ligand A has 3 HBAs, while Ligand B has 6. Lower HBA is generally preferred for better permeability.

**QED:** Both ligands have similar, good QED values (0.783 and 0.793), indicating drug-like properties.

**DILI:** Ligand A (12.72) has a much lower DILI risk than Ligand B (51.84). This is a significant advantage for A.

**BBB:** Ligand A (81.70) has a substantially better BBB penetration percentile than Ligand B (72.74). For a CNS target like DRD2, this is a critical factor.

**Caco-2 Permeability:** Ligand A (-4.677) has a slightly better (less negative) Caco-2 value than Ligand B (-5.226), suggesting better intestinal absorption.

**Aqueous Solubility:** Both have similar poor aqueous solubility (-2.924 and -3.033). This could pose formulation challenges, but isn't a dealbreaker.

**hERG Inhibition:** Ligand A (0.754) has a slightly higher hERG risk than Ligand B (0.185). This is a negative for A, but the difference isn't huge.

**Microsomal Clearance:** Ligand B (-10.638) has a significantly lower (better) microsomal clearance than Ligand A (24.134), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand B (-16.209) has a much longer in vitro half-life than Ligand A (9.818), which is desirable.

**P-gp Efflux:** Ligand A (0.217) has a much lower P-gp efflux liability than Ligand B (0.106), which is beneficial for CNS penetration.

**Binding Affinity:** Both ligands have very similar and strong binding affinities (-8.5 and -8.2 kcal/mol). The difference is less than the 1.5 kcal/mol threshold.

**Overall Assessment:**

Ligand A is superior due to its significantly better BBB penetration, lower DILI risk, and lower P-gp efflux. While Ligand B has better metabolic stability and half-life, the CNS target prioritization makes BBB and reduced efflux more crucial. The slight hERG risk with A is manageable given the strong binding affinity.

Output:
1
2025-04-17 06:41:06,128 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (338.367 and 341.459 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (100.1) is slightly above the optimal <90 for CNS targets, but still reasonable. Ligand B (61.36) is well within the desired range. This favors Ligand B.

**logP:** Both ligands have logP values (1.877 and 2.198) within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Both ligands have 1 HBD and a reasonable number of HBAs (6 and 5 respectively), satisfying the criteria.

**QED:** Both ligands have good QED scores (0.692 and 0.89), indicating good drug-like properties.

**DILI:** Ligand A (85.072) has a higher DILI risk than Ligand B (44.979). This is a significant negative for Ligand A.

**BBB:** Both ligands have good BBB penetration (74.796 and 81.349), exceeding the 70% threshold for CNS targets. Ligand B is slightly better.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.953), which is unusual and suggests poor permeability. This is a concern for both.

**Aqueous Solubility:** Both ligands have negative solubility values (-3.8 and -3.001), indicating very poor aqueous solubility, which is a major drawback.

**hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.169 and 0.741).

**Microsomal Clearance:** Ligand A (58.533) has lower microsomal clearance than Ligand B (79.029), suggesting better metabolic stability. This favors Ligand A.

**In vitro Half-Life:** Ligand B (-9.932) has a longer in vitro half-life than Ligand A (-5.855). This favors Ligand B.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.397 and 0.1).

**Binding Affinity:** Both ligands have excellent binding affinities (-9.4 and -9.1 kcal/mol). The difference of 0.3 kcal/mol is not substantial enough to outweigh other factors.

**Overall Assessment:**

Ligand B is preferable. While both ligands have issues with Caco-2 permeability and aqueous solubility, Ligand B has a significantly lower DILI risk, better TPSA, and a longer half-life. The slightly better BBB penetration also contributes to its favorability. Although Ligand A has better metabolic stability, the higher DILI risk is a major concern. For a CNS target like DRD2, minimizing potential toxicity is crucial.

Output:
1
2025-04-17 06:41:06,128 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 drug candidates, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight (MW):** Both ligands (348.374 and 345.403 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (79.62) is significantly better than Ligand B (98.61). For CNS targets, we want TPSA <= 90, so Ligand A is preferable.

**3. logP:** Both ligands have good logP values (2.007 and 1.66), falling within the optimal 1-3 range.

**4. H-Bond Donors (HBD):** Both ligands are acceptable (1 and 0 respectively), well below the threshold of 5.

**5. H-Bond Acceptors (HBA):** Both ligands are acceptable (4 each), below the threshold of 10.

**6. QED:** Ligand A (0.826) has a much better QED score than Ligand B (0.304). A score >= 0.5 is desirable, and Ligand A is excellent.

**7. DILI:** Both ligands have low DILI risk (44.63 and 41.877), both below the 60 threshold.

**8. BBB:** Ligand A (85.421) has a significantly higher BBB percentile than Ligand B (56.65). For a CNS target like DRD2, >70 is desirable, and Ligand A is much closer to this target.

**9. Caco-2 Permeability:** Ligand A (-4.604) and Ligand B (-4.519) are similar and both indicate poor permeability.

**10. Aqueous Solubility:** Ligand A (-3.136) is slightly better than Ligand B (-1.311), but both are poor.

**11. hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.145 and 0.129).

**12. Microsomal Clearance (Cl_mic):** Ligand A (27.584) has a higher Cl_mic than Ligand B (11.307), indicating faster metabolism and lower metabolic stability. This is a negative for Ligand A.

**13. In vitro Half-Life (t1/2):** Ligand B (15.104) has a significantly longer half-life than Ligand A (-7.748). This is a strong positive for Ligand B.

**14. P-gp Efflux:** Both ligands have low P-gp efflux liability (0.072 and 0.011).

**15. Binding Affinity:** Ligand A (-9.1) has a significantly stronger binding affinity than Ligand B (-7.3). A >1.5 kcal/mol advantage is considered substantial, and this difference is more than enough to outweigh some of the ADME drawbacks.

**Overall Assessment:**

Ligand A excels in key GPCR properties: TPSA, BBB, QED, and, most importantly, binding affinity. While its metabolic stability (Cl_mic) and solubility are concerns, the strong binding affinity and good BBB penetration are crucial for a CNS target. Ligand B has a better half-life, but its lower affinity and poorer BBB penetration make it less promising. The substantial affinity advantage of Ligand A is a major factor.

Output:
1
2025-04-17 06:41:06,129 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (370.559 and 345.399 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (78.43) is significantly better than Ligand B (111.55). For CNS targets, we want TPSA <= 90, and A is comfortably within this range, while B is pushing the limit.

**logP:** Both ligands have acceptable logP values (2.04 and 0.881), falling within the 1-3 range.

**H-Bond Donors/Acceptors:** Both have reasonable HBD (3 and 4) and HBA (4 and 5) counts, well within the guidelines.

**QED:** Both ligands have similar QED scores (0.611 and 0.605), indicating good drug-likeness.

**DILI:** Ligand A (21.287) has a much lower DILI risk than Ligand B (50.989). This is a significant advantage.

**BBB:** Ligand A (42.497) has a better BBB percentile than Ligand B (25.32). While both are below the desirable >70 for CNS targets, A is closer.

**Caco-2 Permeability:** Both have negative Caco-2 values (-5.378 and -5.315), which is unusual and suggests poor permeability. However, the values are very similar.

**Aqueous Solubility:** Both have negative solubility values (-2.97 and -2.64), indicating poor aqueous solubility. Again, they are comparable.

**hERG Inhibition:** Both ligands exhibit low hERG inhibition risk (0.148 and 0.042).

**Microsomal Clearance:** Ligand A (49.934) has a better (lower) microsomal clearance than Ligand B (-8.961). This suggests better metabolic stability for Ligand A.

**In vitro Half-Life:** Ligand A (-13.206) has a longer in vitro half-life than Ligand B (-29.604).

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.036 and 0.02).

**Binding Affinity:** Both ligands have excellent binding affinities (-8.6 and -9.4 kcal/mol). Ligand B is slightly better (-9.4 vs -8.6), but the difference is not substantial enough to outweigh other factors.

**Overall Assessment:**

Ligand A is the more promising candidate. While both have good binding affinity, Ligand A excels in critical ADME properties for CNS drug development: lower DILI risk, better BBB penetration, lower microsomal clearance, and longer half-life. Its TPSA is also significantly better than Ligand B's. The slight advantage in binding affinity of Ligand B is not enough to overcome these significant ADME benefits of Ligand A.

Output:
1
2025-04-17 06:41:06,129 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (378.904 and 368.459 Da) fall within the ideal range of 200-500 Da.

**TPSA:** Ligand A (53.6) is excellent, well below the 90 target for CNS drugs. Ligand B (113.44) is higher, but still potentially acceptable, though less ideal.

**logP:** Ligand A (4.967) is slightly high, potentially leading to solubility issues or off-target interactions. Ligand B (0.022) is very low, which will likely hinder permeability and potentially binding.

**H-Bond Donors/Acceptors:** Ligand A (2 HBD, 4 HBA) is within acceptable limits. Ligand B (3 HBD, 7 HBA) is also within limits, but higher HBA could impact permeability.

**QED:** Both ligands have similar QED scores (0.659 and 0.652), indicating good drug-like properties.

**DILI:** Ligand A (70.221) has a higher DILI risk than Ligand B (55.176), but both are reasonably acceptable.

**BBB:** Ligand A (43.001) has a moderate BBB penetration, which is a concern for a CNS target. Ligand B (35.673) is even lower, making CNS penetration unlikely.

**Caco-2:** Ligand A (-4.914) is a negative value, which is unusual and suggests poor permeability. Ligand B (-5.719) is similarly poor.

**Solubility:** Ligand A (-5.183) has very poor aqueous solubility, consistent with its high logP. Ligand B (-1.513) is also poor, but slightly better than A.

**hERG:** Ligand A (0.658) has a moderate hERG risk, while Ligand B (0.034) has a very low risk.

**Microsomal Clearance:** Ligand A (36.812) has moderate clearance. Ligand B (-6.466) has negative clearance, which is not physically possible and likely indicates an issue with the prediction or data.

**In vitro Half-Life:** Ligand A (39.47) has a reasonable half-life. Ligand B (15.578) has a shorter half-life, which could require more frequent dosing.

**P-gp Efflux:** Ligand A (0.483) has moderate P-gp efflux, while Ligand B (0.036) has very low efflux.

**Binding Affinity:** Both ligands have excellent binding affinities (-9.2 and -8.3 kcal/mol). Ligand A is slightly better (-9.2 kcal/mol).

**Overall Assessment:**

Ligand A has a better binding affinity and more favorable TPSA, but suffers from high logP, poor solubility, moderate BBB penetration, and moderate P-gp efflux. Ligand B has a lower logP and very low P-gp efflux and hERG risk, but its BBB penetration is very poor, and it has a shorter half-life. The extremely negative clearance for Ligand B is a red flag.

Given the GPCR-specific priorities, BBB penetration is crucial for a CNS target like DRD2. While both ligands have poor BBB scores, Ligand A's slightly better profile in other key areas (affinity, TPSA) and the questionable clearance value for Ligand B make it the marginally better candidate, *assuming* the solubility and permeability issues can be addressed through formulation or further structural modification.

Output:
0
2025-04-17 06:41:06,129 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (349.431 and 345.403 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (107.53) is higher than Ligand B (80.56). For CNS targets, TPSA should be <= 90, so Ligand B is better here.

**logP:** Ligand A (0.161) is quite low, potentially hindering membrane permeability. Ligand B (-0.165) is also low, but slightly less so. Both are below the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A has 4 HBD and 4 HBA, which is acceptable. Ligand B has 0 HBD and 6 HBA, also acceptable.

**QED:** Ligand B (0.708) has a significantly better QED score than Ligand A (0.37), indicating better overall drug-likeness.

**DILI:** Ligand A (25.165) has a much lower DILI risk than Ligand B (44.707), which is a significant advantage.

**BBB:** Ligand B (71.617) has a much better BBB penetration percentile than Ligand A (37.379). This is *critical* for a CNS target like DRD2.

**Caco-2 Permeability:** Ligand A (-5.336) has very poor Caco-2 permeability, suggesting poor absorption. Ligand B (-4.549) is also poor, but slightly better.

**Aqueous Solubility:** Both ligands have poor aqueous solubility (-1.767 and -1.82 respectively).

**hERG Inhibition:** Ligand A (0.062) has a very low hERG risk, a major advantage. Ligand B (0.136) is slightly higher, but still relatively low.

**Microsomal Clearance:** Ligand B (-3.545) has a *much* lower (better) microsomal clearance than Ligand A (14.702), indicating greater metabolic stability.

**In vitro Half-Life:** Ligand B (0.221) has a slightly better in vitro half-life than Ligand A (-10.267).

**P-gp Efflux:** Ligand A (0.017) has very low P-gp efflux, which is good for CNS penetration. Ligand B (0.101) is slightly higher.

**Binding Affinity:** Ligand A (-8.7 kcal/mol) has a significantly stronger binding affinity than Ligand B (-7.7 kcal/mol). This is a substantial advantage, potentially outweighing some ADME drawbacks.

**Overall Assessment:**

Ligand A has a superior binding affinity and lower DILI risk and P-gp efflux. However, its low logP, poor Caco-2 permeability, and significantly lower BBB penetration are major concerns for a CNS target.

Ligand B has a better TPSA, QED, BBB penetration, and metabolic stability. While its logP is also low, its overall profile is more favorable for CNS drug development, especially considering the importance of BBB penetration for DRD2. The higher binding affinity of Ligand A is attractive, but the poor ADME properties, particularly BBB, are likely to limit its *in vivo* efficacy.

Output:
1
2025-04-17 06:41:06,129 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (351.466 and 368.88 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (61.44) is better than Ligand B (49.41), both are below the 90 A^2 threshold for CNS targets.

**logP:** Ligand A (1.623) is within the optimal 1-3 range, while Ligand B (3.319) is at the higher end but still acceptable.

**H-Bond Donors/Acceptors:** Ligand A has 2 HBD and 3 HBA, while Ligand B has 1 HBD and 2 HBA. Both are within acceptable limits.

**QED:** Both ligands have reasonable QED scores (0.621 and 0.553), indicating good drug-likeness.

**DILI:** Ligand A (10.392) has a significantly lower DILI risk than Ligand B (28.112). This is a major advantage for Ligand A.

**BBB:** Ligand B (90.112) has a higher BBB penetration percentile than Ligand A (70.105), which is a critical factor for CNS targets like DRD2.

**Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and suggests poor permeability. However, the scale is not specified, so it's hard to interpret.

**Aqueous Solubility:** Both have negative solubility values, indicating poor solubility.

**hERG:** Both ligands have very low hERG inhibition liability (0.523 and 0.378), which is excellent.

**Microsomal Clearance:** Ligand A (-11.043) has a much lower (better) microsomal clearance than Ligand B (38.194), indicating greater metabolic stability.

**In vitro Half-Life:** Ligand A (9.509) has a longer half-life than Ligand B (-6.522).

**P-gp Efflux:** Ligand A (0.028) has much lower P-gp efflux liability than Ligand B (0.171), which is crucial for CNS penetration.

**Binding Affinity:** Both ligands have excellent binding affinities (-7.9 and -8.1 kcal/mol), with Ligand B being slightly better. However, the difference is small.

**Overall Assessment:**

While Ligand B has a slightly better binding affinity and significantly better BBB penetration, Ligand A demonstrates a superior ADME profile. Specifically, its lower DILI risk, lower microsomal clearance, longer half-life, and significantly lower P-gp efflux are all highly desirable. The slightly lower BBB score for Ligand A can potentially be mitigated through formulation strategies. Given the importance of metabolic stability and reduced toxicity for CNS drugs, and the relatively small difference in binding affinity, Ligand A is the more promising candidate.

Output:
0
2025-04-17 06:41:06,129 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (425.352 Da) is slightly higher than Ligand B (356.388 Da), but both are acceptable.

**TPSA:** Ligand A (88.32) is closer to the ideal range for CNS targets (<=90) than Ligand B (49.41). This is a significant advantage for brain penetration.

**logP:** Both ligands have good logP values (A: 2.881, B: 3.123), falling within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A (HBD=2, HBA=5) and Ligand B (HBD=1, HBA=2) both have reasonable numbers of H-bond donors and acceptors, well within the guidelines.

**QED:** Both ligands have the same QED score (0.787), indicating good drug-likeness.

**DILI:** Ligand A (76.968) has a higher DILI risk than Ligand B (27.336). This is a negative for Ligand A.

**BBB:** Ligand B (85.072) has a significantly better BBB percentile than Ligand A (52.889). This is a crucial advantage for a CNS target like DRD2.

**Caco-2 Permeability:** Ligand A (-5.419) has a worse Caco-2 permeability than Ligand B (-4.498), suggesting lower intestinal absorption.

**Aqueous Solubility:** Ligand A (-2.956) has a slightly better aqueous solubility than Ligand B (-3.604).

**hERG:** Both ligands have low hERG inhibition liability (A: 0.611, B: 0.115), which is positive. Ligand B is even better.

**Microsomal Clearance:** Ligand A (27.121) has a lower microsomal clearance than Ligand B (32.987), indicating better metabolic stability.

**In vitro Half-Life:** Ligand A (24.642) has a better in vitro half-life than Ligand B (-20.302).

**P-gp Efflux:** Ligand A (0.207) has lower P-gp efflux liability than Ligand B (0.053), which is beneficial for CNS exposure.

**Binding Affinity:** Ligand B (-8.3 kcal/mol) has a slightly better binding affinity than Ligand A (-7.7 kcal/mol). While the difference is not huge, it's still a factor.

**Overall Assessment:**

Ligand B is the stronger candidate. While Ligand A has slightly better solubility and metabolic stability, Ligand B excels in the most critical areas for a CNS-targeting GPCR ligand: BBB penetration (85.072 vs 52.889), lower DILI risk (27.336 vs 76.968), and slightly better binding affinity (-8.3 vs -7.7). The TPSA value of Ligand B is also more favorable for CNS penetration. The small difference in affinity is likely outweighed by the significant advantage in BBB and safety profiles.

Output:
1
2025-04-17 06:41:06,130 - INFO - Reasoning:

Let's analyze Ligand A and Ligand B based on the provided guidelines, prioritizing GPCR-specific properties (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (335.451 and 348.447 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (44.37) is significantly better than Ligand B (76.46). For CNS targets, TPSA should be <= 90, and ideally lower. Ligand A is much closer to the ideal range for CNS penetration.

**logP:** Ligand A (4.411) is higher than the optimal 1-3 range, but not drastically so. Ligand B (1.462) is on the lower side, potentially hindering permeation.

**H-Bond Donors/Acceptors:** Ligand A (HBD=2, HBA=3) and Ligand B (HBD=1, HBA=5) both have acceptable numbers of H-bond donors and acceptors.

**QED:** Both ligands have similar QED values (0.769 and 0.722), indicating good drug-likeness.

**DILI:** Ligand A (47.538) has a slightly higher DILI risk than Ligand B (40.171), but both are below the concerning threshold of 60.

**BBB:** This is a critical parameter for a CNS target like DRD2. Ligand A (89.88) has a significantly higher BBB percentile than Ligand B (65.335). This is a major advantage for Ligand A.

**Caco-2 Permeability:** Both have negative values, which is unusual. Assuming these are logP-scale values, they indicate poor permeability. However, the absolute value is smaller for Ligand A (-4.908 vs -4.642), suggesting slightly better permeability.

**Aqueous Solubility:** Both ligands have poor aqueous solubility (-3.834 and -1.165).

**hERG:** Ligand A (0.945) has a slightly higher hERG risk than Ligand B (0.38), but both are relatively low.

**Microsomal Clearance:** Ligand A (-3.282) has a much lower (better) microsomal clearance than Ligand B (34.944), indicating greater metabolic stability.

**In vitro Half-Life:** Ligand A (14.661 hours) has a significantly longer half-life than Ligand B (-15.415 hours).

**P-gp Efflux:** Ligand A (0.471) has lower P-gp efflux than Ligand B (0.091), which is favorable for CNS penetration.

**Binding Affinity:** Ligand A (-8.6 kcal/mol) has a slightly better binding affinity than Ligand B (-7.8 kcal/mol). While both are good, the 0.8 kcal/mol difference is significant enough to consider.

**Overall Assessment:**

Ligand A is the superior candidate. It excels in crucial areas for CNS GPCR targets: TPSA, BBB, metabolic stability (Cl_mic & t1/2), P-gp efflux, and binding affinity. While Ligand A has a slightly higher logP and DILI risk, these are outweighed by its advantages in CNS penetration and pharmacokinetics. Ligand B's lower logP and poor BBB penetration are significant drawbacks.

Output:
1
2025-04-17 06:41:06,130 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (374.463 and 364.519 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (137.9) is close to the upper limit for good oral absorption and acceptable for CNS targets, while Ligand B (72.87) is well below the 90 threshold for CNS targets, suggesting better potential for brain penetration.

**logP:** Ligand A (-0.212) is a bit low, potentially hindering membrane permeability. Ligand B (2.753) is within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A has 4 HBD and 5 HBA, which are acceptable. Ligand B has 0 HBD and 8 HBA, also acceptable.

**QED:** Both ligands have good QED scores (0.523 and 0.826), indicating drug-like properties.

**DILI:** Ligand A (26.793) has a significantly lower DILI risk than Ligand B (55.68).

**BBB:** Ligand B (66.499) has a substantially better BBB percentile than Ligand A (37.301). This is a critical advantage for a CNS target like DRD2.

**Caco-2 Permeability:** Both have negative Caco-2 values (-5.624 and -5.456), which is unusual and suggests poor permeability. However, these values are on a log scale and should be interpreted cautiously.

**Aqueous Solubility:** Both ligands have very poor aqueous solubility (-1.313 and -4.044). This is a significant drawback.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.289 and 0.277).

**Microsomal Clearance:** Ligand A (-27.698) has a much lower (better) microsomal clearance than Ligand B (75.719), indicating greater metabolic stability.

**In vitro Half-Life:** Ligand A (26.899) has a longer half-life than Ligand B (0.951).

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.008 and 0.348).

**Binding Affinity:** Ligand A (-8.3) has a significantly stronger binding affinity than Ligand B (0.0). This is a substantial advantage.

**Overall Assessment:**

Ligand A has a much stronger binding affinity and better metabolic stability (lower Cl_mic, longer t1/2) and lower DILI risk. However, its logP is low, and BBB penetration is poor. Ligand B has a better logP and significantly better BBB penetration, but its binding affinity is very weak, and it has a higher DILI risk and poorer metabolic stability.

Given the GPCR-specific priorities, BBB is crucial for CNS targets. While Ligand B's affinity is weak, the substantial difference in BBB penetration (66.5% vs 37.3%) is a major factor. The strong binding affinity of Ligand A is attractive, but without reasonable BBB penetration, it's less likely to be effective *in vivo* for a CNS target. The poor solubility of both is a concern that would need to be addressed through formulation strategies. However, the combination of better logP, BBB, and acceptable (though not ideal) ADME properties makes Ligand B slightly more promising, *assuming* the binding affinity can be improved through further optimization.

Output:
1
2025-04-17 06:41:06,130 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (364.431 and 371.478 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (104.45) is higher than Ligand B (79.37). For CNS targets, we prefer TPSA <= 90, so Ligand B is better here.

**logP:** Ligand A (-0.01) is quite low, potentially hindering permeability. Ligand B (1.981) is within the optimal 1-3 range. This is a significant advantage for Ligand B.

**H-Bond Donors/Acceptors:** Both have 1 HBD, which is good. Ligand A has 8 HBA, while Ligand B has 4. Both are acceptable (<=10), but Ligand B is preferable.

**QED:** Both ligands have good QED scores (0.773 and 0.795), indicating drug-like properties.

**DILI:** Ligand A (69.872) has a higher DILI risk than Ligand B (49.399), though both are reasonably acceptable.

**BBB:** Ligand B (62.117) has a significantly better BBB percentile than Ligand A (41.838). This is *crucial* for a CNS target like DRD2.

**Caco-2 Permeability:** Both have negative values (-5.49 and -4.91), which is unusual and suggests poor permeability. However, these values are on a scale where negative values are possible, and direct comparison is difficult without knowing the scale's specifics.

**Aqueous Solubility:** Both have negative values (-1.388 and -2.867), suggesting poor solubility. Again, the scale is unknown.

**hERG Inhibition:** Ligand A (0.02) has a slightly lower hERG risk than Ligand B (0.443), which is good.

**Microsomal Clearance:** Ligand A (6.266) has lower clearance than Ligand B (29.813), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (34.945) has a longer half-life than Ligand B (-10.338). This is a significant advantage for Ligand A.

**P-gp Efflux:** Ligand A (0.052) has lower P-gp efflux than Ligand B (0.174), which is desirable for CNS penetration.

**Binding Affinity:** Ligand B (-8.5 kcal/mol) has a stronger binding affinity than Ligand A (-6.8 kcal/mol). This >1.5 kcal/mol difference is substantial and can outweigh some ADME drawbacks.

**Overall Assessment:**

Ligand B is the stronger candidate. While Ligand A has better metabolic stability and half-life, Ligand B excels in the most critical areas for a CNS-targeting GPCR: logP, BBB penetration, and binding affinity. The significantly better BBB and affinity of Ligand B outweigh the slightly higher DILI and P-gp efflux. The lower TPSA of Ligand B is also beneficial. The poor Caco-2 and solubility values are concerning for both, but the primary goal is CNS penetration, where Ligand B has a clear advantage.



Output:
1
2025-04-17 06:41:06,130 - INFO - Reasoning:

Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (347.463 and 353.419 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (100.35) is better than Ligand B (104.9). Both are reasonably close to the 90 A^2 threshold for CNS targets, but A is preferable.

**3. logP:** Ligand A (1.285) and Ligand B (0.85) are both within the optimal 1-3 range, but A is slightly better.

**4. H-Bond Donors:** Ligand A (3) is slightly higher than Ligand B (2), but both are acceptable (<=5).

**5. H-Bond Acceptors:** Ligand A (4) is lower than Ligand B (6). Lower is better, making A preferable.

**6. QED:** Both ligands have similar QED values (0.764 and 0.682), indicating good drug-likeness.

**7. DILI:** Ligand A (21.946) has a significantly lower DILI risk than Ligand B (52.927). This is a major advantage for Ligand A.

**8. BBB:** Ligand A (64.831) has a substantially better BBB penetration percentile than Ligand B (49.787). This is *critical* for a CNS target like DRD2, giving A a significant edge.

**9. Caco-2 Permeability:** Both have negative values (-5.14 and -5.186), which is unusual and suggests poor permeability. This is a drawback for both, but doesn't differentiate them.

**10. Aqueous Solubility:** Both have negative values (-1.882 and -0.869), indicating poor solubility. This is a concern for both, but again doesn't differentiate.

**11. hERG Inhibition:** Ligand A (0.395) has a lower hERG inhibition liability than Ligand B (0.176), indicating a lower risk of cardiotoxicity.

**12. Microsomal Clearance:** Ligand A (-45.048) has a *much* lower (better) microsomal clearance than Ligand B (22.976), suggesting greater metabolic stability.

**13. In vitro Half-Life:** Ligand A (21.628) has a longer in vitro half-life than Ligand B (-15.095), which is desirable.

**14. P-gp Efflux:** Ligand A (0.007) has a much lower P-gp efflux liability than Ligand B (0.06), which is crucial for CNS penetration.

**15. Binding Affinity:** Ligand B (-7.3) has a slightly better binding affinity than Ligand A (-8.7). While affinity is important, the difference of 1.4 kcal/mol is not enough to overcome the significant ADME advantages of Ligand A.

**Overall:**

Ligand A is the superior candidate. It demonstrates significantly better ADME properties, particularly regarding BBB penetration, DILI risk, metabolic stability (Cl_mic), P-gp efflux, and hERG inhibition. While Ligand B has a slightly better binding affinity, the substantial improvements in ADME properties for Ligand A, especially its superior BBB penetration, outweigh this difference for a CNS-targeted GPCR like DRD2.

Output:
1
2025-04-17 06:41:06,131 - INFO - Batch 302 complete. Total preferences: 4832
2025-04-17 06:41:06,131 - INFO - Processing batch 303/512...
2025-04-17 06:41:45,705 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (354.403 and 356.507 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (86.33) is slightly higher than Ligand B (81.08), but both are below the 90 A^2 threshold desirable for CNS targets.

**3. logP:** Ligand A (1.154) and Ligand B (1.641) are both within the optimal 1-3 range.

**4. H-Bond Donors:** Ligand A (1) is better than Ligand B (2). Lower HBD generally improves permeability.

**5. H-Bond Acceptors:** Ligand A (6) is higher than Ligand B (4). Both are within the acceptable limit of 10.

**6. QED:** Both ligands have good QED scores (0.501 and 0.658 respectively), indicating good drug-like properties. Ligand B is slightly better.

**7. DILI:** Ligand A (54.789) has a higher DILI risk than Ligand B (5.971). This is a significant advantage for Ligand B.

**8. BBB:** Ligand A (75.572) has a better BBB penetration percentile than Ligand B (61.225). This is crucial for a CNS target like DRD2.

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.655 and -4.656), which is unusual and suggests poor permeability. This is a concern for both.

**10. Aqueous Solubility:** Both ligands have negative solubility values (-1.26 and -1.159), indicating poor aqueous solubility. This is a concern for both.

**11. hERG Inhibition:** Both ligands have low hERG inhibition risk (0.366 and 0.544 respectively).

**12. Microsomal Clearance:** Ligand B (28.258) has lower microsomal clearance than Ligand A (40.854), indicating better metabolic stability.

**13. In vitro Half-Life:** Ligand A (-17.342) has a longer in vitro half-life than Ligand B (-14.011).

**14. P-gp Efflux:** Ligand A (0.081) has lower P-gp efflux than Ligand B (0.106), which is favorable for CNS penetration.

**15. Binding Affinity:** Ligand B (-7.0) has a slightly better binding affinity than Ligand A (-6.7). While the difference is not huge, it's enough to consider.

**Overall Assessment:**

Ligand B is the more promising candidate. While Ligand A has better BBB penetration and in vitro half-life, Ligand B has a significantly lower DILI risk, better metabolic stability (lower Cl_mic), and slightly better binding affinity. The lower DILI risk is a major advantage, and the slight improvement in affinity is a bonus. The poor Caco-2 and solubility are concerns for both, but can potentially be addressed through formulation strategies. Given the GPCR-specific priorities, the balance of properties favors Ligand B.

Output:
1
2025-04-17 06:41:45,706 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (357.841 Da) and Ligand B (333.395 Da) are both acceptable.

**2. TPSA:**  Ligand A (56.15) is excellent for CNS penetration, well below 90. Ligand B (71.32) is still reasonable, but less optimal.

**3. logP:** Ligand A (4.161) is slightly high, potentially leading to solubility issues or off-target interactions. Ligand B (3.34) is within the optimal range (1-3).

**4. H-Bond Donors:** Ligand A (1) and Ligand B (2) are both acceptable, below the threshold of 5.

**5. H-Bond Acceptors:** Ligand A (5) and Ligand B (4) are both acceptable, below the threshold of 10.

**6. QED:** Both ligands have good QED values (A: 0.696, B: 0.704), indicating drug-like properties.

**7. DILI:** Both ligands have relatively high DILI risk (A: 72.819, B: 77.627), but are still within a range that isn't immediately disqualifying.

**8. BBB:**  Ligand A (57.154) is concerningly low for a CNS target. Ligand B (70.919) is better, approaching the desirable >70 threshold.

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.789 and -4.601), which is unusual and suggests poor permeability. This is a significant drawback for both.

**10. Aqueous Solubility:** Both ligands have negative solubility values (-4.711 and -4.289), indicating very poor aqueous solubility. This is a major concern.

**11. hERG Inhibition:** Both ligands show low hERG inhibition risk (A: 0.608, B: 0.555).

**12. Microsomal Clearance:** Ligand A (92.26) has higher clearance than Ligand B (42.689), meaning Ligand B is more metabolically stable.

**13. In vitro Half-Life:** Ligand A (109.887) has a longer half-life than Ligand B (-4.331).

**14. P-gp Efflux:** Ligand A (0.45) has lower P-gp efflux than Ligand B (0.083), suggesting better CNS exposure.

**15. Binding Affinity:** Ligand B (-9.6) has a slightly better binding affinity than Ligand A (-9.3). While the difference is small, it's still a factor.

**Overall Assessment:**

Despite Ligand B's slightly better affinity, the critical factor is BBB penetration. Ligand A's BBB percentile is very low (57.154), making it unlikely to reach the target in the brain effectively. Ligand B (70.919) is better, but still not ideal. Both ligands have poor solubility and permeability. However, for a CNS target, BBB is paramount. Ligand B has a better profile overall, with a more favorable logP, better metabolic stability, and a higher (though still not great) BBB score.

Output:
1
2025-04-17 06:41:45,706 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (350.503 and 355.41 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (58.64) is significantly better than Ligand B (95.67). For CNS targets, we want TPSA <= 90, so Ligand A is much more favorable.

**logP:** Both ligands have good logP values (2.759 and 1.628), falling within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A (HBD=1, HBA=3) is preferable to Ligand B (HBD=2, HBA=5) as it has fewer hydrogen bond forming groups, potentially aiding membrane permeability. Both are within acceptable limits.

**QED:** Both ligands have good QED scores (0.651 and 0.775), indicating drug-like properties.

**DILI:** Ligand A (30.322) has a lower DILI risk than Ligand B (54.168), which is a positive attribute. Both are below the concerning threshold of 60.

**BBB:** Ligand A (71.772) has a significantly better BBB penetration percentile than Ligand B (59.868). A value >70 is desirable for CNS targets, and Ligand A is closer to that mark.

**Caco-2 Permeability:** Both have negative values (-4.725 and -4.911), which is unusual and requires further investigation. However, the values are similar.

**Aqueous Solubility:** Both ligands have negative solubility values (-2.646 and -2.081). This is concerning and suggests formulation challenges.

**hERG Inhibition:** Both ligands have low hERG inhibition liability (0.228 and 0.326), which is good.

**Microsomal Clearance:** Ligand A (74.774) has a higher microsomal clearance than Ligand B (29.062), meaning it's metabolized faster. Lower clearance is preferred.

**In vitro Half-Life:** Ligand B (-6.282) has a better (longer) in vitro half-life than Ligand A (-7.044).

**P-gp Efflux:** Ligand A (0.241) has a lower P-gp efflux liability than Ligand B (-7.5), which is desirable for CNS penetration.

**Binding Affinity:** Ligand B (-6.282 kcal/mol) has a slightly better binding affinity than Ligand A (-7.044 kcal/mol). While a difference of >1.5 kcal/mol is significant, the difference here is less than 1 kcal/mol and can be overcome by other favorable properties.

**Overall Assessment:**

Considering the GPCR-specific priorities, Ligand A is the more promising candidate. Its significantly better TPSA and BBB penetration are crucial for CNS drug development. While Ligand B has slightly better affinity and half-life, Ligand A's superior TPSA, BBB, lower DILI risk, and lower P-gp efflux outweigh these advantages. The solubility issues are a concern for both, but can potentially be addressed through formulation strategies. The higher clearance of Ligand A is a drawback, but not as critical as the CNS penetration issues with Ligand B.

Output:
0
2025-04-17 06:41:45,706 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B based on the provided guidelines, prioritizing GPCR-specific properties (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (366.487 and 375.447 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (75.63) is excellent, well below the 90 A^2 threshold for CNS targets. Ligand B (130.67) is higher, but still potentially acceptable, though less ideal.

**logP:** Ligand A (1.806) is within the optimal 1-3 range. Ligand B (-0.537) is below 1, which could hinder permeation.

**H-Bond Donors/Acceptors:** Ligand A (0 HBD, 6 HBA) is favorable. Ligand B (3 HBD, 6 HBA) is also acceptable, but the 3 HBDs are slightly less desirable.

**QED:** Both ligands have reasonable QED scores (0.815 and 0.522), suggesting good drug-like properties.

**DILI:** Both ligands have acceptable DILI risk (47.964 and 52.734), both below the 60 threshold.

**BBB:** Ligand A (79.682) has a very good BBB percentile, exceeding the 70% target for CNS drugs. Ligand B (67.158) is lower, which is a significant drawback for a CNS target like DRD2.

**Caco-2 Permeability:** Ligand A (-4.734) has poor Caco-2 permeability. Ligand B (-5.411) is similarly poor.

**Aqueous Solubility:** Both ligands have very poor aqueous solubility (-2.687 and -1.515). This is a concern for formulation and bioavailability, but can sometimes be mitigated.

**hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.35 and 0.055).

**Microsomal Clearance:** Ligand A (43.638) has moderate clearance, while Ligand B (3.808) has very low clearance, indicating better metabolic stability.

**In vitro Half-Life:** Ligand A (8.402 hours) has a reasonable half-life. Ligand B (5.191 hours) is shorter, potentially requiring more frequent dosing.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.35 and 0.027), which is favorable for CNS penetration.

**Binding Affinity:** Ligand B (-7.3 kcal/mol) has significantly stronger binding affinity than Ligand A (0.0 kcal/mol). This is a substantial advantage, potentially outweighing some of its ADME drawbacks.

**Overall Assessment:**

While Ligand B has a better binding affinity and metabolic stability, its lower logP and BBB penetration are major concerns for a CNS-targeting drug. Ligand A has a much better BBB score and logP, which are critical for CNS penetration, but suffers from very poor binding affinity and Caco-2 permeability. The strong binding affinity of Ligand B is very attractive, but the poor BBB penetration is a major hurdle. Given the importance of CNS penetration for DRD2, and the fact that the affinity difference is large, Ligand B is the better candidate, but would require significant medicinal chemistry effort to improve its BBB score.

Output:
1
2025-04-17 06:41:45,706 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (352.479 and 361.467 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (72.96) is excellent, well below the 90 A^2 threshold for CNS targets. Ligand B (82.53) is still reasonable but less optimal.

**logP:** Ligand A (0.302) is quite low, potentially hindering membrane permeability. Ligand B (1.063) is better, falling within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A (1 HBD, 4 HBA) is good. Ligand B (2 HBD, 5 HBA) is also acceptable.

**QED:** Both ligands have good QED scores (0.746 and 0.841), indicating drug-like properties.

**DILI:** Ligand A (7.445) has a very low DILI risk, which is excellent. Ligand B (59.907) is higher, indicating a moderate risk, but still below the concerning 60 threshold.

**BBB:** This is a crucial parameter for a CNS target like DRD2. Ligand A (54.634) has a moderate BBB penetration, while Ligand B (25.359) is significantly lower and undesirable.

**Caco-2 Permeability:** Both have negative values (-5.276 and -5.151), which is unusual and suggests poor permeability. However, these values are on a scale where negative values are possible, and direct comparison is difficult without knowing the scale's specifics.

**Aqueous Solubility:** Both have negative values (-0.207 and -2.795), indicating poor solubility.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.209 and 0.167).

**Microsomal Clearance:** Ligand A (-4.342) suggests very low clearance and excellent metabolic stability. Ligand B (31.685) indicates significantly higher clearance, meaning faster metabolism.

**In vitro Half-Life:** Ligand A (-6.965) suggests a very long half-life, while Ligand B (-23.028) suggests a very short half-life.

**P-gp Efflux:** Ligand A (0.003) has very low P-gp efflux, which is highly desirable for CNS penetration. Ligand B (0.131) has slightly higher efflux, but still relatively low.

**Binding Affinity:** Ligand B (-9.2 kcal/mol) has a much stronger binding affinity than Ligand A (-0.0 kcal/mol). This is a substantial difference.

**Overall Assessment:**

Ligand B has a significantly better binding affinity, which is paramount. While its BBB penetration is lower than ideal, the substantial affinity advantage (-9.2 vs -0.0 kcal/mol) can potentially compensate for this, especially considering its acceptable logP and P-gp efflux. Ligand A's excellent TPSA, DILI, metabolic stability, and P-gp efflux are attractive, but its extremely weak binding affinity makes it unlikely to be a viable candidate. The poor solubility and Caco-2 permeability are concerns for both, but can be addressed with formulation strategies.



Output:
1
2025-04-17 06:41:45,706 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight (MW):** Both ligands (351.447 and 363.523 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (95.58) is slightly above the preferred <90 for CNS targets, but still reasonable. Ligand B (38.77) is excellent, well below 90, indicating good potential for brain penetration.

**3. logP:** Ligand A (0.827) is a bit low, potentially hindering membrane permeability. Ligand B (3.791) is within the optimal 1-3 range.

**4. H-Bond Donors (HBD):** Both ligands have acceptable HBD counts (2 and 0, respectively), well below the limit of 5.

**5. H-Bond Acceptors (HBA):** Both ligands have acceptable HBA counts (4 each), below the limit of 10.

**6. QED:** Both ligands have similar QED values (0.693 and 0.627), indicating good drug-like properties.

**7. DILI:** Both ligands have low DILI risk (27.336 and 26.018 percentile), which is favorable.

**8. BBB:** Ligand A (78.48%) is good, but Ligand B (84.141%) is excellent, exceeding the desirable >70% threshold for CNS targets. This is a significant advantage for Ligand B.

**9. Caco-2 Permeability:** Ligand A (-5.305) has poor Caco-2 permeability. Ligand B (-4.883) also has poor Caco-2 permeability.

**10. Aqueous Solubility:** Both ligands have poor aqueous solubility (-2.438 and -3.786).

**11. hERG Inhibition:** Ligand A (0.048) has very low hERG inhibition risk, which is excellent. Ligand B (0.677) has a slightly higher, but still acceptable, hERG risk.

**12. Microsomal Clearance:** Ligand A (7.602) has lower microsomal clearance, suggesting better metabolic stability than Ligand B (74.412).

**13. In vitro Half-Life:** Ligand A (-17.63) has a negative half-life, which is not possible. This is a red flag. Ligand B (24.655) has a reasonable half-life.

**14. P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.009 and 0.736), which is favorable for CNS penetration.

**15. Binding Affinity:** Both ligands have strong binding affinities (-7.7 and -7.5 kcal/mol). The difference of 0.2 kcal/mol is not substantial enough to outweigh other factors.

**Overall Assessment:**

Ligand A has a problematic negative in vitro half-life, which is a critical issue. While it has excellent hERG inhibition profile and lower clearance, the half-life issue is a dealbreaker. Ligand B excels in BBB penetration and has a reasonable half-life, despite slightly higher hERG risk and clearance. The better BBB penetration and reasonable ADME profile of Ligand B, combined with comparable binding affinity, make it the more promising candidate.

Output:
1
2025-04-17 06:41:45,706 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (346.431 and 359.442 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (88.41) is better than Ligand B (71.11) as it is closer to the optimal <90 for CNS targets.

**logP:** Ligand A (2.415) is within the optimal 1-3 range. Ligand B (0.596) is slightly low, potentially hindering permeation.

**H-Bond Donors:** Ligand A (3) is acceptable, while Ligand B (1) is also good.

**H-Bond Acceptors:** Both ligands have 5 HBA, which is within the acceptable limit of <=10.

**QED:** Both ligands have good QED scores (0.685 and 0.752, respectively), indicating drug-likeness.

**DILI:** Ligand A (54.634) has a higher DILI risk than Ligand B (25.165). This is a negative for Ligand A.

**BBB:** Ligand B (78.907) significantly outperforms Ligand A (32.144) in BBB penetration, which is critical for a CNS target like DRD2.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.938 and -4.936), which is unusual and suggests poor permeability. This is a significant drawback for both.

**Aqueous Solubility:** Both ligands have negative solubility values (-1.739 and -1.416), which is also concerning and suggests poor solubility.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.674 and 0.527).

**Microsomal Clearance:** Ligand B (-18.569) has a much lower (better) microsomal clearance than Ligand A (-1.317), indicating greater metabolic stability.

**In vitro Half-Life:** Ligand B (-11.463) has a longer in vitro half-life than Ligand A (25.045), which is desirable.

**P-gp Efflux:** Ligand A (0.124) has lower P-gp efflux than Ligand B (0.031), which is favorable for CNS penetration.

**Binding Affinity:** Both ligands have comparable binding affinities (-8.0 and -7.9 kcal/mol), which are excellent. The difference is negligible.

**Overall Assessment:**

While Ligand A has slightly better TPSA and P-gp efflux, Ligand B is superior in almost all other critical parameters for a CNS-targeting GPCR. Specifically, the significantly better BBB penetration, lower DILI risk, and improved metabolic stability (lower Cl_mic and longer t1/2) of Ligand B outweigh the minor advantages of Ligand A. The negative Caco-2 and solubility values are concerning for both, but can potentially be addressed through formulation strategies.

Output:
1
2025-04-17 06:41:45,706 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 drug candidates, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (352.406 and 349.431 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (70.08) is significantly better than Ligand B (84.67). For CNS targets, TPSA < 90 is preferred, and A is closer to the optimal <60 range. B is pushing the upper limit.

**3. logP:** Ligand B (1.629) is better than Ligand A (0.054). A logP of 1-3 is optimal, and A is quite low, potentially hindering membrane permeability. B is within the ideal range.

**4. H-Bond Donors:** Both ligands have 1 HBD, which is acceptable.

**5. H-Bond Acceptors:** Ligand A has 4 HBAs, and Ligand B has 5. Both are within the acceptable limit of <=10.

**6. QED:** Both ligands have good QED scores (0.686 and 0.809), indicating good drug-like properties.

**7. DILI:** Ligand A (16.13) has a much lower DILI risk than Ligand B (39.046). This is a significant advantage for A.

**8. BBB:** Both ligands have excellent BBB penetration (74.06 and 75.727), exceeding the desirable >70 threshold for CNS targets.

**9. Caco-2:** Both have negative Caco-2 values, which is unusual and difficult to interpret without knowing the scale. However, the values are similar.

**10. Solubility:** Both have negative solubility values, also unusual. Again, the values are similar.

**11. hERG:** Both ligands have low hERG inhibition risk (0.255 and 0.302).

**12. Cl_mic:** Ligand A (6.713) has significantly lower microsomal clearance than Ligand B (51.796), indicating better metabolic stability.

**13. t1/2:** Ligand A (3.783) has a shorter half-life than Ligand B (-15.186). The negative value for B is concerning.

**14. Pgp:** Ligand A (0.044) has much lower P-gp efflux liability than Ligand B (0.134), which is crucial for CNS penetration.

**15. Binding Affinity:** Ligand B (-8.2) has a slightly better binding affinity than Ligand A (-7.8), but the difference is relatively small (0.4 kcal/mol).

**Overall Assessment:**

While Ligand B has a slightly better binding affinity and logP, Ligand A is superior in almost all other critical ADME properties. Specifically, its significantly lower DILI risk, much better metabolic stability (lower Cl_mic), lower P-gp efflux, and lower TPSA are highly advantageous. The lower logP of Ligand A is a concern, but the other benefits likely outweigh this drawback, especially given the relatively small affinity difference. For a CNS target like DRD2, minimizing efflux and maximizing brain penetration are paramount, and Ligand A excels in these areas.

Output:
0
2025-04-17 06:41:45,707 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (367.833 and 354.466 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (78.95) is higher than Ligand B (58.64). For a CNS target like DRD2, TPSA should be <= 90. Both are within this range, but B is preferable.

**3. logP:** Ligand A (1.387) and Ligand B (2.15) are both within the optimal 1-3 range.

**4. H-Bond Donors:** Both ligands have 1 HBD, which is acceptable (<=5).

**5. H-Bond Acceptors:** Ligand A has 4 HBAs, and Ligand B has 3. Both are below the acceptable limit of 10.

**6. QED:** Both ligands have similar QED values (0.761 and 0.762), indicating good drug-likeness.

**7. DILI:** Ligand A (45.832) has a slightly higher DILI risk than Ligand B (25.475), but both are below the concerning threshold of 60.

**8. BBB:** This is a critical parameter for CNS targets. Ligand B (91.702) has a significantly higher BBB penetration percentile than Ligand A (65.374). This is a major advantage for B.

**9. Caco-2 Permeability:** Both have negative values (-4.722 and -4.678), indicating poor permeability. This is a concern for both.

**10. Aqueous Solubility:** Both have negative values (-2.57 and -2.414), indicating poor solubility. This is a concern for both.

**11. hERG Inhibition:** Ligand A (0.088) has a lower hERG inhibition risk than Ligand B (0.762), which is preferable.

**12. Microsomal Clearance:** Ligand A (-6.114) has a much lower (better) microsomal clearance than Ligand B (21.728), suggesting greater metabolic stability.

**13. In vitro Half-Life:** Ligand B (17.518) has a longer half-life than Ligand A (-9.329), which is generally desirable.

**14. P-gp Efflux:** Ligand A (0.018) has a much lower P-gp efflux liability than Ligand B (0.23), which is a significant advantage for CNS penetration.

**15. Binding Affinity:** Ligand B (-7.9) has a slightly better (more negative) binding affinity than Ligand A (-7.5). While both are good, the 0.4 kcal/mol difference is noteworthy.

**Overall Assessment:**

Ligand B excels in BBB penetration and has a slightly better binding affinity and half-life. However, Ligand A has better metabolic stability (lower Cl_mic), lower P-gp efflux, and lower hERG inhibition risk. The superior BBB penetration of Ligand B is the most important factor for a CNS target like DRD2. The difference in binding affinity is not large enough to overcome the significant advantage of B in BBB penetration.

Output:
1
2025-04-17 06:41:45,707 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (341.382 and 383.319 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (55.4) is significantly better than Ligand B (61.36). For CNS targets, we want TPSA <= 90, and A is closer to the optimal <=60 range.

**3. logP:** Both ligands have good logP values (4.072 and 4.234), falling within the 1-3 range, though slightly above the ideal.

**4. H-Bond Donors:** Ligand A (1) is preferable to Ligand B (3). Lower HBD generally improves permeability.

**5. H-Bond Acceptors:** Ligand A (3) is preferable to Ligand B (2). Lower HBA generally improves permeability.

**6. QED:** Both ligands have acceptable QED values (0.806 and 0.729), indicating good drug-like properties.

**7. DILI:** Ligand A (76.115) has a significantly higher DILI risk than Ligand B (18.379). This is a major drawback for Ligand A.

**8. BBB:** Both ligands have excellent BBB penetration (79.721 and 74.176), exceeding the desirable >70% threshold for CNS targets.

**9. Caco-2:** Both ligands have negative Caco-2 values (-4.326 and -4.596). This is unusual and suggests poor permeability.

**10. Solubility:** Both ligands have negative solubility values (-5.229 and -4.327). This is also unusual and suggests poor solubility.

**11. hERG:** Both ligands have low hERG inhibition risk (0.255 and 0.669).

**12. Cl_mic:** Ligand B (-3.012) has a *much* lower (better) microsomal clearance than Ligand A (69.679). This indicates better metabolic stability for Ligand B.

**13. t1/2:** Ligand B (30.796) has a significantly longer in vitro half-life than Ligand A (7.812).

**14. Pgp:** Both ligands have very low Pgp efflux liability (0.396 and 0.272), which is good for CNS penetration.

**15. Binding Affinity:** Ligand B (-9.9) has a slightly better binding affinity than Ligand A (-9.0). While both are excellent, the difference is significant.

**Overall Assessment:**

Despite the unusual negative Caco-2 and solubility values for both compounds, Ligand B is the more promising candidate. While Ligand A has a slightly better TPSA, Ligand B excels in critical areas: significantly lower DILI risk, much better metabolic stability (Cl_mic), longer half-life, and slightly improved binding affinity. The GPCR-specific priorities of BBB, logP, Pgp, TPSA, and affinity are all reasonably well addressed by Ligand B. The DILI risk of Ligand A is a major concern.

Output:
1
2025-04-17 06:41:45,707 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (352.431 and 351.491 Da) fall within the ideal range of 200-500 Da.

**TPSA:** Ligand A (107.89) is higher than the preferred <90 for CNS targets, while Ligand B (70.67) is well within the range. This is a significant advantage for Ligand B.

**logP:** Ligand A (0.395) is quite low, potentially hindering membrane permeability. Ligand B (1.153) is better, falling within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A has 4 HBD and 5 HBA, acceptable values. Ligand B has 2 HBD and 4 HBA, also acceptable and potentially slightly better for permeability.

**QED:** Both ligands have good QED scores (0.518 and 0.722), indicating good drug-like properties.

**DILI:** Ligand A (29.934) has a slightly higher DILI risk than Ligand B (18.418), but both are below the concerning threshold of 60.

**BBB:** This is crucial for a CNS target like DRD2. Ligand A (29.508) has a poor BBB percentile, while Ligand B (74.835) is excellent, exceeding the desirable >70 threshold.

**Caco-2 Permeability:** Ligand A (-5.365) shows poor permeability, while Ligand B (-4.864) is slightly better, but still not ideal.

**Aqueous Solubility:** Both ligands have very poor aqueous solubility (-2.373 and -2.041), which could pose formulation challenges.

**hERG Inhibition:** Ligand A (0.191) has a slightly higher hERG risk than Ligand B (0.34), but both are relatively low.

**Microsomal Clearance:** Ligand A (3.25) has much lower microsomal clearance than Ligand B (42.962), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (25.575) has a longer half-life than Ligand B (-0.637), which is a positive attribute.

**P-gp Efflux:** Ligand A (0.006) shows very low P-gp efflux, which is favorable for CNS penetration. Ligand B (0.039) also shows low P-gp efflux, but slightly higher than A.

**Binding Affinity:** Ligand A (-8.3 kcal/mol) has significantly stronger binding affinity than Ligand B (0.0 kcal/mol). This is a substantial advantage for Ligand A, potentially outweighing some of its ADME drawbacks.

**Overall Assessment:**

Ligand B excels in BBB penetration and has a better TPSA and logP. However, Ligand A boasts a *much* stronger binding affinity (-8.3 vs 0 kcal/mol). While Ligand A's low logP and Caco-2 permeability are concerns, the dramatically improved binding affinity is a major factor, especially for a GPCR target where achieving sufficient receptor occupancy is critical. The better metabolic stability (lower Cl_mic) and longer half-life of Ligand A also contribute to its favorability. The poor solubility of both is a concern that would need to be addressed through formulation strategies.

Output:
1
2025-04-17 06:41:45,707 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (390.527 Da) is slightly higher than Ligand B (358.36 Da), but both are acceptable.

**TPSA:** Ligand A (93.64) is borderline for CNS targets (ideally <90), while Ligand B (61.8) is well within the desired range. This is a significant advantage for Ligand B.

**logP:** Both ligands have good logP values (Ligand A: 1.847, Ligand B: 2.671), falling within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A has 0 HBD and 6 HBA, which is good. Ligand B has 2 HBD and 3 HBA, also acceptable.

**QED:** Both ligands have good QED scores (Ligand A: 0.779, Ligand B: 0.87), indicating good drug-like properties.

**DILI:** Ligand A has a DILI risk of 60.527, which is approaching the higher risk threshold (>60). Ligand B has a much lower DILI risk of 20.9, a significant advantage.

**BBB:** This is crucial for a CNS target. Ligand A has a BBB penetration of 45.715, which is below the desirable >70 threshold. Ligand B has a BBB penetration of 81.504, which is excellent.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.624 and -4.509), which is unusual and difficult to interpret without further context. However, it suggests poor permeability.

**Aqueous Solubility:** Both ligands have negative solubility values (-4.137 and -3.046), also unusual and suggesting poor solubility.

**hERG Inhibition:** Ligand A (0.292) has a slightly higher hERG risk than Ligand B (0.702), but both are relatively low.

**Microsomal Clearance:** Ligand A has a higher microsomal clearance (66.576) than Ligand B (13.095), indicating lower metabolic stability.

**In vitro Half-Life:** Ligand A has a negative half-life (-40.005), which is problematic. Ligand B has a negative half-life as well (-11.147) but is less negative.

**P-gp Efflux:** Ligand A has no P-gp efflux liability (0.072), which is good. Ligand B also has low P-gp efflux (0.081).

**Binding Affinity:** Ligand B (-8.9 kcal/mol) has a significantly stronger binding affinity than Ligand A (-0.0 kcal/mol). This is a major advantage, potentially outweighing some ADME concerns.

**Overall Assessment:**

Ligand B is clearly the more promising candidate. It excels in the critical areas for a CNS-targeting GPCR: BBB penetration, binding affinity, and DILI risk. While both ligands have issues with Caco-2 permeability and aqueous solubility, the superior affinity and BBB penetration of Ligand B, coupled with its lower DILI risk, make it the better choice. The lower clearance and better half-life (less negative) are also favorable.



Output:
1
2025-04-17 06:41:45,707 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B based on the provided guidelines, prioritizing properties crucial for GPCRs, especially for a CNS target like DRD2.

**1. Molecular Weight:** Both ligands (341.455 and 367.852 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (71.09) is better than Ligand B (51.39) as it is closer to the optimal range of <=90 for CNS targets.

**3. logP:** Ligand A (2.434) is optimal (1-3), while Ligand B (4.132) is approaching the upper limit and could potentially cause solubility issues or off-target interactions.

**4. H-Bond Donors:** Ligand A (2) is good, and Ligand B (0) is also acceptable.

**5. H-Bond Acceptors:** Ligand A (3) is good, and Ligand B (5) is also acceptable.

**6. QED:** Both ligands have similar, good QED values (0.638 and 0.688, both > 0.5).

**7. DILI:** Both ligands have similar, low DILI risk (36.487 and 37.263, both < 40).

**8. BBB:** Ligand B (91.043) significantly outperforms Ligand A (56.96) in BBB penetration, a critical factor for CNS drug candidates. This is a major advantage for Ligand B.

**9. Caco-2 Permeability:** Ligand A (-4.535) and Ligand B (-4.863) both have negative values, which is unusual. Assuming these are percentile scores, lower values indicate poorer permeability. Both are poor, but similar.

**10. Aqueous Solubility:** Both ligands have similar, very poor aqueous solubility (-3.738 and -3.681). This is a concern for both.

**11. hERG Inhibition:** Both ligands show low hERG inhibition liability (0.434 and 0.821).

**12. Microsomal Clearance:** Ligand A (44.626) has lower clearance than Ligand B (58.615), suggesting better metabolic stability.

**13. In vitro Half-Life:** Ligand B (49.746) has a much longer half-life than Ligand A (-16.736). This is a significant advantage for Ligand B.

**14. P-gp Efflux:** Both ligands have low P-gp efflux liability (0.106 and 0.679).

**15. Binding Affinity:** Ligand A (-9.1) has a significantly stronger binding affinity than Ligand B (-8.3). This is a substantial advantage for Ligand A.

**Overall Assessment:**

Ligand A has a superior binding affinity and better metabolic stability (lower Cl_mic). However, Ligand B excels in BBB penetration and in vitro half-life, both crucial for CNS targets. The higher logP of Ligand B is a slight concern, but the dramatic difference in BBB penetration and half-life outweighs this. The binding affinity difference is significant, but a good BBB score is essential for a CNS drug.

Given the GPCR-specific priorities (BBB, logP, Pgp, TPSA, affinity), and the fact that DRD2 is a CNS target, **Ligand B is the more promising candidate**. The strong BBB penetration and longer half-life are critical for achieving sufficient brain exposure.

Output:
1
2025-04-17 06:41:45,707 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (352.395 and 344.411 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (118.45) is borderline for CNS penetration, being slightly above the preferred <90. Ligand B (67.87) is excellent, well below 90, and highly favorable for CNS penetration.

**logP:** Ligand A (-1.127) is quite low, potentially hindering membrane permeability. Ligand B (1.578) is within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A has 2 HBD and 7 HBA, acceptable values. Ligand B has 1 HBD and 4 HBA, also acceptable.

**QED:** Both ligands have good QED scores (0.474 and 0.763), indicating reasonable drug-likeness.

**DILI:** Ligand A (51.648) has a moderate DILI risk, while Ligand B (35.285) has a lower, more favorable risk.

**BBB:** Ligand A (40.791) has poor predicted BBB penetration. Ligand B (87.515) has excellent predicted BBB penetration, a critical factor for a CNS target like DRD2.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.497 and -4.722), which is unusual and suggests poor permeability. However, these values are on a log scale and can be difficult to interpret directly.

**Aqueous Solubility:** Both ligands have negative solubility values (-0.871 and -2.333), indicating poor aqueous solubility. This could pose formulation challenges.

**hERG Inhibition:** Ligand A (0.028) has very low hERG inhibition risk, which is excellent. Ligand B (0.379) has a slightly higher, but still relatively low, hERG risk.

**Microsomal Clearance:** Ligand A (-6.852) suggests very low clearance and high metabolic stability, which is favorable. Ligand B (24.156) indicates faster clearance and lower metabolic stability.

**In vitro Half-Life:** Ligand A (7.09) has a reasonable half-life. Ligand B (15.983) has a longer, more desirable half-life.

**P-gp Efflux:** Ligand A (0.009) has very low P-gp efflux, which is excellent for CNS penetration. Ligand B (0.059) also has low P-gp efflux, but slightly higher than Ligand A.

**Binding Affinity:** Both ligands have very good binding affinities (-7.9 and -7.6 kcal/mol). The difference of 0.3 kcal/mol is not substantial enough to override other significant differences.

**Overall Assessment:**

Ligand B is the stronger candidate. While both have good affinity, Ligand B excels in key areas for a CNS-targeting GPCR: significantly better BBB penetration (87.515 vs 40.791), a more favorable logP (1.578 vs -1.127), and a lower DILI risk. Although it has faster clearance, the superior BBB penetration and logP are more critical for DRD2 engagement. The negative Caco-2 and solubility values are concerning for both, but can potentially be addressed through formulation strategies.

Output:
1
2025-04-17 06:41:45,707 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (353.463 and 350.415 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (78.95) is better than Ligand B (81.01). Both are below the 90 A^2 threshold desirable for CNS targets, but A is closer to the ideal.

**3. logP:** Ligand B (1.528) is better than Ligand A (0.492). A logP of 0.492 is quite low and may hinder membrane permeability. Ligand B is within the optimal 1-3 range.

**4. H-Bond Donors:** Both ligands have 1 HBD, which is acceptable (<=5).

**5. H-Bond Acceptors:** Both ligands have 5 HBA, which is acceptable (<=10).

**6. QED:** Both ligands have reasonable QED scores (0.643 and 0.596), indicating good drug-like properties.

**7. DILI:** Ligand B (43.971) has a significantly lower DILI risk than Ligand A (12.214). This is a major advantage for Ligand B.

**8. BBB:** Ligand B (70.997) has a much better BBB penetration score than Ligand A (44.668). This is *critical* for a CNS target like DRD2.

**9. Caco-2 Permeability:** Both have negative values, which is unusual and suggests poor permeability. However, the scale is not defined, so it is difficult to interpret.

**10. Aqueous Solubility:** Both have negative values, which is also unusual.

**11. hERG Inhibition:** Both ligands have low hERG inhibition liability (0.201 and 0.371).

**12. Microsomal Clearance:** Ligand A (-13.842) has significantly lower (better) microsomal clearance than Ligand B (39.622), suggesting better metabolic stability.

**13. In vitro Half-Life:** Ligand B (10.657) has a longer half-life than Ligand A (-10.542).

**14. P-gp Efflux:** Ligand A (0.01) has very low P-gp efflux, which is ideal. Ligand B (0.129) is also low, but higher than A.

**15. Binding Affinity:** Ligand A (-7.7) has a slightly better binding affinity than Ligand B (0.0).

**Overall Assessment:**

While Ligand A has slightly better affinity and P-gp efflux, Ligand B is significantly better in several crucial areas for a CNS-targeting GPCR: BBB penetration, DILI risk, and in vitro half-life. The low logP of Ligand A is a significant concern, potentially hindering its ability to cross cell membranes. The better metabolic stability of Ligand A is a plus, but can be addressed through structural modifications. The superior BBB penetration and lower toxicity profile of Ligand B make it the more promising candidate.

Output:
1
2025-04-17 06:41:45,707 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B based on the provided guidelines, prioritizing GPCR-specific properties (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (338.411 Da) is slightly lower, which could be beneficial for permeability.

**TPSA:** Ligand A (58.44) is excellent for CNS penetration, well below the 90 A^2 threshold. Ligand B (67.87) is still reasonable, but less optimal.

**logP:** Ligand A (0.676) is a bit low, potentially hindering permeation. Ligand B (2.04) is within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Both have acceptable HBD/HBA counts (A: 0/4, B: 1/4), well within the recommended limits.

**QED:** Both ligands have reasonable QED scores (A: 0.742, B: 0.527), indicating good drug-like properties.

**DILI:** Both have low DILI risk (A: 23.769, B: 33.695), which is favorable.

**BBB:** Ligand B (93.486) has a significantly higher BBB percentile than Ligand A (67.701). This is a *critical* advantage for a CNS target like DRD2.

**Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and suggests potential issues with the experimental setup or prediction method. However, we can still compare the *magnitude* of the negative values. Ligand A (-4.426) is slightly less negative than Ligand B (-4.687), suggesting potentially better permeability.

**Aqueous Solubility:** Both have negative solubility values, which is also unusual. Again, comparing magnitudes, Ligand A (-2.44) is slightly better than Ligand B (-2.643).

**hERG Inhibition:** Both have low hERG inhibition risk (A: 0.298, B: 0.62).

**Microsomal Clearance:** Ligand A (16.071) has a lower microsomal clearance than Ligand B (4.707), indicating better metabolic stability.

**In vitro Half-Life:** Ligand B (-20.934) has a significantly longer in vitro half-life than Ligand A (-11.102). This is a substantial advantage.

**P-gp Efflux:** Both have very low P-gp efflux liability (A: 0.035, B: 0.029), which is good for CNS penetration.

**Binding Affinity:** Ligand B (-8.6 kcal/mol) has a stronger binding affinity than Ligand A (-7.1 kcal/mol). This difference (1.5 kcal/mol) is significant and can outweigh some ADME drawbacks.

**Overall Assessment:**

While Ligand A has slightly better permeability predictions (Caco-2, solubility) and metabolic stability, Ligand B excels in the most crucial areas for a CNS-targeting GPCR: **BBB penetration and binding affinity**. The significantly higher BBB score and stronger binding affinity of Ligand B are compelling advantages. The longer half-life is also a positive factor. The slightly lower logP of Ligand A is a concern, and the superior affinity of Ligand B likely compensates for any minor permeability issues.

Output:
1
2025-04-17 06:41:45,707 - INFO - Batch 303 complete. Total preferences: 4848
2025-04-17 06:41:45,707 - INFO - Processing batch 304/512...
2025-04-17 06:42:34,269 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (347.375 and 345.443 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (97.11) is slightly above the optimal <90 for CNS targets, but still reasonable. Ligand B (62.74) is excellent, well below 90.

**logP:** Ligand A (0.213) is quite low, potentially hindering permeation. Ligand B (1.417) is within the optimal 1-3 range. This is a significant advantage for Ligand B.

**H-Bond Donors/Acceptors:** Both have acceptable HBD counts (0). Ligand A has 7 HBA, which is at the upper limit, while Ligand B has 4, which is preferable.

**QED:** Both ligands have good QED scores (0.664 and 0.828), indicating drug-like properties.

**DILI:** Ligand A (66.421) has a higher DILI risk than Ligand B (19.698), which is a substantial concern.

**BBB:** Both ligands show good BBB penetration (71.772 and 73.943), exceeding the 70% threshold for CNS targets.

**Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and suggests a potential issue with the data or modeling. However, the values are similar, so this doesn't strongly favor either.

**Aqueous Solubility:** Both have negative solubility values, again suggesting a potential data issue. The values are similar, so this doesn't strongly favor either.

**hERG:** Both ligands show low hERG inhibition risk (0.143 and 0.258).

**Microsomal Clearance:** Ligand A (85.834) has higher microsomal clearance than Ligand B (18.779), meaning it's less metabolically stable.

**In vitro Half-Life:** Ligand B (-6.886) has a negative half-life, which is impossible. Ligand A (11.359) has a reasonable half-life. This is a major red flag for Ligand B.

**P-gp Efflux:** Both have very low P-gp efflux liability (0.041 and 0.047), which is good for CNS penetration.

**Binding Affinity:** Ligand B (-8.6 kcal/mol) has a slightly better binding affinity than Ligand A (-7.7 kcal/mol), although both are strong binders.

**Overall Assessment:**

Ligand B is significantly better. While both have good BBB penetration and acceptable hERG risk, Ligand B excels in logP, DILI, microsomal clearance, and binding affinity. Ligand A's low logP and higher DILI risk are major drawbacks. The negative half-life for Ligand B is a data quality issue, but even ignoring that, the other factors strongly favor Ligand A.

Output:
1
2025-04-17 06:42:34,269 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B based on the provided guidelines, prioritizing GPCR-specific properties (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (348.487 Da) is slightly preferred as it's closer to the lower end, potentially aiding permeability.

**TPSA:** Ligand A (67.43) is significantly better than Ligand B (82.37). For CNS targets, TPSA should be <=90, and A is comfortably within this range, while B is approaching the upper limit. This favors A.

**logP:** Both ligands have good logP values (A: 2.908, B: 1.976), falling within the optimal 1-3 range. A is slightly higher, which could be beneficial for membrane permeability, but not drastically.

**H-Bond Donors/Acceptors:** Ligand A (HBD=2, HBA=3) is slightly better than Ligand B (HBD=0, HBA=8). While both are acceptable, a moderate number of H-bonds can aid solubility without significantly hindering permeability.

**QED:** Both ligands have good QED scores (A: 0.597, B: 0.711), indicating good drug-like properties. B is slightly better here.

**DILI:** Ligand A (26.367) has a much lower DILI risk than Ligand B (87.747). This is a significant advantage for A.

**BBB:** Ligand A (69.678) has a better BBB percentile than Ligand B (58.278). While both are not ideal (>70 is desirable), A is closer. This is a critical factor for a CNS target like DRD2.

**Caco-2 Permeability:** Ligand A (-4.959) has a more negative Caco-2 value than Ligand B (-5.012). Lower values indicate lower permeability, but the difference is negligible.

**Aqueous Solubility:** Ligand A (-3.115) has a slightly better solubility than Ligand B (-2.891).

**hERG Inhibition:** Both ligands have very low hERG inhibition risk (A: 0.408, B: 0.176), which is excellent.

**Microsomal Clearance:** Ligand A (71.886) has a higher microsomal clearance than Ligand B (10.351), meaning it's metabolized faster. This is a disadvantage for A.

**In vitro Half-Life:** Ligand B (20.691) has a significantly longer in vitro half-life than Ligand A (-24.091). This is a significant advantage for B.

**P-gp Efflux:** Both ligands have similar P-gp efflux liability (A: 0.533, B: 0.382).

**Binding Affinity:** Both ligands have the same binding affinity (-8.3 kcal/mol), which is excellent. This removes affinity as a differentiating factor.

**Overall Assessment:**

Considering all factors, especially the GPCR-specific priorities, **Ligand A is the more promising candidate**. While Ligand B has better metabolic stability (lower Cl_mic and higher t1/2) and a slightly higher QED, Ligand A excels in crucial areas for CNS penetration: lower TPSA, lower DILI risk, and a better BBB percentile. The slightly better solubility of A is also a plus. The difference in metabolic stability, while important, can potentially be addressed through structural modifications during lead optimization.



Output:
0
2025-04-17 06:42:34,270 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (342.355 and 351.491 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (117.52) is slightly above the preferred <90 for CNS targets, but still reasonable. Ligand B (81.67) is excellent, well below 90.

**logP:** Both ligands have good logP values (1.294 and 0.89), falling within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Both have 3 HBD and 4 HBA, which are within acceptable limits.

**QED:** Both ligands have acceptable QED scores (0.713 and 0.607), indicating good drug-like properties.

**DILI:** Ligand A has a significantly higher DILI risk (87.01 percentile) compared to Ligand B (6.669 percentile). This is a major concern for Ligand A.

**BBB:** Both ligands have good BBB penetration (67.584% and 68.321%), exceeding the 70% threshold, making them both viable for CNS targets.

**Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and suggests poor permeability. However, these values are on a scale where negative values are possible, and direct comparison is difficult without knowing the scale's specifics.

**Aqueous Solubility:** Both have negative solubility values, which is also unusual and suggests poor solubility. Similar to Caco-2, direct comparison is difficult.

**hERG:** Both ligands have low hERG inhibition liability (0.422 and 0.416), which is favorable.

**Microsomal Clearance:** Ligand A has a much higher (more negative) microsomal clearance (-17.801) than Ligand B (-9.024), indicating faster metabolism and lower metabolic stability.

**In vitro Half-Life:** Ligand B has a significantly longer in vitro half-life (7.072 hours) than Ligand A (-12.252 hours), which is a substantial advantage.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.017 and 0.018), which is excellent for CNS penetration.

**Binding Affinity:** Ligand A has a slightly better binding affinity (-9.6 kcal/mol) than Ligand B (-7.9 kcal/mol). This is a 1.7 kcal/mol difference, which is significant and could potentially outweigh some of the ADME drawbacks.

**Overall Assessment:**

While Ligand A has a slightly better binding affinity, its significantly higher DILI risk and faster metabolic clearance are major drawbacks. Ligand B has a much more favorable safety profile (DILI) and better metabolic stability (half-life), and its binding affinity is still quite good. Given the GPCR-specific priorities, and the importance of safety and metabolic stability for CNS drugs, Ligand B is the more promising candidate.

Output:
1
2025-04-17 06:42:34,270 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (365.861 and 370.471 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (61.88) is significantly better than Ligand B (92.01). For CNS targets, TPSA should be <= 90, so Ligand A is preferable.

**3. logP:** Both ligands have acceptable logP values (2.371 and 1.188), falling within the 1-3 range. Ligand A is slightly better.

**4. H-Bond Donors:** Ligand A (1) is better than Ligand B (2). Lower HBD generally improves permeability.

**5. H-Bond Acceptors:** Ligand A (3) is better than Ligand B (6). Lower HBA also generally improves permeability.

**6. QED:** Ligand A (0.894) is significantly better than Ligand B (0.635), indicating a more drug-like profile.

**7. DILI:** Ligand A (33.152) has a much lower DILI risk than Ligand B (60.682). This is a significant advantage for Ligand A.

**8. BBB:** Ligand A (77.162) has a much better BBB penetration score than Ligand B (28.848). This is *critical* for a CNS target like DRD2.

**9. Caco-2:** Ligand A (-4.523) and Ligand B (-5.439) both have negative values, which is unusual. Higher values are better, but the difference is not decisive.

**10. Solubility:** Both ligands have similar, very poor aqueous solubility (-2.627 and -2.538). This is a potential issue for both, but not a deciding factor.

**11. hERG:** Ligand A (0.581) has a slightly better hERG profile than Ligand B (0.154), indicating lower cardiotoxicity risk.

**12. Cl_mic:** Ligand A (-12.153) has a much lower (better) microsomal clearance than Ligand B (21.526), suggesting greater metabolic stability.

**13. t1/2:** Ligand B (31.879) has a significantly longer in vitro half-life than Ligand A (2.39). This is a positive for Ligand B, but may not outweigh other factors.

**14. Pgp:** Ligand A (0.082) has a much lower P-gp efflux liability than Ligand B (0.165), which is crucial for CNS penetration.

**15. Binding Affinity:** Ligand A (-7.5) has a slightly better binding affinity than Ligand B (-6.7). While both are good, the difference is not substantial enough to overcome the other advantages of Ligand A.

**Overall Assessment:**

Ligand A is significantly superior to Ligand B. It excels in key properties for a CNS-targeting GPCR ligand: TPSA, BBB penetration, DILI risk, Pgp efflux, and metabolic stability. While Ligand B has a longer half-life, Ligand A's superior ADME profile and slightly better affinity make it the more promising drug candidate.

Output:
0
2025-04-17 06:42:34,270 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight (MW):**
* Ligand A: 409.28 Da - Within the ideal range (200-500 Da).
* Ligand B: 346.427 Da - Within the ideal range (200-500 Da).
Both are acceptable.

**2. Topological Polar Surface Area (TPSA):**
* Ligand A: 64.8 - Excellent, well below the 90 A^2 threshold for CNS targets.
* Ligand B: 73.99 - Still good, below 90 A^2, but higher than A.
A is slightly better.

**3. Lipophilicity (logP):**
* Ligand A: 3.257 - Optimal (1-3).
* Ligand B: 2.027 - Optimal (1-3).
Both are good.

**4. H-Bond Donors (HBD):**
* Ligand A: 0 - Acceptable, well below the limit of 5.
* Ligand B: 1 - Acceptable, below the limit of 5.
Both are good.

**5. H-Bond Acceptors (HBA):**
* Ligand A: 6 - Acceptable, below the limit of 10.
* Ligand B: 4 - Acceptable, below the limit of 10.
Both are good.

**6. QED:**
* Ligand A: 0.683 - Good, above the 0.5 threshold.
* Ligand B: 0.909 - Excellent, well above the 0.5 threshold.
B is better.

**7. DILI:**
* Ligand A: 65.568 - Moderate risk. Above the preferred <40, but not extremely high.
* Ligand B: 21.753 - Low risk, excellent.
B is significantly better.

**8. BBB:**
* Ligand A: 77.937 - Very good, above the 70% threshold for CNS targets.
* Ligand B: 63.901 - Good, but below the 70% threshold.
A is better.

**9. Caco-2 Permeability:**
* Ligand A: -4.922 - This is a negative value, which is unusual and suggests poor permeability.
* Ligand B: -4.722 - Also negative, suggesting poor permeability, but slightly better than A.
Both are concerning, but B is marginally better.

**10. Aqueous Solubility:**
* Ligand A: -3.238 - Poor solubility.
* Ligand B: -1.731 - Poor solubility, but slightly better than A.
B is marginally better.

**11. hERG Inhibition:**
* Ligand A: 0.664 - Low risk.
* Ligand B: 0.362 - Very low risk.
B is better.

**12. Microsomal Clearance (Cl_mic):**
* Ligand A: 52.506 - Moderate clearance.
* Ligand B: 7.255 - Low clearance, indicating better metabolic stability.
B is significantly better.

**13. In vitro Half-Life (t1/2):**
* Ligand A: 29.632 - Moderate half-life.
* Ligand B: 37.574 - Good half-life.
B is better.

**14. P-gp Efflux:**
* Ligand A: 0.531 - Moderate efflux.
* Ligand B: 0.125 - Low efflux, which is desirable for CNS penetration.
B is significantly better.

**15. Binding Affinity:**
* Ligand A: -8.4 kcal/mol
* Ligand B: -8.4 kcal/mol
Affinity is identical.

**Overall Assessment:**

While both ligands have good binding affinity, Ligand B consistently outperforms Ligand A in critical ADME properties, especially those prioritized for GPCRs targeting the CNS. Ligand B has a lower DILI risk, better BBB penetration, lower P-gp efflux, better metabolic stability (lower Cl_mic and longer t1/2), and a better QED score. Although both have poor Caco-2 permeability and solubility, B is slightly better in those aspects. The superior ADME profile of Ligand B outweighs any potential benefits of Ligand A's slightly better BBB.

Output:
1
2025-04-17 06:42:34,270 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (347.35 and 354.45 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (92.43) is slightly higher than Ligand B (84.94), but both are below the 90 A^2 threshold desirable for CNS targets.

**logP:** Ligand A (0.984) is a bit low, potentially hindering permeability. Ligand B (1.518) is better, falling within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A has 0 HBD and 6 HBA, while Ligand B has 1 HBD and 5 HBA. Both are within acceptable limits (HBD <= 5, HBA <= 10).

**QED:** Ligand A (0.819) has a significantly better QED score than Ligand B (0.553), indicating better overall drug-likeness.

**DILI:** Ligand A (68.98) has a higher DILI risk than Ligand B (45.37), but both are below the concerning 60 percentile.

**BBB:** Both ligands have good BBB penetration, with Ligand A at 77.59% and Ligand B at 73.83%. Both are above the 70% threshold for CNS targets.

**Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and suggests a potential issue with the data or modeling. However, the magnitude is similar.

**Aqueous Solubility:** Both ligands have negative solubility values, indicating poor aqueous solubility. Ligand A (-1.124) is slightly better than Ligand B (-2.397).

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.108 and 0.224, respectively).

**Microsomal Clearance:** Ligand A (27.875) has a lower microsomal clearance than Ligand B (51.189), suggesting better metabolic stability.

**In vitro Half-Life:** Both have negative half-life values, which is not physically meaningful. This is likely an artifact of the modeling.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.029 and 0.034), which is excellent for CNS penetration.

**Binding Affinity:** Ligand B (-8.0 kcal/mol) has a significantly stronger binding affinity than Ligand A (-6.9 kcal/mol). This is a >1.1 kcal/mol difference, which is substantial.

**Conclusion:**

While Ligand A has better QED and slightly better solubility, Ligand B's significantly stronger binding affinity (-8.0 vs -6.9 kcal/mol) is the most crucial factor for a GPCR ligand, especially considering the acceptable BBB penetration and P-gp efflux for both. The slightly higher logP of Ligand B also favors permeability. The differences in DILI and Cl_mic are not substantial enough to outweigh the affinity advantage. The negative solubility and half-life values are concerning but may be data artifacts.

Output:
1
2025-04-17 06:42:34,271 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (356.463 and 352.475 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (87.15) is better than Ligand B (70.08), both are below the 90 A^2 threshold for CNS targets.

**logP:** Both ligands have acceptable logP values (0.901 and 1.435), falling within the 1-3 range. Ligand B is slightly better.

**H-Bond Donors/Acceptors:** Both have 1 HBD and a reasonable number of HBAs (5 and 4 respectively), satisfying the <5 HBD and <10 HBA guidelines.

**QED:** Both ligands have good QED scores (0.588 and 0.785), indicating drug-likeness. Ligand B is better.

**DILI:** Ligand A (14.541) has a significantly lower DILI risk than Ligand B (30.981). This is a substantial advantage for Ligand A.

**BBB:** Ligand A (64.715) has a better BBB penetration percentile than Ligand B (53.974), although neither are above the desirable 70% threshold.

**Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and suggests poor permeability. Ligand A (-4.161) is slightly better than Ligand B (-4.279).

**Aqueous Solubility:** Both have negative solubility values, indicating poor solubility. Ligand A (-1.256) is slightly better than Ligand B (-1.735).

**hERG Inhibition:** Both ligands have low hERG inhibition liability (0.289 and 0.474), which is good.

**Microsomal Clearance:** Ligand A (94.213) has a higher microsomal clearance than Ligand B (37.055), indicating lower metabolic stability. This is a significant disadvantage for Ligand A.

**In vitro Half-Life:** Ligand B (23.12) has a longer in vitro half-life than Ligand A (-36.403), which is a major advantage.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.07 and 0.147), which is good for CNS penetration.

**Binding Affinity:** Ligand B (-7.5 kcal/mol) has a slightly better binding affinity than Ligand A (-7.0 kcal/mol). While the difference is less than the 1.5 kcal/mol threshold to outweigh other issues, it is still a positive.

**Overall Assessment:**

Ligand A has advantages in DILI risk and slightly better BBB penetration and permeability/solubility. However, Ligand B has a significantly better in vitro half-life, better QED, and slightly better binding affinity. The major drawback of Ligand A is its higher microsomal clearance, which suggests it will be rapidly metabolized. For a CNS target, metabolic stability and reasonable half-life are crucial. While neither ligand is ideal regarding BBB penetration, Ligand B's overall profile is more favorable.

Output:
1
2025-04-17 06:42:34,271 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (347.39 and 346.471 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (71.53) is slightly higher than Ligand B (69.64). Both are below the 90 A^2 threshold desirable for CNS targets, which is good.

**3. logP:** Both ligands have good logP values (1.727 and 2.001), falling within the optimal 1-3 range.

**4. H-Bond Donors:** Ligand A has 1 HBD, and Ligand B has 2. Both are within the acceptable limit of <=5.

**5. H-Bond Acceptors:** Ligand A has 4 HBA, and Ligand B has 3. Both are within the acceptable limit of <=10.

**6. QED:** Ligand A (0.88) has a slightly better QED score than Ligand B (0.765), indicating a more drug-like profile.

**7. DILI:** Ligand A (48.623) has a higher DILI risk than Ligand B (15.471). This is a significant drawback for Ligand A.

**8. BBB:** Ligand A (82.009) has a significantly better BBB penetration percentile than Ligand B (48.197). This is a crucial factor for a CNS target like DRD2.

**9. Caco-2 Permeability:** Ligand A (-4.398) has a worse Caco-2 permeability than Ligand B (-4.953). Lower values are less desirable.

**10. Aqueous Solubility:** Ligand A (-3.029) has slightly better aqueous solubility than Ligand B (-3.652).

**11. hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.468 and 0.235).

**12. Microsomal Clearance:** Ligand B (45.286) has a lower microsomal clearance than Ligand A (27.041), suggesting better metabolic stability.

**13. In vitro Half-Life:** Ligand B (-2.264) has a significantly longer in vitro half-life than Ligand A (-33.519).

**14. P-gp Efflux:** Ligand A (0.034) has a lower P-gp efflux liability than Ligand B (0.135), which is favorable for CNS penetration.

**15. Binding Affinity:** Ligand B (-9.9 kcal/mol) has a stronger binding affinity than Ligand A (-8.8 kcal/mol). This is a substantial difference (1.1 kcal/mol), and affinity is a primary driver.

**Overall Assessment:**

Ligand A has a better BBB score and lower P-gp efflux, which are important for CNS penetration. However, it suffers from a higher DILI risk, worse metabolic stability (higher Cl_mic, shorter half-life), and weaker binding affinity. Ligand B has a significantly stronger binding affinity, lower DILI risk, better metabolic stability, and a longer half-life, outweighing its slightly lower BBB score and higher P-gp efflux. The affinity difference is particularly important for a GPCR target.

Output:
1
2025-04-17 06:42:34,271 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (351.451 and 346.475 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (122.27) is slightly above the optimal <90 for CNS targets, but still reasonable. Ligand B (67.23) is excellent, well below the 90 threshold.

**3. logP:** Ligand A (0.424) is quite low, potentially hindering membrane permeability. Ligand B (2.373) is within the optimal 1-3 range.

**4. H-Bond Donors:** Ligand A (4) is acceptable. Ligand B (1) is also good.

**5. H-Bond Acceptors:** Ligand A (6) is acceptable. Ligand B (4) is also good.

**6. QED:** Both ligands have good QED scores (0.592 and 0.771), indicating drug-like properties.

**7. DILI:** Ligand A (43.932) has a moderate DILI risk, while Ligand B (21.946) has a low DILI risk, which is preferable.

**8. BBB:** Ligand A (63.358) has a moderate BBB penetration, while Ligand B (74.874) has a good BBB penetration, exceeding the >70% threshold for CNS targets. This is a significant advantage for Ligand B.

**9. Caco-2 Permeability:** Ligand A (-5.456) has poor Caco-2 permeability. Ligand B (-4.919) also has poor Caco-2 permeability.

**10. Aqueous Solubility:** Both ligands have very poor aqueous solubility (-2.325 and -2.112). This is a concern for both.

**11. hERG Inhibition:** Both ligands have low hERG inhibition risk (0.252 and 0.284).

**12. Microsomal Clearance:** Ligand A (4.102) has lower clearance, suggesting better metabolic stability than Ligand B (34.988).

**13. In vitro Half-Life:** Ligand A (0.687) has a very short half-life. Ligand B (-1.568) also has a short half-life, but is slightly better than Ligand A.

**14. P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.022 and 0.111), which is favorable for CNS penetration.

**15. Binding Affinity:** Ligand B (-7.9 kcal/mol) has a slightly better binding affinity than Ligand A (-8.5 kcal/mol). While the difference is small, it's still a positive for Ligand B.

**Overall Assessment:**

Ligand B is the more promising candidate. While both have solubility issues and poor Caco-2 permeability, Ligand B excels in key GPCR-specific properties: better logP, significantly better BBB penetration, and a lower DILI risk. The slightly better binding affinity of Ligand B further supports this conclusion. Ligand A's low logP is a major drawback, potentially limiting its ability to cross cell membranes and reach the target in the CNS. Although Ligand A has better metabolic stability, the other factors weigh more heavily in favor of Ligand B for a CNS-targeting GPCR like DRD2.

Output:
1
2025-04-17 06:42:34,271 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (348.451 Da) is slightly preferred as it's closer to the lower end, potentially aiding permeability.

**TPSA:** Ligand A (112.66) is better than Ligand B (79.31). Both are below the 140 A^2 threshold for oral absorption, and Ligand B is even better suited for CNS penetration being below 90 A^2.

**logP:** Ligand A (1.49) is within the optimal range (1-3). Ligand B (-0.273) is slightly below 1, which could hinder permeation. This is a significant drawback for Ligand B.

**H-Bond Donors/Acceptors:** Ligand A has 3 HBD and 5 HBA, which are acceptable. Ligand B has 1 HBD and 6 HBA, also acceptable.

**QED:** Both ligands have good QED scores (A: 0.626, B: 0.701), indicating good drug-like properties.

**DILI:** Both ligands have low DILI risk (A: 49.632, B: 39.899), which is positive.

**BBB:** Ligand B (76.658) has a significantly better BBB percentile than Ligand A (62.699). This is a crucial advantage for a CNS target like DRD2.

**Caco-2 Permeability:** Ligand A (-5.476) has poor Caco-2 permeability, indicating poor intestinal absorption. Ligand B (-4.773) is also poor, but slightly better than Ligand A.

**Aqueous Solubility:** Both ligands have poor aqueous solubility (A: -2.362, B: -1.602).

**hERG Inhibition:** Both ligands have very low hERG inhibition risk (A: 0.051, B: 0.228).

**Microsomal Clearance:** Ligand B (13.664) has lower microsomal clearance than Ligand A (26.335), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (-12.235) has a negative half-life, which is concerning. Ligand B (-7.284) is also negative, but less so.

**P-gp Efflux:** Both ligands have low P-gp efflux (A: 0.045, B: 0.053), which is favorable for CNS penetration.

**Binding Affinity:** Ligand A (-8.2 kcal/mol) has a stronger binding affinity than Ligand B (-6.6 kcal/mol). This is a substantial advantage, exceeding the 1.5 kcal/mol threshold.

**Overall Assessment:**

Ligand A has a significantly better binding affinity, which is paramount for GPCR targets. However, its poor Caco-2 permeability and negative in vitro half-life are major concerns. Ligand B has better BBB penetration, metabolic stability, and a slightly better Caco-2 permeability, but its lower logP and weaker binding affinity are drawbacks.

Considering the GPCR-specific priorities, the strong binding affinity of Ligand A is the most important factor. While the ADME properties are not ideal, they might be optimized further through medicinal chemistry efforts. The difference in binding affinity (-8.2 vs -6.6) is substantial and likely outweighs the ADME concerns, especially given the low P-gp efflux for both.

Output:
1
2025-04-17 06:42:34,271 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (352.45 and 345.49 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (58.64) is significantly better than Ligand B (64.41). For CNS targets, we want TPSA <= 90, and ideally closer to 60. Ligand A is closer to this ideal.

**3. logP:** Both ligands have good logP values (2.072 and 2.812), falling within the optimal 1-3 range. Ligand B is slightly higher, which could potentially lead to off-target effects, but it's not a major concern.

**4. H-Bond Donors:** Ligand A has 1 HBD, and Ligand B has 0. Both are acceptable (<=5).

**5. H-Bond Acceptors:** Both ligands have 3 HBAs, which is well within the acceptable limit of <=10.

**6. QED:** Both ligands have similar QED values (0.771 and 0.679), both above the 0.5 threshold, indicating good drug-like properties.

**7. DILI:** Ligand A (21.4%) has a slightly higher DILI risk than Ligand B (18.4%), but both are well below the concerning threshold of 60%.

**8. BBB:** This is a critical parameter for a CNS target like DRD2. Ligand A has a significantly higher BBB penetration percentile (95.66%) compared to Ligand B (78.98%). This is a major advantage for Ligand A.

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.497 and -4.591). These values are unusual and suggest poor permeability. However, Caco-2 values can be unreliable and are less important than BBB for CNS targets.

**10. Aqueous Solubility:** Both ligands have negative solubility values (-2.96 and -3.093). Similar to Caco-2, these are unusual and suggest poor solubility. Solubility can be improved with formulation strategies.

**11. hERG Inhibition:** Both ligands have low hERG inhibition liability (0.665 and 0.609), which is good.

**12. Microsomal Clearance:** Ligand B (58.325) has a significantly lower microsomal clearance than Ligand A (22.35). Lower clearance indicates better metabolic stability, which is a positive.

**13. In vitro Half-Life:** Ligand B (-9.981) has a longer in vitro half-life than Ligand A (-7.957). This is also a positive for Ligand B.

**14. P-gp Efflux:** Both ligands have low P-gp efflux liability (0.134 and 0.384), which is favorable for CNS penetration.

**15. Binding Affinity:** Ligand A (-8.9 kcal/mol) has a slightly better binding affinity than Ligand B (-7.7 kcal/mol). This 1.2 kcal/mol difference is significant and can outweigh some ADME drawbacks.

**Overall Assessment:**

Ligand A is the stronger candidate. While Ligand B has better metabolic stability and half-life, Ligand A's superior BBB penetration (95.7% vs 78.9%), lower TPSA, and slightly better binding affinity are more critical for a CNS-targeting GPCR like DRD2. The solubility and permeability concerns are present in both, but can potentially be addressed through formulation. The slightly higher DILI risk for Ligand A is not a major concern given its other favorable properties.

Output:
1
2025-04-17 06:42:34,271 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (345.418 and 351.422 Da).

**TPSA:** Ligand A (53.51) is significantly better than Ligand B (62.74). For CNS targets, we want TPSA <= 90, both are within this range, but A is closer to the optimal < 60 range.

**logP:** Both ligands have acceptable logP values (2.575 and 1.45), falling within the 1-3 range. Ligand A is slightly better.

**H-Bond Donors/Acceptors:** Both have 0 HBD and 4 HBA, which are reasonable.

**QED:** Both ligands have good QED scores (0.787 and 0.64), indicating drug-like properties.

**DILI:** Ligand A has a higher DILI risk (64.327%) than Ligand B (23.226%). This is a significant drawback for Ligand A.

**BBB:** Both ligands have excellent BBB penetration (90.074% and 87.941%).

**Caco-2 Permeability:** Both have negative Caco-2 values which is unusual and suggests poor permeability.

**Aqueous Solubility:** Both have negative solubility values which is also unusual and suggests poor solubility.

**hERG:** Both ligands have low hERG inhibition risk (0.41 and 0.479).

**Microsomal Clearance:** Ligand A has higher microsomal clearance (66.905) than Ligand B (22.46), indicating lower metabolic stability.

**In vitro Half-Life:** Ligand B has a much longer in vitro half-life (6.336 hours) compared to Ligand A (-35.375 hours, which is nonsensical and likely an error).

**P-gp Efflux:** Both have low P-gp efflux liability (0.526 and 0.069).

**Binding Affinity:** Ligand B has a better binding affinity (-7.4 kcal/mol) than Ligand A (-8.2 kcal/mol). While A is slightly better, the difference is not substantial enough to outweigh other factors.

**Overall Assessment:**

Ligand B is the more promising candidate. While Ligand A has slightly better TPSA and logP, Ligand B has a significantly lower DILI risk, much better metabolic stability (lower Cl_mic, positive t1/2), and a better binding affinity. The negative Caco-2 and solubility values are concerning for both, but the other ADME properties of Ligand B are superior.

Output:
1
2025-04-17 06:42:34,272 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (393.412 and 386.363 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (88.16) is better than Ligand B (29.54). For CNS targets, a TPSA <= 90 is preferred. Ligand A is close to the upper limit, while Ligand B is well within.

**3. logP:** Ligand A (2.294) is optimal (1-3), while Ligand B (4.875) is slightly high. High logP can lead to solubility issues and off-target effects.

**4. H-Bond Donors:** Ligand A (2) is good, while Ligand B (0) is also acceptable.

**5. H-Bond Acceptors:** Ligand A (6) is good, while Ligand B (2) is also acceptable.

**6. QED:** Ligand A (0.786) is excellent, indicating good drug-like properties. Ligand B (0.537) is acceptable but less ideal.

**7. DILI:** Ligand A (88.251) has a higher DILI risk than Ligand B (12.796). This is a significant drawback for Ligand A.

**8. BBB:** Ligand B (83.986) has a significantly better BBB penetration score than Ligand A (53.742). This is *crucial* for a CNS target like DRD2.

**9. Caco-2 Permeability:** Ligand A (-5.249) has poor Caco-2 permeability, indicating poor intestinal absorption. Ligand B (-4.422) is also poor, but slightly better.

**10. Aqueous Solubility:** Ligand A (-3.144) has poor aqueous solubility. Ligand B (-5.426) is even worse.

**11. hERG Inhibition:** Ligand A (0.258) is better than Ligand B (0.892), indicating a lower risk of cardiotoxicity.

**12. Microsomal Clearance:** Ligand A (13.883) has lower clearance, suggesting better metabolic stability than Ligand B (102.043).

**13. In vitro Half-Life:** Ligand A (54.995) has a longer half-life than Ligand B (28.044).

**14. P-gp Efflux:** Ligand A (0.238) has lower P-gp efflux, which is favorable for CNS penetration, compared to Ligand B (0.683).

**15. Binding Affinity:** Ligand B (-7.0) has a slightly better binding affinity than Ligand A (-8.7). While A is better, the difference is less than the 1.5kcal/mol threshold.

**Overall Assessment:**

Despite Ligand A having a slightly better binding affinity and better metabolic stability, Ligand B is the more promising candidate. The significantly better BBB penetration (83.986 vs. 53.742) and much lower DILI risk (12.796 vs. 88.251) outweigh the minor advantages of Ligand A. The poor solubility and permeability of both are concerning, but can be addressed with formulation strategies. For a CNS target, BBB penetration is paramount, and Ligand B excels in this area.

Output:
1
2025-04-17 06:42:34,272 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (348.451 Da) is slightly lower, which can be beneficial for permeability.

**TPSA:** Ligand A (97.35) is better than Ligand B (66.91) as it is closer to the ideal range for CNS targets (<=90).

**logP:** Ligand A (0.746) is suboptimal, being slightly below the preferred range of 1-3. Ligand B (4.054) is high, potentially leading to solubility issues and off-target effects.

**H-Bond Donors/Acceptors:** Ligand A (HBD=1, HBA=6) is better than Ligand B (HBD=2, HBA=4) as it is closer to the ideal range.

**QED:** Ligand A (0.847) has a better QED score than Ligand B (0.539), indicating a more drug-like profile.

**DILI:** Both ligands have similar, acceptable DILI risk (Ligand A: 35.595, Ligand B: 36.293).

**BBB:** Both ligands have good BBB penetration (Ligand A: 71.733, Ligand B: 78.48). Ligand B is slightly better, but both are above the 70% threshold.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.125 and -5.105), which is unusual and suggests poor permeability. This is a significant concern for both.

**Aqueous Solubility:** Both ligands have negative solubility values (-1.339 and -3.517), indicating poor aqueous solubility. Ligand B is worse.

**hERG Inhibition:** Ligand A (0.088) has a much lower hERG inhibition risk than Ligand B (0.551), which is a significant advantage.

**Microsomal Clearance:** Ligand A (16.536) has a lower microsomal clearance than Ligand B (53.614), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand B (99.545) has a significantly longer in vitro half-life than Ligand A (-13.345). This is a major advantage for Ligand B.

**P-gp Efflux:** Ligand A (0.035) has a much lower P-gp efflux liability than Ligand B (0.51), which is crucial for CNS penetration.

**Binding Affinity:** Ligand B (-8.3) has a slightly better binding affinity than Ligand A (-7.9), but the difference is relatively small (0.4 kcal/mol).

**Overall Assessment:**

Ligand A is preferable despite the slightly weaker binding affinity. Its superior TPSA, QED, lower logP, lower hERG risk, lower P-gp efflux, and better metabolic stability outweigh the small difference in binding affinity. The negative Caco-2 and solubility values are concerning for both, but Ligand A is better in this regard. The longer half-life of Ligand B is attractive, but the other ADME properties of Ligand A are more favorable for a CNS-targeting GPCR ligand.

Output:
0
2025-04-17 06:42:34,272 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (359.495 and 368.455 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (73.2) is significantly better than Ligand B (107.89). For CNS targets, we want TPSA <= 90, and A is comfortably within this range, while B is above.

**logP:** Ligand A (3.026) is optimal (1-3). Ligand B (-0.166) is quite low, potentially hindering permeation.

**H-Bond Donors/Acceptors:** Ligand A (1 HBD, 4 HBA) is preferable to Ligand B (4 HBD, 6 HBA). Both are within acceptable limits, but fewer H-bonds generally improve permeability.

**QED:** Both ligands have reasonable QED scores (0.901 and 0.508), indicating good drug-like properties.

**DILI:** Both ligands have acceptable DILI risk (50.136 and 42.536), below the 60 threshold.

**BBB:** This is crucial for a CNS target. Ligand A (60.682) is moderate, while Ligand B (13.726) is very poor.

**Caco-2 Permeability:** Ligand A (-4.989) is poor, while Ligand B (-5.993) is also poor. This isn't ideal, but not a primary concern given the other factors.

**Aqueous Solubility:** Ligand A (-3.464) and Ligand B (-2.054) are both poor. Solubility is a concern, but can often be addressed through formulation.

**hERG:** Both ligands have low hERG risk (0.604 and 0.12).

**Microsomal Clearance:** Ligand A (21.015) is higher than Ligand B (5.371), indicating faster metabolism and lower *in vivo* exposure.

**In vitro Half-Life:** Ligand B (9.022) has a much longer half-life than Ligand A (1.511).

**P-gp Efflux:** Ligand A (0.297) has lower P-gp efflux than Ligand B (0.031), which is positive for CNS penetration.

**Binding Affinity:** Ligand A (-8.8 kcal/mol) has a significantly stronger binding affinity than Ligand B (-7.7 kcal/mol). This >1.5 kcal/mol difference is a major advantage.

**Overall Assessment:**

Ligand A is significantly better despite the slightly higher Cl_mic and lower half-life. The superior TPSA, logP, BBB penetration, and *much* stronger binding affinity outweigh the drawbacks. Ligand B's poor logP and extremely low BBB penetration are major liabilities for a CNS-targeted GPCR. The longer half-life of B is a benefit, but not enough to overcome its other weaknesses.

Output:
1
2025-04-17 06:42:34,272 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B based on the provided guidelines, prioritizing GPCR-specific properties (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (354.4 & 365.5 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (116.84) is slightly higher than Ligand B (107.19), but both are below the 140 threshold for oral absorption and reasonably close to the 90 target for CNS penetration. Ligand B is preferable here.

**logP:** Ligand A (-0.47) is a bit low, potentially hindering permeation. Ligand B (0.455) is better, falling within the optimal 1-3 range. This favors Ligand B.

**H-Bond Donors/Acceptors:** Both ligands have 3 HBDs and 5 HBAs, which are acceptable.

**QED:** Ligand B (0.58) has a better QED score than Ligand A (0.362), indicating a more drug-like profile.

**DILI:** Ligand A (42.8) has a lower DILI risk than Ligand B (56.8), which is preferable.

**BBB:** Ligand A (78.79) has a significantly better BBB penetration percentile than Ligand B (66.615). This is a crucial advantage for a CNS target like DRD2.

**Caco-2 Permeability:** Both have negative values, indicating poor permeability. Ligand A (-5.308) is slightly better than Ligand B (-5.818).

**Aqueous Solubility:** Both have negative values, indicating poor solubility. Ligand A (-1.595) is slightly better than Ligand B (-2.849).

**hERG:** Ligand A (0.054) has a lower hERG inhibition liability than Ligand B (0.339), which is preferable.

**Microsomal Clearance:** Ligand A (16.009) has lower microsomal clearance than Ligand B (21.424), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (2.063) has a positive half-life, whereas Ligand B (-17.122) has a negative half-life. This is a significant advantage for Ligand A.

**P-gp Efflux:** Ligand A (0.006) has a much lower P-gp efflux liability than Ligand B (0.026), which is crucial for CNS exposure.

**Binding Affinity:** Ligand A (-7.5 kcal/mol) has a slightly better binding affinity than Ligand B (-6.6 kcal/mol), though both are good.

**Overall Assessment:**

Ligand A excels in BBB penetration, P-gp efflux, metabolic stability, and binding affinity, all critical for a CNS-targeting GPCR. While Ligand B has a slightly better logP and QED, the superior CNS properties of Ligand A outweigh these benefits. The slightly lower DILI risk of Ligand A is also a plus.

Output:
1
2025-04-17 06:42:34,273 - INFO - Batch 304 complete. Total preferences: 4864
2025-04-17 06:42:34,273 - INFO - Processing batch 305/512...
2025-04-17 06:43:18,118 - INFO - Reasoning:

Let's analyze Ligand A and Ligand B based on the provided guidelines, prioritizing GPCR-specific properties (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (344.46 and 357.43 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (75.19) is significantly better than Ligand B (98.74). For CNS targets, TPSA should be <= 90, and A is comfortably within this range, while B is close to the upper limit.

**logP:** Ligand A (2.329) is optimal (1-3). Ligand B (-0.022) is below 1, which could hinder permeation.

**H-Bond Donors/Acceptors:** Ligand A (HBD=1, HBA=4) and Ligand B (HBD=3, HBA=4) are both acceptable, falling within the recommended limits.

**QED:** Ligand A (0.824) is excellent, indicating high drug-likeness. Ligand B (0.532) is acceptable but less favorable.

**DILI:** Ligand A (31.563) has a lower DILI risk than Ligand B (45.25). Both are below the concerning threshold of 60, but A is preferable.

**BBB:** Ligand A (74.292) shows good BBB penetration, exceeding the 70% threshold for CNS targets. Ligand B (47.809) is considerably lower, posing a significant concern for CNS exposure.

**Caco-2 Permeability:** Ligand A (-5.029) and Ligand B (-4.749) have negative values, which are difficult to interpret without knowing the scale. However, they are similar.

**Aqueous Solubility:** Both ligands have negative solubility values (-2.139 and -1.751), indicating poor aqueous solubility. This is a concern for both, but not a deciding factor.

**hERG Inhibition:** Ligand A (0.146) has a much lower hERG inhibition liability than Ligand B (0.493), which is a significant advantage.

**Microsomal Clearance:** Ligand A (31.69) has lower microsomal clearance than Ligand B (40.732), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (-9.413) has a negative half-life, which is difficult to interpret. Ligand B (-31.209) is also negative and worse.

**P-gp Efflux:** Ligand A (0.019) has very low P-gp efflux liability, which is excellent for CNS penetration. Ligand B (0.216) is higher, potentially reducing CNS exposure.

**Binding Affinity:** Ligand A (-8.5 kcal/mol) has a stronger binding affinity than Ligand B (-7.2 kcal/mol). The difference is 1.3 kcal/mol, which is substantial enough to potentially outweigh some ADME drawbacks.

**Overall Assessment:**

Ligand A is clearly superior. It excels in key GPCR-relevant properties: TPSA, logP, BBB penetration, P-gp efflux, and binding affinity. It also demonstrates a better safety profile (lower DILI, lower hERG). While both have solubility concerns, Ligand A's overall profile is much more favorable for development as a CNS-active drug targeting DRD2.

Output:
1
2025-04-17 06:43:18,118 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (347.459 and 346.431 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (45.25) is significantly better than Ligand B (95.42). For CNS targets, TPSA should be <= 90, and A is comfortably within this range, while B is borderline and less favorable.

**3. logP:** Both ligands have good logP values (1.316 and 1.055), falling within the optimal 1-3 range.

**4. H-Bond Donors:** Ligand A (0) is preferable to Ligand B (2). Fewer HBDs generally improve permeability.

**5. H-Bond Acceptors:** Both have 5 HBA, which is acceptable (<=10).

**6. QED:** Both have good QED scores (0.804 and 0.831), indicating drug-like properties.

**7. DILI:** Ligand A (34.82) has a lower DILI risk than Ligand B (44.513), both are acceptable (<40 is good, >60 is high risk).

**8. BBB:** This is a critical parameter for CNS targets. Ligand A (80.884) has a much higher BBB percentile than Ligand B (52.811). A value >70 is desirable, and A is closer to this threshold.

**9. Caco-2 Permeability:** Both have negative values, which is unusual. However, the magnitude of the negative value for Ligand A (-4.37) is less than that of Ligand B (-4.984), suggesting slightly better permeability.

**10. Aqueous Solubility:** Both have negative solubility values, which is also unusual. Ligand A (-1.067) is slightly better than Ligand B (-1.798).

**11. hERG Inhibition:** Both ligands show low hERG inhibition liability (0.671 and 0.174), which is good.

**12. Microsomal Clearance:** Ligand A (3.428) has lower microsomal clearance than Ligand B (15.793), indicating better metabolic stability.

**13. In vitro Half-Life:** Ligand A (15.505) has a longer in vitro half-life than Ligand B (-4.651), which is desirable.

**14. P-gp Efflux:** Ligand A (0.05) has lower P-gp efflux liability than Ligand B (0.035), suggesting better CNS exposure.

**15. Binding Affinity:** Both ligands have excellent binding affinities (-8.0 and -6.9 kcal/mol). Ligand A is 1.1 kcal/mol more potent, which is a significant advantage.

**Overall Assessment:**

Ligand A consistently outperforms Ligand B across most crucial parameters, especially those prioritized for GPCRs targeting the CNS. Its superior BBB penetration, lower TPSA, better metabolic stability (lower Cl_mic, longer t1/2), lower P-gp efflux, and significantly stronger binding affinity make it a much more promising drug candidate. While both have unusual solubility and Caco-2 values, the other advantages of A outweigh these concerns.

Output:
1
2025-04-17 06:43:18,119 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (347.415 Da) is slightly lower, which is generally favorable for permeability. Ligand B (389.283 Da) is also acceptable.

**TPSA:** Ligand A (93.46) is better than Ligand B (74.77) as it is closer to the ideal range for CNS targets (<=90).

**logP:** Both ligands have good logP values (Ligand A: 1.656, Ligand B: 1.299), falling within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A has 2 HBD and 5 HBA, while Ligand B has 1 HBD and 5 HBA. Both are within acceptable limits (<=5 HBD, <=10 HBA).

**QED:** Both ligands have similar QED values (Ligand A: 0.732, Ligand B: 0.712), indicating good drug-like properties.

**DILI:** Both ligands have acceptable DILI risk (Ligand A: 46.413, Ligand B: 49.593), well below the 60 threshold.

**BBB:** Ligand A (58.007) is lower than Ligand B (66.072). For a CNS target like DRD2, a higher BBB percentile is preferred.

**Caco-2 Permeability:** Ligand A (-5.318) and Ligand B (-4.723) both have negative values, which is unusual. Lower values indicate poor permeability.

**Aqueous Solubility:** Both ligands have negative solubility values (Ligand A: -1.086, Ligand B: -2.543), which is concerning.

**hERG Inhibition:** Both ligands have very low hERG inhibition risk (Ligand A: 0.118, Ligand B: 0.447).

**Microsomal Clearance:** Ligand A (7.026) has significantly lower microsomal clearance than Ligand B (14.596), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand B (7.957) has a slightly longer half-life than Ligand A (6.554).

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (Ligand A: 0.058, Ligand B: 0.013).

**Binding Affinity:** Ligand A (-7.9 kcal/mol) has a slightly better binding affinity than Ligand B (-8.0 kcal/mol). While the difference is small, it is still a factor.

**Overall Assessment:**

Considering the GPCR-specific priorities, Ligand A is slightly favored. While Ligand B has a better BBB penetration, Ligand A has a better TPSA, lower microsomal clearance (better metabolic stability), and comparable binding affinity. The solubility and Caco-2 permeability are poor for both, but the better metabolic stability of Ligand A is a significant advantage for a CNS drug.

Output:
1
2025-04-17 06:43:18,119 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B based on the provided guidelines, prioritizing GPCR-specific properties (BBB, logP, Pgp, TPSA, and affinity) for DRD2.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (396.292 Da) is slightly higher than Ligand B (351.451 Da), but both are acceptable.

**TPSA:** Ligand A (58.53) is excellent for CNS penetration, well below the 90 A^2 threshold. Ligand B (101.56) is higher, but still potentially acceptable, though less optimal for CNS targets.

**logP:** Ligand A (4.109) is a bit high, potentially leading to solubility issues and off-target effects. Ligand B (-0.32) is too low, which could hinder membrane permeability and reduce CNS exposure.

**H-Bond Donors/Acceptors:** Ligand A (2 HBD, 4 HBA) and Ligand B (3 HBD, 5 HBA) both fall within acceptable ranges.

**QED:** Both ligands have good QED scores (A: 0.534, B: 0.596), indicating good drug-like properties.

**DILI:** Ligand A (72.858) has a higher DILI risk than Ligand B (15.51), which is a significant concern.

**BBB:** Ligand A (68.282) has a reasonably good BBB penetration percentile, while Ligand B (16.363) is very poor. This is a critical factor for a DRD2 ligand.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.532 and -5.602), which is unusual and suggests poor permeability. However, these values are on a scale where negative values are possible and don't necessarily disqualify a compound.

**Aqueous Solubility:** Both ligands have very poor aqueous solubility (-4.124 and -0.83). This is a concern, especially given Ligand A's already high logP.

**hERG Inhibition:** Ligand A (0.848) has a slightly higher hERG risk than Ligand B (0.069), but both are relatively low.

**Microsomal Clearance:** Ligand B (-9.064) has a negative clearance, which is not physically possible and indicates a highly stable compound. Ligand A (37.816) has a moderate clearance.

**In vitro Half-Life:** Ligand B (-26.203) has a negative half-life, which is not physically possible. Ligand A (28.953) has a reasonable half-life.

**P-gp Efflux:** Ligand A (0.667) has moderate P-gp efflux, while Ligand B (0.003) has very low P-gp efflux. This is favorable for CNS penetration.

**Binding Affinity:** Ligand A (-10.2 kcal/mol) has significantly stronger binding affinity than Ligand B (-7.5 kcal/mol). This is a substantial advantage.

**Overall Assessment:**

Ligand A has a much stronger binding affinity, a reasonable BBB score, and acceptable H-bond properties. However, it suffers from a higher DILI risk, high logP, and poor solubility. Ligand B has a lower DILI risk and better P-gp efflux, but its BBB penetration is very poor, its logP is too low, and its affinity is significantly weaker.

Despite the drawbacks, the significantly higher binding affinity of Ligand A, coupled with its acceptable (though not ideal) BBB score, makes it the more promising candidate. The potency advantage is likely to outweigh the ADME liabilities, especially if solubility can be improved through formulation strategies. The negative values for Caco-2 and half-life for Ligand B are concerning and suggest potential issues with the data or the compound itself.

Output:
1
2025-04-17 06:43:18,119 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (352.395 and 358.404 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (111.73) is better than Ligand B (49.41) as it is closer to the <90 A^2 threshold for CNS targets. Ligand B is still acceptable, but A is preferable.

**logP:** Ligand A (-1.489) is a bit low, potentially hindering permeability. Ligand B (2.32) is within the optimal 1-3 range. This is a significant advantage for Ligand B.

**H-Bond Donors/Acceptors:** Both have acceptable HBD (1) and HBA (6/2) counts, well within the guidelines.

**QED:** Both ligands have good QED scores (0.599 and 0.839), indicating good drug-like properties.

**DILI:** Ligand A (65.568) has a higher DILI risk than Ligand B (15.355). This is a clear advantage for Ligand B.

**BBB:** Ligand B (90.074) is significantly better than Ligand A (49.593) in terms of predicted BBB penetration, which is crucial for a CNS target like DRD2.

**Caco-2 Permeability:** Ligand A (-5.418) and Ligand B (-4.916) have similar, poor Caco-2 permeability.

**Aqueous Solubility:** Ligand A (-0.899) and Ligand B (-3.179) both have poor aqueous solubility.

**hERG:** Ligand A (0.027) has a very low hERG risk, while Ligand B (0.492) is slightly higher but still acceptable.

**Microsomal Clearance:** Ligand A (-11.905) has a much lower (better) microsomal clearance than Ligand B (4.388), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (-19.917) has a much longer half-life than Ligand B (1.423), which is desirable.

**P-gp Efflux:** Ligand A (0.004) has very low P-gp efflux, while Ligand B (0.069) is slightly higher. Lower is better for CNS exposure.

**Binding Affinity:** Ligand B (-8.7 kcal/mol) has a stronger binding affinity than Ligand A (-7.6 kcal/mol). This 1.1 kcal/mol difference is substantial and can outweigh some of the ADME drawbacks of Ligand B.

**Overall Assessment:**

Ligand B excels in key areas for a CNS-targeting GPCR ligand: strong binding affinity, excellent BBB penetration, and low DILI risk. While its logP is good and TPSA is acceptable, its solubility, Caco-2 permeability, and metabolic stability are less ideal. However, the strong affinity and BBB penetration are critical for DRD2, and the difference in binding energy is significant. Ligand A has better metabolic stability and lower P-gp efflux, but its poor BBB penetration and lower affinity are major drawbacks.

Output:
1
2025-04-17 06:43:18,119 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (347.342 and 369.575 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (84.86) is better than Ligand B (52.65). Both are below the 90 A^2 threshold desirable for CNS targets, but A is closer to the upper limit.

**logP:** Both ligands (2.056 and 2.357) are within the optimal 1-3 range.

**H-Bond Donors:** Ligand A (2) is slightly higher than Ligand B (1), but both are acceptable (<=5).

**H-Bond Acceptors:** Ligand A (5) is slightly higher than Ligand B (4), but both are acceptable (<=10).

**QED:** Both ligands have good QED scores (0.592 and 0.678), indicating good drug-like properties.

**DILI:** Ligand A (58.589) has a higher DILI risk than Ligand B (8.026). This is a significant drawback for Ligand A.

**BBB:** Ligand B (76.347) has a significantly better BBB penetration percentile than Ligand A (57.852). This is crucial for a CNS target like DRD2.

**Caco-2 Permeability:** Ligand A (-4.841) has worse Caco-2 permeability than Ligand B (-5.018), but both are very poor.

**Aqueous Solubility:** Ligand A (-3.594) has worse aqueous solubility than Ligand B (-2.246), but both are very poor.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.694 and 0.579).

**Microsomal Clearance:** Ligand B (61.057) has lower microsomal clearance than Ligand A (89.331), indicating better metabolic stability.

**In vitro Half-Life:** Ligand B (11.014) has a much longer in vitro half-life than Ligand A (-25.566). This is a significant advantage for Ligand B.

**P-gp Efflux:** Ligand A (0.271) has lower P-gp efflux than Ligand B (0.02). This is a positive for Ligand A, suggesting better CNS exposure.

**Binding Affinity:** Ligand A (-9.3) has a significantly stronger binding affinity than Ligand B (-6.7). This is a substantial advantage for Ligand A.

**Overall Assessment:**

While Ligand A boasts a superior binding affinity, its significantly higher DILI risk, poorer BBB penetration, worse metabolic stability, and shorter half-life are major concerns. Ligand B, despite a weaker binding affinity, presents a much more favorable ADMET profile, particularly its excellent BBB penetration, low DILI risk, and improved metabolic stability. The difference in binding affinity (-2.6 kcal/mol) is substantial, but the ADMET advantages of Ligand B are likely to outweigh this difference, especially considering the importance of CNS penetration and safety for a DRD2 targeting drug.

Output:
1
2025-04-17 06:43:18,119 - INFO - Reasoning:

Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (355.322 Da) is slightly lower, which is generally favorable for permeability. Ligand B (367.519 Da) is also good.

**TPSA:** Ligand A (121.22) is borderline for CNS penetration, being slightly above the preferred <90 threshold. Ligand B (61.68) is excellent for CNS penetration. This is a significant advantage for Ligand B.

**logP:** Ligand A (-1.357) is a bit low, potentially hindering membrane permeability. Ligand B (0.317) is closer to the optimal range (1-3), but still on the lower side.

**H-Bond Donors/Acceptors:** Ligand A has 3 HBD and 7 HBA, which are acceptable. Ligand B has 0 HBD and 6 HBA, also acceptable.

**QED:** Both ligands have similar QED values (0.612 and 0.65), indicating good drug-likeness.

**DILI:** Ligand A (71.345) has a higher DILI risk than Ligand B (21.753). This is a clear advantage for Ligand B.

**BBB:** Ligand B (59.946) has a significantly better BBB penetration percentile than Ligand A (29.74). This is crucial for a CNS target like DRD2.

**Caco-2 Permeability:** Both have negative Caco-2 values which is unusual and suggests a potential issue with the data. However, the magnitude of the negative value for Ligand A (-5.036) is larger than Ligand B (-5.216), suggesting slightly better permeability for Ligand B.

**Aqueous Solubility:** Both have negative solubility values, which is also unusual. Ligand A (-1.641) is slightly better than Ligand B (-0.445).

**hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.071 and 0.274).

**Microsomal Clearance:** Ligand A (-20.244) has a much lower (better) microsomal clearance than Ligand B (19.427), indicating better metabolic stability.

**In vitro Half-Life:** Ligand A (-33.097) has a much longer in vitro half-life than Ligand B (-11.401). This is a significant advantage for Ligand A.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.004 and 0.028).

**Binding Affinity:** Ligand A (-8.8 kcal/mol) has a significantly stronger binding affinity than Ligand B (-6.2 kcal/mol). This is a substantial advantage for Ligand A, potentially outweighing some of its ADME drawbacks.

**Overall Assessment:**

While Ligand A has superior binding affinity and metabolic stability, Ligand B excels in properties critical for CNS penetration (TPSA, BBB, and lower DILI). The significantly stronger binding affinity of Ligand A (-8.8 vs -6.2 kcal/mol) is a major factor. The difference of 2.6 kcal/mol is substantial and can often compensate for less-than-ideal ADME properties, especially given the low hERG risk for both compounds. The lower TPSA and better BBB of Ligand B are attractive, but the affinity difference is too large to ignore.

Output:
0
2025-04-17 06:43:18,119 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (350.547 and 347.503 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (49.41) is better than Ligand B (43.86). Both are below the 90 A^2 threshold desirable for CNS targets, which is excellent.

**3. logP:** Ligand A (4.138) is slightly higher than the optimal range (1-3) but still potentially acceptable. Ligand B (2.134) is well within the optimal range.

**4. H-Bond Donors:** Ligand A (1) is better than Ligand B (0). Both are within the acceptable limit of <=5.

**5. H-Bond Acceptors:** Ligand A (2) is better than Ligand B (3). Both are within the acceptable limit of <=10.

**6. QED:** Both ligands have the same QED score (0.732), indicating good drug-likeness.

**7. DILI:** Ligand B (10.237) has a significantly lower DILI risk than Ligand A (22.722), which is a major advantage.

**8. BBB:** Both ligands show excellent BBB penetration (Ligand A: 82.474, Ligand B: 85.731), exceeding the >70% threshold for CNS targets. Ligand B is slightly better.

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.688 and -4.758), which is unusual and suggests poor permeability. However, these values are on a log scale and are difficult to interpret without more context.

**10. Aqueous Solubility:** Both ligands have negative solubility values (-3.374 and -1.74), indicating poor aqueous solubility. This is a concern for bioavailability. Ligand B is slightly better.

**11. hERG Inhibition:** Both ligands have low hERG inhibition risk (0.699 and 0.587).

**12. Microsomal Clearance:** Ligand B (23.813) has significantly lower microsomal clearance than Ligand A (67.607), indicating better metabolic stability.

**13. In vitro Half-Life:** Ligand B (-11.893) has a slightly better in vitro half-life than Ligand A (-12.669).

**14. P-gp Efflux:** Ligand A (0.503) has better P-gp efflux properties than Ligand B (0.127), meaning it is less likely to be pumped out of the brain, which is crucial for CNS targets.

**15. Binding Affinity:** Ligand B (-9.9 kcal/mol) has a *much* stronger binding affinity than Ligand A (-0.0 kcal/mol). This is a decisive advantage, as a >1.5 kcal/mol difference can outweigh other drawbacks.

**Overall Assessment:**

While Ligand A has slightly better TPSA and P-gp efflux, Ligand B excels in almost every other critical parameter. The significantly lower DILI risk, better metabolic stability (lower Cl_mic, better t1/2), and, most importantly, *vastly* superior binding affinity make Ligand B the far more promising drug candidate. The negative Caco-2 and solubility values are concerning for both, but the strong affinity of Ligand B suggests it might overcome these issues.

Output:
1
2025-04-17 06:43:18,119 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (346.435 Da) is slightly lower, which could be advantageous for permeability.

**TPSA:** Ligand A (92.15) is better than Ligand B (76.88) as it is closer to the desirable threshold of <=90 for CNS targets.

**logP:** Ligand B (2.939) is optimal (1-3), while Ligand A (-0.074) is below 1, potentially hindering permeation. This is a significant drawback for Ligand A.

**H-Bond Donors/Acceptors:** Ligand A (2 HBD, 6 HBA) and Ligand B (1 HBD, 7 HBA) both fall within acceptable ranges.

**QED:** Both ligands have good QED scores (A: 0.703, B: 0.747), indicating drug-like properties.

**DILI:** Ligand A (32.261) has a much lower DILI risk than Ligand B (61.497), which is a significant advantage.

**BBB:** Ligand B (62.156) has a better BBB penetration percentile than Ligand A (53.083), but neither are above the highly desirable >70 threshold.

**Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and potentially problematic. However, the scale is not specified, so it's difficult to interpret.

**Aqueous Solubility:** Both have negative solubility values, which is also concerning. Again, the scale is unknown.

**hERG:** Ligand A (0.067) shows a lower hERG inhibition liability than Ligand B (0.367), which is favorable.

**Microsomal Clearance:** Ligand A (-17.575) has a much lower (better) microsomal clearance than Ligand B (9.447), indicating greater metabolic stability.

**In vitro Half-Life:** Ligand B (63.791) has a significantly longer in vitro half-life than Ligand A (-11.029), which is a positive attribute.

**P-gp Efflux:** Ligand A (0.012) has much lower P-gp efflux liability than Ligand B (0.279), which is crucial for CNS penetration.

**Binding Affinity:** Ligand B (-9 kcal/mol) has a stronger binding affinity than Ligand A (-7 kcal/mol). This is a substantial advantage, potentially outweighing some ADME concerns.

**Overall Assessment:**

Ligand B has a better binding affinity and longer half-life, which are important. However, Ligand A excels in safety (lower DILI, lower hERG), metabolic stability (lower Cl_mic), and P-gp efflux. The biggest concern with Ligand A is its low logP, which could severely limit its ability to cross cell membranes, including the BBB. Ligand B's logP is optimal. While Ligand B's BBB is slightly better, it's still not ideal. Given the importance of affinity for GPCR ligands, and the fact that the difference in affinity (-9 vs -7) is substantial, Ligand B is the more promising candidate despite its higher DILI and P-gp efflux.

Output:
1
2025-04-17 06:43:18,119 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (347.419 Da) is slightly lower, which could be beneficial for permeability. Ligand B (365.499 Da) is also good.

**TPSA:** Both ligands have TPSA values below the 90 A^2 threshold for CNS targets. Ligand A (86.28 A^2) is slightly higher than Ligand B (78.51 A^2), making Ligand B more favorable for CNS penetration.

**logP:** Both ligands have logP values within the optimal range (1-3). Ligand A (2.889) is closer to the upper end, while Ligand B (1.482) is closer to the lower end. This is a slight advantage for Ligand A regarding membrane permeability.

**H-Bond Donors/Acceptors:** Ligand A has 0 HBD and 7 HBA, while Ligand B has 2 HBD and 4 HBA. Both are within acceptable limits (<=5 HBD and <=10 HBA).

**QED:** Both ligands have QED values above 0.5 (Ligand A: 0.845, Ligand B: 0.718), indicating good drug-like properties. Ligand A is slightly better.

**DILI:** Ligand A has a DILI risk of 60.682%, which is approaching the higher risk threshold (>60%). Ligand B has a significantly lower DILI risk (35.052%), a major advantage.

**BBB:** Ligand A has excellent BBB penetration (92.4%), while Ligand B has good BBB penetration (73.633%). Ligand A is superior here, which is critical for a CNS target.

**Caco-2 Permeability:** Ligand A has a negative Caco-2 value (-4.151), which is unusual and suggests poor permeability. Ligand B has a negative value as well (-5.245), but slightly worse.

**Aqueous Solubility:** Both ligands have negative solubility values (-3.98 for A, -2.309 for B), indicating poor aqueous solubility. This is a concern for both, but slightly less so for Ligand B.

**hERG Inhibition:** Both ligands have very low hERG inhibition liability (0.174 and 0.724 respectively), which is excellent.

**Microsomal Clearance:** Ligand A has a higher microsomal clearance (57.951) than Ligand B (37.201), suggesting lower metabolic stability. Ligand B is preferable.

**In vitro Half-Life:** Ligand A has a negative half-life (-21.214), which is problematic. Ligand B has a negative half-life as well (-11.974), but is slightly better.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.179 and 0.048 respectively), which is favorable for CNS penetration. Ligand B is slightly better.

**Binding Affinity:** Both ligands have excellent binding affinity (-8.0 and -8.2 kcal/mol respectively). Ligand B is slightly better.

**Overall Assessment:**

Ligand A excels in BBB penetration and QED, but suffers from potentially problematic DILI risk, poor Caco-2 permeability, and lower metabolic stability. The negative half-life is also a significant concern.

Ligand B has a much better safety profile (lower DILI), better metabolic stability (lower Cl_mic), slightly better affinity, and lower P-gp efflux. While its BBB penetration is lower than Ligand A, it's still acceptable (73.633%). The Caco-2 permeability and solubility are also concerns, but less severe than for Ligand A.

Given the GPCR-specific priorities and the overall profile, **Ligand B is the more promising drug candidate.** The lower DILI risk and improved metabolic stability outweigh the slightly lower BBB penetration.

Output:
1
2025-04-17 06:43:18,120 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (346.293 and 340.358 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (96.97) is slightly above the optimal <90 for CNS targets but still reasonable. Ligand B (86.02) is excellent, well below 90.

**3. logP:** Both ligands have good logP values (1.995 and 2.988), falling within the 1-3 range. Ligand B is slightly more lipophilic, which could be beneficial for membrane permeability.

**4. H-Bond Donors:** Ligand A (2) and Ligand B (4) are both within the acceptable limit of <=5.

**5. H-Bond Acceptors:** Ligand A (5) and Ligand B (2) are both within the acceptable limit of <=10.

**6. QED:** Both ligands have acceptable QED scores (0.753 and 0.588), indicating reasonable drug-likeness.

**7. DILI:** Both ligands have high DILI risk (96.627 and 90.694), which is a concern. However, this is an *in silico* prediction and needs experimental validation.

**8. BBB:** Both ligands have good BBB penetration (65.607 and 67.313). While not exceeding the desirable >70, they are both acceptable for a CNS target.

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.854 and -5.148). This is unusual and suggests a potential issue with intestinal absorption, but these values may be artifacts of the prediction method.

**10. Aqueous Solubility:** Both ligands have very poor aqueous solubility (-4.525 and -4.861). This is a significant drawback.

**11. hERG Inhibition:** Both ligands have low hERG inhibition risk (0.414 and 0.69), which is good.

**12. Microsomal Clearance:** Ligand A (-1.912) has lower (better) microsomal clearance than Ligand B (6.159), suggesting better metabolic stability.

**13. In vitro Half-Life:** Ligand B (100.987) has a significantly longer in vitro half-life than Ligand A (69.269), which is desirable.

**14. P-gp Efflux:** Both ligands have low P-gp efflux liability (0.163 and 0.201), which is favorable for CNS penetration.

**15. Binding Affinity:** Ligand B (-11 kcal/mol) has a substantially stronger binding affinity than Ligand A (-9.6 kcal/mol). This >1.5 kcal/mol difference in affinity is a major advantage, potentially outweighing some of the ADME drawbacks.

**Overall Assessment:**

Ligand B is the more promising candidate. The significantly stronger binding affinity (-11 vs -9.6 kcal/mol) is the most important factor, especially for a GPCR target. While both ligands have poor solubility and high DILI risk, the longer half-life of Ligand B is also a plus. The slightly better TPSA of Ligand B is also favorable. The negative Caco-2 values are concerning for both, but the strong affinity of Ligand B makes it worth further investigation despite this.

Output:
1
2025-04-17 06:43:18,120 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (349.471 and 349.431 Da) fall comfortably within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (56.79) is significantly better than Ligand B (80.76). For CNS targets, we want TPSA <= 90, and A is much closer to the ideal <=60 range. B is approaching a concerning level.

**3. logP:** Ligand A (3.808) is optimal (1-3). Ligand B (1.476) is on the lower side, potentially hindering permeability.

**4. H-Bond Donors:** Both have 1 HBD, which is good.

**5. H-Bond Acceptors:** Ligand A has 4 HBA, and Ligand B has 5. Both are acceptable (<=10).

**6. QED:** Both ligands have similar and good QED values (0.736 and 0.754, respectively), indicating drug-likeness.

**7. DILI:** Ligand A (42.458) has a slightly higher DILI risk than Ligand B (31.524), but both are below the concerning threshold of 60.

**8. BBB:** Both ligands show excellent BBB penetration (74.874 and 77.472), exceeding the desirable >70% for CNS targets.

**9. Caco-2 Permeability:** Ligand A (-4.154) is better than Ligand B (-4.578), indicating better intestinal absorption.

**10. Aqueous Solubility:** Ligand A (-4.437) is better than Ligand B (-1.421).

**11. hERG Inhibition:** Both ligands have low hERG inhibition risk (0.486 and 0.36, respectively).

**12. Microsomal Clearance:** Ligand A (90.231) has a higher clearance than Ligand B (8.876), suggesting lower metabolic stability. This is a significant drawback for A.

**13. In vitro Half-Life:** Ligand B (8.888) has a much longer half-life than Ligand A (-6.498). This is a major advantage for B.

**14. P-gp Efflux:** Ligand A (0.436) has lower P-gp efflux than Ligand B (0.03), which is favorable for CNS exposure.

**15. Binding Affinity:** Ligand A (-7.7 kcal/mol) has a slightly better binding affinity than Ligand B (-7.5 kcal/mol). While the difference is small (0.2 kcal/mol), it is still a positive for A.

**Overall Assessment:**

Ligand A has a better affinity and P-gp efflux profile, and a better TPSA. However, Ligand B has a significantly better logP, solubility, metabolic stability (lower Cl_mic and higher t1/2), and a lower DILI risk. Considering the GPCR-specific priorities, the better logP, metabolic stability, and solubility of Ligand B outweigh the slightly better affinity of Ligand A. CNS penetration is good for both, but metabolic stability is critical for maintaining sufficient brain exposure.

Output:
1
2025-04-17 06:43:18,120 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (336.355 and 349.431 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (115.72) is slightly above the optimal <90 for CNS targets, but still reasonable. Ligand B (78.95) is excellent, well below 90.

**3. logP:** Ligand A (2.468) is within the optimal 1-3 range. Ligand B (0.143) is quite low, potentially hindering permeability.

**4. H-Bond Donors:** Ligand A (3) and Ligand B (1) are both within the acceptable limit of <=5.

**5. H-Bond Acceptors:** Ligand A (5) and Ligand B (4) are both within the acceptable limit of <=10.

**6. QED:** Both ligands have similar and good QED values (0.677 and 0.683), indicating good drug-like properties.

**7. DILI:** Ligand A (96.316) has a high DILI risk, which is a significant concern. Ligand B (23.032) has a very low DILI risk, a major advantage.

**8. BBB:** Ligand A (45.715) has a moderate BBB penetration, which is not ideal for a CNS target like DRD2. Ligand B (54.944) is also moderate, but slightly better.

**9. Caco-2:** Both ligands have negative Caco-2 values (-5.182 and -4.727), which is unusual and suggests poor permeability. This is a red flag for both.

**10. Solubility:** Both ligands have negative solubility values (-4.681 and -1.939), also unusual and concerning.

**11. hERG:** Both ligands have very low hERG inhibition liability (0.59 and 0.148), which is positive.

**12. Cl_mic:** Ligand A (39.252) has a higher microsomal clearance than Ligand B (6.138), suggesting lower metabolic stability.

**13. t1/2:** Ligand A (17.602) has a longer in vitro half-life than Ligand B (9.696).

**14. Pgp:** Both ligands have very low Pgp efflux liability (0.033 and 0.011), which is favorable for CNS penetration.

**15. Binding Affinity:** Both ligands have the same strong binding affinity (-8.8 kcal/mol).

**Overall Assessment:**

Despite both ligands having excellent binding affinity, Ligand B is significantly more promising. The major deciding factor is the drastically lower DILI risk (23.032 vs. 96.316). While both have concerning Caco-2 and solubility values, the lower DILI risk and slightly better BBB penetration of Ligand B outweigh the slightly better metabolic stability (longer half-life) of Ligand A. The low logP of Ligand B is a concern, but could potentially be addressed through structural modifications. The negative Caco-2 and solubility values are problematic for both, and would need to be investigated and improved.

Output:
1
2025-04-17 06:43:18,120 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (363.361 Da) is slightly lower, which could be advantageous for permeability.

**TPSA:** Both ligands are below the 140 A^2 threshold for oral absorption, but only Ligand A (99.18 A^2) is closer to the stricter <90 A^2 target for CNS penetration. Ligand B (105.39 A^2) is a bit higher.

**logP:** Ligand A (-1.033) is below the optimal 1-3 range, potentially hindering permeation. Ligand B (1.419) is within the optimal range. This is a significant advantage for Ligand B.

**H-Bond Donors/Acceptors:** Both have 2 HBD and 5 HBA, which are within acceptable limits.

**QED:** Both ligands have reasonable QED values (A: 0.588, B: 0.818), indicating good drug-like properties. Ligand B is better here.

**DILI:** Both have acceptable DILI risk (A: 35.634, B: 51.105), below the 60 threshold.

**BBB:** Ligand A (51.26%) has a moderate BBB penetration, while Ligand B (54.13%) is also moderate. Neither is >70, which is desirable for CNS targets, but they are relatively close.

**Caco-2 Permeability:** Ligand A (-4.947) has poor Caco-2 permeability, while Ligand B (-5.282) is also poor. Both are quite low, suggesting absorption issues.

**Aqueous Solubility:** Ligand A (-0.422) has slightly better solubility than Ligand B (-2.83).

**hERG Inhibition:** Both ligands have very low hERG inhibition risk (A: 0.149, B: 0.102).

**Microsomal Clearance:** Ligand A (-18.322) has a lower (better) microsomal clearance than Ligand B (-8.168), indicating better metabolic stability.

**In vitro Half-Life:** Ligand A (-39.051) has a longer half-life than Ligand B (-22.783).

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (A: 0.009, B: 0.032), which is good for CNS exposure.

**Binding Affinity:** Ligand A (-8.0 kcal/mol) has a slightly better binding affinity than Ligand B (-8.8 kcal/mol). This is a significant advantage for Ligand A, potentially outweighing some ADME drawbacks.

**Overall Assessment:**

While Ligand A has better affinity and metabolic stability, Ligand B excels in logP, QED, and has a more favorable TPSA. The biggest drawback for Ligand A is its low logP, which could severely limit its ability to cross cell membranes and reach the brain. Both have poor Caco-2 permeability. Given the GPCR-specific priority for BBB penetration and the importance of logP for CNS drugs, Ligand B appears to be the more promising candidate, despite the slightly weaker binding affinity. The difference in binding affinity (0.8 kcal/mol) is not substantial enough to overcome the significant logP disadvantage of Ligand A.

Output:
1
2025-04-17 06:43:18,121 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (369.447 Da) is slightly higher than Ligand B (350.503 Da), but both are acceptable.

**TPSA:** Ligand A (120.5) is borderline for CNS penetration, being above the preferred <90. Ligand B (58.64) is excellent, well below the threshold. This is a significant advantage for Ligand B.

**logP:** Ligand A (0.609) is quite low, potentially hindering membrane permeability. Ligand B (3.432) is optimal. This is a major advantage for Ligand B.

**H-Bond Donors/Acceptors:** Ligand A has 3 HBD and 5 HBA, which are acceptable. Ligand B has 1 HBD and 3 HBA, also acceptable and slightly more favorable.

**QED:** Both ligands have good QED values (A: 0.672, B: 0.793), indicating good drug-like properties. Ligand B is slightly better.

**DILI:** Ligand A (77.782) has a higher DILI risk than Ligand B (29.779). This is a significant advantage for Ligand B.

**BBB:** Ligand A (64.017) has a moderate BBB penetration, while Ligand B (87.01) is excellent, exceeding the desirable >70 threshold. This is a crucial advantage for a CNS target like DRD2.

**Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and suggests poor permeability. However, the scale is not specified, so it's hard to interpret.

**Aqueous Solubility:** Both have negative solubility values, which is also unusual.

**hERG Inhibition:** Both ligands show very low hERG inhibition risk (A: 0.037, B: 0.537).

**Microsomal Clearance:** Ligand A (7.735) has lower clearance than Ligand B (69.711), suggesting better metabolic stability. This is an advantage for Ligand A.

**In vitro Half-Life:** Ligand A (-13.75) has a negative half-life, which is not physically possible and likely an error. Ligand B (-3.059) also has a negative half-life, indicating a problem with the data.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (A: 0.029, B: 0.239), which is favorable for CNS penetration.

**Binding Affinity:** Both ligands have similar and strong binding affinities (A: -9.3 kcal/mol, B: -8.9 kcal/mol). The difference of 0.4 kcal/mol is not substantial enough to outweigh other significant differences.

**Overall Assessment:**

Ligand B is the stronger candidate. While Ligand A has better metabolic stability (lower Cl_mic), Ligand B excels in crucial properties for a CNS-targeting GPCR ligand: significantly lower TPSA, optimal logP, excellent BBB penetration, and lower DILI risk. The questionable half-life values for both compounds are a concern, but the other advantages of Ligand B are more compelling.



Output:
1
2025-04-17 06:43:18,121 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands fall within the ideal range (200-500 Da). Ligand A (342.443 Da) is slightly better, being closer to the lower end which can aid permeability.

**TPSA:** Ligand A (69.04) is significantly better than Ligand B (99.1). For CNS targets, TPSA < 90 is preferred, and Ligand A is comfortably within this range, while Ligand B is approaching the upper limit.

**logP:** Ligand A (2.477) is optimal (1-3), while Ligand B (0.386) is quite low. Low logP can hinder membrane permeability. This is a significant advantage for Ligand A.

**H-Bond Donors/Acceptors:** Ligand A (HBD=1, HBA=5) and Ligand B (HBD=3, HBA=5) are both acceptable.

**QED:** Both ligands have reasonable QED values (Ligand A: 0.8, Ligand B: 0.598), indicating good drug-like properties.

**DILI:** Ligand A (16.285) has a lower DILI risk than Ligand B (21.636), which is preferable.

**BBB:** Both ligands have similar BBB penetration (Ligand A: 57.852, Ligand B: 54.13). Neither are ideal (>70), but this is less critical if other properties are strong.

**Caco-2 Permeability:** Ligand A (-4.746) has better Caco-2 permeability than Ligand B (-5.124).

**Aqueous Solubility:** Ligand A (-1.927) has better aqueous solubility than Ligand B (-1.538).

**hERG Inhibition:** Both ligands have very low hERG inhibition risk (Ligand A: 0.37, Ligand B: 0.207).

**Microsomal Clearance:** Ligand A (51.729) has a higher (worse) microsomal clearance than Ligand B (0.049). This suggests Ligand B is more metabolically stable.

**In vitro Half-Life:** Ligand A (-10.158) has a significantly longer in vitro half-life than Ligand B (7.757).

**P-gp Efflux:** Ligand A (0.089) has lower P-gp efflux than Ligand B (0.059), which is beneficial for CNS penetration.

**Binding Affinity:** Ligand A (-8.3 kcal/mol) has a slightly better binding affinity than Ligand B (-7.5 kcal/mol). While both are good, the 0.8 kcal/mol difference is noticeable.

**Overall Assessment:**

Ligand A is the stronger candidate. It excels in key GPCR properties like logP, TPSA, and has a better binding affinity. While Ligand B has better metabolic stability (lower Cl_mic), the superior permeability, solubility, and CNS-relevant properties of Ligand A outweigh this advantage. The affinity difference, while not huge, also favors Ligand A.

Output:
1
2025-04-17 06:43:18,121 - INFO - Batch 305 complete. Total preferences: 4880
2025-04-17 06:43:18,121 - INFO - Processing batch 306/512...
2025-04-17 06:44:04,628 - INFO - Reasoning:

Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (362.901 and 354.491 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (49.41) is significantly better than Ligand B (59.08). For CNS targets, we want TPSA <= 90, and ideally closer to 60. Ligand A is much closer to the ideal range.

**3. logP:** Ligand A (4.198) is slightly higher than the optimal 1-3 range, but still acceptable. Ligand B (2.932) is within the optimal range. However, for a GPCR, a slightly higher logP can be tolerated if other properties are favorable.

**4. H-Bond Donors:** Ligand A (1) is better than Ligand B (0). While both are low, having one HBD can sometimes improve solubility without drastically impacting permeability.

**5. H-Bond Acceptors:** Ligand A (2) is better than Ligand B (4). Lower HBA is generally preferred for better permeability.

**6. QED:** Ligand A (0.853) is significantly better than Ligand B (0.447), indicating a more drug-like profile.

**7. DILI:** Ligand A (47.693) has a better DILI score than Ligand B (16.673), suggesting lower potential for liver injury.

**8. BBB:** Both ligands have excellent BBB penetration (Ligand A: 92.323, Ligand B: 89.027), exceeding the desirable >70 threshold for CNS targets.

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.448 and -4.054). This is unusual and potentially problematic, suggesting poor intestinal absorption. However, for CNS targets, this is less critical as BBB penetration is the primary concern.

**10. Aqueous Solubility:** Both ligands have very poor aqueous solubility (-5.712 and -2.169). This is a significant drawback, but can sometimes be overcome with formulation strategies.

**11. hERG Inhibition:** Ligand A (0.547) has a lower hERG inhibition risk than Ligand B (0.798), which is favorable.

**12. Microsomal Clearance:** Ligand B (94.584) has higher microsomal clearance than Ligand A (74.312), indicating lower metabolic stability.

**13. In vitro Half-Life:** Ligand A (66.497) has a much longer in vitro half-life than Ligand B (-9.268), which is a significant advantage.

**14. P-gp Efflux:** Ligand A (0.37) has lower P-gp efflux than Ligand B (0.227), which is beneficial for CNS exposure.

**15. Binding Affinity:** Ligand A (-9.1 kcal/mol) has a slightly better binding affinity than Ligand B (-6.9 kcal/mol). This 1.5+ kcal/mol difference is substantial and can outweigh some of the ADME drawbacks.

**Overall Assessment:**

Ligand A is the superior candidate. It has a better QED score, lower DILI risk, lower hERG risk, significantly longer half-life, lower P-gp efflux, and a stronger binding affinity. While both have poor solubility and Caco-2 permeability, the strong BBB penetration mitigates the importance of Caco-2 for a CNS target. Ligand A's better ADME properties, particularly the longer half-life and better metabolic stability, combined with its superior affinity, make it a more promising drug candidate.

Output:
1
2025-04-17 06:44:04,629 - INFO - Reasoning:

Let's analyze Ligand A and Ligand B based on the provided guidelines, prioritizing GPCR-specific properties (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (368.455 and 359.417 Da) fall within the ideal range of 200-500 Da.

**TPSA:** Ligand A (112.57) is better than Ligand B (67.59). Both are below 90, which is excellent for CNS penetration.

**logP:** Both ligands have good logP values (1.811 and 2.725), falling within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A has 3 HBD and 4 HBA, while Ligand B has 1 HBD and 5 HBA. Both are within acceptable limits (<=5 HBD and <=10 HBA).

**QED:** Both ligands have good QED scores (0.648 and 0.775), indicating good drug-likeness.

**DILI:** Ligand A (63.862) has a higher DILI risk than Ligand B (39.046). This is a negative for Ligand A.

**BBB:** Ligand B (87.01) has a significantly higher BBB penetration score than Ligand A (47.111). This is a *major* advantage for Ligand B, given DRD2 is a CNS target.

**Caco-2 Permeability:** Ligand A (-5.51) has poorer Caco-2 permeability than Ligand B (-4.6). Both are negative values, suggesting poor permeability, but B is better.

**Aqueous Solubility:** Ligand A (-2.857) has poorer aqueous solubility than Ligand B (-2.028). Both are negative, indicating poor solubility.

**hERG Inhibition:** Ligand A (0.051) shows slightly lower hERG inhibition risk than Ligand B (0.358), which is favorable.

**Microsomal Clearance:** Ligand B (33.548) has lower microsomal clearance than Ligand A (11.202), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (-35.163) has a much longer in vitro half-life than Ligand B (-15.282). This is a significant advantage for Ligand A.

**P-gp Efflux:** Ligand A (0.009) has much lower P-gp efflux liability than Ligand B (0.089), which is highly desirable for CNS penetration.

**Binding Affinity:** Ligand B (-7.2) has a slightly better binding affinity than Ligand A (-8.3). While A is better, the difference is small.

**Overall Assessment:**

Ligand B excels in crucial areas for a CNS-targeting GPCR ligand: significantly better BBB penetration, lower DILI risk, and better metabolic stability. While Ligand A has a longer half-life and lower P-gp efflux, the superior BBB penetration of Ligand B outweighs these benefits. The slight affinity difference is not enough to overcome the ADME advantages of Ligand B.

Output:
1
2025-04-17 06:44:04,629 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (366.849 and 343.431 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (97.55) is slightly higher than Ligand B (83.02), but both are below the 90 A^2 threshold desirable for CNS targets.

**logP:** Both ligands have good logP values (1.463 and 1.719), falling within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Both have 2 HBD and are within the acceptable range. Ligand A has 5 HBA, and Ligand B has 4, both are under the 10 limit.

**QED:** Both ligands have good QED scores (0.794 and 0.867), indicating good drug-like properties.

**DILI:** Ligand A (59.403) has a higher DILI risk than Ligand B (41.334), but both are below the concerning 60 threshold.

**BBB:** This is a critical parameter for a CNS target like DRD2. Ligand A has a significantly better BBB penetration percentile (80.264) compared to Ligand B (39.046).

**Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and indicates poor permeability. However, the values are similar (-5.083 vs -5.24).

**Aqueous Solubility:** Both have negative solubility values, indicating poor solubility. Again, values are similar (-3.226 vs -2.314).

**hERG:** Both ligands have low hERG inhibition liability (0.408 and 0.349), which is favorable.

**Microsomal Clearance:** Ligand A (-0.657) has a lower (better) microsomal clearance than Ligand B (15.684), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (2.218) has a shorter half-life than Ligand B (-29.455), which is unfavorable.

**P-gp Efflux:** Ligand A (0.027) has a much lower P-gp efflux liability than Ligand B (0.043), which is beneficial for CNS penetration.

**Binding Affinity:** Ligand B (-8.4 kcal/mol) has a slightly better binding affinity than Ligand A (-7.7 kcal/mol). The difference is 0.7 kcal/mol, which is significant but not overwhelming.

**Overall Assessment:**

Ligand A is the better candidate. While Ligand B has slightly better binding affinity, Ligand A excels in crucial ADME properties for CNS drug development. Specifically, its significantly higher BBB penetration (80.264 vs 39.046), lower P-gp efflux, and better metabolic stability (lower Cl_mic) outweigh the small difference in binding affinity. The slightly shorter half-life of Ligand A is a concern but could potentially be addressed through structural modifications. The similar solubility and Caco-2 values are drawbacks for both, but the superior CNS-related properties of Ligand A make it the more promising candidate.

Output:
1
2025-04-17 06:44:04,629 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B based on the provided guidelines, prioritizing GPCR-specific properties (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (346.519 Da) is slightly lower, which could be beneficial for permeability, but both are acceptable.

**TPSA:** Ligand A (50.16) is significantly better than Ligand B (69.64). For CNS targets, we want TPSA <= 90, and ideally closer to 60. Ligand A is much closer to this ideal.

**logP:** Ligand A (4.034) is slightly higher than the optimal range (1-3), but still acceptable. Ligand B (1.727) is on the lower side, potentially hindering permeation.

**H-Bond Donors/Acceptors:** Ligand A (HBD=1, HBA=3) has fewer H-bonds than Ligand B (HBD=2, HBA=5), which is generally preferable for better permeability. Both are within acceptable limits.

**QED:** Ligand A (0.895) has a higher QED score than Ligand B (0.555), indicating better overall drug-likeness.

**DILI:** Ligand B (34.277) has a lower DILI risk than Ligand A (20.279), which is favorable.

**BBB:** Both ligands have good BBB penetration (Ligand A: 78.79, Ligand B: 70.027), but Ligand A is better, exceeding 70%.

**Caco-2 Permeability:** Both have negative Caco-2 values which is unusual. We will assume these are percentile scores, and therefore higher is better. Ligand A (-4.546) is better than Ligand B (-4.917).

**Aqueous Solubility:** Both have negative solubility values, which is unusual. We will assume these are percentile scores, and therefore higher is better. Ligand A (-3.636) is better than Ligand B (-2.573).

**hERG Inhibition:** Both ligands have low hERG inhibition risk (Ligand A: 0.588, Ligand B: 0.734).

**Microsomal Clearance:** Ligand B (-0.244) has significantly lower (better) microsomal clearance than Ligand A (52.683), indicating greater metabolic stability.

**In vitro Half-Life:** Ligand B (-3.997) has a longer in vitro half-life than Ligand A (23.864), which is desirable.

**P-gp Efflux:** Ligand A (0.296) has lower P-gp efflux than Ligand B (0.266), which is favorable for CNS exposure.

**Binding Affinity:** Ligand A (-9.1 kcal/mol) has significantly stronger binding affinity than Ligand B (-6.9 kcal/mol). This is a substantial advantage, potentially outweighing some of the ADME drawbacks of Ligand A.

**Overall Assessment:**

Ligand A excels in key GPCR properties: TPSA, BBB, and, most importantly, binding affinity. Its QED is also much higher. While Ligand B has better metabolic stability (lower Cl_mic, longer t1/2) and lower DILI risk, the significantly stronger binding affinity of Ligand A, coupled with its acceptable BBB and TPSA, makes it the more promising drug candidate. The difference in affinity (>2 kcal/mol) is substantial enough to compensate for the slightly higher DILI risk and higher Cl_mic.

Output:
1
2025-04-17 06:44:04,629 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 drug candidates, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (347.415 Da) is slightly preferred as it's closer to the lower end, potentially aiding permeability.

**TPSA:** Ligand A (74.61) is significantly better than Ligand B (84.22). For CNS targets, TPSA should be <= 90, and A is comfortably within this range, while B is approaching the upper limit.

**logP:** Ligand A (2.854) is optimal (1-3), while Ligand B (4.393) is a bit high. Higher logP can lead to solubility issues and off-target interactions.

**H-Bond Donors/Acceptors:** Ligand A (HBD=1, HBA=7) is better than Ligand B (HBD=3, HBA=3). Lower HBD/HBA generally improves permeability.

**QED:** Both ligands have acceptable QED values (A: 0.776, B: 0.587), indicating reasonable drug-likeness.

**DILI:** Ligand A (64.986) has a lower DILI risk than Ligand B (82.551), which is a significant advantage.

**BBB:** Ligand B (79.488) has a better BBB penetration percentile than Ligand A (57.619). This is a critical factor for CNS targets like DRD2.

**Caco-2 Permeability:** Ligand A (-4.412) is better than Ligand B (-5.083), indicating better intestinal absorption.

**Aqueous Solubility:** Ligand A (-4.635) is better than Ligand B (-5.07), which is important for formulation and bioavailability.

**hERG Inhibition:** Both ligands have similar hERG inhibition liability (A: 0.409, B: 0.687), and are at relatively low risk.

**Microsomal Clearance:** Ligand B (64.923) has lower microsomal clearance than Ligand A (92.553), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand B (81.075) has a significantly longer in vitro half-life than Ligand A (6.644).

**P-gp Efflux:** Ligand A (0.118) has lower P-gp efflux liability than Ligand B (0.48), which is favorable for CNS exposure.

**Binding Affinity:** Ligand B (-10.1 kcal/mol) has a substantially stronger binding affinity than Ligand A (-7.5 kcal/mol). This is a major advantage, potentially outweighing some of the ADME drawbacks. The difference of 2.6 kcal/mol is significant.

**Overall Assessment:**

While Ligand A has better ADME properties (TPSA, logP, DILI, solubility, Caco-2, P-gp), Ligand B's significantly superior binding affinity (-10.1 vs -7.5 kcal/mol) and longer half-life are compelling. The better BBB of Ligand B is also a plus for a CNS target. The higher logP and DILI of Ligand B are concerns, but the potency advantage is likely to be decisive.

Output:
1
2025-04-17 06:44:04,629 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (371.361 and 347.375 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (92.7) is better than Ligand B (113.35). For CNS targets, we want TPSA <= 90, so Ligand A is closer to this threshold.

**3. logP:** Ligand A (2.578) is optimal (1-3), while Ligand B (0.751) is a bit low, potentially hindering permeation.

**4. H-Bond Donors:** Both ligands have 2 HBD, which is within the acceptable limit of <=5.

**5. H-Bond Acceptors:** Ligand A has 5 HBA, and Ligand B has 6. Both are within the acceptable limit of <=10.

**6. QED:** Both ligands have similar QED values (0.762 and 0.764), indicating good drug-likeness.

**7. DILI:** Both ligands have similar DILI risk (69.678 and 70.958), which is acceptable (below 80).

**8. BBB:** Ligand B (46.762) has a significantly better BBB percentile than Ligand A (33.734). This is a critical factor for CNS targets like DRD2.

**9. Caco-2 Permeability:** Both have negative Caco-2 values (-5.359 and -5.258), which is unusual and suggests poor permeability. However, these values are on a scale where negative values are possible and don't necessarily indicate a complete block.

**10. Aqueous Solubility:** Both have negative solubility values (-3.62 and -2.471), which is also unusual. Again, these values are on a scale where negative values are possible.

**11. hERG Inhibition:** Both ligands have low hERG inhibition liability (0.658 and 0.21), which is good.

**12. Microsomal Clearance:** Ligand A (17.297) has higher microsomal clearance than Ligand B (13.009), indicating lower metabolic stability.

**13. In vitro Half-Life:** Ligand B (-10.719) has a negative half-life, which is not possible. This suggests a problem with the data or a very rapidly metabolized compound. Ligand A (33.149) has a reasonable half-life.

**14. P-gp Efflux:** Both ligands have low P-gp efflux liability (0.136 and 0.028), which is desirable for CNS penetration.

**15. Binding Affinity:** Both ligands have very similar and strong binding affinities (-8.8 and -8.5 kcal/mol). The difference of 0.3 kcal/mol is unlikely to be decisive.

**Overall Assessment:**

While Ligand B has a better BBB percentile, the negative in vitro half-life is a major red flag. A negative half-life is biologically impossible and indicates a significant issue with the compound or the data. Ligand A, despite a lower BBB score, has a reasonable half-life and better TPSA. The slightly better logP of Ligand A also favors it. Given the importance of metabolic stability and a plausible half-life, Ligand A is the more promising candidate.

Output:
0
2025-04-17 06:44:04,629 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight (MW):** Both ligands are within the ideal range (200-500 Da). Ligand A (394.871 Da) is slightly higher than Ligand B (342.483 Da), but both are acceptable.

**2. TPSA:** Ligand A (58.64) is higher than Ligand B (41.57). For CNS targets, we prefer TPSA <= 90. Both are well within this range, but Ligand B is better.

**3. logP:** Both ligands have good logP values (A: 3.386, B: 3.478), falling within the optimal 1-3 range. No significant difference here.

**4. H-Bond Donors (HBD):** Both have 1 HBD, which is acceptable (<=5).

**5. H-Bond Acceptors (HBA):** Ligand A has 4 HBAs, and Ligand B has 3. Both are within the acceptable limit of <=10.

**6. QED:** Both ligands have good QED scores (A: 0.771, B: 0.86), indicating good drug-like properties. Ligand B is slightly better.

**7. DILI:** Ligand A (55.68) has a higher DILI risk than Ligand B (19.698). This is a significant advantage for Ligand B.

**8. BBB:** Ligand A (82.862) and Ligand B (90.927) both have excellent BBB penetration potential, exceeding the desirable >70 threshold for CNS targets. Ligand B is slightly better.

**9. Caco-2 Permeability:** Both have negative Caco-2 values (-4.775 and -4.498). This is unusual and suggests poor permeability. However, these values are on a scale where negative values are possible and don't necessarily preclude development.

**10. Aqueous Solubility:** Both have negative solubility values (-4.122 and -3.813), which is also unusual. Similar to Caco-2, these values suggest poor solubility, but are not necessarily disqualifying.

**11. hERG Inhibition:** Both ligands have low hERG inhibition risk (A: 0.612, B: 0.744).

**12. Microsomal Clearance (Cl_mic):** Ligand A (22.621) has lower clearance than Ligand B (91.297), indicating better metabolic stability. This is a significant advantage for Ligand A.

**13. In vitro Half-Life:** Ligand A (-0.423) has a shorter half-life than Ligand B (11.955). This is a significant advantage for Ligand B.

**14. P-gp Efflux:** Both ligands have low P-gp efflux liability (A: 0.285, B: 0.322).

**15. Binding Affinity:** Ligand B (-7.5 kcal/mol) has a slightly better binding affinity than Ligand A (-8.4 kcal/mol). While A is stronger, the difference is not substantial enough to outweigh other factors.

**Overall Assessment:**

Ligand B is the more promising candidate. It has a lower DILI risk, better BBB penetration, a better QED score, and a significantly longer in vitro half-life. While Ligand A has better metabolic stability (lower Cl_mic) and slightly better binding affinity, the advantages of Ligand B in terms of safety (DILI), CNS penetration (BBB), and duration of action (t1/2) are more critical for a CNS-targeting GPCR like DRD2. The negative Caco-2 and solubility values are concerning for both, but might be addressable through formulation strategies.



Output:
1
2025-04-17 06:44:04,630 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (377.46 and 345.46 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (84.66) is better than Ligand B (45.23). Both are below the 90 A^2 threshold for CNS targets, but A is closer to the ideal.

**logP:** Both ligands have good logP values (2.03 and 3.30 respectively), falling within the optimal 1-3 range. Ligand B is slightly higher, which *could* be a minor concern for solubility, but is still acceptable.

**H-Bond Donors/Acceptors:** Ligand A has 2 HBD and 4 HBA, while Ligand B has 1 HBD and 3 HBA. Both are within acceptable limits (<=5 HBD and <=10 HBA).

**QED:** Ligand A (0.726) has a better QED score than Ligand B (0.581), indicating a more drug-like profile.

**DILI:** Ligand A (20.51) has a significantly lower DILI risk than Ligand B (18.53). Both are good, but A is preferable.

**BBB:** Ligand B (94.26) has a better BBB penetration percentile than Ligand A (89.03). This is a critical factor for a CNS target like DRD2.

**Caco-2 Permeability:** Ligand A (-5.14) has a worse Caco-2 permeability than Ligand B (-4.68).

**Aqueous Solubility:** Ligand A (-2.05) has a worse aqueous solubility than Ligand B (-3.42).

**hERG:** Both ligands have low hERG inhibition liability (0.95 and 0.82 respectively), which is good.

**Microsomal Clearance:** Ligand A (-18.16) has a significantly lower (better) microsomal clearance than Ligand B (73.25). This suggests better metabolic stability for Ligand A.

**In vitro Half-Life:** Ligand B (19.77) has a much longer in vitro half-life than Ligand A (-10.66).

**P-gp Efflux:** Ligand A (0.1) has a much lower P-gp efflux liability than Ligand B (0.53). Lower P-gp efflux is highly desirable for CNS penetration.

**Binding Affinity:** Ligand A (-8.1 kcal/mol) has a slightly better binding affinity than Ligand B (-7.9 kcal/mol). While the difference is small, it's still a positive for Ligand A.

**Overall Assessment:**

Ligand A excels in several key areas: TPSA, QED, DILI, microsomal clearance, and P-gp efflux. It also has slightly better binding affinity. However, Ligand B has a superior BBB penetration and in vitro half-life. Considering the GPCR-specific priorities, BBB is crucial for CNS targets. While Ligand A's P-gp efflux is very favorable, the substantial difference in BBB penetration favors Ligand B. The slightly better half-life of B also contributes. The solubility and Caco-2 permeability are both poor for both compounds, but are less critical than the CNS penetration.

Output:
1
2025-04-17 06:44:04,630 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight (MW):** Both ligands (341.386 and 360.523 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (47.48) is significantly better than Ligand B (58.2). For CNS targets, we want TPSA <= 90, and ideally lower. Ligand A is much closer to the ideal range.

**3. logP:** Both ligands have good logP values (3.601 and 3.824), falling within the optimal 1-3 range.

**4. H-Bond Donors (HBD):** Ligand A (0) is preferable to Ligand B (2). Lower HBD generally improves permeability.

**5. H-Bond Acceptors (HBA):** Ligand A (5) is better than Ligand B (3). Both are within the acceptable range of <=10.

**6. QED:** Both ligands have good QED scores (0.685 and 0.758), indicating drug-like properties.

**7. DILI:** Ligand A (70.88) has a higher DILI risk than Ligand B (46.026). This is a negative for Ligand A, but not a dealbreaker.

**8. BBB:** Ligand A (77.2) has a significantly better BBB penetration percentile than Ligand B (62.97). This is *critical* for a CNS target like DRD2.

**9. Caco-2 Permeability:** Ligand A (-4.409) shows poor Caco-2 permeability, whereas Ligand B (-5.03) is even worse. Both are quite poor, but Ligand A is slightly better.

**10. Aqueous Solubility:** Ligand A (-4.203) is slightly better than Ligand B (-3.727), but both are poor.

**11. hERG:** Ligand A (0.921) has a lower hERG risk than Ligand B (0.325), which is favorable.

**12. Microsomal Clearance (Cl_mic):** Ligand A (75.62) has higher clearance than Ligand B (50.067), indicating lower metabolic stability. This is a negative for Ligand A.

**13. In vitro Half-Life:** Ligand A (28.621) has a shorter half-life than Ligand B (23.64). This is a negative for Ligand A.

**14. P-gp Efflux:** Ligand A (0.564) shows lower P-gp efflux than Ligand B (0.551), which is preferable for CNS penetration.

**15. Binding Affinity:** Both ligands have excellent binding affinities (-8.5 and -8.9 kcal/mol). The difference is minimal.

**Overall Assessment:**

Despite Ligand A having a higher DILI risk and poorer metabolic stability (higher Cl_mic, shorter t1/2), its superior BBB penetration (77.2 vs 62.97), lower TPSA (47.48 vs 58.2), and lower P-gp efflux make it the more promising candidate for a CNS-targeting drug like a DRD2 ligand. The strong binding affinity is comparable for both. The better BBB and TPSA outweigh the slightly higher DILI and poorer metabolic properties, especially given the importance of CNS penetration for this target.

Output:
0
2025-04-17 06:44:04,630 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 drug candidates, considering the provided guidelines and GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (366.531 and 363.868 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (67.23) is higher than Ligand B (55.63). For CNS targets, TPSA should be <= 90, so both are acceptable, but B is better.

**3. logP:** Ligand A (2.158) is within the optimal 1-3 range. Ligand B (3.588) is slightly higher, but still acceptable.

**4. H-Bond Donors:** Both ligands have 1 HBD, which is within the acceptable limit of <= 5.

**5. H-Bond Acceptors:** Both ligands have 5 HBA, which is within the acceptable limit of <= 10.

**6. QED:** Ligand B (0.901) has a significantly higher QED than Ligand A (0.727), indicating a more drug-like profile.

**7. DILI:** Ligand A (29.624) has a lower DILI risk than Ligand B (47.305), suggesting better hepatotoxicity potential.

**8. BBB:** This is a critical parameter for CNS targets. Ligand B (88.445) has a much higher BBB penetration percentile than Ligand A (38.038). This is a major advantage for Ligand B.

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.307 and -5.055). This is unusual and suggests poor intestinal absorption. However, for a CNS target, intestinal absorption is less critical than BBB penetration.

**10. Aqueous Solubility:** Ligand A (-1.38) has better aqueous solubility than Ligand B (-4.104).

**11. hERG Inhibition:** Both ligands have low hERG inhibition risk (0.482 and 0.337).

**12. Microsomal Clearance:** Ligand A (25.86) has lower microsomal clearance than Ligand B (33.779), indicating better metabolic stability.

**13. In vitro Half-Life:** Ligand B (22.859) has a significantly longer in vitro half-life than Ligand A (-2.539).

**14. P-gp Efflux:** Both ligands have low P-gp efflux liability (0.061 and 0.557).

**15. Binding Affinity:** Ligand B (-8.4 kcal/mol) has a stronger binding affinity than Ligand A (-7.0 kcal/mol). This is a substantial difference (1.4 kcal/mol) and a significant advantage.

**Overall Assessment:**

While Ligand A has advantages in DILI risk, solubility and metabolic stability, Ligand B is significantly better regarding the GPCR-specific priorities for a CNS target. The much higher BBB penetration (88.445 vs 38.038) and stronger binding affinity (-8.4 vs -7.0 kcal/mol) outweigh the slightly higher DILI risk and lower solubility. The longer half-life is also a positive attribute. The negative Caco-2 values are concerning, but less critical for a CNS-focused drug.

Output:
1
2025-04-17 06:44:04,630 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (350.459 and 350.547 Da) fall comfortably within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (66.92) is slightly higher than Ligand B (58.2). Both are below the 90 A^2 threshold desirable for CNS targets, but Ligand B is closer to the optimal range.

**3. logP:** Ligand A (1.825) is within the optimal 1-3 range. Ligand B (4.04) is slightly above this, potentially leading to solubility issues and off-target interactions, but not drastically so.

**4. H-Bond Donors:** Ligand A (0) is preferable to Ligand B (2) as fewer H-bond donors generally improve permeability.

**5. H-Bond Acceptors:** Ligand A (4) is slightly higher than Ligand B (2). Both are within the acceptable range of <=10.

**6. QED:** Both ligands have similar QED values (0.71 and 0.659), indicating good drug-like properties.

**7. DILI:** Ligand A (12.718) has a slightly higher DILI risk than Ligand B (9.151), but both are below the concerning threshold of 40.

**8. BBB:** Ligand A (76.541) and Ligand B (82.396) both have good BBB penetration, exceeding the 70% threshold for CNS targets. Ligand B is slightly better.

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.36 and -4.593). This is unusual and suggests poor permeability. However, these values are on a log scale, and the negative values are likely representing very low permeability.

**10. Aqueous Solubility:** Both ligands have negative solubility values (-1.67 and -5.165), indicating very poor aqueous solubility. This is a significant concern.

**11. hERG Inhibition:** Both ligands have low hERG inhibition risk (0.283 and 0.476).

**12. Microsomal Clearance:** Ligand A (77.294) has lower microsomal clearance than Ligand B (97.049), suggesting better metabolic stability.

**13. In vitro Half-Life:** Ligand A (-19.347) has a more negative half-life, which is not possible. This is likely an error in the data. Ligand B (-8.111) also has a negative value, which is also not possible.

**14. P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.038 and 0.064), which is favorable for CNS penetration.

**15. Binding Affinity:** Both ligands have similar and strong binding affinities (-8.2 and -8.4 kcal/mol). The difference is minimal.

**Overall Assessment:**

Despite the unusual negative values for Caco-2 and solubility, both ligands have strong binding affinity and good BBB penetration. However, Ligand B has a slightly better BBB score, lower DILI risk, and a more favorable TPSA. Ligand A has better metabolic stability (lower Cl_mic) and fewer H-bond donors. The solubility issues are a major concern for both. Given the slight edge in overall ADME properties and the slightly better BBB penetration, I would favor Ligand B.

Output:
1
2025-04-17 06:44:04,630 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 drug candidates, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (341.419 Da) is slightly lower, which could be advantageous for permeability.

**TPSA:** Ligand A (78.66) is significantly better than Ligand B (94.48). For CNS targets, TPSA < 90 is preferred, and A is closer to this threshold.

**logP:** Both ligands have very low logP values (A: 0.037, B: 0.193). This is a significant concern as it suggests poor membrane permeability. While not ideal, B is slightly better than A.

**H-Bond Donors/Acceptors:** Both ligands have acceptable HBD/HBA counts (A: 1/7, B: 2/7), falling within the recommended ranges.

**QED:** Both ligands have reasonable QED scores (A: 0.774, B: 0.571), indicating drug-like properties. Ligand A is better here.

**DILI:** Both ligands have acceptable DILI risk (A: 69.756, B: 60.915), below the 60 threshold.

**BBB:** Ligand A (83.87) has a substantially better BBB percentile than Ligand B (60.023). This is *critical* for a CNS target like DRD2.

**Caco-2 Permeability:** Ligand A (-4.969) has a worse Caco-2 permeability than Ligand B (-5.622), but both are very poor.

**Aqueous Solubility:** Both ligands have poor aqueous solubility (A: -2.09, B: -2.149).

**hERG Inhibition:** Both ligands show low hERG inhibition risk (A: 0.581, B: 0.185), which is good.

**Microsomal Clearance:** Ligand A (53.762) has a significantly lower microsomal clearance than Ligand B (18.958), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (4.097) has a shorter half-life than Ligand B (20.968).

**P-gp Efflux:** Both ligands have low P-gp efflux liability (A: 0.055, B: 0.021), which is favorable for CNS penetration.

**Binding Affinity:** Ligand B (-7.1 kcal/mol) has a slightly better binding affinity than Ligand A (-8.1 kcal/mol). Although A is better, the difference is not substantial enough to outweigh the other factors.

**Overall Assessment:**

Ligand A is the stronger candidate. While both have poor logP and solubility, Ligand A's superior BBB penetration, lower microsomal clearance, and better QED significantly outweigh the slightly better affinity of Ligand B. The BBB is a crucial factor for CNS drug development, and Ligand A's 83.87 percentile is much more promising than Ligand B's 60.023 percentile. The improved metabolic stability (lower Cl_mic) is also a key advantage.

Output:
0
2025-04-17 06:44:04,631 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (378.847 Da) is slightly higher, but acceptable. Ligand B (347.419 Da) is also good.

**TPSA:** Ligand A (58.64) is excellent, well below the 90 A^2 threshold for CNS targets. Ligand B (89.87) is still reasonable, but closer to the upper limit.

**logP:** Ligand A (3.383) is optimal. Ligand B (-0.477) is significantly below the optimal range and could hinder membrane permeability.

**H-Bond Donors/Acceptors:** Both ligands have acceptable HBD (1) and HBA (Ligand A: 3, Ligand B: 6) counts.

**QED:** Both ligands have good QED scores (Ligand A: 0.545, Ligand B: 0.795), indicating drug-like properties. Ligand B is slightly better here.

**DILI:** Both have low DILI risk (Ligand A: 41.101, Ligand B: 35.673), which is favorable.

**BBB:** Ligand A has a very high BBB penetration percentile (90.074), which is excellent for a CNS target. Ligand B's BBB percentile (21.908) is quite low and a major concern.

**Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and suggests a potential issue with the calculation or data quality. However, we can still compare them relatively.

**Aqueous Solubility:** Both have negative solubility values, which is also unusual.

**hERG Inhibition:** Both ligands show low hERG inhibition liability (Ligand A: 0.661, Ligand B: 0.05), which is good.

**Microsomal Clearance:** Ligand A has a moderate clearance (20.43 mL/min/kg). Ligand B has a very low (negative) clearance (-0.469 mL/min/kg), suggesting high metabolic stability.

**In vitro Half-Life:** Ligand A has a negative half-life (-21.092 hours), which is not physically possible and indicates a data issue. Ligand B has a short half-life (7.236 hours).

**P-gp Efflux:** Ligand A has low P-gp efflux liability (0.084), which is good. Ligand B also has low P-gp efflux liability (0.011), which is also good.

**Binding Affinity:** Ligand A has a stronger binding affinity (-8.2 kcal/mol) than Ligand B (-7.2 kcal/mol). This 1 kcal/mol difference is significant.

**Overall Assessment:**

Ligand A is clearly the better candidate. While it has a slightly higher molecular weight and a questionable half-life value, its excellent BBB penetration, optimal logP, strong binding affinity, and acceptable ADME properties outweigh these minor drawbacks. Ligand B's very low logP and poor BBB penetration are significant liabilities for a CNS-targeting drug. The negative values for Caco-2 and solubility are concerning, but the primary driver for selection is the BBB and logP.

Output:
1
2025-04-17 06:44:04,631 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (350.503 Da) is slightly lower, which could be beneficial for permeability. Ligand B (385.848 Da) is also good.

**TPSA:** Both ligands have TPSA values (A: 78.43, B: 82.53) below the 90 A^2 threshold for CNS targets, which is positive.

**logP:** Both ligands have good logP values (A: 2.375, B: 1.096) within the optimal range of 1-3. Ligand A is slightly better.

**H-Bond Donors/Acceptors:** Ligand A (HBD=3, HBA=3) and Ligand B (HBD=2, HBA=5) both fall within acceptable ranges.

**QED:** Both ligands have good QED values (A: 0.66, B: 0.811), indicating good drug-like properties. Ligand B is slightly better.

**DILI:** Ligand A (16.751) has a significantly lower DILI risk than Ligand B (65.568), which is a major advantage.

**BBB:** Ligand A (46.026) has a slightly better BBB penetration percentile than Ligand B (43.001), although both are below the desirable >70 for CNS targets.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.754 and -4.996), which is unusual and indicates poor permeability. This is a significant concern for both.

**Aqueous Solubility:** Both ligands have negative solubility values (-3.081 and -2.651), indicating very poor aqueous solubility. This is a substantial drawback.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (A: 0.306, B: 0.327).

**Microsomal Clearance:** Ligand A (46.489) has a higher microsomal clearance than Ligand B (-0.307), suggesting lower metabolic stability. Ligand B is better here.

**In vitro Half-Life:** Ligand A (-6.272) has a shorter in vitro half-life than Ligand B (-7.763), indicating faster metabolism. Ligand B is better.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (A: 0.244, B: 0.131), which is good for CNS penetration. Ligand B is slightly better.

**Binding Affinity:** Both ligands have the same binding affinity (-8.6 kcal/mol), which is excellent.

**Overall Assessment:**

While both ligands have good binding affinity, Ligand A is preferable due to its significantly lower DILI risk and slightly better logP and BBB penetration. The poor Caco-2 permeability and solubility are concerning for both, but the DILI risk is a critical factor. Ligand B has better metabolic stability and P-gp efflux, but the high DILI risk is a major red flag.

Output:
0
2025-04-17 06:44:04,631 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (363.479 and 348.403 Da) fall within the ideal range of 200-500 Da.

**TPSA:** Ligand A (72.47) is significantly better than Ligand B (99.25). For CNS targets, we want TPSA <= 90, so Ligand A is preferable.

**logP:** Both ligands have acceptable logP values (1.774 and 2.657, respectively), falling within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Both have 1 HBD, which is good. Ligand A has 4 HBA, while Ligand B has 7. Both are within the acceptable limit of <=10, but Ligand A is slightly better.

**QED:** Both ligands have high QED scores (0.885 and 0.912), indicating good drug-like properties.

**DILI:** Ligand A (42.226) has a lower DILI risk than Ligand B (73.245). Both are below 60, so the risk is moderate, but A is better.

**BBB:** Ligand A (71.772) has a better BBB penetration percentile than Ligand B (65.568). While both are reasonably good, a value >70 is desirable for CNS targets, and A is closer.

**Caco-2 Permeability:** Ligand A (-5.152) has worse Caco-2 permeability than Ligand B (-4.427). Higher values are better, so B is slightly preferred here.

**Aqueous Solubility:** Both have very poor aqueous solubility (-2.756 and -3.381). This is a concern for both, but B is slightly worse.

**hERG Inhibition:** Both ligands have low hERG inhibition liability (0.46 and 0.293), which is good.

**Microsomal Clearance:** Ligand A (21.685) has significantly lower microsomal clearance than Ligand B (56.082), indicating better metabolic stability.

**In vitro Half-Life:** Ligand A (18.096 hours) has a much longer half-life than Ligand B (-31.005 hours). The negative value for B is concerning and suggests very rapid metabolism.

**P-gp Efflux:** Ligand A (0.219) has lower P-gp efflux than Ligand B (0.082), which is preferable for CNS exposure.

**Binding Affinity:** Ligand A (-9.3 kcal/mol) has a slightly better binding affinity than Ligand B (-8.6 kcal/mol). While both are excellent, the 0.7 kcal/mol difference is significant and can outweigh minor ADME drawbacks.

**Overall Assessment:**

Considering the GPCR-specific priorities, Ligand A is the stronger candidate. It has a better TPSA, BBB, DILI, metabolic stability (lower Cl_mic, longer t1/2), P-gp efflux, and binding affinity. While Ligand B has slightly better Caco-2 permeability, the advantages of Ligand A in CNS penetration and metabolic stability are more critical for a DRD2 ligand. The poor solubility is a concern for both, but can be addressed with formulation strategies.

Output:
1
2025-04-17 06:44:04,631 - INFO - Okay, let's analyze these two ligands for their potential as DRD2 drug candidates. DRD2 is a GPCR in the CNS, so BBB penetration, logP, Pgp efflux, TPSA, and binding affinity are paramount.

**Ligand A: [423.229, 49.85, 2.838, 0., 3., 0.732, 56.301, 88.29, -4.552, -3.363, 0.598, 38.082, -15.769, 0.336, -8.6]**
**Ligand B: [345.399, 95.57, 2.096, 1., 6., 0.44, 33.346, 67.468, -4.357, -3.815, 0.358, 100.076, 18.263, 0.031, -6.9]**

Here's a breakdown, property by property:

1. **MW:** A (423.229) is good, within the 200-500 range. B (345.399) is also good. No clear advantage here.
2. **TPSA:** A (49.85) is excellent, well below the 90 target for CNS drugs. B (95.57) is higher, but still potentially acceptable, though less ideal. A is better.
3. **logP:** A (2.838) is optimal (1-3). B (2.096) is slightly lower, but still within range. A is slightly better.
4. **HBD:** A (0) is good. B (1) is acceptable. A is better.
5. **HBA:** A (3) is good. B (6) is higher, but still within the acceptable limit of 10. A is better.
6. **QED:** A (0.732) is excellent, indicating good drug-likeness. B (0.44) is lower, suggesting a less favorable overall profile. A is significantly better.
7. **DILI:** A (56.301) is acceptable (below 60). B (33.346) is very good, lower risk. B is better.
8. **BBB:** A (88.29) is excellent, exceeding the 70% threshold for CNS targets. B (67.468) is lower, making CNS penetration less favorable. A is significantly better.
9. **Caco-2:** Both are negative values, which is unusual. Assuming these are log values, A (-4.552) is better than B (-4.357), indicating better absorption.
10. **Solubility:** Both are negative values, again unusual. A (-3.363) is better than B (-3.815), suggesting better solubility.
11. **hERG:** A (0.598) is better than B (0.358), indicating lower cardiotoxicity risk. A is better.
12. **Cl_mic:** A (38.082) is lower than B (100.076), indicating better metabolic stability. A is better.
13. **t1/2:** A (-15.769) is better than B (18.263), indicating a longer half-life. A is better.
14. **Pgp:** A (0.336) is lower than B (0.031), indicating lower P-gp efflux and better CNS exposure. A is better.
15. **Affinity:** A (-8.6) is significantly better than B (-6.9). This is a substantial advantage (over 1.5 kcal/mol difference).

**Overall Assessment:**

Ligand A consistently outperforms Ligand B across most critical parameters, especially BBB penetration, QED, metabolic stability, and, crucially, binding affinity. While Ligand B has a slightly better DILI score, the superior profile of Ligand A, particularly its excellent CNS penetration potential and strong binding affinity, makes it the more promising drug candidate for targeting DRD2. The affinity difference is large enough to outweigh the slightly higher DILI risk.

Output:
1
2025-04-17 06:44:04,631 - INFO - Batch 306 complete. Total preferences: 4896
2025-04-17 06:44:04,631 - INFO - Processing batch 307/512...
2025-04-17 06:44:47,004 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (352.519 and 367.431 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (69.64) is excellent, well below the 90 A^2 threshold for CNS targets. Ligand B (106.42) is still reasonable but less optimal, exceeding the preferred threshold.

**logP:** Ligand A (2.719) is within the optimal 1-3 range. Ligand B (-0.251) is significantly lower, potentially hindering membrane permeability and CNS penetration despite a good BBB score.

**H-Bond Donors/Acceptors:** Ligand A (HBD=2, HBA=3) and Ligand B (HBD=1, HBA=7) both meet the criteria of <=5 HBD and <=10 HBA.

**QED:** Both ligands have good QED scores (A: 0.594, B: 0.754), indicating drug-like properties.

**DILI:** Ligand A (12.408) has a much lower DILI risk than Ligand B (82.939), a significant advantage.

**BBB:** Both ligands have excellent BBB penetration (A: 70.143, B: 70.803), meeting the >70% threshold for CNS targets.

**Caco-2 Permeability:** Ligand A (-4.772) and Ligand B (-5.236) both have negative Caco-2 values, which is unusual and suggests poor permeability. However, these values are on a scale where negative values are possible and don't necessarily disqualify a compound.

**Aqueous Solubility:** Both ligands have poor aqueous solubility (-2.466 and -2.962). This could pose formulation challenges.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (A: 0.679, B: 0.446).

**Microsomal Clearance:** Ligand A (53.598) has a higher microsomal clearance than Ligand B (45.324), suggesting lower metabolic stability.

**In vitro Half-Life:** Ligand A (-16.863) has a negative half-life, which is not physically possible and indicates a problem with the data or the model. Ligand B (-4.742) also has a negative half-life.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (A: 0.6, B: 0.029), which is favorable for CNS penetration.

**Binding Affinity:** Ligand A (-7.9 kcal/mol) has a slightly better binding affinity than Ligand B (-8.0 kcal/mol). While the difference is small, it is still a factor.

**Overall Assessment:**

Ligand A is preferable despite the negative half-life and slightly higher clearance. The significantly lower DILI risk, better TPSA, and acceptable logP make it a more promising candidate. The negative half-life is a major concern, but could be an artifact of the prediction model. Ligand B's very low logP is a significant drawback, potentially limiting its ability to cross the blood-brain barrier despite the good BBB percentile score.

Output:
1
2025-04-17 06:44:47,005 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B based on the provided guidelines and GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (351.407 Da) and Ligand B (325.46 Da) are both acceptable.

**TPSA:** Ligand A (114.47) is borderline acceptable for CNS targets (<=90 is preferred), while Ligand B (37.19) is excellent. This is a significant advantage for Ligand B.

**logP:** Both ligands have good logP values (Ligand A: 1.483, Ligand B: 2.288), falling within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A has 3 HBD and 7 HBA, which are acceptable. Ligand B has 0 HBD and 5 HBA, also acceptable.

**QED:** Both ligands have good QED scores (Ligand A: 0.544, Ligand B: 0.864), indicating good drug-like properties. Ligand B is better here.

**DILI:** Ligand A (78.054) has a higher DILI risk than Ligand B (39.473). This favors Ligand B.

**BBB:** Ligand B (91.392) has a significantly higher BBB penetration percentile than Ligand A (66.188). This is a crucial advantage for a CNS target like DRD2.

**Caco-2 Permeability:** Both have negative Caco-2 values (-4.833 and -4.855), which is unusual and suggests poor permeability. This is a concern for both, but doesn't differentiate them.

**Aqueous Solubility:** Both have negative solubility values (-3.119 and -1.992), indicating poor aqueous solubility. This is a concern for both, but doesn't differentiate them.

**hERG Inhibition:** Ligand A (0.108) has a slightly lower hERG inhibition risk than Ligand B (0.739), which is a small advantage for A.

**Microsomal Clearance:** Ligand A (42.129) and Ligand B (39.717) have similar microsomal clearance values, suggesting comparable metabolic stability.

**In vitro Half-Life:** Ligand B (-2.849) has a negative half-life, which is not physically meaningful. Ligand A (16.728) has a reasonable half-life. This is a significant advantage for Ligand A.

**P-gp Efflux:** Ligand A (0.018) has very low P-gp efflux liability, which is excellent. Ligand B (0.291) has a higher, but still relatively low, P-gp efflux liability.

**Binding Affinity:** Ligand B (-9.6 kcal/mol) has a significantly stronger binding affinity than Ligand A (-7.9 kcal/mol). This is a substantial advantage, potentially outweighing some ADME drawbacks.

**Overall Assessment:**

Ligand B excels in key GPCR-relevant properties: TPSA, BBB penetration, and, most importantly, binding affinity. While Ligand A has a better half-life and lower P-gp efflux, the superior affinity and BBB penetration of Ligand B are more critical for a CNS-targeting drug. The lower DILI risk of Ligand B is also a positive factor. The negative Caco-2 and solubility values are concerning for both, but can be addressed through formulation strategies.

Output:
1
2025-04-17 06:44:47,005 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (359.411 and 368.499 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (108.05) is higher than Ligand B (67.87). For CNS targets, TPSA < 90 is preferred. Ligand B is significantly better here.

**3. logP:** Ligand A (0.19) is quite low, potentially hindering membrane permeability. Ligand B (2.286) is within the optimal 1-3 range. This is a significant advantage for Ligand B.

**4. H-Bond Donors:** Ligand A (2) and Ligand B (1) are both acceptable.

**5. H-Bond Acceptors:** Ligand A (6) and Ligand B (5) are both acceptable.

**6. QED:** Both ligands have similar, high QED values (0.81 and 0.802), indicating good drug-like properties.

**7. DILI:** Ligand A (61.884) has a slightly higher DILI risk than Ligand B (39.046), but both are reasonably acceptable.

**8. BBB:** Ligand B (69.833) has a significantly better BBB percentile than Ligand A (39.667). This is *critical* for a CNS target like DRD2.

**9. Caco-2 Permeability:** Ligand A (-5.675) has very poor Caco-2 permeability, while Ligand B (-4.639) is better, but still not great.

**10. Aqueous Solubility:** Both ligands have very poor aqueous solubility (-2.707 and -2.96). This could pose formulation challenges.

**11. hERG Inhibition:** Both ligands have low hERG inhibition risk (0.172 and 0.461).

**12. Microsomal Clearance:** Ligand A (-12.043) has a much lower (better) microsomal clearance than Ligand B (37.337), suggesting better metabolic stability.

**13. In vitro Half-Life:** Ligand B (34.196) has a longer half-life than Ligand A (-24.32), which is preferable.

**14. P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.009 and 0.177).

**15. Binding Affinity:** Ligand B (-7.1) has a significantly stronger binding affinity than Ligand A (-9.3). A 1.5 kcal/mol advantage in binding is substantial.

**Overall Assessment:**

Ligand B is the stronger candidate. While both have solubility issues, Ligand B excels in key areas for a CNS GPCR target: significantly better BBB penetration, a more favorable logP, and a much stronger binding affinity. The improved half-life also contributes to its favorability. Although Ligand A has better metabolic stability, the superior CNS penetration and binding of Ligand B outweigh this advantage.

Output:
1
2025-04-17 06:44:47,005 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the guidelines and GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (345.403 and 351.418 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (101.65) is slightly above the optimal <90 for CNS targets, but still reasonable. Ligand B (55.84) is excellent, well below the 90 threshold.

**logP:** Ligand A (0.162) is quite low, potentially hindering permeability. Ligand B (3.101) is within the optimal 1-3 range. This is a significant advantage for Ligand B.

**H-Bond Donors/Acceptors:** Ligand A has 1 HBD and 6 HBA, acceptable. Ligand B has 0 HBD and 4 HBA, also acceptable.

**QED:** Both ligands have good QED scores (0.582 and 0.686), indicating drug-like properties.

**DILI:** Ligand A (51.648) has a slightly higher DILI risk than Ligand B (32.183), but both are below the concerning 60 threshold.

**BBB:** Ligand B (87.553) has a significantly better BBB penetration percentile than Ligand A (70.686). This is crucial for a CNS target like DRD2.

**Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and suggests potential issues with the data or modeling. However, the magnitude is similar.

**Aqueous Solubility:** Both ligands have negative solubility values, which is also unusual.

**hERG:** Both ligands show low hERG inhibition liability (0.243 and 0.488).

**Microsomal Clearance:** Ligand A (-3.172) has a much lower (better) microsomal clearance than Ligand B (71.605), suggesting greater metabolic stability.

**In vitro Half-Life:** Ligand A (-37.629) has a much longer half-life than Ligand B (9.424), which is desirable.

**P-gp Efflux:** Ligand A (0.003) has very low P-gp efflux, which is excellent for CNS penetration. Ligand B (0.266) is slightly higher, but still reasonable.

**Binding Affinity:** Both ligands have very similar binding affinities (-7.7 and -7.4 kcal/mol), both being strong binders. The difference of 0.3 kcal/mol is unlikely to be decisive.

**Overall Assessment:**

Ligand B excels in key GPCR-specific properties: logP and BBB. Its TPSA is also much better. While Ligand A has better metabolic stability (lower Cl_mic) and a longer half-life, the poor logP and lower BBB penetration are significant drawbacks for a CNS target. The similar binding affinities make the ADME properties the deciding factor.

Output:
1
2025-04-17 06:44:47,006 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B based on the provided guidelines, prioritizing GPCR-specific properties (BBB, logP, Pgp, TPSA, and affinity) for DRD2.

**Molecular Weight:** Both ligands are within the ideal range (352.435 and 349.431 Da).

**TPSA:** Both ligands have TPSA values below 90 (A: 90.98, B: 84.67), which is favorable for CNS penetration. Ligand B is slightly better here.

**logP:** Ligand A (-0.351) is below the optimal range (1-3), potentially hindering permeation. Ligand B (1.978) is within the optimal range. This is a significant advantage for Ligand B.

**H-Bond Donors/Acceptors:** Ligand A (HBD=2, HBA=4) and Ligand B (HBD=1, HBA=5) both fall within acceptable ranges.

**QED:** Both ligands have good QED scores (A: 0.613, B: 0.776), indicating drug-likeness. Ligand B is slightly better.

**DILI:** Ligand A (18.728) has a lower DILI risk than Ligand B (28.306), which is a positive attribute.

**BBB:** Both ligands have excellent BBB penetration (A: 73.245, B: 76.58), exceeding the desirable threshold of 70. Ligand B is marginally better.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.923 and -4.223), which is unusual and suggests poor permeability. This is a concern for both.

**Aqueous Solubility:** Both ligands have negative solubility values (-0.701 and -2.747), indicating poor aqueous solubility. Ligand A is slightly better.

**hERG Inhibition:** Both ligands have low hERG inhibition liability (A: 0.285, B: 0.17), which is good.

**Microsomal Clearance:** Ligand A (-6.93) has significantly lower microsomal clearance than Ligand B (53.474), suggesting better metabolic stability. This is a major advantage for Ligand A.

**In vitro Half-Life:** Ligand A (6.074) has a shorter half-life than Ligand B (11.56), which is less desirable.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (A: 0.004, B: 0.066), which is excellent for CNS exposure. Ligand A is slightly better.

**Binding Affinity:** Ligand B (-8.0 kcal/mol) has a stronger binding affinity than Ligand A (-7.7 kcal/mol). This is a significant advantage for Ligand B, potentially outweighing some ADME drawbacks.

**Overall Assessment:**

While Ligand A has better metabolic stability (lower Cl_mic) and slightly better DILI, Pgp efflux, and solubility, Ligand B excels in key GPCR-relevant properties: logP is within the optimal range, and binding affinity is superior. The negative Caco-2 and solubility values are concerning for both, but the stronger binding affinity of Ligand B, combined with its acceptable BBB and logP, makes it the more promising candidate. The difference in binding affinity (0.3 kcal/mol) is substantial enough to offset the slightly higher DILI and clearance.

Output:
1
2025-04-17 06:44:47,006 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (344.459 Da) is slightly lower, which could be beneficial for permeability. Ligand B (406.284 Da) is also acceptable.

**TPSA:** Both ligands have TPSA values below the 90 A^2 threshold for CNS targets. Ligand A (82.26 A^2) is slightly higher than Ligand B (73.14 A^2), favoring B.

**logP:** Both ligands have logP values within the optimal range (1-3). Ligand A (1.838) is slightly lower, while Ligand B (2.268) is closer to the middle of the range.

**H-Bond Donors/Acceptors:** Ligand A has 4 HBD and 3 HBA, while Ligand B has 0 HBD and 6 HBA. Both are within acceptable limits (<=5 HBD and <=10 HBA).

**QED:** Both ligands have good QED scores (>0.5), indicating drug-like properties. Ligand B (0.762) is slightly better than Ligand A (0.658).

**DILI:** Ligand A (35.052) has a lower DILI risk than Ligand B (51.338), which is a significant advantage.

**BBB:** Ligand B (70.997) has a better BBB penetration percentile than Ligand A (62.389), which is crucial for a CNS target like DRD2.

**Caco-2 Permeability:** Ligand A (-5.509) has a worse Caco-2 permeability than Ligand B (-4.624).

**Aqueous Solubility:** Both ligands have very poor aqueous solubility (-2.08 and -2.975 respectively). This is a concern for both, but could be mitigated with formulation strategies.

**hERG Inhibition:** Both ligands show low hERG inhibition risk (0.23 and 0.28 respectively).

**Microsomal Clearance:** Ligand A (-0.285) has a much lower (better) microsomal clearance than Ligand B (58.099), indicating better metabolic stability.

**In vitro Half-Life:** Ligand A (8.484 hours) has a significantly longer half-life than Ligand B (-26.91 hours), which is a major advantage.

**P-gp Efflux:** Ligand A (0.041) has a much lower P-gp efflux liability than Ligand B (0.134), which is favorable for CNS penetration.

**Binding Affinity:** Ligand A (-9.9 kcal/mol) has a significantly stronger binding affinity than Ligand B (-8.6 kcal/mol). This difference of 1.3 kcal/mol is substantial and can outweigh some ADME drawbacks.

**Overall Assessment:**

Ligand A has a superior binding affinity, better metabolic stability (lower Cl_mic, longer t1/2), lower P-gp efflux, and lower DILI risk. While Ligand B has slightly better BBB penetration and TPSA, the significantly stronger binding affinity and improved ADME properties of Ligand A make it the more promising drug candidate. The difference in binding affinity is large enough to compensate for the slightly lower BBB score.

Output:
1
2025-04-17 06:44:47,006 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (356.369 and 352.431 Da) fall comfortably within the ideal 200-500 Da range.

**TPSA:** Ligand A (81.86) is excellent, well below the 90 A^2 threshold for CNS targets. Ligand B (100.8) is still reasonable, but less optimal.

**logP:** Both ligands (1.571 and 1.744) are within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A (1 HBD, 5 HBA) is better than Ligand B (3 HBD, 5 HBA) regarding the number of HBDs. Both are within acceptable HBA limits.

**QED:** Both ligands have similar QED values (0.75 and 0.628), indicating good drug-like properties.

**DILI:** Both ligands have low DILI risk (30.089 and 36.099 percentile), which is favorable.

**BBB:** This is a critical parameter for a CNS target like DRD2. Ligand A has a very high BBB penetration (94.843%), significantly better than Ligand B (50.795%).

**Caco-2 Permeability:** Ligand A (-4.71) has poor Caco-2 permeability, while Ligand B (-5.028) is also poor. This is a potential concern for oral bioavailability, but less critical for CNS targets where direct delivery is possible.

**Aqueous Solubility:** Ligand A (-2.658) has poor aqueous solubility, while Ligand B (-1.683) is also poor. This could pose formulation challenges.

**hERG Inhibition:** Both ligands have low hERG inhibition liability (0.634 and 0.232), which is good.

**Microsomal Clearance:** Ligand A (9.571) has a lower microsomal clearance than Ligand B (4.552), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (-13.52) has a much longer in vitro half-life than Ligand B (48.892), which is a significant advantage.

**P-gp Efflux:** Ligand A (0.088) has lower P-gp efflux liability than Ligand B (0.144), which is beneficial for CNS penetration.

**Binding Affinity:** Ligand A (-8.2 kcal/mol) has a slightly better binding affinity than Ligand B (-7.9 kcal/mol). While the difference is small, it's still a positive factor.

**Overall Assessment:**

Ligand A is the stronger candidate. Its superior BBB penetration, better metabolic stability (lower Cl_mic, longer t1/2), lower P-gp efflux, and slightly better binding affinity outweigh its poorer Caco-2 permeability and aqueous solubility. For a CNS target, BBB penetration is paramount, and Ligand A excels in this area.

Output:
1
2025-04-17 06:44:47,006 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (351.407 and 346.475 Da) fall well within the ideal range of 200-500 Da.

**TPSA:** Ligand A (128.34) is slightly above the optimal <90 for CNS targets, but still reasonable. Ligand B (75.19) is excellent, well below 90.

**logP:** Ligand A (0.185) is quite low, potentially hindering permeability. Ligand B (2.517) is within the optimal 1-3 range. This is a significant advantage for Ligand B.

**H-Bond Donors/Acceptors:** Ligand A has 3 HBD and 6 HBA, which are acceptable. Ligand B has 1 HBD and 4 HBA, also acceptable.

**QED:** Both ligands have good QED scores (0.518 and 0.859), indicating drug-like properties. Ligand B is better here.

**DILI:** Both ligands have low DILI risk (46.84 and 35.556), which is positive. Ligand B is slightly better.

**BBB:** Ligand A has a good BBB percentile (71.772), exceeding the 70% threshold. Ligand B (68.282) is close, but slightly below the desirable threshold.

**Caco-2 Permeability:** Ligand A (-5.665) and Ligand B (-4.718) both have negative values, which is unusual and suggests low permeability. The values are close, so this isn't a major differentiator.

**Aqueous Solubility:** Both ligands have very poor aqueous solubility (-2.787 and -3.689). This is a significant drawback for both.

**hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.122 and 0.519), which is excellent.

**Microsomal Clearance:** Ligand A (25.246) has lower clearance than Ligand B (66.19), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (21.805) has a longer half-life than Ligand B (-1.481), which is a significant advantage.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.032 and 0.052), which is excellent for CNS penetration.

**Binding Affinity:** Both ligands have the same binding affinity (-7.2 kcal/mol), which is very strong.

**Overall Assessment:**

Ligand B excels in logP and QED, and has a better DILI score. However, its BBB penetration is slightly lower than Ligand A. Ligand A has better metabolic stability (lower Cl_mic) and a longer half-life. The solubility is poor for both. Considering the GPCR-specific priorities, logP and BBB are crucial for CNS targets. While Ligand A has a better BBB, Ligand B's significantly improved logP is more important for overall brain exposure. The similar binding affinity means that the ADME properties become the deciding factor. Given the poor solubility of both, the better logP and QED of Ligand B make it slightly more promising, assuming formulation strategies can address the solubility issue.

Output:
1
2025-04-17 06:44:47,006 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (345.4) is slightly better, being closer to the lower end which can aid permeability.

**TPSA:** Ligand B (84.39) is significantly better than Ligand A (111.45). For CNS targets, TPSA < 90 is preferred, and Ligand B comfortably meets this, while Ligand A is pushing the limit.

**logP:** Both ligands have good logP values (A: 1.195, B: 3.081) within the optimal 1-3 range. Ligand B is closer to the upper end, which could potentially lead to some off-target effects, but is still acceptable.

**H-Bond Donors/Acceptors:** Ligand A has 3 HBD and 5 HBA, while Ligand B has 1 HBD and 7 HBA. Both are within acceptable limits (<=5 HBD, <=10 HBA).

**QED:** Both ligands have reasonable QED scores (A: 0.484, B: 0.69), with Ligand B being slightly more drug-like.

**DILI:** Both ligands have similar, acceptable DILI risk (A: 41.411, B: 41.838), both below the 60% threshold.

**BBB:** This is a crucial parameter for CNS targets. Ligand B (83.133) is *much* better than Ligand A (39.279). A BBB percentile >70 is desirable, and Ligand B is approaching that, while Ligand A is significantly lower.

**Caco-2 Permeability:** Both have negative Caco-2 values (-5.014 and -5.14), which is unusual and suggests poor permeability. However, these values are on a scale where negative values are possible and don't necessarily disqualify a compound.

**Aqueous Solubility:** Both ligands have very poor aqueous solubility (-2.942 and -2.0). This is a significant concern for bioavailability.

**hERG Inhibition:** Both have low hERG inhibition risk (A: 0.429, B: 0.95).

**Microsomal Clearance:** Ligand A (-3.492) has a lower (better) microsomal clearance than Ligand B (14.691), indicating better metabolic stability.

**In vitro Half-Life:** Ligand B (33.535) has a significantly longer half-life than Ligand A (7.925), which is a major advantage.

**P-gp Efflux:** Ligand A (0.043) has a much lower P-gp efflux liability than Ligand B (0.856), suggesting better CNS exposure.

**Binding Affinity:** Ligand B (-11.5 kcal/mol) has a *much* stronger binding affinity than Ligand A (-6.7 kcal/mol). This is a >4.5 kcal/mol difference, which is substantial and can outweigh many ADME drawbacks.

**Overall Assessment:**

While Ligand A has better metabolic stability and P-gp efflux, Ligand B excels in the most critical areas for a CNS-targeting GPCR ligand: **BBB penetration and binding affinity**. The significantly stronger binding affinity of Ligand B is a major advantage. The improved QED and half-life also contribute to its favorability. The poor solubility is a concern for both, but can be addressed with formulation strategies. The TPSA is also much better for Ligand B.

Output:
1
2025-04-17 06:44:47,007 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (354.535 Da and 366.487 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (42.01) is excellent, well below the 90 A^2 threshold for CNS targets. Ligand B (114.18) is higher but still potentially acceptable, though less ideal.

**logP:** Ligand A (3.913) is at the upper end of the optimal range (1-3), but still acceptable. Ligand B (1.153) is a bit low, potentially hindering membrane permeability.

**H-Bond Donors/Acceptors:** Ligand A (0 HBD, 4 HBA) is favorable. Ligand B (3 HBD, 5 HBA) is also reasonable.

**QED:** Ligand A (0.75) is good, indicating strong drug-likeness. Ligand B (0.569) is acceptable, but lower.

**DILI:** Ligand A (4.343) has a very low DILI risk. Ligand B (36.409) is also relatively low, but higher than A.

**BBB:** Ligand A (93.408) has excellent BBB penetration potential, exceeding the >70% threshold. Ligand B (45.056) is significantly lower and concerning for a CNS target.

**Caco-2 Permeability:** Ligand A (-4.358) has poor Caco-2 permeability, which is a negative. Ligand B (-5.651) is even worse.

**Aqueous Solubility:** Both ligands have very poor aqueous solubility (-2.542 and -2.405 respectively). This is a significant drawback for both.

**hERG:** Both ligands show very low hERG inhibition liability (0.91 and 0.079), which is excellent.

**Microsomal Clearance:** Ligand A (38.65) has moderate clearance, while Ligand B (26.584) has lower clearance, suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (-7.742) has a very long half-life, which is highly desirable. Ligand B (-6.662) also has a good half-life, but shorter than A.

**P-gp Efflux:** Ligand A (0.279) has low P-gp efflux, which is good for CNS penetration. Ligand B (0.019) has very low P-gp efflux, which is even better.

**Binding Affinity:** Ligand A (-7.3) has slightly better binding affinity than Ligand B (-6.8). While both are good, the 0.5 kcal/mol difference is noticeable.

**Overall Assessment:**

Ligand A excels in key areas for a CNS-targeting GPCR: TPSA, BBB penetration, DILI risk, and binding affinity. Its half-life is also excellent. The main drawbacks are its poor Caco-2 permeability and solubility. Ligand B has better metabolic stability and P-gp efflux, but its lower BBB penetration, lower QED, and lower binding affinity are significant concerns. Given the importance of BBB penetration for a CNS target like DRD2, and the relatively small advantage in metabolic stability for Ligand B, Ligand A is the more promising candidate. The solubility and permeability issues can be addressed with formulation strategies.

Output:
1
2025-04-17 06:44:47,007 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 drug candidates, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (347.459 and 370.523 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (63.57) is significantly better than Ligand B (94.48). For CNS targets, TPSA < 90 is preferred, and A is comfortably within this range, while B is approaching the upper limit.

**3. logP:** Ligand A (1.658) is optimal (1-3), while Ligand B (0.117) is quite low, potentially hindering membrane permeability.

**4. H-Bond Donors:** Both ligands have acceptable HBD counts (1 and 2, respectively), well below the threshold of 5.

**5. H-Bond Acceptors:** Both ligands have acceptable HBA counts (4 and 8, respectively), below the threshold of 10.

**6. QED:** Both ligands have good QED scores (0.575 and 0.633), indicating drug-like properties.

**7. DILI:** Ligand A (11.322) has a much lower DILI risk than Ligand B (50.291), which is a significant advantage.

**8. BBB:** Ligand A (71.19) has a good BBB penetration percentile, exceeding the desirable >70% threshold for CNS targets. Ligand B (52.617) is considerably lower, raising concerns about CNS exposure.

**9. Caco-2 Permeability:** Both have negative values, which is unusual. Assuming these are logP-scale values, they indicate very poor permeability.

**10. Aqueous Solubility:** Both have negative values, indicating very poor solubility.

**11. hERG Inhibition:** Both ligands have low hERG inhibition liability (0.33 and 0.758), which is good.

**12. Microsomal Clearance:** Ligand A (7.041) has a lower (better) microsomal clearance than Ligand B (33.73), suggesting greater metabolic stability.

**13. In vitro Half-Life:** Ligand A (9.627) has a better in vitro half-life than Ligand B (5.183).

**14. P-gp Efflux:** Both ligands have low P-gp efflux liability (0.095 and 0.083), which is favorable for CNS penetration.

**15. Binding Affinity:** Ligand A (-7.7 kcal/mol) has a slightly better binding affinity than Ligand B (-7.4 kcal/mol). While the difference is not huge, it's enough to be considered, especially given the other advantages of Ligand A.

**Overall Assessment:**

Ligand A is significantly more promising. It excels in critical properties for a CNS-targeting GPCR ligand: TPSA, logP, BBB penetration, DILI risk, metabolic stability, and half-life. While both have issues with Caco-2 and solubility, Ligand A's superior BBB and lower DILI risk are decisive advantages. The slightly better binding affinity further supports its selection.

Output:
1
2025-04-17 06:44:47,007 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B based on the provided guidelines, prioritizing GPCR-specific properties (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (364.515 and 355.391 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (88.32) is excellent, falling well below the 90 A^2 threshold for CNS targets. Ligand B (108.87) is still reasonable but less optimal.

**logP:** Both ligands have good logP values (2.294 and 1.811), within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A (2 HBD, 5 HBA) and Ligand B (1 HBD, 8 HBA) both have acceptable numbers of H-bond donors and acceptors, well within the guidelines.

**QED:** Both ligands have good QED scores (0.839 and 0.738), indicating good drug-like properties.

**DILI:** Ligand A (39.434) has a much lower DILI risk than Ligand B (67.895), which is approaching the higher risk threshold.

**BBB:** Ligand A (88.329) has a significantly better BBB penetration percentile than Ligand B (68.67). This is a *critical* factor for a CNS target like DRD2.

**Caco-2 Permeability:** Ligand A (-5.278) and Ligand B (-4.14) both have negative Caco-2 values, indicating poor permeability. This is a concern for both, but the negative value is slightly less for Ligand B.

**Aqueous Solubility:** Both ligands have poor aqueous solubility (-3.358 and -3.602). This is a drawback, but can sometimes be mitigated with formulation strategies.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.715 and 0.3).

**Microsomal Clearance:** Ligand A (23.867) has a lower microsomal clearance than Ligand B (118.826), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (-6.512) has a more negative in vitro half-life, which means a longer half-life, which is desirable. Ligand B (-42.588) has a very negative half-life, indicating a very short half-life.

**P-gp Efflux:** Ligand A (0.224) has lower P-gp efflux liability than Ligand B (0.025), which is favorable for CNS penetration.

**Binding Affinity:** Ligand A (-7.8 kcal/mol) has a slightly better binding affinity than Ligand B (-7.2 kcal/mol). While both are good, the 0.6 kcal/mol difference is significant.

**Overall Assessment:**

Ligand A is clearly superior. It has a better BBB score, lower DILI risk, better metabolic stability (lower Cl_mic, longer t1/2), lower P-gp efflux, and slightly better binding affinity. While both have poor solubility and Caco-2 permeability, the CNS-focused priorities (BBB, Pgp) and the safety profile (DILI) strongly favor Ligand A. The slightly better affinity further solidifies its position.

Output:
1
2025-04-17 06:44:47,007 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (360.479 and 348.443 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (53.76) is significantly better than Ligand B (89.87). For CNS targets, we want TPSA <= 90, and A is comfortably within this range, while B is approaching the upper limit.

**logP:** Ligand A (3.137) is optimal (1-3), while Ligand B (0.275) is quite low, potentially hindering membrane permeability and CNS penetration.

**H-Bond Donors/Acceptors:** Ligand A (0 HBD, 4 HBA) and Ligand B (3 HBD, 4 HBA) are both acceptable.

**QED:** Both ligands have reasonable QED values (0.795 and 0.665), indicating good drug-like properties.

**DILI:** Ligand A (25.126) has a much lower DILI risk than Ligand B (13.959), suggesting better hepatotoxicity potential. Both are below the 40 threshold.

**BBB:** Ligand A (62.233) has a better BBB percentile than Ligand B (43.971), although ideally, we want >70 for CNS targets. A is closer to this target.

**Caco-2 Permeability:** Ligand A (-4.883) and Ligand B (-5.026) both have negative values, which is unusual and suggests very poor permeability. This is a concern for both.

**Aqueous Solubility:** Both ligands have very poor aqueous solubility (-2.522 and -2.223). This could pose formulation challenges.

**hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.354 and 0.192).

**Microsomal Clearance:** Ligand A (38.393) has a higher microsomal clearance than Ligand B (31.593), indicating potentially lower metabolic stability.

**In vitro Half-Life:** Ligand A (56.168) has a significantly longer half-life than Ligand B (3.162), which is a major advantage.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.177 and 0.03).

**Binding Affinity:** Both ligands have excellent binding affinity (-8.0 and -8.1 kcal/mol), with B being slightly better. However, the difference is small and likely less important than the other ADME properties.

**Overall Assessment:**

Ligand A is the more promising candidate. While both have poor solubility and Caco-2 permeability, Ligand A excels in crucial areas for CNS drug development: TPSA, logP, BBB, DILI risk, and in vitro half-life. The slightly better BBB and lower DILI risk are significant advantages. The slightly higher clearance of A is a concern, but the longer half-life mitigates this. Ligand B's low logP is a major drawback, likely hindering its ability to cross the blood-brain barrier despite the affinity.

Output:
1
2025-04-17 06:44:47,008 - INFO - Reasoning:

Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (360.204 and 363.527 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (137.46) is borderline acceptable for CNS penetration, being slightly above the preferred <90, but still reasonable. Ligand B (66.22) is excellent, well below the 90 threshold. This favors Ligand B.

**3. logP:** Ligand A (1.689) is within the optimal range of 1-3. Ligand B (4.102) is slightly above this, potentially leading to solubility issues and off-target effects, but not drastically so.

**4. H-Bond Donors:** Ligand A (1) is good. Ligand B (0) is also good.

**5. H-Bond Acceptors:** Ligand A (8) is acceptable. Ligand B (5) is also acceptable.

**6. QED:** Ligand A (0.376) is below the 0.5 threshold, indicating a less drug-like profile. Ligand B (0.697) is above 0.5, suggesting better drug-likeness. This favors Ligand B.

**7. DILI:** Ligand A (99.147) has a very high DILI risk, which is a major concern. Ligand B (39.705) has a low DILI risk, which is very favorable. This strongly favors Ligand B.

**8. BBB:** Both ligands have good BBB penetration (Ligand A: 72.16, Ligand B: 76.309), exceeding the 70% threshold for CNS targets. Ligand B is slightly better.

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 values which is unusual and suggests a potential issue with the data.

**10. Aqueous Solubility:** Both ligands have negative solubility values which is unusual and suggests a potential issue with the data.

**11. hERG:** Both ligands have low hERG inhibition liability (Ligand A: 0.378, Ligand B: 0.693), which is good.

**12. Microsomal Clearance:** Ligand A (80.406) has moderate clearance, while Ligand B (105.179) has higher clearance, suggesting lower metabolic stability. This favors Ligand A.

**13. In vitro Half-Life:** Ligand A (0.16) has a very short half-life. Ligand B (-14.877) has a negative half-life which is not possible. This is a major red flag for Ligand B.

**14. P-gp Efflux:** Ligand A (0.198) has low P-gp efflux, which is good for CNS exposure. Ligand B (0.402) also has low P-gp efflux.

**15. Binding Affinity:** Ligand A (-9.1 kcal/mol) has significantly stronger binding affinity than Ligand B (-6.5 kcal/mol). This is a substantial advantage for Ligand A, potentially outweighing some of its ADME drawbacks.

**Overall Assessment:**

While Ligand B initially appears better due to its lower TPSA, higher QED, and significantly lower DILI risk, the negative half-life is a critical flaw. The strong binding affinity of Ligand A (-9.1 kcal/mol) is a major advantage and could potentially be optimized to address its higher DILI risk and shorter half-life. The DILI risk is concerning, but can be addressed through structural modifications. The short half-life can also be improved. The negative values for Caco-2 and solubility suggest data issues, but the binding affinity is the most important factor here.

Output:
0
2025-04-17 06:44:47,008 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (357.885 and 351.535 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (39.6) is better than Ligand B (43.86). Both are below the 90 Angstrom threshold for CNS targets, which is good.

**3. logP:** Ligand A (3.82) is optimal, while Ligand B (2.602) is slightly lower but still acceptable.

**4. H-Bond Donors:** Ligand A (1) is preferable to Ligand B (0). While both are low, having some H-bond donors can aid solubility.

**5. H-Bond Acceptors:** Ligand A (4) is slightly higher than Ligand B (3), but both are within the acceptable range of <=10.

**6. QED:** Ligand A (0.906) is significantly better than Ligand B (0.675), indicating a more drug-like profile.

**7. DILI:** Ligand B (7.057) has a much lower DILI risk than Ligand A (43.932), which is a significant advantage.

**8. BBB:** Ligand B (90.035) has a better BBB penetration percentile than Ligand A (85.072). Both are good (>70), but Ligand B is superior for a CNS target.

**9. Caco-2 Permeability:** Ligand A (-4.757) has better Caco-2 permeability than Ligand B (-4.436).

**10. Aqueous Solubility:** Ligand B (-1.597) has better aqueous solubility than Ligand A (-3.886).

**11. hERG Inhibition:** Ligand A (0.911) has a slightly higher hERG inhibition risk than Ligand B (0.531), though both are relatively low.

**12. Microsomal Clearance:** Ligand B (52.898) has a lower microsomal clearance, suggesting better metabolic stability, than Ligand A (49.32).

**13. In vitro Half-Life:** Ligand A (61.027) has a much longer half-life than Ligand B (3.091). This is a significant advantage.

**14. P-gp Efflux:** Ligand A (0.767) has lower P-gp efflux than Ligand B (0.043), which is preferable for CNS exposure.

**15. Binding Affinity:** Ligand A (-10.0) has a significantly stronger binding affinity than Ligand B (-6.9). This is a substantial advantage, potentially outweighing some ADME drawbacks.

**Overall Assessment:**

Ligand A has a much stronger binding affinity and a longer half-life. However, Ligand B demonstrates a significantly better safety profile (lower DILI), better BBB penetration, and improved metabolic stability. The superior affinity of Ligand A is a major plus, and the P-gp efflux is also favorable. Considering the GPCR-specific priorities, the strong binding affinity of Ligand A is the most important factor. While Ligand B has better ADME properties overall, the difference in binding affinity is substantial enough to make Ligand A the more promising candidate, assuming the DILI risk can be mitigated through further optimization.

Output:
1
2025-04-17 06:44:47,008 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (344.371 Da) is slightly lower, which could be beneficial for permeability. Ligand B (382.448 Da) is also acceptable.

**TPSA:** Ligand A (117.08) is borderline for CNS penetration, being slightly above the preferred <90. Ligand B (75.27) is excellent, well below 90, indicating good potential for CNS penetration.

**logP:** Both ligands have acceptable logP values (Ligand A: 1.191, Ligand B: 2.642), falling within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A has 3 HBD and 5 HBA, which are reasonable. Ligand B has 2 HBD and 3 HBA, also good.

**QED:** Both ligands have acceptable QED values (Ligand A: 0.723, Ligand B: 0.602), indicating good drug-like properties.

**DILI:** Ligand A (77.898) has a higher DILI risk than Ligand B (44.591). This is a significant drawback for Ligand A.

**BBB:** Ligand B (80.574) has a significantly better BBB penetration score than Ligand A (29.159). This is a crucial advantage for a CNS target like DRD2.

**Caco-2 Permeability:** Ligand A (-5.698) has poor Caco-2 permeability. Ligand B (-4.864) is also poor, but slightly better than A.

**Aqueous Solubility:** Both ligands have very poor aqueous solubility (-3.054 and -4.235). This could pose formulation challenges.

**hERG Inhibition:** Ligand A (0.024) has a very low hERG risk, which is excellent. Ligand B (0.561) has a slightly elevated risk, but still relatively low.

**Microsomal Clearance:** Ligand A (-26.667) has a much lower (better) microsomal clearance than Ligand B (50.2). This suggests better metabolic stability for Ligand A.

**In vitro Half-Life:** Ligand A (-15.714) has a shorter half-life than Ligand B (-31.667), though both are negative values indicating rapid clearance.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (Ligand A: 0.024, Ligand B: 0.146), which is favorable for CNS exposure.

**Binding Affinity:** Ligand B (-8.1 kcal/mol) has a significantly stronger binding affinity than Ligand A (0.0 kcal/mol). This is a major advantage, potentially outweighing some of the ADME drawbacks.

**Overall Assessment:**

Ligand B is the more promising candidate. While both have solubility issues, Ligand B excels in the critical areas for a CNS GPCR target: BBB penetration and binding affinity. The significantly better BBB score and much stronger binding affinity outweigh the slightly higher DILI and hERG risk, and the worse metabolic stability compared to Ligand A. Ligand A's poor Caco-2 permeability and very weak binding affinity are major limitations.

Output:
1
2025-04-17 06:44:47,008 - INFO - Batch 307 complete. Total preferences: 4912
2025-04-17 06:44:47,008 - INFO - Processing batch 308/512...
2025-04-17 06:45:35,459 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 drug candidates, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (354.439 Da) is slightly lower, which is generally favorable for permeability. Ligand B (385.266 Da) is also acceptable.

**TPSA:** Ligand A (84.73) is excellent, falling well below the 90 A^2 threshold for CNS targets. Ligand B (49.41) is even better, indicating potentially improved brain penetration.

**logP:** Both ligands have good logP values (A: 2.924, B: 3.298), falling within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A has 2 HBD and 6 HBA, which is acceptable. Ligand B has 1 HBD and 2 HBA, which is also good.

**QED:** Both ligands have reasonable QED values (A: 0.754, B: 0.639), suggesting good drug-like properties.

**DILI:** Ligand A (85.847) has a higher DILI risk than Ligand B (57.697). This is a significant concern for Ligand A.

**BBB:** Ligand B (86.623) has a significantly better BBB percentile than Ligand A (74.292). This is a crucial advantage for a CNS target like DRD2.

**Caco-2 Permeability:** Both have negative Caco-2 values (-5.033 and -4.953), which is unusual and suggests poor permeability. However, these values are on a log scale, and the absolute values are similar, so this isn't a major differentiator.

**Aqueous Solubility:** Both ligands have very poor aqueous solubility (-4.269 and -4.358). This could pose formulation challenges.

**hERG:** Both ligands have low hERG inhibition liability (A: 0.343, B: 0.554), which is positive.

**Microsomal Clearance:** Ligand B (14.968) has a much lower microsomal clearance than Ligand A (54.416), indicating better metabolic stability.

**In vitro Half-Life:** Ligand B (-17.217) has a negative half-life, which is impossible. This is a red flag and suggests potential issues with the data or the molecule itself. Ligand A (21.855) has a reasonable half-life.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (A: 0.306, B: 0.242), which is favorable for CNS penetration.

**Binding Affinity:** Both ligands have excellent binding affinities (A: -10.1 kcal/mol, B: -9.5 kcal/mol). Ligand A is slightly better, but the difference is relatively small.

**Overall Assessment:**

Ligand B is the more promising candidate. While its in vitro half-life is nonsensical, its superior BBB penetration, lower DILI risk, and better metabolic stability outweigh the slightly weaker binding affinity and poor solubility. Ligand A's higher DILI risk is a significant concern. The negative half-life for Ligand B is a major data quality issue that would need to be investigated. However, assuming the half-life is a data error, the other properties favor Ligand B.

Output:
1
2025-04-17 06:45:35,459 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (363.571 and 359.499 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (53.16) is significantly better than Ligand B (74.86).  For CNS targets, we want TPSA <= 90, and A is much closer to the ideal <=60. B is pushing the upper limit and could have permeability issues.

**3. logP:** Both ligands have good logP values (3.429 and 4.085), within the optimal 1-3 range, although B is slightly higher.

**4. H-Bond Donors:** Both have 3 HBD, which is acceptable.

**5. H-Bond Acceptors:** Ligand A has 4 HBA, while Ligand B has 6. Both are acceptable, but A is preferable.

**6. QED:** Both have reasonable QED values (0.695 and 0.565), indicating good drug-like properties.

**7. DILI:** Both have concerning DILI risk (18.418 and 77.084). B is significantly higher, indicating a greater potential for liver injury.

**8. BBB:** Ligand A (77.898) has a much better BBB percentile than Ligand B (64.25). For a CNS target like DRD2, >70 is desirable, and A is closer to that threshold.

**9. Caco-2:** Ligand A (-5.343) and Ligand B (-5.548) both have negative Caco-2 values, which is unusual and suggests poor permeability. However, the scale is not specified, so it's hard to interpret.

**10. Solubility:** Both have very poor aqueous solubility (-2.485 and -3.72). This is a significant drawback for both, but B is worse.

**11. hERG:** Both have low hERG risk (0.742 and 0.882), which is good.

**12. Cl_mic:** Ligand A (29.175) has a lower microsomal clearance than Ligand B (88.956), indicating better metabolic stability.

**13. t1/2:** Ligand B (119.391) has a significantly longer in vitro half-life than Ligand A (44.099). This is a positive for B.

**14. Pgp:** Ligand A (0.139) has a much lower P-gp efflux liability than Ligand B (0.646), which is crucial for CNS penetration.

**15. Binding Affinity:** Both ligands have excellent binding affinities (-7.7 and -7.8 kcal/mol). The difference is minimal.

**Overall Assessment:**

Considering the GPCR-specific priorities, Ligand A is the better candidate. While both have poor solubility and concerning DILI scores, A excels in TPSA, BBB, Pgp efflux, and metabolic stability (Cl_mic). The slightly longer half-life of B is a benefit, but it's outweighed by the superior CNS penetration potential of A due to its lower TPSA, higher BBB, and lower Pgp efflux. The similar binding affinities mean that the ADME properties become the deciding factor.

Output:
0
2025-04-17 06:45:35,459 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (344.5 and 343.5 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (40.62) is significantly better than Ligand B (73.99). For CNS targets, we want TPSA <= 90, and ideally closer to 60. Ligand A is well within this range, while Ligand B is approaching the upper limit and less favorable.

**3. logP:** Both ligands have good logP values (3.801 and 2.972), falling within the optimal 1-3 range.

**4. H-Bond Donors:** Ligand A (0) is preferable to Ligand B (3). Fewer HBDs generally improve permeability.

**5. H-Bond Acceptors:** Both have 2 HBA, which is acceptable.

**6. QED:** Ligand A (0.815) has a much better QED score than Ligand B (0.571), indicating a more drug-like profile.

**7. DILI:** Ligand A (37.73) has a slightly higher DILI risk than Ligand B (27.03), but both are below the 40% threshold and are considered low risk.

**8. BBB:** Ligand A (81.89) has a better BBB penetration percentile than Ligand B (69.48). Both are reasonably good, but >70 is desirable for CNS targets, and A is closer.

**9. Caco-2 Permeability:** Ligand A (-4.256) has worse Caco-2 permeability than Ligand B (-4.824). However, these values are negative and hard to interpret without knowing the scale.

**10. Aqueous Solubility:** Both ligands have poor aqueous solubility (-4.073 and -3.844). This could pose formulation challenges, but is less critical than CNS penetration for a CNS target.

**11. hERG Inhibition:** Both ligands have low hERG inhibition risk (0.648 and 0.415).

**12. Microsomal Clearance:** Ligand B (54.02) has lower microsomal clearance than Ligand A (68.8), suggesting better metabolic stability.

**13. In vitro Half-Life:** Ligand A (15.39) has a longer half-life than Ligand B (-13.24). A positive half-life is preferable.

**14. P-gp Efflux:** Ligand A (0.501) has lower P-gp efflux than Ligand B (0.096), which is favorable for CNS exposure.

**15. Binding Affinity:** Ligand B (-8.0) has a slightly better binding affinity than Ligand A (-7.6). However, the difference is only 0.4 kcal/mol, which is less significant than the ADME advantages of Ligand A.

**Overall Assessment:**

Considering the GPCR-specific priorities, Ligand A is the more promising candidate. It has a significantly better TPSA, QED, and BBB penetration, and lower P-gp efflux. While Ligand B has slightly better affinity and metabolic stability, the ADME advantages of Ligand A, particularly its superior CNS penetration profile, outweigh this small difference in binding.

Output:
1
2025-04-17 06:45:35,460 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (345.403 and 356.482 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (102.16) is higher than the preferred <90 for CNS targets, while Ligand B (60.85) is well within the optimal range. This is a significant advantage for Ligand B.

**logP:** Both ligands (1.272 and 2.514) are within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A has 2 HBD and 8 HBA, while Ligand B has 1 HBD and 3 HBA. Both are within acceptable limits (<=5 HBD and <=10 HBA).

**QED:** Both ligands have similar QED values (0.787 and 0.762), indicating good drug-likeness.

**DILI:** Ligand A (56.572) has a moderate DILI risk, while Ligand B (19.232) has a very low risk. This is a clear advantage for Ligand B.

**BBB:** Ligand A (48.352) has a moderate BBB penetration, while Ligand B (92.904) has excellent BBB penetration. This is a critical advantage for a CNS target like DRD2.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.894 and -4.286). These values are unusual and difficult to interpret without further context, but suggest poor permeability.

**Aqueous Solubility:** Both ligands have negative solubility values (-2.094 and -2.369). Similar to Caco-2, these are unusual and suggest poor solubility.

**hERG Inhibition:** Ligand A (0.092) has a slightly higher hERG risk than Ligand B (0.552), but both are relatively low.

**Microsomal Clearance:** Ligand A (6.877) has a lower microsomal clearance (better metabolic stability) than Ligand B (29.505).

**In vitro Half-Life:** Ligand A (-1.589) has a shorter in vitro half-life than Ligand B (-12.435).

**P-gp Efflux:** Ligand A (0.019) has very low P-gp efflux liability, which is favorable. Ligand B (0.164) also has low P-gp efflux, but slightly higher than A.

**Binding Affinity:** Ligand A (-9.2 kcal/mol) has a slightly stronger binding affinity than Ligand B (-6.9 kcal/mol). The difference is 2.3 kcal/mol, which is significant.

**Overall Assessment:**

While Ligand A has a slightly better binding affinity and lower P-gp efflux, Ligand B is significantly better in several key areas for a CNS-targeting GPCR: TPSA, BBB penetration, and DILI risk. The lower TPSA and high BBB penetration of Ligand B are particularly important for brain exposure. The lower DILI risk is also a significant advantage. The difference in binding affinity, while notable, can potentially be overcome with further optimization, whereas improving TPSA or BBB is much more challenging.

Output:
1
2025-04-17 06:45:35,460 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (358.869 and 360.845 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (56.33) is significantly better than Ligand B (67.23). For CNS targets, we want TPSA <= 90, both are within this range, but A is more favorable.

**logP:** Ligand A (3.979) is slightly higher than Ligand B (2.498), both are within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A has 2 HBD and 2 HBA, while Ligand B has 1 HBD and 4 HBA. Both are within acceptable limits (<=5 HBD and <=10 HBA).

**QED:** Both ligands have good QED scores (0.81 and 0.91), indicating good drug-like properties.

**DILI:** Ligand A (39.667) has a lower DILI risk than Ligand B (59.287). Both are below 60, but A is preferable.

**BBB:** Both ligands have similar, and good, BBB penetration (67.352% and 68.166%). Both are above the 70% threshold, making them both viable for CNS targets.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.994 and -4.954), which is unusual and suggests poor permeability. This is a significant concern for both.

**Aqueous Solubility:** Both ligands have negative solubility values (-4.288 and -3.494), indicating very poor aqueous solubility. This is a major drawback for both.

**hERG Inhibition:** Ligand A (0.811) has a slightly higher hERG inhibition risk than Ligand B (0.329). B is preferable here.

**Microsomal Clearance:** Ligand A (4.097) has a much lower microsomal clearance than Ligand B (14.556), indicating better metabolic stability. This is a significant advantage for A.

**In vitro Half-Life:** Ligand A (31.206 hours) has a longer half-life than Ligand B (24.538 hours). This is a positive for A.

**P-gp Efflux:** Ligand A (0.369) has lower P-gp efflux liability than Ligand B (0.179). Lower is better, so A is preferable.

**Binding Affinity:** Both ligands have excellent binding affinities (-9.3 and -8.7 kcal/mol). Ligand A is slightly better (-9.3 kcal/mol).

**Overall Assessment:**

Ligand A is superior. While both compounds share some drawbacks (poor Caco-2 and solubility), Ligand A demonstrates advantages in key areas: lower DILI risk, better metabolic stability (lower Cl_mic, longer t1/2), lower P-gp efflux, and slightly better binding affinity. The TPSA is also more favorable for CNS penetration. The slightly higher hERG risk for A is a concern, but outweighed by the other benefits.

Output:
1
2025-04-17 06:45:35,460 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (369.372 and 346.427 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Both ligands have TPSA values (71.84 and 71.78) that are acceptable for oral absorption (<140) but slightly high for optimal CNS penetration (<90).

**3. logP:** Ligand A (3.737) is at the higher end of the optimal range (1-3), while Ligand B (2.469) is well within it. Ligand A's higher logP *could* lead to off-target effects, but isn't a dealbreaker.

**4. H-Bond Donors:** Ligand A (2) and Ligand B (1) both meet the HBD criteria (<=5).

**5. H-Bond Acceptors:** Ligand A (5) and Ligand B (4) both meet the HBA criteria (<=10).

**6. QED:** Both ligands have good QED scores (0.736 and 0.77), indicating drug-like properties.

**7. DILI:** Ligand A (88.639) has a higher DILI risk than Ligand B (60.062). Ligand B is preferable here.

**8. BBB:** This is critical for a CNS target. Ligand A (75.998) has a better BBB percentile than Ligand B (63.94), which is a significant advantage.

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 values, which is unusual and suggests very poor permeability. This is a major concern for both.

**10. Aqueous Solubility:** Both ligands have negative solubility values, which is also a major concern.

**11. hERG Inhibition:** Ligand A (0.547) has a slightly higher hERG risk than Ligand B (0.163), making Ligand B preferable.

**12. Microsomal Clearance:** Ligand B (32.072) has a slightly lower microsomal clearance than Ligand A (28.66), suggesting better metabolic stability.

**13. In vitro Half-Life:** Ligand A (81.118) has a significantly longer half-life than Ligand B (25.067), which is a strong advantage.

**14. P-gp Efflux:** Ligand A (0.368) has lower P-gp efflux than Ligand B (0.081), which is preferable for CNS penetration.

**15. Binding Affinity:** Ligand A (-9.5 kcal/mol) has a significantly stronger binding affinity than Ligand B (-8.0 kcal/mol). This is a substantial advantage that can potentially overcome some of the ADME liabilities.

**Overall Assessment:**

Despite the poor Caco-2 and solubility values for both compounds, Ligand A stands out due to its significantly higher binding affinity (-9.5 vs -8.0 kcal/mol) and better BBB penetration (75.998 vs 63.94). The longer half-life and lower P-gp efflux also contribute to its favorability. While Ligand B has a slightly better safety profile (lower DILI, hERG), the potency and CNS penetration advantages of Ligand A are more crucial for a DRD2 target. The poor permeability and solubility would need to be addressed in further optimization, but the strong binding and BBB are a good starting point.

Output:
1
2025-04-17 06:45:35,460 - INFO - Okay, let's analyze these two ligands for their potential as DRD2 drug candidates. DRD2 is a GPCR in the CNS, so BBB penetration, logP, Pgp efflux, TPSA, and binding affinity are paramount.

**Ligand A:** [337.419, 46.61, 4.19, 0, 3, 0.789, 69.639, 75.921, -4.434, -5.775, 0.786, 119.593, 26.085, 0.708, -9.7]
**Ligand B:** [345.447, 70.47, 0.454, 1, 5, 0.787, 31.563, 51.221, -5.149, -1.152, 0.131, 11.376, 3.441, 0.017, -8]

**1. Molecular Weight:** Both ligands are within the ideal range (200-500 Da). A (337.419) is slightly preferred.

**2. TPSA:** Ligand A (46.61) is excellent, well below the 90 A^2 threshold for CNS targets. Ligand B (70.47) is still reasonable but less ideal.

**3. logP:** Ligand A (4.19) is at the higher end of the optimal range, potentially raising concerns about solubility and off-target effects. Ligand B (0.454) is *too* low, likely hindering permeability.

**4. H-Bond Donors:** Ligand A (0) is good. Ligand B (1) is acceptable.

**5. H-Bond Acceptors:** Ligand A (3) is good. Ligand B (5) is acceptable.

**6. QED:** Both ligands have similar, good QED values (A: 0.789, B: 0.787).

**7. DILI:** Ligand A (69.639) is moderately risky, but acceptable. Ligand B (31.563) is excellent, indicating low liver injury risk.

**8. BBB:** Ligand A (75.921) is very good, exceeding the >70% threshold for CNS targets. Ligand B (51.221) is significantly lower and concerning for CNS penetration.

**9. Caco-2:** Ligand A (-4.434) is very poor. Ligand B (-5.149) is also very poor. Both are problematic.

**10. Solubility:** Ligand A (-5.775) is very poor. Ligand B (-1.152) is poor, but better than A.

**11. hERG:** Ligand A (0.786) is acceptable. Ligand B (0.131) is excellent, indicating very low cardiotoxicity risk.

**12. Cl_mic:** Ligand A (119.593) is moderate. Ligand B (11.376) is very low, indicating good metabolic stability.

**13. t1/2:** Ligand A (26.085) is reasonable. Ligand B (3.441) is short, potentially requiring frequent dosing.

**14. Pgp:** Ligand A (0.708) is acceptable. Ligand B (0.017) is excellent, suggesting minimal efflux.

**15. Binding Affinity:** Ligand A (-9.7) is significantly stronger than Ligand B (-8). This is a substantial advantage.

**Overall Assessment:**

Ligand A excels in binding affinity and BBB penetration, crucial for a CNS GPCR target. However, it has poor Caco-2 permeability and solubility, and a moderately elevated DILI risk. Ligand B has better safety profiles (DILI, hERG, Pgp) and metabolic stability, but suffers from poor BBB penetration and a significantly weaker binding affinity.

Despite the drawbacks of Ligand A, the substantial binding affinity advantage (-9.7 vs -8) and good BBB penetration outweigh its other issues, *especially* for a CNS target like DRD2. The solubility and permeability issues could potentially be addressed through formulation strategies. The DILI risk is moderate and could be further investigated. Ligand B's weak affinity is a major hurdle that is unlikely to be overcome with further optimization.

Therefore, I predict **Ligand A** is the more viable drug candidate.

Output:
1
2025-04-17 06:45:35,461 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (370.49 and 346.475 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (58.64) is excellent, well below the 90 A^2 threshold for CNS targets. Ligand B (78.09) is still reasonable but less optimal.

**3. logP:** Both ligands have good logP values (2.447 and 2.303), falling within the optimal 1-3 range.

**4. H-Bond Donors:** Ligand A (1) and Ligand B (2) are both acceptable, below the 5 threshold.

**5. H-Bond Acceptors:** Ligand A (4) and Ligand B (3) are both acceptable, below the 10 threshold.

**6. QED:** Both ligands have good QED scores (0.836 and 0.795), indicating good drug-like properties.

**7. DILI:** Ligand A (41.373) has a slightly higher DILI risk than Ligand B (13.687), but both are below the concerning 60 threshold.

**8. BBB:** This is a critical parameter for a CNS target like DRD2. Ligand A (82.823) has a significantly better BBB percentile than Ligand B (55.332). This is a major advantage for Ligand A.

**9. Caco-2 Permeability:** Ligand A (-4.588) and Ligand B (-5.056) both have negative values, which is unusual and suggests poor permeability. However, the scale is not specified, so it's difficult to interpret.

**10. Aqueous Solubility:** Both ligands have very poor aqueous solubility (-2.882 and -1.837). This is a significant drawback for both.

**11. hERG Inhibition:** Both ligands have low hERG inhibition risk (0.763 and 0.37).

**12. Microsomal Clearance:** Ligand B (18.241) has lower microsomal clearance than Ligand A (31.453), indicating better metabolic stability.

**13. In vitro Half-Life:** Ligand B (-18.015) has a longer in vitro half-life than Ligand A (-22.725).

**14. P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.19 and 0.031), which is favorable for CNS penetration.

**15. Binding Affinity:** Both ligands have excellent binding affinity (-8.1 and -8.0 kcal/mol). The difference is minimal.

**Overall Assessment:**

Ligand A is superior due to its significantly better BBB penetration (82.823 vs 55.332). While Ligand B has slightly better metabolic stability and half-life, the ability to cross the blood-brain barrier is paramount for a DRD2 ligand targeting CNS disorders. The solubility issues are concerning for both, but can potentially be addressed through formulation strategies. The similar binding affinities make the BBB difference the deciding factor.

Output:
1
2025-04-17 06:45:35,461 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (467.136 Da) is towards the higher end, while Ligand B (345.399 Da) is comfortably within the range.

**TPSA:** Ligand A (46.92) is excellent for CNS penetration, well below the 90 A^2 threshold. Ligand B (103.94) is higher, but still potentially acceptable, though less ideal.

**logP:** Ligand A (4.504) is slightly above the optimal range (1-3), potentially leading to solubility issues or off-target interactions. Ligand B (-0.909) is significantly below the optimal range, which could hinder permeation.

**H-Bond Donors/Acceptors:** Ligand A (HBD=1, HBA=3) and Ligand B (HBD=2, HBA=4) both have reasonable numbers of hydrogen bond donors and acceptors, falling within acceptable limits.

**QED:** Both ligands have similar QED values (A: 0.617, B: 0.63), indicating good drug-like properties.

**DILI:** Ligand A (71.694) has a higher DILI risk than Ligand B (33.424), but both are below the concerning threshold of 60.

**BBB:** Ligand A (84.219) has a significantly better BBB percentile than Ligand B (52.656). This is a crucial advantage for a CNS target like DRD2.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.01 and -4.837), which is unusual and suggests poor permeability. This is a significant drawback for both.

**Aqueous Solubility:** Both ligands have negative solubility values (-4.714 and -2.406), indicating very poor aqueous solubility. This is a major concern for formulation and bioavailability.

**hERG Inhibition:** Ligand A (0.786) has a slightly higher hERG risk than Ligand B (0.188), but both are relatively low.

**Microsomal Clearance:** Ligand A (64.827) has a higher microsomal clearance than Ligand B (8.801), indicating lower metabolic stability.

**In vitro Half-Life:** Ligand B (-32.73) has a negative half-life, which is not physically possible and indicates a severe instability issue. Ligand A (110.702) has a good in vitro half-life.

**P-gp Efflux:** Ligand A (0.814) has a higher P-gp efflux liability than Ligand B (0.054). Lower P-gp efflux is preferred for CNS penetration.

**Binding Affinity:** Ligand A (-9.3 kcal/mol) has a significantly stronger binding affinity than Ligand B (-7.8 kcal/mol). This is a substantial advantage, potentially outweighing some of its other drawbacks.

**Overall Assessment:**

Ligand A is the stronger candidate despite some drawbacks. Its superior binding affinity (-9.3 kcal/mol vs -7.8 kcal/mol) and significantly better BBB penetration (84.219% vs 52.656%) are critical for a CNS-targeting GPCR like DRD2. While its logP is slightly high and its DILI risk is moderate, these are less concerning than the extremely poor in vitro half-life and P-gp efflux of Ligand B. The negative Caco-2 and solubility values are concerning for both, but could be addressed with formulation strategies. Ligand B's negative half-life is a dealbreaker.

Output:
1
2025-04-17 06:45:35,461 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B against the provided guidelines, prioritizing GPCR-specific properties (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (348.422 and 342.443 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (76.44) is better than Ligand B (62.06). Both are below the 90 A^2 threshold for CNS targets, which is excellent.

**logP:** Ligand A (0.974) is slightly below the optimal 1-3 range, but acceptable. Ligand B (3.507) is within the optimal range.

**H-Bond Donors:** Ligand A (1) is better than Ligand B (0). Lower is generally preferred for BBB penetration.

**H-Bond Acceptors:** Ligand A (4) is better than Ligand B (6). Both are within the acceptable limit of 10.

**QED:** Both ligands have good QED scores (0.803 and 0.832, respectively), indicating drug-like properties.

**DILI:** Ligand A (12.796) has a significantly lower DILI risk than Ligand B (49.438). This is a major advantage for Ligand A.

**BBB:** Both ligands have excellent BBB penetration (74.292 and 73.672, respectively), meeting the >70% threshold for CNS targets.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.971 and -4.884), which is unusual and suggests poor permeability. This is a concern for both.

**Aqueous Solubility:** Both ligands have negative solubility values (-2.922 and -3.764), indicating very poor aqueous solubility. This is a significant drawback for both.

**hERG Inhibition:** Ligand A (0.584) has a lower hERG inhibition risk than Ligand B (0.302), which is preferable.

**Microsomal Clearance:** Ligand A (8.496) has a much lower microsomal clearance than Ligand B (65.297), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (-0.638) has a slightly better half-life than Ligand B (-37.807).

**P-gp Efflux:** Ligand A (0.011) has a significantly lower P-gp efflux liability than Ligand B (0.192), which is crucial for CNS exposure.

**Binding Affinity:** Ligand B (-9.0) has a stronger binding affinity than Ligand A (-8.1). The difference is 0.9 kcal/mol, which is substantial.

**Overall Assessment:**

Ligand B has a significantly better binding affinity (-9.0 vs -8.1 kcal/mol). However, Ligand A demonstrates superior ADME properties, particularly in terms of DILI risk, microsomal clearance, and P-gp efflux. The lower DILI and P-gp efflux of Ligand A are very important for CNS drug development. While both have poor solubility and Caco-2 permeability, the affinity difference is significant. Given the importance of affinity for GPCRs, and the fact that the other ADME properties of Ligand A are considerably better, I would choose Ligand B.

Output:
1
2025-04-17 06:45:35,461 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (352.41 and 364.877 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (78.67) is slightly higher than Ligand B (67.23). Both are below the 90 A^2 threshold desirable for CNS targets, but B is better.

**3. logP:** Ligand A (0.458) is quite low, potentially hindering permeability. Ligand B (1.791) is within the optimal 1-3 range. This is a significant advantage for B.

**4. H-Bond Donors:** Both have 1 HBD, which is acceptable.

**5. H-Bond Acceptors:** Ligand A has 5 HBA, and Ligand B has 4. Both are below the 10 threshold.

**6. QED:** Both ligands have very similar QED values (0.781 and 0.782), indicating good drug-likeness.

**7. DILI:** Ligand A (52.113) has a higher DILI risk than Ligand B (32.687). Both are below 60, so the risk is moderate, but B is preferable.

**8. BBB:** Ligand B (80.07) has a significantly better BBB penetration percentile than Ligand A (70.803). This is a crucial factor for a CNS target like DRD2.

**9. Caco-2 Permeability:** Ligand A (-4.592) has poor Caco-2 permeability, while Ligand B (-5.095) is also poor, but slightly better.

**10. Aqueous Solubility:** Ligand A (-0.859) has slightly better solubility than Ligand B (-2.865).

**11. hERG Inhibition:** Both ligands show very low hERG inhibition liability (0.258 and 0.123), which is excellent.

**12. Microsomal Clearance:** Both ligands have similar microsomal clearance values (24.048 and 26.695 mL/min/kg).

**13. In vitro Half-Life:** Ligand B (-11.813) has a slightly longer in vitro half-life than Ligand A (-17.541).

**14. P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.159 and 0.086), which is favorable for CNS penetration.

**15. Binding Affinity:** Both ligands have excellent binding affinity (-8.2 and -8.4 kcal/mol), with Ligand B being slightly better. The difference is less than 1.5 kcal/mol, so this is not a decisive factor.

**Overall Assessment:**

Ligand B is the stronger candidate. While both have good affinity and drug-like properties, Ligand B excels in key areas for a CNS GPCR target: better logP, significantly improved BBB penetration, and lower DILI risk. Ligand A's low logP and poor Caco-2 permeability are concerning.

Output:
1
2025-04-17 06:45:35,462 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (363.849 and 345.447 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (88.05) is better than Ligand B (61.68) as it is closer to the ideal <90 for CNS targets. Ligand B is quite low, which *could* be a concern for binding.

**logP:** Ligand A (3.42) is optimal (1-3). Ligand B (-0.026) is significantly lower, potentially hindering membrane permeability and CNS penetration.

**H-Bond Donors/Acceptors:** Ligand A (3 HBD, 4 HBA) and Ligand B (0 HBD, 5 HBA) both fall within acceptable limits (<=5 HBD, <=10 HBA).

**QED:** Both ligands have good QED scores (0.734 and 0.772), indicating drug-like properties.

**DILI:** Ligand A (83.443) has a higher DILI risk than Ligand B (22.683). This is a significant drawback for Ligand A.

**BBB:** Ligand A (60.876) and Ligand B (59.093) are both below the desirable >70 for CNS targets. However, the BBB score is less critical if other properties are highly favorable.

**Caco-2 Permeability:** Ligand A (-4.902) and Ligand B (-4.837) are both very poor, indicating very low intestinal absorption.

**Aqueous Solubility:** Ligand A (-4.754) and Ligand B (-0.468) are both poor.

**hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.336 and 0.166).

**Microsomal Clearance:** Ligand A (36.655) has a higher clearance than Ligand B (16.976), suggesting lower metabolic stability.

**In vitro Half-Life:** Ligand A (119.734) has a much longer half-life than Ligand B (2.963).

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.092 and 0.017).

**Binding Affinity:** Both ligands have the same binding affinity (-8.2 kcal/mol), which is excellent.

**Overall Assessment:**

While Ligand A has a longer half-life, its significantly higher DILI risk, higher microsomal clearance, and poor Caco-2 permeability are major concerns. Ligand B, despite its lower logP and BBB, has a much better safety profile (lower DILI) and better metabolic stability. The similar binding affinity makes the ADME properties the deciding factor. The low logP of Ligand B is a concern, but could potentially be addressed through further medicinal chemistry optimization.

Output:
1
2025-04-17 06:45:35,462 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (343.475 and 342.355 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (62.19) is significantly better than Ligand B (98.39). For CNS targets, TPSA should be <= 90, and A is comfortably within this range, while B is close to the upper limit and less desirable.

**3. logP:** Ligand A (4.253) is slightly higher than the optimal range (1-3), but still potentially acceptable. Ligand B (2.758) is within the ideal range. However, for a GPCR, slightly higher logP can be tolerated if other parameters are favorable.

**4. H-Bond Donors:** Both ligands have 2 HBD, which is within the acceptable limit of <= 5.

**5. H-Bond Acceptors:** Ligand A has 4 HBA, and Ligand B has 6. Both are within the acceptable limit of <= 10.

**6. QED:** Both ligands have similar QED values (0.753 and 0.695), indicating good drug-like properties.

**7. DILI:** Ligand A (63.862) has a lower DILI risk than Ligand B (93.292). This is a significant advantage for A.

**8. BBB:** Ligand A (68.554) has a better BBB penetration percentile than Ligand B (59.674). While both are below the ideal >70, A is closer. This is crucial for a CNS target like DRD2.

**9. Caco-2 Permeability:** Both have negative values (-4.85 and -4.921). This is unusual and suggests poor permeability. However, the values are very close.

**10. Aqueous Solubility:** Both ligands have negative values (-4.768 and -4.222). This suggests very poor aqueous solubility, which is a concern.

**11. hERG Inhibition:** Ligand A (0.733) has a lower hERG inhibition liability than Ligand B (0.346), indicating a lower risk of cardiotoxicity.

**12. Microsomal Clearance:** Ligand B (78.593) has a higher microsomal clearance than Ligand A (58.554), meaning it is metabolized faster. Lower clearance is preferred for better metabolic stability.

**13. In vitro Half-Life:** Ligand A (129.704) has a longer in vitro half-life than Ligand B (112.215), which is desirable.

**14. P-gp Efflux:** Ligand A (0.548) has lower P-gp efflux liability than Ligand B (0.126). Lower efflux is crucial for CNS exposure.

**15. Binding Affinity:** Ligand B (-8.7 kcal/mol) has a slightly better binding affinity than Ligand A (-8.3 kcal/mol). While this is a positive for B, the difference (0.4 kcal/mol) is not substantial enough to outweigh the significant advantages of A in other critical ADME properties.

**Overall Assessment:**

Ligand A is the more promising candidate. While Ligand B has a slightly better binding affinity, Ligand A excels in crucial ADME properties for a CNS-targeting GPCR: lower DILI risk, better BBB penetration, lower P-gp efflux, longer half-life, lower hERG inhibition, and a more favorable TPSA. The solubility and Caco-2 permeability are poor for both, but these can be addressed with formulation strategies. The slightly higher logP of A is less concerning given its other advantages.



Output:
0
2025-04-17 06:45:35,462 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (357.445 and 346.383 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (52.65) is excellent, well below the 90 A^2 threshold for CNS targets. Ligand B (104.71) is higher, but still potentially acceptable, though less ideal.

**logP:** Both ligands have logP values (1.871 and 2.101) within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A (HBD=1, HBA=3) is better than Ligand B (HBD=3, HBA=5) in terms of these parameters, suggesting potentially improved permeability.

**QED:** Both ligands have reasonable QED scores (0.836 and 0.679), indicating good drug-like properties.

**DILI:** Ligand A (8.337 percentile) has a significantly lower DILI risk than Ligand B (36.603 percentile). This is a substantial advantage.

**BBB:** Ligand A (87.553 percentile) has a much higher predicted BBB penetration than Ligand B (43.699 percentile). This is *critical* for a CNS target like DRD2.

**Caco-2 Permeability:** Ligand A (-4.914) and Ligand B (-5.001) have similar, very low Caco-2 permeability values. This is a concern for oral bioavailability, but less critical for a CNS target where direct brain delivery is possible.

**Aqueous Solubility:** Both ligands have very poor aqueous solubility (-1.522 and -2.505). This could pose formulation challenges.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.615 and 0.232).

**Microsomal Clearance:** Ligand A (-32.822) has much lower (better) microsomal clearance than Ligand B (13.439). This suggests greater metabolic stability.

**In vitro Half-Life:** Ligand A (-12.515) has a longer in vitro half-life than Ligand B (38.431).

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.02 and 0.049).

**Binding Affinity:** Both ligands have very similar and excellent binding affinities (-8.3 and -8.4 kcal/mol). The difference is negligible.

**Overall Assessment:**

Ligand A is significantly better due to its superior BBB penetration, lower DILI risk, lower microsomal clearance, and longer half-life. While both have poor solubility and Caco-2 permeability, the CNS target mitigates the importance of the latter. The similar binding affinities make the ADME/Tox properties the deciding factors.

Output:
1
2025-04-17 06:45:35,462 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (341.415 and 352.519 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (80.12) is better than Ligand B (67.43), both are below the 90 A^2 threshold for CNS targets.

**3. logP:** Ligand A (1.47) is within the optimal range (1-3), while Ligand B (3.341) is at the higher end, potentially raising solubility concerns.

**4. H-Bond Donors:** Ligand A (1) is preferable to Ligand B (2), as fewer donors generally improve permeability.

**5. H-Bond Acceptors:** Ligand A (5) is preferable to Ligand B (3).

**6. QED:** Ligand A (0.913) has a significantly better QED score than Ligand B (0.468), indicating a more drug-like profile.

**7. DILI:** Ligand A (47.77) has a slightly higher DILI risk than Ligand B (26.871), but both are below the concerning threshold of 60.

**8. BBB:** Ligand B (73.75) has a better BBB penetration percentile than Ligand A (67.119), which is a crucial factor for CNS targets like DRD2.

**9. Caco-2 Permeability:** Both ligands have very negative Caco-2 values (-4.823 and -4.822), which is unusual and suggests a potential issue with the data or a very poor permeability.

**10. Aqueous Solubility:** Both ligands have very negative solubility values (-1.322 and -3.194), which is also unusual and suggests a potential issue with the data or a very poor solubility.

**11. hERG Inhibition:** Ligand A (0.253) shows a lower hERG inhibition liability than Ligand B (0.583), which is favorable.

**12. Microsomal Clearance:** Ligand A (-2.953) has a lower (better) microsomal clearance than Ligand B (67.917), indicating greater metabolic stability.

**13. In vitro Half-Life:** Ligand B (-10.455) has a longer in vitro half-life than Ligand A (-8.5), which is generally desirable.

**14. P-gp Efflux:** Ligand A (0.03) has much lower P-gp efflux liability than Ligand B (0.395), which is crucial for CNS penetration.

**15. Binding Affinity:** Ligand B (-7.6) has a slightly better binding affinity than Ligand A (-7.4), but the difference is small (0.2 kcal/mol).

**Overall Assessment:**

Despite Ligand B having slightly better BBB penetration and binding affinity, Ligand A is the stronger candidate. Ligand A demonstrates superior drug-likeness (QED), lower P-gp efflux, lower hERG inhibition, and significantly better metabolic stability (lower Cl_mic). The slightly better BBB of Ligand B is outweighed by these advantages, especially considering the importance of metabolic stability and reduced efflux for CNS targets. The negative Caco-2 and solubility values for both are concerning and would require further investigation, but the other properties favor Ligand A.

Output:
0
2025-04-17 06:45:35,462 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (348.443 and 349.519 Da) fall comfortably within the ideal 200-500 Da range.

**TPSA:** Ligand A (66.92) is slightly above the optimal <90 for CNS targets, but still reasonable. Ligand B (52.65) is excellent, well below 90.

**logP:** Ligand A (1.581) is within the optimal 1-3 range. Ligand B (2.548) is also good, leaning towards the higher end of optimal.

**H-Bond Donors/Acceptors:** Ligand A (0 HBD, 4 HBA) is favorable. Ligand B (1 HBD, 3 HBA) is also good. Both are within acceptable limits.

**QED:** Both ligands have good QED scores (0.54 and 0.768, respectively), indicating drug-like properties. Ligand B is slightly better.

**DILI:** Both ligands have low DILI risk (49.903 and 4.653 percentile), which is excellent. Ligand B is significantly better.

**BBB:** Both ligands show good BBB penetration (76.968 and 79.217 percentile), exceeding the 70% threshold for CNS targets. Ligand B is slightly better.

**Caco-2 Permeability:** Ligand A (-3.992) has poor Caco-2 permeability, indicating poor intestinal absorption. Ligand B (-5.027) is even worse.

**Aqueous Solubility:** Ligand A (-2.705) and Ligand B (-1.546) both have poor aqueous solubility.

**hERG Inhibition:** Ligand A (0.136) has very low hERG inhibition risk, which is excellent. Ligand B (0.585) is slightly higher, but still relatively low.

**Microsomal Clearance:** Ligand A (94.699) has high microsomal clearance, suggesting poor metabolic stability. Ligand B (-2.043) has *negative* clearance, which is not physically possible and indicates a data error or unusual behavior. This is a major red flag.

**In vitro Half-Life:** Ligand A (-21.491) has a negative half-life, which is not physically possible and indicates a data error or unusual behavior. Ligand B (-2.044) also has a negative half-life, indicating a data error or unusual behavior.

**P-gp Efflux:** Ligand A (0.116) has low P-gp efflux, which is favorable for CNS penetration. Ligand B (0.035) has even lower P-gp efflux, which is even more favorable.

**Binding Affinity:** Ligand B (-8.2 kcal/mol) has a significantly stronger binding affinity than Ligand A (-6.7 kcal/mol). This is a >1.5 kcal/mol advantage, which can outweigh other drawbacks.

**Overall Assessment:**

Despite both ligands having some issues with solubility and Caco-2 permeability, Ligand B is the stronger candidate. Its superior binding affinity (-8.2 vs -6.7 kcal/mol) is a major advantage. However, the negative values for microsomal clearance and half-life are concerning and suggest data quality issues. Ligand A also has these issues. Ignoring those data points, Ligand B is better due to its superior binding affinity, slightly better BBB, and lower DILI risk.

Output:
1
2025-04-17 06:45:35,463 - INFO - Batch 308 complete. Total preferences: 4928
2025-04-17 06:45:35,463 - INFO - Processing batch 309/512...
2025-04-17 06:46:16,108 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (371.487 and 350.423 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (64.11) is excellent, well below the 90 A^2 threshold for CNS targets. Ligand B (121.03) is higher, but still potentially acceptable, though less ideal.

**logP:** Ligand A (4.117) is slightly high, potentially leading to solubility issues or off-target interactions. Ligand B (0.957) is quite low, which could hinder membrane permeability and CNS penetration.

**H-Bond Donors/Acceptors:** Ligand A (1 HBD, 6 HBA) is favorable. Ligand B (4 HBD, 5 HBA) is also reasonable.

**QED:** Both ligands have similar QED values (0.661 and 0.603), indicating good drug-likeness.

**DILI:** Ligand A (88.212) has a higher DILI risk than Ligand B (60.915), which is a concern.

**BBB:** Ligand B (69.794) has a significantly better BBB percentile than Ligand A (46.646). This is a critical advantage for a CNS target like DRD2.

**Caco-2 Permeability:** Both have negative Caco-2 values (-5.001 and -5.282), which is unusual and suggests poor permeability. This needs further investigation, but is a negative for both.

**Aqueous Solubility:** Both ligands have very poor aqueous solubility (-4.631 and -2.252). This is a significant drawback.

**hERG Inhibition:** Ligand A (0.551) has a slightly higher hERG risk than Ligand B (0.038), which is preferable.

**Microsomal Clearance:** Ligand B (-19.666) has a much lower (better) microsomal clearance than Ligand A (75.952), indicating greater metabolic stability.

**In vitro Half-Life:** Ligand B (8.666 hours) has a longer half-life than Ligand A (3.357 hours).

**P-gp Efflux:** Ligand A (0.365) has lower P-gp efflux liability than Ligand B (0.005), which is favorable for CNS penetration.

**Binding Affinity:** Ligand B (-9.0 kcal/mol) has a substantially stronger binding affinity than Ligand A (-8.3 kcal/mol). This 1.7 kcal/mol difference is significant and can outweigh some of the ADME drawbacks.

**Overall Assessment:**

While Ligand A has a slightly better hERG profile and P-gp efflux, Ligand B is superior overall, particularly for a CNS target. The significantly better BBB penetration, stronger binding affinity, and improved metabolic stability (lower Cl_mic, longer t1/2) outweigh the slightly higher DILI risk and lower logP. The poor solubility and Caco-2 permeability are concerns for both, but can potentially be addressed with formulation strategies. The affinity difference is substantial enough to prioritize Ligand B.

Output:
1
2025-04-17 06:46:16,108 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (348.491 Da) is slightly preferred as it's closer to the lower end, potentially aiding permeability.

**TPSA:** Ligand A (68.7) is excellent, well below the 90 A^2 threshold for CNS targets. Ligand B (109.41) is higher, but still reasonable, though less ideal for CNS penetration.

**logP:** Ligand A (2.094) is optimal (1-3). Ligand B (0.189) is quite low, potentially hindering membrane permeability and reducing brain exposure. This is a significant drawback.

**H-Bond Donors/Acceptors:** Both have acceptable HBD (2) and HBA (4 for A, 5 for B) counts, falling within the guidelines.

**QED:** Ligand A (0.826) has a superior QED score, indicating better drug-likeness than Ligand B (0.56).

**DILI:** Ligand A (4.692) has a very low DILI risk. Ligand B (49.903) is higher, suggesting a moderate risk.

**BBB:** Ligand A (63.784) has a reasonable BBB penetration, but could be better. Ligand B (72.586) is better, exceeding the 70% threshold for CNS targets. However, this advantage is likely offset by its poor logP.

**Caco-2 Permeability:** Ligand A (-4.758) is poor, indicating low intestinal absorption. Ligand B (-5.545) is also poor.

**Aqueous Solubility:** Ligand A (-1.026) is poor. Ligand B (-2.604) is even worse.

**hERG Inhibition:** Both ligands show low hERG inhibition risk (0.616 and 0.399 respectively).

**Microsomal Clearance:** Ligand A (6.659) has moderate clearance. Ligand B (0.93) has very low clearance, suggesting good metabolic stability.

**In vitro Half-Life:** Ligand A (36.067) has a reasonable half-life. Ligand B (-8.509) has a very long half-life, which is a positive.

**P-gp Efflux:** Ligand A (0.012) has very low P-gp efflux, which is excellent for CNS penetration. Ligand B (0.03) also has low P-gp efflux, but slightly higher than A.

**Binding Affinity:** Ligand A (-8.2 kcal/mol) has a significantly stronger binding affinity than Ligand B (-7.7 kcal/mol). This 0.5 kcal/mol difference is substantial and can outweigh some ADME drawbacks.

**Overall Assessment:**

Ligand A is the stronger candidate despite some ADME liabilities. Its superior binding affinity (-8.2 vs -7.7 kcal/mol) and better drug-likeness (QED) are critical. While its Caco-2 and solubility are poor, the low P-gp efflux and acceptable (though not ideal) BBB penetration, combined with the strong binding, make it more promising. Ligand B's low logP is a major concern, likely severely limiting its ability to cross the blood-brain barrier despite the better BBB percentile score. The improved metabolic stability of B is a plus, but not enough to overcome the permeability issues.

Output:
1
2025-04-17 06:46:16,108 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (351.447 and 365.39 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (89.95) is excellent, falling well below the 90 A^2 threshold for CNS targets. Ligand B (108.05) is still reasonable but less optimal.

**logP:** Ligand A (-0.016) is slightly below the optimal 1-3 range, potentially hindering permeability. Ligand B (0.517) is also on the lower side, but slightly better than A.

**H-Bond Donors/Acceptors:** Both have 2 HBDs, which is good. Ligand A has 4 HBAs, and Ligand B has 6 HBAs. Both are within the acceptable range of <=10.

**QED:** Both ligands have good QED scores (0.682 and 0.824), indicating drug-like properties.

**DILI:** Ligand A (22.024) has a significantly lower DILI risk than Ligand B (74.254), which is a substantial advantage.

**BBB:** Ligand A (29.275) has poor BBB penetration, while Ligand B (53.354) is still suboptimal but better. This is a critical factor for a CNS target like DRD2.

**Caco-2 Permeability:** Both have negative Caco-2 values (-4.698 and -5.063), which is unusual and suggests poor permeability. This is concerning for both.

**Aqueous Solubility:** Both ligands have negative solubility values (-0.959 and -3.232), indicating very poor aqueous solubility. This is a major drawback for both.

**hERG:** Both ligands have low hERG inhibition risk (0.121 and 0.295).

**Microsomal Clearance:** Ligand A (10.175) has better metabolic stability (lower clearance) than Ligand B (-20.029).

**In vitro Half-Life:** Ligand A (-29.722) has a very short in vitro half-life, which is a significant negative. Ligand B (-15.44) is better, but still not ideal.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.009 and 0.039), which is favorable for CNS penetration.

**Binding Affinity:** Ligand B (-8.3 kcal/mol) has a slightly better binding affinity than Ligand A (-7.8 kcal/mol), but the difference is not huge.

**Overall Assessment:**

Ligand A has a much better safety profile (DILI) and metabolic stability (Cl_mic), but suffers from very poor BBB penetration and a very short half-life. Ligand B has slightly better BBB penetration and affinity, but a significantly higher DILI risk. The poor solubility and permeability are concerning for both.

Given the GPCR-specific priorities, BBB penetration is crucial for DRD2. While Ligand B's BBB score is still not great, it is substantially better than Ligand A's. The slightly better affinity of Ligand B, combined with its better (though still suboptimal) BBB, outweighs the higher DILI risk, *assuming* the DILI risk can be mitigated through further optimization. The poor solubility and permeability are major issues for both, but can potentially be addressed with formulation strategies.

Output:
1
2025-04-17 06:46:16,108 - INFO - Reasoning:

Let's analyze Ligand A and Ligand B based on the provided guidelines, prioritizing GPCR-specific properties (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (360.351 and 348.462 Da) fall within the ideal range of 200-500 Da.

**TPSA:** Ligand A (49.41) is significantly better than Ligand B (58.2). For CNS targets, we want TPSA <= 90, both are under this threshold, but A is closer to the ideal.

**logP:** Both ligands have good logP values (2.821 and 2.572), falling within the optimal range of 1-3.

**H-Bond Donors/Acceptors:** Ligand A (HBD=1, HBA=2) is slightly better than Ligand B (HBD=2, HBA=2) in terms of minimizing H-bonding, which can help with permeability.

**QED:** Both ligands have similar QED values (0.821 and 0.802), indicating good drug-likeness.

**DILI:** Ligand A (35.983) has a slightly higher DILI risk than Ligand B (21.908), but both are below the concerning threshold of 60.

**BBB:** Ligand B (84.025) has a slightly better BBB penetration percentile than Ligand A (79.333), but both are above the desirable 70% threshold for CNS targets.

**Caco-2 Permeability:** Both ligands show poor Caco-2 permeability (-4.408 and -4.759). This is a concern for oral absorption, but less critical for a CNS target where direct delivery or alternative routes might be considered.

**Aqueous Solubility:** Both ligands have very poor aqueous solubility (-3.032 and -3.951). This could pose formulation challenges.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.714 and 0.409).

**Microsomal Clearance:** Ligand A (8.716) has a lower microsomal clearance than Ligand B (15.204), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand B (-2.306) has a negative half-life, which is not physically possible and indicates an issue with the data. Ligand A (5.223) has a reasonable half-life.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.027 and 0.053), which is excellent for CNS penetration.

**Binding Affinity:** Ligand A (-9.4 kcal/mol) has a significantly stronger binding affinity than Ligand B (-8.1 kcal/mol). This 1.3 kcal/mol difference is substantial and can often outweigh minor ADME drawbacks.

**Overall Assessment:**

Ligand A is the stronger candidate. While Ligand B has a slightly better BBB score and lower DILI, Ligand A's significantly superior binding affinity (-9.4 vs -8.1 kcal/mol) and more reasonable in vitro half-life are crucial advantages, especially for a GPCR target like DRD2. The slightly higher DILI risk of Ligand A is less concerning given the other favorable properties. Both ligands have poor solubility and Caco-2 permeability, but these are less critical for a CNS target.

Output:
1
2025-04-17 06:46:16,109 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (407.352 Da) is slightly higher, but acceptable. Ligand B (344.415 Da) is also good.

**TPSA:** Ligand A (41.57) is excellent for CNS penetration, well below 90. Ligand B (100.19) is higher, but still potentially acceptable, though less ideal.

**logP:** Ligand A (4.86) is a bit high, potentially leading to solubility issues or off-target interactions. Ligand B (1.09) is quite low, which could hinder membrane permeability and CNS penetration.

**H-Bond Donors/Acceptors:** Ligand A (HBD=1, HBA=2) is optimal. Ligand B (HBD=3, HBA=4) is also reasonable.

**QED:** Both ligands have acceptable QED values (A: 0.709, B: 0.531), indicating good drug-like properties.

**DILI:** Ligand A (39.938) has a very favorable DILI score. Ligand B (54.556) is higher, indicating a moderate risk, but still not alarming.

**BBB:** Ligand A (88.988) has a very good BBB percentile, highly desirable for a CNS target. Ligand B (61.109) is significantly lower, which is a major drawback for DRD2 targeting.

**Caco-2 Permeability:** Ligand A (-4.217) has poor Caco-2 permeability. Ligand B (-5.323) is even worse. Both are problematic.

**Aqueous Solubility:** Ligand A (-5.876) has poor aqueous solubility. Ligand B (-2.423) is better, but still not great.

**hERG Inhibition:** Ligand A (0.731) has a low hERG risk. Ligand B (0.138) has a very low hERG risk. Both are favorable.

**Microsomal Clearance:** Ligand A (94.487) has high microsomal clearance, suggesting rapid metabolism and potentially low bioavailability. Ligand B (4.397) has very low clearance, indicating good metabolic stability.

**In vitro Half-Life:** Ligand A (44.187) has a moderate half-life. Ligand B (14.84) has a short half-life.

**P-gp Efflux:** Ligand A (0.476) has moderate P-gp efflux. Ligand B (0.033) has very low P-gp efflux, which is highly desirable for CNS penetration.

**Binding Affinity:** Ligand B (-9.2 kcal/mol) has significantly stronger binding affinity than Ligand A (-7.3 kcal/mol). This is a substantial advantage.

**Overall Assessment:**

Ligand B has a much better binding affinity and lower P-gp efflux, which are critical for CNS GPCR targets. While its logP is low and Caco-2 permeability is poor, the strong affinity might overcome these issues. The low metabolic clearance is also a significant advantage. Ligand A has a better BBB score, but its high logP, poor solubility, and high clearance are significant liabilities. The difference in binding affinity is substantial (>1.5 kcal/mol).

Output:
1
2025-04-17 06:46:16,109 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (346.387 and 359.461 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (104.39) is higher than the preferred <90 for CNS targets, while Ligand B (58.22) is well within the optimal range. This is a significant advantage for Ligand B.

**logP:** Ligand A (-0.126) is quite low, potentially hindering membrane permeability. Ligand B (3.709) is closer to the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A has 2 HBD and 5 HBA, which are acceptable. Ligand B has 1 HBD and 3 HBA, also acceptable.

**QED:** Both ligands have reasonable QED scores (0.368 and 0.693), with Ligand B being notably better.

**DILI:** Ligand A (44.164) is slightly higher than the preferred <40, indicating a moderate risk. Ligand B (27.685) is good, with low DILI risk.

**BBB:** Ligand A (23.071) has poor BBB penetration, a critical drawback for a CNS target. Ligand B (82.009) demonstrates excellent BBB penetration, a major advantage.

**Caco-2 Permeability:** Both have negative values, which is unusual. Assuming these are percentile scores, Ligand B (-4.723) is slightly better than Ligand A (-5.338), but both are poor.

**Aqueous Solubility:** Both ligands have negative solubility values, which is also unusual. Assuming these are percentile scores, Ligand A (-1.686) is slightly better than Ligand B (-2.908), but both are poor.

**hERG Inhibition:** Ligand A (0.14) shows a very low risk of hERG inhibition, while Ligand B (0.781) has a slightly higher, but still acceptable, risk.

**Microsomal Clearance:** Ligand A (-6.742) suggests good metabolic stability (negative values are better). Ligand B (73.627) indicates rapid clearance, which is undesirable.

**In vitro Half-Life:** Ligand A (-17.741) suggests a long half-life, while Ligand B (-9.853) suggests a shorter half-life.

**P-gp Efflux:** Ligand A (0.033) has low P-gp efflux, which is good. Ligand B (0.272) has slightly higher efflux, but still reasonable.

**Binding Affinity:** Both ligands have similar binding affinities (-7.7 and -6.8 kcal/mol), with Ligand A being slightly better. However, the 0.9 kcal/mol difference is likely outweighed by the significant ADME advantages of Ligand B.

**Overall Assessment:**

Ligand B is the superior candidate. While Ligand A has slightly better affinity and metabolic stability, Ligand B excels in crucial properties for a CNS-targeting GPCR ligand: TPSA, logP, BBB penetration, and DILI risk. The poor Caco-2 and solubility values are concerning for both, but can potentially be addressed with formulation strategies. The difference in BBB penetration is the most significant factor, as it directly impacts CNS exposure.

Output:
1
2025-04-17 06:46:16,109 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (349.519 and 352.435 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (43.86) is excellent, well below the 90 A^2 threshold for CNS targets. Ligand B (107.55) is higher but still potentially acceptable, though less ideal.

**3. logP:** Ligand A (2.356) is optimal (1-3). Ligand B (0.48) is low, potentially hindering permeation.

**4. H-Bond Donors:** Ligand A (0) is good. Ligand B (3) is acceptable, within the limit of 5.

**5. H-Bond Acceptors:** Ligand A (3) is good. Ligand B (5) is acceptable, within the limit of 10.

**6. QED:** Both ligands have reasonable QED values (0.765 and 0.56), indicating drug-like properties.

**7. DILI:** Ligand A (11.4) has a very low DILI risk. Ligand B (43.622) is higher, but still within an acceptable range.

**8. BBB:** Ligand A (84.878) has excellent BBB penetration potential, exceeding the >70% threshold. Ligand B (34.626) is significantly lower, a major drawback for a CNS target.

**9. Caco-2:** Ligand A (-4.368) and Ligand B (-5.399) both have negative Caco-2 values. This is unusual and suggests poor permeability. However, these values are on a scale where negative values are possible, and the absolute magnitude matters less than the trend.

**10. Solubility:** Both ligands have poor aqueous solubility (-1.587 and -1.681). This could pose formulation challenges.

**11. hERG:** Both ligands have low hERG inhibition liability (0.684 and 0.49).

**12. Cl_mic:** Ligand A (36.998) has a higher microsomal clearance than Ligand B (14.578), suggesting lower metabolic stability.

**13. t1/2:** Ligand B (2.789) has a slightly longer in vitro half-life than Ligand A (-2.535).

**14. Pgp:** Ligand A (0.219) has lower P-gp efflux liability than Ligand B (0.156), which is favorable for CNS exposure.

**15. Affinity:** Both ligands have the same binding affinity (-7.4 kcal/mol), which is excellent.

**Overall Assessment:**

Given the GPCR-specific priorities, Ligand A is the superior candidate. The most critical factor is the significantly better BBB penetration (84.878% vs. 34.626%). While Ligand A has a higher Cl_mic, the strong BBB penetration and optimal logP outweigh this drawback. Both have similar affinity and acceptable safety profiles. The low solubility of both is a concern, but formulation strategies can potentially address this. Ligand B's poor BBB penetration makes it a less attractive candidate for a CNS target like DRD2.

Output:
0
2025-04-17 06:46:16,109 - INFO - Reasoning:

Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (432.296 Da) is slightly higher, but acceptable. Ligand B (348.349 Da) is also good.

**2. TPSA:** Ligand A (99.52) is approaching the upper limit for CNS targets (<=90), while Ligand B (67.43) is well within the desirable range. This favors Ligand B.

**3. logP:** Both ligands have good logP values (Ligand A: 2.234, Ligand B: 3.121), falling within the optimal 1-3 range. Ligand B is slightly higher, potentially offering better membrane permeability.

**4. H-Bond Donors:** Ligand A (1) and Ligand B (2) are both within the acceptable limit of <=5.

**5. H-Bond Acceptors:** Ligand A (7) and Ligand B (3) are both within the acceptable limit of <=10.

**6. QED:** Both ligands have good QED scores (Ligand A: 0.674, Ligand B: 0.843), indicating good drug-like properties. Ligand B is slightly better.

**7. DILI:** Ligand A (91.47) has a higher DILI risk than Ligand B (81.427), though both are reasonably low.

**8. BBB:** This is crucial for a CNS target. Ligand B (73.362) has a significantly better BBB percentile than Ligand A (51.803). This is a major advantage for Ligand B.

**9. Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and suggests a potential issue with the data or the model. However, the values are close enough that this isn't a deciding factor.

**10. Aqueous Solubility:** Both have negative solubility values, which is also unusual. Again, the values are close enough that this isn't a deciding factor.

**11. hERG Inhibition:** Both ligands have low hERG inhibition risk (Ligand A: 0.407, Ligand B: 0.625).

**12. Microsomal Clearance:** Ligand B (45.19) has lower microsomal clearance than Ligand A (51.725), suggesting better metabolic stability.

**13. In vitro Half-Life:** Ligand A (11.908) has a slightly longer half-life than Ligand B (8.644).

**14. P-gp Efflux:** Ligand A (0.378) has lower P-gp efflux than Ligand B (0.181), which is favorable for CNS penetration.

**15. Binding Affinity:** Ligand B (-9.2 kcal/mol) has a significantly stronger binding affinity than Ligand A (-8.3 kcal/mol). This is a substantial advantage, exceeding the 1.5 kcal/mol difference threshold.

**Overall Assessment:**

Ligand B is the stronger candidate. It has a better BBB score, lower TPSA, better metabolic stability (lower Cl_mic), and significantly higher binding affinity. While Ligand A has slightly better P-gp efflux and half-life, the advantages of Ligand B in terms of CNS penetration (BBB, TPSA, Pgp) and potency (affinity) outweigh these minor drawbacks.

Output:
1
2025-04-17 06:46:16,109 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (338.411 and 348.487 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (87.04) is better than Ligand B (69.64). Both are below the 90 A^2 threshold desirable for CNS targets.

**logP:** Ligand A (3.762) is slightly higher than Ligand B (2.415), both are within the optimal 1-3 range, but A is approaching the upper limit.

**H-Bond Donors:** Both ligands have 2 HBD, which is acceptable.

**H-Bond Acceptors:** Ligand A has 4 HBA, and Ligand B has 3. Both are below the 10 threshold.

**QED:** Ligand A (0.753) is slightly better than Ligand B (0.662), both are above the 0.5 threshold.

**DILI:** Ligand A (69.911) has a higher DILI risk than Ligand B (13.3). This is a significant drawback for Ligand A.

**BBB:** Ligand B (66.344) has a better BBB penetration percentile than Ligand A (51.415). While both are not ideal (>70), B is closer. This is crucial for a CNS target like DRD2.

**Caco-2 Permeability:** Ligand A (-4.827) has a worse Caco-2 permeability than Ligand B (-4.632). Lower values are less favorable.

**Aqueous Solubility:** Ligand A (-5.59) has worse aqueous solubility than Ligand B (-1.981). Solubility is important for formulation.

**hERG Inhibition:** Ligand A (0.728) has a higher hERG inhibition liability than Ligand B (0.212). Lower is better, making Ligand B preferable.

**Microsomal Clearance:** Ligand A (95.637) has a higher microsomal clearance than Ligand B (44.998), meaning it's less metabolically stable.

**In vitro Half-Life:** Ligand B (-26.614) has a much longer in vitro half-life than Ligand A (36.882). This is a significant advantage for Ligand B.

**P-gp Efflux:** Ligand A (0.411) has lower P-gp efflux liability than Ligand B (0.105). Lower is better, meaning A has better CNS exposure potential.

**Binding Affinity:** Both ligands have similar binding affinities (-8.5 and -8.7 kcal/mol), which are excellent and comparable. The difference is negligible.

**Overall Assessment:**

Ligand B is the stronger candidate. While Ligand A has slightly better logP and P-gp efflux, Ligand B excels in crucial areas for a CNS-targeting GPCR: significantly lower DILI risk, better BBB penetration, improved solubility, lower hERG inhibition, and a much longer half-life. The comparable binding affinity makes the ADME advantages of Ligand B decisive.

Output:
1
2025-04-17 06:46:16,110 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the acceptable range (200-500 Da). Ligand A (335.319 Da) is slightly preferred as it's closer to the lower end, potentially aiding permeability.

**TPSA:** Ligand A (105.06) is better than Ligand B (53.51). For CNS targets, TPSA < 90 is desirable, and Ligand B is significantly better in this regard.

**logP:** Both ligands have good logP values (A: 2.411, B: 3.114), falling within the optimal 1-3 range. Ligand B is slightly higher, which *could* be a minor concern for solubility, but isn't a major issue.

**H-Bond Donors/Acceptors:** Ligand A has 2 HBD and 5 HBA, while Ligand B has 0 HBD and 5 HBA. Both are within acceptable limits (HBD <= 5, HBA <= 10).

**QED:** Both ligands have similar QED values (A: 0.765, B: 0.717), indicating good drug-like properties.

**DILI:** Ligand A (98.527) has a significantly higher DILI risk than Ligand B (65.568). This is a substantial negative for Ligand A.

**BBB:** Ligand B (86.041) has a much better BBB penetration percentile than Ligand A (61.342). This is a critical advantage for a CNS target like DRD2.

**Caco-2 Permeability:** Both have negative values (-4.653 and -4.778), which is unusual and requires further investigation. It's difficult to interpret without knowing the scale.

**Aqueous Solubility:** Both ligands have negative solubility values (-5.675 and -4.109), which is also concerning. Again, the scale is unknown, but this suggests poor solubility.

**hERG Inhibition:** Ligand A (0.239) has a slightly lower hERG inhibition risk than Ligand B (0.524), which is a minor positive.

**Microsomal Clearance:** Ligand B (63.163) has a much higher microsomal clearance than Ligand A (5.553), indicating faster metabolism and potentially lower exposure. This is a significant negative for Ligand B.

**In vitro Half-Life:** Ligand A (14.383) has a longer in vitro half-life than Ligand B (10.676), which is desirable.

**P-gp Efflux:** Ligand A (0.196) has lower P-gp efflux liability than Ligand B (0.472), which is beneficial for CNS penetration.

**Binding Affinity:** Ligand B (-7.4 kcal/mol) has a significantly stronger binding affinity than Ligand A (-10.2 kcal/mol). This is a major advantage, potentially outweighing some of the ADME drawbacks.

**Overall Assessment:**

Ligand B has a much better binding affinity and significantly better BBB penetration, which are crucial for a CNS GPCR target. While it has higher microsomal clearance, the strong binding affinity could compensate for this. Ligand A has a lower DILI risk and better metabolic stability, but its weaker binding affinity and lower BBB penetration are major drawbacks. The solubility and Caco-2 permeability are concerning for both, but the affinity and BBB of Ligand B are more compelling.

Output:
1
2025-04-17 06:46:16,110 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (350.503 and 349.431 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (58.64) is excellent, well below the 90 A^2 threshold for CNS targets. Ligand B (84.67) is still reasonable but higher, potentially impacting BBB penetration.

**3. logP:** Both ligands have good logP values (2.76 and 1.59), falling within the optimal 1-3 range. Ligand A's is slightly preferred.

**4. H-Bond Donors:** Both have 1 HBD, which is acceptable.

**5. H-Bond Acceptors:** Ligand A has 3 HBA, and Ligand B has 5. Both are within the acceptable limit of 10.

**6. QED:** Both ligands have good QED scores (0.651 and 0.873), indicating good drug-like properties. Ligand B is slightly better here.

**7. DILI:** Ligand A (16.751 percentile) has a significantly lower DILI risk than Ligand B (35.983 percentile). This is a substantial advantage for Ligand A.

**8. BBB:** This is crucial for a CNS target like DRD2. Ligand A has a very good BBB penetration score (83.288 percentile), exceeding the desirable >70 threshold. Ligand B's BBB score (51.493 percentile) is considerably lower and less promising.

**9. Caco-2 Permeability:** Ligand A (-4.4) and Ligand B (-5.093) both have negative values, which is unusual and suggests poor permeability. However, the scale isn't defined, so it's hard to interpret.

**10. Aqueous Solubility:** Ligand A (-3.187) and Ligand B (-0.997) both have negative values, indicating poor solubility.

**11. hERG Inhibition:** Both ligands show very low hERG inhibition risk (0.47 and 0.099 percentile), which is excellent.

**12. Microsomal Clearance:** Ligand A (95.752 percentile) has a higher microsomal clearance, indicating faster metabolism and lower metabolic stability. Ligand B (16.924 percentile) has a lower clearance, suggesting better metabolic stability.

**13. In vitro Half-Life:** Ligand A (-13.421 hours) has a negative half-life, which is not possible. This is a red flag. Ligand B (-1.749 hours) also has a negative half-life, which is also not possible.

**14. P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.317 and 0.054 percentile), which is favorable for CNS penetration.

**15. Binding Affinity:** Both ligands have excellent binding affinities (-8.0 and -8.6 kcal/mol). Ligand B is slightly more potent.

**Overall Assessment:**

Despite Ligand B having a slightly better QED and binding affinity, Ligand A is the more promising candidate. The critical factors are its significantly lower DILI risk and, most importantly, its much better BBB penetration (83.3% vs 51.5%). The negative half-life values are concerning for both, but the other ADME properties of Ligand A are generally more favorable for a CNS-targeting drug. The higher metabolic clearance of Ligand A is a drawback, but can potentially be addressed through structural modifications.

Output:
1
2025-04-17 06:46:16,110 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B based on the provided guidelines, prioritizing GPCR-specific properties (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (347.463 and 343.431 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (106.96) is slightly above the optimal <90 for CNS targets, but still reasonable. Ligand B (78.43) is excellent, well below 90.

**logP:** Ligand A (3.367) is within the optimal 1-3 range. Ligand B (0.538) is quite low, potentially hindering permeability.

**H-Bond Donors/Acceptors:** Ligand A (HBD=2, HBA=3) is good. Ligand B (HBD=1, HBA=5) is also acceptable.

**QED:** Ligand B (0.863) has a significantly better QED score than Ligand A (0.319), indicating a more drug-like profile.

**DILI:** Ligand B (23.11) has a much lower DILI risk than Ligand A (35.75), a significant advantage.

**BBB:** Ligand B (79.992) has a very good BBB penetration score, exceeding the desirable >70 threshold for CNS targets. Ligand A (55.293) is lower, which is concerning for a CNS target like DRD2.

**Caco-2 Permeability:** Ligand A (-4.758) has poor Caco-2 permeability. Ligand B (-5.054) is also poor, but slightly better than A.

**Aqueous Solubility:** Ligand A (-3.206) has poor aqueous solubility. Ligand B (-1.353) is also poor, but better than A.

**hERG:** Both ligands have low hERG inhibition risk (0.215 and 0.417, respectively).

**Microsomal Clearance:** Ligand B (1.871) has significantly lower microsomal clearance than Ligand A (51.602), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand B (-11.898) has a much longer in vitro half-life than Ligand A (-3.486).

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.118 and 0.006, respectively).

**Binding Affinity:** Both ligands have comparable and excellent binding affinities (-8.1 and -8.9 kcal/mol). The difference of 0.8 kcal/mol is not substantial enough to outweigh other significant differences.

**Overall Assessment:**

Ligand B is clearly superior. While both have good binding affinity, Ligand B excels in crucial ADME properties for a CNS-targeting GPCR: significantly better BBB penetration, lower DILI risk, lower microsomal clearance (better metabolic stability), longer half-life, and a much higher QED score. The lower logP of Ligand B is a concern, but the strong BBB penetration suggests it can overcome this. Ligand A's poor BBB, high DILI, and poor metabolic stability are major drawbacks.

Output:
1
2025-04-17 06:46:16,110 - INFO - Reasoning:

Let's analyze Ligand A and Ligand B based on the provided guidelines, prioritizing GPCR-specific properties (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (424.339 Da) is slightly higher than Ligand B (374.853 Da), but both are acceptable.

**TPSA:** Ligand A (46.92) is excellent for CNS penetration, well below the 90 A^2 threshold. Ligand B (77) is higher, but still potentially acceptable, although less ideal.

**logP:** Both ligands have good logP values (A: 4.136, B: 3.753), falling within the optimal 1-3 range, although A is slightly higher. This could potentially lead to off-target effects, but isn't a dealbreaker.

**H-Bond Donors/Acceptors:** Both have 1 HBD, which is good. Ligand A has 4 HBA, and Ligand B has 6. Both are within the acceptable limit of 10, but Ligand A is preferable.

**QED:** Both ligands have similar QED values (A: 0.647, B: 0.688), indicating good drug-likeness.

**DILI:** Ligand B (89.802) has a significantly higher DILI risk than Ligand A (55.487). This is a major concern.

**BBB:** Ligand A (88.91) has a very good BBB penetration percentile, exceeding the desirable >70 threshold for CNS targets. Ligand B (32.571) is poor, indicating limited CNS exposure. This is a critical difference for a DRD2 ligand.

**Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and suggests poor permeability. This is a potential issue for both, but the scale is not clearly defined.

**Aqueous Solubility:** Both have negative solubility values, indicating poor solubility. This is a potential issue for both, but the scale is not clearly defined.

**hERG Inhibition:** Ligand A (0.916) has a slightly higher hERG risk than Ligand B (0.32), but both are relatively low.

**Microsomal Clearance:** Ligand B (41.91) has significantly lower microsomal clearance than Ligand A (82.477), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (61.066) has a longer in vitro half-life than Ligand B (-0.741), which is desirable.

**P-gp Efflux:** Ligand A (0.947) has a higher P-gp efflux liability than Ligand B (0.258), which is less desirable.

**Binding Affinity:** Ligand B (-8.8 kcal/mol) has a slightly better binding affinity than Ligand A (-9.0 kcal/mol). While the difference is small, it's still a positive for Ligand B.

**Overall Assessment:**

Considering the GPCR-specific priorities, Ligand A is the more promising candidate. The significantly better BBB penetration (88.91 vs 32.571) is crucial for a CNS target like DRD2. While Ligand B has slightly better affinity and metabolic stability, the high DILI risk and poor BBB penetration outweigh these benefits. The slightly higher P-gp efflux of Ligand A is a minor concern that could be addressed through further optimization.



Output:
1
2025-04-17 06:46:16,110 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (364.423 and 346.387 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (93.73) is excellent, falling well below the 90 A^2 threshold for CNS targets. Ligand B (133.36) is higher, but still potentially acceptable, though less ideal.

**logP:** Ligand A (2.22) is optimal (1-3). Ligand B (-0.378) is below 1, which could hinder permeation. This is a significant drawback.

**H-Bond Donors/Acceptors:** Both ligands have 2 HBD and 5 HBA, which are within acceptable limits.

**QED:** Both ligands have similar QED values (0.701 and 0.7), indicating good drug-likeness.

**DILI:** Ligand A (83.598) has a higher DILI risk than Ligand B (33.695), but both are reasonably low.

**BBB:** Ligand A (65.607) has a better BBB percentile than Ligand B (54.091). While both are not ideal (>70), A is preferable for a CNS target.

**Caco-2 Permeability:** Ligand A (-4.963) has a more negative Caco-2 value, indicating lower permeability. Ligand B (-5.556) is also low, but slightly worse.

**Aqueous Solubility:** Ligand A (-4.049) is slightly better than Ligand B (-2.64).

**hERG:** Both ligands have very low hERG risk (0.556 and 0.072).

**Microsomal Clearance:** Ligand A (37.616) has higher microsomal clearance than Ligand B (-10.77). This suggests Ligand B is more metabolically stable.

**In vitro Half-Life:** Ligand B (-2.708) has a more negative half-life, indicating a shorter half-life. Ligand A (-12.319) is much worse.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.229 and 0.002).

**Binding Affinity:** Both ligands have the same binding affinity (-8.5 kcal/mol), which is excellent.

**Overall Assessment:**

Given the GPCR-specific priorities, Ligand A is slightly favored. While its Caco-2 permeability and in vitro half-life are worse, its significantly better logP and BBB penetration are crucial for CNS targets. Ligand B's low logP is a major concern, as it could severely limit brain exposure. The better metabolic stability of Ligand B is a plus, but can be addressed through structural modifications. The similar affinity makes the ADME properties the deciding factor.

Output:
1
2025-04-17 06:46:16,110 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (352.475 and 352.454 Da) fall comfortably within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (78.87) is significantly better than Ligand B (87.46). For CNS targets, we want TPSA <= 90, and A is closer to the ideal range.

**3. logP:** Both ligands have good logP values (2.182 and 1.539), falling within the optimal 1-3 range. Ligand A is slightly higher, which could be beneficial for membrane permeability.

**4. H-Bond Donors:** Ligand A (2) and Ligand B (3) are both acceptable, being less than 5.

**5. H-Bond Acceptors:** Both ligands have 4 H-bond acceptors, well within the acceptable limit of 10.

**6. QED:** Ligand B (0.619) has a slightly better QED score than Ligand A (0.492), indicating a more drug-like profile. However, A is still reasonably acceptable.

**7. DILI:** Ligand B (24.506) has a much lower DILI risk than Ligand A (19.426), which is a significant advantage. Lower DILI is always preferred.

**8. BBB:** Ligand B (67.701) has a considerably better BBB penetration percentile than Ligand A (56.611). For a CNS target like DRD2, BBB penetration is crucial, and >70 is desirable. B is closer to this threshold.

**9. Caco-2 Permeability:** Ligand A (-4.784) has better Caco-2 permeability than Ligand B (-5.297), suggesting better intestinal absorption.

**10. Aqueous Solubility:** Ligand A (-2.292) has better aqueous solubility than Ligand B (-1.97), which is a positive attribute.

**11. hERG Inhibition:** Ligand A (0.258) has a lower hERG inhibition liability than Ligand B (0.7), making it safer from a cardiotoxicity perspective.

**12. Microsomal Clearance:** Ligand B (11.295) has a lower microsomal clearance than Ligand A (33.381), indicating better metabolic stability.

**13. In vitro Half-Life:** Ligand B (-1.286) has a longer in vitro half-life than Ligand A (-5.454), which is desirable.

**14. P-gp Efflux:** Both ligands have a P-gp efflux value of 0.044 and 0.015 respectively, which is excellent, indicating minimal efflux.

**15. Binding Affinity:** Both ligands have the same binding affinity (-8.0 kcal/mol), which is excellent and strong.

**Overall Assessment:**

While Ligand A has advantages in solubility, Caco-2 permeability, and hERG inhibition, Ligand B is superior in several critical areas for a CNS-targeting GPCR: BBB penetration, DILI risk, metabolic stability (lower Cl_mic), and in vitro half-life. The significantly better BBB penetration and lower DILI risk of Ligand B outweigh the slight advantages of Ligand A. The equal binding affinity makes the ADME properties the deciding factor.

Output:
1
2025-04-17 06:46:16,110 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (356.392 and 377.388 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (58.95) is excellent, well below the 90 A^2 threshold for CNS targets. Ligand B (71.53) is still reasonable but less optimal, slightly higher.

**logP:** Ligand A (3.704) is at the upper end of the optimal range (1-3), while Ligand B (2.487) is well within the optimal range.

**H-Bond Donors/Acceptors:** Ligand A has 2 HBD and 4 HBA, both acceptable. Ligand B has 1 HBD and 5 HBA, also acceptable.

**QED:** Both ligands have good QED scores (0.795 and 0.822), indicating good drug-like properties.

**DILI:** Ligand A (61.07) has a higher DILI risk than Ligand B (46.452). This is a negative for Ligand A.

**BBB:** Both ligands have good BBB penetration (67.197 and 68.592), exceeding the 70% threshold, which is crucial for CNS targets.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.887 and -4.713), which is unusual and suggests poor permeability. However, these values are on a log scale and represent ratios, so interpretation requires caution.

**Aqueous Solubility:** Both ligands have negative solubility values (-4.241 and -3.266), indicating poor aqueous solubility. This could pose formulation challenges.

**hERG Inhibition:** Ligand A (0.835) has a slightly higher hERG risk than Ligand B (0.274), which is preferable.

**Microsomal Clearance:** Ligand A (42.96) has a higher microsomal clearance than Ligand B (-2.013). This suggests Ligand B is more metabolically stable.

**In vitro Half-Life:** Ligand A (37.508) has a longer half-life than Ligand B (-0.638). This is a positive for Ligand A.

**P-gp Efflux:** Ligand A (0.328) has lower P-gp efflux than Ligand B (0.032), which is desirable for CNS exposure.

**Binding Affinity:** Ligand B (-9.1 kcal/mol) has a significantly stronger binding affinity than Ligand A (-8.7 kcal/mol). This 1.4 kcal/mol difference is substantial and can outweigh some ADME drawbacks.

**Overall Assessment:**

Ligand B is the better candidate. While Ligand A has a longer half-life and lower P-gp efflux, Ligand B's significantly stronger binding affinity (-9.1 vs -8.7 kcal/mol) is a major advantage, especially for a GPCR target. Ligand B also has a lower DILI risk and better metabolic stability (lower Cl_mic). Both have poor solubility and permeability, but the potency advantage of Ligand B is likely to be more impactful in driving forward development.

Output:
1
2025-04-17 06:46:16,111 - INFO - Batch 309 complete. Total preferences: 4944
2025-04-17 06:46:16,111 - INFO - Processing batch 310/512...
2025-04-17 06:46:55,850 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (348.487 and 356.442 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (58.64) is excellent, well below the 90 A^2 threshold for CNS targets. Ligand B (116.29) is higher, but still potentially acceptable, although less desirable.

**3. logP:** Both ligands have good logP values (2.487 and 1.129), falling within the optimal 1-3 range. Ligand A is slightly preferred here.

**4. H-Bond Donors:** Ligand A (1) and Ligand B (2) are both within the acceptable limit of <=5.

**5. H-Bond Acceptors:** Ligand A (3) and Ligand B (4) are both within the acceptable limit of <=10.

**6. QED:** Ligand A (0.83) has a significantly better QED score than Ligand B (0.644), indicating better overall drug-likeness.

**7. DILI:** Ligand A (12.641) has a much lower DILI risk than Ligand B (28.693), which is a significant advantage.

**8. BBB:** Ligand A (76.813) has a better BBB penetration percentile than Ligand B (68.67), which is crucial for a CNS target like DRD2.

**9. Caco-2 Permeability:** Ligand A (-4.84) has a negative value, which is unusual and suggests poor permeability. Ligand B (-5.175) is also poor.

**10. Aqueous Solubility:** Both ligands have very poor aqueous solubility (-3.158 and -2.008). This is a concern, but can sometimes be mitigated with formulation strategies.

**11. hERG Inhibition:** Both ligands have low hERG inhibition risk (0.389 and 0.504).

**12. Microsomal Clearance:** Ligand A (36.255) and Ligand B (32.092) are comparable. Lower is better, so B is slightly favored.

**13. In vitro Half-Life:** Ligand A (12.142) has a better in vitro half-life than Ligand B (-8.655).

**14. P-gp Efflux:** Ligand A (0.097) has a lower P-gp efflux liability than Ligand B (0.057), which is favorable for CNS penetration.

**15. Binding Affinity:** Ligand A (-8.2 kcal/mol) has a slightly better binding affinity than Ligand B (-7.1 kcal/mol). While both are good, the 1.1 kcal/mol difference is substantial and can outweigh some ADME drawbacks.

**Overall Assessment:**

Ligand A is the superior candidate. It has better QED, DILI, BBB, in vitro half-life, P-gp efflux, and binding affinity. While both have poor solubility and Caco-2 permeability, the stronger affinity and better CNS-related properties of Ligand A make it more likely to succeed as a DRD2-targeting drug. The difference in binding affinity is significant enough to potentially overcome the solubility issues.

Output:
1
2025-04-17 06:46:55,851 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (387.433 and 364.471 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Both ligands have TPSA values (101.29 and 98.92) below the 140 A^2 threshold for good oral absorption, but are above the more stringent 90 A^2 for CNS targets. This is a moderate concern for both, but not disqualifying.

**3. logP:** Ligand A (1.177) is within the optimal range of 1-3. Ligand B (2.378) is also within range, but closer to the upper limit.

**4. H-Bond Donors:** Ligand A (3) and Ligand B (2) are both acceptable, below the 5 threshold.

**5. H-Bond Acceptors:** Both ligands (5) are below the 10 threshold.

**6. QED:** Both ligands have similar QED values (0.733 and 0.713), indicating good drug-like properties.

**7. DILI:** Ligand A (75.572) has a higher DILI risk than Ligand B (66.421), but both are below the concerning 60 percentile.

**8. BBB:** This is a critical parameter for a CNS target like DRD2. Ligand A (68.864) has a significantly better BBB percentile than Ligand B (36.409). This is a major advantage for Ligand A.

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.707 and -5.178), which is unusual and likely indicates poor permeability. This is a significant drawback for both.

**10. Aqueous Solubility:** Both ligands have negative solubility values (-2.075 and -3.541), indicating poor solubility. This is a concern for both.

**11. hERG Inhibition:** Both ligands have low hERG inhibition risk (0.44 and 0.369).

**12. Microsomal Clearance:** Ligand B (21.441) has a lower (better) microsomal clearance than Ligand A (5.984), suggesting better metabolic stability.

**13. In vitro Half-Life:** Ligand B (27.419) has a longer half-life than Ligand A (33.354), which is favorable.

**14. P-gp Efflux:** Both ligands have low P-gp efflux liability (0.239 and 0.229), which is good.

**15. Binding Affinity:** Ligand B (-6.9 kcal/mol) has a slightly better binding affinity than Ligand A (-9.2 kcal/mol). However, the difference is not substantial enough to outweigh other factors.

**Overall Assessment:**

Ligand A is the more promising candidate. While both have issues with Caco-2 permeability and solubility, Ligand A's significantly better BBB penetration (68.864 vs 36.409) is crucial for a CNS-targeting drug. The slightly better affinity of Ligand B is not enough to compensate for the poor BBB score. Ligand B has better metabolic stability and half-life, but these are secondary considerations compared to CNS penetration for a DRD2 ligand.

Output:
0
2025-04-17 06:46:55,851 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (378.877 Da) is slightly higher than Ligand B (341.415 Da), but both are acceptable.

**TPSA:** Ligand A (60.44) is significantly better than Ligand B (90.98). For CNS targets, we want TPSA <= 90, so Ligand A is much more favorable.

**logP:** Ligand A (3.989) is within the optimal range (1-3), while Ligand B (1.404) is at the lower end. Lower logP can hinder permeation, making Ligand A preferable.

**H-Bond Donors/Acceptors:** Ligand A (0 HBD, 4 HBA) and Ligand B (2 HBD, 4 HBA) both have reasonable numbers of H-bonds.

**QED:** Both ligands have good QED values (Ligand A: 0.755, Ligand B: 0.831), indicating good drug-like properties.

**DILI:** Ligand A (84.917) has a higher DILI risk than Ligand B (52.385). This is a negative for Ligand A, but not a dealbreaker if other properties are strong.

**BBB:** This is crucial for a CNS target like DRD2. Ligand A (61.962) is moderately good, while Ligand B (29.934) is poor. This is a significant advantage for Ligand A.

**Caco-2 Permeability:** Both have negative values, which is unusual and suggests a problem with the data or modeling. However, we can still compare the *magnitude* of the negativity. Ligand A (-4.74) is less negative than Ligand B (-5.479), suggesting slightly better permeability.

**Aqueous Solubility:** Both have negative values, indicating low solubility. Ligand A (-5.065) is slightly better than Ligand B (-2.048).

**hERG Inhibition:** Both ligands have low hERG inhibition risk (Ligand A: 0.351, Ligand B: 0.44).

**Microsomal Clearance:** Ligand A (49.217) has a better (lower) microsomal clearance than Ligand B (-19.716), indicating better metabolic stability.

**In vitro Half-Life:** Ligand A (14.111 hours) has a significantly longer half-life than Ligand B (-15.196 hours).

**P-gp Efflux:** Both have very low P-gp efflux (Ligand A: 0.353, Ligand B: 0.026). Ligand B is slightly better.

**Binding Affinity:** Ligand A (-9.4 kcal/mol) has a considerably stronger binding affinity than Ligand B (-8.7 kcal/mol). This difference of 0.7 kcal/mol is substantial and can outweigh minor ADME drawbacks.

**Overall:**

Ligand A is superior due to its significantly better TPSA, logP, BBB penetration, microsomal clearance, and, most importantly, binding affinity. While Ligand A has a higher DILI risk, the strong affinity and favorable CNS penetration properties make it a more promising candidate. Ligand B's low logP and poor BBB penetration are major drawbacks for a CNS-targeting drug.

Output:
1
2025-04-17 06:46:55,851 - INFO - Reasoning:

Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (346.471 and 354.535 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (66.48) is better than Ligand B (69.64). Both are below the 90 A^2 threshold desirable for CNS targets, but A is closer to optimal.

**3. logP:** Both ligands have good logP values (2.006 and 3.109), falling within the 1-3 range. Ligand B is slightly higher, which *could* be a minor concern for solubility, but isn't a dealbreaker.

**4. H-Bond Donors:** Ligand A (1) is preferable to Ligand B (2). Lower HBD generally improves permeability.

**5. H-Bond Acceptors:** Both ligands have 3 HBA, which is acceptable.

**6. QED:** Both ligands have similar QED values (0.775 and 0.704), indicating good drug-likeness.

**7. DILI:** Ligand A (12.098) has a significantly lower DILI risk than Ligand B (9.965), a major advantage.

**8. BBB:** Ligand A (74.292) has a better BBB percentile than Ligand B (65.801). This is *critical* for a CNS target like DRD2.

**9. Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and suggests poor permeability. However, the scale isn't defined, so it's hard to interpret.

**10. Aqueous Solubility:** Both ligands have negative solubility values, which is also unusual and suggests poor solubility.

**11. hERG Inhibition:** Ligand A (0.136) has a much lower hERG inhibition liability than Ligand B (0.588), a significant safety advantage.

**12. Microsomal Clearance:** Ligand B (58.17) has significantly lower microsomal clearance than Ligand A (13.939), indicating better metabolic stability.

**13. In vitro Half-Life:** Ligand A (-13.06) has a negative half-life, which is not possible and suggests an issue with the data. Ligand B (-3.926) also has a negative half-life, also problematic.

**14. P-gp Efflux:** Ligand A (0.032) has much lower P-gp efflux liability than Ligand B (0.121), which is beneficial for CNS penetration.

**15. Binding Affinity:** Ligand B (-7.3 kcal/mol) has a slightly better binding affinity than Ligand A (-8.5 kcal/mol). While affinity is important, the difference here is not substantial enough to outweigh the other significant advantages of Ligand A.

**Overall Assessment:**

Ligand A is the superior candidate. It demonstrates significantly better predicted safety (lower DILI, lower hERG), better BBB penetration, and lower P-gp efflux. While Ligand B has slightly better affinity and metabolic stability, the other ADME/Tox properties of Ligand A are substantially more favorable, especially for a CNS-targeting drug. The negative half-life values are concerning for both, but the other advantages of A are more compelling.

Output:
1
2025-04-17 06:46:55,851 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (349.563 and 357.443 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (26.79) is excellent, well below the 90 A^2 threshold for CNS targets. Ligand B (92.59) is higher, but still potentially acceptable, though less ideal.

**logP:** Ligand A (3.079) is optimal (1-3). Ligand B (1.113) is at the lower end, potentially impacting permeability.

**H-Bond Donors/Acceptors:** Ligand A (0 HBD, 3 HBA) is favorable. Ligand B (1 HBD, 7 HBA) is also acceptable, but slightly higher counts could affect permeability.

**QED:** Both ligands have similar QED values (0.763 and 0.71), indicating good drug-like properties.

**DILI:** Ligand A (4.188) has a very low DILI risk. Ligand B (79.604) has a significantly higher, though not alarming, DILI risk.

**BBB:** Ligand A (93.408) has excellent BBB penetration potential, exceeding the desirable >70% threshold. Ligand B (47.15) is considerably lower, which is a major concern for a CNS target like DRD2.

**Caco-2 Permeability:** Ligand A (-4.38) has poor Caco-2 permeability, which is a concern. Ligand B (-5.93) is also poor, but slightly worse.

**Aqueous Solubility:** Both ligands have very poor aqueous solubility (-1.136 and -1.97). This could pose formulation challenges.

**hERG Inhibition:** Both ligands show low hERG inhibition risk (0.883 and 0.139).

**Microsomal Clearance:** Ligand A (24.93) has lower microsomal clearance, suggesting better metabolic stability. Ligand B (45.41) has higher clearance.

**In vitro Half-Life:** Ligand A (-15.027) has a very short half-life, which is a significant drawback. Ligand B (-9.611) is better, but still short.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.125 and 0.112), which is good for CNS penetration.

**Binding Affinity:** Both ligands have very similar and strong binding affinities (-7.4 and -7.3 kcal/mol). The difference is negligible.

**Overall Assessment:**

Ligand A excels in TPSA, DILI, BBB, and metabolic stability (Cl_mic). However, its poor Caco-2 permeability and extremely short half-life are major liabilities. Ligand B has a higher DILI risk and lower BBB penetration, but its other properties are less concerning.

Given the importance of BBB penetration for a CNS target like DRD2, **Ligand A is the more promising candidate despite its permeability and half-life issues.** These can potentially be addressed through prodrug strategies or formulation approaches. The significantly lower BBB score for Ligand B is a more difficult hurdle to overcome.

Output:
0
2025-04-17 06:46:55,851 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (337.419 Da) is slightly preferred due to being lower.

**TPSA:** Ligand A (46.61) is significantly better than Ligand B (50.27). Both are below the 90 A^2 threshold for CNS targets, but A is closer to optimal.

**logP:** Both ligands have good logP values (A: 4.19, B: 3.646), falling within the 1-3 range. Ligand B is slightly better here.

**H-Bond Donors/Acceptors:** Both have acceptable HBD counts (0). Ligand A has 3 HBAs and Ligand B has 6. Lower is generally better, favoring Ligand A.

**QED:** Both ligands have reasonable QED scores (A: 0.789, B: 0.631), indicating good drug-like properties. Ligand A is better.

**DILI:** Ligand A (69.639) has a higher DILI risk than Ligand B (50.136), making B slightly preferable.

**BBB:** Both ligands have good BBB penetration (A: 75.921, B: 71.966), exceeding the 70% threshold for CNS targets. Ligand A is slightly better.

**Caco-2 Permeability:** Ligand A (-4.434) has a worse Caco-2 permeability than Ligand B (-5.489). Lower values indicate poorer permeability, favoring Ligand B.

**Aqueous Solubility:** Both ligands have poor aqueous solubility (A: -5.775, B: -3.785). Ligand B is better.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (A: 0.786, B: 0.66), which is favorable. Ligand B is slightly better.

**Microsomal Clearance:** Ligand A (119.593) has higher microsomal clearance than Ligand B (35.322), indicating lower metabolic stability. Ligand B is significantly better.

**In vitro Half-Life:** Ligand A (26.085) has a longer in vitro half-life than Ligand B (7.254), which is preferable.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (A: 0.708, B: 0.399). Ligand B is better.

**Binding Affinity:** Ligand A (-9.7 kcal/mol) has a significantly stronger binding affinity than Ligand B (-6.4 kcal/mol). This is a substantial advantage (>1.5 kcal/mol difference).

**Overall Assessment:**

While Ligand B performs better in several ADME properties (DILI, Caco-2, Solubility, hERG, Cl_mic, Pgp), the significantly superior binding affinity of Ligand A (-9.7 vs -6.4 kcal/mol) is a decisive factor. The strong binding can potentially compensate for some of the ADME drawbacks, especially given the acceptable BBB penetration. For a GPCR target, affinity is paramount, and the difference here is substantial.

Output:
1
2025-04-17 06:46:55,851 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (346.43 & 360.46 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Both ligands (67.87 & 66.91) are below the 90 A^2 threshold for CNS targets, which is excellent.

**3. logP:** Both ligands (2.43 & 2.92) are within the optimal 1-3 range.

**4. H-Bond Donors:** Ligand A (1) is preferable to Ligand B (2) as lower HBDs generally improve permeability.

**5. H-Bond Acceptors:** Ligand A (4) is preferable to Ligand B (5) for the same reason as above.

**6. QED:** Both ligands (0.66 & 0.82) are above the 0.5 threshold, indicating good drug-like properties. Ligand B is slightly better here.

**7. DILI:** Both ligands have relatively high DILI risk (41.33 & 89.65). Ligand B is significantly higher, which is a concern.

**8. BBB:** Ligand A (89.03%) is significantly better than Ligand B (70.65%) in terms of predicted BBB penetration, a critical factor for CNS targets like DRD2.

**9. Caco-2 Permeability:** Both have negative values (-4.65 & -4.72), which is unusual and suggests poor permeability. However, these values are on a scale where negative values are possible, and direct comparison is difficult without knowing the scale's specifics.

**10. Aqueous Solubility:** Both have negative values (-2.35 & -4.69), again suggesting poor solubility. Similar to Caco-2, the scale is unknown.

**11. hERG Inhibition:** Both ligands have low hERG inhibition risk (0.56 & 0.85), which is good.

**12. Microsomal Clearance:** Ligand B (57.76) has lower microsomal clearance than Ligand A (61.53), suggesting better metabolic stability.

**13. In vitro Half-Life:** Ligand B (27.51) has a significantly longer half-life than Ligand A (1.05), which is a major advantage.

**14. P-gp Efflux:** Ligand A (0.15) has lower P-gp efflux than Ligand B (0.31), which is favorable for CNS penetration.

**15. Binding Affinity:** Ligand B (-8.6 kcal/mol) has a slightly better binding affinity than Ligand A (-8.2 kcal/mol), a 0.4 kcal/mol difference.

**Overall Assessment:**

While Ligand B has a slightly better binding affinity and a significantly longer half-life, Ligand A is superior due to its much better predicted BBB penetration (89% vs 70%), lower P-gp efflux, and lower DILI risk. The difference in binding affinity (0.4 kcal/mol) is not substantial enough to outweigh the significant advantages of Ligand A, especially considering the importance of CNS penetration for a DRD2 target. The poor solubility and permeability are concerning for both, but can be addressed through formulation strategies.

Output:
0
2025-04-17 06:46:55,851 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (370.896 and 364.389 Da) are within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (41.57) is excellent, well below the 90 A^2 threshold for CNS targets. Ligand B (104.73) is higher, but still potentially acceptable, though less ideal.

**3. logP:** Ligand A (4.428) is slightly high, potentially leading to solubility issues or off-target interactions. Ligand B (0.457) is quite low, which could hinder membrane permeability and CNS penetration.

**4. H-Bond Donors:** Ligand A (1) is good. Ligand B (3) is acceptable, but higher.

**5. H-Bond Acceptors:** Ligand A (3) is good. Ligand B (5) is acceptable, but higher.

**6. QED:** Ligand A (0.833) is very good, indicating high drug-likeness. Ligand B (0.569) is acceptable, but lower.

**7. DILI:** Ligand A (20.396) has a very low DILI risk. Ligand B (36.448) is also relatively low, but higher than A.

**8. BBB:** Ligand A (69.407) has a good BBB percentile, though ideally >70. Ligand B (67.197) is similar, but also slightly below the ideal threshold.

**9. Caco-2:** Both ligands have negative Caco-2 values (-4.499 and -4.938), which is unusual and suggests poor permeability. This is a significant concern for both.

**10. Solubility:** Both ligands have negative solubility values (-4.006 and -2.17), indicating very poor aqueous solubility. This is a major drawback.

**11. hERG:** Ligand A (0.908) has a low hERG risk. Ligand B (0.279) also has a low hERG risk.

**12. Cl_mic:** Ligand A (36.921) has a moderate microsomal clearance. Ligand B (44.89) has a higher clearance, suggesting faster metabolism.

**13. t1/2:** Ligand A (39.193) has a reasonable in vitro half-life. Ligand B (-53.462) has a drastically negative half-life, which is biologically implausible and indicates a very short half-life.

**14. Pgp:** Ligand A (0.366) has low P-gp efflux liability. Ligand B (0.025) has very low P-gp efflux liability.

**15. Binding Affinity:** Ligand A (-8.5 kcal/mol) has a significantly stronger binding affinity than Ligand B (-7.7 kcal/mol). This 1.5 kcal/mol difference is substantial.

**Overall Assessment:**

Despite both compounds having issues with Caco-2 and solubility, Ligand A is the more promising candidate. Its superior binding affinity, lower DILI risk, better QED, and more reasonable metabolic clearance outweigh its slightly higher logP. Ligand B's extremely negative in vitro half-life is a critical flaw, making it unlikely to be a viable drug candidate. While both need improvement in solubility and permeability, Ligand A provides a better starting point for optimization.

Output:
0
2025-04-17 06:46:55,852 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (347.459 Da) is slightly lower, which can be advantageous for permeability. Ligand B (385.408 Da) is also acceptable.

**TPSA:** Ligand A (45.25) is excellent, well below the 90 A^2 threshold for CNS targets. Ligand B (95.58) is higher, but still potentially acceptable, though less ideal for brain penetration.

**logP:** Ligand A (1.316) is within the optimal range (1-3). Ligand B (0.579) is a bit low, potentially hindering membrane permeability.

**H-Bond Donors/Acceptors:** Ligand A (0 HBD, 5 HBA) is good. Ligand B (2 HBD, 4 HBA) is also acceptable.

**QED:** Both ligands have reasonable QED values (Ligand A: 0.804, Ligand B: 0.67), indicating good drug-like properties.

**DILI:** Ligand A (34.82) has a very favorable DILI score, indicating low liver injury risk. Ligand B (42.613) is slightly higher, but still within an acceptable range.

**BBB:** Ligand A (80.884) has a significantly better BBB percentile than Ligand B (66.421). This is a crucial factor for a CNS target like DRD2.

**Caco-2 Permeability:** Ligand A (-4.37) has a negative Caco-2 value, which is unusual and suggests poor permeability. Ligand B (-5.154) also has a negative value, indicating poor permeability.

**Aqueous Solubility:** Both ligands have negative solubility values, which is concerning. Ligand A (-1.067) is slightly better than Ligand B (-2.452).

**hERG Inhibition:** Both ligands have very low hERG inhibition risk (Ligand A: 0.671, Ligand B: 0.276).

**Microsomal Clearance:** Ligand A (3.428) has a lower microsomal clearance than Ligand B (11.059), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (15.505 hours) has a much longer half-life than Ligand B (-38.435 hours, which is nonsensical and indicates very rapid degradation).

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (Ligand A: 0.05, Ligand B: 0.01).

**Binding Affinity:** Both ligands have similar and strong binding affinities (Ligand A: -8 kcal/mol, Ligand B: -8.6 kcal/mol). The difference is minor.

**Overall Assessment:**

Ligand A is significantly better overall. While both have poor Caco-2 and solubility, Ligand A excels in BBB penetration, metabolic stability (lower Cl_mic, longer t1/2), and has a much better DILI score. The slightly better logP of Ligand A also contributes to its favorability. The similar binding affinities mean that the ADME properties are the deciding factors. The negative half-life for Ligand B is a major red flag.

Output:
1
2025-04-17 06:46:55,852 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (368.5 & 375.5 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (78.87) is significantly better than Ligand B (104.81). For CNS targets, we want TPSA <= 90, so Ligand A is preferable.

**3. logP:** Both ligands have good logP values (0.941 & 0.832), falling within the optimal 1-3 range.

**4. H-Bond Donors:** Both have 2 HBD, which is acceptable (<=5).

**5. H-Bond Acceptors:** Both have 5 HBA, which is acceptable (<=10).

**6. QED:** Ligand A (0.722) has a slightly better QED than Ligand B (0.654), indicating better drug-likeness. Both are above the 0.5 threshold.

**7. DILI:** Ligand A (36.293) has a much lower DILI risk than Ligand B (48.313). Both are below 60, but A is significantly better.

**8. BBB:** Ligand B (54.866) has a substantially better BBB penetration score than Ligand A (17.914). This is a *critical* factor for a CNS target like DRD2.

**9. Caco-2:** Both have negative Caco-2 values (-4.965 & -5.205), which is unusual and suggests poor permeability. This is a significant drawback for both.

**10. Solubility:** Both have negative solubility values (-2.559 & -2.568), indicating poor aqueous solubility. This is also a significant drawback.

**11. hERG:** Both have low hERG risk (0.162 & 0.307).

**12. Cl_mic:** Ligand A (31.599) has a much lower microsomal clearance than Ligand B (6.791), suggesting better metabolic stability.

**13. t1/2:** Ligand A (-2.148) has a more favorable (less negative) in vitro half-life than Ligand B (-46.245).

**14. Pgp:** Ligand A (0.142) has a lower P-gp efflux liability than Ligand B (0.038), meaning it's less likely to be pumped out of the brain.

**15. Binding Affinity:** Ligand B (-7.6) has a slightly better binding affinity than Ligand A (-7.3), but the difference is relatively small (0.3 kcal/mol).

**Overall Assessment:**

Ligand B has a significantly better BBB score, which is paramount for a CNS target. However, Ligand A excels in most other ADME properties (DILI, Cl_mic, t1/2, Pgp) and has a comparable binding affinity. The poor Caco-2 and solubility for both are concerning, but can potentially be addressed with formulation strategies. Given the importance of BBB penetration for DRD2, and the relatively small affinity difference, Ligand B is the more promising candidate *despite* its worse ADME profile.

Output:
1
2025-04-17 06:46:55,852 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (376.356 and 348.451 Da) fall within the ideal 200-500 Da range.

**TPSA:** Both ligands have TPSA values (94.56 and 93.01) that are acceptable for oral absorption (<140) but slightly high for optimal CNS penetration (<90).

**logP:** Ligand A (3.041) is optimal, while Ligand B (0.851) is a bit low, potentially hindering permeation.

**H-Bond Donors/Acceptors:** Ligand A (2 HBD, 5 HBA) and Ligand B (1 HBD, 6 HBA) both fall within acceptable ranges.

**QED:** Both ligands have good QED scores (0.808 and 0.823), indicating drug-like properties.

**DILI:** Ligand A (72.276) has a higher DILI risk than Ligand B (49.128), but both are still reasonably acceptable.

**BBB:** Ligand A (66.344) has a slightly better BBB percentile than Ligand B (55.642), although both are below the desirable >70 for CNS targets.

**Caco-2 Permeability:** Ligand A (-4.806) has worse Caco-2 permeability than Ligand B (-5.238), indicating lower intestinal absorption.

**Aqueous Solubility:** Ligand A (-3.782) has worse aqueous solubility than Ligand B (-1.443).

**hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.476 and 0.026).

**Microsomal Clearance:** Ligand A (16.214) has higher microsomal clearance than Ligand B (8.267), indicating lower metabolic stability.

**In vitro Half-Life:** Ligand A (-14.245) has a worse in vitro half-life than Ligand B (6.475).

**P-gp Efflux:** Ligand A (0.236) has lower P-gp efflux than Ligand B (0.05), which is favorable for CNS exposure.

**Binding Affinity:** Both ligands have excellent binding affinity (-8.4 and -8.5 kcal/mol), with Ligand B being slightly better. The affinity difference is minimal, and both are well below the -7.0 kcal/mol threshold.

**Overall Assessment:**

Considering the GPCR-specific priorities, Ligand B is slightly more favorable. While Ligand A has a better P-gp efflux profile, Ligand B compensates with a better logP, lower DILI risk, better Caco-2 permeability, better aqueous solubility, and better metabolic stability (lower Cl_mic and better t1/2). The slightly better affinity of Ligand B is a minor advantage. The BBB values are both suboptimal, but Ligand B is closer to the desired threshold.

Output:
1
2025-04-17 06:46:55,852 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (350.478 and 368.415 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (40.62) is better than Ligand B (49.41). Both are below the 90 A^2 threshold for CNS targets, but A is closer to the optimal range.

**3. logP:** Both ligands have similar logP values (3.344 and 3.599), falling within the optimal 1-3 range.

**4. H-Bond Donors:** Ligand A (0) is slightly better than Ligand B (1) as fewer HBDs generally improve permeability.

**5. H-Bond Acceptors:** Both ligands have 2 HBA, which is acceptable.

**6. QED:** Both ligands have similar QED values (0.689 and 0.666), indicating good drug-like properties.

**7. DILI:** Ligand A (19.271) has a lower DILI risk than Ligand B (24.893), which is preferable.

**8. BBB:** Ligand B (93.874) has a significantly better BBB penetration percentile than Ligand A (86.972). This is a crucial factor for a CNS target like DRD2.

**9. Caco-2 Permeability:** Both ligands have similar, very negative Caco-2 values (-4.422 and -4.415). This is unusual and suggests a potential issue with intestinal absorption, but the scale is not defined, and negative values might indicate a different measurement.

**10. Aqueous Solubility:** Both ligands have similar, very negative solubility values (-3.548 and -3.654). Similar to Caco-2, this is unusual and requires further investigation.

**11. hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.587 and 0.594).

**12. Microsomal Clearance:** Ligand B (46.486) has a lower microsomal clearance than Ligand A (54.813), indicating better metabolic stability.

**13. In vitro Half-Life:** Ligand A (5.531) has a longer in vitro half-life than Ligand B (-5.476). This is desirable.

**14. P-gp Efflux:** Both ligands have low P-gp efflux liability (0.154 and 0.09).

**15. Binding Affinity:** Ligand A (-7.8 kcal/mol) has a slightly better binding affinity than Ligand B (-7.6 kcal/mol). While the difference is small, it's still a positive.

**Overall Assessment:**

Ligand B excels in BBB penetration, a critical factor for CNS drug development. It also has better metabolic stability (lower Cl_mic). However, Ligand A has a slightly better binding affinity, a longer half-life, and a lower DILI risk. The negative values for Caco-2 and solubility are concerning for both, but the difference in BBB is significant. Given the importance of CNS penetration for DRD2, and the relatively small difference in binding affinity, Ligand B is the more promising candidate.

Output:
1
2025-04-17 06:46:55,852 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (346.431 Da) is slightly lower, which could be advantageous for permeability, but both are acceptable.

**TPSA:** Ligand A (84.42) is better than Ligand B (66.32) as it is closer to the optimal range for CNS targets (<=90).

**logP:** Ligand A (1.642) is within the optimal range (1-3), while Ligand B (3.248) is at the higher end but still acceptable.

**H-Bond Donors/Acceptors:** Both ligands have 1 HBD and a reasonable number of HBAs (5 and 6 respectively). This is favorable for both solubility and permeability.

**QED:** Both ligands have good QED scores (0.773 and 0.865), indicating good drug-like properties.

**DILI:** Ligand A (48.779) has a lower DILI risk than Ligand B (65.568), which is a significant advantage.

**BBB:** Ligand A (77.898) has a significantly better BBB penetration percentile than Ligand B (49.787). This is *critical* for a CNS target like DRD2.

**Caco-2 Permeability:** Ligand A (-4.42) has a worse Caco-2 permeability than Ligand B (-5.128).

**Aqueous Solubility:** Ligand A (-2.899) has a slightly better aqueous solubility than Ligand B (-3.867).

**hERG:** Both ligands have low hERG inhibition liability (0.236 and 0.396), which is good.

**Microsomal Clearance:** Ligand A (77.337) has a higher microsomal clearance than Ligand B (54.348), suggesting lower metabolic stability.

**In vitro Half-Life:** Ligand B (-0.785) has a better in vitro half-life than Ligand A (-34.526).

**P-gp Efflux:** Ligand A (0.079) has a lower P-gp efflux liability than Ligand B (0.207), which is beneficial for CNS penetration.

**Binding Affinity:** Ligand A (-7.8 kcal/mol) has a slightly better binding affinity than Ligand B (-7.3 kcal/mol). While the difference is not huge (0.5 kcal/mol), it is still a positive factor.

**Overall Assessment:**

Ligand A is the stronger candidate. The significantly better BBB penetration (77.9% vs 49.8%), lower DILI risk, and slightly better binding affinity outweigh the slightly worse Caco-2 permeability and higher microsomal clearance. The lower P-gp efflux also supports better CNS exposure. For a GPCR target in the CNS, BBB penetration is paramount, and Ligand A excels in this area.

Output:
0
2025-04-17 06:46:55,853 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (345.355 Da) is slightly lower, which is generally favorable for permeability. Ligand B (381.885 Da) is also good.

**TPSA:** Both ligands have TPSA values below the 140 A^2 threshold for good oral absorption. Importantly, both are also below the 90 A^2 threshold desirable for CNS targets. Ligand B (85.43 A^2) is slightly better than Ligand A (93.9 A^2).

**logP:** Both ligands have logP values within the optimal range of 1-3. Ligand A (1.874) is slightly lower, while Ligand B (2.353) is closer to the middle of the range.

**H-Bond Donors/Acceptors:** Ligand A (1 HBD, 6 HBA) is better than Ligand B (3 HBD, 4 HBA) in terms of balancing solubility and permeability.

**QED:** Both ligands have acceptable QED values (>0.5), indicating good drug-like properties. Ligand A (0.854) is significantly better than Ligand B (0.743).

**DILI:** Ligand A (77.433) has a higher DILI risk than Ligand B (55.642), but both are below the concerning threshold of 60.

**BBB:** This is a critical parameter for a CNS target like DRD2. Ligand A (74.292) has a significantly better BBB penetration percentile than Ligand B (25.708). This is a major advantage for Ligand A.

**Caco-2 Permeability:** Ligand A (-4.501) has a worse Caco-2 permeability than Ligand B (-5.198). Lower values indicate lower permeability.

**Aqueous Solubility:** Both ligands have poor aqueous solubility (-3.305 and -3.521 respectively).

**hERG Inhibition:** Both ligands show low hERG inhibition risk (0.18 and 0.525 respectively).

**Microsomal Clearance:** Ligand B (8.096) has a much lower microsomal clearance than Ligand A (95.704), indicating better metabolic stability.

**In vitro Half-Life:** Ligand B (-12.121) has a longer in vitro half-life than Ligand A (-33.21), which is desirable.

**P-gp Efflux:** Both ligands show low P-gp efflux liability (0.16 and 0.241 respectively).

**Binding Affinity:** Ligand B (-8.3 kcal/mol) has a significantly stronger binding affinity than Ligand A (0.0 kcal/mol). This is a substantial advantage for Ligand B.

**Overall Assessment:**

While Ligand A has better QED, BBB, and H-bonding properties, Ligand B's significantly stronger binding affinity (-8.3 vs 0.0 kcal/mol) and better metabolic stability (lower Cl_mic, longer t1/2) are crucial advantages. The difference in binding affinity is large enough to outweigh the drawbacks of slightly lower BBB and QED. Although Ligand A has a better BBB score, the affinity difference is so significant that it is likely Ligand B will still achieve sufficient CNS exposure.

Output:
1
2025-04-17 06:46:55,853 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (346.343 and 350.459 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (121.72) is slightly above the optimal <90 for CNS targets, but still reasonable. Ligand B (71.78) is excellent, well below 90.

**logP:** Ligand A (-0.958) is a bit low, potentially hindering permeation. Ligand B (3.394) is within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A (2 HBD, 7 HBA) and Ligand B (1 HBD, 4 HBA) both have acceptable numbers of H-bond donors and acceptors.

**QED:** Both ligands have good QED scores (0.674 and 0.702), indicating drug-like properties.

**DILI:** Ligand A (74.409) has a higher DILI risk than Ligand B (27.142), which is a significant concern.

**BBB:** This is crucial for a CNS target. Ligand A (48.779) has a moderate BBB penetration, while Ligand B (86.002) is excellent, exceeding the desirable >70 threshold.

**Caco-2 Permeability:** Both have negative Caco-2 values which is unusual and suggests issues with the prediction method or the molecules themselves. However, we can still compare them. Ligand A (-4.962) is worse than Ligand B (-4.191).

**Aqueous Solubility:** Both ligands have negative solubility values, which is also unusual. Ligand A (-1.673) is slightly better than Ligand B (-3.43).

**hERG:** Ligand A (0.087) has a very low hERG risk, while Ligand B (0.626) has a slightly elevated risk, but still acceptable.

**Microsomal Clearance:** Ligand A (19.04) has lower clearance than Ligand B (92.824), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (-10.383) has a negative half-life, which is not possible. Ligand B (29.518) has a reasonable half-life.

**P-gp Efflux:** Ligand A (0.031) has very low P-gp efflux, which is favorable for CNS penetration. Ligand B (0.164) has slightly higher efflux.

**Binding Affinity:** Ligand B (-7.8 kcal/mol) has a slightly better binding affinity than Ligand A (-8.5 kcal/mol), although both are excellent.

**Overall Assessment:**

Ligand B is the stronger candidate. While Ligand A has a slightly better binding affinity and lower P-gp efflux, Ligand B excels in critical areas for a CNS-targeting GPCR: significantly better BBB penetration, a much lower DILI risk, and a reasonable half-life. The logP value for Ligand B is also optimal, while Ligand A's is suboptimal. The unusual negative values for Caco-2 and solubility are concerning for both, but the other advantages of Ligand B outweigh this.

Output:
1
2025-04-17 06:46:55,853 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (353.348 and 348.418 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (77.04) is slightly higher than Ligand B (69.64). Both are below the 90 A^2 threshold desirable for CNS targets, but B is preferable.

**3. logP:** Both ligands have good logP values (2.009 and 1.701), falling within the optimal 1-3 range.

**4. H-Bond Donors:** Ligand A (1) is better than Ligand B (2) as fewer HBDs generally improve permeability.

**5. H-Bond Acceptors:** Ligand A (5) is better than Ligand B (3) as fewer HBAs generally improve permeability.

**6. QED:** Ligand A (0.916) has a significantly higher QED than Ligand B (0.769), indicating a more drug-like profile.

**7. DILI:** Ligand B (23.614) has a much lower DILI risk than Ligand A (56.572), which is a significant advantage.

**8. BBB:** Ligand A (87.088) has a better BBB percentile than Ligand B (57.968), which is critical for a CNS target like DRD2.

**9. Caco-2 Permeability:** Ligand A (-4.888) has better Caco-2 permeability than Ligand B (-4.441).

**10. Aqueous Solubility:** Ligand A (-2.695) has better aqueous solubility than Ligand B (-2.048).

**11. hERG Inhibition:** Both ligands have low hERG inhibition risk (0.638 and 0.774).

**12. Microsomal Clearance:** Ligand A (-33.474) has a much lower (better) microsomal clearance than Ligand B (35.78). This suggests better metabolic stability for Ligand A.

**13. In vitro Half-Life:** Ligand A (2.713) has a better in vitro half-life than Ligand B (-22.805).

**14. P-gp Efflux:** Ligand A (0.093) has a lower P-gp efflux liability than Ligand B (0.136), which is favorable for CNS penetration.

**15. Binding Affinity:** Ligand B (-7.3) has a slightly better binding affinity than Ligand A (-9.0). While A is better, the difference is not substantial enough to outweigh other factors.

**Overall Assessment:**

Ligand A excels in QED, metabolic stability (Cl_mic, t1/2), BBB penetration, Caco-2 permeability, solubility, and P-gp efflux. Ligand B's primary advantage is its significantly lower DILI risk. However, the superior BBB penetration of Ligand A is crucial for a CNS target like DRD2. The slightly stronger affinity of Ligand B is not enough to overcome the other advantages of Ligand A, especially regarding CNS exposure and metabolic stability.

Output:
1
2025-04-17 06:46:55,853 - INFO - Batch 310 complete. Total preferences: 4960
2025-04-17 06:46:55,853 - INFO - Processing batch 311/512...
2025-04-17 06:47:35,355 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B against the provided guidelines, prioritizing GPCR-specific properties (BBB, logP, Pgp, TPSA, and affinity) for DRD2.

**Molecular Weight:** Both ligands (353.463 and 350.329 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (98.74) is better than Ligand B (108.9), both are below the 140 threshold for oral absorption, and importantly, Ligand A is closer to the <90 target for CNS penetration.

**logP:** Both ligands have similar logP values (0.417 and 0.416), which is on the low side of optimal (1-3). This could potentially hinder permeation, but isn't a dealbreaker.

**H-Bond Donors/Acceptors:** Both have 3 HBDs, which is good. Ligand A has 4 HBAs, while Ligand B has 6. Lower HBA is generally preferred.

**QED:** Both ligands have good QED scores (0.551 and 0.625), indicating drug-like properties.

**DILI:** Ligand A (8.647) has a significantly lower DILI risk than Ligand B (67.003). This is a substantial advantage.

**BBB:** Ligand A (35.324) has a very poor BBB percentile, while Ligand B (67.119) is better, but still not ideal (target >70). This is a major drawback for Ligand A.

**Caco-2 Permeability:** Both have negative Caco-2 values (-5.144 and -5.193), which is unusual and suggests poor permeability.

**Aqueous Solubility:** Both have negative solubility values (-1.309 and -2.678), also unusual and suggesting poor solubility.

**hERG:** Both have low hERG inhibition liability (0.205 and 0.314), which is good.

**Microsomal Clearance:** Ligand A (15.801) has significantly lower microsomal clearance than Ligand B (44.309), indicating better metabolic stability.

**In vitro Half-Life:** Ligand A (-18.375) has a negative half-life, which is not possible. Ligand B (15.85) is reasonable. This is a major issue for Ligand A.

**P-gp Efflux:** Both have very low P-gp efflux liability (0.035 and 0.017), which is favorable for CNS penetration.

**Binding Affinity:** Ligand B (-8.9 kcal/mol) has a significantly stronger binding affinity than Ligand A (-7.3 kcal/mol). This is a substantial advantage, potentially outweighing some ADME concerns.

**Overall Assessment:**

Despite Ligand B's better affinity, the significant advantages of Ligand A in terms of DILI risk and metabolic stability are compelling. However, the extremely poor BBB penetration and impossible half-life for Ligand A are fatal flaws. Ligand B, while having a higher DILI risk and faster clearance, has a much better BBB score and a reasonable half-life. The affinity difference is significant, but not insurmountable. Given the CNS target, a reasonable BBB score is crucial, and Ligand B is the only one that provides that.

Output:
1
2025-04-17 06:47:35,355 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (346.471 Da) is slightly lower, which could be beneficial for permeability.

**TPSA:** Ligand A (50.8) is excellent for CNS penetration, well below the 90 A^2 threshold. Ligand B (100.29) is higher, but still potentially acceptable, though less ideal.

**logP:** Ligand A (3.322) is optimal. Ligand B (1.178) is a bit low, potentially hindering membrane permeability.

**H-Bond Donors/Acceptors:** Ligand A (HBD=1, HBA=3) and Ligand B (HBD=3, HBA=4) both have reasonable numbers of H-bond donors and acceptors, falling within the acceptable ranges.

**QED:** Ligand A (0.86) has a higher QED score than Ligand B (0.672), indicating better overall drug-likeness.

**DILI:** Ligand A (22.8) has a much lower DILI risk than Ligand B (58.511), a significant advantage.

**BBB:** Ligand A (89.027) has excellent predicted BBB penetration, exceeding the desirable 70% threshold. Ligand B (54.246) is considerably lower, raising concerns about CNS exposure.

**Caco-2 Permeability:** Ligand A (-4.278) and Ligand B (-5.315) both have negative Caco-2 values, which is unusual. These values are likely on a log scale, and thus represent very low permeability.

**Aqueous Solubility:** Both ligands have very poor aqueous solubility (-3.152 and -3.092). This could pose formulation challenges.

**hERG Inhibition:** Both ligands show low hERG inhibition risk (0.561 and 0.389).

**Microsomal Clearance:** Ligand A (41.018) has higher microsomal clearance than Ligand B (26.133), suggesting lower metabolic stability.

**In vitro Half-Life:** Ligand B (-31.083) has a very negative half-life, which is concerning. Ligand A (2.776) is positive, indicating a reasonable half-life.

**P-gp Efflux:** Both ligands show low P-gp efflux liability (0.094 and 0.053), which is favorable for CNS penetration.

**Binding Affinity:** Both ligands have very similar and strong binding affinities (-8.4 and -8.3 kcal/mol). The difference is negligible.

**Conclusion:**

Considering all factors, especially the GPCR-specific priorities, **Ligand A is the more promising candidate.** It has superior BBB penetration, lower DILI risk, better QED, and a more reasonable in vitro half-life. While both have poor solubility and Caco-2 permeability, the strong CNS target engagement combined with the other favorable properties of Ligand A make it the better choice. The slightly higher clearance of Ligand A is a minor concern compared to the significant drawbacks of Ligand B.

Output:
1
2025-04-17 06:47:35,356 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (364.869 and 360.523 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (52.6) is slightly higher than Ligand B (42.43). Both are below the 90 Angstroms threshold desirable for CNS targets, making both favorable.

**3. logP:** Both ligands have a logP around 4.1-4.3, which is slightly above the optimal range of 1-3. This could potentially lead to solubility issues or off-target interactions, but is not a dealbreaker.

**4. H-Bond Donors:** Both have 0 HBD, which is good for permeability.

**5. H-Bond Acceptors:** Both have 4 HBA, which is within the acceptable range of <=10.

**6. QED:** Both have QED values above 0.68, indicating good drug-likeness.

**7. DILI:** Ligand A (29.003) has a lower DILI risk than Ligand B (35.091), which is preferable.

**8. BBB:** Both ligands have high BBB penetration (80.574 and 79.217), exceeding the desirable >70 threshold for CNS targets. This is a significant positive for both.

**9. Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and potentially problematic. However, these values are on a strange scale and may not be directly comparable.

**10. Aqueous Solubility:** Both have negative solubility values, which is also unusual and suggests poor aqueous solubility. This is a concern, but can be mitigated with formulation strategies.

**11. hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.405 and 0.403).

**12. Microsomal Clearance:** Ligand A (99.016) has a much higher microsomal clearance than Ligand B (65.98). This suggests Ligand A will be metabolized more quickly, leading to a shorter duration of action.

**13. In vitro Half-Life:** Ligand B (-14.974) has a longer in vitro half-life than Ligand A (15.952). This is a significant advantage for Ligand B.

**14. P-gp Efflux:** Both ligands have low P-gp efflux liability (0.217 and 0.396).

**15. Binding Affinity:** Ligand A (-8.3 kcal/mol) has a significantly stronger binding affinity than Ligand B (-6.6 kcal/mol). This is a >1.5 kcal/mol difference, which is a major advantage and can outweigh some ADME drawbacks.

**Overall Assessment:**

While both ligands have good BBB penetration and acceptable physicochemical properties, Ligand A's significantly stronger binding affinity (-8.3 kcal/mol vs -6.6 kcal/mol) is a decisive factor. The higher clearance of Ligand A is a concern, but the potency advantage is substantial. The unusual Caco-2 and solubility values are shared by both and require further investigation, but do not negate the potency difference. The lower DILI risk for Ligand A is also a plus.

Output:
1
2025-04-17 06:47:35,356 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (349.362 and 345.447 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (87.74) is better than Ligand B (95.04), both are below the 90 A^2 threshold for CNS targets.

**logP:** Both ligands have good logP values (2.026 and 1.837), falling within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A (2 HBD, 4 HBA) is slightly better than Ligand B (1 HBD, 6 HBA) in terms of balancing solubility and permeability. Both are within acceptable limits.

**QED:** Both ligands have acceptable QED scores (0.814 and 0.761), indicating good drug-likeness.

**DILI:** Ligand A (65.529) has a higher DILI risk than Ligand B (32.067). This is a significant drawback for Ligand A.

**BBB:** Ligand A (60.644) has a better BBB penetration score than Ligand B (53.625), but both are below the desirable >70 percentile for CNS targets.

**Caco-2 Permeability:** Ligand A (-4.556) has a worse Caco-2 permeability than Ligand B (-5.245). Lower values indicate poorer permeability.

**Aqueous Solubility:** Ligand A (-3.619) has better aqueous solubility than Ligand B (-1.698).

**hERG Inhibition:** Ligand A (0.252) has a lower hERG inhibition liability than Ligand B (0.505), which is preferable.

**Microsomal Clearance:** Ligand A (-1.84) has a lower microsomal clearance than Ligand B (34.031), indicating better metabolic stability.

**In vitro Half-Life:** Ligand A (22.287) has a longer in vitro half-life than Ligand B (6.124), which is desirable.

**P-gp Efflux:** Ligand A (0.07) has lower P-gp efflux liability than Ligand B (0.16), which is better for CNS exposure.

**Binding Affinity:** Ligand B (-7.9 kcal/mol) has a significantly stronger binding affinity than Ligand A (-9.2 kcal/mol). This is a crucial advantage, exceeding the 1.5 kcal/mol threshold.

**Overall Assessment:**

While Ligand A has some advantages (better TPSA, lower P-gp efflux, better metabolic stability, longer half-life, better solubility, and lower hERG inhibition), Ligand B's substantially stronger binding affinity (-7.9 vs -9.2 kcal/mol) is the most important factor, especially for a GPCR target. The lower DILI risk of Ligand B is also a significant benefit. Although Ligand B's BBB penetration is not ideal, the stronger affinity could potentially compensate for that.

Output:
1
2025-04-17 06:47:35,356 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (386.901 and 402.34 Da) fall within the ideal range of 200-500 Da.

**TPSA:** Ligand A (92.34) is slightly above the optimal <90 for CNS targets, but still reasonable. Ligand B (36.66) is excellent, well below 90.

**logP:** Ligand A (1.471) is within the optimal 1-3 range. Ligand B (3.358) is also within the optimal range, but closer to the upper limit.

**H-Bond Donors/Acceptors:** Ligand A has 2 HBD and 4 HBA, both acceptable. Ligand B has 0 HBD and 5 HBA, also acceptable.

**QED:** Both ligands have good QED scores (0.742 and 0.79), indicating good drug-like properties.

**DILI:** Ligand A (65.491) has a higher DILI risk than Ligand B (30.826). This is a significant negative for Ligand A.

**BBB:** Ligand B (66.576) has a substantially better BBB penetration score than Ligand A (43.001). This is *critical* for a CNS target like DRD2.

**Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and suggests a potential issue with the data or modeling. However, we'll proceed with the other parameters.

**Aqueous Solubility:** Both have negative solubility values, also unusual.

**hERG:** Both ligands have very low hERG inhibition risk (0.102 and 0.843).

**Microsomal Clearance:** Ligand A (-9.323) has a *much* lower (better) microsomal clearance than Ligand B (68.076), indicating greater metabolic stability.

**In vitro Half-Life:** Ligand A (40.177) has a longer half-life than Ligand B (-41.07), which is desirable.

**P-gp Efflux:** Ligand A (0.114) has lower P-gp efflux liability than Ligand B (0.667), which is beneficial for CNS exposure.

**Binding Affinity:** Both ligands have excellent binding affinities (-9.2 and -8.4 kcal/mol). Ligand A is slightly better (-9.2 kcal/mol).

**Overall Assessment:**

Ligand A has a slightly better binding affinity and significantly better metabolic stability, half-life, and P-gp efflux. However, its DILI risk is considerably higher, and its BBB penetration is significantly worse than Ligand B. Given that DRD2 is a CNS target, BBB penetration is paramount. The lower DILI risk of Ligand B is also a major advantage. While Ligand A's affinity is marginally better, the ADME properties of Ligand B, particularly the BBB score, outweigh this small difference.

Output:
1
2025-04-17 06:47:35,356 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (351.447 and 362.411 Da) fall within the ideal range of 200-500 Da.

**TPSA:** Ligand A (87.74) is excellent, falling well below the 90 A^2 threshold for CNS targets. Ligand B (98.51) is still reasonable, but less optimal.

**logP:** Ligand A (0.614) is a bit low, potentially hindering permeability. Ligand B (2.534) is within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Both have 2 HBDs, which is good. Ligand A has 4 HBAs, and Ligand B has 8 HBAs. Both are acceptable, but Ligand A is slightly better.

**QED:** Both ligands have similar QED values (0.596 and 0.594), indicating good drug-likeness.

**DILI:** Ligand A (29.236) has a much lower DILI risk than Ligand B (89.763), which is a significant advantage.

**BBB:** Ligand B (68.205) has a better BBB penetration percentile than Ligand A (47.111). This is a crucial factor for a CNS target like DRD2.

**Caco-2 Permeability:** Both have negative Caco-2 values (-5.026 and -5.143), which is unusual and suggests poor permeability. This is concerning for both.

**Aqueous Solubility:** Both have negative solubility values (-0.978 and -4.292), indicating very poor aqueous solubility. This is a major drawback for both compounds.

**hERG Inhibition:** Ligand A (0.115) has a much lower hERG inhibition liability than Ligand B (0.866), which is a significant safety advantage.

**Microsomal Clearance:** Ligand B (91.518) has a much higher microsomal clearance than Ligand A (8.755), indicating faster metabolism and potentially lower *in vivo* exposure.

**In vitro Half-Life:** Ligand A (-14.303) has a negative half-life, which is not physically possible and suggests an issue with the data or the compound's stability. Ligand B (6.874) has a reasonable half-life.

**P-gp Efflux:** Ligand A (0.006) has very low P-gp efflux, which is favorable for CNS penetration. Ligand B (0.534) has moderate P-gp efflux.

**Binding Affinity:** Ligand B (-8.4 kcal/mol) has a significantly stronger binding affinity than Ligand A (-7.2 kcal/mol). This 1.2 kcal/mol difference is substantial and could outweigh some of the ADME drawbacks.

**Overall Assessment:**

Ligand B has a stronger binding affinity and better BBB penetration, which are critical for a CNS GPCR target. However, it suffers from significantly higher DILI risk, higher microsomal clearance, and moderate P-gp efflux. Ligand A has better safety profiles (DILI, hERG) and lower efflux, but its logP is low, BBB penetration is poor, and its half-life is nonsensical. The poor solubility for both is a major concern.

Despite the solubility issues, the superior binding affinity of Ligand B is a strong driver. The difference in affinity is large enough to potentially overcome the other issues with further optimization.

Output:
1
2025-04-17 06:47:35,357 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 drug candidates, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (341.455 and 365.543 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (54.34) is better than Ligand B (47.36). Both are below the 90 A^2 threshold for CNS targets, which is excellent.

**logP:** Both ligands have good logP values (2.59 and 3.182), falling within the optimal 1-3 range. Ligand B is slightly higher, potentially leading to some solubility concerns, but still acceptable.

**H-Bond Donors/Acceptors:** Ligand A (1 HBD, 3 HBA) and Ligand B (0 HBD, 5 HBA) both have reasonable numbers of H-bond donors and acceptors, well within the guidelines.

**QED:** Ligand A (0.895) has a significantly better QED score than Ligand B (0.664), indicating a more drug-like profile.

**DILI:** Both ligands have similar, low DILI risk (26.095 and 26.638 percentile).

**BBB:** Ligand B (83.249%) has a substantially better BBB penetration score than Ligand A (65.607%). This is a *critical* advantage for a CNS target like DRD2.

**Caco-2 Permeability:** Both have negative Caco-2 values (-4.923 and -4.639), which is unusual and suggests poor permeability. However, these values are on a logarithmic scale and may not be directly comparable.

**Aqueous Solubility:** Both ligands have very poor aqueous solubility (-3.134 and -3.464). This is a significant drawback.

**hERG Inhibition:** Both ligands show low hERG inhibition liability (0.39 and 0.649), which is good.

**Microsomal Clearance:** Ligand B (93.131) has a much higher microsomal clearance than Ligand A (25.281), indicating faster metabolism and potentially lower in vivo exposure.

**In vitro Half-Life:** Ligand B (29.854 hours) has a longer half-life than Ligand A (7.055 hours), which is a positive attribute.

**P-gp Efflux:** Both ligands show low P-gp efflux liability (0.103 and 0.365), which is favorable for CNS penetration.

**Binding Affinity:** Ligand A (-8.9 kcal/mol) has a significantly stronger binding affinity than Ligand B (-6.6 kcal/mol). This is a substantial advantage, exceeding the 1.5 kcal/mol difference threshold.

**Overall Assessment:**

While Ligand B has a much better BBB score and longer half-life, the significantly superior binding affinity of Ligand A (-8.9 vs -6.6 kcal/mol) is a major deciding factor. The affinity difference is large enough to potentially overcome the lower BBB and shorter half-life, especially considering the poor solubility of both compounds. The better QED score of Ligand A further supports its selection. The solubility issue is a concern for both, but could be addressed with formulation strategies.

Output:
0
2025-04-17 06:47:35,357 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (350.463 and 341.415 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (85.25) is significantly better than Ligand B (99.81). For CNS targets, we want TPSA <= 90, so Ligand A is preferable.

**3. logP:** Both ligands have acceptable logP values (1.347 and 0.784), falling within the optimal range of 1-3.

**4. H-Bond Donors:** Both have 2 HBD, which is within the acceptable limit of <=5.

**5. H-Bond Acceptors:** Both have 5 HBA, also within the acceptable limit of <=10.

**6. QED:** Both ligands have good QED scores (0.667 and 0.747), indicating good drug-like properties.

**7. DILI:** Ligand A (13.106) has a much lower DILI risk than Ligand B (39.201). This is a significant advantage for Ligand A.

**8. BBB:** Ligand A (62.621) has a better BBB percentile than Ligand B (51.26), but neither are above the desirable 70% threshold. However, given the CNS target, this is a critical factor, and Ligand A is better.

**9. Caco-2 Permeability:** Both have negative values, indicating poor Caco-2 permeability. Ligand A (-5.048) is slightly better than Ligand B (-5.286), but both are concerning.

**10. Aqueous Solubility:** Both have negative values, indicating poor solubility. Ligand A (-1.006) is slightly better than Ligand B (-2.249).

**11. hERG Inhibition:** Both ligands have low hERG inhibition risk (0.358 and 0.324).

**12. Microsomal Clearance:** Ligand B (17.154) has lower microsomal clearance than Ligand A (30.133), suggesting better metabolic stability.

**13. In vitro Half-Life:** Ligand B (-1.862) has a slightly better in vitro half-life than Ligand A (-8.386).

**14. P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.029 and 0.031).

**15. Binding Affinity:** Ligand B (-8.0) has a slightly better binding affinity than Ligand A (-7.2), a difference of 0.8 kcal/mol. While a 1.5 kcal/mol advantage is usually significant, 0.8 kcal/mol is less decisive.

**Overall Assessment:**

Ligand A is the better candidate. While Ligand B has slightly better binding affinity and metabolic stability, Ligand A significantly outperforms it in crucial areas for a CNS-targeting GPCR: lower DILI risk, better BBB penetration, and lower TPSA. The slightly better solubility of Ligand A is also a plus. The affinity difference between the two is not large enough to overcome the ADME advantages of Ligand A.

Output:
1
2025-04-17 06:47:35,357 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (343.471 and 357.523 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (65.2) is significantly higher than Ligand B (38.13). For a CNS target like DRD2, TPSA should ideally be <=90, so both are acceptable, but B is much better.

**logP:** Both ligands have good logP values (2.899 and 3.942), falling within the optimal 1-3 range. Ligand B is slightly higher, which could be beneficial for membrane permeability, but also could increase off-target effects.

**H-Bond Donors/Acceptors:** Ligand A has 2 HBD and 2 HBA, while Ligand B has 0 HBD and 4 HBA. Both are within acceptable limits (<=5 HBD, <=10 HBA).

**QED:** Both ligands have similar QED values (0.808 and 0.785), indicating good drug-likeness.

**DILI:** Ligand A (43.389) has a slightly higher DILI risk than Ligand B (21.985), but both are below the concerning threshold of 60.

**BBB:** Ligand B (89.492) has a substantially higher BBB penetration percentile than Ligand A (74.254). This is a critical advantage for a CNS target.

**Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and suggests a potential issue with the prediction method. However, the values are similar (-4.974 and -5.001).

**Aqueous Solubility:** Both ligands have very poor predicted aqueous solubility (-3.918 and -3.797). This is a significant drawback that would require formulation strategies.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.361 and 0.635).

**Microsomal Clearance:** Ligand B (88.3) has a significantly higher microsomal clearance than Ligand A (44.224), indicating faster metabolism and potentially lower in vivo exposure.

**In vitro Half-Life:** Ligand A (-23.332) has a longer in vitro half-life than Ligand B (4.411), which is a positive attribute.

**P-gp Efflux:** Both ligands have similar low P-gp efflux liability (0.239 and 0.615).

**Binding Affinity:** Both ligands have excellent binding affinities (-9.0 and -8.5 kcal/mol). The difference of 0.5 kcal/mol is not substantial enough to outweigh other factors.

**Conclusion:**

Considering the GPCR-specific priorities, Ligand B is the more promising candidate. Its significantly higher BBB penetration (89.492 vs. 74.254) is a major advantage for a CNS target. While its metabolic clearance is higher, the superior BBB penetration and lower TPSA outweigh this concern. Both have poor solubility, which needs to be addressed, but this is a formulation challenge rather than an inherent property issue.

Output:
1
2025-04-17 06:47:35,357 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (353.423 and 346.515 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (125.35) is slightly above the optimal <90 for CNS targets, but still reasonable. Ligand B (58.2) is excellent, well below the threshold.

**logP:** Ligand A (-0.902) is a bit low, potentially hindering permeability. Ligand B (3.402) is excellent, falling within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A (4 HBD, 6 HBA) is acceptable. Ligand B (2 HBD, 2 HBA) is also good, potentially offering better permeability due to fewer hydrogen bonds.

**QED:** Ligand A (0.458) is below the desirable 0.5 threshold, indicating a less drug-like profile. Ligand B (0.819) is excellent, suggesting good drug-like properties.

**DILI:** Both ligands have low DILI risk (37.224 and 33.23), both below the 40 threshold.

**BBB:** Ligand A (20.822) has a very poor BBB percentile, making CNS penetration unlikely. Ligand B (73.866) is excellent, exceeding the desirable >70 threshold for CNS targets. This is a major advantage.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.552 and -4.68), which is unusual and suggests issues with the data or the compounds themselves. However, we'll proceed assuming these are relative values and focus on the other parameters.

**Aqueous Solubility:** Both ligands have negative solubility values (-1.219 and -4.326), which is also unusual.

**hERG Inhibition:** Both ligands show low hERG inhibition liability (0.107 and 0.415), which is good.

**Microsomal Clearance:** Ligand A (12.115) and Ligand B (24.097) have moderate microsomal clearance. Lower is preferred, but these aren't alarmingly high.

**In vitro Half-Life:** Ligand B (38.02 hours) has a better half-life than Ligand A (23.39 hours).

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.01 and 0.142), which is favorable.

**Binding Affinity:** Ligand B (-9.4 kcal/mol) has significantly stronger binding affinity than Ligand A (-7.7 kcal/mol). This >1.5 kcal/mol difference is substantial and can outweigh minor ADME drawbacks.

**Conclusion:**

Considering all factors, especially the GPCR-specific priorities for a CNS target like DRD2, **Ligand B is significantly more promising**. It has excellent BBB penetration, a favorable logP, a high QED score, strong binding affinity, and acceptable ADME properties. Ligand A's poor BBB penetration and lower affinity are major drawbacks. The negative solubility and Caco-2 values are concerning for both, but the overall profile of Ligand B is far superior.

Output:
1
2025-04-17 06:47:35,357 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 drug candidates, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (341.459 Da) is slightly lower, which could be advantageous for permeability.

**TPSA:** Ligand A (63.05) is significantly better than Ligand B (97.11). A TPSA under 90 is preferred for CNS targets, and Ligand A is comfortably within this range, while Ligand B is approaching the upper limit.

**logP:** Both ligands have good logP values (A: 2.182, B: 1.762), falling within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A (HBD=1, HBA=5) has a more favorable profile than Ligand B (HBD=2, HBA=6). Lower values generally improve permeability.

**QED:** Both ligands have similar QED values (A: 0.838, B: 0.81), indicating good drug-likeness.

**DILI:** Ligand A (32.299) has a much lower DILI risk than Ligand B (76.076). This is a significant advantage.

**BBB:** Ligand A (70.919) has a slightly better BBB penetration percentile than Ligand B (63.862). While both are reasonably good, >70 is desirable for CNS targets, and A is closer.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.006 and -5.004). This is unusual and suggests poor permeability based on this metric. However, the absolute values are very similar.

**Aqueous Solubility:** Both ligands have negative solubility values (-2.627 and -3.771), indicating poor aqueous solubility. This is a concern for both.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (A: 0.158, B: 0.233).

**Microsomal Clearance:** Ligand A (56.535) has a higher microsomal clearance than Ligand B (25.109), suggesting faster metabolism and potentially lower in vivo exposure.

**In vitro Half-Life:** Ligand B (-24.464) has a significantly longer in vitro half-life than Ligand A (8.56). This is a major advantage for Ligand B.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (A: 0.093, B: 0.239).

**Binding Affinity:** Ligand A (-8.5 kcal/mol) has a significantly stronger binding affinity than Ligand B (-7.4 kcal/mol). This 1.1 kcal/mol difference is substantial and can outweigh some ADME drawbacks.

**Overall Assessment:**

Ligand A excels in binding affinity, TPSA, DILI risk, and BBB penetration. However, it has a higher microsomal clearance and shorter half-life. Ligand B has a longer half-life, but suffers from higher DILI risk, a less favorable TPSA, and weaker binding affinity.

Given the GPCR-specific priorities, the strong binding affinity of Ligand A is a major advantage. The slightly better BBB and lower DILI risk further support its selection. While the metabolic stability is a concern, it might be addressable through structural modifications. The relatively similar Caco-2 and solubility issues affect both compounds.

Output:
1
2025-04-17 06:47:35,358 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (376.519 Da) is slightly higher than Ligand B (344.455 Da), but both are acceptable.

**TPSA:** Ligand A (88.1) is closer to the ideal TPSA for CNS targets (<=90), while Ligand B (69.64) is even better.

**logP:** Ligand A (0.507) is quite low, potentially hindering permeability. Ligand B (2.856) is within the optimal range (1-3). This is a significant advantage for Ligand B.

**H-Bond Donors/Acceptors:** Both ligands have 2 HBD and a reasonable number of HBA (6 for A, 3 for B), falling within acceptable limits.

**QED:** Both ligands have good QED scores (0.578 for A, 0.882 for B), indicating drug-like properties. Ligand B is better here.

**DILI:** Both ligands have low DILI risk (26.444 and 30.322 percentiles), which is favorable.

**BBB:** Ligand A (34.083) has a poor BBB percentile, making CNS penetration unlikely. Ligand B (60.76) is better, but still not ideal (>70 is preferred).

**Caco-2 Permeability:** Ligand A (-5.135) has very poor Caco-2 permeability, suggesting poor intestinal absorption. Ligand B (-4.822) is slightly better, but still low.

**Aqueous Solubility:** Both ligands have poor aqueous solubility (-1.855 and -4.285). This could pose formulation challenges.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.254 and 0.369), which is good.

**Microsomal Clearance:** Ligand A (37.045) has lower microsomal clearance than Ligand B (50.581), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (13.47 hours) has a positive half-life, while Ligand B (-22.067 hours) has a negative half-life, which is not possible and likely an error in the data.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.033 and 0.111), which is favorable for CNS penetration.

**Binding Affinity:** Ligand B (-7.4 kcal/mol) has significantly stronger binding affinity than Ligand A (0.0 kcal/mol). This is a decisive advantage.

**Overall Assessment:**

Ligand B is significantly more promising. While its BBB penetration isn't optimal, it's far better than Ligand A's. Its logP is within the ideal range, it has a much stronger binding affinity, and its QED is higher. The negative half-life for Ligand B is a data error and cannot be used for comparison. Ligand A's extremely low logP, poor Caco-2 permeability and very weak binding affinity make it a poor candidate.

Output:
1
2025-04-17 06:47:35,358 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B against the provided guidelines, prioritizing GPCR-specific properties (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (350.419 and 370.559 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (116.48) is better than Ligand B (66.48). For CNS targets, TPSA should be <=90, so Ligand B is preferable.

**logP:** Ligand A (-0.125) is too low, potentially hindering permeation. Ligand B (3.079) is within the optimal 1-3 range. This is a significant advantage for Ligand B.

**H-Bond Donors/Acceptors:** Ligand A has 4 HBD and 6 HBA, which are acceptable. Ligand B has 1 HBD and 3 HBA, also acceptable.

**QED:** Both ligands have good QED scores (0.547 and 0.731), indicating drug-like properties.

**DILI:** Ligand A (35.905) has a slightly higher DILI risk than Ligand B (22.993), but both are below the concerning threshold of 60.

**BBB:** This is crucial for a CNS target like DRD2. Ligand B (79.798) has a much better BBB percentile than Ligand A (32.726). This is a major advantage for Ligand B.

**Caco-2 Permeability:** Both have negative values, indicating poor permeability.

**Aqueous Solubility:** Both have negative values, indicating poor solubility.

**hERG Inhibition:** Ligand A (0.095) has a slightly lower hERG risk than Ligand B (0.607), which is preferable.

**Microsomal Clearance:** Ligand A (-12.535) has a much lower (better) microsomal clearance than Ligand B (66.159), indicating greater metabolic stability.

**In vitro Half-Life:** Ligand A (0.312) has a very short half-life, while Ligand B (-50.125) has a very long half-life.

**P-gp Efflux:** Ligand A (0.004) has very low P-gp efflux liability, which is excellent for CNS penetration. Ligand B (0.105) is also low, but higher than A.

**Binding Affinity:** Ligand B (-9.1 kcal/mol) has a slightly better binding affinity than Ligand A (-8.6 kcal/mol). While the difference is not huge, it's still a positive for Ligand B.

**Overall Assessment:**

Ligand B is the stronger candidate. While Ligand A has better metabolic stability and lower P-gp efflux, Ligand B excels in the most critical areas for a CNS-targeting GPCR: BBB penetration, logP, and binding affinity. The slightly higher hERG risk and clearance of Ligand B are less concerning given its superior CNS properties. The TPSA of Ligand B is also more favorable.

Output:
1
2025-04-17 06:47:35,358 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B based on the provided guidelines, prioritizing GPCR-specific properties (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (345.407 Da) is slightly lower, which could be beneficial for permeability, but both are acceptable.

**TPSA:** Ligand A (106.73) is excellent for CNS penetration, falling well below the 90 A^2 threshold. Ligand B (37.61) is also very good.

**logP:** Ligand A (0.862) is a bit low, potentially hindering permeation. Ligand B (4.738) is higher, approaching the upper limit where solubility issues might arise, but it's still within a reasonable range.

**H-Bond Donors/Acceptors:** Ligand A has 2 HBD and 7 HBA, which are acceptable. Ligand B has 0 HBD and 4 HBA, also acceptable.

**QED:** Both ligands have reasonable QED scores (A: 0.774, B: 0.647), indicating good drug-like properties.

**DILI:** Ligand A (64.521) has a higher DILI risk than Ligand B (43.777), which is preferable.

**BBB:** This is a critical parameter for CNS targets like DRD2. Ligand B (84.451) has a significantly higher BBB penetration percentile than Ligand A (49.748). This is a major advantage for Ligand B.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values, which is unusual and suggests poor permeability. However, the scale is not specified, so it's difficult to interpret.

**Aqueous Solubility:** Both ligands have negative solubility values, which is also unusual and suggests poor solubility.

**hERG Inhibition:** Ligand A (0.068) has a very low hERG inhibition risk, which is excellent. Ligand B (0.894) has a higher, but still moderate, risk.

**Microsomal Clearance:** Ligand A (8.461) has lower microsomal clearance, indicating better metabolic stability than Ligand B (75.11).

**In vitro Half-Life:** Ligand B (15.622) has a significantly longer in vitro half-life than Ligand A (-0.82). This is a significant advantage for Ligand B.

**P-gp Efflux:** Ligand A (0.055) has very low P-gp efflux liability, which is excellent for CNS penetration. Ligand B (0.646) has moderate P-gp efflux.

**Binding Affinity:** Ligand A (-7.6 kcal/mol) has a slightly better binding affinity than Ligand B (-7.2 kcal/mol), but the difference is relatively small.

**Overall Assessment:**

Ligand B is the more promising candidate. While Ligand A has better metabolic stability and lower hERG risk, Ligand B excels in the critical areas for a CNS-targeting GPCR ligand: significantly higher BBB penetration, a longer half-life, and acceptable P-gp efflux. The slightly lower affinity of Ligand B is likely outweighed by its superior pharmacokinetic properties for CNS delivery. The unusual negative values for Caco-2 and solubility are concerning for both, but the BBB advantage of B is compelling.

Output:
1
2025-04-17 06:47:35,358 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (365.539 Da and 370.471 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (49.77) is excellent, well below the 90 A^2 threshold for CNS targets. Ligand B (92.78) is higher, but still potentially acceptable, though less ideal.

**logP:** Ligand A (4.073) is at the upper end of the optimal range (1-3), potentially raising concerns about solubility and off-target effects. Ligand B (1.462) is good, falling comfortably within the optimal range.

**H-Bond Donors/Acceptors:** Both ligands have 1 HBD, which is good. Ligand A has 4 HBA, and Ligand B has 6 HBA. Both are within the acceptable limit of 10.

**QED:** Both ligands have similar QED values (0.827 and 0.762), indicating good drug-like properties.

**DILI:** Ligand A (16.906) has a significantly lower DILI risk than Ligand B (63.707), which is a substantial advantage.

**BBB:** Ligand A (79.488) has a much better BBB penetration percentile than Ligand B (30.167). This is *critical* for a CNS target like DRD2.

**Caco-2 Permeability:** Both have negative values, which is unusual. However, the magnitude of the negative value for Ligand A (-4.443) is smaller than that of Ligand B (-4.844), suggesting slightly better permeability.

**Aqueous Solubility:** Both have negative values, indicating poor solubility. Ligand A (-4.179) is slightly better than Ligand B (-2.183).

**hERG Inhibition:** Ligand A (0.613) has a slightly higher hERG risk than Ligand B (0.077), but both are relatively low.

**Microsomal Clearance:** Ligand A (107.103) has higher microsomal clearance than Ligand B (58.589), indicating lower metabolic stability.

**In vitro Half-Life:** Both ligands have similar in vitro half-lives (-3.104 and -3.071).

**P-gp Efflux:** Ligand A (0.798) has slightly higher P-gp efflux than Ligand B (0.046), meaning Ligand B is less likely to be pumped out of the brain.

**Binding Affinity:** Ligand B (-8.0 kcal/mol) has a significantly stronger binding affinity than Ligand A (-7.1 kcal/mol). This is a 1.1 kcal/mol difference, which is a substantial advantage.

**Overall Assessment:**

While Ligand B has a superior binding affinity, Ligand A has significantly better BBB penetration, lower DILI risk, and better TPSA. Given that this is a CNS target, BBB penetration is paramount. The strong affinity of Ligand B is attractive, but the poor BBB penetration is a major drawback. The lower DILI risk of Ligand A is also a significant positive. The slightly better solubility and permeability of Ligand A also contribute to its favorability. Although Ligand A has a higher Cl_mic, the difference isn't drastic and could be addressed in further optimization.

Output:
0
2025-04-17 06:47:35,359 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (368.369 Da and 342.443 Da) fall within the ideal range of 200-500 Da.

**TPSA:** Ligand A (100.97) is slightly above the optimal <90 for CNS targets, but still reasonable. Ligand B (67.23) is well within the desired range.

**logP:** Ligand A (0.708) is a bit low, potentially hindering permeability. Ligand B (1.685) is better, falling within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Both ligands have acceptable HBD (1) and HBA (7/4) counts, well below the thresholds of 5 and 10 respectively.

**QED:** Ligand A (0.806) has a better QED score than Ligand B (0.606), indicating a more drug-like profile.

**DILI:** Ligand B (32.726) has a significantly lower DILI risk than Ligand A (84.296), which is a major advantage.

**BBB:** Both ligands have good BBB penetration (71.307 and 70.415), exceeding the 70% threshold for CNS targets.

**Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and suggests poor permeability. This is a concern for both.

**Aqueous Solubility:** Both ligands have negative solubility values, which is also concerning.

**hERG:** Both ligands have very low hERG inhibition risk (0.102 and 0.086).

**Microsomal Clearance:** Ligand A (4.379) has a much lower microsomal clearance than Ligand B (24.6), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand B (-10.695) has a significantly longer in vitro half-life than Ligand A (-3.74), which is a positive.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.049 and 0.051).

**Binding Affinity:** Both ligands have excellent binding affinity (-7.9 and -7.8 kcal/mol), which is comparable and strong. The difference of 0.1 kcal/mol is not significant enough to be a deciding factor.

**Overall Assessment:**

Ligand B is slightly favored due to its better logP, significantly lower DILI risk, and longer half-life. While Ligand A has a better QED and lower Cl_mic, the lower DILI risk of Ligand B is a critical advantage for a CNS drug candidate. The negative Caco-2 and solubility values are concerning for both, and would need to be addressed in further optimization. However, given the comparable affinity and the importance of safety and CNS penetration, Ligand B appears to be the more promising candidate.

Output:
1
2025-04-17 06:47:35,359 - INFO - Batch 311 complete. Total preferences: 4976
2025-04-17 06:47:35,359 - INFO - Processing batch 312/512...
2025-04-17 06:48:16,385 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (342.443 and 344.459 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (90.01) is better than Ligand B (67.23) as it is closer to the ideal TPSA for CNS targets (<=90). Ligand B is excellent.

**logP:** Both ligands have good logP values (2.688 and 1.916), falling within the optimal 1-3 range.

**H-Bond Donors:** Ligand A has 2 HBD, and Ligand B has 1. Both are within the acceptable limit of <=5.

**H-Bond Acceptors:** Both ligands have 4 HBA, well below the limit of <=10.

**QED:** Both ligands have high QED scores (0.81 and 0.857), indicating good drug-like properties.

**DILI:** Ligand A (66.615) has a higher DILI risk than Ligand B (32.881). This is a significant drawback for Ligand A.

**BBB:** Ligand B (68.864) has a better BBB penetration percentile than Ligand A (53.587). For a CNS target like DRD2, this is a critical advantage.

**Caco-2 Permeability:** Both have negative values, which is unusual. Assuming these are percentile scores, Ligand A (-4.873) is worse than Ligand B (-4.933).

**Aqueous Solubility:** Ligand A (-3.832) is worse than Ligand B (-2.522).

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.393 and 0.221).

**Microsomal Clearance:** Ligand B (24.32) has significantly lower microsomal clearance than Ligand A (64.41), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand B (-0.248) has a slightly better in vitro half-life than Ligand A (-1.618).

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.155 and 0.067).

**Binding Affinity:** Ligand B (-9.3 kcal/mol) has a slightly better binding affinity than Ligand A (-8.9 kcal/mol). While both are excellent, the difference is meaningful.

**Overall Assessment:**

Ligand B is superior to Ligand A. It has a significantly lower DILI risk, better BBB penetration, lower microsomal clearance (better metabolic stability), and slightly better binding affinity. While Ligand A has a slightly better TPSA, the other advantages of Ligand B, particularly the lower DILI and better BBB, are more important for a CNS-targeting drug.

Output:
1
2025-04-17 06:48:16,385 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (356.388 Da) is slightly lower, which could be beneficial for permeability.

**TPSA:** Ligand A (41.57) is significantly better than Ligand B (68.02). For CNS targets, we want TPSA <= 90, and ideally lower. Ligand A is well within this range, while Ligand B is approaching the upper limit.

**logP:** Both ligands have similar logP values around 4.1, which is slightly above the optimal range (1-3) but not drastically so. This could potentially lead to some solubility issues, but isn't a dealbreaker.

**H-Bond Donors/Acceptors:** Both have 1 HBD, which is good. Ligand A has 2 HBA, while Ligand B has 4. Both are within the acceptable limit of <=10, but lower is generally preferred.

**QED:** Ligand A (0.882) has a much better QED score than Ligand B (0.676), indicating a more drug-like profile.

**DILI:** Ligand B (90.384) has a significantly higher DILI risk than Ligand A (22.683). This is a major concern for Ligand B.

**BBB:** Ligand A (89.763) has a substantially better BBB penetration score than Ligand B (77.627). This is critical for a CNS target like DRD2.

**Caco-2 Permeability:** Ligand A (-4.385) has better Caco-2 permeability than Ligand B (-4.777), suggesting better intestinal absorption.

**Aqueous Solubility:** Ligand A (-4.283) has better aqueous solubility than Ligand B (-5.346).

**hERG:** Both ligands have low hERG inhibition liability, with Ligand A (0.813) being slightly better than Ligand B (0.447).

**Microsomal Clearance:** Ligand B (59.647) has a lower microsomal clearance than Ligand A (41.647), indicating better metabolic stability.

**In vitro Half-Life:** Ligand B (5.094) has a longer half-life than Ligand A (-16.073). This is a positive for Ligand B.

**P-gp Efflux:** Ligand A (0.291) has lower P-gp efflux liability than Ligand B (0.3), meaning better CNS exposure.

**Binding Affinity:** Ligand B (-10.4) has a significantly stronger binding affinity than Ligand A (-9.0). This is a substantial advantage for Ligand B. A difference of >1.5 kcal/mol can outweigh some ADME concerns.

**Overall Assessment:**

Ligand A excels in ADME properties (TPSA, BBB, QED, DILI, solubility, permeability, P-gp efflux) making it a more balanced candidate. However, Ligand B has a significantly better binding affinity (-10.4 vs -9.0 kcal/mol). The difference in affinity is substantial. While Ligand B has a higher DILI risk and lower BBB, the strong binding could potentially allow for a lower dose, mitigating some of the toxicity concerns. Considering the GPCR-specific priorities, BBB is crucial, but strong affinity is also paramount. Given the substantial affinity difference, I believe Ligand B is the more promising candidate, *despite* its ADME drawbacks.

Output:
1
2025-04-17 06:48:16,386 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (390.952 and 386.503 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (49.41) is excellent, well below the 90 A^2 threshold for CNS targets. Ligand B (111.89) is higher, but still potentially acceptable, though less ideal.

**logP:** Ligand A (3.043) is optimal (1-3). Ligand B (0.431) is quite low, which could hinder membrane permeability and CNS penetration.

**H-Bond Donors/Acceptors:** Both ligands have acceptable HBD counts (1). Ligand A has 3 HBA, which is good. Ligand B has 10 HBA, which is at the upper limit and could negatively impact permeability.

**QED:** Both ligands have reasonable QED values (0.734 and 0.65), indicating good drug-like properties.

**DILI:** Ligand A (23.187) has a very low DILI risk, which is excellent. Ligand B (77.627) has a higher DILI risk, though not critically high.

**BBB:** Ligand A (95.58) has excellent BBB penetration potential, crucial for a CNS target like DRD2. Ligand B (58.085) has significantly lower BBB penetration, a major drawback.

**Caco-2 Permeability:** Ligand A (-4.968) has poor Caco-2 permeability. Ligand B (-5.655) also has poor Caco-2 permeability.

**Aqueous Solubility:** Ligand A (-4.244) has poor aqueous solubility. Ligand B (-1.797) has slightly better aqueous solubility.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.737 and 0.092).

**Microsomal Clearance:** Ligand A (47.306) has moderate microsomal clearance. Ligand B (6.12) has very low clearance, indicating better metabolic stability.

**In vitro Half-Life:** Ligand A (-17.696) has a negative half-life, which is not physically possible and indicates an issue with the data. Ligand B (5.734) has a short half-life.

**P-gp Efflux:** Ligand A (0.327) has low P-gp efflux, which is favorable for CNS penetration. Ligand B (0.157) also has low P-gp efflux.

**Binding Affinity:** Ligand A (-7.7 kcal/mol) has a significantly stronger binding affinity than Ligand B (-6.8 kcal/mol). This 0.9 kcal/mol difference is substantial and could outweigh some of the ADME drawbacks.

**Overall Assessment:**

Ligand A is the stronger candidate despite its poor Caco-2 permeability and aqueous solubility. Its excellent BBB penetration, low DILI risk, strong binding affinity, and low P-gp efflux are highly favorable for a DRD2 ligand. The negative in vitro half-life is a data quality concern, but the strong affinity is a significant advantage. Ligand B's low logP and lower BBB penetration are major drawbacks, even though it has better metabolic stability.

Output:
1
2025-04-17 06:48:16,386 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (350.413 and 372.535 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (72.11) is better than Ligand B (65.12). Both are below the 90 A^2 threshold desirable for CNS targets, but A is closer to the ideal.

**3. logP:** Ligand A (2.391) is within the optimal 1-3 range. Ligand B (-0.283) is below 1, which might hinder permeation. This is a significant disadvantage for B.

**4. H-Bond Donors:** Both ligands have 1 HBD, which is acceptable (<=5).

**5. H-Bond Acceptors:** Ligand A has 4 HBA, and Ligand B has 6. Both are within the acceptable range (<=10), but A is preferable.

**6. QED:** Ligand A (0.909) has a significantly better QED score than Ligand B (0.663), indicating a more drug-like profile.

**7. DILI:** Both ligands have low DILI risk (A: 26.018, B: 21.52), which is good.

**8. BBB:** Ligand A (96.394) has excellent BBB penetration, exceeding the desirable >70% threshold. Ligand B (34.199) has poor BBB penetration, a critical drawback for a CNS target like DRD2.

**9. Caco-2:** Ligand A (-4.82) and Ligand B (-5.29) both have negative Caco-2 values, which is unusual and suggests poor permeability. However, the scale is not specified, so it's hard to interpret.

**10. Solubility:** Ligand A (-2.341) and Ligand B (-1.081) both have negative solubility values, indicating poor aqueous solubility.

**11. hERG:** Both ligands have very low hERG risk (A: 0.317, B: 0.205).

**12. Cl_mic:** Ligand A (15.423) has a slightly higher microsomal clearance than Ligand B (12.122), suggesting slightly lower metabolic stability, but both are acceptable.

**13. t1/2:** Ligand A (-16.571) has a negative in vitro half-life, which is concerning. Ligand B (1.22) has a short half-life, but is at least positive.

**14. Pgp:** Both ligands have very low P-gp efflux liability (A: 0.03, B: 0.004).

**15. Binding Affinity:** Ligand A (-8.9 kcal/mol) has a significantly stronger binding affinity than Ligand B (-6.1 kcal/mol). This >1.5 kcal/mol difference is substantial and can outweigh some ADME drawbacks.

**Overall Assessment:**

Ligand A is the superior candidate. While it has a concerning negative in vitro half-life, its strong binding affinity, excellent BBB penetration, favorable logP and TPSA, and good QED score outweigh its weaknesses. Ligand B's poor logP and BBB penetration are major liabilities for a CNS-targeting drug, despite its slightly better half-life. The affinity difference is also substantial.

Output:
1
2025-04-17 06:48:16,386 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B based on the provided guidelines, prioritizing GPCR-specific properties (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (387.439 and 382.957 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (129.72) is better than Ligand B (41.57) as it is closer to the optimal range for CNS targets (<=90). Ligand B is quite low, which *could* indicate poor interactions, but isn't a dealbreaker.

**logP:** Ligand A (-0.727) is suboptimal, being slightly below the preferred 1-3 range. Ligand B (4.653) is too high, potentially causing solubility issues and off-target effects.

**H-Bond Donors/Acceptors:** Ligand A (2 HBD, 6 HBA) is better than Ligand B (1 HBD, 3 HBA) as it is closer to the ideal range.

**QED:** Both ligands have good QED scores (0.703 and 0.823), indicating good drug-like properties.

**DILI:** Ligand A (72.547) has a higher DILI risk than Ligand B (50.136), but both are acceptable.

**BBB:** Ligand B (88.91) significantly outperforms Ligand A (25.397) in BBB penetration, a critical factor for CNS targets like DRD2.

**Caco-2 Permeability:** Ligand A (-5.502) is poor, while Ligand B (-4.835) is also poor, but slightly better.

**Aqueous Solubility:** Ligand A (-2.775) is poor, while Ligand B (-4.825) is also poor.

**hERG Inhibition:** Ligand A (0.045) has a very low hERG risk, while Ligand B (0.829) has a slightly higher, but still acceptable risk.

**Microsomal Clearance:** Ligand A (-17.764) has a much lower (better) microsomal clearance than Ligand B (75.869), indicating greater metabolic stability.

**In vitro Half-Life:** Ligand A (68.248) has a longer half-life than Ligand B (45.882).

**P-gp Efflux:** Ligand A (0.016) has much lower P-gp efflux liability than Ligand B (0.487), which is crucial for CNS penetration.

**Binding Affinity:** Both ligands have comparable binding affinities (-8.9 and -8.6 kcal/mol), both of which are excellent. The difference is not substantial enough to override other factors.

**Overall Assessment:**

Ligand B excels in BBB penetration, which is paramount for a DRD2 ligand. However, its high logP and P-gp efflux liability are significant drawbacks. Ligand A, while having a suboptimal logP and lower BBB, compensates with superior metabolic stability (lower Cl_mic, longer t1/2), lower P-gp efflux, and a better TPSA. Considering the balance of properties, and the critical importance of CNS penetration *and* avoiding rapid metabolism/efflux for a CNS target, Ligand A is the more promising candidate.



Output:
0
2025-04-17 06:48:16,386 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (354.332 and 348.491 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (69.04) is excellent, well below the 90 A^2 threshold for CNS targets. Ligand B (74.33) is still reasonable, but slightly higher.

**3. logP:** Both ligands have good logP values (2.497 and 2.053), falling within the optimal 1-3 range.

**4. H-Bond Donors:** Ligand A has 1 HBD, and Ligand B has 2. Both are acceptable (<=5).

**5. H-Bond Acceptors:** Ligand A has 5 HBA, and Ligand B has 4. Both are acceptable (<=10).

**6. QED:** Ligand A (0.916) has a superior QED score compared to Ligand B (0.716), indicating better overall drug-likeness.

**7. DILI:** Ligand A (80.651) has a higher DILI risk than Ligand B (21.908). This is a significant drawback for Ligand A.

**8. BBB:** Ligand A (87.476) has a much higher BBB penetration percentile than Ligand B (52.036). This is a critical advantage for a CNS target like DRD2.

**9. Caco-2 Permeability:** Ligand A (-4.675) has worse Caco-2 permeability than Ligand B (-5.107), but both are quite poor.

**10. Aqueous Solubility:** Ligand A (-3.454) has slightly better aqueous solubility than Ligand B (-1.346), but both are poor.

**11. hERG Inhibition:** Both ligands have low hERG inhibition risk (0.366 and 0.47).

**12. Microsomal Clearance:** Ligand A (14.626) has lower microsomal clearance than Ligand B (19.449), suggesting better metabolic stability.

**13. In vitro Half-Life:** Ligand A (-31.162) has a much longer in vitro half-life than Ligand B (59.219). This is a significant advantage.

**14. P-gp Efflux:** Ligand A (0.108) has lower P-gp efflux than Ligand B (0.017), which is favorable for CNS penetration.

**15. Binding Affinity:** Both ligands have similar and strong binding affinities (-9.4 and -8.1 kcal/mol). The difference of 1.3 kcal/mol is not substantial enough to override other factors.

**Overall Assessment:**

Ligand A excels in BBB penetration, metabolic stability (lower Cl_mic, longer t1/2), and P-gp efflux. It also has a better QED score. However, its DILI risk is considerably higher. Ligand B has a much lower DILI risk, but suffers from poorer BBB penetration, higher P-gp efflux, and lower metabolic stability.

Given the CNS target (DRD2), BBB penetration is paramount. The substantial advantage of Ligand A in BBB (87.476 vs 52.036) and P-gp efflux, coupled with its better metabolic stability, outweighs the higher DILI risk, especially considering the affinity is comparable. While DILI is a concern, it can be addressed in later optimization stages.

Output:
1
2025-04-17 06:48:16,387 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (340.467 Da) is slightly lower, which could be advantageous for permeability. Ligand B (399.299 Da) is also good.

**TPSA:** Ligand A (41.57) is excellent, well below the 90 A^2 threshold for CNS targets. Ligand B (89.26) is higher but still acceptable, though less ideal for CNS penetration.

**logP:** Both ligands have good logP values (A: 3.981, B: 3.002), falling within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A (HBD=1, HBA=3) and Ligand B (HBD=2, HBA=3) both have reasonable numbers of H-bond donors and acceptors, well within the limits.

**QED:** Both ligands have good QED scores (A: 0.905, B: 0.81), indicating strong drug-like properties.

**DILI:** Ligand A (31.718) has a significantly lower DILI risk than Ligand B (80.458), which is a major advantage.

**BBB:** Ligand A (89.957) has a much better BBB penetration percentile than Ligand B (56.495). This is crucial for a CNS target like DRD2.

**Caco-2 Permeability:** Ligand A (-4.603) has a worse Caco-2 permeability than Ligand B (-5.05). However, this is a less critical parameter than BBB for CNS targets.

**Aqueous Solubility:** Both ligands have poor aqueous solubility (-3.982 and -4.405 respectively). This could pose formulation challenges, but is not a dealbreaker.

**hERG Inhibition:** Ligand A (0.789) has a slightly higher hERG inhibition risk than Ligand B (0.344), but both are relatively low.

**Microsomal Clearance:** Ligand A (58.581) has a higher microsomal clearance than Ligand B (15.247), indicating lower metabolic stability. This is a disadvantage for Ligand A.

**In vitro Half-Life:** Ligand B (1.674) has a slightly longer half-life than Ligand A (26.104), but the values are not directly comparable (one is hours, one is percentile).

**P-gp Efflux:** Ligand A (0.407) has lower P-gp efflux liability than Ligand B (0.234), which is favorable for CNS exposure.

**Binding Affinity:** Ligand B (-9.9 kcal/mol) has a significantly stronger binding affinity than Ligand A (-8.6 kcal/mol). This is a substantial advantage that could outweigh some of the ADME drawbacks.

**Overall Assessment:**

Ligand B has a significantly stronger binding affinity, which is paramount for GPCR targets. While Ligand A has better BBB penetration and lower DILI risk, the difference in affinity is substantial (1.3 kcal/mol). The higher metabolic clearance of Ligand A is also a concern. Given the GPCR-specific priorities, the increased potency of Ligand B is the deciding factor.

Output:
1
2025-04-17 06:48:16,387 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B based on the provided guidelines, prioritizing GPCR-specific properties (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (360.885 and 352.519 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (64.33) is better than Ligand B (49.85). Both are below 90, which is favorable for CNS penetration.

**logP:** Both ligands have good logP values (3.594 and 3.243), within the optimal 1-3 range.

**H-Bond Donors:** Ligand A has 1 HBD, while Ligand B has 0. Both are acceptable (<=5).

**H-Bond Acceptors:** Both ligands have 3 HBAs, well within the acceptable limit of <=10.

**QED:** Ligand A (0.892) has a significantly better QED score than Ligand B (0.661), indicating a more drug-like profile.

**DILI:** Ligand A (9.965) has a much lower DILI risk than Ligand B (22.8), suggesting better hepatotoxicity potential.

**BBB:** Both ligands have excellent BBB penetration (73.672 and 77.239), exceeding the desirable threshold of >70 for CNS targets. Ligand B is slightly better.

**Caco-2:** Both have negative Caco-2 values, which is unusual and likely indicates poor permeability. However, these values are on a different scale and difficult to interpret without knowing the scale.

**Solubility:** Both ligands have negative solubility values, which is also unusual and suggests very poor aqueous solubility. Again, difficult to interpret without knowing the scale.

**hERG:** Both ligands have low hERG inhibition liability (0.774 and 0.373), indicating a low risk of cardiotoxicity.

**Microsomal Clearance:** Ligand B (82.917) has significantly higher microsomal clearance than Ligand A (21.128), meaning Ligand A is more metabolically stable.

**In vitro Half-Life:** Ligand B (35.087) has a much longer in vitro half-life than Ligand A (2.27), which is a positive attribute.

**P-gp Efflux:** Ligand A (0.204) has lower P-gp efflux liability than Ligand B (0.084), suggesting better CNS exposure.

**Binding Affinity:** Ligand A (-8.6 kcal/mol) has a significantly stronger binding affinity than Ligand B (-7.0 kcal/mol). The difference of 1.6 kcal/mol is substantial and can outweigh minor ADME drawbacks.

**Overall Assessment:**

Ligand A is the stronger candidate. While Ligand B has a slightly better BBB and longer half-life, Ligand A excels in crucial areas: significantly higher binding affinity, better QED, lower DILI risk, and lower P-gp efflux. The improved metabolic stability (lower Cl_mic) is also a significant advantage. The negative values for Caco-2 and Solubility are concerning for both, but the substantial affinity difference of Ligand A makes it more likely to be optimized to address these issues.

Output:
1
2025-04-17 06:48:16,387 - INFO - Reasoning:

Let's analyze Ligand A and Ligand B based on the provided guidelines, prioritizing GPCR-specific properties (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands fall within the ideal range (200-500 Da). Ligand A (421.316 Da) is at the higher end, while Ligand B (352.475 Da) is more optimal.

**TPSA:** Both ligands have TPSA values (72.2 and 75.71) slightly above the ideal <90 for CNS targets, but still reasonably acceptable.

**logP:** Ligand A (4.376) is higher than optimal (1-3), potentially leading to solubility issues and off-target effects. Ligand B (2.119) is within the ideal range. This is a significant advantage for Ligand B.

**H-Bond Donors/Acceptors:** Both ligands have acceptable HBD (1) and HBA (5/4) counts.

**QED:** Both ligands have QED values above 0.5, indicating good drug-likeness.

**DILI:** Ligand A (79.643) has a higher DILI risk than Ligand B (12.136). This is a substantial negative for Ligand A.

**BBB:** Both ligands have good BBB penetration (58.899 and 78.092), with Ligand B being slightly better. A value >70 is preferred, but both are reasonably good for a CNS target.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values, which is unusual and requires further investigation. However, we'll proceed assuming these represent low permeability.

**Aqueous Solubility:** Both ligands have negative solubility values, indicating poor aqueous solubility. This is a concern for both, but potentially more so for Ligand A given its higher logP.

**hERG Inhibition:** Both ligands show low hERG inhibition liability, which is positive.

**Microsomal Clearance:** Ligand A (55.273) and Ligand B (53.758) have similar microsomal clearance values, suggesting comparable metabolic stability.

**In vitro Half-Life:** Ligand B (-14.178) has a significantly *longer* in vitro half-life than Ligand A (93.711). This is a major advantage for Ligand B.

**P-gp Efflux:** Ligand A (0.777) has higher P-gp efflux liability than Ligand B (0.031). Lower P-gp efflux is crucial for CNS penetration, making Ligand B superior.

**Binding Affinity:** Both ligands have very similar and strong binding affinities (-8.4 and -8.3 kcal/mol). The difference is negligible.

**Overall Assessment:**

Ligand B is the superior candidate. While both have some drawbacks (poor solubility, negative Caco-2 values), Ligand B excels in key areas for a CNS-targeting GPCR: better logP, significantly lower DILI risk, longer half-life, and substantially lower P-gp efflux. The similar binding affinities mean these ADME/Tox advantages outweigh any minor differences in potency.

Output:
1
2025-04-17 06:48:16,387 - INFO - Reasoning:

Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (380.413 and 393.443 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (104.73) is better than Ligand B (128.08). For CNS targets, we want TPSA <= 90, so both are a bit high, but A is closer.

**logP:** Ligand A (0.228) is quite low, potentially hindering permeability. Ligand B (0.063) is even lower. Both are below the optimal 1-3 range, and could present absorption challenges.

**H-Bond Donors/Acceptors:** Ligand A has 3 HBD and 6 HBA, which are acceptable. Ligand B has 1 HBD and 8 HBA, also acceptable, but slightly higher HBA could affect permeability.

**QED:** Ligand B (0.512) has a better QED score than Ligand A (0.37), indicating a more drug-like profile.

**DILI:** Ligand A (35.285) has a significantly lower DILI risk than Ligand B (84.645), a major advantage.

**BBB:** Ligand B (75.998) has a better BBB penetration percentile than Ligand A (59.364). While both are not ideal (>70 is preferred), B is closer to the threshold.

**Caco-2 Permeability:** Both have negative Caco-2 values (-5.384 and -5.034), which is unusual and suggests poor permeability.

**Aqueous Solubility:** Both have negative solubility values (-1.71 and -2.967), also unusual and suggesting poor solubility.

**hERG:** Ligand A (0.108) has a lower hERG inhibition liability than Ligand B (0.547), which is favorable.

**Microsomal Clearance:** Ligand B (19.889) has a lower microsomal clearance than Ligand A (31.616), indicating better metabolic stability.

**In vitro Half-Life:** Ligand A (-31.826) has a more negative half-life, which is not good. Ligand B (-24.233) is also negative, but less so.

**P-gp Efflux:** Ligand A (0.022) has a much lower P-gp efflux liability than Ligand B (0.087), which is crucial for CNS penetration.

**Binding Affinity:** Ligand B (-7.2 kcal/mol) has a significantly stronger binding affinity than Ligand A (-6.2 kcal/mol). This is a substantial advantage, potentially outweighing some ADME concerns.

**Overall Assessment:**

Ligand B is superior due to its significantly better binding affinity (-7.2 vs -6.2 kcal/mol) and improved BBB penetration (75.998 vs 59.364). While its DILI risk is higher, the strong binding and better CNS penetration are critical for a DRD2 ligand. The lower metabolic clearance of Ligand B is also a positive. The poor solubility and permeability of both are concerning, but could be addressed with formulation strategies. The lower P-gp efflux of ligand A is a plus, but is overshadowed by the much stronger binding of ligand B.



Output:
1
2025-04-17 06:48:16,387 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (354.403 and 349.341 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (85.38) is better than Ligand B (88.91). Both are below the 90 A^2 threshold desirable for CNS targets, but A is closer to optimal.

**3. logP:** Ligand A (-0.17) is suboptimal, being below the preferred 1-3 range. Ligand B (1.578) is within the optimal range. This is a significant advantage for Ligand B.

**4. H-Bond Donors:** Ligand A (0) is excellent. Ligand B (2) is acceptable, but more donors can sometimes hinder permeability.

**5. H-Bond Acceptors:** Ligand A (6) is good. Ligand B (5) is also good.

**6. QED:** Ligand B (0.794) is significantly better than Ligand A (0.422), indicating a more drug-like profile.

**7. DILI:** Ligand A (32.222) has a much lower DILI risk than Ligand B (76.425). This is a substantial advantage for Ligand A.

**8. BBB:** Ligand B (73.75) is better than Ligand A (61.613), although both are reasonably good for a CNS target. A score >70 is preferred, and B is closer.

**9. Caco-2:** Ligand A (-4.529) is very poor, indicating very low intestinal absorption. Ligand B (-5.293) is also poor, but slightly better than A.

**10. Solubility:** Ligand A (-1.048) is poor. Ligand B (-3.18) is even worse. Both have solubility issues.

**11. hERG:** Both ligands have very low hERG risk (0.077 and 0.223, respectively).

**12. Cl_mic:** Ligand A (24.977) has lower microsomal clearance, suggesting better metabolic stability than Ligand B (3.311). This is a significant advantage for Ligand A.

**13. t1/2:** Ligand B (17.163) has a much longer in vitro half-life than Ligand A (-3.099). This is a major advantage for Ligand B.

**14. Pgp:** Both ligands have very low P-gp efflux liability (0.014 and 0.028, respectively).

**15. Binding Affinity:** Ligand B (-8.7 kcal/mol) has a significantly stronger binding affinity than Ligand A (-6.7 kcal/mol). This is a crucial advantage, potentially outweighing some ADME drawbacks.

**Overall Assessment:**

Ligand B has a superior binding affinity and better BBB penetration, and a longer half-life. However, it has a higher DILI risk and worse solubility. Ligand A has better metabolic stability, lower DILI, and a slightly better TPSA, but suffers from poor logP, Caco-2 permeability, and solubility, and a weaker binding affinity.

Given the GPCR-specific priorities, the strong binding affinity and acceptable BBB of Ligand B are compelling. While the DILI risk is a concern, it might be mitigated through structural modifications. The poor solubility of both compounds is a concern, but formulation strategies could potentially address this. The significantly stronger binding affinity of Ligand B is likely to be the most important factor for *in vivo* efficacy.

Output:
1
2025-04-17 06:48:16,388 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 drug candidates, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight (MW):** Both ligands (348.49 & 357.45 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (58.64) is excellent, well below the 90 A^2 threshold for CNS targets. Ligand B (96.97) is higher, but still potentially acceptable, though less ideal.

**3. logP:** Ligand A (2.368) is optimal (1-3). Ligand B (0.757) is a bit low, potentially hindering membrane permeability.

**4. H-Bond Donors (HBD):** Both ligands have acceptable HBD counts (1 & 2, respectively), well below the 5 threshold.

**5. H-Bond Acceptors (HBA):** Ligand A (3) and Ligand B (6) are both within the acceptable range of <=10.

**6. QED:** Ligand A (0.719) is good, indicating strong drug-likeness. Ligand B (0.492) is lower, suggesting a less favorable overall drug-like profile.

**7. DILI:** Ligand A (13.61) has a very low DILI risk. Ligand B (27.26) is higher, but still relatively low risk.

**8. BBB:** This is critical for a CNS target like DRD2. Ligand A (83.60) has a good BBB percentile. Ligand B (58.01) is considerably lower, raising concerns about CNS penetration.

**9. Caco-2 Permeability:** Ligand A (-4.648) is poor. Ligand B (-5.347) is also poor. Both are negative values which is not ideal.

**10. Aqueous Solubility:** Ligand A (-3.343) and Ligand B (-1.363) are both poor.

**11. hERG:** Both ligands have low hERG inhibition risk (0.606 and 0.279, respectively).

**12. Microsomal Clearance (Cl_mic):** Ligand A (66.79) has a higher clearance than Ligand B (27.8), suggesting lower metabolic stability.

**13. In vitro Half-Life:** Ligand B (-24.871) has a much longer in vitro half-life than Ligand A (-11.882), which is a significant advantage.

**14. P-gp Efflux:** Ligand A (0.245) has a lower P-gp efflux liability than Ligand B (0.013), which is favorable for CNS penetration.

**15. Binding Affinity:** Ligand A (-7.4 kcal/mol) has a significantly stronger binding affinity than Ligand B (-0.0 kcal/mol). This is a major advantage.

**Overall Assessment:**

Ligand A excels in key areas for a CNS GPCR target: TPSA, logP, BBB, and, crucially, binding affinity. While its Caco-2 permeability and solubility are poor, and its metabolic stability is not ideal, the strong binding affinity and good BBB penetration are compelling. Ligand B has a better half-life and lower P-gp efflux, but its lower logP, weaker binding affinity, and significantly lower BBB penetration make it a less attractive candidate. The affinity difference is substantial enough to outweigh the ADME concerns with Ligand A, especially given the importance of potency for GPCR ligands.

Output:
1
2025-04-17 06:48:16,388 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (344.455 and 349.479 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (58.64) is significantly better than Ligand B (88.17). For CNS targets, we want TPSA <= 90, and A is comfortably within this range while B is approaching the upper limit. This favors A.

**3. logP:** Both ligands have similar logP values (2.527 and 2.483), both within the optimal 1-3 range.

**4. H-Bond Donors:** Ligand A (1) is better than Ligand B (3). Lower HBD generally improves permeability.

**5. H-Bond Acceptors:** Ligand A (3) is better than Ligand B (6). Lower HBA also generally improves permeability.

**6. QED:** Ligand A (0.863) has a higher QED than Ligand B (0.635), indicating a more drug-like profile.

**7. DILI:** Ligand B (48.119) has a slightly lower DILI risk than Ligand A (31.563), but both are below the concerning threshold of 60.

**8. BBB:** Ligand A (78.751) has a better BBB penetration percentile than Ligand B (70.686). While both are reasonably good, A is closer to the desirable >70 threshold for CNS targets.

**9. Caco-2 Permeability:** Ligand A (-4.587) is better than Ligand B (-5.104). Higher values indicate better absorption.

**10. Aqueous Solubility:** Both ligands have similar, poor aqueous solubility (-2.882 and -2.98). This is a potential concern for both, but not a deciding factor.

**11. hERG Inhibition:** Both ligands have similar, low hERG inhibition risk (0.549 and 0.629).

**12. Microsomal Clearance:** Ligand A (49.696) has a lower microsomal clearance than Ligand B (70.359), suggesting better metabolic stability.

**13. In vitro Half-Life:** Ligand A (-21.029) has a longer in vitro half-life than Ligand B (26.793).

**14. P-gp Efflux:** Ligand A (0.429) has lower P-gp efflux liability than Ligand B (0.068). Lower P-gp efflux is highly desirable for CNS penetration.

**15. Binding Affinity:** Ligand B (-8.1) has a slightly better binding affinity than Ligand A (-9.2). While A has a better affinity, the difference is not substantial enough to outweigh the ADME advantages of A.

**Overall Assessment:**

Ligand A consistently outperforms Ligand B in key ADME properties crucial for CNS drug development, including TPSA, HBD, HBA, BBB, microsomal clearance, P-gp efflux, and in vitro half-life. While Ligand B has slightly better binding affinity and lower DILI, the ADME profile of Ligand A is significantly more favorable, especially considering the target is a CNS GPCR. The improved BBB penetration and reduced efflux liability of Ligand A are particularly important.

Output:
1
2025-04-17 06:48:16,388 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (343.391 and 363.805 Da) fall within the ideal 200-500 Da range.

**TPSA:** Both ligands (105.04 and 103.34) are slightly above the optimal <90 for CNS targets, but still reasonable.

**logP:** Ligand A (0.059) is quite low, potentially hindering membrane permeability. Ligand B (0.594) is better, but still on the lower side of the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A has 2 HBD and 7 HBA, while Ligand B has 1 HBD and 6 HBA. Both are within acceptable limits (<=5 HBD and <=10 HBA).

**QED:** Both ligands have good QED scores (0.761 and 0.809), indicating drug-like properties.

**DILI:** Both ligands have similar DILI risk (64.831 and 60.178), placing them in a moderate risk category, but not alarming.

**BBB:** Both ligands have similar BBB penetration (59.131 and 60.838), which is below the desirable >70 for CNS targets. This is a significant concern for both.

**Caco-2 Permeability:** Both have negative Caco-2 values (-5.474 and -5.021), which is unusual and suggests poor permeability. This is a major red flag.

**Aqueous Solubility:** Both have very poor aqueous solubility (-1.436 and -2.453). This will likely cause formulation challenges.

**hERG Inhibition:** Both ligands show very low hERG inhibition risk (0.222 and 0.051), which is excellent.

**Microsomal Clearance:** Ligand A (-45.013) has a much lower (better) microsomal clearance than Ligand B (-4.2). This suggests better metabolic stability for Ligand A.

**In vitro Half-Life:** Ligand A (24.009 hours) has a significantly longer half-life than Ligand B (-9.717 hours).

**P-gp Efflux:** Both have very low P-gp efflux liability (0.013 and 0.053), which is favorable for CNS penetration.

**Binding Affinity:** Ligand B (-8.6 kcal/mol) has a slightly better binding affinity than Ligand A (-7.3 kcal/mol). The difference is 1.3 kcal/mol which is significant.

**Overall Assessment:**

While Ligand B has a slightly better binding affinity, Ligand A is preferable due to its significantly better metabolic stability (lower Cl_mic) and longer half-life. Both have poor solubility and permeability, and suboptimal BBB penetration. However, the improved PK properties of Ligand A, coupled with a still-strong binding affinity, make it the more promising candidate. The low logP of Ligand A is a concern, but the better metabolic profile is more critical for a GPCR target.

Output:
1
2025-04-17 06:48:16,388 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B based on the provided guidelines, prioritizing GPCR-specific properties (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (334.427 Da) is slightly lower, which could be beneficial for permeability, but both are acceptable.

**TPSA:** Ligand A (63.21) is better than Ligand B (40.62). For CNS targets, we want TPSA <= 90, both are well within this range, but A is slightly higher and could potentially hinder BBB penetration compared to B.

**logP:** Ligand B (3.945) is higher than Ligand A (2.268). While both are within the optimal 1-3 range, B is closer to the upper limit. This could potentially lead to solubility issues, but is still acceptable.

**H-Bond Donors/Acceptors:** Ligand A has 1 HBD and 6 HBA, while Ligand B has 0 HBD and 2 HBA. Both are within acceptable limits (<=5 HBD and <=10 HBA).

**QED:** Ligand A (0.796) has a significantly better QED score than Ligand B (0.554), indicating a more drug-like profile.

**DILI:** Ligand B (21.869) has a much lower DILI risk than Ligand A (79.682), which is a substantial advantage.

**BBB:** Ligand B (97.674) has a significantly higher BBB penetration percentile than Ligand A (69.407). This is *critical* for a CNS target like DRD2.

**Caco-2 Permeability:** Ligand A (-4.882) and Ligand B (-4.224) both have negative values, which is unusual and suggests poor permeability. However, the scale is not specified, so it's difficult to interpret.

**Aqueous Solubility:** Both ligands have poor aqueous solubility (-2.261 and -3.887 respectively).

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.937 and 0.91 respectively).

**Microsomal Clearance:** Ligand A (1.196) has much lower microsomal clearance than Ligand B (74.9), indicating better metabolic stability.

**In vitro Half-Life:** Ligand A (-28.503) has a negative half-life, which is nonsensical. Ligand B (3.676) has a very short half-life, which is not ideal.

**P-gp Efflux:** Ligand A (0.194) has lower P-gp efflux than Ligand B (0.445), which is favorable for CNS exposure.

**Binding Affinity:** Ligand B (-7.8 kcal/mol) has a significantly stronger binding affinity than Ligand A (-9.2 kcal/mol). This is a substantial advantage, and can outweigh some ADME drawbacks.

**Overall Assessment:**

Ligand B is the stronger candidate. While it has a slightly higher logP and a shorter half-life, its *significantly* better BBB penetration (97.674 vs 69.407) and binding affinity (-7.8 vs -9.2 kcal/mol) are decisive for a CNS-targeting GPCR like DRD2. The lower DILI risk is also a major plus. The nonsensical half-life for Ligand A is a significant red flag.



Output:
1
2025-04-17 06:48:16,389 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (345.403 and 348.487 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (115.19) is higher than the preferred <90 for CNS targets, but not drastically so. Ligand B (67.43) is excellent, well below the 90 threshold.

**3. logP:** Ligand A (0.222) is quite low, potentially hindering membrane permeability. Ligand B (2.847) is within the optimal 1-3 range.

**4. H-Bond Donors:** Both ligands have 2 HBD, which is acceptable.

**5. H-Bond Acceptors:** Ligand A has 5 HBA, acceptable. Ligand B has 3 HBA, also acceptable.

**6. QED:** Ligand A (0.733) has a better QED score than Ligand B (0.497), indicating a more drug-like profile.

**7. DILI:** Ligand A (42.807) has a slightly higher DILI risk than Ligand B (21.52), but both are below the concerning 60 percentile.

**8. BBB:** Ligand B (57.193) has a significantly better BBB penetration score than Ligand A (37.65). This is a critical factor for a CNS target like DRD2.

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.147 and -5.152), which is unusual and suggests poor permeability. This is a significant concern for both.

**10. Aqueous Solubility:** Both ligands have negative solubility values (-1.903 and -2.602), also unusual and indicating poor solubility.

**11. hERG Inhibition:** Both ligands have low hERG inhibition risk (0.324 and 0.356).

**12. Microsomal Clearance:** Ligand A (11.737) has a lower (better) microsomal clearance than Ligand B (40.323), suggesting better metabolic stability.

**13. In vitro Half-Life:** Ligand A (23.129) has a longer half-life than Ligand B (-12.134).

**14. P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.024 and 0.169).

**15. Binding Affinity:** Ligand B (-8.0) has a slightly better binding affinity than Ligand A (-7.8), although the difference is small.

**Overall Assessment:**

Despite Ligand A's better QED and metabolic stability, Ligand B is the more promising candidate. The significantly better BBB penetration (57.193 vs 37.65) and more optimal logP (2.847 vs 0.222) are crucial for a CNS-targeting GPCR like DRD2. While both have concerningly low/negative Caco-2 and solubility values, the improved brain penetration potential of Ligand B outweighs the benefits of Ligand A's slightly better ADME properties. The small difference in binding affinity is not enough to overcome the permeability and CNS exposure advantages of Ligand B.

Output:
1
2025-04-17 06:48:16,389 - INFO - Batch 312 complete. Total preferences: 4992
2025-04-17 06:48:16,389 - INFO - Processing batch 313/512...
2025-04-17 06:49:04,690 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (359.5 & 341.4 Da) fall within the ideal range of 200-500 Da.

**TPSA:** Ligand A (63.13) is significantly better than Ligand B (88.08). For CNS targets, we want TPSA <= 90, and A is comfortably within that, while B is approaching the upper limit.

**logP:** Ligand A (3.513) is optimal (1-3), while Ligand B (1.553) is on the lower side. Lower logP can hinder permeation, especially into the CNS.

**H-Bond Donors/Acceptors:** Ligand A (HBD=2, HBA=4) and Ligand B (HBD=1, HBA=5) both have acceptable numbers of H-bond donors and acceptors.

**QED:** Both ligands have good QED scores (A: 0.709, B: 0.861), indicating good drug-like properties.

**DILI:** Both ligands have similar, moderate DILI risk (A: 53.43, B: 57.15). Neither is particularly concerning.

**BBB:** Ligand A (49.83) is lower than Ligand B (57.74). While both are not ideal (>70 is desirable), B is better.

**Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and difficult to interpret without knowing the scale. However, the values are similar.

**Aqueous Solubility:** Both have negative solubility values, which is also unusual. Again, the values are similar.

**hERG:** Both ligands have very low hERG risk (A: 0.499, B: 0.217).

**Microsomal Clearance:** Ligand A (77.08) has higher clearance than Ligand B (40.77), suggesting lower metabolic stability.

**In vitro Half-Life:** Ligand B (24.67) has a shorter half-life than Ligand A (54.44).

**P-gp Efflux:** Ligand A (0.264) has lower P-gp efflux than Ligand B (0.068), which is favorable for CNS penetration.

**Binding Affinity:** Ligand B (-8.6 kcal/mol) has a slightly better binding affinity than Ligand A (-8.3 kcal/mol). While the difference is small, it's a factor.

**Overall Assessment:**

Considering the GPCR-specific priorities, Ligand A is better. Its superior logP and TPSA are crucial for CNS penetration. While Ligand B has a slightly better binding affinity and BBB, the lower logP and higher TPSA of Ligand B are significant drawbacks. The lower P-gp efflux of Ligand A is also a plus. The better metabolic stability (lower Cl_mic and longer t1/2) of Ligand A is also a positive.

Output:
1
2025-04-17 06:49:04,691 - INFO - Reasoning:

Let's analyze Ligand A and Ligand B based on the provided guidelines, prioritizing GPCR-specific properties (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (334.354 and 342.527 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (61.4) is higher than the ideal <90 for CNS targets, but still reasonable. Ligand B (24.5) is excellent, well below the threshold. This favors Ligand B.

**logP:** Both ligands (3.184 and 3.693) are within the optimal 1-3 range. Ligand B is slightly higher, which could potentially lead to off-target effects, but isn't a major concern.

**H-Bond Donors/Acceptors:** Ligand A (0 HBD, 4 HBA) and Ligand B (1 HBD, 3 HBA) both have acceptable numbers of H-bond donors and acceptors.

**QED:** Both ligands have good QED scores (0.687 and 0.853), indicating drug-likeness. Ligand B is slightly better.

**DILI:** Ligand A (72.509) has a moderate DILI risk, while Ligand B (1.745) has a very low risk. This strongly favors Ligand B.

**BBB:** This is a critical parameter for CNS targets. Ligand A has a BBB percentile of 79.217, which is good, but Ligand B is significantly better at 92.594. This is a major advantage for Ligand B.

**Caco-2 Permeability:** Both have negative values, which is unusual. Assuming these are logP-scale values, lower values indicate poorer permeability. Ligand B (-4.951) is worse than Ligand A (-4.347) in this regard, but Caco-2 is less important than BBB for CNS targets.

**Aqueous Solubility:** Both have negative values, indicating poor solubility. Ligand B (-2.864) is slightly better than Ligand A (-4.682).

**hERG:** Both ligands have low hERG inhibition liability (0.922 and 0.947), which is good.

**Microsomal Clearance:** Ligand A (62.168) has higher clearance than Ligand B (8.647), suggesting lower metabolic stability. This favors Ligand B.

**In vitro Half-Life:** Ligand A (20.95) has a longer half-life than Ligand B (6.258). This favors Ligand A.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.68 and 0.126), which is good, but Ligand B is much better.

**Binding Affinity:** Ligand A (-8.8 kcal/mol) has a slightly better binding affinity than Ligand B (-8.1 kcal/mol). While a 0.7 kcal/mol difference is noticeable, the ADME advantages of Ligand B are substantial.

**Overall Assessment:**

Ligand B consistently outperforms Ligand A in key areas for a CNS-targeting GPCR ligand: lower DILI risk, significantly better BBB penetration, lower microsomal clearance (better metabolic stability), and lower P-gp efflux. While Ligand A has a slightly better binding affinity and half-life, the ADME profile of Ligand B is far superior and more likely to translate into a viable drug candidate. The TPSA of Ligand B is also excellent.

Output:
1
2025-04-17 06:49:04,691 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (351.397 and 351.447 Da) fall comfortably within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (54.34) is significantly better than Ligand B (96.53). For CNS targets, TPSA should be <= 90, and A is much closer to this threshold. B is considerably higher, potentially hindering BBB penetration.

**3. logP:** Ligand A (2.092) is optimal (1-3). Ligand B (0.506) is a bit low, potentially impacting permeability.

**4. H-Bond Donors:** Ligand A (1) is good. Ligand B (3) is acceptable but less ideal.

**5. H-Bond Acceptors:** Ligand A (3) is good. Ligand B (4) is acceptable.

**6. QED:** Ligand A (0.903) is excellent, indicating high drug-likeness. Ligand B (0.395) is poor, suggesting potential issues.

**7. DILI:** Ligand A (22.8) has a very low DILI risk. Ligand B (15.2) also has a low risk, but A is better.

**8. BBB:** Ligand A (95.967) has excellent predicted BBB penetration. Ligand B (69.135) is decent, but significantly lower than A. This is a *critical* factor for a CNS target like DRD2.

**9. Caco-2:** Ligand A (-4.677) is poor. Ligand B (-5.405) is also poor. Both are negative, which isn't ideal, but the scale isn't fully defined here.

**10. Solubility:** Ligand A (-2.851) is poor. Ligand B (-1.102) is also poor, but better than A.

**11. hERG:** Both ligands have very low hERG risk (0.397 and 0.127 respectively).

**12. Cl_mic:** Ligand A (4.128) has a moderate clearance. Ligand B (-0.563) has negative clearance, which is a positive sign for metabolic stability.

**13. t1/2:** Ligand A (-0.26) has a short half-life. Ligand B (-11.859) has a very long half-life.

**14. Pgp:** Both ligands have very low Pgp efflux liability (0.042 and 0.011 respectively).

**15. Binding Affinity:** Ligand A (-8.7 kcal/mol) has a significantly stronger binding affinity than Ligand B (-7.4 kcal/mol). The 1.3 kcal/mol difference is substantial and can outweigh some ADME drawbacks.

**Overall Assessment:**

Ligand A is clearly superior. While both have issues with Caco-2 and solubility, Ligand A excels in the most critical areas for a CNS-targeting GPCR: BBB penetration, TPSA, QED, and, most importantly, binding affinity. The strong affinity of Ligand A (-8.7 kcal/mol) is a major advantage. Ligand B's lower logP and significantly higher TPSA are concerning for CNS penetration, and its poor QED score raises red flags. The longer half-life of B is a plus, but not enough to overcome the other deficiencies.

Output:
1
2025-04-17 06:49:04,691 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 drug candidates, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (345.443 and 348.403 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (69.72) is significantly better than Ligand B (102.74). For CNS targets, TPSA should be <= 90, so Ligand A is preferable.

**3. logP:** Both ligands have acceptable logP values (0.944 and 0.627), falling within the 1-3 range.

**4. H-Bond Donors:** Both have 1 HBD, which is within the acceptable limit of <=5.

**5. H-Bond Acceptors:** Ligand A has 3 HBAs, while Ligand B has 5. Both are below the limit of <=10, but A is slightly better.

**6. QED:** Ligand B (0.785) has a better QED score than Ligand A (0.384), indicating a more drug-like profile overall.

**7. DILI:** Both ligands have low DILI risk (29.081 and 32.842), both well below the 40 threshold.

**8. BBB:** Ligand B (71.811) has a significantly better BBB penetration percentile than Ligand A (54.944). For a CNS target like DRD2, >70 is desirable, but 71.811 is closer than 54.944.

**9. Caco-2 Permeability:** Both have negative Caco-2 values (-4.596 and -4.749). These values are difficult to interpret without knowing the scale, but the similarity suggests similar absorption issues.

**10. Aqueous Solubility:** Both have negative solubility values (-1.773 and -1.952). Again, the scale is unknown, but the similarity suggests similar solubility challenges.

**11. hERG Inhibition:** Both ligands show very low hERG inhibition liability (0.098 and 0.16), which is excellent.

**12. Microsomal Clearance:** Ligand B (-43.109) has a much lower (better) microsomal clearance than Ligand A (27.597), indicating greater metabolic stability.

**13. In vitro Half-Life:** Ligand B (-2.376) has a slightly better in vitro half-life than Ligand A (-29.763).

**14. P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.014 and 0.007), which is favorable for CNS penetration.

**15. Binding Affinity:** Both ligands have very similar and strong binding affinities (-7.4 and -7.5 kcal/mol). The difference is negligible.

**Overall Assessment:**

Ligand B is superior due to its significantly better BBB penetration (71.811 vs 54.944), lower microsomal clearance (-43.109 vs 27.597), and slightly better in vitro half-life (-2.376 vs -29.763). While Ligand A has a better TPSA, the BBB and metabolic stability advantages of Ligand B are more critical for a CNS GPCR target. The QED score is also better for Ligand B. The binding affinity is essentially the same.

Output:
1
2025-04-17 06:49:04,691 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight (MW):** Both ligands (348.487 and 346.475 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (58.64) is significantly better than Ligand B (76.02). For CNS targets, we want TPSA <= 90, and A is much closer to the optimal <=60 range. B is pushing the upper limit.

**3. logP:** Both ligands have good logP values (2.799 and 3.192), falling within the optimal 1-3 range.

**4. H-Bond Donors (HBD):** Both ligands are acceptable (1 and 2, respectively), well below the limit of 5.

**5. H-Bond Acceptors (HBA):** Both ligands are acceptable (3 and 4, respectively), well below the limit of 10.

**6. QED:** Both ligands have reasonable QED scores (0.686 and 0.532), indicating drug-like properties, with A being slightly better.

**7. DILI:** Ligand A (15.471) has a much lower DILI risk than Ligand B (48.313). This is a significant advantage for A.

**8. BBB:** Ligand A (81.815) has a slightly better BBB penetration percentile than Ligand B (78.596). While both are good, A is closer to the desirable >70 threshold for CNS targets.

**9. Caco-2:** Both have negative Caco-2 permeability values, which is unusual and suggests a potential issue with in vitro permeability assessment. However, the magnitude of negativity is similar.

**10. Solubility:** Both have negative solubility values, again unusual. The values are similar in magnitude.

**11. hERG:** Both ligands have low hERG inhibition liability (0.444 and 0.406), which is good.

**12. Cl_mic:** Ligand A (61.723) has lower microsomal clearance than Ligand B (68.305), suggesting better metabolic stability.

**13. t1/2:** Ligand B (20.338) has a longer in vitro half-life than Ligand A (11.445). This is a positive for B.

**14. Pgp:** Both ligands have very low P-gp efflux liability (0.141 and 0.465), which is excellent for CNS penetration.

**15. Binding Affinity:** Both ligands have excellent binding affinity (-8.0 and -8.1 kcal/mol). The difference is negligible.

**Overall Assessment:**

Considering the GPCR-specific priorities, Ligand A is the better candidate. It has a significantly lower DILI risk, a better TPSA, a slightly better BBB score, and lower microsomal clearance. While Ligand B has a longer half-life, the other advantages of Ligand A outweigh this benefit. The similar affinity values mean that the ADME properties become the deciding factor.

Output:
1
2025-04-17 06:49:04,692 - INFO - Reasoning:

Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight (MW):** Both ligands are within the ideal range (200-500 Da). Ligand A (348.487 Da) is slightly lower, which could be advantageous for permeability. Ligand B (371.815 Da) is also good.

**2. TPSA:** Ligand A (67.43) is higher than Ligand B (62.3). For CNS targets, we want TPSA <= 90, so both are acceptable, but Ligand B is slightly better.

**3. logP:** Both ligands have good logP values (Ligand A: 2.559, Ligand B: 3.003), falling within the optimal 1-3 range. Ligand B is slightly higher, which could potentially lead to off-target effects, but is still within acceptable limits.

**4. H-Bond Donors (HBD):** Both ligands are within the acceptable limit of <=5. Ligand A has 2, and Ligand B has 1.

**5. H-Bond Acceptors (HBA):** Both ligands are within the acceptable limit of <=10. Both have 3.

**6. QED:** Both ligands have good QED scores (Ligand A: 0.629, Ligand B: 0.782), indicating good drug-like properties. Ligand B is better.

**7. DILI:** Ligand A (14.889) has a significantly lower DILI risk than Ligand B (52.772). This is a major advantage for Ligand A.

**8. BBB:** This is critical for a CNS target like DRD2. Ligand B (94.339) has a much higher BBB penetration percentile than Ligand A (56.534). This is a substantial advantage for Ligand B.

**9. Caco-2 Permeability:** Ligand A (-5.111) has worse Caco-2 permeability than Ligand B (-4.621). Higher values are better.

**10. Aqueous Solubility:** Ligand A (-2.486) has worse aqueous solubility than Ligand B (-3.624). Higher values are better.

**11. hERG Inhibition:** Both ligands have low hERG inhibition risk (Ligand A: 0.252, Ligand B: 0.556). Ligand A is better.

**12. Microsomal Clearance:** Ligand A (32.14) has lower microsomal clearance than Ligand B (45.696), suggesting better metabolic stability.

**13. In vitro Half-Life:** Ligand A (-15.484) has a much worse in vitro half-life than Ligand B (4.266).

**14. P-gp Efflux:** Ligand A (0.066) has lower P-gp efflux than Ligand B (0.228), which is beneficial for CNS exposure.

**15. Binding Affinity:** Both ligands have very similar and strong binding affinities (Ligand A: -8.3 kcal/mol, Ligand B: -8.5 kcal/mol). The difference is negligible.

**Overall Assessment:**

Ligand B excels in BBB penetration, which is paramount for a CNS target. It also has a better QED, Caco-2 permeability, and in vitro half-life. While its DILI risk is higher, the strong BBB penetration and favorable ADME properties (except DILI) make it a more promising candidate. Ligand A has a lower DILI risk and better P-gp efflux, but its significantly lower BBB penetration is a major drawback. The affinity is nearly identical. Given the GPCR-specific priorities, BBB is the most important factor here.

Output:
1
2025-04-17 06:49:04,692 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 drug candidates, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (348.447 and 367.921 Da) fall within the ideal range of 200-500 Da.

**TPSA:** Ligand A (96.11) is better than Ligand B (58.36) as it is closer to the ideal range for CNS targets (<=90). Ligand B is excellent.

**logP:** Both ligands have good logP values (1.612 and 3.389), falling within the optimal 1-3 range. Ligand B is slightly higher, which *could* be beneficial for membrane permeability but needs to be balanced against solubility.

**H-Bond Donors/Acceptors:** Ligand A has 3 HBD and 4 HBA, while Ligand B has 1 HBD and 4 HBA. Both are within acceptable limits (<=5 HBD and <=10 HBA).

**QED:** Both ligands have good QED scores (0.652 and 0.838), indicating good drug-like properties.

**DILI:** Ligand A (41.024) has a slightly higher DILI risk than Ligand B (19.736), but both are below the concerning threshold of 60.

**BBB:** Ligand A (78.79) has a better BBB percentile than Ligand B (62.97), which is crucial for a CNS target like DRD2. Both are reasonably good, but A is preferable.

**Caco-2 Permeability:** Ligand A (-5.425) has a much worse Caco-2 permeability than Ligand B (-4.662).

**Aqueous Solubility:** Ligand A (-2.504) has a slightly better aqueous solubility than Ligand B (-3.13), though both are very poor.

**hERG:** Both ligands have similar, low hERG inhibition liabilities (0.575 and 0.594).

**Microsomal Clearance:** Ligand B (61.903) has a significantly higher microsomal clearance than Ligand A (41.52), indicating faster metabolism and potentially lower *in vivo* exposure.

**In vitro Half-Life:** Ligand A (-11.753) has a much longer in vitro half-life than Ligand B (16.819).

**P-gp Efflux:** Both ligands have similar P-gp efflux liabilities (0.209 and 0.666).

**Binding Affinity:** Ligand B (-7.8 kcal/mol) has a significantly stronger binding affinity than Ligand A (-8.8 kcal/mol). This is a substantial advantage.

**Overall Assessment:**

While Ligand A has better BBB penetration, solubility, and metabolic stability (lower Cl_mic, longer t1/2), Ligand B's significantly improved binding affinity (-7.8 vs -8.8 kcal/mol) is a major advantage, especially for a GPCR target. The difference in affinity is likely to outweigh the slightly poorer ADME properties of Ligand B. The lower DILI risk for Ligand B is also a positive factor. Although the Caco-2 permeability is not great for either, the strong binding affinity of Ligand B makes it a more promising starting point for optimization.

Output:
1
2025-04-17 06:49:04,692 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (362.5 and 346.5 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (76.88) is higher than Ligand B (58.64). For CNS targets, TPSA should be <=90, so both are acceptable, but B is better.

**3. logP:** Ligand A (3.471) is slightly higher than Ligand B (2.241), both falling within the optimal 1-3 range.

**4. H-Bond Donors:** Both ligands have 1 HBD, which is good.

**5. H-Bond Acceptors:** Ligand A has 5 HBA, while Ligand B has 3. Both are acceptable (<=10).

**6. QED:** Both ligands have very similar QED values (0.853 and 0.849), indicating good drug-likeness.

**7. DILI:** Ligand A (72.82) has a higher DILI risk than Ligand B (35.60). B is significantly better here.

**8. BBB:** Ligand A (78.21) has a slightly better BBB penetration percentile than Ligand B (71.38). Both are above the desirable 70% threshold for CNS targets.

**9. Caco-2 Permeability:** Ligand A (-4.749) has worse Caco-2 permeability than Ligand B (-4.876). Lower values are less desirable.

**10. Aqueous Solubility:** Ligand A (-4.399) has worse aqueous solubility than Ligand B (-3.401). Lower values are less desirable.

**11. hERG Inhibition:** Ligand A (0.569) has a slightly higher hERG inhibition liability than Ligand B (0.261). B is better.

**12. Microsomal Clearance:** Ligand A (46.73) has higher microsomal clearance than Ligand B (38.76). Lower clearance is preferred for metabolic stability, so B is better.

**13. In vitro Half-Life:** Ligand A (-9.986) has a much worse in vitro half-life than Ligand B (6.835). B is significantly better.

**14. P-gp Efflux:** Ligand A (0.252) has lower P-gp efflux liability than Ligand B (0.155). Lower efflux is better for CNS exposure, so A is better.

**15. Binding Affinity:** Ligand A (-8.1) has a significantly stronger binding affinity than Ligand B (-9.0). This is a substantial advantage.

**Overall Assessment:**

Ligand A has a significantly better binding affinity, and slightly better BBB penetration and P-gp efflux. However, Ligand B excels in almost all ADME properties: lower DILI risk, better Caco-2 permeability, better aqueous solubility, lower hERG inhibition, lower microsomal clearance, and a significantly better in vitro half-life. The difference in binding affinity (-8.1 vs -9.0) is substantial, and can often outweigh minor ADME drawbacks. Given the GPCR target and the importance of CNS penetration, the superior ADME profile of Ligand B, coupled with a still very strong binding affinity, makes it the more promising candidate.

Output:
1
2025-04-17 06:49:04,692 - INFO - Okay, let's analyze these two ligands for their potential as DRD2 drug candidates. DRD2 is a GPCR in the CNS, so BBB penetration, logP, Pgp efflux, TPSA, and binding affinity are paramount.

**Ligand A: [411.275, 76.14, 3.555, 2, 4, 0.738, 62.815, 66.77, -4.688, -4.538, 0.234, 87.491, 8.105, 0.037, -8.8]**

*   **MW:** 411.275 Da - Acceptable.
*   **TPSA:** 76.14  - Good, below the 90 threshold for CNS targets.
*   **logP:** 3.555 - Excellent, within the optimal 1-3 range.
*   **HBD:** 2 - Acceptable.
*   **HBA:** 4 - Acceptable.
*   **QED:** 0.738 - Very good, indicates strong drug-likeness.
*   **DILI:** 62.815 - Moderate risk, but not alarming.
*   **BBB:** 66.77 - Acceptable, but could be better for a CNS target.
*   **Caco-2:** -4.688 - Poor permeability.
*   **Solubility:** -4.538 - Very poor solubility.
*   **hERG:** 0.234 - Low risk.
*   **Cl_mic:** 87.491 - High metabolic clearance, which is unfavorable.
*   **t1/2:** 8.105 - Relatively short half-life.
*   **Pgp:** 0.037 - Low efflux, favorable for CNS penetration.
*   **Affinity:** -8.8 kcal/mol - Excellent binding affinity.

**Ligand B: [350.419, 87.9, 0.025, 1, 6, 0.809, 38.736, 39.24, -4.755, 0.06, 0.256, -14.53, 7.092, 0.023, -7.9]**

*   **MW:** 350.419 Da - Acceptable.
*   **TPSA:** 87.9 - Borderline for CNS targets, slightly above the ideal 90 threshold.
*   **logP:** 0.025 - Very low, potentially hindering permeation.
*   **HBD:** 1 - Acceptable.
*   **HBA:** 6 - Acceptable.
*   **QED:** 0.809 - Very good, indicates strong drug-likeness.
*   **DILI:** 38.736 - Low risk.
*   **BBB:** 39.24 - Poor BBB penetration, a major drawback for a CNS target.
*   **Caco-2:** -4.755 - Poor permeability.
*   **Solubility:** 0.06 - Very poor solubility.
*   **hERG:** 0.256 - Low risk.
*   **Cl_mic:** -14.53 - Very low metabolic clearance, highly favorable.
*   **t1/2:** 7.092 - Relatively short half-life.
*   **Pgp:** 0.023 - Low efflux, favorable for CNS penetration.
*   **Affinity:** -7.9 kcal/mol - Good binding affinity, but less potent than Ligand A.

**Comparison and Decision:**

Ligand A has significantly better binding affinity (-8.8 vs -7.9 kcal/mol). While its DILI risk is higher, the difference isn't drastic. The major drawbacks for Ligand A are its poor Caco-2 permeability, poor solubility, and high metabolic clearance. However, its Pgp efflux is very low and its logP is optimal, which are important for CNS penetration.

Ligand B suffers from extremely poor logP and BBB penetration, making CNS exposure unlikely despite low Pgp efflux. Its metabolic stability is excellent, but this is less critical than CNS penetration for a DRD2 target.

Despite the ADME concerns with Ligand A, the significantly stronger binding affinity and reasonable logP/Pgp profile make it the more promising candidate. Optimization efforts could focus on improving solubility and metabolic stability.

1
2025-04-17 06:49:04,693 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (388.842 Da) is slightly higher than Ligand B (339.439 Da), but both are acceptable.

**2. TPSA:** Ligand A (32.34) is excellent, well below the 90 A^2 threshold for CNS targets. Ligand B (43.86) is still reasonable but less optimal.

**3. logP:** Ligand A (4.806) is a bit high, potentially leading to solubility issues and off-target interactions. Ligand B (1.355) is within the optimal range (1-3).

**4. H-Bond Donors:** Ligand A (1) and Ligand B (0) are both acceptable, being less than 5.

**5. H-Bond Acceptors:** Both ligands have 3 H-bond acceptors, which is well within the acceptable limit of 10.

**6. QED:** Both ligands have similar QED values (0.818 and 0.778), indicating good drug-likeness.

**7. DILI:** Ligand A (56.689) has a moderate DILI risk, but is still acceptable. Ligand B (19.426) has a significantly lower DILI risk, which is a major advantage.

**8. BBB:** Ligand A (88.135) has a very good BBB penetration percentile, exceeding the desirable 70% threshold for CNS targets. Ligand B (61.691) is lower, and while not terrible, it's less favorable.

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.822 and -4.421), which is unusual and suggests poor permeability. This is a concern for both.

**10. Aqueous Solubility:** Both ligands have very poor aqueous solubility (-5.302 and -1.331). This is a significant drawback, especially given Ligand A's high logP.

**11. hERG Inhibition:** Both ligands have low hERG inhibition risk (0.805 and 0.319).

**12. Microsomal Clearance:** Ligand A (64.971) has higher microsomal clearance, indicating lower metabolic stability. Ligand B (4.425) has much lower clearance, suggesting better metabolic stability.

**13. In vitro Half-Life:** Ligand A (27.269) has a shorter half-life compared to Ligand B (4.73).

**14. P-gp Efflux:** Ligand A (0.648) has moderate P-gp efflux, while Ligand B (0.045) has very low P-gp efflux, which is highly desirable for CNS penetration.

**15. Binding Affinity:** Both ligands have excellent binding affinity (-9.4 and -9.0 kcal/mol), with Ligand A being slightly stronger. The difference is less than 1.5 kcal/mol, so it's not a decisive factor.

**Overall Assessment:**

Ligand A has a better BBB score and slightly better binding affinity, but suffers from higher logP, higher DILI risk, higher microsomal clearance, shorter half-life, and moderate P-gp efflux. Ligand B has a lower logP, significantly lower DILI risk, better metabolic stability, longer half-life, and very low P-gp efflux. The poor Caco-2 and aqueous solubility are concerns for both, but can potentially be addressed with formulation strategies.

Given the GPCR-specific priorities and the importance of CNS penetration, Ligand B is the more promising candidate due to its superior ADME properties (lower DILI, better metabolic stability, lower P-gp efflux) despite slightly lower BBB and binding affinity. The lower logP also mitigates potential solubility and off-target issues.

Output:
1
2025-04-17 06:49:04,693 - INFO - Reasoning:

Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (344.455 and 351.403 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (74.35) is excellent, well below the 90 A^2 threshold for CNS targets. Ligand B (104.81) is still reasonable but less optimal, approaching the 140 A^2 limit for oral absorption and further from the ideal for CNS penetration.

**3. logP:** Ligand A (3.225) is within the optimal 1-3 range. Ligand B (-0.429) is significantly below this, which could hinder membrane permeability and potentially reduce CNS exposure.

**4. H-Bond Donors:** Both ligands have acceptable HBD counts (3 and 2, respectively), staying within the recommended limit of 5.

**5. H-Bond Acceptors:** Both ligands have acceptable HBA counts (3 and 5, respectively), staying within the recommended limit of 10.

**6. QED:** Both ligands have similar QED values (0.688 and 0.606), indicating good drug-like properties.

**7. DILI:** Ligand A (40.287) has a slightly higher DILI risk than Ligand B (26.444), but both are below the concerning threshold of 60.

**8. BBB:** Both ligands have good BBB penetration (64.87% and 67.701%), but neither exceeds the desirable 70% threshold.

**9. Caco-2 Permeability:** Ligand A (-4.629) has poor Caco-2 permeability. Ligand B (-5.313) is also poor, but slightly worse.

**10. Aqueous Solubility:** Ligand A (-4.201) has poor aqueous solubility. Ligand B (-2.511) is also poor, but slightly better.

**11. hERG Inhibition:** Both ligands show very low hERG inhibition risk (0.808 and 0.044).

**12. Microsomal Clearance:** Ligand A (31.704) has moderate clearance. Ligand B (-3.09) has negative clearance, which is not physically possible and likely indicates an issue with the prediction or data.

**13. In vitro Half-Life:** Ligand A (15.43) has a reasonable half-life. Ligand B (-1.522) has a negative half-life, which is not physically possible and likely indicates an issue with the prediction or data.

**14. P-gp Efflux:** Ligand A (0.266) has low P-gp efflux, which is favorable for CNS penetration. Ligand B (0.006) has very low P-gp efflux, which is even more favorable.

**15. Binding Affinity:** Both ligands have excellent binding affinities (-9.2 and -8.9 kcal/mol), with Ligand A being slightly more potent. The difference (0.3 kcal/mol) is not substantial enough to outweigh other factors.

**Overall Assessment:**

Ligand A has a better logP and slightly better affinity, but suffers from poor Caco-2 permeability and aqueous solubility. Ligand B has a better logP, lower P-gp efflux, and lower DILI risk. However, the negative values for clearance and half-life for Ligand B are concerning and likely indicate data errors. Given the importance of BBB penetration for a CNS target like DRD2, and considering the more reliable ADME properties of Ligand A, I would choose Ligand A.

Output:
1
2025-04-17 06:49:04,693 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (361.463 and 354.401 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (56.79) is significantly better than Ligand B (74.33). For CNS targets, we want TPSA <= 90, and A is comfortably within this range, while B is approaching the upper limit.

**logP:** Ligand A (3.635) is optimal (1-3), while Ligand B (1.137) is on the lower side. A logP below 1 can hinder permeation, which is a concern for CNS penetration.

**H-Bond Donors/Acceptors:** Ligand A (HBD=1, HBA=5) and Ligand B (HBD=2, HBA=4) are both within acceptable limits (<=5 HBD and <=10 HBA).

**QED:** Both ligands have good QED scores (A=0.693, B=0.803), indicating drug-like properties.

**DILI:** Ligand A (53.742) has a moderate DILI risk, but Ligand B (14.036) is very low, which is a significant advantage.

**BBB:** Both ligands have good BBB penetration (A=79.721, B=70.88), but A is slightly better. Both are above the 70% threshold desirable for CNS targets.

**Caco-2 Permeability:** Ligand A (-4.586) shows poor Caco-2 permeability, while Ligand B (-5.045) is also poor. This is a concern for oral absorption, but less critical for a CNS target where direct administration or enhanced delivery strategies might be employed.

**Aqueous Solubility:** Ligand A (-4.358) and Ligand B (-1.481) both exhibit poor aqueous solubility.

**hERG Inhibition:** Ligand A (0.75) has a slightly higher hERG risk than Ligand B (0.425), but both are relatively low.

**Microsomal Clearance:** Ligand A (75.004) has higher microsomal clearance than Ligand B (-43.588), indicating lower metabolic stability. This is a significant drawback for A.

**In vitro Half-Life:** Ligand A (8.564) has a shorter half-life than Ligand B (-10.318), further supporting the lower metabolic stability of A.

**P-gp Efflux:** Ligand A (0.671) has lower P-gp efflux than Ligand B (0.007), which is favorable for CNS exposure.

**Binding Affinity:** Ligand A (-7.8 kcal/mol) has a significantly stronger binding affinity than Ligand B (-8.5 kcal/mol). This is a substantial advantage that could potentially outweigh some of the ADME drawbacks.

**Overall Assessment:**

While Ligand A boasts a superior binding affinity and better P-gp efflux, Ligand B presents a much more favorable ADME profile, particularly regarding DILI risk, metabolic stability (lower Cl_mic and longer t1/2), and slightly better BBB. The lower logP of Ligand B is a concern, but the significantly better metabolic stability and lower toxicity profile are crucial for drug development. The affinity difference, while notable, may be surmountable with further optimization of Ligand B. Given the GPCR-specific priorities, the improved ADME properties of Ligand B make it a more promising starting point.

Output:
1
2025-04-17 06:49:04,693 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (353.463 and 345.355 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (87.74) is excellent, falling well below the 90 A^2 threshold for CNS targets. Ligand B (124.69) is still reasonable but less optimal, approaching the 140 A^2 limit for oral absorption.

**3. logP:** Ligand A (0.991) is at the lower end of the optimal 1-3 range, potentially impacting permeability. Ligand B (0.566) is even lower, raising concerns about membrane permeability.

**4. H-Bond Donors:** Ligand A (2) is good. Ligand B (4) is acceptable, but closer to the upper limit.

**5. H-Bond Acceptors:** Ligand A (4) is good. Ligand B (6) is acceptable.

**6. QED:** Both ligands have similar QED values (0.637 and 0.628), indicating good drug-like properties.

**7. DILI:** Ligand A (30.826) has a significantly lower DILI risk than Ligand B (56.727), which is a substantial advantage.

**8. BBB:** This is a crucial factor for a CNS target like DRD2. Ligand A (69.523) shows a good BBB penetration percentile, while Ligand B (12.059) is very poor, making it less likely to reach the target in the brain.

**9. Caco-2 Permeability:** Ligand A (-4.817) and Ligand B (-5.863) both have negative values, which is unusual and suggests poor permeability. However, the scale isn't specified, so it's difficult to interpret precisely.

**10. Aqueous Solubility:** Both ligands have poor aqueous solubility (-1.039 and -2.327). This could pose formulation challenges.

**11. hERG Inhibition:** Both ligands show very low hERG inhibition risk (0.085 and 0.095).

**12. Microsomal Clearance:** Ligand A (43.238) has a higher microsomal clearance than Ligand B (-3.496), meaning it's metabolized faster. Ligand B exhibits negative clearance, which is not physically possible and likely represents an artifact of the prediction method.

**13. In vitro Half-Life:** Ligand A (-15.487) has a negative half-life, which is not physically possible. Ligand B (-13.568) also has a negative half-life. These values are likely prediction errors.

**14. P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.03 and 0.011), which is favorable for CNS penetration.

**15. Binding Affinity:** Ligand B (-8.9 kcal/mol) has a significantly stronger binding affinity than Ligand A (-7.2 kcal/mol). This is a 1.7 kcal/mol difference, which is substantial enough to potentially overcome some ADME drawbacks.

**Overall Assessment:**

Despite the stronger binding affinity of Ligand B, the extremely poor BBB penetration (12.059) and the unrealistic negative values for clearance and half-life are major red flags. Ligand A, while having a slightly weaker affinity, presents a much more favorable ADME profile, particularly its good BBB penetration (69.523) and lower DILI risk. The negative values for half-life and clearance for both compounds are concerning and suggest issues with the prediction methods, but the magnitude of the difference in BBB penetration is a decisive factor.

Output:
1
2025-04-17 06:49:04,694 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (363.527 and 366.487 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (71.09) is significantly better than Ligand B (94.56). For CNS targets, we want TPSA <= 90, so Ligand A is preferable.

**3. logP:** Ligand A (2.938) is optimal (1-3), while Ligand B (0.958) is a bit low, potentially hindering permeation.

**4. H-Bond Donors:** Ligand A (2) and Ligand B (3) are both acceptable (<=5).

**5. H-Bond Acceptors:** Ligand A (4) and Ligand B (6) are both acceptable (<=10).

**6. QED:** Ligand A (0.781) is better than Ligand B (0.593), indicating a more drug-like profile.

**7. DILI:** Ligand B (59.752) has a higher DILI risk than Ligand A (37.805), although both are reasonably low.

**8. BBB:** Ligand A (61.38) is better than Ligand B (35.014). A BBB percentile >70 is desirable for CNS targets, and Ligand A is closer to this threshold.

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.464 and -5.512), which is unusual and suggests poor permeability. However, these values are on a different scale and hard to interpret directly.

**10. Aqueous Solubility:** Both ligands have negative solubility values (-3.177 and -2.096), which is also unusual.

**11. hERG Inhibition:** Both ligands have low hERG inhibition risk (0.429 and 0.552).

**12. Microsomal Clearance:** Ligand B (8.424) has a much lower microsomal clearance than Ligand A (52.629), suggesting better metabolic stability.

**13. In vitro Half-Life:** Ligand B (18.58) has a longer half-life than Ligand A (4.368), which is generally desirable.

**14. P-gp Efflux:** Ligand A (0.149) has lower P-gp efflux than Ligand B (0.023), which is favorable for CNS penetration.

**15. Binding Affinity:** Ligand A (-8.7 kcal/mol) has a slightly better binding affinity than Ligand B (-7.7 kcal/mol). While both are good, the 1 kcal/mol difference is significant.

**Overall Assessment:**

Considering the GPCR-specific priorities, Ligand A is the better candidate. It has a lower TPSA, a more optimal logP, a better BBB score, and a slightly better binding affinity. While Ligand B has better metabolic stability and half-life, the CNS target necessitates prioritizing BBB penetration and TPSA, where Ligand A excels. The negative Caco-2 and solubility values are concerning for both, but the superior CNS-related properties of Ligand A make it the more promising candidate.

Output:
1
2025-04-17 06:49:04,694 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B based on the provided guidelines, prioritizing GPCR-specific properties (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (349.337 and 358.41 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (63.69) is excellent, well below the 90 A^2 threshold for CNS targets. Ligand B (87.15) is still acceptable, but closer to the 90 A^2 limit.

**logP:** Ligand A (2.974) is optimal (1-3). Ligand B (0.498) is low, potentially hindering permeability.

**H-Bond Donors/Acceptors:** Both ligands have 1 HBD, which is good. Ligand A has 4 HBA, and Ligand B has 5 HBA, both within the acceptable limit of 10.

**QED:** Ligand A (0.925) is very strong, indicating excellent drug-likeness. Ligand B (0.699) is also good, but lower than A.

**DILI:** Ligand A (87.204) has a higher DILI risk than Ligand B (32.726). This is a concern for Ligand A.

**BBB:** Ligand A (72.237) has a good BBB percentile, desirable for a CNS target. Ligand B (59.791) is significantly lower, raising concerns about CNS penetration.

**Caco-2 Permeability:** Both have negative values, which is unusual. Assuming these are percentile scores, they are very low, suggesting poor intestinal absorption.

**Aqueous Solubility:** Both ligands have negative values, which is unusual. Assuming these are percentile scores, they are very low, suggesting poor solubility.

**hERG:** Both ligands have low hERG inhibition liability (0.327 and 0.453), which is good.

**Microsomal Clearance:** Ligand A (12.831) has lower clearance, indicating better metabolic stability than Ligand B (25.394).

**In vitro Half-Life:** Ligand B (-9.926) has a longer half-life than Ligand A (-7.027).

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.047 and 0.104), which is favorable for CNS penetration.

**Binding Affinity:** Ligand B (-7.5) has a slightly better binding affinity than Ligand A (-9.0). However, the difference is not substantial enough to overcome the other significant drawbacks of Ligand B.

**Overall Assessment:**

Ligand A is the better candidate despite the higher DILI risk. Its superior TPSA, logP, BBB penetration, and metabolic stability outweigh the DILI concern. Ligand B's low logP and significantly lower BBB penetration are major drawbacks for a CNS-targeted GPCR. While Ligand B has a slightly better binding affinity, the ADME properties of Ligand A are much more favorable for drug development.

Output:
1
2025-04-17 06:49:04,694 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (349.431 and 335.415 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (73.66) is better than Ligand B (78.86). Both are below the 90 A^2 threshold for CNS targets, but A is closer to the optimal range.

**3. logP:** Both ligands have good logP values (2.038 and 2.557), falling within the 1-3 range.

**4. H-Bond Donors:** Ligand A (0) is preferable to Ligand B (2). Fewer HBDs generally improve permeability.

**5. H-Bond Acceptors:** Ligand A (6) is better than Ligand B (7). Lower HBA is generally preferred.

**6. QED:** Both ligands have acceptable QED values (0.778 and 0.687), indicating good drug-like properties.

**7. DILI:** Ligand A (43.66) has a significantly lower DILI risk than Ligand B (63.086). This is a substantial advantage.

**8. BBB:** Ligand A (73.827) has a much better BBB penetration percentile than Ligand B (40.675). This is *critical* for a CNS target like DRD2.

**9. Caco-2 Permeability:** Ligand A (-4.358) is better than Ligand B (-5.358), indicating better intestinal absorption.

**10. Aqueous Solubility:** Ligand A (-2.026) is better than Ligand B (-3.062).

**11. hERG Inhibition:** Ligand A (0.211) has a lower hERG inhibition liability than Ligand B (0.729), reducing cardiotoxicity risk.

**12. Microsomal Clearance:** Ligand A (45.933) has lower microsomal clearance than Ligand B (67.547), suggesting better metabolic stability.

**13. In vitro Half-Life:** Ligand B (45.932) has a longer half-life than Ligand A (12.862). This is a positive for Ligand B, but the other advantages of A outweigh this.

**14. P-gp Efflux:** Ligand A (0.097) has lower P-gp efflux liability than Ligand B (0.014), which is beneficial for CNS exposure.

**15. Binding Affinity:** Ligand B (-9.0) has a slightly better binding affinity than Ligand A (-7.5). While affinity is important, the 1.5 kcal/mol difference is not enough to overcome the significant ADME advantages of Ligand A.

**Overall:** Ligand A is the superior candidate. It has better TPSA, HBD, HBA, DILI, BBB, Caco-2 permeability, solubility, hERG, and P-gp efflux profiles. While Ligand B has a slightly better binding affinity and in vitro half-life, the substantial improvements in ADME properties, particularly BBB penetration and DILI risk, make Ligand A the more promising drug candidate for a CNS target like DRD2.

Output:
0
2025-04-17 06:49:04,694 - INFO - Batch 313 complete. Total preferences: 5008
2025-04-17 06:49:04,695 - INFO - Processing batch 314/512...
2025-04-17 06:49:46,211 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (356.47 and 351.49 Da) fall comfortably within the ideal 200-500 Da range.

**TPSA:** Ligand A (33.2) is excellent, well below the 90 A^2 threshold for CNS targets. Ligand B (61.88) is higher, but still potentially acceptable, though less ideal.

**logP:** Ligand A (4.805) is a bit high, potentially leading to solubility issues and off-target interactions. Ligand B (1.108) is low, which might hinder membrane permeability.

**H-Bond Donors/Acceptors:** Ligand A (0 HBD, 3 HBA) and Ligand B (1 HBD, 4 HBA) both have reasonable numbers of H-bond donors and acceptors, falling within the suggested limits.

**QED:** Both ligands have similar QED values (0.74 and 0.746), indicating good drug-like properties.

**DILI:** Ligand A (56.88) has a moderate DILI risk, while Ligand B (11.21) has a very low risk. This is a significant advantage for Ligand B.

**BBB:** Ligand A (91.70) shows excellent BBB penetration, a critical factor for a CNS target like DRD2. Ligand B (70.26) is also good, but lower than Ligand A.

**Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and suggests potential issues with the calculation or data quality. However, we'll proceed assuming these represent low permeability.

**Aqueous Solubility:** Ligand A (-5.581) has very poor aqueous solubility, consistent with its high logP. Ligand B (-1.06) has better, though still poor, solubility.

**hERG Inhibition:** Ligand A (0.75) has a moderate hERG risk, while Ligand B (0.407) has a lower risk.

**Microsomal Clearance:** Ligand A (102.08) has higher microsomal clearance, indicating lower metabolic stability. Ligand B (31.824) has much lower clearance, suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (33.97 hours) has a reasonable half-life. Ligand B (17.134 hours) has a shorter half-life, which might necessitate more frequent dosing.

**P-gp Efflux:** Ligand A (0.631) shows moderate P-gp efflux, while Ligand B (0.042) shows very low efflux. This is a significant advantage for Ligand B, as it will lead to higher CNS exposure.

**Binding Affinity:** Ligand A (-8.9 kcal/mol) has a substantially stronger binding affinity than Ligand B (-0.0 kcal/mol). This is a major advantage for Ligand A, potentially outweighing some of its ADME drawbacks.

**Overall Assessment:**

Ligand A excels in binding affinity and BBB penetration, crucial for DRD2 targeting. However, it suffers from poor solubility, higher DILI risk, higher hERG risk, and lower metabolic stability. Ligand B has a much better safety profile (lower DILI, hERG, and P-gp efflux) and better metabolic stability, but its binding affinity is very weak and its logP is low.

Given the strong emphasis on affinity for GPCRs, and the substantial difference in binding energy (-8.9 vs -0.0 kcal/mol), **Ligand A is the more promising candidate despite its ADME liabilities.** Optimization efforts could focus on improving its solubility and metabolic stability while retaining its potent binding affinity.



Output:
0
2025-04-17 06:49:46,211 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (338.37 & 381.57 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (115.16) is higher than the preferred <90 for CNS targets, but not drastically so. Ligand B (62.3) is excellent, well below the threshold.

**logP:** Both ligands (3.56 & 3.40) are within the optimal 1-3 range.

**H-Bond Donors & Acceptors:** Ligand A has 2 HBD and 3 HBA, which is good. Ligand B has 1 HBD and 5 HBA, also acceptable.

**QED:** Ligand B (0.794) has a significantly better QED score than Ligand A (0.493), indicating a more drug-like profile.

**DILI:** Ligand A (65.723) has a higher DILI risk than Ligand B (48.468), though both are reasonably acceptable.

**BBB:** Ligand B (67.197) has a significantly better BBB penetration percentile than Ligand A (48.895). This is *critical* for a CNS target like DRD2.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.322 and -5.036), which is unusual and suggests poor permeability. This is a significant concern for both.

**Aqueous Solubility:** Both ligands have negative solubility values (-3.209 and -3.792), indicating very poor aqueous solubility. This is a major drawback for both.

**hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.028 and 0.176).

**Microsomal Clearance:** Ligand A (-4.341) has a much lower (better) microsomal clearance than Ligand B (46.074), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (7.749) has a better in vitro half-life than Ligand B (-3.629).

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.019 and 0.163).

**Binding Affinity:** Ligand A (-8.6 kcal/mol) has a significantly stronger binding affinity than Ligand B (-7.4 kcal/mol). This is a substantial advantage.

**Overall Assessment:**

Ligand A has a superior binding affinity and better metabolic stability (lower Cl_mic, longer t1/2). However, Ligand B excels in BBB penetration and has a better QED score. Both suffer from poor Caco-2 permeability and aqueous solubility. Given the importance of BBB penetration for a CNS target like DRD2, and the substantial difference in affinity, Ligand A is the more promising candidate *despite* the lower BBB score. The stronger binding affinity could potentially overcome the permeability and solubility issues with appropriate formulation strategies.

Output:
0
2025-04-17 06:49:46,211 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (360.523 and 344.411 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (40.62) is significantly better than Ligand B (73.99). For CNS targets, we want TPSA <= 90, and ideally closer to 60. Ligand A is well within this range, while Ligand B is approaching the upper limit and could present permeability challenges.

**logP:** Both ligands have good logP values (2.237 and 1.911), falling within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A (0 HBD, 3 HBA) is slightly better than Ligand B (1 HBD, 4 HBA) in terms of balancing solubility and permeability. Both are acceptable.

**QED:** Both ligands have good QED scores (0.725 and 0.905), indicating good drug-like properties.

**DILI:** Ligand A (47.77) has a slightly higher DILI risk than Ligand B (35.634), but both are below the concerning threshold of 60.

**BBB:** Ligand A (79.139) has a significantly better BBB percentile than Ligand B (63.164). A value >70 is desirable for CNS targets, and Ligand A is closer to this goal. This is a critical advantage for DRD2.

**Caco-2 Permeability:** Ligand A (-4.925) has slightly better Caco-2 permeability than Ligand B (-4.484), indicating better intestinal absorption.

**Aqueous Solubility:** Ligand A (-3.61) has slightly better aqueous solubility than Ligand B (-1.541).

**hERG Inhibition:** Ligand A (0.564) has a lower hERG inhibition liability than Ligand B (0.153), which is a positive attribute.

**Microsomal Clearance:** Ligand B (6.252) has significantly lower microsomal clearance than Ligand A (50.461), suggesting better metabolic stability. This is a key advantage for Ligand B.

**In vitro Half-Life:** Ligand B (52.311) has a longer in vitro half-life than Ligand A (-9.016), which is desirable for less frequent dosing.

**P-gp Efflux:** Ligand A (0.352) has lower P-gp efflux liability than Ligand B (0.18), which is beneficial for CNS exposure.

**Binding Affinity:** Ligand B (-8.4) has a slightly better binding affinity than Ligand A (-7.9). While both are excellent, the 0.5 kcal/mol difference is notable.

**Overall Assessment:**

Ligand A excels in TPSA, BBB, and P-gp efflux, all crucial for CNS penetration and targeting DRD2. However, Ligand B has superior metabolic stability (lower Cl_mic, longer t1/2) and slightly better binding affinity. The difference in binding affinity is not substantial enough to outweigh the significant advantage Ligand A has in BBB penetration. Given DRD2 is a CNS target, optimizing for brain exposure is paramount.

Output:
0
2025-04-17 06:49:46,212 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (365.5 & 344.4 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (102.22) is higher than Ligand B (86.37). For CNS targets, TPSA should be <= 90. Ligand B is better here.

**3. logP:** Both ligands have similar logP values (1.101 & 1.108), falling within the optimal 1-3 range.

**4. H-Bond Donors:** Ligand A (3) is higher than Ligand B (1). Both are acceptable, but lower is generally preferred for BBB penetration. Ligand B is better.

**5. H-Bond Acceptors:** Ligand A (5) is higher than Ligand B (4). Both are acceptable, but lower is generally preferred for BBB penetration. Ligand B is better.

**6. QED:** Both ligands have good QED scores (0.64 & 0.832), indicating good drug-like properties.

**7. DILI:** Ligand A (23.85) has a significantly lower DILI risk than Ligand B (51.88). This is a major advantage for Ligand A.

**8. BBB:** Ligand A (27.65) has a lower BBB penetration percentile than Ligand B (49.40). While neither is ideal (>70 desirable), Ligand B is better.

**9. Caco-2 Permeability:** Ligand A (-5.621) has worse Caco-2 permeability than Ligand B (-4.862). Higher values are better. Ligand B is better.

**10. Aqueous Solubility:** Ligand A (-1.899) has better aqueous solubility than Ligand B (-2.242). Higher values are better. Ligand A is better.

**11. hERG Inhibition:** Ligand A (0.729) has a slightly higher hERG inhibition liability than Ligand B (0.264). Lower is better, so Ligand B is better.

**12. Microsomal Clearance:** Ligand A (-3.899) has lower (better) microsomal clearance than Ligand B (30.162). This suggests better metabolic stability for Ligand A.

**13. In vitro Half-Life:** Ligand A (-24.771) has a lower in vitro half-life than Ligand B (-19.979). Longer half-life is generally preferred. Ligand B is better.

**14. P-gp Efflux:** Ligand A (0.075) has lower P-gp efflux than Ligand B (0.088). Lower efflux is better for CNS exposure. Ligand A is better.

**15. Binding Affinity:** Ligand A (-8.4) has a significantly stronger binding affinity than Ligand B (-7.9). A >1.5 kcal/mol advantage is very significant and can outweigh other drawbacks.

**Overall Assessment:**

Ligand A has a significantly better binding affinity and lower DILI risk, and better metabolic stability (lower Cl_mic) and P-gp efflux. While Ligand A has a lower BBB and Caco-2 permeability, its superior binding affinity (-8.4 kcal/mol vs -7.9 kcal/mol) and lower DILI risk are critical advantages, especially given the GPCR target class. The difference in binding affinity is substantial enough to potentially overcome the slightly less favorable BBB and permeability. Ligand B has better BBB, Caco-2, and half-life, but the weaker binding affinity and higher DILI risk are concerning.

Output:
0
2025-04-17 06:49:46,212 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (353.849 and 345.447 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (42.24) is significantly better than Ligand B (99.81). For CNS targets, TPSA should be <=90, and A is comfortably within this range, while B is pushing the limit and may suffer from reduced brain penetration.

**3. logP:** Ligand A (4.995) is slightly high, but still within a tolerable range. Ligand B (1.547) is a bit low, potentially hindering membrane permeability.

**4. H-Bond Donors:** Both have acceptable HBD counts (1 and 2, respectively), well below the threshold of 5.

**5. H-Bond Acceptors:** Both have acceptable HBA counts (2 and 5, respectively), well below the threshold of 10.

**6. QED:** Both ligands have good QED values (0.717 and 0.817), indicating drug-like properties.

**7. DILI:** Ligand A (59.907) has a higher DILI risk than Ligand B (38.969). This is a negative for A, but not a deal-breaker at this stage.

**8. BBB:** Ligand A (62.854) has a better BBB percentile than Ligand B (57.619). While neither is >70 (highly desirable), A is closer. This is crucial for a CNS target like DRD2.

**9. Caco-2:** Both have negative Caco-2 values, which is unusual and suggests a potential issue with the data or modeling. However, we'll proceed assuming these represent low permeability.

**10. Solubility:** Both have negative solubility values, which is also unusual. Again, assuming this indicates low solubility.

**11. hERG:** Ligand A (0.691) has a slightly higher hERG risk than Ligand B (0.197). B is much preferred here.

**12. Cl_mic:** Ligand B (25.318) has significantly lower microsomal clearance than Ligand A (62.41), suggesting better metabolic stability.

**13. t1/2:** Ligand A (185.663) has a much longer in vitro half-life than Ligand B (10.762). This is a significant advantage for A.

**14. Pgp:** Ligand A (0.757) has lower P-gp efflux liability than Ligand B (0.025). Lower Pgp is better for CNS penetration, favoring A.

**15. Binding Affinity:** Ligand A (-10.2 kcal/mol) has a *much* stronger binding affinity than Ligand B (-8.5 kcal/mol). This is a >1.5 kcal/mol difference and is a major deciding factor.

**Overall Assessment:**

Despite Ligand A's slightly higher DILI and logP, its significantly superior binding affinity, better BBB penetration, lower Pgp efflux, and longer half-life outweigh these drawbacks. Ligand B has better hERG and Cl_mic, but the affinity difference is too large to ignore, especially for a GPCR where potency is critical. The TPSA value for Ligand B is also concerning for CNS penetration.

Output:
1
2025-04-17 06:49:46,212 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (350.463 and 360.523 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (76.46) is better than Ligand B (45.59). For CNS targets, we want TPSA <= 90, both are within this range, but A is closer to the upper limit.

**logP:** Ligand A (1.133) is optimal (1-3), while Ligand B (4.686) is high. High logP can lead to solubility issues and off-target interactions.

**H-Bond Donors/Acceptors:** Both have 1 HBD and 5 HBA, which are within acceptable limits.

**QED:** Both ligands have similar QED values (0.763 and 0.705), indicating good drug-likeness.

**DILI:** Ligand A (27.569) has a significantly lower DILI risk than Ligand B (11.322). This is a major advantage for Ligand A.

**BBB:** Ligand B (76.813) has a better BBB penetration percentile than Ligand A (64.793). This is a crucial factor for CNS targets like DRD2. However, the difference isn't massive.

**Caco-2 Permeability:** Both have negative Caco-2 values (-5.021 and -4.996). This is unusual and suggests poor permeability. It's difficult to interpret without knowing the scale.

**Aqueous Solubility:** Ligand A (-0.84) is better than Ligand B (-5.669). Solubility is important, and B's value is quite poor.

**hERG Inhibition:** Ligand A (0.143) has a much lower hERG inhibition liability than Ligand B (0.889). This is a significant safety advantage for Ligand A.

**Microsomal Clearance:** Ligand A (25.735) has lower microsomal clearance than Ligand B (119.528), indicating better metabolic stability.

**In vitro Half-Life:** Ligand A (20.098) has a longer in vitro half-life than Ligand B (-7.22).

**P-gp Efflux:** Ligand A (0.019) has much lower P-gp efflux liability than Ligand B (0.442). Lower efflux is highly desirable for CNS penetration.

**Binding Affinity:** Both ligands have excellent binding affinity (-7.3 and -7.4 kcal/mol), with Ligand B being slightly better. However, the difference is minimal and likely not enough to overcome the ADME deficiencies.

**Overall Assessment:**

Ligand A is superior due to its significantly better ADME profile. While Ligand B has slightly better BBB penetration and binding affinity, its high logP, poor solubility, high DILI risk, high hERG inhibition, high P-gp efflux, and high microsomal clearance are major drawbacks. Ligand A balances good potency with a much more favorable safety and pharmacokinetic profile. The slightly lower BBB for A is less concerning than the other issues with B.

Output:
0
2025-04-17 06:49:46,212 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (341.455 and 358.404 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (64.41) is better than Ligand B (49.41). Both are below the 90 A^2 threshold for CNS targets, which is excellent.

**3. logP:** Both ligands have good logP values (2.484 and 3.094), falling within the optimal 1-3 range.

**4. H-Bond Donors:** Ligand A (0) is preferable to Ligand B (1). Fewer HBDs generally improve permeability.

**5. H-Bond Acceptors:** Ligand A (3) is preferable to Ligand B (4). Fewer HBAs generally improve permeability.

**6. QED:** Both ligands have similar and good QED values (0.725 and 0.794), indicating good drug-like properties.

**7. DILI:** Ligand A (21.598) has a significantly lower DILI risk than Ligand B (57.697). This is a major advantage for Ligand A.

**8. BBB:** Ligand B (93.757) has a substantially better BBB penetration percentile than Ligand A (71.811). This is a critical factor for a CNS target like DRD2.

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.853 and -4.723), which is unusual and requires further investigation. However, the values are very similar.

**10. Aqueous Solubility:** Both ligands have negative solubility values (-3.044 and -4.954), which is also unusual and problematic. Solubility is a concern for both.

**11. hERG Inhibition:** Ligand A (0.515) has a lower hERG inhibition liability than Ligand B (0.916), indicating a lower risk of cardiotoxicity.

**12. Microsomal Clearance:** Ligand B (30.676) has lower microsomal clearance than Ligand A (25.329), suggesting better metabolic stability.

**13. In vitro Half-Life:** Ligand B (36.116) has a significantly longer in vitro half-life than Ligand A (-4.496). This is a significant advantage for Ligand B.

**14. P-gp Efflux:** Ligand A (0.162) has lower P-gp efflux liability than Ligand B (0.399), which is favorable for CNS penetration.

**15. Binding Affinity:** Ligand B (-9.4 kcal/mol) has a significantly stronger binding affinity than Ligand A (-7.6 kcal/mol). This is a substantial advantage, potentially outweighing some ADME drawbacks.

**Overall Assessment:**

Ligand B excels in BBB penetration and binding affinity, both crucial for a CNS GPCR target. It also has better metabolic stability (lower Cl_mic and longer t1/2). However, it has a higher DILI risk and P-gp efflux. Ligand A has a lower DILI risk, hERG inhibition, and P-gp efflux, but its BBB penetration and binding affinity are significantly weaker.

The superior binding affinity of Ligand B (-9.4 kcal/mol vs -7.6 kcal/mol) is a substantial advantage. Given the importance of potency for GPCRs, and the relatively good (though not ideal) ADME properties of Ligand B, it is the more promising candidate. While the DILI risk is higher, it might be mitigated through structural modifications.

Output:
1
2025-04-17 06:49:46,213 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (397.733 Da) is slightly higher than Ligand B (360.37 Da), but both are acceptable.

**TPSA:** Ligand A (41.13) is excellent for CNS penetration, well below the 90 A^2 threshold. Ligand B (97.11) is higher, but still potentially acceptable, though less ideal.

**logP:** Ligand A (4.929) is a bit high, potentially leading to solubility issues or off-target interactions. Ligand B (2.412) is within the optimal range (1-3).

**H-Bond Donors/Acceptors:** Both ligands have 2 HBD, which is good. Ligand A has 2 HBA, which is also good. Ligand B has 6 HBA, which is higher, potentially impacting permeability.

**QED:** Both ligands have similar QED scores (A: 0.751, B: 0.704), indicating good drug-likeness.

**DILI:** Ligand A (48.623) has a lower DILI risk than Ligand B (93.874), which is a significant advantage.

**BBB:** Ligand A (75.378) has a much better BBB percentile than Ligand B (35.556). This is crucial for a CNS target like DRD2.

**Caco-2 Permeability:** Ligand A (-4.962) has a negative Caco-2 value, indicating poor permeability. Ligand B (-5.197) is also poor, but similar to A.

**Aqueous Solubility:** Ligand A (-5.261) has poor aqueous solubility, consistent with its high logP. Ligand B (-2.905) is better, but still not great.

**hERG Inhibition:** Ligand A (0.824) has a low hERG risk, which is favorable. Ligand B (0.071) has a very low hERG risk, which is excellent.

**Microsomal Clearance:** Ligand A (43.281) has moderate clearance. Ligand B (-6.496) has negative clearance, which is highly unusual and likely an error or indicates exceptional metabolic stability.

**In vitro Half-Life:** Ligand A (106.608) has a good half-life. Ligand B (-15.442) has a negative half-life, which is impossible and indicates a data issue.

**P-gp Efflux:** Ligand A (0.371) has low P-gp efflux, which is good for CNS penetration. Ligand B (0.022) has very low P-gp efflux, which is even better.

**Binding Affinity:** Ligand A (-10.3 kcal/mol) has significantly stronger binding affinity than Ligand B (-8.5 kcal/mol). This is a substantial advantage that can potentially overcome some of its ADME liabilities.

**Overall Assessment:**

Ligand A has a much stronger binding affinity and a significantly better BBB score, which are critical for a CNS GPCR target. While its logP is high and solubility is low, the strong affinity might compensate. Its DILI risk is also lower. Ligand B has better solubility and hERG, but its significantly weaker affinity and poor BBB penetration make it a less promising candidate. The negative values for clearance and half-life for Ligand B are highly suspect and raise concerns about data quality.

Output:
1
2025-04-17 06:49:46,213 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (433.368 Da) is slightly higher, but still acceptable. Ligand B (356.394 Da) is preferable.

**TPSA:** Ligand A (59.08) is excellent for CNS penetration, well below the 90 A^2 threshold. Ligand B (92.01) is higher, but still reasonably good. Ligand A is better here.

**logP:** Ligand A (2.371) is optimal. Ligand B (0.665) is a bit low, potentially hindering membrane permeability. Ligand A is significantly better.

**H-Bond Donors/Acceptors:** Ligand A (0 HBD, 6 HBA) is favorable. Ligand B (2 HBD, 5 HBA) is also acceptable. No clear winner here.

**QED:** Both ligands have good QED scores (Ligand A: 0.59, Ligand B: 0.749), indicating good drug-like properties. Ligand B is slightly better.

**DILI:** Both have acceptable DILI risk (Ligand A: 29.391, Ligand B: 35.595). Ligand A is slightly better.

**BBB:** Ligand A (72.082) has a good BBB percentile, exceeding the 70% threshold. Ligand B (64.831) is lower, which is a concern for a CNS target. Ligand A is better.

**Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and suggests a potential issue with the data or modeling. However, we can still compare the relative values; Ligand A (-4.712) is better (less negative) than Ligand B (-4.895).

**Aqueous Solubility:** Both have negative solubility values, which is also unusual. Ligand A (-1.888) is slightly better than Ligand B (-1.384).

**hERG Inhibition:** Both have low hERG inhibition risk (Ligand A: 0.732, Ligand B: 0.24). Ligand B is better here.

**Microsomal Clearance:** Ligand A (77.593) has higher clearance than Ligand B (5.048), indicating lower metabolic stability. Ligand B is much better.

**In vitro Half-Life:** Ligand A (27.5 hours) has a longer half-life than Ligand B (2.1 hours). Ligand A is better.

**P-gp Efflux:** Ligand A (0.219) has lower P-gp efflux than Ligand B (0.027), suggesting better CNS exposure. Ligand A is better.

**Binding Affinity:** Ligand B (-7.2 kcal/mol) has a significantly stronger binding affinity than Ligand A (-6.2 kcal/mol). This is a substantial advantage.

**Overall Assessment:**

Ligand B has a significantly better binding affinity, lower microsomal clearance, and lower hERG risk. However, it has a lower logP and BBB penetration. Ligand A excels in BBB, logP, P-gp efflux, and half-life, but suffers from weaker binding affinity and higher clearance.

Given the GPCR-specific priorities, BBB penetration and affinity are crucial. While Ligand B's lower logP and BBB are concerns, the 1 kcal/mol difference in binding affinity is substantial and can often outweigh minor ADME drawbacks, especially if further optimization can address the logP and BBB issues. The improved metabolic stability (lower Cl_mic) of Ligand B is also a significant advantage.

Output:
1
2025-04-17 06:49:46,213 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (372.893 and 401.945 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (67.87) is significantly better than Ligand B (96.87). For CNS targets, we want TPSA <= 90, so Ligand A is preferable.

**3. logP:** Both ligands have a logP around 2.6, which is optimal (1-3).

**4. H-Bond Donors:** Ligand A (1) is better than Ligand B (2). Lower is generally preferred.

**5. H-Bond Acceptors:** Ligand A (4) is better than Ligand B (7). Lower is generally preferred.

**6. QED:** Both ligands have good QED scores (0.551 and 0.673), indicating good drug-like properties.

**7. DILI:** Ligand A (31.989) has a much lower DILI risk than Ligand B (77.627).  Ligand A is well below the 40% threshold, while Ligand B is approaching the high-risk zone.

**8. BBB:** Ligand A (73.401) has a significantly better BBB penetration score than Ligand B (34.277).  For a CNS target like DRD2, >70% is desirable, and Ligand A is closer to this threshold.

**9. Caco-2 Permeability:** Both are negative, indicating poor permeability. However, the scale is not specified, so it's difficult to interpret the absolute values.

**10. Aqueous Solubility:** Both are negative, indicating poor solubility. Again, the scale is not specified.

**11. hERG Inhibition:** Both ligands show very low hERG inhibition risk (0.449 and 0.13).

**12. Microsomal Clearance:** Both ligands have similar microsomal clearance rates (20.413 and 21.853).

**13. In vitro Half-Life:** Ligand A (-4.866) has a much better (longer) in vitro half-life than Ligand B (47.454).

**14. P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.141 and 0.357).

**15. Binding Affinity:** Both ligands have very similar and excellent binding affinities (-7.8 and -7.7 kcal/mol). The difference is negligible.

**Overall Assessment:**

Ligand A is clearly superior due to its significantly better TPSA, DILI risk, BBB penetration, and in vitro half-life. While both ligands have good logP, QED, hERG, P-gp, and binding affinity, the ADME properties of Ligand A are much more favorable for a CNS-targeting drug. The lower TPSA and higher BBB are particularly important for DRD2.

Output:
1
2025-04-17 06:49:46,213 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (351.447 Da) and Ligand B (339.439 Da) are both acceptable.

**TPSA:** Both ligands have TPSA values below 90, which is good for CNS penetration. Ligand A (82.11) is slightly higher than Ligand B (73.99), but both are favorable.

**logP:** Ligand A (-0.56) is a bit low, potentially hindering permeation. Ligand B (2.885) is within the optimal range (1-3). This is a significant advantage for Ligand B.

**H-Bond Donors/Acceptors:** Ligand A (2 HBD, 5 HBA) and Ligand B (3 HBD, 2 HBA) both fall within acceptable limits.

**QED:** Both ligands have good QED scores (A: 0.694, B: 0.783), indicating drug-like properties.

**DILI:** Ligand A (4.769) has a very low DILI risk, which is excellent. Ligand B (59.984) is approaching a higher risk level, though not critically high.

**BBB:** Ligand A (49.864) has a moderate BBB penetration score. Ligand B (55.642) is also moderate, but slightly better. Both are below the desirable >70 for CNS targets, but Ligand B is marginally better.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.05 and -5.036), which is unusual and suggests poor permeability. This is a significant concern for both.

**Aqueous Solubility:** Both ligands have negative solubility values (-0.933 and -4.324), indicating very poor aqueous solubility. This is a major issue for both compounds.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (A: 0.142, B: 0.51).

**Microsomal Clearance:** Ligand A (-33.453) has a much lower (better) microsomal clearance than Ligand B (27.528), indicating greater metabolic stability.

**In vitro Half-Life:** Ligand B (15.328 hours) has a significantly longer half-life than Ligand A (5.916 hours). This is a substantial advantage for Ligand B.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (A: 0.003, B: 0.302), which is favorable for CNS exposure.

**Binding Affinity:** Both ligands have strong binding affinities (A: -8.6 kcal/mol, B: -9.4 kcal/mol). Ligand B is slightly stronger, but the difference is relatively small.

**Overall Assessment:**

Ligand B is the more promising candidate. While both have solubility and permeability issues (negative Caco-2 and solubility values), Ligand B has a more favorable logP, a longer half-life, and slightly better BBB penetration. The slightly stronger binding affinity of Ligand B is a bonus. Ligand A's advantage is its lower DILI risk and better metabolic stability, but the other ADME properties of Ligand B are more favorable for a CNS-targeting GPCR ligand. The solubility and permeability issues would need to be addressed in either case through formulation or further chemical modifications.

Output:
1
2025-04-17 06:49:46,214 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (341.455 Da) is slightly lower, which could be beneficial for permeability.

**TPSA:** Ligand A (52.65) is significantly better than Ligand B (84.94). For CNS targets, we want TPSA <= 90, and ideally closer to 60. Ligand A is much closer to the ideal range.

**logP:** Ligand A (2.736) is optimal (1-3). Ligand B (0.331) is quite low, potentially hindering permeation and reducing binding affinity.

**H-Bond Donors/Acceptors:** Both have acceptable HBD (1) and HBA (A: 3, B: 5) counts.

**QED:** Ligand A (0.916) has a much better QED score than Ligand B (0.551), indicating a more drug-like profile.

**DILI:** Both have relatively low DILI risk (A: 22.838, B: 29.391), but A is slightly better.

**BBB:** Ligand A (92.09) has excellent BBB penetration, exceeding the desirable >70 threshold. Ligand B (59.403) is considerably lower, a significant drawback for a CNS target.

**Caco-2 Permeability:** Ligand A (-4.764) is better than Ligand B (-4.484), suggesting better intestinal absorption.

**Aqueous Solubility:** Ligand A (-2.259) is better than Ligand B (-0.852), which is important for formulation.

**hERG Inhibition:** Ligand A (0.798) has a lower hERG risk than Ligand B (0.068).

**Microsomal Clearance:** Ligand A (0.949) has lower clearance than Ligand B (19.098), indicating better metabolic stability.

**In vitro Half-Life:** Ligand A (52.876) has a much longer half-life than Ligand B (-33.129).

**P-gp Efflux:** Ligand A (0.084) has lower P-gp efflux than Ligand B (0.017), which is favorable for CNS exposure.

**Binding Affinity:** Ligand A (-9.5 kcal/mol) has a significantly stronger binding affinity than Ligand B (-7.8 kcal/mol). This >1.5 kcal/mol difference is substantial and can outweigh minor ADME drawbacks.

**Overall:**

Ligand A consistently outperforms Ligand B across almost all relevant parameters, especially those prioritized for GPCRs targeting the CNS. The superior BBB penetration, logP, metabolic stability, half-life, P-gp efflux, and significantly stronger binding affinity of Ligand A make it a much more promising drug candidate. Ligand B's low logP and poor BBB penetration are major concerns.

Output:
1
2025-04-17 06:49:46,214 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (356.491 and 345.487 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (45.48) is significantly better than Ligand B (58.36). For CNS targets, TPSA should be <= 90, both are well within this, but A is preferable.

**3. logP:** Both ligands have good logP values (3.927 and 3.464), falling within the optimal 1-3 range.

**4. H-Bond Donors:** Both have 1 HBD, which is acceptable.

**5. H-Bond Acceptors:** Both have 4 HBA, which is acceptable.

**6. QED:** Both ligands have good QED scores (0.797 and 0.912), indicating good drug-like properties. Ligand B is slightly better here.

**7. DILI:** Ligand A (35.75) has a slightly higher DILI risk than Ligand B (21.442), but both are below the concerning threshold of 60.

**8. BBB:** Both ligands have excellent BBB penetration (74.719 and 73.866), exceeding the desirable 70% for CNS targets. They are very similar here.

**9. Caco-2 Permeability:** Ligand A (-5.397) is worse than Ligand B (-4.641) - lower values indicate lower permeability.

**10. Aqueous Solubility:** Ligand A (-3.409) is worse than Ligand B (-2.851) - lower values indicate lower solubility.

**11. hERG Inhibition:** Both ligands show low hERG inhibition risk (0.861 and 0.493), which is good. Ligand B is better.

**12. Microsomal Clearance:** Ligand A (24.164) has a higher microsomal clearance than Ligand B (21.969), indicating lower metabolic stability.

**13. In vitro Half-Life:** Ligand B (5.977) has a slightly longer in vitro half-life than Ligand A (47.051) - note the units are inconsistent here and the value for A appears to be an error. Assuming the units for A are also hours, B is preferable.

**14. P-gp Efflux:** Ligand A (0.413) has lower P-gp efflux than Ligand B (0.557), which is favorable for CNS penetration.

**15. Binding Affinity:** Both ligands have excellent binding affinities (-8.7 and -8.5 kcal/mol). The difference of 0.2 kcal/mol is not substantial enough to override other factors.

**Overall Assessment:**

Considering the GPCR-specific priorities, Ligand B is slightly more favorable. While Ligand A has better P-gp efflux, Ligand B demonstrates better solubility, Caco-2 permeability, DILI risk, and in vitro half-life. The TPSA value of Ligand A is also more favorable. The binding affinity difference is negligible. Given the importance of good ADME properties for CNS drugs, the slight advantages of Ligand B outweigh the benefit of lower P-gp efflux in Ligand A.

Output:
1
2025-04-17 06:49:46,214 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (345.403 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (118.09) is slightly above the optimal <90 for CNS targets, but acceptable. Ligand B (95.33) is well within the desired range. This favors Ligand B.

**3. logP:** Ligand A (0.379) is quite low, potentially hindering membrane permeability. Ligand B (1.715) is better, falling within the optimal 1-3 range. This favors Ligand B.

**4. H-Bond Donors:** Ligand A (3) is acceptable. Ligand B (1) is even better, potentially improving permeability. This favors Ligand B.

**5. H-Bond Acceptors:** Ligand A (4) is acceptable. Ligand B (5) is also acceptable.

**6. QED:** Both ligands have good QED scores (A: 0.662, B: 0.91), indicating drug-like properties. Ligand B is slightly better.

**7. DILI:** Ligand A (46.956) has a lower DILI risk than Ligand B (63.746), which is a positive for Ligand A.

**8. BBB:** Ligand A (28.306) has a poor BBB percentile, making CNS penetration unlikely. Ligand B (43.001) is significantly better, though still not ideal (aim for >70). This strongly favors Ligand B.

**9. Caco-2:** Both have negative Caco-2 values, which is unusual and difficult to interpret without knowing the scale. However, the magnitude suggests poor permeability for both.

**10. Solubility:** Both have negative solubility values, again making comparison difficult.

**11. hERG:** Both ligands have very low hERG risk (A: 0.419, B: 0.432).

**12. Cl_mic:** Ligand A (-35.059) shows a negative value, which is unusual and likely indicates very *low* metabolic clearance (highly stable). Ligand B (27.326) shows moderate metabolic clearance. This favors Ligand A.

**13. t1/2:** Ligand A (4.206) has a short half-life. Ligand B (-49.582) has a very short half-life, which is concerning.

**14. Pgp:** Both ligands have very low Pgp efflux liability (A: 0.019, B: 0.088).

**15. Binding Affinity:** Ligand B (-7.1 kcal/mol) has a significantly stronger binding affinity than Ligand A (-8.3 kcal/mol). This is a major advantage for Ligand B.

**Overall Assessment:**

While Ligand A has a lower DILI risk and potentially better metabolic stability (negative Cl_mic), its poor BBB penetration and low logP are significant drawbacks for a CNS target like DRD2. Ligand B, despite a slightly higher DILI risk, excels in key areas for CNS drug development: better TPSA, logP, and, crucially, a much better BBB percentile and significantly stronger binding affinity. The stronger binding affinity can often compensate for minor ADME deficiencies.

Output:
1
2025-04-17 06:49:46,214 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (347.5) is slightly lower, which could be favorable for permeability.

**TPSA:** Ligand A (38.77) is excellent for CNS penetration, well below the 90 A^2 threshold. Ligand B (75.94) is higher but still reasonable, though less ideal for CNS targets.

**logP:** Ligand A (4.073) is at the higher end of the optimal range, potentially leading to solubility issues. Ligand B (2.69) is well within the optimal range.

**H-Bond Donors/Acceptors:** Ligand A (0 HBD, 3 HBA) is favorable. Ligand B (1 HBD, 7 HBA) is also acceptable, though slightly higher in HBA count.

**QED:** Both ligands have good QED values (A: 0.599, B: 0.768), indicating drug-like properties.

**DILI:** Both ligands have acceptable DILI risk (A: 29.2, B: 67.3). Ligand A is significantly better.

**BBB:** Ligand A (64.1%) is good, but Ligand B (70.4%) is better, exceeding the 70% threshold desirable for CNS targets.

**Caco-2:** Ligand A (-4.612) is very poor, suggesting poor intestinal absorption. Ligand B (-5.319) is also poor, but slightly better than A.

**Solubility:** Both ligands have poor aqueous solubility (-3.72 and -3.095 respectively).

**hERG:** Both ligands have low hERG inhibition risk (A: 0.769, B: 0.454). Ligand B is better.

**Microsomal Clearance:** Ligand A (88.923) has higher clearance, indicating lower metabolic stability. Ligand B (40.046) has significantly lower clearance, which is a major advantage.

**In vitro Half-Life:** Ligand B (10.878 hours) has a longer half-life than Ligand A (7.884 hours).

**P-gp Efflux:** Ligand A (0.852) has higher P-gp efflux, which is undesirable for CNS penetration. Ligand B (0.117) has very low P-gp efflux, a significant advantage.

**Binding Affinity:** Ligand A (-7.7 kcal/mol) has a slightly better binding affinity than Ligand B (-7.4 kcal/mol). This 0.3 kcal/mol difference is potentially significant.

**Overall Assessment:**

While Ligand A has slightly better binding affinity and a lower DILI risk, Ligand B demonstrates superior ADME properties crucial for a CNS-targeting GPCR ligand. Specifically, its better BBB penetration, lower P-gp efflux, significantly lower microsomal clearance (longer half-life), and acceptable logP outweigh the slight difference in binding affinity. The poor Caco-2 values for both are a concern, but less critical for a CNS-focused drug. The higher TPSA of Ligand B is less ideal, but still within a reasonable range.

Output:
1
2025-04-17 06:49:46,214 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (344.415 and 346.515 Da) fall comfortably within the ideal 200-500 Da range.

**TPSA:** Ligand A (78.53) is significantly better than Ligand B (49.41). For a CNS target like DRD2, a TPSA below 90 is desirable, and A is closer to this threshold.

**logP:** Ligand A (1.064) is within the optimal 1-3 range. Ligand B (3.953) is at the higher end, potentially leading to solubility issues or off-target interactions, but still acceptable.

**H-Bond Donors/Acceptors:** Both have 1 HBD, which is good. Ligand A has 4 HBA, and Ligand B has 2. Both are within the acceptable limits (<=10).

**QED:** Both ligands have reasonable QED scores (0.829 and 0.784), indicating good drug-like properties.

**DILI:** Ligand A (42.691) has a slightly higher DILI risk than Ligand B (30.593), but both are below the concerning threshold of 60.

**BBB:** Ligand A (80.419) has a better BBB penetration percentile than Ligand B (78.558), which is crucial for a CNS target. Although both are good, A is preferable.

**Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and suggests poor permeability. However, the scale is not specified, so it is difficult to interpret.

**Aqueous Solubility:** Both have negative solubility values, which is also unusual. This suggests poor aqueous solubility.

**hERG Inhibition:** Both ligands have low hERG inhibition liability (0.418 and 0.319), which is good.

**Microsomal Clearance:** Ligand A (25.329) has a lower microsomal clearance than Ligand B (59.863), indicating better metabolic stability.

**In vitro Half-Life:** Ligand A (-17.052) has a *negative* half-life, which is impossible. This is a significant red flag. Ligand B (-1.734) also has a negative half-life, which is also a red flag.

**P-gp Efflux:** Ligand A (0.069) has much lower P-gp efflux liability than Ligand B (0.409), which is highly desirable for CNS penetration.

**Binding Affinity:** Ligand A (-8.2 kcal/mol) has a significantly stronger binding affinity than Ligand B (-0.0 kcal/mol). This is a major advantage, potentially outweighing some of the ADME drawbacks.

**Overall Assessment:**

Despite the unusual negative values for Caco-2 and solubility, the most significant factor is the binding affinity. Ligand A binds *much* more strongly to DRD2. The better BBB penetration, lower P-gp efflux, and lower microsomal clearance of Ligand A further support its selection. The negative half-life is a major concern, but could be an artifact of the data. Ligand B's affinity is essentially non-existent.

Output:
1
2025-04-17 06:49:46,215 - INFO - Batch 314 complete. Total preferences: 5024
2025-04-17 06:49:46,215 - INFO - Processing batch 315/512...
2025-04-17 06:50:39,373 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (353.442 and 363.439 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (79.26) is significantly better than Ligand B (92.51). For CNS targets, we want TPSA <= 90, so Ligand A is preferable.

**logP:** Ligand A (0.529) is a bit low, potentially hindering permeability, while Ligand B (1.024) is better, falling within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A has 2 HBD and 5 HBA, which is good. Ligand B has 1 HBD and 6 HBA, also acceptable.

**QED:** Both ligands have good QED scores (0.679 and 0.859), indicating drug-like properties.

**DILI:** Ligand A (30.516) has a much lower DILI risk than Ligand B (59.131). This is a significant advantage for Ligand A.

**BBB:** Ligand A (83.676) has a substantially better BBB penetration score than Ligand B (71.229).  This is *critical* for a CNS target like DRD2.

**Caco-2 Permeability:** Ligand A (-4.863) and Ligand B (-5.141) both have negative values, which is unusual and suggests poor permeability. However, the scale isn't defined, so it's hard to interpret.

**Aqueous Solubility:** Ligand A (-1.385) and Ligand B (-3.497) both have negative solubility values, suggesting poor solubility.

**hERG Inhibition:** Ligand A (0.225) has a much lower hERG inhibition liability than Ligand B (0.06). This is a significant safety advantage for Ligand A.

**Microsomal Clearance:** Ligand A (25.572) has a higher microsomal clearance than Ligand B (21.98), suggesting faster metabolism. This is a slight disadvantage for Ligand A.

**In vitro Half-Life:** Ligand A (-3.915) has a much longer in vitro half-life than Ligand B (-19.164). This is a significant advantage for Ligand A.

**P-gp Efflux:** Ligand A (0.01) has a much lower P-gp efflux liability than Ligand B (0.087). This is very important for CNS penetration.

**Binding Affinity:** Both ligands have very similar and excellent binding affinities (-7.9 and -7.7 kcal/mol). The difference is negligible.

**Overall Assessment:**

Ligand A is clearly superior. While Ligand B has a slightly better logP, Ligand A excels in almost all other critical parameters, especially those prioritized for GPCRs targeting the CNS: BBB penetration, DILI risk, hERG inhibition, P-gp efflux, and in vitro half-life. The TPSA is also significantly better for Ligand A. The similar binding affinities make these ADME properties the deciding factors.

Output:
1
2025-04-17 06:50:39,373 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (385.823 Da) is slightly higher than Ligand B (354.382 Da), but both are acceptable.

**TPSA:** Ligand A (62.39) is excellent for CNS penetration, being well below the 90 A^2 threshold. Ligand B (87.91) is still reasonable, but less optimal.

**logP:** Ligand A (3.867) is at the upper end of the optimal range (1-3), potentially raising concerns about solubility and off-target effects. Ligand B (-0.016) is significantly below the optimal range and could have permeability issues.

**H-Bond Donors/Acceptors:** Ligand A (3 HBD, 3 HBA) is well within the acceptable limits. Ligand B (1 HBD, 6 HBA) is also acceptable, though the higher HBA count could slightly impact permeability.

**QED:** Both ligands have good QED scores (Ligand A: 0.659, Ligand B: 0.818), indicating drug-like properties.

**DILI:** Ligand A (81.078) has a higher DILI risk than Ligand B (54.323), which is preferable.

**BBB:** Ligand B (78.713) has a significantly better BBB percentile than Ligand A (64.211). This is a crucial factor for a CNS target like DRD2.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values which is unusual and suggests poor permeability.

**Aqueous Solubility:** Both ligands have negative solubility values, which is also unusual and suggests poor solubility.

**hERG:** Ligand A (0.663) has a slightly higher hERG risk than Ligand B (0.153), which is preferable.

**Microsomal Clearance:** Ligand B (0.065) has a much lower microsomal clearance than Ligand A (20.726), indicating better metabolic stability.

**In vitro Half-Life:** Ligand B (-23.934) has a negative half-life, which is nonsensical. Ligand A (65.55) has a good in vitro half-life.

**P-gp Efflux:** Ligand A (0.366) has lower P-gp efflux liability than Ligand B (0.02), which is preferable for CNS penetration.

**Binding Affinity:** Ligand B (-7.7 kcal/mol) has a significantly stronger binding affinity than Ligand A (-9.3 kcal/mol). This is a substantial advantage.

**Overall Assessment:**

While Ligand A has better hERG and P-gp efflux, Ligand B's superior BBB penetration, significantly stronger binding affinity, and lower DILI risk are more important for a CNS GPCR target. The lower clearance of Ligand B is also a significant advantage. The negative values for Caco-2 and solubility are concerning for both, but the binding affinity difference is substantial enough to prioritize Ligand B.

Output:
1
2025-04-17 06:50:39,374 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (342.443 and 355.507 Da) fall within the ideal range of 200-500 Da.

**TPSA:** Ligand A (67.23) is significantly better than Ligand B (38.25). For CNS targets, we want TPSA <= 90, and ideally closer to 60. Ligand A is closer to this ideal.

**logP:** Ligand A (1.685) is within the optimal 1-3 range. Ligand B (4.061) is pushing the upper limit and could potentially lead to solubility issues or off-target interactions.

**H-Bond Donors/Acceptors:** Ligand A has 1 HBD and 4 HBA, while Ligand B has 0 HBD and 5 HBA. Both are within acceptable limits (<=5 HBD and <=10 HBA).

**QED:** Both ligands have good QED scores (0.606 and 0.751, respectively), indicating good drug-like properties.

**DILI:** Ligand A (32.726) has a slightly higher DILI risk than Ligand B (24.544), but both are below the 40 threshold and considered good.

**BBB:** Ligand B (88.833) has a significantly better BBB penetration score than Ligand A (70.415). This is a crucial factor for CNS targets like DRD2.

**Caco-2 Permeability:** Both have negative values, which is unusual. Assuming these are logP-scale values, lower values indicate poorer permeability. They are similarly poor.

**Aqueous Solubility:** Both ligands have negative solubility values which is also unusual. Assuming these are logS values, lower values indicate poorer solubility. They are similarly poor.

**hERG Inhibition:** Ligand A (0.086) has a much lower hERG inhibition liability than Ligand B (0.869), making it safer from a cardiotoxicity perspective.

**Microsomal Clearance:** Ligand A (24.6 mL/min/kg) has a lower microsomal clearance than Ligand B (57.936 mL/min/kg), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (-10.695) has a negative half-life, which is not physically possible. This is likely an error in the data. Ligand B (16.816) has a reasonable half-life.

**P-gp Efflux:** Ligand A (0.051) has lower P-gp efflux liability than Ligand B (0.654), which is favorable for CNS penetration.

**Binding Affinity:** Ligand A (-7.8 kcal/mol) has a slightly better binding affinity than Ligand B (-7.2 kcal/mol). While both are good, the 1.5 kcal/mol difference is significant enough to consider.

**Overall Assessment:**

Ligand A excels in TPSA, logP, hERG, metabolic stability (Cl_mic), and P-gp efflux. Its binding affinity is also slightly better. The biggest drawback is the negative half-life value, which is likely a data error. Ligand B shines in BBB penetration, but suffers from a higher logP, higher hERG risk, and poorer metabolic stability.

Given the GPCR-specific priorities, especially BBB, and the strong binding affinity of Ligand A, I would lean towards Ligand A *if* the half-life data can be corrected. The better TPSA, logP, and safety profile (hERG) also contribute to its favorability. The difference in BBB is not enough to outweigh the other advantages of Ligand A.

Output:
0
2025-04-17 06:50:39,374 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (367.471 and 381.523 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (100.55) is slightly above the optimal <90 for CNS targets, while Ligand B (92.5) is closer to the ideal range.

**logP:** Ligand A (0.689) is a bit low, potentially hindering permeation. Ligand B (1.136) is better, falling within the 1-3 optimal range.

**H-Bond Donors/Acceptors:** Ligand A has 3 HBD and 6 HBA, which are acceptable. Ligand B has 2 HBD and 5 HBA, also acceptable.

**QED:** Both ligands have good QED scores (0.658 and 0.741, respectively), indicating drug-like properties.

**DILI:** Ligand A (54.323) has a slightly higher DILI risk than Ligand B (36.293), but both are reasonably low.

**BBB:** This is a critical parameter for CNS targets. Ligand B (74.486) has a significantly better BBB percentile than Ligand A (41.024). This is a major advantage for Ligand B.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.36 and -5.605), which is unusual and suggests poor permeability. However, these values are on a log scale, and the negative values are not directly comparable without knowing the base of the log.

**Aqueous Solubility:** Both ligands have negative solubility values (-1.048 and -2.242), indicating poor aqueous solubility. This could be a formulation challenge.

**hERG Inhibition:** Both ligands show very low hERG inhibition risk (0.059 and 0.189).

**Microsomal Clearance:** Ligand A (9.56) has lower microsomal clearance than Ligand B (24.107), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (24.223) has a longer in vitro half-life than Ligand B (-19.648). The negative value for Ligand B is concerning and likely indicates rapid degradation.

**P-gp Efflux:** Both ligands show very low P-gp efflux liability (0.016 and 0.097).

**Binding Affinity:** Ligand B (-8.3 kcal/mol) has a slightly better binding affinity than Ligand A (-7.5 kcal/mol). While the difference is less than the 1.5 kcal/mol threshold, it's still a positive factor.

**Overall Assessment:**

Ligand B is the more promising candidate. Its significantly better BBB penetration is crucial for a CNS target like DRD2. The slightly better logP and binding affinity also contribute to its favorability. While Ligand A has better metabolic stability and half-life, the BBB is the deciding factor here. The negative Caco-2 and solubility values for both are concerning, but can potentially be addressed through formulation strategies. The negative half-life for Ligand B is a significant red flag.

Output:
1
2025-04-17 06:50:39,374 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (350.379 Da) is slightly lower, which is generally favorable for permeability. Ligand B (363.755 Da) is also good.

**TPSA:** Ligand A (118.45) is better than Ligand B (72.7). For CNS targets, TPSA should be <=90, so Ligand B is significantly better in this regard.

**logP:** Ligand A (-0.483) is suboptimal. A logP between 1-3 is preferred, and this is below 1, potentially hindering permeation. Ligand B (3.57) is excellent, falling within the optimal range.

**H-Bond Donors/Acceptors:** Ligand A (2 HBD, 7 HBA) is better than Ligand B (1 HBD, 5 HBA) in terms of balancing solubility and permeability. Both are within acceptable limits.

**QED:** Both ligands have similar QED values (0.74 and 0.703), indicating good drug-like properties.

**DILI:** Ligand A (64.056) has a lower DILI risk than Ligand B (94.378), which is a significant advantage.

**BBB:** Both ligands have good BBB penetration (Ligand A: 58.434, Ligand B: 69.678). Ligand B is slightly better, but both are below the desirable >70 threshold for CNS targets.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.046 and -4.938). This is unusual and suggests poor permeability.

**Aqueous Solubility:** Both ligands have negative solubility values (-1.638 and -4.82). This is also unusual and suggests poor solubility.

**hERG Inhibition:** Ligand A (0.047) has a very low hERG risk, which is excellent. Ligand B (0.22) is slightly higher but still relatively low.

**Microsomal Clearance:** Ligand A (-28.981) has a much lower (better) microsomal clearance than Ligand B (44.853), indicating greater metabolic stability.

**In vitro Half-Life:** Ligand A (-15.919) has a negative half-life, which is unusual and suggests rapid degradation. Ligand B (2.538) has a short half-life, but it is a positive value.

**P-gp Efflux:** Ligand A (0.007) has very low P-gp efflux, which is excellent for CNS penetration. Ligand B (0.204) is slightly higher, but still reasonable.

**Binding Affinity:** Ligand B (-9.8 kcal/mol) has a significantly stronger binding affinity than Ligand A (-8.5 kcal/mol). This >1.5 kcal/mol difference is a major advantage.

**Overall Assessment:**

Ligand B is superior due to its significantly better binding affinity and optimal logP. While Ligand A has advantages in DILI, hERG, and P-gp efflux, the strong binding affinity of Ligand B outweighs these benefits, especially for a GPCR target where potency is crucial. The TPSA of Ligand B is also much better. The negative values for Caco-2 and solubility are concerning for both, but the potency advantage of Ligand B is substantial.

Output:
1
2025-04-17 06:50:39,374 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (361.829 and 384.523 Da) fall within the ideal 200-500 Da range.

**TPSA:** Both ligands have TPSA values (82.53 and 82.78) slightly above the optimal 90 for CNS targets, but still reasonably acceptable.

**logP:** Ligand A (3.137) is slightly higher than Ligand B (1.805). Both are within the 1-3 optimal range, but Ligand B is closer to the lower bound, which *could* indicate permeability issues.

**H-Bond Donors/Acceptors:** Both have 2 HBDs, which is good. Ligand A has 4 HBAs, and Ligand B has 6. Both are within the acceptable limit of 10, but Ligand A is slightly better.

**QED:** Both ligands have good QED scores (0.791 and 0.806), indicating good drug-like properties.

**DILI:** Ligand A (84.374) has a higher DILI risk than Ligand B (45.25). This is a significant drawback for Ligand A.

**BBB:** Ligand A (38.852) has a very low BBB penetration percentile, making it unlikely to effectively reach the target in the CNS. Ligand B (36.216) also has a low BBB percentile, but it is slightly better than Ligand A.

**Caco-2 Permeability:** Both have negative Caco-2 values (-5.281 and -5.163), which is unusual and suggests poor permeability. This is a concern for both compounds.

**Aqueous Solubility:** Both have very poor aqueous solubility (-3.505 and -3.438). This could pose formulation challenges.

**hERG Inhibition:** Both have very low hERG inhibition liability (0.046 and 0.167), which is excellent.

**Microsomal Clearance:** Ligand A (18.919) has lower microsomal clearance than Ligand B (23.872), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (11.978) has a slightly longer half-life than Ligand B (10.306).

**P-gp Efflux:** Both have very low P-gp efflux liability (0.038), which is favorable for CNS penetration.

**Binding Affinity:** Ligand A (-8.7 kcal/mol) has a significantly stronger binding affinity than Ligand B (-7.6 kcal/mol). This is a 1.1 kcal/mol difference, which is substantial and could outweigh some of the ADME drawbacks.

**Overall Assessment:**

Ligand A has a much better binding affinity, better metabolic stability, and a slightly longer half-life. However, it suffers from a significantly higher DILI risk and critically, *very* poor BBB penetration. Ligand B has a lower DILI risk, but its binding affinity is weaker, and its BBB penetration is also poor.

Given the CNS target (DRD2), BBB penetration is paramount. While both compounds struggle in this area, Ligand A's extremely low BBB score, combined with the higher DILI risk, makes it a less attractive candidate despite its superior affinity. The slightly better BBB score of Ligand B, coupled with its lower DILI risk, makes it marginally more promising, even with the weaker binding. Further optimization would be needed to improve the BBB penetration and Caco-2 permeability of both compounds.

Output:
1
2025-04-17 06:50:39,374 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (386.546 and 379.781 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (98.54) is higher than the preferred <90 for CNS targets, but not drastically so. Ligand B (29.54) is excellent, well below the threshold.

**3. logP:** Ligand A (2.936) is within the optimal 1-3 range. Ligand B (4.004) is slightly above, potentially leading to solubility issues or off-target interactions, but still acceptable.

**4. H-Bond Donors:** Ligand A (1) and Ligand B (0) are both within the acceptable limit of <=5.

**5. H-Bond Acceptors:** Ligand A (5) and Ligand B (2) are both within the acceptable limit of <=10.

**6. QED:** Both ligands have good QED scores (0.421 and 0.552), indicating reasonable drug-likeness. Ligand B is slightly better.

**7. DILI:** Ligand A (68.903) has a higher DILI risk than Ligand B (37.999), which is preferable.

**8. BBB:** Ligand A (72.819) and Ligand B (88.406) both have good BBB penetration, exceeding the 70% threshold for CNS targets. Ligand B is better.

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 values, which is unusual and suggests poor permeability. This is a significant concern for both.

**10. Aqueous Solubility:** Both ligands have negative solubility values, which is also unusual and indicates very poor solubility. This is a major drawback for both.

**11. hERG Inhibition:** Both ligands show low hERG inhibition risk (0.819 and 0.653), which is good.

**12. Microsomal Clearance:** Ligand A (91.463) has higher microsomal clearance than Ligand B (88.615), indicating lower metabolic stability.

**13. In vitro Half-Life:** Ligand B (-25.752) has a significantly longer predicted half-life than Ligand A (-11.448).

**14. P-gp Efflux:** Ligand A (0.598) has a slightly higher P-gp efflux liability than Ligand B (0.233), meaning Ligand B is more likely to cross the BBB and have better oral bioavailability.

**15. Binding Affinity:** Ligand B (-7.8 kcal/mol) has a significantly stronger binding affinity than Ligand A (-0.0 kcal/mol). This is a crucial advantage, potentially outweighing some of the ADME concerns.

**Overall Assessment:**

While both ligands have issues with Caco-2 permeability and aqueous solubility, Ligand B is the stronger candidate. Its superior binding affinity, better BBB penetration, lower DILI risk, longer half-life, and lower P-gp efflux outweigh the slightly higher logP. The large difference in binding affinity is a key factor. The poor solubility and permeability would need to be addressed through formulation strategies or further chemical modifications, but the strong binding and favorable CNS properties make Ligand B a more promising starting point.

Output:
1
2025-04-17 06:50:39,374 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B based on the provided guidelines, prioritizing GPCR-specific properties (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (368.455 and 354.422 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (85.89) is slightly above the optimal <90 for CNS targets, while Ligand B (68.73) is well within the range. This favors Ligand B.

**logP:** Both ligands have logP values (2.491 and 2.742) within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A has 2 HBD and 6 HBA, while Ligand B has 0 HBD and 5 HBA. Both are within acceptable limits.

**QED:** Both ligands have good QED scores (0.517 and 0.646), indicating drug-like properties.

**DILI:** Ligand A has a DILI risk of 65.103, which is moderately high. Ligand B has a much lower DILI risk (29.314), a significant advantage.

**BBB:** Ligand A has a BBB penetration of 65.452, which is acceptable but not ideal for a CNS target. Ligand B has a significantly higher BBB penetration (82.396), making it more promising for CNS activity.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.811 and -4.037), which is unusual and suggests poor permeability. However, these values are on a scale where negative values are possible, and the absolute magnitude isn't directly interpretable without knowing the scale's specifics.

**Aqueous Solubility:** Both ligands have negative solubility values (-3.095 and -1.668), which is also unusual and suggests poor solubility. Similar to Caco-2, the scale is needed for proper interpretation.

**hERG:** Both ligands have low hERG inhibition liability (0.662 and 0.303), which is favorable.

**Microsomal Clearance:** Ligand A has a lower microsomal clearance (51.936) than Ligand B (81.569), indicating better metabolic stability.

**In vitro Half-Life:** Ligand A has a longer half-life (5.325 hours) than Ligand B (2.884 hours).

**P-gp Efflux:** Ligand A has a slightly higher P-gp efflux liability (0.158) than Ligand B (0.096), which is less desirable.

**Binding Affinity:** Ligand A has a better binding affinity (-7.1 kcal/mol) than Ligand B (-6.7 kcal/mol). This is a substantial difference and a major advantage for Ligand A.

**Overall Assessment:**

While Ligand A has a superior binding affinity and better metabolic stability/half-life, Ligand B excels in crucial areas for CNS GPCR targets: TPSA, BBB penetration, and DILI risk. The difference in binding affinity (-0.4 kcal/mol) is significant, but the improved CNS penetration and reduced toxicity of Ligand B are compelling. Given the importance of BBB penetration for CNS targets like DRD2, and the lower DILI risk, Ligand B appears to be the more viable drug candidate.

Output:
1
2025-04-17 06:50:39,374 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (351.451 and 358.404 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (93.78) is better than Ligand B (49.41) as it is closer to the <90 threshold for CNS targets. Ligand B is very low, which might indicate poor interactions with the receptor.

**logP:** Ligand A (-1.477) is suboptimal, being below the ideal 1-3 range. Ligand B (3.094) is within the optimal range. This favors Ligand B.

**H-Bond Donors/Acceptors:** Ligand A has 3 HBD and 5 HBA, which are acceptable. Ligand B has 1 HBD and 4 HBA, also acceptable.

**QED:** Both ligands have reasonable QED values (0.464 and 0.794), indicating drug-like properties, with Ligand B being better.

**DILI:** Ligand A (12.059) has a significantly lower DILI risk than Ligand B (57.697), which is a strong advantage for Ligand A.

**BBB:** Ligand B (93.757) has a much higher BBB penetration percentile than Ligand A (28.693). This is a critical advantage for a CNS target like DRD2.

**Caco-2 Permeability:** Ligand A (-5.919) and Ligand B (-4.723) both have negative values, which is unusual and suggests poor permeability.

**Aqueous Solubility:** Ligand A (-0.667) and Ligand B (-4.954) both have negative values, indicating poor solubility.

**hERG:** Ligand A (0.124) has a lower hERG inhibition liability than Ligand B (0.916), which is preferable.

**Microsomal Clearance:** Ligand A (-25.067) has a much lower (better) microsomal clearance than Ligand B (30.676), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand B (36.116) has a significantly longer half-life than Ligand A (7.044), which is desirable.

**P-gp Efflux:** Ligand A (0.001) has a much lower P-gp efflux liability than Ligand B (0.399), which is a significant advantage for CNS penetration.

**Binding Affinity:** Ligand B (-9.4 kcal/mol) has a stronger binding affinity than Ligand A (-7.8 kcal/mol). This is a substantial advantage, potentially outweighing some ADME drawbacks.

**Overall Assessment:**

Ligand B excels in BBB penetration and binding affinity, which are crucial for a CNS GPCR target. It also has a better QED and half-life. However, it suffers from higher DILI risk and P-gp efflux. Ligand A has better DILI, hERG, P-gp, and clearance profiles, but its BBB penetration is poor and its affinity is weaker.

Given the importance of CNS penetration and strong binding for DRD2, the superior affinity and BBB of Ligand B are decisive. While the DILI and P-gp efflux are concerns, they might be addressed through further optimization. The weaker affinity of Ligand A is a more fundamental issue.

Output:
1
2025-04-17 06:50:39,374 - INFO - Okay, let's analyze these two ligands for their potential as DRD2 drug candidates. DRD2 is a GPCR in the CNS, so BBB penetration, logP, Pgp efflux, TPSA, and binding affinity are paramount.

**Ligand A: [398.304, 47.04, 4.672, 1, 4, 0.588, 54.944, 53.16, -5.26, -3.91, 0.954, 41.483, 14.218, 0.675, -8.6]**

*   **MW:** 398.304 Da - Good, within the ideal range.
*   **TPSA:** 47.04 A<sup>2</sup> - Excellent, well below the 90 A<sup>2</sup> threshold for CNS targets.
*   **logP:** 4.672 - Slightly high, potentially leading to solubility issues or off-target interactions, but not drastically so.
*   **HBD:** 1 - Good.
*   **HBA:** 4 - Good.
*   **QED:** 0.588 - Good, above the 0.5 threshold.
*   **DILI:** 54.944 - Moderate risk, but acceptable.
*   **BBB:** 53.16 - Marginal for CNS, ideally >70. This is a significant drawback.
*   **Caco-2:** -5.26 - Very poor permeability. A major issue.
*   **Solubility:** -3.91 - Very poor solubility. A major issue.
*   **hERG:** 0.954 - Relatively low risk.
*   **Cl_mic:** 41.483 mL/min/kg - Moderate clearance, suggesting moderate metabolic stability.
*   **t1/2:** 14.218 hours - Good in vitro half-life.
*   **Pgp:** 0.675 - Moderate P-gp efflux, could limit CNS exposure.
*   **Affinity:** -8.6 kcal/mol - Excellent binding affinity.

**Ligand B: [352.519, 67.43, 3.197, 2, 3, 0.593, 27.801, 69.407, -4.868, -2.998, 0.376, 58.155, 8.406, 0.096, -7.5]**

*   **MW:** 352.519 Da - Good, within the ideal range.
*   **TPSA:** 67.43 A<sup>2</sup> - Acceptable, but higher than Ligand A. Still potentially okay for CNS.
*   **logP:** 3.197 - Good, within the optimal range.
*   **HBD:** 2 - Good.
*   **HBA:** 3 - Good.
*   **QED:** 0.593 - Good, above the 0.5 threshold.
*   **DILI:** 27.801 - Very low risk.
*   **BBB:** 69.407 - Good BBB penetration, desirable for CNS targets.
*   **Caco-2:** -4.868 - Poor permeability, but better than Ligand A.
*   **Solubility:** -2.998 - Poor solubility, but better than Ligand A.
*   **hERG:** 0.376 - Very low risk.
*   **Cl_mic:** 58.155 mL/min/kg - Higher clearance, suggesting lower metabolic stability than Ligand A.
*   **t1/2:** 8.406 hours - Shorter half-life than Ligand A.
*   **Pgp:** 0.096 - Low P-gp efflux, favorable for CNS exposure.
*   **Affinity:** -7.5 kcal/mol - Good binding affinity, but 1.1 kcal/mol weaker than Ligand A.

**Comparison & Decision:**

Ligand A has a significantly stronger binding affinity (-8.6 kcal/mol vs -7.5 kcal/mol). However, it suffers from very poor Caco-2 permeability and aqueous solubility, and a marginal BBB score. Ligand B, while having a slightly weaker affinity, has a much better BBB score (69.4 vs 53.16), lower DILI risk, lower Pgp efflux, and better (though still poor) solubility and permeability.

For a CNS target like DRD2, BBB penetration is critical. The significantly better BBB score of Ligand B, coupled with its lower efflux and DILI risk, outweighs the slightly weaker binding affinity. The poor permeability and solubility of Ligand A are major hurdles that would be difficult to overcome. While the affinity difference is notable, it's unlikely to translate into a significant *in vivo* advantage if the compound can't reach the brain.

Therefore, I would choose **Ligand B** as the more viable drug candidate.

1
2025-04-17 06:50:39,375 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (335.411 and 347.507 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (72.7) is better than Ligand B (64.86). Both are below the 90 A^2 threshold desirable for CNS targets.

**logP:** Both ligands have good logP values (2.966 and 3.063), falling within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Both have 1 HBD, which is good. Ligand A has 5 HBA, and Ligand B has 6. Both are acceptable, being under 10.

**QED:** Ligand B (0.857) has a significantly better QED score than Ligand A (0.532), indicating a more drug-like profile.

**DILI:** Ligand A (69.911) has a higher DILI risk than Ligand B (37.301). This is a significant advantage for Ligand B.

**BBB:** Ligand B (85.033) has a substantially better BBB penetration percentile than Ligand A (65.529). This is *critical* for a CNS target like DRD2.

**Caco-2 Permeability:** Both are negative, which is unusual and suggests poor permeability. However, the scale is not specified, so it's hard to interpret.

**Aqueous Solubility:** Both ligands have negative solubility values (-3.188 and -3.239), which is concerning. Solubility is a potential issue for both, but not a deciding factor.

**hERG Inhibition:** Both ligands have low hERG inhibition liability (0.499 and 0.356), which is good.

**Microsomal Clearance:** Ligand A (93.005) has a higher microsomal clearance than Ligand B (27.217), indicating lower metabolic stability. Ligand B is much better here.

**In vitro Half-Life:** Ligand B (10.223) has a significantly longer in vitro half-life than Ligand A (-34.681). This is a major advantage for Ligand B.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.427 and 0.209), which is favorable for CNS penetration. Ligand B is slightly better.

**Binding Affinity:** Both ligands have similar and strong binding affinities (-8.9 and -8.5 kcal/mol). The difference of 0.4 kcal/mol is not large enough to outweigh other significant differences.

**Overall:**

Ligand B is clearly superior. While both have good MW, logP, and affinity, Ligand B excels in crucial areas for CNS drug development: BBB penetration, DILI risk, metabolic stability (lower Cl_mic, longer t1/2), and QED. The better BBB and lower toxicity profile of Ligand B are especially important for a DRD2 ligand. The solubility issues are a concern for both, but can be addressed with formulation strategies.



Output:
1
2025-04-17 06:50:39,375 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (346.45 and 347.371 Da) fall comfortably within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (70.39) is significantly better than Ligand B (120.78). For CNS targets, we want TPSA <= 90, and A is within this range while B exceeds it. This is a substantial advantage for A.

**3. logP:** Ligand A (1.117) is within the optimal 1-3 range. Ligand B (0.347) is slightly below 1, which *could* indicate permeability issues, though not drastically.

**4. H-Bond Donors:** Both have 3-4 HBD, which is acceptable (<=5).

**5. H-Bond Acceptors:** Ligand A has 4 HBA, and Ligand B has 6. Both are acceptable (<=10), but A is preferable.

**6. QED:** Ligand A (0.764) has a better QED score than Ligand B (0.551), indicating a more drug-like profile.

**7. DILI:** Ligand A (8.647%) has a much lower DILI risk than Ligand B (49.632%). This is a significant advantage for A.

**8. BBB:** Ligand A (75.029%) has a much higher BBB penetration score than Ligand B (30.942%). This is *critical* for a CNS target like DRD2, making A far superior.

**9. Caco-2:** Both have negative Caco-2 values (-5.61 and -5.76), which is unusual and suggests poor permeability. However, these values are on a scale where negative values are possible, and direct comparison is difficult without knowing the scale's specifics.

**10. Solubility:** Both have negative solubility values (-0.855 and -2.629), again suggesting poor solubility. Similar to Caco-2, direct comparison is limited.

**11. hERG:** Both have very low hERG inhibition risk (0.8 and 0.064), which is excellent.

**12. Cl_mic:** Ligand A (-24.158) has a much lower (better) microsomal clearance than Ligand B (3.148). This suggests better metabolic stability for A.

**13. t1/2:** Ligand A (17.346 hours) has a longer in vitro half-life than Ligand B (-3.967 hours). This is a significant advantage for A.

**14. Pgp:** Both have very low Pgp efflux liability (0.018 and 0.019).

**15. Binding Affinity:** Ligand A (-9.9 kcal/mol) has a significantly stronger binding affinity than Ligand B (-8.4 kcal/mol). This is a substantial advantage for A.

**Overall Assessment:**

Ligand A is clearly superior to Ligand B. It excels in almost every critical parameter, particularly BBB penetration, TPSA, DILI risk, metabolic stability (Cl_mic and t1/2), and binding affinity. While both have issues with Caco-2 and solubility, the overall profile of Ligand A is far more favorable for development as a CNS-targeting drug. The strong affinity of Ligand A can potentially compensate for the solubility/permeability concerns.

Output:
1
2025-04-17 06:50:39,375 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (345.4 and 348.4 Da) fall comfortably within the ideal 200-500 Da range.

**TPSA:** Ligand A (107.35) is slightly higher than Ligand B (97.43). Both are below the 140 A^2 threshold for oral absorption, but ideally, for a CNS target like DRD2, we want <90 A^2. Ligand B is closer to this target.

**logP:** Ligand A (0.51) is quite low, potentially hindering membrane permeability. Ligand B (1.152) is better, falling within the optimal 1-3 range. This is a significant advantage for Ligand B.

**H-Bond Donors/Acceptors:** Ligand A has 4 HBD and 5 HBA, while Ligand B has 2 HBD and 4 HBA. Both are within acceptable limits, but Ligand B's lower HBD count could be beneficial for permeability.

**QED:** Both ligands have similar QED values (0.612 and 0.655), indicating good drug-likeness.

**DILI:** Ligand A has a DILI risk of 65.491, which is concerning (high risk). Ligand B has a much lower DILI risk of 27.879, a significant advantage.

**BBB:** Ligand A has a BBB penetration of 32.726%, which is poor for a CNS target. Ligand B has a much better BBB penetration of 50.64%, exceeding the desirable >70% threshold. This is a critical advantage for Ligand B.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.092 and -5.155). These values are unusual and difficult to interpret directly without further context, but suggest poor permeability.

**Aqueous Solubility:** Both ligands have negative solubility values (-2.581 and -1.834), which is also unusual and suggests very low solubility.

**hERG Inhibition:** Ligand A (0.256) has a slightly higher hERG risk than Ligand B (0.074), though both are relatively low.

**Microsomal Clearance:** Ligand A (-19.225) has a much lower (better) microsomal clearance than Ligand B (25.334), indicating greater metabolic stability.

**In vitro Half-Life:** Ligand A (-8.417) has a negative half-life, which is not physically meaningful. Ligand B (5.258) has a reasonable half-life.

**P-gp Efflux:** Ligand A (0.051) has lower P-gp efflux than Ligand B (0.014), which is favorable for CNS penetration.

**Binding Affinity:** Ligand A (-9.6 kcal/mol) has a significantly stronger binding affinity than Ligand B (-7.7 kcal/mol). This is a substantial advantage for Ligand A, potentially outweighing some of its ADME liabilities. However, the unusual values for solubility, Caco-2, and half-life for ligand A raise concerns about the reliability of the data.

**Overall Assessment:**

Despite the stronger binding affinity of Ligand A, its poor BBB penetration, high DILI risk, and questionable ADME properties (negative solubility and half-life) make it a less attractive candidate. Ligand B, while having a slightly weaker binding affinity, exhibits significantly better BBB penetration, a much lower DILI risk, and more reasonable ADME properties. Given the CNS target (DRD2), BBB penetration is paramount. The difference in binding affinity (1.9 kcal/mol) might be overcome with further optimization of Ligand B.

Output:
1
2025-04-17 06:50:39,375 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B based on the provided guidelines, prioritizing GPCR-specific properties (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (356.438 Da) is slightly better, being closer to the lower end which can aid permeability.

**TPSA:** Both ligands have TPSA values below 90, which is favorable for CNS penetration. Ligand A (59.08) is better than Ligand B (48.47) in this regard.

**logP:** Ligand A (1.24) is within the optimal range (1-3), while Ligand B (3.809) is approaching the upper limit. While not a dealbreaker, higher logP can sometimes lead to off-target effects and solubility issues.

**H-Bond Donors/Acceptors:** Ligand A (0 HBD, 4 HBA) and Ligand B (1 HBD, 5 HBA) both have acceptable numbers of H-bond donors and acceptors.

**QED:** Both ligands have similar QED values (0.76 and 0.707), indicating good drug-likeness.

**DILI:** Ligand A (17.449) has a significantly lower DILI risk than Ligand B (77.045). This is a major advantage for Ligand A.

**BBB:** Both ligands have excellent BBB penetration (Ligand A: 89.027, Ligand B: 83.521), exceeding the desirable threshold of 70. Ligand A is slightly better.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values, which is unusual and suggests a potential issue with the data or modeling. However, we'll proceed assuming these represent relative permeability, and a less negative value is better. Ligand A (-4.397) is better than Ligand B (-4.962).

**Aqueous Solubility:** Ligand A (-1.331) has better solubility than Ligand B (-4.595).

**hERG Inhibition:** Ligand A (0.425) has a much lower hERG inhibition liability than Ligand B (0.926), reducing the risk of cardiotoxicity.

**Microsomal Clearance:** Ligand A (0.138) has significantly lower microsomal clearance than Ligand B (55.008), indicating better metabolic stability.

**In vitro Half-Life:** Ligand A (-4.814) has a shorter half-life than Ligand B (42.34). This is a drawback for Ligand A, but can be mitigated through formulation strategies.

**P-gp Efflux:** Ligand A (0.027) has much lower P-gp efflux liability than Ligand B (0.774), improving CNS exposure.

**Binding Affinity:** Ligand B (-10.0 kcal/mol) has a significantly stronger binding affinity than Ligand A (-4.814 kcal/mol). This is a substantial advantage for Ligand B. The difference of 5.19 kcal/mol is large enough to potentially outweigh some of the ADME drawbacks.

**Overall Assessment:**

Ligand A excels in ADME properties (DILI, BBB, solubility, hERG, clearance, P-gp efflux) and TPSA, making it a safer and more likely to reach the brain. However, Ligand B has a much stronger binding affinity, which is crucial for efficacy. Considering this is a GPCR target in the CNS, a balance is needed. The substantial difference in binding affinity (-5.19 kcal/mol) is a significant factor. While Ligand A's superior ADME profile is attractive, the potency advantage of Ligand B is likely to be more impactful, assuming some of the ADME liabilities can be addressed through further optimization.

Output:
1
2025-04-17 06:50:39,376 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (366.893 and 337.402 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (67.23) is slightly higher than Ligand B (64.84), but both are below the 90 A^2 threshold desirable for CNS targets.

**3. logP:** Ligand A (2.246) is within the optimal 1-3 range. Ligand B (3.331) is slightly higher, but still acceptable.

**4. H-Bond Donors:** Both ligands have 1 HBD, which is within the ideal limit of <=5.

**5. H-Bond Acceptors:** Ligand A has 4 HBAs, and Ligand B has 5. Both are below the limit of <=10.

**6. QED:** Both ligands have good QED scores (0.804 and 0.927, respectively), indicating good drug-like properties.

**7. DILI:** Ligand A (34.277) has a lower DILI risk than Ligand B (63.862). This is a significant advantage for Ligand A.

**8. BBB:** Ligand B (91.392) has a significantly higher BBB penetration percentile than Ligand A (67.817). This is a crucial factor for a CNS target like DRD2.

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.107 and -4.872). These values are unusual and suggest poor permeability. However, Caco-2 values can be unreliable and are less important than other parameters in this case.

**10. Aqueous Solubility:** Both ligands have negative solubility values (-3.125 and -4.866). Similar to Caco-2, these are unusual and suggest poor solubility.

**11. hERG Inhibition:** Ligand A (0.224) has a lower hERG inhibition liability than Ligand B (0.973). This is a positive for Ligand A.

**12. Microsomal Clearance:** Ligand B (72.795) has higher microsomal clearance than Ligand A (36.861), indicating lower metabolic stability.

**13. In vitro Half-Life:** Ligand A (-7.15) has a much longer in vitro half-life than Ligand B (22.693).

**14. P-gp Efflux:** Ligand A (0.141) has lower P-gp efflux liability than Ligand B (0.34). This is favorable for CNS penetration.

**15. Binding Affinity:** Both ligands have excellent binding affinities (-8.4 and -8.6 kcal/mol). The difference is minimal.

**Overall Assessment:**

Ligand B excels in BBB penetration, a critical factor for CNS targets. However, Ligand A demonstrates a superior safety profile (lower DILI, lower hERG), better metabolic stability (lower Cl_mic, longer t1/2), and lower P-gp efflux. While both have poor solubility and permeability, the other advantages of Ligand A, particularly the safety and metabolic properties, outweigh the BBB advantage of Ligand B. The binding affinity is comparable.

Output:
0
2025-04-17 06:50:39,376 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (364.47 and 341.42 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (84.5) is excellent, well below the 90 threshold for CNS targets. Ligand B (108.48) is still reasonable but less optimal, being above 90.

**3. logP:** Both ligands have good logP values (2.005 and 1.189), falling within the 1-3 range.

**4. H-Bond Donors:** Ligand A (2) and Ligand B (3) are both acceptable, being less than 5.

**5. H-Bond Acceptors:** Ligand A (4) and Ligand B (6) are both acceptable, being less than 10.

**6. QED:** Ligand A (0.837) has a superior QED score compared to Ligand B (0.653), indicating better overall drug-likeness.

**7. DILI:** Ligand A (67.003) has a slightly higher DILI risk than Ligand B (56.844), but both are still within an acceptable range (<60 is good).

**8. BBB:** Ligand B (67.041) has a better BBB penetration percentile than Ligand A (44.668). This is a critical factor for a CNS target like DRD2.

**9. Caco-2 Permeability:** Ligand A (-4.869) has a significantly *better* Caco-2 permeability than Ligand B (-5.756). A less negative value indicates better permeability.

**10. Aqueous Solubility:** Ligand A (-2.926) has slightly better solubility than Ligand B (-2.361).

**11. hERG Inhibition:** Both ligands show very low hERG inhibition liability (0.212).

**12. Microsomal Clearance:** Ligand B (34.93) has a lower microsomal clearance than Ligand A (59.144), suggesting better metabolic stability.

**13. In vitro Half-Life:** Ligand A (-18.221) has a longer in vitro half-life than Ligand B (-4.957).

**14. P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.223 and 0.083).

**15. Binding Affinity:** Both ligands have excellent binding affinities (-9.2 and -8.8 kcal/mol). Ligand A has a slightly better affinity, but the difference is less than 1.5 kcal/mol.

**Overall Assessment:**

Ligand A has a better QED, TPSA, Caco-2 permeability, solubility, and half-life. However, Ligand B has a significantly better BBB penetration and lower microsomal clearance. Considering DRD2 is a CNS target, BBB penetration is paramount. While Ligand A has a slightly better affinity, the difference isn't substantial enough to outweigh the superior BBB score of Ligand B. The lower clearance of Ligand B is also a significant advantage.

Output:
1
2025-04-17 06:50:39,376 - INFO - Batch 315 complete. Total preferences: 5040
2025-04-17 06:50:39,376 - INFO - Processing batch 316/512...
2025-04-17 06:51:26,934 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (348.443 Da) is slightly better, being closer to the lower end which can aid permeability.

**TPSA:** Ligand A (82.78) is significantly better than Ligand B (48.99). For CNS targets, TPSA should be <= 90, and lower is preferred. Ligand A is well within this range, while Ligand B is also acceptable but less optimal.

**logP:** Both ligands have logP values within the optimal range (1-3). Ligand A (2.108) is slightly better positioned than Ligand B (4.187), as the latter is approaching the upper limit where solubility issues can arise.

**H-Bond Donors/Acceptors:** Ligand A (2 HBD, 4 HBA) and Ligand B (1 HBD, 4 HBA) are both acceptable.

**QED:** Both ligands have reasonable QED values (A: 0.825, B: 0.772), indicating good drug-like properties.

**DILI:** Ligand A (17.216) has a much lower DILI risk than Ligand B (37.185), which is a significant advantage.

**BBB:** Ligand A (67.352) has a better BBB penetration percentile than Ligand B (55.797). While both are not ideal (>70 is desirable), A is closer. This is crucial for a CNS target like DRD2.

**Caco-2 Permeability:** Ligand A (-4.766) has a worse Caco-2 permeability than Ligand B (-5.601). Lower values here indicate lower permeability.

**Aqueous Solubility:** Ligand A (-2.344) has better aqueous solubility than Ligand B (-3.893).

**hERG Inhibition:** Both ligands have similar, low hERG inhibition risk (A: 0.488, B: 0.658).

**Microsomal Clearance:** Ligand A (8.028) has a lower microsomal clearance than Ligand B (69.202), indicating better metabolic stability.

**In vitro Half-Life:** Ligand A (28.047) has a significantly longer in vitro half-life than Ligand B (-18.46).

**P-gp Efflux:** Ligand A (0.128) has a lower P-gp efflux liability than Ligand B (0.396), which is beneficial for CNS exposure.

**Binding Affinity:** Ligand A (-7.5 kcal/mol) has a slightly better binding affinity than Ligand B (-6.6 kcal/mol). While both are good, the 0.9 kcal/mol difference is substantial enough to be a deciding factor.

**Overall:** Considering all factors, Ligand A is the more promising drug candidate. It excels in critical areas for CNS GPCR targets: TPSA, BBB, DILI, metabolic stability (Cl_mic & t1/2), P-gp efflux, and binding affinity. While Ligand B has slightly better Caco-2 permeability, the advantages of Ligand A in other key parameters outweigh this.



Output:
1
2025-04-17 06:51:26,935 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (350.503 and 349.391 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (78.43) is significantly better than Ligand B (129.37). For CNS targets, TPSA should be <=90, and A is comfortably within that range, while B is pushing the limit and potentially hindering BBB penetration.

**3. logP:** Ligand A (2.378) is optimal (1-3), while Ligand B (-1.432) is below 1, which could impede permeation.

**4. H-Bond Donors:** Both ligands have acceptable HBD counts (3 for A, 4 for B), within the <=5 guideline.

**5. H-Bond Acceptors:** Ligand A (3) is better than Ligand B (7), as we prefer HBA <=10.

**6. QED:** Both ligands have reasonable QED values (0.529 and 0.405), above the 0.5 threshold, indicating good drug-like properties.

**7. DILI:** Ligand A (10.857) has a much lower DILI risk than Ligand B (55.797). Lower is better, and A is well below the 40% threshold, while B is concerningly high.

**8. BBB:** Ligand A (48.313) has a better BBB percentile than Ligand B (27.026), but both are less than the desirable >70 for CNS targets. However, A is significantly better.

**9. Caco-2:** Ligand A (-4.689) and Ligand B (-5.712) both have negative values, which is unusual. Higher values are better, suggesting better intestinal absorption. This is a weakness for both, but the values are difficult to directly compare without knowing the scale.

**10. Solubility:** Ligand A (-3.089) and Ligand B (-1.427) both have negative solubility values. Higher is better, so both are suboptimal.

**11. hERG:** Both ligands have very low hERG risk (0.225 and 0.034), which is excellent.

**12. Cl_mic:** Ligand B (-20.448) has a lower (better) microsomal clearance than Ligand A (40.912), indicating greater metabolic stability.

**13. t1/2:** Ligand B (-2.712) has a longer in vitro half-life than Ligand A (-15.623), which is also desirable.

**14. Pgp:** Ligand A (0.145) has lower P-gp efflux liability than Ligand B (0.006), which is better for CNS exposure.

**15. Binding Affinity:** Ligand A (-7.6) has a slightly better binding affinity than Ligand B (-7.2). While both are good (<-7.0), the 0.4 kcal/mol difference is noticeable.

**Overall Assessment:**

Ligand A is superior despite Ligand B having better metabolic stability and half-life. Ligand A excels in critical areas for a CNS-targeting GPCR ligand: TPSA, logP, DILI risk, and BBB penetration. The slightly better binding affinity is a bonus. Ligand B's low logP and high DILI risk are significant drawbacks. While metabolic stability is important, it can be addressed through structural modifications, whereas poor BBB penetration and high toxicity are harder to fix.

Output:
1
2025-04-17 06:51:26,935 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (347.443 and 358.507 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (57.78) is slightly higher than Ligand B (53.33). Both are below the 90 A^2 threshold for CNS targets, which is good.

**3. logP:** Ligand A (4.53) is slightly higher than Ligand B (3.952). Ligand A is pushing the upper limit of the optimal range (1-3), potentially leading to solubility issues, while Ligand B is well within the optimal range.

**4. H-Bond Donors:** Ligand A (2) is better than Ligand B (0). A small number of HBDs are generally preferred for BBB penetration.

**5. H-Bond Acceptors:** Ligand A (3) and Ligand B (4) are both acceptable, falling under the 10 threshold.

**6. QED:** Both ligands have good QED scores (0.57 and 0.774), indicating good drug-like properties.

**7. DILI:** Ligand A (80.923) has a significantly higher DILI risk than Ligand B (38.813). This is a major concern for Ligand A.

**8. BBB:** Ligand B (80.264) has a much better BBB penetration score than Ligand A (55.874). For a CNS target like DRD2, this is a critical advantage.

**9. Caco-2 Permeability:** Both have negative values, indicating poor permeability. However, the scale is not specified, so it's hard to interpret.

**10. Aqueous Solubility:** Both have negative values, indicating poor solubility. Again, the scale is not specified.

**11. hERG Inhibition:** Both ligands have low hERG inhibition risk (0.866 and 0.604).

**12. Microsomal Clearance:** Ligand B (75.502) has higher microsomal clearance than Ligand A (57.857), indicating faster metabolism and potentially lower *in vivo* exposure.

**13. In vitro Half-Life:** Ligand A (-15.672) has a negative half-life, which is impossible. This is a red flag. Ligand B (24.417) has a reasonable half-life.

**14. P-gp Efflux:** Ligand A (0.792) has slightly lower P-gp efflux than Ligand B (0.677), which is favorable for CNS penetration.

**15. Binding Affinity:** Ligand B (-7.6 kcal/mol) has significantly better binding affinity than Ligand A (-10.7 kcal/mol). A difference of >1.5 kcal/mol is a substantial advantage.

**Overall Assessment:**

Ligand B is clearly the superior candidate. It has a significantly better BBB score, lower DILI risk, much better binding affinity, and a reasonable half-life. While its metabolic clearance is higher, the other advantages outweigh this drawback. Ligand A has a concerningly high DILI risk, a poor BBB score, and an impossible half-life value. The slightly better P-gp efflux of Ligand A is not enough to compensate for these significant issues.

Output:
1
2025-04-17 06:51:26,935 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (365.4 and 351.4 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (72.88) is excellent for CNS penetration, well below the 90 A^2 threshold. Ligand B (112.73) is higher, but still potentially acceptable, though less ideal.

**logP:** Ligand A (0.915) is at the lower end of optimal, potentially hindering permeation. Ligand B (0.014) is very low, raising concerns about permeability.

**H-Bond Donors/Acceptors:** Both have 3 HBD and 4 HBA, which are within acceptable limits.

**QED:** Both ligands have reasonable QED scores (0.711 and 0.626), indicating good drug-like properties.

**DILI:** Ligand A (18.07) has a slightly higher DILI risk than Ligand B (14.23), but both are below the 40 threshold and considered good.

**BBB:** This is critical for a CNS target. Ligand A (67.70) is better than Ligand B (50.33), but both are below the desirable >70 percentile.

**Caco-2 Permeability:** Ligand A (-4.982) has poor Caco-2 permeability, while Ligand B (-5.354) is also poor.

**Aqueous Solubility:** Both ligands have very poor aqueous solubility (-0.501 and -1.944). This is a significant drawback.

**hERG Inhibition:** Ligand A (0.421) has a very low hERG risk, which is excellent. Ligand B (0.091) also has a low hERG risk.

**Microsomal Clearance:** Ligand A (-17.94) has a very low (good) microsomal clearance, indicating high metabolic stability. Ligand B (8.737) has a positive value, indicating faster clearance and lower metabolic stability.

**In vitro Half-Life:** Ligand A (-34.47) has a very long in vitro half-life, which is highly desirable. Ligand B (-2.934) has a very short half-life.

**P-gp Efflux:** Both ligands show very low P-gp efflux liability (0.026 and 0.006), which is excellent for CNS penetration.

**Binding Affinity:** Ligand B (-7.7 kcal/mol) has a significantly stronger binding affinity than Ligand A (0.0 kcal/mol). This is a substantial advantage.

**Overall Assessment:**

Ligand B has a much better binding affinity, which is the most important factor. However, it suffers from very low logP, poor solubility, and faster clearance. Ligand A has better BBB penetration, metabolic stability, and half-life, but its binding affinity is extremely weak.

Despite the better affinity of Ligand B, the extremely poor logP and solubility are major concerns. The low logP will severely limit its ability to cross cell membranes, including the BBB, negating the benefit of low P-gp efflux. The poor solubility will likely lead to poor bioavailability. Ligand A's affinity is too weak to be a viable candidate, even with its better ADME properties.

However, considering the substantial affinity difference (-7.7 vs 0.0 kcal/mol), and the fact that solubility and logP can be improved through medicinal chemistry efforts, Ligand B is the more promising starting point.

Output:
1
2025-04-17 06:51:26,935 - INFO - Reasoning:

Let's analyze Ligand A and Ligand B for their potential as DRD2 drug candidates, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight (MW):** Both ligands (349.431 and 360.435 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Both ligands have TPSA values (80.76 and 81.43) below the 90 A^2 threshold for CNS targets, which is good.

**3. logP:** Ligand A (1.284) is optimal, while Ligand B (3.17) is at the higher end of the optimal range.

**4. H-Bond Donors (HBD):** Both ligands have 1 HBD, well within the acceptable limit of 5.

**5. H-Bond Acceptors (HBA):** Ligand A has 5 HBA, and Ligand B has 6. Both are below the 10 limit.

**6. QED:** Both ligands have high QED scores (0.81 and 0.828), indicating good drug-like properties.

**7. DILI:** Ligand A (38.503) has a significantly lower DILI risk than Ligand B (63.707). This is a substantial advantage.

**8. BBB:** Ligand A (70.492) has a better BBB percentile than Ligand B (64.172), although both are reasonably good. For a CNS target like DRD2, maximizing BBB penetration is crucial.

**9. Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and suggests poor permeability. However, the scale is not specified, so it is hard to interpret.

**10. Aqueous Solubility:** Both have negative solubility values, which is also unusual.

**11. hERG Inhibition:** Both ligands have very low hERG inhibition liability (0.14 and 0.098), which is excellent.

**12. Microsomal Clearance (Cl_mic):** Ligand A (28.063) has significantly lower microsomal clearance than Ligand B (64.054), indicating better metabolic stability.

**13. In vitro Half-Life:** Ligand A (-3.192) has a more negative half-life, which is unusual and suggests a shorter half-life. Ligand B (1.375) is better.

**14. P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.029 and 0.207), which is beneficial for CNS penetration.

**15. Binding Affinity:** Ligand B (-9.0 kcal/mol) has a significantly stronger binding affinity than Ligand A (-7.6 kcal/mol). This is a 1.4 kcal/mol difference, which is a substantial advantage and can outweigh some ADME drawbacks.

**Overall Assessment:**

Ligand B has a significantly better binding affinity, which is the most important factor. While Ligand A has better DILI and Cl_mic, the difference in affinity is substantial. The slightly lower BBB and higher DILI of Ligand B are less concerning given the strong binding. The unusual negative values for Caco-2 and solubility are a concern for both, but the affinity difference is the deciding factor.

Output:
1
2025-04-17 06:51:26,935 - INFO - Okay, let's analyze these two ligands for their potential as DRD2 drug candidates.

**Ligand A:** [343.383, 107.53 ,   0.684,   4.   ,   4.   ,   0.476,  59.131,  59.054, -5.29 ,  -2.44 ,   0.051,  -4.415,  10.828,   0.008, -10.6  ]
**Ligand B:** [350.438,  58.56 ,   1.666,   0.   ,   5.   ,   0.749,  25.204,  92.012, -4.368,  -1.059,   0.57 ,   7.975,  27.657,   0.033,  -6.9  ]

**Step-by-step comparison:**

1. **MW:** Both ligands are within the ideal range (200-500 Da). Ligand A (343.383) is slightly lower, which *could* be beneficial for permeability, but isn't a major concern for either.
2. **TPSA:** Ligand A (107.53) is higher than the preferred <90 for CNS targets, while Ligand B (58.56) is excellent. This is a significant advantage for Ligand B.
3. **logP:** Ligand A (0.684) is a bit low, potentially hindering membrane permeability. Ligand B (1.666) is better, falling within the optimal 1-3 range.
4. **HBD:** Ligand A (4) is acceptable, while Ligand B (0) is even better, potentially improving permeability.
5. **HBA:** Both ligands have acceptable HBA counts (4 and 5, respectively).
6. **QED:** Both ligands have reasonable QED scores (0.476 and 0.749), with Ligand B being noticeably better.
7. **DILI:** Ligand A (59.131) has a moderate DILI risk, while Ligand B (25.204) has a low risk. This favors Ligand B.
8. **BBB:** This is critical for a CNS target like DRD2. Ligand A (59.054) is below the desirable >70 threshold, while Ligand B (92.012) is excellent. This is a major advantage for Ligand B.
9. **Caco-2:** Both have negative values, which is unusual. Assuming these are log scale values, both have poor Caco-2 permeability.
10. **Solubility:** Both have negative solubility values, which is also unusual. Assuming these are log scale values, both have poor solubility.
11. **hERG:** Both ligands have very low hERG inhibition risk.
12. **Cl_mic:** Ligand A (-4.415) suggests potentially *low* metabolic stability (negative values are unusual, and might indicate a prediction issue). Ligand B (7.975) is more reasonable, suggesting moderate clearance.
13. **t1/2:** Ligand B (27.657) has a significantly longer in vitro half-life than Ligand A (10.828), which is desirable.
14. **Pgp:** Ligand A (0.008) has very low P-gp efflux, which is good. Ligand B (0.033) is also very low, but slightly higher.
15. **Affinity:** Ligand A (-10.6) has a *much* stronger binding affinity than Ligand B (-6.9). This is a substantial advantage for Ligand A. A difference of 3.7 kcal/mol is significant.

**Overall Assessment:**

While Ligand A boasts a significantly better binding affinity, Ligand B has a superior ADME profile, particularly regarding CNS penetration (BBB), TPSA, DILI risk, and in vitro half-life. The low logP and TPSA of Ligand B are highly favorable for a CNS-targeting GPCR. The questionable metabolic stability of Ligand A is a concern. The difference in affinity is substantial, but the ADME properties of Ligand B are so much better that they likely outweigh the affinity difference, especially considering the potential for optimization of Ligand B's binding.

**Output:**
1
2025-04-17 06:51:26,935 - INFO - Reasoning:

Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands are within the acceptable range (200-500 Da). Ligand A (450.236 Da) is higher, but not excessively so. Ligand B (341.455 Da) is lower, which *could* be beneficial for permeability, but is still well above the 250 Da cutoff.

**2. TPSA:** Ligand A (101.14) is pushing the upper limit for CNS targets (<=90), while Ligand B (57.5) is well within the desired range. This is a significant advantage for B.

**3. logP:** Both ligands have good logP values (A: 2.857, B: 2.218), falling within the optimal 1-3 range.

**4. H-Bond Donors:** Both have 2 HBD, which is acceptable.

**5. H-Bond Acceptors:** Ligand A has 6 HBA, and Ligand B has 4. Both are within the acceptable limit of <=10.

**6. QED:** Ligand B (0.847) has a significantly better QED score than Ligand A (0.458), indicating a more drug-like profile.

**7. DILI:** Ligand A (88.251) has a higher DILI risk than Ligand B (24.622). This is a clear advantage for Ligand B.

**8. BBB:** Ligand B (51.997) has a better BBB percentile than Ligand A (20.202), though both are not ideal. However, for a CNS target like DRD2, higher BBB is crucial.

**9. Caco-2:** Ligand A (-5.656) has a very poor Caco-2 permeability, while Ligand B (-4.868) is also poor, but slightly better.

**10. Solubility:** Ligand A (-4.174) has slightly better solubility than Ligand B (-2.124).

**11. hERG:** Both ligands have low hERG risk (A: 0.113, B: 0.844).

**12. Cl_mic:** Ligand B (31.062) has lower microsomal clearance than Ligand A (43.321), suggesting better metabolic stability.

**13. t1/2:** Ligand B (68.92) has a much longer in vitro half-life than Ligand A (-13.696). This is a substantial advantage.

**14. Pgp:** Ligand A (0.204) has lower P-gp efflux than Ligand B (0.573), which is favorable for CNS penetration.

**15. Binding Affinity:** Both ligands have very similar and strong binding affinities (A: -8.7 kcal/mol, B: -8.4 kcal/mol). The difference of 0.3 kcal/mol is unlikely to outweigh the significant ADME advantages of Ligand B.

**Overall Assessment:**

Ligand B is the superior candidate. While Ligand A has slightly better solubility and Pgp efflux, Ligand B excels in critical areas for a CNS-targeting GPCR ligand: TPSA, QED, DILI, BBB, metabolic stability (Cl_mic and t1/2). The only slight drawback is the Pgp efflux, but this is less concerning than the higher TPSA and DILI risk of Ligand A. The similar binding affinities make the ADME advantages of Ligand B decisive.

Output:
1
2025-04-17 06:51:26,935 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (419.235 Da) is higher, but still acceptable. Ligand B (350.459 Da) is slightly preferable.

**TPSA:** Ligand A (80.91) is borderline for CNS targets (ideally <90), while Ligand B (66.92) is well within the desired range. This favors Ligand B.

**logP:** Ligand A (4.5) is a bit high, potentially leading to solubility issues and off-target effects. Ligand B (2.134) is optimal. This is a significant advantage for Ligand B.

**H-Bond Donors/Acceptors:** Ligand A (1 HBD, 6 HBA) and Ligand B (0 HBD, 4 HBA) both fall within acceptable ranges.

**QED:** Both ligands have good QED scores (A: 0.529, B: 0.713), indicating drug-like properties. Ligand B is slightly better.

**DILI:** Ligand A has a very high DILI risk (99.729%), which is a major concern. Ligand B has a much lower DILI risk (34.742%), making it significantly safer.

**BBB:** Ligand A (56.456%) has a moderate BBB penetration, while Ligand B (78.286%) has excellent BBB penetration. Given that DRD2 is a CNS target, this is a crucial advantage for Ligand B.

**Caco-2 Permeability:** Ligand A (-4.807) has poor Caco-2 permeability, while Ligand B (-3.911) is slightly better, but still not great.

**Aqueous Solubility:** Ligand A (-5.61) has very poor aqueous solubility, which could hinder formulation and bioavailability. Ligand B (-2.589) is better, but still low.

**hERG Inhibition:** Ligand A (0.582) has a moderate hERG risk, while Ligand B (0.129) has a very low risk. This favors Ligand B.

**Microsomal Clearance:** Ligand A (65.522) has moderate clearance, while Ligand B (105.085) has high clearance, suggesting lower metabolic stability. This favors Ligand A, though not strongly.

**In vitro Half-Life:** Ligand A (68.227) has a reasonable half-life, while Ligand B (-17.406) has a very short half-life. This is a significant advantage for Ligand A.

**P-gp Efflux:** Ligand A (0.536) has moderate P-gp efflux, while Ligand B (0.044) has very low efflux. This is a major advantage for Ligand B, especially for CNS penetration.

**Binding Affinity:** Ligand A (-10.3 kcal/mol) has significantly stronger binding affinity than Ligand B (-8.1 kcal/mol). This is a substantial advantage for Ligand A, potentially outweighing some of its ADME drawbacks.

**Overall Assessment:**

Ligand B excels in key GPCR/CNS-relevant properties: TPSA, logP, BBB, DILI, and P-gp efflux. Its lower hERG risk is also a significant benefit. However, its poor Caco-2 permeability, solubility, and short half-life are concerning.

Ligand A has a much higher binding affinity, which is very attractive. However, its high DILI risk, poor solubility, and moderate P-gp efflux are major liabilities. The high logP is also a concern.

Despite the superior affinity of Ligand A, the combination of severe toxicity (DILI) and poor ADME properties makes it a less viable candidate. Ligand B's more balanced profile, particularly its favorable CNS penetration and safety, makes it the more promising starting point for drug development. The ADME issues with Ligand B could be addressed through further optimization.

Output:
1
2025-04-17 06:51:26,935 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the acceptable range (200-500 Da). Ligand A (332.363 Da) is preferable as it's lower.

**TPSA:** Ligand A (90.68) is excellent for CNS penetration, falling well below the 90 A^2 threshold. Ligand B (53.6) is also very good.

**logP:** Both ligands have logP values within the optimal range (1-3), with Ligand A (2.657) being slightly more favorable. Ligand B (4.468) is pushing the upper limit and could potentially have solubility issues.

**H-Bond Donors/Acceptors:** Both ligands have 2 HBD and 4/3 HBA, which are within acceptable limits.

**QED:** Both ligands have QED values above 0.5, indicating good drug-likeness. Ligand A (0.769) is slightly better than Ligand B (0.609).

**DILI:** Ligand A (85.227) has a higher DILI risk than Ligand B (65.684). This is a negative for Ligand A.

**BBB:** Ligand B (68.554) has a significantly better BBB percentile than Ligand A (35.983). This is a *major* advantage for Ligand B, given DRD2 is a CNS target.

**Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and suggests poor permeability. Ligand A (-5.1) is slightly better than Ligand B (-4.802).

**Aqueous Solubility:** Both have negative solubility values, indicating poor solubility. Ligand A (-5.41) is slightly better than Ligand B (-5.244).

**hERG Inhibition:** Both ligands show low hERG inhibition risk. Ligand A (0.67) is slightly better than Ligand B (0.904).

**Microsomal Clearance:** Ligand A (14.178) has significantly lower microsomal clearance than Ligand B (113.274), indicating better metabolic stability.

**In vitro Half-Life:** Ligand A (33.788) has a shorter half-life than Ligand B (57.759), but both are reasonable.

**P-gp Efflux:** Ligand A (0.263) has lower P-gp efflux liability than Ligand B (0.594), which is favorable for CNS penetration.

**Binding Affinity:** Ligand B (-7.4 kcal/mol) has a significantly stronger binding affinity than Ligand A (-9.7 kcal/mol). This is a substantial advantage, potentially outweighing some ADME concerns.

**Overall Assessment:**

While Ligand A has better metabolic stability (lower Cl_mic) and slightly better logP, TPSA, and hERG, Ligand B excels in the most critical areas for a CNS-targeting GPCR ligand: **BBB penetration and binding affinity**. The significantly stronger binding affinity of Ligand B (-7.4 vs -9.7 kcal/mol) is a major advantage. The better BBB score (68.554 vs 35.983) is also crucial. The higher DILI risk for Ligand A is also concerning.

Output:
1
2025-04-17 06:51:26,935 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (352.366 and 354.466 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (108.73) is better than Ligand B (67.43). For CNS targets, we want TPSA <= 90, so both are acceptable, but A is closer to the upper limit.

**3. logP:** Ligand A (-0.227) is below the optimal 1-3 range, potentially hindering permeation. Ligand B (2.509) is within the optimal range. This is a significant advantage for B.

**4. H-Bond Donors:** Both ligands have 2 HBD, which is within the acceptable limit of <=5.

**5. H-Bond Acceptors:** Ligand A has 4 HBA, and Ligand B has 3. Both are below the acceptable limit of <=10.

**6. QED:** Both ligands have QED values above 0.5 (0.737 and 0.658), indicating good drug-likeness.

**7. DILI:** Ligand A (44.63) has a higher DILI risk than Ligand B (19.155). Lower is better, so B is preferable.

**8. BBB:** Ligand B (83.288) has a significantly higher BBB penetration percentile than Ligand A (64.637). This is *critical* for a CNS target like DRD2.

**9. Caco-2 Permeability:** Ligand A (-5.045) has poor Caco-2 permeability, while Ligand B (-4.527) is slightly better, but still poor.

**10. Aqueous Solubility:** Both ligands have very poor aqueous solubility (-2.8 and -2.536). This could pose formulation challenges.

**11. hERG Inhibition:** Ligand A (0.345) has a slightly lower hERG inhibition risk than Ligand B (0.514), but both are relatively low.

**12. Microsomal Clearance:** Ligand A (-12.726) has much lower microsomal clearance (better metabolic stability) than Ligand B (52.62).

**13. In vitro Half-Life:** Ligand A (-4.496) has a longer in vitro half-life than Ligand B (12.06).

**14. P-gp Efflux:** Ligand A (0.012) has very low P-gp efflux, which is excellent for CNS penetration. Ligand B (0.14) has slightly higher efflux, but still relatively low.

**15. Binding Affinity:** Both ligands have excellent binding affinities (-8.0 and -9.1 kcal/mol). Ligand B is slightly better.

**Overall Assessment:**

While Ligand A has better metabolic stability (lower Cl_mic, longer t1/2) and lower P-gp efflux, its poor logP and lower BBB penetration are major drawbacks for a CNS-targeting drug. Ligand B excels in the critical areas for CNS GPCRs: good logP, excellent BBB penetration, and slightly better binding affinity. The slightly higher DILI and clearance are less concerning given the strong CNS penetration profile.

Output:
1
2025-04-17 06:51:26,936 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B based on the provided guidelines, prioritizing GPCR-specific properties (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (349.431 and 349.475 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (78.95) is slightly higher than Ligand B (69.72). Both are below the 90 A^2 threshold desirable for CNS targets, but Ligand B is preferable.

**logP:** Ligand A (0.514) is quite low, potentially hindering permeability. Ligand B (1.256) is better, falling within the optimal 1-3 range. This is a significant advantage for Ligand B.

**H-Bond Donors/Acceptors:** Both have 1 HBD, which is good. Ligand A has 4 HBA, while Ligand B has 3. Both are acceptable (<=10).

**QED:** Ligand B (0.812) has a higher QED score than Ligand A (0.593), indicating better overall drug-likeness.

**DILI:** Ligand A (20.047) has a higher DILI risk than Ligand B (10.237), though both are relatively low and considered good.

**BBB:** Ligand B (79.992) has a significantly higher BBB penetration percentile than Ligand A (43.583). This is a *critical* advantage for a CNS target like DRD2.

**Caco-2 Permeability:** Ligand A (-5.038) has worse Caco-2 permeability than Ligand B (-4.755), although both are negative and indicate poor permeability.

**Aqueous Solubility:** Ligand A (-1.062) has slightly better aqueous solubility than Ligand B (-2.362).

**hERG:** Ligand A (0.107) has a lower hERG inhibition liability than Ligand B (0.342), which is preferable.

**Microsomal Clearance:** Ligand B (42.782) has significantly lower microsomal clearance than Ligand A (6.731), indicating better metabolic stability.

**In vitro Half-Life:** Ligand B (-5.807) has a longer in vitro half-life than Ligand A (-3.77), which is desirable.

**P-gp Efflux:** Ligand A (0.011) has lower P-gp efflux liability than Ligand B (0.028), which is preferable for CNS penetration.

**Binding Affinity:** Ligand B (-7.9 kcal/mol) has a stronger binding affinity than Ligand A (-7.3 kcal/mol). This is a substantial advantage, exceeding the 1.5 kcal/mol threshold.

**Overall Assessment:**

Ligand B is clearly superior. While Ligand A has slightly better hERG and P-gp efflux, Ligand B excels in the most critical areas for a CNS-targeting GPCR: BBB penetration, binding affinity, metabolic stability (lower Cl_mic, longer t1/2), and drug-likeness (higher QED). The improved logP of Ligand B is also a significant benefit. The higher affinity of Ligand B can potentially offset the slightly less favorable hERG and P-gp properties.

Output:
1
2025-04-17 06:51:26,936 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (346.383 and 349.431 Da) fall comfortably within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (87.15) is better than Ligand B (89.43). Both are below the 90 A^2 threshold for CNS targets, which is good.

**3. logP:** Both ligands have similar logP values (1.514 and 1.544), falling within the optimal 1-3 range.

**4. H-Bond Donors:** Ligand A has 1 HBD, while Ligand B has 2. Both are within the acceptable limit of <=5.

**5. H-Bond Acceptors:** Ligand A has 4 HBA, and Ligand B has 5. Both are within the acceptable limit of <=10.

**6. QED:** Ligand A (0.873) has a significantly better QED score than Ligand B (0.577), indicating a more drug-like profile.

**7. DILI:** Both ligands have acceptable DILI risk (50.523 and 55.176, both <60).

**8. BBB:** Ligand A (76.037) has a substantially better BBB percentile than Ligand B (59.093). This is a *critical* factor for a CNS target like DRD2.

**9. Caco-2:** Ligand A (-4.472) and Ligand B (-5.2) both have negative Caco-2 values, indicating poor permeability. This is a concern for both.

**10. Solubility:** Ligand A (-2.241) and Ligand B (-3.017) both have negative solubility values, indicating poor solubility. This is a concern for both.

**11. hERG:** Both ligands have low hERG inhibition risk (0.02 and 0.204).

**12. Cl_mic:** Ligand A (22.417) has lower microsomal clearance than Ligand B (27.479), suggesting better metabolic stability.

**13. t1/2:** Ligand A (-18.46) has a negative in vitro half-life, which is concerning. Ligand B (11.049) has a positive half-life, which is better.

**14. Pgp:** Both ligands have very low Pgp efflux liability (0.006 and 0.114).

**15. Binding Affinity:** Ligand B (-7.6 kcal/mol) has a significantly stronger binding affinity than Ligand A (0.0 kcal/mol). This is a major advantage, potentially outweighing some of the ADME drawbacks.

**Overall Assessment:**

While Ligand A has better QED, BBB, and metabolic stability, the significantly stronger binding affinity of Ligand B (-7.6 vs 0.0 kcal/mol) is a decisive factor. The difference in affinity is substantial (>1.5 kcal/mol advantage). Although Ligand B has a lower BBB score and a less favorable half-life, the strong binding is likely to drive efficacy. The poor Caco-2 and solubility of both compounds would need to be addressed through formulation or further chemical modification, but the potency advantage of Ligand B is too significant to ignore.

Output:
1
2025-04-17 06:51:26,936 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 drug candidates, considering the provided guidelines and GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (360.351 and 352.475 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (49.41) is significantly better than Ligand B (76.66). For CNS targets, we want TPSA <= 90, and A is comfortably within this range, while B is approaching the upper limit. This favors A.

**3. logP:** Both ligands have acceptable logP values (2.821 and 1.795), falling within the optimal 1-3 range. Ligand A is slightly higher, which could be beneficial for membrane permeability.

**4. H-Bond Donors:** Both have acceptable HBD counts (1 and 2, respectively), well below the threshold of 5.

**5. H-Bond Acceptors:** Both have acceptable HBA counts (2 and 4, respectively), below the threshold of 10.

**6. QED:** Ligand A (0.821) has a substantially better QED score than Ligand B (0.62), indicating a more drug-like profile.

**7. DILI:** Ligand A (35.983) has a lower DILI risk than Ligand B (25.669), which is favorable.

**8. BBB:** Ligand A (79.333) has a significantly higher BBB penetration percentile than Ligand B (66.266). This is *crucial* for a CNS target like DRD2, and strongly favors A.

**9. Caco-2 Permeability:** Both have negative Caco-2 values (-4.408 and -4.494). These values are unusual and likely represent logPapp values, where lower (more negative) values indicate lower permeability. Both are poor, but similar.

**10. Aqueous Solubility:** Both have negative solubility values (-3.032 and -2.832). These are also unusual and likely represent logS values, where lower (more negative) values indicate lower solubility. Both are poor, but similar.

**11. hERG Inhibition:** Ligand A (0.714) has a slightly higher hERG inhibition risk than Ligand B (0.151), but both are relatively low.

**12. Microsomal Clearance:** Ligand B (75.178) has a much higher microsomal clearance than Ligand A (8.716), suggesting lower metabolic stability. This favors A.

**13. In vitro Half-Life:** Ligand A (5.223) has a longer in vitro half-life than Ligand B (-11.706). The negative value for B is concerning and suggests rapid degradation. This strongly favors A.

**14. P-gp Efflux:** Ligand A (0.027) has a much lower P-gp efflux liability than Ligand B (0.127), indicating better potential for CNS exposure. This favors A.

**15. Binding Affinity:** Ligand A (-9.4 kcal/mol) has a significantly stronger binding affinity than Ligand B (-7.6 kcal/mol). The difference of 1.8 kcal/mol is substantial and can outweigh minor ADME drawbacks.

**Overall Assessment:**

Ligand A consistently outperforms Ligand B across most critical parameters, especially those prioritized for GPCRs targeting the CNS (BBB, TPSA, Pgp). The significantly better BBB penetration, lower P-gp efflux, stronger binding affinity, and improved metabolic stability (lower Cl_mic and longer t1/2) make Ligand A a much more promising drug candidate. While both have poor Caco-2 and solubility values, the superior profile of A outweighs this concern.

Output:
1
2025-04-17 06:51:26,936 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (367.486 and 354.407 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (54.45) is excellent, well below the 90 A^2 threshold for CNS targets. Ligand B (108.05) is higher, but still potentially acceptable, though less ideal.

**logP:** Ligand A (2.82) is optimal (1-3). Ligand B (-1.669) is significantly lower, which could hinder membrane permeability and CNS penetration.

**H-Bond Donors/Acceptors:** Ligand A (0 HBD, 3 HBA) is favorable. Ligand B (2 HBD, 6 HBA) is also reasonable, but higher HBA could slightly impact permeability.

**QED:** Both ligands have acceptable QED scores (0.822 and 0.552, both >0.5).

**DILI:** Ligand A (34.665) has a lower DILI risk than Ligand B (26.755), both are good.

**BBB:** Ligand A (92.749) has excellent BBB penetration potential, exceeding the 70% threshold. Ligand B (29.74) is very poor for CNS penetration. This is a critical difference given the target.

**Caco-2 Permeability:** Ligand A (-4.651) has poor Caco-2 permeability. Ligand B (-5.175) also has poor Caco-2 permeability.

**Aqueous Solubility:** Ligand A (-3.374) has poor aqueous solubility. Ligand B (-0.425) has poor aqueous solubility.

**hERG Inhibition:** Ligand A (0.562) has a very low hERG risk. Ligand B (0.021) has a very low hERG risk.

**Microsomal Clearance:** Ligand A (34.17) has moderate clearance. Ligand B (3.252) has very low clearance, indicating better metabolic stability.

**In vitro Half-Life:** Ligand A (0.656) has a short half-life. Ligand B (-20.296) has a very long half-life.

**P-gp Efflux:** Ligand A (0.308) has low P-gp efflux liability, which is good for CNS exposure. Ligand B (0.003) has very low P-gp efflux liability, which is even better.

**Binding Affinity:** Ligand A (-8.2 kcal/mol) has a significantly stronger binding affinity than Ligand B (-6.9 kcal/mol). The difference of 1.3 kcal/mol is substantial.

**Overall Assessment:**

Ligand A is superior due to its excellent BBB penetration, strong binding affinity, and low hERG risk. While its Caco-2 permeability and aqueous solubility are poor, the strong affinity and favorable CNS properties outweigh these drawbacks for a CNS-targeting GPCR like DRD2. Ligand B's poor logP and BBB penetration are major liabilities, despite its improved metabolic stability and P-gp efflux profile. The affinity difference is also significant.

Output:
1
2025-04-17 06:51:26,936 - INFO - Reasoning:

Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (356.323 and 347.411 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (83.8) is better than Ligand B (76.07). Both are below the 90 A^2 threshold desirable for CNS targets, which is excellent.

**3. logP:** Both ligands have good logP values (3.051 and 2.427), falling within the optimal 1-3 range.

**4. H-Bond Donors:** Ligand A (3) is slightly higher than Ligand B (1), but both are within the acceptable limit of <=5.

**5. H-Bond Acceptors:** Ligand A (3) and Ligand B (4) are both within the acceptable limit of <=10.

**6. QED:** Both ligands have good QED values (0.739 and 0.8), indicating good drug-like properties.

**7. DILI:** Both ligands have acceptable DILI risk (65.103 and 60.915), below the concerning threshold of 60.

**8. BBB:** Ligand A (87.67) significantly outperforms Ligand B (55.332) in BBB penetration. This is *crucial* for a CNS target like DRD2.

**9. Caco-2 Permeability:** Ligand A (-5.363) is slightly better than Ligand B (-4.644), indicating better intestinal absorption.

**10. Aqueous Solubility:** Ligand A (-4.113) is better than Ligand B (-2.706), suggesting improved formulation potential.

**11. hERG Inhibition:** Ligand A (0.861) is better than Ligand B (0.138), indicating lower cardiotoxicity risk.

**12. Microsomal Clearance:** Ligand A (-2.904) is significantly better than Ligand B (9.323). Lower clearance means greater metabolic stability, a desirable trait.

**13. In vitro Half-Life:** Ligand A (24.774) is better than Ligand B (10.386), suggesting a longer duration of action.

**14. P-gp Efflux:** Ligand A (0.304) is better than Ligand B (0.051), meaning less efflux and potentially better CNS exposure.

**15. Binding Affinity:** Ligand B (-8.2) has a significantly stronger binding affinity than Ligand A (-10). This is a substantial advantage. However, the difference is not large enough to overcome the multiple ADME advantages of Ligand A.

**Overall Assessment:**

While Ligand B has a slightly better binding affinity, Ligand A demonstrates significantly superior ADME properties, particularly regarding BBB penetration (87.67 vs 55.332), microsomal clearance, and P-gp efflux. For a CNS GPCR target like DRD2, these factors are paramount. The better BBB penetration of Ligand A will likely translate to higher brain exposure and efficacy. The improved metabolic stability and reduced efflux also contribute to a more favorable pharmacokinetic profile.

Output:
1
2025-04-17 06:51:26,936 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (349.475 and 352.385 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Both ligands (74.57 and 75.19) are below the 90 A^2 threshold desirable for CNS targets, which is excellent.

**3. logP:** Both ligands have similar logP values (1.944 and 1.965), falling comfortably within the optimal 1-3 range.

**4. H-Bond Donors:** Ligand A has 2 HBD, while Ligand B has 1. Both are acceptable (<=5).

**5. H-Bond Acceptors:** Both ligands have 4 HBA, well within the acceptable limit of <=10.

**6. QED:** Both ligands have good QED scores (0.753 and 0.794), indicating drug-like properties.

**7. DILI:** Ligand A (24.467) has a significantly lower DILI risk than Ligand B (52.695). This is a substantial advantage.

**8. BBB:** Ligand B (87.476) has a much higher BBB penetration percentile than Ligand A (47.732). This is a *critical* advantage for a CNS target like DRD2.

**9. Caco-2 Permeability:** Both have negative Caco-2 values (-4.737 and -4.776). This is unusual and suggests poor permeability. However, these values are on a log scale and are difficult to interpret without knowing the original units. We'll consider this a neutral point for now, but it's a flag for further investigation.

**10. Aqueous Solubility:** Both ligands have negative solubility values (-1.715 and -1.894). Similar to Caco-2, these are on a log scale and suggest poor solubility. This is a concern, but not a deal-breaker if other properties are strong.

**11. hERG Inhibition:** Both ligands show low hERG inhibition risk (0.343 and 0.412).

**12. Microsomal Clearance:** Ligand A (23.067) has a higher microsomal clearance than Ligand B (10.211), indicating lower metabolic stability. Ligand B is preferred here.

**13. In vitro Half-Life:** Ligand B (-15.151) has a significantly longer in vitro half-life than Ligand A (4.414). This is a major advantage.

**14. P-gp Efflux:** Ligand A (0.164) has lower P-gp efflux liability than Ligand B (0.03). Lower P-gp efflux is generally preferred, especially for CNS targets, giving a slight edge to Ligand A.

**15. Binding Affinity:** Ligand B (-8.9 kcal/mol) has a slightly stronger binding affinity than Ligand A (-8.2 kcal/mol). While the difference is not huge, it's still a positive for Ligand B.

**Overall Assessment:**

Ligand B clearly wins out. While Ligand A has a better DILI profile and slightly lower P-gp efflux, Ligand B's *significantly* higher BBB penetration, longer half-life, and slightly better binding affinity are far more important for a CNS GPCR target like DRD2. The negative Caco-2 and solubility values are concerning for both, but can potentially be addressed through formulation strategies. The improved metabolic stability (lower Cl_mic) of Ligand B is also a significant benefit.

Output:
1
2025-04-17 06:51:26,936 - INFO - Batch 316 complete. Total preferences: 5056
2025-04-17 06:51:26,936 - INFO - Processing batch 317/512...
2025-04-17 06:52:08,016 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (362.836 Da) is slightly lower, which could be beneficial for permeability.

**TPSA:** Ligand A (57.26) is significantly better than Ligand B (86.88). For CNS targets, TPSA should be <= 90, and A is comfortably within this range, while B is approaching the upper limit.

**logP:** Both ligands have good logP values (A: 3.839, B: 3.363), falling within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A (HBD=2, HBA=3) is slightly more favorable than Ligand B (HBD=3, HBA=4), but both are acceptable.

**QED:** Both ligands have reasonable QED scores (A: 0.849, B: 0.743), indicating good drug-like properties.

**DILI:** Both ligands have similar DILI risk (A: 74.99, B: 73.672), and are within an acceptable range (<80).

**BBB:** Ligand A (80.419) has a significantly better BBB percentile than Ligand B (48.468). This is *critical* for a CNS target like DRD2.

**Caco-2 Permeability:** Ligand A (-4.777) has a more favorable Caco-2 permeability than Ligand B (-5.23), suggesting better intestinal absorption.

**Aqueous Solubility:** Ligand A (-5.126) has slightly better solubility than Ligand B (-4.527).

**hERG:** Both ligands have low hERG inhibition liability (A: 0.644, B: 0.305), which is good.

**Microsomal Clearance:** Ligand A (51.949) has a higher microsomal clearance than Ligand B (34.91), suggesting lower metabolic stability.

**In vitro Half-Life:** Ligand A (53.839) has a longer in vitro half-life than Ligand B (13.791).

**P-gp Efflux:** Ligand A (0.319) has lower P-gp efflux liability than Ligand B (0.293), which is favorable for CNS penetration.

**Binding Affinity:** Both ligands have excellent binding affinity (-9.6 kcal/mol for A and -9.3 kcal/mol for B). The difference of 0.3 kcal/mol is not substantial enough to outweigh the ADME advantages of Ligand A.

**Conclusion:**

Considering the GPCR-specific priorities, Ligand A is the superior candidate. Its significantly better BBB penetration, lower TPSA, and better Caco-2 permeability, coupled with a comparable binding affinity, make it more likely to be a viable drug candidate for DRD2. While Ligand A has slightly higher clearance, the other advantages outweigh this drawback.

Output:
1
2025-04-17 06:52:08,016 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 drug candidates, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands fall within the ideal range (200-500 Da). Ligand A (403.28 Da) is slightly higher, but acceptable. Ligand B (350.419 Da) is also good.

**TPSA:** Ligand A (59.73) is excellent for CNS penetration, well below the 90 A^2 threshold. Ligand B (96.55) is higher, but still potentially acceptable, though less ideal.

**logP:** Ligand A (3.335) is within the optimal range (1-3). Ligand B (0.572) is quite low, which could hinder membrane permeability and CNS penetration, despite its other properties.

**H-Bond Donors/Acceptors:** Ligand A (0 HBD, 5 HBA) is good. Ligand B (2 HBD, 5 HBA) is also acceptable.

**QED:** Both ligands have good QED scores (A: 0.656, B: 0.782), indicating drug-like properties.

**DILI:** Ligand A (72.043) has a higher DILI risk than Ligand B (46.413), but both are below the concerning threshold of 60.

**BBB:** Ligand A (73.594) has a very good BBB percentile, highly desirable for a CNS target. Ligand B (47.693) is significantly lower, raising concerns about CNS exposure.

**Caco-2 Permeability:** Both have negative Caco-2 values which is unusual and may indicate issues with the prediction method or the compounds themselves. However, we can still compare their relative values. Ligand A (-4.728) is better than Ligand B (-4.914).

**Aqueous Solubility:** Both ligands have negative solubility values, which is also unusual. Ligand B (-2.576) is slightly better than Ligand A (-3.656).

**hERG Inhibition:** Both ligands show low hERG inhibition liability (A: 0.755, B: 0.27), which is favorable.

**Microsomal Clearance:** Ligand A (107.195) has higher clearance than Ligand B (-10.691), suggesting lower metabolic stability. Ligand B's negative value is unusual and may indicate very high stability.

**In vitro Half-Life:** Ligand A (37.57 hours) has a reasonable half-life. Ligand B (22.331 hours) is shorter, potentially requiring more frequent dosing.

**P-gp Efflux:** Ligand A (0.775) shows moderate P-gp efflux, while Ligand B (0.029) shows very low efflux, which is excellent for CNS penetration.

**Binding Affinity:** Ligand A (-7.9 kcal/mol) has significantly stronger binding affinity than Ligand B (-6.8 kcal/mol). This is a substantial difference (1.1 kcal/mol), and can often outweigh minor ADME drawbacks.

**Overall Assessment:**

Ligand A excels in binding affinity and BBB penetration, which are critical for a CNS GPCR target. While its DILI risk and clearance are slightly higher, the strong binding and good CNS penetration are significant advantages. Ligand B has better P-gp efflux and a slightly better DILI profile, but its low logP and significantly lower BBB penetration are major drawbacks for a CNS-targeting drug. The affinity difference is also substantial.

Output:
1
2025-04-17 06:52:08,016 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 drug candidates, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (353.398 and 346.427 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (89.35) is better than Ligand B (80.57), both are below the 90 A^2 threshold for CNS targets, which is excellent.

**3. logP:** Ligand B (2.287) is within the optimal 1-3 range, while Ligand A (0.129) is significantly low. Low logP can hinder membrane permeability.

**4. H-Bond Donors:** Ligand A (1) is preferable to Ligand B (2). Fewer HBDs generally improve permeability.

**5. H-Bond Acceptors:** Ligand A (6) is preferable to Ligand B (4). Fewer HBAs generally improve permeability.

**6. QED:** Ligand A (0.831) has a much higher QED score than Ligand B (0.408), indicating a more drug-like profile.

**7. DILI:** Ligand B (33.695) has a significantly lower DILI risk than Ligand A (49.515), which is a substantial advantage.

**8. BBB:** Ligand A (71.811) has a better BBB percentile than Ligand B (56.805), though both are acceptable. This is a critical factor for a CNS target like DRD2.

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5 and -5.011), which is unusual and problematic. It suggests poor intestinal absorption.

**10. Aqueous Solubility:** Both ligands have negative solubility values (-1.471 and -1.986), which is also problematic and suggests poor solubility.

**11. hERG Inhibition:** Ligand A (0.073) has a lower hERG inhibition liability than Ligand B (0.288), which is preferable.

**12. Microsomal Clearance:** Ligand A (1.472) has a significantly lower microsomal clearance than Ligand B (32.158), indicating better metabolic stability.

**13. In vitro Half-Life:** Ligand A (-9.213) has a much longer in vitro half-life than Ligand B (14.152).

**14. P-gp Efflux:** Ligand A (0.014) has a much lower P-gp efflux liability than Ligand B (0.159), which is crucial for CNS penetration.

**15. Binding Affinity:** Ligand B (-8.2) has a slightly better binding affinity than Ligand A (-7.5), a difference of 0.7 kcal/mol.

**Overall Assessment:**

Despite Ligand B having slightly better affinity and DILI risk, Ligand A is the stronger candidate. The significantly better BBB penetration, lower P-gp efflux, lower microsomal clearance, longer half-life, and higher QED outweigh the small affinity difference. The low logP of Ligand A is a concern, but the other favorable properties are more critical for a CNS GPCR target. The negative Caco-2 and solubility values are concerning for both, and would require further investigation and potential formulation strategies.

Output:
1
2025-04-17 06:52:08,016 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (342.439 and 347.415 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (58.64) is significantly better than Ligand B (87.74). For CNS targets, we want TPSA <= 90, and A is comfortably within this range, while B is approaching the upper limit.

**3. logP:** Both ligands have similar logP values (1.891 and 1.981), falling within the optimal 1-3 range.

**4. H-Bond Donors:** Ligand A (1) is preferable to Ligand B (2). Lower HBD generally improves permeability.

**5. H-Bond Acceptors:** Ligand A (3) is preferable to Ligand B (4). Lower HBA generally improves permeability.

**6. QED:** Ligand A (0.913) is better than Ligand B (0.815), indicating a more drug-like profile.

**7. DILI:** Ligand A (30.826) has a significantly lower DILI risk than Ligand B (50.64). Both are below the 60 threshold, but A is much safer.

**8. BBB:** Both ligands have good BBB penetration (76.658 and 70.686), but Ligand A is slightly better. A value >70 is desirable for CNS targets, and both meet this.

**9. Caco-2 Permeability:** Both have negative Caco-2 values (-4.336 and -4.536), which is unusual and suggests poor permeability. However, these values are on a scale where negative values are possible, and the absolute values are similar.

**10. Aqueous Solubility:** Both have negative solubility values (-2.979 and -2.456), which is also unusual. Similar to Caco-2, the absolute values are close.

**11. hERG Inhibition:** Both ligands show low hERG inhibition liability (0.327 and 0.123), which is good.

**12. Microsomal Clearance:** Ligand B (15.797) has significantly lower microsomal clearance than Ligand A (55.584), suggesting better metabolic stability.

**13. In vitro Half-Life:** Ligand A (28.776) has a much longer in vitro half-life than Ligand B (-5.989). A negative half-life is unusual and problematic.

**14. P-gp Efflux:** Ligand A (0.139) has lower P-gp efflux than Ligand B (0.038), which is desirable for CNS exposure.

**15. Binding Affinity:** Ligand B (-9.4) has a slightly better binding affinity than Ligand A (-8.5). This is a 0.9 kcal/mol difference, which is significant.

**Overall Assessment:**

While Ligand B has a slightly better binding affinity, Ligand A is superior in most other critical ADME properties, particularly TPSA, QED, DILI, BBB, and in vitro half-life. The negative Caco-2 and solubility values are concerning for both, but their similarity suggests a potential issue with the prediction method rather than a fundamental difference between the compounds. The significantly better metabolic stability of Ligand B is a positive, but the other advantages of Ligand A, especially its lower DILI risk and better CNS penetration potential (higher BBB, lower Pgp), make it the more promising candidate for a CNS-targeting drug like a DRD2 ligand.

Output:
1
2025-04-17 06:52:08,017 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (344.415 Da) is slightly lower, which is generally favorable for permeability.

**2. TPSA:** Both ligands have TPSA values below 90 (A: 84.42, B: 81.33), which is excellent for CNS penetration.

**3. logP:** Both ligands have optimal logP values (A: 1.706, B: 1.106), falling within the 1-3 range.

**4. H-Bond Donors:** Ligand A (1 HBD) is preferable to Ligand B (2 HBDs). Fewer HBDs generally improve permeability.

**5. H-Bond Acceptors:** Ligand A (5 HBA) is preferable to Ligand B (4 HBA).

**6. QED:** Ligand A (0.899) has a significantly better QED score than Ligand B (0.736), indicating a more drug-like profile.

**7. DILI:** Ligand A (63.125) has a higher DILI risk than Ligand B (47.693), but both are reasonably acceptable.

**8. BBB:** Both ligands have similar BBB penetration (A: 67.895, B: 63.125). Both are acceptable, but ideally, we'd want >70 for a CNS target.

**9. Caco-2 Permeability:** Ligand A (-4.692) shows better Caco-2 permeability than Ligand B (-5.308).

**10. Aqueous Solubility:** Ligand A (-3.116) shows better aqueous solubility than Ligand B (-2.934).

**11. hERG Inhibition:** Both ligands have very low hERG inhibition risk (A: 0.196, B: 0.341).

**12. Microsomal Clearance:** Ligand B (-30.761) has a lower (better) microsomal clearance than Ligand A (32.254), suggesting greater metabolic stability.

**13. In vitro Half-Life:** Ligand B (-12.708) has a longer in vitro half-life than Ligand A (-19.331).

**14. P-gp Efflux:** Both ligands have very low P-gp efflux liability (A: 0.13, B: 0.052).

**15. Binding Affinity:** Ligand B (-7.4 kcal/mol) has a significantly stronger binding affinity than Ligand A (-9.0 kcal/mol). This is a substantial advantage.

**Overall Assessment:**

While Ligand A has better QED, solubility, and Caco-2 permeability, Ligand B's significantly stronger binding affinity (-7.4 vs -9.0 kcal/mol) and improved metabolic stability (lower Cl_mic and longer t1/2) are crucial for a GPCR target. The difference in binding affinity is substantial enough to outweigh the slightly less favorable QED and solubility of Ligand B. Both have acceptable BBB penetration.

Output:
1
2025-04-17 06:52:08,017 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (358.36 and 345.443 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (61.8) is significantly better than Ligand B (80.32). For CNS targets, we want TPSA <= 90, and A is comfortably within that, while B is approaching the upper limit.

**logP:** Both ligands have good logP values (2.671 and 1.657), falling within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Both have 2 HBDs, which is good. Ligand A has 3 HBAs, and Ligand B has 4. Both are acceptable (<=10).

**QED:** Ligand A (0.87) is superior to Ligand B (0.632), indicating a more drug-like profile.

**DILI:** Ligand A (20.9) has a much lower DILI risk than Ligand B (28.306), which is a significant advantage.

**BBB:** Ligand A (81.504) has a much better BBB penetration percentile than Ligand B (43.777). This is *critical* for a CNS target like DRD2.

**Caco-2 Permeability:** Both have negative Caco-2 values (-4.509 and -4.848), which is unusual and suggests poor permeability. However, the absolute values are similar.

**Aqueous Solubility:** Both have negative solubility values (-3.046 and -2.064), indicating poor aqueous solubility. This is a concern for both.

**hERG:** Ligand A (0.702) has a slightly higher hERG risk than Ligand B (0.164), but both are relatively low.

**Microsomal Clearance:** Ligand A (13.095) has a higher microsomal clearance than Ligand B (8.354), meaning it's less metabolically stable.

**In vitro Half-Life:** Ligand A (-11.147) has a *much* worse in vitro half-life than Ligand B (12.343). This is a major drawback for Ligand A.

**P-gp Efflux:** Ligand A (0.081) has a lower P-gp efflux liability than Ligand B (0.022), which is favorable for CNS penetration.

**Binding Affinity:** Ligand A (-8.9 kcal/mol) has a significantly stronger binding affinity than Ligand B (-7.4 kcal/mol). This is a substantial advantage, potentially outweighing some of the ADME concerns.

**Overall Assessment:**

While Ligand A has a superior binding affinity and better BBB penetration, its poor metabolic stability (high Cl_mic, very low t1/2) and moderate DILI risk are concerning. Ligand B has better metabolic stability and lower DILI, but its BBB penetration is poor and its affinity is weaker. Given the importance of BBB penetration for a CNS target like DRD2, and the significant affinity advantage of Ligand A, I would lean towards Ligand A *if* the metabolic stability issues could be addressed through structural modifications. However, considering the current data, the substantial difference in half-life makes Ligand B the more viable candidate.

Output:
1
2025-04-17 06:52:08,017 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (348.462 and 348.359 Da) fall comfortably within the ideal 200-500 Da range.

**TPSA:** Ligand A (40.62) is significantly better than Ligand B (119.49). For CNS targets, TPSA should be <=90, and A is well within this, while B is considerably above. This is a major advantage for A.

**logP:** Ligand A (2.503) is optimal (1-3), while Ligand B (0.383) is quite low, potentially hindering permeation.

**H-Bond Donors/Acceptors:** Ligand A (0 HBD, 2 HBA) is better than Ligand B (2 HBD, 7 HBA) in terms of balancing solubility and permeability.

**QED:** Both ligands have good QED scores (A: 0.474, B: 0.774), indicating reasonable drug-likeness. B is slightly better here.

**DILI:** Ligand A (16.324) has a much lower DILI risk than Ligand B (68.825). This is a significant advantage for A.

**BBB:** Ligand A (91.237) has excellent BBB penetration, exceeding the desirable >70% threshold. Ligand B (50.64) is considerably lower and less favorable for a CNS target.

**Caco-2 Permeability:** Ligand A (-4.344) has poor Caco-2 permeability. Ligand B (-5.262) is also poor, but slightly worse.

**Aqueous Solubility:** Ligand A (-3.271) has poor aqueous solubility. Ligand B (-2.109) is better, but still not ideal.

**hERG:** Both ligands have low hERG inhibition risk (A: 0.721, B: 0.128). B is slightly better here.

**Microsomal Clearance:** Ligand A (34.098) has higher microsomal clearance than Ligand B (12.382), indicating lower metabolic stability. B is better here.

**In vitro Half-Life:** Ligand A (-10.346) has a negative half-life, which is not physically possible and indicates a problem with the data or modeling. Ligand B (21.556) has a reasonable half-life.

**P-gp Efflux:** Ligand A (0.23) has lower P-gp efflux than Ligand B (0.024), which is favorable for CNS exposure.

**Binding Affinity:** Ligand B (-8.6 kcal/mol) has a significantly stronger binding affinity than Ligand A (-6.9 kcal/mol). This is a substantial advantage for B, potentially outweighing some of its ADME drawbacks.

**Overall Assessment:**

While Ligand B boasts a superior binding affinity, Ligand A has a much better profile regarding CNS penetration (BBB, TPSA, logP), lower DILI risk, and better P-gp efflux. The negative half-life for Ligand A is a major red flag. Ligand B's low logP and high DILI are concerns, but the significantly improved binding affinity is a strong positive. Considering the GPCR-specific priorities, and the importance of CNS penetration for a DRD2 target, Ligand A is the better candidate *if* the half-life data can be corrected. However, given the negative half-life, and the strong binding affinity of Ligand B, I am leaning toward Ligand B.

Output:
1
2025-04-17 06:52:08,017 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (341.367 and 349.431 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (104.31) is higher than Ligand B (78.95). For CNS targets, we prefer TPSA <= 90, so Ligand B is better here.

**logP:** Ligand A (1.715) is within the optimal 1-3 range. Ligand B (0.514) is slightly below 1, which *could* indicate permeability issues, though not severely. Ligand A is better.

**H-Bond Donors:** Ligand A (3) is acceptable, while Ligand B (1) is also good.

**H-Bond Acceptors:** Both ligands have 4 HBA, which is within the acceptable limit of <=10.

**QED:** Ligand A (0.768) has a better QED score than Ligand B (0.593), indicating a more drug-like profile.

**DILI:** Ligand B (20.047) has a significantly lower DILI risk than Ligand A (82.784). This is a major advantage for Ligand B.

**BBB:** Both ligands have similar BBB penetration (Ligand A: 45.211, Ligand B: 43.583). Neither is outstanding (>70), but they are comparable.

**Caco-2:** Both have negative Caco-2 values, which is unusual and likely indicates poor permeability based on the scale used.

**Solubility:** Both ligands have negative solubility values, suggesting poor aqueous solubility.

**hERG:** Both ligands have very low hERG inhibition risk (Ligand A: 0.069, Ligand B: 0.107).

**Microsomal Clearance:** Ligand A (-16.738) has *much* lower (better) microsomal clearance than Ligand B (6.731). This suggests greater metabolic stability for Ligand A.

**In vitro Half-Life:** Ligand A (-1.46) has a negative half-life, which is not possible. This is a significant red flag. Ligand B (-3.77) also has a negative half-life, which is problematic.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (Ligand A: 0.012, Ligand B: 0.011).

**Binding Affinity:** Ligand A (-9.4 kcal/mol) has a significantly stronger binding affinity than Ligand B (-7.3 kcal/mol). This is a substantial advantage, potentially outweighing some ADME drawbacks.

**Overall Assessment:**

Ligand A has a much better binding affinity and metabolic stability. However, its DILI risk is high, and its in vitro half-life is nonsensical. Ligand B has a lower DILI risk, better TPSA, but weaker affinity and poorer metabolic stability.

Given the importance of affinity for GPCRs, and the fact that the difference in affinity is >1.5 kcal/mol, I would tentatively favor Ligand A *if* the half-life and DILI issues could be addressed through structural modifications. However, the negative half-life is a major concern. The DILI risk is also concerning. Considering these issues, and the similar BBB values, Ligand B is the more viable candidate as is.

Output:
1
2025-04-17 06:52:08,018 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (358.452 and 384.933 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (42.74) is excellent, well below the 90 A^2 threshold for CNS targets. Ligand B (67.23) is higher but still acceptable, though less ideal.

**logP:** Ligand A (3.968) is at the upper end of the optimal range (1-3), while Ligand B (2.26) is closer to the lower end. Both are acceptable, but Ligand A's higher logP might aid in membrane permeability.

**H-Bond Donors/Acceptors:** Both ligands have 1 HBD and a reasonable number of HBAs (4 and 5 respectively). This is within acceptable limits.

**QED:** Both ligands have good QED scores (0.679 and 0.764), indicating good drug-like properties.

**DILI:** Ligand A (14.036) has a very low DILI risk, significantly better than Ligand B (47.693).

**BBB:** This is crucial for a CNS target. Ligand A (92.323) has excellent BBB penetration, exceeding the desirable >70% threshold. Ligand B (31.912) is poor, falling well below the threshold.

**Caco-2 Permeability:** Ligand A (-4.727) and Ligand B (-5.025) both have negative values, which is unusual and suggests poor permeability. However, the scale is not specified, so it's hard to interpret.

**Aqueous Solubility:** Both ligands have very poor aqueous solubility (-3.637 and -3.697). This is a significant drawback.

**hERG Inhibition:** Ligand A (0.829) has a slightly higher hERG risk than Ligand B (0.089), but both are relatively low.

**Microsomal Clearance:** Ligand A (8.323) has lower microsomal clearance than Ligand B (56.629), indicating better metabolic stability.

**In vitro Half-Life:** Ligand A (13.751) has a longer half-life than Ligand B (8.653).

**P-gp Efflux:** Ligand A (0.606) has lower P-gp efflux than Ligand B (0.074), suggesting better CNS exposure.

**Binding Affinity:** Ligand A (-8.5 kcal/mol) has a significantly stronger binding affinity than Ligand B (-7.7 kcal/mol). This 1.8 kcal/mol difference is substantial and can outweigh some ADME drawbacks.

**Conclusion:**

Considering all factors, especially the GPCR-specific priorities for CNS targets, **Ligand A is the superior candidate.** Its excellent BBB penetration, strong binding affinity, low DILI risk, better metabolic stability, and lower P-gp efflux outweigh its slightly higher logP and poor solubility. While both have poor solubility and Caco-2 permeability, the superior CNS penetration and binding affinity of Ligand A make it the more promising drug candidate.

Output:
1
2025-04-17 06:52:08,018 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B based on the provided guidelines, prioritizing GPCR-specific properties (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (343.471) is slightly better, being closer to the lower end which can aid permeability.

**TPSA:** Ligand A (44.81) is excellent for CNS penetration, well below the 90 A^2 threshold. Ligand B (102.67) is higher, but still potentially acceptable, though less ideal.

**logP:** Ligand A (2.642) is within the optimal range (1-3). Ligand B (-0.354) is below 1, which could hinder permeation. This is a significant drawback for Ligand B.

**H-Bond Donors/Acceptors:** Ligand A (HBD=1, HBA=3) and Ligand B (HBD=2, HBA=7) both fall within acceptable limits.

**QED:** Both ligands have reasonable QED values (A: 0.918, B: 0.661), indicating good drug-like properties.

**DILI:** Ligand A (13.804) has a much lower DILI risk than Ligand B (21.791). This is a significant advantage.

**BBB:** Ligand A (90.617) has excellent BBB penetration, exceeding the 70% threshold. Ligand B (17.1) is very poor for CNS penetration. This is a critical difference given the target (DRD2).

**Caco-2 Permeability:** Ligand A (-4.325) and Ligand B (-5.141) both have negative values, suggesting poor permeability. This is not ideal, but less critical than BBB for a CNS target.

**Aqueous Solubility:** Both ligands have poor aqueous solubility (-2.251 and -2.159 respectively). This could pose formulation challenges, but can be addressed.

**hERG Inhibition:** Ligand A (0.81) has a lower hERG risk than Ligand B (0.044).

**Microsomal Clearance:** Ligand A (0.659) has significantly lower microsomal clearance, indicating better metabolic stability, than Ligand B (17.842).

**In vitro Half-Life:** Ligand A (4.962) has a longer half-life than Ligand B (-1.813).

**P-gp Efflux:** Ligand A (0.16) has lower P-gp efflux, which is favorable for CNS exposure, compared to Ligand B (0.007).

**Binding Affinity:** Ligand A (-8.2 kcal/mol) has a significantly stronger binding affinity than Ligand B (-6.7 kcal/mol). This difference in affinity is substantial (>1.5 kcal/mol) and can outweigh some ADME drawbacks.

**Overall:**

Ligand A is clearly superior. It has better BBB penetration, lower DILI risk, better metabolic stability, longer half-life, lower P-gp efflux, and significantly higher binding affinity. While both have solubility and Caco-2 permeability concerns, the CNS target prioritization makes BBB and P-gp crucial, and Ligand A excels in these areas. Ligand B's negative logP and poor BBB penetration are major liabilities.

Output:
1
2025-04-17 06:52:08,018 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (339.439 and 368.503 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (65.2) is significantly better than Ligand B (96.11). For CNS targets, TPSA < 90 is preferred, and A is comfortably within this range, while B is close to the upper limit and less desirable.

**3. logP:** Ligand A (3.243) is optimal (1-3), while Ligand B (1.57) is on the lower side. While not terrible, lower logP can sometimes hinder permeability.

**4. H-Bond Donors:** Ligand A (2) is good, while Ligand B (3) is acceptable but slightly less favorable.

**5. H-Bond Acceptors:** Ligand A (2) is good, while Ligand B (5) is acceptable, but higher.

**6. QED:** Both ligands have reasonable QED values (0.821 and 0.615), indicating good drug-like properties.

**7. DILI:** Ligand A (65.917) has a higher DILI risk than Ligand B (43.738), which is a negative for A.

**8. BBB:** Both ligands have similar BBB penetration (62.117 and 62.97). While not exceptionally high (>70), they are both acceptable for a CNS target.

**9. Caco-2:** Both have negative Caco-2 values, which is unusual and difficult to interpret without knowing the scale. Assuming these are negative log values, lower values indicate better permeability, and they are similar.

**10. Solubility:** Both have negative solubility values, which is also unusual. Assuming these are negative log values, lower values indicate better solubility, and they are similar.

**11. hERG:** Ligand A (0.521) has a slightly higher hERG risk than Ligand B (0.22), which is a negative for A.

**12. Cl_mic:** Ligand B (32.927) has significantly better metabolic stability (lower clearance) than Ligand A (50.241). This is a significant advantage for B.

**13. t1/2:** Ligand A (54.021) has a longer half-life than Ligand B (6.628), which is a positive for A.

**14. Pgp:** Ligand A (0.393) has lower P-gp efflux liability than Ligand B (0.032), which is a positive for A, and crucial for CNS penetration.

**15. Binding Affinity:** Ligand A (-8.7 kcal/mol) has a significantly stronger binding affinity than Ligand B (-7.5 kcal/mol). This >1.5 kcal/mol difference is a major advantage for A, potentially outweighing some of its ADME drawbacks.

**Overall Assessment:**

Ligand A has a superior binding affinity and better Pgp efflux profile. Its TPSA is also more favorable. However, it has higher DILI and hERG risk, and slightly worse metabolic stability. Ligand B has better DILI, hERG, and metabolic stability, but a weaker binding affinity and higher TPSA.

Given the GPCR-specific priorities, the strong binding affinity of Ligand A is a critical factor. The difference in affinity is substantial. While the ADME properties of Ligand A are not ideal (DILI, hERG), these can potentially be addressed through further optimization. The weaker affinity of Ligand B is a more difficult property to improve.

Output:
1
2025-04-17 06:52:08,018 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (376.523 and 373.475 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (121.6) is slightly above the optimal <90 for CNS targets, but still reasonable. Ligand B (104.81) is better, falling comfortably under 90.

**logP:** Ligand A (0.371) is quite low, potentially hindering permeability. Ligand B (-0.257) is also low, with similar concerns. Both are below the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A (3 HBD, 4 HBA) is within acceptable limits. Ligand B (2 HBD, 6 HBA) is also acceptable.

**QED:** Both ligands have reasonable QED scores (0.477 and 0.596), indicating acceptable drug-likeness. Ligand B is slightly better.

**DILI:** Both ligands have similar, relatively low DILI risk (33.695 and 43.544), both below the 40 threshold.

**BBB:** Ligand A (43.815) and Ligand B (41.528) both have low BBB penetration, which is a significant drawback for a CNS target like DRD2. This is a critical factor.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.38 and -5.84), which is unusual and suggests very poor permeability. This is concerning.

**Aqueous Solubility:** Both ligands have negative solubility values (-1.785 and -1.335), indicating very poor aqueous solubility. This is a major issue for bioavailability.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.219 and 0.077), which is positive.

**Microsomal Clearance:** Ligand A (40.419) has a moderate clearance, while Ligand B (-13.115) has a negative clearance, which is not physically possible and suggests an issue with the data or modeling.

**In vitro Half-Life:** Both ligands have negative half-lives (-7.543 and -8.388), which is not physically possible and indicates a problem with the data.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.006 and 0.009), which is favorable for CNS penetration.

**Binding Affinity:** Both ligands have very similar and strong binding affinities (-7.1 and -7.2 kcal/mol). The difference is negligible.

**Overall Assessment:**

Both ligands have significant issues with solubility, permeability, and BBB penetration. The negative values for Caco-2, solubility, and half-life are particularly concerning and suggest data errors or significant modeling limitations. However, considering the available (though flawed) data, Ligand B is slightly preferable due to its better TPSA, QED, and slightly better (less negative) clearance and half-life values. The affinity is essentially the same. The negative clearance and half-life values for Ligand B are highly suspect, but given the overall profile, it is marginally better than Ligand A.

Output:
1
2025-04-17 06:52:08,019 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (364.47 and 350.46 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (76.66) is better than Ligand B (87.47). Both are below 90, which is good for CNS penetration, but A is closer to the optimal range.

**3. logP:** Both ligands have good logP values (1.091 and 1.48), falling within the 1-3 range.

**4. H-Bond Donors:** Both have 2 HBD, which is acceptable.

**5. H-Bond Acceptors:** Both have 5 HBA, which is acceptable.

**6. QED:** Ligand A (0.818) has a slightly better QED than Ligand B (0.741), indicating a more drug-like profile.

**7. DILI:** Ligand A (40.29) is better than Ligand B (15.55). Both are good, but B is significantly lower risk.

**8. BBB:** Ligand B (62.97) is better than Ligand A (56.84). While both are not ideal (>70), B is closer to the desired threshold for CNS targets.

**9. Caco-2:** Ligand A (-5.13) is better than Ligand B (-5.40). Higher values indicate better intestinal absorption.

**10. Solubility:** Ligand B (-1.11) is better than Ligand A (-2.65). Higher values are better.

**11. hERG:** Both ligands have very low hERG inhibition risk (0.093 and 0.165).

**12. Cl_mic:** Ligand B (6.54) has a significantly lower microsomal clearance than Ligand A (47.66), suggesting better metabolic stability.

**13. t1/2:** Ligand A (7.90) has a longer in vitro half-life than Ligand B (-4.88). Longer is preferred.

**14. Pgp:** Ligand A (0.056) has lower P-gp efflux liability than Ligand B (0.028), which is favorable for CNS penetration.

**15. Binding Affinity:** Ligand B (-7.6 kcal/mol) has a stronger binding affinity than Ligand A (-7.1 kcal/mol). This is a significant advantage (0.5 kcal/mol difference).

**Overall Assessment:**

Ligand B has a better binding affinity, lower DILI risk, better BBB penetration, and better metabolic stability (lower Cl_mic). While Ligand A has a slightly better QED, Caco-2, and in vitro half-life, the advantages of Ligand B in affinity, BBB, and metabolic stability are more important for a CNS-targeting GPCR like DRD2. The 0.5 kcal/mol difference in binding affinity is substantial enough to outweigh the minor drawbacks of Ligand B.

Output:
1
2025-04-17 06:52:08,019 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 drug candidates, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (352.406 and 341.411 Da) fall within the ideal 200-500 Da range. No significant difference here.

**2. TPSA:** Ligand A (87.66) is slightly higher than Ligand B (63.69). For CNS targets, we prefer TPSA <= 90, so both are acceptable, but Ligand B is better.

**3. logP:** Both ligands have good logP values (2.604 and 3.257), falling within the optimal 1-3 range. Ligand B is slightly higher, which *could* be a minor advantage for membrane permeability, but isn't a major concern for either.

**4. H-Bond Donors:** Ligand A has 3 HBD, and Ligand B has 1. Both are within the preferred limit of <= 5. Ligand B is better here.

**5. H-Bond Acceptors:** Both ligands have 4 HBA, well within the acceptable limit of <= 10.

**6. QED:** Both ligands have good QED scores (0.687 and 0.907), indicating good drug-like properties. Ligand B is better.

**7. DILI:** Ligand A (41.954) has a lower DILI risk than Ligand B (56.727). This is a significant advantage for Ligand A.

**8. BBB:** Ligand A (80.264) has a better BBB penetration percentile than Ligand B (73.594). This is crucial for a CNS target like DRD2, making Ligand A more promising.

**9. Caco-2 Permeability:** Both have negative Caco-2 values (-4.344 and -4.423). This is unusual and suggests poor permeability. However, these values are on a scale where negative values are possible, and the absolute difference is small.

**10. Aqueous Solubility:** Both have negative solubility values (-3.575 and -3.532). Again, this is unusual and suggests poor solubility. The difference is minimal.

**11. hERG Inhibition:** Both ligands have low hERG inhibition liability (0.455 and 0.62), which is good.

**12. Microsomal Clearance:** Ligand A (58.219) has higher microsomal clearance than Ligand B (28.96). This means Ligand B is more metabolically stable, which is desirable.

**13. In vitro Half-Life:** Ligand A (22.047) has a longer half-life than Ligand B (8.772). This is a positive for Ligand A.

**14. P-gp Efflux:** Ligand A (0.179) has lower P-gp efflux than Ligand B (0.05). Lower efflux is better for CNS exposure, favoring Ligand A.

**15. Binding Affinity:** Ligand A (-8.9 kcal/mol) has a slightly better binding affinity than Ligand B (-8.1 kcal/mol). While both are excellent, the 0.8 kcal/mol difference is meaningful and can outweigh some ADME drawbacks.

**Overall Assessment:**

Ligand A is the better candidate. While Ligand B has a slightly better TPSA, QED, and metabolic stability, Ligand A excels in critical areas for a CNS GPCR target: BBB penetration, P-gp efflux, binding affinity, and has a lower DILI risk and longer half-life. The affinity difference is substantial enough to compensate for the slightly higher TPSA and clearance.

Output:
1
2025-04-17 06:52:08,019 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (354.51 and 356.813 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (58.2) is significantly better than Ligand B (67.23). For CNS targets, we want TPSA <= 90, and ideally closer to 60. Ligand A is much closer to this ideal.

**3. logP:** Both ligands have good logP values (3.457 and 2.937), falling within the optimal 1-3 range.

**4. H-Bond Donors:** Ligand A (2) is slightly higher than Ligand B (1), but both are within the acceptable limit of <=5.

**5. H-Bond Acceptors:** Ligand A (2) is lower than Ligand B (4), which is preferable. We want to keep HBA <= 10.

**6. QED:** Both ligands have good QED scores (0.623 and 0.781), indicating good drug-like properties.

**7. DILI:** Ligand A (27.453) has a much lower DILI risk than Ligand B (89.608). This is a significant advantage for Ligand A.

**8. BBB:** Ligand A (67.701) is lower than Ligand B (78.79). However, both are reasonably good, and >70 is desirable for CNS targets. Ligand B is better here.

**9. Caco-2 Permeability:** Ligand A (-4.451) has worse Caco-2 permeability than Ligand B (-4.879). Lower values are worse.

**10. Aqueous Solubility:** Ligand A (-4.692) has worse aqueous solubility than Ligand B (-4.2). Lower values are worse.

**11. hERG Inhibition:** Both ligands have low hERG inhibition risk (0.683 and 0.547).

**12. Microsomal Clearance:** Ligand A (48.451) has lower microsomal clearance than Ligand B (70.94), suggesting better metabolic stability.

**13. In vitro Half-Life:** Ligand B (112.977) has a much longer in vitro half-life than Ligand A (3.518). This is a significant advantage for Ligand B.

**14. P-gp Efflux:** Ligand A (0.114) has lower P-gp efflux than Ligand B (0.616), which is beneficial for CNS penetration.

**15. Binding Affinity:** Ligand B (-9.3) has a significantly stronger binding affinity than Ligand A (-7.3). A difference of >1.5 kcal/mol is considered substantial and can outweigh other drawbacks.

**Overall Assessment:**

While Ligand A has advantages in TPSA, DILI, and P-gp efflux, Ligand B's significantly stronger binding affinity (-9.3 vs -7.3 kcal/mol) and longer half-life are major advantages, especially for a GPCR target. The better BBB penetration of Ligand B is also a plus. The higher DILI risk of Ligand B is a concern, but the substantial affinity advantage likely outweighs this, especially during lead optimization where modifications can be made to address the DILI risk.

Output:
1
2025-04-17 06:52:08,019 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (348.487 Da) is slightly lower, which is generally favorable for permeability. Ligand B (371.434 Da) is also acceptable.

**TPSA:** Ligand A (49.85) is excellent, well below the 90 A^2 threshold for CNS targets. Ligand B (114.43) is higher, but still potentially acceptable, though less ideal.

**logP:** Ligand A (2.629) is optimal (1-3). Ligand B (0.771) is a bit low, potentially hindering permeation.

**H-Bond Donors/Acceptors:** Ligand A (0 HBD, 3 HBA) is excellent. Ligand B (3 HBD, 5 HBA) is also acceptable, but more polar.

**QED:** Both ligands have good QED scores (A: 0.665, B: 0.593), indicating drug-like properties.

**DILI:** Both ligands show low DILI risk (A: 34.781, B: 35.479), both well below the 40 threshold.

**BBB:** Ligand A (79.721) has a better BBB percentile than Ligand B (74.254), which is crucial for a CNS target like DRD2. Both are above 70, which is good.

**Caco-2 Permeability:** Ligand A (-4.103) shows better Caco-2 permeability than Ligand B (-5.381).

**Aqueous Solubility:** Both ligands show poor aqueous solubility (-2.809 and -2.849). This could pose formulation challenges, but is less critical than CNS penetration for a CNS target.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (A: 0.513, B: 0.309).

**Microsomal Clearance:** Ligand A (86.241) has a higher microsomal clearance than Ligand B (26.402), indicating lower metabolic stability. Ligand B is much better here.

**In vitro Half-Life:** Ligand B (4.106) has a slightly longer half-life than Ligand A (16.065), but the values are reversed in the scale, so A is better.

**P-gp Efflux:** Ligand A (0.285) has lower P-gp efflux than Ligand B (0.074), which is favorable for CNS exposure.

**Binding Affinity:** Ligand B (-7.9 kcal/mol) has a significantly stronger binding affinity than Ligand A (-7.1 kcal/mol). This 0.8 kcal/mol difference is substantial and can outweigh some ADME drawbacks.

**Overall Assessment:**

Ligand B has a significantly better binding affinity, which is paramount for GPCR targets. While Ligand B has a slightly lower BBB and a lower logP, the substantial affinity advantage likely compensates for these. Ligand B also has better metabolic stability (lower Cl_mic). Ligand A has better Caco-2 permeability and P-gp efflux, but these are less critical than affinity and metabolic stability for a CNS target.

Output:
1
2025-04-17 06:52:08,019 - INFO - Batch 317 complete. Total preferences: 5072
2025-04-17 06:52:08,020 - INFO - Processing batch 318/512...
2025-04-17 06:52:49,015 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (346.475 Da) is slightly lower, which *could* be beneficial for permeability, but both are acceptable.

**TPSA:** Ligand A (67.23) is excellent for CNS penetration, well below the 90 A^2 threshold. Ligand B (125.8) is higher, but still potentially acceptable, though less ideal.

**logP:** Ligand A (2.594) is optimal. Ligand B (1.118) is a bit low, potentially hindering membrane permeability.

**H-Bond Donors/Acceptors:** Ligand A (HBD=1, HBA=4) is favorable. Ligand B (HBD=3, HBA=8) is also acceptable, but slightly higher values could impact permeability.

**QED:** Both ligands have acceptable QED values (A: 0.699, B: 0.595), indicating reasonable drug-likeness.

**DILI:** Ligand A (23.226) has a significantly lower DILI risk than Ligand B (98.061), which is a major concern.

**BBB:** Ligand A (76.309) has a much better BBB penetration score than Ligand B (49.011). This is *critical* for a CNS target like DRD2.

**Caco-2 Permeability:** Ligand A (-4.827) is poor, while Ligand B (-5.539) is also poor. Both are unfavorable.

**Aqueous Solubility:** Both ligands have poor aqueous solubility (-2.48 and -3.486 respectively). This could pose formulation challenges, but is less critical than BBB penetration for a CNS target.

**hERG:** Both ligands have low hERG inhibition risk (A: 0.393, B: 0.527).

**Microsomal Clearance:** Ligand A (64.198) has higher microsomal clearance than Ligand B (39.565), suggesting lower metabolic stability.

**In vitro Half-Life:** Ligand B (24.073) has a significantly longer in vitro half-life than Ligand A (-2.365), which is a positive attribute.

**P-gp Efflux:** Ligand A (0.26) has lower P-gp efflux liability than Ligand B (0.026), which is favorable for CNS exposure.

**Binding Affinity:** Ligand B (-8.1 kcal/mol) has a slightly better binding affinity than Ligand A (-7.5 kcal/mol). This is a 0.6 kcal/mol difference, which is not a huge advantage, but still relevant.

**Overall Assessment:**

Ligand A is superior due to its significantly better BBB penetration (76.3 vs 49.0), much lower DILI risk (23.2 vs 98.1), and lower P-gp efflux. While Ligand B has slightly better binding affinity and in vitro half-life, the ADME properties of Ligand A are far more favorable for a CNS-targeting drug. The poor Caco-2 permeability is a concern for both, but less critical for a CNS target where direct brain penetration is key.



Output:
0
2025-04-17 06:52:49,016 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (360.772 and 358.429 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (71.35) is higher than Ligand B (58.64). For CNS targets, we prefer TPSA <= 90, so both are acceptable, but B is better.

**3. logP:** Both ligands have good logP values (3.015 and 2.344), falling within the optimal 1-3 range.

**4. H-Bond Donors:** Both have 1 HBD, which is within the acceptable limit of <=5.

**5. H-Bond Acceptors:** Ligand A has 4 HBAs, and Ligand B has 3. Both are below the acceptable limit of <=10.

**6. QED:** Both ligands have reasonable QED scores (0.909 and 0.76), indicating good drug-like properties.

**7. DILI:** Ligand A has a DILI risk of 89.221, which is high. Ligand B has a much lower DILI risk of 15.587, which is excellent. This is a significant advantage for Ligand B.

**8. BBB:** Ligand A has a BBB penetration of 58.821, which is below the desirable threshold of >70 for CNS targets. Ligand B has a BBB penetration of 95.269, which is excellent. This is a critical advantage for Ligand B.

**9. Caco-2 Permeability:** Both have negative Caco-2 values (-4.571 and -4.608). These values are unusual and suggest poor permeability, but are on a similar scale.

**10. Aqueous Solubility:** Both have negative solubility values (-5.005 and -2.388). These are also unusual and suggest poor solubility, but are on a similar scale.

**11. hERG Inhibition:** Both ligands have low hERG inhibition liability (0.677 and 0.583), which is good.

**12. Microsomal Clearance:** Ligand A has a higher microsomal clearance (21.756) than Ligand B (1.156), suggesting lower metabolic stability. Ligand B is significantly better here.

**13. In vitro Half-Life:** Ligand A has a longer half-life (43.279) than Ligand B (-1.095). However, the negative value for B is suspect and may indicate an issue with the data.

**14. P-gp Efflux:** Ligand A has a Pgp efflux liability of 0.337, while Ligand B has 0.051. Lower is better, so Ligand B is preferred.

**15. Binding Affinity:** Both ligands have very similar binding affinities (-8.6 and -8.5 kcal/mol). The difference is negligible.

**Overall Assessment:**

Ligand B is significantly better overall, primarily due to its excellent BBB penetration (95.269 vs 58.821), much lower DILI risk (15.587 vs 89.221), and lower P-gp efflux (0.051 vs 0.337). While Ligand A has a slightly longer in vitro half-life, the negative value for Ligand B's half-life is concerning, but the other advantages of Ligand B outweigh this. The similar binding affinities mean that the improved ADME properties of Ligand B are the deciding factor.

Output:
1
2025-04-17 06:52:49,016 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (349.431 and 346.387 Da) fall comfortably within the ideal 200-500 Da range.

**TPSA:** Ligand A (80.76) is excellent, well below the 90 A^2 threshold for CNS targets. Ligand B (115.29) is higher, but still potentially acceptable, though less optimal.

**logP:** Ligand A (2.146) is within the optimal 1-3 range. Ligand B (0.947) is slightly below 1, which *could* indicate permeability issues, but isn't a dealbreaker.

**H-Bond Donors/Acceptors:** Ligand A (1 HBD, 5 HBA) and Ligand B (2 HBD, 5 HBA) both have reasonable numbers of H-bond donors and acceptors, well within the guidelines.

**QED:** Both ligands have acceptable QED values (0.824 and 0.713, respectively), indicating good drug-like properties.

**DILI:** Ligand A (35.712) has a significantly lower DILI risk than Ligand B (57.387), which is a positive attribute.

**BBB:** This is crucial for a CNS target. Ligand A (80.07) has a much better BBB percentile than Ligand B (40.364). This is a major advantage for Ligand A.

**Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and indicates poor permeability. However, these values are on a scale where negative values are possible, and the absolute magnitude matters less than the trend.

**Aqueous Solubility:** Both have negative solubility values, which is also unusual. Again, the absolute magnitude is important, and Ligand A (-1.794) is slightly better than Ligand B (-4.037).

**hERG:** Both ligands have very low hERG inhibition liability (0.407 and 0.143), which is excellent.

**Microsomal Clearance:** Ligand A (31.636) has lower microsomal clearance than Ligand B (42.734), indicating better metabolic stability.

**In vitro Half-Life:** Ligand A (-12.253) has a more negative half-life, which is unusual, but in this context likely means a shorter half-life. Ligand B (-27.218) is even shorter. This is a drawback for both, but less critical than other factors.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.034 and 0.019), which is favorable for CNS penetration.

**Binding Affinity:** Ligand A (-7.5 kcal/mol) has a slightly better binding affinity than Ligand B (-7.2 kcal/mol), although the difference is relatively small.

**Conclusion:**

Considering all factors, and prioritizing BBB penetration, logP, and affinity for a CNS GPCR target like DRD2, **Ligand A is the more promising candidate.** It has a significantly better BBB percentile, lower DILI risk, better metabolic stability, and slightly better binding affinity. While both ligands have issues with Caco-2 and solubility, Ligand A performs better in these areas as well. The slightly better logP of Ligand A also contributes to its favorability.

Output:
0
2025-04-17 06:52:49,016 - INFO - Reasoning:

Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (361.877 and 363.933 Da) fall comfortably within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (64.86) is significantly higher than the preferred <90 for CNS targets, while Ligand B (36.44) is well within the range. This is a substantial advantage for Ligand B.

**3. logP:** Both ligands have logP values within the optimal 1-3 range (2.87 and 3.986). Ligand B is slightly higher, which *could* be a minor concern for solubility, but isn't a dealbreaker.

**4. H-Bond Donors:** Ligand A has 1 HBD, which is acceptable. Ligand B has 0, also acceptable.

**5. H-Bond Acceptors:** Ligand A has 6 HBA, within the acceptable limit. Ligand B has 3, also acceptable.

**6. QED:** Both ligands have reasonable QED values (0.4 and 0.7). Ligand B's QED is better, indicating a more drug-like profile.

**7. DILI:** Ligand A has a DILI risk of 30.4%, which is good (low risk). Ligand B has a DILI risk of 12.6%, even better.

**8. BBB:** This is critical for a CNS target like DRD2. Ligand A has a BBB penetration of 54.091%, which is below the desirable >70%. Ligand B has a BBB penetration of 88.29%, which is excellent.

**9. Caco-2 Permeability:** Both have negative Caco-2 values (-5.15 and -4.892). This is unusual and suggests poor permeability, but the scale is not defined. It's difficult to interpret without knowing the units or scale.

**10. Aqueous Solubility:** Both ligands have negative solubility values (-2.686 and -3.011), which is also unusual and suggests poor solubility. Again, the scale is undefined.

**11. hERG Inhibition:** Both ligands have low hERG inhibition risk (0.356 and 0.822).

**12. Microsomal Clearance:** Ligand A has a lower Cl_mic (23.698) than Ligand B (71.002), indicating better metabolic stability. This is a positive for Ligand A.

**13. In vitro Half-Life:** Ligand A has a negative half-life (-12.728), which is not physically possible and indicates a problem with the data. Ligand B has a half-life of 11.841 hours, which is reasonable.

**14. P-gp Efflux:** Both ligands have low P-gp efflux liability (0.215 and 0.528), which is good.

**15. Binding Affinity:** Both ligands have the same binding affinity (-7.5 kcal/mol), which is excellent.

**Overall Assessment:**

Ligand B is significantly more promising. While Ligand A has better metabolic stability (lower Cl_mic) and a slightly lower DILI risk, Ligand B excels in the crucial areas for a CNS GPCR target: TPSA, BBB penetration, and QED. The negative values for Caco-2 and Solubility are concerning for both, but the much better TPSA and BBB of Ligand B outweigh these concerns. The nonsensical half-life value for Ligand A is a major red flag.

Output:
1
2025-04-17 06:52:49,016 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (347.415 and 342.439 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (84.67) is better than Ligand B (58.64). Both are below the 90 A^2 threshold desirable for CNS targets, but Ligand B is significantly lower, potentially improving brain penetration.

**3. logP:** Both ligands have good logP values (1.343 and 1.945), falling within the optimal 1-3 range. Ligand B is slightly higher, which might be beneficial for membrane permeability.

**4. H-Bond Donors:** Both ligands have 1 HBD, which is acceptable.

**5. H-Bond Acceptors:** Ligand A has 5 HBA, and Ligand B has 3. Both are within the acceptable limit of 10.

**6. QED:** Ligand A (0.869) has a higher QED score than Ligand B (0.771), indicating better overall drug-likeness.

**7. DILI:** Ligand A (35.634) has a slightly higher DILI risk than Ligand B (28.112), but both are below the concerning threshold of 60.

**8. BBB:** Both ligands have identical BBB penetration (77.821%), which is good, but not excellent. Further optimization might be needed to reach >80%.

**9. Caco-2 Permeability:** Ligand A (-5.12) has worse Caco-2 permeability than Ligand B (-4.672). Higher values are better, so Ligand B is preferable here.

**10. Aqueous Solubility:** Ligand A (-1.056) has better aqueous solubility than Ligand B (-2.07). Solubility is important for formulation.

**11. hERG Inhibition:** Ligand A (0.068) has a lower hERG inhibition liability than Ligand B (0.365), which is a significant advantage for safety.

**12. Microsomal Clearance:** Ligand A (22.839) has higher microsomal clearance than Ligand B (14.966), meaning it's less metabolically stable. This is a drawback for Ligand A.

**13. In vitro Half-Life:** Ligand B (-11.732) has a significantly longer in vitro half-life than Ligand A (-7.617), indicating better metabolic stability.

**14. P-gp Efflux:** Ligand A (0.039) has lower P-gp efflux liability than Ligand B (0.081), which is favorable for CNS penetration.

**15. Binding Affinity:** Ligand B (-8.5) has a slightly better binding affinity than Ligand A (-8.3), although the difference is small.

**Overall Assessment:**

While Ligand A has a better QED and lower P-gp efflux, Ligand B demonstrates superior ADME properties, including better Caco-2 permeability, significantly better metabolic stability (lower Cl_mic and longer t1/2), and a slightly better binding affinity. The slightly improved hERG profile of Ligand A is a plus, but the metabolic stability of Ligand B is more critical for a GPCR target requiring sustained CNS exposure. Given the GPCR-specific priorities, the improved metabolic stability and permeability of Ligand B outweigh the minor advantages of Ligand A.

Output:
1
2025-04-17 06:52:49,016 - INFO - Reasoning:

Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (343.358 and 344.499 Da) fall comfortably within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (75.29) is higher than Ligand B (49.41). For a CNS target like DRD2, a TPSA below 90 is preferred, and ideally below 60. Ligand B is significantly better in this regard.

**3. logP:** Both ligands have good logP values (2.407 and 3.588), falling within the optimal 1-3 range. Ligand B is slightly higher, which could be beneficial for membrane permeability, but not drastically so.

**4. H-Bond Donors:** Both have 1 HBD, which is acceptable.

**5. H-Bond Acceptors:** Ligand A has 4 HBA, and Ligand B has 2. Both are within the acceptable limit of 10.

**6. QED:** Both ligands have good QED scores (0.668 and 0.775), indicating good drug-like properties.

**7. DILI:** Ligand A (72.586) has a higher DILI risk than Ligand B (32.92). Lower is better, and Ligand B is significantly better here.

**8. BBB:** Ligand A (67.584) and Ligand B (76.735) both have reasonably good BBB penetration, but Ligand B is better, exceeding 70% which is desirable for CNS targets.

**9. Caco-2:** Both have negative Caco-2 values, which is unusual and potentially problematic. It's difficult to interpret without knowing the scale, but it suggests poor permeability.

**10. Solubility:** Both have negative solubility values, also unusual and potentially problematic.

**11. hERG:** Both have low hERG inhibition liability (0.614 and 0.474), which is good.

**12. Cl_mic:** Ligand A (40.931) has lower microsomal clearance than Ligand B (93.166), suggesting better metabolic stability. This is a positive for Ligand A.

**13. t1/2:** Ligand A (-21.143) has a negative in vitro half-life, which is not possible. Ligand B (-12.579) also has a negative value. This is a significant data quality issue for both.

**14. Pgp:** Ligand A (0.156) has lower P-gp efflux liability than Ligand B (0.579), which is favorable for CNS penetration.

**15. Binding Affinity:** Ligand B (-9.6 kcal/mol) has a significantly stronger binding affinity than Ligand A (-7.7 kcal/mol). This is a substantial advantage, exceeding the 1.5 kcal/mol threshold.

**Overall Assessment:**

Despite the questionable Caco-2, solubility, and half-life data, Ligand B is the more promising candidate. Its superior BBB penetration, lower DILI risk, and *significantly* stronger binding affinity outweigh the slightly higher logP and Pgp efflux. The lower TPSA is also a significant advantage for CNS penetration. The metabolic stability is worse for Ligand B, but the potency difference is large enough to potentially overcome this with structural modifications. The negative half-life values are concerning and would need to be investigated, but the other factors strongly favor Ligand B.

Output:
1
2025-04-17 06:52:49,017 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (347.459 and 345.407 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (57.0) is significantly better than Ligand B (115.99).  For CNS targets, we want TPSA <= 90, and A is comfortably within this range, while B is above. This is a significant advantage for A.

**logP:** Both ligands have acceptable logP values (1.991 and 1.537), falling within the 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A (0 HBD, 4 HBA) is slightly more favorable than Ligand B (1 HBD, 5 HBA) regarding the balance of solubility and permeability.

**QED:** Ligand A (0.836) has a better QED score than Ligand B (0.495), indicating a more drug-like profile.

**DILI:** Both ligands have relatively low DILI risk (20.9 and 58.395 percentiles), but A is clearly better.

**BBB:** Ligand A (59.131) and Ligand B (62.311) are both reasonably good, but neither exceeds the desirable >70 percentile for CNS targets. However, given the other factors, this is less critical.

**Caco-2 Permeability:** Ligand A (-4.609) has poor Caco-2 permeability, while Ligand B (-5.092) is also poor. This is a concern for both, but not a deciding factor.

**Aqueous Solubility:** Ligand A (-0.64) has slightly better solubility than Ligand B (-2.641).

**hERG Inhibition:** Both ligands show low hERG inhibition liability (0.415 and 0.152), which is good.

**Microsomal Clearance:** Both have similar microsomal clearance (8.452 and 8.004 mL/min/kg).

**In vitro Half-Life:** Ligand A (43.096 hours) has a significantly longer half-life than Ligand B (2.49 hours), which is a major advantage.

**P-gp Efflux:** Ligand A (0.13) has lower P-gp efflux than Ligand B (0.031), which is favorable for CNS penetration.

**Binding Affinity:** Ligand B (-7.2 kcal/mol) has a slightly better binding affinity than Ligand A (-7.0 kcal/mol), but the difference is small (0.2 kcal/mol). Considering the other ADME properties, this difference is unlikely to be decisive.

**Overall Assessment:**

Ligand A is superior due to its significantly lower TPSA, better QED, lower DILI, longer half-life, and lower P-gp efflux. While Ligand B has slightly better binding affinity, the overall ADME profile of Ligand A is much more promising for a CNS-targeting drug. The lower TPSA and better predicted BBB penetration of Ligand A are particularly important for a DRD2 ligand.

Output:
1
2025-04-17 06:52:49,017 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (351.447 Da) and Ligand B (339.439 Da) are both acceptable.

**TPSA:** Ligand A (71.11) is better than Ligand B (47.36). For CNS targets, we want TPSA <= 90, both are well within this range, but lower is preferable.

**logP:** Ligand B (3.586) is better than Ligand A (0.259). Optimal logP is 1-3. Ligand A is significantly below this range, which could hinder permeability. Ligand B is at the upper end but still acceptable.

**H-Bond Donors:** Ligand A (1) is better than Ligand B (0).  Both are acceptable.

**H-Bond Acceptors:** Ligand A (5) is slightly worse than Ligand B (4). Both are acceptable.

**QED:** Ligand A (0.787) is better than Ligand B (0.545). Higher QED is desirable, indicating better drug-like properties.

**DILI:** Ligand B (43.66) is significantly better than Ligand A (11.245). Lower DILI is crucial. Ligand A's DILI is concerningly high.

**BBB:** Ligand B (77.084) is better than Ligand A (65.839). For CNS targets, >70 is desirable. Ligand B is closer to this threshold.

**Caco-2:** Ligand A (-5.208) is better than Ligand B (-4.735). Higher Caco-2 permeability is preferred, but both are negative values, which is unusual and requires further investigation.

**Solubility:** Ligand A (-1.32) is better than Ligand B (-3.923). Higher solubility is preferred, but both are negative values, which is unusual and requires further investigation.

**hERG:** Both ligands have very low hERG inhibition liability (0.24 and 0.771 respectively), which is excellent.

**Cl_mic:** Ligand A (-25.297) is better than Ligand B (108.792). Lower microsomal clearance indicates better metabolic stability. Ligand B has a high clearance, which is a significant drawback.

**t1/2:** Ligand A (11.599) is better than Ligand B (-28.479). Longer half-life is preferred. Ligand B has a negative half-life, which is not possible and suggests an issue with the data.

**Pgp:** Ligand A (0.006) is significantly better than Ligand B (0.666). Lower P-gp efflux is crucial for CNS penetration.

**Binding Affinity:** Both ligands have similar binding affinities (-8.3 and -8.4 kcal/mol). This is a strong binding affinity, and the difference is negligible.

**Overall Assessment:**

Ligand B has a better logP and BBB, which are important for CNS GPCR targets. However, Ligand A excels in QED, DILI, Cl_mic, t1/2, and Pgp efflux. The significantly higher DILI risk and poor metabolic stability (high Cl_mic) and implausible half-life of Ligand B are major concerns. The very low logP of Ligand A is a drawback, but the strong binding affinity might compensate. Considering the GPCR-specific priorities and the overall profile, Ligand A is the more promising candidate.

Output:
0
2025-04-17 06:52:49,017 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight (MW):** Both ligands (357.431 and 344.499 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (79.55) is higher than Ligand B (40.62). For CNS targets, TPSA <= 90 is preferred. Ligand B is significantly better here.

**3. logP:** Both ligands have good logP values (2.772 and 3.227), falling within the optimal 1-3 range.

**4. H-Bond Donors (HBD):** Ligand A has 1 HBD, while Ligand B has 0. Both are acceptable (<=5).

**5. H-Bond Acceptors (HBA):** Ligand A has 6 HBA, and Ligand B has 2. Both are within the acceptable range (<=10).

**6. QED:** Both ligands have the same QED (0.735), indicating good drug-likeness.

**7. DILI:** Ligand A (47.034) has a slightly higher DILI risk than Ligand B (31.524). Both are below the concerning threshold of 60, but lower is better.

**8. BBB:** Ligand B (78.868) has a significantly higher BBB percentile than Ligand A (58.123). This is a *critical* advantage for a CNS target like DRD2.

**9. Caco-2 Permeability:** Ligand A (-4.478) and Ligand B (-4.74) both have negative values, indicating poor permeability. This is a concern for both, but the difference is minimal.

**10. Aqueous Solubility:** Ligand A (-4.46) and Ligand B (-3.906) both have negative values, indicating poor solubility. This is a concern for both, but the difference is minimal.

**11. hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.417 and 0.382).

**12. Microsomal Clearance (Cl_mic):** Ligand B (72.263) has a higher Cl_mic than Ligand A (51.424), suggesting faster metabolism and lower metabolic stability. Ligand A is better here.

**13. In vitro Half-Life:** Ligand B (24.26) has a longer half-life than Ligand A (16.067). This is a positive for Ligand B.

**14. P-gp Efflux:** Both ligands have low P-gp efflux liability (0.276 and 0.505).

**15. Binding Affinity:** Both ligands have the same binding affinity (-8.1 kcal/mol), which is excellent.

**Overall Assessment:**

While Ligand A has slightly better metabolic stability (lower Cl_mic), Ligand B is significantly superior in terms of BBB penetration (78.868 vs. 58.123) and has a longer half-life. Given that DRD2 is a CNS target, BBB penetration is paramount. The lower TPSA of Ligand B is also beneficial for CNS penetration. The slightly higher DILI risk of Ligand A is a minor concern compared to the significant advantage of Ligand B's BBB score.

Output:
1
2025-04-17 06:52:49,017 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (360.33 and 352.406 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (33.95) is excellent, well below the 90 A^2 threshold for CNS targets. Ligand B (75.71) is higher, but still potentially acceptable, though less ideal.

**3. logP:** Ligand A (4.145) is slightly high, potentially leading to solubility issues or off-target interactions. Ligand B (1.038) is low, which could hinder permeation.

**4. H-Bond Donors:** Both have acceptable HBD counts (0 for A, 1 for B), well under the limit of 5.

**5. H-Bond Acceptors:** Both have acceptable HBA counts (4 for both), well under the limit of 10.

**6. QED:** Both ligands have good QED values (0.717 and 0.767), indicating good drug-like properties.

**7. DILI:** Ligand A (56.805) has a moderate DILI risk, while Ligand B (33.579) has a lower risk, which is favorable.

**8. BBB:** Ligand A (94.261) has excellent BBB penetration, highly desirable for a CNS target. Ligand B (83.715) is good, but not as high as Ligand A.

**9. Caco-2:** Both have negative Caco-2 values (-4.659 and -4.701), which is unusual and suggests poor permeability. This is a significant concern for both.

**10. Solubility:** Both have negative solubility values (-5.134 and -2.296), indicating very poor aqueous solubility. This is a major drawback for both compounds.

**11. hERG:** Both have low hERG inhibition liability (0.88 and 0.318), which is good.

**12. Cl_mic:** Ligand A (17.654) has lower microsomal clearance than Ligand B (21.48), suggesting better metabolic stability.

**13. t1/2:** Ligand A (5.589) has a longer in vitro half-life than Ligand B (-3.197), which is preferred.

**14. Pgp:** Ligand A (0.556) has lower P-gp efflux liability than Ligand B (0.064), which is highly desirable for CNS penetration.

**15. Binding Affinity:** Ligand A (-9.8 kcal/mol) has a significantly stronger binding affinity than Ligand B (-7.9 kcal/mol). This is a substantial advantage, potentially outweighing some of the ADME concerns.

**Overall Assessment:**

Despite both compounds having significant solubility and permeability issues (Caco-2 and Solubility), Ligand A is the more promising candidate. Its superior BBB penetration, lower Pgp efflux, better metabolic stability (lower Cl_mic, longer t1/2), and *much* stronger binding affinity outweigh the slightly higher logP and moderate DILI risk. The strong affinity suggests that even with imperfect ADME properties, Ligand A might still achieve sufficient target engagement *in vivo*. Ligand B's lower logP is concerning for permeability, and its weaker affinity is a major disadvantage.

Output:
1
2025-04-17 06:52:49,018 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (349.391 and 350.503 Da) fall comfortably within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (108.77) is higher than the preferred <90 for CNS targets, but still potentially acceptable. Ligand B (60.85) is excellent, well below the 90 threshold. This is a significant advantage for Ligand B.

**3. logP:** Both ligands have good logP values (1.393 and 2.589), falling within the optimal 1-3 range.

**4. H-Bond Donors:** Ligand A (3) is acceptable, while Ligand B (1) is even better, minimizing potential permeability issues.

**5. H-Bond Acceptors:** Ligand A (6) and Ligand B (3) are both within the acceptable limit of 10.

**6. QED:** Both ligands have good QED scores (0.548 and 0.793), indicating drug-like properties. Ligand B is slightly better.

**7. DILI:** Ligand A (62.35) has a moderate DILI risk, while Ligand B (30.71) has a lower risk. This favors Ligand B.

**8. BBB:** Both ligands show good BBB penetration (59.48 and 63.048), but neither exceeds the desirable >70 threshold. Ligand B is slightly better.

**9. Caco-2 Permeability:** Ligand A (-5.093) has poor Caco-2 permeability, which is a concern. Ligand B (-4.657) is also poor, but slightly better.

**10. Aqueous Solubility:** Both ligands have poor aqueous solubility (-2.802 and -1.812). This could pose formulation challenges.

**11. hERG Inhibition:** Both ligands have low hERG inhibition risk (0.432 and 0.302).

**12. Microsomal Clearance:** Ligand A (-10.01) has significantly lower (better) microsomal clearance than Ligand B (46.085), indicating greater metabolic stability. This is a major advantage for Ligand A.

**13. In vitro Half-Life:** Ligand A (25.887) has a longer half-life than Ligand B (3.768). This is a significant advantage for Ligand A.

**14. P-gp Efflux:** Ligand A (0.018) has very low P-gp efflux, which is excellent for CNS penetration. Ligand B (0.245) also has low P-gp efflux, but higher than Ligand A.

**15. Binding Affinity:** Ligand A (-9.6) has a substantially stronger binding affinity than Ligand B (-0.0). This is a decisive advantage for Ligand A.

**Overall Assessment:**

While Ligand B has advantages in TPSA, DILI, and QED, Ligand A is significantly better in terms of metabolic stability (Cl_mic, t1/2), P-gp efflux, and, most importantly, binding affinity. The strong binding affinity of Ligand A (-9.6 kcal/mol) can likely overcome the slightly higher TPSA and poorer Caco-2 permeability. The longer half-life and lower P-gp efflux also contribute to better CNS exposure. Given the GPCR-specific priorities, the superior affinity and pharmacokinetic properties of Ligand A make it the more promising drug candidate.

Output:
1
2025-04-17 06:52:49,018 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (353.409 and 343.402 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (58.56) is slightly above the optimal <90 for CNS targets, but still reasonable. Ligand B (52.65) is well within the desired range.

**3. logP:** Ligand A (3.495) is at the higher end of the optimal 1-3 range, while Ligand B (1.232) is at the lower end. While Ligand A's logP isn't alarming, Ligand B's lower value *could* hinder permeation.

**4. H-Bond Donors:** Ligand A (2) and Ligand B (1) are both within the acceptable limit of <=5.

**5. H-Bond Acceptors:** Both ligands (A: 3, B: 3) are well below the acceptable limit of <=10.

**6. QED:** Both ligands have similar QED values (A: 0.851, B: 0.791), indicating good drug-like properties.

**7. DILI:** Both ligands have low DILI risk (A: 37.34, B: 36.06), below the 40 threshold.

**8. BBB:** Both ligands exhibit excellent BBB penetration (A: 75.805, B: 78.635), exceeding the desirable >70 threshold for CNS targets.

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 values, which is unusual and suggests a potential issue with the data or modeling. However, we'll proceed assuming these represent low permeability.

**10. Aqueous Solubility:** Both ligands have negative solubility values, which is also unusual. Again, we'll assume this indicates poor solubility.

**11. hERG Inhibition:** Both ligands show very low hERG inhibition risk (A: 0.325, B: 0.352).

**12. Microsomal Clearance:** Ligand A (3.826) has a higher microsomal clearance than Ligand B (0.284), suggesting lower metabolic stability.

**13. In vitro Half-Life:** Ligand B (-3.15) has a significantly longer in vitro half-life than Ligand A (5.388).

**14. P-gp Efflux:** Both ligands have very low P-gp efflux liability (A: 0.06, B: 0.036).

**15. Binding Affinity:** Ligand A (-9.6 kcal/mol) has a substantially stronger binding affinity than Ligand B (-8.4 kcal/mol). This is a >1.2 kcal/mol difference, which is significant.

**Overall Assessment:**

While both compounds have good BBB penetration and low DILI/hERG risks, Ligand A stands out due to its significantly stronger binding affinity (-9.6 vs -8.4 kcal/mol). This difference in potency is likely to outweigh the slightly higher TPSA and microsomal clearance. The negative Caco-2 and solubility values are concerning for both, but the strong affinity of Ligand A makes it more likely to be optimized to overcome these issues. Ligand B's lower logP and shorter half-life are also less favorable.

Output:
1
2025-04-17 06:52:49,018 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (346.431 and 351.407 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (78.67) is significantly better than Ligand B (115.21). For CNS targets, we want TPSA <= 90, and A is comfortably within this range, while B exceeds it. This is a significant advantage for A.

**3. logP:** Ligand A (1.047) is within the optimal 1-3 range. Ligand B (-0.338) is slightly below 1, which *could* indicate permeability issues, though not drastically.

**4. H-Bond Donors:** Ligand A (1) and Ligand B (2) are both acceptable, being <= 5.

**5. H-Bond Acceptors:** Ligand A (5) and Ligand B (7) are both acceptable, being <= 10.

**6. QED:** Ligand A (0.827) is excellent, indicating high drug-likeness. Ligand B (0.465) is lower, but still potentially acceptable.

**7. DILI:** Both ligands have relatively low DILI risk (A: 52.462, B: 38.232), below the 60 threshold. B is slightly better here.

**8. BBB:** Ligand B (52.423) is better than Ligand A (39.977) in terms of BBB penetration. However, both are below the desirable >70 for CNS targets.

**9. Caco-2:** Ligand A (-4.867) and Ligand B (-5.073) both have negative Caco-2 values, which is unusual and suggests poor permeability. This is a concern for both.

**10. Solubility:** Both ligands have very poor aqueous solubility (-1.387 and -1.134 respectively). This is a significant drawback for both.

**11. hERG:** Both ligands have very low hERG inhibition risk (A: 0.225, B: 0.038). B is slightly better here.

**12. Cl_mic:** Ligand A (36.921) has lower microsomal clearance than Ligand B (43.046), suggesting better metabolic stability.

**13. t1/2:** Ligand A (-0.529) has a slightly better (less negative) in vitro half-life than Ligand B (-11.318).

**14. Pgp:** Ligand A (0.229) has lower P-gp efflux liability than Ligand B (0.023), which is favorable for CNS penetration.

**15. Binding Affinity:** Both ligands have the same excellent binding affinity (-7.9 kcal/mol).

**Overall Assessment:**

Considering the GPCR-specific priorities, Ligand A is more promising. While Ligand B has slightly better BBB penetration and DILI/hERG profiles, Ligand A's significantly lower TPSA is a major advantage for CNS penetration. The lower Pgp efflux liability and better metabolic stability (lower Cl_mic) also favor Ligand A. The poor solubility and Caco-2 values are concerning for both, but the other advantages of A outweigh those of B. The equal binding affinity removes that as a differentiating factor.



Output:
0
2025-04-17 06:52:49,018 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (349.366 and 363.443 Da) fall within the ideal 200-500 Da range.

**TPSA:** Both ligands (95.5 and 96.33) are close to the 90 A^2 threshold for CNS targets, but still acceptable.

**logP:** Ligand A (-0.234) is slightly low, potentially hindering permeability. Ligand B (-0.608) is also low, but marginally better than A. Both are below the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A (1 HBD, 5 HBA) is better than Ligand B (2 HBD, 6 HBA) in terms of balancing solubility and permeability.

**QED:** Both ligands have good QED scores (0.813 and 0.747), indicating drug-likeness.

**DILI:** Both ligands have acceptable DILI risk (64.793 and 59.403), below the concerning threshold of 60.

**BBB:** This is a crucial parameter for a CNS target like DRD2. Ligand A (60.295) is moderately good, but Ligand B (25.863) is significantly lower and concerning.

**Caco-2 Permeability:** Both have negative values (-4.803 and -5.504), which is unusual and suggests poor permeability. This is a red flag for both.

**Aqueous Solubility:** Both ligands have very poor aqueous solubility (-1.518 and -2.14). This is a major drawback.

**hERG Inhibition:** Both ligands show very low hERG inhibition risk (0.146 and 0.068).

**Microsomal Clearance:** Ligand A (-4.144) has a lower (better) microsomal clearance than Ligand B (4.025), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (-16.551) has a longer (better) in vitro half-life than Ligand B (11.571).

**P-gp Efflux:** Both ligands show very low P-gp efflux liability (0.017 and 0.022), which is favorable for CNS penetration.

**Binding Affinity:** Ligand B (-8.1 kcal/mol) has a slightly better binding affinity than Ligand A (-7.7 kcal/mol). This difference of 0.4 kcal/mol is not huge, but could be relevant.

**Overall Assessment:**

Ligand A is superior due to its better BBB penetration, lower microsomal clearance, longer half-life, and fewer H-bonds. While both have poor solubility and Caco-2 permeability, the improved CNS properties of Ligand A are more critical for a DRD2 target. The slightly better affinity of Ligand B is not enough to overcome the significant disadvantage in BBB penetration.

Output:
1
2025-04-17 06:52:49,019 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (365.4 and 367.8 Da) fall comfortably within the ideal 200-500 Da range.

**TPSA:** Ligand A (87.3) is better than Ligand B (75.0). Both are below the 90 A^2 threshold for CNS targets, which is good.

**logP:** Ligand A (1.501) is better than Ligand B (0.504). Both are within the optimal 1-3 range, but Ligand B is on the lower side, potentially hindering permeability.

**H-Bond Donors & Acceptors:** Ligand A has 3 HBD and 3 HBA, while Ligand B has 1 HBD and 5 HBA. Both are within acceptable limits (<=5 HBD and <=10 HBA).

**QED:** Ligand B (0.844) has a slightly better QED score than Ligand A (0.639), suggesting a more drug-like profile.

**DILI:** Ligand A (27.5) has a significantly lower DILI risk than Ligand B (39.2), which is a substantial advantage.

**BBB:** Ligand A (80.962) has a much better BBB penetration score than Ligand B (50.523). This is *critical* for a CNS target like DRD2.

**Caco-2 Permeability:** Both have negative Caco-2 values (-4.987 and -4.61), which is unusual and difficult to interpret without further context. However, it doesn't strongly favor either ligand.

**Aqueous Solubility:** Both have negative solubility values (-2.452 and -2.118), which is also unusual. Again, doesn't strongly favor either.

**hERG:** Both ligands have very low hERG inhibition risk (0.213 and 0.262).

**Microsomal Clearance:** Both have similar microsomal clearance rates (16.412 and 16.298 mL/min/kg).

**In vitro Half-Life:** Ligand A (-10.79) has a much longer in vitro half-life than Ligand B (33.535). This is a significant advantage.

**P-gp Efflux:** Both have very low P-gp efflux liability (0.019 and 0.039).

**Binding Affinity:** Ligand A (-7.9 kcal/mol) has a slightly better binding affinity than Ligand B (-7.3 kcal/mol). While the difference is not huge, it's still a positive for Ligand A.

**Overall Assessment:**

Considering the GPCR-specific priorities, Ligand A is the stronger candidate. Its superior BBB penetration, lower DILI risk, longer half-life, and slightly better binding affinity outweigh Ligand B's slightly better QED score and logP. The negative solubility and Caco-2 values are concerning for both, but the other factors strongly favor Ligand A.

Output:
1
2025-04-17 06:52:49,019 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (347.415 and 345.443 Da) fall comfortably within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (100.45) is slightly above the optimal <90 for CNS targets, while Ligand B (84.23) is well within the desired range. This gives a slight edge to Ligand B.

**3. logP:** Ligand A (0.639) is a bit low, potentially hindering membrane permeability. Ligand B (2.504) is within the optimal 1-3 range. This is a significant advantage for Ligand B.

**4. H-Bond Donors:** Both ligands have 2 HBD, which is acceptable.

**5. H-Bond Acceptors:** Ligand A has 5 HBA, and Ligand B has 4 HBA, both acceptable.

**6. QED:** Both ligands have high QED scores (0.777 and 0.795), indicating good drug-like properties.

**7. DILI:** Ligand A (49.283) has a slightly higher DILI risk than Ligand B (35.983), though both are reasonably low.

**8. BBB:** Ligand B (71.811) has a significantly better BBB percentile than Ligand A (56.534). This is a crucial advantage for a CNS target like DRD2.

**9. Caco-2 Permeability:** Ligand A (-5.22) and Ligand B (-4.943) both have negative Caco-2 values, which is unusual and suggests poor permeability. However, the scale is not specified, so it's difficult to interpret.

**10. Aqueous Solubility:** Both ligands have very poor aqueous solubility (-2.85 and -2.849). This is a concern for both, but can be addressed with formulation strategies.

**11. hERG Inhibition:** Both ligands have low hERG inhibition risk (0.295 and 0.34).

**12. Microsomal Clearance:** Ligand A (6.772) has lower microsomal clearance than Ligand B (50.28), suggesting better metabolic stability. This is a positive for Ligand A.

**13. In vitro Half-Life:** Ligand A (25.207) has a longer in vitro half-life than Ligand B (-12.603). This is a significant advantage for Ligand A.

**14. P-gp Efflux:** Ligand A (0.036) has much lower P-gp efflux than Ligand B (0.157). Lower P-gp efflux is desirable for CNS penetration, favoring Ligand A.

**15. Binding Affinity:** Ligand B (-9.8 kcal/mol) has a significantly stronger binding affinity than Ligand A (-7.8 kcal/mol). This is a substantial advantage for Ligand B, potentially outweighing some of its ADME drawbacks.

**Overall Assessment:**

Ligand B excels in binding affinity and BBB penetration, both critical for a CNS-targeting GPCR. While its logP is good, its P-gp efflux is higher and its metabolic stability is lower than Ligand A. However, the stronger binding affinity of Ligand B is a major advantage. Ligand A has better metabolic stability, P-gp efflux, and half-life, but its lower affinity and poorer BBB penetration are significant drawbacks.

Considering the GPCR-specific priorities, the superior binding affinity and BBB penetration of Ligand B outweigh its slightly less favorable ADME properties.

Output:
1
2025-04-17 06:52:49,019 - INFO - Batch 318 complete. Total preferences: 5088
2025-04-17 06:52:49,019 - INFO - Processing batch 319/512...
2025-04-17 06:53:29,038 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B based on the provided guidelines, prioritizing GPCR-specific properties (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (341.455 Da) is slightly lower, which could be beneficial for permeability, but both are acceptable.

**TPSA:** Ligand A (56.27) is excellent for CNS penetration, well below the 90 A^2 threshold. Ligand B (73.4) is still reasonable but less optimal.

**logP:** Ligand A (4.665) is a bit high, potentially leading to solubility issues or off-target effects. Ligand B (2.545) is within the optimal range (1-3).

**H-Bond Donors/Acceptors:** Both ligands have acceptable HBD/HBA counts. Ligand A (1 HBD, 5 HBA) and Ligand B (2 HBD, 4 HBA) are both within the recommended limits.

**QED:** Both ligands have similar, good QED values (A: 0.793, B: 0.799), indicating good drug-like properties.

**DILI:** Ligand A (49.787) has a slightly higher DILI risk than Ligand B (29.314), but both are below the concerning threshold of 60.

**BBB:** Ligand A (74.835) has a significantly better BBB penetration percentile than Ligand B (52.772). This is a crucial advantage for a CNS target like DRD2.

**Caco-2 Permeability:** Ligand A (-4.414) shows poor permeability, while Ligand B (-5.322) is even worse. Both are quite low, which is concerning.

**Aqueous Solubility:** Ligand A (-4.972) has slightly better solubility than Ligand B (-3.59), but both are quite poor.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (A: 0.652, B: 0.471).

**Microsomal Clearance:** Ligand A (75.764) has higher clearance than Ligand B (6.692), indicating lower metabolic stability. This is a significant disadvantage for Ligand A.

**In vitro Half-Life:** Ligand B (-20.769) has a much longer in vitro half-life than Ligand A (1.794), suggesting slower metabolism and potentially less frequent dosing.

**P-gp Efflux:** Ligand A (0.284) has lower P-gp efflux liability than Ligand B (0.21), which is favorable for CNS exposure.

**Binding Affinity:** Ligand A (-8.9 kcal/mol) has a significantly stronger binding affinity than Ligand B (-7.3 kcal/mol). This >1.5 kcal/mol difference is a major advantage, potentially outweighing some ADME drawbacks.

**Overall Assessment:**

Ligand A has a superior binding affinity and better BBB penetration and P-gp efflux. However, it suffers from poorer Caco-2 permeability, higher microsomal clearance, and a shorter half-life. Ligand B has better ADME properties (lower clearance, longer half-life, better logP) but significantly weaker binding affinity.

Given the GPCR-specific priorities, the strong binding affinity and good BBB penetration of Ligand A are compelling. While its ADME properties are less ideal, optimization efforts could focus on improving metabolic stability and permeability. The substantial affinity difference makes Ligand A the more promising starting point.

Output:
1
2025-04-17 06:53:29,038 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (349.406 and 348.403 Da) fall comfortably within the ideal 200-500 Da range.

**TPSA:** Ligand A (71.53) is excellent, well below the 90 A^2 threshold for CNS targets. Ligand B (84.86) is still reasonable but less optimal, approaching the upper limit.

**logP:** Ligand A (2.009) is within the optimal 1-3 range. Ligand B (0.669) is slightly low, potentially hindering permeability.

**H-Bond Donors/Acceptors:** Ligand A (1 HBD, 4 HBA) and Ligand B (0 HBD, 6 HBA) both have acceptable numbers of H-bond donors and acceptors.

**QED:** Both ligands have good QED scores (0.903 and 0.703), indicating good drug-like properties.

**DILI:** Ligand A (53.432) has a slightly better DILI score than Ligand B (63.629), suggesting a lower risk of liver injury. Both are acceptable, but lower is preferred.

**BBB:** Ligand A (85.847) has a significantly better BBB percentile than Ligand B (72.354). This is a crucial advantage for a CNS target like DRD2.

**Caco-2 Permeability:** Ligand A (-4.617) and Ligand B (-4.344) have similar, very poor Caco-2 permeability scores. This is a concern for oral bioavailability.

**Aqueous Solubility:** Ligand A (-2.775) has slightly better solubility than Ligand B (-0.967), though both are poor.

**hERG:** Both ligands have very low hERG inhibition liability (0.299 and 0.087), which is excellent.

**Microsomal Clearance:** Ligand A (11.506) has a much lower microsomal clearance than Ligand B (34.664), indicating better metabolic stability.

**In vitro Half-Life:** Ligand A (3.453) has a positive half-life, while Ligand B (-26.475) has a negative half-life. This is a significant advantage for Ligand A.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.043 and 0.011), which is favorable for CNS penetration.

**Binding Affinity:** Both ligands have the same excellent binding affinity (-7.5 kcal/mol).

**Overall Assessment:**

Ligand A is superior due to its significantly better BBB penetration, lower microsomal clearance, and better in vitro half-life. While both have poor Caco-2 permeability and solubility, the CNS target prioritizes BBB, which Ligand A excels at. The slightly better DILI score also contributes to its favorability. The equal binding affinity removes that as a differentiating factor.

Output:
1
2025-04-17 06:53:29,038 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B based on the provided guidelines, prioritizing GPCR-specific properties (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (350.463 and 351.403 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (85.25) is excellent for CNS penetration, being well below 90. Ligand B (110.53) is still reasonable, but less optimal.

**logP:** Ligand A (2.285) is within the optimal 1-3 range. Ligand B (0.88) is slightly low, potentially hindering permeation.

**H-Bond Donors/Acceptors:** Both ligands have 2 HBD and 5-6 HBA, which are acceptable.

**QED:** Both ligands have good QED scores (0.634 and 0.673), indicating drug-likeness.

**DILI:** Ligand A (52.966) has a slightly higher DILI risk than Ligand B (32.61), but both are below the concerning threshold of 60.

**BBB:** Both ligands have very good BBB penetration (68.399 and 68.476), exceeding the desirable >70% threshold for CNS targets. This is a critical factor.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values, which is unusual and suggests a potential issue with the data or modeling. However, we'll proceed assuming these represent low permeability.

**Aqueous Solubility:** Both have negative solubility values, which is also unusual. Again, we'll proceed cautiously.

**hERG:** Both ligands have very low hERG inhibition risk (0.34 and 0.037), which is excellent.

**Microsomal Clearance:** Ligand A (32.365) has significantly lower microsomal clearance than Ligand B (60.506), indicating better metabolic stability.

**In vitro Half-Life:** Ligand A (6.155) has a longer half-life than Ligand B (-4.409), which is preferable.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.065 and 0.017), which is excellent for CNS exposure.

**Binding Affinity:** Ligand A (-7.8 kcal/mol) has a slightly better binding affinity than Ligand B (-7.5 kcal/mol). While the difference is not huge, it's a positive factor.

**Overall Assessment:**

Considering the GPCR-specific priorities, Ligand A is more favorable. It has a better TPSA, logP, metabolic stability (lower Cl_mic, longer t1/2), and slightly better binding affinity. While both have good BBB penetration and low P-gp efflux, Ligand A's superior ADME properties, particularly its TPSA and logP, make it a more promising candidate for a CNS-targeting drug. The negative solubility and Caco-2 values are concerning for both, but the other factors outweigh this.

Output:
1
2025-04-17 06:53:29,038 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 drug candidates, considering the provided guidelines and GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (352.475 and 337.431 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (81.08) is excellent, well below the 90 A^2 threshold for CNS targets. Ligand B (91.41) is slightly higher but still acceptable.

**logP:** Ligand A (1.294) is optimal. Ligand B (2.732) is also good, within the 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A (HBD=2, HBA=4) and Ligand B (HBD=3, HBA=6) both have reasonable H-bond properties, within the suggested limits.

**QED:** Ligand A (0.755) has a better QED score than Ligand B (0.585), indicating a more drug-like profile.

**DILI:** Ligand A (13.067) has a significantly lower DILI risk than Ligand B (52.966), which is a major advantage.

**BBB:** This is a critical parameter for a CNS target like DRD2. Ligand A (66.499) has a moderate BBB penetration, while Ligand B (19.349) is quite poor.

**Caco-2 Permeability:** Ligand A (-4.69) has poor Caco-2 permeability, while Ligand B (-5.823) is even worse. This is a concern for oral bioavailability, but less critical for a CNS target where direct delivery or other routes may be considered.

**Aqueous Solubility:** Both ligands have poor aqueous solubility (-2.067 and -2.671 respectively).

**hERG:** Both ligands have low hERG inhibition risk (0.3 and 0.684 respectively).

**Microsomal Clearance:** Ligand A (34.733) has a higher microsomal clearance than Ligand B (25.027), suggesting lower metabolic stability.

**In vitro Half-Life:** Ligand B (24.012) has a significantly longer in vitro half-life than Ligand A (-7.658), which is a positive attribute.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.052 and 0.037 respectively), which is favorable for CNS penetration.

**Binding Affinity:** Ligand B (-8.9 kcal/mol) has a stronger binding affinity than Ligand A (-7.0 kcal/mol). This is a substantial difference (over 1.9 kcal/mol), which can outweigh some ADME drawbacks.

**Overall Assessment:**

Ligand B has a significantly better binding affinity and a longer half-life. However, Ligand A excels in DILI risk and has a better QED score and a more acceptable BBB penetration. The poor BBB penetration of Ligand B is a significant concern for a CNS target. While the affinity of Ligand B is stronger, the difference might be overcome with further optimization of Ligand A. The lower DILI risk of Ligand A is a substantial safety advantage. Considering the GPCR-specific priorities, the balance tips towards Ligand A due to its better safety profile and acceptable BBB, despite the slightly weaker binding affinity.

Output:
0
2025-04-17 06:53:29,038 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (344.46 and 372.53 Da) fall within the ideal 200-500 Da range.

**TPSA:** Both ligands (76.02 and 78.87) are below the 90 A^2 threshold desirable for CNS targets, which is excellent.

**logP:** Ligand A (2.455) is optimal, while Ligand B (1.269) is slightly below the preferred range, potentially hindering permeation.

**H-Bond Donors/Acceptors:** Both have 2 HBDs, which is good. Ligand A has 4 HBAs, and Ligand B has 5. Both are within the acceptable limit of <=10.

**QED:** Both ligands have good QED scores (0.562 and 0.637), indicating drug-like properties.

**DILI:** Ligand A (29.624) has a lower DILI risk than Ligand B (18.224), which is a significant advantage.

**BBB:** Both ligands have reasonably good BBB penetration (62.737 and 60.838), but are below the >70% target. This is a moderate concern, but not disqualifying.

**Caco-2 Permeability:** Both have negative Caco-2 values, indicating poor permeability. This is a significant drawback for both.

**Aqueous Solubility:** Both have negative solubility values, indicating poor solubility. This is a significant drawback for both.

**hERG:** Both ligands have very low hERG inhibition risk (0.321 and 0.238), which is excellent.

**Microsomal Clearance:** Ligand A (40.773) has higher microsomal clearance than Ligand B (29.941), suggesting lower metabolic stability.

**In vitro Half-Life:** Ligand B (-2.351) has a negative half-life, which is problematic. Ligand A has a half-life of 18.819, which is better.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.137 and 0.04), which is excellent for CNS penetration.

**Binding Affinity:** Ligand B (-7.8 kcal/mol) has a slightly better binding affinity than Ligand A (-7.5 kcal/mol). This 0.3 kcal/mol difference is potentially significant, but needs to be weighed against other factors.

**Overall Assessment:**

Ligand B has a slightly better binding affinity, but suffers from a negative in vitro half-life and lower logP. Ligand A has better DILI risk, a positive half-life, and a more optimal logP. The negative Caco-2 and solubility for both are concerning and would require significant optimization. However, given the importance of metabolic stability and DILI risk for a CNS drug, and the relatively small difference in binding affinity, Ligand A appears to be the more promising candidate.

Output:
0
2025-04-17 06:53:29,038 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (390.795 Da) is slightly higher than Ligand B (362.455 Da), but both are acceptable.

**TPSA:** Ligand A (80.52) is excellent for CNS penetration, falling well below the 90 A^2 threshold. Ligand B (97.12) is still reasonable but less optimal.

**logP:** Ligand A (4.05) is at the higher end of the optimal range, potentially leading to solubility issues. Ligand B (1.93) is slightly below the ideal range, potentially impacting permeability.

**H-Bond Donors/Acceptors:** Ligand A (0 HBD, 4 HBA) is favorable. Ligand B (2 HBD, 6 HBA) is also acceptable, though slightly higher.

**QED:** Both ligands have good QED scores (A: 0.569, B: 0.784), indicating drug-like properties. Ligand B is better here.

**DILI:** Ligand A (84.684) has a higher DILI risk than Ligand B (69.135), which is preferable.

**BBB:** Ligand A (64.482) has a better BBB percentile than Ligand B (52.191), which is critical for a CNS target like DRD2.

**Caco-2 Permeability:** Ligand A (-4.35) has poor Caco-2 permeability, while Ligand B (-5.247) is also poor. Both are significantly negative.

**Aqueous Solubility:** Ligand A (-5.754) has very poor aqueous solubility, which is a major concern. Ligand B (-2.812) is better, but still poor.

**hERG:** Ligand A (0.696) has a lower hERG risk than Ligand B (0.102), which is beneficial.

**Microsomal Clearance:** Ligand A (48.584) has higher microsomal clearance than Ligand B (36.2), indicating lower metabolic stability.

**In vitro Half-Life:** Ligand A (76.06) has a longer half-life than Ligand B (-12.789), which is a positive.

**P-gp Efflux:** Ligand A (0.498) has lower P-gp efflux than Ligand B (0.16), which is favorable for CNS penetration.

**Binding Affinity:** Both ligands have excellent binding affinities (A: -9.1 kcal/mol, B: -8.1 kcal/mol). Ligand A is slightly better (-9.1 vs -8.1).

**Overall Assessment:**

Ligand A has a superior binding affinity, better BBB penetration, lower P-gp efflux, and a longer half-life. However, it suffers from very poor aqueous solubility, higher DILI risk, and higher microsomal clearance. Ligand B has better solubility, lower DILI, and better QED, but its BBB penetration is significantly lower, and its affinity is slightly worse.

Given the importance of BBB penetration for a CNS target like DRD2, and the substantial affinity advantage of Ligand A, I believe **Ligand A** is the more promising candidate, *despite* its solubility issues. Solubility can be addressed through formulation strategies. The affinity difference is significant enough to potentially outweigh the ADME drawbacks.

Output:
0
2025-04-17 06:53:29,038 - INFO - Reasoning:

Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (344.415 and 346.515 Da) fall comfortably within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (108.02) is better than Ligand B (49.41). For CNS targets, we want TPSA <= 90, so Ligand B is significantly better.

**3. logP:** Both ligands have acceptable logP values (2.118 and 3.668), falling within the 1-3 range. Ligand B is slightly higher, which could potentially lead to solubility issues, but it's not a major concern.

**4. H-Bond Donors:** Ligand A (2) and Ligand B (1) are both within the acceptable limit of <=5.

**5. H-Bond Acceptors:** Ligand A (5) and Ligand B (2) are both within the acceptable limit of <=10.

**6. QED:** Both ligands have good QED scores (0.751 and 0.79), indicating good drug-like properties.

**7. DILI:** Ligand A (27.685) has a much lower DILI risk than Ligand B (10.585). This is a significant advantage for Ligand A.

**8. BBB:** Ligand B (81.737) has a substantially better BBB penetration percentile than Ligand A (70.027). This is a *critical* factor for a CNS target like DRD2.

**9. Caco-2 Permeability:** Ligand A (-4.759) and Ligand B (-4.632) both have negative values, which is unusual and suggests poor permeability.

**10. Aqueous Solubility:** Both ligands have very poor aqueous solubility (-3.101 and -3.955). This is a concern for both, but could be mitigated with formulation strategies.

**11. hERG Inhibition:** Both ligands have low hERG inhibition risk (0.333 and 0.554).

**12. Microsomal Clearance:** Ligand B (80.69) has a higher microsomal clearance than Ligand A (32.576), indicating lower metabolic stability.

**13. In vitro Half-Life:** Ligand A (-20.282) has a longer in vitro half-life than Ligand B (-8.852).

**14. P-gp Efflux:** Ligand A (0.016) has significantly lower P-gp efflux liability than Ligand B (0.151). Lower P-gp efflux is highly desirable for CNS penetration.

**15. Binding Affinity:** Both ligands have excellent binding affinities (-7.9 and -8.8 kcal/mol). Ligand B is slightly better (-8.8 kcal/mol), but the difference is not huge.

**Overall Assessment:**

While Ligand A has advantages in DILI risk, metabolic stability, and P-gp efflux, Ligand B is superior in BBB penetration and has slightly better binding affinity. Given that this is a CNS target (DRD2), BBB penetration is paramount. The slightly better affinity of Ligand B further strengthens its position. The poor solubility of both is a concern, but can potentially be addressed during formulation.

Output:
1
2025-04-17 06:53:29,039 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (346.43 and 339.44 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (75.71) is slightly higher than Ligand B (64.41). Both are below the 90 A^2 threshold desirable for CNS targets, but Ligand B is preferable.

**logP:** Ligand A (1.535) is within the optimal 1-3 range. Ligand B (2.828) is also within range, but closer to the upper limit.

**H-Bond Donors/Acceptors:** Ligand A has 1 HBD and 4 HBA, while Ligand B has 0 HBD and 3 HBA. Both are within acceptable limits (<=5 HBD, <=10 HBA).

**QED:** Both ligands have good QED scores (0.725 and 0.775, respectively), indicating drug-like properties.

**DILI:** Both ligands have low DILI risk (30.83 and 34.63 percentile), which is favorable.

**BBB:** Both ligands exhibit good BBB penetration (70.03% and 79.06%), crucial for CNS targets. Ligand B is better here.

**Caco-2 Permeability:** Both have negative Caco-2 values (-4.182 and -4.594), which is unusual and suggests poor permeability. This is a significant concern.

**Aqueous Solubility:** Both have negative solubility values (-2.045 and -3.691), indicating very poor aqueous solubility. This is a major drawback.

**hERG Inhibition:** Ligand A (0.129) has a lower hERG inhibition risk than Ligand B (0.821), which is preferable.

**Microsomal Clearance:** Ligand B (59.004) has lower microsomal clearance than Ligand A (77.21), indicating better metabolic stability.

**In vitro Half-Life:** Ligand B (-4.674) has a longer in vitro half-life than Ligand A (-16.325), which is desirable.

**P-gp Efflux:** Ligand A (0.048) has lower P-gp efflux than Ligand B (0.467), which is favorable for CNS exposure.

**Binding Affinity:** Ligand B (-8.9 kcal/mol) has a significantly stronger binding affinity than Ligand A (-7.7 kcal/mol). This difference of 1.2 kcal/mol is substantial and can outweigh some of the ADME drawbacks.

**Overall Assessment:**

Despite the poor Caco-2 and solubility profiles for both, Ligand B is the more promising candidate. Its superior binding affinity (-8.9 vs -7.7 kcal/mol), better BBB penetration (79.06 vs 70.03), lower microsomal clearance, and longer half-life outweigh the slightly higher hERG risk and P-gp efflux. The stronger binding affinity is a critical advantage for a GPCR target. The poor solubility and permeability would need to be addressed through formulation strategies, but the core pharmacodynamic properties of Ligand B are more favorable.

Output:
1
2025-04-17 06:53:29,039 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B based on the provided guidelines, prioritizing GPCR-specific properties (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (371.459 and 370.881 Da) fall within the ideal 200-500 Da range.

**TPSA:** Both ligands have TPSA values (89.99 and 87.47) below the 90 A^2 threshold desirable for CNS targets, which is excellent.

**logP:** Ligand A (0.599) is a bit low, potentially hindering permeation. Ligand B (2.217) is within the optimal 1-3 range. This favors Ligand B.

**H-Bond Donors/Acceptors:** Ligand A (1 HBD, 7 HBA) and Ligand B (2 HBD, 5 HBA) both fall within acceptable limits (<=5 HBD, <=10 HBA).

**QED:** Both ligands have good QED scores (0.673 and 0.695), indicating drug-like properties.

**DILI:** Ligand A (55.525) has a slightly higher DILI risk than Ligand B (38.038), but both are below the concerning 60 percentile.

**BBB:** This is a critical parameter for CNS targets. Ligand B (70.609) is significantly better than Ligand A (53.587), exceeding the desirable >70 percentile.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.144 and -5.033), which is unusual and suggests poor permeability. This is a significant drawback for both.

**Aqueous Solubility:** Both ligands have negative solubility values (-1.143 and -2.782), which is also concerning. This could lead to formulation challenges.

**hERG Inhibition:** Both ligands show low hERG inhibition liability (0.124 and 0.246), which is good.

**Microsomal Clearance:** Ligand A (21.035 mL/min/kg) has a lower clearance than Ligand B (43.519 mL/min/kg), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand B (77.441 hours) has a much longer half-life than Ligand A (-1.352 hours). This is a major advantage for Ligand B.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.021 and 0.081), which is favorable for CNS penetration.

**Binding Affinity:** Ligand B (-7.2 kcal/mol) has a significantly stronger binding affinity than Ligand A (-6.1 kcal/mol). This difference of 1.1 kcal/mol is substantial and can outweigh some of the ADME drawbacks.

**Overall Assessment:**

Ligand B is the stronger candidate. While both have issues with Caco-2 permeability and solubility, Ligand B excels in the critical areas for a CNS-targeting GPCR ligand: significantly better BBB penetration, a longer half-life, and a substantially higher binding affinity. The slightly better logP of Ligand B also contributes to its favorability. The lower DILI risk is a bonus.



Output:
1
2025-04-17 06:53:29,039 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (360.391 and 367.515 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (115.56) is slightly above the optimal <90 for CNS targets, but still reasonable. Ligand B (91.32) is excellent, falling well within the desired range.

**logP:** Both ligands have acceptable logP values (1.156 and 2.512), falling within the 1-3 range. Ligand B is slightly better, being closer to the optimal value.

**H-Bond Donors/Acceptors:** Ligand A has 2 HBD and 5 HBA, while Ligand B has 3 HBD and 5 HBA. Both are within acceptable limits (<=5 HBD and <=10 HBA).

**QED:** Ligand A (0.776) has a better QED score than Ligand B (0.583), indicating a more drug-like profile.

**DILI:** Ligand A (94.106) has a higher DILI risk than Ligand B (56.146). This is a significant negative for Ligand A.

**BBB:** Both ligands have reasonable BBB penetration (67.817 and 65.801). While not exceeding 70, they are not drastically low, and the difference isn't huge.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.399 and -5.188), which is unusual and suggests poor permeability. This is a concern for both.

**Aqueous Solubility:** Both have very poor aqueous solubility (-3.324 and -3.569). This is a major drawback for both compounds.

**hERG Inhibition:** Ligand A (0.202) has a lower hERG risk than Ligand B (0.601), which is favorable.

**Microsomal Clearance:** Ligand A (27.111) has lower microsomal clearance than Ligand B (36.611), indicating better metabolic stability.

**In vitro Half-Life:** Ligand A (10.435) has a longer half-life than Ligand B (-8.263). The negative value for Ligand B is concerning.

**P-gp Efflux:** Ligand A (0.242) has lower P-gp efflux than Ligand B (0.496), which is desirable for CNS penetration.

**Binding Affinity:** Ligand B (-8.8 kcal/mol) has a significantly stronger binding affinity than Ligand A (-10.1 kcal/mol). This is a substantial advantage for Ligand B.

**Overall Assessment:**

Ligand B has a superior binding affinity and a lower DILI risk. While its QED is lower, the affinity difference is substantial. Both compounds have poor solubility and permeability, which are significant drawbacks. However, the stronger binding affinity of Ligand B, coupled with the lower DILI risk, outweighs the slightly lower QED and slightly higher P-gp efflux. The better TPSA of Ligand B is also a plus.

Output:
1
2025-04-17 06:53:29,039 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 drug candidates, considering the provided guidelines and GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (384.38 Da) is slightly higher than Ligand B (360.567 Da), but both are acceptable.

**TPSA:** Ligand A (102.44) is higher than the preferred <90 for CNS targets, while Ligand B (33.2) is excellent. This is a significant advantage for Ligand B.

**logP:** Ligand A (2.123) is within the optimal range (1-3). Ligand B (4.831) is slightly high, potentially leading to solubility issues or off-target effects.

**H-Bond Donors/Acceptors:** Ligand A has 2 HBD and 7 HBA, both within acceptable limits. Ligand B has 0 HBD and 3 HBA, also acceptable.

**QED:** Both ligands have similar QED values (0.747 and 0.728), indicating good drug-likeness.

**DILI:** Ligand A (83.637) has a higher DILI risk than Ligand B (31.214). This is a clear advantage for Ligand B.

**BBB:** Both ligands have excellent BBB penetration (Ligand A: 85.498, Ligand B: 84.141), exceeding the >70% threshold for CNS targets.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.103 and -5.179), which is unusual and difficult to interpret without more context. However, since both are similarly negative, it doesn't differentiate them.

**Aqueous Solubility:** Both ligands have negative solubility values (-3.253 and -4.127), also unusual. Again, the similarity doesn't help in differentiation.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.362 and 0.454), which is good.

**Microsomal Clearance:** Ligand A (55.88) has lower microsomal clearance than Ligand B (95.573), indicating better metabolic stability. This favors Ligand A.

**In vitro Half-Life:** Ligand A (2.31) has a shorter half-life than Ligand B (-8.392), which is a negative.

**P-gp Efflux:** Ligand A (0.047) has lower P-gp efflux, which is favorable for CNS exposure. Ligand B (0.608) has higher P-gp efflux. This favors Ligand A.

**Binding Affinity:** Both ligands have very similar and strong binding affinities (-7.5 and -7.6 kcal/mol). The difference is negligible.

**Overall Assessment:**

Ligand B excels in TPSA and DILI, which are important for a CNS drug. However, its higher logP is a concern. Ligand A has better metabolic stability (lower Cl_mic), lower P-gp efflux, and a slightly better half-life, which are also crucial for CNS penetration and efficacy. Considering the GPCR-specific priorities, the lower TPSA of Ligand B is a significant advantage, outweighing the slightly higher logP. The lower DILI risk is also a strong point.

Output:
1
2025-04-17 06:53:29,040 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (383.382 Da) is slightly higher than Ligand B (349.431 Da), but both are acceptable.

**TPSA:** Ligand A (46.17) is excellent for CNS penetration, well below the 90 A^2 threshold. Ligand B (95.58) is higher, but still potentially acceptable, though less ideal.

**logP:** Ligand A (4.002) is at the upper limit of the optimal range, potentially leading to solubility issues. Ligand B (0.378) is quite low, which could hinder membrane permeability and CNS penetration.

**H-Bond Donors/Acceptors:** Ligand A (1 HBD, 2 HBA) and Ligand B (2 HBD, 4 HBA) both have reasonable numbers of H-bond donors and acceptors, unlikely to cause major issues.

**QED:** Both ligands have similar QED values (0.799 and 0.75), indicating good drug-like properties.

**DILI:** Ligand A (45.25) has a slightly better DILI score than Ligand B (24.544), indicating lower potential for liver injury.

**BBB:** Ligand A (85.459) has a significantly better BBB percentile than Ligand B (45.444), which is crucial for a CNS target like DRD2.

**Caco-2 Permeability:** Ligand A (-4.618) has a negative Caco-2 value, which is unusual and suggests poor permeability. Ligand B (-5.257) is also negative and similarly concerning.

**Aqueous Solubility:** Ligand A (-6.367) and Ligand B (-1.681) both have poor aqueous solubility. This is a concern, but can sometimes be mitigated with formulation strategies.

**hERG Inhibition:** Ligand A (0.785) has a slightly higher hERG risk than Ligand B (0.022), which is preferable.

**Microsomal Clearance:** Ligand B (-10.797) has a much lower (better) microsomal clearance than Ligand A (42.829), suggesting greater metabolic stability.

**In vitro Half-Life:** Ligand B (-13.368) has a much longer in vitro half-life than Ligand A (28.642), which is a significant advantage.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.274 and 0.007), which is favorable for CNS penetration.

**Binding Affinity:** Ligand A (-9.0 kcal/mol) has a significantly stronger binding affinity than Ligand B (-8.4 kcal/mol). This is a substantial advantage, potentially outweighing some of the ADME drawbacks.

**Overall Assessment:**

Ligand A has a superior binding affinity and a much better BBB percentile, which are critical for a CNS GPCR target. However, it suffers from poorer Caco-2 permeability, higher microsomal clearance, and lower solubility. Ligand B has better ADME properties (lower clearance, longer half-life, lower hERG risk), but its significantly weaker binding affinity is a major drawback.

Given the importance of affinity for GPCRs, and the relatively high BBB score of Ligand A, I would prioritize Ligand A for further optimization, despite its ADME liabilities. The strong binding affinity provides a good starting point, and the ADME issues might be addressed through structural modifications.

Output:
1
2025-04-17 06:53:29,040 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (352.519 and 346.431 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (67.43) is significantly better than Ligand B (108.29). For CNS targets, we want TPSA <= 90, and A is comfortably within that range, while B is above.

**logP:** Ligand A (3.193) is optimal (1-3), while Ligand B (1.435) is on the lower side, potentially hindering permeation.

**H-Bond Donors/Acceptors:** Both have similar HBD (2 vs 3) and HBA (3 vs 3) counts, both acceptable.

**QED:** Both ligands have similar, good QED values (0.659 and 0.678).

**DILI:** Ligand A (19.426) has a much lower DILI risk than Ligand B (38.116), indicating a safer profile.

**BBB:** This is a critical parameter for CNS targets. Ligand A has a BBB percentile of 75.378, which is excellent (>70). Ligand B's BBB percentile is only 41.644, which is considerably less desirable.

**Caco-2 Permeability:** Ligand A (-4.486) and Ligand B (-5.363) both have negative values, which is unusual. Assuming these are logP-like scales, lower values indicate lower permeability. B is slightly worse.

**Aqueous Solubility:** Both have similar, very poor solubility (-3.709 and -3.487). This could pose formulation challenges.

**hERG:** Both ligands have low hERG inhibition liability (0.192 and 0.136).

**Microsomal Clearance:** Ligand B (-9.76) has significantly *lower* (better) microsomal clearance than Ligand A (68.48). This suggests better metabolic stability for Ligand B.

**In vitro Half-Life:** Ligand B (-18.182) has a much longer half-life than Ligand A (4.851).

**P-gp Efflux:** Both have very low P-gp efflux liability (0.056 and 0.023).

**Binding Affinity:** Ligand A (-7.6 kcal/mol) has slightly better binding affinity than Ligand B (-8.7 kcal/mol). While both are excellent, the difference is not huge.

**Overall Assessment:**

Ligand A excels in TPSA, logP, BBB, and DILI, all crucial for a CNS-targeting GPCR ligand. While its solubility and clearance are not ideal, its superior BBB penetration and lower DILI risk outweigh these drawbacks. Ligand B has better metabolic stability and half-life, but its significantly higher TPSA and lower BBB penetration are major concerns for CNS activity. The slightly better affinity of Ligand A is a bonus.

Output:
1
2025-04-17 06:53:29,040 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (351.382 and 342.355 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (89.35) is excellent, falling below the 90 Angstroms threshold for CNS targets. Ligand B (97.6) is still reasonable but less optimal.

**logP:** Ligand A (0.318) is quite low, potentially hindering permeability. Ligand B (3.367) is within the optimal 1-3 range. This is a significant advantage for Ligand B.

**H-Bond Donors/Acceptors:** Both have 1 HBD, which is good. Ligand A has 6 HBA, and Ligand B has 5 HBA, both acceptable.

**QED:** Ligand A (0.825) has a better QED score than Ligand B (0.678), indicating a more drug-like profile overall.

**DILI:** Ligand B (87.166) has a higher DILI risk than Ligand A (60.915). This is a negative for Ligand B.

**BBB:** Ligand A (87.553) has a significantly better BBB penetration percentile than Ligand B (68.903). This is crucial for a CNS target like DRD2.

**Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and suggests poor permeability. However, the scale isn't specified, so it's hard to interpret.

**Aqueous Solubility:** Both have negative solubility values, which is also unusual. Again, the scale is unknown.

**hERG:** Both ligands have very low hERG inhibition risk (0.123 and 0.468).

**Microsomal Clearance:** Ligand A (5.317) has a much lower microsomal clearance than Ligand B (17.005), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (-3.431) has a negative half-life, which is not possible. Ligand B (-17.284) also has a negative half-life. These values are likely errors or indicate very rapid degradation.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.061 and 0.115), which is favorable for CNS penetration.

**Binding Affinity:** Both ligands have very similar and strong binding affinities (-8.5 and -8.6 kcal/mol). The difference is negligible.

**Overall Assessment:**

Despite Ligand A's better QED and lower DILI risk, Ligand B is the more promising candidate due to its optimal logP value, which is critical for permeability and CNS penetration. Ligand A's low logP is a significant concern. The BBB percentile for Ligand A is better, but the logP issue outweighs this benefit. The negative half-life values for both are concerning and need investigation, but don't drastically change the ranking at this stage.

Output:
1
2025-04-17 06:53:29,040 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (345.487 Da) is slightly lower, which could be beneficial for permeability. Ligand B (388.917 Da) is also acceptable.

**TPSA:** Ligand A (68.02) is excellent, well below the 90 A^2 threshold for CNS targets. Ligand B (78.87) is still reasonable but less optimal.

**logP:** Ligand A (4.857) is at the higher end of the optimal range, potentially leading to solubility issues or off-target interactions. Ligand B (2.004) is within the ideal range.

**H-Bond Donors/Acceptors:** Ligand A (1 HBD, 4 HBA) and Ligand B (2 HBD, 5 HBA) both fall within acceptable limits (<=5 HBD and <=10 HBA).

**QED:** Both ligands have good QED scores (A: 0.728, B: 0.779), indicating drug-like properties.

**DILI:** Both ligands have similar and acceptable DILI risk (A: 52.036, B: 50.136), below the 60 threshold.

**BBB:** Ligand A (75.805) has a significantly better BBB percentile than Ligand B (65.917). This is a crucial advantage for a CNS target like DRD2.

**Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and suggests a potential issue with the prediction method or the compounds themselves. However, we will proceed with the other parameters for comparison.

**Aqueous Solubility:** Both ligands have very poor predicted aqueous solubility (A: -5.595, B: -3.718). This is a concern, but can sometimes be mitigated with formulation strategies.

**hERG Inhibition:** Both ligands show low hERG inhibition risk (A: 0.857, B: 0.777).

**Microsomal Clearance:** Ligand A (93.795) has a higher microsomal clearance than Ligand B (14.276), suggesting Ligand B is more metabolically stable.

**In vitro Half-Life:** Ligand B (20.675 hours) has a significantly longer half-life than Ligand A (53.492 hours). This is a major advantage for dosing convenience.

**P-gp Efflux:** Ligand A (0.504) has lower P-gp efflux liability than Ligand B (0.181), which is beneficial for CNS exposure.

**Binding Affinity:** Both ligands have the same excellent binding affinity (-8.6 kcal/mol).

**Overall Assessment:**

Ligand A excels in BBB penetration and P-gp efflux, which are critical for CNS GPCR targets. However, it has a higher logP and higher microsomal clearance, leading to a shorter half-life and potentially lower metabolic stability. Ligand B has better metabolic stability (lower Cl_mic) and a longer half-life, but suffers from poorer BBB penetration and higher P-gp efflux.

Given the importance of CNS penetration for DRD2, and the equal binding affinities, Ligand A is the slightly more promising candidate. The higher logP and clearance are manageable drawbacks compared to the significant advantage in BBB penetration.

Output:
0
2025-04-17 06:53:29,041 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (342.483 and 344.419 Da) fall comfortably within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (49.41) is excellent, well below the 90 Angstroms threshold for CNS targets. Ligand B (89.07) is higher, but still acceptable, though less optimal for brain penetration.

**3. logP:** Ligand A (2.89) is within the optimal 1-3 range. Ligand B (0.481) is a bit low, potentially hindering membrane permeability.

**4. H-Bond Donors:** Both ligands have 1 HBD, which is good.

**5. H-Bond Acceptors:** Ligand A has 2 HBA, and Ligand B has 7 HBA. Both are within the acceptable limit of 10, but Ligand A is preferable.

**6. QED:** Both ligands have good QED scores (0.545 and 0.789), indicating drug-like properties.

**7. DILI:** Ligand A (7.135) has a very low DILI risk. Ligand B (29.081) is higher, but still relatively low.

**8. BBB:** This is a critical parameter for a CNS target like DRD2. Ligand A scores very well (72.276), exceeding the desirable >70 threshold. Ligand B (46.336) is significantly lower and less promising for CNS penetration.

**9. Caco-2 Permeability:** Ligand A (-4.724) has poor Caco-2 permeability. Ligand B (-5.328) is also poor, but slightly worse.

**10. Aqueous Solubility:** Ligand A (-3.296) and Ligand B (-0.703) both have poor solubility.

**11. hERG Inhibition:** Both ligands show very low hERG inhibition risk (0.337 and 0.212).

**12. Microsomal Clearance:** Ligand A (9.561) has lower clearance than Ligand B (15.173), suggesting better metabolic stability.

**13. In vitro Half-Life:** Ligand A (2.671) has a short half-life, while Ligand B (-25.347) has a very long half-life.

**14. P-gp Efflux:** Both ligands have low P-gp efflux liability (0.069).

**15. Binding Affinity:** Ligand B (-7.7) has a slightly better binding affinity than Ligand A (-7.4), a difference of 0.3 kcal/mol.

**Overall Assessment:**

Despite the slightly better affinity of Ligand B, Ligand A is the more promising candidate. The significantly better BBB penetration (72.276 vs 46.336) and lower TPSA of Ligand A are crucial for a CNS-targeting drug. While Ligand A has poor Caco-2 permeability and solubility, these can be addressed through formulation strategies. The better metabolic stability (lower Cl_mic) of Ligand A is also a plus. The 0.3 kcal/mol difference in binding affinity is unlikely to overcome the substantial pharmacokinetic advantages of Ligand A for a CNS target.

Output:
1
2025-04-17 06:53:29,041 - INFO - Batch 319 complete. Total preferences: 5104
2025-04-17 06:53:29,041 - INFO - Processing batch 320/512...
2025-04-17 06:54:18,419 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (339.4 and 350.4 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (98.98) is better than Ligand B (107.61). Both are below the 140 threshold for oral absorption, and Ligand A is closer to the <90 desired for CNS targets.

**logP:** Ligand A (1.056) is within the optimal 1-3 range. Ligand B (-0.711) is slightly below 1, which could hinder permeation, though not drastically.

**H-Bond Donors/Acceptors:** Ligand A (1 HBD, 5 HBA) is preferable to Ligand B (3 HBD, 4 HBA). Both are within acceptable limits, but fewer H-bonds generally improve permeability.

**QED:** Ligand A (0.887) has a significantly better QED score than Ligand B (0.569), indicating a more drug-like profile.

**DILI:** Ligand A (43.9%) has a slightly higher DILI risk than Ligand B (33.3%), but both are acceptable (<60%).

**BBB:** Ligand B (51.2%) has a substantially better BBB penetration percentile than Ligand A (41.1%). This is a critical advantage for a CNS target like DRD2.

**Caco-2 Permeability:** Ligand A (-5.228) has a worse Caco-2 permeability than Ligand B (-4.938), suggesting lower intestinal absorption.

**Aqueous Solubility:** Ligand A (-1.663) has better aqueous solubility than Ligand B (-2.601).

**hERG:** Both ligands have very low hERG inhibition risk (0.174 and 0.055, respectively).

**Microsomal Clearance:** Ligand A (-8.28) has a much lower (better) microsomal clearance than Ligand B (0.556), indicating greater metabolic stability.

**In vitro Half-Life:** Ligand A (5.72) has a longer in vitro half-life than Ligand B (-3.663), which is desirable.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.004 and 0.008, respectively).

**Binding Affinity:** Both ligands have the same binding affinity (-8.2 kcal/mol), which is excellent.

**Overall Assessment:**

While Ligand B has a significantly better BBB score, Ligand A excels in most other ADME properties (TPSA, logP, QED, Cl_mic, t1/2, solubility). The binding affinity is identical. Given the importance of BBB penetration for CNS targets, Ligand B initially appears more promising. However, the substantial improvements in metabolic stability (Cl_mic, t1/2) and drug-likeness (QED) of Ligand A, coupled with acceptable BBB penetration, make it a stronger overall candidate. The slightly lower Caco-2 permeability of Ligand A is a minor concern, potentially addressable through formulation strategies.

Output:
1
2025-04-17 06:54:18,420 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (346.471 Da) is slightly better positioned.

**TPSA:** Ligand A (78.43) is significantly better than Ligand B (98.74). For CNS targets, we want TPSA <= 90, and A is comfortably within this range, while B is approaching the upper limit.

**logP:** Ligand A (2.183) is optimal (1-3), while Ligand B (0.443) is a bit low, potentially hindering permeation.

**H-Bond Donors/Acceptors:** Both have 3 HBDs, which is good. Ligand A has 3 HBAs, and Ligand B has 5. Both are acceptable, but fewer is generally preferred.

**QED:** Both ligands have similar QED values (0.675 and 0.626), indicating good drug-likeness.

**DILI:** Ligand A (15.394) has a lower DILI risk than Ligand B (12.796), which is preferable.

**BBB:** This is crucial for a CNS target like DRD2. Ligand A (57.464) is moderate, while Ligand B (24.738) is quite low. This is a significant disadvantage for Ligand B.

**Caco-2 Permeability:** Ligand A (-4.687) is better than Ligand B (-5.618), indicating better intestinal absorption.

**Aqueous Solubility:** Ligand A (-2.255) is better than Ligand B (-1.04), which is good for formulation.

**hERG:** Both ligands have low hERG inhibition liability (0.278 and 0.233).

**Microsomal Clearance:** Ligand A (32.173) has higher clearance than Ligand B (-1.906), meaning Ligand B is more metabolically stable.

**In vitro Half-Life:** Ligand B (-40.183) has a significantly longer half-life than Ligand A (-0.909), which is a major advantage.

**P-gp Efflux:** Both ligands have similar P-gp efflux liability (0.058 and 0.008).

**Binding Affinity:** Ligand A (-8.9 kcal/mol) has a slightly stronger binding affinity than Ligand B (-7.4 kcal/mol). While both are good, the 1.5 kcal/mol difference favors A.

**Overall Assessment:**

Ligand A excels in key GPCR properties like TPSA, logP, and binding affinity, and has a reasonable BBB score. While its metabolic stability isn't ideal, its overall profile is more favorable for CNS penetration and target engagement. Ligand B has a better half-life and metabolic stability, but its low BBB penetration and suboptimal logP are significant drawbacks for a DRD2 ligand.

Output:
1
2025-04-17 06:54:18,420 - INFO - Reasoning:

Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (383.861 Da) is slightly higher than Ligand B (343.479 Da), but both are acceptable.

**TPSA:** Ligand A (112.55) is borderline for CNS penetration, being above the preferred <90. Ligand B (71.76) is excellent, well below the threshold.

**logP:** Both ligands have good logP values (A: 1.076, B: 2.223), falling within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A (HBD=3, HBA=6) and Ligand B (HBD=1, HBA=7) both have acceptable numbers of H-bond donors and acceptors.

**QED:** Both ligands have good QED scores (A: 0.706, B: 0.867), indicating good drug-like properties.

**DILI:** Ligand A (84.025) has a higher DILI risk than Ligand B (52.423). While both are below the concerning >60 threshold, Ligand B is preferable.

**BBB:** This is critical for a CNS target. Ligand A (40.946) has a poor BBB percentile, while Ligand B (63.901) is better, though still not ideal (>70 is preferred).

**Caco-2 Permeability:** Both have negative Caco-2 values which is unusual. This suggests poor permeability.

**Aqueous Solubility:** Both have negative solubility values which is also unusual.

**hERG:** Both ligands have very low hERG inhibition liability (A: 0.098, B: 0.404), which is excellent.

**Microsomal Clearance:** Ligand A (-14.103) has a much lower (better) microsomal clearance than Ligand B (17.906), suggesting greater metabolic stability.

**In vitro Half-Life:** Ligand B (33.74) has a significantly longer in vitro half-life than Ligand A (11.147).

**P-gp Efflux:** Both ligands have low P-gp efflux liability (A: 0.067, B: 0.058), which is good for CNS penetration.

**Binding Affinity:** Ligand B (-9.1 kcal/mol) has a slightly better binding affinity than Ligand A (-8.3 kcal/mol). While the difference is not huge, it's a positive factor.

**Overall Assessment:**

Ligand B is the more promising candidate. While its BBB penetration isn't ideal, it's significantly better than Ligand A's. It also has a lower DILI risk, a longer half-life, and a slightly better binding affinity. Ligand A has better metabolic stability, but the poor BBB penetration is a major drawback for a CNS target like DRD2. The unusual negative values for Caco-2 and solubility are concerning for both, and would require further investigation. However, considering the GPCR-specific priorities, Ligand B is the superior choice.

Output:
1
2025-04-17 06:54:18,420 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight (MW):** Both ligands (352.387 and 373.465 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (117.87) is better than Ligand B (49.77) as it is closer to the <90 A^2 threshold for CNS targets. Ligand B is still acceptable, but A is preferable.

**3. logP:** Ligand B (3.429) is optimal (1-3), while Ligand A (0.166) is quite low, potentially hindering permeation. This is a significant drawback for Ligand A.

**4. H-Bond Donors (HBD):** Both ligands have acceptable HBD counts (3 for A, 1 for B), well below the limit of 5.

**5. H-Bond Acceptors (HBA):** Both ligands have acceptable HBA counts (6 for A, 4 for B), well below the limit of 10.

**6. QED:** Both ligands have good QED scores (0.574 for A, 0.797 for B), indicating drug-like properties. Ligand B is slightly better.

**7. DILI:** Ligand B (20.9) has a much lower DILI risk than Ligand A (49.477), making it safer.

**8. BBB:** Ligand B (86.545) has a significantly higher BBB penetration percentile than Ligand A (52.268). This is crucial for a CNS target like DRD2, and strongly favors Ligand B.

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.886 and -4.492), which is unusual and suggests poor permeability. However, these values are on a different scale and direct comparison is difficult.

**10. Aqueous Solubility:** Both ligands have negative solubility values (-1.655 and -3.433), again suggesting poor solubility. Similar to Caco-2, direct comparison is difficult.

**11. hERG Inhibition:** Ligand A (0.209) has a lower hERG inhibition risk than Ligand B (0.711), which is preferable.

**12. Microsomal Clearance:** Both ligands have similar microsomal clearance values (41.744 and 47.509 mL/min/kg), suggesting comparable metabolic stability.

**13. In vitro Half-Life:** Ligand B (22.871 hours) has a significantly longer half-life than Ligand A (4.047 hours), which is a major advantage.

**14. P-gp Efflux:** Ligand A (0.093) has a lower P-gp efflux liability than Ligand B (0.544), which is favorable for CNS penetration.

**15. Binding Affinity:** Ligand A (-7.4 kcal/mol) has a slightly better binding affinity than Ligand B (-6.9 kcal/mol). While a 0.5 kcal/mol difference is good, it's unlikely to overcome the significant ADME deficiencies of Ligand A.

**Overall Assessment:**

Ligand B is the superior candidate. While Ligand A has slightly better binding affinity and lower P-gp efflux, Ligand B excels in crucial areas for a CNS-targeting GPCR ligand: significantly better BBB penetration, lower DILI risk, a more optimal logP, and a much longer half-life. The poor logP of Ligand A is a major concern, potentially hindering its ability to reach the brain. The better BBB, DILI, and half-life of Ligand B outweigh the small affinity difference.

Output:
1
2025-04-17 06:54:18,420 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (332.363 and 359.499 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (90.68) is slightly above the preferred <90 for CNS targets, while Ligand B (72.7) is well within the range. This favors Ligand B.

**3. logP:** Both ligands have good logP values (2.657 and 3.533), falling within the optimal 1-3 range. Ligand B is slightly higher, which *could* be a minor concern, but not a dealbreaker.

**4. H-Bond Donors:** Ligand A (2) and Ligand B (1) are both acceptable, being less than 5. Ligand B is slightly better.

**5. H-Bond Acceptors:** Ligand A (4) and Ligand B (6) are both acceptable, being less than 10.

**6. QED:** Both ligands have good QED scores (0.769 and 0.906), indicating good drug-like properties. Ligand B is slightly better.

**7. DILI:** Ligand A (85.227) has a higher DILI risk than Ligand B (72.043). Lower is better, so Ligand B is favored.

**8. BBB:** This is crucial for a CNS target like DRD2. Ligand A (35.983) has a very poor BBB penetration percentile, while Ligand B (60.993) is significantly better, although still not ideal (>70 is desirable). This is a major advantage for Ligand B.

**9. Caco-2:** Both ligands have negative Caco-2 values (-5.1 and -5.118), which is unusual and suggests poor permeability. This is a concern for both, but doesn't differentiate them.

**10. Solubility:** Both ligands have very poor aqueous solubility (-5.41 and -4.04). This is a significant drawback for both, potentially hindering bioavailability.

**11. hERG:** Both ligands have very low hERG inhibition liability (0.67 and 0.155), which is excellent.

**12. Cl_mic:** Ligand A (14.178) has lower microsomal clearance than Ligand B (35.885), suggesting better metabolic stability. This favors Ligand A.

**13. t1/2:** Ligand A (33.788) has a longer in vitro half-life than Ligand B (14.41). This is a significant advantage for Ligand A.

**14. Pgp:** Both ligands have very low P-gp efflux liability (0.263 and 0.429), which is good for CNS penetration.

**15. Binding Affinity:** Both ligands have excellent binding affinities (-9.7 and -9.4 kcal/mol). The difference of 0.3 kcal/mol is not substantial enough to outweigh other factors.

**Overall Assessment:**

While Ligand A has better metabolic stability (lower Cl_mic) and a longer half-life, its extremely poor BBB penetration (35.983%) is a critical flaw for a CNS-targeting drug. Ligand B, despite slightly higher logP and lower metabolic stability, exhibits significantly better BBB penetration (60.993%), a lower DILI risk, and a slightly better QED score. Given the GPCR-specific priorities, particularly BBB penetration for CNS targets, Ligand B is the more promising candidate. The solubility issues are a concern for both, but can potentially be addressed with formulation strategies.

Output:
1
2025-04-17 06:54:18,420 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (374.706 and 350.415 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (97.16) is better than Ligand B (103.01), both are below the 140 threshold for oral absorption, and closer to the <90 desired for CNS targets.

**logP:** Ligand A (3.713) is optimal, while Ligand B (0.972) is a bit low, potentially hindering permeation.

**H-Bond Donors/Acceptors:** Ligand A (HBD=2, HBA=5) and Ligand B (HBD=3, HBA=5) both are within acceptable ranges.

**QED:** Ligand B (0.754) has a better QED score than Ligand A (0.472), suggesting a more drug-like profile.

**DILI:** Ligand A (92.051) has a higher DILI risk than Ligand B (44.552). This is a significant negative for Ligand A.

**BBB:** Ligand A (65.335) has a better BBB penetration score than Ligand B (15.432). This is a critical advantage for a CNS target like DRD2.

**Caco-2 Permeability:** Both have negative values, which is unusual. Assuming these are logP values, they indicate poor permeability.

**Aqueous Solubility:** Both have negative values, which is unusual. Assuming these are logS values, they indicate poor solubility.

**hERG Inhibition:** Ligand A (0.416) has a slightly higher hERG risk than Ligand B (0.067), but both are reasonably low.

**Microsomal Clearance:** Ligand A (54.257) has a higher microsomal clearance than Ligand B (1.24), indicating lower metabolic stability.

**In vitro Half-Life:** Ligand A (50.452) has a longer half-life than Ligand B (9.096).

**P-gp Efflux:** Ligand A (0.286) has lower P-gp efflux liability than Ligand B (0.019), which is favorable for CNS penetration.

**Binding Affinity:** Ligand A (-9.3 kcal/mol) has a significantly stronger binding affinity than Ligand B (-7.8 kcal/mol). This is a substantial advantage, potentially outweighing some of its ADME drawbacks.

**Overall Assessment:**

Ligand A has a superior binding affinity and better BBB penetration and P-gp efflux, which are crucial for CNS GPCR targets. However, it has a higher DILI risk and lower metabolic stability. Ligand B has a better QED score, lower DILI, and better metabolic stability, but its lower logP and significantly poorer BBB penetration are major drawbacks for a CNS target. The substantial difference in binding affinity (-1.5 kcal/mol) is a key factor. Given the importance of potency for GPCRs, and the need for CNS penetration, the stronger binding affinity and better BBB of Ligand A are likely to be more important than its slightly worse ADME profile.

Output:
1
2025-04-17 06:54:18,420 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (337.419 and 350.547 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (46.61) is significantly better than Ligand B (49.41). Both are below the 90 A^2 threshold for CNS targets, but A is closer to optimal.

**3. logP:** Both ligands have good logP values (3.759 and 3.994), falling within the 1-3 range.

**4. H-Bond Donors:** Ligand A (0) is preferable to Ligand B (1). Fewer HBDs generally improve permeability.

**5. H-Bond Acceptors:** Ligand A (3) is slightly better than Ligand B (2), but both are acceptable.

**6. QED:** Both ligands have similar QED values (0.784 and 0.706), indicating good drug-likeness.

**7. DILI:** Ligand A (69.135) has a higher DILI risk than Ligand B (9.035). This is a significant drawback for Ligand A.

**8. BBB:** Ligand B (87.088) has a substantially better BBB penetration score than Ligand A (70.609). This is crucial for a CNS target like DRD2.

**9. Caco-2 Permeability:** Both have negative values, which is unusual. Assuming these are logP values, Ligand A (-4.463) is worse than Ligand B (-4.526), indicating poorer permeability.

**10. Aqueous Solubility:** Both have negative values. Assuming these are logS values, Ligand A (-5.547) is worse than Ligand B (-3.808), indicating poorer solubility.

**11. hERG Inhibition:** Both ligands have low hERG inhibition liability (0.695 and 0.717), which is good.

**12. Microsomal Clearance:** Ligand B (69.715) has lower microsomal clearance than Ligand A (121.842), suggesting better metabolic stability.

**13. In vitro Half-Life:** Ligand B (-17.463) has a negative half-life, which is impossible. This is a major red flag. Ligand A (5.729) has a reasonable half-life.

**14. P-gp Efflux:** Both ligands have low P-gp efflux liability (0.46 and 0.246), which is good.

**15. Binding Affinity:** Ligand A (-9.7 kcal/mol) has a significantly stronger binding affinity than Ligand B (-7.5 kcal/mol). This is a substantial advantage.

**Overall Assessment:**

Despite Ligand A's superior binding affinity, the combination of higher DILI risk, lower BBB penetration, and the impossible half-life value for Ligand B make Ligand B the more promising candidate. The strong affinity of Ligand A is tempting, but the ADME properties are concerning. Ligand B, while having a weaker affinity, has a much better safety profile (lower DILI), better BBB penetration, and more reasonable ADME properties. The negative half-life for Ligand B is a serious concern, but could be an experimental error.

Output:
1
2025-04-17 06:54:18,420 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (369.531 and 362.455 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (74.69) is better than Ligand B (76.46). Both are reasonably good for CNS penetration, being below the 90 A^2 threshold, but A is closer to the optimal range.

**logP:** Ligand A (2.974) is optimal, while Ligand B (0.61) is a bit low, potentially hindering membrane permeability.

**H-Bond Donors:** Ligand A (2) and Ligand B (1) are both acceptable.

**H-Bond Acceptors:** Both ligands have 6 HBA, which is within the acceptable range.

**QED:** Both ligands have good QED scores (0.773 and 0.817), indicating drug-like properties.

**DILI:** Ligand A (37.922) has a significantly lower DILI risk than Ligand B (60.217), placing it in the "good" category while B is borderline high risk.

**BBB:** Ligand B (68.399) has a better BBB penetration percentile than Ligand A (43.079). This is a crucial factor for CNS targets like DRD2.

**Caco-2 Permeability:** Ligand A (-4.697) has worse Caco-2 permeability than Ligand B (-5.355). Both are poor.

**Aqueous Solubility:** Both ligands have very poor aqueous solubility (-2.459 and -2.058).

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.48 and 0.156).

**Microsomal Clearance:** Ligand B (9.726) has lower microsomal clearance than Ligand A (34.643), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand B (15.237) has a slightly longer half-life than Ligand A (14.894).

**P-gp Efflux:** Ligand A (0.255) has lower P-gp efflux liability than Ligand B (0.065), which is favorable for CNS penetration.

**Binding Affinity:** Ligand B (-8.5 kcal/mol) has a significantly stronger binding affinity than Ligand A (-7.8 kcal/mol). This is a substantial advantage, potentially outweighing some ADME drawbacks.

**Overall Assessment:**

Ligand B has a stronger binding affinity and better BBB penetration, which are critical for a CNS-targeting GPCR like DRD2. It also exhibits better metabolic stability (lower Cl_mic) and a slightly longer half-life. However, it has a higher DILI risk and lower logP. Ligand A has a lower DILI risk and better logP, but its affinity and BBB penetration are significantly worse. The difference in binding affinity (-0.7 kcal/mol) is substantial and, combined with the better BBB, makes Ligand B the more promising candidate despite the higher DILI risk. The poor solubility and Caco-2 permeability are concerns for both, but can be addressed with formulation strategies.

Output:
1
2025-04-17 06:54:18,421 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (348.49 and 350.42 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (78.43) is significantly better than Ligand B (128.69). For CNS targets, TPSA should be <= 90, and A is comfortably within that, while B is pushing the limit.

**logP:** Ligand A (2.439) is optimal (1-3), while Ligand B (0.689) is a bit low, potentially hindering membrane permeability.

**H-Bond Donors/Acceptors:** Ligand A (HBD=3, HBA=3) and Ligand B (HBD=4, HBA=6) both fall within acceptable ranges.

**QED:** Ligand A (0.69) is better than Ligand B (0.469), indicating a more drug-like profile.

**DILI:** Ligand A (20.9) has a much lower DILI risk than Ligand B (54.56). This is a significant advantage.

**BBB:** Ligand A (44.98) is better than Ligand B (9.62), although both are not ideal. However, for a CNS target like DRD2, a higher BBB is crucial, making A more favorable.

**Caco-2 Permeability:** Ligand A (-4.717) is better than Ligand B (-5.645), indicating better intestinal absorption.

**Aqueous Solubility:** Ligand A (-3.182) is better than Ligand B (-2.178), suggesting better formulation potential.

**hERG:** Both ligands have low hERG inhibition liability (0.174 and 0.337), which is good.

**Microsomal Clearance:** Ligand B (-10.681) has a lower (better) microsomal clearance than Ligand A (50.25), indicating better metabolic stability.

**In vitro Half-Life:** Ligand B (-7.274) has a longer half-life than Ligand A (-9.025), which is generally desirable.

**P-gp Efflux:** Ligand A (0.143) has lower P-gp efflux than Ligand B (0.131), which is favorable for CNS penetration.

**Binding Affinity:** Both ligands have excellent binding affinity (-8.4 and -8.0 kcal/mol). The difference of 0.4 kcal/mol is not substantial enough to outweigh the other significant differences.

**Overall:** Considering the GPCR-specific priorities, Ligand A is the better candidate. It has a significantly better TPSA, logP, BBB, DILI, solubility, and Caco-2 permeability. While Ligand B has better metabolic stability and half-life, the advantages of Ligand A in CNS penetration and safety profile are more critical for a DRD2 ligand.

Output:
0
2025-04-17 06:54:18,421 - INFO - Okay, let's analyze these two ligands for their potential as DRD2 drug candidates. DRD2 is a GPCR in the CNS, so we'll prioritize BBB, logP, Pgp, TPSA, and affinity.

**Ligand A:** [354.407, 120.   ,  -1.578,   4.   ,   6.   ,   0.391,  36.254,  21.753, -5.354,  -0.588,   0.044,  -6.846, -23.125,   0.003,  -7.4  ]
**Ligand B:** [355.429,  58.36 ,   2.708,   1.   ,   4.   ,   0.693,  20.279,  86.08 , -4.219,  -3.056,   0.549,  32.53 ,   0.76 ,   0.139,  -7.   ]

**Step-by-step comparison:**

1. **MW:** Both ligands are within the ideal range (354-355 Da). No clear advantage.
2. **TPSA:** Ligand A (120) is higher than the ideal <90 for CNS targets, but Ligand B (58.36) is excellent. This is a significant advantage for Ligand B.
3. **logP:** Ligand A (-1.578) is a bit low, potentially hindering permeability. Ligand B (2.708) is within the optimal 1-3 range. Advantage: Ligand B.
4. **HBD:** Ligand A (4) is acceptable, Ligand B (1) is even better. Advantage: Ligand B.
5. **HBA:** Both ligands have 4 HBA, which is acceptable. No clear advantage.
6. **QED:** Ligand A (0.391) is below the desirable 0.5 threshold, indicating a less drug-like profile. Ligand B (0.693) is above the threshold. Advantage: Ligand B.
7. **DILI:** Ligand A (36.254) is good (low risk). Ligand B (20.279) is even better. Advantage: Ligand B.
8. **BBB:** Ligand A (21.753) is very poor for a CNS target. Ligand B (86.08) is excellent, exceeding the >70 desirable threshold. This is a *major* advantage for Ligand B.
9. **Caco-2:** Ligand A (-5.354) is very poor. Ligand B (-4.219) is also poor, but slightly better. Advantage: Ligand B.
10. **Solubility:** Ligand A (-0.588) is poor. Ligand B (-3.056) is also poor. No clear advantage.
11. **hERG:** Ligand A (0.044) is very low risk. Ligand B (0.549) is slightly higher, but still acceptable. Advantage: Ligand A.
12. **Cl_mic:** Ligand A (-6.846) indicates very rapid clearance, which is undesirable. Ligand B (32.53) suggests faster clearance than ideal, but is significantly better than Ligand A. Advantage: Ligand B.
13. **t1/2:** Ligand A (-23.125) is extremely short, a significant drawback. Ligand B (0.76) is very short, but still better than A. Advantage: Ligand B.
14. **Pgp:** Ligand A (0.003) is very low efflux, which is good. Ligand B (0.139) is also low. Advantage: Ligand A.
15. **Affinity:** Ligand A (-7.4) is slightly better than Ligand B (-7.0). While a 0.4 kcal/mol difference is not huge, it's noticeable. Advantage: Ligand A.

**Overall Assessment:**

Ligand B overwhelmingly outperforms Ligand A, particularly regarding critical properties for a CNS-targeting GPCR like DRD2. The excellent BBB penetration, favorable TPSA and logP, better QED, and significantly improved metabolic stability (Cl_mic, t1/2) outweigh the slightly weaker affinity. Ligand A's poor BBB, high clearance, and low QED are major liabilities. While Ligand A has a slightly better affinity and lower Pgp efflux, these are less important than the ADME properties for a CNS drug.

1
2025-04-17 06:54:18,421 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (348.447 and 346.347 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (76.46) is significantly better than Ligand B (126.38). For CNS targets, we want TPSA <= 90, and A is comfortably within this range, while B exceeds it.

**3. logP:** Ligand A (1.29) is within the optimal 1-3 range. Ligand B (-0.474) is slightly below 1, which *could* indicate permeability issues, though not drastically.

**4. H-Bond Donors:** Ligand A (1) is good. Ligand B (2) is acceptable, but slightly higher.

**5. H-Bond Acceptors:** Ligand A (5) is good. Ligand B (8) is higher, potentially impacting permeability.

**6. QED:** Both ligands have good QED scores (0.595 and 0.749), indicating drug-like properties.

**7. DILI:** Ligand A (36.409) has a much lower DILI risk than Ligand B (56.301). Both are below 60, but A is preferable.

**8. BBB:** Ligand A (71.268) has a significantly better BBB penetration percentile than Ligand B (37.263).  >70 is desirable for CNS targets, and A is closer to that threshold.

**9. Caco-2 Permeability:** Ligand A (-4.689) is worse than Ligand B (-5.06). Lower values here are less desirable, but both are quite poor.

**10. Aqueous Solubility:** Ligand A (-1.504) is better than Ligand B (-2.442), though both are quite poor.

**11. hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.381 and 0.066).

**12. Microsomal Clearance:** Ligand A (26.072) has a lower (better) microsomal clearance than Ligand B (11.093), indicating greater metabolic stability.

**13. In vitro Half-Life:** Ligand A (0.784) has a slightly better in vitro half-life than Ligand B (-4.722).

**14. P-gp Efflux:** Ligand A (0.048) has a much lower P-gp efflux liability than Ligand B (0.028), which is crucial for CNS penetration.

**15. Binding Affinity:** Ligand B (-8.9 kcal/mol) has a stronger binding affinity than Ligand A (-7.6 kcal/mol). This is a significant advantage (1.3 kcal/mol difference).

**Overall Assessment:**

While Ligand B has a superior binding affinity, Ligand A is substantially better across several critical ADME properties, particularly those important for CNS penetration (BBB, TPSA, Pgp). The lower TPSA, better BBB, lower DILI, and lower P-gp efflux of Ligand A are very compelling. The affinity difference, while notable, might be overcome with further optimization of Ligand A. The poor Caco-2 and solubility for both are concerning, but can be addressed with formulation strategies. Given the target (DRD2 in the CNS), prioritizing CNS penetration and safety is crucial.

Output:
0
2025-04-17 06:54:18,421 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (345.355 and 351.447 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (93.9) is slightly above the preferred <90 for CNS targets, but still reasonable. Ligand B (75.88) is well within the desired range.

**logP:** Ligand A (0.459) is quite low, potentially hindering membrane permeability. Ligand B (2.109) is within the optimal 1-3 range. This is a significant advantage for Ligand B.

**H-Bond Donors/Acceptors:** Ligand A has 1 HBD and 6 HBA, which are acceptable. Ligand B has 0 HBD and 5 HBA, also acceptable.

**QED:** Ligand A (0.457) is below the desirable threshold of 0.5, indicating a less drug-like profile. Ligand B (0.752) is above 0.5, suggesting better drug-likeness.

**DILI:** Ligand A (62.854) has a moderate DILI risk, while Ligand B (34.626) has a lower risk.

**BBB:** This is crucial for a CNS target. Ligand A (59.364) has a poor BBB percentile. Ligand B (83.404) has a very good BBB percentile, a major advantage.

**Caco-2 Permeability:** Both have negative values, which is unusual. However, the magnitude suggests Ligand A (-4.851) has worse permeability than Ligand B (-4.472).

**Aqueous Solubility:** Both have negative values, indicating poor solubility. Ligand B (-0.731) is slightly better than Ligand A (-2.22).

**hERG:** Both ligands have low hERG inhibition liability (0.111 and 0.313 respectively), which is good.

**Microsomal Clearance:** Ligand A (7.466) has lower clearance than Ligand B (52.265), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (-29.146) has a very negative half-life, which is concerning. Ligand B (-12.516) is also negative but less so.

**P-gp Efflux:** Both have very low P-gp efflux liability (0.041 and 0.125 respectively), which is favorable for CNS penetration.

**Binding Affinity:** Ligand B (-7.2 kcal/mol) has a slightly better binding affinity than Ligand A (-8.0 kcal/mol). While A is better, the difference is not substantial enough to outweigh the other significant issues.

**Overall Assessment:**

Ligand B is significantly more promising. While Ligand A has a slightly better binding affinity, Ligand B excels in crucial areas for a CNS-targeting GPCR ligand: better logP, significantly higher BBB penetration, better QED, and lower DILI risk. The metabolic stability of Ligand A is better, but the poor BBB and logP of Ligand A are major drawbacks.

Output:
1
2025-04-17 06:54:18,421 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (373.519 and 388.464 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (118.36) is better than Ligand B (69.26). For CNS targets, TPSA should be <=90, and Ligand B is well within this range, while Ligand A is slightly above.

**logP:** Ligand B (2.583) is optimal (1-3), while Ligand A (0.889) is a bit low, potentially hindering membrane permeability.

**H-Bond Donors/Acceptors:** Ligand A (HBD=3, HBA=4) has a more favorable balance than Ligand B (HBD=1, HBA=6). While both are within acceptable limits, excessive HBA can sometimes reduce permeability.

**QED:** Both ligands have good QED scores (A: 0.556, B: 0.675), indicating good drug-like properties.

**DILI:** Ligand A (33.928) has a significantly lower DILI risk than Ligand B (58.744), which is a major advantage.

**BBB:** Ligand A (55.176) has a better BBB percentile than Ligand B (43.66), although both are below the desirable >70 for CNS targets.

**Caco-2 Permeability:** Ligand A (-5.346) has a worse Caco-2 permeability than Ligand B (-5.012).

**Aqueous Solubility:** Ligand A (-2.933) has a worse aqueous solubility than Ligand B (-2.078).

**hERG:** Both ligands have very low hERG risk (A: 0.093, B: 0.677).

**Microsomal Clearance:** Ligand B (32.865) has a lower microsomal clearance than Ligand A (37.789), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand B (-2.698) has a better in vitro half-life than Ligand A (-52.772).

**P-gp Efflux:** Ligand A (0.038) has a much lower P-gp efflux liability than Ligand B (0.475), which is crucial for CNS penetration.

**Binding Affinity:** Ligand B (-7.9 kcal/mol) has a slightly better binding affinity than Ligand A (-7.5 kcal/mol). However, the difference is relatively small (0.4 kcal/mol).

**Overall Assessment:**

Considering the GPCR-specific priorities, Ligand A looks more promising. While Ligand B has a slightly better affinity and metabolic stability, Ligand A's significantly lower DILI risk, better BBB penetration, and substantially lower P-gp efflux are critical advantages for a CNS-targeting drug. The lower logP of Ligand A is a concern, but the other benefits likely outweigh this drawback.

Output:
1
2025-04-17 06:54:18,421 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (349.391 and 344.415 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (121.23) is slightly above the optimal <90 for CNS targets, but still reasonable. Ligand B (98.22) is excellent, well below the 90 threshold.

**3. logP:** Both ligands have good logP values (1.329 and 1.444), falling within the optimal 1-3 range.

**4. H-Bond Donors:** Both have 2 HBD, which is acceptable (<=5).

**5. H-Bond Acceptors:** Ligand A has 5 HBA and Ligand B has 4 HBA, both within the acceptable limit of <=10.

**6. QED:** Both ligands have good QED scores (0.593 and 0.763), indicating good drug-like properties.

**7. DILI:** Ligand A (63.746) has a higher DILI risk than Ligand B (43.66). While both are below the concerning 60 threshold, lower is better.

**8. BBB:** Ligand A (65.18) has a slightly better BBB penetration percentile than Ligand B (56.029), but both are below the desirable >70 for CNS targets.

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.868 and -4.781) which is unusual. These values are likely errors or indicate very poor permeability.

**10. Aqueous Solubility:** Both ligands have negative solubility values (-3.559 and -3.907) which is also unusual and indicates very poor solubility.

**11. hERG:** Both ligands have low hERG inhibition liability (0.208 and 0.333), which is good.

**12. Microsomal Clearance:** Ligand B (-11.523) has a significantly *lower* (better) microsomal clearance than Ligand A (11.571). This suggests better metabolic stability for Ligand B.

**13. In vitro Half-Life:** Ligand B (12.912) has a longer in vitro half-life than Ligand A (-5.106), which is desirable.

**14. P-gp Efflux:** Both ligands have low P-gp efflux liability (0.099 and 0.102), which is good.

**15. Binding Affinity:** Ligand A (-8.5 kcal/mol) has a slightly better binding affinity than Ligand B (-7.9 kcal/mol). This is a 0.6 kcal/mol difference, which is significant.

**Overall Assessment:**

Despite the better affinity of Ligand A, the significantly better ADME profile of Ligand B makes it the more promising candidate. Ligand B has a lower DILI risk, better metabolic stability (lower Cl_mic, longer t1/2), and a slightly better solubility. The affinity difference, while present, is not large enough to overcome the ADME advantages of Ligand B. The negative Caco-2 and solubility values are concerning for both, and would need to be addressed through further optimization. However, given the choice between these two, Ligand B is the better starting point.

Output:
1
2025-04-17 06:54:18,422 - INFO - Reasoning:

Let's analyze Ligand A and Ligand B based on the provided guidelines, prioritizing GPCR-specific properties (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (365.37 and 353.42 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (128.5) is better than Ligand B (138.63). For CNS targets, we want TPSA <= 90, so both are above this optimal value, but A is closer.

**logP:** Ligand A (1.662) is better than Ligand B (0.582). Both are within the 1-3 range, but B is quite low, potentially hindering permeation.

**H-Bond Donors/Acceptors:** Ligand A (1 HBD, 8 HBA) is preferable to Ligand B (3 HBD, 5 HBA). Both are within acceptable limits, but A's lower HBD count is slightly better.

**QED:** Ligand A (0.446) is better than Ligand B (0.254). Both are below the desired 0.5, indicating suboptimal drug-likeness, but A is closer.

**DILI:** Ligand B (20.9) is significantly better than Ligand A (96.55). This is a major advantage for Ligand B.

**BBB:** Ligand A (66.58) is *much* better than Ligand B (10.51). For a CNS target like DRD2, BBB penetration is crucial, and A is far superior.

**Caco-2 Permeability:** Ligand A (-4.933) is better than Ligand B (-5.211), but both are negative, which is unusual and requires further investigation. Higher values are preferred.

**Aqueous Solubility:** Ligand A (-4.578) is better than Ligand B (-1.162), but both are negative, indicating poor solubility.

**hERG Inhibition:** Ligand A (0.276) is much better than Ligand B (0.084). Lower hERG inhibition is crucial for avoiding cardiotoxicity.

**Microsomal Clearance:** Ligand A (75.64) is worse than Ligand B (26.19). Lower clearance is preferred for better metabolic stability, giving an advantage to B.

**In vitro Half-Life:** Ligand A (38.19) is better than Ligand B (-9.97). A longer half-life is generally desirable.

**P-gp Efflux:** Ligand A (0.224) is better than Ligand B (0.022). Lower P-gp efflux is preferred, especially for CNS targets, giving an advantage to A.

**Binding Affinity:** Ligand A (-8.7 kcal/mol) is significantly better than Ligand B (-6.9 kcal/mol). This is a substantial difference in potency, and a >1.5 kcal/mol advantage can often outweigh other drawbacks.

**Overall Assessment:**

Ligand A has a significantly better binding affinity and BBB penetration, which are critical for a CNS GPCR target. It also has better TPSA, logP, QED, hERG inhibition, and P-gp efflux. However, Ligand B has a much lower DILI risk and better metabolic stability (lower Cl_mic). The superior affinity and BBB of Ligand A are likely to be more important for *in vivo* efficacy at the DRD2 receptor, outweighing the DILI and metabolic stability concerns, especially during lead optimization.

Output:
1
2025-04-17 06:54:18,422 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (340.423 Da) is slightly better positioned than Ligand B (365.43 Da).

**TPSA:** Ligand A (59.59) is excellent, well below the 90 A^2 threshold for CNS targets. Ligand B (73.74) is still reasonable but less optimal.

**logP:** Ligand A (3.773) is within the optimal range (1-3). Ligand B (0.622) is quite low, potentially hindering membrane permeability and CNS penetration.

**H-Bond Donors/Acceptors:** Ligand A (HBD=2, HBA=3) and Ligand B (HBD=1, HBA=5) both fall within acceptable limits.

**QED:** Ligand A (0.891) has a significantly higher QED score than Ligand B (0.591), indicating better overall drug-likeness.

**DILI:** Both ligands have acceptable DILI risk (Ligand A: 70.531, Ligand B: 61.031), though Ligand A is slightly higher.

**BBB:** Ligand A (85.072) has a very good BBB percentile, exceeding the desirable >70% threshold for CNS targets. Ligand B (54.595) is considerably lower, raising concerns about CNS exposure.

**Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and suggests potential issues with the data or modeling. However, we can still compare their relative values; Ligand A (-4.596) is slightly better than Ligand B (-4.615).

**Aqueous Solubility:** Both ligands have negative solubility values, which is also unusual. Ligand B (-1.847) is slightly better than Ligand A (-4.948).

**hERG Inhibition:** Ligand A (0.808) has a lower hERG inhibition risk than Ligand B (0.415).

**Microsomal Clearance:** Ligand A (83.85) has higher clearance than Ligand B (6.013), suggesting lower metabolic stability.

**In vitro Half-Life:** Ligand A (20.594) has a longer half-life than Ligand B (-15.706).

**P-gp Efflux:** Ligand A (0.504) shows lower P-gp efflux liability than Ligand B (0.082), which is favorable for CNS penetration.

**Binding Affinity:** Ligand B (-7.1 kcal/mol) has a significantly stronger binding affinity than Ligand A (-9.9 kcal/mol). This is a substantial advantage.

**Overall Assessment:**

While Ligand B boasts a superior binding affinity, its low logP and lower BBB penetration are significant drawbacks for a CNS-targeting drug. Ligand A, despite a weaker affinity, exhibits a much more favorable ADME profile, particularly regarding BBB penetration, logP, and P-gp efflux. The difference in binding affinity (1.5 kcal/mol) is substantial, but the ADME properties of Ligand A are much more aligned with the requirements for a successful CNS drug. Given the GPCR-specific priorities, especially BBB, and the importance of getting the drug to the target, Ligand A is the more promising candidate.

Output:
0
2025-04-17 06:54:18,422 - INFO - Batch 320 complete. Total preferences: 5120
2025-04-17 06:54:18,422 - INFO - Processing batch 321/512...
2025-04-17 06:54:59,617 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (382.5 and 355.5 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (87.66) is better than Ligand B (98.68). Both are below the 140 threshold for oral absorption, and Ligand A is closer to the preferred <90 for CNS targets.

**3. logP:** Both ligands have good logP values (1.98 and 1.49), falling within the optimal 1-3 range.

**4. H-Bond Donors:** Both have 3 HBD, which is acceptable.

**5. H-Bond Acceptors:** Ligand A has 6 HBA, and Ligand B has 5. Both are within the acceptable limit of 10.

**6. QED:** Both have reasonable QED scores (0.651 and 0.59), indicating good drug-like properties.

**7. DILI:** Ligand A (55.5) has a higher DILI risk than Ligand B (16.5), which is a significant drawback.

**8. BBB:** Ligand A (36.1) and Ligand B (32.8) both have low BBB penetration. This is concerning for a CNS target like DRD2, but we need to consider other factors.

**9. Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and suggests poor permeability.

**10. Aqueous Solubility:** Both have negative solubility values, which is also unusual and suggests poor solubility.

**11. hERG Inhibition:** Both ligands have low hERG inhibition risk (0.428 and 0.597).

**12. Microsomal Clearance:** Ligand A (57.2) has higher clearance than Ligand B (20.6), indicating lower metabolic stability.

**13. In vitro Half-Life:** Ligand B (-19.6) has a negative half-life, which is nonsensical. Ligand A (42.2) is reasonable.

**14. P-gp Efflux:** Both have low P-gp efflux liability (0.51 and 0.40).

**15. Binding Affinity:** Ligand A (-7.9 kcal/mol) has a significantly stronger binding affinity than Ligand B (-6.6 kcal/mol). This is a 1.3 kcal/mol difference, which is substantial and can outweigh some ADME drawbacks.

**Overall Assessment:**

Despite the poor Caco-2 and solubility values for both, Ligand A is the better candidate. The significantly stronger binding affinity (-7.9 vs -6.6 kcal/mol) is a major advantage for a GPCR target. While Ligand A has a higher DILI risk and lower BBB penetration than Ligand B, the strong binding is likely to be more impactful in driving efficacy. The negative half-life for Ligand B is a showstopper. The DILI risk for Ligand A could potentially be mitigated through structural modifications.

Output:
1
2025-04-17 06:54:59,617 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (384.307 and 373.425 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (74.25) is excellent, well below the 90 A^2 threshold for CNS targets. Ligand B (82.53) is still reasonable, but less optimal.

**logP:** Ligand A (3.519) is at the upper end of the optimal range (1-3), while Ligand B (1.353) is at the lower end. While both are within range, higher logP can sometimes be beneficial for GPCRs to facilitate membrane interactions.

**H-Bond Donors/Acceptors:** Both ligands have 3 HBDs, which is acceptable. Ligand A has 3 HBAs, and Ligand B has 5 HBAs. Both are within the acceptable limit of 10.

**QED:** Both ligands have similar QED values (0.696 and 0.63), indicating good drug-like properties.

**DILI:** Ligand A (29.042) has a significantly lower DILI risk than Ligand B (52.152), which is a substantial advantage.

**BBB:** Ligand A (64.637) has a better BBB percentile than Ligand B (55.06), although both are below the desirable >70% for CNS targets.

**Caco-2 Permeability:** Ligand A (-4.72) shows poor Caco-2 permeability, while Ligand B (-5.028) is also poor. This is a concern for oral bioavailability.

**Aqueous Solubility:** Ligand A (-4.51) has poor aqueous solubility, while Ligand B (-1.738) is slightly better.

**hERG:** Both ligands have low hERG inhibition liability (0.373 and 0.215), which is good.

**Microsomal Clearance:** Ligand B (-13.317) has a significantly lower (better) microsomal clearance than Ligand A (18.335), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand B (18.609) has a longer in vitro half-life than Ligand A (34.14), which is favorable.

**P-gp Efflux:** Ligand A (0.166) has lower P-gp efflux liability than Ligand B (0.058), which is beneficial for CNS exposure.

**Binding Affinity:** Ligand A (-8.6 kcal/mol) has a significantly stronger binding affinity than Ligand B (-7.6 kcal/mol). This >1.5 kcal/mol difference is a major advantage, potentially outweighing some of the ADME drawbacks.

**Overall Assessment:**

Ligand A has a significantly better binding affinity and lower DILI risk, and better P-gp efflux. However, it has poor Caco-2 permeability and aqueous solubility, and higher microsomal clearance. Ligand B has better metabolic stability and half-life, but weaker binding affinity and higher DILI risk. Considering the GPCR-specific priorities, the strong binding affinity of Ligand A is a critical factor. While the ADME properties of Ligand A are not ideal, they could potentially be improved through further optimization. The substantial affinity difference makes Ligand A the more promising candidate.

Output:
1
2025-04-17 06:54:59,617 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (350.447 and 372.925 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (58.12) is better than Ligand B (55.35). Both are below the 90 A^2 threshold for CNS targets, which is excellent.

**3. logP:** Ligand A (3.84) is within the optimal 1-3 range, while Ligand B (4.809) is slightly higher. While still acceptable, the higher logP of B could potentially lead to off-target effects or solubility issues.

**4. H-Bond Donors:** Ligand A (1) is preferable to Ligand B (2) as lower HBD generally improves permeability.

**5. H-Bond Acceptors:** Ligand A (5) is preferable to Ligand B (4).

**6. QED:** Ligand A (0.78) is significantly better than Ligand B (0.481), indicating a more drug-like profile.

**7. DILI:** Ligand A (90.733) has a higher DILI risk than Ligand B (67.429). This is a concern for Ligand A.

**8. BBB:** Ligand A (73.827) has a much better BBB penetration percentile than Ligand B (55.874). This is *critical* for a CNS target like DRD2.

**9. Caco-2 Permeability:** Ligand A (-4.895) is better than Ligand B (-4.993). Both are negative, which is not ideal, but A is slightly better.

**10. Aqueous Solubility:** Ligand A (-4.901) is slightly better than Ligand B (-4.45). Both are poor, but A is slightly less poor.

**11. hERG Inhibition:** Ligand A (0.758) is better than Ligand B (0.884), indicating lower cardiotoxicity risk.

**12. Microsomal Clearance:** Ligand A (93.79) has a higher clearance than Ligand B (41.581), meaning it's less metabolically stable. This is a significant drawback for Ligand A.

**13. In vitro Half-Life:** Ligand A (75.587) has a good half-life, but Ligand B (127.948) is significantly better.

**14. P-gp Efflux:** Ligand A (0.9) is slightly better than Ligand B (0.92), indicating less efflux.

**15. Binding Affinity:** Ligand A (-10.9 kcal/mol) has a *much* stronger binding affinity than Ligand B (-8.5 kcal/mol). This is a substantial advantage, potentially outweighing some of the ADME drawbacks.

**Overall Assessment:**

Ligand A has a significantly better binding affinity and BBB penetration, which are paramount for a CNS GPCR target. It also has better TPSA, logP, H-bond characteristics, and slightly better permeability and solubility. However, it suffers from higher DILI risk and significantly higher microsomal clearance (lower metabolic stability). Ligand B has a better safety profile (lower DILI) and metabolic stability, but its lower affinity and BBB penetration are major drawbacks.

The strong binding affinity and good BBB of Ligand A are compelling. While the DILI and clearance are concerns, these could potentially be addressed through further optimization. The lower affinity of Ligand B makes it less likely to be a viable starting point, even with a better safety profile.

Output:
1
2025-04-17 06:54:59,617 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (346.362 and 352.356 Da) fall comfortably within the ideal 200-500 Da range.

**TPSA:** Ligand A (80.41) is better than Ligand B (49.41) regarding TPSA. Both are below the 90 A^2 threshold for CNS targets, but A is slightly higher and could potentially impact BBB penetration.

**logP:** Both ligands have excellent logP values (2.941 and 2.653) within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Both have 1 HBD, which is good. Ligand A has 5 HBA, while Ligand B has 2. Both are within the acceptable limits (<=10).

**QED:** Ligand B (0.909) has a significantly higher QED score than Ligand A (0.667), indicating a more drug-like profile.

**DILI:** Ligand B (45.328) has a much lower DILI risk than Ligand A (69.95), making it safer from a liver toxicity perspective.

**BBB:** Ligand B (93.098) has a substantially higher BBB penetration percentile than Ligand A (77.2). This is a critical advantage for a CNS target like DRD2.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values, which is unusual and could indicate issues with the calculation or data quality. However, we can compare the absolute values. Ligand A (-4.71) is slightly worse than Ligand B (-4.618).

**Aqueous Solubility:** Both have negative solubility values, which is also unusual. Ligand A (-4.209) is slightly worse than Ligand B (-3.7).

**hERG:** Both ligands have low hERG inhibition liability (0.774 and 0.511), which is good.

**Microsomal Clearance:** Ligand B (6.498) has significantly lower microsomal clearance than Ligand A (68.288), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand B (-8.689) has a longer in vitro half-life than Ligand A (49.141), which is desirable.

**P-gp Efflux:** Ligand B (0.102) has much lower P-gp efflux liability than Ligand A (0.37), which is beneficial for CNS exposure.

**Binding Affinity:** Ligand B (-10.3 kcal/mol) has a significantly stronger binding affinity than Ligand A (-8.3 kcal/mol). This is a substantial advantage, potentially outweighing minor ADME drawbacks.

**Overall Assessment:**

Ligand B is clearly superior. It has a better QED score, significantly lower DILI risk, much higher BBB penetration, lower microsomal clearance, longer half-life, lower P-gp efflux, and, most importantly, a substantially stronger binding affinity. While both have unusual solubility and Caco-2 values, the overall profile of Ligand B is far more promising for development as a DRD2-targeting drug.

Output:
1
2025-04-17 06:54:59,618 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B based on the provided guidelines, prioritizing GPCR-specific properties (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (349.431) is slightly lower, which could be beneficial for permeability, but both are acceptable.

**TPSA:** Ligand A (89.43) is excellent for CNS penetration, being well below 90. Ligand B (56.75) is also very good.

**logP:** Ligand A (0.827) is a bit low, potentially hindering permeation. Ligand B (1.618) is better, falling within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A has 2 HBD and 5 HBA, which is good. Ligand B has 0 HBD and 6 HBA, also acceptable.

**QED:** Both ligands have reasonable QED scores (A: 0.763, B: 0.654), indicating good drug-like properties.

**DILI:** Ligand A (25.165) has a significantly lower DILI risk than Ligand B (52.85). This is a substantial advantage.

**BBB:** Ligand B (78.519) has a better BBB percentile than Ligand A (67.158), which is important for CNS targets. However, A is still reasonably good.

**Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and suggests poor permeability. This is a concern for both.

**Aqueous Solubility:** Both ligands have negative solubility values, indicating poor solubility. This is a significant drawback for both.

**hERG:** Ligand A (0.118) has a much lower hERG risk than Ligand B (0.57). This is a crucial safety advantage.

**Microsomal Clearance:** Ligand B (56.625) has higher microsomal clearance than Ligand A (29.46), indicating lower metabolic stability.

**In vitro Half-Life:** Ligand B (10.462) has a longer half-life than Ligand A (-2.105), which is a positive. However, A's negative value is concerning.

**P-gp Efflux:** Ligand A (0.014) has significantly lower P-gp efflux liability than Ligand B (0.108), which is beneficial for CNS exposure.

**Binding Affinity:** Ligand B (-7.6) has a slightly better binding affinity than Ligand A (-8.5). While A is stronger, the difference is not substantial enough to outweigh other factors.

**Overall Assessment:**

Ligand A excels in safety (DILI, hERG, P-gp) and has a better metabolic profile (lower Cl_mic). Ligand B has a slightly better BBB and half-life, and marginally better affinity. However, the significant advantages of Ligand A in safety and metabolic stability, combined with its acceptable TPSA and reasonable affinity, make it the more promising candidate. The poor solubility and Caco-2 values are concerns for both, but can be addressed with formulation strategies. The lower DILI and hERG risks for Ligand A are particularly important for a CNS-targeting drug.

Output:
0
2025-04-17 06:54:59,618 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (380.539 Da) is slightly higher than Ligand B (348.491 Da), but both are acceptable.

**TPSA:** Ligand A (65.54) is significantly better than Ligand B (86.88). For CNS targets, we want TPSA <= 90, and ideally closer to 60. Ligand A is much closer to the ideal range.

**logP:** Ligand A (0.968) is a bit low, potentially hindering permeability. Ligand B (2.949) is within the optimal 1-3 range. This favors Ligand B.

**H-Bond Donors/Acceptors:** Ligand A (HBD=1, HBA=6) is better than Ligand B (HBD=3, HBA=3). Fewer H-bonds generally improve permeability.

**QED:** Ligand B (0.641) has a slightly better QED score than Ligand A (0.453), indicating a more drug-like profile.

**DILI:** Both ligands have similar DILI risk (around 40%), which is acceptable.

**BBB:** Ligand B (74.758) has a significantly higher BBB penetration percentile than Ligand A (53.781). This is a crucial factor for a CNS target like DRD2, strongly favoring Ligand B.

**Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and suggests poor permeability. However, the scale isn't specified, so it's hard to interpret.

**Aqueous Solubility:** Both have negative solubility values, also unusual. Again, the scale is unknown.

**hERG:** Both have low hERG inhibition liability, which is good.

**Microsomal Clearance:** Ligand A (30.728) has lower microsomal clearance than Ligand B (61.928), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (-16.058) has a negative half-life, which is not possible. This is a significant red flag. Ligand B (-4.134) is also negative, but less so.

**P-gp Efflux:** Both have very low P-gp efflux liability (0.052 and 0.254 respectively), which is favorable for CNS penetration.

**Binding Affinity:** Ligand B (-7.9 kcal/mol) has a significantly stronger binding affinity than Ligand A (0.0 kcal/mol). This is a major advantage, potentially outweighing some ADME drawbacks.

**Overall Assessment:**

Ligand B is clearly superior. While Ligand A has better TPSA and metabolic stability, Ligand B's significantly higher BBB penetration, much stronger binding affinity, and better QED score are decisive. The negative half-life for Ligand A is a critical flaw. The slightly higher logP of Ligand B is acceptable given the strong affinity and BBB penetration.



Output:
1
2025-04-17 06:54:59,618 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (354.47 and 354.403 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (64.68) is significantly better than Ligand B (102.01). For CNS targets, we want TPSA <= 90, and A is comfortably within that, while B exceeds it. This is a substantial advantage for A.

**logP:** Both ligands have acceptable logP values (0.551 and 0.411), falling within the 1-3 range, though on the lower end.

**H-Bond Donors/Acceptors:** Ligand A has 2 HBD and 4 HBA, while Ligand B has 1 HBD and 6 HBA. Both are within acceptable limits (<=5 HBD and <=10 HBA).

**QED:** Both ligands have similar QED values (0.625 and 0.5), indicating good drug-likeness.

**DILI:** Ligand A (11.206) has a much lower DILI risk than Ligand B (40.403). This is a significant advantage for A.

**BBB:** Ligand A (77.2) has a substantially better BBB penetration percentile than Ligand B (54.246).  For a CNS target like DRD2, >70 is desirable, and A is closer to that threshold.

**Caco-2 Permeability:** Ligand A (-5.228) has worse Caco-2 permeability than Ligand B (-4.83). However, Caco-2 is less critical than BBB for CNS targets.

**Aqueous Solubility:** Ligand A (-0.803) has slightly better solubility than Ligand B (-1.586).

**hERG Inhibition:** Ligand A (0.413) has a lower hERG inhibition risk than Ligand B (0.089).

**Microsomal Clearance:** Ligand A (-3.152) has significantly lower microsomal clearance (better metabolic stability) than Ligand B (30.209).

**In vitro Half-Life:** Ligand A (1.343) has a shorter half-life than Ligand B (-15.825). This is a drawback for A, but potentially manageable.

**P-gp Efflux:** Ligand A (0.006) has much lower P-gp efflux liability than Ligand B (0.031). Lower efflux is crucial for CNS exposure.

**Binding Affinity:** Ligand A (-8.1 kcal/mol) has a slightly better binding affinity than Ligand B (-7.1 kcal/mol). While both are good, the 1 kcal/mol difference is meaningful.

**Overall Assessment:**

Ligand A is significantly better overall. It excels in key GPCR/CNS-relevant properties: TPSA, BBB, DILI, P-gp efflux, and metabolic stability. Its binding affinity is also slightly better. While its Caco-2 permeability and in vitro half-life are less favorable than Ligand B, the substantial advantages in CNS penetration and safety profiles outweigh these drawbacks. Ligand B's higher TPSA and DILI risk are major concerns.

Output:
1
2025-04-17 06:54:59,618 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B based on the provided guidelines, prioritizing GPCR-specific properties (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (343.471 and 350.478 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (64.41) is better than Ligand B (49.41). Both are below the 90 A^2 threshold for CNS targets, which is excellent.

**logP:** Both ligands have good logP values (2.732 and 3.204), falling within the optimal 1-3 range. Ligand B is slightly higher, which *could* be a minor negative if it impacts solubility.

**H-Bond Donors/Acceptors:** Ligand A has 0 HBD and 3 HBA, while Ligand B has 1 HBD and 2 HBA. Both are within acceptable limits (<=5 HBD and <=10 HBA).

**QED:** Both ligands have similar and good QED scores (0.737 and 0.766), indicating good drug-like properties.

**DILI:** Ligand A (17.41) has a significantly lower DILI risk than Ligand B (19.426). Both are below 40, which is good.

**BBB:** Ligand B (91.508) has a substantially better BBB penetration score than Ligand A (81.543). This is a critical advantage for a CNS target like DRD2.

**Caco-2 Permeability:** Both have negative Caco-2 values (-4.542 and -4.752), which is unusual and suggests poor permeability. This is a significant concern for both.

**Aqueous Solubility:** Both ligands have poor aqueous solubility (-3.527 and -3.847). This could pose formulation challenges.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.406 and 0.802).

**Microsomal Clearance:** Ligand B (43.32) has lower microsomal clearance than Ligand A (49.441), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand B (-8.842) has a longer in vitro half-life than Ligand A (-4.651), which is desirable.

**P-gp Efflux:** Ligand A (0.09) has lower P-gp efflux than Ligand B (0.354), which is beneficial for CNS exposure.

**Binding Affinity:** Ligand B (-8.4) has a slightly better binding affinity than Ligand A (-7.4), a difference of 1 kcal/mol. This is a meaningful difference.

**Overall Assessment:**

While Ligand A has better TPSA, DILI, and P-gp efflux, Ligand B excels in the most crucial areas for a CNS GPCR target: BBB penetration and binding affinity. The difference in BBB (91.5 vs 81.5) is substantial, and the slightly improved affinity (-8.4 vs -7.4) further strengthens Ligand B's profile. The better metabolic stability and half-life of Ligand B are also positive attributes. The poor Caco-2 and solubility are concerns for both, but can potentially be addressed with formulation strategies.

Output:
1
2025-04-17 06:54:59,619 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (428.766 Da) is higher, but still acceptable. Ligand B (351.451 Da) is slightly better.

**TPSA:** Ligand A (76.1) is excellent, falling well below the 90 A^2 threshold for CNS targets. Ligand B (99.49) is still reasonable, but less optimal.

**logP:** Ligand A (1.256) is within the optimal range (1-3). Ligand B (-0.264) is below 1, which could hinder permeation. This is a significant disadvantage for Ligand B.

**H-Bond Donors/Acceptors:** Ligand A (HBD=1, HBA=7) is good. Ligand B (HBD=3, HBA=6) is also acceptable, but slightly higher HBD count could be a minor concern.

**QED:** Both ligands have similar QED values (A: 0.669, B: 0.628), indicating good drug-like properties.

**DILI:** Ligand A (33.773) has a much lower DILI risk than Ligand B (13.92). This is a substantial advantage for Ligand A.

**BBB:** Ligand A (47.848) has a better BBB percentile than Ligand B (31.601), though both are not ideal (>70 is preferred). However, given the other factors, this difference is less critical.

**Caco-2 Permeability:** Both have negative values (-5.648 and -5.402), which is unusual and suggests poor permeability. This is a concern for both, but the scale isn't clearly defined, so the impact is hard to assess.

**Aqueous Solubility:** Both have negative values (-1.693 and -1.188), also unusual and suggesting poor solubility. Similar to Caco-2, the scale is unclear.

**hERG:** Ligand A (0.586) has a lower hERG risk than Ligand B (0.218), which is preferable.

**Microsomal Clearance:** Ligand A (-9.508) has significantly lower (better) microsomal clearance than Ligand B (-20.396), indicating greater metabolic stability.

**In vitro Half-Life:** Ligand A (-2.688) has a slightly better in vitro half-life than Ligand B (8.749).

**P-gp Efflux:** Ligand A (0.016) has a much lower P-gp efflux liability than Ligand B (0.008), which is crucial for CNS penetration.

**Binding Affinity:** Ligand A (-8.3 kcal/mol) has a slightly better binding affinity than Ligand B (-7.8 kcal/mol). While the difference is not huge, it's enough to be considered.

**Overall Assessment:**

Ligand A is clearly superior. It has better logP, significantly lower DILI and P-gp efflux, better metabolic stability (lower Cl_mic), slightly better affinity, and a better BBB percentile. While both have issues with Caco-2 and solubility, Ligand A's overall profile is much more favorable for development as a CNS-targeting drug. Ligand B's low logP is a major drawback.

Output:
1
2025-04-17 06:54:59,619 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (346.395 and 355.391 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (118.79) is slightly above the optimal <90 for CNS targets, but still reasonable. Ligand B (92.12) is well within the desired range.

**logP:** Ligand A (-0.171) is a bit low, potentially hindering permeation. Ligand B (0.238) is better, falling within the 1-3 range, but still on the lower side.

**H-Bond Donors/Acceptors:** Ligand A has 1 HBD and 8 HBA, which are acceptable. Ligand B has 0 HBD and 9 HBA, also acceptable.

**QED:** Both ligands have good QED scores (0.704 and 0.642), indicating drug-like properties.

**DILI:** Both ligands have relatively high DILI risk (68.631 and 61.109), but below the concerning >60 threshold.

**BBB:** Ligand B (70.027) is significantly better than Ligand A (51.066) in terms of BBB penetration, which is crucial for a CNS target like DRD2.

**Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and suggests poor permeability. However, these values are on a different scale and difficult to compare directly.

**Aqueous Solubility:** Both ligands have poor aqueous solubility (-1.188 and -1.338). This could pose formulation challenges.

**hERG Inhibition:** Ligand A (0.035) shows very low hERG inhibition risk, which is excellent. Ligand B (0.218) has slightly higher risk, but still relatively low.

**Microsomal Clearance:** Ligand A (29.957) has lower microsomal clearance than Ligand B (70.083), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (10.663) has a shorter half-life than Ligand B (-39.303). The negative value for Ligand B is concerning and likely an error or indicates very rapid degradation.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.018 and 0.067), which is favorable for CNS penetration.

**Binding Affinity:** Ligand A (-7.8 kcal/mol) has a significantly stronger binding affinity than Ligand B (-6.9 kcal/mol). This is a substantial advantage (over 1 kcal/mol difference).

**Overall Assessment:**

While Ligand A has a better binding affinity and metabolic stability, Ligand B excels in BBB penetration, a critical factor for CNS drug development. The negative half-life for Ligand B is a major red flag, suggesting rapid metabolism or an issue with the assay. Ligand A's logP is a concern, but the strong binding affinity might compensate. Considering the importance of BBB penetration for DRD2 and the problematic half-life of Ligand B, Ligand A appears to be the more promising candidate, despite its slightly lower logP.

Output:
0
2025-04-17 06:54:59,619 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (347.459 Da) is slightly lower, which could be beneficial for permeability. Ligand B (376.806 Da) is also good.

**TPSA:** Ligand A (72.88) is better than Ligand B (50.27) as it is closer to the ideal range for CNS targets (<=90).

**logP:** Ligand A (1.228) is within the optimal range (1-3). Ligand B (3.839) is at the higher end of the optimal range, potentially increasing off-target effects and decreasing solubility, but not drastically.

**H-Bond Donors/Acceptors:** Ligand A has 2 HBD and 4 HBA, which are reasonable. Ligand B has 0 HBD and 3 HBA, also acceptable.

**QED:** Both ligands have similar QED values (0.84 and 0.709), indicating good drug-likeness.

**DILI:** Ligand A (17.914) has a significantly lower DILI risk than Ligand B (37.456), which is a major advantage.

**BBB:** Ligand B (95.502) has a much higher BBB penetration percentile than Ligand A (69.523). This is a critical factor for a CNS target like DRD2.

**Caco-2 Permeability:** Ligand A (-4.815) and Ligand B (-4.317) both have negative Caco-2 values, which is unusual and suggests poor permeability. However, these values are on a scale where negative values are possible, and the difference isn't huge.

**Aqueous Solubility:** Ligand A (-1.401) has slightly better solubility than Ligand B (-3.78), although both are poor.

**hERG Inhibition:** Ligand A (0.622) has a slightly higher hERG risk than Ligand B (0.263), which is preferable.

**Microsomal Clearance:** Ligand B (51.453) has a much higher microsomal clearance than Ligand A (0.777), suggesting lower metabolic stability.

**In vitro Half-Life:** Ligand A (10.118) has a significantly longer in vitro half-life than Ligand B (-4.939), which is a substantial advantage.

**P-gp Efflux:** Ligand A (0.086) has a lower P-gp efflux liability than Ligand B (0.222), which is beneficial for CNS exposure.

**Binding Affinity:** Ligand B (-7.9) has a slightly better binding affinity than Ligand A (-8.3), but the difference is small (0.4 kcal/mol). Given the other factors, this difference is unlikely to be decisive.

**Overall Assessment:**

Ligand A excels in DILI risk, metabolic stability (low Cl_mic, long t1/2), P-gp efflux, and TPSA. Ligand B's main advantage is its superior BBB penetration. However, the significantly higher DILI risk and poorer metabolic stability of Ligand B are major concerns. While BBB is critical, a high DILI risk can derail a drug candidate. The slightly better affinity of Ligand B doesn't outweigh the other drawbacks.

Output:
0
2025-04-17 06:54:59,619 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (331.419 Da) is slightly lower, which could be beneficial for permeability. Ligand B (356.413 Da) is also good.

**TPSA:** Ligand A (38.13) is excellent, well below the 90 A^2 threshold for CNS targets. Ligand B (60.85) is still reasonable, but less optimal.

**logP:** Ligand A (3.892) is at the higher end of the optimal range (1-3), but still acceptable. Ligand B (1.952) is towards the lower end, potentially hindering permeability.

**H-Bond Donors/Acceptors:** Both ligands have a reasonable number of HBDs (0/1) and HBAs (3/3), falling within the recommended limits.

**QED:** Both ligands have good QED scores (0.73 and 0.766), indicating good drug-like properties.

**DILI:** Ligand A (64.211) shows a moderate risk of DILI. Ligand B (16.208) has a much lower, and preferable, DILI risk.

**BBB:** Both ligands exhibit excellent BBB penetration (Ligand A: 88.329, Ligand B: 89.608), exceeding the desirable >70% threshold for CNS targets.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.82 and -4.636), which is unusual and suggests poor permeability. This is a significant concern.

**Aqueous Solubility:** Both ligands have negative solubility values (-4.089 and -1.977), indicating very poor aqueous solubility. This is a major drawback.

**hERG Inhibition:** Both ligands show low hERG inhibition risk (0.835 and 0.537).

**Microsomal Clearance:** Ligand A (54.211) has higher microsomal clearance than Ligand B (1.543), suggesting lower metabolic stability. Ligand B is significantly better in this regard.

**In vitro Half-Life:** Ligand B (-15.77) has a longer in vitro half-life than Ligand A (-19.374), which is desirable.

**P-gp Efflux:** Both ligands show low P-gp efflux liability (0.711 and 0.095), which is good for CNS exposure. Ligand B is better.

**Binding Affinity:** Ligand A (-8.6 kcal/mol) has a slightly better binding affinity than Ligand B (-7.9 kcal/mol). This is a significant advantage.

**Overall Assessment:**

While Ligand A has a slightly better binding affinity, Ligand B is superior in several critical ADME properties. Specifically, Ligand B has a much lower DILI risk, significantly better metabolic stability (lower Cl_mic, longer t1/2), and lower P-gp efflux. The negative Caco-2 and solubility values are concerning for both, but the other advantages of Ligand B outweigh the slightly weaker binding. The GPCR-specific priorities heavily favor Ligand B due to its improved BBB penetration, lower Pgp efflux, and better metabolic stability.

Output:
1
2025-04-17 06:54:59,619 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B based on the provided guidelines, prioritizing GPCR-specific properties (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (364.368 Da) is slightly lower, which could be beneficial for permeability.

**TPSA:** Ligand A (98.32) is better than Ligand B (104.53), both are below 140, but Ligand A is closer to the preferred <90 for CNS targets.

**logP:** Ligand A (1.39) is optimal, while Ligand B (0.053) is quite low, potentially hindering membrane permeability.

**H-Bond Donors/Acceptors:** Ligand A (HBD=3, HBA=4) and Ligand B (HBD=2, HBA=6) both fall within acceptable ranges.

**QED:** Both ligands have good QED scores (A: 0.577, B: 0.66), indicating drug-likeness.

**DILI:** Ligand A (35.479) has a significantly lower DILI risk than Ligand B (44.087), both are acceptable but A is preferred.

**BBB:** Ligand A (67.041) has a much better BBB penetration percentile than Ligand B (42.924). This is *critical* for a CNS target like DRD2.

**Caco-2 Permeability:** Ligand A (-5.198) is better than Ligand B (-5.719).

**Aqueous Solubility:** Ligand A (-1.609) is better than Ligand B (-1.028).

**hERG Inhibition:** Ligand A (0.645) is better than Ligand B (0.375).

**Microsomal Clearance:** Ligand A (11.801) has lower clearance than Ligand B (28.48), indicating better metabolic stability.

**In vitro Half-Life:** Ligand A (-29.935) has a much longer half-life than Ligand B (-8.745).

**P-gp Efflux:** Ligand A (0.15) has lower P-gp efflux liability than Ligand B (0.053), which is favorable for CNS penetration.

**Binding Affinity:** Ligand B (-8.1 kcal/mol) has a slightly better binding affinity than Ligand A (-7.7 kcal/mol). However, the difference is less than 1.5 kcal/mol, and can be overcome by better ADME properties.

**Overall Assessment:**

Ligand A is significantly better overall, especially considering the target is a CNS GPCR. Its superior BBB penetration, lower DILI risk, better metabolic stability (lower Cl_mic, longer t1/2), and lower P-gp efflux outweigh the slightly weaker binding affinity compared to Ligand B. Ligand B's low logP is a major concern, potentially limiting its ability to cross cell membranes and reach the brain.



Output:
0
2025-04-17 06:54:59,620 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (343.387 Da) is slightly lower, which could be advantageous for permeability.

**2. TPSA:** Ligand A (108.62) is better than Ligand B (139.96). For CNS targets, TPSA should be <= 90, so Ligand A is closer to this threshold. Ligand B is pushing the limit.

**3. logP:** Both ligands have similar logP values (A: 0.292, B: 0.389), both are quite low. While not terrible, values between 1-3 are optimal. This could limit membrane permeability.

**4. H-Bond Donors:** Both have 3 HBD, which is within the acceptable range.

**5. H-Bond Acceptors:** Ligand A has 6 HBA, while Ligand B has 8. Both are acceptable, but Ligand A is slightly better.

**6. QED:** Both ligands have similar QED values (A: 0.626, B: 0.594), indicating reasonable drug-likeness.

**7. DILI:** Ligand A (65.684) has a lower DILI risk than Ligand B (86.39). Both are above the preferred <40, but A is considerably better.

**8. BBB:** Ligand A (45.56) has a lower BBB percentile than Ligand B (50.679). Both are suboptimal for a CNS target (ideally >70). This is a significant drawback for both, but B is slightly better.

**9. Caco-2:** Both have negative Caco-2 values, which is unusual and suggests poor permeability.

**10. Solubility:** Both have negative solubility values, which is also unusual and suggests poor solubility.

**11. hERG:** Both ligands have low hERG inhibition liability (A: 0.236, B: 0.362), which is good.

**12. Cl_mic:** Ligand A (11.337) has a slightly lower microsomal clearance than Ligand B (8.095), indicating better metabolic stability.

**13. t1/2:** Ligand B (10.647) has a longer in vitro half-life than Ligand A (8.431), which is generally desirable.

**14. Pgp:** Both ligands have low P-gp efflux liability (A: 0.06, B: 0.129), which is good for CNS penetration.

**15. Binding Affinity:** Ligand A (-8.9 kcal/mol) has a slightly better binding affinity than Ligand B (-8.4 kcal/mol). While both are excellent, the 0.5 kcal/mol difference is noteworthy.

**Overall Assessment:**

Considering the GPCR-specific priorities, Ligand A is the slightly better candidate. While both have suboptimal BBB penetration and logP values, Ligand A has a better TPSA, lower DILI risk, better metabolic stability (lower Cl_mic), and a slightly stronger binding affinity. The affinity difference, although small, is enough to tip the balance given the other factors. The negative Caco-2 and Solubility values are concerning for both and would require further investigation/modification.

Output:
0
2025-04-17 06:54:59,620 - INFO - Reasoning:

Let's analyze Ligand A and Ligand B based on the provided guidelines, prioritizing GPCR-specific properties (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (344.375 Da) is slightly lower than Ligand B (371.825 Da), which is not a major concern.

**TPSA:** Ligand B (96.77) is significantly better than Ligand A (124.16). For CNS targets, we want TPSA <= 90. Ligand B is within this range, while Ligand A exceeds it. This is a significant advantage for Ligand B.

**logP:** Both ligands have low logP values (A: 0.329, B: 0.236). While optimal is 1-3, these are quite low and could hinder membrane permeability. However, given the CNS target, this isn't a dealbreaker as we can rely on other factors like Pgp and BBB.

**H-Bond Donors/Acceptors:** Ligand A has 3 HBD and 7 HBA, while Ligand B has 1 HBD and 6 HBA. Both are within acceptable limits (<=5 HBD and <=10 HBA).

**QED:** Both ligands have similar QED values (A: 0.694, B: 0.66), indicating good drug-like properties.

**DILI:** Ligand A (76.425) has a higher DILI risk than Ligand B (56.572), though both are reasonably acceptable.

**BBB:** Ligand B (81.388) has a substantially better BBB percentile than Ligand A (58.317). This is *critical* for a CNS target like DRD2.

**Caco-2 Permeability:** Ligand A (-5.63) has worse Caco-2 permeability than Ligand B (-4.801), indicating lower intestinal absorption.

**Aqueous Solubility:** Ligand A (-3.396) has worse aqueous solubility than Ligand B (-2.261).

**hERG Inhibition:** Both ligands have very low hERG inhibition risk (A: 0.227, B: 0.06).

**Microsomal Clearance:** Ligand B (10.843) has significantly lower microsomal clearance than Ligand A (27.73), indicating better metabolic stability.

**In vitro Half-Life:** Ligand B (-2.825) has a longer in vitro half-life than Ligand A (-22.372).

**P-gp Efflux:** Ligand A (0.029) has lower P-gp efflux than Ligand B (0.013), which is better for CNS penetration. However, both are very low, suggesting minimal efflux.

**Binding Affinity:** Ligand A (-8.8 kcal/mol) has a significantly stronger binding affinity than Ligand B (-6.7 kcal/mol). This is a substantial advantage for Ligand A. A difference of >1.5 kcal/mol can often outweigh other ADME concerns.

**Overall Assessment:**

While Ligand A has a superior binding affinity, Ligand B demonstrates a much more favorable ADME profile, particularly regarding CNS penetration (BBB, TPSA, Pgp) and metabolic stability (Cl_mic, t1/2). The significantly better BBB penetration and lower TPSA of Ligand B are crucial for a CNS target. The stronger affinity of Ligand A is attractive, but the ADME liabilities, especially the lower BBB and higher clearance, are concerning. The difference in affinity, while substantial, may be overcome with further optimization of Ligand B.

Output:
1
2025-04-17 06:54:59,620 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (352.381 and 348.487 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (72.2) is better than Ligand B (58.64). Both are below the 90 Angstrom threshold for CNS targets, which is excellent.

**3. logP:** Ligand A (4.359) is slightly higher than the optimal range (1-3), while Ligand B (2.824) is within the optimal range. This favors Ligand B.

**4. H-Bond Donors:** Both ligands have 1 HBD, which is within the acceptable limit of <=5.

**5. H-Bond Acceptors:** Ligand A has 4 HBAs, and Ligand B has 3. Both are below the acceptable limit of <=10.

**6. QED:** Ligand A (0.838) has a significantly better QED score than Ligand B (0.515), indicating a more drug-like profile.

**7. DILI:** Ligand A (70.686) has a higher DILI risk than Ligand B (8.918). This is a significant advantage for Ligand B.

**8. BBB:** Ligand A (89.027) has a better BBB penetration percentile than Ligand B (80.07). This is crucial for a CNS target like DRD2, favoring Ligand A.

**9. Caco-2 Permeability:** Ligand A (-4.404) shows poor Caco-2 permeability, while Ligand B (-4.533) is also poor, but slightly worse.

**10. Aqueous Solubility:** Ligand A (-5.095) has very poor aqueous solubility, while Ligand B (-2.003) is also poor, but better than Ligand A.

**11. hERG Inhibition:** Both ligands have low hERG inhibition risk (0.643 and 0.539, respectively).

**12. Microsomal Clearance:** Ligand A (57.746) has lower microsomal clearance than Ligand B (64.763), suggesting better metabolic stability.

**13. In vitro Half-Life:** Ligand A (59.281) has a longer in vitro half-life than Ligand B (-10.729), which is a significant advantage.

**14. P-gp Efflux:** Both ligands have low P-gp efflux liability (0.61 and 0.093, respectively). Ligand B is slightly better.

**15. Binding Affinity:** Ligand A (-8.9 kcal/mol) has a significantly stronger binding affinity than Ligand B (-7.6 kcal/mol). This is a substantial advantage for Ligand A, potentially outweighing some of its ADME drawbacks.

**Overall Assessment:**

Ligand A excels in binding affinity, BBB penetration, QED, and metabolic stability (lower Cl_mic, longer t1/2). However, it suffers from poor solubility, poor Caco-2 permeability, and a higher DILI risk. Ligand B has better logP, DILI, and P-gp efflux.

Considering the GPCR-specific priorities, BBB penetration and affinity are paramount for CNS targets. Ligand A's significantly stronger binding affinity (-8.9 vs -7.6 kcal/mol) and good BBB (89.027) are compelling advantages. While the solubility and DILI are concerns, these can potentially be addressed through formulation strategies or further chemical modifications. The affinity difference is large enough to potentially overcome the ADME liabilities.

Output:
1
2025-04-17 06:54:59,620 - INFO - Batch 321 complete. Total preferences: 5136
2025-04-17 06:54:59,621 - INFO - Processing batch 322/512...
2025-04-17 06:55:40,569 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (352.425 and 348.487 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (50.36) is significantly better than Ligand B (67.43). For CNS targets, we want TPSA <= 90, both are within this range, but A is preferable.

**logP:** Ligand A (4.205) is slightly higher than the optimal 1-3 range, while Ligand B (2.25) is well within the optimal range. This favors Ligand B initially, but the difference isn't massive.

**H-Bond Donors/Acceptors:** Both have 2 HBDs, which is acceptable. Ligand A has 2 HBAs, while Ligand B has 3. Both are within the acceptable limit of <=10.

**QED:** Ligand A (0.834) has a better QED score than Ligand B (0.671), indicating a more drug-like profile.

**DILI:** Ligand A (35.246) has a higher DILI risk than Ligand B (10.818). This is a significant advantage for Ligand B.

**BBB:** Both ligands have good BBB penetration (Ligand A: 77.239, Ligand B: 76.619), exceeding the desirable >70 threshold for CNS targets.

**Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and suggests poor permeability. However, the scale isn't specified, so it's difficult to interpret.

**Aqueous Solubility:** Both have negative solubility values, which is also unusual. Again, difficult to interpret without knowing the scale.

**hERG:** Both ligands show low hERG inhibition liability (Ligand A: 0.494, Ligand B: 0.423), which is good.

**Microsomal Clearance:** Both have similar microsomal clearance values (Ligand A: 37.739, Ligand B: 37.294).

**In vitro Half-Life:** Ligand A (39.455) has a longer half-life than Ligand B (16.014), which is preferable.

**P-gp Efflux:** Ligand A (0.236) has lower P-gp efflux than Ligand B (0.077), which is a significant advantage for CNS penetration.

**Binding Affinity:** Ligand A (-10.1 kcal/mol) has a *much* stronger binding affinity than Ligand B (-7.7 kcal/mol). This is a difference of 2.4 kcal/mol, which is substantial and can outweigh many ADME drawbacks.

**Overall Assessment:**

Ligand A has a significantly better binding affinity and a better QED score, longer half-life and lower P-gp efflux. Ligand B has a lower DILI risk and a more optimal logP. However, the large difference in binding affinity (-10.1 vs -7.7 kcal/mol) is the most critical factor for a GPCR target. The better BBB penetration and lower P-gp efflux of Ligand A further support its potential for CNS activity. While the DILI risk is slightly higher for Ligand A, it's still within an acceptable range.

Output:
1
2025-04-17 06:55:40,569 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (354.519 and 373.9 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (41.99) is better than Ligand B (47.36). Both are below the 90 A^2 threshold for CNS targets, which is good.

**logP:** Ligand A (4.842) is slightly higher than the optimal 1-3 range, potentially leading to solubility issues. Ligand B (3.744) is within the optimal range.

**H-Bond Donors/Acceptors:** Ligand A has 1 HBD and 3 HBA, while Ligand B has 0 HBD and 4 HBA. Both are within acceptable limits.

**QED:** Both ligands have reasonable QED scores (0.835 and 0.763), indicating good drug-like properties.

**DILI:** Ligand A (44.281) has a slightly higher DILI risk than Ligand B (22.993), but both are below the concerning threshold of 60.

**BBB:** Ligand B (95.076) has a significantly better BBB penetration score than Ligand A (72.547). This is a *critical* advantage for a CNS target like DRD2.

**Caco-2 Permeability:** Both have negative Caco-2 values which is unusual and suggests potential issues with the data or modeling. However, the values are similar.

**Aqueous Solubility:** Both ligands have very poor aqueous solubility (-5.218 and -3.562). This is a significant drawback for both.

**hERG Inhibition:** Both ligands show low hERG inhibition risk (0.517 and 0.611).

**Microsomal Clearance:** Ligand A (85.169) has higher microsomal clearance than Ligand B (43.527), indicating lower metabolic stability.

**In vitro Half-Life:** Ligand B (6.174) has a longer in vitro half-life than Ligand A (25.969).

**P-gp Efflux:** Ligand A (0.366) has lower P-gp efflux liability than Ligand B (0.179), which is favorable for CNS penetration.

**Binding Affinity:** Ligand B (-7.1 kcal/mol) has a significantly stronger binding affinity than Ligand A (-10.3 kcal/mol). This is a substantial advantage.

**Overall Assessment:**

While Ligand A has a slightly better TPSA and P-gp efflux, Ligand B excels in the most crucial areas for a CNS-targeting GPCR ligand: BBB penetration and binding affinity. The stronger binding affinity (-7.1 vs -10.3 kcal/mol) is a significant advantage that can potentially offset the slightly higher logP and lower P-gp score. The improved BBB penetration (95.076 vs 72.547) is also a major factor. The better half-life and lower clearance of Ligand B are also positive. The solubility is poor for both, but this can be addressed with formulation strategies.

Output:
1
2025-04-17 06:55:40,570 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (354.401 and 358.429 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (76.02) is slightly higher than Ligand B (58.64). Both are below the 90 A^2 threshold for CNS targets, but B is preferable.

**3. logP:** Both ligands have good logP values (2.649 and 2.344), falling within the optimal range of 1-3.

**4. H-Bond Donors:** Ligand A (2) and Ligand B (1) are both within the acceptable limit of <= 5. B is slightly better.

**5. H-Bond Acceptors:** Ligand A (4) and Ligand B (3) are both within the acceptable limit of <= 10. B is slightly better.

**6. QED:** Both ligands have good QED values (0.705 and 0.793), indicating good drug-like properties. Ligand B is slightly better.

**7. DILI:** Ligand A (52.85) has a slightly higher DILI risk than Ligand B (26.095). B is significantly better.

**8. BBB:** Ligand B (90.617) has a substantially better BBB penetration score than Ligand A (85.498). This is a *critical* factor for a CNS target like DRD2.

**9. Caco-2 Permeability:** Ligand A (-4.744) and Ligand B (-4.545) have similar, and poor, Caco-2 permeability.

**10. Aqueous Solubility:** Ligand A (-3.934) and Ligand B (-2.298) have poor aqueous solubility. B is slightly better.

**11. hERG Inhibition:** Both ligands have low hERG inhibition risk (0.241 and 0.49), which is good.

**12. Microsomal Clearance:** Ligand B (5.46) has a lower microsomal clearance than Ligand A (35.514), suggesting better metabolic stability. This is a significant advantage.

**13. In vitro Half-Life:** Ligand B (7.37) has a significantly longer in vitro half-life than Ligand A (-1.328). This is a major advantage.

**14. P-gp Efflux:** Ligand A (0.145) has lower P-gp efflux than Ligand B (0.052), which is preferable for CNS exposure.

**15. Binding Affinity:** Both ligands have excellent binding affinities (-8.4 and -8.5 kcal/mol). The difference is negligible.

**Overall Assessment:**

Ligand B is clearly superior. It has a significantly better BBB score, lower DILI risk, lower microsomal clearance (better metabolic stability), and a longer in vitro half-life. While Ligand A has slightly lower P-gp efflux, the other advantages of Ligand B outweigh this minor difference. Both have acceptable logP, MW, TPSA, QED, and excellent binding affinity.

Output:
1
2025-04-17 06:55:40,570 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (378.877 Da) is slightly higher than Ligand B (350.503 Da), but both are acceptable.

**2. TPSA:** Ligand A (52.6) is significantly better than Ligand B (69.64). For CNS targets, we want TPSA <= 90, and ideally closer to 60. Ligand A is much closer to the ideal range.

**3. logP:** Ligand A (4.772) is a bit high, potentially leading to solubility issues or off-target interactions. Ligand B (2.186) is within the optimal range (1-3).

**4. H-Bond Donors:** Both ligands are acceptable. Ligand A has 0 HBD, and Ligand B has 2.

**5. H-Bond Acceptors:** Both ligands are acceptable. Ligand A has 5 HBA, and Ligand B has 3.

**6. QED:** Both ligands have good QED values (A: 0.722, B: 0.798), indicating good drug-like properties.

**7. DILI:** Ligand B (4.692) has a much lower DILI risk than Ligand A (70.415). This is a significant advantage for Ligand B.

**8. BBB:** Both ligands have good BBB penetration (A: 77.588, B: 71.733), exceeding the >70% threshold for CNS targets.

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.826 and -4.673). This is unusual and suggests poor permeability. However, these values are on a scale where negative values are possible, and a direct comparison is difficult without knowing the scale's specifics.

**10. Aqueous Solubility:** Both ligands have negative solubility values (-4.545 and -2.752), indicating poor solubility. This is a concern, especially for Ligand A with its higher logP.

**11. hERG Inhibition:** Both ligands have low hERG inhibition risk (A: 0.225, B: 0.488).

**12. Microsomal Clearance:** Ligand B (41.268) has lower microsomal clearance than Ligand A (77.326), suggesting better metabolic stability.

**13. In vitro Half-Life:** Ligand A (39.205) has a longer in vitro half-life than Ligand B (-8.622). This is a positive for Ligand A.

**14. P-gp Efflux:** Both ligands have low P-gp efflux liability (A: 0.506, B: 0.017). Ligand B is significantly better.

**15. Binding Affinity:** Both ligands have excellent binding affinity (A: -9.7 kcal/mol, B: -9.1 kcal/mol). The difference is 0.6 kcal/mol, which is not substantial enough to outweigh other significant differences.

**Overall Assessment:**

Ligand B is the better candidate. While Ligand A has a slightly longer half-life and comparable affinity, Ligand B excels in several crucial areas: lower logP, significantly lower DILI risk, lower microsomal clearance, and lower P-gp efflux. The TPSA value for Ligand A is also much more favorable for CNS penetration. The negative Caco-2 and solubility values are concerning for both, but the other advantages of Ligand B make it the more promising candidate.

Output:
1
2025-04-17 06:55:40,570 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B based on the provided guidelines, prioritizing GPCR-specific properties (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (402.288 Da) is slightly higher than Ligand B (356.457 Da), but both are acceptable.

**TPSA:** Ligand A (55.4) is higher than Ligand B (40.62). For CNS targets, we want TPSA <= 90, so both are acceptable, but B is better.

**logP:** Both ligands have good logP values (A: 3.513, B: 3.309), falling within the optimal range of 1-3.

**H-Bond Donors/Acceptors:** Ligand A has 1 HBD and 3 HBA, while Ligand B has 0 HBD and 2 HBA. Both are within acceptable limits (<=5 HBD, <=10 HBA).

**QED:** Both ligands have similar QED values (A: 0.779, B: 0.762), indicating good drug-likeness.

**DILI:** Ligand A (61.303) has a higher DILI risk than Ligand B (23.187).  B is significantly better here, falling well below the 40% threshold.

**BBB:** Ligand B (97.208) has a significantly higher BBB penetration percentile than Ligand A (70.88). This is a *critical* advantage for a CNS target like DRD2.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.722 and -4.416). These values are unusual and suggest poor permeability, but the scale isn't clearly defined.

**Aqueous Solubility:** Both ligands have negative solubility values (-4.236 and -3.066). Again, the scale is unclear, but these suggest poor solubility.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (A: 0.492, B: 0.637).

**Microsomal Clearance:** Ligand A (99.114) has significantly higher microsomal clearance than Ligand B (30.418), indicating lower metabolic stability.

**In vitro Half-Life:** Ligand B (-17.986) has a negative half-life, which is problematic. Ligand A (58.638) has a reasonable half-life.

**P-gp Efflux:** Ligand A (0.358) has lower P-gp efflux liability than Ligand B (0.251), which is favorable for CNS penetration.

**Binding Affinity:** Ligand A (-8.6 kcal/mol) has a significantly stronger binding affinity than Ligand B (-0.0 kcal/mol). This is a substantial advantage.

**Overall Assessment:**

While Ligand A has a superior binding affinity and a reasonable half-life, Ligand B demonstrates a much better safety profile (lower DILI) and, crucially, significantly better predicted BBB penetration. The large difference in binding affinity is a concern, but the poor half-life of ligand B is a major drawback. However, for a CNS target, BBB penetration is paramount. The strong binding affinity of A could potentially overcome some ADME liabilities. Considering the importance of BBB for CNS targets, and the substantial difference in predicted penetration, I favor Ligand A despite its higher DILI and clearance.

Output:
1
2025-04-17 06:55:40,570 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (348.462 and 349.431 Da) fall comfortably within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (49.41) is excellent, well below the 90 A^2 threshold for CNS targets. Ligand B (104.46) is higher, but still potentially acceptable, though less ideal.

**3. logP:** Ligand A (3.49) is optimal. Ligand B (1.155) is a bit low, potentially hindering membrane permeability.

**4. H-Bond Donors:** Ligand A (1) is good. Ligand B (3) is acceptable, but edging towards the higher end of the preferred range.

**5. H-Bond Acceptors:** Ligand A (2) is good. Ligand B (5) is also acceptable.

**6. QED:** Both ligands have similar QED values (0.767 and 0.715), indicating good drug-like properties.

**7. DILI:** Both ligands have low DILI risk (32.61 and 34.82), which is positive.

**8. BBB:** This is a critical parameter for a CNS target like DRD2. Ligand A excels with a BBB percentile of 89.802. Ligand B is significantly lower at 38.077, which is a major drawback.

**9. Caco-2 Permeability:** Ligand A (-4.602) is poor, indicating low intestinal absorption. Ligand B (-5.383) is also poor, but slightly worse.

**10. Aqueous Solubility:** Ligand A (-3.693) is poor. Ligand B (-1.285) is also poor, but better than Ligand A.

**11. hERG Inhibition:** Ligand A (0.914) has a slightly higher hERG risk than Ligand B (0.048).

**12. Microsomal Clearance:** Ligand A (46.499) has higher clearance than Ligand B (20.225), meaning it's less metabolically stable.

**13. In vitro Half-Life:** Ligand B (-8.683) has a longer half-life than Ligand A (-6.614).

**14. P-gp Efflux:** Ligand A (0.7) has higher P-gp efflux than Ligand B (0.038), meaning less CNS exposure.

**15. Binding Affinity:** Both ligands have very similar and excellent binding affinities (-9.2 and -8.7 kcal/mol). The difference is not substantial enough to override other factors.

**Overall Assessment:**

Ligand A is superior due to its significantly better BBB penetration (89.8% vs 38.1%). While it has some drawbacks (lower Caco-2, solubility, and higher P-gp efflux and clearance), the crucial factor for a CNS-targeting drug is the ability to cross the blood-brain barrier. The similar binding affinities make the BBB difference the deciding factor.

Output:
1
2025-04-17 06:55:40,570 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (350.419 and 347.463 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (109.5) is higher than the preferred <90 for CNS targets, while Ligand B (70.47) is well within the range. This is a significant advantage for Ligand B.

**logP:** Ligand A (-0.014) is slightly low, potentially hindering permeation. Ligand B (0.791) is within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A has 3 HBD and 4 HBA, which are acceptable. Ligand B has 1 HBD and 5 HBA, also acceptable.

**QED:** Both ligands have good QED scores (0.696 and 0.792), indicating drug-like properties.

**DILI:** Ligand A (47.344) has a higher DILI risk than Ligand B (19.271), suggesting potential liver toxicity concerns.

**BBB:** Ligand B (77.898) has a significantly better BBB penetration score than Ligand A (16.363). This is crucial for a CNS target like DRD2.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.099 and -5.095), which is unusual and difficult to interpret without further context. However, it doesn't strongly sway the decision.

**Aqueous Solubility:** Both ligands have negative solubility values (-2.193 and -1.162), also unusual.

**hERG Inhibition:** Ligand A (0.166) has a slightly higher hERG inhibition liability than Ligand B (0.459).

**Microsomal Clearance:** Ligand A (-4.892) has a more negative value, indicating lower clearance and better metabolic stability than Ligand B (3.215).

**In vitro Half-Life:** Ligand A (-9.219) has a more negative value, indicating a longer half-life than Ligand B (8.535).

**P-gp Efflux:** Ligand A (0.018) has a lower P-gp efflux liability than Ligand B (0.013), which is favorable for CNS penetration.

**Binding Affinity:** Both ligands have very similar and strong binding affinities (-8.2 and -8.4 kcal/mol). The difference is negligible.

**Overall Assessment:**

Ligand B is significantly better due to its superior TPSA, logP, BBB penetration, and lower DILI risk. While Ligand A has better metabolic stability and half-life, the CNS-specific requirements for DRD2 (BBB, TPSA, logP) are more critical. The similar binding affinities make these ADME properties the deciding factors.

Output:
1
2025-04-17 06:55:40,570 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B based on the provided guidelines, prioritizing GPCR-specific properties (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (340.442 Da) is slightly better, being closer to the lower end, potentially aiding permeability.

**TPSA:** Ligand A (55.12) is significantly better than Ligand B (72.88). For CNS targets, we want TPSA <= 90, and ideally closer to 60. Ligand A is much closer to this ideal.

**logP:** Ligand A (4.513) is higher than the optimal range (1-3), but still potentially manageable. Ligand B (0.669) is quite low, which could severely hinder membrane permeability and CNS penetration.

**H-Bond Donors/Acceptors:** Both ligands have acceptable HBD (2) and HBA (2 for A, 4 for B) counts.

**QED:** Ligand A (0.805) has a significantly better QED score than Ligand B (0.686), indicating a more drug-like profile.

**DILI:** Ligand B (33.579) has a much lower DILI risk than Ligand A (55.68). This is a significant advantage for Ligand B.

**BBB:** Ligand A (80.962) has a much better BBB penetration percentile than Ligand B (53.083). This is *critical* for a CNS target like DRD2.

**Caco-2 Permeability:** Both have negative values, which is unusual. Assuming these are logP-scale values, they both indicate poor permeability.

**Aqueous Solubility:** Both have negative values, indicating poor solubility.

**hERG Inhibition:** Ligand A (0.837) has a slightly higher hERG risk than Ligand B (0.322), but both are relatively low.

**Microsomal Clearance:** Ligand B (-7.08) has a *much* lower (better) microsomal clearance than Ligand A (70.326), suggesting greater metabolic stability.

**In vitro Half-Life:** Ligand B (-9.656) has a much longer in vitro half-life than Ligand A (25.659), indicating greater stability.

**P-gp Efflux:** Ligand A (0.303) has lower P-gp efflux liability than Ligand B (0.055), which is beneficial for CNS exposure.

**Binding Affinity:** Ligand A (-10.1 kcal/mol) has a significantly stronger binding affinity than Ligand B (-7.8 kcal/mol). This is a substantial advantage, potentially outweighing some of the ADME drawbacks.

**Overall Assessment:**

Ligand A excels in binding affinity and BBB penetration, which are crucial for a CNS-targeting GPCR. However, it has higher DILI risk, higher microsomal clearance, and a higher logP. Ligand B has a better safety profile (lower DILI), better metabolic stability (lower Cl_mic, longer t1/2), and lower P-gp efflux, but suffers from poor logP and significantly lower binding affinity.

The difference in binding affinity (~2.3 kcal/mol) is substantial. For a GPCR, achieving high receptor occupancy is often paramount. The better BBB of Ligand A is also a major advantage. While the ADME properties of Ligand A are not ideal, they might be optimized further through medicinal chemistry efforts, whereas improving the affinity of Ligand B by 2.3 kcal/mol would likely be much more challenging.

Output:
1
2025-04-17 06:55:40,570 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 drug candidates, considering the provided guidelines and GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (368.499 and 380.476 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (75.71) is higher than Ligand B (49.41). For CNS targets, TPSA should be <= 90, so both are acceptable, but B is significantly better.

**logP:** Ligand A (1.577) is within the optimal 1-3 range. Ligand B (3.382) is at the higher end of optimal, but still acceptable.

**H-Bond Donors:** Both ligands have 1 HBD, which is within the acceptable limit of <= 5.

**H-Bond Acceptors:** Ligand A has 5 HBA, and Ligand B has 3. Both are below the acceptable limit of <= 10.

**QED:** Ligand A (0.721) has a better QED score than Ligand B (0.493), indicating a more drug-like profile.

**DILI:** Ligand A (21.908) has a lower DILI risk than Ligand B (18.108), which is preferable.

**BBB:** Ligand B (85.111) has a significantly higher BBB penetration percentile than Ligand A (71.501). This is a crucial advantage for a CNS target like DRD2.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.13 and -5.008), which is unusual and suggests poor permeability. However, the scale is not defined, so it's hard to interpret.

**Aqueous Solubility:** Both ligands have negative solubility values (-2.432 and -4.184), which is also unusual and suggests poor solubility. Again, the scale is undefined.

**hERG Inhibition:** Ligand A (0.23) has a lower hERG inhibition liability than Ligand B (0.696), which is preferable.

**Microsomal Clearance:** Ligand B (53.736) has a higher microsomal clearance than Ligand A (40.897), indicating lower metabolic stability.

**In vitro Half-Life:** Ligand A (-9.659) has a longer in vitro half-life than Ligand B (-3.78), which is preferable.

**P-gp Efflux:** Ligand A (0.045) has lower P-gp efflux liability than Ligand B (0.269), which is beneficial for CNS exposure.

**Binding Affinity:** Ligand B (-7.1) has a slightly better binding affinity than Ligand A (-8.0). However, the difference is relatively small, and A already has excellent affinity.

**Overall Assessment:**

Ligand A has better QED, DILI, hERG, metabolic stability (lower Cl_mic, longer t1/2), and P-gp efflux. Ligand B has a significantly higher BBB penetration, which is paramount for a CNS target. The negative Caco-2 and solubility values are concerning for both, but the difference in BBB is substantial enough to outweigh the other advantages of A. The slightly better affinity of B is a bonus.

Output:
1
2025-04-17 06:55:40,571 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (353.419 and 346.427 Da) fall within the ideal range of 200-500 Da.

**TPSA:** Ligand A (113.17) is slightly above the preferred <90 for CNS targets, but still reasonable. Ligand B (73.99) is excellent, well below 90.

**logP:** Ligand A (-0.735) is a bit low, potentially hindering permeability. Ligand B (2.046) is within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A (2 HBD, 5 HBA) and Ligand B (1 HBD, 4 HBA) both have acceptable numbers of H-bond donors and acceptors.

**QED:** Both ligands have good QED scores (0.632 and 0.847), indicating drug-like properties.

**DILI:** Both ligands have low DILI risk (22.451 and 29.779), which is positive.

**BBB:** Both ligands have good BBB penetration (63.474 and 66.188), but ideally, we'd want >70 for a CNS target.

**Caco-2 Permeability:** Both have negative Caco-2 values (-4.897 and -4.701), which is unusual and suggests poor permeability. This is a significant concern.

**Aqueous Solubility:** Both have negative solubility values (-1.176 and -1.648), which is also concerning.

**hERG:** Both ligands have very low hERG risk (0.178 and 0.136).

**Microsomal Clearance:** Ligand A (-0.583) has a negative clearance, which is not physically possible and suggests an issue with the data. Ligand B (15.139) has a relatively high clearance, indicating faster metabolism.

**In vitro Half-Life:** Ligand A (-25.607) has a negative half-life, also not physically possible and indicating a data issue. Ligand B (26.415) has a reasonable half-life.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.029 and 0.168), which is good for CNS penetration.

**Binding Affinity:** Ligand B (-7.2 kcal/mol) has a slightly better binding affinity than Ligand A (-7.9 kcal/mol), although the difference is small.

**Overall Assessment:**

Ligand A has significant data quality issues (negative clearance and half-life), making it unreliable. While its affinity is slightly better, the data inconsistencies are a major red flag. Ligand B, while having a higher clearance, has more reasonable ADME properties overall, and a good binding affinity. The logP is optimal, TPSA is excellent, and P-gp efflux is low. While Caco-2 and solubility are concerning, they are less critical than the data issues with Ligand A.

Output:
1
2025-04-17 06:55:40,571 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (370.467 and 351.462 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (89.9) is excellent, falling below the 90 threshold for CNS targets. Ligand B (47.56) is also good, well below the threshold.

**3. logP:** Ligand A (2.473) is optimal (1-3). Ligand B (4.927) is slightly high, potentially leading to solubility issues or off-target interactions, but still within a tolerable range.

**4. H-Bond Donors:** Both ligands have 1 HBD, which is within the acceptable limit of <=5.

**5. H-Bond Acceptors:** Ligand A has 6 HBA, and Ligand B has 4 HBA, both well below the limit of <=10.

**6. QED:** Both ligands have similar QED values (0.742 and 0.764), indicating good drug-like properties.

**7. DILI:** Ligand A (45.522) has a slightly higher DILI risk than Ligand B (33.191), but both are below the concerning threshold of 60.

**8. BBB:** Both ligands exhibit excellent BBB penetration (71.578 and 72.896), exceeding the desirable 70% for CNS targets.

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 values, which is unusual. Assuming these are logP-scale values, they indicate poor permeability. However, the negative values are similar, so this isn't a major differentiator.

**10. Aqueous Solubility:** Both ligands have negative solubility values, which is also unusual. Again, assuming logS values, they indicate poor solubility. Similar to Caco-2, this isn't a major differentiator.

**11. hERG Inhibition:** Both ligands show low hERG inhibition liability (0.261 and 0.515), which is favorable.

**12. Microsomal Clearance:** Ligand A (45.656) has significantly lower microsomal clearance than Ligand B (107.476), suggesting better metabolic stability.

**13. In vitro Half-Life:** Ligand A (5.107) has a shorter half-life than Ligand B (15.87), but both are reasonable.

**14. P-gp Efflux:** Both ligands have low P-gp efflux liability (0.561 and 0.142), which is good for CNS exposure. Ligand B is slightly better here.

**15. Binding Affinity:** Both ligands have identical binding affinities (-8.6 kcal/mol), which is excellent and a strong driving force for both.

**Overall Assessment:**

Both ligands have strong binding affinity and good BBB penetration, which are crucial for a CNS-targeting GPCR like DRD2. Ligand A has a more favorable logP and significantly better metabolic stability (lower Cl_mic and longer half-life). While Ligand B has slightly lower P-gp efflux, the difference isn't substantial enough to outweigh the advantages of Ligand A's improved metabolic profile. The solubility and permeability issues are similar for both, and would need to be addressed in further optimization.

Output:
1
2025-04-17 06:55:40,571 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 drug candidates, considering the provided guidelines and GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (354.407 and 344.455 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (119.14) is borderline for CNS penetration, slightly above the preferred <90, while Ligand B (78.43) is excellent, well below 90.

**logP:** Ligand A (-1.125) is a bit low, potentially hindering permeability. Ligand B (2.925) is optimal.

**H-Bond Donors/Acceptors:** Both have 3 HBDs, which is acceptable. Ligand A has 7 HBAs, while Ligand B has 3. Both are within the acceptable limit of 10, but Ligand B is preferable.

**QED:** Both ligands have good QED scores (0.541 and 0.603), indicating good drug-like properties.

**DILI:** Both have low DILI risk (21.287 and 20.24), which is positive.

**BBB:** This is a critical parameter for a CNS target like DRD2. Ligand A has a BBB percentile of 11.981, which is very poor. Ligand B has a much better BBB percentile of 67.623, although ideally >70.

**Caco-2 Permeability:** Ligand A (-5.453) shows poor permeability, while Ligand B (-4.647) is slightly better, but still not ideal.

**Aqueous Solubility:** Ligand A (0.33) has very poor solubility, while Ligand B (-3.116) also has poor solubility.

**hERG Inhibition:** Ligand A (0.031) shows very low hERG inhibition risk, which is excellent. Ligand B (0.526) is slightly higher, but still acceptable.

**Microsomal Clearance:** Ligand A (0.585) has low clearance, indicating good metabolic stability. Ligand B (48.759) has high clearance, suggesting rapid metabolism.

**In vitro Half-Life:** Ligand A (-6.855) has a very short half-life, while Ligand B (8.73) has a longer half-life.

**P-gp Efflux:** Ligand A (0.004) shows very low P-gp efflux, which is excellent for CNS penetration. Ligand B (0.42) is higher, indicating some efflux.

**Binding Affinity:** Ligand B (-8.4 kcal/mol) has a significantly stronger binding affinity than Ligand A (-7.1 kcal/mol). This >1.5 kcal/mol difference is substantial and can outweigh some ADME drawbacks.

**Overall Assessment:**

Ligand B is the superior candidate. While its solubility and Caco-2 permeability are not ideal, its significantly improved BBB penetration, much stronger binding affinity, and acceptable safety profiles (DILI, hERG) outweigh the drawbacks. Ligand A suffers from extremely poor BBB penetration and solubility, and a shorter half-life, making it a less viable candidate despite its good metabolic stability and low P-gp efflux. The strong affinity of Ligand B is a major advantage for a GPCR target.

Output:
1
2025-04-17 06:55:40,571 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (352.391 and 354.495 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (108.05) is slightly above the optimal <90 for CNS targets, but still reasonable. Ligand B (84.91) is excellent, well below 90.

**logP:** Ligand A (-1.769) is a bit low, potentially hindering permeability. Ligand B (-0.348) is better, falling within the 1-3 range, though still on the lower side.

**H-Bond Donors/Acceptors:** Ligand A (2 HBD, 6 HBA) and Ligand B (3 HBD, 5 HBA) both have acceptable numbers of H-bond donors and acceptors.

**QED:** Both ligands have good QED scores (0.582 and 0.555), indicating drug-like properties.

**DILI:** Ligand A (52.966) has a moderate DILI risk, but is acceptable. Ligand B (5.312) has a very low DILI risk, which is highly favorable.

**BBB:** Ligand A (55.332) has a moderate BBB penetration, which is not ideal for a CNS target. Ligand B (30.71) has poor BBB penetration, making it less attractive.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.221 and -5.454), which is unusual and suggests poor permeability. This is a significant concern for both.

**Aqueous Solubility:** Both ligands have negative solubility values (-1.735 and -0.125), which is also unusual and suggests poor solubility. This is a significant concern for both.

**hERG Inhibition:** Ligand A (0.017) has very low hERG inhibition risk, which is excellent. Ligand B (0.288) has a slightly higher, but still low, hERG risk.

**Microsomal Clearance:** Ligand A (-6.524) has a very low (and negative) microsomal clearance, indicating high metabolic stability. Ligand B (0.615) has a low clearance, but not as favorable as Ligand A.

**In vitro Half-Life:** Ligand A (-20.07) has a very long half-life, which is excellent. Ligand B (5.391) has a shorter half-life.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.005 and 0.007), which is favorable for CNS penetration.

**Binding Affinity:** Ligand B (-7.5 kcal/mol) has a slightly better binding affinity than Ligand A (-7.3 kcal/mol), although the difference is small.

**Overall Assessment:**

Despite both ligands having issues with Caco-2 and Solubility, Ligand A has a better overall profile for a CNS-targeting drug. Its superior metabolic stability (lower Cl_mic, longer t1/2), lower DILI risk, and excellent hERG profile are significant advantages. While its BBB penetration isn't ideal, it's better than Ligand B's. The slightly weaker affinity of Ligand A is less concerning given its other favorable properties. The negative solubility and permeability values are concerning for both, and would need to be addressed through formulation or structural modification.

Output:
0
2025-04-17 06:55:40,571 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (362.459 Da) and Ligand B (348.403 Da) are both acceptable.

**TPSA:**  Ligand A (95.12) is better than Ligand B (113.33). For CNS targets, we want TPSA <= 90, so Ligand A is closer to this threshold.

**logP:** Both ligands have similar logP values (A: 0.45, B: 0.522), which are a bit low. Ideally, we want 1-3. This might slightly hinder permeability, but isn't a dealbreaker if other properties are favorable.

**H-Bond Donors/Acceptors:** Ligand A (0 HBD, 7 HBA) is preferable to Ligand B (3 HBD, 5 HBA). Lower HBDs generally improve BBB penetration.

**QED:** Both ligands have similar and acceptable QED values (A: 0.772, B: 0.734), indicating good drug-like properties.

**DILI:** Ligand A (63.086) has a slightly higher DILI risk than Ligand B (56.572), but both are still within an acceptable range (<60 is good).

**BBB:** Ligand A (50.795) has significantly better BBB penetration potential than Ligand B (37.456). This is *critical* for a CNS target like DRD2.

**Caco-2 Permeability:** Ligand A (-4.979) has a worse Caco-2 permeability than Ligand B (-5.416). However, Caco-2 values are negative here, so a less negative value is better.

**Aqueous Solubility:** Ligand A (-3.524) has better aqueous solubility than Ligand B (-2.335).

**hERG:** Both ligands have very low hERG inhibition risk (A: 0.128, B: 0.051).

**Microsomal Clearance:** Ligand B (-1.761) has much better metabolic stability (lower clearance) than Ligand A (39.186).

**In vitro Half-Life:** Ligand B (15.458) has a significantly longer in vitro half-life than Ligand A (-8.552). This is a major advantage.

**P-gp Efflux:** Ligand A (0.121) has lower P-gp efflux liability than Ligand B (0.02). Lower P-gp efflux is desirable for CNS exposure.

**Binding Affinity:** Both ligands have the same binding affinity (-8 kcal/mol), which is excellent.

**Overall Assessment:**

Ligand A excels in TPSA, BBB, solubility, and P-gp efflux. However, Ligand B has superior metabolic stability (Cl_mic and t1/2) and a slightly lower DILI risk. The *most important* factor for a CNS GPCR target is BBB penetration, and Ligand A has a significantly higher BBB percentile (50.795) compared to Ligand B (37.456). While Ligand B's metabolic stability is attractive, the difference in BBB penetration outweighs this benefit.

Output:
0
2025-04-17 06:55:40,571 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (349.475 and 361.921 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (78.51) is better than Ligand B (49.74). For CNS targets, we want TPSA <= 90, both are within this range, but A is closer to the upper limit.

**3. logP:** Ligand A (1.614) is optimal (1-3), while Ligand B (3.994) is approaching the higher end of the optimal range.

**4. H-Bond Donors:** Ligand A (2) is acceptable, and Ligand B (1) is also good.

**5. H-Bond Acceptors:** Ligand A (3) is acceptable, and Ligand B (4) is also good.

**6. QED:** Both ligands have similar QED values (0.715 and 0.734), indicating good drug-likeness.

**7. DILI:** Ligand A (15.122) has a significantly lower DILI risk than Ligand B (21.481). This is a substantial advantage for A.

**8. BBB:** Ligand B (70.997) has a slightly better BBB penetration percentile than Ligand A (66.344). Both are above the 70% threshold desirable for CNS targets, but B is better.

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.023 and -5.292), which is unusual and suggests poor permeability. This is a concern for both.

**10. Aqueous Solubility:** Both ligands have negative solubility values (-1.886 and -3.236), indicating poor aqueous solubility. This is a concern for both.

**11. hERG Inhibition:** Ligand A (0.24) has a much lower hERG inhibition liability than Ligand B (0.763). This is a significant safety advantage for A.

**12. Microsomal Clearance:** Ligand A (-1.179) has a lower (better) microsomal clearance than Ligand B (32.527), indicating better metabolic stability.

**13. In vitro Half-Life:** Ligand B (34.754) has a much longer in vitro half-life than Ligand A (-2.227). This is a significant advantage for B.

**14. P-gp Efflux:** Ligand A (0.043) has a much lower P-gp efflux liability than Ligand B (0.413), which is crucial for CNS penetration.

**15. Binding Affinity:** Ligand B (-8.1) has a slightly better binding affinity than Ligand A (-8.6). While a 1.5 kcal/mol difference is usually significant, in this case, the other ADME properties are more concerning.

**Overall Assessment:**

Ligand A is the better candidate. While Ligand B has a slightly better binding affinity and half-life, Ligand A demonstrates significantly better safety profiles (lower DILI and hERG), lower P-gp efflux (critical for CNS penetration), and better metabolic stability. The negative Caco-2 and solubility values are concerning for both, but the superior ADME profile of Ligand A outweighs the small affinity advantage of Ligand B, especially considering we are targeting a CNS GPCR.

Output:
0
2025-04-17 06:55:40,572 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (334.419 and 361.442 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (44.95) is significantly better than Ligand B (62.39). For CNS targets, we want TPSA <= 90, and ideally lower. Ligand A is much closer to the optimal range.

**logP:** Both ligands have a logP around 3.3-3.4, which is within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Both have 1 HBD, which is good. Ligand A has 3 HBA, while Ligand B has 6. Lower HBA is generally preferred, making Ligand A slightly better.

**QED:** Both ligands have similar QED values (0.673 and 0.667), indicating good drug-likeness.

**DILI:** Ligand A (22.993) has a much lower DILI risk than Ligand B (47.15). This is a significant advantage for Ligand A.

**BBB:** Ligand A (77.627) has a substantially better BBB penetration percentile than Ligand B (51.415).  Given that DRD2 is a CNS target, this is a *critical* advantage for Ligand A. A value >70 is desirable, and Ligand A is closer to that threshold.

**Caco-2 Permeability:** Ligand A (-4.744) shows poor Caco-2 permeability, while Ligand B (-5.216) is also poor. This is a potential concern for both, but not a major differentiator.

**Aqueous Solubility:** Both have negative solubility values, indicating poor solubility. Ligand A (-3.314) is slightly better than Ligand B (-2.881).

**hERG:** Both ligands have similar, low hERG inhibition liability (0.819 and 0.833).

**Microsomal Clearance:** Both have similar microsomal clearance values (44.082 and 45.105), suggesting comparable metabolic stability.

**In vitro Half-Life:** Ligand A (6.161 hours) has a shorter half-life than Ligand B (32.751 hours). This is a disadvantage for Ligand A.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.377 and 0.625).

**Binding Affinity:** Ligand B (-7.8 kcal/mol) has a significantly stronger binding affinity than Ligand A (-9.0 kcal/mol). This is a substantial advantage for Ligand B. However, the difference is not as large as the difference in BBB.

**Overall Assessment:**

Despite the stronger binding affinity of Ligand B, Ligand A is the more promising candidate. The significantly better BBB penetration (77.63 vs 51.42), lower DILI risk (22.99 vs 47.15), and lower TPSA (44.95 vs 62.39) outweigh the weaker binding affinity and shorter half-life. For a CNS target like DRD2, achieving sufficient brain exposure is paramount, and Ligand A is far superior in this regard. The difference in binding affinity, while notable, is less critical than ensuring the drug can reach its target in the brain.



Output:
0
2025-04-17 06:55:40,572 - INFO - Batch 322 complete. Total preferences: 5152
2025-04-17 06:55:40,572 - INFO - Processing batch 323/512...
2025-04-17 06:56:21,187 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (344.367 and 349.475 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (98.61) is slightly above the optimal <90 for CNS targets, but still reasonable. Ligand B (74.57) is excellent, well below 90.

**3. logP:** Both ligands have good logP values (2.587 and 1.699), falling within the 1-3 range.

**4. H-Bond Donors:** Ligand A has 1 HBD, and Ligand B has 2. Both are acceptable (<=5).

**5. H-Bond Acceptors:** Ligand A has 7 HBA, and Ligand B has 4. Both are acceptable (<=10).

**6. QED:** Both ligands have high QED scores (0.804 and 0.85), indicating good drug-like properties.

**7. DILI:** Ligand A (65.762) has a moderate DILI risk, while Ligand B (16.092) has a very low DILI risk. This is a significant advantage for Ligand B.

**8. BBB:** Ligand A (40.675) has a low BBB penetration percentile, which is a major concern for a CNS target like DRD2. Ligand B (53.974) has a better, though still not ideal, BBB percentile.

**9. Caco-2:** Both ligands have negative Caco-2 values, which is unusual and suggests poor permeability. This is a potential issue for both.

**10. Solubility:** Both ligands have negative solubility values, indicating poor aqueous solubility. This is a concern for both.

**11. hERG:** Both ligands have very low hERG inhibition liability (0.107 and 0.168), which is excellent.

**12. Cl_mic:** Ligand A has a higher microsomal clearance (113.999) than Ligand B (11.481), suggesting lower metabolic stability. This favors Ligand B.

**13. t1/2:** Ligand A has a negative in vitro half-life (-40.507), which is problematic. Ligand B has a negative half-life as well (-12.658), but less negative than Ligand A.

**14. Pgp:** Both ligands have very low P-gp efflux liability (0.103 and 0.056), which is good.

**15. Binding Affinity:** Both ligands have similar and strong binding affinities (-8.5 and -8.3 kcal/mol). The difference is minimal.

**Overall Assessment:**

Given the GPCR-specific priorities, BBB penetration is crucial for a CNS target like DRD2. Ligand A's low BBB percentile (40.675) is a major drawback. While Ligand B's BBB percentile (53.974) isn't ideal, it's significantly better. Furthermore, Ligand B exhibits a much lower DILI risk and better metabolic stability (lower Cl_mic). Although both have issues with Caco-2 and solubility, the ADME profile of Ligand B is superior, especially considering the importance of CNS penetration for DRD2. The similar binding affinities make the ADME differences the deciding factor.

Output:
1
2025-04-17 06:56:21,187 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (365.4 & 370.6 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (72.88) is slightly higher than Ligand B (66.48), but both are below the 90 A^2 threshold desirable for CNS targets.

**logP:** Ligand A (0.749) is a bit low, potentially hindering permeability. Ligand B (2.769) is within the optimal 1-3 range. This favors Ligand B.

**H-Bond Donors/Acceptors:** Ligand A has 2 HBD and 4 HBA, while Ligand B has 1 HBD and 3 HBA. Both are within acceptable limits.

**QED:** Both ligands have similar QED values (0.729 and 0.714), indicating good drug-likeness.

**DILI:** Ligand A (21.95) has a significantly lower DILI risk than Ligand B (40.05). This is a strong advantage for Ligand A.

**BBB:** Ligand B (72.24) has a better BBB penetration percentile than Ligand A (64.83), which is important for a CNS target like DRD2.

**Caco-2 Permeability:** Ligand A (-4.859) shows poor Caco-2 permeability, while Ligand B (-5.05) is also poor, but slightly better.

**Aqueous Solubility:** Ligand A (-1.259) has better aqueous solubility than Ligand B (-3.905).

**hERG:** Both ligands have low hERG inhibition liability (0.655 and 0.611), which is good.

**Microsomal Clearance:** Ligand A (-9.151) has a much lower (better) microsomal clearance than Ligand B (86.201), indicating better metabolic stability.

**In vitro Half-Life:** Ligand A (-9.644) has a significantly longer in vitro half-life than Ligand B (-40.592).

**P-gp Efflux:** Ligand A (0.023) has much lower P-gp efflux liability than Ligand B (0.308), which is crucial for CNS penetration.

**Binding Affinity:** Both ligands have very similar and strong binding affinities (-8.5 and -8.1 kcal/mol). The difference is less than the 1.5 kcal/mol threshold.

**Overall Assessment:**

Ligand B has advantages in BBB penetration and logP, which are important for CNS GPCRs. However, Ligand A excels in safety (DILI), metabolic stability (Cl_mic, t1/2), and P-gp efflux, which are also critical for CNS drug development. The slightly lower logP of Ligand A is a concern, but the substantial improvements in other ADME properties, particularly the P-gp efflux and metabolic stability, outweigh this drawback. The similar binding affinities make these factors the deciding ones.

Output:
0
2025-04-17 06:56:21,187 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (364.406 and 364.511 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (93.84) is slightly above the optimal <90 for CNS targets, but still reasonable. Ligand B (66.57) is well within the desired range. This favors Ligand B.

**3. logP:** Ligand A (0.731) is a bit low, potentially hindering permeability. Ligand B (3.912) is near the upper end of the optimal range (1-3) but still acceptable. This favors Ligand B.

**4. H-Bond Donors:** Ligand A (2) and Ligand B (1) are both within the acceptable limit of <=5. Ligand B is slightly better.

**5. H-Bond Acceptors:** Ligand A (7) and Ligand B (5) are both within the acceptable limit of <=10. Ligand B is slightly better.

**6. QED:** Ligand A (0.816) has a better QED score than Ligand B (0.694), indicating better overall drug-likeness. This favors Ligand A.

**7. DILI:** Ligand A (75.262) has a higher DILI risk than Ligand B (39.395). This strongly favors Ligand B.

**8. BBB:** Both ligands have good BBB penetration (Ligand A: 68.941, Ligand B: 67.546), but neither exceeds the desirable >70 threshold. This is a neutral point.

**9. Caco-2:** Both have negative Caco-2 values, which is unusual and suggests a potential issue with the data or modeling. This is hard to interpret.

**10. Solubility:** Both have negative solubility values, which is also unusual. This is hard to interpret.

**11. hERG:** Ligand A (0.158) has a much lower hERG inhibition liability than Ligand B (0.797), indicating a lower risk of cardiotoxicity. This favors Ligand A.

**12. Cl_mic:** Ligand A (6.454) has significantly lower microsomal clearance than Ligand B (97.882), suggesting better metabolic stability. This strongly favors Ligand A.

**13. t1/2:** Ligand A (5.125) has a shorter half-life than Ligand B (38.918). This favors Ligand B.

**14. Pgp:** Ligand A (0.061) has much lower P-gp efflux liability than Ligand B (0.917), which is crucial for CNS penetration. This strongly favors Ligand A.

**15. Binding Affinity:** Ligand A (-8.0) has a significantly stronger binding affinity than Ligand B (-6.3). This is a substantial advantage, potentially outweighing some ADME drawbacks.

**Overall Assessment:**

While Ligand B has better TPSA, logP, and a lower DILI risk, Ligand A excels in critical areas for a CNS-targeting GPCR ligand. Its superior binding affinity (-8.0 vs -6.3), lower P-gp efflux, and lower microsomal clearance are significant advantages. The lower hERG risk is also a positive. The slightly lower QED and BBB penetration are less concerning given the strong binding and improved metabolic/efflux properties. The unusual negative values for Caco-2 and solubility are concerning, but the other factors outweigh these issues.

Output:
1
2025-04-17 06:56:21,187 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (343.387 and 347.419 Da) fall comfortably within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (105.12) is better than Ligand B (112.91). For CNS targets, TPSA should be <= 90, so both are slightly above ideal, but A is closer.

**3. logP:** Both ligands have good logP values (1.162 and 1.851), falling within the optimal range of 1-3.

**4. H-Bond Donors:** Both have 3 HBD, which is acceptable.

**5. H-Bond Acceptors:** Both have 5 HBA, which is acceptable.

**6. QED:** Both have similar QED values (0.685 and 0.641), indicating good drug-likeness.

**7. DILI:** Both have relatively high DILI risk (77.007 and 73.09), but below the concerning threshold of 60.

**8. BBB:** Ligand A (56.146) has a significantly better BBB percentile than Ligand B (36.371). This is a *critical* factor for a CNS target like DRD2.

**9. Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and suggests poor permeability. However, these values are on a strange scale, and the absolute value isn't directly comparable without knowing the scale's specifics.

**10. Aqueous Solubility:** Both have negative solubility values, which is also unusual. Again, the scale is unknown, making direct comparison difficult.

**11. hERG Inhibition:** Both ligands show low hERG inhibition liability (0.18 and 0.275), which is good.

**12. Microsomal Clearance:** Ligand A (-5.461) has a more negative value, indicating lower clearance and thus better metabolic stability than Ligand B (54.645).

**13. In vitro Half-Life:** Ligand A (57.486) has a better in vitro half-life than Ligand B (0.18).

**14. P-gp Efflux:** Ligand A (0.075) has much lower P-gp efflux liability than Ligand B (0.262). Lower P-gp efflux is highly desirable for CNS penetration.

**15. Binding Affinity:** Ligand B (-7.9 kcal/mol) has a significantly stronger binding affinity than Ligand A (-9.6 kcal/mol). This is a substantial advantage.

**Overall Assessment:**

While Ligand B has a superior binding affinity, Ligand A is a more promising drug candidate due to its significantly better BBB penetration (56.146 vs. 36.371), lower P-gp efflux (0.075 vs 0.262), and improved metabolic stability (lower Cl_mic and higher t1/2). For a CNS target like DRD2, good CNS penetration and reduced efflux are paramount, and these factors outweigh the affinity difference. The unusual negative values for Caco-2 and solubility are concerning, but the other properties of Ligand A are more favorable overall.

Output:
0
2025-04-17 06:56:21,188 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 drug candidates, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (362.499 Da) is slightly higher than Ligand B (350.463 Da), but both are acceptable.

**TPSA:** Ligand A (75.19) is better than Ligand B (86.95). For CNS targets, we want TPSA <= 90, both are within this range, but A is preferable.

**logP:** Ligand A (2.323) is optimal (1-3), while Ligand B (0.067) is quite low. Low logP can hinder membrane permeability. This is a significant advantage for Ligand A.

**H-Bond Donors/Acceptors:** Both have 1 HBD and are within acceptable limits. Ligand A has 5 HBA while Ligand B has 4. Both are acceptable.

**QED:** Both ligands have reasonable QED scores (A: 0.788, B: 0.687), indicating good drug-like properties.

**DILI:** Ligand A (35.983) has a lower DILI risk than Ligand B (5.894), which is a positive.

**BBB:** Both ligands have similar BBB penetration (A: 65.607, B: 64.986). Neither exceeds the desirable >70 percentile, but they are reasonably close.

**Caco-2 Permeability:** Both have negative Caco-2 values (-5.167 and -5.353), which is unusual and suggests poor permeability. However, these values are on a log scale and are difficult to interpret without knowing the base.

**Aqueous Solubility:** Both have negative solubility values (-2.935 and -0.881), also unusual and suggesting poor solubility. Again, interpretation is difficult without knowing the scale.

**hERG:** Both ligands have very low hERG inhibition liability (A: 0.076, B: 0.247), which is excellent.

**Microsomal Clearance:** Ligand A (40.124) has higher microsomal clearance than Ligand B (-10.179). This suggests Ligand B is more metabolically stable, which is desirable.

**In vitro Half-Life:** Ligand B (-28.499) has a much longer in vitro half-life than Ligand A (-6.499). This is a significant advantage for Ligand B.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (A: 0.118, B: 0.006), which is excellent for CNS penetration.

**Binding Affinity:** Both ligands have similar and strong binding affinities (A: -8.3 kcal/mol, B: -8.6 kcal/mol). The difference is minimal.

**Overall Assessment:**

Considering the GPCR-specific priorities, Ligand A is more promising. While Ligand B has better metabolic stability and half-life, Ligand A has a much better logP value, which is crucial for CNS penetration. The similar binding affinities mean that the improved physicochemical properties of Ligand A outweigh the slightly better metabolic profile of Ligand B. The negative Caco-2 and solubility values are concerning for both, but the logP difference is the deciding factor.

Output:
1
2025-04-17 06:56:21,188 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (354.495 and 344.423 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (76.12) is significantly better than Ligand B (118.01). For CNS targets, TPSA should be <= 90, and A is comfortably within this range, while B is above.

**logP:** Ligand A (-0.254) is a bit low, potentially hindering permeability. Ligand B (0.36) is better, falling within the optimal 1-3 range, though still on the lower side.

**H-Bond Donors/Acceptors:** Ligand A (2 HBD, 5 HBA) is preferable to Ligand B (3 HBD, 9 HBA). Both are acceptable, but fewer H-bonds generally improve permeability.

**QED:** Both ligands have similar QED values (0.688 and 0.687), indicating good drug-likeness.

**DILI:** Ligand A (5.079) has a much lower DILI risk than Ligand B (58.705). This is a significant advantage for A.

**BBB:** Ligand A (18.147) has a very poor BBB percentile, making CNS penetration unlikely. Ligand B (58.123) is also not ideal, but substantially better than A. This is a critical drawback for A.

**Caco-2 Permeability:** Both have negative Caco-2 values (-5.079 and -5.639), which is unusual and suggests poor permeability. However, these values are on a scale where negative values are possible, and direct comparison is difficult without knowing the scale's specifics.

**Aqueous Solubility:** Both have very low solubility (-0.009 and -2.161), which could pose formulation challenges.

**hERG Inhibition:** Ligand A (0.177) has a lower hERG inhibition liability than Ligand B (0.458), which is favorable.

**Microsomal Clearance:** Ligand A (2.652) has significantly lower microsomal clearance than Ligand B (16.42), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (1.122) has a slightly lower in vitro half-life than Ligand B (2.819), but both are relatively low.

**P-gp Efflux:** Ligand A (0.008) has very low P-gp efflux liability, which is excellent for CNS exposure. Ligand B (0.008) is similar.

**Binding Affinity:** Ligand B (-8.7 kcal/mol) has a substantially stronger binding affinity than Ligand A (-7.6 kcal/mol). This is a >1 kcal/mol advantage, which can outweigh some ADME drawbacks.

**Overall Assessment:**

While Ligand A has advantages in DILI risk, metabolic stability, and P-gp efflux, its extremely poor BBB penetration is a deal-breaker for a CNS target like DRD2. Ligand B, despite having a higher DILI risk and slightly lower metabolic stability, possesses a significantly stronger binding affinity and a much better (though still not ideal) BBB percentile. The stronger binding affinity is a crucial factor for GPCRs. The TPSA is higher for B, but the affinity difference is significant.

Output:
1
2025-04-17 06:56:21,188 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 drug candidates, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (348.4 & 350.5 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (99.1) is higher than the preferred <90 for CNS targets, while Ligand B (49.85) is well within the range. This is a significant advantage for Ligand B.

**3. logP:** Ligand A (0.991) is a bit low, potentially hindering permeation. Ligand B (2.402) is within the optimal 1-3 range.

**4. H-Bond Donors:** Ligand A (3) is acceptable, Ligand B (0) is also good.

**5. H-Bond Acceptors:** Ligand A (5) is acceptable, Ligand B (3) is also good.

**6. QED:** Both ligands have good QED scores (0.526 and 0.608 respectively), indicating drug-like properties.

**7. DILI:** Ligand A (22.3%) has a slightly higher DILI risk than Ligand B (6.8%), but both are considered low risk (<40).

**8. BBB:** Ligand B (92.9%) has a significantly higher predicted BBB penetration than Ligand A (64.1%). This is a crucial advantage for a CNS target like DRD2.

**9. Caco-2 Permeability:** Ligand A (-4.737) has worse Caco-2 permeability than Ligand B (-4.409), although both are negative values suggesting poor permeability.

**10. Aqueous Solubility:** Ligand A (-1.385) has better aqueous solubility than Ligand B (-2.372).

**11. hERG Inhibition:** Ligand A (0.363) has a lower hERG inhibition liability than Ligand B (0.735), which is preferable.

**12. Microsomal Clearance:** Ligand B (77.269) has a much higher microsomal clearance than Ligand A (8.15), indicating faster metabolism and potentially lower *in vivo* exposure.

**13. In vitro Half-Life:** Ligand B (-10.703) has a much longer in vitro half-life than Ligand A (-7.444).

**14. P-gp Efflux:** Ligand A (0.035) has lower P-gp efflux liability than Ligand B (0.195), which is beneficial for CNS penetration.

**15. Binding Affinity:** Both ligands have excellent binding affinities (-8.1 and -7.5 kcal/mol). Ligand A is slightly better (-8.1 kcal/mol), but the difference is less than 1.5 kcal/mol, so it's not a decisive factor.

**Overall Assessment:**

Ligand B is the stronger candidate. While Ligand A has slightly better affinity and lower P-gp efflux, Ligand B excels in crucial areas for a CNS-targeting GPCR: significantly better BBB penetration (92.9% vs 64.1%), a more favorable TPSA (49.85 vs 99.1), and a longer half-life. The slightly higher hERG risk for Ligand B is a concern, but manageable. The lower logP of Ligand A is a significant drawback.

Output:
1
2025-04-17 06:56:21,188 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (346.435 and 348.487 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (92.15) is slightly above the optimal <90 for CNS targets, but still reasonable. Ligand B (58.64) is excellent, well below 90.

**logP:** Ligand A (-0.074) is a bit low, potentially hindering permeability. Ligand B (2.801) is nearly ideal.

**H-Bond Donors/Acceptors:** Ligand A (2 HBD, 6 HBA) is good. Ligand B (1 HBD, 3 HBA) is also very good. Both are within acceptable limits.

**QED:** Both ligands have good QED scores (0.703 and 0.751), indicating drug-like properties.

**DILI:** Ligand A (32.261) has a slightly higher DILI risk than Ligand B (9.771), but both are below the concerning threshold of 60.

**BBB:** This is a critical parameter for a CNS target like DRD2. Ligand A (53.083) has a moderate BBB penetration, while Ligand B (85.459) is excellent, exceeding the desirable >70 threshold.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.185 and -4.697), which is unusual and suggests poor permeability. However, these values are on a log scale and should be interpreted cautiously.

**Aqueous Solubility:** Both ligands have negative solubility values (-1.712 and -2.51), which is also unusual and suggests poor solubility.

**hERG:** Both ligands show low hERG inhibition liability (0.067 and 0.512), which is favorable.

**Microsomal Clearance:** Ligand A (-17.575) has a much lower (better) microsomal clearance than Ligand B (45.531), indicating greater metabolic stability.

**In vitro Half-Life:** Ligand A (-11.029) has a negative half-life, which is not physically possible and suggests an issue with the data. Ligand B (-0.846) is also negative, but less extreme.

**P-gp Efflux:** Ligand A (0.012) has very low P-gp efflux liability, which is excellent for CNS penetration. Ligand B (0.176) is also low, but higher than Ligand A.

**Binding Affinity:** Ligand B (-8.2 kcal/mol) has a slightly better binding affinity than Ligand A (-7.0 kcal/mol). While both are good, the 1.2 kcal/mol difference is significant.

**Overall Assessment:**

Ligand B is the stronger candidate. It excels in key GPCR properties: excellent BBB penetration, a near-ideal logP, and strong binding affinity. While its metabolic stability is not as good as Ligand A, the superior BBB and affinity outweigh this drawback. The negative Caco-2 and solubility values are concerning for both, but the overall profile of Ligand B is more promising for CNS drug development. The unusual half-life values for both compounds suggest potential data quality issues.

Output:
1
2025-04-17 06:56:21,189 - INFO - Reasoning:

Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (367.427 and 366.531 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (100.73) is slightly above the optimal <90 for CNS targets, but still reasonable. Ligand B (78.35) is excellent, well below 90.

**logP:** Ligand A (0.104) is quite low, potentially hindering membrane permeability. Ligand B (3.006) is within the optimal 1-3 range. This is a significant advantage for Ligand B.

**H-Bond Donors/Acceptors:** Both have 2 HBD and 6 HBA, which are acceptable values.

**QED:** Both ligands have good QED scores (0.769 and 0.775), indicating drug-like properties.

**DILI:** Ligand A (62.195) has a higher DILI risk than Ligand B (43.622), though both are within acceptable limits (<60 is good).

**BBB:** This is crucial for a CNS target like DRD2. Ligand A (23.187) has a very poor BBB penetration percentile. Ligand B (78.558) is excellent, exceeding the desirable >70 threshold.

**Caco-2 Permeability:** Ligand A (-5.346) shows very poor permeability. Ligand B (-5.139) is also poor, but slightly better than Ligand A.

**Aqueous Solubility:** Both ligands have poor aqueous solubility (-2.795 and -3.179). This could pose formulation challenges, but is less critical than BBB penetration for a CNS drug.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.165 and 0.709).

**Microsomal Clearance:** Ligand A (-20.93) has a significantly lower (better) microsomal clearance than Ligand B (47.432), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (19.515) has a longer half-life than Ligand B (9.973).

**P-gp Efflux:** Ligand A (0.015) has very low P-gp efflux, which is favorable for CNS penetration. Ligand B (0.408) has moderate P-gp efflux.

**Binding Affinity:** Both ligands have similar, strong binding affinities (-8.5 and -8.2 kcal/mol). The difference is not substantial enough to override other factors.

**Overall Assessment:**

Ligand B is significantly more promising due to its excellent BBB penetration (78.558), optimal logP (3.006), and acceptable DILI risk. While Ligand A has better metabolic stability (lower Cl_mic) and P-gp efflux, its extremely poor BBB penetration and low logP are major drawbacks for a CNS-targeting drug. The slightly better affinity of Ligand A is not enough to compensate for these deficiencies.



Output:
1
2025-04-17 06:56:21,189 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (338.415 and 350.459 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (76.77) is better than Ligand B (78.87). Both are below the 90 A^2 threshold desirable for CNS targets, but A is closer to optimal.

**3. logP:** Both ligands have good logP values (2.86 and 3.149), falling within the 1-3 range.

**4. H-Bond Donors:** Both have 2 HBD, which is acceptable.

**5. H-Bond Acceptors:** Ligand A has 5 HBA, and Ligand B has 4. Both are within the acceptable limit of 10.

**6. QED:** Both have good QED scores (0.695 and 0.792), indicating good drug-like properties.

**7. DILI:** Ligand A (61.691) has a higher DILI risk than Ligand B (18.922). This is a significant drawback for Ligand A.

**8. BBB:** Both ligands have acceptable BBB penetration (62.466 and 64.444). While not exceeding 70, they are reasonably good for a GPCR.

**9. Caco-2 Permeability:** Both have negative Caco-2 values (-5.07 and -4.708), which is unusual and suggests poor permeability. This is a concern for both, but the values are similar.

**10. Aqueous Solubility:** Both have negative solubility values (-3.963 and -3.672), indicating poor aqueous solubility. This is a concern for both.

**11. hERG Inhibition:** Ligand A (0.555) has a slightly higher hERG risk than Ligand B (0.713).

**12. Microsomal Clearance:** Ligand A (71.686) has a lower microsomal clearance than Ligand B (107.093), suggesting better metabolic stability.

**13. In vitro Half-Life:** Ligand A (14.238 hours) has a longer half-life than Ligand B (-13.817 hours). The negative value for B is concerning and likely indicates rapid degradation.

**14. P-gp Efflux:** Ligand A (0.164) has lower P-gp efflux than Ligand B (0.025), which is favorable for CNS penetration.

**15. Binding Affinity:** Ligand A (-8.5 kcal/mol) has a significantly stronger binding affinity than Ligand B (-7.1 kcal/mol). This is a 1.4 kcal/mol difference, which is substantial and can outweigh some ADME drawbacks.

**Overall Assessment:**

While Ligand A has a higher DILI risk and slightly higher hERG risk, its significantly superior binding affinity (-8.5 vs -7.1 kcal/mol), lower P-gp efflux, and longer half-life make it the more promising candidate. The negative Caco-2 and solubility values are concerning for both, but the strong binding affinity of Ligand A suggests it might still be worth pursuing with formulation strategies to address these issues. Ligand B's negative half-life is a major red flag.

Output:
0
2025-04-17 06:56:21,189 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 drug candidates, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (460.266 Da) is higher, but still acceptable. Ligand B (347.434 Da) is lower, potentially favoring permeability.

**TPSA:** Ligand A (50.16) is better than Ligand B (62.3) as it is closer to the ideal <90 for CNS targets. Ligand B is still within a reasonable range, but less optimal.

**logP:** Both ligands have good logP values (A: 4.369, B: 3.451) falling within the 1-3 range. Ligand A is slightly higher, which *could* present solubility issues, but isn't a major concern.

**H-Bond Donors/Acceptors:** Both have 1 HBD and 3 HBA, which are within the acceptable limits.

**QED:** Both ligands have acceptable QED scores (A: 0.69, B: 0.487), with Ligand A being slightly more drug-like.

**DILI:** Ligand A (52.772) has a higher DILI risk than Ligand B (37.456), which is preferable.

**BBB:** Ligand A (94.261) has a significantly better BBB penetration score than Ligand B (82.047). This is *critical* for a CNS target like DRD2.

**Caco-2 Permeability:** Both have negative Caco-2 values (-4.873 and -4.747), which is unusual and suggests poor permeability. However, these values are on a log scale and need careful interpretation. A negative value doesn't necessarily disqualify a compound, but warrants further investigation.

**Aqueous Solubility:** Both have poor aqueous solubility (-5.234 and -3.244). This is a concern, but can be addressed with formulation strategies.

**hERG Inhibition:** Ligand A (0.854) has a slightly higher hERG risk than Ligand B (0.487), which is less desirable.

**Microsomal Clearance:** Ligand B (50.317) has a higher microsomal clearance than Ligand A (31.225), meaning A is more metabolically stable.

**In vitro Half-Life:** Ligand A (3.806) has a longer half-life than Ligand B (-11.599). The negative value for B is concerning and indicates very rapid metabolism.

**P-gp Efflux:** Ligand A (0.517) has lower P-gp efflux than Ligand B (0.219), which is better for CNS exposure.

**Binding Affinity:** Ligand A (-10.1 kcal/mol) has a significantly stronger binding affinity than Ligand B (-8.4 kcal/mol). This is a substantial advantage.

**Overall Assessment:**

Ligand A is the stronger candidate. While it has a slightly higher DILI and hERG risk, its significantly better BBB penetration, metabolic stability (lower Cl_mic, longer t1/2), lower P-gp efflux, and *much* stronger binding affinity outweigh these drawbacks. The affinity difference is particularly important for a GPCR target. The poor solubility and Caco-2 permeability are concerns for both, but can potentially be addressed through formulation.

Output:
1
2025-04-17 06:56:21,189 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (344.296 Da) is slightly lower, which could be favorable for permeability.

**TPSA:** Both ligands have TPSA values below the 90 A^2 threshold desirable for CNS targets. Ligand B (71.09 A^2) is slightly better than Ligand A (81.57 A^2).

**logP:** Both ligands have logP values within the optimal range (1-3), with Ligand A (3.383) being slightly higher than Ligand B (4.124). While Ligand B is still acceptable, the higher logP could potentially lead to solubility issues or off-target interactions.

**H-Bond Donors/Acceptors:** Both ligands have acceptable HBD (2) and HBA (3-4) counts, falling within the recommended limits.

**QED:** Both ligands have QED values above 0.5, indicating good drug-like properties.

**DILI:** Both ligands have high DILI risk, but Ligand B (77.007) is lower than Ligand A (86.855), making it slightly preferable in terms of liver toxicity.

**BBB:** Ligand A (64.056) has a significantly better BBB percentile than Ligand B (31.989). This is a critical factor for a CNS target like DRD2.

**Caco-2 Permeability:** Both ligands have negative Caco-2 permeability values, which is unusual and suggests poor intestinal absorption. This is a significant drawback for both.

**Aqueous Solubility:** Both ligands have very poor aqueous solubility (-5.153 and -4.25). This is a major concern for bioavailability.

**hERG Inhibition:** Both ligands have low hERG inhibition risk.

**Microsomal Clearance:** Ligand B (33.32 mL/min/kg) has a higher microsomal clearance than Ligand A (10.782 mL/min/kg), indicating faster metabolism and potentially lower in vivo exposure.

**In vitro Half-Life:** Ligand B (78.469 hours) has a longer in vitro half-life than Ligand A (26.064 hours).

**P-gp Efflux:** Both ligands have very low P-gp efflux liability.

**Binding Affinity:** Both ligands have very similar and excellent binding affinities (-9.5 and -9.4 kcal/mol). The difference is negligible.

**Overall Assessment:**

While Ligand B has a slightly better DILI score, longer half-life, and lower TPSA, Ligand A's significantly better BBB penetration is the deciding factor for a CNS target like DRD2. The poor solubility and Caco-2 permeability are concerns for both, but the ability to cross the blood-brain barrier is paramount.

Output:
0
2025-04-17 06:56:21,190 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (342.439 and 345.487 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (70.59) is higher than Ligand B (54.34). For a CNS target like DRD2, we ideally want TPSA <= 90, so both are acceptable, but B is better.

**3. logP:** Ligand A (4.324) is higher than the optimal range (1-3), potentially causing solubility issues and off-target effects. Ligand B (2.961) is within the optimal range. This favors B.

**4. H-Bond Donors:** Ligand A (3) is acceptable (<=5). Ligand B (1) is even better.

**5. H-Bond Acceptors:** Both ligands (A: 3, B: 3) are well within the acceptable limit of <=10.

**6. QED:** Both ligands have good QED values (A: 0.669, B: 0.892), indicating drug-like properties. B is slightly better.

**7. DILI:** Ligand A (55.68) has a higher DILI risk than Ligand B (31.291). Both are below the concerning threshold of 60, but B is preferable.

**8. BBB:** This is critical for a CNS target. Ligand B (77.511) has a significantly higher BBB penetration percentile than Ligand A (36.177). This is a major advantage for B.

**9. Caco-2 Permeability:** Both have negative values (-5.129 and -4.712), which is unusual and difficult to interpret without further context. However, the values are similar.

**10. Aqueous Solubility:** Both have negative values (-4.724 and -2.791), suggesting poor aqueous solubility. This is a concern, especially given Ligand A's higher logP.

**11. hERG Inhibition:** Both ligands have low hERG inhibition risk (A: 0.745, B: 0.436).

**12. Microsomal Clearance:** Ligand A (87.522) has higher microsomal clearance than Ligand B (33.339), indicating lower metabolic stability. B is better.

**13. In vitro Half-Life:** Ligand A (27.352) has a longer half-life than Ligand B (16.816), which is generally desirable.

**14. P-gp Efflux:** Ligand A (0.389) has lower P-gp efflux than Ligand B (0.251), which is favorable for CNS exposure.

**15. Binding Affinity:** Ligand A (-8.9 kcal/mol) has a significantly stronger binding affinity than Ligand B (-7.7 kcal/mol). This is a substantial advantage for A, potentially outweighing some of its ADME drawbacks. A difference of >1.5 kcal/mol is considered significant.

**Overall Assessment:**

While Ligand A has a superior binding affinity, Ligand B demonstrates a much more favorable ADME profile, particularly regarding BBB penetration (critical for a CNS target), logP, DILI, and metabolic stability. The substantial difference in BBB penetration and the more favorable logP of Ligand B are key factors. The stronger binding of Ligand A is attractive, but the poor ADME properties, especially the high logP and lower BBB, raise concerns about its viability as a drug candidate.

Output:
1
2025-04-17 06:56:21,190 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (358.394 Da) is slightly better than Ligand B (394.871 Da) as it's closer to the lower end, potentially aiding permeability.

**TPSA:** Both ligands have TPSA values below the 90 A^2 threshold for CNS targets, which is good. Ligand B (58.64 A^2) is significantly better than Ligand A (72.24 A^2) in this regard, suggesting better CNS penetration potential.

**logP:** Both ligands have logP values within the optimal range (1-3). Ligand B (3.386) is slightly closer to the upper limit, while Ligand A (4.495) is a bit high, potentially raising concerns about solubility and off-target effects.

**H-Bond Donors/Acceptors:** Both ligands have 1 HBD and 4 HBA, which are within acceptable limits.

**QED:** Both ligands have good QED scores (>0.5), indicating drug-like properties. Ligand B (0.771) is slightly better than Ligand A (0.551).

**DILI:** Ligand B (55.68) has a significantly lower DILI risk than Ligand A (89.841), which is a major advantage.

**BBB:** Both ligands have good BBB penetration percentiles (>70). Ligand B (82.862) is slightly better than Ligand A (76.89).

**Caco-2 Permeability:** Both ligands have negative Caco-2 values, which is unusual and difficult to interpret. However, the values are similar.

**Aqueous Solubility:** Both ligands have negative solubility values, again unusual. The values are similar.

**hERG Inhibition:** Both ligands have low hERG inhibition liability, which is good.

**Microsomal Clearance:** Ligand B (22.621 mL/min/kg) has significantly lower microsomal clearance than Ligand A (79.279 mL/min/kg), indicating better metabolic stability.

**In vitro Half-Life:** Ligand B (-0.423 hours) has a very short half-life, which is a significant drawback. Ligand A (84.204 hours) has a very long half-life, which is a major advantage.

**P-gp Efflux:** Both ligands have low P-gp efflux liability, which is good.

**Binding Affinity:** Ligand A (-9.7 kcal/mol) has a significantly stronger binding affinity than Ligand B (-8.4 kcal/mol). This is a substantial advantage.

**Overall Assessment:**

Ligand A excels in binding affinity and in vitro half-life. However, it has a higher logP, higher DILI risk, and higher microsomal clearance. Ligand B has better TPSA, lower DILI, lower clearance, and a slightly better BBB score. The difference in binding affinity is significant (1.3 kcal/mol), and for a GPCR, this can often outweigh minor ADME concerns. The long half-life of Ligand A is also a significant benefit. While the solubility and Caco-2 values are concerning for both, the superior affinity and half-life of Ligand A make it the more promising candidate.

Output:
1
2025-04-17 06:56:21,190 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (368.499 and 343.427 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (75.71) is slightly above the optimal <90 for CNS targets, but still reasonable. Ligand B (66.65) is well within the desired range.

**3. logP:** Ligand A (1.578) is within the optimal 1-3 range. Ligand B (2.707) is also good, leaning towards the higher end of optimal.

**4. H-Bond Donors:** Ligand A (1) and Ligand B (0) are both acceptable, below the threshold of 5.

**5. H-Bond Acceptors:** Ligand A (5) and Ligand B (4) are both acceptable, below the threshold of 10.

**6. QED:** Both ligands have good QED scores (0.746 and 0.775), indicating drug-like properties.

**7. DILI:** Both ligands have low DILI risk (37.611 and 35.673), which is favorable.

**8. BBB:** This is a critical parameter for a CNS target like DRD2. Ligand A has a BBB percentile of 71.733, which is good (>70). Ligand B has a significantly lower BBB percentile of 54.634, which is less desirable.

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.802 and -4.642). This is unusual and suggests poor permeability. However, these values are on a scale where negative values are possible and don't necessarily disqualify a compound.

**10. Aqueous Solubility:** Both ligands have negative solubility values (-3.555 and -1.033). Similar to Caco-2, this is not ideal, but not necessarily a dealbreaker, especially if other properties are strong.

**11. hERG Inhibition:** Both ligands have low hERG inhibition risk (0.242 and 0.487).

**12. Microsomal Clearance:** Ligand A (93.823) has a higher microsomal clearance than Ligand B (57.789), suggesting lower metabolic stability.

**13. In vitro Half-Life:** Ligand B (44.977) has a much longer in vitro half-life than Ligand A (3.565), which is a significant advantage.

**14. P-gp Efflux:** Both ligands have low P-gp efflux liability (0.09 and 0.094), which is good for CNS penetration.

**15. Binding Affinity:** Ligand B (-8.4 kcal/mol) has a significantly stronger binding affinity than Ligand A (-7.0 kcal/mol). This >1.5 kcal/mol difference is substantial and can outweigh some ADME drawbacks.

**Overall Assessment:**

While Ligand B has better metabolic stability (lower Cl_mic, longer t1/2) and significantly stronger binding affinity, Ligand A has a much better predicted BBB penetration. Given that this is a CNS target, BBB penetration is paramount. However, the substantial affinity difference of Ligand B is a major factor. The slightly lower BBB penetration of Ligand B may be overcome with formulation strategies, but the stronger binding is a more fundamental advantage. Considering the overall profile, the stronger binding affinity of Ligand B is more likely to translate to *in vivo* efficacy, even with a slightly lower BBB score.

Output:
1
2025-04-17 06:56:21,190 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (352.435 and 352.366 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (107.55) is slightly higher than Ligand B (104.97). Both are below the 140 A^2 threshold for oral absorption, and reasonably close to the 90 A^2 target for CNS penetration.

**3. logP:** Ligand A (0.936) is better than Ligand B (0.147). Ligand B is quite low, which could hinder permeation. Optimal logP is 1-3, and A falls within this range, while B is below.

**4. H-Bond Donors:** Ligand A (3) is slightly higher than Ligand B (2), but both are acceptable (<=5).

**5. H-Bond Acceptors:** Both ligands have 5 H-bond acceptors, which is within the acceptable range (<=10).

**6. QED:** Ligand A (0.706) has a significantly better QED score than Ligand B (0.448). A higher QED suggests a more drug-like profile.

**7. DILI:** Ligand A (56.146) has a lower DILI risk than Ligand B (68.98). Both are acceptable, but A is preferable.

**8. BBB:** Both ligands have similar BBB penetration (Ligand A: 48.313, Ligand B: 49.787). These are acceptable, but not ideal (>70) for a CNS target.

**9. Caco-2 Permeability:** Ligand A (-4.809) has slightly better Caco-2 permeability than Ligand B (-5.044).

**10. Aqueous Solubility:** Ligand A (-2.529) has slightly better aqueous solubility than Ligand B (-2.366).

**11. hERG Inhibition:** Both ligands have low hERG inhibition risk (Ligand A: 0.265, Ligand B: 0.353).

**12. Microsomal Clearance:** Ligand A (4.813) has a higher microsomal clearance than Ligand B (-5.673). This means Ligand B is more metabolically stable, which is desirable.

**13. In vitro Half-Life:** Ligand A (-39.019) has a shorter in vitro half-life than Ligand B (-28.149). Ligand B is preferable.

**14. P-gp Efflux:** Both ligands have very low P-gp efflux liability (Ligand A: 0.051, Ligand B: 0.012).

**15. Binding Affinity:** Both ligands have the same binding affinity (-7.7 kcal/mol), which is excellent.

**Overall Assessment:**

While both ligands have excellent binding affinity, Ligand A is superior overall. It has a better QED score, lower DILI risk, slightly better permeability and solubility, and a better logP value. Ligand B has a better metabolic stability profile (lower Cl_mic, longer t1/2), but the advantages of Ligand A in other key areas outweigh this benefit, especially considering the importance of logP and QED for GPCRs. The BBB values are similar and not optimal for either.

Output:
1
2025-04-17 06:56:21,190 - INFO - Batch 323 complete. Total preferences: 5168
2025-04-17 06:56:21,191 - INFO - Processing batch 324/512...
2025-04-17 06:57:01,791 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 drug candidates, considering the provided guidelines and GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (366.53 and 347.42 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (78.43) is significantly better than Ligand B (105.12). For CNS targets, we want TPSA <= 90, and A is comfortably within this range, while B exceeds it.

**logP:** Ligand A (2.685) is optimal (1-3). Ligand B (-0.33) is below 1, which could hinder permeation.

**H-Bond Donors/Acceptors:** Both have acceptable HBD (3) and HBA (4/5) counts, well within the guidelines.

**QED:** Both ligands have good QED scores (0.588 and 0.628), indicating drug-likeness.

**DILI:** Ligand A (23.58) has a much lower DILI risk than Ligand B (47.62), both being acceptable but A is preferable.

**BBB:** Ligand A (50.45) is lower than Ligand B (65.37). While >70 is desirable for CNS targets, 65.37 is a reasonable value. However, considering the other factors, this difference isn't decisive.

**Caco-2 Permeability:** Both have negative Caco-2 values (-5.066 and -5.408), which is unusual and suggests poor permeability. This is a significant concern for both.

**Aqueous Solubility:** Both have negative solubility values (-2.971 and -1.918), indicating very poor solubility. This is a major drawback for both, potentially hindering bioavailability.

**hERG Inhibition:** Both ligands show low hERG inhibition risk (0.383 and 0.135).

**Microsomal Clearance:** Ligand A (72.95) has higher clearance than Ligand B (3.72). Lower clearance is better for metabolic stability, so Ligand B is preferable here.

**In vitro Half-Life:** Ligand B (29.77) has a longer half-life than Ligand A (21.21), which is a positive attribute.

**P-gp Efflux:** Both ligands show low P-gp efflux liability (0.16 and 0.028), which is good for CNS exposure.

**Binding Affinity:** Ligand B (-8.9 kcal/mol) has a significantly stronger binding affinity than Ligand A (-7.5 kcal/mol). This >1.5 kcal/mol difference is substantial and can outweigh some of the ADME drawbacks.

**Overall Assessment:**

Ligand A has better TPSA, logP, and DILI. However, Ligand B has a significantly stronger binding affinity, better BBB penetration, lower microsomal clearance (better metabolic stability), and a longer half-life. Both suffer from poor solubility and Caco-2 permeability. Given the GPCR-specific emphasis on affinity, and the substantial difference in binding energy, Ligand B is the more promising candidate *despite* its poorer logP and solubility. The stronger binding could potentially be optimized through further medicinal chemistry efforts to address the solubility and permeability issues.

Output:
1
2025-04-17 06:57:01,791 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (407.327 Da) is slightly higher than Ligand B (349.475 Da), but both are acceptable.

**2. TPSA:** Ligand A (41.13) is excellent for CNS penetration, well below the 90 A^2 threshold. Ligand B (66.65) is still reasonable, but less optimal than A.

**3. logP:** Ligand A (4.891) is a bit high, potentially leading to solubility issues and off-target effects. Ligand B (2.982) is within the optimal range (1-3).

**4. H-Bond Donors:** Ligand A (2) is good. Ligand B (0) is also acceptable.

**5. H-Bond Acceptors:** Ligand A (1) is good. Ligand B (4) is acceptable, but higher.

**6. QED:** Both ligands have good QED scores (A: 0.631, B: 0.792), indicating drug-like properties.

**7. DILI:** Ligand A (46.297) has a moderate DILI risk, while Ligand B (33.501) has a lower risk. This favors Ligand B.

**8. BBB:** Both ligands have good BBB penetration (A: 78.751, B: 81.388), but Ligand B is slightly better. Both are above the 70% threshold.

**9. Caco-2 Permeability:** Both have negative values, which is unusual. Assuming these are logP values, they indicate poor permeability.

**10. Aqueous Solubility:** Both have negative values, indicating poor solubility.

**11. hERG Inhibition:** Ligand A (0.936) has a slightly higher hERG risk than Ligand B (0.408). This favors Ligand B.

**12. Microsomal Clearance:** Ligand A (87.472) has higher clearance, suggesting lower metabolic stability, compared to Ligand B (76.987). This favors Ligand B.

**13. In vitro Half-Life:** Ligand A (77.15) has a significantly longer half-life than Ligand B (11.218). This is a strong advantage for Ligand A.

**14. P-gp Efflux:** Ligand A (0.738) has lower P-gp efflux liability than Ligand B (0.253), which is favorable for CNS exposure.

**15. Binding Affinity:** Ligand B (-7.4 kcal/mol) has a significantly stronger binding affinity than Ligand A (-10.0 kcal/mol). This is a major advantage for Ligand B, potentially outweighing some of its ADME drawbacks.

**Overall Assessment:**

While Ligand A has a longer half-life and lower P-gp efflux, Ligand B excels in several critical areas for a CNS-targeting GPCR ligand: better logP, lower DILI risk, lower hERG risk, better metabolic stability, and *significantly* stronger binding affinity. The stronger affinity is a substantial advantage. The slightly lower BBB and higher P-gp efflux of Ligand B are less concerning given its superior binding.

Output:
1
2025-04-17 06:57:01,791 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (349.391 and 346.431 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (117.43) is slightly above the preferred <90 for CNS targets, but still reasonable. Ligand B (107.11) is better, falling comfortably below 90.

**3. logP:** Ligand A (-0.219) is quite low, potentially hindering membrane permeability. Ligand B (0.743) is within the optimal 1-3 range. This is a significant advantage for Ligand B.

**4. H-Bond Donors:** Ligand A (2) and Ligand B (4) are both acceptable, being less than 5.

**5. H-Bond Acceptors:** Ligand A (6) and Ligand B (4) are both acceptable, being less than 10.

**6. QED:** Both ligands have good QED scores (0.627 and 0.57), indicating drug-like properties.

**7. DILI:** Both have low DILI risk (37.999 and 30.826), which is positive.

**8. BBB:** Ligand A (53.974) has a moderate BBB penetration, while Ligand B (28.306) is quite low. This is a major drawback for Ligand B, given DRD2 is a CNS target.

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.419 and -5.614), which is unusual and suggests poor permeability. However, these values are on a log scale and can be misleading without context.

**10. Aqueous Solubility:** Both ligands have very poor aqueous solubility (-1.132 and -1.559). This is a concern for formulation and bioavailability.

**11. hERG Inhibition:** Both ligands show very low hERG inhibition risk (0.015 and 0.069).

**12. Microsomal Clearance:** Ligand A (8.968) has a moderate clearance, while Ligand B (-12.922) has a negative clearance, which is not physically possible and likely indicates an issue with the data or model.

**13. In vitro Half-Life:** Ligand A (7.283) has a reasonable half-life, while Ligand B (-7.425) has a negative half-life, again indicating a data issue.

**14. P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.004 and 0.011), which is favorable for CNS penetration.

**15. Binding Affinity:** Ligand A (-8.3 kcal/mol) has a slightly better binding affinity than Ligand B (-8.8 kcal/mol). While the difference is not huge, it's a consideration.

**Overall Assessment:**

Ligand B has a better logP and TPSA, but suffers from a very poor BBB score, negative clearance and half-life values, which are highly problematic. Ligand A has a lower logP, but a more reasonable BBB score, and positive clearance/half-life values. The negative values for clearance and half-life for Ligand B suggest a serious issue with the data or the prediction model, making it unreliable. While Ligand A's logP is suboptimal, its better BBB penetration and more reliable ADME properties make it the more promising candidate.

Output:
0
2025-04-17 06:57:01,792 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B based on the provided guidelines, prioritizing GPCR properties (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (349.391) is slightly lower, which could be beneficial for permeability.

**TPSA:** Ligand A (137.07) is close to the upper limit for good oral absorption and acceptable for CNS targets, while Ligand B (62.3) is excellent, well below the 90 A^2 threshold for CNS targets. This favors Ligand B.

**logP:** Ligand A (-0.336) is below the optimal range (1-3) and could indicate poor membrane permeability. Ligand B (2.463) is within the optimal range. This strongly favors Ligand B.

**H-Bond Donors/Acceptors:** Ligand A has 4 HBD and 6 HBA, which are acceptable. Ligand B has 1 HBD and 4 HBA, also acceptable. No clear advantage here.

**QED:** Both ligands have good QED scores (A: 0.507, B: 0.821), indicating drug-like properties. Ligand B is better.

**DILI:** Both ligands have relatively high DILI risk (A: 51.144, B: 60.682), but are still below the concerning 60 threshold. No major difference.

**BBB:** Ligand A (18.845) has a very low BBB penetration percentile, making it unlikely to effectively reach the CNS target. Ligand B (83.404) has excellent BBB penetration. This is a critical advantage for a CNS target like DRD2.

**Caco-2 Permeability:** Ligand A (-5.842) has very poor Caco-2 permeability, consistent with its low logP. Ligand B (-4.57) is also poor, but better than A.

**Aqueous Solubility:** Both have poor aqueous solubility (A: -1.682, B: -4.173). This could pose formulation challenges.

**hERG Inhibition:** Both ligands have very low hERG inhibition risk (A: 0.018, B: 0.262).

**Microsomal Clearance:** Ligand A (1.382) has lower microsomal clearance, suggesting better metabolic stability than Ligand B (30.751).

**In vitro Half-Life:** Ligand A (-29.124) has a very short in vitro half-life, while Ligand B (-8.709) is better, but still not ideal.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (A: 0.023, B: 0.032).

**Binding Affinity:** Both ligands have similar and strong binding affinities (A: -8.4 kcal/mol, B: -8.1 kcal/mol). The difference of 0.3 kcal/mol is not substantial enough to outweigh other factors.

**Overall Assessment:**

Ligand B is significantly more promising due to its superior BBB penetration, optimal logP, and better TPSA. While Ligand A has slightly better metabolic stability, the poor CNS penetration and low logP are major drawbacks for a DRD2 (CNS target) drug candidate. The similar binding affinities make the ADME properties the deciding factor.

Output:
1
2025-04-17 06:57:01,792 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (340.398 and 341.411 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (55.13) is excellent, well below the 90 A^2 threshold for CNS targets. Ligand B (82.27) is still reasonable, but less optimal.

**3. logP:** Ligand A (4.659) is slightly high, potentially leading to solubility issues or off-target interactions. Ligand B (1.375) is low, which might hinder membrane permeability.

**4. H-Bond Donors:** Ligand A (1) is good. Ligand B (2) is also acceptable.

**5. H-Bond Acceptors:** Both ligands have 3 HBA, which is within the acceptable range.

**6. QED:** Ligand A (0.884) has a very strong drug-like profile. Ligand B (0.466) is below the 0.5 threshold, indicating a less favorable drug-like profile.

**7. DILI:** Ligand A (71.113) has a moderate DILI risk. Ligand B (38.309) has a low DILI risk, which is a significant advantage.

**8. BBB:** Ligand A (88.29) has excellent BBB penetration potential, crucial for a CNS target like DRD2. Ligand B (35.673) has very poor predicted BBB penetration.

**9. Caco-2:** Both have negative Caco-2 values which is unusual and suggests a problem with the prediction method.

**10. Solubility:** Both have negative solubility values which is unusual and suggests a problem with the prediction method.

**11. hERG:** Ligand A (0.776) has a low hERG risk. Ligand B (0.362) also has a low hERG risk.

**12. Cl_mic:** Ligand A (64.671) has moderate microsomal clearance. Ligand B (-2.243) has very low (and potentially unrealistic) clearance, suggesting high metabolic stability.

**13. t1/2:** Ligand A (76.441) has a good in vitro half-life. Ligand B (-24.15) has a very short (and potentially unrealistic) half-life.

**14. Pgp:** Ligand A (0.882) has moderate P-gp efflux liability. Ligand B (0.11) has very low P-gp efflux liability, which is beneficial for CNS exposure.

**15. Binding Affinity:** Both ligands have very strong binding affinities (-9.5 and -8.9 kcal/mol). The difference of 0.6 kcal/mol is not substantial enough to override other significant differences.

**Overall Assessment:**

Ligand A excels in BBB penetration, QED, and has a good half-life. Its logP is a slight concern. Ligand B has a better DILI score and lower Pgp efflux, but suffers from poor BBB penetration and a low QED score. For a CNS target like DRD2, BBB penetration is paramount. The strong affinity of both compounds is positive, but the poor BBB score of Ligand B is a deal-breaker.

Output:
1
2025-04-17 06:57:01,792 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (343.471 and 350.467 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (62.3) is excellent, well below the 90 A^2 threshold for CNS targets. Ligand B (83.36) is higher, but still potentially acceptable, though less ideal.

**3. logP:** Ligand A (3.315) is optimal. Ligand B (0.29) is quite low, which could hinder membrane permeability and CNS penetration.

**4. H-Bond Donors:** Both ligands have 1 HBD, which is within the acceptable limit of <=5.

**5. H-Bond Acceptors:** Ligand A has 3 HBAs, and Ligand B has 6 HBAs. Both are within the acceptable limit of <=10.

**6. QED:** Both ligands have QED values above 0.5 (0.773 and 0.692), indicating good drug-like properties.

**7. DILI:** Ligand A (32.028) has a lower DILI risk than Ligand B (19.038), which is preferable.

**8. BBB:** Ligand A (59.364) has a better BBB percentile than Ligand B (48.74), though neither are >70. This is a critical factor for CNS targets like DRD2.

**9. Caco-2 Permeability:** Ligand A (-4.694) has a worse Caco-2 permeability than Ligand B (-5.399).

**10. Aqueous Solubility:** Ligand A (-3.246) has a better aqueous solubility than Ligand B (0.001).

**11. hERG Inhibition:** Ligand A (0.218) has a lower hERG inhibition liability than Ligand B (0.087), which is favorable.

**12. Microsomal Clearance:** Ligand B (-12.52) has a much lower (better) microsomal clearance than Ligand A (38.804), indicating greater metabolic stability.

**13. In vitro Half-Life:** Ligand B (1.563) has a longer in vitro half-life than Ligand A (-4.891).

**14. P-gp Efflux:** Ligand A (0.066) has a lower P-gp efflux liability than Ligand B (0.012), which is preferable for CNS penetration.

**15. Binding Affinity:** Ligand A (-8.3 kcal/mol) has a significantly stronger binding affinity than Ligand B (-7.5 kcal/mol). This is a substantial advantage.

**Overall Assessment:**

While Ligand B has better metabolic stability (lower Cl_mic, longer t1/2) and slightly better Caco-2 permeability, Ligand A is significantly better overall, especially considering the GPCR-specific priorities. Ligand A has a much stronger binding affinity, better BBB penetration, lower DILI risk, and lower hERG inhibition. The lower logP of Ligand B is a major concern for CNS penetration. The affinity difference is also quite large (>1 kcal/mol), which can often outweigh minor ADME drawbacks.

Output:
1
2025-04-17 06:57:01,792 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (341.39 and 341.411 Da) fall comfortably within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (83.6) is better than Ligand B (54.78). For CNS targets, we want TPSA <= 90, both are within this range, but A is closer to the upper limit.

**3. logP:** Ligand A (2.38) is optimal (1-3), while Ligand B (0.591) is a bit low, potentially hindering permeation.

**4. H-Bond Donors:** Ligand A (1) and Ligand B (0) are both acceptable (<=5).

**5. H-Bond Acceptors:** Ligand A (5) and Ligand B (4) are both acceptable (<=10).

**6. QED:** Ligand A (0.874) is significantly better than Ligand B (0.514), indicating a more drug-like profile.

**7. DILI:** Ligand A (56.727) has a higher DILI risk than Ligand B (19.465). This is a concern for Ligand A.

**8. BBB:** Ligand A (81.039) has a much better BBB penetration percentile than Ligand B (62.233). This is *critical* for a CNS target like DRD2.

**9. Caco-2:** Ligand A (-4.685) and Ligand B (-4.57) are both very poor. This suggests very poor intestinal absorption for both.

**10. Solubility:** Ligand A (-4.121) and Ligand B (-1.312) are both poor.

**11. hERG:** Both ligands have low hERG inhibition risk (0.418 and 0.236).

**12. Cl_mic:** Ligand A (22.004) has a higher microsomal clearance than Ligand B (17.19), suggesting lower metabolic stability.

**13. t1/2:** Ligand A (0.014) has a very short half-life, while Ligand B (8.169) is better.

**14. Pgp:** Ligand A (0.222) has lower P-gp efflux than Ligand B (0.039), which is favorable for CNS penetration.

**15. Binding Affinity:** Ligand A (-9.3 kcal/mol) has a significantly stronger binding affinity than Ligand B (-7.5 kcal/mol). This is a substantial advantage.

**Overall Assessment:**

Despite Ligand A's higher DILI risk and lower metabolic stability, its *significantly* stronger binding affinity (-9.3 vs -7.5 kcal/mol) and superior BBB penetration (81.039 vs 62.233) are decisive factors. The affinity difference is large enough to potentially overcome the ADME liabilities, especially given the importance of potency for GPCR targets. Ligand B's low logP is a significant concern.

Output:
1
2025-04-17 06:57:01,792 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (365.905 and 351.422 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (52.65) is significantly better than Ligand B (75.44). For CNS targets, we want TPSA <= 90, and ideally closer to 60. Ligand A is much closer to this ideal.

**logP:** Both ligands have acceptable logP values (3.866 and 2.161), falling within the 1-3 range. Ligand A is slightly higher, which could be beneficial for membrane permeability, but isn't a major concern for either.

**H-Bond Donors/Acceptors:** Both ligands have 1 HBD and a reasonable number of HBAs (2 for A, 4 for B), satisfying the <=5 and <=10 rules respectively.

**QED:** Both ligands have similar QED values (0.884 and 0.882), indicating good drug-likeness.

**DILI:** Ligand A (43.273) has a slightly higher DILI risk than Ligand B (34.277), but both are below the concerning threshold of 60.

**BBB:** Both ligands exhibit excellent BBB penetration (87.941 and 82.745), which is crucial for a CNS target like DRD2. Ligand A is slightly better.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values which is unusual and suggests a potential issue with the data. However, we can still compare them. Ligand A (-4.52) is slightly better than Ligand B (-4.934).

**Aqueous Solubility:** Ligand A (-4.588) is slightly better than Ligand B (-1.905).

**hERG:** Ligand A (0.751) has a slightly higher hERG risk than Ligand B (0.25), but both are relatively low.

**Microsomal Clearance:** Ligand B (19.875) has significantly lower microsomal clearance than Ligand A (46.02), suggesting better metabolic stability. This is a significant advantage for Ligand B.

**In vitro Half-Life:** Ligand B (-30.147) has a significantly longer in vitro half-life than Ligand A (60.57), further supporting its better metabolic stability.

**P-gp Efflux:** Ligand A (0.097) has lower P-gp efflux than Ligand B (0.192), which is favorable for CNS penetration.

**Binding Affinity:** Both ligands have excellent binding affinities (-8.6 and -8.0 kcal/mol). Ligand A has a 0.6 kcal/mol advantage, which is substantial and can outweigh some ADME drawbacks.

**Overall Assessment:**

Ligand A excels in TPSA, BBB penetration, P-gp efflux, and crucially, binding affinity. Ligand B shines in metabolic stability (lower Cl_mic and longer t1/2). Given the GPCR-specific priorities, the strong binding affinity of Ligand A and its favorable BBB and P-gp properties are highly desirable. While Ligand B's metabolic stability is attractive, the difference in affinity is significant enough to favor Ligand A. The slightly higher DILI risk of Ligand A is acceptable given its other advantages.

Output:
1
2025-04-17 06:57:01,793 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (382.287 Da and 361.471 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (49.77) is excellent, well below the 90 A^2 threshold for CNS targets. Ligand B (78.43) is higher but still reasonably good, though less optimal.

**logP:** Ligand A (4.092) is at the upper end of the optimal range (1-3), potentially leading to solubility issues. Ligand B (1.149) is slightly below the optimal range, which could affect permeability.

**H-Bond Donors/Acceptors:** Both have acceptable HBD counts (1). Ligand A has 4 HBA, which is good. Ligand B has 6 HBA, which is also acceptable but slightly higher.

**QED:** Both ligands have good QED scores (0.699 and 0.87), indicating good drug-like properties.

**DILI:** Ligand A (26.289) has a very low DILI risk, which is excellent. Ligand B (52.423) is still reasonably low, but higher than Ligand A.

**BBB:** Ligand A (57.619) has a moderate BBB penetration, which is concerning for a CNS target like DRD2. Ligand B (62.233) is also moderate, but slightly better than Ligand A.

**Caco-2 Permeability:** Both have negative Caco-2 values (-4.616 and -4.983), which is unusual and suggests poor permeability. This is a significant drawback for both.

**Aqueous Solubility:** Both have negative solubility values (-4.265 and -2.508), indicating very poor aqueous solubility. This is a major concern.

**hERG Inhibition:** Ligand A (0.886) has a low hERG risk, which is good. Ligand B (0.187) has a very low hERG risk, which is excellent.

**Microsomal Clearance:** Ligand B (38.015) has significantly lower microsomal clearance than Ligand A (82.26), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (47.653) has a better in vitro half-life than Ligand B (6.331).

**P-gp Efflux:** Ligand A (0.591) has lower P-gp efflux than Ligand B (0.064), which is desirable for CNS penetration.

**Binding Affinity:** Ligand B (-9.5 kcal/mol) has a significantly stronger binding affinity than Ligand A (-7.9 kcal/mol). This is a substantial advantage, potentially outweighing some ADME drawbacks.

**Overall Assessment:**

Ligand B is the stronger candidate despite some ADME concerns. The significantly improved binding affinity (-9.5 vs -7.9 kcal/mol) is a major advantage for a GPCR target. While both ligands have poor solubility and permeability (negative Caco-2 and solubility values), the better metabolic stability (lower Cl_mic) and lower P-gp efflux of Ligand B are beneficial. The slightly better BBB value of Ligand B is also a plus. Ligand A's lower DILI risk is good, but the affinity difference is more critical. Addressing the solubility and permeability issues through formulation or structural modifications would be the next step with Ligand B.

Output:
1
2025-04-17 06:57:01,793 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B based on the provided guidelines, prioritizing GPCR-specific properties (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (345.443 Da) is slightly lower, which could be beneficial for permeability.

**TPSA:** Ligand A (71.53) is significantly better than Ligand B (92.78). For CNS targets, we want TPSA <= 90, so Ligand A is preferable.

**logP:** Ligand A (2.389) is optimal (1-3), while Ligand B (0.343) is quite low, potentially hindering permeation. This is a significant advantage for Ligand A.

**H-Bond Donors/Acceptors:** Both have acceptable HBD (1) and HBA (4 for A, 5 for B) counts.

**QED:** Both ligands have good QED scores (0.824 and 0.726, both > 0.5).

**DILI:** Both have low DILI risk (35.983 and 32.571, both < 40).

**BBB:** Ligand A (83.986) is much better than Ligand B (68.321). A BBB percentile >70 is desirable for CNS targets, and Ligand A is closer to this threshold.

**Caco-2 Permeability:** Ligand A (-4.638) is better than Ligand B (-5.022), indicating better intestinal absorption.

**Aqueous Solubility:** Ligand A (-2.574) is better than Ligand B (-1.265).

**hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.486 and 0.099).

**Microsomal Clearance:** Ligand B (-6.708) has a negative value, indicating potentially *lower* clearance and better metabolic stability than Ligand A (25.673). This is a positive for Ligand B.

**In vitro Half-Life:** Ligand B (18.202) has a longer half-life than Ligand A (-1.996). This is a positive for Ligand B.

**P-gp Efflux:** Both have very low P-gp efflux liability (0.141 and 0.027).

**Binding Affinity:** Ligand B (-8.2) has a slightly better binding affinity than Ligand A (-8.0). However, the difference is small (0.2 kcal/mol) and may not be enough to overcome the other significant drawbacks of Ligand B.

**Overall Assessment:**

Ligand A is significantly better overall, particularly regarding TPSA, logP, and BBB penetration, all crucial for a CNS-targeting GPCR ligand. While Ligand B has better metabolic stability and half-life, the poor logP and lower BBB penetration are major concerns. The small difference in binding affinity is unlikely to compensate for these deficiencies.

Output:
1
2025-04-17 06:57:01,793 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B based on the provided guidelines, prioritizing GPCR-specific properties (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (350.48 and 352.39 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (49.41) is excellent for CNS penetration (<90), while Ligand B (102.96) is higher, but still potentially acceptable.

**logP:** Ligand A (3.512) is optimal (1-3). Ligand B (0.224) is significantly low, which could hinder membrane permeability and potentially reduce binding affinity.

**H-Bond Donors/Acceptors:** Ligand A (HBD=1, HBA=2) is good. Ligand B (HBD=2, HBA=6) is also reasonable, but the higher HBA could slightly impact permeability.

**QED:** Ligand A (0.797) is excellent, indicating good drug-likeness. Ligand B (0.368) is below the desirable threshold of 0.5, suggesting a less favorable drug-like profile.

**DILI:** Ligand A (20.822) has a very low DILI risk. Ligand B (51.338) is higher, indicating a moderate risk, but still not alarming.

**BBB:** Ligand A (96.161) has excellent predicted BBB penetration, crucial for a CNS target like DRD2. Ligand B (60.45) is considerably lower, raising concerns about sufficient CNS exposure.

**Caco-2 Permeability:** Ligand A (-4.674) is concerningly low, suggesting poor intestinal absorption. Ligand B (-5.494) is also low, but slightly better than A.

**Aqueous Solubility:** Ligand A (-3.903) and Ligand B (-1.878) both have negative solubility values, indicating poor aqueous solubility. This could pose formulation challenges.

**hERG Inhibition:** Ligand A (0.644) and Ligand B (0.098) both show low hERG inhibition risk.

**Microsomal Clearance:** Ligand A (31.187) has a moderate clearance, while Ligand B (20.695) is lower, suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (-1.145) has a short half-life, which could necessitate frequent dosing. Ligand B (-17.196) has a very short half-life, even more concerning than A.

**P-gp Efflux:** Ligand A (0.27) has low P-gp efflux, which is favorable for CNS penetration. Ligand B (0.044) also has low P-gp efflux.

**Binding Affinity:** Both ligands have comparable binding affinities (-7.9 kcal/mol and -7.8 kcal/mol). The difference is negligible.

**Overall Assessment:**

Ligand A is significantly better due to its superior BBB penetration, optimal logP, and excellent QED score. While its Caco-2 permeability and in vitro half-life are concerns, the strong BBB score and good affinity outweigh these drawbacks for a CNS-targeted GPCR. Ligand B's low logP and poor QED are major liabilities, and its lower BBB penetration further diminishes its potential. The slightly better metabolic stability of B is not enough to compensate for these issues.

Output:
1
2025-04-17 06:57:01,793 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (339.366 Da) is slightly lower, which could be advantageous for permeability. Ligand B (363.483 Da) is also good.

**TPSA:** Ligand A (48.3) is excellent, well below the 90 A^2 threshold for CNS targets. Ligand B (78.51) is still reasonable, but less optimal, being closer to the 140 A^2 threshold for oral absorption.

**logP:** Ligand A (3.163) is within the optimal range (1-3). Ligand B (1.666) is at the lower end of the optimal range, potentially impacting permeability.

**H-Bond Donors/Acceptors:** Ligand A (0 HBD, 4 HBA) and Ligand B (2 HBD, 4 HBA) both have acceptable numbers of H-bond donors and acceptors.

**QED:** Both ligands have good QED scores (Ligand A: 0.671, Ligand B: 0.755), indicating good drug-like properties.

**DILI:** Ligand A (75.184) has a higher DILI risk than Ligand B (36.681), which is a significant concern.

**BBB:** Ligand A (82.823) has a significantly better BBB penetration score than Ligand B (56.689). This is crucial for a CNS target like DRD2.

**Caco-2 Permeability:** Ligand A (-4.462) has poor Caco-2 permeability, while Ligand B (-5.393) is also poor, but slightly worse.

**Aqueous Solubility:** Ligand A (-4.491) has poor aqueous solubility, while Ligand B (-1.85) is slightly better, but still poor.

**hERG Inhibition:** Ligand A (0.783) has a slightly higher hERG risk than Ligand B (0.196), but both are relatively low.

**Microsomal Clearance:** Ligand A (91.215) has higher microsomal clearance, indicating faster metabolism, than Ligand B (52.858).

**In vitro Half-Life:** Ligand A (-0.475) has a very short in vitro half-life, while Ligand B (14.953) has a much longer half-life.

**P-gp Efflux:** Ligand A (0.545) has lower P-gp efflux, which is favorable for CNS penetration, than Ligand B (0.066).

**Binding Affinity:** Both ligands have excellent binding affinities (-9.9 kcal/mol and -9.0 kcal/mol, respectively). Ligand A has a slightly better affinity.

**Overall Assessment:**

Ligand A excels in TPSA, BBB, P-gp efflux, and binding affinity. However, its high DILI risk, poor Caco-2 permeability, poor solubility, and short half-life are major drawbacks.

Ligand B has a lower DILI risk, better half-life, and slightly better solubility. However, it has a lower BBB score, higher P-gp efflux, and a slightly weaker binding affinity.

Given the importance of BBB penetration for a CNS target, and the significant DILI risk associated with Ligand A, **Ligand B is the more promising candidate despite its slightly lower affinity and BBB score.** The lower DILI and improved metabolic stability are critical factors. Further optimization of Ligand B could focus on improving its BBB penetration and affinity.

Output:
1
2025-04-17 06:57:01,794 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (343.383 Da) is slightly lower, which could be beneficial for permeability.

**TPSA:** Ligand A (111.45) is better than Ligand B (139.34). For CNS targets, TPSA should be <= 90, so Ligand A is closer to this threshold.

**logP:** Ligand A (0.194) is quite low, potentially hindering membrane permeability. Ligand B (-1.119) is also low, but slightly better than A. Both are below the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A has 3 HBD and 5 HBA, while Ligand B has 4 HBD and 6 HBA. Both are within acceptable limits.

**QED:** Ligand A (0.584) has a better QED score than Ligand B (0.485), indicating a more drug-like profile.

**DILI:** Ligand A (33.85) has a significantly lower DILI risk than Ligand B (42.691), which is a major advantage.

**BBB:** Ligand B (37.96) has a much better BBB penetration percentile than Ligand A (14.153). This is a critical factor for a CNS target like DRD2.

**Caco-2 Permeability:** Ligand A (-4.918) has a worse Caco-2 permeability than Ligand B (-5.834). Both are poor, but B is slightly better.

**Aqueous Solubility:** Ligand A (-2.543) has better solubility than Ligand B (-1.356).

**hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.27 and 0.058 respectively).

**Microsomal Clearance:** Ligand A (4.707) has a lower microsomal clearance than Ligand B (1.481), indicating better metabolic stability.

**In vitro Half-Life:** Both ligands have negative half-lives (-8.417 and -8.867), which is unusual and likely indicates a rapid degradation. Ligand B has a slightly more negative value, suggesting faster degradation.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.036 and 0.01 respectively).

**Binding Affinity:** Ligand B (-8.7 kcal/mol) has a significantly stronger binding affinity than Ligand A (-6.5 kcal/mol). This is a substantial difference (>1.5 kcal/mol) and is a major driving force.

**Overall Assessment:**

Ligand B excels in binding affinity and BBB penetration, which are crucial for a CNS-targeting GPCR. While its logP is still suboptimal, the strong binding affinity might compensate. Ligand A has better DILI and metabolic stability, but its poor BBB penetration is a significant drawback for a CNS drug. The difference in binding affinity is large enough to outweigh the benefits of A's slightly better ADME properties.

Output:
1
2025-04-17 06:57:01,794 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 drug candidates, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (364.511 and 348.399 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (67.43) is significantly better than Ligand B (81.01). For CNS targets, we want TPSA <= 90, and A is closer to the ideal <=60 range. B is pushing the upper limit.

**3. logP:** Ligand A (3.656) is optimal (1-3), while Ligand B (0.887) is a bit low, potentially hindering membrane permeability.

**4. H-Bond Donors:** Both ligands have acceptable HBD counts (2 and 1, respectively), well below the threshold of 5.

**5. H-Bond Acceptors:** Both ligands have acceptable HBA counts (4 and 5, respectively), well below the threshold of 10.

**6. QED:** Both ligands have good QED scores (0.757 and 0.772), indicating good drug-like properties.

**7. DILI:** Ligand A (41.915) has a lower DILI risk than Ligand B (60.101). Both are acceptable, but A is preferable.

**8. BBB:** Ligand A (73.866) has a significantly better BBB penetration percentile than Ligand B (46.413). This is *critical* for a CNS target like DRD2.

**9. Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and suggests a potential issue with the data or modeling. However, the values are close enough to not be a major differentiator.

**10. Aqueous Solubility:** Both have negative solubility values, which is also unusual. Again, difficult to interpret, but not a major differentiator.

**11. hERG:** Both ligands have very low hERG risk (0.523 and 0.158).

**12. Microsomal Clearance:** Ligand A (92.79) has higher microsomal clearance than Ligand B (0.757), suggesting lower metabolic stability. This is a drawback for A.

**13. In vitro Half-Life:** Ligand B (21.185) has a longer in vitro half-life than Ligand A (11.971). This is a positive for B.

**14. P-gp Efflux:** Ligand A (0.15) has lower P-gp efflux liability than Ligand B (0.072), which is favorable for CNS penetration.

**15. Binding Affinity:** Ligand B (-7.8 kcal/mol) has a slightly better binding affinity than Ligand A (-8.1 kcal/mol). While A is better, the difference is small.

**Overall Assessment:**

Considering the GPCR-specific priorities, Ligand A is the stronger candidate. Its superior BBB penetration, lower DILI risk, and lower P-gp efflux outweigh its slightly higher clearance and slightly weaker affinity. The TPSA and logP values for A are also more favorable. While the Caco-2 and solubility values are concerning for both, the differences in CNS-relevant properties are more impactful.

Output:
1
2025-04-17 06:57:01,794 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (342.37 and 352.475 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (49.85) is excellent, well below the 90 A^2 threshold for CNS targets. Ligand B (67.87) is still reasonable, but less optimal.

**3. logP:** Ligand A (2.922) is within the optimal 1-3 range. Ligand B (1.724) is slightly lower, potentially impacting permeability, but not critically.

**4. H-Bond Donors:** Both ligands have acceptable HBD counts (0 for A, 1 for B), well below the 5 threshold.

**5. H-Bond Acceptors:** Both ligands have acceptable HBA counts (3 for A, 4 for B), below the 10 threshold.

**6. QED:** Both ligands have good QED scores (0.858 and 0.79), indicating drug-like properties.

**7. DILI:** Ligand A (77.123) has a higher DILI risk than Ligand B (15.82), which is a significant concern.

**8. BBB:** Both ligands have excellent BBB penetration (89.492 and 81.698), exceeding the >70% threshold for CNS targets.

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 values, which is unusual and requires further investigation. However, we can proceed with relative comparison.

**10. Aqueous Solubility:** Both ligands have negative solubility values, also unusual. This is a potential formulation challenge for both.

**11. hERG Inhibition:** Both ligands have low hERG inhibition risk (0.708 and 0.297).

**12. Microsomal Clearance:** Ligand A (33.385) has higher microsomal clearance than Ligand B (15.196), suggesting lower metabolic stability.

**13. In vitro Half-Life:** Ligand B (-0.111) has a slightly better (less negative) in vitro half-life than Ligand A (-23.973).

**14. P-gp Efflux:** Both ligands have low P-gp efflux liability (0.369 and 0.034), which is favorable for CNS penetration.

**15. Binding Affinity:** Ligand A (-8.8 kcal/mol) has a significantly stronger binding affinity than Ligand B (-7.7 kcal/mol). This 1.1 kcal/mol difference is substantial and could outweigh some ADME drawbacks.

**Overall Assessment:**

Ligand A has a superior binding affinity and excellent BBB penetration and TPSA. However, its higher DILI risk and lower metabolic stability (higher Cl_mic, shorter half-life) are concerning. Ligand B has a better safety profile (lower DILI) and better metabolic stability, but its binding affinity is weaker and TPSA is slightly higher.

Given the importance of potency for GPCR ligands, and the substantial affinity difference, I would prioritize Ligand A *despite* the DILI risk. The DILI risk could potentially be mitigated through structural modifications during lead optimization. The strong binding affinity provides a better starting point for optimization.

Output:
1
2025-04-17 06:57:01,794 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (343.43 & 350.37 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (73.74) is significantly better than Ligand B (87.14). For CNS targets, we want TPSA <= 90, and A is comfortably within that, while B is approaching the upper limit.

**3. logP:** Both ligands have acceptable logP values (1.53 & 2.43), falling within the optimal 1-3 range.

**4. H-Bond Donors:** Ligand A (1) is preferable to Ligand B (3). Fewer HBDs generally improve permeability.

**5. H-Bond Acceptors:** Ligand A (4) is preferable to Ligand B (5). Fewer HBAs generally improve permeability.

**6. QED:** Both ligands have reasonable QED values (0.84 & 0.75), indicating good drug-like properties.

**7. DILI:** Ligand A (38.81) has a much lower DILI risk than Ligand B (61.19). This is a significant advantage for A.

**8. BBB:** Ligand A (52.27) has a slightly better BBB percentile than Ligand B (48.28), though both are below the desirable >70 for CNS targets. However, given the other factors, this difference is less critical.

**9. Caco-2:** Ligand A (-4.65) has a better (less negative) Caco-2 permeability value than Ligand B (-5.20).

**10. Solubility:** Ligand A (-1.17) has a better (less negative) solubility value than Ligand B (-3.82). Better solubility is generally preferred.

**11. hERG:** Both ligands have very low hERG inhibition liability (0.27 & 0.55), indicating a low risk of cardiotoxicity.

**12. Cl_mic:** Ligand A (15.57) has a significantly lower microsomal clearance than Ligand B (57.71). This suggests better metabolic stability for Ligand A.

**13. t1/2:** Ligand A (-2.94) has a better (less negative) in vitro half-life than Ligand B (-21.91). This suggests better in vitro stability for Ligand A.

**14. Pgp:** Ligand A (0.08) has a much lower Pgp efflux liability than Ligand B (0.06). Lower Pgp efflux is crucial for CNS penetration.

**15. Binding Affinity:** Both ligands have excellent binding affinities (-8.8 & -9.2 kcal/mol). Ligand B is slightly better, but the difference is relatively small and can be outweighed by other factors.

**Overall Assessment:**

Ligand A is the stronger candidate. While Ligand B has slightly better binding affinity, Ligand A excels in almost all ADME properties critical for a CNS-targeting GPCR ligand. Specifically, its lower TPSA, DILI risk, Pgp efflux, and microsomal clearance, coupled with better solubility and half-life, make it a more promising drug candidate. The slightly lower BBB score for A is less concerning given its superior profile in other key areas.

Output:
1
2025-04-17 06:57:01,795 - INFO - Batch 324 complete. Total preferences: 5184
2025-04-17 06:57:01,795 - INFO - Processing batch 325/512...
2025-04-17 06:57:43,685 - INFO - Reasoning:

Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (374.819 and 345.403 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (78.67) is significantly better than Ligand B (88.83). For CNS targets, we want TPSA <= 90, and A is closer to the optimal range.

**3. logP:** Both ligands have acceptable logP values (1.979 and 0.733), falling within the 1-3 range.

**4. H-Bond Donors:** Both ligands have reasonable HBD counts (2 and 1, respectively), well below the threshold of 5.

**5. H-Bond Acceptors:** Ligand B (6) is slightly higher than Ligand A (3), but both are within the acceptable limit of 10.

**6. QED:** Both ligands have similar and good QED values (0.827 and 0.799), indicating good drug-like properties.

**7. DILI:** Ligand A (39.938) has a much lower DILI risk than Ligand B (57.193). Both are below 60, but A is preferable.

**8. BBB:** This is a critical parameter for CNS targets. Ligand A (85.498) has a significantly higher BBB penetration percentile than Ligand B (57.193).  A value >70 is desirable, and A is much closer.

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 values, which is unusual and suggests poor permeability. However, the scale is not specified, so it's hard to interpret.

**10. Aqueous Solubility:** Both ligands have negative solubility values, which is also unusual and suggests poor solubility. Again, the scale is not specified.

**11. hERG Inhibition:** Both ligands have low hERG inhibition liability (0.679 and 0.252), which is good.

**12. Microsomal Clearance:** Ligand B (16.289) has a much higher microsomal clearance than Ligand A (0.006). This indicates Ligand A is much more metabolically stable.

**13. In vitro Half-Life:** Ligand A (-14.728) has a much longer in vitro half-life than Ligand B (10.009).

**14. P-gp Efflux:** Ligand A (0.037) has lower P-gp efflux liability than Ligand B (0.014), which is favorable for CNS penetration.

**15. Binding Affinity:** Both ligands have very similar and strong binding affinities (-8.2 kcal/mol and -8.1 kcal/mol). The difference is negligible.

**Overall Assessment:**

Ligand A is clearly superior. It has a better TPSA, lower DILI risk, significantly better BBB penetration, much lower microsomal clearance, longer half-life, and lower P-gp efflux. While both have similar affinity, the ADME properties of Ligand A make it a much more promising drug candidate for a CNS target like DRD2. The negative solubility and Caco-2 values are concerning for both, but the other advantages of A outweigh these issues.

Output:
1
2025-04-17 06:57:43,686 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (381.395 Da) is slightly higher than Ligand B (347.459 Da), but both are acceptable.

**TPSA:** Ligand A (62.3) is excellent for CNS penetration, well below the 90 A^2 threshold. Ligand B (72.88) is still reasonable, but less optimal.

**logP:** Both ligands have good logP values (A: 2.392, B: 1.241), falling within the 1-3 range.

**H-Bond Donors/Acceptors:** Both have acceptable HBD (A:1, B:2) and HBA (A:4, B:4) counts, well below the thresholds of 5 and 10, respectively.

**QED:** Both ligands have similar and good QED values (A: 0.738, B: 0.705), indicating good drug-like properties.

**DILI:** Ligand A (46.103) has a moderate DILI risk, while Ligand B (8.026) has a very low risk. This is a significant advantage for Ligand B.

**BBB:** Ligand A (74.719) has a good BBB penetration percentile, exceeding the 70% threshold. Ligand B (46.413) is considerably lower, which is a major drawback for a CNS target.

**Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and suggests poor permeability. However, the scale isn't specified, so it's hard to interpret.

**Aqueous Solubility:** Both ligands have negative solubility values, which is also unusual and suggests poor solubility. Again, the scale is unclear.

**hERG:** Both ligands show low hERG inhibition liability (A: 0.305, B: 0.376), which is favorable.

**Microsomal Clearance:** Ligand A (17.899) has a moderate clearance, while Ligand B (-0.643) has a negative clearance, suggesting very high metabolic stability. This is a strong advantage for Ligand B.

**In vitro Half-Life:** Ligand A (-28.489) has a negative half-life, which is not possible. Ligand B (-4.39) also has a negative half-life, indicating issues with the data.

**P-gp Efflux:** Both ligands show low P-gp efflux liability (A: 0.107, B: 0.012), which is good for CNS penetration.

**Binding Affinity:** Both ligands have very strong binding affinities (A: -8.7 kcal/mol, B: -8.4 kcal/mol). The difference of 0.3 kcal/mol is not substantial enough to outweigh other factors.

**Overall Assessment:**

Ligand B has several advantages: significantly lower DILI risk, much better metabolic stability (Cl_mic), and lower P-gp efflux. While its BBB penetration is lower than Ligand A, the superior safety and pharmacokinetic properties are more important for overall drug development. The negative values for Caco-2 and solubility are concerning for both, but the other advantages of B are more compelling. The negative half-life values for both are likely data errors.

Output:
1
2025-04-17 06:57:43,686 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (366.571 and 385.512 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (49.41) is excellent, well below the 90 A^2 threshold for CNS targets. Ligand B (69.64) is still reasonable, but less optimal.

**logP:** Ligand A (3.657) is within the optimal 1-3 range. Ligand B (2.088) is slightly lower, potentially impacting permeability, but still acceptable.

**H-Bond Donors/Acceptors:** Ligand A has 1 HBD and 3 HBA, which are good values. Ligand B has 0 HBD and 6 HBA, also acceptable, though the higher HBA count could slightly affect permeability.

**QED:** Ligand A (0.748) has a very good drug-likeness score. Ligand B (0.552) is still above the 0.5 threshold, but less favorable.

**DILI:** Ligand A (41.373) has a low DILI risk. Ligand B (29.895) has an even lower DILI risk, which is excellent.

**BBB:** Ligand A (72.005) has a good BBB penetration score, exceeding the 70% threshold. Ligand B (96.006) is *excellent*, significantly higher, and a major advantage for a CNS target.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.215 and -4.974). This is unusual and suggests poor permeability in this *in vitro* assay. However, these values are on a scale where negative values are possible and don't necessarily disqualify a compound.

**Aqueous Solubility:** Both ligands have very poor aqueous solubility (-4.78 and -2.333). This is a significant concern for bioavailability and formulation.

**hERG Inhibition:** Ligand A (0.604) has a low hERG risk. Ligand B (0.819) also has a low hERG risk.

**Microsomal Clearance:** Ligand A (107.135) has a moderate microsomal clearance. Ligand B (53.495) has a lower clearance, indicating better metabolic stability, which is a positive.

**In vitro Half-Life:** Ligand A (8.763) has a reasonable half-life. Ligand B (-53.647) has a *very* negative half-life, which is nonsensical and likely an error or outlier. This is a major red flag.

**P-gp Efflux:** Ligand A (0.624) has low P-gp efflux, which is good for CNS penetration. Ligand B (0.185) has even lower P-gp efflux, which is a significant advantage.

**Binding Affinity:** Ligand A (0.0) has a weak binding affinity. Ligand B (-9.3) has *exceptionally* strong binding affinity, exceeding the > -7.0 kcal/mol threshold by a large margin. This is a huge advantage that could potentially overcome some of the ADME liabilities.

**Overall Assessment:**

Ligand B stands out due to its exceptionally strong binding affinity and excellent BBB penetration, coupled with low DILI and P-gp efflux. While its solubility is poor and its reported half-life is nonsensical, the binding affinity is so strong that it could compensate for these issues. Ligand A has better solubility and a more reasonable half-life, but its binding affinity is significantly weaker. The poor half-life for Ligand B is concerning and needs further investigation, but the affinity advantage is too significant to ignore.

Output:
1
2025-04-17 06:57:43,686 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (356.463 and 362.539 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (79.31) is better than Ligand B (40.62). Both are below the 90 A^2 threshold desirable for CNS targets, but Ligand B is significantly lower, which is advantageous for brain penetration.

**logP:** Ligand A (0.504) is quite low, potentially hindering membrane permeability. Ligand B (4.03) is higher, nearing the upper limit of the optimal range, which could lead to solubility issues but is generally acceptable.

**H-Bond Donors/Acceptors:** Ligand A has 1 HBD and 5 HBA, while Ligand B has 0 HBD and 3 HBA. Both are within acceptable limits.

**QED:** Both ligands have reasonable QED values (0.685 and 0.566, respectively), indicating good drug-like properties.

**DILI:** Ligand A (23.924) has a significantly lower DILI risk than Ligand B (30.128), which is a positive attribute.

**BBB:** Ligand B (84.141) has a much higher BBB penetration percentile than Ligand A (38.852). This is a *critical* advantage for a CNS target like DRD2.

**Caco-2 Permeability:** Ligand A (-4.379) has a negative Caco-2 value, which is concerning and suggests poor intestinal absorption. Ligand B (-4.808) is also negative, but the difference isn't substantial.

**Aqueous Solubility:** Ligand A (-0.664) has slightly better solubility than Ligand B (-3.783), but both are quite poor.

**hERG Inhibition:** Ligand A (0.408) has a lower hERG risk than Ligand B (0.792), which is preferable.

**Microsomal Clearance:** Ligand B (69.036) has a higher microsomal clearance than Ligand A (31.649), indicating faster metabolism and potentially lower *in vivo* exposure.

**In vitro Half-Life:** Ligand B (26.051) has a longer half-life than Ligand A (5.361), which is a positive attribute.

**P-gp Efflux:** Ligand A (0.162) has lower P-gp efflux liability than Ligand B (0.843), which is beneficial for CNS exposure.

**Binding Affinity:** Both ligands have very strong binding affinities (-7.8 and -7.6 kcal/mol). The difference of 0.2 kcal/mol is not substantial enough to outweigh other significant differences.

**Overall Assessment:**

While Ligand A has a lower DILI risk and P-gp efflux, Ligand B is significantly better regarding BBB penetration, which is paramount for a CNS target. The longer half-life of Ligand B is also a plus. The lower logP of Ligand A is a major concern, and its negative Caco-2 value is also unfavorable. The slightly higher hERG risk of Ligand B is a manageable concern given its strong CNS penetration.

Output:
1
2025-04-17 06:57:43,686 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (359.415 and 363.502 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (116.8) is borderline for CNS penetration, being above the preferred <90, but still potentially acceptable. Ligand B (36.44) is excellent, well below the 90 threshold.

**logP:** Ligand A (0.304) is quite low, potentially hindering membrane permeability. Ligand B (3.713) is optimal, falling within the 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A has 1 HBD and 8 HBA, acceptable values. Ligand B has 0 HBD and 4 HBA, also acceptable.

**QED:** Both ligands have similar QED values (0.793 and 0.752), indicating good drug-likeness.

**DILI:** Ligand A has a DILI risk of 67%, considered high. Ligand B has a much lower DILI risk of 21.9%, which is favorable.

**BBB:** Ligand A has a BBB penetration of 48.352%, below the desirable >70% for CNS targets. Ligand B shows excellent BBB penetration at 94.029%. This is a significant advantage for Ligand B.

**Caco-2 Permeability:** Ligand A has a negative Caco-2 value (-5.599), indicating poor permeability. Ligand B also has a negative Caco-2 value (-4.501), but it's slightly less negative than Ligand A.

**Aqueous Solubility:** Both ligands have poor aqueous solubility (-2.982 and -3.395).

**hERG Inhibition:** Ligand A (0.071) has very low hERG inhibition risk. Ligand B (0.793) has a slightly higher, but still relatively low, hERG risk.

**Microsomal Clearance:** Ligand A (6.796) has lower microsomal clearance than Ligand B (53.901), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand B (44.095) has a significantly longer in vitro half-life than Ligand A (-0.413), which is a major advantage.

**P-gp Efflux:** Ligand A (0.031) has very low P-gp efflux liability, which is good. Ligand B (0.364) has slightly higher P-gp efflux, but it's still reasonable.

**Binding Affinity:** Ligand B (-7.1 kcal/mol) has a slightly better binding affinity than Ligand A (-8.2 kcal/mol). While A is stronger, the difference isn't substantial enough to overcome the other significant drawbacks.

**Overall Assessment:**

Ligand B is the superior candidate. While both have solubility issues, Ligand B excels in key areas for a CNS-targeting GPCR ligand: excellent BBB penetration, optimal logP, lower DILI risk, and a longer half-life. Ligand A's low logP, poor Caco-2 permeability, and high DILI risk are significant concerns. The slightly better affinity of Ligand A is not enough to compensate for these liabilities.

Output:
1
2025-04-17 06:57:43,687 - INFO - Reasoning:

Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (361.364 and 344.371 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (83.48) is significantly better than Ligand B (117.52). For CNS targets, we want TPSA <= 90, and A is comfortably within that range, while B is above.

**3. logP:** Both ligands have acceptable logP values (1.73 and 0.483), falling within the 1-3 range. Ligand A is slightly preferred.

**4. H-Bond Donors:** Both have 3 HBD, which is acceptable.

**5. H-Bond Acceptors:** Both have 4 HBA, which is acceptable.

**6. QED:** Both have similar QED values (0.691 and 0.689), indicating good drug-likeness.

**7. DILI:** Ligand A (14.851) has a much lower DILI risk than Ligand B (65.646). This is a significant advantage for A.

**8. BBB:** Ligand A (77.937) has a much better BBB penetration percentile than Ligand B (43.815). This is *crucial* for a CNS target like DRD2.

**9. Caco-2 Permeability:** Ligand A (-4.723) is better than Ligand B (-5.981), indicating better intestinal absorption.

**10. Aqueous Solubility:** Ligand A (-2.002) is better than Ligand B (-3.181), indicating better solubility.

**11. hERG Inhibition:** Both ligands have low hERG inhibition risk (0.337 and 0.159).

**12. Microsomal Clearance:** Ligand A (-9.116) has a lower (better) microsomal clearance than Ligand B (-18.126), suggesting better metabolic stability.

**13. In vitro Half-Life:** Ligand A (16.78) has a better in vitro half-life than Ligand B (-16.384).

**14. P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.028 and 0.018).

**15. Binding Affinity:** Both ligands have similar and excellent binding affinities (-8.6 and -9.1 kcal/mol). The difference is negligible.

**Overall Assessment:**

Ligand A is significantly better than Ligand B across multiple critical ADME properties, especially BBB penetration and DILI risk. While both have good binding affinity, the superior ADME profile of Ligand A makes it a much more promising drug candidate for a CNS target like DRD2. The lower TPSA, better BBB, lower DILI, and improved metabolic stability all contribute to a higher likelihood of success.

Output:
1
2025-04-17 06:57:43,687 - INFO - Reasoning:

Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (351.447 and 376.831 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (113.66) is better than Ligand B (69.64) as it is closer to the optimal range for CNS targets (<=90). Ligand B is excellent.

**3. logP:** Ligand A (0.555) is quite low, potentially hindering permeability. Ligand B (3.305) is within the optimal 1-3 range. This is a significant advantage for Ligand B.

**4. H-Bond Donors:** Ligand A (3) is acceptable, while Ligand B (2) is even better, balancing solubility and permeability.

**5. H-Bond Acceptors:** Ligand A (5) is acceptable, while Ligand B (3) is even better, balancing solubility and permeability.

**6. QED:** Both ligands have good QED scores (0.62 and 0.731), indicating drug-like properties.

**7. DILI:** Both ligands have elevated DILI risk (16.092 and 27.608), but these are relatively close and not a major differentiator at this stage.

**8. BBB:** Ligand B (55.138) is significantly better than Ligand A (26.91) in terms of predicted BBB penetration. This is *critical* for a CNS target like DRD2.

**9. Caco-2 Permeability:** Ligand A (-5.266) and Ligand B (-5.014) are both poor, indicating low intestinal absorption.

**10. Aqueous Solubility:** Ligand A (-1.726) and Ligand B (-3.21) are both poor, indicating low solubility.

**11. hERG Inhibition:** Ligand A (0.189) is better than Ligand B (0.652), indicating lower cardiotoxicity risk.

**12. Microsomal Clearance:** Ligand A (-12.347) has much lower (better) microsomal clearance than Ligand B (58.726), suggesting greater metabolic stability.

**13. In vitro Half-Life:** Ligand B (15.141) has a longer half-life than Ligand A (6.406).

**14. P-gp Efflux:** Ligand A (0.007) has very low P-gp efflux, which is excellent for CNS penetration. Ligand B (0.081) is also low, but not as favorable.

**15. Binding Affinity:** Ligand B (-7.9 kcal/mol) has a 0.8 kcal/mol stronger binding affinity than Ligand A (-7.1 kcal/mol). This is a substantial difference and can outweigh some ADME drawbacks.

**Overall Assessment:**

While Ligand A has better metabolic stability (lower Cl_mic) and P-gp efflux, Ligand B is superior overall due to its significantly better BBB penetration, optimal logP, and stronger binding affinity. The improved BBB penetration is crucial for a CNS target. The slightly higher hERG risk of Ligand B is a concern, but the substantial affinity advantage and better logP/BBB profile likely outweigh this.

Output:
1
2025-04-17 06:57:43,687 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (346.515 and 347.375 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (58.2) is excellent, well below the 90 A^2 threshold for CNS targets. Ligand B (119.24) is higher, but still potentially acceptable, though less ideal.

**logP:** Ligand A (3.262) is optimal. Ligand B (1.493) is on the lower side, potentially hindering permeability.

**H-Bond Donors:** Both ligands have 2 HBD, which is within the acceptable limit of 5.

**H-Bond Acceptors:** Ligand A has 2 HBA, within the limit of 10. Ligand B has 7 HBA, still within the limit, but higher.

**QED:** Both ligands have similar QED values (0.695 and 0.694), indicating good drug-likeness.

**DILI:** Ligand A (28.189) has a much lower DILI risk than Ligand B (68.399). This is a significant advantage for Ligand A.

**BBB:** Ligand A (51.415) has a moderate BBB penetration, while Ligand B (67.197) is better, but still below the desirable >70 for CNS targets.

**Caco-2 Permeability:** Both have negative Caco-2 values (-4.556 and -4.896), which is unusual and suggests poor permeability. This is a concern for both.

**Aqueous Solubility:** Both have negative solubility values (-4.419 and -2.9), indicating poor aqueous solubility. This is a concern for both.

**hERG Inhibition:** Ligand A (0.188) has a lower hERG inhibition risk than Ligand B (0.404).

**Microsomal Clearance:** Ligand A (39.063) has lower microsomal clearance, suggesting better metabolic stability, compared to Ligand B (51.252).

**In vitro Half-Life:** Ligand A (11.857 hours) has a longer half-life than Ligand B (-30.449 hours - a negative value is concerning).

**P-gp Efflux:** Ligand A (0.176) has lower P-gp efflux liability than Ligand B (0.051), meaning it is less likely to be pumped out of the brain, improving CNS exposure.

**Binding Affinity:** Both ligands have very similar and excellent binding affinities (-8.5 and -8.6 kcal/mol). The difference is negligible.

**Overall Assessment:**

Ligand A is superior due to its better predicted ADME properties. Specifically, its lower DILI risk, lower P-gp efflux, lower microsomal clearance, and longer half-life are all significant advantages. While both have issues with Caco-2 permeability and solubility, the other factors weigh heavily in favor of Ligand A. Ligand B's higher TPSA and lower logP are also less desirable for a CNS-targeting GPCR ligand.

Output:
0
2025-04-17 06:57:43,687 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (341.411 and 342.443 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (68.46) is significantly better than Ligand B (79.04). For CNS targets, TPSA should be <= 90, and A is closer to the optimal <=60 range. B is pushing the upper limit.

**3. logP:** Both ligands have good logP values (2.725 and 2.61), falling within the optimal 1-3 range.

**4. H-Bond Donors:** Ligand A (0) is preferable to Ligand B (3). Fewer HBDs generally improve permeability.

**5. H-Bond Acceptors:** Ligand A (5) is better than Ligand B (3). Both are within the acceptable range of <=10.

**6. QED:** Both ligands have acceptable QED values (0.808 and 0.755), indicating good drug-like properties.

**7. DILI:** Ligand A (43.117) has a slightly higher DILI risk than Ligand B (31.563), but both are below the concerning threshold of 60.

**8. BBB:** Both ligands have excellent BBB penetration (79.992 and 78.209), which is crucial for a CNS target like DRD2.

**9. Caco-2 Permeability:** Ligand A (-4.905) is better than Ligand B (-4.759), indicating slightly better intestinal absorption.

**10. Aqueous Solubility:** Ligand A (-2.827) is better than Ligand B (-3.048).

**11. hERG Inhibition:** Ligand A (0.171) is better than Ligand B (0.512), indicating lower cardiotoxicity risk.

**12. Microsomal Clearance:** Ligand B (20.297) has a lower microsomal clearance than Ligand A (41.986), suggesting better metabolic stability.

**13. In vitro Half-Life:** Ligand B (16.546) has a longer in vitro half-life than Ligand A (-16.285), which is desirable.

**14. P-gp Efflux:** Ligand A (0.494) is better than Ligand B (0.052), indicating lower P-gp efflux and potentially better CNS exposure.

**15. Binding Affinity:** Ligand B (-9.5) has a slightly better binding affinity than Ligand A (-9.1), but the difference is small (0.4 kcal/mol).

**Overall Assessment:**

Ligand A excels in several key areas for a CNS-targeting GPCR: lower TPSA, fewer HBDs, better solubility, lower hERG risk, and lower P-gp efflux. While Ligand B has better metabolic stability and a slightly better binding affinity, the advantages of Ligand A in permeability and safety (hERG, Pgp) are more significant for CNS drug development. The small difference in binding affinity is unlikely to outweigh the ADME/Tox benefits of Ligand A.

Output:
1
2025-04-17 06:57:43,687 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (342.443 and 357.479 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (86.88) is better than Ligand B (73.2). Both are below the 90 A^2 threshold desirable for CNS targets.

**logP:** Ligand A (1.545) is within the optimal 1-3 range. Ligand B (2.941) is also within the optimal range, but closer to the upper limit.

**H-Bond Donors/Acceptors:** Ligand A has 3 HBD and 3 HBA, while Ligand B has 1 HBD and 4 HBA. Both are acceptable, staying within the recommended limits.

**QED:** Both ligands have good QED scores (0.626 and 0.842, respectively), indicating drug-like properties.

**DILI:** Ligand A (37.999) has a significantly lower DILI risk than Ligand B (60.682). This is a substantial advantage for Ligand A.

**BBB:** Ligand A (39.162) has a lower BBB penetration percentile than Ligand B (60.993). This is a significant advantage for Ligand B, given that DRD2 is a CNS target.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.225 and -5.021), which is unusual and suggests poor permeability. However, the scale isn't specified, so it's hard to interpret.

**Aqueous Solubility:** Both ligands have negative solubility values (-3.362 and -4.487), which is also unusual and suggests poor solubility. Again, the scale isn't specified.

**hERG:** Ligand A (0.117) has a lower hERG inhibition liability than Ligand B (0.584), indicating a lower risk of cardiotoxicity.

**Microsomal Clearance:** Ligand A (-8.103) has a more negative (lower) microsomal clearance, suggesting better metabolic stability than Ligand B (37.561).

**In vitro Half-Life:** Ligand A (-6.537) has a more negative (longer) in vitro half-life than Ligand B (-4.346), suggesting better stability.

**P-gp Efflux:** Ligand A (0.066) has lower P-gp efflux liability than Ligand B (0.43), which is favorable for CNS penetration.

**Binding Affinity:** Both ligands have similar binding affinities (-8.7 and -8.1 kcal/mol). Ligand A is slightly better, but the difference is less than 1.5 kcal/mol.

**Overall Assessment:**

Ligand A excels in safety parameters (DILI, hERG) and metabolic stability (Cl_mic, t1/2, P-gp). It also has a slightly better binding affinity. However, Ligand B has a significantly better BBB penetration score. Given that DRD2 is a CNS target, BBB penetration is crucial. While Ligand A has better ADME properties overall, the substantial difference in BBB penetration favors Ligand B.

Output:
1
2025-04-17 06:57:43,688 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (340.358 Da and 352.429 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (86.02) is better than Ligand B (66.91), both are below the 90 A^2 threshold for CNS targets.

**3. logP:** Both ligands have good logP values (2.988 and 3.641), falling within the optimal 1-3 range. Ligand B is slightly higher, which could be a minor concern for solubility.

**4. H-Bond Donors:** Ligand A (4) is slightly higher than Ligand B (2), but both are within the acceptable limit of 5.

**5. H-Bond Acceptors:** Ligand A (2) is lower than Ligand B (4), both are within the acceptable limit of 10.

**6. QED:** Both ligands have good QED scores (0.588 and 0.767), indicating good drug-like properties. Ligand B is slightly better.

**7. DILI:** Ligand A has a significantly higher DILI risk (90.694) compared to Ligand B (47.848). This is a major drawback for Ligand A.

**8. BBB:** Ligand B (82.047) has a considerably better BBB penetration percentile than Ligand A (67.313). This is critical for a CNS target like DRD2.

**9. Caco-2 Permeability:** Both have negative values, indicating poor permeability. Ligand A (-5.148) is worse than Ligand B (-4.898).

**10. Aqueous Solubility:** Both have negative values, indicating poor solubility. Ligand A (-4.861) is slightly worse than Ligand B (-3.853).

**11. hERG Inhibition:** Both ligands have low hERG inhibition risk (0.69 and 0.652).

**12. Microsomal Clearance:** Ligand B (44.464) has a much lower microsomal clearance than Ligand A (6.159), suggesting better metabolic stability.

**13. In vitro Half-Life:** Ligand A (100.987) has a much longer half-life than Ligand B (33.179).

**14. P-gp Efflux:** Ligand A (0.201) has a slightly lower P-gp efflux than Ligand B (0.208), which is favorable.

**15. Binding Affinity:** Ligand A (-11.0) has a significantly stronger binding affinity than Ligand B (0.0). This is a substantial advantage.

**Overall Assessment:**

While Ligand A boasts a significantly stronger binding affinity and a slightly better P-gp efflux profile, its high DILI risk, lower BBB penetration, and worse Caco-2 permeability are major concerns. Ligand B, despite its weaker binding affinity, presents a much more favorable ADME-Tox profile, with lower DILI risk, better BBB penetration, and improved metabolic stability. For a CNS target like DRD2, BBB penetration and safety (DILI) are paramount. The substantial difference in binding affinity *could* be overcome with further optimization of Ligand B, whereas mitigating the safety concerns of Ligand A would likely require more extensive structural changes.

Output:
1
2025-04-17 06:57:43,688 - INFO - Reasoning:

Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (366.487 and 340.467 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (90.54) is borderline acceptable for CNS targets (<=90), while Ligand B (40.62) is well within the desired range. This favors Ligand B.

**3. logP:** Both ligands have good logP values (1.481 and 2.758), falling within the optimal 1-3 range.

**4. H-Bond Donors:** Ligand A has 3 HBD, which is acceptable. Ligand B has 0, also acceptable.

**5. H-Bond Acceptors:** Ligand A has 4 HBA, acceptable. Ligand B has 2, also acceptable.

**6. QED:** Both ligands have similar QED values (0.712 and 0.725), indicating good drug-likeness.

**7. DILI:** Ligand A (29.081) has a slightly higher DILI risk than Ligand B (17.836), but both are below the concerning threshold of 40.

**8. BBB:** This is a critical parameter for CNS targets. Ligand B (87.476) has a significantly higher BBB penetration percentile than Ligand A (53.664). This is a major advantage for Ligand B.

**9. Caco-2 Permeability:** Ligand A (-5.559) and Ligand B (-4.793) both have negative values, which is unusual and suggests poor permeability. However, the scale is not specified, making direct comparison difficult.

**10. Aqueous Solubility:** Both ligands have negative solubility values (-1.845 and -3.276), indicating poor aqueous solubility. This is a concern for both.

**11. hERG Inhibition:** Both ligands have low hERG inhibition liability (0.23 and 0.368), which is favorable.

**12. Microsomal Clearance:** Ligand A (-15.485) has a lower (better) microsomal clearance than Ligand B (53.724), suggesting greater metabolic stability.

**13. In vitro Half-Life:** Ligand A (25.714) has a longer half-life than Ligand B (-6.997). This is a significant advantage for Ligand A.

**14. P-gp Efflux:** Ligand A (0.014) has much lower P-gp efflux liability than Ligand B (0.328), which is highly desirable for CNS penetration.

**15. Binding Affinity:** Ligand B (-8.8 kcal/mol) has a slightly better binding affinity than Ligand A (-7.8 kcal/mol). While the difference is not huge, it's still a positive for Ligand B.

**Overall Assessment:**

Ligand B excels in BBB penetration and has a slightly better binding affinity. Ligand A has better metabolic stability (lower Cl_mic), longer half-life, and lower P-gp efflux. However, the superior BBB penetration of Ligand B is paramount for a CNS target like DRD2. While both have solubility issues, the CNS target profile heavily favors Ligand B. The slightly better affinity of B also contributes.

Output:
1
2025-04-17 06:57:43,688 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (354.422 and 351.403 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (78.87) is significantly better than Ligand B (92.09). For CNS targets, we want TPSA <= 90, so Ligand A is preferable.

**3. logP:** Ligand B (1.109) is slightly better than Ligand A (0.492), falling more squarely within the optimal 1-3 range. Ligand A is a bit low, potentially hindering permeation.

**4. H-Bond Donors:** Ligand A (2) is slightly higher than Ligand B (1), but both are acceptable (<=5).

**5. H-Bond Acceptors:** Ligand A (4) is lower than Ligand B (5), and both are within the acceptable range (<=10).

**6. QED:** Ligand B (0.708) has a better QED score than Ligand A (0.467), indicating a more drug-like profile.

**7. DILI:** Ligand A (12.524) has a much lower DILI risk than Ligand B (43.738). This is a significant advantage for Ligand A.

**8. BBB:** Ligand A (68.98) is better than Ligand B (61.38), but both are below the desirable >70 for CNS targets. However, given that both are relatively close, this isn't a decisive factor.

**9. Caco-2:** Both ligands have negative Caco-2 values (-4.727 and -4.915), which is unusual and suggests poor permeability. This is a concern for both.

**10. Solubility:** Both ligands have negative solubility values (-1.573 and -1.535), indicating very poor aqueous solubility. This is a significant drawback for both.

**11. hERG:** Both ligands have very low hERG inhibition risk (0.347 and 0.103).

**12. Cl_mic:** Ligand A (-12.853) has a much lower (better) microsomal clearance than Ligand B (44.388), indicating greater metabolic stability.

**13. t1/2:** Ligand B (22.293) has a significantly longer in vitro half-life than Ligand A (3.503).

**14. Pgp:** Both ligands have very low P-gp efflux liability (0.039 and 0.013).

**15. Binding Affinity:** Ligand A (-7.5) has a slightly better binding affinity than Ligand B (-7.1). While the difference is not huge (1.5 kcal/mol), it's enough to consider.

**Overall Assessment:**

Considering the GPCR-specific priorities, Ligand A is the better candidate. While Ligand B has a better QED and half-life, Ligand A excels in crucial areas: TPSA, DILI risk, and metabolic stability (Cl_mic). The slightly better binding affinity of Ligand A further supports this conclusion. The poor Caco-2 and solubility are concerning for both, but can be addressed with formulation strategies. The slightly lower logP of Ligand A is a minor drawback compared to the advantages it offers.

Output:
0
2025-04-17 06:57:43,688 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 drug candidates, considering the provided guidelines and GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (344.327 and 350.419 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (126.48) is slightly above the optimal <90 for CNS targets, but still reasonable. Ligand B (85.69) is excellent, well below 90.

**3. logP:** Ligand A (0.978) is at the lower end of the optimal 1-3 range, potentially impacting permeability. Ligand B (0.37) is quite low, raising concerns about membrane permeability.

**4. H-Bond Donors:** Ligand A (2) and Ligand B (1) are both within the acceptable limit of <=5.

**5. H-Bond Acceptors:** Ligand A (7) and Ligand B (6) are both within the acceptable limit of <=10.

**6. QED:** Both ligands have good QED scores (0.717 and 0.796), indicating good drug-like properties.

**7. DILI:** Ligand A (79.527) has a higher DILI risk than Ligand B (46.297). Ligand B is preferable here.

**8. BBB:** Ligand B (76.231) has a better BBB penetration percentile than Ligand A (65.064), which is crucial for a CNS target like DRD2.

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.957 and -4.816), which is unusual and suggests poor permeability. However, these values are on a scale where negative values are possible, and direct comparison is difficult without knowing the scale's specifics.

**10. Aqueous Solubility:** Both ligands have negative solubility values (-4.035 and -1.276), which is also unusual and suggests poor solubility. Again, direct comparison is difficult without knowing the scale.

**11. hERG Inhibition:** Both ligands have low hERG inhibition risk (0.303 and 0.07).

**12. Microsomal Clearance:** Ligand B (0.897) has significantly lower microsomal clearance than Ligand A (31.915), suggesting better metabolic stability.

**13. In vitro Half-Life:** Ligand B (17.908) has a longer in vitro half-life than Ligand A (38.007).

**14. P-gp Efflux:** Ligand A (0.101) has lower P-gp efflux than Ligand B (0.028), suggesting better CNS exposure.

**15. Binding Affinity:** Ligand B (-9.1 kcal/mol) has a significantly stronger binding affinity than Ligand A (-8.0 kcal/mol) - a difference of 1.1 kcal/mol, which is substantial.

**Overall Assessment:**

While both ligands have some drawbacks, Ligand B is the more promising candidate. Its superior BBB penetration, significantly better binding affinity, lower DILI risk, and improved metabolic stability outweigh the slightly lower logP and P-gp efflux. The lower logP is a concern, but the strong affinity could compensate. The negative solubility and Caco-2 values are concerning for both, but the other factors favor Ligand B.

Output:
1
2025-04-17 06:57:43,688 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (361.873 and 348.447 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (56.15) is excellent, well below the 90 A^2 threshold for CNS targets. Ligand B (96.11) is higher, but still potentially acceptable, though less ideal.

**logP:** Ligand A (3.771) is at the upper end of the optimal range (1-3), while Ligand B (1.775) is at the lower end. A slightly higher logP is generally preferred for CNS penetration, but 3.771 is still reasonable.

**H-Bond Donors/Acceptors:** Ligand A (HBD=1, HBA=5) and Ligand B (HBD=3, HBA=4) both have acceptable numbers of H-bond donors and acceptors.

**QED:** Both ligands have good QED scores (0.602 and 0.683), indicating good drug-like properties.

**DILI:** Ligand A (42.458) has a slightly higher DILI risk than Ligand B (52.423), but both are below the concerning threshold of 60.

**BBB:** This is a crucial parameter for a CNS target like DRD2. Ligand A (62.233) has a significantly better BBB percentile than Ligand B (50.679).

**Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and suggests poor permeability. However, the scale is not specified, so it's difficult to interpret.

**Aqueous Solubility:** Both have negative solubility values, which is also unusual and suggests poor solubility.

**hERG Inhibition:** Ligand A (0.508) has a slightly higher hERG risk than Ligand B (0.153), but both are relatively low.

**Microsomal Clearance:** Ligand A (87.09) has a higher microsomal clearance than Ligand B (9.063), indicating lower metabolic stability. This is a significant drawback for Ligand A.

**In vitro Half-Life:** Ligand B (-10.821) has a negative half-life, which is not possible. This is likely an error in the data. Ligand A (19.851) has a reasonable half-life.

**P-gp Efflux:** Ligand A (0.366) has lower P-gp efflux liability than Ligand B (0.044), which is favorable for CNS penetration.

**Binding Affinity:** Both ligands have similar, strong binding affinities (-8.8 kcal/mol and -8.1 kcal/mol). The difference of 0.7 kcal/mol is not substantial enough to override other considerations.

**Overall Assessment:**

Ligand A excels in TPSA, P-gp efflux, and has a better BBB score. However, it suffers from higher microsomal clearance and a slightly higher DILI risk. Ligand B has a better logP, lower DILI, and lower hERG risk, but its BBB penetration is significantly worse. The negative values for Caco-2 and solubility are concerning for both, but the biggest issue is the negative half-life for Ligand B. Given the importance of BBB penetration for a CNS target and the questionable half-life of Ligand B, Ligand A appears to be the more promising candidate despite its slightly higher clearance.

Output:
0
2025-04-17 06:57:43,689 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (337.375 and 348.443 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (64.63) is significantly better than Ligand B (78.87). For CNS targets, we want TPSA <= 90, and A is comfortably within that range, while B is approaching the upper limit.

**3. logP:** Both ligands have good logP values (2.831 and 2.777), falling within the optimal 1-3 range.

**4. H-Bond Donors:** Ligand A (1) is preferable to Ligand B (2). Lower HBD generally improves permeability.

**5. H-Bond Acceptors:** Both ligands have the same number of HBA (4), which is acceptable (<=10).

**6. QED:** Ligand A (0.852) has a slightly better QED than Ligand B (0.792), indicating a more drug-like profile. Both are above the 0.5 threshold.

**7. DILI:** Ligand B (60.682) has a slightly higher DILI risk than Ligand A (55.409). Both are acceptable (<60 is good), but A is preferred.

**8. BBB:** This is a critical parameter for a CNS target. Ligand A (66.615) has a significantly better BBB percentile than Ligand B (36.177). A value >70 is desirable, and A is closer to that target.

**9. Caco-2 Permeability:** Ligand A (-4.48) has a worse Caco-2 permeability than Ligand B (-5.022). Lower values are less favorable.

**10. Aqueous Solubility:** Ligand B (-2.038) has better aqueous solubility than Ligand A (-4.116).

**11. hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.415 and 0.088).

**12. Microsomal Clearance:** Ligand B (18.842) has a much lower microsomal clearance than Ligand A (44.343), indicating better metabolic stability.

**13. In vitro Half-Life:** Ligand B (-6.861) has a longer in vitro half-life than Ligand A (-15.39).

**14. P-gp Efflux:** Ligand A (0.178) has lower P-gp efflux than Ligand B (0.016), which is desirable for CNS penetration.

**15. Binding Affinity:** Ligand B (-7.5) has a significantly stronger binding affinity than Ligand A (-10.5). This is a substantial advantage, potentially outweighing some ADME drawbacks.

**Overall Assessment:**

While Ligand B has superior binding affinity, metabolic stability, solubility, and half-life, Ligand A excels in BBB penetration and has a better safety profile (lower DILI). Given that this is a CNS target (DRD2), BBB penetration is paramount. The significantly better BBB score of Ligand A, combined with its acceptable TPSA and logP, makes it the more promising candidate, despite the weaker binding affinity. The 1.5 kcal/mol difference in binding affinity is not enough to overcome the substantial difference in predicted brain exposure.

Output:
0
2025-04-17 06:57:43,689 - INFO - Batch 325 complete. Total preferences: 5200
2025-04-17 06:57:43,689 - INFO - Processing batch 326/512...
2025-04-17 06:58:28,740 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B based on the provided guidelines, prioritizing GPCR-specific properties (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (356.337 and 344.455 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (128.88) is borderline for CNS targets, slightly above the preferred <90, but acceptable. Ligand B (58.64) is excellent, well below the threshold.

**logP:** Ligand A (0.721) is a bit low, potentially hindering permeation. Ligand B (2.351) is within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Both have acceptable HBD (1) and HBA (6 for A, 3 for B) counts, well within the limits.

**QED:** Both ligands have reasonable QED scores (0.438 and 0.753), with Ligand B being significantly better.

**DILI:** Ligand A (60.217) is approaching a concerning DILI risk, while Ligand B (24.661) is excellent.

**BBB:** Both ligands have good BBB penetration (68.941 and 69.407), exceeding the 70% threshold, which is positive for CNS targets.

**Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and suggests a potential issue with the data or modeling. However, we will proceed assuming these values represent permeability, with lower values indicating lower permeability.

**Aqueous Solubility:** Both have negative solubility values, which is also unusual.

**hERG Inhibition:** Both ligands show very low hERG inhibition risk (0.155 and 0.183).

**Microsomal Clearance:** Ligand A (-10.923) has a much lower (better) microsomal clearance than Ligand B (36.769), indicating greater metabolic stability.

**In vitro Half-Life:** Ligand A (4.628) has a slightly longer half-life than Ligand B (1.37), which is favorable.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.014 and 0.11).

**Binding Affinity:** Ligand B (-8.9 kcal/mol) has a significantly stronger binding affinity than Ligand A (-7.2 kcal/mol), a difference of 1.7 kcal/mol, which is substantial.

**Overall Assessment:**

Ligand B is the stronger candidate. While Ligand A has better metabolic stability and half-life, Ligand B excels in key areas for a CNS-targeting GPCR ligand: significantly better binding affinity, a much lower DILI risk, a better logP value, and a lower TPSA. The stronger binding affinity of Ligand B is likely to outweigh the slightly less favorable metabolic profile of Ligand A. The unusual negative values for Caco-2 and Solubility are concerning, but the other factors strongly favor Ligand B.

Output:
1
2025-04-17 06:58:28,740 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (345.418 and 353.507 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (62.71) is slightly higher than Ligand B (53.09). Both are below the 90 A^2 threshold desirable for CNS targets, but Ligand B is better.

**logP:** Both ligands have good logP values (2.023 and 1.594), falling within the optimal 1-3 range. Ligand B is slightly lower, which could slightly improve solubility.

**H-Bond Donors:** Ligand A has 1 HBD, while Ligand B has 0. Both are within the acceptable limit of <=5.

**H-Bond Acceptors:** Both ligands have 4 HBAs, well within the acceptable limit of <=10.

**QED:** Ligand A (0.87) has a higher QED score than Ligand B (0.705), indicating a more drug-like profile.

**DILI:** Ligand A (16.479) has a significantly higher DILI risk than Ligand B (5.312). This is a major concern for Ligand A.

**BBB:** Both ligands have good BBB penetration (Ligand A: 78.868, Ligand B: 70.027), but Ligand A is better, exceeding the 70% threshold.

**Caco-2 Permeability:** Ligand A (-5.124) has poorer Caco-2 permeability than Ligand B (-4.535). Lower values are less desirable.

**Aqueous Solubility:** Ligand A (-1.227) has poorer aqueous solubility than Ligand B (-0.48). Lower values are less desirable.

**hERG Inhibition:** Ligand A (0.95) has a slightly higher hERG inhibition risk than Ligand B (0.565). Both are relatively low risk.

**Microsomal Clearance:** Ligand A (9.886) has higher microsomal clearance than Ligand B (2.601), indicating lower metabolic stability.

**In vitro Half-Life:** Ligand A (10.372) has a slightly longer in vitro half-life than Ligand B (7.485).

**P-gp Efflux:** Ligand A (0.148) has slightly higher P-gp efflux than Ligand B (0.075). Lower efflux is better for CNS penetration.

**Binding Affinity:** Ligand A (-9.0) has significantly stronger binding affinity than Ligand B (-0.0). This is a substantial advantage.

**Overall Assessment:**

Ligand A has a much stronger binding affinity, better BBB penetration, and a higher QED score. However, it suffers from significantly higher DILI risk, poorer Caco-2 permeability, poorer solubility, higher microsomal clearance, and higher P-gp efflux. Ligand B has a much better safety profile (lower DILI), better permeability, solubility, and metabolic stability.

Despite the significantly better affinity of Ligand A, the high DILI risk is a major red flag. The difference in binding affinity (-9.0 vs -0.0) is enormous, but DILI is a critical factor. While affinity can sometimes outweigh other issues, a DILI risk of 16.479 is concerning. Given the GPCR-specific focus on CNS penetration and safety, and the substantial difference in DILI, Ligand B is the more promising candidate. It's a weaker binder, but the improved safety and ADME properties are more valuable in this context.

Output:
1
2025-04-17 06:58:28,740 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight (MW):** Both ligands (352.381 and 361.423 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (59.5) is excellent, well below the 90 A^2 threshold for CNS targets. Ligand B (99.5) is higher, but still potentially acceptable, though less ideal.

**3. logP:** Ligand A (2.621) is optimal (1-3). Ligand B (1.316) is on the lower end, potentially hindering permeability.

**4. H-Bond Donors (HBD):** Both ligands are within the acceptable limit of 5 (A: 0, B: 1).

**5. H-Bond Acceptors (HBA):** Both ligands are within the acceptable limit of 10 (A: 4, B: 6).

**6. QED:** Both ligands have reasonable QED scores (A: 0.785, B: 0.608), indicating good drug-like properties.

**7. DILI:** Ligand A (38.503) has a lower DILI risk than Ligand B (61.807), which is approaching a higher risk category.

**8. BBB:** This is a critical parameter for DRD2. Ligand A (97.945) shows excellent BBB penetration, while Ligand B (56.65) is significantly lower and less desirable.

**9. Caco-2:** Both have negative values, which is unusual. Assuming these are logP-scale values, lower values indicate poorer permeability. Ligand A (-4.024) is worse than Ligand B (-4.89).

**10. Solubility:** Both have negative values, which is unusual. Assuming these are logS-scale values, lower values indicate poorer solubility. Ligand A (-3.431) is better than Ligand B (-3.043).

**11. hERG:** Both ligands have low hERG risk (A: 0.454, B: 0.44).

**12. Cl_mic:** Ligand B (42.299) has lower microsomal clearance, suggesting better metabolic stability than Ligand A (77.29).

**13. t1/2:** Ligand B (20.832) has a longer in vitro half-life than Ligand A (-17.611), which is a significant advantage.

**14. Pgp:** Both ligands have low P-gp efflux liability (A: 0.191, B: 0.169).

**15. Binding Affinity:** Both ligands have very similar and strong binding affinities (A: -8.6 kcal/mol, B: -8.0 kcal/mol). The difference of 0.6 kcal/mol is not substantial enough to outweigh other factors.

**Overall Assessment:**

Ligand A is superior due to its excellent TPSA, logP, and particularly its high BBB penetration. While Ligand B has better metabolic stability (lower Cl_mic and longer t1/2), the significantly lower BBB penetration is a major drawback for a CNS target like DRD2. The slightly better solubility of A is also a plus. The affinity difference is minimal.

Output:
1
2025-04-17 06:58:28,740 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (355.5 & 364.5 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (54.02) is significantly better than Ligand B (60.85). For CNS targets, we want TPSA <= 90, and A is closer to the optimal <= 60 range.

**logP:** Both ligands have good logP values (4.091 & 2.671), falling within the 1-3 range. Ligand A is slightly higher, which *could* be a minor concern for solubility, but not a dealbreaker.

**H-Bond Donors/Acceptors:** Ligand A (2 HBD, 4 HBA) and Ligand B (1 HBD, 4 HBA) both have acceptable numbers of H-bond donors and acceptors.

**QED:** Both ligands have good QED scores (0.786 & 0.874), indicating good drug-like properties.

**DILI:** Ligand A (49.787) has a slightly higher DILI risk than Ligand B (23.653), but both are below the concerning threshold of 60.

**BBB:** Ligand A (80.419) has a better BBB percentile than Ligand B (74.486). Both are above 70, which is desirable for CNS targets.

**Caco-2 Permeability:** Ligand A (-5.004) has a worse Caco-2 permeability than Ligand B (-4.684). Lower values indicate lower permeability.

**Aqueous Solubility:** Ligand A (-4.017) has worse aqueous solubility than Ligand B (-2.812).

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.666 & 0.479).

**Microsomal Clearance:** Ligand A (79.38) has higher microsomal clearance than Ligand B (52.311), suggesting lower metabolic stability.

**In vitro Half-Life:** Ligand A (46.751) has a longer in vitro half-life than Ligand B (5.619).

**P-gp Efflux:** Ligand A (0.741) has slightly higher P-gp efflux than Ligand B (0.292). Lower is better for CNS penetration.

**Binding Affinity:** Both ligands have excellent binding affinity (-8.9 & -8.7 kcal/mol). The difference of 0.2 kcal/mol is not substantial enough to outweigh other factors.

**Overall Assessment:**

Ligand A excels in TPSA, BBB, and in vitro half-life. However, it suffers from lower Caco-2 permeability, lower aqueous solubility, higher microsomal clearance, and higher P-gp efflux compared to Ligand B. Given the importance of BBB penetration for a CNS target like DRD2, and the relatively small difference in binding affinity, Ligand B appears to be the more promising candidate. The better ADME properties of Ligand B (lower clearance, better solubility, lower P-gp efflux) are likely to translate to better *in vivo* exposure.

Output:
1
2025-04-17 06:58:28,741 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (342.439 and 346.475 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (54.71) is significantly better than Ligand B (83.12). For CNS targets, we want TPSA <= 90, and A is comfortably within this range, while B is approaching the upper limit.

**3. logP:** Both ligands have good logP values (3.226 and 2.43), falling within the optimal 1-3 range.

**4. H-Bond Donors:** Ligand A (1) is preferable to Ligand B (3). Fewer HBDs generally improve permeability.

**5. H-Bond Acceptors:** Both ligands have the same number of HBA (4), which is acceptable (<=10).

**6. QED:** Ligand A (0.876) has a much better QED score than Ligand B (0.675), indicating a more drug-like profile.

**7. DILI:** Ligand A (8.492) has a much lower DILI risk than Ligand B (51.493). This is a significant advantage for A.

**8. BBB:** Both ligands have excellent BBB penetration (74.564 and 77.511), exceeding the desirable >70 threshold for CNS targets.

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.791 and -4.806), which is unusual and suggests poor permeability. However, these values are very similar and don't differentiate the ligands.

**10. Aqueous Solubility:** Both ligands have negative solubility values (-2.157 and -3.542), indicating poor aqueous solubility. Again, the difference is minimal.

**11. hERG Inhibition:** Ligand A (0.854) shows slightly lower hERG inhibition liability than Ligand B (0.575), which is preferable.

**12. Microsomal Clearance:** Ligand A (-5.222) has a significantly lower (better) microsomal clearance than Ligand B (54.241), suggesting greater metabolic stability.

**13. In vitro Half-Life:** Ligand A (34.623) has a much longer in vitro half-life than Ligand B (16.453), which is a major advantage.

**14. P-gp Efflux:** Ligand A (0.187) has a much lower P-gp efflux liability than Ligand B (0.064), which is crucial for CNS penetration.

**15. Binding Affinity:** Both ligands have excellent binding affinities (-8.9 and -9.0 kcal/mol), with a very slight advantage to Ligand B. However, this small difference is outweighed by the superior ADME properties of Ligand A.

**Overall Assessment:**

Ligand A consistently outperforms Ligand B across most critical ADME properties, especially DILI, metabolic stability (Cl_mic, t1/2), and P-gp efflux. While both have good BBB penetration and affinity, Ligand A's better overall profile makes it a more promising drug candidate. The slightly lower TPSA and QED scores of Ligand A are also beneficial.

Output:
0
2025-04-17 06:58:28,741 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (350.547 and 351.447 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (40.62) is excellent, well below the 90 A^2 threshold for CNS targets. Ligand B (86.79) is higher, but still potentially acceptable, though less ideal.

**logP:** Ligand A (4.256) is slightly high, potentially leading to solubility issues or off-target interactions. Ligand B (0.723) is quite low, which could hinder membrane permeability and CNS penetration.

**H-Bond Donors/Acceptors:** Ligand A (0 HBD, 2 HBA) is favorable. Ligand B (1 HBD, 4 HBA) is also within acceptable limits.

**QED:** Both ligands have reasonable QED values (0.436 and 0.62), indicating moderate drug-likeness.

**DILI:** Ligand A (9.965) has a very low DILI risk, which is excellent. Ligand B (16.053) is also low, but higher than A.

**BBB:** Ligand A (84.917) has a very good BBB penetration score, highly desirable for a CNS target. Ligand B (65.064) is lower, significantly reducing its potential for CNS exposure.

**Caco-2 Permeability:** Both have negative Caco-2 values (-4.516 and -4.972), which is unusual and suggests poor permeability. This is a significant concern for both.

**Aqueous Solubility:** Both ligands have negative solubility values (-3.433 and -0.963), indicating very poor aqueous solubility. This is a major drawback.

**hERG Inhibition:** Ligand A (0.865) has a low hERG risk. Ligand B (0.098) also has a very low hERG risk.

**Microsomal Clearance:** Ligand A (80.378) has a relatively high microsomal clearance, suggesting faster metabolism. Ligand B (16.822) has a much lower clearance, indicating better metabolic stability.

**In vitro Half-Life:** Ligand A (-11.727) has a very short in vitro half-life. Ligand B (-18.716) has an even shorter half-life.

**P-gp Efflux:** Ligand A (0.654) has moderate P-gp efflux. Ligand B (0.014) has very low P-gp efflux, which is favorable for CNS penetration.

**Binding Affinity:** Ligand B (-8.4 kcal/mol) has a significantly stronger binding affinity than Ligand A (-7.1 kcal/mol). This is a substantial advantage.

**Overall Assessment:**

Despite the poor Caco-2 and solubility for both, Ligand B is the more promising candidate. Its significantly stronger binding affinity (-8.4 vs -7.1 kcal/mol) outweighs the slightly higher logP and lower BBB. The much lower microsomal clearance and P-gp efflux of Ligand B are also highly advantageous for CNS exposure and duration of action. Ligand A's better TPSA and DILI are offset by its weaker binding, higher clearance, and lower BBB. The solubility and permeability issues would need to be addressed through formulation strategies for either compound.

Output:
1
2025-04-17 06:58:28,741 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (433.328 Da) is slightly higher, but acceptable. Ligand B (376.519 Da) is also good.

**2. TPSA:**  Ligand A (112.81) is borderline for CNS targets (ideally <90), but not drastically outside. Ligand B (92.78) is much better, falling comfortably within the desired range for CNS penetration.

**3. logP:** Both ligands have good logP values (A: 0.83, B: 0.98), falling within the optimal 1-3 range.

**4. H-Bond Donors:** Ligand A (2) and Ligand B (1) are both acceptable, being less than 5.

**5. H-Bond Acceptors:** Ligand A (4) and Ligand B (5) are both acceptable, being less than 10.

**6. QED:** Both ligands have reasonable QED values (A: 0.716, B: 0.682), indicating good drug-like properties.

**7. DILI:** Ligand A (52.152) has a slightly higher DILI risk than Ligand B (45.56), but both are below the concerning threshold of 60.

**8. BBB:** Both ligands have similar and good BBB penetration (A: 62.117, B: 62.854). While >70 is desirable, these are reasonable starting points.

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.034 and -5.111). This is unusual and suggests poor permeability. However, these values are on a log scale and can be misleading.

**10. Aqueous Solubility:** Both ligands have negative solubility values (-3.25 and -1.545), indicating very poor aqueous solubility. This is a significant concern for bioavailability.

**11. hERG Inhibition:** Both ligands show very low hERG inhibition risk (A: 0.204, B: 0.324).

**12. Microsomal Clearance:** Ligand A (1.853) has significantly lower microsomal clearance than Ligand B (27.267), suggesting better metabolic stability. This is a major advantage.

**13. In vitro Half-Life:** Ligand A (-24.032) has a very negative half-life, which is not physically possible. This is likely an error in the data. Ligand B (27.197) has a reasonable half-life.

**14. P-gp Efflux:** Ligand A (0.017) has very low P-gp efflux, which is excellent for CNS penetration. Ligand B (0.055) is also low, but slightly higher.

**15. Binding Affinity:** Ligand A (-9.1 kcal/mol) has *significantly* stronger binding affinity than Ligand B (-0.0 kcal/mol). This is a massive difference and likely outweighs many of the other drawbacks.

**Overall Assessment:**

Despite the issues with solubility and Caco-2 permeability for both, Ligand A is the far superior candidate due to its dramatically stronger binding affinity (-9.1 vs -0.0 kcal/mol) and much better metabolic stability (lower Cl_mic). The low P-gp efflux is also beneficial. The negative half-life for ligand A is a data error, but the strong affinity makes it the better choice. While the TPSA is slightly higher than ideal, the affinity advantage is substantial.

Output:
1
2025-04-17 06:58:28,741 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (364.515 and 357.439 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (86.88) is excellent, well below the 90 A^2 threshold for CNS targets. Ligand B (96.87) is still reasonable but less optimal.

**3. logP:** Ligand A (2.445) is within the optimal range of 1-3. Ligand B (1.194) is at the lower end, potentially impacting permeability.

**4. H-Bond Donors:** Ligand A (3) and Ligand B (2) are both acceptable, below the 5 threshold.

**5. H-Bond Acceptors:** Ligand A (4) and Ligand B (6) are both within the acceptable limit of 10.

**6. QED:** Both ligands have similar QED values (0.595 and 0.519), indicating good drug-like properties.

**7. DILI:** Ligand A (29.624) has a significantly lower DILI risk than Ligand B (63.125). This is a substantial advantage.

**8. BBB:** Ligand A (53.781) has a better BBB penetration percentile than Ligand B (34.044), although both are below the desirable >70% for CNS targets. However, A is closer.

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.555 and -5.493), which is unusual and suggests poor permeability. This is a significant concern for both.

**10. Aqueous Solubility:** Both ligands have negative solubility values (-3.25 and -2.457), also unusual and suggesting poor solubility. This is a concern for both.

**11. hERG Inhibition:** Both ligands show very low hERG inhibition risk (0.33 and 0.155).

**12. Microsomal Clearance:** Ligand A (24.474) has a higher microsomal clearance than Ligand B (2.982), indicating lower metabolic stability.

**13. In vitro Half-Life:** Ligand B (6.979) has a significantly longer in vitro half-life than Ligand A (2.696).

**14. P-gp Efflux:** Both ligands show very low P-gp efflux liability (0.064 and 0.06).

**15. Binding Affinity:** Ligand B (-7.9 kcal/mol) has a slightly better binding affinity than Ligand A (-7.6 kcal/mol). This is a 0.3 kcal/mol difference, which is not huge, but could be relevant.

**Overall Assessment:**

Considering the GPCR-specific priorities, Ligand A is more promising. While both have issues with Caco-2 and solubility, Ligand A has a significantly better DILI score and a better (though still suboptimal) BBB percentile. The slightly weaker binding affinity of Ligand A is outweighed by its superior safety profile and potential for CNS exposure. Ligand B's longer half-life is a plus, but the higher DILI risk is a major concern.

Output:
1
2025-04-17 06:58:28,741 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (408.34 Da) is slightly higher than Ligand B (364.511 Da), but both are acceptable.

**TPSA:** Ligand A (58.22) is excellent for CNS penetration, well below the 90 A^2 threshold. Ligand B (67.43) is still reasonable, but less optimal.

**logP:** Ligand A (4.125) is slightly high, potentially leading to solubility issues or off-target interactions. Ligand B (1.569) is quite low, which might hinder membrane permeability.

**H-Bond Donors/Acceptors:** Both ligands have acceptable HBD (1 & 2 respectively) and HBA (4 each) counts.

**QED:** Both ligands have similar and good QED values (0.777 and 0.702), indicating good drug-like properties.

**DILI:** Ligand A (26.018) has a significantly lower DILI risk than Ligand B (33.346), which is a major advantage.

**BBB:** Ligand A (74.292) has a much better BBB penetration score than Ligand B (54.478). This is *critical* for a CNS target like DRD2.

**Caco-2 Permeability:** Ligand A (-4.973) has a negative value, indicating poor permeability. Ligand B (-5.232) is also poor, but slightly worse.

**Aqueous Solubility:** Both ligands have very poor aqueous solubility (-4.04 and -3.272 respectively). This is a concern, but can sometimes be mitigated with formulation strategies.

**hERG Inhibition:** Ligand A (0.894) has a slightly higher hERG risk than Ligand B (0.222), which is a negative.

**Microsomal Clearance:** Ligand A (67.49) has higher clearance than Ligand B (30.149), suggesting lower metabolic stability.

**In vitro Half-Life:** Ligand B (19.573) has a significantly longer half-life than Ligand A (-5.127).

**P-gp Efflux:** Ligand A (0.373) has lower P-gp efflux liability than Ligand B (0.084), which is favorable for CNS exposure.

**Binding Affinity:** Both ligands have very similar and excellent binding affinities (-7.9 and -7.7 kcal/mol). The difference is not substantial enough to be decisive.

**Overall Assessment:**

Considering the GPCR-specific priorities, Ligand A is the stronger candidate. The significantly better BBB penetration (74.292 vs 54.478) and lower DILI risk (26.018 vs 33.346) outweigh its slightly higher logP, clearance, and hERG risk. While both have poor solubility and Caco-2 permeability, these are formulation challenges that can potentially be addressed. The affinity is comparable. The improved BBB is crucial for CNS drug development.

Output:
1
2025-04-17 06:58:28,742 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (354.378 and 341.415 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (92.01) is slightly above the optimal <90 for CNS targets, but still reasonable. Ligand B (72.58) is well within the desired range.

**3. logP:** Ligand A (1.118) is within the optimal 1-3 range. Ligand B (0.275) is a bit low, potentially hindering membrane permeability.

**4. H-Bond Donors:** Ligand A (2) and Ligand B (0) are both acceptable, being <=5.

**5. H-Bond Acceptors:** Both ligands (A: 5, B: 5) are within the acceptable limit of <=10.

**6. QED:** Both ligands have good QED scores (A: 0.766, B: 0.791), indicating drug-like properties.

**7. DILI:** Both ligands have low DILI risk (A: 33.579, B: 30.787), which is favorable.

**8. BBB:** This is a critical parameter for a CNS target like DRD2. Ligand A has a good BBB percentile (86.817), while Ligand B's BBB percentile (49.826) is considerably lower and less desirable.

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 values, which is unusual and suggests a potential issue with the data or modeling. However, we must proceed with the available information.

**10. Aqueous Solubility:** Both ligands have negative solubility values, also unusual.

**11. hERG Inhibition:** Both ligands show low hERG inhibition liability (A: 0.511, B: 0.473), which is good.

**12. Microsomal Clearance:** Ligand A (-3.874) has a negative clearance, which is not physically possible and likely an artifact of the prediction. Ligand B (21.7) has a higher clearance, indicating faster metabolism.

**13. In vitro Half-Life:** Ligand A (8.943) has a reasonable half-life. Ligand B (17.902) has a longer half-life, which is generally preferred.

**14. P-gp Efflux:** Both ligands have very low P-gp efflux liability (A: 0.056, B: 0.01), which is excellent for CNS penetration.

**15. Binding Affinity:** Both ligands have strong binding affinities (A: -8.0 kcal/mol, B: -8.2 kcal/mol). Ligand B is slightly better, but the difference is small.

**Overall Assessment:**

Despite the unusual negative values for Caco-2 and solubility, the most significant difference lies in the BBB penetration. Ligand A's significantly higher BBB percentile (86.817 vs. 49.826) is a major advantage for a CNS-targeting drug. While Ligand B has a slightly better binding affinity and half-life, the superior BBB penetration of Ligand A outweighs these benefits, especially given the GPCR-specific priorities. The negative clearance for Ligand A is concerning, but could be an artifact of the prediction.

Output:
1
2025-04-17 06:58:28,742 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (361.442 Da) is slightly higher than Ligand B (348.403 Da), but both are acceptable.

**TPSA:** Ligand A (63.25) is significantly better than Ligand B (127.32). For CNS targets, we want TPSA <= 90, and Ligand A is comfortably within this range, while Ligand B exceeds it. This is a major advantage for Ligand A.

**logP:** Ligand A (2.724) is optimal (1-3), while Ligand B (0.796) is a bit low, potentially hindering membrane permeability.

**H-Bond Donors/Acceptors:** Ligand A (HBD=2, HBA=5) and Ligand B (HBD=3, HBA=5) are both within acceptable limits.

**QED:** Both ligands have reasonable QED values (Ligand A: 0.828, Ligand B: 0.671), indicating good drug-like properties.

**DILI:** Ligand A (61.807) has a higher DILI risk than Ligand B (36.952). This is a negative for Ligand A, but not a deal-breaker at this stage.

**BBB:** Ligand A (70.531) has a significantly better BBB penetration score than Ligand B (58.434). This is crucial for a CNS target like DRD2.

**Caco-2 Permeability:** Both have negative values which is unusual, but the magnitude is similar.

**Aqueous Solubility:** Both have negative values which is unusual, but the magnitude is similar.

**hERG:** Ligand A (0.618) has a slightly higher hERG risk than Ligand B (0.091). This is a negative for Ligand A.

**Microsomal Clearance:** Ligand B (-6.848) has a negative clearance, which is unusual and suggests very high metabolic stability. Ligand A (28.607) has a positive clearance, indicating faster metabolism.

**In vitro Half-Life:** Ligand B (15.027) has a slightly longer half-life than Ligand A (16.392).

**P-gp Efflux:** Ligand A (0.124) has a lower P-gp efflux liability than Ligand B (0.027), which is favorable for CNS penetration.

**Binding Affinity:** Ligand B (-8.2 kcal/mol) has a slightly better binding affinity than Ligand A (-9.0 kcal/mol). While Ligand A has a better affinity, the difference is not substantial enough to overcome the other significant ADME advantages of Ligand B.

**Overall Assessment:**

Ligand A excels in TPSA and BBB penetration, critical for CNS GPCRs. However, it has higher DILI and hERG risks, and a less favorable logP. Ligand B, while having a slightly lower affinity, demonstrates superior metabolic stability (negative Cl_mic), lower DILI and hERG risk, and acceptable BBB penetration. The TPSA is a concern, but the superior metabolic profile and safety aspects of Ligand B outweigh this drawback, especially considering the relatively small difference in binding affinity.

Output:
1
2025-04-17 06:58:28,742 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (366.439 and 350.459 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (89.59) is better than Ligand B (76.66), both are below the 90 A^2 threshold for CNS targets.

**3. logP:** Both ligands have similar logP values (1.581 and 1.668), falling within the optimal 1-3 range.

**4. H-Bond Donors:** Ligand A (0) is preferable to Ligand B (2) as fewer HBDs generally improve permeability.

**5. H-Bond Acceptors:** Ligand A (6) is slightly higher than Ligand B (4), but both are within the acceptable limit of 10.

**6. QED:** Both ligands have similar QED values (0.801 and 0.732) indicating good drug-like properties.

**7. DILI:** Ligand A (67.623) has a higher DILI risk than Ligand B (31.679). This is a significant drawback for Ligand A.

**8. BBB:** Ligand A (73.284) has a significantly better BBB percentile than Ligand B (40.558). This is a crucial factor for a CNS target like DRD2.

**9. Caco-2 Permeability:** Ligand A (-4.68) is worse than Ligand B (-5.096), indicating lower intestinal absorption.

**10. Aqueous Solubility:** Both ligands have poor aqueous solubility (-2.36 and -2.196).

**11. hERG Inhibition:** Ligand A (0.089) has a lower hERG inhibition risk than Ligand B (0.226).

**12. Microsomal Clearance:** Ligand A (53.759) has higher microsomal clearance than Ligand B (3.692), meaning it's less metabolically stable.

**13. In vitro Half-Life:** Both ligands have similar in vitro half-lives (19.653 and 19.562 hours).

**14. P-gp Efflux:** Ligand A (0.189) has lower P-gp efflux than Ligand B (0.033), which is favorable for CNS penetration.

**15. Binding Affinity:** Both ligands have very similar and excellent binding affinities (-8.3 and -8.4 kcal/mol). The difference is negligible.

**Overall Assessment:**

Ligand A excels in BBB penetration and P-gp efflux, crucial for CNS targets. It also has a lower hERG risk. However, it has a higher DILI risk and higher microsomal clearance, which are significant concerns. Ligand B has a much better safety profile (lower DILI) and metabolic stability, but suffers from poor BBB penetration.

Given the importance of CNS penetration for a DRD2 ligand, and the similar binding affinities, Ligand A is slightly more promising *despite* the higher DILI and clearance. The lower P-gp efflux and better BBB penetration are likely to result in higher brain exposure, which is critical for efficacy. Further optimization could focus on reducing the DILI risk and improving metabolic stability of Ligand A.

Output:
1
2025-04-17 06:58:28,742 - INFO - Reasoning:

Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight (MW):** Both ligands are within the ideal range (200-500 Da). Ligand A (345.443 Da) is slightly lower, which could be beneficial for permeability. Ligand B (361.913 Da) is also good.

**2. TPSA:** Ligand A (86.34) is excellent, falling well below the 90 A^2 threshold for CNS targets. Ligand B (29.54) is even better, indicating potentially improved BBB penetration.

**3. logP:** Ligand A (2.803) is optimal. Ligand B (4.591) is slightly higher, potentially leading to solubility issues or off-target interactions, but still within a reasonable range.

**4. H-Bond Donors (HBD):** Ligand A (1) is good. Ligand B (0) is also good.

**5. H-Bond Acceptors (HBA):** Ligand A (4) is good. Ligand B (2) is also good.

**6. QED:** Both ligands have acceptable QED values (Ligand A: 0.889, Ligand B: 0.767), indicating good drug-like properties.

**7. DILI:** Ligand A (43.66) has a slightly higher DILI risk than Ligand B (24.157), but both are below the concerning threshold of 60.

**8. BBB:** This is a critical parameter for a CNS target like DRD2. Ligand A (70.919) is acceptable, but Ligand B (91.392) is *excellent*, significantly increasing the likelihood of CNS exposure.

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.568 and -4.591), which is unusual and suggests poor permeability. This is a significant drawback for both compounds.

**10. Aqueous Solubility:** Both ligands have negative solubility values (-3.638 and -4.9), which is also unusual and suggests poor solubility. This is a significant drawback for both compounds.

**11. hERG Inhibition:** Both ligands have low hERG inhibition risk (0.668 and 0.783).

**12. Microsomal Clearance:** Ligand A (21.063) has lower clearance, indicating better metabolic stability, than Ligand B (102.754).

**13. In vitro Half-Life:** Ligand A (20.565) has a longer half-life than Ligand B (31.753).

**14. P-gp Efflux:** Both ligands have low P-gp efflux liability (0.322 and 0.735).

**15. Binding Affinity:** Ligand B (-8.7 kcal/mol) has a slightly better binding affinity than Ligand A (-8.2 kcal/mol). While the difference is not huge, it's a positive factor.

**Overall Assessment:**

Despite the unusual negative Caco-2 and solubility values for both compounds, Ligand B is the more promising candidate. Its superior BBB penetration (91.392 vs 70.919) is a major advantage for a CNS-targeted GPCR like DRD2. The slightly better binding affinity (-8.7 vs -8.2) further supports this conclusion. While Ligand A has better metabolic stability and half-life, the BBB is a more critical factor for CNS penetration. The poor permeability and solubility are concerning for both, and would need to be addressed through further optimization.

Output:
1
2025-04-17 06:58:28,743 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (353.463 Da) is slightly better, being closer to the lower end which can aid permeability.

**TPSA:** Both ligands have TPSA values below 90, which is good for CNS penetration. Ligand A (89.95) is slightly better than Ligand B (69.04) but both are favorable.

**logP:** Ligand A (0.371) is quite low, potentially hindering membrane permeability. Ligand B (3.503) is within the optimal range (1-3). This is a significant advantage for Ligand B.

**H-Bond Donors/Acceptors:** Ligand A has 2 HBD and 4 HBA, which is acceptable. Ligand B has 1 HBD and 5 HBA, also acceptable.

**QED:** Both ligands have good QED scores (A: 0.675, B: 0.796), indicating drug-like properties.

**DILI:** Ligand A (16.402) has a much lower DILI risk than Ligand B (58.511). This is a substantial advantage for Ligand A.

**BBB:** Ligand B (62.466) has a better BBB percentile than Ligand A (20.938). This is a key factor for CNS targets like DRD2.

**Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and suggests poor permeability.

**Aqueous Solubility:** Both have negative solubility values, which is also unusual and suggests poor solubility.

**hERG:** Both ligands have low hERG inhibition liability (A: 0.136, B: 0.177).

**Microsomal Clearance:** Ligand A (11.83) has significantly lower microsomal clearance than Ligand B (94.645), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (11.444) has a positive half-life, while Ligand B (-22.745) has a negative half-life, which is not possible. This is a major red flag for Ligand B.

**P-gp Efflux:** Ligand A (0.012) has very low P-gp efflux liability, while Ligand B (0.322) has slightly higher, but still low, efflux.

**Binding Affinity:** Ligand B (-8.7 kcal/mol) has a significantly stronger binding affinity than Ligand A (-0.0 kcal/mol). This is a very substantial advantage for Ligand B.

**Overall Assessment:**

Despite Ligand B's superior binding affinity and BBB penetration, the negative in vitro half-life is a critical flaw. The low logP of Ligand A is concerning, but the significantly better DILI, metabolic stability, and P-gp efflux profile, combined with a plausible half-life, make it the more promising candidate. The substantial difference in binding affinity is a concern, but can potentially be addressed through further optimization. The negative values for Caco-2 and solubility are concerning for both, but might be experimental artifacts or indicate issues that can be addressed with formulation.

Output:
0
2025-04-17 06:58:28,743 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (345.443 and 349.475 Da) fall comfortably within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (70.49) is better than Ligand B (69.72). Both are below the 90 A^2 threshold desirable for CNS targets, which is excellent.

**3. logP:** Ligand A (2.489) is slightly higher than Ligand B (1.566), both are within the optimal 1-3 range. Ligand B is a bit lower and could potentially have absorption issues, but it's not a major concern.

**4. H-Bond Donors:** Ligand A (2) is slightly higher than Ligand B (1), both are within the acceptable limit of <=5.

**5. H-Bond Acceptors:** Ligand A (5) is higher than Ligand B (3), both are within the acceptable limit of <=10.

**6. QED:** Ligand A (0.757) is significantly better than Ligand B (0.56), indicating a more drug-like profile.

**7. DILI:** Ligand A (8.181) is *much* better than Ligand B (31.563). This is a significant advantage for Ligand A, as lower DILI risk is crucial.

**8. BBB:** Ligand A (79.062) is considerably better than Ligand B (68.321). For a CNS target like DRD2, a BBB percentile >70 is highly desirable. Ligand A is closer to this threshold.

**9. Caco-2:** Ligand A (-5.345) is worse than Ligand B (-4.724). Lower (more negative) values indicate lower permeability. This is a slight negative for Ligand A.

**10. Solubility:** Ligand A (-3.167) is worse than Ligand B (-2.07). Lower (more negative) values indicate lower solubility. This is a slight negative for Ligand A.

**11. hERG:** Ligand A (0.904) is slightly higher than Ligand B (0.469), indicating a slightly higher risk of hERG inhibition.

**12. Cl_mic:** Ligand A (7.455) is *much* better than Ligand B (53.744). Lower microsomal clearance indicates better metabolic stability, a significant advantage for Ligand A.

**13. t1/2:** Ligand A (-34.235) is worse than Ligand B (-24.636). Lower (more negative) values indicate shorter half-life. This is a negative for Ligand A.

**14. Pgp:** Ligand A (0.079) is *much* better than Ligand B (0.252). Lower P-gp efflux is highly desirable for CNS penetration.

**15. Binding Affinity:** Ligand A (-8.7 kcal/mol) is significantly better than Ligand B (-6.6 kcal/mol). This is a substantial advantage, exceeding the 1.5 kcal/mol difference that can outweigh other drawbacks.

**Overall Assessment:**

Ligand A is clearly superior. While it has some minor drawbacks in Caco-2 permeability, solubility, and half-life, its significantly better BBB penetration, lower DILI risk, lower P-gp efflux, and *much* stronger binding affinity outweigh these concerns. Ligand B's higher DILI risk and lower BBB penetration are significant liabilities for a CNS drug candidate. The affinity difference is also substantial.

Output:
0
2025-04-17 06:58:28,743 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (330.351 and 345.378 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (96.45) is slightly above the optimal <90 for CNS targets, but still reasonable. Ligand B (90.98) is better, falling just within the preferred range.

**3. logP:** Both ligands have good logP values (2.345 and 1.468), falling within the 1-3 range. Ligand B is slightly better, being closer to 1.

**4. H-Bond Donors:** Both have 2 HBD, which is within the acceptable limit of <=5.

**5. H-Bond Acceptors:** Ligand A has 5 HBA, and Ligand B has 4. Both are within the acceptable limit of <=10.

**6. QED:** Both ligands have good QED scores (0.599 and 0.829), indicating good drug-like properties. Ligand B is better.

**7. DILI:** Ligand A has a DILI risk of 92.633, which is high. Ligand B has a DILI risk of 51.221, which is much better (still moderate, but significantly lower).

**8. BBB:** This is critical for a CNS target like DRD2. Ligand A has a BBB penetration of 40.403%, which is poor. Ligand B has a BBB penetration of 61.652%, which is better, though still not ideal (we want >70%).

**9. Caco-2:** Both have negative Caco-2 values (-5.558 and -4.979), which is unusual and suggests poor permeability. These values are difficult to interpret without further context, but generally, a higher value is preferred.

**10. Solubility:** Both have negative solubility values (-4.154 and -2.105), also unusual and indicating poor aqueous solubility.

**11. hERG:** Both ligands have low hERG inhibition risk (0.511 and 0.415).

**12. Cl_mic:** Ligand A has a clearance of 31.065 mL/min/kg, while Ligand B has a clearance of -11.972 mL/min/kg. A negative clearance is not physically meaningful, and suggests an issue with the data. Assuming the data is correct, Ligand A is better here.

**13. t1/2:** Ligand A has a negative half-life (-9.016 hours), which is not physically possible. Ligand B has a half-life of -32.295 hours, also not physically possible. These values are problematic.

**14. Pgp:** Ligand A has a Pgp efflux liability of 0.152, and Ligand B has 0.025. Ligand B is much better, indicating less P-gp efflux.

**15. Binding Affinity:** Ligand A has a binding affinity of -10.8 kcal/mol, which is excellent. Ligand B has a binding affinity of -8.7 kcal/mol, which is also good, but significantly weaker than Ligand A.

**Overall Assessment:**

Despite the questionable values for Caco-2, solubility, and half-life, the most significant differences lie in DILI, BBB, and binding affinity. Ligand A has a much higher DILI risk and significantly poorer BBB penetration than Ligand B. However, Ligand A's binding affinity is substantially stronger (-10.8 vs -8.7 kcal/mol).

Given the GPCR-specific priorities, BBB penetration is crucial for CNS targets. While Ligand A's affinity is superior, the poor BBB penetration and high DILI risk are major drawbacks. Ligand B, despite the weaker affinity, has a better BBB profile and a much lower DILI risk, making it a more promising starting point for further optimization. The negative values for clearance and half-life are concerning and would need to be investigated.

Output:
1
2025-04-17 06:58:28,743 - INFO - Batch 326 complete. Total preferences: 5216
2025-04-17 06:58:28,743 - INFO - Processing batch 327/512...
2025-04-17 06:59:10,418 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 drug candidates, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (352.406 and 362.417 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (78.87) is significantly better than Ligand B (89.87). For CNS targets, we want TPSA <= 90, and A is closer to the optimal range.

**3. logP:** Both ligands have good logP values (1.334 and 1.052), falling within the 1-3 range.

**4. H-Bond Donors:** Ligand A (2) is preferable to Ligand B (3), as lower HBD generally improves permeability.

**5. H-Bond Acceptors:** Both ligands have the same number of HBA (4), which is acceptable (<=10).

**6. QED:** Ligand A (0.776) has a better QED score than Ligand B (0.602), indicating a more drug-like profile.

**7. DILI:** Both ligands have low DILI risk (30.438 and 25.165), which is good.

**8. BBB:** Ligand A (76.309) has a slightly better BBB percentile than Ligand B (70.182). Both are above 70, which is desirable for CNS targets, but A is closer to optimal.

**9. Caco-2 Permeability:** Ligand A (-4.319) is better than Ligand B (-4.826). Higher values indicate better absorption.

**10. Aqueous Solubility:** Both are similarly poor (-1.76 and -1.876). This could be a formulation challenge for both.

**11. hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.452 and 0.451).

**12. Microsomal Clearance:** Ligand B (-10.196) has significantly lower (better) microsomal clearance than Ligand A (27.207). This suggests better metabolic stability for Ligand B.

**13. In vitro Half-Life:** Ligand B (5.724) has a slightly longer half-life than Ligand A (5.145).

**14. P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.087 and 0.037).

**15. Binding Affinity:** Both ligands have identical and excellent binding affinity (-7.7 kcal/mol).

**Overall Assessment:**

While Ligand B has better metabolic stability (lower Cl_mic) and a slightly longer half-life, Ligand A is superior in several key areas for a CNS-targeting GPCR: TPSA, BBB penetration, Caco-2 permeability, and QED. The slightly better BBB and TPSA of Ligand A are crucial for CNS penetration. The difference in metabolic stability is not substantial enough to outweigh the advantages of Ligand A, especially given the excellent binding affinity shared by both.

Output:
1
2025-04-17 06:59:10,419 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (336.395 and 346.435 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (57.92) is significantly better than Ligand B (90.89). For CNS targets, we want TPSA <= 90, and A is comfortably within that range, while B is right at the upper limit. This favors A.

**3. logP:** Both ligands have similar logP values (1.87 and 1.882), both falling within the optimal 1-3 range.

**4. H-Bond Donors:** Ligand A (0) is preferable to Ligand B (1). Fewer HBDs generally improve membrane permeability.

**5. H-Bond Acceptors:** Ligand A (4) is better than Ligand B (8). Lower HBA counts are generally preferred for CNS penetration.

**6. QED:** Both ligands have reasonable QED values (0.841 and 0.78), indicating good drug-like properties.

**7. DILI:** Ligand A (59.093) has a slightly higher DILI risk than Ligand B (41.411), but both are acceptable (<60 is good).

**8. BBB:** Both ligands have excellent BBB penetration (74.835 and 76.696), exceeding the desirable >70 threshold for CNS targets.

**9. Caco-2 Permeability:** Ligand A (-4.723) has worse Caco-2 permeability than Ligand B (-5.211). Lower (more negative) values indicate poorer permeability.

**10. Aqueous Solubility:** Both ligands have similar and poor aqueous solubility (-1.953 and -1.942). This could pose formulation challenges, but isn't a deciding factor.

**11. hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.573 and 0.153).

**12. Microsomal Clearance:** Ligand A (49.184) has a slightly higher microsomal clearance than Ligand B (47.355), suggesting slightly lower metabolic stability.

**13. In vitro Half-Life:** Ligand A (-37.908) has a much longer in vitro half-life than Ligand B (-3.958). This is a significant advantage.

**14. P-gp Efflux:** Ligand A (0.206) has lower P-gp efflux than Ligand B (0.112), which is favorable for CNS exposure.

**15. Binding Affinity:** Ligand B (-7.4) has a slightly better binding affinity than Ligand A (-8.1). However, the difference is only 0.7 kcal/mol, and other factors are more important.

**Overall Assessment:**

Ligand A is the stronger candidate. While Ligand B has slightly better affinity and Caco-2 permeability, Ligand A excels in critical properties for a CNS-targeting GPCR ligand: lower TPSA, fewer H-bonds, lower P-gp efflux, and a significantly longer half-life. The slightly higher DILI risk for A is less concerning than the higher TPSA and HBA of B. The affinity difference is not substantial enough to overcome these ADME advantages.

Output:
1
2025-04-17 06:59:10,419 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (362.496 and 368.474 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (41.13) is significantly better than Ligand B (75.27). For CNS targets, we want TPSA <= 90, and ideally much lower. Ligand A is well within this range, while Ligand B is approaching the upper limit and less favorable.

**logP:** Both ligands have good logP values (3.27 and 2.123), falling within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Both have 2 HBD, which is good. Ligand A has 1 HBA, while Ligand B has 3. Both are acceptable, being <= 10.

**QED:** Both ligands have similar and acceptable QED values (0.761 and 0.774), indicating good drug-like properties.

**DILI:** Ligand A (53.936) has a slightly higher DILI risk than Ligand B (37.728), but both are below the concerning threshold of 60.

**BBB:** Ligand A (70.26) has a better BBB percentile than Ligand B (68.67), both are reasonably good, but A is slightly better. For a CNS target like DRD2, >70 is desirable.

**Caco-2 Permeability:** Ligand A (-4.59) has worse Caco-2 permeability than Ligand B (-4.924). Lower numbers indicate lower permeability.

**Aqueous Solubility:** Ligand A (-5.071) has worse aqueous solubility than Ligand B (-3.074). Higher numbers are better.

**hERG Inhibition:** Ligand A (0.902) has a higher hERG inhibition risk than Ligand B (0.542). Lower is better.

**Microsomal Clearance:** Ligand B (20.233) has significantly lower microsomal clearance than Ligand A (75.334), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand B (-22.792) has a much longer in vitro half-life than Ligand A (60.895). This is a significant advantage.

**P-gp Efflux:** Ligand A (0.582) has better P-gp efflux profile than Ligand B (0.165). Lower is better.

**Binding Affinity:** Ligand B (-9.9 kcal/mol) has a *much* stronger binding affinity than Ligand A (0.0 kcal/mol). This is a decisive advantage. A difference of >1.5 kcal/mol can outweigh other drawbacks.

**Overall Assessment:**

While Ligand A has better TPSA and BBB, Ligand B's significantly stronger binding affinity (-9.9 vs 0.0 kcal/mol) and superior metabolic stability (lower Cl_mic, longer t1/2) are crucial for a GPCR target. The slightly higher TPSA of Ligand B is less concerning given its potent binding. The better P-gp efflux of ligand A is helpful, but the affinity difference is much more important.

Output:
1
2025-04-17 06:59:10,419 - INFO - Reasoning:

Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (350.503 and 347.463 Da) fall comfortably within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (69.64) is significantly better than Ligand B (88.17). For CNS targets, we want TPSA <= 90, and A is closer to the ideal <=60 range. B is pushing the upper limit.

**3. logP:** Both ligands have good logP values (2.469 and 2.093), falling within the optimal 1-3 range.

**4. H-Bond Donors:** Both have acceptable HBD counts (2 and 3 respectively), well below the 5 threshold.

**5. H-Bond Acceptors:** Ligand A (3) is better than Ligand B (6), both are below the 10 threshold.

**6. QED:** Both ligands have reasonable QED values (0.741 and 0.667), indicating good drug-like properties.

**7. DILI:** Ligand A (12.369) has a much lower DILI risk than Ligand B (39.201). This is a significant advantage for A.

**8. BBB:** Ligand B (74.641) has a better BBB penetration percentile than Ligand A (61.497). While both are reasonably good, B is closer to the desirable >70 for CNS targets.

**9. Caco-2 Permeability:** Ligand A (-4.582) has worse Caco-2 permeability than Ligand B (-5.241). Lower values are less favorable.

**10. Aqueous Solubility:** Ligand A (-2.694) has worse solubility than Ligand B (-2.026). Both are poor, but B is slightly better.

**11. hERG Inhibition:** Both ligands have low hERG inhibition risk (0.231 and 0.344).

**12. Microsomal Clearance:** Ligand B (31.215) has a lower microsomal clearance than Ligand A (36.77), indicating better metabolic stability.

**13. In vitro Half-Life:** Ligand B (25.845) has a significantly longer in vitro half-life than Ligand A (-1.553). This is a major advantage for B.

**14. P-gp Efflux:** Ligand A (0.116) has lower P-gp efflux than Ligand B (0.019), which is preferable for CNS penetration.

**15. Binding Affinity:** Both ligands have very similar and excellent binding affinities (-8.4 and -8.5 kcal/mol). This difference is negligible.

**Overall Assessment:**

While Ligand B has better BBB penetration and metabolic stability (longer half-life, lower Cl_mic), Ligand A has a much better safety profile (lower DILI) and lower P-gp efflux. The TPSA is also significantly better for Ligand A. Given the importance of CNS penetration for a DRD2 ligand, BBB is crucial. However, the significantly lower DILI risk of Ligand A is a major factor. Considering the similar binding affinities, the lower DILI risk and better TPSA of Ligand A make it the more promising candidate, despite the slightly lower BBB.

Output:
0
2025-04-17 06:59:10,419 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (352.475 and 360.336 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (67.87) is significantly better than Ligand B (99.15). For CNS targets, we want TPSA <= 90, so Ligand A is preferable.

**logP:** Both ligands have acceptable logP values (1.441 and 1.054), falling within the 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A (HBD=1, HBA=4) is better than Ligand B (HBD=4, HBA=4). Lower HBD is generally preferred for BBB penetration.

**QED:** Both ligands have good QED scores (0.504 and 0.62), indicating good drug-like properties.

**DILI:** Ligand A (29.74) has a much lower DILI risk than Ligand B (63.397). This is a significant advantage for Ligand A.

**BBB:** Ligand A (54.634) has a better BBB percentile than Ligand B (48.275), although both are below the desirable >70 for CNS targets.

**Caco-2:** Ligand B (-5.455) has a better Caco-2 permeability than Ligand A (-4.402).

**Solubility:** Ligand B (-2.49) has better solubility than Ligand A (-1.737).

**hERG:** Both ligands have low hERG inhibition liability (0.397 and 0.573).

**Microsomal Clearance:** Ligand A (13.282) has a higher (worse) microsomal clearance than Ligand B (9.286). This suggests Ligand B is more metabolically stable.

**In vitro Half-Life:** Ligand B (11.34) has a longer in vitro half-life than Ligand A (-3.623).

**P-gp Efflux:** Ligand A (0.089) has lower P-gp efflux liability than Ligand B (0.066), which is favorable for CNS penetration.

**Binding Affinity:** Ligand B (-9.4 kcal/mol) has a significantly stronger binding affinity than Ligand A (-7.5 kcal/mol). This is a substantial advantage, potentially outweighing some of the ADME drawbacks. The difference is >1.5 kcal/mol.

**Overall Assessment:**

While Ligand A has better TPSA, DILI risk, and P-gp efflux, Ligand B's significantly stronger binding affinity (-9.4 vs -7.5 kcal/mol) is the most important factor for a GPCR target. The improved metabolic stability (lower Cl_mic, longer t1/2) of Ligand B is also a significant benefit. Although Ligand B's BBB penetration is not ideal, the higher affinity may compensate for this.

Output:
1
2025-04-17 06:59:10,419 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (382.291 Da) is slightly higher than Ligand B (337.431 Da), but both are acceptable.

**TPSA:** Ligand A (98.5) is approaching the upper limit for CNS targets (<=90), while Ligand B (64.45) is well within the ideal range. This favors Ligand B.

**logP:** Both ligands have good logP values (A: 2.351, B: 3.106), falling within the optimal 1-3 range. Ligand B is slightly higher, which could be beneficial for membrane permeability, but not drastically.

**H-Bond Donors/Acceptors:** Both have 1 HBD, which is good. Ligand A has 6 HBA, while Ligand B has 7. Both are acceptable given the other parameters.

**QED:** Both ligands have reasonable QED values (A: 0.77, B: 0.608), indicating good drug-like properties.

**DILI:** Ligand A has a significantly higher DILI risk (98.565%) than Ligand B (73.245%). This is a major concern for Ligand A.

**BBB:** Ligand A has a much better BBB penetration percentile (83.288%) than Ligand B (57.852%). This is a critical factor for a CNS target like DRD2, strongly favoring Ligand A.

**Caco-2 Permeability:** Both have negative Caco-2 values (-4.572 and -4.917), which is unusual and suggests poor permeability. This is a drawback for both, but the values are similar.

**Aqueous Solubility:** Both have negative solubility values (-4.371 and -3.558), indicating poor solubility. This is a concern for both, but again, similar.

**hERG Inhibition:** Ligand A (0.576) has a slightly lower hERG risk than Ligand B (0.867), which is preferable.

**Microsomal Clearance:** Ligand B has a higher microsomal clearance (40.188 mL/min/kg) than Ligand A (25.084 mL/min/kg), indicating faster metabolism and potentially lower exposure. This favors Ligand A.

**In vitro Half-Life:** Ligand B has a longer in vitro half-life (40.74 hours) than Ligand A (20.455 hours), which is generally desirable.

**P-gp Efflux:** Ligand A (0.141) has a significantly lower P-gp efflux liability than Ligand B (0.706). Lower P-gp efflux is crucial for CNS penetration, favoring Ligand A.

**Binding Affinity:** Ligand B (-9.0 kcal/mol) has a slightly better binding affinity than Ligand A (-8.6 kcal/mol). While a 1.5 kcal/mol difference is significant, the other ADME properties are more concerning for Ligand A.

**Overall Assessment:**

Ligand A has a significantly better BBB, lower P-gp efflux, lower microsomal clearance, and lower hERG risk. However, its DILI risk is very high. Ligand B has better affinity and half-life, but suffers from poorer BBB penetration, higher P-gp efflux, and higher DILI risk.

Given the importance of BBB penetration for a CNS target like DRD2, and the unacceptable DILI risk of Ligand A, **Ligand B** is the more promising candidate, despite its other drawbacks. The affinity difference, while notable, can potentially be addressed through further optimization. The DILI risk of Ligand A is a major red flag.

Output:
1
2025-04-17 06:59:10,419 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (346.293 and 349.391 Da) fall comfortably within the ideal 200-500 Da range.

**TPSA:** Ligand A (96.97) is excellent, well below the 90 A^2 threshold for CNS targets. Ligand B (129.23) is higher, but still potentially acceptable, though less ideal.

**logP:** Ligand A (1.995) is optimal. Ligand B (-0.164) is quite low, potentially hindering membrane permeability and CNS penetration.

**H-Bond Donors/Acceptors:** Ligand A (2 HBD, 5 HBA) is well within acceptable limits. Ligand B (4 HBD, 6 HBA) is also acceptable, but slightly higher.

**QED:** Both ligands have reasonable QED values (0.753 and 0.524), indicating good drug-like properties.

**DILI:** Ligand A (96.627) has a higher DILI risk than Ligand B (63.978), which is a concern. However, DILI prediction is not always reliable.

**BBB:** This is crucial for a CNS target like DRD2. Ligand A (65.607) is moderate, while Ligand B (20.977) is very low, suggesting poor brain penetration.

**Caco-2 Permeability:** Ligand A (-4.854) shows poor permeability. Ligand B (-5.634) is also poor.

**Aqueous Solubility:** Ligand A (-4.525) and Ligand B (-2.568) both have poor solubility.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.414 and 0.3), which is positive.

**Microsomal Clearance:** Ligand A (-1.912) indicates relatively good metabolic stability (lower clearance). Ligand B (9.996) suggests faster metabolism.

**In vitro Half-Life:** Ligand A (69.269 hours) has a significantly longer half-life than Ligand B (7.31 hours).

**P-gp Efflux:** Ligand A (0.163) has lower P-gp efflux, which is favorable for CNS penetration. Ligand B (0.022) also has low P-gp efflux.

**Binding Affinity:** Both ligands have excellent binding affinities (-9.6 and -8.1 kcal/mol). Ligand A is slightly better (-9.6 kcal/mol).

**Overall Assessment:**

Ligand A is superior despite the higher DILI risk. Its key advantages are its optimal logP, better BBB penetration, longer half-life, and slightly better binding affinity. Ligand B's low logP is a major drawback for a CNS-targeting drug, as is its poor BBB penetration. While Ligand B has a lower predicted DILI risk, the other ADME properties of Ligand A are more favorable for CNS drug development.

Output:
0
2025-04-17 06:59:10,419 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (346.431 Da) is slightly better, being closer to the lower end which can aid permeability.

**TPSA:** Ligand A (67.67) is significantly better than Ligand B (90.55). For CNS targets, TPSA should be <= 90, and A is comfortably within this range, while B is right at the upper limit.

**logP:** Ligand A (1.169) is optimal, while Ligand B (3.797) is approaching the higher end of the optimal range. While still acceptable, higher logP can sometimes lead to solubility issues and off-target interactions.

**H-Bond Donors/Acceptors:** Ligand A (0 HBD, 5 HBA) is preferable to Ligand B (4 HBD, 7 HBA). Lower HBD/HBA generally improves permeability.

**QED:** Ligand A (0.768) has a better QED score than Ligand B (0.5), indicating a more drug-like profile.

**DILI:** Ligand A (44.087) has a much lower DILI risk than Ligand B (76.464). This is a significant advantage.

**BBB:** Ligand A (63.086) shows moderate BBB penetration, while Ligand B (49.011) is lower. While both are not ideal (>70 is desirable), A is better.

**Caco-2 Permeability:** Ligand A (-4.354) has better Caco-2 permeability than Ligand B (-5.395).

**Aqueous Solubility:** Ligand A (-0.775) has better aqueous solubility than Ligand B (-4.997).

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.318 and 0.695 respectively), which is good.

**Microsomal Clearance:** Ligand A (27.917) has lower microsomal clearance than Ligand B (70.713), indicating better metabolic stability.

**In vitro Half-Life:** Ligand A (-21.762) has a longer in vitro half-life than Ligand B (50.981).

**P-gp Efflux:** Ligand A (0.089) has lower P-gp efflux liability than Ligand B (0.193), which is important for CNS penetration.

**Binding Affinity:** Both ligands have similar, strong binding affinities (-8.3 and -8.5 kcal/mol). The difference is negligible.

**Overall Assessment:**

Ligand A consistently outperforms Ligand B across most critical ADME properties, especially TPSA, DILI, BBB, solubility, metabolic stability, and P-gp efflux. While both have good binding affinity, the superior ADME profile of Ligand A makes it a significantly more promising drug candidate for a CNS target like DRD2.

Output:
1
2025-04-17 06:59:10,420 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B based on the provided guidelines, prioritizing GPCR-specific properties (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (350.463 Da) is slightly lower, which could be beneficial for permeability.

**TPSA:** Ligand A (85.25) is significantly better than Ligand B (58.22), falling well within the desirable range for CNS targets (<=90). Ligand B is excellent as well.

**logP:** Ligand A (1.697) is optimal, while Ligand B (4.052) is approaching the upper limit. While still acceptable, higher logP can sometimes lead to off-target effects and solubility issues.

**H-Bond Donors/Acceptors:** Ligand A has 2 HBD and 5 HBA, while Ligand B has 1 HBD and 6 HBA. Both are within acceptable limits.

**QED:** Both ligands have similar QED values (0.818 and 0.764), indicating good drug-likeness.

**DILI:** Ligand A (25.359) has a much lower DILI risk than Ligand B (75.107). This is a significant advantage for Ligand A.

**BBB:** Ligand A (40.093) is lower than Ligand B (46.762), but both are below the desirable threshold of >70 for CNS targets. This is a weakness for both, but less so for Ligand B.

**Caco-2 Permeability:** Ligand A (-4.77) is much worse than Ligand B (-5.12), indicating lower intestinal absorption.

**Aqueous Solubility:** Ligand A (-1.424) is better than Ligand B (-5.402).

**hERG Inhibition:** Ligand A (0.124) has a much lower hERG inhibition liability than Ligand B (0.578). This is a significant safety advantage for Ligand A.

**Microsomal Clearance:** Ligand A (7.374) has a lower microsomal clearance than Ligand B (106.918), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (0.5) has a much shorter half-life than Ligand B (-5.522).

**P-gp Efflux:** Ligand A (0.014) has a much lower P-gp efflux liability than Ligand B (0.495), which is crucial for CNS penetration.

**Binding Affinity:** Ligand A (-7.1) has a slightly better binding affinity than Ligand B (-6.7). While the difference is not huge, it's still a positive for Ligand A.

**Overall Assessment:**

Ligand A is superior due to its significantly better safety profile (lower DILI, lower hERG), better metabolic stability (lower Cl_mic), and lower P-gp efflux, which is critical for CNS penetration. While its BBB penetration is not ideal, it is comparable to Ligand B. The slightly better binding affinity and solubility also contribute to its favorability. Ligand B's higher logP and significantly worse metabolic stability are concerning.

Output:
0
2025-04-17 06:59:10,420 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (350.423 and 366.451 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (112.85) is better than Ligand B (123.13). Both are below the 140 A^2 threshold for oral absorption, and closer to the <90 A^2 desired for CNS targets.

**logP:** Ligand A (0.345) is quite low, potentially hindering membrane permeability. Ligand B (-0.084) is also low, but slightly better. Both are below the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Both have 1 HBD, which is good. Ligand A has 5 HBA, acceptable. Ligand B has 9 HBA, which is approaching the upper limit of 10 and could potentially impact permeability.

**QED:** Ligand B (0.726) has a significantly better QED score than Ligand A (0.438), indicating a more drug-like profile.

**DILI:** Ligand A (16.673) has a much lower DILI risk than Ligand B (59.597), a significant advantage.

**BBB:** Ligand B (62.117) has a substantially better BBB penetration score than Ligand A (27.84). This is *critical* for a CNS target like DRD2.

**Caco-2 Permeability:** Both have negative Caco-2 values (-5.168 and -5.705), which is unusual and suggests poor permeability.

**Aqueous Solubility:** Both have negative solubility values (-0.553 and -1.545), also unusual and indicating very low solubility.

**hERG:** Both have low hERG inhibition liability (0.236 and 0.048), which is positive.

**Microsomal Clearance:** Ligand A (-19.318) has a much lower (better) microsomal clearance than Ligand B (20.469), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (18.49) has a better in vitro half-life than Ligand B (-1.154).

**P-gp Efflux:** Both have very low P-gp efflux liability (0.008 and 0.013), which is favorable.

**Binding Affinity:** Both have excellent binding affinities (-7.0 and -6.9 kcal/mol), very close in value.

**Overall Assessment:**

Ligand B clearly wins on BBB penetration, a crucial factor for CNS drug development. It also has a better QED score. However, Ligand A exhibits significantly lower DILI risk and better metabolic stability (lower Cl_mic and higher t1/2). The low logP and solubility for both are concerning, but the strong binding affinity might compensate. Given the importance of BBB penetration for a CNS target, and the relatively small difference in binding affinity, Ligand B is the more promising candidate *despite* its higher DILI risk. Further optimization would be needed to address the solubility and logP issues for both.

Output:
1
2025-04-17 06:59:10,420 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (448.77) is towards the higher end, while Ligand B (348.447) is more optimal.

**2. TPSA:** Both ligands have TPSA values (84.22 and 85.77) slightly above the preferred <90 for CNS targets, but not drastically so.

**3. logP:** Ligand A (3.426) is within the optimal range (1-3). Ligand B (0.199) is significantly *below* the optimal range, which could hinder membrane permeability and CNS penetration.

**4. H-Bond Donors:** Both have 2 HBD, which is acceptable.

**5. H-Bond Acceptors:** Both have 5 HBA, which is acceptable.

**6. QED:** Both ligands have good QED scores (0.709 and 0.735), indicating drug-like properties.

**7. DILI:** Ligand A (81.039) has a higher DILI risk than Ligand B (16.44). This is a significant negative for Ligand A.

**8. BBB:** Ligand A (44.785) has a very low BBB penetration percentile, making it unlikely to reach the target in the CNS. Ligand B (28.655) also has a low BBB percentile, but it is still better than Ligand A.

**9. Caco-2:** Both have negative Caco-2 values, which is unusual and suggests poor permeability.

**10. Solubility:** Both have negative solubility values, which is also unusual and suggests poor solubility.

**11. hERG:** Both ligands have low hERG inhibition liability (0.407 and 0.244), which is good.

**12. Cl_mic:** Ligand A (41.787) has a higher microsomal clearance than Ligand B (-20.557).  Negative clearance suggests very high metabolic stability, which is a significant advantage for Ligand B.

**13. t1/2:** Ligand A (29.679) has a longer in vitro half-life than Ligand B (4.664).

**14. Pgp:** Ligand A (0.487) has a higher Pgp efflux liability than Ligand B (0.013). Lower Pgp is preferred, especially for CNS targets, making Ligand B better.

**15. Binding Affinity:** Both ligands have similar and strong binding affinities (-8.4 and -8.2 kcal/mol). The difference is less than the 1.5 kcal/mol threshold.

**Overall Assessment:**

Considering the GPCR-specific priorities, Ligand B is the more promising candidate. While both have issues with Caco-2 and solubility, Ligand B has substantially better predicted BBB penetration, lower DILI risk, and significantly lower Pgp efflux, and much better metabolic stability. The slightly lower binding affinity of Ligand B is unlikely to be a major issue given its superior ADME properties. Ligand A's very poor BBB penetration and higher DILI risk are major drawbacks.

Output:
1
2025-04-17 06:59:10,420 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 drug candidates, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (362.352 and 347.459 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (88.41) is slightly above the optimal <90 for CNS targets, but still reasonable. Ligand B (75.44) is excellent, well below 90.

**logP:** Ligand A (1.581) is within the optimal 1-3 range. Ligand B (2.763) is also good, leaning towards the higher end but still acceptable.

**H-Bond Donors/Acceptors:** Ligand A (3 HBD, 6 HBA) is favorable. Ligand B (1 HBD, 4 HBA) is also very good. Both are well within the recommended limits.

**QED:** Both ligands have good QED scores (0.669 and 0.889), indicating drug-like properties.

**DILI:** Ligand A (54.323) is better than Ligand B (33.889) in terms of DILI risk, both are acceptable.

**BBB:** Ligand B (82.513) has a significantly better BBB penetration score than Ligand A (70.648). This is a crucial advantage for a CNS target like DRD2.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.849 and -4.674), which is unusual and suggests poor permeability. However, these values are on a log scale and should be interpreted cautiously.

**Aqueous Solubility:** Both ligands have negative solubility values (-2.396 and -3.012), which is also unusual. This suggests poor aqueous solubility.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.501 and 0.357).

**Microsomal Clearance:** Ligand A (49.17) has a lower microsomal clearance than Ligand B (63.367), indicating better metabolic stability.

**In vitro Half-Life:** Ligand B (-22.193) has a negative in vitro half-life, which is not possible and suggests an error or unusual behavior. Ligand A (10.56) has a reasonable half-life.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.09 and 0.043), which is favorable for CNS penetration.

**Binding Affinity:** Ligand B (-8.8 kcal/mol) has a slightly better binding affinity than Ligand A (-8.3 kcal/mol). While the difference is not huge, it's a positive factor.

**Overall Assessment:**

Ligand B is the stronger candidate. Its significantly better BBB penetration (82.513 vs 70.648) is a major advantage for a CNS target. The slightly improved binding affinity (-8.8 vs -8.3) also contributes. The negative half-life for Ligand B is concerning and could be a data error, but even ignoring that, the superior BBB score makes it more promising. While Ligand A has better metabolic stability (lower Cl_mic), the BBB is more critical for DRD2. The solubility and permeability issues are shared by both, and would need to be addressed in further optimization.

Output:
1
2025-04-17 06:59:10,420 - INFO - Reasoning:

Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (370.431 and 348.407 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (106.71) is better than Ligand B (120.12). For CNS targets, we want TPSA <= 90, so both are slightly above the ideal, but A is closer.

**3. logP:** Ligand A (0.644) is slightly low, potentially hindering permeation. Ligand B (-0.508) is even lower, raising more concerns about permeability. Both are below the optimal 1-3 range.

**4. H-Bond Donors:** Ligand A (1) is good. Ligand B (2) is acceptable.

**5. H-Bond Acceptors:** Ligand A (7) is good. Ligand B (6) is good.

**6. QED:** Both ligands have good QED scores (A: 0.558, B: 0.623), indicating drug-like properties.

**7. DILI:** Ligand A (74.215) has a higher DILI risk than Ligand B (30.942). This is a significant drawback for Ligand A.

**8. BBB:** Ligand A (82.474) has a much better BBB penetration score than Ligand B (38.852). This is *critical* for a CNS target like DRD2.

**9. Caco-2 Permeability:** Ligand A (-4.881) has worse Caco-2 permeability than Ligand B (-5.455). Both are poor, but B is slightly worse.

**10. Aqueous Solubility:** Ligand A (-3.153) has better solubility than Ligand B (-1.579). Solubility is important for formulation.

**11. hERG Inhibition:** Both ligands have very low hERG inhibition risk (A: 0.216, B: 0.074).

**12. Microsomal Clearance:** Ligand A (36.793) has higher microsomal clearance than Ligand B (6.301), meaning it's less metabolically stable.

**13. In vitro Half-Life:** Ligand A (5.516) has a shorter half-life than Ligand B (32.844).

**14. P-gp Efflux:** Ligand A (0.08) has slightly higher P-gp efflux than Ligand B (0.007). Lower is better for CNS penetration.

**15. Binding Affinity:** Ligand A (-7.5 kcal/mol) has a slightly better binding affinity than Ligand B (-7.2 kcal/mol). While the difference is not huge, it's a positive for Ligand A.

**Overall Assessment:**

Ligand A has a better binding affinity and significantly better BBB penetration, which are crucial for a CNS GPCR target. However, it has a higher DILI risk and poorer metabolic stability (higher Cl_mic, shorter t1/2). Ligand B has a better safety profile (lower DILI) and better metabolic stability, but its BBB penetration is very poor, and its logP is concerning.

Given the importance of BBB penetration for CNS targets, and the relatively small difference in binding affinity, Ligand A is the more promising candidate *despite* its slightly worse ADME properties. The DILI risk could potentially be mitigated through structural modifications. The poor logP of both compounds is a concern, but could also be addressed in subsequent optimization.



Output:
1
2025-04-17 06:59:10,421 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 drug candidates, prioritizing GPCR-specific properties (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (347.459 and 355.385 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (63.57) is better than Ligand B (66.65). Both are below the 90 A^2 threshold desirable for CNS targets, but A is closer to optimal.

**logP:** Ligand A (1.658) and Ligand B (2.1) are both within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A has 1 HBD and 4 HBA, while Ligand B has 0 HBD and 4 HBA. Both are within acceptable limits (<=5 HBD, <=10 HBA).

**QED:** Ligand B (0.811) has a significantly better QED score than Ligand A (0.575), indicating a more drug-like profile.

**DILI:** Ligand A (11.322) has a much lower DILI risk than Ligand B (44.048). This is a significant advantage for Ligand A.

**BBB:** Ligand B (86.39) has a substantially higher BBB penetration percentile than Ligand A (71.19). This is a critical advantage for a CNS target like DRD2.

**Caco-2 Permeability:** Ligand A (-5.004) has worse Caco-2 permeability than Ligand B (-4.536).

**Aqueous Solubility:** Ligand A (-1.334) has worse aqueous solubility than Ligand B (-1.539).

**hERG:** Both ligands have very low hERG inhibition liability (0.33 and 0.274, respectively), indicating minimal cardiotoxicity risk.

**Microsomal Clearance:** Ligand A (7.041) has significantly lower microsomal clearance than Ligand B (26.74), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand B (-38.236) has a much longer in vitro half-life than Ligand A (9.627).

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.095 and 0.094, respectively).

**Binding Affinity:** Ligand B (-8.3 kcal/mol) has a slightly better binding affinity than Ligand A (-7.7 kcal/mol). This 0.6 kcal/mol difference is meaningful, but not overwhelming.

**Overall Assessment:**

Ligand B excels in BBB penetration and in vitro half-life, both crucial for CNS drug development. Its QED score is also superior, and it has a slightly better binding affinity. However, Ligand A demonstrates a significantly lower DILI risk and better metabolic stability (lower Cl_mic). The difference in binding affinity is not large enough to outweigh the DILI and metabolic stability advantages of Ligand A. Given the importance of minimizing off-target effects and ensuring reasonable drug exposure in the brain, Ligand A appears to be the more promising candidate.

Output:
1
2025-04-17 06:59:10,421 - INFO - Reasoning:

Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (372.487 and 349.519 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (104.73) is higher than the preferred <90 for CNS targets, but not drastically so. Ligand B (52.65) is excellent, well below the threshold.

**3. logP:** Both ligands have good logP values (1.318 and 2.403), falling within the optimal 1-3 range.

**4. H-Bond Donors:** Ligand A (3) and Ligand B (1) are both acceptable, below the limit of 5.

**5. H-Bond Acceptors:** Ligand A (5) and Ligand B (3) are both acceptable, below the limit of 10.

**6. QED:** Both ligands have good QED scores (0.574 and 0.801), indicating good drug-like properties.

**7. DILI:** Both ligands have low DILI risk (25.514 and 5.312), both well below the 40 threshold.

**8. BBB:** Ligand A (53.509) is concerningly low for a CNS target. Ligand B (61.923) is also suboptimal, but better than A. A value >70 is desirable.

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.888 and -4.884). This is unusual and suggests poor permeability.

**10. Aqueous Solubility:** Both ligands have negative solubility values (-1.202 and -2.034). This is also unusual and suggests poor solubility.

**11. hERG Inhibition:** Both ligands have low hERG inhibition risk (0.493 and 0.659).

**12. Microsomal Clearance:** Ligand A (20.207) and Ligand B (18.667) have similar microsomal clearance values. Lower is better, but these aren't alarming.

**13. In vitro Half-Life:** Ligand A (19.377) has a slightly longer half-life than Ligand B (14.885).

**14. P-gp Efflux:** Ligand A (0.118) has significantly lower P-gp efflux liability than Ligand B (0.047), which is favorable for CNS penetration.

**15. Binding Affinity:** Ligand B (-8.2 kcal/mol) has a slightly better binding affinity than Ligand A (-7.8 kcal/mol). While both are good, the 0.4 kcal/mol difference is notable.

**Overall Assessment:**

Despite the unusual negative values for Caco-2 and solubility, the most critical factor for a CNS-targeting GPCR like DRD2 is BBB penetration. Ligand A's BBB percentile (53.509) is significantly lower than Ligand B's (61.923). Ligand B also has a slightly better binding affinity and lower P-gp efflux. While both have suboptimal BBB penetration, Ligand B is still the better candidate due to its slightly improved ADME properties and binding. The negative Caco-2 and solubility values would need to be investigated further, but are less critical than BBB for a CNS target.

Output:
1
2025-04-17 06:59:10,421 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (348.487 Da) is slightly lower, which is generally favorable for permeability. Ligand B (367.333 Da) is also good.

**TPSA:** Ligand A (60.85) is significantly better than Ligand B (12.47). For CNS targets, we want TPSA <= 90, and ideally lower. Ligand A is well within this range, while Ligand B is excellent.

**logP:** Ligand A (2.201) is within the optimal range (1-3). Ligand B (4.426) is higher, potentially leading to solubility issues and off-target interactions.

**H-Bond Donors/Acceptors:** Ligand A has 1 HBD and 3 HBA, which are acceptable. Ligand B has 0 HBD and 2 HBA, also acceptable.

**QED:** Both ligands have good QED scores (A: 0.513, B: 0.545), indicating drug-like properties.

**DILI:** Ligand A (5.312) has a much lower DILI risk than Ligand B (25.553). This is a significant advantage for Ligand A.

**BBB:** Ligand B (97.014) has a much higher BBB penetration score than Ligand A (65.607). This is a critical factor for a CNS target like DRD2.

**Caco-2 Permeability:** Both have negative values, indicating poor permeability. Ligand A (-4.679) is slightly better than Ligand B (-4.68).

**Aqueous Solubility:** Ligand A (-1.14) is better than Ligand B (-4.924).

**hERG:** Ligand A (0.451) has a lower hERG inhibition liability than Ligand B (0.977), which is preferable.

**Microsomal Clearance:** Ligand A (35.881) has higher clearance than Ligand B (21.43), meaning Ligand B is more metabolically stable.

**In vitro Half-Life:** Ligand B (37.558) has a longer half-life than Ligand A (-1.402), which is a positive attribute.

**P-gp Efflux:** Ligand A (0.127) has lower P-gp efflux liability than Ligand B (0.752), which is beneficial for CNS exposure.

**Binding Affinity:** Ligand B (-8.2 kcal/mol) has a slightly better binding affinity than Ligand A (-7.7 kcal/mol). While a 1.5 kcal/mol difference is significant, the other factors need to be considered.

**Overall Assessment:**

Ligand B excels in BBB penetration and binding affinity, which are crucial for a CNS GPCR target. However, it has a higher logP, higher DILI risk, and higher P-gp efflux. Ligand A has better solubility, lower DILI and P-gp efflux, and a more favorable hERG profile. Considering the balance of properties, and the importance of minimizing off-target effects (DILI) and maximizing CNS exposure (P-gp, BBB), Ligand B is the more promising candidate despite the slightly lower scores in solubility and DILI. The strong binding affinity and excellent BBB penetration outweigh the drawbacks.

Output:
1
2025-04-17 06:59:10,421 - INFO - Batch 327 complete. Total preferences: 5232
2025-04-17 06:59:10,421 - INFO - Processing batch 328/512...
2025-04-17 06:59:52,916 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (342.443 and 362.47 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (67.35) is higher than Ligand B (49.41). For CNS targets, we want TPSA <= 90, so both are acceptable, but B is better.

**logP:** Both ligands have good logP values (2.898 and 3.295), falling within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Both have 1 HBD, which is good. Ligand A has 5 HBA, while Ligand B has 3. Both are within the acceptable limit of <=10.

**QED:** Both ligands have good QED scores (0.799 and 0.893), indicating good drug-like properties.

**DILI:** Ligand A (57.348) has a slightly higher DILI risk than Ligand B (43.389), but both are below the concerning threshold of 60.

**BBB:** Ligand B (86.894) has a significantly better BBB penetration percentile than Ligand A (61.613). This is a *critical* factor for a CNS target like DRD2.

**Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and suggests poor permeability. However, the scale is not specified, so it's hard to interpret.

**Aqueous Solubility:** Both have negative solubility values, which is also unusual. Again, the scale is unknown.

**hERG:** Both ligands have low hERG inhibition liability (0.655 and 0.575), which is favorable.

**Microsomal Clearance:** Ligand B (49.803) has significantly lower microsomal clearance than Ligand A (94.011), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand B (0.034) has a slightly better in vitro half-life than Ligand A (-0.367).

**P-gp Efflux:** Ligand A (0.104) has lower P-gp efflux than Ligand B (0.22), which is preferable for CNS penetration.

**Binding Affinity:** Ligand B (-9.5 kcal/mol) has a significantly stronger binding affinity than Ligand A (-8.5 kcal/mol). This is a substantial difference (>1.5 kcal/mol) and can outweigh minor ADME drawbacks.

**Overall Assessment:**

Ligand B is the superior candidate. While Ligand A has slightly better P-gp efflux, Ligand B excels in the most critical areas for a CNS-targeting GPCR: significantly better BBB penetration, stronger binding affinity, and lower microsomal clearance. The slightly higher DILI risk of Ligand A is less concerning than the poorer CNS exposure predicted for Ligand A.

Output:
1
2025-04-17 06:59:52,916 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (343.383 and 357.376 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (83.92) is better than Ligand B (47.36). Both are below the 90 A^2 threshold for CNS targets, but A is closer to the upper limit.

**logP:** Both ligands have good logP values (1.88 and 2.633), falling within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A has 2 HBD and 6 HBA, while Ligand B has 0 HBD and 5 HBA. Both are within acceptable limits.

**QED:** Ligand A (0.862) has a significantly better QED score than Ligand B (0.616), indicating a more drug-like profile.

**DILI:** Ligand B (33.307) has a much lower DILI risk than Ligand A (62.815), which is a significant advantage.

**BBB:** Ligand B (96.161) has a substantially higher BBB penetration score than Ligand A (55.176). This is *critical* for a CNS target like DRD2.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.845 and -4.289), which is unusual and suggests poor permeability. However, these values are on a log scale and the absolute value is more important. They are relatively similar.

**Aqueous Solubility:** Both ligands have negative solubility values (-3.246 and -3.033), indicating poor aqueous solubility. This is a concern, but can sometimes be overcome with formulation strategies.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.498 and 0.664).

**Microsomal Clearance:** Ligand B (67.614) has higher microsomal clearance than Ligand A (6.406), indicating faster metabolism and potentially lower *in vivo* exposure.

**In vitro Half-Life:** Ligand A (-13.704) has a more negative (longer) half-life than Ligand B (-14.677).

**P-gp Efflux:** Ligand B (0.432) has higher P-gp efflux than Ligand A (0.027). Lower P-gp efflux is preferred, making Ligand A better.

**Binding Affinity:** Ligand A (-8.6 kcal/mol) has a significantly stronger binding affinity than Ligand B (-0.0 kcal/mol). This is a major advantage, potentially outweighing some of the ADME drawbacks.

**Overall Assessment:**

Ligand B excels in BBB penetration and DILI risk, which are crucial for a CNS GPCR target. However, its binding affinity is extremely weak. Ligand A has a much stronger binding affinity, a better QED score, and lower P-gp efflux, but suffers from a higher DILI risk and lower BBB penetration.

Given the importance of binding affinity for GPCRs, and the fact that the difference in affinity (-8.6 vs -0.0 kcal/mol) is substantial, I believe Ligand A is the more promising candidate, *despite* its drawbacks. The poor BBB penetration could potentially be addressed through structural modifications, but a weak binder is unlikely to be improved significantly.

Output:
1
2025-04-17 06:59:52,916 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (346.515 and 346.391 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (24.94) is excellent for CNS penetration, well below the 90 A^2 threshold. Ligand B (121.89) is higher, but still potentially acceptable, though less ideal.

**logP:** Ligand A (3.538) is optimal. Ligand B (0.845) is low, potentially hindering membrane permeability and CNS entry.

**H-Bond Donors/Acceptors:** Ligand A (0 HBD, 4 HBA) is favorable. Ligand B (3 HBD, 6 HBA) is also acceptable, but slightly higher counts could impact permeability.

**QED:** Both ligands have reasonable QED values (0.754 and 0.609), indicating good drug-like properties.

**DILI:** Ligand A (3.645) has a very low DILI risk. Ligand B (73.982) is significantly higher, raising a potential safety concern.

**BBB:** Ligand A (83.055) has excellent BBB penetration potential. Ligand B (29.042) is very poor, a major drawback for a CNS target.

**Caco-2 Permeability:** Ligand A (-4.738) is poor, while Ligand B (-5.373) is also poor. This is less critical given the focus on BBB penetration for DRD2.

**Aqueous Solubility:** Both ligands have very poor aqueous solubility (-1.814 and -2.769). This could pose formulation challenges, but might be mitigated by other properties.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.955 and 0.311).

**Microsomal Clearance:** Ligand A (20.475) has moderate clearance, while Ligand B (5.632) has very low clearance, suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (-6.647) has a negative half-life, which is unusual and suggests rapid degradation. Ligand B (-27.686) is even worse.

**P-gp Efflux:** Ligand A (0.219) has low P-gp efflux, which is good. Ligand B (0.014) has very low P-gp efflux, which is even better.

**Binding Affinity:** Ligand B (-8.1 kcal/mol) has a significantly stronger binding affinity than Ligand A (-7.2 kcal/mol). This 0.9 kcal/mol difference is substantial.

**Overall Assessment:**

Despite the stronger binding affinity of Ligand B, several factors strongly favor Ligand A. The most critical are the significantly better BBB penetration (83.055 vs 29.042) and the much lower DILI risk (3.645 vs 73.982). While Ligand A has a poorer half-life and Caco-2 permeability, these are less critical for a CNS target like DRD2 where BBB penetration is paramount. Ligand B's poor BBB penetration and higher DILI risk are major liabilities. The affinity difference, while significant, can potentially be addressed through further optimization of Ligand A.

Output:
0
2025-04-17 06:59:52,916 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (367.515 and 345.443 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (61.88) is significantly better than Ligand B (71.53). For CNS targets, we want TPSA <= 90, and ideally closer to 60. Ligand A is much closer to the ideal range.

**3. logP:** Ligand B (2.305) is better than Ligand A (0.427). An optimal logP is 1-3, and Ligand B falls within this range, while Ligand A is below 1, which could hinder permeation.

**4. H-Bond Donors:** Both have 1 HBD, which is good.

**5. H-Bond Acceptors:** Ligand A has 5, and Ligand B has 4. Both are acceptable (<=10).

**6. QED:** Ligand B (0.77) has a better QED score than Ligand A (0.498), indicating better overall drug-likeness.

**7. DILI:** Ligand A (21.598) has a much lower DILI risk than Ligand B (32.377). This is a significant advantage for Ligand A.

**8. BBB:** Ligand B (68.282) has a better BBB penetration percentile than Ligand A (42.924). For a CNS target like DRD2, >70 is desirable, but 68.282 is still considerably better than 42.924.

**9. Caco-2 Permeability:** Ligand A (-4.964) has a more negative Caco-2 value, which is unusual and suggests very poor permeability. Ligand B (-4.505) is also poor, but slightly better.

**10. Aqueous Solubility:** Both have negative solubility values, indicating poor solubility. Ligand A (-1.254) is slightly better than Ligand B (-2.114).

**11. hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.205 and 0.254, respectively).

**12. Microsomal Clearance:** Ligand A (-11.807) has significantly lower (better) microsomal clearance than Ligand B (33.834). This suggests better metabolic stability for Ligand A.

**13. In vitro Half-Life:** Ligand B (14.416) has a much longer in vitro half-life than Ligand A (2.622).

**14. P-gp Efflux:** Both have low P-gp efflux liability (0.063 and 0.042, respectively).

**15. Binding Affinity:** Ligand B (-7.7 kcal/mol) has a slightly better binding affinity than Ligand A (-7.1 kcal/mol). While both are good, the 0.6 kcal/mol difference is noteworthy.

**Overall Assessment:**

Ligand A excels in DILI risk and metabolic stability (Cl_mic) and has a better TPSA. However, it suffers from poor Caco-2 permeability and a lower BBB score. Ligand B has better logP, QED, BBB, and in vitro half-life, and a slightly better binding affinity.

Given the GPCR-specific priorities, BBB is crucial for CNS targets. While Ligand B doesn't reach the ideal >70, it's substantially better than Ligand A. The slightly better affinity of Ligand B, combined with its better logP and QED, outweigh the advantages of Ligand A, despite the higher DILI risk. The poor Caco-2 permeability of Ligand A is a significant concern.

Output:
1
2025-04-17 06:59:52,917 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (344.46 and 358.87 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (65.54) is higher than Ligand B (51.02). For CNS targets, we want TPSA <= 90, so both are acceptable, but B is better.

**logP:** Ligand A (1.662) is within the optimal 1-3 range. Ligand B (3.541) is slightly higher, but still acceptable.

**H-Bond Donors:** Ligand A has 1 HBD, Ligand B has 0. Both are good, below the threshold of 5.

**H-Bond Acceptors:** Both ligands have 4 HBAs, well within the acceptable limit of 10.

**QED:** Ligand A (0.902) has a very high QED, indicating excellent drug-likeness. Ligand B (0.793) is still good, but lower.

**DILI:** Ligand A (20.40) has a significantly lower DILI risk than Ligand B (26.95), both are acceptable but A is preferred.

**BBB:** Ligand B (84.84) has a much higher BBB penetration percentile than Ligand A (62.62). This is a *critical* advantage for a CNS target like DRD2.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.735 and -4.88), which is unusual and suggests poor permeability. This is a concern for both.

**Aqueous Solubility:** Both ligands have negative solubility values (-1.739 and -3.924), indicating very poor aqueous solubility, which is a significant drawback.

**hERG Inhibition:** Ligand A (0.231) has a lower hERG inhibition liability than Ligand B (0.508), making it safer from a cardiotoxicity perspective.

**Microsomal Clearance:** Ligand A (3.918) has a significantly lower microsomal clearance than Ligand B (69.748), indicating better metabolic stability.

**In vitro Half-Life:** Ligand A (5.172) has a longer in vitro half-life than Ligand B (2.107), which is desirable.

**P-gp Efflux:** Ligand A (0.025) has a much lower P-gp efflux liability than Ligand B (0.271), which is a significant advantage for CNS penetration.

**Binding Affinity:** Ligand B (-7.6 kcal/mol) has a slightly better binding affinity than Ligand A (-8.2 kcal/mol). While the difference is not huge (less than 1.5 kcal/mol), it's still a factor.

**Overall Assessment:**

Ligand A excels in drug-likeness (QED), safety (DILI, hERG), metabolic stability (Cl_mic, t1/2), and P-gp efflux. Ligand B's main advantage is its superior BBB penetration and slightly better binding affinity. However, the poor Caco-2 and solubility for both are concerning. Considering the GPCR-specific priorities, BBB is crucial for CNS targets. While Ligand A has many favorable properties, the substantial BBB advantage of Ligand B is very important. The slightly better affinity of Ligand B also contributes.

Output:
1
2025-04-17 06:59:52,917 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (378.451 and 359.294 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (133.91) is better than Ligand B (41.49) as it is closer to the <90 threshold for CNS targets. Ligand B is significantly higher, which could hinder BBB penetration.

**logP:** Ligand A (-2.206) is lower than optimal (1-3), potentially causing permeability issues. Ligand B (3.705) is within the optimal range.

**H-Bond Donors/Acceptors:** Ligand A (3 HBD, 7 HBA) and Ligand B (2 HBD, 3 HBA) both have acceptable numbers of H-bond donors and acceptors.

**QED:** Ligand B (0.818) has a significantly better QED score than Ligand A (0.387), indicating a more drug-like profile.

**DILI:** Both ligands have low DILI risk (Ligand A: 41.838, Ligand B: 38.736), below the 40 threshold.

**BBB:** Ligand B (63.048) has a much better BBB percentile than Ligand A (35.401). This is a critical factor for a CNS target like DRD2.

**Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and requires further investigation. However, the values are similar (-5.507 and -5.063).

**Aqueous Solubility:** Both ligands exhibit poor aqueous solubility (-1.347 and -4.226).

**hERG Inhibition:** Ligand A (0.032) has a very low hERG risk, while Ligand B (0.922) has a moderate risk.

**Microsomal Clearance:** Ligand B (31.514) has a lower microsomal clearance than Ligand A (44.321), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand B (7.664 hours) has a significantly longer in vitro half-life than Ligand A (-51.506 hours). The negative value for Ligand A is concerning and likely an error.

**P-gp Efflux:** Ligand A (0.004) has very low P-gp efflux, which is favorable for CNS penetration. Ligand B (0.469) has moderate P-gp efflux.

**Binding Affinity:** Ligand B (-9.8 kcal/mol) has a significantly stronger binding affinity than Ligand A (-7.2 kcal/mol). This is a substantial advantage, potentially outweighing some of the ADME drawbacks.

**Overall Assessment:**

Ligand B is the more promising candidate. It has a better logP, QED, BBB, microsomal clearance, in vitro half-life, and, most importantly, a much stronger binding affinity. While Ligand A has lower P-gp efflux and hERG risk, the superior affinity and CNS penetration potential of Ligand B are more critical for a DRD2 ligand. The TPSA of Ligand A is better, but the other advantages of Ligand B are more impactful.



Output:
1
2025-04-17 06:59:52,917 - INFO - Reasoning:

Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (340.354 Da and 373.503 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Both ligands have TPSA values around 62-63 A<sup>2</sup>, which is excellent for CNS penetration (well below the 90 A<sup>2</sup> threshold).

**3. logP:** Ligand A (3.373) is slightly higher than Ligand B (2.652), both within the optimal 1-3 range.

**4. H-Bond Donors:** Ligand A has 0 HBD, while Ligand B has 1. Both are acceptable.

**5. H-Bond Acceptors:** Ligand A has 4 HBA, and Ligand B has 5. Both are within the acceptable limit of 10.

**6. QED:** Ligand A (0.859) has a significantly higher QED score than Ligand B (0.647), indicating better overall drug-likeness.

**7. DILI:** Both ligands have similar DILI risk (67.429% and 66.576%), placing them in a moderate risk category. This isn't a major differentiating factor.

**8. BBB:** Ligand A (76.541%) has a considerably higher BBB penetration score than Ligand B (57.852%). This is a *critical* factor for a CNS target like DRD2.

**9. Caco-2 Permeability:** Ligand A (-4.089) has a better Caco-2 permeability than Ligand B (-5.429).

**10. Aqueous Solubility:** Ligand A (-4.179) has a slightly better aqueous solubility than Ligand B (-2.171).

**11. hERG Inhibition:** Both ligands have low hERG inhibition liability (0.708% and 0.32%), which is favorable.

**12. Microsomal Clearance:** Ligand A (10.231 mL/min/kg) has a lower microsomal clearance than Ligand B (60.94 mL/min/kg), suggesting better metabolic stability.

**13. In vitro Half-Life:** Ligand A (-17.866 hours) has a significantly longer in vitro half-life than Ligand B (-0.053 hours). This is a major advantage.

**14. P-gp Efflux:** Ligand A (0.314) has lower P-gp efflux liability than Ligand B (0.343), which is preferable for CNS exposure.

**15. Binding Affinity:** Both ligands have very similar and strong binding affinities (-9.8 kcal/mol and -8.6 kcal/mol). The difference of 1.2 kcal/mol is not substantial enough to outweigh the other ADME differences.

**Overall Assessment:**

Ligand A is clearly superior. It has a better QED score, significantly better BBB penetration, better Caco-2 permeability, better solubility, lower microsomal clearance (better metabolic stability), a longer half-life, and lower P-gp efflux. While both have acceptable logP and hERG values, and similar DILI risk, the ADME properties of Ligand A make it a much more promising drug candidate for targeting the DRD2 receptor in the CNS.

Output:
1
2025-04-17 06:59:52,917 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (346.435 and 350.459 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (104.7) is higher than the preferred <90 for CNS targets, while Ligand B (75.71) is well within the range. This is a significant advantage for Ligand B.

**logP:** Both ligands have good logP values (1.156 and 1.442), falling within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A has 3 HBD and 5 HBA, which are acceptable. Ligand B has 1 HBD and 4 HBA, also acceptable, and potentially slightly better due to fewer hydrogen bonds.

**QED:** Both ligands have good QED scores (0.667 and 0.736), indicating good drug-like properties.

**DILI:** Ligand A (48.662) has a moderate DILI risk, while Ligand B (19.659) has a very low risk. This is a significant advantage for Ligand B.

**BBB:** Ligand A (27.491) has a poor BBB penetration percentile, making it less likely to reach the target in the CNS. Ligand B (80.884) has excellent BBB penetration, a crucial factor for a DRD2 ligand.

**Caco-2 Permeability:** Ligand A (-5.821) has poor Caco-2 permeability, while Ligand B (-4.544) is slightly better, but still not ideal.

**Aqueous Solubility:** Both ligands have poor aqueous solubility (-2.02 and -2.503). This could pose formulation challenges, but is less critical than BBB penetration for a CNS target.

**hERG Inhibition:** Ligand A (0.065) has a very low hERG risk, while Ligand B (0.328) has a slightly higher, but still acceptable, risk.

**Microsomal Clearance:** Ligand A (6.437) has lower microsomal clearance than Ligand B (68.747), indicating better metabolic stability.

**In vitro Half-Life:** Ligand A (9.668) has a reasonable half-life, but Ligand B (-20.853) has a negative half-life, which is not possible. This is likely an error in the data, but it is a significant red flag.

**P-gp Efflux:** Ligand A (0.015) has very low P-gp efflux, which is favorable for CNS penetration. Ligand B (0.075) has slightly higher efflux, but still relatively low.

**Binding Affinity:** Ligand B (-7.7 kcal/mol) has a slightly better binding affinity than Ligand A (-8.3 kcal/mol), but the difference is small.

**Overall Assessment:**

Ligand B is significantly better due to its excellent BBB penetration (80.884), low DILI risk (19.659), and acceptable TPSA (75.71). While Ligand A has better metabolic stability and a slightly better binding affinity, the poor BBB penetration makes it a less viable candidate for a CNS target like DRD2. The negative half-life for Ligand B is concerning, but we will assume it is a data error.

Output:
1
2025-04-17 06:59:52,917 - INFO - Reasoning:

Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (355.374 and 362.861 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (116.48) is slightly above the optimal <90 for CNS targets, but still reasonable. Ligand B (67.23) is excellent, well below 90.

**logP:** Ligand A (-2.205) is a bit low, potentially hindering permeability. Ligand B (1.986) is within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A has 2 HBD and 8 HBA, which are acceptable. Ligand B has 1 HBD and 4 HBA, also acceptable.

**QED:** Both ligands have good QED scores (0.594 and 0.814), indicating drug-like properties.

**DILI:** Ligand A (38.813) has a lower DILI risk than Ligand B (49.593), both are acceptable.

**BBB:** This is critical for a CNS target. Ligand A (34.005) has a poor BBB percentile, while Ligand B (74.447) is very good, exceeding the desirable >70 threshold.

**Caco-2 Permeability:** Ligand A (-5.631) shows poor permeability, while Ligand B (-4.946) is slightly better, but still not ideal.

**Aqueous Solubility:** Ligand A (-0.381) and Ligand B (-3.92) both show poor solubility.

**hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.033 and 0.178).

**Microsomal Clearance:** Ligand A (-20.253) has a very low (good) clearance, suggesting high metabolic stability. Ligand B (1.325) has a higher clearance, indicating faster metabolism.

**In vitro Half-Life:** Ligand A (-0.918) has a short half-life, while Ligand B (3.09) has a longer half-life.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.005 and 0.232).

**Binding Affinity:** Ligand B (-8.9 kcal/mol) has a significantly stronger binding affinity than Ligand A (-7.3 kcal/mol). This >1.5 kcal/mol difference is substantial and can outweigh some ADME drawbacks.

**Overall Assessment:**

While Ligand A has better metabolic stability (lower Cl_mic) and lower DILI risk, its poor BBB penetration and low logP are major drawbacks for a CNS target like DRD2. Ligand B, despite slightly higher DILI and faster metabolism, excels in BBB penetration, has a more favorable logP, and, crucially, a significantly stronger binding affinity. The strong affinity of Ligand B is a key advantage that outweighs its minor ADME concerns.

Output:
1
2025-04-17 06:59:52,918 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (384.483 and 341.415 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (93.53) is slightly above the preferred <90 for CNS targets, while Ligand B (80.12) is comfortably below. This gives a slight edge to Ligand B.

**logP:** Ligand A (0.672) is a bit low, potentially hindering permeability. Ligand B (2.238) is within the optimal 1-3 range. This is a significant advantage for Ligand B.

**H-Bond Donors/Acceptors:** Both have 1 HBD, which is good. Ligand A has 7 HBA, while Ligand B has 5. Both are acceptable (<=10), but Ligand B is slightly better.

**QED:** Both ligands have good QED scores (0.757 and 0.904), indicating good drug-like properties.

**DILI:** Ligand A (81.427) has a higher DILI risk than Ligand B (64.793), although both are reasonably acceptable.

**BBB:** Ligand A (53.936) has a lower BBB penetration percentile than Ligand B (62.156). While neither are *high* (ideally >70), Ligand B is better for a CNS target.

**Caco-2 Permeability:** Both have negative Caco-2 values (-5.394 and -4.86), which is unusual and suggests poor permeability. This is a significant concern for both.

**Aqueous Solubility:** Both have negative solubility values (-2.511 and -3.516), which is also concerning. Poor solubility can hinder bioavailability.

**hERG:** Both ligands have very low hERG inhibition risk (0.197 and 0.185).

**Microsomal Clearance:** Both have relatively low microsomal clearance (28.22 and 25.826 mL/min/kg), suggesting reasonable metabolic stability.

**In vitro Half-Life:** Both have very short in vitro half-lives (1.684 and 6.415 hours), which is not ideal.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.033 and 0.03). This is good for CNS penetration.

**Binding Affinity:** Both ligands have excellent binding affinities (-8.3 and -8.1 kcal/mol). The difference of 0.2 kcal/mol is not substantial enough to be decisive on its own.

**Overall Assessment:**

Ligand B is the better candidate. While both have issues with Caco-2 permeability and solubility, Ligand B has a more favorable logP, TPSA, and BBB percentile. The slightly lower DILI risk is also a plus. The binding affinity difference is minimal. Given the importance of BBB penetration and logP for CNS GPCR targets like DRD2, Ligand B is the more promising candidate.

Output:
1
2025-04-17 06:59:52,918 - INFO - Reasoning:

Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (411.769 Da) is slightly higher than Ligand B (358.473 Da), but both are acceptable.

**2. TPSA:** Ligand A (63.24) is higher than Ligand B (41.57). For CNS targets, TPSA should be <= 90. Both are within this range, but Ligand B is significantly better.

**3. logP:** Both ligands have good logP values (A: 4.408, B: 4.049), falling within the optimal 1-3 range, though slightly above. Ligand B is preferable as it's closer to the optimal range.

**4. H-Bond Donors:** Both have 1 HBD, which is within the acceptable limit of <= 5.

**5. H-Bond Acceptors:** Both have 3 HBA, also within the acceptable limit of <= 10.

**6. QED:** Both ligands have similar QED values (A: 0.758, B: 0.729), indicating good drug-likeness.

**7. DILI:** Ligand A (88.484) has a higher DILI risk than Ligand B (7.057). This is a significant concern for Ligand A.

**8. BBB:** Ligand B (91.702) has a much higher BBB penetration percentile than Ligand A (36.448). This is *critical* for a CNS target like DRD2.

**9. Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and suggests poor permeability. However, the scale is not specified, so it's difficult to interpret.

**10. Aqueous Solubility:** Both have negative solubility values, which is also unusual. Again, the scale is unspecified.

**11. hERG Inhibition:** Ligand A (0.671) has a slightly lower hERG inhibition risk than Ligand B (0.932), but both are relatively low.

**12. Microsomal Clearance:** Ligand A (12.715) has lower microsomal clearance than Ligand B (23.387), suggesting better metabolic stability.

**13. In vitro Half-Life:** Ligand A (78.462) has a significantly longer in vitro half-life than Ligand B (14.239).

**14. P-gp Efflux:** Ligand A (0.595) has lower P-gp efflux liability than Ligand B (0.315), which is favorable for CNS penetration.

**15. Binding Affinity:** Ligand A (-9.1 kcal/mol) has a slightly better binding affinity than Ligand B (-8.1 kcal/mol). This is a 1.0 kcal/mol difference, which is substantial.

**Overall Assessment:**

While Ligand A has a slightly better binding affinity and metabolic stability, Ligand B is significantly superior in terms of BBB penetration (91.702 vs 36.448) and DILI risk (7.057 vs 88.484). For a CNS target like DRD2, BBB penetration is paramount. The lower DILI risk is also a major advantage. The slightly weaker affinity of Ligand B can potentially be optimized in subsequent iterations of drug design. The TPSA is also more favorable for Ligand B.

Output:
1
2025-04-17 06:59:52,918 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (381.278 and 362.348 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (32.34) is excellent, well below the 90 A^2 threshold for CNS targets. Ligand B (67.87) is higher, but still potentially acceptable, though less ideal.

**logP:** Ligand A (4.368) is slightly high, potentially leading to solubility issues or off-target effects. Ligand B (1.221) is quite low, which might hinder membrane permeability.

**H-Bond Donors/Acceptors:** Both ligands have a reasonable number of HBD (1) and HBA (A: 2, B: 4), staying within the recommended limits.

**QED:** Both ligands have good QED scores (A: 0.798, B: 0.817), indicating drug-like properties.

**DILI:** Ligand A (54.789) has a slightly higher DILI risk than Ligand B (47.964), but both are below the concerning 60 percentile.

**BBB:** Ligand B (90.229) has a significantly better BBB penetration score than Ligand A (83.288). This is a crucial advantage for a CNS target like DRD2.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.771 and -4.518), which is unusual and suggests poor permeability. This is a significant concern for both.

**Aqueous Solubility:** Both ligands have negative solubility values (-4.886 and -2.495), indicating very poor aqueous solubility. This is a major drawback.

**hERG Inhibition:** Ligand A (0.896) has a slightly higher hERG inhibition risk than Ligand B (0.246). Lower is better here.

**Microsomal Clearance:** Ligand A (61.368) has a higher microsomal clearance than Ligand B (15.963), suggesting lower metabolic stability.

**In vitro Half-Life:** Ligand B (-36.93) has a negative half-life, which is impossible and indicates a serious issue with the data or the molecule's stability. Ligand A (64.676) has a reasonable half-life.

**P-gp Efflux:** Ligand A (0.647) has a lower P-gp efflux liability than Ligand B (0.077), which is favorable for CNS penetration.

**Binding Affinity:** Ligand A (-10.5 kcal/mol) has a *much* stronger binding affinity than Ligand B (-8.0 kcal/mol). This is a substantial difference and a major advantage for Ligand A.

**Overall Assessment:**

Ligand A has a significantly better binding affinity and a more reasonable half-life, despite its higher logP and slightly higher DILI risk. However, the negative Caco-2 and solubility values are concerning for both. Ligand B has better BBB penetration and lower hERG risk, but its much weaker binding affinity is a critical disadvantage. The negative half-life for Ligand B is a showstopper.

Given the importance of binding affinity for GPCRs, and the fact that the difference in affinity is so large, Ligand A is the more promising candidate, *assuming* the solubility and permeability issues can be addressed through formulation or further chemical modification.

Output:
1
2025-04-17 06:59:52,918 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (350.503 and 344.423 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (66.48) is significantly better than Ligand B (101.28). For CNS targets, we want TPSA <= 90, and A is comfortably within that, while B exceeds it. This is a significant advantage for A.

**logP:** Ligand A (2.949) is optimal (1-3), while Ligand B (0.178) is quite low, potentially hindering membrane permeability. This favors A.

**H-Bond Donors/Acceptors:** Both ligands have acceptable HBD (1) and HBA (A: 3, B: 8) counts, staying within the recommended limits.

**QED:** Both ligands have good QED scores (A: 0.513, B: 0.807), indicating drug-like properties. B is slightly better here.

**DILI:** Ligand A (35.712) has a lower DILI risk than Ligand B (55.525), which is preferable.

**BBB:** Both ligands have good BBB penetration (A: 71.811, B: 70.648), exceeding the 70% threshold for CNS targets. This is comparable.

**Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and suggests potential issues with the data or modeling. However, the magnitude is similar.

**Aqueous Solubility:** Both have negative solubility values, again unusual. The values are similar.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (A: 0.422, B: 0.691), which is good.

**Microsomal Clearance:** Ligand A (57.45) has a higher (worse) microsomal clearance than Ligand B (29.818), suggesting faster metabolism. This favors B.

**In vitro Half-Life:** Ligand B (14.015) has a much longer half-life than Ligand A (-17.768), which is a significant advantage.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (A: 0.242, B: 0.005), which is desirable for CNS penetration. B is slightly better.

**Binding Affinity:** Ligand A (-7.9 kcal/mol) has a slightly better binding affinity than Ligand B (-7.5 kcal/mol). While both are good, the 0.4 kcal/mol difference is notable.

**Overall Assessment:**

Considering the GPCR-specific priorities, Ligand A is the stronger candidate. Its superior TPSA and logP values are crucial for CNS penetration. Although Ligand B has a better QED, lower clearance, longer half-life, and slightly lower Pgp efflux, the significantly better TPSA and logP of Ligand A, combined with its slightly better binding affinity, outweigh these benefits. The negative solubility and Caco-2 values are concerning for both, but the differences in other key properties are more decisive.

Output:
1
2025-04-17 06:59:52,919 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (359.5 & 354.5 Da) fall comfortably within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (82.7) is better than Ligand B (89.9) as it is closer to the desirable <90 A^2 for CNS targets.

**3. logP:** Both ligands have good logP values (2.53 & 1.30), falling within the optimal 1-3 range. Ligand A is slightly better.

**4. H-Bond Donors:** Both have 3 HBD, which is acceptable (<=5).

**5. H-Bond Acceptors:** Ligand A has 5 HBA, and Ligand B has 4. Both are within the acceptable range (<=10).

**6. QED:** Both ligands have similar QED values (0.73 & 0.69), indicating good drug-like properties.

**7. DILI:** Ligand A (64.8%) has a higher DILI risk than Ligand B (10.6%). This is a significant drawback for Ligand A.

**8. BBB:** Both ligands have reasonably good BBB penetration (68.3% and 63.1%), but neither exceeds the highly desirable >70% threshold.

**9. Caco-2 Permeability:** Ligand A (-5.86) has a worse Caco-2 permeability than Ligand B (-4.86). Lower values indicate lower permeability.

**10. Aqueous Solubility:** Ligand A (-2.20) has worse aqueous solubility than Ligand B (-1.66).

**11. hERG Inhibition:** Ligand A (0.55) has a slightly higher hERG inhibition risk than Ligand B (0.20), but both are relatively low.

**12. Microsomal Clearance:** Ligand A (0.27) has lower microsomal clearance than Ligand B (4.70), indicating better metabolic stability.

**13. In vitro Half-Life:** Ligand A (16.0) has a much longer in vitro half-life than Ligand B (-8.5). This is a significant advantage for Ligand A.

**14. P-gp Efflux:** Ligand A (0.36) has a lower P-gp efflux liability than Ligand B (0.04), which is preferable for CNS penetration.

**15. Binding Affinity:** Ligand B (-8.2 kcal/mol) has a significantly stronger binding affinity than Ligand A (-0.0 kcal/mol). This is a crucial factor.

**Overall Assessment:**

While Ligand A has advantages in metabolic stability (lower Cl_mic), P-gp efflux, and half-life, its significantly weaker binding affinity (-0.0 kcal/mol) and higher DILI risk are major concerns. Ligand B, despite slightly worse ADME properties in some areas, boasts a much stronger binding affinity (-8.2 kcal/mol). For a GPCR target like DRD2, strong binding affinity is paramount, and can often outweigh minor ADME deficiencies that can be addressed through further optimization. The DILI risk for ligand B is also very low.

Output:
1
2025-04-17 06:59:52,919 - INFO - Reasoning:

Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (348.33 and 344.499 Da) fall comfortably within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (90.7) is borderline acceptable for CNS targets (<=90), while Ligand B (49.41) is well within the desired range. This is a significant advantage for Ligand B.

**3. logP:** Both ligands have good logP values (3.702 and 3.298), falling within the optimal 1-3 range.

**4. H-Bond Donors:** Both have 1 HBD, which is acceptable.

**5. H-Bond Acceptors:** Ligand A has 5 HBA, and Ligand B has 2. Both are within the acceptable limit of <=10.

**6. QED:** Both ligands have similar QED values (0.635 and 0.628), indicating good drug-likeness.

**7. DILI:** Ligand A has a concerning DILI risk (87.049%), categorized as high risk (>60). Ligand B has a much lower DILI risk (29.236%), which is a major advantage.

**8. BBB:** Ligand A has a BBB penetration of 61.535%, which is below the desirable >70% for CNS targets. Ligand B shows excellent BBB penetration (73.672%), a crucial factor for DRD2 targeting.

**9. Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and suggests poor permeability. However, the scale isn't specified, so it's hard to interpret.

**10. Aqueous Solubility:** Both have negative solubility values, also unusual. This suggests poor solubility.

**11. hERG Inhibition:** Both ligands have low hERG inhibition liability (0.652 and 0.245), which is favorable.

**12. Microsomal Clearance:** Ligand A (55.862) and Ligand B (47.179) have similar microsomal clearance values. Lower is better, but neither is particularly problematic.

**13. In vitro Half-Life:** Ligand A (26.62 hours) has a better in vitro half-life than Ligand B (-11.256 hours). However, the negative value for B is suspect and may indicate an issue with the data.

**14. P-gp Efflux:** Both have low P-gp efflux liability (0.388 and 0.131), which is good for CNS exposure.

**15. Binding Affinity:** Both ligands have excellent binding affinities (-8.7 and -8.2 kcal/mol), with Ligand A being slightly stronger. However, the difference is less than 1.5 kcal/mol, so it's unlikely to outweigh other factors.

**Overall Assessment:**

Considering the GPCR-specific priorities, Ligand B is the more promising candidate. Its superior BBB penetration, significantly lower DILI risk, and lower TPSA outweigh the slightly weaker binding affinity and questionable half-life value. Ligand A's high DILI risk and suboptimal BBB penetration are major drawbacks.

Output:
1
2025-04-17 06:59:52,919 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (344.415 and 367.555 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (88.33) is excellent, falling well below the 90 A^2 threshold for CNS targets. Ligand B (38.77) is also very good.

**3. logP:** Ligand A (2.109) is optimal (1-3). Ligand B (4.755) is slightly higher, potentially raising concerns about solubility and off-target effects, but still within a reasonable range.

**4. H-Bond Donors:** Ligand A (1) is good. Ligand B (0) is also acceptable.

**5. H-Bond Acceptors:** Ligand A (5) is good. Ligand B (4) is also good.

**6. QED:** Ligand A (0.792) is excellent, indicating a strong drug-like profile. Ligand B (0.599) is acceptable, but less ideal.

**7. DILI:** Ligand A (49.283) has a moderate DILI risk. Ligand B (22.024) has a lower, more favorable DILI risk.

**8. BBB:** Ligand A (52.617) is moderate for BBB penetration. Ligand B (89.957) is *very* good, exceeding the >70% threshold desirable for CNS targets. This is a significant advantage.

**9. Caco-2:** Both ligands have negative Caco-2 values (-5.141 and -4.924), which is unusual and suggests poor permeability. This is a major concern for both.

**10. Solubility:** Both ligands have negative solubility values (-1.178 and -4.0), indicating very poor aqueous solubility. This is a significant drawback for both.

**11. hERG:** Ligand A (0.244) has a low hERG risk. Ligand B (0.821) has a slightly higher, but still acceptable, hERG risk.

**12. Cl_mic:** Ligand A (49.553) has moderate metabolic clearance. Ligand B (104.662) has higher clearance, suggesting lower metabolic stability.

**13. t1/2:** Ligand A (17.852) has a moderate half-life. Ligand B (35.305) has a longer, more desirable half-life.

**14. Pgp:** Ligand A (0.024) has very low P-gp efflux liability, which is excellent for CNS penetration. Ligand B (0.888) has higher P-gp efflux, which could limit CNS exposure.

**15. Binding Affinity:** Ligand B (-7.1 kcal/mol) has a significantly stronger binding affinity than Ligand A (-8.3 kcal/mol). This difference of 1.2 kcal/mol is substantial and can outweigh some ADME drawbacks.

**Overall Assessment:**

Despite both ligands having poor Caco-2 and solubility, Ligand B emerges as the more promising candidate. Its superior BBB penetration (89.957% vs 52.617%), longer half-life, and *significantly* stronger binding affinity (-7.1 vs -8.3 kcal/mol) are crucial advantages for a CNS-targeting GPCR like DRD2. While Ligand B has higher metabolic clearance and Pgp efflux, the affinity difference is substantial enough to warrant further optimization efforts focused on improving its metabolic stability and reducing efflux. Ligand A's lower affinity makes it less likely to succeed, even with its slightly better Pgp profile.

Output:
1
2025-04-17 06:59:52,919 - INFO - Batch 328 complete. Total preferences: 5248
2025-04-17 06:59:52,919 - INFO - Processing batch 329/512...
2025-04-17 07:00:36,187 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B based on the provided guidelines, prioritizing GPCR-specific properties (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (348.407 and 341.411 Da) fall within the ideal range of 200-500 Da.

**TPSA:** Ligand A (105.28) is higher than Ligand B (66.24). For CNS targets, TPSA should be <= 90. Ligand B is significantly better in this regard.

**logP:** Ligand A (0.122) is quite low, potentially hindering membrane permeability. Ligand B (2.968) is within the optimal 1-3 range. This is a significant advantage for Ligand B.

**H-Bond Donors/Acceptors:** Ligand A has 2 HBD and 7 HBA, while Ligand B has 0 HBD and 6 HBA. Both are within acceptable limits.

**QED:** Ligand A (0.67) has a better QED score than Ligand B (0.419), indicating a more drug-like profile.

**DILI:** Ligand A (42.769) has a lower DILI risk than Ligand B (64.637), which is preferable.

**BBB:** Ligand B (70.648) has a significantly better BBB percentile than Ligand A (35.091). This is *critical* for a CNS target like DRD2.

**Caco-2 Permeability:** Ligand A (-5.395) shows poor Caco-2 permeability, while Ligand B (-4.515) is slightly better, but still not great.

**Aqueous Solubility:** Ligand A (-1.178) has slightly better solubility than Ligand B (-3.699), but both are quite low.

**hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.076 and 0.105 respectively).

**Microsomal Clearance:** Ligand A (27.142) has lower microsomal clearance than Ligand B (56.164), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (50.72) has a significantly longer half-life than Ligand B (-14.602).

**P-gp Efflux:** Ligand A (0.026) has much lower P-gp efflux than Ligand B (0.482), which is beneficial for CNS penetration.

**Binding Affinity:** Ligand B (-7.7 kcal/mol) has a slightly better binding affinity than Ligand A (-7.1 kcal/mol), although the difference is relatively small.

**Overall Assessment:**

While Ligand A has a better QED, lower DILI, better metabolic stability, longer half-life, and lower P-gp efflux, its poor logP and BBB penetration are major drawbacks for a CNS target. Ligand B, despite a higher DILI risk and lower QED, excels in the critical areas of logP and BBB, and has a slightly better binding affinity. The superior BBB penetration and acceptable logP of Ligand B outweigh the other drawbacks, making it the more promising candidate for DRD2.

Output:
1
2025-04-17 07:00:36,188 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (407.352 Da) is slightly higher than Ligand B (354.491 Da), but both are acceptable.

**TPSA:** Ligand A (41.57) is excellent for CNS penetration, well below the 90 A^2 threshold. Ligand B (81.08) is higher, but still potentially acceptable, though less ideal.

**logP:** Ligand A (4.86) is a bit high, potentially leading to solubility issues or off-target interactions. Ligand B (1.394) is within the optimal range (1-3).

**H-Bond Donors/Acceptors:** Ligand A (HBD=1, HBA=2) and Ligand B (HBD=2, HBA=4) both have reasonable numbers of H-bond donors and acceptors, falling within the guidelines.

**QED:** Both ligands have good QED values (Ligand A: 0.709, Ligand B: 0.755), indicating a generally drug-like profile.

**DILI:** Ligand A (39.938) has a very good DILI score, indicating low liver injury risk. Ligand B (14.541) is also excellent.

**BBB:** Ligand A (88.988) has a significantly better BBB penetration score than Ligand B (57.619). This is a critical advantage for a CNS target like DRD2.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.217 and -4.634), which is unusual and suggests poor permeability. This is a significant concern for both.

**Aqueous Solubility:** Both ligands have negative solubility values (-5.876 and -1.728), indicating very poor aqueous solubility. This is a major drawback for both.

**hERG Inhibition:** Ligand A (0.731) has a slightly higher hERG risk than Ligand B (0.279), but both are relatively low.

**Microsomal Clearance:** Ligand A (94.487) has high microsomal clearance, suggesting rapid metabolism. Ligand B (18.949) has much lower clearance, indicating better metabolic stability.

**In vitro Half-Life:** Ligand A (44.187) has a moderate half-life, while Ligand B (-0.999) has a very short (or even negative) half-life, which is extremely concerning.

**P-gp Efflux:** Ligand A (0.476) has lower P-gp efflux than Ligand B (0.074), meaning it's less likely to be pumped out of the brain, improving CNS exposure.

**Binding Affinity:** Ligand B (-8.0 kcal/mol) has a slightly better binding affinity than Ligand A (-7.3 kcal/mol), a difference of 0.7 kcal/mol. While significant, the other ADME properties are more concerning.

**Overall Assessment:**

Ligand A excels in BBB penetration and DILI risk, and has acceptable TPSA and QED. However, its high logP, high clearance, and poor solubility are significant drawbacks. Ligand B has better logP, lower clearance, and slightly better affinity, but its BBB penetration is much lower, and its in vitro half-life is extremely poor.

Given the importance of BBB penetration for a CNS target like DRD2, and considering the relatively small difference in binding affinity, **Ligand A is the more promising candidate**, despite its drawbacks. The poor solubility and permeability of both compounds would need to be addressed through formulation or structural modifications, but the better CNS exposure potential of Ligand A makes it the better starting point.

Output:
0
2025-04-17 07:00:36,188 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (435.384 and 382.555 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Both ligands have TPSA values (78.87 and 78.35) that are acceptable for oral absorption (<140), but slightly high for optimal CNS penetration (<90). This is a minor concern, as other factors are more critical for CNS targets.

**3. logP:** Both ligands have logP values (2.2 and 2.463) within the optimal 1-3 range.

**4. H-Bond Donors:** Both ligands have 2 HBD, which is within the acceptable limit of <=5.

**5. H-Bond Acceptors:** Ligand A has 5 HBA, and Ligand B has 7 HBA. Both are acceptable, being <=10.

**6. QED:** Both ligands have QED values (0.687 and 0.787) above 0.5, indicating good drug-likeness.

**7. DILI:** Ligand A (25.979%) has a significantly lower DILI risk than Ligand B (67.003%). This is a substantial advantage for Ligand A.

**8. BBB:** Ligand B (73.517%) has a considerably higher BBB penetration percentile than Ligand A (46.762%). This is a *major* advantage for Ligand B, given that DRD2 is a CNS target.

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.139 and -5.46), which is unusual and suggests poor permeability. However, these values are on a strange scale and difficult to interpret directly.

**10. Aqueous Solubility:** Both ligands have negative solubility values (-3.133 and -3.719), also unusual and suggesting poor solubility.

**11. hERG Inhibition:** Both ligands have low hERG inhibition risk (0.923 and 0.495).

**12. Microsomal Clearance:** Ligand B (37.463) has lower microsomal clearance than Ligand A (42.702), indicating better metabolic stability.

**13. In vitro Half-Life:** Ligand B (33.813 hours) has a significantly longer in vitro half-life than Ligand A (-21.46 hours). This is a substantial advantage for Ligand B.

**14. P-gp Efflux:** Both ligands have low P-gp efflux liability (0.654 and 0.094). Ligand B is better here.

**15. Binding Affinity:** Both ligands have very similar binding affinities (-8.2 and -8.0 kcal/mol). The difference is minimal.

**Overall Assessment:**

Ligand B is superior due to its significantly better BBB penetration (73.5% vs 46.8%), longer half-life (33.8 vs -21.5), lower P-gp efflux, and lower DILI risk. While both have issues with predicted solubility and Caco-2 permeability, the CNS target prioritization makes BBB the most important factor. The slight advantage in metabolic stability also favors Ligand B. The binding affinities are essentially the same.

Output:
1
2025-04-17 07:00:36,188 - INFO - Reasoning:

Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (353.423 and 344.415 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (139.97) is borderline but acceptable for CNS penetration, while Ligand B (87.32) is excellent, well below the 90 A^2 threshold. This favors Ligand B.

**3. logP:** Ligand A (-0.089) is a bit low, potentially hindering membrane permeability. Ligand B (1.256) is within the optimal 1-3 range. This strongly favors Ligand B.

**4. H-Bond Donors:** Ligand A (5) is at the upper limit of acceptable, while Ligand B (2) is excellent. This favors Ligand B.

**5. H-Bond Acceptors:** Both ligands (A: 5, B: 4) are well within the acceptable limit of 10.

**6. QED:** Both ligands have good QED scores (A: 0.444, B: 0.805), but Ligand B is significantly better, suggesting a more drug-like profile.

**7. DILI:** Ligand A (54.478) has a slightly better DILI risk profile than Ligand B (60.682), but both are acceptable.

**8. BBB:** Ligand B (47.809) has a much better BBB percentile than Ligand A (30.748). This is *critical* for a CNS target like DRD2, giving a significant advantage to Ligand B.

**9. Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and suggests poor permeability. However, the scale is not specified, so it's hard to interpret.

**10. Aqueous Solubility:** Both have negative solubility values, which is also unusual.

**11. hERG Inhibition:** Both ligands have low hERG inhibition risk (A: 0.121, B: 0.38).

**12. Microsomal Clearance:** Ligand A (-5.129) has a *negative* clearance, which is impossible and likely an error in the data. Ligand B (25.253) is high, indicating rapid metabolism. This is a major drawback for Ligand B.

**13. In vitro Half-Life:** Ligand A (-10.27) has a negative half-life, which is impossible and likely an error in the data. Ligand B (-0.192) is also negative and problematic.

**14. P-gp Efflux:** Both ligands have very low P-gp efflux liability (A: 0.012, B: 0.063), which is favorable for CNS penetration.

**15. Binding Affinity:** Both ligands have similar, strong binding affinities (A: -8.1 kcal/mol, B: -8.3 kcal/mol). The difference is minimal.

**Overall Assessment:**

Despite the issues with clearance and half-life data for both compounds, Ligand B appears to be the better candidate. It has a superior logP, TPSA, QED, and BBB percentile, all of which are crucial for a CNS-targeting GPCR. The affinity is comparable. The negative values for clearance and half-life are concerning, but the other properties of Ligand B are significantly more favorable. Ligand A has impossible values for clearance and half-life, making it less reliable.

Output:
1
2025-04-17 07:00:36,189 - INFO - Reasoning:

Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (339.443 and 334.427 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (80.66) is better than Ligand B (63.21). Both are below the 90 A^2 threshold for CNS targets, which is excellent.

**3. logP:** Ligand A (3.864) is slightly higher than Ligand B (2.268), both are within the optimal 1-3 range.

**4. H-Bond Donors:** Both ligands have 1 HBD, which is acceptable.

**5. H-Bond Acceptors:** Ligand A has 5 HBA, and Ligand B has 6. Both are below the 10 threshold.

**6. QED:** Ligand A (0.918) has a significantly better QED score than Ligand B (0.796), indicating better overall drug-likeness.

**7. DILI:** Both ligands have similar DILI risk (79.333 and 79.682 percentile), and are relatively high, but not alarmingly so.

**8. BBB:** Ligand A (73.517) has a better BBB penetration percentile than Ligand B (69.407). Both are acceptable, but >70 is preferred for CNS targets.

**9. Caco-2 Permeability:** Both have negative Caco-2 values (-4.785 and -4.882). This is unusual and suggests poor permeability. However, these values are on a log scale and should be interpreted cautiously.

**10. Aqueous Solubility:** Both ligands have negative solubility values (-5.325 and -2.261). This suggests very poor aqueous solubility, which is a significant concern.

**11. hERG Inhibition:** Ligand A (0.17) has a much lower hERG inhibition liability than Ligand B (0.937), which is a major advantage.

**12. Microsomal Clearance:** Ligand A (61.058) has higher microsomal clearance than Ligand B (1.196), meaning it's less metabolically stable. This is a drawback for Ligand A.

**13. In vitro Half-Life:** Ligand B (-28.503) has a significantly longer in vitro half-life than Ligand A (15.899). This is a substantial advantage for Ligand B.

**14. P-gp Efflux:** Ligand A (0.154) has lower P-gp efflux liability than Ligand B (0.194), which is favorable for CNS penetration.

**15. Binding Affinity:** Ligand B (-9.2 kcal/mol) has a slightly better binding affinity than Ligand A (-8.5 kcal/mol). This difference is significant, exceeding the 1.5 kcal/mol threshold where affinity can outweigh other issues.

**Overall Assessment:**

Despite Ligand A's better TPSA, QED, and lower P-gp efflux, Ligand B is the stronger candidate. The superior binding affinity (-9.2 vs -8.5 kcal/mol) is a critical advantage for a GPCR target. Furthermore, Ligand B has a significantly longer in vitro half-life, which is crucial for maintaining therapeutic concentrations. While both have poor solubility and permeability, the affinity and half-life benefits of Ligand B are more impactful for initial optimization. The hERG risk is also much lower for Ligand A, but can be addressed during lead optimization.

Output:
1
2025-04-17 07:00:36,189 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (356.813) is slightly higher than Ligand B (347.415), but both are acceptable.

**TPSA:** Ligand A (70.99) is excellent for CNS penetration, well below the 90 A^2 threshold. Ligand B (98.74) is higher, but still potentially acceptable, though less ideal.

**logP:** Ligand A (2.651) is optimal. Ligand B (-0.604) is significantly lower, potentially hindering membrane permeability and CNS entry.

**H-Bond Donors/Acceptors:** Ligand A (HBD=1, HBA=4) and Ligand B (HBD=3, HBA=4) both have reasonable numbers of H-bond donors and acceptors.

**QED:** Ligand A (0.728) has a better QED score than Ligand B (0.441), indicating better overall drug-likeness.

**DILI:** Ligand A (74.952) has a higher DILI risk than Ligand B (18.573). This is a concern for Ligand A.

**BBB:** Ligand A (54.866) has a moderate BBB penetration, while Ligand B (28.538) is considerably lower. For a CNS target like DRD2, a higher BBB value is strongly preferred.

**Caco-2 Permeability:** Both have negative values, which is unusual. Assuming these are percentile scores, Ligand A (-5.21) is better than Ligand B (-4.843), suggesting slightly better intestinal absorption.

**Aqueous Solubility:** Ligand A (-3.871) is better than Ligand B (-1.701), indicating better solubility.

**hERG Inhibition:** Ligand A (0.614) has a lower hERG risk than Ligand B (0.116), which is favorable.

**Microsomal Clearance:** Ligand A (18.395) has a higher microsomal clearance than Ligand B (-4.789), suggesting lower metabolic stability.

**In vitro Half-Life:** Ligand A (-2.647) has a shorter half-life than Ligand B (-9.538), which is a negative.

**P-gp Efflux:** Ligand A (0.414) has lower P-gp efflux than Ligand B (0.006), which is beneficial for CNS exposure.

**Binding Affinity:** Ligand A (-10.2 kcal/mol) has a significantly stronger binding affinity than Ligand B (-7.6 kcal/mol). This is a substantial advantage, potentially outweighing some of the ADME drawbacks of Ligand A.

**Overall Assessment:**

Ligand A has a much stronger binding affinity, better logP, better solubility, lower hERG risk, and lower P-gp efflux. However, it has a higher DILI risk and a shorter half-life. Ligand B has a lower DILI risk and longer half-life, but its significantly lower logP and BBB penetration are major drawbacks for a CNS target. The substantial affinity difference (-2.6 kcal/mol) is a significant advantage for Ligand A. Given the GPCR-specific priorities, the strong affinity and reasonable BBB of Ligand A, despite its other issues, make it the more promising candidate. The DILI risk could be addressed with further structural modifications.

Output:
1
2025-04-17 07:00:36,189 - INFO - Reasoning:

Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (349.362 and 350.463 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (99.6) is slightly higher than Ligand B (85.25). For CNS targets, we prefer TPSA <= 90, so Ligand B is better here.

**3. logP:** Ligand A (0.822) is a bit low, potentially hindering permeability. Ligand B (2.285) is within the optimal 1-3 range. Ligand B is superior.

**4. H-Bond Donors:** Both have 2 HBD, which is acceptable (<=5).

**5. H-Bond Acceptors:** Both have 5 HBA, also acceptable (<=10).

**6. QED:** Ligand A (0.82) is better than Ligand B (0.634), indicating a more drug-like profile.

**7. DILI:** Both ligands have acceptable DILI risk (Ligand A: 49.283, Ligand B: 52.966), below the 60 threshold.

**8. BBB:** Both ligands have good BBB penetration (Ligand A: 65.801, Ligand B: 68.399), but both are below the desirable >70 for CNS targets. Ligand B is slightly better.

**9. Caco-2:** Both have negative Caco-2 values (-4.987 and -5.075). This is unusual and suggests poor permeability.

**10. Solubility:** Both have negative solubility values (-2.239 and -2.963). This is also unusual and suggests poor solubility.

**11. hERG:** Both ligands have very low hERG risk (Ligand A: 0.051, Ligand B: 0.34).

**12. Cl_mic:** Ligand A (-6.088) has significantly lower (better) microsomal clearance than Ligand B (32.365). This suggests better metabolic stability for Ligand A.

**13. t1/2:** Ligand A (-0.814) has a negative in vitro half-life, which is not possible. Ligand B (6.155) has a reasonable half-life. This is a major red flag for Ligand A.

**14. Pgp:** Both have very low Pgp efflux liability (Ligand A: 0.009, Ligand B: 0.065).

**15. Binding Affinity:** Ligand B (-7.8 kcal/mol) has a slightly better (more negative) binding affinity than Ligand A (-8.0 kcal/mol). While the difference is small, it's a positive for Ligand B.

**Overall Assessment:**

Despite Ligand A having a slightly better QED and binding affinity, the negative and unrealistic in vitro half-life is a critical flaw. The negative Caco-2 and solubility values for both are concerning. Ligand B has a more favorable logP, TPSA, and a reasonable half-life, making it the more promising candidate, even with slightly lower QED and affinity.

Output:
1
2025-04-17 07:00:36,189 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B based on the provided guidelines, prioritizing GPCR-specific properties (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (364.471 Da) is slightly lower, which could be beneficial for permeability.

**TPSA:** Ligand A (92.35) is better than Ligand B (21.7). For CNS targets, TPSA should be <=90, so Ligand A is closer to the ideal range. Ligand B is exceptionally low, which might indicate a lack of necessary interactions.

**logP:** Ligand A (2.688) is within the optimal range (1-3). Ligand B (4.842) is higher, potentially leading to solubility issues and off-target interactions.

**H-Bond Donors/Acceptors:** Ligand A has 1 HBD and 7 HBA, while Ligand B has 0 HBD and 4 HBA. Both are within acceptable limits.

**QED:** Ligand A (0.812) has a better QED score than Ligand B (0.584), indicating a more drug-like profile.

**DILI:** Ligand A (55.448) has a higher DILI risk than Ligand B (11.439). This is a negative for Ligand A.

**BBB:** Ligand B (85.459) has a significantly better BBB penetration percentile than Ligand A (76.192). This is crucial for a CNS target like DRD2.

**Caco-2 Permeability:** Ligand A (-4.805) has better Caco-2 permeability than Ligand B (-4.58).

**Aqueous Solubility:** Ligand A (-4.179) has better solubility than Ligand B (-4.824).

**hERG:** Ligand A (0.253) has a lower hERG inhibition liability than Ligand B (0.966), which is favorable.

**Microsomal Clearance:** Ligand B (84.483) has a higher microsomal clearance than Ligand A (56.019), indicating lower metabolic stability.

**In vitro Half-Life:** Ligand B (62.667) has a longer in vitro half-life than Ligand A (17.989).

**P-gp Efflux:** Ligand A (0.291) has lower P-gp efflux liability than Ligand B (0.738), which is better for CNS exposure.

**Binding Affinity:** Ligand A (-7.3 kcal/mol) has a slightly better binding affinity than Ligand B (-6.4 kcal/mol). While both are good, the 1.9 kcal/mol difference is significant.

**Overall Assessment:**

Ligand A has a better overall profile, particularly regarding TPSA, logP, QED, hERG, P-gp efflux, and binding affinity. The improved binding affinity and favorable ADME properties (lower logP, better solubility, lower P-gp efflux, lower hERG) outweigh the slightly higher DILI risk. Ligand B has excellent BBB penetration, but its high logP, poorer solubility, higher P-gp efflux, and lower QED are concerning. The better affinity of Ligand A is also a significant advantage for a GPCR target.

Output:
1
2025-04-17 07:00:36,189 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (350.419 and 345.495 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (93.53) is slightly above the optimal <90 for CNS targets, but still reasonable. Ligand B (62.11) is well within the desired range.

**logP:** Ligand A (0.647) is a bit low, potentially hindering membrane permeability. Ligand B (2.446) is within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Both ligands have 1 HBD and a reasonable number of HBAs (6 and 7 respectively), satisfying the <5 HBD and <10 HBA guidelines.

**QED:** Both ligands have good QED scores (0.76 and 0.832), indicating drug-like properties.

**DILI:** Both ligands have elevated DILI risk (31.718 and 65.529), but Ligand A has a lower risk. Ideally, both would be under 40.

**BBB:** Ligand B (86.894) has a significantly better BBB percentile than Ligand A (63.358). This is a crucial advantage for a CNS target like DRD2.

**Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and requires further investigation. However, the magnitude is similar, so this doesn't strongly favor either.

**Aqueous Solubility:** Both have negative solubility values, which is also unusual. Again, the magnitude is similar.

**hERG:** Both ligands have low hERG inhibition liability (0.305 and 0.97), which is good.

**Microsomal Clearance:** Ligand A (42.187) has lower microsomal clearance than Ligand B (50.206), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand B (31.64) has a significantly longer in vitro half-life than Ligand A (-11.24), which is a major advantage.

**P-gp Efflux:** Ligand A (0.034) has much lower P-gp efflux liability than Ligand B (0.367), which is highly desirable for CNS penetration.

**Binding Affinity:** Both ligands have excellent binding affinities (-7.9 and -8.1 kcal/mol), with Ligand B being slightly better. The difference is less than 1.5 kcal/mol, so it's not a decisive factor on its own.

**Overall Assessment:**

Ligand B excels in BBB penetration and in vitro half-life, both critical for CNS drug development. Its logP is also more favorable. Ligand A has lower DILI risk and P-gp efflux, and better metabolic stability. However, the superior BBB penetration and half-life of Ligand B, combined with its slightly better affinity, outweigh the advantages of Ligand A. The low logP of Ligand A is a significant concern.

Output:
1
2025-04-17 07:00:36,190 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (346.45 & 342.48 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (49.41) is slightly higher than Ligand B (40.62). Both are below the 90 A^2 threshold desirable for CNS targets, but Ligand B is preferable.

**logP:** Ligand A (2.286) is within the optimal 1-3 range. Ligand B (3.836) is pushing the upper limit, but still acceptable.

**H-Bond Donors:** Ligand A (1) is preferable to Ligand B (0) as having at least one HBD can aid solubility.

**H-Bond Acceptors:** Both ligands have 2 HBA, which is within the acceptable range of <=10.

**QED:** Ligand B (0.837) has a significantly better QED score than Ligand A (0.541), indicating a more drug-like profile.

**DILI:** Ligand A (12.14) has a much lower DILI risk than Ligand B (39.20). This is a significant advantage for Ligand A.

**BBB:** Ligand B (94.49) has a substantially higher BBB penetration score than Ligand A (87.86). This is a crucial factor for a CNS target like DRD2, making Ligand B more promising.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values, which is unusual and suggests poor permeability. Ligand A (-4.578) is slightly worse than Ligand B (-4.452).

**Aqueous Solubility:** Both ligands have negative solubility values, which is also unusual and suggests poor solubility. Ligand A (-2.955) is slightly worse than Ligand B (-3.938).

**hERG:** Both ligands have low hERG inhibition liability (0.652 and 0.558), which is good.

**Microsomal Clearance:** Ligand B (65.33) has a significantly higher microsomal clearance than Ligand A (16.28), indicating lower metabolic stability.

**In vitro Half-Life:** Ligand B (6.99) has a longer half-life than Ligand A (1.04), which is preferable.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.115 and 0.572), which is good for CNS penetration.

**Binding Affinity:** Ligand B (-8.9 kcal/mol) has a significantly stronger binding affinity than Ligand A (-7.7 kcal/mol). This is a major advantage, potentially outweighing some of the ADME drawbacks.

**Overall Assessment:**

Ligand B excels in BBB penetration and binding affinity, both critical for a CNS GPCR target. While its DILI risk is higher and metabolic stability lower, the substantial improvement in affinity (-1.2 kcal/mol difference) and BBB penetration makes it the more promising candidate. The slightly better QED score also supports this. Ligand A's lower DILI is attractive, but the weaker binding and lower BBB penetration are significant drawbacks.

Output:
1
2025-04-17 07:00:36,190 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (364.837 and 362.499 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (104.7) is higher than the preferred <90 for CNS targets, but not drastically so. Ligand B (72.21) is well within the desired range. This favors Ligand B.

**3. logP:** Ligand A (1.653) is within the optimal range of 1-3. Ligand B (3.731) is slightly higher, nearing the upper limit, but still acceptable.

**4. H-Bond Donors:** Ligand A (3) and Ligand B (2) are both within the acceptable limit of <=5.

**5. H-Bond Acceptors:** Ligand A (5) and Ligand B (7) are both within the acceptable limit of <=10.

**6. QED:** Ligand A (0.724) has a better QED score than Ligand B (0.493), indicating a more drug-like profile.

**7. DILI:** Both ligands have similar DILI risk (65.374 and 68.437), both being moderately high but not alarming.

**8. BBB:** Ligand B (82.823) significantly outperforms Ligand A (58.511) in BBB penetration, which is *critical* for a CNS target like DRD2.

**9. Caco-2 Permeability:** Both have negative values, which is unusual. The magnitude suggests poor permeability for both.

**10. Aqueous Solubility:** Both have negative values, suggesting poor solubility.

**11. hERG Inhibition:** Ligand A (0.177) shows lower hERG inhibition liability than Ligand B (0.886), which is favorable.

**12. Microsomal Clearance:** Ligand A (-6.109) has significantly lower (better) microsomal clearance than Ligand B (103.044), indicating better metabolic stability.

**13. In vitro Half-Life:** Ligand B (119.981) has a much longer half-life than Ligand A (32.088).

**14. P-gp Efflux:** Ligand A (0.046) has significantly lower P-gp efflux liability than Ligand B (0.582), which is beneficial for CNS penetration.

**15. Binding Affinity:** Ligand A (-8.8 kcal/mol) has a stronger binding affinity than Ligand B (-7.5 kcal/mol). This is a substantial difference (1.3 kcal/mol), and can often outweigh other ADME concerns.

**Overall Assessment:**

While Ligand B excels in BBB penetration and has a longer half-life, Ligand A demonstrates a significantly stronger binding affinity (-8.8 vs -7.5 kcal/mol) and better metabolic stability (lower Cl_mic) and P-gp efflux. The stronger binding affinity is a major advantage for a GPCR target. The TPSA of Ligand A is slightly higher, but not critically so. The lower P-gp efflux and hERG inhibition of Ligand A are also favorable. Considering the GPCR-specific priorities, the superior affinity and favorable ADME properties of Ligand A make it the more promising candidate.

Output:
0
2025-04-17 07:00:36,190 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (343.43 & 350.42 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (82.27) is better than Ligand B (87.9). Both are below the 90 A^2 threshold for CNS targets, but A is closer to the ideal.

**3. logP:** Ligand A (1.423) is within the optimal 1-3 range. Ligand B (0.025) is *very* low, potentially hindering membrane permeability. This is a significant drawback.

**4. H-Bond Donors:** Ligand A (2) and Ligand B (1) are both acceptable (<=5).

**5. H-Bond Acceptors:** Ligand A (3) and Ligand B (6) are both acceptable (<=10).

**6. QED:** Ligand B (0.809) has a higher QED score than Ligand A (0.553), suggesting better overall drug-likeness.

**7. DILI:** Ligand B (38.74) has a lower DILI risk than Ligand A (16.44), which is favorable.

**8. BBB:** Ligand A (42.81) has a slightly better BBB penetration percentile than Ligand B (39.24), but both are below the desirable >70% for CNS targets.

**9. Caco-2:** Ligand A (-5.199) has a much better Caco-2 permeability than Ligand B (-4.755), indicating better intestinal absorption.

**10. Solubility:** Ligand B (0.06) has better aqueous solubility than Ligand A (-1.685).

**11. hERG:** Both ligands have very low hERG inhibition risk (0.206 and 0.256).

**12. Cl_mic:** Ligand A (-21.524) has a much lower (better) microsomal clearance than Ligand B (-14.53), indicating greater metabolic stability.

**13. t1/2:** Ligand B (7.092) has a longer in vitro half-life than Ligand A (-11.477).

**14. Pgp:** Ligand A (0.087) has lower P-gp efflux than Ligand B (0.023), which is favorable for CNS penetration.

**15. Binding Affinity:** Ligand B (-7.9) has a slightly better binding affinity than Ligand A (-8.3). However, the difference is relatively small.

**Overall Assessment:**

While Ligand B has a higher QED, lower DILI, and longer half-life, its extremely low logP is a major concern. This suggests poor membrane permeability and potentially very limited absorption and CNS penetration, despite the slightly better BBB percentile. Ligand A, despite a lower QED and slightly higher DILI, has a much more favorable logP, better Caco-2 permeability, lower Pgp efflux, and better metabolic stability. The affinity difference is minor and outweighed by the ADME advantages of Ligand A. For a CNS target like DRD2, good CNS penetration is critical, and Ligand A is more likely to achieve that.

Output:
1
2025-04-17 07:00:36,190 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (377.905 and 373.953 Da) fall within the ideal range of 200-500 Da.

**TPSA:** Ligand A (90.55) is borderline acceptable for CNS penetration, while Ligand B (21.06) is excellent, well below the 90 A^2 threshold. This is a significant advantage for Ligand B.

**logP:** Both ligands have logP values (3.797 and 4.997) within the optimal range of 1-3, though Ligand B is pushing the upper limit.

**H-Bond Donors/Acceptors:** Ligand A has 4 HBD and 7 HBA, which are acceptable. Ligand B has 0 HBD and 4 HBA, also acceptable.

**QED:** Both ligands have similar QED values (0.5 and 0.581), indicating good drug-likeness.

**DILI:** Ligand A has a DILI risk of 76.464, which is concerning (high risk). Ligand B has a much lower DILI risk of 38.891, which is good.

**BBB:** Ligand A has a BBB penetration of 49.011, which is below the desirable threshold of 70 for CNS targets. Ligand B has a BBB penetration of 70.609, meeting the threshold. This is a major advantage for Ligand B.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.395 and -5.241), which is unusual and suggests poor permeability. However, these values are on a log scale and are likely indicating very low permeability.

**Aqueous Solubility:** Both ligands have negative solubility values (-4.997 and -4.122), indicating poor aqueous solubility.

**hERG Inhibition:** Ligand A (0.695) has a slightly higher hERG risk than Ligand B (0.902), though both are relatively low.

**Microsomal Clearance:** Ligand A (70.713) has a higher microsomal clearance than Ligand B (56.208), suggesting lower metabolic stability.

**In vitro Half-Life:** Ligand A (50.981) has a slightly longer half-life than Ligand B (42.654).

**P-gp Efflux:** Ligand A (0.193) has lower P-gp efflux than Ligand B (0.809), which is favorable for CNS exposure.

**Binding Affinity:** Both ligands have very similar and strong binding affinities (-8.5 and -8.3 kcal/mol). The difference of 0.2 kcal/mol is not substantial enough to override other factors.

**Overall Assessment:**

Ligand B is the better candidate. While both have good binding affinity and acceptable QED, Ligand B excels in critical areas for a CNS-targeting GPCR ligand: significantly lower DILI risk, better BBB penetration, and lower P-gp efflux. Ligand A's high DILI risk and poor BBB penetration are major drawbacks. The slightly longer half-life of Ligand A is not enough to compensate for these issues. The poor solubility and permeability of both ligands are concerns that would need to be addressed in further optimization, but are less critical than the safety and CNS penetration issues.

Output:
1
2025-04-17 07:00:36,191 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B based on the provided guidelines, prioritizing GPCR-specific properties (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (352.331 and 348.491 Da) fall within the ideal range of 200-500 Da.

**TPSA:** Ligand A (32.34) is excellent, well below the 90 A^2 threshold for CNS targets. Ligand B (55.89) is still reasonable, but less optimal.

**logP:** Ligand A (3.247) is within the optimal range (1-3). Ligand B (0.526) is quite low, potentially hindering permeation.

**H-Bond Donors/Acceptors:** Both have acceptable HBD (1) counts. Ligand A has 2 HBA, while Ligand B has 4. Both are within the acceptable limit of 10.

**QED:** Both ligands have good QED scores (0.677 and 0.805), indicating good drug-like properties.

**DILI:** Ligand A (49.011) has a slightly higher DILI risk than Ligand B (5.894), but both are below the concerning threshold of 60.

**BBB:** Ligand A (89.608) has a significantly better BBB penetration percentile than Ligand B (70.609). This is a crucial advantage for a CNS target like DRD2.

**Caco-2 Permeability:** Ligand A (-4.617) has a negative value, which is unusual and suggests very poor permeability. Ligand B (-5.123) is also poor, but similar to A.

**Aqueous Solubility:** Ligand A (-3.717) and Ligand B (-1.161) both have negative solubility values, indicating poor aqueous solubility.

**hERG Inhibition:** Ligand A (0.939) has a slightly higher hERG risk than Ligand B (0.281), but both are relatively low.

**Microsomal Clearance:** Ligand A (-5.201) has a negative clearance, which is unusual and suggests very high metabolic stability. Ligand B (2.955) has a low clearance, indicating good metabolic stability.

**In vitro Half-Life:** Ligand A (3.303) has a shorter half-life than Ligand B (5.006).

**P-gp Efflux:** Ligand A (0.5) has lower P-gp efflux liability than Ligand B (0.008), which is favorable for CNS penetration.

**Binding Affinity:** Ligand B (-7.5 kcal/mol) has a significantly stronger binding affinity than Ligand A (-10.1 kcal/mol). This is a substantial advantage.

**Overall Assessment:**

Despite Ligand A's excellent TPSA and P-gp efflux, its poor Caco-2 permeability and solubility, combined with a weaker binding affinity, make it less attractive. Ligand B, while having a slightly higher TPSA and lower logP, compensates with a significantly improved binding affinity and better BBB penetration, and lower P-gp efflux. The strong binding affinity of Ligand B is likely to outweigh the minor drawbacks in other properties.

Output:
1
2025-04-17 07:00:36,191 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the acceptable range (200-500 Da). Ligand A (473.14 Da) is at the higher end, while Ligand B (352.431 Da) is more favorably positioned.

**TPSA:** Ligand A (56.15) is better than Ligand B (77.1). For CNS targets, we want TPSA <= 90, both are within this range, but A is better.

**logP:** Ligand A (3.948) is optimal, while Ligand B (1.679) is on the lower side. A logP between 1-3 is preferred, so A is better.

**H-Bond Donors/Acceptors:** Both have acceptable HBD counts (1). Ligand B has a slightly higher HBA count (5) compared to Ligand A (4), but both are within the acceptable limit of <=10.

**QED:** Both ligands have good QED values (A: 0.735, B: 0.779), indicating good drug-like properties.

**DILI:** Ligand B (51.105) has a significantly lower DILI risk than Ligand A (76.425). This is a major advantage for Ligand B.

**BBB:** Ligand A (89.725) has a much better BBB penetration score than Ligand B (67.158). Given that DRD2 is a CNS target, this is a crucial factor favoring Ligand A.

**Caco-2 Permeability:** Ligand B (-5.011) has a negative Caco-2 value, which is very concerning. Ligand A (-4.554) is also negative, but less so. Both are poor.

**Aqueous Solubility:** Ligand B (-1.79) has very poor solubility, while Ligand A (-6.334) is also poor.

**hERG Inhibition:** Ligand B (0.172) has a very low hERG inhibition liability, which is excellent. Ligand A (0.583) is slightly higher, but still relatively low.

**Microsomal Clearance:** Ligand B (-2.471) has a negative clearance, which is highly favorable, indicating very high metabolic stability. Ligand A (76.617) has a high clearance, suggesting rapid metabolism.

**In vitro Half-Life:** Ligand B (14.729) has a better half-life than Ligand A (24.562).

**P-gp Efflux:** Ligand A (0.715) has a higher P-gp efflux liability than Ligand B (0.031). Lower P-gp efflux is preferred, especially for CNS drugs, favoring Ligand B.

**Binding Affinity:** Ligand B (-8.6 kcal/mol) has a significantly stronger binding affinity than Ligand A (0.0 kcal/mol). This is a substantial advantage for Ligand B, potentially outweighing some of its ADME drawbacks.

**Overall Assessment:**

Ligand B has a much better binding affinity and significantly lower DILI and P-gp efflux. It also has superior metabolic stability (negative Cl_mic). However, its BBB penetration is lower, solubility is very poor, and Caco-2 permeability is extremely poor.

Ligand A has better BBB penetration and a more optimal logP, but suffers from higher DILI risk, higher P-gp efflux, and significantly weaker binding affinity.

Considering the GPCR-specific priorities, the strong binding affinity of Ligand B is a major advantage. While its BBB penetration is not ideal, the difference isn't as significant as the >8 kcal/mol difference in binding affinity. The poor solubility and permeability are concerns, but these can potentially be addressed through formulation strategies. The low DILI and P-gp efflux are also highly desirable.

Output:
1
2025-04-17 07:00:36,191 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (357.41 and 352.475 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (64.11) is significantly better than Ligand B (86.71). For CNS targets, we want TPSA <= 90, and A is comfortably within this range, while B is approaching the upper limit.

**3. logP:** Ligand A (4.147) is a bit high, potentially leading to solubility issues, but still within a reasonable range. Ligand B (1.365) is on the lower side, which could hinder permeation. Optimal is 1-3.

**4. H-Bond Donors:** Ligand A (1) is preferable to Ligand B (2). Lower is generally better for permeability.

**5. H-Bond Acceptors:** Ligand A (5) is better than Ligand B (4). Both are acceptable, but lower is better.

**6. QED:** Both ligands have similar QED values (0.72 and 0.656), indicating good drug-like properties.

**7. DILI:** Ligand A (88.251) has a higher DILI risk than Ligand B (9.655). This is a significant drawback for Ligand A.

**8. BBB:** Ligand A (64.831) has a better BBB percentile than Ligand B (53.16). This is crucial for a CNS target like DRD2.

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.922 and -4.942). This is unusual and suggests poor permeability. However, these values are on a scale where negative values are possible, and direct comparison is difficult without knowing the scale's specifics.

**10. Aqueous Solubility:** Both ligands have negative solubility values (-5.148 and -0.991). Again, these are on a scale where negative values are possible, and direct comparison is difficult.

**11. hERG Inhibition:** Ligand A (0.623) has a slightly higher hERG risk than Ligand B (0.181). Lower is better.

**12. Microsomal Clearance:** Ligand B (10.231) has a much lower microsomal clearance than Ligand A (70.519), indicating better metabolic stability.

**13. In vitro Half-Life:** Ligand B (-10.89) has a longer in vitro half-life than Ligand A (-24.598). Longer is better.

**14. P-gp Efflux:** Ligand A (0.519) has lower P-gp efflux than Ligand B (0.025), which is favorable for CNS penetration.

**15. Binding Affinity:** Ligand A (-9.8 kcal/mol) has significantly better binding affinity than Ligand B (-7.6 kcal/mol). This is a substantial advantage (over 2 kcal/mol difference).

**Overall Assessment:**

Ligand A has a much stronger binding affinity and better BBB penetration and P-gp efflux, which are critical for a CNS GPCR target. However, it suffers from higher DILI risk, higher hERG risk, and significantly higher microsomal clearance. Ligand B has a better safety profile (lower DILI, hERG) and better metabolic stability, but its lower affinity and BBB penetration are concerning.

The affinity difference is quite large. While the ADME properties of Ligand A are less ideal, the strong binding could potentially overcome some of these issues. The lower DILI and hERG of Ligand B are attractive, but the weaker binding is a significant drawback for a GPCR target where potency is key. Considering the GPCR-specific priorities, the binding affinity is the most important factor, and the improved BBB penetration of Ligand A is also crucial.

Output:
1
2025-04-17 07:00:36,191 - INFO - Batch 329 complete. Total preferences: 5264
2025-04-17 07:00:36,191 - INFO - Processing batch 330/512...
2025-04-17 07:01:19,671 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (348.397 and 356.463 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (41.37) is excellent, well below the 90 A^2 threshold for CNS targets. Ligand B (99.1) is higher, but still potentially acceptable, though less ideal.

**logP:** Ligand A (3.019) is optimal (1-3). Ligand B (0.456) is quite low, potentially hindering membrane permeability and CNS penetration.

**H-Bond Donors/Acceptors:** Ligand A (0 HBD, 4 HBA) is favorable. Ligand B (3 HBD, 5 HBA) is also acceptable.

**QED:** Both ligands have reasonable QED scores (0.856 and 0.601), indicating good drug-like properties.

**DILI:** Ligand A (41.877) has a slightly higher DILI risk than Ligand B (19.271), but both are below the concerning 60 threshold.

**BBB:** Ligand A (90.733) has a significantly better BBB percentile than Ligand B (49.128). This is a crucial factor for a CNS target like DRD2.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values, which is unusual and requires further investigation. However, the magnitude of negativity is similar.

**Aqueous Solubility:** Both ligands have negative solubility values, also unusual. Again, the magnitudes are similar.

**hERG:** Ligand A (0.892) has a slightly higher hERG risk than Ligand B (0.303), but both are relatively low.

**Microsomal Clearance:** Ligand A (49.756) has a higher microsomal clearance than Ligand B (7.205), suggesting lower metabolic stability.

**In vitro Half-Life:** Ligand B (-14.712) has a more negative half-life, which is not possible. This is a red flag. Ligand A (-25.031) also has a negative half-life, which is also problematic.

**P-gp Efflux:** Ligand A (0.512) has a slightly higher P-gp efflux liability than Ligand B (0.023), but both are relatively low.

**Binding Affinity:** Ligand B (-6.5 kcal/mol) has a significantly stronger binding affinity than Ligand A (-0.0 kcal/mol). This is a substantial advantage.

**Overall Assessment:**

While Ligand B has a much better binding affinity, its low logP and questionable half-life are major concerns. The negative values for Caco-2 and solubility are also problematic. Ligand A, despite its weaker binding, has a much more favorable profile regarding CNS penetration (BBB, TPSA, logP) and is more likely to reach the target in the brain. The negative half-life for both is a serious issue that needs to be addressed, but the overall profile of A is more promising. Given the GPCR-specific priorities, the better BBB penetration and more favorable ADME properties of Ligand A outweigh the affinity difference.

Output:
1
2025-04-17 07:01:19,671 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (345.443 Da) is slightly lower, which could be beneficial for permeability. Ligand B (371.949 Da) is also good.

**2. TPSA:** Ligand A (72.36) is better than Ligand B (49.77) as it is closer to the ideal range for CNS targets (<=90).

**3. logP:** Ligand A (1.607) is within the optimal range (1-3). Ligand B (3.963) is at the higher end, potentially causing solubility issues or off-target interactions, but still acceptable.

**4. H-Bond Donors:** Ligand A (2) and Ligand B (1) are both within the acceptable limit of <=5.

**5. H-Bond Acceptors:** Ligand A (4) and Ligand B (3) are both within the acceptable limit of <=10.

**6. QED:** Both ligands have reasonable QED scores (Ligand A: 0.823, Ligand B: 0.702), indicating good drug-like properties.

**7. DILI:** Ligand A (42.846) has a lower DILI risk than Ligand B (8.104), which is a significant advantage.

**8. BBB:** Ligand B (75.301) has a better BBB penetration score than Ligand A (67.584), which is crucial for a CNS target like DRD2.

**9. Caco-2 Permeability:** Ligand A (-5.057) has a worse Caco-2 permeability than Ligand B (-4.549).

**10. Aqueous Solubility:** Ligand A (-2.319) has a worse aqueous solubility than Ligand B (-3.722).

**11. hERG Inhibition:** Ligand A (0.286) has a lower hERG inhibition liability than Ligand B (0.765), which is a positive.

**12. Microsomal Clearance:** Ligand B (83.97) has a much higher microsomal clearance than Ligand A (4.899), indicating lower metabolic stability.

**13. In vitro Half-Life:** Ligand A (26.587) and Ligand B (26.384) have similar in vitro half-lives.

**14. P-gp Efflux:** Ligand A (0.075) has much lower P-gp efflux liability than Ligand B (0.672), which is highly desirable for CNS penetration.

**15. Binding Affinity:** Ligand B (-7.4) has a slightly better binding affinity than Ligand A (-8.1). However, the difference is not substantial enough to outweigh other significant ADME differences.

**Overall Assessment:**

Ligand A demonstrates a more favorable ADME profile, particularly regarding DILI risk, P-gp efflux, and microsomal clearance. While Ligand B has slightly better BBB penetration and binding affinity, the superior ADME properties of Ligand A, especially the lower P-gp efflux and DILI risk, make it a more promising drug candidate for a CNS target like DRD2. The slightly lower BBB score of Ligand A can potentially be addressed through further optimization, while improving the ADME profile of Ligand B would likely be more challenging.

Output:
0
2025-04-17 07:01:19,671 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (366.487 Da and 348.531 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (78.68) is higher than Ligand B (58.2). For CNS targets, we want TPSA <= 90, so both are acceptable, but B is preferable.

**logP:** Ligand A (1.079) is within the optimal 1-3 range. Ligand B (3.937) is at the higher end but still acceptable.

**H-Bond Donors/Acceptors:** Ligand A has 1 HBD and 6 HBA, while Ligand B has 2 HBD and 2 HBA. Both are within the acceptable limits (<=5 HBD and <=10 HBA).

**QED:** Both ligands have similar QED values (0.778 and 0.714), indicating good drug-likeness.

**DILI:** Ligand A (52.617) has a slightly higher DILI risk than Ligand B (27.104), but both are below the concerning threshold of 60.

**BBB:** Both ligands have similar BBB penetration (65.413% and 65.374%). While ideally >70 for CNS targets, these are reasonably good.

**Caco-2 Permeability:** Ligand A (-5.303) has worse Caco-2 permeability than Ligand B (-4.727), indicating potentially lower intestinal absorption.

**Aqueous Solubility:** Ligand A (-2.03) has better aqueous solubility than Ligand B (-4.889). Solubility is important for formulation.

**hERG Inhibition:** Ligand A (0.287) has a lower hERG inhibition risk than Ligand B (0.575), which is preferable.

**Microsomal Clearance:** Ligand B (54.305) has lower microsomal clearance than Ligand A (24.354), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand B (17.099) has a longer in vitro half-life than Ligand A (-18.083), which is desirable.

**P-gp Efflux:** Ligand A (0.074) has lower P-gp efflux than Ligand B (0.246), which is important for CNS exposure.

**Binding Affinity:** Ligand A (-6.5 kcal/mol) has significantly better binding affinity than Ligand B (0.0 kcal/mol). This is a crucial factor, and a difference of 6.5 kcal/mol is substantial.

**Overall Assessment:**

Ligand A has a significantly stronger binding affinity, which is the most important factor for a GPCR ligand. It also has better solubility and lower hERG risk. However, Ligand B has better metabolic stability (lower Cl_mic, longer t1/2), slightly better TPSA, and lower DILI risk. The P-gp efflux is lower for A, which is good for CNS penetration. Considering the large difference in binding affinity, the drawbacks of Ligand A (slightly worse metabolic stability) are likely outweighed by its potency.

Output:
1
2025-04-17 07:01:19,671 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (345.487 Da) is slightly lower, which is generally favorable for permeability. Ligand B (372.853 Da) is also acceptable.

**2. TPSA:** Ligand A (43.86) is excellent, well below the 90 A^2 threshold for CNS targets. Ligand B (87.9) is higher, but still potentially acceptable, though less ideal for CNS penetration.

**3. logP:** Ligand A (2.052) is optimal. Ligand B (0.3) is quite low, which could hinder membrane permeability and CNS penetration.

**4. H-Bond Donors:** Both ligands are within the acceptable limit of 5. Ligand A has 0, and Ligand B has 1.

**5. H-Bond Acceptors:** Ligand A (3) and Ligand B (6) are both within the acceptable limit of 10.

**6. QED:** Both ligands have good QED scores (A: 0.581, B: 0.803), indicating drug-like properties.

**7. DILI:** Ligand A (13.649) has a much lower DILI risk than Ligand B (63.086), which is a significant advantage.

**8. BBB:** Ligand A (78.519) has a good BBB percentile, desirable for a CNS target. Ligand B (32.803) is poor, indicating limited brain penetration.

**9. Caco-2:** Both have negative values, suggesting poor permeability. This is unusual and requires further investigation in a real-world scenario, but we'll proceed with relative comparison.

**10. Solubility:** Both have negative solubility values, again unusual. Ligand A (-1.782) is slightly better than Ligand B (-2.078).

**11. hERG:** Both ligands have very low hERG risk (A: 0.525, B: 0.092).

**12. Cl_mic:** Ligand B (20.086) has a lower microsomal clearance, suggesting better metabolic stability than Ligand A (44.733).

**13. t1/2:** Ligand B (9.101) has a longer in vitro half-life than Ligand A (-11.683).

**14. Pgp:** Ligand A (0.153) has lower P-gp efflux liability, which is beneficial for CNS exposure, compared to Ligand B (0.075).

**15. Affinity:** Ligand A (-7.1 kcal/mol) has a slightly better binding affinity than Ligand B (-6.5 kcal/mol). While the difference isn't huge, it's enough to potentially outweigh some ADME drawbacks.

**Overall Assessment:**

Ligand A is significantly better suited as a CNS drug candidate targeting DRD2. It has a much better BBB score, lower DILI risk, optimal logP, and acceptable TPSA. While Ligand B has better metabolic stability (lower Cl_mic and longer t1/2), the poor BBB penetration and high DILI risk are major drawbacks for a CNS target. The slightly better affinity of Ligand A further supports its selection.

Output:
0
2025-04-17 07:01:19,671 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (352.41 and 355.32 Da) fall comfortably within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (76.46) is slightly higher than Ligand B (72.28), but both are below the 90 A^2 threshold desirable for CNS targets.

**3. logP:** Ligand A (0.614) is a bit low, potentially hindering permeability. Ligand B (1.685) is better, falling within the optimal 1-3 range.

**4. H-Bond Donors:** Both ligands have 1 HBD, which is acceptable.

**5. H-Bond Acceptors:** Ligand A has 5 HBA, and Ligand B has 6 HBA, both are within the acceptable limit of 10.

**6. QED:** Both ligands have high QED scores (0.814 and 0.827), indicating good drug-like properties.

**7. DILI:** Ligand A (41.566) has a lower DILI risk than Ligand B (61.574). This is a significant advantage for Ligand A.

**8. BBB:** Ligand A (94.184) has a substantially higher BBB penetration percentile than Ligand B (82.086). This is crucial for a CNS target like DRD2.

**9. Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and suggests poor permeability. However, the scale is not specified, so it's difficult to interpret.

**10. Aqueous Solubility:** Both ligands have very poor aqueous solubility (-2.21 and -2.599). This is a concern for both.

**11. hERG Inhibition:** Both ligands show low hERG inhibition liability (0.537 and 0.342), which is favorable.

**12. Microsomal Clearance:** Ligand A (5.082) has significantly lower microsomal clearance than Ligand B (37.479), suggesting better metabolic stability.

**13. In vitro Half-Life:** Ligand A (16.227) has a longer in vitro half-life than Ligand B (0.842). This is a significant advantage.

**14. P-gp Efflux:** Ligand A (0.128) shows much lower P-gp efflux liability than Ligand B (0.035), which is beneficial for CNS exposure.

**15. Binding Affinity:** Ligand B (-8.7) has a slightly better binding affinity than Ligand A (-8.4), but the difference is only 0.3 kcal/mol. Given the other ADME advantages of Ligand A, this small difference in binding is unlikely to be decisive.

**Overall Assessment:**

Ligand A is the superior candidate. While Ligand B has slightly better binding affinity, Ligand A excels in critical ADME properties for a CNS-targeting GPCR: significantly better BBB penetration, lower DILI risk, lower microsomal clearance, longer half-life, and lower P-gp efflux. The slightly lower logP of Ligand A is a minor drawback compared to these substantial advantages. The poor solubility is a concern for both, but can be addressed with formulation strategies.

Output:
0
2025-04-17 07:01:19,671 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight (MW):** Both ligands (348.395 and 344.499 Da) fall comfortably within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (82.06) is better than Ligand B (58.2). For CNS targets, we want TPSA <= 90, both are within this range, but A is slightly higher.

**3. logP:** Both ligands have good logP values (2.313 and 2.728), falling within the optimal 1-3 range.

**4. H-Bond Donors (HBD):** Both ligands are acceptable (1 and 2 respectively), well below the threshold of 5.

**5. H-Bond Acceptors (HBA):** Ligand A (6) and Ligand B (2) are both good, below the 10 threshold.

**6. QED:** Ligand A (0.823) has a significantly better QED score than Ligand B (0.698), indicating a more drug-like profile.

**7. DILI:** Ligand A (34.393) has a much lower DILI risk than Ligand B (15.859), which is a significant advantage.

**8. BBB:** Ligand A (77.239) has a better BBB percentile than Ligand B (54.246). While >70 is desirable, 77.239 is a substantial improvement over 54.246 for a CNS target.

**9. Caco-2 Permeability:** Ligand A (-4.288) and Ligand B (-4.652) both have negative values, which is unusual and suggests poor permeability. However, the scale isn't specified, so it's hard to interpret the magnitude.

**10. Aqueous Solubility:** Both ligands have poor aqueous solubility (-3.488 and -4.868). This could be a formulation challenge.

**11. hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.275 and 0.123).

**12. Microsomal Clearance:** Ligand B (12.629) has a lower microsomal clearance than Ligand A (54.332), suggesting better metabolic stability.

**13. In vitro Half-Life:** Ligand B (6.83) has a longer in vitro half-life than Ligand A (-15.709). This is a significant advantage.

**14. P-gp Efflux:** Both ligands have low P-gp efflux liability (0.11 and 0.066).

**15. Binding Affinity:** Ligand A (-8.8 kcal/mol) has a slightly better binding affinity than Ligand B (-7.7 kcal/mol). This 1.1 kcal/mol difference is substantial enough to potentially outweigh some ADME drawbacks.

**Overall Assessment:**

Ligand A is preferable. While Ligand B has better metabolic stability and half-life, Ligand A excels in critical areas for a CNS-targeting GPCR ligand: better BBB penetration, a significantly lower DILI risk, a higher QED score, and a slightly improved binding affinity. The solubility is a concern for both, but the other advantages of Ligand A make it the more promising candidate.

Output:
1
2025-04-17 07:01:19,671 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (386.42 Da) is slightly higher than Ligand B (352.507 Da), but both are acceptable.

**2. TPSA:** Ligand A (59.06) is higher than Ligand B (33.43). For CNS targets, we want TPSA <= 90, so both are within range, but Ligand B is significantly better.

**3. logP:** Both ligands have similar logP values (A: 4.547, B: 4.637), both slightly above the optimal range of 1-3. This could potentially lead to solubility issues or off-target interactions, but is not a dealbreaker.

**4. H-Bond Donors:** Ligand A has 1 HBD, Ligand B has 0. Both are within the acceptable limit of <=5.

**5. H-Bond Acceptors:** Both ligands have 5 HBAs, which is acceptable (<=10).

**6. QED:** Ligand A (0.675) has a better QED score than Ligand B (0.554), indicating a more drug-like profile.

**7. DILI:** Ligand A (95.347) has a significantly higher DILI risk than Ligand B (47.266). This is a major concern for Ligand A.

**8. BBB:** Ligand B (83.443) has a much better BBB penetration percentile than Ligand A (67.701). For a CNS target like DRD2, this is a critical advantage.

**9. Caco-2 Permeability:** Both show poor Caco-2 permeability (-4.833 and -4.95). This suggests poor intestinal absorption, but is less critical for CNS drugs where direct delivery is possible.

**10. Aqueous Solubility:** Both have very poor aqueous solubility (-4.534 and -4.194). This could pose formulation challenges.

**11. hERG Inhibition:** Both ligands have low hERG inhibition risk (0.69 and 0.712).

**12. Microsomal Clearance:** Ligand B (75.811) has a higher microsomal clearance than Ligand A (42.26), indicating faster metabolism and potentially lower exposure.

**13. In vitro Half-Life:** Ligand A (74.994) has a significantly longer in vitro half-life than Ligand B (-18.819). This is a substantial advantage for Ligand A.

**14. P-gp Efflux:** Both have low P-gp efflux liability (0.622 and 0.56).

**15. Binding Affinity:** Ligand B (-7.5 kcal/mol) has a significantly stronger binding affinity than Ligand A (-9.0 kcal/mol). This is a major advantage for Ligand B.

**Overall Assessment:**

While Ligand A has a better QED and a longer half-life, its significantly higher DILI risk and lower BBB penetration are major drawbacks for a CNS-targeted drug. Ligand B, despite its slightly lower QED and faster metabolism, has a much better safety profile (lower DILI), superior BBB penetration, and significantly stronger binding affinity. The strong binding affinity of Ligand B can potentially offset some of the ADME liabilities. Considering the GPCR-specific priorities, Ligand B is the more promising candidate.

Output:
1
2025-04-17 07:01:19,672 - INFO - Reasoning:

Let's analyze Ligand A and Ligand B against the provided guidelines, prioritizing GPCR-specific properties (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (348.487 and 362.767 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (61.8) and Ligand B (59.81) are both below the 90 A^2 threshold desirable for CNS targets, which is excellent.

**logP:** Ligand A (1.843) is within the optimal 1-3 range. Ligand B (4.023) is slightly above, potentially raising concerns about solubility and off-target effects, but still within a manageable range.

**H-Bond Donors/Acceptors:** Both ligands have acceptable HBD (2 and 1 respectively) and HBA (4 each) counts.

**QED:** Both ligands have similar QED scores (0.715 and 0.713), indicating good drug-likeness.

**DILI:** Ligand A (10.624) has a much lower DILI risk than Ligand B (89.337). This is a significant advantage for Ligand A.

**BBB:** Ligand B (81.621) has a significantly better BBB penetration percentile than Ligand A (51.997). This is a crucial factor for a CNS target like DRD2.

**Caco-2 Permeability:** Both have negative Caco-2 values (-4.754 and -4.86). This is unusual and suggests poor permeability. However, these values are on a scale where negative values are possible.

**Aqueous Solubility:** Both ligands have very poor aqueous solubility (-1.811 and -5.314). This is a major concern for both.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.801 and 0.613).

**Microsomal Clearance:** Ligand A (34.776) has lower microsomal clearance than Ligand B (46.271), indicating better metabolic stability.

**In vitro Half-Life:** Ligand B (14.075) has a longer in vitro half-life than Ligand A (5.842), which is preferable.

**P-gp Efflux:** Ligand A (0.343) has lower P-gp efflux liability than Ligand B (0.629), which is beneficial for CNS exposure.

**Binding Affinity:** Ligand B (-10.6 kcal/mol) has a significantly stronger binding affinity than Ligand A (-8.1 kcal/mol). This >1.5 kcal/mol difference is substantial and can outweigh some ADME drawbacks.

**Overall Assessment:**

The decision hinges on balancing affinity, BBB, and ADME properties. Ligand B's superior affinity and BBB penetration are strong positives, crucial for CNS drug development. However, its high DILI risk and poorer metabolic stability are significant concerns. Ligand A has a much better safety profile (DILI) and metabolic stability, but its lower affinity and BBB penetration are drawbacks.

Given the importance of strong target engagement and CNS penetration for a DRD2 ligand, and acknowledging that ADME issues can sometimes be addressed through formulation or structural modifications, **Ligand B is the more promising candidate despite its drawbacks.** The substantial affinity advantage is likely to be more impactful than the ADME liabilities, especially at the early stages of drug discovery.

Output:
1
2025-04-17 07:01:19,672 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (374.809 and 345.403 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Both ligands (105.07 and 104.12) are slightly above the optimal <90 for CNS targets, but still reasonable.

**3. logP:** Ligand A (2.882) is optimal, while Ligand B (1.363) is a bit low, potentially hindering membrane permeability.

**4. H-Bond Donors:** Both have 2 HBD, which is within the acceptable limit of <=5.

**5. H-Bond Acceptors:** Ligand A has 6 HBA, and Ligand B has 5, both within the acceptable limit of <=10.

**6. QED:** Both ligands have good QED scores (0.711 and 0.823), indicating drug-like properties.

**7. DILI:** Ligand A has a very high DILI risk (99.341), which is a major concern. Ligand B has a much lower DILI risk (41.877), which is good.

**8. BBB:** Ligand A has a very low BBB penetration (12.99), making it unlikely to reach the CNS target. Ligand B has a significantly better BBB penetration (60.256), although still not optimal (>70).

**9. Caco-2 Permeability:** Both have negative Caco-2 values (-5.338 and -5.381), which is unusual and suggests poor permeability. This could be a data issue, but is a negative signal.

**10. Aqueous Solubility:** Both have negative solubility values (-3.297 and -1.517), also unusual and suggesting poor solubility.

**11. hERG Inhibition:** Both ligands show very low hERG inhibition risk (0.026 and 0.029).

**12. Microsomal Clearance:** Ligand A has a negative clearance (-5.856), which is not physically meaningful and suggests a data error. Ligand B has a negative clearance (-6.132), also not physically meaningful.

**13. In vitro Half-Life:** Ligand A has a negative half-life (-5.264), while Ligand B has a positive half-life (5.163). The negative value for A is a data error.

**14. P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.034 and 0.013).

**15. Binding Affinity:** Both ligands have very similar and strong binding affinities (-9.4 and -9.1 kcal/mol). The difference of 0.3 kcal/mol is unlikely to be decisive.

**Overall Assessment:**

Despite similar binding affinities, Ligand B is significantly more promising. The critical factors are the drastically lower DILI risk and substantially better (though not ideal) BBB penetration. The negative values for Caco-2, solubility, and clearance are concerning and require further investigation, but the DILI and BBB differences are decisive. Ligand A's extremely high DILI risk and very poor BBB penetration make it a very unlikely drug candidate.

Output:
1
2025-04-17 07:01:19,672 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B against the provided guidelines, with emphasis on GPCR-specific properties (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (370.431 and 362.308 Da) fall within the ideal range of 200-500 Da.

**TPSA:** Ligand A (132.46) is slightly above the optimal <90 for CNS targets, but still reasonable. Ligand B (127.32) is better, falling comfortably below 140 and closer to the CNS target.

**logP:** Ligand A (-0.802) is a bit low, potentially hindering permeation. Ligand B (0.12) is better, within the optimal 1-3 range, though on the lower end.

**H-Bond Donors/Acceptors:** Both ligands have 3 HBD and 6/5 HBA, respectively, which are acceptable values.

**QED:** Both ligands have similar QED values (0.575 and 0.566), indicating good drug-likeness.

**DILI:** Ligand A (78.325) has a higher DILI risk than Ligand B (41.915). This is a significant negative for Ligand A.

**BBB:** Ligand B (74.564) has a substantially better BBB penetration percentile than Ligand A (27.763). This is *critical* for a CNS target like DRD2.

**Caco-2 Permeability:** Both have negative values which is unusual. Assuming these are percentile scores, both are very poor.

**Aqueous Solubility:** Both ligands have very poor aqueous solubility (-2.196 and -2.973). This could pose formulation challenges.

**hERG Inhibition:** Both ligands show very low hERG inhibition risk (0.062 and 0.093).

**Microsomal Clearance:** Ligand A (-12.316) has a much lower (better) microsomal clearance than Ligand B (26.493), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (14.083) has a longer half-life than Ligand B (-4.571).

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.012 and 0.016).

**Binding Affinity:** Ligand B (-8.4 kcal/mol) has a slightly better binding affinity than Ligand A (-7.3 kcal/mol). While the difference is not huge, it's still a factor.

**Overall Assessment:**

Ligand B is the more promising candidate. Its significantly better BBB penetration and lower DILI risk are major advantages for a CNS-targeting drug. While Ligand A has better metabolic stability and half-life, the poor BBB and higher DILI risk are dealbreakers. The slightly better affinity of Ligand B further supports its selection. The poor Caco-2 and solubility are concerns for both, but can be addressed with formulation strategies.



Output:
1
2025-04-17 07:01:19,672 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (346.383 and 353.463 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (80.86) is excellent, well below the 90 A^2 threshold for CNS targets. Ligand B (90.9) is slightly higher but still acceptable.

**logP:** Ligand A (2.21) is optimal (1-3). Ligand B (-0.121) is quite low, potentially hindering membrane permeability and CNS penetration.

**H-Bond Donors/Acceptors:** Ligand A (1 HBD, 5 HBA) and Ligand B (3 HBD, 5 HBA) both meet the criteria of <=5 HBD and <=10 HBA.

**QED:** Ligand A (0.859) has a very strong drug-like profile. Ligand B (0.566) is acceptable but less ideal.

**DILI:** Ligand A (73.245) has a moderate DILI risk, but is still acceptable. Ligand B (6.747) has a very low DILI risk, which is excellent.

**BBB:** Ligand A (74.758) has good BBB penetration. Ligand B (39.55) is significantly lower, a major concern for a CNS target like DRD2.

**Caco-2 Permeability:** Ligand A (-4.471) has poor Caco-2 permeability. Ligand B (-5.133) is also poor.

**Aqueous Solubility:** Ligand A (-4.036) has poor aqueous solubility. Ligand B (-0.647) is also poor.

**hERG:** Both ligands (0.69 and 0.103) have low hERG inhibition liability, which is positive.

**Microsomal Clearance:** Ligand A (35.665) has moderate clearance. Ligand B (7.417) has very low clearance, suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (-14.164) has a very short half-life. Ligand B (19.352) has a reasonable half-life.

**P-gp Efflux:** Ligand A (0.151) has low P-gp efflux, which is good. Ligand B (0.004) has very low P-gp efflux, which is excellent.

**Binding Affinity:** Ligand B (-7.9 kcal/mol) has a slightly better binding affinity than Ligand A (-8.3 kcal/mol), but the difference is small.

**Overall Assessment:**

Ligand A has better TPSA, QED, and P-gp efflux. However, Ligand B excels in DILI risk, metabolic stability (Cl_mic and t1/2), and P-gp efflux. The biggest drawback for Ligand B is its low logP and consequently, poor BBB penetration. However, the relatively small affinity difference between the two ligands, coupled with the significant issues with Ligand A's permeability and half-life, make Ligand B the more promising candidate. While the low logP is a concern, it might be addressable through structural modifications. The poor permeability and short half-life of Ligand A are more difficult to overcome.

Output:
1
2025-04-17 07:01:19,672 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (341.415 Da) is slightly better positioned.

**TPSA:** Ligand B (71.09) is significantly better than Ligand A (110.67). For CNS targets, we want TPSA <= 90, and Ligand B is comfortably within this range, while Ligand A is pushing the limit.

**logP:** Ligand A (1.804) is optimal (1-3), while Ligand B (4.124) is a bit high. While not drastically over the limit, higher logP can lead to off-target effects and solubility issues.

**H-Bond Donors/Acceptors:** Both ligands have reasonable HBD (3 and 2 respectively) and HBA (4 each) counts, falling within acceptable ranges.

**QED:** Both ligands have good QED scores (0.657 and 0.812), indicating good drug-like properties.

**DILI:** Ligand A (56.96) has a significantly lower DILI risk than Ligand B (77.007). This is a substantial advantage.

**BBB:** Ligand A (49.748) has a better BBB penetration percentile than Ligand B (31.989). This is *critical* for a CNS target like DRD2.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values, which is unusual and suggests poor permeability. However, the scale is not specified, so it's difficult to interpret.

**Aqueous Solubility:** Both ligands have negative solubility values, suggesting poor solubility. Again, the scale is not specified, making interpretation difficult.

**hERG Inhibition:** Both ligands have low hERG inhibition liability (0.173 and 0.466), which is good.

**Microsomal Clearance:** Ligand B (33.32) has a higher microsomal clearance than Ligand A (14.214), indicating faster metabolism and potentially lower *in vivo* exposure.

**In vitro Half-Life:** Ligand A (-24.768) has a significantly longer in vitro half-life than Ligand B (78.469). This is a major advantage.

**P-gp Efflux:** Ligand A (0.052) has much lower P-gp efflux liability than Ligand B (0.141), which is crucial for CNS penetration.

**Binding Affinity:** Ligand B (-9.4) has a slightly better binding affinity than Ligand A (-8.5). While a 0.9 kcal/mol difference is noticeable, it may not outweigh the significant ADME advantages of Ligand A.

**Overall Assessment:**

Ligand A is the stronger candidate. While Ligand B has slightly better binding affinity, Ligand A excels in critical ADME properties for a CNS-targeting GPCR: significantly better BBB penetration, lower DILI risk, lower P-gp efflux, and a longer half-life. The TPSA of Ligand A is less ideal, but the other advantages are more impactful. The negative Caco-2 and solubility values are concerning for both, but the other benefits of Ligand A are more compelling.



Output:
0
2025-04-17 07:01:19,672 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (347.415 and 372.531 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (111.55) is slightly above the preferred <90 for CNS targets, but still reasonable. Ligand B (92.34) is well within the desired range.

**logP:** Both ligands have good logP values (1.443 and 1.648), falling within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A has 4 HBD and 5 HBA, while Ligand B has 2 HBD and 4 HBA. Both are within acceptable limits (<=5 HBD and <=10 HBA).

**QED:** Both ligands have good QED scores (0.532 and 0.61), indicating good drug-like properties.

**DILI:** Ligand A (21.791) has a much lower DILI risk than Ligand B (34.626), which is a significant advantage.

**BBB:** Ligand B (63.28) has a substantially better BBB penetration percentile than Ligand A (23.808). This is *critical* for a CNS target like DRD2.

**Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual. Assuming these are percentile scores, it suggests poor permeability for both.

**Aqueous Solubility:** Both ligands have similar, very poor aqueous solubility (-2.277 and -2.209). This could pose formulation challenges.

**hERG Inhibition:** Ligand A (0.065) has a much lower hERG inhibition liability than Ligand B (0.319), which is a positive.

**Microsomal Clearance:** Ligand B (37.39) has a significantly higher microsomal clearance than Ligand A (9.326), indicating faster metabolism and potentially lower *in vivo* exposure.

**In vitro Half-Life:** Ligand A (-10.92) has a longer in vitro half-life than Ligand B (5.234), which is favorable.

**P-gp Efflux:** Ligand A (0.024) shows much lower P-gp efflux liability than Ligand B (0.147), which is beneficial for CNS penetration.

**Binding Affinity:** Ligand B (-8.0) has a slightly better binding affinity than Ligand A (-7.6), but the difference is less than 1.5 kcal/mol.

**Overall Assessment:**

Ligand B excels in BBB penetration and binding affinity, which are crucial for a CNS GPCR target. However, it suffers from higher DILI risk, higher microsomal clearance, greater P-gp efflux, and a slightly higher hERG risk. Ligand A, while having a lower BBB score, demonstrates a much more favorable safety profile (lower DILI, hERG), better metabolic stability (lower Cl_mic, longer t1/2), and lower P-gp efflux. The difference in binding affinity is not substantial enough to outweigh the ADME/Tox advantages of Ligand A. Given the importance of CNS penetration, the better BBB score of Ligand B is a strong point, but the other factors suggest Ligand A is the more promising candidate overall.

Output:
1
2025-04-17 07:01:19,672 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the acceptable range (200-500 Da). Ligand A (383.514 Da) is slightly preferred as it's closer to the ideal range.

**TPSA:** Ligand A (66.06) is significantly better than Ligand B (79.37). For CNS targets, TPSA should be <=90, and lower is better. Ligand A is well within this range, while Ligand B is approaching the upper limit.

**logP:** Ligand A (3.644) is optimal, while Ligand B (1.807) is a bit low, potentially hindering membrane permeability.

**H-Bond Donors/Acceptors:** Both ligands have 1 HBD and 5 HBA, which are within acceptable limits.

**QED:** Both ligands have similar QED values (0.53 and 0.592), indicating good drug-likeness.

**DILI:** Both ligands have similar DILI risk (64.133 and 65.374), indicating moderate risk.

**BBB:** Ligand A (74.292) has a significantly better BBB percentile than Ligand B (44.979). This is *critical* for a CNS target like DRD2.

**Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and suggests a potential issue with the data or modeling. However, we'll proceed assuming this represents low permeability.

**Aqueous Solubility:** Both have negative solubility values, again suggesting a potential issue.

**hERG:** Both ligands have low hERG inhibition liability (0.848 and 0.56), which is good.

**Microsomal Clearance:** Ligand A (81.147) has higher microsomal clearance than Ligand B (25.684), suggesting lower metabolic stability.

**In vitro Half-Life:** Ligand B (26.003) has a slightly longer half-life than Ligand A (22.895).

**P-gp Efflux:** Ligand A (0.607) has slightly higher P-gp efflux liability than Ligand B (0.165), which is less desirable.

**Binding Affinity:** Ligand B (-8.6 kcal/mol) has a significantly stronger binding affinity than Ligand A (-7.5 kcal/mol). This is a substantial advantage. A difference of >1.5 kcal/mol can often outweigh other ADME concerns.

**Overall Assessment:**

While Ligand A has better TPSA, logP, and BBB, Ligand B's significantly stronger binding affinity (-8.6 vs -7.5 kcal/mol) is a major advantage. The difference in binding affinity is likely to overcome the slightly less favorable BBB and logP values of Ligand B. The lower P-gp efflux for Ligand B is also a positive. The negative Caco-2 and solubility values are concerning for both, but the binding affinity difference is the most important factor here.

Output:
1
2025-04-17 07:01:19,672 - INFO - Reasoning:

Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (382.291 and 373.479 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (98.5) is better than Ligand B (108.21). Both are reasonably good for CNS penetration, being under 140, but A is closer to the preferred <90 for CNS targets.

**3. logP:** Ligand A (2.351) is optimal (1-3). Ligand B (-1.265) is significantly lower, potentially hindering permeability and reducing brain exposure.

**4. H-Bond Donors:** Both have acceptable HBD counts (1 and 2, respectively), well below the limit of 5.

**5. H-Bond Acceptors:** Both have acceptable HBA counts (6), well below the limit of 10.

**6. QED:** Both ligands have reasonable QED values (0.77 and 0.576), indicating good drug-like properties.

**7. DILI:** Ligand A (98.565) has a high DILI risk, while Ligand B (21.753) has a very low risk. This is a significant drawback for Ligand A.

**8. BBB:** Ligand A (83.288) has a good BBB penetration percentile, while Ligand B (62.97) is lower, though not terrible. This favors Ligand A, but the high DILI risk needs consideration.

**9. Caco-2 Permeability:** Ligand A (-4.572) has poor Caco-2 permeability, while Ligand B (-5.449) is also poor. Both are negative values, which is unusual and suggests low permeability.

**10. Aqueous Solubility:** Ligand A (-4.371) has poor aqueous solubility, while Ligand B (-1.211) is also poor.

**11. hERG Inhibition:** Ligand A (0.576) has a low hERG risk, while Ligand B (0.077) has a very low risk.

**12. Microsomal Clearance:** Ligand A (25.084) has a moderate clearance, while Ligand B (-6.383) has a *negative* clearance, which is impossible and indicates a data error or unusual metabolic behavior. This is a major red flag for Ligand B.

**13. In vitro Half-Life:** Ligand A (20.455) has a reasonable half-life, while Ligand B (-0.228) has a negative half-life, which is impossible and further supports the data quality concerns for Ligand B.

**14. P-gp Efflux:** Ligand A (0.141) has low P-gp efflux, which is favorable for CNS penetration. Ligand B (0.002) has extremely low P-gp efflux, which is even more favorable.

**15. Binding Affinity:** Ligand A (-8.6 kcal/mol) has significantly stronger binding affinity than Ligand B (-7.0 kcal/mol). This is a substantial advantage for Ligand A.

**Overall Assessment:**

Despite the high DILI risk, Ligand A is the more promising candidate. Its significantly stronger binding affinity (-8.6 vs -7.0 kcal/mol) is a major advantage, and it has a better BBB percentile (83.288 vs 62.97) and P-gp efflux (0.141 vs 0.002) than Ligand B. While Ligand A's solubility and Caco-2 permeability are poor, these can potentially be addressed through formulation strategies.

Ligand B has several critical issues: a negative microsomal clearance and half-life are impossible values and indicate a serious problem with the data or the compound's stability. The lower logP is also a concern for CNS penetration.

Output:
1
2025-04-17 07:01:19,672 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (393.481 and 352.479 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (80.32) is excellent, well below the 90 A^2 threshold for CNS targets. Ligand B (90.54) is slightly above, but still acceptable.

**logP:** Ligand A (1.667) is optimal. Ligand B (0.422) is a bit low, potentially hindering membrane permeability.

**H-Bond Donors/Acceptors:** Ligand A (HBD=2, HBA=6) and Ligand B (HBD=3, HBA=4) both have reasonable H-bond counts, within the acceptable limits.

**QED:** Ligand A (0.667) has a better QED score than Ligand B (0.497), indicating a more drug-like profile.

**DILI:** Ligand A (63.009) has a higher DILI risk than Ligand B (24.622), which is a significant negative.

**BBB:** Ligand A (71.539) has a much better BBB penetration percentile than Ligand B (54.983). This is crucial for a CNS target like DRD2.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values, which is unusual and suggests potential issues with intestinal absorption. However, these values are on a scale where negative values are possible, and we need to consider other factors.

**Aqueous Solubility:** Both ligands have negative solubility values, which is also unusual.

**hERG:** Both ligands have very low hERG inhibition liability (0.373 and 0.224), which is positive.

**Microsomal Clearance:** Ligand A (12.115) has a significantly lower microsomal clearance than Ligand B (25.328), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (2.765) has a slightly better in vitro half-life than Ligand B (-0.992).

**P-gp Efflux:** Ligand A (0.081) has significantly lower P-gp efflux liability than Ligand B (0.009), which is highly desirable for CNS penetration.

**Binding Affinity:** Ligand B (-7.6 kcal/mol) has a slightly better binding affinity than Ligand A (-7.4 kcal/mol), but the difference is small.

**Overall Assessment:**

Ligand A excels in BBB penetration, P-gp efflux, and metabolic stability. While its DILI risk is higher, its superior CNS penetration properties and lower efflux are critical for a DRD2 ligand. Ligand B has a slightly better binding affinity and lower DILI risk, but its poor BBB penetration and higher P-gp efflux are major drawbacks. Given the GPCR-specific priorities, particularly BBB and P-gp for CNS targets, Ligand A is the more promising candidate. The slight affinity difference can potentially be optimized later.

Output:
1
2025-04-17 07:01:19,672 - INFO - Batch 330 complete. Total preferences: 5280
2025-04-17 07:01:19,672 - INFO - Processing batch 331/512...
2025-04-17 07:01:59,851 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (343.471 and 351.462 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (44.81) is better than Ligand B (38.77) as it's closer to the <90 A^2 threshold for CNS targets.

**3. logP:** Both ligands have good logP values (2.642 and 3.48), falling within the optimal 1-3 range. Ligand B is slightly higher, which could potentially lead to off-target effects, but it's not a major concern.

**4. H-Bond Donors:** Ligand A has 1 HBD, while Ligand B has 0. Both are acceptable (<=5).

**5. H-Bond Acceptors:** Both ligands have 3 HBAs, well within the acceptable limit of <=10.

**6. QED:** Ligand A (0.918) has a significantly better QED score than Ligand B (0.72), indicating a more drug-like profile.

**7. DILI:** Both ligands have relatively low DILI risk (13.804 and 14.696), below the 40 threshold.

**8. BBB:** Ligand B (95.696) has a substantially higher BBB penetration percentile than Ligand A (90.617). This is a *critical* advantage for a CNS target like DRD2.

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.325 and -4.291), which is unusual and suggests poor permeability. This is a significant drawback for both.

**10. Aqueous Solubility:** Both ligands have very poor aqueous solubility (-2.251 and -2.714). This is a major concern for formulation and bioavailability.

**11. hERG Inhibition:** Both ligands have low hERG inhibition risk (0.81 and 0.938).

**12. Microsomal Clearance:** Ligand B (77.669) has a much higher microsomal clearance than Ligand A (0.659), indicating faster metabolism and potentially lower exposure.

**13. In vitro Half-Life:** Ligand B (22.502) has a significantly longer in vitro half-life than Ligand A (4.962). This is a positive attribute.

**14. P-gp Efflux:** Both ligands have low P-gp efflux liability (0.16 and 0.509).

**15. Binding Affinity:** Ligand B (-7.6 kcal/mol) has a slightly better binding affinity than Ligand A (-8.2 kcal/mol). While A is better, the difference is not huge.

**Overall Assessment:**

Ligand B is favored due to its superior BBB penetration (95.7% vs 90.6%) and longer half-life (22.5 vs 4.96). The slightly better affinity of Ligand A is outweighed by the significantly better CNS penetration of Ligand B. Both have poor solubility and Caco-2 permeability, which are major liabilities that would need to be addressed in further optimization. The higher metabolic clearance of Ligand B is a concern, but the improved BBB penetration is more critical for a CNS target.

Output:
1
2025-04-17 07:01:59,851 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 drug candidates, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (363.845 and 353.507 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (67.6) is better than Ligand B (70.67). Both are below the 90 Angstrom threshold for CNS targets, but A is closer to the ideal.

**logP:** Ligand A (3.754) is optimal, while Ligand B (1.544) is on the lower side, potentially hindering permeability.

**H-Bond Donors/Acceptors:** Ligand A (1 HBD, 5 HBA) is preferable to Ligand B (2 HBD, 4 HBA). Both are within acceptable limits.

**QED:** Both ligands have reasonable QED scores (0.876 and 0.694), indicating good drug-like properties.

**DILI:** Ligand A (72.043) has a higher DILI risk than Ligand B (8.802). This is a significant drawback for Ligand A.

**BBB:** Ligand A (77.007) has a much better BBB penetration score than Ligand B (58.278). This is crucial for a CNS target like DRD2.

**Caco-2 Permeability:** Ligand A (-4.664) has worse Caco-2 permeability than Ligand B (-4.941). Both are negative, indicating poor permeability.

**Aqueous Solubility:** Ligand A (-4.711) has worse solubility than Ligand B (-1.012).

**hERG:** Ligand A (0.608) has a slightly higher hERG risk than Ligand B (0.32), but both are relatively low.

**Microsomal Clearance:** Ligand B (24.483) has lower microsomal clearance (better metabolic stability) than Ligand A (46.795).

**In vitro Half-Life:** Ligand A (10.936) has a longer half-life than Ligand B (-3.575).

**P-gp Efflux:** Ligand A (0.504) has lower P-gp efflux than Ligand B (0.009), which is favorable for CNS penetration.

**Binding Affinity:** Ligand B (-7.2) has a slightly better binding affinity than Ligand A (-9.2). However, the difference is not substantial enough to outweigh other factors.

**Overall Assessment:**

Ligand A excels in BBB penetration, P-gp efflux, and in vitro half-life. However, it suffers from higher DILI risk, lower solubility, and worse Caco-2 permeability. Ligand B has a better safety profile (lower DILI), better metabolic stability, and slightly better binding affinity, but its BBB penetration is a significant concern for a CNS target.

Considering the GPCR-specific priorities, BBB penetration is paramount for DRD2. While Ligand A has a higher DILI risk, the substantial advantage in BBB penetration and P-gp efflux outweighs this concern. The slightly better affinity of Ligand B is not enough to overcome its poor BBB score.

Output:
1
2025-04-17 07:01:59,851 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B based on the provided guidelines, prioritizing GPCR-specific properties (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (367.559 and 387.615 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (48.72) is significantly better than Ligand B (61.44). For CNS targets, we want TPSA <= 90, and ideally lower. Ligand A is well within this range, while Ligand B is approaching the upper limit.

**logP:** Ligand A (3.809) is slightly higher than Ligand B (2.316), both are within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A (HBD=1, HBA=4) has fewer H-bonds than Ligand B (HBD=2, HBA=5). Both are acceptable, but fewer is generally preferred for better permeability.

**QED:** Both ligands have similar QED values (0.639 and 0.669), indicating good drug-likeness.

**DILI:** Ligand A (18.108) has a slightly higher DILI risk than Ligand B (15.936), but both are well below the concerning threshold of 60.

**BBB:** This is a critical parameter for CNS targets. Ligand A (78.209) has a much higher BBB percentile than Ligand B (50.795). A value >70 is desirable, and Ligand A is closer to this target.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.11 and -5.569), which is unusual and suggests poor permeability. This is a significant drawback for both.

**Aqueous Solubility:** Both ligands have negative solubility values (-3.257 and -2.321), indicating poor aqueous solubility. This is a concern for formulation and bioavailability.

**hERG Inhibition:** Ligand A (0.916) has a slightly higher hERG inhibition liability than Ligand B (0.398), but both are relatively low risk.

**Microsomal Clearance:** Ligand B (16.332) has lower microsomal clearance than Ligand A (84.712), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (86.609) has a significantly longer in vitro half-life than Ligand B (17.988). This is a major advantage for Ligand A.

**P-gp Efflux:** Ligand A (0.378) has lower P-gp efflux liability than Ligand B (0.069), which is beneficial for CNS exposure.

**Binding Affinity:** Ligand B (-0.0 kcal/mol) has a much weaker binding affinity than Ligand A (-6.9 kcal/mol). This is a decisive factor; a difference of >1.5 kcal/mol often outweighs other drawbacks.

**Overall Assessment:**

Despite the poor Caco-2 and solubility for both, Ligand A is the superior candidate. Its significantly stronger binding affinity (-6.9 kcal/mol vs -0.0 kcal/mol), better BBB penetration (78.209 vs 50.795), lower P-gp efflux, and longer half-life outweigh the slightly higher DILI risk and higher microsomal clearance. The lower TPSA is also advantageous. The affinity difference is substantial and likely to be crucial for efficacy.

Output:
1
2025-04-17 07:01:59,852 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (345.4 and 347.4 Da) fall comfortably within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (73.66) is excellent, well below the 90 A^2 threshold for CNS targets. Ligand B (110.32) is higher, but still potentially acceptable, though less ideal.

**3. logP:** Ligand A (1.152) is within the optimal 1-3 range. Ligand B (0.041) is quite low, potentially hindering membrane permeability and CNS penetration.

**4. H-Bond Donors:** Ligand A (0) is good. Ligand B (2) is acceptable.

**5. H-Bond Acceptors:** Ligand A (6) is good. Ligand B (5) is good.

**6. QED:** Both ligands (0.777 and 0.783) have excellent drug-likeness scores.

**7. DILI:** Ligand A (51.69%) has a slightly higher DILI risk than Ligand B (43.66%), but both are below the concerning 60% threshold.

**8. BBB:** This is a critical parameter for a CNS target like DRD2. Ligand A (91.198%) has a very high BBB penetration score, which is excellent. Ligand B (55.138%) is significantly lower and concerning for CNS exposure.

**9. Caco-2 Permeability:** Ligand A (-4.531) and Ligand B (-5.487) both have negative values, indicating poor permeability. This is a weakness for both, but less critical given the CNS target.

**10. Aqueous Solubility:** Both ligands have poor aqueous solubility (-1.682 and -2.339). This could present formulation challenges.

**11. hERG Inhibition:** Both ligands have low hERG inhibition risk (0.327 and 0.132).

**12. Microsomal Clearance:** Ligand A (68.943) has a moderate clearance. Ligand B (-1.19) has a very low (and likely unrealistic) clearance, suggesting high metabolic stability. However, extremely low clearance can sometimes indicate poor metabolism and potential for drug-drug interactions.

**13. In vitro Half-Life:** Ligand A (-3.583) has a negative half-life, which is unrealistic. Ligand B (15.254) has a reasonable half-life.

**14. P-gp Efflux:** Both ligands have low P-gp efflux liability (0.199 and 0.012), which is favorable for CNS penetration.

**15. Binding Affinity:** Ligand B (-8.7 kcal/mol) has a significantly stronger binding affinity than Ligand A (-7.5 kcal/mol), a difference of 1.2 kcal/mol. This is a substantial advantage.

**Overall Assessment:**

Despite Ligand B's superior binding affinity, Ligand A is the more promising candidate. The critical factor is the BBB penetration. Ligand A's 91.2% BBB score is excellent and far surpasses Ligand B's 55.1%. The low logP of Ligand B is also a significant concern. While Ligand B has better affinity and metabolic stability, the poor BBB penetration and logP severely limit its potential as a CNS-active drug. The unrealistic half-life of Ligand A is a data quality issue that would need to be investigated.



Output:
0
2025-04-17 07:01:59,852 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (348.487 and 350.507 Da) fall comfortably within the ideal 200-500 Da range.

**TPSA:** Ligand A (49.85) is better than Ligand B (47.1). Both are below the 90 A^2 threshold desirable for CNS targets, indicating good potential for brain penetration.

**logP:** Ligand A (2.465) is within the optimal 1-3 range. Ligand B (0.584) is slightly low, potentially hindering membrane permeability.

**H-Bond Donors & Acceptors:** Both ligands have a reasonable number of HBDs (0) and HBAs (3 & 4 respectively), falling within acceptable limits.

**QED:** Both ligands have good QED scores (0.693 and 0.728), indicating drug-like properties.

**DILI:** Ligand A (13.494) has a significantly lower DILI risk than Ligand B (3.373), which is a major advantage.

**BBB:** Both ligands have excellent BBB penetration (80.07% and 78.868%), exceeding the desirable >70% threshold for CNS targets.

**Caco-2 Permeability:** Ligand A (-4.651) and Ligand B (-4.783) both have negative values, which is unusual. It's difficult to interpret without knowing the scale. However, they are similar.

**Aqueous Solubility:** Ligand A (-3.142) and Ligand B (-0.051) both have negative values, indicating poor solubility. Ligand B is slightly better.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.493 and 0.527).

**Microsomal Clearance:** Ligand B (-10.221) has significantly lower microsomal clearance than Ligand A (60.947), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand B (-10.867) has a much longer in vitro half-life than Ligand A (0.643), which is a significant advantage.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.214 and 0.008), which is good for CNS exposure. Ligand B is better.

**Binding Affinity:** Both ligands have identical binding affinities (-7.1 kcal/mol), which is excellent.

**Overall Assessment:**

While both ligands have excellent binding affinity and BBB penetration, Ligand B is superior due to its significantly better metabolic stability (lower Cl_mic, longer t1/2), lower DILI risk, and lower P-gp efflux. The slightly lower logP of Ligand B is a minor concern, but the other advantages outweigh this drawback. Solubility is a concern for both, but can be addressed with formulation strategies.

Output:
1
2025-04-17 07:01:59,852 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (346.475 and 365.459 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (87.46) is excellent, falling well below the 90 A^2 threshold for CNS targets. Ligand B (127.19) is higher, but still acceptable, though less optimal.

**3. logP:** Both ligands have good logP values (1.653 and 2.344), within the optimal 1-3 range.

**4. H-Bond Donors:** Both have 3 HBD, which is within the acceptable limit of <=5.

**5. H-Bond Acceptors:** Ligand A has 4 HBA, and Ligand B has 5 HBA, both within the acceptable limit of <=10.

**6. QED:** Both ligands have low QED scores (0.43 and 0.371), indicating they are not particularly drug-like. This is a concern, but can be addressed in later optimization stages.

**7. DILI:** Ligand A (24.157) has a significantly lower DILI risk than Ligand B (44.281). This is a substantial advantage.

**8. BBB:** Ligand A (53.974) has a much better BBB penetration percentile than Ligand B (27.879). This is *critical* for a CNS target like DRD2.

**9. Caco-2 Permeability:** Both have negative Caco-2 values (-5.047 and -5.335), which is unusual and suggests poor permeability. This is a significant drawback for both.

**10. Aqueous Solubility:** Both have negative solubility values (-1.67 and -2.169), indicating very poor aqueous solubility. This is a major concern for formulation and bioavailability.

**11. hERG Inhibition:** Both ligands have low hERG inhibition risk (0.474 and 0.155).

**12. Microsomal Clearance:** Ligand A (-16.993) has a much lower (better) microsomal clearance than Ligand B (15.515), indicating greater metabolic stability.

**13. In vitro Half-Life:** Ligand B (24.014) has a significantly longer in vitro half-life than Ligand A (3.646). This is a positive for Ligand B.

**14. P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.065 and 0.08).

**15. Binding Affinity:** Ligand B (-7.1 kcal/mol) has a slightly better binding affinity than Ligand A (-8.1 kcal/mol). While the difference is not huge, it is noticeable.

**Overall Assessment:**

Despite Ligand B's slightly better affinity and half-life, Ligand A is the more promising candidate. The significantly better BBB penetration, lower DILI risk, and lower microsomal clearance of Ligand A are crucial advantages for a CNS-targeting GPCR. The poor solubility and Caco-2 permeability are concerns for both, but these are properties that can be more readily addressed through structural modifications during lead optimization. The improved safety profile of Ligand A (lower DILI) is also a significant factor.



Output:
0
2025-04-17 07:01:59,852 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (352.41 and 348.462 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (93.7) is slightly above the optimal <90 for CNS targets, but still reasonable. Ligand B (58.2) is excellent, well below 90.

**logP:** Both ligands (2.131 and 2.572) are within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A has 4 HBD and 3 HBA, which are acceptable. Ligand B has 2 HBD and 2 HBA, also acceptable.

**QED:** Both ligands have good QED scores (0.606 and 0.802), indicating good drug-like properties.

**DILI:** Ligand A (46.336) has a moderate DILI risk, while Ligand B (21.908) has a very low DILI risk, which is a significant advantage.

**BBB:** This is critical for a CNS target. Ligand A (53.16) is okay, but Ligand B (84.025) is excellent, exceeding the desirable >70 threshold.

**Caco-2 Permeability:** Both have negative values, which is unusual and suggests poor permeability. However, the scale isn't specified, so it's hard to interpret.

**Aqueous Solubility:** Both ligands have negative solubility values, indicating poor aqueous solubility. This is a concern for both.

**hERG:** Both ligands have low hERG inhibition liability (0.449 and 0.409), which is good.

**Microsomal Clearance:** Ligand A (-2.161) has a negative clearance, which is not physically possible and likely an error. Ligand B (15.204) has a moderate clearance.

**In vitro Half-Life:** Ligand A (52.454) has a good half-life. Ligand B (-2.306) has a negative half-life, which is not physically possible and likely an error.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.072 and 0.053), which is favorable for CNS penetration.

**Binding Affinity:** Both ligands have very similar and strong binding affinities (-8.8 and -8.1 kcal/mol). The difference of 0.7 kcal/mol is not substantial enough to outweigh other factors.

**Overall Assessment:**

Ligand B is significantly better due to its superior BBB penetration (84.025 vs 53.16), much lower DILI risk (21.908 vs 46.336), and excellent TPSA (58.2). While both have issues with solubility and Caco-2 permeability, the CNS-specific properties are paramount for DRD2. The negative values for clearance and half-life for Ligand A and Ligand B, respectively, are concerning and suggest potential data errors or limitations in the prediction methods. However, even ignoring those, Ligand B's profile is superior.

Output:
1
2025-04-17 07:01:59,852 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (371.384 Da) is slightly lower, which could be advantageous for permeability.

**TPSA:** Ligand A (73.2) is significantly better than Ligand B (104.37). For CNS targets, we want TPSA <= 90, and Ligand A is comfortably within that range, while Ligand B is above.

**logP:** Both ligands have acceptable logP values, falling within the 1-3 range. Ligand A (2.222) is slightly better than Ligand B (0.611), which is closer to the lower limit and might indicate permeability issues.

**H-Bond Donors/Acceptors:** Ligand A (HBD=1, HBA=4) has a more favorable profile than Ligand B (HBD=3, HBA=5). Lower values generally improve permeability.

**QED:** Ligand A (0.863) has a much better QED score than Ligand B (0.534), indicating a more drug-like profile.

**DILI:** Ligand B (43.117) has a lower DILI risk than Ligand A (55.68), which is preferable.

**BBB:** Ligand A (81.582) has a significantly higher BBB penetration percentile than Ligand B (44.979). This is *critical* for a CNS target like DRD2.

**Caco-2 Permeability:** Ligand A (-4.859) has a better Caco-2 permeability than Ligand B (-5.652), indicating better intestinal absorption.

**Aqueous Solubility:** Ligand A (-3.611) has better aqueous solubility than Ligand B (-2.511).

**hERG:** Both ligands have very low hERG inhibition liability (0.656 and 0.071 respectively), which is excellent.

**Microsomal Clearance:** Ligand A (4.112) has lower microsomal clearance than Ligand B (40.908), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (-11.308) has a much longer in vitro half-life than Ligand B (-36.868).

**P-gp Efflux:** Ligand A (0.107) has lower P-gp efflux liability than Ligand B (0.043), which is favorable for CNS exposure.

**Binding Affinity:** Ligand B (-7.6) has a slightly better binding affinity than Ligand A (-9.0). However, the difference is relatively small, and the other ADME properties of Ligand A are much more favorable.

**Overall Assessment:**

Ligand A is significantly better overall. While Ligand B has slightly better binding affinity, Ligand A excels in crucial properties for a CNS-targeting GPCR ligand: TPSA, BBB penetration, QED, metabolic stability, half-life, and P-gp efflux. The superior BBB penetration and drug-like properties of Ligand A outweigh the minor affinity difference.

Output:
1
2025-04-17 07:01:59,852 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (432.296 Da) is slightly higher, but still acceptable. Ligand B (345.443 Da) is lower, potentially aiding permeability.

**TPSA:** Both ligands have TPSA values below the 140 A^2 threshold for good oral absorption. Ligand A (99.52 A^2) is higher than Ligand B (83.71 A^2). For a CNS target like DRD2, a TPSA < 90 A^2 is preferred, so Ligand B is better in this regard.

**logP:** Both ligands have logP values within the optimal range (1-3). Ligand A (2.234) is slightly higher than Ligand B (0.771). While both are acceptable, Ligand B's lower logP might raise concerns about membrane permeability.

**H-Bond Donors/Acceptors:** Both ligands have acceptable HBD (1) and HBA (Ligand A: 7, Ligand B: 3) counts, falling within the recommended limits.

**QED:** Both ligands have good QED values (A: 0.674, B: 0.767), indicating a generally drug-like profile.

**DILI:** Ligand A has a significantly higher DILI risk (91.47%) compared to Ligand B (14.541%). This is a major concern for Ligand A.

**BBB:** Ligand B has a much better BBB penetration percentile (69.911%) than Ligand A (51.803%). This is crucial for a CNS target like DRD2.

**Caco-2 Permeability:** Ligand A (-4.911) has a more negative Caco-2 value, suggesting *lower* permeability than Ligand B (-5.18), which is also poor.

**Aqueous Solubility:** Both have negative solubility values, indicating poor solubility. Ligand A (-3.332) is slightly better than Ligand B (-2.303).

**hERG Inhibition:** Both ligands have low hERG inhibition risk (A: 0.407, B: 0.235).

**Microsomal Clearance:** Ligand B has a lower microsomal clearance (11.606 mL/min/kg) than Ligand A (51.725 mL/min/kg), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand B has a negative half-life (-13.89 hours), which is problematic. Ligand A has a half-life of 11.908 hours, which is better.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (A: 0.378, B: 0.022). Ligand B is slightly better.

**Binding Affinity:** Both ligands have excellent binding affinities (A: -8.3 kcal/mol, B: -8.8 kcal/mol). Ligand B is slightly better.

**Overall Assessment:**

Ligand B is the more promising candidate. While it has a concerning negative in vitro half-life, its superior BBB penetration, lower DILI risk, better TPSA, and slightly better binding affinity outweigh the drawbacks of its lower logP and solubility. Ligand A's high DILI risk is a significant red flag. The slightly better half-life of Ligand A doesn't compensate for the other issues.

Output:
1
2025-04-17 07:01:59,853 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (344.5 and 358.5 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (49.41) is excellent, well below the 90 A^2 threshold for CNS targets. Ligand B (78.09) is still reasonable but less optimal, approaching the 140 A^2 limit for oral absorption and further from the ideal for CNS penetration.

**logP:** Ligand A (3.588) is within the optimal 1-3 range. Ligand B (2.088) is slightly lower, but still acceptable.

**H-Bond Donors/Acceptors:** Ligand A (1 HBD, 2 HBA) and Ligand B (2 HBD, 4 HBA) both have reasonable numbers of H-bond donors and acceptors, well within the guidelines.

**QED:** Both ligands have good QED scores (0.775 and 0.878), indicating good drug-like properties.

**DILI:** Ligand A (32.92) has a significantly lower DILI risk than Ligand B (58.434). This is a strong advantage for Ligand A.

**BBB:** Ligand A (76.735) has a much better BBB penetration percentile than Ligand B (50.523). This is *critical* for a CNS target like DRD2.

**Caco-2 Permeability:** Ligand A (-4.743) shows poor Caco-2 permeability, while Ligand B (-5.306) is also poor. This is a potential issue for both, but less critical given the CNS target.

**Aqueous Solubility:** Ligand A (-3.753) and Ligand B (-3.228) both exhibit poor aqueous solubility. This could pose formulation challenges.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.474 and 0.322).

**Microsomal Clearance:** Ligand A (93.166) has a higher microsomal clearance than Ligand B (14.153), indicating faster metabolism and potentially lower *in vivo* exposure. This is a significant drawback for Ligand A.

**In vitro Half-Life:** Ligand B (-19.872) has a much longer *in vitro* half-life than Ligand A (-12.579). This is a positive for Ligand B.

**P-gp Efflux:** Ligand A (0.579) has slightly lower P-gp efflux than Ligand B (0.102), which is favorable for CNS penetration.

**Binding Affinity:** Both ligands have excellent binding affinities (-9.6 and -8.4 kcal/mol). Ligand A is slightly better (-9.6 kcal/mol), but the difference (1.2 kcal/mol) isn't large enough to overcome its other weaknesses.

**Overall Assessment:**

Ligand A excels in TPSA, BBB, and binding affinity, but suffers from poor Caco-2 permeability, high microsomal clearance, and a higher DILI risk. Ligand B has a better BBB than Ligand A, a significantly better metabolic stability profile (lower Cl_mic, longer t1/2), and lower DILI risk, although its TPSA is less ideal. Given the importance of BBB penetration and metabolic stability for a CNS GPCR target, and the relatively small difference in binding affinity, Ligand B is the more promising candidate.

Output:
1
2025-04-17 07:01:59,853 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (346.391 and 363.414 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (121.89) is slightly above the optimal <90 for CNS targets, but still reasonable. Ligand B (91.32) is excellent, falling well within the desired range.

**3. logP:** Ligand A (0.922) is a bit low, potentially hindering permeability. Ligand B (2.369) is much better, falling within the optimal 1-3 range.

**4. H-Bond Donors:** Both ligands have 3 HBD, which is acceptable.

**5. H-Bond Acceptors:** Ligand A has 6 HBA, and Ligand B has 5. Both are within the acceptable limit of <=10.

**6. QED:** Both ligands have similar QED values (0.653 and 0.628), indicating good drug-likeness.

**7. DILI:** Both ligands have similar DILI risk (63.94 and 62.505), placing them in a moderate risk category. This isn't a dealbreaker, but requires further investigation.

**8. BBB:** Ligand A (47.15) has a concerningly low BBB percentile, suggesting poor CNS penetration. Ligand B (39.007) is also low, but slightly better than A. Both are below the desirable >70 for CNS targets.

**9. Caco-2:** Both ligands have negative Caco-2 values (-5.163 and -5.344), which is unusual and suggests poor permeability. This is a significant concern.

**10. Solubility:** Both ligands have negative solubility values (-2.564 and -3.321), also unusual and indicating poor aqueous solubility.

**11. hERG:** Both ligands have low hERG inhibition liability (0.199 and 0.445), which is favorable.

**12. Cl_mic:** Ligand A (12.974) has a lower microsomal clearance than Ligand B (50.11), suggesting better metabolic stability.

**13. t1/2:** Ligand A (-23.32) has a very negative in vitro half-life, which is concerning. Ligand B (-18.002) is also negative, but less so.

**14. Pgp:** Both ligands have very low Pgp efflux liability (0.004 and 0.178), which is excellent for CNS penetration.

**15. Binding Affinity:** Both ligands have the same binding affinity (-8.1 kcal/mol), which is excellent and a strong point in their favor.

**Overall Assessment:**

Despite the equal binding affinity, Ligand B is the more promising candidate. While both have issues with Caco-2 and solubility, Ligand B has a better logP and TPSA, which are crucial for GPCRs. The slightly better BBB percentile and lower Cl_mic are also advantages. Ligand A's very low BBB and negative half-life are significant drawbacks. The negative values for Caco-2 and solubility are concerning for both, but might be artifacts of the prediction method. Further experimental validation is needed.

Output:
1
2025-04-17 07:01:59,853 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (348.447 and 384.523 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Both ligands have TPSA values (76.46 and 75.71) below the 90 A^2 threshold desirable for CNS targets, which is excellent.

**3. logP:** Both ligands have logP values (1.68 and 1.751) within the optimal 1-3 range.

**4. H-Bond Donors:** Both have 1 HBD, well within the acceptable limit of 5.

**5. H-Bond Acceptors:** Both have 5 HBA, also within the acceptable limit of 10.

**6. QED:** Both ligands have high QED scores (0.849 and 0.839), indicating good drug-like properties.

**7. DILI:** Both ligands have acceptable DILI risk (46.452 and 48.313 percentile), well below the concerning threshold of 60.

**8. BBB:** Both ligands exhibit good BBB penetration (72.625 and 70.648 percentile), exceeding the 70% threshold, which is crucial for a CNS target like DRD2.

**9. Caco-2 Permeability:** Both have negative Caco-2 values (-4.699 and -5.005). This is unusual, and suggests poor permeability. However, Caco-2 values can be unreliable and are less important than BBB for CNS targets.

**10. Aqueous Solubility:** Both have negative solubility values (-2.684 and -3.443). This is also concerning, but can sometimes be overcome with formulation strategies.

**11. hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.554 and 0.373 percentile), which is excellent.

**12. Microsomal Clearance:** Ligand A (67.643) has higher microsomal clearance than Ligand B (46.125). This suggests Ligand B is more metabolically stable.

**13. In vitro Half-Life:** Ligand A (-22.044) has a more negative half-life than Ligand B (-13.225), indicating a shorter half-life and faster metabolism.

**14. P-gp Efflux:** Both ligands show low P-gp efflux liability (0.192 and 0.214 percentile), which is favorable for CNS penetration.

**15. Binding Affinity:** Ligand B (-8.5 kcal/mol) has a slightly stronger binding affinity than Ligand A (-8.0 kcal/mol). While both are excellent, the 0.5 kcal/mol difference is significant.

**Overall Assessment:**

Both ligands are promising. However, Ligand B is slightly favored due to its better metabolic stability (lower Cl_mic, longer t1/2) and slightly stronger binding affinity. The solubility and Caco-2 values are concerning for both, but the strong BBB penetration mitigates some of those concerns for a CNS target. The difference in binding affinity, while small, combined with the improved metabolic profile, tips the balance in favor of Ligand B.

Output:
1
2025-04-17 07:01:59,853 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (345.407 Da) is slightly lower, which can be beneficial for permeability. Ligand B (367.555 Da) is also good.

**TPSA:** Ligand A (124.78) is better than Ligand B (38.77) as it is closer to the optimal range for CNS targets (<=90). Ligand B is quite high, potentially hindering BBB penetration.

**logP:** Ligand A (0.984) is within the optimal range (1-3), while Ligand B (4.755) is slightly high. High logP can lead to solubility issues and off-target interactions.

**H-Bond Donors/Acceptors:** Ligand A has 2 HBD and 5 HBA, which is acceptable. Ligand B has 0 HBD and 4 HBA, also acceptable.

**QED:** Both ligands have reasonable QED values (A: 0.316, B: 0.599). Ligand B is better here, indicating a more drug-like profile.

**DILI:** Both ligands have low DILI risk (A: 41.14, B: 22.024), which is good. Ligand B is slightly better.

**BBB:** This is a crucial parameter for CNS targets. Ligand A (31.718) has a poor BBB percentile, while Ligand B (89.957) is excellent. This is a significant advantage for Ligand B.

**Caco-2 Permeability:** Ligand A (-5.311) has poor Caco-2 permeability, while Ligand B (-4.924) is also poor.

**Aqueous Solubility:** Ligand A (-1.509) has poor solubility, and Ligand B (-4) is even worse.

**hERG Inhibition:** Both ligands have very low hERG inhibition risk (A: 0.062, B: 0.821), which is excellent.

**Microsomal Clearance:** Ligand A (18.601) has lower clearance than Ligand B (104.662), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand B (35.305) has a significantly longer half-life than Ligand A (1.295), which is desirable.

**P-gp Efflux:** Ligand A (0.007) has very low P-gp efflux, which is excellent for CNS penetration. Ligand B (0.888) has moderate P-gp efflux, which is less ideal.

**Binding Affinity:** Ligand A (-7.5) has a slightly better binding affinity than Ligand B (-7.1), but the difference is not substantial enough to overcome other significant drawbacks.

**Overall Assessment:**

Ligand B excels in BBB penetration and has a longer half-life, both critical for a CNS-targeting drug. While its logP is slightly high and solubility is poor, these can potentially be addressed through formulation strategies. Ligand A suffers from very poor BBB penetration and Caco-2 permeability, despite having slightly better binding affinity and lower clearance. Given the GPCR-specific priorities, especially BBB penetration for a CNS target like DRD2, Ligand B is the more promising candidate.

Output:
1
2025-04-17 07:01:59,854 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (348.418 and 356.495 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (75.79) is better than Ligand B (62.98). Both are below the 90 A^2 threshold for CNS targets, which is excellent.

**logP:** Ligand A (1.228) is within the optimal 1-3 range. Ligand B (4.505) is higher, potentially leading to solubility issues and off-target interactions.

**H-Bond Donors:** Both ligands have 2 HBD, which is acceptable.

**H-Bond Acceptors:** Ligand A has 4 HBA, while Ligand B has 6. Both are within the acceptable limit of 10.

**QED:** Ligand A (0.858) has a better QED score than Ligand B (0.712), indicating a more drug-like profile.

**DILI:** Ligand A (13.261) has a significantly lower DILI risk than Ligand B (56.146), a major advantage.

**BBB:** Ligand A (89.957) has a much better BBB penetration score than Ligand B (69.95). This is critical for a CNS target like DRD2.

**Caco-2 Permeability:** Ligand A (-4.675) has worse Caco-2 permeability than Ligand B (-5.282), but both are very poor.

**Aqueous Solubility:** Ligand A (-1.734) has better aqueous solubility than Ligand B (-4.748).

**hERG Inhibition:** Both ligands have similar hERG inhibition liability (0.798 and 0.73), which is relatively low risk.

**Microsomal Clearance:** Ligand A (-5.226) has lower microsomal clearance than Ligand B (80.18), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand B (78.824) has a much longer in vitro half-life than Ligand A (3.004).

**P-gp Efflux:** Ligand A (0.107) has lower P-gp efflux than Ligand B (0.353), which is favorable for CNS penetration.

**Binding Affinity:** Both ligands have the same binding affinity (-8.4 kcal/mol), which is excellent.

**Overall Assessment:**

Ligand A is superior due to its significantly better BBB penetration, lower DILI risk, better QED, better solubility, lower P-gp efflux, and lower microsomal clearance. While Ligand B has a longer half-life and slightly better Caco-2 permeability, the CNS-relevant properties of Ligand A are far more important for a DRD2 ligand. The higher logP of Ligand B is also a concern.

Output:
0
2025-04-17 07:01:59,854 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (399.6) is slightly higher than Ligand B (359.5).

**TPSA:** Both ligands have TPSA values above the optimal 90 A^2 for CNS targets (Ligand A: 62.3, Ligand B: 64.86). This is a slight concern for both, potentially hindering BBB penetration, but not disqualifying.

**logP:** Both ligands have good logP values (Ligand A: 2.869, Ligand B: 3.373) falling within the 1-3 range.

**H-Bond Donors/Acceptors:** Both ligands have acceptable HBD (1) and HBA (6 & 7) counts, well within the guidelines.

**QED:** Both ligands have reasonable QED scores (Ligand A: 0.843, Ligand B: 0.744), indicating good drug-like properties.

**DILI:** Both ligands have acceptable DILI risk (Ligand A: 69.174, Ligand B: 49.011), below the concerning threshold of 60.

**BBB:** This is a critical parameter for a CNS target like DRD2. Ligand B (77.511) significantly outperforms Ligand A (43.583) in BBB penetration, exceeding the desirable >70 percentile.

**Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and suggests poor permeability. However, these values are on a strange scale, so it's hard to interpret.

**Aqueous Solubility:** Both ligands have poor aqueous solubility (-3.833 and -3.191). This could pose formulation challenges.

**hERG Inhibition:** Both ligands show very low hERG inhibition risk (0.296 and 0.261).

**Microsomal Clearance:** Both have similar microsomal clearance rates (Ligand A: 47.5, Ligand B: 47.806), suggesting comparable metabolic stability.

**In vitro Half-Life:** Ligand B (-3.77) has a slightly worse in vitro half-life than Ligand A (3.367).

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.296 and 0.267).

**Binding Affinity:** Ligand B (-6.9 kcal/mol) has a slightly better binding affinity than Ligand A (-6.5 kcal/mol), although the difference is less than the 1.5 kcal/mol threshold where ADME drawbacks can be overlooked.

**Conclusion:**

Considering the GPCR-specific priorities, **Ligand B is the more promising candidate.** The significantly higher BBB penetration (77.511 vs 43.583) is a major advantage for a CNS drug targeting DRD2. While both have some drawbacks (poor solubility, slightly high TPSA), Ligand B's superior BBB score and slightly better binding affinity outweigh the minor disadvantage in half-life.

Output:
1
2025-04-17 07:01:59,854 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (344.503) is slightly preferred as it's closer to the lower end, potentially aiding permeability.

**TPSA:** Ligand A (59.81) is significantly better than Ligand B (76.19). For CNS targets, TPSA should be <= 90, and lower is better. Ligand A is well within this range, while Ligand B is approaching the upper limit.

**logP:** Both ligands have good logP values (A: 3.607, B: 2.415) falling within the optimal 1-3 range. Ligand A is slightly higher, which could be beneficial for membrane permeability, but needs to be balanced against solubility.

**H-Bond Donors/Acceptors:** Both have 1 HBD, which is good. Ligand A has 4 HBA, and Ligand B has 6. Both are acceptable (<=10), but Ligand A is slightly better.

**QED:** Both ligands have similar and good QED scores (A: 0.733, B: 0.795), indicating good drug-like properties.

**DILI:** Ligand A (27.22) has a significantly lower DILI risk than Ligand B (51.493). This is a major advantage for Ligand A.

**BBB:** Both ligands have good BBB penetration (A: 69.833, B: 68.05). While >70 is desirable, both are reasonably high, suggesting decent CNS exposure.

**Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and suggests poor permeability. However, the scale is not specified, so it's difficult to interpret.

**Aqueous Solubility:** Both have negative solubility values, which is also unusual. Again, the scale is not specified.

**hERG:** Both have very low hERG inhibition liability (A: 0.224, B: 0.208), which is excellent.

**Microsomal Clearance:** Ligand A (71.711) has higher microsomal clearance than Ligand B (62.065), indicating potentially lower metabolic stability.

**In vitro Half-Life:** Ligand B (42.494) has a much longer in vitro half-life than Ligand A (-6.551). This is a significant advantage for Ligand B.

**P-gp Efflux:** Both have low P-gp efflux liability (A: 0.388, B: 0.163), which is good for CNS exposure. Ligand B is slightly better.

**Binding Affinity:** Ligand B (-7.1) has a slightly better binding affinity than Ligand A (-8.8). However, the difference is not substantial enough to outweigh other factors.

**Overall Assessment:**

Considering the GPCR-specific priorities, Ligand A is the more promising candidate. Its lower TPSA, significantly lower DILI risk, and comparable BBB penetration are key advantages. While Ligand B has a better half-life and slightly better affinity, the lower TPSA and DILI of Ligand A are more critical for a CNS-targeting GPCR ligand. The unusual negative values for Caco-2 and solubility are concerning for both, but the other factors favor Ligand A.

Output:
0
2025-04-17 07:01:59,854 - INFO - Batch 331 complete. Total preferences: 5296
2025-04-17 07:01:59,854 - INFO - Processing batch 332/512...
2025-04-17 07:02:47,856 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B against the provided guidelines, prioritizing GPCR characteristics (BBB, logP, Pgp, TPSA, and affinity).

**Ligand A:**

*   **MW:** 344.543 Da - Good (within 200-500 range)
*   **TPSA:** 24.5 A<sup>2</sup> - Excellent (well below 90 A<sup>2</sup> for CNS targets)
*   **logP:** 3.929 - Good (within 1-3 range, slightly high but acceptable)
*   **HBD:** 1 - Good (<=5)
*   **HBA:** 3 - Good (<=10)
*   **QED:** 0.876 - Excellent (>=0.5)
*   **DILI:** 9.965 - Excellent (low risk, <40)
*   **BBB:** 85.343 - Excellent (very high, >70)
*   **Caco-2:** -4.745 - Poor (negative value suggests very low permeability)
*   **Solubility:** -2.652 - Poor (negative value suggests very low solubility)
*   **hERG:** 0.907 - Good (low risk)
*   **Cl_mic:** 18.427 mL/min/kg - Moderate (could be better, but not alarming)
*   **t1/2:** 6.087 hours - Moderate (could be better)
*   **Pgp:** 0.266 - Excellent (low efflux, good for CNS penetration)
*   **Affinity:** -8.7 kcal/mol - Excellent (strong binding)

**Ligand B:**

*   **MW:** 379.479 Da - Good (within 200-500 range)
*   **TPSA:** 128.03 A<sup>2</sup> - Moderate (above the ideal 90 A<sup>2</sup> for CNS, but not drastically)
*   **logP:** -0.293 - Poor (below 1, may impede permeation)
*   **HBD:** 2 - Good (<=5)
*   **HBA:** 6 - Good (<=10)
*   **QED:** 0.53 - Moderate (just above 0.5)
*   **DILI:** 35.789 - Good (low risk, <40)
*   **BBB:** 73.284 - Good (above 70, acceptable for CNS)
*   **Caco-2:** -5.508 - Poor (negative value suggests very low permeability)
*   **Solubility:** -1.627 - Poor (negative value suggests very low solubility)
*   **hERG:** 0.098 - Excellent (very low risk)
*   **Cl_mic:** 16.5 mL/min/kg - Good (relatively low clearance)
*   **t1/2:** 14.046 hours - Excellent (long half-life)
*   **Pgp:** 0.011 - Excellent (very low efflux)
*   **Affinity:** -6.0 kcal/mol - Good (strong binding, but significantly weaker than Ligand A)

**Comparison and Decision:**

Both ligands have significant issues with Caco-2 permeability and aqueous solubility. However, for a CNS target like DRD2, the BBB is paramount. Ligand A has a substantially higher BBB penetration (85.343%) compared to Ligand B (73.284%). Furthermore, Ligand A exhibits a much stronger binding affinity (-8.7 kcal/mol vs -6.0 kcal/mol). While Ligand B has a slightly better half-life, the superior affinity and BBB penetration of Ligand A outweigh this advantage. The logP of ligand A is slightly higher, but still within an acceptable range.

Therefore, Ligand A is the more promising drug candidate.

Output:
1
2025-04-17 07:02:47,856 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (347.455 and 365.499 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (70.0) and Ligand B (71.53) are both below the 90 A^2 threshold for CNS targets, which is excellent.

**3. logP:** Ligand A (2.666) and Ligand B (1.916) are both within the optimal range of 1-3.

**4. H-Bond Donors:** Ligand A (2) and Ligand B (1) are both acceptable, being less than 5.

**5. H-Bond Acceptors:** Both ligands (A: 5, B: 5) are within the acceptable limit of 10.

**6. QED:** Ligand A (0.802) has a better QED score than Ligand B (0.679), indicating a more drug-like profile.

**7. DILI:** Ligand A (4.343) has a significantly lower DILI risk than Ligand B (27.259). This is a major advantage for Ligand A.

**8. BBB:** Ligand B (80.264) has a superior BBB penetration percentile compared to Ligand A (68.36). This is a critical factor for CNS targets like DRD2.

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.871 and -4.912), which is unusual and suggests poor permeability. This is a significant concern for both.

**10. Aqueous Solubility:** Both ligands have negative solubility values (-2.301 and -2.245), indicating very poor aqueous solubility. This is a major drawback for both.

**11. hERG Inhibition:** Ligand A (0.817) has a slightly higher hERG inhibition risk than Ligand B (0.431), but both are relatively low.

**12. Microsomal Clearance:** Ligand A (36.792) has a lower microsomal clearance than Ligand B (44.006), suggesting better metabolic stability.

**13. In vitro Half-Life:** Ligand B (10.355) has a significantly longer in vitro half-life than Ligand A (-5.959). This is a strong advantage for Ligand B.

**14. P-gp Efflux:** Ligand A (0.128) has a lower P-gp efflux liability than Ligand B (0.058), which is favorable for CNS penetration.

**15. Binding Affinity:** Ligand A (-8.2 kcal/mol) has a significantly stronger binding affinity than Ligand B (-6.9 kcal/mol). This is a substantial advantage, potentially outweighing some of the ADME drawbacks.

**Overall Assessment:**

While Ligand B has better BBB penetration and a longer half-life, Ligand A possesses a significantly stronger binding affinity and a much lower DILI risk. The poor Caco-2 and solubility for both are concerning, but the superior affinity of Ligand A, coupled with the lower DILI, makes it the more promising candidate. The difference in affinity (>1.5 kcal/mol) is substantial enough to prioritize over the slightly better BBB of Ligand B, especially considering the lower DILI risk.

Output:
0
2025-04-17 07:02:47,856 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 drug candidates, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (366.571 Da) is slightly higher than Ligand B (351.403 Da), but both are acceptable.

**TPSA:** Ligand A (49.41) is excellent for CNS penetration, well below the 90 A^2 threshold. Ligand B (96.11) is higher, but still potentially acceptable, though less ideal.

**logP:** Ligand A (3.657) is within the optimal range (1-3). Ligand B (1.139) is on the lower side, potentially hindering permeability.

**H-Bond Donors/Acceptors:** Both ligands have 1 HBD, which is good. Ligand A has 3 HBA, and Ligand B has 6 HBA. Both are within the acceptable limit of 10, but Ligand B's higher HBA count could slightly impact permeability.

**QED:** Both ligands have good QED scores (A: 0.748, B: 0.877), indicating drug-like properties.

**DILI:** Both ligands have acceptable DILI risk (A: 41.373, B: 51.725), below the 60 threshold.

**BBB:** Ligand A (72.005) has a significantly better BBB percentile than Ligand B (63.862). This is a crucial advantage for a CNS target like DRD2.

**Caco-2 Permeability:** Ligand A (-5.215) has a negative Caco-2 value which is unusual and suggests poor permeability. Ligand B (-4.86) is also negative, but slightly less so.

**Aqueous Solubility:** Both ligands have poor aqueous solubility (-4.78 and -1.804 respectively). This could pose formulation challenges.

**hERG Inhibition:** Ligand A (0.604) has a very low hERG risk, which is excellent. Ligand B (0.233) also has very low hERG risk.

**Microsomal Clearance:** Ligand A (107.135) has higher microsomal clearance, suggesting lower metabolic stability. Ligand B (29.474) has much lower clearance, indicating better metabolic stability.

**In vitro Half-Life:** Ligand A (8.763) has a shorter half-life than Ligand B (-20.877). The negative value for ligand B is unusual and may indicate a very long half-life or an issue with the assay.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (A: 0.624, B: 0.143). This is favorable for CNS penetration.

**Binding Affinity:** Ligand B (-7.5 kcal/mol) has a significantly stronger binding affinity than Ligand A (-0.0 kcal/mol). This is a major advantage, potentially outweighing some of the ADME drawbacks.

**Overall Assessment:**

Ligand B has a much stronger binding affinity, better metabolic stability, and a lower P-gp efflux. However, Ligand A has a better BBB score and a much lower hERG risk. The negative Caco-2 values for both are concerning, but the significantly better affinity of Ligand B is a strong driver. Given the GPCR-specific priorities, the strong affinity of Ligand B is the most important factor. While its logP is lower and TPSA is higher, the substantial binding advantage is likely to be more impactful in driving efficacy.

Output:
1
2025-04-17 07:02:47,856 - INFO - Okay, let's analyze these two ligands for their potential as DRD2 drug candidates. DRD2 is a GPCR in the CNS, so BBB penetration, logP, Pgp efflux, TPSA, and binding affinity are paramount.

**Ligand A:** [347.35 , 100.35 ,   0.558,   2.   ,   6.   ,   0.79 ,  78.441,  58.782, -5.052,  -2.412,   0.153, -15.317,  11.288,   0.003,  -7.8  ]
**Ligand B:** [346.515,  49.41 ,   3.832,   1.   ,   2.   ,   0.621,  25.436,  77.472, -4.702,  -3.932,   0.472,  54.541, -19.911,   0.198,  -9.2  ]

**1. Molecular Weight:** Both ligands are within the ideal range (200-500 Da). No clear advantage here.

**2. TPSA:** Ligand A (100.35) is higher than the preferred <90 for CNS targets, but not drastically so. Ligand B (49.41) is excellent, well below the threshold. **Advantage: B**

**3. logP:** Ligand A (0.558) is quite low, potentially hindering membrane permeability. Ligand B (3.832) is near the optimal range (1-3). **Advantage: B**

**4. H-Bond Donors:** Both ligands are within the acceptable limit of <=5. Ligand A has 2, and Ligand B has 1. No significant difference.

**5. H-Bond Acceptors:** Both ligands are within the acceptable limit of <=10. Ligand A has 6, and Ligand B has 2. No significant difference.

**6. QED:** Both ligands have acceptable QED values (>0.5). No clear advantage.

**7. DILI:** Ligand A (78.441) has a higher DILI risk than Ligand B (25.436). **Advantage: B**

**8. BBB:** Ligand B (77.472) has a significantly better BBB percentile than Ligand A (58.782). This is *critical* for a CNS target. **Advantage: B**

**9. Caco-2 Permeability:** Ligand A (-5.052) has poor Caco-2 permeability, indicating poor absorption. Ligand B (-4.702) is also poor, but slightly better. **Advantage: B**

**10. Aqueous Solubility:** Both ligands have very poor solubility. This is a concern for both, but less critical than BBB for CNS drugs.

**11. hERG Inhibition:** Both ligands have low hERG inhibition risk. No significant difference.

**12. Microsomal Clearance:** Ligand A (-15.317) has a lower (better) microsomal clearance than Ligand B (54.541), suggesting better metabolic stability. **Advantage: A**

**13. In vitro Half-Life:** Ligand A (11.288) has a shorter half-life than Ligand B (-19.911). **Advantage: B**

**14. P-gp Efflux:** Ligand A (0.003) has very low P-gp efflux, which is excellent. Ligand B (0.198) is also low, but higher. **Advantage: A**

**15. Binding Affinity:** Ligand B (-9.2 kcal/mol) has a stronger binding affinity than Ligand A (-7.8 kcal/mol). This is a substantial difference (>1.5 kcal/mol) and can outweigh some ADME drawbacks. **Advantage: B**

**Overall Assessment:**

While Ligand A has advantages in metabolic stability (Cl_mic) and P-gp efflux, Ligand B is clearly superior overall, especially considering the CNS target. Ligand B has a much better TPSA, logP, BBB penetration, DILI risk, and significantly stronger binding affinity. The poor solubility is a concern for both, but can be addressed with formulation strategies. The slightly worse metabolic stability and P-gp efflux of Ligand B are less critical given its superior CNS penetration and potency.

1
2025-04-17 07:02:47,857 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B based on the provided guidelines, prioritizing GPCR-specific properties (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (343.427 Da) is slightly lower, which could be favorable for permeability, but both are acceptable.

**TPSA:** Ligand A (75.43) is significantly better than Ligand B (131.59). For CNS targets, TPSA should be <= 90, and Ligand A is comfortably within this range, while Ligand B is approaching the upper limit.

**logP:** Ligand A (1.947) is optimal (1-3), while Ligand B (0.564) is a bit low, potentially hindering permeation.

**H-Bond Donors/Acceptors:** Both ligands have acceptable HBD (1) and HBA (Ligand A: 5, Ligand B: 8) counts.

**QED:** Both ligands have good QED scores (A: 0.921, B: 0.844), indicating drug-likeness.

**DILI:** Ligand A (58.395) has a better DILI score than Ligand B (87.01), indicating a lower risk of liver injury.

**BBB:** Both ligands have excellent BBB penetration (A: 79.682, B: 80.419), exceeding the desirable threshold of >70.

**Caco-2 Permeability:** Both have negative Caco-2 values, which is odd and hard to interpret without knowing the scale. However, we can assume they are similarly poor.

**Aqueous Solubility:** Both have negative solubility values, which is also odd. Again, we assume similar solubility.

**hERG:** Ligand A (0.726) has a slightly better hERG profile than Ligand B (0.359), indicating lower cardiotoxicity risk.

**Microsomal Clearance:** Ligand A (57.664) has a higher (worse) microsomal clearance than Ligand B (33.042), suggesting lower metabolic stability.

**In vitro Half-Life:** Ligand B (-50.854) has a very negative half-life, which is problematic. Ligand A (13.981) is much better.

**P-gp Efflux:** Ligand A (0.593) has a better P-gp efflux profile than Ligand B (0.034), which is crucial for CNS exposure.

**Binding Affinity:** Ligand B (-8.3 kcal/mol) has a slightly better binding affinity than Ligand A (-7.5 kcal/mol). This is a significant advantage.

**Overall Assessment:**

While Ligand B has slightly better binding affinity, Ligand A is superior in most other critical ADME properties, particularly TPSA, logP, DILI, P-gp efflux, and *especially* in vitro half-life. The significantly better metabolic stability (lower Cl_mic, higher t1/2) and P-gp efflux profile of Ligand A are crucial for CNS drug development. The slightly weaker binding affinity of Ligand A can potentially be optimized further, while fixing the severe issues with Ligand B's half-life and P-gp efflux would be much more challenging.

Output:
1
2025-04-17 07:02:47,857 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (346.431 and 347.419 Da) fall comfortably within the ideal 200-500 Da range.

**TPSA:** Ligand A (83.44) is significantly better than Ligand B (120.32). For CNS targets, we want TPSA <= 90, and A is well within this range, while B is pushing the limit.

**logP:** Ligand A (0.545) is slightly lower than optimal (1-3), but still reasonable. Ligand B (-0.268) is quite low, potentially hindering membrane permeability.

**H-Bond Donors/Acceptors:** Ligand A (2 HBD, 5 HBA) is generally better balanced than Ligand B (4 HBD, 4 HBA). Both are within acceptable ranges.

**QED:** Both ligands have similar, acceptable QED values (0.755 and 0.566, both >= 0.5).

**DILI:** Ligand A (22.451) has a lower DILI risk than Ligand B (20.9), both are good.

**BBB:** This is crucial for a CNS target like DRD2. Ligand A (58.627) has a significantly better BBB percentile than Ligand B (44.436). While ideally >70, A is considerably closer to that target.

**Caco-2 Permeability:** Ligand A (-5.274) is worse than Ligand B (-6.321), but both are negative, indicating poor permeability.

**Aqueous Solubility:** Ligand A (-1.093) is better than Ligand B (-2.476), both are poor.

**hERG:** Both ligands have very low hERG risk (0.199 and 0.173).

**Microsomal Clearance:** Ligand A (-17.428) has a much lower (better) microsomal clearance than Ligand B (-22.052), indicating greater metabolic stability.

**In vitro Half-Life:** Ligand A (-9.456) has a slightly better in vitro half-life than Ligand B (-1.645).

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.007 and 0.004).

**Binding Affinity:** Both ligands have similar, excellent binding affinities (-8.5 and -8.7 kcal/mol). This is a strong point for both.

**Overall Assessment:**

Ligand A is the superior candidate. While both have good binding affinity, Ligand A excels in critical areas for CNS penetration: TPSA, BBB, and microsomal clearance. Its slightly better solubility and lower DILI risk further strengthen its profile. Ligand B's low logP and higher TPSA are significant drawbacks for a CNS-targeting drug.

Output:
0
2025-04-17 07:02:47,857 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (345.4) is slightly lower, which could be beneficial for permeability.

**TPSA:** Ligand A (80.8) is better than Ligand B (60.9) as it is closer to the ideal range for CNS targets (<=90).

**logP:** Ligand B (2.515) is optimal (1-3), while Ligand A (0.305) is quite low, potentially hindering membrane permeability and brain penetration. This is a significant drawback for a CNS target.

**H-Bond Donors/Acceptors:** Both ligands have acceptable HBD (1) and HBA (5/4) counts.

**QED:** Both ligands have good QED scores (0.593 and 0.894), indicating good drug-like properties.

**DILI:** Ligand B (33.7) has a much lower DILI risk than Ligand A (52.2), which is a significant advantage.

**BBB:** Both ligands have reasonably good BBB penetration (66.6% and 62.1%), but neither is outstanding (>70%).

**Caco-2 Permeability:** Ligand A (-4.485) has a more negative Caco-2 value, indicating poorer intestinal absorption than Ligand B (-5.138).

**Aqueous Solubility:** Ligand A (-1.791) has better aqueous solubility than Ligand B (-3.472).

**hERG:** Both ligands have low hERG inhibition risk (0.216 and 0.312).

**Microsomal Clearance:** Ligand A (-0.126) has a lower (better) microsomal clearance than Ligand B (45.222), suggesting greater metabolic stability.

**In vitro Half-Life:** Ligand A (-19.811) has a more negative (better) in vitro half-life than Ligand B (-11.193).

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.047 and 0.114).

**Binding Affinity:** Both ligands have similar, strong binding affinities (-6.6 and -6.2 kcal/mol). The difference of 0.4 kcal/mol is not substantial enough to override other ADME concerns.

**Overall Assessment:**

While Ligand A has better metabolic stability (lower Cl_mic, better t1/2) and solubility, its significantly lower logP is a major concern for CNS penetration. Ligand B, despite slightly worse metabolic stability, has a much more favorable logP, lower DILI risk, and acceptable BBB penetration. For a CNS target like DRD2, achieving adequate brain exposure is paramount, making logP a critical factor.

Output:
1
2025-04-17 07:02:47,857 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (348.403 and 345.403 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (115.65) is slightly above the preferred <90 for CNS targets, but still reasonable. Ligand B (97.62) is better, falling comfortably under 90.

**3. logP:** Ligand A (-0.246) is a bit low, potentially hindering membrane permeability. Ligand B (0.948) is much better, residing within the optimal 1-3 range.

**4. H-Bond Donors:** Ligand A (3) and Ligand B (2) both meet the HBD <= 5 criteria.

**5. H-Bond Acceptors:** Both ligands (6) are within the acceptable HBA <= 10 range.

**6. QED:** Both ligands have similar QED values (0.53 and 0.521), indicating good drug-likeness.

**7. DILI:** Ligand A (46.297) has a significantly lower DILI risk than Ligand B (65.878), making it more favorable from a toxicity perspective.

**8. BBB:** Ligand A (38.426) has a lower BBB percentile than Ligand B (57.852). While neither is >70, Ligand B is better positioned for CNS penetration.

**9. Caco-2:** Both ligands have negative Caco-2 values (-5.433 and -5.37), which is unusual and suggests poor permeability. This is a significant concern for both.

**10. Solubility:** Both ligands have negative solubility values (-0.441 and -1.791), indicating very poor aqueous solubility. This is a major drawback for both.

**11. hERG:** Ligand A (0.059) has a very low hERG risk, while Ligand B (0.248) is slightly higher but still relatively low.

**12. Cl_mic:** Ligand A (11.694) has a lower microsomal clearance than Ligand B (49.798), suggesting better metabolic stability.

**13. t1/2:** Ligand B (18.675) has a longer in vitro half-life than Ligand A (12.385), which is generally desirable.

**14. Pgp:** Ligand A (0.014) has a much lower P-gp efflux liability than Ligand B (0.081), which is crucial for CNS penetration.

**15. Binding Affinity:** Ligand B (-8.0 kcal/mol) has a significantly stronger binding affinity than Ligand A (-7.1 kcal/mol), exceeding the >1.5 kcal/mol advantage threshold.

**Overall Assessment:**

While both ligands have significant drawbacks (poor Caco-2 and solubility), Ligand B's substantially stronger binding affinity (-8.0 vs -7.1 kcal/mol) and better BBB penetration (57.852 vs 38.426) are critical advantages for a CNS-targeting GPCR like DRD2. The longer half-life of Ligand B is also beneficial. Ligand A has a better DILI score and lower Pgp efflux, but the affinity difference is too large to ignore. The low logP of Ligand A is also concerning.

Output:
1
2025-04-17 07:02:47,858 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (361.833 and 349.431 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (82.19) is significantly better than Ligand B (93.46). For CNS targets, we want TPSA <= 90, so Ligand A is preferable.

**logP:** Both ligands have good logP values (1.682 and 1.294), falling within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A (HBD=1, HBA=4) is slightly better than Ligand B (HBD=2, HBA=5) in terms of adhering to the <5 HBD and <10 HBA guidelines.

**QED:** Ligand A (0.898) has a much better QED score than Ligand B (0.621), indicating a more drug-like profile.

**DILI:** Ligand A (56.883) has a higher DILI risk than Ligand B (14.541). This is a significant drawback for Ligand A.

**BBB:** Ligand B (51.609) has a substantially better BBB percentile than Ligand A (32.765). For a CNS target like DRD2, BBB penetration is crucial, making Ligand B more attractive.

**Caco-2 Permeability:** Both have negative values, which is unusual. Assuming these represent logP-like scales, lower values suggest poorer permeability. They are fairly similar, but Ligand A (-5.068) is slightly better than Ligand B (-4.796).

**Aqueous Solubility:** Both have negative values, indicating poor solubility. They are similar in this regard.

**hERG:** Both ligands have very low hERG inhibition liability (0.382 and 0.071), which is excellent.

**Microsomal Clearance:** Ligand B (27.208) has a much higher microsomal clearance than Ligand A (0.05). Lower clearance is preferred for metabolic stability, so Ligand A is better.

**In vitro Half-Life:** Ligand A (-22.221) has a much longer in vitro half-life than Ligand B (-3.052). This is a significant advantage for Ligand A.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.036 and 0.007), which is excellent.

**Binding Affinity:** Ligand A (-7.6 kcal/mol) has a slightly better binding affinity than Ligand B (-7.3 kcal/mol). While both are good, the 0.3 kcal/mol difference could be significant.

**Overall Assessment:**

Ligand A excels in binding affinity, half-life, and metabolic stability. However, it suffers from a higher DILI risk and significantly poorer BBB penetration. Ligand B has a much better BBB score and lower DILI risk, but its affinity is slightly weaker and it has poorer metabolic stability.

Considering the GPCR-specific priorities, BBB penetration is paramount for a CNS target like DRD2. The substantial difference in BBB (51.609 vs 32.765) and the lower DILI risk of Ligand B outweigh the slightly better affinity and half-life of Ligand A.

Output:
1
2025-04-17 07:02:47,858 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B based on the provided guidelines, prioritizing GPCR-specific properties (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (348.443 and 351.491 Da) fall within the ideal range of 200-500 Da.

**TPSA:** Ligand A (67.87) is significantly better than Ligand B (81.67). For CNS targets, TPSA should be <=90, both are within this range, but A is closer to the ideal <60 range.

**logP:** Both ligands have acceptable logP values (1.684 and 1.036), falling within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A (HBD=1, HBA=4) is slightly better than Ligand B (HBD=3, HBA=4) in terms of HBD count, keeping within the desirable range of <=5. HBA is the same for both.

**QED:** Ligand A (0.814) has a considerably higher QED score than Ligand B (0.61), indicating better overall drug-likeness.

**DILI:** Ligand A (38.503) has a lower DILI risk than Ligand B (4.382), both are good, but A is better.

**BBB:** Ligand A (73.827) has a slightly better BBB percentile than Ligand B (68.127). Both are reasonably good for a CNS target, but A is closer to the desirable >70 threshold.

**Caco-2 Permeability:** Ligand A (-4.198) has a worse Caco-2 permeability than Ligand B (-5.205). Lower values indicate poorer permeability.

**Aqueous Solubility:** Ligand A (-2.349) has a slightly better solubility than Ligand B (-1.923).

**hERG Inhibition:** Both ligands have very low hERG inhibition liability (0.192 and 0.34), indicating minimal cardiotoxicity risk.

**Microsomal Clearance:** Ligand A (67.506) has a higher microsomal clearance than Ligand B (-3.238), indicating lower metabolic stability. This is a significant drawback for Ligand A.

**In vitro Half-Life:** Ligand A (-3.186) has a shorter half-life than Ligand B (-15.342). This is another significant drawback for Ligand A.

**P-gp Efflux:** Ligand A (0.069) has lower P-gp efflux than Ligand B (0.008), which is favorable for CNS penetration.

**Binding Affinity:** Ligand B (-7.9) has a slightly better binding affinity than Ligand A (-7.7). While both are excellent, the difference is small.

**Overall Assessment:**

Ligand A excels in TPSA, QED, DILI, and BBB, and P-gp efflux. However, it suffers from significantly higher microsomal clearance and shorter half-life, which are critical for *in vivo* efficacy. Ligand B has slightly weaker BBB penetration and QED, but demonstrates superior metabolic stability (lower Cl_mic) and a longer half-life. Given the importance of metabolic stability and duration of action for CNS drugs, Ligand B is the more promising candidate despite the slightly weaker BBB and QED scores. The small affinity difference is less important than the ADME advantages of Ligand B.

Output:
1
2025-04-17 07:02:47,858 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (345.4 and 351.4 Da) fall comfortably within the ideal 200-500 Da range.

**TPSA:** Ligand A (86.78) is better than Ligand B (62.3). Both are below the 90 A^2 threshold desirable for CNS targets.

**logP:** Both ligands have good logP values (1.581 and 1.941), falling within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A has 0 HBD and 5 HBA, while Ligand B has 1 HBD and 3 HBA. Both are within acceptable limits.

**QED:** Both ligands have similar, good QED scores (0.83 and 0.852), indicating drug-like properties.

**DILI:** Both ligands have low DILI risk (37.03 and 38.35), which is favorable.

**BBB:** Ligand A has a significantly better BBB penetration score (78.91%) than Ligand B (86.08%). This is a crucial advantage for a CNS target like DRD2.

**Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and suggests a potential issue with the data or modeling. However, the values are similar (-4.256 and -4.669).

**Aqueous Solubility:** Both have negative solubility values, which is also unusual. Again, the values are similar (-2.065 and -2.648).

**hERG Inhibition:** Ligand A (0.521) shows slightly better hERG inhibition liability than Ligand B (0.362), indicating a lower risk of cardiotoxicity.

**Microsomal Clearance:** Ligand A (-0.132) has a lower (better) microsomal clearance than Ligand B (10.318). This suggests greater metabolic stability for Ligand A.

**In vitro Half-Life:** Ligand A (34.184) has a significantly longer in vitro half-life than Ligand B (-24.656). This is a major advantage.

**P-gp Efflux:** Both ligands show strong P-gp efflux liability (-8 and -9). This is not ideal, but similar for both.

**Binding Affinity:** Both ligands have similar binding affinities (-8 and -9 kcal/mol), which are both excellent.

**Overall Assessment:**

Ligand A is superior due to its significantly better BBB penetration (78.91% vs 86.08%), lower microsomal clearance, and longer in vitro half-life. While both ligands have similar binding affinities and acceptable ADME properties, the improved pharmacokinetic profile of Ligand A makes it a more promising drug candidate for a CNS target like DRD2. The negative solubility and Caco-2 values are concerning for both, but the other advantages of Ligand A outweigh this.

Output:
1
2025-04-17 07:02:47,858 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (387.53 and 355.41 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (97.39) is higher than Ligand B (57.7). For a CNS target like DRD2, TPSA should be <= 90. Ligand A is slightly above this, while Ligand B is well within the desired range.

**3. logP:** Both ligands have good logP values (2.569 and 3.965), falling within the optimal 1-3 range. Ligand B is slightly higher, potentially increasing permeability but also raising concerns about off-target effects.

**4. H-Bond Donors:** Ligand A (2) and Ligand B (1) are both acceptable, being <=5.

**5. H-Bond Acceptors:** Ligand A (6) and Ligand B (4) are both acceptable, being <=10.

**6. QED:** Both ligands have similar and good QED values (0.749 and 0.779), indicating good drug-like properties.

**7. DILI:** Ligand A (77.55%) has a higher DILI risk than Ligand B (35.40%). This is a significant drawback for Ligand A.

**8. BBB:** Ligand A (63.47%) and Ligand B (76.74%) both have reasonably good BBB penetration, but Ligand B is better, exceeding 70% which is desirable for CNS targets.

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.853 and -4.986). These values are unusual and suggest poor permeability. However, negative values are sometimes artifacts of the prediction method and should be interpreted cautiously.

**10. Aqueous Solubility:** Both ligands have negative solubility values (-3.723 and -3.744), suggesting poor solubility. Similar to Caco-2, these values should be interpreted cautiously.

**11. hERG Inhibition:** Ligand A (0.326) has a slightly lower hERG risk than Ligand B (0.909), which is preferable.

**12. Microsomal Clearance:** Ligand A (23.013) has a higher microsomal clearance than Ligand B (18.643), indicating lower metabolic stability.

**13. In vitro Half-Life:** Ligand A (33.439) has a longer half-life than Ligand B (9.822), which is a positive attribute.

**14. P-gp Efflux:** Ligand A (0.184) has lower P-gp efflux than Ligand B (0.352), which is beneficial for CNS exposure.

**15. Binding Affinity:** Ligand B (-7.3 kcal/mol) has a significantly stronger binding affinity than Ligand A (-8.1 kcal/mol). A difference of 0.8 kcal/mol is substantial and can outweigh minor ADME drawbacks.

**Overall Assessment:**

While Ligand A has a longer half-life and lower P-gp efflux, Ligand B is superior overall. Ligand B has a lower DILI risk, better BBB penetration, a significantly stronger binding affinity, and a more favorable TPSA. The slightly higher logP of Ligand B is a minor concern compared to the advantages it offers. The negative Caco-2 and solubility values are concerning for both, but the affinity difference is significant enough to favor Ligand B.

Output:
1
2025-04-17 07:02:47,858 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (357.445 and 359.51 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (52.65) is significantly higher than the preferred <90 for CNS targets, while Ligand B (20.31) is excellent. This is a major advantage for Ligand B.

**logP:** Ligand A (1.727) is within the optimal 1-3 range. Ligand B (4.866) is slightly above, potentially raising concerns about solubility and off-target effects, but not drastically so.

**H-Bond Donors/Acceptors:** Ligand A has 1 HBD and 3 HBA, well within acceptable limits. Ligand B has 0 HBD and 2 HBA, also good.

**QED:** Ligand A (0.815) has a better QED score than Ligand B (0.585), indicating a more drug-like profile overall.

**DILI:** Ligand A (15.2) has a much lower DILI risk than Ligand B (32.648), which is a significant advantage.

**BBB:** Ligand A (81.039) is good, but Ligand B (96.2) is excellent, exceeding the >70 desirable threshold for CNS targets. This is a crucial point for DRD2.

**Caco-2 Permeability:** Both have negative values (-4.744 and -4.965), which is unusual and likely indicates poor permeability. However, these values are on a scale where negative values are possible and don't necessarily preclude development.

**Aqueous Solubility:** Both ligands have negative solubility values (-1.481 and -4.58), suggesting poor aqueous solubility. This is a concern, but can sometimes be overcome with formulation strategies.

**hERG Inhibition:** Ligand A (0.559) has a slightly lower hERG risk than Ligand B (0.936), which is preferable.

**Microsomal Clearance:** Ligand A (-14.461) has much lower (better) microsomal clearance than Ligand B (90.527), indicating greater metabolic stability.

**In vitro Half-Life:** Ligand A (-6.411) has a negative half-life, which is unusual and likely an artifact of the prediction method. Ligand B (33.831) has a reasonable half-life.

**P-gp Efflux:** Ligand A (0.041) has much lower P-gp efflux than Ligand B (0.927), which is highly desirable for CNS penetration.

**Binding Affinity:** Ligand B (-7.7 kcal/mol) has a slightly better binding affinity than Ligand A (-8.3 kcal/mol). While the difference is small, it is still a factor.

**Overall Assessment:**

Ligand B excels in BBB penetration and binding affinity, both critical for a CNS-targeting GPCR like DRD2. However, it suffers from higher DILI risk, higher P-gp efflux, and worse metabolic stability (higher Cl_mic). Ligand A has a better safety profile (lower DILI, P-gp efflux, and better metabolic stability) and a slightly better QED score, but its TPSA is higher and BBB is lower.

Given the importance of CNS penetration for DRD2, and the relatively small difference in binding affinity, the superior BBB score of Ligand B outweighs its other drawbacks. The higher TPSA of Ligand A is a significant concern for CNS penetration. While solubility and permeability are concerns for both, these can be addressed through formulation.

Output:
1
2025-04-17 07:02:47,859 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B against the provided guidelines, prioritizing GPCR-specific properties (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (348.407 and 369.418 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (129.73) is slightly above the optimal <90 for CNS targets, but still reasonable. Ligand B (87.74) is excellent, well below 90.

**logP:** Ligand A (0.205) is quite low, potentially hindering permeability. Ligand B (1.495) is within the optimal 1-3 range. This is a significant advantage for Ligand B.

**H-Bond Donors/Acceptors:** Ligand A has 3 HBD and 6 HBA, acceptable values. Ligand B has 2 HBD and 5 HBA, also acceptable.

**QED:** Both ligands have good QED scores (0.645 and 0.845), indicating drug-like properties.

**DILI:** Ligand A (53.044) has a better DILI score than Ligand B (65.258), suggesting lower liver injury risk. However, both are within an acceptable range.

**BBB:** Ligand A (52.811) has a moderate BBB penetration, while Ligand B (60.644) is also moderate. Neither is >70, which is desirable for CNS targets, but Ligand B is slightly better.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.714 and -4.938), which is unusual and suggests poor permeability. This is a concern for both.

**Aqueous Solubility:** Both ligands have negative solubility values (-1.85 and -3.176), indicating poor aqueous solubility. This is a significant drawback for both.

**hERG Inhibition:** Ligand A (0.008) has very low hERG inhibition risk, which is excellent. Ligand B (0.154) is slightly higher, but still relatively low.

**Microsomal Clearance:** Ligand A (-14.497) and Ligand B (-7.908) both have negative clearance values, which is not physically meaningful. This suggests the values were likely reported as percentiles and are interpreted as low clearance (good metabolic stability). Ligand B appears to have slightly better metabolic stability.

**In vitro Half-Life:** Ligand A (-15.951) and Ligand B (-22.302) both have negative half-life values, which is also not physically meaningful. Similar to clearance, these are likely percentiles, indicating long half-lives (desirable). Ligand B appears to have a longer half-life.

**P-gp Efflux:** Ligand A (0.025) has very low P-gp efflux, which is highly desirable for CNS penetration. Ligand B (0.043) is also low, but slightly higher.

**Binding Affinity:** Ligand B (-8.9 kcal/mol) has a significantly stronger binding affinity than Ligand A (-7.0 kcal/mol). This >1.5 kcal/mol difference is a major advantage, potentially outweighing some of the ADME drawbacks.

**Overall Assessment:**

Ligand B is the stronger candidate. While both have issues with solubility and Caco-2 permeability, Ligand B has a significantly better logP, binding affinity, and slightly better BBB penetration and metabolic stability. The stronger binding affinity is a critical advantage for a GPCR target. Ligand A's lower DILI risk is a plus, but the affinity difference is more impactful.

Output:
1
2025-04-17 07:02:47,859 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (348.443 and 344.419 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (70.08) is excellent, well below the 90 A^2 threshold for CNS targets. Ligand B (101.06) is still reasonable but less optimal, being above 90.

**3. logP:** Both ligands have good logP values (1.084 and 1.355), falling within the optimal 1-3 range.

**4. H-Bond Donors:** Ligand A (1) is preferable to Ligand B (3). Fewer HBDs generally improve permeability.

**5. H-Bond Acceptors:** Ligand A (4) is better than Ligand B (7). Lower HBA counts are generally preferred for CNS penetration.

**6. QED:** Both ligands have acceptable QED values (0.775 and 0.631), indicating reasonable drug-likeness.

**7. DILI:** Ligand A (17.72) has a significantly lower DILI risk than Ligand B (45.638), which is a substantial advantage.

**8. BBB:** Ligand A (71.035) has a much better BBB penetration percentile than Ligand B (52.036). This is *critical* for a CNS target like DRD2.

**9. Caco-2 Permeability:** Ligand A (-4.592) and Ligand B (-5.301) both have negative values, which is unusual. Without knowing the scale, it's hard to interpret, but they are similar.

**10. Aqueous Solubility:** Ligand A (-2.327) and Ligand B (-1.917) both have negative values, which is also unusual. Similar to Caco-2, it's hard to interpret without knowing the scale.

**11. hERG Inhibition:** Both ligands show low hERG inhibition liability (0.315 and 0.236), which is good.

**12. Microsomal Clearance:** Ligand A (12.539) has a lower microsomal clearance than Ligand B (31.899), suggesting better metabolic stability.

**13. In vitro Half-Life:** Ligand A (18.806) has a longer in vitro half-life than Ligand B (24.668), which is a positive.

**14. P-gp Efflux:** Ligand A (0.074) shows very low P-gp efflux liability, which is excellent for CNS penetration. Ligand B (0.006) is even lower, but the difference is minor.

**15. Binding Affinity:** Ligand B (-8.0) has a slightly better binding affinity than Ligand A (-7.2), a difference of 0.8 kcal/mol. While affinity is important, the ADME properties of Ligand A are significantly more favorable.

**Overall Assessment:**

Ligand A is the superior candidate. While Ligand B has slightly better binding affinity, Ligand A excels in crucial ADME properties for a CNS-targeting GPCR. Specifically, its significantly better BBB penetration, lower DILI risk, lower microsomal clearance, and lower HBD/HBA counts make it a much more promising drug candidate. The difference in affinity (0.8 kcal/mol) is unlikely to outweigh these substantial ADME advantages.

Output:
1
2025-04-17 07:02:47,859 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (355.467 and 345.487 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (63.05) is higher than Ligand B (43.86). For a CNS target like DRD2, we ideally want TPSA <= 90, so both are acceptable, but B is better.

**3. logP:** Ligand A (4.22) is higher than Ligand B (2.052). While both are within the 1-3 range, A is pushing the upper limit and could present solubility issues. B is closer to optimal.

**4. H-Bond Donors:** Ligand A (1) is better than Ligand B (0). While both are acceptable, a single donor can aid solubility.

**5. H-Bond Acceptors:** Ligand A (5) is higher than Ligand B (3). Both are within the acceptable range of <= 10.

**6. QED:** Both ligands have good QED scores (0.532 and 0.581, respectively), indicating drug-like properties.

**7. DILI:** Ligand A (83.598) has a significantly higher DILI risk than Ligand B (13.649). This is a major concern for Ligand A.

**8. BBB:** Ligand A (81.078) has a slightly better BBB penetration than Ligand B (78.519), but both are good (>70).

**9. Caco-2:** Ligand A (-4.918) and Ligand B (-4.526) both have negative values, which is unusual. Assuming these are log scale values, lower values indicate poorer permeability.

**10. Solubility:** Ligand A (-4.8) has worse solubility than Ligand B (-1.782). Solubility is a concern for Ligand A given its higher logP.

**11. hERG:** Ligand A (0.796) has a slightly higher hERG risk than Ligand B (0.525), but both are relatively low.

**12. Cl_mic:** Ligand A (124.331) has a higher microsomal clearance than Ligand B (44.733), indicating lower metabolic stability.

**13. t1/2:** Ligand A (22.796) has a longer half-life than Ligand B (-11.683). The negative value for B is concerning and likely an error or indicates very rapid metabolism.

**14. Pgp:** Ligand A (0.638) has a higher Pgp efflux liability than Ligand B (0.153). Lower Pgp is preferred, making B better.

**15. Binding Affinity:** Ligand A (-8.5) has a significantly stronger binding affinity than Ligand B (-7.1). This is a substantial advantage.

**Overall Assessment:**

Ligand A has a much better binding affinity and a slightly better BBB score and half-life. However, it suffers from significantly higher DILI risk, higher logP (potential solubility issues), higher Pgp efflux, and higher metabolic clearance. Ligand B has a better safety profile (DILI, Pgp), better logP and TPSA, and better metabolic stability. The difference in binding affinity (-8.5 vs -7.1) is significant, but the safety concerns with Ligand A are substantial. Given the GPCR-specific priorities and the importance of a favorable safety profile, especially for a CNS target, Ligand B is the more promising candidate despite the slightly weaker affinity.

Output:
1
2025-04-17 07:02:47,859 - INFO - Batch 332 complete. Total preferences: 5312
2025-04-17 07:02:47,859 - INFO - Processing batch 333/512...
2025-04-17 07:03:32,802 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (363.483 Da) is slightly lower, which could be beneficial for permeability.

**TPSA:** Both ligands have TPSA values below 90 (A: 84.23, B: 78.51), which is excellent for CNS penetration.

**logP:** Both ligands have good logP values (A: 3.32, B: 2.283), falling within the optimal range of 1-3. Ligand A is slightly higher, potentially leading to some off-target interactions, but still acceptable.

**H-Bond Donors/Acceptors:** Both have 2 HBD and 5/4 HBA, respectively, which are within acceptable limits.

**QED:** Both ligands have QED values above 0.5 (A: 0.753, B: 0.788), indicating good drug-like properties.

**DILI:** Both ligands have relatively high DILI risk, but below 70 (A: 69.678, B: 59.093). Ligand B has a lower DILI risk, which is preferable.

**BBB:** Ligand B (49.787%) has a significantly better BBB percentile than Ligand A (21.326%). This is a *critical* advantage for a CNS target like DRD2.

**Caco-2 Permeability & Aqueous Solubility:** Both ligands have negative Caco-2 values and negative solubility values, which is unusual and suggests these values may be on a different scale than expected. However, the relative values are similar between the two ligands.

**hERG Inhibition:** Both ligands have very low hERG inhibition liability (A: 0.25, B: 0.233), which is excellent.

**Microsomal Clearance:** Ligand A (44.963 mL/min/kg) has a higher microsomal clearance than Ligand B (13.202 mL/min/kg), indicating lower metabolic stability. This is a significant drawback for Ligand A.

**In vitro Half-Life:** Ligand B (24.886 hours) has a longer in vitro half-life than Ligand A (55.214 hours). This is a positive for Ligand B, suggesting less frequent dosing potential.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (A: 0.181, B: 0.182).

**Binding Affinity:** Ligand B (-7.6 kcal/mol) has a slightly better binding affinity than Ligand A (-7.3 kcal/mol). While the difference is small, it's still a positive for Ligand B.

**Overall:** Considering the GPCR-specific priorities, Ligand B is the superior candidate. Its significantly better BBB penetration, lower DILI risk, improved metabolic stability (lower Cl_mic, longer t1/2), and slightly better binding affinity outweigh the minor differences in other properties. The similar logP and TPSA values are both favorable.

Output:
1
2025-04-17 07:03:32,802 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (356.304 and 361.398 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (100.27) is slightly above the optimal <90 for CNS targets, but still reasonable. Ligand B (85.2) is well within the desired range.

**logP:** Ligand A (0.815) is a bit low, potentially hindering permeability. Ligand B (2.958) is excellent, falling squarely within the 1-3 optimal range.

**H-Bond Donors/Acceptors:** Ligand A has 3 HBD and 6 HBA, which are acceptable. Ligand B has 1 HBD and 7 HBA, also acceptable.

**QED:** Both ligands have reasonable QED scores (0.753 and 0.68), indicating good drug-like properties.

**DILI:** Ligand A (67.468) has a higher DILI risk than Ligand B (89.415). Both are acceptable, but B is better.

**BBB:** Ligand A (59.442) has a moderate BBB penetration, while Ligand B (66.305) is better. Both are below the desirable >70 for CNS targets, but Ligand B is closer.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.792 and -4.642), which is unusual and suggests poor permeability. This is a significant concern for both.

**Aqueous Solubility:** Both ligands have negative solubility values (-2.5 and -3.719), which is also unusual and indicates very poor solubility. This is a major drawback for both.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.234 and 0.351).

**Microsomal Clearance:** Ligand A (-4.335) has a lower (better) microsomal clearance than Ligand B (85.639), indicating greater metabolic stability.

**In vitro Half-Life:** Ligand A (-21.038) has a longer half-life than Ligand B (-11.136).

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.03 and 0.304), which is favorable for CNS penetration.

**Binding Affinity:** Both ligands have excellent binding affinities (-8.6 and -9.5 kcal/mol). Ligand B is slightly better.

**Overall Assessment:**

While both ligands have excellent binding affinity, Ligand B is the more promising candidate. It has a better logP, a lower DILI risk, slightly better BBB penetration, and a superior binding affinity. The main concerns for both are the negative Caco-2 and solubility values, which need to be addressed through structural modifications. However, given the GPCR-specific priorities, Ligand B's better logP and BBB penetration give it an edge. The improved metabolic stability of Ligand A is a plus, but the other factors favor Ligand B.

Output:
1
2025-04-17 07:03:32,803 - INFO - Reasoning:

Let's analyze Ligand A and Ligand B for their potential as DRD2 drug candidates, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (416.159 Da) is slightly higher, but acceptable. Ligand B (354.451 Da) is also good.

**TPSA:** Ligand A (113.56) is borderline for CNS penetration, being slightly above the preferred <90, but still potentially acceptable. Ligand B (93.19) is better, falling comfortably within the desired range for CNS targets.

**logP:** Ligand A (2.552) is optimal. Ligand B (-0.951) is significantly below the optimal range and could indicate poor membrane permeability.

**H-Bond Donors/Acceptors:** Ligand A (0 HBD, 8 HBA) is favorable. Ligand B (2 HBD, 5 HBA) is also acceptable.

**QED:** Both ligands have reasonable QED values (Ligand A: 0.404, Ligand B: 0.575), suggesting reasonable drug-likeness. Ligand B is slightly better.

**DILI:** Both have low DILI risk (Ligand A: 97.984, Ligand B: 8.414), with Ligand B being significantly better.

**BBB:** Ligand A (75.107) has a good BBB percentile, desirable for a CNS target. Ligand B (17.216) has a very poor BBB percentile, a major concern.

**Caco-2 Permeability:** Ligand A (-4.635) has poor Caco-2 permeability, suggesting poor absorption. Ligand B (-5.623) is even worse.

**Aqueous Solubility:** Ligand A (-5.149) has poor aqueous solubility. Ligand B (0.365) is slightly better, but still low.

**hERG Inhibition:** Both have very low hERG inhibition risk (Ligand A: 0.369, Ligand B: 0.026).

**Microsomal Clearance:** Ligand A (103.099) has moderate clearance. Ligand B (2) has very low clearance, indicating good metabolic stability.

**In vitro Half-Life:** Ligand A (43.628 hours) has a reasonable half-life. Ligand B (-14.617 hours) is problematic, indicating rapid metabolism or instability.

**P-gp Efflux:** Ligand A (0.426) has moderate P-gp efflux. Ligand B (0.003) has very low P-gp efflux, which is highly desirable for CNS penetration.

**Binding Affinity:** Ligand A (-8.1 kcal/mol) has significantly better binding affinity than Ligand B (-6.5 kcal/mol). This is a substantial difference (1.6 kcal/mol) and can outweigh some ADME drawbacks.

**Overall Assessment:**

Ligand A has a strong binding affinity and acceptable BBB penetration, but suffers from poor Caco-2 permeability and solubility. Ligand B has better TPSA, DILI, P-gp efflux, and metabolic stability, but its logP is very low, its BBB penetration is extremely poor, and its binding affinity is significantly weaker.

Given the GPCR-specific priorities, and particularly the importance of BBB penetration for a CNS target like DRD2, Ligand A is the more promising candidate *despite* its permeability and solubility issues. The strong binding affinity (-8.1 kcal/mol) is a major advantage that could be addressed through further optimization of physicochemical properties. The poor BBB of Ligand B is a nearly insurmountable obstacle.

Output:
1
2025-04-17 07:03:32,803 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (358.295 Da and 361.467 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Both ligands have TPSA values (71.26 and 71.53) that are acceptable for oral absorption (<140) but slightly higher than optimal for CNS penetration (<90). However, this is not a dealbreaker, especially if other properties are favorable.

**3. logP:** Ligand A (2.816) is within the optimal range (1-3), while Ligand B (1.855) is at the lower end. While lower logP can sometimes indicate permeability issues, it's not a major concern here.

**4. H-Bond Donors:** Both ligands have 1 HBD, which is within the acceptable limit of <=5.

**5. H-Bond Acceptors:** Both ligands have 5 HBA, which is within the acceptable limit of <=10.

**6. QED:** Ligand A (0.833) has a significantly better QED score than Ligand B (0.642), indicating a more drug-like profile.

**7. DILI:** Ligand A (83.715) has a higher DILI risk than Ligand B (64.288). This is a concern for Ligand A.

**8. BBB:** Ligand A (85.459) shows significantly better BBB penetration potential than Ligand B (64.482). This is a crucial advantage for a CNS target like DRD2.

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 values, which is unusual and suggests poor permeability. However, these values can be unreliable and should be interpreted cautiously.

**10. Aqueous Solubility:** Both ligands have negative solubility values, which is also unusual and suggests poor solubility. Again, these values should be interpreted cautiously.

**11. hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.296 and 0.216), which is excellent.

**12. Microsomal Clearance:** Ligand A (37.851) has a higher microsomal clearance than Ligand B (20.107), suggesting lower metabolic stability.

**13. In vitro Half-Life:** Ligand B (-0.034) has a slightly longer in vitro half-life than Ligand A (1.375).

**14. P-gp Efflux:** Both ligands have low P-gp efflux liability (0.132 and 0.247), which is favorable for CNS penetration.

**15. Binding Affinity:** Ligand A (-9.6 kcal/mol) has a significantly stronger binding affinity than Ligand B (-8.4 kcal/mol). This is a substantial advantage, potentially outweighing some of the ADME drawbacks.

**Overall Assessment:**

Ligand A has a superior binding affinity and better BBB penetration, which are critical for a CNS GPCR target. While it has a higher DILI risk and lower metabolic stability, the strong binding affinity could allow for a lower dose, potentially mitigating the DILI risk. Ligand B has a better safety profile (lower DILI, better metabolic stability) but weaker binding affinity and poorer BBB penetration. Given the importance of potency and CNS penetration for DRD2, Ligand A is the more promising candidate.

Output:
1
2025-04-17 07:03:32,803 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight (MW):** Both ligands (374.522 and 349.519 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (66.48) is slightly higher than Ligand B (52.65). Both are below the 90 A^2 threshold desirable for CNS targets, but B is better.

**3. logP:** Both ligands have good logP values (1.884 and 2.118), falling within the optimal 1-3 range.

**4. H-Bond Donors (HBD):** Both have 1 HBD, which is good.

**5. H-Bond Acceptors (HBA):** Both have 3 HBA, which is good.

**6. QED:** Both have good QED scores (0.594 and 0.846), indicating drug-like properties. Ligand B is better.

**7. DILI:** Ligand A (19.542) has a slightly higher DILI risk than Ligand B (9.616), but both are well below the concerning threshold of 60.

**8. BBB:** Ligand A (90.772) has a better BBB percentile than Ligand B (83.56), which is crucial for a CNS target like DRD2.

**9. Caco-2 Permeability:** Ligand A (-4.685) has worse Caco-2 permeability than Ligand B (-4.801). Lower values are less desirable.

**10. Aqueous Solubility:** Both have very poor aqueous solubility (-2.199 and -2.17). This is a significant drawback for both, but not a deciding factor between the two.

**11. hERG Inhibition:** Both ligands have low hERG inhibition risk (0.785 and 0.516).

**12. Microsomal Clearance (Cl_mic):** Ligand A (30.707) has a slightly lower microsomal clearance than Ligand B (32.588), suggesting better metabolic stability.

**13. In vitro Half-Life:** Ligand A (-12.834) has a longer in vitro half-life than Ligand B (-10.661), which is favorable.

**14. P-gp Efflux:** Ligand A (0.41) has lower P-gp efflux than Ligand B (0.057), which is better for CNS penetration.

**15. Binding Affinity:** Both ligands have very similar and excellent binding affinities (-7.7 and -7.8 kcal/mol). The difference is negligible.

**Overall Assessment:**

Ligand A has a better BBB score, lower P-gp efflux, and slightly better metabolic stability and half-life. Ligand B has a better QED and slightly better TPSA. The solubility is poor for both, and the affinity is essentially the same. Given the importance of BBB penetration for a CNS target like DRD2, and the slightly better metabolic profile of Ligand A, I would favor Ligand A.

Output:
0
2025-04-17 07:03:32,803 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (348.447 and 364.471 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (96.25) is slightly higher than Ligand B (84.42). Both are below the 90 A^2 threshold desirable for CNS targets, but Ligand B is preferable.

**3. logP:** Both ligands have optimal logP values (1.752 and 1.632), falling within the 1-3 range.

**4. H-Bond Donors:** Ligand A has 3 HBD, while Ligand B has 1. Both are within the acceptable limit of <=5. Ligand B is preferable.

**5. H-Bond Acceptors:** Ligand A has 5 HBA, and Ligand B has 6. Both are within the acceptable limit of <=10.

**6. QED:** Both ligands have good QED scores (0.624 and 0.821), indicating drug-like properties. Ligand B is better.

**7. DILI:** Ligand A (39.201) has a lower DILI risk than Ligand B (68.282), which is a significant advantage.

**8. BBB:** Ligand A (73.905) has a better BBB penetration percentile than Ligand B (64.211). This is crucial for a CNS target like DRD2.

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.835 and -4.882), which is unusual and suggests poor permeability. This is a concern for both.

**10. Aqueous Solubility:** Both ligands have negative solubility values (-2.507 and -2.71), indicating poor aqueous solubility. This is a concern for both.

**11. hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.191 and 0.168).

**12. Microsomal Clearance:** Ligand A (35.529) has lower microsomal clearance than Ligand B (46.415), suggesting better metabolic stability.

**13. In vitro Half-Life:** Ligand A (19.942) has a longer in vitro half-life than Ligand B (-16.226). This is a significant advantage.

**14. P-gp Efflux:** Both ligands have low P-gp efflux liability (0.159 and 0.152).

**15. Binding Affinity:** Ligand B (-8.8 kcal/mol) has a slightly better binding affinity than Ligand A (-8.1 kcal/mol). This 0.7 kcal/mol difference is significant and can outweigh some ADME drawbacks.

**Overall Assessment:**

While Ligand A has advantages in DILI, BBB, and metabolic stability, Ligand B's superior binding affinity is a critical factor for a GPCR target. The difference in binding affinity is substantial enough to compensate for the slightly higher DILI risk and lower BBB. The poor Caco-2 and solubility are concerns for both, but can be addressed with formulation strategies. Given the GPCR-specific emphasis on affinity, Ligand B is the more promising candidate.

Output:
1
2025-04-17 07:03:32,803 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (354.397 and 359.323 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (49.85) is significantly better than Ligand B (71.09). For CNS targets, we want TPSA <= 90, and ideally closer to 60. Ligand A is much closer to the ideal range.

**3. logP:** Both ligands have good logP values (2.122 and 2.299), falling within the optimal 1-3 range.

**4. H-Bond Donors:** Ligand A (0) is preferable to Ligand B (2). Fewer HBDs generally improve permeability.

**5. H-Bond Acceptors:** Both ligands have 3 HBA, which is acceptable.

**6. QED:** Both ligands have similar QED values (0.754 and 0.734), indicating good drug-likeness.

**7. DILI:** Ligand A (23.536) has a much lower DILI risk than Ligand B (49.283). This is a significant advantage.

**8. BBB:** Ligand A (96.006) has a substantially higher BBB penetration percentile than Ligand B (83.482). This is *critical* for a CNS target like DRD2.

**9. Caco-2 Permeability:** Ligand A (-4.305) is slightly better than Ligand B (-4.884) but both are negative, indicating poor permeability.

**10. Aqueous Solubility:** Ligand A (-2.091) is better than Ligand B (-2.991), but both are poor.

**11. hERG Inhibition:** Ligand A (0.744) has a lower hERG risk than Ligand B (0.343).

**12. Microsomal Clearance:** Ligand A (7.409) has higher clearance than Ligand B (2.281), meaning it's less metabolically stable. This is a drawback for Ligand A.

**13. In vitro Half-Life:** Ligand B (-5.879) has a much longer in vitro half-life than Ligand A (5.936). This is a significant advantage for Ligand B.

**14. P-gp Efflux:** Ligand A (0.098) has lower P-gp efflux than Ligand B (0.049), which is favorable for CNS penetration.

**15. Binding Affinity:** Ligand B (-9.0) has a significantly stronger binding affinity than Ligand A (-7.8). This is a substantial advantage, potentially outweighing some ADME concerns.

**Overall Assessment:**

While Ligand B has a superior binding affinity and better metabolic stability (longer half-life), Ligand A excels in crucial properties for a CNS-targeting GPCR ligand: TPSA, BBB penetration, and lower DILI risk. The difference in binding affinity (-1.2 kcal/mol) is significant, but the substantial improvement in BBB (96 vs 83) and the much lower DILI risk of Ligand A are compelling. The slightly higher clearance of Ligand A is a concern, but could potentially be addressed through structural modifications. Given the GPCR-specific priorities, the superior CNS penetration profile of Ligand A is decisive.

Output:
1
2025-04-17 07:03:32,804 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (374.853 and 359.495 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (79.9) is slightly higher than Ligand B (62.3). Both are below the 90 A^2 threshold desirable for CNS targets, but Ligand B is preferable.

**logP:** Ligand A (4.011) is a bit high, potentially leading to solubility issues and off-target effects. Ligand B (3.25) is within the optimal 1-3 range. This favors Ligand B.

**H-Bond Donors/Acceptors:** Ligand A has 2 HBD and 5 HBA, while Ligand B has 1 HBD and 4 HBA. Both are within acceptable limits.

**QED:** Both ligands have good QED scores (0.637 and 0.825), indicating good drug-like properties.

**DILI:** Ligand A (92.284) has a significantly higher DILI risk than Ligand B (44.436). This is a major concern for Ligand A.

**BBB:** Ligand B (54.866) has a much better BBB penetration percentile than Ligand A (31.02). This is crucial for a CNS target like DRD2 and strongly favors Ligand B.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.305 and -5.035), which is unusual and suggests poor permeability. However, these values are on a log scale, and the absolute difference isn't huge.

**Aqueous Solubility:** Both ligands have negative solubility values (-5.149 and -3.41). This indicates poor aqueous solubility, but Ligand B is slightly better.

**hERG:** Both ligands have low hERG inhibition liability (0.406 and 0.601), which is good.

**Microsomal Clearance:** Ligand A (46.37) has lower microsomal clearance than Ligand B (84.97), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (21.855) has a longer in vitro half-life than Ligand B (12.92), which is desirable.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.508 and 0.287), which is good for CNS penetration.

**Binding Affinity:** Both ligands have strong binding affinities (-9.5 and -8.6 kcal/mol). Ligand A is slightly better (-9.5 kcal/mol), but the difference is less than 1.5 kcal/mol, so it doesn't outweigh the other significant drawbacks.

**Overall Assessment:**

Ligand B is the more promising candidate. While both have poor Caco-2 and solubility, Ligand B excels in crucial areas for a CNS GPCR target: significantly better BBB penetration, lower DILI risk, and a more optimal logP. The slightly better metabolic stability and half-life of Ligand A are not enough to compensate for these critical deficiencies.

Output:
1
2025-04-17 07:03:32,804 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 drug candidates, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (377.868 Da) is slightly higher than Ligand B (344.411 Da), but both are acceptable.

**TPSA:** Ligand A (46.17) is excellent for CNS penetration, well below the 90 A^2 threshold. Ligand B (82.78) is higher, but still potentially acceptable, though less ideal.

**logP:** Ligand A (3.988) is at the upper end of the optimal range (1-3), while Ligand B (2.172) is closer to the lower end. Both are within the acceptable range, but Ligand A's higher logP could lead to off-target effects or solubility issues.

**H-Bond Donors/Acceptors:** Ligand A (HBD=1, HBA=3) and Ligand B (HBD=2, HBA=4) both have reasonable numbers of H-bond donors and acceptors, well within the suggested limits.

**QED:** Both ligands have good QED scores (Ligand A: 0.611, Ligand B: 0.806), indicating a generally drug-like profile. Ligand B is slightly better here.

**DILI:** Ligand A (54.207) has a moderate DILI risk, while Ligand B (34.781) has a low DILI risk. This favors Ligand B.

**BBB:** Ligand A (85.459) has a very good BBB penetration score, exceeding the 70% threshold for CNS targets. Ligand B (56.572) is lower, significantly reducing its potential for CNS activity. This is a major advantage for Ligand A.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.81 and -4.692). These values are unusual and likely indicate issues with the prediction method or the molecule itself. However, we can't definitively say which is better based on this.

**Aqueous Solubility:** Both ligands have negative solubility values (-4.728 and -2.412). Similar to Caco-2, these are problematic and suggest poor solubility. Ligand B is slightly better here.

**hERG Inhibition:** Both ligands have low hERG inhibition liability (Ligand A: 0.412, Ligand B: 0.346), which is favorable.

**Microsomal Clearance:** Ligand A (67.606) has a higher microsomal clearance than Ligand B (26.376), suggesting lower metabolic stability. This favors Ligand B.

**In vitro Half-Life:** Ligand A (-4.829) has a very short predicted half-life, while Ligand B (72.462) has a long half-life. This is a significant advantage for Ligand B.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (Ligand A: 0.443, Ligand B: 0.042). Ligand B is significantly better here, which is crucial for CNS penetration.

**Binding Affinity:** Ligand A (-9.7 kcal/mol) has a significantly stronger binding affinity than Ligand B (-8.7 kcal/mol). This is a substantial advantage for Ligand A, potentially outweighing some of its ADME drawbacks.

**Overall Assessment:**

Ligand A excels in binding affinity and BBB penetration, which are critical for a CNS-targeting GPCR. However, it has concerns regarding DILI risk, metabolic stability (high Cl_mic, short half-life), and potentially solubility. Ligand B has better ADME properties (lower DILI, better metabolic stability, lower P-gp efflux), but significantly weaker binding affinity and lower BBB penetration.

Given the importance of strong binding affinity for GPCRs and the CNS target, the superior affinity of Ligand A is a decisive factor. While its ADME profile isn't ideal, optimization efforts could potentially address those issues. The weaker affinity of Ligand B is a more difficult hurdle to overcome.

Output:
1
2025-04-17 07:03:32,804 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (350.463 and 346.406 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (76.46) is slightly higher than Ligand B (65.54). Both are below the 90 A^2 threshold for CNS targets, which is good. Ligand B is preferable here.

**3. logP:** Both ligands have good logP values (1.368 and 1.74), falling within the optimal 1-3 range. Ligand B is slightly higher, potentially offering better membrane permeability.

**4. H-Bond Donors:** Both have 1 HBD, which is acceptable.

**5. H-Bond Acceptors:** Ligand A has 5 HBA, and Ligand B has 4. Both are below the 10 threshold.

**6. QED:** Both ligands have high QED scores (0.806 and 0.844), indicating good drug-like properties.

**7. DILI:** Ligand A (33.307) has a significantly lower DILI risk than Ligand B (60.915). This is a major advantage for Ligand A.

**8. BBB:** Ligand B (80.031) has a better BBB penetration percentile than Ligand A (73.517). This is crucial for a CNS target like DRD2.

**9. Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and likely indicates a problem with the prediction method. However, the values are similar.

**10. Aqueous Solubility:** Both have negative solubility values, also likely an issue with the prediction. Again, values are similar.

**11. hERG Inhibition:** Both have low hERG inhibition risk (0.347 and 0.431).

**12. Microsomal Clearance:** Both have similar microsomal clearance values (33.324 and 34.223).

**13. In vitro Half-Life:** Ligand B (12.196 hours) has a significantly longer half-life than Ligand A (2.062 hours). This is a substantial advantage for Ligand B.

**14. P-gp Efflux:** Both have very low P-gp efflux liability (0.057 and 0.027).

**15. Binding Affinity:** Ligand B (-8.3 kcal/mol) has a stronger binding affinity than Ligand A (-7.6 kcal/mol). The difference of 0.7 kcal/mol is significant and can outweigh some ADME drawbacks.

**Overall Assessment:**

Ligand B is stronger in terms of affinity and BBB penetration, both critical for a CNS GPCR target. It also has a longer half-life. However, Ligand A has a much lower DILI risk. The affinity difference is significant, and the BBB value for Ligand B is excellent. Considering the importance of CNS penetration for DRD2, and the substantial affinity advantage, the lower DILI risk of Ligand A is less critical than the superior CNS properties and potency of Ligand B.

Output:
1
2025-04-17 07:03:32,804 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (342.355 and 342.439 Da) fall comfortably within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (95.43) is higher than Ligand B (58.64). For a CNS target like DRD2, TPSA should be <=90 for good brain penetration. Ligand A is slightly above this threshold, while Ligand B is well below. This favors Ligand B.

**3. logP:** Both ligands have good logP values (1.653 and 1.488), falling within the optimal 1-3 range.

**4. H-Bond Donors:** Both have 1 HBD, which is within the acceptable limit of <=5.

**5. H-Bond Acceptors:** Ligand A has 8 HBAs, while Ligand B has 3. Both are within the acceptable limit of <=10. Ligand B is significantly lower, which is generally favorable for permeability.

**6. QED:** Both ligands have reasonable QED values (0.753 and 0.608), indicating good drug-like properties.

**7. DILI:** Ligand A has a DILI risk of 80.186, which is considered high risk (>60). Ligand B has a much lower DILI risk of 15.626, which is excellent. This is a significant advantage for Ligand B.

**8. BBB:** Ligand A has a BBB penetration of 43.699%, while Ligand B has 52.811%. While both are not ideal (>70 is desirable for CNS targets), Ligand B is better.

**9. Caco-2 Permeability:** Ligand A (-4.909) and Ligand B (-4.738) both have negative Caco-2 permeability values, indicating poor permeability.

**10. Aqueous Solubility:** Both ligands have very poor aqueous solubility (-2.878 and -2.544). This is a concern for both, but not a deciding factor.

**11. hERG Inhibition:** Both ligands show very low hERG inhibition risk (0.504 and 0.104).

**12. Microsomal Clearance:** Ligand A (35.347) has higher microsomal clearance than Ligand B (12.824), suggesting lower metabolic stability. Ligand B is preferred.

**13. In vitro Half-Life:** Ligand A (7.605) has a longer half-life than Ligand B (3.509). This is a slight advantage for Ligand A.

**14. P-gp Efflux:** Ligand A (0.203) has lower P-gp efflux than Ligand B (0.046), suggesting better CNS exposure. This is a slight advantage for Ligand A.

**15. Binding Affinity:** Ligand B (-8.3 kcal/mol) has a slightly better binding affinity than Ligand A (-9.0 kcal/mol). While A is better, the difference is small and can be overcome by other factors.

**Overall Assessment:**

Ligand B is significantly better due to its lower DILI risk, lower TPSA, lower HBA count, lower microsomal clearance, and better BBB penetration. While Ligand A has a slightly longer half-life and lower P-gp efflux, the substantial advantage of Ligand B in terms of safety (DILI) and CNS penetration (TPSA, BBB) outweighs these minor benefits. The binding affinity difference is small.

Output:
1
2025-04-17 07:03:32,805 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (340.463 and 349.475 Da) fall comfortably within the ideal 200-500 Da range.

**TPSA:** Ligand A (46.53) is significantly better than Ligand B (61.88). For CNS targets, we want TPSA <= 90, and ideally closer to 60. Ligand A is much closer to this ideal.

**logP:** Ligand A (4.503) is higher than the optimal 1-3 range, potentially causing solubility issues, but still manageable. Ligand B (1.005) is quite low, which could hinder permeability.

**H-Bond Donors/Acceptors:** Both have acceptable HBD (1) counts. Ligand B has a slightly higher HBA count (4 vs 3), but both are within the acceptable limit of 10.

**QED:** Both ligands have good QED scores (0.596 and 0.823), indicating drug-like properties.

**DILI:** Ligand A (24.195) has a much lower DILI risk than Ligand B (8.026), which is a significant advantage.

**BBB:** Both ligands have reasonable BBB penetration (66.266 and 63.048). While >70 is desirable, these are not terrible, and the difference isn't huge.

**Caco-2 Permeability:** Both have negative Caco-2 values (-4.505 and -4.835), which is unusual and suggests poor permeability. This is a concern for both.

**Aqueous Solubility:** Both have negative solubility values (-5.591 and -0.891), indicating very poor aqueous solubility. This is a major drawback for both, but potentially more problematic for Ligand A given its higher logP.

**hERG Inhibition:** Ligand A (0.822) has a slightly higher hERG risk than Ligand B (0.172), but both are relatively low.

**Microsomal Clearance:** Ligand A (101.222) has a higher microsomal clearance than Ligand B (1.225), meaning it's less metabolically stable. This is a significant disadvantage for Ligand A.

**In vitro Half-Life:** Ligand B (19.709) has a much longer in vitro half-life than Ligand A (1.823), which is a major advantage.

**P-gp Efflux:** Ligand A (0.848) has slightly higher P-gp efflux liability than Ligand B (0.005), meaning less CNS exposure is expected.

**Binding Affinity:** Ligand A (-9.2 kcal/mol) has a substantially stronger binding affinity than Ligand B (-8.0 kcal/mol). This is a significant advantage for Ligand A, potentially outweighing some of its ADME liabilities. A difference of >1.5 kcal/mol is considered substantial.

**Overall Assessment:**

Ligand A has a much stronger binding affinity, a lower DILI risk, and a better TPSA. However, it suffers from higher logP, higher microsomal clearance, shorter half-life, and higher P-gp efflux. Ligand B has better ADME properties (lower logP, better metabolic stability, longer half-life, lower P-gp efflux), but significantly weaker binding affinity.

Given the GPCR target and the importance of CNS penetration, the strong binding affinity of Ligand A is a critical factor. While its ADME properties are not ideal, optimization efforts could potentially address these issues. The large difference in binding affinity (-9.2 vs -8.0) is a substantial advantage that likely outweighs the ADME concerns, *especially* if the goal is to achieve potent receptor occupancy in the brain.

Output:
1
2025-04-17 07:03:32,805 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (366.4 and 346.4 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (136.55) is slightly above the optimal <90 for CNS targets, but still reasonable. Ligand B (96.11) is excellent, well below 90.

**logP:** Ligand A (0.729) is a bit low, potentially hindering permeability. Ligand B (1.095) is better, still on the lower side but acceptable.

**H-Bond Donors/Acceptors:** Both have 3 HBDs, which is good. Ligand A has 7 HBAs, while Ligand B has 4. Both are within the acceptable range of <=10, but Ligand B is preferable.

**QED:** Both ligands have good QED scores (0.589 and 0.718), indicating good drug-like properties.

**DILI:** Ligand A has a DILI risk of 64.133, which is moderately high. Ligand B has a much lower DILI risk of 31.369, a significant advantage.

**BBB:** Ligand A has a BBB penetration of 69.678%, close to the desirable threshold of >70%. Ligand B has 58.24%, which is lower and less favorable for a CNS target.

**Caco-2:** Both have negative Caco-2 values (-5.795 and -5.512), which is unusual and suggests poor permeability. This is a significant concern for both.

**Solubility:** Both ligands have very poor aqueous solubility (-2.408 and -2.152). This is a major drawback for both compounds.

**hERG:** Both ligands have low hERG inhibition risk (0.326 and 0.129).

**Cl_mic:** Ligand A has a moderate microsomal clearance (47.428), while Ligand B has very low clearance (0.24), indicating better metabolic stability.

**t1/2:** Ligand A has a negative in vitro half-life (-18.268), which is problematic. Ligand B has a short half-life (5.155), but it's positive and better than Ligand A.

**Pgp:** Ligand A has a low Pgp efflux liability (0.099), which is good for CNS penetration. Ligand B also has very low Pgp efflux (0.01), which is even better.

**Binding Affinity:** Ligand B (-8.6 kcal/mol) has a significantly stronger binding affinity than Ligand A (-7.8 kcal/mol). This 0.8 kcal/mol difference is substantial and can outweigh some of the ADME drawbacks.

**Overall Assessment:**

Ligand B is the stronger candidate. While both have solubility and Caco-2 permeability issues, Ligand B has a significantly better binding affinity, lower DILI risk, and better metabolic stability. The lower BBB penetration is a concern, but the superior affinity and other favorable properties make it more promising. Ligand A's higher DILI risk and negative half-life are major drawbacks.

Output:
1
2025-04-17 07:03:32,805 - INFO - Reasoning:

Let's analyze Ligand A and Ligand B against the provided guidelines, prioritizing GPCR-specific properties (BBB, logP, Pgp, TPSA, and affinity) for DRD2.

**Molecular Weight:** Both ligands (345.443 and 343.395 Da) fall comfortably within the ideal 200-500 Da range.

**TPSA:** Ligand A (82.27) is excellent, well below the 90 A^2 threshold for CNS targets. Ligand B (118.6) is higher, but still potentially acceptable, though less ideal.

**logP:** Ligand A (1.554) is within the optimal 1-3 range. Ligand B (0.696) is slightly below 1, which could potentially hinder permeation, but isn't a major concern.

**H-Bond Donors/Acceptors:** Ligand A (2 HBD, 3 HBA) and Ligand B (3 HBD, 10 HBA) both fall within acceptable limits (<=5 HBD, <=10 HBA). Ligand B's higher HBA count might slightly impact permeability.

**QED:** Both ligands have reasonable QED scores (0.821 and 0.511), indicating good drug-like properties. Ligand A is better.

**DILI:** Ligand A (24.04) has a significantly lower DILI risk than Ligand B (77.782), which is a substantial advantage.

**BBB:** This is a critical parameter for DRD2. Ligand A (77.549) has a good BBB percentile, exceeding the 70% threshold. Ligand B (46.413) is considerably lower, raising concerns about CNS penetration.

**Caco-2 Permeability:** Both have negative values, which is unusual. Assuming these are logP values, they suggest poor permeability.

**Aqueous Solubility:** Both have negative values, which is also unusual. Assuming these are logS values, they suggest poor solubility.

**hERG:** Both ligands have low hERG inhibition liability (0.598 and 0.608), which is positive.

**Microsomal Clearance:** Ligand A (8.722) has a lower microsomal clearance than Ligand B (17.949), indicating better metabolic stability.

**In vitro Half-Life:** Ligand A (-22.592) has a much longer in vitro half-life than Ligand B (26.848).

**P-gp Efflux:** Ligand A (0.106) has lower P-gp efflux liability than Ligand B (0.028), suggesting better CNS exposure.

**Binding Affinity:** Ligand A (-8.8 kcal/mol) has a significantly stronger binding affinity than Ligand B (-7.5 kcal/mol). This 1.3 kcal/mol difference is substantial and can outweigh minor ADME drawbacks.

**Overall Assessment:**

Ligand A is clearly superior. It excels in critical GPCR parameters like BBB penetration, binding affinity, and metabolic stability. It also has a much lower DILI risk. While both have unusual solubility and permeability data, the other advantages of Ligand A make it the more promising candidate.

Output:
1
2025-04-17 07:03:32,805 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (345.403 and 349.431 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (95.5) is better than Ligand B (104.46). Both are below the 140 A^2 threshold for oral absorption, and Ligand A is closer to the desirable <90 A^2 for CNS targets.

**3. logP:** Ligand B (1.585) is better than Ligand A (0.127). Ligand A's logP is quite low, potentially hindering membrane permeability. Ligand B is within the optimal 1-3 range.

**4. H-Bond Donors:** Ligand A (1) is better than Ligand B (3). Lower HBD generally improves permeability.

**5. H-Bond Acceptors:** Both ligands have the same number of HBA (5), which is acceptable (<=10).

**6. QED:** Ligand A (0.84) is significantly better than Ligand B (0.628), indicating a more drug-like profile.

**7. DILI:** Ligand B (42.575) has a lower DILI risk than Ligand A (54.285), which is preferable.

**8. BBB:** Ligand A (64.095) has a better BBB penetration percentile than Ligand B (58.821), which is critical for a CNS target like DRD2.

**9. Caco-2 Permeability:** Ligand A (-5.058) has better Caco-2 permeability than Ligand B (-4.797), indicating better intestinal absorption.

**10. Aqueous Solubility:** Ligand B (-3.234) has better aqueous solubility than Ligand A (-1.542).

**11. hERG Inhibition:** Ligand A (0.073) has a lower hERG inhibition liability than Ligand B (0.166), which is desirable.

**12. Microsomal Clearance:** Ligand A (-1.071) has a lower (better) microsomal clearance than Ligand B (44.35). This suggests better metabolic stability for Ligand A.

**13. In vitro Half-Life:** Ligand B (-9.9) has a longer in vitro half-life than Ligand A (0.298).

**14. P-gp Efflux:** Ligand A (0.007) has much lower P-gp efflux liability than Ligand B (0.12). Lower P-gp efflux is crucial for CNS penetration.

**15. Binding Affinity:** Ligand A (-8.9 kcal/mol) has a slightly better binding affinity than Ligand B (-8.1 kcal/mol). While both are strong binders, the 1.5 kcal/mol difference is significant.

**Overall Assessment:**

Ligand A excels in several key areas for a CNS-targeting GPCR ligand: TPSA, BBB, P-gp efflux, metabolic stability (Cl_mic), hERG, and binding affinity. While Ligand B has better logP and solubility, the superior CNS penetration profile of Ligand A, coupled with its strong binding affinity and lower off-target liabilities, makes it the more promising candidate. The low logP of Ligand A is a concern, but the strong affinity and excellent BBB penetration may compensate.

Output:
1
2025-04-17 07:03:32,805 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (354.841 and 357.426 Da) fall comfortably within the ideal 200-500 Da range.

**TPSA:** Ligand A (60.23) is excellent, well below the 90 A^2 threshold for CNS targets. Ligand B (87.74) is still reasonable but closer to the upper limit, potentially impacting BBB penetration.

**logP:** Ligand A (3.059) is optimal. Ligand B (0.239) is quite low, which could hinder membrane permeability and reduce CNS exposure.

**H-Bond Donors/Acceptors:** Ligand A (0 HBD, 4 HBA) and Ligand B (2 HBD, 4 HBA) both have acceptable numbers of H-bond donors and acceptors.

**QED:** Both ligands have similar QED values (0.85 and 0.713), indicating good drug-likeness.

**DILI:** Ligand A (71.19) has a higher DILI risk than Ligand B (22.257), which is a significant concern.

**BBB:** Ligand B (76.464) has a better BBB percentile than Ligand A (66.188), which is crucial for CNS targets like DRD2.

**Caco-2 Permeability:** Both have negative Caco-2 values (-4.666 and -4.764), which is unusual and suggests poor permeability. However, these values are on a log scale and can be misleading.

**Aqueous Solubility:** Both have negative solubility values (-3.948 and -1.574), which is also unusual and suggests poor solubility.

**hERG:** Ligand A (0.703) has a slightly higher hERG risk than Ligand B (0.174), but both are relatively low.

**Microsomal Clearance:** Ligand B (6.931) has significantly lower microsomal clearance than Ligand A (43.216), indicating better metabolic stability.

**In vitro Half-Life:** Ligand B (-7.049) has a longer in vitro half-life than Ligand A (-3.651).

**P-gp Efflux:** Ligand A (0.276) has lower P-gp efflux liability than Ligand B (0.007), which is favorable for CNS penetration.

**Binding Affinity:** Ligand B (-7.9 kcal/mol) has a significantly stronger binding affinity than Ligand A (-9.4 kcal/mol). This is a substantial advantage, potentially outweighing some of the ADME drawbacks.

**Overall Assessment:**

While Ligand A has a better P-gp profile, Ligand B is superior in most critical aspects for a CNS-targeting GPCR ligand. Specifically, its significantly stronger binding affinity, better BBB penetration, lower DILI risk, and improved metabolic stability (lower Cl_mic and longer t1/2) are highly desirable. The lower logP of Ligand B is a concern, but the strong affinity might compensate for this. The unusual Caco-2 and solubility values are concerning and would need further investigation. However, considering the GPCR-specific priorities, Ligand B appears to be the more promising candidate.

Output:
1
2025-04-17 07:03:32,806 - INFO - Batch 333 complete. Total preferences: 5328
2025-04-17 07:03:32,806 - INFO - Processing batch 334/512...
2025-04-17 07:04:13,814 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (354.491 and 367.833 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (78.87) is significantly better than Ligand B (92.51). For CNS targets, we want TPSA <= 90, so Ligand A is preferable.

**logP:** Both ligands have good logP values (1.562 and 1.077), falling within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A (2 HBD, 4 HBA) is slightly better than Ligand B (1 HBD, 5 HBA) in terms of balancing solubility and permeability, although both are acceptable.

**QED:** Both ligands have similar QED values (0.759 and 0.728), indicating good drug-like properties.

**DILI:** Ligand A (16.285) has a much lower DILI risk than Ligand B (36.797). This is a significant advantage for Ligand A.

**BBB:** Ligand A (70.609) has a better BBB penetration percentile than Ligand B (65.452). While both are reasonably good, exceeding 70 is desirable for CNS targets, and A is closer.

**Caco-2 Permeability:** Ligand A (-4.449) has a much better Caco-2 permeability than Ligand B (-5.18). Higher values indicate better intestinal absorption.

**Aqueous Solubility:** Ligand A (-1.525) has better aqueous solubility than Ligand B (-2.16).

**hERG Inhibition:** Ligand A (0.208) has a lower hERG inhibition liability than Ligand B (0.05). This is a significant advantage for Ligand A.

**Microsomal Clearance:** Ligand B (6.221) has a lower microsomal clearance than Ligand A (29.48). Lower clearance indicates better metabolic stability, favoring Ligand B.

**In vitro Half-Life:** Ligand B (-11.987) has a significantly longer in vitro half-life than Ligand A (-0.75). This is a strong advantage for Ligand B.

**P-gp Efflux:** Ligand A (0.036) has lower P-gp efflux liability than Ligand B (0.067), which is preferable for CNS exposure.

**Binding Affinity:** Ligand B (-8.5 kcal/mol) has a stronger binding affinity than Ligand A (-7.0 kcal/mol). This is a substantial advantage for Ligand B, potentially outweighing some ADME drawbacks. The difference is >1.5 kcal/mol.

**Overall Assessment:**

While Ligand B has superior binding affinity and metabolic stability (lower Cl_mic, longer t1/2), Ligand A demonstrates a more favorable ADME profile overall, particularly regarding TPSA, DILI, BBB, Caco-2 permeability, solubility, and hERG. The stronger affinity of Ligand B is a significant plus, but the improved safety and CNS penetration potential of Ligand A are crucial for a CNS target like DRD2. Considering the GPCR-specific priorities, the better BBB and lower toxicity profile of Ligand A are very important.

Output:
1
2025-04-17 07:04:13,814 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (353.419 and 344.415 Da) fall within the ideal 200-500 Da range.

**TPSA:** Both ligands have TPSA values (99.18 and 94.56) that are acceptable for oral absorption (<140), but a bit high for optimal CNS penetration (<90).

**logP:** Both ligands have low logP values (0.121 and 0.213), which is a concern. Values between 1-3 are preferred for good permeability and avoiding off-target effects. These are both quite low and could hinder brain penetration.

**H-Bond Donors/Acceptors:** Ligand A (2 HBD, 5 HBA) and Ligand B (3 HBD, 5 HBA) both have reasonable numbers of hydrogen bond donors and acceptors, staying within the guidelines.

**QED:** Both ligands have QED values (0.661 and 0.615) above 0.5, indicating good drug-like properties.

**DILI:** Ligand A (19.426) has a slightly higher DILI risk than Ligand B (13.571), but both are below the concerning threshold of 40, indicating low liver injury risk.

**BBB:** This is a critical parameter for a CNS target like DRD2. Ligand A (51.687) has a significantly better BBB percentile than Ligand B (35.595). While neither is *ideal* (>70), Ligand A is considerably better.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.953 and -5.607), which is unusual and suggests very poor intestinal absorption. This is a significant drawback for both.

**Aqueous Solubility:** Both ligands have very poor aqueous solubility (-0.928 and -1.466). This is a major issue for formulation and bioavailability.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.242 and 0.077), which is positive.

**Microsomal Clearance:** Ligand B (-9.662) has a lower (better) microsomal clearance than Ligand A (-4.284), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand B (-0.755) has a slightly better in vitro half-life than Ligand A (-19.599), although both are very poor.

**P-gp Efflux:** Both ligands show very low P-gp efflux liability (0.011 and 0.005), which is favorable for CNS penetration.

**Binding Affinity:** Both ligands have excellent binding affinities (-8.0 and -8.5 kcal/mol), with Ligand B being slightly more potent. However, the affinity difference (0.5 kcal/mol) is unlikely to overcome the significant ADME deficiencies.

**Conclusion:**

Despite the similar binding affinities, **Ligand A** is the more promising candidate. The primary driver is its significantly better BBB penetration (51.687 vs. 35.595). While both have poor logP and solubility, the BBB is a crucial factor for CNS targets. The slightly better DILI profile of Ligand B is overshadowed by its poorer BBB penetration. Both compounds require significant optimization to improve solubility, permeability, and logP, but Ligand A provides a better starting point due to its improved chance of reaching the target in the brain.

Output:
0
2025-04-17 07:04:13,814 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (395.26 Da) is slightly higher than Ligand B (350.459 Da), but both are acceptable.

**TPSA:** Ligand A (71.92) is better than Ligand B (81.08) as it is closer to the <90 A^2 threshold for CNS targets.

**logP:** Ligand A (4.392) is higher than the optimal range (1-3), potentially causing solubility and off-target issues. Ligand B (1.092) is slightly below the optimal range, which might affect permeation, but is less concerning than Ligand A's high logP.

**H-Bond Donors/Acceptors:** Both ligands have 2 HBDs, which is good. Ligand A has 2 HBAs, while Ligand B has 4. Both are within acceptable limits (<=10).

**QED:** Both ligands have similar QED values (0.642 and 0.703), indicating good drug-likeness.

**DILI:** Ligand A (89.88) has a significantly higher DILI risk than Ligand B (13.339). This is a major concern for Ligand A.

**BBB:** Ligand A (71.888) has a better BBB penetration percentile than Ligand B (60.876), which is crucial for a CNS target like DRD2.

**Caco-2 Permeability:** Ligand A (-5.037) has poor Caco-2 permeability, while Ligand B (-4.689) is also not great, but slightly better.

**Aqueous Solubility:** Ligand A (-6.426) has very poor aqueous solubility, which is a significant drawback. Ligand B (-1.628) is better, but still not ideal.

**hERG Inhibition:** Ligand A (0.877) has a slightly higher hERG inhibition risk than Ligand B (0.279).

**Microsomal Clearance:** Ligand A (61.383) has higher microsomal clearance than Ligand B (15.938), indicating lower metabolic stability.

**In vitro Half-Life:** Ligand A (96.6) has a much longer in vitro half-life than Ligand B (-11.504).

**P-gp Efflux:** Ligand A (0.652) has lower P-gp efflux than Ligand B (0.135), which is favorable for CNS penetration.

**Binding Affinity:** Ligand A (-9.7 kcal/mol) has a significantly stronger binding affinity than Ligand B (-7.6 kcal/mol). This is a substantial advantage.

**Overall Assessment:**

Ligand A has a much stronger binding affinity and better BBB penetration and P-gp efflux, but suffers from high DILI risk, poor solubility, and poor Caco-2 permeability. Ligand B has a better safety profile (lower DILI, hERG), better solubility, and slightly better Caco-2 permeability, but weaker binding affinity and lower BBB penetration.

Given the importance of binding affinity for GPCRs, and the fact that the difference in affinity (-9.7 vs -7.6) is substantial (a >2 kcal/mol advantage), I believe Ligand A is the more promising candidate *despite* its drawbacks. The poor solubility and permeability could potentially be addressed through formulation strategies. The DILI risk is concerning, but could be investigated further with more detailed studies. The strong binding affinity is a significant advantage that could outweigh the ADME liabilities.

Output:
1
2025-04-17 07:04:13,815 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (341.411 and 368.459 Da) fall within the ideal 200-500 Da range.

**TPSA:** Both ligands have TPSA values around 93.5, which is acceptable but borderline for CNS penetration. Ideally, we'd prefer <90.

**logP:** Ligand A (1.77) is optimal, while Ligand B (-0.271) is below the preferred range and could have permeability issues.

**H-Bond Donors/Acceptors:** Ligand A (3 HBD, 3 HBA) is good. Ligand B (1 HBD, 7 HBA) is also acceptable, though the higher HBA count might slightly impact permeability.

**QED:** Both ligands have good QED scores (0.683 and 0.712), indicating drug-like properties.

**DILI:** Ligand A (42.458) has a lower DILI risk than Ligand B (60.644), which is a significant advantage.

**BBB:** Ligand A (77.2) has a substantially better BBB percentile than Ligand B (50.407). This is *critical* for a CNS target like DRD2.

**Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and suggests poor permeability. However, the scale is not specified, so it is difficult to interpret.

**Aqueous Solubility:** Both have negative solubility values, which is also unusual and suggests poor solubility.

**hERG:** Both ligands have very low hERG inhibition liability (0.339 and 0.04), which is excellent.

**Microsomal Clearance:** Both have similar, relatively low, microsomal clearance values (25.217 and 23.227 mL/min/kg), indicating reasonable metabolic stability.

**In vitro Half-Life:** Ligand A (24.111 hours) has a much longer half-life than Ligand B (-27.652 hours). The negative value for Ligand B is concerning and likely indicates rapid degradation.

**P-gp Efflux:** Both have low P-gp efflux liability (0.036 and 0.011), which is favorable for CNS penetration.

**Binding Affinity:** Ligand A (-8.3 kcal/mol) has a slightly better binding affinity than Ligand B (-7.6 kcal/mol). While the difference is not huge, it's still a positive factor.

**Overall Assessment:**

Ligand A is significantly better than Ligand B. The key advantages of Ligand A are its superior BBB penetration, lower DILI risk, and longer half-life. While both have issues with Caco-2 and solubility, the BBB is paramount for a CNS target. Ligand B's negative half-life is a major red flag. The slightly better affinity of Ligand A further solidifies its position as the more promising candidate.

Output:
1
2025-04-17 07:04:13,815 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (369.422 Da) is slightly higher than Ligand B (343.471 Da), but both are acceptable.

**TPSA:** Ligand A (126.21) is borderline for CNS penetration, being above the preferred <90 threshold. Ligand B (65.2) is well within the ideal range for CNS targets. This is a significant advantage for Ligand B.

**logP:** Ligand A (-0.176) is quite low, potentially hindering membrane permeability. Ligand B (2.899) is almost ideal. This is a major advantage for Ligand B.

**H-Bond Donors/Acceptors:** Ligand A has 4 HBD and 6 HBA, which are acceptable. Ligand B has 2 HBD and 2 HBA, which are also acceptable and potentially more favorable for permeability.

**QED:** Both ligands have good QED scores (Ligand A: 0.554, Ligand B: 0.808), indicating good drug-like properties. Ligand B is better.

**DILI:** Ligand A (69.329) has a higher DILI risk than Ligand B (43.389), though both are below the concerning 60 threshold.

**BBB:** Ligand A (68.399) is borderline for good CNS penetration. Ligand B (74.254) is better, exceeding the 70% threshold. This is a crucial advantage for a CNS target like DRD2.

**Caco-2 Permeability:** Both have negative values, indicating poor permeability. Ligand A (-5.837) is worse than Ligand B (-4.974).

**Aqueous Solubility:** Both have negative values, indicating poor solubility. Ligand A (-2.178) is slightly better than Ligand B (-3.918).

**hERG Inhibition:** Both have low hERG inhibition risk (Ligand A: 0.183, Ligand B: 0.361).

**Microsomal Clearance:** Ligand A (-11.823) has significantly lower (better) microsomal clearance than Ligand B (44.224), suggesting greater metabolic stability.

**In vitro Half-Life:** Ligand A (-5.04) has a shorter half-life than Ligand B (-23.332).

**P-gp Efflux:** Ligand A (0.021) has very low P-gp efflux, which is good for CNS penetration. Ligand B (0.239) is slightly higher, but still acceptable.

**Binding Affinity:** Ligand A (-8.2 kcal/mol) has a significantly stronger binding affinity than Ligand B (-9.0 kcal/mol). This is a substantial advantage for Ligand A.

**Overall Assessment:**

While Ligand A has a superior binding affinity and better metabolic stability, Ligand B excels in several critical properties for a CNS-targeting GPCR ligand: lower TPSA, optimal logP, better BBB penetration, and a better QED score. The significantly better logP and BBB of Ligand B are particularly important for DRD2, outweighing the affinity advantage of Ligand A. The poor Caco-2 and solubility for both are concerning, but can be addressed through formulation strategies.

Output:
1
2025-04-17 07:04:13,815 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (356.419 and 348.443 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (110.8) is higher than the preferred <90 for CNS targets, while Ligand B (59.08) is well within the optimal range. This is a significant advantage for Ligand B.

**logP:** Ligand A (0.682) is a bit low, potentially hindering permeation. Ligand B (1.207) is better, falling within the 1-3 optimal range.

**H-Bond Donors/Acceptors:** Ligand A has 2 HBD and 6 HBA, which are acceptable. Ligand B has 0 HBD and 4 HBA, also acceptable.

**QED:** Both ligands have good QED scores (0.557 and 0.649), indicating drug-like properties.

**DILI:** Ligand A (58.666) has a moderate DILI risk, while Ligand B (22.722) has a low DILI risk. This favors Ligand B.

**BBB:** Ligand A (46.026) has a low BBB penetration percentile, which is a major drawback for a CNS target like DRD2. Ligand B (77.976) has a very good BBB penetration percentile, a significant advantage.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.13 and -4.692), which is unusual and suggests poor permeability. However, these values are on a log scale, and the absolute values are similar.

**Aqueous Solubility:** Both ligands have negative solubility values (-2.115 and -1.658), indicating poor aqueous solubility. This could pose formulation challenges.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.104 and 0.336).

**Microsomal Clearance:** Ligand A (19.655) has lower microsomal clearance than Ligand B (43.3), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (-0.508) has a slightly longer in vitro half-life than Ligand B (1.92), but both are negative, which is unusual.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.064 and 0.079), which is favorable for CNS penetration.

**Binding Affinity:** Ligand B (-7.9 kcal/mol) has a slightly better binding affinity than Ligand A (-7.4 kcal/mol), although the difference is relatively small.

**Overall Assessment:**

Ligand B is significantly better suited as a DRD2 ligand due to its superior BBB penetration (77.976 vs 46.026), lower DILI risk (22.722 vs 58.666), and more favorable TPSA (59.08 vs 110.8). While Ligand A has slightly better metabolic stability and half-life, the CNS-related properties of Ligand B are far more critical for a DRD2 target. The slightly better affinity of Ligand B further supports this conclusion.

Output:
1
2025-04-17 07:04:13,815 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (348.407 and 368.459 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (136.06) is slightly above the optimal <90 for CNS targets, but still reasonable. Ligand B (101.49) is well within the desired range.

**logP:** Ligand A (0.924) is a bit low, potentially hindering permeation. Ligand B (0.346) is even lower, raising more concerns about permeability.

**H-Bond Donors/Acceptors:** Ligand A (HBD=3, HBA=4) is better balanced. Ligand B (HBD=1, HBA=6) is acceptable, but the higher HBA count could slightly impact permeability.

**QED:** Ligand B (0.745) has a significantly better QED score than Ligand A (0.26), indicating a more drug-like profile.

**DILI:** Ligand A (30.942) has a much lower DILI risk than Ligand B (66.499), which is a significant advantage.

**BBB:** Ligand B (75.029) has a substantially better BBB penetration score than Ligand A (54.168), which is crucial for a CNS target like DRD2.

**Caco-2 Permeability:** Ligand A (-5.671) has a worse Caco-2 permeability than Ligand B (-4.74). Both are negative, indicating poor permeability.

**Aqueous Solubility:** Ligand A (-1.923) has better aqueous solubility than Ligand B (-3.097).

**hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.102 and 0.258 respectively).

**Microsomal Clearance:** Ligand A (-0.869) has a lower (better) microsomal clearance than Ligand B (43.223), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (13.301) has a better in vitro half-life than Ligand B (-52.89).

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.005 and 0.044 respectively).

**Binding Affinity:** Both ligands have similar binding affinities (-8.7 and -8.2 kcal/mol), which are both excellent. The difference of 0.5 kcal/mol is not substantial enough to be the deciding factor.

**Overall Assessment:**

While Ligand A has better DILI, metabolic stability, and half-life, Ligand B excels in BBB penetration and QED, both of which are critical for CNS GPCR targets. The significantly better BBB score of Ligand B outweighs the advantages of Ligand A, especially considering the similar binding affinities. The lower logP of Ligand B is a concern, but the strong BBB penetration suggests it can overcome this limitation.

Output:
1
2025-04-17 07:04:13,816 - INFO - Reasoning:

Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (393.531 and 345.487 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (117.85) is borderline for CNS penetration, slightly above the preferred <90, but potentially acceptable. Ligand B (75.43) is excellent for CNS penetration.

**3. logP:** Ligand A (-0.584) is a bit low, potentially hindering membrane permeability. Ligand B (3.146) is optimal.

**4. H-Bond Donors:** Ligand A (1) and Ligand B (2) are both within the acceptable limit of <=5.

**5. H-Bond Acceptors:** Ligand A (5) and Ligand B (3) are both within the acceptable limit of <=10.

**6. QED:** Both ligands (0.621 and 0.561) have good drug-likeness scores, exceeding the 0.5 threshold.

**7. DILI:** Both ligands have low DILI risk (31.718 and 30.826), both well below the 40 threshold.

**8. BBB:** Ligand B (71.772) has a significantly better BBB percentile than Ligand A (58.511). Both are acceptable, but B is preferred for a CNS target.

**9. Caco-2:** Both have negative values, which is unusual. Assuming these are log scale values, lower values indicate poorer permeability. Both are poor.

**10. Solubility:** Both have negative values, which is unusual. Assuming these are log scale values, lower values indicate poorer solubility. Both are poor.

**11. hERG:** Ligand A (0.125) has a very low hERG risk, which is excellent. Ligand B (0.771) has a slightly higher, but still acceptable, hERG risk.

**12. Cl_mic:** Ligand A (-1.033) has a negative clearance, which is unusual and suggests very high metabolic stability. Ligand B (53.532) has a moderate clearance.

**13. t1/2:** Ligand A (-17.072) has a negative half-life, which is impossible. This is a red flag. Ligand B (10.05) has a reasonable in vitro half-life.

**14. Pgp:** Ligand A (0.02) has very low P-gp efflux, which is excellent for CNS penetration. Ligand B (0.107) also has low P-gp efflux.

**15. Binding Affinity:** Ligand B (-7.9 kcal/mol) has a slightly better binding affinity than Ligand A (-7.3 kcal/mol), although both are good.

**Overall Assessment:**

Ligand A has several concerning properties: a low logP, a negative in vitro half-life, and a negative microsomal clearance. These are likely errors or indicate significant issues with the molecule. While its Pgp and hERG are excellent, the other issues outweigh these benefits.

Ligand B, while not perfect, presents a much more viable profile. It has a good logP, acceptable TPSA, good BBB penetration, reasonable metabolic stability, and a slightly better binding affinity.

Output:
1
2025-04-17 07:04:13,816 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (354.535 Da and 366.487 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (49.85) is excellent, well below the 90 A^2 threshold for CNS targets. Ligand B (79.74) is higher but still potentially acceptable, though less ideal.

**logP:** Ligand A (3.323) is optimal (1-3). Ligand B (1.402) is on the lower side, potentially hindering membrane permeability.

**H-Bond Donors/Acceptors:** Ligand A (0 HBD, 3 HBA) is favorable. Ligand B (2 HBD, 8 HBA) is acceptable, but the higher HBA count could slightly impact permeability.

**QED:** Both ligands have good QED scores (0.761 and 0.81), indicating drug-like properties.

**DILI:** Ligand A (26.095) has a very low DILI risk. Ligand B (60.217) is approaching a moderate risk, but not alarming.

**BBB:** Ligand A (81.776) has excellent BBB penetration potential. Ligand B (69.678) is lower, which is a significant drawback for a CNS target like DRD2.

**Caco-2 Permeability:** Ligand A (-4.122) has poor Caco-2 permeability, which is concerning. Ligand B (-5.095) is even worse.

**Aqueous Solubility:** Both ligands have very poor aqueous solubility (-2.919 and -2.719). This is a significant formulation challenge.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.368 and 0.598).

**Microsomal Clearance:** Ligand A (80.372) has higher microsomal clearance, suggesting faster metabolism. Ligand B (47.701) is better in this regard, indicating greater metabolic stability.

**In vitro Half-Life:** Ligand B (43.011) has a significantly longer in vitro half-life than Ligand A (11.166).

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.093 and 0.045), which is good for CNS penetration.

**Binding Affinity:** Ligand B (-7.8 kcal/mol) has a substantially stronger binding affinity than Ligand A (-6.8 kcal/mol). This 1.0 kcal/mol difference is significant and can outweigh some ADME drawbacks.

**Overall Assessment:**

While Ligand A has better TPSA and DILI, its poor Caco-2 permeability and lower binding affinity are major concerns. Ligand B, despite the slightly higher TPSA and DILI, possesses a significantly stronger binding affinity and a longer half-life. The biggest drawback for Ligand B is the lower BBB penetration, but the strong binding affinity is a critical factor for GPCRs. The poor solubility of both compounds is a shared issue that would need to be addressed in formulation. Given the importance of affinity for GPCR targets, and the relatively acceptable BBB score for Ligand B, it is the more promising candidate.

Output:
1
2025-04-17 07:04:13,816 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (355.454 and 348.399 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (61.88) is significantly better than Ligand B (92.01). For CNS targets, we want TPSA <= 90, so Ligand A is preferable.

**3. logP:** Both ligands have acceptable logP values (1.67 and 0.575), falling within the 1-3 range. Ligand A is slightly better.

**4. H-Bond Donors:** Both ligands are acceptable (1 and 2, respectively), well below the threshold of 5.

**5. H-Bond Acceptors:** Both ligands are acceptable (4 and 5, respectively), below the threshold of 10.

**6. QED:** Both ligands have good QED scores (0.531 and 0.555), indicating good drug-like properties.

**7. DILI:** Both ligands have low DILI risk (28.189 and 20.512 percentiles), which is favorable.

**8. BBB:** Ligand A (86.545) has a much better BBB penetration percentile than Ligand B (46.568). This is *critical* for a CNS target like DRD2.

**9. Caco-2 Permeability:** Both have negative values, which is unusual and suggests poor permeability. However, the scale isn't specified, so it's hard to interpret.

**10. Aqueous Solubility:** Both have negative values, indicating poor solubility.

**11. hERG Inhibition:** Both ligands have low hERG inhibition risk (0.485 and 0.361 percentiles), which is good.

**12. Microsomal Clearance:** Ligand B (-9.851) has a much lower (better) microsomal clearance than Ligand A (4.931). This suggests greater metabolic stability for Ligand B.

**13. In vitro Half-Life:** Ligand B (0.375) has a slightly better in vitro half-life than Ligand A (-2.922).

**14. P-gp Efflux:** Both ligands have low P-gp efflux liability (0.078 and 0.151 percentiles), which is favorable for CNS penetration.

**15. Binding Affinity:** Ligand A (-8.2 kcal/mol) has a significantly stronger binding affinity than Ligand B (-7.2 kcal/mol). This ~1.0 kcal/mol difference is substantial and can outweigh some ADME drawbacks.

**Overall Assessment:**

Ligand A is the stronger candidate. While Ligand B has better metabolic stability and half-life, Ligand A's superior BBB penetration and significantly stronger binding affinity are crucial for a CNS GPCR target. The TPSA is also much better for Ligand A. The solubility and Caco-2 permeability are poor for both, but the binding affinity and BBB are the most important factors here.

Output:
1
2025-04-17 07:04:13,816 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (358.467 and 357.451 Da) fall within the ideal range of 200-500 Da.

**TPSA:** Ligand A (83.98) is excellent, being below the 90 A^2 threshold for CNS targets. Ligand B (107.97) is still reasonable but less optimal, being above 90 A^2.

**logP:** Ligand A (2.216) is within the optimal 1-3 range. Ligand B (-0.348) is below 1, which could hinder permeation.

**H-Bond Donors/Acceptors:** Both have acceptable HBD (2/3) and HBA (5/5) counts, well within the guidelines.

**QED:** Ligand A (0.758) has a better QED score than Ligand B (0.495), indicating superior drug-likeness.

**DILI:** Ligand A (45.522) has a lower DILI risk than Ligand B (15.626), which is preferable.

**BBB:** Ligand A (62.117) has a better BBB percentile than Ligand B (25.979). While >70 is desirable, 62.117 is still a reasonable starting point, especially considering the affinity difference.

**Caco-2 Permeability:** Both have negative Caco-2 values (-5.624 and -5.166), which is unusual and suggests poor permeability. This is a significant concern for both.

**Aqueous Solubility:** Both have negative solubility values (-2.475 and -1.072), indicating poor aqueous solubility. This could pose formulation challenges.

**hERG Inhibition:** Both ligands show very low hERG inhibition risk (0.053 and 0.105).

**Microsomal Clearance:** Ligand A (27.274) has a higher microsomal clearance than Ligand B (15.552), suggesting lower metabolic stability.

**In vitro Half-Life:** Ligand B (0.047) has a very short half-life, while Ligand A (24.252) is much better.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.099 and 0.009).

**Binding Affinity:** Ligand A (-9.1 kcal/mol) has a significantly stronger binding affinity than Ligand B (-7.7 kcal/mol). This is a >1.5 kcal/mol advantage, which can outweigh some ADME drawbacks.

**Overall Assessment:**

Ligand A is the stronger candidate. Its superior binding affinity, better BBB penetration, lower DILI risk, and better QED score are significant advantages. While both have poor Caco-2 and solubility, the strong binding affinity of Ligand A makes it more likely to be optimized to overcome these issues. The better half-life of Ligand A is also a plus. Ligand B's low logP and very short half-life are major drawbacks.

Output:
1
2025-04-17 07:04:13,816 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (391.23 and 372.466 Da) fall within the ideal 200-500 Da range.

**TPSA:** Both ligands (97.55 and 98.58) are close to the 90 A^2 threshold for CNS targets, but still acceptable.

**logP:** Both ligands have good logP values (1.617 and 0.741), falling within the optimal 1-3 range. Ligand A is slightly better.

**H-Bond Donors/Acceptors:** Ligand A (2 HBD, 5 HBA) is better than Ligand B (3 HBD, 7 HBA) as it has fewer H-bonds, potentially improving permeability. Both are within acceptable limits.

**QED:** Both ligands have acceptable QED scores (0.764 and 0.677), indicating good drug-like properties.

**DILI:** Ligand A (64.599) has a slightly higher DILI risk than Ligand B (58.976), but both are below the concerning 60 threshold.

**BBB:** This is a crucial parameter for CNS targets. Ligand A (79.062) has a significantly better BBB penetration score than Ligand B (43.505). This is a major advantage for Ligand A.

**Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and suggests poor permeability. However, the scale isn't specified, so it's difficult to interpret.

**Aqueous Solubility:** Both have negative solubility values, also unusual. Again, the scale is unknown, making interpretation difficult.

**hERG:** Both ligands have low hERG inhibition liability (0.378 and 0.429), which is good.

**Microsomal Clearance:** Ligand A (-15.413) has a much lower (better) microsomal clearance than Ligand B (21.768), indicating greater metabolic stability.

**In vitro Half-Life:** Ligand A (-8.358) has a negative half-life, which is nonsensical. Ligand B (-24.001) also has a negative half-life, indicating a problem with the data.

**P-gp Efflux:** Both have very low P-gp efflux liability (0.029 and 0.074), which is favorable for CNS penetration.

**Binding Affinity:** Ligand A (-9.2 kcal/mol) has a slightly better binding affinity than Ligand B (-7.9 kcal/mol). While both are good, the 1.3 kcal/mol difference is significant enough to potentially overcome minor ADME drawbacks.

**Conclusion:**

Considering all factors, **Ligand A is the more promising drug candidate**. Its superior BBB penetration, lower microsomal clearance, and slightly better binding affinity outweigh the slightly higher DILI risk. The negative values for Caco-2 and solubility are concerning and need further investigation, but the other properties strongly favor Ligand A.

Output:
1
2025-04-17 07:04:13,817 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (407.264 Da) is slightly higher than Ligand B (346.402 Da), but both are acceptable.

**2. TPSA:** Ligand A (71.89) is higher than Ligand B (58.64). For CNS targets, we prefer TPSA <= 90. Both are within this range, but Ligand B is more favorable.

**3. logP:** Both ligands have good logP values (Ligand A: 2.604, Ligand B: 2.9). Both fall within the optimal 1-3 range.

**4. H-Bond Donors:** Both have 1 HBD, which is within the acceptable limit of <=5.

**5. H-Bond Acceptors:** Ligand A has 6 HBAs, and Ligand B has 3. Both are below the acceptable limit of <=10. Ligand B is preferable.

**6. QED:** Both ligands have acceptable QED values (Ligand A: 0.743, Ligand B: 0.636), exceeding the 0.5 threshold.

**7. DILI:** Both have relatively low DILI risk (Ligand A: 36.293, Ligand B: 57.658), both below the 60 threshold. Ligand A is slightly better.

**8. BBB:** This is crucial for a CNS target like DRD2. Ligand B (81.776) has a significantly higher BBB percentile than Ligand A (57.852). This is a major advantage for Ligand B.

**9. Caco-2:** Both have negative Caco-2 values (-4.724 and -4.525), which is unusual and suggests poor permeability. However, the scale is not specified, so it's difficult to interpret.

**10. Solubility:** Both have negative solubility values (-3.928 and -3.211), again suggesting poor solubility. The scale is not specified, so it's difficult to interpret.

**11. hERG:** Both have low hERG inhibition liability (Ligand A: 0.75, Ligand B: 0.8). This is good.

**12. Cl_mic:** Ligand A (48.882) has lower microsomal clearance than Ligand B (65.803), indicating better metabolic stability.

**13. t1/2:** Ligand A (-12.869) has a negative half-life, which is not possible. Ligand B (2.138) has a short half-life, but it's a plausible value.

**14. Pgp:** Both have low Pgp efflux liability (Ligand A: 0.299, Ligand B: 0.438). This is good.

**15. Binding Affinity:** Both have very similar and strong binding affinities (Ligand A: -8.8 kcal/mol, Ligand B: -8.9 kcal/mol). The difference is negligible.

**Overall Assessment:**

Ligand B is the more promising candidate. While Ligand A has slightly better DILI and Cl_mic, Ligand B excels in BBB penetration, which is paramount for a CNS target. It also has a lower TPSA and fewer HBAs, both favorable for CNS penetration. The negative values for Caco-2 and solubility are concerning for both, but the significantly higher BBB value for Ligand B outweighs the other minor drawbacks. The implausible half-life value for Ligand A is also a significant concern.

Output:
1
2025-04-17 07:04:13,817 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (346.431 and 350.459 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (87.32) is better than Ligand B (75.71), both are below the 90 A^2 threshold for CNS targets.

**3. logP:** Both ligands have acceptable logP values (1.041 and 1.524), falling within the optimal 1-3 range.

**4. H-Bond Donors:** Ligand A (2) is slightly higher than Ligand B (1), but both are within the acceptable limit of <=5.

**5. H-Bond Acceptors:** Both ligands have the same number of H-bond acceptors (4), which is well below the limit of 10.

**6. QED:** Both ligands have good QED scores (0.654 and 0.788), indicating good drug-like properties.

**7. DILI:** Ligand A (32.028) has a slightly higher DILI risk than Ligand B (19.698), but both are below the 40 threshold, indicating low risk.

**8. BBB:** Ligand B (74.06) has a significantly better BBB penetration score than Ligand A (56.766). This is a crucial factor for a CNS target like DRD2.

**9. Caco-2 Permeability:** Ligand A (-5.001) has a worse Caco-2 permeability than Ligand B (-4.753).

**10. Aqueous Solubility:** Both ligands have poor aqueous solubility (-2.013 and -2.216). This could be a formulation challenge, but is less critical than BBB penetration for a CNS target.

**11. hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.146 and 0.184).

**12. Microsomal Clearance:** Ligand A (8.25) has significantly lower microsomal clearance than Ligand B (21.09), suggesting better metabolic stability.

**13. In vitro Half-Life:** Ligand B (-5.297) has a longer in vitro half-life than Ligand A (-0.945).

**14. P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.038 and 0.053).

**15. Binding Affinity:** Ligand A (-7.7) has a stronger binding affinity than Ligand B (-7.2). The difference is 0.5kcal/mol, which is significant.

**Overall Assessment:**

While Ligand A has a better binding affinity and metabolic stability, Ligand B's significantly improved BBB penetration (74.06 vs 56.766) is the deciding factor for a CNS target like DRD2. The 0.5 kcal/mol difference in binding affinity can potentially be overcome with further optimization, but improving BBB penetration is often more challenging. The slightly longer half-life of Ligand B is also a plus.

Output:
1
2025-04-17 07:04:13,817 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (363.868 and 370.563 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (55.63) is better than Ligand B (57.17). Both are below the 90 A^2 threshold for CNS targets, which is good.

**3. logP:** Ligand A (3.588) is optimal, while Ligand B (1.807) is on the lower side. A logP between 1-3 is preferred, so Ligand A is better here. Lower logP can lead to poor membrane permeability.

**4. H-Bond Donors:** Both ligands have 1 HBD, which is within the acceptable limit of <=5.

**5. H-Bond Acceptors:** Ligand A has 5 HBA, and Ligand B has 6. Both are within the acceptable limit of <=10.

**6. QED:** Ligand A (0.901) has a significantly better QED score than Ligand B (0.595), indicating a more drug-like profile.

**7. DILI:** Ligand A (47.305) has a slightly higher DILI risk than Ligand B (6.282), but both are below the concerning threshold of 60.

**8. BBB:** Ligand A (88.445) has a much better BBB penetration percentile than Ligand B (71.617). For a CNS target like DRD2, this is a critical advantage.

**9. Caco-2:** Both have negative values, which is unusual. Assuming these are logP-scaled values, lower numbers indicate poorer permeability. Ligand A (-5.055) is slightly better than Ligand B (-5.469).

**10. Solubility:** Ligand A (-4.104) is better than Ligand B (-1.734), indicating better aqueous solubility.

**11. hERG:** Ligand A (0.337) has a lower hERG inhibition liability than Ligand B (0.743), which is favorable.

**12. Cl_mic:** Ligand A (33.779) has a lower microsomal clearance than Ligand B (5.144), suggesting better metabolic stability.

**13. t1/2:** Ligand A (22.859) has a longer in vitro half-life than Ligand B (6.825).

**14. Pgp:** Ligand A (0.557) has lower P-gp efflux liability than Ligand B (0.046), which is beneficial for CNS penetration.

**15. Binding Affinity:** Ligand A (-8.4 kcal/mol) has a significantly stronger binding affinity than Ligand B (-5.7 kcal/mol). This >1.5 kcal/mol difference is substantial and can outweigh minor ADME drawbacks.

**Overall Assessment:**

Ligand A consistently outperforms Ligand B across most crucial parameters, especially those prioritized for GPCRs targeting the CNS. The significantly better BBB penetration, binding affinity, QED, metabolic stability, and lower Pgp efflux make Ligand A a much more promising drug candidate. While Ligand A has a slightly higher DILI risk, it's still within an acceptable range, and the other advantages are compelling.

Output:
1
2025-04-17 07:04:13,817 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (370.381 and 358.439 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (96.37) is excellent for CNS penetration, being under the 90 A^2 threshold. Ligand B (111.21) is slightly higher but still reasonable.

**logP:** Ligand A (3.388) is optimal. Ligand B (-1.28) is significantly low, potentially hindering membrane permeability and CNS entry.

**H-Bond Donors/Acceptors:** Both have 3 HBD and 6 HBA, which are within acceptable limits.

**QED:** Both ligands have reasonable QED scores (0.533 and 0.443), indicating drug-like properties.

**DILI:** Ligand A (85.266) has a higher DILI risk than Ligand B (22.334). This is a concern for Ligand A.

**BBB:** Ligand A (71.578) has a good BBB percentile, desirable for a CNS target. Ligand B (30.012) is quite low, suggesting poor brain penetration.

**Caco-2:** Both have negative Caco-2 values, which is unusual and suggests potential issues with intestinal absorption. However, the scale is unspecified and these values might be percentile scores where negative values are possible.

**Solubility:** Both ligands have negative solubility values, again unusual and potentially problematic.

**hERG:** Both ligands have very low hERG inhibition liability, which is good.

**Microsomal Clearance:** Ligand A (60.933) has moderate clearance, while Ligand B (-25.485) has a negative clearance, which is not physically possible and indicates an issue with the data or model.

**In vitro Half-Life:** Ligand A (9.044 hours) has a reasonable half-life. Ligand B (-2.737 hours) has a negative half-life, which is not physically possible.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability, which is favorable.

**Binding Affinity:** Ligand A (-8.8 kcal/mol) has a significantly stronger binding affinity than Ligand B (-7.3 kcal/mol). This 1.5 kcal/mol difference is substantial and can outweigh some ADME drawbacks.

**Overall Assessment:**

Ligand A is significantly better despite the higher DILI risk. The superior binding affinity, good BBB penetration, and acceptable logP and TPSA make it a more promising candidate for a CNS-targeting drug like one for DRD2. Ligand B's very low logP and BBB penetration are major drawbacks, and the negative clearance and half-life values raise serious concerns about data quality or model predictions. The DILI risk for Ligand A is a concern that would need to be addressed through structural modifications, but it's a more tractable problem than fundamentally poor pharmacokinetic properties.

Output:
1
2025-04-17 07:04:13,818 - INFO - Batch 334 complete. Total preferences: 5344
2025-04-17 07:04:13,818 - INFO - Processing batch 335/512...
2025-04-17 07:05:03,743 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (364.515 and 348.447 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (74.33) is better than Ligand B (78.67). Both are below the 90 A^2 threshold desirable for CNS targets, but A is closer to optimal.

**3. logP:** Both ligands have good logP values (1.81 and 1.299), falling within the 1-3 range.

**4. H-Bond Donors:** Ligand A (2) is slightly higher than Ligand B (1), but both are within the acceptable limit of 5.

**5. H-Bond Acceptors:** Both ligands have 5 H-bond acceptors, which is within the acceptable limit of 10.

**6. QED:** Both ligands have good QED scores (0.738 and 0.84), indicating good drug-like properties.

**7. DILI:** Ligand A (31.524) has a lower DILI risk than Ligand B (25.359), suggesting a safer profile.

**8. BBB:** Ligand B (73.401) has a slightly better BBB penetration percentile than Ligand A (63.784). This is a critical factor for CNS targets like DRD2.

**9. Caco-2 Permeability:** Ligand A (-5.175) has worse Caco-2 permeability than Ligand B (-4.64).

**10. Aqueous Solubility:** Ligand A (-2.345) has worse aqueous solubility than Ligand B (-1.443).

**11. hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.453 and 0.355).

**12. Microsomal Clearance:** Ligand B (3.611) has significantly lower microsomal clearance than Ligand A (33.932), indicating better metabolic stability.

**13. In vitro Half-Life:** Ligand B (3.981) has a significantly longer in vitro half-life than Ligand A (45.887).

**14. P-gp Efflux:** Ligand A (0.048) has lower P-gp efflux liability than Ligand B (0.103), which is favorable for CNS penetration.

**15. Binding Affinity:** Ligand B (-9.0 kcal/mol) has a significantly stronger binding affinity than Ligand A (-7.8 kcal/mol). This is a substantial advantage, exceeding the 1.5 kcal/mol threshold.

**Overall Assessment:**

While Ligand A has slightly better TPSA and P-gp efflux, Ligand B excels in the most critical areas for a CNS-targeting GPCR ligand. Specifically, its superior BBB penetration, significantly improved metabolic stability (lower Cl_mic and longer t1/2), and *much* stronger binding affinity outweigh the minor drawbacks in TPSA and P-gp. The better solubility of Ligand B is also a plus. The difference in binding affinity is substantial and likely to overcome any minor ADME differences.

Output:
1
2025-04-17 07:05:03,743 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (364.4 and 352.4 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (106.33) is higher than Ligand B (85.38). For CNS targets, TPSA should be <=90, so Ligand B is preferable.

**logP:** Ligand A (1.464) and Ligand B (0.42) are both within the optimal 1-3 range, but Ligand A is better. Ligand B is a bit low, potentially impacting permeability.

**H-Bond Donors:** Ligand A (2) is better than Ligand B (0). While 0 is acceptable, some HBD can aid solubility.

**H-Bond Acceptors:** Ligand A (4) is lower than Ligand B (6), which is preferable. Lower HBA generally improves permeability.

**QED:** Both ligands (0.757 and 0.682) have good drug-likeness scores (>0.5).

**DILI:** Ligand A (77.55) has a higher DILI risk than Ligand B (52.35), making Ligand B more favorable.

**BBB:** Both ligands have good BBB penetration (63.94% and 69.21%), but Ligand B is slightly better. Both are above the desirable 70% threshold, but close.

**Caco-2 Permeability:** Ligand A (-5.023) has worse Caco-2 permeability than Ligand B (-4.477), indicating lower intestinal absorption.

**Aqueous Solubility:** Ligand A (-3.299) has worse solubility than Ligand B (-1.72).

**hERG Inhibition:** Ligand A (0.33) has a slightly higher hERG risk than Ligand B (0.057), making Ligand B safer.

**Microsomal Clearance:** Ligand A (0.959) has lower microsomal clearance than Ligand B (9.582), indicating better metabolic stability. This is a significant advantage for Ligand A.

**In vitro Half-Life:** Ligand A (-0.253) has a longer half-life than Ligand B (-3.783), which is desirable.

**P-gp Efflux:** Ligand A (0.24) has lower P-gp efflux than Ligand B (0.07), which is preferable for CNS exposure.

**Binding Affinity:** Ligand A (-8.2 kcal/mol) has a stronger binding affinity than Ligand B (-7.7 kcal/mol). This 1.5 kcal/mol difference is substantial and can outweigh some ADME drawbacks.

**Overall Assessment:**

Ligand A has a significantly better binding affinity and metabolic stability (lower Cl_mic, longer t1/2) and lower P-gp efflux. However, Ligand B has better TPSA, lower DILI risk, better solubility, and lower hERG risk. The affinity difference is the most critical factor for a GPCR. While Ligand B has better ADME properties overall, the stronger binding of Ligand A is a decisive advantage, especially considering the CNS target.

Output:
1
2025-04-17 07:05:03,743 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B based on the provided guidelines, prioritizing GPCR-specific properties (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (349.45 and 343.383 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (44.81) is excellent, well below the 90 A^2 threshold for CNS targets. Ligand B (93.46) is above this threshold, which is a concern for CNS penetration.

**logP:** Both ligands have good logP values (2.04 and 1.434), falling within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A (HBD=1, HBA=4) and Ligand B (HBD=2, HBA=5) both have acceptable numbers of hydrogen bond donors and acceptors, well within the limits of 5 and 10 respectively.

**QED:** Both ligands have reasonable QED scores (0.884 and 0.756), indicating good drug-like properties.

**DILI:** Ligand A (16.479) has a significantly lower DILI risk than Ligand B (52.385), which is a major advantage.

**BBB:** Ligand A (93.408) demonstrates excellent BBB penetration, exceeding the desirable threshold of 70. Ligand B (74.292) is still reasonably good, but significantly lower than Ligand A.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.555 and -4.891), which is unusual and suggests poor permeability. However, these values are on a log scale, and the negative values indicate very low permeability.

**Aqueous Solubility:** Both ligands have negative solubility values (-1.405 and -2.815), indicating poor aqueous solubility.

**hERG Inhibition:** Ligand A (0.851) has a slightly higher hERG inhibition risk than Ligand B (0.168), but both are relatively low.

**Microsomal Clearance:** Ligand A (6.272) has a lower microsomal clearance than Ligand B (28.624), indicating better metabolic stability.

**In vitro Half-Life:** Ligand A (41.275) has a longer in vitro half-life than Ligand B (-3.393), which is a positive attribute.

**P-gp Efflux:** Ligand A (0.138) has a lower P-gp efflux liability than Ligand B (0.123), suggesting better CNS exposure.

**Binding Affinity:** Ligand B (-9.3 kcal/mol) has a slightly better binding affinity than Ligand A (-8.1 kcal/mol). However, the difference is less than 1.5 kcal/mol, and can be offset by other factors.

**Overall Assessment:**

Ligand A is the stronger candidate. While Ligand B has slightly better binding affinity, Ligand A excels in critical ADME properties for a CNS-targeting GPCR drug. Specifically, its superior TPSA, BBB penetration, lower DILI risk, better metabolic stability (lower Cl_mic, longer t1/2), and lower P-gp efflux are all highly favorable. The poor Caco-2 and solubility are concerns for both, but are less critical for a CNS-focused drug where BBB penetration is paramount.

Output:
1
2025-04-17 07:05:03,743 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (357.36 and 361.32 Da) fall comfortably within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (93.46) is better than Ligand B (105.64). For CNS targets, we want TPSA <= 90, so Ligand A is closer to this threshold.

**3. logP:** Both ligands have good logP values (1.657 and 1.298), falling within the optimal 1-3 range.

**4. H-Bond Donors:** Both have 2 HBD, which is acceptable.

**5. H-Bond Acceptors:** Ligand A has 5 HBA, and Ligand B has 4. Both are within the acceptable limit of <= 10.

**6. QED:** Both ligands have good QED scores (0.656 and 0.824), indicating good drug-like properties.

**7. DILI:** Both ligands have similar DILI risk (49.94 and 52.70), both being good (below 60).

**8. BBB:** Ligand A (85.73) has a significantly better BBB penetration percentile than Ligand B (77.71). This is a crucial factor for CNS targets like DRD2.

**9. Caco-2 Permeability:** Ligand A (-4.417) is better than Ligand B (-5.102), indicating better intestinal absorption.

**10. Aqueous Solubility:** Ligand A (-2.898) is better than Ligand B (-3.516), suggesting better solubility.

**11. hERG Inhibition:** Both ligands show low hERG inhibition liability (0.179 and 0.369), which is good.

**12. Microsomal Clearance:** Ligand B (-10.368) has a lower (better) microsomal clearance than Ligand A (34.347), suggesting greater metabolic stability.

**13. In vitro Half-Life:** Ligand B (-9.964) has a better in vitro half-life than Ligand A (-10.603).

**14. P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.038 and 0.041).

**15. Binding Affinity:** Ligand B (-8.9 kcal/mol) has a slightly better binding affinity than Ligand A (-8.2 kcal/mol). This difference of 0.7 kcal/mol is significant, but needs to be weighed against other factors.

**Overall Assessment:**

While Ligand B has a slightly better binding affinity and metabolic stability, Ligand A excels in properties critical for CNS penetration: TPSA and, most importantly, BBB. The difference in BBB (85.73 vs 77.71) is substantial. Given that DRD2 is a CNS target, maximizing BBB penetration is paramount. The slightly weaker affinity of Ligand A can potentially be optimized in subsequent iterations of drug design, but improving BBB is often more challenging. The better Caco-2 and Solubility also favor Ligand A.

Output:
1
2025-04-17 07:05:03,743 - INFO - Reasoning:

Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight (MW):**
* Ligand A: 488.249 Da - Within the ideal range (200-500 Da).
* Ligand B: 344.455 Da - Also within the ideal range.
* *Advantage: Neither is problematic.*

**2. Topological Polar Surface Area (TPSA):**
* Ligand A: 71.25  - Good for CNS penetration (below 90).
* Ligand B: 60.85 - Excellent for CNS penetration.
* *Advantage: Ligand B slightly better.*

**3. Lipophilicity (logP):**
* Ligand A: 4.479 - A bit high, potentially leading to solubility issues and off-target effects.
* Ligand B: 1.424 - Optimal range (1-3).
* *Advantage: Ligand B significantly better.*

**4. H-Bond Donors (HBD):**
* Ligand A: 2 - Acceptable.
* Ligand B: 1 - Acceptable.
* *Advantage: Neither is problematic.*

**5. H-Bond Acceptors (HBA):**
* Ligand A: 5 - Acceptable.
* Ligand B: 3 - Acceptable.
* *Advantage: Neither is problematic.*

**6. QED:**
* Ligand A: 0.623 - Good drug-like properties.
* Ligand B: 0.606 - Good drug-like properties.
* *Advantage: Neither is problematic.*

**7. DILI Risk:**
* Ligand A: 67.313 - Moderate risk.
* Ligand B: 8.414 - Very low risk.
* *Advantage: Ligand B significantly better.*

**8. BBB Penetration:**
* Ligand A: 86.041 - Excellent BBB penetration.
* Ligand B: 61.109 - Good, but not as high as Ligand A.
* *Advantage: Ligand A better.*

**9. Caco-2 Permeability:**
* Ligand A: -5.092 - Poor permeability.
* Ligand B: -4.638 - Poor permeability.
* *Advantage: Neither is problematic.*

**10. Aqueous Solubility:**
* Ligand A: -4.599 - Poor solubility.
* Ligand B: -2.341 - Poor solubility.
* *Advantage: Ligand B slightly better.*

**11. hERG Inhibition:**
* Ligand A: 0.894 - Low risk.
* Ligand B: 0.31 - Very low risk.
* *Advantage: Ligand B better.*

**12. Microsomal Clearance:**
* Ligand A: 60.496 - Moderate clearance.
* Ligand B: 16.939 - Low clearance (better metabolic stability).
* *Advantage: Ligand B significantly better.*

**13. In vitro Half-Life:**
* Ligand A: 31.217 - Moderate half-life.
* Ligand B: -3.825 - Very short half-life.
* *Advantage: Ligand A better.*

**14. P-gp Efflux:**
* Ligand A: 0.807 - Moderate efflux.
* Ligand B: 0.091 - Low efflux (better CNS exposure).
* *Advantage: Ligand B significantly better.*

**15. Binding Affinity:**
* Ligand A: -9.7 kcal/mol - Excellent affinity.
* Ligand B: -7.9 kcal/mol - Good affinity.
* *Advantage: Ligand A significantly better.*

**Overall Assessment:**

Ligand A has a significantly better binding affinity and BBB penetration, and a longer half-life. However, it suffers from higher logP, moderate DILI risk, moderate P-gp efflux, and poor solubility/permeability. Ligand B has superior ADME properties across the board (lower logP, DILI, P-gp efflux, better metabolic stability, and slightly better solubility) but a weaker binding affinity.

Given the GPCR-specific priorities, and the substantial difference in binding affinity (-9.7 vs -7.9 kcal/mol), the stronger binding of Ligand A is a major advantage that can potentially outweigh its ADME liabilities. While the ADME profile of Ligand B is superior, the difference in binding affinity is substantial enough that further optimization of Ligand A is likely to be more fruitful than starting with Ligand B.

Output:
1
2025-04-17 07:05:03,744 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (381.372) is slightly higher than Ligand B (365.503), but both are acceptable.

**TPSA:** Ligand A (89.54) is better than Ligand B (61.68) as it is closer to the ideal range for CNS targets (<=90). Ligand B is also good, but A has a slight advantage.

**logP:** Ligand A (1.847) is within the optimal range (1-3). Ligand B (-0.073) is slightly below 1, which *could* indicate permeability issues, though not drastically.

**H-Bond Donors/Acceptors:** Ligand A (HBD=1, HBA=5) and Ligand B (HBD=0, HBA=6) both have reasonable numbers of H-bond donors and acceptors, well within the guidelines.

**QED:** Both ligands have good QED scores (Ligand A: 0.548, Ligand B: 0.731), indicating good drug-like properties. Ligand B is slightly better here.

**DILI:** Ligand A (63.086) has a higher DILI risk than Ligand B (25.126). This is a significant drawback for Ligand A.

**BBB:** Ligand A (82.009) has a significantly better BBB penetration percentile than Ligand B (53.781). This is a crucial advantage for a CNS target like DRD2.

**Caco-2 Permeability:** Ligand A (-4.764) has a negative Caco-2 value, which is concerning. Ligand B (-5.181) is also negative, indicating poor intestinal absorption. However, for a CNS target, intestinal absorption is less critical than BBB penetration.

**Aqueous Solubility:** Ligand A (-3.247) and Ligand B (-0.897) both have negative solubility values, indicating poor solubility. This could pose formulation challenges.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (Ligand A: 0.703, Ligand B: 0.143), which is good. Ligand B is slightly better.

**Microsomal Clearance:** Ligand A (72.483) has a higher microsomal clearance than Ligand B (16.683), suggesting lower metabolic stability. Ligand B is significantly better.

**In vitro Half-Life:** Ligand A (-24.985) has a negative half-life, which is problematic. Ligand B (1.751) has a short half-life, but it's a positive value.

**P-gp Efflux:** Ligand A (0.127) has lower P-gp efflux liability than Ligand B (0.019), which is favorable for CNS penetration.

**Binding Affinity:** Ligand A (-8.6 kcal/mol) has a significantly stronger binding affinity than Ligand B (-6.9 kcal/mol). This is a substantial advantage, potentially outweighing some of the ADME drawbacks.

**Overall Assessment:**

Ligand A has a much better binding affinity and BBB penetration, which are critical for a CNS GPCR target. However, it suffers from higher DILI risk, higher clearance, and a negative in vitro half-life. Ligand B has better ADME properties (lower DILI, lower clearance, better solubility, lower P-gp efflux), but its binding affinity is considerably weaker and its BBB penetration is poor.

Given the importance of potency and CNS penetration for DRD2, the stronger binding affinity and better BBB penetration of Ligand A are more compelling, despite its ADME liabilities. Optimization efforts could focus on improving the metabolic stability and reducing the DILI risk of Ligand A.

Output:
1
2025-04-17 07:05:03,744 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight (MW):** Both ligands (349.435 and 350.547 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (121.44) is borderline acceptable for CNS targets (ideally <90), while Ligand B (49.41) is excellent. This is a significant advantage for Ligand B.

**3. logP:** Ligand A (0.292) is quite low, potentially hindering membrane permeability. Ligand B (4.28) is slightly high, but still within a reasonable range.

**4. H-Bond Donors (HBD):** Ligand A (3) and Ligand B (1) both meet the criteria of <=5.

**5. H-Bond Acceptors (HBA):** Ligand A (6) and Ligand B (2) both meet the criteria of <=10.

**6. QED:** Both ligands have good QED scores (0.702 and 0.745), indicating drug-like properties.

**7. DILI:** Ligand A (36.099) has a slightly higher DILI risk than Ligand B (21.791), but both are below the concerning threshold of 60.

**8. BBB:** Ligand B (83.288) has a significantly better BBB penetration prediction than Ligand A (66.499). This is crucial for a CNS target like DRD2.

**9. Caco-2 Permeability:** Ligand A (-5.268) has poor Caco-2 permeability, which is concerning. Ligand B (-4.7) is also poor, but slightly better.

**10. Aqueous Solubility:** Ligand A (-2.182) and Ligand B (-4.246) both have poor aqueous solubility.

**11. hERG Inhibition:** Both ligands have low hERG inhibition risk (0.423 and 0.62).

**12. Microsomal Clearance:** Ligand A (0.54) has much lower microsomal clearance than Ligand B (75.869), suggesting better metabolic stability.

**13. In vitro Half-Life:** Ligand A (0.328) has a very short in vitro half-life, while Ligand B (-4.847) is also short, but less so.

**14. P-gp Efflux:** Ligand A (0.01) has very low P-gp efflux, which is favorable for CNS penetration. Ligand B (0.444) has moderate P-gp efflux.

**15. Binding Affinity:** Ligand A (-8.7 kcal/mol) has a slightly better binding affinity than Ligand B (-8.3 kcal/mol), but the difference is relatively small.

**Overall Assessment:**

While Ligand A has slightly better binding affinity and metabolic stability (lower Cl_mic and Pgp efflux), Ligand B excels in key properties for a CNS-targeting GPCR ligand. Specifically, its significantly lower TPSA and higher BBB penetration are major advantages. The slightly higher logP of Ligand B is acceptable, and its DILI risk is lower. The poor Caco-2 and solubility of both are drawbacks, but can potentially be addressed with formulation strategies. Given the importance of CNS penetration for DRD2, Ligand B is the more promising candidate.

Output:
1
2025-04-17 07:05:03,744 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (362.461 and 373.475 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (78.43) is significantly better than Ligand B (96.97). For CNS targets, we want TPSA <= 90, and A is comfortably within that, while B is nearing the upper limit.

**logP:** Ligand A (2.64) is optimal (1-3), while Ligand B (-0.764) is below 1, potentially hindering permeation. This is a significant disadvantage for B.

**H-Bond Donors/Acceptors:** Ligand A (3 HBD, 3 HBA) and Ligand B (2 HBD, 6 HBA) both have reasonable numbers, within the guidelines.

**QED:** Both ligands have acceptable QED values (0.636 and 0.489), though A is better.

**DILI:** Both ligands have low DILI risk (30.399 and 27.026), which is good.

**BBB:** Ligand A (57.736) has a better BBB percentile than Ligand B (44.668), though both are below the desirable >70 for CNS targets. Still, A is better positioned.

**Caco-2 Permeability:** Ligand A (-4.838) has a worse Caco-2 permeability than Ligand B (-5.587). However, Caco-2 values are often difficult to interpret and less reliable than other parameters.

**Aqueous Solubility:** Ligand A (-3.256) has better aqueous solubility than Ligand B (-2.053).

**hERG:** Both ligands have very low hERG risk (0.523 and 0.214).

**Microsomal Clearance:** Ligand A (57.704) has higher microsomal clearance than Ligand B (9.517), indicating lower metabolic stability. This is a disadvantage for A.

**In vitro Half-Life:** Ligand B (-1.604) has a better in vitro half-life than Ligand A (-23.198).

**P-gp Efflux:** Ligand A (0.071) has lower P-gp efflux than Ligand B (0.011), which is favorable for CNS penetration.

**Binding Affinity:** Both ligands have the same binding affinity (-6.8 kcal/mol), which is excellent.

**Overall Assessment:**

Ligand A is superior due to its better logP, TPSA, BBB, and P-gp efflux. While it has a higher microsomal clearance and lower in vitro half-life, the improvements in permeability-related properties (logP, TPSA, BBB, Pgp) are crucial for a CNS-targeting GPCR like DRD2. Ligand B's low logP is a major concern, potentially limiting its ability to cross the blood-brain barrier despite its slightly better half-life. The equal binding affinity means that ADME properties become the deciding factor.

Output:
1
2025-04-17 07:05:03,744 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (338.338 and 344.459 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (62.55) is excellent, well below the 90 target for CNS drugs. Ligand B (78.09) is still reasonable, but less optimal.

**3. logP:** Ligand A (3.686) is at the higher end of the optimal range (1-3), while Ligand B (2.839) is well within the optimal range.

**4. H-Bond Donors:** Ligand A (1) is good. Ligand B (2) is also acceptable.

**5. H-Bond Acceptors:** Both ligands have 3 HBA, which is within the acceptable limit of 10.

**6. QED:** Ligand A (0.775) has a better QED score than Ligand B (0.641), indicating a more drug-like profile.

**7. DILI:** Ligand A (90.151) has a significantly higher DILI risk than Ligand B (54.983). This is a major concern for Ligand A.

**8. BBB:** Ligand A (87.088) has excellent BBB penetration, while Ligand B (58.86) is lower, though not terrible. This is a critical factor for a CNS target like DRD2.

**9. Caco-2 Permeability:** Ligand A (-4.518) has poor Caco-2 permeability, while Ligand B (-5.361) is also poor, but slightly better.

**10. Aqueous Solubility:** Ligand A (-4.731) has poor aqueous solubility, while Ligand B (-3.313) is slightly better.

**11. hERG:** Ligand A (0.786) has a lower hERG risk than Ligand B (0.242).

**12. Microsomal Clearance:** Both ligands have similar microsomal clearance (Ligand A: 52.284, Ligand B: 48.488), suggesting comparable metabolic stability.

**13. In vitro Half-Life:** Ligand A (81.517) has a significantly longer half-life than Ligand B (8.935).

**14. P-gp Efflux:** Ligand A (0.562) has a lower P-gp efflux liability than Ligand B (0.177), suggesting better CNS exposure.

**15. Binding Affinity:** Ligand B (-7.5 kcal/mol) has a significantly stronger binding affinity than Ligand A (-10.3 kcal/mol). This is a substantial advantage.

**Overall Assessment:**

Ligand A excels in BBB penetration, half-life, and P-gp efflux, but suffers from high DILI risk, poor solubility, and poor Caco-2 permeability. Ligand B has a much better binding affinity, lower DILI risk, and slightly better solubility and Caco-2 permeability. While Ligand A has a better BBB score, the significantly stronger binding affinity of Ligand B (-7.5 vs -10.3 kcal/mol) is a key advantage for a GPCR target. The lower DILI risk for Ligand B is also a significant factor. The difference in binding affinity is large enough to outweigh the slightly lower BBB and solubility of Ligand B.

Output:
1
2025-04-17 07:05:03,744 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 drug candidates, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (353.344 and 383.748 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (58.36) is significantly better than Ligand B (30.29). For a CNS target like DRD2, TPSA < 90 is preferred, and Ligand B is much closer to the ideal range.

**logP:** Ligand A (2.627) is within the optimal 1-3 range. Ligand B (4.081) is slightly higher, potentially leading to solubility issues or off-target interactions, but still acceptable.

**H-Bond Donors/Acceptors:** Ligand A has 1 HBD and 4 HBA, while Ligand B has 0 HBD and 4 HBA. Both are within acceptable limits (<=5 HBD and <=10 HBA).

**QED:** Both ligands have reasonable QED values (0.833 and 0.643, respectively), indicating good drug-like properties.

**DILI:** Both ligands have similar, acceptable DILI risk (48.158 and 47.77 percentile).

**BBB:** Both ligands exhibit excellent BBB penetration (88.135 and 87.98 percentile), which is crucial for a CNS target.

**Caco-2 Permeability:** Both ligands show poor Caco-2 permeability (-4.396 and -4.565). This is a concern for oral absorption.

**Aqueous Solubility:** Both ligands have very poor aqueous solubility (-3.404 and -4.557). This is a significant drawback.

**hERG Inhibition:** Ligand A (0.61) has a slightly lower hERG risk than Ligand B (0.906), which is preferable.

**Microsomal Clearance:** Ligand B (53.773) has a higher microsomal clearance than Ligand A (26.34), indicating faster metabolism and potentially lower *in vivo* exposure.

**In vitro Half-Life:** Ligand A (-5.482) has a shorter half-life than Ligand B (18.292).

**P-gp Efflux:** Both ligands show low P-gp efflux liability (0.21 and 0.694).

**Binding Affinity:** Both ligands have very strong binding affinity (-8.4 and -8.0 kcal/mol). The difference of 0.4 kcal/mol is not substantial enough to outweigh other factors.

**Overall Assessment:**

Ligand A has a better TPSA and lower microsomal clearance, suggesting better CNS penetration and metabolic stability. However, it has a shorter half-life and slightly higher hERG risk. Ligand B has a longer half-life, but its TPSA is higher and its microsomal clearance is worse. Both have poor solubility and Caco-2 permeability. Given the importance of TPSA and metabolic stability for CNS GPCR targets, and the relatively small difference in binding affinity, Ligand A is slightly more promising.

Output:
1
2025-04-17 07:05:03,744 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (360.401 and 348.359 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (59.08) is excellent, well below the 90 A^2 threshold for CNS targets. Ligand B (109.83) is higher, but still potentially acceptable, though less ideal.

**logP:** Ligand A (0.937) is slightly below the optimal 1-3 range, potentially impacting permeability. Ligand B (0.601) is even lower, raising more concerns about permeability.

**H-Bond Donors/Acceptors:** Ligand A (0 HBD, 4 HBA) is favorable. Ligand B (2 HBD, 7 HBA) is also acceptable, but slightly higher counts could affect permeability.

**QED:** Both ligands have good QED scores (0.634 and 0.786), indicating good drug-like properties.

**DILI:** Ligand A (19.891) has a much lower DILI risk than Ligand B (72.703), which is a significant advantage.

**BBB:** This is critical for a CNS target like DRD2. Ligand A (95.347) has excellent BBB penetration, exceeding the desirable >70% threshold. Ligand B (34.626) has very poor predicted BBB penetration, a major drawback.

**Caco-2 Permeability:** Ligand A (-4.45) and Ligand B (-5.088) both have negative values, which is unusual. These values are likely scaled and indicate poor permeability. However, the BBB score for Ligand A suggests it can still cross the blood-brain barrier despite the low Caco-2 value.

**Aqueous Solubility:** Both ligands have negative solubility values (-1.084 and -2.263), suggesting poor aqueous solubility. This could pose formulation challenges.

**hERG Inhibition:** Ligand A (0.504) has a low hERG risk. Ligand B (0.221) also shows low hERG risk.

**Microsomal Clearance:** Ligand A (19.091) has a higher microsomal clearance than Ligand B (5.878), indicating lower metabolic stability.

**In vitro Half-Life:** Ligand B (23.017) has a significantly longer in vitro half-life than Ligand A (1.655), which is a positive attribute.

**P-gp Efflux:** Ligand A (0.076) has very low P-gp efflux, which is excellent for CNS penetration. Ligand B (0.051) also has low P-gp efflux.

**Binding Affinity:** Ligand A (-8.0) has a significantly stronger binding affinity than Ligand B (-0.0). This is a decisive advantage.

**Overall Assessment:**

Ligand A is the superior candidate. While it has slightly lower logP and solubility, and higher clearance, its *exceptional* BBB penetration (95.347), significantly lower DILI risk, and *much* stronger binding affinity (-8.0 kcal/mol) outweigh these drawbacks. The poor BBB penetration of Ligand B is a deal-breaker for a CNS target. The large difference in binding affinity is also a critical factor.

Output:
0
2025-04-17 07:05:03,745 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (364.511 and 348.495 Da) fall within the ideal 200-500 Da range.

**TPSA:** Both ligands have TPSA values (58.64 and 57.5) below the 90 A^2 threshold desirable for CNS targets, which is excellent.

**logP:** Ligand A (1.665) is within the optimal 1-3 range. Ligand B (0.859) is slightly below 1, which *could* indicate potential permeability issues, but isn't a dealbreaker.

**H-Bond Donors/Acceptors:** Ligand A (1 HBD, 4 HBA) and Ligand B (0 HBD, 6 HBA) both have reasonable numbers of H-bond donors and acceptors, well within the guidelines.

**QED:** Both ligands have similar QED values (0.698 and 0.697), indicating good drug-like properties.

**DILI:** Ligand A (18.108) has a slightly higher DILI risk than Ligand B (10.198), but both are below the concerning threshold of 40.

**BBB:** Ligand B (64.056) has a significantly better BBB penetration percentile than Ligand A (56.534). This is a *critical* advantage for a CNS target like DRD2.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.006 and -5.161), which is unusual and suggests poor permeability. However, these values are on a log scale and are difficult to interpret without knowing the original units.

**Aqueous Solubility:** Both ligands have negative solubility values (-3.447 and -0.071), indicating poor aqueous solubility. This could present formulation challenges.

**hERG Inhibition:** Both ligands have low hERG inhibition liability (0.265 and 0.277), which is favorable.

**Microsomal Clearance:** Ligand A (19.705) has a higher microsomal clearance than Ligand B (-10.298). This suggests Ligand B is more metabolically stable, which is a positive.

**In vitro Half-Life:** Ligand A (-1.789) has a shorter in vitro half-life than Ligand B (0.072). This further supports Ligand B's better metabolic stability.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.102 and 0.02), which is good for CNS penetration.

**Binding Affinity:** Ligand B (-7.9 kcal/mol) has a significantly stronger binding affinity than Ligand A (-7.2 kcal/mol). This 0.7 kcal/mol difference is substantial and can outweigh some of the ADME drawbacks.

**Conclusion:**

Considering all factors, **Ligand B** is the more promising drug candidate. While both have issues with Caco-2 and solubility, Ligand B's superior BBB penetration, significantly stronger binding affinity, and improved metabolic stability (lower Cl_mic, longer t1/2) outweigh the slightly higher DILI risk and lower logP. The stronger affinity is particularly important for a GPCR target.

Output:
1
2025-04-17 07:05:03,745 - INFO - Reasoning:

Let's analyze Ligand A and Ligand B based on the provided guidelines, prioritizing GPCR-specific properties (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (449.204 Da) is at the higher end, while Ligand B (352.475 Da) is more favorably positioned.

**TPSA:** Ligand A (104.31) is above the optimal 90 for CNS targets, potentially hindering BBB penetration. Ligand B (59.08) is well below 90, a significant advantage.

**logP:** Both ligands have good logP values (A: 3.148, B: 2.191) within the 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A has 3 HBD and 4 HBA, acceptable values. Ligand B has 0 HBD and 4 HBA, also acceptable.

**QED:** Both ligands have good QED scores (A: 0.533, B: 0.659), indicating drug-like properties. Ligand B is slightly better.

**DILI:** Ligand A has a high DILI risk (97.712), a major concern. Ligand B has a very low DILI risk (10.818), a significant advantage.

**BBB:** Ligand A has a very low BBB penetration (22.218), making it unlikely to effectively target a CNS receptor like DRD2. Ligand B has excellent BBB penetration (90.074), a critical advantage for CNS targets.

**Caco-2 Permeability:** Ligand A has a negative Caco-2 value (-5.6), which is unusual and suggests poor permeability. Ligand B also has a negative value (-4.405), but is slightly better.

**Aqueous Solubility:** Both have negative solubility values, indicating poor solubility. Ligand A (-4.834) is slightly worse than Ligand B (-1.877).

**hERG Inhibition:** Both ligands have low hERG inhibition risk (A: 0.163, B: 0.322).

**Microsomal Clearance:** Ligand A has a very high microsomal clearance (-16.288), indicating poor metabolic stability. Ligand B has a moderate clearance (34.158), which is better.

**In vitro Half-Life:** Ligand A has a moderate half-life (50.953 hours). Ligand B has a very short half-life (-2.061 hours), a significant drawback.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (A: 0.052, B: 0.069).

**Binding Affinity:** Ligand A has a better binding affinity (-9.2 kcal/mol) than Ligand B (-7.6 kcal/mol). This is a substantial difference.

**Overall Assessment:**

Despite Ligand A's superior binding affinity, its poor BBB penetration, high DILI risk, and high microsomal clearance are major liabilities. Ligand B, while having a slightly weaker affinity, possesses excellent BBB penetration, a very low DILI risk, and better metabolic stability. For a CNS target like DRD2, BBB penetration is paramount. The 1.6 kcal/mol difference in affinity, while significant, can potentially be overcome with further optimization of Ligand B, whereas addressing the severe ADME issues of Ligand A would be far more challenging.

Output:
1
2025-04-17 07:05:03,745 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 drug candidates, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (349.431 and 344.459 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (78.95) is significantly better than Ligand B (86.88). For CNS targets, we want TPSA <= 90, and A is closer to the optimal range for CNS penetration.

**3. logP:** Ligand B (2.137) is within the optimal 1-3 range, while Ligand A (0.143) is quite low, potentially hindering membrane permeability.

**4. H-Bond Donors:** Ligand A (1) is preferable to Ligand B (3). Fewer HBDs generally improve permeability.

**5. H-Bond Acceptors:** Ligand A (4) is slightly better than Ligand B (3), but both are acceptable.

**6. QED:** Both ligands are similar (0.683 and 0.641), indicating good drug-like properties.

**7. DILI:** Both ligands have relatively low DILI risk (23.032 and 26.755), suggesting minimal liver injury potential.

**8. BBB:** Both ligands have similar BBB penetration (54.944 and 56.96). Neither is ideal (>70), but this isn't a dealbreaker if other properties are strong.

**9. Caco-2 Permeability:** Ligand A (-4.727) is significantly worse than Ligand B (-5.341). Lower values indicate poorer permeability.

**10. Aqueous Solubility:** Ligand A (-1.939) is slightly better than Ligand B (-2.946).

**11. hERG Inhibition:** Both ligands show very low hERG inhibition risk (0.148 and 0.365).

**12. Microsomal Clearance:** Ligand A (6.138) has significantly lower clearance than Ligand B (30.213), indicating better metabolic stability.

**13. In vitro Half-Life:** Ligand A (9.696) has a better half-life than Ligand B (-19.273).

**14. P-gp Efflux:** Ligand A (0.011) has significantly lower P-gp efflux liability than Ligand B (0.123), which is crucial for CNS penetration.

**15. Binding Affinity:** Both ligands have excellent binding affinity (-8.8 and -8.0 kcal/mol). Ligand A is slightly better.

**Overall Assessment:**

While Ligand B has a better logP, Ligand A excels in several crucial areas for a CNS-targeting GPCR: lower TPSA, fewer HBDs, lower P-gp efflux, lower microsomal clearance, better half-life, and slightly better affinity. The low logP of Ligand A is a concern, but the strong affinity and favorable ADME properties (especially P-gp and metabolic stability) outweigh this drawback. The Caco-2 permeability is a concern for Ligand A, but not insurmountable.

Output:
0
2025-04-17 07:05:03,745 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight (MW):** Both ligands (352.312 and 348.418 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Both ligands have a TPSA of 67.43, which is acceptable for oral absorption but slightly high for optimal CNS penetration (ideally <90, but closer to 60 is better).

**3. logP:** Ligand A (3.521) is slightly higher than Ligand B (2.48). Both are within the optimal 1-3 range, but A is edging towards potential solubility issues.

**4. H-Bond Donors (HBD):** Both have 2 HBD, which is within the acceptable limit of <=5.

**5. H-Bond Acceptors (HBA):** Both have 3 HBA, well within the acceptable limit of <=10.

**6. QED:** Both ligands have good QED scores (0.654 and 0.795, respectively), indicating drug-like properties. Ligand B is slightly better.

**7. DILI:** Ligand A (85.886) has a significantly higher DILI risk than Ligand B (40.83). This is a major concern for Ligand A.

**8. BBB:** Ligand B (89.841) has a better BBB penetration percentile than Ligand A (76.735).  For a CNS target like DRD2, this is a critical advantage.

**9. Caco-2 Permeability:** Both have negative Caco-2 values (-4.33 and -4.523). This is unusual and suggests poor permeability. However, negative values can sometimes occur in modeling and don't necessarily preclude activity.

**10. Aqueous Solubility:** Both have negative solubility values (-5.26 and -3.925). This is also concerning, but not necessarily a dealbreaker if other properties are favorable.

**11. hERG Inhibition:** Both ligands have low hERG inhibition risk (0.577 and 0.538).

**12. Microsomal Clearance (Cl_mic):** Ligand B (17.358 mL/min/kg) has significantly lower microsomal clearance than Ligand A (101.071 mL/min/kg), indicating better metabolic stability.

**13. In vitro Half-Life:** Ligand B (22.38 hours) has a longer in vitro half-life than Ligand A (32.255 hours). This is a positive for Ligand B.

**14. P-gp Efflux:** Both ligands have low P-gp efflux liability (0.261 and 0.178).

**15. Binding Affinity:** Both ligands have excellent binding affinities (-9.7 and -8.7 kcal/mol). Ligand A has a slightly better affinity, but the difference (1 kcal/mol) is likely not enough to overcome its other weaknesses.

**Overall Assessment:**

Ligand B is the superior candidate. While both have similar MW, TPSA, HBD/HBA, and excellent binding affinity, Ligand B demonstrates significantly better ADMET properties. Specifically, its lower DILI risk, higher BBB penetration, lower microsomal clearance, and longer half-life make it a much more promising drug candidate for a CNS target like DRD2. The slight difference in binding affinity is outweighed by the substantial improvements in safety and pharmacokinetic properties.

Output:
1
2025-04-17 07:05:03,745 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (345.4) is slightly lower, which could be beneficial for permeability.

**TPSA:** Ligand A (88.69) is better than Ligand B (74.65), both are below the 90 A^2 threshold for CNS targets, but A is closer to the ideal.

**logP:** Ligand A (2.972) is optimal (1-3 range). Ligand B (0.106) is significantly lower, which raises concerns about permeability and potentially potency.

**H-Bond Donors:** Both have 1 HBD, which is within the acceptable limit.

**H-Bond Acceptors:** Ligand A has 6 HBA, and Ligand B has 5. Both are within the acceptable limit of 10.

**QED:** Ligand A (0.92) has a much better QED score than Ligand B (0.775), indicating a more drug-like profile.

**DILI:** Ligand B (40.869) has a significantly lower DILI risk than Ligand A (65.762). This is a positive for Ligand B.

**BBB:** Ligand A (62.35) is better than Ligand B (55.603), but neither are above the desirable 70% threshold for CNS targets.

**Caco-2 Permeability:** Ligand A (-4.526) has better Caco-2 permeability than Ligand B (-5.37), indicating better intestinal absorption.

**Aqueous Solubility:** Ligand A (-3.608) has better aqueous solubility than Ligand B (-1.445).

**hERG Inhibition:** Ligand A (0.199) has a slightly higher hERG inhibition risk than Ligand B (0.077), but both are fairly low.

**Microsomal Clearance:** Ligand B (27.905) has lower microsomal clearance than Ligand A (22.141), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand B (15.03) has a significantly longer half-life than Ligand A (2.981).

**P-gp Efflux:** Ligand A (0.111) has lower P-gp efflux than Ligand B (0.043), which is favorable for CNS exposure.

**Binding Affinity:** Ligand B (-6.7 kcal/mol) has a better binding affinity than Ligand A (-9.0 kcal/mol). This is a substantial difference, exceeding the 1.5 kcal/mol advantage threshold.

**Overall Assessment:**

While Ligand A has better solubility, Caco-2 permeability, and P-gp efflux, Ligand B significantly outperforms it in binding affinity, metabolic stability (lower Cl_mic, longer t1/2), and DILI risk. The low logP of Ligand B is a concern, but the substantial binding affinity advantage (-6.7 vs -9.0 kcal/mol) can often compensate for minor ADME drawbacks, especially for a GPCR target. The QED score is also acceptable for Ligand B. Given the importance of binding affinity for GPCRs, and the reasonable ADME profile of Ligand B, it is the more promising candidate.

Output:
1
2025-04-17 07:05:03,745 - INFO - Batch 335 complete. Total preferences: 5360
2025-04-17 07:05:03,745 - INFO - Processing batch 336/512...
2025-04-17 07:05:46,775 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (344.375 Da) is slightly lower, which could be beneficial for permeability. Ligand B (399.969 Da) is also good.

**TPSA:** Ligand A (125.02) is closer to the ideal range for CNS targets (<=90) than Ligand B (62.3). This is a significant advantage for brain penetration.

**logP:** Ligand A (0.505) is a bit low, potentially hindering membrane permeability. Ligand B (3.193) is within the optimal range (1-3).

**H-Bond Donors/Acceptors:** Ligand A has 2 HBD and 7 HBA, while Ligand B has 1 HBD and 5 HBA. Both are within acceptable limits.

**QED:** Both ligands have good QED values (A: 0.753, B: 0.825), indicating good drug-like properties.

**DILI:** Both ligands have similar DILI risk (A: 56.572, B: 56.689), and are within acceptable limits (<60).

**BBB:** Ligand A has a significantly better BBB percentile (71.733) than Ligand B (61.264). This is a crucial factor for a CNS target like DRD2.

**Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and suggests a potential issue with the data or modeling. However, we can consider this as indicating poor permeability for both.

**Aqueous Solubility:** Both have negative solubility values, again suggesting a potential data issue.

**hERG Inhibition:** Both ligands have very low hERG inhibition risk (A: 0.04, B: 0.41).

**Microsomal Clearance:** Ligand A (15.839) has a lower microsomal clearance than Ligand B (32.039), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (-10.586) has a negative half-life, which is not physically possible and indicates a data issue. Ligand B (0.033) is very short.

**P-gp Efflux:** Ligand A (0.037) has a much lower P-gp efflux liability than Ligand B (0.271), which is favorable for CNS penetration.

**Binding Affinity:** Both ligands have the same binding affinity (-8.4 kcal/mol), which is excellent.

**Overall Assessment:**

Despite the issues with Caco-2, solubility, and half-life data, Ligand A is the more promising candidate. Its superior TPSA, BBB penetration, lower P-gp efflux, and lower microsomal clearance outweigh the slightly lower logP. The binding affinity is identical, so the ADME properties become the deciding factors. Ligand B's higher logP and P-gp efflux are less desirable for a CNS-targeting GPCR.

Output:
0
2025-04-17 07:05:46,776 - INFO - Reasoning:

Let's analyze Ligand A and Ligand B against the provided guidelines, prioritizing GPCR-specific properties (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (356.5 and 344.4 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (81.08) is excellent for CNS penetration, well below the 90 A^2 threshold. Ligand B (116.14) is higher, but still potentially acceptable, though less ideal.

**logP:** Ligand A (1.641) is within the optimal 1-3 range. Ligand B (0.089) is quite low, which could hinder permeability and potentially reduce binding affinity.

**H-Bond Donors/Acceptors:** Ligand A (HBD=2, HBA=4) and Ligand B (HBD=3, HBA=6) both have reasonable numbers of H-bond donors and acceptors, staying within the suggested limits.

**QED:** Both ligands have good QED scores (A: 0.658, B: 0.711), indicating drug-like properties.

**DILI:** Ligand A (5.971) has a very favorable DILI score, indicating low liver injury risk. Ligand B (66.421) is significantly higher, raising a concern about potential hepatotoxicity.

**BBB:** This is a crucial parameter for a CNS target like DRD2. Ligand A has a BBB percentile of 61.225, which is acceptable but not outstanding. Ligand B has a very low BBB percentile (15.083), making it unlikely to achieve sufficient CNS exposure.

**Caco-2 Permeability:** Ligand A (-4.656) and Ligand B (-5.388) both have negative Caco-2 values, which is unusual. It's difficult to interpret without knowing the scale. However, lower values generally indicate poorer permeability.

**Aqueous Solubility:** Both ligands have negative solubility values (-1.159 and -2.491), which is also unusual. Again, without knowing the scale, it's hard to assess, but lower values suggest poor solubility.

**hERG Inhibition:** Both ligands show low hERG inhibition liability (A: 0.544, B: 0.211), which is positive.

**Microsomal Clearance:** Ligand A (28.258) has a higher microsomal clearance than Ligand B (-12.038). Lower clearance is preferred for metabolic stability, giving Ligand B an advantage here.

**In vitro Half-Life:** Ligand B (-2.728) has a slightly longer in vitro half-life than Ligand A (-14.011), which is favorable.

**P-gp Efflux:** Ligand A (0.106) has lower P-gp efflux liability than Ligand B (0.077), which is better for CNS penetration.

**Binding Affinity:** Both ligands have strong binding affinities (A: -7.0 kcal/mol, B: -9.1 kcal/mol). Ligand B is 2.1 kcal/mol more potent, which is a substantial advantage and could potentially offset some of its ADME drawbacks.

**Overall Assessment:**

Despite Ligand B's superior binding affinity, its significantly higher DILI risk and extremely poor BBB penetration are major concerns. The low logP also raises questions about its ability to cross cell membranes. Ligand A, while having a slightly weaker affinity, presents a much more balanced profile with a favorable DILI score, acceptable BBB penetration, and a reasonable logP.

Output:
1
2025-04-17 07:05:46,776 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B based on the provided guidelines, prioritizing GPCR-specific properties (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (344.455 Da) is slightly lower, which could be beneficial for permeability, but both are acceptable.

**TPSA:** Both ligands have TPSA values below 90 (Ligand A: 78.43, Ligand B: 77.22), which is excellent for CNS penetration.

**logP:** Ligand A (2.011) is within the optimal range (1-3). Ligand B (3.596) is slightly higher, but still acceptable.

**H-Bond Donors/Acceptors:** Ligand A has 3 HBD and 3 HBA, while Ligand B has 1 HBD and 5 HBA. Both are within reasonable limits (<=5 HBD and <=10 HBA).

**QED:** Both ligands have good QED scores (Ligand A: 0.449, Ligand B: 0.729). Ligand B is significantly better, suggesting a more drug-like profile.

**DILI:** Ligand A (23.691) has a much lower DILI risk than Ligand B (16.285). This is a significant advantage for Ligand A.

**BBB:** This is a crucial parameter for CNS targets. Ligand B (65.839) has a substantially higher BBB percentile than Ligand A (31.214). This is a major advantage for Ligand B.

**Caco-2 Permeability:** Both have negative values, indicating poor permeability. Ligand A (-4.692) is slightly worse than Ligand B (-4.804).

**Aqueous Solubility:** Both ligands have very poor aqueous solubility (-2.411 and -3.235). This is a concern for both, but more so for Ligand B.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.654 and 0.721).

**Microsomal Clearance:** Ligand A (-2.336) has a negative clearance, indicating high metabolic stability, which is preferable. Ligand B (52.687) has a high clearance, suggesting rapid metabolism.

**In vitro Half-Life:** Ligand A (15.486 hours) has a better half-life than Ligand B (-4.286 hours).

**P-gp Efflux:** Ligand A (0.215) has lower P-gp efflux than Ligand B (0.388), which is favorable for CNS penetration.

**Binding Affinity:** Both ligands have excellent binding affinity (-7.8 kcal/mol and -7.0 kcal/mol). Ligand A is slightly better, but the difference is not huge.

**Overall Assessment:**

Ligand B excels in BBB penetration and has a better QED score. However, Ligand A has a significantly lower DILI risk, better metabolic stability (lower Cl_mic), longer half-life, and lower P-gp efflux. The superior BBB of Ligand B is a strong point, but the combination of lower DILI, better metabolic stability, and lower efflux for Ligand A makes it a more promising candidate, particularly considering the solubility issues are present in both. The slight affinity advantage of Ligand A also contributes.

Output:
0
2025-04-17 07:05:46,776 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 drug candidates, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (380.901 and 380.417 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (67.66) is significantly better than Ligand B (114.18). For CNS targets, we want TPSA <= 90, so Ligand A is much closer to this threshold. Ligand B is considerably higher and may struggle with BBB penetration.

**3. logP:** Ligand A (2.337) is optimal (1-3). Ligand B (0.469) is low, potentially hindering permeation.

**4. H-Bond Donors:** Both ligands have 2 HBD, which is within the acceptable limit of <= 5.

**5. H-Bond Acceptors:** Ligand A has 6 HBA, and Ligand B has 7. Both are within the acceptable limit of <= 10.

**6. QED:** Both ligands have reasonable QED values (0.799 and 0.644), indicating good drug-like properties.

**7. DILI:** Both ligands have similar DILI risk (55.176 and 57.58), which are acceptable (below 60).

**8. BBB:** Ligand A (47.693) is considerably lower than Ligand B (61.535). While neither is >70, Ligand B is better positioned for CNS penetration.

**9. Caco-2 Permeability:** Ligand A (-5.369) and Ligand B (-4.988) both have negative values, which is unusual. Lower values suggest poor permeability.

**10. Aqueous Solubility:** Both ligands have very poor aqueous solubility (-1.926 and -2.074). This is a concern for formulation.

**11. hERG Inhibition:** Ligand A (0.587) is slightly higher than Ligand B (0.072), suggesting a slightly higher potential for hERG inhibition, but both are relatively low.

**12. Microsomal Clearance:** Ligand B (-6.287) has a negative clearance, which is not possible. This is likely an error in the data. Ligand A (10.296) has a reasonable clearance.

**13. In vitro Half-Life:** Ligand A (16.289) has a longer half-life than Ligand B (-8.055). Again, the negative half-life for Ligand B is a data error.

**14. P-gp Efflux:** Ligand A (0.205) has lower P-gp efflux than Ligand B (0.057), which is favorable for CNS exposure.

**15. Binding Affinity:** Ligand B (-7.7) has a significantly stronger binding affinity than Ligand A (-9.0). This is a substantial advantage.

**Overall Assessment:**

Ligand B has a much stronger binding affinity, which is a critical factor for GPCR targets. However, it suffers from a low logP, high TPSA, and questionable (likely erroneous) ADME properties (negative clearance and half-life). Ligand A has better ADME properties (TPSA, logP, Pgp, clearance, half-life), but its binding affinity is weaker.

Given the importance of BBB penetration and logP for CNS GPCRs, and the significant affinity advantage of Ligand B, I would cautiously favor Ligand B *if* the negative clearance and half-life values are corrected. The affinity difference is large enough to potentially overcome the ADME liabilities, assuming they can be addressed through further optimization. However, the data issues with Ligand B are concerning.

Considering the errors in Ligand B's data, and the better, more reliable ADME profile of Ligand A, I will choose Ligand A.

Output:
1
2025-04-17 07:05:46,777 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (361.458 and 348.487 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (90.9) is better than Ligand B (67.43). Both are below the 90 A^2 threshold desirable for CNS targets.

**logP:** Ligand B (2.25) is optimal (1-3), while Ligand A (0.075) is quite low, potentially hindering membrane permeability.

**H-Bond Donors/Acceptors:** Ligand A (3 HBD, 5 HBA) and Ligand B (2 HBD, 3 HBA) both have acceptable numbers of H-bond donors and acceptors.

**QED:** Both ligands have good QED scores (0.512 and 0.628, respectively), indicating drug-like properties.

**DILI:** Ligand B (23.885) has a significantly lower DILI risk than Ligand A (5.196), which is a major advantage.

**BBB:** Both ligands have reasonably good BBB penetration (Ligand A: 53.16, Ligand B: 57.154). However, neither exceeds 70, which would be highly desirable for a CNS target.

**Caco-2 Permeability:** Both have negative Caco-2 values (-5.087 and -5.096), which is unusual and suggests poor permeability. This is a concern for both.

**Aqueous Solubility:** Both have negative solubility values (-0.7 and -3.109) which is also unusual and suggests poor solubility.

**hERG:** Ligand A (0.247) has a lower hERG risk than Ligand B (0.53), which is favorable.

**Microsomal Clearance:** Ligand A (-10.294) has a much lower (better) microsomal clearance than Ligand B (47.656), indicating greater metabolic stability.

**In vitro Half-Life:** Ligand B (-4.067) has a longer half-life than Ligand A (0.514), which is preferable.

**P-gp Efflux:** Ligand A (0.01) has a significantly lower P-gp efflux liability than Ligand B (0.392), which is crucial for CNS penetration.

**Binding Affinity:** Ligand B (-8.4 kcal/mol) has a significantly stronger binding affinity than Ligand A (-7.2 kcal/mol). This >1.5 kcal/mol difference is substantial and can outweigh some ADME drawbacks.

**Overall Assessment:**

Ligand B has a much better binding affinity and a lower DILI risk. While its logP is good, its P-gp efflux is higher than Ligand A's. Ligand A has a better logP, lower P-gp efflux, and better metabolic stability, but suffers from weaker binding and higher DILI risk. Given the importance of affinity for GPCRs, and the substantial difference in binding energy, Ligand B is the more promising candidate despite its slightly higher P-gp efflux and DILI risk. The negative Caco-2 and solubility values are concerning for both, but can be addressed through formulation strategies.

Output:
1
2025-04-17 07:05:46,777 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (371.547 and 347.459 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (61.88) is significantly better than Ligand B (75.44). For CNS targets, TPSA should be <= 90, and lower is preferred. Ligand A is much closer to the optimal range.

**3. logP:** Both ligands have acceptable logP values (1.755 and 2.689), falling within the 1-3 range.

**4. H-Bond Donors:** Both have 1 HBD, which is good.

**5. H-Bond Acceptors:** Ligand A has 5 HBA, and Ligand B has 4. Both are acceptable (<=10).

**6. QED:** Ligand A (0.704) has a better QED score than Ligand B (0.55), indicating a more drug-like profile.

**7. DILI:** Ligand A (11.361) has a much lower DILI risk than Ligand B (26.871). Both are below 40, indicating low risk, but A is considerably better.

**8. BBB:** Ligand A (67.701) has a lower BBB penetration than Ligand B (75.533). While both are reasonably good, Ligand B is better for a CNS target.

**9. Caco-2 Permeability:** Ligand A (-5.685) has worse Caco-2 permeability than Ligand B (-4.731). Lower values indicate lower permeability.

**10. Aqueous Solubility:** Ligand A (-1.232) has slightly better aqueous solubility than Ligand B (-1.828).

**11. hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.366 and 0.254).

**12. Microsomal Clearance:** Ligand A (1.966) has significantly lower microsomal clearance than Ligand B (66.333), suggesting better metabolic stability.

**13. In vitro Half-Life:** Ligand A (3.97) has a slightly shorter in vitro half-life than Ligand B (3.371), but the difference is small.

**14. P-gp Efflux:** Ligand A (0.015) has much lower P-gp efflux than Ligand B (0.335), which is crucial for CNS penetration.

**15. Binding Affinity:** Ligand B (-8.1) has a significantly stronger binding affinity than Ligand A (-6.9). This is a >1.2 kcal/mol advantage, which is substantial.

**Overall Assessment:**

Ligand B has a superior binding affinity and better BBB penetration, which are critical for a CNS GPCR target like DRD2. However, Ligand A excels in several ADME properties: TPSA, QED, DILI, microsomal clearance, and P-gp efflux. The lower TPSA and P-gp efflux of Ligand A suggest better CNS exposure despite the slightly lower BBB score. The significantly better metabolic stability (lower Cl_mic) and lower DILI risk of Ligand A are also important advantages.

The binding affinity difference is significant, but the combined improvements in ADME properties for Ligand A, particularly the lower TPSA and P-gp efflux, make it a more promising starting point for optimization. While Ligand B's affinity is attractive, its higher TPSA, P-gp efflux, and DILI risk are concerning.

Output:
0
2025-04-17 07:05:46,777 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (364.833 Da) is slightly lower, which could be advantageous for permeability.

**TPSA:** Ligand A (82.61) is significantly better than Ligand B (111.63). For CNS targets, TPSA < 90 is preferred, and A is comfortably within this range, while B is pushing the limit.

**logP:** Ligand A (0.475) is lower than the optimal 1-3 range, potentially hindering permeability. Ligand B (-0.061) is even lower, raising more concerns about membrane penetration.

**H-Bond Donors/Acceptors:** Ligand A (HBD=1, HBA=4) is better than Ligand B (HBD=3, HBA=7) in terms of balancing solubility and permeability.

**QED:** Both ligands have acceptable QED values (A: 0.77, B: 0.573), indicating reasonable drug-likeness.

**DILI:** Both ligands have relatively low DILI risk (A: 30.942, B: 37.844), which is good.

**BBB:** Ligand A (33.346) has a very low BBB penetration percentile, which is a major drawback for a CNS target like DRD2. Ligand B (27.801) is even worse. This is a critical failure for both.

**Caco-2 Permeability:** Both have negative Caco-2 values which is unusual and indicates poor permeability.

**Aqueous Solubility:** Both ligands have poor aqueous solubility (-2.399 and -1.207 respectively).

**hERG Inhibition:** Both ligands show very low hERG inhibition risk (A: 0.081, B: 0.232), which is positive.

**Microsomal Clearance:** Ligand A (-6.818) has a lower (better) microsomal clearance than Ligand B (-12.279), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (7.713 hours) has a longer half-life than Ligand B (-3.019 hours), which is desirable.

**P-gp Efflux:** Ligand A (0.004) has a significantly lower P-gp efflux liability than Ligand B (0.038), which is crucial for CNS penetration.

**Binding Affinity:** Ligand B (-8.2 kcal/mol) has a slightly better binding affinity than Ligand A (-7.9 kcal/mol), but the difference is small (0.3 kcal/mol) and may not outweigh the significant ADME deficiencies.

**Overall Assessment:**

Despite the slightly better affinity of Ligand B, Ligand A is the more promising candidate. The major issue for both is the extremely poor BBB penetration. However, Ligand A has a better TPSA, lower P-gp efflux, better metabolic stability, and a longer half-life. While its logP is suboptimal, the combination of these factors makes it marginally more likely to be optimized into a viable drug candidate. The poor BBB penetration of both compounds would need to be addressed through structural modifications.

Output:
0
2025-04-17 07:05:46,778 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (342.443 and 363.462 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (69.04) is significantly better than Ligand B (85.0). For CNS targets, we want TPSA <= 90, and A is comfortably within that, while B is approaching the upper limit.

**3. logP:** Both ligands have good logP values (2.477 and 2.858), falling within the optimal 1-3 range.

**4. H-Bond Donors:** Both have 1 HBD, which is acceptable.

**5. H-Bond Acceptors:** Ligand A has 5 HBA, and Ligand B has 6. Both are within the acceptable limit of <=10.

**6. QED:** Both have similar QED values (0.8 and 0.853), indicating good drug-likeness.

**7. DILI:** Ligand B (61.574) has a higher DILI risk than Ligand A (16.285). This is a significant advantage for A.

**8. BBB:** Ligand B (85.459) has a substantially better BBB penetration score than Ligand A (57.852). This is a critical factor for a CNS target like DRD2.

**9. Caco-2 Permeability:** Both have negative Caco-2 values (-4.746 and -4.885). These values are unusual and likely indicate poor permeability in this assay. However, the negative values are similar, so this isn't a major differentiator.

**10. Aqueous Solubility:** Both have negative solubility values (-1.927 and -3.93). Similar to Caco-2, these are concerning but comparable.

**11. hERG Inhibition:** Both ligands have low hERG inhibition risk (0.37 and 0.454).

**12. Microsomal Clearance:** Ligand B (34.842) has significantly lower microsomal clearance than Ligand A (51.729), suggesting better metabolic stability.

**13. In vitro Half-Life:** Ligand A has a much longer in vitro half-life (-10.158 hours) than Ligand B (8.19 hours).

**14. P-gp Efflux:** Both have low P-gp efflux liability (0.089 and 0.137).

**15. Binding Affinity:** Ligand A (-8.3 kcal/mol) has a slightly better binding affinity than Ligand B (-7.4 kcal/mol). While the difference is less than the 1.5 kcal/mol threshold, it's still a positive for A.

**Overall Assessment:**

Ligand A excels in DILI risk, half-life, and TPSA, and has slightly better affinity. Ligand B shines in BBB penetration and metabolic stability. Given that this is a CNS target (DRD2), BBB penetration is paramount. However, the significantly lower DILI risk for Ligand A is a major advantage, and the slightly better affinity contributes. The longer half-life of A is also beneficial. The comparable, and both poor, Caco-2 and solubility values are a concern for both, but can be addressed with formulation strategies.

Considering the balance, the superior BBB of Ligand B is compelling, but the significantly lower DILI risk of Ligand A, coupled with its better half-life and affinity, makes it the more promising candidate.

Output:
0
2025-04-17 07:05:46,778 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (365.47 and 345.443 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (46.61) is excellent, well below the 90 A^2 threshold for CNS targets. Ligand B (69.72) is higher, but still potentially acceptable.

**logP:** Ligand A (4.039) is at the upper end of the optimal range (1-3), potentially raising concerns about solubility and off-target effects. Ligand B (0.944) is below the optimal range and could have permeability issues.

**H-Bond Donors/Acceptors:** Both ligands have reasonable HBD (0/1) and HBA (3/3) counts, satisfying the <5 and <10 rules, respectively.

**QED:** Ligand A (0.709) has a good drug-likeness score. Ligand B (0.384) is significantly lower, indicating a less favorable drug-like profile.

**DILI:** Ligand A (63.397) has a moderate DILI risk, while Ligand B (29.081) has a low DILI risk.

**BBB:** Ligand A (59.325) has a moderate BBB penetration, while Ligand B (54.944) is also moderate. Both are below the desirable >70 for CNS targets, but not dramatically so.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.287 and -4.596), which is unusual and suggests poor permeability. These values are likely errors or indicate very poor absorption.

**Aqueous Solubility:** Both ligands have negative solubility values (-5.808 and -1.773), which is also unusual and suggests very poor solubility. These values are likely errors or indicate very poor solubility.

**hERG Inhibition:** Ligand A (0.775) has a slightly higher hERG risk than Ligand B (0.098).

**Microsomal Clearance:** Ligand A (118.214) has a higher clearance, suggesting lower metabolic stability. Ligand B (27.597) has a lower clearance, indicating better metabolic stability.

**In vitro Half-Life:** Ligand A (3.684) has a shorter half-life. Ligand B (-29.763) has a very negative half-life, which is likely an error.

**P-gp Efflux:** Ligand A (0.524) has moderate P-gp efflux liability. Ligand B (0.014) has very low P-gp efflux liability, which is favorable for CNS penetration.

**Binding Affinity:** Ligand A (-8.9 kcal/mol) has significantly stronger binding affinity than Ligand B (-7.4 kcal/mol). This >1.5 kcal/mol difference is a major advantage.

**Overall Assessment:**

Despite the unusual negative values for Caco-2 and solubility, the most important factor for a CNS GPCR target like DRD2 is binding affinity. Ligand A has a substantially stronger binding affinity (-8.9 kcal/mol vs -7.4 kcal/mol). While Ligand A has a higher logP and moderate DILI risk, the strong affinity is likely to outweigh these drawbacks. Ligand B's lower affinity, combined with its lower QED, makes it less promising. The lower P-gp efflux for Ligand B is a positive, but not enough to overcome the affinity difference.

Output:
1
2025-04-17 07:05:46,778 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 drug candidates, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (356.388 and 356.352 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (49.41) is significantly better than Ligand B (87.75). For a CNS target like DRD2, TPSA should be <=90, and A is comfortably within this range, while B is approaching the upper limit.

**3. logP:** Both ligands have good logP values (3.465 and 2.895), falling within the optimal 1-3 range.

**4. H-Bond Donors:** Ligand A (1) is preferable to Ligand B (3). Lower HBD generally improves permeability.

**5. H-Bond Acceptors:** Ligand A (2) is preferable to Ligand B (6). Lower HBA generally improves permeability.

**6. QED:** Both ligands have acceptable QED values (0.849 and 0.738), indicating good drug-like properties.

**7. DILI:** Ligand A (39.434) has a much lower DILI risk than Ligand B (61.962).  A DILI percentile <40 is ideal, so A is significantly better.

**8. BBB:** Ligand A (88.29) has a substantially higher BBB penetration percentile than Ligand B (75.339). This is *critical* for a CNS target like DRD2, making A far more promising.

**9. Caco-2 Permeability:** Ligand A (-4.756) and Ligand B (-4.91) both have negative values, indicating poor permeability. However, the scale isn't specified, so it's hard to interpret the absolute difference.

**10. Aqueous Solubility:** Both ligands have poor aqueous solubility (-3.696 and -4.296). This could pose formulation challenges, but is less critical than BBB penetration for a CNS drug.

**11. hERG Inhibition:** Ligand A (0.801) has a slightly higher hERG risk than Ligand B (0.519). However, both are relatively low, and this isn't a major concern.

**12. Microsomal Clearance:** Ligand A (57.066) has a higher microsomal clearance than Ligand B (24.593), indicating lower metabolic stability. This is a drawback for A.

**13. In vitro Half-Life:** Ligand B (-1.295) has a negative half-life, which is concerning and likely an error or indicates very rapid degradation. Ligand A (7.444) has a reasonable half-life.

**14. P-gp Efflux:** Ligand A (0.296) has a lower P-gp efflux liability than Ligand B (0.037), which is beneficial for CNS exposure.

**15. Binding Affinity:** Ligand A (-9.5 kcal/mol) has a slightly better binding affinity than Ligand B (-8.7 kcal/mol). While both are strong binders, the 0.8 kcal/mol difference is significant.

**Overall Assessment:**

Ligand A is the superior candidate. Its significantly better BBB penetration, lower DILI risk, lower HBD/HBA counts, and slightly better binding affinity outweigh its higher microsomal clearance and slightly higher hERG risk. The negative half-life for Ligand B is a major red flag. The GPCR-specific priorities of BBB and logP strongly favor Ligand A.

Output:
1
2025-04-17 07:05:46,778 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (345.407 Da) is slightly lower, which could be beneficial for permeability, but both are acceptable.

**TPSA:** Ligand A (97.94) is better than Ligand B (26.63) for CNS penetration, falling comfortably under the 90 A^2 threshold. Ligand B is excellent.

**logP:** Ligand A (0.086) is quite low, potentially hindering membrane permeability and brain penetration. Ligand B (3.909) is within the optimal range (1-3). This is a significant advantage for Ligand B.

**H-Bond Donors/Acceptors:** Ligand A (1 HBD, 7 HBA) and Ligand B (0 HBD, 4 HBA) both have reasonable numbers of H-bond donors and acceptors, well within the guidelines.

**QED:** Both ligands have acceptable QED values (Ligand A: 0.828, Ligand B: 0.668), indicating good drug-like properties.

**DILI:** Ligand A (54.556) has a higher DILI risk than Ligand B (22.838), suggesting potential liver toxicity concerns.

**BBB:** Ligand B (92.943) has a significantly higher BBB percentile than Ligand A (57.193). This is a crucial advantage for a CNS target like DRD2.

**Caco-2 Permeability:** Ligand A (-5.172) has poor Caco-2 permeability, while Ligand B (-4.789) is also low, but slightly better.

**Aqueous Solubility:** Ligand A (-1.147) and Ligand B (-3.916) both have poor aqueous solubility.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (Ligand A: 0.082, Ligand B: 0.947).

**Microsomal Clearance:** Ligand B (57.598) has higher microsomal clearance than Ligand A (25.96), suggesting faster metabolism and potentially lower exposure.

**In vitro Half-Life:** Ligand B (32.794) has a longer in vitro half-life than Ligand A (28.12), which is favorable.

**P-gp Efflux:** Ligand A (0.051) has lower P-gp efflux liability than Ligand B (0.749), which is beneficial for CNS exposure.

**Binding Affinity:** Both ligands have excellent binding affinity (-8.0 kcal/mol and -8.2 kcal/mol respectively), with Ligand B being slightly better. The affinity difference is small and likely less important than the ADME differences.

**Overall Assessment:**

Ligand B is the superior candidate. While Ligand A has slightly better P-gp efflux, Ligand B excels in critical areas for a CNS GPCR target: significantly better BBB penetration, a more favorable logP, lower DILI risk, and a slightly longer half-life. The slightly higher clearance of Ligand B is a minor drawback compared to the significant advantages in CNS penetration and safety. The similar binding affinities make the ADME profile the deciding factor.

Output:
1
2025-04-17 07:05:46,779 - INFO - Reasoning:

Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (384.351 Da) is slightly higher than Ligand B (359.539 Da), but both are acceptable.

**TPSA:** Ligand A (86.71) is better than Ligand B (45.23). For CNS targets, we want TPSA <= 90, and both are well within this range. Ligand B is significantly better, suggesting improved BBB penetration potential.

**logP:** Ligand A (1.137) is within the optimal range (1-3), while Ligand B (3.183) is at the higher end. Both are acceptable, but Ligand A's lower logP might indicate better solubility.

**H-Bond Donors/Acceptors:** Ligand A has 2 HBD and 4 HBA, while Ligand B has 1 HBD and 4 HBA. Both are within the acceptable limits (<=5 HBD and <=10 HBA).

**QED:** Both ligands have good QED scores (Ligand A: 0.72, Ligand B: 0.847), indicating a generally drug-like profile. Ligand B is slightly better.

**DILI:** Ligand A has a DILI risk of 63.513, which is approaching the higher risk threshold (>60). Ligand B has a much lower DILI risk (16.208), a significant advantage.

**BBB:** Ligand A has a BBB penetration of 55.797, which is below the desirable threshold of >70 for CNS targets. Ligand B has a much higher BBB penetration (79.566), a crucial advantage for a DRD2 ligand.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.273 and -5.258). These values are difficult to interpret without knowing the scale, but negative values are not ideal.

**Aqueous Solubility:** Both ligands have negative solubility values (-3.556 and -3.487). Similar to Caco-2, these are difficult to interpret without the scale, but negative values are not ideal.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.486 and 0.57).

**Microsomal Clearance:** Ligand A (26.653) has lower microsomal clearance than Ligand B (69.397), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (11.229) has a slightly longer half-life than Ligand B (9.326).

**P-gp Efflux:** Ligand A (0.103) has lower P-gp efflux liability than Ligand B (0.219), which is favorable for CNS penetration.

**Binding Affinity:** Ligand B (-7.8 kcal/mol) has a significantly stronger binding affinity than Ligand A (-8.8 kcal/mol). This is a substantial advantage, potentially outweighing some of the ADME drawbacks of Ligand A.

**Overall Assessment:**

Ligand B is the stronger candidate. While Ligand A has better metabolic stability and P-gp efflux, Ligand B excels in the most critical areas for a CNS-targeting GPCR ligand: **BBB penetration and binding affinity**. The significantly lower DILI risk for Ligand B is also a major benefit. The slightly higher logP of Ligand B is not a major concern given its strong affinity.

Output:
1
2025-04-17 07:05:46,779 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (359.373 and 358.429 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (95.67) is slightly above the preferred <90 for CNS targets, but still reasonable. Ligand B (66.57) is well within the optimal range for CNS penetration. This gives a slight edge to Ligand B.

**3. logP:** Ligand A (1.568) is within the optimal range (1-3). Ligand B (3.898) is approaching the upper limit, but still acceptable.

**4. H-Bond Donors:** Both ligands have acceptable HBD counts (2 and 1, respectively), well below the threshold of 5.

**5. H-Bond Acceptors:** Both ligands have acceptable HBA counts (5 and 4, respectively), below the threshold of 10.

**6. QED:** Both ligands have similar QED values (0.77 and 0.727), indicating good drug-like properties.

**7. DILI:** Ligand A (43.234) has a slightly higher DILI risk than Ligand B (21.753), which is preferable.

**8. BBB:** Ligand B (94.61) has a significantly higher BBB penetration percentile than Ligand A (75.572). This is a crucial advantage for a CNS target like DRD2.

**9. Caco-2 Permeability:** Ligand A (-4.595) has a lower Caco-2 permeability than Ligand B (-4.301), suggesting potentially poorer intestinal absorption.

**10. Aqueous Solubility:** Ligand A (-2.485) has slightly better aqueous solubility than Ligand B (-3.712).

**11. hERG Inhibition:** Ligand A (0.261) has a lower hERG inhibition risk than Ligand B (0.877), which is beneficial.

**12. Microsomal Clearance:** Ligand B (61.377) has higher microsomal clearance than Ligand A (33.281), indicating faster metabolism and potentially lower exposure.

**13. In vitro Half-Life:** Ligand A (-38.058) has a longer in vitro half-life than Ligand B (-8.501), which is preferable.

**14. P-gp Efflux:** Ligand A (0.028) has significantly lower P-gp efflux liability than Ligand B (0.52), suggesting better CNS exposure.

**15. Binding Affinity:** Ligand A (-7.6) has a slightly better binding affinity than Ligand B (-7.0), although both are excellent. The 0.6 kcal/mol difference is significant.

**Overall Assessment:**

While Ligand A has a better binding affinity, longer half-life, lower P-gp efflux, and lower hERG risk, Ligand B excels in BBB penetration and has a lower DILI risk. Given the CNS target (DRD2), BBB penetration is paramount. The slightly stronger binding affinity of Ligand A is outweighed by the superior CNS penetration of Ligand B. The lower DILI risk of Ligand B is also a positive factor.

Output:
1
2025-04-17 07:05:46,779 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B based on the provided guidelines, prioritizing GPCR-specific properties (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (356.373) is slightly lower, which could be beneficial for permeability.

**TPSA:** Ligand A (98.32) is closer to the desirable threshold of 90 for CNS targets than Ligand B (78.87). Both are acceptable, but A is slightly less favorable.

**logP:** Ligand A (0.988) is at the lower end of the optimal range (1-3), potentially hindering permeation. Ligand B (0.401) is even lower, raising more concerns about permeability.

**H-Bond Donors/Acceptors:** Both ligands have acceptable HBD (3/2) and HBA (4/4) counts.

**QED:** Both ligands have reasonable QED values (0.752 and 0.65), indicating good drug-likeness.

**DILI:** Ligand B (35.479) has a significantly lower DILI risk than Ligand A (62.233), making it more favorable from a toxicity perspective.

**BBB:** Ligand B (64.831) has a better BBB percentile than Ligand A (57.425), which is crucial for CNS targets like DRD2. While both are below the ideal >70, B is better.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values, which is unusual and suggests poor permeability. However, the scale is not specified, so it's difficult to interpret this fully.

**Aqueous Solubility:** Both ligands have negative solubility values, which is also unusual and suggests poor solubility.

**hERG Inhibition:** Both ligands show low hERG inhibition liability (0.329 and 0.474), which is good.

**Microsomal Clearance:** Ligand A (-4.66) has a more negative value, indicating lower clearance and thus better metabolic stability than Ligand B (-13.206).

**In vitro Half-Life:** Ligand A (-35.675) has a more negative value, suggesting a longer half-life than Ligand B (-20.833).

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.039 and 0.018), which is favorable for CNS penetration.

**Binding Affinity:** Both ligands have comparable binding affinities (-8.4 and -8.5 kcal/mol), which are excellent. The difference is negligible.

**Overall Assessment:**

Considering the GPCR-specific priorities, Ligand B is slightly more promising. Its better BBB penetration and significantly lower DILI risk are key advantages. While its logP is lower than ideal, the strong binding affinity might compensate. Ligand A has better metabolic stability and half-life, but the higher DILI risk and lower BBB penetration are concerning for a CNS target. The negative solubility and Caco-2 values for both are a concern, but the binding affinity is strong enough to warrant further investigation of Ligand B.

Output:
1
2025-04-17 07:05:46,780 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B based on the provided guidelines, prioritizing GPCR-specific properties (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (374.39 Da) is slightly lower, which could be advantageous for permeability.

**TPSA:** Both ligands have TPSA values below 140, and even below 100, which is excellent for CNS penetration. Ligand A (102.01) is slightly higher than Ligand B (98.58), but both are very good.

**logP:** Ligand A (0.835) is a bit low, potentially hindering membrane permeability. Ligand B (2.392) is within the optimal range (1-3). This is a significant advantage for Ligand B.

**H-Bond Donors/Acceptors:** Ligand A (1 HBD, 6 HBA) and Ligand B (3 HBD, 6 HBA) both fall within acceptable limits.

**QED:** Both ligands have reasonable QED scores (A: 0.74, B: 0.633), indicating good drug-like properties.

**DILI:** Ligand A (69.833) has a higher DILI risk than Ligand B (41.993), although both are below the concerning threshold of 60.

**BBB:** Both ligands show good BBB penetration (A: 70.415, B: 63.009), but Ligand A is slightly better, exceeding the 70% threshold.

**Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and suggests a potential issue with the data or modeling. However, the negative values suggest poor permeability.

**Aqueous Solubility:** Both have negative solubility values, which is also unusual and suggests a potential issue with the data or modeling.

**hERG Inhibition:** Both ligands have very low hERG inhibition risk (A: 0.094, B: 0.598), which is excellent.

**Microsomal Clearance:** Ligand A (11.461) has significantly lower microsomal clearance than Ligand B (36.265), indicating better metabolic stability.

**In vitro Half-Life:** Ligand A (47.095) has a substantially longer half-life than Ligand B (5.003), which is a major advantage.

**P-gp Efflux:** Ligand A (0.054) has much lower P-gp efflux liability than Ligand B (0.114), which is crucial for CNS penetration.

**Binding Affinity:** Ligand B (-8.0 kcal/mol) has a slightly better binding affinity than Ligand A (-7.9 kcal/mol), but the difference is minimal.

**Overall Assessment:**

While Ligand A has a slightly better BBB score and significantly better metabolic stability, half-life, and P-gp efflux, its low logP is a major concern. Ligand B has a more optimal logP and a slightly better binding affinity. Considering the GPCR-specific priorities, logP and Pgp are critical for CNS targets. The slightly better logP of Ligand B, coupled with its acceptable BBB penetration, makes it the more promising candidate despite the slightly lower metabolic stability and higher P-gp efflux.

Output:
1
2025-04-17 07:05:46,780 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (357.34 and 394.806 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Both ligands have TPSA values (81.73 and 81.22) that are acceptable for oral absorption (<140), but slightly higher than optimal for CNS penetration (<90).

**3. logP:** Ligand A (1.399) is within the optimal range (1-3), while Ligand B (2.368) is also acceptable, leaning towards the higher end.

**4. H-Bond Donors:** Ligand A (0) is excellent, minimizing potential issues with permeability. Ligand B (1) is also good.

**5. H-Bond Acceptors:** Ligand A (7) is good, below the 10 threshold. Ligand B (5) is also good.

**6. QED:** Both ligands have similar QED values (0.808 and 0.782), indicating good drug-like properties.

**7. DILI:** Ligand A (69.135) has a slightly higher DILI risk than Ligand B (60.295), but both are reasonably acceptable.

**8. BBB:** Ligand B (82.939) has a significantly better BBB penetration percentile than Ligand A (72.315). This is a crucial factor for a CNS target like DRD2.

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.869 and -4.893), which is unusual and suggests poor permeability. This is a significant concern.

**10. Aqueous Solubility:** Both ligands have negative solubility values (-2.301 and -3.283), indicating poor aqueous solubility. This is also a concern for bioavailability.

**11. hERG Inhibition:** Ligand A (0.092) has a very low hERG risk, which is excellent. Ligand B (0.305) has a slightly higher, but still acceptable, hERG risk.

**12. Microsomal Clearance:** Ligand A (15.383) has a lower microsomal clearance than Ligand B (41.945), suggesting better metabolic stability.

**13. In vitro Half-Life:** Ligand A (-19.199) has a negative half-life, which is not physically possible and indicates a data issue. Ligand B (14.783) has a reasonable in vitro half-life.

**14. P-gp Efflux:** Ligand A (0.032) has very low P-gp efflux liability, which is favorable for CNS penetration. Ligand B (0.361) has a slightly higher, but still acceptable, P-gp efflux liability.

**15. Binding Affinity:** Ligand A (-8.6 kcal/mol) has a significantly stronger binding affinity than Ligand B (-7.0 kcal/mol). This is a substantial advantage.

**Overall Assessment:**

Despite the concerning Caco-2 and solubility values for both, Ligand A stands out due to its superior binding affinity (-8.6 vs -7.0 kcal/mol) and lower P-gp efflux. The significantly better affinity likely outweighs the slightly higher DILI risk and the problematic half-life value. The lower clearance is also a positive. Ligand B has a better BBB score, but the weaker affinity is a major drawback. The negative half-life for ligand A is concerning, but could be an outlier or data error. Given the importance of affinity for GPCRs, and the relatively good BBB score of ligand A, it is the more promising candidate.

Output:
0
2025-04-17 07:05:46,780 - INFO - Batch 336 complete. Total preferences: 5376
2025-04-17 07:05:46,780 - INFO - Processing batch 337/512...
2025-04-17 07:06:28,041 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight (MW):** Both ligands (345.403 and 352.519 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (104.29) is slightly above the optimal <90 for CNS targets, but still reasonable. Ligand B (58.64) is excellent, well below 90. This favors Ligand B.

**3. logP:** Both ligands have good logP values (1.021 and 2.837), falling within the 1-3 range. Ligand B is slightly better positioned within the optimal range.

**4. H-Bond Donors (HBD):** Both ligands have acceptable HBD counts (2 and 1, respectively), well below the limit of 5.

**5. H-Bond Acceptors (HBA):** Both ligands have acceptable HBA counts (7 and 3, respectively), below the limit of 10.

**6. QED:** Both ligands have similar and good QED values (0.838 and 0.8), indicating good drug-like properties.

**7. DILI:** Ligand A has a DILI risk of 72.043, which is approaching the higher risk threshold (>60). Ligand B has a much lower DILI risk of 26.095, which is excellent. This strongly favors Ligand B.

**8. BBB:** Ligand A has a BBB penetration of 70.919, which is acceptable but not outstanding. Ligand B has a significantly higher BBB penetration of 80.884, which is very desirable for a CNS target like DRD2. This is a major advantage for Ligand B.

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.997 and -4.442). This is unusual and suggests poor permeability. However, the scale is not specified, so it's hard to interpret.

**10. Aqueous Solubility:** Both ligands have negative solubility values (-3.57 and -2.482). Similar to Caco-2, the scale is unknown, making interpretation difficult.

**11. hERG Inhibition:** Both ligands have low hERG inhibition risk (0.468 and 0.339), which is good.

**12. Microsomal Clearance:** Ligand A has a lower microsomal clearance (10.955) compared to Ligand B (54.549), suggesting better metabolic stability. This favors Ligand A.

**13. In vitro Half-Life:** Both ligands have similar and negative in vitro half-lives (-9.222 and -9.482). Again, the scale is unknown.

**14. P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.08 and 0.088), which is excellent and promotes CNS exposure.

**15. Binding Affinity:** Ligand A has a slightly better binding affinity (-8.4 kcal/mol) than Ligand B (-7.9 kcal/mol). This is a 0.5 kcal/mol difference, which is significant but not overwhelming.

**Overall Assessment:**

Ligand B clearly outperforms Ligand A in several critical areas for a CNS-targeting GPCR ligand. It has a significantly better BBB score, lower DILI risk, and a more favorable TPSA. While Ligand A has better metabolic stability (lower Cl_mic) and slightly better binding affinity, the advantages of Ligand B in terms of CNS penetration and safety profile are more important. The affinity difference is not large enough to overcome these advantages.

Output:
1
2025-04-17 07:06:28,041 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (344.375 and 352.475 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (111.03) is slightly above the optimal <90 for CNS targets, but still reasonable. Ligand B (59.08) is excellent, well below 90.

**logP:** Ligand A (-0.168) is quite low, potentially hindering membrane permeability. Ligand B (2.191) is within the optimal 1-3 range. This is a significant advantage for Ligand B.

**H-Bond Donors/Acceptors:** Ligand A (2 HBD, 7 HBA) is acceptable. Ligand B (0 HBD, 4 HBA) is also good, with fewer H-bonds potentially aiding permeability.

**QED:** Both ligands have acceptable QED values (0.779 and 0.659, respectively), indicating good drug-like properties.

**DILI:** Ligand A (81.078) has a higher DILI risk than Ligand B (10.818). This is a substantial negative for Ligand A.

**BBB:** Ligand A (43.583) has a poor BBB penetration percentile, making it less suitable for a CNS target like DRD2. Ligand B (90.074) has excellent BBB penetration, a critical advantage.

**Caco-2 Permeability:** Ligand A (-5.419) shows poor permeability. Ligand B (-4.405) is also not great, but slightly better.

**Aqueous Solubility:** Both ligands have very poor aqueous solubility (-1.775 and -1.877, respectively). This could pose formulation challenges.

**hERG Inhibition:** Ligand A (0.048) has a very low hERG risk, which is positive. Ligand B (0.322) is slightly higher, but still relatively low.

**Microsomal Clearance:** Ligand A (4.956) has lower clearance than Ligand B (34.158), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (19.895) has a longer half-life than Ligand B (-2.061).

**P-gp Efflux:** Ligand A (0.003) has very low P-gp efflux, which is excellent for CNS penetration. Ligand B (0.069) is also low, but higher than Ligand A.

**Binding Affinity:** Both ligands have the same binding affinity (-7.6 kcal/mol), which is excellent and removes this as a differentiating factor.

**Overall Assessment:**

Ligand B is significantly more promising. While both have poor solubility, Ligand B excels in crucial areas for a CNS-targeting GPCR ligand: excellent BBB penetration, a favorable logP, low DILI risk, and acceptable P-gp efflux. Ligand A's low logP and poor BBB penetration are major drawbacks. Although Ligand A has better metabolic stability and a slightly longer half-life, the ADME advantages of Ligand B outweigh these factors, especially given the equal binding affinity.

Output:
1
2025-04-17 07:06:28,042 - INFO - Reasoning:

Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (336.347 Da) is slightly lower, which is generally favorable for permeability.

**2. TPSA:** Ligand A (68.71) is excellent, well below the 90 A^2 threshold for CNS targets. Ligand B (85.09) is still reasonable but less optimal.

**3. logP:** Ligand A (3.997) is at the upper end of the optimal range (1-3), but still acceptable. Ligand B (1.446) is lower, potentially hindering permeation.

**4. H-Bond Donors:** Ligand A (0) is ideal. Ligand B (2) is acceptable.

**5. H-Bond Acceptors:** Ligand A (6) is good. Ligand B (7) is also acceptable.

**6. QED:** Both ligands have good QED values (A: 0.525, B: 0.736), indicating drug-like properties.

**7. DILI:** Ligand A (95.89) has a high DILI risk, which is a significant concern. Ligand B (47.421) has a much lower, and acceptable, DILI risk.

**8. BBB:** Ligand A (76.037) has a good BBB penetration percentile. Ligand B (55.991) is lower, which is a disadvantage for a CNS target like DRD2.

**9. Caco-2:** Both have negative values, which is unusual. Assuming these are logP-scale values, Ligand A (-4.477) suggests very poor permeability, while Ligand B (-5.589) is even worse. This is a major red flag for both.

**10. Solubility:** Ligand A (-6.505) has very poor solubility. Ligand B (-1.812) is also poor, but comparatively better.

**11. hERG:** Ligand A (0.815) has a low hERG risk. Ligand B (0.28) is even lower, which is excellent.

**12. Cl_mic:** Ligand A (134.103) has a relatively high microsomal clearance, suggesting lower metabolic stability. Ligand B (6.167) has very low clearance, indicating good metabolic stability.

**13. t1/2:** Ligand A (65.546) has a reasonable in vitro half-life. Ligand B (36.625) is shorter, but not drastically so.

**14. Pgp:** Ligand A (0.736) has moderate P-gp efflux. Ligand B (0.211) has low P-gp efflux, which is favorable for CNS penetration.

**15. Binding Affinity:** Ligand B (-8.8 kcal/mol) has a slightly better binding affinity than Ligand A (-8.3 kcal/mol), but the difference is not substantial enough to override other major drawbacks.

**Overall Assessment:**

Ligand A has a good BBB score and acceptable TPSA and logP, but is severely hampered by its high DILI risk, poor solubility, poor Caco-2 permeability, and higher metabolic clearance.

Ligand B has a lower DILI risk, better metabolic stability, lower P-gp efflux, and a slightly better binding affinity. While its BBB score is lower and its logP is less optimal, these are less critical concerns than the issues with Ligand A. The poor Caco-2 values for both are concerning, but the other properties of Ligand B make it the more promising candidate.

Output:
1
2025-04-17 07:06:28,042 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (351.403 and 346.391 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (107.97) is better than Ligand B (121.89). For CNS targets, we prefer TPSA <= 90, so both are somewhat high, but A is closer.

**3. logP:** Ligand B (0.845) is better than Ligand A (-1.368). The optimal range is 1-3, so B is within range, while A is below 1, potentially hindering permeation.

**4. H-Bond Donors:** Both ligands have 3 HBD, which is acceptable (<=5).

**5. H-Bond Acceptors:** Ligand A has 5 HBA, and Ligand B has 6. Both are within the acceptable range (<=10).

**6. QED:** Ligand B (0.609) is better than Ligand A (0.369). A QED >= 0.5 is desirable, and B is closer to this threshold.

**7. DILI:** Ligand A (25.165) is significantly better than Ligand B (73.982). Lower DILI is crucial, and A is well below the 40% threshold, while B is above 60%, indicating higher liver injury risk.

**8. BBB:** Ligand A (25.863) is slightly better than Ligand B (29.042), but both are quite low. For a CNS target like DRD2, >70% is desirable. Both ligands have poor predicted BBB penetration.

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.132 and -5.373), which is unusual and suggests poor permeability.

**10. Aqueous Solubility:** Both ligands have negative solubility values (-1.21 and -2.769), also unusual and suggesting poor solubility.

**11. hERG Inhibition:** Ligand A (0.044) is better than Ligand B (0.311). Lower hERG inhibition is preferred.

**12. Microsomal Clearance:** Ligand A (-14.437) is much better than Ligand B (5.632). Lower clearance indicates better metabolic stability.

**13. In vitro Half-Life:** Both ligands have similar negative half-life values (-28.296 and -27.686), which is not realistic.

**14. P-gp Efflux:** Ligand A (0.006) is significantly better than Ligand B (0.014). Lower P-gp efflux is crucial for CNS penetration.

**15. Binding Affinity:** Ligand B (-8.1) is better than Ligand A (-7.6). A difference of 0.5 kcal/mol is significant and can outweigh some ADME drawbacks.

**Overall Assessment:**

Despite the similar MW, Ligand B has a better logP and binding affinity. However, Ligand A has a much better safety profile (DILI, hERG) and better metabolic stability (Cl_mic). Both have poor predicted BBB penetration, Caco-2 permeability, and solubility. Given the GPCR-specific priorities and the importance of safety and metabolic stability for chronic CNS therapies, the lower DILI and better metabolic stability of Ligand A are more compelling, even with the slightly weaker binding affinity. The slightly better Pgp efflux for A also helps.

Output:
0
2025-04-17 07:06:28,042 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B based on the provided guidelines, prioritizing GPCR-specific properties (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (360.376 and 351.491 Da) fall within the ideal range of 200-500 Da.

**TPSA:** Ligand A (71.19) is excellent, well below the 90 A^2 threshold for CNS targets. Ligand B (78.51) is still reasonable, but less optimal.

**logP:** Ligand A (3.532) is at the higher end of the optimal range (1-3), while Ligand B (1.858) is towards the lower end. While both are within range, a slightly higher logP can be beneficial for GPCRs.

**H-Bond Donors/Acceptors:** Both ligands have 2 HBD and 3 HBA, which are within acceptable limits.

**QED:** Ligand A (0.807) has a significantly better QED score than Ligand B (0.466), indicating a more drug-like profile.

**DILI:** Ligand A (52.113) has a moderate DILI risk, while Ligand B (19.038) has a very low DILI risk. This favors Ligand B.

**BBB:** Ligand A (85.227) has excellent BBB penetration (above 70%), crucial for a CNS target like DRD2. Ligand B (61.691) is lower, and while not terrible, is less desirable.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.384 and -4.688), which is unusual and suggests poor permeability. However, these values are on a scale where negative values are possible and don't necessarily disqualify a compound.

**Aqueous Solubility:** Both ligands have negative solubility values (-4.087 and -1.773), suggesting poor aqueous solubility. This is a concern, but can sometimes be overcome with formulation strategies.

**hERG Inhibition:** Both ligands show very low hERG inhibition risk (0.534 and 0.199).

**Microsomal Clearance:** Ligand A (37.083) and Ligand B (41.662) have similar microsomal clearance values.

**In vitro Half-Life:** Ligand A (-21.134) has a negative half-life, which is not physically possible and indicates a data error or unusual behavior. Ligand B (-3.996) is also negative, but less extreme.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.166 and 0.04).

**Binding Affinity:** Ligand A (-9.1 kcal/mol) has a significantly stronger binding affinity than Ligand B (-7.6 kcal/mol). This is a substantial advantage, potentially outweighing some of the ADME concerns.

**Overall Assessment:**

Ligand A excels in BBB penetration and, critically, binding affinity. Its QED score is also much better. However, its negative in vitro half-life is a major red flag. Ligand B has a better safety profile (lower DILI) but weaker affinity and poorer BBB penetration. The negative half-life for ligand A is a significant issue that casts doubt on its viability. While the affinity difference is substantial, a negative half-life suggests rapid metabolism or instability, making it unlikely to achieve sufficient *in vivo* exposure.

Output:
1
2025-04-17 07:06:28,042 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B based on the provided guidelines, prioritizing GPCR-specific properties (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (346.45 and 356.482 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (56.73) is significantly better than Ligand B (67.43). For CNS targets, TPSA should be <= 90, and ideally lower. Ligand A is much closer to the ideal range.

**logP:** Both ligands (2.565 and 2.61) are within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Both ligands have acceptable HBD (2) and HBA (4/3) counts, well within the guidelines.

**QED:** Ligand A (0.881) has a much better QED score than Ligand B (0.591), indicating a more drug-like profile.

**DILI:** Ligand A (15.2) has a significantly lower DILI risk than Ligand B (26.871), which is a substantial advantage.

**BBB:** Both ligands have good BBB penetration (77.821 and 73.711), exceeding the desirable >70 threshold for CNS targets. Ligand A is slightly better.

**Caco-2 Permeability:** Ligand A (-5.294) and Ligand B (-4.762) both have negative values, which is unusual and potentially problematic. However, the scale isn't fully defined, so we'll proceed cautiously.

**Aqueous Solubility:** Both ligands have negative solubility values (-2.169 and -3.119), indicating poor aqueous solubility. This is a concern for both.

**hERG Inhibition:** Ligand A (0.911) has a lower hERG inhibition liability than Ligand B (0.528), which is preferable.

**Microsomal Clearance:** Ligand A (-13.827) has a much lower (better) microsomal clearance than Ligand B (54.349), indicating greater metabolic stability.

**In vitro Half-Life:** Ligand A (6.285) has a shorter half-life than Ligand B (14.937), which is a slight disadvantage.

**P-gp Efflux:** Ligand A (0.275) has a lower P-gp efflux liability than Ligand B (0.101), which is beneficial for CNS penetration.

**Binding Affinity:** Ligand B (-7.3) has a slightly better binding affinity than Ligand A (-9.2). However, the difference is 1.9 kcal/mol, which is significant, but can be outweighed by other factors.

**Overall Assessment:**

Ligand A is significantly better overall. It excels in crucial ADME properties like TPSA, QED, DILI, microsomal clearance, and P-gp efflux. While Ligand B has slightly better binding affinity and half-life, the substantial advantages of Ligand A in ADME, particularly its lower DILI risk and better TPSA, make it the more promising drug candidate for a CNS target like DRD2. The poor solubility is a concern for both, but can potentially be addressed with formulation strategies.



Output:
0
2025-04-17 07:06:28,042 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (354.535 Da) and Ligand B (346.366 Da) are both acceptable.

**TPSA:** Ligand A (58.64) is excellent, well below the 90 A^2 threshold for CNS targets. Ligand B (97.98) is higher, but still potentially acceptable, though less ideal.

**logP:** Ligand A (3.227) is optimal. Ligand B (0.916) is a bit low, potentially hindering membrane permeability.

**H-Bond Donors/Acceptors:** Ligand A (HBD=1, HBA=3) and Ligand B (HBD=2, HBA=4) both fall within acceptable limits.

**QED:** Both ligands have good QED scores (A: 0.728, B: 0.787), indicating good drug-like properties.

**DILI:** Ligand A (20.279) has a much lower DILI risk than Ligand B (70.958). This is a significant advantage for Ligand A.

**BBB:** Ligand A (71.307) has a good BBB penetration percentile, exceeding the 70% threshold for CNS targets. Ligand B (45.754) is significantly lower, which is a major drawback for a DRD2 ligand.

**Caco-2 Permeability:** Ligand A (-4.328) and Ligand B (-5.038) both have negative values, indicating poor permeability. However, the scale is not specified, so it's difficult to interpret the absolute difference.

**Aqueous Solubility:** Both ligands have poor aqueous solubility (-3.463 and -2.019 respectively). This could pose formulation challenges.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (A: 0.564, B: 0.322).

**Microsomal Clearance:** Ligand A (78.478) has a higher microsomal clearance than Ligand B (-17.587). This suggests Ligand B is more metabolically stable.

**In vitro Half-Life:** Ligand B (-18.103) has a significantly longer in vitro half-life than Ligand A (6.342).

**P-gp Efflux:** Ligand A (0.105) has lower P-gp efflux liability than Ligand B (0.021). Lower P-gp efflux is desirable for CNS exposure.

**Binding Affinity:** Both ligands have excellent binding affinity (-7.0 and -7.9 kcal/mol). Ligand B is slightly better, but the difference is likely not substantial enough to overcome its other weaknesses.

**Overall Assessment:**

Ligand A is the stronger candidate. While both have good affinity, Ligand A excels in crucial areas for a CNS-targeting GPCR ligand: TPSA, BBB penetration, and DILI risk. Ligand B's lower logP, poor BBB penetration, and higher DILI risk are significant concerns. Although Ligand B has better metabolic stability and half-life, these can be addressed through structural modifications. The primary goal is to get the drug into the brain, and Ligand A is far more likely to achieve that.

Output:
1
2025-04-17 07:06:28,042 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (370.381 and 355.523 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (96.37) is slightly above the optimal <90 for CNS targets, but still reasonable. Ligand B (70.67) is excellent, well below 90.

**logP:** Ligand A (3.388) is at the upper end of the optimal range (1-3), while Ligand B (1.931) is closer to the lower end. Both are acceptable, but Ligand A's higher logP *could* lead to off-target interactions.

**H-Bond Donors/Acceptors:** Ligand A (HBD=3, HBA=6) and Ligand B (HBD=2, HBA=4) both have reasonable numbers of H-bond donors and acceptors, well within the guidelines.

**QED:** Both ligands have good QED scores (A: 0.533, B: 0.663), indicating good drug-like properties. Ligand B is slightly better.

**DILI:** Ligand A has a concerningly high DILI risk (85.266), while Ligand B has a very low risk (5.312). This is a significant advantage for Ligand B.

**BBB:** Both ligands have good BBB penetration (A: 71.578, B: 73.129), exceeding the >70% threshold for CNS targets. Ligand B is slightly better.

**Caco-2:** Both have negative Caco-2 values which is unusual and likely indicates a data error. We will proceed assuming these are percentile values, and that higher is better.

**Aqueous Solubility:** Both ligands have very poor aqueous solubility (-4.828 and -2.198). This is a significant drawback for both, potentially hindering formulation and bioavailability.

**hERG:** Ligand A (0.22) has a slightly higher hERG risk than Ligand B (0.563), though both are relatively low.

**Microsomal Clearance:** Ligand A (60.933) has a higher microsomal clearance than Ligand B (27.454), indicating lower metabolic stability.

**In vitro Half-Life:** Ligand B (-6.669) has a longer in vitro half-life than Ligand A (9.044), suggesting better stability.

**P-gp Efflux:** Ligand A (0.105) has lower P-gp efflux liability than Ligand B (0.028), which is favorable for CNS penetration.

**Binding Affinity:** Ligand A (-8.8 kcal/mol) has a significantly stronger binding affinity than Ligand B (-6.4 kcal/mol). This is a substantial advantage for Ligand A, potentially outweighing some of its ADME drawbacks. The difference is >1.5 kcal/mol.

**Overall Assessment:**

Ligand A has a much stronger binding affinity, which is a critical factor for GPCRs. However, its high DILI risk and higher microsomal clearance are major concerns. Ligand B has a better safety profile (much lower DILI), better metabolic stability (lower Cl_mic, longer t1/2), and slightly better BBB penetration, but its binding affinity is significantly weaker.

Considering the GPCR-specific priorities, the strong affinity of Ligand A is compelling. While the DILI risk is concerning, it might be mitigated through structural modifications during lead optimization. The difference in affinity is large enough to prioritize Ligand A for further investigation, with a focus on addressing the DILI liability.

Output:
1
2025-04-17 07:06:28,042 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (362.392 and 352.494 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Both ligands have TPSA values (58.64 and 58.2) below the 90 A^2 threshold for CNS targets, which is excellent.

**3. logP:** Ligand A (2.253) is within the optimal 1-3 range. Ligand B (3.352) is slightly higher but still acceptable.

**4. H-Bond Donors:** Ligand A (1) and Ligand B (2) both meet the <=5 criteria.

**5. H-Bond Acceptors:** Ligand A (3) and Ligand B (2) both meet the <=10 criteria.

**6. QED:** Both ligands have reasonable QED scores (0.835 and 0.738), indicating good drug-like properties.

**7. DILI:** Both ligands have low DILI risk (24.195 and 23.032 percentiles), which is favorable.

**8. BBB:** Ligand A (91.198) has a significantly better BBB penetration percentile than Ligand B (83.094). This is a crucial advantage for a CNS target like DRD2.

**9. Caco-2 Permeability:** Both have negative Caco-2 values (-4.607 and -4.717), which is unusual and suggests poor permeability. However, these values are on a log scale, and the negative values indicate very low permeability.

**10. Aqueous Solubility:** Both ligands have very poor aqueous solubility (-2.846 and -3.578). This is a significant drawback.

**11. hERG Inhibition:** Both ligands show low hERG inhibition risk (0.375 and 0.644), which is good.

**12. Microsomal Clearance:** Ligand A (16.395 mL/min/kg) has a lower microsomal clearance than Ligand B (33.54 mL/min/kg), suggesting better metabolic stability.

**13. In vitro Half-Life:** Ligand A (-4.318 hours) has a longer in vitro half-life than Ligand B (-2.588 hours), which is beneficial.

**14. P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.067 and 0.365), which is good for CNS penetration.

**15. Binding Affinity:** Both ligands have comparable and strong binding affinities (-8.4 and -8.5 kcal/mol). The difference is negligible.

**Overall Assessment:**

While both ligands have good binding affinity and acceptable physicochemical properties, Ligand A is superior due to its significantly better BBB penetration (91.2% vs 83.1%), lower microsomal clearance, and longer half-life. The poor solubility and permeability are shared drawbacks, but the improved CNS exposure potential of Ligand A outweighs these concerns, especially for a CNS target like DRD2.

Output:
1
2025-04-17 07:06:28,042 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (367.49 and 343.295 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (81.99) is significantly better than Ligand B (135.55). For CNS targets, we want TPSA <= 90, so Ligand A is preferable.

**logP:** Ligand A (2.949) is optimal (1-3), while Ligand B (1.173) is on the lower side, potentially hindering permeability.

**H-Bond Donors:** Both have 2 HBD, which is within the acceptable limit of <= 5.

**H-Bond Acceptors:** Ligand A has 4 HBA, and Ligand B has 7. Both are within the acceptable limit of <= 10, but Ligand A is better.

**QED:** Ligand A (0.777) has a better QED score than Ligand B (0.589), indicating a more drug-like profile.

**DILI:** Ligand A (37.03) has a much lower DILI risk than Ligand B (99.263). This is a significant advantage for Ligand A.

**BBB:** Ligand A (74.641) has a good BBB percentile, exceeding the desirable >70 threshold for CNS targets. Ligand B (31.756) is very poor for CNS penetration.

**Caco-2 Permeability:** Ligand A (-4.977) and Ligand B (-5.257) both have negative values, indicating poor permeability.

**Aqueous Solubility:** Ligand A (-3.691) and Ligand B (-3.292) both have negative values, indicating poor solubility.

**hERG Inhibition:** Ligand A (0.817) has a lower hERG risk than Ligand B (0.018).

**Microsomal Clearance:** Ligand A (81.349) has a higher microsomal clearance than Ligand B (26.508), suggesting lower metabolic stability.

**In vitro Half-Life:** Ligand A (8.351) has a positive half-life, while Ligand B (-16.699) has a negative half-life, suggesting poor stability.

**P-gp Efflux:** Ligand A (0.276) has significantly lower P-gp efflux than Ligand B (0.015), which is crucial for CNS exposure.

**Binding Affinity:** Ligand B (-8.9 kcal/mol) has a slightly better binding affinity than Ligand A (-7.6 kcal/mol). However, the difference is not substantial enough to overcome the significant ADME advantages of Ligand A.

**Overall:** Considering the GPCR-specific priorities, Ligand A is the more promising candidate. It has better TPSA, logP, BBB penetration, DILI risk, P-gp efflux, and QED. While Ligand B has slightly better binding affinity, Ligand A's superior ADME properties, particularly its BBB penetration and lower toxicity, make it a more viable drug candidate for a CNS target like DRD2.

Output:
1
2025-04-17 07:06:28,043 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (355.467 and 362.539 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (75.86) is better than Ligand B (43.78) as it is closer to the <90 A^2 threshold for CNS targets.

**logP:** Ligand A (2.962) is optimal (1-3), while Ligand B (4.412) is slightly higher, potentially leading to solubility issues or off-target interactions.

**H-Bond Donors/Acceptors:** Ligand A has 2 HBD and 7 HBA, which are acceptable. Ligand B has 1 HBD and 3 HBA, also acceptable.

**QED:** Both ligands have good QED scores (0.736 and 0.865, respectively), indicating good drug-like properties.

**DILI:** Ligand A (69.135) has a higher DILI risk than Ligand B (10.585). This is a significant drawback for Ligand A.

**BBB:** Ligand B (85.731) has a significantly better BBB penetration percentile than Ligand A (54.905). This is crucial for a CNS target like DRD2.

**Caco-2 Permeability:** Ligand A (-5.352) has a worse Caco-2 permeability than Ligand B (-4.703).

**Aqueous Solubility:** Ligand A (-2.679) has a worse aqueous solubility than Ligand B (-3.335).

**hERG:** Both ligands have low hERG inhibition liability (0.883 and 0.743, respectively).

**Microsomal Clearance:** Ligand A (22.146) has a lower microsomal clearance than Ligand B (35.014), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand B (8.514) has a significantly longer in vitro half-life than Ligand A (-1.712).

**P-gp Efflux:** Ligand A (0.557) has a lower P-gp efflux liability than Ligand B (0.471), which is favorable for CNS penetration.

**Binding Affinity:** Both ligands have excellent binding affinities (-9.1 and -9.0 kcal/mol), with a very slight advantage to Ligand A. However, this small difference is unlikely to outweigh the other significant differences.

**Overall Assessment:**

Ligand B is the more promising candidate. While Ligand A has a slightly better binding affinity and lower P-gp efflux, Ligand B excels in critical areas for a CNS-targeting GPCR: significantly better BBB penetration, lower DILI risk, and a longer half-life. The slightly higher logP of Ligand B is a minor concern compared to the substantial advantages in BBB and safety (DILI). The better solubility and Caco-2 permeability also contribute to its favorability.

Output:
1
2025-04-17 07:06:28,043 - INFO - Reasoning:

Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (347.46 & 348.35 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (53.09) is significantly better than Ligand B (86.88). For CNS targets, we want TPSA <= 90, and A is comfortably within this range, while B is approaching the upper limit.

**3. logP:** Ligand B (1.931) is better than Ligand A (0.426). The optimal range is 1-3, and B falls nicely within it. A is a bit low, potentially hindering membrane permeability.

**4. H-Bond Donors:** Ligand A (0) is preferable to Ligand B (3). Lower HBD generally improves permeability.

**5. H-Bond Acceptors:** Ligand A (4) is slightly better than Ligand B (3). Both are within the acceptable range of <=10.

**6. QED:** Both ligands have good QED scores (0.68 and 0.745, respectively), indicating good drug-like properties.

**7. DILI:** Ligand A (44.94) has a much lower DILI risk than Ligand B (68.592). Lower is better, and A is well below the 60% threshold for high risk.

**8. BBB:** Ligand B (70.415) has a slightly better BBB penetration percentile than Ligand A (61.38). Both are above the 70% threshold, but B is closer.

**9. Caco-2 Permeability:** Ligand A (-4.26) is better than Ligand B (-4.919). Higher values indicate better intestinal absorption.

**10. Aqueous Solubility:** Ligand A (-1.116) is better than Ligand B (-3.176). Higher values are preferred.

**11. hERG Inhibition:** Both ligands have low hERG inhibition risk (0.381 and 0.298, respectively).

**12. Microsomal Clearance:** Ligand B (-7.702) has a lower (better) microsomal clearance than Ligand A (26.593). Lower clearance indicates greater metabolic stability.

**13. In vitro Half-Life:** Ligand B (-11.706) has a significantly longer in vitro half-life than Ligand A (-8.707).

**14. P-gp Efflux:** Ligand A (0.13) has lower P-gp efflux liability than Ligand B (0.042). Lower efflux is preferable for CNS exposure.

**15. Binding Affinity:** Ligand B (-9.1 kcal/mol) has a stronger binding affinity than Ligand A (-7.4 kcal/mol). This is a significant advantage (1.7 kcal/mol difference).

**Overall Assessment:**

While Ligand B has a better logP, BBB, metabolic stability (Cl_mic, t1/2), and *significantly* better binding affinity, Ligand A excels in TPSA, DILI, Caco-2 permeability, solubility, and P-gp efflux. The stronger binding affinity of Ligand B is a major advantage, and the difference of 1.7 kcal/mol is likely to outweigh the drawbacks in TPSA and DILI. The slightly better BBB of B also supports its potential for CNS penetration. Considering the GPCR-specific priorities, the superior affinity of Ligand B makes it the more promising candidate.

Output:
1
2025-04-17 07:06:28,043 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (345.355 and 350.375 Da) fall comfortably within the ideal 200-500 Da range.

**TPSA:** Ligand A (116.8) is slightly above the optimal <90 for CNS targets, but still reasonable. Ligand B (113.77) is also slightly above, but similarly acceptable.

**logP:** Ligand A (1.206) is within the optimal 1-3 range. Ligand B (-0.453) is slightly below 1, which *could* indicate permeability issues, but isn't a dealbreaker.

**H-Bond Donors/Acceptors:** Both ligands have 2 HBD and 6-7 HBA, which are within acceptable limits (<=5 HBD and <=10 HBA).

**QED:** Both ligands have similar QED values (0.621 and 0.64), indicating good drug-like properties.

**DILI:** Ligand A (65.452) has a higher DILI risk than Ligand B (53.858), but both are below the concerning threshold of 60.

**BBB:** This is a critical parameter for a CNS target like DRD2. Ligand A (62.117) has a moderate BBB penetration, while Ligand B (37.301) is significantly lower. This is a major disadvantage for Ligand B.

**Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and suggests poor permeability. However, these values are on a strange scale, and may not be directly comparable.

**Aqueous Solubility:** Both ligands have negative solubility values, which is also unusual. Again, the scale is unclear, but suggests poor solubility.

**hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.585 and 0.048).

**Microsomal Clearance:** Ligand A (23.013) has a higher microsomal clearance than Ligand B (-10.846). A negative value for Ligand B suggests *very* high metabolic stability, which is a significant advantage.

**In vitro Half-Life:** Ligand A (25.642) has a moderate half-life. Ligand B (-7.974) has a negative half-life, which is not physically possible, and indicates a problem with the data or the prediction method.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.14 and 0.006), which is favorable for CNS penetration.

**Binding Affinity:** Both ligands have excellent binding affinities (-8.2 and -7.9 kcal/mol). The difference of 0.3 kcal/mol is not substantial enough to outweigh other factors.

**Overall Assessment:**

Ligand B has a significantly better metabolic stability profile (negative Cl_mic and half-life, though the latter is suspect). However, its BBB penetration is considerably lower than Ligand A, which is a critical drawback for a CNS-targeting drug. The negative solubility and Caco-2 values are concerning for both, but the BBB is the deciding factor. Given the importance of CNS penetration for DRD2, Ligand A is the more promising candidate despite its slightly higher DILI risk and clearance.

Output:
0
2025-04-17 07:06:28,043 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (377.413 and 349.431 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Both ligands (87.74 and 86.02) are below the 90 A^2 threshold for CNS targets, which is excellent.

**3. logP:** Ligand A (1.715) is within the optimal 1-3 range. Ligand B (0.651) is slightly below 1, potentially hindering permeation.

**4. H-Bond Donors:** Both ligands have 2 HBD, which is acceptable.

**5. H-Bond Acceptors:** Ligand A has 4 HBA, and Ligand B has 5 HBA, both within the acceptable limit of 10.

**6. QED:** Both ligands have similar QED values (0.79 and 0.737), indicating good drug-like properties.

**7. DILI:** Ligand A (58.434) has a higher DILI risk than Ligand B (40.132), but both are reasonably acceptable.

**8. BBB:** Ligand A (67.468) has a significantly better BBB penetration percentile than Ligand B (32.144). This is a crucial advantage for a CNS target like DRD2.

**9. Caco-2 Permeability:** Ligand A (-4.899) has worse Caco-2 permeability than Ligand B (-5.108), but both are poor.

**10. Aqueous Solubility:** Ligand A (-2.489) has slightly better solubility than Ligand B (-0.671), but both are poor.

**11. hERG Inhibition:** Both ligands have low hERG inhibition risk (0.441 and 0.281).

**12. Microsomal Clearance:** Ligand A (3.98) has lower microsomal clearance than Ligand B (7.05), indicating better metabolic stability.

**13. In vitro Half-Life:** Ligand A (-16.186) has a much longer in vitro half-life than Ligand B (21.713). This is a significant advantage.

**14. P-gp Efflux:** Ligand A (0.049) has much lower P-gp efflux than Ligand B (0.164), which is highly desirable for CNS penetration.

**15. Binding Affinity:** Ligand B (-7.7 kcal/mol) has a slightly better binding affinity than Ligand A (-8.0 kcal/mol). However, the difference is minimal.

**Overall Assessment:**

Ligand A is the stronger candidate. While Ligand B has slightly better binding affinity, Ligand A excels in crucial ADME properties for a CNS-targeting GPCR. Specifically, its superior BBB penetration, lower P-gp efflux, and longer half-life outweigh the small difference in binding affinity. Ligand A also has better metabolic stability (lower Cl_mic). The slightly higher DILI risk is a minor concern compared to the significant advantages in CNS penetration and pharmacokinetic properties.

Output:
1
2025-04-17 07:06:28,043 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B based on the provided guidelines, prioritizing GPCR-specific properties (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (344.415 and 347.459 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (85.25) is slightly higher than Ligand B (78.51), but both are below the 90 A^2 threshold desirable for CNS targets.

**logP:** Ligand A (1.929) is within the optimal 1-3 range, while Ligand B (0.853) is slightly below 1. While lower logP can sometimes indicate solubility issues, it's not a major concern here.

**H-Bond Donors/Acceptors:** Both ligands have 2 HBD and 4-5 HBA, which are within acceptable limits.

**QED:** Both ligands have QED values (0.812 and 0.747) above 0.5, indicating good drug-like properties.

**DILI:** Ligand A (80.69) has a higher DILI risk than Ligand B (8.453). This is a significant drawback for Ligand A.

**BBB:** Ligand B (64.87) has a substantially better BBB penetration percentile than Ligand A (34.936). This is *critical* for a CNS target like DRD2.

**Caco-2 Permeability:** Ligand A (-4.711) has a worse Caco-2 permeability than Ligand B (-5.394). Both are negative, indicating poor permeability.

**Aqueous Solubility:** Ligand A (-3.418) has slightly better aqueous solubility than Ligand B (-1.235).

**hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.181 and 0.176).

**Microsomal Clearance:** Ligand B (-15.698) has significantly lower (better) microsomal clearance than Ligand A (37.87). This suggests better metabolic stability for Ligand B.

**In vitro Half-Life:** Ligand B (-3.734) has a longer in vitro half-life than Ligand A (9.209), indicating better stability.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.08 and 0.007).

**Binding Affinity:** Ligand B (-8.8 kcal/mol) has a slightly better binding affinity than Ligand A (-8.3 kcal/mol). While the difference is not huge, it's a positive for Ligand B.

**Overall Assessment:**

Ligand B is the superior candidate. Its significantly better BBB penetration, lower DILI risk, improved metabolic stability (lower Cl_mic and longer t1/2), and slightly better binding affinity outweigh the slightly lower logP and Caco-2 permeability. The CNS target (DRD2) necessitates high BBB penetration, making this the most important factor.

Output:
1
2025-04-17 07:06:28,043 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (352.431 Da) is slightly lower, which could be beneficial for permeability. Ligand B (372.824 Da) is also good.

**TPSA:** Ligand A (95.94) is slightly above the optimal <90 for CNS targets, but still reasonable. Ligand B (75.71) is excellent, well below 90, suggesting better CNS penetration potential.

**logP:** Ligand A (0.105) is quite low, potentially hindering membrane permeability and CNS entry. Ligand B (1.672) is within the optimal 1-3 range. This is a significant advantage for Ligand B.

**H-Bond Donors/Acceptors:** Ligand A has 2 HBD and 5 HBA, which are acceptable. Ligand B has 1 HBD and 4 HBA, also acceptable and potentially slightly better due to fewer hydrogen bonds.

**QED:** Both ligands have good QED scores (A: 0.646, B: 0.762), indicating drug-like properties. Ligand B is slightly better.

**DILI:** Both ligands have relatively low DILI risk (A: 23.846, B: 42.846), both below the 40 threshold.

**BBB:** Ligand A (42.226) has a moderate BBB penetration score, while Ligand B (76.309) is excellent, exceeding the desirable >70 threshold for CNS targets. This is a major advantage for Ligand B.

**Caco-2:** Both have negative Caco-2 values, which is unusual and suggests poor permeability. However, the scale is not specified, so this is hard to interpret.

**Solubility:** Both have negative solubility values, which is also unusual and suggests poor solubility. The scale is not specified, so this is hard to interpret.

**hERG:** Both ligands show very low hERG inhibition risk (A: 0.042, B: 0.279).

**Microsomal Clearance:** Ligand A (7.87 mL/min/kg) has lower clearance than Ligand B (4.182 mL/min/kg), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (1.601 hours) has a shorter half-life than Ligand B (-11.663 hours). A negative half-life is unusual and likely indicates a very stable compound.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (A: 0.04, B: 0.075).

**Binding Affinity:** Ligand B (-8.8 kcal/mol) has a slightly better binding affinity than Ligand A (-8.5 kcal/mol), although the difference is small.

**Overall Assessment:**

Ligand B is significantly better suited as a DRD2 ligand. Its superior logP, TPSA, and BBB penetration scores are crucial for CNS drug development. While Ligand A has slightly better metabolic stability, the differences in these parameters are less critical than the improvements in CNS penetration and permeability offered by Ligand B. The slightly better affinity of Ligand B further supports this conclusion.

Output:
1
2025-04-17 07:06:28,043 - INFO - Batch 337 complete. Total preferences: 5392
2025-04-17 07:06:28,043 - INFO - Processing batch 338/512...
2025-04-17 07:07:08,919 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (347.459 and 345.407 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (87.3) is better than Ligand B (108.8). For CNS targets, we want TPSA <= 90. Ligand A is within this range, while Ligand B is slightly above.

**3. logP:** Ligand A (1.699) is better than Ligand B (0.524). Both are within the 1-3 range, but Ligand B is closer to the lower limit, potentially hindering permeation.

**4. H-Bond Donors:** Ligand A (3) is slightly higher than Ligand B (2), but both are acceptable (<=5).

**5. H-Bond Acceptors:** Ligand B (6) is higher than Ligand A (3). Both are within the acceptable range (<=10).

**6. QED:** Ligand B (0.84) is better than Ligand A (0.613). Both are above the 0.5 threshold, indicating good drug-like properties.

**7. DILI:** Ligand A (24.544) is significantly better than Ligand B (51.997). Lower DILI is crucial, and Ligand A is well below the 40% threshold, while Ligand B is approaching a moderate risk.

**8. BBB:** Ligand A (59.364) is slightly lower than Ligand B (62.776). Both are reasonably good, but ideally >70 for CNS targets.

**9. Caco-2:** Both ligands have negative Caco-2 values (-5.462 and -5.264). This is unusual and suggests poor permeability. However, these values are on a scale where negative values are possible, and direct comparison is difficult without knowing the scale's specifics.

**10. Solubility:** Both ligands have negative solubility values (-2.403 and -2.201). Similar to Caco-2, this is unusual and makes direct comparison difficult.

**11. hERG:** Ligand A (0.05) is better than Ligand B (0.292). Lower hERG inhibition is preferred.

**12. Cl_mic:** Ligand B (-11.166) is better than Ligand A (18.945). Lower microsomal clearance indicates better metabolic stability.

**13. t1/2:** Ligand A (21.368) is better than Ligand B (-12.127). Longer half-life is generally desirable.

**14. Pgp:** Ligand A (0.052) is better than Ligand B (0.06). Lower P-gp efflux is preferred for CNS exposure.

**15. Binding Affinity:** Ligand A (-9.4 kcal/mol) is significantly better than Ligand B (-7.7 kcal/mol). This is a substantial difference in potency. A >1.5 kcal/mol advantage often outweighs minor ADME drawbacks.

**Overall Assessment:**

Ligand A is the stronger candidate. While Ligand B has slightly better QED and Cl_mic, Ligand A excels in the most critical areas for a CNS-targeting GPCR ligand: significantly higher binding affinity, lower DILI risk, better TPSA, better logP, and better hERG inhibition. The negative Caco-2 and solubility values are concerning for both, but the substantial affinity advantage of Ligand A makes it more likely to be optimized to overcome these issues.

Output:
1
2025-04-17 07:07:08,920 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (346.383 and 356.463 Da) fall within the ideal range of 200-500 Da.

**TPSA:** Ligand A (90.65) is slightly above the preferred <90 for CNS targets, but still reasonable. Ligand B (84.94) is excellent, well below 90.

**logP:** Both ligands have good logP values (1.906 and 2.48), falling within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Both have 1 HBD, which is good. Ligand A has 7 HBA, while Ligand B has 5. Both are acceptable (<=10).

**QED:** Both ligands have similar QED values (0.734 and 0.708), indicating good drug-likeness.

**DILI:** Ligand A (65.568) has a higher DILI risk than Ligand B (46.956). This is a significant negative for Ligand A.

**BBB:** Ligand B (78.054) has a significantly better BBB penetration score than Ligand A (63.319).  Given this is a CNS target, this is a crucial advantage for Ligand B.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.42 and -4.317), which is unusual and suggests poor permeability. However, these values are on a log scale and are likely representing very low permeability.

**Aqueous Solubility:** Both ligands have negative solubility values (-3.556 and -2.391), indicating poor aqueous solubility.

**hERG:** Both ligands have low hERG inhibition liability (0.236 and 0.299), which is good.

**Microsomal Clearance:** Ligand A (112.336) has a higher microsomal clearance than Ligand B (43.844), indicating lower metabolic stability.

**In vitro Half-Life:** Ligand B (-4.142) has a longer in vitro half-life than Ligand A (-11.436).

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.659 and 0.077), which is good, especially for CNS penetration. Ligand B is better here.

**Binding Affinity:** Ligand B (-7.6 kcal/mol) has a slightly better binding affinity than Ligand A (-7.1 kcal/mol). While the difference is not huge, it's enough to be considered.

**Overall Assessment:**

Ligand B is the stronger candidate. It excels in key areas for a CNS-targeting GPCR ligand: better BBB penetration, lower DILI risk, improved metabolic stability (lower Cl_mic and longer t1/2), and slightly better binding affinity. While both have poor solubility and permeability, the other advantages of Ligand B outweigh this drawback. The slightly better affinity of Ligand B, combined with its superior ADME properties, makes it the more promising drug candidate.

Output:
1
2025-04-17 07:07:08,920 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (350.375 and 348.491 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (104.98) is higher than Ligand B (59.39). For CNS targets, TPSA should be <= 90. Ligand B is significantly better in this regard.

**logP:** Ligand A (-0.959) is lower than the optimal 1-3 range, potentially hindering permeability. Ligand B (2.267) is within the optimal range.

**H-Bond Donors:** Both have 1 HBD, which is acceptable.

**H-Bond Acceptors:** Ligand A has 6 HBA, and Ligand B has 5. Both are within the acceptable limit of <= 10.

**QED:** Both ligands have good QED scores (0.635 and 0.857, respectively), indicating drug-like properties.

**DILI:** Ligand A (22.024) has a lower DILI risk than Ligand B (13.532), which is favorable.

**BBB:** Ligand B (74.292) has a significantly higher BBB penetration percentile than Ligand A (51.803). This is *critical* for a CNS target like DRD2.

**Caco-2 Permeability:** Ligand A (-5.217) and Ligand B (-4.81) both have negative Caco-2 permeability values, which is unusual and suggests poor intestinal absorption. However, for a CNS drug, intestinal absorption is less critical than BBB penetration.

**Aqueous Solubility:** Both have very poor aqueous solubility (-1.258 and -1.375, respectively). This could pose formulation challenges.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.105 and 0.473).

**Microsomal Clearance:** Ligand A (5.441) has lower microsomal clearance than Ligand B (44.11), indicating better metabolic stability.

**In vitro Half-Life:** Ligand B (-8.309) has a longer half-life than Ligand A (14.644).

**P-gp Efflux:** Ligand A (0.002) has very low P-gp efflux, which is excellent for CNS penetration. Ligand B (0.06) is also low, but higher than Ligand A.

**Binding Affinity:** Ligand A (-7.8 kcal/mol) has a slightly better binding affinity than Ligand B (-6.8 kcal/mol). However, the difference is less than the 1.5 kcal/mol threshold where affinity overwhelmingly dictates selection.

**Overall Assessment:**

Ligand B is the more promising candidate. While Ligand A has slightly better affinity and lower DILI risk, Ligand B excels in crucial areas for a CNS-targeting GPCR: significantly better TPSA, optimal logP, and *much* higher BBB penetration. The longer half-life of Ligand B is also a plus. The poor solubility of both compounds is a concern, but can potentially be addressed through formulation strategies. The slightly higher clearance of Ligand B is less concerning given the strong BBB penetration.



Output:
1
2025-04-17 07:07:08,920 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B based on the provided guidelines, prioritizing GPCR-specific properties (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (352.391 and 345.535 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (105.92) is better than Ligand B (55.63). For CNS targets, TPSA should be <=90, and both meet this criterion, but A is closer to the upper limit.

**logP:** Ligand A (-0.636) is suboptimal, being below the preferred 1-3 range. Ligand B (4.12) is high, potentially causing solubility and off-target issues.

**H-Bond Donors/Acceptors:** Ligand A (HBD=2, HBA=7) and Ligand B (HBD=1, HBA=5) both have acceptable numbers of H-bond donors and acceptors.

**QED:** Both ligands have good QED scores (A: 0.676, B: 0.77), indicating drug-like properties.

**DILI:** Ligand A (40.597) is slightly higher than Ligand B (32.105), but both are below the concerning threshold of 60.

**BBB:** Ligand B (81.621) has a significantly better BBB percentile than Ligand A (62.854). This is a crucial factor for a CNS target like DRD2.

**Caco-2 Permeability:** Ligand A (-4.876) and Ligand B (-5.307) both have negative values, which is unusual. Lower values indicate poorer permeability.

**Aqueous Solubility:** Ligand A (-1.851) and Ligand B (-4.289) both have negative values, indicating poor solubility.

**hERG Inhibition:** Ligand A (0.102) has a lower hERG inhibition liability than Ligand B (0.406), which is favorable.

**Microsomal Clearance:** Ligand A (-5.545) has a much lower (better) microsomal clearance than Ligand B (42.743), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (0.899) has a lower in vitro half-life than Ligand B (4.79).

**P-gp Efflux:** Ligand A (0.008) has a much lower P-gp efflux liability than Ligand B (0.605), which is very important for CNS penetration.

**Binding Affinity:** Ligand A (-7.2 kcal/mol) has a slightly better binding affinity than Ligand B (-6.7 kcal/mol). While both are good, the 1.5 kcal/mol difference is significant.

**Overall Assessment:**

Ligand B excels in BBB penetration, which is paramount for a DRD2 ligand. However, it suffers from a high logP, potentially poor solubility, and higher P-gp efflux. Ligand A has a lower logP, better metabolic stability (lower Cl_mic), lower P-gp efflux, and slightly better binding affinity. While its BBB is lower, the combination of better ADME properties and comparable affinity makes it a more promising candidate. The slightly lower affinity of Ligand B can potentially be optimized, but addressing its high logP and P-gp efflux will be more challenging.

Output:
0
2025-04-17 07:07:08,920 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (341.39 and 345.44 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (56.15) is excellent, well below the 90 A^2 threshold for CNS targets. Ligand B (91.32) is higher, but still potentially acceptable, though less ideal.

**logP:** Both ligands have good logP values (3.00 and 2.12), falling within the 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A (1 HBD, 4 HBA) and Ligand B (3 HBD, 4 HBA) both meet the criteria of <=5 HBD and <=10 HBA.

**QED:** Both ligands have acceptable QED scores (0.776 and 0.706), indicating good drug-like properties.

**DILI:** Ligand A (75.38) has a higher DILI risk than Ligand B (26.60). This is a significant drawback for Ligand A.

**BBB:** Ligand A (74.37) has a significantly better BBB penetration percentile than Ligand B (53.97). This is a crucial advantage for a CNS target like DRD2.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.578 and -4.966), which is unusual and suggests poor permeability. This is a concern for both.

**Aqueous Solubility:** Both ligands have negative solubility values (-4.23 and -3.392), indicating very poor aqueous solubility. This is a significant formulation challenge for both.

**hERG Inhibition:** Ligand A (0.851) has a slightly higher hERG risk than Ligand B (0.106). Ligand B is much preferred here.

**Microsomal Clearance:** Ligand A (84.27) has higher microsomal clearance than Ligand B (47.13), suggesting lower metabolic stability. Ligand B is preferred.

**In vitro Half-Life:** Ligand B (-39.71) has a significantly longer in vitro half-life than Ligand A (22.85), which is a major advantage.

**P-gp Efflux:** Ligand A (0.657) has lower P-gp efflux liability than Ligand B (0.041), meaning it's less likely to be pumped out of the brain. This is a positive for Ligand A.

**Binding Affinity:** Ligand A (-9.4 kcal/mol) has a stronger binding affinity than Ligand B (-8.5 kcal/mol). This is a substantial advantage for Ligand A.

**Overall Assessment:**

Ligand A has a superior binding affinity and better BBB penetration and P-gp efflux, which are critical for CNS GPCR targets. However, it suffers from higher DILI risk, higher microsomal clearance, and shorter half-life. Ligand B has a much better safety profile (lower DILI, hERG) and better metabolic stability (lower Cl_mic, longer t1/2), but weaker affinity and poorer BBB penetration.

Given the importance of strong binding affinity for GPCRs and the need for CNS penetration, the stronger affinity and better BBB of Ligand A outweigh its drawbacks, *provided* the DILI risk can be mitigated through structural modifications. The poor solubility and Caco-2 permeability are shared concerns that would need to be addressed for either molecule.

Output:
1
2025-04-17 07:07:08,920 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (392.263 Da) is slightly higher than Ligand B (362.348 Da), but both are acceptable.

**TPSA:** Ligand A (67.16) is much better than Ligand B (98.66). For CNS targets, we want TPSA <= 90, so Ligand A is preferable.

**logP:** Ligand A (4.927) is high, potentially causing solubility and off-target issues. Ligand B (1.561) is within the optimal range (1-3). This favors Ligand B.

**H-Bond Donors/Acceptors:** Ligand A (0 HBD, 4 HBA) is better than Ligand B (4 HBD, 4 HBA) in terms of balancing solubility and permeability.

**QED:** Ligand A (0.591) is better than Ligand B (0.475), indicating a more drug-like profile.

**DILI:** Ligand A (93.68) has a significantly higher DILI risk than Ligand B (42.187). This is a major concern for Ligand A.

**BBB:** Ligand A (28.887) has very poor predicted BBB penetration, while Ligand B (49.903) is better, but still not ideal (>70 is desirable). This is a critical disadvantage for Ligand A, given the CNS target.

**Caco-2 Permeability:** Ligand A (-4.354) has poor Caco-2 permeability, while Ligand B (-5.173) is also poor. Both are unfavorable.

**Aqueous Solubility:** Ligand A (-6.478) has very poor solubility, while Ligand B (-2.789) is slightly better, but still poor.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.655 and 0.747 respectively), which is good.

**Microsomal Clearance:** Ligand A (1.642) has lower clearance than Ligand B (8.48), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (72.73) has a much longer half-life than Ligand B (18.941), which is a significant advantage.

**P-gp Efflux:** Ligand A (0.355) has lower P-gp efflux than Ligand B (0.165), meaning better CNS exposure.

**Binding Affinity:** Ligand B (-7.9 kcal/mol) has a significantly better binding affinity than Ligand A (-9.6 kcal/mol). A 1.5 kcal/mol advantage is substantial.

**Overall Assessment:**

Despite Ligand A's better half-life and P-gp efflux, its poor BBB penetration, high DILI risk, high logP, and poor solubility are major drawbacks. Ligand B, while having a lower QED and higher clearance, has a significantly better binding affinity, a more acceptable logP, and a lower DILI risk. The binding affinity difference is large enough to potentially overcome the other ADME deficiencies, especially considering optimization potential. The BBB penetration of Ligand B is still a concern, but less so than Ligand A's.

Output:
1
2025-04-17 07:07:08,920 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (357.426 and 348.378 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (78.95) is excellent, well below the 90 A^2 threshold for CNS targets. Ligand B (95.25) is still reasonable but closer to the upper limit.

**logP:** Both ligands have logP values (1.461 and 1.749) within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A (1 HBD, 4 HBA) is favorable. Ligand B (4 HBD, 3 HBA) is acceptable, though slightly higher HBD count could potentially affect permeability.

**QED:** Ligand A (0.811) has a very good QED score, indicating high drug-likeness. Ligand B (0.49) is below the 0.5 threshold, suggesting a less ideal drug-like profile.

**DILI:** Ligand A (27.608) has a low DILI risk. Ligand B (83.172) has a significantly higher DILI risk, which is concerning.

**BBB:** Both ligands have good BBB penetration (71.772 and 81.776), exceeding the 70% threshold. Ligand B is slightly better.

**Caco-2 Permeability:** Ligand A (-4.392) has poor Caco-2 permeability, which is a significant drawback. Ligand B (-5.138) is also poor, but slightly worse.

**Aqueous Solubility:** Ligand A (-1.804) has poor aqueous solubility. Ligand B (-3.553) is even worse.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.234 and 0.48).

**Microsomal Clearance:** Ligand A (24.833) has moderate clearance, while Ligand B (-0.393) has negative clearance, which is highly favorable, suggesting excellent metabolic stability.

**In vitro Half-Life:** Ligand A (-7.475) has a very long half-life, which is excellent. Ligand B (28.192) has a reasonable half-life.

**P-gp Efflux:** Both ligands have very low P-gp efflux (0.02 and 0.119), which is favorable for CNS penetration.

**Binding Affinity:** Ligand B (-9.8 kcal/mol) has a significantly stronger binding affinity than Ligand A (-8.2 kcal/mol). This >1.5 kcal/mol difference is substantial and can outweigh some ADME drawbacks.

**Overall Assessment:**

Ligand B has a superior binding affinity and excellent metabolic stability (negative Cl_mic). While its solubility and Caco-2 permeability are poor, and DILI risk is higher, the strong affinity and metabolic stability are crucial for a GPCR target like DRD2. Ligand A has better TPSA and DILI, but its poor Caco-2 permeability and weaker binding affinity are significant disadvantages. The strong binding of Ligand B is likely to drive sufficient brain exposure despite permeability issues.

Output:
1
2025-04-17 07:07:08,920 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (353.423 and 361.507 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (119.64) is excellent, falling well below the 90 A^2 threshold for CNS targets. Ligand B (38.77) is also good, but less optimal than A.

**logP:** Ligand A (-1.063) is a bit low, potentially hindering permeability. Ligand B (3.391) is within the optimal 1-3 range. This is a significant advantage for B.

**H-Bond Donors/Acceptors:** Ligand A has 4 HBD and 4 HBA, which is acceptable. Ligand B has 0 HBD and 4 HBA, also acceptable.

**QED:** Both ligands have similar QED values (0.466 and 0.499), indicating moderate drug-likeness.

**DILI:** Both ligands have low DILI risk (22.761 and 21.675 percentile), which is favorable.

**BBB:** Ligand B (90.074) has a significantly better BBB penetration percentile than Ligand A (65.839). This is a crucial advantage for a CNS target like DRD2.

**Caco-2 Permeability:** Ligand A (-5.442) has poor Caco-2 permeability, while Ligand B (-4.864) is slightly better, but still not great.

**Aqueous Solubility:** Ligand A (-0.981) has poor aqueous solubility, while Ligand B (-3.39) is even worse. This could pose formulation challenges for both.

**hERG Inhibition:** Ligand A (0.03) has a very low hERG risk, which is excellent. Ligand B (0.736) has a slightly higher, but still acceptable, risk.

**Microsomal Clearance:** Ligand A (-23.696) has very low microsomal clearance, indicating high metabolic stability. Ligand B (104.233) has high clearance, suggesting rapid metabolism. This is a significant drawback for B.

**In vitro Half-Life:** Ligand A (2.928 hours) has a short half-life, while Ligand B (2.253 hours) is even shorter.

**P-gp Efflux:** Ligand A (0.001) has very low P-gp efflux, which is excellent for CNS penetration. Ligand B (0.561) has moderate P-gp efflux.

**Binding Affinity:** Ligand A (-7.5 kcal/mol) has a slightly better binding affinity than Ligand B (-7.2 kcal/mol), but the difference is relatively small.

**Overall Assessment:**

Ligand A excels in metabolic stability (low Cl_mic, low Pgp efflux) and hERG safety, and has a slightly better affinity. However, its low logP and poor Caco-2 permeability are concerning. Ligand B has a much better logP and significantly better BBB penetration, which are critical for a CNS GPCR target. While its metabolic stability is a concern, the difference in binding affinity is not large enough to outweigh the advantages of B's improved pharmacokinetic properties for CNS delivery.

Output:
1
2025-04-17 07:07:08,921 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (343.43 & 348.45 Da) are within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (65.79) is better than Ligand B (67.67). Both are below the 90 A^2 threshold desirable for CNS targets, but lower is preferred.

**3. logP:** Both ligands have good logP values (1.768 & 1.361), falling within the optimal 1-3 range. Ligand B is slightly lower, which *could* indicate slightly better solubility, but the difference is minimal.

**4. H-Bond Donors:** Ligand A has 1 HBD, while Ligand B has 0. Both are acceptable (<=5).

**5. H-Bond Acceptors:** Ligand A has 4 HBA, and Ligand B has 5. Both are within the acceptable range (<=10).

**6. QED:** Both ligands have similar QED values (0.868 & 0.824), indicating good drug-likeness.

**7. DILI:** Ligand A (32.03%) has a slightly better DILI score than Ligand B (35.75%), indicating a lower risk of liver injury. Both are below the 40% threshold.

**8. BBB:** This is a critical parameter for a CNS target like DRD2. Ligand B (85.46%) significantly outperforms Ligand A (62.93%). This is a major advantage for Ligand B.

**9. Caco-2 Permeability:** Ligand A (-5.014) has better Caco-2 permeability than Ligand B (-4.477). Higher values indicate better absorption.

**10. Aqueous Solubility:** Ligand A (-1.17) has better aqueous solubility than Ligand B (-1.6).

**11. hERG Inhibition:** Both ligands show very low hERG inhibition liability (0.423 & 0.209), which is excellent.

**12. Microsomal Clearance:** Ligand A (2.763) has lower microsomal clearance than Ligand B (28.31), suggesting better metabolic stability.

**13. In vitro Half-Life:** Ligand A (58.931) has a much longer in vitro half-life than Ligand B (1.571). This is a significant advantage for Ligand A.

**14. P-gp Efflux:** Ligand A (0.041) has lower P-gp efflux liability than Ligand B (0.079), meaning it's less likely to be pumped out of the brain, improving CNS exposure.

**15. Binding Affinity:** Both ligands have very similar binding affinities (-8.7 & -8.5 kcal/mol). The difference is negligible.

**Overall Assessment:**

Ligand B has a significantly better BBB score (85.46% vs 62.93%), which is paramount for a CNS target. While Ligand A has advantages in metabolic stability (lower Cl_mic, longer t1/2), Caco-2 permeability, solubility, and P-gp efflux, the superior BBB penetration of Ligand B outweighs these benefits. The binding affinities are nearly identical. For a CNS GPCR, getting the drug *into* the brain is often the biggest hurdle.

Output:
1
2025-04-17 07:07:08,921 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 drug candidates, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (365.409 and 355.463 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Both ligands have TPSA values (62.53 and 62.3) that are acceptable for oral absorption (<140) but slightly higher than optimal for CNS penetration (<90). This is a minor concern, but worth noting.

**3. logP:** Both ligands have logP values (3.085 and 2.884) within the optimal range of 1-3.

**4. H-Bond Donors:** Both ligands have 1 HBD, which is within the acceptable limit of <=5.

**5. H-Bond Acceptors:** Ligand A has 6 HBA, and Ligand B has 4 HBA, both within the acceptable limit of <=10.

**6. QED:** Both ligands have good QED scores (0.729 and 0.839), indicating good drug-like properties.

**7. DILI:** Both ligands have relatively high DILI risk (77.549 and 72.586), but below the concerning threshold of >60. This is a potential area for optimization, but not a deal-breaker at this stage.

**8. BBB:** Both ligands exhibit good BBB penetration (80.264 and 71.462), with Ligand A being slightly better. A value >70 is desirable for CNS targets, and both are reasonably close.

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 permeability values (-4.817 and -4.926). This is unusual and suggests poor intestinal absorption. However, these values can sometimes be unreliable and require experimental validation.

**10. Aqueous Solubility:** Both ligands have very poor aqueous solubility (-2.615 and -3.332). This is a significant drawback and could hinder formulation and bioavailability.

**11. hERG Inhibition:** Both ligands have low hERG inhibition risk (0.782 and 0.338). Ligand B is slightly better here.

**12. Microsomal Clearance:** Ligand A has a higher microsomal clearance (14.907) than Ligand B (56.254), suggesting lower metabolic stability.

**13. In vitro Half-Life:** Ligand B has a significantly longer in vitro half-life (9.588 hours) than Ligand A (58.716 hours). This is a major advantage for Ligand B.

**14. P-gp Efflux:** Ligand A shows moderate P-gp efflux (0.558) while Ligand B shows very low P-gp efflux (0.287). Lower P-gp efflux is preferred, especially for CNS targets, making Ligand B more favorable.

**15. Binding Affinity:** Ligand B has a significantly stronger binding affinity (-9.3 kcal/mol) compared to Ligand A (-8.3 kcal/mol). This >1.5 kcal/mol difference in affinity is a substantial advantage, and can often outweigh minor ADME drawbacks.

**Overall Assessment:**

While both ligands have some weaknesses (poor solubility, negative Caco-2 values), Ligand B is the more promising candidate. Its superior binding affinity, longer half-life, lower P-gp efflux, and slightly better hERG profile outweigh the slightly higher DILI risk and marginally lower BBB penetration compared to Ligand A. The strong affinity suggests a higher likelihood of achieving efficacy, and the improved pharmacokinetic properties (half-life, P-gp) are crucial for CNS drug development.



Output:
1
2025-04-17 07:07:08,921 - INFO - Reasoning:

Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (352.435 and 348.422 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (127.34) is higher than the preferred <90 for CNS targets, while Ligand B (75.19) is well within the range. This is a significant advantage for Ligand B.

**3. logP:** Ligand A (0.467) is quite low, potentially hindering membrane permeability. Ligand B (2.117) is within the optimal 1-3 range. This favors Ligand B.

**4. H-Bond Donors:** Ligand A (5) is at the upper limit, while Ligand B (1) is excellent.

**5. H-Bond Acceptors:** Ligand A (5) is acceptable, while Ligand B (4) is also good.

**6. QED:** Ligand B (0.904) has a much better drug-likeness score than Ligand A (0.465).

**7. DILI:** Ligand A (29.43) has a lower DILI risk than Ligand B (41.218), which is a slight advantage.

**8. BBB:** Ligand B (83.908) has a significantly higher BBB penetration percentile than Ligand A (17.565). This is *critical* for a CNS target like DRD2.

**9. Caco-2 Permeability:** Ligand A (-5.577) has poor Caco-2 permeability, while Ligand B (-4.756) is slightly better, but still not ideal.

**10. Aqueous Solubility:** Ligand A (-1.805) and Ligand B (-3.274) both have poor aqueous solubility.

**11. hERG Inhibition:** Ligand A (0.061) has a very low hERG risk, a significant advantage. Ligand B (0.402) is slightly higher, but still relatively low.

**12. Microsomal Clearance:** Ligand A (-5.878) has a negative value, suggesting very low clearance and high metabolic stability, which is excellent. Ligand B (37.154) has a higher clearance, indicating faster metabolism.

**13. In vitro Half-Life:** Ligand A (-14.444) has a negative value, suggesting a very long half-life, which is excellent. Ligand B (-6.949) has a shorter half-life.

**14. P-gp Efflux:** Ligand A (0.017) has very low P-gp efflux, which is ideal for CNS penetration. Ligand B (0.12) has slightly higher efflux, but still reasonable.

**15. Binding Affinity:** Ligand A (-8.5) has a significantly stronger binding affinity than Ligand B (-0.0). This is a substantial advantage for Ligand A.

**Overall Assessment:**

While Ligand A has a superior binding affinity and better metabolic stability/half-life, its poor logP, TPSA, and Caco-2 permeability are major drawbacks for CNS penetration. Ligand B excels in properties crucial for CNS drug development: TPSA, logP, and especially BBB penetration. The significantly better BBB score of Ligand B outweighs the affinity difference, especially considering the affinity of Ligand B is still reasonable. The lower DILI risk of Ligand A is a minor benefit, but not enough to overcome the permeability issues.

Output:
1
2025-04-17 07:07:08,921 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (345.491 and 342.418 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (73.31) is higher than Ligand B (50.16). For CNS targets, TPSA should be <= 90, so both are acceptable, but B is better.

**logP:** Both ligands have good logP values (2.334 and 2.751), falling within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A has 3 HBD and 6 HBA, while Ligand B has 1 HBD and 4 HBA. Both are within acceptable limits (<=5 HBD and <=10 HBA).

**QED:** Both ligands have good QED scores (0.735 and 0.787), indicating good drug-like properties.

**DILI:** Both ligands have low DILI risk (29.857 and 27.414), below the 40 threshold.

**BBB:** This is a critical parameter for CNS targets. Ligand B (92.323) has a significantly higher BBB percentile than Ligand A (70.143). This is a major advantage for B.

**Caco-2 Permeability:** Ligand A (-5.222) and Ligand B (-4.957) both have negative values, which is unusual and suggests poor permeability. However, the scale is not specified, so it's difficult to interpret.

**Aqueous Solubility:** Both ligands have negative solubility values (-2.228 and -3.632). This is concerning, as solubility is important for bioavailability.

**hERG Inhibition:** Both ligands have low hERG inhibition liability (0.784 and 0.619), which is good.

**Microsomal Clearance:** Ligand A (-4.071) has a lower (better) microsomal clearance than Ligand B (59.365). This suggests better metabolic stability for A.

**In vitro Half-Life:** Ligand B (10.715 hours) has a significantly longer half-life than Ligand A (65.85). This is a significant advantage for B.

**P-gp Efflux:** Ligand A (0.022) has a much lower P-gp efflux liability than Ligand B (0.303). This is a major advantage for A, as it suggests better CNS exposure.

**Binding Affinity:** Ligand B (-9.0 kcal/mol) has a stronger binding affinity than Ligand A (-8.3 kcal/mol). This is a significant advantage for B, as it outweighs some of the ADME drawbacks.

**Overall Assessment:**

Ligand B is the stronger candidate. While Ligand A has better metabolic stability and lower P-gp efflux, Ligand B's superior BBB penetration and significantly stronger binding affinity are more critical for a CNS-targeting GPCR like DRD2. The longer half-life of B is also a positive. The solubility issues are a concern for both, but the potency and brain penetration of B are more important in this context.

Output:
1
2025-04-17 07:07:08,921 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (347.39 and 362.411 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (80.32) is excellent, well below the 90 A^2 threshold for CNS targets. Ligand B (102.74) is still reasonable but less optimal.

**logP:** Ligand A (0.765) is a bit low, potentially hindering permeability. Ligand B (0.597) is even lower, raising more concerns about membrane penetration.

**H-Bond Donors/Acceptors:** Ligand A (2 HBD, 4 HBA) is good. Ligand B (1 HBD, 6 HBA) is also acceptable.

**QED:** Both ligands have good QED scores (0.681 and 0.848), indicating generally drug-like properties.

**DILI:** Ligand A (33.695) has a significantly lower DILI risk than Ligand B (68.941), which is a substantial advantage.

**BBB:** Ligand A (76.658) has a good BBB penetration percentile, exceeding the 70% threshold for CNS targets. Ligand B (49.826) is considerably lower, suggesting poor brain exposure. This is a critical difference for a DRD2 ligand.

**Caco-2 Permeability:** Both have negative Caco-2 values which is unusual, and suggests poor permeability.

**Aqueous Solubility:** Both ligands have negative solubility values, which is also unusual and suggests poor solubility.

**hERG:** Ligand A (0.093) has a very low hERG risk. Ligand B (0.219) is slightly higher, but still relatively low.

**Microsomal Clearance:** Ligand A (8.919) has a lower microsomal clearance, indicating better metabolic stability. Ligand B (-14.978) has a negative clearance, which is not possible and suggests a data error or unusual behavior.

**In vitro Half-Life:** Ligand A (-5.49) has a negative half-life, which is not possible and suggests a data error or unusual behavior. Ligand B (-7.634) also has a negative half-life, suggesting similar data issues.

**P-gp Efflux:** Ligand A (0.008) has very low P-gp efflux, which is excellent for CNS penetration. Ligand B (0.048) is slightly higher, but still relatively low.

**Binding Affinity:** Ligand A (-7.3 kcal/mol) has a slightly better binding affinity than Ligand B (0.0 kcal/mol). The difference in affinity is substantial.

**Overall Assessment:**

Ligand A is significantly more promising. It has a better BBB score, lower DILI risk, better metabolic stability (lower Cl_mic), and a superior binding affinity. While its logP is slightly low, the strong BBB penetration and excellent affinity likely outweigh this drawback. The negative values for Caco-2, solubility, and half-life are concerning and would require further investigation, but the other properties strongly favor Ligand A. Ligand B's poor BBB penetration and higher DILI risk are major drawbacks, and its binding affinity is very poor.

Output:
1
2025-04-17 07:07:08,921 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (348.407 and 353.463 Da) fall comfortably within the ideal 200-500 Da range.

**TPSA:** Ligand A (120.08) is slightly above the optimal <90 for CNS targets, while Ligand B (98.74) is within the desired range. This gives a slight edge to Ligand B.

**logP:** Ligand A (-0.457) is a bit low, potentially hindering membrane permeability. Ligand B (0.561) is better, falling within the 1-3 range, but still on the lower side.

**H-Bond Donors/Acceptors:** Both ligands have 3 HBD and 5/4 HBA, respectively, which are acceptable values.

**QED:** Both ligands have similar QED values (0.622 and 0.623), indicating good drug-likeness.

**DILI:** Ligand A (52.346) has a higher DILI risk than Ligand B (14.114). This is a significant advantage for Ligand B.

**BBB:** Ligand A (30.748) has a low BBB penetration percentile, which is a major drawback for a CNS target like DRD2. Ligand B (28.189) is also low, but slightly better than A. Both are significantly below the desirable >70.

**Caco-2 Permeability:** Both have negative Caco-2 values (-5.76 and -5.291), which is unusual and suggests poor permeability.

**Aqueous Solubility:** Both have negative solubility values (-1.942 and -1.153), indicating poor aqueous solubility.

**hERG:** Both ligands have very low hERG inhibition liability (0.063 and 0.079), which is excellent.

**Microsomal Clearance:** Ligand A (-28.122) has a much lower (better) microsomal clearance than Ligand B (-6.167), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (11.078) has a longer half-life than Ligand B (3.822).

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.011), which is favorable for CNS penetration.

**Binding Affinity:** Ligand B (-7.6 kcal/mol) has a significantly stronger binding affinity than Ligand A (0.0 kcal/mol). This is a crucial advantage, potentially outweighing some of the ADME concerns.

**Overall Assessment:**

While both ligands have issues with BBB penetration and solubility, Ligand B is clearly superior. Its significantly stronger binding affinity (-7.6 vs 0.0 kcal/mol) is a major advantage for a GPCR target. Furthermore, it has a much lower DILI risk and better TPSA. Ligand A has better metabolic stability (lower Cl_mic) and longer half-life, but these are less critical than affinity and safety for initial candidate selection. The low BBB values for both are concerning, but the strong affinity of Ligand B suggests it might still achieve sufficient CNS exposure.

Output:
1
2025-04-17 07:07:08,922 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 drug candidates, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (363.336 and 383.445 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (91.76) is slightly above the optimal <90 for CNS targets, but still reasonable. Ligand B (53.51) is excellent, well below 90. This favors Ligand B.

**3. logP:** Both ligands (2.283 and 2.688) are within the optimal 1-3 range.

**4. H-Bond Donors:** Ligand A (2) and Ligand B (0) are both acceptable (<=5).

**5. H-Bond Acceptors:** Both ligands (5) are within the acceptable range (<=10).

**6. QED:** Both ligands (0.804 and 0.819) have high QED scores, indicating good drug-like properties.

**7. DILI:** Ligand A (56.96) and Ligand B (62.233) are both acceptable, below the 60 threshold for high risk, but B is slightly higher.

**8. BBB:** This is critical for a CNS target. Ligand A (64.444) is okay, but Ligand B (88.872) is significantly better, exceeding the desirable >70 threshold. This is a major advantage for Ligand B.

**9. Caco-2 Permeability:** Both ligands have negative values (-4.476 and -4.496), which is unusual and suggests poor permeability. This is a concern for both.

**10. Aqueous Solubility:** Both ligands have negative values (-3.172 and -3.443), indicating poor aqueous solubility. This is a significant drawback for both.

**11. hERG Inhibition:** Both ligands (0.405 and 0.607) have low hERG inhibition risk, which is good.

**12. Microsomal Clearance:** Ligand A (35.791) has a slightly higher clearance than Ligand B (32.718), suggesting lower metabolic stability. This favors Ligand B.

**13. In vitro Half-Life:** Ligand B (7.45) has a much longer half-life than Ligand A (-10.861), which is a substantial advantage.

**14. P-gp Efflux:** Both ligands (0.082 and 0.163) have low P-gp efflux, which is favorable for CNS penetration.

**15. Binding Affinity:** Ligand B (-8.6 kcal/mol) has a stronger binding affinity than Ligand A (-7.7 kcal/mol). This 0.9 kcal/mol difference is significant and can outweigh some of the ADME drawbacks.

**Overall Assessment:**

Ligand B is the stronger candidate. While both have issues with Caco-2 permeability and aqueous solubility, Ligand B excels in the critical areas for a CNS GPCR target: significantly better BBB penetration (88.872 vs 64.444), a longer half-life (7.45 vs -10.861), and a stronger binding affinity (-8.6 vs -7.7 kcal/mol). The slightly higher DILI risk for Ligand B is less concerning than the poorer BBB and half-life of Ligand A.

Output:
1
2025-04-17 07:07:08,922 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (365.459 and 360.483 Da) are within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (123.14) is slightly above the optimal <90 for CNS targets, but still reasonable. Ligand B (78.25) is excellent, well below 90.

**3. logP:** Both ligands (1.937 and 1.889) fall within the optimal 1-3 range.

**4. H-Bond Donors:** Ligand A (3) is acceptable. Ligand B (1) is also good, potentially offering better permeability.

**5. H-Bond Acceptors:** Ligand A (7) is acceptable. Ligand B (6) is also good.

**6. QED:** Both ligands have good QED scores (0.584 and 0.784), indicating drug-like properties. Ligand B is slightly better.

**7. DILI:** Ligand A (63.164) has a moderate DILI risk. Ligand B (21.946) has a significantly lower DILI risk, which is a major advantage.

**8. BBB:** Both ligands have reasonable BBB penetration (55.215 and 61.923). While neither exceeds the desirable >70, Ligand B is slightly better.

**9. Caco-2 Permeability:** Both have negative Caco-2 values which is unusual and suggests poor permeability.

**10. Aqueous Solubility:** Both have negative solubility values which is also unusual and suggests poor solubility.

**11. hERG:** Both ligands have low hERG risk (0.452 and 0.589).

**12. Microsomal Clearance:** Ligand A (37.295) has a moderate clearance, while Ligand B (41.171) is slightly higher. Lower is preferred.

**13. In vitro Half-Life:** Ligand A (-27.079) has a very negative half-life, which is not possible. Ligand B (3.572) has a short half-life, but is at least a positive value.

**14. P-gp Efflux:** Both ligands have very low P-gp efflux (0.072 and 0.054), which is favorable for CNS penetration.

**15. Binding Affinity:** Both ligands have excellent binding affinities (-7.9 and -7.8 kcal/mol). The difference is minimal.

**Overall Assessment:**

Ligand B is the more promising candidate. While both have good affinity and acceptable logP/TPSA values, Ligand B significantly outperforms Ligand A in terms of DILI risk, QED, and has a more plausible half-life. The slightly better BBB penetration and lower TPSA also contribute to its favorability. The negative Caco-2 and solubility values are concerning for both, but the other advantages of Ligand B outweigh this drawback.

Output:
1
2025-04-17 07:07:08,922 - INFO - Batch 338 complete. Total preferences: 5408
2025-04-17 07:07:08,922 - INFO - Processing batch 339/512...
2025-04-17 07:07:58,520 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (348.443 Da) is slightly lower, which could be beneficial for permeability, but both are acceptable.

**TPSA:** Ligand A (76.66) is better than Ligand B (57.69). For CNS targets, we want TPSA <= 90, both are well within this range.

**logP:** Both ligands have good logP values (A: 1.183, B: 2.565), falling within the optimal 1-3 range. Ligand B is slightly higher, which might be a minor concern for off-target effects, but it's not a major issue.

**H-Bond Donors/Acceptors:** Ligand A (HBD=2, HBA=4) is slightly more balanced than Ligand B (HBD=0, HBA=3). Both are within acceptable limits (HBD <= 5, HBA <= 10).

**QED:** Both ligands have similar QED values (A: 0.678, B: 0.647), indicating good drug-like properties (>= 0.5).

**DILI:** Ligand A (29.081) has a significantly lower DILI risk than Ligand B (16.324). This is a substantial advantage for Ligand A.

**BBB:** Both ligands exhibit excellent BBB penetration (A: 74.913, B: 79.139), both exceeding the desirable threshold of >70 for CNS targets. Ligand B is slightly better.

**Caco-2 Permeability:** Ligand A (-5.214) has a worse Caco-2 permeability than Ligand B (-4.489). Higher values are better, so Ligand B is preferred here.

**Aqueous Solubility:** Ligand A (-1.768) has slightly better aqueous solubility than Ligand B (-2.36).

**hERG Inhibition:** Ligand A (0.144) has a much lower hERG inhibition liability than Ligand B (0.689). This is a crucial advantage for Ligand A, minimizing cardiotoxicity risk.

**Microsomal Clearance:** Ligand A (35.534) has a lower microsomal clearance than Ligand B (63.201), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (4.965) has a shorter in vitro half-life than Ligand B (-16.945). This is a disadvantage for Ligand A.

**P-gp Efflux:** Ligand A (0.054) has significantly lower P-gp efflux liability than Ligand B (0.518). Lower efflux is highly desirable for CNS penetration and bioavailability.

**Binding Affinity:** Ligand B (-8.0) has a significantly stronger binding affinity than Ligand A (0.0). This is a major advantage for Ligand B. The difference of 8 kcal/mol is substantial.

**Overall Assessment:**

While Ligand A has advantages in DILI risk, hERG inhibition, P-gp efflux, and metabolic stability, the overwhelmingly stronger binding affinity of Ligand B (-8.0 kcal/mol vs 0.0 kcal/mol) is the deciding factor. A difference of this magnitude can often overcome minor ADME drawbacks. The slightly higher logP and P-gp efflux of Ligand B are manageable, and its BBB penetration is excellent. The shorter half-life of Ligand A is also a concern.

Output:
1
2025-04-17 07:07:58,520 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (345.439 and 364.511 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (60.55) is better than Ligand B (58.64). Both are below the 90 Angstrom threshold desirable for CNS targets, but lower is better.

**3. logP:** Ligand A (4.239) is higher than the optimal range (1-3), potentially leading to solubility issues. Ligand B (1.665) is within the optimal range. This is a significant advantage for Ligand B.

**4. H-Bond Donors:** Both ligands have 1 HBD, which is within the acceptable limit of <=5.

**5. H-Bond Acceptors:** Both ligands have 4 HBA, which is within the acceptable limit of <=10.

**6. QED:** Both ligands have acceptable QED scores (0.602 and 0.698, respectively), indicating good drug-like properties.

**7. DILI:** Ligand A (62.931) has a higher DILI risk than Ligand B (18.108). This is a significant negative for Ligand A.

**8. BBB:** Ligand A (69.988) has a better BBB penetration percentile than Ligand B (56.534), which is crucial for a CNS target like DRD2.

**9. Caco-2 Permeability:** Ligand A (-4.867) has better Caco-2 permeability than Ligand B (-5.006).

**10. Aqueous Solubility:** Ligand A (-4.945) has better aqueous solubility than Ligand B (-3.447).

**11. hERG Inhibition:** Ligand A (0.862) has a slightly higher hERG inhibition risk than Ligand B (0.265), but both are relatively low.

**12. Microsomal Clearance:** Ligand A (93.611) has significantly higher microsomal clearance than Ligand B (19.705), indicating lower metabolic stability. This is a major drawback for Ligand A.

**13. In vitro Half-Life:** Ligand A (-11.965) has a shorter in vitro half-life than Ligand B (-1.789).

**14. P-gp Efflux:** Ligand A (0.779) has lower P-gp efflux than Ligand B (0.102), which is favorable for CNS penetration.

**15. Binding Affinity:** Ligand A (-8.7 kcal/mol) has a significantly stronger binding affinity than Ligand B (-7.2 kcal/mol). This is a substantial advantage for Ligand A, potentially outweighing some of its ADME drawbacks.

**Overall Assessment:**

While Ligand A boasts superior binding affinity and BBB penetration, its higher DILI risk, significantly higher microsomal clearance, and shorter half-life are major concerns. Ligand B, despite weaker binding, exhibits a much more favorable ADME profile, particularly regarding metabolic stability (lower Cl_mic) and safety (lower DILI). The logP value for Ligand B is also much better. Given the GPCR-specific priorities, a balance between potency and ADME properties is crucial. The substantial difference in binding affinity (-8.7 vs -7.2) is significant, but the ADME liabilities of Ligand A are too substantial.

Output:
1
2025-04-17 07:07:58,521 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (342.439 and 383.901 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (70.59) is better than Ligand B (80.32). Both are below the 90 A^2 threshold desirable for CNS targets, but A is closer to the optimal range.

**3. logP:** Ligand B (2.567) is better than Ligand A (4.324). Ligand A is a bit high, potentially leading to solubility issues or off-target interactions. Ligand B is within the optimal 1-3 range.

**4. H-Bond Donors:** Ligand A (3) is slightly higher than Ligand B (2), but both are acceptable (<=5).

**5. H-Bond Acceptors:** Ligand B (5) is better than Ligand A (3), but both are acceptable (<=10).

**6. QED:** Both ligands have good QED scores (0.669 and 0.756, both > 0.5).

**7. DILI:** Ligand B (65.568) has a higher DILI risk than Ligand A (55.68), but both are acceptable.

**8. BBB:** Ligand B (68.941) is significantly better than Ligand A (36.177). This is a *critical* factor for a CNS target like DRD2.

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.129 and -5.001), which is unusual and suggests poor permeability. This is a significant concern for both.

**10. Aqueous Solubility:** Both ligands have negative solubility values (-4.724 and -4.115), indicating poor aqueous solubility. This is a concern for both.

**11. hERG Inhibition:** Ligand A (0.745) has a slightly higher hERG risk than Ligand B (0.306), but both are relatively low.

**12. Microsomal Clearance:** Ligand B (64.436) has lower microsomal clearance than Ligand A (87.522), suggesting better metabolic stability.

**13. In vitro Half-Life:** Both ligands have similar in vitro half-lives (27.352 and 27.783 hours).

**14. P-gp Efflux:** Ligand A (0.389) has lower P-gp efflux than Ligand B (0.227), which is favorable for CNS penetration.

**15. Binding Affinity:** Ligand A (-8.9 kcal/mol) has a slightly better binding affinity than Ligand B (-8.2 kcal/mol). This difference of 0.7 kcal/mol is notable.

**Overall Assessment:**

While Ligand A has better affinity and lower P-gp efflux, Ligand B is superior in terms of BBB penetration and metabolic stability (lower Cl_mic). The poor Caco-2 and solubility for both are concerning, but can potentially be addressed with formulation strategies. Given the importance of BBB penetration for a CNS target like DRD2, and the relatively small difference in binding affinity, Ligand B is the more promising candidate.

Output:
1
2025-04-17 07:07:58,521 - INFO - Here's a step-by-step comparison of Ligand A and Ligand B, followed by my final decision:

**1. Molecular Weight (MW):**
*   Ligand A: 349.385 Da - Within the ideal range (200-500 Da).
*   Ligand B: 354.466 Da - Within the ideal range (200-500 Da).
*   *Both are acceptable.*

**2. Topological Polar Surface Area (TPSA):**
*   Ligand A: 53.52 A<sup>2</sup> - Excellent for CNS penetration (well below 90 A<sup>2</sup>).
*   Ligand B: 67.43 A<sup>2</sup> - Still good for CNS penetration, but higher than Ligand A.
*   *Ligand A is preferred.*

**3. Lipophilicity (logP):**
*   Ligand A: 2.27 - Optimal (1-3).
*   Ligand B: 2.509 - Optimal (1-3).
*   *Both are acceptable.*

**4. H-Bond Donors (HBD):**
*   Ligand A: 1 - Meets the criteria (<=5).
*   Ligand B: 2 - Meets the criteria (<=5).
*   *Both are acceptable.*

**5. H-Bond Acceptors (HBA):**
*   Ligand A: 6 - Meets the criteria (<=10).
*   Ligand B: 3 - Meets the criteria (<=10).
*   *Both are acceptable.*

**6. Quantitative Estimate of Drug-likeness (QED):**
*   Ligand A: 0.894 - Excellent drug-like properties.
*   Ligand B: 0.658 - Good drug-like properties, but lower than Ligand A.
*   *Ligand A is preferred.*

**7. DILI Risk (DILI):**
*   Ligand A: 76.386 - Moderate risk.
*   Ligand B: 19.155 - Low risk.
*   *Ligand B is preferred.*

**8. Blood-Brain Barrier Penetration (BBB):**
*   Ligand A: 76.309 - Good, but not exceptional.
*   Ligand B: 83.288 - Very good.
*   *Ligand B is preferred (critical for a CNS target).*

**9. Caco-2 Permeability:**
*   Ligand A: -4.301 - Poor permeability.
*   Ligand B: -4.527 - Poor permeability.
*   *Both are similar and problematic.*

**10. Aqueous Solubility:**
*   Ligand A: -3.073 - Poor solubility.
*   Ligand B: -2.536 - Poor solubility, but slightly better than Ligand A.
*   *Ligand B is slightly preferred.*

**11. hERG Inhibition:**
*   Ligand A: 0.532 - Low risk.
*   Ligand B: 0.514 - Low risk.
*   *Both are acceptable.*

**12. Microsomal Clearance (Cl_mic):**
*   Ligand A: 44.218 mL/min/kg - Moderate clearance.
*   Ligand B: 52.62 mL/min/kg - Moderate clearance.
*   *Both are similar.*

**13. In vitro Half-Life (t1/2):**
*   Ligand A: 7.97 hours - Moderate.
*   Ligand B: 12.06 hours - Better.
*   *Ligand B is preferred.*

**14. P-gp Efflux:**
*   Ligand A: 0.061 - Low efflux (good).
*   Ligand B: 0.14 - Low efflux (good).
*   *Both are acceptable.*

**15. Binding Affinity (kcal/mol):**
*   Ligand A: -8.4 kcal/mol - Excellent.
*   Ligand B: -9.1 kcal/mol - Exceptional (0.7 kcal/mol advantage).
*   *Ligand B is strongly preferred.*

**Overall Assessment:**

Ligand B demonstrates a clear advantage in several critical areas for a CNS-targeting GPCR like DRD2. While both compounds have poor Caco-2 permeability and solubility, Ligand B's superior BBB penetration, lower DILI risk, longer half-life, and significantly stronger binding affinity (-9.1 vs -8.4 kcal/mol) outweigh the minor drawbacks. The 0.7 kcal/mol difference in binding affinity is substantial and could translate to a significant improvement in efficacy.

1
2025-04-17 07:07:58,521 - INFO - Reasoning:

Let's analyze Ligand A and Ligand B for their potential as DRD2 drug candidates, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight (MW):** Both ligands (360.82 and 351.491 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (42.66) is significantly better than Ligand B (61.88). For CNS targets, we want TPSA <= 90, and A is comfortably within this range, while B is approaching the upper limit.

**3. logP:** Ligand A (4.099) is higher than the optimal 1-3 range, but still potentially manageable. Ligand B (1.395) is a bit low, potentially hindering permeation.

**4. H-Bond Donors (HBD):** Both are acceptable (0 and 1, respectively), well below the limit of 5.

**5. H-Bond Acceptors (HBA):** Both are acceptable (5 and 4, respectively), well below the limit of 10.

**6. QED:** Both ligands have good QED values (0.645 and 0.786), indicating drug-like properties.

**7. DILI:** Ligand A (75.766) has a higher DILI risk than Ligand B (14.075). This is a significant drawback for Ligand A.

**8. BBB:** Ligand A (77.007) has a better BBB penetration percentile than Ligand B (67.546). This is crucial for a CNS target like DRD2.

**9. Caco-2:** Both have negative values, which is unusual. Assuming these are logP-scale values, they indicate poor permeability.

**10. Solubility:** Both have negative values, indicating poor solubility.

**11. hERG:** Ligand A (0.678) has a slightly higher hERG risk than Ligand B (0.444), but both are relatively low.

**12. Cl_mic:** Ligand A (75.358) has a higher microsomal clearance than Ligand B (10.379), suggesting lower metabolic stability.

**13. t1/2:** Ligand A (53.764) has a longer half-life than Ligand B (20.271).

**14. Pgp:** Ligand A (0.88) has higher P-gp efflux liability than Ligand B (0.046). Lower Pgp is preferred for CNS penetration.

**15. Binding Affinity:** Ligand A (-8.8 kcal/mol) has a significantly stronger binding affinity than Ligand B (-7.5 kcal/mol). This is a substantial advantage.

**Overall Assessment:**

Ligand A has a much stronger binding affinity and better BBB penetration, which are critical for a CNS GPCR target. However, it suffers from higher DILI risk, higher Pgp efflux, and higher microsomal clearance. Ligand B has a better safety profile (lower DILI, Pgp, Cl_mic) but weaker affinity and lower BBB penetration.

The difference in binding affinity (-8.8 vs -7.5 kcal/mol) is significant (1.3 kcal/mol), and can potentially outweigh the ADME drawbacks of Ligand A, *especially* given the importance of potency for GPCRs. The BBB value for Ligand A is also quite good (77%). While the DILI risk is a concern, it's not extremely high. The higher Pgp and Cl_mic could be addressed through further optimization.

Output:
1
2025-04-17 07:07:58,521 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (366.849 and 351.407 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (97.55) is excellent, falling well below the 90 A^2 threshold for CNS targets. Ligand B (116.68) is higher but still potentially acceptable, though less optimal.

**logP:** Ligand A (1.463) is within the optimal 1-3 range. Ligand B (-0.966) is slightly below 1, which *could* indicate permeability issues, but is not a severe concern.

**H-Bond Donors/Acceptors:** Ligand A (2 HBD, 5 HBA) is well within the guidelines. Ligand B (3 HBD, 7 HBA) is also acceptable.

**QED:** Both ligands have reasonable QED scores (0.794 and 0.524), indicating drug-like properties. Ligand A is better.

**DILI:** Ligand A (59.403) has a moderate DILI risk, but is acceptable. Ligand B (31.097) has a significantly lower DILI risk, which is a strong positive.

**BBB:** Ligand A (80.264) has a good BBB penetration percentile, exceeding the 70% threshold for CNS targets. Ligand B (50.523) is significantly lower and concerning for CNS penetration.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.083 and -5.139). These values are unusual and difficult to interpret without additional context. However, they both suggest poor permeability.

**Aqueous Solubility:** Both ligands have negative solubility values (-3.226 and -1.162). Similar to Caco-2, these are unusual and suggest poor solubility.

**hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.408 and 0.124).

**Microsomal Clearance:** Ligand A (-0.657) has a lower (better) microsomal clearance than Ligand B (-6.469), indicating better metabolic stability.

**In vitro Half-Life:** Ligand A (2.218) has a longer half-life than Ligand B (-15.256), which is desirable.

**P-gp Efflux:** Ligand A (0.027) has very low P-gp efflux, which is excellent for CNS penetration. Ligand B (0.002) is even lower, which is also excellent.

**Binding Affinity:** Ligand A (-7.7 kcal/mol) has a slightly better binding affinity than Ligand B (-7.1 kcal/mol), although both are excellent.

**Overall Assessment:**

Ligand A excels in BBB penetration, metabolic stability, and half-life. Its affinity is slightly better. While its solubility and Caco-2 values are concerning, its strong BBB score and overall drug-like properties make it a more promising candidate. Ligand B has a lower DILI risk, but its significantly lower BBB penetration is a major drawback for a CNS target like DRD2. The solubility and Caco-2 values are also concerning.

Output:
1
2025-04-17 07:07:58,521 - INFO - Reasoning:

Let's analyze Ligand A and Ligand B based on the provided guidelines, prioritizing GPCR-specific properties (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (404.308 Da) is slightly higher than Ligand B (350.419 Da), but both are acceptable.

**TPSA:** Ligand A (70.23) is significantly better than Ligand B (105.48). For CNS targets, TPSA should be <= 90, so Ligand A is preferable.

**logP:** Ligand A (3.429) is optimal (1-3), while Ligand B (0.302) is quite low, potentially hindering permeation. This favors Ligand A.

**H-Bond Donors/Acceptors:** Both have 3 HBD, which is good. Ligand B has 6 HBA, while Ligand A has 3. Both are within acceptable limits (<=10), but Ligand A is slightly better.

**QED:** Both ligands have similar QED values (0.62 and 0.656), indicating good drug-likeness.

**DILI:** Ligand A (65.762) has a higher DILI risk than Ligand B (49.205), which is less desirable.

**BBB:** Ligand A (67.352) is better than Ligand B (53.509), but both are below the desirable threshold of >70 for CNS targets. However, given that we are targeting DRD2, a CNS target, this is a critical parameter.

**Caco-2 Permeability:** Both have negative Caco-2 values (-5.056 and -5.107), which is unusual and suggests poor permeability. This is a significant concern for both.

**Aqueous Solubility:** Both have negative solubility values (-4.713 and -1.579), also unusual and suggesting poor solubility.

**hERG:** Ligand A (0.811) has a slightly higher hERG risk than Ligand B (0.098). Lower is better, so Ligand B is preferable here.

**Microsomal Clearance:** Ligand A (30.818) has a higher clearance than Ligand B (0.745), indicating lower metabolic stability. Ligand B is preferable.

**In vitro Half-Life:** Ligand A (86.427) has a much longer half-life than Ligand B (33.013), which is desirable.

**P-gp Efflux:** Ligand A (0.282) has lower P-gp efflux than Ligand B (0.029), which is better for CNS exposure.

**Binding Affinity:** Ligand A (-9.1 kcal/mol) has a significantly stronger binding affinity than Ligand B (-7.9 kcal/mol). This is a substantial advantage, potentially outweighing some ADME drawbacks. The difference is >1.5 kcal/mol.

**Overall Assessment:**

Ligand A excels in binding affinity, TPSA, logP, P-gp efflux, and in vitro half-life. Ligand B has better DILI, hERG, and microsomal clearance. However, the significantly stronger binding affinity of Ligand A (-9.1 vs -7.9 kcal/mol) is a major advantage, especially for a GPCR target. While both have concerning permeability and solubility issues, the superior affinity and better BBB penetration (though still suboptimal) of Ligand A make it the more promising candidate. The lower P-gp efflux also contributes to better CNS exposure potential.



Output:
1
2025-04-17 07:07:58,522 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (397.232 Da) is slightly higher than Ligand B (346.431 Da), but both are acceptable.

**TPSA:** Ligand A (70.63) is better than Ligand B (76.46) as it is closer to the ideal TPSA for CNS targets (<90).

**logP:** Ligand A (3.003) is optimal, while Ligand B (0.965) is a bit low, potentially hindering membrane permeability.

**H-Bond Donors/Acceptors:** Both ligands have acceptable HBD/HBA counts (Ligand A: 0/5, Ligand B: 1/5).

**QED:** Both ligands have good QED scores (Ligand A: 0.633, Ligand B: 0.779), indicating drug-like properties.

**DILI:** Ligand A (83.637) has a higher DILI risk than Ligand B (45.173). This is a significant drawback for Ligand A.

**BBB:** Ligand B (65.374) has a better BBB penetration score than Ligand A (59.791), although both are below the desirable >70 for CNS targets.

**Caco-2 Permeability:** Ligand A (-4.716) shows poor Caco-2 permeability, while Ligand B (-5.082) is also poor, but slightly better.

**Aqueous Solubility:** Ligand A (-4.828) has poor aqueous solubility, while Ligand B (-1.186) is also poor, but better than Ligand A.

**hERG Inhibition:** Ligand A (0.858) has a higher hERG inhibition risk than Ligand B (0.166). This is a significant safety concern for Ligand A.

**Microsomal Clearance:** Ligand B (2.928) has a much lower microsomal clearance than Ligand A (80.85), indicating better metabolic stability.

**In vitro Half-Life:** Ligand B (6.32) has a longer in vitro half-life than Ligand A (11.163).

**P-gp Efflux:** Both ligands have low P-gp efflux liability (Ligand A: 0.693, Ligand B: 0.03). Ligand B is significantly better.

**Binding Affinity:** Ligand B (-7.8 kcal/mol) has a significantly stronger binding affinity than Ligand A (-0.0 kcal/mol). This is the most critical factor.

**Overall Assessment:**

Ligand B is the superior candidate. While its BBB penetration isn't ideal, its significantly higher binding affinity, lower DILI risk, lower hERG inhibition, better metabolic stability (lower Cl_mic and longer t1/2), and lower P-gp efflux outweigh the slightly lower logP and BBB. Ligand A's poor solubility, permeability, high DILI and hERG risk, and very weak binding affinity make it a poor candidate despite its acceptable MW and TPSA. The substantial affinity difference (>1.5 kcal/mol) makes Ligand B the clear choice.

Output:
1
2025-04-17 07:07:58,522 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (342.439 Da and 338.455 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (69.64) is slightly above the optimal <90 for CNS targets, but still reasonable. Ligand B (50.16) is excellent, well below 90.

**3. logP:** Both ligands have a logP of around 3.1, which is optimal.

**4. H-Bond Donors:** Ligand A has 2 HBD, and Ligand B has 1. Both are within the acceptable limit of <=5.

**5. H-Bond Acceptors:** Ligand A has 3 HBA, and Ligand B has 4. Both are within the acceptable limit of <=10.

**6. QED:** Ligand B (0.88) has a significantly better QED score than Ligand A (0.638), indicating a more drug-like profile.

**7. DILI:** Ligand A (20.279) has a much lower DILI risk than Ligand B (30.516), which is a significant advantage.

**8. BBB:** Ligand B (89.104) has a substantially higher BBB penetration percentile than Ligand A (64.676). This is *critical* for a CNS target like DRD2.

**9. Caco-2 Permeability:** Both have negative values, indicating poor permeability. Ligand A (-4.674) is slightly worse than Ligand B (-4.898).

**10. Aqueous Solubility:** Both have negative values, indicating poor solubility. Ligand A (-4.168) is slightly better than Ligand B (-3.058).

**11. hERG Inhibition:** Ligand A (0.399) has a lower hERG risk than Ligand B (0.875), which is preferable.

**12. Microsomal Clearance:** Ligand B (69.731) has a higher microsomal clearance than Ligand A (48.85), meaning it's metabolized faster. This is a disadvantage.

**13. In vitro Half-Life:** Ligand A (-5.095) has a longer in vitro half-life than Ligand B (6.653). This is a significant advantage.

**14. P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.028 and 0.639 respectively), which is good.

**15. Binding Affinity:** Both ligands have very similar and excellent binding affinities (-8.6 kcal/mol and -8.2 kcal/mol). The difference of 0.4 kcal/mol is not substantial enough to be a deciding factor.

**Overall Assessment:**

While Ligand A has advantages in DILI risk, metabolic stability (lower Cl_mic, longer t1/2), and slightly better solubility, Ligand B *strongly* excels in BBB penetration (89.104 vs 64.676) and has a better QED score. For a CNS target like DRD2, BBB penetration is paramount. The higher BBB score of Ligand B outweighs the advantages of Ligand A.

Output:
1
2025-04-17 07:07:58,522 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (369.535 and 349.362 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (69.73) is excellent, well below the 90 A^2 threshold for CNS targets. Ligand B (98.74) is higher but still reasonable, though less optimal for CNS penetration.

**3. logP:** Both ligands have good logP values (1.205 and 1.511), falling within the optimal 1-3 range.

**4. H-Bond Donors:** Ligand A (2) and Ligand B (3) are both acceptable, staying within the recommended limit of 5.

**5. H-Bond Acceptors:** Ligand A (7) and Ligand B (4) are both within the acceptable range of <=10.

**6. QED:** Both ligands have good QED scores (0.604 and 0.702), indicating good drug-like properties.

**7. DILI:** Ligand A (35.169) has a significantly lower DILI risk than Ligand B (67.313). This is a substantial advantage for Ligand A.

**8. BBB:** Both ligands have good BBB penetration percentiles (78.209 and 76.464), exceeding the 70% threshold for CNS targets. Ligand A is slightly better.

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.956 and -4.906). This is unusual and suggests poor permeability. However, these values are on a log scale, and the negative values indicate very low permeability.

**10. Aqueous Solubility:** Both ligands have negative solubility values (-1.502 and -3.194), suggesting very poor aqueous solubility. This is a significant drawback for both.

**11. hERG Inhibition:** Ligand A (0.913) has a slightly higher hERG risk than Ligand B (0.215), but both are relatively low.

**12. Microsomal Clearance:** Ligand A (14.96) has a higher microsomal clearance than Ligand B (1.857), indicating lower metabolic stability. This is a disadvantage for Ligand A.

**13. In vitro Half-Life:** Ligand A (29.019) has a slightly longer half-life than Ligand B (28.771).

**14. P-gp Efflux:** Ligand A (0.058) has a much lower P-gp efflux liability than Ligand B (0.022), which is highly desirable for CNS penetration.

**15. Binding Affinity:** Ligand B (-8.7 kcal/mol) has a significantly stronger binding affinity than Ligand A (-6.9 kcal/mol). This is a >1.5 kcal/mol advantage, which can outweigh some ADME drawbacks.

**Overall Assessment:**

Ligand B has a substantially better binding affinity. While Ligand A has advantages in DILI risk and P-gp efflux, the difference in binding affinity is significant. The poor solubility and permeability are concerning for both, but the potency of Ligand B is a major factor, especially for a GPCR target where achieving sufficient receptor occupancy is crucial. The slightly better metabolic stability of Ligand B is also a plus.

Output:
1
2025-04-17 07:07:58,522 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (348.407) is slightly lower, which could be beneficial for permeability.

**TPSA:** Ligand A (134.07) is excellent for CNS penetration, being below the 90 A^2 threshold. Ligand B (47.36) is also very good.

**logP:** Ligand A (-0.415) is a bit low, potentially hindering membrane permeability. Ligand B (2.899) is within the optimal range (1-3). This is a significant advantage for Ligand B.

**H-Bond Donors/Acceptors:** Ligand A (3 HBD, 5 HBA) and Ligand B (0 HBD, 4 HBA) both fall within acceptable limits.

**QED:** Both ligands have good QED scores (A: 0.549, B: 0.679), indicating drug-like properties.

**DILI:** Ligand A (45.25) has a slightly higher DILI risk than Ligand B (31.524), but both are reasonably low.

**BBB:** Ligand B (91.896) has a significantly higher BBB penetration percentile than Ligand A (54.866). This is a critical advantage for a CNS target like DRD2.

**Caco-2 Permeability:** Ligand A (-6.273) has poor Caco-2 permeability, while Ligand B (-4.551) is also poor, but less so.

**Aqueous Solubility:** Both have negative solubility values, indicating poor solubility. Ligand A (-1.582) is slightly better than Ligand B (-2.473).

**hERG Inhibition:** Ligand A (0.041) has a very low hERG risk, which is excellent. Ligand B (0.635) is higher, but still relatively low.

**Microsomal Clearance:** Ligand A (-24.459) has a much lower (better) microsomal clearance than Ligand B (51.206), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (-10.896) has a negative half-life, which is unusual and suggests rapid metabolism or instability. Ligand B (0.413) has a very short half-life.

**P-gp Efflux:** Ligand A (0.016) has very low P-gp efflux, which is favorable for CNS penetration. Ligand B (0.217) has slightly higher efflux, but still reasonably low.

**Binding Affinity:** Ligand A (-8.7 kcal/mol) has a significantly stronger binding affinity than Ligand B (-6.8 kcal/mol). This is a substantial advantage, potentially outweighing some of the ADME concerns.

**Overall Assessment:**

Ligand A has a significantly better binding affinity and metabolic stability (lower Cl_mic), and lower P-gp efflux. However, its logP is low, Caco-2 permeability is poor, and BBB penetration is moderate. Ligand B excels in BBB penetration and has a good logP, but suffers from weaker binding affinity and poorer metabolic stability.

Given the GPCR-specific priorities, BBB penetration is crucial for CNS targets. The strong affinity of Ligand A is a major plus, and its low P-gp efflux is also beneficial. While its logP and Caco-2 permeability are concerns, the substantial affinity advantage (-1.9 kcal/mol difference) could compensate for these issues, especially if formulation strategies can address the solubility and permeability challenges. The significantly better BBB of Ligand B is appealing, but the weaker binding affinity is a major drawback.

Output:
0
2025-04-17 07:07:58,523 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (370.316 Da) is slightly lower, which could be beneficial for permeability. Ligand B (404.348 Da) is also good.

**TPSA:** Ligand A (105.56) is above the optimal <90 for CNS targets, but not drastically so. Ligand B (30.49) is excellent, well below the threshold, suggesting good CNS penetration potential.

**logP:** Ligand A (1.361) is within the optimal range (1-3). Ligand B (4.927) is higher, potentially leading to solubility issues and off-target interactions.

**H-Bond Donors/Acceptors:** Ligand A has 2 HBD and 7 HBA, which are acceptable. Ligand B has 1 HBD and 3 HBA, also acceptable.

**QED:** Both ligands have similar QED values (A: 0.721, B: 0.677), indicating good drug-likeness.

**DILI:** Ligand A has a high DILI risk (96.161), which is a significant concern. Ligand B has a much lower DILI risk (18.728), a major advantage.

**BBB:** Ligand A's BBB penetration (40.016) is poor, making it less suitable for a CNS target like DRD2. Ligand B has excellent BBB penetration (78.596), a crucial benefit.

**Caco-2 Permeability:** Ligand A shows poor Caco-2 permeability (-5.148). Ligand B also shows poor Caco-2 permeability (-4.878).

**Aqueous Solubility:** Both ligands have poor aqueous solubility (-3.446 and -4.323 respectively).

**hERG:** Ligand A has a very low hERG risk (0.143), which is excellent. Ligand B has a slightly higher, but still acceptable, hERG risk (0.931).

**Microsomal Clearance:** Ligand A has a low microsomal clearance (6.557), indicating good metabolic stability. Ligand B has a significantly higher clearance (64.626), suggesting faster metabolism.

**In vitro Half-Life:** Ligand A has a negative half-life (-31.201), which is not possible and likely an error. Ligand B has a reasonable half-life (21.207).

**P-gp Efflux:** Ligand A shows low P-gp efflux (0.096), which is favorable for CNS penetration. Ligand B shows moderate P-gp efflux (0.714).

**Binding Affinity:** Ligand B (-9.7 kcal/mol) has a significantly stronger binding affinity than Ligand A (-8.7 kcal/mol). This 1 kcal/mol difference is substantial and can outweigh some ADME drawbacks.

**Overall Assessment:**

Ligand B is the more promising candidate. While its logP is a bit high and Caco-2 permeability is low, it excels in crucial areas for a CNS-targeting GPCR ligand: excellent BBB penetration, significantly lower DILI risk, superior binding affinity, and good metabolic stability. Ligand A suffers from poor BBB penetration and a very high DILI risk, and its negative half-life is a red flag. The stronger binding affinity of Ligand B is a significant advantage.

Output:
1
2025-04-17 07:07:58,523 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (351.324 and 351.447 Da) fall comfortably within the ideal 200-500 Da range.

**TPSA:** Ligand A (38.77) is excellent, well below the 90 A^2 threshold for CNS targets. Ligand B (78.95) is higher, but still potentially acceptable, though less ideal.

**logP:** Ligand A (3.083) is optimal (1-3). Ligand B (0.531) is quite low, potentially hindering membrane permeability and CNS penetration.

**H-Bond Donors/Acceptors:** Ligand A (0 HBD, 3 HBA) is favorable. Ligand B (1 HBD, 4 HBA) is also acceptable.

**QED:** Both ligands have similar QED values (0.85 and 0.801), indicating good drug-likeness.

**DILI:** Ligand A (80.962) has a higher DILI risk than Ligand B (18.728), which is a significant concern.

**BBB:** Both ligands have high BBB penetration (91.508 and 80.031), which is crucial for a CNS target like DRD2.

**Caco-2 Permeability:** Ligand A (-4.068) has poor Caco-2 permeability, while Ligand B (-4.824) is also poor, but slightly worse.

**Aqueous Solubility:** Ligand A (-3.814) has poor aqueous solubility, while Ligand B (-0.885) is slightly better.

**hERG:** Ligand A (0.546) has a low hERG risk, while Ligand B (0.079) has a very low hERG risk.

**Microsomal Clearance:** Ligand A (48.017) has moderate clearance, while Ligand B (1.913) has very low clearance, indicating better metabolic stability.

**In vitro Half-Life:** Ligand A (-40.965) has a very long half-life, while Ligand B (6.975) has a short half-life.

**P-gp Efflux:** Ligand A (0.243) has low P-gp efflux, which is good for CNS penetration. Ligand B (0.009) has extremely low P-gp efflux, even better.

**Binding Affinity:** Ligand A (-7.3) has a slightly better binding affinity than Ligand B (-0.0). This is a substantial difference.

**Overall Assessment:**

Ligand A has a better binding affinity and acceptable BBB penetration and P-gp efflux. However, it suffers from poor Caco-2 permeability, poor aqueous solubility, and a higher DILI risk. Ligand B has excellent metabolic stability (low Cl_mic), very low P-gp efflux, and a significantly lower DILI risk. However, its logP is very low, and its binding affinity is extremely weak.

Given the GPCR-specific priorities, BBB and affinity are critical. While Ligand A has a much better affinity, the very poor solubility and permeability, combined with the higher DILI risk, are major drawbacks. Ligand B's extremely low affinity is a dealbreaker, even with its favorable ADME properties. However, the large affinity difference between the two ligands is substantial.

Considering the significant affinity advantage of Ligand A, and the possibility of addressing the solubility/permeability issues through formulation or prodrug strategies, it is the more promising candidate despite its drawbacks.

Output:
0
2025-04-17 07:07:58,523 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (346.343 and 353.507 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (126.32) is slightly above the preferred <90 for CNS targets, but still reasonable. Ligand B (81.67) is excellent, well below 90.

**logP:** Ligand A (0.128) is quite low, potentially hindering membrane permeability. Ligand B (1.279) is much better, falling within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Both have 3 HBDs, which is acceptable. Ligand A has 6 HBAs, while Ligand B has 4. Both are within the acceptable limit of 10.

**QED:** Both ligands have reasonable QED scores (0.706 and 0.546), indicating good drug-like properties.

**DILI:** Ligand A has a high DILI risk (85.653), which is a significant concern. Ligand B has a very low DILI risk (5.584), a major advantage.

**BBB:** Ligand A has a very low BBB penetration (27.801), making it unlikely to effectively reach the target in the CNS. Ligand B has a much better BBB penetration (67.197), though ideally, we'd want >70.

**Caco-2 Permeability:** Ligand A shows poor Caco-2 permeability (-5.734). Ligand B shows poor Caco-2 permeability (-4.975).

**Aqueous Solubility:** Both ligands have poor aqueous solubility (-2.978 and -1.395).

**hERG Inhibition:** Both ligands have low hERG inhibition liability (0.052 and 0.394).

**Microsomal Clearance:** Ligand A has a very low (good) microsomal clearance (-21.523), indicating high metabolic stability. Ligand B has a moderate clearance (15.877).

**In vitro Half-Life:** Ligand A has a reasonable in vitro half-life (29.641). Ligand B has a poor in vitro half-life (-24.534).

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.019 and 0.009), which is favorable for CNS penetration.

**Binding Affinity:** Ligand A (-8.3 kcal/mol) has a slightly better binding affinity than Ligand B (-7.3 kcal/mol), but the difference is not substantial enough to overcome the other significant drawbacks.

**Overall Assessment:**

Ligand B is the more promising candidate. While its Caco-2 permeability and in vitro half-life are poor, its significantly lower DILI risk, better logP, and substantially improved BBB penetration outweigh the slightly weaker binding affinity compared to Ligand A. Ligand A's high DILI risk and very poor BBB penetration are major liabilities that are difficult to overcome. The GPCR-specific priorities strongly favor Ligand B.

Output:
1
2025-04-17 07:07:58,523 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (346.475 Da) is slightly lower, which could be beneficial for permeability. Ligand B (387.527 Da) is also acceptable.

**TPSA:** Both ligands have TPSA values (A: 76.02, B: 79.81) below the 90 A^2 threshold for CNS targets, which is good.

**logP:** Ligand A (3.026) is optimal (1-3). Ligand B (1.151) is a bit low, potentially hindering membrane permeability.

**H-Bond Donors/Acceptors:** Ligand A (HBD=2, HBA=4) and Ligand B (HBD=0, HBA=7) both fall within acceptable ranges.

**QED:** Both ligands have reasonable QED values (A: 0.745, B: 0.698), indicating good drug-like properties.

**DILI:** Ligand A (39.395) has a lower DILI risk than Ligand B (64.172), which is a significant advantage.

**BBB:** Both ligands exhibit excellent BBB penetration (A: 82.241, B: 83.288), exceeding the desirable 70% threshold for CNS targets.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.845 and -4.619), which is unusual and suggests poor permeability. This is a concern for both compounds.

**Aqueous Solubility:** Both ligands have negative solubility values (-3.439 and -2.546), which is also concerning and suggests poor solubility.

**hERG:** Both ligands have low hERG inhibition liability (A: 0.472, B: 0.266), which is positive.

**Microsomal Clearance:** Ligand A (53.553) has a higher microsomal clearance than Ligand B (14.833), indicating lower metabolic stability.

**In vitro Half-Life:** Ligand B (21.484 hours) has a longer half-life than Ligand A (29.211 hours), which is desirable.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (A: 0.408, B: 0.241), which is good for CNS exposure.

**Binding Affinity:** Ligand A (-8.8 kcal/mol) has a significantly stronger binding affinity than Ligand B (-7.5 kcal/mol), a difference of 1.3 kcal/mol. This is a substantial advantage that can outweigh some ADME drawbacks.

**Conclusion:**

Despite the unusual negative Caco-2 and solubility values for both compounds, Ligand A is the more promising candidate. The significantly stronger binding affinity (-8.8 vs -7.5 kcal/mol) is a major advantage for a GPCR target. It also has a lower DILI risk. Although its microsomal clearance is higher than Ligand B, the affinity difference is substantial enough to prioritize Ligand A. The poor Caco-2 and solubility would need to be addressed through formulation or structural modifications, but the strong binding and favorable BBB penetration make it a better starting point.

Output:
1
2025-04-17 07:07:58,524 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (335.367 and 347.419 Da) fall within the ideal 200-500 Da range.

**TPSA:** Both ligands (95.83 and 96.41) are close to the 90 A^2 threshold for CNS targets, but still acceptable.

**logP:** Ligand A (1.872) is optimal, while Ligand B (0.946) is slightly below the preferred range of 1-3, potentially hindering permeation.

**H-Bond Donors/Acceptors:** Ligand A (HBD=3, HBA=5) and Ligand B (HBD=2, HBA=7) both have reasonable H-bond counts, within the suggested limits.

**QED:** Both ligands have good QED scores (0.53 and 0.862), indicating drug-like properties.

**DILI:** Ligand A (82.241) has a higher DILI risk than Ligand B (52.772). This is a significant drawback for Ligand A.

**BBB:** Ligand B (24.351) has a slightly better BBB penetration percentile than Ligand A (20.124), but both are quite low and concerning for a CNS target.

**Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and suggests poor permeability.

**Aqueous Solubility:** Both have negative solubility values, which is also unusual and suggests poor solubility.

**hERG:** Both ligands have low hERG inhibition liability (0.607 and 0.096), which is favorable.

**Microsomal Clearance:** Ligand B (6.185) has significantly lower microsomal clearance than Ligand A (18.877), indicating better metabolic stability.

**In vitro Half-Life:** Ligand B (17.763) has a longer in vitro half-life than Ligand A (70.631).

**P-gp Efflux:** Ligand A (0.316) has lower P-gp efflux liability than Ligand B (0.062), which is better for CNS exposure.

**Binding Affinity:** Ligand B (-8.5 kcal/mol) has a significantly stronger binding affinity than Ligand A (-10.1 kcal/mol). This is a substantial advantage, potentially outweighing some ADME concerns.

**Overall Assessment:**

Ligand B is the more promising candidate. While its BBB penetration is low, its significantly better binding affinity (-8.5 vs -10.1 kcal/mol), lower DILI risk, and improved metabolic stability (lower Cl_mic and longer t1/2) are crucial advantages. Ligand A has a better P-gp profile, but the higher DILI risk and weaker binding are major concerns. The slightly lower logP of Ligand B is less concerning than the other drawbacks of Ligand A.

Output:
1
2025-04-17 07:07:58,524 - INFO - Batch 339 complete. Total preferences: 5424
2025-04-17 07:07:58,524 - INFO - Processing batch 340/512...
2025-04-17 07:08:50,522 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight (MW):** Both ligands are within the ideal range (200-500 Da). Ligand A (410.247 Da) is slightly higher than Ligand B (345.403 Da), but both are acceptable.

**2. TPSA:** Ligand A (100.35) is borderline for CNS targets (ideally <90), while Ligand B (93.25) is closer to the desired range. This gives a slight edge to Ligand B.

**3. logP:** Both ligands have good logP values (Ligand A: 2.801, Ligand B: 1.619), falling within the optimal 1-3 range.

**4. H-Bond Donors (HBD):** Ligand A (3) is acceptable, while Ligand B (1) is also good.

**5. H-Bond Acceptors (HBA):** Ligand A (3) is acceptable, while Ligand B (6) is also within the acceptable range (<=10).

**6. QED:** Both ligands have good QED values (Ligand A: 0.71, Ligand B: 0.889), indicating good drug-like properties. Ligand B is slightly better.

**7. DILI:** Ligand A (66.731) is moderately risky, while Ligand B (78.247) is also moderately risky, but higher. Both are acceptable but warrant further investigation.

**8. BBB:** This is crucial for a CNS target. Ligand A has a very good BBB percentile (83.831), while Ligand B has a poor BBB percentile (30.089). This is a significant advantage for Ligand A.

**9. Caco-2 Permeability:** Ligand A (-4.998) and Ligand B (-5.401) both have negative values, which is unusual and suggests poor permeability. However, the scale is not specified, so it's difficult to interpret.

**10. Aqueous Solubility:** Both ligands have very poor solubility (-3.725 and -2.024 respectively). This is a significant drawback for both.

**11. hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.451 and 0.013 respectively).

**12. Microsomal Clearance:** Ligand A (-5.855) and Ligand B (-8.837) both have negative values, which is unusual and suggests very slow clearance.

**13. In vitro Half-Life:** Ligand A (29.336) has a reasonable half-life, while Ligand B (-2.976) has a negative half-life, which is impossible.

**14. P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.037 and 0.034 respectively).

**15. Binding Affinity:** Ligand A (-9.7 kcal/mol) has a significantly stronger binding affinity than Ligand B (0.0 kcal/mol). This is a major advantage for Ligand A.

**Overall Assessment:**

Ligand A is the stronger candidate. While both have solubility issues, Ligand A's superior BBB penetration, significantly stronger binding affinity, and reasonable half-life outweigh its slightly higher TPSA and DILI risk. Ligand B's extremely poor BBB penetration and impossible half-life make it a much less viable candidate. The negative values for Caco-2 and Cl_mic are concerning and require further investigation, but the large difference in binding affinity and BBB are decisive.

Output:
1
2025-04-17 07:08:50,523 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (362.55 and 353.463 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (58.44) is significantly better than Ligand B (71.11). For CNS targets, we want TPSA <= 90, both are under, but A is much closer to the optimal range.

**logP:** Ligand A (1.899) is optimal (1-3), while Ligand B (0.239) is a bit low, potentially hindering permeation.

**H-Bond Donors/Acceptors:** Ligand A (0 HBD, 4 HBA) and Ligand B (1 HBD, 5 HBA) are both acceptable, falling within the recommended limits.

**QED:** Both ligands have good QED scores (0.772 and 0.693, both > 0.5).

**DILI:** Ligand A (34.703) has a much lower DILI risk than Ligand B (8.104), indicating better potential for liver safety.

**BBB:** Both ligands have similar BBB penetration (54.634 and 55.642). While not exceptional (>70), they aren't drastically low either.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.928 and -4.822), which is unusual and suggests poor permeability. This is a significant concern for both.

**Aqueous Solubility:** Both ligands have negative solubility values (-2.206 and -1.242), which is also concerning, indicating poor solubility.

**hERG Inhibition:** Ligand A (0.186) has a lower hERG risk than Ligand B (0.418), which is preferable.

**Microsomal Clearance:** Ligand B (-14.443) has a much lower (better) microsomal clearance than Ligand A (34.85), suggesting greater metabolic stability.

**In vitro Half-Life:** Ligand B (-9.155) has a longer in vitro half-life than Ligand A (-7.464), which is desirable.

**P-gp Efflux:** Both ligands have very low P-gp efflux (0.258 and 0.014), which is good for CNS exposure.

**Binding Affinity:** Ligand B (-7.7 kcal/mol) has a slightly better binding affinity than Ligand A (-7.464 kcal/mol). This 0.24 kcal/mol difference is not huge, but is noticeable.

**Overall Assessment:**

Ligand A excels in TPSA, logP, DILI, and hERG risk. Ligand B has better metabolic stability (Cl_mic), half-life, and a slightly better binding affinity. However, the poor Caco-2 and solubility for both are significant drawbacks. Considering the GPCR-specific priorities, the slightly better logP and lower DILI/hERG of Ligand A, coupled with its better TPSA, make it a more promising starting point despite the similar BBB values and slightly weaker affinity. The better metabolic stability of Ligand B is attractive, but can be addressed through structural modifications. The poor solubility and permeability are more fundamental issues.

Output:
0
2025-04-17 07:08:50,523 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (346.515 Da) is slightly lower, which could be beneficial for permeability. Ligand B (363.805 Da) is also acceptable.

**TPSA:** Ligand A (40.62) is excellent, well below the 90 A^2 threshold for CNS targets. Ligand B (95.5) is higher, but still potentially acceptable, though less ideal for CNS penetration.

**logP:** Ligand A (3.476) is within the optimal range (1-3). Ligand B (-0.139) is significantly lower, which is a major concern for CNS penetration as it suggests poor membrane permeability.

**H-Bond Donors/Acceptors:** Ligand A (0 HBD, 2 HBA) is favorable. Ligand B (1 HBD, 5 HBA) is also reasonable, though slightly higher in HBA count.

**QED:** Both ligands have acceptable QED values (Ligand A: 0.715, Ligand B: 0.58), indicating reasonable drug-likeness.

**DILI:** Ligand A (12.408) has a much lower DILI risk than Ligand B (63.668), making it safer from a liver toxicity perspective.

**BBB:** Ligand A (85.149) has a very good BBB percentile, highly desirable for a CNS target like DRD2. Ligand B (44.746) is significantly lower, raising concerns about CNS exposure.

**Caco-2 Permeability:** Ligand A (-4.451) has a negative value, which is unusual and suggests poor permeability. Ligand B (-4.921) is also negative and similarly concerning. These values are likely on a log scale, so both are very poorly permeable.

**Aqueous Solubility:** Ligand A (-3.415) and Ligand B (-1.97) both have negative solubility values, suggesting poor aqueous solubility.

**hERG Inhibition:** Ligand A (0.53) shows a low risk of hERG inhibition. Ligand B (0.018) is even lower, indicating minimal hERG liability.

**Microsomal Clearance:** Ligand A (78.994) has a higher microsomal clearance, suggesting faster metabolism. Ligand B (-6.921) has a negative clearance, which is unusual and could indicate very high metabolic stability.

**In vitro Half-Life:** Ligand A (-4.507) has a negative half-life, which is unusual. Ligand B (-10.546) is even more negative, suggesting exceptionally long *in vitro* stability.

**P-gp Efflux:** Ligand A (0.384) has a relatively low P-gp efflux liability. Ligand B (0.014) has very low P-gp efflux, which is favorable for CNS penetration.

**Binding Affinity:** Both ligands have comparable and strong binding affinities (Ligand A: -8.6 kcal/mol, Ligand B: -8.3 kcal/mol).  The difference of 0.3 kcal/mol is not substantial enough to override other significant differences.

**Overall Assessment:**

Ligand A is clearly superior due to its excellent BBB penetration, lower DILI risk, and favorable TPSA and logP values. While the Caco-2 permeability and *in vitro* half-life values are unusual, the strong binding affinity and favorable CNS-related properties outweigh these concerns. Ligand B's very low logP is a major drawback, severely limiting its potential for CNS penetration despite its low P-gp efflux. The negative clearance and half-life values are also concerning and require further investigation, but less critical than the logP issue.

Output:
0
2025-04-17 07:08:50,523 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (350.438 and 340.467 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (67.23) is better than Ligand B (44.12) as it is closer to the optimal range for CNS targets (<=90). Ligand B is excellent.

**3. logP:** Ligand A (2.008) is within the optimal 1-3 range. Ligand B (4.475) is slightly higher, potentially leading to solubility issues and off-target interactions, but still within a tolerable range.

**4. H-Bond Donors:** Ligand A (1) is good. Ligand B (0) is also good.

**5. H-Bond Acceptors:** Both Ligand A (4) and Ligand B (4) are within the acceptable limit of <=10.

**6. QED:** Both ligands have similar QED values (0.78 and 0.754), indicating good drug-likeness.

**7. DILI:** Ligand A (39.822) has a slightly higher DILI risk than Ligand B (35.595), but both are below the 40 threshold, indicating low risk.

**8. BBB:** Ligand A (91.508) has a significantly better BBB penetration percentile than Ligand B (75.998). This is a *critical* factor for a CNS target like DRD2.

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 values, which is unusual and suggests a potential issue with the data or a very poor permeability. However, we will proceed with the comparison assuming these values represent a scaled percentile.

**10. Aqueous Solubility:** Ligand A (-3.094) has better solubility than Ligand B (-6.217).

**11. hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.49 and 0.4).

**12. Microsomal Clearance:** Ligand B (100.471) has a much higher microsomal clearance than Ligand A (38.733), suggesting lower metabolic stability.

**13. In vitro Half-Life:** Ligand A (-12.764) has a longer in vitro half-life than Ligand B (-9.609).

**14. P-gp Efflux:** Both ligands have low P-gp efflux liability (0.111 and 0.294).

**15. Binding Affinity:** Ligand B (-8.4 kcal/mol) has a slightly better binding affinity than Ligand A (-7.3 kcal/mol). The difference is 1.1 kcal/mol, which is significant.

**Overall Assessment:**

While Ligand B has a slightly better binding affinity, Ligand A is the more promising candidate. The key advantages of Ligand A are its significantly better BBB penetration (91.508 vs 75.998), better solubility, and improved metabolic stability (lower Cl_mic and longer half-life). For a CNS target like DRD2, BBB penetration is paramount, and Ligand A excels in this area. The 1.1 kcal/mol difference in binding affinity can potentially be optimized in later stages of drug development.

Output:
0
2025-04-17 07:08:50,523 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (359.861 and 348.447 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (71.01) is significantly better than Ligand B (87.46). For CNS targets, we want TPSA <= 90, and A is comfortably within that range, while B is approaching the upper limit.

**3. logP:** Ligand A (3.889) is optimal (1-3), while Ligand B (1.53) is on the lower side. While not terrible, lower logP can hinder permeability.

**4. H-Bond Donors:** Ligand A (1) is good. Ligand B (2) is acceptable, but slightly less favorable.

**5. H-Bond Acceptors:** Ligand A (4) is good. Ligand B (5) is acceptable.

**6. QED:** Both ligands have similar QED values (0.898 and 0.867), indicating good drug-likeness.

**7. DILI:** Ligand A (61.729) has a higher DILI risk than Ligand B (29.818). This is a significant drawback for Ligand A.

**8. BBB:** Ligand A (83.094) has a much better BBB penetration percentile than Ligand B (61.535). This is *critical* for a CNS target like DRD2.

**9. Caco-2 Permeability:** Both have negative Caco-2 values (-4.944 and -4.867), which is unusual and suggests poor permeability. This is a concern for both.

**10. Aqueous Solubility:** Both have negative solubility values (-3.922 and -2.513), which is also unusual and suggests poor solubility. This is a concern for both.

**11. hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.323 and 0.113).

**12. Microsomal Clearance:** Ligand A (28.624) has lower microsomal clearance than Ligand B (30.713), suggesting better metabolic stability.

**13. In vitro Half-Life:** Ligand B (-9.311) has a longer in vitro half-life than Ligand A (27.371).

**14. P-gp Efflux:** Ligand A (0.076) has lower P-gp efflux than Ligand B (0.027), which is favorable for CNS penetration.

**15. Binding Affinity:** Both ligands have excellent binding affinities (-9.6 and -8.6 kcal/mol). Ligand A is slightly better (-9.6 kcal/mol).

**Overall Assessment:**

Ligand A has a better BBB score, lower P-gp efflux, and slightly better affinity, which are all highly desirable for a CNS GPCR target. However, it has a significantly higher DILI risk. Ligand B has a lower DILI risk and better half-life, but suffers from poorer BBB penetration and a less optimal logP.

Given the importance of CNS penetration for DRD2, and the relatively small difference in binding affinity, Ligand A is the more promising candidate *despite* the higher DILI risk. The DILI risk could potentially be mitigated through structural modifications. The poor permeability and solubility are shared concerns that would need to be addressed in either case.

Output:
1
2025-04-17 07:08:50,524 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (344.5 & 364.5 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (49.41) is significantly better than Ligand B (74.41). For CNS targets, we want TPSA <= 90, and ideally closer to 60. Ligand A is much closer to this ideal.

**3. logP:** Both ligands have good logP values (3.614 & 2.846), falling within the optimal 1-3 range.

**4. H-Bond Donors:** Both have acceptable HBD counts (1 & 2), well below the limit of 5.

**5. H-Bond Acceptors:** Ligand A (2) is better than Ligand B (7), closer to the ideal of <=10.

**6. QED:** Both ligands have reasonable QED scores (0.744 & 0.667), indicating good drug-likeness.

**7. DILI:** Ligand A (11.4) has a much lower DILI risk than Ligand B (19.93). Both are below the 40 threshold, but A is preferable.

**8. BBB:** This is critical for a CNS target like DRD2. Ligand A (82.28) has a significantly better BBB percentile than Ligand B (32.92). A value > 70 is desirable, and A is much closer.

**9. Caco-2 Permeability:** Ligand A (-4.308) has a worse Caco-2 permeability than Ligand B (-5.406). Lower values indicate lower permeability.

**10. Aqueous Solubility:** Ligand A (-3.867) has a slightly better solubility than Ligand B (-2.858).

**11. hERG Inhibition:** Both ligands have low hERG inhibition liability (0.723 & 0.632), which is good.

**12. Microsomal Clearance:** Ligand A (86.669) has a higher microsomal clearance than Ligand B (36.242), meaning it's less metabolically stable. This is a negative for Ligand A.

**13. In vitro Half-Life:** Ligand B (23.716) has a significantly longer in vitro half-life than Ligand A (9.229). This is a significant advantage for B.

**14. P-gp Efflux:** Both ligands have low P-gp efflux liability (0.123 & 0.233), which is good.

**15. Binding Affinity:** Ligand A (-8.1 kcal/mol) has a significantly stronger binding affinity than Ligand B (-6.9 kcal/mol). This is a substantial advantage for A, potentially outweighing some ADME concerns.

**Overall Assessment:**

Ligand A excels in key GPCR properties: TPSA, BBB, and, most importantly, binding affinity. While its microsomal clearance is higher (less desirable), the strong binding affinity (-8.1 kcal/mol) is a major advantage. Ligand B has a better half-life and slightly better Caco-2 permeability, but its significantly lower BBB penetration and weaker binding affinity are major drawbacks for a CNS target. Given the importance of CNS penetration and potency for DRD2, Ligand A is the more promising candidate.

Output:
1
2025-04-17 07:08:50,524 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (347.379 and 358.435 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (120.25) is better than Ligand B (128.12). Both are below the 140 A^2 threshold for oral absorption, but closer to the 90 A^2 target for CNS penetration.

**3. logP:** Both ligands (-0.784 and -0.917) are a bit low. Ideally, we want 1-3. This could hinder permeation, but isn't a dealbreaker if other properties are favorable.

**4. H-Bond Donors:** Ligand A (2) is preferable to Ligand B (5). Lower HBD generally improves permeability.

**5. H-Bond Acceptors:** Ligand A (7) is preferable to Ligand B (6). Lower HBA generally improves permeability.

**6. QED:** Ligand A (0.727) has a significantly better QED score than Ligand B (0.322), indicating a more drug-like profile.

**7. DILI:** Ligand A (69.872) has a higher DILI risk than Ligand B (18.457). This is a concern for Ligand A.

**8. BBB:** Ligand A (34.975) has a significantly lower BBB penetration percentile than Ligand B (23.187). This is a major drawback for Ligand A, given DRD2 is a CNS target.

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.321 and -5.554), which is unusual and suggests poor permeability.

**10. Aqueous Solubility:** Both have negative solubility values (-1.293 and -1.269), which is also unusual.

**11. hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.066 and 0.091).

**12. Microsomal Clearance:** Ligand A (11.269) has lower microsomal clearance than Ligand B (19.3), suggesting better metabolic stability.

**13. In vitro Half-Life:** Ligand A (-18.955) has a much lower in vitro half-life than Ligand B (4.89), indicating faster metabolism.

**14. P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.013 and 0.014).

**15. Binding Affinity:** Both ligands have similar and good binding affinities (-7.6 and -7.8 kcal/mol).

**Overall Assessment:**

Despite the similar binding affinities, Ligand B is the more promising candidate. While its DILI risk is low, its BBB penetration is significantly better than Ligand A's, which is critical for a CNS target like DRD2. Ligand A has a better QED and metabolic stability, but the poor BBB penetration and higher DILI risk are significant concerns. The negative Caco-2 and solubility values are concerning for both, but potentially addressable through formulation.

Output:
1
2025-04-17 07:08:50,524 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B based on the provided guidelines, prioritizing GPCR-specific properties (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (359.769 Da and 352.519 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (86.31) is better than Ligand B (58.64). Both are below the 90 A^2 threshold for CNS targets, but Ligand B is significantly lower, which is favorable.

**logP:** Ligand A (4.457) is higher than the optimal range (1-3), potentially causing solubility issues. Ligand B (3.291) is within the optimal range. This favors Ligand B.

**H-Bond Donors/Acceptors:** Both have 1 HBD, which is good. Ligand A has 6 HBA, while Ligand B has 3. Both are acceptable (<=10), but Ligand B is better.

**QED:** Both ligands have good QED scores (0.579 and 0.614), indicating drug-like properties.

**DILI:** Ligand A has a very high DILI risk (99.341), which is a major concern. Ligand B has a much lower and acceptable DILI risk (11.322). This strongly favors Ligand B.

**BBB:** Ligand B (77.2) is significantly better than Ligand A (30.71) for CNS penetration. This is a crucial factor for DRD2, a CNS target.

**Caco-2 Permeability:** Ligand A (-4.993) is worse than Ligand B (-4.491). Both are negative, indicating poor permeability.

**Aqueous Solubility:** Ligand A (-5.942) is worse than Ligand B (-3.089). Both are poor, but Ligand B is better.

**hERG:** Both ligands have low hERG inhibition liability (0.696 and 0.657), which is good.

**Microsomal Clearance:** Ligand A (32.716) is better than Ligand B (36.711), indicating better metabolic stability.

**In vitro Half-Life:** Ligand A (79.331) is much better than Ligand B (2.993), suggesting a longer duration of action.

**P-gp Efflux:** Ligand A (0.688) is better than Ligand B (0.165), indicating lower P-gp efflux and potentially better CNS exposure.

**Binding Affinity:** Ligand A (-9.2 kcal/mol) has a significantly stronger binding affinity than Ligand B (-7.0 kcal/mol). This is a substantial advantage.

**Overall Assessment:**

While Ligand A has a significantly better binding affinity and better metabolic stability and P-gp efflux, its extremely high DILI risk and poor BBB penetration are major drawbacks. Ligand B, despite having slightly weaker affinity, presents a much more favorable ADME-Tox profile, particularly its significantly lower DILI risk and much improved BBB penetration, which are critical for a CNS drug targeting DRD2. The difference in binding affinity (2.2 kcal/mol) is substantial, but can potentially be overcome with further optimization, whereas the DILI and BBB issues with Ligand A are harder to address without significant structural changes.

Output:
1
2025-04-17 07:08:50,524 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (347.459 and 352.475 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (82.43) is better than Ligand B (89.87). Both are below the 90 A^2 threshold for CNS targets, but A is closer to the ideal.

**3. logP:** Both ligands have good logP values (2.425 and 1.052), falling within the optimal 1-3 range. Ligand A is slightly better.

**4. H-Bond Donors:** Ligand A (1) is better than Ligand B (3). Lower HBD is generally preferred for BBB penetration.

**5. H-Bond Acceptors:** Both ligands have the same number of HBA (4), which is acceptable (<=10).

**6. QED:** Ligand B (0.639) has a slightly better QED score than Ligand A (0.454), indicating a more drug-like profile.

**7. DILI:** Ligand A (16.208) has a lower DILI risk than Ligand B (13.804), which is preferable.

**8. BBB:** This is a critical parameter for CNS targets. Ligand A (74.719) has a significantly higher BBB percentile than Ligand B (41.062). This is a major advantage for Ligand A.

**9. Caco-2 Permeability:** Ligand A (-4.969) and Ligand B (-5.093) both have negative values, which is unusual and suggests very poor permeability. This is a potential concern for both.

**10. Aqueous Solubility:** Ligand A (-2.292) and Ligand B (-1.723) both have negative solubility values, indicating poor aqueous solubility. This could pose formulation challenges.

**11. hERG Inhibition:** Both ligands have low hERG inhibition risk (0.469 and 0.289, respectively).

**12. Microsomal Clearance:** Ligand B (12.327) has a slightly higher microsomal clearance than Ligand A (11.592), meaning A is more metabolically stable.

**13. In vitro Half-Life:** Ligand A (-17.115) has a much longer in vitro half-life than Ligand B (0.517), which is a significant advantage.

**14. P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.027 and 0.138, respectively), which is good.

**15. Binding Affinity:** Both ligands have the same binding affinity (-8.0 kcal/mol), which is excellent.

**Overall Assessment:**

Ligand A is the better candidate. While Ligand B has a slightly better QED, Ligand A excels in the critical GPCR-specific parameters for CNS targets: significantly higher BBB penetration, lower DILI risk, and a much longer in vitro half-life. The similar binding affinity means the ADME advantages of Ligand A outweigh the slightly lower QED score. Both ligands have poor Caco-2 permeability and solubility, which would need to be addressed during optimization, but these are less critical than BBB for a CNS target.

Output:
1
2025-04-17 07:08:50,524 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (355.419 and 345.378 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (84.34) is excellent, well below the 90 A^2 threshold for CNS targets. Ligand B (93.88) is still reasonable but less optimal.

**3. logP:** Ligand A (3.87) is at the upper end of the optimal range (1-3) but acceptable. Ligand B (0.944) is quite low, potentially hindering membrane permeability and CNS penetration.

**4. H-Bond Donors:** Ligand A (2) and Ligand B (3) are both within the acceptable limit of <=5.

**5. H-Bond Acceptors:** Ligand A (6) and Ligand B (3) are both within the acceptable limit of <=10.

**6. QED:** Both ligands have good QED scores (0.726 and 0.68), indicating drug-like properties.

**7. DILI:** Ligand A (94.649) has a high DILI risk, which is a significant concern. Ligand B (39.55) has a much lower, and acceptable, DILI risk.

**8. BBB:** Ligand A (19.542) has very poor predicted BBB penetration. Ligand B (75.107) has good BBB penetration, a critical factor for a CNS target like DRD2.

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.035 and -5.289), which is unusual and suggests poor permeability. However, these values are on a log scale and are difficult to interpret without more context.

**10. Aqueous Solubility:** Both ligands have negative solubility values (-4.699 and -2.432), also unusual and suggesting poor aqueous solubility.

**11. hERG Inhibition:** Both ligands have low hERG inhibition risk (0.442 and 0.616).

**12. Microsomal Clearance:** Ligand A (57.181) has moderate clearance, while Ligand B (-9.595) has negative clearance, which is not physically possible and indicates a potential issue with the prediction.

**13. In vitro Half-Life:** Ligand A (-4.395) has a negative half-life, which is not physically possible. Ligand B (-28.643) also has a negative half-life, indicating a problem with the prediction for both compounds.

**14. P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.45 and 0.02), which is favorable for CNS penetration.

**15. Binding Affinity:** Both ligands have very strong binding affinities (-9.9 and -9.0 kcal/mol). The difference is 0.9 kcal/mol, which is not substantial enough to overcome the significant ADME deficiencies of Ligand A.

**Conclusion:**

Despite similar binding affinities, Ligand B is the more promising candidate. Its significantly better BBB penetration, lower DILI risk, and more reasonable logP outweigh the questionable Caco-2 and solubility predictions and the problematic clearance/half-life predictions. Ligand A's poor BBB penetration and high DILI risk are major drawbacks that are unlikely to be overcome. The negative values for Caco-2, solubility, clearance and half-life for both compounds suggest issues with the prediction model and should be investigated further with experimental data.

Output:
1
2025-04-17 07:08:50,525 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B based on the provided guidelines, prioritizing GPCR-specific properties (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (428.714 Da) is higher, but still acceptable. Ligand B (348.418 Da) is slightly preferred.

**TPSA:** Both ligands have TPSA values below the 90 A^2 threshold for CNS targets. Ligand A (84.08 A^2) is slightly higher than Ligand B (71.34 A^2), making Ligand B more favorable for brain penetration.

**logP:** Both ligands have logP values within the optimal range (1-3). Ligand A (3.398) is at the higher end, potentially increasing off-target effects, while Ligand B (2.918) is more optimal.

**H-Bond Donors/Acceptors:** Both have 2 HBD and a reasonable number of HBA (4 for A, 3 for B). No significant difference here.

**QED:** Both ligands have good QED scores (0.6 and 0.83), indicating drug-likeness. Ligand B is slightly better.

**DILI:** Ligand A (70.105) has a higher DILI risk than Ligand B (37.767). This is a significant advantage for Ligand B.

**BBB:** This is a crucial parameter for CNS targets. Ligand B (76.541) has a much better BBB percentile than Ligand A (41.411). This is a major advantage for Ligand B.

**Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and suggests poor permeability. However, the scale is not specified, so it's hard to interpret. Ligand A (-5.502) is slightly worse.

**Aqueous Solubility:** Both ligands have poor aqueous solubility (-3.41 and -3.59). This could pose formulation challenges, but is not a deciding factor.

**hERG Inhibition:** Both have low hERG inhibition risk (0.741 and 0.324). Ligand B is slightly better.

**Microsomal Clearance:** Ligand A (57.471) has higher microsomal clearance than Ligand B (14.817), indicating lower metabolic stability. Ligand B is significantly better.

**In vitro Half-Life:** Ligand B (31.657 hours) has a longer half-life than Ligand A (27.676 hours), which is preferable.

**P-gp Efflux:** Both have low P-gp efflux liability (0.295 and 0.123). Ligand B is better.

**Binding Affinity:** Ligand B (-8.8 kcal/mol) has a slightly better binding affinity than Ligand A (-8.1 kcal/mol). While the difference is not huge, it's still a positive for Ligand B.

**Overall:** Ligand B consistently outperforms Ligand A across most critical parameters, especially BBB penetration, DILI risk, metabolic stability, and P-gp efflux. The slightly better binding affinity further strengthens its position. While both have solubility issues, the other advantages of Ligand B make it a more promising drug candidate for a CNS target like DRD2.

Output:
1
2025-04-17 07:08:50,525 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (340.423 and 361.921 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (70.4) is better than Ligand B (49.74). For CNS targets, we want TPSA <= 90, both are well within this range, but A is slightly higher.

**3. logP:** Both ligands have good logP values (3.175 and 3.994), falling within the optimal 1-3 range. Ligand B is slightly higher, which could potentially lead to off-target effects, but is still acceptable.

**4. H-Bond Donors:** Ligand A has 0 HBD, while Ligand B has 1. Both are within the acceptable limit of <= 5.

**5. H-Bond Acceptors:** Both ligands have 4 HBA, which is well below the acceptable limit of <= 10.

**6. QED:** Both ligands have good QED scores (0.61 and 0.734), indicating good drug-like properties.

**7. DILI:** Ligand A (30.903) has a significantly lower DILI risk than Ligand B (21.481). This is a strong advantage for Ligand A.

**8. BBB:** Ligand A (81.233) has a slightly better BBB penetration percentile than Ligand B (70.997). Both are reasonably good, but A is preferable for a CNS target.

**9. Caco-2 Permeability:** Ligand A (-4.185) has worse Caco-2 permeability than Ligand B (-5.292). Lower values indicate lower permeability, so B is better here.

**10. Aqueous Solubility:** Ligand A (-3.624) has slightly better aqueous solubility than Ligand B (-3.236). Both are poor, but A is less poor.

**11. hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.721 and 0.763).

**12. Microsomal Clearance:** Ligand A (69.934) has a higher microsomal clearance than Ligand B (32.527), indicating faster metabolism and lower metabolic stability. This is a significant drawback for Ligand A.

**13. In vitro Half-Life:** Ligand B (34.754) has a much longer in vitro half-life than Ligand A (-13.283). This is a major advantage for Ligand B.

**14. P-gp Efflux:** Both ligands have low P-gp efflux liability (0.221 and 0.413).

**15. Binding Affinity:** Ligand B (-8.1) has a slightly stronger binding affinity than Ligand A (-7.8). While the difference is not huge, it's still a positive for Ligand B.

**Overall Assessment:**

Ligand A excels in BBB penetration and DILI risk, and has slightly better solubility. However, it suffers from significantly higher microsomal clearance and a shorter half-life, which are critical for *in vivo* efficacy. Ligand B, while having slightly lower BBB and higher DILI, possesses a substantially longer half-life, better Caco-2 permeability, and a slightly better binding affinity. Given the GPCR-specific priorities, the improved metabolic stability and half-life of Ligand B outweigh the slight disadvantages in BBB and DILI.

Output:
1
2025-04-17 07:08:50,525 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 drug candidates, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (349.431 and 350.503 Da) fall comfortably within the ideal 200-500 Da range.

**TPSA:** Ligand A (82.45) is slightly above the optimal <90 for CNS targets, but still reasonable. Ligand B (58.64) is excellent, well below 90.

**logP:** Both ligands have good logP values (2.088 and 3.047), falling within the 1-3 range.

**H-Bond Donors/Acceptors:** Both have 1 HBD, which is good. Ligand A has 6 HBA, which is acceptable. Ligand B has 3 HBA, which is also good.

**QED:** Both ligands have acceptable QED scores (0.795 and 0.616), indicating good drug-like properties.

**DILI:** Ligand A (64.211) has a higher DILI risk than Ligand B (11.361). This is a significant negative for Ligand A.

**BBB:** Both ligands have excellent BBB penetration (82.086 and 80.574), which is crucial for a CNS target like DRD2.

**Caco-2 Permeability:** Both have negative Caco-2 values which is unusual and suggests issues with the data or modeling. However, we can still compare them. Ligand A (-4.832) is slightly worse than Ligand B (-4.638).

**Aqueous Solubility:** Both ligands have negative solubility values which is unusual and suggests issues with the data or modeling. Ligand A (-3.3) is slightly worse than Ligand B (-2.104).

**hERG:** Both ligands have very low hERG inhibition risk (0.181 and 0.361).

**Microsomal Clearance:** Ligand A (64.098) has lower microsomal clearance, indicating better metabolic stability, than Ligand B (70.666).

**In vitro Half-Life:** Ligand B (17.409 hours) has a significantly longer half-life than Ligand A (-10.408 hours). The negative value for Ligand A is concerning.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.187 and 0.036), which is favorable for CNS penetration.

**Binding Affinity:** Ligand A (-8.5 kcal/mol) has a slightly better binding affinity than Ligand B (-7.5 kcal/mol). This 1 kcal/mol difference is noteworthy, but not overwhelming.

**Overall Assessment:**

Ligand B is the stronger candidate. While Ligand A has slightly better affinity and metabolic stability, Ligand B has a significantly lower DILI risk, a better TPSA, and a much more reasonable in vitro half-life. The lower DILI risk is a major advantage, as liver toxicity is a common reason for drug failure. The better TPSA is also favorable for CNS penetration. The difference in binding affinity (1 kcal/mol) is not substantial enough to overcome the other advantages of Ligand B.

Output:
1
2025-04-17 07:08:50,525 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (358.389 Da) is slightly higher than Ligand B (346.475 Da), but both are acceptable.

**TPSA:** Ligand A (87.32) is closer to the desirable threshold of 90 for CNS targets than Ligand B (60.25). This favors Ligand B, as lower TPSA generally correlates with better BBB penetration.

**logP:** Ligand A (0.897) is a bit low, potentially hindering permeability. Ligand B (2.886) is within the optimal range (1-3). This is a significant advantage for Ligand B.

**H-Bond Donors/Acceptors:** Ligand A has 2 HBD and 4 HBA, while Ligand B has 0 HBD and 5 HBA. Both are within acceptable limits.

**QED:** Both ligands have good QED scores (Ligand A: 0.723, Ligand B: 0.822), indicating drug-like properties.

**DILI:** Ligand A (36.254) has a lower DILI risk than Ligand B (44.63), which is preferable.

**BBB:** Ligand B (80.613) has a substantially better BBB percentile than Ligand A (62.97). This is a critical advantage for a CNS target like DRD2.

**Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and suggests poor permeability. However, the scale is not specified, so it's hard to interpret.

**Aqueous Solubility:** Both have negative solubility values, which is also unusual and suggests poor solubility.

**hERG:** Ligand A (0.585) has a lower hERG risk than Ligand B (0.137), which is preferable.

**Microsomal Clearance:** Ligand A (-16.997) has a much lower (better) microsomal clearance than Ligand B (48.269), suggesting greater metabolic stability.

**In vitro Half-Life:** Ligand A (-15.714) has a longer half-life than Ligand B (15.906), which is preferable.

**P-gp Efflux:** Ligand A (0.024) has a much lower P-gp efflux liability than Ligand B (0.349), meaning it's less likely to be pumped out of the brain, improving CNS exposure.

**Binding Affinity:** Ligand B (-8.3 kcal/mol) has a slightly better binding affinity than Ligand A (-7.7 kcal/mol). While the difference is not huge, it's a positive for Ligand B.

**Overall Assessment:**

While Ligand A has advantages in DILI, metabolic stability (Cl_mic, t1/2), P-gp efflux, and hERG, Ligand B excels in BBB penetration, logP, and has slightly better binding affinity. For a CNS GPCR target like DRD2, BBB penetration and logP are paramount. The better BBB score of Ligand B, combined with its optimal logP, outweighs the advantages of Ligand A. The slightly better affinity of Ligand B further supports this conclusion.

Output:
1
2025-04-17 07:08:50,526 - INFO - Okay, let's analyze these two ligands for their potential as DRD2 drug candidates. DRD2 is a GPCR in the CNS, so BBB penetration, logP, Pgp efflux, TPSA, and binding affinity are key.

**Ligand A: [338.411, 68.44, 1.327, 2, 3, 0.868, 44.048, 73.827, -4.901, -3.141, 0.757, 14.8, -24.866, 0.074, -10.2]**

*   **MW:** 338.411 Da - Good, within the ideal range.
*   **TPSA:** 68.44  - Excellent, well below the 90 target for CNS.
*   **logP:** 1.327 - Good, within the optimal range.
*   **HBD:** 2 - Acceptable.
*   **HBA:** 3 - Acceptable.
*   **QED:** 0.868 - Excellent, highly drug-like.
*   **DILI:** 44.048 - Good, low risk.
*   **BBB:** 73.827 - Good, above the 70% threshold for CNS targets.
*   **Caco-2:** -4.901 - Poor, suggests limited intestinal absorption.
*   **Solubility:** -3.141 - Poor, suggests low aqueous solubility.
*   **hERG:** 0.757 - Low risk.
*   **Cl_mic:** 14.8 mL/min/kg - Moderate, could be better.
*   **t1/2:** -24.866 - Very poor, extremely short half-life.
*   **Pgp:** 0.074 - Low efflux, favorable for CNS penetration.
*   **Affinity:** -10.2 kcal/mol - Excellent, very strong binding.

**Ligand B: [374.453, 58.64, 1.685, 1, 4, 0.719, 31.989, 84.878, -4.686, -2.999, 0.373, 30.047, -15.431, 0.069, -7.9]**

*   **MW:** 374.453 Da - Good, within the ideal range.
*   **TPSA:** 58.64 - Excellent, well below the 90 target for CNS.
*   **logP:** 1.685 - Good, within the optimal range.
*   **HBD:** 1 - Acceptable.
*   **HBA:** 4 - Acceptable.
*   **QED:** 0.719 - Good, drug-like.
*   **DILI:** 31.989 - Good, low risk.
*   **BBB:** 84.878 - Excellent, very high CNS penetration potential.
*   **Caco-2:** -4.686 - Poor, suggests limited intestinal absorption.
*   **Solubility:** -2.999 - Poor, suggests low aqueous solubility.
*   **hERG:** 0.373 - Low risk.
*   **Cl_mic:** 30.047 mL/min/kg - Moderate to High, suggests faster metabolism.
*   **t1/2:** -15.431 - Poor, short half-life, but better than Ligand A.
*   **Pgp:** 0.069 - Low efflux, favorable for CNS penetration.
*   **Affinity:** -7.9 kcal/mol - Very Good, strong binding.

**Comparison and Decision:**

Both ligands have good MW, TPSA, logP, and low HBD/HBA counts. Both also have poor Caco-2 permeability and solubility. However, several key differences stand out. Ligand A has a significantly better binding affinity (-10.2 kcal/mol vs -7.9 kcal/mol). Ligand B has a much better BBB score (84.878 vs 73.827). Ligand A has a terrible *in vitro* half-life, while Ligand B's is still poor, but better. Ligand A's metabolic clearance is also lower, indicating better metabolic stability.

Given the importance of CNS penetration for a DRD2 target, and the strong binding affinity of Ligand A, I believe **Ligand A** is the more promising candidate *despite* its very short half-life. The strong binding affinity could potentially compensate for the poor half-life, and formulation strategies could be explored to address the solubility issue. The better BBB score of Ligand B is attractive, but the 2.3 kcal/mol difference in binding affinity is substantial.

Output:
1
2025-04-17 07:08:50,526 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (352.387 and 350.419 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (102.96) is better than Ligand B (115.65). For CNS targets, we want TPSA <= 90, so both are slightly above, but A is closer.

**3. logP:** Ligand B (0.7) is slightly better than Ligand A (0.224). Both are a bit low, potentially hindering membrane permeability, but B is closer to the optimal 1-3 range.

**4. H-Bond Donors:** Ligand A (2) is preferable to Ligand B (3). Lower is generally better for permeability.

**5. H-Bond Acceptors:** Both ligands have 6 HBA, which is acceptable.

**6. QED:** Ligand B (0.695) has a better QED score than Ligand A (0.368), indicating a more drug-like profile.

**7. DILI:** Ligand B (56.572) has a slightly lower DILI risk than Ligand A (51.338), both are acceptable.

**8. BBB:** Ligand A (60.45) has a significantly better BBB penetration percentile than Ligand B (22.295). This is *critical* for a CNS target like DRD2.

**9. Caco-2 Permeability:** Ligand A (-5.494) has better Caco-2 permeability than Ligand B (-5.184).

**10. Aqueous Solubility:** Ligand A (-1.878) has better aqueous solubility than Ligand B (-2.707).

**11. hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.098 and 0.104).

**12. Microsomal Clearance:** Ligand B (3.362) has significantly lower microsomal clearance than Ligand A (20.695), indicating better metabolic stability.

**13. In vitro Half-Life:** Both have negative half-lives (-17.196 and -17.847). This is unusual and likely indicates a rapid degradation *in vitro*. However, the values are similar.

**14. P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.044 and 0.038).

**15. Binding Affinity:** Both ligands have very similar binding affinities (-7.8 and -7.7 kcal/mol), which are excellent.

**Overall Assessment:**

While Ligand B has a better QED and lower Cl_mic, the *massive* difference in BBB penetration favors Ligand A. For a CNS target like DRD2, getting the drug into the brain is paramount. Ligand A's superior BBB score outweighs the slight advantages of Ligand B in other ADME properties. The similar binding affinities make the BBB difference the deciding factor.

Output:
0
2025-04-17 07:08:50,526 - INFO - Batch 340 complete. Total preferences: 5440
2025-04-17 07:08:50,526 - INFO - Processing batch 341/512...
2025-04-17 07:09:31,772 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B based on the provided guidelines, prioritizing GPCR-specific properties (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (341.411 Da) is slightly lower than Ligand B (367.49 Da), which is not a significant difference.

**TPSA:** Both ligands have TPSA values below 90 (Ligand A: 73.48, Ligand B: 69.22), which is good for CNS penetration. Ligand B is slightly better.

**logP:** Ligand A (1.547) is within the optimal range (1-3), while Ligand B (3.227) is at the higher end of optimal.

**H-Bond Donors/Acceptors:** Ligand A (HBD=1, HBA=3) and Ligand B (HBD=2, HBA=4) both have reasonable numbers of H-bond donors and acceptors.

**QED:** Both ligands have acceptable QED values (Ligand A: 0.83, Ligand B: 0.715), indicating good drug-like properties.

**DILI:** Ligand A (49.787) has a slightly higher DILI risk than Ligand B (26.328), but both are below the concerning threshold of 60.

**BBB:** Both ligands exhibit good BBB penetration (Ligand A: 53.044, Ligand B: 54.789). This is crucial for a CNS target like DRD2. The difference is minimal.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.009 and -5.296). This is unusual and suggests poor permeability. However, these values are on a scale where negative values are possible, and direct comparison is difficult without knowing the scale's specifics.

**Aqueous Solubility:** Both ligands have negative solubility values (-3.225 and -2.332), indicating poor aqueous solubility. Similar to Caco-2, the scale is unknown.

**hERG Inhibition:** Ligand A (0.257) has a much lower hERG inhibition liability than Ligand B (0.782), which is a significant advantage.

**Microsomal Clearance:** Ligand A (15.928) has a lower microsomal clearance than Ligand B (33.359), indicating better metabolic stability.

**In vitro Half-Life:** Ligand A (-29.464) has a much longer in vitro half-life than Ligand B (-2.772). This is a substantial benefit.

**P-gp Efflux:** Ligand A (0.092) has a lower P-gp efflux liability than Ligand B (0.576), which is favorable for CNS exposure.

**Binding Affinity:** Ligand B (-7.0 kcal/mol) has a significantly stronger binding affinity than Ligand A (-0.0 kcal/mol). This is a very large difference and a major factor.

**Overall Assessment:**

Ligand B has a significantly better binding affinity, which is the most critical factor. While Ligand A has advantages in terms of hERG, metabolic stability, P-gp efflux, and half-life, the substantial difference in binding affinity (-7.0 vs -0.0 kcal/mol) likely outweighs these benefits. The negative Caco-2 and solubility values are concerning for both, but the potency advantage of Ligand B is compelling.

Output:
1
2025-04-17 07:09:31,772 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 drug candidates, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (349.431 Da) is slightly lower, which could be beneficial for permeability.

**TPSA:** Ligand A (78.95) is better than Ligand B (82.53), both are below the 90 A^2 threshold for CNS targets, but A is closer to the ideal.

**logP:** Ligand A (0.165) is quite low, potentially hindering membrane permeability. Ligand B (2.609) is within the optimal range (1-3). This is a significant advantage for Ligand B.

**H-Bond Donors:** Ligand A (1) and Ligand B (2) are both acceptable.

**H-Bond Acceptors:** Ligand A (4) and Ligand B (5) are both acceptable.

**QED:** Both ligands have good QED scores (A: 0.784, B: 0.836), suggesting good drug-like properties.

**DILI:** Ligand A (21.946) has a much lower DILI risk than Ligand B (63.513). This is a substantial advantage for Ligand A.

**BBB:** Ligand A (68.205) is close to the desired threshold (>70), while Ligand B (66.033) is slightly lower.

**Caco-2 Permeability:** Ligand A (-4.734) has poor Caco-2 permeability. Ligand B (-5.018) is also poor, but slightly worse than A.

**Aqueous Solubility:** Ligand A (-1.407) has poor solubility. Ligand B (-3.841) has even worse solubility.

**hERG Inhibition:** Ligand A (0.135) has very low hERG inhibition risk, while Ligand B (0.724) has a moderate risk. This is a significant advantage for Ligand A.

**Microsomal Clearance:** Ligand A (-8.736) has very low microsomal clearance (highly metabolically stable), while Ligand B (24.072) has higher clearance. This is a major advantage for Ligand A.

**In vitro Half-Life:** Ligand A (5.007) has a moderate half-life. Ligand B (3.194) has a shorter half-life.

**P-gp Efflux:** Ligand A (0.01) has very low P-gp efflux, which is excellent for CNS penetration. Ligand B (0.281) has higher efflux.

**Binding Affinity:** Ligand A (-8.3 kcal/mol) has significantly better binding affinity than Ligand B (0.0 kcal/mol). This is a decisive advantage for Ligand A.

**Overall Assessment:**

While Ligand A has poor solubility and Caco-2 permeability, its superior binding affinity, low DILI risk, low hERG risk, very low P-gp efflux, and excellent metabolic stability (low Cl_mic, longer half-life) are compelling advantages. The slightly lower BBB penetration is less concerning given the strong affinity and low efflux. Ligand B's logP is good, but it is significantly weaker in binding affinity, has higher DILI and hERG risk, and higher P-gp efflux.

Considering the GPCR-specific priorities, especially the importance of BBB, logP, Pgp, TPSA, and affinity, Ligand A is the more promising candidate. The strong binding affinity can potentially overcome some of the ADME liabilities, and the low efflux and metabolic stability are crucial for CNS drug development.

Output:
0
2025-04-17 07:09:31,772 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 drug candidates, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (346.293 and 345.491 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (96.97) is slightly above the preferred <90 for CNS targets, but still reasonable. Ligand B (71.43) is well within the desired range. This favors Ligand B.

**3. logP:** Ligand A (1.995) is optimal. Ligand B (3.78) is approaching the upper limit, but still acceptable.

**4. H-Bond Donors:** Both ligands have 2 HBD, which is within the acceptable limit of <=5.

**5. H-Bond Acceptors:** Ligand A has 5 HBA, and Ligand B has 6. Both are within the acceptable limit of <=10.

**6. QED:** Both ligands have good QED scores (0.753 and 0.85), indicating good drug-like properties.

**7. DILI:** Ligand A (96.627) has a higher DILI risk than Ligand B (41.373). This is a significant advantage for Ligand B.

**8. BBB:** Ligand B (89.763) has a substantially better BBB penetration score than Ligand A (65.607). This is crucial for a CNS target like DRD2 and heavily favors Ligand B.

**9. Caco-2 Permeability:** Ligand A (-4.854) has better Caco-2 permeability than Ligand B (-5.011), but the difference is minor.

**10. Aqueous Solubility:** Both ligands have very poor aqueous solubility (-4.525 and -4.359). This is a concern for both, but not a deciding factor between them.

**11. hERG Inhibition:** Ligand A (0.414) has a slightly lower hERG inhibition risk than Ligand B (0.798), which is preferable.

**12. Microsomal Clearance:** Ligand A (-1.912) has lower (better) microsomal clearance than Ligand B (45.616), indicating greater metabolic stability. This is a significant advantage for Ligand A.

**13. In vitro Half-Life:** Ligand A (69.269) has a much longer in vitro half-life than Ligand B (32.815). This is a substantial advantage for Ligand A.

**14. P-gp Efflux:** Ligand A (0.163) has lower P-gp efflux than Ligand B (0.263), which is better for CNS exposure.

**15. Binding Affinity:** Both ligands have excellent binding affinity (-9.6 and -9.0 kcal/mol). The difference of 0.6 kcal/mol is not enough to outweigh other factors.

**Overall Assessment:**

While Ligand A has advantages in metabolic stability (Cl_mic, t1/2) and P-gp efflux, Ligand B excels in critical areas for a CNS GPCR target: BBB penetration and DILI risk. The significantly better BBB score of Ligand B is the most important factor. The lower DILI risk is also a major plus. The slightly higher hERG risk for Ligand B is a minor concern compared to the BBB and DILI benefits.

Output:
1
2025-04-17 07:09:31,772 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (352.312 and 344.499 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (78.43) is higher than Ligand B (49.41). For a CNS target like DRD2, TPSA should be <= 90, so both are acceptable, but B is significantly better.

**3. logP:** Both ligands have good logP values (2.281 and 3.422), falling within the optimal 1-3 range. Ligand B is slightly higher, which could be beneficial for membrane permeability.

**4. H-Bond Donors:** Ligand A has 3 HBD, and Ligand B has 1. Both are within the acceptable limit of <=5.

**5. H-Bond Acceptors:** Ligand A has 3 HBA, and Ligand B has 2. Both are within the acceptable limit of <=10.

**6. QED:** Both ligands have reasonable QED values (0.739 and 0.614), indicating good drug-like properties.

**7. DILI:** Ligand A has a DILI risk of 69.678, which is approaching the higher risk threshold (>60). Ligand B has a much lower DILI risk of 19.426, which is excellent.

**8. BBB:** Ligand A has a BBB penetration of 38.736, which is below the desirable threshold of >70 for CNS targets. Ligand B has a BBB penetration of 69.833, which is close to the desired threshold. This is a significant advantage for Ligand B.

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.755 and -4.643), which is unusual and suggests poor permeability. However, these values are on a scale where negative values are possible and don't necessarily disqualify the compounds.

**10. Aqueous Solubility:** Both ligands have negative solubility values (-3.72 and -3.645), which is also unusual, but not necessarily disqualifying.

**11. hERG Inhibition:** Both ligands have low hERG inhibition risk (0.519 and 0.209).

**12. Microsomal Clearance:** Ligand A has a lower Cl_mic (11.67) than Ligand B (49.139), indicating better metabolic stability.

**13. In vitro Half-Life:** Ligand A has a longer half-life (32.034) than Ligand B (-10.984). This is a significant advantage for Ligand A.

**14. P-gp Efflux:** Ligand A has a Pgp efflux liability of 0.143, while Ligand B has 0.122. Both are relatively low, but B is slightly better.

**15. Binding Affinity:** Ligand B has a significantly better binding affinity (-7.7 kcal/mol) than Ligand A (-10.1 kcal/mol). This is a substantial advantage, potentially outweighing some of the ADME drawbacks of Ligand A.

**Overall Assessment:**

While Ligand A has better metabolic stability and half-life, Ligand B excels in critical areas for a CNS-targeting GPCR: lower DILI risk, significantly better BBB penetration, and a much stronger binding affinity. The slightly higher logP of Ligand B is also favorable. The negative Caco-2 and solubility values are concerning for both, but the strong affinity of Ligand B makes it more likely to overcome these issues.

Output:
1
2025-04-17 07:09:31,772 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (348.447) is slightly lower, which is generally favorable for permeability.

**TPSA:** Ligand A (88.76) is excellent for CNS penetration, being well below 90. Ligand B (42.43) is also very good.

**logP:** Ligand A (1.399) is within the optimal range (1-3). Ligand B (3.989) is approaching the upper limit, potentially raising concerns about solubility and off-target effects, but is still acceptable.

**H-Bond Donors/Acceptors:** Ligand A has 1 HBD and 5 HBA, which are reasonable. Ligand B has 0 HBD and 4 HBA, also acceptable.

**QED:** Both ligands have QED values above 0.5 (A: 0.869, B: 0.762), indicating good drug-like properties.

**DILI:** Ligand A (38.852) has a slightly higher DILI risk than Ligand B (29.624), but both are below the 40 threshold and considered good.

**BBB:** Ligand B (92.943) has a significantly higher BBB penetration percentile than Ligand A (78.209). This is a crucial advantage for a CNS target like DRD2.

**Caco-2 Permeability:** Both have negative values, which is unusual. Assuming these are logP-like scales, lower values indicate poorer permeability. Ligand A (-4.926) is worse than Ligand B (-4.677).

**Aqueous Solubility:** Ligand A (-0.708) has slightly better solubility than Ligand B (-3.529).

**hERG:** Both ligands have low hERG inhibition risk (A: 0.396, B: 0.565).

**Microsomal Clearance:** Ligand A (0.917) has much lower microsomal clearance than Ligand B (60.58), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (12.775) has a longer half-life than Ligand B (16.351).

**P-gp Efflux:** Ligand A (0.015) has significantly lower P-gp efflux liability than Ligand B (0.53), which is favorable for CNS exposure.

**Binding Affinity:** Ligand B (-7.1) has a slightly better binding affinity than Ligand A (-8.1). However, the difference is relatively small (1.0 kcal/mol) and may not outweigh other factors.

**Overall Assessment:**

Ligand B excels in BBB penetration and has a slightly better binding affinity. However, Ligand A has superior metabolic stability (lower Cl_mic), longer half-life, lower P-gp efflux, and better solubility. The improved CNS penetration of Ligand B is a strong point, but the combination of metabolic stability and reduced efflux for Ligand A is also highly desirable. Given the importance of BBB for CNS targets, and the relatively small difference in binding affinity, Ligand B is the more promising candidate.

Output:
1
2025-04-17 07:09:31,772 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (367.427 and 388.599 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (82.89) is better than Ligand B (66.48), both are below the 90 A^2 threshold for CNS targets.

**logP:** Both ligands have good logP values (1.422 and 2.028), falling within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A has 0 HBD and 7 HBA, while Ligand B has 1 HBD and 4 HBA. Both are within acceptable limits (<=5 HBD and <=10 HBA).

**QED:** Both ligands have similar QED scores (0.795 and 0.783), indicating good drug-likeness.

**DILI:** Ligand A (69.446) has a higher DILI risk than Ligand B (31.563). This is a significant negative for Ligand A.

**BBB:** Both ligands have reasonable BBB penetration (48.972 and 45.909), but neither exceeds the desirable >70 percentile for CNS targets.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.498 and -4.963), which is unusual and suggests poor permeability. This is a concern for both.

**Aqueous Solubility:** Both ligands have negative solubility values (-2.889 and -2.57), indicating very poor aqueous solubility. This is a major drawback for both.

**hERG Inhibition:** Ligand A (0.567) has a slightly higher hERG inhibition risk than Ligand B (0.148).

**Microsomal Clearance:** Ligand B (37.383) has lower microsomal clearance than Ligand A (53.635), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand B (-3.373) has a longer in vitro half-life than Ligand A (-4.046).

**P-gp Efflux:** Ligand A (0.487) has a slightly lower P-gp efflux liability than Ligand B (0.052), which is better for CNS exposure.

**Binding Affinity:** Ligand B (-8.0 kcal/mol) has a significantly stronger binding affinity than Ligand A (-7.4 kcal/mol). This >1.5 kcal/mol difference is a substantial advantage.

**Overall Assessment:**

Ligand B is the better candidate. While both have issues with solubility and Caco-2 permeability, Ligand B has a significantly better binding affinity, lower DILI risk, and better metabolic stability. The stronger binding affinity is a key advantage for a GPCR ligand, and the lower DILI risk is crucial for safety. The slightly better P-gp efflux for Ligand A is overshadowed by the other benefits of Ligand B.

Output:
1
2025-04-17 07:09:31,772 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (343.387 Da) is slightly lower, which could be beneficial for permeability. Ligand B (372.481 Da) is also acceptable.

**TPSA:** Ligand A (105.12) is borderline for CNS penetration, being above the preferred <90. Ligand B (49.41) is excellent, well below the threshold. This is a significant advantage for Ligand B.

**logP:** Ligand A (0.945) is a little low, potentially hindering membrane permeability. Ligand B (3.245) is optimal.

**H-Bond Donors/Acceptors:** Ligand A has 3 HBD and 5 HBA, which are acceptable. Ligand B has 1 HBD and 3 HBA, also acceptable and potentially slightly better for permeability due to fewer hydrogen bonds.

**QED:** Both ligands have good QED scores (A: 0.567, B: 0.762), indicating drug-likeness. Ligand B is better.

**DILI:** Ligand A has a DILI risk of 87.786, which is high and concerning. Ligand B has a much lower DILI risk of 27.608, a major advantage.

**BBB:** Ligand A has a BBB penetration of 51.842, which is below the desirable >70% for CNS targets. Ligand B has a BBB penetration of 85.033, which is excellent.

**Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and suggests a potential issue with the data or modeling. However, the values are on a similar scale, so this isn't a major differentiator.

**Aqueous Solubility:** Both have negative solubility values, again suggesting a potential data issue. The values are similar.

**hERG Inhibition:** Ligand A (0.177) has a slightly lower hERG risk than Ligand B (0.669), but both are relatively low.

**Microsomal Clearance:** Ligand A (6.214) has lower clearance than Ligand B (62.999), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (70.236) has a significantly longer half-life than Ligand B (1.264), which is highly desirable.

**P-gp Efflux:** Ligand A (0.101) has lower P-gp efflux than Ligand B (0.243), which is beneficial for CNS exposure.

**Binding Affinity:** Ligand A (-8.9 kcal/mol) has a significantly stronger binding affinity than Ligand B (-7.7 kcal/mol). This is a substantial advantage, potentially outweighing some of the ADME drawbacks.

**Overall Assessment:**

Ligand B excels in properties critical for CNS penetration (TPSA, BBB, logP) and has a much lower DILI risk. However, Ligand A has significantly better binding affinity and a longer half-life, and lower P-gp efflux. The high DILI risk for Ligand A is a significant concern. The stronger binding of Ligand A is a major factor, and could be optimized to mitigate the DILI risk. The difference in binding affinity (-1.2 kcal/mol) is substantial.

Output:
0
2025-04-17 07:09:31,773 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (347.394 and 349.391 Da) fall comfortably within the ideal 200-500 Da range.

**TPSA:** Ligand A (98.17) is excellent, falling well below the 90 A^2 threshold for CNS targets. Ligand B (130.67) is higher, but still potentially acceptable, though less ideal.

**logP:** Ligand A (2.823) is optimal (1-3). Ligand B (-0.68) is significantly lower, which could hinder membrane permeability and CNS penetration.

**H-Bond Donors/Acceptors:** Ligand A (1 HBD, 3 HBA) is very good. Ligand B (3 HBD, 7 HBA) is slightly higher, but still within reasonable limits.

**QED:** Both ligands have acceptable QED values (0.466 and 0.656), indicating reasonable drug-likeness.

**DILI:** Ligand A (35.828) has a lower DILI risk than Ligand B (47.964), which is preferable. Both are below the 60 threshold.

**BBB:** Ligand A (71.539) has a significantly better BBB percentile than Ligand B (46.336). This is *critical* for a CNS target like DRD2.

**Caco-2 Permeability:** Ligand A (-4.777) and Ligand B (-5.452) both have negative values, which is unusual. It's difficult to interpret without knowing the scale, but generally, higher values are better.

**Aqueous Solubility:** Ligand A (-3.247) and Ligand B (-1.501) both have negative values, indicating poor solubility. This could be a formulation challenge.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.549 and 0.171).

**Microsomal Clearance:** Ligand A (7.974) has a lower (better) microsomal clearance than Ligand B (-24.003). This suggests better metabolic stability for Ligand A.

**In vitro Half-Life:** Ligand B (1.989) has a longer half-life than Ligand A (-0.908).

**P-gp Efflux:** Ligand A (0.021) has a much lower P-gp efflux liability than Ligand B (0.002), meaning it's less likely to be pumped out of the brain, improving CNS exposure.

**Binding Affinity:** Both ligands have excellent binding affinities (-8.6 and -8.8 kcal/mol), with Ligand B being slightly better. However, the difference is small and likely less important than the ADME differences.

**Conclusion:**

Considering all factors, especially the GPCR-specific priorities, **Ligand A is the more promising drug candidate.** It has a superior BBB score, better logP, lower DILI risk, lower P-gp efflux, and better metabolic stability (lower Cl_mic). While Ligand B has slightly better affinity and half-life, the ADME properties of Ligand A are significantly more favorable for CNS penetration and overall drug-likeness. The poor solubility of both is a concern, but can potentially be addressed with formulation strategies.

Output:
0
2025-04-17 07:09:31,773 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (426.332 Da) is slightly higher, but still acceptable. Ligand B (364.379 Da) is also good.

**TPSA:** Ligand A (55.84) is excellent, well below the 90 A^2 threshold for CNS targets. Ligand B (104.68) is higher, but still potentially acceptable, though less ideal for CNS penetration.

**logP:** Ligand A (3.603) is within the optimal range (1-3). Ligand B (1.929) is at the lower end of optimal, potentially impacting permeability.

**H-Bond Donors/Acceptors:** Ligand A (0 HBD, 4 HBA) and Ligand B (0 HBD, 8 HBA) both have reasonable H-bond characteristics. Ligand B has more HBA, which could slightly impact permeability.

**QED:** Both ligands have acceptable QED values (Ligand A: 0.709, Ligand B: 0.566), indicating good drug-like properties.

**DILI:** Ligand A (70.841) has a higher DILI risk than Ligand B (88.019). This is a concern for Ligand A, but not a deal-breaker at this stage.

**BBB:** Both ligands have good BBB penetration (Ligand A: 52.191, Ligand B: 70.182). Ligand B is better, exceeding the 70% threshold, which is highly desirable for a CNS target like DRD2.

**Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and indicates poor permeability. This is a significant drawback for both.

**Aqueous Solubility:** Both ligands have very poor aqueous solubility (-5.722 and -3.611). This is a major issue for both, potentially hindering bioavailability.

**hERG Inhibition:** Ligand A (0.753) has a slightly higher risk of hERG inhibition than Ligand B (0.123).

**Microsomal Clearance:** Ligand B (33.847) has significantly lower microsomal clearance than Ligand A (106.457), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (19.242) has a longer half-life than Ligand B (5.266), which is favorable.

**P-gp Efflux:** Ligand A (0.555) has lower P-gp efflux than Ligand B (0.048), which is better for CNS exposure.

**Binding Affinity:** Ligand B (-8.8 kcal/mol) has a slightly better binding affinity than Ligand A (-8.1 kcal/mol). While the difference is not huge, it's a noticeable advantage.

**Overall Assessment:**

Despite both compounds having significant solubility and permeability issues, Ligand B appears slightly more promising. It has better BBB penetration, lower DILI risk, significantly better metabolic stability (lower Cl_mic), and a slightly better binding affinity. While Ligand A has a longer half-life and lower P-gp efflux, the solubility and DILI concerns are more significant drawbacks. The slightly better affinity and CNS properties of Ligand B outweigh the shorter half-life.

Output:
1
2025-04-17 07:09:31,773 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (349.431 and 356.499 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (78.95) is better than Ligand B (57.18). Both are below 90, which is favorable for CNS penetration.

**3. logP:** Ligand B (2.583) is within the optimal 1-3 range, while Ligand A (0.002) is significantly below 1, potentially hindering membrane permeability. This is a substantial negative for Ligand A.

**4. H-Bond Donors:** Both ligands have 1 HBD, which is acceptable.

**5. H-Bond Acceptors:** Ligand A has 4 HBA, and Ligand B has 7 HBA. Both are within the acceptable limit of 10.

**6. QED:** Ligand B (0.909) has a much higher QED score than Ligand A (0.575), indicating better overall drug-likeness.

**7. DILI:** Ligand B (63.513) has a higher DILI risk than Ligand A (19.426). This favors Ligand A.

**8. BBB:** Ligand B (90.772) has a significantly better BBB penetration percentile than Ligand A (59.442). This is a critical advantage for a CNS target like DRD2.

**9. Caco-2 Permeability:** Ligand A (-4.612) has a much worse Caco-2 permeability than Ligand B (-5.177). Both are negative values, indicating poor permeability.

**10. Aqueous Solubility:** Ligand A (-0.817) has slightly better solubility than Ligand B (-3.335).

**11. hERG Inhibition:** Ligand A (0.049) has a lower hERG inhibition risk than Ligand B (0.905). This is favorable for Ligand A.

**12. Microsomal Clearance:** Ligand A (-16.182) has much lower (better) microsomal clearance than Ligand B (41.504), suggesting better metabolic stability.

**13. In vitro Half-Life:** Ligand A (-14.568) has a longer in vitro half-life than Ligand B (13.735).

**14. P-gp Efflux:** Ligand A (0.009) has a lower P-gp efflux liability than Ligand B (0.102), which is beneficial for CNS exposure.

**15. Binding Affinity:** Both ligands have similar binding affinities (-8.3 and -8.1 kcal/mol). The difference is minimal.

**Overall Assessment:**

Ligand B excels in BBB penetration and QED, which are crucial for a CNS GPCR target. While its DILI risk is higher, its superior BBB and drug-likeness outweigh this concern. Ligand A has better metabolic stability and lower P-gp efflux, but its very low logP is a major drawback, likely hindering its ability to cross cell membranes and reach the target in the brain. The slightly better solubility and lower hERG risk are not enough to compensate for the poor logP.

Output:
1
2025-04-17 07:09:31,773 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (380.495 and 348.506 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (109.73) is higher than the ideal <90 for CNS targets, but not drastically so. Ligand B (32.34) is excellent, well below the threshold.

**logP:** Ligand A (0.936) is a little low, potentially hindering permeation. Ligand B (4.793) is above the optimal range (1-3) and could lead to solubility issues or off-target interactions, but is not excessively high.

**H-Bond Donors/Acceptors:** Ligand A (HBD=2, HBA=6) is within acceptable limits. Ligand B (HBD=1, HBA=2) is also good.

**QED:** Both ligands have good QED scores (0.767 and 0.801), indicating drug-like properties.

**DILI:** Ligand A (72.586) has a higher DILI risk than Ligand B (31.291), which is preferable.

**BBB:** Ligand B (92.672) has a significantly higher BBB penetration percentile than Ligand A (63.048). This is a *critical* advantage for a CNS target like DRD2.

**Caco-2 Permeability:** Ligand A (-5.495) has poor Caco-2 permeability, which is concerning. Ligand B (-4.599) is also not great, but better than A.

**Aqueous Solubility:** Ligand A (-2.859) has poor aqueous solubility. Ligand B (-5.143) is even worse.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.684 and 0.962).

**Microsomal Clearance:** Ligand A (8.15) has lower microsomal clearance than Ligand B (48.177), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand B (15.1) has a longer half-life than Ligand A (11.12).

**P-gp Efflux:** Ligand A (0.068) has much lower P-gp efflux liability than Ligand B (0.663). Lower P-gp efflux is beneficial for CNS penetration.

**Binding Affinity:** Both ligands have excellent binding affinity (-8.3 and -8.5 kcal/mol), with Ligand B being slightly better. The affinity difference is not substantial enough to overcome other significant ADME differences.

**Overall Assessment:**

While Ligand A has better metabolic stability and lower P-gp efflux, Ligand B is significantly better regarding BBB penetration, a crucial factor for CNS targets. The lower DILI risk for Ligand B is also a positive. The solubility and Caco-2 permeability are poor for both, but the BBB advantage of Ligand B outweighs the other drawbacks.

Output:
1
2025-04-17 07:09:31,773 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (351.407 and 353.463 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (120.58) is slightly above the optimal <90 for CNS targets, but still reasonable. Ligand B (101.73) is better, falling comfortably below 90.

**logP:** Ligand A (-0.819) is a bit low, potentially hindering permeability. Ligand B (0.954) is better, within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A has 3 HBD and 7 HBA, which are acceptable. Ligand B has 2 HBD and 4 HBA, also acceptable.

**QED:** Both ligands have similar QED scores (0.637 and 0.603), indicating good drug-likeness.

**DILI:** Ligand A (45.25) has a moderate DILI risk, while Ligand B (12.718) has a very low DILI risk, a significant advantage.

**BBB:** Ligand A (18.961) has a very low BBB penetration, a major drawback for a CNS target. Ligand B (58.24) has a much better BBB penetration, although still not ideal (>70).

**Caco-2 Permeability:** Both have negative Caco-2 values (-5.484 and -5.393), which is unusual and suggests poor permeability. This needs further investigation, but it's a concern for both.

**Aqueous Solubility:** Both ligands have negative solubility values (-0.707 and -1.609), indicating poor aqueous solubility. This is a concern for both.

**hERG Inhibition:** Ligand A (0.01) has a very low hERG risk, which is excellent. Ligand B (0.226) has a slightly higher, but still acceptable, hERG risk.

**Microsomal Clearance:** Ligand A (-16.135) has a very high microsomal clearance, indicating poor metabolic stability. Ligand B (-4.416) has a better, but still not ideal, clearance.

**In vitro Half-Life:** Ligand A (10.384) has a relatively short in vitro half-life. Ligand B (-12.754) has a very short half-life.

**P-gp Efflux:** Ligand A (0.009) has very low P-gp efflux, which is good for CNS penetration. Ligand B (0.022) also has low P-gp efflux.

**Binding Affinity:** Ligand B (-7.9 kcal/mol) has a slightly better binding affinity than Ligand A (-7.3 kcal/mol), although both are good. The 0.6 kcal/mol difference is not huge, but is still a factor.

**Overall Assessment:**

Ligand B is the more promising candidate. While both have issues with Caco-2 permeability and aqueous solubility, Ligand B excels in key areas for a CNS-targeting GPCR: significantly lower DILI risk, substantially better BBB penetration, and slightly improved binding affinity. Ligand A's very poor BBB penetration is a major concern, outweighing its slightly better hERG profile. The lower metabolic clearance of Ligand B is also preferable.

Output:
1
2025-04-17 07:09:31,774 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (378.395 Da) is slightly higher, but acceptable. Ligand B (349.475 Da) is also good.

**TPSA:** Ligand A (139.8) is borderline acceptable for CNS targets (<=90 is preferred) but still reasonable. Ligand B (64.09) is excellent, well below the 90 threshold.

**logP:** Both ligands have good logP values (Ligand A: 1.655, Ligand B: 1.001), falling within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A has 2 HBD and 9 HBA, which are acceptable. Ligand B has 1 HBD and 4 HBA, also acceptable.

**QED:** Both ligands have good QED scores (Ligand A: 0.516, Ligand B: 0.769), indicating good drug-like properties. Ligand B is slightly better.

**DILI:** Ligand A has a high DILI risk (99.069), which is a significant concern. Ligand B has a very low DILI risk (5.894), a major advantage.

**BBB:** Ligand A has a low BBB penetration (23.149), which is problematic for a CNS target. Ligand B has a much better BBB penetration (62.621), although still not ideal (>70 is desirable).

**Caco-2 Permeability:** Ligand A has a negative Caco-2 value (-5.774), indicating poor permeability. Ligand B also has a negative Caco-2 value (-4.773), also indicating poor permeability.

**Aqueous Solubility:** Both ligands have negative solubility values (Ligand A: -3.191, Ligand B: -0.496), suggesting poor aqueous solubility. Ligand B is slightly better.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (Ligand A: 0.347, Ligand B: 0.125).

**Microsomal Clearance:** Ligand A has a higher microsomal clearance (19.387) than Ligand B (6.02), indicating lower metabolic stability.

**In vitro Half-Life:** Ligand A has a longer half-life (14.009) than Ligand B (5.644).

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (Ligand A: 0.089, Ligand B: 0.022).

**Binding Affinity:** Both ligands have very similar and strong binding affinities (Ligand A: -8.2 kcal/mol, Ligand B: -8.1 kcal/mol). The difference is negligible.

**Overall Assessment:**

Ligand B is significantly better due to its much lower DILI risk and better BBB penetration. While both have poor Caco-2 permeability and solubility, the CNS target prioritizes BBB. The slightly longer half-life of Ligand A is a minor advantage, but it is outweighed by the significant liabilities of high DILI risk and poor BBB penetration. The similar binding affinities make the ADME properties the deciding factor.

Output:
1
2025-04-17 07:09:31,774 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (346.391 and 359.415 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (113.24) is slightly higher than Ligand B (108.92), but both are below the 140 A^2 threshold for good oral absorption and reasonably close to the <90 A^2 target for CNS penetration.

**3. logP:** Both ligands have logP values around 1 (0.953 and 1.069), which is optimal for permeability and avoiding solubility issues.

**4. H-Bond Donors:** Both have 2 HBD, which is within the acceptable limit of <=5.

**5. H-Bond Acceptors:** Ligand A has 7 HBA, while Ligand B has 8. Both are below the 10 limit.

**6. QED:** Both ligands have QED values above 0.7 (0.772 and 0.717), indicating good drug-like properties.

**7. DILI:** Ligand A (55.603) has a significantly lower DILI risk than Ligand B (88.057). This is a major advantage for Ligand A.

**8. BBB:** Both ligands have similar BBB penetration (35.518 and 36.836). These are both below the desirable >70 percentile for CNS targets, but not drastically so.

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.691 and -5.393), which is unusual and suggests poor permeability. However, these values are on a scale where negative values are possible, and the absolute values are relatively close.

**10. Aqueous Solubility:** Both ligands have very poor aqueous solubility (-2.588 and -3.189). This is a concern for formulation and bioavailability.

**11. hERG Inhibition:** Ligand A (0.082) has a much lower hERG inhibition liability than Ligand B (0.727), indicating a lower risk of cardiotoxicity. This is a significant advantage for Ligand A.

**12. Microsomal Clearance:** Ligand A (39.091) has a higher microsomal clearance than Ligand B (10.463), suggesting lower metabolic stability. This is a disadvantage for Ligand A.

**13. In vitro Half-Life:** Ligand A (-10.011) has a shorter in vitro half-life than Ligand B (-6.756). This is a disadvantage for Ligand A.

**14. P-gp Efflux:** Ligand A (0.023) has a much lower P-gp efflux liability than Ligand B (0.045), which is favorable for CNS exposure.

**15. Binding Affinity:** Ligand B (-7.3 kcal/mol) has a slightly better binding affinity than Ligand A (-8.3 kcal/mol). While A is better, the difference is not substantial enough to outweigh other factors.

**Overall Assessment:**

Considering the GPCR-specific priorities, Ligand A is the more promising candidate. While Ligand B has slightly better binding affinity and metabolic stability, Ligand A exhibits significantly lower DILI risk and hERG inhibition, and lower P-gp efflux. The BBB penetration is similar for both, and both have poor solubility and Caco-2 permeability. The lower DILI and hERG risks are critical for CNS drug development, making Ligand A the preferred choice.

Output:
0
2025-04-17 07:09:31,774 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 drug candidates, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (342.443 and 347.459 Da) fall comfortably within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (75.5) is higher than Ligand B (61.88). For CNS targets, we prefer TPSA <= 90, so both are acceptable, but B is better.

**3. logP:** Ligand A (2.397) is within the optimal 1-3 range. Ligand B (0.781) is slightly below 1, which *could* indicate permeability issues. This is a strike against B.

**4. H-Bond Donors:** Ligand A (2) and Ligand B (1) both meet the <=5 criteria.

**5. H-Bond Acceptors:** Both ligands (4) are well below the <=10 threshold.

**6. QED:** Both ligands have good QED scores (0.687 and 0.764, respectively), indicating drug-like properties.

**7. DILI:** Ligand A (46.297) has a moderate DILI risk, but is still acceptable. Ligand B (12.757) has a very low DILI risk, which is a significant advantage.

**8. BBB:** This is crucial for a CNS target like DRD2. Ligand A has a BBB percentile of 83.831, which is excellent (>70). Ligand B has a BBB percentile of 61.031, which is below the desirable threshold. This is a major strike against B.

**9. Caco-2 Permeability:** Ligand A (-5.042) and Ligand B (-4.578) both have negative values, which is unusual and suggests poor permeability. However, the scale isn't clearly defined, so it's hard to interpret.

**10. Aqueous Solubility:** Both ligands have poor aqueous solubility (-3.169 and -1.617, respectively). This could pose formulation challenges, but isn't a dealbreaker if other properties are strong.

**11. hERG Inhibition:** Both ligands show low hERG inhibition risk (0.683 and 0.238, respectively).

**12. Microsomal Clearance:** Ligand A (58.318) has higher clearance than Ligand B (1.985), meaning B is more metabolically stable.

**13. In vitro Half-Life:** Ligand B (3.245) has a longer half-life than Ligand A (-2.535).

**14. P-gp Efflux:** Ligand A (0.161) has lower P-gp efflux than Ligand B (0.009), which is better for CNS exposure.

**15. Binding Affinity:** Ligand B (-8.7 kcal/mol) has a slightly better binding affinity than Ligand A (-8.1 kcal/mol). This 0.6 kcal/mol difference is not large enough to overcome the other significant drawbacks of Ligand B.

**Overall Assessment:**

Ligand A is the stronger candidate. While it has a slightly higher TPSA and moderate DILI risk, its significantly better BBB penetration, better P-gp efflux, and acceptable logP outweigh the slightly weaker binding affinity and higher clearance compared to Ligand B. Ligand B's low logP and poor BBB penetration are critical weaknesses for a CNS-targeted GPCR.

Output:
1
2025-04-17 07:09:31,774 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (352.483 and 348.374 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (106.17) is higher than Ligand B (79.62). For CNS targets, we prefer TPSA <= 90. Ligand B is significantly better here.

**3. logP:** Both ligands have good logP values (1.558 and 2.007), falling within the optimal 1-3 range.

**4. H-Bond Donors:** Ligand A (4) is higher than Ligand B (1). Lower is generally preferred, but both are acceptable.

**5. H-Bond Acceptors:** Ligand A (5) and Ligand B (4) are both within the acceptable limit of <= 10.

**6. QED:** Both ligands have good QED scores (0.54 and 0.826), indicating good drug-like properties. Ligand B is better.

**7. DILI:** Ligand A (14.385) has a much lower DILI risk than Ligand B (44.63). This is a significant advantage for Ligand A.

**8. BBB:** Ligand B (85.421) has a much better BBB penetration percentile than Ligand A (52.579). This is *critical* for a CNS target like DRD2.

**9. Caco-2 Permeability:** Ligand A (-5.698) has poorer Caco-2 permeability than Ligand B (-4.604).

**10. Aqueous Solubility:** Ligand A (-1.558) has poorer aqueous solubility than Ligand B (-3.136).

**11. hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.432 and 0.145).

**12. Microsomal Clearance:** Ligand A (-20.125) has a much lower (better) microsomal clearance than Ligand B (27.584), indicating greater metabolic stability.

**13. In vitro Half-Life:** Ligand A (24.471) has a better in vitro half-life than Ligand B (-7.748).

**14. P-gp Efflux:** Ligand A (0.023) has much lower P-gp efflux liability than Ligand B (0.072), which is highly desirable for CNS penetration.

**15. Binding Affinity:** Ligand B (-9.1) has a slightly better binding affinity than Ligand A (-8.2). While a 1.5 kcal/mol advantage is significant, the other ADME properties are more important in this case.

**Overall Assessment:**

Ligand B excels in BBB penetration and binding affinity, which are crucial for a CNS GPCR target. However, it suffers from higher DILI risk, poorer metabolic stability (higher Cl_mic), and higher P-gp efflux. Ligand A has a better safety profile (lower DILI), better metabolic stability, lower P-gp efflux, and a better half-life. While its BBB penetration is lower, the combination of improved ADME properties and acceptable affinity makes it a more promising candidate. The difference in binding affinity (0.9 kcal/mol) is not large enough to overcome the significant ADME advantages of Ligand A.

Output:
1
2025-04-17 07:09:31,774 - INFO - Batch 341 complete. Total preferences: 5456
2025-04-17 07:09:31,774 - INFO - Processing batch 342/512...
2025-04-17 07:10:14,516 - INFO - Reasoning:

Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (350.478 and 357.391 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (49.41) is significantly better than Ligand B (20.31). For a CNS target like DRD2, a TPSA <= 90 is desirable, and Ligand A is closer to this threshold. Ligand B is excellent.

**3. logP:** Both ligands have good logP values (3.204 and 4.488), falling within the optimal 1-3 range, although Ligand B is slightly higher.

**4. H-Bond Donors:** Ligand A has 1 HBD, while Ligand B has 0. Both are acceptable.

**5. H-Bond Acceptors:** Ligand A has 2 HBA, and Ligand B has 1. Both are within the acceptable limit of <=10.

**6. QED:** Both ligands have reasonable QED values (0.766 and 0.687), indicating good drug-like properties.

**7. DILI:** Ligand A (19.426%) has a lower DILI risk than Ligand B (26.173%), which is preferable.

**8. BBB:** Both ligands show excellent BBB penetration (Ligand A: 91.508%, Ligand B: 94.261%). Both are above the 70% threshold for CNS targets. Ligand B is slightly better.

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.752 and -4.259). These values are unusual and suggest poor permeability. However, negative values are sometimes observed in modeling and don't necessarily preclude activity.

**10. Aqueous Solubility:** Both ligands have negative solubility values (-3.847 and -5.323), indicating very poor aqueous solubility. This is a significant concern for bioavailability.

**11. hERG Inhibition:** Both ligands have low hERG inhibition risk (0.802 and 0.825).

**12. Microsomal Clearance:** Ligand A (43.32) has lower microsomal clearance than Ligand B (58.752), suggesting better metabolic stability.

**13. In vitro Half-Life:** Ligand A (-8.842) has a significantly longer in vitro half-life than Ligand B (15.617).

**14. P-gp Efflux:** Both ligands have low P-gp efflux liability (0.354 and 0.616), which is good for CNS exposure.

**15. Binding Affinity:** Both ligands have very similar and excellent binding affinities (-8.4 and -8.5 kcal/mol). The difference is negligible.

**Overall Assessment:**

While both ligands have excellent binding affinity and BBB penetration, Ligand A is superior due to its lower DILI risk, better metabolic stability (lower Cl_mic, longer t1/2), and more reasonable TPSA. The solubility and Caco-2 permeability are problematic for both, but the other advantages of Ligand A outweigh these concerns.

Output:
1
2025-04-17 07:10:14,516 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (355.429 and 411.571 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Both ligands have TPSA values (47.36 and 47.02) below the 90 A^2 threshold desirable for CNS targets, which is excellent.

**3. logP:** Both ligands have logP values (2.926 and 3.492) within the optimal range of 1-3.

**4. H-Bond Donors:** Ligand A (0 HBD) is preferable to Ligand B (1 HBD) as fewer HBDs generally improve permeability.

**5. H-Bond Acceptors:** Ligand A (4 HBA) is preferable to Ligand B (6 HBA) for the same reason as above.

**6. QED:** Both ligands have similar QED values (0.756 and 0.704), indicating good drug-like properties.

**7. DILI:** Ligand A (35.285 percentile) has a significantly lower DILI risk than Ligand B (44.979 percentile). This is a substantial advantage.

**8. BBB:** Ligand A (97.751 percentile) has a much higher predicted BBB penetration than Ligand B (87.864 percentile). This is *critical* for a CNS target like DRD2.

**9. Caco-2 Permeability:** Both have negative values, which is unusual and suggests poor permeability. However, the scale is not specified, so it's hard to interpret.

**10. Aqueous Solubility:** Both have negative values, which is unusual and suggests poor solubility. However, the scale is not specified, so it's hard to interpret.

**11. hERG Inhibition:** Both ligands have low hERG inhibition risk (0.669 and 0.981).

**12. Microsomal Clearance:** Ligand A (35.896 mL/min/kg) has lower microsomal clearance than Ligand B (44.849 mL/min/kg), indicating better metabolic stability.

**13. In vitro Half-Life:** Ligand B (27.484 hours) has a significantly longer half-life than Ligand A (6.95 hours). This is a positive for Ligand B.

**14. P-gp Efflux:** Both ligands have low P-gp efflux liability (0.18 and 0.94).

**15. Binding Affinity:** Ligand B (-8.4 kcal/mol) has a stronger binding affinity than Ligand A (-7.2 kcal/mol). This is a 1.2 kcal/mol difference, which is significant and could outweigh some ADME drawbacks.

**Overall Assessment:**

While Ligand B has a superior binding affinity and longer half-life, Ligand A demonstrates a significantly better safety profile (lower DILI) and, crucially, much better predicted BBB penetration. For a CNS target like DRD2, BBB penetration is paramount. The difference in binding affinity, while notable, might be overcome with further optimization. The better ADME properties of Ligand A (lower DILI, lower Cl_mic, better HBD/HBA) make it a more promising starting point for drug development.

Output:
0
2025-04-17 07:10:14,516 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (346.446 and 342.443 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (55.56) is better than Ligand B (58.44). Both are below the 90 A^2 threshold desirable for CNS targets, but A is closer to optimal.

**3. logP:** Ligand A (3.164) is within the optimal 1-3 range. Ligand B (1.902) is a bit low, potentially hindering permeability.

**4. H-Bond Donors:** Ligand A (1) is preferable to Ligand B (0), as some H-bond donors can aid solubility.

**5. H-Bond Acceptors:** Ligand A (3) is preferable to Ligand B (4).

**6. QED:** Both ligands have good QED scores (0.915 and 0.843), indicating good drug-like properties.

**7. DILI:** Both ligands have acceptable DILI risk (22.489 and 25.591), well below the 40% threshold.

**8. BBB:** This is a critical parameter for a CNS target like DRD2. Ligand A (92.943) is *significantly* better than Ligand B (77.2), exceeding the desirable >70% threshold.

**9. Caco-2 Permeability:** Ligand A (-4.914) is better than Ligand B (-4.584), indicating higher intestinal absorption.

**10. Aqueous Solubility:** Ligand A (-2.291) is better than Ligand B (-1.313), indicating better solubility.

**11. hERG Inhibition:** Both ligands have low hERG inhibition risk (0.824 and 0.295), which is good.

**12. Microsomal Clearance:** Ligand A (22.228) has lower clearance than Ligand B (35.249), suggesting better metabolic stability.

**13. In vitro Half-Life:** Ligand A (23.405) has a longer half-life than Ligand B (-6.003), which is preferable.

**14. P-gp Efflux:** Ligand A (0.219) has lower P-gp efflux liability than Ligand B (0.129), meaning more drug will reach the brain.

**15. Binding Affinity:** Both ligands have excellent binding affinity (-8.0 and -7.8 kcal/mol). The difference of 0.2 kcal/mol is not substantial enough to outweigh the other advantages of Ligand A.

**Overall:** Ligand A is superior to Ligand B. It has a better BBB score, logP, solubility, metabolic stability, longer half-life, and lower P-gp efflux. While both have good affinity and acceptable safety profiles, Ligand A's improved pharmacokinetic properties, particularly its BBB penetration, make it the more promising drug candidate for a CNS target like DRD2.

Output:
1
2025-04-17 07:10:14,517 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (360.4 & 348.4 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (135.76) is slightly above the optimal <90 for CNS targets, but still reasonable. Ligand B (88.32) is excellent, well within the desired range.

**3. logP:** Both ligands have good logP values (1.057 & 1.96), falling within the 1-3 range.

**4. H-Bond Donors:** Ligand A (3) and Ligand B (2) are both acceptable, being less than 5.

**5. H-Bond Acceptors:** Ligand A (6) and Ligand B (4) are both acceptable, being less than 10.

**6. QED:** Both ligands have good QED scores (0.625 & 0.851), indicating good drug-like properties.

**7. DILI:** Both ligands have relatively high DILI risk (96.51 & 41.88), but Ligand B is significantly better.

**8. BBB:** This is a critical parameter for a CNS target like DRD2. Ligand A has a BBB percentile of 40.79, which is poor. Ligand B has a much better BBB percentile of 89.03, exceeding the desirable >70 threshold.

**9. Caco-2 Permeability:** Ligand A (-5.431) and Ligand B (-4.939) have negative values, which is unusual. Lower values indicate poor permeability.

**10. Aqueous Solubility:** Both ligands have poor aqueous solubility (-3.479 & -2.679).

**11. hERG Inhibition:** Both ligands have low hERG inhibition risk (0.227 & 0.493).

**12. Microsomal Clearance:** Ligand A (17.505) has a higher clearance than Ligand B (4.295), suggesting lower metabolic stability.

**13. In vitro Half-Life:** Ligand A (-17.169) has a very short half-life, while Ligand B (-16.744) is also short, but slightly better.

**14. P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.04 & 0.023), which is good for CNS penetration.

**15. Binding Affinity:** Both ligands have excellent binding affinities (-8.9 & -9.1 kcal/mol), with Ligand B being slightly better. The difference is less than 1.5 kcal/mol, so it's not a decisive factor on its own.

**Overall Assessment:**

While both ligands have good binding affinity and acceptable physicochemical properties, Ligand B is significantly more promising due to its substantially better BBB penetration (89% vs 41%), lower DILI risk, and lower microsomal clearance. The TPSA is also much more favorable for CNS penetration. Although both have poor solubility and Caco-2 permeability, the superior BBB and safety profile of Ligand B outweigh these drawbacks.

Output:
1
2025-04-17 07:10:14,517 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (349.431 and 355.435 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (100.29) is slightly above the preferred <90 for CNS targets, while Ligand B (93.89) is closer to the ideal range. This gives a slight edge to Ligand B.

**3. logP:** Ligand A (1.266) and Ligand B (0.878) are both within the optimal 1-3 range.

**4. H-Bond Donors:** Ligand A (3) is acceptable, while Ligand B (1) is even better, minimizing potential permeability issues.

**5. H-Bond Acceptors:** Ligand A (4) and Ligand B (7) are both within the acceptable limit of 10.

**6. QED:** Ligand A (0.658) is better than Ligand B (0.495), indicating a more drug-like profile.

**7. DILI:** Ligand A (55.758) has a higher DILI risk than Ligand B (38.62), which is preferable.

**8. BBB:** Ligand A (50.523) and Ligand B (59.597) are both below the desirable >70 for CNS targets, but Ligand B is closer.

**9. Caco-2:** Ligand A (-5.004) and Ligand B (-4.543) are both negative, indicating poor permeability. This is a concern for both.

**10. Solubility:** Ligand A (-2.825) and Ligand B (-0.58) are both negative, indicating poor solubility. Ligand B is slightly better.

**11. hERG:** Both ligands have low hERG inhibition risk (0.161 and 0.252 respectively).

**12. Cl_mic:** Ligand A (11.048) has a lower microsomal clearance, suggesting better metabolic stability than Ligand B (77.187). This is a significant advantage for Ligand A.

**13. t1/2:** Ligand A (-16.644) has a negative in vitro half-life, which is concerning. Ligand B (-22.304) is also negative, but less so. Both are very poor.

**14. Pgp:** Both ligands have low P-gp efflux liability (0.055 and 0.1 respectively).

**15. Affinity:** Ligand A (-7.9 kcal/mol) has a significantly better binding affinity than Ligand B (-6 kcal/mol). This is a substantial advantage, potentially outweighing some of the ADME drawbacks.

**Overall Assessment:**

Ligand A has a superior binding affinity and better metabolic stability (lower Cl_mic). However, it has a worse in vitro half-life and higher DILI risk. Ligand B has a slightly better TPSA, logP, and BBB penetration, but significantly weaker binding affinity.

Given the GPCR-specific priorities, *affinity is paramount*. The 1.9 kcal/mol difference in binding affinity is substantial. While Ligand A's DILI risk is a concern, it is a manageable risk compared to the significant potency difference. The negative half-life is concerning, but can be addressed with structural modifications. The slightly better BBB of Ligand B is not enough to overcome the affinity gap.

Output:
1
2025-04-17 07:10:14,517 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (350.394 and 348.443 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (87.46) is slightly above the optimal <90 for CNS targets, but still reasonable. Ligand B (75.71) is excellent, well below 90.

**3. logP:** Ligand A (0.259) is quite low, potentially hindering permeability. Ligand B (1.508) is within the optimal 1-3 range. This is a significant advantage for Ligand B.

**4. H-Bond Donors:** Ligand A (2) and Ligand B (1) are both acceptable, below the threshold of 5.

**5. H-Bond Acceptors:** Ligand A (5) and Ligand B (4) are both acceptable, below the threshold of 10.

**6. QED:** Ligand A (0.746) is good, indicating strong drug-like properties. Ligand B (0.448) is lower, suggesting a less ideal overall profile, though not disqualifying.

**7. DILI:** Ligand A (41.838) has a slightly higher DILI risk than Ligand B (25.785), but both are below the concerning threshold of 60.

**8. BBB:** Ligand A (55.332) has a moderate BBB penetration, while Ligand B (63.009) is better. For a CNS target like DRD2, higher BBB is preferred.

**9. Caco-2:** Both ligands have negative Caco-2 values (-5.151 and -4.641), which is unusual and suggests poor permeability. This is a concern for both.

**10. Solubility:** Both ligands have negative solubility values (-1.022 and -2.038), which is also unusual and suggests poor solubility. This is a concern for both.

**11. hERG:** Both ligands have very low hERG inhibition risk (0.231 and 0.113).

**12. Cl_mic:** Ligand A (-15.758) has a *much* lower (better) microsomal clearance than Ligand B (40.883), indicating greater metabolic stability.

**13. t1/2:** Ligand A (-14.405) has a negative in vitro half-life, which is unusual. Ligand B (-19.274) also has a negative half-life. This suggests rapid metabolism for both, but the negative values are concerning.

**14. Pgp:** Both ligands have very low P-gp efflux liability (0.026 and 0.043).

**15. Binding Affinity:** Ligand A (-7.9 kcal/mol) has a significantly stronger binding affinity than Ligand B (-6.4 kcal/mol). This is a substantial advantage for Ligand A, potentially outweighing some of its ADME drawbacks.

**Overall Assessment:**

Ligand A has a much stronger binding affinity and better metabolic stability (lower Cl_mic). However, it suffers from a low logP, which could limit permeability, and a moderate BBB score. Ligand B has a better logP, TPSA, and BBB score, but its binding affinity is significantly weaker and its metabolic stability is poorer.

Given the GPCR-specific priorities, the strong binding affinity of Ligand A is a major advantage. While the low logP is a concern, it might be addressable through further optimization. The better BBB of Ligand B is helpful, but the substantial difference in binding affinity is likely more critical for a CNS target. The negative Caco-2 and solubility values are concerning for both and would require investigation, but the affinity difference is the deciding factor.

Output:
1
2025-04-17 07:10:14,517 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (346.435 and 369.491 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (103.87) is better than Ligand B (110.44) as it is closer to the <90 A^2 threshold for CNS targets.

**logP:** Both ligands (0.978 and 1.15) are within the optimal 1-3 range.

**H-Bond Donors:** Both ligands have 2 HBD, which is acceptable (<=5).

**H-Bond Acceptors:** Ligand A (5) is better than Ligand B (7), keeping in mind the <=10 threshold.

**QED:** Ligand A (0.827) has a better QED score than Ligand B (0.711), indicating a more drug-like profile.

**DILI:** Both ligands have similar DILI risk (52.617 and 54.75), both being acceptable (<60).

**BBB:** Ligand B (74.37) has a significantly better BBB penetration percentile than Ligand A (60.644). This is a critical advantage for a CNS target like DRD2.

**Caco-2 Permeability:** Both have negative values (-5.543 and -5.126), which is unusual and difficult to interpret without knowing the scale. However, they are similar.

**Aqueous Solubility:** Both ligands have negative values (-2.574 and -2.776), indicating poor solubility. This is a concern, but can sometimes be overcome with formulation strategies.

**hERG Inhibition:** Ligand A (0.049) has a lower hERG inhibition liability than Ligand B (0.427), which is preferable.

**Microsomal Clearance:** Both ligands have similar microsomal clearance (14.135 and 13.141), suggesting similar metabolic stability.

**In vitro Half-Life:** Ligand A (-13.922) has a significantly longer in vitro half-life than Ligand B (4.34). This is a positive attribute.

**P-gp Efflux:** Ligand A (0.067) has lower P-gp efflux liability than Ligand B (0.095), which is beneficial for CNS penetration.

**Binding Affinity:** Both ligands have very similar binding affinities (-7.8 and -7.7 kcal/mol). The difference is negligible.

**Overall Assessment:**

Ligand A has advantages in TPSA, HBA, QED, hERG, half-life, and P-gp efflux. Ligand B's main advantage is its significantly better BBB penetration. Given that DRD2 is a CNS target, BBB penetration is paramount. While Ligand A has a slightly better overall ADME profile, the superior BBB score of Ligand B outweighs these benefits.

Output:
1
2025-04-17 07:10:14,517 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (353.39 and 350.459 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (73.86) is slightly higher than Ligand B (66.92). Both are below the 90 A^2 threshold desirable for CNS targets, but Ligand B is preferable.

**logP:** Ligand A (3.016) is within the optimal range (1-3), while Ligand B (1.991) is at the lower end. While lower logP can sometimes improve solubility, for a CNS target, a slightly higher logP like that of Ligand A is generally preferred for better membrane permeability.

**H-Bond Donors/Acceptors:** Ligand A has 1 HBD and 6 HBA, while Ligand B has 0 HBD and 4 HBA. Both are within acceptable limits (<=5 HBD and <=10 HBA).

**QED:** Ligand A (0.76) has a better QED score than Ligand B (0.562), indicating a more drug-like profile.

**DILI:** Ligand B (30.748) has a significantly lower DILI risk than Ligand A (63.552). This is a substantial advantage for Ligand B.

**BBB:** Ligand A (86.08) has a better BBB penetration percentile than Ligand B (73.672). This is a crucial factor for a CNS target like DRD2, making Ligand A more promising.

**Caco-2 Permeability:** Ligand A (-4.025) has a worse Caco-2 permeability than Ligand B (-4.481).

**Aqueous Solubility:** Ligand A (-4.679) has a worse aqueous solubility than Ligand B (-2.342).

**hERG Inhibition:** Ligand B (0.295) has a lower hERG inhibition liability than Ligand A (0.625), which is a positive attribute.

**Microsomal Clearance:** Ligand B (71.137) has a lower microsomal clearance than Ligand A (112.525), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand B (-9.274) has a worse in vitro half-life than Ligand A (42.943).

**P-gp Efflux:** Ligand B (0.172) has a lower P-gp efflux liability than Ligand A (0.435), which is beneficial for CNS penetration.

**Binding Affinity:** Ligand A (-8.2 kcal/mol) has a significantly stronger binding affinity than Ligand B (-6.9 kcal/mol). This is a major advantage, potentially outweighing some of the ADME drawbacks. The difference of 1.3 kcal/mol is substantial.

**Overall Assessment:**

Ligand A excels in binding affinity and BBB penetration, which are critical for a CNS GPCR target. However, it has higher DILI risk, worse solubility, and higher P-gp efflux. Ligand B has a better safety profile (lower DILI, hERG, P-gp) and better metabolic stability, but its binding affinity and BBB penetration are lower.

Given the strong affinity advantage of Ligand A (-8.2 kcal/mol vs -6.9 kcal/mol) and the importance of BBB penetration for a CNS target, I believe Ligand A is the more promising candidate, despite its slightly less favorable ADME properties. The potency difference is significant enough to warrant further optimization focusing on improving its ADME profile.

Output:
1
2025-04-17 07:10:14,518 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (369.491 Da) is slightly higher than Ligand B (346.45 Da), but both are acceptable.

**TPSA:** Ligand A (92.51) is borderline for CNS penetration, being slightly above the preferred <90. Ligand B (38.82) is excellent, well below 90, indicating better potential for crossing the blood-brain barrier.

**logP:** Ligand A (0.584) is quite low, potentially hindering membrane permeability. Ligand B (1.324) is better, falling within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A has 2 HBD and 7 HBA, which are reasonable. Ligand B has 1 HBD and 4 HBA, also acceptable.

**QED:** Both ligands have good QED values (A: 0.683, B: 0.835), suggesting drug-like properties.

**DILI:** Both ligands have low DILI risk (A: 36.293, B: 35.052), which is positive.

**BBB:** This is a critical parameter for a CNS target like DRD2. Ligand A has a BBB percentile of 45.909, which is below the desirable >70. Ligand B has a significantly higher BBB percentile of 70.26, making it much more promising for CNS penetration.

**Caco-2 Permeability:** Both have negative Caco-2 values (-5.28 and -4.92), which is unusual and suggests poor permeability. However, these values are on a log scale and negative values are not necessarily disqualifying, but warrant further investigation.

**Aqueous Solubility:** Both ligands have poor aqueous solubility (-1.547 and -1.808). This could pose formulation challenges.

**hERG Inhibition:** Ligand A (0.284) has a slightly higher hERG risk than Ligand B (0.8), though both are relatively low.

**Microsomal Clearance:** Ligand A (-0.255) has a negative clearance, which is unusual and suggests very high metabolic stability. Ligand B (4.56) has a moderate clearance.

**In vitro Half-Life:** Ligand A (19.637 hours) has a longer half-life than Ligand B (-7.233 hours), which is generally desirable.

**P-gp Efflux:** Ligand A (0.021) has very low P-gp efflux, which is excellent. Ligand B (0.072) also has low P-gp efflux, but slightly higher than A.

**Binding Affinity:** Ligand A (-7.5 kcal/mol) has a slightly better binding affinity than Ligand B (-7.233 kcal/mol). However, the difference is not substantial enough to outweigh the significant ADME advantages of Ligand B.

**Overall:** While Ligand A has slightly better affinity and metabolic stability, Ligand B is significantly better in terms of BBB penetration, logP, and has a good QED score. Given that DRD2 is a CNS target, BBB penetration is paramount. The better logP of Ligand B also supports better membrane permeability.

Output:
1
2025-04-17 07:10:14,518 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (345.487 and 348.487 Da) fall comfortably within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (43.86) is significantly better than Ligand B (58.64). For CNS targets, we want TPSA <= 90, and ideally closer to 60. Ligand A is much closer to this ideal.

**3. logP:** Both ligands have acceptable logP values (1.576 and 2.367), falling within the optimal 1-3 range. Ligand B is slightly higher, which could potentially lead to some off-target effects, but it's not a major concern.

**4. H-Bond Donors:** Ligand A (0) and Ligand B (1) are both acceptable.

**5. H-Bond Acceptors:** Both ligands have 3 H-bond acceptors, which is within the acceptable range of <= 10.

**6. QED:** Both ligands have reasonable QED scores (0.763 and 0.685), indicating good drug-like properties.

**7. DILI:** Ligand A (6.282) has a much lower DILI risk than Ligand B (21.636). This is a significant advantage for Ligand A.

**8. BBB:** Both ligands have good BBB penetration (72.741 and 79.682). Ligand B is slightly better, but both are above the desirable 70% threshold for CNS targets.

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.692 and -4.556). This is unusual and suggests poor permeability. However, these values are on a log scale and the negative values are not necessarily indicative of a complete lack of permeability.

**10. Aqueous Solubility:** Both ligands have negative solubility values (-2.579 and -3.514). This is also unusual and suggests poor solubility.

**11. hERG Inhibition:** Both ligands have low hERG inhibition risk (0.477 and 0.622).

**12. Microsomal Clearance:** Ligand A (33.835) has significantly lower microsomal clearance than Ligand B (48.443), indicating better metabolic stability.

**13. In vitro Half-Life:** Ligand A (14.901) has a longer in vitro half-life than Ligand B (4.532).

**14. P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.013 and 0.151).

**15. Binding Affinity:** Ligand B (-7.7) has a slightly better binding affinity than Ligand A (-7.5), but the difference is relatively small (0.2 kcal/mol).

**Overall Assessment:**

While Ligand B has slightly better BBB penetration and binding affinity, Ligand A is superior in almost all other critical ADME properties. Specifically, Ligand A has a much lower DILI risk, lower microsomal clearance, a longer half-life, and a significantly lower TPSA. Given the GPCR-specific priorities, the lower TPSA and improved safety profile (DILI) of Ligand A are particularly important. The small difference in binding affinity (0.2 kcal/mol) is unlikely to outweigh the substantial ADME advantages of Ligand A.

Output:
0
2025-04-17 07:10:14,518 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (365.5 and 372.3 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (91.32) is slightly above the preferred <90 for CNS targets, while Ligand B (58.64) is well within the range. This favors Ligand B.

**3. logP:** Both ligands have good logP values (2.156 and 1.964), falling within the optimal 1-3 range.

**4. H-Bond Donors:** Ligand A has 3 HBD, which is acceptable. Ligand B has 1 HBD, also acceptable.

**5. H-Bond Acceptors:** Ligand A has 5 HBA, acceptable. Ligand B has 3 HBA, also acceptable.

**6. QED:** Both ligands have similar QED values (0.658 and 0.663), indicating good drug-likeness.

**7. DILI:** Ligand A (42.1%) has a slightly higher DILI risk than Ligand B (37.1%), but both are below the concerning 60% threshold.

**8. BBB:** This is a crucial parameter for a CNS target. Ligand A has a BBB percentile of 42.575%, while Ligand B has 89.531%. This is a *significant* advantage for Ligand B.

**9. Caco-2 Permeability:** Both have negative values, indicating poor permeability. However, the scale is not specified, so it's hard to interpret.

**10. Aqueous Solubility:** Both have negative values, indicating poor solubility. Again, the scale is not specified.

**11. hERG Inhibition:** Ligand A (0.083) has a very low hERG inhibition risk, slightly better than Ligand B (0.533).

**12. Microsomal Clearance:** Ligand A (18.778) has a higher microsomal clearance than Ligand B (3.195), suggesting lower metabolic stability. This favors Ligand B.

**13. In vitro Half-Life:** Ligand A (10.194) has a shorter half-life than Ligand B (-12.81), indicating faster metabolism. This favors Ligand B.

**14. P-gp Efflux:** Ligand A (0.11) has lower P-gp efflux liability than Ligand B (0.05), which is favorable for CNS penetration.

**15. Binding Affinity:** Ligand A (-8.0) has a slightly better binding affinity than Ligand B (-7.4), a difference of 0.6 kcal/mol. While a difference of >1.5kcal/mol is usually decisive, 0.6kcal/mol is less impactful given the other factors.

**Overall Assessment:**

Ligand B is the stronger candidate. Its significantly better BBB penetration (89.531% vs 42.575%) and improved metabolic stability (lower Cl_mic and longer t1/2) are critical advantages for a CNS-targeting GPCR ligand. While Ligand A has slightly better affinity and lower P-gp efflux, the difference in affinity is not substantial enough to outweigh the benefits of Ligand B's superior pharmacokinetic properties, especially BBB penetration. The slightly lower hERG risk of Ligand A is a minor benefit.

Output:
1
2025-04-17 07:10:14,518 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (369.799 and 368.543 Da) fall comfortably within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (46.84) is significantly better than Ligand B (58.64). For CNS targets, we want TPSA <= 90, and ideally closer to 60. Ligand A is much closer to this ideal.

**3. logP:** Both ligands have good logP values (3.151 and 2.442), falling within the optimal 1-3 range.

**4. H-Bond Donors:** Ligand A (0) is preferable to Ligand B (1). Fewer HBDs generally improve permeability.

**5. H-Bond Acceptors:** Both ligands have 4 HBA, which is acceptable (<=10).

**6. QED:** Both ligands have reasonable QED values (0.835 and 0.669), indicating good drug-like properties.

**7. DILI:** Ligand A (51.183) has a slightly higher DILI risk than Ligand B (15.083). This is a negative for Ligand A, but not a dealbreaker at this stage.

**8. BBB:** Ligand A (96.084) has a significantly higher BBB penetration percentile than Ligand B (77.821). This is *crucial* for a CNS target like DRD2.

**9. Caco-2 Permeability:** Ligand A (-4.531) is worse than Ligand B (-5.035), indicating lower intestinal absorption. However, for a CNS target, intestinal absorption is less critical than BBB penetration.

**10. Aqueous Solubility:** Ligand A (-4.188) is slightly worse than Ligand B (-3.086). Solubility is important, but not as critical as BBB for CNS drugs.

**11. hERG:** Both ligands have similar, low hERG inhibition liability (0.552 and 0.573).

**12. Microsomal Clearance:** Ligand B (55.004) has lower microsomal clearance than Ligand A (39.042), suggesting better metabolic stability.

**13. In vitro Half-Life:** Ligand A (-18.181) has a much worse in vitro half-life than Ligand B (-0.57). This is a significant negative for Ligand A.

**14. P-gp Efflux:** Ligand A (0.189) has lower P-gp efflux than Ligand B (0.111), which is desirable for CNS exposure.

**15. Binding Affinity:** Both ligands have very similar and excellent binding affinities (-8.4 and -8.1 kcal/mol). The difference is negligible.

**Overall Assessment:**

Ligand A excels in BBB penetration and P-gp efflux, which are paramount for CNS GPCR targets. However, it suffers from a higher DILI risk, poorer metabolic stability (higher Cl_mic, shorter t1/2), and lower Caco-2 permeability. Ligand B has better metabolic stability and a lower DILI risk, but significantly worse BBB penetration. Given the importance of CNS penetration for DRD2, the superior BBB score of Ligand A outweighs its other drawbacks.

Output:
0
2025-04-17 07:10:14,519 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (346.387 and 345.443 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (110.26) is higher than the preferred <90 for CNS targets, while Ligand B (73.64) is well within the desired range. This is a significant advantage for Ligand B.

**3. logP:** Both ligands have good logP values (2.236 and 1.722), falling within the optimal 1-3 range.

**4. H-Bond Donors:** Ligand A has 2 HBD, which is acceptable. Ligand B has 0, also acceptable.

**5. H-Bond Acceptors:** Ligand A has 6 HBA, within the limit of 10. Ligand B has 4, also within the limit.

**6. QED:** Both ligands have reasonable QED values (0.859 and 0.781), indicating good drug-like properties.

**7. DILI:** Ligand A has a DILI risk of 69.484, which is approaching the higher risk threshold (>60). Ligand B has a much lower DILI risk of 19.891, a significant advantage.

**8. BBB:** Ligand A has a BBB penetration of 62.97, which is below the desirable >70 for CNS targets. Ligand B has a BBB penetration of 73.905, exceeding the threshold. This is a major advantage for Ligand B.

**9. Caco-2 Permeability:** Ligand A (-4.904) and Ligand B (-4.31) both have negative values, which is unusual. It's difficult to interpret without knowing the scale, but lower values generally indicate poorer permeability.

**10. Aqueous Solubility:** Both ligands have negative solubility values (-3.357 and -2.306). Again, the scale is unknown, but lower values suggest poorer solubility.

**11. hERG Inhibition:** Ligand A (0.091) and Ligand B (0.581) both have low hERG inhibition liability, which is good.

**12. Microsomal Clearance:** Ligand A (33.374) has a higher microsomal clearance than Ligand B (18.871), suggesting lower metabolic stability.

**13. In vitro Half-Life:** Ligand A (-6.845) has a shorter in vitro half-life than Ligand B (-1.644).

**14. P-gp Efflux:** Ligand A (0.077) has lower P-gp efflux than Ligand B (0.053), which is slightly better for CNS exposure.

**15. Binding Affinity:** Both ligands have very similar binding affinities (-8.3 and -8.1 kcal/mol). The difference is minimal and unlikely to be decisive.

**Overall Assessment:**

Ligand B is the superior candidate. While both have acceptable MW, logP, QED, and affinity, Ligand B significantly outperforms Ligand A in crucial areas for a CNS-targeting GPCR ligand: TPSA, BBB penetration, and DILI risk. It also exhibits better metabolic stability (lower Cl_mic) and a longer in vitro half-life. The slightly higher P-gp efflux of Ligand B is a minor drawback compared to the substantial advantages it possesses.

Output:
1
2025-04-17 07:10:14,519 - INFO - Reasoning:

Let's analyze Ligand A and Ligand B for their potential as DRD2 drug candidates, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (348.491 and 352.435 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (74.33) is significantly better than Ligand B (96.69). For CNS targets, TPSA should be <= 90, so Ligand A is preferable.

**3. logP:** Ligand A (2.053) is optimal (1-3). Ligand B (0.411) is quite low, potentially hindering permeation.

**4. H-Bond Donors:** Both ligands have 2 HBD, which is within the acceptable limit of <=5.

**5. H-Bond Acceptors:** Ligand A has 4 HBA, and Ligand B has 6. Both are within the acceptable limit of <=10.

**6. QED:** Both ligands have similar QED values (0.716 and 0.741), indicating good drug-likeness.

**7. DILI:** Ligand A (21.908) has a much lower DILI risk than Ligand B (47.15). This is a significant advantage for Ligand A.

**8. BBB:** Ligand A (52.036) has a better BBB percentile than Ligand B (30.128). While both are below the desirable >70 for CNS targets, Ligand A is closer.

**9. Caco-2 Permeability:** Ligand A (-5.107) has slightly better Caco-2 permeability than Ligand B (-4.927).

**10. Aqueous Solubility:** Both ligands have very poor aqueous solubility (-1.346 and -1.122). This could be a formulation challenge for both.

**11. hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.47 and 0.142).

**12. Microsomal Clearance:** Ligand A (19.449) has a lower microsomal clearance than Ligand B (22.792), suggesting better metabolic stability.

**13. In vitro Half-Life:** Ligand A (59.219) has a significantly longer in vitro half-life than Ligand B (7.934).

**14. P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.017 and 0.016).

**15. Binding Affinity:** Both ligands have excellent binding affinity (-8.1 and -8.0 kcal/mol). The difference is minimal.

**Overall Assessment:**

Ligand A is clearly superior. It has a better TPSA, logP, DILI risk, BBB penetration, Caco-2 permeability, microsomal clearance, and in vitro half-life. While both have poor solubility, the other advantages of Ligand A outweigh this drawback. The similar binding affinities mean that the improved ADME properties of Ligand A make it the more promising drug candidate.

Output:
1
2025-04-17 07:10:14,519 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B against the provided guidelines, prioritizing GPCR-specific properties (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (350.459 Da) is slightly lower, which could be beneficial for permeability.

**TPSA:** Ligand A (67.87) is better than Ligand B (87.66). For CNS targets, we want TPSA <= 90, both are within this range, but A is closer to the ideal.

**logP:** Ligand A (1.503) is optimal, while Ligand B (0.076) is quite low. Low logP can hinder membrane permeability. This is a significant advantage for Ligand A.

**H-Bond Donors/Acceptors:** Both have acceptable HBD (1) and HBA (A: 4, B: 6) counts.

**QED:** Both ligands have similar, good QED scores (A: 0.763, B: 0.706).

**DILI:** Ligand A (31.718) has a much lower DILI risk than Ligand B (67.739), indicating better predicted liver safety.

**BBB:** Both ligands have good BBB penetration (A: 63.358, B: 67.158), but neither exceeds the desirable >70 threshold.

**Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and suggests a potential issue with the modeling or data. However, the magnitude is similar.

**Aqueous Solubility:** Both have negative solubility values, also unusual. Again, the magnitude is similar.

**hERG Inhibition:** Both ligands show very low hERG inhibition risk (A: 0.232, B: 0.156).

**Microsomal Clearance:** Ligand A (45.418) has higher predicted clearance than Ligand B (21.012), suggesting lower metabolic stability.

**In vitro Half-Life:** Ligand B (-25.354) has a negative half-life, which is not physically possible and indicates a problem with the data. Ligand A (9.839) is reasonable.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (A: 0.05, B: 0.015).

**Binding Affinity:** Ligand B (-6.7 kcal/mol) has significantly stronger binding affinity than Ligand A (0.0 kcal/mol). This is a substantial advantage for Ligand B.

**Overall Assessment:**

Ligand A has advantages in logP, TPSA, DILI, and a reasonable half-life. However, the *dramatic* difference in binding affinity (B is -6.7 vs. A is 0.0) is the most important factor. While Ligand A has better ADME properties overall, the lack of significant binding makes it unlikely to be effective. Ligand B's strong binding, despite its lower logP and higher DILI, is more likely to translate to efficacy. The negative half-life for B is a red flag, but could be an artifact of the prediction.

Output:
1
2025-04-17 07:10:14,519 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (352.475 Da) is slightly lower, which *could* be beneficial for permeability, but both are acceptable.

**TPSA:** Ligand A (59.08) is excellent for CNS penetration, well below the 90 A^2 threshold. Ligand B (78.87) is still reasonable, but less optimal.

**logP:** Both ligands have good logP values (A: 1.679, B: 2.004), falling within the 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A (0 HBD, 4 HBA) is better than Ligand B (2 HBD, 5 HBA) in terms of maintaining a balance between solubility and permeability.

**QED:** Both have similar and good QED scores (A: 0.775, B: 0.779), indicating good drug-like properties.

**DILI:** Ligand A (30.903) has a significantly lower DILI risk than Ligand B (50.136), which is a major advantage.

**BBB:** Ligand A (84.8) has a much higher BBB penetration percentile than Ligand B (65.917). This is *critical* for a CNS target like DRD2.

**Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and suggests a potential issue with the data or modeling. However, the values are similar (-4.033 for A, -4.983 for B), so this isn't a major differentiator.

**Aqueous Solubility:** Both have negative solubility values, again suggesting a potential data issue. Ligand B (-3.718) is slightly worse than Ligand A (-1.532).

**hERG:** Both ligands have low hERG inhibition liability (A: 0.343, B: 0.777), which is positive.

**Microsomal Clearance:** Ligand A (30.592) has a higher microsomal clearance than Ligand B (14.276), indicating faster metabolism and potentially lower in vivo exposure.

**In vitro Half-Life:** Ligand B (20.675 hours) has a significantly longer half-life than Ligand A (-11.713 hours), which is a clear advantage.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (A: 0.085, B: 0.181).

**Binding Affinity:** Ligand B (-8.6 kcal/mol) has a slightly better binding affinity than Ligand A (-7.7 kcal/mol). This 0.9 kcal/mol difference is significant, but not overwhelming.

**Overall Assessment:**

Ligand A is clearly superior due to its significantly better BBB penetration (84.8 vs 65.917), lower DILI risk (30.903 vs 50.136), and more favorable TPSA (59.08 vs 78.87). While Ligand B has a slightly better binding affinity and longer half-life, the CNS-related properties are paramount for a DRD2 ligand. The lower clearance of Ligand B is a plus, but can potentially be addressed through structural modifications. The issues with Caco-2 and solubility are concerning for both, but the other advantages of A outweigh these.

Output:
0
2025-04-17 07:10:14,520 - INFO - Batch 342 complete. Total preferences: 5472
2025-04-17 07:10:14,520 - INFO - Processing batch 343/512...
2025-04-17 07:10:56,632 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (346.435 and 342.527 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (123.56) is excellent, falling below the 90 A^2 threshold for CNS targets. Ligand B (32.34) is also very good, well below the threshold.

**logP:** Ligand A (1.028) is at the lower end of the optimal 1-3 range, which *could* be a minor issue for permeability. Ligand B (3.584) is slightly above the optimal range, potentially raising concerns about solubility and off-target effects, but still acceptable.

**H-Bond Donors/Acceptors:** Ligand A has 3 HBD and 5 HBA, which are both within acceptable limits. Ligand B has 1 HBD and 2 HBA, also good.

**QED:** Both ligands have good QED scores (0.546 and 0.717), indicating good drug-like properties.

**DILI:** Ligand A (36.758) has a low DILI risk, which is favorable. Ligand B (9.771) has an even *lower* DILI risk, which is excellent.

**BBB:** This is crucial for a CNS target. Ligand A (41.838) is moderately good, but could be better. Ligand B (91.314) is *very* good, exceeding the >70% threshold. This is a significant advantage.

**Caco-2 Permeability:** Ligand A (-5.751) has poor Caco-2 permeability. Ligand B (-4.975) also has poor Caco-2 permeability.

**Aqueous Solubility:** Ligand A (-1.691) has poor aqueous solubility. Ligand B (-4.798) also has poor aqueous solubility.

**hERG Inhibition:** Ligand A (0.13) has very low hERG inhibition risk, excellent. Ligand B (0.893) has a slightly higher, but still acceptable, hERG risk.

**Microsomal Clearance:** Ligand A (0.463) has very low microsomal clearance, indicating good metabolic stability. Ligand B (57.809) has high microsomal clearance, indicating poor metabolic stability.

**In vitro Half-Life:** Ligand A (12.8) has a reasonable half-life. Ligand B (5.157) has a shorter half-life, which is less desirable.

**P-gp Efflux:** Ligand A (0.016) has very low P-gp efflux, which is excellent for CNS penetration. Ligand B (0.363) has moderate P-gp efflux, which is less favorable.

**Binding Affinity:** Ligand B (-7.4 kcal/mol) has a slightly better binding affinity than Ligand A (-7.1 kcal/mol), although the difference is small.

**Overall Assessment:**

Ligand B is the stronger candidate. While both have acceptable MW, QED, and H-bond characteristics, Ligand B excels in the critical areas for a CNS-targeting GPCR: BBB penetration (91.314% vs 41.838%), P-gp efflux (lower), and has a slightly better binding affinity. Ligand A has better metabolic stability and lower hERG risk, but the superior CNS penetration of Ligand B is more important for this target. The poor Caco-2 and solubility of both compounds are a concern, but can be addressed with formulation strategies.

Output:
1
2025-04-17 07:10:56,633 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (351.407 and 353.463 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (105.56) is better than Ligand B (121.52). For CNS targets, we want TPSA <= 90, so A is closer to that target.

**3. logP:** Ligand A (0.869) is slightly better than Ligand B (0.593). Both are a bit low, potentially hindering permeation, but not drastically.

**4. H-Bond Donors:** Ligand A (2) is preferable to Ligand B (4). Lower HBD generally improves permeability.

**5. H-Bond Acceptors:** Ligand A (7) is preferable to Ligand B (4). Lower HBA generally improves permeability.

**6. QED:** Ligand A (0.783) is better than Ligand B (0.485), indicating a more drug-like profile.

**7. DILI:** Ligand B (13.3) is significantly better than Ligand A (75.649), indicating a much lower risk of drug-induced liver injury. This is a major advantage for Ligand B.

**8. BBB:** Ligand A (60.76) is better than Ligand B (34.626). For a CNS target like DRD2, a BBB percentile > 70 is desirable. Ligand A is closer, but still not ideal.

**9. Caco-2 Permeability:** Ligand A (-4.541) is better than Ligand B (-5.775), indicating better intestinal absorption.

**10. Aqueous Solubility:** Ligand A (-2.936) is better than Ligand B (-1.757), suggesting better solubility.

**11. hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.136 and 0.11).

**12. Microsomal Clearance:** Ligand B (0.955) is much better than Ligand A (34.44), indicating significantly improved metabolic stability.

**13. In vitro Half-Life:** Ligand B (8.007) is much better than Ligand A (-12.585), suggesting a longer half-life.

**14. P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.017 and 0.035).

**15. Binding Affinity:** Ligand B (-8.0) has a slightly better binding affinity than Ligand A (-7.4). While the difference is not huge, it's still a positive for Ligand B.

**Overall Assessment:**

Ligand B excels in ADME properties (DILI, Cl_mic, t1/2) and has slightly better binding affinity. Ligand A has a better BBB score and slightly better solubility and Caco-2 permeability. However, the significantly lower DILI risk and improved metabolic stability of Ligand B are critical advantages, especially considering the CNS target. While Ligand A's BBB is better, it's still not in the ideal range, and the other ADME liabilities are substantial. The small advantage in affinity isn't enough to overcome these issues.

Output:
1
2025-04-17 07:10:56,633 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (356.813 and 349.479 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (64.16) is excellent, well below the 90 A^2 threshold for CNS targets. Ligand B (72.28) is still reasonable, but less optimal.

**logP:** Ligand A (3.452) is at the upper end of the optimal range (1-3), while Ligand B (1.759) is at the lower end. For a CNS target, a slightly higher logP is often preferred for BBB penetration, but both are acceptable.

**H-Bond Donors/Acceptors:** Ligand A (0 HBD, 5 HBA) and Ligand B (1 HBD, 6 HBA) both have reasonable numbers of H-bond donors and acceptors, within the guidelines.

**QED:** Both ligands have similar QED values (0.721 and 0.735), indicating good drug-like properties.

**DILI:** Ligand A (84.219) has a higher DILI risk than Ligand B (34.781). This is a significant negative for Ligand A.

**BBB:** Ligand B (77.472) has a better BBB percentile than Ligand A (68.166), which is crucial for a CNS target like DRD2.

**Caco-2 Permeability:** Ligand A (-4.952) has poor Caco-2 permeability, while Ligand B (-5.144) is also poor, but slightly better.

**Aqueous Solubility:** Ligand A (-3.903) has poor aqueous solubility, while Ligand B (-1.35) is also poor, but better than A.

**hERG:** Both ligands have very low hERG inhibition liability (0.33 and 0.165), which is excellent.

**Microsomal Clearance:** Ligand B (33.699) has lower microsomal clearance than Ligand A (46.255), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand B (27.582) has a significantly longer in vitro half-life than Ligand A (7.509).

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.277 and 0.067), which is favorable for CNS penetration.

**Binding Affinity:** Ligand B (-7.2 kcal/mol) has a stronger binding affinity than Ligand A (-9.7 kcal/mol). This is a substantial difference.

**Overall Assessment:**

Ligand B is the superior candidate. While both have poor Caco-2 and solubility, Ligand B excels in the most critical areas for a CNS-targeting GPCR ligand: BBB penetration, metabolic stability (lower Cl_mic, longer t1/2), lower DILI risk, and significantly stronger binding affinity. The slightly lower logP of Ligand B is less concerning given its superior BBB score. Ligand A's higher DILI risk and weaker affinity are significant drawbacks.

Output:
1
2025-04-17 07:10:56,633 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B based on the provided guidelines, prioritizing GPCR-specific properties (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (363.483 and 348.447 Da) fall within the ideal 200-500 Da range.

**TPSA:** Both ligands (84.23 and 87.46) are below the 90 A^2 threshold desirable for CNS targets, which is good.

**logP:** Ligand A (2.925) is optimal (1-3), while Ligand B (0.737) is slightly below the ideal range, potentially hindering permeation.

**H-Bond Donors/Acceptors:** Both ligands have 2 HBD and 5 HBA, which are within acceptable limits.

**QED:** Both ligands have QED values above 0.6, indicating good drug-likeness.

**DILI:** Ligand A (63.978) has a higher DILI risk than Ligand B (26.095). This is a significant negative for Ligand A.

**BBB:** Ligand B (53.703) has a significantly better BBB penetration percentile than Ligand A (42.032). This is crucial for a CNS target like DRD2.

**Caco-2 Permeability:** Ligand A (-5.224) has worse Caco-2 permeability than Ligand B (-4.81), although both are negative values indicating low permeability.

**Aqueous Solubility:** Ligand A (-2.863) has worse aqueous solubility than Ligand B (-1.383).

**hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.291 and 0.1).

**Microsomal Clearance:** Ligand B (31.472) has lower microsomal clearance than Ligand A (67.971), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand B (-4.577) has a negative half-life, which is unusual. Ligand A (37.492) has a more reasonable half-life.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.148 and 0.044).

**Binding Affinity:** Ligand A (-8.5 kcal/mol) has a significantly stronger binding affinity than Ligand B (-7.0 kcal/mol). This is a substantial advantage.

**Overall Assessment:**

While Ligand A boasts a superior binding affinity, its significantly higher DILI risk, lower BBB penetration, and worse solubility are major drawbacks. Ligand B, despite slightly weaker binding, presents a much more favorable ADME-Tox profile, particularly its excellent BBB penetration and lower DILI risk. Given the CNS target (DRD2), BBB penetration is paramount. The 1.5 kcal/mol difference in binding affinity can potentially be overcome with further optimization of Ligand B, whereas mitigating the ADME liabilities of Ligand A would likely be more challenging.

Output:
1
2025-04-17 07:10:56,633 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (340.379 and 346.431 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (89.87) is excellent, below the 90 threshold for CNS targets. Ligand B (93.7) is slightly higher but still acceptable.

**3. logP:** Ligand A (2.686) is optimal (1-3). Ligand B (1.663) is a bit low, potentially hindering permeability.

**4. H-Bond Donors:** Both ligands have 3-4 HBD, which is within the acceptable limit of <=5.

**5. H-Bond Acceptors:** Both ligands have 4 HBA, well below the acceptable limit of <=10.

**6. QED:** Both ligands have QED values above 0.6, indicating good drug-likeness.

**7. DILI:** Ligand A (60.527) has a higher DILI risk than Ligand B (32.61). This is a significant negative for Ligand A.

**8. BBB:** Ligand B (68.748) has a significantly better BBB penetration percentile than Ligand A (33.928). This is crucial for a CNS target like DRD2.

**9. Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and suggests a potential issue with the data or modeling. However, the values are similar, so this isn't a major differentiator.

**10. Aqueous Solubility:** Both have negative solubility values, again suggesting potential data issues. The values are similar.

**11. hERG Inhibition:** Both have low hERG inhibition risk (0.461 and 0.421).

**12. Microsomal Clearance:** Ligand A (-17.402) has a more negative (lower) clearance, indicating better metabolic stability than Ligand B (-12.785).

**13. In vitro Half-Life:** Ligand A (-22.067) has a more negative (longer) half-life, indicating better stability than Ligand B (-5.276).

**14. P-gp Efflux:** Both have very low P-gp efflux liability (0.042 and 0.007).

**15. Binding Affinity:** Ligand B (-9.6 kcal/mol) has a slightly better binding affinity than Ligand A (-8.7 kcal/mol). While the difference isn't huge, it's enough to be considered.

**Overall Assessment:**

Ligand B is the more promising candidate. Its significantly better BBB penetration is a major advantage for a CNS target. While Ligand A has better metabolic stability and half-life, the lower BBB penetration and higher DILI risk are concerning. The slightly better affinity of Ligand B further supports its selection. The similar Caco-2 and solubility values are less impactful given the other differences.

Output:
1
2025-04-17 07:10:56,634 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 drug candidates, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (408.267 Da) is slightly higher, but acceptable. Ligand B (351.447 Da) is also good.

**TPSA:** Ligand A (47.56) is excellent, well below the 90 A^2 threshold for CNS targets. Ligand B (95.67) is higher, but still potentially acceptable, though less ideal for CNS penetration.

**logP:** Ligand A (4.376) is slightly high, potentially leading to solubility issues or off-target interactions. Ligand B (1.225) is quite low, which could hinder membrane permeability.

**H-Bond Donors/Acceptors:** Ligand A (HBD=1, HBA=3) is favorable. Ligand B (HBD=2, HBA=5) is also acceptable.

**QED:** Both ligands have similar QED values (A: 0.817, B: 0.734), indicating good drug-like properties.

**DILI:** Ligand A (70.26) has a moderate DILI risk. Ligand B (32.377) has a very low DILI risk, which is a significant advantage.

**BBB:** Ligand A (78.868) shows good BBB penetration, desirable for a CNS target. Ligand B (32.532) has poor predicted BBB penetration, a major drawback.

**Caco-2 Permeability:** Ligand A (-4.474) has poor Caco-2 permeability. Ligand B (-5.098) also has poor Caco-2 permeability.

**Aqueous Solubility:** Ligand A (-5.449) has poor aqueous solubility. Ligand B (-1.657) has slightly better, but still poor, aqueous solubility.

**hERG Inhibition:** Ligand A (0.821) has a slightly elevated hERG risk. Ligand B (0.202) has a very low hERG risk, a significant advantage.

**Microsomal Clearance:** Ligand A (76.238) has moderate microsomal clearance. Ligand B (17.553) has low microsomal clearance, indicating better metabolic stability.

**In vitro Half-Life:** Ligand A (77.311) has a good in vitro half-life. Ligand B (9.525) has a very short in vitro half-life, which is a concern.

**P-gp Efflux:** Ligand A (0.693) has moderate P-gp efflux. Ligand B (0.093) has very low P-gp efflux, which is favorable for CNS penetration.

**Binding Affinity:** Ligand A (-9.6 kcal/mol) has significantly stronger binding affinity than Ligand B (-8.3 kcal/mol). This is a substantial advantage, potentially outweighing some of its other drawbacks.

**Overall Assessment:**

Ligand A excels in binding affinity and BBB penetration, crucial for a CNS GPCR target. However, it suffers from high logP, poor Caco-2 permeability, poor solubility, moderate DILI risk, and moderate P-gp efflux.

Ligand B has a better safety profile (lower DILI, hERG, and P-gp efflux) and better metabolic stability, but its low logP and poor BBB penetration are major concerns for a CNS target. The significantly weaker binding affinity is also a substantial disadvantage.

Given the importance of binding affinity for GPCRs and the need for CNS penetration, **Ligand A is the more promising candidate despite its drawbacks.** The strong binding affinity could be optimized with further modifications to address the solubility and permeability issues. The poor BBB of Ligand B is a difficult property to improve substantially.

Output:
1
2025-04-17 07:10:56,634 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (350.39 Da) is slightly lower, which is generally favorable for permeability. Ligand B (388.421 Da) is also acceptable.

**2. TPSA:** Ligand A (89.31) is excellent, falling well below the 90 Angstroms threshold for CNS targets. Ligand B (95.42) is still reasonable but less optimal, potentially hindering BBB penetration.

**3. logP:** Ligand A (3.553) is slightly above the optimal range (1-3) but still acceptable. Ligand B (1.299) is on the lower side, potentially leading to poor membrane permeability.

**4. H-Bond Donors:** Ligand A (1) is good. Ligand B (2) is also acceptable.

**5. H-Bond Acceptors:** Ligand A (4) is good. Ligand B (7) is higher, but still within the acceptable limit of 10.

**6. QED:** Both ligands have good QED scores (Ligand A: 0.601, Ligand B: 0.805), indicating drug-like properties. Ligand B is slightly better.

**7. DILI:** Ligand A (53.819) has a lower DILI risk than Ligand B (77.743), which is preferable.

**8. BBB:** This is a critical parameter for CNS targets. Ligand A (81.737) has a significantly better BBB percentile than Ligand B (49.011).

**9. Caco-2 Permeability:** Ligand A (-4.436) has poor Caco-2 permeability. Ligand B (-5.242) is even worse. Both are unfavorable.

**10. Aqueous Solubility:** Ligand A (-4.227) has poor solubility. Ligand B (-2.742) is slightly better, but still unfavorable.

**11. hERG Inhibition:** Both ligands have low hERG inhibition risk (Ligand A: 0.227, Ligand B: 0.147).

**12. Microsomal Clearance:** Ligand A (38.126) has higher clearance than Ligand B (-2.926), suggesting lower metabolic stability. Ligand B is much more metabolically stable.

**13. In vitro Half-Life:** Ligand A (-0.158) has a very short half-life. Ligand B (9.682) has a much longer half-life, which is desirable.

**14. P-gp Efflux:** Both ligands exhibit low P-gp efflux (Ligand A: 0.268, Ligand B: 0.069). Ligand B is slightly better.

**15. Binding Affinity:** Ligand A (-9.1 kcal/mol) has a significantly stronger binding affinity than Ligand B (-7.3 kcal/mol). This is a substantial advantage.

**Overall Assessment:**

While Ligand B has better metabolic stability (lower Cl_mic, longer t1/2) and a slightly better QED, Ligand A's superior binding affinity (-9.1 vs -7.3 kcal/mol) and significantly better BBB penetration (81.7 vs 49.0) are crucial for a CNS-targeting GPCR like DRD2. The lower DILI risk for Ligand A is also a positive factor. The poor Caco-2 and solubility of Ligand A are concerns, but these can potentially be addressed through formulation strategies. The strong binding affinity of Ligand A is likely to outweigh these drawbacks.

Output:
1
2025-04-17 07:10:56,634 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (349.435 and 370.559 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (100.35) is slightly above the preferred <90 for CNS targets, but still reasonable. Ligand B (49.85) is excellent, well below 90.

**3. logP:** Ligand A (0.2) is quite low, potentially hindering membrane permeability. Ligand B (2.783) is within the optimal 1-3 range. This is a significant advantage for Ligand B.

**4. H-Bond Donors:** Ligand A (2) is acceptable. Ligand B (0) is also good, potentially improving permeability.

**5. H-Bond Acceptors:** Ligand A (6) is acceptable. Ligand B (4) is also good.

**6. QED:** Both ligands have similar QED values (0.764 and 0.721), indicating good drug-like properties.

**7. DILI:** Ligand A (42.807) has a slightly higher DILI risk than Ligand B (25.475), but both are below the concerning threshold of 60.

**8. BBB:** Both ligands have good BBB penetration (60.527% and 69.407%), but Ligand B is better. A value >70 is desirable, but both are reasonably good.

**9. Caco-2:** Ligand A (-5.169) has poor Caco-2 permeability, while Ligand B (-4.615) is slightly better, but still poor.

**10. Solubility:** Both ligands have poor aqueous solubility (-1.744 and -2.28). This could pose formulation challenges.

**11. hERG:** Both ligands have very low hERG inhibition risk (0.233 and 0.297).

**12. Cl_mic:** Ligand A (2.273) has lower microsomal clearance, suggesting better metabolic stability than Ligand B (53.592).

**13. t1/2:** Ligand A (-9.169) has a negative in vitro half-life, which is not possible. This is a red flag. Ligand B (12.292) has a reasonable half-life.

**14. Pgp:** Both ligands have very low P-gp efflux liability (0.038 and 0.206), which is favorable for CNS penetration.

**15. Binding Affinity:** Ligand A (-8.5 kcal/mol) has significantly better binding affinity than Ligand B (0.0 kcal/mol). This is a substantial advantage, potentially outweighing some of its ADME drawbacks.

**Overall Assessment:**

Ligand A has a much stronger binding affinity, which is a critical factor for GPCR ligands. However, its extremely low logP and negative in vitro half-life are major concerns. Ligand B has better ADME properties (logP, TPSA, BBB, Cl_mic, t1/2), but its binding affinity is very weak.

Considering the GPCR-specific priorities, BBB is important, and Ligand B is slightly better. However, the substantial difference in binding affinity (-8.5 vs 0.0 kcal/mol) is likely to be decisive. While Ligand A's low logP is a concern, it might be addressable through prodrug strategies or formulation techniques. The negative half-life is a significant issue, but could be a data error.

Output:
1
2025-04-17 07:10:56,634 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (337.423 Da) is slightly preferred due to being closer to the lower end, potentially aiding permeability.

**TPSA:** Ligand A (47.36) is excellent, well below the 90 A^2 threshold for CNS targets. Ligand B (112.81) is higher, but still potentially acceptable, though less ideal.

**logP:** Ligand A (2.809) is optimal (1-3). Ligand B (-0.148) is significantly lower, which could hinder membrane permeability and brain penetration. This is a major drawback for a CNS target.

**H-Bond Donors/Acceptors:** Ligand A (0 HBD, 4 HBA) is favorable. Ligand B (2 HBD, 5 HBA) is also acceptable, but slightly less optimal.

**QED:** Both ligands have similar QED values (0.601 and 0.549), indicating good drug-likeness.

**DILI:** Ligand A (48.817) has a moderate DILI risk, but is acceptable. Ligand B (25.204) has a very low DILI risk, which is excellent.

**BBB:** Ligand A (84.762) has excellent BBB penetration potential. Ligand B (48.972) is considerably lower, raising concerns about CNS exposure.

**Caco-2 Permeability:** Ligand A (-4.964) is poor. Ligand B (-5.522) is also poor.

**Aqueous Solubility:** Ligand A (-2.169) is poor. Ligand B (-0.511) is slightly better, but still poor.

**hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.663 and 0.089).

**Microsomal Clearance:** Ligand A (80.305) has higher clearance than Ligand B (41.524), suggesting lower metabolic stability.

**In vitro Half-Life:** Ligand B (-36.317) has a significantly longer half-life than Ligand A (-11.528).

**P-gp Efflux:** Ligand A (0.686) has moderate P-gp efflux. Ligand B (0.002) has very low P-gp efflux, which is highly desirable for CNS penetration.

**Binding Affinity:** Ligand A (-8.4 kcal/mol) has a significantly stronger binding affinity than Ligand B (-6.4 kcal/mol). This is a substantial advantage.

**Overall Assessment:**

Despite Ligand B having a better DILI score, P-gp efflux, and half-life, Ligand A is the more promising candidate. The crucial factors are the significantly stronger binding affinity (-8.4 vs -6.4 kcal/mol) and the excellent BBB penetration (84.762). The lower logP of Ligand B is a major concern for a CNS-targeting drug, as it will likely struggle to cross the blood-brain barrier. While Ligand A's Caco-2 permeability and solubility are poor, these can potentially be addressed through formulation strategies. The affinity difference is large enough to outweigh the ADME liabilities of Ligand A, especially given the importance of potency for GPCR ligands.

Output:
1
2025-04-17 07:10:56,634 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 drug candidates, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight (MW):** Both ligands (355.507 and 343.475 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (35.58) is excellent, well below the 90 A^2 threshold for CNS targets. Ligand B (54.26) is still reasonable, but higher and less favorable.

**3. logP:** Both ligands (3.138 and 2.69) are within the optimal 1-3 range.

**4. H-Bond Donors (HBD):** Ligand A (1) and Ligand B (0) are both acceptable, below the limit of 5.

**5. H-Bond Acceptors (HBA):** Ligand A (2) and Ligand B (5) are both acceptable, below the limit of 10.

**6. QED:** Both ligands (0.808 and 0.809) have excellent drug-likeness scores.

**7. DILI:** Both ligands (47.034 and 48.546) have low DILI risk, well below the 60 threshold.

**8. BBB:** Both ligands have good BBB penetration (74.292 and 79.139), exceeding the 70% desirable level for CNS targets. Ligand B is slightly better here.

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.824 and -4.723), which is unusual and suggests poor permeability. This is a significant concern.

**10. Aqueous Solubility:** Both ligands have negative solubility values (-4.043 and -2.83), which is also a concern. Poor solubility can hinder bioavailability.

**11. hERG Inhibition:** Both ligands have low hERG inhibition risk (0.881 and 0.53).

**12. Microsomal Clearance:** Ligand A (77.03) is better than Ligand B (87.403), indicating better metabolic stability.

**13. In vitro Half-Life:** Ligand A (15.302) has a slightly longer half-life than Ligand B (19.68).

**14. P-gp Efflux:** Both ligands have low P-gp efflux liability (0.579 and 0.344), which is favorable for CNS penetration. Ligand B is better here.

**15. Binding Affinity:** Both ligands have very good binding affinity (-8.8 and -8.5 kcal/mol). Ligand A has a slight advantage (-8.8 vs -8.5).

**Overall Assessment:**

Both ligands have excellent binding affinity and drug-like properties (QED, DILI, BBB). However, the negative Caco-2 and solubility values are major red flags. Considering the GPCR-specific priorities, TPSA is important, and Ligand A has a lower TPSA. Ligand A also has better metabolic stability (lower Cl_mic) and a slightly longer half-life. The affinity difference, while present, is relatively small. Given the issues with permeability and solubility, the slightly better ADME profile of Ligand A makes it the more promising candidate.

Output:
0
2025-04-17 07:10:56,635 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B based on the provided guidelines, prioritizing GPCR-specific properties (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (348.422 and 353.507 Da) fall within the ideal range of 200-500 Da.

**TPSA:** Ligand A (67.23) is better than Ligand B (70.67). Both are below the 90 A^2 threshold desirable for CNS targets, but A is closer to the optimal range.

**logP:** Both ligands have a logP of around 1.5, which is optimal.

**H-Bond Donors/Acceptors:** Ligand A has 1 HBD and 4 HBA, while Ligand B has 2 HBD and 4 HBA. Both are within acceptable limits.

**QED:** Ligand A (0.822) has a significantly better QED score than Ligand B (0.694), indicating a more drug-like profile.

**DILI:** Ligand B (5.235) has a much lower DILI risk than Ligand A (51.648), which is a significant advantage.

**BBB:** Ligand A (82.435) has a better BBB penetration percentile than Ligand B (72.043), which is crucial for CNS targets like DRD2.

**Caco-2 Permeability:** Both have negative values, which is unusual, but A (-4.761) is slightly better than B (-4.887).

**Aqueous Solubility:** Both have negative values, which is unusual. A (-2.581) is slightly better than B (-1.682).

**hERG:** Both ligands have low hERG inhibition liability (0.41 and 0.443), indicating low cardiotoxicity risk.

**Microsomal Clearance:** Ligand B (25.256) has a slightly higher microsomal clearance than Ligand A (22.258), meaning A is more metabolically stable.

**In vitro Half-Life:** Ligand A (-7.667) has a significantly longer in vitro half-life than Ligand B (2.621).

**P-gp Efflux:** Ligand A (0.128) has a lower P-gp efflux liability than Ligand B (0.005), which is favorable for CNS penetration.

**Binding Affinity:** Both ligands have very similar binding affinities (-7.7 and -7.5 kcal/mol), which are both excellent. The difference is less than the 1.5 kcal/mol threshold.

**Overall Assessment:**

Ligand A excels in BBB penetration, QED, in vitro half-life, and P-gp efflux. Ligand B has a significantly better DILI score. Considering the target is a CNS GPCR (DRD2), BBB penetration is paramount. While DILI is important, the strong BBB score and better overall drug-likeness of Ligand A outweigh the slightly higher DILI risk. The similar binding affinities make the ADME properties the deciding factor.

Output:
1
2025-04-17 07:10:56,635 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (366.849 and 383.583 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (95.42) is higher than Ligand B (52.65). For a CNS target like DRD2, TPSA should be <=90. Ligand A is slightly above this, while Ligand B is well within the desired range. This favors Ligand B.

**3. logP:** Both ligands have similar logP values (1.426 and 1.45), falling within the optimal 1-3 range.

**4. H-Bond Donors:** Ligand A has 2 HBD, and Ligand B has 1. Both are acceptable (<=5).

**5. H-Bond Acceptors:** Both ligands have 5 HBA, which is acceptable (<=10).

**6. QED:** Both ligands have similar QED values (0.712 and 0.704), indicating good drug-like properties (>=0.5).

**7. DILI:** Ligand A (50.95) has a higher DILI risk than Ligand B (22.257). Lower is better, so Ligand B is favored.

**8. BBB:** Both ligands have reasonably good BBB penetration (35.983 and 50.679). However, for a CNS target, >70 is desirable. Ligand B is closer to this threshold.

**9. Caco-2 Permeability:** Ligand A (-4.919) has worse Caco-2 permeability than Ligand B (-5.435). Lower values are less desirable.

**10. Aqueous Solubility:** Both have poor aqueous solubility (-2.042 and -2.262). This is a potential issue for both, but not a deciding factor.

**11. hERG Inhibition:** Both ligands have low hERG inhibition risk (0.243 and 0.37).

**12. Microsomal Clearance:** Ligand A (33.24) has higher microsomal clearance than Ligand B (20.061). Lower clearance is preferred for metabolic stability, favoring Ligand B.

**13. In vitro Half-Life:** Ligand B (7.254) has a significantly longer in vitro half-life than Ligand A (1.842). This is a significant advantage for Ligand B.

**14. P-gp Efflux:** Both ligands have low P-gp efflux liability (0.043 and 0.061).

**15. Binding Affinity:** Ligand B (-7.7 kcal/mol) has slightly better binding affinity than Ligand A (-7.5 kcal/mol). While both are good, the 0.2 kcal/mol difference is enough to be considered, especially given the other favorable properties of Ligand B.

**Overall Assessment:**

Ligand B consistently outperforms Ligand A across several crucial parameters for a CNS-targeting GPCR ligand. It has a lower TPSA, lower DILI risk, better BBB penetration, lower microsomal clearance, a longer half-life, and slightly better binding affinity. While both have poor solubility, the other advantages of Ligand B make it a more promising drug candidate.

Output:
1
2025-04-17 07:10:56,635 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B based on the provided guidelines, prioritizing GPCR-specific properties (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (340.427) is slightly better positioned.

**TPSA:** Ligand A (67.23) is significantly better than Ligand B (107.53). For CNS targets, we want TPSA <= 90, and A is closer to this threshold.

**logP:** Ligand A (1.827) is optimal (1-3), while Ligand B (-0.352) is below 1, potentially hindering permeation.

**H-Bond Donors/Acceptors:** Ligand A (HBD=1, HBA=5) is preferable to Ligand B (HBD=4, HBA=4) as it has a lower number of HBDs. Both are within acceptable limits.

**QED:** Ligand A (0.902) is excellent, indicating strong drug-likeness. Ligand B (0.35) is poor.

**DILI:** Ligand A (61.07) has a moderate risk, while Ligand B (33.773) has a lower risk.

**BBB:** Ligand A (75.107) is good for CNS penetration, exceeding the 70% threshold. Ligand B (40.326) is significantly lower and less desirable.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.983 and -4.966), which is unusual and suggests poor permeability. However, these values are on a scale where negative values are possible, and direct comparison is difficult without knowing the scale's specifics.

**Aqueous Solubility:** Both ligands have negative solubility values (-3.456 and -2.069), again suggesting poor solubility. Similar to Caco-2, the scale is unknown.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.592 and 0.587).

**Microsomal Clearance:** Ligand A (48.176) has higher clearance than Ligand B (13.18), indicating lower metabolic stability.

**In vitro Half-Life:** Ligand B (-16.12) has a significantly longer half-life than Ligand A (-6.87).

**P-gp Efflux:** Ligand A (0.211) has lower P-gp efflux liability than Ligand B (0.034), which is favorable for CNS exposure.

**Binding Affinity:** Ligand A (-8.7 kcal/mol) has a substantially stronger binding affinity than Ligand B (-7.4 kcal/mol). The 1.3 kcal/mol difference is significant.

**Overall Assessment:**

Ligand A is the stronger candidate. Despite a slightly higher DILI risk and higher microsomal clearance, its superior BBB penetration, optimal logP, excellent QED, and significantly better binding affinity outweigh these drawbacks. The TPSA is also much more favorable for CNS penetration. Ligand B's low logP and poor BBB penetration are major concerns for a CNS-targeting drug. The longer half-life of Ligand B is a positive, but the affinity difference is more critical.

Output:
1
2025-04-17 07:10:56,635 - INFO - Reasoning:

Let's analyze Ligand A and Ligand B based on the provided guidelines, prioritizing GPCR-specific properties (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (349.475 Da) is slightly lower, which could be beneficial for permeability.

**TPSA:** Ligand A (78.51) is significantly better than Ligand B (106.96). For CNS targets, TPSA < 90 is preferred, and Ligand A is comfortably within this range, while Ligand B is approaching the upper limit.

**logP:** Both ligands have acceptable logP values (A: 1.755, B: 3.366), falling within the optimal 1-3 range. Ligand B is slightly higher, which *could* lead to solubility issues, but isn't a major concern.

**H-Bond Donors/Acceptors:** Both ligands have reasonable HBD (2) and HBA (A: 3, B: 4) counts, satisfying the <5 and <10 rules, respectively.

**QED:** Ligand A (0.717) has a much better QED score than Ligand B (0.296), indicating a more drug-like profile.

**DILI:** Ligand A (32.299) has a lower DILI risk than Ligand B (47.964), which is preferable. Both are below the concerning threshold of 60.

**BBB:** Ligand A (55.487) has a significantly better BBB penetration percentile than Ligand B (43.273). For a CNS target like DRD2, >70 is desirable, but A is substantially better than B.

**Caco-2 Permeability:** Ligand A (-4.844) and Ligand B (-5.023) both have negative Caco-2 values, which is unusual and suggests poor permeability. However, the scale is not specified, so it's hard to interpret.

**Aqueous Solubility:** Both ligands have very poor aqueous solubility (-2.393 and -3.383 respectively). This is a significant drawback.

**hERG Inhibition:** Ligand A (0.089) shows lower hERG inhibition liability than Ligand B (0.496), which is a positive attribute.

**Microsomal Clearance:** Ligand B (25.449) has lower microsomal clearance than Ligand A (32.449), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand B (25.266) has a much longer in vitro half-life than Ligand A (-2.615), which is a major advantage.

**P-gp Efflux:** Ligand A (0.028) has much lower P-gp efflux liability than Ligand B (0.1), which is crucial for CNS penetration.

**Binding Affinity:** Ligand B (-7.5 kcal/mol) has a stronger binding affinity than Ligand A (-8.1 kcal/mol). While both are excellent, the difference is relatively small.

**Overall Assessment:**

Considering the GPCR-specific priorities, Ligand A is the more promising candidate. Its superior TPSA, BBB penetration, QED, lower DILI risk, and significantly lower P-gp efflux outweigh the slightly weaker binding affinity and poorer metabolic stability. The solubility is a concern for both, but can be addressed with formulation strategies. Ligand B's better half-life is a plus, but the poorer BBB and higher P-gp efflux are significant drawbacks for a CNS target.

Output:
0
2025-04-17 07:10:56,636 - INFO - Reasoning:

Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (352.475 and 366.849 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (84.5) is excellent, well below the 90 threshold for CNS targets. Ligand B (97.55) is still reasonable, but less optimal.

**3. logP:** Both ligands have good logP values (2.106 and 1.463), falling within the 1-3 range.

**4. H-Bond Donors:** Both have 2 HBD, which is within the acceptable limit of 5.

**5. H-Bond Acceptors:** Ligand A has 4 HBA, and Ligand B has 5, both within the acceptable limit of 10.

**6. QED:** Both ligands have good QED scores (0.665 and 0.794), indicating good drug-like properties.

**7. DILI:** Ligand A (18.418) has a significantly lower DILI risk than Ligand B (59.403). This is a major advantage for Ligand A.

**8. BBB:** Ligand B (80.264) has a much better BBB penetration score than Ligand A (56.34). This is crucial for a CNS target like DRD2.

**9. Caco-2 Permeability:** Ligand A (-4.744) has poor Caco-2 permeability. Ligand B (-5.083) is also poor, but slightly worse.

**10. Aqueous Solubility:** Ligand A (-1.825) has better aqueous solubility than Ligand B (-3.226).

**11. hERG Inhibition:** Ligand A (0.088) has a very low hERG inhibition risk, while Ligand B (0.408) is slightly higher.

**12. Microsomal Clearance:** Ligand A (24.288) has higher microsomal clearance than Ligand B (-0.657), indicating lower metabolic stability. This is a disadvantage for Ligand A.

**13. In vitro Half-Life:** Ligand A (8.396) has a lower in vitro half-life than Ligand B (2.218).

**14. P-gp Efflux:** Ligand A (0.06) has lower P-gp efflux than Ligand B (0.027), which is favorable for CNS penetration.

**15. Binding Affinity:** Ligand B (-7.7 kcal/mol) has a slightly better binding affinity than Ligand A (-8.0 kcal/mol). While the difference is small, it's still a factor.

**Overall Assessment:**

Ligand B excels in BBB penetration and binding affinity, both critical for a CNS GPCR target. However, it has a significantly higher DILI risk. Ligand A has a much better safety profile (DILI, hERG) and better solubility, but suffers from poorer BBB penetration and metabolic stability.

Considering the balance, the slightly better affinity and *much* better BBB penetration of Ligand B outweigh its higher DILI risk, especially given the potential for further optimization to mitigate that risk. The poor metabolic stability of Ligand A is a significant concern.

Output:
1
2025-04-17 07:10:56,636 - INFO - Reasoning:

Let's analyze Ligand A and Ligand B for their potential as DRD2 drug candidates, considering the provided guidelines and GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (345.403 and 369.872 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (102.05) is slightly above the optimal <90 for CNS targets, but still reasonable. Ligand B (56.07) is excellent, well below 90.

**3. logP:** Ligand A (1.028) is at the low end of the optimal 1-3 range, potentially impacting permeability. Ligand B (3.259) is well within the optimal range.

**4. H-Bond Donors:** Ligand A (2) and Ligand B (0) are both acceptable, below the threshold of 5.

**5. H-Bond Acceptors:** Both ligands (A: 6, B: 6) are below the threshold of 10.

**6. QED:** Both ligands (A: 0.661, B: 0.668) have good drug-likeness scores, exceeding 0.5.

**7. DILI:** Ligand A (57.619) has a moderate DILI risk, but is still acceptable. Ligand B (39.899) has a lower, more favorable DILI risk.

**8. BBB:** This is crucial for a CNS target. Ligand A (51.725) has a moderate BBB penetration, while Ligand B (77.898) demonstrates excellent BBB penetration, exceeding the desirable >70 threshold.

**9. Caco-2 Permeability:** Ligand A (-5.634) has poor Caco-2 permeability, which is concerning. Ligand B (-4.576) is also low, but better than A.

**10. Aqueous Solubility:** Ligand A (-1.423) has poor solubility. Ligand B (-3.3) has even worse solubility.

**11. hERG Inhibition:** Ligand A (0.088) has very low hERG inhibition risk, excellent. Ligand B (0.65) has a slightly higher, but still acceptable, hERG risk.

**12. Microsomal Clearance:** Ligand A (38.739) has a moderate clearance. Ligand B (74.67) has a high clearance, suggesting faster metabolism.

**13. In vitro Half-Life:** Ligand A (-5.845) has a very short half-life, a significant drawback. Ligand B (55.188) has a long half-life, which is favorable.

**14. P-gp Efflux:** Ligand A (0.029) has very low P-gp efflux, which is excellent for CNS penetration. Ligand B (0.309) has moderate P-gp efflux.

**15. Binding Affinity:** Ligand A (-7.4) has slightly better binding affinity than Ligand B (-7.1), but the difference is relatively small (0.3 kcal/mol).

**Overall Assessment:**

While Ligand A has slightly better binding affinity and lower P-gp efflux, its poor Caco-2 permeability, solubility, and short half-life are major liabilities. Ligand B, despite slightly weaker affinity, exhibits superior BBB penetration, a more favorable DILI profile, and a significantly longer half-life. Given the GPCR-specific priorities for CNS targets, the excellent BBB penetration and favorable pharmacokinetic properties of Ligand B outweigh the minor difference in binding affinity.

Output:
1
2025-04-17 07:10:56,636 - INFO - Batch 343 complete. Total preferences: 5488
2025-04-17 07:10:56,636 - INFO - Processing batch 344/512...
2025-04-17 07:11:39,351 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (352.435 and 345.487 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (90.98) is better than Ligand B (63.13). Both are below the 90 A^2 threshold for CNS targets, which is excellent.

**logP:** Ligand B (3.095) is optimal (1-3), while Ligand A (0.098) is quite low, potentially hindering membrane permeability. This is a significant drawback for Ligand A.

**H-Bond Donors/Acceptors:** Both have 2 HBDs, which is acceptable. Ligand A has 5 HBAs, while Ligand B has 3. Both are within the acceptable range of <=10.

**QED:** Both ligands have good QED scores (0.634 and 0.711, respectively), indicating drug-like properties.

**DILI:** Ligand B (28.887) has a lower DILI risk than Ligand A (35.944), which is preferable. Both are below the 40 threshold.

**BBB:** Ligand B (65.801) has a significantly better BBB penetration percentile than Ligand A (38.426). For a CNS target like DRD2, this is a critical advantage.

**Caco-2 Permeability:** Ligand A (-5.156) has a worse Caco-2 permeability than Ligand B (-4.601), though both are negative, indicating poor permeability.

**Aqueous Solubility:** Ligand A (-0.402) has better solubility than Ligand B (-3.133).

**hERG Inhibition:** Ligand A (0.061) has a lower hERG risk than Ligand B (0.342), which is better.

**Microsomal Clearance:** Ligand A (-22.927) has a much lower (better) microsomal clearance than Ligand B (47.509), indicating better metabolic stability.

**In vitro Half-Life:** Ligand B (27.242) has a longer half-life than Ligand A (-7.097), which is generally desirable.

**P-gp Efflux:** Ligand A (0.003) has a much lower P-gp efflux liability than Ligand B (0.198), which is crucial for CNS penetration.

**Binding Affinity:** Ligand B (-8.0) has a slightly better binding affinity than Ligand A (-7.6). While the difference is not huge, it is still a positive for Ligand B.

**Overall Assessment:**

Ligand B clearly outperforms Ligand A. The most significant advantages for Ligand B are its superior BBB penetration, better logP, and longer half-life. While Ligand A has better metabolic stability and lower P-gp efflux, the poor logP and low BBB penetration are major drawbacks for a CNS-targeting drug. The slightly better affinity of Ligand B further solidifies its position as the more promising candidate.

Output:
1
2025-04-17 07:11:39,352 - INFO - Reasoning:

Let's analyze Ligand A and Ligand B for their potential as DRD2 drug candidates, considering the provided guidelines and GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (346.431 and 342.483 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (99.66) is higher than the preferred <90 for CNS targets, but not drastically so. Ligand B (40.62) is excellent, well below the threshold.

**3. logP:** Ligand A (1.165) is within the optimal range (1-3). Ligand B (3.095) is also within the optimal range, leaning towards the higher end but still acceptable.

**4. H-Bond Donors:** Ligand A (3) is acceptable. Ligand B (0) is also acceptable.

**5. H-Bond Acceptors:** Ligand A (4) is acceptable. Ligand B (2) is also acceptable.

**6. QED:** Ligand A (0.476) is slightly below the desirable threshold of 0.5. Ligand B (0.829) is excellent, indicating good drug-like properties.

**7. DILI:** Ligand A (47.77) is good, below the 60% threshold. Ligand B (26.173) is even better, indicating very low DILI risk.

**8. BBB:** This is critical for a CNS target. Ligand A (50.679) is moderate, but below the desirable >70%. Ligand B (85.459) is excellent, exceeding the 70% threshold.

**9. Caco-2 Permeability:** Ligand A (-5.319) is very poor. Ligand B (-4.471) is also poor, but slightly better than A. Both are concerning.

**10. Aqueous Solubility:** Both ligands have very poor aqueous solubility (-2.491 and -2.693 respectively). This is a significant drawback for both.

**11. hERG Inhibition:** Ligand A (0.125) shows low hERG inhibition risk, which is good. Ligand B (0.572) is slightly higher, but still relatively low risk.

**12. Microsomal Clearance:** Ligand A (-2.639) indicates good metabolic stability (negative value). Ligand B (77.701) suggests rapid metabolic clearance, a significant negative.

**13. In vitro Half-Life:** Ligand A (-6.734) suggests a long half-life, which is desirable. Ligand B (-29.873) suggests a very short half-life, a major concern.

**14. P-gp Efflux:** Ligand A (0.021) indicates low P-gp efflux, which is favorable for CNS penetration. Ligand B (0.288) shows slightly higher P-gp efflux, but still relatively low.

**15. Binding Affinity:** Both ligands have excellent binding affinity (-8.2 and -8.3 kcal/mol), with a very minor advantage to Ligand B. This strong binding is a major positive for both.

**Overall Assessment:**

While both ligands exhibit excellent binding affinity, Ligand B is the superior candidate. It has a much better BBB score (85.459 vs 50.679), a significantly better QED score (0.829 vs 0.476), and a lower DILI risk (26.173 vs 47.77). Although both have poor solubility and Caco-2 permeability, the superior CNS penetration profile of Ligand B, coupled with its better metabolic stability (lower Cl_mic and longer half-life) and drug-likeness, makes it the more promising candidate. The slightly higher Pgp efflux is less concerning than the other drawbacks of Ligand A.

Output:
1
2025-04-17 07:11:39,352 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (368.474 and 349.391 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (67.43) is excellent, well below the 90 A^2 threshold for CNS targets. Ligand B (120.18) is higher, but still potentially acceptable, though less ideal.

**logP:** Ligand A (3.215) is optimal (1-3). Ligand B (-0.366) is significantly lower, which could hinder membrane permeability and CNS penetration.

**H-Bond Donors/Acceptors:** Ligand A (2 HBD, 4 HBA) and Ligand B (3 HBD, 5 HBA) both fall within acceptable ranges (<=5 HBD, <=10 HBA).

**QED:** Both ligands have good QED scores (0.665 and 0.685), indicating drug-like properties.

**DILI:** Ligand A (47.732) has a lower DILI risk than Ligand B (68.592), which is preferable.

**BBB:** This is crucial for a CNS target. Ligand A (73.672) has a very good BBB percentile, exceeding the desirable >70 threshold. Ligand B (37.379) is significantly lower, raising concerns about CNS exposure.

**Caco-2 Permeability:** Ligand A (-4.525) has poor Caco-2 permeability. Ligand B (-5.158) is also poor.

**Aqueous Solubility:** Ligand A (-4.627) and Ligand B (-2.863) both have poor solubility.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.438 and 0.15), which is positive.

**Microsomal Clearance:** Ligand A (72.491) has a higher microsomal clearance than Ligand B (1.813), suggesting lower metabolic stability. Ligand B is much better here.

**In vitro Half-Life:** Ligand A (-18.138) has a negative half-life, which is not possible and likely indicates an issue with the data or model. Ligand B (5.095) has a reasonable half-life.

**P-gp Efflux:** Ligand A (0.157) has lower P-gp efflux than Ligand B (0.012), which is favorable for CNS penetration.

**Binding Affinity:** Ligand B (-8.0 kcal/mol) has a significantly stronger binding affinity than Ligand A (-7.5 kcal/mol). This is a substantial advantage.

**Overall Assessment:**

Despite the strong affinity of Ligand B, its poor logP and BBB penetration are major drawbacks for a CNS-targeting drug. The negative half-life for Ligand A is a red flag. However, Ligand A's superior BBB penetration, better DILI profile, and lower P-gp efflux, combined with acceptable TPSA and logP, make it the more promising candidate, even with the slightly weaker binding affinity. The poor Caco-2 and solubility are concerns that could be addressed through formulation strategies. The negative half-life for Ligand A is a data quality issue that would need to be resolved.

Output:
1
2025-04-17 07:11:39,352 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 drug candidates, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (350.503 and 359.499 Da) fall comfortably within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (58.64) is significantly better than Ligand B (90.7). For CNS targets, we want TPSA <= 90, so Ligand A is preferable.

**3. logP:** Both ligands have good logP values (2.737 and 3.419), falling within the optimal 1-3 range. Ligand B is slightly higher, which *could* be a minor concern for solubility, but not a major issue.

**4. H-Bond Donors:** Ligand A (1) is better than Ligand B (2). Lower is generally preferred.

**5. H-Bond Acceptors:** Ligand A (3) is better than Ligand B (6). Lower is generally preferred.

**6. QED:** Both ligands have acceptable QED values (0.801 and 0.753), indicating good drug-like properties.

**7. DILI:** Ligand A (21.714) has a much lower DILI risk than Ligand B (70.221). This is a significant advantage for Ligand A.

**8. BBB:** Ligand A (77.898) has a slightly better BBB penetration percentile than Ligand B (70.531). Both are reasonably good, but for a CNS target, higher is better.

**9. Caco-2:** Ligand A (-4.782) and Ligand B (-5.085) have negative values, which is unusual and suggests poor permeability. This is a concern for both, but the scale is not clearly defined.

**10. Solubility:** Ligand A (-2.942) and Ligand B (-3.93) have negative values, which suggests poor solubility. This is a concern for both, but the scale is not clearly defined.

**11. hERG:** Both ligands have low hERG inhibition liability (0.437 and 0.77), which is good.

**12. Cl_mic:** Ligand A (79.874) has slightly lower microsomal clearance than Ligand B (82.588), suggesting better metabolic stability.

**13. t1/2:** Ligand A (-8.733) has a much more negative in vitro half-life than Ligand B (75.099). This is a significant advantage for Ligand A.

**14. Pgp:** Both ligands have very low P-gp efflux liability (0.32 and 0.339), which is excellent for CNS penetration.

**15. Binding Affinity:** Ligand B (-7.9) has a significantly stronger binding affinity than Ligand A (-0). This is a substantial advantage for Ligand B, potentially outweighing some of its ADME drawbacks.

**Overall Assessment:**

Ligand B has a much better binding affinity, which is crucial for GPCR targets. However, Ligand A has significantly better ADME properties: lower DILI risk, better TPSA, better HBD/HBA counts, and better metabolic stability (lower Cl_mic and better t1/2). The slightly better BBB for Ligand A is also a plus. The Caco-2 and solubility values are concerning for both, but the magnitude of the affinity difference is substantial. Given the importance of affinity for GPCRs, and the fact that the ADME differences, while favorable for A, aren't catastrophic for B, I would lean towards Ligand B.

Output:
1
2025-04-17 07:11:39,352 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 drug candidates, considering the provided guidelines and GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (353.419 and 344.423 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (120.68) is slightly above the optimal <90 for CNS targets, but still reasonable. Ligand B (100.86) is better, falling comfortably below 90.

**logP:** Ligand A (-0.142) is quite low, potentially hindering membrane permeability. Ligand B (0.985) is much better, falling within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A (3 HBD, 6 HBA) is within acceptable limits. Ligand B (2 HBD, 8 HBA) is also acceptable.

**QED:** Both ligands have good QED scores (0.53 and 0.736, respectively), indicating good drug-like properties.

**DILI:** Ligand A (27.685) has a much lower DILI risk than Ligand B (54.478), a significant advantage.

**BBB:** Ligand B (59.984) has a better BBB percentile than Ligand A (32.144), which is crucial for a CNS target like DRD2. However, both are below the desirable >70.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.538 and -5.486), which is unusual and suggests poor permeability. This is a concern for both.

**Aqueous Solubility:** Both ligands have negative solubility values (-1.201 and -1.65), indicating poor aqueous solubility. This could pose formulation challenges.

**hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.183 and 0.068).

**Microsomal Clearance:** Ligand A (-17.226) has significantly lower (better) microsomal clearance than Ligand B (9.987), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand B (32.171) has a slightly longer half-life than Ligand A (29.715).

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.018 and 0.004).

**Binding Affinity:** Ligand B (-8.1 kcal/mol) has a slightly better binding affinity than Ligand A (-7.7 kcal/mol), although the difference is not huge.

**Overall Assessment:**

Ligand B is better regarding BBB penetration and binding affinity, both critical for a CNS GPCR target. However, Ligand A has a significantly lower DILI risk and better metabolic stability (lower Cl_mic). The low logP of Ligand A is a major drawback, potentially limiting its ability to cross cell membranes. The negative Caco-2 and solubility values are concerning for both, but might be addressable with formulation strategies.

Considering the GPCR-specific priorities, the slightly better affinity and BBB of Ligand B outweigh the lower DILI and better metabolic stability of Ligand A, *provided* the permeability issues can be overcome. The difference in affinity isn't large enough to completely dismiss Ligand A, but the CNS target necessitates prioritizing BBB.

Output:
1
2025-04-17 07:11:39,353 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (349.387 and 351.418 Da) are within the ideal range of 200-500 Da.

**TPSA:** Ligand A (123.66) is borderline for CNS penetration, slightly above the preferred <90, but potentially acceptable. Ligand B (51.91) is excellent, well below the threshold.

**logP:** Ligand A (0.386) is quite low, potentially hindering membrane permeability. Ligand B (3.065) is optimal.

**H-Bond Donors/Acceptors:** Ligand A has 3 HBD and 5 HBA, which are acceptable. Ligand B has 0 HBD and 4 HBA, also acceptable.

**QED:** Both ligands have good QED scores (0.685 and 0.722), indicating drug-like properties.

**DILI:** Ligand A (42.458) has a moderate DILI risk, while Ligand B (29.391) has a lower risk.

**BBB:** This is crucial for a CNS target. Ligand A (59.791) is concerningly low, suggesting poor brain penetration. Ligand B (96.161) is excellent, highly desirable for DRD2.

**Caco-2 Permeability:** Ligand A (-5.75) is very poor, indicating very low intestinal absorption. Ligand B (-4.316) is also poor, but better than Ligand A.

**Aqueous Solubility:** Both ligands have negative solubility values (-2.554 and -3.855), which is unusual and suggests very low solubility. This could be a significant formulation challenge.

**hERG Inhibition:** Ligand A (0.022) has a very low hERG risk, which is positive. Ligand B (0.582) has a slightly higher, but still acceptable, hERG risk.

**Microsomal Clearance:** Ligand A (-0.033) suggests very slow clearance and high metabolic stability, which is good. Ligand B (44.171) has a high clearance, indicating rapid metabolism.

**In vitro Half-Life:** Ligand A (17.359) has a moderate half-life. Ligand B (44.402) has a long half-life, which is favorable.

**P-gp Efflux:** Ligand A (0.005) has very low P-gp efflux, which is excellent for CNS penetration. Ligand B (0.19) has a slightly higher, but still relatively low, P-gp efflux.

**Binding Affinity:** Ligand B (-7.1 kcal/mol) has a slightly better binding affinity than Ligand A (-7.8 kcal/mol). While the difference is small, it's still a factor.

**Overall Assessment:**

Ligand B is significantly more promising. Its excellent BBB penetration, optimal logP, lower DILI risk, and longer half-life outweigh the slightly higher hERG risk and rapid metabolism. Ligand A's poor BBB penetration and low logP are major drawbacks for a CNS target like DRD2. While Ligand A has better metabolic stability, the other ADME properties of Ligand B are far more favorable for CNS drug development. The solubility issues of both are concerning, but can potentially be addressed with formulation strategies.



Output:
1
2025-04-17 07:11:39,353 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (374.478 Da) is slightly higher than Ligand B (347.507 Da), but both are acceptable.

**TPSA:** Ligand A (84.5) is better than Ligand B (54.26). Both are below the 90 A^2 threshold for CNS targets, but Ligand B is significantly better.

**logP:** Both ligands have good logP values (Ligand A: 1.573, Ligand B: 2.659), falling within the optimal 1-3 range. Ligand B is slightly more lipophilic, which could be beneficial for membrane permeability.

**H-Bond Donors:** Ligand A has 2 HBD, and Ligand B has 0. Both are within the acceptable limit of 5.

**H-Bond Acceptors:** Both ligands have 5 HBA, which is within the acceptable limit of 10.

**QED:** Both ligands have similar QED values (Ligand A: 0.63, Ligand B: 0.645), indicating good drug-like properties.

**DILI:** Ligand A (35.789) has a slightly higher DILI risk than Ligand B (13.532), but both are below the concerning threshold of 40.

**BBB:** Ligand B (83.831) has a significantly better BBB penetration score than Ligand A (74.254). This is a critical factor for a CNS target like DRD2.

**Caco-2 Permeability:** Ligand A (-4.823) has a lower Caco-2 permeability than Ligand B (-4.974). Both are negative, indicating poor permeability.

**Aqueous Solubility:** Ligand A (-2.953) has lower aqueous solubility than Ligand B (-0.914).

**hERG Inhibition:** Both ligands have low hERG inhibition risk (Ligand A: 0.171, Ligand B: 0.414).

**Microsomal Clearance:** Ligand B (31.493) has a lower microsomal clearance than Ligand A (57.048), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand B (7.66) has a longer in vitro half-life than Ligand A (-8.436).

**P-gp Efflux:** Ligand A (0.025) has a lower P-gp efflux liability than Ligand B (0.318), which is favorable for CNS penetration.

**Binding Affinity:** Both ligands have excellent binding affinities (Ligand A: -7.0 kcal/mol, Ligand B: -7.6 kcal/mol). Ligand B is slightly more potent.

**Overall Assessment:**

Ligand B is the more promising candidate. While Ligand A has slightly better P-gp efflux, Ligand B excels in several key areas crucial for a CNS-targeting GPCR ligand: significantly better BBB penetration, lower DILI risk, better metabolic stability (lower Cl_mic and longer t1/2), and slightly better binding affinity. The better TPSA and solubility also contribute to its favorability. The small difference in Caco-2 permeability is less critical given the CNS target.



Output:
1
2025-04-17 07:11:39,353 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (350.434 Da) is slightly lower, which could be advantageous for permeability. Ligand B (387.908 Da) is also acceptable.

**TPSA:** Ligand A (49.85) is excellent, well below the 90 Angstroms threshold for CNS targets. Ligand B (62.3) is still reasonable, but less optimal.

**logP:** Both ligands have good logP values (A: 2.343, B: 2.984), falling within the 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A (HBD=0, HBA=4) and Ligand B (HBD=1, HBA=4) both have acceptable numbers of hydrogen bond donors and acceptors.

**QED:** Both ligands have good QED values (A: 0.765, B: 0.815), indicating drug-like properties.

**DILI:** Ligand A (13.843) has a significantly lower DILI risk than Ligand B (41.411). This is a major advantage for Ligand A.

**BBB:** Ligand A (88.174) has a much higher BBB penetration percentile than Ligand B (69.523). This is crucial for a CNS target like DRD2.

**Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and suggests potential issues with the prediction method. However, the values are similar (-4.213 for A, -4.586 for B).

**Aqueous Solubility:** Both ligands have very poor predicted aqueous solubility (A: -1.664, B: -3.727). This is a concern, but can sometimes be overcome with formulation strategies.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (A: 0.717, B: 0.428).

**Microsomal Clearance:** Ligand A (44.147) has higher microsomal clearance than Ligand B (35.123), suggesting Ligand B is more metabolically stable.

**In vitro Half-Life:** Ligand B (-7.5) has a significantly longer predicted half-life than Ligand A (-0.034). This is a substantial advantage.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (A: 0.125, B: 0.193).

**Binding Affinity:** Both ligands have excellent binding affinities (A: -8.4 kcal/mol, B: -8.0 kcal/mol). Ligand A is slightly better, but the difference is relatively small.

**Overall Assessment:**

Considering the GPCR-specific priorities, Ligand A is the more promising candidate. Its superior BBB penetration (88.174 vs 69.523) and significantly lower DILI risk (13.843 vs 41.411) are major advantages. While Ligand B has a better half-life and slightly better metabolic stability, the CNS target necessitates high BBB penetration and low toxicity, which Ligand A delivers. The small difference in binding affinity is outweighed by these ADME/Tox benefits.



Output:
0
2025-04-17 07:11:39,353 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B based on the provided guidelines, prioritizing GPCR-specific properties (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (335.451 and 351.372 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (59.22) is significantly better than Ligand B (67.89). For CNS targets, TPSA should be <= 90, both are within this range, but A is closer to the optimal value.

**logP:** Both ligands have good logP values (3.388 and 3.943), falling within the 1-3 range. Ligand B is slightly higher, which *could* indicate potential off-target effects, but it's not a major concern.

**H-Bond Donors/Acceptors:** Ligand A has 1 HBD and 3 HBA, while Ligand B has 0 HBD and 3 HBA. Both are acceptable, well within the limits of 5 HBD and 10 HBA.

**QED:** Both ligands have good QED scores (0.911 and 0.807), indicating drug-like properties.

**DILI:** Ligand A (16.712) has a much lower DILI risk than Ligand B (26.793). This is a significant advantage for Ligand A.

**BBB:** Both ligands have excellent BBB penetration (77.705 and 74.37), both are above the desirable 70% threshold for CNS targets. Ligand A is slightly better.

**Caco-2 Permeability:** Ligand A (-4.833) has better Caco-2 permeability than Ligand B (-4.24). Higher values indicate better absorption.

**Aqueous Solubility:** Ligand A (-2.187) has better aqueous solubility than Ligand B (-3.932).

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.695 and 0.802).

**Microsomal Clearance:** Ligand A (15.613) has significantly lower microsomal clearance than Ligand B (59.264), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (17.63) has a longer in vitro half-life than Ligand B (-9.547). This is a significant advantage for Ligand A.

**P-gp Efflux:** Ligand A (0.29) has lower P-gp efflux than Ligand B (0.175), meaning it's less likely to be pumped out of the brain, leading to better CNS exposure.

**Binding Affinity:** Ligand A (-8.7 kcal/mol) has a stronger binding affinity than Ligand B (-7.2 kcal/mol).  The 1.5 kcal/mol difference is substantial and can outweigh minor ADME drawbacks.

**Overall Assessment:**

Ligand A consistently outperforms Ligand B across most critical parameters, especially DILI, metabolic stability (Cl_mic and t1/2), P-gp efflux, solubility, Caco-2 permeability, and crucially, binding affinity. While both have good BBB penetration and logP values, the superior profile of Ligand A makes it the more promising drug candidate for targeting DRD2.

Output:
1
2025-04-17 07:11:39,354 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (367.877 and 348.403 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (73.83) is significantly better than Ligand B (99.25). For CNS targets, we want TPSA <= 90, so Ligand A is preferable.

**logP:** Both ligands (2.851 and 2.657) are within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A (HBD=3, HBA=4) is slightly better than Ligand B (HBD=1, HBA=7) in terms of balancing solubility and permeability.

**QED:** Both ligands have good QED scores (0.748 and 0.912), indicating good drug-like properties.

**DILI:** Ligand A (41.179) has a lower DILI risk than Ligand B (73.245), which is favorable.

**BBB:** Both ligands have reasonably good BBB penetration (61.923 and 65.568), but neither exceeds the desirable >70 threshold.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values, which is unusual and difficult to interpret without knowing the scale. However, they are similar in magnitude.

**Aqueous Solubility:** Both ligands have negative solubility values, again unusual and difficult to interpret. They are similar in magnitude.

**hERG Inhibition:** Ligand A (0.656) has a slightly higher hERG risk than Ligand B (0.293), which is less desirable.

**Microsomal Clearance:** Ligand A (5.827) has significantly lower microsomal clearance than Ligand B (56.082), indicating better metabolic stability.

**In vitro Half-Life:** Ligand A (86.649) has a much longer in vitro half-life than Ligand B (-31.005). This is a significant advantage.

**P-gp Efflux:** Ligand A (0.148) has lower P-gp efflux liability than Ligand B (0.082), which is better for CNS exposure.

**Binding Affinity:** Both ligands have excellent binding affinities (-8.3 and -8.6 kcal/mol). Ligand B is slightly better, but the difference is small and may not be practically significant.

**Overall Assessment:**

Considering the GPCR-specific priorities, Ligand A is the better candidate. While Ligand B has a slightly better binding affinity and lower hERG risk, Ligand A excels in TPSA, DILI, metabolic stability (lower Cl_mic, longer t1/2), and P-gp efflux. The lower TPSA and better metabolic stability are particularly important for a CNS target like DRD2. The slightly higher hERG risk of Ligand A could be addressed through further optimization.

Output:
1
2025-04-17 07:11:39,354 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (348.575) is slightly better positioned.

**TPSA:** Ligand A (32.34) is excellent for CNS penetration, well below the 90 A^2 threshold. Ligand B (99.77) is higher, potentially hindering BBB penetration, though still within a reasonable range.

**logP:** Ligand A (4.9) is a bit high, potentially leading to solubility issues or off-target interactions. Ligand B (1.821) is closer to the optimal range (1-3).

**H-Bond Donors/Acceptors:** Ligand A (HBD=1, HBA=2) is favorable. Ligand B (HBD=3, HBA=5) is acceptable, but slightly higher.

**QED:** Both ligands have similar QED values (A: 0.74, B: 0.731), indicating good drug-likeness.

**DILI:** Ligand A (13.532) has a much lower DILI risk than Ligand B (58.395), a significant advantage.

**BBB:** Ligand A (79.992) has a good BBB percentile, desirable for a CNS target. Ligand B (30.477) is considerably lower, raising concerns about CNS exposure.

**Caco-2 Permeability:** Ligand A (-4.883) shows poor permeability. Ligand B (-5.782) is also poor, but slightly worse.

**Aqueous Solubility:** Ligand A (-4.344) has poor solubility. Ligand B (-2.318) is better, but still not ideal.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (A: 0.895, B: 0.525).

**Microsomal Clearance:** Ligand A (62.387) has moderate clearance. Ligand B (-9.188) has *negative* clearance, which is not physically possible and indicates an issue with the data or modeling. This is a major red flag.

**In vitro Half-Life:** Ligand A (8.915) has a reasonable half-life. Ligand B (-11.8) has a negative half-life, which is impossible and indicates a data issue.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (A: 0.433, B: 0.062), which is favorable for CNS penetration.

**Binding Affinity:** Ligand B (-8.2 kcal/mol) has a significantly stronger binding affinity than Ligand A (-0.0 kcal/mol). This is a substantial advantage, potentially outweighing some ADME concerns *if* the ADME issues aren't insurmountable.

**Overall Assessment:**

Despite Ligand B's superior binding affinity, the negative values for microsomal clearance and in vitro half-life are critical flaws. These indicate a fundamental problem with the data or the molecule's predicted metabolism, making it highly unlikely to be a viable drug candidate. Ligand A, while having a higher logP and poorer solubility/permeability, has a much more reasonable ADME profile and a good BBB score. The difference in binding affinity is large, but a compound with a negative clearance is essentially non-developable.

Output:
0
2025-04-17 07:11:39,354 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (354.491 and 366.527 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (89.87) is better than Ligand B (67.34) as it is closer to the ideal range for CNS targets (<=90). Ligand B is also very good.

**3. logP:** Both ligands have good logP values (1.44 and 2.98), falling within the optimal 1-3 range.

**4. H-Bond Donors:** Ligand A (3) is slightly higher than ideal (<=5), but still acceptable. Ligand B (0) is excellent.

**5. H-Bond Acceptors:** Both ligands have 4 H-bond acceptors, which is well within the acceptable limit of <=10.

**6. QED:** Both ligands have similar and good QED values (0.697 and 0.744), indicating good drug-like properties.

**7. DILI:** Ligand B (31.718) has a significantly lower DILI risk than Ligand A (16.092), which is a substantial advantage.

**8. BBB:** Ligand B (87.67) has a much higher BBB penetration percentile than Ligand A (60.76). This is *critical* for a CNS target like DRD2.

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.856 and -4.741), which is unusual and potentially problematic. However, these values are close and likely represent similar issues with the assay or modeling.

**10. Aqueous Solubility:** Both ligands have similar and poor aqueous solubility (-2.707 and -2.739). This could pose formulation challenges.

**11. hERG Inhibition:** Ligand A (0.18) has a lower hERG inhibition liability than Ligand B (0.476), which is favorable.

**12. Microsomal Clearance:** Ligand B (63.122) has a higher microsomal clearance than Ligand A (19.154), indicating faster metabolism and potentially lower exposure.

**13. In vitro Half-Life:** Ligand A (-8.445) has a longer in vitro half-life than Ligand B (-2.383), which is a positive attribute.

**14. P-gp Efflux:** Ligand A (0.05) has a much lower P-gp efflux liability than Ligand B (0.533). This is important for CNS penetration.

**15. Binding Affinity:** Ligand B (-7.4 kcal/mol) has a slightly better binding affinity than Ligand A (-8.0 kcal/mol). While A is better, the difference is not substantial enough to outweigh other factors.

**Overall Assessment:**

Ligand B is the stronger candidate. While Ligand A has a slightly better binding affinity, longer half-life, and lower hERG risk, Ligand B excels in the most critical areas for a CNS-targeting GPCR: BBB penetration, lower DILI risk, and lower P-gp efflux. The higher BBB value is particularly important for DRD2. The difference in affinity is not large enough to overcome these advantages.



Output:
1
2025-04-17 07:11:39,354 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (348.531 and 364.515 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (58.2) is significantly better than Ligand B (66.4). For CNS targets, we want TPSA <= 90, and ideally closer to 60. Ligand A is much closer to the ideal range.

**3. logP:** Ligand A (3.938) is slightly higher than optimal (1-3) but still acceptable. Ligand B (1.993) is at the lower end of the optimal range, potentially impacting permeability.

**4. H-Bond Donors:** Ligand A (2) is good. Ligand B (0) is also acceptable.

**5. H-Bond Acceptors:** Ligand A (2) is good. Ligand B (6) is higher, but still within the acceptable limit of 10.

**6. QED:** Both ligands have good QED values (0.628 and 0.719), indicating drug-like properties.

**7. DILI:** Ligand A (20.24) has a much lower DILI risk than Ligand B (72.005). This is a significant advantage for Ligand A.

**8. BBB:** Ligand A (75.378) is good, but Ligand B (91.198) is excellent. This is a critical factor for a CNS target like DRD2.

**9. Caco-2 Permeability:** Both ligands have very poor Caco-2 permeability (-4.77 and -4.738). This is a concern for oral bioavailability, but less critical for a CNS target where direct delivery or other routes might be considered.

**10. Aqueous Solubility:** Both ligands have poor aqueous solubility (-4.747 and -3.123). This could pose formulation challenges.

**11. hERG Inhibition:** Ligand A (0.577) shows lower hERG inhibition risk than Ligand B (0.751), which is preferable.

**12. Microsomal Clearance:** Ligand A (81.484) has higher microsomal clearance than Ligand B (73.309), indicating lower metabolic stability.

**13. In vitro Half-Life:** Ligand B (5.605) has a significantly longer in vitro half-life than Ligand A (0.679). This is a substantial advantage for Ligand B.

**14. P-gp Efflux:** Ligand A (0.542) shows lower P-gp efflux than Ligand B (0.268), which is more favorable for CNS penetration.

**15. Binding Affinity:** Ligand A (-8.2 kcal/mol) has a better binding affinity than Ligand B (-7.6 kcal/mol). The difference of 0.6 kcal/mol is significant and can outweigh some ADME drawbacks.

**Overall Assessment:**

Ligand A has a better balance of properties, particularly regarding DILI risk, TPSA, and binding affinity. While Ligand B has a superior BBB score and in vitro half-life, the higher DILI risk and lower affinity are concerning. The slightly higher logP of Ligand A is less of a concern given its excellent affinity. The poor Caco-2 and solubility are drawbacks for both, but less critical for a CNS target. Considering the GPCR-specific priorities, the strong affinity and lower toxicity profile of Ligand A make it the more promising candidate.

Output:
1
2025-04-17 07:11:39,355 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (346.427 and 354.491 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (59.08) is excellent, well below the 90 A^2 threshold for CNS targets. Ligand B (78.87) is still reasonable, but less optimal.

**3. logP:** Both ligands have good logP values (0.963 and 1.704), falling within the 1-3 range.

**4. H-Bond Donors:** Ligand A (0) is ideal. Ligand B (2) is acceptable.

**5. H-Bond Acceptors:** Ligand A (4) is good. Ligand B (5) is also acceptable.

**6. QED:** Both ligands have similar and good QED values (0.712 and 0.735), indicating good drug-like properties.

**7. DILI:** Ligand A (24.234) has a much lower DILI risk than Ligand B (15.006), which is a significant advantage.

**8. BBB:** This is crucial for a CNS target like DRD2. Ligand A (71.733) has a good BBB percentile, exceeding the 70% threshold. Ligand B (51.842) is considerably lower, raising concerns about CNS penetration.

**9. Caco-2 Permeability:** Both have negative values, which is unusual. However, the magnitude of the negative value for Ligand A (-4.138) is less than Ligand B (-4.544), suggesting slightly better permeability.

**10. Aqueous Solubility:** Both ligands have negative values, which is also unusual. The value for Ligand A (-1.609) is better than Ligand B (-2.416).

**11. hERG Inhibition:** Ligand A (0.072) has a very low hERG risk, while Ligand B (0.425) is slightly higher but still acceptable.

**12. Microsomal Clearance:** Ligand B (77.165) has a much higher microsomal clearance than Ligand A (16.518), indicating faster metabolism and potentially lower exposure.

**13. In vitro Half-Life:** Ligand A (8.827) has a positive half-life, while Ligand B (-14.461) has a negative half-life, which is not good.

**14. P-gp Efflux:** Ligand A (0.021) has very low P-gp efflux liability, which is excellent for CNS penetration. Ligand B (0.276) is higher, potentially limiting brain exposure.

**15. Binding Affinity:** Ligand A (-9.2 kcal/mol) has a significantly stronger binding affinity than Ligand B (-6.7 kcal/mol). This >1.5 kcal/mol difference is substantial and can outweigh minor ADME drawbacks.

**Overall Assessment:**

Ligand A is clearly the superior candidate. It has a better BBB score, lower DILI risk, lower P-gp efflux, better metabolic stability (lower Cl_mic, positive t1/2), and significantly stronger binding affinity. While both have acceptable logP and QED values, Ligand A's profile is much more favorable for a CNS-targeting drug.

Output:
1
2025-04-17 07:11:39,355 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 drug candidates, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (376.513 and 348.443 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (49.41) is significantly better than Ligand B (71.78). For CNS targets, we want TPSA <= 90, and ideally closer to 60. Ligand A is much closer to this ideal.

**3. logP:** Both ligands have good logP values (3.31 and 2.291), falling within the optimal 1-3 range.

**4. H-Bond Donors:** Both have 1 HBD, which is acceptable.

**5. H-Bond Acceptors:** Ligand A has 3 HBAs, and Ligand B has 4. Both are acceptable (<=10).

**6. QED:** Both ligands have good QED scores (0.595 and 0.886), indicating drug-like properties. Ligand B is slightly better here.

**7. DILI:** Both ligands have very similar, and acceptable, DILI risk (15.743 and 15.432 percentile).

**8. BBB:** Ligand A (94.184) has a significantly higher BBB penetration percentile than Ligand B (84.374). This is *critical* for a CNS target like DRD2.

**9. Caco-2 Permeability:** Ligand A (-4.981) has slightly better Caco-2 permeability than Ligand B (-4.516).

**10. Aqueous Solubility:** Both ligands have poor aqueous solubility (-2.94 and -2.542). This could pose formulation challenges, but is less critical than BBB for a CNS drug.

**11. hERG Inhibition:** Both ligands have low hERG inhibition risk (0.8 and 0.591).

**12. Microsomal Clearance:** Ligand A (34.036) has a slightly higher microsomal clearance than Ligand B (31.876), indicating slightly lower metabolic stability.

**13. In vitro Half-Life:** Ligand B (21.064) has a significantly longer in vitro half-life than Ligand A (-2.011). This is a positive for Ligand B.

**14. P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.17 and 0.198).

**15. Binding Affinity:** Ligand B (-7.6) has a slightly stronger binding affinity than Ligand A (-7.1). While a 0.5 kcal/mol difference is good, the other factors are more important.

**Overall Assessment:**

Ligand A is the better candidate. While Ligand B has slightly better affinity and half-life, Ligand A's significantly superior TPSA and BBB penetration are crucial for a CNS-targeting GPCR. The slightly higher clearance of Ligand A is a minor drawback compared to the potential for better brain exposure.

Output:
1
2025-04-17 07:11:39,355 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (344.46 and 355.39 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (74.33) is excellent for CNS penetration, being well below 90. Ligand B (125.13) is higher, but still potentially acceptable, though less ideal.

**logP:** Ligand A (2.759) is optimal (1-3). Ligand B (-0.469) is significantly lower, which could hinder membrane permeability and CNS penetration.

**H-Bond Donors/Acceptors:** Ligand A (2 HBD, 3 HBA) is well within the desirable ranges. Ligand B (3 HBD, 7 HBA) is also acceptable, but higher HBA could impact permeability.

**QED:** Both ligands have reasonable QED values (0.866 and 0.63), indicating good drug-like properties.

**DILI:** Ligand A (39.201) has a lower DILI risk than Ligand B (29.973), which is preferable.

**BBB:** Ligand A (82.358) has a significantly better BBB percentile than Ligand B (42.497). This is a *critical* advantage for a CNS target like DRD2.

**Caco-2 Permeability:** Ligand A (-4.682) and Ligand B (-4.964) both have negative values, which is unusual and suggests very poor permeability. However, the scale isn't specified, so it's hard to interpret.

**Aqueous Solubility:** Ligand A (-3.455) and Ligand B (-1.02) both have negative values, suggesting poor solubility.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.489 and 0.143).

**Microsomal Clearance:** Ligand B (-10.218) has a much lower (better) microsomal clearance than Ligand A (38.573), indicating greater metabolic stability.

**In vitro Half-Life:** Ligand B (-2.759) has a longer half-life than Ligand A (12.005), which is preferable.

**P-gp Efflux:** Ligand A (0.088) has a lower P-gp efflux liability than Ligand B (0.019), meaning it's less likely to be pumped out of the brain, improving CNS exposure.

**Binding Affinity:** Ligand A (-9.1 kcal/mol) has a significantly stronger binding affinity than Ligand B (-7.5 kcal/mol). This >1.5 kcal/mol difference is a major advantage, potentially outweighing some ADME drawbacks.

**Conclusion:**

While Ligand B has better metabolic stability and half-life, Ligand A is the superior candidate. The significantly stronger binding affinity (-9.1 vs -7.5 kcal/mol) and, crucially, the much better BBB penetration (82.36% vs 42.50%) are decisive for a CNS-targeting GPCR like DRD2. The slightly higher DILI risk and clearance of Ligand A are less concerning given the superior potency and brain exposure. The low logP of Ligand B is a significant drawback.

Output:
1
2025-04-17 07:11:39,355 - INFO - Batch 344 complete. Total preferences: 5504
2025-04-17 07:11:39,355 - INFO - Processing batch 345/512...
2025-04-17 07:12:27,078 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (352.385 and 347.438 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (58.44) is excellent, well below the 90 A^2 threshold for CNS targets. Ligand B (64.86) is still reasonable but less optimal.

**logP:** Both ligands have good logP values (2.08 and 2.839), falling within the 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A (0 HBD, 4 HBA) is slightly better than Ligand B (1 HBD, 6 HBA) in terms of balancing solubility and permeability. Both are within acceptable limits.

**QED:** Ligand A (0.837) has a significantly higher QED score than Ligand B (0.588), indicating better overall drug-likeness.

**DILI:** Ligand A (47.421) has a slightly higher DILI risk than Ligand B (39.589), but both are below the concerning threshold of 60.

**BBB:** This is a critical parameter for a CNS target like DRD2. Ligand A has a very high BBB penetration percentile (93.757), substantially better than Ligand B (70.182).

**Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and problematic. However, the absolute value is smaller for Ligand A (-4.574 vs -5.003), suggesting slightly better permeability.

**Aqueous Solubility:** Both ligands have poor aqueous solubility (-2.72 and -3.273). This could be a formulation challenge, but is not a dealbreaker if other properties are strong.

**hERG Inhibition:** Both ligands show very low hERG inhibition risk (0.293 and 0.496).

**Microsomal Clearance:** Ligand A (17.386) has a significantly lower microsomal clearance than Ligand B (62.923), indicating better metabolic stability.

**In vitro Half-Life:** Ligand A (-10.737) has a negative half-life, which is not physically possible and indicates a problem with the data or the molecule. Ligand B (13.771) is reasonable.

**P-gp Efflux:** Both ligands show very low P-gp efflux liability (0.096 and 0.339).

**Binding Affinity:** Ligand B (-7.1 kcal/mol) has a slightly better binding affinity than Ligand A (-9.0 kcal/mol). However, the difference is not substantial enough to overcome the other significant advantages of Ligand A.

**Overall Assessment:**

Ligand A is superior despite the negative half-life value. The extremely high BBB penetration (93.757), excellent TPSA (58.44), high QED (0.837), and low microsomal clearance (17.386) make it a much more promising candidate for a CNS-targeting drug like a DRD2 ligand. While the negative half-life is concerning, it might be a data error. Ligand B's lower BBB penetration and higher clearance are significant drawbacks. The slightly better affinity of Ligand B is not enough to compensate for these issues.

Output:
0
2025-04-17 07:12:27,079 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (343.471 and 356.482 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (71.09) is better than Ligand B (78.43). Both are below the 90 A^2 threshold desirable for CNS targets, but A is closer to the optimal range.

**3. logP:** Both ligands have good logP values (2.461 and 2.348), falling within the 1-3 range.

**4. H-Bond Donors:** Ligand A (2) is preferable to Ligand B (3). Lower HBD generally improves permeability.

**5. H-Bond Acceptors:** Both ligands have the same number of HBA (3), which is acceptable (<=10).

**6. QED:** Ligand A (0.677) has a slightly higher QED than Ligand B (0.526), indicating a more drug-like profile.

**7. DILI:** Ligand A (18.728) has a significantly lower DILI risk than Ligand B (8.53). This is a major advantage for Ligand A.

**8. BBB:** Ligand B (76.464) has a better BBB penetration score than Ligand A (61.923). While both are reasonably good, B is closer to the desirable >70 threshold for CNS targets.

**9. Caco-2 Permeability:** Ligand A (-4.987) shows better Caco-2 permeability than Ligand B (-4.697), indicating better intestinal absorption.

**10. Aqueous Solubility:** Both ligands have very poor aqueous solubility (-2.484 and -2.765). This is a concern for both, but not a deciding factor.

**11. hERG Inhibition:** Both ligands have low hERG inhibition risk (0.253 and 0.465).

**12. Microsomal Clearance:** Ligand B (36.064) has lower microsomal clearance than Ligand A (47.598), suggesting better metabolic stability.

**13. In vitro Half-Life:** Ligand A (-27.009) has a longer in vitro half-life than Ligand B (-11.024). This is a positive for Ligand A.

**14. P-gp Efflux:** Ligand A (0.148) has lower P-gp efflux than Ligand B (0.105), which is favorable for CNS penetration.

**15. Binding Affinity:** Ligand B (-7.4) has a slightly better binding affinity than Ligand A (-8.8). The difference is 1.4 kcal/mol, which is significant.

**Overall Assessment:**

Ligand A excels in several key areas: DILI risk, in vitro half-life, Caco-2 permeability, and P-gp efflux. Its TPSA and QED are also slightly better. Ligand B's main advantage is its slightly better BBB penetration and binding affinity. However, the significantly lower DILI risk of Ligand A and its better metabolic properties (longer half-life) are crucial for drug development. The affinity difference, while notable, can potentially be optimized in later stages of drug design. Given the GPCR-specific priorities, and the importance of minimizing toxicity and maximizing CNS exposure, Ligand A appears to be the more promising candidate.

Output:
0
2025-04-17 07:12:27,079 - INFO - Reasoning:

Let's analyze Ligand A and Ligand B based on the provided guidelines, prioritizing GPCR-specific properties (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (456.667 Da) is higher, but still acceptable. Ligand B (367.515 Da) is slightly better.

**TPSA:** Ligand A (55.4) is excellent for CNS penetration, well below the 90 A^2 threshold. Ligand B (101.29) is higher, but still reasonable, though less favorable for CNS targets.

**logP:** Ligand A (4.857) is a bit high, potentially leading to solubility issues or off-target interactions. Ligand B (1.186) is closer to the optimal range (1-3) and is preferable.

**H-Bond Donors/Acceptors:** Ligand A (HBD=1, HBA=3) and Ligand B (HBD=3, HBA=4) both have acceptable numbers of hydrogen bond donors and acceptors.

**QED:** Ligand A (0.718) has a better QED score than Ligand B (0.57), indicating a more drug-like profile.

**DILI:** Ligand A (90.927) has a significantly higher DILI risk than Ligand B (14.696). This is a major concern for Ligand A.

**BBB:** Ligand A (59.868) has a moderate BBB penetration, while Ligand B (61.419) is also moderate. Both are below the desirable >70 percentile for CNS targets, but not dramatically so.

**Caco-2 Permeability:** Ligand A (-4.678) shows poor Caco-2 permeability, which is concerning. Ligand B (-5.685) is also poor, but slightly better.

**Aqueous Solubility:** Ligand A (-5.195) has very poor aqueous solubility, likely due to its high logP. Ligand B (-2.919) is better, but still low.

**hERG Inhibition:** Ligand A (0.795) has a slightly higher hERG risk than Ligand B (0.165). Ligand B is much better here.

**Microsomal Clearance:** Ligand A (14.071) has lower microsomal clearance than Ligand B (43.265), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (63.519) has a longer in vitro half-life than Ligand B (0.127), which is a significant advantage.

**P-gp Efflux:** Ligand A (0.778) has lower P-gp efflux than Ligand B (0.011), which is favorable for CNS penetration.

**Binding Affinity:** Ligand B (-7.9 kcal/mol) has a significantly stronger binding affinity than Ligand A (-9.0 kcal/mol). This is a substantial advantage, potentially outweighing some of the ADME drawbacks.

**Overall Assessment:**

Ligand B is the more promising candidate. While its solubility and Caco-2 permeability are low, its significantly better binding affinity, lower DILI risk, and lower hERG inhibition liability are crucial advantages. Ligand A's high logP, poor solubility, and high DILI risk are major drawbacks, even with its better QED and metabolic stability. The stronger affinity of Ligand B is likely to be more impactful for efficacy, and the lower toxicity risks are critical for drug development.



Output:
1
2025-04-17 07:12:27,079 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (348.378) is slightly lower, which is generally favorable for permeability. Ligand B (369.937) is also acceptable.

**TPSA:** Ligand A (95.42) is borderline for CNS targets (ideally <90), but still potentially acceptable. Ligand B (52.65) is excellent, well below the 90 threshold, indicating better potential for brain penetration.

**logP:** Ligand A (0.664) is a bit low, potentially hindering membrane permeability. Ligand B (2.09) is within the optimal range (1-3).

**H-Bond Donors/Acceptors:** Ligand A has 2 HBD and 5 HBA, which is reasonable. Ligand B has 1 HBD and 3 HBA, also reasonable.

**QED:** Ligand A (0.78) has a better QED score than Ligand B (0.526), suggesting a more drug-like profile.

**DILI:** Ligand A (65.491) has a higher DILI risk than Ligand B (11.555). This is a significant concern for Ligand A.

**BBB:** Both ligands have similar BBB penetration (Ligand A: 66.344, Ligand B: 66.576), both are acceptable but not outstanding.

**Caco-2 Permeability:** Ligand A (-4.797) has poor Caco-2 permeability, indicating poor intestinal absorption. Ligand B (-5.067) is also poor, but slightly better than A.

**Aqueous Solubility:** Both ligands have very poor aqueous solubility (-1.985 and -1.76 respectively). This could pose formulation challenges.

**hERG Inhibition:** Ligand A (0.188) has a slightly higher hERG risk than Ligand B (0.793), but both are relatively low.

**Microsomal Clearance:** Ligand A (-1.747) has a lower (better) microsomal clearance than Ligand B (43.184), indicating greater metabolic stability.

**In vitro Half-Life:** Ligand A (-14.309) has a very poor in vitro half-life, while Ligand B (-11.585) is also poor, but better than A.

**P-gp Efflux:** Ligand A (0.018) shows very low P-gp efflux, which is excellent for CNS exposure. Ligand B (0.128) is slightly higher, but still relatively low.

**Binding Affinity:** Ligand A (-8.6 kcal/mol) has a significantly stronger binding affinity than Ligand B (-7.8 kcal/mol). This is a substantial advantage.

**Overall Assessment:**

Ligand A has a significantly better binding affinity and lower P-gp efflux, which are crucial for a CNS GPCR target like DRD2. However, it suffers from poor Caco-2 permeability, a higher DILI risk, and a very short in vitro half-life. The low logP is also a concern.

Ligand B has better physicochemical properties (TPSA, logP) and a lower DILI risk, but its binding affinity is weaker.

Considering the GPCR-specific priorities, the strong affinity of Ligand A is a major advantage that could potentially outweigh its drawbacks, *if* the permeability and metabolic stability issues can be addressed through structural modifications. The DILI risk is also a concern that would need to be mitigated. However, the difference in binding affinity (-0.8 kcal/mol) is substantial and often a key driver in lead optimization.

Output:
1
2025-04-17 07:12:27,080 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B based on the provided criteria, prioritizing GPCR-specific properties (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (353.423 Da) is slightly better, being closer to the lower end which can aid permeability.

**TPSA:** Ligand B (78.38) is significantly better than Ligand A (97.72). For CNS targets, TPSA < 90 is preferred, and Ligand B is comfortably within this range while Ligand A is approaching the upper limit.

**logP:** Ligand B (3.537) is higher than Ligand A (1.026). While both are within the 1-3 optimal range, Ligand B is nearing the upper limit. Ligand A's lower logP might hinder permeation.

**H-Bond Donors/Acceptors:** Ligand A (HBD=2, HBA=6) is slightly better than Ligand B (HBD=0, HBA=7) in terms of balancing solubility and permeability.

**QED:** Ligand A (0.788) has a significantly better QED score than Ligand B (0.543), indicating a more drug-like profile.

**DILI:** Ligand A (35.324) has a much lower DILI risk than Ligand B (76.464). This is a significant advantage for Ligand A.

**BBB:** Ligand B (77.627) has a considerably higher BBB penetration percentile than Ligand A (60.915). This is crucial for a CNS target like DRD2.

**Caco-2 Permeability:** Ligand A (-4.675) has a more negative Caco-2 value, indicating lower permeability than Ligand B (-4.52).

**Aqueous Solubility:** Ligand A (-1.064) has better aqueous solubility than Ligand B (-5.923).

**hERG:** Both ligands have very low hERG inhibition liability (0.255 and 0.23, respectively), indicating minimal cardiotoxicity risk.

**Microsomal Clearance:** Ligand B (81.781) has a much higher microsomal clearance than Ligand A (3.82), suggesting lower metabolic stability.

**In vitro Half-Life:** Ligand B (14.154) has a longer in vitro half-life than Ligand A (2.574).

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.012 and 0.342, respectively).

**Binding Affinity:** Ligand B (-7.7 kcal/mol) has a significantly stronger binding affinity than Ligand A (-6.7 kcal/mol). This 1.0 kcal/mol difference is substantial and can outweigh some ADME drawbacks.

**Overall Assessment:**

Ligand B excels in BBB penetration and binding affinity, which are critical for a CNS GPCR target. However, it suffers from higher DILI risk and lower metabolic stability. Ligand A has better ADME properties (lower DILI, better solubility, better QED, lower clearance) but weaker binding affinity and lower BBB.

Given the strong preference for binding affinity in GPCR drug discovery, and the significant 1.0 kcal/mol advantage of Ligand B, I believe Ligand B is the more promising candidate, despite its ADME liabilities. The higher binding affinity provides a larger margin for optimization of ADME properties.

Output:
1
2025-04-17 07:12:27,080 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 drug candidates, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (336.435 Da) is slightly lower, which could be advantageous for permeability. Ligand B (368.371 Da) is still acceptable.

**2. TPSA:** Ligand A (41.57) is excellent, well below the 90 Angstroms threshold for CNS targets. Ligand B (69.64) is higher but still reasonable, though less optimal for CNS penetration.

**3. logP:** Ligand A (3.705) is at the upper end of the optimal range (1-3), potentially raising concerns about solubility and off-target effects. Ligand B (1.959) is excellent, falling squarely within the optimal range.

**4. H-Bond Donors:** Both ligands have acceptable HBD counts (Ligand A: 1, Ligand B: 2), well below the 5 threshold.

**5. H-Bond Acceptors:** Both ligands have acceptable HBA counts (Ligand A: 3, Ligand B: 3), well below the 10 threshold.

**6. QED:** Ligand A (0.925) has a very high QED score, indicating excellent drug-likeness. Ligand B (0.508) is just above the 0.5 threshold, indicating reasonable drug-likeness.

**7. DILI Risk:** Ligand A (54.789) has a moderate DILI risk, but is still acceptable. Ligand B (33.695) has a low DILI risk, which is a significant advantage.

**8. BBB Penetration:** Ligand A (91.586) has excellent BBB penetration, exceeding the desirable 70% threshold. Ligand B (54.478) is below the 70% threshold, which is a major drawback for a CNS target.

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 values, which is unusual and difficult to interpret without further context. However, the magnitude of the negative values is similar, so this isn't a major differentiator.

**10. Aqueous Solubility:** Both ligands have negative solubility values, which is also unusual. Again, the values are similar in magnitude.

**11. hERG Inhibition:** Ligand A (0.919) has a slightly elevated hERG risk, but still within an acceptable range. Ligand B (0.499) has a lower hERG risk, which is preferable.

**12. Microsomal Clearance:** Ligand A (92.773) has high microsomal clearance, suggesting poor metabolic stability. Ligand B (0.544) has very low microsomal clearance, indicating excellent metabolic stability.

**13. In vitro Half-Life:** Ligand A (5.171) has a moderate in vitro half-life. Ligand B (-2.894) has a very short in vitro half-life, which is a significant disadvantage.

**14. P-gp Efflux:** Ligand A (0.715) has moderate P-gp efflux, while Ligand B (0.066) has very low P-gp efflux, which is highly desirable for CNS penetration.

**15. Binding Affinity:** Ligand A (-9.0) has significantly stronger binding affinity than Ligand B (-0.0). This is a substantial advantage, potentially outweighing some of its ADME drawbacks.

**Overall Assessment:**

Ligand A excels in binding affinity and BBB penetration, and has good QED. However, it suffers from higher logP, higher DILI risk, high microsomal clearance, and moderate P-gp efflux. Ligand B has better ADME properties (lower logP, lower DILI, low P-gp efflux, excellent metabolic stability), but its binding affinity is very weak.

Given the importance of affinity for GPCRs, and the substantial difference in binding energy (-9.0 vs -0.0 kcal/mol), Ligand A is the more promising candidate *despite* its ADME liabilities. The strong binding affinity provides a larger window for optimization of the ADME properties. The poor affinity of Ligand B is a more difficult hurdle to overcome.

Output:
1
2025-04-17 07:12:27,080 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (390.456 Da) is slightly higher than Ligand B (341.415 Da), but both are acceptable.

**TPSA:** Ligand A (58.12) is excellent for CNS penetration, well below the 90 A^2 threshold. Ligand B (107.77) is higher but still reasonable, though less ideal for CNS targets.

**logP:** Ligand A (4.853) is a bit high, potentially leading to solubility issues and off-target interactions. Ligand B (1.136) is very low, which could hinder membrane permeability and potentially reduce binding affinity.

**H-Bond Donors/Acceptors:** Ligand A (HBD=1, HBA=5) and Ligand B (HBD=2, HBA=5) both fall within acceptable ranges.

**QED:** Both ligands have reasonable QED values (A: 0.812, B: 0.689), indicating good drug-like properties.

**DILI:** Ligand A (68.98) has a higher DILI risk than Ligand B (42.846), which is preferable.

**BBB:** This is a critical parameter for a CNS target like DRD2. Ligand A has a very high BBB penetration percentile (94.843), which is excellent. Ligand B's BBB percentile (57.193) is significantly lower and less desirable.

**Caco-2 Permeability:** Ligand A (-4.817) and Ligand B (-5.249) both have negative Caco-2 values, indicating poor permeability.

**Aqueous Solubility:** Ligand A (-4.872) and Ligand B (-2.429) both have negative solubility values, indicating poor solubility.

**hERG Inhibition:** Ligand A (0.779) has a slightly higher hERG risk than Ligand B (0.098), which is preferable.

**Microsomal Clearance:** Ligand A (35.042) has a higher microsomal clearance than Ligand B (0.366), meaning it is less metabolically stable.

**In vitro Half-Life:** Ligand A (-7.844) has a longer half-life than Ligand B (-4.806).

**P-gp Efflux:** Ligand A (0.581) has lower P-gp efflux liability than Ligand B (0.011), which is beneficial for CNS penetration.

**Binding Affinity:** Ligand B (-8.1 kcal/mol) has a slightly better binding affinity than Ligand A (-9.3 kcal/mol). However, the difference is not substantial enough to overcome the other significant drawbacks of Ligand B.

**Overall Assessment:**

Ligand A is the more promising candidate. While its logP is a bit high and Caco-2 permeability and solubility are poor, it excels in BBB penetration, has acceptable DILI and P-gp efflux, and a good half-life. The slightly weaker binding affinity is outweighed by its superior ADME properties, particularly its high BBB penetration, which is crucial for a CNS-targeting drug. Ligand B's low logP and poor BBB penetration are major drawbacks that make it less likely to be a viable drug candidate, despite its slightly better binding affinity.

Output:
1
2025-04-17 07:12:27,080 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (347.459 and 374.853 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (75.44) is better than Ligand B (77.0) and both are below the 90 A^2 threshold for CNS targets.

**logP:** Ligand A (2.858) is optimal, while Ligand B (3.753) is slightly higher but still acceptable.

**H-Bond Donors:** Both ligands have 1 HBD, which is within the desirable limit of <=5.

**H-Bond Acceptors:** Ligand A has 4 HBAs, and Ligand B has 6. Both are within the acceptable limit of <=10, but Ligand A is preferable.

**QED:** Ligand A (0.858) has a significantly better QED score than Ligand B (0.688), indicating a more drug-like profile.

**DILI:** Ligand A (41.373) has a much lower DILI risk than Ligand B (89.802). This is a significant advantage for Ligand A.

**BBB:** Ligand A (84.606) has a significantly higher BBB penetration percentile than Ligand B (32.571). This is *crucial* for a CNS target like DRD2.

**Caco-2 Permeability:** Both have negative values, which is unusual. However, the magnitude is similar, so this isn't a major differentiator.

**Aqueous Solubility:** Both have negative values, indicating poor solubility. Ligand B (-4.023) is slightly worse than Ligand A (-2.58).

**hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.357 and 0.32), which is excellent.

**Microsomal Clearance:** Ligand A (47.424) and Ligand B (41.91) are similar, indicating comparable metabolic stability.

**In vitro Half-Life:** Ligand A (-19.822) has a worse half-life than Ligand B (-0.741). This is a drawback for Ligand A.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.282 and 0.258), which is favorable for CNS penetration.

**Binding Affinity:** Both ligands have excellent binding affinities (-9.4 and -8.8 kcal/mol). Ligand A is slightly better (-9.4 kcal/mol).

**Overall Assessment:**

Ligand A is significantly better due to its superior BBB penetration (84.6 vs 32.6), lower DILI risk (41.4 vs 89.8), and higher QED score (0.858 vs 0.688). While Ligand A has a slightly worse in vitro half-life, the other advantages, particularly the BBB penetration, outweigh this drawback for a CNS-targeting drug. The binding affinity difference is small.

Output:
1
2025-04-17 07:12:27,080 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (375.563 and 367.475 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (48.99) is excellent, well below the 90 A^2 threshold for CNS targets. Ligand B (89.35) is pushing the limit, but still potentially acceptable.

**logP:** Ligand A (4.093) is at the higher end of the optimal range (1-3), potentially leading to solubility issues. Ligand B (1.411) is a bit low, potentially hindering permeation.

**H-Bond Donors/Acceptors:** Both have acceptable HBD counts (1). Ligand A (4 HBA) is better than Ligand B (7 HBA). Higher HBA can sometimes reduce permeability.

**QED:** Both ligands have good QED scores (0.53 and 0.784), indicating drug-like properties.

**DILI:** Ligand A (39.667) has a lower DILI risk than Ligand B (63.513), which is a significant advantage.

**BBB:** Ligand A (39.822) has a lower BBB penetration than Ligand B (45.677). While both are below the desirable >70 for CNS targets, Ligand B is slightly better.

**Caco-2 Permeability:** Both have negative Caco-2 values (-5.32 and -5.237) which is unusual and suggests poor permeability.

**Aqueous Solubility:** Both have negative solubility values (-3.495 and -2.738), indicating very poor aqueous solubility.

**hERG:** Ligand A (0.834) has a slightly higher hERG risk than Ligand B (0.068), which is a significant advantage for Ligand B.

**Microsomal Clearance:** Ligand A (89.125) has a higher microsomal clearance than Ligand B (40.213), indicating faster metabolism and lower metabolic stability.

**In vitro Half-Life:** Ligand A (-0.024) has a very short half-life, while Ligand B (-12.192) is also short, but less so.

**P-gp Efflux:** Ligand A (0.469) has lower P-gp efflux than Ligand B (0.062), which is a positive for CNS exposure.

**Binding Affinity:** Ligand A (-7.7 kcal/mol) has a significantly stronger binding affinity than Ligand B (-6.6 kcal/mol) - a difference of 1.1 kcal/mol. This is a substantial advantage.

**Overall Assessment:**

The primary trade-off is between potency (affinity) and ADME properties. Ligand A has a much stronger binding affinity, which is crucial for GPCRs. However, it suffers from higher metabolic clearance, lower BBB penetration, and poorer solubility. Ligand B has better BBB penetration and lower hERG risk, but significantly weaker binding affinity.

Given the importance of strong binding for GPCRs, and the fact that the affinity difference is substantial (1.1 kcal/mol), I would prioritize Ligand A despite its ADME drawbacks. The poor solubility and permeability could potentially be addressed through formulation strategies. The higher DILI risk is also a concern, but potentially manageable. The stronger binding is likely to translate to greater efficacy.

Output:
0
2025-04-17 07:12:27,081 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (356.413 and 344.463 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (60.85) is better than Ligand B (68.1). Both are below the 90 A^2 threshold desirable for CNS targets, but A is closer to optimal.

**logP:** Both ligands have good logP values (1.644 and 2.433), falling within the 1-3 range.

**H-Bond Donors/Acceptors:** Both have 1 HBD, which is good. Ligand A has 3 HBA, while Ligand B has 7.  Ligand A is preferable here as it is closer to the <10 HBA guideline.

**QED:** Both ligands have acceptable QED values (0.833 and 0.793), indicating good drug-like properties.

**DILI:** Ligand A (13.804) has a significantly lower DILI risk than Ligand B (36.332). This is a substantial advantage.

**BBB:** Both have very good BBB penetration (75.107 and 74.176), exceeding the 70% threshold for CNS targets.

**Caco-2 Permeability:** Both have negative Caco-2 values (-4.572 and -5.165), which is unusual and indicates poor permeability. However, since we are prioritizing CNS targets, intestinal absorption is less critical.

**Aqueous Solubility:** Both have negative solubility values (-2.164 and -2.532), indicating poor solubility. This could be a formulation challenge, but is less critical for CNS targets if BBB penetration is good.

**hERG:** Both ligands have low hERG inhibition risk (0.509 and 0.467).

**Microsomal Clearance:** Ligand A (22.967) has lower microsomal clearance than Ligand B (30.159), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand B has a much longer in vitro half-life (25.399 hours) than Ligand A (-2.029 hours). This is a significant advantage for Ligand B.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.015 and 0.129).

**Binding Affinity:** Ligand A (-8.8 kcal/mol) has a significantly stronger binding affinity than Ligand B (-7.5 kcal/mol). This 1.3 kcal/mol difference is substantial and can outweigh some ADME drawbacks.

**Overall Assessment:**

Ligand A excels in binding affinity and DILI risk, and has better TPSA and HBA counts. Ligand B has a better half-life. However, the substantial difference in binding affinity (-8.8 vs -7.5 kcal/mol) and the significantly lower DILI risk for Ligand A make it the more promising candidate, despite the shorter half-life. The good BBB penetration of both mitigates concerns about poor Caco-2 and solubility.

Output:
1
2025-04-17 07:12:27,081 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (350.459 Da) is slightly preferred as it's closer to the lower end, potentially aiding permeability.

**TPSA:** Ligand A (78.87) is significantly better than Ligand B (68.55). For CNS targets, we want TPSA <= 90, and lower is better. Ligand A is closer to the ideal range.

**logP:** Ligand A (1.241) is optimal (1-3). Ligand B (4.063) is at the higher end of acceptable, potentially causing solubility issues and off-target interactions.

**H-Bond Donors/Acceptors:** Ligand A (2 HBD, 4 HBA) is preferable to Ligand B (0 HBD, 5 HBA). Both are within acceptable limits, but a balance is good.

**QED:** Both ligands have similar QED values (0.353 and 0.39), indicating moderate drug-likeness.

**DILI:** Ligand A (6.669) has a much lower DILI risk than Ligand B (68.864), a significant advantage.

**BBB:** Ligand A (54.478) is better than Ligand B (18.651), but neither is ideal (>70). However, given that DRD2 is a CNS target, BBB penetration is critical. Ligand A is substantially better in this regard.

**Caco-2 Permeability:** Ligand A (-4.83) is better than Ligand B (-4.446), indicating better intestinal absorption.

**Aqueous Solubility:** Ligand A (-1.235) is better than Ligand B (-6.446), which is a major concern for Ligand B.

**hERG Inhibition:** Ligand A (0.248) has a lower hERG risk than Ligand B (0.537).

**Microsomal Clearance:** Ligand A (2.501) has a much lower microsomal clearance than Ligand B (91.713), indicating better metabolic stability.

**In vitro Half-Life:** Ligand A (-13.382) has a much longer in vitro half-life than Ligand B (34.391).

**P-gp Efflux:** Ligand A (0.052) has a much lower P-gp efflux liability than Ligand B (0.296), which is crucial for CNS penetration.

**Binding Affinity:** Both ligands have very similar binding affinities (-7.4 and -7.5 kcal/mol). This is a minor difference, and other factors become more important.

**Overall Assessment:**

Ligand A is significantly superior to Ligand B across almost all ADME-Tox properties. While neither ligand has excellent BBB penetration, Ligand A is much better in this regard. Ligand A also has lower DILI risk, better solubility, better metabolic stability, lower P-gp efflux, and lower hERG risk. The similar binding affinities make the ADME differences the deciding factor.

Output:
0
2025-04-17 07:12:27,081 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (449.7) is towards the higher end, while Ligand B (364.5) is more optimal.

**TPSA:** Ligand A (78.9) is excellent for CNS penetration, well below the 90 A^2 threshold. Ligand B (88.33) is still reasonable, but less ideal.

**logP:** Both ligands have good logP values (A: 3.807, B: 2.669) falling within the 1-3 range.

**H-Bond Donors/Acceptors:** Both ligands have acceptable HBD (A: 0, B: 1) and HBA (A: 6, B: 6) counts.

**QED:** Both ligands have good QED scores (A: 0.493, B: 0.778), with Ligand B being significantly better.

**DILI:** Ligand A (89.066) has a higher DILI risk than Ligand B (55.991). This is a significant concern for A.

**BBB:** Ligand A (40.52) has a poor BBB percentile, making CNS penetration unlikely. Ligand B (58.821) is better, but still not ideal (we want >70).

**Caco-2 Permeability:** Ligand A (-4.655) has very poor Caco-2 permeability. Ligand B (-5.08) is also poor, but slightly better.

**Aqueous Solubility:** Both ligands have poor aqueous solubility (A: -4.855, B: -1.947).

**hERG Inhibition:** Both ligands have low hERG inhibition risk (A: 0.47, B: 0.418).

**Microsomal Clearance:** Ligand A (55.672) has lower microsomal clearance than Ligand B (86.155), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (91.009) has a much longer in vitro half-life than Ligand B (-21.729). This is a significant advantage for A.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (A: 0.53, B: 0.112).

**Binding Affinity:** Ligand B (-7.7 kcal/mol) has a slightly better binding affinity than Ligand A (-7.4 kcal/mol), although the difference is small.

**Overall Assessment:**

Ligand B is the more promising candidate. While its BBB penetration isn't ideal, it's significantly better than Ligand A's. It also has a better QED score and a much lower DILI risk. The slight advantage in binding affinity for Ligand B is a bonus. Ligand A suffers from poor BBB penetration, poor Caco-2 permeability, and a higher DILI risk, outweighing its better metabolic stability and longer half-life. Given the CNS target (DRD2), BBB penetration is critical.

Output:
1
2025-04-17 07:12:27,081 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (350.423 and 348.487 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (109.22) is higher than the preferred <90 for CNS targets, while Ligand B (60.85) is well within the optimal range. This is a significant advantage for Ligand B.

**logP:** Ligand A (-0.243) is quite low, potentially hindering membrane permeability. Ligand B (2.509) is within the optimal 1-3 range. This favors Ligand B.

**H-Bond Donors/Acceptors:** Ligand A has 2 HBD and 6 HBA, which are acceptable. Ligand B has 1 HBD and 3 HBA, also acceptable.

**QED:** Both ligands have similar QED values (0.688 and 0.613), indicating good drug-likeness.

**DILI:** Ligand A (62.233) has a moderate DILI risk, while Ligand B (13.959) has a very low risk. This is a substantial advantage for Ligand B.

**BBB:** Ligand A (43.583) has a relatively low BBB penetration percentile, which is concerning for a CNS target. Ligand B (68.127) has a much better BBB percentile, exceeding the desirable >70 threshold. This is a critical advantage for Ligand B.

**Caco-2 Permeability:** Ligand A (-5.661) has poor Caco-2 permeability, consistent with its low logP. Ligand B (-4.54) is also not great, but better than A.

**Aqueous Solubility:** Both ligands have poor aqueous solubility (-1.163 and -1.571). This could pose formulation challenges, but isn't a dealbreaker if other properties are favorable.

**hERG Inhibition:** Ligand A (0.024) has very low hERG inhibition risk, while Ligand B (0.22) is slightly higher, but still acceptable.

**Microsomal Clearance:** Ligand A (2.659) has lower clearance, suggesting better metabolic stability than Ligand B (22.628).

**In vitro Half-Life:** Ligand A (25.727) has a longer half-life than Ligand B (-4.157). This is a positive for Ligand A.

**P-gp Efflux:** Ligand A (0.011) has very low P-gp efflux, which is excellent for CNS penetration. Ligand B (0.13) is slightly higher, but still relatively low.

**Binding Affinity:** Ligand B (-8.3 kcal/mol) has significantly stronger binding affinity than Ligand A (0.0 kcal/mol). This is a major advantage for Ligand B, and can potentially offset some of its ADME drawbacks.

**Overall Assessment:**

Ligand B is clearly the more promising candidate. While both have solubility issues, Ligand B excels in key areas for a CNS-targeting GPCR ligand: TPSA, logP, BBB penetration, DILI risk, and, most importantly, binding affinity. The stronger affinity of Ligand B is a significant advantage. Although Ligand A has better metabolic stability and P-gp efflux, the superior BBB penetration and binding affinity of Ligand B outweigh these benefits.

Output:
1
2025-04-17 07:12:27,082 - INFO - Okay, let's analyze these two ligands for their potential as DRD2 drug candidates. DRD2 is a GPCR in the CNS, so BBB penetration, logP, Pgp efflux, TPSA, and binding affinity are key.

**Ligand A: [370.431, 115.89 ,  -0.385,   2.   ,   5.   ,   0.662,  65.491,  46.762, -5.314,  -2.091,   0.113,  -2.881,  -6.641,   0.015,  -7.7  ]**

*   **MW:** 370.431 Da - Within the ideal range (200-500).
*   **TPSA:** 115.89 - Acceptable, but approaching the upper limit for CNS targets (ideally <90).
*   **logP:** -0.385 - Suboptimal. Too low, potentially hindering membrane permeability.
*   **HBD:** 2 - Good.
*   **HBA:** 5 - Good.
*   **QED:** 0.662 - Good, indicates drug-likeness.
*   **DILI:** 65.491 - Moderate risk.
*   **BBB:** 46.762 - Below the desired threshold of >70 for CNS targets. A significant concern.
*   **Caco-2:** -5.314 - Very poor permeability.
*   **Solubility:** -2.091 - Very poor solubility.
*   **hERG:** 0.113 - Low risk.
*   **Cl_mic:** -2.881 - Good, indicates low metabolic clearance.
*   **t1/2:** -6.641 - Good, indicates long half-life.
*   **Pgp:** 0.015 - Low efflux, favorable for CNS exposure.
*   **Affinity:** -7.7 kcal/mol - Excellent binding affinity.

**Ligand B: [358.467,  76.02 ,   1.844,   2.   ,   5.   ,   0.742,  61.07 ,  55.603, -5.533,  -3.061,   0.242,  60.729,  27.224,   0.136,  -9.   ]**

*   **MW:** 358.467 Da - Within the ideal range (200-500).
*   **TPSA:** 76.02 - Excellent, well within the ideal range for CNS targets.
*   **logP:** 1.844 - Optimal.
*   **HBD:** 2 - Good.
*   **HBA:** 5 - Good.
*   **QED:** 0.742 - Good, indicates drug-likeness.
*   **DILI:** 61.07 - Moderate risk.
*   **BBB:** 55.603 - Below the desired threshold of >70, but better than Ligand A.
*   **Caco-2:** -5.533 - Very poor permeability.
*   **Solubility:** -3.061 - Very poor solubility.
*   **hERG:** 0.242 - Low risk.
*   **Cl_mic:** 60.729 - High metabolic clearance, a concern.
*   **t1/2:** 27.224 - Moderate half-life.
*   **Pgp:** 0.136 - Low efflux, favorable for CNS exposure.
*   **Affinity:** -9.0 kcal/mol - Exceptional binding affinity, significantly better than Ligand A.

**Comparison and Decision:**

While both ligands have poor Caco-2 permeability and solubility, Ligand B is significantly more promising. Its logP is optimal, TPSA is excellent for CNS penetration, and, crucially, its binding affinity is *much* stronger (-9.0 vs -7.7 kcal/mol). This substantial affinity advantage outweighs the higher metabolic clearance (Cl_mic) and lower BBB compared to Ligand A. Ligand A's negative logP and very low BBB are major drawbacks. The slightly higher DILI risk for both is manageable.

Therefore, Ligand B is the more viable drug candidate.

1
2025-04-17 07:12:27,082 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (341.455 and 343.391 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (62.3) is excellent, well below the 90 A^2 threshold for CNS targets. Ligand B (128.45) is higher, but still potentially acceptable, though less ideal.

**logP:** Ligand A (2.608) is optimal (1-3). Ligand B (0.027) is very low, which is a significant concern for permeability and CNS penetration.

**H-Bond Donors/Acceptors:** Ligand A (1 HBD, 3 HBA) is good. Ligand B (4 HBD, 5 HBA) is also acceptable, but slightly higher.

**QED:** Ligand A (0.916) is excellent, indicating high drug-likeness. Ligand B (0.588) is acceptable, but lower than A.

**DILI:** Ligand A (38.93) has a low DILI risk. Ligand B (58.24) is higher, indicating a moderate risk, but still not alarming.

**BBB:** Ligand A (78.015) has good BBB penetration. Ligand B (23.769) has very poor predicted BBB penetration, a critical drawback for a CNS target like DRD2.

**Caco-2 Permeability:** Ligand A (-4.896) is concerningly low. Ligand B (-6.296) is even lower. Both suggest poor intestinal absorption, but this is less critical for CNS drugs where direct delivery or high permeability across the BBB is prioritized.

**Aqueous Solubility:** Ligand A (-2.962) is low, but not drastically so. Ligand B (-1.289) is also low.

**hERG Inhibition:** Both ligands (0.294 and 0.114) have very low predicted hERG inhibition, which is excellent.

**Microsomal Clearance:** Ligand A (37.691) has moderate clearance. Ligand B (-43.481) has negative clearance, which is unusual and likely an artifact of the prediction method, but suggests very high metabolic stability.

**In vitro Half-Life:** Ligand A (2.189 hours) is relatively short. Ligand B (8.23 hours) is better.

**P-gp Efflux:** Both ligands (0.231 and 0.006) have low P-gp efflux, which is favorable for CNS penetration.

**Binding Affinity:** Ligand A (-9.5 kcal/mol) has significantly stronger binding affinity than Ligand B (-7.9 kcal/mol). This is a substantial advantage.

**Overall Assessment:**

Ligand A is superior due to its excellent TPSA, optimal logP, good BBB penetration, strong binding affinity, and low DILI risk. While its Caco-2 permeability and solubility are not ideal, these are less critical for a CNS-targeted drug. Ligand B suffers from a very low logP and poor BBB penetration, which are major drawbacks for DRD2 targeting. The higher metabolic stability and half-life of Ligand B are not enough to overcome these significant deficiencies. The large affinity difference also favors Ligand A.

Output:
1
2025-04-17 07:12:27,082 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (357.435 and 342.439 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (72.7) is higher than Ligand B (53.76). For a CNS target like DRD2, we ideally want TPSA <= 90, so both are acceptable, but B is better.

**3. logP:** Both ligands have good logP values (2.351 and 2.871), falling within the optimal 1-3 range.

**4. H-Bond Donors:** Ligand A (1) is preferable to Ligand B (0). While both are acceptable, having at least one HBD can aid solubility.

**5. H-Bond Acceptors:** Ligand A (6) is higher than Ligand B (3). Both are within the acceptable limit of <=10, but B is better.

**6. QED:** Both ligands have good QED scores (0.776 and 0.845), indicating good drug-like properties.

**7. DILI:** Ligand A (61.962) has a higher DILI risk than Ligand B (30.942). Lower DILI is preferred, so B is better.

**8. BBB:** This is a critical parameter for CNS targets. Ligand B (83.288) has a significantly higher BBB percentile than Ligand A (49.244). This is a major advantage for B.

**9. Caco-2 Permeability:** Ligand A (-5.057) has worse Caco-2 permeability than Ligand B (-4.424). Higher values are better.

**10. Aqueous Solubility:** Ligand A (-2.814) has worse aqueous solubility than Ligand B (-2.286). Higher values are better.

**11. hERG Inhibition:** Both ligands have low hERG inhibition risk (0.579 and 0.366).

**12. Microsomal Clearance:** Ligand A (24.878) has lower microsomal clearance than Ligand B (55.597), suggesting better metabolic stability. This is a positive for A.

**13. In vitro Half-Life:** Ligand B (40.595) has a longer in vitro half-life than Ligand A (22.731). Longer half-life is generally preferred.

**14. P-gp Efflux:** Ligand A (0.278) has lower P-gp efflux than Ligand B (0.336), meaning it's less likely to be pumped out of the brain, which is good.

**15. Binding Affinity:** Ligand B (-8.2 kcal/mol) has a slightly better binding affinity than Ligand A (-9.2 kcal/mol). While A has a slightly better affinity, the difference is not substantial enough to outweigh other factors.

**Overall Assessment:**

Ligand B clearly emerges as the more promising candidate. Its superior BBB penetration (83.288 vs 49.244), lower DILI risk, longer half-life, and better Caco-2 permeability and solubility outweigh the slightly better affinity and lower clearance of Ligand A. For a CNS target like DRD2, BBB penetration is paramount, and Ligand B excels in this area.

Output:
1
2025-04-17 07:12:27,082 - INFO - Batch 345 complete. Total preferences: 5520
2025-04-17 07:12:27,083 - INFO - Processing batch 346/512...
2025-04-17 07:13:10,708 - INFO - Reasoning:

Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (350.459 and 370.431 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (67.87) is excellent, well below the 90 A^2 threshold for CNS targets. Ligand B (129.56) is higher, but still acceptable, though less ideal.

**3. logP:** Ligand A (1.335) is within the optimal 1-3 range. Ligand B (-1.007) is slightly below 1, which *could* indicate permeability issues, but isn't a dealbreaker.

**4. H-Bond Donors:** Ligand A (1) is good. Ligand B (2) is also acceptable.

**5. H-Bond Acceptors:** Ligand A (4) is good. Ligand B (7) is slightly higher, but still within the acceptable limit of 10.

**6. QED:** Ligand A (0.812) is excellent, indicating high drug-likeness. Ligand B (0.679) is still reasonable, above the 0.5 threshold.

**7. DILI:** Ligand A (18.728) has a very low DILI risk. Ligand B (60.954) is higher, indicating a moderate risk, but not excessively concerning.

**8. BBB:** Ligand A (77.2) is good, exceeding the 70% threshold for CNS targets. Ligand B (19.814) is significantly lower, a major drawback for a CNS target like DRD2.

**9. Caco-2 Permeability:** Ligand A (-4.771) is concerningly low. Ligand B (-5.462) is also low, but similar to A.

**10. Aqueous Solubility:** Ligand A (-1.831) is low. Ligand B (-0.99) is slightly better, but still low.

**11. hERG Inhibition:** Both ligands (0.228 and 0.063) show very low hERG inhibition risk, which is excellent.

**12. Microsomal Clearance:** Ligand A (21.597) has moderate clearance. Ligand B (-18.175) has *negative* clearance, which is not physically possible and likely an error in the data. This is a significant red flag.

**13. In vitro Half-Life:** Ligand A (19.874) has a reasonable half-life. Ligand B (14.55) is lower, but not drastically so.

**14. P-gp Efflux:** Both ligands (0.029 and 0.008) show very low P-gp efflux, which is highly desirable for CNS penetration.

**15. Binding Affinity:** Ligand A (-7.9) has a significantly stronger binding affinity than Ligand B (0.0). This is a substantial advantage.

**Overall Assessment:**

Ligand A is clearly superior. While its Caco-2 and solubility are low, its excellent BBB penetration, strong binding affinity, low DILI risk, and good QED outweigh these drawbacks. Ligand B suffers from a very poor BBB score and an impossible negative microsomal clearance, making it a much less viable candidate. The large difference in binding affinity (-7.9 vs 0.0) is also a critical factor.

Output:
1
2025-04-17 07:13:10,708 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 drug candidates, considering the provided guidelines and GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (364.431 and 356.392 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (109.22) is higher than the preferred <90 for CNS targets, while Ligand B (61.88) is well within the range. This is a significant advantage for Ligand B.

**logP:** Ligand A (1.008) is at the lower end of optimal, potentially hindering permeation. Ligand B (4.065) is slightly above the optimal range, potentially leading to solubility issues, but still acceptable.

**H-Bond Donors/Acceptors:** Ligand A has 2 HBD and 7 HBA, both within acceptable limits. Ligand B has 1 HBD and 3 HBA, also within limits.

**QED:** Both ligands have similar and good QED values (0.819 and 0.849).

**DILI:** Ligand A (82.241) has a higher DILI risk than Ligand B (45.444). This is a concern for Ligand A.

**BBB:** Ligand B (84.219) has a significantly better BBB penetration percentile than Ligand A (53.781). This is crucial for a CNS target like DRD2.

**Caco-2 Permeability:** Ligand A (-5.078) shows poor Caco-2 permeability, suggesting poor intestinal absorption. Ligand B (-4.694) is slightly better, but still not ideal.

**Aqueous Solubility:** Both ligands have poor aqueous solubility (-3.114 and -4.199). This could pose formulation challenges, but is less critical than BBB penetration for a CNS drug.

**hERG:** Both ligands have low hERG inhibition liability (0.165 and 0.796).

**Microsomal Clearance:** Ligand A (0.063) has very low microsomal clearance, suggesting high metabolic stability. Ligand B (37.736) has higher clearance, indicating faster metabolism.

**In vitro Half-Life:** Ligand A (55.124) has a longer in vitro half-life than Ligand B (17.871).

**P-gp Efflux:** Ligand A (0.018) has very low P-gp efflux, which is favorable for CNS penetration. Ligand B (0.135) has slightly higher efflux.

**Binding Affinity:** Both ligands have very similar and strong binding affinities (-8.6 and -8.0 kcal/mol). The difference is less than the 1.5 kcal/mol threshold.

**Overall Assessment:**

Ligand B is the more promising candidate. While its logP is slightly high and solubility is poor, its significantly better BBB penetration (84.219 vs 53.781) and lower DILI risk (45.444 vs 82.241) are crucial advantages for a CNS-targeting drug. The slightly higher metabolic clearance and lower half-life of Ligand B are less concerning than the poor BBB penetration of Ligand A. The similar binding affinities mean that the ADME advantages of Ligand B outweigh any minor potency differences.

Output:
1
2025-04-17 07:13:10,709 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (371.409 and 348.422 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (71.53) is better than Ligand B (74.33). Both are below the 90 A^2 threshold for CNS targets, which is good.

**3. logP:** Both ligands have good logP values (2.27 and 1.414), falling within the optimal 1-3 range. Ligand B is slightly lower, which *could* indicate slightly better solubility, but isn't a major concern.

**4. H-Bond Donors:** Ligand A (1) is preferable to Ligand B (2). Lower HBD generally improves permeability.

**5. H-Bond Acceptors:** Ligand A (5) is preferable to Ligand B (4). Lower HBA generally improves permeability.

**6. QED:** Both ligands have similar QED values (0.771 and 0.763), indicating good drug-likeness.

**7. DILI:** Ligand B (43.66) has a significantly lower DILI risk than Ligand A (80.535). This is a substantial advantage for Ligand B.

**8. BBB:** Ligand B (70.531) has a slightly better BBB penetration percentile than Ligand A (66.266). While both are above 70, which is desirable for CNS targets, Ligand B is better.

**9. Caco-2 Permeability:** Ligand A (-4.873) has better Caco-2 permeability than Ligand B (-4.721).

**10. Aqueous Solubility:** Ligand B (-1.698) has better aqueous solubility than Ligand A (-3.687).

**11. hERG Inhibition:** Both ligands have low hERG inhibition risk (0.658 and 0.389).

**12. Microsomal Clearance:** Ligand A (46.09) has lower microsomal clearance than Ligand B (9.84). This suggests better metabolic stability for Ligand A.

**13. In vitro Half-Life:** Ligand A (-32.108) has a significantly longer in vitro half-life than Ligand B (0.444). This is a major advantage for Ligand A.

**14. P-gp Efflux:** Ligand A (0.22) has lower P-gp efflux than Ligand B (0.026). Lower P-gp efflux is better for CNS exposure.

**15. Binding Affinity:** Both ligands have very similar binding affinities (-8.5 and -8.2 kcal/mol). The difference is less than the 1.5 kcal/mol threshold where affinity overwhelmingly dictates choice.

**Overall Assessment:**

Ligand A has advantages in metabolic stability (lower Cl_mic, longer t1/2), Caco-2 permeability, and P-gp efflux. However, Ligand B demonstrates a significantly lower DILI risk and slightly better BBB penetration and aqueous solubility. Given the GPCR-specific priorities, BBB and lower toxicity (DILI) are crucial. The slight advantage in BBB and the substantial advantage in DILI for Ligand B outweigh the benefits of Ligand A's metabolic stability and permeability. The similar binding affinity further supports this conclusion.

Output:
1
2025-04-17 07:13:10,709 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (370.515 Da and 346.431 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (67.87) is better than Ligand B (84.42). For CNS targets, we want TPSA <= 90, both are within this range, but A is closer to the optimal <60 for good CNS penetration.

**logP:** Both ligands have acceptable logP values (1.288 and 1.5), falling within the 1-3 range.

**H-Bond Donors/Acceptors:** Both have 1 HBD and 5 HBA, which are within acceptable limits.

**QED:** Both have good QED scores (0.714 and 0.873), indicating drug-like properties.

**DILI:** Both have relatively low DILI risk (30.438 and 43.428), below the concerning threshold of 60.

**BBB:** Ligand B (70.531) has a better BBB percentile than Ligand A (67.623). Both are reasonably good, but B is slightly more promising for CNS penetration.

**Caco-2 Permeability:** Both have negative Caco-2 values which is unusual. Assuming these are logP values, both are poor.

**Aqueous Solubility:** Both have negative solubility values which is unusual.

**hERG:** Both have very low hERG inhibition liability (0.419 and 0.19), indicating a low risk of cardiotoxicity.

**Microsomal Clearance:** Both have similar microsomal clearance values (40.279 and 43.862), suggesting comparable metabolic stability.

**In vitro Half-Life:** Ligand B (-13.989) has a significantly *shorter* half-life than Ligand A (6.855). This is a major drawback for B.

**P-gp Efflux:** Both have very low P-gp efflux liability (0.065 and 0.075), which is favorable for CNS exposure.

**Binding Affinity:** Ligand B (-7.8 kcal/mol) has a significantly stronger binding affinity than Ligand A (-6.5 kcal/mol). This is a 1.3 kcal/mol difference, which is substantial and can outweigh some ADME drawbacks.

**Overall Assessment:**

Ligand B has a better BBB score and significantly stronger binding affinity. However, its significantly shorter in vitro half-life is a critical concern. A short half-life translates to frequent dosing, potentially reducing patient compliance and increasing the risk of side effects. Ligand A has a better TPSA and a more reasonable half-life. While its affinity is lower, the difference might be acceptable given the better overall ADME profile. Considering the GPCR-specific priorities, the balance tips towards Ligand A due to the importance of metabolic stability and reasonable CNS penetration.

Output:
0
2025-04-17 07:13:10,709 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 drug candidates, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (350.434 and 355.41 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (58.64) is excellent, well below the 90 A^2 threshold for CNS targets. Ligand B (111.55) is higher, but still potentially acceptable, though less optimal.

**logP:** Ligand A (2.609) is within the optimal 1-3 range. Ligand B (1.348) is at the lower end, which *could* hinder permeability.

**H-Bond Donors/Acceptors:** Ligand A (HBD=1, HBA=3) is favorable. Ligand B (HBD=4, HBA=5) is slightly higher, but still within reasonable limits.

**QED:** Ligand A (0.803) has a strong drug-like profile. Ligand B (0.534) is acceptable, but less ideal.

**DILI:** Ligand A (21.055) has a very low DILI risk. Ligand B (45.483) is moderate, but still acceptable.

**BBB:** This is critical for a CNS target like DRD2. Ligand A (89.531) has excellent BBB penetration potential. Ligand B (33.656) is significantly lower and concerning for CNS exposure.

**Caco-2:** Ligand A (-4.391) and Ligand B (-5.024) both have negative values, which is unusual. It's difficult to interpret without knowing the scale, but generally lower values indicate poorer permeability.

**Solubility:** Both ligands have negative solubility values (-2.368 and -2.202 respectively), again, the scale is unknown.

**hERG:** Both ligands show low hERG inhibition risk (0.741 and 0.247).

**Microsomal Clearance:** Ligand A (-2.594) has negative clearance, which is not physically possible. This is likely an error in the data. Ligand B (21.488) has a higher clearance, indicating faster metabolism.

**In vitro Half-Life:** Ligand A (5.363) has a reasonable half-life. Ligand B (3.899) is shorter.

**P-gp Efflux:** Ligand A (0.092) shows low P-gp efflux, which is good for CNS penetration. Ligand B (0.065) also shows low P-gp efflux.

**Binding Affinity:** Ligand A (-8.1 kcal/mol) has a significantly stronger binding affinity than Ligand B (-7.8 kcal/mol). While both are good, the 0.3 kcal/mol difference is meaningful.

**Overall Assessment:**

Ligand A is clearly superior. It has better TPSA, logP, QED, DILI, *significantly* better BBB penetration, and stronger binding affinity. The negative clearance value for Ligand A is a data anomaly, but even ignoring that, the other properties are more favorable. Ligand B's lower BBB penetration is a major drawback for a CNS target. The slightly better affinity of A also outweighs any minor ADME concerns.

Output:
1
2025-04-17 07:13:10,709 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B based on the provided guidelines, prioritizing GPCR-specific properties (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (347.375 and 349.475 Da) fall within the ideal range of 200-500 Da.

**TPSA:** Ligand A (92.84) is slightly above the optimal <90 for CNS targets, but still reasonable. Ligand B (71.53) is well within the desired range. This favors Ligand B.

**logP:** Both ligands have good logP values (1.986 and 2.195), falling within the 1-3 range.

**H-Bond Donors/Acceptors:** Both have 1 HBD, which is good. Ligand A has 6 HBA, while Ligand B has 4. Both are acceptable (<=10), but Ligand B is slightly better.

**QED:** Ligand A (0.916) has a significantly higher QED than Ligand B (0.742), indicating better overall drug-likeness. This favors Ligand A.

**DILI:** Ligand A (80.962) has a higher DILI risk than Ligand B (21.985). This is a significant advantage for Ligand B.

**BBB:** Both ligands have excellent BBB penetration (74.719% and 73.401%), exceeding the 70% threshold for CNS targets. This is comparable for both.

**Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and potentially problematic. It's difficult to interpret without knowing the scale, but it suggests poor permeability.

**Aqueous Solubility:** Both have negative solubility values, which is also unusual and problematic. It suggests poor solubility.

**hERG:** Both have low hERG inhibition liability (0.323 and 0.568), which is good.

**Microsomal Clearance:** Ligand A (23.806) has significantly lower microsomal clearance than Ligand B (57.771), indicating better metabolic stability. This favors Ligand A.

**In vitro Half-Life:** Ligand A (18.058) has a longer in vitro half-life than Ligand B (12.567), which is desirable. This favors Ligand A.

**P-gp Efflux:** Both have very low P-gp efflux liability (0.055 and 0.074), which is excellent for CNS penetration. This is comparable for both.

**Binding Affinity:** Ligand B (-7.8 kcal/mol) has a slightly better binding affinity than Ligand A (-8.6 kcal/mol). While both are excellent, the difference is relatively small.

**Overall Assessment:**

Ligand A excels in QED, metabolic stability (Cl_mic), and half-life. However, it has a significantly higher DILI risk. Ligand B has a much lower DILI risk and a slightly better binding affinity, and a lower TPSA. Considering the CNS target and the importance of minimizing toxicity (DILI), Ligand B appears to be the more promising candidate, despite the slightly lower QED and slightly weaker binding affinity. The lower TPSA of Ligand B is also beneficial for CNS penetration.



Output:
1
2025-04-17 07:13:10,710 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (351.451 and 340.391 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (91.65) is better than Ligand B (103.41). Both are reasonably good for CNS penetration, being under 140, and Ligand A is closer to the preferred <90 for CNS targets.

**logP:** Both ligands have similar logP values (0.489 and 0.524), which are a bit low. While not ideal, they aren't drastically outside the 1-3 range. This could potentially be compensated for by other favorable properties.

**H-Bond Donors/Acceptors:** Ligand A has 3 HBD and 6 HBA, while Ligand B has 1 HBD and 8 HBA. Both are within acceptable limits (<=5 HBD and <=10 HBA).

**QED:** Both ligands have good QED scores (0.622 and 0.702), indicating good drug-like properties.

**DILI:** Ligand A (8.22) has a significantly lower DILI risk than Ligand B (69.988). This is a major advantage for Ligand A.

**BBB:** Ligand A (17.914) has a much better BBB percentile than Ligand B (36.487). This is critical for a CNS target like DRD2.

**Caco-2 Permeability:** Both have negative Caco-2 values (-5.36 and -5.469), which is unusual and suggests poor permeability. This is a concern for both.

**Aqueous Solubility:** Ligand A (0.175) has very poor solubility, while Ligand B (-1.683) is even worse. This is a significant drawback for both, potentially hindering formulation and bioavailability.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.505 and 0.118).

**Microsomal Clearance:** Ligand A (-27.644) has a much lower (better) microsomal clearance than Ligand B (16.729), indicating greater metabolic stability.

**In vitro Half-Life:** Ligand A (25.06) has a longer half-life than Ligand B (10.244), which is desirable.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.019 and 0.021), which is good for CNS penetration.

**Binding Affinity:** Ligand B (-8.8 kcal/mol) has a slightly better binding affinity than Ligand A (-7.5 kcal/mol). However, the difference is not exceptionally large (1.3 kcal/mol), and can potentially be overcome by other favorable properties.

**Overall Assessment:**

Ligand A is significantly better overall, despite the slightly weaker binding affinity. Its superior BBB penetration, much lower DILI risk, better metabolic stability (lower Cl_mic, longer t1/2), and better TPSA outweigh the slightly weaker binding. The poor solubility and Caco-2 permeability are concerning for both, but formulation strategies might address the solubility issue. The CNS target prioritization heavily favors Ligand A due to its significantly improved BBB score.

Output:
0
2025-04-17 07:13:10,710 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (353.463 and 365.503 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Both ligands have TPSA values (78.95 and 79.26) below the 90 Angstroms threshold desirable for CNS targets, which is good.

**3. logP:** Both ligands have logP values (0.633 and 0.719) which are a bit low. Ideally, we want 1-3. This could potentially hinder permeability.

**4. H-Bond Donors:** Ligand A (1 HBD) is better than Ligand B (2 HBDs) in terms of permeability.

**5. H-Bond Acceptors:** Ligand A (4 HBA) is better than Ligand B (6 HBA) in terms of permeability.

**6. QED:** Both ligands have similar QED values (0.786 and 0.777), indicating good drug-like properties.

**7. DILI:** Ligand A (31.563) has a significantly lower DILI risk than Ligand B (48.623), which is a major advantage.

**8. BBB:** Ligand A (52.268) has a slightly better BBB percentile than Ligand B (48.313), but both are below the desirable >70 for CNS targets.

**9. Caco-2 Permeability:** Ligand A (-4.561) has a worse Caco-2 permeability than Ligand B (-5.555).

**10. Aqueous Solubility:** Ligand A (-1.263) has better aqueous solubility than Ligand B (-2.184).

**11. hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.142 and 0.19).

**12. Microsomal Clearance:** Ligand A (18.916) has lower microsomal clearance than Ligand B (29.851), suggesting better metabolic stability.

**13. In vitro Half-Life:** Ligand B (25.249) has a longer in vitro half-life than Ligand A (9.668).

**14. P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.013 and 0.02).

**15. Binding Affinity:** Ligand B (-7.4 kcal/mol) has a significantly stronger binding affinity than Ligand A (-6.3 kcal/mol). This is a 1.1 kcal/mol difference, which is substantial and can outweigh some ADME drawbacks.

**Overall Assessment:**

Ligand B has a significantly better binding affinity, which is the most crucial factor. While its DILI risk and BBB penetration are slightly worse than Ligand A, the substantial difference in affinity (-7.4 vs -6.3) is likely to be more impactful for efficacy. The slightly longer half-life of Ligand B is also a positive. The lower logP values for both are a concern, but the stronger binding of Ligand B may compensate for this.

Output:
1
2025-04-17 07:13:10,710 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (374.459 and 354.447 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (102.01) is slightly above the optimal <90 for CNS targets, while Ligand B (88.1) is within the desired range. This gives a slight edge to Ligand B.

**logP:** Ligand A (-0.463) is a bit low, potentially hindering permeability. Ligand B (0.474) is closer to the optimal 1-3 range. This favors Ligand B.

**H-Bond Donors/Acceptors:** Ligand A (HBD=1, HBA=6) and Ligand B (HBD=2, HBA=5) both have reasonable numbers of H-bond donors and acceptors, well within the guidelines.

**QED:** Both ligands have acceptable QED scores (0.671 and 0.489), indicating reasonable drug-likeness. Ligand A is slightly better.

**DILI:** Ligand A (41.76) has a slightly higher DILI risk than Ligand B (25.553), although both are below the concerning threshold of 60. Ligand B is preferred.

**BBB:** This is crucial for a CNS target like DRD2. Ligand A has a good BBB penetration percentile (70.454), exceeding the desirable >70 threshold. Ligand B (56.805) is significantly lower, a major drawback. This is a significant advantage for Ligand A.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.865 and -4.714) which is unusual and indicates very poor permeability.

**Aqueous Solubility:** Both ligands have negative solubility values (-1.153 and -1.034) which is also unusual and indicates very poor solubility.

**hERG Inhibition:** Ligand A (0.082) has a very low hERG risk, while Ligand B (0.332) is slightly higher, but still acceptable. Ligand A is preferred.

**Microsomal Clearance:** Ligand A (-0.569) suggests better metabolic stability (lower clearance) than Ligand B (9.904). This is a strong advantage for Ligand A.

**In vitro Half-Life:** Ligand A (31.195) has a much longer half-life than Ligand B (8.8). This is a significant advantage for Ligand A.

**P-gp Efflux:** Ligand A (-9) suggests lower P-gp efflux, which is beneficial for CNS penetration. Ligand B (0.038) suggests some P-gp efflux. Ligand A is preferred.

**Binding Affinity:** Ligand B (-7.4) has a significantly stronger binding affinity than Ligand A (-9). This is a substantial advantage for Ligand B, potentially outweighing some of the ADME drawbacks.

**Overall Assessment:**

While Ligand B has a superior binding affinity, Ligand A demonstrates a much more favorable ADME profile, particularly regarding BBB penetration, metabolic stability, and P-gp efflux. The significantly better BBB (70.454 vs 56.805) and lower P-gp efflux are critical for CNS drug development. The improved metabolic stability (lower Cl_mic and longer t1/2) also contribute to a more promising profile. The slightly lower logP and TPSA of Ligand B are beneficial, but the affinity difference is substantial.

Considering the GPCR-specific priorities and the overall balance of properties, the stronger binding affinity of Ligand B is likely to outweigh the ADME concerns.

Output:
1
2025-04-17 07:13:10,710 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (358.463 and 338.455 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (75.27) is slightly above the optimal <90 for CNS targets, while Ligand B (70.07) is comfortably below. This favors Ligand B.

**3. logP:** Ligand A (2.473) is within the optimal 1-3 range. Ligand B (3.727) is a bit higher, potentially edging towards solubility issues, but still acceptable.

**4. H-Bond Donors:** Ligand A (2) and Ligand B (3) are both within the acceptable limit of <=5.

**5. H-Bond Acceptors:** Ligand A (3) and Ligand B (5) are both within the acceptable limit of <=10.

**6. QED:** Ligand A (0.747) has a better QED score than Ligand B (0.53), indicating a more drug-like profile.

**7. DILI:** Both ligands have similar DILI risk (60.799 and 56.727), both being acceptable (<60 is preferred, but these are not alarming).

**8. BBB:** Ligand B (80.031) has a significantly better BBB penetration score than Ligand A (52.772). This is a *critical* advantage for a CNS target like DRD2.

**9. Caco-2 Permeability:** Ligand A (-4.747) shows poor Caco-2 permeability, while Ligand B (-5.051) is also poor, but slightly better.

**10. Aqueous Solubility:** Both ligands have poor aqueous solubility (-3.778 and -4.03). This could pose formulation challenges, but is less critical than BBB for a CNS drug.

**11. hERG Inhibition:** Ligand A (0.294) shows lower hERG inhibition risk than Ligand B (0.919), which is favorable.

**12. Microsomal Clearance:** Ligand B (69.218) has a higher microsomal clearance than Ligand A (32.648), suggesting faster metabolism and potentially lower exposure.

**13. In vitro Half-Life:** Ligand A (-20.474) has a negative half-life, which is not physically possible and indicates an issue with the data. Ligand B (34.465) has a reasonable half-life.

**14. P-gp Efflux:** Ligand A (0.105) has lower P-gp efflux than Ligand B (0.409), which is beneficial for CNS penetration.

**15. Binding Affinity:** Ligand B (-8.4 kcal/mol) has a significantly stronger binding affinity than Ligand A (-10.1 kcal/mol). This is a substantial advantage, and can often outweigh minor ADME concerns.

**Overall Assessment:**

While Ligand A has a better QED and lower hERG risk and P-gp efflux, Ligand B's *significantly* better BBB penetration and substantially stronger binding affinity are decisive advantages for a DRD2 ligand. The slightly higher logP and clearance of Ligand B are less concerning given the strong affinity and improved CNS exposure. The negative half-life for Ligand A is a major red flag.

Output:
1
2025-04-17 07:13:10,710 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (369.893 Da) and Ligand B (350.507 Da) are both acceptable.

**TPSA:** Ligand A (87.3) is borderline, but acceptable for a CNS target. Ligand B (47.1) is excellent, well below the 90 Angstrom threshold for CNS penetration.

**logP:** Ligand A (1.836) is optimal. Ligand B (0.584) is a bit low, potentially hindering membrane permeability, although not drastically.

**H-Bond Donors:** Ligand A (3) is within the acceptable limit. Ligand B (0) is also good.

**H-Bond Acceptors:** Ligand A (3) is within the acceptable limit. Ligand B (4) is also good.

**QED:** Both ligands have good QED scores (Ligand A: 0.61, Ligand B: 0.728), indicating drug-like properties.

**DILI:** Ligand A (21.946) has a low DILI risk. Ligand B (3.373) has a very low DILI risk, which is excellent.

**BBB:** Ligand A (59.093) is below the desirable threshold of 70% for CNS targets. Ligand B (78.868) is very good, exceeding the 70% threshold. This is a significant advantage for Ligand B.

**Caco-2 Permeability:** Ligand A (-5.07) and Ligand B (-4.783) are both negative, suggesting poor permeability. However, these values are on a scale where negative values are common and don't necessarily preclude activity.

**Aqueous Solubility:** Ligand A (-3.088) and Ligand B (-0.051) are both negative, indicating poor solubility.

**hERG Inhibition:** Both ligands have very low hERG inhibition risk (Ligand A: 0.1, Ligand B: 0.527).

**Microsomal Clearance:** Ligand A (47.774) has moderate clearance. Ligand B (-10.221) has negative clearance, which is excellent and indicates high metabolic stability.

**In vitro Half-Life:** Ligand A (17.609) has a moderate half-life. Ligand B (-10.867) has a negative half-life, which is excellent.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (Ligand A: 0.017, Ligand B: 0.008).

**Binding Affinity:** Ligand A (-7.9 kcal/mol) has a slightly better binding affinity than Ligand B (-7.1 kcal/mol), but the difference is less than 1.5 kcal/mol.

**Overall Assessment:**

Ligand B is the more promising candidate. While Ligand A has slightly better binding affinity, Ligand B excels in several key areas crucial for CNS drug development: significantly better BBB penetration (78.9% vs 59.1%), superior metabolic stability (negative Cl_mic and t1/2), and a very low DILI risk. The slightly lower logP of Ligand B is a minor concern, but the substantial advantages in BBB, metabolic stability, and safety outweigh this drawback. The TPSA is also much more favorable for CNS penetration.

Output:
1
2025-04-17 07:13:10,711 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (355.385 and 349.567 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (65.64) is better than Ligand B (55.63) as it is closer to the ideal <90 for CNS targets.

**3. logP:** Ligand A (1.32) is optimal (1-3), while Ligand B (4.971) is high and could lead to solubility issues and off-target interactions.

**4. H-Bond Donors:** Both have 1 HBD, which is within the acceptable limit of <=5.

**5. H-Bond Acceptors:** Ligand A has 3 HBAs, and Ligand B has 5. Both are within the acceptable limit of <=10.

**6. QED:** Ligand A (0.886) has a significantly better QED score than Ligand B (0.72), indicating better overall drug-likeness.

**7. DILI:** Ligand A (27.801) has a much lower DILI risk than Ligand B (40.83). Both are acceptable, but A is preferred.

**8. BBB:** Ligand B (82.009) has a slightly better BBB penetration percentile than Ligand A (77.821), but both are reasonably good for a CNS target.

**9. Caco-2:** Ligand A (-4.538) is better than Ligand B (-5.149). Higher values indicate better intestinal absorption.

**10. Solubility:** Ligand A (-2.515) is better than Ligand B (-4.689). Higher values indicate better solubility.

**11. hERG:** Both ligands have low hERG inhibition liability (0.661 and 0.498 respectively), which is good.

**12. Cl_mic:** Ligand A (10.507) has a significantly lower microsomal clearance than Ligand B (56.492), suggesting better metabolic stability.

**13. t1/2:** Ligand A (-26.738) has a much longer in vitro half-life than Ligand B (11.579).

**14. Pgp:** Ligand A (0.045) has significantly lower P-gp efflux liability than Ligand B (0.744), which is crucial for CNS penetration.

**15. Binding Affinity:** Ligand B (0.0) has a better binding affinity than Ligand A (-7.4). However, the difference is not large enough to overcome the multiple ADME deficiencies of ligand B.

**Overall Assessment:**

Ligand A is the superior candidate. While Ligand B has slightly better BBB penetration and binding affinity, Ligand A excels in almost all other critical ADME properties. Specifically, Ligand A has a much better logP, QED, DILI, Cl_mic, t1/2, and Pgp efflux profile. These factors are particularly important for a CNS-targeting GPCR like DRD2. The slightly lower BBB and affinity of Ligand A are outweighed by its significantly improved drug-like properties and reduced potential for metabolic clearance and efflux.

Output:
1
2025-04-17 07:13:10,711 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (350.369 and 363.483 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (86.88) is better than Ligand B (62.74), both are below the 90 A^2 threshold for CNS targets.

**3. logP:** Both ligands have good logP values (2.067 and 1.706), falling within the optimal 1-3 range.

**4. H-Bond Donors:** Ligand A has 3 HBD, which is acceptable. Ligand B has 0, which is also acceptable.

**5. H-Bond Acceptors:** Ligand A has 3 HBA, acceptable. Ligand B has 5 HBA, also acceptable.

**6. QED:** Both ligands have good QED scores (0.745 and 0.799), indicating good drug-like properties.

**7. DILI:** Ligand A (70.803) has a higher DILI risk than Ligand B (27.026). This is a significant drawback for Ligand A.

**8. BBB:** Ligand B (69.252) is slightly better than Ligand A (59.093), but both are below the desirable >70 percentile for CNS targets. However, given the other parameters, this isn't a dealbreaker.

**9. Caco-2:** Both have negative Caco-2 values, which is unusual and suggests poor permeability. However, these values are on a strange scale, and it's difficult to interpret without knowing the scale's range.

**10. Solubility:** Both ligands have negative solubility values, again, unusual and difficult to interpret.

**11. hERG:** Both ligands have low hERG inhibition liability (0.432 and 0.249), which is good.

**12. Cl_mic:** Both have similar microsomal clearance values (32.016 and 33.83), suggesting comparable metabolic stability.

**13. t1/2:** Ligand B (13.723) has a significantly longer in vitro half-life than Ligand A (-11.497). This is a major advantage for Ligand B.

**14. Pgp:** Both ligands have low Pgp efflux liability (0.091 and 0.088), which is good for CNS penetration.

**15. Binding Affinity:** Both ligands have excellent binding affinities (-8.8 and -8.5 kcal/mol). The difference of 0.3 kcal/mol is not substantial enough to outweigh other factors.

**Overall Assessment:**

Ligand B is the more promising candidate. While both have good affinity and acceptable physicochemical properties, Ligand B has a significantly lower DILI risk and a much longer in vitro half-life. The slightly better BBB value for Ligand B also contributes to its favorability. The negative Caco-2 and solubility values are concerning for both, but the other advantages of Ligand B outweigh these issues.

Output:
1
2025-04-17 07:13:10,711 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B based on the provided guidelines, prioritizing GPCR-specific properties (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (367.559 and 350.419 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (61.44) is significantly better than Ligand B (113.06). For CNS targets, TPSA should be <= 90, and A is comfortably within this range, while B exceeds it. This is a significant advantage for A.

**logP:** Ligand A (1.872) is optimal (1-3), while Ligand B (0.126) is quite low, potentially hindering permeation. This favors A.

**H-Bond Donors/Acceptors:** Ligand A (HBD=2, HBA=4) and Ligand B (HBD=3, HBA=5) are both acceptable, falling within the recommended limits.

**QED:** Both ligands have reasonable QED values (A: 0.779, B: 0.648), indicating good drug-like properties.

**DILI:** Ligand A (6.204) has a much lower DILI risk than Ligand B (51.609). This is a strong advantage for A.

**BBB:** Ligand A (66.344) has a better BBB percentile than Ligand B (46.413), although ideally, we want >70 for CNS targets. Still, A is closer to the desired threshold.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.557 and -5.19), which is unusual and suggests poor permeability. However, the scale is not defined, so it's difficult to interpret.

**Aqueous Solubility:** Both ligands have negative solubility values (-1.865 and -2.935), also unusual and suggesting poor solubility. Again, the scale is undefined.

**hERG:** Ligand A (0.385) has a lower hERG risk than Ligand B (0.072), which is preferable.

**Microsomal Clearance:** Ligand A (-7.97) has a much lower (better) microsomal clearance than Ligand B (-3.841). This suggests better metabolic stability for A.

**In vitro Half-Life:** Ligand A (3.475) has a better in vitro half-life than Ligand B (-13.975).

**P-gp Efflux:** Ligand A (0.011) has a significantly lower P-gp efflux liability than Ligand B (0.026), which is crucial for CNS penetration.

**Binding Affinity:** Ligand A (-9.5 kcal/mol) has a substantially stronger binding affinity than Ligand B (-8.4 kcal/mol). This is a decisive advantage, exceeding the 1.5 kcal/mol difference threshold.

**Overall Assessment:**

Ligand A consistently outperforms Ligand B across almost all relevant parameters, especially those prioritized for GPCRs targeting the CNS. Its superior TPSA, logP, BBB, DILI, metabolic stability, P-gp efflux, and *significantly* stronger binding affinity make it the far more promising drug candidate. While both have issues with Caco-2 and solubility (likely scale-related), the other advantages of A outweigh these concerns.

Output:
1
2025-04-17 07:13:10,711 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (341.415 and 357.483 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (88.91) is excellent, falling well below the 90 A^2 threshold for CNS targets. Ligand B (55.95) is also very good, comfortably under the threshold.

**3. logP:** Both ligands have acceptable logP values (1.237 and 2.778), falling within the optimal 1-3 range.

**4. H-Bond Donors:** Ligand A has 2 HBD, which is good. Ligand B has 0, also acceptable.

**5. H-Bond Acceptors:** Ligand A has 5 HBA, within the limit. Ligand B has 6 HBA, also within the limit.

**6. QED:** Both ligands have reasonable QED values (0.756 and 0.653), indicating good drug-like properties.

**7. DILI:** Both ligands have low DILI risk (43.273 and 41.373 percentile), which is favorable.

**8. BBB:** This is a critical parameter for a CNS target like DRD2. Ligand A has a BBB penetration of 46.026%, which is below the desirable >70% threshold. Ligand B shows significantly better BBB penetration at 62.233%, though still not ideal, it's substantially better than Ligand A.

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.48 and -5.524). This is unusual and suggests poor permeability. However, these values are on a log scale, and negative values are not uncommon.

**10. Aqueous Solubility:** Both ligands have poor aqueous solubility (-1.113 and -1.988). This could pose formulation challenges.

**11. hERG Inhibition:** Both ligands show very low hERG inhibition risk (0.257 and 0.485 percentile), which is excellent.

**12. Microsomal Clearance:** Ligand A has a negative Cl_mic (-9.092 mL/min/kg), which is highly unusual and suggests exceptional metabolic stability. Ligand B has a positive Cl_mic (58.546 mL/min/kg), indicating faster metabolism.

**13. In vitro Half-Life:** Ligand A has a half-life of 6.746 hours, which is reasonable. Ligand B has a longer half-life of 9.024 hours, which is preferable.

**14. P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.008 and 0.268 percentile), which is highly desirable for CNS penetration.

**15. Binding Affinity:** Ligand A has a stronger binding affinity (-8.3 kcal/mol) compared to Ligand B (-7.0 kcal/mol). This is a significant advantage (1.3 kcal/mol difference).

**Overall Assessment:**

While Ligand A has a superior binding affinity and exceptional metabolic stability, its significantly lower BBB penetration is a major drawback for a CNS-targeting drug. Ligand B, despite a slightly weaker affinity, exhibits better BBB penetration and a longer half-life. The better BBB penetration of Ligand B outweighs the affinity difference, especially considering the acceptable affinity of -7.0 kcal/mol. The negative Caco-2 and solubility values are concerning for both, but can potentially be addressed with formulation strategies.

Output:
1
2025-04-17 07:13:10,712 - INFO - Reasoning:

Let's analyze Ligand A and Ligand B for their potential as DRD2 drug candidates, considering the provided guidelines and GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight (MW):** Both ligands (350.383 and 350.459 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (138.99) is borderline but acceptable for CNS penetration, while Ligand B (67.87) is excellent, well below the 90 A^2 threshold for CNS targets. This is a significant advantage for Ligand B.

**3. logP:** Ligand A (-0.955) is a bit low, potentially hindering membrane permeability. Ligand B (1.503) is within the optimal range of 1-3. This favors Ligand B.

**4. H-Bond Donors (HBD):** Ligand A (4) is acceptable, while Ligand B (1) is even better, potentially improving permeability.

**5. H-Bond Acceptors (HBA):** Ligand A (8) is acceptable, and Ligand B (4) is also good.

**6. QED:** Both ligands have good QED scores (0.484 and 0.763 respectively), indicating reasonable drug-likeness. Ligand B is better.

**7. DILI:** Ligand A (57.929) has a moderate DILI risk, while Ligand B (31.718) has a lower risk. This favors Ligand B.

**8. BBB:** Ligand A (23.924) has very poor predicted BBB penetration, a critical drawback for a CNS target. Ligand B (63.358) has good BBB penetration. This is a major advantage for Ligand B.

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.841 and -4.752), which is unusual and suggests poor permeability. However, these values are on a scale where negative values are possible, and the absolute magnitude is important. They are relatively similar.

**10. Aqueous Solubility:** Both ligands have poor aqueous solubility (-1.207 and -1.935). This could pose formulation challenges.

**11. hERG Inhibition:** Ligand A (0.04) shows very low hERG inhibition risk, while Ligand B (0.232) has a slightly higher, but still low, risk. Ligand A is slightly better here.

**12. Microsomal Clearance:** Both ligands have similar microsomal clearance rates (-11.255 and -45.418 mL/min/kg), suggesting similar metabolic stability. Ligand A is slightly better.

**13. In vitro Half-Life:** Ligand A (45.543 hours) has a much longer half-life than Ligand B (9.839 hours). This is a significant advantage for Ligand A.

**14. P-gp Efflux:** Ligand A (0.006) has very low P-gp efflux, which is excellent for CNS penetration. Ligand B (0.05) also has low P-gp efflux, but slightly higher.

**15. Binding Affinity:** Ligand A (-8 kcal/mol) has significantly better binding affinity than Ligand B (-0 kcal/mol). This is a substantial advantage for Ligand A.

**Overall Assessment:**

While Ligand A has a superior binding affinity and half-life, its poor BBB penetration and low logP are major concerns for a CNS-targeting drug. Ligand B excels in key GPCR-specific properties: TPSA, logP, BBB penetration, and DILI risk. The significantly stronger binding affinity of Ligand A is a strong point, but the poor predicted CNS exposure makes it less likely to be a viable drug candidate. The difference in affinity (8 vs 0) is substantial, but not insurmountable if other properties could be improved. However, given the current data, Ligand B is the more promising candidate due to its favorable ADME properties for CNS penetration.

Output:
1
2025-04-17 07:13:10,712 - INFO - Batch 346 complete. Total preferences: 5536
2025-04-17 07:13:10,712 - INFO - Processing batch 347/512...
2025-04-17 07:13:51,295 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (357.479 and 382.555 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (55.63) is significantly better than Ligand B (74.33). For CNS targets, we want TPSA <= 90, and A is comfortably within that range, while B is approaching the upper limit.

**logP:** Ligand A (3.911) is slightly higher than Ligand B (2.439), both within the optimal 1-3 range, but A is closer to the upper limit.

**H-Bond Donors/Acceptors:** Ligand A (HBD=1, HBA=5) and Ligand B (HBD=2, HBA=6) are both acceptable, falling within the recommended limits.

**QED:** Both ligands have similar QED values (0.728 and 0.709), indicating good drug-likeness.

**DILI:** Ligand A (62.35) has a slightly higher DILI risk than Ligand B (56.146), but both are reasonably acceptable (below 60 is good).

**BBB:** This is a crucial parameter for a CNS target like DRD2. Ligand B (75.805) has a significantly better BBB penetration percentile than Ligand A (28.383). This is a major advantage for B.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.102 and -5.298), which is unusual and suggests poor permeability. This is a concern for both.

**Aqueous Solubility:** Both ligands have negative solubility values (-3.288 and -3.828), indicating very poor aqueous solubility. This is a significant drawback for both.

**hERG Inhibition:** Ligand A (0.418) has a lower hERG inhibition liability than Ligand B (0.756), which is preferable.

**Microsomal Clearance:** Ligand B (51.116) has a lower microsomal clearance than Ligand A (72.133), indicating better metabolic stability.

**In vitro Half-Life:** Ligand B (7.834 hours) has a longer half-life than Ligand A (4.55 hours), which is desirable.

**P-gp Efflux:** Ligand A (0.637) has lower P-gp efflux than Ligand B (0.189), which is favorable for CNS penetration.

**Binding Affinity:** Ligand A (-8.8 kcal/mol) has a significantly stronger binding affinity than Ligand B (-6.5 kcal/mol). This is a substantial advantage for A, potentially outweighing some of its ADME drawbacks. The difference is >1.5 kcal/mol.

**Overall Assessment:**

While Ligand B has superior BBB penetration and metabolic stability, the significantly stronger binding affinity of Ligand A (-8.8 vs -6.5 kcal/mol) is a decisive factor. The difference in affinity is large enough to compensate for the poorer BBB and slightly higher DILI risk. The poor solubility and permeability are concerns for both, but these can potentially be addressed through formulation strategies. Given the GPCR-specific prioritization, the strong binding affinity of Ligand A makes it the more promising candidate.

Output:
0
2025-04-17 07:13:51,296 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B based on the provided guidelines, prioritizing GPCR-specific properties (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (348.45 & 353.47 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (96.25) is better than Ligand B (101.56). Both are below the 140 threshold for oral absorption and reasonably close to the 90 threshold for CNS targets, but A is preferable.

**logP:** Ligand A (0.906) is slightly better than Ligand B (0.252). While both are on the lower side of the optimal 1-3 range, A is closer. B's logP is quite low, potentially hindering permeation.

**H-Bond Donors/Acceptors:** Both ligands have 3 HBDs and 5 HBAs, which are within acceptable limits.

**QED:** Ligand A (0.712) has a significantly better QED score than Ligand B (0.56), indicating a more drug-like profile.

**DILI:** Ligand A (20.98) has a much lower DILI risk than Ligand B (13.53), which is a significant advantage.

**BBB:** Ligand A (52.42) has a substantially better BBB penetration percentile than Ligand B (19.04). This is *critical* for a CNS target like DRD2.

**Caco-2 Permeability:** Ligand A (-5.001) is better than Ligand B (-5.486), indicating better intestinal absorption.

**Aqueous Solubility:** Ligand A (-1.373) is better than Ligand B (-0.144), suggesting better solubility.

**hERG:** Both ligands have low hERG inhibition liability (0.261 and 0.354, respectively).

**Microsomal Clearance:** Ligand A (7.321) has higher (worse) microsomal clearance than Ligand B (-2.606), suggesting lower metabolic stability. This is a drawback for A.

**In vitro Half-Life:** Ligand A (2.085) has a shorter half-life than Ligand B (-9.586). This is a drawback for A.

**P-gp Efflux:** Ligand A (0.008) has significantly lower P-gp efflux liability than Ligand B (0.03). Lower efflux is highly desirable for CNS penetration.

**Binding Affinity:** Ligand A (-8.5 kcal/mol) has a significantly stronger binding affinity than Ligand B (-7.0 kcal/mol). This is a substantial advantage that can outweigh some of the ADME drawbacks. The difference is >1.5 kcal/mol.

**Overall Assessment:**

Ligand A is the stronger candidate. While it has some drawbacks in terms of metabolic stability (higher Cl_mic) and half-life, its superior BBB penetration, lower DILI risk, better QED, better solubility, lower P-gp efflux, and *significantly* stronger binding affinity outweigh these concerns. The strong affinity is a major driver, and the improved CNS penetration profile is essential for a DRD2 target. Ligand B's very low logP and poor BBB penetration are major liabilities.

Output:
1
2025-04-17 07:13:51,296 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (367.743 and 383.901 Da) fall within the ideal range of 200-500 Da.

**TPSA:** Both ligands (81.93 and 82.53) are reasonably close to the 90 A^2 threshold for CNS targets, but slightly above. This isn't a major concern, but it's a point to consider.

**logP:** Ligand A (3.006) is optimal, while Ligand B (1.923) is slightly low, potentially impacting permeability.

**H-Bond Donors/Acceptors:** Ligand A (HBD=1, HBA=6) and Ligand B (HBD=2, HBA=5) both have acceptable numbers of H-bond donors and acceptors.

**QED:** Both ligands have good QED scores (0.701 and 0.813), indicating good drug-like properties.

**DILI:** Ligand A has a high DILI risk (98.41 percentile), which is a significant concern. Ligand B has a much lower DILI risk (51.338 percentile), making it more favorable.

**BBB:** Ligand A has a good BBB penetration score (61.38 percentile), while Ligand B's BBB penetration is considerably lower (33.656 percentile). This is a crucial factor for a CNS target like DRD2.

**Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and suggests a potential issue with the data or modeling. We'll proceed cautiously.

**Aqueous Solubility:** Both ligands have very poor aqueous solubility (-4.56 and -3.415). This could pose formulation challenges.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.406 and 0.159).

**Microsomal Clearance:** Ligand A has a moderate clearance (48.867 mL/min/kg), while Ligand B has a *negative* clearance (-1.814 mL/min/kg). Negative clearance is physically impossible and indicates a data error or modeling artifact.

**In vitro Half-Life:** Ligand A has a reasonable half-life (10.466 hours), while Ligand B has a very short half-life (40.18 hours).

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.299 and 0.125), which is good for CNS penetration.

**Binding Affinity:** Both ligands have the same excellent binding affinity (-8.5 kcal/mol).

**Overall Assessment:**

Ligand A has a better BBB score and a more optimal logP, but its extremely high DILI risk is a major red flag. Ligand B has a much lower DILI risk, which is a critical advantage. However, its lower BBB penetration and negative microsomal clearance are concerning. The negative clearance is a significant data quality issue. Considering the importance of minimizing toxicity (DILI) and the fact that both ligands have equivalent binding affinity, Ligand B is the more promising candidate *despite* its issues, as the DILI risk for Ligand A is almost certainly a dealbreaker. The negative clearance for Ligand B needs to be investigated and corrected, but the lower DILI risk makes it the better starting point for optimization.

Output:
1
2025-04-17 07:13:51,296 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (351.359 and 360.401 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (119.01) is borderline for CNS penetration, slightly above the preferred <90, while Ligand B (67.87) is excellent.

**logP:** Ligand A (-0.733) is a bit low, potentially hindering membrane permeability. Ligand B (1.36) is within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A has 3 HBD and 7 HBA, acceptable values. Ligand B has 1 HBD and 4 HBA, also acceptable.

**QED:** Both ligands have reasonable QED scores (0.289 and 0.696), with Ligand B being significantly better.

**DILI:** Ligand A (60.915) has a higher DILI risk than Ligand B (32.842), indicating a potential liver toxicity concern.

**BBB:** This is crucial for a CNS target. Ligand A (17.449) has very poor predicted BBB penetration. Ligand B (90.694) is excellent, exceeding the >70 desirable threshold.

**Caco-2 Permeability:** Both have negative values (-5.365 and -4.818), which is unusual and requires further investigation. However, the scale is not specified, so it's hard to interpret.

**Aqueous Solubility:** Both have negative values (-2.08 and -1.803), also unusual and requiring further investigation.

**hERG Inhibition:** Both ligands show low hERG inhibition risk (0.146 and 0.447).

**Microsomal Clearance:** Ligand A (-17.71) shows a better (lower) microsomal clearance than Ligand B (-13.28), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (-30.057) has a worse (shorter) half-life than Ligand B (-2.955).

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.024 and 0.025).

**Binding Affinity:** Ligand B (-8.2 kcal/mol) has a slightly better binding affinity than Ligand A (-7.0 kcal/mol). While the difference is less than the 1.5 kcal/mol threshold, it's still a positive factor.

**Overall Assessment:**

Ligand B is significantly more promising. Its excellent BBB penetration, favorable logP, lower DILI risk, and better QED score outweigh the slightly worse metabolic stability and half-life compared to Ligand A. The affinity difference is not substantial enough to favor Ligand A. Ligand A's poor BBB penetration and higher DILI risk are major drawbacks for a CNS-targeted drug. The negative solubility and Caco-2 values for both are concerning and would require experimental validation.

Output:
1
2025-04-17 07:13:51,296 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B based on the provided guidelines, prioritizing GPCR-specific properties (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (375.443) is slightly higher than Ligand B (346.427), but both are acceptable.

**TPSA:** Ligand A (83.53) is better than Ligand B (98.66). For CNS targets, we want TPSA <= 90, so Ligand A is preferable.

**logP:** Both ligands have good logP values (A: 0.996, B: 1.273), falling within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A (HBD=0, HBA=7) is better than Ligand B (HBD=4, HBA=4). Lower HBD is generally preferred for BBB penetration.

**QED:** Both ligands have acceptable QED values (A: 0.703, B: 0.559), indicating reasonable drug-likeness.

**DILI:** Ligand A (72.819) has a higher DILI risk than Ligand B (14.541). This is a significant drawback for Ligand A.

**BBB:** Ligand A (70.531) has a good BBB penetration percentile, while Ligand B (21.908) is quite poor. This is a crucial factor for a CNS target like DRD2, favoring Ligand A.

**Caco-2 Permeability:** Ligand A (-4.623) has poor Caco-2 permeability, while Ligand B (-5.417) is also poor.

**Aqueous Solubility:** Both ligands have poor aqueous solubility (A: -3.019, B: -2.659).

**hERG Inhibition:** Both ligands have low hERG inhibition risk (A: 0.542, B: 0.126).

**Microsomal Clearance:** Both ligands have similar microsomal clearance (A: 35.113, B: 36.528).

**In vitro Half-Life:** Both ligands have negative in vitro half-life values (A: -24.392, B: -26.453), which is unusual and suggests rapid degradation.

**P-gp Efflux:** Ligand A (0.19) has lower P-gp efflux liability than Ligand B (0.017), which is favorable for CNS penetration.

**Binding Affinity:** Ligand B (-8.4 kcal/mol) has significantly better binding affinity than Ligand A (0.0 kcal/mol). This is a major advantage for Ligand B. A difference of >1.5 kcal/mol can outweigh other drawbacks.

**Overall Assessment:**

Despite Ligand A's better TPSA, BBB, and P-gp properties, the significantly superior binding affinity of Ligand B (-8.4 vs 0.0 kcal/mol) is the deciding factor. The large affinity difference is likely to outweigh the higher DILI risk and poorer BBB penetration of Ligand B. The poor solubility and Caco-2 permeability are concerns for both, but can be addressed with formulation strategies. The negative half-life values are concerning for both, and would require further investigation.

Output:
1
2025-04-17 07:13:51,296 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (369.49 and 392.54 Da) fall within the ideal range of 200-500 Da.

**TPSA:** Ligand A (78.95) is significantly better than Ligand B (92.78). For CNS targets, we want TPSA <= 90, so Ligand A is preferable.

**logP:** Both ligands have good logP values (1.077 and 0.848), falling within the optimal range of 1-3.

**H-Bond Donors/Acceptors:** Both have 1 HBD, which is good. Ligand B has 6 HBA, slightly higher than Ligand A's 5, but both are acceptable (<=10).

**QED:** Ligand A (0.726) has a better QED score than Ligand B (0.554), indicating a more drug-like profile.

**DILI:** Ligand A (42.54) has a lower DILI risk than Ligand B (53.55), both are acceptable (<60 is good).

**BBB:** Ligand A (63.13) has a slightly better BBB percentile than Ligand B (60.72), but both are below the desirable >70 for CNS targets. This is a weakness for both, but less so for A.

**Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and suggests poor permeability. Ligand A (-4.993) is slightly better than Ligand B (-5.199), but both are concerning.

**Aqueous Solubility:** Both have negative solubility values, indicating very poor solubility. Ligand A (-2.318) is slightly better than Ligand B (-3.21).

**hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.143 and 0.282).

**Microsomal Clearance:** Ligand A (12.61) has significantly lower microsomal clearance than Ligand B (85.83), indicating better metabolic stability.

**In vitro Half-Life:** Ligand A (1.21) has a very short half-life, while Ligand B (-62.40) is even worse (negative values are problematic).

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.026 and 0.041).

**Binding Affinity:** Ligand A (-7.7 kcal/mol) has a slightly better binding affinity than Ligand B (-6.7 kcal/mol). A difference of 1 kcal/mol is significant.

**Overall Assessment:**

Ligand A is superior to Ligand B. While both have weaknesses regarding BBB penetration and solubility, Ligand A excels in TPSA, QED, metabolic stability (Cl_mic), and binding affinity. The better binding affinity, coupled with the lower TPSA and better metabolic stability, outweighs the slightly lower BBB score. The negative Caco-2 and solubility values are concerning for both and would require attention during lead optimization (e.g., prodrug strategies).

Output:
0
2025-04-17 07:13:51,296 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (350.47 and 366.45 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (92.15) is better than Ligand B (132). For CNS targets, we want TPSA <= 90, so Ligand A is closer to this threshold. Ligand B is significantly higher, potentially hindering BBB penetration.

**3. logP:** Ligand A (0.56) is slightly better than Ligand B (0.336), but both are quite low. A logP between 1-3 is optimal. These low values could indicate poor membrane permeability.

**4. H-Bond Donors:** Ligand A (2) is preferable to Ligand B (3). Lower HBD generally improves permeability.

**5. H-Bond Acceptors:** Both ligands have 6 HBA, which is acceptable (<=10).

**6. QED:** Both ligands have similar QED values (0.679 and 0.62), indicating reasonable drug-likeness.

**7. DILI:** Ligand A (24.58) has a much lower DILI risk than Ligand B (77.12). This is a significant advantage for Ligand A.

**8. BBB:** Ligand A (60.45) has a better BBB percentile than Ligand B (46.41), but both are below the desirable >70 for CNS targets. However, Ligand A is closer.

**9. Caco-2:** Both have negative Caco-2 values (-5.355 and -5.422), which is unusual and difficult to interpret without knowing the scale. It suggests poor permeability.

**10. Solubility:** Both have negative solubility values (-1.211 and -2.012), again unusual and suggesting poor aqueous solubility.

**11. hERG:** Both ligands have low hERG inhibition liability (0.283 and 0.215), which is good.

**12. Cl_mic:** Ligand A (-1.269) has a lower (better) microsomal clearance than Ligand B (3.208), indicating greater metabolic stability.

**13. t1/2:** Ligand A (9.034) has a shorter in vitro half-life than Ligand B (16.527), which is less desirable.

**14. Pgp:** Ligand A (0.023) has significantly lower P-gp efflux liability than Ligand B (0.058), which is a major advantage for CNS penetration.

**15. Binding Affinity:** Ligand B (-8.9 kcal/mol) has a slightly better binding affinity than Ligand A (-8.2 kcal/mol). This is a 0.7 kcal/mol difference, which is noticeable but not overwhelmingly large.

**Overall Assessment:**

Considering the GPCR-specific priorities, Ligand A is the more promising candidate. While Ligand B has a slightly better binding affinity, Ligand A excels in crucial ADME properties for CNS drugs: lower DILI risk, better BBB penetration (though still suboptimal), lower P-gp efflux, and better metabolic stability. The lower TPSA of Ligand A is also beneficial. The slightly shorter half-life of Ligand A is a drawback, but can potentially be addressed through structural modifications. The low logP and solubility are concerns for both, but the other advantages of Ligand A outweigh this.

Output:
0
2025-04-17 07:13:51,296 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight (MW):** Both ligands are within the ideal range (200-500 Da). Ligand A (402.351 Da) is slightly higher than Ligand B (363.575 Da), but both are acceptable.

**2. TPSA:** Ligand A (67.07) is higher than Ligand B (37.19). For CNS targets, we want TPSA <= 90. Both are within this range, but Ligand B is significantly better.

**3. logP:** Both ligands have good logP values (A: 3.701, B: 3.623), falling within the optimal 1-3 range.

**4. H-Bond Donors (HBD):** Ligand A has 1 HBD, and Ligand B has 0. Both are within the acceptable limit of <=5.

**5. H-Bond Acceptors (HBA):** Ligand A has 7 HBA, and Ligand B has 6. Both are below the limit of <=10.

**6. QED:** Ligand A (0.826) has a higher QED than Ligand B (0.646), indicating a more drug-like profile.

**7. DILI:** Ligand A (59.48) has a higher DILI risk than Ligand B (16.053). Ligand B is significantly better here, falling well below the 40% threshold.

**8. BBB:** Ligand A (73.943) and Ligand B (69.523) both have reasonably good BBB penetration, but Ligand A is slightly better. A value >70 is desirable for CNS targets.

**9. Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and suggests poor permeability. However, the scale is not specified, so it's hard to interpret.

**10. Aqueous Solubility:** Both have negative solubility values, again unusual and suggesting poor solubility. The scale is not specified.

**11. hERG Inhibition:** Ligand A (0.36) has a lower hERG inhibition risk than Ligand B (0.915), which is preferable.

**12. Microsomal Clearance (Cl_mic):** Ligand A (26.378) has a higher Cl_mic than Ligand B (19.99), meaning it's cleared more quickly and has lower metabolic stability.

**13. In vitro Half-Life:** Ligand B (28.915) has a longer in vitro half-life than Ligand A (18.965), which is desirable.

**14. P-gp Efflux:** Ligand A (0.572) has higher P-gp efflux than Ligand B (0.37), meaning less CNS exposure. Ligand B is better.

**15. Binding Affinity:** Ligand A (-6.9 kcal/mol) has a slightly better binding affinity than Ligand B (-6.5 kcal/mol). This 1.5 kcal/mol difference is significant.

**Overall Assessment:**

While Ligand A has a slightly better binding affinity and QED, Ligand B demonstrates a significantly better safety profile (lower DILI), better metabolic stability (lower Cl_mic, longer t1/2), and lower P-gp efflux. Crucially, Ligand B has a much lower TPSA, which is highly desirable for CNS penetration. The slight advantage in binding affinity of Ligand A is likely outweighed by the superior ADME properties of Ligand B, particularly for a CNS target like DRD2.

Output:
1
2025-04-17 07:13:51,296 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (341.371 and 342.399 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (106.94) is slightly above the optimal <90 for CNS targets, but still reasonable. Ligand B (80.37) is well within the desired range.

**logP:** Ligand A (2.952) is optimal. Ligand B (1.202) is a bit low, potentially hindering permeability.

**H-Bond Donors/Acceptors:** Both ligands have 1 HBD, which is good. Ligand A has 7 HBA, and Ligand B has 5 HBA, both acceptable.

**QED:** Both ligands have good QED scores (0.704 and 0.905), indicating drug-like properties.

**DILI:** Ligand A (81.233) has a higher DILI risk than Ligand B (56.805), which is preferable.

**BBB:** Ligand A (79.721) and Ligand B (55.603) both have reasonable BBB penetration, but Ligand A is better. A score >70 is desirable for CNS targets, and Ligand A is closer.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.207 and -5.256), which is unusual and suggests poor permeability. This is a significant concern for both.

**Aqueous Solubility:** Both ligands have negative solubility values (-3.086 and -1.957), indicating very poor aqueous solubility. This is a major drawback.

**hERG:** Both ligands have low hERG inhibition liability (0.267 and 0.138), which is good.

**Microsomal Clearance:** Ligand A (37.976) has higher microsomal clearance than Ligand B (17.974), suggesting lower metabolic stability.

**In vitro Half-Life:** Ligand B (34.906) has a longer in vitro half-life than Ligand A (19.507), which is favorable.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.229 and 0.025), which is good for CNS penetration. Ligand B is slightly better.

**Binding Affinity:** Ligand B (-7.7 kcal/mol) has a significantly better binding affinity than Ligand A (-9.4 kcal/mol). This 1.7 kcal/mol difference is substantial and could outweigh some of the ADME drawbacks.

**Overall Assessment:**

While both ligands have significant issues with solubility and Caco-2 permeability, Ligand B's substantially stronger binding affinity (-7.7 vs -9.4 kcal/mol) and better DILI score make it the more promising candidate. The improved half-life and slightly lower P-gp efflux also contribute. The lower logP is a concern, but the strong affinity could compensate. The TPSA is also better for Ligand B.



Output:
1
2025-04-17 07:13:51,296 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B based on the provided guidelines, prioritizing GPCR-specific properties (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (364.555 and 352.475 Da) fall within the ideal range of 200-500 Da.

**TPSA:** Ligand A (49.41) is excellent, well below the 90 A^2 threshold for CNS targets. Ligand B (70.08) is still reasonable, but less optimal.

**logP:** Ligand A (4.518) is slightly high, potentially leading to solubility issues or off-target effects. Ligand B (1.414) is a bit low, potentially hindering permeation.

**H-Bond Donors/Acceptors:** Both ligands have acceptable HBD (1) and HBA (3 & 4) counts.

**QED:** Both ligands have good QED scores (0.621 and 0.831), indicating drug-like properties.

**DILI:** Ligand A (35.479) has a low DILI risk, which is favorable. Ligand B (9.616) has an even lower DILI risk, which is excellent.

**BBB:** Ligand A (69.407) has a good BBB percentile, desirable for a CNS target. Ligand B (54.478) has a lower BBB percentile, a significant drawback.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values, which is unusual and suggests poor permeability. However, the scale is not defined, so it's hard to interpret.

**Aqueous Solubility:** Both ligands have negative solubility values, which is also unusual and suggests poor solubility.

**hERG:** Both ligands have low hERG inhibition liability (0.525 and 0.385), which is good.

**Microsomal Clearance:** Ligand A (115.552) has higher microsomal clearance, suggesting faster metabolism. Ligand B (14.374) has much lower clearance, indicating better metabolic stability.

**In vitro Half-Life:** Ligand A (48.436) has a reasonable half-life. Ligand B (10.521) has a shorter half-life, which could necessitate more frequent dosing.

**P-gp Efflux:** Ligand A (0.361) has lower P-gp efflux, which is favorable for CNS penetration. Ligand B (0.118) has even lower P-gp efflux, which is excellent.

**Binding Affinity:** Ligand A (-7.5 kcal/mol) has a slightly better binding affinity than Ligand B (-7.1 kcal/mol), but the difference is relatively small.

**Overall Assessment:**

Ligand A excels in BBB penetration and has slightly better affinity, but suffers from a higher logP and higher clearance. Ligand B has superior metabolic stability (lower Cl_mic), lower P-gp efflux, and a very low DILI risk. The lower BBB penetration is a concern, but the other advantages, particularly the metabolic stability and lower efflux, are significant for a GPCR targeting the CNS. The slightly weaker binding affinity of Ligand B can potentially be improved through further optimization.

Output:
1
2025-04-17 07:13:51,297 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (378.807) is slightly higher than Ligand B (346.431), but both are acceptable.

**TPSA:** Ligand A (107.11) is slightly above the optimal 90 for CNS targets, while Ligand B (91.48) is closer to the ideal range. This gives a slight edge to Ligand B.

**logP:** Ligand A (1.486) and Ligand B (0.852) are both within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A has 4 HBD and 4 HBA, while Ligand B has 2 HBD and 6 HBA. Both are within acceptable limits (<=5 HBD and <=10 HBA).

**QED:** Both ligands have good QED scores (Ligand A: 0.576, Ligand B: 0.847), indicating drug-like properties. Ligand B is better here.

**DILI:** Ligand A (61.691) has a higher DILI risk than Ligand B (44.203), though both are reasonably acceptable.

**BBB:** This is crucial for a CNS target like DRD2. Ligand A (48.972) has a moderate BBB penetration, while Ligand B (29.12) is significantly lower. This is a major drawback for Ligand B.

**Caco-2 Permeability:** Both have negative values, which is unusual. Assuming these are logP-like scales, lower values indicate lower permeability. Both are poor.

**Aqueous Solubility:** Both ligands have negative values, indicating poor solubility.

**hERG Inhibition:** Both ligands have very low hERG inhibition risk (Ligand A: 0.322, Ligand B: 0.137), which is excellent.

**Microsomal Clearance:** Ligand A (-16.106) has a much lower (better) microsomal clearance than Ligand B (9.557), indicating greater metabolic stability.

**In vitro Half-Life:** Ligand A (4.318) has a slightly longer half-life than Ligand B (-3.281).

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (Ligand A: 0.035, Ligand B: 0.054), which is favorable for CNS penetration.

**Binding Affinity:** Ligand B (-9.0 kcal/mol) has a significantly stronger binding affinity than Ligand A (-8.2 kcal/mol). This is a substantial advantage.

**Overall Assessment:**

While Ligand B has a better QED, lower DILI, and significantly better binding affinity, its poor BBB penetration is a major concern for a CNS target. Ligand A, despite slightly less favorable ADME properties, has a much better BBB score and acceptable metabolic stability. The binding affinity difference is significant, but the BBB is paramount for DRD2. Given the importance of CNS penetration for DRD2, and the relatively small difference in affinity, Ligand A is the more promising candidate.

Output:
0
2025-04-17 07:13:51,297 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 drug candidates, considering the provided guidelines and GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (360.435 and 348.451 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (98.49) is slightly higher than Ligand B (93.01), but both are below the 140 threshold for oral absorption and reasonably close to the 90 target for CNS penetration.

**logP:** Ligand A (1.761) is within the optimal 1-3 range. Ligand B (0.851) is a bit low, potentially hindering permeation.

**H-Bond Donors & Acceptors:** Ligand A has 2 HBD and 4 HBA, while Ligand B has 1 HBD and 6 HBA. Both are within acceptable limits (<=5 HBD and <=10 HBA).

**QED:** Both ligands have a QED of 0.82, indicating good drug-likeness.

**DILI:** Ligand A (66.615) has a higher DILI risk than Ligand B (49.128). This is a negative for Ligand A.

**BBB:** Ligand A (62.97) has a slightly higher BBB penetration percentile than Ligand B (55.642), but both are below the desirable >70 for CNS targets.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.072 and -5.238), which is unusual and suggests poor permeability. This is a significant concern for both.

**Aqueous Solubility:** Both ligands have negative solubility values (-3.872 and -1.443), indicating very poor aqueous solubility. This is a major drawback for both.

**hERG Inhibition:** Ligand A (0.335) has a slightly higher hERG inhibition risk than Ligand B (0.026).

**Microsomal Clearance:** Ligand B (8.267) has significantly lower microsomal clearance than Ligand A (60.438), indicating better metabolic stability.

**In vitro Half-Life:** Ligand B (6.475) has a longer in vitro half-life than Ligand A (-12.879).

**P-gp Efflux:** Ligand A (0.229) has lower P-gp efflux liability than Ligand B (0.05), which is favorable for CNS exposure.

**Binding Affinity:** Ligand B (-8.5 kcal/mol) has a stronger binding affinity than Ligand A (-9.9 kcal/mol). This is a substantial advantage for Ligand B.

**Overall Assessment:**

While Ligand A has a slightly better BBB and P-gp profile, Ligand B is superior in most critical aspects. Ligand B exhibits:

*   Stronger binding affinity (-8.5 vs -9.9 kcal/mol)
*   Lower DILI risk (49.128 vs 66.615)
*   Significantly better metabolic stability (lower Cl_mic)
*   Longer in vitro half-life
*   Lower hERG risk

The poor Caco-2 and solubility for both are concerning, but the stronger affinity and better ADME properties of Ligand B make it the more promising candidate. The affinity difference is significant enough to potentially overcome the solubility/permeability issues with further optimization.

Output:
1
2025-04-17 07:13:51,297 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (338.407 and 344.507 Da) fall comfortably within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (58.64) is significantly better than Ligand B (72.86). For a CNS target like DRD2, we want TPSA <= 90, and A is much closer to the optimal <=60 range. B is getting higher and could present permeability issues.

**3. logP:** Both ligands have good logP values (3.519 and 3.624), falling within the optimal 1-3 range.

**4. H-Bond Donors:** Both have 1 HBD, which is acceptable.

**5. H-Bond Acceptors:** Ligand A has 4 HBAs, and Ligand B has 6. Both are within the acceptable limit of <=10, but A is preferable.

**6. QED:** Ligand A (0.848) has a better QED score than Ligand B (0.703), indicating a more drug-like profile.

**7. DILI:** Ligand A (65.452) has a higher DILI risk than Ligand B (30.671). This is a significant drawback for Ligand A.

**8. BBB:** Ligand B (95.541) has a *much* better BBB penetration percentile than Ligand A (85.459). For a CNS target, this is a critical advantage.

**9. Caco-2 Permeability:** Ligand A (-4.479) has a worse Caco-2 permeability than Ligand B (-5.444). Lower values are less desirable.

**10. Aqueous Solubility:** Ligand A (-4.867) has worse aqueous solubility than Ligand B (-2.181).

**11. hERG Inhibition:** Both ligands have relatively low hERG inhibition risk (0.817 and 0.985).

**12. Microsomal Clearance:** Ligand A (86.292) has a higher microsomal clearance than Ligand B (20.078), meaning it's less metabolically stable.

**13. In vitro Half-Life:** Ligand B (3.406) has a longer in vitro half-life than Ligand A (17.081).

**14. P-gp Efflux:** Ligand A (0.529) has lower P-gp efflux than Ligand B (0.757), which is favorable for CNS penetration.

**15. Binding Affinity:** Ligand B (-8.0) has a slightly better binding affinity than Ligand A (-7.9). While the difference is small, it's still a positive for Ligand B.

**Overall Assessment:**

Ligand B is the stronger candidate. While Ligand A has a slightly better P-gp efflux, Ligand B excels in the most critical areas for a CNS GPCR target: BBB penetration, metabolic stability (lower Cl_mic, longer t1/2), DILI risk, and solubility. The slightly better affinity of Ligand B further supports this conclusion. The higher TPSA of Ligand B is a minor concern, but the substantial benefits in other areas outweigh this drawback.

Output:
1
2025-04-17 07:13:51,297 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (358.479 and 352.475 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Both ligands have TPSA values (77.1 and 78.87) that are above the optimal <90 for CNS targets, but not drastically so. This is a minor concern.

**3. logP:** Both ligands have logP values (1.061 and 1.461) within the optimal 1-3 range.

**4. H-Bond Donors:** Ligand A (1 HBD) is better than Ligand B (2 HBDs) as lower HBDs are generally preferred.

**5. H-Bond Acceptors:** Ligand A (5 HBA) is slightly better than Ligand B (4 HBA) as lower HBA are generally preferred.

**6. QED:** Both ligands have good QED scores (0.632 and 0.734), indicating good drug-like properties.

**7. DILI:** Ligand A (26.406) has a significantly lower DILI risk than Ligand B (21.946). This is a substantial advantage.

**8. BBB:** Ligand A (54.983) has a better BBB penetration percentile than Ligand B (43.777). While neither is >70, A is closer and more favorable for a CNS target.

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.646 and -4.685), which is unusual and suggests poor permeability. This is a significant drawback for both.

**10. Aqueous Solubility:** Both ligands have negative solubility values (-1.604 and -2.316), indicating very poor aqueous solubility. This is a major concern for both.

**11. hERG Inhibition:** Both ligands have low hERG inhibition risk (0.279 and 0.287).

**12. Microsomal Clearance:** Ligand A (47.721) has higher microsomal clearance than Ligand B (32.711), meaning it's less metabolically stable. This favors Ligand B.

**13. In vitro Half-Life:** Ligand B (15.751 hours) has a significantly longer in vitro half-life than Ligand A (6.441 hours). This is a major advantage for Ligand B.

**14. P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.038 and 0.105), which is good for CNS penetration.

**15. Binding Affinity:** Ligand A (-7.5 kcal/mol) has a slightly better binding affinity than Ligand B (-0.0 kcal/mol). This is a significant advantage, and can often outweigh other drawbacks.

**Overall Assessment:**

Ligand A has a significantly better binding affinity and lower DILI risk, and better BBB penetration. However, Ligand B has better metabolic stability (lower Cl_mic, longer t1/2). Both have poor solubility and permeability. Given the importance of binding affinity for GPCRs, and the lower DILI risk, Ligand A is the more promising candidate, despite its slightly higher clearance. The affinity difference is substantial enough to potentially overcome the solubility/permeability issues with appropriate formulation strategies.

Output:
1
2025-04-17 07:13:51,298 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (351.447 and 366.824 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (100.29) is slightly above the optimal <90 for CNS targets, but still reasonable. Ligand B (79.18) is well within the desired range. This favors Ligand B.

**3. logP:** Both ligands have logP values (2.074 and 2.8) within the optimal 1-3 range.

**4. H-Bond Donors:** Both have 3 HBD, which is acceptable.

**5. H-Bond Acceptors:** Both have 4 HBA, which is acceptable.

**6. QED:** Both ligands have good QED scores (0.624 and 0.761), indicating drug-like properties.

**7. DILI:** Ligand A (36.758) has a lower DILI risk than Ligand B (56.223), which is favorable.

**8. BBB:** Ligand A (59.364) has a significantly better BBB penetration percentile than Ligand B (47.344). This is a crucial advantage for a CNS target like DRD2.

**9. Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and suggests poor permeability. However, the scale is not specified, so it's hard to interpret.

**10. Aqueous Solubility:** Both have negative solubility values, which is also unusual and suggests poor solubility. Again, the scale is not specified.

**11. hERG Inhibition:** Both ligands have low hERG inhibition risk (0.213 and 0.407).

**12. Microsomal Clearance:** Ligand B (-12.24) has a *negative* microsomal clearance, which is impossible. This is a significant red flag and suggests an issue with the data. Ligand A (50.793) is reasonable.

**13. In vitro Half-Life:** Ligand A (7.59) has a shorter half-life than Ligand B (21.758), which is less desirable.

**14. P-gp Efflux:** Both have low P-gp efflux liability (0.054 and 0.078).

**15. Binding Affinity:** Both ligands have the same binding affinity (-8.3 kcal/mol), which is excellent.

**Overall Assessment:**

While Ligand B has a better TPSA and longer half-life, the negative microsomal clearance is a critical flaw. It indicates a data error or a fundamentally problematic property. Ligand A, despite having a slightly higher TPSA and shorter half-life, has a much more reasonable ADME profile, including a better BBB score and a plausible microsomal clearance. Given the importance of BBB penetration for a CNS target like DRD2, and the questionable data for Ligand B, Ligand A is the more promising candidate.

Output:
0
2025-04-17 07:13:51,298 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (364.43 and 378.49 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (93.12) is slightly above the preferred <90 for CNS targets, but still reasonable. Ligand B (49.85) is excellent, well below the threshold.

**logP:** Ligand A (0.542) is quite low, potentially hindering membrane permeability. Ligand B (2.107) is within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A has 1 HBD and 7 HBA, which are acceptable. Ligand B has 0 HBD and 4 HBA, also acceptable.

**QED:** Both ligands have reasonable QED scores (0.842 and 0.71), indicating good drug-like properties.

**DILI:** Ligand A (62.66) has a moderate DILI risk, while Ligand B (31.49) has a low DILI risk, which is favorable.

**BBB:** Ligand A (71.50) has a good BBB penetration percentile, but Ligand B (85.73) is significantly better, exceeding the >70 desirable threshold for CNS targets. This is a major advantage for Ligand B.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.992 and -4.464), which is unusual and suggests poor permeability. However, these values are on a scale where negative values are possible and don't necessarily disqualify a compound.

**Aqueous Solubility:** Both ligands have negative solubility values (-2.667 and -2.906), which also suggests poor solubility.

**hERG:** Ligand A (0.157) has a very low hERG risk, which is excellent. Ligand B (0.643) has a slightly higher, but still acceptable, hERG risk.

**Microsomal Clearance:** Ligand A (16.80) has lower microsomal clearance than Ligand B (39.31), indicating better metabolic stability.

**In vitro Half-Life:** Ligand A (13.77) has a longer in vitro half-life than Ligand B (-6.87), which is a significant advantage.

**P-gp Efflux:** Ligand A (0.077) has very low P-gp efflux, which is favorable for CNS penetration. Ligand B (0.191) has slightly higher P-gp efflux, but still relatively low.

**Binding Affinity:** Both ligands have excellent binding affinities (-7.6 and -6.9 kcal/mol). Ligand A has a slightly better affinity, but the difference (0.7 kcal/mol) isn't substantial enough to outweigh other factors.

**Overall Assessment:**

Ligand B is the stronger candidate. While Ligand A has slightly better affinity and metabolic stability, Ligand B excels in crucial GPCR-specific properties: significantly better BBB penetration, lower DILI risk, and a more optimal logP value. The lower TPSA of Ligand B is also beneficial. The negative Caco-2 and solubility values are concerning for both, but can potentially be addressed through formulation strategies. Given the importance of CNS penetration for a DRD2 ligand, Ligand B's superior BBB score is decisive.

Output:
1
2025-04-17 07:13:51,298 - INFO - Batch 347 complete. Total preferences: 5552
2025-04-17 07:13:51,298 - INFO - Processing batch 348/512...
2025-04-17 07:14:33,876 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (349.463 and 345.447 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (55.63) is significantly better than Ligand B (79.26). For CNS targets, we want TPSA <= 90, and A is comfortably within that, while B is approaching the upper limit.

**logP:** Ligand A (4.036) is a bit high, potentially causing solubility issues, but still within a reasonable range. Ligand B (0.622) is quite low, which could hinder membrane permeability and thus brain penetration.

**H-Bond Donors/Acceptors:** Ligand A (1 HBD, 6 HBA) is better than Ligand B (2 HBD, 5 HBA). Both are within acceptable limits.

**QED:** Ligand B (0.82) has a slightly better QED score than Ligand A (0.591), suggesting a more inherently drug-like profile.

**DILI:** Ligand A (72.392) has a higher DILI risk than Ligand B (31.873). This is a significant drawback for Ligand A.

**BBB:** Ligand B (72.237) has a better BBB penetration score than Ligand A (57.619). Both are above 70, which is good for CNS targets, but B is better.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.515 and -5.421), which is unusual and suggests poor permeability. This is a concern for both.

**Aqueous Solubility:** Both ligands have negative solubility values (-3.495 and -1.714), which is also concerning.

**hERG Inhibition:** Ligand A (0.813) has a slightly higher hERG risk than Ligand B (0.501), but both are relatively low.

**Microsomal Clearance:** Ligand B (-1.784) has a significantly *lower* (better) microsomal clearance than Ligand A (54.576). This indicates better metabolic stability for Ligand B.

**In vitro Half-Life:** Ligand B (20.83) has a substantially longer half-life than Ligand A (42.654).

**P-gp Efflux:** Ligand A (0.733) has a slightly lower P-gp efflux liability than Ligand B (0.032), which is favorable for CNS penetration.

**Binding Affinity:** Ligand A (-10.4 kcal/mol) has a *much* stronger binding affinity than Ligand B (-8.4 kcal/mol). This is a very substantial difference.

**Overall Assessment:**

The most critical factor for a CNS-targeting GPCR like DRD2 is brain penetration. While both ligands have acceptable BBB scores, Ligand B has a better score, lower DILI risk, better metabolic stability (lower Cl_mic, longer t1/2) and a better QED. Ligand A's main advantage is its significantly stronger binding affinity. However, the substantial difference in affinity might be enough to overcome the ADME drawbacks of Ligand A. The high DILI risk of Ligand A is a major concern. The low logP of Ligand B is a concern, but could be addressed through structural modifications.

Given the importance of BBB penetration, metabolic stability, and lower toxicity for CNS drugs, and the fact that the affinity difference is so large, I believe Ligand A is the more promising candidate, despite its higher DILI risk and logP. Further optimization could address the DILI and logP issues.

Output:
0
2025-04-17 07:14:33,877 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (353.375 and 359.363 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (129.75) is borderline acceptable for CNS targets (ideally <90), while Ligand B (40.54) is excellent, well below the threshold. This is a significant advantage for Ligand B.

**logP:** Ligand A (-1.224) is a bit low, potentially hindering membrane permeability. Ligand B (4.252) is high, potentially causing solubility issues or off-target interactions, but still within a reasonable range.

**H-Bond Donors/Acceptors:** Ligand A has 4 HBD and 6 HBA, which are acceptable. Ligand B has 1 HBD and 2 HBA, which is also good.

**QED:** Both ligands have similar QED values (0.433 and 0.428), indicating moderate drug-likeness.

**DILI:** Ligand A (54.323) has a higher DILI risk than Ligand B (16.479), which is a clear advantage for B.

**BBB:** Ligand B (66.188) has a significantly better BBB penetration percentile than Ligand A (18.185). This is *critical* for a CNS target like DRD2.

**Caco-2 Permeability:** Ligand A (-5.624) has poor Caco-2 permeability, while Ligand B (-4.686) is also poor, but slightly better.

**Aqueous Solubility:** Ligand A (-1.744) has poor solubility, while Ligand B (-4.257) is even worse. This is a concern for both, but more so for B.

**hERG Inhibition:** Ligand A (0.087) has a very low hERG risk, which is excellent. Ligand B (0.915) has a slightly elevated risk, but not alarmingly high.

**Microsomal Clearance:** Ligand A (-19.626) has a very low (good) microsomal clearance, indicating high metabolic stability. Ligand B (65.014) has high clearance, suggesting rapid metabolism. This is a significant advantage for A.

**In vitro Half-Life:** Ligand A (1.872) has a short half-life, while Ligand B (13.564) has a much longer half-life. This is a strong point for B.

**P-gp Efflux:** Ligand A (0.009) has very low P-gp efflux, which is excellent for CNS penetration. Ligand B (0.415) has moderate P-gp efflux.

**Binding Affinity:** Ligand A (-7.8) has a slightly better binding affinity than Ligand B (-7.5). While both are good, the 1.5 kcal/mol difference is notable.

**Overall Assessment:**

Ligand B excels in BBB penetration, DILI risk, and in vitro half-life. Its TPSA is also significantly better. However, it suffers from higher logP, poor solubility, and higher P-gp efflux. Ligand A has better metabolic stability (lower Cl_mic), lower P-gp efflux, and a slightly better binding affinity, but its BBB penetration is very poor and its solubility is low.

Given the GPCR-specific priorities, *BBB penetration is paramount for a CNS target*. Ligand B's significantly higher BBB percentile (66.188 vs. 18.185) outweighs the advantages of Ligand A, despite the solubility and logP concerns. The better half-life of B is also a plus. While the affinity difference is small, the other ADME properties of B are more favorable for CNS drug development.

Output:
1
2025-04-17 07:14:33,877 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B against the provided guidelines, prioritizing GPCR-specific properties (BBB, logP, Pgp, TPSA, and affinity) for DRD2.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (401.857 Da) is slightly higher, but acceptable. Ligand B (350.415 Da) is also good.

**TPSA:** Ligand A (116.07) is borderline for CNS targets (ideally <90), while Ligand B (97.64) is closer to the desired range. This favors Ligand B.

**logP:** Both ligands have good logP values (A: 1.974, B: 1.482), falling within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A (HBD=1, HBA=9) and Ligand B (HBD=2, HBA=5) both have reasonable numbers of H-bond donors and acceptors, within the suggested limits.

**QED:** Both ligands have good QED scores (A: 0.664, B: 0.726), indicating drug-like properties.

**DILI:** Ligand A has a very high DILI risk (99.806%), which is a significant concern. Ligand B has a much lower, and acceptable, DILI risk (52.656%). This strongly favors Ligand B.

**BBB:** Ligand A has a moderate BBB penetration (46.026%), while Ligand B has a lower BBB penetration (28.655%). While both are not ideal, DRD2 is a CNS target, so BBB is important.

**Caco-2 Permeability:** Ligand A (-4.908) and Ligand B (-5.169) both have negative Caco-2 permeability values, which is unusual and suggests poor intestinal absorption.

**Aqueous Solubility:** Both ligands have very poor aqueous solubility (A: -3.759, B: -1.875). This could pose formulation challenges.

**hERG Inhibition:** Ligand A (0.265) has a slightly higher hERG risk than Ligand B (0.078), but both are relatively low.

**Microsomal Clearance:** Ligand A (45.321) has a higher microsomal clearance than Ligand B (3.239), suggesting lower metabolic stability. Ligand B is much better in this regard.

**In vitro Half-Life:** Ligand A (110.316 hours) has a significantly longer half-life than Ligand B (16.376 hours). This is a positive for Ligand A.

**P-gp Efflux:** Ligand A (0.433) has a lower P-gp efflux liability than Ligand B (0.049), which is desirable for CNS penetration.

**Binding Affinity:** Ligand B (-7.7 kcal/mol) has a better binding affinity than Ligand A (-8.0 kcal/mol). Although the difference is small, it is still a factor.

**Overall Assessment:**

Ligand A has a longer half-life and slightly better affinity, but its extremely high DILI risk and moderate BBB penetration are major drawbacks. Ligand B has a lower DILI risk, better metabolic stability, and a more favorable TPSA. While its BBB penetration isn't ideal, it's less concerning than the high DILI risk of Ligand A. The slightly lower affinity of Ligand B is outweighed by its superior ADME properties, especially the DILI score.

Output:
1
2025-04-17 07:14:33,877 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (365.865 and 350.415 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (76.31) is excellent, well below the 90 A^2 threshold for CNS targets. Ligand B (87.15) is still reasonable, but less optimal.

**logP:** Ligand A (3.068) is within the optimal 1-3 range. Ligand B (0.301) is quite low, potentially hindering membrane permeability and CNS penetration.

**H-Bond Donors/Acceptors:** Both ligands have acceptable HBD (1) and HBA (7 for A, 5 for B) counts, staying within the recommended limits.

**QED:** Both ligands have good QED scores (0.842 and 0.737), indicating drug-like properties.

**DILI:** Ligand A (43.234) has a moderate DILI risk, while Ligand B (14.23) has a very low risk. This favors Ligand B.

**BBB:** Ligand A excels with a BBB percentile of 85.459, highly desirable for a CNS target. Ligand B's BBB percentile is significantly lower at 32.765, a major drawback.

**Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and suggests a potential issue with the data or modeling. However, we will proceed assuming these represent low permeability.

**Aqueous Solubility:** Both have negative solubility values, which is also unusual and suggests a potential issue with the data or modeling.

**hERG Inhibition:** Both ligands show low hERG inhibition liability (0.784 and 0.091), which is positive.

**Microsomal Clearance:** Ligand A (44.075) has a higher microsomal clearance than Ligand B (21.795), indicating potentially lower metabolic stability.

**In vitro Half-Life:** Ligand B has a slightly better in vitro half-life (3.306 hours) than Ligand A (-9.144 hours - negative values are unusual and may indicate rapid degradation).

**P-gp Efflux:** Ligand A (0.081) has lower P-gp efflux liability than Ligand B (0.04), which is beneficial for CNS penetration.

**Binding Affinity:** Ligand A (-8.0 kcal/mol) has a slightly better binding affinity than Ligand B (-7.2 kcal/mol), though both are good. The 0.8 kcal/mol difference is significant.

**Overall Assessment:**

Despite Ligand B's lower DILI risk, Ligand A is the stronger candidate. The critical factor is the significantly higher BBB penetration (85.459 vs. 32.765). For a CNS target like DRD2, this is paramount. The slightly better binding affinity of Ligand A further supports this conclusion. While Ligand A has a higher Cl_mic, the strong BBB penetration is likely to outweigh this drawback. The unusual negative values for Caco-2 and solubility are concerning, but the relative comparison still favors A.

Output:
1
2025-04-17 07:14:33,877 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (359.86 and 372.48 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (63.25) is higher than Ligand B (49.41). For a CNS target like DRD2, we ideally want TPSA <= 90, so both are acceptable, but B is better.

**logP:** Ligand A (4.27) is slightly higher than the optimal range (1-3), potentially leading to solubility issues. Ligand B (2.877) is within the optimal range. This favors B.

**H-Bond Donors/Acceptors:** Ligand A has 2 HBD and 4 HBA, while Ligand B has 1 HBD and 3 HBA. Both are within acceptable limits (<=5 HBD and <=10 HBA).

**QED:** Both ligands have reasonable QED values (0.855 and 0.73), indicating good drug-like properties.

**DILI:** Ligand A (63.63%) has a higher DILI risk than Ligand B (20.40%). This is a significant advantage for B.

**BBB:** Ligand A (71.38%) and Ligand B (92.94%) both have good BBB penetration, but Ligand B is significantly better, exceeding the desirable >70% threshold. This is crucial for a CNS target.

**Caco-2 Permeability:** Both have negative Caco-2 values (-4.764 and -4.874). These values are difficult to interpret without knowing the scale, but a negative value suggests poor permeability.

**Aqueous Solubility:** Both ligands have negative solubility values (-5.129 and -3.976), indicating poor aqueous solubility. This is a concern, especially for Ligand A with its higher logP.

**hERG:** Both ligands have low hERG inhibition liability (0.769 and 0.83), which is good.

**Microsomal Clearance:** Ligand A (60.66) has higher microsomal clearance than Ligand B (44.85), suggesting lower metabolic stability. B is favored.

**In vitro Half-Life:** Ligand A (116.13) has a longer half-life than Ligand B (-1.07). This is a positive for A, but the negative value for B is concerning.

**P-gp Efflux:** Ligand A (0.623) has lower P-gp efflux than Ligand B (0.137), which is favorable for CNS penetration.

**Binding Affinity:** Ligand B (-7.6 kcal/mol) has a significantly stronger binding affinity than Ligand A (-9.1 kcal/mol). This is a major advantage for B, potentially outweighing some of its ADME drawbacks.

**Overall Assessment:**

Ligand B is the stronger candidate. It has a better logP, significantly lower DILI risk, superior BBB penetration, lower microsomal clearance, and, most importantly, a much stronger binding affinity. While both have poor solubility and Caco-2 permeability, the strong affinity and favorable CNS properties of Ligand B make it more likely to succeed as a DRD2-targeting drug. The longer half-life of Ligand A is a plus, but the negative value for B is concerning and needs further investigation.



Output:
1
2025-04-17 07:14:33,878 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (352.341 and 341.455 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (85.37) is slightly above the preferred <90 for CNS targets, but still reasonable. Ligand B (73.2) is excellent, well below 90.

**logP:** Both ligands have good logP values (2.805 and 2.39), falling within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A (2 HBD, 6 HBA) and Ligand B (1 HBD, 3 HBA) both have acceptable numbers of H-bond donors and acceptors, well within the guidelines.

**QED:** Both ligands have good QED scores (0.778 and 0.801), indicating good drug-like properties.

**DILI:** Ligand A (87.902) has a concerningly high DILI risk (above 60), while Ligand B (15.859) has a very low DILI risk, which is a significant advantage.

**BBB:** Ligand A (55.021) has a moderate BBB penetration, below the desirable >70 for CNS targets. Ligand B (71.268) is much better, exceeding the 70% threshold.

**Caco-2 Permeability:** Both have negative Caco-2 values (-4.628 and -4.803), which is unusual and suggests poor permeability. This is a significant concern for both.

**Aqueous Solubility:** Both have negative solubility values (-4.134 and -3.772), also unusual and indicating very poor aqueous solubility. This is a major drawback for both compounds.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.388 and 0.406).

**Microsomal Clearance:** Ligand A (32.374) has a higher microsomal clearance than Ligand B (10.932), suggesting lower metabolic stability.

**In vitro Half-Life:** Ligand B (1.316) has a slightly better in vitro half-life than Ligand A (-13.214), though both are poor.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.206 and 0.057), which is favorable for CNS penetration.

**Binding Affinity:** Both ligands have very similar and excellent binding affinities (-8.7 kcal/mol). The difference is negligible.

**Conclusion:**

Despite similar binding affinities, **Ligand B is the more promising candidate.** The primary reasons are its significantly lower DILI risk and substantially better BBB penetration. While both compounds suffer from poor Caco-2 permeability and aqueous solubility, the DILI and BBB issues with Ligand A are more critical for a CNS-targeting drug. The slightly better metabolic stability (lower Cl_mic) and half-life of Ligand B further support this conclusion.

Output:
1
2025-04-17 07:14:33,878 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (361.471 and 359.503 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (92.94) is better than Ligand B (101.64). For CNS targets, we want TPSA <= 90, so Ligand A is closer to this threshold.

**3. logP:** Both ligands have good logP values (3.204 and 3.751), falling within the optimal 1-3 range. Ligand B is slightly higher, which could potentially lead to off-target effects, but it's not a major concern.

**4. H-Bond Donors:** Ligand A (2) is preferable to Ligand B (3). Lower HBD generally improves permeability.

**5. H-Bond Acceptors:** Ligand A (7) is preferable to Ligand B (8). Lower HBA generally improves permeability.

**6. QED:** Ligand A (0.701) has a significantly better QED score than Ligand B (0.463), indicating a more drug-like profile.

**7. DILI:** Ligand A (76.309) has a higher DILI risk than Ligand B (69.135), but both are acceptable.

**8. BBB:** Ligand A (72.315) has a better BBB percentile than Ligand B (60.45). For a CNS target like DRD2, a BBB > 70 is desirable, and Ligand A is closer to this.

**9. Caco-2 Permeability:** Ligand A (-5.484) has better Caco-2 permeability than Ligand B (-5.314), indicating better intestinal absorption.

**10. Aqueous Solubility:** Ligand A (-3.688) has better aqueous solubility than Ligand B (-4.017).

**11. hERG Inhibition:** Ligand A (0.374) has a lower hERG inhibition risk than Ligand B (0.556), which is preferable.

**12. Microsomal Clearance:** Ligand A (78.006) has a higher microsomal clearance than Ligand B (75.796), meaning it's less metabolically stable. This is a slight negative for Ligand A.

**13. In vitro Half-Life:** Ligand B (18.059) has a longer in vitro half-life than Ligand A (31.21), which is preferable.

**14. P-gp Efflux:** Ligand A (0.332) has lower P-gp efflux liability than Ligand B (0.137), which is better for CNS exposure.

**15. Binding Affinity:** Ligand B (-8.0) has a slightly better binding affinity than Ligand A (-7.8). However, the difference is relatively small (0.2 kcal/mol).

**Overall Assessment:**

Ligand A is generally superior due to its better TPSA, QED, BBB, Caco-2 permeability, solubility, and lower hERG risk and P-gp efflux. While Ligand B has slightly better affinity and half-life, the advantages of Ligand A in key GPCR-relevant properties (BBB, TPSA, Pgp) and overall drug-likeness outweigh these minor differences.

Output:
0
2025-04-17 07:14:33,878 - INFO - Reasoning:

Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (345.443 and 352.494 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (82.53) is significantly better than Ligand B (49.41). For a CNS target like DRD2, TPSA should be <= 90, and both meet this, but A is closer to the upper limit, which could be a slight concern.

**3. logP:** Ligand A (1.425) is within the optimal 1-3 range. Ligand B (3.16) is at the higher end of optimal, potentially increasing off-target interactions, but still acceptable.

**4. H-Bond Donors:** Ligand A (2) and Ligand B (1) both have acceptable HBD counts (<=5).

**5. H-Bond Acceptors:** Ligand A (4) and Ligand B (2) both have acceptable HBA counts (<=10).

**6. QED:** Both ligands have similar QED values (0.817 and 0.798), indicating good drug-like properties.

**7. DILI:** Ligand A (19.465) has a significantly lower DILI risk than Ligand B (24.506). Both are below the 40 threshold, indicating low risk.

**8. BBB:** This is a crucial parameter for CNS targets. Ligand B (97.286) has *excellent* BBB penetration, far exceeding Ligand A (47.46). This is a major advantage for Ligand B.

**9. Caco-2 Permeability:** Ligand A (-5.278) has poor Caco-2 permeability. Ligand B (-4.595) is also poor, but slightly better than A.

**10. Aqueous Solubility:** Ligand A (-0.93) has slightly better solubility than Ligand B (-3.805), but both are quite poor.

**11. hERG Inhibition:** Both ligands show low hERG inhibition liability (0.14 and 0.762), which is good.

**12. Microsomal Clearance:** Ligand A (-16.915) has a lower (better) microsomal clearance than Ligand B (37.89). This suggests better metabolic stability for Ligand A.

**13. In vitro Half-Life:** Ligand A (12.49) has a slightly better in vitro half-life than Ligand B (-16.024).

**14. P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.033 and 0.46).

**15. Binding Affinity:** Both ligands have very strong binding affinity (-8.5 and -8.9 kcal/mol). The difference is minimal.

**Overall Assessment:**

Ligand B is the stronger candidate. While Ligand A has better metabolic stability and slightly better solubility, Ligand B's *exceptional* BBB penetration (97.286) is the deciding factor for a CNS target like DRD2. The slightly higher logP of Ligand B is a minor concern, but the substantial benefit of high BBB penetration outweighs this. The binding affinity is comparable between the two.

Output:
1
2025-04-17 07:14:33,878 - INFO - Reasoning:

Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (369.4 and 346.4 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (122.74) is slightly above the optimal <90 for CNS targets, while Ligand B (102.32) is closer to this threshold and therefore preferable.

**3. logP:** Ligand A (0.702) is a bit low, potentially hindering permeability. Ligand B (0.543) is also on the lower side, but still within an acceptable range.

**4. H-Bond Donors:** Ligand A (1) and Ligand B (2) are both within the acceptable limit of <=5.

**5. H-Bond Acceptors:** Ligand A (8) and Ligand B (6) are both within the acceptable limit of <=10.

**6. QED:** Both ligands have similar QED values (0.537 and 0.528), indicating good drug-like properties.

**7. DILI:** Ligand A (87.01) has a higher DILI risk than Ligand B (66.15), making Ligand B more favorable.

**8. BBB:** Ligand A (61.535) has a better BBB penetration percentile than Ligand B (44.591). This is a significant advantage for a CNS target like DRD2.

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 values, which is unusual and suggests poor permeability. However, the magnitude is similar.

**10. Aqueous Solubility:** Both ligands have negative solubility values, also unusual. Again, the magnitude is similar.

**11. hERG Inhibition:** Both ligands show very low hERG inhibition risk (0.166 and 0.026).

**12. Microsomal Clearance:** Ligand A (39.691) has lower microsomal clearance than Ligand B (45.404), suggesting better metabolic stability.

**13. In vitro Half-Life:** Ligand A (-32.567) has a significantly longer in vitro half-life than Ligand B (-2.219). This is a substantial advantage.

**14. P-gp Efflux:** Both ligands show very low P-gp efflux liability (0.336 and 0.011).

**15. Binding Affinity:** Ligand A (-7.5) has a slightly better binding affinity than Ligand B (-7.3). While the difference is small (0.2 kcal/mol), it's still a positive factor.

**Overall Assessment:**

Ligand A has advantages in BBB penetration, metabolic stability (lower Cl_mic, longer t1/2), and binding affinity. Ligand B has a lower DILI risk and a more favorable TPSA. The lower logP values for both are a concern, but the affinity difference between A and B is enough to outweigh this. The superior BBB penetration and half-life of Ligand A are crucial for a CNS target.

Output:
1
2025-04-17 07:14:33,879 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (360.401 and 344.415 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (78.87) is significantly better than Ligand B (91.23). For CNS targets, we want TPSA <= 90, so Ligand A is preferable.

**3. logP:** Both ligands have acceptable logP values (1.766 and 2.215), falling within the optimal 1-3 range.

**4. H-Bond Donors:** Both have 2 HBD, which is within the acceptable limit of <=5.

**5. H-Bond Acceptors:** Both have 4 HBA, within the acceptable limit of <=10.

**6. QED:** Both ligands have good QED scores (0.757 and 0.87), indicating good drug-like properties.

**7. DILI:** Ligand A (20.783) has a much lower DILI risk than Ligand B (60.644). This is a significant advantage for Ligand A.

**8. BBB:** This is a critical parameter for CNS targets. Ligand A (76.347) has a much higher BBB percentile than Ligand B (61.962).  A value >70 is desirable, and Ligand A is closer to this threshold.

**9. Caco-2 Permeability:** Ligand A (-5.284) shows poor Caco-2 permeability, while Ligand B (-4.954) is slightly better, but both are quite low.

**10. Aqueous Solubility:** Ligand A (-1.82) has slightly better solubility than Ligand B (-3.063).

**11. hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.362 and 0.186).

**12. Microsomal Clearance:** Ligand A (-10.841) has significantly lower (better) microsomal clearance than Ligand B (19.764), indicating greater metabolic stability.

**13. In vitro Half-Life:** Ligand B (23.79) has a much longer in vitro half-life than Ligand A (1.299). This is a positive for Ligand B.

**14. P-gp Efflux:** Ligand A (0.077) has lower P-gp efflux than Ligand B (0.096), which is preferable for CNS penetration.

**15. Binding Affinity:** Ligand B (-9.0) has a significantly stronger binding affinity than Ligand A (-7.8). This is a substantial advantage for Ligand B, potentially outweighing some ADME drawbacks.

**Overall Assessment:**

While Ligand B boasts a superior binding affinity, Ligand A has a much better safety profile (lower DILI), better BBB penetration, and improved metabolic stability. The improved BBB and lower DILI are crucial for a CNS-targeting drug. The lower Caco-2 permeability of Ligand A is a concern, but the stronger affinity of Ligand B might be enough to overcome some permeability issues. However, the significantly better ADME properties of Ligand A, particularly the BBB and DILI, make it the more promising candidate.

Output:
1
2025-04-17 07:14:33,879 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (347.415 Da) is slightly lower, which could be beneficial for permeability.

**TPSA:** Ligand A (93.46) is better than Ligand B (51.02) for CNS penetration, being closer to the <90 A^2 target. Ligand B is excellent.

**logP:** Both ligands have good logP values (A: 1.639, B: 3.257), falling within the optimal 1-3 range. Ligand B is slightly higher, which could potentially lead to off-target effects, but it's still acceptable.

**H-Bond Donors/Acceptors:** Ligand A has 2 HBD and 5 HBA, while Ligand B has 0 HBD and 5 HBA. Both are within acceptable limits.

**QED:** Both ligands have good QED scores (A: 0.551, B: 0.747), indicating good drug-like properties. Ligand B is better.

**DILI:** Ligand A (47.693) has a higher DILI risk than Ligand B (22.489), which is a significant advantage for B.

**BBB:** Ligand B (80.845) has a significantly better BBB penetration percentile than Ligand A (71.811). This is crucial for a CNS target like DRD2.

**Caco-2 Permeability:** Ligand A (-4.461) has a worse Caco-2 permeability than Ligand B (-5.108).

**Aqueous Solubility:** Both ligands have poor aqueous solubility (-3.143 and -3.581 respectively). This could pose formulation challenges.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (A: 0.339, B: 0.452).

**Microsomal Clearance:** Ligand B (90.353) has a much higher microsomal clearance than Ligand A (35.07). This suggests Ligand A is more metabolically stable.

**In vitro Half-Life:** Ligand A (-11.927) has a much longer in vitro half-life than Ligand B (23.433).

**P-gp Efflux:** Ligand A (0.242) has lower P-gp efflux liability than Ligand B (0.334), which is favorable for CNS penetration.

**Binding Affinity:** Ligand A (-7.5 kcal/mol) has a slightly better binding affinity than Ligand B (-6.8 kcal/mol). While the difference is not huge, it's a positive for A.

**Overall Assessment:**

Ligand B excels in BBB penetration, DILI risk, and QED. These are critical factors for a CNS-targeting GPCR. While Ligand A has better metabolic stability (lower Cl_mic, longer t1/2) and slightly better binding affinity, the superior CNS penetration and safety profile of Ligand B outweigh these advantages. The solubility is a concern for both, but can be addressed with formulation strategies.

Output:
1
2025-04-17 07:14:33,879 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (378.376 and 382.429 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Both ligands (84.42 and 84.94) are below the 90 A^2 threshold for CNS targets, which is excellent.

**3. logP:** Ligand A (1.494) is optimal, while Ligand B (0.561) is slightly below the preferred range of 1-3. This could potentially hinder membrane permeability for Ligand B.

**4. H-Bond Donors:** Both ligands have 1 HBD, which is within the acceptable limit of <=5.

**5. H-Bond Acceptors:** Ligand A has 6 HBAs, and Ligand B has 5. Both are below the acceptable limit of <=10.

**6. QED:** Ligand A (0.858) has a higher QED than Ligand B (0.696), indicating a more drug-like profile.

**7. DILI:** Both ligands have low DILI risk (46.53 and 42.536 percentile), which is favorable.

**8. BBB:** Both ligands exhibit excellent BBB penetration (89.027 and 89.957 percentile), crucial for a CNS target like DRD2.

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.774 and -4.983). This is unusual and requires careful interpretation. Negative values often indicate issues with the assay or the compound's behavior. However, given the other favorable properties, this isn't a dealbreaker *yet*.

**10. Aqueous Solubility:** Both ligands have negative solubility values (-2.947 and -2.632). Similar to Caco-2, this is concerning and suggests potential formulation challenges.

**11. hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.204 and 0.56 percentile), which is excellent.

**12. Microsomal Clearance:** Ligand B (-8.583) has significantly lower (better) microsomal clearance than Ligand A (15.614). This suggests greater metabolic stability for Ligand B.

**13. In vitro Half-Life:** Ligand B (-14.5) has a much longer in vitro half-life than Ligand A (-9.121), indicating slower metabolism and potentially less frequent dosing.

**14. P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.03 and 0.04 percentile), which is ideal for CNS penetration.

**15. Binding Affinity:** Ligand B (-8.2 kcal/mol) has a slightly better binding affinity than Ligand A (-7.6 kcal/mol). This 0.6 kcal/mol difference is significant and could outweigh some of the minor ADME drawbacks of Ligand B.

**Overall Assessment:**

While both ligands have good overall profiles, Ligand B is slightly more promising. Its superior binding affinity, significantly better metabolic stability (lower Cl_mic and longer t1/2), and comparable BBB penetration outweigh the slightly lower logP. The negative Caco-2 and solubility values are concerning for both, but these can potentially be addressed through formulation strategies. Ligand A's higher QED is a plus, but the difference isn't substantial enough to overcome Ligand B's better potency and metabolic properties.



Output:
1
2025-04-17 07:14:33,879 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (358.454 and 369.447 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (67.87) is excellent, well below the 90 A^2 threshold for CNS targets. Ligand B (109.58) is higher, but still potentially acceptable, though less ideal.

**logP:** Ligand A (1.531) is within the optimal 1-3 range. Ligand B (-0.967) is slightly below 1, which *could* indicate permeability issues, but isn't a dealbreaker given the other properties.

**H-Bond Donors/Acceptors:** Ligand A (HBD=1, HBA=4) is favorable. Ligand B (HBD=2, HBA=8) is also acceptable, but the higher HBA count could slightly impact permeability.

**QED:** Ligand A (0.643) is good, indicating strong drug-like properties. Ligand B (0.426) is lower, suggesting a less ideal overall drug-like profile.

**DILI:** Ligand A (26.444) has a much lower DILI risk than Ligand B (50.795), which is a significant advantage.

**BBB:** This is critical for a CNS target like DRD2. Ligand A (97.325) shows excellent BBB penetration potential. Ligand B (29.546) is very poor, a major drawback.

**Caco-2 Permeability:** Ligand A (-4.543) is negative, indicating poor permeability. Ligand B (-5.63) is also negative and worse. This is concerning for both, but can be offset by good BBB penetration.

**Aqueous Solubility:** Both have negative solubility values, suggesting poor aqueous solubility. Ligand A (-2.456) is slightly better than Ligand B (-1.047).

**hERG Inhibition:** Both ligands show very low hERG inhibition risk (0.69 and 0.04 respectively), which is excellent.

**Microsomal Clearance:** Ligand A (52.333) has a higher clearance than Ligand B (17.919), indicating lower metabolic stability.

**In vitro Half-Life:** Ligand B (-16.774) has a negative half-life, which is problematic. Ligand A (11.259) has a reasonable half-life.

**P-gp Efflux:** Both ligands have very low P-gp efflux (0.087 and 0.037 respectively), which is favorable for CNS penetration.

**Binding Affinity:** Both ligands have very similar and strong binding affinities (-7.2 and -7.1 kcal/mol). The difference is negligible.

**Overall Assessment:**

Ligand A is the superior candidate. While its Caco-2 permeability and solubility are poor, its excellent BBB penetration (97.325), lower DILI risk, and reasonable half-life outweigh these drawbacks, especially given the strong binding affinity. Ligand B's extremely poor BBB penetration is a deal-breaker for a CNS-targeted drug, despite its slightly better metabolic stability.

Output:
0
2025-04-17 07:14:33,880 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B based on the provided guidelines, prioritizing GPCR-specific properties (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (352.435 Da) is slightly lower, which could be beneficial for permeability.

**TPSA:** Both ligands have TPSA values below 90, which is good for CNS penetration. Ligand B (76.89) is slightly better than Ligand A (87.78).

**logP:** Ligand A (-0.195) is quite low, potentially hindering membrane permeability. Ligand B (3.137) is within the optimal range (1-3). This is a significant advantage for Ligand B.

**H-Bond Donors/Acceptors:** Ligand A (HBD=1, HBA=6) and Ligand B (HBD=2, HBA=8) both fall within acceptable limits.

**QED:** Both ligands have similar QED values (A: 0.795, B: 0.71), indicating good drug-likeness.

**DILI:** Ligand A (21.326) has a much lower DILI risk than Ligand B (88.251). This is a strong positive for Ligand A.

**BBB:** Ligand B (69.407) has a better BBB percentile than Ligand A (46.917), but both are below the desirable >70 threshold for CNS targets.

**Caco-2 Permeability:** Ligand A (-4.674) has a negative Caco-2 value, which is concerning. Ligand B (-5.19) is also negative, but slightly worse.

**Aqueous Solubility:** Both have negative solubility values, which is not ideal.

**hERG:** Both ligands show low hERG inhibition liability (A: 0.387, B: 0.827).

**Microsomal Clearance:** Ligand A (3.917) has a lower microsomal clearance than Ligand B (64.511), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (-15.041) has a negative half-life, which is problematic. Ligand B (5.61) is positive, indicating a better in vitro half-life.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (A: 0.06, B: 0.533).

**Binding Affinity:** Both ligands have the same binding affinity (-8.2 kcal/mol), which is excellent.

**Overall Assessment:**

Ligand B has a much better logP and BBB percentile, crucial for CNS penetration. However, it has a significantly higher DILI risk and higher microsomal clearance. Ligand A has a lower DILI risk and better metabolic stability, but its low logP and poor Caco-2 permeability are major drawbacks. The negative half-life for Ligand A is also a serious concern.

Given the importance of CNS penetration for DRD2 (a CNS target), and the strong binding affinity being equal, Ligand B is slightly more promising *despite* the higher DILI risk. The logP value is critical, and the better BBB percentile is also important. The DILI risk could potentially be mitigated through structural modifications. The poor permeability of Ligand A is a harder problem to solve.

Output:
1
2025-04-17 07:14:33,880 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B based on the provided guidelines, prioritizing GPCR-specific properties (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (340.379 Da) is slightly lower, which could be beneficial for permeability.

**TPSA:** Both are below the 140 A^2 threshold for oral absorption, but importantly, below the 90 A^2 threshold for CNS targets. Ligand B (75.27 A^2) is slightly better than Ligand A (79.73 A^2).

**logP:** Both ligands have optimal logP values (between 1 and 3). Ligand B (1.914) is slightly lower than Ligand A (2.713), potentially improving solubility but slightly reducing membrane permeability.

**H-Bond Donors/Acceptors:** Both ligands have acceptable HBD (1 & 2) and HBA (4 & 4) counts.

**QED:** Both ligands have good QED scores (>0.5), indicating drug-likeness.

**DILI:** Ligand B (61.07) has a significantly lower DILI risk than Ligand A (82.939), a substantial advantage.

**BBB:** Ligand B (75.107) has a much better BBB penetration percentile than Ligand A (52.617). This is *critical* for a CNS target like DRD2.

**Caco-2 Permeability:** Ligand A (-4.624) has a more negative Caco-2 value, indicating *lower* permeability than Ligand B (-5.204).

**Aqueous Solubility:** Both have negative solubility values, suggesting poor solubility. Ligand B (-2.903) is slightly better than Ligand A (-3.394).

**hERG Inhibition:** Both have very low hERG inhibition risk.

**Microsomal Clearance:** Ligand B (-11.679) has a significantly lower (better) microsomal clearance than Ligand A (8.428), indicating greater metabolic stability.

**In vitro Half-Life:** Ligand B (-17.527) has a much longer in vitro half-life than Ligand A (10.092), a significant advantage.

**P-gp Efflux:** Both have low P-gp efflux liability. Ligand A (0.017) is slightly lower than Ligand B (0.176), but the difference is small.

**Binding Affinity:** Ligand B (-9.1 kcal/mol) has a slightly better binding affinity than Ligand A (-8.6 kcal/mol). While the difference is less than the 1.5 kcal/mol threshold, it contributes to the overall better profile of Ligand B.

**Overall Assessment:**

Ligand B clearly outperforms Ligand A across several critical parameters for a CNS-targeting GPCR. The most significant advantages are its superior BBB penetration, lower DILI risk, improved metabolic stability (lower Cl_mic and longer t1/2), and slightly better binding affinity. While both have solubility concerns, Ligand B is marginally better. The better TPSA and slightly lower logP of Ligand B are also favorable.

Output:
1
2025-04-17 07:14:33,880 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (365.861 and 368.499 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (53.09) is excellent, well below the 90 A^2 threshold for CNS targets. Ligand B (89.87) is still acceptable but closer to the upper limit.

**logP:** Ligand A (2.243) is optimal. Ligand B (1.169) is a bit low, potentially hindering permeability.

**H-Bond Donors/Acceptors:** Ligand A (0 HBD, 4 HBA) is favorable. Ligand B (3 HBD, 5 HBA) is also acceptable, though slightly higher.

**QED:** Both ligands have reasonable QED values (0.751 and 0.61), indicating good drug-like properties.

**DILI:** Ligand A (47.693) has a lower DILI risk than Ligand B (23.653), which is preferable.

**BBB:** This is a critical parameter for a CNS target like DRD2. Ligand A (94.261) shows excellent BBB penetration, while Ligand B (36.371) is significantly lower and concerning.

**Caco-2 Permeability:** Ligand A (-4.413) has poor Caco-2 permeability, which is a concern. Ligand B (-5.254) is even worse.

**Aqueous Solubility:** Ligand A (-3.083) has poor aqueous solubility. Ligand B (-1.641) is also poor, but slightly better.

**hERG:** Both ligands have low hERG inhibition risk (0.535 and 0.369), which is good.

**Microsomal Clearance:** Ligand A (7.086) has lower microsomal clearance, suggesting better metabolic stability than Ligand B (34.275).

**In vitro Half-Life:** Ligand B (35.356) has a much longer in vitro half-life than Ligand A (2.95), which is a significant advantage.

**P-gp Efflux:** Ligand A (0.091) has lower P-gp efflux, which is favorable for CNS penetration. Ligand B (0.147) is slightly higher.

**Binding Affinity:** Ligand A (-8.4 kcal/mol) has significantly stronger binding affinity than Ligand B (-6.7 kcal/mol). This is a substantial advantage, potentially outweighing some of its ADME drawbacks.

**Overall Assessment:**

Ligand A excels in key areas for a CNS GPCR target: TPSA, logP, BBB penetration, P-gp efflux, and, crucially, binding affinity. While its Caco-2 permeability and aqueous solubility are poor, the strong binding affinity and excellent BBB penetration are highly attractive. Ligand B has a better half-life, but suffers from poor BBB penetration and a weaker binding affinity. Given the importance of CNS penetration for DRD2, and the significant binding affinity advantage of Ligand A, it is the more promising candidate.

Output:
1
2025-04-17 07:14:33,880 - INFO - Batch 348 complete. Total preferences: 5568
2025-04-17 07:14:33,880 - INFO - Processing batch 349/512...
2025-04-17 07:15:17,189 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (343.427 and 349.479 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (87.3) is better than Ligand B (70.47). Both are below the 90 A^2 threshold for CNS targets, which is excellent.

**3. logP:** Both ligands have acceptable logP values (0.636 and 0.72), falling within the 1-3 range.

**4. H-Bond Donors:** Ligand A has 3 HBD, while Ligand B has 1. Both are within the acceptable limit of <=5.

**5. H-Bond Acceptors:** Ligand A has 3 HBA, and Ligand B has 5. Both are within the acceptable limit of <=10.

**6. QED:** Ligand B (0.787) has a significantly better QED score than Ligand A (0.376), indicating a more drug-like profile.

**7. DILI:** Ligand B (11.206) has a much lower DILI risk than Ligand A (27.608), which is a significant advantage.

**8. BBB:** Ligand B (55.797) has a substantially better BBB penetration percentile than Ligand A (30.128). This is *critical* for a CNS target like DRD2.

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.037 and -5.066), which is unusual and suggests poor permeability. This is a concern for both.

**10. Aqueous Solubility:** Both ligands have negative solubility values (-2.972 and -0.237), indicating poor aqueous solubility. This is a concern for both.

**11. hERG Inhibition:** Ligand A (0.031) has a slightly higher hERG inhibition risk than Ligand B (0.25), but both are relatively low.

**12. Microsomal Clearance:** Ligand B (4.857) has a lower microsomal clearance than Ligand A (22.291), suggesting better metabolic stability.

**13. In vitro Half-Life:** Ligand A (-17.036) has a negative half-life, which is not physically possible and indicates a problem with the data or the molecule. Ligand B (4.985) has a reasonable half-life.

**14. P-gp Efflux:** Ligand A (0.03) has very low P-gp efflux, which is good. Ligand B (0.006) has even lower P-gp efflux, which is excellent.

**15. Binding Affinity:** Ligand B (-7.2 kcal/mol) has a significantly stronger binding affinity than Ligand A (-8.2 kcal/mol). A difference of 1 kcal/mol is substantial.

**Overall Assessment:**

Ligand B is clearly the superior candidate. While both have issues with Caco-2 and solubility, Ligand B excels in the critical areas for a CNS GPCR target: BBB penetration, DILI risk, metabolic stability, and, most importantly, binding affinity. The negative half-life for Ligand A is a showstopper. The stronger binding affinity of Ligand B (-7.2 kcal/mol) is a significant advantage that outweighs any minor drawbacks.

Output:
1
2025-04-17 07:15:17,189 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (384.303 and 362.861 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (38.77) is significantly better than Ligand B (94.88). For CNS targets, we want TPSA <= 90, and A is comfortably within that, while B exceeds it. This is a major advantage for A.

**3. logP:** Both ligands have good logP values (4.385 and 3.208), falling within the optimal 1-3 range. Ligand B is slightly better.

**4. H-Bond Donors:** Ligand A (0) is preferable to Ligand B (2). Fewer HBDs generally improve permeability.

**5. H-Bond Acceptors:** Both have 4 HBA, which is acceptable.

**6. QED:** Both ligands have similar, good QED values (0.725 and 0.728).

**7. DILI:** Both have acceptable DILI risk (34.587 and 38.658), well below the 60 threshold.

**8. BBB:** Both ligands have excellent BBB penetration (74.37 and 74.176), exceeding the desirable >70 threshold for CNS targets.

**9. Caco-2 Permeability:** Both have negative Caco-2 values (-4.571 and -4.829). This is unusual and suggests poor permeability, but the scale isn't defined, so it's hard to interpret.

**10. Aqueous Solubility:** Both have negative solubility values (-4.865 and -3.987). Again, the scale is undefined, but suggests poor solubility.

**11. hERG Inhibition:** Both ligands show low hERG inhibition risk (0.595 and 0.466).

**12. Microsomal Clearance:** Ligand A (64.262) has higher clearance than Ligand B (35.856), indicating lower metabolic stability. This favors B.

**13. In vitro Half-Life:** Ligand B (27.131) has a significantly longer half-life than Ligand A (2.657), which is a significant advantage.

**14. P-gp Efflux:** Ligand A (0.224) has lower P-gp efflux than Ligand B (0.032), suggesting better CNS exposure. This favors A.

**15. Binding Affinity:** Ligand B (-8.3 kcal/mol) has a stronger binding affinity than Ligand A (-7.6 kcal/mol). This is a substantial advantage (0.7 kcal/mol difference), and can often outweigh minor ADME concerns.

**Overall Assessment:**

While Ligand A has a much better TPSA and P-gp efflux, Ligand B's superior binding affinity (-8.3 vs -7.6 kcal/mol) and longer half-life are critical for a GPCR drug candidate. The slightly higher clearance of Ligand A is a concern, but the affinity difference is substantial. The negative Caco-2 and solubility values are concerning for both, but the affinity advantage of B is likely to be more impactful in driving *in vivo* efficacy.

Output:
1
2025-04-17 07:15:17,189 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (376.385 Da) is slightly higher than Ligand B (347.459 Da), but both are acceptable.

**TPSA:** Ligand A (117.26) is borderline for CNS penetration, being above the preferred <90, but still potentially acceptable. Ligand B (53.09) is excellent, well below the threshold.

**logP:** Ligand A (0.546) is a bit low, potentially hindering membrane permeability. Ligand B (0.426) is also low, presenting a similar concern. Both are below the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A has 3 HBD and 5 HBA, which are reasonable. Ligand B has 0 HBD and 4 HBA, also acceptable.

**QED:** Ligand B (0.68) has a better QED score than Ligand A (0.452), indicating a more drug-like profile.

**DILI:** Ligand A (68.903) has a higher DILI risk than Ligand B (44.94), which is preferable.

**BBB:** Ligand A (73.711) has a better BBB penetration percentile than Ligand B (61.38), which is crucial for a CNS target like DRD2.

**Caco-2 Permeability:** Ligand A (-5.372) has poor Caco-2 permeability, while Ligand B (-4.26) is also poor, but slightly better.

**Aqueous Solubility:** Ligand A (-2.915) has poor aqueous solubility, and Ligand B (-1.116) is also poor.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.409 and 0.381, respectively).

**Microsomal Clearance:** Ligand A (17.714) has lower microsomal clearance than Ligand B (26.593), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (-28.265) has a very negative half-life, indicating very rapid metabolism. Ligand B (-8.707) is also negative, but less so.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.045 and 0.13, respectively), which is good for CNS penetration.

**Binding Affinity:** Ligand A (-8.4 kcal/mol) has a significantly stronger binding affinity than Ligand B (-7.4 kcal/mol). This 1.0 kcal/mol difference is substantial and can outweigh some ADME deficiencies.

**Overall Assessment:**

While Ligand B has better QED, DILI, and TPSA, Ligand A's significantly stronger binding affinity (-8.4 vs -7.4 kcal/mol) and better BBB penetration (73.7 vs 61.4) are critical advantages for a CNS-targeting GPCR. The lower metabolic stability (higher Cl_mic, negative t1/2) and poor solubility/permeability of Ligand A are concerns, but these could potentially be addressed through further optimization. The affinity difference is large enough to prioritize Ligand A.

Output:
1
2025-04-17 07:15:17,189 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (349.406 and 373.45 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (57.0) is excellent, well below the 90 A^2 threshold for CNS targets. Ligand B (91.76) is higher, approaching the upper limit for good oral absorption (140) but less ideal for CNS penetration.

**logP:** Both ligands have good logP values (1.386 and 0.873), falling within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A (0 HBD, 4 HBA) is favorable. Ligand B (2 HBD, 6 HBA) is also acceptable, but slightly higher counts could potentially affect permeability.

**QED:** Both ligands have reasonable QED scores (0.81 and 0.657), indicating good drug-like properties.

**DILI:** Ligand A (15.51) has a significantly lower DILI risk than Ligand B (55.487), which is a substantial advantage.

**BBB:** Ligand A (93.37) has excellent BBB penetration, exceeding the desirable >70% threshold. Ligand B (77.782) is still reasonably good, but lower than Ligand A.

**Caco-2 Permeability:** Ligand A (-4.558) and Ligand B (-5.016) both have negative values, which is unusual and suggests very poor permeability. However, the scale is not specified, so it's difficult to interpret.

**Aqueous Solubility:** Both ligands have poor aqueous solubility (-2.017 and -3.3). This could pose formulation challenges.

**hERG Inhibition:** Ligand A (0.488) has a lower hERG risk than Ligand B (0.924), which is preferable.

**Microsomal Clearance:** Ligand A (4.371) has a lower microsomal clearance than Ligand B (38.894), indicating better metabolic stability.

**In vitro Half-Life:** Ligand A (7.716) has a longer in vitro half-life than Ligand B (3.278), which is desirable.

**P-gp Efflux:** Ligand A (0.062) exhibits significantly lower P-gp efflux than Ligand B (0.213), which is crucial for CNS penetration.

**Binding Affinity:** Ligand B (-7.2 kcal/mol) has a slightly better binding affinity than Ligand A (-9.7 kcal/mol). While a 1.5 kcal/mol advantage is often significant, the overall ADME profile is more important in this case.

**Overall Assessment:**

Ligand A is the stronger candidate. It excels in key GPCR properties like BBB penetration, P-gp efflux, and metabolic stability. Its lower DILI risk and hERG inhibition liability are also significant advantages. While its solubility is poor, and Caco-2 permeability is questionable, the superior CNS-related properties and safety profile outweigh the slightly weaker binding affinity compared to Ligand B.

Output:
0
2025-04-17 07:15:17,189 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (368.463 and 346.515 Da) fall within the ideal range of 200-500 Da.

**TPSA:** Ligand A (115.89) is slightly above the preferred <90 for CNS targets, but not drastically so. Ligand B (40.62) is excellent, well below the threshold.

**logP:** Ligand A (-0.893) is a bit low, potentially hindering permeation. Ligand B (3.308) is within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A has 2 HBD and 8 HBA, which are reasonable. Ligand B has 0 HBD and 2 HBA, also acceptable.

**QED:** Both ligands have good QED scores (0.711 and 0.766), indicating drug-like properties.

**DILI:** Ligand A (37.999) has a slightly higher DILI risk than Ligand B (15.471), but both are below the concerning threshold of 60.

**BBB:** This is critical for a CNS target. Ligand A (43.932) has a moderate BBB penetration, while Ligand B (90.5) is excellent, exceeding the desirable >70 threshold.

**Caco-2 Permeability:** Both have negative values, indicating poor permeability. However, the scale is not provided, so it's difficult to assess the magnitude of the issue.

**Aqueous Solubility:** Both ligands have negative solubility values, which is concerning.

**hERG Inhibition:** Both ligands show low hERG inhibition risk (0.306 and 0.658).

**Microsomal Clearance:** Ligand A (-18.283) has a negative clearance, which is unusual and suggests very high metabolic stability. Ligand B (63.064) has a higher clearance, indicating faster metabolism.

**In vitro Half-Life:** Ligand A (4.471) has a shorter half-life than Ligand B (-3.015, which is also unusual).

**P-gp Efflux:** Ligand A (0.014) has very low P-gp efflux liability, which is excellent for CNS penetration. Ligand B (0.461) has a moderate P-gp efflux liability.

**Binding Affinity:** Ligand B (-8.8 kcal/mol) has a significantly stronger binding affinity than Ligand A (-6.4 kcal/mol), exceeding the >1.5 kcal/mol advantage threshold.

**Overall Assessment:**

Ligand B is the more promising candidate. Its superior BBB penetration, optimal logP, and significantly stronger binding affinity outweigh the slightly higher clearance. While both have solubility issues, the strong binding of Ligand B suggests it might still be effective at lower concentrations, potentially mitigating solubility concerns. The negative values for Caco-2 and half-life are concerning and require further investigation, but the overall profile of Ligand B is more favorable for a CNS-targeting GPCR.

Output:
1
2025-04-17 07:15:17,189 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight (MW):** Both ligands (355.523 and 361.446 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (72.88) is significantly better than Ligand B (82.7). For CNS targets, we want TPSA <= 90, and A is comfortably within this range, while B is approaching the upper limit.

**3. logP:** Ligand A (1.479) is optimal, while Ligand B (3.559) is higher, potentially leading to solubility issues and off-target interactions, although still within the acceptable 1-3 range.

**4. H-Bond Donors (HBD):** Both ligands have acceptable HBD counts (2 and 3 respectively), well below the threshold of 5.

**5. H-Bond Acceptors (HBA):** Both ligands have acceptable HBA counts (4 and 5 respectively), well below the threshold of 10.

**6. QED:** Both ligands have similar QED values (0.692 and 0.536), indicating reasonable drug-likeness. Ligand A is slightly better.

**7. DILI:** Ligand A (6.282) has a much lower DILI risk than Ligand B (86.002). This is a significant advantage for A.

**8. BBB:** Ligand B (70.415) has a better BBB penetration percentile than Ligand A (55.487). While >70 is desirable, 70 is still good, and this is a key advantage for B.

**9. Caco-2 Permeability:** Ligand A (-4.811) has better Caco-2 permeability than Ligand B (-5.633).

**10. Aqueous Solubility:** Ligand A (-1.075) has better aqueous solubility than Ligand B (-4.083).

**11. hERG Inhibition:** Ligand A (0.544) has a lower hERG inhibition liability than Ligand B (0.896). This is a safety advantage for A.

**12. Microsomal Clearance:** Ligand A (-9.653) has significantly lower microsomal clearance, indicating better metabolic stability, compared to Ligand B (76.601).

**13. In vitro Half-Life:** Ligand B (82.127) has a much longer in vitro half-life than Ligand A (-4.964). This is a significant advantage for B.

**14. P-gp Efflux:** Ligand A (0.028) has significantly lower P-gp efflux liability than Ligand B (0.483), which is crucial for CNS penetration.

**15. Binding Affinity:** Ligand B (-8.7 kcal/mol) has a stronger binding affinity than Ligand A (-7.5 kcal/mol). This is a 1.2 kcal/mol difference, which is substantial and could outweigh some ADME drawbacks.

**Overall Assessment:**

Ligand B has a superior binding affinity and a longer half-life, which are very important. It also has good BBB penetration. However, it suffers from higher logP, significantly higher DILI risk, higher P-gp efflux, and lower solubility. Ligand A excels in ADME properties (lower DILI, better solubility, lower P-gp efflux, better metabolic stability) and has a reasonable affinity.

Considering the GPCR-specific priorities, BBB is crucial, but not at the expense of safety and metabolic stability. The substantial difference in DILI risk and P-gp efflux favors Ligand A. The improved ADME profile of Ligand A, coupled with acceptable affinity, makes it a more promising starting point for optimization, even with slightly lower affinity. The higher affinity of B could be pursued later through structure-based design, starting from the more favorable ADME scaffold of A.

Output:
0
2025-04-17 07:15:17,190 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B based on the provided guidelines, prioritizing GPCR-specific properties (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (345.447 Da) is slightly lower, which could be advantageous for permeability, but both are acceptable.

**TPSA:** Both ligands have TPSA values (71.33 and 74.09) that are below the 90 A^2 threshold for CNS targets, which is good.

**logP:** Both ligands have logP values within the optimal range (1-3). Ligand B (2.692) is slightly higher, potentially leading to some solubility concerns, but still acceptable.

**H-Bond Donors/Acceptors:** Ligand A (0 HBD, 5 HBA) and Ligand B (1 HBD, 7 HBA) both fall within acceptable limits (<=5 HBD and <=10 HBA).

**QED:** Both ligands have good QED scores (0.761 and 0.797), indicating drug-like properties.

**DILI:** Both ligands have acceptable DILI risk (44.591 and 52.772, both <60).

**BBB:** This is a crucial parameter for a CNS target like DRD2. Ligand B (83.249) has a significantly higher BBB percentile than Ligand A (64.521). This is a major advantage for Ligand B.

**Caco-2 Permeability:** Ligand A (-4.951) shows poor Caco-2 permeability, while Ligand B (-5.338) is also poor. This isn't ideal, but not a dealbreaker if other properties are strong.

**Aqueous Solubility:** Both ligands have negative solubility values, indicating poor aqueous solubility. Ligand B (-3.421) is slightly worse than Ligand A (-1.698).

**hERG Inhibition:** Both ligands have low hERG inhibition liability (0.124 and 0.12), which is good.

**Microsomal Clearance:** Ligand A (17.768 mL/min/kg) has a higher microsomal clearance than Ligand B (10.862 mL/min/kg), indicating lower metabolic stability.

**In vitro Half-Life:** Both ligands have similar in vitro half-lives (6.804 and 7.82 hours).

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.071 and 0.099), which is excellent for CNS penetration.

**Binding Affinity:** Ligand A (-7.0 kcal/mol) has a slightly better binding affinity than Ligand B (-0.0 kcal/mol). However, the difference is substantial and outweighs the other drawbacks of Ligand B.

**Overall Assessment:**

While Ligand A has a slightly better MW and binding affinity, Ligand B's significantly higher BBB penetration (83.249 vs 64.521) is the deciding factor for a CNS-targeting drug. The better metabolic stability (lower Cl_mic) of Ligand B is also a positive. The solubility issues are a concern for both, but can be addressed with formulation strategies. The affinity difference, while present, is less critical than the improved CNS exposure predicted by the BBB score.

Output:
1
2025-04-17 07:15:17,190 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight (MW):** Both ligands are within the ideal range (200-500 Da). Ligand A (377.363 Da) is slightly higher than Ligand B (344.411 Da), but both are acceptable.

**2. TPSA:** Ligand A (63.25) is better than Ligand B (71.78). For CNS targets, we want TPSA <= 90, both are within this range, but A is preferable.

**3. logP:** Ligand A (4.052) is slightly high, potentially leading to solubility issues or off-target interactions. Ligand B (1.95) is optimal. This favors Ligand B.

**4. H-Bond Donors (HBD):** Both ligands have acceptable HBD counts (A: 2, B: 1).

**5. H-Bond Acceptors (HBA):** Both ligands have acceptable HBA counts (A: 4, B: 4).

**6. QED:** Both ligands have similar and acceptable QED values (A: 0.716, B: 0.695).

**7. DILI:** Ligand A (75.184) has a significantly higher DILI risk than Ligand B (24.544). This is a major concern for Ligand A.

**8. BBB:** Ligand A (78.519) has a better BBB penetration percentile than Ligand B (68.67). This is a crucial factor for a CNS target like DRD2, favoring Ligand A.

**9. Caco-2 Permeability:** Ligand A (-4.974) and Ligand B (-4.269) both have negative values, which is unusual and suggests very poor permeability. This is a significant drawback for both.

**10. Aqueous Solubility:** Ligand A (-4.793) and Ligand B (-3.207) both have negative values, indicating poor solubility. This is a concern for both, but less so for B.

**11. hERG Inhibition:** Both ligands have low hERG inhibition risk (A: 0.527, B: 0.229), which is good. Ligand B is slightly better.

**12. Microsomal Clearance:** Ligand A (85.808) has higher microsomal clearance than Ligand B (25.183), indicating lower metabolic stability. This favors Ligand B.

**13. In vitro Half-Life:** Ligand B (14.752) has a significantly longer in vitro half-life than Ligand A (2.67). This is a substantial advantage for Ligand B.

**14. P-gp Efflux:** Ligand A (0.219) has lower P-gp efflux liability than Ligand B (0.092), which is beneficial for CNS exposure. This favors Ligand A.

**15. Binding Affinity:** Ligand A (-9.4 kcal/mol) has a significantly stronger binding affinity than Ligand B (-7.3 kcal/mol). This is a major advantage for Ligand A, potentially outweighing some of its ADME drawbacks.

**Overall Assessment:**

Ligand A has a superior binding affinity and better BBB penetration and P-gp efflux, which are critical for a CNS GPCR target. However, it suffers from higher DILI risk, higher clearance, shorter half-life, and a potentially problematic logP. Ligand B has better ADME properties (lower DILI, better clearance, longer half-life, optimal logP) but weaker binding affinity.

The difference in binding affinity (-9.4 vs -7.3 kcal/mol) is substantial (2.1 kcal/mol). Given the importance of potency for GPCRs, and the potential to mitigate some ADME issues through further optimization, the stronger binding affinity of Ligand A is the deciding factor.

Output:
1
2025-04-17 07:15:17,190 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (384.849 and 368.266 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (122.75) is slightly above the optimal <90 for CNS targets, while Ligand B (97.87) is comfortably within the range. This gives a slight edge to Ligand B.

**logP:** Both ligands have good logP values (1.503 and 2.32), falling within the 1-3 optimal range.

**H-Bond Donors/Acceptors:** Ligand A has 3 HBD and 8 HBA, while Ligand B has 2 HBD and 6 HBA. Both are within acceptable limits (<=5 HBD and <=10 HBA).

**QED:** Both ligands have reasonable QED scores (0.488 and 0.79), with Ligand B being better.

**DILI:** Ligand A has a high DILI risk (97.131 percentile), which is concerning. Ligand B has a much lower DILI risk (64.172 percentile), making it significantly safer.

**BBB:** This is crucial for a CNS target. Ligand A has a BBB penetration of 30.593%, which is poor. Ligand B has a much better BBB penetration of 79.488%, which is highly desirable.

**Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and suggests poor permeability. However, the scale is not specified, so it's hard to interpret.

**Aqueous Solubility:** Both ligands have negative solubility values, which is also unusual and suggests poor solubility. Again, the scale is not specified.

**hERG Inhibition:** Both ligands have very low hERG inhibition liability (0.125 and 0.088), which is excellent.

**Microsomal Clearance:** Ligand A (22.564 mL/min/kg) has higher clearance than Ligand B (15.601 mL/min/kg), indicating lower metabolic stability.

**In vitro Half-Life:** Ligand B (17.429 hours) has a significantly longer half-life than Ligand A (4.424 hours), which is a major advantage.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.126 and 0.088), which is good for CNS penetration.

**Binding Affinity:** Ligand B (-8.9 kcal/mol) has a significantly stronger binding affinity than Ligand A (-7.7 kcal/mol). This difference of 1.2 kcal/mol is substantial and can outweigh minor ADME drawbacks.

**Conclusion:**

Considering all factors, especially the GPCR-specific priorities, **Ligand B is the far superior candidate**. It has a much better BBB penetration, lower DILI risk, longer half-life, and significantly stronger binding affinity. While both have issues with Caco-2 and solubility, the superior CNS properties and potency of Ligand B make it the more viable drug candidate.

Output:
1
2025-04-17 07:15:17,190 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (363.424 and 359.495 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (61.44) is better than Ligand B (54.43). Both are below the 90 A^2 threshold for CNS targets, which is good.

**3. logP:** Ligand A (2.214) is within the optimal range (1-3). Ligand B (3.551) is slightly higher, but still acceptable.

**4. H-Bond Donors:** Ligand A (2) and Ligand B (1) are both within the acceptable limit of <=5.

**5. H-Bond Acceptors:** Ligand A (3) and Ligand B (6) are both within the acceptable limit of <=10.

**6. QED:** Both ligands have similar QED values (0.66 and 0.635), indicating good drug-likeness.

**7. DILI:** Ligand A (12.524) has a significantly lower DILI risk than Ligand B (27.414). This is a major advantage for Ligand A.

**8. BBB:** Ligand A (85.459) has a much higher BBB penetration percentile than Ligand B (54.013). This is *critical* for a CNS target like DRD2.

**9. Caco-2 Permeability:** Both have negative values, which is unusual. Assuming these are logP values, they indicate poor permeability.

**10. Aqueous Solubility:** Both have negative values, indicating poor solubility.

**11. hERG Inhibition:** Ligand A (0.574) has a lower hERG inhibition risk than Ligand B (0.892), which is preferable.

**12. Microsomal Clearance:** Ligand A (0.473) has a much lower microsomal clearance than Ligand B (30.666), indicating better metabolic stability.

**13. In vitro Half-Life:** Ligand B (86.801) has a significantly longer in vitro half-life than Ligand A (-17.229). This is a potential advantage for Ligand B, but the negative value for Ligand A is concerning.

**14. P-gp Efflux:** Ligand A (0.035) has a much lower P-gp efflux liability than Ligand B (0.692), which is crucial for CNS penetration.

**15. Binding Affinity:** Ligand B (-7.3 kcal/mol) has a slightly better binding affinity than Ligand A (-8.1 kcal/mol). While this is a positive for Ligand B, the difference is not substantial enough to outweigh the significant ADME advantages of Ligand A.

**Overall Assessment:**

Ligand A is the superior candidate. While Ligand B has slightly better binding affinity and in vitro half-life, Ligand A demonstrates significantly better ADME properties, particularly regarding BBB penetration, DILI risk, metabolic stability, and P-gp efflux. For a CNS target like DRD2, these factors are paramount. The negative values for Caco-2 and solubility are concerning for both, but can be addressed with formulation strategies.



Output:
0
2025-04-17 07:15:17,190 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (373.519 and 350.457 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (109.57) is higher than the ideal <90 for CNS targets, while Ligand B (32.26) is excellent. This is a significant advantage for Ligand B.

**logP:** Ligand A (0.99) is a bit low, potentially hindering permeation. Ligand B (3.749) is within the optimal 1-3 range.

**H-Bond Donors:** Ligand A (2) and Ligand B (0) are both acceptable, being <=5.

**H-Bond Acceptors:** Both ligands (A: 4, B: 4) are within the acceptable range of <=10.

**QED:** Both ligands have good QED scores (A: 0.595, B: 0.813), indicating drug-like properties.

**DILI:** Both ligands have acceptable DILI risk (A: 33.152, B: 56.844), both below the 60 threshold.

**BBB:** Ligand A (60.644) is below the desirable >70 for CNS targets. Ligand B (97.518) is excellent, indicating high potential for brain penetration. This is a major advantage for Ligand B.

**Caco-2:** Ligand A (-5.153) and Ligand B (-4.604) are both negative, which is unusual and suggests poor permeability. However, the scale isn't specified, so it's hard to interpret.

**Solubility:** Both ligands have negative solubility values (A: -2.356, B: -5), which is concerning. Solubility is crucial for bioavailability.

**hERG:** Both ligands have low hERG inhibition risk (A: 0.195, B: 0.883).

**Microsomal Clearance:** Ligand A (57.326) has lower clearance than Ligand B (76.631), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (-37.2) has a negative half-life, which is impossible and likely an error in the data. Ligand B (22.369) is reasonable.

**P-gp Efflux:** Ligand A (0.061) has lower P-gp efflux liability than Ligand B (0.473), which is favorable for CNS exposure.

**Binding Affinity:** Ligand A (-7.2) has a slightly better binding affinity than Ligand B (-0.0). This is a significant advantage for Ligand A.

**Overall Assessment:**

Despite Ligand A's slightly better binding affinity, Ligand B is the more promising candidate. The critical factors for a CNS-targeting GPCR like DRD2 are BBB penetration and TPSA. Ligand B excels in both of these areas, with a BBB percentile of 97.518 and a TPSA of 32.26. Ligand A's BBB is only 60.644 and TPSA is 109.57. While Ligand A has better affinity and lower P-gp efflux, the poor BBB and higher TPSA are significant drawbacks. The negative half-life for Ligand A is also a major red flag, suggesting a data error.

Output:
1
2025-04-17 07:15:17,190 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (350.419 and 348.443 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (93.63) is slightly above the optimal <90 for CNS targets, but still reasonable. Ligand B (71.78) is well within the desired range.

**logP:** Both ligands have good logP values (2.717 and 2.552), falling within the 1-3 optimal range.

**H-Bond Donors/Acceptors:** Both have 1 HBD, which is good. Ligand A has 6 HBA, while Ligand B has 4. Both are acceptable (<=10).

**QED:** Both ligands have good QED scores (0.699 and 0.769), indicating good drug-like properties.

**DILI:** Ligand A (55.176) has a slightly higher DILI risk than Ligand B (43.079), but both are below the concerning threshold of 60.

**BBB:** Both ligands have good BBB penetration (70.492 and 65.839), but Ligand A is better, exceeding the 70% threshold.

**Caco-2 Permeability:** Both have negative Caco-2 values, indicating poor permeability. This is a concern for both.

**Aqueous Solubility:** Both ligands have very poor aqueous solubility (-2.105 and -3.525). This is a significant drawback.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.567 and 0.686).

**Microsomal Clearance:** Ligand B (73.384) has higher microsomal clearance than Ligand A (64.614), suggesting lower metabolic stability.

**In vitro Half-Life:** Ligand A (30.298) has a longer half-life than Ligand B (12.541), which is preferable.

**P-gp Efflux:** Both have low P-gp efflux liability (0.064 and 0.282), which is good for CNS penetration.

**Binding Affinity:** Ligand B (-7.7 kcal/mol) has a slightly better binding affinity than Ligand A (-7.6 kcal/mol), although the difference is small.

**Overall Assessment:**

Considering the GPCR-specific priorities, BBB penetration is crucial. Ligand A has a slightly better BBB score. Solubility is a major concern for both, but Ligand A has better metabolic stability (lower Cl_mic and longer t1/2). The affinity difference is minimal. Given the slightly better BBB, metabolic stability, and comparable affinity, Ligand A is marginally more promising. However, the poor solubility of both is a significant hurdle.

Output:
0
2025-04-17 07:15:17,190 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (362.417 and 356.392 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (78.87) is better than Ligand B (61.88). Both are below 90, which is favorable for CNS penetration.

**logP:** Ligand A (1.028) is within the optimal 1-3 range. Ligand B (4.065) is at the higher end, potentially leading to solubility issues and off-target effects.

**H-Bond Donors/Acceptors:** Ligand A has 2 HBD and 4 HBA, while Ligand B has 1 HBD and 3 HBA. Both are within acceptable limits.

**QED:** Both ligands have good QED scores (0.676 and 0.849, respectively), indicating drug-like properties.

**DILI:** Ligand A (17.449) has a significantly lower DILI risk than Ligand B (45.444). This is a major advantage for Ligand A.

**BBB:** Both ligands have excellent BBB penetration (82.474 and 84.219), exceeding the desirable >70 threshold for CNS targets.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values, which is unusual and suggests poor permeability. However, the scale is not specified, so it's hard to interpret.

**Aqueous Solubility:** Both ligands have negative solubility values, which is also unusual.

**hERG Inhibition:** Both ligands show low hERG inhibition risk (0.587 and 0.796).

**Microsomal Clearance:** Ligand A (0.474) has much lower microsomal clearance than Ligand B (37.736), indicating better metabolic stability.

**In vitro Half-Life:** Ligand A (-11.215) has a negative half-life, which is not possible. Ligand B (17.871) is reasonable.

**P-gp Efflux:** Ligand A (0.047) has much lower P-gp efflux liability than Ligand B (0.135), which is favorable for CNS exposure.

**Binding Affinity:** Ligand B (-8.0) has a slightly better binding affinity than Ligand A (-7.8), but the difference is not substantial enough to outweigh the other factors.

**Overall Assessment:**

Ligand A is significantly better overall. It has a lower DILI risk, better metabolic stability (lower Cl_mic), lower P-gp efflux, and a more favorable logP. While Ligand B has slightly better affinity, the other ADME properties of Ligand A make it a more promising drug candidate, especially considering the importance of BBB penetration and metabolic stability for CNS targets like DRD2. The negative values for Caco-2 and solubility are concerning for both, but the other advantages of Ligand A are more compelling.

Output:
1
2025-04-17 07:15:17,190 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B based on the provided guidelines, prioritizing GPCR-specific properties (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (348.403 and 349.479 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (100.63) is slightly above the optimal 90 for CNS targets, but acceptable. Ligand B (81.33) is well within the desired range.

**logP:** Ligand A (0.819) is a bit low, potentially hindering permeation. Ligand B (1.334) is better, falling within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Both have 2 HBDs, which is good. Ligand A has 6 HBAs, while Ligand B has 4. Both are acceptable, being under the 10 limit.

**QED:** Ligand B (0.84) has a significantly better QED score than Ligand A (0.506), indicating a more drug-like profile.

**DILI:** Ligand A (57.736) has a moderate DILI risk, while Ligand B (17.72) has a very low risk.

**BBB:** Ligand B (68.67) has a considerably higher BBB penetration percentile than Ligand A (57.619). This is a critical advantage for a CNS target like DRD2.

**Caco-2 Permeability:** Ligand A (-4.867) shows poor Caco-2 permeability, suggesting poor intestinal absorption. Ligand B (-5.05) is similarly poor.

**Aqueous Solubility:** Both ligands have very poor aqueous solubility (-1.651 and -1.754 respectively). This is a concern for formulation.

**hERG Inhibition:** Both ligands show low hERG inhibition liability (0.17 and 0.42 respectively).

**Microsomal Clearance:** Ligand B (-7.439) has a significantly lower (better) microsomal clearance than Ligand A (45.94). This suggests better metabolic stability.

**In vitro Half-Life:** Ligand B (-6.519) has a longer in vitro half-life than Ligand A (5.488).

**P-gp Efflux:** Both ligands show very low P-gp efflux liability (0.026 and 0.037 respectively).

**Binding Affinity:** Ligand B (-7.7 kcal/mol) has a stronger binding affinity than Ligand A (-6.6 kcal/mol). This is a substantial difference, exceeding the 1.5 kcal/mol threshold where affinity can outweigh other drawbacks.

**Overall Assessment:**

Ligand B is significantly better across multiple key parameters. It has a superior QED score, lower DILI risk, substantially better BBB penetration, improved metabolic stability (lower Cl_mic and longer t1/2), and, most importantly, a much stronger binding affinity for DRD2. While both have poor solubility and Caco-2 permeability, the superior CNS penetration and affinity of Ligand B make it a much more promising drug candidate for a CNS target like DRD2. The slightly lower logP of Ligand A is a concern, and is outweighed by the advantages of Ligand B.

Output:
1
2025-04-17 07:15:17,191 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (359.495 and 360.382 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (54.46) is significantly better than Ligand B (94.17). For CNS targets, we want TPSA <= 90, so Ligand A is much closer to this threshold. Ligand B is considerably higher and may have reduced brain penetration.

**3. logP:** Ligand A (2.825) is optimal (1-3). Ligand B (-0.2) is too low, potentially hindering membrane permeability and overall absorption.

**4. H-Bond Donors:** Both have 1 HBD, which is acceptable (<=5).

**5. H-Bond Acceptors:** Ligand A has 5 HBA, Ligand B has 6. Both are within the acceptable range (<=10).

**6. QED:** Ligand A (0.862) is better than Ligand B (0.66), indicating a more drug-like profile.

**7. DILI:** Ligand A (68.05) is slightly higher than Ligand B (50.989), but both are within a reasonable range (<60 is good).

**8. BBB:** Both ligands have good BBB penetration (Ligand A: 67.003, Ligand B: 68.127), exceeding the desirable >70% for CNS targets. However, the other properties of Ligand A make it more likely to *achieve* that penetration.

**9. Caco-2 Permeability:** Both have negative Caco-2 values (-4.986 and -4.851), which is unusual and suggests poor permeability. This is a significant concern for both.

**10. Aqueous Solubility:** Both have negative solubility values (-2.971 and -1.296), also unusual and concerning. Poor solubility can hinder absorption.

**11. hERG Inhibition:** Ligand A (0.865) is slightly higher than Ligand B (0.09), suggesting a slightly higher risk of hERG inhibition, but both are relatively low.

**12. Microsomal Clearance:** Ligand A (54.586) has higher clearance than Ligand B (3.209), meaning it's less metabolically stable.

**13. In vitro Half-Life:** Ligand A (54.609) has a longer half-life than Ligand B (0.861), which is preferable.

**14. P-gp Efflux:** Both have 0 P-gp efflux, which is good.

**15. Binding Affinity:** Both have the same binding affinity (0 kcal/mol).

**Overall Assessment:**

Despite the unusual Caco-2 and solubility values for both, Ligand A is the better candidate. Its superior logP, TPSA, and QED scores are crucial for a CNS-targeting GPCR. While Ligand A has higher microsomal clearance, its longer half-life partially mitigates this. Ligand B's very low logP is a major drawback, likely hindering its ability to cross cell membranes and reach the brain, even with good BBB percentile.

Output:
1
2025-04-17 07:15:17,191 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (356.463 and 355.391 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Both ligands (107.89 and 108.87) are above the optimal <90 for CNS targets, but not drastically so. This is a moderate concern for both.

**3. logP:** Ligand A (0.336) is quite low, potentially hindering membrane permeability. Ligand B (1.811) is better, falling within the optimal 1-3 range. This is a significant advantage for Ligand B.

**4. H-Bond Donors:** Ligand A (4) is acceptable. Ligand B (1) is even better, minimizing potential permeability issues.

**5. H-Bond Acceptors:** Ligand A (5) is acceptable. Ligand B (8) is slightly higher, but still within the reasonable limit of 10.

**6. QED:** Both ligands have reasonable QED values (0.476 and 0.738), indicating drug-like properties, with Ligand B being better.

**7. DILI:** Ligand A (15.238) has a much lower DILI risk than Ligand B (67.895). This is a substantial advantage for Ligand A.

**8. BBB:** Ligand A (35.595) has a very poor BBB penetration percentile. Ligand B (68.67) is better, but still not ideal (aim for >70 for CNS targets). This is a major drawback for Ligand A.

**9. Caco-2:** Ligand A (-5.019) has a very poor Caco-2 permeability, while Ligand B (-4.14) is slightly better, but still not great.

**10. Solubility:** Ligand A (-2.218) has poor solubility, while Ligand B (-3.602) is even worse. Both are problematic.

**11. hERG:** Both ligands have low hERG inhibition liability (0.148 and 0.3), which is good.

**12. Cl_mic:** Ligand A (42.318) has lower microsomal clearance than Ligand B (118.826), suggesting better metabolic stability. This favors Ligand A.

**13. t1/2:** Ligand A (-7.253) has a very short in vitro half-life, while Ligand B (-42.588) is even shorter. Both are very poor.

**14. Pgp:** Both ligands have very low P-gp efflux liability (0.035 and 0.025), which is favorable for CNS penetration.

**15. Binding Affinity:** Both ligands have very similar and strong binding affinities (-7.5 and -7.2 kcal/mol). The difference of 0.3 kcal/mol is unlikely to be decisive.

**Overall Assessment:**

Ligand B has a better logP and QED, and a significantly better BBB penetration compared to Ligand A. However, Ligand A has a much lower DILI risk and better metabolic stability (lower Cl_mic). Both have poor solubility and short half-lives. Given the GPCR-specific priority of BBB penetration for CNS targets, and the fact that the affinity difference is small, Ligand B is the more promising candidate despite the higher DILI risk. The slightly better logP and BBB penetration are crucial for a CNS-targeting drug. The DILI risk can potentially be mitigated through further structural modifications.

Output:
1
2025-04-17 07:15:17,191 - INFO - Batch 349 complete. Total preferences: 5584
2025-04-17 07:15:17,191 - INFO - Processing batch 350/512...
2025-04-17 07:15:57,985 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 drug candidates, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (355.356 and 367.877 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (56.26) is excellent, well below the 90 A^2 threshold for CNS targets. Ligand B (73.83) is still reasonable but less optimal.

**logP:** Ligand A (3.726) is at the higher end of the optimal range (1-3), while Ligand B (2.851) is well within the optimal range.

**H-Bond Donors/Acceptors:** Ligand A (0 HBD, 4 HBA) and Ligand B (3 HBD, 4 HBA) both have acceptable numbers of H-bond donors and acceptors.

**QED:** Both ligands have similar QED values (0.756 and 0.748), indicating good drug-likeness.

**DILI:** Ligand A (23.653) has a significantly lower DILI risk than Ligand B (41.179), which is a substantial advantage.

**BBB:** This is a critical parameter for a CNS target like DRD2. Ligand A (95.618) has excellent BBB penetration, exceeding the desirable >70 percentile. Ligand B (61.923) is considerably lower, raising concerns about brain exposure.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.395 and -4.802). This is unusual and suggests poor permeability. However, these values are on a log scale and may indicate very low permeability rather than a negative value.

**Aqueous Solubility:** Both ligands have negative solubility values (-4.132 and -3.306), again suggesting poor solubility.

**hERG:** Both ligands show low hERG inhibition liability (0.369 and 0.656).

**Microsomal Clearance:** Ligand A (53.551) has a higher microsomal clearance than Ligand B (5.827), indicating faster metabolism and potentially lower *in vivo* exposure.

**In vitro Half-Life:** Ligand B (86.649) has a much longer *in vitro* half-life than Ligand A (-10.33), suggesting better metabolic stability.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.523 and 0.148).

**Binding Affinity:** Both ligands have very similar and strong binding affinities (-9.6 and -8.3 kcal/mol). The affinity difference (1.3 kcal/mol) is not substantial enough to outweigh other significant differences.

**Conclusion:**

Considering all factors, **Ligand A** is the more promising drug candidate. While Ligand B has a longer half-life, Ligand A excels in crucial areas for CNS drug development: significantly lower DILI risk and, most importantly, much better predicted BBB penetration. The TPSA is also more favorable for Ligand A. Although both have poor predicted solubility and permeability, the superior BBB penetration of Ligand A makes it a better starting point for optimization, as CNS exposure is paramount for DRD2 targeting.

Output:
1
2025-04-17 07:15:57,985 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (345.305 and 346.519 Da) fall comfortably within the ideal 200-500 Da range.

**TPSA:** Ligand A (76.12) is better than Ligand B (59.07). Both are below the 90 A^2 threshold desirable for CNS targets, but Ligand B is closer to the optimal range.

**logP:** Ligand A (2.705) is within the optimal 1-3 range. Ligand B (4.334) is slightly higher, potentially increasing off-target effects and decreasing solubility.

**H-Bond Donors/Acceptors:** Both ligands have 2 HBD and 4/5 HBA, which are acceptable and balance solubility and permeability.

**QED:** Both ligands have QED values (0.763 and 0.652) above 0.5, indicating good drug-like properties.

**DILI:** Ligand A (97.712) has a significantly higher DILI risk than Ligand B (24.932). This is a major concern for Ligand A.

**BBB:** Ligand B (84.141) has a much better BBB penetration percentile than Ligand A (48.313). This is crucial for a CNS target like DRD2.

**Caco-2 Permeability:** Ligand A (-4.454) and Ligand B (-4.845) both have negative Caco-2 values, which is unusual and suggests poor permeability. However, the scale is not specified, so it's difficult to interpret the absolute impact.

**Aqueous Solubility:** Both ligands have very poor aqueous solubility (-4.929 and -4.483). This could pose formulation challenges.

**hERG Inhibition:** Ligand A (0.692) has a slightly lower hERG inhibition risk than Ligand B (0.911), but both are relatively low.

**Microsomal Clearance:** Ligand B (86.611) has a much higher microsomal clearance than Ligand A (6.58). This suggests Ligand A is more metabolically stable.

**In vitro Half-Life:** Ligand B (36.197) has a significantly longer in vitro half-life than Ligand A (0.577). This is a positive for Ligand B.

**P-gp Efflux:** Ligand A (0.3) has lower P-gp efflux liability than Ligand B (0.298), which is favorable for CNS penetration.

**Binding Affinity:** Ligand B (-8.5 kcal/mol) has a slightly better binding affinity than Ligand A (-9.3 kcal/mol). While the difference is small, it's still a factor.

**Overall Assessment:**

Ligand B is significantly better overall, despite the slightly higher logP. Its superior BBB penetration (84.141 vs 48.313), lower DILI risk (24.932 vs 97.712), and longer half-life are critical advantages for a CNS-targeting drug. The slightly better binding affinity of Ligand B further supports this conclusion. While both have poor solubility and Caco-2 permeability, the CNS target prioritization makes BBB and metabolic stability more important. Ligand A's high DILI risk is a major red flag.

Output:
1
2025-04-17 07:15:57,985 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (356.4 and 350.4 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (93.2) is slightly above the optimal <90 for CNS targets, while Ligand B (67.7) is well within the desired range. This favors Ligand B.

**logP:** Ligand A (-1.29) is a bit low, potentially hindering permeation. Ligand B (0.32) is within the optimal 1-3 range. This favors Ligand B.

**H-Bond Donors:** Ligand A (2) and Ligand B (0) are both acceptable (<=5).

**H-Bond Acceptors:** Both ligands (5) are within the acceptable range (<=10).

**QED:** Both ligands have good QED scores (0.65 and 0.73), indicating drug-like properties.

**DILI:** Both have low DILI risk (30.3 and 32.0), which is good.

**BBB:** This is a crucial parameter for CNS targets. Ligand A (20.9) has a very poor BBB penetration score, while Ligand B (84.7) is excellent. This is a major advantage for Ligand B.

**Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and indicates poor permeability. However, the scale is not specified, so it's difficult to interpret.

**Aqueous Solubility:** Ligand A (0.16) has very poor solubility, while Ligand B (-1.14) is also poor. This is a concern for both, but the negative value for B is worse.

**hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.08 and 0.26), which is excellent.

**Microsomal Clearance:** Ligand A (-9.9) has a very low (good) clearance, indicating high metabolic stability. Ligand B (19.0) has a higher clearance, suggesting faster metabolism. This favors Ligand A.

**In vitro Half-Life:** Ligand A (-17.97) has a very long half-life, while Ligand B (-28.8) is even longer. Both are excellent.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.004 and 0.03), which is favorable for CNS penetration.

**Binding Affinity:** Ligand A (-8.6 kcal/mol) has a slightly better binding affinity than Ligand B (-7.8 kcal/mol). This is a significant advantage for Ligand A.

**Overall Assessment:**

While Ligand A has a better binding affinity and metabolic stability, its poor logP, TPSA, and *extremely* poor BBB penetration are major drawbacks for a CNS target. Ligand B, despite slightly weaker binding and faster metabolism, excels in the critical areas of TPSA, logP, and especially BBB penetration. The substantial difference in BBB (21% vs 85%) is a decisive factor. The slightly better affinity of A is unlikely to overcome the permeability issues.

Output:
1
2025-04-17 07:15:57,985 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (348.45 & 350.42 Da) fall comfortably within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (68.62) is significantly better than Ligand B (87.91). For CNS targets, we want TPSA <= 90, and A is closer to the optimal <=60 range. B is pushing the upper limit.

**3. logP:** Ligand A (1.74) is within the optimal 1-3 range. Ligand B (0.636) is a bit low, potentially hindering membrane permeability.

**4. H-Bond Donors:** Both have 1 HBD, which is good.

**5. H-Bond Acceptors:** Ligand A has 5 HBA, and Ligand B has 6. Both are acceptable (<=10).

**6. QED:** Ligand A (0.903) is excellent, indicating high drug-likeness. Ligand B (0.776) is still good, but not as strong.

**7. DILI:** Both have low DILI risk (A: 32.3, B: 29.9), both well below the 40% threshold.

**8. BBB:** Ligand A (81.5%) has a much better BBB penetration score than Ligand B (67.6%). This is *critical* for a CNS target like DRD2.

**9. Caco-2:** Both have negative Caco-2 values, which is unusual and suggests poor permeability. However, these values are on a strange scale, and the absolute value isn't as important as the trend.

**10. Solubility:** Both have negative solubility values, which is also unusual.

**11. hERG:** Both have very low hERG inhibition liability (A: 0.2, B: 0.187), which is excellent.

**12. Cl_mic:** Ligand A (2.03) has significantly lower microsomal clearance than Ligand B (9.71), indicating better metabolic stability.

**13. t1/2:** Ligand A (28.62) has a much longer in vitro half-life than Ligand B (8.62).

**14. Pgp:** Both have very low P-gp efflux liability (A: 0.044, B: 0.03), which is good for CNS penetration.

**15. Binding Affinity:** Ligand A (-9.3 kcal/mol) has a significantly stronger binding affinity than Ligand B (-7.5 kcal/mol). This is a substantial difference (>1.5 kcal/mol advantage).

**Overall Assessment:**

Ligand A is clearly superior. It excels in almost all key parameters, particularly BBB penetration, metabolic stability (Cl_mic & t1/2), and binding affinity. While both have some issues with Caco-2 and solubility, the much stronger affinity and superior CNS properties of Ligand A outweigh any potential drawbacks. The TPSA value is also much more favorable for CNS penetration.



Output:
1
2025-04-17 07:15:57,985 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (350.415 and 358.364 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (88.1) is better than Ligand B (76.14). Both are below the 90 A^2 threshold for CNS targets, but A is closer to the ideal.

**3. logP:** Both ligands have good logP values (1.541 and 2.37), falling within the optimal 1-3 range. Ligand B is slightly higher, which *could* be beneficial for membrane permeability, but isn't a major difference.

**4. H-Bond Donors:** Both have 2 HBD, which is within the acceptable limit of <=5.

**5. H-Bond Acceptors:** Both have 5 HBA, also within the acceptable limit of <=10.

**6. QED:** Both ligands have good QED scores (0.728 and 0.845), indicating good drug-like properties. Ligand B is slightly better.

**7. DILI:** Ligand A (22.14) has a significantly lower DILI risk than Ligand B (52.385). This is a substantial advantage for Ligand A.

**8. BBB:** Ligand B (85.537) has a much better BBB penetration score than Ligand A (70.997). This is a critical advantage for a CNS target like DRD2.

**9. Caco-2 Permeability:** Ligand A (-4.247) has better Caco-2 permeability than Ligand B (-4.699).

**10. Aqueous Solubility:** Ligand A (-1.546) has better aqueous solubility than Ligand B (-3.126).

**11. hERG Inhibition:** Both ligands have low hERG inhibition risk (0.266 and 0.294).

**12. Microsomal Clearance:** Ligand B (13.52) has a significantly lower microsomal clearance than Ligand A (38.013), suggesting better metabolic stability.

**13. In vitro Half-Life:** Ligand B (15.63) has a longer in vitro half-life than Ligand A (-13.762). This is a significant advantage.

**14. P-gp Efflux:** Both ligands have low P-gp efflux (0.081 and 0.033). Ligand B is slightly better.

**15. Binding Affinity:** Both ligands have excellent binding affinity (-8.3 and -8.7 kcal/mol). Ligand B is slightly better (-8.7 kcal/mol).

**Overall Assessment:**

Ligand B clearly excels in BBB penetration (85.537 vs 70.997), metabolic stability (lower Cl_mic and longer t1/2), and has a slightly better binding affinity. These are crucial for a CNS GPCR target. While Ligand A has better DILI and solubility, the BBB and metabolic stability advantages of Ligand B are more important in this context. The slight improvement in affinity for Ligand B further supports its selection.

Output:
1
2025-04-17 07:15:57,986 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 drug candidates, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (352.523 and 349.431 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (47.1) is excellent, well below the 90 A^2 threshold for CNS targets. Ligand B (96.87) is higher, but still potentially acceptable, though less ideal.

**logP:** Ligand A (1.262) is within the optimal 1-3 range. Ligand B (0.375) is slightly low, potentially hindering permeation.

**H-Bond Donors/Acceptors:** Ligand A (0 HBD, 4 HBA) is good. Ligand B (3 HBD, 4 HBA) is also acceptable.

**QED:** Both ligands have good QED scores (0.617 and 0.735), indicating drug-like properties.

**DILI:** Ligand A (2.986) has a very low DILI risk. Ligand B (29.624) is higher, but still below the concerning 60 threshold.

**BBB:** This is critical for a CNS target. Ligand A (87.941) has a very good BBB percentile. Ligand B (25.979) is significantly lower and a major drawback.

**Caco-2 Permeability:** Both have negative values (-4.936 and -4.97), which is unusual and suggests poor permeability. However, these values are on a scale where negative values are possible, and don't necessarily disqualify a compound.

**Aqueous Solubility:** Ligand A (0.179) has very low solubility, which is a concern. Ligand B (-1.736) is even worse.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.523 and 0.343).

**Microsomal Clearance:** Ligand A (0.326) has very low clearance, indicating good metabolic stability. Ligand B (1.093) is slightly higher, but still reasonable.

**In vitro Half-Life:** Both have very long half-lives (-26.936 and -29.078 hours).

**P-gp Efflux:** Both have very low P-gp efflux liability (0.007 and 0.096).

**Binding Affinity:** Ligand B (-8.2 kcal/mol) has a significantly stronger binding affinity than Ligand A (-6.8 kcal/mol). This is a substantial advantage.

**Overall Assessment:**

Ligand A excels in BBB penetration, metabolic stability (low Cl_mic), and DILI risk. However, its solubility is very poor, and its binding affinity is weaker. Ligand B has a much stronger binding affinity, which is a significant advantage for GPCRs. While its BBB penetration is a concern, the substantial affinity difference could potentially overcome this, especially with formulation strategies. The solubility is also a concern for Ligand B.

Given the GPCR-specific priorities, the strong affinity of Ligand B is the deciding factor, despite its lower BBB and solubility. The affinity difference (>1.5 kcal/mol) outweighs the ADME drawbacks, and formulation strategies could be explored to address solubility and BBB concerns.

Output:
1
2025-04-17 07:15:57,986 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (347.375) is slightly lower, which could be beneficial for permeability, but both are acceptable.

**TPSA:** Ligand A (124.35) is borderline for CNS penetration, being above the ideal <90, but still potentially passable. Ligand B (82.97) is excellent, well below the threshold. This is a significant advantage for Ligand B.

**logP:** Ligand A (0.029) is very low, which is a major concern. It suggests poor membrane permeability and potentially poor binding. Ligand B (0.532) is also on the lower side, but significantly better than Ligand A.

**H-Bond Donors/Acceptors:** Ligand A has 3 HBD and 6 HBA, which are acceptable. Ligand B has 1 HBD and 6 HBA, also acceptable.

**QED:** Both ligands have good QED scores (A: 0.677, B: 0.793), indicating generally drug-like properties.

**DILI:** Ligand A (69.523) has a higher DILI risk than Ligand B (33.773), which is preferable.

**BBB:** Both have similar, relatively low BBB penetration (A: 25.94, B: 27.491). Neither is ideal (>70), but this is less critical if other properties are strong.

**Caco-2 Permeability:** Ligand A (-5.637) shows very poor Caco-2 permeability, consistent with its low logP. Ligand B (-4.726) is also poor, but better than A.

**Aqueous Solubility:** Both have very poor aqueous solubility (A: -1.328, B: -0.445). This could pose formulation challenges.

**hERG Inhibition:** Both ligands show very low hERG inhibition risk (A: 0.029, B: 0.202), which is excellent.

**Microsomal Clearance:** Ligand A (-3.144) has a negative value, indicating potentially very low clearance (highly stable). Ligand B (16.171) has a higher clearance, suggesting faster metabolism. This favors Ligand A.

**In vitro Half-Life:** Ligand A (-3.376) has a negative value, which is unusual and suggests a very long half-life. Ligand B (4.094) has a reasonable half-life.

**P-gp Efflux:** Both ligands show very low P-gp efflux (A: 0.008, B: 0.083), which is favorable for CNS penetration.

**Binding Affinity:** Ligand A (-7.1) has a slightly better binding affinity than Ligand B (-6.8). However, the difference (0.3 kcal/mol) is not substantial enough to overcome the significant ADME deficiencies of Ligand A.

**Conclusion:**

Considering the GPCR-specific priorities, Ligand B is the more promising candidate. While its BBB penetration isn't ideal, its significantly better logP, TPSA, and lower DILI risk outweigh the slightly weaker binding affinity and higher clearance compared to Ligand A. Ligand A's extremely low logP and poor Caco-2 permeability are major liabilities that would likely hinder its development, despite its slightly better affinity and potentially very long half-life.

Output:
1
2025-04-17 07:15:57,986 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (338.455 Da) is slightly lower, which could be beneficial for permeability.

**TPSA:** Ligand A (58.95) is excellent for CNS penetration, well below 90. Ligand B (78.25) is still reasonable but less optimal.

**logP:** Ligand A (4.601) is a bit high, potentially leading to solubility issues or off-target interactions. Ligand B (1.889) is closer to the optimal range (1-3).

**H-Bond Donors/Acceptors:** Ligand A (2 HBD, 3 HBA) and Ligand B (1 HBD, 6 HBA) both fall within acceptable limits.

**QED:** Both ligands have reasonable QED scores (A: 0.859, B: 0.784), indicating good drug-like properties.

**DILI:** Ligand A (64.754) has a moderate DILI risk, while Ligand B (21.946) has a very low risk. This is a significant advantage for Ligand B.

**BBB:** Ligand A (89.066) has excellent BBB penetration, exceeding the 70% threshold. Ligand B (61.923) is lower, which is a concern for a CNS target.

**Caco-2 Permeability:** Both have negative Caco-2 values which is unusual and likely indicates a problem with the prediction method.

**Aqueous Solubility:** Both ligands have negative solubility values, which is also unusual and likely indicates a problem with the prediction method.

**hERG:** Both ligands have low hERG inhibition liability (A: 0.548, B: 0.589).

**Microsomal Clearance:** Both ligands have similar microsomal clearance values (A: 40.475, B: 41.171).

**In vitro Half-Life:** Ligand A (91.432) has a significantly longer half-life than Ligand B (3.572), which is a major advantage.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (A: 0.732, B: 0.054). Ligand B is slightly better.

**Binding Affinity:** Ligand A (-10.6 kcal/mol) has a substantially stronger binding affinity than Ligand B (-7.8 kcal/mol). This is a crucial factor, as a >1.5 kcal/mol advantage can outweigh other drawbacks.

**Overall Assessment:**

Ligand A excels in binding affinity and BBB penetration, and has a good half-life. Its main drawbacks are a slightly high logP and moderate DILI risk. Ligand B has a better safety profile (lower DILI) and logP, but significantly weaker binding affinity and lower BBB penetration.

Given the importance of strong binding affinity for GPCRs, and the CNS target, the superior affinity of Ligand A (-10.6 kcal/mol vs -7.8 kcal/mol) is the deciding factor. While the higher logP and DILI risk of Ligand A are concerns, they might be addressed through further optimization. The lower affinity of Ligand B is a more difficult hurdle to overcome.

Output:
1
2025-04-17 07:15:57,986 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (343.335 and 353.419 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (112.93) is slightly above the optimal <90 for CNS targets, but still reasonable. Ligand B (105.76) is better, falling comfortably under 90.

**logP:** Ligand A (2.338) is within the optimal 1-3 range. Ligand B (0.169) is quite low, potentially hindering permeation.

**H-Bond Donors:** Both ligands have 3 HBD, which is acceptable.

**H-Bond Acceptors:** Ligand A has 4 HBA, and Ligand B has 5. Both are within the acceptable limit of <=10.

**QED:** Both ligands have QED values above 0.5 (0.711 and 0.605), indicating good drug-like properties.

**DILI:** Ligand A (89.88) has a higher DILI risk than Ligand B (32.299), which is a significant concern.

**BBB:** Ligand B (66.848) has a substantially better BBB penetration percentile than Ligand A (29.275). This is *critical* for a CNS target like DRD2.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.351 and -5.075), which is unusual and suggests poor permeability. However, these values are on a scale where negative values are possible and don't necessarily preclude development.

**Aqueous Solubility:** Both ligands have negative solubility values (-3.128 and -1.929), indicating poor aqueous solubility.

**hERG:** Both ligands have low hERG inhibition liability (0.056 and 0.117), which is favorable.

**Microsomal Clearance:** Ligand A (-0.875) has slightly better (lower) microsomal clearance than Ligand B (0.783), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (-15.95) has a much longer in vitro half-life than Ligand B (-1.071), which is a significant advantage.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.026 and 0.006), which is good for CNS penetration.

**Binding Affinity:** Both ligands have very similar and strong binding affinities (-9.2 and -8.6 kcal/mol). The difference of 0.6 kcal/mol is not substantial enough to outweigh other factors.

**Conclusion:**

Despite Ligand A's better metabolic stability and half-life, Ligand B is the more promising candidate. The significantly better BBB penetration (66.848 vs 29.275) and much lower DILI risk (32.299 vs 89.88) are crucial advantages for a CNS-targeting drug. While the logP of Ligand B is a concern, the strong binding affinity and low P-gp efflux may compensate to some extent. The poor solubility and Caco-2 values are drawbacks for both, but can potentially be addressed through formulation strategies.

Output:
1
2025-04-17 07:15:57,986 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (360.527 and 366.527 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (61.92) is better than Ligand B (67.34). Both are below the 90 A^2 threshold desirable for CNS targets, but A is closer to optimal.

**3. logP:** Both ligands have good logP values (3.139 and 2.98), falling within the 1-3 range.

**4. H-Bond Donors:** Both have 0 HBD, which is acceptable.

**5. H-Bond Acceptors:** Ligand A has 5 HBA, and Ligand B has 4. Both are below the 10 limit.

**6. QED:** Both ligands have similar and good QED values (0.714 and 0.744), indicating good drug-like properties.

**7. DILI:** Ligand A (17.216) has a significantly lower DILI risk than Ligand B (31.718). This is a major advantage for Ligand A.

**8. BBB:** Ligand B (87.67) has a better BBB penetration percentile than Ligand A (79.139). Both are above 70, which is good for CNS targets, but B is better.

**9. Caco-2 Permeability:** Ligand A (-4.982) has worse Caco-2 permeability than Ligand B (-4.741). Both are negative, indicating poor permeability, but B is slightly better.

**10. Aqueous Solubility:** Ligand A (-3.294) has worse aqueous solubility than Ligand B (-2.739). Both are negative, indicating poor solubility, but B is slightly better.

**11. hERG Inhibition:** Both ligands have low hERG inhibition risk (0.641 and 0.476).

**12. Microsomal Clearance:** Ligand B (63.122) has lower microsomal clearance than Ligand A (76.566), suggesting better metabolic stability.

**13. In vitro Half-Life:** Ligand B (-2.383) has a longer in vitro half-life than Ligand A (-14.874). This is a significant advantage for Ligand B.

**14. P-gp Efflux:** Both ligands have low P-gp efflux liability (0.432 and 0.533).

**15. Binding Affinity:** Ligand B (-7.4 kcal/mol) has a stronger binding affinity than Ligand A (-6.7 kcal/mol). This is a 0.7 kcal/mol difference, which is substantial and can outweigh some ADME drawbacks.

**Overall Assessment:**

Ligand B is superior due to its significantly better binding affinity (-7.4 vs -6.7 kcal/mol), better BBB penetration (87.67 vs 79.139), and improved metabolic stability (lower Cl_mic and longer t1/2). While Ligand A has a lower DILI risk, the affinity difference and CNS penetration of Ligand B are more critical for a DRD2 targeting drug. The slight improvements in Caco-2 and solubility for Ligand B are also beneficial.

Output:
1
2025-04-17 07:15:57,986 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (350.369 Da and 343.362 Da) fall within the ideal range of 200-500 Da.

**TPSA:** Ligand A (68.18) is excellent, well below the 90 A^2 threshold for CNS targets. Ligand B (101.21) is still reasonable but less optimal, being above 90 A^2.

**logP:** Ligand A (2.877) is within the optimal range of 1-3. Ligand B (1.75) is at the lower end, potentially impacting permeability.

**H-Bond Donors/Acceptors:** Both have 2 HBD and acceptable HBA counts (4 and 5 respectively).

**QED:** Both ligands have good QED scores (0.871 and 0.827), indicating good drug-like properties.

**DILI:** Ligand A (73.982) and Ligand B (85.964) both have acceptable DILI risk, below the concerning threshold of 60.

**BBB:** This is crucial for a CNS target. Ligand A excels with a BBB percentile of 90.617, while Ligand B is significantly lower at 62.233.

**Caco-2 Permeability:** Ligand A (-4.78) and Ligand B (-5.106) both have negative values, which is unusual and suggests very low permeability. This is a significant concern for both.

**Aqueous Solubility:** Both ligands have very poor aqueous solubility (-4.044 and -3.159 respectively). This could pose formulation challenges.

**hERG:** Both ligands have low hERG inhibition liability (0.451 and 0.399), which is positive.

**Microsomal Clearance:** Ligand A (19.135) has a higher clearance than Ligand B (2.076), suggesting lower metabolic stability.

**In vitro Half-Life:** Ligand B (-17.79) has a negative half-life, which is not possible. This is a data error and a major red flag. Ligand A (52.866) has a reasonable half-life.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.166 and 0.013), which is favorable for CNS penetration.

**Binding Affinity:** Both ligands have excellent binding affinity (-9.7 kcal/mol and -9.0 kcal/mol). The difference of 0.7 kcal/mol is not substantial enough to overcome other significant differences.

**Conclusion:**

Despite both ligands having excellent binding affinity, Ligand A is the more promising candidate. Its significantly better BBB penetration (90.617 vs 62.233) is critical for a CNS-targeting drug. While both have poor solubility and Caco-2 permeability, the problematic negative half-life value for Ligand B is a deal-breaker. Ligand A also has a more reasonable (though still not ideal) microsomal clearance.

Output:
1
2025-04-17 07:15:57,987 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (444.738 Da) is higher, but still acceptable. Ligand B (355.479 Da) is slightly better.

**TPSA:** Ligand A (71.53) is better than Ligand B (87.74). For CNS targets, we want TPSA <= 90, both are within this range, but A is closer to the optimal value.

**logP:** Ligand A (3.406) is optimal (1-3), while Ligand B (1.215) is on the lower end. Lower logP can hinder permeation, making A preferable.

**H-Bond Donors/Acceptors:** Ligand A (HBD=1, HBA=5) and Ligand B (HBD=2, HBA=4) both fall within acceptable limits (<=5 HBD, <=10 HBA).

**QED:** Both ligands have good QED scores (A: 0.569, B: 0.617), indicating drug-like properties.

**DILI:** Ligand A (85.227) has a significantly higher DILI risk than Ligand B (19.271). This is a major concern for Ligand A.

**BBB:** Ligand A (69.252) has a better BBB percentile than Ligand B (54.362). This is crucial for a CNS target like DRD2.

**Caco-2:** Ligand A (-4.793) and Ligand B (-5.151) both have negative Caco-2 permeability values, which is unusual and suggests poor absorption. This is a drawback for both.

**Aqueous Solubility:** Ligand A (-4.45) and Ligand B (-1.099) both have negative solubility values, which is also unusual and suggests poor solubility. This is a drawback for both.

**hERG:** Both ligands have very low hERG inhibition liability (A: 0.21, B: 0.173), which is excellent.

**Microsomal Clearance:** Ligand A (43.997) has higher microsomal clearance than Ligand B (15.782), indicating lower metabolic stability.

**In vitro Half-Life:** Ligand A (16.302) has a longer half-life than Ligand B (8.814).

**P-gp Efflux:** Ligand A (0.231) has lower P-gp efflux than Ligand B (0.014), which is favorable for CNS penetration.

**Binding Affinity:** Ligand A (-9.2 kcal/mol) has significantly stronger binding affinity than Ligand B (-0.0 kcal/mol). This is a substantial advantage for Ligand A, potentially outweighing some of its ADME drawbacks.

**Overall Assessment:**

Ligand A has a much stronger binding affinity and better BBB penetration, and P-gp efflux, which are critical for a CNS GPCR target. However, it has a significantly higher DILI risk and lower metabolic stability. Ligand B has a lower DILI risk and better metabolic stability, but its binding affinity is very weak and BBB penetration is poor.

Given the importance of potency and CNS penetration for DRD2, the superior binding affinity of Ligand A is a decisive factor, despite its higher DILI risk and lower metabolic stability. These ADME properties could potentially be improved through further optimization.

Output:
1
2025-04-17 07:15:57,987 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight (MW):** Both ligands (352.475 and 362.455 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (70.08) is significantly better than Ligand B (87.46). For CNS targets, we want TPSA <= 90, and A is comfortably within that range, while B is approaching the upper limit.

**3. logP:** Both ligands have acceptable logP values (1.414 and 2.05), falling within the optimal 1-3 range.

**4. H-Bond Donors (HBD):** Both ligands have acceptable HBD counts (1 and 2, respectively), well below the threshold of 5.

**5. H-Bond Acceptors (HBA):** Both ligands have acceptable HBA counts (4 and 6, respectively), below the threshold of 10.

**6. QED:** Both ligands have similar and good QED scores (0.812 and 0.823), indicating good drug-likeness.

**7. DILI:** Ligand A (20.861) has a much lower DILI risk than Ligand B (64.25). This is a significant advantage for A.

**8. BBB:** Ligand A (51.764) has a better BBB percentile than Ligand B (33.385). While both are below the desirable >70 for CNS targets, A is closer.

**9. Caco-2:** Ligand A (-4.465) and Ligand B (-5.383) both have negative Caco-2 values, which is unusual and suggests poor permeability.

**10. Solubility:** Ligand A (-1.777) is slightly better than Ligand B (-2.427), but both are poor.

**11. hERG:** Both ligands have low hERG risk (0.477 and 0.516).

**12. Cl_mic:** Ligand A (20.249) has a lower microsomal clearance than Ligand B (37.844), indicating better metabolic stability.

**13. t1/2:** Ligand A (24.676) has a longer in vitro half-life than Ligand B (-0.153).

**14. Pgp:** Ligand A (0.152) has a lower Pgp efflux liability than Ligand B (0.299), which is favorable for CNS penetration.

**15. Binding Affinity:** Ligand B (-7.9) has a slightly better binding affinity than Ligand A (-7.2), a 0.7 kcal/mol difference. While affinity is crucial, the other ADME properties are also important.

**Overall Assessment:**

Ligand A is significantly better overall. While Ligand B has a slightly better binding affinity, Ligand A excels in critical ADME properties for a CNS-targeting GPCR: lower DILI risk, better BBB penetration, lower Pgp efflux, better metabolic stability (lower Cl_mic and longer t1/2), and lower TPSA. The difference in affinity (0.7 kcal/mol) is unlikely to outweigh these substantial ADME advantages. The poor Caco-2 and solubility for both compounds are concerning, but can be addressed through formulation strategies.

Output:
0
2025-04-17 07:15:57,987 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (342.483 and 346.431 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (49.41) is excellent, well below the 90 A^2 threshold for CNS targets. Ligand B (95.42) is higher, but still potentially acceptable, though less optimal.

**3. logP:** Ligand A (3.081) is within the optimal 1-3 range. Ligand B (0.994) is slightly below 1, which could indicate permeability issues.

**4. H-Bond Donors:** Both ligands have acceptable HBD counts (1 and 2, respectively), well below the 5 threshold.

**5. H-Bond Acceptors:** Ligand A (2) is good. Ligand B (5) is also acceptable, below the 10 threshold.

**6. QED:** Both ligands have good QED scores (0.789 and 0.829), indicating good drug-like properties.

**7. DILI:** Ligand A (17.836) has a much lower DILI risk than Ligand B (39.667), which is a significant advantage.

**8. BBB:** Ligand A (81.698) has a significantly better BBB penetration percentile than Ligand B (61.846). This is crucial for a CNS target like DRD2.

**9. Caco-2 Permeability:** Ligand A (-4.558) has a negative Caco-2 value, which is concerning. Ligand B (-5.039) is also negative. This suggests poor intestinal absorption for both, but is less critical for a CNS target where direct delivery is possible.

**10. Aqueous Solubility:** Both ligands have very poor aqueous solubility (-3.135 and -2.014). This could pose formulation challenges.

**11. hERG Inhibition:** Both ligands have low hERG inhibition risk (0.523 and 0.383).

**12. Microsomal Clearance:** Ligand B (9.158) has a much lower microsomal clearance than Ligand A (78.695), suggesting better metabolic stability.

**13. In vitro Half-Life:** Ligand A (-17.577) has a negative half-life, which is not possible and likely indicates an issue with the data or prediction method. Ligand B (-10.934) is also negative.

**14. P-gp Efflux:** Both ligands have low P-gp efflux liability (0.295 and 0.093), which is positive for CNS penetration.

**15. Binding Affinity:** Both ligands have excellent binding affinities (-8.7 and -9.2 kcal/mol), with Ligand B being slightly better. The affinity difference is small and likely less important than the ADME differences.

**Overall Assessment:**

Ligand A is superior despite the negative Caco-2 and half-life values. Its significantly better BBB penetration (81.7% vs 61.8%), lower DILI risk (17.8% vs 39.7%), and acceptable logP outweigh the slightly better affinity and metabolic stability of Ligand B. The negative half-life for Ligand A is concerning, but could be an artifact of the prediction. The poor solubility is a concern for both, but can be addressed with formulation strategies. Given the CNS target, BBB penetration is paramount.

Output:
1
2025-04-17 07:15:57,987 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (340.339 and 349.435 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (109.3) is slightly higher than Ligand B (107.4), but both are reasonably close to the <140 for oral absorption and acceptable for a CNS target, though ideally below 90.

**3. logP:** Ligand A (0.272) is quite low, potentially hindering membrane permeability. Ligand B (1.996) is much better, falling within the optimal 1-3 range. This is a significant advantage for Ligand B.

**4. H-Bond Donors:** Ligand A (3) is higher than Ligand B (1). While both are within the acceptable limit of 5, lower is generally preferred for better permeability.

**5. H-Bond Acceptors:** Ligand A (5) and Ligand B (4) are both acceptable (<=10).

**6. QED:** Ligand A (0.697) has a better QED score than Ligand B (0.466), indicating a more drug-like profile overall.

**7. DILI:** Ligand A (81.427) has a significantly higher DILI risk than Ligand B (30.748). This is a major concern for Ligand A.

**8. BBB:** Ligand B (76.89) has a substantially better BBB penetration percentile than Ligand A (53.974). This is crucial for a CNS target like DRD2.

**9. Caco-2 Permeability:** Ligand A (-5.136) has very poor Caco-2 permeability, while Ligand B (-4.774) is also not great, but comparatively better.

**10. Aqueous Solubility:** Both ligands have poor aqueous solubility (-3.863 and -2.765 respectively). This could pose formulation challenges.

**11. hERG Inhibition:** Both ligands show low hERG inhibition risk (0.13 and 0.162 respectively).

**12. Microsomal Clearance:** Ligand A (-7.149) has a much lower (better) microsomal clearance than Ligand B (25.745), suggesting better metabolic stability.

**13. In vitro Half-Life:** Ligand A (41.944) has a better in vitro half-life than Ligand B (-3.433).

**14. P-gp Efflux:** Ligand A (0.043) has lower P-gp efflux than Ligand B (0.011), which is positive for CNS penetration.

**15. Binding Affinity:** Ligand A (-10.7 kcal/mol) has a significantly stronger binding affinity than Ligand B (-7.0 kcal/mol). This is a substantial advantage for Ligand A, potentially outweighing some of its ADME drawbacks.

**Overall Assessment:**

Despite Ligand A's superior binding affinity, its poor logP, high DILI risk, and relatively low BBB penetration are major drawbacks. Ligand B, while having a weaker affinity, possesses a much more favorable ADME profile, particularly its better logP, significantly lower DILI risk, and improved BBB penetration. For a CNS target like DRD2, a balance between potency and brain penetration is critical. The difference in affinity (3.7 kcal/mol) *might* be overcome with further optimization of Ligand B, whereas fixing Ligand A's ADME issues would likely require more substantial structural changes that could compromise its binding.

Output:
1
2025-04-17 07:15:57,987 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (343.387 and 352.475 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (93.26) is slightly above the optimal <90 for CNS targets, but still reasonable. Ligand B (70.08) is excellent, well below 90.

**logP:** Both ligands have a logP around 1.4, which is optimal (1-3).

**H-Bond Donors/Acceptors:** Both have 1 HBD, which is good. Ligand A has 6 HBA, while Ligand B has 4. Both are acceptable (<=10).

**QED:** Both ligands have high QED scores (0.848 and 0.831), indicating good drug-like properties.

**DILI:** Ligand A (58.511) has a moderate DILI risk, while Ligand B (9.616) has a very low risk. This is a significant advantage for Ligand B.

**BBB:** Ligand A (68.941) has a reasonable BBB penetration, but Ligand B (54.478) is lower. While >70 is desirable, both are not ideal.

**Caco-2 Permeability:** Ligand A (-5.131) has poor Caco-2 permeability, which is concerning. Ligand B (-4.508) is also poor, but slightly better.

**Aqueous Solubility:** Both ligands have very poor aqueous solubility (-2.552 and -0.965). This could pose formulation challenges.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.159 and 0.385).

**Microsomal Clearance:** Ligand A (30.541) has moderate clearance, while Ligand B (14.374) has lower clearance, suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (-21.478) has a very short half-life, which is a major drawback. Ligand B (10.521) has a better, though still not ideal, half-life.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.054 and 0.118), which is good for CNS penetration.

**Binding Affinity:** Ligand A (-8.2 kcal/mol) has a significantly stronger binding affinity than Ligand B (-7.1 kcal/mol). This is a substantial advantage.

**Overall Assessment:**

The primary trade-off is between affinity (Ligand A) and ADME properties (Ligand B). Ligand A's much stronger binding affinity is a significant positive. However, its poor Caco-2 permeability and very short half-life are major concerns. Ligand B has better ADME properties (lower DILI, better metabolic stability, slightly better Caco-2), but its affinity is weaker.

Given the GPCR-specific emphasis on BBB, logP, Pgp, TPSA, and affinity, and considering the substantial affinity difference, I would lean towards **Ligand A** despite its ADME liabilities. The stronger binding could potentially be optimized through structural modifications without completely sacrificing the other properties. The poor half-life and permeability are areas for focused medicinal chemistry efforts.

Output:
0
2025-04-17 07:15:57,987 - INFO - Batch 350 complete. Total preferences: 5600
2025-04-17 07:15:57,988 - INFO - Processing batch 351/512...
2025-04-17 07:16:41,714 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight (MW):** Both ligands (343.427 and 347.459 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (78.19) is slightly higher than Ligand B (69.72). Both are below the 90 A^2 threshold desirable for CNS targets, but Ligand B is preferable.

**3. logP:** Ligand A (3.659) is within the optimal range (1-3), but approaching the upper limit. Ligand B (1.149) is also within range, but closer to the lower limit. For a GPCR, a slightly higher logP can be beneficial for membrane permeability, so Ligand A has a slight edge here.

**4. H-Bond Donors (HBD):** Both ligands have acceptable HBD counts (2 and 1, respectively), well below the 5 threshold. Ligand B is slightly better.

**5. H-Bond Acceptors (HBA):** Both ligands have 3 HBA, which is within the acceptable limit of 10.

**6. QED:** Both ligands have similar QED values (0.829 and 0.811), indicating good drug-likeness.

**7. DILI:** Ligand A (62.35) has a higher DILI risk than Ligand B (17.759). This is a significant advantage for Ligand B.

**8. BBB:** Ligand B (71.539) has a considerably better BBB penetration percentile than Ligand A (54.866). This is *critical* for a CNS target like DRD2.

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.665 and -4.896), indicating poor permeability. This is a concern for both, but the values are similar.

**10. Aqueous Solubility:** Both ligands have negative solubility values (-4.983 and -2.635), indicating poor solubility. Ligand B is slightly better.

**11. hERG Inhibition:** Both ligands have low hERG inhibition risk (0.591 and 0.134), which is good. Ligand B is preferable.

**12. Microsomal Clearance:** Ligand A (37.809) has higher microsomal clearance than Ligand B (10.657), indicating lower metabolic stability. Ligand B is preferable.

**13. In vitro Half-Life:** Ligand B (3.792) has a longer in vitro half-life than Ligand A (13.349). This is a significant advantage for Ligand B.

**14. P-gp Efflux:** Ligand A (0.263) has higher P-gp efflux liability than Ligand B (0.053). Lower P-gp efflux is preferred, giving Ligand B an advantage.

**15. Binding Affinity:** Ligand A (-8.7 kcal/mol) has a significantly stronger binding affinity than Ligand B (-7.5 kcal/mol). This is a substantial advantage for Ligand A, and could potentially outweigh some of its ADME drawbacks. The difference is >1.5 kcal/mol.

**Overall Assessment:**

While Ligand A has a superior binding affinity, Ligand B demonstrates a much more favorable ADME profile, particularly regarding BBB penetration (71.539 vs 54.866), DILI risk (17.759 vs 62.35), metabolic stability (lower Cl_mic), and P-gp efflux. Given the CNS target (DRD2), BBB penetration is paramount. The substantial difference in binding affinity *might* be overcome with further optimization of Ligand B, whereas addressing the ADME issues of Ligand A would likely require more extensive structural modifications.

Output:
1
2025-04-17 07:16:41,715 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (410.587 Da) is slightly higher, but acceptable. Ligand B (351.403 Da) is also good.

**TPSA:** Both ligands have TPSA values below the 140 A^2 threshold for oral absorption (A: 112.81, B: 107.97). Both are also below the 90 A^2 target for CNS penetration, which is excellent.

**logP:** Both ligands have logP values between 1-3 (A: -0.505, B: -0.247). Ligand A is slightly outside the optimal range, being a bit too hydrophilic. Ligand B is closer to the optimal range.

**H-Bond Donors/Acceptors:** Ligand A (HBD=2, HBA=7) and Ligand B (HBD=3, HBA=5) both fall within acceptable limits.

**QED:** Both ligands have good QED values (A: 0.567, B: 0.647), indicating drug-like properties.

**DILI:** Ligand A (58.705) has a higher DILI risk than Ligand B (36.177). This is a significant advantage for Ligand B.

**BBB:** Ligand A (48.779) has a better BBB penetration percentile than Ligand B (30.128). This is a crucial factor for a CNS target like DRD2.

**Caco-2 Permeability:** Both ligands have negative Caco-2 permeability values, which is unusual and suggests poor permeability. However, the scale is not specified, so it's hard to interpret.

**Aqueous Solubility:** Both ligands have negative aqueous solubility values, which is also unusual. Again, the scale is not specified.

**hERG:** Both ligands have low hERG inhibition risk (A: 0.686, B: 0.062). Ligand B is significantly better.

**Microsomal Clearance:** Ligand A (4.447) has a lower (better) microsomal clearance than Ligand B (-52.282). This indicates better metabolic stability for Ligand A.

**In vitro Half-Life:** Ligand A (-4.877) has a negative in vitro half-life, which is not possible. This is a red flag. Ligand B (0.703) has a short half-life, but it is at least a plausible value.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (A: 0.024, B: 0.005). This is good for CNS penetration.

**Binding Affinity:** Both ligands have strong binding affinities (A: -7.0 kcal/mol, B: -8.0 kcal/mol). Ligand B is 1 kcal/mol better, which is a substantial advantage.

**Overall Assessment:**

Ligand B is the better candidate. While Ligand A has a better BBB score, the negative in vitro half-life is a major concern. Ligand B has a better binding affinity, significantly lower DILI risk, and a lower hERG risk. The slightly lower BBB score of Ligand B is less concerning than the problematic half-life of Ligand A. The negative values for Caco-2 and solubility are concerning for both, but the other factors heavily favor Ligand B.

Output:
1
2025-04-17 07:16:41,715 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (344.503 and 359.499 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Both ligands have TPSA values around 60, well below the 90 threshold for CNS targets. This is excellent for brain penetration.

**3. logP:** Both ligands have logP values around 3.5-3.6, falling within the optimal 1-3 range.

**4. H-Bond Donors:** Ligand A has 1 HBD, and Ligand B has 0. Both are acceptable (<=5).

**5. H-Bond Acceptors:** Ligand A has 4 HBA, and Ligand B has 7. Both are within the acceptable range of <=10, but Ligand A is preferable.

**6. QED:** Ligand A (0.733) has a significantly higher QED than Ligand B (0.554), indicating a more drug-like profile.

**7. DILI:** Ligand A (27.22) has a much lower DILI risk than Ligand B (47.15), which is a significant advantage.

**8. BBB:** Ligand A (69.833) has a slightly better BBB percentile than Ligand B (64.482), though both are reasonably good. A value >70 is highly desirable, and neither quite reaches that.

**9. Caco-2:** Both have negative Caco-2 values, which is unusual and requires further investigation. However, the magnitude is similar, so it doesn't strongly differentiate them.

**10. Solubility:** Ligand A (-4.259) has slightly better solubility than Ligand B (-2.971).

**11. hERG:** Ligand A (0.224) has a much lower hERG inhibition liability than Ligand B (0.742), which is a critical safety advantage.

**12. Cl_mic:** Ligand B (55.063) has a lower microsomal clearance than Ligand A (71.711), suggesting better metabolic stability.

**13. t1/2:** Ligand B (40.183) has a significantly longer in vitro half-life than Ligand A (-6.551), which is a major advantage.

**14. Pgp:** Ligand A (0.388) has lower P-gp efflux liability than Ligand B (0.41), which is slightly better for CNS exposure.

**15. Binding Affinity:** Ligand A (-8.8 kcal/mol) has a stronger binding affinity than Ligand B (-6.7 kcal/mol). This is a substantial difference (over 2 kcal/mol) and a key driver in the decision.

**Overall Assessment:**

Ligand A is the stronger candidate. While Ligand B has better metabolic stability (lower Cl_mic and longer t1/2), Ligand A excels in crucial areas: significantly better binding affinity, lower DILI risk, lower hERG risk, and a higher QED score. The stronger binding affinity is particularly important for a GPCR target and can often compensate for minor ADME deficiencies. The lower safety liabilities (DILI and hERG) are also critical.

Output:
1
2025-04-17 07:16:41,715 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (365.909 and 361.471 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (61.36) is significantly better than Ligand B (88.39). For CNS targets, we want TPSA <= 90, and A is comfortably within this range, while B is approaching the upper limit.

**3. logP:** Both ligands have good logP values (2.536 and 1.353), falling within the optimal 1-3 range.

**4. H-Bond Donors:** Both ligands have acceptable HBD counts (1 and 2 respectively), well below the threshold of 5.

**5. H-Bond Acceptors:** Both ligands have acceptable HBA counts (5 and 6 respectively), below the threshold of 10.

**6. QED:** Both ligands have similar and good QED values (0.785 and 0.777), indicating good drug-like properties.

**7. DILI:** Ligand A (22.838) has a much lower DILI risk than Ligand B (69.717). This is a significant advantage for A.

**8. BBB:** Ligand A (92.943) has a substantially better BBB penetration percentile than Ligand B (61.691).  This is *critical* for a CNS target like DRD2.

**9. Caco-2 Permeability:** Both have negative values, which is unusual. However, the magnitude is similar, and this is less critical than other parameters for CNS targets.

**10. Aqueous Solubility:** Both have negative values, indicating poor solubility. This is a drawback for both, but not a deciding factor given the CNS target.

**11. hERG Inhibition:** Both ligands show very low hERG inhibition risk (0.577 and 0.301), which is excellent.

**12. Microsomal Clearance:** Ligand A (11.407) has lower microsomal clearance than Ligand B (36.407), suggesting better metabolic stability.

**13. In vitro Half-Life:** Ligand A (26.538) has a longer in vitro half-life than Ligand B (11.061), which is desirable.

**14. P-gp Efflux:** Both ligands exhibit very low P-gp efflux (0.034 and 0.036), which is favorable for CNS penetration.

**15. Binding Affinity:** Both ligands have very similar and strong binding affinities (-8.7 and -8.4 kcal/mol). The difference is less than 0.5 kcal/mol, so it's unlikely to be a deciding factor.

**Overall Assessment:**

Ligand A is significantly superior to Ligand B. It has a much better BBB score, lower DILI risk, better metabolic stability (lower Cl_mic, longer t1/2), and a more favorable TPSA. While both have similar binding affinities and acceptable physicochemical properties, the improved ADME profile of Ligand A, especially its BBB penetration, makes it the more promising drug candidate for targeting DRD2.

Output:
1
2025-04-17 07:16:41,715 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (363.53 and 346.34 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (61.44) is excellent, well below the 90 A^2 threshold for CNS targets. Ligand B (132.64) is higher, but still potentially acceptable, though less optimal.

**logP:** Ligand A (2.13) is within the optimal 1-3 range. Ligand B (-0.55) is below 1, which could hinder permeation.

**H-Bond Donors/Acceptors:** Ligand A (2 HBD, 4 HBA) is well within acceptable limits. Ligand B (3 HBD, 6 HBA) is also acceptable.

**QED:** Both ligands have reasonable QED scores (0.84 and 0.66), suggesting good drug-like properties.

**DILI:** Ligand A (13.3 percentile) has a significantly lower DILI risk than Ligand B (75.03 percentile). This is a major advantage for Ligand A.

**BBB:** Ligand A (59.36 percentile) is better than Ligand B (46.34 percentile), although ideally, we'd want >70 for a CNS target.

**Caco-2 Permeability:** Both have negative values, indicating poor permeability. This is a concern for both.

**Aqueous Solubility:** Both have negative values, indicating poor solubility. This is a concern for both.

**hERG:** Both ligands have low hERG inhibition liability (0.21 and 0.13), which is good.

**Microsomal Clearance:** Ligand A (0.61 mL/min/kg) has much lower clearance, indicating better metabolic stability, than Ligand B (4.05 mL/min/kg).

**In vitro Half-Life:** Ligand A (-3.34 hours) is substantially better than Ligand B (0.27 hours).

**P-gp Efflux:** Both have very low P-gp efflux liability (0.027 and 0.026), which is good.

**Binding Affinity:** Ligand B (-8.7 kcal/mol) has a significantly stronger binding affinity than Ligand A (-7.7 kcal/mol). This is a 1.0 kcal/mol difference, which is substantial.

**Overall Assessment:**

Ligand B has a superior binding affinity, which is a key factor. However, it suffers from a poor logP, high DILI risk, and higher metabolic clearance. Ligand A, while having a slightly weaker affinity, presents a much more favorable ADME-Tox profile, with lower DILI risk, better BBB penetration, and improved metabolic stability. Considering the GPCR-specific priorities, the balance leans towards Ligand A due to its better predicted CNS exposure and safety profile. The affinity difference, while significant, might be overcome with further optimization of Ligand A.

Output:
0
2025-04-17 07:16:41,715 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B based on the provided guidelines, prioritizing GPCR-specific properties (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (340.427 and 348.487 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (70.44) is significantly better than Ligand B (78.43). For CNS targets, TPSA should be <= 90, both are within this range, but A is closer to the optimal value.

**logP:** Both ligands have good logP values (3.35 and 2.439), falling within the 1-3 range. Ligand A is slightly higher, which *could* be beneficial for membrane permeability, but isn't a major concern for either.

**H-Bond Donors/Acceptors:** Ligand A (2 HBD, 5 HBA) and Ligand B (3 HBD, 3 HBA) both have acceptable numbers of H-bond donors and acceptors, well below the thresholds of 5 and 10, respectively.

**QED:** Both ligands have similar and acceptable QED values (0.623 and 0.69).

**DILI:** Ligand A (69.135) has a slightly higher DILI risk than Ligand B (20.9), but both are below the concerning threshold of 60.

**BBB:** This is a critical parameter for a CNS target like DRD2. Ligand A has a significantly higher BBB penetration percentile (70.997) compared to Ligand B (44.979). This is a major advantage for Ligand A.

**Caco-2 Permeability:** Ligand A (-5.18) and Ligand B (-4.717) both have negative values, indicating poor permeability. This is a concern for both, but the values are similar.

**Aqueous Solubility:** Both ligands have poor aqueous solubility (-3.561 and -3.182). This could pose formulation challenges, but isn't a deciding factor given the other parameters.

**hERG Inhibition:** Ligand A (0.904) has a slightly higher hERG inhibition risk than Ligand B (0.174), but both are relatively low.

**Microsomal Clearance:** Ligand B (50.25) has significantly higher microsomal clearance than Ligand A (5.015), suggesting lower metabolic stability.

**In vitro Half-Life:** Ligand A (18.044) has a longer in vitro half-life than Ligand B (-9.025), which is a positive attribute.

**P-gp Efflux:** Ligand A (0.358) has lower P-gp efflux liability than Ligand B (0.143), which is favorable for CNS penetration.

**Binding Affinity:** Both ligands have very similar and strong binding affinities (-8.9 kcal/mol and -8.4 kcal/mol). The difference of 0.5 kcal/mol is not substantial enough to override other important ADME properties.

**Conclusion:**

Considering the GPCR-specific priorities, Ligand A is the more promising candidate. Its significantly better BBB penetration, lower P-gp efflux, longer half-life, and lower microsomal clearance outweigh the slightly higher DILI and hERG risk. While both have poor solubility and Caco-2 permeability, these are secondary concerns compared to CNS penetration and metabolic stability for a DRD2 target.

Output:
0
2025-04-17 07:16:41,715 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (363.845 and 353.438 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Both ligands have TPSA values (62.74 and 63.57) that are acceptable for oral absorption (<140) but a bit high for optimal CNS penetration (<90).

**3. logP:** Ligand A (2.359) is optimal, while Ligand B (1.439) is slightly low, potentially hindering permeation.

**4. H-Bond Donors:** Both have acceptable HBD counts (0 and 1, respectively).

**5. H-Bond Acceptors:** Both ligands have 4 HBAs, which is within the acceptable range.

**6. QED:** Both ligands have similar QED values (0.77 and 0.769), indicating good drug-likeness.

**7. DILI:** Ligand A (40.364) has a slightly higher DILI risk than Ligand B (19.504), but both are below the concerning threshold of 60.

**8. BBB:** This is a crucial parameter for a CNS target like DRD2. Ligand B (85.343) has a significantly higher BBB percentile than Ligand A (63.203). This is a major advantage for Ligand B.

**9. Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and suggests poor permeability. This is a concern for both.

**10. Aqueous Solubility:** Both have negative solubility values, which is also unusual and a concern.

**11. hERG Inhibition:** Both ligands show low hERG inhibition liability (0.292 and 0.423), which is favorable.

**12. Microsomal Clearance:** Ligand A (47.219) has higher microsomal clearance than Ligand B (8.055), suggesting lower metabolic stability.

**13. In vitro Half-Life:** Ligand B (8.897) has a significantly longer in vitro half-life than Ligand A (-16.958), indicating better stability.

**14. P-gp Efflux:** Both ligands have low P-gp efflux liability (0.053 and 0.124), which is good for CNS exposure.

**15. Binding Affinity:** Ligand A (-7.9 kcal/mol) has a slightly better binding affinity than Ligand B (-7.4 kcal/mol), but the difference is less than 1.5 kcal/mol.

**Overall Assessment:**

While Ligand A has a slightly better binding affinity, Ligand B is significantly better in terms of BBB penetration, metabolic stability (lower Cl_mic, longer t1/2), and DILI risk. For a CNS target like DRD2, BBB penetration is paramount. The improved metabolic stability of Ligand B is also a significant advantage. The slight difference in binding affinity is unlikely to outweigh these substantial ADME benefits.

Output:
1
2025-04-17 07:16:41,715 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B based on the provided guidelines, keeping in mind DRD2 is a GPCR, so BBB, logP, Pgp, TPSA, and affinity are key.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (422.754 Da) is slightly higher than Ligand B (368.503 Da), but both are acceptable.

**TPSA:** Ligand A (54.02) is excellent for CNS penetration, well below the 90 Angstrom threshold. Ligand B (85.77) is higher, but still potentially acceptable, though less ideal.

**logP:** Ligand A (4.558) is a bit high, potentially leading to solubility issues and off-target effects. Ligand B (0.619) is quite low, which could hinder membrane permeability.

**H-Bond Donors/Acceptors:** Both ligands have 2 HBD and a reasonable number of HBA (3 for A, 6 for B). This is acceptable for both.

**QED:** Both ligands have good QED scores (0.688 and 0.769), indicating drug-like properties.

**DILI:** Ligand A (48.081) has a moderate DILI risk, while Ligand B (13.61) has a very low risk. This favors Ligand B.

**BBB:** Ligand A (65.219) has a good BBB percentile, suggesting reasonable CNS penetration. Ligand B (22.955) has a very low BBB percentile, making CNS exposure unlikely. This is a major advantage for Ligand A.

**Caco-2 Permeability:** Both have negative Caco-2 values which is unusual and difficult to interpret without further context.

**Aqueous Solubility:** Both have negative solubility values which is unusual and difficult to interpret without further context.

**hERG:** Ligand A (0.504) has a slightly higher hERG risk than Ligand B (0.101), favoring Ligand B.

**Microsomal Clearance:** Ligand A (39.518) has a moderate clearance, while Ligand B (-33.782) has a negative clearance, which is unusual and suggests very high metabolic stability. This favors Ligand B.

**In vitro Half-Life:** Ligand A (84.471) has a good in vitro half-life, while Ligand B (-6.242) has a very short half-life. This favors Ligand A.

**P-gp Efflux:** Ligand A (0.154) has low P-gp efflux, which is good for CNS penetration. Ligand B (0.013) has very low P-gp efflux, which is even better. This favors Ligand B.

**Binding Affinity:** Ligand A (-7.2 kcal/mol) has a slightly better binding affinity than Ligand B (-6.7 kcal/mol). While the difference isn't huge, it's a significant advantage.

**Overall Assessment:**

Ligand B excels in safety (DILI, hERG, Pgp efflux, and metabolic stability). However, its extremely low BBB penetration is a critical drawback for a CNS target like DRD2. Ligand A has a better BBB score and a slightly better binding affinity, and acceptable safety parameters. While its logP is a bit high, the better CNS exposure and affinity are more important for a GPCR in the brain.

Output:
1
2025-04-17 07:16:41,715 - INFO - Reasoning:

Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (390.311 and 350.507 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (87.3) is slightly above the preferred <90 for CNS targets, but still reasonable. Ligand B (55.89) is excellent, well below 90.

**3. logP:** Both ligands have good logP values (2.155 and 1.617), falling within the optimal 1-3 range.

**4. H-Bond Donors:** Ligand A has 3 HBD, which is acceptable. Ligand B has 1 HBD, also good.

**5. H-Bond Acceptors:** Both have 3 HBA, well within the acceptable limit of 10.

**6. QED:** Both ligands have good QED scores (0.608 and 0.792), indicating good drug-like properties.

**7. DILI:** Ligand A (24.234) has a low DILI risk, well below the 40 threshold. Ligand B (7.871) is even better, indicating very low liver injury risk.

**8. BBB:** Ligand A (64.87) is borderline for good CNS penetration, while Ligand B (81.155) is excellent, exceeding the 70% threshold. This is a significant advantage for Ligand B.

**9. Caco-2 Permeability:** Ligand A (-5.606) has poor Caco-2 permeability. Ligand B (-4.719) is also poor, but slightly better than A.

**10. Aqueous Solubility:** Both ligands have poor aqueous solubility (-2.59 and -1.316). This could pose formulation challenges.

**11. hERG Inhibition:** Ligand A (0.22) has a low hERG risk. Ligand B (0.615) is slightly higher, but still relatively low.

**12. Microsomal Clearance:** Ligand A (3.82) has a relatively low clearance, suggesting better metabolic stability. Ligand B (-7.889) has a *negative* clearance, which is not physically possible and likely indicates an issue with the prediction or data. This is a major red flag.

**13. In vitro Half-Life:** Ligand A (26.194) has a reasonable half-life. Ligand B (2.586) has a very short half-life, which is undesirable.

**14. P-gp Efflux:** Ligand A (0.043) has low P-gp efflux, which is good for CNS penetration. Ligand B (0.026) is even better.

**15. Binding Affinity:** Ligand A (-9.2 kcal/mol) has a significantly stronger binding affinity than Ligand B (-7.7 kcal/mol). This is a substantial advantage for Ligand A, potentially outweighing some of its ADME drawbacks. The difference is >1.5 kcal/mol.

**Overall Assessment:**

While Ligand B excels in BBB penetration, P-gp efflux, and DILI risk, its negative microsomal clearance and very short half-life are critical liabilities. A negative clearance is a clear indication of a flawed prediction and suggests significant instability. Ligand A, despite slightly less favorable BBB and Caco-2 permeability, has a much stronger binding affinity and a reasonable metabolic profile. The strong binding affinity of Ligand A is likely to be a dominant factor in its potential success, especially for a GPCR target where potency is crucial.

Output:
1
2025-04-17 07:16:41,716 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (370.881 and 381.973 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (77.07) is better than Ligand B (30.29). For CNS targets, TPSA should be <=90, both are within range, but A is closer to the ideal.

**logP:** Ligand A (1.18) is within the optimal 1-3 range. Ligand B (4.616) is slightly high, potentially leading to solubility issues and off-target interactions.

**H-Bond Donors/Acceptors:** Ligand A has 3 HBD and 6 HBA, both acceptable. Ligand B has 0 HBD and 5 HBA, also acceptable.

**QED:** Both ligands have good QED scores (0.596 and 0.6), indicating good drug-like properties.

**DILI:** Ligand A (44.63) has a slightly higher DILI risk than Ligand B (33.501), but both are below the concerning threshold of 60.

**BBB:** Both ligands have similar BBB penetration (45.444 and 48.895), which is not ideal for a CNS target (aim for >70). However, this is not a deciding factor between the two.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.007 and -5.061), which is unusual and suggests poor permeability. This is a significant concern for both.

**Aqueous Solubility:** Both ligands have negative solubility values (-2.291 and -4.536), indicating very poor aqueous solubility. This is a major drawback.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.886 and 0.919), which is good.

**Microsomal Clearance:** Ligand A (-5.246) has a negative clearance, indicating very high metabolic stability, which is excellent. Ligand B (88.65) has a high clearance, suggesting rapid metabolism.

**In vitro Half-Life:** Ligand A (18.689) has a shorter half-life than Ligand B (49.809), but both are reasonable.

**P-gp Efflux:** Ligand A (0.058) has very low P-gp efflux, which is highly desirable for CNS penetration. Ligand B (0.792) has moderate P-gp efflux.

**Binding Affinity:** Ligand A (-7.6 kcal/mol) has a slightly better binding affinity than Ligand B (-7.3 kcal/mol). While the difference is not huge, it's enough to consider, especially given the other factors.

**Overall Assessment:**

Ligand A is the better candidate. Although both have poor solubility and permeability, Ligand A has significantly better metabolic stability (lower Cl_mic, negative value is excellent), lower P-gp efflux (crucial for CNS penetration), and slightly better binding affinity. Ligand B's higher logP and rapid metabolism are significant drawbacks. While the BBB values are not ideal for either, the other advantages of Ligand A make it the more promising starting point for optimization.

Output:
0
2025-04-17 07:16:41,716 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (352.475 and 350.503 Da) fall comfortably within the ideal 200-500 Da range.

**TPSA:** Ligand A (70.08) is better than Ligand B (67.43). Both are below the 90 A^2 threshold desirable for CNS targets, indicating good potential for brain penetration.

**logP:** Ligand A (1.41) is within the optimal range (1-3), while Ligand B (2.951) is approaching the upper limit. This suggests Ligand A might have a slight advantage in terms of solubility and reduced off-target interactions.

**H-Bond Donors/Acceptors:** Ligand A has 1 HBD and 4 HBA, while Ligand B has 2 HBD and 3 HBA. Both are within acceptable limits (<=5 HBD and <=10 HBA).

**QED:** Ligand A (0.812) has a significantly better QED score than Ligand B (0.694), indicating a more drug-like profile.

**DILI:** Ligand A (15.2) has a much lower DILI risk than Ligand B (28.887), which is a significant advantage.

**BBB:** Ligand B (73.517) has a substantially better BBB penetration percentile than Ligand A (56.65). This is a crucial factor for a CNS target like DRD2.

**Caco-2 Permeability:** Ligand A (-4.282) and Ligand B (-4.773) both have negative Caco-2 permeability values, which is unusual and suggests poor intestinal absorption. However, for a CNS target, this is less critical than BBB penetration.

**Aqueous Solubility:** Ligand A (-1.225) and Ligand B (-2.813) both have negative solubility values, which is also concerning.

**hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.197 and 0.286, respectively).

**Microsomal Clearance:** Ligand A (25.719) has a lower microsomal clearance than Ligand B (67.772), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (24.64) has a significantly longer in vitro half-life than Ligand B (-0.619).

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.115 and 0.12, respectively).

**Binding Affinity:** Ligand B (-9.0 kcal/mol) has a significantly stronger binding affinity than Ligand A (-7.9 kcal/mol). This is a substantial advantage, potentially outweighing some of the ADME drawbacks.

**Overall Assessment:**

Ligand B has a significantly better binding affinity and BBB penetration, which are the most critical factors for a CNS GPCR target. While Ligand A has better QED, DILI, metabolic stability, and half-life, the substantial difference in binding affinity and BBB penetration of Ligand B is likely to be more impactful. The lower solubility of both compounds is a concern, but can be addressed through formulation strategies.

Output:
1
2025-04-17 07:16:41,716 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (365.396 and 367.921 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (72.88) is better than Ligand B (47.36). Both are below 90, which is favorable for CNS penetration.

**logP:** Ligand A (0.915) is slightly lower than ideal (1-3), but acceptable. Ligand B (3.798) is closer to the optimal range.

**H-Bond Donors:** Ligand A (2) is preferable to Ligand B (0). A small number of HBDs is generally good for permeability.

**H-Bond Acceptors:** Both ligands have 4 HBA, which is within the acceptable limit of <=10.

**QED:** Both ligands have similar QED values (0.711 and 0.702), indicating good drug-likeness.

**DILI:** Ligand A (18.069) has a slightly higher DILI risk than Ligand B (16.092), but both are below the concerning threshold of 40.

**BBB:** Ligand B (87.631) has a significantly higher BBB percentile than Ligand A (67.701). This is a crucial advantage for a CNS target like DRD2.

**Caco-2 Permeability:** Ligand A (-4.982) has worse Caco-2 permeability than Ligand B (-4.662). Both are negative, indicating poor permeability, but B is slightly better.

**Aqueous Solubility:** Ligand A (-0.501) has slightly better solubility than Ligand B (-2.874), but both are poor.

**hERG Inhibition:** Ligand A (0.421) has a lower hERG inhibition liability than Ligand B (0.661), which is favorable.

**Microsomal Clearance:** Ligand A (-17.94) has a much lower (better) microsomal clearance than Ligand B (77.685). This indicates greater metabolic stability for Ligand A.

**In vitro Half-Life:** Ligand A (-34.47) has a longer in vitro half-life than Ligand B (16.213). This is a significant advantage.

**P-gp Efflux:** Ligand A (0.026) has a much lower P-gp efflux liability than Ligand B (0.685). Lower P-gp efflux is highly desirable for CNS penetration.

**Binding Affinity:** Ligand B (-7.0) has a significantly stronger binding affinity than Ligand A (0.0). This is a major advantage, and can often outweigh minor ADME deficiencies.

**Overall Assessment:**

Ligand B has a superior BBB score and binding affinity, which are the most important factors for a CNS GPCR target like DRD2. While Ligand A has better metabolic stability, lower P-gp efflux, and lower hERG risk, the substantial difference in binding affinity and BBB penetration of Ligand B outweighs these benefits. The slightly higher logP of Ligand B is also favorable.

Output:
1
2025-04-17 07:16:41,716 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (365.455 and 356.394 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (80.23) is better than Ligand B (84.94). Both are below the 90 A^2 threshold for CNS targets, but A is closer to the ideal.

**3. logP:** Ligand A (1.455) is within the optimal range of 1-3. Ligand B (0.279) is slightly low, potentially hindering permeation.

**4. H-Bond Donors:** Both ligands have 1 HBD, which is acceptable.

**5. H-Bond Acceptors:** Ligand A has 6 HBA, and Ligand B has 5. Both are within the acceptable range of <=10.

**6. QED:** Ligand A (0.857) has a significantly better QED score than Ligand B (0.663), indicating better overall drug-likeness.

**7. DILI:** Ligand A (49.128) has a slightly higher DILI risk than Ligand B (29.43), but both are below the concerning threshold of 60.

**8. BBB:** Ligand B (87.67) has a substantially better BBB penetration percentile than Ligand A (68.127). This is a critical factor for a CNS target like DRD2.

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 values, which is unusual and suggests poor permeability. However, the scale is not specified, so it's difficult to interpret.

**10. Aqueous Solubility:** Both ligands have negative solubility values, which is also unusual and suggests poor solubility. Again, the scale is not specified.

**11. hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.244 and 0.226).

**12. Microsomal Clearance:** Ligand A (18.89) has a lower microsomal clearance than Ligand B (19.662), suggesting better metabolic stability.

**13. In vitro Half-Life:** Ligand B (-8.786) has a negative half-life, which is not physically possible and likely indicates an issue with the data. Ligand A (36.688) has a reasonable half-life.

**14. P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.174 and 0.019).

**15. Binding Affinity:** Ligand B (-7.6 kcal/mol) has a slightly better binding affinity than Ligand A (-8.0 kcal/mol). However, the difference is small.

**Overall Assessment:**

Ligand B excels in BBB penetration, which is paramount for a CNS target. However, its QED is lower, and it has a problematic negative in vitro half-life. Ligand A has a better QED, more reasonable half-life, and better TPSA, but its BBB penetration is lower. The slightly better affinity of Ligand B is not enough to overcome its other drawbacks. Given the importance of BBB for CNS drug development, and the questionable half-life of Ligand B, Ligand A appears to be the more viable candidate.

Output:
1
2025-04-17 07:16:41,716 - INFO - Okay, let's analyze these two ligands for their potential as DRD2 drug candidates. DRD2 is a GPCR in the CNS, so BBB penetration, logP, Pgp efflux, TPSA, and binding affinity are key.

**Ligand A:** [343.402, 52.65, 1.232, 1, 3, 0.791, 36.06, 78.635, -4.41, -2.38, 0.352, 0.284, -3.15, 0.036, -8.4]
**Ligand B:** [362.499, 83.98, 2.442, 2, 5, 0.814, 41.024, 61.923, -5.043, -3.472, 0.191, 29.39, 29.211, 0.121, -8.4]

**Step-by-step comparison:**

1. **MW:** Both are within the ideal range (200-500 Da). A (343.4) is slightly preferred due to being a bit lower.
2. **TPSA:** A (52.65) is excellent for CNS penetration (well below 90). B (83.98) is still reasonable but less optimal.
3. **logP:** A (1.232) is good, within the 1-3 range. B (2.442) is also acceptable, but trending towards the higher end.
4. **HBD:** Both A (1) and B (2) are within the acceptable limit of 5.
5. **HBA:** A (3) and B (5) are both within the acceptable limit of 10.
6. **QED:** Both are good (A: 0.791, B: 0.814), indicating drug-like properties.
7. **DILI:** Both are reasonably low risk (A: 36.06, B: 41.024), below the 40 threshold.
8. **BBB:** A (78.635) is very good, exceeding the 70% threshold for CNS targets. B (61.923) is lower, which is a significant drawback.
9. **Caco-2:** A (-4.41) and B (-5.043) are both negative, indicating poor permeability. This is concerning for both, but less critical for CNS drugs where BBB is prioritized.
10. **Solubility:** Both are very poor (-2.38 and -3.472). This is a major concern for both compounds and would require formulation strategies.
11. **hERG:** Both are very low risk (A: 0.352, B: 0.191).
12. **Cl_mic:** A (0.284) is much better (lower clearance) than B (29.39), suggesting better metabolic stability.
13. **t1/2:** A (-3.15) is better than B (29.211), indicating a longer half-life.
14. **Pgp:** A (0.036) is much lower (less efflux) than B (0.121), which is crucial for CNS penetration.
15. **Affinity:** Both have the same binding affinity (-8.4 kcal/mol), which is excellent.

**Overall Assessment:**

Ligand A is significantly better. While both have poor solubility and Caco-2 permeability, the superior BBB penetration (78.6% vs 61.9%), lower Pgp efflux, and much better metabolic stability (lower Cl_mic, longer t1/2) of Ligand A make it a far more promising candidate for a CNS-targeting drug like a DRD2 modulator. The similar binding affinity removes that as a differentiating factor. The lower TPSA of Ligand A also contributes to its favorability.

Output:
1
2025-04-17 07:16:41,717 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (346.39 and 353.46 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (110.28) is higher than Ligand B (87.74). For CNS targets, TPSA should be <= 90. Ligand B is preferable here.

**logP:** Ligand A (0.718) is slightly higher than Ligand B (0.54). Both are a bit low, potentially hindering permeation, but within an acceptable range.

**H-Bond Donors:** Both have 2 HBD, which is good.

**H-Bond Acceptors:** Ligand A has 6 HBA, and Ligand B has 4. Both are within the acceptable limit of <=10.

**QED:** Both ligands have similar QED values (0.704 and 0.699), indicating good drug-likeness.

**DILI:** Ligand A (64.37) has a higher DILI risk than Ligand B (8.10). This is a significant advantage for Ligand B.

**BBB:** Both ligands have reasonable BBB penetration (Ligand A: 56.61, Ligand B: 59.64). However, >70 is desirable for CNS targets. Neither is optimal, but they are comparable.

**Caco-2:** Both have negative Caco-2 values (-4.886 and -4.857), which is unusual and suggests poor permeability. This is a concern for both.

**Solubility:** Both have negative solubility values (-2.232 and -1.712), indicating very poor aqueous solubility. This is a significant drawback for both, potentially hindering bioavailability.

**hERG:** Ligand A (0.031) has a slightly higher hERG risk than Ligand B (0.158), but both are very low risk.

**Microsomal Clearance:** Ligand A (27.02) has higher microsomal clearance than Ligand B (8.788), meaning it's less metabolically stable. Ligand B is preferable.

**In vitro Half-Life:** Ligand A (8.232) has a longer half-life than Ligand B (-4.83). This is a positive for Ligand A.

**P-gp Efflux:** Ligand A (0.005) has very low P-gp efflux, which is excellent for CNS penetration. Ligand B (0.004) is also very low, and the difference is negligible.

**Binding Affinity:** Ligand A (-8.4 kcal/mol) has a significantly stronger binding affinity than Ligand B (-7.4 kcal/mol). This 1.0 kcal/mol difference is substantial and can outweigh some ADME drawbacks.

**Overall Assessment:**

While both compounds have issues with solubility and Caco-2 permeability, Ligand A's superior binding affinity (-8.4 vs -7.4 kcal/mol) and lower P-gp efflux, coupled with a longer half-life, make it the more promising candidate. The lower DILI risk of Ligand B is attractive, but the substantial affinity difference of Ligand A is a critical advantage for a GPCR target. The slightly higher TPSA of Ligand A is a minor concern compared to the affinity benefit.

Output:
1
2025-04-17 07:16:41,717 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (343.43 and 360.48 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (65.72) is better than Ligand B (76.14). Both are below the 90 A^2 threshold for CNS targets, but A is closer to optimal.

**logP:** Ligand A (3.55) is slightly higher than Ligand B (2.94), both within the optimal 1-3 range.

**H-Bond Donors:** Ligand A (0) is preferable to Ligand B (2). Fewer HBDs generally improve permeability.

**H-Bond Acceptors:** Both ligands have 6 HBA, which is acceptable (<=10).

**QED:** Both ligands have similar QED values (0.798 and 0.757), indicating good drug-likeness.

**DILI:** Ligand B (53.74) has a lower DILI risk than Ligand A (60.92), making it slightly more favorable.

**BBB:** Both ligands have excellent BBB penetration (78.75 and 81.50), exceeding the desirable >70 threshold for CNS targets.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values, which is unusual and suggests a potential issue with the data or modeling. However, the values are similar (-4.999 and -4.782).

**Aqueous Solubility:** Both ligands have negative solubility values, which is also unusual. Again, the values are similar (-4.474 and -3.867).

**hERG Inhibition:** Ligand A (0.378) shows a lower hERG inhibition risk than Ligand B (0.72), which is a significant advantage.

**Microsomal Clearance:** Ligand B (70.38) has lower microsomal clearance than Ligand A (97.18), indicating better metabolic stability.

**In vitro Half-Life:** Ligand B (31.56) has a significantly longer half-life than Ligand A (-9.33), which is a major advantage.

**P-gp Efflux:** Ligand A (0.512) has lower P-gp efflux than Ligand B (0.074), which is highly desirable for CNS penetration.

**Binding Affinity:** Ligand B (-8.4 kcal/mol) has a significantly stronger binding affinity than Ligand A (-0.0 kcal/mol). This is a crucial factor, as a >1.5 kcal/mol advantage can outweigh other drawbacks.

**Overall Assessment:**

Ligand B has a much stronger binding affinity, better metabolic stability (lower Cl_mic, longer t1/2), and lower DILI risk. While Ligand A has better hERG and P-gp properties, the substantial difference in binding affinity and metabolic profile of Ligand B outweighs these advantages. The negative Caco-2 and solubility values are concerning for both, but the affinity difference is so large that it is likely to be the dominant factor.

Output:
1
2025-04-17 07:16:41,717 - INFO - Batch 351 complete. Total preferences: 5616
2025-04-17 07:16:41,717 - INFO - Processing batch 352/512...
2025-04-17 07:17:23,944 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (358.36 and 353.507 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (61.8) is significantly better than Ligand B (70.67). For CNS targets, we want TPSA <= 90, and ideally closer to 60. Ligand A is much closer to the ideal range.

**3. logP:** Both ligands have good logP values (2.671 and 1.566), falling within the optimal 1-3 range. Ligand A is slightly better.

**4. H-Bond Donors:** Both have 2 HBD, which is acceptable (<=5).

**5. H-Bond Acceptors:** Ligand A has 3 HBA, and Ligand B has 4. Both are within the acceptable range (<=10).

**6. QED:** Ligand A (0.87) has a much better QED score than Ligand B (0.462). A score >= 0.5 is desired, and Ligand A is excellent.

**7. DILI:** Ligand A (20.9) has a significantly lower DILI risk than Ligand B (5.584). Both are good (<40), but A is preferable.

**8. BBB:** Ligand A (81.504) has a much better BBB penetration percentile than Ligand B (67.623). For a CNS target like DRD2, >70 is highly desirable, and A is closer to this threshold.

**9. Caco-2:** Both have negative Caco-2 values (-4.509 and -4.829), which is unusual and suggests poor permeability. This is a significant drawback for both.

**10. Solubility:** Both have negative solubility values (-3.046 and -1.219), indicating poor aqueous solubility. This is also a significant drawback for both.

**11. hERG:** Both ligands have low hERG inhibition liability (0.702 and 0.331), which is good.

**12. Cl_mic:** Ligand A (13.095) has a lower microsomal clearance than Ligand B (33.15), indicating better metabolic stability.

**13. t1/2:** Ligand A (-11.147) has a longer in vitro half-life than Ligand B (-21.305), which is preferable.

**14. Pgp:** Both ligands have very low Pgp efflux liability (0.081 and 0.006). This is excellent for CNS penetration.

**15. Binding Affinity:** Ligand A (-8.9 kcal/mol) has a significantly stronger binding affinity than Ligand B (-7.2 kcal/mol). This is a crucial factor, and the 1.7 kcal/mol difference is substantial.

**Overall Assessment:**

Ligand A is superior to Ligand B across most key parameters, especially regarding CNS penetration (BBB, TPSA, Pgp), metabolic stability (Cl_mic, t1/2), drug-likeness (QED), and binding affinity. While both have poor Caco-2 and solubility, the strong affinity and favorable CNS properties of Ligand A outweigh these drawbacks. The significantly better binding affinity is a major advantage.

Output:
1
2025-04-17 07:17:23,944 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (343.431 Da) is slightly lower, which could be beneficial for permeability. Ligand B (384.523 Da) is also acceptable.

**TPSA:** Both ligands have TPSA values (81.07 and 82.78) that are reasonably good for CNS penetration, being below the 90 A^2 threshold.

**logP:** Both ligands have optimal logP values (2.548 and 1.805) falling within the 1-3 range. Ligand B's logP is slightly lower, which might slightly improve solubility but could potentially impact permeability.

**H-Bond Donors/Acceptors:** Both ligands have 2 HBD and 5/6 HBA, which are within acceptable limits.

**QED:** Both ligands have good QED scores (0.897 and 0.806), indicating good drug-like properties.

**DILI:** Ligand A has a DILI risk of 62.737, placing it in the moderate risk category. Ligand B has a lower DILI risk (45.25), which is preferable.

**BBB:** Ligand A shows excellent BBB penetration (79.721), which is highly desirable for a CNS target like DRD2. Ligand B's BBB penetration (36.216) is significantly lower and a major drawback.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values, which is unusual and suggests a potential issue with the data or modeling. However, we can still compare them relatively. Ligand A (-4.88) is slightly better than Ligand B (-5.163).

**Aqueous Solubility:** Both ligands have negative solubility values, which is also unusual. Ligand A (-4.089) is slightly better than Ligand B (-3.438).

**hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.442 and 0.167).

**Microsomal Clearance:** Ligand B has a significantly lower microsomal clearance (23.872) than Ligand A (75.515), indicating better metabolic stability.

**In vitro Half-Life:** Ligand B has a longer in vitro half-life (10.306 hours) than Ligand A (35.518 hours). This seems counterintuitive given the clearance data, and may be an error in the provided data.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.242 and 0.038).

**Binding Affinity:** Ligand B has a significantly stronger binding affinity (-7.6 kcal/mol) compared to Ligand A (-10.2 kcal/mol). This is a substantial difference and a major advantage for Ligand B.

**Overall Assessment:**

While Ligand A has excellent BBB penetration, the significantly stronger binding affinity of Ligand B (-7.6 vs -10.2 kcal/mol) outweighs the lower BBB score. The lower DILI risk and improved metabolic stability (lower Cl_mic) of Ligand B are also beneficial. The unusual negative Caco-2 and solubility values are concerning, but the affinity difference is substantial enough to prioritize Ligand B.

Output:
1
2025-04-17 07:17:23,944 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (351.378 and 354.447 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (93.89) is excellent, falling well below the 90 A^2 threshold for CNS targets. Ligand B (110.1) is still reasonable, but less optimal, exceeding the 90 A^2 threshold.

**3. logP:** Ligand A (0.544) is a bit low, potentially hindering permeation. Ligand B (-0.22) is even lower, raising concerns about membrane permeability.

**4. H-Bond Donors:** Ligand A (2) is good. Ligand B (4) is acceptable, but closer to the upper limit.

**5. H-Bond Acceptors:** Both ligands (A: 5, B: 5) are good, well below the 10 limit.

**6. QED:** Ligand A (0.597) is better than Ligand B (0.482), indicating a more drug-like profile.

**7. DILI:** Ligand A (63.009) has a higher DILI risk than Ligand B (14.308), which is a significant concern.

**8. BBB:** Ligand A (78.868) has a good BBB percentile, desirable for a CNS target. Ligand B (23.187) is very poor for CNS penetration.

**9. Caco-2:** Both ligands have negative Caco-2 values (-5.037 and -5.214), which is unusual and suggests poor intestinal absorption. This is a red flag for both.

**10. Solubility:** Both ligands have negative solubility values (-2.269 and -1.165), indicating poor aqueous solubility. This is also a concern.

**11. hERG:** Both ligands have low hERG inhibition liability (0.544 and 0.183), which is positive.

**12. Cl_mic:** Ligand A (2.648) has a lower (better) microsomal clearance than Ligand B (0.606), suggesting greater metabolic stability.

**13. t1/2:** Ligand A (-9.277) has a negative in vitro half-life, which is not physically possible and indicates an issue with the data or prediction method. Ligand B (13.569) has a reasonable half-life.

**14. Pgp:** Ligand A (0.021) has very low P-gp efflux, which is excellent for CNS exposure. Ligand B (0.008) also has very low P-gp efflux.

**15. Binding Affinity:** Ligand A (-8.4 kcal/mol) has a significantly stronger binding affinity than Ligand B (-7.8 kcal/mol). This is a substantial advantage.

**Overall Assessment:**

Despite Ligand A's higher DILI risk and the impossible half-life value, its superior BBB penetration, lower Cl_mic, significantly stronger binding affinity, and lower Pgp efflux make it the more promising candidate. The negative Caco-2 and solubility values are concerning for both, but can potentially be addressed through formulation strategies. The negative half-life for Ligand A is a major data quality issue, but the other factors still lean towards it being preferable. Ligand B's poor BBB penetration is a deal-breaker for a CNS target like DRD2.

Output:
1
2025-04-17 07:17:23,944 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B based on the provided guidelines, prioritizing GPCR-specific properties (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (351.403 Da) is slightly better, being closer to the lower end which can aid permeability.

**TPSA:** Ligand A (89.13) is excellent for CNS penetration, being well below 90. Ligand B (117.17) is still acceptable but less ideal.

**logP:** Ligand A (-0.12) is a bit low, potentially hindering permeation. Ligand B (1.737) is within the optimal range (1-3). This is a significant advantage for Ligand B.

**H-Bond Donors/Acceptors:** Both ligands have reasonable HBD (2/3) and HBA (6/6) counts, falling within the acceptable ranges.

**QED:** Ligand A (0.645) has a better QED score than Ligand B (0.471), indicating a more drug-like profile.

**DILI:** Ligand A (31.524) has a much lower DILI risk than Ligand B (94.765). This is a substantial advantage for Ligand A.

**BBB:** Ligand A (60.799) has a moderate BBB penetration, while Ligand B (24.079) is poor. For a CNS target like DRD2, this is a critical difference favoring Ligand A.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values, which is unusual and suggests potential issues with permeability assessment. However, the absolute value is larger for Ligand A (-5.038 vs -5.774), potentially indicating slightly better permeability.

**Aqueous Solubility:** Both ligands have negative solubility values, which is also unusual. The absolute value is larger for Ligand B (-3.676 vs -1.508), suggesting it may have slightly lower solubility.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.211 and 0.499 respectively).

**Microsomal Clearance:** Ligand A (-0.5) has significantly lower microsomal clearance, suggesting better metabolic stability than Ligand B (13.557).

**In vitro Half-Life:** Ligand A (-27.081) has a much longer in vitro half-life than Ligand B (34.38).

**P-gp Efflux:** Ligand A (0.005) has very low P-gp efflux, which is favorable for CNS exposure. Ligand B (0.094) is also low, but higher than A.

**Binding Affinity:** Ligand B (-9.5 kcal/mol) has a stronger binding affinity than Ligand A (-7.5 kcal/mol). This is a 2 kcal/mol difference, which is substantial and could potentially outweigh some ADME drawbacks.

**Overall Assessment:**

Ligand A excels in crucial CNS-related properties: BBB penetration, DILI risk, metabolic stability (low Cl_mic and long t1/2), and P-gp efflux. While its logP is suboptimal, its overall profile is more balanced for a CNS-targeting drug. Ligand B's primary advantage is its superior binding affinity, but it suffers from poor BBB penetration, high DILI risk, and poorer metabolic stability. Given the importance of CNS penetration for DRD2, and the significant differences in DILI and metabolic stability, Ligand A is the more promising candidate. The 2 kcal/mol difference in binding affinity, while significant, is less critical than the ADME properties in this context.

Output:
0
2025-04-17 07:17:23,944 - INFO - Reasoning:

Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (344.46 & 348.44 Da) fall comfortably within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (64.68) is significantly better than Ligand B (68.82). Both are below the 90 A^2 threshold desirable for CNS targets, but A is closer to optimal.

**3. logP:** Ligand A (3.569) is within the optimal 1-3 range. Ligand B (1.766) is a bit low, potentially hindering membrane permeability.

**4. H-Bond Donors:** Both ligands have 2 HBD, which is acceptable.

**5. H-Bond Acceptors:** Ligand A has 2 HBA, while Ligand B has 6. Ligand A is preferable here, as higher HBA can sometimes negatively impact permeability.

**6. QED:** Both ligands have reasonable QED values (0.877 and 0.732), indicating good drug-like properties.

**7. DILI:** Ligand A (39.434) has a slightly higher DILI risk than Ligand B (27.995), but both are below the concerning 60 percentile.

**8. BBB:** This is critical for a CNS target. Ligand A (69.794) is significantly better than Ligand B (59.364). Ligand A is close to the desirable >70 percentile, while B is further away.

**9. Caco-2:** Ligand A (-4.717) and Ligand B (-5.067) both have negative Caco-2 values, which is unusual and suggests poor permeability. This is a significant drawback for both.

**10. Solubility:** Ligand A (-3.759) and Ligand B (-2.04) both have negative solubility values, indicating poor aqueous solubility. This is a concern for bioavailability.

**11. hERG:** Both ligands have low hERG risk (0.737 and 0.801).

**12. Cl_mic:** Ligand A (19.504) has lower microsomal clearance than Ligand B (24.232), suggesting better metabolic stability.

**13. t1/2:** Ligand A (29.868) has a longer in vitro half-life than Ligand B (-3.192). This is a significant advantage.

**14. Pgp:** Both ligands have very low Pgp efflux liability (0.107 and 0.094).

**15. Binding Affinity:** Ligand A (-8.1 kcal/mol) has a slightly better binding affinity than Ligand B (-7.8 kcal/mol). While the difference is not huge, it's a positive factor.

**Overall Assessment:**

Considering the GPCR-specific priorities, Ligand A is the more promising candidate. It has better TPSA, logP, BBB penetration, metabolic stability (lower Cl_mic, longer t1/2), and binding affinity. While both have poor Caco-2 and solubility, the superior BBB and affinity of Ligand A outweigh these drawbacks, especially for a CNS target like DRD2.

Output:
1
2025-04-17 07:17:23,944 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (385.869 Da) is slightly higher than Ligand B (352.435 Da), but both are acceptable.

**TPSA:** Ligand A (77.88) is better than Ligand B (106.78). For CNS targets, we want TPSA <= 90, so Ligand A is closer to the ideal.

**logP:** Ligand A (3.38) is optimal (1-3), while Ligand B (1.296) is at the lower end of the range and could potentially have permeability issues.

**H-Bond Donors/Acceptors:** Ligand A (HBD=1, HBA=7) and Ligand B (HBD=2, HBA=6) both fall within acceptable limits.

**QED:** Both ligands have good QED values (A: 0.526, B: 0.649), indicating drug-like properties.

**DILI:** Ligand A (71.423) has a higher DILI risk than Ligand B (58.976), but both are still reasonably low.

**BBB:** Ligand B (67.546) has a significantly better BBB penetration percentile than Ligand A (46.375). This is a crucial factor for a CNS target like DRD2.

**Caco-2 Permeability:** Ligand A (-4.7) has better Caco-2 permeability than Ligand B (-5.114), although both are negative values which is unusual and suggests poor permeability.

**Aqueous Solubility:** Ligand A (-3.962) has slightly better aqueous solubility than Ligand B (-2.152), but both are poor.

**hERG Inhibition:** Both ligands have very low hERG inhibition risk (A: 0.307, B: 0.327).

**Microsomal Clearance:** Ligand B (30.413) has significantly lower microsomal clearance than Ligand A (65.629), indicating better metabolic stability.

**In vitro Half-Life:** Ligand A (50.75) has a longer in vitro half-life than Ligand B (5.728), which is desirable.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (A: 0.579, B: 0.034), with Ligand B being slightly better.

**Binding Affinity:** Ligand A (-7.8 kcal/mol) has a significantly stronger binding affinity than Ligand B (-6.5 kcal/mol). This is a substantial advantage.

**Overall Assessment:**

While Ligand B has a better BBB score and lower clearance, Ligand A's significantly stronger binding affinity (-7.8 vs -6.5 kcal/mol) is a major advantage, and outweighs the slightly worse BBB and clearance. The better TPSA and logP of Ligand A also contribute to its favorability. The poor solubility and Caco-2 permeability of both are concerning, but can potentially be addressed through formulation strategies. Given the importance of affinity for GPCR ligands, and the fact that the difference in affinity is >1.5 kcal/mol, Ligand A is the more promising candidate.

Output:
1
2025-04-17 07:17:23,945 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 drug candidates, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (347.503 and 339.395 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (43.86) is significantly better than Ligand B (62.74). For CNS targets, we want TPSA <= 90, both are under this threshold, but A is much closer to the optimal range.

**logP:** Both ligands have good logP values (1.968 and 1.178) within the 1-3 range.

**H-Bond Donors/Acceptors:** Both have acceptable HBD (0) and HBA (3 and 4 respectively) counts, well within the guidelines.

**QED:** Both ligands have similar QED scores (0.784 and 0.776), indicating good drug-likeness.

**DILI:** Ligand A (5.894) has a much lower DILI risk than Ligand B (31.679), which is a significant advantage.

**BBB:** This is critical for a CNS target. Ligand A has a very good BBB percentile (84.064), while Ligand B is considerably lower (43.893).

**Caco-2 Permeability:** Ligand A (-4.694) and Ligand B (-4.33) are both negative, indicating poor permeability. This is a concern for both, but not a deciding factor.

**Aqueous Solubility:** Both ligands have poor aqueous solubility (-1.331 and -2.608 respectively). This could pose formulation challenges.

**hERG Inhibition:** Ligand A (0.662) has a slightly higher hERG risk than Ligand B (0.207), but both are relatively low.

**Microsomal Clearance:** Both ligands have similar microsomal clearance (24.356 and 23.715 mL/min/kg), suggesting comparable metabolic stability.

**In vitro Half-Life:** Ligand A (-2.405) has a much longer in vitro half-life than Ligand B (-14.327). This is a significant advantage.

**P-gp Efflux:** Ligand A (0.075) has a lower P-gp efflux liability than Ligand B (0.025), meaning it's less likely to be pumped out of the brain, improving CNS exposure.

**Binding Affinity:** Ligand B (-8.2 kcal/mol) has a significantly stronger binding affinity than Ligand A (0.0 kcal/mol). This is a substantial advantage, potentially outweighing some of the ADME drawbacks.

**Overall Assessment:**

While Ligand B boasts a superior binding affinity, Ligand A has a much more favorable ADME profile, particularly regarding BBB penetration, DILI risk, and in vitro half-life. For a CNS target like DRD2, good brain penetration is paramount. The substantial difference in BBB (84.064 vs 43.893) and the lower DILI risk for Ligand A are compelling. The difference in binding affinity is significant, but not insurmountable, and could potentially be improved through further optimization of Ligand A. Given the GPCR-specific priorities, the better ADME profile of Ligand A is more crucial.

Output:
1
2025-04-17 07:17:23,945 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (362.455 and 355.435 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (96.6) is excellent, falling well below the 90 A^2 threshold for CNS targets. Ligand B (116.76) is higher but still reasonable, though less optimal.

**3. logP:** Ligand A (0.81) is slightly below the optimal 1-3 range, potentially impacting permeability. Ligand B (-0.546) is even lower, raising concerns about membrane penetration.

**4. H-Bond Donors:** Ligand A (1) is good. Ligand B (4) is higher, potentially impacting permeability.

**5. H-Bond Acceptors:** Both ligands (A: 5, B: 5) are within the acceptable limit of 10.

**6. QED:** Ligand A (0.802) is excellent, indicating high drug-likeness. Ligand B (0.414) is below the 0.5 threshold, suggesting a less favorable drug-like profile.

**7. DILI:** Ligand A (47.964) has a low DILI risk. Ligand B (17.449) also has a low DILI risk, but is slightly higher than A.

**8. BBB:** Ligand A (62.699) has a moderate BBB penetration, but is below the desirable >70% for CNS targets. Ligand B (53.548) is even lower, making CNS penetration a significant concern.

**9. Caco-2:** Both ligands have negative Caco-2 values (-5.22 and -5.482), which is unusual and likely indicates poor permeability. This is a significant red flag for both compounds.

**10. Solubility:** Both ligands have negative solubility values (-2.12 and -1.253), which is also unusual and indicates poor aqueous solubility.

**11. hERG:** Both ligands have very low hERG inhibition risk (0.132 and 0.056).

**12. Cl_mic:** Ligand A (-8.199) has a negative clearance, which is not physically possible and likely an error in the data. Ligand B (13.467) has a moderate clearance.

**13. t1/2:** Ligand A (-10.237) has a negative half-life, which is not physically possible. Ligand B (2.138) has a very short half-life.

**14. Pgp:** Both ligands have very low Pgp efflux liability (0.061 and 0.003).

**15. Binding Affinity:** Ligand B (-7.9) has a slightly better binding affinity than Ligand A (-7.7). However, the difference is small (0.2 kcal/mol) and may not be enough to overcome the other significant drawbacks.

**Overall Assessment:**

Both compounds have serious issues with Caco-2 permeability, aqueous solubility, and in vitro half-life. The negative values for clearance and half-life for Ligand A are particularly concerning and suggest data errors. While Ligand B has slightly better affinity, its lower QED, lower BBB penetration, and short half-life make it less attractive. Given the data quality issues with Ligand A, and the slightly better (though still problematic) profile of Ligand B, I would cautiously favor Ligand B *only* if the negative values for Ligand A can be verified or corrected. However, both compounds require substantial optimization.

Output:
1
2025-04-17 07:17:23,945 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (340.427 and 350.419 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (70.39) is significantly better than Ligand B (87.91). For CNS targets, TPSA < 90 is preferred, and A is closer to the optimal <60 range. B is pushing the upper limit.

**3. logP:** Ligand A (3.01) is optimal (1-3). Ligand B (0.636) is low, potentially hindering permeation.

**4. H-Bond Donors:** Ligand A (2) and Ligand B (1) are both acceptable (<=5).

**5. H-Bond Acceptors:** Ligand A (4) and Ligand B (6) are both acceptable (<=10).

**6. QED:** Both ligands have good QED scores (A: 0.902, B: 0.776), indicating good drug-like properties.

**7. DILI:** Ligand A (63.203) has a higher DILI risk than Ligand B (29.934). This is a drawback for A.

**8. BBB:** Both ligands have comparable BBB penetration (A: 68.282, B: 67.623). While not exceeding 70, they are reasonably good for CNS targets.

**9. Caco-2:** Both ligands have negative Caco-2 values, which is unusual and suggests a potential issue with the data or modeling. However, we can't reliably compare based on this.

**10. Solubility:** Both ligands have negative solubility values, again suggesting a potential issue with the data.

**11. hERG:** Ligand A (0.633) has a slightly higher hERG risk than Ligand B (0.187), but both are relatively low.

**12. Cl_mic:** Ligand A (46.223) has a much lower (better) microsomal clearance than Ligand B (9.711), indicating greater metabolic stability.

**13. t1/2:** Ligand A (36.462) has a longer in vitro half-life than Ligand B (8.624), which is desirable.

**14. Pgp:** Ligand A (0.196) has a lower P-gp efflux liability than Ligand B (0.03), which is beneficial for CNS exposure.

**15. Binding Affinity:** Ligand A (-8.1 kcal/mol) has a significantly stronger binding affinity than Ligand B (-7.5 kcal/mol). This >1.5 kcal/mol difference is substantial and can outweigh some ADME drawbacks.

**Overall Assessment:**

Ligand A is the stronger candidate. While it has a slightly higher DILI risk, its superior TPSA, logP, metabolic stability (Cl_mic, t1/2), Pgp efflux, and *significantly* better binding affinity outweigh this concern. The lower logP of Ligand B is a significant disadvantage for CNS penetration, and its higher Pgp efflux and lower metabolic stability are also unfavorable. The negative solubility and Caco-2 values are concerning for both, but the other properties of A make it the better choice.

Output:
1
2025-04-17 07:17:23,945 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (362.539 and 348.487 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Both ligands have TPSA values (49.41 and 49.85) below the 90 Angstroms threshold for CNS targets, which is good.

**3. logP:** Both ligands have logP values (2.839 and 2.895) within the optimal 1-3 range.

**4. H-Bond Donors:** Ligand A has 1 HBD, while Ligand B has 0. Both are acceptable (<=5).

**5. H-Bond Acceptors:** Both ligands have 3 HBA, which is well within the acceptable limit of <=10.

**6. QED:** Ligand A (0.765) has a better QED score than Ligand B (0.475), indicating a more drug-like profile.

**7. DILI:** Ligand A (16.014%) has a significantly lower DILI risk than Ligand B (17.836%). Both are good, but A is preferable.

**8. BBB:** Ligand B (92.827%) has a substantially higher BBB penetration percentile than Ligand A (80.264%). This is a *critical* advantage for a CNS target like DRD2.

**9. Caco-2 Permeability:** Ligand A (-5.168) has worse Caco-2 permeability than Ligand B (-4.684).

**10. Aqueous Solubility:** Ligand A (-3.564) has worse aqueous solubility than Ligand B (-1.912).

**11. hERG Inhibition:** Both ligands have low hERG inhibition risk (0.494 and 0.678, respectively).

**12. Microsomal Clearance:** Ligand A (51.866) has a lower microsomal clearance than Ligand B (63.647), suggesting better metabolic stability.

**13. In vitro Half-Life:** Ligand B (-8.118) has a slightly better in vitro half-life than Ligand A (-7.596).

**14. P-gp Efflux:** Ligand A (0.145) has significantly lower P-gp efflux liability than Ligand B (0.458). Lower P-gp efflux is highly desirable for CNS penetration.

**15. Binding Affinity:** Ligand B (-8.118 kcal/mol) has a stronger binding affinity than Ligand A (-7.596 kcal/mol). This is a 0.522 kcal/mol difference, which is significant and can outweigh some ADME drawbacks.

**Overall Assessment:**

Ligand B excels in BBB penetration and binding affinity, two crucial factors for a DRD2 ligand. While Ligand A has advantages in QED, DILI, microsomal clearance, and P-gp efflux, the superior BBB and binding affinity of Ligand B are more important for this CNS GPCR target. The slightly better half-life of B is a bonus. The solubility and Caco-2 permeability are not ideal for either, but the stronger binding and better CNS penetration of B make it the more promising candidate.

Output:
1
2025-04-17 07:17:23,945 - INFO - Reasoning:

Let's analyze Ligand A and Ligand B against the provided guidelines, prioritizing GPCR-specific properties (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (399.705 Da) is slightly higher than Ligand B (345.487 Da), but both are acceptable.

**TPSA:** Ligand A (50.36) is better than Ligand B (64.41). For CNS targets, TPSA should be <= 90, both are well within this range, but A is preferable.

**logP:** Ligand A (4.705) is a bit high, potentially leading to solubility issues or off-target effects. Ligand B (2.812) is within the optimal range (1-3). This favors Ligand B.

**H-Bond Donors/Acceptors:** Ligand A has 2 HBD and 3 HBA, while Ligand B has 0 HBD and 3 HBA. Both are within acceptable limits.

**QED:** Both ligands have similar QED values (A: 0.766, B: 0.679), indicating good drug-likeness.

**DILI:** Ligand A (65.491) has a higher DILI risk than Ligand B (18.418). This is a significant advantage for Ligand B.

**BBB:** Both ligands have excellent BBB penetration (A: 74.796, B: 78.984), exceeding the desirable threshold of >70. Ligand B is slightly better.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values, which is unusual and suggests poor permeability. This is a concern for both.

**Aqueous Solubility:** Both ligands have very poor aqueous solubility (A: -5.43, B: -3.093). This is a major drawback for both.

**hERG Inhibition:** Ligand A (0.825) has a slightly higher hERG risk than Ligand B (0.609), but both are relatively low.

**Microsomal Clearance:** Ligand B (58.325) has lower microsomal clearance than Ligand A (26.632), indicating better metabolic stability. This favors Ligand B.

**In vitro Half-Life:** Ligand B (-9.981) has a negative half-life, which is not physically possible and suggests an issue with the data or the molecule's stability. Ligand A (65.435) has a reasonable half-life. This is a significant concern for Ligand B.

**P-gp Efflux:** Ligand A (0.43) has lower P-gp efflux than Ligand B (0.384), meaning it's less likely to be pumped out of the brain, which is good for CNS penetration.

**Binding Affinity:** Ligand A (-10.5 kcal/mol) has significantly stronger binding affinity than Ligand B (-7.7 kcal/mol). This is a substantial advantage for Ligand A, potentially outweighing some of its ADME drawbacks.

**Overall Assessment:**

Despite Ligand A's higher logP and DILI risk, its *much* stronger binding affinity (-10.5 vs -7.7 kcal/mol) is a critical advantage for a GPCR target. The difference of 2.8 kcal/mol is substantial and likely to translate to greater efficacy. While both have poor solubility and Caco-2 permeability, the strong binding of A may compensate. The negative half-life for Ligand B is a major red flag.

Output:
1
2025-04-17 07:17:23,945 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (337.423 Da) is slightly preferred due to being closer to the lower end, potentially aiding permeability.

**TPSA:** Ligand A (48.31) is excellent for CNS penetration, well below the 90 A^2 threshold. Ligand B (67.43) is still reasonable, but less optimal.

**logP:** Both ligands have logP values around 3.4, which is within the optimal range (1-3). No significant difference here.

**H-Bond Donors/Acceptors:** Ligand A has 1 HBD and 5 HBA, while Ligand B has 2 HBD and 3 HBA. Both are within acceptable limits (<=5 HBD and <=10 HBA).

**QED:** Both ligands have good QED scores (0.685 and 0.706), indicating good drug-like properties.

**DILI:** Both ligands have acceptable DILI risk (Ligand A: 40.403, Ligand B: 48.158), below the 60 threshold.

**BBB:** This is a critical parameter for CNS targets. Ligand A has a BBB percentile of 57.968, while Ligand B has 74.952. Ligand B is significantly better in terms of predicted BBB penetration.

**Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and suggests poor permeability. However, the scale is not specified, so it's hard to interpret.

**Aqueous Solubility:** Both have negative solubility values, which is also unusual. Again, the scale is not specified.

**hERG Inhibition:** Ligand A (0.922) has a slightly higher hERG risk than Ligand B (0.328), but both are relatively low.

**Microsomal Clearance:** Ligand A (38.377) has a lower microsomal clearance than Ligand B (93.424), indicating better metabolic stability.

**In vitro Half-Life:** Ligand A (-33.482) has a much longer in vitro half-life than Ligand B (9.871). This is a significant advantage.

**P-gp Efflux:** Ligand A (0.573) has lower P-gp efflux liability than Ligand B (0.332), which is favorable for CNS exposure.

**Binding Affinity:** Ligand B (-9.5 kcal/mol) has a substantially stronger binding affinity than Ligand A (-8.7 kcal/mol). This difference of 0.8 kcal/mol is significant and could outweigh some of the ADME drawbacks of Ligand B.

**Overall Assessment:**

Ligand B excels in BBB penetration and binding affinity, the two most crucial factors for a CNS GPCR target like DRD2. While Ligand A has better metabolic stability and P-gp efflux, the superior affinity and BBB score of Ligand B are more important. The unusual negative values for Caco-2 and solubility are concerning for both, but the binding affinity advantage of Ligand B is substantial.

Output:
1
2025-04-17 07:17:23,945 - INFO - Reasoning:

Let's analyze Ligand A and Ligand B based on the provided guidelines, prioritizing GPCR-specific properties (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (348.355 and 347.415 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (111.49) is slightly higher than Ligand B (102.68). Both are below the 140 A^2 threshold for oral absorption, but for a CNS target like DRD2, we ideally want <90 A^2. Ligand B is closer to this target.

**logP:** Ligand A (2.398) is within the optimal 1-3 range. Ligand B (1.28) is at the lower end, potentially impacting permeability.

**H-Bond Donors/Acceptors:** Ligand A has 1 HBD and 7 HBA, while Ligand B has 3 HBD and 5 HBA. Both are within acceptable limits.

**QED:** Both ligands have good QED scores (0.604 and 0.719, respectively), indicating drug-like properties.

**DILI:** Ligand A (88.057) has a higher DILI risk than Ligand B (60.45). While both are not ideal, Ligand B is preferable.

**BBB:** This is a critical parameter for CNS targets. Ligand A has a BBB percentile of 57.736, while Ligand B has 64.599. Ligand B is better, but both are below the desirable >70 threshold.

**Caco-2 Permeability:** Ligand A (-4.653) and Ligand B (-5.241) both have negative values, indicating poor permeability.

**Aqueous Solubility:** Both ligands have very poor aqueous solubility (-3.245 and -2.263 respectively). This could present formulation challenges.

**hERG Inhibition:** Ligand A (0.099) has a slightly lower hERG risk than Ligand B (0.387), which is favorable.

**Microsomal Clearance:** Ligand A (106.579) has a higher microsomal clearance than Ligand B (-26.375). This suggests Ligand B is more metabolically stable.

**In vitro Half-Life:** Ligand B (9.629 hours) has a significantly longer half-life than Ligand A (-41.377 hours). This is a major advantage for dosing frequency.

**P-gp Efflux:** Ligand A (0.174) has lower P-gp efflux liability than Ligand B (0.016), which is better for CNS exposure.

**Binding Affinity:** Ligand B (-7.8 kcal/mol) has a slightly better binding affinity than Ligand A (-7.6 kcal/mol). While the difference is small, it's still a positive factor.

**Overall Assessment:**

Considering the GPCR-specific priorities, Ligand B appears to be the better candidate. While its logP is lower, its superior BBB penetration, significantly better metabolic stability (lower Cl_mic and longer t1/2), and slightly better binding affinity outweigh the drawbacks. The lower DILI risk is also a plus. Ligand A has a slight edge in P-gp efflux and hERG, but the metabolic and CNS penetration advantages of Ligand B are more critical for a DRD2 targeting drug.

Output:
1
2025-04-17 07:17:23,946 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (386.21 and 379.848 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Both ligands (80.32 and 81.91) are below the 90 A^2 threshold for CNS targets, which is excellent.

**3. logP:** Ligand A (3.953) is slightly higher than Ligand B (2.539), but both are within the optimal 1-3 range. Ligand B is closer to the lower end, which *could* indicate potential permeability issues, but isn't a major concern.

**4. H-Bond Donors:** Ligand A (2) and Ligand B (1) both meet the <=5 criteria.

**5. H-Bond Acceptors:** Ligand A (4) and Ligand B (6) both meet the <=10 criteria.

**6. QED:** Both ligands have good QED scores (0.763 and 0.825), indicating good drug-like properties.

**7. DILI:** Ligand A (85.77) has a higher DILI risk than Ligand B (74.99). This is a negative for Ligand A.

**8. BBB:** Ligand B (71.268) has a better BBB penetration percentile than Ligand A (61.535). This is a significant advantage for Ligand B, given that DRD2 is a CNS target.

**9. Caco-2 Permeability:** Ligand A (-4.472) has significantly worse Caco-2 permeability than Ligand B (-5.098). Both are negative values, but Ligand A is less negative, indicating slightly better permeability.

**10. Aqueous Solubility:** Ligand A (-5.021) has slightly better aqueous solubility than Ligand B (-4.728).

**11. hERG Inhibition:** Ligand A (0.363) has a lower hERG inhibition risk than Ligand B (0.711), which is favorable.

**12. Microsomal Clearance:** Ligand B (20.098) has significantly lower microsomal clearance than Ligand A (78.123), suggesting better metabolic stability. This is a strong advantage for Ligand B.

**13. In vitro Half-Life:** Ligand B (-3.871) has a much longer in vitro half-life than Ligand A (73.843). This is a major advantage for Ligand B.

**14. P-gp Efflux:** Ligand A (0.127) has lower P-gp efflux than Ligand B (0.167), which is favorable for CNS penetration.

**15. Binding Affinity:** Ligand B (-9.0 kcal/mol) has a significantly stronger binding affinity than Ligand A (-8.3 kcal/mol). This is a substantial advantage for Ligand B, potentially outweighing some of the minor ADME drawbacks.

**Overall Assessment:**

Ligand B is the stronger candidate. While Ligand A has slightly better hERG and P-gp profiles, Ligand B excels in the most critical areas for a CNS-targeting GPCR ligand: BBB penetration, metabolic stability (low Cl_mic, long t1/2), and binding affinity. The DILI risk for Ligand B is also lower. The difference in binding affinity (-9.0 vs -8.3) is substantial and likely to be a key driver of efficacy.

Output:
1
2025-04-17 07:17:23,946 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (371.459 Da) is slightly lower, which could be beneficial for permeability. Ligand B (404.363 Da) is also good.

**TPSA:** Ligand A (103.86) is better than Ligand B (47.36) as it's closer to the ideal range for CNS targets (<90). Ligand B's TPSA is relatively high and could hinder BBB penetration.

**logP:** Ligand A (-0.852) is a bit low, potentially impacting membrane permeability. Ligand B (4.636) is significantly higher, potentially causing solubility issues and off-target interactions, although it aids in membrane permeability.

**H-Bond Donors/Acceptors:** Ligand A has 1 HBD and 5 HBA, while Ligand B has 0 HBD and 5 HBA. Both are within acceptable limits.

**QED:** Both ligands have acceptable QED values (A: 0.678, B: 0.573), indicating reasonable drug-likeness.

**DILI:** Ligand A (35.712) has a lower DILI risk than Ligand B (47.732), which is preferable.

**BBB:** Ligand B (71.229) has a better BBB percentile than Ligand A (65.801), which is a crucial factor for CNS targets like DRD2. However, the difference is not massive.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.266 and -5.021), which is unusual and suggests poor permeability. This is a significant concern for both.

**Aqueous Solubility:** Both ligands have negative solubility values (-1.808 and -3.635), which is also concerning and suggests poor solubility.

**hERG Inhibition:** Ligand A (0.029) has a very low hERG risk, which is excellent. Ligand B (0.693) has a higher, but still relatively low, hERG risk.

**Microsomal Clearance:** Ligand A (-3.579) has a lower (better) microsomal clearance than Ligand B (71.94), indicating better metabolic stability.

**In vitro Half-Life:** Ligand B (77.62) has a much longer in vitro half-life than Ligand A (14.028), which is a significant advantage.

**P-gp Efflux:** Ligand A (0.011) has a very low P-gp efflux liability, which is excellent for CNS penetration. Ligand B (0.851) has higher P-gp efflux, which is less desirable.

**Binding Affinity:** Both ligands have similar and good binding affinities (-7.6 kcal/mol and -7.4 kcal/mol). The difference of 0.2 kcal/mol is not substantial enough to be a deciding factor.

**Overall Assessment:**

Ligand A has better TPSA, DILI, hERG, microsomal clearance, and P-gp efflux. Ligand B has a better BBB and in vitro half-life. Both have poor Caco-2 permeability and solubility. Given the importance of BBB penetration for a CNS target like DRD2, Ligand B initially seems more promising. However, Ligand A's superior safety profile (DILI, hERG) and metabolic stability (Cl_mic) are also very important. The poor permeability and solubility of both are major drawbacks that would need to be addressed through formulation or further chemical modification. Considering the balance, Ligand A's better ADME properties (especially safety and metabolic stability) and only slightly lower BBB, combined with comparable affinity, make it the more viable candidate.

Output:
0
2025-04-17 07:17:23,946 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (355.5 and 343.3 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (52.65) is significantly better than Ligand B (59.32). For CNS targets, we want TPSA <= 90, and ideally closer to 60. Ligand A is much closer to the ideal range.

**logP:** Both ligands have acceptable logP values (2.211 and 3.834), falling within the 1-3 range. Ligand B is slightly higher, which *could* indicate potential off-target effects, but isn't a major concern.

**H-Bond Donors/Acceptors:** Ligand A has 1 HBD and 3 HBA, while Ligand B has 0 HBD and 4 HBA. Both are within acceptable limits (<=5 HBD and <=10 HBA).

**QED:** Both ligands have similar QED values (0.762 and 0.792), indicating good drug-like properties.

**DILI:** Ligand A (14.541) has a much lower DILI risk than Ligand B (65.529). This is a significant advantage for Ligand A.

**BBB:** Ligand A (91.974) has a substantially better BBB penetration prediction than Ligand B (84.374). This is *critical* for a CNS target like DRD2. A value >70 is desirable, and Ligand A exceeds that.

**Caco-2 Permeability:** Ligand A (-4.638) has poorer Caco-2 permeability than Ligand B (-3.846), but both are negative values, indicating low permeability. This is a potential drawback for both, but less critical than BBB for a CNS target.

**Aqueous Solubility:** Ligand A (-2.291) has better aqueous solubility than Ligand B (-5.293). Solubility is important for formulation.

**hERG:** Both ligands have low hERG inhibition risk (0.892 and 0.71).

**Microsomal Clearance:** Ligand B (83.581) has a significantly higher microsomal clearance than Ligand A (8.743), suggesting Ligand A is more metabolically stable.

**In vitro Half-Life:** Ligand A (-16.144) has a much longer in vitro half-life than Ligand B (12.758). This is a significant advantage.

**P-gp Efflux:** Ligand A (0.229) has lower P-gp efflux liability than Ligand B (0.321), which is favorable for CNS penetration.

**Binding Affinity:** Ligand B (-9.4) has a slightly better binding affinity than Ligand A (-8.2). This is a 1.2 kcal/mol difference, which is significant, but needs to be weighed against the other factors.

**Overall Assessment:**

Ligand A is superior due to its significantly better BBB penetration, lower DILI risk, improved metabolic stability (lower Cl_mic, longer t1/2), lower P-gp efflux, and better solubility. While Ligand B has slightly better binding affinity, the ADME/Tox profile of Ligand A is far more favorable, especially for a CNS-targeting drug. The difference in affinity (1.2 kcal/mol) is unlikely to outweigh the substantial improvements in drug-like properties offered by Ligand A.

Output:
0
2025-04-17 07:17:23,946 - INFO - Batch 352 complete. Total preferences: 5632
2025-04-17 07:17:23,946 - INFO - Processing batch 353/512...
2025-04-17 07:18:04,752 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (374.409 and 364.427 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (84.5) is excellent, falling well below the 90 A^2 threshold for CNS targets. Ligand B (101.91) is still reasonable but less optimal, being closer to the 140 A^2 threshold for oral absorption.

**3. logP:** Both ligands have good logP values (2.113 and 1.228), falling within the optimal 1-3 range. Ligand A is slightly better.

**4. H-Bond Donors:** Both have 2 HBD, which is within the acceptable limit of <=5.

**5. H-Bond Acceptors:** Ligand A has 5 HBA, and Ligand B has 7. Both are within the acceptable limit of <=10, but Ligand A is slightly better.

**6. QED:** Both ligands have good QED scores (0.539 and 0.818), indicating drug-like properties. Ligand B is better here.

**7. DILI:** Both ligands have relatively high DILI risk (61.574 and 67.119). This is a concern, but not a deal-breaker at this stage.

**8. BBB:** Ligand A (66.925) has a significantly better BBB penetration percentile than Ligand B (45.56). This is *critical* for a CNS target like DRD2.

**9. Caco-2 Permeability:** Ligand A (-4.849) has better Caco-2 permeability than Ligand B (-4.738), suggesting better intestinal absorption.

**10. Aqueous Solubility:** Ligand A (-3.526) has better aqueous solubility than Ligand B (-2.623).

**11. hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.463 and 0.141).

**12. Microsomal Clearance:** Ligand B (5.723) has significantly lower microsomal clearance than Ligand A (64.633), indicating better metabolic stability.

**13. In vitro Half-Life:** Ligand B (28.168) has a longer in vitro half-life than Ligand A (23.741).

**14. P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.115 and 0.092).

**15. Binding Affinity:** Both ligands have the same binding affinity (-8.4 kcal/mol), which is excellent.

**Overall Assessment:**

While Ligand B has a better QED, lower Cl_mic, and longer t1/2, the *critical* advantage of Ligand A is its significantly higher predicted BBB penetration (66.925 vs 45.56). For a CNS target like DRD2, this is paramount. The slightly better TPSA and solubility of Ligand A also contribute to its favorability. The DILI risk is a concern for both, but can be addressed in later optimization stages. Given the equal binding affinity, the improved CNS penetration profile of Ligand A makes it the more promising candidate.

Output:
0
2025-04-17 07:18:04,752 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (348.418 and 348.443 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (66.48) is significantly better than Ligand B (87.66). For CNS targets, TPSA should be <= 90, and A is comfortably within this range, while B is approaching the upper limit. This favors A.

**3. logP:** Both ligands have good logP values (1.623 and 1.362), falling within the optimal 1-3 range.

**4. H-Bond Donors:** Ligand A (1) is better than Ligand B (3). Lower HBD generally improves permeability.

**5. H-Bond Acceptors:** Ligand A (3) is better than Ligand B (4). Lower HBA generally improves permeability.

**6. QED:** Both ligands have acceptable QED values (0.606 and 0.694), indicating good drug-like properties.

**7. DILI:** Ligand A (32.803) has a slightly higher DILI risk than Ligand B (22.955), but both are below the 40 threshold, indicating low risk.

**8. BBB:** This is a critical parameter for CNS targets. Ligand A (92.943) has a *much* higher BBB penetration percentile than Ligand B (31.873). This is a major advantage for A.

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.021 and -5.015), which is unusual and suggests poor permeability. However, these values are very close, so this is not a major differentiator.

**10. Aqueous Solubility:** Both ligands have negative solubility values (-2.767 and -2.429), indicating poor solubility. Again, these are very similar.

**11. hERG Inhibition:** Both ligands have low hERG inhibition risk (0.124 and 0.247).

**12. Microsomal Clearance:** Ligand A (18.098) has lower microsomal clearance than Ligand B (36.38), suggesting better metabolic stability.

**13. In vitro Half-Life:** Ligand A (-35.758) has a negative half-life, which is concerning. Ligand B (18.066) has a positive half-life, indicating better in vitro stability. This favors B.

**14. P-gp Efflux:** Both ligands have low P-gp efflux liability (0.211 and 0.045).

**15. Binding Affinity:** Both ligands have the same binding affinity (-8.0 kcal/mol), so this parameter does not differentiate them.

**Overall Assessment:**

Ligand A is significantly better due to its superior TPSA, lower HBD/HBA, and *much* higher predicted BBB penetration. While Ligand A has a concerning negative in vitro half-life, the importance of BBB penetration for a CNS target like DRD2 outweighs this concern, particularly given the similar binding affinities. The slightly higher DILI risk for A is not a major concern as both are well below the threshold.

Output:
1
2025-04-17 07:18:04,752 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (353.354 and 348.531 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (107.37) is better than Ligand B (41.57). For CNS targets, we want TPSA <= 90, and Ligand A is closer to this threshold. Ligand B is excellent.

**logP:** Ligand A (-0.851) is suboptimal, being below the preferred 1-3 range. Ligand B (2.92) is within the optimal range. This is a significant advantage for Ligand B.

**H-Bond Donors/Acceptors:** Ligand A (2 HBD, 7 HBA) is acceptable. Ligand B (1 HBD, 3 HBA) is also acceptable and slightly better.

**QED:** Both ligands have good QED scores (0.714 and 0.802), indicating good drug-like properties.

**DILI:** Ligand A (66.964) has a higher DILI risk than Ligand B (19.426). This favors Ligand B.

**BBB:** Both ligands have good BBB penetration (77.627 and 85.033), exceeding the 70% threshold for CNS targets. Ligand B is slightly better.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values, which is unusual and suggests poor permeability. However, the scale is not specified, so it's difficult to interpret.

**Aqueous Solubility:** Both ligands have negative solubility values, which is also unusual. Again, the scale is not specified, making interpretation difficult.

**hERG:** Ligand A (0.031) has a very low hERG risk, which is excellent. Ligand B (0.746) is higher, representing a moderate risk. This is a point in favor of Ligand A.

**Microsomal Clearance:** Ligand A (-5.514) has a negative clearance, which is not physically possible. This is likely an error in the data. Ligand B (61.101) has a higher clearance, indicating faster metabolism. This favors Ligand A *if* the value is correct.

**In vitro Half-Life:** Ligand A (38.036) has a reasonable half-life. Ligand B (19.858) has a shorter half-life. This favors Ligand A.

**P-gp Efflux:** Ligand A (0.013) has very low P-gp efflux, which is excellent for CNS penetration. Ligand B (0.316) has a higher, but still relatively low, P-gp efflux. This strongly favors Ligand A.

**Binding Affinity:** Both ligands have excellent binding affinities (-7.8 and -8.0 kcal/mol). Ligand B is slightly better, but the difference is small.

**Overall Assessment:**

Considering the GPCR-specific priorities, Ligand A is the better candidate. While Ligand B has a better logP, Ligand A excels in BBB penetration, P-gp efflux, and hERG inhibition. The negative clearance value for Ligand A is concerning, but assuming it's a data error, the other properties make it more promising. The slightly better affinity of Ligand B is unlikely to outweigh the superior ADME properties of Ligand A, especially for a CNS target like DRD2.

Output:
0
2025-04-17 07:18:04,752 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (353.491 and 388.49 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (36.44) is excellent, well below the 90 A^2 threshold for CNS targets. Ligand B (103.95) is higher, but still potentially acceptable, though less ideal.

**logP:** Ligand A (3.539) is at the upper end of the optimal range (1-3), while Ligand B (2.222) is closer to the lower end. Both are acceptable, but A's higher logP might aid BBB penetration.

**H-Bond Donors/Acceptors:** Ligand A (0 HBD, 4 HBA) and Ligand B (3 HBD, 5 HBA) both have reasonable numbers of H-bond donors and acceptors, falling within the recommended limits.

**QED:** Ligand A (0.775) has a better QED score than Ligand B (0.573), indicating a more drug-like profile.

**DILI:** Ligand B (83.792) has a significantly higher DILI risk than Ligand A (61.07). This is a substantial negative for Ligand B.

**BBB:** Ligand A (85.847) has a much higher BBB penetration percentile than Ligand B (43.815). This is *critical* for a CNS target like DRD2.

**Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and requires further investigation. However, the magnitude of negativity is similar.

**Aqueous Solubility:** Both ligands have negative solubility values, which is also unusual. Again, the magnitudes are similar.

**hERG:** Both ligands have low hERG inhibition liability (0.793 and 0.632 respectively).

**Microsomal Clearance:** Ligand A (59.762) has higher microsomal clearance than Ligand B (46.708), suggesting lower metabolic stability.

**In vitro Half-Life:** Ligand B (1.776) has a shorter in vitro half-life than Ligand A (-8.355), which is a negative.

**P-gp Efflux:** Ligand A (0.603) has slightly lower P-gp efflux liability than Ligand B (0.302), which is favorable.

**Binding Affinity:** Both ligands have very similar and excellent binding affinities (-9.1 and -8.4 kcal/mol). The difference of 0.7 kcal/mol is not substantial enough to override other factors.

**Conclusion:**

Considering the GPCR-specific priorities, Ligand A is the better candidate. Its superior BBB penetration, lower DILI risk, and better QED score outweigh the slightly higher microsomal clearance. While both have unusual solubility and Caco-2 values, the other factors strongly favor Ligand A for development as a DRD2-targeting drug.

Output:
1
2025-04-17 07:18:04,752 - INFO - Here's a step-by-step reasoning for choosing between Ligand A and Ligand B as a drug candidate for DRD2, followed by the final output:

**Step-by-step comparison:**

1. **MW:** Both ligands (356.813 and 346.431 Da) fall within the ideal 200-500 Da range. No clear advantage here.

2. **TPSA:** Both ligands (68.21 and 68.88) are below the 90 A^2 threshold desirable for CNS targets, indicating good potential for brain penetration. Very similar.

3. **logP:** Ligand A (3.491) is optimal (1-3), while Ligand B (0.418) is quite low, potentially hindering membrane permeability. This is a significant advantage for Ligand A.

4. **HBD:** Ligand A (0) is excellent, minimizing potential issues with hydrogen bonding and maximizing permeability. Ligand B (1) is acceptable, but less ideal.

5. **HBA:** Ligand A (6) is within the acceptable range. Ligand B (4) is also good.

6. **QED:** Both ligands have good QED scores (0.515 and 0.727), indicating generally drug-like properties. Ligand B is slightly better.

7. **DILI:** Ligand A (82.319) has a higher DILI risk than Ligand B (19.426). This is a significant drawback for Ligand A.

8. **BBB:** Ligand A (65.297) has a better BBB percentile than Ligand B (55.176), which is important for a CNS target like DRD2.

9. **Caco-2:** Ligand A (-4.543) is worse than Ligand B (-5.304), suggesting lower intestinal absorption.

10. **Solubility:** Ligand A (-4.02) is worse than Ligand B (-1.083), which could pose formulation challenges.

11. **hERG:** Both ligands have very low hERG inhibition risk (0.445 and 0.227). No significant difference.

12. **Cl_mic:** Ligand A (119.652) has higher microsomal clearance than Ligand B (-10.905), indicating lower metabolic stability. This is a disadvantage for Ligand A.

13. **t1/2:** Ligand A (72.011) has a longer in vitro half-life than Ligand B (0.683). This is a significant advantage for Ligand A.

14. **Pgp:** Ligand A (0.106) has lower P-gp efflux liability than Ligand B (0.01), which is favorable for CNS penetration.

15. **Binding Affinity:** Ligand B (-8.0 kcal/mol) has a slightly better binding affinity than Ligand A (-7.6 kcal/mol). While the difference is not huge, it's still a factor.

**GPCR-Specific Considerations:**

For a GPCR like DRD2, BBB penetration, logP, Pgp efflux, TPSA, and binding affinity are crucial. Ligand A has better BBB and Pgp properties, and a reasonable TPSA and logP. Ligand B has a better binding affinity and QED, but a significantly lower logP and higher DILI risk. The lower logP of Ligand B is a major concern for CNS penetration.

**Overall Assessment:**

While Ligand A has drawbacks in DILI risk, Caco-2 permeability, and solubility, its superior logP, BBB, Pgp, and half-life properties are more critical for a CNS-targeting GPCR. The slightly better binding affinity of Ligand B is not enough to overcome the permeability issues.

Output:
1
2025-04-17 07:18:04,753 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (344.46 and 347.42 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (66.4) is significantly better than Ligand B (105.12). For CNS targets, we want TPSA <= 90, and A is comfortably within this range, while B exceeds it.

**logP:** Ligand A (2.347) is optimal (1-3), while Ligand B (-0.33) is below 1, which could hinder permeation.

**H-Bond Donors/Acceptors:** Ligand A (0 HBD, 4 HBA) is preferable. Ligand B has 3 HBD and 5 HBA, which is acceptable but less ideal.

**QED:** Both ligands have reasonable QED scores (0.794 and 0.628), indicating good drug-like properties.

**DILI:** Ligand A (31.49) has a much lower DILI risk than Ligand B (47.62), both are below the 60 threshold, but A is clearly better.

**BBB:** Ligand A (86.82) has a significantly better BBB penetration percentile than Ligand B (65.37). For CNS targets, >70 is desirable, and A is closer to that target.

**Caco-2 Permeability:** Ligand A (-4.82) is better than Ligand B (-5.408), higher values are better.

**Aqueous Solubility:** Ligand A (-2.283) is better than Ligand B (-1.918), higher values are better.

**hERG:** Both ligands have very low hERG inhibition risk (0.371 and 0.135).

**Microsomal Clearance:** Ligand A (39.04) has higher clearance than Ligand B (3.72), meaning B is more metabolically stable.

**In vitro Half-Life:** Ligand A (-12.669) has a negative half-life, which is not possible, and indicates a problem with the data. Ligand B (29.77) has a reasonable half-life.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.329 and 0.028).

**Binding Affinity:** Both ligands have similar, strong binding affinities (-8.4 and -8.9 kcal/mol). The difference is negligible.

**Overall Assessment:**

Considering the GPCR-specific priorities, Ligand A is the stronger candidate. Its superior TPSA, logP, BBB penetration, and lower DILI risk outweigh the slightly higher microsomal clearance. The negative half-life for Ligand A is a major red flag, and while the binding affinity is similar, the other ADME properties of Ligand A are more favorable for CNS penetration and reduced toxicity.

Output:
1
2025-04-17 07:18:04,753 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (362.496 and 348.403 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (41.13) is excellent, well below the 90 Angstroms threshold for CNS targets. Ligand B (103.53) is higher, but still potentially acceptable, though less ideal.

**3. logP:** Ligand A (3.27) is optimal (1-3). Ligand B (0.736) is quite low, potentially hindering membrane permeability and CNS penetration.

**4. H-Bond Donors:** Ligand A (2) and Ligand B (3) are both within the acceptable limit of <=5.

**5. H-Bond Acceptors:** Ligand A (1) and Ligand B (4) are both within the acceptable limit of <=10.

**6. QED:** Both ligands have reasonable QED values (0.761 and 0.66), indicating good drug-like properties.

**7. DILI:** Ligand A (53.936) has a lower DILI risk than Ligand B (50.33), both are good.

**8. BBB:** Ligand A (70.26) has a good BBB penetration percentile, exceeding the desirable >70% threshold for CNS targets. Ligand B (58.976) is significantly lower, raising concerns about CNS exposure.

**9. Caco-2 Permeability:** Ligand A (-4.59) and Ligand B (-5.063) both have negative values, indicating poor permeability.

**10. Aqueous Solubility:** Ligand A (-5.071) and Ligand B (-2.301) both have negative values, indicating poor solubility.

**11. hERG Inhibition:** Ligand A (0.902) has a lower hERG inhibition risk than Ligand B (0.168).

**12. Microsomal Clearance:** Ligand A (75.334) has a higher (worse) microsomal clearance than Ligand B (1.099), suggesting faster metabolism.

**13. In vitro Half-Life:** Ligand A (60.895) has a longer half-life than Ligand B (-21.888), which is a positive attribute.

**14. P-gp Efflux:** Ligand A (0.582) has a lower P-gp efflux liability than Ligand B (0.021), which is favorable for CNS penetration.

**15. Binding Affinity:** Ligand B (-8.2 kcal/mol) has a significantly stronger binding affinity than Ligand A (0.0 kcal/mol). This is a substantial advantage.

**Overall Assessment:**

Ligand B has a much stronger binding affinity, which is a crucial factor for GPCR ligands. However, its low logP and lower BBB penetration are significant drawbacks. Ligand A has better ADME properties, particularly logP and BBB, but its binding affinity is very weak.

Considering the GPCR-specific priorities, the strong affinity of Ligand B is compelling. While the lower logP and BBB are concerns, these could potentially be addressed through further structural modifications. The weak affinity of Ligand A is a more difficult hurdle to overcome.

Output:
1
2025-04-17 07:18:04,753 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (344.371 and 347.375 Da) are within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (126.55) is better than Ligand B (133.14). Both are reasonably close to the 140 threshold for oral absorption, but for a CNS target, we ideally want <90. Ligand A is closer.

**3. logP:** Ligand A (-0.725) is slightly lower than optimal (1-3), potentially hindering permeation. Ligand B (0.32) is also on the lower side but better than A.

**4. H-Bond Donors:** Ligand A (3) and Ligand B (4) are both acceptable, being less than 5.

**5. H-Bond Acceptors:** Both ligands (6) are within the acceptable limit of 10.

**6. QED:** Both ligands have similar QED values (0.647 and 0.615), indicating good drug-like properties.

**7. DILI:** Ligand A (34.277) has a significantly lower DILI risk than Ligand B (69.019). This is a major advantage for Ligand A.

**8. BBB:** Both ligands have similar, relatively low BBB penetration (21.171 and 21.714). This is a concern for a CNS target like DRD2, as >70 is desirable.

**9. Caco-2:** Both have negative Caco-2 values (-5.346 and -5.53), which is unusual and suggests poor permeability. This is a significant drawback for both.

**10. Solubility:** Both have negative solubility values (-2.339 and -2.227), which is also concerning.

**11. hERG:** Both ligands have low hERG inhibition liability (0.157 and 0.132), which is good.

**12. Cl_mic:** Ligand A (-34.326) has a much lower (better) microsomal clearance than Ligand B (-4.033). This indicates greater metabolic stability for Ligand A.

**13. t1/2:** Ligand A (17.223) has a longer in vitro half-life than Ligand B (-26.525). This is a positive for Ligand A.

**14. Pgp:** Both ligands have very low Pgp efflux liability (0.003 and 0.046), which is favorable for CNS penetration.

**15. Binding Affinity:** Both ligands have similar and strong binding affinities (-8.7 and -7.9 kcal/mol). This is a key factor, and the difference isn't substantial enough to be decisive on its own.

**Overall Assessment:**

Despite the similar binding affinities, Ligand A is the more promising candidate. It has a significantly lower DILI risk, better metabolic stability (lower Cl_mic, longer t1/2), and a slightly better TPSA. While both have poor predicted Caco-2 and solubility, the lower DILI and improved metabolic properties of Ligand A outweigh the slight advantage Ligand B has in logP. The BBB penetration is a concern for both, but can potentially be addressed with further modifications.

Output:
0
2025-04-17 07:18:04,753 - INFO - Reasoning:

Let's analyze Ligand A and Ligand B based on the provided guidelines, prioritizing GPCR-specific properties (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (354.347 and 364.423 Da) fall within the ideal range of 200-500 Da.

**TPSA:** Ligand A (33.29) is excellent, well below the 90 A^2 threshold for CNS targets. Ligand B (93.73) is significantly higher, exceeding the optimal range and potentially hindering BBB penetration.

**logP:** Ligand A (4.282) is slightly high, potentially leading to solubility issues or off-target interactions, but still within a manageable range. Ligand B (1.392) is on the lower side, which could limit its ability to cross cell membranes.

**H-Bond Donors/Acceptors:** Both ligands have acceptable HBD (2) counts. Ligand B has a higher HBA count (6) compared to Ligand A (3), but both are within the acceptable limit of 10.

**QED:** Ligand A (0.787) has a good drug-likeness score, while Ligand B (0.227) is quite low, indicating a less favorable overall drug-like profile.

**DILI:** Both ligands have similar and acceptable DILI risk (65.839 and 64.327 percentile).

**BBB:** Ligand A (85.576) has a very good BBB penetration score, highly desirable for a CNS target like DRD2. Ligand B (54.517) is considerably lower, raising concerns about its ability to reach the target in the brain.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.038 and -5.115), which is unusual and difficult to interpret without further context. However, the values are very similar.

**Aqueous Solubility:** Both ligands have negative solubility values (-4.372 and -2.559), which is also unusual. Again, the values are similar.

**hERG Inhibition:** Ligand A (0.958) has a slightly higher hERG risk than Ligand B (0.201), but both are relatively low.

**Microsomal Clearance:** Both ligands have similar microsomal clearance values (24.311 and 21.457 mL/min/kg), indicating comparable metabolic stability.

**In vitro Half-Life:** Ligand A (5.635 hours) has a longer half-life than Ligand B (-11.276 hours), which is generally preferred. The negative value for Ligand B is concerning.

**P-gp Efflux:** Ligand A (0.603) has a lower P-gp efflux liability than Ligand B (0.043), which is beneficial for CNS penetration.

**Binding Affinity:** Ligand A (-9.8 kcal/mol) has a significantly stronger binding affinity than Ligand B (-7.5 kcal/mol). This >1.5 kcal/mol difference is substantial and can outweigh minor ADME drawbacks.

**Conclusion:**

Considering all factors, especially the GPCR-specific priorities, **Ligand A is the more promising drug candidate.** It has superior BBB penetration, a better QED score, a longer half-life, lower P-gp efflux, and significantly higher binding affinity. While its logP is slightly elevated, the strong affinity and favorable CNS penetration profile outweigh this concern. Ligand B's poor TPSA, low QED, and lower BBB penetration make it less attractive.



Output:
1
2025-04-17 07:18:04,754 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (354.407 and 347.415 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (126.46) is slightly above the optimal <90 for CNS targets, while Ligand B (93.46) is closer to the desired range. This gives a slight edge to Ligand B.

**logP:** Ligand A (-0.007) is quite low, potentially hindering membrane permeability. Ligand B (1.639) is within the optimal 1-3 range. This is a significant advantage for Ligand B.

**H-Bond Donors/Acceptors:** Ligand A has 3 HBD and 7 HBA, which are acceptable. Ligand B has 2 HBD and 5 HBA, also acceptable.

**QED:** Both ligands have good QED scores (0.507 and 0.551), indicating good drug-like properties.

**DILI:** Ligand A (54.634) has a slightly higher DILI risk than Ligand B (47.693), but both are reasonably low.

**BBB:** This is a critical parameter for CNS targets. Ligand A has a BBB percentile of 30.167, which is quite low. Ligand B has a much better BBB percentile of 71.811, exceeding the desirable >70 threshold. This is a major advantage for Ligand B.

**Caco-2 Permeability:** Both have negative values, indicating poor permeability. Ligand A (-5.396) is worse than Ligand B (-4.461).

**Aqueous Solubility:** Both have negative values, indicating poor solubility. Ligand A (-1.281) is slightly better than Ligand B (-3.143).

**hERG Inhibition:** Ligand A (0.049) has a very low hERG risk, while Ligand B (0.339) is slightly higher. This is a minor advantage for Ligand A.

**Microsomal Clearance:** Ligand A (28.316) has lower clearance than Ligand B (35.07), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (0.051) has a very short half-life, while Ligand B (-11.927) has a negative value, which is unusual and suggests rapid degradation or an issue with the assay.

**P-gp Efflux:** Ligand A (0.08) has lower P-gp efflux than Ligand B (0.242), which is favorable for CNS penetration.

**Binding Affinity:** Both ligands have very similar and excellent binding affinities (-7.6 and -7.5 kcal/mol). The difference is negligible.

**Overall Assessment:**

Ligand B clearly outperforms Ligand A. While Ligand A has a slightly better hERG profile and clearance, Ligand B excels in crucial areas for a CNS-targeting GPCR ligand: significantly better logP, a much higher BBB percentile, and lower P-gp efflux. The TPSA is also more favorable for Ligand B. The negative Caco-2 and solubility values are concerning for both, but the superior CNS penetration profile of Ligand B outweighs these drawbacks. The unusual negative half-life for Ligand B is a concern that would need further investigation, but the overall profile is more promising.

Output:
1
2025-04-17 07:18:04,754 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (365.861 and 348.443 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (55.85) is better than Ligand B (59.08). Both are reasonably good for CNS penetration, being below the 90 A^2 threshold, but A is closer to the optimal range.

**3. logP:** Ligand A (3.305) is within the optimal range (1-3), while Ligand B (1.207) is at the lower end, potentially hindering permeation.

**4. H-Bond Donors:** Ligand A (1) is preferable to Ligand B (0) as it provides some hydrogen bonding potential.

**5. H-Bond Acceptors:** Ligand A (6) is slightly higher than Ligand B (4), but both are within the acceptable limit of 10.

**6. QED:** Both ligands have similar QED values (0.735 and 0.649), indicating good drug-like properties.

**7. DILI:** Ligand B (22.722) has a significantly lower DILI risk than Ligand A (60.682). This is a major advantage for Ligand B.

**8. BBB:** Ligand B (77.976) has a much better BBB penetration percentile than Ligand A (59.325). This is crucial for a CNS target like DRD2.

**9. Caco-2 Permeability:** Both have negative values, indicating poor permeability. Ligand A (-4.778) is slightly worse than Ligand B (-4.692).

**10. Aqueous Solubility:** Both have negative values, indicating poor solubility. Ligand A (-3.25) is slightly worse than Ligand B (-1.658).

**11. hERG Inhibition:** Ligand A (0.735) has a slightly higher hERG inhibition risk than Ligand B (0.336), but both are reasonably low.

**12. Microsomal Clearance:** Ligand A (35.565) has lower microsomal clearance, suggesting better metabolic stability, than Ligand B (43.3).

**13. In vitro Half-Life:** Ligand A (72.068) has a significantly longer in vitro half-life than Ligand B (1.92). This is a strong advantage for Ligand A.

**14. P-gp Efflux:** Ligand A (0.172) has lower P-gp efflux liability than Ligand B (0.079), which is favorable for CNS exposure.

**15. Binding Affinity:** Ligand B (-7.9 kcal/mol) has a slightly better binding affinity than Ligand A (-7.5 kcal/mol). While the difference is not huge, it's still a positive for Ligand B.

**Overall Assessment:**

Ligand B excels in key areas for CNS drug development: BBB penetration, lower DILI risk, and slightly better binding affinity. While Ligand A has better metabolic stability (lower Cl_mic, longer t1/2) and lower P-gp efflux, the superior BBB and safety profile of Ligand B outweigh these advantages. The slightly lower logP of Ligand B is a concern, but the strong affinity and excellent BBB suggest it can still achieve sufficient brain exposure.

Output:
1
2025-04-17 07:18:04,754 - INFO - Reasoning:

Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (385.869 and 351.451 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (77.88) is better than Ligand B (80.65). Both are reasonably good for CNS penetration, being below the 90 A^2 threshold, but A is closer to the ideal.

**3. logP:** Ligand A (3.38) is optimal, while Ligand B (1.12) is a bit low, potentially hindering membrane permeability.

**4. H-Bond Donors:** Ligand A (1) is preferable to Ligand B (2). Lower HBD generally improves permeability.

**5. H-Bond Acceptors:** Ligand A (7) is preferable to Ligand B (6).

**6. QED:** Ligand B (0.803) has a higher QED score than Ligand A (0.526), suggesting a more generally drug-like profile. However, this is less critical than CNS penetration for a CNS target.

**7. DILI:** Ligand B (31.059) has a significantly lower DILI risk than Ligand A (71.423). This is a substantial advantage for Ligand B.

**8. BBB:** Ligand B (89.143) has a much higher BBB penetration percentile than Ligand A (46.375). This is *critical* for a DRD2 ligand targeting CNS disorders.

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 values, which is unusual and suggests a potential issue with the data or modeling. However, the values are similar (-4.7 and -4.837).

**10. Aqueous Solubility:** Ligand A (-3.962) has better solubility than Ligand B (-1.237).

**11. hERG Inhibition:** Both ligands have low hERG inhibition risk (0.307 and 0.411).

**12. Microsomal Clearance:** Ligand A (65.629) has higher clearance than Ligand B (7.285), meaning Ligand B is more metabolically stable.

**13. In vitro Half-Life:** Ligand B (27.488) has a longer half-life than Ligand A (50.75). This is a positive for Ligand B.

**14. P-gp Efflux:** Ligand A (0.579) has slightly lower P-gp efflux than Ligand B (0.011), which is preferable.

**15. Binding Affinity:** Ligand A (-7.8 kcal/mol) has a slightly better binding affinity than Ligand B (-7.3 kcal/mol). While a 0.5 kcal/mol difference is not huge, it's a positive for Ligand A.

**Overall Assessment:**

Despite Ligand A having slightly better affinity and solubility, Ligand B is the more promising candidate. The significantly higher BBB penetration (89.143 vs 46.375), lower DILI risk, and improved metabolic stability (lower Cl_mic and longer t1/2) outweigh the minor affinity difference. For a CNS target like DRD2, BBB penetration is paramount. The slightly lower logP of Ligand B is a concern, but the substantial BBB advantage makes it the better choice.

Output:
1
2025-04-17 07:18:04,754 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (345.355 and 350.39 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (124.69) is slightly above the preferred <90 for CNS targets, while Ligand B (78.87) is well within the optimal range. This favors Ligand B.

**logP:** Ligand A (0.566) is quite low, potentially hindering membrane permeability. Ligand B (1.459) is better, falling within the 1-3 range. This is a significant advantage for Ligand B.

**H-Bond Donors/Acceptors:** Ligand A has 4 HBD and 6 HBA, which are acceptable. Ligand B has 2 HBD and 4 HBA, also acceptable, and potentially slightly better for permeability due to fewer hydrogen bonds.

**QED:** Both ligands have similar QED values (0.628 and 0.601), indicating good drug-likeness.

**DILI:** Ligand A (56.727) has a higher DILI risk than Ligand B (35.285). This favors Ligand B.

**BBB:** Ligand B (76.619) shows significantly better BBB penetration potential than Ligand A (12.059). This is a *critical* advantage for a CNS target like DRD2.

**Caco-2 Permeability:** Ligand A (-5.863) has poor Caco-2 permeability, while Ligand B (-4.715) is slightly better, but still not ideal.

**Aqueous Solubility:** Both ligands have very poor aqueous solubility (-2.327 and -1.591). This could pose formulation challenges, but is less critical than BBB penetration for a CNS drug.

**hERG Inhibition:** Ligand A (0.095) has a slightly lower hERG risk than Ligand B (0.358), which is a minor advantage.

**Microsomal Clearance:** Ligand A (-3.496) has a more negative value, indicating lower clearance and better metabolic stability than Ligand B (3.163).

**In vitro Half-Life:** Ligand B (-17.768) has a longer in vitro half-life than Ligand A (-13.568), which is favorable.

**P-gp Efflux:** Ligand A (0.011) shows very low P-gp efflux, which is excellent. Ligand B (0.058) is also low, but slightly higher.

**Binding Affinity:** Both ligands have very similar and strong binding affinities (-8.9 and -8.1 kcal/mol). The difference of 0.8 kcal/mol is not substantial enough to outweigh the other significant differences.

**Overall Assessment:**

Ligand B is the superior candidate. While both have good binding affinity, Ligand B excels in crucial properties for a CNS-targeting GPCR ligand: significantly better BBB penetration, a lower DILI risk, and a more favorable logP. The slightly better TPSA and half-life also contribute to its advantage. The solubility issues are a concern for both, but can be addressed with formulation strategies. Ligand A's poor logP and BBB penetration are major drawbacks.

Output:
1
2025-04-17 07:18:04,754 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (337.383 and 347.365 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (107.87) is slightly above the optimal <90 for CNS targets, but still reasonable. Ligand B (63.25) is excellent, well below 90. This favors Ligand B.

**3. logP:** Both ligands have good logP values (2.01 and 3.032), falling within the 1-3 range.

**4. H-Bond Donors:** Both have acceptable HBD counts (3 and 2 respectively), below the threshold of 5.

**5. H-Bond Acceptors:** Both have acceptable HBA counts (3), below the threshold of 10.

**6. QED:** Both ligands have good QED scores (0.68 and 0.874), indicating good drug-like properties.

**7. DILI:** Both ligands have relatively high DILI risk (66.421 and 61.07), but are still within a range that isn't immediately disqualifying.

**8. BBB:** This is a critical parameter for a CNS target like DRD2. Ligand B (86.817) has a significantly higher BBB percentile than Ligand A (59.984). This is a major advantage for Ligand B.

**9. Caco-2 Permeability:** Ligand A (-5.558) has poor Caco-2 permeability, while Ligand B (-4.25) is slightly better but still not ideal.

**10. Aqueous Solubility:** Both have poor aqueous solubility (-3.828 and -3.926). This could pose formulation challenges, but isn't a dealbreaker at this stage.

**11. hERG Inhibition:** Both ligands show low hERG inhibition risk (0.491 and 0.274).

**12. Microsomal Clearance:** Ligand A (-14.092) has much lower (better) microsomal clearance than Ligand B (56.877), suggesting greater metabolic stability.

**13. In vitro Half-Life:** Ligand A (13.78) has a much longer in vitro half-life than Ligand B (-25.522). This is a significant advantage for Ligand A.

**14. P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.061 and 0.099).

**15. Binding Affinity:** Both ligands have excellent binding affinity (-9.8 and -9.7 kcal/mol), which is very strong. The difference of 0.1 kcal/mol is negligible.

**Overall Assessment:**

Ligand B excels in BBB penetration and TPSA, which are crucial for CNS GPCR targets. However, Ligand A demonstrates superior metabolic stability (lower Cl_mic) and a longer half-life. The Caco-2 permeability is poor for both, and solubility is also a concern. The affinity is comparable. Given the importance of BBB penetration for a CNS target, and the relatively small difference in affinity, Ligand B is the more promising candidate. The longer half-life of Ligand A is attractive, but can potentially be addressed through prodrug strategies.

Output:
1
2025-04-17 07:18:04,754 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (364.873 and 351.411 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (64.36) is excellent, well below the 90 A^2 threshold for CNS targets. Ligand B (126.45) is higher, but still potentially acceptable, though less ideal.

**logP:** Ligand A (4.232) is slightly high, potentially leading to solubility issues or off-target interactions. Ligand B (-0.696) is quite low, which could hinder membrane permeability and CNS penetration.

**H-Bond Donors/Acceptors:** Ligand A (HBD=1, HBA=4) is within acceptable limits. Ligand B (HBD=2, HBA=6) is also acceptable.

**QED:** Both ligands have reasonable QED values (0.832 and 0.701), indicating good drug-like properties.

**DILI:** Ligand A (57.542) has a moderate DILI risk, while Ligand B (37.611) has a lower, more favorable DILI risk.

**BBB:** Ligand A (69.407) has a good BBB percentile, desirable for a CNS target. Ligand B (56.65) is significantly lower, which is a major drawback.

**Caco-2 Permeability:** Ligand A (-4.763) has poor Caco-2 permeability, which is concerning. Ligand B (-5.637) is also poor, but slightly worse.

**Aqueous Solubility:** Ligand A (-4.802) has poor aqueous solubility, consistent with its high logP. Ligand B (-1.117) has slightly better solubility, but still not ideal.

**hERG Inhibition:** Ligand A (0.556) has a low hERG risk, which is good. Ligand B (0.017) has a very low hERG risk, even better.

**Microsomal Clearance:** Ligand A (86.661) has relatively high microsomal clearance, suggesting faster metabolism. Ligand B (-16.408) has negative clearance, which is unusual and likely an artifact of the prediction method, but suggests very high metabolic stability.

**In vitro Half-Life:** Ligand A (29.318 hours) has a reasonable half-life. Ligand B (14.286 hours) is shorter, but still potentially acceptable.

**P-gp Efflux:** Ligand A (0.287) has low P-gp efflux, which is favorable for CNS penetration. Ligand B (0.003) has extremely low P-gp efflux, even better.

**Binding Affinity:** Both ligands have excellent binding affinities (-8.7 kcal/mol and -8.0 kcal/mol). Ligand A has a slightly better affinity, but the difference is not huge.

**Overall Assessment:**

Ligand A has a better BBB score, slightly better affinity, and low P-gp efflux. However, it suffers from poor Caco-2 permeability and solubility, and moderate DILI risk. Ligand B has a lower DILI risk, extremely low P-gp efflux, and very low hERG risk. The biggest drawback for Ligand B is its poor BBB penetration and low logP.

Given the importance of BBB penetration for a CNS target like DRD2, and the relatively small difference in binding affinity, Ligand A is the more promising candidate, despite its drawbacks. The solubility and permeability issues might be addressed through formulation strategies.

Output:
0
2025-04-17 07:18:04,754 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 drug candidates, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (422.241 Da) is slightly higher than Ligand B (347.394 Da), but both are acceptable.

**TPSA:** Ligand A (46.61) is excellent for CNS penetration, well below the 90 A^2 threshold. Ligand B (87.31) is higher, but still potentially acceptable, although less ideal.

**logP:** Ligand A (3.681) is optimal. Ligand B (2.255) is a little low, potentially impacting permeability.

**H-Bond Donors/Acceptors:** Ligand A (0 HBD, 3 HBA) is favorable. Ligand B (2 HBD, 7 HBA) is also reasonable, though slightly higher counts.

**QED:** Both ligands have good QED scores (A: 0.681, B: 0.829), indicating good drug-like properties.

**DILI:** Ligand A (35.867) has a lower DILI risk than Ligand B (59.403), which is a significant advantage.

**BBB:** Ligand A (89.492) has a much better BBB penetration score than Ligand B (67.701). This is *critical* for a CNS target like DRD2.

**Caco-2 Permeability:** Ligand A (-4.523) has poor Caco-2 permeability, while Ligand B (-5.184) is also poor. This is a concern for both, but less critical given the CNS target.

**Aqueous Solubility:** Ligand A (-4.509) and Ligand B (-3.455) both have poor aqueous solubility.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (A: 0.768, B: 0.506).

**Microsomal Clearance:** Ligand A (75.373) has higher microsomal clearance than Ligand B (31.217), indicating lower metabolic stability.

**In vitro Half-Life:** Ligand B (36.388) has a much longer in vitro half-life than Ligand A (-11.113), which is a significant advantage.

**P-gp Efflux:** Ligand A (0.274) has lower P-gp efflux than Ligand B (0.067), which is favorable for CNS penetration.

**Binding Affinity:** Ligand B (-8.7 kcal/mol) has a significantly stronger binding affinity than Ligand A (-7.7 kcal/mol). This 1 kcal/mol difference is substantial and can outweigh some ADME drawbacks.

**Overall Assessment:**

While Ligand B has a superior binding affinity and better metabolic stability (longer half-life, lower Cl_mic), Ligand A has a much better BBB score and lower DILI risk. Considering DRD2 is a CNS target, BBB penetration is paramount. The stronger affinity of Ligand B is a significant plus, but the lower BBB and higher DILI risk are concerning. The P-gp efflux is also better for Ligand A. The poor Caco-2 and solubility are issues for both, but less critical for CNS drugs.

Given the importance of BBB penetration for a CNS GPCR target, and the relatively small difference in affinity, I favor Ligand A.

Output:
0
2025-04-17 07:18:04,755 - INFO - Batch 353 complete. Total preferences: 5648
2025-04-17 07:18:04,755 - INFO - Processing batch 354/512...
2025-04-17 07:18:46,090 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (370.877 and 348.491 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (71.78) is better than Ligand B (55.89). Both are below the 90 A^2 threshold desirable for CNS targets.

**logP:** Ligand A (3.249) is within the optimal 1-3 range. Ligand B (0.851) is slightly below this, potentially hindering permeation.

**H-Bond Donors/Acceptors:** Both ligands have 1 HBD and 4 HBA, which are acceptable.

**QED:** Both ligands have similar QED values (0.799 and 0.723), indicating good drug-likeness.

**DILI:** Ligand A (29.546) has a much lower DILI risk than Ligand B (8.375), which is a significant advantage.

**BBB:** Ligand A (82.086) has a better BBB penetration percentile than Ligand B (61.729). This is crucial for a CNS target like DRD2.

**Caco-2 Permeability:** Ligand A (-4.697) is worse than Ligand B (-5.095). Lower values indicate lower permeability.

**Aqueous Solubility:** Ligand A (-3.65) is better than Ligand B (-0.153).

**hERG Inhibition:** Ligand A (0.53) has a slightly higher hERG risk than Ligand B (0.202), but both are relatively low.

**Microsomal Clearance:** Ligand A (14.948) has higher microsomal clearance than Ligand B (3.023), suggesting lower metabolic stability.

**In vitro Half-Life:** Ligand A (60.896) has a longer half-life than Ligand B (-14.1).

**P-gp Efflux:** Ligand A (0.185) has lower P-gp efflux liability than Ligand B (0.005), which is favorable for CNS penetration.

**Binding Affinity:** Ligand B (-7.7 kcal/mol) has a slightly better binding affinity than Ligand A (-7.2 kcal/mol), but the difference is relatively small.

**Overall Assessment:**

Ligand A is preferable. While Ligand B has slightly better binding affinity and Caco-2 permeability, Ligand A demonstrates significantly better predicted safety (lower DILI), better BBB penetration, better solubility, lower P-gp efflux, and a longer half-life. Given the GPCR-specific priorities, the improved CNS penetration (BBB and P-gp) and safety profile of Ligand A outweigh the minor difference in binding affinity. The lower metabolic stability of Ligand A is a concern, but can be addressed through structural modifications.

Output:
1
2025-04-17 07:18:46,091 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 drug candidates, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight (MW):** Both ligands (335.382 and 346.431 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (37.61) is excellent, well below the 90 A^2 threshold for CNS targets. Ligand B (84.42) is higher but still acceptable, though less ideal.

**3. logP:** Ligand A (3.946) is at the upper end of the optimal range (1-3), while Ligand B (1.319) is at the lower end. Ligand A's higher logP could potentially lead to off-target effects, but is not a major concern.

**4. H-Bond Donors (HBD):** Both ligands have acceptable HBD counts (0 for A, 1 for B), well below the limit of 5.

**5. H-Bond Acceptors (HBA):** Ligand A (3) and Ligand B (5) are both within the acceptable limit of 10.

**6. QED:** Both ligands have good QED scores (0.675 and 0.869), indicating good drug-like properties.

**7. DILI:** Ligand A (68.05) has a higher DILI risk than Ligand B (52.656), but both are below the concerning threshold of 60.

**8. BBB:** Ligand A (93.408) has a significantly better BBB penetration percentile than Ligand B (68.282). This is a crucial advantage for a CNS target like DRD2.

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.488 and -4.817). This is unusual and suggests poor permeability. However, these values are on a log scale and may not be directly comparable.

**10. Aqueous Solubility:** Both ligands have negative solubility values (-4.786 and -1.555), indicating poor aqueous solubility. This could be a formulation challenge.

**11. hERG Inhibition:** Ligand A (0.821) has a slightly higher hERG risk than Ligand B (0.102). This is a potential safety concern for Ligand A.

**12. Microsomal Clearance:** Ligand A (90.221) has higher microsomal clearance than Ligand B (9.965), suggesting lower metabolic stability.

**13. In vitro Half-Life:** Ligand B (1.64) has a very short in vitro half-life, while Ligand A (39.911) has a much longer half-life.

**14. P-gp Efflux:** Ligand A (0.585) has lower P-gp efflux than Ligand B (0.013), which is favorable for CNS penetration.

**15. Binding Affinity:** Ligand B (-7.5 kcal/mol) has a significantly stronger binding affinity than Ligand A (-9.4 kcal/mol). This is a major advantage, potentially outweighing some of the ADME drawbacks.

**Overall Assessment:**

Ligand B has a superior binding affinity, lower hERG risk, better metabolic stability (lower Cl_mic), and lower DILI risk. However, Ligand A has a much better BBB penetration and longer half-life. Given the CNS target, BBB penetration is paramount. While Ligand B's affinity is stronger, the difference is not substantial enough to overcome Ligand A's superior BBB and half-life, especially considering the poor permeability and solubility of both compounds. The P-gp efflux is also better for Ligand A.

Output:
1
2025-04-17 07:18:46,091 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (363.435 and 366.889 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (81.7) is slightly higher than Ligand B (78.43). Both are below the 90 A^2 threshold for CNS targets, which is good.

**3. logP:** Both ligands have good logP values (3.171 and 3.361), falling within the optimal 1-3 range.

**4. H-Bond Donors:** Ligand A has 1 HBD, while Ligand B has 3. Both are within the acceptable limit of <=5.

**5. H-Bond Acceptors:** Ligand A has 6 HBA, and Ligand B has 3. Both are comfortably below the 10 HBA threshold.

**6. QED:** Both ligands have good QED scores (0.642 and 0.722), indicating good drug-like properties.

**7. DILI:** Ligand A has a DILI risk of 77.123, which is concerning, placing it in the higher risk category (>60). Ligand B has a much lower DILI risk of 35.828, which is favorable.

**8. BBB:** Ligand A has a BBB penetration of 73.672, which is good, but Ligand B has 67.623, which is acceptable but less desirable.

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.341 and -4.762), which is unusual and suggests poor permeability. This is a significant drawback for both.

**10. Aqueous Solubility:** Both ligands have very poor aqueous solubility (-5.212 and -4.052). This is a major concern for formulation and bioavailability.

**11. hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.467 and 0.35). This is positive.

**12. Microsomal Clearance:** Ligand A (102.928) has a higher microsomal clearance than Ligand B (32.911), suggesting lower metabolic stability.

**13. In vitro Half-Life:** Ligand B (44.435) has a slightly longer half-life than Ligand A (40.425).

**14. P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.246 and 0.092), which is good for CNS exposure.

**15. Binding Affinity:** Ligand B (-9.0 kcal/mol) has a significantly stronger binding affinity than Ligand A (-8.3 kcal/mol). This difference of 0.7 kcal/mol is substantial and can outweigh some ADME drawbacks.

**Overall Assessment:**

While both ligands have issues with Caco-2 permeability and solubility, Ligand B is the more promising candidate. Its significantly stronger binding affinity, lower DILI risk, and slightly better metabolic stability outweigh the slightly lower BBB penetration compared to Ligand A. The poor solubility and permeability are serious concerns that would need to be addressed through formulation or further chemical modifications, but the superior affinity and safety profile of Ligand B make it the better starting point.

Output:
1
2025-04-17 07:18:46,091 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (342.443 and 354.466 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (78.09) is better than Ligand B (55.57). Both are below the 90 A^2 threshold desirable for CNS targets.

**logP:** Ligand A (1.268) is within the optimal 1-3 range. Ligand B (3.872) is approaching the upper limit, but still acceptable.

**H-Bond Donors/Acceptors:** Ligand A has 2 HBD and 3 HBA, while Ligand B has 0 HBD and 4 HBA. Both are within acceptable limits (<=5 HBD and <=10 HBA).

**QED:** Ligand A (0.846) has a significantly better QED score than Ligand B (0.675), indicating a more drug-like profile.

**DILI:** Ligand A (27.22) has a lower DILI risk than Ligand B (18.534), both are good.

**BBB:** Ligand B (96.355) has a *much* higher BBB penetration percentile than Ligand A (49.128). This is a critical advantage for a CNS target like DRD2.

**Caco-2 Permeability:** Ligand A (-5.198) has a worse Caco-2 permeability than Ligand B (-3.965).

**Aqueous Solubility:** Ligand A (-2.008) has a worse solubility than Ligand B (-3.964).

**hERG:** Both ligands have very low hERG inhibition risk (0.071 and 0.878 respectively).

**Microsomal Clearance:** Ligand A (-4.857) has a much lower (better) microsomal clearance than Ligand B (96.226), indicating greater metabolic stability.

**In vitro Half-Life:** Ligand A (-2.039) has a worse half-life than Ligand B (-12.299).

**P-gp Efflux:** Ligand A (0.047) has a lower P-gp efflux liability than Ligand B (0.768), which is favorable for CNS penetration.

**Binding Affinity:** Ligand A (-9.5 kcal/mol) has a significantly stronger binding affinity than Ligand B (-7.1 kcal/mol). This is a substantial advantage.

**Overall Assessment:**

Ligand A has a superior QED, lower DILI, better metabolic stability (lower Cl_mic), lower P-gp efflux, and *much* stronger binding affinity. However, Ligand B has a dramatically better BBB penetration percentile, which is paramount for a CNS-targeting drug. The affinity difference is >2kcal/mol, which is a substantial advantage that can help overcome some ADME deficiencies. Considering the importance of BBB penetration for DRD2 (a CNS target), and the significant advantage in binding affinity of Ligand A, I would choose Ligand A.

Output:
1
2025-04-17 07:18:46,091 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B based on the provided guidelines, prioritizing GPCR-specific properties (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (363.527 and 367.427 Da) fall within the ideal range of 200-500 Da.

**TPSA:** Ligand A (71.09) is significantly better than Ligand B (116.67). For CNS targets, TPSA should be <= 90, and A is comfortably within this range, while B is pushing the limit.

**logP:** Ligand A (3.301) is optimal (1-3), while Ligand B (-0.2) is quite low, potentially hindering permeation.

**H-Bond Donors/Acceptors:** Both have acceptable HBD (2) and HBA (A: 4, B: 6) counts.

**QED:** Both ligands have good QED scores (A: 0.696, B: 0.761), indicating drug-likeness.

**DILI:** Ligand A (34.393) has a lower DILI risk than Ligand B (43.66), both are acceptable.

**BBB:** Ligand A (53.897) has a better BBB percentile than Ligand B (38.232). While >70 is desirable, A is closer, and B is quite low, which is a significant drawback for a CNS target like DRD2.

**Caco-2 Permeability:** Both have negative Caco-2 values (-5.093 and -5.263), which is unusual and suggests poor permeability. However, these values are on a scale where negative values are possible, and direct comparison is difficult without knowing the scale's specifics.

**Aqueous Solubility:** Both have negative solubility values (-3.392 and -2.899), indicating poor aqueous solubility.

**hERG:** Both ligands have low hERG inhibition liability (A: 0.411, B: 0.061), which is good.

**Microsomal Clearance:** Ligand A (51.874) has a higher microsomal clearance than Ligand B (-19.501). Lower clearance is preferred for metabolic stability, so Ligand B is better here.

**In vitro Half-Life:** Ligand A (8.105) has a longer half-life than Ligand B (3.147), which is desirable.

**P-gp Efflux:** Ligand A (0.341) has lower P-gp efflux liability than Ligand B (0.009), which is better for CNS exposure.

**Binding Affinity:** Both ligands have comparable and strong binding affinities (-8.1 and -8.3 kcal/mol). The difference is minimal.

**Overall Assessment:**

Considering the GPCR-specific priorities, Ligand A is significantly better. Its superior TPSA, logP, and BBB penetration are crucial for CNS drug development. While Ligand B has better metabolic stability (lower Cl_mic), the poor logP and BBB scores are major drawbacks. The comparable binding affinity makes the ADME advantages of Ligand A decisive. The negative Caco-2 and solubility values are concerning for both, but the other factors favor A.

Output:
1
2025-04-17 07:18:46,091 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (354.328 and 350.547 Da) fall comfortably within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (62.55) is slightly higher than Ligand B (58.2). Both are below the 90 A^2 threshold desirable for CNS targets, which is good.

**3. logP:** Both ligands have logP values around 4 (4.218 and 4.04). This is slightly above the optimal range of 1-3, potentially leading to solubility issues or off-target interactions, but not drastically so.

**4. H-Bond Donors:** Ligand A has 1 HBD, while Ligand B has 2. Both are within the acceptable limit of <=5.

**5. H-Bond Acceptors:** Ligand A has 3 HBA, and Ligand B has 2. Both are well below the 10 HBA limit.

**6. QED:** Ligand A (0.834) has a significantly better QED score than Ligand B (0.659), indicating a more drug-like profile.

**7. DILI:** Ligand A (72.005) has a higher DILI risk than Ligand B (18.302). This is a significant negative for Ligand A.

**8. BBB:** Ligand A (96.161) has a substantially better BBB penetration percentile than Ligand B (74.758). This is crucial for a CNS target like DRD2.

**9. Caco-2 Permeability:** Both have negative Caco-2 values (-4.611 and -4.589), which is unusual and suggests poor permeability. This is a concern for both.

**10. Aqueous Solubility:** Both have negative solubility values (-4.962 and -4.802), indicating very poor aqueous solubility. This is a significant drawback for both.

**11. hERG Inhibition:** Ligand A (0.772) has a slightly higher hERG inhibition risk than Ligand B (0.575), but both are reasonably low.

**12. Microsomal Clearance:** Ligand B (76.63) has a much higher microsomal clearance than Ligand A (19.731), meaning Ligand A is more metabolically stable.

**13. In vitro Half-Life:** Ligand A (26.539) has a longer in vitro half-life than Ligand B (9.739), which is favorable.

**14. P-gp Efflux:** Ligand A (0.498) exhibits lower P-gp efflux than Ligand B (0.233), suggesting better CNS exposure.

**15. Binding Affinity:** Ligand A (-9.5 kcal/mol) has a significantly stronger binding affinity than Ligand B (-7.5 kcal/mol). This is a substantial advantage for Ligand A, potentially outweighing some of its ADME drawbacks.

**Overall Assessment:**

Ligand A has a much stronger binding affinity and better BBB penetration, longer half-life, and lower P-gp efflux, all critical for a CNS GPCR target. However, it has a higher DILI risk and slightly worse solubility. Ligand B has a lower DILI risk but significantly weaker binding affinity, lower BBB penetration, and poorer metabolic stability.

Given the importance of potency and CNS penetration for DRD2, the superior binding affinity and BBB score of Ligand A outweigh its higher DILI risk and solubility concerns. The difference in binding affinity is substantial (>1.5 kcal/mol).

Output:
1
2025-04-17 07:18:46,091 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (349.339 and 362.348 Da) fall within the ideal range of 200-500 Da.

**TPSA:** Ligand A (108.0) is slightly above the optimal <90 for CNS targets, but still reasonable. Ligand B (67.87) is excellent, well below 90.

**logP:** Ligand A (0.166) is quite low, potentially hindering permeability. Ligand B (1.221) is within the optimal 1-3 range. This is a significant advantage for Ligand B.

**H-Bond Donors/Acceptors:** Both have acceptable HBD counts (1). Ligand A has 7 HBAs, while Ligand B has 4. Both are within the acceptable limits, but Ligand B is slightly better.

**QED:** Both ligands have reasonable QED scores (0.424 and 0.817), with Ligand B being significantly better, indicating a more drug-like profile.

**DILI:** Ligand A (62.815) has a higher DILI risk than Ligand B (47.964), although both are acceptable.

**BBB:** Ligand B (90.229) has a much better BBB penetration percentile than Ligand A (75.805). This is crucial for a CNS target like DRD2.

**Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and suggests potential issues with the data or prediction method. However, the magnitude is similar.

**Aqueous Solubility:** Both have negative solubility values, which is also unusual. Again, the magnitude is similar.

**hERG:** Both ligands have low hERG inhibition liability (0.09 and 0.246), which is good.

**Microsomal Clearance:** Ligand A (48.462) has a higher microsomal clearance than Ligand B (15.963), meaning it's likely to be metabolized more quickly.

**In vitro Half-Life:** Ligand B (-36.93) has a much longer in vitro half-life than Ligand A (-8.956). This is a significant advantage.

**P-gp Efflux:** Both ligands show low P-gp efflux liability (0.088 and 0.077).

**Binding Affinity:** Both ligands have comparable binding affinities (-6.8 and -8.0 kcal/mol). Ligand B is 1.2 kcal/mol better, which is a substantial difference and can outweigh some ADME drawbacks.

**Overall Assessment:**

Ligand B is significantly better overall. It has a more favorable logP, TPSA, QED, BBB penetration, in vitro half-life, and binding affinity. While both have unusual solubility and Caco-2 values, the other advantages of Ligand B, particularly its BBB penetration and binding affinity, make it the more promising drug candidate for a CNS target like DRD2. The lower clearance and better half-life also contribute to its superior profile.

Output:
1
2025-04-17 07:18:46,092 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (408.231 Da) is slightly higher than Ligand B (345.359 Da), but both are acceptable.

**TPSA:** Ligand A (91.97) is better than Ligand B (121.45). For CNS targets, we want TPSA <= 90, so Ligand A is closer to this threshold. Ligand B is significantly higher and less favorable.

**logP:** Ligand A (2.063) is within the optimal range (1-3). Ligand B (0.205) is quite low, potentially hindering membrane permeability and CNS penetration.

**H-Bond Donors/Acceptors:** Both ligands have 2 HBDs and around 6-7 HBAs, which are within acceptable limits.

**QED:** Both ligands have similar QED values (0.812 and 0.794), indicating good drug-likeness.

**DILI:** Both ligands have similar DILI risk (80.807 and 61.031), indicating moderate risk. This isn't a major differentiating factor.

**BBB:** Ligand A (53.432) has a significantly better BBB percentile than Ligand B (27.142). For a CNS target like DRD2, a BBB > 70 is desirable, but 53.432 is much better than 27.142.

**Caco-2 Permeability:** Ligand A (-4.941) is better than Ligand B (-5.152). Both are negative, but A is less negative.

**Aqueous Solubility:** Ligand A (-3.881) is better than Ligand B (-1.866). Both are negative, but A is less negative.

**hERG:** Ligand A (0.824) has a lower hERG risk than Ligand B (0.104). Lower is better.

**Microsomal Clearance:** Ligand A (14.782) has a lower microsomal clearance than Ligand B (23.645), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (60.881) has a much longer in vitro half-life than Ligand B (-17.54). This is a significant advantage.

**P-gp Efflux:** Ligand A (0.377) has lower P-gp efflux liability than Ligand B (0.016). Lower is better for CNS penetration.

**Binding Affinity:** Ligand B (-8.4 kcal/mol) has a substantially better binding affinity than Ligand A (0.0 kcal/mol). This is a very large difference.

**Overall Assessment:**

While Ligand B has a significantly better binding affinity, Ligand A has superior ADME properties, particularly regarding BBB penetration, metabolic stability, and P-gp efflux. Considering DRD2 is a CNS target, the ADME properties are crucial. The large difference in binding affinity is a concern, but the poor ADME profile of Ligand B makes it less likely to reach the target in the brain. Ligand A, despite its weaker binding, has a much higher chance of achieving therapeutic concentrations in the CNS.

Output:
0
2025-04-17 07:18:46,092 - INFO - Reasoning:

Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (345.527 Da) is slightly lower, which could be advantageous for permeability, while Ligand B (366.491 Da) is also well within the range.

**TPSA:** Ligand A (40.54) is excellent, well below the 90 A^2 threshold for CNS targets. Ligand B (81.67) is higher, but still potentially acceptable, though less ideal for brain penetration.

**logP:** Ligand A (4.844) is at the higher end of the optimal range, potentially leading to solubility issues or off-target interactions. Ligand B (-0.249) is significantly lower than optimal and may have poor membrane permeability.

**H-Bond Donors/Acceptors:** Both ligands have 1 HBD, which is good. Ligand A has 2 HBA, and Ligand B has 7 HBA. The higher HBA count in Ligand B could impact permeability.

**QED:** Both ligands have similar QED values (0.801 and 0.795), indicating good drug-like properties.

**DILI:** Ligand A (20.861) has a much lower DILI risk than Ligand B (37.767), which is a significant advantage.

**BBB:** Both ligands have reasonably good BBB penetration (Ligand A: 66.344, Ligand B: 67.623), but ideally, we'd want >70% for a CNS target.

**Caco-2 Permeability:** Ligand A (-4.355) has poor predicted Caco-2 permeability, which is concerning. Ligand B (-5.075) is also poor.

**Aqueous Solubility:** Ligand A (-4.849) has poor predicted solubility. Ligand B (-1.554) is also poor, but slightly better than Ligand A.

**hERG Inhibition:** Ligand A (0.777) has a slightly higher risk of hERG inhibition than Ligand B (0.273), which is preferable.

**Microsomal Clearance:** Ligand A (83.092) has a higher microsomal clearance, indicating faster metabolism. Ligand B (-4.01) has negative clearance, which is not realistic and suggests a potential issue with the prediction method, but generally indicates high metabolic stability.

**In vitro Half-Life:** Ligand A (25.731) has a shorter half-life than Ligand B (3.456).

**P-gp Efflux:** Ligand A (0.79) has a slightly higher P-gp efflux liability than Ligand B (0.067), which is less desirable for CNS penetration.

**Binding Affinity:** Ligand A (-8.9 kcal/mol) has a significantly stronger binding affinity than Ligand B (-7.1 kcal/mol). This 1.8 kcal/mol difference is substantial and could outweigh some of the ADME drawbacks.

**Overall Assessment:**

Ligand A has a significantly better binding affinity and lower DILI risk, which are major positives. However, it suffers from poor Caco-2 permeability, solubility, and higher P-gp efflux. Ligand B has better solubility and lower P-gp efflux, but its logP is very low, and its affinity is considerably weaker. Given the importance of affinity for GPCRs, and the fact that the difference is substantial (1.8 kcal/mol), Ligand A is the more promising candidate *despite* its ADME liabilities. Optimization efforts could focus on improving its solubility and permeability while retaining its strong binding affinity.

Output:
0
2025-04-17 07:18:46,092 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (343.43 & 380.48 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (86.34) is excellent, well below the 90 A^2 threshold for CNS targets. Ligand B (92.78) is still reasonable but slightly less favorable.

**logP:** Ligand A (2.286) is optimal (1-3). Ligand B (0.539) is a bit low, potentially hindering membrane permeability.

**H-Bond Donors/Acceptors:** Both have 1 HBD, which is good. Ligand A has 4 HBA, and Ligand B has 5 HBA, both acceptable (<=10).

**QED:** Ligand A (0.858) has a superior QED score compared to Ligand B (0.663), indicating better overall drug-likeness.

**DILI:** Ligand A (22.84) has a significantly lower DILI risk than Ligand B (38.58), which is a major advantage.

**BBB:** Ligand A (63.01) is acceptable but not outstanding for a CNS target. Ligand B (81.70) is better, exceeding 70% and indicating good potential for brain penetration.

**Caco-2 Permeability:** Both have negative Caco-2 values (-4.991 and -4.934), which is unusual and suggests poor permeability. This is a significant concern for both.

**Aqueous Solubility:** Both have negative solubility values (-2.284 and -1.86). This is also concerning and suggests formulation challenges.

**hERG:** Both ligands have low hERG inhibition risk (0.425 and 0.338).

**Microsomal Clearance:** Ligand A (-5.692) shows *much* lower (better) microsomal clearance than Ligand B (-12.824), indicating greater metabolic stability.

**In vitro Half-Life:** Ligand A (22.843) has a better in vitro half-life than Ligand B (0.845).

**P-gp Efflux:** Both have very low P-gp efflux liability (0.066 and 0.043).

**Binding Affinity:** Ligand A (-7.7 kcal/mol) has a slightly better binding affinity than Ligand B (-7.1 kcal/mol). While the difference is less than the 1.5 kcal/mol threshold to completely override other issues, it's still a positive factor.

**Overall Assessment:**

Ligand A is the stronger candidate. While both ligands have concerning permeability and solubility issues, Ligand A excels in crucial areas: lower DILI risk, better metabolic stability (lower Cl_mic, longer t1/2), superior QED, and slightly better binding affinity. Ligand B's better BBB penetration is a plus, but the higher DILI risk and poorer metabolic stability are significant drawbacks. The negative Caco-2 and solubility values for both are red flags that would require further investigation (e.g., salt formation, prodrug strategies) but are not disqualifying at this stage.

Output:
0
2025-04-17 07:18:46,092 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (342.443 Da) is slightly better being closer to the lower end, which can aid permeability.

**TPSA:** Ligand A (75.19) is significantly better than Ligand B (103.95). For CNS targets, we want TPSA <= 90, and A is comfortably within this range while B is pushing the limit.

**logP:** Both ligands have acceptable logP values (A: 1.886, B: 2.222), falling within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A (HBD=1, HBA=4) is preferable to Ligand B (HBD=3, HBA=5) as lower values generally improve permeability. Both are within acceptable limits.

**QED:** Both ligands have similar QED values (A: 0.578, B: 0.573), indicating good drug-likeness.

**DILI:** Ligand A (35.091) has a much lower DILI risk than Ligand B (83.792). This is a significant advantage for A.

**BBB:** Ligand A (60.838) has a better BBB percentile than Ligand B (43.815), although neither are above the desired >70 for CNS targets. However, A is closer.

**Caco-2 Permeability:** Ligand A (-4.834) has a more positive Caco-2 value than Ligand B (-5.626), suggesting better intestinal absorption.

**Aqueous Solubility:** Both ligands have negative solubility values, indicating poor aqueous solubility. Ligand A (-2.353) is slightly better than Ligand B (-2.63).

**hERG Inhibition:** Both ligands show low hERG inhibition liability (A: 0.382, B: 0.632), which is good.

**Microsomal Clearance:** Ligand A (33.091) has a lower microsomal clearance than Ligand B (46.708), indicating better metabolic stability.

**In vitro Half-Life:** Ligand A (-10.044) has a longer in vitro half-life than Ligand B (1.776), which is a significant advantage.

**P-gp Efflux:** Ligand A (0.06) has a much lower P-gp efflux liability than Ligand B (0.302). This is crucial for CNS penetration.

**Binding Affinity:** Ligand B (-8.4 kcal/mol) has a slightly better binding affinity than Ligand A (-7.3 kcal/mol). The difference is 1.1 kcal/mol, which is not substantial enough to outweigh the significant ADME advantages of Ligand A.

**Overall:** Considering the GPCR-specific priorities, Ligand A is the more promising candidate. It has better TPSA, DILI, BBB, Caco-2 permeability, metabolic stability, P-gp efflux, and half-life. While Ligand B has slightly better binding affinity, the ADME profile of Ligand A is far superior, especially regarding CNS penetration (BBB and P-gp).



Output:
0
2025-04-17 07:18:46,093 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (355.821 and 363.389 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (47.56) is significantly better than Ligand B (67.01). For CNS targets, we want TPSA <= 90, and ideally closer to 60. Ligand A is much closer to this ideal.

**3. logP:** Both ligands have similar logP values (4.555 and 4.475), both slightly above the optimal range of 1-3, but not drastically so. This could potentially lead to some off-target effects, but isn't a major discriminator here.

**4. H-Bond Donors:** Ligand A (1) is better than Ligand B (2). Fewer HBDs generally improve permeability.

**5. H-Bond Acceptors:** Ligand A (3) is better than Ligand B (5). Similar to HBDs, lower HBA is preferred.

**6. QED:** Ligand A (0.821) has a significantly better QED score than Ligand B (0.634), indicating a more drug-like profile.

**7. DILI:** Both ligands have high DILI risk (89.996 and 88.484), which is a concern. This would require further investigation and potential structural modifications.

**8. BBB:** Ligand A (73.168) has a better BBB percentile than Ligand B (66.499). While both are above 60, exceeding 70 is desirable for CNS targets, and A is closer.

**9. Caco-2:** Both have negative Caco-2 values (-4.544 and -4.992), which is unusual and suggests poor permeability. This is a significant drawback for both.

**10. Solubility:** Both have negative solubility values (-5.98 and -5.573), indicating poor aqueous solubility. This is also a significant drawback.

**11. hERG:** Both ligands have low hERG inhibition risk (0.703 and 0.766).

**12. Cl_mic:** Ligand A (50.188) has lower microsomal clearance than Ligand B (86.587), suggesting better metabolic stability.

**13. t1/2:** Ligand A (96.895) has a much longer in vitro half-life than Ligand B (-4.878). This is a major advantage.

**14. Pgp:** Ligand A (0.705) has lower P-gp efflux liability than Ligand B (0.48), which is favorable for CNS penetration.

**15. Binding Affinity:** Ligand B (-8.6) has a slightly better binding affinity than Ligand A (-9.1). While a 1.5 kcal/mol advantage is often significant, the other ADME properties of Ligand A are much more favorable.

**Overall Assessment:**

Ligand A is the better candidate. While Ligand B has slightly better binding affinity, Ligand A demonstrates superior drug-like properties across several critical ADME parameters, particularly TPSA, QED, BBB, metabolic stability (Cl_mic & t1/2), and P-gp efflux. The negative Caco-2 and solubility values are concerning for both, but the overall profile of Ligand A is more promising for CNS penetration and oral availability. The high DILI risk is a concern for both and would need to be addressed.

Output:
0
2025-04-17 07:18:46,093 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (345.4 and 350.3 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (88.58) is excellent, falling well below the 90 A^2 threshold for CNS targets. Ligand B (44.1) is also very good, even better than A.

**3. logP:** Ligand A (2.563) is optimal (1-3). Ligand B (4.134) is slightly higher, approaching the upper limit, but still acceptable.

**4. H-Bond Donors:** Ligand A (1) is good. Ligand B (0) is also good.

**5. H-Bond Acceptors:** Ligand A (5) is good. Ligand B (2) is also good.

**6. QED:** Ligand A (0.9) is excellent. Ligand B (0.761) is still good, above the 0.5 threshold.

**7. DILI:** Both ligands have acceptable DILI risk (Ligand A: 54.87, Ligand B: 48.04), below the 60% threshold.

**8. BBB:** Ligand A (71.23%) is good, exceeding the 70% target. Ligand B (84.37%) is *excellent* and significantly better than A. This is a critical factor for a CNS target like DRD2.

**9. Caco-2 Permeability:** Both are negative, indicating poor permeability. Ligand A (-4.734) is slightly better than Ligand B (-4.209).

**10. Aqueous Solubility:** Both are negative, indicating poor solubility. Ligand A (-2.798) is slightly better than Ligand B (-5.062).

**11. hERG Inhibition:** Both ligands have very low hERG risk (0.199 and 0.932).

**12. Microsomal Clearance:** Ligand A (41.3) is better than Ligand B (51.4), indicating better metabolic stability.

**13. In vitro Half-Life:** Ligand A (-20.33) is better than Ligand B (-15.65), indicating a longer half-life.

**14. P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.118 and 0.4).

**15. Binding Affinity:** Both ligands have the same binding affinity (-8.3 kcal/mol), which is excellent.

**Overall Assessment:**

Both ligands are promising, with good potency and acceptable safety profiles. However, Ligand B stands out due to its significantly better BBB penetration (84.4% vs 71.2%). Considering DRD2 is a CNS target, this is the most important differentiating factor. While Ligand A has slightly better metabolic stability and half-life, the superior BBB penetration of Ligand B outweighs these minor advantages.

Output:
1
2025-04-17 07:18:46,093 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (349.431 and 341.455 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (85.87) is better than Ligand B (62.3). For CNS targets, we want TPSA <= 90, both are within this range, but A is closer to the upper limit.

**3. logP:** Ligand B (2.825) is better than Ligand A (0.928). The optimal range is 1-3, and B falls nicely within it, while A is slightly below 1, potentially hindering permeation.

**4. H-Bond Donors:** Ligand A (2) is slightly higher than Ligand B (1), but both are acceptable (<=5).

**5. H-Bond Acceptors:** Ligand A (4) is slightly higher than Ligand B (3), but both are acceptable (<=10).

**6. QED:** Both ligands have good QED scores (0.828 and 0.865), indicating good drug-like properties.

**7. DILI:** Both ligands have acceptable DILI risk (40.83 and 32.261, both < 40).

**8. BBB:** Ligand B (70.958) is significantly better than Ligand A (29.74). For a CNS target like DRD2, BBB penetration is crucial, and B is desirable (>70), while A is quite low.

**9. Caco-2 Permeability:** Ligand A (-4.847) is better than Ligand B (-4.373). Higher values are better, but both are negative, indicating poor permeability.

**10. Aqueous Solubility:** Ligand A (-1.562) is better than Ligand B (-2.92). Higher values are better, but both are negative, indicating poor solubility.

**11. hERG Inhibition:** Both ligands have low hERG inhibition risk (0.269 and 0.221).

**12. Microsomal Clearance:** Ligand A (-2.941) is much better than Ligand B (51.336). Lower clearance indicates better metabolic stability.

**13. In vitro Half-Life:** Ligand A (-12.941) is much better than Ligand B (12.893). Longer half-life is generally preferred.

**14. P-gp Efflux:** Both ligands have low P-gp efflux liability (0.036 and 0.027).

**15. Binding Affinity:** Ligand B (-7.8) is slightly better than Ligand A (-8.0). Both are excellent, but the difference is minimal.

**Overall Assessment:**

While Ligand A has better metabolic stability and half-life, Ligand B excels in crucial areas for a CNS-targeting GPCR: significantly better BBB penetration (70.958 vs 29.74) and a more optimal logP (2.825 vs 0.928). The slightly better affinity of Ligand B is a bonus. The lower logP of Ligand A is a significant concern for CNS penetration. Given the GPCR-specific priorities, Ligand B is the more promising candidate.

Output:
1
2025-04-17 07:18:46,093 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B based on the provided guidelines, prioritizing GPCR-specific properties (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (349.431 and 353.507 Da) fall within the ideal range of 200-500 Da.

**TPSA:** Both ligands have TPSA values (80.76 and 78.51) below 90, which is favorable for CNS penetration.

**logP:** Both ligands have logP values (2.706 and 1.88) within the optimal range of 1-3. Ligand B is slightly lower, which *could* indicate slightly better solubility, but both are acceptable.

**H-Bond Donors/Acceptors:** Ligand A (HBD=1, HBA=5) and Ligand B (HBD=2, HBA=4) both have reasonable H-bond donor and acceptor counts, well within the guidelines.

**QED:** Ligand A (0.827) has a higher QED score than Ligand B (0.588), indicating a more drug-like profile overall.

**DILI:** Ligand A (49.593) has a significantly better DILI percentile than Ligand B (11.322), indicating a lower risk of drug-induced liver injury. This is a substantial advantage.

**BBB:** Both ligands have excellent BBB penetration (Ligand A: 79.294, Ligand B: 70.027), exceeding the desirable threshold of 70. Ligand A is better.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.299 and -4.951). These are unusual and suggest poor permeability. However, the scale isn't defined, so it's hard to interpret.

**Aqueous Solubility:** Both ligands have negative solubility values (-3.043 and -2.118), again unusual and suggesting poor solubility.

**hERG:** Both ligands have very low hERG inhibition liability (0.389 and 0.431).

**Microsomal Clearance:** Ligand A (86.138) has a higher microsomal clearance than Ligand B (17.166), meaning it's likely to be metabolized faster. This is a disadvantage for Ligand A.

**In vitro Half-Life:** Ligand B (-25.19) has a slightly better (less negative) in vitro half-life than Ligand A (-30.21), suggesting better stability.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.046 and 0.038), which is favorable for CNS exposure.

**Binding Affinity:** Ligand B (-7.3) has a slightly better binding affinity than Ligand A (-7.1), although the difference is small (0.2 kcal/mol).

**Overall Assessment:**

Ligand A has a significantly better DILI score and a higher QED, and slightly better BBB penetration. Ligand B has a better in vitro half-life and a marginally better binding affinity. The biggest drawback for Ligand A is its higher microsomal clearance. However, the lower DILI risk and higher QED of Ligand A are more important considerations, especially given the similar binding affinities. The negative Caco-2 and solubility values are concerning for both, but the other factors weigh more heavily in this case.

Output:
1
2025-04-17 07:18:46,094 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (348.378 and 368.499 Da) fall within the ideal 200-500 Da range.

**TPSA:** Both ligands have TPSA values (86.63 and 87.66) below the 90 A^2 threshold for CNS targets, which is excellent.

**logP:** Both ligands have logP values (1.184 and 0.991) within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A (1 HBD, 5 HBA) is slightly better than Ligand B (3 HBD, 5 HBA) in terms of HBD count, but both are acceptable.

**QED:** Ligand A (0.886) has a significantly better QED score than Ligand B (0.689), indicating a more drug-like profile.

**DILI:** Both ligands have acceptable DILI risk (50.291 and 48.313 percentile), below the 60 threshold.

**BBB:** This is a critical parameter for a CNS target like DRD2. Ligand A has a much higher BBB penetration percentile (79.411) compared to Ligand B (28.189). This is a major advantage for Ligand A.

**Caco-2 Permeability:** Ligand A (-4.497) and Ligand B (-5.505) both have negative values, which is unusual. A higher value is preferred, but the difference isn't decisive.

**Aqueous Solubility:** Both ligands have poor aqueous solubility (-2.434 and -2.175). This could pose formulation challenges, but isn't a deal-breaker at this stage.

**hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.098 and 0.118 percentile).

**Microsomal Clearance:** Ligand B (11.127 mL/min/kg) has a lower microsomal clearance than Ligand A (21.334 mL/min/kg), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand B (19.044 hours) has a longer in vitro half-life than Ligand A (-14.149 hours). This is a significant advantage for Ligand B.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.023 and 0.049 percentile).

**Binding Affinity:** Both ligands have very similar and strong binding affinities (-8.4 and -8.1 kcal/mol). The difference of 0.3 kcal/mol is not substantial enough to outweigh other differences.

**Overall Assessment:**

Ligand A excels in BBB penetration and QED, which are crucial for a CNS-targeting GPCR ligand. Ligand B has better metabolic stability (lower Cl_mic) and a longer half-life. However, the significantly better BBB score for Ligand A is the deciding factor, given the target is DRD2. While solubility is a concern for both, the superior CNS penetration potential of Ligand A makes it the more promising candidate.

Output:
0
2025-04-17 07:18:46,094 - INFO - Batch 354 complete. Total preferences: 5664
2025-04-17 07:18:46,094 - INFO - Processing batch 355/512...
2025-04-17 07:19:28,154 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (357.303 and 350.39 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (47.56) is significantly better than Ligand B (95.5). For CNS targets, TPSA should be <=90, and A is comfortably within that range, while B is close to the upper limit and less desirable.

**logP:** Ligand A (4.053) is slightly higher than the optimal 1-3 range, but still acceptable. Ligand B (2.514) is well within the optimal range.

**H-Bond Donors/Acceptors:** Ligand A (HBD=1, HBA=3) and Ligand B (HBD=3, HBA=4) both have reasonable numbers of H-bond donors and acceptors, falling within the guidelines.

**QED:** Both ligands have similar QED values (0.794 and 0.671), indicating good drug-likeness.

**DILI:** Ligand A (76.309) has a higher DILI risk than Ligand B (35.479). This is a significant drawback for Ligand A.

**BBB:** Both ligands have acceptable BBB penetration (Ligand A: 68.786, Ligand B: 63.746). However, neither exceeds the desirable >70% threshold.

**Caco-2 Permeability:** Ligand A (-4.381) and Ligand B (-5.075) both have negative Caco-2 values, indicating poor permeability.

**Aqueous Solubility:** Ligand A (-4.968) and Ligand B (-3.706) both have poor aqueous solubility.

**hERG Inhibition:** Ligand A (0.687) has a slightly higher hERG risk than Ligand B (0.14), which is preferable.

**Microsomal Clearance:** Ligand A (63.158) has a higher microsomal clearance than Ligand B (35.056), indicating lower metabolic stability.

**In vitro Half-Life:** Ligand B (-12.303) has a significantly longer in vitro half-life than Ligand A (-0.766).

**P-gp Efflux:** Ligand A (0.193) has lower P-gp efflux liability than Ligand B (0.026), which is favorable for CNS penetration.

**Binding Affinity:** Both ligands have very similar and strong binding affinities (-9.4 and -8.8 kcal/mol). The difference is less than the 1.5 kcal/mol threshold.

**Overall Assessment:**

While both ligands have good binding affinity, Ligand B is the more promising candidate. It has a significantly lower DILI risk, better metabolic stability (lower Cl_mic, longer t1/2), and lower hERG inhibition. Although Ligand A has slightly better P-gp efflux, the other ADME properties of Ligand B are superior, especially the lower DILI risk. The TPSA of Ligand A is better, but the other factors outweigh this benefit.

Output:
1
2025-04-17 07:19:28,154 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B based on the provided guidelines, prioritizing GPCR-specific properties (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (367.515 and 355.523 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (71.53) is slightly higher than Ligand B (61.88). Both are below the 90 A^2 threshold desirable for CNS targets, but Ligand B is preferable.

**logP:** Ligand A (2.766) and Ligand B (1.598) are both within the optimal 1-3 range. Ligand A is slightly better.

**H-Bond Donors/Acceptors:** Both ligands have 1 HBD and 4-5 HBA, which are acceptable.

**QED:** Both ligands have similar QED values (0.767 and 0.786), indicating good drug-likeness.

**DILI:** Ligand A (46.801) has a higher DILI risk than Ligand B (12.059). Ligand B is significantly better here.

**BBB:** Ligand B (71.811) has a substantially higher BBB penetration percentile than Ligand A (59.325). This is a *critical* advantage for a CNS target like DRD2.

**Caco-2 Permeability:** Ligand A (-5.079) has worse Caco-2 permeability than Ligand B (-4.412), indicating lower intestinal absorption.

**Aqueous Solubility:** Ligand A (-2.593) has worse solubility than Ligand B (-1.964).

**hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.461 and 0.501).

**Microsomal Clearance:** Ligand A (66.195) has higher microsomal clearance than Ligand B (47.943), suggesting lower metabolic stability.

**In vitro Half-Life:** Ligand B (5.03) has a slightly longer half-life than Ligand A (10.986).

**P-gp Efflux:** Ligand A (0.127) shows slightly higher P-gp efflux liability than Ligand B (0.013). Lower P-gp efflux is preferred for CNS penetration.

**Binding Affinity:** Ligand B (-7.7 kcal/mol) has a slightly better binding affinity than Ligand A (-8.0 kcal/mol). While the difference is small, it is still a positive for Ligand B.

**Overall Assessment:**

Ligand B is the stronger candidate. While Ligand A has slightly better logP and binding affinity, Ligand B excels in crucial areas for a CNS-targeting GPCR: significantly better BBB penetration, lower DILI risk, better Caco-2 permeability, better solubility, lower P-gp efflux, and improved metabolic stability. The small difference in binding affinity is outweighed by these substantial ADME advantages.

Output:
1
2025-04-17 07:19:28,154 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (356.407 and 351.447 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (110.25) is higher than the preferred <90 for CNS targets, while Ligand B (78.95) is comfortably below. This favors Ligand B.

**logP:** Ligand A (1.684) is within the optimal 1-3 range. Ligand B (0.387) is slightly below 1, which *could* indicate permeability issues. This favors Ligand A.

**H-Bond Donors/Acceptors:** Ligand A has 3 HBD and 6 HBA, both acceptable. Ligand B has 1 HBD and 4 HBA, also acceptable. No clear advantage here.

**QED:** Both ligands have good QED scores (0.659 and 0.746), indicating good drug-like properties.

**DILI:** Ligand A has a DILI risk of 88.29, which is high. Ligand B has a much lower DILI risk of 27.414, a significant advantage.

**BBB:** Both ligands show reasonable BBB penetration (63.629% and 61.613%), but neither exceeds the desirable >70% threshold for CNS targets.

**Caco-2 Permeability:** Ligand A (-5.581) has poor Caco-2 permeability, while Ligand B (-4.454) is slightly better, but still not great.

**Aqueous Solubility:** Ligand A (-3.441) and Ligand B (-1.237) both have poor aqueous solubility.

**hERG Inhibition:** Ligand A (0.57) has a slightly higher hERG risk than Ligand B (0.119), favoring Ligand B.

**Microsomal Clearance:** Ligand A (25.601) has higher microsomal clearance than Ligand B (13.737), meaning Ligand B is more metabolically stable.

**In vitro Half-Life:** Ligand A (77.738 hours) has a significantly longer half-life than Ligand B (20.312 hours), which is a strong advantage.

**P-gp Efflux:** Ligand A (0.38) shows lower P-gp efflux than Ligand B (0.051), meaning Ligand A is less likely to be pumped out of the brain.

**Binding Affinity:** Ligand A (-10.4 kcal/mol) has a *much* stronger binding affinity than Ligand B (-8.6 kcal/mol). This is a substantial advantage, potentially outweighing some of the ADME drawbacks.

**Overall Assessment:**

Ligand A has a significantly better binding affinity and longer half-life, and lower P-gp efflux. However, it suffers from a high DILI risk, poor Caco-2 permeability, and a TPSA slightly above the ideal range. Ligand B has better TPSA, lower DILI, hERG and clearance, but significantly weaker binding affinity and a shorter half-life.

Given the importance of affinity for GPCRs, and the fact that the difference in binding energy is substantial (1.8 kcal/mol), I believe Ligand A is the more promising candidate *despite* its ADME liabilities. The strong binding could potentially be optimized through further structural modifications, while the DILI risk might be mitigated with structural changes. The poor permeability is a concern, but could be addressed through formulation strategies.

Output:
0
2025-04-17 07:19:28,154 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (393.531 Da) is slightly higher than Ligand B (352.475 Da), but both are acceptable.

**TPSA:** Ligand A (117.85) is borderline for CNS penetration, being above the preferred <90, while Ligand B (67.87) is well within the ideal range for CNS targets. This is a significant advantage for Ligand B.

**logP:** Ligand A (-0.584) is a bit low, potentially hindering membrane permeability. Ligand B (1.724) is within the optimal 1-3 range. This favors Ligand B.

**H-Bond Donors/Acceptors:** Both ligands have 1 HBD and a reasonable number of HBAs (5 and 4 respectively). No major concerns here.

**QED:** Both ligands have good QED scores (0.621 and 0.79), indicating good drug-like properties.

**DILI:** Both ligands have acceptable DILI risk (31.718 and 35.673 percentiles).

**BBB:** Ligand A (58.511) has a moderate BBB penetration, while Ligand B (67.623) is better, but still not ideal (>70 is desirable). However, considering the TPSA difference, Ligand B is favored.

**Caco-2 Permeability:** Both have negative values, indicating poor permeability. This is a concern for both.

**Aqueous Solubility:** Both ligands have negative values, indicating poor solubility. This is a concern for both.

**hERG Inhibition:** Both ligands show low hERG inhibition risk (0.125 and 0.212).

**Microsomal Clearance:** Ligand A (-1.033) has a negative clearance, which is unusual and likely an error. Ligand B (44.826) has a higher clearance, suggesting faster metabolism. This is a significant advantage for Ligand A, assuming the negative value is an error.

**In vitro Half-Life:** Ligand A (-17.072) has a negative half-life, which is impossible and likely an error. Ligand B (10.325) has a reasonable half-life.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.02 and 0.104).

**Binding Affinity:** Ligand A (-7.3) has a significantly stronger binding affinity than Ligand B (0.0). This is a major advantage for Ligand A. A difference of >1.5 kcal/mol can outweigh ADME drawbacks.

**Overall Assessment:**

Despite the issues with the clearance and half-life of Ligand A, its significantly superior binding affinity (-7.3 kcal/mol vs 0.0 kcal/mol) is a decisive factor. The negative values for clearance and half-life are likely errors. Ligand B has better TPSA and logP, but the affinity difference is too large to ignore, especially for a GPCR target where potency is crucial.

Output:
1
2025-04-17 07:19:28,155 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B based on the provided guidelines, prioritizing GPCR-specific properties (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (345.4 and 349.4 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (78.95) is significantly better than Ligand B (139.27). For CNS targets, TPSA should be <=90, and A comfortably meets this while B is close to the upper limit. This is a significant advantage for A.

**logP:** Ligand A (2.155) is optimal (1-3), while Ligand B (-1.926) is below 1, potentially hindering permeation. This favors A.

**H-Bond Donors/Acceptors:** Ligand A (1 HBD, 4 HBA) and Ligand B (2 HBD, 9 HBA) both fall within acceptable ranges, but B is closer to the upper limit for HBA.

**QED:** Ligand A (0.848) is excellent, indicating high drug-likeness. Ligand B (0.636) is still acceptable, but less favorable.

**DILI:** Ligand B (65.57) has a higher DILI risk than Ligand A (57.39), though both are reasonably acceptable.

**BBB:** Ligand A (83.09) has a much better BBB percentile than Ligand B (24.00). This is *critical* for a CNS target like DRD2.

**Caco-2 Permeability:** Ligand A (-4.64) and Ligand B (-5.701) both have negative values, which is unusual and requires careful interpretation. Lower (more negative) values suggest poor permeability. However, the scale isn't fully defined, so we'll consider this less decisive.

**Aqueous Solubility:** Ligand A (-2.637) and Ligand B (-1.205) both have negative values, suggesting poor solubility. This is a concern, but can be addressed with formulation strategies.

**hERG:** Both ligands have very low hERG risk (0.335 and 0.031 respectively).

**Microsomal Clearance:** Ligand A (24.84) has higher microsomal clearance than Ligand B (6.117), indicating lower metabolic stability. This favors B.

**In vitro Half-Life:** Ligand B (15.07) has a longer half-life than Ligand A (24.124), which is desirable.

**P-gp Efflux:** Ligand A (0.051) has slightly higher P-gp efflux than Ligand B (0.011), which is less favorable.

**Binding Affinity:** Ligand B (-0.0 kcal/mol) has significantly weaker binding affinity than Ligand A (-8.7 kcal/mol). This is a *major* advantage for A. A difference of >1.5 kcal/mol is considered significant, and here it's a massive 8.7 kcal/mol difference.

**Overall Assessment:**

Ligand A is significantly better despite having slightly higher clearance and P-gp efflux. Its superior TPSA, logP, BBB penetration, and *especially* its dramatically stronger binding affinity outweigh the minor drawbacks. Ligand B's poor logP and very low BBB penetration are major liabilities for a CNS-targeting drug. The binding affinity is also a critical factor, and the difference is substantial.

Output:
1
2025-04-17 07:19:28,155 - INFO - Reasoning:

Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (344.46 and 355.44 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (67.23) is excellent, well below the 90 A^2 threshold for CNS targets. Ligand B (118.97) is higher, but still potentially acceptable, though less ideal.

**logP:** Ligand A (2.515) is optimal (1-3). Ligand B (-0.692) is below 1, which could hinder permeation.

**H-Bond Donors/Acceptors:** Ligand A (1 HBD, 4 HBA) is favorable. Ligand B (4 HBD, 5 HBA) is also acceptable, but higher HBD count could slightly affect permeability.

**QED:** Ligand A (0.826) is very good, indicating high drug-likeness. Ligand B (0.387) is significantly lower, raising concerns about its overall drug-like properties.

**DILI:** Ligand A (39.94) has a low DILI risk. Ligand B (17.45) also has a low DILI risk.

**BBB:** Ligand A (82.47) has excellent BBB penetration potential. Ligand B (20.82) is very poor for CNS penetration. This is a critical difference given the target.

**Caco-2 Permeability:** Ligand A (-4.849) is concerning, suggesting poor intestinal absorption. Ligand B (-5.595) is also poor.

**Aqueous Solubility:** Ligand A (-3.877) is poor. Ligand B (-1.249) is also poor.

**hERG:** Both ligands have very low hERG risk (0.359 and 0.034 respectively).

**Microsomal Clearance:** Ligand A (49.32) is moderate, while Ligand B (8.88) is very low, suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (5.26) is relatively short. Ligand B (-7.54) is very long, a significant advantage.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.133 and 0.01 respectively).

**Binding Affinity:** Ligand A (-7.9) has a slightly better binding affinity than Ligand B (-7.1). However, the difference is less than the 1.5 kcal/mol threshold where affinity can override other issues.

**Overall Assessment:**

Ligand A excels in TPSA, QED, BBB, and binding affinity. However, it suffers from poor Caco-2 permeability and aqueous solubility. Ligand B has better metabolic stability (lower Cl_mic, longer t1/2) and a slightly lower P-gp efflux, but is significantly weaker in terms of QED and, critically, BBB penetration. Given that DRD2 is a CNS target, the superior BBB penetration of Ligand A is a major advantage. While its solubility and permeability are concerns, these can potentially be addressed through formulation strategies. The poor BBB penetration of Ligand B is a more difficult issue to overcome.

Output:
1
2025-04-17 07:19:28,155 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (404.304 Da) is slightly higher, but acceptable. Ligand B (348.491 Da) is also good.

**TPSA:** Both ligands have TPSA values around 47, which is above the ideal <90 for CNS targets, but not drastically so. This isn't a major differentiating factor.

**logP:** Ligand A (4.446) is a bit high, potentially leading to solubility issues and off-target interactions. Ligand B (0.506) is quite low, which could hinder membrane permeability and reduce CNS exposure.

**H-Bond Donors/Acceptors:** Ligand A has 1 HBD and 3 HBA, which is within acceptable limits. Ligand B has 0 HBD and 4 HBA, also acceptable.

**QED:** Ligand A (0.801) has a strong drug-like profile. Ligand B (0.497) is below the 0.5 threshold, indicating a less favorable overall drug-likeness.

**DILI:** Ligand A (62.699) has a moderate DILI risk. Ligand B (13.3) has a very low DILI risk, a significant advantage.

**BBB:** Ligand A (65.801) has a moderate BBB penetration, which is not ideal for a CNS target. Ligand B (54.517) has even lower BBB penetration, a major drawback.

**Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and suggests poor permeability.

**Aqueous Solubility:** Both have negative solubility values, which is also unusual and suggests poor solubility.

**hERG Inhibition:** Ligand A (0.73) has a slightly higher hERG risk than Ligand B (0.255), but both are relatively low.

**Microsomal Clearance:** Ligand A (79.015) has a higher clearance, implying lower metabolic stability. Ligand B (7.489) has a much lower clearance, indicating better metabolic stability.

**In vitro Half-Life:** Ligand A (71.892) has a reasonable half-life. Ligand B (-11.855) has a negative half-life, which is impossible and likely an error in the data.

**P-gp Efflux:** Ligand A (0.776) has moderate P-gp efflux. Ligand B (0.01) has very low P-gp efflux, which is a significant advantage for CNS penetration.

**Binding Affinity:** Ligand A (-9.4 kcal/mol) has significantly stronger binding affinity than Ligand B (-6.4 kcal/mol). This is a substantial advantage, potentially outweighing some of the ADME drawbacks.

**Overall Assessment:**

Ligand A has a stronger binding affinity and better QED, but suffers from higher logP, moderate BBB penetration, and higher clearance. Ligand B has better ADME properties (lower DILI, lower clearance, lower P-gp efflux), but significantly weaker binding affinity and a problematic negative half-life.

Given the importance of binding affinity for GPCRs, and the substantial difference (-3 kcal/mol is significant), Ligand A is the more promising candidate *despite* its ADME liabilities. The strong binding could potentially be optimized through further medicinal chemistry efforts to address the logP and BBB issues. The negative half-life for Ligand B is a showstopper.

Output:
1
2025-04-17 07:19:28,155 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (361.47 and 348.49 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Both ligands have TPSA values (80.32 and 78.43) below the 90 A^2 threshold desirable for CNS targets, which is good.

**3. logP:** Both ligands have logP values (3.17 and 2.44) within the optimal 1-3 range.

**4. H-Bond Donors:** Ligand A (2) and Ligand B (3) are both within the acceptable limit of <=5.

**5. H-Bond Acceptors:** Ligand A (5) and Ligand B (3) are both within the acceptable limit of <=10.

**6. QED:** Ligand A (0.828) has a significantly better QED score than Ligand B (0.69), indicating a more drug-like profile.

**7. DILI:** Ligand A (73.98) has a higher DILI risk than Ligand B (20.9), which is a negative.

**8. BBB:** Ligand A (46.34) and Ligand B (44.98) both have low BBB penetration, which is a significant concern for a CNS target like DRD2. However, they are relatively similar.

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.808 and -4.717). This is unusual and suggests poor permeability.

**10. Aqueous Solubility:** Both ligands have negative solubility values (-4.355 and -3.182), indicating very poor aqueous solubility.

**11. hERG Inhibition:** Both ligands have low hERG inhibition liability (0.473 and 0.174), which is good.

**12. Microsomal Clearance:** Ligand A (78.35) has higher microsomal clearance than Ligand B (50.25), suggesting lower metabolic stability.

**13. In vitro Half-Life:** Ligand B (-9.025) has a significantly longer in vitro half-life than Ligand A (0.898), which is a major advantage.

**14. P-gp Efflux:** Both ligands have low P-gp efflux liability (0.132 and 0.143), which is good.

**15. Binding Affinity:** Ligand A (-7.9 kcal/mol) has a slightly better binding affinity than Ligand B (-8.4 kcal/mol). While the difference is small, it's still a positive.

**Overall Assessment:**

Despite the similar BBB and Caco-2 permeability values, Ligand A is slightly favored due to its better QED score and marginally better binding affinity. However, the DILI risk is significantly higher for Ligand A. Ligand B has a much better in vitro half-life, which is a crucial factor for drug development. The poor solubility and permeability are concerning for both, but the longer half-life of Ligand B could potentially compensate for some of those issues. Given the importance of metabolic stability and the relatively small difference in binding affinity, I would lean towards Ligand B.

Output:
1
2025-04-17 07:19:28,155 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (346.431 and 358.404 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (113.32) is slightly above the optimal <90 for CNS targets, but still reasonable. Ligand B (49.41) is excellent, well below 90.

**logP:** Both ligands have good logP values (2.591 and 3.094), falling within the 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A has 4 HBD and 3 HBA, which is acceptable. Ligand B has 1 HBD and 4 HBA, also acceptable.

**QED:** Both ligands have reasonable QED scores (0.496 and 0.794), with Ligand B being significantly better, indicating a more drug-like profile.

**DILI:** Ligand A (61.07) has a slightly higher DILI risk than Ligand B (57.697), but both are still within an acceptable range (<60 is good).

**BBB:** This is a critical parameter for CNS targets. Ligand B (93.757) has a much higher BBB penetration percentile than Ligand A (75.378). This is a significant advantage for Ligand B.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.889 and -4.723), which is unusual and suggests poor permeability. This is a concern for both.

**Aqueous Solubility:** Both ligands have negative solubility values (-4.716 and -4.954), indicating poor aqueous solubility, which could hinder formulation and bioavailability.

**hERG Inhibition:** Ligand A (0.4) has a slightly lower hERG inhibition liability than Ligand B (0.916), which is preferable.

**Microsomal Clearance:** Ligand B (30.676) has a lower microsomal clearance than Ligand A (38.157), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand B (36.116) has a longer in vitro half-life than Ligand A (22.657), which is desirable.

**P-gp Efflux:** Ligand A (0.09) has a lower P-gp efflux liability than Ligand B (0.399), which is beneficial for CNS exposure.

**Binding Affinity:** Ligand B (-9.4 kcal/mol) has a *much* stronger binding affinity than Ligand A (0.0 kcal/mol). This is the most significant difference between the two ligands. A difference of >1.5 kcal/mol often outweighs other ADME drawbacks.

**Overall Assessment:**

While both ligands have issues with Caco-2 permeability and aqueous solubility, Ligand B is clearly superior due to its significantly higher BBB penetration, much stronger binding affinity, lower microsomal clearance, and longer half-life. The slightly higher P-gp efflux is a minor concern compared to the substantial benefits of the other parameters. Ligand A's low binding affinity is a major drawback.

Output:
1
2025-04-17 07:19:28,155 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 drug candidates, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (371.453 and 369.446 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (71.09) is slightly higher than Ligand B (64.43). Both are below the 90 A^2 threshold desirable for CNS targets, which is good.

**logP:** Both ligands have good logP values (2.608 and 2.835), falling within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A has 2 HBD and 4 HBA, while Ligand B has 0 HBD and 5 HBA. Both are within acceptable limits (<=5 HBD and <=10 HBA).

**QED:** Both ligands have similar QED values (0.621 and 0.628), indicating good drug-likeness.

**DILI:** Ligand A (35.983) has a significantly lower DILI risk than Ligand B (14.23). This is a substantial advantage for Ligand A.

**BBB:** Both ligands have excellent BBB penetration (81 and 83.094 percentile), exceeding the desirable >70 threshold for CNS targets.

**Caco-2 Permeability:** Both ligands have negative Caco-2 permeability values (-4.68 and -4.451). This is unusual and suggests poor intestinal absorption. However, for a CNS target, intestinal absorption is less critical than BBB penetration.

**Aqueous Solubility:** Both ligands have negative solubility values (-3.086 and -1.827). This is a concern, but can be mitigated with formulation strategies.

**hERG Inhibition:** Both ligands show low hERG inhibition liability (0.301 and 0.445), which is favorable.

**Microsomal Clearance:** Ligand A (37.059) has lower microsomal clearance than Ligand B (64.97), indicating better metabolic stability.

**In vitro Half-Life:** Ligand A (-3.406) has a more negative (longer) in vitro half-life than Ligand B (13.649). This is a significant advantage.

**P-gp Efflux:** Ligand A (0.049) has much lower P-gp efflux liability than Ligand B (0.218), which is crucial for CNS penetration.

**Binding Affinity:** Ligand A (-8.3 kcal/mol) has a significantly stronger binding affinity than Ligand B (-6.4 kcal/mol). This >1.5 kcal/mol difference is a major advantage, potentially outweighing minor ADME drawbacks.

**Overall Assessment:**

Ligand A is superior to Ligand B. It has a much lower DILI risk, better metabolic stability (lower Cl_mic, longer t1/2), lower P-gp efflux, and significantly stronger binding affinity. While both have similar BBB penetration and logP, the combined advantages of Ligand A make it the more promising drug candidate. The negative Caco-2 and solubility values are concerns, but less critical for a CNS-targeted GPCR.

Output:
1
2025-04-17 07:19:28,155 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (359.352 and 361.431 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (71.33) is significantly better than Ligand B (105.9). For CNS targets, we want TPSA <= 90, and A is comfortably within that range, while B exceeds it.

**3. logP:** Ligand A (1.108) is within the optimal 1-3 range. Ligand B (0.257) is a bit low, potentially hindering permeability.

**4. H-Bond Donors:** Both have acceptable HBD counts (0 for A, 1 for B), well below the threshold of 5.

**5. H-Bond Acceptors:** Ligand A (5) is better than Ligand B (8), but both are within the acceptable limit of 10.

**6. QED:** Both ligands have reasonable QED values (0.811 and 0.74), indicating good drug-like properties.

**7. DILI:** Ligand A (50.911) has a lower DILI risk than Ligand B (74.409), which is preferable.

**8. BBB:** Ligand A (85.925) has a much higher BBB penetration percentile than Ligand B (52.811). This is *critical* for a CNS target like DRD2.

**9. Caco-2 Permeability:** Ligand A (-4.568) is better than Ligand B (-5.647), indicating better intestinal absorption.

**10. Aqueous Solubility:** Ligand A (-2.064) is better than Ligand B (-1.303), indicating better solubility.

**11. hERG Inhibition:** Both ligands show very low hERG inhibition liability (0.232 and 0.009), which is excellent.

**12. Microsomal Clearance:** Both have similar microsomal clearance values (16.648 and 17.871), suggesting comparable metabolic stability.

**13. In vitro Half-Life:** Ligand A (-21.351) has a longer in vitro half-life than Ligand B (-3.072), which is favorable.

**14. P-gp Efflux:** Both ligands show low P-gp efflux liability (0.076 and 0.065).

**15. Binding Affinity:** Ligand B (-7.9) has a slightly better binding affinity than Ligand A (-7.5), but the difference is only 0.4 kcal/mol. Given the other significant advantages of Ligand A, this difference is unlikely to be decisive.

**Conclusion:**

Considering all factors, especially the GPCR-specific priorities (BBB, logP, TPSA), Ligand A is the more promising drug candidate. Its superior BBB penetration, lower TPSA, better logP, lower DILI risk, better solubility, and longer half-life outweigh the slightly weaker binding affinity compared to Ligand B.

Output:
1
2025-04-17 07:19:28,155 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight (MW):** Both ligands (352.385 and 366.487 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Both ligands (75.19 and 75.63) are below the 90 A^2 threshold for CNS targets, which is excellent.

**3. logP:** Both ligands (1.965 and 1.806) are within the optimal range of 1-3, indicating good potential for membrane permeability.

**4. H-Bond Donors (HBD):** Ligand A (1) is preferable to Ligand B (0) as having at least one HBD can improve solubility.

**5. H-Bond Acceptors (HBA):** Ligand A (4) is preferable to Ligand B (6) as lower HBA generally improves permeability.

**6. QED:** Both ligands have good QED scores (0.794 and 0.815), suggesting good drug-like properties.

**7. DILI:** Both ligands have acceptable DILI risk (52.695 and 47.964), below the 60 threshold. Ligand B is slightly better.

**8. BBB:** Ligand A (87.476) has a significantly better BBB penetration percentile than Ligand B (79.682). This is a crucial advantage for a CNS target like DRD2.

**9. Caco-2 Permeability:** Both have negative Caco-2 values (-4.776 and -4.734), which is unusual and suggests poor permeability. However, these values are on a log scale and are likely indicating very low permeability.

**10. Aqueous Solubility:** Both have negative solubility values (-1.894 and -2.687) which is also unusual and suggests poor solubility.

**11. hERG Inhibition:** Both ligands have low hERG inhibition risk (0.412 and 0.35).

**12. Microsomal Clearance (Cl_mic):** Ligand A (10.211) has a lower microsomal clearance than Ligand B (43.638), indicating better metabolic stability.

**13. In vitro Half-Life:** Ligand A (-15.151) has a significantly longer in vitro half-life than Ligand B (8.402).

**14. P-gp Efflux:** Ligand A (0.03) has a much lower P-gp efflux liability than Ligand B (0.35), which is highly desirable for CNS penetration.

**15. Binding Affinity:** Ligand B (0.0 kcal/mol) has a significantly better binding affinity than Ligand A (-8.9 kcal/mol). This is a substantial advantage.

**Overall Assessment:**

While Ligand B boasts a superior binding affinity, Ligand A demonstrates a more favorable ADME profile, particularly regarding BBB penetration (87.5% vs 79.7%), P-gp efflux (0.03 vs 0.35), and metabolic stability (lower Cl_mic and longer t1/2). The difference in binding affinity (0 vs -8.9 kcal/mol) is significant, but the improved CNS penetration and reduced efflux of Ligand A could compensate for the slightly weaker binding, especially considering the challenges of achieving sufficient brain exposure. Given the GPCR-specific priorities, the better BBB and P-gp properties of Ligand A outweigh the binding affinity advantage of Ligand B.

Output:
1
2025-04-17 07:19:28,155 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (407.352 Da) is slightly higher than Ligand B (361.833 Da), but both are acceptable.

**TPSA:** Ligand A (41.57) is excellent for CNS penetration, well below the 90 A^2 threshold. Ligand B (88.08) is higher, but still potentially acceptable, though less ideal for CNS targets.

**logP:** Ligand A (4.86) is a bit high, potentially leading to solubility issues or off-target interactions. Ligand B (2.114) is within the optimal range (1-3).

**H-Bond Donors/Acceptors:** Both ligands have 1 HBD, which is good. Ligand A has 2 HBA, and Ligand B has 5 HBA. Both are within acceptable limits (<=10).

**QED:** Both ligands have good QED scores (A: 0.709, B: 0.851), indicating good drug-like properties.

**DILI:** Ligand A (39.938) has a lower DILI risk than Ligand B (71.85), which is a significant advantage.

**BBB:** Ligand A (88.988) has a much better BBB penetration score than Ligand B (43.932). This is crucial for a CNS target like DRD2.

**Caco-2 Permeability:** Both have negative Caco-2 values which is unusual and suggests a potential issue with the data. However, we will proceed assuming this is a data artifact.

**Aqueous Solubility:** Both ligands have very poor aqueous solubility (-5.876 and -3.094 respectively). This is a concern, but can sometimes be mitigated with formulation strategies.

**hERG:** Ligand A (0.731) has a slightly higher hERG risk than Ligand B (0.198), but both are relatively low.

**Microsomal Clearance:** Ligand A (94.487) has a higher microsomal clearance than Ligand B (44.511), suggesting lower metabolic stability.

**In vitro Half-Life:** Ligand A (44.187) has a slightly longer half-life than Ligand B (39.98), but the difference is not substantial.

**P-gp Efflux:** Ligand A (0.476) has lower P-gp efflux liability than Ligand B (0.115), which is favorable for CNS penetration.

**Binding Affinity:** Ligand B (-8.9 kcal/mol) has a significantly stronger binding affinity than Ligand A (-7.3 kcal/mol). This is a substantial advantage (1.6 kcal/mol difference).

**Overall Assessment:**

Ligand B has a significantly better binding affinity, a more optimal logP, and lower P-gp efflux. However, Ligand A has a much better BBB score, lower DILI risk, and lower P-gp efflux. The poor solubility of both is a concern. Given the importance of BBB penetration for a CNS target like DRD2, and the substantial affinity advantage of Ligand B, I believe Ligand B is the more promising candidate, despite the higher DILI risk and lower BBB score. The affinity difference is large enough to potentially overcome the other drawbacks.

Output:
1
2025-04-17 07:19:28,156 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (353.463 and 347.463 Da) are within the ideal range of 200-500 Da.

**2. TPSA:** Both ligands (107.53 and 106.96) are below the 140 A^2 threshold for oral absorption, but slightly above the more stringent 90 A^2 for CNS targets. This is not a major concern, as other factors can compensate.

**3. logP:** Ligand A (0.75) is a bit low, potentially hindering permeation. Ligand B (3.367) is within the optimal range of 1-3. This favors Ligand B.

**4. H-Bond Donors:** Ligand A (4) is acceptable, while Ligand B (2) is even better, potentially improving permeability.

**5. H-Bond Acceptors:** Both ligands (A: 4, B: 3) are well within the acceptable limit of 10.

**6. QED:** Ligand A (0.516) is marginally drug-like, while Ligand B (0.319) is below the 0.5 threshold, indicating a less favorable drug-like profile. This favors Ligand A.

**7. DILI Risk:** Ligand A (15.898) has a significantly lower DILI risk than Ligand B (35.75). This is a strong advantage for Ligand A.

**8. BBB Penetration:** Ligand A (46.568) has a lower BBB percentile than Ligand B (55.293). While neither is above the desirable >70 for CNS targets, Ligand B is better.

**9. Caco-2 Permeability:** Ligand A (-5.325) has poor Caco-2 permeability, while Ligand B (-4.758) is slightly better, but both are quite low.

**10. Aqueous Solubility:** Ligand A (-1.396) has slightly better solubility than Ligand B (-3.206).

**11. hERG Inhibition:** Both ligands have very low hERG inhibition risk (A: 0.047, B: 0.215).

**12. Microsomal Clearance:** Ligand A (16.955) has lower microsomal clearance than Ligand B (51.602), suggesting better metabolic stability. This favors Ligand A.

**13. In vitro Half-Life:** Ligand A (-2.495) has a slightly longer in vitro half-life than Ligand B (-3.486).

**14. P-gp Efflux:** Both ligands have very low P-gp efflux liability (A: 0.006, B: 0.118).

**15. Binding Affinity:** Ligand B (-8.1 kcal/mol) has a significantly stronger binding affinity than Ligand A (-7.4 kcal/mol). This is a substantial advantage for Ligand B, potentially outweighing some of its ADME drawbacks. The difference is >1.5 kcal/mol.

**Overall Assessment:**

Ligand B has a superior binding affinity and better BBB penetration, which are crucial for a CNS target like DRD2. However, it has a higher DILI risk and a lower QED score. Ligand A has a better safety profile (lower DILI) and better metabolic stability, but its logP is low and its affinity is weaker.

Given the strong affinity advantage of Ligand B (-8.1 vs -7.4 kcal/mol), and its better BBB penetration, I believe it is the more promising candidate, despite the slightly higher DILI risk. The affinity difference is significant enough to warrant further optimization focused on mitigating the DILI risk.

Output:
1
2025-04-17 07:19:28,156 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B based on the provided guidelines, prioritizing GPCR-specific properties (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (357.845 and 346.431 Da) fall within the ideal 200-500 Da range.

**TPSA:** Both ligands have TPSA values (76.73 and 74.65) that are above the optimal <90 for CNS targets, but not drastically so. This is a minor concern.

**logP:** Ligand A (3.306) is within the optimal 1-3 range. Ligand B (0.265) is significantly below this, which is a major drawback as it may hinder permeation.

**H-Bond Donors/Acceptors:** Both ligands have acceptable HBD (1) and HBA (6 & 5) counts, well within the guidelines.

**QED:** Both ligands have similar QED values (0.699 and 0.613), indicating good drug-likeness.

**DILI:** Ligand A (70.492) has a higher DILI risk than Ligand B (32.959). This is a negative for Ligand A, but not a disqualifier.

**BBB:** Both ligands have similar BBB penetration percentiles (57.852 and 58.782). Neither is above the desirable >70 for CNS targets, but they are comparable.

**Caco-2 Permeability:** Ligand A (-5.592) has a negative Caco-2 permeability, which is concerning. Ligand B (-4.913) is also negative, but less so.

**Aqueous Solubility:** Both ligands have very poor aqueous solubility (-3.198 and -1.01). This is a significant issue for both, potentially impacting bioavailability.

**hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.261 and 0.071).

**Microsomal Clearance:** Ligand A (35.967) has higher microsomal clearance than Ligand B (10.736), suggesting lower metabolic stability.

**In vitro Half-Life:** Ligand B (-12.362) has a negative in vitro half-life, which is a major concern. Ligand A (35.941) is positive, indicating a longer half-life.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.138 and 0.017).

**Binding Affinity:** Ligand A (-9.5 kcal/mol) has a significantly stronger binding affinity than Ligand B (-7.9 kcal/mol). This is a substantial advantage, potentially outweighing some of the ADME drawbacks.

**Overall Assessment:**

Ligand A has a superior binding affinity and better metabolic stability (longer half-life) despite a higher DILI risk. The biggest drawback for Ligand A is its poor Caco-2 permeability and aqueous solubility. However, the strong affinity is a major positive. Ligand B suffers from a very low logP, poor half-life, and while its DILI risk is lower, its affinity is considerably weaker. For a CNS target, the logP of Ligand B is particularly concerning as it will significantly limit brain penetration.

Given the GPCR-specific priorities, the strong binding affinity of Ligand A is the most important factor. While its ADME properties are not ideal, they might be improved through further optimization. The poor logP of Ligand B is a more fundamental issue that is harder to overcome.

Output:
1
2025-04-17 07:19:28,156 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (345.443 and 346.471 Da) fall comfortably within the ideal 200-500 Da range.

**TPSA:** Ligand A (91.22) is slightly above the preferred <90 for CNS targets, but still reasonable. Ligand B (58.64) is excellent, well below 90.

**logP:** Both ligands have good logP values (1.508 and 2.431), falling within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A has 2 HBD and 4 HBA, while Ligand B has 1 HBD and 3 HBA. Both are within acceptable limits (<=5 HBD and <=10 HBA).

**QED:** Both ligands have similar QED values (0.79 and 0.778), indicating good drug-likeness.

**DILI:** Ligand A (33.695) has a slightly higher DILI risk than Ligand B (13.532), but both are below the concerning threshold of 40, indicating low risk.

**BBB:** This is a crucial parameter for CNS targets. Ligand B (71.229) has a significantly better BBB percentile than Ligand A (62.97). This is a major advantage for Ligand B.

**Caco-2 Permeability:** Ligand A (-5.046) exhibits poor Caco-2 permeability, suggesting poor intestinal absorption. Ligand B (-4.786) is also poor, but slightly better than Ligand A.

**Aqueous Solubility:** Both ligands have very poor aqueous solubility (-3.474 and -2.6), which could pose formulation challenges.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.352 and 0.296).

**Microsomal Clearance:** Both ligands have similar microsomal clearance values (29.252 and 29.143), indicating similar metabolic stability.

**In vitro Half-Life:** Ligand A (14.453) has a longer half-life than Ligand B (4.266), which is generally desirable.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.062 and 0.047), which is favorable for CNS penetration.

**Binding Affinity:** Ligand A (-8.9 kcal/mol) has a slightly better binding affinity than Ligand B (-8.5 kcal/mol). This 0.4 kcal/mol difference is significant, but needs to be weighed against other factors.

**Overall Assessment:**

While Ligand A has a slightly better binding affinity and longer half-life, Ligand B is superior due to its significantly better BBB penetration (71.229 vs 62.97) and lower DILI risk. The TPSA is also much more favorable. The difference in binding affinity (0.4 kcal/mol) is not large enough to outweigh the substantial advantages of Ligand B regarding CNS penetration and safety. The poor solubility and Caco-2 permeability are concerns for both, but can potentially be addressed with formulation strategies.

Output:
1
2025-04-17 07:19:28,156 - INFO - Batch 355 complete. Total preferences: 5680
2025-04-17 07:19:28,156 - INFO - Processing batch 356/512...
2025-04-17 07:20:08,374 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (356.34 and 348.378 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (52.6) is significantly better than Ligand B (90.87).  For CNS targets, we want TPSA <= 90, so Ligand A is much more favorable.

**3. logP:** Both ligands have good logP values (2.962 and 2.848), falling within the optimal 1-3 range.

**4. H-Bond Donors:** Ligand A (0) is preferable to Ligand B (2) as fewer HBDs generally improve permeability.

**5. H-Bond Acceptors:** Both ligands have 4 HBA, which is acceptable (<=10).

**6. QED:** Both ligands have good QED values (0.601 and 0.801), indicating good drug-like properties. Ligand B is slightly better.

**7. DILI:** Ligand A (48.313) has a lower DILI risk than Ligand B (72.043). Both are acceptable, but A is better.

**8. BBB:** Ligand A (97.131) has a *much* higher predicted BBB penetration than Ligand B (66.964). This is a critical advantage for a CNS target like DRD2.

**9. Caco-2 Permeability:** Both have negative values, indicating poor permeability. However, the scale is not specified, so it is difficult to interpret.

**10. Aqueous Solubility:** Both have negative values, indicating poor solubility. Again, the scale is not specified, making interpretation difficult.

**11. hERG:** Both ligands have very low hERG inhibition liability (0.366 and 0.468), which is excellent.

**12. Microsomal Clearance:** Ligand A (57.128) has higher clearance than Ligand B (7.62). This suggests Ligand B is more metabolically stable, which is desirable.

**13. In vitro Half-Life:** Ligand B (12.696) has a significantly longer half-life than Ligand A (-10.95). This is a major advantage for Ligand B.

**14. P-gp Efflux:** Both ligands have low P-gp efflux liability (0.298 and 0.116), which is good. Ligand B is slightly better.

**15. Binding Affinity:** Both ligands have excellent binding affinities (-9.0 and -8.5 kcal/mol). Ligand A has a 0.5 kcal/mol advantage, which is significant.

**Overall Assessment:**

While Ligand B has advantages in metabolic stability (lower Cl_mic, longer t1/2) and slightly better P-gp efflux, Ligand A is significantly superior in terms of BBB penetration and TPSA, both crucial for CNS GPCR targets. The slightly better binding affinity of Ligand A further strengthens its position. The DILI risk is also lower for Ligand A. The poor solubility and permeability are concerns for both, but the CNS focus makes BBB and TPSA paramount.

Output:
1
2025-04-17 07:20:08,374 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (362.411 and 367.764 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (112.44) is higher than Ligand B (89.55). For CNS targets, we prefer TPSA <= 90. Ligand B is better here.

**3. logP:** Both ligands (2.662 and 2.861) are within the optimal 1-3 range.

**4. H-Bond Donors:** Ligand A (0) is better than Ligand B (2). Fewer HBDs generally improve permeability.

**5. H-Bond Acceptors:** Both ligands have 5 HBA, which is acceptable (<=10).

**6. QED:** Ligand B (0.605) has a better QED score than Ligand A (0.354), indicating a more drug-like profile.

**7. DILI:** Ligand A (65.646) has a lower DILI risk than Ligand B (95.386). This is a significant advantage for Ligand A.

**8. BBB:** Ligand A (78.558) has a significantly better BBB penetration percentile than Ligand B (54.595). This is crucial for a CNS target like DRD2.

**9. Caco-2:** Both have negative values, which is unusual. Assuming these are percentile scores, Ligand A (-4.435) is slightly better than Ligand B (-4.59).

**10. Solubility:** Both have negative values, indicating poor solubility. Ligand A (-4.292) is slightly better than Ligand B (-4.754).

**11. hERG:** Both ligands have low hERG inhibition liability (0.466 and 0.346).

**12. Cl_mic:** Ligand A (70.414) has lower microsomal clearance than Ligand B (80.03), suggesting better metabolic stability.

**13. t1/2:** Ligand B (43.439) has a significantly longer in vitro half-life than Ligand A (-20.81). This is a substantial advantage for Ligand B.

**14. Pgp:** Both ligands have very low P-gp efflux liability (0.197 and 0.111).

**15. Binding Affinity:** Both ligands have similar binding affinities (-8.5 and -8.6 kcal/mol), which are excellent.

**Overall Assessment:**

While Ligand B has a better QED and a much longer half-life, Ligand A excels in crucial areas for a CNS-targeting GPCR ligand: significantly better BBB penetration, lower DILI risk, and lower microsomal clearance. The TPSA is also more favorable for Ligand A. Given the importance of CNS penetration for DRD2, and the acceptable affinity of both compounds, Ligand A is the more promising candidate.

Output:
0
2025-04-17 07:20:08,374 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (360.479 and 350.383 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (66.48) is excellent, well below the 90 A^2 threshold for CNS targets. Ligand B (139.85) is approaching the upper limit for good oral absorption (140 A^2) and is less desirable for CNS penetration.

**logP:** Ligand A (3.079) is optimal (1-3). Ligand B (-1.734) is too low, potentially hindering permeation.

**H-Bond Donors/Acceptors:** Ligand A (HBD=1, HBA=3) is within acceptable limits. Ligand B (HBD=3, HBA=9) is borderline, with the HBA count being relatively high.

**QED:** Ligand A (0.824) is excellent, indicating strong drug-likeness. Ligand B (0.488) is below the 0.5 threshold, suggesting a less favorable drug-like profile.

**DILI:** Ligand B (64.521) has a higher DILI risk than Ligand A (55.913), though both are reasonably acceptable.

**BBB:** Ligand A (72.237) has a good BBB penetration percentile, exceeding the 70% target for CNS drugs. Ligand B (19.93) is very poor for CNS penetration.

**Caco-2 Permeability:** Ligand A (-4.762) and Ligand B (-5.924) both have negative Caco-2 values, indicating poor permeability. This is a concern for both, but less critical given the CNS target.

**Aqueous Solubility:** Ligand A (-4.935) and Ligand B (-0.97) both have negative solubility values, indicating poor solubility.

**hERG Inhibition:** Ligand A (0.632) has a low hERG risk. Ligand B (0.031) also has a very low hERG risk.

**Microsomal Clearance:** Ligand A (50.463) has moderate clearance. Ligand B (3.694) has very low clearance, which is favorable for metabolic stability.

**In vitro Half-Life:** Ligand B (17.636) has a significantly longer half-life than Ligand A (5.204).

**P-gp Efflux:** Ligand A (0.171) has low P-gp efflux, which is good. Ligand B (0.021) has very low P-gp efflux, which is even better.

**Binding Affinity:** Ligand A (-11.2 kcal/mol) has a significantly stronger binding affinity than Ligand B (-7.5 kcal/mol). The difference of 3.7 kcal/mol is substantial and can outweigh many ADME drawbacks.

**Conclusion:**

Despite Ligand B's better metabolic stability (lower Cl_mic, longer t1/2) and P-gp efflux, Ligand A is the superior candidate. The significantly stronger binding affinity (-11.2 vs -7.5 kcal/mol) is a major advantage, especially for a GPCR target. Additionally, Ligand A's superior TPSA and BBB penetration are critical for CNS activity. While Ligand A has moderate clearance and solubility issues, these can potentially be addressed through formulation or structural modifications. The poor logP and Caco-2 values of Ligand B are more difficult to overcome.

Output:
1
2025-04-17 07:20:08,374 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (340.39 Da) is slightly lower, which is generally favorable for permeability.

**TPSA:** Ligand A (100.97) is better than Ligand B (114.34) as it is closer to the <90 target for CNS penetration.

**logP:** Ligand A (0.804) is slightly lower than the optimal 1-3 range, but still acceptable. Ligand B (-0.7) is below 1, which could hinder permeation.

**H-Bond Donors/Acceptors:** Ligand A (1 HBD, 6 HBA) and Ligand B (2 HBD, 6 HBA) both fall within reasonable limits.

**QED:** Ligand A (0.864) has a higher QED score than Ligand B (0.65), indicating better overall drug-likeness.

**DILI:** Ligand B (58.434) has a slightly lower DILI risk than Ligand A (65.452), but both are acceptable.

**BBB:** Ligand B (68.864) has a slightly better BBB penetration percentile than Ligand A (64.133), but both are below the desirable >70 for CNS targets.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values, which is unusual and suggests poor permeability.

**Aqueous Solubility:** Both ligands have negative solubility values, which is also unusual and suggests poor solubility.

**hERG Inhibition:** Ligand A (0.086) has a much lower hERG inhibition liability than Ligand B (0.333), which is a significant advantage.

**Microsomal Clearance:** Ligand B (-7.842) has a much lower (better) microsomal clearance than Ligand A (3.865), indicating greater metabolic stability.

**In vitro Half-Life:** Ligand B (43.177) has a significantly longer in vitro half-life than Ligand A (-6.435), which is highly desirable.

**P-gp Efflux:** Ligand A (0.009) has a much lower P-gp efflux liability than Ligand B (0.068), which is favorable for CNS exposure.

**Binding Affinity:** Both ligands have excellent binding affinities (-8.7 kcal/mol and -8.2 kcal/mol). Ligand A has a slightly better affinity, but the difference is small.

**Overall Assessment:**

Considering the GPCR-specific priorities, Ligand A is slightly favored. While Ligand B has better metabolic stability (lower Cl_mic and longer t1/2) and a slightly better BBB score, Ligand A has a better TPSA, QED, lower hERG risk, and lower P-gp efflux. The slightly better affinity of Ligand A, combined with its more favorable ADME properties (especially hERG and P-gp), makes it a more promising candidate. The negative Caco-2 and solubility values are concerning for both, but could be addressed through formulation strategies.

Output:
0
2025-04-17 07:20:08,375 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (378.47 and 368.587 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (112.81) is better than Ligand B (49.41). For CNS targets, TPSA should be <= 90, and Ligand B is well within this range, while Ligand A is slightly above.

**3. logP:** Ligand B (3.699) is closer to the optimal 1-3 range than Ligand A (-0.795). A negative logP can indicate poor membrane permeability.

**4. H-Bond Donors:** Both ligands have acceptable HBD counts (2 and 1 respectively), well below the threshold of 5.

**5. H-Bond Acceptors:** Both ligands have acceptable HBA counts (5 and 3 respectively), well below the threshold of 10.

**6. QED:** Both ligands have good QED scores (0.651 and 0.675), indicating drug-like properties.

**7. DILI:** Ligand B (24.234) has a significantly lower DILI risk than Ligand A (44.668), which is a major advantage.

**8. BBB:** Ligand B (83.249) has a much higher BBB penetration score than Ligand A (66.033). This is *critical* for a CNS target like DRD2.

**9. Caco-2 Permeability:** Ligand A (-5.477) has a worse Caco-2 permeability compared to Ligand B (-4.903), though both are negative, which is unusual and requires further investigation.

**10. Aqueous Solubility:** Ligand A (-1.564) has slightly better solubility than Ligand B (-3.899).

**11. hERG Inhibition:** Both ligands have low hERG inhibition risk (0.283 and 0.617).

**12. Microsomal Clearance:** Ligand A (-3.031) has a lower (better) microsomal clearance than Ligand B (101.952), indicating greater metabolic stability.

**13. In vitro Half-Life:** Ligand A (-26.171) has a much longer in vitro half-life than Ligand B (-10.27), which is a significant advantage.

**14. P-gp Efflux:** Ligand A (0.041) has lower P-gp efflux than Ligand B (0.303), which is desirable for CNS penetration.

**15. Binding Affinity:** Both ligands have the same binding affinity (-7.1 kcal/mol), which is excellent.

**Overall Assessment:**

While Ligand A has better metabolic stability (lower Cl_mic, longer t1/2) and P-gp efflux, Ligand B is significantly better in terms of CNS penetration (higher BBB, lower Pgp) and safety (lower DILI). The negative logP of Ligand A is a concern, potentially hindering its ability to cross cell membranes. Given the GPCR-specific priorities for DRD2, BBB penetration and minimizing off-target effects (DILI) are paramount. The similar binding affinity makes these factors the deciding ones.

Output:
1
2025-04-17 07:20:08,376 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 drug candidates, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (406.276) is slightly higher than Ligand B (371.373), but both are acceptable.

**TPSA:** Ligand A (66.84) is better than Ligand B (115.16). For CNS targets, we want TPSA <= 90, so Ligand A is closer to this threshold. Ligand B is significantly higher and could hinder BBB penetration.

**logP:** Both ligands have good logP values (A: 2.911, B: 1.228) within the optimal range of 1-3.

**H-Bond Donors/Acceptors:** Ligand A (HBD=1, HBA=4) and Ligand B (HBD=0, HBA=6) both have reasonable numbers of H-bond donors and acceptors, falling within the guidelines.

**QED:** Ligand A (0.75) has a better QED score than Ligand B (0.44), indicating a more drug-like profile.

**DILI:** Both ligands have moderate DILI risk (A: 59.984, B: 63.164). Neither is particularly concerning, but lower is always preferred.

**BBB:** Ligand B (67.972) has a slightly better BBB percentile than Ligand A (54.207), but both are below the desirable >70 for CNS targets. This is a critical factor, and both will likely require further optimization.

**Caco-2 Permeability:** Ligand A (-4.683) has a worse Caco-2 permeability than Ligand B (-5.028). Lower values indicate poorer permeability.

**Aqueous Solubility:** Ligand A (-3.046) has better solubility than Ligand B (-1.544).

**hERG Inhibition:** Ligand A (0.8) has a slightly higher hERG risk than Ligand B (0.092). Lower is better here.

**Microsomal Clearance:** Ligand B (5.81) has significantly lower microsomal clearance than Ligand A (72.396), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (5.213) has a better in vitro half-life than Ligand B (-1.538).

**P-gp Efflux:** Ligand A (0.539) has lower P-gp efflux than Ligand B (0.043), which is favorable for CNS penetration.

**Binding Affinity:** Ligand A (-8.9 kcal/mol) has a significantly stronger binding affinity than Ligand B (-7.1 kcal/mol). This is a substantial difference (>1.5 kcal/mol advantage) and can outweigh some ADME drawbacks.

**Overall Assessment:**

Ligand A demonstrates a significantly better binding affinity and a more favorable QED score. While its BBB penetration is not ideal, its superior affinity and lower P-gp efflux are compelling. Ligand B has better metabolic stability (lower Cl_mic) and slightly better BBB, but its weaker binding affinity and higher TPSA are significant drawbacks, especially for a CNS target. The stronger binding of Ligand A is likely to be more impactful for efficacy.

Output:
1
2025-04-17 07:20:08,376 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B based on the provided guidelines, keeping in mind DRD2 is a GPCR and thus BBB, logP, Pgp, TPSA, and affinity are paramount.

**Molecular Weight:** Both ligands (360.845 and 364.486 Da) are within the ideal 200-500 Da range.

**TPSA:** Ligand A (78.09) is better than Ligand B (42.43). For CNS targets, TPSA should be <=90, both are well within this range, but A is slightly higher.

**logP:** Both ligands have good logP values (2.471 and 3.503), falling within the optimal 1-3 range. Ligand B is slightly higher, which *could* indicate a potential for off-target effects, but isn't a major concern.

**H-Bond Donors/Acceptors:** Ligand A has 2 HBD and 3 HBA, while Ligand B has 0 HBD and 4 HBA. Both are within acceptable limits (<=5 HBD and <=10 HBA).

**QED:** Ligand A (0.869) has a better QED score than Ligand B (0.725), indicating a more drug-like profile.

**DILI:** Ligand A (56.844) has a slightly higher DILI risk than Ligand B (49.399), but both are below the concerning threshold of 60.

**BBB:** This is a critical parameter for a CNS target. Ligand B (87.515) *significantly* outperforms Ligand A (60.372). A BBB percentile >70 is desirable, and Ligand B is much closer to that goal.

**Caco-2 Permeability:** Ligand A (-5.227) has a negative Caco-2 value, which is unusual and suggests poor permeability. Ligand B (-4.121) is also negative, but less so.

**Aqueous Solubility:** Both ligands have poor aqueous solubility (-3.749 and -4.941). This is a potential issue for formulation, but can sometimes be overcome.

**hERG Inhibition:** Ligand A (0.167) has a slightly lower hERG risk than Ligand B (0.55).

**Microsomal Clearance:** Ligand A (-1.368) has lower (better) microsomal clearance than Ligand B (113.513), indicating better metabolic stability. This is a significant advantage for A.

**In vitro Half-Life:** Ligand A (-38.719) has a very negative half-life, which is concerning. Ligand B (-26.949) is also negative, but less so.

**P-gp Efflux:** Ligand A (0.09) has lower P-gp efflux than Ligand B (0.184), which is favorable for CNS penetration.

**Binding Affinity:** Ligand B (-6.9 kcal/mol) has a significantly stronger binding affinity than Ligand A (0.0 kcal/mol). This is a major advantage for Ligand B. A difference of >1.5 kcal/mol often outweighs other drawbacks.

**Overall Assessment:**

While Ligand A has better QED, metabolic stability, and P-gp efflux, Ligand B's *much* higher BBB penetration and significantly stronger binding affinity are decisive. The negative Caco-2 and half-life values for both are concerning, but the potency and CNS penetration of Ligand B are more critical for a DRD2 target. The slightly higher logP of B is a minor concern compared to the substantial benefit in affinity and BBB.

Output:
1
2025-04-17 07:20:08,376 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (364.324 and 342.439 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (97.55) is slightly higher than the ideal <90 for CNS targets, but still reasonable. Ligand B (67.43) is well within the desired range.

**logP:** Ligand A (0.759) is a bit low, potentially hindering permeability. Ligand B (2.364) is within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A has 1 HBD and 7 HBA, which are acceptable. Ligand B has 2 HBD and 3 HBA, also acceptable.

**QED:** Both ligands have similar QED values (0.775 and 0.748), indicating good drug-like properties.

**DILI:** Both ligands have similar DILI risk (56.34 and 56.844), placing them in a moderate risk category. This isn't a major differentiator.

**BBB:** Ligand A has a significantly better BBB penetration percentile (76.037) compared to Ligand B (67.623). This is a crucial factor for a CNS target like DRD2.

**Caco-2 Permeability:** Ligand A (-4.437) and Ligand B (-4.67) have similar, negative Caco-2 permeability values, which is unusual and suggests poor intestinal absorption. This isn't a primary concern for a CNS target where direct delivery is possible.

**Aqueous Solubility:** Both ligands have poor aqueous solubility (-2.543 and -3.036). This could pose formulation challenges, but is less critical for CNS drugs that can bypass first-pass metabolism.

**hERG Inhibition:** Both ligands show low hERG inhibition liability (0.172 and 0.317), which is favorable.

**Microsomal Clearance:** Ligand A (37.357) has lower microsomal clearance than Ligand B (57.6), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (-23.536) has a much longer in vitro half-life than Ligand B (-10.564), which is a significant advantage.

**P-gp Efflux:** Both ligands show low P-gp efflux liability (0.117 and 0.177), which is good for CNS penetration.

**Binding Affinity:** Ligand B (-8.8 kcal/mol) has a slightly better binding affinity than Ligand A (-7.8 kcal/mol). This 1 kcal/mol difference is significant, but needs to be weighed against other factors.

**Overall Assessment:**

Ligand B has a better logP and binding affinity. However, Ligand A excels in BBB penetration and metabolic stability (lower Cl_mic, longer t1/2). Given the CNS target and the importance of brain exposure, the superior BBB score of Ligand A is a major advantage. The slightly better affinity of Ligand B is not enough to overcome Ligand A's better pharmacokinetic properties for a CNS-acting drug.

Output:
0
2025-04-17 07:20:08,376 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (342.403 and 344.459 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (87.12) is better than Ligand B (67.23) as it is closer to the ideal range for CNS targets (<=90).

**3. logP:** Both ligands have acceptable logP values (1.36 and 2.216, respectively), falling within the optimal range of 1-3. Ligand B is slightly higher, potentially offering better membrane permeability.

**4. H-Bond Donors:** Both have 1 HBD, which is within the acceptable limit of <=5.

**5. H-Bond Acceptors:** Ligand A has 5 HBA, and Ligand B has 4. Both are within the acceptable limit of <=10.

**6. QED:** Ligand A (0.859) has a significantly better QED score than Ligand B (0.609), indicating a more drug-like profile.

**7. DILI:** Ligand A (59.907) has a higher DILI risk than Ligand B (12.718). This is a significant drawback for Ligand A.

**8. BBB:** Ligand B (66.188) has a better BBB percentile than Ligand A (51.415). While both are not optimal (>70), Ligand B is closer. This is crucial for a CNS target like DRD2.

**9. Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and suggests poor permeability. However, the scale isn't defined, so it's hard to interpret.

**10. Aqueous Solubility:** Both have negative solubility values, which is also unusual and suggests poor solubility.

**11. hERG:** Both have very low hERG inhibition liability (0.507 and 0.246, respectively), which is excellent.

**12. Microsomal Clearance:** Ligand A (18.732) has higher microsomal clearance than Ligand B (15.889), indicating lower metabolic stability.

**13. In vitro Half-Life:** Ligand B (-10.823) has a longer in vitro half-life than Ligand A (-24.777).

**14. P-gp Efflux:** Both have very low P-gp efflux liability (0.04 and 0.057, respectively), which is favorable for CNS penetration.

**15. Binding Affinity:** Ligand B (-8.4 kcal/mol) has a slightly better binding affinity than Ligand A (-7.9 kcal/mol). While the difference is not huge, it's enough to consider.

**Overall Assessment:**

Ligand A has a better QED and TPSA, but suffers from higher DILI risk and lower BBB penetration, and worse metabolic stability. Ligand B has a better BBB, lower DILI, better metabolic stability, and slightly better binding affinity. Given the CNS target (DRD2), BBB penetration and safety (DILI) are paramount. The slight advantage in binding affinity of Ligand B, combined with its superior ADME properties, makes it the more promising candidate.

Output:
1
2025-04-17 07:20:08,377 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (361.511 and 347.419 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (62.3) is excellent, well below the 90 A^2 threshold for CNS targets. Ligand B (92.77) is higher, but still potentially acceptable, though less ideal.

**logP:** Ligand A (3.227) is optimal. Ligand B (-0.376) is significantly low, which could hinder membrane permeability and CNS penetration.

**H-Bond Donors & Acceptors:** Ligand A (HBD=1, HBA=4) and Ligand B (HBD=2, HBA=5) both have reasonable numbers of H-bond donors and acceptors, staying within the guidelines.

**QED:** Both ligands have similar QED values (0.791 and 0.728), indicating good drug-like properties.

**DILI:** Ligand A (46.375) has a slightly higher DILI risk than Ligand B (37.185), but both are below the concerning threshold of 60.

**BBB:** This is a critical parameter for a CNS target like DRD2. Ligand A shows a very good BBB penetration percentile (70.105). Ligand B is very poor (11.555).

**Caco-2 Permeability:** Ligand A (-4.904) and Ligand B (-5.263) both have negative values, which is unusual and suggests poor permeability. However, these values are on a scale that is not immediately clear without context, so we will consider this with caution.

**Aqueous Solubility:** Ligand A (-3.58) and Ligand B (-0.734) both have negative solubility values, which is also unusual and suggests poor solubility. Again, we will consider this with caution.

**hERG:** Ligand A (0.519) and Ligand B (0.165) both have low hERG inhibition liability, which is favorable.

**Microsomal Clearance:** Ligand A (55.119) has moderate clearance, while Ligand B (-11.521) has negative clearance, which is not possible and indicates an issue with the data.

**In vitro Half-Life:** Ligand A (5.365) has a reasonable half-life. Ligand B (-28.472) has a negative half-life, which is not possible and indicates an issue with the data.

**P-gp Efflux:** Ligand A (0.565) and Ligand B (0.033) both have low P-gp efflux liability, which is good.

**Binding Affinity:** Both ligands have similar and strong binding affinities (-8.1 and -8.3 kcal/mol). The difference is negligible.

**Conclusion:**

Ligand A is significantly better due to its superior BBB penetration (70.105 vs 11.555), optimal logP (3.227 vs -0.376), and more reasonable values for clearance and half-life. While Ligand B has a slightly better binding affinity, the poor logP and extremely low BBB penetration make it a much less viable candidate for a CNS-targeting drug. The negative values for clearance and half-life for Ligand B also raise concerns about data quality.

Output:
1
2025-04-17 07:20:08,377 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (354.422 and 377.535 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (71.78) is better than Ligand B (53.51). Both are below the 90 A^2 threshold desirable for CNS targets, but A is closer to the upper limit.

**3. logP:** Both ligands have good logP values (2.39 and 3.331), falling within the optimal 1-3 range. Ligand B is slightly higher, which *could* be a minor drawback if it impacts solubility.

**4. H-Bond Donors:** Ligand A has 1 HBD, while Ligand B has 0. Both are within the acceptable limit of <=5.

**5. H-Bond Acceptors:** Ligand A has 4 HBA, and Ligand B has 5. Both are within the acceptable limit of <=10.

**6. QED:** Both ligands have acceptable QED scores (0.851 and 0.776), indicating good drug-like properties.

**7. DILI:** Ligand A (29.236) has a significantly lower DILI risk than Ligand B (48.081). This is a substantial advantage for Ligand A.

**8. BBB:** Ligand A (89.027) has a much better BBB penetration percentile than Ligand B (77.084). This is *critical* for a CNS target like DRD2, making Ligand A significantly more promising.

**9. Caco-2 Permeability:** Both have negative values (-4.291 and -4.539). This is unusual and suggests poor permeability. However, the values are very close.

**10. Aqueous Solubility:** Both have negative values (-2.959 and -2.609). This is also unusual and suggests poor solubility. Again, the values are very close.

**11. hERG Inhibition:** Ligand A (0.538) has a slightly higher hERG risk than Ligand B (0.274), but both are relatively low.

**12. Microsomal Clearance:** Ligand B (60.298) has a higher microsomal clearance than Ligand A (24.328), indicating faster metabolism and lower metabolic stability. This favors Ligand A.

**13. In vitro Half-Life:** Ligand B (20.366) has a longer in vitro half-life than Ligand A (14.087), which is a slight advantage for Ligand B.

**14. P-gp Efflux:** Ligand A (0.077) has significantly lower P-gp efflux liability than Ligand B (0.209). Lower P-gp efflux is crucial for CNS penetration, favoring Ligand A.

**15. Binding Affinity:** Both ligands have excellent binding affinities (-7.7 and -7.0 kcal/mol). Ligand A is slightly better (-7.7 kcal/mol), but the difference is small.

**Overall Assessment:**

Ligand A is the superior candidate. While both ligands have good potency, Ligand A excels in several critical ADME properties for a CNS-targeting GPCR: significantly lower DILI risk, much better BBB penetration, lower P-gp efflux, and lower microsomal clearance. The slight advantage in affinity further supports this conclusion. The poor Caco-2 and solubility values are concerning for both, but the other advantages of Ligand A outweigh these drawbacks.

Output:
1
2025-04-17 07:20:08,377 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (347.315 and 350.463 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (29.02) is excellent, well below the 90 A^2 threshold for CNS targets. Ligand B (76.46) is higher but still potentially acceptable, though less ideal.

**logP:** Ligand A (4.35) is slightly high, potentially leading to solubility issues or off-target interactions. Ligand B (1.685) is within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A (0 HBD, 3 HBA) is favorable. Ligand B (1 HBD, 5 HBA) is also acceptable.

**QED:** Both ligands have good QED scores (0.613 and 0.812), indicating good drug-like properties.

**DILI:** Ligand A (74.021) has a higher DILI risk than Ligand B (37.03), which is preferable.

**BBB:** Ligand A (93.68) has excellent BBB penetration, crucial for a CNS target like DRD2. Ligand B (61.846) is significantly lower, raising concerns about CNS exposure.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.786 and -4.526). These values are unusual and suggest potential issues with permeability prediction. However, we can still compare them relatively.

**Aqueous Solubility:** Both ligands have negative solubility values (-5.846 and -2.877). Again, these are unusual, but Ligand B appears slightly better.

**hERG Inhibition:** Ligand A (0.927) has a slightly higher hERG risk than Ligand B (0.355).

**Microsomal Clearance:** Ligand A (47.567) and Ligand B (41.597) have similar microsomal clearance values.

**In vitro Half-Life:** Ligand A (11.07 hours) has a longer half-life than Ligand B (1.144 hours), which is desirable.

**P-gp Efflux:** Ligand A (0.767) has a lower P-gp efflux liability than Ligand B (0.082), which is beneficial for CNS penetration.

**Binding Affinity:** Ligand B (-7.1 kcal/mol) has a slightly better binding affinity than Ligand A (-9.9 kcal/mol). However, the difference is not substantial enough to outweigh the other factors.

**Overall Assessment:**

Ligand A excels in BBB penetration, P-gp efflux, and in vitro half-life, all critical for CNS drug development. While its logP is slightly high and DILI risk is elevated, these are less concerning than the poor BBB penetration of Ligand B. Ligand B has better affinity and lower DILI, but its significantly lower BBB score is a major drawback for a DRD2 ligand.

Output:
1
2025-04-17 07:20:08,377 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (352.435 Da and 361.873 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (99.77) is slightly above the optimal <90 for CNS targets, but still reasonable. Ligand B (53.51) is excellent, well below 90.

**3. logP:** Ligand A (-0.02) is a bit low, potentially hindering permeability. Ligand B (2.383) is within the optimal 1-3 range.

**4. H-Bond Donors:** Ligand A (3) is acceptable. Ligand B (0) is also good.

**5. H-Bond Acceptors:** Ligand A (4) is acceptable. Ligand B (3) is also good.

**6. QED:** Both ligands have good QED scores (0.508 and 0.827), indicating drug-like properties. Ligand B is better.

**7. DILI:** Ligand A (14.696) has a very low DILI risk, which is excellent. Ligand B (35.479) is also low, but higher than A.

**8. BBB:** Both ligands have good BBB penetration (78.945 and 75.611). Ligand A is slightly better.

**9. Caco-2:** Both have negative Caco-2 values which is unusual and suggests poor permeability.

**10. Solubility:** Both have negative solubility values which is unusual and suggests poor solubility.

**11. hERG:** Both ligands have low hERG inhibition risk (0.218 and 0.317).

**12. Cl_mic:** Ligand A (-10.845) has a negative clearance, which is impossible and likely an error in the data. Ligand B (36.047) has a high clearance, which is undesirable.

**13. t1/2:** Ligand A (6) is a reasonable half-life. Ligand B (-30.379) is impossible and likely an error in the data.

**14. Pgp:** Both ligands have low Pgp efflux liability (0.009 and 0.208).

**15. Binding Affinity:** Ligand B (-8.4) has a significantly stronger binding affinity than Ligand A (-7.5), a difference of 0.9 kcal/mol. This is a substantial advantage.

**Overall Assessment:**

Ligand A has a better BBB, lower DILI, but a problematic logP and an impossible Cl_mic and t1/2 values. Ligand B has a superior logP, a much stronger binding affinity, and better QED. However, its Cl_mic is high. The negative values for Caco-2 and Solubility for both are concerning and need further investigation. Given the importance of binding affinity for GPCRs, and the relatively better overall profile of Ligand B despite the high Cl_mic, I would prioritize Ligand B. The high Cl_mic could potentially be addressed through structural modifications. The negative values for Caco-2 and Solubility are red flags that need to be investigated.

Output:
1
2025-04-17 07:20:08,377 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (347.375 and 342.483 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (116.42) is higher than the preferred <90 for CNS targets, while Ligand B (49.41) is excellent. This is a significant advantage for Ligand B.

**logP:** Ligand A (0.207) is quite low, potentially hindering membrane permeability. Ligand B (2.891) is within the optimal 1-3 range. This favors Ligand B.

**H-Bond Donors/Acceptors:** Ligand A has 3 HBD and 5 HBA, acceptable values. Ligand B has 1 HBD and 2 HBA, also acceptable and potentially better for permeability.

**QED:** Both ligands have similar QED values (0.619 and 0.596), indicating good drug-likeness.

**DILI:** Ligand A (76.503) has a higher DILI risk than Ligand B (16.789), which is a significant concern.

**BBB:** Ligand B (65.801) has a substantially better BBB percentile than Ligand A (39.511). This is crucial for a CNS target like DRD2 and heavily favors Ligand B.

**Caco-2 Permeability:** Ligand A (-5.631) shows poor permeability, while Ligand B (-4.776) is slightly better but still not ideal.

**Aqueous Solubility:** Both ligands have poor aqueous solubility (-2.782 and -3.496). This could pose formulation challenges, but is less critical than BBB penetration for CNS drugs.

**hERG Inhibition:** Both ligands show low hERG inhibition risk (0.105 and 0.254).

**Microsomal Clearance:** Ligand A (23.909) has lower clearance than Ligand B (40.554), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (16.552) has a longer half-life than Ligand B (-15.106), which is a positive attribute.

**P-gp Efflux:** Both ligands show low P-gp efflux liability (0.014 and 0.131).

**Binding Affinity:** Ligand A (-8.4 kcal/mol) has a significantly stronger binding affinity than Ligand B (0.0 kcal/mol). This is a major advantage for Ligand A.

**Overall Assessment:**

While Ligand A boasts a superior binding affinity, its poor logP, low BBB penetration, and higher DILI risk are major drawbacks. Ligand B, despite its weaker affinity, exhibits much better physicochemical properties for CNS penetration (TPSA, logP, BBB) and a significantly lower DILI risk. The substantial difference in binding affinity is a concern, but the improved ADME properties of Ligand B, particularly its BBB penetration, are critical for a CNS-targeting drug. Given the GPCR-specific priorities, and the fact that a 1.5kcal/mol advantage can outweigh ADME drawbacks, the substantial differences in ADME properties outweigh the binding affinity difference.

Output:
1
2025-04-17 07:20:08,378 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (386.279 and 354.441 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (81.67) is slightly above the optimal <90 for CNS targets, but still reasonable. Ligand B (40.62) is excellent, well below the threshold.

**logP:** Both ligands have good logP values (1.437 and 2.941), falling within the 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A has 3 HBD and 4 HBA, which are acceptable. Ligand B has 0 HBD and 2 HBA, also acceptable.

**QED:** Both ligands have similar QED scores (0.734 and 0.731), indicating good drug-likeness.

**DILI:** Both have moderate DILI risk (44.281 and 47.305), not a major concern at this stage.

**BBB:** This is a critical parameter for a CNS target. Ligand A has a BBB percentile of 24.855, which is quite low and a significant drawback. Ligand B has a much higher BBB percentile of 96.278, which is excellent.

**Caco-2 Permeability:** Ligand A shows poor Caco-2 permeability (-5.284), suggesting poor intestinal absorption. Ligand B also shows poor Caco-2 permeability (-4.324), but is slightly better than Ligand A.

**Aqueous Solubility:** Both ligands have poor aqueous solubility (-2.723 and -3.003). This might require formulation strategies.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.194 and 0.67).

**Microsomal Clearance:** Ligand A has a negative Cl_mic (-40.083), which is unusual and likely indicates very slow clearance/high metabolic stability. Ligand B has a Cl_mic of 46.987, which is reasonable.

**In vitro Half-Life:** Ligand A has a relatively long half-life (20.145 hours), while Ligand B has a shorter half-life (-11.153 hours).

**P-gp Efflux:** Ligand A has very low P-gp efflux (0.089), which is favorable for CNS penetration. Ligand B has moderate P-gp efflux (0.245).

**Binding Affinity:** Both ligands have strong binding affinities (-8.8 and -9.0 kcal/mol). Ligand B is slightly better.

**Overall Assessment:**

Ligand B is the more promising candidate. While both have similar binding affinities and acceptable physicochemical properties, Ligand B's significantly higher BBB penetration (96.278 vs 24.855) is a decisive advantage for a CNS-targeting drug. The slightly better affinity and acceptable metabolic stability further support this conclusion. Although both have poor solubility and Caco-2 permeability, these can be addressed with formulation strategies. Ligand A's extremely low BBB penetration is a major obstacle to its development as a CNS drug.

Output:
1
2025-04-17 07:20:08,378 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B based on the provided guidelines, prioritizing GPCR-specific properties (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (356.388 and 361.873 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (40.62) is significantly better than Ligand B (62.3), falling well below the 90 A^2 threshold for CNS targets. Ligand B is higher, potentially hindering BBB penetration.

**logP:** Both ligands (2.438 and 2.765) are within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A (0 HBD, 2 HBA) is preferable to Ligand B (1 HBD, 3 HBA) as lower counts generally improve permeability. Both are within acceptable limits.

**QED:** Both ligands have similar and good QED scores (0.561 and 0.572), indicating good drug-like properties.

**DILI:** Ligand A (12.641) has a much lower DILI risk than Ligand B (41.411), which is a significant advantage.

**BBB:** This is a crucial parameter for a CNS target like DRD2. Ligand A (91.314) has excellent BBB penetration, exceeding the desirable >70 percentile. Ligand B (67.08) is lower, potentially limiting CNS exposure.

**Caco-2 Permeability:** Ligand A (-4.464) and Ligand B (-5.044) both have negative Caco-2 values, which is unusual and suggests poor permeability. However, the scale is not specified, so it's hard to interpret.

**Aqueous Solubility:** Both ligands have similar, very poor aqueous solubility (-3.031 and -2.885). This could pose formulation challenges.

**hERG:** Both ligands have low hERG inhibition liability (0.481 and 0.347), which is good.

**Microsomal Clearance:** Ligand A (8.315) has significantly lower microsomal clearance than Ligand B (38.462), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (-3.163) has a longer in vitro half-life than Ligand B (-11.487), which is desirable.

**P-gp Efflux:** Ligand A (0.081) has much lower P-gp efflux liability than Ligand B (0.228), meaning it's less likely to be pumped out of the brain, improving CNS exposure.

**Binding Affinity:** Ligand B (-8.0) has a slightly better binding affinity than Ligand A (-7.9), but the difference is small (0.1 kcal/mol). Given the other significant advantages of Ligand A, this difference is unlikely to be decisive.

**Conclusion:**

Considering all factors, especially the GPCR-specific priorities (BBB, logP, Pgp, TPSA) and the overall ADME profile, **Ligand A is the more promising drug candidate**. It exhibits superior BBB penetration, lower DILI risk, better metabolic stability, lower P-gp efflux, and a favorable TPSA, outweighing the slightly weaker binding affinity compared to Ligand B.

Output:
1
2025-04-17 07:20:08,378 - INFO - Batch 356 complete. Total preferences: 5696
2025-04-17 07:20:08,378 - INFO - Processing batch 357/512...
2025-04-17 07:20:53,664 - INFO - Reasoning:

Let's analyze Ligand A and Ligand B for their potential as DRD2 drug candidates, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (336.479 Da) is slightly lower, which is generally favorable for permeability.

**2. TPSA:** Ligand A (32.34) is excellent for CNS penetration, well below the 90 A^2 threshold. Ligand B (114.19) is higher, but still potentially acceptable, though less ideal for CNS targets.

**3. logP:** Ligand A (4.714) is a bit high, potentially leading to solubility issues or off-target interactions. Ligand B (1.791) is within the optimal range (1-3).

**4. H-Bond Donors:** Both ligands have acceptable HBD counts (Ligand A: 1, Ligand B: 2), well below the 5 threshold.

**5. H-Bond Acceptors:** Ligand A (1) is excellent. Ligand B (7) is acceptable, but approaching the upper limit of 10.

**6. QED:** Ligand A (0.861) has a significantly better QED score than Ligand B (0.648), indicating a more drug-like profile.

**7. DILI:** Ligand A (39.628) has a much lower DILI risk than Ligand B (92.672), which is a significant advantage.

**8. BBB:** Ligand A (85.615) has a very good BBB penetration score, exceeding the 70% threshold. Ligand B (38.775) is poor for CNS penetration.

**9. Caco-2 Permeability:** Ligand A (-4.41) is very poor. Ligand B (-5.754) is also poor.

**10. Aqueous Solubility:** Ligand A (-5.368) is poor. Ligand B (-2.748) is also poor.

**11. hERG Inhibition:** Both ligands have low hERG inhibition risk (Ligand A: 0.929, Ligand B: 0.265).

**12. Microsomal Clearance:** Ligand A (75.057) has a moderate clearance. Ligand B (0.174) has very low clearance, suggesting high metabolic stability.

**13. In vitro Half-Life:** Ligand A (35.693) has a moderate half-life. Ligand B (42.258) has a longer half-life, which is desirable.

**14. P-gp Efflux:** Both ligands show low P-gp efflux (Ligand A: 0.619, Ligand B: 0.065). Ligand B is better.

**15. Binding Affinity:** Ligand B (-8.3 kcal/mol) has a significantly stronger binding affinity than Ligand A (-9.0 kcal/mol). This is a substantial advantage.

**Overall Assessment:**

Ligand B has a much stronger binding affinity and better metabolic stability (lower Cl_mic, longer t1/2), and lower P-gp efflux. However, Ligand A excels in crucial CNS-related properties: TPSA, BBB penetration, QED, and DILI risk. Ligand A's logP is higher, which could be a concern, but the superior CNS properties and lower DILI risk are compelling. The poor Caco-2 and solubility for both are concerning, but can be addressed with formulation strategies. Given the target is a CNS GPCR (DRD2), the BBB penetration and lower DILI risk of Ligand A are paramount. The affinity difference, while significant, might be overcome with further optimization of Ligand A.

Output:
0
2025-04-17 07:20:53,664 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight (MW):** Both ligands (370.318 and 348.447 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (58.64) is significantly better than Ligand B (76.46). For CNS targets, we want TPSA <= 90, and ideally closer to 60. Ligand A is much closer to this ideal.

**3. logP:** Both ligands have a logP around 1.68, which is optimal (1-3).

**4. H-Bond Donors (HBD):** Both have 1 HBD, which is within the acceptable limit of <=5.

**5. H-Bond Acceptors (HBA):** Ligand A has 3 HBA, and Ligand B has 5. Both are within the acceptable limit of <=10.

**6. QED:** Ligand B (0.849) has a better QED score than Ligand A (0.572), indicating a more drug-like profile overall.

**7. DILI:** Both ligands have the same DILI risk (46.452%), which is good (below 40 is preferred, but this is acceptable).

**8. BBB:** Ligand A (95.308%) has a *much* higher BBB penetration score than Ligand B (72.625%). This is a critical advantage for a CNS target like DRD2.

**9. Caco-2 Permeability:** Ligand A (-4.864) shows better Caco-2 permeability than Ligand B (-4.699). While both are negative, a more negative value suggests better permeability.

**10. Aqueous Solubility:** Ligand A (-1.969) has slightly better solubility than Ligand B (-2.684).

**11. hERG Inhibition:** Ligand A (0.272) has a lower hERG inhibition liability than Ligand B (0.554), which is preferable.

**12. Microsomal Clearance:** Ligand A (-3.486) has a lower (better) microsomal clearance than Ligand B (67.643). This indicates greater metabolic stability.

**13. In vitro Half-Life:** Ligand A (-12.355) has a longer in vitro half-life than Ligand B (-22.044).

**14. P-gp Efflux:** Ligand A (0.03) has much lower P-gp efflux liability than Ligand B (0.192). Lower P-gp efflux is crucial for CNS penetration.

**15. Binding Affinity:** Both ligands have the same binding affinity (-8.0 kcal/mol), which is excellent.

**Overall Assessment:**

While Ligand B has a slightly better QED score, Ligand A significantly outperforms it in several key areas crucial for a CNS-targeting GPCR ligand: TPSA, BBB penetration, microsomal clearance, P-gp efflux, and hERG inhibition. The superior BBB penetration and lower efflux of Ligand A are particularly important for ensuring sufficient drug exposure in the brain. The better metabolic stability (lower Cl_mic) and longer half-life are also beneficial. The similar binding affinity removes that as a differentiating factor.

Output:
1
2025-04-17 07:20:53,664 - INFO - Reasoning:

Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (343.362 and 340.383 Da) fall comfortably within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (81.07) is significantly better than Ligand B (92.35). For CNS targets, we want TPSA <= 90, so Ligand A is preferable.

**3. logP:** Both ligands have good logP values (2.696 and 2.49), falling within the optimal 1-3 range.

**4. H-Bond Donors:** Ligand A (2) is slightly better than Ligand B (3), as lower HBD counts generally improve permeability.

**5. H-Bond Acceptors:** Both ligands have the same HBA count (5), which is acceptable (<=10).

**6. QED:** Both ligands have reasonable QED values (0.746 and 0.587), indicating good drug-like properties. Ligand A is slightly better.

**7. DILI:** Ligand A (83.598) has a slightly higher DILI risk than Ligand B (77.394), but both are below the concerning threshold of 60.

**8. BBB:** Both ligands have similar BBB penetration percentiles (63.358 and 66.421). While neither exceeds the desirable >70 for CNS targets, they are both reasonable.

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.906 and -4.87), which is unusual and suggests poor permeability. This is a significant concern for both.

**10. Aqueous Solubility:** Both ligands have very poor aqueous solubility (-3.82 and -4.048). This is a major drawback for oral bioavailability.

**11. hERG Inhibition:** Both ligands show low hERG inhibition liability (0.551 and 0.319), which is positive.

**12. Microsomal Clearance:** Ligand A (43.491) has lower microsomal clearance than Ligand B (55.478), indicating better metabolic stability.

**13. In vitro Half-Life:** Ligand A (34.946) has a longer in vitro half-life than Ligand B (26.721), which is desirable.

**14. P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.168 and 0.087), which is good for CNS exposure.

**15. Binding Affinity:** Both ligands have excellent binding affinities (-9.8 and -9.5 kcal/mol). The difference of 0.3 kcal/mol is not substantial enough to outweigh other factors.

**Overall Assessment:**

Considering the GPCR-specific priorities, Ligand A is slightly more favorable. It has a lower TPSA, better metabolic stability (lower Cl_mic, longer t1/2), and a slightly better QED score. While both have poor Caco-2 permeability and solubility, the other advantages of Ligand A make it a marginally better candidate. The similar BBB values and excellent affinities mean that the ADME properties are the deciding factors here.

Output:
0
2025-04-17 07:20:53,665 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 drug candidates, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (354.382 and 341.371 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (121.6) is slightly above the optimal <90 for CNS targets, but still reasonable. Ligand B (109.8) is better, being closer to the desired range.

**logP:** Ligand A (0.332) is quite low, potentially hindering permeability. Ligand B (0.095) is even lower, raising significant concerns about membrane penetration. Both are below the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A has 3 HBD and 4 HBA, which are acceptable. Ligand B has 2 HBD and 5 HBA, also acceptable.

**QED:** Both ligands have good QED scores (0.61 and 0.726), indicating good drug-like properties.

**DILI:** Ligand A (39.201) has a lower DILI risk than Ligand B (58.86), which is preferable.

**BBB:** Ligand A has a significantly better BBB penetration percentile (89.066) than Ligand B (44.901). This is a *critical* advantage for a CNS target like DRD2.

**Caco-2 Permeability:** Both have negative Caco-2 values (-5.232 and -5.569), which is unusual and suggests poor permeability. This is likely related to the low logP values.

**Aqueous Solubility:** Both have negative solubility values (-2.896 and -2.387), which is also unusual and concerning.

**hERG:** Both ligands have very low hERG inhibition liability (0.053 and 0.121), which is excellent.

**Microsomal Clearance:** Ligand A (0.251) has much lower microsomal clearance than Ligand B (-19.148), indicating better metabolic stability. This is a significant advantage.

**In vitro Half-Life:** Ligand A (-1.231) has a slightly better (less negative) in vitro half-life than Ligand B (-0.865).

**P-gp Efflux:** Both have very low P-gp efflux liability (0.006 and 0.012), which is favorable for CNS penetration.

**Binding Affinity:** Ligand A (-8.5 kcal/mol) has a slightly better binding affinity than Ligand B (-7.8 kcal/mol), although both are good. The difference is 0.7 kcal/mol, which is meaningful.

**Overall Assessment:**

Ligand A is the stronger candidate. While both have issues with logP and solubility, Ligand A's superior BBB penetration, lower DILI risk, and better metabolic stability (lower Cl_mic) are crucial advantages for a CNS-targeting GPCR. The slightly better binding affinity further supports this conclusion. The low logP and solubility are significant drawbacks for both, but these might be addressed through prodrug strategies or formulation techniques.

Output:
0
2025-04-17 07:20:53,665 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 drug candidates, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (361.511 Da) is slightly higher than Ligand B (343.427 Da), but both are acceptable.

**TPSA:** Ligand A (58.37) is excellent for CNS penetration, well below the 90 A^2 threshold. Ligand B (91.32) is approaching the upper limit for CNS targets, but still potentially acceptable.

**logP:** Ligand A (3.892) is at the upper end of the optimal range (1-3), but still acceptable. Ligand B (1.567) is a bit low, potentially hindering membrane permeability.

**H-Bond Donors/Acceptors:** Ligand A (HBD=1, HBA=5) is favorable. Ligand B (HBD=3, HBA=4) is also acceptable.

**QED:** Both ligands have reasonably good QED values (A: 0.813, B: 0.708), indicating good drug-like properties.

**DILI:** Ligand A (40.752) has a slightly higher DILI risk than Ligand B (35.75), but both are below the concerning threshold of 60.

**BBB:** This is a critical parameter for CNS targets. Ligand A (87.088) has a significantly better BBB percentile than Ligand B (53.315). This is a major advantage for Ligand A.

**Caco-2 Permeability:** Ligand A (-5.362) has poor Caco-2 permeability, while Ligand B (-4.976) is also poor, but slightly better.

**Aqueous Solubility:** Both ligands have very poor aqueous solubility (-3.274 and -2.301 respectively). This could present formulation challenges.

**hERG Inhibition:** Ligand A (0.881) has a slightly higher hERG risk than Ligand B (0.059). Ligand B is very favorable in this regard.

**Microsomal Clearance:** Ligand A (55.278) has a higher microsomal clearance than Ligand B (7.74), suggesting lower metabolic stability.

**In vitro Half-Life:** Ligand A (8.82) has a longer half-life than Ligand B (-7.752), which is a positive attribute.

**P-gp Efflux:** Ligand A (0.796) has a lower P-gp efflux liability than Ligand B (0.014), which is beneficial for CNS exposure.

**Binding Affinity:** Ligand B (-7.9 kcal/mol) has a slightly better binding affinity than Ligand A (-7.4 kcal/mol). However, the difference is only 0.5 kcal/mol, which, while noticeable, might not be enough to overcome other significant ADME differences.

**Overall Assessment:**

Considering the GPCR-specific priorities, Ligand A is the more promising candidate. Its significantly better BBB penetration (87.09% vs 53.32%), lower P-gp efflux, and longer half-life outweigh the slightly weaker binding affinity and higher DILI/hERG risk. The poor Caco-2 and solubility are concerns for both, but can be addressed with formulation strategies. Ligand B's lower logP and poorer BBB penetration are significant drawbacks for a CNS-targeting drug.

Output:
0
2025-04-17 07:20:53,665 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 drug candidates, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (359.442 and 349.519 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (87.74) is better than Ligand B (52.65). Both are below the 90 A^2 threshold for CNS targets, but Ligand B is significantly lower, which is favorable for brain penetration.

**logP:** Ligand B (1.975) is better than Ligand A (0.631). Both are within the optimal 1-3 range, but Ligand A is slightly low, potentially hindering permeation.

**H-Bond Donors/Acceptors:** Ligand A has 2 HBD and 4 HBA, while Ligand B has 1 HBD and 3 HBA. Both are within acceptable limits (<=5 HBD, <=10 HBA).

**QED:** Both ligands have good QED values (0.56 and 0.648, respectively), indicating good drug-like properties.

**DILI:** Ligand B (6.592) has a much lower DILI risk than Ligand A (22.528), which is a significant advantage.

**BBB:** Ligand A (70.803) has a slightly better BBB percentile than Ligand B (64.87), but both are above the 70% threshold, which is good for CNS targets.

**Caco-2 Permeability:** Ligand A (-4.948) has better Caco-2 permeability than Ligand B (-4.528).

**Aqueous Solubility:** Both ligands have very poor aqueous solubility (-1.692 and -1.62, respectively). This is a concern for both, but is less critical for CNS targets where direct IV administration is possible.

**hERG Inhibition:** Both ligands have low hERG inhibition liability (0.346 and 0.46, respectively).

**Microsomal Clearance:** Ligand A (16.145) has lower microsomal clearance than Ligand B (18.922), indicating better metabolic stability.

**In vitro Half-Life:** Ligand A (-10.872) has a much longer in vitro half-life than Ligand B (-1.644). This is a significant advantage.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.034 and 0.017, respectively).

**Binding Affinity:** Ligand B (-7.5) has slightly better binding affinity than Ligand A (-7.4). While the difference is small, it is still a factor.

**Overall Assessment:**

Ligand B has a better balance of properties, particularly regarding DILI risk and logP. The slightly better affinity of Ligand B, combined with the lower DILI and better logP, outweigh the slightly lower BBB and shorter half-life compared to Ligand A. The TPSA of Ligand B is also more favorable for CNS penetration. While both have poor solubility, this is less critical for a CNS target.

Output:
1
2025-04-17 07:20:53,665 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B based on the provided guidelines, prioritizing GPCR-specific properties (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands fall within the ideal range (200-500 Da). Ligand A (339.439 Da) is slightly lower, which could be beneficial for permeability.

**TPSA:** Ligand A (54.34) is significantly better than Ligand B (71). For CNS targets, we want TPSA <= 90, and ideally closer to 60. Ligand A is much closer to the ideal range.

**logP:** Ligand A (4.423) is a bit high, potentially causing solubility issues or off-target effects. Ligand B (2.18) is within the optimal range (1-3).

**H-Bond Donors/Acceptors:** Both ligands have acceptable HBD (1) and HBA (3 for A, 5 for B) counts.

**QED:** Both ligands have similar QED values (0.842 and 0.781), indicating good drug-likeness.

**DILI:** Ligand A (63.125) has a higher DILI risk than Ligand B (33.618). This is a significant concern.

**BBB:** Ligand A (87.864) has a much better BBB penetration percentile than Ligand B (61.38). This is crucial for a CNS target like DRD2.

**Caco-2 Permeability:** Ligand A (-4.638) has poor Caco-2 permeability, while Ligand B (-5.057) is also poor. Both are negative values, suggesting low permeability.

**Aqueous Solubility:** Ligand A (-5.145) has worse aqueous solubility than Ligand B (-3.142).

**hERG:** Ligand A (0.608) has a slightly higher hERG risk than Ligand B (0.189).

**Microsomal Clearance:** Ligand A (69.531) has higher microsomal clearance than Ligand B (31.571), indicating lower metabolic stability.

**In vitro Half-Life:** Ligand A (48.422) has a longer half-life than Ligand B (2.124).

**P-gp Efflux:** Ligand A (0.757) has a lower P-gp efflux liability than Ligand B (0.062), which is favorable for CNS penetration.

**Binding Affinity:** Ligand A (-8.8 kcal/mol) has a significantly stronger binding affinity than Ligand B (-7.7 kcal/mol). This 1.1 kcal/mol difference is substantial and can outweigh some ADME drawbacks.

**Overall Assessment:**

Ligand A excels in BBB penetration and binding affinity, which are critical for a CNS GPCR target. However, it suffers from higher DILI risk, poor solubility, and higher clearance. Ligand B has a better safety profile (lower DILI, hERG) and solubility, but its BBB penetration and binding affinity are significantly weaker.

Given the importance of strong binding affinity and BBB penetration for DRD2, and the fact that the affinity difference is substantial, I would favor **Ligand A**, despite its ADME liabilities. The higher affinity could allow for a lower dose, potentially mitigating some of the toxicity concerns. Further optimization would focus on improving solubility, reducing DILI risk, and improving metabolic stability.

Output:
1
2025-04-17 07:20:53,666 - INFO - Reasoning:

Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (341.371 and 349.431 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (97.19) is better than Ligand B (104.46). Both are below the 140 A^2 threshold for oral absorption and reasonably close to the 90 A^2 target for CNS penetration, but A is preferable.

**3. logP:** Ligand B (1.646) is better than Ligand A (0.434). Both are within the optimal 1-3 range, but A is quite low, potentially hindering membrane permeability.

**4. H-Bond Donors:** Ligand A (1) is better than Ligand B (3). Lower HBD generally improves permeability.

**5. H-Bond Acceptors:** Ligand A (6) is better than Ligand B (5). Both are within the acceptable range.

**6. QED:** Ligand A (0.87) is superior to Ligand B (0.694), indicating a more drug-like profile.

**7. DILI:** Ligand B (35.479) is significantly better than Ligand A (68.903), indicating a lower risk of drug-induced liver injury. This is a substantial advantage for Ligand B.

**8. BBB:** Ligand A (58.007) is better than Ligand B (37.65). This is a critical factor for a CNS target like DRD2, and A has a better percentile.

**9. Caco-2 Permeability:** Ligand A (-5.146) is better than Ligand B (-4.931). Higher values indicate better absorption.

**10. Aqueous Solubility:** Ligand A (-2.385) is better than Ligand B (-2.272). Both are poor, but A is slightly better.

**11. hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.204 and 0.166, respectively).

**12. Microsomal Clearance:** Ligand A (-4.213) is significantly better than Ligand B (-0.583). Lower clearance indicates better metabolic stability.

**13. In vitro Half-Life:** Ligand A (-8.242) is better than Ligand B (23.11). A negative value is better here, indicating a longer half-life.

**14. P-gp Efflux:** Ligand A (0.013) is much better than Ligand B (0.092). Lower P-gp efflux is crucial for CNS penetration.

**15. Binding Affinity:** Both ligands have excellent binding affinity (-9.7 and -8.7 kcal/mol). Ligand A is 1 kcal/mol better.

**Overall Assessment:**

Ligand A excels in BBB penetration, metabolic stability, P-gp efflux, and binding affinity. Ligand B has a much better DILI score and a slightly better logP. The difference in binding affinity (1 kcal/mol) is significant, and the superior BBB penetration and P-gp efflux of Ligand A are critical for a CNS target. While Ligand B's lower DILI risk is attractive, the other ADME properties of Ligand A are more favorable for DRD2 targeting.

Output:
1
2025-04-17 07:20:53,666 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B against the provided guidelines, prioritizing GPCR-specific properties (BBB, logP, Pgp, TPSA, and affinity) for DRD2.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (346.343 Da) and Ligand B (336.399 Da) are comparable.

**TPSA:** Ligand A (117.79) is slightly above the optimal <90 for CNS targets, while Ligand B (94.8) is within the desired range. This favors Ligand B.

**logP:** Ligand A (0.241) is quite low, potentially hindering permeability. Ligand B (1.758) is within the optimal 1-3 range. This is a significant advantage for Ligand B.

**H-Bond Donors/Acceptors:** Ligand A has 2 HBD and 7 HBA, while Ligand B has 1 HBD and 6 HBA. Both are within acceptable limits.

**QED:** Both ligands have good QED scores (Ligand A: 0.769, Ligand B: 0.914), indicating drug-like properties. Ligand B is slightly better.

**DILI:** Ligand A (63.397) has a higher DILI risk than Ligand B (54.285), though both are reasonably acceptable.

**BBB:** This is crucial for a CNS target like DRD2. Ligand A (36.293) has a low BBB percentile, suggesting poor brain penetration. Ligand B (51.687) is better, but still not ideal (aim for >70).

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.284 and -5.179), which is unusual and suggests poor permeability. This is a concern for both.

**Aqueous Solubility:** Both ligands have very poor aqueous solubility (-1.957 and -2.271). This could pose formulation challenges.

**hERG Inhibition:** Both ligands show very low hERG inhibition risk (0.093 and 0.237).

**Microsomal Clearance:** Ligand A (2.766) has lower clearance than Ligand B (-14.188), suggesting better metabolic stability. This is a positive for Ligand A.

**In vitro Half-Life:** Ligand A (-26.7) has a negative half-life, which is not physically possible and indicates a problem with the data or the molecule. Ligand B (15.432) has a reasonable half-life.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.01 and 0.007), which is favorable for CNS penetration.

**Binding Affinity:** Ligand A (-8.1 kcal/mol) has significantly stronger binding affinity than Ligand B (-5.9 kcal/mol). This is a substantial advantage for Ligand A, potentially outweighing some of its ADME drawbacks.

**Overall Assessment:**

Ligand B has better TPSA, logP, QED, and BBB penetration than Ligand A. However, Ligand A boasts a much stronger binding affinity (-8.1 vs -5.9 kcal/mol). The low logP and poor BBB of Ligand A are major concerns, but the significantly higher affinity could compensate. The negative half-life for Ligand A is a red flag, suggesting a data issue. Considering the importance of affinity for GPCRs, and the relatively modest improvements in ADME properties for Ligand B, the stronger binding of Ligand A makes it the more promising candidate *if* the half-life data is corrected.

Output:
1
2025-04-17 07:20:53,666 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (344.459 Da) is slightly lower, which is generally favorable for permeability.

**TPSA:** Ligand A (67.23) is significantly better than Ligand B (88.4). For CNS targets, TPSA < 90 is preferred, and A is closer to the optimal <60 range.

**logP:** Both ligands have acceptable logP values (A: 2.081, B: 0.975), falling within the 1-3 range. Ligand A is slightly better.

**H-Bond Donors/Acceptors:** Ligand A (HBD=1, HBA=4) is preferable to Ligand B (HBD=0, HBA=7) as it strikes a better balance for permeability and solubility.

**QED:** Both ligands have reasonable QED scores (A: 0.832, B: 0.691), indicating good drug-like properties.

**DILI:** Ligand A (19.426) has a much lower DILI risk than Ligand B (55.021). This is a significant advantage.

**BBB:** Both ligands have good BBB penetration (A: 67.08, B: 68.554), but neither exceeds the desirable >70 threshold.

**Caco-2 Permeability:** Both have negative values, indicating poor permeability. Ligand A (-4.912) is slightly better than Ligand B (-5.242).

**Aqueous Solubility:** Both have negative solubility values. Ligand A (-1.491) is slightly better than Ligand B (-2.526).

**hERG Inhibition:** Both ligands show very low hERG inhibition risk (A: 0.218, B: 0.106).

**Microsomal Clearance:** Ligand A (27.991) has lower microsomal clearance than Ligand B (37.663), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (-13.175) has a significantly *longer* in vitro half-life than Ligand B (-57.593). This is a major advantage.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (A: 0.049, B: 0.038).

**Binding Affinity:** Ligand B (-7.3 kcal/mol) has a slightly better binding affinity than Ligand A (-8.2 kcal/mol). However, the difference is relatively small and can be overcome by other favorable properties.

**Overall Assessment:**

Ligand A is superior to Ligand B. While Ligand B has a slightly better binding affinity, Ligand A excels in several critical ADME properties, including lower DILI risk, better TPSA, better metabolic stability (lower Cl_mic and longer t1/2), and slightly better logP and solubility. Given the GPCR-specific focus on BBB, logP, Pgp, TPSA, and affinity, Ligand A's superior ADME profile, particularly the lower DILI and improved metabolic stability, outweigh the minor affinity difference.

Output:
1
2025-04-17 07:20:53,666 - INFO - Reasoning:

Let's analyze Ligand A and Ligand B based on the provided criteria, prioritizing GPCR-specific properties (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (352.431 and 348.359 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (96.89) is significantly better than Ligand B (114.76). For CNS targets, TPSA should be <= 90, and A is closer to this threshold.

**logP:** Both ligands have good logP values (1.684 and 1.863), falling within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A (HBD=3, HBA=5) is slightly better than Ligand B (HBD=1, HBA=8) in terms of balancing solubility and permeability.

**QED:** Both ligands have acceptable QED values (0.649 and 0.595), indicating reasonable drug-likeness.

**DILI:** Ligand A (43.932) has a much lower DILI risk than Ligand B (59.713), making it safer.

**BBB:** Ligand A (49.011) has a lower BBB penetration than Ligand B (51.493), but both are below the desirable >70 for CNS targets. This is a weakness for both, but less so for B.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.546 and -4.881), which is unusual and suggests poor permeability. This is a significant concern for both.

**Aqueous Solubility:** Both ligands have negative solubility values (-2.66 and -2.379), indicating poor aqueous solubility. This is a significant concern for both.

**hERG Inhibition:** Ligand A (0.702) has a slightly lower hERG inhibition risk than Ligand B (0.441), which is preferable.

**Microsomal Clearance:** Ligand A (62.127) has higher microsomal clearance than Ligand B (26.669), indicating lower metabolic stability. This is a drawback for A.

**In vitro Half-Life:** Ligand A (-56.174) has a negative half-life, which is not possible and suggests an issue with the data. Ligand B (-28.563) is also negative, indicating data issues for both.

**P-gp Efflux:** Ligand A (0.17) has significantly lower P-gp efflux liability than Ligand B (0.433), which is crucial for CNS penetration.

**Binding Affinity:** Ligand B (-8.3 kcal/mol) has a slightly better binding affinity than Ligand A (-7.8 kcal/mol). While the difference is not huge, it's enough to potentially overcome some ADME drawbacks.

**Overall Assessment:**

Considering the GPCR-specific priorities, Ligand B is slightly favored despite its higher DILI risk and P-gp efflux. The slightly better binding affinity and BBB penetration outweigh the other drawbacks. The negative half-life and Caco-2 values are concerning for both, and would require further investigation. However, the lower P-gp efflux of Ligand A is a strong point in its favor, but is not enough to overcome the better binding affinity of Ligand B.

Output:
1
2025-04-17 07:20:53,667 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (378.426 and 378.372 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (138.67) is borderline for CNS targets, just above the preferred <90, but acceptable. Ligand B (86.71) is excellent, well below the 90 threshold. This favors Ligand B.

**3. logP:** Ligand A (-1.323) is a bit low, potentially hindering membrane permeability. Ligand B (1.824) is within the optimal 1-3 range. This significantly favors Ligand B.

**4. H-Bond Donors:** Ligand A (3) and Ligand B (2) are both acceptable, below the limit of 5.

**5. H-Bond Acceptors:** Ligand A (5) and Ligand B (4) are both acceptable, below the limit of 10.

**6. QED:** Both ligands have good QED scores (0.526 and 0.837), indicating drug-like properties. Ligand B is better.

**7. DILI:** Both have acceptable DILI risk (39.434 and 50.64), below the 60 threshold.

**8. BBB:** Ligand A (54.013) is moderately low, while Ligand B (66.615) is better, but still not ideal (aim for >70). However, given the other factors, this isn't a dealbreaker.

**9. Caco-2:** Both have negative Caco-2 values (-5.891 and -5.113), which is unusual and suggests poor permeability. This is a concern for both.

**10. Solubility:** Both have negative solubility values (-1.973 and -3.975), indicating poor aqueous solubility. This is a significant drawback for both.

**11. hERG:** Both have very low hERG risk (0.087 and 0.794).

**12. Cl_mic:** Ligand A (-27.934) has a much lower (better) microsomal clearance than Ligand B (21.673), indicating greater metabolic stability. This favors Ligand A.

**13. t1/2:** Ligand A (21.851) has a longer in vitro half-life than Ligand B (-22.245). This favors Ligand A.

**14. Pgp:** Both have very low P-gp efflux liability (0.016 and 0.08).

**15. Binding Affinity:** Ligand B (-8.2) has a slightly better binding affinity than Ligand A (-7.9). While the difference is small, it's within the range where it could outweigh some ADME drawbacks.

**Overall Assessment:**

Ligand B has a better logP and TPSA, which are crucial for CNS penetration and GPCR binding. Its QED is also higher. However, Ligand A has superior metabolic stability (lower Cl_mic) and a longer half-life. Both have poor Caco-2 and solubility. The slightly better affinity of Ligand B, combined with its superior logP and TPSA, outweigh the metabolic advantages of Ligand A.

Output:
1
2025-04-17 07:20:53,667 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (363.34 and 344.499 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (132.24) is better than Ligand B (49.41). For CNS targets, we want TPSA <= 90, so Ligand A is closer to this threshold, which is favorable for brain penetration.

**logP:** Ligand A (-0.468) is slightly low, potentially hindering permeability. Ligand B (3.732) is within the optimal 1-3 range. This favors Ligand B.

**H-Bond Donors/Acceptors:** Ligand A has 4 HBD and 6 HBA, which are acceptable. Ligand B has 1 HBD and 2 HBA, also acceptable.

**QED:** Both ligands have good QED scores (0.486 and 0.79), indicating drug-like properties. Ligand B is slightly better.

**DILI:** Ligand A (42.536) has a slightly higher DILI risk than Ligand B (29.701), but both are reasonably low.

**BBB:** Ligand B (77.705) has a significantly better BBB penetration percentile than Ligand A (49.205). This is a crucial factor for a CNS target like DRD2, strongly favoring Ligand B.

**Caco-2 Permeability:** Ligand A (-5.961) has poor Caco-2 permeability, while Ligand B (-4.78) is also poor, but slightly better.

**Aqueous Solubility:** Both ligands have negative solubility values, which is unusual and indicates very poor solubility. This is a significant drawback for both, but the scale is not defined, so the negative values may not be directly comparable.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.428 and 0.395).

**Microsomal Clearance:** Ligand A (-38.637) has a much lower (better) microsomal clearance than Ligand B (62.064), indicating better metabolic stability.

**In vitro Half-Life:** Ligand A (39.661) has a longer in vitro half-life than Ligand B (-15.447). This is a positive for Ligand A.

**P-gp Efflux:** Ligand A (0.027) has very low P-gp efflux, which is excellent for CNS penetration. Ligand B (0.285) also has low P-gp efflux, but higher than Ligand A.

**Binding Affinity:** Ligand A (-7.7) has a slightly better binding affinity than Ligand B (0.0). This is a significant advantage.

**Overall Assessment:**

Ligand B excels in BBB penetration and has a good logP. However, its metabolic stability is poor (high Cl_mic, short half-life). Ligand A has better metabolic stability, a slightly better binding affinity, and very low P-gp efflux, but suffers from a low logP and poor Caco-2 permeability. Given the importance of CNS penetration for a DRD2 ligand, and the relatively small difference in binding affinity, the superior BBB score of Ligand B is the deciding factor. The poor solubility of both is a concern, but can potentially be addressed with formulation strategies.

Output:
1
2025-04-17 07:20:53,667 - INFO - Okay, let's analyze these two ligands for their potential as DRD2 drug candidates. DRD2 is a GPCR in the CNS, so BBB penetration, logP, Pgp efflux, TPSA, and binding affinity are paramount.

**Ligand A:** [378.313, 78.43, 2.065, 3, 3, 0.447, 29.003, 65.452, -5.052, -2.881, 0.551, 23.262, 0.376, 0.057, -8.1]
**Ligand B:** [349.391, 122.14, 1.249, 3, 6, 0.555, 58.24, 31.214, -5.769, -1.832, 0.035, -1.666, 11.691, 0.017, -7]

Here's a breakdown of each property:

1. **MW:** Both are within the ideal range (200-500 Da). A (378.313) is slightly higher than B (349.391), but both are acceptable.
2. **TPSA:** A (78.43) is excellent for CNS penetration (well below 90). B (122.14) is higher, but still potentially acceptable, though less ideal.
3. **logP:** A (2.065) is optimal. B (1.249) is a bit low, potentially hindering membrane permeability.
4. **HBD:** Both have 3 HBD, which is within the acceptable limit of 5.
5. **HBA:** A has 3 HBA, while B has 6. Both are within the limit of 10, but A is preferable.
6. **QED:** Both are reasonably good (A: 0.447, B: 0.555), indicating drug-like properties. B is slightly better.
7. **DILI:** A (29.003) is very good (low risk). B (58.24) is moderate, but still acceptable.
8. **BBB:** A (65.452) is good, exceeding the 70% threshold for CNS targets. B (31.214) is poor, a significant drawback for a CNS target.
9. **Caco-2:** Both have negative values, indicating poor permeability. This is unusual and requires further investigation, but the magnitude of negativity is important. A (-5.052) is worse than B (-5.769).
10. **Solubility:** Both have negative values, suggesting poor solubility. A (-2.881) is slightly better than B (-1.832).
11. **hERG:** Both are very low risk (A: 0.551, B: 0.035). B is even better.
12. **Cl_mic:** A (23.262) is moderate, indicating reasonable metabolic stability. B (-1.666) is excellent, suggesting very high metabolic stability.
13. **t1/2:** A (0.376) is very short. B (11.691) is much better.
14. **Pgp:** A (0.057) is very low, indicating minimal P-gp efflux. B (0.017) is even lower, which is excellent.
15. **Affinity:** A (-8.1) is significantly better than B (-7). This is a substantial advantage.

**Overall Assessment:**

Ligand A has a much better BBB score and a significantly stronger binding affinity. These are critical for a CNS GPCR target like DRD2. While Ligand B has slightly better QED, metabolic stability, and Pgp efflux, the poor BBB penetration is a major issue. The slightly lower logP of B is also a concern. The better affinity of A can likely overcome some of its slightly less favorable ADME properties.

Therefore, I recommend **Ligand A** as the more promising drug candidate.

Output:
1
2025-04-17 07:20:53,667 - INFO - Reasoning:
Let's analyze both ligands against the provided guidelines, prioritizing GPCR-specific properties (BBB, logP, Pgp, TPSA, and affinity).

**Ligand A:**

*   **MW:** 346.427 Da - Good (within 200-500 range).
*   **TPSA:** 67.87 A<sup>2</sup> - Excellent (well below 90 A<sup>2</sup> for CNS targets).
*   **logP:** 3.56 - Good (within optimal 1-3 range, slightly high but acceptable).
*   **HBD:** 1 - Good (<=5).
*   **HBA:** 4 - Good (<=10).
*   **QED:** 0.8 - Excellent (>=0.5).
*   **DILI:** 55.06 - Acceptable (below 60, low risk).
*   **BBB:** 85.033 - Excellent (very high, >70, ideal for CNS).
*   **Caco-2:** -4.53 - Poor (negative value suggests very low permeability).
*   **Solubility:** -3.901 - Poor (negative value suggests very low solubility).
*   **hERG:** 0.682 - Good (low risk).
*   **Cl_mic:** 0.53 mL/min/kg - Excellent (very low clearance, high metabolic stability).
*   **t1/2:** 8.844 hours - Good.
*   **Pgp:** 0.404 - Good (low efflux).
*   **Affinity:** -9.3 kcal/mol - Excellent (very strong binding).

**Ligand B:**

*   **MW:** 353.375 Da - Good (within 200-500 range).
*   **TPSA:** 121.11 A<sup>2</sup> - Marginal (above 90 A<sup>2</sup>, potentially problematic for CNS penetration).
*   **logP:** 0.166 - Poor (below 1, may impede permeation).
*   **HBD:** 3 - Good (<=5).
*   **HBA:** 6 - Good (<=10).
*   **QED:** 0.544 - Acceptable (>=0.5).
*   **DILI:** 47.732 - Good (below 40, low risk).
*   **BBB:** 24.777 - Poor (very low, unlikely to cross BBB).
*   **Caco-2:** -5.43 - Poor (negative value suggests very low permeability).
*   **Solubility:** -0.886 - Poor (negative value suggests very low solubility).
*   **hERG:** 0.16 - Good (low risk).
*   **Cl_mic:** -31.563 mL/min/kg - Excellent (very low clearance, high metabolic stability).
*   **t1/2:** 13.725 hours - Excellent.
*   **Pgp:** 0.02 - Excellent (very low efflux).
*   **Affinity:** -8.1 kcal/mol - Good (strong binding, but less than Ligand A).

**Comparison & Decision:**

While Ligand B has excellent metabolic stability (Cl_mic, t1/2) and Pgp efflux properties, its poor logP, TPSA, BBB, Caco-2 permeability, and solubility are significant drawbacks, especially for a CNS target like DRD2. Ligand A, despite having slightly higher logP, excels in key CNS-relevant properties: TPSA, BBB, and particularly its *much* stronger binding affinity (-9.3 vs -8.1 kcal/mol). The affinity difference is substantial enough to outweigh the slightly higher logP of Ligand A. The poor permeability and solubility of Ligand B are major concerns.

Output:
1
2025-04-17 07:20:53,668 - INFO - Reasoning:

Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (350.463 and 348.443 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (87.46) is better than Ligand B (59.08). For CNS targets, we want TPSA <= 90, both are within this range, but A is closer to the upper limit.

**3. logP:** Both ligands have good logP values (1.246 and 1.557), falling within the optimal 1-3 range.

**4. H-Bond Donors:** Ligand A has 2 HBDs, and Ligand B has 0. Both are acceptable (<=5).

**5. H-Bond Acceptors:** Ligand A has 5 HBAs, and Ligand B has 4. Both are acceptable (<=10).

**6. QED:** Both ligands have good QED scores (0.739 and 0.774), indicating good drug-like properties.

**7. DILI:** Ligand A (32.299) has a slightly higher DILI risk than Ligand B (24.544), but both are below the 40 threshold, indicating low risk.

**8. BBB:** This is a critical parameter for CNS targets. Ligand B (67.352) has a significantly better BBB penetration percentile than Ligand A (54.634). A value >70 is desirable, and B is closer to that.

**9. Caco-2 Permeability:** Ligand A (-4.724) has better Caco-2 permeability than Ligand B (-4.595). Higher is better, but both are negative values, indicating poor permeability.

**10. Aqueous Solubility:** Ligand A (-1.183) has slightly better aqueous solubility than Ligand B (-1.69), but both are poor.

**11. hERG Inhibition:** Both ligands have low hERG inhibition risk (0.192 and 0.319).

**12. Microsomal Clearance:** Ligand B (50.542) has lower microsomal clearance than Ligand A (12.831), suggesting better metabolic stability.

**13. In vitro Half-Life:** Ligand A (12.018) has a longer in vitro half-life than Ligand B (5.707).

**14. P-gp Efflux:** Both ligands have low P-gp efflux liability (0.052 and 0.033).

**15. Binding Affinity:** Ligand B (-8.7 kcal/mol) has a significantly stronger binding affinity than Ligand A (-7.7 kcal/mol). This is a >1 kcal/mol advantage, which can outweigh minor ADME drawbacks.

**Overall Assessment:**

While Ligand A has slightly better Caco-2 permeability and in vitro half-life, Ligand B is superior in several key areas for a CNS-targeting GPCR ligand. Specifically, its significantly higher BBB penetration (67.352 vs 54.634) and substantially stronger binding affinity (-8.7 vs -7.7 kcal/mol) are decisive advantages. The lower DILI and improved metabolic stability (lower Cl_mic) further support Ligand B's candidacy.

Output:
1
2025-04-17 07:20:53,668 - INFO - Batch 357 complete. Total preferences: 5712
2025-04-17 07:20:53,668 - INFO - Processing batch 358/512...
2025-04-17 07:21:33,684 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (343.446 and 338.451 Da) fall comfortably within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (41.29) is significantly better than Ligand B (55.56). For CNS targets, we want TPSA <= 90, and ideally closer to 60. Ligand A is much closer to this ideal.

**3. logP:** Both ligands have acceptable logP values (4.176 and 3.453), falling within the 1-3 range, though Ligand A is slightly higher.

**4. H-Bond Donors:** Both have 1 HBD, which is good.

**5. H-Bond Acceptors:** Both have 4 HBA, which is also good.

**6. QED:** Both ligands have high QED scores (0.886 and 0.868), indicating good drug-like properties.

**7. DILI:** Ligand A (18.961) has a slightly higher DILI risk than Ligand B (11.09), but both are well below the concerning threshold of 60.

**8. BBB:** Both ligands have excellent BBB penetration (89.104 and 84.413), exceeding the desirable >70 threshold for CNS targets.

**9. Caco-2 Permeability:** Both have negative Caco-2 values (-4.959 and -4.807), which is unusual and suggests poor permeability. This is a significant concern.

**10. Aqueous Solubility:** Both have negative solubility values (-3.898 and -2.442), indicating very poor aqueous solubility. This is also a significant concern.

**11. hERG Inhibition:** Both ligands show low hERG inhibition liability (0.847 and 0.939), which is favorable.

**12. Microsomal Clearance:** Ligand B (23.197) has significantly lower microsomal clearance than Ligand A (70.414), suggesting better metabolic stability.

**13. In vitro Half-Life:** Ligand B (1.024) has a slightly better in vitro half-life than Ligand A (-19.793).

**14. P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.452 and 0.193), which is excellent for CNS penetration.

**15. Binding Affinity:** Ligand B (-9.6 kcal/mol) has a slightly better binding affinity than Ligand A (-9.0 kcal/mol). While both are excellent, the 0.6 kcal/mol difference is notable.

**Overall Assessment:**

Despite the poor Caco-2 and solubility profiles for both compounds, Ligand B is slightly more promising. Its superior binding affinity, lower microsomal clearance, and slightly better half-life outweigh the slightly higher DILI risk. The TPSA is a concern for Ligand B, but not as critical as the metabolic stability. The BBB penetration is excellent for both. Given the GPCR-specific priorities, the binding affinity and metabolic stability are key.

Output:
1
2025-04-17 07:21:33,684 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (358.473 and 342.399 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (49.41) is excellent, well below the 90 A^2 threshold for CNS targets. Ligand B (95.73) is higher, but still potentially acceptable, though less ideal.

**logP:** Ligand A (3.747) is within the optimal 1-3 range. Ligand B (0.874) is slightly low, which could hinder membrane permeability.

**H-Bond Donors/Acceptors:** Ligand A (HBD=1, HBA=2) is favorable. Ligand B (HBD=3, HBA=5) is also acceptable, but slightly higher.

**QED:** Both ligands have good QED scores (0.638 and 0.751), indicating good drug-like properties.

**DILI:** Ligand A (11.09) has a much lower DILI risk than Ligand B (47.421). This is a significant advantage for Ligand A.

**BBB:** Ligand A (93.292) has excellent BBB penetration, exceeding the desirable >70% threshold. Ligand B (41.14) is considerably lower, raising concerns about CNS exposure.

**Caco-2 Permeability:** Ligand A (-4.509) has poor Caco-2 permeability, which is a concern. Ligand B (-5.23) is similarly poor.

**Aqueous Solubility:** Ligand A (-3.102) and Ligand B (-1.983) both have poor aqueous solubility.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.799 and 0.314).

**Microsomal Clearance:** Ligand B (-24.957) has significantly lower microsomal clearance than Ligand A (54.434), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand B (18.153) has a longer in vitro half-life than Ligand A (-11.009).

**P-gp Efflux:** Ligand A (0.208) has lower P-gp efflux liability than Ligand B (0.022), which is favorable for CNS penetration.

**Binding Affinity:** Both ligands have very good binding affinity (-8.6 kcal/mol and -9.4 kcal/mol). Ligand B is slightly better, but the difference is likely not substantial enough to overcome other deficiencies.

**Overall Assessment:**

Considering the GPCR-specific priorities, Ligand A is the more promising candidate. Its excellent BBB penetration and low DILI risk are crucial for a CNS-targeting drug. While its Caco-2 permeability and aqueous solubility are poor, these can potentially be addressed through formulation strategies. Ligand B's lower logP, higher DILI, and significantly lower BBB penetration are major drawbacks. Although it has better metabolic stability and slightly better affinity, these advantages are outweighed by the ADME concerns.

Output:
1
2025-04-17 07:21:33,685 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B based on the provided guidelines, prioritizing GPCR-specific properties (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (348.487 Da) is slightly better being closer to the lower end, potentially aiding permeability.

**TPSA:** Ligand A (49.85) is excellent for CNS penetration, well below the 90 A^2 threshold. Ligand B (86.88) is higher, but still potentially acceptable, though less ideal.

**logP:** Both ligands have good logP values (A: 2.607, B: 2.969), falling within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A (HBD=0, HBA=3) has a more favorable profile for CNS penetration than Ligand B (HBD=3, HBA=5). Fewer H-bonds generally improve BBB penetration.

**QED:** Both ligands have acceptable QED values (A: 0.634, B: 0.565), indicating reasonable drug-likeness.

**DILI:** Ligand A (6.747) has a significantly lower DILI risk than Ligand B (75.145), which is a major concern.

**BBB:** Ligand A (84.917) has a very good BBB percentile, exceeding the desirable >70 threshold. Ligand B (50.485) is considerably lower, raising concerns about CNS exposure.

**Caco-2 Permeability:** Ligand A (-4.443) has poor Caco-2 permeability. Ligand B (-5.721) is even worse.

**Aqueous Solubility:** Both ligands have poor aqueous solubility (A: -2.019, B: -3.989). This could pose formulation challenges.

**hERG:** Both ligands have low hERG inhibition risk (A: 0.371, B: 0.659).

**Microsomal Clearance:** Both ligands have similar microsomal clearance values (A: 53.891, B: 51.74), suggesting comparable metabolic stability.

**In vitro Half-Life:** Ligand A (-4.832) has a shorter in vitro half-life than Ligand B (22.892).

**P-gp Efflux:** Ligand A (0.048) has very low P-gp efflux, which is highly desirable for CNS penetration. Ligand B (0.393) has higher P-gp efflux.

**Binding Affinity:** Ligand B (-8.1) has a slightly better binding affinity than Ligand A (-7.9), but the difference is small (0.2 kcal/mol) and may not outweigh other factors.

**Overall Assessment:**

Ligand A is the stronger candidate. While its Caco-2 permeability and in vitro half-life are concerning, its significantly better BBB penetration, lower DILI risk, and lower P-gp efflux are crucial advantages for a CNS-targeting GPCR like DRD2. The small difference in binding affinity is unlikely to overcome the substantial ADME benefits of Ligand A. The poor solubility is a formulation challenge, but potentially addressable.

Output:
0
2025-04-17 07:21:33,685 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (352.431 and 349.431 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (88.1) is excellent, falling well below the 90 A^2 threshold for CNS targets. Ligand B (96.53) is still reasonable but less optimal.

**3. logP:** Ligand A (0.085) is quite low, potentially hindering membrane permeability. Ligand B (0.259) is also low, but slightly better than A. Both are below the optimal 1-3 range.

**4. H-Bond Donors:** Ligand A (2) and Ligand B (3) are both acceptable (<=5).

**5. H-Bond Acceptors:** Ligand A (5) and Ligand B (4) are both acceptable (<=10).

**6. QED:** Both ligands have good QED values (0.634 and 0.641), indicating drug-like properties.

**7. DILI:** Ligand A (15.743) has a significantly lower DILI risk than Ligand B (25.94). This is a substantial advantage.

**8. BBB:** Ligand A (68.282) has a much better BBB penetration percentile than Ligand B (43.699). This is *critical* for a CNS target like DRD2.

**9. Caco-2 Permeability:** Ligand A (-4.819) has a worse Caco-2 permeability than Ligand B (-5.32).

**10. Aqueous Solubility:** Ligand A (-1.275) has better aqueous solubility than Ligand B (-1.667).

**11. hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.213 and 0.099).

**12. Microsomal Clearance:** Ligand A (26.154) has higher microsomal clearance than Ligand B (-5.441), indicating lower metabolic stability. This is a negative for Ligand A.

**13. In vitro Half-Life:** Ligand B (10.074) has a significantly longer in vitro half-life than Ligand A (-1.37). This is a substantial advantage for B.

**14. P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.021 and 0.013).

**15. Binding Affinity:** Ligand B (-8.7 kcal/mol) has a stronger binding affinity than Ligand A (-7.8 kcal/mol). This is a 0.9 kcal/mol difference, which is significant and can outweigh some ADME drawbacks.

**Overall Assessment:**

While Ligand A has better TPSA, DILI, and solubility, Ligand B wins on several crucial factors for a CNS GPCR target. The significantly better BBB penetration, stronger binding affinity, and longer half-life of Ligand B outweigh the slightly higher TPSA and lower solubility. The lower metabolic stability of Ligand A is also a concern. The affinity difference is also substantial enough to make Ligand B the better candidate.

Output:
1
2025-04-17 07:21:33,685 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (347.463 and 350.503 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (98.17) is slightly higher than Ligand B (78.43). For CNS targets, we prefer TPSA <= 90, so Ligand B is better here.

**3. logP:** Both ligands have good logP values (3.01 and 2.375), falling within the optimal 1-3 range.

**4. H-Bond Donors:** Ligand A (1) is preferable to Ligand B (3) as lower HBDs generally improve permeability.

**5. H-Bond Acceptors:** Both ligands have the same number of HBA (3), which is acceptable (<=10).

**6. QED:** Ligand B (0.629) has a better QED score than Ligand A (0.454), indicating a more drug-like profile.

**7. DILI:** Both ligands have similar, relatively low DILI risk (15.587 and 15.006 percentile).

**8. BBB:** This is a critical parameter for CNS targets. Ligand A has a significantly better BBB penetration (77.162%) than Ligand B (53.432%). A value >70 is desirable, and Ligand A is closer to this threshold.

**9. Caco-2 Permeability:** Ligand A (-4.881) and Ligand B (-4.799) have similar Caco-2 permeability values.

**10. Aqueous Solubility:** Both ligands have similar, poor aqueous solubility (-3.192 and -3.07). This could pose formulation challenges, but isn't a dealbreaker.

**11. hERG Inhibition:** Both ligands have low hERG inhibition liability (0.356 and 0.277), which is good.

**12. Microsomal Clearance:** Ligand A (37.625) has lower microsomal clearance than Ligand B (50.178), suggesting better metabolic stability.

**13. In vitro Half-Life:** Ligand A (-9.925) has a slightly longer in vitro half-life than Ligand B (-10.609).

**14. P-gp Efflux:** Both ligands have low P-gp efflux liability (0.039 and 0.202), which is favorable for CNS penetration.

**15. Binding Affinity:** Ligand B (-8.5 kcal/mol) has a slightly better binding affinity than Ligand A (-7.9 kcal/mol). A difference of 0.6 kcal/mol is significant, and can often outweigh minor ADME drawbacks.

**Overall Assessment:**

While Ligand B has a better QED and slightly better affinity, Ligand A has a significantly better BBB penetration and lower microsomal clearance. Given the CNS target (DRD2), BBB is paramount. The slightly better affinity of Ligand B is helpful, but the substantial difference in BBB makes Ligand A a more promising candidate. The lower clearance of Ligand A also suggests it will have better pharmacokinetic properties.

Output:
0
2025-04-17 07:21:33,686 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (331.379 Da) is slightly lower, which could be beneficial for permeability.

**2. TPSA:** Both ligands have TPSA values below 90, which is good for CNS penetration. Ligand A (64.74) is better than Ligand B (67.87).

**3. logP:** Both ligands have optimal logP values (1-3). Ligand A (3.07) is slightly higher than Ligand B (1.971).

**4. H-Bond Donors:** Both have 1 HBD, which is within the acceptable limit.

**5. H-Bond Acceptors:** Ligand A has 5 HBA, and Ligand B has 4 HBA, both within the acceptable limit of 10.

**6. QED:** Both ligands have good QED scores (A: 0.625, B: 0.759), indicating drug-like properties. Ligand B is slightly better.

**7. DILI:** Ligand A has a significantly higher DILI risk (88.251) than Ligand B (16.402). This is a major concern for Ligand A.

**8. BBB:** Both ligands have good BBB penetration (A: 73.556, B: 68.437), but Ligand A is slightly better.

**9. Caco-2 Permeability:** Ligand A (-5.134) has poor Caco-2 permeability, while Ligand B (-4.461) is also poor but better than A.

**10. Aqueous Solubility:** Both ligands have very poor aqueous solubility (-4.499 and -2.296).

**11. hERG Inhibition:** Ligand A (0.736) has a higher hERG risk than Ligand B (0.331).

**12. Microsomal Clearance:** Ligand A (60.02) has higher microsomal clearance than Ligand B (46.098), indicating lower metabolic stability.

**13. In vitro Half-Life:** Ligand B (6.106 hours) has a significantly shorter half-life than Ligand A (69.917 hours).

**14. P-gp Efflux:** Ligand A (0.554) has lower P-gp efflux than Ligand B (0.049), which is favorable for CNS penetration.

**15. Binding Affinity:** Ligand B (-7.6 kcal/mol) has significantly stronger binding affinity than Ligand A (-9.0 kcal/mol).

**Overall Assessment:**

While Ligand A shows slightly better BBB penetration and P-gp efflux, its significantly higher DILI risk, poor Caco-2 permeability, higher hERG risk, higher clearance, and weaker binding affinity are major drawbacks. Ligand B, despite having a shorter half-life and slightly lower BBB, presents a much more favorable safety profile (low DILI, low hERG) and significantly stronger binding affinity. The strong binding affinity of Ligand B can potentially outweigh the shorter half-life, especially given the possibility of structural modifications to improve metabolic stability.

Output:
1
2025-04-17 07:21:33,686 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (355.479 and 362.905 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (73.32) is slightly higher than Ligand B (69.02), but both are below the 90 A^2 threshold desirable for CNS targets.

**logP:** Ligand A (0.199) is significantly lower than the optimal 1-3 range, potentially hindering permeability. Ligand B (3.625) is within the optimal range. This is a substantial advantage for Ligand B.

**H-Bond Donors/Acceptors:** Both have 1 HBD, which is good. Ligand A has 5 HBA, while Ligand B has 4. Both are acceptable.

**QED:** Ligand B (0.839) has a much higher QED score than Ligand A (0.448), indicating a more drug-like profile.

**DILI:** Ligand A (6.747) has a very low DILI risk, better than Ligand B (22.024), but both are below the concerning 60 percentile.

**BBB:** Ligand B (75.727) has a significantly better BBB penetration score than Ligand A (37.379). This is *critical* for a CNS target like DRD2.

**Caco-2 Permeability:** Ligand A (-4.735) has very poor Caco-2 permeability, while Ligand B (-4.937) is also poor.

**Aqueous Solubility:** Ligand A (0.365) has poor solubility, while Ligand B (-3.994) is even worse. Solubility is a concern for both, but less critical than permeability for CNS targets.

**hERG Inhibition:** Ligand A (0.461) shows lower hERG inhibition risk than Ligand B (0.709), which is preferable.

**Microsomal Clearance:** Ligand A (10.17) has lower microsomal clearance than Ligand B (29.645), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand B (11.259) has a longer in vitro half-life than Ligand A (-10.86), which is desirable.

**P-gp Efflux:** Ligand A (0.031) shows much lower P-gp efflux liability than Ligand B (0.228), which is a significant advantage for CNS penetration.

**Binding Affinity:** Ligand B (-7.0) has a slightly better binding affinity than Ligand A (-6.9), but the difference is small.

**Overall Assessment:**

Ligand B clearly outperforms Ligand A. The most important factors for a CNS-targeting GPCR like DRD2 are BBB penetration, logP, and P-gp efflux. Ligand B excels in BBB (75.727 vs 37.379) and has a much more favorable logP (3.625 vs 0.199). While Ligand A has better P-gp efflux and lower DILI, the superior CNS penetration profile of Ligand B outweighs these benefits. The slightly better affinity and half-life of Ligand B are also positive. The poor solubility and Caco-2 permeability are concerns for both, but less critical for a CNS target where direct absorption is less important than BBB penetration.

Output:
1
2025-04-17 07:21:33,686 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (350.503 and 352.41 Da) fall comfortably within the ideal 200-500 Da range.

**TPSA:** Ligand A (58.64) is excellent, well below the 90 A^2 threshold for CNS targets. Ligand B (95.42) is higher, but still potentially acceptable, though less optimal.

**logP:** Ligand A (2.594) is within the optimal 1-3 range. Ligand B (0.946) is a bit low, potentially hindering membrane permeability.

**H-Bond Donors/Acceptors:** Ligand A (HBD=1, HBA=3) and Ligand B (HBD=2, HBA=5) both have reasonable numbers of H-bond donors and acceptors, well within the guidelines.

**QED:** Both ligands have good QED scores (0.695 and 0.795), indicating good drug-like properties.

**DILI:** Ligand A (5.894) has a very low DILI risk, which is excellent. Ligand B (26.871) is higher, but still within an acceptable range.

**BBB:** Ligand A (78.79) has a good BBB percentile, desirable for a CNS target. Ligand B (71.19) is also reasonable, but slightly lower.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.608 and -4.791), which is unusual and suggests either poor permeability or an issue with the measurement. This is a red flag for both.

**Aqueous Solubility:** Both ligands have negative solubility values (-2.519 and -1.394), which is also unusual and concerning.

**hERG:** Both ligands have low hERG inhibition liability (0.53 and 0.462), which is good.

**Microsomal Clearance:** Ligand A (76.154) has a higher microsomal clearance, suggesting faster metabolism. Ligand B (-14.217) has a negative clearance, which is not physically possible and indicates a problem with the data.

**In vitro Half-Life:** Ligand A (-11.771) and Ligand B (-13.059) both have negative half-lives, which is not physically possible and indicates a problem with the data.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.082 and 0.021), which is favorable for CNS penetration.

**Binding Affinity:** Both ligands have similar and strong binding affinities (-8.0 and -8.6 kcal/mol). The difference is less than 1.5 kcal/mol, so this isn't a major differentiating factor.

**Overall Assessment:**

Despite the issues with Caco-2, solubility, half-life, and clearance data, Ligand A appears slightly more promising due to its lower DILI risk, better TPSA, and slightly better BBB penetration. The negative values for Caco-2, solubility, half-life, and clearance are concerning and would require further investigation/experimental validation. However, given the available data, Ligand A is marginally better.

Output:
0
2025-04-17 07:21:33,686 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (364.471 and 344.415 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (104.53) is slightly above the preferred <90 for CNS targets, while Ligand B (84.42) is comfortably within the range. This gives a slight edge to Ligand B.

**3. logP:** Both ligands have good logP values (1.245 and 0.932), falling within the optimal 1-3 range.

**4. H-Bond Donors:** Ligand A (3) and Ligand B (1) are both acceptable, being less than 5. Ligand B is better here.

**5. H-Bond Acceptors:** Ligand A (4) and Ligand B (5) are both acceptable, being less than 10.

**6. QED:** Both ligands have good QED scores (0.54 and 0.859), indicating good drug-like properties. Ligand B is better.

**7. DILI:** Both ligands have similar DILI risk (40.287 and 40.403), both being acceptable (<40 is good).

**8. BBB:** This is a critical parameter for a CNS target like DRD2. Ligand B (87.553) has a significantly higher BBB percentile than Ligand A (55.874). This is a major advantage for Ligand B.

**9. Caco-2 Permeability:** Both have negative values, which is unusual. However, the magnitude of the negative value is important. Ligand A (-5.359) is worse than Ligand B (-4.707).

**10. Aqueous Solubility:** Both have negative values, which is also unusual. Ligand A (-2.389) is slightly better than Ligand B (-2.708).

**11. hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.067 and 0.34), which is excellent.

**12. Microsomal Clearance:** Ligand A (-1.016) has a lower (better) microsomal clearance than Ligand B (43.251), suggesting better metabolic stability.

**13. In vitro Half-Life:** Ligand B (6.578) has a significantly longer half-life than Ligand A (-3.029). This is a significant advantage for Ligand B.

**14. P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.028 and 0.046), which is excellent.

**15. Binding Affinity:** Both ligands have very similar and excellent binding affinities (-8.8 and -8.4 kcal/mol). The difference of 0.4 kcal/mol is not substantial enough to be decisive.

**Overall Assessment:**

Ligand B is the stronger candidate. While Ligand A has slightly better metabolic stability, Ligand B excels in crucial areas for CNS penetration: significantly higher BBB penetration (87.553 vs 55.874), a better TPSA (84.42 vs 104.53), a longer half-life (6.578 vs -3.029), and a better QED score (0.859 vs 0.54). Given the GPCR-specific priorities, the improved BBB and half-life outweigh the slightly better metabolic stability of Ligand A.



Output:
1
2025-04-17 07:21:33,686 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (339.439 and 346.515 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (62.3) is better than Ligand B (40.62). Both are below the 90 A^2 threshold for CNS targets, but A is slightly higher, potentially impacting BBB penetration less.

**3. logP:** Ligand B (3.308) is slightly higher than Ligand A (1.921), but both are within the optimal 1-3 range.

**4. H-Bond Donors:** Ligand A (1) is better than Ligand B (0). Lower is generally preferred for BBB penetration.

**5. H-Bond Acceptors:** Ligand A (3) is slightly higher than Ligand B (2), but both are acceptable.

**6. QED:** Ligand A (0.891) is better than Ligand B (0.783), indicating a more drug-like profile.

**7. DILI:** Both ligands have relatively low DILI risk (16.789 and 15.781, respectively).

**8. BBB:** Both ligands have excellent BBB penetration (76.347 and 79.721, respectively), exceeding the >70% threshold. Ligand B is slightly better.

**9. Caco-2 Permeability:** Ligand A (-5.012) is worse than Ligand B (-4.682). Lower values here indicate poorer permeability.

**10. Aqueous Solubility:** Ligand A (-1.98) is better than Ligand B (-3.947). Higher solubility is generally preferred.

**11. hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.263 and 0.549, respectively).

**12. Microsomal Clearance:** Ligand B (64.388) has significantly lower microsomal clearance than Ligand A (11.088), suggesting better metabolic stability.

**13. In vitro Half-Life:** Ligand B (-5.258) has a better half-life than Ligand A (-12.697).

**14. P-gp Efflux:** Ligand A (0.06) is significantly better than Ligand B (0.44), indicating lower P-gp efflux and therefore better CNS exposure.

**15. Binding Affinity:** Ligand B (-8.1) has a slightly better binding affinity than Ligand A (-9.0). While A is better, the difference is not substantial enough to outweigh other factors.

**Overall Assessment:**

Ligand B demonstrates superior ADME properties (BBB, metabolic stability, half-life) and a slightly better binding affinity. While Ligand A has a better QED and P-gp efflux profile, the improvements in metabolic stability and half-life for Ligand B are crucial for a CNS-targeting drug. The slightly better BBB penetration of Ligand B also contributes to its favorability.

Output:
1
2025-04-17 07:21:33,687 - INFO - Reasoning:

Let's analyze Ligand A and Ligand B for their potential as DRD2 drug candidates, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight (MW):** Both ligands (348.403 and 350.463 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (93.53) is slightly above the optimal <90 for CNS targets, but still reasonable. Ligand B (85.25) is well within the desired range.

**3. logP:** Ligand A (0.289) is quite low, potentially hindering membrane permeability. Ligand B (2.285) is within the optimal 1-3 range. This is a significant advantage for Ligand B.

**4. H-Bond Donors (HBD):** Both are acceptable (1 and 2 respectively), staying below the 5 threshold.

**5. H-Bond Acceptors (HBA):** Both are acceptable (6 and 5 respectively), staying below the 10 threshold.

**6. QED:** Both ligands have good QED scores (0.746 and 0.634), indicating drug-like properties.

**7. DILI:** Ligand A (38.387) has a lower DILI risk than Ligand B (52.966), which is a positive.

**8. BBB:** Both ligands have similar, good BBB penetration (67.08% and 68.399%), exceeding the 70% threshold for CNS targets.

**9. Caco-2 Permeability:** Both have negative values, indicating poor permeability. However, the scale is not specified, so it's difficult to interpret.

**10. Aqueous Solubility:** Both ligands have very poor aqueous solubility (-1.678 and -2.963). This is a significant drawback for both.

**11. hERG Inhibition:** Both ligands show very low hERG inhibition risk (0.04 and 0.34), which is excellent.

**12. Microsomal Clearance (Cl_mic):** Both have similar, moderate clearance rates (32.637 and 32.365 mL/min/kg).

**13. In vitro Half-Life:** Ligand B (6.155 hours) has a significantly longer half-life than Ligand A (-2.109 hours). This is a major advantage for Ligand B.

**14. P-gp Efflux:** Both show very low P-gp efflux liability (0.008 and 0.065), which is favorable for CNS penetration.

**15. Binding Affinity:** Both ligands have identical and strong binding affinities (-7.8 kcal/mol).

**Overall Assessment:**

While Ligand A has a slightly better DILI score, Ligand B is significantly better overall, especially considering the GPCR-specific priorities. Ligand B has a much more favorable logP, a longer half-life, and a better TPSA. The poor solubility is a concern for both, but the improved permeability characteristics of Ligand B (higher logP) and its longer half-life outweigh the slightly higher DILI risk. The equal binding affinity removes that as a differentiating factor.

Output:
1
2025-04-17 07:21:33,687 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (351.403 and 349.431 Da) fall comfortably within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (99.52) is slightly higher than Ligand B (96.53), but both are below the 140 A^2 threshold for good oral absorption and reasonably close to the 90 A^2 target for CNS penetration.

**3. logP:** Ligand A (1.469) is within the optimal 1-3 range. Ligand B (0.259) is a bit low, potentially hindering membrane permeability.

**4. H-Bond Donors:** Ligand A (1) is preferable to Ligand B (3). Fewer HBDs generally improve permeability.

**5. H-Bond Acceptors:** Ligand A (7) is better than Ligand B (4), as lower HBA counts generally improve permeability.

**6. QED:** Both ligands have similar and acceptable QED values (0.615 and 0.641, both > 0.5).

**7. DILI:** Ligand A (60.915) has a higher DILI risk than Ligand B (25.94), which is a significant drawback.

**8. BBB:** Ligand A (68.554) has a better BBB penetration percentile than Ligand B (43.699). This is a critical factor for a CNS target like DRD2.

**9. Caco-2 Permeability:** Ligand A (-4.421) has a worse Caco-2 permeability than Ligand B (-5.32).

**10. Aqueous Solubility:** Ligand A (-3.19) has a better aqueous solubility than Ligand B (-1.667).

**11. hERG:** Both ligands have very low hERG inhibition liability (0.156 and 0.099), which is excellent.

**12. Microsomal Clearance:** Ligand A (51.704) has a higher microsomal clearance than Ligand B (-5.441). This suggests Ligand B is more metabolically stable.

**13. In vitro Half-Life:** Ligand B (10.074) has a significantly longer in vitro half-life than Ligand A (3.923).

**14. P-gp Efflux:** Ligand A (0.13) has a lower P-gp efflux liability than Ligand B (0.013), which is favorable for CNS exposure.

**15. Binding Affinity:** Ligand B (-8.7 kcal/mol) has a substantially stronger binding affinity than Ligand A (-6.8 kcal/mol). This difference of 1.9 kcal/mol is significant and can outweigh some ADME drawbacks.

**Overall Assessment:**

Ligand B is the stronger candidate. While Ligand A has a better BBB score and P-gp efflux profile, Ligand B's significantly higher binding affinity (-8.7 vs -6.8 kcal/mol) is a major advantage, especially for a GPCR target. Furthermore, Ligand B exhibits better metabolic stability (lower Cl_mic, longer t1/2) and a much lower DILI risk. The slightly lower logP and BBB for Ligand B are less concerning given the substantial affinity advantage and improved safety profile.

Output:
1
2025-04-17 07:21:33,687 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 drug candidates, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (351.441 and 353.507 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (36.44) is significantly better than Ligand B (61.88). For CNS targets, we want TPSA <= 90, and ideally closer to 60. Ligand A is well within this range, while Ligand B is pushing the upper limit and could face permeability challenges.

**3. logP:** Ligand A (3.445) is optimal (1-3), while Ligand B (1.497) is on the lower side. Lower logP can hinder membrane permeability.

**4. H-Bond Donors:** Both ligands have acceptable HBD counts (0 for A, 1 for B), well below the threshold of 5.

**5. H-Bond Acceptors:** Both ligands have acceptable HBA counts (3 for A, 4 for B), below the threshold of 10.

**6. QED:** Both ligands have similar QED values (0.834 and 0.786), indicating good drug-like properties.

**7. DILI:** Ligand A (23.11) has a much lower DILI risk than Ligand B (5.7). Lower is better, and A is well below the 40% threshold, while B is also good but higher than A.

**8. BBB:** Ligand A (96.743) has excellent BBB penetration, exceeding the desirable >70% threshold. Ligand B (76.851) is still reasonable but significantly lower than A. This is a critical factor for a CNS target like DRD2.

**9. Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and difficult to interpret without knowing the scale. However, the magnitude is similar.

**10. Aqueous Solubility:** Both ligands have negative solubility values, again unusual and difficult to interpret.

**11. hERG Inhibition:** Ligand A (0.928) has a slightly higher hERG risk than Ligand B (0.319), but both are relatively low.

**12. Microsomal Clearance:** Ligand A (12.838) has higher clearance than Ligand B (10.076), indicating lower metabolic stability.

**13. In vitro Half-Life:** Ligand B (-8.533) has a much longer in vitro half-life than Ligand A (9.554). This is a significant advantage for B.

**14. P-gp Efflux:** Ligand A (0.313) has lower P-gp efflux than Ligand B (0.016), which is favorable for CNS penetration.

**15. Binding Affinity:** Ligand B (-7.3) has a significantly stronger binding affinity than Ligand A (-0). This is a substantial advantage, potentially outweighing some ADME drawbacks.

**Overall Assessment:**

Ligand B has a significantly better binding affinity and a longer half-life. However, Ligand A excels in TPSA, logP, BBB penetration, and DILI risk. Given the GPCR-specific priorities, the strong BBB penetration of Ligand A is a major advantage for a CNS target. The significantly better affinity of Ligand B is compelling, but the lower BBB and higher TPSA are concerning. The difference in affinity is large enough to potentially overcome the slightly less favorable ADME profile of Ligand B.

Output:
1
2025-04-17 07:21:33,687 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B based on the provided guidelines, prioritizing GPCR-specific properties (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (343.431 and 354.451 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (101.21) is better than Ligand B (116.6). Both are below the 140 threshold for oral absorption, but Ligand A is closer to the preferred <90 for CNS targets.

**logP:** Both ligands have good logP values (1.214 and 1.083), falling within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A (HBD=2, HBA=5) is slightly better than Ligand B (HBD=4, HBA=7) in terms of balancing solubility and permeability.

**QED:** Ligand A (0.837) has a significantly higher QED score than Ligand B (0.497), indicating a more drug-like profile.

**DILI:** Ligand B (34.122) has a lower DILI risk than Ligand A (47.964), which is favorable.

**BBB:** Ligand A (73.866) has a significantly better BBB penetration percentile than Ligand B (56.883). This is a *critical* advantage for a CNS target like DRD2.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.009 and -5.022), which is unusual and suggests poor permeability. However, the values are very close.

**Aqueous Solubility:** Both ligands have negative solubility values (-2.964 and -2.344) which is also unusual and suggests poor solubility. Again, the values are very close.

**hERG Inhibition:** Both ligands show low hERG inhibition liability (0.223 and 0.335), which is good.

**Microsomal Clearance:** Ligand A (27.112) has a lower microsomal clearance than Ligand B (57.979), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (-10.268) has a slightly better (less negative) in vitro half-life than Ligand B (-13.986).

**P-gp Efflux:** Ligand A (0.006) has a much lower P-gp efflux liability than Ligand B (0.09), which is beneficial for CNS exposure.

**Binding Affinity:** Ligand B (-7.2 kcal/mol) has a slightly better binding affinity than Ligand A (-8.3 kcal/mol). While this is a positive for Ligand B, the difference is relatively small.

**Overall Assessment:**

Despite Ligand B having a slightly better binding affinity and lower DILI risk, Ligand A is the stronger candidate. The significantly better BBB penetration (73.866 vs 56.883), higher QED (0.837 vs 0.497), lower P-gp efflux (0.006 vs 0.09), and lower microsomal clearance (27.112 vs 57.979) of Ligand A are crucial for a CNS-targeting GPCR like DRD2. The small affinity difference is outweighed by these ADME/PK advantages.

Output:
1
2025-04-17 07:21:33,687 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (343.427 and 349.435 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (84.23) is excellent, well below the 90 A^2 threshold for CNS targets. Ligand B (109.58) is still reasonable, but less optimal.

**3. logP:** Ligand A (2.218) is within the optimal range of 1-3. Ligand B (0.009) is significantly low, potentially hindering membrane permeability.

**4. H-Bond Donors:** Ligand A (2) and Ligand B (3) are both acceptable, below the 5 limit.

**5. H-Bond Acceptors:** Ligand A (4) and Ligand B (6) are both acceptable, below the 10 limit.

**6. QED:** Both ligands have acceptable QED values (0.776 and 0.64), indicating good drug-like properties.

**7. DILI:** Both ligands have low DILI risk (31.601 and 35.75), which is positive.

**8. BBB:** Ligand A (58.627) is concerningly low for a CNS target. Ligand B (71.772) is better, exceeding the 70% threshold, and is a significant advantage.

**9. Caco-2 Permeability:** Ligand A (-4.986) is very poor, indicating very low intestinal absorption. Ligand B (-5.544) is also poor, but slightly better than A.

**10. Aqueous Solubility:** Ligand A (-2.66) and Ligand B (-1.928) are both poor, but B is slightly better.

**11. hERG Inhibition:** Ligand A (0.124) has very low hERG inhibition risk. Ligand B (0.449) is slightly higher, but still acceptable.

**12. Microsomal Clearance:** Ligand A (31.699) is moderate. Ligand B (-23.645) is excellent, indicating high metabolic stability. The negative value suggests very slow clearance.

**13. In vitro Half-Life:** Ligand A (14.934) is moderate. Ligand B (0.13) is very short, a significant drawback.

**14. P-gp Efflux:** Ligand A (0.075) has very low P-gp efflux liability, which is highly desirable for CNS penetration. Ligand B (0.004) is even lower, an advantage.

**15. Binding Affinity:** Ligand B (-8.2 kcal/mol) has a slightly better binding affinity than Ligand A (-7.9 kcal/mol), but the difference is small.

**Overall Assessment:**

Ligand B excels in BBB penetration and metabolic stability (Cl_mic), which are crucial for a CNS GPCR target. While its logP is low and solubility is poor, the strong binding affinity and extremely low P-gp efflux can potentially compensate for these drawbacks. Ligand A has better TPSA and hERG, but suffers from poor BBB penetration and Caco-2 permeability, making it less likely to reach the target in the brain. The superior BBB and metabolic stability of Ligand B outweigh the slightly lower logP and solubility.

Output:
1
2025-04-17 07:21:33,688 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (348.393 and 344.39 Da) fall comfortably within the ideal 200-500 Da range.

**TPSA:** Ligand A (40.62) is significantly better than Ligand B (86.09). For CNS targets, we want TPSA <= 90, and A is much closer to the optimal <=60 range. B is pushing the upper limit and could face permeability issues.

**logP:** Both ligands have acceptable logP values (3.072 and 1.881, respectively) within the 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A (0 HBD, 2 HBA) is preferable to Ligand B (1 HBD, 4 HBA). Lower counts generally improve permeability.

**QED:** Both ligands have good QED scores (0.824 and 0.903), indicating good drug-like properties.

**DILI:** Both ligands have low DILI risk (36.06 and 35.634), which is excellent.

**BBB:** Both ligands have very good BBB penetration (84.684 and 82.474), exceeding the desirable >70 threshold for CNS targets.

**Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual. Assuming these are logP values, both are very poor.

**Aqueous Solubility:** Both ligands have very poor aqueous solubility (-2.656 and -3.079). This is a significant drawback.

**hERG Inhibition:** Both ligands show low hERG inhibition liability (0.687 and 0.501), which is favorable.

**Microsomal Clearance:** Ligand B (-14.348) has a much lower (better) microsomal clearance than Ligand A (26.461), indicating greater metabolic stability.

**In vitro Half-Life:** Ligand B (-6.528) has a significantly longer in vitro half-life than Ligand A (-2.488), which is desirable.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.27 and 0.014), which is excellent for CNS penetration.

**Binding Affinity:** Both ligands have identical binding affinities (-9.7 kcal/mol), which is excellent and strong.

**Overall Assessment:**

While both ligands have excellent binding affinity and BBB penetration, Ligand A is superior due to its significantly lower TPSA. The lower TPSA suggests better permeability. Ligand B has better metabolic stability and half-life, but the higher TPSA is a major concern for a CNS target. The poor solubility of both is concerning, but can potentially be addressed with formulation strategies. Given the importance of TPSA for CNS penetration and the equal binding affinity, Ligand A is the slightly more promising candidate.

Output:
0
2025-04-17 07:21:33,688 - INFO - Batch 358 complete. Total preferences: 5728
2025-04-17 07:21:33,688 - INFO - Processing batch 359/512...
2025-04-17 07:22:18,271 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (355.825 and 374.472 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (81.99) is better than Ligand B (41.99) as it is closer to the <90 threshold for CNS targets. Ligand B is excellent.

**logP:** Both ligands have logP values (3.244 and 4.766) within the optimal 1-3 range, but Ligand B is slightly higher. While still acceptable, higher logP can sometimes lead to off-target effects.

**H-Bond Donors/Acceptors:** Both ligands have reasonable HBD (2 and 1) and HBA (3 and 3) counts, well within the acceptable limits.

**QED:** Both ligands have similar QED values (0.863 and 0.807), indicating good drug-like properties.

**DILI:** Ligand A (63.862) has a higher DILI risk than Ligand B (48.546), suggesting a potentially greater risk of liver injury.

**BBB:** Ligand B (89.725) significantly outperforms Ligand A (56.844) in BBB penetration, which is *critical* for a CNS target like DRD2.

**Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and suggests either poor permeability or an issue with the prediction method. This is a flag for both, but doesn't clearly differentiate them.

**Aqueous Solubility:** Both have negative solubility values, which is also unusual. This is another flag for both.

**hERG Inhibition:** Both ligands show low hERG inhibition liability (0.584 and 0.45), which is positive.

**Microsomal Clearance:** Both ligands have similar microsomal clearance values (51.763 and 52.053), indicating comparable metabolic stability.

**In vitro Half-Life:** Ligand A (30.747 hours) has a significantly longer half-life than Ligand B (2.703 hours). This is a substantial advantage for Ligand A.

**P-gp Efflux:** Ligand A (0.092) exhibits lower P-gp efflux than Ligand B (0.554), which is favorable for CNS penetration.

**Binding Affinity:** Both ligands have excellent binding affinities (-9.4 and -8.9 kcal/mol). Ligand A has a slightly better affinity, but the difference is less than 1.5 kcal/mol, so it's not a decisive factor on its own.

**Overall Assessment:**

While Ligand A has a slightly better binding affinity and longer half-life, Ligand B is clearly superior due to its significantly higher predicted BBB penetration (89.725 vs 56.844) and lower DILI risk. For a CNS target like DRD2, BBB penetration is paramount. The lower P-gp efflux of Ligand A is also beneficial, but the difference isn't enough to overcome the substantial BBB advantage of Ligand B. The unusual solubility and Caco-2 values for both are concerning and would require experimental validation.

Output:
1
2025-04-17 07:22:18,271 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (451.68) is higher, but still acceptable. Ligand B (367.76) is also good.

**TPSA:** Both ligands have TPSA values below 90, which is favorable for CNS penetration. Ligand A (68.29) is slightly higher than Ligand B (57.78), but both are good.

**logP:** Both ligands have logP values around 4.3-4.7, which is slightly high. While >4 can cause issues, it's not a dealbreaker, especially for a GPCR where some lipophilicity is often needed for membrane interaction.

**H-Bond Donors/Acceptors:** Ligand A has 1 HBD and 5 HBA, while Ligand B has 2 HBD and 2 HBA. Both are within acceptable limits (<=5 HBD and <=10 HBA).

**QED:** Both ligands have good QED scores (A: 0.554, B: 0.703), indicating drug-like properties. Ligand B is slightly better here.

**DILI:** Both ligands have high DILI risk (A: 92.05, B: 84.68). This is a concern, but can be addressed in later optimization stages.

**BBB:** Both ligands have good BBB penetration (A: 81.47, B: 75.11), which is crucial for a CNS target like DRD2. Ligand A has a slightly better BBB score.

**Caco-2 Permeability:** Both have negative Caco-2 values (-4.21 and -4.90). This is unusual and suggests poor permeability. It's likely an artifact of the prediction method, but a concern.

**Aqueous Solubility:** Both ligands have very poor aqueous solubility (-5.48 and -5.56). This is a significant drawback, potentially hindering bioavailability.

**hERG Inhibition:** Both ligands show low hERG inhibition risk (A: 0.23, B: 0.71). This is positive.

**Microsomal Clearance:** Ligand B has significantly lower microsomal clearance (32.30) compared to Ligand A (87.53), indicating better metabolic stability.

**In vitro Half-Life:** Ligand B has a longer in vitro half-life (67.89) than Ligand A (39.86), which is desirable.

**P-gp Efflux:** Both ligands show low P-gp efflux liability (A: 0.45, B: 0.47). This is good for CNS exposure.

**Binding Affinity:** Ligand B has a significantly stronger binding affinity (-10.4 kcal/mol) than Ligand A (-8.6 kcal/mol). This is a substantial advantage, potentially outweighing some of the ADME drawbacks.

**Overall Assessment:**

Ligand B is the better candidate. While both have issues with solubility and DILI, Ligand B's significantly stronger binding affinity (-10.4 vs -8.6 kcal/mol) and better metabolic stability (lower Cl_mic and longer t1/2) are critical advantages. The slightly better QED score also contributes. The BBB values are comparable. The poor Caco-2 values are concerning for both, but might be prediction artifacts. The affinity difference is large enough to prioritize Ligand B for further optimization, focusing on improving solubility and mitigating DILI risk.

Output:
1
2025-04-17 07:22:18,271 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (362.5 and 358.8 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (76.02) is significantly better than Ligand B (105.83). For CNS targets, we want TPSA <= 90, and A is comfortably within this range, while B is above.

**3. logP:** Both ligands have good logP values (3.123 and 2.288), falling within the optimal 1-3 range.

**4. H-Bond Donors:** Both have 2 HBD, which is acceptable.

**5. H-Bond Acceptors:** Ligand A has 5 HBA, while Ligand B has 7. Both are within the acceptable limit of <=10.

**6. QED:** Both ligands have similar QED values (0.709 and 0.696), indicating good drug-likeness.

**7. DILI:** Ligand A (32.38) has a much lower DILI risk than Ligand B (85.50). This is a significant advantage for A.

**8. BBB:** Ligand A (59.09) is lower than Ligand B (68.75), but both are below the desirable >70 for CNS targets. However, the difference is not substantial enough to be decisive on its own.

**9. Caco-2:** Both have negative Caco-2 values, which is unusual and likely indicates poor permeability. This is a concern for both.

**10. Solubility:** Both have negative solubility values, also unusual and indicating poor solubility. This is a concern for both.

**11. hERG:** Both ligands have low hERG inhibition liability (0.66 and 0.566), which is good.

**12. Cl_mic:** Ligand A (39.28) has lower microsomal clearance than Ligand B (53.70), suggesting better metabolic stability.

**13. t1/2:** Both have similar in vitro half-lives (24.57 and 26.42 hours).

**14. Pgp:** Ligand A (0.199) has significantly lower P-gp efflux liability than Ligand B (0.018), which is a major advantage for CNS penetration.

**15. Binding Affinity:** Ligand B (-8.9 kcal/mol) has a slightly better binding affinity than Ligand A (-8.4 kcal/mol), but the difference is only 0.5 kcal/mol. Considering the other ADME properties, this difference is unlikely to outweigh the other advantages of Ligand A.

**Overall Assessment:**

Ligand A is the better candidate. It has a significantly lower DILI risk, lower P-gp efflux, and better TPSA. While Ligand B has slightly better binding affinity, the other ADME properties of Ligand A are more favorable, especially for a CNS target like DRD2. The lower TPSA and Pgp efflux of Ligand A suggest it will have better brain penetration, despite both having suboptimal BBB scores.

Output:
1
2025-04-17 07:22:18,271 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (359.411 and 350.507 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (109.04) is higher than the preferred <90 for CNS targets, while Ligand B (55.89) is well within the range. This is a significant advantage for Ligand B.

**3. logP:** Both ligands have acceptable logP values (1.265 and 1.617), falling within the optimal 1-3 range.

**4. H-Bond Donors:** Ligand A has 2 HBD, and Ligand B has 1. Both are acceptable (<=5).

**5. H-Bond Acceptors:** Ligand A has 7 HBA, and Ligand B has 3. Both are acceptable (<=10).

**6. QED:** Both ligands have good QED scores (0.835 and 0.792), indicating drug-like properties.

**7. DILI:** Ligand A (80.651) has a higher DILI risk than Ligand B (7.871). This is a significant negative for Ligand A.

**8. BBB:** Ligand B (81.155) has a much better BBB penetration percentile than Ligand A (52.889). This is crucial for a CNS target like DRD2.

**9. Caco-2 Permeability:** Ligand A (-5.239) has a negative Caco-2 value, which is concerning. Ligand B (-4.719) is also negative, but less so.

**10. Aqueous Solubility:** Ligand A (-3.56) and Ligand B (-1.316) both have negative solubility values, indicating poor solubility.

**11. hERG Inhibition:** Both ligands have low hERG inhibition risk (0.412 and 0.615).

**12. Microsomal Clearance:** Ligand B (-7.889) has a negative clearance, which is excellent, indicating high metabolic stability. Ligand A (11.57) has a positive clearance, indicating faster metabolism.

**13. In vitro Half-Life:** Ligand B (2.586) has a shorter half-life than Ligand A (16.184). However, the negative clearance of Ligand B suggests the *in vivo* half-life could be longer than predicted.

**14. P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.083 and 0.026).

**15. Binding Affinity:** Ligand A (-8.5 kcal/mol) has slightly better binding affinity than Ligand B (-7.7 kcal/mol), but the difference is less than 1.5 kcal/mol.

**Overall Assessment:**

Ligand B is the superior candidate. While Ligand A has slightly better binding affinity, Ligand B excels in crucial ADME properties for a CNS-targeting GPCR. Specifically, its significantly lower TPSA, much better BBB penetration, lower DILI risk, and superior metabolic stability (negative clearance) outweigh the small difference in binding affinity. The negative Caco-2 and solubility values are concerns for both, but can be addressed with formulation strategies.

Output:
1
2025-04-17 07:22:18,272 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (381.445 and 355.483 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Both ligands (95.58 and 93.78) are reasonably close to the 90 A^2 threshold for CNS targets, though slightly above. This isn't a major concern, but keeping it lower is preferable.

**3. logP:** Ligand A (-0.576) is slightly below the optimal range (1-3), potentially hindering permeation. Ligand B (-0.985) is even lower, raising more concern.

**4. H-Bond Donors:** Ligand A (2) and Ligand B (3) are both within the acceptable limit of <=5.

**5. H-Bond Acceptors:** Both ligands (5) are within the acceptable limit of <=10.

**6. QED:** Ligand A (0.616) has a better QED score than Ligand B (0.494), indicating a more drug-like profile.

**7. DILI:** Ligand A (32.842) has a significantly lower DILI risk than Ligand B (18.457), which is a substantial advantage.

**8. BBB:** Ligand A (64.831) has a much better BBB penetration percentile than Ligand B (35.207). This is *critical* for a CNS target like DRD2.

**9. Caco-2 Permeability:** Both are very negative (-5.456 and -5.422), suggesting poor intestinal absorption. This isn't a primary concern for CNS drugs, as the route of administration and BBB penetration are more important.

**10. Aqueous Solubility:** Both are very negative (-1.557 and -0.785), indicating poor aqueous solubility. This could pose formulation challenges.

**11. hERG Inhibition:** Both ligands show very low hERG inhibition risk (0.113 and 0.1).

**12. Microsomal Clearance:** Ligand A (-12.298) has a much lower (better) microsomal clearance than Ligand B (10.167), indicating greater metabolic stability.

**13. In vitro Half-Life:** Ligand A (7.012) has a better in vitro half-life than Ligand B (-11.839).

**14. P-gp Efflux:** Both ligands show very low P-gp efflux liability (0.008 and 0.001).

**15. Binding Affinity:** Ligand A (-7.5 kcal/mol) has a slightly better binding affinity than Ligand B (-6.9 kcal/mol), although the difference is not huge.

**Overall Assessment:**

Ligand A is significantly better than Ligand B. While both have issues with logP and solubility, Ligand A excels in crucial areas for a CNS GPCR drug: BBB penetration, DILI risk, metabolic stability (Cl_mic and t1/2), and QED. The slightly better binding affinity further supports choosing Ligand A. The lower logP is a concern, but the superior ADME properties and safety profile of Ligand A outweigh this drawback.

Output:
1
2025-04-17 07:22:18,272 - INFO - Okay, let's analyze these two ligands for their potential as DRD2 drug candidates. DRD2 is a GPCR in the CNS, so BBB penetration, logP, Pgp efflux, TPSA, and binding affinity are paramount.

**Ligand A: [347.415, 82.44, 0.682, 1, 5, 0.745, 23.769, 57.968, -4.646, -1.351, 0.077, 6.813, 10.852, 0.016, -7.5]**
**Ligand B: [356.394, 103.01, 0.707, 3, 5, 0.668, 21.636, 53.587, -4.856, -2.464, 0.368, -2.567, 17.2, 0.031, -8]**

Here's a breakdown of each property:

1. **MW:** Both are within the ideal range (200-500 Da). A (347.415) is slightly preferred due to being lower.
2. **TPSA:** A (82.44) is excellent for CNS penetration (well below 90). B (103.01) is still acceptable, but less ideal.
3. **logP:** Both are good (around 0.7), falling within the optimal 1-3 range. B (0.707) is marginally better.
4. **HBD:** A (1) is preferred over B (3). Lower HBD generally improves permeability.
5. **HBA:** Both are at 5, which is acceptable.
6. **QED:** Both are good (>0.5), A (0.745) is slightly better.
7. **DILI:** Both are low risk (<40), A (23.769) is slightly lower than B (21.636).
8. **BBB:** A (57.968) is better than B (53.587), although both are below the desirable >70 for CNS targets. This is a significant drawback for both.
9. **Caco-2:** A (-4.646) and B (-4.856) are both very poor, indicating poor intestinal absorption. This is a concern, but less critical for CNS drugs where direct delivery is possible.
10. **Solubility:** A (-1.351) is better than B (-2.464), indicating better aqueous solubility.
11. **hERG:** A (0.077) is much better than B (0.368), indicating a lower risk of cardiotoxicity.
12. **Cl_mic:** A (6.813) is higher than B (-2.567), meaning A has faster metabolic clearance and lower metabolic stability. B is significantly better here.
13. **t1/2:** B (17.2) has a significantly longer in vitro half-life than A (10.852). This is a major advantage for B.
14. **Pgp:** A (0.016) is much better than B (0.031), indicating lower P-gp efflux and better potential for CNS exposure.
15. **Affinity:** B (-8) is 1.5 kcal/mol better than A (-7.5). This is a substantial difference and a major advantage for B.

**Overall Assessment:**

While both compounds have issues (particularly the low BBB penetration and Caco-2 permeability), **Ligand B** is the more promising candidate. The significantly improved binding affinity (-8 vs -7.5 kcal/mol) and longer half-life (17.2 vs 10.852 hours) outweigh the slightly less favorable TPSA, HBD, and Pgp efflux. The better metabolic stability (lower Cl_mic) is also a significant plus. Although A has a better hERG profile, the affinity difference is substantial enough to prioritize B.

Output:
1
2025-04-17 07:22:18,272 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (345.403 and 350.438 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (120.04) is slightly above the optimal <90 for CNS targets, but still reasonable. Ligand B (83.12) is excellent, well below 90.

**logP:** Ligand A (0.791) is a bit low, potentially hindering permeability. Ligand B (2.275) is within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Both have 3 HBDs, which is acceptable. Ligand A has 6 HBAs, while Ligand B has 4. Both are within the acceptable limits of <=10.

**QED:** Both ligands have similar QED values (0.704 and 0.672), indicating good drug-likeness.

**DILI:** Both ligands have similar, acceptable DILI risk (52.036 and 49.864 percentile).

**BBB:** This is crucial for a CNS target. Ligand A has a BBB percentile of 47.964, which is below the desirable >70. Ligand B excels with a BBB percentile of 77.976.

**Caco-2 Permeability:** Ligand A (-5.184) shows poor permeability. Ligand B (-4.925) is also poor, but slightly better.

**Aqueous Solubility:** Both ligands have poor aqueous solubility (-2.571 and -3.277). This could pose formulation challenges.

**hERG Inhibition:** Ligand A (0.152) has a very low hERG risk, which is excellent. Ligand B (0.526) is slightly higher but still relatively low.

**Microsomal Clearance:** Ligand A (-13.51) indicates low clearance and good metabolic stability. Ligand B (13.962) indicates faster clearance.

**In vitro Half-Life:** Ligand A (32.567 hours) has a good half-life. Ligand B (11.506 hours) is shorter, potentially requiring more frequent dosing.

**P-gp Efflux:** Ligand A (0.01) shows very low P-gp efflux, which is excellent for CNS penetration. Ligand B (0.046) is also low.

**Binding Affinity:** Ligand B (-8.0 kcal/mol) has a slightly better binding affinity than Ligand A (-7.7 kcal/mol), although the difference is not huge.

**Overall Assessment:**

Ligand B is the stronger candidate. While both have acceptable MW, QED, and DILI, Ligand B significantly outperforms Ligand A in key GPCR-specific properties: BBB penetration and logP. The slightly better affinity of Ligand B further supports its selection. Although both have poor solubility, the superior BBB and logP of Ligand B, coupled with its better metabolic stability (lower Cl_mic and longer t1/2), make it more likely to reach the target in the CNS and exert its effect.

Output:
1
2025-04-17 07:22:18,272 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 drug candidates, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight (MW):** Both ligands (354.403 and 346.471 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (99.89) is higher than Ligand B (58.64). For CNS targets, TPSA should be <= 90. Ligand B is preferable here.

**3. logP:** Both ligands have good logP values (1.923 and 2.267), falling within the optimal 1-3 range.

**4. H-Bond Donors (HBD):** Both have 1 HBD, which is acceptable.

**5. H-Bond Acceptors (HBA):** Ligand A has 7 HBA, and Ligand B has 3 HBA. Both are below the threshold of 10.

**6. QED:** Both ligands have similar QED values (0.712 and 0.72), indicating good drug-like properties.

**7. DILI:** Ligand A (62.272) has a higher DILI risk than Ligand B (25.126). Ligand B is significantly better.

**8. BBB:** Both ligands show good BBB penetration (73.401 and 70.415), exceeding the desirable >70 threshold for CNS targets.

**9. Caco-2 Permeability:** Both have negative Caco-2 values (-4.762 and -4.882). These values are unusual and suggest poor permeability. However, the scale isn't specified, so it's hard to interpret.

**10. Aqueous Solubility:** Both have negative solubility values (-1.586 and -3.03). Again, the scale is unknown, but negative values suggest poor solubility.

**11. hERG Inhibition:** Both ligands have low hERG inhibition risk (0.106 and 0.381).

**12. Microsomal Clearance (Cl_mic):** Both have similar microsomal clearance (66.273 and 65.432 mL/min/kg), indicating moderate metabolic stability.

**13. In vitro Half-Life:** Ligand A (-7.477) has a longer half-life than Ligand B (0.783).

**14. P-gp Efflux:** Both have low P-gp efflux liability (0.02 and 0.107), which is good for CNS penetration.

**15. Binding Affinity:** Ligand B (-8.1 kcal/mol) has a significantly stronger binding affinity than Ligand A (-7.2 kcal/mol). This >1.5 kcal/mol difference is substantial and can outweigh minor ADME drawbacks.

**Overall Assessment:**

Ligand B is the better candidate. While both have acceptable MW, logP, QED, hERG, and P-gp efflux, Ligand B excels in several critical areas: significantly lower DILI risk, a lower TPSA, and a substantially stronger binding affinity. The negative Caco-2 and solubility values are concerning for both, but the strong affinity of Ligand B makes it more likely to overcome these issues with formulation strategies. The longer half-life of Ligand A is a plus, but the superior affinity and safety profile of Ligand B are more important for a GPCR target.

Output:
1
2025-04-17 07:22:18,272 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (340.427 and 350.463 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Both ligands have TPSA values (88.99 and 87.46) below the 90 Angstroms threshold for CNS targets, which is excellent.

**3. logP:** Both ligands have logP values (2.414 and 2.156) within the optimal 1-3 range.

**4. H-Bond Donors:** Both ligands have 2 HBD, which is acceptable.

**5. H-Bond Acceptors:** Ligand A has 3 HBA, and Ligand B has 5 HBA. Both are below the 10 threshold, but Ligand A is preferable.

**6. QED:** Ligand A (0.862) has a significantly better QED score than Ligand B (0.714), indicating better overall drug-likeness.

**7. DILI:** Ligand A (56.689) has a higher DILI risk than Ligand B (45.677), but both are below the concerning 60 threshold.

**8. BBB:** Ligand B (62.621) has a notably higher BBB percentile than Ligand A (53.044). This is a crucial advantage for a CNS target like DRD2.

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.78 and -4.748), which is unusual and suggests poor permeability. This is a significant drawback for both.

**10. Aqueous Solubility:** Both ligands have negative solubility values (-4.003 and -3.316), indicating very poor aqueous solubility. This is a major concern for bioavailability.

**11. hERG Inhibition:** Both ligands have low hERG inhibition risk (0.331 and 0.187).

**12. Microsomal Clearance:** Ligand B (81.155) has a much higher microsomal clearance than Ligand A (23.235), meaning it will be metabolized more quickly. Lower clearance is preferred.

**13. In vitro Half-Life:** Ligand A (6.867) has a longer in vitro half-life than Ligand B (-21.582). A negative value for half-life is unusual and suggests very rapid degradation.

**14. P-gp Efflux:** Both ligands have low P-gp efflux liability (0.063 and 0.196).

**15. Binding Affinity:** Ligand A (-8.7 kcal/mol) has a significantly stronger binding affinity than Ligand B (-7.2 kcal/mol). This is a substantial advantage, potentially outweighing some ADME concerns.

**Overall Assessment:**

Ligand A has a better QED, longer half-life, and significantly better binding affinity. However, Ligand B has a much better BBB penetration and lower DILI risk. Both ligands suffer from poor solubility and permeability. The strong binding affinity of Ligand A (-8.7 kcal/mol) is a major advantage, and the difference of 1.5 kcal/mol is significant. While BBB is important, the potency advantage of Ligand A is likely to be more impactful, especially if formulation strategies can be employed to address the solubility/permeability issues.

Output:
1
2025-04-17 07:22:18,273 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B based on the provided guidelines, prioritizing GPCR-specific properties (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (348.443) is slightly lower, which could be beneficial for permeability.

**TPSA:** Ligand A (78.87) is excellent for CNS penetration, well below the 90 A^2 threshold. Ligand B (98.17) is still reasonable but less optimal.

**logP:** Both ligands have acceptable logP values (A: 1.034, B: 2.716), falling within the 1-3 range. Ligand B is closer to the upper end, potentially raising concerns about off-target effects, but not critically.

**H-Bond Donors/Acceptors:** Both ligands have reasonable HBD (A: 2, B: 1) and HBA (A: 4, B: 4) counts, well within the guidelines.

**QED:** Ligand A (0.778) has a significantly better QED score than Ligand B (0.351), indicating a more drug-like profile.

**DILI:** Both ligands have low DILI risk (A: 34.277, B: 26.561), which is favorable.

**BBB:** Ligand A (38.387) has a poor BBB percentile, a major drawback for a CNS target like DRD2. Ligand B (55.176) is better, but still not ideal (aim for >70).

**Caco-2 Permeability:** Ligand A (-4.793) has very poor Caco-2 permeability, suggesting poor intestinal absorption. Ligand B (-5.428) is similarly poor.

**Aqueous Solubility:** Both ligands have very poor aqueous solubility (A: -1.488, B: -2.768). This could pose formulation challenges.

**hERG Inhibition:** Both ligands show very low hERG inhibition risk (A: 0.073, B: 0.415).

**Microsomal Clearance:** Ligand A (16.667) has lower microsomal clearance than Ligand B (49.257), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (-18.877) has a very short in vitro half-life, while Ligand B (13.678) is slightly better, but still not great.

**P-gp Efflux:** Both ligands show very low P-gp efflux liability (A: 0.027, B: 0.046), which is beneficial for CNS exposure.

**Binding Affinity:** Ligand B (-7.3) has a significantly stronger binding affinity than Ligand A (0). This is a crucial advantage, potentially outweighing some of the ADME drawbacks. A difference of >1.5 kcal/mol is considered significant.

**Overall Assessment:**

While Ligand A has better QED and metabolic stability, its extremely poor BBB penetration and Caco-2 permeability are major liabilities for a CNS drug. Ligand B, despite having a lower QED and higher clearance, possesses a significantly stronger binding affinity and a better (though still suboptimal) BBB score. Given the GPCR-specific priority for BBB penetration and the substantial affinity advantage of Ligand B, it is the more promising candidate. The solubility issues of both compounds would need to be addressed through formulation strategies.

Output:
1
2025-04-17 07:22:18,273 - INFO - Reasoning:

Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (352.308 and 356.507 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (44.76) is significantly better than Ligand B (76.66). For CNS targets, we want TPSA <= 90, and A is comfortably within that range, while B is approaching the upper limit.

**3. logP:** Ligand A (4.269) is slightly higher than the optimal 1-3 range, while Ligand B (2.262) is well within the range. However, for a GPCR, a slightly higher logP isn't necessarily detrimental if other properties are favorable.

**4. H-Bond Donors:** Ligand A (0) is preferable to Ligand B (2). Fewer H-bond donors generally improve membrane permeability.

**5. H-Bond Acceptors:** Both ligands have 4 H-bond acceptors, which is acceptable (<=10).

**6. QED:** Both ligands have similar QED values (0.771 and 0.629), both indicating good drug-like properties (>=0.5).

**7. DILI:** Ligand A (86.623) has a significantly higher DILI risk than Ligand B (16.44). This is a major concern for Ligand A.

**8. BBB:** Ligand A (84.529) has a better BBB penetration percentile than Ligand B (72.276). This is crucial for a CNS target like DRD2.

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.296 and -4.337). This is unusual and suggests poor permeability. However, these values are on a scale where negative values are possible, and direct comparison is difficult without knowing the scale's specifics.

**10. Aqueous Solubility:** Both ligands have negative solubility values (-5.294 and -2.022), indicating poor aqueous solubility. This is a concern for both.

**11. hERG Inhibition:** Ligand A (0.634) has a slightly higher hERG risk than Ligand B (0.374), but both are relatively low.

**12. Microsomal Clearance:** Ligand A (55.364) has higher microsomal clearance than Ligand B (35.098), meaning it's less metabolically stable.

**13. In vitro Half-Life:** Ligand B (-8.705) has a significantly longer in vitro half-life than Ligand A (-1.255).

**14. P-gp Efflux:** Ligand A (0.755) has higher P-gp efflux than Ligand B (0.022), which is undesirable for CNS penetration.

**15. Binding Affinity:** Ligand A (-9.1 kcal/mol) has a significantly stronger binding affinity than Ligand B (-7.3 kcal/mol). This is a substantial advantage.

**Overall Assessment:**

Ligand A has a much stronger binding affinity and better BBB penetration, which are highly desirable for a DRD2 ligand. However, it suffers from significantly higher DILI risk, higher P-gp efflux, and faster metabolic clearance. Ligand B has a better safety profile (lower DILI), better metabolic stability, and lower P-gp efflux, but its binding affinity is weaker and its TPSA is higher.

The difference in binding affinity (-1.8 kcal/mol) is significant. While the ADME properties of Ligand A are concerning, the potency advantage might be enough to warrant further optimization, *if* the DILI risk can be mitigated through structural modifications. However, given the high DILI risk and the relatively acceptable profile of Ligand B, I would initially favor Ligand B as the more viable starting point for drug development.

Output:
1
2025-04-17 07:22:18,273 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (357.451 and 368.478 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (89.13) is better than Ligand B (67.35), both are below the 90 A^2 threshold for CNS targets.

**3. logP:** Both ligands have a logP around 2.0 (2.043 and 2.048), which is optimal.

**4. H-Bond Donors:** Ligand A (2) is slightly higher than Ligand B (1), but both are within the acceptable limit of 5.

**5. H-Bond Acceptors:** Ligand A (5) is slightly higher than Ligand B (6), both are within the acceptable limit of 10.

**6. QED:** Ligand A (0.752) has a better QED score than Ligand B (0.587), indicating better drug-likeness.

**7. DILI:** Ligand A (21.675) has a significantly lower DILI risk than Ligand B (47.654). This is a substantial advantage.

**8. BBB:** Ligand A (81.504) has a better BBB penetration percentile than Ligand B (77.084), both are reasonably good, but A is better. This is a critical factor for a CNS target like DRD2.

**9. Caco-2 Permeability:** Ligand A (-4.679) has a better Caco-2 permeability than Ligand B (-4.986), both are negative values.

**10. Aqueous Solubility:** Ligand A (-2.392) has a better aqueous solubility than Ligand B (-3.321).

**11. hERG Inhibition:** Both ligands have similar hERG inhibition liability (0.304 and 0.479), both are low risk.

**12. Microsomal Clearance:** Ligand A (-6.933) has a much lower (better) microsomal clearance than Ligand B (57.641). This suggests better metabolic stability for Ligand A.

**13. In vitro Half-Life:** Ligand A (9.023) has a much longer in vitro half-life than Ligand B (3.245).

**14. P-gp Efflux:** Ligand A (0.007) has a significantly lower P-gp efflux liability than Ligand B (0.077), which is favorable for CNS penetration.

**15. Binding Affinity:** Ligand B (-8.7) has a slightly better binding affinity than Ligand A (-8.2), but the difference is less than 1.5 kcal/mol.

**Overall Assessment:**

Ligand A consistently outperforms Ligand B across most crucial ADME-Tox properties, including DILI, BBB, metabolic stability (Cl_mic and t1/2), and P-gp efflux. While Ligand B has a marginally better binding affinity, the superior ADME profile of Ligand A, especially its improved BBB penetration and reduced toxicity risk, makes it a more promising drug candidate for a CNS target like DRD2. The slightly better affinity of B is not enough to overcome the significant ADME advantages of A.

Output:
1
2025-04-17 07:22:18,273 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (376.737 Da) is slightly higher than Ligand B (347.375 Da), but both are acceptable.

**TPSA:** Ligand A (51.22) is significantly better than Ligand B (127.42). For CNS targets, we want TPSA <= 90, so Ligand A is much more favorable. Ligand B's high TPSA could hinder BBB penetration.

**logP:** Ligand A (4.306) is a bit high, potentially leading to solubility issues or off-target interactions. Ligand B (-1.363) is too low, which could impede permeation. Ideally, we want 1-3.

**H-Bond Donors/Acceptors:** Ligand A (HBD=1, HBA=3) is better than Ligand B (HBD=4, HBA=5) in terms of balancing solubility and permeability. Both are within acceptable limits, but A is slightly preferred.

**QED:** Ligand A (0.791) has a better drug-likeness score than Ligand B (0.489).

**DILI:** Ligand A (67.739) has a higher DILI risk than Ligand B (47.964), but both are below the concerning threshold of 60.

**BBB:** Ligand A (68.864) has a significantly better BBB percentile than Ligand B (23.071). This is *critical* for a CNS target like DRD2.

**Caco-2 Permeability:** Ligand A (-4.65) and Ligand B (-5.893) both have negative values, indicating poor permeability. This is a concern for both, but the scale is not clearly defined, so it's hard to interpret the magnitude of the difference.

**Aqueous Solubility:** Ligand A (-4.404) and Ligand B (-2.52) both have negative values, indicating poor solubility. Again, the scale is not clear, making interpretation difficult.

**hERG Inhibition:** Ligand A (0.498) has a slightly higher hERG risk than Ligand B (0.068), but both are relatively low.

**Microsomal Clearance:** Ligand B (-20.985) has much lower (better) microsomal clearance than Ligand A (39.254), suggesting greater metabolic stability.

**In vitro Half-Life:** Ligand B (-5.49) has a shorter half-life than Ligand A (23.814).

**P-gp Efflux:** Ligand A (0.321) has lower P-gp efflux than Ligand B (0.004), which is desirable for CNS exposure.

**Binding Affinity:** Both ligands have strong binding affinities (-9.2 kcal/mol and -8.4 kcal/mol, respectively). Ligand A is slightly better (-9.2 kcal/mol), but the difference is not huge.

**Overall Assessment:**

Ligand A is the stronger candidate. While its logP is slightly high, its significantly better TPSA and BBB penetration, coupled with a slightly better binding affinity and lower P-gp efflux, make it more likely to reach the target in the CNS. Ligand B's high TPSA and poor BBB penetration are major drawbacks for a CNS-targeted drug. The better metabolic stability of Ligand B is a plus, but can be addressed during optimization.

Output:
1
2025-04-17 07:22:18,274 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (362.392 and 372.487 Da) fall within the ideal range of 200-500 Da.

**TPSA:** Ligand A (67.43) is significantly better than Ligand B (85.89). For CNS targets, we want TPSA <= 90, and A is comfortably within that range, while B is approaching the upper limit.

**logP:** Both ligands have acceptable logP values (2.711 and 1.044), falling within the optimal 1-3 range. Ligand A is slightly preferred due to being closer to the middle of the range.

**H-Bond Donors/Acceptors:** Both have 2 HBD, which is good. Ligand A has 3 HBA, while Ligand B has 6. Lower HBA is generally preferred for better permeability, making Ligand A slightly better.

**QED:** Both ligands have reasonable QED scores (0.376 and 0.662), with Ligand B being better.

**DILI:** Ligand A (23.963) has a much lower DILI risk than Ligand B (44.862), indicating a safer profile.

**BBB:** This is crucial for a CNS target like DRD2. Ligand A has a BBB percentile of 83.676, which is excellent (>70). Ligand B's BBB percentile is only 49.515, which is considerably lower and a significant drawback.

**Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and suggests poor permeability. However, the absolute value is smaller for Ligand A (-4.736 vs -4.97), suggesting slightly better permeability.

**Aqueous Solubility:** Both have negative solubility values, indicating poor solubility. Ligand A (-3.606) is slightly better than Ligand B (-2.414).

**hERG:** Both ligands have very low hERG inhibition liability (0.543 and 0.106), which is excellent.

**Microsomal Clearance:** Ligand A (8.054) has a lower microsomal clearance than Ligand B (60.449), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (-13.493) has a significantly longer in vitro half-life than Ligand B (-0.577).

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.035 and 0.058), which is good.

**Binding Affinity:** Ligand A (-7.9 kcal/mol) has a slightly better binding affinity than Ligand B (-7.5 kcal/mol), although the difference is not huge.

**Overall:** Considering the GPCR-specific priorities, Ligand A is the much stronger candidate. Its superior BBB penetration, lower TPSA, lower DILI risk, better metabolic stability (lower Cl_mic and longer t1/2), and slightly better binding affinity outweigh the slightly better QED of Ligand B. The poor solubility and Caco-2 permeability are concerns for both, but can be addressed with formulation strategies.



Output:
0
2025-04-17 07:22:18,274 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (379.957 Da) is slightly higher than Ligand B (351.451 Da), but both are acceptable.

**TPSA:** Ligand A (45.23) is excellent for CNS penetration, well below the 90 A^2 threshold. Ligand B (99.49) is higher, but still potentially acceptable, though less ideal.

**logP:** Ligand A (3.806) is within the optimal range (1-3). Ligand B (-0.714) is significantly lower, which could hinder membrane permeability and CNS penetration.

**H-Bond Donors/Acceptors:** Ligand A (HBD=1, HBA=4) is well within the acceptable limits. Ligand B (HBD=3, HBA=6) is also acceptable, but slightly higher, potentially impacting permeability.

**QED:** Both ligands have reasonable QED values (A: 0.812, B: 0.602), indicating good drug-like properties.

**DILI:** Ligand A (39.24) has a low DILI risk. Ligand B (8.957) has a very low DILI risk, which is positive.

**BBB:** Ligand A (89.143) has a very good BBB percentile, highly desirable for a CNS target. Ligand B (13.455) has a very poor BBB percentile, a major drawback.

**Caco-2:** Both have negative Caco-2 values, which is unusual and difficult to interpret without more context. However, the magnitude suggests poor permeability for both.

**Solubility:** Both ligands have negative solubility values, which is also unusual. This suggests very low aqueous solubility, potentially causing formulation challenges.

**hERG:** Ligand A (0.651) has a low hERG risk. Ligand B (0.05) has a very low hERG risk, which is positive.

**Cl_mic:** Ligand A (57.867) has moderate metabolic clearance. Ligand B (-8.51) has negative clearance, which is not physically possible and likely indicates an issue with the data.

**t1/2:** Ligand A (1.01) has a short half-life. Ligand B (9.924) has a longer half-life, which is preferable.

**Pgp:** Ligand A (0.347) has low P-gp efflux, which is good for CNS penetration. Ligand B (0.001) has very low P-gp efflux, also good.

**Binding Affinity:** Ligand A (-8.8 kcal/mol) has significantly better binding affinity than Ligand B (-7.0 kcal/mol). The 1.8 kcal/mol difference is substantial and can often outweigh minor ADME concerns.

**Overall Assessment:**

Ligand A is the stronger candidate. While both have issues with Caco-2 and solubility, Ligand A's significantly better binding affinity and excellent BBB penetration outweigh its slightly higher TPSA and moderate metabolic clearance. Ligand B's very poor BBB penetration is a critical flaw for a CNS target, despite its longer half-life and lower DILI/hERG risk. The negative clearance for Ligand B is also a red flag.

Output:
1
2025-04-17 07:22:18,274 - INFO - Reasoning:

Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (348.447 and 350.419 Da) fall comfortably within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (75.63) is significantly better than Ligand B (104.39). For CNS targets, we want TPSA <= 90, and A is closer to this threshold.

**3. logP:** Both ligands have acceptable logP values (1.141 and 0.69), falling within the 1-3 range. Ligand A is slightly better.

**4. H-Bond Donors:** Ligand A (0) is preferable to Ligand B (2). Fewer HBDs generally improve permeability.

**5. H-Bond Acceptors:** Both have 5 HBA, which is acceptable (<=10).

**6. QED:** Both ligands have similar QED values (0.634 and 0.6), indicating good drug-like properties.

**7. DILI:** Both ligands have low DILI risk (37.069 and 39.744), both below the 40 threshold.

**8. BBB:** Ligand A (83.055) has a significantly higher BBB percentile than Ligand B (36.448). This is *critical* for a CNS target like DRD2. A value >70 is desirable, and A is much closer.

**9. Caco-2 Permeability:** Ligand A (-4.368) is better than Ligand B (-5.155) - higher values are better.

**10. Aqueous Solubility:** Ligand A (-0.624) is better than Ligand B (-1.726) - higher values are better.

**11. hERG Inhibition:** Both ligands have very low hERG risk (0.162 and 0.075).

**12. Microsomal Clearance:** Ligand B (16.831) has lower microsomal clearance than Ligand A (34.135), suggesting better metabolic stability.

**13. In vitro Half-Life:** Ligand B (-15.614) has a negative half-life, which is not physically possible and indicates a significant issue. Ligand A (12.54) is reasonable.

**14. P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.022 and 0.016).

**15. Binding Affinity:** Ligand B (-8.6 kcal/mol) has a slightly better binding affinity than Ligand A (-7.0 kcal/mol). However, the difference is not substantial enough to outweigh the significant ADME advantages of Ligand A.

**Overall Assessment:**

Ligand A is the superior candidate. While Ligand B has slightly better binding affinity, Ligand A excels in critical ADME properties for a CNS-targeting GPCR, especially BBB penetration and TPSA. The negative half-life reported for Ligand B is a major red flag. Ligand A's combination of reasonable potency, good drug-likeness, low toxicity risk, and favorable CNS penetration profile makes it the more viable drug candidate.

Output:
1
2025-04-17 07:22:18,274 - INFO - Batch 359 complete. Total preferences: 5744
2025-04-17 07:22:18,274 - INFO - Processing batch 360/512...
2025-04-17 07:23:02,400 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (353.438 and 367.431 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (78.51) is excellent, well below the 90 A^2 threshold for CNS targets. Ligand B (107.77) is still reasonable but less optimal, exceeding the preferred threshold.

**logP:** Ligand A (1.006) is within the optimal range (1-3). Ligand B (-0.433) is slightly below 1, potentially hindering permeation.

**H-Bond Donors/Acceptors:** Both have 2 HBDs, which is good. Ligand A has 3 HBAs, and Ligand B has 7 HBAs. Both are acceptable, but Ligand A is slightly better.

**QED:** Both ligands have good QED scores (0.792 and 0.699), indicating drug-like properties.

**DILI:** Ligand A (14.269) has a much lower DILI risk than Ligand B (69.95), which is a significant advantage.

**BBB:** Ligand A (83.831) has a very good BBB penetration percentile, exceeding the 70% threshold for CNS targets. Ligand B (39.511) is considerably lower, raising concerns about CNS exposure.

**Caco-2 Permeability:** Ligand A (-4.979) and Ligand B (-5.606) have negative values, which is unusual and suggests poor permeability. However, the scale isn't specified, so it's difficult to interpret definitively.

**Aqueous Solubility:** Both have negative solubility values (-2.277 and -2.09), which is concerning. Solubility issues could limit bioavailability.

**hERG:** Both ligands have low hERG inhibition risk (0.245 and 0.134).

**Microsomal Clearance:** Ligand A (-4.431) has a negative clearance, which is excellent, indicating high metabolic stability. Ligand B (22.276) has a higher clearance, suggesting faster metabolism.

**In vitro Half-Life:** Ligand A (0.475) has a very short half-life, which is a drawback. Ligand B (1.451) is slightly better, but still not ideal.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.012 and 0.025), which is positive for CNS penetration.

**Binding Affinity:** Ligand B (-7.5 kcal/mol) has a slightly better binding affinity than Ligand A (-8.2 kcal/mol). However, the difference is relatively small, and other factors are more important.

**Overall Assessment:**

Considering the GPCR-specific priorities, Ligand A is the more promising candidate. It has significantly better BBB penetration, a much lower DILI risk, and superior metabolic stability (negative Cl_mic). While Ligand B has slightly better binding affinity, the advantages of Ligand A in ADME properties, particularly BBB and DILI, outweigh this difference for a CNS target like DRD2. The solubility and Caco-2 permeability are concerns for both, but can be addressed with formulation strategies.

Output:
0
2025-04-17 07:23:02,400 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (358.482 and 364.515 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (33.2) is excellent, well below the 90 A^2 threshold for CNS targets. Ligand B (63.41) is higher, but still reasonable, though less optimal for CNS penetration.

**logP:** Ligand A (4.866) is slightly high, potentially leading to solubility issues or off-target interactions. Ligand B (2.705) is within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A (0 HBD, 3 HBA) is favorable. Ligand B (1 HBD, 7 HBA) is also acceptable, though slightly higher in HBA count.

**QED:** Both ligands have similar QED values (0.691 and 0.702), indicating good drug-likeness.

**DILI:** Both ligands have similar, acceptable DILI risk (39.201 and 40.054).

**BBB:** This is a critical parameter for CNS targets. Ligand A exhibits a significantly higher BBB penetration percentile (84.374) compared to Ligand B (55.099). This is a major advantage for Ligand A.

**Caco-2 Permeability:** Both ligands show negative Caco-2 values which is unusual and suggests a potential issue with the data or prediction method. However, we can still compare them. Ligand A (-4.7) is slightly better than Ligand B (-5.292) in this regard.

**Aqueous Solubility:** Both ligands have very poor predicted aqueous solubility (-4.888 and -2.298). This is a concern, especially for Ligand A with its higher logP.

**hERG Inhibition:** Both ligands have low hERG inhibition liability (0.598 and 0.698), which is good.

**Microsomal Clearance:** Ligand A (74.562) has a higher microsomal clearance than Ligand B (60.108), indicating potentially lower metabolic stability.

**In vitro Half-Life:** Ligand B (13.256 hours) has a significantly longer predicted half-life than Ligand A (3.819 hours). This is a substantial advantage for Ligand B.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.582 and 0.524), which is favorable for CNS penetration.

**Binding Affinity:** Ligand A (-8.7 kcal/mol) has a considerably stronger binding affinity than Ligand B (-6.7 kcal/mol). This difference of 2 kcal/mol is substantial and can outweigh some of the ADME drawbacks.

**Overall Assessment:**

Ligand A excels in binding affinity and BBB penetration, which are crucial for a CNS-targeting GPCR. However, it suffers from higher logP, higher clearance, and shorter half-life, and very poor solubility. Ligand B has better solubility, metabolic stability (lower Cl_mic, longer t1/2), and a more optimal logP, but its BBB penetration and binding affinity are significantly weaker.

Given the importance of strong binding and BBB penetration for CNS GPCR targets, and the magnitude of the difference in affinity (2 kcal/mol), **Ligand A is the more promising candidate despite its ADME liabilities**. Further optimization could focus on improving its solubility and metabolic stability while maintaining its high affinity and BBB penetration.

Output:
0
2025-04-17 07:23:02,401 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (349.431 and 346.427 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (100.55) is slightly higher than the preferred <90 for CNS targets, but still reasonable. Ligand B (67.87) is well within the ideal range. This favors Ligand B.

**3. logP:** Both ligands have good logP values (2.25 and 1.9), falling within the optimal 1-3 range.

**4. H-Bond Donors:** Ligand A (3) is acceptable, while Ligand B (1) is even better, potentially leading to improved permeability.

**5. H-Bond Acceptors:** Both ligands have acceptable HBA counts (5 and 4 respectively).

**6. QED:** Both ligands have good QED scores (0.656 and 0.846), indicating good drug-like properties. Ligand B is slightly better.

**7. DILI:** Both ligands have low DILI risk (38.116 and 31.718), which is favorable. Ligand B is slightly better.

**8. BBB:** Both ligands show good BBB penetration (65.452 and 65.839). While ideally >70, these are acceptable for a starting point. They are very similar.

**9. Caco-2 Permeability:** Both have negative Caco-2 values (-4.582 and -4.399) which is unusual and suggests poor permeability. This is a concern for both.

**10. Aqueous Solubility:** Both have negative solubility values (-2.215 and -2.894) which is also unusual and suggests poor solubility. This is a concern for both.

**11. hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.157 and 0.266), which is excellent.

**12. Microsomal Clearance:** Ligand A (36.651) has higher clearance than Ligand B (25.742), indicating lower metabolic stability. This favors Ligand B.

**13. In vitro Half-Life:** Ligand B (-8.293) has a longer half-life than Ligand A (24.778), which is preferable.

**14. P-gp Efflux:** Both ligands show very low P-gp efflux liability (0.047 and 0.07), which is excellent for CNS penetration.

**15. Binding Affinity:** Ligand B (-8.5 kcal/mol) has a slightly stronger binding affinity than Ligand A (-8.2 kcal/mol). While the difference is small, it's within the range where it could outweigh minor ADME drawbacks.

**Overall Assessment:**

Ligand B consistently outperforms Ligand A in several key areas: TPSA, HBD, QED, DILI, microsomal clearance, and in vitro half-life. The binding affinity is also slightly better for Ligand B. While both have concerning Caco-2 and solubility values, Ligand B's overall profile is more favorable for development as a DRD2 ligand, particularly given the GPCR-specific emphasis on BBB, logP, and metabolic stability.

Output:
1
2025-04-17 07:23:02,401 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the acceptable range (200-500 Da). Ligand A (332.367 Da) is slightly preferred as it's closer to the lower end, potentially aiding permeability.

**TPSA:** Ligand A (88.49) is excellent for CNS penetration, being well below 90. Ligand B (48) is also very good.

**logP:** Both ligands have good logP values (A: 2.002, B: 2.879), falling within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A has 2 HBD and 5 HBA, while Ligand B has 0 HBD and 6 HBA. Both are acceptable, but ligand A's HBD count might contribute to better solubility.

**QED:** Both ligands have good QED scores (A: 0.585, B: 0.61), indicating drug-like properties.

**DILI:** Ligand A (80.651) has a higher DILI risk than Ligand B (40.752). This is a significant drawback for Ligand A.

**BBB:** Ligand B (79.682) has a significantly better BBB percentile than Ligand A (41.218). This is a crucial factor for a CNS target like DRD2.

**Caco-2 Permeability:** Ligand A (-5.637) has a worse Caco-2 permeability than Ligand B (-4.942).

**Aqueous Solubility:** Both ligands have poor aqueous solubility (-3.416 and -3.036 respectively). This could pose formulation challenges, but is less critical than BBB for CNS targets.

**hERG Inhibition:** Ligand A (0.473) has a slightly lower hERG inhibition liability than Ligand B (0.749), which is favorable.

**Microsomal Clearance:** Ligand A (37.333) has a much lower microsomal clearance than Ligand B (105.972), indicating better metabolic stability.

**In vitro Half-Life:** Ligand A (-8.325) has a much longer in vitro half-life than Ligand B (24.656). This is a significant advantage for Ligand A.

**P-gp Efflux:** Ligand A (0.152) shows lower P-gp efflux liability than Ligand B (0.608), which is beneficial for CNS exposure.

**Binding Affinity:** Ligand A (-9.7 kcal/mol) has a significantly stronger binding affinity than Ligand B (-6.8 kcal/mol). This is a substantial advantage that can outweigh some of the ADME drawbacks.

**Overall Assessment:**

While Ligand A has a better binding affinity, metabolic stability, P-gp efflux, and half-life, its higher DILI risk and significantly lower BBB penetration are major concerns for a CNS drug. Ligand B, despite its weaker affinity, exhibits a much more favorable BBB profile and lower DILI risk. Given the importance of BBB penetration for DRD2, and the substantial difference in BBB percentile, Ligand B is the more promising candidate. The affinity difference, while significant, might be overcome with further optimization of Ligand B.

Output:
1
2025-04-17 07:23:02,401 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 drug candidates, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (352.406 Da and 359.348 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (70.08) is significantly better than Ligand B (84.23). For CNS targets, we want TPSA <= 90, and A is closer to the optimal <=60 range. B is pushing the upper limit.

**3. logP:** Ligand A (0.054) is quite low, potentially hindering membrane permeability. Ligand B (2.506) is within the optimal 1-3 range. This is a significant advantage for B.

**4. H-Bond Donors:** Ligand A (1) is good. Ligand B (2) is also acceptable.

**5. H-Bond Acceptors:** Both ligands have 4 HBA, which is within the acceptable range of <=10.

**6. QED:** Both ligands have good QED scores (0.686 and 0.733), indicating drug-like properties.

**7. DILI:** Ligand A (16.13) has a much lower DILI risk than Ligand B (56.689). This is a substantial advantage for A.

**8. BBB:** Ligand B (85.615) has a significantly better BBB penetration percentile than Ligand A (74.06). This is crucial for a CNS target like DRD2.

**9. Caco-2 Permeability:** Both have negative values, which are not ideal. However, -4.467 (Ligand A) is better than -4.56 (Ligand B).

**10. Aqueous Solubility:** Both have negative values, indicating poor solubility. -2.332 (Ligand A) is slightly better than -3.363 (Ligand B).

**11. hERG Inhibition:** Both ligands have low hERG inhibition risk (0.255 and 0.219).

**12. Microsomal Clearance:** Ligand A (6.713) has a much lower microsomal clearance than Ligand B (48.131), indicating better metabolic stability.

**13. In vitro Half-Life:** Ligand A (3.783) has a shorter half-life than Ligand B (-44.058). The negative value for B is unusual and suggests a very long half-life, which is a positive.

**14. P-gp Efflux:** Ligand A (0.044) has lower P-gp efflux liability than Ligand B (0.106), meaning it's less likely to be pumped out of the brain.

**15. Binding Affinity:** Ligand B (-8.2 kcal/mol) has a slightly better binding affinity than Ligand A (-7.8 kcal/mol). While the difference is not huge, it's a factor.

**Overall Assessment:**

Ligand B excels in BBB penetration and binding affinity, which are critical for a CNS GPCR target. Its logP is also optimal. However, it suffers from higher DILI risk, higher P-gp efflux, and significantly higher microsomal clearance.

Ligand A has a better safety profile (lower DILI), better metabolic stability, and lower P-gp efflux. However, its logP is very low, which is a major concern for brain penetration.

Considering the trade-offs, the improved BBB penetration and binding affinity of Ligand B outweigh its drawbacks, especially given that the affinity difference is substantial enough to potentially overcome minor ADME issues. The lower metabolic stability could be addressed through structural modifications.

Output:
1
2025-04-17 07:23:02,401 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (347.459 and 346.475 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (74.43) is better than Ligand B (78.09). Both are below the 90 A^2 threshold desirable for CNS targets, but A is closer to the optimal range.

**3. logP:** Both ligands (2.825 and 2.375) fall within the optimal 1-3 range. Ligand A is slightly better.

**4. H-Bond Donors:** Both have 2 HBD, which is acceptable (<=5).

**5. H-Bond Acceptors:** Both have 3 HBA, which is acceptable (<=10).

**6. QED:** Both have reasonable QED scores (0.489 and 0.639). Ligand B is slightly better, indicating a more drug-like profile.

**7. DILI:** Ligand A (32.842) has a slightly higher DILI risk than Ligand B (16.208), but both are below the concerning threshold of 60.

**8. BBB:** Ligand A (66.615) has a slightly better BBB percentile than Ligand B (60.644). While both are below the desirable >70 for CNS targets, A is closer.

**9. Caco-2:** Both have negative Caco-2 values (-5.133 and -5.031), which is unusual and suggests poor permeability. This is a significant drawback for both.

**10. Solubility:** Both have negative solubility values (-3.081 and -2.585), indicating very poor aqueous solubility. This is a major concern for both compounds.

**11. hERG:** Both ligands have low hERG inhibition liability (0.593 and 0.381), which is good.

**12. Cl_mic:** Ligand A (27.237) has a lower microsomal clearance than Ligand B (40.282), suggesting better metabolic stability.

**13. t1/2:** Ligand A (-24.646) has a more negative in vitro half-life than Ligand B (-17.97). A more negative value indicates a shorter half-life, which is unfavorable.

**14. Pgp:** Both have very low Pgp efflux liability (0.1 and 0.178), which is favorable for CNS penetration.

**15. Binding Affinity:** Both ligands have the same binding affinity (-7.6 kcal/mol), which is excellent.

**Overall Assessment:**

Both ligands have significant drawbacks (poor Caco-2 and solubility). However, considering the GPCR-specific priorities, Ligand A is slightly more favorable. It has a better TPSA, slightly better BBB penetration, and lower microsomal clearance (better metabolic stability). While its half-life is shorter, the superior TPSA and metabolic stability, coupled with the equal binding affinity, give it a slight edge. The poor solubility and permeability are major issues that would need to be addressed through formulation or structural modification for either compound.

Output:
0
2025-04-17 07:23:02,401 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (346.431 and 344.375 Da) fall comfortably within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (97.12) is significantly better than Ligand B (119.28). For CNS targets, we want TPSA <= 90, so Ligand A is closer to this threshold. Ligand B is considerably higher and may have reduced brain penetration.

**3. logP:** Ligand A (2.204) is optimal (1-3), while Ligand B (0.333) is quite low. A logP below 1 can hinder permeation. This is a significant advantage for Ligand A.

**4. H-Bond Donors:** Both ligands have 2 HBD, which is within the acceptable limit of <=5.

**5. H-Bond Acceptors:** Ligand A has 5 HBA, and Ligand B has 7. Both are within the acceptable limit of <=10, but Ligand A is slightly better.

**6. QED:** Both ligands have good QED scores (0.738 and 0.828), indicating good drug-like properties.

**7. DILI:** Ligand A (45.173) has a lower DILI risk than Ligand B (60.915). Both are acceptable (<60 is good), but A is preferable.

**8. BBB:** Ligand A (68.205) and Ligand B (73.827) both have reasonably good BBB penetration, but B is slightly better. However, the TPSA and logP of B are concerning.

**9. Caco-2 Permeability:** Ligand A (-4.862) and Ligand B (-5.502) both have negative values, indicating poor permeability. This is a concern for both, but the lower value for B is worse.

**10. Aqueous Solubility:** Ligand A (-3.254) and Ligand B (-2.391) both have negative values, indicating poor solubility. B is slightly better, but both are problematic.

**11. hERG Inhibition:** Ligand A (0.048) has a very low hERG risk, while Ligand B (0.306) is slightly higher. A is clearly better here.

**12. Microsomal Clearance:** Ligand A (22.841) has a lower (better) microsomal clearance than Ligand B (-10.34). This suggests better metabolic stability for Ligand A.

**13. In vitro Half-Life:** Ligand A (1.716) has a shorter half-life than Ligand B (-17.883). This is a drawback for Ligand A, but the difference is substantial, and could be addressed in optimization.

**14. P-gp Efflux:** Ligand A (0.026) has much lower P-gp efflux liability than Ligand B (0.017). Lower efflux is desirable for CNS exposure, making A preferable.

**15. Binding Affinity:** Ligand B (-8.8 kcal/mol) has a slightly better binding affinity than Ligand A (-7.7 kcal/mol). This is a 1.1 kcal/mol difference, which is significant, but not overwhelming given the ADME issues with Ligand B.

**Overall Assessment:**

Ligand A is the more promising candidate. While Ligand B has slightly better affinity and BBB penetration, Ligand A excels in critical ADME properties like logP, TPSA, DILI, hERG, and P-gp efflux. The lower logP and higher TPSA of Ligand B are significant liabilities for a CNS-targeting drug, potentially hindering brain penetration. The better metabolic stability (lower Cl_mic) of Ligand A is also a major advantage. The shorter half-life of A is a concern, but is a property that can be more readily optimized than fundamental issues like poor logP.

Output:
1
2025-04-17 07:23:02,401 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (354.519 and 347.503 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (41.99) is significantly better than Ligand B (61.44). For CNS targets, we want TPSA <= 90, and ideally closer to 60. Ligand A is much closer to this ideal.

**3. logP:** Ligand A (4.842) is higher than the optimal 1-3 range, potentially causing solubility issues. Ligand B (2.084) is within the optimal range. However, for a GPCR, some lipophilicity is often tolerated and can aid in membrane permeability.

**4. H-Bond Donors:** Both have acceptable HBD counts (1 and 2 respectively), well below the limit of 5.

**5. H-Bond Acceptors:** Both have acceptable HBA counts (3 each), below the limit of 10.

**6. QED:** Both have reasonable QED values (0.835 and 0.693), indicating good drug-like properties.

**7. DILI:** Ligand A (44.281) has a higher DILI risk than Ligand B (11.361). This is a significant advantage for Ligand B.

**8. BBB:** Ligand A (72.547) has a better BBB penetration percentile than Ligand B (68.282), which is crucial for a CNS target like DRD2. While both are reasonably good, A is better.

**9. Caco-2 Permeability:** Both have negative Caco-2 values (-4.894 and -4.868), which is unusual and suggests poor permeability. This is a concern for both.

**10. Aqueous Solubility:** Both have very poor aqueous solubility (-5.218 and -2.157). This is a major drawback for both, but potentially manageable with formulation strategies.

**11. hERG Inhibition:** Both have low hERG inhibition risk (0.517 and 0.235).

**12. Microsomal Clearance:** Ligand A (85.169) has a higher microsomal clearance than Ligand B (42.922), indicating lower metabolic stability. This favors Ligand B.

**13. In vitro Half-Life:** Ligand A (25.969) has a longer half-life than Ligand B (2.132). This is a positive for Ligand A.

**14. P-gp Efflux:** Ligand A (0.366) has lower P-gp efflux than Ligand B (0.054), which is favorable for CNS penetration.

**15. Binding Affinity:** Ligand B (-7.7 kcal/mol) has a significantly stronger binding affinity than Ligand A (-10.3 kcal/mol). This is a substantial advantage for Ligand B, and can often outweigh minor ADME drawbacks.

**Overall Assessment:**

While Ligand A has better BBB penetration and *slightly* better P-gp efflux, Ligand B has a much stronger binding affinity, lower DILI risk, and better metabolic stability. The significantly improved binding affinity of Ligand B (-7.7 vs -10.3 kcal/mol) is a critical factor for a GPCR target. The lower DILI and better metabolic stability are also important advantages. The poor solubility and Caco-2 permeability are concerns for both, but the strong binding of Ligand B makes it a more promising starting point for optimization.

Output:
1
2025-04-17 07:23:02,402 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (356.403 and 347.503 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (82.29) is better than Ligand B (52.65). For CNS targets, TPSA should be <= 90, both meet this criterion, but lower is preferred.

**logP:** Ligand A (3.465) is within the optimal 1-3 range, while Ligand B (2.492) is slightly lower. Both are acceptable, but A is slightly better for membrane permeability.

**H-Bond Donors/Acceptors:** Ligand A (0 HBD, 7 HBA) and Ligand B (1 HBD, 3 HBA) are both favorable, well within the recommended limits.

**QED:** Both ligands have good QED scores (0.603 and 0.72), indicating drug-like properties.

**DILI:** Ligand A (87.049) has a significantly higher DILI risk than Ligand B (13.61). This is a major concern for Ligand A.

**BBB:** Ligand B (76.658) has a much better BBB penetration percentile than Ligand A (59.597). For a CNS target like DRD2, this is a critical advantage.

**Caco-2 Permeability:** Ligand A (-4.857) has worse Caco-2 permeability than Ligand B (-4.925). Both are negative, indicating poor permeability, but A is slightly better.

**Aqueous Solubility:** Ligand A (-4.158) has slightly worse solubility than Ligand B (-1.245). Both are poor, but B is better.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.153 and 0.33).

**Microsomal Clearance:** Ligand A (107.701) has higher microsomal clearance than Ligand B (31.393), indicating lower metabolic stability.

**In vitro Half-Life:** Ligand B (-1.288) has a much longer in vitro half-life than Ligand A (-23.587).

**P-gp Efflux:** Ligand A (0.65) has slightly higher P-gp efflux than Ligand B (0.107). Lower P-gp efflux is preferred for CNS penetration.

**Binding Affinity:** Ligand B (-7.3 kcal/mol) has a slightly better binding affinity than Ligand A (-9.0 kcal/mol). While A is stronger, the difference is not substantial enough to overcome its other weaknesses.

**Conclusion:**

Considering the GPCR-specific priorities, Ligand B is the more promising candidate. Its significantly better BBB penetration, much lower DILI risk, improved metabolic stability (lower Cl_mic, longer t1/2), and lower P-gp efflux outweigh the slightly weaker binding affinity and lower logP. Ligand A's high DILI risk and poor BBB penetration are major drawbacks for a CNS-targeting drug.

Output:
1
2025-04-17 07:23:02,402 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (379.479 Da) is slightly higher than Ligand B (344.411 Da), but both are acceptable.

**TPSA:** Ligand A (139.03) is borderline for CNS penetration, just above the preferred <90, while Ligand B (71.78) is excellent for CNS penetration. This is a significant advantage for Ligand B.

**logP:** Ligand A (-1.196) is a bit low, potentially hindering membrane permeability. Ligand B (1.797) is within the optimal range (1-3). This favors Ligand B.

**H-Bond Donors/Acceptors:** Ligand A has 3 HBD and 6 HBA, which are acceptable. Ligand B has 1 HBD and 4 HBA, also acceptable.

**QED:** Both ligands have good QED scores (Ligand A: 0.484, Ligand B: 0.799), indicating drug-like properties. Ligand B is better here.

**DILI:** Ligand A (53.47) has a moderate DILI risk, while Ligand B (29.818) has a lower risk. This favors Ligand B.

**BBB:** Ligand A (21.791) has very poor predicted BBB penetration, a critical drawback for a CNS target. Ligand B (68.554) has good BBB penetration. This is a major advantage for Ligand B.

**Caco-2 Permeability:** Ligand A (-5.645) shows poor permeability, while Ligand B (-4.353) is slightly better, but still not great.

**Aqueous Solubility:** Ligand A (-0.879) has poor solubility, while Ligand B (-2.647) is even worse. This could pose formulation challenges for both, but is more concerning for Ligand B.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (Ligand A: 0.09, Ligand B: 0.253).

**Microsomal Clearance:** Ligand A (4.885) has lower clearance, suggesting better metabolic stability than Ligand B (-10.519). This favors Ligand A.

**In vitro Half-Life:** Ligand A (-46.407) has a very short half-life, which is a significant negative. Ligand B (17.991) has a more reasonable half-life.

**P-gp Efflux:** Both ligands show low P-gp efflux (Ligand A: 0.038, Ligand B: 0.05), which is positive for CNS penetration.

**Binding Affinity:** Ligand B (-7.9 kcal/mol) has a slightly better binding affinity than Ligand A (-6.9 kcal/mol). While the difference is less than the 1.5 kcal/mol threshold, it contributes to the overall preference for Ligand B.

**Overall Assessment:**

Ligand B is significantly more promising due to its superior BBB penetration, better logP, lower DILI risk, and a slightly better binding affinity. While Ligand A has better metabolic stability (lower Cl_mic), the poor BBB penetration and short half-life are critical drawbacks for a CNS-targeted GPCR like DRD2. The solubility issues for both are concerning, but can potentially be addressed with formulation strategies.



Output:
1
2025-04-17 07:23:02,402 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (360.435 and 345.399 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (79.73) is significantly better than Ligand B (96.53). For CNS targets, we want TPSA <= 90, and A is closer to this threshold.

**logP:** Both ligands have good logP values (2.252 and 1.138), falling within the optimal 1-3 range. Ligand A is slightly better.

**H-Bond Donors/Acceptors:** Ligand A (HBD=1, HBA=6) is preferable to Ligand B (HBD=3, HBA=4) as it has fewer hydrogen bond donors, potentially improving membrane permeability.

**QED:** Ligand A (0.828) has a significantly higher QED score than Ligand B (0.486), indicating a more drug-like profile.

**DILI:** Ligand A (72.664) has a slightly higher DILI risk than Ligand B (54.789), but both are acceptable (<60 is good).

**BBB:** Ligand A (63.048) has a slightly lower BBB penetration percentile than Ligand B (59.093), but both are below the desired >70 for CNS targets. This is a weakness for both, but less critical than other factors.

**Caco-2 Permeability:** Ligand A (-4.539) has a worse Caco-2 permeability than Ligand B (-5.158), indicating lower intestinal absorption.

**Aqueous Solubility:** Ligand A (-2.826) has a worse aqueous solubility than Ligand B (-2.468).

**hERG:** Both ligands have very low hERG inhibition liability (0.295 and 0.041), which is excellent.

**Microsomal Clearance:** Ligand A (77.792) has a higher microsomal clearance than Ligand B (20.215), suggesting lower metabolic stability. This is a significant drawback for Ligand A.

**In vitro Half-Life:** Ligand A (-3.957) has a shorter in vitro half-life than Ligand B (-8.192), further supporting the lower metabolic stability of Ligand A.

**P-gp Efflux:** Ligand A (0.347) has a slightly higher P-gp efflux liability than Ligand B (0.009), which is undesirable for CNS penetration.

**Binding Affinity:** Both ligands have the same binding affinity (-8.1 kcal/mol), which is excellent and meets the criteria of < -7.0 kcal/mol.

**Overall Assessment:**

Despite similar binding affinities, Ligand B is the more promising candidate. It has a lower TPSA, better QED, lower DILI, better Caco-2 permeability, better solubility, significantly better metabolic stability (lower Cl_mic and longer t1/2), and lower P-gp efflux. While both have suboptimal BBB penetration, the superior ADME properties of Ligand B outweigh this concern. Ligand A's higher clearance and shorter half-life are significant liabilities.

Output:
1
2025-04-17 07:23:02,402 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (378.519 and 385.512 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (66.48) is better than Ligand B (69.64). Both are below the 90 A^2 threshold for CNS targets, but A is closer to the ideal.

**3. logP:** Ligand A (3.241) is within the optimal 1-3 range. Ligand B (2.088) is slightly lower, but still acceptable.

**4. H-Bond Donors:** Ligand A (1) is better than Ligand B (0). While both are acceptable, having one HBD can sometimes improve solubility.

**5. H-Bond Acceptors:** Ligand A (4) is better than Ligand B (6). Lower HBA is generally preferred for better permeability.

**6. QED:** Ligand A (0.888) is significantly better than Ligand B (0.552), indicating a more drug-like profile.

**7. DILI:** Ligand A (60.062) is higher than Ligand B (29.895), suggesting a greater potential for liver injury. This is a significant drawback for Ligand A.

**8. BBB:** Ligand A (89.531) is good, but Ligand B (96.006) is excellent, exceeding 90% and highly desirable for a CNS target like DRD2.

**9. Caco-2:** Both ligands have negative Caco-2 values (-5.032 and -4.974). This is unusual and suggests poor permeability. It's difficult to interpret without further context, but it's a negative for both.

**10. Solubility:** Both ligands have negative solubility values (-3.826 and -2.333). This is also unusual and suggests poor aqueous solubility. It's a negative for both.

**11. hERG:** Both ligands have low hERG inhibition liability (0.635 and 0.819), which is good.

**12. Cl_mic:** Ligand A (26.241) has lower microsomal clearance than Ligand B (53.495), suggesting better metabolic stability.

**13. t1/2:** Ligand A (32.716) has a positive in vitro half-life, while Ligand B (-53.647) has a negative value. This is a significant advantage for Ligand A.

**14. Pgp:** Both ligands have low P-gp efflux liability (0.513 and 0.185), which is good for CNS penetration.

**15. Binding Affinity:** Both ligands have the same binding affinity (-9.3 kcal/mol), which is excellent.

**Overall Assessment:**

While Ligand A has better QED, t1/2, Cl_mic, HBD, HBA, and TPSA, Ligand B significantly outperforms it in BBB penetration and has a much lower DILI risk. The negative Caco-2 and solubility values are concerning for both, but the superior BBB of Ligand B, combined with the lower DILI risk, makes it the more promising candidate for a CNS-targeting drug like a DRD2 ligand. The strong affinity is equal for both, so the ADME properties become the deciding factor.

Output:
1
2025-04-17 07:23:02,402 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (352.391 Da) is slightly lower, which could be beneficial for permeability. Ligand B (388.421 Da) is also good.

**TPSA:** Ligand A (114.63) is better than Ligand B (95.42) as it is closer to the ideal range for CNS targets (<=90).

**logP:** Ligand B (1.299) is within the optimal range (1-3), while Ligand A (0.083) is quite low, potentially hindering permeation. This is a significant drawback for Ligand A.

**H-Bond Donors/Acceptors:** Both ligands have acceptable HBD and HBA counts. Ligand A has 1 HBD and 7 HBA, while Ligand B has 2 HBD and 7 HBA.

**QED:** Both ligands have good QED scores (Ligand A: 0.659, Ligand B: 0.805), indicating drug-like properties. Ligand B is better.

**DILI:** Ligand B (77.743) has a higher DILI risk than Ligand A (47.46), but both are below the concerning threshold of 60.

**BBB:** Ligand A (74.758) has a significantly better BBB penetration percentile than Ligand B (49.011). This is a crucial advantage for a CNS target like DRD2.

**Caco-2 Permeability:** Ligand A (-4.935) has a more negative Caco-2 value, indicating poorer permeability than Ligand B (-5.242).

**Aqueous Solubility:** Ligand A (-0.822) has slightly better solubility than Ligand B (-2.742).

**hERG Inhibition:** Both ligands have very low hERG inhibition risk (Ligand A: 0.038, Ligand B: 0.147).

**Microsomal Clearance:** Ligand B (-2.926) has a negative value, indicating very slow clearance and high metabolic stability, which is a significant advantage over Ligand A (36.995).

**In Vitro Half-Life:** Ligand B (9.682 hours) has a much longer half-life than Ligand A (2.506 hours).

**P-gp Efflux:** Both ligands have low P-gp efflux liability (Ligand A: 0.026, Ligand B: 0.069).

**Binding Affinity:** Ligand A (-7.8 kcal/mol) has a slightly better binding affinity than Ligand B (-7.3 kcal/mol). While the difference is not huge, it's a positive for Ligand A.

**Overall Assessment:**

Ligand A excels in BBB penetration and binding affinity, but suffers from a very low logP, which could severely limit its ability to cross cell membranes. Ligand B has a better logP, excellent metabolic stability (negative Cl_mic), longer half-life, and a good QED score. While its BBB penetration is lower, the overall ADME profile is more favorable. The slightly weaker binding affinity of Ligand B is less concerning given its superior pharmacokinetic properties. For a CNS target, a balance between potency and brain penetration is critical, and Ligand B appears to strike a better balance.

Output:
1
2025-04-17 07:23:02,402 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (347.463 and 349.435 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (72.54) is significantly better than Ligand B (88.37). For CNS targets, TPSA should be <= 90, and A is closer to the ideal range for CNS penetration.

**3. logP:** Ligand A (0.743) is slightly lower than optimal (1-3), but still acceptable. Ligand B (-0.413) is below 1, which could hinder permeation.

**4. H-Bond Donors:** Both ligands are acceptable (1 and 2, respectively), staying within the <=5 guideline.

**5. H-Bond Acceptors:** Both ligands are acceptable (4 and 6, respectively), staying within the <=10 guideline.

**6. QED:** Both ligands have similar and good QED values (0.79 and 0.773), indicating good drug-like properties.

**7. DILI:** Ligand A (16.092) has a much lower DILI risk than Ligand B (23.032). Lower is better, and A is well below the concerning threshold of 60.

**8. BBB:** Ligand A (68.205) has a significantly better BBB penetration percentile than Ligand B (51.454). For a CNS target like DRD2, >70 is desirable, but A is considerably better than B.

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.175 and -5.156), which is unusual and suggests poor permeability. However, the values are very similar.

**10. Aqueous Solubility:** Both ligands have negative solubility values (-0.948 and -1.545), indicating poor aqueous solubility. Solubility is a concern for both.

**11. hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.212 and 0.338).

**12. Microsomal Clearance:** Ligand A (-3.681) has a lower (better) microsomal clearance than Ligand B (-4.003), indicating better metabolic stability.

**13. In vitro Half-Life:** Ligand A (-15.57) has a much longer in vitro half-life than Ligand B (28.85). Longer half-life is generally preferred.

**14. P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.008 and 0.009).

**15. Binding Affinity:** Ligand B (-8.4 kcal/mol) has a slightly better binding affinity than Ligand A (-7.7 kcal/mol). However, the difference is only 0.7 kcal/mol, which is not a huge advantage.

**Overall Assessment:**

Considering the GPCR-specific priorities, Ligand A is the more promising candidate. It has a significantly better BBB score, lower DILI risk, better metabolic stability (lower Cl_mic, longer t1/2), and a more favorable TPSA. While Ligand B has slightly better binding affinity, the differences in ADME properties, particularly BBB and DILI, outweigh this small advantage. The poor Caco-2 and solubility are concerns for both, but can be addressed with formulation strategies.

Output:
0
2025-04-17 07:23:02,402 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 drug candidates, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (342.483 and 368.543 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (49.41) is significantly better than Ligand B (62.66). For CNS targets, we want TPSA <= 90, and A is much closer to the ideal range.

**3. logP:** Both ligands have acceptable logP values (3.029 and 3.632), falling within the 1-3 range.

**4. H-Bond Donors:** Both have 1 HBD, which is good.

**5. H-Bond Acceptors:** Ligand A has 2 HBA, while Ligand B has 5. Both are within the acceptable limit of <=10, but A is preferable.

**6. QED:** Ligand A (0.854) has a better QED score than Ligand B (0.761), indicating better overall drug-likeness.

**7. DILI:** Ligand A (40.054) has a slightly higher DILI risk than Ligand B (33.579), but both are below the concerning threshold of 60.

**8. BBB:** Ligand A (69.523) has a better BBB percentile than Ligand B (62.737), although both are reasonably good. For CNS targets, >70 is desirable, so both are somewhat suboptimal, but A is better.

**9. Caco-2 Permeability:** Ligand A (-4.996) is better than Ligand B (-4.265), indicating better intestinal absorption.

**10. Aqueous Solubility:** Ligand A (-4.541) is better than Ligand B (-3.985), indicating better solubility.

**11. hERG Inhibition:** Ligand A (0.294) has a much lower hERG inhibition liability than Ligand B (0.519), which is a significant advantage.

**12. Microsomal Clearance:** Ligand B (85.83) has a higher microsomal clearance than Ligand A (51.015), indicating lower metabolic stability.

**13. In vitro Half-Life:** Ligand A (5.24) has a shorter half-life than Ligand B (-19.831). This is a negative for Ligand A.

**14. P-gp Efflux:** Ligand A (0.408) has a lower P-gp efflux liability than Ligand B (0.565), which is favorable for CNS penetration.

**15. Binding Affinity:** Ligand B (-7.0) has a slightly better binding affinity than Ligand A (-9.0). This is a significant advantage for Ligand B.

**Overall Assessment:**

While Ligand B has a slightly better binding affinity, Ligand A demonstrates superior ADME properties crucial for CNS drug development. Specifically, its lower TPSA, better solubility, lower hERG risk, and lower P-gp efflux are all highly advantageous. The better BBB percentile and QED score further support Ligand A. The shorter half-life of Ligand A is a concern, but can potentially be addressed through structural modifications. The affinity difference is not large enough to outweigh the ADME benefits of Ligand A.

Output:
0
2025-04-17 07:23:02,403 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (346.515 Da) is slightly better positioned.

**TPSA:** Ligand A (40.62) is excellent for CNS penetration, well below the 90 A^2 threshold. Ligand B (129.89) is higher, but still potentially acceptable, though less ideal.

**logP:** Ligand A (3.929) is at the upper end of the optimal range (1-3), but still acceptable. Ligand B (0.368) is quite low, which could hinder membrane permeability and CNS penetration.

**H-Bond Donors/Acceptors:** Ligand A (0 HBD, 2 HBA) is favorable. Ligand B (3 HBD, 7 HBA) is also acceptable, but slightly higher counts could impact permeability.

**QED:** Both ligands have good QED scores (A: 0.518, B: 0.721), indicating drug-like properties.

**DILI:** Ligand A (17.41) has a significantly lower DILI risk than Ligand B (64.754), which is a substantial advantage.

**BBB:** Ligand A (79.256) has excellent BBB penetration potential, exceeding the 70% threshold. Ligand B (48.662) is considerably lower, raising concerns about CNS exposure.

**Caco-2 Permeability:** Ligand A (-4.785) has poor Caco-2 permeability. Ligand B (-5.921) is also poor.

**Aqueous Solubility:** Both ligands have poor aqueous solubility (-3.699 and -2.579 respectively).

**hERG Inhibition:** Both ligands have low hERG inhibition risk (A: 0.733, B: 0.4).

**Microsomal Clearance:** Ligand A (63.321) has moderate clearance. Ligand B (-33.266) has *negative* clearance, which is not physically possible and indicates an issue with the data or prediction method. This is a major red flag.

**In vitro Half-Life:** Ligand A (-3.644) has a negative half-life, which is not physically possible. Ligand B (-28.436) also has a negative half-life. This is another major red flag.

**P-gp Efflux:** Both ligands have very low P-gp efflux (A: 0.738, B: 0.021), which is beneficial for CNS penetration.

**Binding Affinity:** Ligand B (-8.5 kcal/mol) has a significantly stronger binding affinity than Ligand A (-0.0 kcal/mol). This is a substantial advantage, potentially outweighing some ADME concerns *if* the ADME issues aren't insurmountable.

**Overall Assessment:**

Despite the significantly stronger binding affinity of Ligand B, the negative values for microsomal clearance and in vitro half-life are critical flaws. These suggest fundamental issues with the predicted metabolic profile, making it highly unlikely to be a viable drug candidate. Ligand A, while having weaker affinity, has a much better predicted ADME profile, particularly regarding BBB penetration and DILI risk. The poor Caco-2 permeability and solubility are concerns, but potentially addressable through formulation strategies.

Output:
1
2025-04-17 07:23:02,403 - INFO - Batch 360 complete. Total preferences: 5760
2025-04-17 07:23:02,403 - INFO - Processing batch 361/512...
2025-04-17 07:23:45,437 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (347.415 Da) is slightly lower, which could be advantageous for permeability.

**TPSA:** Both ligands are below the 140 A^2 threshold for oral absorption and reasonably close to the 90 A^2 target for CNS penetration. Ligand A (97.37 A^2) is slightly higher than Ligand B (95.74 A^2), but both are acceptable.

**logP:** Ligand A (2.949) is optimal (1-3). Ligand B (0.492) is quite low, potentially hindering membrane permeability and CNS penetration. This is a significant drawback for a CNS target.

**H-Bond Donors/Acceptors:** Ligand A (2 HBD, 5 HBA) and Ligand B (1 HBD, 6 HBA) both fall within acceptable ranges.

**QED:** Both ligands have good QED scores (A: 0.765, B: 0.809), indicating drug-like properties.

**DILI:** Ligand A (53.354) has a better DILI score than Ligand B (60.799), suggesting a lower risk of liver injury.

**BBB:** Ligand B (68.554) has a significantly better BBB percentile than Ligand A (54.634). This is a crucial factor for a CNS target like DRD2.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values, which is unusual and suggests poor permeability. However, the scale is not specified, so it's difficult to interpret.

**Aqueous Solubility:** Both ligands have negative solubility values, again, difficult to interpret without knowing the scale.

**hERG:** Both ligands have very low hERG inhibition liability (A: 0.314, B: 0.379), which is excellent.

**Microsomal Clearance:** Ligand B (27.386) has significantly lower microsomal clearance than Ligand A (69.339), indicating better metabolic stability.

**In vitro Half-Life:** Ligand B (-50.903) has a negative half-life, which is not possible. This is a major red flag and suggests an issue with the data or the compound itself. Ligand A (17.224) has a reasonable half-life.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (A: 0.105, B: 0.1), which is favorable for CNS penetration.

**Binding Affinity:** Both ligands have the same binding affinity (-8.1 kcal/mol), which is excellent.

**Conclusion:**

Despite Ligand B's better BBB penetration and lower microsomal clearance, the extremely low logP and nonsensical half-life are major concerns. The low logP suggests poor permeability, which would negate the benefit of good BBB penetration. The negative half-life is a critical data quality issue. Ligand A, while having a slightly lower BBB score, has a much more reasonable logP, a plausible half-life, and a lower DILI risk. Therefore, Ligand A is the more viable drug candidate.

Output:
0
2025-04-17 07:23:45,438 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (374.453 and 348.353 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (78.43) is better than Ligand B (86.88). Both are below the 90 A^2 threshold for CNS targets, but A is closer to the optimal range.

**3. logP:** Both ligands have good logP values (2.598 and 1.931), falling within the 1-3 range.

**4. H-Bond Donors:** Both have 3 HBD, which is acceptable.

**5. H-Bond Acceptors:** Ligand A has 4 HBA, and Ligand B has 3. Both are within the acceptable limit of 10.

**6. QED:** Both ligands have good QED scores (0.621 and 0.745), indicating good drug-like properties.

**7. DILI:** Ligand A (36.06) has a significantly lower DILI risk than Ligand B (68.592). This is a major advantage for Ligand A.

**8. BBB:** Ligand B (70.415) has a better BBB penetration percentile than Ligand A (48.003). This is a crucial factor for CNS targets like DRD2.

**9. Caco-2 Permeability:** Ligand A (-5.681) has worse Caco-2 permeability than Ligand B (-4.919), indicating potentially poorer intestinal absorption.

**10. Aqueous Solubility:** Both ligands have poor aqueous solubility (-3.35 and -3.176). This could pose formulation challenges.

**11. hERG Inhibition:** Both ligands show low hERG inhibition liability (0.464 and 0.298).

**12. Microsomal Clearance:** Ligand B (-7.702) has a much lower (better) microsomal clearance than Ligand A (89.06), suggesting better metabolic stability.

**13. In vitro Half-Life:** Ligand B (-11.706) has a longer in vitro half-life than Ligand A (-13.638).

**14. P-gp Efflux:** Ligand A (0.083) has lower P-gp efflux than Ligand B (0.042), which is favorable for CNS penetration.

**15. Binding Affinity:** Both ligands have excellent binding affinities (-8.1 and -9.1 kcal/mol). Ligand B is slightly better, with a 1.0 kcal/mol advantage.

**Overall Assessment:**

Ligand B has a significant advantage in BBB penetration and metabolic stability (lower Cl_mic and longer half-life), and slightly better binding affinity. However, Ligand A has a much lower DILI risk and better P-gp efflux. Given the importance of BBB penetration for a CNS target like DRD2, and the slight advantage in binding affinity, Ligand B is the more promising candidate. The DILI risk of Ligand A is concerning, and while P-gp efflux is favorable, the difference isn't substantial enough to outweigh the benefits of Ligand B's superior CNS properties.

Output:
1
2025-04-17 07:23:45,438 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B based on the provided guidelines, prioritizing GPCR-specific properties (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (349.479 and 352.475 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (89.38) is better than Ligand B (59.08) as it is closer to the ideal <90 for CNS targets. Ligand B is quite low, which might raise concerns about solubility.

**logP:** Both ligands have acceptable logP values (3.064 and 1.677), falling within the optimal 1-3 range. Ligand A is slightly better, being closer to the upper end of the range.

**H-Bond Donors/Acceptors:** Both ligands have a reasonable number of HBD (0) and HBA (3 & 4), satisfying the <5 and <10 rules, respectively.

**QED:** Both ligands have good QED scores (0.401 and 0.633), indicating reasonable drug-likeness. Ligand B is better here.

**DILI:** Ligand A (19.232) has a higher DILI risk than Ligand B (15.898), but both are below the 40 threshold, indicating low risk.

**BBB:** Both ligands have excellent BBB penetration (78.829 and 77.782), exceeding the desirable >70 threshold for CNS targets.

**Caco-2 Permeability:** Both ligands have negative Caco-2 permeability values (-4.59 and -4.523). This is unusual and suggests a potential issue with the data or the model used to predict it. It's difficult to interpret without more context, but it doesn't immediately disqualify either compound.

**Aqueous Solubility:** Both ligands have negative solubility values (-2.08 and -1.221). Similar to Caco-2, this is unusual and concerning. It suggests very poor aqueous solubility, which could hinder bioavailability.

**hERG Inhibition:** Both ligands have low hERG inhibition liability (0.322 and 0.404), which is good.

**Microsomal Clearance:** Ligand B (27.554) has significantly lower microsomal clearance than Ligand A (44.508), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand B (12.733 hours) has a much longer half-life than Ligand A (-2.39 hours). This is a significant advantage for dosing convenience.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.047 and 0.161), which is favorable for CNS exposure.

**Binding Affinity:** Ligand B (-7.0 kcal/mol) has a slightly better binding affinity than Ligand A (-6.8 kcal/mol). While the difference is small, it's within the range where it could outweigh minor ADME drawbacks.

**Overall Assessment:**

Ligand B is the stronger candidate. While Ligand A has a slightly better TPSA and logP, Ligand B excels in crucial areas for a CNS-targeting GPCR drug: significantly better metabolic stability (lower Cl_mic), longer half-life, and slightly improved binding affinity. The negative solubility and Caco-2 values are concerning for both, but the other advantages of Ligand B make it more promising.

Output:
1
2025-04-17 07:23:45,438 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (344.46 and 355.44 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (75.19) is excellent, well below the 90 A^2 threshold for CNS targets. Ligand B (113.6) is higher, but still potentially acceptable, though less ideal.

**logP:** Ligand A (2.329) is optimal (1-3). Ligand B (0.113) is quite low, which could hinder membrane permeability and CNS penetration.

**H-Bond Donors/Acceptors:** Ligand A (1 HBD, 4 HBA) is good. Ligand B (3 HBD, 5 HBA) is also acceptable.

**QED:** Ligand A (0.824) is very good, indicating high drug-likeness. Ligand B (0.508) is acceptable, but lower than Ligand A.

**DILI:** Both ligands have low DILI risk (31.56 and 27.34 percentile), which is positive.

**BBB:** Ligand A (74.29%) has excellent BBB penetration, exceeding the 70% threshold. Ligand B (51.11%) is significantly lower and concerning for a CNS target.

**Caco-2 Permeability:** Both have negative values (-5.029 and -5.479), which is unusual. Assuming these are logP-like scales, lower values indicate poorer permeability.

**Aqueous Solubility:** Both have negative values (-2.139 and -1.963), also unusual. Lower values indicate poorer solubility.

**hERG:** Both ligands have very low hERG risk (0.146 and 0.128).

**Microsomal Clearance:** Ligand A (31.69 mL/min/kg) is moderate. Ligand B (25.95 mL/min/kg) is slightly better.

**In vitro Half-Life:** Ligand A (-9.413 hours) is negative, which is unusual. Ligand B (-22.416 hours) is even more negative. This suggests rapid metabolism or instability.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.019 and 0.017).

**Binding Affinity:** Ligand A (-8.5 kcal/mol) has a slightly better binding affinity than Ligand B (-7.9 kcal/mol). While both are good, the 0.6 kcal/mol difference is notable.

**Overall Assessment:**

Ligand A is significantly better suited as a CNS-targeting drug candidate. Its superior BBB penetration, optimal logP, higher QED, and slightly better binding affinity outweigh any minor drawbacks. Ligand B's low logP and poor BBB penetration are major concerns for a DRD2 ligand, as it would likely have limited brain exposure. The unusual negative values for Caco-2 and solubility are also concerning and would require further investigation.

Output:
0
2025-04-17 07:23:45,438 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (347.415 and 340.423 Da) fall comfortably within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (82.45) is better than Ligand B (60.85). Both are below the 90 A^2 threshold desirable for CNS targets, but A is closer to the upper limit.

**3. logP:** Both ligands have good logP values (2.05 and 1.422), falling within the optimal 1-3 range.

**4. H-Bond Donors:** Both have 1 HBD, which is acceptable.

**5. H-Bond Acceptors:** Ligand A has 6 HBAs, and Ligand B has 3. Both are below the 10 threshold.

**6. QED:** Both ligands have similar, high QED values (0.846 and 0.844), indicating good drug-like properties.

**7. DILI:** Ligand A (57.387) has a higher DILI risk than Ligand B (30.516). This is a significant drawback for Ligand A.

**8. BBB:** Ligand A (75.378) has a better BBB percentile than Ligand B (52.268). This is crucial for a CNS target like DRD2.

**9. Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and suggests poor permeability. However, the scale is not specified, so it's difficult to interpret.

**10. Aqueous Solubility:** Both have negative solubility values, which is also unusual. Again, the scale is not specified.

**11. hERG Inhibition:** Both ligands have low hERG inhibition liability (0.193 and 0.239).

**12. Microsomal Clearance:** Ligand A (77.298) has higher microsomal clearance than Ligand B (24.422), suggesting lower metabolic stability.

**13. In vitro Half-Life:** Ligand B (16.027) has a significantly longer in vitro half-life than Ligand A (-12.97). This is a major advantage for Ligand B.

**14. P-gp Efflux:** Ligand A (0.115) has lower P-gp efflux than Ligand B (0.051), which is favorable for CNS penetration.

**15. Binding Affinity:** Ligand B (-8.4 kcal/mol) has a *much* stronger binding affinity than Ligand A (0 kcal/mol). This is the most critical factor.

**Overall Assessment:**

Ligand B is the superior candidate. While Ligand A has a better BBB score and lower P-gp efflux, the significantly stronger binding affinity of Ligand B (-8.4 vs 0 kcal/mol) outweighs the advantages of Ligand A. Furthermore, Ligand B has a much lower DILI risk and a significantly longer half-life, both of which are crucial for drug development. The negative solubility and Caco-2 values are concerning for both, but the binding affinity difference is so large that it dominates the decision.

Output:
1
2025-04-17 07:23:45,438 - INFO - Reasoning:

Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (341.455 and 363.531 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (62.3) is slightly above the optimal <90 for CNS targets, but still reasonable. Ligand B (56.07) is excellent, well below 90.

**3. logP:** Both ligands have good logP values (2.715 and 3.413), falling within the 1-3 range. Ligand B is slightly higher, which could be a minor concern for solubility but isn't a dealbreaker.

**4. H-Bond Donors:** Ligand A (1) is good. Ligand B (0) is also good.

**5. H-Bond Acceptors:** Ligand A (3) is good. Ligand B (7) is acceptable, but approaching the upper limit of 10.

**6. QED:** Both ligands have acceptable QED values (0.809 and 0.719), indicating good drug-like properties.

**7. DILI:** Ligand A (27.065) has a much lower DILI risk than Ligand B (47.538), which is a significant advantage.

**8. BBB:** Both ligands have excellent BBB penetration (72.78% and 74.641%), exceeding the desirable >70% threshold for CNS targets.

**9. Caco-2 Permeability:** Ligand A (-4.825) has poor Caco-2 permeability, while Ligand B (-5.42) is also poor, though slightly worse.

**10. Aqueous Solubility:** Ligand A (-3.269) has poor aqueous solubility, while Ligand B (-2.972) is also poor.

**11. hERG Inhibition:** Both ligands show low hERG inhibition risk (0.385 and 0.645).

**12. Microsomal Clearance:** Ligand A (70.074) has higher microsomal clearance than Ligand B (59.967), indicating lower metabolic stability.

**13. In vitro Half-Life:** Ligand A (-13.083) has a very short in vitro half-life, a major drawback. Ligand B (11.274) has a much better, longer half-life.

**14. P-gp Efflux:** Both ligands have low P-gp efflux (0.074 and 0.317), which is favorable for CNS penetration.

**15. Binding Affinity:** Ligand B (-7.7 kcal/mol) has a significantly stronger binding affinity than Ligand A (-9.2 kcal/mol). This is a substantial advantage.

**Overall Assessment:**

While Ligand A has a lower DILI risk, its poor Caco-2 permeability, very short half-life, and weaker binding affinity are major concerns. Ligand B, despite a slightly higher DILI risk, has a significantly stronger binding affinity, a longer half-life, and acceptable BBB penetration. The stronger binding affinity is likely to outweigh the slightly increased DILI risk, especially given the relatively moderate DILI percentile of 47.538. The GPCR-specific priorities heavily favor Ligand B due to its superior affinity and acceptable CNS penetration properties.

Output:
1
2025-04-17 07:23:45,438 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (339.483 and 348.487 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (46.92) is significantly better than Ligand B (69.64). For CNS targets, we want TPSA <= 90, and ideally closer to 60. Ligand A is well within this range, while Ligand B is approaching the upper limit and less favorable.

**3. logP:** Ligand A (4.619) is slightly high, potentially leading to solubility issues or off-target interactions. Ligand B (2.247) is within the optimal 1-3 range.

**4. H-Bond Donors:** Ligand A (1) and Ligand B (2) are both acceptable, being <= 5.

**5. H-Bond Acceptors:** Both ligands (A: 3, B: 3) are well below the limit of 10.

**6. QED:** Ligand A (0.887) has a better QED score than Ligand B (0.766), indicating a more drug-like profile.

**7. DILI:** Ligand A (55.021) has a higher DILI risk than Ligand B (14.541). This is a significant drawback for Ligand A.

**8. BBB:** Ligand A (95.657) has excellent BBB penetration, a crucial factor for a CNS target like DRD2. Ligand B (65.025) is lower, though not terrible, it's substantially worse than Ligand A.

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.639 and -4.673), which is unusual and suggests poor permeability. This is a concern for both, but doesn't differentiate them.

**10. Aqueous Solubility:** Both ligands have negative solubility values (-5.557 and -2.661), indicating poor aqueous solubility. This is a concern for both, but less so for Ligand B.

**11. hERG Inhibition:** Ligand A (0.883) has a slightly higher hERG risk than Ligand B (0.162), although both are relatively low.

**12. Microsomal Clearance:** Ligand B (39.607) has significantly lower microsomal clearance than Ligand A (64.366), suggesting better metabolic stability.

**13. In vitro Half-Life:** Ligand A (86.568) has a longer in vitro half-life than Ligand B (-7.926). This is a positive for Ligand A.

**14. P-gp Efflux:** Ligand A (0.857) has lower P-gp efflux than Ligand B (0.054), which is favorable for CNS penetration.

**15. Binding Affinity:** Ligand A (-8.9 kcal/mol) has a slightly better binding affinity than Ligand B (-8.1 kcal/mol). While both are excellent, the 0.8 kcal/mol difference is noteworthy.

**Overall Assessment:**

Ligand A excels in BBB penetration, binding affinity, P-gp efflux, and in vitro half-life. However, it has a higher DILI risk and a logP that is a bit too high. Ligand B has better logP, DILI, and metabolic stability, but suffers from lower BBB penetration and a slightly weaker binding affinity.

Given the GPCR-specific priorities, particularly the importance of BBB penetration for a CNS target, and the strong binding affinity of Ligand A, I would favor **Ligand A** despite its higher DILI risk. The excellent BBB penetration and affinity are likely to outweigh the DILI concern, especially with further optimization. The slightly elevated logP can also be addressed in subsequent iterations.

Output:
1
2025-04-17 07:23:45,438 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (350.423 and 338.367 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (104.31) is higher than Ligand B (79.54). For CNS targets, we prefer TPSA <= 90, so Ligand B is significantly better here.

**logP:** Ligand A (0.75) is a bit low, potentially hindering permeation. Ligand B (1.299) is better, falling within the optimal 1-3 range.

**H-Bond Donors:** Ligand A (1) and Ligand B (0) are both acceptable, being <= 5.

**H-Bond Acceptors:** Ligand A (7) and Ligand B (5) are both acceptable, being <= 10.

**QED:** Both ligands have good QED scores (0.781 and 0.825, respectively), indicating good drug-like properties.

**DILI:** Both ligands have acceptable DILI risk (52.656 and 59.442), below the concerning threshold of 60.

**BBB:** Ligand A (78.907) has a better BBB percentile than Ligand B (61.768). A value >70 is desirable for CNS targets, and A is closer.

**Caco-2:** Both ligands have negative Caco-2 values (-4.95 and -4.971). This is unusual and suggests poor permeability.

**Solubility:** Both ligands have negative solubility values (-1.947 and -2.59). This is also unusual and suggests poor solubility.

**hERG:** Both ligands have low hERG risk (0.211 and 0.149).

**Microsomal Clearance:** Ligand A (49.59) has lower microsomal clearance than Ligand B (27.718), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (-18.423) has a negative half-life, which is not possible. Ligand B (36.148) has a reasonable half-life.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.051 and 0.134).

**Binding Affinity:** Ligand B (-9.8 kcal/mol) has a significantly stronger binding affinity than Ligand A (-7.3 kcal/mol). This is a >1.5 kcal/mol advantage, which can outweigh other drawbacks.

**Overall Assessment:**

Ligand B is the stronger candidate. While Ligand A has a slightly better BBB score and lower clearance, Ligand B's significantly improved binding affinity (-9.8 vs -7.3 kcal/mol) is a major advantage for a GPCR target. The better logP and lower TPSA of Ligand B are also favorable for CNS penetration. The negative values for Caco-2 and solubility are concerning for both, but the potency advantage of Ligand B is likely to be more impactful in early optimization. The negative half-life for Ligand A is a critical flaw.

Output:
1
2025-04-17 07:23:45,439 - INFO - Reasoning:

Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (394.871 Da) is slightly higher than Ligand B (348.447 Da), but both are acceptable.

**2. TPSA:** Ligand A (58.64) is significantly better than Ligand B (76.46). For CNS targets, we want TPSA <= 90, and ideally closer to 60. Ligand A is much closer to this ideal.

**3. logP:** Ligand A (3.386) is optimal (1-3), while Ligand B (1.748) is on the lower end. While not terrible, lower logP can sometimes hinder permeability.

**4. H-Bond Donors:** Both ligands have 1 HBD, which is within the acceptable limit of <=5.

**5. H-Bond Acceptors:** Ligand A has 4 HBAs, and Ligand B has 5. Both are within the acceptable limit of <=10.

**6. QED:** Both ligands have similar QED values (0.771 and 0.726), indicating good drug-likeness.

**7. DILI:** Ligand A (55.68) has a higher DILI risk than Ligand B (31.989). This is a negative for Ligand A.

**8. BBB:** Ligand A (82.862) has a significantly better BBB penetration percentile than Ligand B (73.943).  For a CNS target like DRD2, >70 is desirable, and Ligand A is closer to this threshold.

**9. Caco-2 Permeability:** Ligand A (-4.775) has worse Caco-2 permeability than Ligand B (-5.316). Lower values are worse.

**10. Aqueous Solubility:** Ligand A (-4.122) has worse aqueous solubility than Ligand B (-1.78). Lower values are worse.

**11. hERG Inhibition:** Both ligands have low hERG inhibition risk (0.612 and 0.216).

**12. Microsomal Clearance:** Ligand A (22.621) has a higher microsomal clearance than Ligand B (16.157), suggesting lower metabolic stability.

**13. In vitro Half-Life:** Ligand B (-8.713) has a longer in vitro half-life than Ligand A (-0.423).

**14. P-gp Efflux:** Ligand A (0.285) has lower P-gp efflux than Ligand B (0.054), which is favorable for CNS penetration.

**15. Binding Affinity:** Both ligands have excellent binding affinity (-8.4 and -8.0 kcal/mol). The difference is 0.4 kcal/mol, which isn't substantial enough to outweigh other factors.

**Overall Assessment:**

Ligand A excels in TPSA and BBB penetration, crucial for a CNS GPCR target. It also has better logP and lower P-gp efflux. However, it suffers from higher DILI risk, worse Caco-2 permeability, worse aqueous solubility and lower metabolic stability.

Ligand B has a better safety profile (lower DILI) and better metabolic stability and solubility, but its TPSA is higher and BBB penetration is lower, which are significant drawbacks for a CNS target.

Considering the GPCR-specific priorities, the superior BBB penetration and TPSA of Ligand A are more important than the slightly better safety profile of Ligand B. The affinity is comparable.

Output:
1
2025-04-17 07:23:45,439 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 drug candidates, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (393.311 and 372.487 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (87.66) is better than Ligand B (76.15), both are below the 90 A^2 threshold for CNS targets.

**logP:** Ligand A (1.655) is within the optimal 1-3 range. Ligand B (0.359) is slightly low, potentially hindering permeation.

**H-Bond Donors/Acceptors:** Ligand A has 3 HBD and 4 HBA, while Ligand B has 0 HBD and 5 HBA. Both are within acceptable limits.

**QED:** Both ligands have good QED scores (0.599 and 0.696, respectively), indicating drug-like properties.

**DILI:** Ligand A (35.673) has a slightly higher DILI risk than Ligand B (20.357), but both are below the concerning threshold of 60.

**BBB:** Ligand B (74.292) has a significantly better BBB penetration score than Ligand A (50.097). This is a critical advantage for a CNS target like DRD2.

**Caco-2 Permeability:** Ligand A (-5.385) has a worse Caco-2 permeability than Ligand B (-4.701), indicating lower intestinal absorption.

**Aqueous Solubility:** Ligand A (-2.529) has a worse aqueous solubility than Ligand B (-1.496).

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.272 and 0.214, respectively).

**Microsomal Clearance:** Ligand A (-1.825) has a better (lower) microsomal clearance than Ligand B (14.256), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (46.361) has a significantly longer in vitro half-life than Ligand B (6.097).

**P-gp Efflux:** Ligand A (0.184) has a lower P-gp efflux liability than Ligand B (0.019), which is favorable for CNS exposure.

**Binding Affinity:** Ligand B (-7.9 kcal/mol) has a slightly better binding affinity than Ligand A (-7.4 kcal/mol). While the difference is not huge, it's a positive factor.

**Overall Assessment:**

Ligand B excels in BBB penetration and has a slightly better binding affinity. While Ligand A has better metabolic stability (lower Cl_mic and longer t1/2) and lower P-gp efflux, the superior BBB score of Ligand B is paramount for a CNS-targeting drug. The slightly lower logP of Ligand B is a minor concern, but the strong affinity and excellent BBB penetration outweigh this.

Output:
1
2025-04-17 07:23:45,439 - INFO - Reasoning:

Let's analyze Ligand A and Ligand B against the provided guidelines, prioritizing GPCR-specific properties (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (342.403 and 368.503 Da) fall within the ideal 200-500 Da range.

**TPSA:** Both ligands (101.8 and 103.95) are slightly above the optimal 90 for CNS targets, but not drastically so.

**logP:** Ligand A (0.403) is quite low, potentially hindering permeation. Ligand B (1.862) is within the optimal 1-3 range. This is a significant advantage for Ligand B.

**H-Bond Donors/Acceptors:** Ligand A (2 HBD, 6 HBA) and Ligand B (3 HBD, 4 HBA) both have acceptable numbers of hydrogen bond donors and acceptors.

**QED:** Both ligands have similar QED values (0.676 and 0.651), indicating reasonable drug-likeness.

**DILI:** Both ligands have acceptable DILI risk (57.387 and 42.613 percentile), below the concerning threshold of 60.

**BBB:** Ligand B (60.838%) has a substantially better BBB penetration score than Ligand A (43.777%). This is a critical factor for a CNS target like DRD2.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.445 and -5.424), which is unusual and suggests poor permeability. However, the scale isn't clearly defined, so it's hard to interpret without more context.

**Aqueous Solubility:** Both ligands have negative solubility values (-1.445 and -2.925), again unusual and suggesting poor solubility. Similar to Caco-2, the scale is unclear.

**hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.057 and 0.303 percentile), which is excellent.

**Microsomal Clearance:** Ligand A (28.936 mL/min/kg) has a slightly higher clearance than Ligand B (26.276 mL/min/kg), suggesting slightly lower metabolic stability.

**In vitro Half-Life:** Ligand B (-31.835 hours) has a significantly longer half-life than Ligand A (-1.768 hours). This is a major advantage for Ligand B.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.016 and 0.264 percentile), which is favorable.

**Binding Affinity:** Both ligands have very similar and strong binding affinities (-8.6 and -8.3 kcal/mol). The difference of 0.3 kcal/mol isn't enough to outweigh other significant differences.

**Conclusion:**

Considering all factors, especially the GPCR-specific priorities, **Ligand B is the more promising drug candidate.** While both have good affinity and low hERG risk, Ligand B demonstrates significantly better BBB penetration, a more favorable logP value, and a substantially longer in vitro half-life. The slightly higher clearance of Ligand A is a minor drawback compared to these advantages. The negative Caco-2 and solubility values are concerning for both, but the other benefits of Ligand B make it the better choice.

Output:
1
2025-04-17 07:23:45,439 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 drug candidates, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (348.49 and 355.48 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (58.64) is excellent, well below the 90 A^2 threshold for CNS targets. Ligand B (90.9) is at the upper limit, but still acceptable.

**logP:** Ligand A (2.49) is optimal (1-3). Ligand B (0.13) is quite low, potentially hindering membrane permeability and CNS penetration.

**H-Bond Donors/Acceptors:** Ligand A (HBD=1, HBA=3) is good. Ligand B (HBD=3, HBA=5) is also acceptable, but slightly higher.

**QED:** Ligand A (0.80) is excellent, indicating strong drug-likeness. Ligand B (0.49) is below the desirable 0.5 threshold, suggesting a less favorable drug-like profile.

**DILI:** Ligand A (22.45) has a very low DILI risk. Ligand B (8.41) also has a low DILI risk, but slightly higher than A.

**BBB:** Ligand A (76.54) has good BBB penetration, exceeding the 70% threshold. Ligand B (36.33) is significantly lower, a major concern for a CNS target like DRD2.

**Caco-2 Permeability:** Ligand A (-4.74) is negative, indicating poor permeability. Ligand B (-5.18) is also negative and similarly poor.

**Aqueous Solubility:** Ligand A (-3.17) and Ligand B (-0.97) both show poor solubility.

**hERG Inhibition:** Both ligands (0.46 and 0.34) have low hERG inhibition risk.

**Microsomal Clearance:** Ligand A (65.92) has moderate clearance, while Ligand B (12.95) has low clearance, indicating better metabolic stability.

**In vitro Half-Life:** Ligand A (8.56) has a moderate half-life. Ligand B (-13.29) has a very short half-life, which is undesirable.

**P-gp Efflux:** Both ligands (0.11 and 0.02) have low P-gp efflux, which is good for CNS penetration.

**Binding Affinity:** Ligand A (-8.4 kcal/mol) has a slightly better binding affinity than Ligand B (-7.5 kcal/mol), although both are good. The 0.9 kcal/mol difference is significant.

**Overall Assessment:**

Ligand A is superior due to its better BBB penetration, higher QED, and slightly better binding affinity. While both have poor Caco-2 and solubility, the CNS target prioritizes BBB. Ligand B's low logP and poor BBB penetration are significant drawbacks. The better metabolic stability of Ligand B is not enough to offset its other weaknesses.

Output:
1
2025-04-17 07:23:45,439 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (351.491 and 382.551 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (92.5) is better than Ligand B (67.43). Both are below the 90 A^2 threshold for CNS targets, which is excellent.

**3. logP:** Both ligands have good logP values (1.82 and 2.542), falling within the optimal 1-3 range. Ligand B is slightly higher, potentially offering better membrane permeability.

**4. H-Bond Donors:** Both have 2 HBD, which is within the acceptable limit of <=5.

**5. H-Bond Acceptors:** Ligand A has 3 HBA, and Ligand B has 5. Both are below the 10 limit, but Ligand A is preferable.

**6. QED:** Ligand A (0.809) has a significantly better QED score than Ligand B (0.678), indicating a more drug-like profile.

**7. DILI:** Ligand A (24.777) has a much lower DILI risk than Ligand B (47.693), which is a significant advantage.

**8. BBB:** Ligand A (72.664) has a slightly better BBB percentile than Ligand B (68.748), both are reasonably good, but A is preferable for a CNS target.

**9. Caco-2 Permeability:** Ligand A (-5.053) has better Caco-2 permeability than Ligand B (-5.546).

**10. Aqueous Solubility:** Both have poor aqueous solubility (-3.62 and -3.009). This could be a formulation challenge for both.

**11. hERG:** Both have very low hERG inhibition liability (0.142 and 0.41), indicating minimal cardiotoxicity risk.

**12. Microsomal Clearance:** Both have similar microsomal clearance (51.009 and 55.487), suggesting comparable metabolic stability.

**13. In vitro Half-Life:** Ligand A (1.043) has a shorter half-life than Ligand B (14.156). This is a significant drawback for Ligand A.

**14. P-gp Efflux:** Ligand A (0.028) has much lower P-gp efflux than Ligand B (0.085). Lower P-gp efflux is crucial for CNS penetration.

**15. Binding Affinity:** Ligand B (-8.1 kcal/mol) has a slightly better binding affinity than Ligand A (-7.6 kcal/mol). While the difference is not huge, it's a factor.

**Overall Assessment:**

Ligand A excels in most ADME properties (DILI, BBB, P-gp efflux, QED, TPSA, Caco-2). Ligand B's primary advantage is its slightly better binding affinity and longer half-life. However, the significantly better ADME profile of Ligand A, particularly its lower DILI and P-gp efflux, makes it a more promising drug candidate for a CNS target like DRD2. The slightly weaker binding affinity of Ligand A can potentially be optimized in subsequent iterations. The longer half-life of Ligand B is a plus, but can also be addressed through prodrug strategies or structural modifications.

Output:
0
2025-04-17 07:23:45,439 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B based on the provided guidelines, prioritizing GPCR-specific properties (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (372.491 Da and 378.519 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (115.97) is better than Ligand B (51.66). For CNS targets, we want TPSA <= 90, and Ligand B is significantly lower, which is favorable for brain penetration.

**logP:** Ligand A (-1.233) is too low, potentially hindering permeation. Ligand B (3.763) is within the optimal 1-3 range. This is a significant advantage for Ligand B.

**H-Bond Donors/Acceptors:** Ligand A has 3 HBD and 6 HBA, while Ligand B has 0 HBD and 6 HBA. Both are within acceptable limits.

**QED:** Ligand B (0.813) has a higher QED score than Ligand A (0.515), indicating better overall drug-likeness.

**DILI:** Ligand A (11.283) has a much lower DILI risk than Ligand B (66.615). This is a substantial advantage for Ligand A.

**BBB:** Ligand B (85.77) has a significantly higher BBB penetration percentile than Ligand A (14.541). This is critical for a CNS target like DRD2.

**Caco-2 Permeability:** Ligand A (-5.978) has poor Caco-2 permeability, while Ligand B (-4.831) is slightly better, but still not great.

**Aqueous Solubility:** Ligand A (-0.806) has slightly better solubility than Ligand B (-3.696).

**hERG:** Ligand A (0.07) shows very low hERG inhibition risk, while Ligand B (0.326) is slightly higher.

**Microsomal Clearance:** Ligand A (-11.696) has a lower (better) microsomal clearance than Ligand B (64.932), suggesting greater metabolic stability.

**In vitro Half-Life:** Ligand A (-7.902) has a longer half-life than Ligand B (4.935).

**P-gp Efflux:** Ligand A (0.007) has very low P-gp efflux, which is excellent for CNS penetration. Ligand B (0.442) has moderate P-gp efflux.

**Binding Affinity:** Ligand B (-8.8 kcal/mol) has a significantly stronger binding affinity than Ligand A (-0.0 kcal/mol). This is a major advantage for Ligand B, potentially outweighing some of its ADME drawbacks.

**Overall Assessment:**

Ligand B excels in binding affinity and BBB penetration, which are paramount for a CNS-targeting GPCR. While its DILI risk and Caco-2 permeability are concerns, the strong binding affinity could allow for a lower dose, potentially mitigating the DILI risk. The moderate P-gp efflux is manageable. Ligand A has better safety profiles (DILI, hERG, P-gp) and metabolic stability, but its weak binding affinity and poor BBB penetration make it a less promising candidate.

Output:
1
2025-04-17 07:23:45,439 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (348.443 and 355.385 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (87.66) is better than Ligand B (62.74). Both are below the 90 A^2 threshold desirable for CNS targets.

**logP:** Ligand A (2.284) and Ligand B (1.731) are both within the optimal 1-3 range.

**H-Bond Donors:** Ligand A has 3 HBD, which is acceptable. Ligand B has 0 HBD, also acceptable.

**H-Bond Acceptors:** Both ligands have 4 HBA, which is within the acceptable limit of <=10.

**QED:** Both ligands have QED values above 0.6, indicating good drug-likeness. Ligand B (0.713) is slightly better than Ligand A (0.629).

**DILI:** Both ligands have low DILI risk (Ligand A: 30.787, Ligand B: 34.936), well below the 40 threshold.

**BBB:** This is a critical parameter for a CNS target like DRD2. Ligand B (96.355) significantly outperforms Ligand A (52.656) in BBB penetration. This is a major advantage for Ligand B.

**Caco-2 Permeability:** Ligand A (-5.017) and Ligand B (-4.123) both have negative values, indicating poor permeability.

**Aqueous Solubility:** Ligand A (-3.04) and Ligand B (-1.541) both have negative values, indicating poor solubility.

**hERG Inhibition:** Both ligands show very low hERG inhibition risk (Ligand A: 0.282, Ligand B: 0.253).

**Microsomal Clearance:** Ligand B (20.737) has a lower microsomal clearance than Ligand A (46.067), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand B (-5.64) has a longer in vitro half-life than Ligand A (-22.048).

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (Ligand A: 0.046, Ligand B: 0.039).

**Binding Affinity:** Both ligands have similar binding affinities (Ligand A: -8.5 kcal/mol, Ligand B: -8.3 kcal/mol). The difference is small and unlikely to be decisive.

**Conclusion:**

While Ligand A has a slightly higher TPSA, Ligand B is superior in almost all other critical parameters for a CNS-targeting GPCR ligand. Specifically, its significantly higher BBB penetration (96.355 vs. 52.656), lower microsomal clearance, and longer half-life make it a much more promising candidate. The binding affinity difference is negligible.

Output:
1
2025-04-17 07:23:45,439 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (333.435 Da) is slightly lower, which could be beneficial for permeability. Ligand B (364.471 Da) is also acceptable.

**TPSA:** Ligand A (56.13) is excellent, well below the 90 A^2 threshold for CNS targets. Ligand B (91.4) is higher, but still potentially acceptable, though less ideal for brain penetration.

**logP:** Ligand A (3.55) is at the upper end of the optimal range (1-3), potentially leading to some solubility issues. Ligand B (0.946) is below the optimal range and could have permeability issues.

**H-Bond Donors/Acceptors:** Ligand A (HBD=1, HBA=3) is good. Ligand B (HBD=2, HBA=5) is also acceptable.

**QED:** Both ligands have similar QED values (A: 0.843, B: 0.761), indicating good drug-like properties.

**DILI:** Ligand A (34.161) has a lower DILI risk than Ligand B (49.011), which is a positive attribute.

**BBB:** Ligand A (83.521) has a significantly higher BBB penetration percentile than Ligand B (41.722). This is *critical* for a CNS target like DRD2.

**Caco-2 Permeability:** Ligand A (-4.612) has a negative Caco-2 value, indicating poor permeability. Ligand B (-5.232) is also poor.

**Aqueous Solubility:** Ligand A (-4.326) and Ligand B (-2.88) both have poor aqueous solubility.

**hERG Inhibition:** Both ligands have low hERG inhibition liability (A: 0.892, B: 0.296), which is good.

**Microsomal Clearance:** Ligand A (34.367) has a higher microsomal clearance than Ligand B (13.485), suggesting lower metabolic stability.

**In vitro Half-Life:** Ligand A (38.796) has a longer half-life than Ligand B (18.067).

**P-gp Efflux:** Ligand A (0.226) has lower P-gp efflux liability than Ligand B (0.051), which is favorable for CNS penetration.

**Binding Affinity:** Ligand A (-9.2 kcal/mol) has a *much* stronger binding affinity than Ligand B (-7.9 kcal/mol). This is a substantial difference, exceeding the 1.5 kcal/mol advantage threshold.

**Overall Assessment:**

Ligand A is the superior candidate despite its poor Caco-2 and solubility. The significantly stronger binding affinity (-9.2 vs -7.9 kcal/mol) and much better BBB penetration (83.521 vs 41.722) outweigh the drawbacks. While the logP is slightly high, the strong affinity suggests it can still bind effectively. The lower DILI risk and better P-gp efflux are also beneficial. Ligand B's low logP and poor BBB penetration are major concerns for a CNS target.

Output:
1
2025-04-17 07:23:45,440 - INFO - Batch 361 complete. Total preferences: 5776
2025-04-17 07:23:45,440 - INFO - Processing batch 362/512...
2025-04-17 07:24:26,050 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B based on the provided guidelines, prioritizing GPCR-specific properties (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (358.435 and 344.459 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (85.38) is slightly above the optimal <90 for CNS targets, but still reasonable. Ligand B (78.09) is excellent, well below 90.

**logP:** Ligand A (1.075) is at the lower end of the optimal 1-3 range, potentially impacting permeability. Ligand B (2.265) is well within the optimal range.

**H-Bond Donors/Acceptors:** Ligand A has 0 HBD and 7 HBA, which is good. Ligand B has 2 HBD and 3 HBA, also acceptable.

**QED:** Both ligands have good QED scores (0.657 and 0.86), indicating drug-like properties.

**DILI:** Both ligands have low DILI risk (41.024 and 30.826), which is favorable.

**BBB:** Both ligands have excellent BBB penetration (79.992 and 75.572), which is crucial for a CNS target like DRD2.

**Caco-2 Permeability:** Ligand A (-3.951) has poor Caco-2 permeability, suggesting poor intestinal absorption. Ligand B (-5.226) is also poor, but slightly worse than Ligand A.

**Aqueous Solubility:** Both ligands have poor aqueous solubility (-1.811 and -3.321). This could pose formulation challenges.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.319 and 0.672), which is good.

**Microsomal Clearance:** Ligand A (84.934) has higher microsomal clearance than Ligand B (30.405), indicating lower metabolic stability.

**In vitro Half-Life:** Ligand B (-23.782) has a longer in vitro half-life than Ligand A (-32.778), which is favorable.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.117 and 0.137), which is good for CNS exposure.

**Binding Affinity:** Ligand B (-8.7 kcal/mol) has significantly stronger binding affinity than Ligand A (-6.1 kcal/mol). This >1.5 kcal/mol difference is a major advantage, potentially outweighing some ADME drawbacks.

**Overall Assessment:**

Ligand B is the better candidate. While both have poor solubility and Caco-2 permeability, Ligand B's superior binding affinity, better logP, lower microsomal clearance, and longer half-life make it more promising. The slightly better TPSA of Ligand B is also a plus. The strong affinity of Ligand B is a critical advantage for a GPCR target, and the acceptable BBB penetration of both compounds supports CNS activity.

Output:
1
2025-04-17 07:24:26,050 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (368.543 and 363.355 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (58.64) is significantly better than Ligand B (65.2). Both are below the 90 A^2 threshold for CNS targets, but A is closer to the optimal range.

**3. logP:** Both ligands have similar logP values (2.464 and 2.446), falling within the optimal 1-3 range.

**4. H-Bond Donors:** Ligand A (1) is preferable to Ligand B (2). Lower HBD generally improves permeability.

**5. H-Bond Acceptors:** Ligand A (4) is preferable to Ligand B (2). Lower HBA generally improves permeability.

**6. QED:** Both ligands have good QED scores (0.635 and 0.763), indicating drug-like properties.

**7. DILI:** Ligand A (17.759) has a much lower DILI risk than Ligand B (47.964). This is a significant advantage for Ligand A.

**8. BBB:** Both ligands have excellent BBB penetration (71.035 and 72.315), exceeding the desirable threshold of 70 for CNS targets.

**9. Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and suggests a potential issue with the data or modeling. However, the values are similar (-4.837 and -4.785).

**10. Aqueous Solubility:** Both have negative solubility values, which is also unusual. Again, the values are similar (-2.848 and -3.317).

**11. hERG Inhibition:** Ligand A (0.357) has a lower hERG inhibition liability than Ligand B (0.672), reducing the risk of cardiotoxicity.

**12. Microsomal Clearance:** Ligand A (68.139) has a higher (worse) microsomal clearance than Ligand B (22.389). This suggests Ligand B is more metabolically stable.

**13. In vitro Half-Life:** Ligand B (-36.181) has a much longer in vitro half-life than Ligand A (-4.875). This is a significant advantage for Ligand B.

**14. P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.104 and 0.112), which is good for CNS exposure.

**15. Binding Affinity:** Ligand B (-8.6 kcal/mol) has a significantly stronger binding affinity than Ligand A (-7.0 kcal/mol). This >1.5 kcal/mol difference is a major advantage, potentially outweighing some ADME drawbacks.

**Overall Assessment:**

While Ligand A excels in DILI risk, TPSA, and hERG inhibition, Ligand B's superior binding affinity and significantly improved metabolic stability (lower Cl_mic, longer t1/2) are crucial for a GPCR drug candidate. The similar BBB and P-gp values are positive for both. The unusual negative values for Caco-2 and solubility are concerning but similar between the two, so don't differentiate them. The strong affinity of Ligand B is likely to be more impactful than the slightly better ADME profile of Ligand A, especially for a CNS target where achieving sufficient brain exposure is paramount.

Output:
1
2025-04-17 07:24:26,050 - INFO - Reasoning:

Let's analyze Ligand A and Ligand B against the provided guidelines, prioritizing GPCR-specific properties (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (341.411 and 354.491 Da) fall within the ideal 200-500 Da range.

**TPSA:** Both ligands (83.36 and 87.66) are below the 90 A^2 threshold for CNS targets, which is excellent.

**logP:** Both ligands (1.321 and 1.469) are within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Both have 3 HBD and 4 HBA, meeting the <5 and <10 criteria, respectively.

**QED:** Ligand A (0.767) has a significantly better QED score than Ligand B (0.554), indicating a more drug-like profile.

**DILI:** Ligand A (38.154) has a slightly higher DILI risk than Ligand B (10.237), but both are below the concerning threshold of 60.

**BBB:** This is crucial for a CNS target like DRD2. Ligand A (65.374) has a considerably better BBB penetration percentile than Ligand B (57.736). This is a major advantage for Ligand A.

**Caco-2 Permeability:** Both have negative Caco-2 values (-4.823 and -4.716), which is unusual and suggests poor permeability. However, these values are on a scale where negative values are possible, and direct comparison is difficult without knowing the scale's specifics.

**Aqueous Solubility:** Both have negative solubility values (-2.353 and -2.06), again indicating poor solubility. Similar to Caco-2, the scale is unclear.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.198 and 0.328).

**Microsomal Clearance:** Ligand A (-16.514) has significantly lower (better) microsomal clearance than Ligand B (42.626), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (16.922 hours) has a much longer half-life than Ligand B (4.856 hours).

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.07 and 0.086), which is favorable for CNS penetration.

**Binding Affinity:** Ligand A (-9.4 kcal/mol) has a slightly better binding affinity than Ligand B (-8.1 kcal/mol). While both are strong binders, the 1.3 kcal/mol difference is significant.

**Overall Assessment:**

Ligand A is the superior candidate. It boasts a better QED score, significantly improved BBB penetration, lower microsomal clearance (better metabolic stability), a longer half-life, and slightly stronger binding affinity. While both have issues with Caco-2 and solubility, the improvements in CNS-relevant properties and overall drug-likeness of Ligand A outweigh these concerns. The affinity difference, combined with the better ADME properties, makes Ligand A the more promising drug candidate.

Output:
1
2025-04-17 07:24:26,051 - INFO - Reasoning:

Let's analyze Ligand A and Ligand B for their potential as DRD2 drug candidates, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (349.381 and 350.415 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (68.06) is excellent, well below the 90 A^2 threshold for CNS targets. Ligand B (96.89) is higher, but still potentially acceptable, though less ideal.

**3. logP:** Ligand A (4.448) is slightly high, potentially leading to solubility issues or off-target interactions. Ligand B (0.392) is quite low, which could hinder membrane permeability and CNS penetration.

**4. H-Bond Donors:** Ligand A (1) is good. Ligand B (3) is acceptable, but higher.

**5. H-Bond Acceptors:** Ligand A (4) is good. Ligand B (5) is acceptable.

**6. QED:** Both ligands have reasonable QED values (0.475 and 0.599), indicating acceptable drug-likeness. Ligand B is slightly better.

**7. DILI:** Ligand A (53.432) has a moderate DILI risk. Ligand B (18.108) has a very low DILI risk, a significant advantage.

**8. BBB:** Ligand A (91.276) has excellent BBB penetration potential. Ligand B (55.332) is considerably lower, which is a major drawback for a CNS target like DRD2.

**9. Caco-2 Permeability:** Both have negative values, which is unusual. Assuming these are percentile scores, Ligand A (-4.932) is worse than Ligand B (-5.018).

**10. Aqueous Solubility:** Both have negative values, which is unusual. Assuming these are percentile scores, Ligand A (-4.395) is better than Ligand B (-1.651).

**11. hERG Inhibition:** Both have low hERG inhibition risk (0.919 and 0.129). Ligand B is better.

**12. Microsomal Clearance:** Ligand A (23.202) has moderate clearance. Ligand B (11.881) has lower clearance, suggesting better metabolic stability.

**13. In vitro Half-Life:** Ligand A (33.688) has a reasonable half-life. Ligand B (-5.468) has a negative half-life, which is not possible and indicates a potential data error.

**14. P-gp Efflux:** Ligand A (0.459) has low P-gp efflux, which is good. Ligand B (0.02) has very low P-gp efflux, even better.

**15. Binding Affinity:** Ligand A (-9.9 kcal/mol) has significantly stronger binding affinity than Ligand B (-8.5 kcal/mol). This is a substantial advantage, potentially outweighing some of its ADME drawbacks.

**Overall Assessment:**

Ligand A excels in binding affinity and BBB penetration, crucial for a CNS GPCR target. Its logP is a bit high, and DILI risk is moderate. Ligand B has better ADME properties (lower DILI, better metabolic stability, lower P-gp efflux), but its significantly weaker binding affinity and poor BBB penetration are major concerns. The difference in binding affinity (1.4 kcal/mol) is substantial. Given the importance of strong binding for GPCRs, and the relatively manageable ADME issues with Ligand A, it is the more promising candidate.

Output:
1
2025-04-17 07:24:26,051 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (387.615 Da) is slightly higher than Ligand B (358.427 Da), but both are acceptable.

**TPSA:** Ligand A (52.65) is significantly better than Ligand B (92.49). For CNS targets, we want TPSA <= 90, so Ligand A is much more favorable.

**logP:** Both ligands have good logP values (A: 2.122, B: 1.354), falling within the optimal range of 1-3.

**H-Bond Donors/Acceptors:** Both have acceptable HBD (1) and HBA (A: 5, B: 7) counts, well below the thresholds of 5 and 10, respectively.

**QED:** Both ligands have reasonable QED values (A: 0.757, B: 0.688), indicating good drug-like properties.

**DILI:** Both ligands have relatively high DILI risk (A: 28.112, B: 74.99). Ligand A is significantly better here, being well below the 40% threshold. Ligand B is quite high, suggesting potential liver toxicity.

**BBB:** Ligand A (64.482) has a better BBB percentile than Ligand B (55.603). While ideally >70 for CNS targets, Ligand A is closer.

**Caco-2 Permeability:** Both have negative Caco-2 values (-5.103 and -5.754), which is unusual and suggests poor permeability. However, these values are on a log scale and may not be directly comparable without knowing the units.

**Aqueous Solubility:** Both have very poor aqueous solubility (-3.533 and -1.976). This is a concern for bioavailability.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (A: 0.359, B: 0.224).

**Microsomal Clearance:** Ligand A (74.383) has higher microsomal clearance than Ligand B (55.048), indicating lower metabolic stability.

**In vitro Half-Life:** Ligand B (22.735 hours) has a significantly longer half-life than Ligand A (3.153 hours). This is a major advantage for Ligand B.

**P-gp Efflux:** Both have low P-gp efflux liability (A: 0.072, B: 0.045), which is good for CNS penetration.

**Binding Affinity:** Ligand B (-8.4 kcal/mol) has a significantly stronger binding affinity than Ligand A (-6.2 kcal/mol). This is a substantial advantage, potentially outweighing some of the ADME drawbacks.

**Overall Assessment:**

Ligand A excels in TPSA and DILI risk, and has a moderately better BBB score. However, it suffers from higher microsomal clearance and a significantly weaker binding affinity. Ligand B has a much stronger binding affinity and a longer half-life, but its TPSA is too high, and its DILI risk is concerning.

Given the GPCR-specific priorities, and the substantial affinity advantage of Ligand B, I would favor Ligand B *despite* its higher TPSA and DILI risk. The strong binding affinity is a critical factor, and optimization efforts could focus on reducing the TPSA and DILI risk while maintaining the potent binding. The longer half-life is also a significant benefit.

Output:
1
2025-04-17 07:24:26,051 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (345.4) is slightly lower, which could be beneficial for permeability.

**TPSA:** Ligand A (93.5) is better than Ligand B (49.4). For CNS targets, TPSA should be <=90, so Ligand A is borderline acceptable, while Ligand B is well within the desired range.

**logP:** Both ligands have good logP values (A: 1.87, B: 2.67), falling within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A has 2 HBD and 5 HBA, while Ligand B has 1 HBD and 3 HBA. Both are within acceptable limits (<=5 HBD and <=10 HBA).

**QED:** Both ligands have good QED scores (A: 0.76, B: 0.84), indicating good drug-like properties.

**DILI:** Ligand A has a DILI risk of 56.3, considered moderate. Ligand B has a much lower DILI risk of 17.2, which is a significant advantage.

**BBB:** Ligand B (75.8%) has a significantly better BBB penetration score than Ligand A (56.5%). This is a critical factor for a CNS target like DRD2.

**Caco-2 Permeability:** Ligand A (-4.86) has a worse Caco-2 permeability than Ligand B (-5.11). Lower values indicate lower permeability.

**Aqueous Solubility:** Ligand A (-2.31) has better aqueous solubility than Ligand B (-3.71).

**hERG:** Both ligands have low hERG inhibition liability (A: 0.33, B: 0.46), which is good.

**Microsomal Clearance:** Ligand B (67.2) has a higher microsomal clearance than Ligand A (34.5), suggesting Ligand A is more metabolically stable.

**In vitro Half-Life:** Ligand A (36.9) has a longer in vitro half-life than Ligand B (4.0), which is desirable.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (A: 0.045, B: 0.083), which is favorable for CNS penetration.

**Binding Affinity:** Both ligands have excellent binding affinity (A: -8.6, B: -8.8). Ligand B is slightly better, but the difference is small.

**Overall Assessment:**

While Ligand A has better solubility and metabolic stability, Ligand B excels in the most critical areas for a CNS-targeting GPCR: BBB penetration and lower DILI risk. The slightly better binding affinity of Ligand B, combined with its superior BBB score, outweighs the advantages of Ligand A. The lower DILI risk is also a significant factor.

Output:
1
2025-04-17 07:24:26,051 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (352.381 and 344.415 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (72.2) is excellent, well below the 90 A^2 threshold for CNS targets. Ligand B (91.23) is slightly higher, but still acceptable, though less optimal for CNS penetration.

**3. logP:** Ligand A (4.359) is a bit high, potentially leading to solubility issues or off-target interactions. Ligand B (2.215) is within the optimal 1-3 range.

**4. H-Bond Donors:** Ligand A (1) and Ligand B (2) are both within the acceptable limit of <=5.

**5. H-Bond Acceptors:** Both ligands (A: 4, B: 4) are well below the 10 limit.

**6. QED:** Both ligands have good QED values (A: 0.838, B: 0.87), indicating drug-like properties.

**7. DILI:** Ligand A (70.686) has a higher DILI risk than Ligand B (60.644), but both are reasonably acceptable.

**8. BBB:** This is crucial for a CNS target like DRD2. Ligand A (89.027) has a significantly better BBB penetration percentile than Ligand B (61.962).

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 values which is unusual and suggests poor permeability.

**10. Aqueous Solubility:** Both ligands have negative solubility values which is also unusual and suggests poor solubility.

**11. hERG Inhibition:** Ligand A (0.643) has a slightly higher hERG risk than Ligand B (0.186), which is preferable.

**12. Microsomal Clearance:** Ligand A (57.746) has a higher clearance than Ligand B (19.764), indicating lower metabolic stability.

**13. In vitro Half-Life:** Ligand A (59.281) has a longer half-life than Ligand B (23.79), which is desirable.

**14. P-gp Efflux:** Ligand A (0.61) shows less P-gp efflux than Ligand B (0.096), which is beneficial for CNS exposure.

**15. Binding Affinity:** Both ligands have excellent binding affinities (A: -8.9 kcal/mol, B: -9.0 kcal/mol). The difference is negligible.

**Overall Assessment:**

While Ligand B has better logP and hERG values, Ligand A is superior due to its significantly better BBB penetration, lower P-gp efflux, and longer half-life. The slightly higher logP and DILI risk of Ligand A are less concerning given the strong binding affinity and crucial CNS properties. The negative Caco-2 and solubility values are concerning for both, but can be addressed with formulation strategies.

Output:
1
2025-04-17 07:24:26,051 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (353.413 and 341.415 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (52.65) is significantly better than Ligand B (71.33). For CNS targets, we want TPSA <= 90, and ideally closer to 60. Ligand A is much closer to this ideal.

**3. logP:** Ligand A (2.677) is within the optimal 1-3 range. Ligand B (0.963) is slightly below 1, potentially hindering permeation.

**4. H-Bond Donors:** Ligand A (1) is good. Ligand B (0) is also acceptable.

**5. H-Bond Acceptors:** Ligand A (2) is good. Ligand B (5) is acceptable, but higher HBA can sometimes impact permeability.

**6. QED:** Ligand A (0.905) is excellent, indicating high drug-likeness. Ligand B (0.571) is acceptable, but lower.

**7. DILI:** Both ligands have similar, and good, DILI risk (47.305 and 46.995 percentile).

**8. BBB:** Ligand A (86.157) is significantly better than Ligand B (63.94). A BBB percentile >70 is desirable for CNS targets, and Ligand A is much closer to this threshold. This is a crucial factor for DRD2.

**9. Caco-2 Permeability:** Both have negative values, which is unusual and likely indicates a scaling issue. However, the magnitude of the negative value is similar, so we can't draw strong conclusions here.

**10. Aqueous Solubility:** Both ligands have negative solubility values, again likely a scaling issue. Similar magnitudes, so not a major differentiator.

**11. hERG:** Ligand A (0.738) is better than Ligand B (0.042), indicating lower cardiotoxicity risk.

**12. Microsomal Clearance:** Ligand A (8.701) has much lower clearance than Ligand B (20.949), suggesting better metabolic stability.

**13. In vitro Half-Life:** Ligand A (1.235) has a very short half-life, while Ligand B (-16.779) is problematic. A negative half-life is not physically possible and suggests a data error.

**14. P-gp Efflux:** Ligand A (0.127) has lower P-gp efflux than Ligand B (0.04), which is favorable for CNS penetration.

**15. Binding Affinity:** Ligand A (-9.3 kcal/mol) has a significantly stronger binding affinity than Ligand B (-7.5 kcal/mol). This is a substantial advantage (>1.5 kcal/mol difference).

**Overall Assessment:**

Ligand A is clearly superior. It has better TPSA, logP, BBB penetration, hERG risk, metabolic stability, P-gp efflux, and *significantly* better binding affinity. While Ligand B has a slightly better HBD count, the advantages of Ligand A outweigh this minor difference. The negative half-life for Ligand B is a major red flag. Given the GPCR target and the need for CNS penetration, Ligand A is the much more promising candidate.

Output:
1
2025-04-17 07:24:26,051 - INFO - Reasoning:

Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (376.375 and 349.431 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (59.06) is excellent, well below the 90 A^2 threshold for CNS targets. Ligand B (79.9) is still reasonable but less optimal, approaching the 90 A^2 limit.

**3. logP:** Both ligands have good logP values (3.241 and 2.096), falling within the 1-3 range. Ligand A is slightly better.

**4. H-Bond Donors:** Both have acceptable HBD counts (1 and 2, respectively), well below the 5 threshold.

**5. H-Bond Acceptors:** Both have acceptable HBA counts (4 each), below the 10 threshold.

**6. QED:** Both ligands have similar and good QED values (0.814 and 0.79), indicating good drug-like properties.

**7. DILI:** Ligand A (52.772) has a slightly better DILI score than Ligand B (47.77), both are good.

**8. BBB:** Both ligands have excellent BBB penetration (75.843 and 71.384), exceeding the desirable >70 threshold for CNS targets.

**9. Caco-2 Permeability:** Both have negative Caco-2 values (-4.894 and -4.781), which is unusual and likely indicates poor permeability. This is a significant concern.

**10. Aqueous Solubility:** Both have negative solubility values (-3.907 and -2.063), also unusual and concerning.

**11. hERG Inhibition:** Both ligands show low hERG inhibition risk (0.782 and 0.34), which is positive.

**12. Microsomal Clearance:** Ligand B (4.354) has significantly lower microsomal clearance than Ligand A (15.275), suggesting better metabolic stability.

**13. In vitro Half-Life:** Ligand A (54.884) has a longer in vitro half-life than Ligand B (39.91), which is favorable.

**14. P-gp Efflux:** Both ligands show low P-gp efflux liability (0.597 and 0.009), which is good for CNS penetration. Ligand B is better.

**15. Binding Affinity:** Ligand B (-7.6 kcal/mol) has a significantly stronger binding affinity than Ligand A (-9.0 kcal/mol). This is a substantial advantage.

**Overall Assessment:**

While both compounds have good BBB penetration and acceptable ADME properties, Ligand B stands out due to its significantly stronger binding affinity (-7.6 vs -9.0 kcal/mol). The lower microsomal clearance of Ligand B is also a plus. The negative Caco-2 and solubility values are concerning for both, but the strong affinity of Ligand B might overcome these issues with appropriate formulation strategies. The slightly better DILI score of Ligand A is not enough to offset the affinity difference.

Output:
1
2025-04-17 07:24:26,051 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (348.487 and 365.769 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (53.01) is excellent, well below the 90 A^2 threshold for CNS targets. Ligand B (94.95) is higher, but still potentially acceptable, though less ideal.

**3. logP:** Both ligands (2.388 and 2.568) are within the optimal 1-3 range.

**4. H-Bond Donors:** Both have 1 HBD, which is good.

**5. H-Bond Acceptors:** Ligand A has 4 HBA, and Ligand B has 7. Both are acceptable, but Ligand A is slightly better.

**6. QED:** Both ligands have similar QED values (0.858 and 0.813), indicating good drug-likeness.

**7. DILI:** Ligand A (11.322) has a significantly lower DILI risk than Ligand B (82.241). This is a major advantage for Ligand A.

**8. BBB:** Both ligands have good BBB penetration (63.784 and 66.576), but neither exceeds the desirable >70% threshold.

**9. Caco-2 Permeability:** Both have negative Caco-2 values (-4.256 and -4.165), which is unusual and suggests poor permeability. This is a concern for both.

**10. Aqueous Solubility:** Ligand A (-1.458) has better solubility than Ligand B (-5.128).

**11. hERG Inhibition:** Both ligands have low hERG inhibition liability (0.838 and 0.278), which is good.

**12. Microsomal Clearance:** Ligand A (39.418) has lower microsomal clearance than Ligand B (76.635), indicating better metabolic stability.

**13. In vitro Half-Life:** Ligand A (16.224) has a longer half-life than Ligand B (1.388).

**14. P-gp Efflux:** Ligand A (0.27) has lower P-gp efflux than Ligand B (0.153), which is favorable for CNS penetration.

**15. Binding Affinity:** Both ligands have very similar and strong binding affinities (-8.4 and -8.0 kcal/mol). The difference is less than 1.5 kcal/mol, so it's not a decisive factor.

**Overall Assessment:**

Ligand A is significantly better due to its lower DILI risk, better solubility, lower microsomal clearance, longer half-life, and lower P-gp efflux. While both have similar affinities and BBB penetration, the improved ADME properties of Ligand A make it a more promising drug candidate. The negative Caco-2 values are concerning for both, but the other advantages of Ligand A outweigh this drawback.

Output:
1
2025-04-17 07:24:26,052 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (346.475 and 385.823 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (68.18) is better than Ligand B (63.99). Both are below the 90 A^2 threshold for CNS targets, which is excellent.

**3. logP:** Ligand A (4.19) is slightly higher than Ligand B (3.026). While both are within the 1-3 range, Ligand A is pushing the upper limit and could potentially have solubility issues.

**4. H-Bond Donors:** Ligand A (2) is slightly higher than Ligand B (1), but both are within the acceptable limit of 5.

**5. H-Bond Acceptors:** Ligand A (5) is slightly higher than Ligand B (4), and both are within the acceptable limit of 10.

**6. QED:** Both ligands have similar QED values (0.823 and 0.734), both above the 0.5 threshold, indicating good drug-like properties.

**7. DILI:** Ligand A (42.846) has a lower DILI risk than Ligand B (82.59). This is a significant advantage for Ligand A.

**8. BBB:** Ligand A (81.698) has a considerably higher BBB penetration percentile than Ligand B (66.227). This is *critical* for a CNS target like DRD2.

**9. Caco-2 Permeability:** Both have negative Caco-2 values, indicating poor permeability. Ligand A (-4.633) is slightly worse than Ligand B (-4.748).

**10. Aqueous Solubility:** Both have negative solubility values, indicating poor solubility. Ligand A (-4.436) is slightly better than Ligand B (-4.237).

**11. hERG Inhibition:** Both ligands have low hERG inhibition risk (0.922 and 0.753).

**12. Microsomal Clearance:** Ligand A (93.74) has higher microsomal clearance than Ligand B (48.896), indicating lower metabolic stability. This is a disadvantage for Ligand A.

**13. In vitro Half-Life:** Ligand A (46.237) has a slightly longer half-life than Ligand B (43.783).

**14. P-gp Efflux:** Ligand A (0.328) has lower P-gp efflux than Ligand B (0.605), which is favorable for CNS penetration.

**15. Binding Affinity:** Ligand B (-9.2 kcal/mol) has a significantly stronger binding affinity than Ligand A (-8.1 kcal/mol). This is a substantial advantage for Ligand B, exceeding the 1.5 kcal/mol difference threshold.

**Overall Assessment:**

While Ligand A has advantages in BBB penetration, DILI risk, and P-gp efflux, the significantly stronger binding affinity of Ligand B (-9.2 vs -8.1 kcal/mol) outweighs these benefits, particularly for a GPCR target. The higher BBB of Ligand A is good, but the difference isn't substantial enough to overcome the potency difference. The metabolic stability of Ligand B is also better.

Output:
1
2025-04-17 07:24:26,052 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (341.5 and 349.4 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (53.16) is excellent, well below the 90 A^2 threshold for CNS targets. Ligand B (89.24) is higher, but still acceptable, though less favorable.

**logP:** Ligand A (3.262) is optimal (1-3). Ligand B (0.161) is significantly low, potentially hindering membrane permeability and CNS penetration.

**H-Bond Donors/Acceptors:** Ligand A (3 HBD, 3 HBA) is well within acceptable limits. Ligand B (0 HBD, 6 HBA) is also acceptable, but the lack of HBDs could impact solubility.

**QED:** Ligand A (0.791) has a strong drug-like profile. Ligand B (0.387) is considerably lower, indicating a less favorable overall drug-likeness.

**DILI:** Ligand A (23.6%) has a very low DILI risk. Ligand B (19.0%) is also low, but slightly higher.

**BBB:** Ligand A (80.6%) shows excellent BBB penetration potential, exceeding the 70% threshold. Ligand B (55.1%) is considerably lower, raising concerns about CNS exposure.

**Caco-2 Permeability:** Ligand A (-5.307) is a negative value, which is unusual and suggests very poor permeability. Ligand B (-4.743) is also poor, but slightly better.

**Aqueous Solubility:** Both ligands have very poor aqueous solubility (-2.192 and -0.629 respectively). This could pose formulation challenges.

**hERG Inhibition:** Both ligands show low hERG inhibition risk (0.785 and 0.643).

**Microsomal Clearance:** Ligand A (-28.973) has a very low (and negative) microsomal clearance, suggesting high metabolic stability. Ligand B (-13.831) is also relatively low, but higher than A.

**In vitro Half-Life:** Ligand A (28.833 hours) has a good in vitro half-life. Ligand B (-0.648 hours) has a very short half-life, which is a major drawback.

**P-gp Efflux:** Both ligands show low P-gp efflux liability (0.232 and 0.034).

**Binding Affinity:** Ligand A (-10.4 kcal/mol) has significantly stronger binding affinity than Ligand B (-6.5 kcal/mol). The difference of 3.9 kcal/mol is substantial and can outweigh many other ADME drawbacks.

**Overall Assessment:**

Ligand A is superior due to its excellent BBB penetration, strong binding affinity, favorable QED, low DILI risk, and high metabolic stability. While its solubility and Caco-2 permeability are poor, the strong affinity and BBB penetration are crucial for a CNS GPCR target like DRD2. Ligand B suffers from a low logP, poor BBB penetration, very short half-life, and significantly weaker binding affinity, making it a less promising candidate despite its acceptable DILI and P-gp efflux.

Output:
1
2025-04-17 07:24:26,052 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (346.471) is slightly better positioned.

**TPSA:** Ligand A (53.01) is significantly better than Ligand B (40.54). For CNS targets, we want TPSA <= 90, and lower is preferable. Ligand A is much closer to the ideal range for CNS penetration.

**logP:** Both ligands have acceptable logP values (Ligand A: 2.677, Ligand B: 4.493). Ligand A is better, as Ligand B is approaching the upper limit where solubility issues can arise.

**H-Bond Donors/Acceptors:** Both have reasonable HBD (1) and HBA (4/5) counts, falling within acceptable limits.

**QED:** Ligand A (0.914) has a significantly better QED score than Ligand B (0.686), indicating a more drug-like profile.

**DILI:** Ligand A (23.536) has a much lower DILI risk than Ligand B (42.187), which is a significant advantage.

**BBB:** Ligand A (86.468) has a substantially better BBB percentile than Ligand B (76.541). This is *critical* for a CNS target like DRD2.

**Caco-2 Permeability:** Ligand A (-4.279) has a worse Caco-2 permeability than Ligand B (-5.282). However, this is less critical than BBB for CNS targets.

**Aqueous Solubility:** Ligand A (-2.293) has a better solubility than Ligand B (-4.841).

**hERG:** Both ligands have low hERG inhibition liability (0.849 and 0.772, respectively), which is good.

**Microsomal Clearance:** Ligand A (2.4) has a much lower microsomal clearance than Ligand B (70.429), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (35.391) has a much longer in vitro half-life than Ligand B (14.963), which is desirable.

**P-gp Efflux:** Ligand A (0.399) has a lower P-gp efflux liability than Ligand B (0.846), which is beneficial for CNS penetration.

**Binding Affinity:** Ligand B (-7.3) has a slightly better binding affinity than Ligand A (-8.0). However, the difference is not substantial enough to outweigh the significant ADME advantages of Ligand A.

**Overall:** Ligand A is significantly superior due to its better BBB, lower DILI, lower clearance, longer half-life, lower P-gp efflux, better solubility, and improved QED. While Ligand B has a slightly better binding affinity, the ADME properties of Ligand A make it a much more promising drug candidate for a CNS target like DRD2.

Output:
0
2025-04-17 07:24:26,052 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (372.55 and 379.873 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (49.41) is excellent, well below the 90 A^2 threshold for CNS targets. Ligand B (96.87) is higher, but still potentially acceptable, though less ideal.

**logP:** Ligand A (3.403) is optimal (1-3). Ligand B (2.401) is also within the optimal range, but closer to the lower bound.

**H-Bond Donors/Acceptors:** Ligand A (HBD=1, HBA=3) is favorable. Ligand B (HBD=2, HBA=6) is also acceptable, but has more HBA.

**QED:** Both ligands have good QED scores (0.697 and 0.831), indicating good drug-like properties.

**DILI:** Ligand A (7.29) has a very low DILI risk. Ligand B (83.676) has a significantly higher DILI risk, which is a major concern.

**BBB:** Ligand A (94.998) has excellent BBB penetration, exceeding the desirable >70% threshold. Ligand B (57.193) has poor BBB penetration, which is a significant drawback for a CNS target like DRD2.

**Caco-2 Permeability:** Ligand A (-4.747) and Ligand B (-5.355) both have negative Caco-2 values, which is unusual and suggests poor permeability. However, the scale isn't specified, so it's hard to interpret.

**Aqueous Solubility:** Both ligands have poor aqueous solubility (-3.803 and -3.206 respectively). This could pose formulation challenges.

**hERG:** Ligand A (0.844) has a relatively low hERG risk. Ligand B (0.276) has a very low hERG risk.

**Microsomal Clearance:** Ligand A (61.194) has moderate clearance. Ligand B (1.569) has very low clearance, suggesting high metabolic stability.

**In vitro Half-Life:** Ligand A (-12.931) has a negative half-life, which is not physically possible and indicates an issue with the data. Ligand B (31.397) has a reasonable half-life.

**P-gp Efflux:** Ligand A (0.172) has low P-gp efflux, which is good. Ligand B (0.09) also has low P-gp efflux.

**Binding Affinity:** Ligand B (-8.0 kcal/mol) has a slightly better binding affinity than Ligand A (-7.6 kcal/mol), but the difference is not substantial enough to overcome the other significant drawbacks.

**Overall Assessment:**

Ligand A is significantly better despite the questionable half-life data. Its excellent BBB penetration, low DILI risk, and acceptable TPSA and logP values make it a much more promising candidate for a CNS-targeting drug like a DRD2 ligand. Ligand B's high DILI risk and poor BBB penetration are major liabilities. While its metabolic stability is good and affinity slightly better, these advantages are outweighed by the significant risks. The negative half-life for Ligand A is concerning and would need further investigation, but the other properties are more favorable.

Output:
1
2025-04-17 07:24:26,052 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B based on the provided guidelines, prioritizing GPCR-specific properties (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (346.431 and 358.36 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (67.67) is slightly higher than Ligand B (61.8). Both are below the 90 A^2 threshold desirable for CNS targets, but Ligand B is closer to optimal.

**logP:** Ligand A (0.787) is a bit low, potentially hindering permeation. Ligand B (1.699) is better, falling within the 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A has 0 HBD and 5 HBA, while Ligand B has 2 HBD and 4 HBA. Both are within acceptable limits.

**QED:** Both ligands have good QED scores (0.764 and 0.813), indicating drug-likeness.

**DILI:** Ligand A (34.471) has a slightly higher DILI risk than Ligand B (21.714), but both are below the concerning threshold of 60.

**BBB:** Ligand B (81.698) has a significantly better BBB penetration score than Ligand A (70.105). This is a crucial advantage for a CNS target like DRD2.

**Caco-2 Permeability:** Both have negative Caco-2 values (-4.573 and -4.636). This is unusual and suggests poor permeability. However, the values are very similar.

**Aqueous Solubility:** Ligand A (0.031) has extremely poor solubility, while Ligand B (-2.701) is also very poor, but slightly better.

**hERG Inhibition:** Ligand A (0.275) has a lower hERG risk than Ligand B (0.597), which is preferable.

**Microsomal Clearance:** Ligand A (24.008) has higher microsomal clearance than Ligand B (13.441), indicating lower metabolic stability.

**In vitro Half-Life:** Ligand B (2.315) has a slightly longer half-life than Ligand A (3.447).

**P-gp Efflux:** Ligand A (0.065) has lower P-gp efflux than Ligand B (0.092), which is advantageous for CNS exposure.

**Binding Affinity:** Ligand A (-8.2 kcal/mol) has a significantly stronger binding affinity than Ligand B (-7.3 kcal/mol). This is a substantial advantage, potentially outweighing some of the ADME drawbacks.

**Overall Assessment:**

While Ligand A has superior binding affinity and lower P-gp efflux, Ligand B demonstrates a significantly better BBB score, better logP, and lower DILI risk. The poor solubility and Caco-2 permeability are concerning for both compounds. However, for a CNS target, BBB penetration is paramount. The substantial affinity difference (-0.9 kcal/mol) is significant, but the improved CNS penetration of Ligand B, coupled with its better logP and lower DILI, makes it the more promising candidate.

Output:
1
2025-04-17 07:24:26,052 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (354.363 and 348.487 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (130.84) is slightly above the optimal <90 for CNS targets, but still reasonable. Ligand B (78.43) is excellent, well below 90.

**logP:** Ligand A (-0.549) is a bit low, potentially hindering permeability. Ligand B (1.988) is within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A has 2 HBD and 7 HBA, both acceptable. Ligand B has 3 HBD and 3 HBA, also acceptable.

**QED:** Both ligands have good QED scores (0.628 and 0.528, respectively), indicating drug-like properties.

**DILI:** Ligand A (54.634) has a moderate DILI risk, while Ligand B (11.128) has a very low risk. This is a significant advantage for Ligand B.

**BBB:** Both ligands have reasonable BBB penetration (34.548 and 53.083), but neither exceeds the desirable >70 percentile.

**Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and suggests poor permeability. However, the scale is not specified, so it's hard to interpret.

**Aqueous Solubility:** Both ligands have negative solubility values, indicating poor aqueous solubility. This is a concern for both.

**hERG Inhibition:** Ligand A (0.04) has a very low hERG risk, while Ligand B (0.268) has a slightly higher, but still acceptable, risk.

**Microsomal Clearance:** Both ligands have moderate microsomal clearance (45.343 and 40.518 mL/min/kg), suggesting moderate metabolic stability.

**In vitro Half-Life:** Ligand A (0.986) has a very short half-life, a significant drawback. Ligand B (-6.828) has a negative half-life, which is not physically possible and suggests an issue with the data.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.01 and 0.141), which is favorable for CNS penetration.

**Binding Affinity:** Ligand B (-7.6 kcal/mol) has a slightly better binding affinity than Ligand A (-7.3 kcal/mol), although the difference is small.

**Overall Assessment:**

Ligand B has several advantages: better logP, significantly lower DILI risk, and slightly better binding affinity. However, the negative half-life is a major red flag and suggests a data error. Ligand A has a better half-life but suffers from a low logP and moderate DILI risk. Considering the GPCR-specific priorities, BBB is important, but affinity and safety (DILI, hERG) are crucial. Given the questionable half-life of Ligand B, and the slightly better overall profile of Ligand A despite its drawbacks, I would cautiously favor Ligand A. However, the data for Ligand B needs to be verified.

Output:
0
2025-04-17 07:24:26,052 - INFO - Batch 362 complete. Total preferences: 5792
2025-04-17 07:24:26,052 - INFO - Processing batch 363/512...
2025-04-17 07:25:15,170 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (348.462 and 381.925 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Both ligands have TPSA values (49.41 and 49.77) below the 90 A^2 threshold for CNS targets, which is excellent.

**3. logP:** Ligand A (2.812) is within the optimal 1-3 range. Ligand B (4.664) is slightly above, potentially raising concerns about solubility and off-target effects, but not drastically.

**4. H-Bond Donors:** Both ligands have 1 HBD, which is within the acceptable limit of <=5.

**5. H-Bond Acceptors:** Ligand A has 2 HBA, and Ligand B has 4 HBA, both are within the acceptable limit of <=10.

**6. QED:** Ligand A (0.853) has a better QED score than Ligand B (0.723), indicating a more drug-like profile.

**7. DILI:** Ligand A (28.383) has a significantly lower DILI risk than Ligand B (36.565), which is a major advantage.

**8. BBB:** Ligand A (79.062) has a much better BBB penetration percentile than Ligand B (51.687). This is *critical* for a CNS target like DRD2.

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.743 and -4.9), which is unusual and suggests poor permeability. However, these values are on a strange scale and are difficult to interpret directly without further context.

**10. Aqueous Solubility:** Both ligands have negative solubility values (-4.232 and -4.587), also unusual and suggesting poor solubility. Similar to Caco-2, these values are hard to interpret.

**11. hERG Inhibition:** Both ligands have low hERG inhibition risk (0.59 and 0.854).

**12. Microsomal Clearance:** Ligand A (24.589) has a lower microsomal clearance than Ligand B (110.366), indicating better metabolic stability.

**13. In vitro Half-Life:** Ligand A (6.954) has a shorter in vitro half-life than Ligand B (44.472). This is a drawback for Ligand A.

**14. P-gp Efflux:** Ligand A (0.205) has significantly lower P-gp efflux liability than Ligand B (0.677), which is beneficial for CNS exposure.

**15. Binding Affinity:** Ligand B (-7.3 kcal/mol) has a slightly better binding affinity than Ligand A (-8.6 kcal/mol). While a difference of 0.3 kcal/mol isn't huge, it's a positive for Ligand B.

**Overall Assessment:**

Despite Ligand B's slightly better binding affinity, Ligand A is the more promising candidate. The key advantages of Ligand A are its significantly better BBB penetration, lower DILI risk, lower P-gp efflux, and lower microsomal clearance. These factors are particularly important for a CNS GPCR target. The slightly shorter half-life of Ligand A is a concern, but potentially addressable through structural modifications. The unusual Caco-2 and solubility values for both compounds are concerning and would require further investigation, but the other factors strongly favor Ligand A.

Output:
0
2025-04-17 07:25:15,170 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (346.475 and 361.364 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (76.02) is better than Ligand B (87.3), both are below the 90 A^2 threshold for CNS targets, but A is preferable.

**logP:** Ligand A (1.862) is within the optimal 1-3 range. Ligand B (0.722) is a bit low, potentially impacting permeability.

**H-Bond Donors/Acceptors:** Ligand A has 2 HBD and 4 HBA, while Ligand B has 3 HBD and 3 HBA. Both are within acceptable limits.

**QED:** Ligand A (0.791) has a better QED score than Ligand B (0.595), indicating a more drug-like profile.

**DILI:** Both ligands have low DILI risk (27.608 and 29.314), both are good.

**BBB:** Ligand B (71.733) has a slightly better BBB penetration percentile than Ligand A (62.233), but both are reasonably good for a CNS target.

**Caco-2 Permeability:** Both ligands have negative Caco-2 permeability values (-5.135 and -5.178), which is unusual and suggests poor intestinal absorption. This is a significant concern for both.

**Aqueous Solubility:** Both ligands have very poor aqueous solubility (-2.383 and -2.548). This is a major drawback.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.111 and 0.221).

**Microsomal Clearance:** Ligand B (-1.658) has a negative microsomal clearance, which is not physically possible and indicates a potential data error or unusual metabolic behavior. Ligand A (30.236) has a moderate clearance.

**In vitro Half-Life:** Ligand B (-6.61) has a negative half-life, which is impossible and indicates a data error. Ligand A (12.332) has a reasonable half-life.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.113 and 0.019), which is favorable for CNS penetration.

**Binding Affinity:** Ligand B (-8.4) has a slightly better binding affinity than Ligand A (-8.0). However, the difference is not substantial enough to overcome the other significant issues with Ligand B.

**Overall Assessment:**

Ligand B has several critical issues: negative and therefore impossible values for microsomal clearance and half-life. These data errors make it a non-starter. While its affinity is slightly better and BBB is slightly higher, the data quality issues are disqualifying. Ligand A, while having poor solubility and Caco-2 permeability, has more reasonable and internally consistent ADME properties.

Output:
1
2025-04-17 07:25:15,170 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B based on the provided guidelines, prioritizing GPCR-specific properties (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (352.385 Da) is slightly lower, which could be beneficial for permeability.

**TPSA:** Ligand A (61.94) is excellent for CNS penetration, well below 90. Ligand B (124.69) is higher, but still potentially acceptable, though less ideal.

**logP:** Ligand A (3.414) is optimal. Ligand B (1.049) is a bit low, potentially hindering membrane permeability.

**H-Bond Donors/Acceptors:** Ligand A (0 HBD, 6 HBA) is favorable. Ligand B (4 HBD, 7 HBA) is also acceptable, but slightly higher counts could impact permeability.

**QED:** Both ligands have reasonable QED scores (A: 0.774, B: 0.525), indicating good drug-like properties.

**DILI:** Both ligands have similar DILI risk (A: 60.411, B: 64.288), placing them in a moderate risk category.

**BBB:** This is a critical parameter for CNS targets. Ligand A has a very high BBB penetration percentile (95.812), significantly better than Ligand B (25.979).

**Caco-2 Permeability:** Ligand A (-4.255) has poor Caco-2 permeability, which is concerning. Ligand B (-5.655) is also poor, but slightly better than A.

**Aqueous Solubility:** Ligand A (-4.085) and Ligand B (-2.631) both have poor aqueous solubility, which could present formulation challenges.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (A: 0.214, B: 0.223).

**Microsomal Clearance:** Ligand A (66.656) has higher clearance, suggesting lower metabolic stability. Ligand B (25.421) has lower clearance, indicating better metabolic stability.

**In vitro Half-Life:** Ligand A (-32.003) has a negative half-life, which is not possible and indicates an error or outlier. Ligand B (65.452) is reasonable.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (A: 0.341, B: 0.215), which is good for CNS exposure.

**Binding Affinity:** Ligand A (-8.7 kcal/mol) has a significantly stronger binding affinity than Ligand B (-7.8 kcal/mol). This 0.9 kcal/mol difference is substantial and can often outweigh minor ADME drawbacks.

**Overall Assessment:**

Despite Ligand A's poor Caco-2 permeability and questionable half-life, its significantly superior binding affinity (-8.7 vs -7.8 kcal/mol) and *excellent* BBB penetration (95.812 vs 25.979) make it the more promising candidate for a CNS-targeting GPCR like DRD2. The strong binding affinity suggests it could be effective at lower doses, potentially mitigating some of the solubility issues. The high BBB penetration is crucial for CNS efficacy. Ligand B's better metabolic stability is a plus, but it's overshadowed by its poor BBB penetration and weaker binding.

Output:
1
2025-04-17 07:25:15,170 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B based on the provided guidelines, prioritizing GPCR-specific properties (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (339.443) is slightly lower, which could be beneficial for permeability.

**TPSA:** Both ligands have TPSA values (73.05 and 76.66) that are acceptable for oral absorption, but borderline for CNS penetration (ideally <90).

**logP:** Ligand A (2.503) is optimal, while Ligand B (0.313) is quite low, potentially hindering membrane permeability and CNS entry. This is a significant disadvantage for a CNS target.

**H-Bond Donors/Acceptors:** Ligand A (HBD=3, HBA=3) and Ligand B (HBD=2, HBA=5) are both within acceptable limits.

**QED:** Both ligands have good QED scores (0.801 and 0.705), indicating drug-likeness.

**DILI:** Ligand A (32.648) has a significantly lower DILI risk than Ligand B (59.829), which is a substantial advantage.

**BBB:** Ligand A (70.105) has a good BBB percentile, exceeding the desirable threshold of 70 for CNS targets. Ligand B (52.036) falls short, indicating limited brain penetration. This is a critical drawback.

**Caco-2 Permeability:** Both have negative values, which is unusual and suggests poor permeability. However, the scale is not specified, so it's difficult to interpret.

**Aqueous Solubility:** Both have negative values, indicating poor solubility. This is a concern for both compounds.

**hERG Inhibition:** Both ligands show low hERG inhibition risk (0.769 and 0.212).

**Microsomal Clearance:** Ligand A (-18.364) has much lower (better) microsomal clearance than Ligand B (24.539), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (13.562) has a longer half-life than Ligand B (17.741).

**P-gp Efflux:** Ligand A (0.071) has lower P-gp efflux liability than Ligand B (0.025), which is favorable for CNS exposure.

**Binding Affinity:** Ligand A (-10.0) has a significantly stronger binding affinity than Ligand B (-7.7). This difference of 2.3 kcal/mol is substantial and can outweigh some ADME drawbacks.

**Conclusion:**

Considering all factors, especially the GPCR-specific priorities, **Ligand A is the more promising drug candidate**. Its superior BBB penetration, optimal logP, lower DILI risk, better metabolic stability (lower Cl_mic), lower P-gp efflux, and significantly stronger binding affinity outweigh its slightly lower molecular weight and solubility concerns. Ligand B's low logP and poor BBB penetration are major liabilities for a CNS-targeted GPCR.

Output:
1
2025-04-17 07:25:15,170 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 drug candidates, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (361.511 and 358.438 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (73.2) is higher than Ligand B (40.62). For CNS targets, TPSA should be <=90, so both are acceptable, but B is significantly better.

**3. logP:** Both ligands have a logP around 3.2 (3.27 and 3.245), which is optimal.

**4. H-Bond Donors:** Ligand A has 1 HBD, while Ligand B has 0. Both are within the acceptable limit of <=5.

**5. H-Bond Acceptors:** Ligand A has 4 HBA, and Ligand B has 3. Both are within the acceptable limit of <=10.

**6. QED:** Both ligands have similar QED values (0.845 and 0.827), indicating good drug-likeness.

**7. DILI:** Ligand A (31.563) has a lower DILI risk than Ligand B (49.593), which is favorable.

**8. BBB:** Ligand B (87.127) has a significantly higher BBB penetration percentile than Ligand A (76.774). This is a critical advantage for a CNS target like DRD2.

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.728 and -4.687), which is unusual and suggests poor permeability. This is a concern for both, but the values are similar.

**10. Aqueous Solubility:** Both ligands have negative solubility values (-4.254 and -3.433), indicating very poor aqueous solubility. This is a significant drawback for both.

**11. hERG Inhibition:** Both ligands have low hERG inhibition risk (0.672 and 0.719).

**12. Microsomal Clearance:** Ligand B (32.962) has lower microsomal clearance than Ligand A (71.876), indicating better metabolic stability.

**13. In vitro Half-Life:** Ligand A (21.417) has a longer in vitro half-life than Ligand B (4.15).

**14. P-gp Efflux:** Ligand A (0.183) has lower P-gp efflux than Ligand B (0.436), which is beneficial for CNS exposure.

**15. Binding Affinity:** Ligand B (-9.3 kcal/mol) has a significantly stronger binding affinity than Ligand A (-8.0 kcal/mol). This is a substantial advantage, potentially outweighing some of the ADME drawbacks.

**Overall Assessment:**

While both compounds have issues with solubility and Caco-2 permeability, Ligand B is the more promising candidate. Its superior BBB penetration (87.127 vs 76.774), significantly stronger binding affinity (-9.3 vs -8.0 kcal/mol), and lower microsomal clearance outweigh the slightly higher DILI risk and higher P-gp efflux. The stronger binding affinity is particularly important for a GPCR target.

Output:
1
2025-04-17 07:25:15,170 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (364.364 and 353.463 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Both ligands have TPSA values (81.08 and 82.11) that are above the optimal <90 for CNS targets, but not drastically so. This is a minor concern.

**3. logP:** Ligand A (0.379) is slightly below the optimal 1-3 range, potentially hindering permeability. Ligand B (-0.025) is even lower, raising more significant permeability concerns.

**4. H-Bond Donors:** Both have 2 HBD, which is within the acceptable limit of <=5.

**5. H-Bond Acceptors:** Ligand A has 4 HBA, and Ligand B has 5 HBA, both within the acceptable limit of <=10.

**6. QED:** Both ligands have QED values (0.759 and 0.672) above 0.5, indicating good drug-like properties.

**7. DILI:** Ligand A (21.171) has a significantly lower DILI risk than Ligand B (12.834), which is a substantial advantage.

**8. BBB:** Ligand A (70.182) has a better BBB percentile than Ligand B (66.925), which is important for CNS targets like DRD2. While both are above 60, A is preferable.

**9. Caco-2:** Both ligands have negative Caco-2 values (-4.795 and -4.726), which is unusual and suggests poor intestinal absorption. This is a significant drawback for both.

**10. Solubility:** Both ligands have negative solubility values (-1.507 and -0.87), indicating very poor aqueous solubility. This is a major concern for both.

**11. hERG:** Both ligands have low hERG inhibition liability (0.424 and 0.228), which is good.

**12. Cl_mic:** Ligand A (-7.962) has a much lower (and therefore better) microsomal clearance than Ligand B (13.115), indicating greater metabolic stability.

**13. t1/2:** Ligand A (-4.373) has a negative in vitro half-life, which is unusual. Ligand B (23.779) has a more reasonable half-life.

**14. Pgp:** Both ligands have very low Pgp efflux liability (0.037 and 0.038), which is favorable for CNS penetration.

**15. Binding Affinity:** Ligand A (-7.3 kcal/mol) has a slightly better binding affinity than Ligand B (-6.4 kcal/mol). While the difference isn't huge, it's enough to consider, especially given the other factors.

**Overall Assessment:**

Ligand A is the better candidate. While both have solubility and Caco-2 issues, Ligand A has a significantly lower DILI risk, better BBB penetration, and better metabolic stability (lower Cl_mic). The slightly better binding affinity is a bonus. Ligand B's lower logP is a more significant concern for permeability.

Output:
1
2025-04-17 07:25:15,171 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (354.376 and 354.402 Da) fall comfortably within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (61.18) is better than Ligand B (43.37). Both are below the 90 A^2 threshold for CNS targets, but A is slightly higher, potentially impacting BBB penetration less favorably.

**3. logP:** Ligand A (2.946) is within the optimal 1-3 range. Ligand B (4.9) is higher, potentially leading to solubility issues and off-target interactions.

**4. H-Bond Donors:** Ligand A (1) is good. Ligand B (0) is also acceptable.

**5. H-Bond Acceptors:** Ligand A (5) is good. Ligand B (4) is also good.

**6. QED:** Ligand A (0.901) is excellent, indicating strong drug-like properties. Ligand B (0.372) is considerably lower, raising concerns about its developability.

**7. DILI:** Ligand A (25.979) has a significantly lower DILI risk than Ligand B (88.057). This is a major advantage for Ligand A.

**8. BBB:** Ligand A (85.925) has a better BBB penetration percentile than Ligand B (65.839). This is crucial for a CNS target like DRD2.

**9. Caco-2 Permeability:** Ligand A (-4.734) and Ligand B (-4.147) both have negative values, suggesting poor permeability. This is a concern for both, but the difference is small.

**10. Aqueous Solubility:** Ligand A (-3.512) is better than Ligand B (-6.569). Solubility is important for formulation and bioavailability.

**11. hERG Inhibition:** Ligand A (0.94) is better than Ligand B (0.287), indicating a lower risk of cardiotoxicity.

**12. Microsomal Clearance:** Ligand A (16.921) has a lower microsomal clearance than Ligand B (129.822), suggesting better metabolic stability.

**13. In vitro Half-Life:** Ligand A (13.369) has a shorter half-life than Ligand B (30.877), but both are acceptable.

**14. P-gp Efflux:** Ligand A (0.267) has lower P-gp efflux liability than Ligand B (0.476), which is favorable for CNS exposure.

**15. Binding Affinity:** Ligand B (-9.1 kcal/mol) has a slightly better binding affinity than Ligand A (-8.2 kcal/mol). While affinity is important, the difference of 0.9 kcal/mol isn't substantial enough to outweigh the significant ADME advantages of Ligand A.

**Overall Assessment:**

Ligand A demonstrates a significantly more favorable ADME profile, with better BBB penetration, lower DILI risk, better solubility, lower hERG inhibition, and lower P-gp efflux. While Ligand B has slightly better binding affinity, the ADME liabilities are substantial, especially the high DILI risk and poor BBB penetration. For a CNS target like DRD2, a good ADME profile is paramount.

Output:
0
2025-04-17 07:25:15,171 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (353.373 and 354.479 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (83.02) is better than Ligand B (64.78), both are below the 90 A^2 threshold for CNS targets.

**logP:** Ligand A (1.714) is within the optimal 1-3 range, while Ligand B (3.561) is at the higher end, potentially leading to solubility issues.

**H-Bond Donors/Acceptors:** Both ligands have 2 HBD and a reasonable number of HBA (4 for A, 3 for B), satisfying the <5 HBD and <10 HBA guidelines.

**QED:** Both ligands have similar QED values (0.795 and 0.711), indicating good drug-likeness.

**DILI:** Both ligands have acceptable DILI risk (43.117 and 48.313), well below the 60 threshold.

**BBB:** Ligand A (66.615) has a better BBB percentile than Ligand B (60.954), though both are less than the desirable >70 for CNS targets.

**Caco-2 Permeability:** Ligand A (-4.921) has a worse Caco-2 permeability than Ligand B (-5.527).

**Aqueous Solubility:** Ligand A (-2.267) has a worse aqueous solubility than Ligand B (-3.631).

**hERG:** Both ligands have low hERG inhibition liability (0.679 and 0.786).

**Microsomal Clearance:** Ligand A (11.526) has a lower microsomal clearance than Ligand B (40.828), indicating better metabolic stability.

**In vitro Half-Life:** Ligand A (-2.886) has a longer in vitro half-life than Ligand B (0.216).

**P-gp Efflux:** Ligand A (0.071) exhibits lower P-gp efflux than Ligand B (0.283), which is favorable for CNS penetration.

**Binding Affinity:** Ligand B (-7.4 kcal/mol) has a significantly stronger binding affinity than Ligand A (-8.0 kcal/mol). The difference of 0.4 kcal/mol is substantial.

**Overall Assessment:**

Ligand B has a superior binding affinity, which is the most crucial factor for GPCR ligands. While Ligand A has better metabolic stability (lower Cl_mic, longer t1/2) and P-gp efflux, the substantial affinity advantage of Ligand B outweighs these benefits. The slightly higher logP of Ligand B is a minor concern, but manageable. The BBB penetration of both is suboptimal, but the stronger binding of B may compensate.

Output:
1
2025-04-17 07:25:15,171 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (353.365 Da and 344.419 Da) fall within the ideal range of 200-500 Da.

**TPSA:** Ligand A (66.84) is excellent, well below the 90 A^2 threshold for CNS targets. Ligand B (101.06) is still reasonable but less optimal, exceeding the preferred threshold.

**logP:** Both ligands have good logP values (2.469 and 1.355), falling within the 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A (1 HBD, 4 HBA) is better than Ligand B (3 HBD, 7 HBA) in terms of balancing solubility and permeability.

**QED:** Ligand A (0.826) has a significantly higher QED score than Ligand B (0.631), indicating a more drug-like profile.

**DILI:** Both ligands have acceptable DILI risk (38.62 and 45.638), below the 60 threshold.

**BBB:** Ligand A excels with a BBB percentile of 81.466, which is highly desirable for a CNS target like DRD2. Ligand B's BBB percentile (52.036) is considerably lower and less favorable.

**Caco-2 Permeability:** Ligand A (-4.198) has poor Caco-2 permeability, while Ligand B (-5.301) is even worse.

**Aqueous Solubility:** Ligand A (-3.172) has slightly better solubility than Ligand B (-1.917).

**hERG Inhibition:** Both ligands show low hERG inhibition risk (0.444 and 0.236).

**Microsomal Clearance:** Ligand A (52.929) has higher microsomal clearance than Ligand B (31.899), suggesting lower metabolic stability.

**In vitro Half-Life:** Ligand B (24.668 hours) has a significantly longer in vitro half-life than Ligand A (1.255 hours).

**P-gp Efflux:** Ligand A (0.193) has lower P-gp efflux liability than Ligand B (0.006), which is beneficial for CNS penetration.

**Binding Affinity:** Ligand B (-8.0 kcal/mol) has a slightly better binding affinity than Ligand A (-7.8 kcal/mol), but the difference is not substantial.

**Overall Assessment:**

Considering the GPCR-specific priorities, Ligand A is the more promising candidate. Its superior BBB penetration, lower TPSA, higher QED, and lower P-gp efflux outweigh its slightly lower binding affinity and poorer Caco-2 permeability. While Ligand B has a longer half-life, the CNS target necessitates good brain penetration, which Ligand A provides to a much greater extent. The difference in binding affinity is not large enough to overcome the significant advantage of Ligand A in terms of CNS penetration and overall drug-likeness.

Output:
1
2025-04-17 07:25:15,171 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (364.511 and 380.941 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Both ligands have TPSA values (49.85 and 49.41) below the 90 A^2 threshold for CNS targets, which is excellent.

**3. logP:** Ligand A (2.936) is optimal, while Ligand B (4.093) is approaching the upper limit of the optimal range.

**4. H-Bond Donors:** Ligand A (0) is favorable, while Ligand B (1) is still acceptable.

**5. H-Bond Acceptors:** Ligand A (4) and Ligand B (3) are both within the acceptable limit of 10.

**6. QED:** Both ligands have good QED scores (0.699 and 0.836), indicating drug-like properties.

**7. DILI:** Ligand A (20.744) has a significantly lower DILI risk than Ligand B (35.634). This is a substantial advantage.

**8. BBB:** Both ligands have excellent BBB penetration (89.298 and 89.686), exceeding the desirable threshold of 70.

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.665 and -4.923), which is unusual and suggests poor permeability. However, these values are on a log scale and a negative value doesn't necessarily preclude development, but it is a flag.

**10. Aqueous Solubility:** Both ligands have very poor aqueous solubility (-2.284 and -5.204). This is a major concern for formulation and bioavailability.

**11. hERG Inhibition:** Both ligands show low hERG inhibition risk (0.731 and 0.683).

**12. Microsomal Clearance:** Ligand A (63.476) has a higher microsomal clearance than Ligand B (52.337), suggesting lower metabolic stability.

**13. In vitro Half-Life:** Ligand B (7.775) has a significantly longer in vitro half-life than Ligand A (-0.364). This is a considerable advantage.

**14. P-gp Efflux:** Both ligands show low P-gp efflux liability (0.436 and 0.372), which is good for CNS exposure.

**15. Binding Affinity:** Ligand B (-9.2 kcal/mol) has a substantially stronger binding affinity than Ligand A (-7.6 kcal/mol). This difference of 1.6 kcal/mol is significant and can outweigh some of the ADME drawbacks.

**Overall Assessment:**

Ligand B is the stronger candidate despite some ADME liabilities. The significantly improved binding affinity (-9.2 vs -7.6 kcal/mol) is a major driver. The longer half-life is also a significant benefit. While both have poor solubility and Caco-2 permeability, the superior affinity and half-life of Ligand B make it more promising. The DILI risk is also lower for Ligand A, but the binding affinity difference is more impactful for a GPCR target.

Output:
1
2025-04-17 07:25:15,171 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (369.487 and 375.965 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (80.76) is excellent for CNS penetration, being well below 90. Ligand B (12.47) is *exceptionally* low, which is generally good for BBB penetration but can sometimes indicate a lack of necessary interactions.

**logP:** Ligand A (1.934) is within the optimal 1-3 range. Ligand B (4.971) is slightly high, potentially leading to solubility issues and off-target interactions, but not drastically so.

**H-Bond Donors/Acceptors:** Ligand A has 1 HBD and 6 HBA, which are acceptable. Ligand B has 0 HBD and 3 HBA, also acceptable.

**QED:** Both ligands have reasonable QED values (0.794 and 0.677), indicating good drug-like properties.

**DILI:** Ligand A (53.742) has a moderate DILI risk, while Ligand B (25.436) has a lower risk. This favors Ligand B.

**BBB:** Ligand A (48.585) has a moderate BBB penetration, while Ligand B (95.851) has *excellent* BBB penetration. This is a major advantage for a CNS target like DRD2.

**Caco-2 Permeability:** Ligand A (-4.821) has poor Caco-2 permeability, which is concerning. Ligand B (-5.227) also has poor Caco-2 permeability, but is slightly better than Ligand A.

**Aqueous Solubility:** Both ligands have very poor aqueous solubility (-2.272 and -4.57). This is a significant drawback for both.

**hERG Inhibition:** Ligand A (0.298) has a very low risk of hERG inhibition, which is excellent. Ligand B (0.956) has a slightly higher risk, but still relatively low.

**Microsomal Clearance:** Ligand A (24.963) has a moderate clearance, while Ligand B (53.375) has a higher clearance. This favors Ligand A, indicating better metabolic stability.

**In vitro Half-Life:** Ligand A (17.309) has a moderate half-life, while Ligand B (9.973) has a shorter half-life. This favors Ligand A.

**P-gp Efflux:** Ligand A (0.127) has low P-gp efflux, which is good. Ligand B (0.884) has a higher P-gp efflux, which is less desirable.

**Binding Affinity:** Ligand B (-8.3 kcal/mol) has a significantly stronger binding affinity than Ligand A (-7.1 kcal/mol). This is a substantial advantage (1.2 kcal/mol difference), and can outweigh some of the ADME drawbacks.

**Overall Assessment:**

Ligand B excels in BBB penetration and binding affinity, which are crucial for a CNS GPCR target. While its logP is slightly high and solubility is poor, the strong affinity and excellent BBB penetration are significant advantages. Ligand A has better metabolic stability and lower P-gp efflux, but its weaker affinity and moderate BBB penetration are less favorable. The Caco-2 permeability is poor for both, which would need to be addressed in further optimization.

Output:
1
2025-04-17 07:25:15,171 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (353.369 and 357.523 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (91.06) is better than Ligand B (54.02). For CNS targets, TPSA should be <= 90, so Ligand A is borderline, while Ligand B is well within the desired range.

**3. logP:** Ligand A (1.519) is optimal, while Ligand B (4.553) is high. A logP > 4 can cause solubility and off-target issues, making Ligand A preferable.

**4. H-Bond Donors:** Both have acceptable HBD counts (3 and 2 respectively), well below the threshold of 5.

**5. H-Bond Acceptors:** Both have acceptable HBA counts (3 and 4 respectively), well below the threshold of 10.

**6. QED:** Both ligands have good QED scores (0.677 and 0.825), indicating good drug-like properties.

**7. DILI:** Ligand A (49.477) has a lower DILI risk than Ligand B (58.666), which is preferable. Both are below the concerning threshold of 60.

**8. BBB:** Ligand B (84.335) has a significantly better BBB penetration score than Ligand A (69.252). For a CNS target like DRD2, >70 is desirable, and Ligand B is closer to this threshold.

**9. Caco-2 Permeability:** Ligand A (-5.124) and Ligand B (-4.854) both have negative values, indicating poor permeability. This is a concern for both.

**10. Aqueous Solubility:** Ligand A (-2.96) and Ligand B (-4.321) both have negative values, indicating poor solubility. This is a concern for both.

**11. hERG Inhibition:** Both ligands have low hERG inhibition risk (0.438 and 0.73).

**12. Microsomal Clearance:** Ligand A (-1.982) has a lower (better) microsomal clearance than Ligand B (48.321), suggesting greater metabolic stability.

**13. In vitro Half-Life:** Ligand A (-25.504) has a much longer in vitro half-life than Ligand B (60.656), which is a significant advantage.

**14. P-gp Efflux:** Ligand A (0.067) has a lower P-gp efflux liability than Ligand B (0.641), which is favorable for CNS penetration.

**15. Binding Affinity:** Both ligands have excellent binding affinities (-9.1 and -8.5 kcal/mol). Ligand A has a 0.6 kcal/mol advantage, which is significant.

**Overall Assessment:**

Ligand A has advantages in logP, DILI, metabolic stability (Cl_mic & t1/2), P-gp efflux, and binding affinity. Ligand B's primary advantage is its significantly better BBB penetration. However, the combination of better ADME properties (especially metabolic stability, P-gp efflux, and logP) and slightly better binding affinity for Ligand A outweighs the BBB advantage of Ligand B. The slightly higher TPSA of Ligand A is a minor concern, but the other benefits are more impactful for a CNS GPCR target.

Output:
0
2025-04-17 07:25:15,171 - INFO - Reasoning:

Let's analyze Ligand A and Ligand B for their potential as DRD2 drug candidates, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (349.5 and 350.4 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (43.86) is significantly better than Ligand B (83.98). For CNS targets, we want TPSA <= 90, and A is comfortably within that range, while B is approaching the upper limit. This is a substantial advantage for A.

**3. logP:** Both ligands have good logP values (2.236 and 2.157), falling within the optimal 1-3 range.

**4. H-Bond Donors:** Ligand A (0) is preferable to Ligand B (2). Fewer HBDs generally improve permeability.

**5. H-Bond Acceptors:** Ligand A (3) is preferable to Ligand B (4). Fewer HBAs generally improve permeability.

**6. QED:** Ligand B (0.75) has a slightly better QED score than Ligand A (0.449), indicating a more drug-like profile. However, this is less critical than other factors for a GPCR target.

**7. DILI:** Ligand A (3.994) has a much lower DILI risk than Ligand B (54.052). This is a significant advantage for A.

**8. BBB:** Both ligands have good BBB penetration (85.615 and 80.962), exceeding the desirable >70 threshold for CNS targets. However, A is slightly better.

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.651 and -4.808), which is unusual and suggests poor permeability. This is a concern for both, but doesn't differentiate them.

**10. Aqueous Solubility:** Both ligands have negative solubility values (-1.023 and -3.316), indicating poor aqueous solubility. This is a concern for both, but B is worse.

**11. hERG Inhibition:** Both ligands have low hERG inhibition risk (0.622 and 0.689).

**12. Microsomal Clearance:** Ligand A (16.121) has significantly lower microsomal clearance than Ligand B (45.26), indicating better metabolic stability.

**13. In vitro Half-Life:** Ligand A (5.974) has a slightly longer in vitro half-life than Ligand B (4.533).

**14. P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.082 and 0.059).

**15. Binding Affinity:** Ligand B (-8.8 kcal/mol) has a significantly stronger binding affinity than Ligand A (-6.8 kcal/mol). This is a substantial advantage for B, potentially outweighing some ADME drawbacks. The difference is >1.5 kcal/mol.

**Overall Assessment:**

While Ligand B has a significantly better binding affinity, Ligand A demonstrates superior ADME properties, particularly regarding TPSA, DILI, and metabolic stability (Cl_mic). The lower TPSA and DILI risk of Ligand A are crucial for CNS drug development. The affinity difference is significant, but a 2 kcal/mol difference isn't insurmountable in lead optimization. Given the GPCR-specific priorities, and the fact that both compounds have acceptable BBB penetration, the better ADME profile of Ligand A makes it the more promising starting point for further development.

Output:
0
2025-04-17 07:25:15,171 - INFO - Okay, let's analyze these two ligands for their potential as DRD2 drug candidates. DRD2 is a GPCR in the CNS, so BBB penetration, logP, Pgp efflux, TPSA, and binding affinity are paramount.

**Ligand A: [410.264, 79.98, 2.417, 1, 5, 0.766, 57.348, 85.459, -4.628, -3.284, 0.862, 13.236, 35.152, 0.717, -8.9]**

*   **MW:** 410.264 Da - Acceptable.
*   **TPSA:** 79.98  - Excellent, well below the 90 threshold for CNS targets.
*   **logP:** 2.417 - Optimal.
*   **HBD:** 1 - Good.
*   **HBA:** 5 - Good.
*   **QED:** 0.766 - Excellent, highly drug-like.
*   **DILI:** 57.348 - Acceptable, below the 60 threshold.
*   **BBB:** 85.459 - Excellent, well above the 70 desirable threshold for CNS targets.
*   **Caco-2:** -4.628 - Poor, indicating low intestinal permeability.
*   **Solubility:** -3.284 - Poor, indicating low aqueous solubility.
*   **hERG:** 0.862 - Low risk.
*   **Cl_mic:** 13.236 mL/min/kg - Moderate clearance, not ideal but not terrible.
*   **t1/2:** 35.152 hours - Good in vitro half-life.
*   **Pgp:** 0.717 - Moderate efflux, could limit CNS exposure.
*   **Affinity:** -8.9 kcal/mol - Excellent, very strong binding.

**Ligand B: [347.419, 107.19, -0.026, 3, 4, 0.602, 34.781, 40.016, -5.652, -1.691, 0.059, -26.871, -24.575, 0.007, -7.6]**

*   **MW:** 347.419 Da - Acceptable.
*   **TPSA:** 107.19 - Borderline, slightly above the 90 threshold for CNS targets.
*   **logP:** -0.026 - Poor, likely to have poor membrane permeability.
*   **HBD:** 3 - Good.
*   **HBA:** 4 - Good.
*   **QED:** 0.602 - Acceptable, but lower than Ligand A.
*   **DILI:** 34.781 - Excellent, very low risk.
*   **BBB:** 40.016 - Poor, far below the 70 threshold for CNS targets.
*   **Caco-2:** -5.652 - Very poor, indicating extremely low intestinal permeability.
*   **Solubility:** -1.691 - Poor, indicating low aqueous solubility.
*   **hERG:** 0.059 - Very low risk.
*   **Cl_mic:** -26.871 mL/min/kg - Very low clearance, indicating high metabolic stability.
*   **t1/2:** -24.575 hours - Very long in vitro half-life.
*   **Pgp:** 0.007 - Very low efflux, potentially good for CNS exposure.
*   **Affinity:** -7.6 kcal/mol - Good, but significantly weaker than Ligand A.

**Comparison and Decision:**

Ligand A has a significantly better binding affinity (-8.9 kcal/mol vs -7.6 kcal/mol) and a much better BBB penetration (85.459 vs 40.016). While Ligand A has poorer Caco-2 and solubility, these are less critical for a CNS target where direct brain delivery is prioritized. Ligand B has excellent metabolic stability and low Pgp efflux, but its poor logP and BBB penetration are major drawbacks. The substantial difference in binding affinity and BBB penetration makes Ligand A the far more promising candidate, despite its slightly less favorable ADME properties. The 1.3 kcal/mol difference in binding affinity is substantial and outweighs the ADME concerns.

1
2025-04-17 07:25:15,172 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (374.849 Da) is slightly higher than Ligand B (347.463 Da), but both are acceptable.

**TPSA:** Ligand A (51.54) is significantly better than Ligand B (77.37). For CNS targets, we want TPSA <= 90, and ideally lower. Ligand A is well within this range, while Ligand B is approaching the upper limit.

**logP:** Ligand A (3.531) is optimal (1-3), while Ligand B (1.562) is on the lower end. Lower logP can hinder permeation, especially across the BBB. This favors Ligand A.

**H-Bond Donors/Acceptors:** Ligand A (0 HBD, 5 HBA) and Ligand B (1 HBD, 5 HBA) are both reasonable. Both are within the acceptable limits.

**QED:** Both ligands have good QED scores (Ligand A: 0.689, Ligand B: 0.784), indicating good drug-like properties.

**DILI:** Ligand A (84.102) has a significantly higher DILI risk than Ligand B (20.047). This is a major concern for Ligand A.

**BBB:** Ligand A (73.866) and Ligand B (68.282) both have reasonably good BBB penetration, but Ligand A is slightly better.  A score >70 is desirable, and both are close.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values, which is unusual and suggests poor permeability. However, the scale isn't specified, so it's hard to interpret.

**Aqueous Solubility:** Both ligands have negative solubility values, which is also unusual and suggests poor solubility. Again, the scale isn't specified.

**hERG:** Ligand A (0.435) has a slightly higher hERG risk than Ligand B (0.104), but both are relatively low.

**Microsomal Clearance:** Ligand A (67.927) has higher microsomal clearance than Ligand B (-2.172). This suggests Ligand B is more metabolically stable, which is desirable.

**In vitro Half-Life:** Ligand A (28.887 hours) has a significantly longer half-life than Ligand B (2.52 hours). This is a significant advantage for Ligand A.

**P-gp Efflux:** Ligand A (0.755) has higher P-gp efflux than Ligand B (0.008). Lower P-gp efflux is preferred, especially for CNS drugs, favoring Ligand B.

**Binding Affinity:** Ligand A (-8.5 kcal/mol) has a substantially stronger binding affinity than Ligand B (-7.0 kcal/mol). This is a very significant advantage for Ligand A, potentially outweighing some of its ADME drawbacks.

**Overall Assessment:**

Ligand A has a much stronger binding affinity and a longer half-life, which are crucial for a GPCR ligand. It also has better TPSA and BBB penetration. However, its significantly higher DILI risk and P-gp efflux are major concerns. Ligand B has a better safety profile (lower DILI, P-gp efflux, hERG) and better metabolic stability, but its lower affinity and higher TPSA are less desirable.

Given the importance of potency for GPCRs, and the significant 1.5 kcal/mol advantage in binding affinity for Ligand A, I would cautiously favor Ligand A *if* the DILI risk could be mitigated through structural modifications. The strong binding affinity suggests that even with some ADME optimization, Ligand A has a higher potential for success.

Output:
1
2025-04-17 07:25:15,172 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the acceptable range (200-500 Da). Ligand A (428.67 Da) is higher, but not excessively so. Ligand B (344.459 Da) is slightly preferred here.

**TPSA:** Ligand A (138.67) is close to the upper limit for good oral absorption and acceptable for CNS targets, but not ideal. Ligand B (65.54) is excellent, well below the 90 A^2 threshold for CNS targets. This is a significant advantage for Ligand B.

**logP:** Both ligands have good logP values (A: 1.922, B: 2.201), falling within the optimal 1-3 range. No clear preference here.

**H-Bond Donors/Acceptors:** Ligand A has 5 HBD and 5 HBA, which is acceptable. Ligand B has 1 HBD and 4 HBA, also acceptable and potentially better for permeability due to fewer hydrogen bonds.

**QED:** Ligand B (0.889) has a much higher QED score than Ligand A (0.366), indicating a more drug-like profile. This is a strong advantage for Ligand B.

**DILI:** Both ligands have acceptable DILI risk (A: 57.348, B: 42.536), below the 60 threshold. Ligand B is slightly better.

**BBB:** Ligand B (81.97) has a significantly higher BBB penetration percentile than Ligand A (44.397). This is *critical* for a CNS target like DRD2, making Ligand B much more promising.

**Caco-2 Permeability:** Ligand A has a negative Caco-2 value (-5.865), which is concerning and suggests poor permeability. Ligand B (-4.711) is also negative, but less so.

**Aqueous Solubility:** Both ligands have negative solubility values, indicating poor aqueous solubility. This is a potential issue for both, but might be manageable with formulation strategies.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (A: 0.557, B: 0.454).

**Microsomal Clearance:** Ligand A (12.827 mL/min/kg) has lower clearance than Ligand B (31.428 mL/min/kg), suggesting better metabolic stability. This is an advantage for Ligand A.

**In vitro Half-Life:** Ligand A (-14.078 hours) has a negative half-life, which is concerning. Ligand B (16.779 hours) has a reasonable half-life.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (A: 0.114, B: 0.03). Ligand B is slightly better.

**Binding Affinity:** Ligand A (-9.1 kcal/mol) has a significantly stronger binding affinity than Ligand B (-7.6 kcal/mol). This is a substantial advantage for Ligand A, potentially outweighing some of its ADME drawbacks.

**Overall Assessment:**

Ligand B excels in key properties for a CNS-targeting GPCR ligand: TPSA, BBB, QED, and P-gp efflux. While its affinity is lower, its superior ADME profile, particularly BBB penetration, makes it a more promising starting point. Ligand A has a much better binding affinity, but suffers from poor TPSA, QED, and a concerning negative in vitro half-life. The difference in affinity (1.5 kcal/mol) is substantial, but the ADME liabilities of Ligand A are significant enough to make Ligand B the better candidate.

Output:
1
2025-04-17 07:25:15,172 - INFO - Batch 363 complete. Total preferences: 5808
2025-04-17 07:25:15,172 - INFO - Processing batch 364/512...
2025-04-17 07:25:56,959 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (350.434 and 353.507 Da) fall comfortably within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (58.64) is significantly better than Ligand B (78.51). For a CNS target like DRD2, we want TPSA <= 90, and ideally closer to 60. Ligand A is much closer to this ideal.

**3. logP:** Both ligands have similar logP values (1.824 and 1.88), both within the optimal 1-3 range.

**4. H-Bond Donors:** Ligand A (1) is preferable to Ligand B (2). Lower HBD generally improves permeability.

**5. H-Bond Acceptors:** Ligand A (3) is preferable to Ligand B (4). Lower HBA generally improves permeability.

**6. QED:** Ligand A (0.744) has a better QED score than Ligand B (0.588), indicating a more drug-like profile.

**7. DILI:** Ligand A (29.159) has a substantially lower DILI risk than Ligand B (11.322). This is a significant advantage.

**8. BBB:** Ligand A (93.098) has a much higher BBB penetration percentile than Ligand B (70.027). This is *critical* for a CNS target like DRD2. >70 is desirable, and Ligand A exceeds this, while B is at the lower end of acceptable.

**9. Caco-2 Permeability:** Ligand A (-4.524) and Ligand B (-4.951) are both poor. However, this is less critical given the BBB data.

**10. Aqueous Solubility:** Ligand A (-2.848) and Ligand B (-2.118) are both poor. This is less critical given the BBB data.

**11. hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.443 and 0.431).

**12. Microsomal Clearance:** Ligand B (17.166) has a lower microsomal clearance than Ligand A (39.571), suggesting better metabolic stability.

**13. In vitro Half-Life:** Ligand B (-25.19) has a longer in vitro half-life than Ligand A (-17.455). This is a positive attribute.

**14. P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.193 and 0.038).

**15. Binding Affinity:** Ligand A (-8.9 kcal/mol) has a significantly stronger binding affinity than Ligand B (-7.3 kcal/mol). This >1.5 kcal/mol difference is a major advantage, and can outweigh some ADME drawbacks.

**Overall Assessment:**

Ligand A is the superior candidate. While Ligand B has better metabolic stability and half-life, Ligand A excels in the most critical areas for a CNS GPCR target: TPSA, BBB penetration, DILI risk, and, most importantly, binding affinity. The strong affinity of Ligand A (-8.9 kcal/mol) is a significant driver, and the excellent BBB score (93.098) makes it highly likely to reach the target in the brain.

Output:
1
2025-04-17 07:25:56,959 - INFO - Reasoning:

Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (344.371) is slightly lower, which could be beneficial for permeability.

**2. TPSA:** Ligand A (101.49) is better than Ligand B (33.2). For CNS targets, TPSA should be <=90, so Ligand A is closer to the ideal range. Ligand B is very low, which might suggest reduced hydrogen bonding and potentially lower specificity.

**3. logP:** Ligand A (0.842) is within the optimal range (1-3), while Ligand B (4.192) is slightly high. High logP can lead to solubility issues and off-target interactions.

**4. H-Bond Donors:** Ligand A (1) is preferable to Ligand B (0). A small number of HBDs is generally good for CNS penetration.

**5. H-Bond Acceptors:** Ligand A (6) is better than Ligand B (2). Both are within the acceptable range of <=10.

**6. QED:** Both ligands have good QED values (A: 0.627, B: 0.72), indicating drug-like properties.

**7. DILI:** Ligand A (79.643) has a higher DILI risk than Ligand B (33.773). This is a significant drawback for Ligand A.

**8. BBB:** Ligand B (93.718) has a significantly better BBB penetration percentile than Ligand A (77.705). This is *critical* for a CNS target like DRD2.

**9. Caco-2 Permeability:** Both have negative values, which is unusual. Assuming these are percentile scores, Ligand A (-4.893) is slightly better than Ligand B (-4.319), but both are very poor.

**10. Aqueous Solubility:** Ligand A (-2.736) is slightly better than Ligand B (-5.039), but both are very poor.

**11. hERG Inhibition:** Ligand A (0.122) has lower hERG inhibition liability than Ligand B (0.677), which is favorable.

**12. Microsomal Clearance:** Ligand A (46.092) has lower microsomal clearance than Ligand B (55.945), suggesting better metabolic stability.

**13. In vitro Half-Life:** Ligand A (18.732) has a longer half-life than Ligand B (0.826), which is desirable.

**14. P-gp Efflux:** Ligand A (0.016) has significantly lower P-gp efflux liability than Ligand B (0.449), which is crucial for CNS exposure.

**15. Binding Affinity:** Both ligands have the same binding affinity (-8.5 kcal/mol), which is excellent.

**Overall Assessment:**

While Ligand A has better metabolic stability, half-life, P-gp efflux, and hERG inhibition, Ligand B is superior in terms of BBB penetration and has a much lower DILI risk. Given that this is a CNS target (DRD2), BBB penetration is paramount. The significantly lower DILI risk of Ligand B is also a major advantage. The slightly higher logP of Ligand B is a concern, but the strong BBB penetration and lower toxicity profile likely outweigh this drawback.

Output:
1
2025-04-17 07:25:56,959 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (355.36 and 344.459 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Both ligands (58.36 and 59.65) are below the 90 A^2 threshold desirable for CNS targets, which is excellent.

**3. logP:** Ligand A (3.536) is slightly higher than Ligand B (1.504). Both are within the optimal 1-3 range, but Ligand B is closer to the lower limit, potentially impacting permeability.

**4. H-Bond Donors:** Both ligands have 1 HBD, which is acceptable.

**5. H-Bond Acceptors:** Ligand A has 4 HBA, and Ligand B has 3. Both are below the 10 threshold.

**6. QED:** Both ligands have good QED scores (0.893 and 0.824), indicating good drug-like properties.

**7. DILI:** Ligand A (32.222) has a slightly higher DILI risk than Ligand B (12.485), but both are well below the concerning threshold of 60.

**8. BBB:** Both ligands have similar and good BBB penetration (66.072% and 66.925%), exceeding the 70% target, which is crucial for CNS targets like DRD2.

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.66 and -4.9), which is unusual and indicates poor permeability. This is a significant concern.

**10. Aqueous Solubility:** Both ligands have negative solubility values (-3.626 and -1.413), indicating poor solubility. This is also a concern.

**11. hERG Inhibition:** Both ligands have low hERG inhibition risk (0.596 and 0.407).

**12. Microsomal Clearance:** Ligand A (68.316) has a higher microsomal clearance than Ligand B (-7.234). Ligand B is negative, which is very favorable, suggesting much better metabolic stability.

**13. In vitro Half-Life:** Ligand B (-10.066) has a significantly longer in vitro half-life than Ligand A (-8.001).

**14. P-gp Efflux:** Both ligands have very low P-gp efflux (0.209 and 0.032), which is excellent for CNS penetration.

**15. Binding Affinity:** Both ligands have very similar and strong binding affinities (-8.2 and -8.3 kcal/mol). The difference is negligible.

**Overall Assessment:**

While both compounds have excellent binding affinity and BBB penetration, Ligand B is superior due to its significantly better metabolic stability (lower Cl_mic, longer t1/2) and lower DILI risk. The negative Caco-2 and solubility values are concerning for both, but metabolic stability is particularly important for GPCR ligands. The slightly better logP of Ligand A is not enough to offset the advantages of Ligand B.

Output:
1
2025-04-17 07:25:56,959 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (362.451 and 356.457 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (68.61) is higher than Ligand B (40.62). For a CNS target like DRD2, TPSA should ideally be <=90, so both are acceptable, but B is significantly better.

**logP:** Ligand A (2.297) and Ligand B (3.474) are both within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A has 0 HBD and 6 HBA, while Ligand B has 0 HBD and 2 HBA. Both are within acceptable limits (<=5 HBD and <=10 HBA).

**QED:** Both ligands have reasonable QED values (0.709 and 0.655), indicating good drug-like properties.

**DILI:** Ligand A (63.746) has a higher DILI risk than Ligand B (42.885). B is preferable here.

**BBB:** This is a critical parameter for CNS targets. Ligand B (96.316) has a much higher BBB penetration percentile than Ligand A (66.77). This is a major advantage for B.

**Caco-2 Permeability:** Both have negative values, which is unusual and suggests a potential issue with the data or a very poor permeability. However, the absolute value for A (-4.381) is worse than B (-4.246).

**Aqueous Solubility:** Both have negative values, suggesting very low solubility. A (-2.26) is slightly better than B (-3.016).

**hERG Inhibition:** Ligand A (0.248) has a slightly lower hERG inhibition risk than Ligand B (0.611), which is preferable.

**Microsomal Clearance:** Ligand A (110.625) has higher microsomal clearance than Ligand B (52.339), indicating lower metabolic stability. B is preferable.

**In vitro Half-Life:** Ligand B (-24.123) has a negative half-life, which is not physically possible and suggests a data error. Ligand A (9.958) has a reasonable half-life. This is a significant drawback for B.

**P-gp Efflux:** Ligand A (0.435) has a slightly lower P-gp efflux liability than Ligand B (0.261), which is preferable.

**Binding Affinity:** Ligand B (-8.1 kcal/mol) has a significantly stronger binding affinity than Ligand A (-7.3 kcal/mol). This >1.5 kcal/mol advantage is substantial and can outweigh some ADME drawbacks.

**Overall Assessment:**

Ligand B is clearly superior due to its significantly better BBB penetration and substantially stronger binding affinity. While it has a concerning negative half-life value and slightly higher hERG risk, the strong affinity and high BBB penetration are crucial for a CNS-targeting GPCR ligand. The DILI risk is also lower for B. The negative half-life for B is a red flag and needs to be investigated, but the other benefits are substantial. Ligand A has a better half-life and lower hERG, but its weaker affinity and lower BBB penetration are significant drawbacks.

Output:
1
2025-04-17 07:25:56,959 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 drug candidates, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (359.451 and 365.459 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (63.69) is significantly better than Ligand B (107.19). For CNS targets, we want TPSA <= 90, and A is comfortably within that, while B exceeds it. This is a significant advantage for A.

**3. logP:** Ligand A (1.942) is within the optimal 1-3 range. Ligand B (0.455) is a bit low, potentially hindering permeability.

**4. H-Bond Donors:** Ligand A (1) is good. Ligand B (3) is acceptable, but higher HBD can sometimes reduce permeability.

**5. H-Bond Acceptors:** Ligand A (6) is good. Ligand B (5) is also good.

**6. QED:** Ligand A (0.884) is excellent, indicating high drug-likeness. Ligand B (0.58) is acceptable, but less optimal.

**7. DILI:** Ligand A (68.476) is better than Ligand B (56.844), indicating a lower risk of drug-induced liver injury. Both are reasonably low.

**8. BBB:** Ligand A (51.454) is lower than Ligand B (66.615). While both are not ideal (>70 desirable), B is better for CNS penetration.

**9. Caco-2 Permeability:** Ligand A (-4.831) is poor. Ligand B (-5.818) is also poor. Both have very low Caco-2 permeability.

**10. Aqueous Solubility:** Ligand A (-2.037) is poor. Ligand B (-2.849) is also poor. Both have low aqueous solubility.

**11. hERG Inhibition:** Both ligands (0.403 and 0.339) show low hERG inhibition risk, which is good.

**12. Microsomal Clearance:** Ligand A (11.973) is significantly better than Ligand B (21.424), suggesting better metabolic stability.

**13. In vitro Half-Life:** Ligand A (1.934) is better than Ligand B (-17.122). A negative half-life is not physically possible and indicates a significant issue with the prediction for Ligand B.

**14. P-gp Efflux:** Ligand A (0.086) is much better than Ligand B (0.026), suggesting lower P-gp efflux and better CNS exposure.

**15. Binding Affinity:** Both ligands have very good binding affinities (-8.0 and -6.6 kcal/mol). Ligand A is 1.4 kcal/mol better, which is a substantial difference and can outweigh some ADME drawbacks.

**Overall Assessment:**

Ligand A is the stronger candidate. While Ligand B has a better BBB score, Ligand A excels in several critical areas: TPSA, logP, QED, metabolic stability (Cl_mic), in vitro half-life, P-gp efflux, and, most importantly, binding affinity. The significantly better affinity of Ligand A (-8.0 vs -6.6 kcal/mol) is a major advantage. The poor Caco-2 and solubility of both are concerns, but can be addressed with formulation strategies. The negative half-life prediction for Ligand B is a red flag.

Output:
1
2025-04-17 07:25:56,960 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (381.851 Da) is slightly higher than Ligand B (353.467 Da), but both are acceptable.

**2. TPSA:** Ligand A (72.88) is significantly better than Ligand B (107.77). For CNS targets, we want TPSA <= 90, and Ligand A is comfortably within this range, while Ligand B is above. This is a significant advantage for Ligand A.

**3. logP:** Ligand A (0.669) is slightly below the optimal 1-3 range, but still reasonable. Ligand B (-0.96) is below 1, which could indicate permeability issues. Ligand A is preferable.

**4. H-Bond Donors:** Both ligands have acceptable HBD counts (Ligand A: 2, Ligand B: 3).

**5. H-Bond Acceptors:** Both ligands have acceptable HBA counts (Ligand A: 4, Ligand B: 5).

**6. QED:** Both ligands have reasonable QED values (Ligand A: 0.686, Ligand B: 0.495), with Ligand A being slightly more drug-like.

**7. DILI:** Ligand A (33.579) has a much lower DILI risk than Ligand B (5.196), which is a significant advantage.

**8. BBB:** Ligand A (53.083) has a better BBB penetration percentile than Ligand B (42.458). While neither is >70, Ligand A is closer and more desirable for a CNS target.

**9. Caco-2 Permeability:** Ligand A (-4.931) is better than Ligand B (-6.188), indicating better intestinal absorption.

**10. Aqueous Solubility:** Ligand A (-1.243) is better than Ligand B (-1.145), though both are quite poor.

**11. hERG Inhibition:** Both ligands have very low hERG inhibition risk (Ligand A: 0.322, Ligand B: 0.048).

**12. Microsomal Clearance:** Ligand A (-7.08) has a much better (lower) microsomal clearance than Ligand B (-17.433), indicating better metabolic stability.

**13. In vitro Half-Life:** Ligand A (-9.656) has a better (longer) in vitro half-life than Ligand B (-23.452).

**14. P-gp Efflux:** Ligand A (0.055) has a lower P-gp efflux liability than Ligand B (0.0). This is a positive for CNS exposure.

**15. Binding Affinity:** Both ligands have similar binding affinities (Ligand A: -7.8 kcal/mol, Ligand B: -7.9 kcal/mol). The difference is negligible.

**Overall Assessment:**

Ligand A consistently outperforms Ligand B across most ADME-Tox properties crucial for CNS drug development, particularly TPSA, BBB, DILI, metabolic stability (Cl_mic and t1/2), and P-gp efflux. While both have similar binding affinities, the superior ADME profile of Ligand A makes it a much more promising drug candidate.

Output:
1
2025-04-17 07:25:56,960 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (346.471 and 361.515 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (67.43) is better than Ligand B (74.81). Both are below the 90 A^2 threshold desirable for CNS targets, but A is closer to the optimal range.

**3. logP:** Both ligands have good logP values (2.026 and 2.759), falling within the 1-3 optimal range.

**4. H-Bond Donors:** Ligand A (2) is reasonable. Ligand B (0) is also acceptable, potentially improving membrane permeability.

**5. H-Bond Acceptors:** Ligand A (3) is good. Ligand B (6) is slightly higher, but still within the acceptable limit of 10.

**6. QED:** Both ligands have good QED scores (0.661 and 0.779), indicating drug-like properties.

**7. DILI:** Ligand A (22.024) has a lower DILI risk than Ligand B (32.454), which is preferable.

**8. BBB:** Both ligands have excellent BBB penetration (72.082 and 72.896), exceeding the 70% threshold for CNS targets.

**9. Caco-2 Permeability:** Ligand A (-5.054) has a worse Caco-2 permeability than Ligand B (-5.21), suggesting B may have slightly better intestinal absorption. However, both are negative values, indicating low permeability.

**10. Aqueous Solubility:** Both ligands have very poor aqueous solubility (-2.771 and -2.745). This is a significant concern for both.

**11. hERG Inhibition:** Ligand A (0.154) has a lower hERG inhibition risk than Ligand B (0.35), which is preferable.

**12. Microsomal Clearance:** Ligand A (37.38) has a lower microsomal clearance than Ligand B (58.405), indicating better metabolic stability.

**13. In vitro Half-Life:** Ligand A (15.114) has a longer in vitro half-life than Ligand B (-15.1), which is a significant advantage.

**14. P-gp Efflux:** Ligand A (0.085) has a lower P-gp efflux liability than Ligand B (0.236), which is beneficial for CNS exposure.

**15. Binding Affinity:** Ligand A (-7.8 kcal/mol) has a significantly stronger binding affinity than Ligand B (-6.8 kcal/mol). This 1.0 kcal/mol difference is substantial and can outweigh some of the ADME drawbacks.

**Overall Assessment:**

Ligand A is the better candidate. While both compounds have poor solubility, Ligand A demonstrates superior binding affinity, lower DILI risk, better metabolic stability (lower Cl_mic and longer t1/2), lower P-gp efflux, and lower hERG inhibition. The stronger binding affinity is a crucial advantage for a GPCR target, and the other improvements in ADME properties make Ligand A more promising despite the shared solubility issue.

Output:
1
2025-04-17 07:25:56,960 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (353.369 and 350.365 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (77.59) is slightly higher than Ligand B (70.59). Both are below the 90 A^2 threshold desirable for CNS targets, but Ligand B is preferable.

**3. logP:** Ligand A (1.956) is within the optimal 1-3 range. Ligand B (3.822) is at the higher end, potentially raising concerns about solubility and off-target effects, but still acceptable.

**4. H-Bond Donors:** Both ligands have 3 HBD, which is within the acceptable limit of <=5.

**5. H-Bond Acceptors:** Ligand A has 4 HBA, and Ligand B has 3. Both are below the acceptable limit of <=10.

**6. QED:** Both ligands have a QED of 0.742, indicating good drug-likeness.

**7. DILI:** Ligand A (45.095) has a lower DILI risk than Ligand B (61.07). This is a significant advantage for Ligand A.

**8. BBB:** Ligand A (76.541) has a better BBB penetration percentile than Ligand B (45.909). This is *critical* for a CNS target like DRD2, making Ligand A much more promising.

**9. Caco-2 Permeability:** Both have negative values (-4.989 and -4.81), indicating poor permeability. This is a potential issue for both, but the values are close.

**10. Aqueous Solubility:** Both have negative values (-3.331 and -4.664), indicating poor solubility. This is a concern for both compounds.

**11. hERG Inhibition:** Both ligands have low hERG inhibition risk (0.935 and 0.691).

**12. Microsomal Clearance:** Ligand A (-33.162) has a significantly lower (better) microsomal clearance than Ligand B (65.886), indicating greater metabolic stability.

**13. In vitro Half-Life:** Ligand A (31.167) has a longer half-life than Ligand B (16.76). This is a positive attribute for Ligand A.

**14. P-gp Efflux:** Both ligands have low P-gp efflux liability (0.233 and 0.203).

**15. Binding Affinity:** Both ligands have identical binding affinities (-9.2 kcal/mol), which is excellent.

**Overall Assessment:**

While both ligands have good binding affinity and acceptable drug-likeness, Ligand A is significantly better due to its superior BBB penetration (76.541 vs 45.909), lower DILI risk (45.095 vs 61.07), lower microsomal clearance (-33.162 vs 65.886), and longer half-life (31.167 vs 16.76). The slightly higher TPSA of Ligand A is a minor drawback compared to these advantages, especially given the importance of BBB penetration for a CNS target.

Output:
1
2025-04-17 07:25:56,960 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (350.419 and 348.491 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (95.74) is slightly above the preferred <90 for CNS targets, but still reasonable. Ligand B (67.23) is well within the optimal range. This favors Ligand B.

**logP:** Ligand A (-0.14) is quite low, potentially hindering membrane permeability. Ligand B (2.522) is within the optimal 1-3 range. This is a significant advantage for Ligand B.

**H-Bond Donors/Acceptors:** Both have 1 HBD, which is good. Ligand A has 6 HBA, and Ligand B has 4 HBA, both within acceptable limits (<=10).

**QED:** Both ligands have good QED scores (0.77 and 0.859), indicating drug-like properties.

**DILI:** Ligand A (53.625) has a moderate DILI risk, while Ligand B (24.351) has a low DILI risk. This favors Ligand B.

**BBB:** Ligand A (42.924) has a low BBB penetration, which is a major concern for a CNS target like DRD2. Ligand B (72.043) has good BBB penetration, exceeding the desirable >70 threshold. This is a crucial advantage for Ligand B.

**Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and suggests poor permeability. However, the scale is not specified, so it is hard to interpret.

**Aqueous Solubility:** Both have negative solubility values, which is also unusual and suggests poor solubility.

**hERG:** Ligand A (0.111) has a very low hERG risk, while Ligand B (0.637) has a slightly elevated, but still acceptable, hERG risk.

**Microsomal Clearance:** Ligand A (20.51) and Ligand B (42.371) both have relatively high microsomal clearance, suggesting moderate metabolic instability.

**In vitro Half-Life:** Ligand A (-3.216) has a negative half-life, which is not possible and suggests an issue with the data. Ligand B (-0.545) also has a negative half-life, indicating a data quality issue.

**P-gp Efflux:** Ligand A (0.068) has low P-gp efflux, which is good. Ligand B (0.218) also has low P-gp efflux, which is good.

**Binding Affinity:** Ligand B (-7.8 kcal/mol) has a slightly better binding affinity than Ligand A (-7.2 kcal/mol), although both are good. The 0.6 kcal/mol difference is significant enough to consider, especially given the other ADME properties.

**Overall Assessment:**

Ligand B is significantly more promising due to its superior logP, BBB penetration, and lower DILI risk. While both have issues with Caco-2 and solubility, the BBB penetration is paramount for a CNS target. The slightly better affinity of Ligand B further strengthens its position. The negative half-life values are concerning and would need to be investigated, but the other factors strongly favor Ligand B.

Output:
1
2025-04-17 07:25:56,960 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 drug candidates, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (364.804 and 345.374 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (68.29) is significantly better than Ligand B (97.21). For CNS targets, we want TPSA <= 90, so Ligand A is much more favorable.

**3. logP:** Both ligands have acceptable logP values (3.227 and 1.616), falling within the 1-3 range. Ligand A is slightly higher, which could be beneficial for membrane permeability, but not excessively high.

**4. H-Bond Donors:** Ligand A (1) is better than Ligand B (3). Lower HBD generally improves permeability.

**5. H-Bond Acceptors:** Both ligands have the same number of HBA (4), which is within the acceptable limit of <= 10.

**6. QED:** Both ligands have similar QED values (0.605 and 0.693), indicating good drug-like properties.

**7. DILI:** Ligand A (72.043) has a higher DILI risk than Ligand B (51.221). This is a negative for Ligand A, but both are reasonably low.

**8. BBB:** Both ligands have excellent BBB penetration (70.531 and 75.107), exceeding the desirable >70 threshold for CNS targets.

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 permeability values (-4.612 and -4.678). This is unusual and suggests a potential issue with the data or the model used to predict it. However, since both are similarly negative, it doesn't differentiate them.

**10. Aqueous Solubility:** Both ligands have negative aqueous solubility values (-3.71 and -3.406). Similar to Caco-2, this is concerning but consistent between the two.

**11. hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.281 and 0.269), which is excellent.

**12. Microsomal Clearance:** Ligand B (24.569) has significantly lower microsomal clearance than Ligand A (92.061). Lower clearance indicates better metabolic stability, a major advantage for Ligand B.

**13. In vitro Half-Life:** Ligand B (-9.072) has a longer in vitro half-life than Ligand A (8.081). This is a positive for Ligand B.

**14. P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.103 and 0.028), which is excellent for CNS penetration.

**15. Binding Affinity:** Ligand B (-8.3) has a slightly better binding affinity than Ligand A (-9.0). While both are excellent, a difference of 0.7 kcal/mol is notable.

**Overall Assessment:**

Ligand B is the more promising candidate. While Ligand A has a slightly better logP, Ligand B excels in several critical areas: TPSA, metabolic stability (Cl_mic, t1/2), and binding affinity. The lower TPSA of Ligand A is attractive, but the significant improvements in metabolic stability and binding affinity of Ligand B outweigh this advantage. Both have good BBB penetration and low hERG risk. The negative Caco-2 and solubility values are concerning for both, but don't differentiate them.

Output:
1
2025-04-17 07:25:56,960 - INFO - Reasoning:

Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight (MW):** Both ligands (361.515 and 342.443 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Both ligands have TPSA values (59.64 and 58.44) below the 90 A^2 threshold for CNS targets, which is excellent.

**3. logP:** Both ligands have logP values (1.665 and 1.546) within the optimal 1-3 range.

**4. H-Bond Donors (HBD):** Ligand A has 3 HBD, which is acceptable. Ligand B has 0 HBD, also acceptable.

**5. H-Bond Acceptors (HBA):** Ligand A has 3 HBA, and Ligand B has 4 HBA, both within the acceptable limit of <=10.

**6. QED:** Both ligands have QED values (0.712 and 0.763) above 0.5, indicating good drug-like properties.

**7. DILI:** Ligand A (18.651) has a lower DILI risk than Ligand B (29.934), which is a positive attribute.

**8. BBB:** Ligand B (73.401) has a significantly better BBB penetration percentile than Ligand A (66.499). This is a crucial factor for a CNS target like DRD2.

**9. Caco-2 Permeability:** Both have negative values, indicating poor permeability. Ligand A (-5.49) is slightly better than Ligand B (-4.676), but both are concerning.

**10. Aqueous Solubility:** Both ligands have negative solubility values, indicating poor aqueous solubility. Ligand A (-1.976) is slightly better than Ligand B (-1.385).

**11. hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.516 and 0.142).

**12. Microsomal Clearance (Cl_mic):** Ligand A (-45.533) has a lower (better) Cl_mic than Ligand B (39.296), suggesting better metabolic stability.

**13. In vitro Half-Life:** Ligand A (39.457) has a longer in vitro half-life than Ligand B (-8.227), which is desirable.

**14. P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.025 and 0.1).

**15. Binding Affinity:** Both ligands have excellent binding affinity (-9.4 and -8.4 kcal/mol). Ligand A is slightly stronger.

**Overall Assessment:**

While Ligand A has slightly better metabolic stability (lower Cl_mic, longer half-life) and a lower DILI risk, Ligand B's significantly higher BBB penetration (73.401 vs 66.499) is a critical advantage for a CNS target like DRD2. The affinity difference is relatively small (1 kcal/mol), and the BBB advantage outweighs the slight differences in other parameters.

Output:
1
2025-04-17 07:25:56,960 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (333.395 Da) is slightly lower, which could be beneficial for permeability.

**2. TPSA:** Ligand A (75.08) is better than Ligand B (60.25). For CNS targets, we want TPSA <= 90, both are well within this range.

**3. logP:** Both ligands have optimal logP values (around 2.8), indicating good partitioning properties.

**4. H-Bond Donors:** Ligand A (2) is preferable to Ligand B (0). Having some H-bond donors can aid solubility.

**5. H-Bond Acceptors:** Ligand B (7) is preferable to Ligand A (4).

**6. QED:** Both ligands have good QED scores (>0.5), indicating drug-like properties. Ligand B (0.739) is slightly better.

**7. DILI:** Both ligands have similar, acceptable DILI risk (around 70 percentile).

**8. BBB:** Ligand B (68.592) is better than Ligand A (57.154). A BBB percentile >70 is desirable for CNS targets, and Ligand B is closer to this threshold.

**9. Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual. However, the magnitude is similar.

**10. Aqueous Solubility:** Both have negative solubility values, which is also unusual. The magnitude is similar.

**11. hERG Inhibition:** Ligand A (0.917) is slightly higher than Ligand B (0.352), suggesting a slightly higher risk of hERG inhibition.

**12. Microsomal Clearance:** Ligand A (52.193) has lower clearance than Ligand B (69.438), indicating better metabolic stability.

**13. In vitro Half-Life:** Ligand A (-22.249) has a much longer half-life than Ligand B (6.279). This is a significant advantage.

**14. P-gp Efflux:** Ligand A (0.533) has lower P-gp efflux liability than Ligand B (0.167), which is beneficial for CNS exposure.

**15. Binding Affinity:** Ligand B (-7.6 kcal/mol) has a significantly stronger binding affinity than Ligand A (-10.1 kcal/mol). This is a major advantage, potentially outweighing some ADME drawbacks.

**Overall Assessment:**

While Ligand A has better metabolic stability (lower Cl_mic, longer t1/2) and lower P-gp efflux, Ligand B's substantially stronger binding affinity (-7.6 vs -10.1 kcal/mol) and better BBB penetration (68.592 vs 57.154) are more critical for a CNS-targeting GPCR like DRD2. The difference in affinity is significant. The slightly higher hERG risk with Ligand B is a concern, but could be addressed with further optimization.

Output:
1
2025-04-17 07:25:56,960 - INFO - Reasoning:

Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (348.447 and 363.571 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (105.48) is slightly above the optimal <90 for CNS targets, but still reasonable. Ligand B (48.99) is excellent, well below the threshold.

**3. logP:** Both ligands have good logP values (2.432 and 4.584), falling within the 1-3 range, although Ligand B is approaching the upper limit.

**4. H-Bond Donors:** Ligand A has 4 HBD, acceptable. Ligand B has 1 HBD, also acceptable.

**5. H-Bond Acceptors:** Ligand A has 4 HBA, acceptable. Ligand B has 3 HBA, acceptable.

**6. QED:** Both ligands have good QED scores (0.627 and 0.698), indicating good drug-like properties.

**7. DILI:** Ligand A (39.667) has a slightly higher DILI risk than Ligand B (21.636), but both are below the concerning threshold of 60.

**8. BBB:** Both ligands exhibit excellent BBB penetration (77.627 and 78.635 percentile), which is crucial for a CNS target like DRD2.

**9. Caco-2:** Both ligands have negative Caco-2 values (-4.943 and -5.13), which is unusual and suggests poor permeability. This is a significant drawback for both.

**10. Solubility:** Both ligands have negative solubility values (-3.221 and -4.541), indicating poor aqueous solubility. This is also a significant drawback.

**11. hERG:** Both ligands have low hERG inhibition risk (0.29 and 0.563).

**12. Cl_mic:** Ligand A (58.797) has a lower microsomal clearance than Ligand B (88.683), suggesting better metabolic stability.

**13. t1/2:** Ligand A (-13.701) has a more negative in vitro half-life, which is problematic. Ligand B (-5.073) is also negative, but less so. Both are concerning.

**14. Pgp:** Both ligands have very low P-gp efflux liability (0.016 and 0.332), which is favorable for CNS penetration.

**15. Binding Affinity:** Ligand B (-7.8 kcal/mol) has a slightly better binding affinity than Ligand A (-8.5 kcal/mol). While both are good, the difference is small.

**Overall Assessment:**

Both ligands have significant drawbacks in Caco-2 permeability and aqueous solubility. However, considering the GPCR-specific priorities, Ligand B appears slightly more promising. It has a better logP value, lower DILI risk, and a slightly better binding affinity. While its metabolic stability is worse, the difference isn't substantial. The negative half-life values are concerning for both, but the less negative value for Ligand B is preferable.

Output:
1
2025-04-17 07:25:56,961 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight (MW):** Both ligands are within the ideal range (200-500 Da). Ligand A (342.395 Da) is slightly lower, which could be advantageous for permeability.

**2. TPSA:** Both ligands are below the 140 A^2 threshold for oral absorption, but only Ligand A (92.43 A^2) is closer to the more stringent <90 A^2 for CNS targets. Ligand B (95.04 A^2) is slightly higher.

**3. logP:** Both ligands have optimal logP values (1-3). Ligand A (2.952) is slightly higher than Ligand B (1.555), which might offer better membrane permeability, but Ligand B is still within a good range.

**4. H-Bond Donors (HBD):** Both ligands are within the acceptable limit of <=5. Ligand A has 2, and Ligand B has 1.

**5. H-Bond Acceptors (HBA):** Both ligands are within the acceptable limit of <=10. Ligand A has 4, and Ligand B has 7.

**6. QED:** Both ligands have reasonably good QED scores (>0.5), indicating drug-likeness. Ligand A (0.871) is better than Ligand B (0.699).

**7. DILI:** Ligand A (72.819%) has a higher DILI risk than Ligand B (35.789%). This is a significant drawback for Ligand A.

**8. BBB:** Ligand B (65.839%) has a significantly better BBB penetration score than Ligand A (44.591%). This is crucial for a CNS target like DRD2.

**9. Caco-2 Permeability:** Ligand A (-4.931) has better Caco-2 permeability than Ligand B (-5.137). However, both are negative, indicating poor permeability.

**10. Aqueous Solubility:** Ligand A (-3.159) has slightly better solubility than Ligand B (-2.003), but both are poor.

**11. hERG Inhibition:** Both ligands have very low hERG inhibition liability, which is good. Ligand A (0.015) is slightly lower than Ligand B (0.392).

**12. Microsomal Clearance:** Ligand A (12.439 mL/min/kg) has a higher clearance than Ligand B (8.022 mL/min/kg), indicating lower metabolic stability.

**13. In vitro Half-Life:** Ligand B (-2.376 hours) has a better in vitro half-life than Ligand A (-29.38 hours).

**14. P-gp Efflux:** Ligand A (0.014) has lower P-gp efflux liability than Ligand B (0.175), which is beneficial for CNS exposure.

**15. Binding Affinity:** Ligand A (-8.8 kcal/mol) has a significantly stronger binding affinity than Ligand B (-7.4 kcal/mol). This is a substantial advantage.

**Overall Assessment:**

While Ligand A boasts a superior binding affinity and better P-gp efflux, its higher DILI risk, poorer BBB penetration, and lower metabolic stability are major concerns. Ligand B, despite a slightly weaker affinity, presents a much more favorable ADME-Tox profile, particularly its significantly better BBB penetration and lower DILI risk, which are critical for a CNS drug targeting DRD2. The difference in binding affinity (1.4 kcal/mol) is significant, but the ADME/Tox profile of Ligand B is more promising.

Output:
1
2025-04-17 07:25:56,961 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (385.247 and 368.503 Da) are within the ideal 200-500 Da range.

**TPSA:** Ligand A (80.68) is better than Ligand B (88.18). Both are below the 90 A^2 threshold desirable for CNS targets, but A is closer to the ideal.

**logP:** Ligand A (3.907) is slightly higher than Ligand B (2.557), both are within the optimal 1-3 range, but A is approaching the upper limit.

**H-Bond Donors:** Both ligands have 2 HBD, which is acceptable.

**H-Bond Acceptors:** Ligand A has 5 HBA, and Ligand B has 6. Both are within the acceptable limit of 10.

**QED:** Ligand A (0.756) has a better QED score than Ligand B (0.439), indicating a more drug-like profile.

**DILI:** Ligand B (59.364) has a lower DILI risk than Ligand A (77.627), which is a significant advantage.

**BBB:** Ligand A (57.154) and Ligand B (51.066) both have BBB penetration below the desirable 70% threshold for CNS targets. However, A is slightly better.

**Caco-2 Permeability:** Ligand A (-4.68) has a worse Caco-2 permeability than Ligand B (-5.116). Lower values indicate lower permeability.

**Aqueous Solubility:** Ligand A (-4.984) has worse aqueous solubility than Ligand B (-2.702).

**hERG Inhibition:** Ligand A (0.471) has a slightly higher hERG inhibition risk than Ligand B (0.213), but both are relatively low.

**Microsomal Clearance:** Ligand B (57.584) has slightly lower microsomal clearance than Ligand A (51.987), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand B (-3.214) has a longer in vitro half-life than Ligand A (44.646).

**P-gp Efflux:** Ligand A (0.332) has lower P-gp efflux than Ligand B (0.214), which is favorable for CNS penetration.

**Binding Affinity:** Ligand A (-8.2 kcal/mol) has a significantly stronger binding affinity than Ligand B (-7.2 kcal/mol). This is a >1 kcal/mol difference, which can outweigh some ADME drawbacks.

**Overall Assessment:**

While Ligand B has better DILI, solubility, metabolic stability and half-life, Ligand A's significantly stronger binding affinity (-8.2 vs -7.2 kcal/mol) and slightly better BBB penetration are crucial for a CNS GPCR target like DRD2. The higher logP of Ligand A is a minor concern, and the slightly higher DILI risk might be manageable with further optimization. The lower Pgp efflux of ligand A is also advantageous. The difference in binding affinity is substantial enough to favor Ligand A despite its other shortcomings.

Output:
1
2025-04-17 07:25:56,961 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (340.343 and 349.381 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (135.17) is slightly above the optimal <90 for CNS targets, but still reasonable. Ligand B (73.2) is excellent, well below 90. This favors Ligand B.

**3. logP:** Both ligands have good logP values (1.51 and 2.021), falling within the 1-3 range.

**4. H-Bond Donors:** Ligand A (4) is acceptable, while Ligand B (1) is even better, minimizing potential permeability issues.

**5. H-Bond Acceptors:** Ligand A (6) is acceptable, and Ligand B (3) is also good.

**6. QED:** Both ligands have good QED scores (0.534 and 0.772), indicating drug-like properties. Ligand B is better.

**7. DILI:** Ligand A (94.765) has a concerningly high DILI risk (above 60). Ligand B (27.414) has a low DILI risk, a significant advantage.

**8. BBB:** Ligand A (44.591) has a poor BBB penetration percentile. Ligand B (92.555) has excellent BBB penetration, crucial for a CNS target like DRD2. This is a major advantage for Ligand B.

**9. Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and problematic. However, the magnitude is similar, so this doesn't strongly differentiate them.

**10. Aqueous Solubility:** Both have negative solubility values, which is also unusual and problematic. Again, the magnitude is similar.

**11. hERG:** Both ligands have very low hERG inhibition liability (0.126 and 0.615), which is excellent.

**12. Microsomal Clearance:** Ligand A (0.554) has lower clearance, suggesting better metabolic stability than Ligand B (2.927).

**13. In vitro Half-Life:** Ligand A (68.84) has a much longer half-life than Ligand B (-10.68). This is a significant advantage for Ligand A.

**14. P-gp Efflux:** Ligand A (0.004) has very low P-gp efflux, which is excellent. Ligand B (0.109) is also low, but higher than A.

**15. Binding Affinity:** Both ligands have strong binding affinities (-9.7 and -8.3 kcal/mol). Ligand A is slightly better (-9.7 kcal/mol).

**Overall Assessment:**

Despite Ligand A having slightly better affinity and metabolic stability (lower Cl_mic, longer t1/2), Ligand B is the stronger candidate. The critical factors are the significantly lower DILI risk and *much* higher BBB penetration of Ligand B. For a CNS target like DRD2, BBB penetration is paramount. The high DILI risk of Ligand A is a major red flag. While Ligand A's affinity is marginally better, the ADME properties of Ligand B are far more favorable for development as a CNS drug.

Output:
1
2025-04-17 07:25:56,961 - INFO - Batch 364 complete. Total preferences: 5824
2025-04-17 07:25:56,961 - INFO - Processing batch 365/512...
2025-04-17 07:26:42,197 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (347.415 and 348.399 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (99.5) is slightly higher than Ligand B (92.01). Both are below the 140 threshold for oral absorption and reasonably close to the 90 target for CNS penetration, but Ligand B is preferable.

**logP:** Ligand A (0.843) is slightly higher than Ligand B (0.575). Both are within the optimal 1-3 range, but closer to the lower end.

**H-Bond Donors/Acceptors:** Ligand A has 1 HBD and 5 HBA, while Ligand B has 2 HBD and 5 HBA. Both are within acceptable limits (<=5 HBD and <=10 HBA).

**QED:** Ligand A (0.76) has a better QED score than Ligand B (0.555), indicating a more drug-like profile.

**DILI:** Ligand B (20.512) has a significantly lower DILI risk than Ligand A (35.052). This is a substantial advantage for Ligand B.

**BBB:** Ligand A (56.65) has a better BBB penetration percentile than Ligand B (46.568). This is a crucial factor for a CNS target like DRD2, making Ligand A initially more appealing.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.535 and -4.735), which is unusual and suggests poor permeability.

**Aqueous Solubility:** Both ligands have negative solubility values (-2.182 and -1.682), which is also unusual and suggests poor solubility.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.213 and 0.361).

**Microsomal Clearance:** Ligand B (-9.851) has a significantly *lower* (better) microsomal clearance than Ligand A (26.229), indicating greater metabolic stability.

**In vitro Half-Life:** Ligand B (0.375) has a slightly lower in vitro half-life than Ligand A (-3.625), but both are very low.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.016 and 0.151).

**Binding Affinity:** Both ligands have very similar binding affinities (-7.3 and -7.2 kcal/mol). The difference is minimal.

**Overall Assessment:**

While Ligand A has a better BBB score and QED, Ligand B demonstrates significantly better safety (lower DILI) and metabolic stability (lower Cl_mic). The binding affinities are nearly identical. Given the GPCR-specific priorities, the improved safety and metabolic stability of Ligand B outweigh the slightly better BBB prediction of Ligand A. The poor Caco-2 and solubility values are concerning for both, but can potentially be addressed with formulation strategies.

Output:
1
2025-04-17 07:26:42,197 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (381.259 Da and 350.459 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (67.43) is significantly better than Ligand B (80.57). For CNS targets, we want TPSA <= 90, and A is closer to the ideal <60. B is pushing the upper limit.

**3. logP:** Ligand A (4.149) is slightly higher than the optimal 1-3 range, but still potentially acceptable. Ligand B (2.664) is well within the optimal range.

**4. H-Bond Donors:** Both have 2 HBDs, which is within the acceptable limit of <=5.

**5. H-Bond Acceptors:** Ligand A has 3 HBAs, and Ligand B has 4. Both are within the acceptable limit of <=10.

**6. QED:** Both ligands have good QED scores (0.79 and 0.855), indicating good drug-like properties.

**7. DILI:** Ligand A (80.109) has a higher DILI risk than Ligand B (39.395). This is a significant negative for Ligand A.

**8. BBB:** Both ligands have reasonably good BBB penetration (54.556% and 56.65%), but neither exceeds the desirable >70% threshold.

**9. Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and suggests poor permeability. However, the scale is not specified, so it's difficult to interpret.

**10. Aqueous Solubility:** Both have negative solubility values, which is also unusual and suggests poor solubility. Again, the scale is unspecified.

**11. hERG Inhibition:** Both ligands have low hERG inhibition risk (0.462 and 0.452).

**12. Microsomal Clearance:** Ligand A (32.152) has lower microsomal clearance than Ligand B (35.534), suggesting better metabolic stability.

**13. In vitro Half-Life:** Ligand A (56.371) has a longer half-life than Ligand B (39.539), which is desirable.

**14. P-gp Efflux:** Both have low P-gp efflux liability (0.294 and 0.095), which is good for CNS penetration.

**15. Binding Affinity:** Ligand B (-7.9 kcal/mol) has a significantly stronger binding affinity than Ligand A (-9.5 kcal/mol). This is a crucial advantage, exceeding the 1.5 kcal/mol difference threshold.

**Overall Assessment:**

While Ligand A has better metabolic stability and half-life, Ligand B is superior due to its significantly stronger binding affinity and lower DILI risk. The higher logP of Ligand A is a concern, and the DILI risk is substantial. The TPSA of Ligand B is a slight drawback, but the affinity difference is large enough to outweigh this. Given the GPCR-specific priorities, the strong binding affinity of Ligand B is the most important factor.

Output:
1
2025-04-17 07:26:42,197 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (356.482 and 350.459 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (60.85) is significantly better than Ligand B (67.87). For CNS targets, we want TPSA <= 90, both are within this range, but A is closer to the optimal range.

**3. logP:** Both ligands have good logP values (2.371 and 1.668), falling within the 1-3 optimal range.

**4. H-Bond Donors:** Both have 1 HBD, which is acceptable.

**5. H-Bond Acceptors:** Ligand A has 3 HBA, and Ligand B has 4. Both are acceptable (<=10).

**6. QED:** Both ligands have similar QED values (0.69 and 0.605), indicating good drug-likeness.

**7. DILI:** Ligand A (13.843) has a much lower DILI risk than Ligand B (37.185). This is a significant advantage for A.

**8. BBB:** Ligand A (88.135) has a substantially higher BBB penetration percentile than Ligand B (61.729). This is *critical* for a CNS target like DRD2.

**9. Caco-2 Permeability:** Ligand A (-4.419) is better than Ligand B (-4.873) but both are negative values, indicating poor permeability.

**10. Aqueous Solubility:** Ligand A (-2.035) is better than Ligand B (-1.635) but both are negative values, indicating poor solubility.

**11. hERG Inhibition:** Ligand A (0.71) has a slightly higher hERG risk than Ligand B (0.129). This is a minor drawback for A, but B is much better.

**12. Microsomal Clearance:** Ligand A (48.689) has higher clearance than Ligand B (23.31). This means B is more metabolically stable.

**13. In vitro Half-Life:** Ligand A (-15.209) has a negative half-life, which is not possible. This is a major red flag. Ligand B (9.489) has a reasonable half-life.

**14. P-gp Efflux:** Ligand A (0.189) has lower P-gp efflux than Ligand B (0.03). This is beneficial for CNS exposure.

**15. Binding Affinity:** Ligand A (-7.5) has a significantly stronger binding affinity than Ligand B (0.0). This is a major advantage for A, potentially outweighing some other drawbacks.

**Overall Assessment:**

Despite the negative half-life value for Ligand A, the significantly better binding affinity (-7.5 vs 0.0), superior BBB penetration (88.135 vs 61.729), and lower DILI risk (13.843 vs 37.185) make it the more promising candidate. The negative half-life is a serious concern that would need to be investigated further (potentially a data error), but the strong binding affinity could allow for a lower dose, potentially mitigating some ADME issues. Ligand B's hERG inhibition is better, but the weak binding affinity is a deal-breaker.

Output:
1
2025-04-17 07:26:42,197 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (357.816 and 359.312 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (54.02) is excellent, well below the 90 A^2 threshold for CNS targets. Ligand B (106.85) is higher, but still potentially acceptable, though less ideal.

**3. logP:** Ligand A (4.144) is slightly high, potentially leading to solubility issues or off-target interactions. Ligand B (1.3) is quite low, which could hinder membrane permeability and brain penetration.

**4. H-Bond Donors:** Both ligands have 2 HBD, which is within the acceptable limit of <=5.

**5. H-Bond Acceptors:** Ligand A has 3 HBA, and Ligand B has 7. Both are within the acceptable limit of <=10, but Ligand B is approaching the upper end.

**6. QED:** Both ligands have similar QED values (0.721 and 0.722), indicating good drug-likeness.

**7. DILI:** Ligand A (80.147) has a higher DILI risk than Ligand B (72.043), but both are reasonably acceptable.

**8. BBB:** Ligand B (83.715) has a significantly better BBB penetration score than Ligand A (70.997). This is a crucial advantage for a CNS target like DRD2.

**9. Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and difficult to interpret without knowing the scale. However, the magnitude of the negative value for Ligand A (-4.954) is less than that of Ligand B (-5.183), suggesting potentially slightly better absorption for A.

**10. Aqueous Solubility:** Ligand A (-4.556) has better solubility than Ligand B (-2.19), which is important given its higher logP.

**11. hERG Inhibition:** Both ligands show very low hERG inhibition risk (0.695 and 0.115), which is excellent.

**12. Microsomal Clearance:** Ligand B (26.632) has significantly lower microsomal clearance than Ligand A (78.175), indicating better metabolic stability.

**13. In vitro Half-Life:** Ligand A (108.88) has a much longer in vitro half-life than Ligand B (-10.423). The negative value for B is concerning and suggests rapid degradation.

**14. P-gp Efflux:** Ligand A (0.307) has lower P-gp efflux liability than Ligand B (0.124), which is favorable for CNS penetration.

**15. Binding Affinity:** Ligand B (-8.2 kcal/mol) has a significantly stronger binding affinity than Ligand A (-9.9 kcal/mol). This is a substantial advantage, potentially outweighing some of its ADME drawbacks.

**Overall Assessment:**

Ligand B excels in binding affinity and BBB penetration, which are critical for a CNS-targeting GPCR. Its lower metabolic stability and slightly higher TPSA are concerns, but the strong affinity and excellent BBB penetration are likely to be more impactful. Ligand A has better solubility, lower P-gp efflux, and a longer half-life, but its higher logP and lower BBB penetration are significant drawbacks. The substantial affinity difference (-8.2 vs -9.9 kcal/mol) heavily favors Ligand B.

Output:
1
2025-04-17 07:26:42,197 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (366.531 and 350.503 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Both ligands have TPSA values (67.84 and 67.43) slightly above the optimal <90 for CNS targets, but still reasonable.

**3. logP:** Both ligands have logP values (2.064 and 2.807) within the optimal 1-3 range. Ligand B is slightly higher, which could be beneficial for membrane permeability.

**4. H-Bond Donors:** Ligand A has 3 HBD, and Ligand B has 2. Both are acceptable (<=5).

**5. H-Bond Acceptors:** Ligand A has 5 HBA, and Ligand B has 3. Both are acceptable (<=10).

**6. QED:** Both ligands have QED values (0.657 and 0.595) above the 0.5 threshold, indicating good drug-like properties.

**7. DILI:** Ligand A has a DILI risk of 43.738, while Ligand B has 12.796. Ligand B is significantly better regarding DILI risk, falling well below the 40 threshold.

**8. BBB:** Ligand A has a BBB penetration of 49.748, while Ligand B has 70.105. Ligand B is considerably better, exceeding the desirable >70 threshold for CNS targets. This is a major advantage.

**9. Caco-2 Permeability:** Ligand A has a negative Caco-2 value (-5.3), which is concerning and suggests poor permeability. Ligand B also has a negative value (-4.772), also concerning.

**10. Aqueous Solubility:** Both ligands have negative solubility values (-2.152 and -2.898), indicating poor aqueous solubility. This is a drawback for both.

**11. hERG Inhibition:** Ligand A has a hERG inhibition risk of 0.803, while Ligand B has 0.372. Ligand B is significantly better, indicating a lower risk of cardiotoxicity.

**12. Microsomal Clearance:** Ligand A has a Cl_mic of 7.772, and Ligand B has 64.213. Ligand A is much better, suggesting greater metabolic stability.

**13. In vitro Half-Life:** Ligand A has a t1/2 of 54.195 hours, while Ligand B has -3.908 hours. Ligand A is significantly better, indicating a longer half-life.

**14. P-gp Efflux:** Ligand A has a Pgp efflux liability of 0.057, while Ligand B has 0.157. Ligand A is better, indicating lower P-gp efflux.

**15. Binding Affinity:** Ligand A has a binding affinity of -7.6 kcal/mol, and Ligand B has -7.8 kcal/mol. Ligand B has a slightly better binding affinity, but the difference is relatively small (0.2 kcal/mol).

**Overall Assessment:**

While Ligand A has better metabolic stability (lower Cl_mic, longer t1/2) and P-gp efflux, Ligand B excels in crucial areas for a CNS-targeting GPCR ligand: significantly better BBB penetration (70.105 vs 49.748), lower DILI risk (12.796 vs 43.738), and lower hERG risk (0.372 vs 0.803). The slightly better affinity of Ligand B further supports its selection. The negative Caco-2 and solubility values are concerning for both, but can potentially be addressed with formulation strategies. Given the importance of BBB penetration for CNS drugs, Ligand B is the more promising candidate.

Output:
1
2025-04-17 07:26:42,197 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (347.434 and 348.487 Da) fall comfortably within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (51.39) is significantly better than Ligand B (58.64).  For CNS targets, we want TPSA <= 90, and ideally closer to 60. Ligand A is much closer to this ideal.

**3. logP:** Ligand A (3.507) is optimal (1-3), while Ligand B (2.204) is at the lower end of the acceptable range. A higher logP generally aids in BBB penetration, making Ligand A favorable.

**4. H-Bond Donors:** Ligand A (0) is preferable to Ligand B (1). Fewer HBDs generally improve permeability.

**5. H-Bond Acceptors:** Ligand A (5) is better than Ligand B (3). Both are within the acceptable range of <=10.

**6. QED:** Both ligands have similar QED values (0.828 and 0.793), indicating good drug-likeness.

**7. DILI:** Ligand A (42.652) has a much lower DILI risk than Ligand B (15.2). This is a significant advantage for Ligand A.

**8. BBB:** Ligand A (96.316) has excellent BBB penetration, exceeding the desirable >70 threshold. Ligand B (63.009) is lower, though not terrible, but significantly less promising for a CNS target.

**9. Caco-2:** Both ligands have negative Caco-2 values (-4.489 and -4.551). This is unusual and suggests poor permeability. However, these values are on a different scale and may not be directly comparable.

**10. Solubility:** Both ligands have negative solubility values (-3.677 and -2.312). This is also unusual and suggests poor aqueous solubility.

**11. hERG:** Both ligands have low hERG inhibition liability (0.958 and 0.215), which is good.

**12. Cl_mic:** Ligand B (-7.92) has a negative microsomal clearance, which is highly unusual and likely an error in the data. Ligand A (37.707) is a more reasonable value, indicating moderate metabolic clearance.

**13. t1/2:** Ligand A (10.049) has a longer in vitro half-life than Ligand B (3.789), which is desirable.

**14. Pgp:** Ligand A (0.562) has lower P-gp efflux liability than Ligand B (0.035), which is beneficial for CNS exposure.

**15. Binding Affinity:** Both ligands have very similar and excellent binding affinities (-8.5 and -8.4 kcal/mol). The difference is negligible.

**Overall Assessment:**

Ligand A is significantly better than Ligand B. It has superior BBB penetration, lower DILI risk, better TPSA, a more optimal logP, lower Pgp efflux, and a longer half-life. The unusual negative values for Caco-2 and solubility are concerning for both, but the other advantages of Ligand A outweigh these concerns. The negative clearance value for Ligand B is a red flag and suggests a data error.

Output:
1
2025-04-17 07:26:42,198 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (380.279 and 361.379 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (84.14) is better than Ligand B (29.54) as it is closer to the ideal range for CNS targets (<=90). Ligand B is exceptionally low, which *could* indicate good BBB penetration, but also potentially reduced binding affinity due to lack of polar interactions.

**3. logP:** Ligand A (2.76) is within the optimal range (1-3). Ligand B (4.296) is slightly higher, potentially increasing the risk of off-target effects and solubility issues.

**4. H-Bond Donors:** Ligand A (2) and Ligand B (0) are both acceptable, being less than 5.

**5. H-Bond Acceptors:** Ligand A (5) and Ligand B (2) are both acceptable, being less than 10.

**6. QED:** Ligand A (0.852) has a significantly better QED score than Ligand B (0.678), indicating a more drug-like profile.

**7. DILI:** Ligand A (52.772) has a slightly higher DILI risk than Ligand B (40.287), but both are below the concerning threshold of 60.

**8. BBB:** Both ligands have excellent BBB penetration (Ligand A: 89.027, Ligand B: 92.904). Ligand B is slightly better, but both are very promising for a CNS target.

**9. Caco-2:** Both have negative Caco-2 values, which is unusual and suggests an issue with the data or the model's prediction. We will proceed cautiously.

**10. Solubility:** Both have negative solubility values, which is also unusual. Again, caution is warranted.

**11. hERG:** Both ligands have low hERG inhibition risk (Ligand A: 0.863, Ligand B: 0.854).

**12. Cl_mic:** Ligand A (0.905) has significantly lower microsomal clearance than Ligand B (46.253), suggesting better metabolic stability. This is a crucial advantage.

**13. t1/2:** Ligand A (10.883) has a longer in vitro half-life than Ligand B (16.488).

**14. Pgp:** Ligand A (0.237) has lower P-gp efflux liability than Ligand B (0.295), which is beneficial for CNS exposure.

**15. Binding Affinity:** Ligand B (-8.8 kcal/mol) has a slightly better binding affinity than Ligand A (-8.4 kcal/mol). This is a 0.4 kcal/mol difference, which is notable, but not overwhelming considering the other factors.

**Overall Assessment:**

While Ligand B has a slightly better binding affinity and BBB penetration, Ligand A is superior overall. Ligand A demonstrates a significantly better QED score, much lower microsomal clearance (better metabolic stability), longer half-life, and lower P-gp efflux. The TPSA is also more favorable. The negative Caco-2 and solubility values are concerning for both, but the other advantages of Ligand A outweigh the slight affinity advantage of Ligand B. Given the GPCR-specific priorities, the improved ADME properties of Ligand A make it the more promising drug candidate.

Output:
1
2025-04-17 07:26:42,198 - INFO - Okay, let's analyze these two ligands for their potential as DRD2 drug candidates.

**Ligand A:** [383.455, 123.17 ,   1.704,   2.   ,   9.   ,   0.728,  92.904,  49.477, -5.062,  -3.119,   0.169,  58.482,  -5.944,   0.154,  -7.6  ]
**Ligand B:** [365.861,  54.04 ,   2.106,   1.   ,   5.   ,   0.885,  14.618,  87.941, -4.911,  -2.262,   0.836,  -4.633,  16.309,   0.056,  -7.9  ]

**Step-by-step comparison:**

1. **MW:** Both ligands are within the ideal range (200-500 Da). Ligand B (365.861) is slightly lower, which *could* be beneficial for permeability, but both are acceptable.
2. **TPSA:** Ligand A (123.17) is borderline for CNS penetration (ideally <90), while Ligand B (54.04) is excellent. This is a significant advantage for B.
3. **logP:** Both ligands have good logP values (1.704 & 2.106), falling within the optimal 1-3 range.
4. **HBD:** Both have acceptable HBD counts (2 & 1).
5. **HBA:** Both have acceptable HBA counts (9 & 5).
6. **QED:** Both have good QED scores (0.728 & 0.885), indicating drug-like properties. Ligand B is slightly better.
7. **DILI:** Ligand A has a very high DILI risk (92.904), which is a major concern. Ligand B has a low DILI risk (14.618), a significant advantage.
8. **BBB:** Ligand B (87.941) has a much better BBB percentile than Ligand A (49.477). This is crucial for a CNS target like DRD2.
9. **Caco-2:** Both have negative Caco-2 values, which is unusual and suggests poor permeability. However, these values are on a scale where negative values are possible, and the absolute magnitude matters less than the trend.
10. **Solubility:** Both have negative solubility values, which is also unusual. Similar to Caco-2, the absolute magnitude is less important than the trend.
11. **hERG:** Both have low hERG inhibition liability, which is good.
12. **Cl_mic:** Ligand B has a negative clearance (-4.633), which is excellent and indicates very high metabolic stability. Ligand A has a moderate clearance (58.482).
13. **t1/2:** Ligand B has a much longer in vitro half-life (16.309) than Ligand A (-5.944).
14. **Pgp:** Ligand A has slightly higher Pgp efflux liability (0.154) than Ligand B (0.056). Lower is better.
15. **Affinity:** Ligand B (-7.9 kcal/mol) has a slightly better binding affinity than Ligand A (-7.6 kcal/mol), though the difference is relatively small.

**GPCR-Specific Priorities:**

For a CNS GPCR like DRD2, BBB penetration, logP, Pgp efflux, TPSA, and affinity are paramount. Ligand B excels in BBB, TPSA, and metabolic stability (Cl_mic and t1/2), and has slightly better affinity. The most significant drawback of Ligand A is its extremely high DILI risk.

**Conclusion:**

Considering all factors, especially the critical importance of BBB penetration and the unacceptable DILI risk associated with Ligand A, **Ligand B is the more promising drug candidate.**

Output:
1
2025-04-17 07:26:42,198 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (355.479 and 358.408 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (82.11) is better than Ligand B (61.28). Both are below the 90 A^2 threshold desirable for CNS targets, but A is slightly higher, potentially impacting BBB penetration.

**logP:** Ligand B (3.137) is optimal (1-3), while Ligand A (0.08) is significantly low, potentially hindering membrane permeability and CNS penetration.

**H-Bond Donors/Acceptors:** Both have 2 HBD and 5 HBA, which are within acceptable limits.

**QED:** Ligand B (0.847) has a much better QED score than Ligand A (0.644), indicating a more drug-like profile.

**DILI:** Ligand B (48.313) has a slightly higher DILI risk than Ligand A (4.459), but both are reasonably low.

**BBB:** Ligand B (77.821) is significantly better than Ligand A (43.971). This is *critical* for a CNS target like DRD2.

**Caco-2 Permeability:** Ligand A (-4.876) and Ligand B (-4.963) both have negative values, which is unusual and suggests very poor permeability. This is a concern for both, but the difference is minimal.

**Aqueous Solubility:** Ligand A (-0.442) is better than Ligand B (-3.95), which is a significant negative value.

**hERG:** Ligand A (0.218) has a lower hERG risk than Ligand B (0.864), which is preferable.

**Microsomal Clearance:** Ligand A (-1.403) has a lower (better) microsomal clearance than Ligand B (27.389), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand B (11.689) has a slightly longer half-life than Ligand A (14.47), but the difference isn't huge.

**P-gp Efflux:** Ligand A (0.002) shows very low P-gp efflux, which is excellent for CNS penetration. Ligand B (0.164) is also relatively low, but higher than A.

**Binding Affinity:** Ligand B (-8.6 kcal/mol) has a significantly stronger binding affinity than Ligand A (-6.4 kcal/mol). This is a >2.2 kcal/mol difference, which is substantial and can outweigh some ADME drawbacks.

**Overall Assessment:**

While Ligand A has better solubility, lower hERG risk, and lower P-gp efflux, its extremely low logP and poor BBB penetration are major drawbacks for a CNS target. Ligand B, despite a slightly higher DILI risk and higher P-gp efflux, has a much better logP, significantly better BBB penetration, and, most importantly, a substantially stronger binding affinity. The strong affinity of Ligand B is likely to overcome the minor ADME concerns.

Output:
1
2025-04-17 07:26:42,198 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (347.419 and 345.443 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (93.78) is slightly above the optimal <90 for CNS targets, but still reasonable. Ligand B (62.74) is excellent, well below 90.

**logP:** Ligand A (-0.653) is a bit low, potentially hindering permeation. Ligand B (1.906) is within the optimal 1-3 range.

**H-Bond Donors:** Ligand A (3) is acceptable. Ligand B (0) is also good, potentially improving permeability.

**H-Bond Acceptors:** Both ligands (A: 5, B: 4) are within the acceptable limit of <=10.

**QED:** Both ligands have good QED scores (A: 0.629, B: 0.765), indicating drug-like properties.

**DILI:** Both have low DILI risk (A: 42.73, B: 40.403), below the 60 threshold.

**BBB:** Ligand B (73.517) is significantly better than Ligand A (57.968) in terms of BBB penetration, which is crucial for a CNS target like DRD2.

**Caco-2 Permeability:** Ligand A (-5.361) is poor, suggesting poor intestinal absorption. Ligand B (-4.226) is also poor, but slightly better than A.

**Aqueous Solubility:** Both ligands have very poor aqueous solubility (-1.296 and -1.641). This could pose formulation challenges.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (A: 0.25, B: 0.217).

**Microsomal Clearance:** Ligand A (-44.383) has a much lower (better) microsomal clearance than Ligand B (43.887), suggesting greater metabolic stability.

**In vitro Half-Life:** Ligand B (5.885) has a longer half-life than Ligand A (-15.22), which is desirable.

**P-gp Efflux:** Both ligands show very low P-gp efflux liability (A: 0.002, B: 0.256).

**Binding Affinity:** Ligand B (-6.8 kcal/mol) has a significantly stronger binding affinity than Ligand A (-8.3 kcal/mol). This is a major advantage.

**Overall Assessment:**

While Ligand A has better metabolic stability (lower Cl_mic), Ligand B excels in key areas for a CNS-targeting GPCR ligand: significantly better BBB penetration, a more optimal logP, and a substantially stronger binding affinity. The slightly poorer metabolic stability of Ligand B is likely outweighed by its superior CNS penetration and binding. The poor solubility of both is a concern, but can be addressed with formulation strategies.

Output:
1
2025-04-17 07:26:42,198 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (368.5 and 352.3 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (78.87) is significantly better than Ligand B (112.7). For CNS targets, TPSA < 90 is preferred, which Ligand A meets, while Ligand B is close to the limit and less desirable.

**3. logP:** Ligand A (0.968) is slightly better than Ligand B (0.183), both are on the lower end of the optimal 1-3 range. Ligand B is quite low and might have permeability issues.

**4. H-Bond Donors:** Both ligands have 2 HBD, which is within the acceptable limit of <=5.

**5. H-Bond Acceptors:** Ligand A has 5 HBA, and Ligand B has 6. Both are within the acceptable limit of <=10.

**6. QED:** Both ligands have similar QED values (0.715 and 0.693), indicating good drug-like properties.

**7. DILI:** Ligand A (34.393) has a lower DILI risk than Ligand B (55.68), which is preferable.

**8. BBB:** Ligand B (70.066) has a significantly better BBB penetration percentile than Ligand A (58.007). This is a crucial factor for a CNS target like DRD2.

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.117 and -5.152), which is unusual and suggests poor permeability. However, these values are on a scale where negative values are possible and don't necessarily preclude development.

**10. Aqueous Solubility:** Both ligands have negative solubility values (-2.031 and -2.661), indicating poor aqueous solubility. This could be a formulation challenge.

**11. hERG Inhibition:** Ligand A (0.744) has a slightly higher hERG inhibition risk than Ligand B (0.126), which is less desirable.

**12. Microsomal Clearance:** Ligand A (30.639) has a higher microsomal clearance than Ligand B (0.425), indicating lower metabolic stability.

**13. In vitro Half-Life:** Ligand B (-16.137) has a much longer in vitro half-life than Ligand A (-31.163).

**14. P-gp Efflux:** Ligand A (0.132) has lower P-gp efflux liability than Ligand B (0.011), which is favorable for CNS penetration.

**15. Binding Affinity:** Both ligands have very similar and strong binding affinities (-7.8 and -7.6 kcal/mol). The difference is negligible.

**Overall Assessment:**

Ligand B excels in BBB penetration and in vitro half-life, which are critical for CNS drug development. However, it has a lower logP and higher P-gp efflux. Ligand A has better TPSA, lower DILI risk, and lower P-gp efflux. The similar binding affinities mean that ADME properties become the deciding factor.

Considering the GPCR-specific priorities, the better BBB penetration of Ligand B is a significant advantage that outweighs its slightly lower logP and higher P-gp efflux. The longer half-life is also a substantial benefit. While both have solubility issues, that is a formulation challenge that can be addressed.

Output:
1
2025-04-17 07:26:42,198 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (363.845 and 354.441 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (67.6) is slightly higher than the ideal <90 for CNS targets, but still acceptable. Ligand B (49.41) is excellent, well below the threshold.

**3. logP:** Both ligands have good logP values (3.754 and 3.07), falling within the optimal 1-3 range.

**4. H-Bond Donors:** Both have 1 HBD, which is within the acceptable limit of <=5.

**5. H-Bond Acceptors:** Ligand A has 5 HBAs, and Ligand B has 2. Both are below the acceptable limit of <=10.

**6. QED:** Both ligands have similar QED values (0.876 and 0.847), indicating good drug-likeness.

**7. DILI:** Ligand A (72.043) has a higher DILI risk than Ligand B (30.942). This is a significant negative for Ligand A.

**8. BBB:** Both ligands show excellent BBB penetration (77.007 and 79.721), exceeding the desirable >70 threshold for CNS targets.

**9. Caco-2 Permeability:** Both have negative Caco-2 values (-4.664 and -4.743). This is unusual and suggests poor permeability, but the scale isn't clear. We'll need to consider this cautiously.

**10. Aqueous Solubility:** Both have negative solubility values (-4.711 and -3.462). Again, the scale is unclear, but suggests poor solubility.

**11. hERG Inhibition:** Both ligands have similar, low hERG inhibition liability (0.608).

**12. Microsomal Clearance:** Ligand B (22.721) has significantly lower microsomal clearance than Ligand A (46.795), indicating better metabolic stability.

**13. In vitro Half-Life:** Ligand B (-5.972) has a negative half-life, which is concerning. Ligand A (10.936) has a reasonable half-life.

**14. P-gp Efflux:** Both ligands have similar, low P-gp efflux liability (0.504 and 0.177).

**15. Binding Affinity:** Ligand A (-9.2 kcal/mol) has a slightly better binding affinity than Ligand B (-8.1 kcal/mol), a difference of 1.1 kcal/mol.

**Overall Assessment:**

Ligand B is the more promising candidate. While both have good logP and BBB penetration, Ligand B has a significantly lower DILI risk and better metabolic stability (lower Cl_mic). The negative Caco-2 and solubility values are concerning for both, but the difference in DILI and metabolic stability are more impactful for overall drug development. The affinity difference, while present, is not large enough to overcome the ADME advantages of Ligand B. The negative half-life for B is a concern, but could be addressed through structural modifications.

Output:
1
2025-04-17 07:26:42,198 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B based on the provided guidelines, prioritizing GPCR-specific properties (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (346.431 and 345.443 Da) fall comfortably within the ideal range of 200-500 Da.

**TPSA:** Ligand A (96.11) is slightly above the optimal <90 for CNS targets, but still reasonable. Ligand B (75.44) is excellent, well below 90.

**logP:** Both ligands have good logP values (1.657 and 2.394), falling within the 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A has 3 HBD and 4 HBA, while Ligand B has 1 HBD and 4 HBA. Both are within acceptable limits.

**QED:** Both ligands have good QED scores (0.667 and 0.889), indicating good drug-likeness.

**DILI:** Ligand A (47.034) has a slightly higher DILI risk than Ligand B (31.64), but both are below the concerning threshold of 60.

**BBB:** This is a critical parameter for a CNS target like DRD2. Ligand B (82.551) shows a significantly better BBB penetration percentile than Ligand A (62.311). This is a major advantage for Ligand B.

**Caco-2 Permeability:** Both have negative Caco-2 values which is unusual and potentially problematic. However, the magnitude is similar.

**Aqueous Solubility:** Both ligands have similarly poor aqueous solubility (-3.439 and -3.256). This could present formulation challenges.

**hERG:** Both ligands have very low hERG inhibition risk (0.385 and 0.393).

**Microsomal Clearance:** Ligand B (48.652) has a higher microsomal clearance than Ligand A (22.064), suggesting faster metabolism and potentially lower *in vivo* exposure.

**In vitro Half-Life:** Ligand A (22.872) has a significantly longer half-life than Ligand B (1.343). This is a substantial advantage for Ligand A.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.086 and 0.267), which is favorable for CNS penetration.

**Binding Affinity:** Ligand B (-9.0 kcal/mol) has a significantly stronger binding affinity than Ligand A (-8.2 kcal/mol). This difference of 0.8 kcal/mol is substantial and can outweigh some ADME drawbacks.

**Overall Assessment:**

While Ligand A has a better half-life and slightly lower DILI risk, Ligand B excels in the most critical areas for a CNS-targeting GPCR ligand: **BBB penetration and binding affinity**. The significantly stronger binding affinity (-9.0 vs -8.2 kcal/mol) is a major advantage. The better TPSA of Ligand B is also beneficial. The faster clearance of Ligand B is a concern, but the superior affinity might compensate for it.

Output:
1
2025-04-17 07:26:42,198 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (355.356 and 339.443 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (46.61) is excellent, well below the 90 A^2 threshold for CNS targets. Ligand B (73.05) is higher but still reasonable, though less optimal for CNS penetration.

**logP:** Both ligands have good logP values (2.838 and 2.503), falling within the 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A (0 HBD, 3 HBA) and Ligand B (3 HBD, 3 HBA) both meet the criteria of <=5 HBD and <=10 HBA.

**QED:** Both ligands have good QED scores (0.603 and 0.801), indicating good drug-like properties.

**DILI:** Both ligands have similar, low DILI risk (32.493 and 32.648 percentile), which is favorable.

**BBB:** This is a critical parameter for a CNS target like DRD2. Ligand A has a very high BBB penetration (97.635%), significantly better than Ligand B (70.105%).

**Caco-2 Permeability:** Ligand A (-4) and Ligand B (-5.328) both have negative values, which is unusual and indicates very poor permeability. This is a significant concern for both.

**Aqueous Solubility:** Both ligands have poor aqueous solubility (-2.961 and -2.482). This could pose formulation challenges.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.6 and 0.769), which is good.

**Microsomal Clearance:** Ligand B (-18.364) has a lower (better) microsomal clearance than Ligand A (81.838), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand B (13.562 hours) has a significantly longer half-life than Ligand A (-15.742 hours).

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.226 and 0.071), which is beneficial for CNS exposure.

**Binding Affinity:** Both ligands have excellent binding affinities (-9.5 and -10 kcal/mol), with Ligand B being slightly stronger. However, the difference is not substantial enough to outweigh other factors.

**Overall Assessment:**

Ligand A excels in TPSA and, crucially, BBB penetration. However, its poor Caco-2 permeability and high microsomal clearance are major drawbacks. Ligand B has better metabolic stability (lower Cl_mic) and a longer half-life, but its BBB penetration is significantly lower than Ligand A's. Given the CNS target, the superior BBB penetration of Ligand A is a decisive advantage, despite its other weaknesses. The poor Caco-2 permeability is a concern, but for a CNS target, this is less critical than getting the drug into the brain.

Output:
1
2025-04-17 07:26:42,198 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (341.411 and 360.445 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (77.25) is higher than Ligand B (58.64). For a CNS target like DRD2, we prefer TPSA <= 90, so both are acceptable, but B is better.

**3. logP:** Ligand A (3.497) is slightly higher than Ligand B (2.589), both within the optimal 1-3 range.

**4. H-Bond Donors:** Both ligands have 1 HBD, which is good.

**5. H-Bond Acceptors:** Ligand A has 6 HBA, while Ligand B has 3. Both are within the acceptable limit of <=10.

**6. QED:** Ligand A (0.858) has a better QED score than Ligand B (0.759), indicating a more drug-like profile.

**7. DILI:** Ligand A (63.513) has a higher DILI risk than Ligand B (16.751). This is a significant advantage for Ligand B.

**8. BBB:** Both ligands have excellent BBB penetration (83.753 and 83.831, respectively). This is crucial for a CNS target.

**9. Caco-2 Permeability:** Both have negative Caco-2 values, indicating poor permeability. This is a concern for both, but doesn't immediately disqualify either.

**10. Aqueous Solubility:** Both have negative solubility values, indicating poor solubility. This is a concern for both.

**11. hERG Inhibition:** Both ligands have low hERG inhibition risk (0.454 and 0.482).

**12. Microsomal Clearance:** Ligand A (58.171) has higher microsomal clearance than Ligand B (20.422), meaning it's less metabolically stable. This favors Ligand B.

**13. In vitro Half-Life:** Ligand A (14.022) has a shorter half-life than Ligand B (-21.509, which is very good). This favors Ligand B.

**14. P-gp Efflux:** Ligand A (0.341) has lower P-gp efflux than Ligand B (0.054), which is better for CNS exposure.

**15. Binding Affinity:** Ligand A (-10.1 kcal/mol) has significantly stronger binding affinity than Ligand B (-7.7 kcal/mol). This is a substantial advantage for Ligand A. A difference of 2.4 kcal/mol is quite significant and can outweigh some ADME drawbacks.

**Overall Assessment:**

Ligand B has better ADME properties (lower DILI, lower Cl_mic, longer half-life, lower P-gp efflux) and a lower TPSA. However, Ligand A has a *much* stronger binding affinity. For a GPCR, especially a CNS target, binding affinity is paramount. While the ADME properties of Ligand A are not ideal (higher DILI and clearance), the strong binding affinity suggests it's more likely to be effective *if* those issues can be addressed through further optimization. The P-gp efflux is also better for Ligand A.

Output:
1
2025-04-17 07:26:42,198 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight (MW):** Both ligands are within the ideal range (200-500 Da). Ligand A (374.819 Da) and Ligand B (359.905 Da) are both acceptable.

**2. TPSA:** Ligand A (76.02) is slightly higher but still reasonable for a CNS target, while Ligand B (46.84) is excellent, well below the 90 A^2 threshold. This favors Ligand B.

**3. logP:** Both ligands have good logP values (Ligand A: 2.056, Ligand B: 3.754), falling within the optimal 1-3 range. Ligand B is slightly higher, potentially increasing permeability, but not excessively.

**4. H-Bond Donors (HBD):** Both ligands are acceptable (Ligand A: 2, Ligand B: 0), well below the limit of 5.

**5. H-Bond Acceptors (HBA):** Both ligands are acceptable (Ligand A: 4, Ligand B: 5), below the limit of 10.

**6. QED:** Both ligands have good QED scores (Ligand A: 0.513, Ligand B: 0.788), indicating drug-like properties. Ligand B is better.

**7. DILI:** Ligand A (48.468) has a moderate DILI risk, while Ligand B (15.82) has a very low risk. This strongly favors Ligand B.

**8. BBB:** Both ligands show good BBB penetration (Ligand A: 83.443, Ligand B: 78.79). Ligand A is slightly better, exceeding 80%. However, both are above the desirable 70% threshold for CNS targets.

**9. Caco-2 Permeability:** Both are negative, which is unusual. This suggests poor intestinal absorption. However, for a CNS target, intestinal absorption is less critical than BBB penetration.

**10. Aqueous Solubility:** Both are very poor (-3.188 and -3.59). This is a concern, but can potentially be addressed through formulation.

**11. hERG Inhibition:** Both are low (Ligand A: 0.26, Ligand B: 0.502), indicating low cardiotoxicity risk.

**12. Microsomal Clearance:** Ligand A (32.541) has lower clearance than Ligand B (37.348), suggesting better metabolic stability.

**13. In vitro Half-Life:** Ligand B (7.882) has a longer half-life than Ligand A (4.079), which is desirable.

**14. P-gp Efflux:** Both are very low (Ligand A: 0.123, Ligand B: 0.23), indicating minimal P-gp efflux, which is positive for CNS penetration.

**15. Binding Affinity:** Ligand B (-8.4 kcal/mol) has a slightly better binding affinity than Ligand A (-8.0 kcal/mol). While the difference is small, it's still a factor.

**Overall Assessment:**

Ligand B is the more promising candidate. It has a significantly lower DILI risk, a better QED score, a longer half-life, and slightly better binding affinity. While Ligand A has a slightly better BBB score and lower microsomal clearance, the advantages of Ligand B in terms of safety (DILI) and drug-like properties outweigh these minor differences. Both have poor solubility, which is a formulation challenge, but not a deal-breaker for CNS drugs.

Output:
1
2025-04-17 07:26:42,199 - INFO - Batch 365 complete. Total preferences: 5840
2025-04-17 07:26:42,199 - INFO - Processing batch 366/512...
2025-04-17 07:27:23,907 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (350.503 and 344.415 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (58.64) is excellent, well below the 90 A^2 threshold for CNS targets. Ligand B (118.01) is higher, but still potentially acceptable, though less ideal.

**logP:** Ligand A (3.047) is optimal. Ligand B (1.062) is a bit low, potentially hindering membrane permeability.

**H-Bond Donors/Acceptors:** Ligand A (HBD=1, HBA=3) is favorable. Ligand B (HBD=4, HBA=4) is slightly higher in HBD, but still within reasonable limits.

**QED:** Both ligands (0.65 and 0.617) have good drug-likeness scores.

**DILI:** Ligand A (5.777) has a very low DILI risk. Ligand B (44.009) is higher, indicating a moderate risk, but not alarming.

**BBB:** This is critical for a CNS target like DRD2. Ligand A (83.87) shows good BBB penetration. Ligand B (40.52) is significantly lower, suggesting poor brain penetration.

**Caco-2 Permeability:** Ligand A (-4.633) has poor Caco-2 permeability, which is concerning. Ligand B (-5.122) is also poor.

**Aqueous Solubility:** Ligand A (-2.139) and Ligand B (-3.59) both have poor aqueous solubility.

**hERG Inhibition:** Both ligands (0.507 and 0.421) show low hERG inhibition risk.

**Microsomal Clearance:** Ligand A (39.351) has moderate clearance. Ligand B (-1.619) has negative clearance, which is not possible and likely an error in the data, but suggests very high metabolic stability.

**In vitro Half-Life:** Ligand A (-13.51) has a negative half-life, which is not possible and likely an error in the data. Ligand B (-27.289) also has a negative half-life.

**P-gp Efflux:** Both ligands (0.126 and 0.028) show low P-gp efflux, which is good for CNS penetration.

**Binding Affinity:** Both ligands have excellent binding affinity (-7.6 and -8.6 kcal/mol). Ligand B is slightly better, but the difference is likely not enough to overcome other deficiencies.

**Overall Assessment:**

Ligand A is superior due to its significantly better BBB penetration (83.87 vs 40.52). While its Caco-2 permeability is poor, the BBB score is the most important factor for a CNS target. Ligand B's low logP and poor BBB penetration are major drawbacks. The negative values for half-life and clearance are suspect and indicate potential data quality issues, but even ignoring those, the BBB score is a dealbreaker.

Output:
1
2025-04-17 07:27:23,908 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (348.443 and 343.515 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (89.87) is excellent, being below the 90 A^2 threshold for CNS targets. Ligand B (37.27) is also very good, well below the threshold.

**3. logP:** Ligand A (2.293) is within the optimal 1-3 range. Ligand B (3.758) is slightly higher but still acceptable.

**4. H-Bond Donors:** Ligand A (3) and Ligand B (1) both meet the <=5 criteria.

**5. H-Bond Acceptors:** Ligand A (4) and Ligand B (3) both meet the <=10 criteria.

**6. QED:** Both ligands have good QED values (0.705 and 0.854, respectively), indicating drug-like properties.

**7. DILI:** Both ligands have similar and acceptable DILI risk (11.128 and 11.09 percentile).

**8. BBB:** This is a critical parameter for a CNS target like DRD2. Ligand B (91.198) is significantly better than Ligand A (50.872), exceeding the desirable >70 threshold.

**9. Caco-2 Permeability:** Ligand A (-5.013) and Ligand B (-4.655) have negative values, which is unusual and indicates poor permeability.

**10. Aqueous Solubility:** Both ligands have poor solubility (-3.285 and -3.886).

**11. hERG Inhibition:** Both ligands show low hERG inhibition risk (0.397 and 0.638).

**12. Microsomal Clearance:** Ligand A (48.637) has lower clearance than Ligand B (59.149), suggesting better metabolic stability.

**13. In vitro Half-Life:** Ligand B (43.993) has a significantly longer half-life than Ligand A (-14.982), which is a major advantage.

**14. P-gp Efflux:** Ligand A (0.014) has very low P-gp efflux, which is excellent. Ligand B (0.165) is slightly higher but still relatively low.

**15. Binding Affinity:** Ligand A (-8.1 kcal/mol) has a stronger binding affinity than Ligand B (-7.0 kcal/mol). The difference is 1.1 kcal/mol, which is substantial.

**Overall Assessment:**

While Ligand A has a better binding affinity and lower P-gp efflux, Ligand B significantly outperforms it in BBB penetration and has a much longer in vitro half-life. For a CNS target like DRD2, BBB penetration is paramount. The 40% difference in BBB percentile is a major advantage for Ligand B. The longer half-life also contributes to better drug-like properties. The superior affinity of Ligand A is somewhat offset by its poor BBB penetration.

Output:
1
2025-04-17 07:27:23,908 - INFO - Reasoning:

Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (359.817 and 358.345 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (88.17) is excellent, falling well below the 90 A^2 threshold for CNS targets. Ligand B (113.33) is still reasonable but less optimal, being above 100.

**3. logP:** Ligand A (3.235) is within the optimal 1-3 range. Ligand B (0.244) is significantly lower, potentially hindering membrane permeability and CNS penetration.

**4. H-Bond Donors:** Both ligands have 3 HBD, which is acceptable.

**5. H-Bond Acceptors:** Ligand A has 6 HBA, and Ligand B has 5. Both are within the acceptable limit of 10.

**6. QED:** Ligand A (0.776) has a better QED score than Ligand B (0.432), indicating a more drug-like profile.

**7. DILI:** Ligand A (85.459) has a higher DILI risk than Ligand B (50.33), which is a concern. However, this can be addressed in later optimization stages.

**8. BBB:** Ligand A (72.896) and Ligand B (83.288) both have good BBB penetration, being above the 70 percentile. Ligand B is slightly better here.

**9. Caco-2:** Both ligands have negative Caco-2 values (-5.121 and -4.881), which is unusual and suggests poor permeability. This is a significant drawback for both.

**10. Solubility:** Both ligands have negative solubility values (-4.214 and -2.947), indicating poor aqueous solubility. This is another significant drawback for both.

**11. hERG:** Both ligands have low hERG inhibition liability (0.284 and 0.3), which is good.

**12. Cl_mic:** Ligand A (23.668) has a slightly higher microsomal clearance than Ligand B (20.409), meaning it might be metabolized faster.

**13. t1/2:** Ligand A (43.273) has a significantly longer in vitro half-life than Ligand B (-1.385). This is a major advantage for Ligand A.

**14. Pgp:** Both ligands have very low P-gp efflux liability (0.073 and 0.048), which is excellent for CNS penetration.

**15. Binding Affinity:** Ligand A (-9.7 kcal/mol) has a considerably stronger binding affinity than Ligand B (-8.2 kcal/mol). This 1.5 kcal/mol difference is substantial and can outweigh some of the ADME concerns.

**Overall Assessment:**

Despite Ligand A's higher DILI risk, its superior binding affinity, better TPSA, better QED, and significantly longer half-life make it the more promising candidate. The lower logP of Ligand B is a major concern for CNS penetration, and its poor in vitro half-life is also detrimental. While both have issues with Caco-2 and solubility, these are properties that can be improved through structural modifications. The strong binding affinity of Ligand A provides a solid foundation for further optimization.

Output:
1
2025-04-17 07:27:23,908 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (348.443 and 350.503 Da) fall comfortably within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (76.66) is slightly higher than Ligand B (58.64). Both are below the 90 A^2 threshold desirable for CNS targets, but Ligand B is preferable.

**3. logP:** Ligand A (1.28) is a bit low, potentially hindering permeation. Ligand B (2.925) is within the optimal 1-3 range. This favors Ligand B.

**4. H-Bond Donors:** Ligand A (2) and Ligand B (1) are both acceptable, below the 5 limit.

**5. H-Bond Acceptors:** Ligand A (4) and Ligand B (3) are both acceptable, below the 10 limit.

**6. QED:** Ligand A (0.785) has a better QED score than Ligand B (0.685), indicating better overall drug-likeness.

**7. DILI:** Ligand A (38.852) has a significantly lower DILI risk than Ligand B (15.006), which is a major advantage.

**8. BBB:** Both ligands have good BBB penetration (Ligand A: 73.943, Ligand B: 72.625), exceeding the 70% threshold for CNS targets. The difference is minimal.

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 values, which is unusual and suggests poor permeability. Ligand A (-4.967) is slightly worse than Ligand B (-4.371).

**10. Aqueous Solubility:** Both ligands have negative solubility values, which is also unusual and suggests poor solubility. Ligand A (-3.046) is slightly worse than Ligand B (-3.218).

**11. hERG Inhibition:** Ligand A (0.243) has a lower hERG inhibition liability than Ligand B (0.567), which is preferable.

**12. Microsomal Clearance:** Ligand A (18.901) has lower microsomal clearance than Ligand B (50.825), indicating better metabolic stability.

**13. In vitro Half-Life:** Ligand A (51.635) has a longer in vitro half-life than Ligand B (-13.353), which is a significant advantage.

**14. P-gp Efflux:** Ligand A (0.021) has much lower P-gp efflux liability than Ligand B (0.126), which is crucial for CNS penetration.

**15. Binding Affinity:** Ligand A (-8.6 kcal/mol) has a significantly stronger binding affinity than Ligand B (-7.2 kcal/mol), exceeding the >1.5 kcal/mol advantage threshold.

**Overall Assessment:**

While Ligand B has a slightly better logP and TPSA, Ligand A excels in several critical areas: significantly stronger binding affinity, lower DILI risk, lower P-gp efflux, longer half-life, lower microsomal clearance, and lower hERG inhibition. The substantial affinity difference (-8.6 vs -7.2 kcal/mol) can outweigh the slightly less optimal logP and TPSA of Ligand A. The poor Caco-2 and solubility values are concerning for both, but can be addressed with formulation strategies. Given the CNS target and GPCR nature, strong affinity, good BBB penetration, and low efflux are paramount.

Output:
1
2025-04-17 07:27:23,908 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (344.459 and 349.519 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (64.68) is slightly higher than Ligand B (52.65). Both are below the 90 A^2 threshold desirable for CNS targets, but B is better.

**3. logP:** Ligand A (3.569) is slightly higher than Ligand B (2.285), both within the optimal 1-3 range.

**4. H-Bond Donors:** Ligand A (2) is higher than Ligand B (1). Both are acceptable (<=5).

**5. H-Bond Acceptors:** Ligand A (2) is lower than Ligand B (3). Both are acceptable (<=10).

**6. QED:** Both ligands have similar QED values (0.877 and 0.718), both above the 0.5 threshold, indicating good drug-likeness.

**7. DILI:** Ligand A (39.434) has a slightly higher DILI risk than Ligand B (5.079), but both are below the concerning 60 percentile. B is significantly better.

**8. BBB:** Ligand A (69.794) has a slightly better BBB penetration than Ligand B (67.584). Both are reasonably good, but ideally >70 for CNS targets.

**9. Caco-2:** Both ligands have negative Caco-2 values (-4.717 and -4.761). This is unusual and suggests poor permeability.

**10. Solubility:** Ligand A (-3.759) has slightly worse solubility than Ligand B (-1.764). Both are poor.

**11. hERG:** Ligand A (0.737) has a slightly higher hERG risk than Ligand B (0.554). Both are relatively low risk.

**12. Cl_mic:** Ligand A (19.504) has a higher microsomal clearance than Ligand B (10.097). This suggests lower metabolic stability for Ligand A.

**13. t1/2:** Ligand A (29.868) has a significantly longer in vitro half-life than Ligand B (-11.606). This is a major advantage for Ligand A.

**14. Pgp:** Ligand A (0.107) has lower P-gp efflux liability than Ligand B (0.022). Lower Pgp is better for CNS exposure.

**15. Binding Affinity:** Both ligands have very similar binding affinities (-8.1 and -8.0 kcal/mol). This difference is negligible.

**Overall Assessment:**

Ligand B demonstrates better ADME properties overall, particularly with a significantly lower DILI risk and lower microsomal clearance. While Ligand A has a longer half-life and lower Pgp efflux, the superior safety profile and metabolic stability of Ligand B outweigh these advantages. The poor Caco-2 and solubility for both ligands are concerning, but can potentially be addressed through formulation strategies. Given the GPCR-specific priorities, the lower TPSA and DILI of Ligand B make it the more promising candidate.

Output:
1
2025-04-17 07:27:23,908 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (376.283 and 349.519 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Both ligands have TPSA values (52.49 and 52.65) slightly above the optimal <90 for CNS targets, but still reasonable.

**3. logP:** Ligand A (4.462) is higher than the optimal 1-3 range, potentially causing solubility issues. Ligand B (2.425) is within the optimal range.

**4. H-Bond Donors:** Ligand A (3) is acceptable. Ligand B (1) is also acceptable.

**5. H-Bond Acceptors:** Both ligands (3) are within the acceptable limit of <=10.

**6. QED:** Both ligands have good QED scores (0.595 and 0.718), indicating drug-likeness.

**7. DILI:** Ligand A (48.623) has a moderate DILI risk, but is still acceptable. Ligand B (11.128) has a very low DILI risk, which is a significant advantage.

**8. BBB:** Ligand B (78.868) has a significantly better BBB penetration percentile than Ligand A (37.34). This is *critical* for a CNS target like DRD2.

**9. Caco-2 Permeability:** Both have negative values which is unusual. This suggests poor permeability.

**10. Aqueous Solubility:** Both ligands have negative solubility values, which is concerning.

**11. hERG Inhibition:** Both ligands have low hERG inhibition risk (0.92 and 0.552).

**12. Microsomal Clearance:** Ligand A (12.141) has lower clearance, suggesting better metabolic stability than Ligand B (37.43).

**13. In vitro Half-Life:** Ligand A (140.185) has a much longer half-life than Ligand B (4.425), which is a significant advantage.

**14. P-gp Efflux:** Ligand A (0.673) has lower P-gp efflux, which is favorable for CNS penetration. Ligand B (0.092) has very low P-gp efflux, which is even more favorable.

**15. Binding Affinity:** Ligand B (-7.7 kcal/mol) has a significantly stronger binding affinity than Ligand A (-9.1 kcal/mol). This is a substantial advantage, and can often outweigh minor ADME drawbacks.

**Overall Assessment:**

While Ligand A has better metabolic stability and half-life, Ligand B excels in the most critical areas for a CNS-targeting GPCR ligand: BBB penetration and binding affinity. The lower DILI risk and very low P-gp efflux are also strong positives. The slightly higher logP of Ligand A is a concern, and the significantly weaker binding affinity is a major drawback. The solubility and Caco-2 permeability are poor for both, but the affinity and BBB are the most important factors here.

Output:
1
2025-04-17 07:27:23,909 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, considering the provided guidelines and GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (338.451 and 366.531 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (75.35) is slightly higher than Ligand B (67.23). Both are below the 90 A^2 threshold desirable for CNS targets, but Ligand B is preferable.

**logP:** Both ligands have good logP values (2.74 and 2.158), falling within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A has 3 HBD and 3 HBA, while Ligand B has 1 HBD and 5 HBA. Both are within acceptable limits (<=5 HBD, <=10 HBA).

**QED:** Both ligands have similar QED values (0.758 and 0.727), indicating good drug-likeness.

**DILI:** Ligand A (15.626) has a significantly lower DILI risk than Ligand B (29.624), which is a substantial advantage.

**BBB:** Ligand A (49.67) has a better BBB percentile than Ligand B (38.038), though both are below the desirable >70 for CNS targets. This is a critical factor for DRD2, given its role in CNS disorders.

**Caco-2 Permeability:** Ligand A (-4.936) has worse Caco-2 permeability than Ligand B (-5.307).

**Aqueous Solubility:** Ligand A (-2.647) has worse aqueous solubility than Ligand B (-1.38).

**hERG:** Both ligands show low hERG inhibition liability (0.731 and 0.482).

**Microsomal Clearance:** Ligand B (25.86) has a much higher microsomal clearance than Ligand A (3.31), indicating poorer metabolic stability.

**In vitro Half-Life:** Ligand A (8.932) has a significantly longer in vitro half-life than Ligand B (-2.539).

**P-gp Efflux:** Ligand A (0.307) has lower P-gp efflux liability than Ligand B (0.061), which is beneficial for CNS penetration.

**Binding Affinity:** Ligand A (-9.5 kcal/mol) has a significantly stronger binding affinity than Ligand B (-7.0 kcal/mol). The difference of 2.5 kcal/mol is substantial and can outweigh some ADME drawbacks.

**Overall Assessment:**

Ligand A is the stronger candidate. While Ligand B has slightly better TPSA and Caco-2 permeability, Ligand A excels in critical areas: significantly better binding affinity, lower DILI risk, better BBB penetration, improved metabolic stability (lower Cl_mic, longer t1/2), and lower P-gp efflux. The superior affinity of Ligand A is a key advantage for a GPCR target, and the improved ADME properties (BBB, DILI, metabolic stability) further support its viability.

Output:
1
2025-04-17 07:27:23,909 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (351.422 and 350.503 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (73.74) is better than Ligand B (62.55). For CNS targets, we want TPSA <= 90, both are within this range, but A is closer to the upper limit.

**3. logP:** Ligand A (1.421) is optimal (1-3), while Ligand B (3.799) is approaching the higher end of the optimal range, potentially increasing off-target interactions.

**4. H-Bond Donors:** Both ligands have 1 HBD, which is within the acceptable limit of <= 5.

**5. H-Bond Acceptors:** Ligand A has 4 HBAs, and Ligand B has 3. Both are within the acceptable limit of <= 10.

**6. QED:** Ligand A (0.841) has a higher QED than Ligand B (0.737), indicating a more drug-like profile.

**7. DILI:** Both ligands have low DILI risk (Ligand A: 29.624, Ligand B: 31.214), both are well below the 40 threshold.

**8. BBB:** This is a critical parameter for CNS targets. Ligand A has a significantly higher BBB penetration (78.945%) compared to Ligand B (54.75%).  A value > 70% is desirable, and Ligand A is closer to this target.

**9. Caco-2 Permeability:** Both have negative values, which is unusual. Assuming these are logP-scale values, lower values indicate poorer permeability. Ligand A (-4.481) is slightly better than Ligand B (-4.462), but both are poor.

**10. Aqueous Solubility:** Both have negative values. Assuming these are logS values, lower values indicate poorer solubility. Ligand B (-2.928) is worse than Ligand A (-0.938).

**11. hERG Inhibition:** Both ligands have low hERG inhibition risk (Ligand A: 0.56, Ligand B: 0.664).

**12. Microsomal Clearance:** Ligand A (14.811) has lower microsomal clearance than Ligand B (73.519), suggesting better metabolic stability.

**13. In vitro Half-Life:** Ligand A (-10.701) has a negative half-life, which is not possible. This is likely an error in the data. Ligand B (113.08) has a very long half-life, which is positive.

**14. P-gp Efflux:** Both ligands have low P-gp efflux liability (Ligand A: 0.063, Ligand B: 0.333), which is good for CNS exposure.

**15. Binding Affinity:** Ligand A (-7.7 kcal/mol) has a slightly better binding affinity than Ligand B (-6.5 kcal/mol). A difference of >1.5 kcal/mol is significant.

**Overall Assessment:**

Ligand A is the stronger candidate. It has a better QED, significantly better BBB penetration, better logP, lower microsomal clearance, and superior binding affinity. While both have acceptable DILI and hERG values, the combination of favorable ADME properties and potency makes Ligand A more promising. The negative half-life for Ligand A is a data error that would need to be investigated, but the other factors strongly favor it.

Output:
1
2025-04-17 07:27:23,909 - INFO - Reasoning:

Let's analyze Ligand A and Ligand B against the provided guidelines, prioritizing GPCR-specific properties (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (350.344 and 361.467 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (66.91) is significantly better than Ligand B (82.53). For CNS targets, TPSA should be <= 90, and A is comfortably within this range, while B is approaching the upper limit.

**logP:** Both ligands have acceptable logP values (3.622 and 2.748), falling within the 1-3 optimal range.

**H-Bond Donors/Acceptors:** Both have 2 HBDs, which is good. Ligand A has 3 HBAs, and Ligand B has 5. Both are within the acceptable limit of <=10, but A is slightly preferable.

**QED:** Both ligands have similar QED values (0.81 and 0.743), indicating good drug-likeness.

**DILI:** Ligand A (76.076) has a higher DILI risk than Ligand B (47.693). This is a significant drawback for Ligand A.

**BBB:** Ligand A (66.731) has a better BBB percentile than Ligand B (36.371). This is *critical* for a CNS target like DRD2.

**Caco-2 Permeability:** Both have negative Caco-2 values which is unusual and suggests poor permeability. Ligand A (-4.922) is slightly better than Ligand B (-5.441), but both are poor.

**Aqueous Solubility:** Both ligands have negative solubility values which is also unusual. Ligand A (-3.936) is slightly better than Ligand B (-3.491), but both are poor.

**hERG:** Both ligands have low hERG inhibition liability (0.537 and 0.618), which is good.

**Microsomal Clearance:** Ligand B (83.084) has significantly higher microsomal clearance than Ligand A (17.811), indicating lower metabolic stability. This is a major disadvantage for Ligand B.

**In vitro Half-Life:** Ligand A (12.251 hours) has a much longer half-life than Ligand B (-19.987 hours). The negative value for B is concerning.

**P-gp Efflux:** Ligand A (0.046) has much lower P-gp efflux liability than Ligand B (0.202), which is favorable for CNS penetration.

**Binding Affinity:** Ligand A (-9.6 kcal/mol) has a slightly better binding affinity than Ligand B (-8.5 kcal/mol). While both are good, the 1.1 kcal/mol difference is notable.

**Overall Assessment:**

Despite the higher DILI risk, Ligand A is the more promising candidate. Its superior BBB penetration, lower P-gp efflux, better metabolic stability (lower Cl_mic, longer t1/2), and slightly better binding affinity outweigh the DILI concern. The TPSA is also much more favorable for CNS penetration. The poor Caco-2 and solubility for both are concerning, but can potentially be addressed through formulation strategies. Ligand B's poor BBB, high clearance, and negative half-life are significant liabilities.

Output:
0
2025-04-17 07:27:23,909 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (347.415 Da) is slightly lower, which could be beneficial for permeability, but both are acceptable.

**TPSA:** Ligand A (102.68) is borderline for CNS penetration, being above the preferred <90. Ligand B (78.67) is well within the desirable range for CNS targets. This is a significant advantage for Ligand B.

**logP:** Both ligands have good logP values (A: 1.28, B: 0.766), falling within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A has 3 HBD and 5 HBA, which are acceptable. Ligand B has 1 HBD and 5 HBA, also acceptable.

**QED:** Both ligands have good QED scores (A: 0.719, B: 0.853), indicating good drug-like properties. Ligand B is slightly better.

**DILI:** Ligand A (60.45) is approaching a concerning level for DILI risk, while Ligand B (39.511) is well below the 40 threshold, indicating a lower risk of liver injury.

**BBB:** Ligand A (64.599) is below the desirable 70% for CNS targets, while Ligand B (71.19) is above it. This is a crucial difference, favoring Ligand B.

**Caco-2 Permeability:** Both have negative Caco-2 values which is unusual and suggests poor permeability. However, these values are on different scales and direct comparison is difficult.

**Aqueous Solubility:** Both have negative solubility values which is also unusual. Again, direct comparison is difficult.

**hERG:** Both ligands have low hERG inhibition liability (A: 0.387, B: 0.272), which is good.

**Microsomal Clearance:** Ligand A (-26.375) has a much lower (better) microsomal clearance than Ligand B (19.758), suggesting greater metabolic stability.

**In vitro Half-Life:** Ligand A (9.629) has a longer half-life than Ligand B (-2.78), which is desirable.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (A: 0.016, B: 0.148), which is excellent for CNS penetration.

**Binding Affinity:** Ligand B (-8.0 kcal/mol) has a slightly better binding affinity than Ligand A (-7.8 kcal/mol), although the difference is not huge.

**Overall Assessment:**

Considering the GPCR-specific priorities, Ligand B is the more promising candidate. While Ligand A has better metabolic stability and half-life, Ligand B excels in crucial areas for CNS drug development: lower DILI risk, better TPSA, and higher BBB penetration. The slightly better binding affinity of Ligand B further supports this conclusion. The differences in Caco-2 and solubility are difficult to interpret given the negative values.

Output:
1
2025-04-17 07:27:23,910 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 drug candidates, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (348.443) is slightly better positioned.

**TPSA:** Ligand A (67.87) is excellent for CNS penetration, well below the 90 A^2 threshold. Ligand B (134.19) is higher, but still potentially acceptable, though less ideal.

**logP:** Ligand A (1.421) is within the optimal range (1-3). Ligand B (-1.047) is slightly low, which could hinder permeability.

**H-Bond Donors/Acceptors:** Ligand A (HBD=1, HBA=4) is better than Ligand B (HBD=4, HBA=7) in terms of maintaining a balance between solubility and permeability.

**QED:** Ligand A (0.582) has a good drug-likeness score, exceeding the 0.5 threshold. Ligand B (0.364) is below this threshold, indicating a less favorable drug-like profile.

**DILI:** Both ligands have low DILI risk (Ligand A: 35.052, Ligand B: 32.183), which is positive.

**BBB:** Ligand A (71.501) has a very good BBB percentile, exceeding the desirable >70% threshold for CNS targets. Ligand B (23.42) is significantly lower and would likely have poor brain penetration. This is a critical difference for a DRD2 ligand.

**Caco-2 Permeability:** Ligand A (-4.587) is poor, while Ligand B (-5.528) is also poor.

**Aqueous Solubility:** Ligand A (-2.592) is poor, while Ligand B (-1.36) is also poor.

**hERG:** Both ligands have low hERG risk (Ligand A: 0.138, Ligand B: 0.153).

**Microsomal Clearance:** Ligand A (29.301) has lower clearance than Ligand B (67.615), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (-3.507) has a negative half-life, which is unusual and suggests rapid degradation. Ligand B (-19.32) is even worse.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (Ligand A: 0.047, Ligand B: 0.042).

**Binding Affinity:** Ligand A (-7.3 kcal/mol) has a slightly better binding affinity than Ligand B (-6.6 kcal/mol), though both are good. The 0.7 kcal/mol difference is significant.

**Overall Assessment:**

Ligand A is the stronger candidate. While both have issues with Caco-2 permeability and solubility, Ligand A excels in BBB penetration (critical for a CNS target like DRD2), has a better QED score, and slightly better binding affinity. The lower microsomal clearance of Ligand A is also a significant advantage. Despite the negative in vitro half-life, the combination of favorable properties makes it more promising. Ligand B's poor BBB score is a major drawback.

Output:
1
2025-04-17 07:27:23,910 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (343.391 Da) is slightly lower, which could be beneficial for permeability. Ligand B (367.852 Da) is also good.

**TPSA:** Ligand A (105.04) is better than Ligand B (69.22). For CNS targets, we want TPSA <= 90, and Ligand B is much closer to this threshold.

**logP:** Ligand A (0.059) is quite low, potentially hindering membrane permeability. Ligand B (3.426) is within the optimal range (1-3). This is a significant advantage for Ligand B.

**H-Bond Donors:** Both ligands have 2 HBD, which is acceptable (<=5).

**H-Bond Acceptors:** Ligand A has 7 HBA, while Ligand B has 3. Both are within the acceptable range (<=10).

**QED:** Both ligands have similar QED values (0.761 and 0.751), indicating good drug-like properties.

**DILI:** Ligand A (64.831) has a higher DILI risk than Ligand B (36.681). Lower DILI is preferred.

**BBB:** Ligand A (59.131) and Ligand B (50.523) both have BBB penetration below the desirable threshold of 70%. However, the difference is not huge.

**Caco-2 Permeability:** Ligand A (-5.474) has very poor Caco-2 permeability, while Ligand B (-4.882) is slightly better.

**Aqueous Solubility:** Ligand A (-1.436) has poor solubility, while Ligand B (-3.72) is even worse. Both are problematic.

**hERG Inhibition:** Ligand A (0.222) has a lower hERG risk than Ligand B (0.88). Lower hERG is preferred.

**Microsomal Clearance:** Ligand A (-45.013) has a much lower (better) microsomal clearance than Ligand B (44.34). This suggests better metabolic stability for Ligand A.

**In vitro Half-Life:** Ligand A (24.009 hours) has a longer half-life than Ligand B (44.309 hours). Longer is generally preferred.

**P-gp Efflux:** Ligand A (0.013) has very low P-gp efflux, which is excellent for CNS penetration. Ligand B (0.62) has moderate P-gp efflux.

**Binding Affinity:** Ligand A (-7.3 kcal/mol) has a slightly better binding affinity than Ligand B (-6.9 kcal/mol). This difference is significant (0.4 kcal/mol).

**Overall Assessment:**

Ligand A has a better binding affinity, lower P-gp efflux, lower DILI, and better metabolic stability. However, its low logP and poor Caco-2 permeability are major concerns. Ligand B has a better logP and TPSA, but suffers from higher DILI, higher P-gp efflux, and lower metabolic stability. Given the GPCR-specific priorities, the logP and TPSA are crucial for CNS penetration. While Ligand A's affinity is better, the poor permeability characteristics are likely to severely limit its *in vivo* exposure in the brain. Ligand B, despite its drawbacks, has a more favorable balance of properties for CNS penetration.

Output:
1
2025-04-17 07:27:23,910 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (352.387 and 354.475 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (85.38) is better than Ligand B (46.34). For CNS targets, TPSA should be <= 90, both meet this criteria, but A is closer to the upper limit.

**3. logP:** Ligand A (0.42) is quite low, potentially hindering permeability. Ligand B (4.546) is high, potentially causing solubility and off-target issues. This is a significant drawback for Ligand B.

**4. H-Bond Donors:** Both ligands have 0 HBD, which is acceptable.

**5. H-Bond Acceptors:** Ligand A (6) and Ligand B (4) are both within the acceptable range of <=10.

**6. QED:** Both ligands have similar QED values (0.682 and 0.652), indicating reasonable drug-likeness.

**7. DILI:** Both ligands have similar DILI risk (52.346 and 57.348), both are acceptable.

**8. BBB:** Ligand A (69.213) and Ligand B (72.664) both have good BBB penetration, exceeding the desirable >70 threshold for CNS targets. Ligand B is slightly better.

**9. Caco-2 Permeability:** Ligand A (-4.477) has poor Caco-2 permeability, while Ligand B (-5.059) is also poor.

**10. Aqueous Solubility:** Ligand A (-1.72) has poor solubility, while Ligand B (-4.835) is even worse.

**11. hERG Inhibition:** Ligand A (0.057) has very low hERG inhibition risk, while Ligand B (0.75) has a slightly higher, but still acceptable, risk.

**12. Microsomal Clearance:** Ligand A (9.582) has lower clearance, indicating better metabolic stability than Ligand B (101.629).

**13. In vitro Half-Life:** Ligand A (-3.783) has a negative half-life, which is not possible. This is a major red flag. Ligand B (29.328) has a reasonable half-life.

**14. P-gp Efflux:** Ligand A (0.07) has low P-gp efflux, which is desirable for CNS exposure. Ligand B (0.805) has slightly higher efflux.

**15. Binding Affinity:** Ligand B (-8.2 kcal/mol) has a significantly stronger binding affinity than Ligand A (-7.7 kcal/mol). This >1.5 kcal/mol difference is substantial and can outweigh some ADME drawbacks.

**Overall Assessment:**

Ligand A has a concerning negative in vitro half-life, making it immediately less viable. While it has better TPSA and P-gp efflux, its very low logP and poor Caco-2 permeability are problematic. Ligand B, despite a higher logP and slightly worse P-gp efflux, has a much better binding affinity, acceptable BBB penetration, and a reasonable half-life. The strong binding affinity is a key advantage for a GPCR ligand.

Output:
1
2025-04-17 07:27:23,910 - INFO - Reasoning:

Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (344.342 and 367.406 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (99.52) is better than Ligand B (109.14). Both are below the 140 A^2 threshold for oral absorption, but for a CNS target like DRD2, we ideally want <90 A^2. Ligand A is closer to this target.

**3. logP:** Ligand A (2.15) is within the optimal 1-3 range. Ligand B (0.831) is slightly below 1, which *could* indicate permeability issues.

**4. H-Bond Donors:** Both ligands have 3 HBD, which is within the acceptable limit of <=5.

**5. H-Bond Acceptors:** Ligand A has 4 HBA, and Ligand B has 7. Both are below the 10 limit, but Ligand A is preferable.

**6. QED:** Ligand A (0.789) has a better QED score than Ligand B (0.672), indicating a more drug-like profile.

**7. DILI:** Ligand B (66.731) has a slightly better DILI score than Ligand A (74.176), but both are acceptable (<60 is ideal, but <80 is generally okay).

**8. BBB:** Ligand A (57.619) has a significantly better BBB percentile than Ligand B (45.909). This is *critical* for a CNS target like DRD2. A value >70 is desirable, and Ligand A is closer.

**9. Caco-2:** Both have negative Caco-2 values (-4.947 and -5.392). This is unusual and suggests poor permeability. However, these values are on a different scale and difficult to interpret without more context.

**10. Solubility:** Both ligands have negative solubility values (-3.256 and -2.544). Again, this is unusual and problematic.

**11. hERG:** Both ligands have very low hERG inhibition risk (0.049 and 0.186).

**12. Cl_mic:** Ligand A (-7.468) has a much lower (better) microsomal clearance than Ligand B (30.466), indicating greater metabolic stability.

**13. t1/2:** Ligand A (-17.699) has a negative in vitro half-life, which is not physically possible. Ligand B (4.839) has a short half-life. This is a significant drawback for both, but the negative value for A is a data quality issue.

**14. Pgp:** Both ligands have very low Pgp efflux liability (0.009 and 0.028).

**15. Binding Affinity:** Both ligands have very similar and strong binding affinities (-7.9 and -7.5 kcal/mol). The difference of 0.4 kcal/mol is not substantial enough to override other factors.

**Overall Assessment:**

Ligand A is the stronger candidate. While both have issues with solubility and Caco-2 permeability, Ligand A excels in critical areas for a CNS GPCR target: better TPSA, logP, BBB penetration, and significantly improved metabolic stability (lower Cl_mic). The negative half-life for Ligand A is a red flag and needs investigation, but the other factors strongly favor it. Ligand B's lower logP and poorer BBB penetration are significant drawbacks.

Output:
1
2025-04-17 07:27:23,910 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (370.881 Da) is slightly higher than Ligand B (345.487 Da), but both are acceptable.

**TPSA:** Ligand A (77.07) is higher than Ligand B (62.3). For CNS targets, we want TPSA <= 90. Both are within this range, but Ligand B is preferable.

**logP:** Ligand A (1.18) is within the optimal range (1-3), while Ligand B (3.191) is at the higher end. Both are acceptable, but Ligand A is slightly better regarding potential off-target effects.

**H-Bond Donors/Acceptors:** Ligand A has 3 HBD and 6 HBA, while Ligand B has 1 HBD and 3 HBA. Both are within the recommended limits (<=5 HBD and <=10 HBA).

**QED:** Both ligands have good QED scores (Ligand A: 0.596, Ligand B: 0.787), indicating good drug-like properties. Ligand B is slightly better.

**DILI:** Ligand A (44.63) has a higher DILI risk than Ligand B (30.593). Lower DILI is preferred, so Ligand B is better.

**BBB:** This is a crucial parameter for CNS targets. Ligand B (70.919) has a significantly better BBB penetration percentile than Ligand A (45.444). This is a major advantage for Ligand B.

**Caco-2 Permeability:** Both have negative values, which is unusual. Assuming these are logP-scale values, lower values indicate poorer permeability. Ligand A (-5.007) is worse than Ligand B (-4.698).

**Aqueous Solubility:** Both have negative values, indicating poor solubility. Ligand A (-2.291) is slightly better than Ligand B (-2.871).

**hERG Inhibition:** Ligand A (0.886) has a slightly higher hERG inhibition risk than Ligand B (0.513). Lower hERG is preferred, so Ligand B is better.

**Microsomal Clearance:** Ligand A (-5.246) has a lower (better) microsomal clearance than Ligand B (56.327). This suggests better metabolic stability for Ligand A.

**In vitro Half-Life:** Ligand A (18.689 hours) has a significantly longer half-life than Ligand B (-3.54 hours). This is a substantial advantage for Ligand A.

**P-gp Efflux:** Ligand A (0.058) has a much lower P-gp efflux liability than Ligand B (0.235). Lower P-gp efflux is preferable, especially for CNS targets, making Ligand A better.

**Binding Affinity:** Both ligands have very similar and excellent binding affinities (Ligand A: -7.6 kcal/mol, Ligand B: -7.7 kcal/mol). The difference is negligible.

**Overall Assessment:**

Ligand B excels in BBB penetration and DILI risk, and has a slightly better QED. However, Ligand A has significantly better metabolic stability (lower Cl_mic, longer t1/2), lower P-gp efflux, and slightly better solubility. Considering the GPCR-specific priorities, the superior BBB penetration of Ligand B is highly desirable. However, the substantial improvements in metabolic stability and reduced efflux for Ligand A are also very important. The difference in binding affinity is negligible. Given the balance, and prioritizing CNS penetration, Ligand B is slightly more promising.

Output:
1
2025-04-17 07:27:23,911 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (349.406 and 343.427 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (77.25) is better than Ligand B (82.53). Both are below the 90 A^2 threshold for CNS targets, which is good.

**logP:** Ligand A (2.929) is within the optimal 1-3 range. Ligand B (1.507) is at the lower end, potentially impacting permeability.

**H-Bond Donors/Acceptors:** Ligand A has 1 HBD and 5 HBA, while Ligand B has 2 HBD and 4 HBA. Both are within acceptable limits.

**QED:** Both ligands have good QED scores (0.667 and 0.767, respectively), indicating drug-like properties.

**DILI:** Ligand A (60.062) has a higher DILI risk than Ligand B (33.579). This is a significant drawback for Ligand A.

**BBB:** Ligand A (89.686) has a significantly better BBB penetration percentile than Ligand B (59.752). This is a crucial advantage for a CNS target like DRD2.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.889 and -4.838). This is unusual and suggests poor permeability.

**Aqueous Solubility:** Both ligands have negative solubility values (-2.702 and -2.586). This is also unusual and suggests poor solubility.

**hERG Inhibition:** Ligand A (0.668) has a slightly higher hERG inhibition risk than Ligand B (0.095). Ligand B is much better here.

**Microsomal Clearance:** Ligand B (20.217) has a lower microsomal clearance than Ligand A (55.088), indicating better metabolic stability.

**In vitro Half-Life:** Ligand B (-16.712) has a negative half-life, which is not possible. This is a major red flag. Ligand A (22.074) is reasonable.

**P-gp Efflux:** Ligand A (0.558) has lower P-gp efflux than Ligand B (0.14), which is favorable for CNS penetration.

**Binding Affinity:** Ligand B (-8.9) has a slightly better binding affinity than Ligand A (-8.4). However, the difference is only 0.5 kcal/mol, which is not substantial enough to overcome other significant drawbacks.

**Overall Assessment:**

Ligand B has better affinity and lower DILI risk, but it has a negative in vitro half-life, which is a critical issue. It also has significantly lower BBB penetration and higher P-gp efflux. Ligand A, while having a higher DILI risk, has a much better BBB score, lower P-gp efflux, and a reasonable half-life. Given the CNS target, BBB penetration is paramount. The slightly better affinity of Ligand B is unlikely to compensate for its poor CNS exposure. The negative half-life for Ligand B is a showstopper.

Output:
1
2025-04-17 07:27:23,911 - INFO - Batch 366 complete. Total preferences: 5856
2025-04-17 07:27:23,911 - INFO - Processing batch 367/512...
2025-04-17 07:28:04,684 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B based on the provided guidelines, prioritizing GPCR-specific properties (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (350.375 and 352.519 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (133.56) is closer to the ideal <90 for CNS targets than Ligand B (58.64), which is excellent.

**logP:** Ligand A (-0.62) is suboptimal, being below the preferred 1-3 range and potentially hindering permeation. Ligand B (3.147) is within the optimal range.

**H-Bond Donors/Acceptors:** Ligand A (HBD=4, HBA=6) is acceptable. Ligand B (HBD=1, HBA=3) is also good, potentially offering better permeability due to fewer hydrogen bonds.

**QED:** Both ligands have good QED scores (A: 0.54, B: 0.716), indicating drug-like properties.

**DILI:** Ligand A (41.45) has a slightly higher DILI risk than Ligand B (23.769), but both are below the concerning threshold of 60.

**BBB:** This is a critical parameter for CNS targets. Ligand B (79.139) has a significantly better BBB percentile than Ligand A (60.566), exceeding the desirable >70 threshold.

**Caco-2 Permeability:** Ligand A (-5.453) has poor Caco-2 permeability, while Ligand B (-4.098) is also low, but better than A.

**Aqueous Solubility:** Both ligands have poor aqueous solubility (-1.204 and -3.107 respectively).

**hERG:** Both ligands have very low hERG risk (0.056 and 0.269 respectively).

**Microsomal Clearance:** Ligand A (-9.104) has a much lower (better) microsomal clearance than Ligand B (98.001), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (-10.572) has a negative half-life, which is not physically possible and indicates an issue with the data or prediction. Ligand B (16.945) has a reasonable half-life.

**P-gp Efflux:** Ligand A (0.003) has very low P-gp efflux, which is favorable for CNS penetration. Ligand B (0.123) also has low P-gp efflux.

**Binding Affinity:** Ligand B (-7.6 kcal/mol) has a slightly better binding affinity than Ligand A (-8.8 kcal/mol). While A is better, the difference is not substantial enough to overcome other significant drawbacks.

**Overall Assessment:**

Ligand B is the more promising candidate. While both have solubility issues, Ligand B excels in crucial areas for a CNS-targeting GPCR ligand: significantly better BBB penetration, a favorable logP, and acceptable metabolic stability. Ligand A's poor Caco-2 permeability and the implausible negative half-life are major concerns. The slightly better affinity of Ligand A is outweighed by these ADME deficiencies.

Output:
1
2025-04-17 07:28:04,685 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (343.471 and 368.543 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (73.99) is better than Ligand B (62.66), both are below the 90 A^2 threshold for CNS targets.

**logP:** Both ligands have good logP values (2.972 and 3.632), falling within the optimal 1-3 range. Ligand B is slightly higher, potentially increasing permeability but also raising concerns about off-target effects.

**H-Bond Donors/Acceptors:** Ligand A (3 HBD, 2 HBA) is slightly better than Ligand B (1 HBD, 5 HBA) in terms of balancing solubility and permeability.

**QED:** Both ligands have good QED scores (0.571 and 0.761), indicating drug-like properties. Ligand B is better.

**DILI:** Both ligands have low DILI risk (27.026 and 33.579), well below the 40 threshold.

**BBB:** Ligand A (69.484) is better than Ligand B (62.737), but both are below the desirable >70 percentile for CNS targets. This is a critical factor for DRD2, so we need to consider this carefully.

**Caco-2 Permeability:** Ligand A (-4.824) is better than Ligand B (-4.265). Higher values indicate better intestinal absorption.

**Aqueous Solubility:** Both ligands have poor aqueous solubility (-3.844 and -3.985). This could pose formulation challenges, but is less critical than BBB penetration for a CNS target.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.415 and 0.519).

**Microsomal Clearance:** Ligand A (54.021) has lower clearance than Ligand B (85.83), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (-13.24) has a longer half-life than Ligand B (-19.831).

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.096 and 0.565).

**Binding Affinity:** Both ligands have similar binding affinities (-8.0 and -7.0 kcal/mol). Ligand A has a slightly better affinity.

**Overall Assessment:**

Ligand A is slightly better overall. While Ligand B has a slightly higher QED and logP, Ligand A excels in BBB penetration (although still suboptimal), metabolic stability (lower Cl_mic, longer t1/2), Caco-2 permeability and binding affinity. Given the importance of BBB penetration for a CNS target like DRD2, Ligand A is the more promising candidate. The slightly better affinity further strengthens this conclusion.

Output:
0
2025-04-17 07:28:04,685 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B based on the provided guidelines, prioritizing GPCR-specific properties (BBB, logP, Pgp, TPSA, and affinity) for DRD2.

**Molecular Weight:** Both ligands (339.439 and 345.359 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (45.67) is significantly better than Ligand B (119.24). For CNS targets, TPSA should be <=90, and A is well within this range, while B exceeds it. This is a major advantage for A.

**logP:** Ligand A (2.46) is optimal (1-3). Ligand B (0.143) is quite low, potentially hindering permeability. This favors A.

**H-Bond Donors/Acceptors:** Ligand A (0 HBD, 4 HBA) and Ligand B (2 HBD, 7 HBA) are both reasonable, falling within acceptable limits.

**QED:** Both ligands have similar QED values (0.862 and 0.791), indicating good drug-likeness.

**DILI:** Ligand A (47.421) has a lower DILI risk than Ligand B (76.464), which is preferable.

**BBB:** Ligand A (81.815) has a significantly higher BBB penetration percentile than Ligand B (53.587). This is *critical* for a CNS target like DRD2, making A much more promising.

**Caco-2 Permeability:** Ligand A (-4.326) and Ligand B (-5.186) both have negative values, which is unusual and suggests poor permeability. However, the scale isn't fully defined, so it's hard to interpret.

**Aqueous Solubility:** Ligand A (-1.293) and Ligand B (-2.184) both have negative solubility values, indicating poor solubility.

**hERG Inhibition:** Ligand A (0.632) has a slightly higher hERG risk than Ligand B (0.039), but both are relatively low.

**Microsomal Clearance:** Ligand A (23.548) has higher clearance than Ligand B (11.865), suggesting lower metabolic stability. This favors B.

**In vitro Half-Life:** Ligand A (36.545) has a longer half-life than Ligand B (6.284), which is desirable.

**P-gp Efflux:** Ligand A (0.187) has lower P-gp efflux than Ligand B (0.008), which is better for CNS exposure.

**Binding Affinity:** Ligand B (-8.3 kcal/mol) has a *much* stronger binding affinity than Ligand A (0.0 kcal/mol). This is a substantial advantage for B. A difference of >1.5 kcal/mol can outweigh other drawbacks.

**Overall Assessment:**

While Ligand A excels in TPSA, BBB, and P-gp efflux, and has a better half-life, Ligand B's significantly superior binding affinity (-8.3 vs 0.0 kcal/mol) is the dominating factor. The lower logP and higher TPSA of Ligand B are concerns, but the substantial binding advantage is likely to outweigh these, especially given the potential for further optimization. The difference in binding affinity is so large that it is likely to be the most important factor in determining which ligand is more likely to be a viable drug candidate.

Output:
1
2025-04-17 07:28:04,685 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (366.571 and 352.391 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (63.4) is significantly better than Ligand B (102.76). For CNS targets, we want TPSA <= 90, and A is comfortably within that, while B is pushing the limit.

**logP:** Ligand A (3.535) is optimal (1-3), while Ligand B (-0.361) is quite low, potentially hindering membrane permeability.

**H-Bond Donors/Acceptors:** Both have 1 HBD, which is good. Ligand A has 3 HBA, and Ligand B has 7 HBA. Both are within the acceptable range of <=10, but Ligand A is preferable.

**QED:** Ligand A (0.89) has a much better QED score than Ligand B (0.672), indicating better overall drug-likeness.

**DILI:** Ligand A (29.546) has a significantly lower DILI risk than Ligand B (49.477). Both are below 60, but A is clearly better.

**BBB:** Ligand A (80.264) has a good BBB penetration percentile, exceeding the desirable >70 threshold for CNS targets. Ligand B (60.527) is lower and less desirable.

**Caco-2 Permeability:** Both have negative Caco-2 values (-4.79 and -4.805), which is unusual and suggests poor permeability. However, these values are on a log scale, and the absolute difference isn't huge.

**Aqueous Solubility:** Both have negative solubility values (-4.218 and -0.692), also unusual. Ligand B is slightly better here.

**hERG Inhibition:** Ligand A (0.86) has a slightly higher hERG risk than Ligand B (0.165), but both are relatively low.

**Microsomal Clearance:** Ligand A (56.363) has a higher microsomal clearance than Ligand B (21.007), indicating lower metabolic stability. This is a negative for A.

**In vitro Half-Life:** Ligand A (-27.951) has a negative half-life, which is not physically possible and indicates a problem with the data or prediction method. Ligand B (-7.789) also has a negative half-life, but is less extreme.

**P-gp Efflux:** Ligand A (0.333) has lower P-gp efflux than Ligand B (0.011), which is favorable for CNS penetration.

**Binding Affinity:** Ligand A (-8.2 kcal/mol) has a significantly stronger binding affinity than Ligand B (-7.3 kcal/mol). This is a substantial advantage, potentially outweighing some of the ADME drawbacks.

**Overall Assessment:**

Ligand A is significantly better in terms of TPSA, logP, QED, DILI, and crucially, BBB penetration and binding affinity. While its microsomal clearance is higher and half-life is problematic (negative value), the strong binding affinity and good CNS penetration profile make it a more promising candidate. Ligand B's low logP and lower BBB penetration are significant drawbacks. The negative half-life values for both are concerning and would require further investigation, but the magnitude of the difference in affinity and BBB for A is substantial.

Output:
1
2025-04-17 07:28:04,685 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (384.929 and 368.865 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (66.48) is significantly better than Ligand B (76.46). For CNS targets, we want TPSA <= 90, and A is closer to the optimal <=60 range. B is pushing the upper limit.

**3. logP:** Ligand A (3.361) is within the optimal 1-3 range. Ligand B (1.583) is at the lower end, potentially hindering permeability.

**4. H-Bond Donors:** Both have 1 HBD, which is good.

**5. H-Bond Acceptors:** Ligand A has 3 HBA, while Ligand B has 5. Both are acceptable (<=10), but A is slightly better.

**6. QED:** Both ligands have similar QED values (0.868 and 0.8), indicating good drug-likeness.

**7. DILI:** Both have similar DILI risk (47.693 and 47.421), indicating low risk.

**8. BBB:** Ligand A (87.67) has a significantly higher BBB penetration percentile than Ligand B (62.854). This is *crucial* for a CNS target like DRD2.

**9. Caco-2 Permeability:** Ligand A (-4.47) is better than Ligand B (-4.886), indicating slightly better intestinal absorption.

**10. Aqueous Solubility:** Ligand A (-4.545) is better than Ligand B (-2.326), indicating better solubility.

**11. hERG Inhibition:** Both ligands have low hERG inhibition liability (0.578 and 0.273).

**12. Microsomal Clearance:** Ligand A (26.408) has higher clearance than Ligand B (12.282), meaning B is more metabolically stable.

**13. In vitro Half-Life:** Ligand A (53.419) has a longer half-life than Ligand B (-0.948), which is desirable.

**14. P-gp Efflux:** Ligand A (0.196) has lower P-gp efflux than Ligand B (0.03), meaning A is less likely to be pumped out of the brain.

**15. Binding Affinity:** Ligand B (-8.2 kcal/mol) has a slightly better binding affinity than Ligand A (-7.6 kcal/mol). While a 0.6 kcal/mol difference is noticeable, the ADME properties of A are far superior for CNS penetration.

**Overall Assessment:**

Ligand A is the stronger candidate. While Ligand B has a slightly better binding affinity, Ligand A excels in critical ADME properties for a CNS-targeting GPCR: TPSA, logP, BBB penetration, solubility, and P-gp efflux. The higher BBB and lower P-gp efflux of Ligand A will likely translate to greater brain exposure and efficacy *in vivo*. The better solubility and TPSA also contribute to better overall drug-like properties. The slightly higher clearance of A is a minor drawback compared to the significant advantages in CNS penetration.

Output:
1
2025-04-17 07:28:04,686 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (367.47 and 351.45 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (81.7) is significantly better than Ligand B (107.53). For CNS targets, we want TPSA <= 90, so Ligand A is preferable.

**logP:** Ligand A (1.883) is within the optimal 1-3 range. Ligand B (0.383) is a bit low, potentially hindering permeability.

**H-Bond Donors/Acceptors:** Ligand A (HBD=1, HBA=5) and Ligand B (HBD=4, HBA=4) both have reasonable numbers of H-bond donors and acceptors.

**QED:** Ligand A (0.71) is better than Ligand B (0.498), indicating a more drug-like profile.

**DILI:** Ligand A (49.244) has a slightly higher DILI risk than Ligand B (28.693), but both are acceptable (<60).

**BBB:** Ligand A (67.546) is better than Ligand B (29.12).  For a CNS target like DRD2, a BBB percentile >70 is desirable, and Ligand A is closer to that threshold.

**Caco-2 Permeability:** Ligand A (-4.885) is worse than Ligand B (-5.488), indicating lower intestinal absorption. However, for a CNS target, intestinal absorption is less critical than BBB penetration.

**Aqueous Solubility:** Ligand A (-3.35) is better than Ligand B (-2.181), indicating better solubility.

**hERG:** Both ligands have very low hERG inhibition risk (0.393 and 0.062, respectively).

**Microsomal Clearance:** Ligand A (70.712) has a higher clearance than Ligand B (27.274), suggesting lower metabolic stability.

**In vitro Half-Life:** Ligand A (-35.551) has a much shorter half-life than Ligand B (-0.566).

**P-gp Efflux:** Both ligands show low P-gp efflux liability (0.092 and 0.036, respectively).

**Binding Affinity:** Both ligands have very similar binding affinities (-8.4 and -8.6 kcal/mol). This is excellent binding for both.

**Overall Assessment:**

Ligand A is superior due to its better TPSA, logP, QED, and crucially, its significantly higher BBB penetration. While Ligand A has a higher DILI risk and lower metabolic stability (higher Cl_mic, shorter t1/2), the strong BBB penetration is a critical advantage for a CNS-targeting drug. The similar binding affinities mean that the ADME properties become the deciding factor.

Output:
1
2025-04-17 07:28:04,686 - INFO - Reasoning:

Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (363.483 and 352.435 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (95.08) is better than Ligand B (137.31). For CNS targets, we want TPSA <= 90, so Ligand A is closer to this threshold. Ligand B is significantly higher, potentially hindering BBB penetration.

**3. logP:** Ligand A (2.222) is optimal (1-3). Ligand B (0.535) is low, which could impede permeation.

**4. H-Bond Donors:** Ligand A (3) is acceptable. Ligand B (5) is at the upper limit of the preferred range.

**5. H-Bond Acceptors:** Ligand A (5) is acceptable. Ligand B (4) is also acceptable.

**6. QED:** Ligand A (0.703) is good, indicating a drug-like profile. Ligand B (0.466) is lower, suggesting a less favorable drug-like profile.

**7. DILI:** Ligand A (54.207) has a moderate DILI risk. Ligand B (35.595) has a lower DILI risk, which is preferable.

**8. BBB:** Ligand A (52.889) has a moderate BBB penetration. Ligand B (24.932) has a low BBB penetration, a significant drawback for a CNS target like DRD2.

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.573 and -5.877), which is unusual and potentially problematic. It suggests poor permeability.

**10. Aqueous Solubility:** Both ligands have negative solubility values (-2.882 and -2.783), also unusual and potentially problematic.

**11. hERG:** Ligand A (0.557) has a low hERG risk. Ligand B (0.243) has an even lower hERG risk, which is excellent.

**12. Microsomal Clearance:** Ligand A (21.727) has a moderate clearance. Ligand B (6.584) has a lower clearance, indicating better metabolic stability.

**13. In vitro Half-Life:** Ligand A (26.179) has a reasonable half-life. Ligand B (-13.123) has a negative half-life, which is impossible and indicates a significant issue with the data or the molecule.

**14. P-gp Efflux:** Ligand A (0.402) has low P-gp efflux, which is good. Ligand B (0.026) has very low P-gp efflux, which is even better.

**15. Binding Affinity:** Ligand A (-9.4 kcal/mol) has a significantly stronger binding affinity than Ligand B (-7.8 kcal/mol). This is a substantial advantage.

**Overall Assessment:**

Despite the unusual negative values for Caco-2 and Solubility, Ligand A is the more promising candidate. Its superior binding affinity (-9.4 vs -7.8 kcal/mol) is a major advantage, and it has a better TPSA and logP. While Ligand B has a slightly lower DILI risk and P-gp efflux, its extremely poor BBB penetration and the impossible negative half-life are dealbreakers. The strong affinity of Ligand A can potentially outweigh its moderate DILI risk and permeability concerns, warranting further investigation.

Output:
1
2025-04-17 07:28:04,686 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (345.487 and 345.374 Da) fall comfortably within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (43.86) is significantly better than Ligand B (67.6). For CNS targets, we want TPSA <= 90, and ideally closer to 60. Ligand A is much closer to this ideal.

**3. logP:** Both ligands have good logP values (2.173 and 2.379), falling within the optimal 1-3 range.

**4. H-Bond Donors:** Ligand A (0) is preferable to Ligand B (1). Fewer HBDs generally improve permeability.

**5. H-Bond Acceptors:** Ligand A (3) is better than Ligand B (5). Lower HBA counts are generally favored for CNS penetration.

**6. QED:** Both ligands have good QED scores (0.737 and 0.921), indicating good drug-like properties. Ligand B is slightly better.

**7. DILI:** Ligand A (19.581) has a much lower DILI risk than Ligand B (62.776). This is a significant advantage for Ligand A.

**8. BBB:** Both ligands have excellent BBB penetration (86.119 and 85.615). This is crucial for a CNS target like DRD2. They are very similar here.

**9. Caco-2 Permeability:** Both have negative Caco-2 values (-4.707 and -4.395). This is unusual and suggests poor permeability. However, these values are on a scale where negative values are possible and don't necessarily disqualify the compounds.

**10. Aqueous Solubility:** Both have negative solubility values (-2.182 and -3.546). Similar to Caco-2, these values are on a scale where negative values are possible.

**11. hERG Inhibition:** Both ligands have low hERG inhibition risk (0.435 and 0.367).

**12. Microsomal Clearance:** Ligand A (47.237) has lower microsomal clearance than Ligand B (75.332), suggesting better metabolic stability.

**13. In vitro Half-Life:** Ligand B (25.666) has a significantly longer in vitro half-life than Ligand A (9.239). This is a positive for Ligand B.

**14. P-gp Efflux:** Both ligands have low P-gp efflux liability (0.293 and 0.401).

**15. Binding Affinity:** Ligand B (-7.5 kcal/mol) has a slightly better binding affinity than Ligand A (-8.2 kcal/mol). While A is better, the difference is not substantial enough to outweigh other factors.

**Overall Assessment:**

Considering the GPCR-specific priorities, Ligand A is the more promising candidate. Its lower TPSA, lower DILI risk, lower microsomal clearance, and fewer H-bonds are all favorable. While Ligand B has a slightly better binding affinity and half-life, the advantages of Ligand A in terms of CNS penetration potential (lower TPSA, lower DILI) and metabolic stability are more critical for a DRD2 ligand.

Output:
0
2025-04-17 07:28:04,686 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (348.403 and 347.415 Da) fall comfortably within the ideal 200-500 Da range.

**TPSA:** Ligand A (118.53) is slightly higher than Ligand B (93.46). Both are below the 140 A^2 threshold for oral absorption and, more importantly, below the 90 A^2 target for CNS penetration, but Ligand B is significantly better.

**logP:** Ligand A (0.605) is a bit low, potentially hindering membrane permeability. Ligand B (1.104) is better, falling within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Both ligands have 2 HBD and 5 HBA, which are acceptable values.

**QED:** Both ligands have high QED scores (0.826 and 0.804), indicating good drug-like properties.

**DILI:** Both ligands have similar, acceptable DILI risk (43.932 and 45.328 percentile).

**BBB:** This is a crucial parameter for a CNS target like DRD2. Ligand A has a BBB percentile of 65.529, while Ligand B has 55.603. Ligand A is better here, but both are below the desirable >70 threshold.

**Caco-2 Permeability:** Both have negative Caco-2 values (-5.33 and -5.559), which is unusual and suggests poor permeability. This is a significant concern for both.

**Aqueous Solubility:** Both have negative solubility values (-1.918 and -0.792), indicating very poor aqueous solubility. This is a major drawback for both compounds.

**hERG Inhibition:** Both ligands show very low hERG inhibition liability (0.096 and 0.115 percentile), which is excellent.

**Microsomal Clearance:** Ligand A (2.411 mL/min/kg) has a lower (better) microsomal clearance than Ligand B (7.537 mL/min/kg), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (-20.871 hours) has a negative half-life, which is not physically possible. Ligand B (6.191 hours) is a reasonable value. The negative value for Ligand A is a major red flag.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.017 and 0.024 percentile), which is favorable for CNS exposure.

**Binding Affinity:** Ligand B (-8.8 kcal/mol) has a significantly stronger binding affinity than Ligand A (-7.9 kcal/mol). This 0.9 kcal/mol difference is substantial and could outweigh some of the ADME drawbacks.

**Overall Assessment:**

Ligand B has a better logP, TPSA, and significantly better binding affinity. However, Ligand A has a better BBB score and microsomal clearance. Both have poor solubility and Caco-2 permeability. The negative half-life for Ligand A is a critical flaw. Considering the GPCR-specific priorities, the stronger binding affinity of Ligand B is a major advantage. While the BBB score isn't ideal, the improved affinity could compensate, especially if formulation strategies can address the solubility issue. The negative half-life for Ligand A is a deal-breaker.

Output:
1
2025-04-17 07:28:04,686 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 drug candidates, considering the provided guidelines and GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (348.487 and 352.41 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (67.43) is significantly better than Ligand B (94.56). For CNS targets, TPSA should be <= 90, so Ligand A is preferable.

**3. logP:** Ligand A (2.416) is within the optimal range (1-3). Ligand B (-0.302) is below 1, which could hinder permeation. This favors Ligand A.

**4. H-Bond Donors:** Both have acceptable HBD counts (2 and 3, respectively).

**5. H-Bond Acceptors:** Both have acceptable HBA counts (3 and 5, respectively).

**6. QED:** Both ligands have similar QED values (0.596 and 0.586), indicating good drug-likeness.

**7. DILI:** Both have relatively low DILI risk (18.34 and 20.279 percentiles), which is good.

**8. BBB:** This is a critical parameter for a CNS target like DRD2. Ligand A has a much higher BBB penetration (75.378%) compared to Ligand B (37.573%). This is a significant advantage for Ligand A.

**9. Caco-2 Permeability:** Ligand A (-4.518) and Ligand B (-5.263) both have negative values, suggesting poor permeability. However, the scale is not specified, making direct comparison difficult.

**10. Aqueous Solubility:** Ligand A (-3.783) and Ligand B (-1.135) both have negative values, suggesting poor solubility. However, the scale is not specified, making direct comparison difficult.

**11. hERG Inhibition:** Both ligands have low hERG inhibition liability (0.289 and 0.136), which is favorable.

**12. Microsomal Clearance:** Ligand A (89.342) has a higher microsomal clearance than Ligand B (-16.365). This suggests Ligand B is more metabolically stable, which is preferable.

**13. In vitro Half-Life:** Ligand A (0.28 hours) has a very short half-life, while Ligand B (-6.777 hours) is also short, but less so. This is a drawback for both, but more so for Ligand A.

**14. P-gp Efflux:** Both ligands have low P-gp efflux liability (0.157 and 0.005), which is good.

**15. Binding Affinity:** Both ligands have very similar and strong binding affinities (-7.8 and -7.7 kcal/mol). The difference is negligible.

**Overall Assessment:**

Ligand A is superior due to its significantly better TPSA and BBB penetration, and acceptable logP. While Ligand B has better metabolic stability (lower Cl_mic) and a slightly better in vitro half-life, the CNS penetration is a critical factor for DRD2, making Ligand A the more promising candidate. The similar binding affinities mean this isn't a deciding factor.

Output:
1
2025-04-17 07:28:04,687 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (364.383 and 364.387 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (49.41) is excellent, well below the 90 A^2 threshold for CNS targets. Ligand B (124.54) is higher, but still potentially acceptable, though less favorable.

**3. logP:** Ligand A (2.759) is optimal (1-3). Ligand B (-0.42) is significantly lower, which could hinder membrane permeability and CNS penetration.

**4. H-Bond Donors:** Both ligands have 1 HBD, which is within the acceptable limit of <=5.

**5. H-Bond Acceptors:** Ligand A has 2 HBA, and Ligand B has 8 HBA. Both are within the acceptable limit of <=10, but Ligand B is approaching the upper end.

**6. QED:** Both ligands have similar QED values (0.78 and 0.758), indicating good drug-like properties.

**7. DILI:** Ligand A (21.946) has a much lower DILI risk than Ligand B (77.549). This is a significant advantage for Ligand A.

**8. BBB:** Ligand A (89.725) has a very good BBB penetration percentile, exceeding the desirable >70% for CNS targets. Ligand B (19.891) has poor predicted BBB penetration.

**9. Caco-2:** Ligand A (-4.591) and Ligand B (-5.138) both have negative Caco-2 values, which is unusual. It suggests very poor permeability.

**10. Solubility:** Ligand A (-3.728) and Ligand B (-2.698) both have negative solubility values, which is also unusual. It suggests very poor solubility.

**11. hERG:** Both ligands have low hERG inhibition liability (0.657 and 0.198), which is good.

**12. Cl_mic:** Ligand A (21.621) has a moderate clearance, while Ligand B (-24.135) has a negative clearance, which is not possible. This suggests a potential issue with the data for Ligand B.

**13. t1/2:** Ligand A (13.836) has a reasonable in vitro half-life. Ligand B (-20.711) has a negative half-life, which is not possible.

**14. Pgp:** Both ligands have very low Pgp efflux liability (0.025 and 0.008), which is favorable for CNS penetration.

**15. Binding Affinity:** Both ligands have very similar and strong binding affinities (-8.9 and -8.5 kcal/mol). The difference is less than 1.5 kcal/mol, so it's not a deciding factor.

**Conclusion:**

Considering all factors, especially the GPCR-specific priorities, **Ligand A is significantly more promising**. It has a much better predicted BBB penetration, lower DILI risk, and a more optimal logP value. While both have unusual Caco-2 and solubility values, the negative clearance and half-life for Ligand B are major red flags, suggesting data issues or inherent instability. The slight advantage in binding affinity of Ligand A is a bonus, but the ADME properties are the primary drivers of this decision.

Output:
1
2025-04-17 07:28:04,687 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (345.403 Da) is slightly lower than Ligand B (385.511 Da), which is generally favorable for permeability.

**2. TPSA:** Both ligands have TPSA values below 140, suggesting reasonable oral absorption. Ligand B (101.77) is better than Ligand A (112.16) and closer to the preferred <90 for CNS targets.

**3. logP:** Both ligands have acceptable logP values (1-3). Ligand A (1.025) is slightly higher than Ligand B (0.531), which is better for membrane permeability.

**4. H-Bond Donors:** Ligand A (4) is slightly higher than Ligand B (2), but both are within the acceptable limit of 5.

**5. H-Bond Acceptors:** Both ligands have 6 H-bond acceptors, which is within the acceptable limit of 10.

**6. QED:** Both ligands have good QED scores (Ligand A: 0.596, Ligand B: 0.789), indicating good drug-like properties. Ligand B is slightly better.

**7. DILI:** Ligand A (67.158) has a higher DILI risk than Ligand B (35.285). This is a significant drawback for Ligand A.

**8. BBB:** Ligand A (32.803) has a very low BBB penetration percentile, making it unlikely to effectively engage DRD2 in the CNS. Ligand B (20.279) also has a low BBB penetration percentile, but it is slightly better than Ligand A.

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 permeability values, which is unusual and suggests poor permeability.

**10. Aqueous Solubility:** Both ligands have negative aqueous solubility values, which is also unusual and suggests poor solubility.

**11. hERG Inhibition:** Both ligands have very low hERG inhibition liability, which is favorable.

**12. Microsomal Clearance:** Ligand A (-40.701) has a more negative (lower) microsomal clearance, indicating better metabolic stability than Ligand B (-10.734).

**13. In vitro Half-Life:** Ligand A (50.156) has a longer in vitro half-life than Ligand B (33.297), which is desirable.

**14. P-gp Efflux:** Both ligands have very low P-gp efflux liability, which is favorable.

**15. Binding Affinity:** Ligand A (-8.0) has a significantly stronger binding affinity than Ligand B (-7.0). This is a substantial advantage that could potentially outweigh some of the ADME drawbacks.

**Overall Assessment:**

Despite Ligand A's superior binding affinity, its poor BBB penetration (32.803) and higher DILI risk (67.158) are major concerns for a CNS target like DRD2. Ligand B, while having a weaker binding affinity, exhibits a slightly better BBB penetration (20.279) and a significantly lower DILI risk (35.285). Given the GPCR-specific priorities, particularly BBB penetration and safety (DILI), Ligand B is the more promising candidate. The affinity difference, while notable, may be overcome with further optimization of Ligand B.

Output:
1
2025-04-17 07:28:04,687 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (373.909 and 360.523 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Both ligands (50.8 and 49.41) are below the 90 A^2 threshold for CNS targets, which is excellent.

**3. logP:** Ligand A (4.853) is slightly high, potentially leading to solubility issues or off-target interactions. Ligand B (3.815) is within the optimal 1-3 range.

**4. H-Bond Donors:** Both have 1 HBD, which is acceptable.

**5. H-Bond Acceptors:** Ligand A has 4 HBA, and Ligand B has 3. Both are below the 10 threshold.

**6. QED:** Both have good QED scores (0.601 and 0.838), indicating drug-like properties.

**7. DILI:** Ligand A (69.833) has a higher DILI risk than Ligand B (36.06). This is a significant concern.

**8. BBB:** Ligand B (80.419) has a much better BBB penetration score than Ligand A (27.259). This is *critical* for a CNS target like DRD2.

**9. Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and suggests poor permeability. However, these values are on a log scale and negative values are not uncommon.

**10. Aqueous Solubility:** Both have negative solubility values, indicating poor aqueous solubility. This is a concern, but can be addressed with formulation strategies.

**11. hERG Inhibition:** Both ligands show low hERG inhibition risk (0.501 and 0.511).

**12. Microsomal Clearance:** Ligand A (63.866) has higher microsomal clearance than Ligand B (43.184), indicating lower metabolic stability.

**13. In vitro Half-Life:** Ligand B (2.015) has a slightly longer half-life than Ligand A (5.738).

**14. P-gp Efflux:** Both have similar P-gp efflux liability (0.77 and 0.341). Ligand B is slightly better.

**15. Binding Affinity:** Ligand A (-9.9 kcal/mol) has a significantly stronger binding affinity than Ligand B (-7.2 kcal/mol). This is a substantial advantage.

**Overall Assessment:**

While Ligand A has a much better binding affinity, its significantly higher DILI risk and poor BBB penetration are major drawbacks for a CNS drug. Ligand B, despite having a weaker binding affinity, possesses a much more favorable safety profile (lower DILI) and, crucially, excellent BBB penetration. The difference in binding affinity (-2.7 kcal/mol) is substantial, but not insurmountable, and could potentially be optimized in future iterations. Given the GPCR-specific priorities, particularly BBB penetration for a CNS target, and the importance of minimizing toxicity, Ligand B is the more promising candidate.

Output:
1
2025-04-17 07:28:04,687 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (345.359 Da) is slightly lower, which is generally favorable for permeability. Ligand B (363.483 Da) is also good.

**TPSA:** Ligand A (122.71) is slightly above the optimal <90 for CNS targets, but still reasonable. Ligand B (88.16) is excellent, falling well within the desired range. This favors Ligand B.

**logP:** Ligand A (0.282) is quite low, potentially hindering membrane permeability. Ligand B (2.067) is within the optimal 1-3 range. This is a significant advantage for Ligand B.

**H-Bond Donors/Acceptors:** Ligand A has 3 HBD and 7 HBA, which are acceptable. Ligand B has 2 HBD and 4 HBA, also acceptable and slightly better due to the lower count.

**QED:** Both ligands have good QED scores (Ligand A: 0.54, Ligand B: 0.776), indicating good drug-like properties. Ligand B is better.

**DILI:** Ligand A (70.686) is approaching a moderate risk for DILI. Ligand B (59.519) has a lower, more favorable DILI risk.

**BBB:** Ligand A (46.995) has a poor BBB penetration score, which is a major drawback for a CNS target like DRD2. Ligand B (59.364) is better, but still not ideal (aim for >70).

**Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and suggests issues with the prediction method or the molecules themselves. We cannot reliably compare based on this metric.

**Aqueous Solubility:** Both ligands have very poor predicted aqueous solubility (-3.232 and -3.131). This is a concern for both, but could be mitigated with formulation strategies.

**hERG Inhibition:** Both ligands have very low predicted hERG inhibition risk (0.222 and 0.154).

**Microsomal Clearance:** Ligand A (-22.151) has a negative clearance, which is not physically possible and indicates a problem with the prediction. Ligand B (45.235) has a moderate clearance.

**In vitro Half-Life:** Ligand A (-29.446) has a negative half-life, again indicating a prediction issue. Ligand B (-48.83) also has a negative half-life. These are unreliable metrics.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.008 and 0.071), which is favorable for CNS penetration.

**Binding Affinity:** Both ligands have very strong binding affinities (-9.6 and -9.1 kcal/mol). The difference of 0.5 kcal/mol is not substantial enough to outweigh other significant differences.

**Overall Assessment:**

Ligand B is significantly more promising. While both have solubility issues, Ligand B excels in key areas for a CNS GPCR target: better logP, lower TPSA, lower DILI risk, and a more reasonable (though still not ideal) BBB prediction. Ligand A suffers from a very poor BBB prediction and questionable clearance/half-life predictions. The negative values for clearance and half-life for both compounds suggest a problem with the prediction model for these compounds.



Output:
1
2025-04-17 07:28:04,687 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (331.339 and 334.507 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (88.31) is excellent for CNS penetration, being well below 90. Ligand B (24.06) is also very good.

**logP:** Ligand A (2.22) is optimal. Ligand B (4.437) is slightly higher, potentially leading to solubility issues or off-target interactions, but still within an acceptable range.

**H-Bond Donors/Acceptors:** Ligand A (1 HBD, 6 HBA) is good. Ligand B (2 HBD, 2 HBA) is also good. Both are within the recommended limits.

**QED:** Both ligands have good QED scores (0.578 and 0.845), indicating drug-like properties.

**DILI:** Ligand A (95.347) has a very high DILI risk, which is a major concern. Ligand B (10.779) has a very low DILI risk, a significant advantage.

**BBB:** Both ligands have excellent BBB penetration (85.149 and 87.631), exceeding the desirable >70 threshold for CNS targets.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values, which is unusual and suggests a potential issue with in vitro permeability assessment. However, we'll proceed with caution, assuming these are relative values and focus on the other parameters.

**Aqueous Solubility:** Both have negative solubility values, which is also unusual.

**hERG:** Ligand A (0.227) has a very low hERG risk. Ligand B (0.935) has a slightly higher hERG risk, but still relatively low.

**Microsomal Clearance:** Ligand A (67.876) has moderate clearance. Ligand B (-9.301) has *negative* clearance, which is impossible and indicates a problem with the data.

**In vitro Half-Life:** Ligand A (22.974) has a reasonable half-life. Ligand B (0.758) has a very short half-life.

**P-gp Efflux:** Ligand A (0.529) has low P-gp efflux, which is favorable for CNS penetration. Ligand B (0.238) also has low P-gp efflux.

**Binding Affinity:** Ligand B (-9.6 kcal/mol) has a significantly stronger binding affinity than Ligand A (-11.4 kcal/mol). This is a substantial advantage.

**Overall Assessment:**

Despite the unusual Caco-2 and solubility values, the key differentiating factors are DILI risk, microsomal clearance, and binding affinity. Ligand A has a very high DILI risk, which is a major red flag. Ligand B has a much lower DILI risk and a significantly stronger binding affinity. While the negative clearance for Ligand B is concerning and suggests a data error, the substantial affinity advantage and low DILI risk outweigh the other concerns.

Output:
1
2025-04-17 07:28:04,688 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the acceptable range (200-500 Da). Ligand A (362.865 Da) is slightly preferred due to being lower in weight.

**TPSA:** Both ligands have TPSA values (61.0 and 54.18) below the 90 A^2 threshold for CNS targets, which is excellent. Ligand B is slightly better here.

**logP:** Both ligands have logP values within the optimal range (1-3). Ligand A (2.051) is slightly better than Ligand B (3.846) as it is closer to the lower end of the range, potentially reducing off-target effects.

**H-Bond Donors/Acceptors:** Ligand A (0 HBD, 7 HBA) and Ligand B (1 HBD, 6 HBA) both fall within the acceptable ranges.

**QED:** Both ligands have similar QED values (0.762 and 0.734), indicating good drug-likeness.

**DILI:** Both ligands have low DILI risk (39.201 and 31.175 percentiles), which is favorable. Ligand B is slightly better.

**BBB:** Ligand A has a significantly better BBB penetration percentile (85.615) compared to Ligand B (68.282). This is a critical advantage for a CNS target like DRD2.

**Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and suggests poor permeability. This is a concern for both.

**Aqueous Solubility:** Both ligands have very poor aqueous solubility (-3.003 and -4.339). This is a significant drawback for both.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.32 and 0.74), which is good. Ligand A is slightly better.

**Microsomal Clearance:** Ligand A (41.423 mL/min/kg) has higher clearance than Ligand B (27.094 mL/min/kg), indicating lower metabolic stability. Ligand B is preferred.

**In vitro Half-Life:** Ligand B has a longer in vitro half-life (-6.842 hours) compared to Ligand A (-1.163 hours). This is a significant advantage for Ligand B.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.238 and 0.572), which is good for CNS penetration. Ligand A is slightly better.

**Binding Affinity:** Both ligands have very similar and strong binding affinities (-7.8 and -7.7 kcal/mol). The difference is negligible.

**Overall Assessment:**

Considering the GPCR-specific priorities, Ligand A is favored due to its superior BBB penetration (85.615 vs 68.282) and slightly better logP and P-gp efflux. While Ligand B has better metabolic stability (lower Cl_mic, longer t1/2) and slightly lower DILI, the BBB penetration is paramount for a CNS target. The solubility and Caco-2 permeability are concerning for both, but the strong binding affinity mitigates these concerns to some extent.

Output:
0
2025-04-17 07:28:04,688 - INFO - Batch 367 complete. Total preferences: 5872
2025-04-17 07:28:04,688 - INFO - Processing batch 368/512...
2025-04-17 07:28:47,335 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (374.547 Da) is slightly lower, which can be advantageous for permeability. Ligand B (403.28 Da) is also acceptable.

**TPSA:** Ligand A (75.71) is better than Ligand B (64.28) as it is closer to the ideal range for CNS targets (<=90).

**logP:** Ligand A (1.595) is within the optimal range (1-3). Ligand B (3.483) is at the higher end of the optimal range, potentially leading to solubility issues, but still acceptable.

**H-Bond Donors/Acceptors:** Ligand A has 1 HBD and 5 HBA, while Ligand B has 0 HBD and 6 HBA. Both are within acceptable limits.

**QED:** Both ligands have similar QED values (0.74 and 0.665), indicating good drug-likeness.

**DILI:** Ligand A (8.53) has a significantly lower DILI risk than Ligand B (75.649), which is a major advantage.

**BBB:** Ligand B (80.69) has a better BBB penetration percentile than Ligand A (69.368). This is a critical factor for CNS targets like DRD2.

**Caco-2 Permeability:** Both have negative Caco-2 values, indicating poor permeability. Ligand A (-4.806) is slightly better than Ligand B (-4.667).

**Aqueous Solubility:** Both have negative solubility values, indicating poor solubility. Ligand A (-1.248) is slightly better than Ligand B (-3.36).

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.484 and 0.792).

**Microsomal Clearance:** Ligand A (5.058) has a much lower microsomal clearance than Ligand B (50.71), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (-10.484) has a much longer in vitro half-life than Ligand B (19.574).

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.011 and 0.498).

**Binding Affinity:** Both ligands have excellent binding affinity (-8 and -9 kcal/mol). Ligand B is slightly better (-9 kcal/mol).

**Overall Assessment:**

Ligand B has a better BBB score and slightly better binding affinity. However, Ligand A has significantly better DILI, metabolic stability (lower Cl_mic, longer t1/2), and slightly better solubility and permeability. The lower DILI and improved metabolic properties of Ligand A are very important considerations. Given the GPCR-specific priorities, and the fact that the affinity difference is relatively small (1 kcal/mol), the superior ADME profile of Ligand A makes it the more promising candidate.

Output:
1
2025-04-17 07:28:47,336 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (350.459 Da and 370.559 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (87.66) is better than Ligand B (66.48) as it is closer to the desired <90 A^2 for CNS targets.

**logP:** Both ligands have good logP values (2.572 and 2.769), falling within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A has 3 HBD and 4 HBA, while Ligand B has 1 HBD and 3 HBA. Both are within acceptable limits (<=5 HBD and <=10 HBA).

**QED:** Both ligands have good QED scores (0.672 and 0.714), indicating good drug-like properties.

**DILI:** Both ligands have low DILI risk (37.728 and 40.054), both below the 40 threshold.

**BBB:** Ligand B (72.237) significantly outperforms Ligand A (28.848) in BBB penetration, which is critical for a CNS target like DRD2.

**Caco-2 Permeability:** Ligand A (-4.711) and Ligand B (-5.05) both have negative Caco-2 permeability values, which is unusual and suggests poor intestinal absorption. This is a concern, but less critical for a CNS target where direct delivery is possible.

**Aqueous Solubility:** Both ligands have poor aqueous solubility (-2.828 and -3.905). This could pose formulation challenges.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.469 and 0.611).

**Microsomal Clearance:** Ligand A (47.92) has lower microsomal clearance than Ligand B (86.201), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand B (-40.592) has a much longer in vitro half-life than Ligand A (-16.828), which is a significant advantage.

**P-gp Efflux:** Ligand A (0.112) has lower P-gp efflux than Ligand B (0.308), which is favorable for CNS penetration.

**Binding Affinity:** Ligand B (-8.1) has a slightly better binding affinity than Ligand A (-7.8), although the difference is relatively small.

**Overall Assessment:**

While Ligand A has better TPSA and P-gp efflux, Ligand B excels in the most critical areas for a CNS GPCR target: BBB penetration and in vitro half-life. The slightly better affinity of Ligand B further strengthens its position. The poor Caco-2 permeability and solubility are drawbacks for both, but less critical given the CNS target. The lower microsomal clearance of Ligand A is a positive, but the superior BBB and half-life of Ligand B outweigh this benefit.

Output:
1
2025-04-17 07:28:47,336 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (384.303 and 362.495 Da) fall within the ideal range of 200-500 Da.

**TPSA:** Ligand A (38.77) is excellent, well below the 90 A^2 threshold for CNS targets. Ligand B (68.29) is higher, but still reasonably acceptable, though less ideal.

**logP:** Both ligands have similar logP values (4.385 and 4.493), slightly above the optimal range of 1-3, but not drastically so. This could potentially lead to some off-target effects or solubility issues, but isn't a dealbreaker.

**H-Bond Donors/Acceptors:** Ligand A has 0 HBD and 4 HBA, while Ligand B has 1 HBD and 4 HBA. Both are within acceptable limits (<=5 HBD and <=10 HBA).

**QED:** Both ligands have similar QED values (0.725 and 0.702), indicating good drug-like properties.

**DILI:** Both ligands have relatively low DILI risk (34.587 and 74.99), with Ligand A being slightly preferable.

**BBB:** This is a critical parameter for a CNS target like DRD2. Ligand A has a significantly higher BBB penetration percentile (74.37) compared to Ligand B (46.336). This is a major advantage for Ligand A.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.571 and -4.683), which is unusual and suggests poor permeability. However, these values are on a log scale and may not be directly comparable without more context.

**Aqueous Solubility:** Both ligands have negative solubility values (-4.865 and -4.57), indicating poor aqueous solubility. This could be a formulation challenge.

**hERG Inhibition:** Both ligands have low hERG inhibition liability (0.595 and 0.509), which is good.

**Microsomal Clearance:** Ligand A has a higher microsomal clearance (64.262) than Ligand B (49.016), suggesting faster metabolism and potentially a shorter half-life.

**In vitro Half-Life:** Ligand B has a significantly longer in vitro half-life (20.941 hours) compared to Ligand A (2.657 hours). This is a substantial advantage for Ligand B.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.224 and 0.562), which is favorable for CNS penetration.

**Binding Affinity:** Ligand B has a stronger binding affinity (-8.6 kcal/mol) compared to Ligand A (-7.6 kcal/mol). This 1 kcal/mol difference is significant and could outweigh some of the ADME drawbacks.

**Overall Assessment:**

While Ligand B has superior binding affinity and a longer half-life, Ligand A's significantly better BBB penetration is a crucial factor for a CNS-targeting drug. The lower metabolic clearance and slightly lower DILI risk also favor Ligand A. The poor solubility and permeability are concerns for both, but the strong affinity of Ligand B might allow for lower doses to compensate. However, the substantial difference in BBB penetration is the deciding factor.

Output:
0
2025-04-17 07:28:47,336 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 drug candidates, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (352.459 and 350.459 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (46.34) is significantly better than Ligand B (71.78). For CNS targets, we want TPSA <= 90, and A is comfortably within that range, while B is approaching the upper limit.

**3. logP:** Ligand A (4.921) is slightly high, potentially causing solubility issues, but still within a reasonable range. Ligand B (2.939) is optimal.

**4. H-Bond Donors:** Both have acceptable HBD counts (0 for A, 1 for B), well below the threshold of 5.

**5. H-Bond Acceptors:** Both have the same HBA count (4), which is well below the threshold of 10.

**6. QED:** Both ligands have good QED values (0.657 and 0.782), indicating good drug-like properties.

**7. DILI:** Ligand A (71.423) has a higher DILI risk than Ligand B (35.867). This is a significant drawback for A.

**8. BBB:** Ligand A (89.492) has a substantially better BBB penetration prediction than Ligand B (75.184). This is a crucial advantage for a CNS target like DRD2.

**9. Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and suggests potential issues with intestinal absorption. However, the scale isn't clearly defined, so it's difficult to interpret.

**10. Aqueous Solubility:** Both have negative solubility values, indicating poor solubility. This is a concern, but can be addressed with formulation strategies.

**11. hERG Inhibition:** Both have low hERG inhibition risk (0.77 and 0.754).

**12. Microsomal Clearance:** Ligand A (94.723) has a higher microsomal clearance than Ligand B (34.701), indicating lower metabolic stability.

**13. In vitro Half-Life:** Ligand A (43.614) has a longer half-life than Ligand B (12.229).

**14. P-gp Efflux:** Ligand A (0.929) has slightly higher P-gp efflux liability than Ligand B (0.391), which is unfavorable.

**15. Binding Affinity:** Ligand A (-10.3 kcal/mol) has a *much* stronger binding affinity than Ligand B (-8.0 kcal/mol). This is a significant advantage, potentially outweighing some of the ADME drawbacks.

**Overall Assessment:**

Ligand A has a superior binding affinity and better BBB penetration, which are critical for a CNS GPCR target. However, it has higher DILI risk, higher P-gp efflux, and lower metabolic stability. Ligand B has better ADME properties (lower DILI, better metabolic stability, lower P-gp efflux) but significantly weaker binding affinity.

The large difference in binding affinity (-2.3 kcal/mol) is a substantial advantage for Ligand A. While the ADME properties of Ligand A are less ideal, the potency difference is likely to be more impactful in driving efficacy, and ADME issues can often be mitigated through further optimization.

Output:
1
2025-04-17 07:28:47,336 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (351.403 and 357.451 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (100.46) is slightly above the optimal <90 for CNS targets, but still reasonable. Ligand B (91.34) is better, falling comfortably under 90.

**3. logP:** Ligand A (-0.343) is a bit low, potentially hindering permeability. Ligand B (-0.788) is also low, but slightly better than A. Both are below the optimal 1-3 range.

**4. H-Bond Donors:** Both ligands have 2 HBD, which is within the acceptable limit of <=5.

**5. H-Bond Acceptors:** Both ligands have 6 HBA, also within the acceptable limit of <=10.

**6. QED:** Both ligands have good QED scores (0.706 and 0.648), indicating drug-like properties.

**7. DILI:** Ligand A (27.608) has a higher DILI risk than Ligand B (13.416). This is a significant advantage for Ligand B.

**8. BBB:** Both ligands have the same BBB penetration (27.608 percentile), which is not ideal for a CNS target (desirable >70). This is a major drawback for both.

**9. Caco-2 Permeability:** Both have negative values (-4.915 and -5.083), indicating poor permeability.

**10. Aqueous Solubility:** Ligand B (0.295) has slightly better solubility than Ligand A (-1.208), but both are poor.

**11. hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.169 and 0.045).

**12. Microsomal Clearance:** Ligand B (-7.646) has a lower (better) microsomal clearance than Ligand A (-5.389), suggesting greater metabolic stability.

**13. In vitro Half-Life:** Ligand A (27.718) has a longer half-life than Ligand B (-9.996). This is a positive for Ligand A.

**14. P-gp Efflux:** Both ligands show very low P-gp efflux liability (0.018 and 0.002), which is excellent for CNS penetration.

**15. Binding Affinity:** Ligand A (-9.0 kcal/mol) has a significantly stronger binding affinity than Ligand B (-6.4 kcal/mol). This is a substantial advantage for Ligand A, potentially outweighing some of its ADME deficiencies.

**Overall Assessment:**

While both ligands have significant drawbacks (low logP, poor Caco-2 permeability, and suboptimal BBB penetration), the substantially stronger binding affinity of Ligand A (-9.0 kcal/mol vs -6.4 kcal/mol) is a critical factor. The difference of 2.6 kcal/mol is substantial and could be overcome with further optimization. Ligand B has a better safety profile (lower DILI, better clearance) but the weaker binding makes it less likely to be a viable starting point. Given the GPCR target and the importance of affinity, I would prioritize Ligand A for further development, with a focus on improving its logP and BBB penetration.

Output:
0
2025-04-17 07:28:47,337 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (366.799 and 354.422 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (72.11) is significantly better than Ligand B (87.66). For CNS targets, we want TPSA <= 90, and A is closer to the ideal <= 60. B is pushing the upper limit.

**3. logP:** Both ligands have good logP values (3.21 and 2.227), falling within the optimal 1-3 range.

**4. H-Bond Donors:** Ligand A (1) is better than Ligand B (3). Lower HBD is generally preferred for CNS penetration.

**5. H-Bond Acceptors:** Both ligands have the same number of HBA (4), which is acceptable (<=10).

**6. QED:** Ligand A (0.905) has a superior QED score compared to Ligand B (0.562), indicating a more drug-like profile.

**7. DILI:** Ligand A (61.07) has a higher DILI risk than Ligand B (34.277). This is a negative for A.

**8. BBB:** Ligand A (86.545) has a significantly better BBB penetration percentile than Ligand B (75.727). This is a critical advantage for a CNS target like DRD2.

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 values, which is unusual and difficult to interpret without additional context. However, the magnitude suggests similar permeability.

**10. Aqueous Solubility:** Both ligands have negative solubility values, which is also unusual. Again, the magnitude suggests similar solubility.

**11. hERG Inhibition:** Ligand A (0.567) has a slightly lower hERG inhibition risk than Ligand B (0.731).

**12. Microsomal Clearance:** Ligand B (40.031) has a significantly lower microsomal clearance than Ligand A (10.418), suggesting better metabolic stability.

**13. In vitro Half-Life:** Ligand B (18.594) has a longer in vitro half-life than Ligand A (-13.678). This is a significant advantage for B.

**14. P-gp Efflux:** Ligand A (0.094) has a much lower P-gp efflux liability than Ligand B (0.219). This is a positive for A, as lower efflux improves CNS exposure.

**15. Binding Affinity:** Both ligands have very similar and strong binding affinities (-7.9 and -7.6 kcal/mol). The difference is less than 1.5 kcal/mol, so it's not a deciding factor.

**Overall Assessment:**

Ligand A excels in TPSA, BBB, QED, and P-gp efflux, all critical for CNS GPCR targets. Ligand B has better DILI, metabolic stability (lower Cl_mic), and in vitro half-life. However, the superior BBB penetration and lower P-gp efflux of Ligand A are more important for DRD2 targeting. While the DILI risk for A is higher, it's still below the 60% threshold considered high risk. The slightly better metabolic stability of B is outweighed by the CNS penetration advantages of A.

Output:
1
2025-04-17 07:28:47,337 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (333.387 Da) is slightly lower, which could be beneficial for permeability. Ligand B (350.459 Da) is also good.

**TPSA:** Ligand A (50.52) is excellent, well below the 90 Angstroms target for CNS penetration. Ligand B (78.87) is higher, but still potentially acceptable, though less ideal.

**logP:** Ligand A (4.091) is at the upper end of the optimal range, potentially leading to solubility issues or off-target interactions. Ligand B (1.214) is low, which might hinder membrane permeability.

**H-Bond Donors/Acceptors:** Ligand A (0 HBD, 3 HBA) is favorable. Ligand B (2 HBD, 4 HBA) is also acceptable.

**QED:** Both ligands have good QED scores (A: 0.661, B: 0.799), indicating good drug-like properties.

**DILI:** Ligand A (67.739) has a moderate DILI risk. Ligand B (14.889) has a very low DILI risk, a significant advantage.

**BBB:** Both ligands have reasonable BBB penetration (A: 52.617, B: 51.066), but neither exceeds the desirable >70 percentile.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.542 and -4.791), which is unusual and suggests poor permeability. This is a concern for both.

**Aqueous Solubility:** Both ligands have negative solubility values (-4.507 and -1.463), indicating very poor aqueous solubility. This is a major drawback for both.

**hERG Inhibition:** Ligand A (0.591) has a slightly higher hERG risk than Ligand B (0.133), which is preferable.

**Microsomal Clearance:** Ligand A (81.425) has higher clearance, suggesting lower metabolic stability. Ligand B (-3.312) has negative clearance, which is not physically possible and likely an error, but suggests very high metabolic stability if interpreted as extremely low clearance.

**In vitro Half-Life:** Ligand A (52.803) has a moderate half-life. Ligand B (21.872) has a shorter half-life.

**P-gp Efflux:** Ligand A (0.62) has moderate P-gp efflux. Ligand B (0.024) has very low P-gp efflux, which is highly desirable for CNS penetration.

**Binding Affinity:** Ligand A (-10.1 kcal/mol) has significantly stronger binding affinity than Ligand B (-8.8 kcal/mol). This is a substantial advantage, potentially outweighing some of the ADME drawbacks.

**Overall Assessment:**

Ligand A has a much stronger binding affinity, which is crucial for a GPCR ligand. However, it has a higher DILI risk, higher clearance, and moderate P-gp efflux. Ligand B has a much lower DILI risk, very low P-gp efflux, and potentially excellent metabolic stability, but its binding affinity is considerably weaker and its logP is low. The poor solubility and permeability are concerning for both.

Given the emphasis on affinity for GPCRs, and the substantial difference in binding energy (-1.3 kcal/mol), I would prioritize Ligand A despite its drawbacks. Optimization efforts could then focus on improving its solubility, reducing DILI risk, and modulating P-gp efflux.

Output:
0
2025-04-17 07:28:47,337 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (343.391 and 352.479 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (111.19) is slightly above the optimal <90 for CNS targets, while Ligand B (95.74) is within the preferred range. This gives a slight edge to Ligand B.

**3. logP:** Both ligands have logP values (0.879 and 1.034) within the optimal 1-3 range.

**4. H-Bond Donors:** Both have 2 HBD, which is acceptable.

**5. H-Bond Acceptors:** Ligand A has 8 HBA, which is acceptable. Ligand B has 3 HBA, which is even better.

**6. QED:** Both ligands have reasonable QED scores (0.832 and 0.716), indicating good drug-like properties.

**7. DILI:** Ligand A (70.88) has a higher DILI risk than Ligand B (18.612). This is a significant advantage for Ligand B.

**8. BBB:** Ligand B (75.107) has a significantly better BBB penetration percentile than Ligand A (58.782). This is crucial for a CNS target like DRD2.

**9. Caco-2:** Both ligands have negative Caco-2 values, which is unusual and suggests poor permeability. However, the scale is not specified, so it's hard to interpret.

**10. Solubility:** Both ligands have negative solubility values, which is also unusual.

**11. hERG:** Both ligands have very low hERG inhibition liability (0.331 and 0.349), which is excellent.

**12. Cl_mic:** Ligand A (-21.004) has a much lower (better) microsomal clearance than Ligand B (19.613). This suggests better metabolic stability for Ligand A.

**13. t1/2:** Both have similar in vitro half-lives (-16.324 and -15.33).

**14. Pgp:** Both ligands have very low Pgp efflux liability (0.015 and 0.02).

**15. Binding Affinity:** Ligand A (-9.2 kcal/mol) has a slightly better binding affinity than Ligand B (-8.3 kcal/mol). This is a 0.9 kcal/mol difference, which is not huge, but still noticeable.

**Overall Assessment:**

While Ligand A has a slightly better binding affinity and metabolic stability, Ligand B excels in crucial areas for a CNS-targeting GPCR ligand: lower DILI risk and significantly better BBB penetration. The TPSA is also more favorable for Ligand B. The unusual negative values for Caco-2 and solubility are concerning for both, but the other factors strongly favor Ligand B. Given the importance of BBB penetration for DRD2, Ligand B is the more promising candidate.

Output:
1
2025-04-17 07:28:47,337 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (353.413 and 359.388 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (63.13) is better than Ligand B (46.61). Both are below the 90 A^2 threshold for CNS targets, but A is slightly higher, potentially impacting BBB penetration less.

**3. logP:** Ligand B (3.645) is higher than Ligand A (2.241). While both are within the optimal 1-3 range, B is approaching the upper limit.

**4. H-Bond Donors:** Ligand A (2) is better than Ligand B (0). Having some HBDs can improve solubility.

**5. H-Bond Acceptors:** Both ligands have 3 HBA, which is acceptable.

**6. QED:** Ligand A (0.753) is better than Ligand B (0.633), indicating a more drug-like profile.

**7. DILI:** Both ligands have low DILI risk (24.544 and 27.026, respectively), which is good.

**8. BBB:** Ligand B (91.508) is significantly better than Ligand A (82.047) in terms of predicted BBB penetration. This is a crucial factor for a CNS target like DRD2.

**9. Caco-2 Permeability:** Ligand A (-4.85) is better than Ligand B (-4.087). Higher (less negative) values indicate better intestinal absorption.

**10. Aqueous Solubility:** Ligand A (-2.887) is better than Ligand B (-3.713).

**11. hERG Inhibition:** Ligand A (0.242) has a lower hERG risk than Ligand B (0.884).

**12. Microsomal Clearance:** Ligand B (103.036) has much higher clearance than Ligand A (24.145), indicating lower metabolic stability.

**13. In vitro Half-Life:** Ligand A (-11.541) has a longer half-life than Ligand B (4.015).

**14. P-gp Efflux:** Ligand A (0.084) shows lower P-gp efflux than Ligand B (0.236), which is favorable for CNS exposure.

**15. Binding Affinity:** Ligand A (-8.6 kcal/mol) has a stronger binding affinity than Ligand B (-6.9 kcal/mol). This is a substantial difference (1.7 kcal/mol), and generally outweighs minor ADME drawbacks.

**Overall Assessment:**

While Ligand B has superior BBB penetration, Ligand A has a significantly stronger binding affinity, better metabolic stability (lower Cl_mic, longer t1/2), lower P-gp efflux, better solubility, and a more favorable QED score. The difference in affinity is substantial. For a GPCR target, strong binding is paramount. The slightly lower BBB score of Ligand A is a concern, but the other advantages, especially the significantly better affinity, outweigh this drawback.

Output:
1
2025-04-17 07:28:47,337 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (343.471 and 343.427 Da) fall comfortably within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (61.44) is significantly better than Ligand B (77.59). For CNS targets, we want TPSA <= 90, and A is much closer to the desirable <60 range. B is pushing the upper limit.

**3. logP:** Both ligands have good logP values (2.568 and 2.683), falling within the optimal 1-3 range.

**4. H-Bond Donors:** Ligand A (2) is preferable to Ligand B (3). Lower HBD generally improves permeability.

**5. H-Bond Acceptors:** Ligand A (3) is preferable to Ligand B (5). Lower HBA generally improves permeability.

**6. QED:** Both ligands have acceptable QED values (0.883 and 0.728), indicating good drug-like properties.

**7. DILI:** Ligand A (13.649) has a much lower DILI risk than Ligand B (52.772). This is a significant advantage for A.

**8. BBB:** Ligand A (73.905) has a better BBB percentile than Ligand B (66.188). While both are reasonably good, A is closer to the desirable >70 threshold for CNS targets.

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.921 and -4.957). This is unusual and suggests poor permeability. However, the values are very similar, so this isn't a major differentiator.

**10. Aqueous Solubility:** Both ligands have negative solubility values (-2.862 and -3.758), indicating poor aqueous solubility. Again, similar and not a major differentiator.

**11. hERG Inhibition:** Both ligands have low hERG inhibition risk (0.713 and 0.81). This is good.

**12. Microsomal Clearance:** Ligand A (-1.938) has a lower (better) microsomal clearance than Ligand B (50.112). This suggests better metabolic stability for A.

**13. In vitro Half-Life:** Ligand A (35.818) has a significantly longer in vitro half-life than Ligand B (0.312). This is a major advantage for A.

**14. P-gp Efflux:** Ligand A (0.05) has a much lower P-gp efflux liability than Ligand B (0.244). Lower P-gp efflux is crucial for CNS penetration.

**15. Binding Affinity:** Both ligands have very similar, strong binding affinities (-8.8 and -8.5 kcal/mol). The difference of 0.3 kcal/mol is unlikely to outweigh the substantial ADME advantages of Ligand A.

**Conclusion:**

Ligand A is significantly more promising due to its superior ADME properties: lower DILI risk, better BBB penetration, lower P-gp efflux, lower microsomal clearance, and longer half-life. While both have similar binding affinities and problematic Caco-2/solubility, the ADME profile of A is much more favorable for a CNS-targeting drug.

Output:
0
2025-04-17 07:28:47,338 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 drug candidates, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (368.459 and 349.475 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (124.27) is slightly above the optimal <90 for CNS targets, but still reasonable. Ligand B (61.88) is excellent, well below the 90 threshold. This favors Ligand B.

**3. logP:** Ligand A (0.356) is quite low, potentially hindering membrane permeability. Ligand B (1.171) is better, falling within the 1-3 optimal range. This favors Ligand B.

**4. H-Bond Donors:** Both ligands have acceptable HBD counts (2 and 1 respectively), well below the limit of 5.

**5. H-Bond Acceptors:** Both ligands have acceptable HBA counts (8 and 4 respectively), well below the limit of 10.

**6. QED:** Both ligands have good QED scores (0.73 and 0.809), indicating good drug-like properties.

**7. DILI:** Ligand A (43.195) is better than Ligand B (15.355) in terms of DILI risk, being further from the high-risk threshold of 60.

**8. BBB:** Ligand A (83.482) has a significantly better BBB percentile than Ligand B (73.517). This is a crucial factor for a CNS target like DRD2, strongly favoring Ligand A.

**9. Caco-2 Permeability:** Ligand A (-5.512) has a negative Caco-2 value, which is unusual and suggests very poor permeability. Ligand B (-4.645) is also poor, but slightly better.

**10. Aqueous Solubility:** Both ligands have poor aqueous solubility (-1.965 and -1.837). This isn't a dealbreaker, but requires formulation considerations.

**11. hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.266 and 0.238).

**12. Microsomal Clearance:** Ligand A (10.193) has lower microsomal clearance than Ligand B (29.51), indicating better metabolic stability.

**13. In vitro Half-Life:** Ligand A (-4.735) has a more negative half-life, which is unusual and suggests a very short half-life. Ligand B (7.716) has a better in vitro half-life.

**14. P-gp Efflux:** Both ligands have low P-gp efflux liability (0.01 and 0.012).

**15. Binding Affinity:** Ligand B (-7.8 kcal/mol) has a slightly better binding affinity than Ligand A (-8.3 kcal/mol). While the difference isn't huge, it's still a positive for Ligand B.

**Overall Assessment:**

Ligand B is generally better regarding key properties like logP, TPSA, and Caco-2 permeability. However, Ligand A has a significantly better BBB penetration score and lower DILI risk. The poor logP and Caco-2 permeability of Ligand A are concerning, and the negative in vitro half-life is a red flag. The slightly better affinity of Ligand B, combined with its more favorable ADME properties (especially TPSA and logP) makes it a more promising candidate, despite the slightly higher DILI risk. The BBB score for Ligand A is good, but the other ADME issues are too significant.

Output:
1
2025-04-17 07:28:47,338 - INFO - Reasoning:

Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (404.268 Da) is slightly higher than Ligand B (352.45 Da), but both are acceptable.

**2. TPSA:** Ligand A (86.36) is approaching the upper limit for CNS targets (<90), while Ligand B (58.64) is well within the desirable range. This favors Ligand B.

**3. logP:** Both ligands have good logP values (A: 2.584, B: 2.357), falling within the optimal 1-3 range.

**4. H-Bond Donors:** Ligand A (3) and Ligand B (1) are both acceptable, being less than 5. Ligand B is preferable.

**5. H-Bond Acceptors:** Ligand A (4) and Ligand B (3) are both acceptable, being less than 10.

**6. QED:** Both ligands have good QED values (A: 0.684, B: 0.773), indicating a drug-like profile. Ligand B is slightly better.

**7. DILI:** Ligand A (88.639) has a significantly higher DILI risk than Ligand B (24.661). This is a major concern for Ligand A.

**8. BBB:** Ligand B (89.725) has a much better BBB penetration percentile than Ligand A (61.613). This is critical for a CNS target like DRD2, strongly favoring Ligand B.

**9. Caco-2 Permeability:** Both have negative values, which is unusual. However, the magnitude is similar.

**10. Aqueous Solubility:** Both have negative values, indicating poor solubility.

**11. hERG Inhibition:** Both ligands have low hERG inhibition risk (A: 0.248, B: 0.453).

**12. Microsomal Clearance:** Ligand B (36.247) has a higher microsomal clearance than Ligand A (18.264), suggesting faster metabolism and potentially lower *in vivo* exposure. This favors Ligand A.

**13. In vitro Half-Life:** Ligand A (37.039) has a longer half-life than Ligand B (-2.827), which is a positive attribute.

**14. P-gp Efflux:** Both ligands have low P-gp efflux liability (A: 0.051, B: 0.122), which is good.

**15. Binding Affinity:** Ligand B (-8.3 kcal/mol) has a stronger binding affinity than Ligand A (-10.1 kcal/mol). This is a significant advantage for Ligand B.

**Overall Assessment:**

Ligand B is the superior candidate. While Ligand A has a slightly longer half-life and lower clearance, the significant advantages of Ligand B in terms of BBB penetration, lower DILI risk, and stronger binding affinity outweigh these minor drawbacks. The lower TPSA of Ligand B is also beneficial for CNS penetration. The higher affinity of Ligand B is a substantial advantage, potentially compensating for any minor ADME deficiencies.

Output:
1
2025-04-17 07:28:47,338 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (330.39 and 348.53 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (42.41) is significantly better than Ligand B (49.41). For CNS targets, we want TPSA <= 90, both are well within this range, but A is preferable.

**logP:** Ligand A (4.959) is slightly higher than the optimal range (1-3), while Ligand B (3.911) is within the optimal range. This favors Ligand B, but the difference isn't drastic.

**H-Bond Donors/Acceptors:** Ligand A (0 HBD, 4 HBA) is better than Ligand B (1 HBD, 2 HBA) in terms of balancing solubility and permeability.

**QED:** Both ligands have good QED scores (0.521 and 0.766, respectively), indicating good drug-like properties.

**DILI:** Ligand A (87.79) has a significantly higher DILI risk than Ligand B (16.21). This is a major concern for Ligand A.

**BBB:** Ligand A (81.47) has a better BBB penetration percentile than Ligand B (73.71). This is a critical advantage for a CNS target like DRD2.

**Caco-2 Permeability:** Ligand A (-5.045) has poorer Caco-2 permeability than Ligand B (-4.37).

**Aqueous Solubility:** Ligand A (-6.148) has poorer aqueous solubility than Ligand B (-4.415).

**hERG:** Ligand A (0.894) has a slightly higher hERG risk than Ligand B (0.166).

**Microsomal Clearance:** Both ligands have similar microsomal clearance values (81.19 and 79.52, respectively).

**In vitro Half-Life:** Ligand A (71.14) has a significantly longer in vitro half-life than Ligand B (3.824). This is a positive for Ligand A.

**P-gp Efflux:** Ligand A (0.937) has higher P-gp efflux liability than Ligand B (0.071). This is a negative for Ligand A, as it reduces CNS exposure.

**Binding Affinity:** Ligand A (-10.8 kcal/mol) has a significantly stronger binding affinity than Ligand B (-7.1 kcal/mol). This is a substantial advantage that can potentially outweigh some of the ADME drawbacks.

**Overall Assessment:**

Ligand A has a much stronger binding affinity and better BBB penetration, and longer half-life, which are crucial for a CNS GPCR target. However, it suffers from higher DILI risk, poorer solubility, higher P-gp efflux, and slightly higher hERG risk. Ligand B has better ADME properties overall, but a significantly weaker binding affinity.

The difference in binding affinity (3.7 kcal/mol) is substantial. Given the importance of potency for GPCRs, and the fact that we can potentially mitigate some of the ADME issues through formulation or structural modifications, Ligand A is the more promising candidate. The strong binding affinity is likely to be more impactful than the ADME liabilities, especially considering the target is in the CNS where getting sufficient drug concentration is a major hurdle.

Output:
1
2025-04-17 07:28:47,338 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (349.519 Da) is slightly better, being closer to the lower end which can aid permeability.

**TPSA:** Ligand A (61.44) is significantly better than Ligand B (37.61). For CNS targets, we want TPSA <= 90, and ideally lower. Ligand A is well within this range, while Ligand B is also good.

**logP:** Ligand A (2.164) is optimal (1-3). Ligand B (4.773) is a bit high, potentially leading to solubility issues and off-target interactions.

**H-Bond Donors/Acceptors:** Ligand A (HBD=2, HBA=3) and Ligand B (HBD=0, HBA=5) both fall within acceptable ranges (<=5 HBD, <=10 HBA).

**QED:** Ligand A (0.74) has a significantly better QED score than Ligand B (0.445), indicating a more drug-like profile.

**DILI:** Ligand A (5.196) has a much lower DILI risk than Ligand B (67.701). This is a major advantage for Ligand A.

**BBB:** Ligand A (84.257) has a much better BBB penetration percentile than Ligand B (66.266). This is crucial for a CNS target like DRD2.

**Caco-2 Permeability:** Ligand A (-4.955) and Ligand B (-5.278) both have negative values, which is unusual and suggests poor permeability. However, the scale isn't specified, so it's hard to interpret.

**Aqueous Solubility:** Both ligands have poor aqueous solubility (-2.67 and -3.867 respectively).

**hERG Inhibition:** Ligand A (0.622) has a lower hERG inhibition liability than Ligand B (0.713), which is preferable.

**Microsomal Clearance:** Ligand A (0.92) has a much lower microsomal clearance than Ligand B (89.814), indicating better metabolic stability.

**In vitro Half-Life:** Ligand A (7.343) has a shorter half-life than Ligand B (16.994), but both are reasonable.

**P-gp Efflux:** Ligand A (0.017) has a much lower P-gp efflux liability than Ligand B (0.803), which is very important for CNS penetration.

**Binding Affinity:** Ligand B (-8.8 kcal/mol) has a significantly stronger binding affinity than Ligand A (-7.0 kcal/mol). This is a substantial advantage. However, the other ADME properties of Ligand A are far superior.

**Overall Assessment:**

While Ligand B has a stronger binding affinity, Ligand A is significantly better overall due to its superior ADME properties, especially its lower DILI risk, higher BBB penetration, lower P-gp efflux, and better metabolic stability. The difference in binding affinity (1.8 kcal/mol) might be overcome with further optimization of Ligand A, while fixing the poor ADME profile of Ligand B would be much more challenging. For a CNS target, BBB penetration and metabolic stability are paramount.

Output:
0
2025-04-17 07:28:47,338 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (345.487 and 355.467 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (43.86) is significantly better than Ligand B (63.91). For CNS targets, we want TPSA <= 90, and ideally closer to 60. Ligand A is much closer to this ideal.

**logP:** Ligand A (1.578) is within the optimal 1-3 range. Ligand B (3.665) is towards the higher end, potentially causing solubility issues or off-target interactions.

**H-Bond Donors/Acceptors:** Both ligands have acceptable HBD (0) and HBA (A: 3, B: 6) counts, well below the thresholds of 5 and 10 respectively.

**QED:** Both ligands have similar QED values (A: 0.777, B: 0.7), indicating good drug-like properties.

**DILI:** Both have relatively low DILI risk (A: 9.539, B: 76.464), but Ligand A is substantially better. A DILI percentile under 40 is preferred.

**BBB:** Both ligands have good BBB penetration (A: 75.727, B: 73.711), exceeding the 70% threshold for CNS targets.

**Caco-2 Permeability:** Both have negative Caco-2 values (-4.789 and -5.105). This is unusual and suggests poor permeability, but the scale isn't specified, so it's hard to interpret.

**Aqueous Solubility:** Both have negative solubility values (-1.688 and -3.47). Again, the scale is unclear, but suggests poor solubility.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (A: 0.502, B: 0.397).

**Microsomal Clearance:** Ligand A (11.055) has a lower microsomal clearance than Ligand B (62.597), indicating better metabolic stability.

**In vitro Half-Life:** Ligand B (34.516) has a significantly longer half-life than Ligand A (10.964). This is a positive for Ligand B.

**P-gp Efflux:** Both have low P-gp efflux liability (A: 0.043, B: 0.545), which is good for CNS exposure.

**Binding Affinity:** Ligand A (-8.8 kcal/mol) has a slightly better binding affinity than Ligand B (-8.2 kcal/mol). While the difference is less than the 1.5 kcal/mol threshold to outweigh significant ADME issues, it's still a positive for Ligand A.

**Overall Assessment:**

Ligand A is superior due to its significantly better TPSA, lower DILI risk, and lower microsomal clearance. While Ligand B has a longer half-life, the other ADME properties of Ligand A are more favorable for a CNS-targeting GPCR ligand. The negative Caco-2 and solubility values are concerning for both, but the other advantages of Ligand A make it the more promising candidate.

Output:
0
2025-04-17 07:28:47,339 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (342.439 Da) is slightly lower, which could be beneficial for permeability. Ligand B (361.913 Da) is also good.

**TPSA:** Ligand A (79.19) is better than Ligand B (29.54) for CNS penetration, being closer to the <90 A^2 target. Ligand B is very low, which is good, but extremely low TPSA can sometimes indicate poor interactions.

**logP:** Both ligands have logP values (3.953 and 4.33) within the optimal range (1-3), but are approaching the upper limit. Ligand B is slightly higher, potentially raising concerns about solubility and off-target effects.

**H-Bond Donors/Acceptors:** Ligand A has 1 HBD and 4 HBA, while Ligand B has 0 HBD and 2 HBA. Both are within acceptable limits (<=5 HBD and <=10 HBA).

**QED:** Ligand A (0.843) has a significantly better QED score than Ligand B (0.484), indicating a more drug-like profile.

**DILI:** Ligand A (59.984) has a higher DILI risk than Ligand B (14.308). This is a significant advantage for Ligand B.

**BBB:** Both ligands have good BBB penetration, but Ligand B (73.013) is slightly better than Ligand A (68.748), which is crucial for a CNS target like DRD2.

**Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and suggests a problem with the prediction method or the compounds themselves. It's hard to draw conclusions here.

**Aqueous Solubility:** Both ligands have very poor predicted aqueous solubility (-5.474 and -5.581). This is a significant drawback for both.

**hERG Inhibition:** Ligand A (0.395) has a slightly better hERG profile than Ligand B (0.732), indicating lower cardiotoxicity risk.

**Microsomal Clearance:** Both ligands have similar microsomal clearance values (92.721 and 93.691), suggesting similar metabolic stability. High values indicate rapid clearance.

**In vitro Half-Life:** Ligand A (23.985 hours) has a significantly longer half-life than Ligand B (6.85 hours). This is a major advantage for Ligand A, potentially allowing for less frequent dosing.

**P-gp Efflux:** Ligand A (0.136) has significantly lower P-gp efflux liability than Ligand B (0.651). Lower efflux is crucial for CNS exposure.

**Binding Affinity:** Ligand B (-7.4 kcal/mol) has a slightly better binding affinity than Ligand A (-8.5 kcal/mol). While both are excellent, the 1.1 kcal/mol difference is noteworthy.

**Overall Assessment:**

Ligand B has a better binding affinity and a significantly lower DILI risk, and better BBB penetration. However, Ligand A has a superior QED score, a much longer half-life, and lower P-gp efflux, and a better hERG profile. The solubility is poor for both, and the Caco-2 values are concerning.

Considering the GPCR-specific priorities, BBB and affinity are key. While Ligand B has a slight edge in these areas, the combination of Ligand A's better QED, longer half-life, and lower P-gp efflux makes it a more promising candidate. The solubility issue is a concern for both, but can be addressed with formulation strategies. The DILI risk of Ligand A is a concern, but may be mitigated with further optimization.

Output:
0
2025-04-17 07:28:47,339 - INFO - Batch 368 complete. Total preferences: 5888
2025-04-17 07:28:47,339 - INFO - Processing batch 369/512...
2025-04-17 07:29:30,518 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B based on the provided guidelines, prioritizing GPCR-specific properties (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (338.411 and 350.423 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (94.04) is excellent for CNS penetration, being well below 90. Ligand B (125.28) is higher, but still potentially acceptable, although less ideal.

**logP:** Ligand A (3.117) is optimal. Ligand B (0.114) is significantly low, potentially hindering membrane permeability and CNS entry.

**H-Bond Donors/Acceptors:** Both ligands have 2 HBD and 5 HBA, which are within acceptable limits.

**QED:** Ligand A (0.897) has a very strong drug-like profile. Ligand B (0.644) is still reasonable, but less favorable.

**DILI:** Ligand A (51.105) has a slightly higher DILI risk than Ligand B (36.836), but both are below the concerning threshold of 60.

**BBB:** Ligand A (55.021) and Ligand B (59.984) both have good BBB penetration, but Ligand B is slightly better.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values, which is unusual and requires further investigation. However, we can still compare their relative values. Ligand A (-5.019) is better than Ligand B (-5.281).

**Aqueous Solubility:** Both ligands have negative solubility values, which is also unusual. Ligand A (-3.427) is better than Ligand B (-2.404).

**hERG:** Both ligands have very low hERG inhibition liability (0.521 and 0.085), which is excellent.

**Microsomal Clearance:** Ligand A (39.556) has a higher clearance than Ligand B (15.765), indicating lower metabolic stability.

**In vitro Half-Life:** Ligand A (-36.288) has a shorter half-life than Ligand B (-22.65), further supporting lower metabolic stability.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.036 and 0.014), which is excellent for CNS penetration.

**Binding Affinity:** Ligand A (-9.7 kcal/mol) has a significantly stronger binding affinity than Ligand B (-7.3 kcal/mol). This is a substantial difference (>1.5 kcal/mol) and a major advantage.

**Conclusion:**

Despite Ligand B having slightly better BBB penetration and lower DILI risk, Ligand A is the superior candidate. Its significantly stronger binding affinity (-9.7 vs -7.3 kcal/mol) outweighs the slightly higher DILI and clearance. The optimal logP of Ligand A is also a major advantage for CNS penetration. The unusual negative values for Caco-2 and solubility warrant further investigation, but the overall profile of Ligand A is more promising for a DRD2 targeting drug.

Output:
1
2025-04-17 07:29:30,518 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (349.435 and 352.435 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (98.14) is slightly above the preferred <90 for CNS targets, while Ligand B (90.98) is closer to the ideal range.

**logP:** Ligand A (0.942) is a bit low, potentially hindering permeation. Ligand B (0.51) is even lower, raising more concerns about permeability.

**H-Bond Donors/Acceptors:** Both have 2 HBDs, which is good. Ligand A has 6 HBAs, and Ligand B has 4 HBAs, both are acceptable.

**QED:** Ligand A (0.714) has a better QED score than Ligand B (0.538), indicating a more drug-like profile.

**DILI:** Ligand B (46.762) has a significantly lower DILI risk than Ligand A (61.691), which is a positive attribute.

**BBB:** Ligand B (70.88) has a much better BBB penetration score than Ligand A (55.176). This is *critical* for a CNS target like DRD2.

**Caco-2 Permeability:** Both have negative Caco-2 values (-5.085 and -5.035), which is unusual and suggests poor permeability. This is a significant concern for both.

**Aqueous Solubility:** Both have negative solubility values (-2.139 and -1.657), which is also concerning.

**hERG Inhibition:** Ligand A (0.108) has a slightly lower hERG risk than Ligand B (0.476), but both are relatively low.

**Microsomal Clearance:** Ligand B (-12.633) has a *much* lower (better) microsomal clearance than Ligand A (40.453), indicating greater metabolic stability.

**In vitro Half-Life:** Ligand B (5.208) has a longer half-life than Ligand A (2.785).

**P-gp Efflux:** Ligand A (0.064) has a lower P-gp efflux liability than Ligand B (0.01), which is favorable for CNS penetration.

**Binding Affinity:** Ligand B (-8.8 kcal/mol) has a significantly stronger binding affinity than Ligand A (-7.9 kcal/mol). This 1.9 kcal/mol difference is substantial and can outweigh many other drawbacks.

**Overall Assessment:**

While both ligands have permeability and solubility issues, Ligand B is the stronger candidate. Its superior BBB penetration (70.88 vs 55.176), significantly improved metabolic stability (lower Cl_mic), longer half-life, and *much* stronger binding affinity (-8.8 vs -7.9 kcal/mol) outweigh the slightly higher P-gp efflux and slightly higher DILI risk. The stronger binding affinity is a major advantage for a GPCR target. The lower logP values are a concern for both, but the improved ADME properties of Ligand B make it more promising.

Output:
1
2025-04-17 07:29:30,518 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (342.399 Da) is slightly lower, which could be beneficial for permeability, but both are acceptable.

**TPSA:** Ligand A (107.11) is higher than Ligand B (79.37). For CNS targets, TPSA < 90 is preferred. Ligand B is significantly better in this regard.

**logP:** Both ligands have good logP values (Ligand A: 1.569, Ligand B: 2.461), falling within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A has 4 HBD and 4 HBA, while Ligand B has 1 HBD and 5 HBA. Both are within acceptable limits (HBD <= 5, HBA <= 10).

**QED:** Both ligands have good QED scores (Ligand A: 0.639, Ligand B: 0.731), indicating drug-like properties.

**DILI:** Ligand A (56.921) has a higher DILI risk than Ligand B (33.773). Lower DILI is preferred.

**BBB:** Ligand B (64.676) has a significantly better BBB penetration score than Ligand A (53.587). This is *critical* for a CNS target like DRD2.

**Caco-2 Permeability:** Both have negative Caco-2 values (-5.202 and -5.043), which is unusual and suggests poor permeability. This is a significant concern for both.

**Aqueous Solubility:** Both have negative solubility values (-2.855 and -2.306), indicating poor solubility. This is also a concern.

**hERG:** Both ligands have very low hERG inhibition liability (0.045 and 0.063), which is excellent.

**Microsomal Clearance:** Ligand A (-29.308) has a much lower (better) microsomal clearance than Ligand B (41.959), suggesting greater metabolic stability.

**In vitro Half-Life:** Ligand A (-8.923) has a shorter in vitro half-life than Ligand B (-22.802).

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.02 and 0.094), which is favorable for CNS penetration.

**Binding Affinity:** Ligand B (-7.8 kcal/mol) has a slightly better binding affinity than Ligand A (-9.5 kcal/mol). While both are excellent, the difference is substantial.

**Overall Assessment:**

Ligand B is the better candidate. While both have issues with Caco-2 and solubility, Ligand B's significantly better BBB penetration (64.676 vs 53.587) and slightly better binding affinity (-7.8 vs -9.5) are decisive for a CNS GPCR target. The lower DILI risk is also a plus. Although Ligand A has better metabolic stability, the BBB and affinity advantages of Ligand B outweigh this benefit.

Output:
1
2025-04-17 07:29:30,518 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (367.559 and 359.388 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (61.44) is higher than Ligand B (46.61). For CNS targets, TPSA should be <=90, both are within this range, but B is better.

**logP:** Ligand A (1.872) is within the optimal 1-3 range. Ligand B (3.707) is slightly higher, nearing the upper limit, but still acceptable.

**H-Bond Donors/Acceptors:** Ligand A has 2 HBD and 4 HBA, while Ligand B has 0 HBD and 3 HBA. Both are within acceptable limits (<=5 HBD and <=10 HBA).

**QED:** Ligand A (0.779) has a better QED score than Ligand B (0.632), indicating a more drug-like profile.

**DILI:** Ligand B (32.454) has a significantly lower DILI risk than Ligand A (6.204), which is a substantial advantage.

**BBB:** Ligand B (93.912) has a much higher BBB penetration percentile than Ligand A (66.344). This is *critical* for a CNS target like DRD2.

**Caco-2 Permeability:** Ligand A (-5.557) shows poor Caco-2 permeability, while Ligand B (-4.115) is slightly better, but still not great.

**Aqueous Solubility:** Ligand A (-1.865) has slightly better solubility than Ligand B (-3.529).

**hERG Inhibition:** Ligand A (0.385) has a lower hERG inhibition liability than Ligand B (0.846), which is favorable.

**Microsomal Clearance:** Ligand B (99.71) has a very high microsomal clearance, indicating rapid metabolism. Ligand A (-7.97) suggests a negative value, which is unusual and likely an error or indicates very high metabolic stability.

**In vitro Half-Life:** Ligand B (6.69) has a longer half-life than Ligand A (3.475).

**P-gp Efflux:** Ligand A (0.011) has much lower P-gp efflux liability than Ligand B (0.301), which is beneficial for CNS penetration.

**Binding Affinity:** Ligand B (-7.1) has a slightly better binding affinity than Ligand A (-9.5). However, the difference is not substantial enough to outweigh other factors.

**Overall Assessment:**

Ligand B excels in BBB penetration and has a significantly lower DILI risk. While its Caco-2 permeability and microsomal clearance are less favorable, the high BBB value is paramount for a CNS target. Ligand A has better QED, lower hERG, and lower P-gp efflux, but its poor BBB penetration is a major drawback. The negative microsomal clearance for Ligand A is suspicious and needs further investigation.

Output:
1
2025-04-17 07:29:30,518 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (367.446 and 346.475 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (72.48) is slightly higher than Ligand B (67.23). Both are below the 90 A^2 threshold desirable for CNS targets, but Ligand B is preferable.

**3. logP:** Ligand A (3.729) is at the upper end of the optimal range (1-3), while Ligand B (2.52) is well within it. Ligand B is preferable.

**4. H-Bond Donors:** Ligand A (2) and Ligand B (1) are both acceptable (<=5). Ligand B is slightly better.

**5. H-Bond Acceptors:** Ligand A (5) and Ligand B (4) are both acceptable (<=10). Ligand B is slightly better.

**6. QED:** Both ligands have very similar and good QED values (0.816 and 0.825, respectively).

**7. DILI:** Ligand A (68.166) has a higher DILI risk than Ligand B (23.536). Ligand B is significantly better.

**8. BBB:** This is a critical parameter for CNS targets. Ligand B (76.231) has a much better BBB penetration percentile than Ligand A (49.864). This is a major advantage for Ligand B.

**9. Caco-2 Permeability:** Ligand A (-4.528) has worse Caco-2 permeability than Ligand B (-5.287). Both are negative, indicating poor permeability, but Ligand A is slightly better.

**10. Aqueous Solubility:** Ligand A (-3.252) has slightly better aqueous solubility than Ligand B (-2.235).

**11. hERG Inhibition:** Ligand A (0.137) has a slightly lower hERG inhibition risk than Ligand B (0.586).

**12. Microsomal Clearance:** Ligand A (49.026) has higher microsomal clearance than Ligand B (36.312), meaning it's less metabolically stable. Ligand B is preferable.

**13. In vitro Half-Life:** Ligand A (10.538) has a longer half-life than Ligand B (-6.566). This is a significant advantage for Ligand A.

**14. P-gp Efflux:** Ligand A (0.183) has lower P-gp efflux than Ligand B (0.127), indicating better potential for CNS exposure.

**15. Binding Affinity:** Both ligands have excellent binding affinities (-7.9 and -7.8 kcal/mol). The difference is minimal.

**Overall Assessment:**

Ligand B is the stronger candidate. While Ligand A has a longer half-life and slightly better P-gp efflux, Ligand B excels in critical areas for a CNS-targeting GPCR ligand: significantly lower DILI risk, much better BBB penetration, and lower microsomal clearance. The slightly better logP and TPSA of Ligand B also contribute to its favorability. The minimal difference in binding affinity doesn't outweigh the substantial advantages of Ligand B in ADME properties crucial for CNS drug development.

Output:
1
2025-04-17 07:29:30,518 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (345.447 and 348.447 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (80.55) is better than Ligand B (87.46). Both are below the 90 A^2 threshold for CNS targets, but A is closer to the ideal.

**3. logP:** Ligand A (3.322) is optimal (1-3), while Ligand B (1.199) is on the lower side. Lower logP can hinder permeation.

**4. H-Bond Donors:** Both ligands have 2 HBD, which is within the acceptable limit of <=5.

**5. H-Bond Acceptors:** Both ligands have 5 HBA, also within the acceptable limit of <=10.

**6. QED:** Ligand A (0.871) has a significantly better QED score than Ligand B (0.622), indicating a more drug-like profile.

**7. DILI:** Ligand A (56.068) has a higher DILI risk than Ligand B (24.312). This is a negative for Ligand A.

**8. BBB:** Ligand A (86.778) has a much better BBB penetration percentile than Ligand B (34.742). This is *critical* for a CNS target like DRD2.

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.62 and -4.682). This is unusual and suggests poor permeability. However, these values are on a scale where negative values are possible and don't necessarily disqualify a compound.

**10. Aqueous Solubility:** Ligand A (-3.976) is slightly better than Ligand B (-1.928), but both are poor. Solubility is a concern for both.

**11. hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.383 and 0.104).

**12. Microsomal Clearance:** Ligand A (40.959) has higher microsomal clearance than Ligand B (29.945), meaning it's less metabolically stable.

**13. In vitro Half-Life:** Ligand B (17.636) has a longer in vitro half-life than Ligand A (37.013). This is a positive for Ligand B.

**14. P-gp Efflux:** Both ligands have low P-gp efflux liability (0.083 and 0.022).

**15. Binding Affinity:** Ligand A (-8.3 kcal/mol) has a significantly stronger binding affinity than Ligand B (-7.1 kcal/mol). This is a substantial advantage.

**Overall Assessment:**

Ligand A excels in BBB penetration and binding affinity, which are paramount for a CNS GPCR target. While it has a higher DILI risk and lower metabolic stability, the strong affinity (-8.3 kcal/mol) can potentially outweigh these drawbacks. Ligand B has a better safety profile (lower DILI) and metabolic stability, but its significantly lower BBB penetration and weaker binding affinity make it less promising. The difference in binding affinity (1.2 kcal/mol) is substantial.

Output:
1
2025-04-17 07:29:30,518 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (366.29 and 348.403 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (83.12) is excellent, falling well below the 90 A^2 threshold for CNS targets. Ligand B (110.26) is still reasonable but less optimal, being above 100 A^2.

**logP:** Both ligands have a logP around 2.3, which is within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A has 3 HBD and 3 HBA, which is good. Ligand B has 2 HBD and 6 HBA, also acceptable, but slightly higher HBA could potentially affect permeability.

**QED:** Both ligands have good QED scores (0.567 and 0.758), indicating good drug-like properties.

**DILI:** Ligand A (61.07) has a slightly higher DILI risk than Ligand B (70.686), but both are acceptable.

**BBB:** This is a critical parameter for a CNS target like DRD2. Ligand A shows a significantly better BBB penetration percentile (80.535) compared to Ligand B (54.517). This is a major advantage for Ligand A.

**Caco-2 Permeability:** Ligand A (-4.709) has a more negative Caco-2 value, which is unusual and suggests *lower* permeability. Ligand B (-5.049) is similarly low. This is a concern for both.

**Aqueous Solubility:** Both ligands have very poor aqueous solubility (-3.327 and -2.9 respectively). This could pose formulation challenges.

**hERG Inhibition:** Both ligands show low hERG inhibition risk (0.186 and 0.203).

**Microsomal Clearance:** Ligand B (66.417) has a lower microsomal clearance than Ligand A (9.688), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand B (-22.619) has a longer in vitro half-life than Ligand A (-17.092), which is desirable.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.006 and 0.14).

**Binding Affinity:** Ligand A (-9.4 kcal/mol) has a significantly stronger binding affinity than Ligand B (-7.8 kcal/mol). This >1.5 kcal/mol difference is substantial and can outweigh some ADME drawbacks.

**Overall Assessment:**

Ligand A has a much stronger binding affinity and better BBB penetration, which are the most important factors for a CNS GPCR target. While its Caco-2 permeability and aqueous solubility are poor, the strong affinity and BBB penetration are significant advantages. Ligand B has better metabolic stability and half-life, but its weaker binding affinity and lower BBB penetration are major drawbacks. Given the importance of CNS penetration and potency for DRD2, Ligand A is the more promising candidate.

Output:
1
2025-04-17 07:29:30,519 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (351.359 Da) is slightly lower, which *could* be beneficial for permeability, but both are acceptable.

**2. TPSA:** Ligand A (102.18) is borderline for CNS penetration, being above the preferred <90. Ligand B (87.3) is excellent, well below 90, suggesting better CNS penetration potential.

**3. logP:** Ligand A (0.208) is quite low, potentially hindering membrane permeability and brain penetration. Ligand B (1.926) is within the optimal range (1-3). This is a significant advantage for Ligand B.

**4. H-Bond Donors:** Ligand A (0) is ideal. Ligand B (3) is acceptable, still within the limit of 5.

**5. H-Bond Acceptors:** Ligand A (7) is good. Ligand B (4) is also good, well below the limit of 10.

**6. QED:** Both ligands have reasonable QED values (A: 0.714, B: 0.561), indicating good drug-like properties. Ligand A is slightly better.

**7. DILI:** Ligand A (62.001) is moderately risky, while Ligand B (52.772) is lower risk. Both are below the concerning threshold of 60, but B is preferable.

**8. BBB:** Ligand A (62.195) is below the desirable threshold of 70 for CNS targets. Ligand B (78.79) is very good, exceeding the 70% threshold. This is a major advantage for Ligand B.

**9. Caco-2:** Ligand A (-4.665) is very poor, indicating poor intestinal absorption. Ligand B (-5.18) is also poor, but marginally better.

**10. Solubility:** Ligand A (-1.644) is poor. Ligand B (-3.93) is even worse. Solubility is a concern for both, but the lower logP of Ligand B might help mitigate this.

**11. hERG:** Ligand A (0.031) has very low hERG risk. Ligand B (0.681) is slightly higher, but still relatively low.

**12. Cl_mic:** Ligand A (-7.071) is excellent, indicating high metabolic stability. Ligand B (49.422) is significantly higher, suggesting faster metabolism and lower stability. This is a major drawback for Ligand B.

**13. t1/2:** Ligand A (-5.54) is excellent, indicating a long in vitro half-life. Ligand B (1.518) is short.

**14. Pgp:** Ligand A (0.056) has low P-gp efflux, which is good for CNS penetration. Ligand B (0.15) is slightly higher, but still relatively low.

**15. Binding Affinity:** Ligand B (-8.6 kcal/mol) has a significantly stronger binding affinity than Ligand A (-0.0 kcal/mol). This is a huge advantage for Ligand B, potentially outweighing some of its ADME drawbacks.

**Overall Assessment:**

While Ligand A has better metabolic stability and half-life, Ligand B is significantly superior in terms of CNS penetration (BBB, TPSA, logP) and, crucially, binding affinity. The strong binding affinity of Ligand B (-8.6 kcal/mol) is a major advantage, and its better BBB penetration is critical for a CNS target like DRD2. The lower metabolic stability and shorter half-life of Ligand B could be addressed through further optimization. The poor solubility of both compounds is a concern, but potentially manageable.

Output:
1
2025-04-17 07:29:30,519 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight (MW):** Both ligands (362.748 and 380.941 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (100.92) is higher than the optimal <90 for CNS targets, but still potentially acceptable. Ligand B (49.41) is excellent, well below the 90 threshold.

**3. logP:** Both ligands (3.502 and 4.093) are within the optimal 1-3 range, though Ligand B is pushing the upper limit.

**4. H-Bond Donors (HBD):** Both ligands (2 and 1) are within the acceptable limit of <=5.

**5. H-Bond Acceptors (HBA):** Both ligands (4 and 3) are within the acceptable limit of <=10.

**6. QED:** Both ligands have good QED scores (0.547 and 0.836), indicating good drug-like properties. Ligand B is better.

**7. DILI:** Ligand A (95.502) has a high DILI risk, which is concerning. Ligand B (35.634) has a much lower and acceptable DILI risk.

**8. BBB:** Ligand A (59.519) has a moderate BBB penetration, which is not ideal for a CNS target. Ligand B (89.686) shows excellent BBB penetration, exceeding the desirable >70 threshold.

**9. Caco-2:** Both have negative Caco-2 values, which is unusual and difficult to interpret without more context. However, it suggests poor permeability.

**10. Solubility:** Both have negative solubility values, which is also unusual and suggests poor solubility.

**11. hERG:** Both ligands have low hERG inhibition risk (0.648 and 0.683).

**12. Cl_mic:** Ligand A (46.906) has lower microsomal clearance than Ligand B (52.337), suggesting better metabolic stability.

**13. t1/2:** Ligand A (55.493) has a longer in vitro half-life than Ligand B (7.775), which is favorable.

**14. Pgp:** Ligand A (0.534) has lower P-gp efflux liability than Ligand B (0.372), which is beneficial for CNS exposure.

**15. Binding Affinity:** Ligand B (-9.2 kcal/mol) has a significantly stronger binding affinity than Ligand A (-10.2 kcal/mol). While A is slightly better, the difference is not substantial enough to outweigh other factors.

**Overall Assessment:**

Ligand B is the superior candidate. While Ligand A has a slightly better binding affinity and metabolic stability, Ligand B excels in crucial areas for a CNS-targeting GPCR: significantly better BBB penetration, a much lower DILI risk, and a better QED score. The lower Pgp efflux for Ligand A is a benefit, but the substantial advantage of Ligand B in BBB penetration and safety profile outweighs this. The unusual Caco-2 and solubility values are a concern for both, but can be addressed with formulation strategies.



Output:
1
2025-04-17 07:29:30,519 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (372.446 and 364.917 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (66.92) is slightly above the optimal <90 for CNS targets, but still reasonable. Ligand B (42.43) is well within the desired range.

**logP:** Ligand A (2.469) is within the optimal 1-3 range. Ligand B (4.233) is a bit high, potentially leading to solubility issues or off-target interactions, but not drastically so.

**H-Bond Donors/Acceptors:** Both ligands have low HBD counts (0) and acceptable HBA counts (4 and 3 respectively), suggesting good permeability.

**QED:** Both ligands have good QED scores (0.614 and 0.727), indicating drug-like properties.

**DILI:** Ligand A (16.402) has a slightly higher DILI risk than Ligand B (13.106), but both are below the concerning threshold of 40.

**BBB:** This is a crucial parameter for a CNS target like DRD2. Ligand B (89.104) has a significantly higher BBB penetration percentile than Ligand A (79.682). This is a major advantage for Ligand B.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.506 and -4.461). This is unusual and suggests a potential issue with in vitro permeability assessment. However, given the other parameters, it's less concerning than a poor BBB score.

**Aqueous Solubility:** Both ligands have negative solubility values (-1.698 and -3.987), which is also unusual and suggests poor aqueous solubility.

**hERG Inhibition:** Ligand A (0.313) shows slightly lower hERG inhibition liability than Ligand B (0.652), which is preferable.

**Microsomal Clearance:** Ligand B (95.933) has a significantly higher microsomal clearance than Ligand A (51.896), indicating faster metabolism and potentially lower in vivo exposure.

**In vitro Half-Life:** Ligand B (20.276 hours) has a much longer in vitro half-life than Ligand A (2.657 hours), which is a significant advantage.

**P-gp Efflux:** Ligand A (0.084) has lower P-gp efflux liability than Ligand B (0.617), which is beneficial for CNS exposure.

**Binding Affinity:** Ligand B (-7.8 kcal/mol) has a substantially stronger binding affinity than Ligand A (-6.6 kcal/mol). This difference of 1.2 kcal/mol is significant and can outweigh some of the ADME drawbacks.

**Overall Assessment:**

Ligand B is the more promising candidate. While its logP is slightly elevated and P-gp efflux is higher, its superior BBB penetration, significantly stronger binding affinity, and longer half-life outweigh these concerns. The lower DILI risk is also a plus. Ligand A has better hERG and P-gp profiles, but the weaker binding and lower BBB penetration are critical drawbacks for a CNS-targeted GPCR. The unusual negative Caco-2 and solubility values for both ligands warrant further investigation, but are less critical than the BBB and affinity differences.

Output:
1
2025-04-17 07:29:30,519 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (357.479 and 352.435 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (64.6) is significantly better than Ligand B (96.69). For CNS targets, we want TPSA <= 90, and A is comfortably within this range, while B is slightly above. This is a significant advantage for A.

**3. logP:** Ligand A (3.506) is optimal (1-3), while Ligand B (0.411) is quite low, potentially hindering membrane permeability. This favors A.

**4. H-Bond Donors:** Ligand A (3) and Ligand B (2) are both acceptable (<=5).

**5. H-Bond Acceptors:** Ligand A (3) and Ligand B (6) are both acceptable (<=10), but B is getting closer to the upper limit.

**6. QED:** Both ligands have good QED scores (A: 0.659, B: 0.741), indicating good drug-like properties.

**7. DILI:** Ligand A (72.354) is higher than Ligand B (47.15), indicating a slightly increased risk of liver injury. However, both are below the concerning threshold of 60.

**8. BBB:** Ligand A (31.485) and Ligand B (30.128) are similar and both quite low. Neither is ideal for a CNS target (>70), but this is less critical if other properties are strong.

**9. Caco-2:** Both ligands have negative Caco-2 values (-5.103 and -4.927), which is unusual and suggests poor permeability. This is a concern for both.

**10. Solubility:** Both ligands have negative solubility values (-4.174 and -1.122), which is also unusual and suggests poor aqueous solubility. This is a concern for both.

**11. hERG:** Both ligands have very low hERG inhibition risk (A: 0.361, B: 0.142).

**12. Cl_mic:** Ligand A (33.908) has a higher microsomal clearance than Ligand B (22.792), indicating potentially lower metabolic stability. This favors B.

**13. t1/2:** Ligand B (7.934) has a slightly longer in vitro half-life than Ligand A (48.236), which is a positive.

**14. Pgp:** Ligand A (0.202) has lower P-gp efflux liability than Ligand B (0.016), which is a significant advantage for CNS penetration.

**15. Binding Affinity:** Ligand B (-8.0) has a slightly better binding affinity than Ligand A (-7.2). However, the difference is only 0.8 kcal/mol, which may not be enough to overcome other significant drawbacks.

**Overall Assessment:**

Ligand A is the better candidate. While its DILI risk is slightly higher and Cl_mic is higher, its significantly better TPSA and logP values are crucial for CNS penetration. The lower Pgp efflux liability also supports better brain exposure. Ligand B's lower logP is a major concern, and while its affinity is slightly better, the other ADME properties of A are more favorable for a CNS-targeting GPCR ligand. The unusual negative values for Caco-2 and solubility are concerning for both, and would need to be investigated further.

Output:
1
2025-04-17 07:29:30,519 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (353.423 and 371.547 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (97.72) is slightly above the optimal <90 for CNS targets, but still reasonable. Ligand B (61.88) is well within the desired range. This favors Ligand B.

**3. logP:** Both ligands have similar logP values (1.026 and 1.059), falling within the optimal 1-3 range.

**4. H-Bond Donors:** Ligand A has 2 HBD, and Ligand B has 1. Both are acceptable (<=5).

**5. H-Bond Acceptors:** Ligand A has 6 HBA, and Ligand B has 5. Both are acceptable (<=10).

**6. QED:** Both ligands have reasonable QED scores (0.788 and 0.691), indicating good drug-like properties.

**7. DILI:** Ligand A (35.324) has a slightly higher DILI risk than Ligand B (16.712), but both are below the concerning threshold of 60.

**8. BBB:** This is a critical parameter for CNS targets. Ligand B (77.084) has a significantly better BBB percentile than Ligand A (60.915). This is a major advantage for Ligand B.

**9. Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and suggests poor permeability. However, the scale is not specified, so it's difficult to interpret.

**10. Aqueous Solubility:** Both ligands have negative solubility values, which is also unusual. Again, the scale is not specified, making interpretation difficult.

**11. hERG Inhibition:** Both ligands show low hERG inhibition risk (0.255 and 0.527).

**12. Microsomal Clearance:** Ligand B (68.202) has a significantly higher microsomal clearance than Ligand A (3.82), indicating lower metabolic stability. This favors Ligand A.

**13. In vitro Half-Life:** Ligand B (22.779) has a longer in vitro half-life than Ligand A (2.574). This favors Ligand B.

**14. P-gp Efflux:** Both ligands have low P-gp efflux liability (0.012 and 0.032).

**15. Binding Affinity:** Ligand A (-6.7 kcal/mol) has a slightly better binding affinity than Ligand B (-5.8 kcal/mol). This is a significant advantage for Ligand A.

**Overall Assessment:**

While Ligand A has better binding affinity and metabolic stability, Ligand B has a substantially better BBB penetration score and a longer half-life. For a CNS target like DRD2, BBB penetration is paramount. The difference in affinity (0.9 kcal/mol) is not large enough to overcome the significant advantage of Ligand B in terms of BBB. The TPSA is also better for Ligand B.

Output:
1
2025-04-17 07:29:30,519 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (344.415 and 347.434 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (87.32) is better than Ligand B (62.3). Both are below the 90 A^2 threshold desirable for CNS targets.

**3. logP:** Both ligands have good logP values (2.26 and 2.71, respectively), falling within the optimal 1-3 range.

**4. H-Bond Donors:** Ligand A has 2 HBD, and Ligand B has 1. Both are within the acceptable limit of <=5.

**5. H-Bond Acceptors:** Ligand A has 4 HBA, and Ligand B has 3. Both are within the acceptable limit of <=10.

**6. QED:** Both ligands have good QED scores (0.787 and 0.833, respectively), indicating good drug-like properties.

**7. DILI:** Ligand A (59.131) has a slightly higher DILI risk than Ligand B (42.071), but both are below the concerning threshold of 60.

**8. BBB:** Ligand B (83.831) significantly outperforms Ligand A (50.097) in BBB penetration. This is a *critical* factor for a CNS target like DRD2.

**9. Caco-2 Permeability:** Ligand A (-5.175) has worse Caco-2 permeability than Ligand B (-4.542), indicating potentially lower intestinal absorption.

**10. Aqueous Solubility:** Both ligands have poor aqueous solubility (-3.59 and -3.051 respectively). This could pose formulation challenges, but is less critical than BBB penetration for a CNS target.

**11. hERG Inhibition:** Both ligands have low hERG inhibition risk (0.371 and 0.477, respectively).

**12. Microsomal Clearance:** Ligand A (9.247) has lower microsomal clearance than Ligand B (55.853), suggesting better metabolic stability.

**13. In vitro Half-Life:** Ligand A (-8.357) has a significantly longer in vitro half-life than Ligand B (-19.934). This is a positive attribute.

**14. P-gp Efflux:** Ligand A (0.031) has much lower P-gp efflux liability than Ligand B (0.12). Lower P-gp efflux is highly desirable for CNS penetration.

**15. Binding Affinity:** Both ligands have comparable and excellent binding affinities (-8.9 and -8.6 kcal/mol). The difference of 0.3 kcal/mol is not substantial enough to override other factors.

**Overall Assessment:**

While Ligand A has better metabolic stability (lower Cl_mic, longer t1/2) and lower P-gp efflux, Ligand B *significantly* excels in BBB penetration (83.831 vs. 50.097). For a CNS target like DRD2, BBB penetration is paramount. The slightly higher DILI risk and worse metabolic stability of Ligand B are less concerning than the poor BBB penetration of Ligand A. The comparable binding affinities further support prioritizing Ligand B.

Output:
1
2025-04-17 07:29:30,519 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B based on the provided guidelines, prioritizing GPCR-specific properties (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (358.368 and 348.451 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (86.89) is excellent for CNS penetration, well below the 90 A^2 threshold. Ligand B (105.28) is still reasonable, but less optimal.

**logP:** Ligand A (3.68) is within the optimal 1-3 range. Ligand B (-0.851) is significantly below this, which could hinder membrane permeability and potentially reduce binding affinity at the target.

**H-Bond Donors/Acceptors:** Ligand A (0 HBD, 4 HBA) is favorable. Ligand B (3 HBD, 6 HBA) is also acceptable, but slightly higher counts could impact permeability.

**QED:** Both ligands have acceptable QED values (0.467 and 0.643), indicating reasonable drug-likeness.

**DILI:** Ligand A (32.067) has a very low DILI risk, which is excellent. Ligand B (14.696) also has a low DILI risk, but higher than A.

**BBB:** Ligand A (93.641) shows excellent BBB penetration, exceeding the desirable >70% threshold. Ligand B (35.052) has poor predicted BBB penetration, a significant drawback for a CNS target like DRD2.

**Caco-2 Permeability:** Ligand A (-4.698) has poor Caco-2 permeability. Ligand B (-6.026) is even worse.

**Aqueous Solubility:** Ligand A (-3.073) has poor aqueous solubility. Ligand B (-0.339) is slightly better, but still poor.

**hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.417 and 0.185), which is positive.

**Microsomal Clearance:** Ligand A (18.005) has moderate clearance. Ligand B (-37.098) has a negative clearance, which is not possible and likely an error in the data. This suggests very high metabolic stability, but the negative value is suspect.

**In vitro Half-Life:** Ligand A (-23.711) has a negative half-life, which is not possible and likely an error in the data. Ligand B (2.082) has a very short half-life.

**P-gp Efflux:** Ligand A (0.229) has low P-gp efflux, which is favorable for CNS penetration. Ligand B (0.004) also has very low P-gp efflux.

**Binding Affinity:** Ligand B (-7.9 kcal/mol) has a slightly better binding affinity than Ligand A (-7.6 kcal/mol), but the difference is relatively small.

**Overall Assessment:**

Ligand A is superior despite the poor Caco-2 and solubility. Its significantly better BBB penetration (93.641 vs 35.052) is crucial for a CNS target. The DILI risk is also lower. While both have issues with solubility and permeability, the ability to cross the BBB is paramount for DRD2. The negative values for clearance and half-life for Ligand A are concerning and likely data errors, but the other properties are more favorable. The negative clearance for Ligand B is a major red flag.

Output:
1
2025-04-17 07:29:30,520 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (354.363 and 348.447 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (133.99) is borderline but acceptable for CNS penetration, while Ligand B (70.95) is excellent, well below the 90 Angstrom threshold for CNS targets. This is a significant advantage for Ligand B.

**3. logP:** Ligand A (-1.231) is a bit low, potentially hindering membrane permeability. Ligand B (1.071) is within the optimal range of 1-3.

**4. H-Bond Donors:** Ligand A (3) is acceptable, while Ligand B (1) is even better, potentially improving permeability.

**5. H-Bond Acceptors:** Ligand A (8) is acceptable, and Ligand B (7) is also good.

**6. QED:** Both ligands have good QED scores (0.576 and 0.873), indicating drug-like properties. Ligand B is slightly better.

**7. DILI:** Both ligands have acceptable DILI risk (43.66 and 47.77), below the 60 threshold.

**8. BBB:** Ligand A (13.377) has very poor predicted BBB penetration, a critical drawback for a CNS target. Ligand B (71.772) has excellent predicted BBB penetration, exceeding the desirable >70 threshold. This is a major advantage for Ligand B.

**9. Caco-2:** Both have negative values which is unusual. Assuming these are percentile scores, both are very poor.

**10. Solubility:** Both ligands have poor aqueous solubility (-1.202 and -1.799). This could pose formulation challenges.

**11. hERG:** Ligand A (0.046) has a very low hERG risk, which is excellent. Ligand B (0.711) has a slightly elevated, but still acceptable, hERG risk.

**12. Cl_mic:** Ligand A (11.535) has a lower microsomal clearance, suggesting better metabolic stability than Ligand B (40.533).

**13. t1/2:** Ligand A (-12.574) has a very short in vitro half-life, which is a significant negative. Ligand B (21.258) has a much better half-life.

**14. Pgp:** Ligand A (0.044) has low P-gp efflux, which is good for CNS exposure. Ligand B (0.032) has even lower P-gp efflux, which is excellent.

**15. Binding Affinity:** Ligand A (-7.3) has a slightly better binding affinity than Ligand B (-0.0).

**Overall Assessment:**

While Ligand A has slightly better binding affinity and lower microsomal clearance, its extremely poor BBB penetration and short half-life are major liabilities for a CNS drug. Ligand B excels in key areas for CNS targets: excellent BBB penetration, good logP, low P-gp efflux, and a reasonable half-life. The slightly weaker binding affinity of Ligand B can potentially be optimized in subsequent iterations, whereas improving BBB penetration for Ligand A would be far more challenging.

Output:
1
2025-04-17 07:29:30,520 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (392.428 Da) is slightly higher than Ligand B (349.41 Da), but both are acceptable.

**TPSA:** Ligand A (66.49) is better than Ligand B (80.12). For CNS targets, we want TPSA <= 90, and ideally closer to 60. Ligand A is closer to the ideal range.

**logP:** Both ligands have good logP values (A: 1.509, B: 0.773), falling within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A has 2 HBD and 5 HBA, while Ligand B has 1 HBD and 5 HBA. Both are within acceptable limits (<=5 HBD, <=10 HBA).

**QED:** Ligand A (0.741) has a higher QED than Ligand B (0.555), indicating a more drug-like profile.

**DILI:** Ligand B (39.046) has a significantly lower DILI risk than Ligand A (83.947). This is a substantial advantage for Ligand B.

**BBB:** Both ligands have reasonably good BBB penetration (A: 61.38, B: 63.125). However, for a CNS target like DRD2, >70 is desirable. Neither hits this, but they are comparable.

**Caco-2 Permeability:** Ligand A (-4.965) has worse Caco-2 permeability than Ligand B (-5.011). Lower values are less favorable.

**Aqueous Solubility:** Ligand A (-3.351) has better aqueous solubility than Ligand B (-2.126).

**hERG:** Both ligands have low hERG inhibition liability (A: 0.453, B: 0.214), which is good.

**Microsomal Clearance:** Ligand B (2.928) has significantly lower microsomal clearance than Ligand A (20.304), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand B (-10.919) has a much longer in vitro half-life than Ligand A (25.847). This is a major advantage for Ligand B.

**P-gp Efflux:** Ligand A (0.269) has lower P-gp efflux than Ligand B (0.034), meaning less efflux and potentially better CNS exposure.

**Binding Affinity:** Both ligands have excellent binding affinities (A: -7.7 kcal/mol, B: -7.0 kcal/mol). Ligand A is slightly better, with a 0.7 kcal/mol advantage.

**Overall Assessment:**

Ligand A has a slight edge in binding affinity and better solubility, but Ligand B excels in critical ADME properties for a CNS target. Specifically, Ligand B has a much lower DILI risk, significantly better metabolic stability (lower Cl_mic, longer t1/2), and lower P-gp efflux. While Ligand A has slightly better BBB penetration, the difference is small, and the other ADME advantages of Ligand B are more compelling. The 0.7 kcal/mol difference in binding affinity is unlikely to outweigh the substantial improvements in ADME properties offered by Ligand B.

Output:
1
2025-04-17 07:29:30,520 - INFO - Batch 369 complete. Total preferences: 5904
2025-04-17 07:29:30,520 - INFO - Processing batch 370/512...
2025-04-17 07:30:14,793 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (358.454 and 381.567 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (78.87) is better than Ligand B (62.3). Both are below 90, which is favorable for CNS penetration.

**logP:** Ligand A (1.409) is within the optimal 1-3 range. Ligand B (3.032) is at the higher end of the optimal range, but still acceptable.

**H-Bond Donors:** Ligand A (2) and Ligand B (1) both meet the <=5 criteria.

**H-Bond Acceptors:** Ligand A (4) and Ligand B (5) both meet the <=10 criteria.

**QED:** Both ligands have good QED values (0.752 and 0.871, respectively), indicating drug-like properties.

**DILI:** Ligand A (20.861) has a significantly lower DILI risk than Ligand B (51.144). This is a major advantage for Ligand A.

**BBB:** Ligand A (70.609) has a better BBB percentile than Ligand B (62.97). Both are reasonably good, but Ligand A is closer to the desirable >70 threshold for CNS targets.

**Caco-2 Permeability:** Ligand A (-4.706) has a worse Caco-2 permeability score than Ligand B (-5.211). Lower values indicate lower permeability.

**Aqueous Solubility:** Ligand A (-1.934) has a better aqueous solubility score than Ligand B (-4.249).

**hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.484 and 0.415, respectively).

**Microsomal Clearance:** Ligand A (11.882) has a lower microsomal clearance than Ligand B (53.715), indicating better metabolic stability.

**In vitro Half-Life:** Ligand A (15.102) has a longer in vitro half-life than Ligand B (8.858).

**P-gp Efflux:** Ligand A (0.081) has a much lower P-gp efflux liability than Ligand B (0.302), which is crucial for CNS penetration.

**Binding Affinity:** Ligand B (-8.3 kcal/mol) has a slightly better binding affinity than Ligand A (-7.2 kcal/mol). This is a 1.1 kcal/mol difference.

**Overall Assessment:**

While Ligand B has a slightly better binding affinity, Ligand A is significantly better across multiple critical ADME properties, especially those prioritized for GPCRs targeting the CNS. Ligand A has a much lower DILI risk, better BBB penetration, lower P-gp efflux, and better metabolic stability (lower Cl_mic and longer t1/2). The 1.1 kcal/mol difference in binding affinity is unlikely to outweigh these substantial advantages in ADME properties.

Output:
0
2025-04-17 07:30:14,794 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (367.515 and 343.467 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (73.22) is higher than Ligand B (46.61). For CNS targets, we prefer TPSA <= 90, so both are acceptable, but B is significantly better.

**logP:** Ligand A (2.386) is within the optimal 1-3 range. Ligand B (4.287) is slightly above, potentially leading to solubility issues and off-target interactions, but not drastically so.

**H-Bond Donors/Acceptors:** Ligand A has 1 HBD and 5 HBA, while Ligand B has 0 HBD and 3 HBA. Both are within acceptable limits (<=5 HBD and <=10 HBA).

**QED:** Both ligands have similar QED values (0.867 and 0.605), indicating good drug-likeness.

**DILI:** Ligand A (37.224) has a lower DILI risk than Ligand B (52.385), which is preferable. Both are below the concerning threshold of 60.

**BBB:** Both ligands have excellent BBB penetration (71.772 and 71.656), satisfying the >70% requirement for CNS targets.

**Caco-2 Permeability:** Ligand A (-5.096) has poorer Caco-2 permeability than Ligand B (-4.5). Higher values are better, so B is slightly favored.

**Aqueous Solubility:** Ligand A (-3.174) has slightly better aqueous solubility than Ligand B (-5.116).

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.6 and 0.308), which is good.

**Microsomal Clearance:** Ligand A (52.811) has lower microsomal clearance than Ligand B (95.521), indicating better metabolic stability. This is a significant advantage.

**In vitro Half-Life:** Ligand A (-27.828) has a longer in vitro half-life than Ligand B (-16.985), which is desirable.

**P-gp Efflux:** Ligand A (0.187) has lower P-gp efflux than Ligand B (0.411), meaning it's less likely to be pumped out of the brain, improving CNS exposure.

**Binding Affinity:** Ligand B (-9.5 kcal/mol) has a stronger binding affinity than Ligand A (-7.4 kcal/mol). This is a substantial difference (>1.5 kcal/mol) and a major factor.

**Overall Assessment:**

While Ligand A has advantages in DILI, metabolic stability, half-life, and P-gp efflux, the significantly stronger binding affinity of Ligand B (-9.5 vs -7.4 kcal/mol) is a decisive advantage, especially for a GPCR target. The slightly higher logP and Caco-2 values of Ligand B are minor drawbacks compared to the substantial binding affinity gain. The TPSA of Ligand B is also significantly better.

Output:
1
2025-04-17 07:30:14,794 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (361.471 and 353.507 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (88.39) is better than Ligand B (70.67). Both are below the 90 A^2 threshold for CNS targets, which is excellent.

**3. logP:** Both ligands have good logP values (1.353 and 1.687), falling within the optimal 1-3 range.

**4. H-Bond Donors:** Both have 2 HBD, which is within the acceptable limit of <=5.

**5. H-Bond Acceptors:** Ligand A (6) is slightly higher than Ligand B (4), but both are below the 10 limit.

**6. QED:** Both ligands have acceptable QED values (0.777 and 0.697), indicating good drug-like properties.

**7. DILI:** Ligand B (6.398) is significantly better than Ligand A (69.717) regarding DILI risk, being much closer to zero. This is a significant advantage for Ligand B.

**8. BBB:** Both ligands have reasonably good BBB penetration (61.691 and 62.582). While >70 is desirable, these are acceptable considering the other parameters.

**9. Caco-2:** Both have negative Caco-2 values (-5.452 and -5.254). These are unusual and suggest poor permeability, which is concerning. However, these values are on a scale where negative values are possible, and their relative difference is small.

**10. Solubility:** Both have negative solubility values (-2.723 and -0.949). Similar to Caco-2, these are unusual and suggest poor solubility. Ligand B is slightly better than Ligand A.

**11. hERG:** Both ligands have low hERG inhibition risk (0.301 and 0.31), which is good.

**12. Cl_mic:** Ligand B (11.513) has a lower microsomal clearance than Ligand A (36.407), indicating better metabolic stability.

**13. t1/2:** Ligand A (11.061) has a longer in vitro half-life than Ligand B (4.748).

**14. Pgp:** Both ligands have very low P-gp efflux liability (0.036 and 0.011). This is excellent for CNS penetration.

**15. Binding Affinity:** Ligand B (-7.7 kcal/mol) has a slightly better binding affinity than Ligand A (-8.4 kcal/mol). While the difference is small, it's still a positive for Ligand B.

**Overall Assessment:**

Ligand B is the more promising candidate. While Ligand A has a slightly better binding affinity and longer half-life, Ligand B excels in crucial areas like DILI risk and metabolic stability (lower Cl_mic). Both have similar BBB penetration and Pgp efflux, and acceptable logP and TPSA values. The lower DILI risk is a significant advantage, and the slightly better affinity, combined with improved metabolic stability, makes Ligand B the preferred choice. The negative Caco-2 and solubility values are concerning for both, but the other advantages of Ligand B outweigh this.

Output:
1
2025-04-17 07:30:14,794 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (456.215 Da) is higher, but still acceptable. Ligand B (357.357 Da) is preferable.

**TPSA:** Both ligands have TPSA values below the 140 A^2 threshold for oral absorption. More importantly, both are below the 90 A^2 target for CNS penetration. Ligand B (84.67 A^2) is slightly better than Ligand A (93.04 A^2).

**logP:** Both ligands have logP values within the optimal range (1-3). Ligand A (2.959) is closer to the upper limit, while Ligand B (1.456) is closer to the lower limit. This is a slight advantage to A, but both are acceptable.

**H-Bond Donors & Acceptors:** Ligand A has 2 HBD and 5 HBA, while Ligand B has 1 HBD and 5 HBA. Both are within the acceptable limits (<=5 HBD and <=10 HBA).

**QED:** Both ligands have good QED scores (Ligand A: 0.557, Ligand B: 0.882). Ligand B is significantly better here, indicating a more drug-like profile.

**DILI:** Both ligands have acceptable DILI risk (Ligand A: 88.639, Ligand B: 57.697). Ligand B has a lower DILI risk, which is preferable.

**BBB:** This is a critical parameter for a CNS target like DRD2. Ligand A has a BBB percentile of 58.278, which is below the desirable threshold of 70. Ligand B has a BBB percentile of 77.007, which is above the threshold. This is a significant advantage for Ligand B.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.383 and -4.633). These values are difficult to interpret without knowing the scale, but generally, a more negative value indicates lower permeability.

**Aqueous Solubility:** Both ligands have negative solubility values (-4.388 and -2.309). Again, without knowing the scale, these are difficult to interpret, but lower values suggest lower solubility.

**hERG Inhibition:** Both ligands have low hERG inhibition liability (Ligand A: 0.535, Ligand B: 0.221). Ligand B is slightly better here.

**Microsomal Clearance:** Ligand A has a higher microsomal clearance (52.715 mL/min/kg) than Ligand B (14.003 mL/min/kg), suggesting lower metabolic stability. Ligand B is preferable.

**In vitro Half-Life:** Ligand B has a negative half-life (-8.721 hours), which is unusual. Ligand A has a half-life of 8.855 hours. This is a clear advantage for Ligand A.

**P-gp Efflux:** Ligand A has a P-gp efflux liability of 0.466, while Ligand B has 0.038. Ligand B is significantly better, indicating lower efflux and better CNS exposure.

**Binding Affinity:** Ligand A has a significantly better binding affinity (-10.2 kcal/mol) than Ligand B (-7.5 kcal/mol). This is a substantial advantage for Ligand A, potentially outweighing some of its ADME drawbacks.

**Overall Assessment:**

Ligand B has a better overall ADME profile, particularly regarding BBB penetration, DILI risk, P-gp efflux, and metabolic stability. However, Ligand A has a *much* stronger binding affinity. The affinity difference (2.7 kcal/mol) is substantial and likely to be critical for efficacy. Given the importance of affinity for GPCR ligands and the acceptable (though not ideal) ADME properties of Ligand A, it is the more promising candidate.

Output:
1
2025-04-17 07:30:14,794 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (364.837 and 363.483 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (104.7) is higher than Ligand B (72.88). For CNS targets, TPSA < 90 is preferred. Ligand B is significantly better in this regard.

**3. logP:** Both ligands have good logP values (1.653 and 1.516), falling within the optimal 1-3 range.

**4. H-Bond Donors:** Ligand A (3) is slightly higher than Ligand B (2), but both are acceptable (<=5).

**5. H-Bond Acceptors:** Both ligands have the same number of H-bond acceptors (5), which is within the acceptable range (<=10).

**6. QED:** Both ligands have good QED scores (0.724 and 0.851), indicating good drug-like properties.

**7. DILI:** Ligand A (65.374) has a higher DILI risk than Ligand B (25.281). Lower DILI is preferred.

**8. BBB:** Ligand A (58.511) and Ligand B (55.021) are both below the desirable threshold of >70 for CNS targets. However, this is less critical if other properties are strongly favorable.

**9. Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and suggests poor permeability. This is a significant concern for both.

**10. Aqueous Solubility:** Both have negative solubility values, also unusual and concerning.

**11. hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.177 and 0.522).

**12. Microsomal Clearance:** Ligand A (-6.109) has a much lower (better) microsomal clearance than Ligand B (1.477), suggesting greater metabolic stability.

**13. In vitro Half-Life:** Ligand A (32.088 hours) has a significantly longer half-life than Ligand B (10.65 hours).

**14. P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.046 and 0.035), which is good for CNS penetration.

**15. Binding Affinity:** Both ligands have excellent binding affinities (-8.8 and -8.5 kcal/mol). The difference of 0.3 kcal/mol is not substantial enough to override other considerations.

**Overall Assessment:**

Considering the GPCR-specific priorities, Ligand B is slightly favored. It has a significantly lower TPSA, lower DILI risk, and a higher QED score. While both have poor Caco-2 and solubility values, the lower TPSA of Ligand B is more beneficial for CNS penetration. Ligand A has better metabolic stability and half-life, but the lower TPSA and DILI of Ligand B are more important for a CNS target like DRD2.

Output:
1
2025-04-17 07:30:14,794 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (347.419 and 343.435 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (111.26) is slightly above the optimal <90 for CNS targets, but still reasonable. Ligand B (96.88) is well within the desired range.

**logP:** Ligand A (0.911) is a bit low, potentially hindering permeability. Ligand B (2.696) is within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A (HBD=2, HBA=6) is better balanced. Ligand B (HBD=3, HBA=8) is acceptable but slightly higher in HBA.

**QED:** Both ligands have reasonable QED scores (0.642 and 0.567), indicating good drug-like properties.

**DILI:** Ligand A (24.855) has a significantly lower DILI risk than Ligand B (66.421), which is a major advantage.

**BBB:** Ligand A (56.534) shows moderate BBB penetration, while Ligand B (40.558) is lower. This is a critical factor for a CNS target like DRD2, favoring Ligand A.

**Caco-2 Permeability:** Both have negative values, indicating poor permeability. Ligand A (-5.329) is slightly better than Ligand B (-4.892).

**Aqueous Solubility:** Both have negative values, indicating poor solubility. Ligand B (-3.975) is slightly better than Ligand A (-1.37).

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.451 and 0.606).

**Microsomal Clearance:** Ligand A (-4.346) has a much lower (better) microsomal clearance than Ligand B (75.726), suggesting greater metabolic stability.

**In vitro Half-Life:** Ligand A (-9.334) has a longer in vitro half-life than Ligand B (15.087).

**P-gp Efflux:** Ligand A (0.008) has very low P-gp efflux, which is excellent for CNS penetration. Ligand B (0.052) is slightly higher, but still relatively low.

**Binding Affinity:** Ligand B (-7.9) has a slightly better binding affinity than Ligand A (-7.5), a 0.4 kcal/mol difference. While affinity is crucial, the other ADME properties are also important.

**Overall Assessment:**

Ligand A is the stronger candidate. While Ligand B has a slightly better binding affinity, Ligand A demonstrates significantly better ADME properties crucial for CNS drug development. Specifically, its lower DILI risk, better BBB penetration, lower microsomal clearance, and longer half-life are highly favorable. The slightly lower logP and TPSA are less concerning given the overall profile. The difference in binding affinity (0.4 kcal/mol) is unlikely to outweigh the substantial ADME advantages of Ligand A.

Output:
1
2025-04-17 07:30:14,794 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (423.16 Da) is slightly higher than Ligand B (358.427 Da), but both are acceptable.

**TPSA:** Both ligands have TPSA values (81.59 and 86.03 respectively) that are above the ideal <90 for CNS targets, but not drastically so. This is a minor concern.

**logP:** Ligand A (4.34) is higher than Ligand B (1.506). While 4.34 is approaching the upper limit, it's still within a reasonable range. Ligand B's logP is quite low, potentially hindering membrane permeability.

**H-Bond Donors/Acceptors:** Ligand A has 4 HBD and 3 HBA, which is good. Ligand B has 0 HBD and 8 HBA. While not terrible, the higher number of HBA in Ligand B could impact permeability.

**QED:** Both ligands have acceptable QED values (0.438 and 0.636), indicating reasonable drug-likeness.

**DILI:** Ligand A (68.903) has a slightly better DILI score than Ligand B (75.184), indicating a lower risk of liver injury.

**BBB:** Both ligands have similar BBB penetration percentiles (46.375 and 47.15 respectively). These are below the desirable >70 for CNS targets, but not dramatically different.

**Caco-2 Permeability:** Ligand A (-5.384) has a significantly *better* (less negative) Caco-2 permeability score than Ligand B (-4.82). This suggests better intestinal absorption for Ligand A.

**Aqueous Solubility:** Ligand A (-4.929) has a slightly better (less negative) solubility score than Ligand B (-1.434).

**hERG Inhibition:** Ligand A (0.747) has a lower hERG inhibition liability than Ligand B (0.113), which is preferable.

**Microsomal Clearance:** Ligand B (54.437) has a higher microsomal clearance than Ligand A (41.834), suggesting faster metabolism and potentially lower in vivo exposure.

**In vitro Half-Life:** Ligand A (30.344) has a significantly longer in vitro half-life than Ligand B (-15.491). This is a major advantage.

**P-gp Efflux:** Ligand A (0.289) has lower P-gp efflux liability than Ligand B (0.065), which is favorable for CNS penetration.

**Binding Affinity:** Ligand A (-9.7 kcal/mol) has a *substantially* better binding affinity than Ligand B (-8.2 kcal/mol). This difference of 1.5 kcal/mol is significant and can outweigh minor ADME drawbacks.

**Overall Assessment:**

Ligand A is clearly the more promising candidate. Its superior binding affinity, better Caco-2 permeability, solubility, hERG profile, longer half-life, and lower P-gp efflux outweigh the slightly higher TPSA and DILI score. Ligand B's low logP and high clearance are significant concerns. The affinity difference is particularly important for a GPCR target.

Output:
1
2025-04-17 07:30:14,794 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (426.742 Da) is slightly higher than Ligand B (391.921 Da), but both are acceptable.

**TPSA:** Ligand A (72.36) is much better than Ligand B (91.76). For CNS targets, we want TPSA <= 90, so Ligand A is preferable.

**logP:** Ligand A (3.614) is optimal (1-3), while Ligand B (1.798) is on the lower end, potentially hindering permeation. Ligand A is favored.

**H-Bond Donors/Acceptors:** Ligand A (HBD=1, HBA=4) is better than Ligand B (HBD=2, HBA=6) in terms of balancing solubility and permeability.

**QED:** Ligand A (0.792) has a significantly better QED score than Ligand B (0.593), indicating better overall drug-likeness.

**DILI:** Ligand A (33.773) has a lower DILI risk than Ligand B (43.273), which is desirable.

**BBB:** Ligand A (80.884) has a significantly higher BBB penetration percentile than Ligand B (28.655). This is *critical* for a CNS target like DRD2, making Ligand A strongly favored.

**Caco-2 Permeability:** Ligand A (-5.267) and Ligand B (-4.807) both have negative values, which is unusual. Without knowing the scale, it's hard to interpret, but they are similar.

**Aqueous Solubility:** Ligand A (-3.703) and Ligand B (-1.591) both have negative values, which is also unusual. Again, hard to interpret without the scale, but B is slightly better.

**hERG:** Ligand A (0.807) has a lower hERG risk than Ligand B (0.342), which is preferable.

**Microsomal Clearance:** Ligand B (32.597) has lower microsomal clearance than Ligand A (14.06), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand B (44.66) has a longer in vitro half-life than Ligand A (18.449), which is desirable.

**P-gp Efflux:** Ligand A (0.638) has lower P-gp efflux than Ligand B (0.25), which is favorable for CNS exposure.

**Binding Affinity:** Ligand A (-8.1 kcal/mol) has a significantly stronger binding affinity than Ligand B (-6.7 kcal/mol). This is a major advantage, potentially outweighing some of the ADME drawbacks of Ligand B.

**Overall:** Considering all factors, especially the critical CNS-related properties (BBB, TPSA, logP) and the significantly better binding affinity, **Ligand A is the much more promising drug candidate.** While Ligand B has better metabolic stability and half-life, the superior BBB penetration, TPSA, logP, QED, and binding affinity of Ligand A make it the clear choice.

Output:
1
2025-04-17 07:30:14,795 - INFO - Reasoning:

Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (372.447 and 360.523 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (121.61) is borderline for CNS targets, slightly above the preferred <90, but acceptable. Ligand B (49.41) is excellent, well below 90. This favors Ligand B.

**3. logP:** Ligand A (-0.441) is a bit low, potentially hindering membrane permeability. Ligand B (3.287) is optimal. This strongly favors Ligand B.

**4. H-Bond Donors:** Ligand A (2) and Ligand B (1) are both within the acceptable limit of <=5.

**5. H-Bond Acceptors:** Ligand A (6) and Ligand B (3) are both within the acceptable limit of <=10.

**6. QED:** Both ligands have good QED scores (0.626 and 0.846), indicating good drug-like properties.

**7. DILI:** Ligand A (63.086) has a moderate DILI risk. Ligand B (14.889) has a very low DILI risk, which is a significant advantage.

**8. BBB:** Ligand A (52.579) has a moderate BBB penetration, while Ligand B (73.556) is very good, exceeding the >70 threshold for CNS targets. This is a major advantage for Ligand B.

**9. Caco-2:** Both ligands have negative Caco-2 values (-5.316 and -5.204), which is unusual and suggests poor permeability. However, these values are on a scale where negative values are possible, and their relative comparison is less informative without knowing the scale's specifics.

**10. Solubility:** Both ligands have negative solubility values (-2.001 and -2.902), again suggesting poor solubility. Similar to Caco-2, the scale is important.

**11. hERG:** Both ligands have low hERG inhibition liability (0.138 and 0.425), indicating a low risk of cardiotoxicity.

**12. Cl_mic:** Both ligands have similar microsomal clearance values (44.608 and 47.95), suggesting comparable metabolic stability.

**13. t1/2:** Ligand A (-13.668) has a negative in vitro half-life, which is not physically possible and likely indicates an issue with the data or the model. Ligand B (-9.151) also has a negative half-life, indicating a similar issue.

**14. Pgp:** Both ligands have very low Pgp efflux liability (0.015 and 0.249), which is favorable for CNS penetration.

**15. Binding Affinity:** Both ligands have the same binding affinity (-8.4 kcal/mol), which is excellent.

**Overall Assessment:**

Despite the unusual negative values for Caco-2 and solubility, Ligand B is clearly superior. It has a much better logP, lower DILI risk, significantly better BBB penetration, and a lower Pgp efflux liability. While the half-life values are problematic for both, the other advantages of Ligand B outweigh this concern, especially given the target is a CNS GPCR where BBB penetration is critical.

Output:
1
2025-04-17 07:30:14,795 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (360.384 and 352.41 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (66.29) is significantly better than Ligand B (98.32). For CNS targets, TPSA should be <= 90, and A is comfortably within this range, while B is close to the upper limit and less desirable.

**logP:** Both ligands have acceptable logP values (0.74 and 1.282, respectively), falling within the 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A (HBD=1, HBA=6) is better than Ligand B (HBD=3, HBA=4) in terms of balancing solubility and permeability.

**QED:** Both ligands have reasonable QED scores (0.858 and 0.718), indicating good drug-like properties.

**DILI:** Ligand A (36.448) has a much lower DILI risk than Ligand B (50.097), which is a significant advantage.

**BBB:** Both ligands exhibit good BBB penetration (76.425 and 70.609), but Ligand A is slightly better. Both are above the 70% threshold for CNS targets.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.067 and -4.974), which is unusual and suggests poor permeability. This is a concern for both, but doesn't differentiate them.

**Aqueous Solubility:** Both ligands have negative solubility values (-1.829 and -3.229), indicating poor aqueous solubility. This is a drawback for both.

**hERG Inhibition:** Ligand A (0.501) has a lower hERG inhibition liability than Ligand B (0.38), which is preferable.

**Microsomal Clearance:** Ligand A (-22.793) has a significantly lower (better) microsomal clearance than Ligand B (9.697), suggesting greater metabolic stability.

**In vitro Half-Life:** Ligand A (8.463) has a better in vitro half-life than Ligand B (1.738).

**P-gp Efflux:** Both ligands show very low P-gp efflux (0.047 and 0.065), which is excellent for CNS penetration.

**Binding Affinity:** Ligand B (-8.1 kcal/mol) has a significantly stronger binding affinity than Ligand A (-0.0 kcal/mol). This is a substantial advantage for Ligand B.

**Overall Assessment:**

While Ligand B has a much better binding affinity, Ligand A excels in almost all ADME-Tox properties. Specifically, Ligand A has a significantly lower DILI risk, better metabolic stability (lower Cl_mic, longer t1/2), and better TPSA. Given the GPCR-specific priorities, the superior ADME profile of Ligand A, combined with acceptable (though not great) affinity and good BBB penetration, makes it the more promising candidate. The large difference in binding affinity is a concern, but can potentially be addressed with further optimization, while fixing the poor ADME properties of Ligand B would be more challenging.

Output:
0
2025-04-17 07:30:14,795 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (347.459 Da) is slightly lower, which could be beneficial for permeability.

**TPSA:** Ligand A (90.46) is excellent for CNS penetration, being under the 90 A^2 threshold. Ligand B (126.13) is higher, potentially hindering BBB penetration.

**logP:** Ligand A (3.345) is optimal. Ligand B (-0.698) is significantly low, which is a major concern for membrane permeability and CNS penetration.

**H-Bond Donors/Acceptors:** Ligand A (HBD=4, HBA=3) and Ligand B (HBD=2, HBA=9) both fall within acceptable ranges, though Ligand B's HBA is approaching the upper limit.

**QED:** Both ligands have similar and acceptable QED values (A: 0.636, B: 0.693).

**DILI:** Ligand A (32.61) has a much lower DILI risk than Ligand B (76.425). This is a significant advantage for Ligand A.

**BBB:** Ligand A (63.125) shows reasonable BBB penetration, while Ligand B (23.071) is very poor, a critical drawback for a CNS target like DRD2.

**Caco-2 Permeability:** Ligand A (-4.658) and Ligand B (-5.755) both have negative Caco-2 values, indicating poor permeability. This is concerning, but less critical than the BBB issue with Ligand B.

**Aqueous Solubility:** Ligand A (-3.949) and Ligand B (-1.461) both have negative solubility values, indicating poor solubility.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (A: 0.616, B: 0.049).

**Microsomal Clearance:** Ligand A (32.475) has a higher, but still reasonable, microsomal clearance than Ligand B (3.67). Lower is better, so Ligand B is favored here.

**In vitro Half-Life:** Ligand A (27.425) has a longer half-life than Ligand B (1.046), which is preferable.

**P-gp Efflux:** Ligand A (0.069) has lower P-gp efflux than Ligand B (0.034), meaning it is less likely to be pumped out of the brain, which is crucial for CNS targets.

**Binding Affinity:** Ligand A (-8.9 kcal/mol) has a significantly stronger binding affinity than Ligand B (-7.4 kcal/mol). This difference of 1.5 kcal/mol is substantial and can outweigh some ADME drawbacks.

**Overall Assessment:**

Ligand A is clearly superior. While both have solubility and permeability concerns, Ligand A excels in crucial areas for a CNS-targeting GPCR ligand: significantly better BBB penetration, lower DILI risk, stronger binding affinity, and lower P-gp efflux. Ligand B's very low logP and poor BBB penetration are major liabilities that outweigh its slightly better metabolic stability.

Output:
1
2025-04-17 07:30:14,795 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (345.443 Da) is slightly lower, which could be beneficial for permeability, while Ligand B (368.503 Da) is also acceptable.

**TPSA:** Both ligands have TPSA values below the 90 A^2 threshold desirable for CNS targets. Ligand A (81.67 A^2) is slightly higher than Ligand B (75.63 A^2), giving a slight edge to B.

**logP:** Both ligands have logP values within the optimal range (1-3). Ligand A (2.595) and Ligand B (2.263) are both good.

**H-Bond Donors/Acceptors:** Ligand A has 3 HBD and 3 HBA, while Ligand B has 0 HBD and 7 HBA. Both are within acceptable limits (<=5 HBD, <=10 HBA).

**QED:** Ligand A (0.767) has a significantly better QED score than Ligand B (0.492), indicating a more drug-like profile.

**DILI:** Ligand A (30.826%) has a much lower DILI risk than Ligand B (64.831%), which is a significant advantage.

**BBB:** Ligand B (85.459%) has a substantially better BBB penetration score than Ligand A (73.75%). This is a crucial factor for a CNS target like DRD2.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values, which is unusual and difficult to interpret without knowing the scale. However, these values are similar and don't strongly differentiate the two.

**Aqueous Solubility:** Both ligands have negative solubility values, again, difficult to interpret without knowing the scale. The values are similar.

**hERG Inhibition:** Both ligands have low hERG inhibition liability (0.516 and 0.686, respectively), which is good.

**Microsomal Clearance:** Ligand A (-25.8 mL/min/kg) has a much lower (better) microsomal clearance than Ligand B (113.805 mL/min/kg), indicating better metabolic stability.

**In vitro Half-Life:** Ligand A (10.671 hours) has a better in vitro half-life than Ligand B (-14.692 hours).

**P-gp Efflux:** Ligand A (0.02) has much lower P-gp efflux liability than Ligand B (0.501), which is favorable for CNS penetration.

**Binding Affinity:** Ligand A (-9.4 kcal/mol) has a significantly stronger binding affinity than Ligand B (-6.5 kcal/mol). This is a substantial advantage, potentially outweighing some ADME drawbacks.

**Overall Assessment:**

Ligand A excels in key areas: binding affinity, metabolic stability (low Cl_mic), P-gp efflux, DILI risk, QED, and in vitro half-life. While Ligand B has a better BBB score, the substantial difference in binding affinity (-2.9 kcal/mol) and the superior ADME profile of Ligand A make it the more promising candidate. The stronger binding affinity is likely to be more impactful than the slightly better BBB penetration of Ligand B, especially considering the other favorable properties of Ligand A.

Output:
1
2025-04-17 07:30:14,795 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (357.288 Da) is slightly higher than Ligand B (335.451 Da), but both are acceptable.

**TPSA:** Ligand A (104.45) is above the optimal 90 for CNS targets, while Ligand B (45.23) is well below. This favors Ligand B significantly for brain penetration.

**logP:** Both ligands have good logP values (A: 2.024, B: 3.454), falling within the 1-3 range. Ligand B is a bit higher, which could potentially lead to off-target effects, but it's not a major concern.

**H-Bond Donors/Acceptors:** Ligand A has 3 HBD and 5 HBA, while Ligand B has 1 HBD and 3 HBA. Both are within acceptable limits (<=5 HBD and <=10 HBA).

**QED:** Both ligands have good QED scores (A: 0.734, B: 0.871), indicating good drug-like properties.

**DILI:** Ligand A has a DILI risk of 60.489%, which is bordering on high risk. Ligand B has a much lower DILI risk (21.791%), a significant advantage.

**BBB:** This is a critical parameter for DRD2. Ligand A has a BBB penetration of 29.934%, which is quite low. Ligand B has a very high BBB penetration (87.864%), making it much more likely to reach the target in the CNS.

**Caco-2 Permeability:** Ligand A has a negative Caco-2 value (-5.939), which is concerning and suggests poor intestinal absorption. Ligand B also has a negative Caco-2 value (-4.876), but it's slightly less negative than Ligand A.

**Aqueous Solubility:** Both ligands have negative solubility values (A: -2.009, B: -3.367), indicating poor aqueous solubility. This could pose formulation challenges.

**hERG Inhibition:** Ligand A has a very low hERG inhibition risk (0.091), which is excellent. Ligand B has a slightly higher risk (0.79), but still relatively low.

**Microsomal Clearance:** Ligand A has a negative Cl_mic (-9.23), which is unusual and suggests very slow clearance/high metabolic stability. Ligand B has a positive Cl_mic (27.089), indicating faster clearance.

**In vitro Half-Life:** Ligand A has a very long in vitro half-life (-20.697), consistent with the low clearance. Ligand B has a shorter half-life (18.758).

**P-gp Efflux:** Ligand A has very low P-gp efflux (0.011), which is favorable for CNS penetration. Ligand B has slightly higher P-gp efflux (0.221).

**Binding Affinity:** Both ligands have excellent binding affinities (A: -8.3 kcal/mol, B: -8.8 kcal/mol). Ligand B is slightly better, but the difference is not huge.

**Overall Assessment:**

Ligand B is the superior candidate. While Ligand A has a slightly better hERG profile and potentially better metabolic stability (negative Cl_mic is unusual), Ligand B excels in the most critical areas for a CNS-targeting GPCR ligand: TPSA, BBB penetration, and DILI risk. The significantly better BBB penetration and lower DILI risk of Ligand B outweigh the minor advantages of Ligand A. The slightly better binding affinity of Ligand B is a bonus.

Output:
1
2025-04-17 07:30:14,795 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (346.475 and 345.443 Da) fall comfortably within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (78.09) is slightly higher than Ligand B (75.44). Both are below the 90 A^2 threshold desirable for CNS targets, which is good.

**3. logP:** Both ligands have good logP values (2.303 and 2.583, respectively), falling within the optimal 1-3 range.

**4. H-Bond Donors:** Ligand A has 2 HBD, and Ligand B has 1. Both are within the acceptable limit of <=5.

**5. H-Bond Acceptors:** Ligand A has 3 HBA, and Ligand B has 4. Both are within the acceptable limit of <=10.

**6. QED:** Both ligands have good QED scores (0.795 and 0.86), indicating good drug-like properties.

**7. DILI:** Ligand A (13.687 percentile) has a significantly lower DILI risk than Ligand B (40.83 percentile). This is a substantial advantage for Ligand A.

**8. BBB:** Ligand B (74.176 percentile) has a better BBB penetration prediction than Ligand A (55.332 percentile). This is a critical factor for a CNS target like DRD2.

**9. Caco-2 Permeability:** Ligand A (-5.056) has worse Caco-2 permeability than Ligand B (-4.585). This suggests lower intestinal absorption for Ligand A.

**10. Aqueous Solubility:** Ligand A (-1.837) has worse aqueous solubility than Ligand B (-2.85).

**11. hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.37 and 0.078, respectively).

**12. Microsomal Clearance:** Ligand B (91.999) has a much higher microsomal clearance than Ligand A (18.241), indicating faster metabolism and potentially lower exposure.

**13. In vitro Half-Life:** Ligand A (-18.015) has a longer in vitro half-life than Ligand B (-9.56).

**14. P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.031 and 0.124, respectively).

**15. Binding Affinity:** Both ligands have excellent binding affinity (-8.0 and -8.7 kcal/mol, respectively). Ligand B is slightly better, but the difference is relatively small.

**Overall Assessment:**

The choice is difficult. Ligand B has a significantly better BBB score and slightly better affinity, which are crucial for a CNS GPCR target. However, Ligand A has a much lower DILI risk and better metabolic stability (lower Cl_mic, longer t1/2). The lower DILI risk is a significant advantage, as liver toxicity is a common reason for drug failure. While BBB is important, a slightly lower BBB can sometimes be compensated for by other factors, especially if the compound has good metabolic stability. The solubility and Caco-2 permeability are worse for Ligand A, but not dramatically so.

Considering the balance of properties, and prioritizing the lower DILI risk and better metabolic stability of Ligand A, I believe it is the more promising candidate.

Output:
0
2025-04-17 07:30:14,795 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B against the provided guidelines, prioritizing GPCR-specific properties (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (373.446) is slightly higher than Ligand B (339.487), but both are acceptable.

**TPSA:** Both ligands have TPSA values around 73, which is acceptable for general oral absorption but a bit high for optimal CNS penetration (ideally <90, but lower is better).

**logP:** Ligand A (1.847) is within the optimal range (1-3). Ligand B (4.067) is slightly above this range, potentially leading to solubility issues and off-target interactions.

**H-Bond Donors/Acceptors:** Both ligands have reasonable HBD/HBA counts (A: 0/5, B: 2/5), falling within the acceptable limits.

**QED:** Both ligands have good QED scores (A: 0.562, B: 0.699), indicating drug-like properties. Ligand B is slightly better here.

**DILI:** Both ligands have low DILI risk (A: 40.054, B: 36.293), which is positive.

**BBB:** This is a critical parameter for a CNS target like DRD2. Ligand A has a significantly higher BBB percentile (91.663) compared to Ligand B (76.696). This is a major advantage for Ligand A.

**Caco-2 Permeability:** Ligand A (-4.406) and Ligand B (-5.047) both have negative Caco-2 values, which is unusual and suggests poor permeability. However, the scale isn't clearly defined, so it's difficult to interpret.

**Aqueous Solubility:** Both ligands have poor aqueous solubility (-2.44 for A, -4.614 for B). This could be a formulation challenge, but is less critical than BBB for a CNS target.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (A: 0.429, B: 0.901), which is favorable.

**Microsomal Clearance:** Ligand A (11.308 mL/min/kg) has a lower microsomal clearance than Ligand B (61.887 mL/min/kg), indicating better metabolic stability.

**In vitro Half-Life:** Ligand A (21.803 hours) has a shorter half-life than Ligand B (47.166 hours). Longer half-life is generally preferred.

**P-gp Efflux:** Ligand A (0.244) has lower P-gp efflux liability than Ligand B (0.441), which is beneficial for CNS exposure.

**Binding Affinity:** Ligand B (-7.6 kcal/mol) has a slightly better binding affinity than Ligand A (-8.7 kcal/mol). While a 1.1 kcal/mol difference is noticeable, the other ADME properties are more important in this case.

**Overall Assessment:**

Ligand A is the more promising candidate. Its significantly higher BBB penetration (91.663 vs. 76.696) is a crucial advantage for a CNS-targeting drug. It also has better metabolic stability (lower Cl_mic) and lower P-gp efflux. While Ligand B has slightly better binding affinity and in vitro half-life, the superior CNS penetration and ADME profile of Ligand A outweigh these benefits. The solubility issues are a concern for both, but can be addressed with formulation strategies.



Output:
0
2025-04-17 07:30:14,796 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 drug candidates, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (361.511 and 354.491 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (73.2) is better than Ligand B (84.5). For CNS targets, we want TPSA <= 90, and both are within this range, but A is closer to the optimal value.

**3. logP:** Both ligands have good logP values (2.653 and 2.555), falling within the optimal 1-3 range.

**4. H-Bond Donors:** Ligand A (1) is preferable to Ligand B (2). Fewer HBDs generally improve permeability.

**5. H-Bond Acceptors:** Both ligands have the same number of HBA (4), which is acceptable (<=10).

**6. QED:** Ligand A (0.738) has a significantly better QED score than Ligand B (0.492), indicating a more drug-like profile.

**7. DILI:** Ligand A (30.593) has a slightly higher DILI risk than Ligand B (21.869), but both are well below the concerning threshold of 60.

**8. BBB:** Ligand B (70.492) has a better BBB penetration percentile than Ligand A (62.117). This is a crucial factor for CNS targets like DRD2.

**9. Caco-2 Permeability:** Ligand A (-5.013) has worse Caco-2 permeability than Ligand B (-4.78). Higher values are better.

**10. Aqueous Solubility:** Ligand A (-3.328) has worse aqueous solubility than Ligand B (-2.311). Higher values are better.

**11. hERG Inhibition:** Both ligands have low hERG inhibition liability (0.478 and 0.367), which is good.

**12. Microsomal Clearance:** Both ligands have similar microsomal clearance (55.838 and 55.23), indicating similar metabolic stability.

**13. In vitro Half-Life:** Ligand B (-10.169) has a significantly longer in vitro half-life than Ligand A (2.327). This is a positive attribute.

**14. P-gp Efflux:** Ligand A (0.063) has lower P-gp efflux liability than Ligand B (0.148), which is preferable for CNS penetration.

**15. Binding Affinity:** Ligand B (-7.3) has a slightly better binding affinity than Ligand A (-7.1), although the difference is small. A difference >1.5 kcal/mol would be more impactful.

**Overall Assessment:**

Ligand B demonstrates a superior BBB penetration (70.492 vs 62.117) and a longer in vitro half-life (-10.169 vs 2.327). While Ligand A has a better QED and lower P-gp efflux, the importance of BBB penetration and metabolic stability (longer half-life) for a CNS target like DRD2 outweighs these advantages. The slightly better binding affinity of Ligand B also contributes to its favorability.

Output:
1
2025-04-17 07:30:14,796 - INFO - Batch 370 complete. Total preferences: 5920
2025-04-17 07:30:14,796 - INFO - Processing batch 371/512...
2025-04-17 07:30:54,647 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (348.403 and 346.431 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Both ligands (95.86 and 96.11) are close to the 90 A^2 threshold for CNS targets, but slightly above. This is not a major concern, but something to consider.

**3. logP:** Ligand A (0.319) is quite low, potentially hindering membrane permeability. Ligand B (1.095) is better, falling within the optimal 1-3 range. This is a significant advantage for Ligand B.

**4. H-Bond Donors:** Ligand A (1) is good. Ligand B (3) is acceptable, but higher HBDs can sometimes reduce permeability.

**5. H-Bond Acceptors:** Ligand A (6) is good. Ligand B (4) is also good.

**6. QED:** Both ligands have acceptable QED values (0.845 and 0.718), indicating good drug-like properties.

**7. DILI:** Ligand A (61.807) has a higher DILI risk than Ligand B (31.369). This is a negative for Ligand A.

**8. BBB:** Ligand A (51.066) has a moderate BBB penetration, while Ligand B (58.24) is slightly better. Both are below the desirable >70 for CNS targets, but Ligand B is closer.

**9. Caco-2:** Ligand A (-4.406) has very poor Caco-2 permeability, indicating poor intestinal absorption. Ligand B (-5.512) is also poor, but slightly better than A.

**10. Solubility:** Both ligands have poor aqueous solubility (-1.532 and -2.152). This could pose formulation challenges.

**11. hERG:** Both ligands have very low hERG inhibition risk (0.237 and 0.129).

**12. Cl_mic:** Ligand A (19.066) has a higher microsomal clearance than Ligand B (0.24), suggesting lower metabolic stability. This is a negative for Ligand A.

**13. t1/2:** Ligand A (-18.602) has a very short in vitro half-life, while Ligand B (5.155) is better.

**14. Pgp:** Both ligands have low P-gp efflux liability (0.135 and 0.01).

**15. Binding Affinity:** Ligand B (-8.6 kcal/mol) has a significantly stronger binding affinity than Ligand A (-7.3 kcal/mol). This is a crucial advantage, exceeding the 1.5 kcal/mol threshold.

**Overall Assessment:**

Ligand B is the superior candidate. While both have issues with solubility and TPSA, Ligand B demonstrates better logP, significantly higher binding affinity, lower DILI risk, better metabolic stability (lower Cl_mic, longer t1/2), and slightly better BBB penetration. The stronger binding affinity of Ligand B is a major advantage that outweighs the minor drawbacks in other properties. The low logP of Ligand A is a significant concern, potentially limiting its ability to cross cell membranes.

Output:
1
2025-04-17 07:30:54,647 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, considering the provided guidelines and GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (345.4 and 338.5 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (121.52) is slightly above the preferred <90 for CNS targets, but still reasonable. Ligand B (51.37) is excellent, well below 90.

**logP:** Ligand A (0.213) is quite low, potentially hindering permeability. Ligand B (2.841) is within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A has 4 HBD and 4 HBA, acceptable. Ligand B has 2 HBD and 2 HBA, also acceptable.

**QED:** Both ligands have good QED scores (0.538 and 0.904), indicating drug-like properties.

**DILI:** Ligand A (31.7) has a much lower DILI risk than Ligand B (56.8). This is a significant advantage for Ligand A.

**BBB:** Ligand B (90.1) has excellent BBB penetration, exceeding the >70 threshold for CNS targets. Ligand A (32.1) is very poor, indicating limited CNS exposure.

**Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual. However, the magnitude is similar, so this isn't a major differentiating factor.

**Aqueous Solubility:** Both have negative solubility values, which is also unusual. Again, the magnitude is similar.

**hERG:** Ligand A (0.141) shows very low hERG inhibition risk, which is excellent. Ligand B (0.851) has a moderate risk.

**Microsomal Clearance:** Ligand A (-1.913) suggests very slow clearance and high metabolic stability. Ligand B (16.386) indicates faster clearance.

**In vitro Half-Life:** Ligand A (9.3) has a reasonable half-life. Ligand B (57.5) has a very long half-life, which is a positive.

**P-gp Efflux:** Ligand A (0.005) has very low P-gp efflux, which is ideal for CNS penetration. Ligand B (0.327) has moderate P-gp efflux.

**Binding Affinity:** Both ligands have comparable and strong binding affinities (-8.2 and -8.4 kcal/mol). The difference is negligible.

**Overall Assessment:**

Ligand B excels in BBB penetration and has a longer half-life. However, Ligand A has a significantly lower DILI risk, better metabolic stability (lower Cl_mic), lower hERG risk, and very low P-gp efflux. The low logP of Ligand A is a concern, but the strong binding affinity might compensate. Given the GPCR-specific priorities, especially BBB and P-gp for CNS targets, and the importance of safety (DILI, hERG), Ligand A is the more promising candidate. While Ligand B's BBB is excellent, the higher DILI and P-gp efflux are drawbacks. The low logP of Ligand A can be addressed through structural modifications, but the safety profile is harder to improve.

Output:
0
2025-04-17 07:30:54,647 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B based on the provided guidelines, prioritizing GPCR-specific properties (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (346.391 and 354.397 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (116.0) is higher than the preferred <90 for CNS targets, while Ligand B (53.76) is well within the range. This is a significant advantage for Ligand B.

**logP:** Ligand A (-0.164) is quite low, potentially hindering permeability. Ligand B (2.707) is within the optimal 1-3 range. This favors Ligand B.

**H-Bond Donors/Acceptors:** Ligand A has 3 HBD and 5 HBA, which are acceptable. Ligand B has 0 HBD and 3 HBA, also acceptable.

**QED:** Both ligands have good QED scores (0.695 and 0.757), indicating drug-like properties.

**DILI:** Ligand A (62.233) has a higher DILI risk than Ligand B (17.72). This favors Ligand B.

**BBB:** Ligand B (83.211) has a significantly better BBB penetration percentile than Ligand A (32.377). This is a critical advantage for a CNS target like DRD2.

**Caco-2 Permeability:** Ligand A (-5.537) shows poor Caco-2 permeability, while Ligand B (-4.691) is slightly better, but still not great.

**Aqueous Solubility:** Both ligands have poor aqueous solubility (-1.349 and -2.287).

**hERG Inhibition:** Both ligands show low hERG inhibition risk (0.114 and 0.518).

**Microsomal Clearance:** Ligand A (-19.179) has a lower (better) microsomal clearance than Ligand B (15.261), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (-27.826) has a lower in vitro half-life than Ligand B (16.167).

**P-gp Efflux:** Ligand A (0.006) has lower P-gp efflux than Ligand B (0.072), which is beneficial for CNS penetration.

**Binding Affinity:** Ligand B (-7.5 kcal/mol) has a slightly better binding affinity than Ligand A (-8.1 kcal/mol). While A is better, the difference is not substantial enough to overcome the other deficiencies.

**Overall Assessment:**

Ligand B is significantly more promising due to its superior BBB penetration, more favorable logP, lower DILI risk, and acceptable TPSA. While Ligand A has slightly better binding affinity and metabolic stability, the poor BBB penetration and low logP are major drawbacks for a CNS-targeting drug. The differences in binding affinity are not large enough to outweigh the ADME advantages of Ligand B.

Output:
1
2025-04-17 07:30:54,647 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (352.41 and 347.375 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (88.67) is excellent, falling well below the 90 A^2 threshold for CNS targets. Ligand B (111.39) is still reasonable but less optimal, being above 100.

**3. logP:** Ligand A (0.187) is quite low, potentially hindering membrane permeability. Ligand B (0.454) is also low, but slightly better than A. Both are below the optimal 1-3 range.

**4. H-Bond Donors:** Ligand A (3) and Ligand B (2) are both within the acceptable limit of <=5.

**5. H-Bond Acceptors:** Ligand A (4) and Ligand B (8) are both within the acceptable limit of <=10.

**6. QED:** Both ligands have good QED scores (0.682 and 0.7), indicating drug-like properties.

**7. DILI:** Ligand A (20.396) has a significantly lower DILI risk than Ligand B (68.903). This is a major advantage for Ligand A.

**8. BBB:** Ligand A (42.846) has a very low BBB penetration percentile, making it unlikely to reach the target in the CNS. Ligand B (27.879) is also low, but slightly better than A. Both are far from the desirable >70.

**9. Caco-2:** Both ligands have negative Caco-2 values (-5.145 and -5.451), which is unusual and suggests poor intestinal absorption.

**10. Solubility:** Both ligands have negative solubility values (-1.049 and -2.059), which is also unusual and suggests poor aqueous solubility.

**11. hERG:** Both ligands have very low hERG inhibition liability (0.418 and 0.11).

**12. Cl_mic:** Ligand A (-35.478) has a negative clearance, which is not physically possible and likely indicates a very stable compound. Ligand B (-14.873) also has a negative clearance.

**13. t1/2:** Ligand A (-6.957) has a negative half-life, which is not physically possible. Ligand B (30.357) has a reasonable in vitro half-life.

**14. Pgp:** Both ligands have very low Pgp efflux liability (0.007 and 0.031).

**15. Binding Affinity:** Both ligands have excellent binding affinities (-8.3 and -8.6 kcal/mol), with Ligand B being slightly better.

**Overall Assessment:**

Despite the similar binding affinities, Ligand A is the more promising candidate. The significantly lower DILI risk is a major advantage. While both have poor predicted BBB penetration, the negative values for Caco-2, solubility, and half-life are concerning. However, negative values for clearance and half-life are not physically possible and likely indicate issues with the prediction model or input data. The low logP values for both are also a concern, but the strong binding affinity might compensate for this.

Considering the GPCR-specific priorities, the lower DILI risk of Ligand A outweighs the slightly better BBB and half-life of Ligand B.

Output:
0
2025-04-17 07:30:54,647 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (347.459 and 349.431 Da) fall comfortably within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (92.5) is slightly higher than Ligand B (84.67). Both are below the 90 A^2 threshold preferred for CNS targets, but B is better.

**3. logP:** Both ligands have good logP values (1.497 and 1.774), falling within the optimal 1-3 range.

**4. H-Bond Donors:** Ligand A has 2 HBD, and Ligand B has 1. Both are acceptable (<=5).

**5. H-Bond Acceptors:** Ligand A has 3 HBA, and Ligand B has 5. Both are acceptable (<=10).

**6. QED:** Ligand B (0.811) has a significantly better QED score than Ligand A (0.596), indicating a more drug-like profile.

**7. DILI:** Ligand B (38.658) has a lower DILI risk than Ligand A (18.108), which is preferable.

**8. BBB:** Ligand B (85.731) has a substantially better BBB percentile than Ligand A (65.103). This is *crucial* for a CNS target like DRD2.

**9. Caco-2 Permeability:** Ligand A (-5.078) has better Caco-2 permeability than Ligand B (-4.395).

**10. Aqueous Solubility:** Both ligands have very poor aqueous solubility (-3.206 and -3.163). This is a concern for both, but not a deciding factor between them.

**11. hERG Inhibition:** Both ligands have low hERG inhibition risk (0.173 and 0.263).

**12. Microsomal Clearance:** Ligand B (46.169) has higher microsomal clearance than Ligand A (41.2), suggesting faster metabolism and lower metabolic stability.

**13. In vitro Half-Life:** Ligand A (-12.079) has a much longer in vitro half-life than Ligand B (-1.256). This is a significant advantage for Ligand A.

**14. P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.053 and 0.287).

**15. Binding Affinity:** Ligand B (-8.7 kcal/mol) has a significantly stronger binding affinity than Ligand A (-0.0 kcal/mol). This is a major advantage, potentially outweighing some ADME concerns.

**Overall Assessment:**

While Ligand A has better Caco-2 permeability and in vitro half-life, Ligand B excels in the most critical areas for a CNS-targeting GPCR ligand: BBB penetration and binding affinity. The significantly stronger binding affinity of Ligand B (-8.7 kcal/mol vs -0.0 kcal/mol) is a decisive factor. The better QED and lower DILI risk further support its selection. The slightly higher clearance of Ligand B is a manageable concern compared to the substantial benefits in affinity and BBB.

Output:
1
2025-04-17 07:30:54,647 - INFO - Reasoning:

Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (342.399 and 348.399 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (94.05) is slightly higher than Ligand B (87.15), but both are below the 90-100 A^2 threshold desirable for CNS targets. Ligand B is preferable here.

**3. logP:** Ligand A (3.696) is within the optimal 1-3 range. Ligand B (-0.064) is significantly lower, which could hinder membrane permeability and CNS penetration. Ligand A is much better.

**4. H-Bond Donors:** Both ligands have 1 HBD, which is acceptable.

**5. H-Bond Acceptors:** Ligand A has 6 HBA, and Ligand B has 5. Both are below the 10 threshold.

**6. QED:** Ligand A (0.777) has a higher QED than Ligand B (0.57), indicating a more drug-like profile.

**7. DILI:** Ligand A (72.043) has a higher DILI risk than Ligand B (36.681). Ligand B is significantly better here.

**8. BBB:** Ligand A (72.082) has a better BBB percentile than Ligand B (61.923), though both are reasonably good.

**9. Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and suggests poor permeability. However, the scale is not specified, so it's difficult to interpret.

**10. Aqueous Solubility:** Both ligands have negative solubility values, which is also unusual and suggests poor solubility.

**11. hERG Inhibition:** Ligand A (0.49) has a slightly higher hERG inhibition liability than Ligand B (0.096). Ligand B is preferable.

**12. Microsomal Clearance:** Ligand A (86.181) has higher microsomal clearance than Ligand B (13.631), indicating lower metabolic stability. Ligand B is much better.

**13. In vitro Half-Life:** Ligand A (44.644) has a shorter half-life than Ligand B (-7.987). The negative value for Ligand B is concerning and likely an error.

**14. P-gp Efflux:** Ligand A (0.423) has lower P-gp efflux liability than Ligand B (0.055), which is desirable for CNS penetration. Ligand A is preferable.

**15. Binding Affinity:** Ligand A (-9.5 kcal/mol) has a significantly stronger binding affinity than Ligand B (-7.8 kcal/mol). This is a substantial advantage.

**Overall Assessment:**

While Ligand B has advantages in DILI, hERG, and microsomal clearance, Ligand A's superior logP, QED, P-gp efflux, and *especially* its significantly stronger binding affinity outweigh these drawbacks. The difference in binding affinity (>1.5 kcal/mol) is a major factor. The BBB values are acceptable for both, and while the solubility and Caco-2 values are concerning for both, the binding affinity is the most important factor for initial hit selection.

Output:
1
2025-04-17 07:30:54,647 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (349.435 and 344.411 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (118.4) is slightly above the ideal <90 for CNS targets, but still reasonable. Ligand B (71.78) is excellent, well below 90.

**logP:** Both ligands have good logP values (1.737 and 1.873), falling within the optimal 1-3 range.

**H-Bond Donors:** Ligand A has 2 HBD, which is acceptable. Ligand B has 1 HBD, also acceptable.

**H-Bond Acceptors:** Both ligands have 4 HBA, which is within the desirable limit of <=10.

**QED:** Ligand B (0.909) has a significantly better QED score than Ligand A (0.205), indicating a more drug-like profile.

**DILI:** Ligand A (15.2) has a much lower DILI risk than Ligand B (27.724), suggesting better hepatotoxicity potential.

**BBB:** Ligand B (76.774) has a significantly higher BBB penetration percentile than Ligand A (17.642). This is a *critical* advantage for a CNS target like DRD2.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.992 and -4.674), which is unusual and suggests poor permeability. However, these values are on a scale where negative values are possible, and direct comparison is difficult without knowing the scale's specifics.

**Aqueous Solubility:** Both ligands have negative solubility values (-1.346 and -2.494), again suggesting poor solubility. Similar to Caco-2, the scale is unknown.

**hERG Inhibition:** Both ligands show low hERG inhibition risk (0.162 and 0.232).

**Microsomal Clearance:** Ligand A (-3.423) has a much lower (better) microsomal clearance than Ligand B (18.464), indicating greater metabolic stability.

**In vitro Half-Life:** Ligand B (42.102) has a significantly longer in vitro half-life than Ligand A (-3.232). This is a positive attribute.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.039 and 0.038).

**Binding Affinity:** Ligand B (-9.1 kcal/mol) has a substantially stronger binding affinity than Ligand A (-6.2 kcal/mol). This is a major advantage, exceeding the 1.5 kcal/mol difference threshold.

**Overall Assessment:**

While Ligand A has better DILI and metabolic stability (lower Cl_mic), Ligand B excels in the most critical areas for a CNS GPCR target: **BBB penetration and binding affinity**. The significantly higher BBB value and stronger binding affinity of Ligand B outweigh the drawbacks of slightly higher DILI risk and faster clearance. The QED score also favors Ligand B. The poor Caco-2 and solubility values are concerning for both, but can be addressed through formulation strategies.

Output:
1
2025-04-17 07:30:54,648 - INFO - Reasoning:

Let's analyze Ligand A and Ligand B against the provided guidelines, prioritizing GPCR-specific properties (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (342.527 Da) is slightly lower, which is generally favorable for permeability.

**TPSA:** Ligand A (23.55) is excellent for CNS penetration, well below the 90 A^2 threshold. Ligand B (69.72) is higher, but still reasonably acceptable, though less ideal for CNS targets.

**logP:** Ligand A (4.183) is slightly above the optimal range (1-3), potentially leading to solubility issues or off-target interactions. Ligand B (2.837) is within the optimal range.

**H-Bond Donors/Acceptors:** Ligand A (0 HBD, 2 HBA) and Ligand B (1 HBD, 3 HBA) both have acceptable numbers of H-bond donors and acceptors.

**QED:** Both ligands have good QED scores (A: 0.742, B: 0.885), indicating drug-like properties.

**DILI:** Ligand A (5.118) has a very low DILI risk. Ligand B (46.801) is higher, but still within an acceptable range.

**BBB:** Ligand A (92.555) has excellent BBB penetration, exceeding the 70% threshold. Ligand B (83.094) is also good, but less favorable than Ligand A. This is a critical advantage for a CNS target like DRD2.

**Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and suggests a potential issue with the data or modeling. However, we'll proceed assuming these represent permeability estimates and that lower values indicate lower permeability.

**Aqueous Solubility:** Both have negative solubility values, which is also unusual and suggests a potential issue with the data or modeling.

**hERG Inhibition:** Ligand A (0.938) has a slightly higher hERG risk than Ligand B (0.637), but both are relatively low.

**Microsomal Clearance:** Ligand A (79.487) has a higher microsomal clearance than Ligand B (34.382), indicating faster metabolism and potentially lower *in vivo* exposure.

**In vitro Half-Life:** Ligand B (-28.922) has a much longer half-life than Ligand A (-7.321), which is a significant advantage.

**P-gp Efflux:** Ligand A (0.448) has lower P-gp efflux than Ligand B (0.089), meaning it's less likely to be pumped out of the brain, enhancing CNS exposure.

**Binding Affinity:** Ligand B (-8.6 kcal/mol) has a significantly stronger binding affinity than Ligand A (-7.8 kcal/mol). This 0.8 kcal/mol difference is substantial and can often outweigh minor ADME drawbacks.

**Overall Assessment:**

Ligand B has a superior binding affinity, a longer half-life, and better metabolic stability (lower Cl_mic). While Ligand A has a slightly better BBB score and lower P-gp efflux, the stronger binding affinity of Ligand B is crucial for a GPCR target, and its longer half-life is a significant advantage. The slightly higher logP of Ligand A is a concern, and the significantly better affinity of Ligand B outweighs the small advantage of Ligand A in BBB and P-gp.

Output:
1
2025-04-17 07:30:54,648 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (339.395 Da) is slightly lower, which could be advantageous for permeability.

**2. TPSA:** Both ligands have TPSA values below 90, which is good for CNS penetration. Ligand A (82.27) is slightly higher than Ligand B (76.66), but both are acceptable.

**3. logP:** Both ligands have logP values within the optimal range (1-3). Ligand A (1.812) and Ligand B (2.123) are both well within this range.

**4. H-Bond Donors:** Both ligands have 2 HBD, which is within the acceptable limit of <=5.

**5. H-Bond Acceptors:** Ligand A has 3 HBA, and Ligand B has 5 HBA, both within the acceptable limit of <=10.

**6. QED:** Ligand A (0.895) has a significantly better QED score than Ligand B (0.737), indicating a more drug-like profile.

**7. DILI:** Ligand A (78.48) has a higher DILI risk than Ligand B (46.142). This is a negative for Ligand A.

**8. BBB:** Ligand B (59.519) has a significantly better BBB penetration percentile than Ligand A (36.177). This is a critical advantage for a CNS target like DRD2.

**9. Caco-2 Permeability:** Ligand A (-4.931) has a much better Caco-2 permeability than Ligand B (-5.086), suggesting better intestinal absorption.

**10. Aqueous Solubility:** Ligand A (-3.748) has better aqueous solubility than Ligand B (-2.23).

**11. hERG Inhibition:** Ligand A (0.14) has a lower hERG inhibition liability than Ligand B (0.444), which is favorable.

**12. Microsomal Clearance:** Ligand B (27.438) has a much higher microsomal clearance than Ligand A (0.091), indicating lower metabolic stability.

**13. In vitro Half-Life:** Ligand B (29.188) has a longer in vitro half-life than Ligand A (-15.075).

**14. P-gp Efflux:** Ligand A (0.088) has lower P-gp efflux liability than Ligand B (0.116). Lower P-gp efflux is favorable for CNS exposure.

**15. Binding Affinity:** Both ligands have very similar binding affinities (-8.6 kcal/mol). The difference is negligible.

**Overall Assessment:**

While Ligand A has a better QED, solubility, Caco-2 permeability, hERG, and P-gp efflux, Ligand B significantly outperforms it in BBB penetration and has a lower DILI risk. For a CNS target like DRD2, BBB penetration is paramount. The lower DILI risk of Ligand B is also a significant advantage. Although Ligand B has higher P-gp efflux and lower solubility, the strong BBB penetration and lower DILI risk outweigh these drawbacks. The similar binding affinities mean potency isn't a differentiating factor.

Output:
1
2025-04-17 07:30:54,648 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (386.455 and 353.423 Da) fall within the ideal 200-500 Da range.

**TPSA:** Both ligands have TPSA values around 133-134, which is slightly above the optimal <90 for CNS targets, but not drastically so. This is a moderate concern for both.

**logP:** Ligand A (0.754) is borderline low, potentially hindering permeability. Ligand B (-0.766) is even lower, raising more significant permeability concerns.

**H-Bond Donors/Acceptors:** Ligand A (2 HBD, 7 HBA) is better balanced. Ligand B (4 HBD, 4 HBA) is acceptable but slightly higher in donors.

**QED:** Ligand A (0.753) has a good drug-likeness score. Ligand B (0.32) is significantly lower, indicating a less drug-like profile.

**DILI:** Ligand A (97.867) has a very high DILI risk, which is a major red flag. Ligand B (23.885) has a low DILI risk, a significant advantage.

**BBB:** Ligand A (39.473) has a poor BBB penetration percentile, making it unlikely to effectively reach the target in the CNS. Ligand B (71.888) has a much better BBB penetration percentile, exceeding the desirable >70 threshold for CNS targets.

**Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and suggests poor permeability. However, the scale is not defined, so the meaning of negative values is unclear.

**Aqueous Solubility:** Both have negative solubility values, also unusual. Again, the scale is undefined.

**hERG:** Both ligands show very low hERG inhibition liability (0.054 and 0.058), which is excellent.

**Microsomal Clearance:** Ligand A (1.039 mL/min/kg) has lower clearance, suggesting better metabolic stability. Ligand B (-8.685 mL/min/kg) has a negative clearance, which is not physically possible and likely indicates an issue with the data.

**In vitro Half-Life:** Ligand A (25.88 hours) has a reasonable half-life. Ligand B (-4.175 hours) has a negative half-life, which is impossible and indicates a data issue.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.105 and 0.003), which is favorable for CNS penetration.

**Binding Affinity:** Ligand A (-8.2 kcal/mol) has a slightly better binding affinity than Ligand B (-7.6 kcal/mol), but the difference is relatively small.

**Overall Assessment:**

Ligand A has better affinity and metabolic stability, but suffers from a very high DILI risk and poor BBB penetration. Ligand B has a much better safety profile (low DILI), significantly better BBB penetration, and acceptable P-gp efflux. The negative values for Caco-2, solubility, and clearance for Ligand B are concerning and suggest data quality issues. However, even with those data concerns, the superior BBB penetration and lower DILI risk of Ligand B outweigh the slightly weaker affinity compared to Ligand A, especially given the GPCR target and the need for CNS exposure.

Output:
1
2025-04-17 07:30:54,648 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (352.435 and 349.387 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (90.98) is excellent, falling below the 90 A^2 threshold for CNS targets. Ligand B (93.9) is slightly higher, but still acceptable.

**3. logP:** Ligand A (-0.209) is a bit low, potentially hindering permeability. Ligand B (0.759) is better, falling within the optimal 1-3 range.

**4. H-Bond Donors:** Ligand A (2) and Ligand B (1) are both within the acceptable limit of <=5.

**5. H-Bond Acceptors:** Ligand A (5) and Ligand B (6) are both within the acceptable limit of <=10.

**6. QED:** Both ligands have good QED scores (0.69 and 0.862, respectively), indicating good drug-like properties.

**7. DILI:** Ligand A (14.23) has a significantly lower DILI risk than Ligand B (67.429). This is a major advantage for Ligand A.

**8. BBB:** Ligand A (46.879) has a lower BBB penetration percentile than Ligand B (63.086). While both are not ideal (>70), Ligand B is better in this regard.

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.208 and -4.919), which is unusual and suggests poor permeability.

**10. Aqueous Solubility:** Both ligands have negative solubility values (-0.796 and -1.341), which is also unusual and suggests poor solubility.

**11. hERG Inhibition:** Both ligands have low hERG inhibition liability (0.185 and 0.204).

**12. Microsomal Clearance:** Ligand A (-38.777) has much lower (better) microsomal clearance than Ligand B (37.963), indicating greater metabolic stability.

**13. In vitro Half-Life:** Ligand A (-7.719) has a lower in vitro half-life than Ligand B (-4.535), which is less desirable.

**14. P-gp Efflux:** Ligand A (0.001) has a much lower P-gp efflux liability than Ligand B (0.045), which is crucial for CNS penetration.

**15. Binding Affinity:** Ligand A (-8.0) has a significantly stronger binding affinity than Ligand B (-0.0). This is a substantial advantage.

**Overall Assessment:**

Despite Ligand A's low logP and negative Caco-2/solubility values, its significantly stronger binding affinity (-8.0 vs -0.0 kcal/mol), lower DILI risk, lower P-gp efflux, and lower microsomal clearance make it the more promising candidate. The affinity difference is so large that it likely outweighs the permeability concerns, especially given the importance of potency for GPCR ligands. Ligand B's better BBB penetration is offset by its higher DILI risk and substantially weaker binding. The negative Caco-2 and solubility values for both are concerning and would need to be addressed through structural modifications, but the starting point of higher affinity and better safety with Ligand A is preferable.

Output:
1
2025-04-17 07:30:54,648 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (346.471 and 347.419 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (67.43) is better than Ligand B (70.91). Both are below the 90 A^2 threshold desirable for CNS targets, but A is closer to the ideal.

**3. logP:** Ligand A (2.293) is within the optimal 1-3 range. Ligand B (-0.725) is below 1, which might hinder permeation. This is a significant drawback for B.

**4. H-Bond Donors:** Ligand A (2) and Ligand B (0) are both acceptable (<=5).

**5. H-Bond Acceptors:** Ligand A (3) and Ligand B (6) are both acceptable (<=10).

**6. QED:** Both ligands have similar QED values (0.695 and 0.703), indicating good drug-likeness.

**7. DILI:** Ligand A (20.589) has a slightly higher DILI risk than Ligand B (17.255), but both are well below the concerning threshold of 60.

**8. BBB:** Both ligands have similar BBB penetration (53.587 and 51.842), which is acceptable but not ideal (>70 is preferred for CNS targets).

**9. Caco-2 Permeability:** Ligand A (-4.629) has worse Caco-2 permeability than Ligand B (-4.755). Both are negative, indicating poor permeability.

**10. Aqueous Solubility:** Ligand A (-3.175) has worse solubility than Ligand B (-0.224). Both are negative, indicating poor solubility.

**11. hERG Inhibition:** Both ligands have low hERG inhibition risk (0.12 and 0.251).

**12. Microsomal Clearance:** Ligand A (22.93) has higher microsomal clearance than Ligand B (5.393), suggesting lower metabolic stability.

**13. In vitro Half-Life:** Ligand B (20.94) has a significantly longer half-life than Ligand A (4.979).

**14. P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.069 and 0.005).

**15. Binding Affinity:** Ligand A (-8.1 kcal/mol) has a significantly stronger binding affinity than Ligand B (-7.1 kcal/mol). This is a >1 kcal/mol advantage, which can outweigh some ADME drawbacks.

**Overall Assessment:**

Ligand A has a much better binding affinity, which is the most critical factor. While Ligand B has slightly better metabolic stability and solubility, Ligand A's superior logP and binding affinity are more important for a CNS GPCR target like DRD2. The slightly higher DILI risk for A is not a major concern given the other properties. The lower Caco-2 and solubility for A are drawbacks, but can potentially be addressed with formulation strategies.

Output:
1
2025-04-17 07:30:54,648 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 drug candidates, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (344.371 and 346.431 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (92.68) is slightly higher than Ligand B (87.46), but both are below the 90 A^2 threshold desirable for CNS targets.

**3. logP:** Ligand A (1.648) is better than Ligand B (0.531). The optimal range is 1-3, and Ligand B is a bit low, potentially hindering permeation.

**4. H-Bond Donors:** Ligand A (0) is preferable to Ligand B (2). Fewer HBDs generally improve permeability.

**5. H-Bond Acceptors:** Ligand A (6) is slightly higher than Ligand B (5), but both are within the acceptable limit of 10.

**6. QED:** Both ligands have similar QED values (0.74 and 0.705), indicating good drug-likeness.

**7. DILI:** Ligand B (33.346) has a lower DILI risk than Ligand A (45.405), making it slightly more favorable in terms of liver toxicity.

**8. BBB:** Ligand A (67.623) has a significantly better BBB penetration percentile than Ligand B (39.395). This is a *critical* factor for a CNS target like DRD2.

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.842 and -4.77), which is unusual and suggests poor permeability. However, these values are on a scale where negative values are possible, and the absolute value is what matters. They are very similar.

**10. Aqueous Solubility:** Both ligands have negative solubility values (-1.615 and -2.348), indicating poor aqueous solubility. Ligand B is slightly worse.

**11. hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.157 and 0.242).

**12. Microsomal Clearance:** Ligand A (37.876) has a higher microsomal clearance than Ligand B (5.38), suggesting lower metabolic stability. Ligand B is much better here.

**13. In vitro Half-Life:** Ligand B (-13.9) has a longer in vitro half-life than Ligand A (-24.454), indicating better stability.

**14. P-gp Efflux:** Ligand A (0.034) has lower P-gp efflux liability than Ligand B (0.109), which is favorable for CNS exposure.

**15. Binding Affinity:** Both ligands have the same binding affinity (-7.9 kcal/mol), which is excellent.

**Overall Assessment:**

While Ligand B has advantages in DILI, metabolic stability (Cl_mic and t1/2), and P-gp efflux, the *significant* difference in BBB penetration (67.623 vs 39.395) heavily favors Ligand A. For a CNS target like DRD2, achieving sufficient brain exposure is paramount. The slightly better logP and lower HBD count of Ligand A also contribute to its favorability. The similar binding affinities mean that the ADME properties become the deciding factors.

Output:
0
2025-04-17 07:30:54,648 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (354.366 and 345.443 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (86.88) is better than Ligand B (91.32). Both are below the 90 A^2 threshold for CNS targets, but A is closer to the ideal.

**3. logP:** Ligand A (2.992) is optimal, while Ligand B (1.781) is slightly lower, potentially impacting permeability.

**4. H-Bond Donors:** Both ligands have 3 HBD, which is acceptable.

**5. H-Bond Acceptors:** Both ligands have 4 HBA, which is acceptable.

**6. QED:** Both ligands have similar QED values (0.484 and 0.47), indicating moderate drug-likeness.

**7. DILI:** Ligand A (99.341) has a very high DILI risk, which is a major concern. Ligand B (46.452) has a much lower, and acceptable, DILI risk.

**8. BBB:** Ligand A (56.068) has a moderate BBB penetration, while Ligand B (27.181) is quite low. For a CNS target like DRD2, BBB penetration is crucial.

**9. Caco-2:** Both ligands have negative Caco-2 values, which is unusual and suggests poor permeability. However, these values can be unreliable and should be interpreted cautiously.

**10. Solubility:** Both ligands have negative solubility values, which is also unusual.

**11. hERG:** Both ligands have low hERG inhibition risk (0.512 and 0.379).

**12. Cl_mic:** Ligand A (2.539) has a lower microsomal clearance, suggesting better metabolic stability than Ligand B (24.49).

**13. t1/2:** Ligand A (52.569) has a much longer in vitro half-life than Ligand B (-28.577).

**14. Pgp:** Ligand A (0.348) has lower P-gp efflux liability than Ligand B (0.068), which is favorable for CNS penetration.

**15. Binding Affinity:** Ligand A (-10.1 kcal/mol) has significantly stronger binding affinity than Ligand B (-7.8 kcal/mol). This is a substantial advantage.

**Overall Assessment:**

Despite Ligand A's superior binding affinity, metabolic stability, and Pgp profile, its extremely high DILI risk is a critical drawback. The poor BBB penetration is also concerning. Ligand B, while having weaker affinity, possesses a much better safety profile (DILI) and a more favorable (though still low) BBB score. The difference in binding affinity (2.3 kcal/mol) is significant, but a high DILI risk is often a project killer.

Considering the GPCR-specific priorities and the overall profile, Ligand B is the more viable candidate, even with its lower affinity. The DILI risk associated with Ligand A is too high to ignore, and further optimization would be needed to address this issue.

Output:
1
2025-04-17 07:30:54,648 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (358.345 and 358.507 Da) fall comfortably within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (96.69) is better than Ligand B (58.2). For CNS targets, we want TPSA <= 90, so Ligand A is closer to the threshold, while Ligand B is well within.

**3. logP:** Ligand B (4.085) is higher than Ligand A (0.376). While optimal logP is 1-3, Ligand B is slightly above, potentially causing solubility issues, but not drastically. Ligand A is quite low, which could hinder permeation.

**4. H-Bond Donors:** Both ligands have 2 HBD, which is within the acceptable limit of <=5.

**5. H-Bond Acceptors:** Ligand A has 6 HBA, and Ligand B has 3. Both are below the limit of <=10.

**6. QED:** Both ligands have similar QED values (0.742 and 0.747), indicating good drug-likeness.

**7. DILI:** Both ligands have similar DILI risk (50.989 and 52.966), both are acceptable.

**8. BBB:** Ligand A (72.858) has a significantly better BBB percentile than Ligand B (64.831). For CNS targets, >70 is desirable, and Ligand A is closer to this threshold.

**9. Caco-2 Permeability:** Ligand A (-4.616) has a worse Caco-2 permeability than Ligand B (-5.14). Lower values indicate lower permeability.

**10. Aqueous Solubility:** Ligand A (-2.393) has better aqueous solubility than Ligand B (-4.15).

**11. hERG Inhibition:** Ligand A (0.224) has a lower hERG inhibition risk than Ligand B (0.731), which is preferable.

**12. Microsomal Clearance:** Ligand A (-2.151) has a lower (better) microsomal clearance than Ligand B (78.19).

**13. In vitro Half-Life:** Ligand B (77.335) has a much longer in vitro half-life than Ligand A (-20.764). This is a significant advantage for dosing considerations.

**14. P-gp Efflux:** Ligand A (0.032) has a much lower P-gp efflux liability than Ligand B (0.518). Lower is better for CNS exposure.

**15. Binding Affinity:** Ligand B (-9.2 kcal/mol) has a stronger binding affinity than Ligand A (-7.9 kcal/mol). This is a substantial difference (>1.5 kcal/mol advantage).

**Overall Assessment:**

Ligand B has a significantly stronger binding affinity and a much better in vitro half-life. While its logP is slightly elevated, the substantial affinity advantage likely outweighs this. Ligand A has better BBB penetration and P-gp efflux, but the weaker binding and shorter half-life are major drawbacks. Considering the GPCR-specific priorities, the strong affinity of Ligand B is paramount, and its other properties are within acceptable ranges.

Output:
1
2025-04-17 07:30:54,649 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (385.961 and 370.871 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (61.44) is better than Ligand B (32.34). For a CNS target like DRD2, TPSA should be <=90, both are well within this range, but lower is preferred. Ligand B is significantly lower.

**3. logP:** Ligand A (3.311) is within the optimal 1-3 range. Ligand B (4.56) is slightly higher, potentially leading to solubility issues or off-target interactions, but still acceptable.

**4. H-Bond Donors:** Ligand A (2) is acceptable, while Ligand B (1) is even better. Both are below the threshold of 5.

**5. H-Bond Acceptors:** Ligand A (4) is acceptable, while Ligand B (2) is even better. Both are below the threshold of 10.

**6. QED:** Both ligands have good QED scores (0.788 and 0.824), indicating drug-like properties.

**7. DILI:** Ligand A (47.926) has a slightly higher DILI risk than Ligand B (39.201), but both are below the concerning threshold of 60.

**8. BBB:** This is a critical parameter for CNS targets. Ligand B (93.408) has a significantly higher BBB penetration percentile than Ligand A (73.168). This is a major advantage for Ligand B.

**9. Caco-2 Permeability:** Ligand A (-5.018) and Ligand B (-4.809) both have negative values, indicating poor permeability. This is a concern for both.

**10. Aqueous Solubility:** Both ligands have poor aqueous solubility (-3.957 and -4.684 respectively).

**11. hERG Inhibition:** Both ligands have low hERG inhibition risk (0.713 and 0.757).

**12. Microsomal Clearance:** Ligand A (14.293) has lower microsomal clearance than Ligand B (43.591), suggesting better metabolic stability.

**13. In vitro Half-Life:** Ligand B (32.613) has a significantly longer in vitro half-life than Ligand A (2.801). This is a significant advantage for Ligand B.

**14. P-gp Efflux:** Ligand A (0.093) has lower P-gp efflux than Ligand B (0.33), which is preferable for CNS penetration.

**15. Binding Affinity:** Ligand B (-8.1) has a slightly stronger binding affinity than Ligand A (-9.0). While A is slightly better, the difference is small and can be overcome by other factors.

**Overall Assessment:**

While Ligand A has slightly better affinity and P-gp efflux, Ligand B is superior overall for a CNS target like DRD2. The significantly higher BBB penetration (93.408 vs 73.168) and longer half-life (32.613 vs 2.801) are crucial advantages. The slightly higher logP of Ligand B is a minor concern, but the benefits outweigh this drawback.

Output:
1
2025-04-17 07:30:54,649 - INFO - Batch 371 complete. Total preferences: 5936
2025-04-17 07:30:54,649 - INFO - Processing batch 372/512...
2025-04-17 07:31:37,534 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (338.382 Da) is slightly lower, which could be advantageous for permeability.

**TPSA:** Ligand A (51.22) is significantly better than Ligand B (87.85). For CNS targets, TPSA should be <= 90, and A is comfortably within this range, while B is approaching the upper limit. This favors A.

**logP:** Ligand A (4.723) is slightly higher than the optimal range (1-3), but still potentially acceptable. Ligand B (3.08) is within the optimal range. However, for a CNS target, a slightly higher logP can be tolerated to aid BBB penetration, making A still competitive.

**H-Bond Donors/Acceptors:** Both have 1 HBD, which is good. Ligand A has 3 HBA, and Ligand B has 6. Lower HBA is generally preferred for better permeability, favoring A.

**QED:** Both ligands have similar QED values (0.732 and 0.648), indicating good drug-likeness.

**DILI:** Ligand A (93.292) has a higher DILI risk than Ligand B (60.915). This is a significant drawback for A.

**BBB:** Ligand B (77.162) has a substantially better BBB percentile than Ligand A (62.233). This is a critical factor for a CNS target like DRD2, strongly favoring B.

**Caco-2 Permeability:** Both have negative Caco-2 values (-4.617 and -4.613), which is unusual and suggests poor permeability. This is a concern for both, but doesn't differentiate them.

**Aqueous Solubility:** Both have negative solubility values (-5.685 and -4.539), indicating poor solubility. This is a concern for both, but doesn't differentiate them.

**hERG Inhibition:** Both have low hERG inhibition risk (0.696 and 0.657), which is good.

**Microsomal Clearance:** Ligand A (113.382) has higher microsomal clearance than Ligand B (108.576), suggesting lower metabolic stability. This favors B.

**In vitro Half-Life:** Ligand B (-27.49) has a significantly longer in vitro half-life than Ligand A (57.293), which is a major advantage for B.

**P-gp Efflux:** Both have low P-gp efflux liability (0.636 and 0.163), which is good, and B is better.

**Binding Affinity:** Ligand A (-9.7 kcal/mol) has a significantly stronger binding affinity than Ligand B (-7.6 kcal/mol). This is a substantial advantage for A. A difference of >1.5 kcal/mol can outweigh other drawbacks.

**Overall Assessment:**

Despite the higher DILI risk and slightly lower BBB for Ligand A, its *much* stronger binding affinity (-9.7 vs -7.6 kcal/mol) is a decisive factor. The affinity difference is large enough to potentially overcome the ADME liabilities. The improved TPSA and HBA count of A also contribute positively. While B has better BBB and metabolic stability, the potency advantage of A is paramount for a GPCR target, especially considering the potential for optimization to mitigate the DILI risk.

Output:
0
2025-04-17 07:31:37,535 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (347.415 and 344.423 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (106.57) is slightly above the ideal <90 for CNS targets, but still reasonable. Ligand B (100.86) is also slightly above, but better than A.

**3. logP:** Ligand A (1.597) is within the optimal 1-3 range. Ligand B (0.985) is a bit low, potentially impacting permeability.

**4. H-Bond Donors:** Both ligands have 2 HBD, which is within the acceptable limit of <=5.

**5. H-Bond Acceptors:** Ligand A has 5 HBA, within the acceptable limit of <=10. Ligand B has 8 HBA, also within the limit, but higher.

**6. QED:** Both ligands have QED values above 0.7, indicating good drug-likeness.

**7. DILI:** Ligand A (32.299) has a significantly lower DILI risk than Ligand B (54.478). This is a substantial advantage for Ligand A.

**8. BBB:** Ligand A (42.032) has a lower BBB percentile than Ligand B (59.984). While both are not ideal (>70), Ligand B is considerably better for CNS penetration.

**9. Caco-2:** Both have negative Caco-2 values, which is unusual and difficult to interpret without knowing the scale. It suggests poor permeability.

**10. Solubility:** Both ligands have negative solubility values, which is also unusual and suggests poor solubility.

**11. hERG:** Both ligands have very low hERG inhibition risk (0.178 and 0.068).

**12. Cl_mic:** Ligand B (9.987) has a significantly lower microsomal clearance than Ligand A (27.167), indicating better metabolic stability.

**13. t1/2:** Both ligands have similar in vitro half-lives (30.878 and 32.171 hours).

**14. Pgp:** Both ligands have very low P-gp efflux liability (0.037 and 0.004).

**15. Binding Affinity:** Ligand B (-8.1 kcal/mol) has a significantly stronger binding affinity than Ligand A (-6.9 kcal/mol). This is a >1.2 kcal/mol difference, which is a substantial advantage that can outweigh some ADME drawbacks.

**Overall Assessment:**

Ligand B has a superior binding affinity and better BBB penetration, which are crucial for a CNS target like DRD2. It also exhibits better metabolic stability (lower Cl_mic). However, Ligand A has a significantly lower DILI risk. The lower logP of Ligand B is a concern, but the strong affinity might compensate. Given the GPCR-specific priorities, the stronger binding affinity and better CNS penetration of Ligand B are more important than the slightly higher DILI risk and lower logP.

Output:
1
2025-04-17 07:31:37,535 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (349.406 and 348.443 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (76.64) is slightly higher than Ligand B (70.08). Both are below the 90 A^2 threshold desirable for CNS targets, but Ligand B is preferable.

**logP:** Both ligands have good logP values (1.522 and 1.084), falling within the optimal 1-3 range. Ligand B is slightly lower, which could slightly improve solubility.

**H-Bond Donors/Acceptors:** Ligand A has 2 HBD and 3 HBA, while Ligand B has 1 HBD and 4 HBA. Both are within acceptable limits (<=5 HBD and <=10 HBA).

**QED:** Both ligands have reasonable QED scores (0.85 and 0.775), indicating good drug-like properties.

**DILI:** Ligand A (40.209) has a slightly higher DILI risk than Ligand B (17.72). Ligand B is significantly better here.

**BBB:** Ligand B (71.035) has a better BBB penetration score than Ligand A (59.093). This is a critical factor for a CNS target like DRD2.

**Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and suggests a potential issue with the model or data. However, the magnitude of the negative value is similar, so it doesn't strongly differentiate the two.

**Aqueous Solubility:** Both ligands have negative solubility values, which is also unusual. Again, the values are similar.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.537 and 0.315).

**Microsomal Clearance:** Ligand B (12.539) has a significantly higher microsomal clearance than Ligand A (2.647), indicating faster metabolism and potentially lower *in vivo* exposure.

**In vitro Half-Life:** Ligand B (18.806) has a much longer half-life than Ligand A (-2.351). This is a significant advantage.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.039 and 0.074).

**Binding Affinity:** Ligand A (-8.8 kcal/mol) has a stronger binding affinity than Ligand B (-7.2 kcal/mol). This is a substantial difference (1.6 kcal/mol), which can outweigh some ADME drawbacks.

**Overall Assessment:**

While Ligand A has a superior binding affinity, Ligand B demonstrates a much more favorable ADME profile, particularly regarding BBB penetration (crucial for a CNS target), DILI risk, and *in vitro* half-life. The difference in binding affinity, while significant, might be overcome with further optimization of Ligand B. The higher metabolic clearance of Ligand B is a concern, but the longer half-life partially mitigates this. Given the GPCR-specific priorities, the better ADME properties of Ligand B make it the more promising candidate.

Output:
1
2025-04-17 07:31:37,535 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (345.349 Da) is slightly lower, which is generally favorable for permeability. Ligand B (383.539 Da) is also acceptable.

**2. TPSA:** Ligand A (84.22) is better than Ligand B (62.74) as it is closer to the ideal range for CNS targets (<=90).

**3. logP:** Both ligands have good logP values (A: 2.554, B: 2.215), falling within the optimal 1-3 range.

**4. H-Bond Donors:** Ligand A has 3 HBD, which is acceptable. Ligand B has 0, which is also acceptable.

**5. H-Bond Acceptors:** Ligand A has 3 HBA, which is acceptable. Ligand B has 6, which is still within the acceptable range of <=10.

**6. QED:** Both ligands have similar and good QED values (A: 0.732, B: 0.78), indicating good drug-like properties.

**7. DILI:** Ligand A (67.856) has a higher DILI risk than Ligand B (44.436). This is a negative for Ligand A.

**8. BBB:** Both ligands have good BBB penetration (A: 76.037, B: 73.517), exceeding the 70% threshold for CNS targets. Ligand A is slightly better.

**9. Caco-2:** Both have negative Caco-2 values, which is unusual and suggests poor permeability. However, the scale is not specified, so it's difficult to interpret.

**10. Solubility:** Both have negative solubility values, which is also unusual and suggests poor solubility. Again, the scale is not specified.

**11. hERG:** Both ligands have low hERG inhibition risk (A: 0.678, B: 0.42).

**12. Cl_mic:** Ligand A (10.079) has a significantly lower microsomal clearance than Ligand B (41.993), indicating better metabolic stability.

**13. t1/2:** Ligand A (26.147 hours) has a longer in vitro half-life than Ligand B (-15.443 hours). The negative value for Ligand B is concerning and likely indicates a very short half-life.

**14. Pgp:** Both ligands have low P-gp efflux liability (A: 0.172, B: 0.28).

**15. Binding Affinity:** Ligand A (-10.2 kcal/mol) has a significantly stronger binding affinity than Ligand B (-7.0 kcal/mol). This is a substantial advantage.

**Overall Assessment:**

Ligand A is superior due to its significantly stronger binding affinity (-10.2 vs -7.0 kcal/mol), better TPSA, lower Cl_mic, and longer half-life. While Ligand A has a slightly higher DILI risk, the substantial improvement in binding affinity and pharmacokinetic properties outweigh this concern, especially for a GPCR target where potency is crucial. The negative values for Caco-2 and solubility are concerning for both, but the superior affinity of Ligand A makes it more likely to be optimized to address these issues.

Output:
1
2025-04-17 07:31:37,535 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the acceptable range (200-500 Da). Ligand A (323.4) is slightly preferred as it's closer to the lower end, potentially aiding permeability.

**TPSA:** Ligand A (50.94) is significantly better than Ligand B (104.81). For CNS targets, TPSA should be <=90, and A is comfortably within this range, while B is pushing the limit.

**logP:** Ligand A (4.999) is high, but still within a potentially acceptable range. Ligand B (0.108) is *very* low, which is a major concern for CNS penetration. It likely won't cross cell membranes effectively.

**H-Bond Donors/Acceptors:** Both have reasonable HBD (2) and HBA (3 for A, 5 for B) counts, not raising significant flags.

**QED:** Both ligands have good QED scores (0.51 and 0.74), indicating drug-like properties.

**DILI:** Ligand A (85.653) has a higher DILI risk than Ligand B (64.831), but both are reasonably acceptable.

**BBB:** Both ligands have similar BBB penetration (52.811 for A, 57.425 for B). Neither is exceptional (>70), but they are in a similar range.

**Caco-2 Permeability:** Ligand A (-5.051) has poor Caco-2 permeability, while Ligand B (-4.865) is also poor, but slightly better.

**Aqueous Solubility:** Both have very poor aqueous solubility (-4.875 and -2.429 respectively). This could pose formulation challenges.

**hERG Inhibition:** Ligand A (0.93) has a slightly higher hERG risk than Ligand B (0.179).

**Microsomal Clearance:** Ligand A (14.484) has a moderate clearance, while Ligand B (-0.083) has a *very* low clearance, suggesting excellent metabolic stability.

**In vitro Half-Life:** Ligand A (32.518) has a moderate half-life, while Ligand B (0.887) has a very short half-life.

**P-gp Efflux:** Ligand A (0.668) has moderate P-gp efflux, while Ligand B (0.02) has very low P-gp efflux, which is favorable for CNS penetration.

**Binding Affinity:** Ligand B (-8.3 kcal/mol) has a significantly stronger binding affinity than Ligand A (-10.8 kcal/mol). This is a substantial advantage.

**Overall Assessment:**

Despite the stronger binding affinity of Ligand B, its extremely low logP is a critical drawback. It's unlikely to effectively cross the blood-brain barrier, rendering it unsuitable for a CNS target like DRD2. Ligand A, while having a higher logP and moderate Caco-2 permeability, has a more reasonable logP and TPSA, and a better balance of properties overall. The affinity difference is significant (1.5 kcal/mol), but the predicted poor CNS exposure of Ligand B outweighs this benefit.

Output:
1
2025-04-17 07:31:37,535 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 drug candidates, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (339.4 and 344.5 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (88.05) is better than Ligand B (58.2). Both are below the 90 A^2 threshold desirable for CNS targets, but A is closer to the upper limit.

**3. logP:** Both ligands have good logP values (3.21 and 3.32), falling within the optimal 1-3 range.

**4. H-Bond Donors:** Ligand A (3) is slightly higher than Ligand B (2), but both are acceptable (<=5).

**5. H-Bond Acceptors:** Ligand A (4) is higher than Ligand B (2), but both are within the acceptable range (<=10).

**6. QED:** Both ligands have similar QED values (0.799 and 0.726), indicating good drug-likeness.

**7. DILI:** Ligand A (73.013) has a higher DILI risk than Ligand B (27.453). This is a significant negative for Ligand A.

**8. BBB:** Ligand A (79.139) has a substantially better BBB penetration score than Ligand B (49.864). This is a crucial advantage for a CNS target like DRD2.

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.981 and -4.966), which is unusual and suggests poor permeability. This is a concern for both.

**10. Aqueous Solubility:** Both ligands have negative solubility values (-4.46 and -4.152), indicating poor aqueous solubility. This is also a concern for both.

**11. hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.343 and 0.271).

**12. Microsomal Clearance:** Both ligands have similar microsomal clearance values (19.643 and 18.961), suggesting similar metabolic stability.

**13. In vitro Half-Life:** Ligand A (56.099) has a much longer half-life than Ligand B (2.423). This is a significant advantage for Ligand A.

**14. P-gp Efflux:** Ligand A (0.201) has a lower P-gp efflux liability than Ligand B (0.175), suggesting better CNS exposure.

**15. Binding Affinity:** Ligand B (-8.4 kcal/mol) has a significantly stronger binding affinity than Ligand A (0.0 kcal/mol). This is a major advantage for Ligand B.

**Overall Assessment:**

Ligand B has a much stronger binding affinity, which is a critical factor. However, Ligand A has a better BBB score, longer half-life, and lower DILI risk. The poor Caco-2 and solubility for both are concerning, but can potentially be addressed with formulation strategies. The large difference in binding affinity outweighs the advantages of Ligand A.

Output:
1
2025-04-17 07:31:37,536 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (378.539) is slightly higher than Ligand B (341.455), but both are acceptable.

**TPSA:** Ligand A (112.81) is borderline for CNS penetration, being above the preferred <90, while Ligand B (71.09) is excellent for CNS targets. This is a significant advantage for Ligand B.

**logP:** Ligand A (-0.148) is quite low, potentially hindering membrane permeability. Ligand B (2.434) is within the optimal range (1-3). This is a clear advantage for Ligand B.

**H-Bond Donors/Acceptors:** Both ligands have 2 HBD and a reasonable number of HBA (5 and 3 respectively for Ligand B, 2 and 5 for Ligand A). No major concerns here.

**QED:** Both ligands have good QED scores (0.549 and 0.638), indicating good drug-like properties.

**DILI:** Ligand A (25.204) has a lower DILI risk than Ligand B (36.487), which is favorable.

**BBB:** Ligand A (48.972) has a concerningly low BBB penetration percentile. Ligand B (56.96) is better, but still not ideal (aim for >70). However, the other properties of Ligand B may compensate.

**Caco-2 Permeability:** Ligand A (-5.522) has poor Caco-2 permeability, while Ligand B (-4.535) is slightly better, but still not great.

**Aqueous Solubility:** Ligand A (-0.511) has poor aqueous solubility, while Ligand B (-3.738) is even worse. This could pose formulation challenges for both.

**hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.089 and 0.434), which is excellent.

**Microsomal Clearance:** Both ligands have similar microsomal clearance values (41.524 and 44.626), indicating moderate metabolic stability.

**In vitro Half-Life:** Ligand A (-36.317) has a very short in vitro half-life, while Ligand B (-16.736) is better, but still relatively short.

**P-gp Efflux:** Both ligands show very low P-gp efflux liability (0.002 and 0.106), which is favorable for CNS penetration.

**Binding Affinity:** Ligand B (-9.1 kcal/mol) has a significantly stronger binding affinity than Ligand A (-6.4 kcal/mol). This >1.5 kcal/mol difference is a major advantage, potentially outweighing some of the ADME drawbacks.

**Overall Assessment:**

Ligand B is the stronger candidate despite some ADME liabilities. Its superior logP, TPSA, and, most importantly, significantly higher binding affinity are crucial for a GPCR target like DRD2. While its BBB penetration and solubility are not ideal, the strong binding and low P-gp efflux could lead to sufficient brain exposure. Ligand A's very low logP, poor Caco-2 permeability, and low BBB penetration are significant drawbacks that are unlikely to be overcome.

Output:
1
2025-04-17 07:31:37,536 - INFO - Reasoning:

Let's analyze Ligand A and Ligand B for their potential as DRD2 drug candidates, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (350.415 and 402.651 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (88.1) is excellent, being below the 90 threshold for CNS targets. Ligand B (50.27) is also very good, well below the threshold.

**3. logP:** Ligand A (2.146) is optimal (1-3). Ligand B (3.646) is slightly higher but still acceptable, though approaching the upper limit where solubility issues could arise.

**4. H-Bond Donors:** Ligand A (2) is good. Ligand B (0) is also good, potentially improving membrane permeability.

**5. H-Bond Acceptors:** Ligand A (5) is good. Ligand B (6) is also acceptable.

**6. QED:** Both ligands have good QED scores (0.581 and 0.631, respectively), indicating drug-like properties.

**7. DILI:** Ligand A (21.442) has a significantly lower DILI risk than Ligand B (50.136). This is a major advantage for Ligand A.

**8. BBB:** Both ligands exhibit excellent BBB penetration (71.229 and 71.966), exceeding the desirable >70 threshold for CNS targets.

**9. Caco-2 Permeability:** Ligand A (-4.944) and Ligand B (-5.489) both have negative values, which is unusual. A higher value is generally preferred. However, given the good logP and TPSA values, this isn't a major concern.

**10. Aqueous Solubility:** Both ligands have poor aqueous solubility (-3.111 and -3.785). This could present formulation challenges, but is not a dealbreaker, especially with good permeability.

**11. hERG Inhibition:** Both ligands show low hERG inhibition risk (0.744 and 0.66), which is favorable.

**12. Microsomal Clearance:** Ligand A (38.248) has a higher microsomal clearance than Ligand B (35.322), suggesting potentially lower metabolic stability.

**13. In vitro Half-Life:** Ligand B (7.254) has a significantly longer in vitro half-life than Ligand A (-28.769). This is a substantial advantage for Ligand B.

**14. P-gp Efflux:** Both ligands have low P-gp efflux liability (0.093 and 0.399), which is good for CNS exposure.

**15. Binding Affinity:** Ligand A (-8.4 kcal/mol) has a considerably stronger binding affinity than Ligand B (-6.4 kcal/mol). This 2 kcal/mol difference is significant and can outweigh some ADME drawbacks.

**Overall Assessment:**

Ligand A has a superior binding affinity and lower DILI risk. Ligand B has a better half-life. Both have good BBB penetration, acceptable logP and TPSA, and low P-gp efflux. The solubility is a concern for both, but the strong affinity of Ligand A and its lower DILI risk make it the more promising candidate. The difference in affinity is substantial enough to offset the slightly higher clearance.

Output:
1
2025-04-17 07:31:37,536 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 drug candidates, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (347.463 Da) is slightly lower, which could be beneficial for permeability.

**TPSA:** Both ligands have TPSA values below 90, which is favorable for CNS penetration. Ligand B (68.52) is slightly better than Ligand A (80.12).

**logP:** Both ligands have logP values within the optimal range (1-3). Ligand A (1.556) is slightly lower, while Ligand B (2.765) is closer to the upper end of the range.

**H-Bond Donors/Acceptors:** Both ligands have acceptable HBD (1) and HBA (Ligand A: 5, Ligand B: 7) counts.

**QED:** Ligand A (0.896) has a significantly better QED score than Ligand B (0.699), indicating a more drug-like profile.

**DILI:** Ligand A (36.952) has a much lower DILI risk than Ligand B (51.221), which is a significant advantage.

**BBB:** Ligand B (80.341) has a substantially better BBB penetration score than Ligand A (48.662). This is a critical factor for a CNS target like DRD2.

**Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and suggests a potential issue with the data or modeling. However, the values are similar.

**Aqueous Solubility:** Both ligands have negative solubility values, again suggesting a potential data issue. The values are similar.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (Ligand A: 0.117, Ligand B: 0.294).

**Microsomal Clearance:** Ligand A (19.903) has a lower microsomal clearance than Ligand B (55.301), suggesting better metabolic stability.

**In vitro Half-Life:** Both ligands have similar in vitro half-lives (Ligand A: 17.272, Ligand B: 19.115).

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (Ligand A: 0.079, Ligand B: 0.243).

**Binding Affinity:** Ligand B (-7.2 kcal/mol) has a significantly stronger binding affinity than Ligand A (-0.0 kcal/mol). This is a major advantage, potentially outweighing some of the ADME drawbacks.

**Overall Assessment:**

Ligand B's superior binding affinity is a very strong point. However, its higher DILI risk and significantly lower QED are concerning. Ligand A has a better safety profile (lower DILI), better QED, and better metabolic stability, but its binding affinity is very weak. The BBB score of Ligand B is also much better, which is crucial for CNS targets.

Considering the GPCR-specific priorities, the strong binding affinity of Ligand B is the most important factor. While the other parameters are not ideal, the large difference in binding energy (-7.2 vs -0.0) suggests that Ligand B is more likely to be a viable starting point for optimization, despite its drawbacks. The ADME properties can be improved through medicinal chemistry efforts, but a weak binder is much harder to improve.

Output:
1
2025-04-17 07:31:37,536 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (346.471 Da) is slightly lower, which could be beneficial for permeability.

**2. TPSA:** Ligand A (42.01) is significantly better than Ligand B (66.88).  For CNS targets, we want TPSA <= 90, and A is comfortably within that range, while B is approaching the upper limit. This favors A.

**3. logP:** Both ligands have good logP values (A: 3.099, B: 3.504), falling within the optimal 1-3 range.

**4. H-Bond Donors:** Both have 0 HBD, which is acceptable.

**5. H-Bond Acceptors:** Ligand A (4) is better than Ligand B (6), but both are within the acceptable limit of <=10.

**6. QED:** Both ligands have reasonable QED values (A: 0.822, B: 0.732), indicating good drug-like properties.

**7. DILI:** Ligand B (82.319) has a significantly higher DILI risk than Ligand A (10.702). This is a major concern for B.

**8. BBB:** Ligand A (77.588) has a much better BBB penetration percentile than Ligand B (62.233).  For a CNS target like DRD2, >70 is desirable, and A is closer to this threshold.

**9. Caco-2:** Both have negative Caco-2 values, which is unusual and difficult to interpret without knowing the scale. However, the values are similar.

**10. Solubility:** Ligand A (-1.215) has slightly better solubility than Ligand B (-4.654).

**11. hERG:** Ligand A (0.779) has a lower hERG inhibition liability than Ligand B (0.243), indicating a lower risk of cardiotoxicity.

**12. Cl_mic:** Ligand A (6.517) has a much lower microsomal clearance than Ligand B (95.702), suggesting better metabolic stability.

**13. t1/2:** Ligand A (-6.306) has a longer in vitro half-life than Ligand B (-15.449).

**14. Pgp:** Ligand A (0.14) has lower P-gp efflux liability than Ligand B (0.081). Lower is better for CNS exposure.

**15. Binding Affinity:** Ligand A (-7.8 kcal/mol) has a slightly better binding affinity than Ligand B (-7.3 kcal/mol). While both are good, the 0.5 kcal/mol difference is noticeable and can outweigh some ADME drawbacks.

**Overall Assessment:**

Ligand A is significantly better across multiple critical ADME properties (DILI, BBB, Cl_mic, t1/2, Pgp) and has a slightly better binding affinity. While both ligands have acceptable logP and QED values, Ligand B's higher DILI risk and poorer BBB penetration are major drawbacks for a CNS-targeted drug. Ligand A's lower TPSA is also advantageous for CNS penetration.



Output:
0
2025-04-17 07:31:37,536 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (345.443 Da) and Ligand B (338.382 Da) are both acceptable.

**TPSA:** Ligand A (74.59) is above the optimal <90 for CNS targets, but still reasonable. Ligand B (40.62) is excellent, well below 90, suggesting better CNS penetration potential.

**logP:** Ligand A (3.886) is at the higher end of the optimal range (1-3), potentially raising concerns about solubility and off-target effects. Ligand B (2.222) is well within the optimal range.

**H-Bond Donors/Acceptors:** Ligand A (1 HBD, 4 HBA) is good. Ligand B (0 HBD, 2 HBA) is also good, with fewer hydrogen bonding groups potentially aiding permeability.

**QED:** Both ligands have acceptable QED values (A: 0.878, B: 0.776), indicating good drug-like properties.

**DILI:** Both ligands have moderate DILI risk (A: 54.75, B: 47.926), which isn't a major concern at these levels.

**BBB:** Ligand A (76.58) is good, exceeding the 70% threshold for CNS targets. Ligand B (87.476) is *excellent*, significantly higher, indicating a strong potential for brain penetration.

**Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and suggests a problem with the data. However, we can still compare them. Ligand A (-4.171) is worse than Ligand B (-4.36).

**Aqueous Solubility:** Both have negative solubility values, which is also unusual. Ligand A (-4.098) is slightly better than Ligand B (-3.585).

**hERG Inhibition:** Both ligands have low hERG inhibition risk (A: 0.699, B: 0.473), which is positive.

**Microsomal Clearance:** Ligand A (47.79) has a higher clearance than Ligand B (18.828), suggesting lower metabolic stability.

**In vitro Half-Life:** Ligand B (-11.122) has a negative half-life, which is problematic. Ligand A (13.562) is reasonable.

**P-gp Efflux:** Ligand A (0.142) has lower P-gp efflux than Ligand B (0.202), which is favorable for CNS penetration.

**Binding Affinity:** Ligand B (-9.4 kcal/mol) has a significantly stronger binding affinity than Ligand A (-7.5 kcal/mol) - a difference of 1.9 kcal/mol. This is a substantial advantage.

**Overall Assessment:**

Ligand B is superior. While both have some issues with Caco-2 and solubility data, Ligand B excels in the most critical areas for a CNS-targeting GPCR ligand: BBB penetration (87.476% vs 76.58%), binding affinity (-9.4 vs -7.5 kcal/mol), and lower P-gp efflux. The stronger affinity can potentially offset the slightly less favorable logP. The negative half-life for Ligand B is concerning, but the substantial affinity advantage makes it the more promising candidate, assuming the half-life issue can be addressed through structural modifications.

Output:
1
2025-04-17 07:31:37,537 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (345.414 and 359.535 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (47.56) is significantly better than Ligand B (29.54). For CNS targets, we want TPSA <= 90, and ideally lower. Ligand A is well within this range, while Ligand B is excellent.

**3. logP:** Both ligands have logP values (4.007 and 4.878) that are slightly above the optimal 1-3 range, but not drastically so. Ligand B is a bit higher, which *could* lead to solubility issues, but is still acceptable.

**4. H-Bond Donors:** Ligand A has 1 HBD, and Ligand B has 0. Both are within the acceptable limit of <=5.

**5. H-Bond Acceptors:** Ligand A has 4 HBA, and Ligand B has 3. Both are within the acceptable limit of <=10.

**6. QED:** Ligand A (0.804) has a better QED score than Ligand B (0.678), indicating a more drug-like profile.

**7. DILI:** Ligand A (49.981) has a higher DILI risk than Ligand B (22.024). This is a significant advantage for Ligand B.

**8. BBB:** Ligand B (73.866) has a substantially better BBB penetration percentile than Ligand A (60.644). This is *critical* for a CNS target like DRD2.

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.295 and -4.74). This is unusual and suggests poor permeability. However, these values are on a scale where negative values are possible and don't necessarily disqualify a compound.

**10. Aqueous Solubility:** Both ligands have negative solubility values (-5.495 and -5.433). Similar to Caco-2, this is not a direct disqualifier but indicates potential formulation challenges.

**11. hERG Inhibition:** Ligand A (0.777) has a slightly higher hERG inhibition risk than Ligand B (0.582), but both are reasonably low.

**12. Microsomal Clearance:** Ligand A (115.451) has a higher microsomal clearance than Ligand B (126.031), meaning it's less metabolically stable.

**13. In vitro Half-Life:** Ligand B (10.96) has a significantly longer in vitro half-life than Ligand A (5.353). This is a major advantage for Ligand B.

**14. P-gp Efflux:** Ligand A (0.213) has lower P-gp efflux than Ligand B (0.792), which is favorable for CNS penetration.

**15. Binding Affinity:** Ligand A (-7.7 kcal/mol) has a slightly better binding affinity than Ligand B (-7.5 kcal/mol). While a 0.2 kcal/mol difference is not huge, it's a positive for Ligand A.

**Overall Assessment:**

While Ligand A has a slightly better binding affinity and P-gp efflux, Ligand B is significantly better in almost all other crucial ADME properties, especially for a CNS target. Ligand B's superior BBB penetration (73.866 vs 60.644), lower DILI risk (22.024 vs 49.981), and longer half-life (10.96 vs 5.353) outweigh the small affinity difference. The lower TPSA of Ligand B is also beneficial.

Output:
1
2025-04-17 07:31:37,537 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (365.861 and 362.459 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (71.53) is significantly better than Ligand B (93.01). For CNS targets, we want TPSA <= 90, so Ligand A is preferable.

**3. logP:** Both ligands have good logP values (2.5 and 1.488), falling within the optimal 1-3 range. Ligand A is slightly better.

**4. H-Bond Donors:** Both have 1 HBD, which is acceptable.

**5. H-Bond Acceptors:** Ligand A has 4 HBAs, and Ligand B has 7. Both are within the acceptable limit of <=10, but Ligand A is better.

**6. QED:** Both ligands have good QED scores (0.567 and 0.87), indicating good drug-likeness. Ligand B is slightly better.

**7. DILI:** Ligand A (47.305) has a lower DILI risk than Ligand B (72.819), making it more favorable.

**8. BBB:** Ligand A (57.619) has a better BBB penetration percentile than Ligand B (43.932). While both are below the desirable >70 for CNS targets, A is closer.

**9. Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and suggests poor permeability. However, the scale is not specified, so we can't directly compare.

**10. Aqueous Solubility:** Both have negative solubility values, which is also unusual. Again, the scale is not specified.

**11. hERG Inhibition:** Both ligands show low hERG inhibition liability (0.511 and 0.191), which is good.

**12. Microsomal Clearance:** Ligand B (30.104) has significantly lower microsomal clearance than Ligand A (48.551), suggesting better metabolic stability. This is a significant advantage for Ligand B.

**13. In vitro Half-Life:** Ligand B (-1.062) has a better in vitro half-life than Ligand A (-7.635).

**14. P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.189 and 0.05), which is excellent for CNS penetration.

**15. Binding Affinity:** Ligand B (-8.4 kcal/mol) has a significantly stronger binding affinity than Ligand A (-7.5 kcal/mol). This >1.5 kcal/mol difference is a major advantage, potentially outweighing some ADME drawbacks.

**Overall Assessment:**

Ligand B has a significantly better binding affinity and improved metabolic stability (lower Cl_mic, better t1/2). While Ligand A has a better TPSA and lower DILI risk, the substantial affinity advantage of Ligand B, coupled with acceptable ADME properties, makes it the more promising candidate. The lower BBB for Ligand B is a concern, but the strong binding may compensate.

Output:
1
2025-04-17 07:31:37,537 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (345.447 and 348.462 Da) fall comfortably within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (98.17) is higher than the optimal <90 for CNS targets, but still potentially acceptable. Ligand B (40.62) is excellent, well below the threshold. This is a significant advantage for Ligand B.

**3. logP:** Both ligands have good logP values (2.476 and 2.337), falling within the 1-3 range.

**4. H-Bond Donors:** Ligand A has 1 HBD, which is good. Ligand B has 0, also good.

**5. H-Bond Acceptors:** Ligand A has 3 HBA, and Ligand B has 2. Both are within the acceptable limit of <=10.

**6. QED:** Ligand B (0.716) has a better QED score than Ligand A (0.47), indicating a more drug-like profile.

**7. DILI:** Ligand B (18.108) has a significantly lower DILI risk than Ligand A (27.026). This is a clear advantage for Ligand B.

**8. BBB:** Ligand B (92.943) has a much higher BBB penetration percentile than Ligand A (55.176). This is *critical* for a CNS target like DRD2, making Ligand B far more promising.

**9. Caco-2 Permeability:** Ligand A (-5.024) and Ligand B (-4.415) both have negative values, which is unusual and suggests poor permeability. However, the scale isn't fully defined, so it's hard to interpret the absolute difference.

**10. Aqueous Solubility:** Both ligands have poor aqueous solubility (-2.588 and -3.666). This could present formulation challenges, but isn't a dealbreaker if other properties are favorable.

**11. hERG Inhibition:** Ligand A (0.269) has a slightly lower hERG risk than Ligand B (0.668), which is preferable.

**12. Microsomal Clearance:** Ligand B (43.246) has a higher microsomal clearance than Ligand A (26.21), indicating faster metabolism and potentially lower *in vivo* exposure. This favors Ligand A.

**13. In vitro Half-Life:** Ligand B (2.447) has a shorter half-life than Ligand A (-1.193). This favors Ligand A.

**14. P-gp Efflux:** Ligand A (0.074) has lower P-gp efflux liability than Ligand B (0.198), which is beneficial for CNS penetration.

**15. Binding Affinity:** Ligand A (-9.4 kcal/mol) has a slightly better binding affinity than Ligand B (-8.0 kcal/mol). While a 1.4 kcal/mol difference is significant, the other ADME properties are more decisive in this case.

**Overall Assessment:**

Ligand B overwhelmingly outperforms Ligand A due to its superior BBB penetration, lower DILI risk, and better QED score. While Ligand A has slightly better affinity, lower P-gp efflux, and better metabolic stability, these advantages are outweighed by Ligand B's favorable CNS penetration profile, a critical factor for a DRD2 ligand. The lower TPSA of Ligand B is also a significant benefit.

Output:
1
2025-04-17 07:31:37,537 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B based on the provided guidelines, prioritizing GPCR properties (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (336.355) is slightly lower, which could be beneficial for permeability.

**TPSA:** Ligand A (86.86) is excellent for CNS penetration, well below the 90 A^2 threshold. Ligand B (96.89) is still reasonable but less optimal.

**logP:** Ligand A (1.342) is within the optimal range (1-3). Ligand B (0.132) is quite low, potentially hindering membrane permeability and CNS entry.

**H-Bond Donors & Acceptors:** Ligand A (HBD=1, HBA=7) and Ligand B (HBD=3, HBA=5) both fall within acceptable limits.

**QED:** Ligand A (0.727) has a significantly better QED score than Ligand B (0.405), indicating a more drug-like profile.

**DILI:** Ligand A (83.017) has a higher DILI risk than Ligand B (13.959), but both are reasonably low.

**BBB:** Ligand A (35.867) has a poor BBB percentile, a major drawback for a CNS target. Ligand B (44.668) is better, though still not ideal (aim for >70).

**Caco-2:** Both show poor Caco-2 permeability (-5.059 and -5.365). This suggests potential absorption issues, but is less critical for CNS targets where direct delivery is possible.

**Solubility:** Both ligands have negative solubility values, indicating poor aqueous solubility. This could be a formulation challenge.

**hERG:** Both ligands have very low hERG inhibition liability (0.549 and 0.188), which is excellent.

**Microsomal Clearance:** Ligand A (41.614) has higher microsomal clearance than Ligand B (22.176), suggesting lower metabolic stability.

**In vitro Half-Life:** Ligand A (-27.626) has a very short half-life, a significant negative. Ligand B (11.954) is better, though still not ideal.

**P-gp Efflux:** Ligand A (0.068) has lower P-gp efflux liability than Ligand B (0.01), which is favorable for CNS penetration.

**Binding Affinity:** Ligand A (-9.5 kcal/mol) has a significantly stronger binding affinity than Ligand B (-8.2 kcal/mol). This 1.3 kcal/mol difference is substantial and could outweigh some of the ADME drawbacks.

**Overall Assessment:**

Despite the strong binding affinity of Ligand A, its poor BBB penetration and short half-life are major concerns for a CNS-targeting drug. The low logP of Ligand B is problematic, but its better BBB and lower clearance, combined with acceptable (though not great) affinity, make it the more promising candidate. The superior QED of Ligand A is a plus, but cannot overcome the CNS penetration issue.

Output:
1
2025-04-17 07:31:37,537 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (362.47 and 354.426 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (58.2) is excellent, well below the 90 A^2 threshold for CNS targets. Ligand B (72.96) is still reasonable but less optimal.

**logP:** Ligand A (3.176) is within the optimal 1-3 range. Ligand B (-0.384) is significantly below this, potentially hindering membrane permeability and CNS penetration.

**H-Bond Donors/Acceptors:** Ligand A (2 HBD, 3 HBA) and Ligand B (1 HBD, 4 HBA) both have acceptable numbers of H-bond donors and acceptors.

**QED:** Both ligands have good QED scores (0.604 and 0.73), indicating drug-like properties.

**DILI:** Ligand A (47.732) has a slightly higher DILI risk than Ligand B (22.257), but both are below the concerning threshold of 60.

**BBB:** Ligand A (77.007) has a significantly better BBB percentile than Ligand B (64.482). This is a critical advantage for a CNS target like DRD2.

**Caco-2 Permeability:** Both ligands show poor Caco-2 permeability (-4.587 and -4.953). This is a concern, but can be mitigated if the compound exhibits good BBB penetration.

**Aqueous Solubility:** Both ligands have very poor aqueous solubility (-4.678 and -0.939). This could pose formulation challenges.

**hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.542 and 0.238).

**Microsomal Clearance:** Ligand A (62.377) has a higher microsomal clearance than Ligand B (-26.982), suggesting faster metabolism and potentially lower *in vivo* exposure.

**In vitro Half-Life:** Ligand A (15.543) has a longer half-life than Ligand B (2.678).

**P-gp Efflux:** Both ligands show low P-gp efflux liability (0.186 and 0.009).

**Binding Affinity:** Both ligands have comparable and excellent binding affinities (-8.7 and -8.6 kcal/mol). The difference is negligible.

**Conclusion:**

Considering the GPCR-specific priorities, Ligand A is the more promising candidate. While both have good affinity, Ligand A's superior TPSA, logP, and especially BBB penetration outweigh its slightly higher DILI and clearance. Ligand B's very low logP is a significant drawback for CNS penetration, and its lower BBB score further diminishes its potential. The poor Caco-2 and solubility are concerns for both, but are secondary to CNS penetration for this target.

Output:
1
2025-04-17 07:31:37,538 - INFO - Batch 372 complete. Total preferences: 5952
2025-04-17 07:31:37,538 - INFO - Processing batch 373/512...
2025-04-17 07:32:19,533 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (347.459 Da and 390.315 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Both ligands have TPSA values (75.44 and 74.09) below the 90 A^2 threshold desirable for CNS targets. This is a positive for both.

**3. logP:** Both ligands have logP values (2.763 and 2.692) within the optimal 1-3 range.

**4. H-Bond Donors:** Both have 1 HBD, which is within the acceptable limit of <=5.

**5. H-Bond Acceptors:** Ligand A has 4 HBAs, and Ligand B has 7. Both are below the 10 limit, but Ligand A is preferable.

**6. QED:** Both ligands have QED values (0.889 and 0.797) above 0.5, indicating good drug-likeness.

**7. DILI:** Ligand A (33.889) has a lower DILI risk than Ligand B (52.772), both are below the 60 threshold, but A is better.

**8. BBB:** Both ligands exhibit excellent BBB penetration (82.513% and 83.249%), exceeding the desirable >70% threshold for CNS targets.

**9. Caco-2 Permeability:** Ligand A (-4.674) and Ligand B (-5.338) both have negative values, indicating poor permeability. This is a concern for both, but B is slightly worse.

**10. Aqueous Solubility:** Both ligands have poor aqueous solubility (-3.012 and -3.421). This could pose formulation challenges.

**11. hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.357 and 0.12).

**12. Microsomal Clearance:** Ligand A (63.367) has higher microsomal clearance than Ligand B (10.862), indicating lower metabolic stability. This is a significant drawback for Ligand A.

**13. In vitro Half-Life:** Ligand A (-22.193) has a negative half-life, which is not possible. This is a major red flag. Ligand B (7.82) has a reasonable half-life.

**14. P-gp Efflux:** Ligand A (0.043) has slightly higher P-gp efflux than Ligand B (0.099), which is preferable.

**15. Binding Affinity:** Ligand A (-8.8 kcal/mol) has significantly stronger binding affinity than Ligand B (0.0 kcal/mol). This is a substantial advantage for Ligand A.

**Overall Assessment:**

Despite Ligand A's superior binding affinity, the negative in vitro half-life is a critical flaw. A negative half-life is not physically possible and indicates a severe issue with the data or the molecule's stability. Ligand B, while having weaker affinity, presents a much more reasonable ADME profile, with acceptable DILI, BBB, hERG, and a positive half-life. The slightly higher P-gp efflux and lower Caco-2 permeability are less concerning than the instability suggested by Ligand A's half-life. Given the importance of metabolic stability and a reasonable half-life for *in vivo* efficacy, Ligand B is the more viable drug candidate.

Output:
1
2025-04-17 07:32:19,533 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (352.435 and 350.463 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (96.55) is slightly above the optimal <90 for CNS targets, but still reasonable. Ligand B (80.48) is well within the desired range.

**logP:** Ligand A (0.881) is a bit low, potentially hindering permeation. Ligand B (1.703) is better, falling within the 1-3 optimal range.

**H-Bond Donors/Acceptors:** Ligand A (2 HBD, 5 HBA) and Ligand B (1 HBD, 6 HBA) both have acceptable counts, well below the thresholds of 5 and 10 respectively.

**QED:** Both ligands have good QED scores (0.759 and 0.894), indicating good drug-like properties.

**DILI:** Ligand A (52.695) has a moderate DILI risk, while Ligand B (26.25) has a significantly lower risk, which is a major advantage.

**BBB:** This is critical for a CNS target. Ligand A (45.56) has a poor BBB percentile, suggesting limited brain penetration. Ligand B (81.582) has excellent BBB penetration.

**Caco-2 Permeability:** Ligand A (-5.033) shows poor permeability, while Ligand B (-4.3) is slightly better, but still suboptimal.

**Aqueous Solubility:** Both ligands have poor aqueous solubility (-1.554 and -2.472), which could pose formulation challenges.

**hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.226 and 0.199).

**Microsomal Clearance:** Ligand A (3.612) has lower clearance, indicating better metabolic stability than Ligand B (11.924).

**In vitro Half-Life:** Ligand A (-14.673) has a very long half-life, a significant advantage. Ligand B (22.439) has a moderate half-life.

**P-gp Efflux:** Both ligands show low P-gp efflux (0.012 and 0.047), which is good for CNS exposure.

**Binding Affinity:** Ligand B (-7.6 kcal/mol) has a slightly better binding affinity than Ligand A (-8.1 kcal/mol). Although the difference isn't huge, it's still a positive factor.

**Overall Assessment:**

Ligand B is the stronger candidate. While Ligand A has a longer half-life and slightly better affinity, Ligand B excels in the most crucial areas for a CNS-targeting GPCR: BBB penetration and DILI risk. The better logP and TPSA of Ligand B also contribute to its improved profile. The solubility issues are a concern for both, but can be addressed through formulation strategies. The metabolic stability of Ligand A is good, but the poor BBB penetration is a dealbreaker for a CNS target.

Output:
1
2025-04-17 07:32:19,533 - INFO - Reasoning:

Let's analyze Ligand A and Ligand B based on the provided guidelines, prioritizing GPCR-specific properties (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (351.407 and 344.455 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (102.06) is better than Ligand B (66.48). For CNS targets, TPSA should be <= 90. Ligand B is well within this range, while Ligand A is slightly above, but not critically so.

**logP:** Ligand B (2.065) is optimal (1-3), while Ligand A (-1.547) is below 1, potentially hindering permeation. This is a significant drawback for Ligand A.

**H-Bond Donors/Acceptors:** Ligand A (2 HBD, 4 HBA) and Ligand B (1 HBD, 3 HBA) both have acceptable counts, well below the thresholds of 5 and 10 respectively.

**QED:** Both ligands have good QED scores (0.605 and 0.75), indicating drug-like properties.

**DILI:** Ligand B (13.843) has a much lower DILI risk than Ligand A (29.042), which is a substantial advantage.

**BBB:** Ligand B (67.119) is better than Ligand A (56.572), but both are below the desirable >70 percentile for CNS targets. However, given that DRD2 is a CNS target, a higher BBB is preferred.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.099 and -4.997), which is unusual and suggests poor permeability. This is a concern for both, but doesn't differentiate them.

**Aqueous Solubility:** Both ligands have negative solubility values (-1.246 and -2.387), indicating poor solubility. This is a concern for both, but doesn't differentiate them.

**hERG:** Both ligands have very low hERG inhibition risk (0.085 and 0.092).

**Microsomal Clearance:** Ligand A (-9.761) has significantly lower (better) microsomal clearance than Ligand B (12.942), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (5.721) has a positive half-life, while Ligand B (-24.151) has a negative half-life. This is highly unusual and suggests Ligand B is rapidly degraded.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.001 and 0.068).

**Binding Affinity:** Ligand B (-8.6 kcal/mol) has a slightly better binding affinity than Ligand A (-7.6 kcal/mol). While both are good, the 1 kcal/mol difference is notable.

**Overall Assessment:**

Ligand B is superior due to its optimal logP, lower DILI risk, better BBB penetration, and better binding affinity. While both have poor Caco-2 and solubility, the logP and DILI differences are critical. Ligand A's negative logP is a significant concern for CNS penetration, and its higher DILI risk is undesirable. Although Ligand A has better metabolic stability, the other factors outweigh this benefit. The negative half-life for Ligand B is concerning, but the other properties are much more favorable.

Output:
1
2025-04-17 07:32:19,533 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (346.406 and 381.567 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (60.25) is better than Ligand B (53.51). Both are below the 90 A^2 threshold for CNS targets, which is excellent.

**3. logP:** Both ligands have good logP values (2.42 and 2.873), falling within the optimal 1-3 range.

**4. H-Bond Donors:** Both have 0 HBD, which is acceptable.

**5. H-Bond Acceptors:** Both have 5 HBA, which is acceptable.

**6. QED:** Both ligands have similar QED values (0.806 and 0.787), indicating good drug-likeness.

**7. DILI:** Ligand A (56.146) has a higher DILI risk than Ligand B (20.861). This is a significant advantage for Ligand B.

**8. BBB:** Ligand A (83.404) has a slightly better BBB penetration percentile than Ligand B (76.851), both are good for CNS targets.

**9. Caco-2 Permeability:** Ligand A (-4.361) has a worse Caco-2 permeability than Ligand B (-4.987).

**10. Aqueous Solubility:** Ligand A (-2.384) has a worse aqueous solubility than Ligand B (-2.797).

**11. hERG Inhibition:** Both ligands have low hERG inhibition risk (0.383 and 0.613).

**12. Microsomal Clearance:** Ligand A (51.43) has a lower microsomal clearance than Ligand B (67.396), suggesting better metabolic stability.

**13. In vitro Half-Life:** Ligand B (-10.991) has a significantly longer in vitro half-life than Ligand A (-7.402). This is a major advantage for Ligand B.

**14. P-gp Efflux:** Ligand A (0.305) has a lower P-gp efflux liability than Ligand B (0.262), which is desirable for CNS penetration.

**15. Binding Affinity:** Ligand A (-8.3) has a slightly better binding affinity than Ligand B (-7.1). This is a 1.2 kcal/mol difference, which is significant.

**Overall Assessment:**

While Ligand A has slightly better affinity and BBB penetration, Ligand B demonstrates a superior ADME profile. Specifically, the significantly lower DILI risk and longer half-life of Ligand B are crucial advantages. The slightly lower P-gp efflux is also beneficial. The difference in binding affinity (1.2 kcal/mol) can potentially be overcome with further optimization, whereas mitigating the higher DILI risk of Ligand A would be more challenging. Given the GPCR-specific priorities, and the importance of a favorable ADME profile for CNS drugs, Ligand B is the more promising candidate.

Output:
1
2025-04-17 07:32:19,533 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (373.806 Da) is slightly higher than Ligand B (356.289 Da), but both are acceptable.

**TPSA:** Ligand A (35.58) is excellent for CNS penetration, well below the 90 A^2 threshold. Ligand B (131.59) is higher, but still potentially acceptable, though less ideal.

**logP:** Ligand A (3.044) is optimal. Ligand B (0.564) is low, potentially hindering membrane permeability and CNS entry.

**H-Bond Donors/Acceptors:** Both have a reasonable number of HBDs (1) and Ligand A has 2 HBAs, while Ligand B has 8. Ligand B's higher HBA count could impact permeability.

**QED:** Both ligands have good QED scores (A: 0.821, B: 0.844), indicating generally drug-like properties.

**DILI:** Ligand A (27.181) has a much lower DILI risk than Ligand B (87.01), which is a significant advantage.

**BBB:** Ligand A (92.555) has excellent predicted BBB penetration, exceeding the 70% threshold. Ligand B (80.419) is lower, though still reasonable, but less desirable for a CNS target.

**Caco-2 Permeability:** Both have negative Caco-2 values (-4.864 and -4.898), which is unusual and suggests poor permeability. However, these values are on a log scale and should be interpreted cautiously.

**Aqueous Solubility:** Both have negative solubility values (-3.953 and -3.058). Similar to Caco-2, these values are on a log scale and suggest poor solubility.

**hERG Inhibition:** Both ligands have low hERG risk (A: 0.882, B: 0.359).

**Microsomal Clearance:** Ligand A (17.023) has lower microsomal clearance than Ligand B (33.042), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (11.198) has a positive half-life, while Ligand B (-50.854) has a negative half-life, which is very concerning.

**P-gp Efflux:** Ligand A (0.235) has lower P-gp efflux than Ligand B (0.034), meaning it's less likely to be pumped out of the brain, improving CNS exposure.

**Binding Affinity:** Both have strong binding affinities (A: -8.7 kcal/mol, B: -8.3 kcal/mol), with Ligand A being slightly better. The 0.4 kcal/mol difference is significant.

**Overall Assessment:**

Ligand A is significantly better. It has a superior BBB score, lower DILI risk, better metabolic stability, lower P-gp efflux, and slightly better binding affinity. While both have poor predicted solubility and permeability, the other advantages of Ligand A, particularly for a CNS target like DRD2, outweigh this drawback. Ligand B's low logP and negative in vitro half-life are major red flags.

Output:
1
2025-04-17 07:32:19,533 - INFO - Reasoning:

Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (345.407 and 361.515 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (130.84) is borderline for CNS targets, slightly above the preferred <90, but acceptable. Ligand B (56.07) is excellent, well below 90, suggesting good CNS penetration potential.

**3. logP:** Ligand A (1.075) is at the lower end of optimal, potentially hindering permeability. Ligand B (3.005) is within the optimal range.

**4. H-Bond Donors:** Ligand A (4) is acceptable. Ligand B (0) is also good, potentially improving membrane permeability.

**5. H-Bond Acceptors:** Ligand A (6) is acceptable. Ligand B (7) is also acceptable.

**6. QED:** Both ligands (0.656 and 0.674) have good drug-likeness scores, above the 0.5 threshold.

**7. DILI:** Ligand A (55.758) has a moderate DILI risk, but still acceptable. Ligand B (37.379) has a lower, and more favorable, DILI risk.

**8. BBB:** Ligand A (58.317) has a moderate BBB penetration score, which is a concern for a CNS target like DRD2. Ligand B (80.38) has a very good BBB penetration score, highly desirable.

**9. Caco-2:** Both ligands have negative Caco-2 values (-5.699 and -5.184), which is unusual and difficult to interpret without further context. It suggests poor permeability.

**10. Solubility:** Both ligands have negative solubility values (-2.085 and -3.355), also unusual and suggesting poor aqueous solubility.

**11. hERG:** Ligand A (0.134) has a very low hERG risk, excellent. Ligand B (0.465) has a slightly higher, but still low, hERG risk.

**12. Cl_mic:** Ligand A (-6.239) has a negative clearance, which is also unusual. Ligand B (66.337) has a high microsomal clearance, indicating rapid metabolism and potentially lower *in vivo* exposure.

**13. t1/2:** Ligand A (-4.217) has a negative half-life, which is not physically meaningful. Ligand B (0.835) has a very short half-life, undesirable.

**14. Pgp:** Ligand A (0.002) has very low P-gp efflux, excellent. Ligand B (0.395) has a moderate P-gp efflux, which could limit CNS exposure.

**15. Binding Affinity:** Ligand A (-8.1) has a significantly stronger binding affinity than Ligand B (-6.8) - a difference of 1.3 kcal/mol. This is a substantial advantage.

**Overall Assessment:**

While Ligand A has a significantly better binding affinity, its negative values for Caco-2, solubility, and half-life are concerning and difficult to reconcile. Ligand B, despite a weaker affinity, has much better predicted CNS penetration (BBB, TPSA, Pgp) and a lower DILI risk. The high clearance and short half-life of Ligand B are drawbacks, but potentially addressable through structural modifications. Given the importance of BBB penetration for a CNS target like DRD2, and the questionable values for Ligand A, I would prioritize Ligand B for further optimization. The affinity difference, while significant, may be overcome with medicinal chemistry efforts.

Output:
1
2025-04-17 07:32:19,534 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (343.343 and 349.431 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (113.86) is better than Ligand B (107.53) as it is closer to the <90 threshold for CNS targets.

**logP:** Ligand A (1.451) is optimal (1-3), while Ligand B (0.161) is quite low, potentially hindering permeability.

**H-Bond Donors/Acceptors:** Ligand A (HBD=1, HBA=9) is preferable to Ligand B (HBD=4, HBA=4). Ligand B's higher HBD count could impact permeability.

**QED:** Ligand A (0.547) is better than Ligand B (0.37), indicating a more drug-like profile.

**DILI:** Ligand A (97.906) has a higher DILI risk than Ligand B (25.165). This is a significant drawback for Ligand A.

**BBB:** Ligand A (68.282) is moderately good, while Ligand B (37.379) is poor for CNS penetration. This is a critical difference given the target.

**Caco-2 Permeability:** Ligand A (-4.831) is better than Ligand B (-5.336) indicating better intestinal absorption.

**Aqueous Solubility:** Ligand A (-3.433) is better than Ligand B (-1.767).

**hERG:** Both ligands have very low hERG inhibition risk (0.335 and 0.062).

**Microsomal Clearance:** Ligand A (66.964) has higher clearance than Ligand B (14.702), indicating lower metabolic stability.

**In vitro Half-Life:** Ligand A (-22.172) has a shorter half-life than Ligand B (-10.267).

**P-gp Efflux:** Ligand A (0.074) has lower P-gp efflux than Ligand B (0.017), which is beneficial for CNS exposure.

**Binding Affinity:** Ligand B (-8.7 kcal/mol) has a significantly stronger binding affinity than Ligand A (-7.5 kcal/mol). This 1.2 kcal/mol difference is substantial and can outweigh some ADME concerns.

**Overall Assessment:**

Ligand A has better TPSA, logP, QED, Caco-2 permeability, solubility, and P-gp efflux. However, it suffers from higher DILI risk, higher clearance, and shorter half-life. Crucially, its BBB penetration is only moderate.

Ligand B has a much stronger binding affinity, significantly lower DILI risk, and better metabolic stability (lower clearance, longer half-life). While its logP is low and BBB penetration is poor, the strong binding affinity is a major advantage for a GPCR target. The lower logP and BBB can potentially be addressed through further optimization, but a strong initial affinity is harder to achieve.

Considering the GPCR-specific priorities, the strong binding affinity of Ligand B is the deciding factor. The lower BBB penetration is a concern, but can be addressed in later stages of optimization. The lower DILI risk is also a significant advantage.

Output:
1
2025-04-17 07:32:19,534 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (352.406 and 350.547 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (76.66) is slightly higher than Ligand B (58.2). Both are below the 90 A^2 threshold for CNS targets, but B is preferable.

**3. logP:** Ligand A (2.085) and Ligand B (4.04) are both within the optimal range of 1-3, but Ligand B is pushing the upper limit.

**4. H-Bond Donors:** Both ligands have 2 HBD, which is within the acceptable limit of <=5.

**5. H-Bond Acceptors:** Ligand A has 4 HBA, and Ligand B has 2. Both are below the acceptable limit of <=10.

**6. QED:** Both ligands have good QED scores (0.632 and 0.694, respectively), indicating good drug-like properties.

**7. DILI:** Ligand A (40.946) has a slightly higher DILI risk than Ligand B (18.302), but both are below the concerning threshold of 60.

**8. BBB:** Both ligands have excellent BBB penetration (88.29% and 84.219%), which is crucial for a CNS target like DRD2. Ligand A is slightly better.

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 values, which is unusual and suggests poor permeability. However, these values are on a strange scale, so it's hard to interpret.

**10. Aqueous Solubility:** Both ligands have negative solubility values, which is also unusual.

**11. hERG Inhibition:** Both ligands have low hERG inhibition risk (0.422 and 0.533), which is good.

**12. Microsomal Clearance:** Ligand A (28.219) has significantly lower microsomal clearance than Ligand B (82.7), indicating better metabolic stability.

**13. In vitro Half-Life:** Ligand A (11.273) has a longer in vitro half-life than Ligand B (4.045), which is desirable.

**14. P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.107 and 0.161), which is excellent for CNS penetration.

**15. Binding Affinity:** Ligand A (-8.7 kcal/mol) has a slightly better binding affinity than Ligand B (-8.1 kcal/mol). While the difference is not huge, it is greater than 1.5 kcal/mol.

**Overall Assessment:**

Considering all parameters, **Ligand A** is the more promising candidate. It has a slightly better BBB score, significantly better metabolic stability (lower Cl_mic, longer t1/2), and a stronger binding affinity. While Ligand B has a lower TPSA and slightly better DILI, the advantages of Ligand A in terms of metabolic stability and binding outweigh these minor differences, especially for a GPCR target where CNS penetration and potency are paramount. The negative solubility and Caco-2 values are concerning for both, but the better overall profile of A makes it the preferred choice.

Output:
0
2025-04-17 07:32:19,534 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (345.487 and 346.471 Da) fall comfortably within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (43.86) is significantly better than Ligand B (60.85). For CNS targets, we want TPSA <= 90, and ideally closer to 60. Ligand A is much closer to this ideal.

**3. logP:** Both ligands have acceptable logP values (1.576 and 2.276), falling within the optimal 1-3 range.

**4. H-Bond Donors:** Ligand A (0) is preferable to Ligand B (1). Fewer HBDs generally improve permeability.

**5. H-Bond Acceptors:** Both ligands have 3 HBA, which is acceptable (<=10).

**6. QED:** Ligand A (0.763) has a significantly better QED score than Ligand B (0.472), indicating a more drug-like profile.

**7. DILI:** Ligand A (6.282) has a much lower DILI risk than Ligand B (20.008). Both are below 40, so acceptable, but A is clearly better.

**8. BBB:** Both ligands exhibit good BBB penetration (72.741 and 77.2). Both are above the desirable 70% threshold for CNS targets. Ligand B is slightly better.

**9. Caco-2 Permeability:** Ligand A (-4.692) is better than Ligand B (-4.514), indicating better intestinal absorption.

**10. Aqueous Solubility:** Ligand A (-2.579) is better than Ligand B (-1.487), indicating better solubility.

**11. hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.477 and 0.328).

**12. Microsomal Clearance:** Ligand A (33.835) has a higher microsomal clearance than Ligand B (12). Lower clearance is preferred for metabolic stability, so Ligand B is better here.

**13. In vitro Half-Life:** Ligand A (14.901) has a longer half-life than Ligand B (-24.305). Longer half-life is desirable.

**14. P-gp Efflux:** Ligand A (0.013) has much lower P-gp efflux than Ligand B (0.17). Lower efflux is crucial for CNS exposure.

**15. Binding Affinity:** Ligand B (-8.0) has a slightly better binding affinity than Ligand A (-7.5). However, the difference is only 0.5 kcal/mol, which is not substantial enough to outweigh the numerous advantages of Ligand A.

**Overall Assessment:**

Ligand A consistently outperforms Ligand B across most critical ADME properties (TPSA, QED, DILI, solubility, P-gp efflux, half-life) and has a comparable, though slightly weaker, binding affinity. The slightly better BBB penetration of Ligand B is not enough to offset the significant advantages of Ligand A, especially considering the importance of low P-gp efflux and good CNS penetration for a DRD2 ligand.

Output:
1
2025-04-17 07:32:19,534 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B based on the provided guidelines, prioritizing GPCR-specific properties (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (369.372 and 353.482 Da) fall within the ideal range of 200-500 Da.

**TPSA:** Ligand A (72.18) is higher than Ligand B (43.86). For a CNS target like DRD2, TPSA should be <=90, so both are acceptable, but B is significantly better.

**logP:** Ligand A (3.394) is within the optimal range (1-3), while Ligand B (2.058) is closer to the lower limit. Both are acceptable, but A is slightly preferred.

**H-Bond Donors/Acceptors:** Ligand A (1 HBD, 6 HBA) and Ligand B (0 HBD, 3 HBA) both have reasonable numbers of H-bond donors and acceptors, well within the guidelines.

**QED:** Both ligands have acceptable QED values (A: 0.765, B: 0.671), indicating good drug-like properties.

**DILI:** Ligand A (91.082) has a higher DILI risk than Ligand B (8.996). This is a significant negative for Ligand A.

**BBB:** Ligand B (96.123) has a much higher BBB penetration percentile than Ligand A (72.741). This is a critical advantage for a CNS target.

**Caco-2 Permeability:** Both have negative values, which is unusual and difficult to interpret without knowing the scale. However, the values are similar (-4.836 and -4.492).

**Aqueous Solubility:** Both have negative values, again unusual, but similar in magnitude (-4.117 and -2.169).

**hERG Inhibition:** Ligand A (0.383) has a slightly higher hERG risk than Ligand B (0.655), but both are reasonably low.

**Microsomal Clearance:** Ligand A (34.889) and Ligand B (39.221) have similar microsomal clearance values.

**In vitro Half-Life:** Ligand B (-0.332) has a negative half-life, which is impossible. This is a major red flag. Ligand A (20.74) has a reasonable half-life.

**P-gp Efflux:** Ligand A (0.444) has lower P-gp efflux liability than Ligand B (0.023). Lower efflux is better for CNS exposure.

**Binding Affinity:** Ligand A (-8.2 kcal/mol) has a significantly stronger binding affinity than Ligand B (-6.7 kcal/mol). This is a substantial advantage, potentially outweighing some ADME drawbacks.

**Overall Assessment:**

Ligand B has a much better BBB score and significantly lower DILI risk, which are crucial for a CNS drug. However, its half-life is impossible, which is a fatal flaw. Ligand A has a superior binding affinity and a reasonable half-life, despite a higher DILI risk and slightly lower BBB penetration. Given the strong affinity of Ligand A, and the implausible half-life of Ligand B, Ligand A is the more promising candidate, assuming the DILI risk can be mitigated through structural modifications.

Output:
1
2025-04-17 07:32:19,534 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (352.475 and 366.443 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (78.87) is significantly better than Ligand B (104.43). For CNS targets, we want TPSA <= 90, and A is comfortably within that range, while B is pushing the limit.

**logP:** Ligand A (2.182) is optimal (1-3), while Ligand B (0.21) is quite low, potentially hindering membrane permeability.

**H-Bond Donors/Acceptors:** Ligand A (HBD=2, HBA=4) and Ligand B (HBD=1, HBA=6) both have reasonable numbers of H-bond donors and acceptors, within the guidelines.

**QED:** Ligand B (0.82) has a better QED score than Ligand A (0.492), suggesting a more drug-like profile overall. However, QED isn't as crucial as other factors for CNS penetration.

**DILI:** Ligand A (19.426) has a much lower DILI risk than Ligand B (69.639), which is a significant advantage.

**BBB:** Both ligands have reasonable BBB penetration (A: 56.611, B: 59.636), but neither exceeds the desirable >70 threshold.

**Caco-2 Permeability:** Both have negative Caco-2 values (-4.784 and -4.963), which is unusual and suggests poor permeability.

**Aqueous Solubility:** Both have negative solubility values (-2.292 and -3.29), indicating very poor aqueous solubility. This is a concern for formulation.

**hERG Inhibition:** Both ligands show low hERG inhibition risk (A: 0.258, B: 0.529).

**Microsomal Clearance:** Ligand B (2.04) has significantly lower microsomal clearance than Ligand A (33.381), indicating better metabolic stability.

**In vitro Half-Life:** Ligand A (-5.454) has a more negative half-life, which is not ideal. Ligand B (-2.062) is better, but still not great.

**P-gp Efflux:** Both ligands show very low P-gp efflux liability (A: 0.044, B: 0.033).

**Binding Affinity:** Ligand B (-8.3) has a slightly better binding affinity than Ligand A (-8.0), but the difference is small (0.3 kcal/mol).

**Overall Assessment:**

Ligand A has a better TPSA and logP, and a much lower DILI risk. Ligand B has a better QED and slightly better affinity and metabolic stability. However, the poor logP of Ligand B is a major drawback for CNS penetration, and the higher DILI risk is also concerning. The slightly better affinity of Ligand B isn't enough to overcome these significant issues. Given the GPCR-specific priorities, the better TPSA, logP, and lower DILI risk of Ligand A make it the more promising candidate, despite its lower QED and less favorable half-life.

Output:
0
2025-04-17 07:32:19,534 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (353.463 and 347.375 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (87.74) is excellent, falling well below the 90 Angstroms threshold for CNS targets. Ligand B (114.39) is still reasonable but less optimal, being above 100.

**3. logP:** Ligand A (0.683) is a bit low, potentially hindering permeability. Ligand B (1.256) is better, falling within the optimal 1-3 range.

**4. H-Bond Donors:** Both ligands have acceptable HBD counts (2 and 1 respectively), well below the 5 limit.

**5. H-Bond Acceptors:** Ligand A (4) is good. Ligand B (7) is also acceptable, but approaching the upper limit of 10.

**6. QED:** Both ligands have reasonable QED scores (0.705 and 0.595), indicating good drug-like properties.

**7. DILI:** Ligand A (11.361) has a significantly lower DILI risk than Ligand B (71.656), which is a substantial advantage.

**8. BBB:** Ligand A (60.644) has a moderate BBB penetration, while Ligand B (51.803) is lower. Both are below the desirable >70 for CNS targets, but A is better.

**9. Caco-2 Permeability:** Both have negative Caco-2 values (-5.056 and -4.697), which is unusual and suggests poor permeability. This is a concern for both.

**10. Aqueous Solubility:** Both have negative solubility values (-1.482 and -2.134), indicating poor aqueous solubility. This is a significant drawback for both.

**11. hERG Inhibition:** Both ligands show very low hERG inhibition risk (0.198 and 0.224), which is excellent.

**12. Microsomal Clearance:** Ligand A (-11.218) has a much lower (better) microsomal clearance than Ligand B (34.301), indicating greater metabolic stability.

**13. In vitro Half-Life:** Ligand A (-1.65) has a slightly better in vitro half-life than Ligand B (-6.775).

**14. P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.01 and 0.318), which is favorable for CNS penetration.

**15. Binding Affinity:** Both ligands have the same binding affinity (-8.1 kcal/mol), which is excellent and strong.

**Overall Assessment:**

Despite both having excellent binding affinity, Ligand A is the more promising candidate. Its superior TPSA, significantly lower DILI risk, better BBB penetration (though still suboptimal), and much lower microsomal clearance outweigh the slightly lower logP and negative Caco-2/Solubility values. The negative Caco-2 and Solubility are concerning for both, but can potentially be addressed through formulation strategies. The lower DILI risk is a critical advantage for clinical development.

Output:
0
2025-04-17 07:32:19,534 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (397.232 Da) is slightly higher than Ligand B (344.459 Da), but both are acceptable.

**2. TPSA:** Both ligands have TPSA values below 90 (Ligand A: 70.63, Ligand B: 67.23), which is favorable for CNS penetration.

**3. logP:** Both ligands have optimal logP values (Ligand A: 3.003, Ligand B: 1.947), falling within the 1-3 range.

**4. H-Bond Donors/Acceptors:** Ligand A has 0 HBD and 5 HBA, while Ligand B has 1 HBD and 4 HBA. Both are within acceptable limits (HBD <= 5, HBA <= 10).

**5. QED:** Both ligands have good QED scores (Ligand A: 0.633, Ligand B: 0.733), indicating drug-like properties.

**6. DILI:** Ligand A has a higher DILI risk (83.637%) compared to Ligand B (36.448%). This is a significant drawback for Ligand A.

**7. BBB:** Ligand B has a slightly better BBB penetration percentile (69.833%) than Ligand A (59.791%), though both are below the desirable >70% for CNS targets.

**8. Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and suggests poor permeability.

**9. Aqueous Solubility:** Both ligands have negative solubility values, indicating poor aqueous solubility.

**10. hERG Inhibition:** Ligand A has a slightly higher hERG inhibition risk (0.858) than Ligand B (0.285).

**11. Microsomal Clearance:** Ligand B has a lower microsomal clearance (40.116) than Ligand A (80.85), suggesting better metabolic stability.

**12. In vitro Half-Life:** Ligand B has a negative in vitro half-life (-8.755), which is concerning and likely indicates rapid degradation. Ligand A has a half-life of 11.163 hours, which is more reasonable.

**13. P-gp Efflux:** Ligand A has no P-gp efflux liability (0.693), while Ligand B has a low efflux liability (0.177). Both are good.

**14. Binding Affinity:** Ligand B has a significantly stronger binding affinity (-7.4 kcal/mol) than Ligand A (-0.0 kcal/mol). This is a crucial difference.

**Overall Assessment:**

Ligand B is the more promising candidate despite the negative Caco-2 and solubility values, and the concerning half-life. The significantly stronger binding affinity (-7.4 kcal/mol vs -0.0 kcal/mol) is a major advantage that can potentially outweigh the ADME drawbacks. The lower DILI risk and better metabolic stability (lower Cl_mic) also favor Ligand B. Ligand A's high DILI risk is a significant concern. While Ligand A has a better half-life, the affinity difference is too large to ignore.

Output:
1
2025-04-17 07:32:19,535 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (346.45 & 348.40 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (49.41) is excellent, well below the 90 A^2 threshold for CNS targets. Ligand B (84.86) is higher but still potentially acceptable, though less ideal.

**3. logP:** Ligand A (2.917) is optimal (1-3). Ligand B (0.585) is low, potentially hindering permeation.

**4. H-Bond Donors:** Ligand A (1) is good. Ligand B (0) is also acceptable.

**5. H-Bond Acceptors:** Ligand A (2) is good. Ligand B (6) is higher, but still within the acceptable limit of 10.

**6. QED:** Both ligands have good QED scores (0.523 and 0.791), indicating drug-like properties.

**7. DILI:** Ligand A (24.622) has a lower DILI risk than Ligand B (42.613), which is preferable.

**8. BBB:** Ligand A (80.613) has a significantly better BBB penetration percentile than Ligand B (68.36). This is *critical* for a CNS target like DRD2.

**9. Caco-2 Permeability:** Ligand A (-4.534) and Ligand B (-4.377) both have negative values, which is unusual and requires further investigation. However, the values are similar.

**10. Aqueous Solubility:** Ligand A (-2.822) and Ligand B (-1.232) both have negative values, indicating poor solubility. This is a concern, but can be addressed with formulation strategies.

**11. hERG Inhibition:** Ligand A (0.853) has a lower hERG risk than Ligand B (0.235).

**12. Microsomal Clearance:** Ligand A (79.761) has a higher microsomal clearance than Ligand B (15.133), suggesting lower metabolic stability.

**13. In vitro Half-Life:** Ligand A (21.408) has a longer half-life than Ligand B (-11.879), which is desirable.

**14. P-gp Efflux:** Ligand A (0.446) has lower P-gp efflux liability than Ligand B (0.015), which is beneficial for CNS exposure.

**15. Binding Affinity:** Ligand B (-8.9 kcal/mol) has a slightly stronger binding affinity than Ligand A (-7.6 kcal/mol). However, the difference is not substantial enough to overcome the significant ADME advantages of Ligand A.

**Overall Assessment:**

Ligand A is the more promising candidate. While Ligand B has slightly better binding affinity, Ligand A excels in crucial ADME properties for a CNS-targeting GPCR: significantly better BBB penetration, lower DILI risk, lower P-gp efflux, and a longer half-life. The logP of Ligand B is a major concern, potentially limiting its ability to cross cell membranes. Although both have poor solubility, this is a formulation challenge that can be addressed. The superior CNS penetration profile of Ligand A makes it the better choice.

Output:
0
2025-04-17 07:32:19,535 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (364.515 and 355.479 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (74.33) is significantly better than Ligand B (89.95). For CNS targets, we want TPSA <= 90, and A is closer to the optimal range.

**3. logP:** Both ligands have acceptable logP values (1.806 and 0.758), falling within the 1-3 range. Ligand A is slightly preferred.

**4. H-Bond Donors:** Both have 2 HBD, which is within the acceptable limit of <= 5.

**5. H-Bond Acceptors:** Ligand A has 5 HBA, and Ligand B has 4. Both are within the acceptable limit of <= 10.

**6. QED:** Both ligands have similar QED values (0.738 and 0.736), indicating good drug-likeness.

**7. DILI:** Ligand A (25.204) has a considerably lower DILI risk than Ligand B (32.299). Both are below the 40 threshold, but A is better.

**8. BBB:** This is a crucial parameter for CNS targets. Ligand A (70.027) has a good BBB percentile, exceeding the desirable >70 threshold. Ligand B (26.367) is significantly lower, indicating poor brain penetration.

**9. Caco-2:** Both have negative values, which is unusual. Assuming these are logP values, they indicate poor permeability.

**10. Solubility:** Both have negative solubility values, indicating poor solubility.

**11. hERG:** Both ligands have very low hERG inhibition liability (0.453 and 0.258), which is excellent.

**12. Cl_mic:** Ligand A (10.817) has a lower microsomal clearance than Ligand B (38.885), suggesting better metabolic stability.

**13. t1/2:** Ligand A (27.593) has a longer in vitro half-life than Ligand B (-12.062). The negative value for B is concerning.

**14. Pgp:** Both ligands have very low P-gp efflux liability (0.038 and 0.025), which is favorable for CNS penetration.

**15. Binding Affinity:** Ligand A (-8.3 kcal/mol) has a significantly stronger binding affinity than Ligand B (-7.0 kcal/mol). This is a substantial advantage.

**Overall Assessment:**

Ligand A is clearly superior. It has a better TPSA, lower DILI risk, significantly better BBB penetration, lower microsomal clearance, longer half-life, and *much* stronger binding affinity. While both have issues with solubility and Caco-2 permeability, the strong affinity and excellent CNS penetration profile of Ligand A outweigh these concerns. The difference in binding affinity (>1.5 kcal/mol) is particularly significant.

Output:
1
2025-04-17 07:32:19,535 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (335.382 and 361.551 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (37.61) is significantly higher than Ligand B (25.61). For CNS targets, TPSA should be <= 90, both are well within this range, but B is better.

**logP:** Ligand A (3.946) is within the optimal 1-3 range, while Ligand B (4.832) is slightly above. This could potentially lead to solubility issues for B, but isn't a critical concern.

**H-Bond Donors/Acceptors:** Both ligands have a reasonable number of HBD (0) and HBA (3 and 4 respectively), satisfying the guidelines.

**QED:** Ligand A (0.675) has a better QED score than Ligand B (0.465), indicating a more drug-like profile.

**DILI:** Ligand A (68.05) has a significantly higher DILI risk than Ligand B (16.092). This is a major concern for A.

**BBB:** Both ligands have excellent BBB penetration (A: 93.408, B: 88.174), exceeding the desirable >70 threshold for CNS targets.

**Caco-2 Permeability:** Ligand A (-4.488) has poor Caco-2 permeability, while Ligand B (-5.422) is also poor, but slightly better.

**Aqueous Solubility:** Both have poor solubility (-4.786 and -4.256 respectively).

**hERG Inhibition:** Both ligands show low hERG inhibition risk (0.821 and 0.919 respectively).

**Microsomal Clearance:** Ligand A (90.221) has higher microsomal clearance than Ligand B (59.398), suggesting lower metabolic stability.

**In vitro Half-Life:** Ligand B (78.276) has a significantly longer in vitro half-life than Ligand A (39.911).

**P-gp Efflux:** Both ligands show low P-gp efflux liability (0.585 and 0.834 respectively).

**Binding Affinity:** Ligand B (-7.8 kcal/mol) has a substantially stronger binding affinity than Ligand A (-9.4 kcal/mol). This is a significant advantage, potentially outweighing some ADME drawbacks.

**Overall Assessment:**

Ligand B is the more promising candidate. While its logP is slightly elevated and solubility is poor, its significantly stronger binding affinity (-7.8 vs -9.4 kcal/mol), lower DILI risk, and longer half-life are major advantages. Ligand A's high DILI risk and poor Caco-2 permeability are substantial drawbacks. The better QED of A is not enough to overcome these issues, especially given the strong affinity of B.

Output:
1
2025-04-17 07:32:19,535 - INFO - Batch 373 complete. Total preferences: 5968
2025-04-17 07:32:19,535 - INFO - Processing batch 374/512...
2025-04-17 07:33:01,734 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (352.523 Da and 363.38 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (55.89) is significantly better than Ligand B (72.88). For CNS targets, we want TPSA <= 90, and ideally closer to 60. Ligand A is much closer to the ideal range.

**logP:** Both ligands have acceptable logP values (1.022 and 0.501), falling within the 1-3 range. Ligand A is slightly better.

**H-Bond Donors/Acceptors:** Ligand A (HBD=1, HBA=4) and Ligand B (HBD=2, HBA=4) both have reasonable numbers of H-bond donors and acceptors.

**QED:** Both ligands have similar QED values (0.776 and 0.766), indicating good drug-likeness.

**DILI:** Ligand A (7.794) has a much lower DILI risk than Ligand B (13.532). This is a significant advantage.

**BBB:** Both ligands have good BBB penetration (72.237 and 71.772), exceeding the desirable threshold of >70 for CNS targets.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.965 and -4.963), which is unusual and suggests poor permeability. This is a concern for both.

**Aqueous Solubility:** Both ligands have negative solubility values (-0.765 and -1.478), indicating poor aqueous solubility. This is a drawback for both.

**hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.388 and 0.338).

**Microsomal Clearance:** Ligand A (25.578) has a much better (lower) microsomal clearance than Ligand B (-31.12). Lower clearance indicates better metabolic stability.

**In vitro Half-Life:** Ligand A (3.02) has a slightly better in vitro half-life than Ligand B (-26.44).

**P-gp Efflux:** Ligand A (0.013) has a much lower P-gp efflux liability than Ligand B (0.007). Lower efflux is crucial for CNS exposure.

**Binding Affinity:** Ligand B (-8.5 kcal/mol) has a significantly stronger binding affinity than Ligand A (0.0 kcal/mol). This is a substantial advantage, potentially outweighing some of the ADME drawbacks.

**Overall Assessment:**

Ligand B has a much stronger binding affinity, which is the most critical factor. However, it suffers from significantly worse DILI risk, higher P-gp efflux, and a much higher microsomal clearance. Ligand A has superior ADME properties across most parameters (TPSA, DILI, Cl_mic, Pgp) but very poor binding affinity.

Given the importance of binding affinity for GPCRs, and the fact that the affinity difference is so large (8.5 vs 0), Ligand B is more likely to be a viable drug candidate *despite* its ADME liabilities. Optimization efforts could then focus on improving the ADME profile of Ligand B.

Output:
1
2025-04-17 07:33:01,734 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (351.382 and 344.43 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (89.35) is excellent, falling below the 90 A^2 threshold for CNS targets. Ligand B (49.41) is also very good, well below the threshold.

**3. logP:** Ligand A (0.318) is a bit low, potentially hindering permeability. Ligand B (2.532) is within the optimal 1-3 range. This is a significant advantage for Ligand B.

**4. H-Bond Donors:** Both ligands have 1 HBD, which is acceptable.

**5. H-Bond Acceptors:** Ligand A has 6 HBA, acceptable. Ligand B has 2 HBA, also acceptable.

**6. QED:** Both ligands have good QED scores (0.825 and 0.779), indicating drug-like properties.

**7. DILI:** Ligand A (60.915) is approaching a concerning DILI risk, while Ligand B (27.608) has a low DILI risk. This favors Ligand B.

**8. BBB:** Ligand A (87.553) has good BBB penetration, but Ligand B (98.022) is exceptional, almost guaranteeing CNS exposure. This is a critical advantage for a DRD2 ligand.

**9. Caco-2 Permeability:** Both have negative Caco-2 values which is unusual and suggests poor permeability.

**10. Aqueous Solubility:** Both have negative solubility values, which is also unusual and suggests poor solubility.

**11. hERG Inhibition:** Ligand A (0.123) has a very low hERG risk, a significant advantage. Ligand B (0.55) is slightly higher, but still relatively low.

**12. Microsomal Clearance:** Ligand A (5.317) has lower clearance, suggesting better metabolic stability. Ligand B (29.448) has significantly higher clearance, which is a drawback.

**13. In vitro Half-Life:** Ligand A (-3.431) has a negative half-life, which is unusual. Ligand B (-18.145) has a very negative half-life, which is even more concerning.

**14. P-gp Efflux:** Ligand A (0.061) has low P-gp efflux, which is favorable for CNS penetration. Ligand B (0.286) has slightly higher P-gp efflux, but still reasonable.

**15. Binding Affinity:** Both ligands have very strong binding affinities (-8.5 and -8.9 kcal/mol). The difference is minimal and unlikely to be decisive.

**Overall Assessment:**

While Ligand A has a better hERG profile and slightly better metabolic stability, Ligand B wins out due to its superior logP, BBB penetration, and lower DILI risk. For a CNS target like DRD2, excellent BBB penetration is paramount, and Ligand B's 98.022 percentile score is highly desirable. The slightly higher logP also suggests better permeability. The negative values for Caco-2 and solubility are concerning for both, but the other advantages of Ligand B outweigh this.

Output:
1
2025-04-17 07:33:01,734 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (353.507 and 351.535 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (72.88) is slightly higher than Ligand B (52.65). Both are below the 90 A^2 threshold for CNS targets, but Ligand B is preferable.

**3. logP:** Both ligands have good logP values (1.233 and 2.65), falling within the optimal 1-3 range. Ligand B is slightly better.

**4. H-Bond Donors:** Ligand A (2) and Ligand B (1) are both within the acceptable limit of <=5. Ligand B is preferable.

**5. H-Bond Acceptors:** Ligand A (4) and Ligand B (3) are both within the acceptable limit of <=10. Ligand B is preferable.

**6. QED:** Both ligands have similar and good QED values (0.753 and 0.767), indicating good drug-like properties.

**7. DILI:** Ligand A (8.802) has a slightly higher DILI risk than Ligand B (7.096), but both are well below the concerning threshold of 60.

**8. BBB:** Both ligands have good BBB penetration (62.854% and 64.482%), but Ligand B is slightly better. While >70% is desirable, these are acceptable.

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.809 and -4.854), which is unusual and suggests poor permeability. This is a significant concern for both.

**10. Aqueous Solubility:** Both ligands have negative solubility values (-1.07 and -1.887), indicating very poor aqueous solubility. This is a major drawback for both.

**11. hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.251 and 0.643).

**12. Microsomal Clearance:** Ligand A (-1.947) has lower (better) microsomal clearance than Ligand B (-1.051), suggesting greater metabolic stability.

**13. In vitro Half-Life:** Ligand A (-13.063) has a much longer in vitro half-life than Ligand B (0.911). This is a significant advantage for Ligand A.

**14. P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.052 and 0.077), which is good for CNS penetration.

**15. Binding Affinity:** Ligand B (-8.1) has a slightly better binding affinity than Ligand A (-8.8). While the difference is small, it is within the range where it could outweigh other drawbacks.

**Overall Assessment:**

Both ligands have significant issues with Caco-2 permeability and aqueous solubility. However, Ligand B has a better logP, TPSA, HBD, HBA, and binding affinity. Ligand A has better metabolic stability (lower Cl_mic) and a longer half-life, which are important considerations. Given the GPCR-specific emphasis on affinity, and the slight edge Ligand B has in that regard, coupled with its slightly better TPSA and logP, I would favor Ligand B. The slightly better binding affinity could be crucial for efficacy. The solubility and permeability issues would need to be addressed through formulation or further chemical modification, but the starting point is better with Ligand B.

Output:
1
2025-04-17 07:33:01,735 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B based on the provided guidelines, prioritizing GPCR-specific properties (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (364.43) is slightly lower, which is generally favorable for permeability.

**TPSA:** Both ligands are below the 140 A^2 threshold for oral absorption. Ligand A (87.38) is better, being closer to the 90 A^2 target for CNS penetration. Ligand B (96.88) is still acceptable but less optimal.

**logP:** Ligand A (1.738) is within the optimal range (1-3). Ligand B (-0.04) is slightly below 1, which *could* indicate permeability issues, though not drastically.

**H-Bond Donors/Acceptors:** Both ligands have acceptable HBD (1 and 0 respectively) and HBA (7 each) counts.

**QED:** Both ligands have good QED scores (0.645 and 0.715), indicating good drug-like properties.

**DILI:** Ligand A (87.282) has a higher DILI risk than Ligand B (78.054), but both are below the concerning 60 threshold.

**BBB:** Both ligands have good BBB penetration (68.67% and 72.819%), but ligand B is slightly better. For a CNS target like DRD2, >70% is desirable, so both are reasonably good.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values, which is unusual and suggests poor permeability. This is a significant concern for both.

**Aqueous Solubility:** Both ligands have negative solubility values, indicating very poor aqueous solubility. This is a major drawback for both compounds.

**hERG Inhibition:** Both ligands show low hERG inhibition risk (0.514 and 0.274).

**Microsomal Clearance:** Ligand B (5.063) has significantly lower microsomal clearance than Ligand A (17.689), indicating better metabolic stability.

**In vitro Half-Life:** Ligand A (22.673) has a longer in vitro half-life than Ligand B (-8.167). However, the negative value for Ligand B is concerning and likely an error.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.285 and 0.116), which is favorable for CNS penetration.

**Binding Affinity:** Ligand B (-8.6 kcal/mol) has a slightly better binding affinity than Ligand A (-7.8 kcal/mol). While both are good, the 0.8 kcal/mol difference is significant enough to consider.

**Overall Assessment:**

Ligand B is slightly favored. While both have solubility and permeability issues (indicated by negative Caco-2 and solubility values), Ligand B has better metabolic stability (lower Cl_mic), slightly better BBB penetration, and a stronger binding affinity. The slightly lower logP of Ligand B is a minor concern, but the improved affinity and metabolic stability outweigh this. The negative half-life for Ligand B is a red flag, but assuming it's an error, the other properties make it more promising.

Output:
1
2025-04-17 07:33:01,735 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 drug candidates, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (341.459 Da) is slightly lower, which could be beneficial for permeability.

**2. TPSA:** Ligand A (54.26) is significantly better than Ligand B (86.71). For CNS targets, TPSA should be <= 90, and A is comfortably within this range, while B is approaching the upper limit. This favors A.

**3. logP:** Both ligands have good logP values (A: 1.529, B: 1.824), falling within the optimal 1-3 range.

**4. H-Bond Donors:** Ligand A (0) is preferable to Ligand B (2). Fewer HBDs generally improve membrane permeability.

**5. H-Bond Acceptors:** Ligand A (5) is preferable to Ligand B (4).

**6. QED:** Both ligands have good QED scores (A: 0.731, B: 0.837), indicating drug-like properties. B is slightly better here.

**7. DILI:** Ligand A (31.563) has a much lower DILI risk than Ligand B (50.64). This is a significant advantage for A.

**8. BBB:** Ligand A (83.443) has a substantially better BBB penetration score than Ligand B (66.615). This is *critical* for a CNS target like DRD2, making A much more promising.

**9. Caco-2 Permeability:** Ligand A (-4.902) is better than Ligand B (-5.113).

**10. Aqueous Solubility:** Ligand A (-1.097) is better than Ligand B (-3.975).

**11. hERG Inhibition:** Ligand A (0.389) has a lower hERG inhibition liability than Ligand B (0.794), reducing the risk of cardiotoxicity.

**12. Microsomal Clearance:** Ligand B (21.673) has a lower microsomal clearance than Ligand A (39.052), suggesting better metabolic stability. This favors B.

**13. In vitro Half-Life:** Ligand A (14.947) has a better in vitro half-life than Ligand B (-22.245).

**14. P-gp Efflux:** Ligand A (0.289) has a lower P-gp efflux liability than Ligand B (0.08), which is favorable for CNS exposure.

**15. Binding Affinity:** Both ligands have very similar, excellent binding affinities (A: -8.4 kcal/mol, B: -8.2 kcal/mol). The difference is not substantial enough to outweigh other factors.

**Overall Assessment:**

Ligand A is significantly better overall, particularly due to its superior BBB penetration, lower DILI risk, lower TPSA, lower HBD, and better solubility. While Ligand B has slightly better metabolic stability (lower Cl_mic), the CNS target profile of DRD2 makes BBB penetration and low DILI risk paramount. The small difference in binding affinity is negligible compared to these crucial ADME properties.

Output:
1
2025-04-17 07:33:01,735 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the acceptable range (200-500 Da). Ligand A (348.359 Da) is slightly preferred as it's closer to the ideal range.

**TPSA:** Ligand B (93.44) is significantly better than Ligand A (124.77). For CNS targets, TPSA < 90 is preferred, and Ligand B meets this criterion while Ligand A does not.

**logP:** Ligand B (2.792) is optimal (1-3), while Ligand A (-0.432) is too low, potentially hindering membrane permeability. This is a significant advantage for Ligand B.

**H-Bond Donors/Acceptors:** Ligand A has 3 HBD and 6 HBA, while Ligand B has 2 HBD and 8 HBA. Both are within acceptable limits, but the lower HBD count of Ligand B is slightly favorable.

**QED:** Ligand B (0.551) has a better QED score than Ligand A (0.333), indicating a more drug-like profile.

**DILI:** Ligand B (78.402) has a higher DILI risk than Ligand A (58.434), but both are reasonably acceptable.

**BBB:** Ligand B (66.886) has a better BBB penetration percentile than Ligand A (45.677). While >70 is desirable, Ligand B is significantly better, which is crucial for a CNS target like DRD2.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.303 and -5.647), which is unusual and suggests poor permeability. This is a concern for both.

**Aqueous Solubility:** Both ligands have negative solubility values (-2.059 and -3.366), also unusual and concerning.

**hERG:** Ligand A (0.018) has a very low hERG risk, while Ligand B (0.432) has a slightly elevated risk. This favors Ligand A.

**Microsomal Clearance:** Ligand A (-13.054) has a much lower (better) microsomal clearance than Ligand B (53.596), indicating better metabolic stability.

**In vitro Half-Life:** Ligand B (49.78) has a significantly longer in vitro half-life than Ligand A (0.293), which is a major advantage.

**P-gp Efflux:** Ligand A (0.006) has very low P-gp efflux, while Ligand B (0.273) has slightly higher efflux. Lower efflux is preferred for CNS penetration, favoring Ligand A.

**Binding Affinity:** Ligand B (-9.5 kcal/mol) has a significantly stronger binding affinity than Ligand A (-7.7 kcal/mol). This >1.5 kcal/mol difference is substantial and can outweigh some ADME drawbacks.

**Overall Assessment:**

Ligand B excels in binding affinity, BBB penetration, QED, and in vitro half-life. However, it suffers from higher DILI risk, higher P-gp efflux, and a less favorable logP. Ligand A has better metabolic stability (lower Cl_mic), lower hERG risk, and lower P-gp efflux, but its binding affinity is weaker, and its TPSA is higher.

Given the GPCR-specific priorities, the strong binding affinity and good BBB penetration of Ligand B are particularly important. While the other ADME properties of Ligand B are not ideal, the substantial binding affinity advantage (-9.5 vs -7.7 kcal/mol) is likely to outweigh these concerns, especially considering optimization potential.

Output:
1
2025-04-17 07:33:01,735 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (340.383 and 350.459 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (79.54) is significantly better than Ligand B (95.5). For CNS targets, we want TPSA <= 90, so Ligand A is preferable.

**3. logP:** Both ligands have good logP values (1.58 and 1.475), falling within the optimal 1-3 range.

**4. H-Bond Donors:** Ligand A (0) is better than Ligand B (3). Fewer HBDs generally improve permeability.

**5. H-Bond Acceptors:** Ligand A (5) is slightly better than Ligand B (4), both are within the acceptable range.

**6. QED:** Ligand A (0.844) is significantly better than Ligand B (0.433). A higher QED indicates a more drug-like profile.

**7. DILI:** Ligand A (49.632) is much better than Ligand B (21.83). Lower DILI risk is crucial.

**8. BBB:** Ligand A (83.986) is significantly better than Ligand B (63.862).  For a CNS target like DRD2, a BBB percentile >70 is highly desirable. Ligand A is much closer to this target.

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.937 and -4.995). This is unusual and requires further investigation. Negative values suggest poor permeability, but the scale is not clearly defined, so it's hard to interpret.

**10. Aqueous Solubility:** Both ligands have negative solubility values (-1.668 and -2.233). Again, the scale is unclear, but these suggest poor solubility.

**11. hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.348 and 0.077).

**12. Microsomal Clearance:** Ligand A (44.115) is higher than Ligand B (25.464), indicating faster clearance and lower metabolic stability. This is a drawback for Ligand A.

**13. In vitro Half-Life:** Ligand B (-32.316) has a significantly longer half-life than Ligand A (3.718). This is a major advantage for Ligand B.

**14. P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.014).

**15. Binding Affinity:** Both ligands have excellent binding affinity (-8.5 and -8.0 kcal/mol). The difference is small and likely not decisive.

**Overall Assessment:**

Ligand A excels in most critical ADME properties for a CNS-targeting GPCR, particularly TPSA, BBB, QED, and DILI. However, Ligand B has a significantly better in vitro half-life and lower microsomal clearance, suggesting better metabolic stability. The negative Caco-2 and solubility values are concerning for both, but the superior CNS penetration profile of Ligand A makes it the more promising candidate, despite the slightly higher clearance. The strong affinity of both compounds is a positive.

Output:
1
2025-04-17 07:33:01,735 - INFO - Reasoning:

Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight (MW):** Both ligands (382.511 and 345.451 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (104.21) is slightly above the preferred <90 for CNS targets, but not drastically. Ligand B (89.66) is well within the desired range.

**3. logP:** Both ligands have good logP values (2.466 and 3.452), falling within the optimal 1-3 range.

**4. H-Bond Donors (HBD):** Both ligands are acceptable (3 and 2 respectively), being less than 5.

**5. H-Bond Acceptors (HBA):** Both ligands are acceptable (7 and 6 respectively), being less than 10.

**6. QED:** Both ligands have good QED scores (0.651 and 0.767), indicating good drug-like properties.

**7. DILI:** Both ligands have similar DILI risk (59.403 and 56.223), and are both acceptable (<60).

**8. BBB:** This is a critical parameter for a CNS target like DRD2. Ligand B (81.815) has a significantly better BBB percentile than Ligand A (54.634). This is a major advantage for Ligand B.

**9. Caco-2 Permeability:** Both have negative values, which is unusual. However, the magnitude is similar, suggesting similar absorption challenges.

**10. Aqueous Solubility:** Both have negative values, which is also unusual. The values are similar, suggesting similar solubility challenges.

**11. hERG Inhibition:** Both ligands have low hERG inhibition risk (0.152 and 0.297).

**12. Microsomal Clearance (Cl_mic):** Both have similar microsomal clearance (49.036 and 57.406), indicating comparable metabolic stability.

**13. In vitro Half-Life:** Ligand A (40.051) has a slightly longer half-life than Ligand B (36.918).

**14. P-gp Efflux:** Both ligands have low P-gp efflux liability (0.15 and 0.115).

**15. Binding Affinity:** Ligand B (-9.0 kcal/mol) has a slightly better binding affinity than Ligand A (-8.7 kcal/mol), although the difference is small.

**Overall Assessment:**

Ligand B is the more promising candidate. While Ligand A has a slightly longer half-life, Ligand B excels in the most critical areas for a CNS-targeting GPCR ligand: significantly better BBB penetration and slightly better binding affinity. The TPSA is also more favorable for Ligand B. The other parameters are comparable between the two. The improved BBB penetration is crucial for ensuring sufficient drug exposure in the brain.

Output:
1
2025-04-17 07:33:01,735 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (348.355 and 350.419 Da) fall within the ideal range of 200-500 Da.

**TPSA:** Ligand A (114.84) is slightly above the optimal <90 for CNS targets, but still reasonable. Ligand B (87.91) is excellent, well below 90.

**logP:** Ligand A (2.451) is within the optimal 1-3 range. Ligand B (0.66) is a bit low, potentially hindering permeability.

**H-Bond Donors:** Both ligands have acceptable HBD counts (2 and 1 respectively), well below the limit of 5.

**H-Bond Acceptors:** Both ligands have acceptable HBA counts (6 each), below the limit of 10.

**QED:** Both ligands have good QED scores (0.612 and 0.727), indicating good drug-like properties.

**DILI:** Ligand A (68.437) has a higher DILI risk than Ligand B (36.099). This is a significant negative for Ligand A.

**BBB:** Ligand B (64.986) has a significantly better BBB penetration percentile than Ligand A (36.526). This is crucial for a CNS target like DRD2.

**Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and suggests a potential issue with the data or modeling. However, the values are similar and don't strongly differentiate the two.

**Aqueous Solubility:** Both have negative solubility values, which is also unusual. Again, the values are similar and don't strongly differentiate the two.

**hERG Inhibition:** Ligand A (0.534) has a slightly higher hERG risk than Ligand B (0.153), but both are relatively low.

**Microsomal Clearance:** Ligand A (42.232) has a higher microsomal clearance than Ligand B (14.799), indicating lower metabolic stability.

**In vitro Half-Life:** Ligand A (25.642) has a longer half-life than Ligand B (1.623).

**P-gp Efflux:** Ligand A (0.427) has lower P-gp efflux than Ligand B (0.009), which is favorable for CNS penetration.

**Binding Affinity:** Ligand B (-7.6 kcal/mol) has a better binding affinity than Ligand A (-8.9 kcal/mol). This is a substantial difference, and affinity is a primary driver.

**Overall Assessment:**

Ligand B is the stronger candidate. While its logP is slightly low, its significantly better BBB penetration, lower DILI risk, lower microsomal clearance, and superior binding affinity outweigh this drawback. The lower P-gp efflux is also a positive for CNS targeting. Ligand A has a better half-life and P-gp efflux, but its higher DILI risk and significantly lower BBB penetration are major concerns for a CNS drug. The affinity difference is also important.

Output:
1
2025-04-17 07:33:01,735 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (350.447 and 370.515 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (58.12) is excellent, well below the 90 A^2 threshold for CNS targets. Ligand B (83.55) is still reasonable but less optimal.

**logP:** Ligand A (3.84) is at the higher end of the optimal range (1-3) but acceptable. Ligand B (1.211) is quite low, potentially hindering membrane permeability.

**H-Bond Donors/Acceptors:** Both ligands have acceptable HBD (1) and HBA (5/4) counts, well within the recommended limits.

**QED:** Both ligands have similar and good QED scores (0.78 and 0.762), indicating good drug-like properties.

**DILI:** Ligand A has a high DILI risk (90.733), which is a significant concern. Ligand B has a much lower DILI risk (26.755), a major advantage.

**BBB:** Ligand A shows excellent BBB penetration (73.827), crucial for a CNS target. Ligand B's BBB penetration (61.535) is lower, though not terrible.

**Caco-2 Permeability:** Ligand A has a negative Caco-2 value (-4.895), which is unusual and suggests poor permeability. Ligand B also has a negative value (-5.037), indicating poor permeability.

**Aqueous Solubility:** Both ligands have poor aqueous solubility (-4.901 and -2.148 respectively).

**hERG Inhibition:** Ligand A has a low hERG risk (0.758), which is good. Ligand B has a very low hERG risk (0.188), even better.

**Microsomal Clearance:** Ligand A has a high microsomal clearance (93.79), suggesting rapid metabolism. Ligand B has a much lower clearance (15.003), indicating better metabolic stability.

**In vitro Half-Life:** Ligand A has a reasonable half-life (75.587), while Ligand B has a very short half-life (14.663).

**P-gp Efflux:** Ligand A has moderate P-gp efflux (0.9). Ligand B has very low P-gp efflux (0.019), which is highly desirable for CNS penetration.

**Binding Affinity:** Ligand A has a significantly stronger binding affinity (-10.9 kcal/mol) compared to Ligand B (-7.8 kcal/mol). This is a substantial advantage, potentially outweighing some of its ADME drawbacks.

**Overall Assessment:**

Ligand A boasts a superior binding affinity and good BBB penetration, but suffers from a high DILI risk, poor Caco-2 permeability, high metabolic clearance, and moderate P-gp efflux. Ligand B has a lower affinity, but exhibits a much better safety profile (low DILI, low hERG), better metabolic stability (low Cl_mic), and very low P-gp efflux. The poor Caco-2 permeability and solubility are concerns for both, but the significantly stronger affinity of Ligand A is a major factor. Given the importance of affinity for GPCR ligands, and the potential to address some ADME issues through further optimization, Ligand A is the more promising candidate.

Output:
1
2025-04-17 07:33:01,735 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (386.361 Da) is slightly higher than Ligand B (342.355 Da), but both are acceptable.

**TPSA:** Ligand A (41.13) is excellent for CNS penetration, well below the 90 A^2 threshold. Ligand B (120.25) is higher, but still potentially acceptable, though less ideal.

**logP:** Ligand A (4.416) is a bit high, potentially leading to solubility issues or off-target effects. Ligand B (0.985) is quite low, which could hinder membrane permeability.

**H-Bond Donors/Acceptors:** Ligand A (HBD=2, HBA=2) is well within the desirable ranges. Ligand B (HBD=4, HBA=5) is also acceptable, but slightly higher.

**QED:** Ligand A (0.753) has a better QED score than Ligand B (0.532), indicating a more drug-like profile.

**DILI:** Ligand B (74.603) has a higher DILI risk than Ligand A (53.625), which is preferable.

**BBB:** This is a critical parameter for a CNS target like DRD2. Ligand A (80.264) has a significantly better BBB percentile than Ligand B (11.206). This is a major advantage for Ligand A.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values, which is unusual and suggests poor permeability. However, the scale is not specified, so it's difficult to interpret.

**Aqueous Solubility:** Both ligands have negative solubility values, indicating poor aqueous solubility. This is a concern, particularly for Ligand A with its higher logP.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (Ligand A: 0.692, Ligand B: 0.389), which is good.

**Microsomal Clearance:** Ligand A (23.535) has a lower microsomal clearance than Ligand B (-2.949), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand B (72.072) has a significantly longer in vitro half-life than Ligand A (2.367), which is a positive attribute.

**P-gp Efflux:** Ligand A (0.229) has lower P-gp efflux liability than Ligand B (0.045), which is beneficial for CNS exposure.

**Binding Affinity:** Ligand B (-8.8 kcal/mol) has a slightly better binding affinity than Ligand A (-8.3 kcal/mol), but the difference is relatively small (0.5 kcal/mol).

**Overall Assessment:**

Ligand A is the better candidate. While its logP is higher and solubility is lower, its superior BBB penetration (80.264 vs 11.206), lower DILI risk, lower P-gp efflux, and better metabolic stability outweigh the slightly weaker binding affinity and solubility concerns. For a CNS target like DRD2, BBB penetration is paramount, and Ligand A clearly excels in this area. The small difference in binding affinity (0.5 kcal/mol) is unlikely to overcome the significant ADME advantages of Ligand A.

Output:
1
2025-04-17 07:33:01,736 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (344.411 and 369.491 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (76.66) is excellent, well below the 90 A^2 threshold for CNS targets. Ligand B (124.03) is still reasonable but less optimal, approaching the 140 A^2 limit for oral absorption and further from the ideal for CNS penetration.

**3. logP:** Ligand A (0.218) is quite low, potentially hindering membrane permeability. Ligand B (1.491) is better, falling within the optimal 1-3 range.

**4. H-Bond Donors:** Both ligands have 2 HBD, which is within the acceptable limit of <=5.

**5. H-Bond Acceptors:** Both ligands have 4 HBA, also within the acceptable limit of <=10.

**6. QED:** Ligand A (0.618) has a good drug-likeness score, exceeding 0.5. Ligand B (0.382) is below 0.5, indicating a less favorable drug-like profile.

**7. DILI:** Both ligands have relatively low DILI risk (29.236 and 33.307 percentiles), suggesting minimal liver injury potential.

**8. BBB:** Ligand A (54.75%) has a moderate BBB penetration score, while Ligand B (46.026%) is even lower. Both are below the desirable >70% for CNS targets, but A is better.

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.133 and -5.231), which is unusual and suggests poor permeability. This is a significant concern.

**10. Aqueous Solubility:** Both ligands have negative solubility values (-2.835 and -2.054), also unusual and indicating poor aqueous solubility. This is also a significant concern.

**11. hERG Inhibition:** Both ligands show very low hERG inhibition risk (0.074 and 0.12), which is excellent.

**12. Microsomal Clearance:** Ligand A (5.521 mL/min/kg) has lower clearance than Ligand B (30.094 mL/min/kg), suggesting better metabolic stability.

**13. In vitro Half-Life:** Ligand A (2.816 hours) has a shorter half-life than Ligand B (-1.22 hours - negative values are suspect, but indicate a very long half-life).

**14. P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.02 and 0.027), which is favorable for CNS exposure.

**15. Binding Affinity:** Ligand B (-7.5 kcal/mol) has a significantly stronger binding affinity than Ligand A (-6.9 kcal/mol). This 0.6 kcal/mol difference is substantial and could outweigh some of the ADME drawbacks.

**Overall Assessment:**

Despite the unusual negative values for Caco-2 and Solubility, Ligand B stands out due to its significantly stronger binding affinity (-7.5 kcal/mol vs -6.9 kcal/mol). The better logP and slightly better BBB penetration (though still suboptimal) also favor Ligand B. While Ligand A has better QED and lower clearance, the affinity difference is crucial for a GPCR target. The negative Caco-2 and Solubility values for both compounds are concerning and would require further investigation (e.g., experimental validation, different prediction models), but the potency advantage of Ligand B is compelling.

Output:
1
2025-04-17 07:33:01,736 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (348.403 Da) is slightly preferred as it's closer to the lower end, potentially aiding permeability.

**TPSA:** Both ligands are below the 140 A^2 threshold for oral absorption and reasonably close to the 90 A^2 target for CNS penetration. Ligand A (95.22 A^2) is slightly better than Ligand B (93.21 A^2).

**logP:** Ligand A (0.085) is quite low, potentially hindering membrane permeability. Ligand B (3.567) is within the optimal range (1-3). This is a significant advantage for Ligand B.

**H-Bond Donors/Acceptors:** Ligand A (HBD=1, HBA=7) and Ligand B (HBD=2, HBA=6) both fall within acceptable limits.

**QED:** Both ligands have good QED scores (A: 0.778, B: 0.736), indicating drug-like properties.

**DILI:** Ligand A (56.805) has a lower DILI risk than Ligand B (99.457), which is a substantial concern.

**BBB:** Ligand A (63.086) has a moderate BBB penetration, while Ligand B (53.703) is lower. While both are below the ideal >70, Ligand A is better.

**Caco-2:** Both have negative Caco-2 values, which is unusual and suggests poor permeability.

**Aqueous Solubility:** Both have negative solubility values, which is also unusual and suggests poor solubility.

**hERG:** Ligand A (0.095) has a very low hERG risk, while Ligand B (0.241) is slightly higher but still relatively low.

**Microsomal Clearance:** Ligand A (45.237 mL/min/kg) has a higher clearance than Ligand B (14.323 mL/min/kg), indicating lower metabolic stability. This favors Ligand B.

**In vitro Half-Life:** Ligand B (19.861 hours) has a significantly longer half-life than Ligand A (0.878 hours), which is a major advantage.

**P-gp Efflux:** Ligand A (0.113) has lower P-gp efflux liability than Ligand B (0.479), which is favorable for CNS exposure.

**Binding Affinity:** Ligand B (-10.1 kcal/mol) has a *much* stronger binding affinity than Ligand A (0.0 kcal/mol). This is a decisive factor. A difference of >1.5 kcal/mol can outweigh many ADME drawbacks.

**Overall Assessment:**

Despite Ligand A's better BBB and lower DILI risk, Ligand B is the stronger candidate. The significantly higher binding affinity (-10.1 vs 0.0 kcal/mol) is a critical advantage for a GPCR ligand. Additionally, Ligand B has better logP, lower microsomal clearance (better metabolic stability), and a much longer half-life. While its DILI risk is higher, the potency advantage is likely to outweigh this concern, especially during lead optimization. The lower BBB is a concern, but can be addressed during optimization. The poor solubility and Caco-2 values for both compounds would need to be addressed.

Output:
1
2025-04-17 07:33:01,736 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (341.419 and 336.395 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (100.27) is slightly higher than the preferred <90 for CNS targets, but still reasonably acceptable. Ligand B (59.39) is excellent, well below the 90 threshold.

**logP:** Both ligands have logP values within the optimal 1-3 range (1.004 and 2.662). Ligand B is slightly higher, potentially offering better membrane permeability.

**H-Bond Donors/Acceptors:** Ligand A (2 HBD, 7 HBA) and Ligand B (1 HBD, 5 HBA) both have acceptable numbers of H-bond donors and acceptors, well within the guidelines.

**QED:** Both ligands have similar QED values (0.808 and 0.799), indicating good drug-likeness.

**DILI:** Ligand A (51.648) has a lower DILI risk than Ligand B (90.965), which is approaching a concerning level.

**BBB:** Ligand B (78.558) has a significantly better BBB percentile than Ligand A (57.425). This is a crucial advantage for a CNS target like DRD2.

**Caco-2 Permeability:** Ligand A (-5.472) shows poor Caco-2 permeability, while Ligand B (-4.635) is slightly better, but still not ideal.

**Aqueous Solubility:** Both ligands have poor aqueous solubility (-2.415 and -3.562). This is a potential formulation challenge, but can sometimes be overcome.

**hERG Inhibition:** Ligand A (0.249) has a lower hERG inhibition risk than Ligand B (0.729).

**Microsomal Clearance:** Ligand B (16.756) has a lower microsomal clearance than Ligand A (29.506), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand B (51.209) has a significantly longer in vitro half-life than Ligand A (5.132), which is a major advantage.

**P-gp Efflux:** Ligand A (0.009) has very low P-gp efflux, which is excellent. Ligand B (0.322) has a moderate P-gp efflux, which could limit CNS exposure.

**Binding Affinity:** Both ligands have very similar and strong binding affinities (-8.6 and -8.7 kcal/mol). The difference is negligible.

**Conclusion:**

While Ligand A has better P-gp efflux and lower hERG risk, Ligand B is superior overall due to its significantly better BBB penetration, longer half-life, lower microsomal clearance, and acceptable TPSA. The higher DILI risk for Ligand B is a concern, but the substantial advantages in CNS penetration and metabolic stability outweigh this drawback, especially given the strong binding affinity is comparable.

Output:
1
2025-04-17 07:33:01,736 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (345.447 Da) is slightly lower, which could be beneficial for permeability, while Ligand B (364.555 Da) is also well within range.

**TPSA:** Ligand A (88.91) is excellent, falling well below the 90 A^2 threshold for CNS targets. Ligand B (49.41) is even better, indicating potentially improved brain penetration.

**logP:** Ligand A (1.579) is within the optimal range (1-3). Ligand B (3.373) is at the higher end of optimal, which could raise concerns about solubility and off-target effects, but is still acceptable.

**H-Bond Donors/Acceptors:** Ligand A has 2 HBD and 5 HBA, which are reasonable. Ligand B has 1 HBD and 3 HBA, also good values.

**QED:** Both ligands have good QED scores (Ligand A: 0.525, Ligand B: 0.781), suggesting drug-like properties. Ligand B is better here.

**DILI:** Ligand A (47.887) has a slightly higher DILI risk than Ligand B (31.214), but both are below the concerning threshold of 60.

**BBB:** This is a critical parameter for CNS targets. Ligand A has a BBB percentile of 58.511, which is not ideal (below 70). Ligand B has a significantly better BBB percentile of 75.107, making it more likely to reach the target in the brain.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.414 and -5.102), which is unusual and suggests poor intestinal absorption. However, for a CNS target, intestinal absorption is less critical than BBB penetration.

**Aqueous Solubility:** Both ligands have very poor aqueous solubility (-1.76 and -3.836). This could pose formulation challenges.

**hERG Inhibition:** Ligand A (0.063) has a very low hERG risk. Ligand B (0.412) is slightly higher, but still relatively low.

**Microsomal Clearance:** Ligand A (36.844) has lower microsomal clearance, suggesting better metabolic stability. Ligand B (54.798) has higher clearance, which could lead to faster metabolism and lower exposure.

**In vitro Half-Life:** Ligand A (-9.136) has a negative half-life, which is not physically meaningful and suggests a very rapid degradation. Ligand B (0.668) has a short half-life, but it's a positive value.

**P-gp Efflux:** Ligand A (0.057) has very low P-gp efflux, which is favorable for CNS penetration. Ligand B (0.255) has slightly higher efflux, but still relatively low.

**Binding Affinity:** Ligand A (-7.9 kcal/mol) has a significantly stronger binding affinity than Ligand B (-0.0 kcal/mol). This is a substantial advantage.

**Overall Assessment:**

While Ligand A has a superior binding affinity, its poor BBB penetration (58.511) and negative/very short half-life are major drawbacks for a CNS target. Ligand B, despite weaker binding affinity, exhibits much better BBB penetration (75.107), lower DILI risk, and a better QED score. The TPSA is also significantly lower for Ligand B, further supporting its potential for CNS entry. The slightly higher logP of Ligand B is a minor concern, but the significant advantage in BBB penetration outweighs this.

Output:
1
2025-04-17 07:33:01,737 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (343.43 and 350.46 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (73.74) is significantly better than Ligand B (104.53). For CNS targets, we want TPSA <= 90, so Ligand A is preferable.

**logP:** Both ligands have good logP values (2.125 and 1.144), falling within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A (1 HBD, 4 HBA) is better than Ligand B (3 HBD, 3 HBA). Both are within acceptable limits, but fewer H-bonds generally improve permeability.

**QED:** Ligand A (0.831) has a substantially higher QED score than Ligand B (0.6), indicating better overall drug-likeness.

**DILI:** Ligand A (35.9) has a slightly higher DILI risk than Ligand B (22.6), but both are below the concerning threshold of 60.

**BBB:** Ligand B (80.031) has a significantly higher BBB penetration percentile than Ligand A (63.94). This is a *critical* factor for a CNS target like DRD2.

**Caco-2 Permeability:** Ligand A (-4.468) has a worse Caco-2 permeability than Ligand B (-5.165).

**Aqueous Solubility:** Both ligands have poor aqueous solubility (-2.554 and -2.769). This could pose formulation challenges.

**hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.136 and 0.146).

**Microsomal Clearance:** Ligand B (25.535) has a significantly lower microsomal clearance than Ligand A (60.48), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand B (-17.974) has a longer in vitro half-life than Ligand A (-34.724).

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.136 and 0.018).

**Binding Affinity:** Ligand B (-8.0) has a slightly better binding affinity than Ligand A (-7.2), although both are excellent (below -7.0). The 0.8 kcal/mol difference is significant.

**Overall Assessment:**

Ligand B excels in BBB penetration, metabolic stability (lower Cl_mic, longer t1/2), and binding affinity. Ligand A has a better TPSA and QED. However, for a CNS target like DRD2, BBB penetration is paramount. The slightly better affinity of Ligand B, combined with its superior BBB score, outweighs the advantages of Ligand A's TPSA and QED. The solubility is a concern for both, but can be addressed with formulation strategies.

Output:
1
2025-04-17 07:33:01,737 - INFO - Batch 374 complete. Total preferences: 5984
2025-04-17 07:33:01,737 - INFO - Processing batch 375/512...
2025-04-17 07:33:43,743 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (352.479 and 350.39 Da) fall comfortably within the ideal 200-500 Da range.

**2. TPSA:** Both ligands are below the 90 A^2 threshold for CNS targets (90.54 and 95.5 A^2 respectively). Ligand A is slightly better.

**3. logP:** Ligand A (0.398) is a bit low, potentially hindering permeability. Ligand B (2.514) is within the optimal 1-3 range. This favors Ligand B.

**4. H-Bond Donors:** Both have 3 HBD, which is acceptable.

**5. H-Bond Acceptors:** Both have 4 HBA, which is acceptable.

**6. QED:** Both have good QED scores (0.56 and 0.671), indicating drug-like properties. Ligand B is slightly better.

**7. DILI:** Ligand A (9.849%) has a much lower DILI risk than Ligand B (35.479%). This is a significant advantage for Ligand A.

**8. BBB:** Ligand B (63.746%) has a significantly better BBB penetration score than Ligand A (43.117%). This is a crucial factor for a CNS target like DRD2, heavily favoring Ligand B.

**9. Caco-2 Permeability:** Both have negative values (-5.724 and -5.075), which is unusual and suggests poor permeability. However, these values are on a scale where negative values are possible and don't necessarily mean the compound *cannot* be absorbed.

**10. Aqueous Solubility:** Both have negative solubility values (-0.611 and -3.706). This is a concern for both, potentially leading to formulation challenges. Ligand B is worse.

**11. hERG Inhibition:** Both have very low hERG inhibition risk (0.148 and 0.14).

**12. Microsomal Clearance:** Ligand A (-15.463) has a much lower (better) microsomal clearance than Ligand B (35.056), indicating greater metabolic stability. This is a significant advantage for Ligand A.

**13. In vitro Half-Life:** Ligand A (5.483) has a slightly better in vitro half-life than Ligand B (-12.303).

**14. P-gp Efflux:** Both have very low P-gp efflux liability (0.005 and 0.026).

**15. Binding Affinity:** Both have excellent binding affinities (-8.2 and -8.8 kcal/mol). Ligand B is slightly better.

**Overall Assessment:**

Ligand B excels in BBB penetration and has a slightly better logP and binding affinity. However, Ligand A demonstrates superior safety (DILI) and metabolic stability (Cl_mic), and a better half-life. Given the importance of CNS penetration for a DRD2 ligand, and the slight edge in affinity, the BBB score is a critical deciding factor. While the solubility of both is a concern, the lower DILI and better metabolic stability of Ligand A are valuable. However, the significantly higher BBB score of Ligand B outweighs these advantages.

Output:
1
2025-04-17 07:33:43,743 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B based on the provided guidelines, prioritizing GPCR-specific properties (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (352.425 and 348.407 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (40.62) is excellent, well below the 90 A^2 threshold for CNS targets. Ligand B (107.35) is higher, but still potentially acceptable, though less ideal.

**logP:** Ligand A (3.708) is within the optimal 1-3 range. Ligand B (0.782) is quite low, potentially hindering permeability.

**H-Bond Donors/Acceptors:** Ligand A (0 HBD, 2 HBA) is favorable. Ligand B (2 HBD, 6 HBA) is also acceptable, though slightly higher.

**QED:** Both ligands have good QED scores (0.554 and 0.769), indicating good drug-like properties.

**DILI:** Ligand A (37.611) has a lower DILI risk than Ligand B (48.662), both are below the 60 threshold.

**BBB:** This is a critical parameter for a CNS target like DRD2. Ligand A has a very high BBB penetration percentile (89.725), which is excellent. Ligand B's BBB penetration (20.085) is very poor, a significant drawback.

**Caco-2 Permeability:** Ligand A (-3.995) has a negative value, which is unusual and suggests poor permeability. Ligand B (-5.039) is also poor.

**Aqueous Solubility:** Ligand A (-2.433) and Ligand B (-1.491) both have negative solubility values, indicating poor solubility.

**hERG Inhibition:** Ligand A (0.875) has a low hERG risk. Ligand B (0.228) also has a very low hERG risk.

**Microsomal Clearance:** Ligand A (76.58) has a higher clearance than Ligand B (14.616), suggesting lower metabolic stability.

**In vitro Half-Life:** Ligand A (23.438) has a longer half-life than Ligand B (-16.365) which is a negative value and indicates very rapid degradation.

**P-gp Efflux:** Ligand A (0.633) has moderate P-gp efflux, while Ligand B (0.034) has very low P-gp efflux, which is favorable for CNS penetration.

**Binding Affinity:** Ligand A (-8.6 kcal/mol) has a significantly stronger binding affinity than Ligand B (-7.0 kcal/mol). The difference of 1.6 kcal/mol is substantial.

**Overall Assessment:**

Despite Ligand A's higher clearance and poor Caco-2 permeability, its *exceptional* BBB penetration and significantly stronger binding affinity outweigh these drawbacks. The low logP of Ligand B and very poor BBB penetration are major concerns for a CNS-targeting drug. While Ligand B has better metabolic stability and P-gp efflux, the affinity difference and BBB penetration are too significant to ignore.

Output:
1
2025-04-17 07:33:43,744 - INFO - Reasoning:

Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (346.402 and 338.375 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (58.64) is excellent, well below the 90 A^2 threshold for CNS targets. Ligand B (134.5) is higher, but still potentially acceptable, though less ideal.

**3. logP:** Ligand A (2.766) is optimal (1-3). Ligand B (1.479) is on the lower side, potentially hindering permeability.

**4. H-Bond Donors:** Ligand A (1) is good. Ligand B (4) is acceptable, but approaching the upper limit.

**5. H-Bond Acceptors:** Ligand A (3) is good. Ligand B (7) is higher, potentially impacting permeability.

**6. QED:** Ligand A (0.806) is excellent, indicating strong drug-likeness. Ligand B (0.512) is acceptable, but less optimal.

**7. DILI:** Ligand A (44.048) has a lower DILI risk than Ligand B (68.282), which is a significant advantage.

**8. BBB:** Ligand A (73.129) has a much better BBB penetration percentile than Ligand B (30.748). This is *critical* for a CNS target like DRD2.

**9. Caco-2 Permeability:** Ligand A (-4.406) is poor, indicating low intestinal absorption. Ligand B (-6.081) is even worse. This is less critical for a CNS target where direct delivery is possible, but still a consideration.

**10. Aqueous Solubility:** Ligand A (-3.239) is poor. Ligand B (-2.76) is also poor. Solubility is less of a concern for CNS drugs if formulation strategies can be employed.

**11. hERG Inhibition:** Both ligands (0.601 and 0.517) show low hERG inhibition risk, which is good.

**12. Microsomal Clearance:** Ligand A (35.557) has a higher clearance than Ligand B (-4.781), suggesting lower metabolic stability. Ligand B is predicted to be more metabolically stable.

**13. In vitro Half-Life:** Ligand A (-15.902) has a very short half-life. Ligand B (3.344) has a short half-life, but is better than Ligand A.

**14. P-gp Efflux:** Ligand A (0.207) has lower P-gp efflux liability than Ligand B (0.01), which is advantageous for CNS penetration.

**15. Binding Affinity:** Both ligands have very similar binding affinities (-8.4 and -8.6 kcal/mol). The difference is negligible.

**Overall Assessment:**

Ligand A is significantly better due to its superior BBB penetration (73.129 vs 30.748), lower DILI risk (44.048 vs 68.282), and lower P-gp efflux (0.207 vs 0.01). While Ligand B has better metabolic stability and a slightly longer half-life, the CNS target prioritization makes BBB and reduced efflux far more important. The TPSA and logP values of Ligand A are also more favorable. The poor Caco-2 and solubility are less concerning given the CNS focus.

Output:
1
2025-04-17 07:33:43,744 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (343.471 and 336.395 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (75.43) is significantly better than Ligand B (85.01). For CNS targets, we want TPSA <= 90, and A is closer to the optimal <=60 range. B is pushing the upper limit.

**3. logP:** Both ligands have acceptable logP values (2.37 and 3.044), falling within the 1-3 range. Ligand B is slightly higher, which *could* indicate potential off-target effects, but isn't a major concern.

**4. H-Bond Donors:** Both have reasonable HBD counts (2 and 3 respectively), well below the 5 threshold.

**5. H-Bond Acceptors:** Both have reasonable HBA counts (3 and 3 respectively), well below the 10 threshold.

**6. QED:** Ligand A (0.885) has a much better QED score than Ligand B (0.683), indicating a more drug-like profile.

**7. DILI:** Both have acceptable DILI risk (38.93 and 44.087), both below the 60 threshold.

**8. BBB:** This is a critical parameter for a CNS target like DRD2. Ligand A has a very good BBB penetration percentile (85.343), exceeding the desirable >70 threshold. Ligand B is poor (26.987), a significant drawback.

**9. Caco-2 Permeability:** Ligand A (-4.987) and Ligand B (-5.595) both have negative values, suggesting poor permeability. This is a concern, but less critical than BBB for a CNS target.

**10. Aqueous Solubility:** Both have poor aqueous solubility (-3.1 and -3.337). This could pose formulation challenges, but can sometimes be overcome.

**11. hERG Inhibition:** Both ligands have low hERG inhibition risk (0.471 and 0.289).

**12. Microsomal Clearance:** Ligand A (42.756) has higher clearance than Ligand B (-4.358). Lower clearance is preferred for metabolic stability, so Ligand B is better here.

**13. In vitro Half-Life:** Ligand B (-14.636) has a significantly longer in vitro half-life than Ligand A (1.45). This is a major advantage for B.

**14. P-gp Efflux:** Ligand A (0.066) has lower P-gp efflux than Ligand B (0.03), which is desirable for better CNS exposure.

**15. Binding Affinity:** Both have excellent binding affinities (-9.5 and -8.9 kcal/mol), well below the -7.0 threshold. Ligand A is slightly stronger.

**Overall Assessment:**

Ligand A excels in TPSA, QED, and crucially, BBB penetration. Its slightly better affinity is a bonus. Ligand B has better metabolic stability (lower Cl_mic, longer t1/2), but its very poor BBB penetration is a deal-breaker for a CNS target. While solubility is a concern for both, it's a secondary issue compared to getting the drug into the brain.

Output:
1
2025-04-17 07:33:43,744 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (350.371 and 365.499 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (98.07) is slightly above the optimal <90 for CNS targets, while Ligand B (71.53) is well within the desired range. This favors Ligand B.

**logP:** Ligand A (0.285) is quite low, potentially hindering membrane permeability. Ligand B (1.855) is within the optimal 1-3 range. This is a significant advantage for Ligand B.

**H-Bond Donors/Acceptors:** Both ligands have 1 HBD and 5-6 HBA, which are acceptable values.

**QED:** Both ligands have good QED scores (0.71 and 0.835), indicating good drug-like properties.

**DILI:** Ligand A (57.348) has a higher DILI risk than Ligand B (38.542), although both are reasonably acceptable.

**BBB:** Both ligands have acceptable BBB penetration (51.415 and 59.984), but neither is exceptionally high.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values, which is unusual and suggests poor permeability. This is a concern for both.

**Aqueous Solubility:** Both ligands have negative solubility values, indicating poor aqueous solubility. This is a significant drawback for both.

**hERG Inhibition:** Both ligands show very low hERG inhibition risk (0.02 and 0.192), which is excellent.

**Microsomal Clearance:** Ligand A (-0.835) has a negative and therefore very low clearance, suggesting high metabolic stability. Ligand B (31.561) has a much higher clearance, indicating faster metabolism. This favors Ligand A.

**In vitro Half-Life:** Ligand A (5.714 hours) has a shorter half-life than Ligand B (8.222 hours).

**P-gp Efflux:** Both ligands show very low P-gp efflux liability (0.022 and 0.053), which is favorable for CNS penetration.

**Binding Affinity:** Ligand B (-7.8 kcal/mol) has a significantly stronger binding affinity than Ligand A (-6.6 kcal/mol). This 1.2 kcal/mol difference is substantial and can outweigh some ADME drawbacks.

**Overall Assessment:**

Ligand B is the stronger candidate. While both have issues with Caco-2 and solubility, Ligand B has a much better logP, a significantly higher binding affinity, and a lower DILI risk. The higher metabolic clearance of Ligand B is a concern, but the superior binding affinity is a critical advantage for a GPCR target. The TPSA is also more favorable for Ligand B.

Output:
1
2025-04-17 07:33:43,744 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 drug candidates, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (363.502) is slightly higher than Ligand B (335.407), but both are acceptable.

**2. TPSA:** Ligand A (36.44) is excellent, well below the 90 Angstroms threshold for CNS targets. Ligand B (56.15) is higher, but still reasonable.

**3. logP:** Both ligands have good logP values (A: 3.685, B: 3.838), falling within the optimal 1-3 range.

**4. H-Bond Donors:** Both ligands have a low number of HBDs (A: 0, B: 1), which is favorable for permeability.

**5. H-Bond Acceptors:** Both ligands have a reasonable number of HBAs (A: 4, B: 4), within the acceptable limit of 10.

**6. QED:** Both ligands have good QED scores (A: 0.718, B: 0.771), indicating drug-like properties.

**7. DILI:** Ligand A (36.293) has a significantly lower DILI risk than Ligand B (72.586). This is a substantial advantage for Ligand A.

**8. BBB:** Ligand A (87.553) has a much better BBB penetration percentile than Ligand B (69.135). This is critical for a CNS target like DRD2.

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 values, which is unusual and suggests poor permeability. However, the scale is not defined, so it's hard to interpret.

**10. Aqueous Solubility:** Both ligands have negative solubility values, which is also unusual.

**11. hERG Inhibition:** Both ligands have low hERG inhibition liability (A: 0.91, B: 0.69), which is good.

**12. Microsomal Clearance:** Ligand B (61.293) has a higher microsomal clearance than Ligand A (43.873), indicating lower metabolic stability.

**13. In vitro Half-Life:** Ligand A (55.17) has a significantly longer in vitro half-life than Ligand B (16.399).

**14. P-gp Efflux:** Both ligands have low P-gp efflux liability (A: 0.665, B: 0.649).

**15. Binding Affinity:** Ligand B (-9.3 kcal/mol) has a stronger binding affinity than Ligand A (-7.7 kcal/mol). This is a 1.6 kcal/mol difference, which is substantial.

**Overall Assessment:**

While Ligand B has a better binding affinity, Ligand A is the more promising candidate due to its superior ADME properties. Specifically, the significantly lower DILI risk, much better BBB penetration, and longer half-life are crucial advantages for a CNS-targeting drug. The difference in binding affinity, while notable, can potentially be overcome with further optimization, whereas poor ADME properties are harder to fix later in development.

Output:
0
2025-04-17 07:33:43,744 - INFO - Reasoning:

Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (346.39 and 376.79 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (106.6) is slightly higher than Ligand B (95.42). Both are below the 140 threshold for oral absorption and reasonably close to the 90 target for CNS penetration, but Ligand B is better.

**3. logP:** Ligand A (-0.23) is significantly lower than the optimal 1-3 range, potentially hindering permeability. Ligand B (1.03) is within the optimal range. This is a significant advantage for Ligand B.

**4. H-Bond Donors:** Both ligands have 2 HBD, which is acceptable.

**5. H-Bond Acceptors:** Both ligands have 5 HBA, which is acceptable.

**6. QED:** Both ligands have similar QED values (0.716 and 0.723), indicating good drug-likeness.

**7. DILI:** Ligand A (62.08) has a higher DILI risk than Ligand B (40.05). Ligand B is preferable.

**8. BBB:** Ligand B (65.80) has a much better BBB penetration percentile than Ligand A (25.48). This is *critical* for a CNS target like DRD2.

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 values, which is unusual and suggests poor permeability. However, the scale is not specified, so we can't interpret the absolute values.

**10. Aqueous Solubility:** Both ligands have negative solubility values, suggesting poor solubility. Again, the scale is not specified.

**11. hERG Inhibition:** Ligand A (0.046) has a slightly lower hERG inhibition risk than Ligand B (0.217), but both are very low.

**12. Microsomal Clearance:** Ligand A (-8.765) has a much lower (better) microsomal clearance than Ligand B (1.47). This suggests greater metabolic stability for Ligand A.

**13. In vitro Half-Life:** Ligand A (-23.632) has a much longer in vitro half-life than Ligand B (-12.733). This is a significant advantage for Ligand A.

**14. P-gp Efflux:** Ligand A (0.016) has a lower P-gp efflux liability than Ligand B (0.012), which is preferable for CNS exposure.

**15. Binding Affinity:** Both ligands have very similar binding affinities (-7.6 and -7.4 kcal/mol). The difference is not substantial enough to override other factors.

**Overall Assessment:**

Ligand B is significantly better due to its superior logP and BBB penetration, both critical for a CNS GPCR target. While Ligand A has better metabolic stability and half-life, the poor logP and BBB penetration are major drawbacks. The slightly higher DILI risk of Ligand A is also a concern.

Output:
1
2025-04-17 07:33:43,744 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (348.447 and 361.404 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (96.25) is slightly above the optimal <90 for CNS targets, but still reasonable. Ligand B (34.84) is excellent, well below 90, suggesting good CNS penetration potential.

**3. logP:** Ligand A (1.048) is at the lower end of the optimal 1-3 range, potentially impacting permeability. Ligand B (3.99) is closer to the upper end, which is good for permeability but could raise solubility concerns.

**4. H-Bond Donors:** Ligand A (3) is within the acceptable limit of <=5. Ligand B (0) is also good, potentially improving membrane permeability.

**5. H-Bond Acceptors:** Ligand A (5) is within the acceptable limit of <=10. Ligand B (4) is also good.

**6. QED:** Both ligands have similar QED values (0.642 and 0.59), indicating reasonable drug-likeness.

**7. DILI:** Both ligands have low DILI risk (27.336 and 20.396), which is favorable.

**8. BBB:** This is a critical parameter for a CNS target. Ligand A has a BBB percentile of 47.344, which is below the desirable >70. Ligand B has a significantly higher BBB percentile of 96.045, making it much more likely to cross the blood-brain barrier.

**9. Caco-2:** Ligand A (-5.1) and Ligand B (-4.63) both have negative values, which is unusual. These values are likely on a log scale, and indicate very poor permeability.

**10. Solubility:** Ligand A (-1.481) and Ligand B (-3.209) both have negative solubility values, suggesting poor aqueous solubility.

**11. hERG:** Ligand A (0.24) has a very low hERG risk, which is excellent. Ligand B (0.983) is slightly higher, but still relatively low.

**12. Cl_mic:** Ligand A (-6.288) has a negative value, which is unusual for microsomal clearance. This likely indicates very low clearance, and therefore high metabolic stability. Ligand B (20.201) has a higher clearance, suggesting faster metabolism.

**13. t1/2:** Ligand A (8.006) has a reasonable in vitro half-life. Ligand B (66.007) has a significantly longer half-life, which is a major advantage.

**14. Pgp:** Ligand A (0.027) has very low P-gp efflux liability, which is excellent for CNS penetration. Ligand B (0.549) has moderate P-gp efflux, which could limit CNS exposure.

**15. Binding Affinity:** Ligand A (-8.7) has a significantly stronger binding affinity than Ligand B (-7.3). This is a substantial advantage (>1.5 kcal/mol difference).

**Overall Assessment:**

While Ligand A has a superior binding affinity and excellent P-gp and hERG profiles, its poor BBB penetration and questionable Caco-2 permeability are major drawbacks for a CNS target. Ligand B, despite slightly weaker binding, exhibits excellent BBB penetration, a longer half-life, and low DILI risk. The combination of these factors, particularly the high BBB value, makes Ligand B the more promising candidate for DRD2 targeting, despite the lower affinity. The affinity difference can be addressed in subsequent optimization rounds.

Output:
1
2025-04-17 07:33:43,745 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (348.403 Da) is slightly lower, which is generally favorable for permeability.

**TPSA:** Ligand A (108.46) is better than Ligand B (132.44). For CNS targets, we want TPSA <= 90, so Ligand A is closer to this target.

**logP:** Ligand A (1.59) is within the optimal range (1-3). Ligand B (-0.594) is below 1, potentially hindering permeation. This is a significant disadvantage for Ligand B.

**H-Bond Donors/Acceptors:** Ligand A (HBD=1, HBA=6) is preferable to Ligand B (HBD=2, HBA=7) as it has fewer hydrogen bond donors and acceptors, which can improve membrane permeability. Both are within acceptable limits.

**QED:** Both ligands have reasonable QED values (A: 0.885, B: 0.593), indicating good drug-like properties. Ligand A is better.

**DILI:** Both have acceptable DILI risk (A: 47.654, B: 52.152), below the 60 threshold.

**BBB:** Ligand A (48.74) is lower than Ligand B (58.782). While both are not ideal (>70 desirable), Ligand B has a better BBB score.

**Caco-2 Permeability:** Ligand A (-4.454) is worse than Ligand B (-5.107). Lower values indicate poorer permeability.

**Aqueous Solubility:** Ligand A (-3.301) is better than Ligand B (-1.831). Higher values are preferred.

**hERG:** Both ligands have very low hERG inhibition liability (A: 0.272, B: 0.08), which is excellent.

**Microsomal Clearance:** Both ligands have similar microsomal clearance (A: 28.218, B: 27.782).

**In vitro Half-Life:** Ligand A (-10.139) is significantly better than Ligand B (-3.661). A longer half-life is generally desirable.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (A: 0.023, B: 0.015).

**Binding Affinity:** Ligand B (-7.4 kcal/mol) has a slightly better binding affinity than Ligand A (-7.1 kcal/mol). However, the difference is not substantial enough to outweigh the significant ADME drawbacks of Ligand B.

**Overall Assessment:**

Ligand A is superior due to its better logP, TPSA, solubility, and half-life. While Ligand B has slightly better BBB penetration and binding affinity, the negative logP and poor solubility are major concerns for CNS penetration and bioavailability. The difference in binding affinity (0.3 kcal/mol) is unlikely to overcome these ADME liabilities. Given the GPCR-specific priorities, Ligand A is the more promising candidate.

Output:
1
2025-04-17 07:33:43,745 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 drug candidates, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (359.861 and 348.443 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (61.36) is significantly better than Ligand B (70.08). For CNS targets, we want TPSA <= 90, and ideally closer to 60. Ligand A is much closer to the ideal.

**3. logP:** Ligand A (3.608) is within the optimal 1-3 range. Ligand B (0.801) is quite low, potentially hindering membrane permeability.

**4. H-Bond Donors:** Both ligands have 1 HBD, which is acceptable.

**5. H-Bond Acceptors:** Both ligands have 4 HBA, which is acceptable.

**6. QED:** Both ligands have similar QED values (0.85 and 0.816), indicating good drug-likeness.

**7. DILI:** Ligand A (62.699) has a higher DILI risk than Ligand B (7.716). This is a significant drawback for Ligand A.

**8. BBB:** Ligand A (93.098) has excellent BBB penetration, exceeding the desirable >70 threshold. Ligand B (73.788) also shows good BBB penetration, but is lower than Ligand A.

**9. Caco-2 Permeability:** Ligand A (-4.805) has poor Caco-2 permeability, while Ligand B (-4.473) is slightly better, but still poor.

**10. Aqueous Solubility:** Ligand A (-4.994) has very poor aqueous solubility, while Ligand B (-1.178) is better, but still low.

**11. hERG Inhibition:** Ligand A (0.616) has a slightly higher hERG risk than Ligand B (0.228).

**12. Microsomal Clearance:** Ligand B (4.731) has significantly lower microsomal clearance (better metabolic stability) than Ligand A (65.377).

**13. In vitro Half-Life:** Ligand B (18.137) has a longer in vitro half-life than Ligand A (24.43).

**14. P-gp Efflux:** Ligand A (0.225) has lower P-gp efflux than Ligand B (0.02), which is favorable for CNS exposure.

**15. Binding Affinity:** Ligand A (-8.1) has a significantly stronger binding affinity than Ligand B (-0.0). This is a major advantage for Ligand A.

**Overall Assessment:**

Ligand A has a much stronger binding affinity and better BBB penetration, which are crucial for a CNS GPCR target like DRD2. However, it suffers from poor solubility, poor Caco-2 permeability, higher DILI risk, and higher hERG risk. Ligand B has better ADME properties (lower DILI, better metabolic stability, longer half-life) but a very weak binding affinity.

The difference in binding affinity (-8.1 vs -0.0 kcal/mol) is substantial. A difference of >1.5 kcal/mol can often outweigh ADME drawbacks, especially if those drawbacks can be addressed through formulation or structural modifications. The poor solubility and permeability of Ligand A are concerning, but potentially manageable. The DILI risk is also a concern, but could be mitigated with further optimization. The strong binding affinity of Ligand A is a significant advantage, and the good BBB penetration is critical for a CNS target.

Output:
1
2025-04-17 07:33:43,745 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (346.431 Da) is slightly lower, which *could* be beneficial for permeability, but both are acceptable.

**TPSA:** Ligand A (83.56) is better than Ligand B (61.88) as it is closer to the ideal range for CNS targets (<=90).

**logP:** Both ligands have good logP values (A: 1.692, B: 1.761), falling within the optimal 1-3 range.

**H-Bond Donors & Acceptors:** Ligand A has 2 HBD and 4 HBA, while Ligand B has 1 HBD and 4 HBA. Both are within acceptable limits (<=5 HBD, <=10 HBA).

**QED:** Ligand A (0.872) has a significantly higher QED score than Ligand B (0.627), indicating better overall drug-likeness.

**DILI:** Ligand A (46.297) has a higher DILI risk than Ligand B (23.924), but both are below the concerning threshold of 60.

**BBB:** Ligand B (66.499) has a better BBB penetration percentile than Ligand A (56.456). While both are not ideal (>70), Ligand B is closer.

**Caco-2 Permeability:** Ligand A (-4.99) has a worse Caco-2 permeability than Ligand B (-5.012). Both are very poor.

**Aqueous Solubility:** Ligand A (-1.482) has a slightly worse aqueous solubility than Ligand B (-1.161). Both are poor.

**hERG Inhibition:** Ligand A (0.095) shows slightly higher hERG inhibition risk than Ligand B (0.41), but both are very low risk.

**Microsomal Clearance:** Ligand A (-13.028) has significantly lower microsomal clearance than Ligand B (33.624), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand B (42.771) has a significantly longer in vitro half-life than Ligand A (3.238).

**P-gp Efflux:** Ligand A (0.01) has a much lower P-gp efflux liability than Ligand B (0.019), which is crucial for CNS penetration.

**Binding Affinity:** Ligand B (-7.0) has a significantly stronger binding affinity than Ligand A (0.0). This is a major advantage, potentially outweighing some ADME drawbacks.

**Overall Assessment:**

Ligand B is the stronger candidate. The significantly improved binding affinity (-7.0 kcal/mol vs 0.0 kcal/mol) is a critical advantage for a GPCR target. While Ligand A has better QED and lower P-gp efflux, the substantial difference in affinity and the better BBB penetration of Ligand B are more important for a CNS-targeting drug. The longer half-life of Ligand B is also a positive attribute. Although both have poor Caco-2 and solubility, the binding affinity is the most important factor here.

Output:
1
2025-04-17 07:33:43,745 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (351.447 and 366.571 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (84.67) is excellent, falling well below the 90 A^2 threshold for CNS targets. Ligand B (42.43) is also very good.

**logP:** Ligand A (3.175) is optimal. Ligand B (4.893) is slightly higher, potentially increasing off-target effects, but still within a reasonable range.

**H-Bond Donors/Acceptors:** Ligand A has 1 HBD and 5 HBA, which is acceptable. Ligand B has 0 HBD and 4 HBA, also acceptable.

**QED:** Both ligands have good QED scores (0.9 and 0.657, respectively), indicating drug-like properties.

**DILI:** Ligand A (44.009) has a slightly higher DILI risk than Ligand B (14.773), but both are below the concerning 60 percentile.

**BBB:** Ligand A (85.111) has good BBB penetration, while Ligand B (91.508) is even better, exceeding 90%. This is a crucial factor for a CNS target like DRD2.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.334 and -4.455), which is unusual and suggests poor permeability. This is a significant drawback.

**Aqueous Solubility:** Both ligands have negative solubility values (-3.859 and -4.443), also indicating poor solubility. This is another significant drawback.

**hERG Inhibition:** Both ligands show very low hERG inhibition risk (0.554 and 0.685).

**Microsomal Clearance:** Ligand A (57.75) has lower microsomal clearance than Ligand B (110.014), indicating better metabolic stability.

**In vitro Half-Life:** Ligand A has a negative half-life (-14.307), which is not physically possible and suggests an issue with the data. Ligand B has a half-life of 11.467 hours, which is reasonable.

**P-gp Efflux:** Ligand A (0.092) has significantly lower P-gp efflux than Ligand B (0.633), which is favorable for CNS penetration.

**Binding Affinity:** Ligand A (-8.2 kcal/mol) has a substantially stronger binding affinity than Ligand B (-6.8 kcal/mol). This is a significant advantage, potentially outweighing some of the ADME drawbacks.

**Overall Assessment:**

Ligand A has a much stronger binding affinity and lower P-gp efflux, which are highly desirable for a CNS GPCR target. However, its negative half-life is a major red flag, suggesting a data error or inherent instability. Ligand B has better BBB penetration and a reasonable half-life, but its affinity is weaker, and P-gp efflux is higher. Despite the issues with solubility and permeability for both, the superior affinity of Ligand A is a compelling factor, *assuming the half-life data is incorrect*. Given the importance of affinity for GPCRs, and the better metabolic stability of A, I would proceed with investigating the source of the negative half-life for Ligand A.

Output:
1
2025-04-17 07:33:43,746 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 drug candidates, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (359.461 and 370.559 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (52.65) is better than Ligand B (49.85) as it is closer to the <90 target for CNS penetration. Both are acceptable.

**3. logP:** Both ligands have good logP values (2.115 and 2.783), falling within the optimal 1-3 range.

**4. H-Bond Donors:** Ligand A (1) is preferable to Ligand B (0) as it provides a slight advantage in solubility. Both are within the acceptable limit of <=5.

**5. H-Bond Acceptors:** Ligand A (3) is preferable to Ligand B (4). Both are within the acceptable limit of <=10.

**6. QED:** Both ligands have similar QED values (0.79 and 0.721), indicating good drug-likeness.

**7. DILI:** Ligand A (9.965) has a significantly lower DILI risk than Ligand B (25.475). This is a major advantage for Ligand A.

**8. BBB:** Ligand A (92.943) has a much higher BBB penetration percentile than Ligand B (69.407). This is crucial for a CNS target like DRD2.

**9. Caco-2 Permeability:** Both ligands have very poor Caco-2 permeability (-4.632 and -4.615). This is a concern for oral bioavailability, but less critical for CNS targets where direct delivery or other routes are possible.

**10. Aqueous Solubility:** Both ligands have poor aqueous solubility (-1.456 and -2.28). This could pose formulation challenges.

**11. hERG Inhibition:** Both ligands have low hERG inhibition risk (0.39 and 0.297).

**12. Microsomal Clearance:** Ligand A (-1.42) has a lower (better) microsomal clearance than Ligand B (53.592), indicating greater metabolic stability.

**13. In vitro Half-Life:** Ligand A (-15.171) has a much longer in vitro half-life than Ligand B (12.292).

**14. P-gp Efflux:** Ligand A (0.018) has significantly lower P-gp efflux liability than Ligand B (0.206). Lower P-gp efflux is highly desirable for CNS penetration.

**15. Binding Affinity:** Ligand B (0.0) has a better binding affinity than Ligand A (-8.3). However, the difference in binding affinity (8.3 kcal/mol) is not enough to overcome the significant advantages of Ligand A in terms of ADME properties, especially BBB penetration and metabolic stability.

**Overall Assessment:**

Ligand A is the superior candidate. While Ligand B has slightly better binding affinity, Ligand A demonstrates significantly better ADME properties, particularly concerning CNS penetration (BBB, P-gp efflux) and safety (DILI). The lower clearance and longer half-life of Ligand A also contribute to its improved profile. For a CNS GPCR target, these factors are more critical than a small difference in binding affinity.

Output:
1
2025-04-17 07:33:43,746 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (337.463 and 349.475 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (29.54) is excellent, well below the 90 A^2 threshold for CNS targets. Ligand B (82.53) is higher but still reasonable, though less favorable.

**logP:** Ligand A (4.407) is slightly high, potentially leading to solubility issues or off-target interactions. Ligand B (2.602) is optimal.

**H-Bond Donors/Acceptors:** Ligand A (0 HBD, 2 HBA) is very favorable. Ligand B (2 HBD, 4 HBA) is also acceptable.

**QED:** Both ligands have reasonable QED values (0.827 and 0.756), indicating good drug-like properties.

**DILI:** Ligand A (42.691) has a slightly higher DILI risk than Ligand B (30.477), but both are below the concerning 60 percentile.

**BBB:** Ligand A (78.558) has a good BBB penetration score, desirable for a CNS target. Ligand B (52.23) is significantly lower, which is a major drawback.

**Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and suggests a potential issue with the data or modeling. However, we'll proceed assuming this represents low permeability.

**Aqueous Solubility:** Both ligands have very poor aqueous solubility (-5.05 and -2.614). This is a significant concern.

**hERG Inhibition:** Both ligands show low hERG inhibition liability (0.884 and 0.575), which is good.

**Microsomal Clearance:** Both have similar microsomal clearance values (70.124 and 71.622), indicating comparable metabolic stability.

**In vitro Half-Life:** Both have negative in vitro half-life values (-14.985 and -13.649), which is unusual and suggests a potential issue with the data or modeling.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.854 and 0.068), which is favorable for CNS penetration.

**Binding Affinity:** Both ligands have similar and strong binding affinities (-8.5 and -8.9 kcal/mol). The difference is negligible.

**Overall Assessment:**

Ligand A excels in TPSA and BBB penetration, which are crucial for CNS GPCR targets. While its logP is slightly elevated and solubility is poor, the strong BBB score and comparable affinity outweigh these drawbacks. Ligand B has a better logP and lower DILI risk, but its significantly lower BBB penetration is a major disadvantage for a CNS-acting drug. The solubility issues are concerning for both, but formulation strategies might mitigate this. Given the importance of CNS penetration for DRD2, Ligand A is the more promising candidate.

Output:
0
2025-04-17 07:33:43,746 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (343.43 and 366.46 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (75.44) is better than Ligand B (55.57). Both are below the 90 A^2 threshold for CNS targets, but A is closer to the upper limit.

**3. logP:** Ligand A (2.164) is within the optimal 1-3 range. Ligand B (3.851) is at the higher end of the optimal range, potentially increasing off-target interactions.

**4. H-Bond Donors:** Ligand A (1) is preferable to Ligand B (0) as it can contribute to solubility.

**5. H-Bond Acceptors:** Ligand A (4) and Ligand B (5) are both acceptable, being under the 10 threshold.

**6. QED:** Ligand A (0.85) is significantly better than Ligand B (0.5), indicating a more drug-like profile.

**7. DILI:** Ligand A (48.82) has a slightly higher DILI risk than Ligand B (34.63), but both are below the concerning 60 threshold.

**8. BBB:** Both ligands show excellent BBB penetration (Ligand A: 81.35%, Ligand B: 88.83%). Ligand B is slightly better here.

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.01 and -4.95), which is unusual and suggests poor permeability. This is a significant concern for both.

**10. Aqueous Solubility:** Both ligands have negative solubility values (-2.784 and -4.285), indicating very poor aqueous solubility. This is a major drawback for both.

**11. hERG Inhibition:** Ligand A (0.289) has a much lower hERG risk than Ligand B (0.661).

**12. Microsomal Clearance:** Ligand A (60.75) has a lower (better) microsomal clearance than Ligand B (121.25), indicating greater metabolic stability.

**13. In vitro Half-Life:** Ligand A (-30.97) has a negative half-life, which is impossible. Ligand B (24.03) has a reasonable half-life. This is a major red flag for Ligand A.

**14. P-gp Efflux:** Both ligands have low P-gp efflux liability (-0.311 and -0.468), which is good for CNS penetration.

**15. Binding Affinity:** Ligand A (-9.0) has a significantly stronger binding affinity than Ligand B (-6.6). This is a substantial advantage.

**Overall Assessment:**

Despite the poor Caco-2 and solubility for both, Ligand A is the more promising candidate. The significantly stronger binding affinity (-9.0 vs -6.6 kcal/mol) is a major advantage that could potentially overcome some of the ADME liabilities. Ligand A also has a better QED score, lower hERG risk, and better metabolic stability. The negative half-life for Ligand A is a serious concern, but the affinity difference is so large that it warrants further investigation into the half-life measurement. Ligand B's higher logP and worse QED make it less attractive.

Output:
1
2025-04-17 07:33:43,746 - INFO - Reasoning:

Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (348.531 and 347.459 Da) fall comfortably within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (58.2) is significantly better than Ligand B (80.32). For CNS targets, we want TPSA <= 90, and A is much closer to the optimal <=60 range. B is pushing the upper limit.

**3. logP:** Both ligands have good logP values (3.793 and 2.388), falling within the 1-3 range.

**4. H-Bond Donors:** Both have 2 HBD, which is acceptable.

**5. H-Bond Acceptors:** Ligand A has 2 HBA, while Ligand B has 4. Both are within the acceptable limit of <=10, but A is preferable.

**6. QED:** Both ligands have similar QED values (0.688 and 0.672), indicating good drug-likeness.

**7. DILI:** Ligand A (27.685) has a lower DILI risk than Ligand B (32.61), both are good.

**8. BBB:** This is crucial for a CNS target like DRD2. Ligand A (71.539) has a significantly better BBB percentile than Ligand B (58.938). A value >70 is desirable, and A is closer.

**9. Caco-2 Permeability:** Both have negative Caco-2 values (-4.679 and -4.766). This is unusual and suggests poor permeability. However, the values are very similar.

**10. Aqueous Solubility:** Both have negative solubility values (-4.778 and -2.592). This is also concerning, but again, similar between the two.

**11. hERG Inhibition:** Both ligands show low hERG inhibition liability (0.351 and 0.406), which is good.

**12. Microsomal Clearance:** Ligand A (63.466) has lower microsomal clearance than Ligand B (68.1), suggesting better metabolic stability.

**13. In vitro Half-Life:** Ligand B (2.762) has a longer in vitro half-life than Ligand A (-1.624). This is a slight advantage for B.

**14. P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.237 and 0.051).

**15. Binding Affinity:** Ligand B (-7.6) has a significantly stronger binding affinity than Ligand A (0). A difference of >1.5 kcal/mol is considered substantial.

**Overall Assessment:**

While Ligand B has a superior binding affinity, Ligand A is more favorable overall due to its significantly better TPSA and BBB penetration. For a CNS target like DRD2, these properties are paramount. The slightly longer half-life of Ligand B is a minor advantage, but it's outweighed by the superior ADME properties of Ligand A. The similar poor Caco-2 and solubility values are concerning for both, but can be addressed with formulation strategies. The stronger binding affinity of B might be able to overcome these issues, but the improved CNS penetration of A is more critical for this target.

Output:
0
2025-04-17 07:33:43,746 - INFO - Batch 375 complete. Total preferences: 6000
2025-04-17 07:33:43,746 - INFO - Processing batch 376/512...
2025-04-17 07:34:23,493 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (360.332 Da) is slightly higher than Ligand B (267.328 Da), but both are acceptable.

**TPSA:** Ligand A (84.5) is better than Ligand B (43.7). For CNS targets, we want TPSA <= 90, and both meet this criterion, but A is closer to the upper limit.

**logP:** Both ligands have good logP values (Ligand A: 1.475, Ligand B: 2.85), falling within the optimal range of 1-3.

**H-Bond Donors/Acceptors:** Both have 2 HBD and a reasonable number of HBA (Ligand A: 4, Ligand B: 3), satisfying the criteria of <=5 HBD and <=10 HBA.

**QED:** Both ligands have similar QED values (Ligand A: 0.753, Ligand B: 0.721), indicating good drug-likeness.

**DILI:** Ligand A (41.838) has a slightly better DILI score than Ligand B (52.695), both are acceptable, but lower is better.

**BBB:** This is a critical parameter for CNS targets. Ligand B (83.908) significantly outperforms Ligand A (60.45). A BBB percentile >70 is desirable, and Ligand B is much closer to this threshold.

**Caco-2 Permeability:** Ligand A (-4.724) is significantly worse than Ligand B (-5.024), indicating lower intestinal absorption.

**Aqueous Solubility:** Ligand A (-2.735) is slightly better than Ligand B (-3.24), but both are poor.

**hERG Inhibition:** Ligand A (0.304) has a lower hERG risk than Ligand B (0.756), which is preferable.

**Microsomal Clearance:** Ligand B (31.328) has a much lower microsomal clearance than Ligand A (60.251), indicating better metabolic stability.

**In vitro Half-Life:** Ligand B (16.712) has a longer half-life than Ligand A (-23.03), which is desirable.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (Ligand A: 0.024, Ligand B: 0.193), which is good for CNS penetration.

**Binding Affinity:** Ligand B (-9.3 kcal/mol) has a slightly better binding affinity than Ligand A (-9.0 kcal/mol). While the difference is small, it's still a factor.

**Overall Assessment:**

Ligand B is the stronger candidate. Its superior BBB penetration (83.9 vs 60.45), lower microsomal clearance, longer half-life, and slightly better binding affinity outweigh the slightly higher hERG risk and lower solubility. The TPSA is also more favorable for CNS penetration. While Ligand A has a slightly better DILI score and hERG, the CNS-specific properties are more critical for a DRD2 ligand.

Output:
1
2025-04-17 07:34:23,494 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (356.438 and 353.467 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (59.08) is excellent, well below the 90 A^2 threshold for CNS targets. Ligand B (86.27) is still reasonable but higher, potentially impacting BBB penetration.

**3. logP:** Ligand A (1.379) is optimal. Ligand B (-0.202) is slightly low, potentially hindering membrane permeability.

**4. H-Bond Donors:** Ligand A (0) is good. Ligand B (2) is acceptable.

**5. H-Bond Acceptors:** Ligand A (4) is good. Ligand B (6) is acceptable.

**6. QED:** Both ligands have reasonable QED values (0.767 and 0.631), indicating good drug-like properties.

**7. DILI:** Ligand A (30.748) has a very low DILI risk. Ligand B (7.949) also has a low DILI risk, but slightly higher than A.

**8. BBB:** This is crucial for a CNS target. Ligand A (89.531) has excellent BBB penetration potential. Ligand B (38.736) has poor BBB penetration.

**9. Caco-2 Permeability:** Ligand A (-4.348) is concerningly low, suggesting poor intestinal absorption. Ligand B (-5.54) is also low, but slightly worse.

**10. Aqueous Solubility:** Ligand A (-1.162) is poor. Ligand B (-0.409) is also poor. Solubility is not a primary concern if BBB penetration is good, but it could affect formulation.

**11. hERG Inhibition:** Both ligands have very low hERG risk (0.314 and 0.106).

**12. Microsomal Clearance:** Ligand A (14.747) has moderate clearance. Ligand B (-17.11) has negative clearance which is not possible and indicates an error or outlier.

**13. In vitro Half-Life:** Ligand A (2.38) has a short half-life. Ligand B (9.736) has a significantly longer half-life.

**14. P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.043 and 0.001).

**15. Binding Affinity:** Ligand B (-7.7) has a significantly stronger binding affinity than Ligand A (0). This is a substantial advantage.

**Overall Assessment:**

Despite the slightly low logP, Ligand B's significantly superior binding affinity (-7.7 kcal/mol vs 0 kcal/mol) and longer half-life are major advantages. The biggest drawback for Ligand B is the poor BBB penetration (38.736). However, the strong binding affinity might compensate for this to some extent, potentially allowing for lower doses to achieve therapeutic effects. Ligand A has excellent BBB penetration but extremely weak binding affinity and poor Caco-2 permeability, making it unlikely to be effective. The negative clearance value for Ligand B is a red flag and needs further investigation, but assuming it's an error, the overall profile is more promising.

Output:
1
2025-04-17 07:34:23,494 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (347.419 and 360.487 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (105.12) is slightly above the optimal <90 for CNS targets, while Ligand B (81.17) is comfortably below. This favors Ligand B.

**logP:** Ligand A (-0.192) is quite low, potentially hindering membrane permeability. Ligand B (1.444) is within the optimal 1-3 range. This is a significant advantage for Ligand B.

**H-Bond Donors/Acceptors:** Ligand A has 3 HBD and 5 HBA, which are acceptable. Ligand B has 2 HBD and 7 HBA, also acceptable.

**QED:** Both ligands have good QED scores (0.567 and 0.835), indicating drug-like properties.

**DILI:** Ligand A (40.287) has a lower DILI risk than Ligand B (68.941), which is a positive for Ligand A.

**BBB:** Ligand A (41.218) has a very low BBB penetration, making it less suitable for a CNS target like DRD2. Ligand B (37.379) is also low, but slightly better than A. Both are below the desirable >70.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.861 and -5.579), which is unusual and suggests poor permeability. This is a concern for both.

**Aqueous Solubility:** Both ligands have negative solubility values (-1.673 and -2.43), indicating very poor aqueous solubility. This is a significant drawback for both.

**hERG Inhibition:** Ligand A (0.029) has a very low hERG risk, while Ligand B (0.64) has a slightly elevated risk. This favors Ligand A.

**Microsomal Clearance:** Ligand A (-14.506) has a much lower (better) microsomal clearance than Ligand B (45.988), indicating better metabolic stability.

**In vitro Half-Life:** Ligand A (22.811 hours) has a longer half-life than Ligand B (11.791 hours), which is desirable.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.008 and 0.043), which is good for CNS penetration.

**Binding Affinity:** Both ligands have excellent binding affinities (-8.5 and -8.0 kcal/mol). The difference of 0.5 kcal/mol is not substantial enough to outweigh other significant differences.

**Overall Assessment:**

Considering the GPCR-specific priorities, Ligand B is favored despite its higher DILI and hERG risk. The primary reason is its significantly better logP value (1.444 vs -0.192), which is crucial for membrane permeability and CNS penetration. While both have poor solubility and Caco-2 permeability, the logP difference is more impactful for a CNS target. Ligand A's very low logP and BBB penetration are major liabilities. Ligand B also has a better TPSA. While Ligand A has better metabolic stability and lower DILI, the permeability issues are too significant to ignore for a CNS-acting drug.

Output:
1
2025-04-17 07:34:23,494 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (350.434 and 348.403 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (58.64) is excellent, well below the 90 A^2 threshold for CNS targets. Ligand B (124.34) is higher, but still potentially acceptable, though less ideal.

**logP:** Ligand A (2.688) is optimal (1-3). Ligand B (0.835) is a bit low, potentially hindering permeation.

**H-Bond Donors/Acceptors:** Ligand A (HBD=1, HBA=3) is good. Ligand B (HBD=3, HBA=6) is also acceptable, but slightly higher counts could impact permeability.

**QED:** Ligand A (0.822) is excellent, indicating strong drug-likeness. Ligand B (0.654) is still acceptable, but lower.

**DILI:** Ligand A (22.8) has a very low DILI risk. Ligand B (54.827) is higher, indicating a moderate risk, but not alarming.

**BBB:** This is crucial for a CNS target. Ligand A (87.088) has excellent BBB penetration potential. Ligand B (20.861) is very poor, a significant drawback.

**Caco-2 Permeability:** Ligand A (-4.329) is poor. Ligand B (-5.263) is even worse. Both are problematic, but the lower the value, the worse the permeability.

**Aqueous Solubility:** Both ligands have poor aqueous solubility (-3.215 and -3.014 respectively). This could pose formulation challenges.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.594 and 0.266 respectively).

**Microsomal Clearance:** Ligand A (51.31) is moderate, suggesting moderate metabolic stability. Ligand B (2.313) is very low, indicating excellent metabolic stability.

**In vitro Half-Life:** Ligand A (-10.144) has a very long half-life. Ligand B (7.855) has a shorter half-life.

**P-gp Efflux:** Ligand A (0.136) has low P-gp efflux, which is good for CNS penetration. Ligand B (0.067) also has low P-gp efflux.

**Binding Affinity:** Both ligands have very similar and excellent binding affinities (-7.8 and -7.7 kcal/mol). The difference is negligible.

**Overall Assessment:**

Ligand A is the superior candidate. While both have similar binding affinities, Ligand A's significantly better BBB penetration (87.088 vs 20.861) is the deciding factor for a CNS target like DRD2. The better TPSA, QED, and lower DILI risk further support this conclusion. The poor Caco-2 permeability and solubility are drawbacks for both, but are less critical than BBB penetration for a CNS drug. Ligand B's excellent metabolic stability is a plus, but it's overshadowed by the poor BBB score.

Output:
0
2025-04-17 07:34:23,494 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, considering the provided guidelines and GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (384.611 and 347.507 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (49.41) is better than Ligand B (54.26). Both are below the 90 A^2 threshold for CNS targets, which is good.

**3. logP:** Both ligands have good logP values (3.159 and 2.659), falling within the optimal 1-3 range.

**4. H-Bond Donors:** Ligand A has 1 HBD, while Ligand B has 0. Both are within the acceptable limit of <=5.

**5. H-Bond Acceptors:** Ligand A has 4 HBA, and Ligand B has 5. Both are within the acceptable limit of <=10.

**6. QED:** Both ligands have reasonable QED values (0.764 and 0.645), indicating good drug-like properties.

**7. DILI:** Ligand A (22.373) has a slightly higher DILI risk than Ligand B (13.532), but both are well below the concerning threshold of 60.

**8. BBB:** Ligand B (83.831) has a significantly better BBB penetration percentile than Ligand A (70.027). This is a crucial factor for a CNS target like DRD2.

**9. Caco-2 Permeability:** Both have negative values, which is unusual. Assuming these are logP values, Ligand A (-5.153) is worse than Ligand B (-4.974)

**10. Aqueous Solubility:** Both ligands have negative solubility values, which is also unusual. Ligand B (-0.914) is slightly better than Ligand A (-3.672).

**11. hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.4 and 0.414).

**12. Microsomal Clearance:** Ligand B (31.493) has a lower microsomal clearance than Ligand A (59.397), suggesting better metabolic stability.

**13. In vitro Half-Life:** Ligand B (7.66) has a longer in vitro half-life than Ligand A (-12.767).

**14. P-gp Efflux:** Both ligands have similar P-gp efflux liability (0.16 and 0.318), both being relatively low.

**15. Binding Affinity:** Ligand B (-7.6 kcal/mol) has a slightly better binding affinity than Ligand A (-7.1 kcal/mol), although the difference is relatively small.

**Overall Assessment:**

Considering the GPCR-specific priorities, Ligand B is the more promising candidate. Its significantly better BBB penetration (83.831 vs 70.027) is a major advantage for a CNS drug. It also exhibits better metabolic stability (lower Cl_mic) and a longer half-life. While Ligand A has a slightly lower DILI risk, the difference is not substantial enough to outweigh the benefits of Ligand B's superior CNS penetration and pharmacokinetic properties. The affinity difference is minimal.

Output:
1
2025-04-17 07:34:23,494 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (359.5 & 366.5 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (70.15) is slightly higher than Ligand B (60.89). For CNS targets, we prefer TPSA <= 90, so both are acceptable, but B is better.

**3. logP:** Both ligands have good logP values (2.478 & 2.365), falling within the optimal 1-3 range.

**4. H-Bond Donors:** Ligand A has 2 HBD, while Ligand B has 0. Both are within the acceptable limit of <=5.

**5. H-Bond Acceptors:** Both ligands have 6 HBA, which is within the acceptable limit of <=10.

**6. QED:** Ligand A (0.855) has a higher QED than Ligand B (0.707), indicating better overall drug-likeness.

**7. DILI:** Ligand B (36.49) has a significantly lower DILI risk than Ligand A (54.75), making it more favorable.

**8. BBB:** Ligand B (75.11) has a much better BBB penetration percentile than Ligand A (68.44). This is *critical* for a CNS target like DRD2.

**9. Caco-2 Permeability:** Ligand A (-5.135) has worse Caco-2 permeability than Ligand B (-4.775).

**10. Aqueous Solubility:** Ligand A (-3.422) has worse aqueous solubility than Ligand B (-1.809).

**11. hERG Inhibition:** Ligand A (0.8) has a slightly higher hERG inhibition risk than Ligand B (0.439).

**12. Microsomal Clearance:** Ligand B (43.41) has slightly lower microsomal clearance than Ligand A (48.05), suggesting better metabolic stability.

**13. In vitro Half-Life:** Ligand A (32.24) has a longer in vitro half-life than Ligand B (22.75).

**14. P-gp Efflux:** Ligand A (0.177) has higher P-gp efflux than Ligand B (0.094). Lower P-gp efflux is preferred, especially for CNS targets.

**15. Binding Affinity:** Ligand B (-5.9 kcal/mol) has a significantly stronger binding affinity than Ligand A (-0.0 kcal/mol). This is a major advantage, potentially outweighing some ADME drawbacks.

**Overall Assessment:**

Ligand B is the superior candidate. While Ligand A has a better QED and slightly longer half-life, Ligand B excels in the most critical areas for a CNS-targeting GPCR ligand: significantly better BBB penetration, a much lower DILI risk, stronger binding affinity, and lower P-gp efflux. The improved solubility and metabolic stability also contribute to its favorability. The difference in binding affinity is substantial and likely to be the deciding factor.

Output:
1
2025-04-17 07:34:23,494 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (388.333 and 354.479 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (49.41) is significantly better than Ligand B (58.12). For a CNS target like DRD2, TPSA should be <= 90, and ideally lower. Ligand A is much closer to the ideal range.

**3. logP:** Both ligands have a logP of approximately 3.4, which is optimal (1-3).

**4. H-Bond Donors:** Both have 1 HBD, which is within the acceptable limit of <=5.

**5. H-Bond Acceptors:** Ligand A has 3 HBA, while Ligand B has 5. Both are within the acceptable limit of <=10.

**6. QED:** Both ligands have good QED scores (0.79 and 0.808), indicating good drug-like properties.

**7. DILI:** Ligand A (46.491) has a better DILI score than Ligand B (61.303). Both are acceptable (<60 is good), but A is preferable.

**8. BBB:** Both ligands have excellent BBB penetration (89.066 and 85.498), exceeding the desirable threshold of >70 for CNS targets.

**9. Caco-2 Permeability:** Ligand A (-4.873) is better than Ligand B (-5.05), but both are negative values, indicating poor permeability.

**10. Aqueous Solubility:** Both ligands have very poor aqueous solubility (-3.593 and -3.594). This is a concern for bioavailability.

**11. hERG Inhibition:** Both ligands have low hERG inhibition risk (0.514 and 0.601), which is good.

**12. Microsomal Clearance:** Ligand B (69.415) has a higher microsomal clearance than Ligand A (9.965), indicating lower metabolic stability. Lower clearance is preferred.

**13. In vitro Half-Life:** Ligand A (-2.04) has a better in vitro half-life than Ligand B (-35.859).

**14. P-gp Efflux:** Both ligands have low P-gp efflux liability (0.16 and 0.253), which is good for CNS penetration.

**15. Binding Affinity:** Ligand A (-9.5 kcal/mol) has a slightly better binding affinity than Ligand B (-8.7 kcal/mol). While both are good, the difference of 0.8 kcal/mol is notable.

**Overall Assessment:**

Ligand A is superior to Ligand B. While both have good BBB penetration and logP values, Ligand A excels in TPSA, DILI, microsomal clearance, in vitro half-life, and binding affinity. The slightly better affinity of Ligand A, combined with its improved ADME properties (lower clearance, better half-life, lower DILI risk, and lower TPSA), makes it the more promising drug candidate. The poor solubility of both is a concern that would need to be addressed during further development, but the other advantages of Ligand A outweigh this drawback.

Output:
1
2025-04-17 07:34:23,494 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 drug candidates, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (341.371 and 346.471 Da) fall within the ideal range of 200-500 Da.

**TPSA:** Ligand A (101.53) is better than Ligand B (62.55). For CNS targets, TPSA should be <=90, so Ligand B is preferable.

**logP:** Ligand A (1.19) is within the optimal range (1-3), while Ligand B (3.638) is approaching the upper limit. Ligand A is slightly better here.

**H-Bond Donors:** Ligand A (2) and Ligand B (1) are both acceptable.

**H-Bond Acceptors:** Ligand A (6) and Ligand B (3) are both acceptable.

**QED:** Ligand A (0.701) is better than Ligand B (0.52), indicating a more drug-like profile.

**DILI:** Ligand B (28.306) has a significantly lower DILI risk than Ligand A (62.35), which is a substantial advantage.

**BBB:** Ligand B (53.587) is significantly better than Ligand A (31.834) in terms of BBB penetration. This is *critical* for a CNS target like DRD2.

**Caco-2 Permeability:** Ligand A (-5.351) has worse Caco-2 permeability than Ligand B (-4.623).

**Aqueous Solubility:** Ligand A (-2.14) has better aqueous solubility than Ligand B (-2.776).

**hERG:** Both ligands have low hERG inhibition liability (0.258 and 0.348 respectively), which is good.

**Microsomal Clearance:** Ligand A (18.4) has lower microsomal clearance than Ligand B (82.646), indicating better metabolic stability.

**In vitro Half-Life:** Ligand B (73.899) has a much longer in vitro half-life than Ligand A (17.514), which is a significant advantage.

**P-gp Efflux:** Ligand A (0.027) has lower P-gp efflux than Ligand B (0.177), which is favorable for CNS exposure.

**Binding Affinity:** Ligand A (-8.7 kcal/mol) has a significantly stronger binding affinity than Ligand B (-7.5 kcal/mol). This is a major advantage, potentially outweighing some ADME drawbacks.

**Overall Assessment:**

While Ligand A has superior binding affinity and better P-gp efflux, Ligand B excels in crucial areas for CNS drug development: BBB penetration, lower DILI risk, and a longer half-life. The difference in binding affinity (-8.7 vs -7.5) is substantial, but the poor BBB penetration of Ligand A is a major concern. Given the GPCR-specific priorities, particularly BBB, and the relatively good affinity of Ligand B, it is the more promising candidate.

Output:
1
2025-04-17 07:34:23,494 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B based on the provided guidelines, prioritizing GPCR-specific properties (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (360.376 and 348.535 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (69.64) is better than Ligand B (59.07) as it is closer to the ideal <90 for CNS targets.

**logP:** Ligand A (1.724) is optimal (1-3), while Ligand B (4.286) is pushing the upper limit and could potentially cause solubility issues or off-target interactions.

**H-Bond Donors/Acceptors:** Both have acceptable HBD (2) and HBA (A: 3, B: 5) counts, well within the guidelines.

**QED:** Both ligands have good QED scores (A: 0.593, B: 0.661), indicating drug-like properties.

**DILI:** Both have low DILI risk (A: 32.028, B: 35.014), below the 40 threshold.

**BBB:** Ligand B (88.29) has a significantly better BBB penetration score than Ligand A (70.997). This is a critical advantage for a CNS target like DRD2.

**Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and suggests poor permeability. However, the scale is not defined, so it is hard to interpret.

**Aqueous Solubility:** Ligand A (-1.669) has better solubility than Ligand B (-4.543).

**hERG:** Both ligands have low hERG inhibition liability (A: 0.419, B: 0.89).

**Microsomal Clearance:** Ligand A (-1.409) shows better metabolic stability (lower clearance) than Ligand B (75.331).

**In vitro Half-Life:** Ligand B (79.189) has a significantly longer half-life than Ligand A (-26.093), which is a positive attribute.

**P-gp Efflux:** Ligand A (0.097) exhibits lower P-gp efflux than Ligand B (0.345), which is favorable for CNS penetration.

**Binding Affinity:** Ligand B (-7.6 kcal/mol) has a substantially stronger binding affinity than Ligand A (-0.0 kcal/mol). This is a major advantage, potentially outweighing some of the other drawbacks.

**Overall Assessment:**

Ligand B has a much stronger binding affinity and a superior BBB score, both crucial for a CNS-targeting GPCR. While its logP is slightly higher and solubility lower than Ligand A, the significant advantage in affinity and BBB penetration outweighs these concerns. Ligand A has better metabolic stability and P-gp efflux, but the weaker binding and lower BBB penetration are major drawbacks.

Output:
1
2025-04-17 07:34:23,495 - INFO - Reasoning:

Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (380.348 and 345.359 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Both ligands (117.09 and 119.24) are slightly above the optimal <90 for CNS targets, but still reasonable.

**3. logP:** Ligand A (1.428) is within the optimal 1-3 range. Ligand B (0.317) is a bit low, potentially hindering membrane permeability.

**4. H-Bond Donors:** Ligand A (3) and Ligand B (2) are both acceptable, below the threshold of 5.

**5. H-Bond Acceptors:** Ligand A (5) and Ligand B (7) are both acceptable, below the threshold of 10.

**6. QED:** Both ligands have good QED scores (0.628 and 0.819), indicating drug-like properties.

**7. DILI:** Both ligands have high DILI risk (81.117 and 86.157), which is a concern. However, this can sometimes be mitigated with structural modifications.

**8. BBB:** Ligand A (52.385) has a lower BBB penetration percentile than Ligand B (49.166). Both are suboptimal for a CNS target, but Ligand B is slightly better.

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.332 and -5.21), which is unusual and suggests poor permeability. This is a significant drawback.

**10. Aqueous Solubility:** Both ligands have negative solubility values (-3.009 and -2.077), which is also unusual and indicates very low aqueous solubility. This is a major formulation challenge.

**11. hERG Inhibition:** Both ligands have low hERG inhibition risk (0.46 and 0.098), which is positive.

**12. Microsomal Clearance:** Ligand A (25.454) has higher microsomal clearance than Ligand B (8.237), suggesting lower metabolic stability.

**13. In vitro Half-Life:** Ligand B (15.927) has a longer in vitro half-life than Ligand A (-24.126), which is a significant advantage.

**14. P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.135 and 0.009), which is favorable for CNS penetration.

**15. Binding Affinity:** Ligand B (-7.7 kcal/mol) has a significantly stronger binding affinity than Ligand A (-8.3 kcal/mol). This 0.6 kcal/mol difference is substantial and can outweigh some ADME drawbacks.

**Overall Assessment:**

Despite both ligands having issues with solubility and Caco-2 permeability, Ligand B is the more promising candidate. Its superior binding affinity (-7.7 vs -8.3 kcal/mol) is a key advantage for a GPCR target. It also has a longer half-life and slightly better BBB penetration. While the DILI risk is high for both, the stronger binding and improved PK properties of Ligand B make it a better starting point for optimization.

Output:
1
2025-04-17 07:34:23,495 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (383.704 and 382.511 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (67.01) is excellent, well below the 90 A^2 threshold for CNS targets. Ligand B (105.39) is higher, but still potentially acceptable, although less favorable.

**3. logP:** Ligand A (3.835) is at the upper end of the optimal range (1-3), but still acceptable. Ligand B (1.526) is lower, potentially leading to permeability issues.

**4. H-Bond Donors:** Both ligands have 2 HBD, which is within the desirable limit of <=5.

**5. H-Bond Acceptors:** Ligand A has 3 HBA, and Ligand B has 6 HBA. Both are within the limit of <=10, but Ligand A is more favorable.

**6. QED:** Both ligands have good QED scores (0.609 and 0.788, respectively), indicating good drug-like properties.

**7. DILI:** Ligand A (66.15) has a moderate DILI risk, while Ligand B (82.435) has a higher risk.

**8. BBB:** This is a critical parameter for CNS targets. Ligand A (65.529) has a good BBB percentile, while Ligand B (39.822) is significantly lower, raising concerns about CNS exposure.

**9. Caco-2 Permeability:** Ligand A (-4.932) and Ligand B (-5.372) have similar, very poor Caco-2 permeability.

**10. Aqueous Solubility:** Ligand A (-4.575) and Ligand B (-2.408) have poor solubility.

**11. hERG Inhibition:** Ligand A (0.566) has a low hERG risk, while Ligand B (0.182) has even lower risk. Both are favorable.

**12. Microsomal Clearance:** Both ligands have similar microsomal clearance (24.841 and 22.621 mL/min/kg), indicating moderate metabolic stability.

**13. In vitro Half-Life:** Ligand A (-7.354) has a significantly longer half-life than Ligand B (28.394).

**14. P-gp Efflux:** Ligand A (0.386) has lower P-gp efflux liability than Ligand B (0.163), which is favorable for CNS penetration.

**15. Binding Affinity:** Ligand B (-7.7 kcal/mol) has a slightly better binding affinity than Ligand A (-8.9 kcal/mol). However, the difference is not substantial enough to outweigh the other significant drawbacks of Ligand B.

**Overall Assessment:**

Ligand A is the more promising candidate. While both have poor Caco-2 permeability and solubility, Ligand A demonstrates a significantly better BBB percentile, lower DILI risk, lower P-gp efflux, and a longer half-life. The slightly weaker binding affinity of Ligand A is compensated by its superior ADME properties, which are crucial for CNS drug development. Ligand B's poor BBB penetration is a major drawback for a DRD2 ligand.

Output:
1
2025-04-17 07:34:23,495 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B based on the provided guidelines, prioritizing GPCR-specific properties (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (364.511 and 355.439 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (49.85) is excellent, well below the 90 A^2 target for CNS drugs. Ligand B (103.95) is higher, but still potentially acceptable, though less ideal.

**logP:** Ligand A (2.936) is optimal (1-3). Ligand B (-0.911) is significantly lower, which could hinder membrane permeability and CNS penetration.

**H-Bond Donors/Acceptors:** Ligand A (0 HBD, 4 HBA) is favorable. Ligand B (2 HBD, 8 HBA) is also reasonable, though the higher HBA count might slightly impact permeability.

**QED:** Both ligands have similar QED values (0.699 and 0.591), indicating good drug-likeness.

**DILI:** Ligand A (20.744) has a much lower DILI risk than Ligand B (30.981), making it safer from a liver toxicity perspective.

**BBB:** This is crucial for a DRD2 ligand. Ligand A (89.298) shows excellent BBB penetration potential. Ligand B (18.302) has very poor predicted BBB penetration.

**Caco-2 Permeability:** Ligand A (-4.665) is poor, while Ligand B (-5.177) is also poor. This is concerning for oral absorption, but less critical for CNS targets where direct delivery or alternative routes are possible.

**Aqueous Solubility:** Ligand A (-2.284) is poor, and Ligand B (0.005) is also poor. This could pose formulation challenges.

**hERG Inhibition:** Ligand A (0.731) has a slightly higher hERG risk than Ligand B (0.052), but both are relatively low.

**Microsomal Clearance:** Ligand A (63.476) has higher clearance than Ligand B (-5.567), suggesting lower metabolic stability.

**In vitro Half-Life:** Ligand A (-0.364) has a very short half-life, while Ligand B (22.54) has a much longer half-life.

**P-gp Efflux:** Ligand A (0.436) has lower P-gp efflux liability than Ligand B (0.018), which is favorable for CNS exposure.

**Binding Affinity:** Ligand A (-7.6 kcal/mol) has a slightly better binding affinity than Ligand B (-6.2 kcal/mol). While both are good, the 1.4 kcal/mol difference is significant.

**Overall Assessment:**

Ligand A is the stronger candidate. Its superior BBB penetration, lower DILI risk, and slightly better binding affinity outweigh its poorer Caco-2 permeability, solubility, and shorter half-life. The negative logP of Ligand B is a significant drawback, severely limiting its ability to cross the blood-brain barrier. While Ligand B has a better half-life, the CNS target necessitates prioritizing BBB penetration and safety.

Output:
1
2025-04-17 07:34:23,495 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight (MW):** Both ligands (353.423 and 361.833 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (125.35) is slightly above the optimal <90 for CNS targets, but still reasonable. Ligand B (88.91) is excellent, well below 90.

**3. logP:** Ligand A (-0.902) is a bit low, potentially hindering membrane permeability. Ligand B (1.773) is within the optimal 1-3 range.

**4. H-Bond Donors (HBD):** Ligand A (4) is acceptable. Ligand B (2) is also good.

**5. H-Bond Acceptors (HBA):** Ligand A (6) is acceptable. Ligand B (5) is also good.

**6. QED:** Ligand B (0.849) has a significantly better QED score than Ligand A (0.458), indicating a more drug-like profile.

**7. DILI:** Ligand A (37.224) has a much lower DILI risk than Ligand B (79.992). This is a significant advantage for Ligand A.

**8. BBB:** Ligand B (43.893) has a considerably better BBB penetration percentile than Ligand A (20.822). This is crucial for a CNS target like DRD2.

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.552 and -5.403), which is unusual and suggests poor permeability. However, these values are on a scale where negative values are possible and don't necessarily disqualify a compound.

**10. Aqueous Solubility:** Both ligands have negative solubility values (-1.219 and -2.939), which is also unusual and suggests poor solubility.

**11. hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.107 and 0.035).

**12. Microsomal Clearance:** Ligand B (1.891) has a much lower microsomal clearance than Ligand A (12.115), indicating better metabolic stability.

**13. In vitro Half-Life:** Ligand B (27.161) has a longer in vitro half-life than Ligand A (23.39).

**14. P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.01 and 0.102).

**15. Binding Affinity:** Ligand A (-7.7) has a significantly stronger binding affinity than Ligand B (-0.0). This is a major advantage for Ligand A.

**Overall Assessment:**

Ligand A has a much stronger binding affinity and a lower DILI risk. However, Ligand B excels in BBB penetration, QED, metabolic stability, and half-life. The low logP of Ligand A is a concern. Given the CNS target (DRD2), BBB penetration is paramount. While Ligand A's affinity is excellent, the poor BBB and lower QED are significant drawbacks. Ligand B's weaker affinity *might* be optimized, but its superior ADME properties, especially BBB, make it a more promising starting point.

Output:
1
2025-04-17 07:34:23,495 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (346.475 and 360.483 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (78.09) is slightly higher than Ligand B (75.02), but both are below the 90 A^2 threshold desirable for CNS targets.

**logP:** Ligand A (2.375) and Ligand B (3.368) are both within the optimal 1-3 range. Ligand B is a bit higher, which could potentially lead to some off-target interactions, but is still acceptable.

**H-Bond Donors/Acceptors:** Ligand A has 2 HBD and 3 HBA, while Ligand B has 1 HBD and 5 HBA. Both are within acceptable limits (<=5 HBD and <=10 HBA).

**QED:** Both ligands have good QED scores (0.639 and 0.781, respectively), indicating drug-like properties.

**DILI:** Ligand A (16.208) has a significantly lower DILI risk than Ligand B (52.191). This is a substantial advantage for Ligand A.

**BBB:** Ligand B (72.431) has a better BBB penetration score than Ligand A (60.644). This is critical for a CNS target like DRD2.

**Caco-2 Permeability:** Both have negative Caco-2 values (-5.031 and -5.225), which is unusual and suggests poor permeability. This is a significant concern for both.

**Aqueous Solubility:** Both have negative solubility values (-2.585 and -4.033), indicating very poor aqueous solubility. This is a major drawback for both compounds.

**hERG Inhibition:** Both ligands have low hERG inhibition liability (0.381 and 0.35), which is good.

**Microsomal Clearance:** Ligand B (65.236) has higher microsomal clearance than Ligand A (40.282), meaning Ligand A is more metabolically stable.

**In vitro Half-Life:** Ligand A (-17.97) has a negative half-life, which is not physically possible and indicates a problem with the data. Ligand B (1.575) has a very short half-life.

**P-gp Efflux:** Both have low P-gp efflux liability (0.178 and 0.385), which is favorable for CNS penetration.

**Binding Affinity:** Ligand B (-7.1 kcal/mol) has a slightly better binding affinity than Ligand A (-7.6 kcal/mol). While the difference is small, it's a positive for Ligand B.

**Overall Assessment:**

Ligand A has a significantly better safety profile (lower DILI) and metabolic stability (lower Cl_mic). However, Ligand B has better BBB penetration and slightly better binding affinity. Both compounds suffer from poor solubility and permeability. The negative half-life for Ligand A is a major red flag, suggesting a data error or significant instability. Considering the GPCR-specific priorities, BBB is crucial for CNS targets. However, the DILI risk for Ligand B is concerning. The small affinity difference is unlikely to outweigh the significant DILI risk and the questionable half-life of Ligand A.

Output:
1
2025-04-17 07:34:23,495 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B based on the provided guidelines, prioritizing GPCR-specific properties (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (349.391 Da) is slightly lower, which could be beneficial for permeability, but both are acceptable.

**TPSA:** Ligand A (122.28) is borderline for CNS targets (<=90 is preferred), while Ligand B (62.3) is excellent, falling well below the threshold. This is a significant advantage for Ligand B regarding brain penetration.

**logP:** Ligand A (-0.074) is quite low, potentially hindering membrane permeability. Ligand B (2.321) is within the optimal range (1-3). This is a clear advantage for Ligand B.

**H-Bond Donors/Acceptors:** Ligand A has 3 HBD and 7 HBA, acceptable values. Ligand B has 1 HBD and 3 HBA, also acceptable and slightly more favorable due to the lower count.

**QED:** Both ligands have good QED scores (A: 0.582, B: 0.85), indicating good drug-like properties. Ligand B is better.

**DILI:** Ligand A (35.169) has a slightly higher DILI risk than Ligand B (17.798), though both are below the concerning threshold of 60.

**BBB:** Ligand B (82.202) has a significantly higher BBB percentile than Ligand A (11.439). This is *crucial* for a CNS target like DRD2.

**Caco-2 Permeability:** Ligand A (-5.728) has poor Caco-2 permeability, while Ligand B (-4.791) is also poor, but slightly better.

**Aqueous Solubility:** Both ligands have very poor aqueous solubility (-1.038 and -2.488 respectively). This is a concern for both, but could be addressed with formulation strategies.

**hERG Inhibition:** Ligand A (0.105) has a slightly lower hERG risk than Ligand B (0.594), but both are relatively low.

**Microsomal Clearance:** Ligand A (9.589) has a higher microsomal clearance than Ligand B (-8.882), suggesting faster metabolism and potentially lower *in vivo* exposure. This favors Ligand B.

**In vitro Half-Life:** Ligand A (12.343) has a longer half-life than Ligand B (-4.173), which is generally desirable.

**P-gp Efflux:** Ligand A (0.015) has very low P-gp efflux liability, which is excellent. Ligand B (0.043) is also low, but slightly higher.

**Binding Affinity:** Ligand B (-9.2 kcal/mol) has a slightly better binding affinity than Ligand A (-7.9 kcal/mol). While both are good, the 1.3 kcal/mol difference is significant and can outweigh some ADME drawbacks.

**Overall Assessment:**

Ligand B is the superior candidate. While both have solubility issues, Ligand B excels in key areas for a CNS-targeting GPCR: significantly better BBB penetration, a more favorable logP, lower DILI risk, better metabolic stability (lower Cl_mic, though half-life is lower), and slightly better binding affinity. Ligand A's low logP and poor Caco-2 permeability are significant drawbacks. The difference in binding affinity, while not enormous, adds to the advantage of Ligand B.

Output:
1
2025-04-17 07:34:23,496 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 drug candidates, considering the provided guidelines and GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (348.462 and 363.908 Da) fall within the ideal range of 200-500 Da.

**TPSA:** Ligand A (49.41) is significantly better than Ligand B (21.06). For CNS targets, we want TPSA <= 90, both are well within this range, but A is still preferable.

**logP:** Ligand A (2.978) is optimal (1-3), while Ligand B (4.893) is slightly higher. While still acceptable, higher logP can lead to off-target effects and solubility issues.

**H-Bond Donors/Acceptors:** Ligand A (HBD=1, HBA=2) and Ligand B (HBD=0, HBA=3) both have reasonable H-bond characteristics, well within the recommended limits.

**QED:** Both ligands have similar QED values (0.794 and 0.728), indicating good drug-likeness.

**DILI:** Ligand A (30.71) has a slightly higher DILI risk than Ligand B (13.804), but both are below the 40 threshold and are considered low risk.

**BBB:** Ligand B (95.967) has a substantially better BBB penetration score than Ligand A (88.019). This is a critical factor for CNS targets like DRD2.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.777 and -4.669), which is unusual and suggests poor permeability. This is a significant concern for both.

**Aqueous Solubility:** Both ligands have negative solubility values (-4.035 and -4.788), indicating very poor aqueous solubility. This is a major drawback.

**hERG Inhibition:** Ligand A (0.506) has a slightly lower hERG inhibition risk than Ligand B (0.94), which is preferable.

**Microsomal Clearance:** Ligand B (33.971) has lower microsomal clearance than Ligand A (56.58), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand B (38.97) has a significantly longer in vitro half-life than Ligand A (-6.96). This is a major advantage.

**P-gp Efflux:** Both ligands have low P-gp efflux scores (0.307 and 0.793), which is good for CNS penetration.

**Binding Affinity:** Both ligands have excellent binding affinities (-8.5 and -8.0 kcal/mol), with Ligand A being slightly more potent. The affinity difference is less than 1.5 kcal/mol, so it's not a decisive factor.

**Overall Assessment:**

Ligand B is superior due to its significantly better BBB penetration (95.967 vs 88.019), longer in vitro half-life (38.97 vs -6.96), and lower microsomal clearance (33.971 vs 56.58). While Ligand A has slightly better affinity and lower hERG risk, these are outweighed by Ligand B's superior pharmacokinetic properties crucial for CNS drug development. The poor Caco-2 and solubility are concerning for both, but can be addressed with formulation strategies.

Output:
1
2025-04-17 07:34:23,496 - INFO - Batch 376 complete. Total preferences: 6016
2025-04-17 07:34:23,496 - INFO - Processing batch 377/512...
2025-04-17 07:35:05,642 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (452.227 Da) is slightly higher than Ligand B (414.319 Da), but both are acceptable.

**TPSA:** Ligand A (80.05) is higher than Ligand B (61.44). For CNS targets, we prefer TPSA <= 90, so both are within range, but B is better.

**logP:** Both ligands have good logP values (A: 3.322, B: 3.74), falling within the optimal 1-3 range. B is slightly more lipophilic, which could be beneficial for membrane permeability, but isn't a major difference.

**H-Bond Donors/Acceptors:** Both have 2 HBDs, which is good. Ligand A has 5 HBAs, while Ligand B has 2. Lower HBA is generally preferred for better permeability, giving B an edge.

**QED:** Both have reasonable QED values (A: 0.443, B: 0.771). Ligand B's QED is significantly better, indicating a more drug-like profile.

**DILI:** Ligand A (80.651) has a higher DILI risk than Ligand B (39.434). This is a significant advantage for Ligand B.

**BBB:** Ligand B (77.2) has a better BBB penetration percentile than Ligand A (63.862).  For a CNS target like DRD2, this is a crucial factor.

**Caco-2 Permeability:** Both have negative Caco-2 values (-5.32 and -4.844). This is unusual and suggests poor permeability. However, these values are on a scale where negative values are possible, and the absolute value is more important. They are fairly similar.

**Aqueous Solubility:** Both have negative solubility values (-4.054 and -4.037). Similar to Caco-2, these are on a scale where negative values are possible.

**hERG:** Both ligands show low hERG inhibition liability (A: 0.819, B: 0.543), which is good.

**Microsomal Clearance:** Ligand B (18.961) has significantly lower microsomal clearance than Ligand A (53.504), indicating better metabolic stability.

**In vitro Half-Life:** Ligand B (18.446 hours) has a longer half-life than Ligand A (72.197 hours). This is a positive attribute for B.

**P-gp Efflux:** Ligand A (0.549) has lower P-gp efflux than Ligand B (0.146), which is beneficial for CNS exposure.

**Binding Affinity:** Both ligands have excellent binding affinity (-9.9 kcal/mol and -9.8 kcal/mol). The difference is minimal and unlikely to be decisive.

**Overall Assessment:**

Ligand B is superior. It has a better QED, significantly lower DILI risk, better BBB penetration, lower microsomal clearance, and a longer in vitro half-life. While Ligand A has slightly better P-gp efflux, the other advantages of Ligand B, particularly the improved ADME properties and CNS penetration, outweigh this. The similar binding affinities make the ADME profile the deciding factor.

Output:
1
2025-04-17 07:35:05,642 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (366.34 Da) is slightly lower, which could be advantageous for permeability. Ligand B (380.476 Da) is also well within range.

**TPSA:** Ligand A (110.77) is above the ideal <90 for CNS targets, but not drastically so. Ligand B (40.62) is excellent, well below the 90 threshold. This favors Ligand B.

**logP:** Ligand A (-0.522) is quite low, potentially hindering membrane permeability and CNS penetration. Ligand B (3.371) is optimal. This is a significant advantage for Ligand B.

**H-Bond Donors/Acceptors:** Ligand A has 4 HBD and 4 HBA. Ligand B has 0 HBD and 3 HBA. Both are within acceptable limits, but Ligand B's lower HBD count might contribute to better permeability.

**QED:** Both ligands have good QED scores (A: 0.486, B: 0.68), indicating reasonable drug-likeness. Ligand B is better.

**DILI:** Ligand A (34.781) has a low DILI risk, which is excellent. Ligand B (15.471) also has a very low DILI risk, comparable to A.

**BBB:** Ligand A (70.88) is acceptable for CNS penetration, but Ligand B (97.131) is outstanding, significantly increasing the likelihood of reaching the target in the brain. This is a major advantage for Ligand B.

**Caco-2 Permeability:** Ligand A (-5.61) has poor Caco-2 permeability. Ligand B (-4.426) is also poor, but slightly better than A.

**Aqueous Solubility:** Both ligands have very poor aqueous solubility (-1.058 and -4.386 respectively). This could pose formulation challenges.

**hERG Inhibition:** Ligand A (0.125) has a very low hERG risk, which is ideal. Ligand B (0.68) has a slightly elevated, but still acceptable, hERG risk.

**Microsomal Clearance:** Ligand A (-8.783) suggests very low clearance and high metabolic stability, which is excellent. Ligand B (51.469) has a much higher clearance, indicating faster metabolism and potentially lower *in vivo* exposure. This is a significant drawback for Ligand B.

**In vitro Half-Life:** Ligand A (-20.392) suggests a very long half-life, which is desirable. Ligand B (-11.5) has a shorter half-life.

**P-gp Efflux:** Ligand A (0.008) shows very low P-gp efflux, which is highly favorable for CNS penetration. Ligand B (0.175) has higher P-gp efflux, potentially reducing brain exposure.

**Binding Affinity:** Ligand A (-8.7 kcal/mol) has a slightly better binding affinity than Ligand B (-7.1 kcal/mol). However, the difference is not substantial enough to overcome the significant ADME deficiencies of Ligand A.

**Overall Assessment:**

Ligand B excels in key GPCR-relevant properties: TPSA, logP, and especially BBB penetration. While its metabolic stability (Cl_mic) and half-life are less favorable, its superior CNS penetration potential and good binding affinity make it the more promising candidate. Ligand A's low logP and poor Caco-2 permeability are major concerns, even with its slightly better affinity and metabolic stability. The excellent BBB score of Ligand B is crucial for a CNS target like DRD2.



Output:
1
2025-04-17 07:35:05,642 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (352.431 and 377.507 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (100.8) is better than Ligand B (127.59). For CNS targets, we want TPSA <= 90, so Ligand A is closer to this threshold.

**logP:** Ligand A (1.744) is optimal (1-3), while Ligand B (0.268) is quite low, potentially hindering permeation.

**H-Bond Donors/Acceptors:** Both have 3 HBD and 5 HBA, which are within acceptable limits.

**QED:** Both ligands have reasonable QED values (0.628 and 0.559), indicating good drug-like properties.

**DILI:** Both ligands have similar, acceptable DILI risk (36.099 and 36.603 percentile).

**BBB:** Ligand B (56.495) has a slightly better BBB penetration percentile than Ligand A (50.795), but both are below the desirable >70 for CNS targets.

**Caco-2 Permeability:** Ligand A (-5.028) shows better Caco-2 permeability than Ligand B (-5.479).

**Aqueous Solubility:** Both ligands have very poor aqueous solubility (-1.683 and -1.72). This is a concern for both.

**hERG:** Both ligands have low hERG inhibition liability (0.232 and 0.189).

**Microsomal Clearance:** Ligand B (31.223) has significantly lower microsomal clearance than Ligand A (4.552), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (48.892) has a much longer in vitro half-life than Ligand B (-35.912).

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.144 and 0.016).

**Binding Affinity:** Ligand A (-7.9 kcal/mol) has a slightly better binding affinity than Ligand B (-7.4 kcal/mol). While both are good, the 0.5 kcal/mol difference is notable.

**Overall Assessment:**

Considering the GPCR-specific priorities, Ligand A is more promising. While both have poor solubility and suboptimal BBB penetration, Ligand A has a better logP, TPSA, Caco-2 permeability, and a slightly better binding affinity. The longer half-life of Ligand A is also a significant advantage. Ligand B's lower clearance is good, but the significantly lower logP and shorter half-life are major drawbacks for a CNS target. The small difference in binding affinity can be outweighed by the more favorable ADME properties of Ligand A.

Output:
1
2025-04-17 07:35:05,643 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B based on the provided guidelines, prioritizing GPCR-specific properties (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (339.351 and 348.491 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (94.32) is slightly above the optimal <90 for CNS targets, but still reasonable. Ligand B (59.39) is excellent, well below 90.

**logP:** Both ligands (2.809 and 3.025) are within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Both ligands have 1 HBD and a reasonable number of HBAs (6 and 5 respectively), satisfying the <5 HBD and <10 HBA criteria.

**QED:** Both ligands have good QED scores (0.735 and 0.912), indicating good drug-like properties.

**DILI:** Ligand A (91.004) has a significantly higher DILI risk than Ligand B (15.471). This is a major concern.

**BBB:** Ligand B (82.513) has a much better BBB penetration score than Ligand A (53.432). This is critical for a CNS target like DRD2.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.735 and -4.608) which is unusual and suggests poor permeability. However, these values are on a scale where negative values are possible, and direct comparison is difficult without knowing the scale's specifics.

**Aqueous Solubility:** Both ligands have negative solubility values (-4.01 and -2.06), suggesting poor aqueous solubility. Again, the scale is unknown.

**hERG:** Both ligands have low hERG inhibition liability (0.209 and 0.54), which is good.

**Microsomal Clearance:** Ligand A (99.25) has very high microsomal clearance, indicating poor metabolic stability. Ligand B (16.799) is much better.

**In vitro Half-Life:** Ligand A (-12.131) has a very short in vitro half-life, while Ligand B (13.076) is better.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.129 and 0.12), which is favorable for CNS penetration.

**Binding Affinity:** Ligand A (-9.7 kcal/mol) has a slightly better binding affinity than Ligand B (-8.3 kcal/mol). This is a 1.4 kcal/mol difference, which is significant.

**Overall Assessment:**

Despite the slightly better binding affinity of Ligand A, its significantly higher DILI risk, poor BBB penetration, and poor metabolic stability (high Cl_mic, short half-life) make it a much less desirable candidate. Ligand B excels in key areas for a CNS GPCR target: good BBB penetration, lower DILI risk, better metabolic stability, and acceptable binding affinity. The negative Caco-2 and solubility values are concerning for both, but the other factors strongly favor Ligand B.

Output:
1
2025-04-17 07:35:05,643 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (347.503 and 359.348 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (52.65) is significantly better than Ligand B (78.51). For CNS targets, we want TPSA <= 90, and A is comfortably within this range, while B is approaching the upper limit.

**3. logP:** Both ligands have good logP values (2.492 and 1.025), falling within the optimal 1-3 range.

**4. H-Bond Donors:** Both have acceptable HBD counts (1 and 2, respectively), well below the threshold of 5.

**5. H-Bond Acceptors:** Both ligands have 3 HBAs, which is within the acceptable limit of 10.

**6. QED:** Both ligands have similar, good QED values (0.72 and 0.736), indicating good drug-like properties.

**7. DILI:** Ligand A (13.61) has a much lower DILI risk than Ligand B (37.61). This is a significant advantage for A.

**8. BBB:** Both ligands have excellent BBB penetration (76.658 and 79.721), exceeding the desirable >70 threshold for CNS targets.

**9. Caco-2 Permeability:** Both have negative Caco-2 values (-4.925 and -4.951), which is unusual and suggests poor permeability. However, these values are very close and don't strongly differentiate the two.

**10. Aqueous Solubility:** Both have negative solubility values (-1.245 and -2.522), indicating poor aqueous solubility. B is worse than A.

**11. hERG Inhibition:** Both ligands show very low hERG inhibition risk (0.33 and 0.069).

**12. Microsomal Clearance:** Ligand A (31.393) has a higher microsomal clearance than Ligand B (-1.499). This suggests Ligand B is more metabolically stable, which is desirable.

**13. In vitro Half-Life:** Ligand B (-29.36) has a much longer in vitro half-life than Ligand A (-1.288), a major advantage.

**14. P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.107 and 0.012).

**15. Binding Affinity:** Ligand B (-8.8 kcal/mol) has significantly stronger binding affinity than Ligand A (-7.3 kcal/mol). This >1.5 kcal/mol difference is substantial and can outweigh some ADME drawbacks.

**Overall Assessment:**

While Ligand A has advantages in TPSA and DILI risk, the significantly stronger binding affinity of Ligand B (-8.8 vs -7.3 kcal/mol) and its much longer half-life are critical for a GPCR target. The slight disadvantage in TPSA is less concerning given the already good BBB penetration of both compounds. The improved metabolic stability (lower Cl_mic, longer t1/2) of Ligand B is also a significant benefit.

Output:
1
2025-04-17 07:35:05,643 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (351.793) is slightly better, being closer to the lower end which can aid permeability.

**TPSA:** Ligand A (62.3) is excellent, well below the 90 A^2 threshold for CNS targets. Ligand B (92.78) is higher, but still acceptable, though less ideal for CNS penetration.

**logP:** Ligand A (3.369) is optimal. Ligand B (0.732) is quite low, potentially hindering membrane permeability and CNS entry.

**H-Bond Donors/Acceptors:** Both have acceptable HBD counts (1). Ligand A has 3 HBAs, while Ligand B has 5. Both are within the reasonable limits.

**QED:** Both ligands have similar, good QED values (0.684 and 0.741), indicating good drug-like properties.

**DILI:** Ligand A (87.631) has a higher DILI risk than Ligand B (47.421). This is a significant drawback for Ligand A.

**BBB:** Ligand A (76.735) has a better BBB percentile than Ligand B (62.35), which is crucial for a CNS target like DRD2.

**Caco-2 Permeability:** Ligand A (-4.682) has a worse Caco-2 permeability score than Ligand B (-4.329).

**Aqueous Solubility:** Ligand A (-5.489) has a worse aqueous solubility than Ligand B (-2.208).

**hERG:** Both ligands have low hERG inhibition liability (0.49 and 0.332), which is good.

**Microsomal Clearance:** Both have similar microsomal clearance values (45.29 and 49.455).

**In vitro Half-Life:** Ligand A (54.125) has a longer half-life than Ligand B (0.206).

**P-gp Efflux:** Ligand A (0.319) has a lower P-gp efflux liability than Ligand B (0.076), which is favorable for CNS penetration.

**Binding Affinity:** Ligand B (-8.1 kcal/mol) has a significantly stronger binding affinity than Ligand A (-10.9 kcal/mol). This is a substantial advantage.

**Overall Assessment:**

Ligand B exhibits a significantly stronger binding affinity, a better logP value, lower DILI risk, and better solubility. While Ligand A has a better BBB score and P-gp efflux, the substantial affinity advantage of Ligand B, coupled with its improved logP and reduced toxicity risk, outweighs these factors. The lower BBB score of Ligand B is partially mitigated by its lower P-gp efflux. The difference in binding affinity is >1.5 kcal/mol, making it a key deciding factor.

Output:
1
2025-04-17 07:35:05,643 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (351.491 and 379.507 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (69.72) is significantly better than Ligand B (75.29). For CNS targets, we want TPSA <= 90, and A is closer to the optimal <=60 range.

**logP:** Both ligands have acceptable logP values (1.787 and 2.721), falling within the 1-3 range.

**H-Bond Donors/Acceptors:** Both have 1 HBD, which is good. Ligand A has 3 HBA, and Ligand B has 6 HBA. Both are within the acceptable limit of <=10, but A is preferable.

**QED:** Both ligands have good QED scores (0.76 and 0.837), indicating drug-like properties.

**DILI:** Ligand A (20.047) has a much lower DILI risk than Ligand B (64.637). This is a significant advantage for A.

**BBB:** Both ligands have similar BBB penetration (65.452 and 65.801). While both are acceptable, ideally we want >70 for CNS targets.

**Caco-2 Permeability:** Ligand A (-4.668) has a worse Caco-2 permeability than Ligand B (-5.103). Lower values indicate poorer permeability.

**Aqueous Solubility:** Ligand A (-2.154) has better aqueous solubility than Ligand B (-3.472).

**hERG Inhibition:** Ligand A (0.122) has a much lower hERG inhibition liability than Ligand B (0.397). This is a crucial safety advantage for A.

**Microsomal Clearance:** Ligand A (54.122) has higher microsomal clearance than Ligand B (24.91), meaning it's less metabolically stable. This is a negative for A.

**In vitro Half-Life:** Ligand A (-9.486) has a shorter in vitro half-life than Ligand B (11.896). This is a negative for A.

**P-gp Efflux:** Ligand A (0.085) has lower P-gp efflux than Ligand B (0.302). Lower efflux is better, especially for CNS targets.

**Binding Affinity:** Ligand A (-8.6 kcal/mol) has a slightly better binding affinity than Ligand B (-6.9 kcal/mol). This is a significant advantage for A, exceeding the 1.5 kcal/mol threshold.

**Overall Assessment:**

Ligand A is the superior candidate. While it has some drawbacks in metabolic stability (higher Cl_mic, shorter t1/2) and Caco-2 permeability, its significantly better DILI score, lower hERG risk, lower P-gp efflux, and superior binding affinity outweigh these concerns. The TPSA is also more favorable for CNS penetration. The slight advantage in solubility is also a plus. The affinity difference is substantial enough to compensate for the ADME liabilities.

Output:
1
2025-04-17 07:35:05,643 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (346.446 Da) is slightly better, being closer to the lower end which can aid permeability.

**TPSA:** Ligand A (58.2) is significantly better than Ligand B (69.64). For CNS targets, TPSA should be <= 90, and lower is preferred. Ligand A is much closer to the optimal range for CNS penetration.

**logP:** Ligand A (4.208) is a bit high, potentially leading to solubility issues, but still within a reasonable range. Ligand B (2.097) is excellent. GPCRs generally benefit from a logP between 1-3, so B is better here.

**H-Bond Donors/Acceptors:** Both have 2 HBDs, which is good. Ligand A has 2 HBAs, while Ligand B has 3. Both are acceptable, staying within the <10 HBA guideline.

**QED:** Both ligands have acceptable QED values (A: 0.4, B: 0.568), indicating reasonable drug-likeness. Ligand B is slightly better.

**DILI:** Both have low DILI risk (A: 40.752, B: 37.767), below the 40 threshold, which is excellent.

**BBB:** Both ligands have good BBB penetration (A: 76.076, B: 72.005), exceeding the 70% threshold for CNS targets. Ligand A is slightly better.

**Caco-2 Permeability:** Ligand A (-4.717) is significantly worse than Ligand B (-5.052). Lower values here suggest poor permeability.

**Aqueous Solubility:** Ligand A (-4.413) is significantly worse than Ligand B (-2.985). Lower values here suggest poor solubility.

**hERG Inhibition:** Ligand A (0.79) is better than Ligand B (0.42), indicating lower risk of cardiotoxicity.

**Microsomal Clearance:** Ligand A (71.419) is higher than Ligand B (9.141), meaning faster clearance and lower metabolic stability. Ligand B is much better.

**In vitro Half-Life:** Ligand A (30.849) is better than Ligand B (-10.897). Longer half-life is generally preferred.

**P-gp Efflux:** Ligand A (0.542) is better than Ligand B (0.274), indicating lower P-gp efflux and better CNS exposure.

**Binding Affinity:** Ligand A (-8.7 kcal/mol) is *significantly* better than Ligand B (0.0 kcal/mol). This is a crucial difference. A >1.5 kcal/mol advantage in binding affinity can often outweigh other ADME drawbacks.

**Overall Assessment:**

While Ligand B has better logP, solubility, and metabolic stability, Ligand A's *much* stronger binding affinity (-8.7 vs 0.0 kcal/mol) is a decisive factor. The superior affinity outweighs the slightly higher logP and poorer solubility/permeability. The good BBB penetration and acceptable DILI risk for Ligand A further support its potential.

Output:
1
2025-04-17 07:35:05,643 - INFO - Reasoning:

Let's analyze Ligand A and Ligand B against the provided guidelines, prioritizing GPCR-specific properties (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (346.395 and 352.479 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (132.75) is slightly above the ideal <90 for CNS targets, but still reasonable. Ligand B (83.03) is excellent, well below 90.

**logP:** Ligand A (0.234) is quite low, potentially hindering permeability. Ligand B (1.286) is better, within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A has 3 HBD and 8 HBA, acceptable. Ligand B has 2 HBD and 5 HBA, also acceptable.

**QED:** Both ligands have reasonable QED scores (0.657 and 0.509), indicating good drug-like properties.

**DILI:** Ligand A (63.746) has a higher DILI risk than Ligand B (12.098). This is a significant negative for Ligand A.

**BBB:** Ligand B (65.801) has a better BBB percentile than Ligand A (58.123), though both are below the desirable >70 for CNS targets.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.785 and -5.186), which is unusual and suggests poor permeability. However, these values are on a scale where negative values are possible, and direct comparison is difficult without knowing the scale's specifics.

**Aqueous Solubility:** Both ligands have negative solubility values (-2.709 and -1.864), indicating poor aqueous solubility.

**hERG Inhibition:** Ligand A (0.037) shows a slightly higher hERG risk than Ligand B (0.454), but both are relatively low.

**Microsomal Clearance:** Ligand B (-0.409) has significantly better metabolic stability (lower clearance) than Ligand A (11.527).

**In vitro Half-Life:** Ligand B (10.112) has a much longer in vitro half-life than Ligand A (-13.457).

**P-gp Efflux:** Ligand A (0.015) has a lower P-gp efflux liability than Ligand B (0.03), which is favorable for CNS penetration.

**Binding Affinity:** Both ligands have comparable binding affinities (-8.5 and -8.0 kcal/mol), both being excellent. The difference is less than 1.5 kcal/mol, so this isn't a deciding factor.

**Overall Assessment:**

Ligand B is clearly superior. While both have issues with Caco-2 and solubility, Ligand B excels in critical areas for a CNS-targeting GPCR: better logP, significantly lower DILI risk, better metabolic stability (Cl_mic and t1/2), and a better (though still suboptimal) BBB score. The slightly higher P-gp efflux of Ligand B is less concerning given its other advantages. Ligand A's low logP and higher DILI risk are significant drawbacks.

Output:
1
2025-04-17 07:35:05,643 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (380.457 and 346.431 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Both ligands have TPSA values (86.71 and 84.3) below 90, which is favorable for CNS penetration.

**3. logP:** Ligand A (0.658) is slightly lower than optimal (1-3), potentially hindering permeation. Ligand B (1.103) is closer to the ideal range.

**4. H-Bond Donors:** Ligand A (2) and Ligand B (1) are both within the acceptable limit of <=5.

**5. H-Bond Acceptors:** Ligand A (4) and Ligand B (5) are both within the acceptable limit of <=10.

**6. QED:** Both ligands have good QED scores (0.615 and 0.809), indicating drug-like properties.

**7. DILI:** Ligand A (24.544) has a significantly lower DILI risk than Ligand B (39.162), which is a major advantage.

**8. BBB:** Both ligands show good BBB penetration (76.231 and 70.182), but Ligand A is better, exceeding the 70% threshold.

**9. Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and suggests poor permeability. This is a concern for both.

**10. Aqueous Solubility:** Both have negative solubility values, which is also unusual and suggests poor solubility. This is a concern for both.

**11. hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.402 and 0.145).

**12. Microsomal Clearance:** Ligand A (17.598) has a higher microsomal clearance than Ligand B (14.148), suggesting lower metabolic stability.

**13. In vitro Half-Life:** Ligand B (-8.357) has a longer in vitro half-life than Ligand A (-20.137), which is a positive.

**14. P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.107 and 0.046), which is excellent for CNS penetration.

**15. Binding Affinity:** Ligand B (-8.7 kcal/mol) has a slightly stronger binding affinity than Ligand A (-7.1 kcal/mol). The difference is 1.6 kcal/mol, which is significant enough to potentially outweigh some ADME drawbacks.

**Overall Assessment:**

While Ligand B has a slightly better binding affinity and half-life, Ligand A demonstrates a significantly lower DILI risk and better BBB penetration. Considering the GPCR-specific priorities, BBB penetration is crucial for CNS targets like DRD2. The lower DILI risk of Ligand A is also a major advantage, as liver toxicity is a common concern in drug development. The slightly lower logP of Ligand A is a minor concern, but the other benefits outweigh this drawback.

Output:
1
2025-04-17 07:35:05,643 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (392.503 Da) is slightly higher than Ligand B (342.33 Da), but both are acceptable.

**TPSA:** Ligand A (123.85) is closer to the ideal range for CNS targets (<=90) than Ligand B (79.13). Both are good, but A is slightly less favorable.

**logP:** Ligand A (-0.232) is below the optimal range (1-3), which could hinder permeability. Ligand B (2.323) is within the optimal range. This is a significant advantage for Ligand B.

**H-Bond Donors:** Ligand A (2) is within the acceptable limit of <=5. Ligand B (0) is also good.

**H-Bond Acceptors:** Ligand A (8) is within the acceptable limit of <=10. Ligand B (7) is also good.

**QED:** Both ligands have good QED scores (A: 0.595, B: 0.662), indicating drug-like properties.

**DILI:** Ligand A (79.139) has a lower DILI risk than Ligand B (88.872), which is preferable.

**BBB:** Both have good BBB penetration (A: 61.691, B: 69.135), but Ligand B is slightly better. For a CNS target like DRD2, >70 is desirable, and neither quite reaches that.

**Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and suggests poor permeability. Ligand A (-5.467) is slightly better than Ligand B (-4.148).

**Aqueous Solubility:** Both have negative solubility values, indicating poor solubility. Ligand A (-2.498) is slightly better than Ligand B (-4.19).

**hERG Inhibition:** Ligand A (0.547) has a slightly higher hERG risk than Ligand B (0.218), which is less desirable.

**Microsomal Clearance:** Ligand A (22.799) has significantly lower microsomal clearance than Ligand B (109.36), indicating better metabolic stability. This is a major advantage for Ligand A.

**In vitro Half-Life:** Ligand A (-7.093) has a much longer in vitro half-life than Ligand B (-35.073), which is highly desirable.

**P-gp Efflux:** Ligand A (0.03) has much lower P-gp efflux than Ligand B (0.195), which is crucial for CNS penetration.

**Binding Affinity:** Ligand B (-8.5 kcal/mol) has a significantly stronger binding affinity than Ligand A (-7.1 kcal/mol). This is a substantial advantage for Ligand B, potentially outweighing some ADME concerns. The difference is >1.5 kcal/mol.

**Overall Assessment:**

Ligand B has a superior binding affinity and a more favorable logP value. However, Ligand A exhibits significantly better metabolic stability (lower Cl_mic, longer t1/2), lower P-gp efflux, and a lower DILI risk. The negative Caco-2 and solubility values are concerning for both, but the strong affinity of Ligand B is a major factor. Given the GPCR-specific emphasis on affinity, and the substantial difference in binding (-8.5 vs -7.1), Ligand B is the more promising candidate despite its drawbacks.

Output:
1
2025-04-17 07:35:05,643 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 drug candidates, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (361.463 and 360.483 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (64.63) is significantly better than Ligand B (71.69). For CNS targets, we want TPSA <= 90, and A is closer to the optimal <=60 range.

**logP:** Both ligands have acceptable logP values (2.965 and 1.877), falling within the 1-3 range. Ligand A is slightly more lipophilic, which could be beneficial for membrane permeability.

**H-Bond Donors/Acceptors:** Both have 1 HBD and 5/6 HBA, which are within acceptable limits.

**QED:** Both ligands have similar, good QED scores (0.857 and 0.852), indicating good drug-like properties.

**DILI:** Ligand A (70.725) has a higher DILI risk than Ligand B (36.758). This is a significant drawback for Ligand A.

**BBB:** Ligand A (70.182) has a slightly better BBB penetration percentile than Ligand B (67.08), but both are reasonably good, exceeding the 70% threshold for CNS targets.

**Caco-2 Permeability:** Ligand A (-4.895) has poor Caco-2 permeability, whereas Ligand B (-5.018) is also poor, but slightly better.

**Aqueous Solubility:** Ligand A (-3.722) has slightly better aqueous solubility than Ligand B (-1.769), which is good.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.876 and 0.627).

**Microsomal Clearance:** Ligand B (21.747) has significantly lower microsomal clearance than Ligand A (39.37), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand B (-23.064) has a longer in vitro half-life than Ligand A (23.775). This is a significant advantage for Ligand B.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.696 and 0.065). Ligand B is significantly better.

**Binding Affinity:** Both ligands have excellent binding affinity (-9.3 and -8.0 kcal/mol). Ligand A has a 1.3 kcal/mol advantage, which is substantial.

**Overall Assessment:**

Ligand A has a stronger binding affinity and slightly better BBB penetration and solubility. However, it suffers from a higher DILI risk, poor Caco-2 permeability, and higher microsomal clearance. Ligand B has a significantly better safety profile (lower DILI), better metabolic stability (lower Cl_mic, longer t1/2), and lower P-gp efflux, which are all crucial for CNS drug development. The 1.3 kcal/mol difference in binding affinity, while significant, can potentially be overcome with further optimization, whereas mitigating the ADME liabilities of Ligand A would be more challenging.

Output:
1
2025-04-17 07:35:05,644 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight (MW):** Both ligands (359.401 and 361.511 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (48.39) is significantly better than Ligand B (56.15). For CNS targets, TPSA should be <= 90, both are within this limit, but A is preferable.

**3. logP:** Both ligands have a logP around 4.0-4.1, slightly above the optimal range of 1-3. This could potentially lead to solubility issues or off-target interactions, but is not a dealbreaker.

**4. H-Bond Donors (HBD):** Both ligands have acceptable HBD counts (2 for A, 1 for B), below the threshold of 5.

**5. H-Bond Acceptors (HBA):** Both ligands have acceptable HBA counts (5 for both), below the threshold of 10.

**6. QED:** Both ligands have good QED values (0.739 and 0.842), indicating good drug-like properties.

**7. DILI:** Ligand A (90.617) has a higher DILI risk than Ligand B (58.976). This is a significant negative for Ligand A.

**8. BBB:** Ligand B (64.948) has a substantially better BBB penetration percentile than Ligand A (48.197). This is a *critical* advantage for a CNS target like DRD2.

**9. Caco-2 Permeability:** Both have negative Caco-2 values which is unusual and suggests poor permeability.

**10. Aqueous Solubility:** Both have negative solubility values, which is also unusual and suggests poor solubility.

**11. hERG Inhibition:** Ligand A (0.762) has a slightly higher hERG inhibition risk than Ligand B (0.277). Lower is better here, favoring Ligand B.

**12. Microsomal Clearance:** Ligand B (59.657) has a higher microsomal clearance than Ligand A (26.176), indicating faster metabolism and potentially lower exposure. Ligand A is preferable here.

**13. In vitro Half-Life:** Ligand A (44.331) has a longer in vitro half-life than Ligand B (23.469), which is a positive attribute.

**14. P-gp Efflux:** Ligand A (0.792) has a slightly higher P-gp efflux liability than Ligand B (0.448). Lower is better, favoring Ligand B.

**15. Binding Affinity:** Ligand A (-9.8 kcal/mol) has a significantly stronger binding affinity than Ligand B (-8.3 kcal/mol). This is a substantial advantage for Ligand A, potentially outweighing some of its ADME drawbacks.

**Overall Assessment:**

While Ligand A boasts a superior binding affinity, Ligand B demonstrates a significantly better safety profile (lower DILI, hERG) and, crucially, much better predicted BBB penetration. Given that DRD2 is a CNS target, BBB penetration is paramount. The difference in binding affinity (-9.8 vs -8.3) is substantial (1.5kcal/mol), but the improved ADMET properties of Ligand B are more important for a CNS drug. The poor solubility and permeability of both compounds are concerning, but can potentially be addressed through formulation strategies.

Output:
1
2025-04-17 07:35:05,644 - INFO - Reasoning:

Let's analyze Ligand A and Ligand B based on the provided guidelines, prioritizing GPCR-specific properties (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands fall within the ideal 200-500 Da range (A: 358.316, B: 407.312).

**TPSA:** Both ligands are below the 140 A^2 threshold for oral absorption, but more importantly, are reasonably close to the 90 A^2 target for CNS penetration (A: 68.73, B: 65.97).

**logP:** Both ligands have good logP values (A: 2.358, B: 3.773), falling within the optimal 1-3 range. Ligand B is slightly higher, which could be a minor concern for solubility but isn't a dealbreaker.

**H-Bond Donors/Acceptors:** Both ligands have acceptable HBD (0) and HBA (A: 5, B: 6) counts.

**QED:** Both ligands have good QED values (A: 0.756, B: 0.706), indicating drug-like properties.

**DILI:** Both ligands have acceptable DILI risk (A: 68.592, B: 62.699), below the concerning threshold of 60.

**BBB:** This is a critical parameter for a CNS target like DRD2. Ligand A has a significantly better BBB penetration percentile (90.772) compared to Ligand B (76.154). This is a major advantage for A.

**Caco-2 Permeability:** Ligand A (-4.122) and Ligand B (-5.247) both have negative values, indicating poor permeability. This is a weakness for both, but the value for A is slightly better.

**Aqueous Solubility:** Both ligands have poor aqueous solubility (-3.429 and -3.194 respectively). This could pose formulation challenges.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (A: 0.434, B: 0.563).

**Microsomal Clearance:** Ligand B has significantly lower microsomal clearance (49.483) than Ligand A (85.244), suggesting better metabolic stability. This is a strong point for B.

**In vitro Half-Life:** Ligand B has a much longer in vitro half-life (14.652 hours) than Ligand A (-44.817 hours). This is a significant advantage for B, potentially allowing for less frequent dosing.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (A: 0.223, B: 0.628), which is good for CNS exposure.

**Binding Affinity:** Ligand B has a stronger binding affinity (-8.2 kcal/mol) compared to Ligand A (-7.6 kcal/mol). This 0.6 kcal/mol difference is substantial and could outweigh some of the ADME drawbacks of B.

**Overall Assessment:**

Ligand A excels in BBB penetration, which is paramount for a CNS-targeting drug. However, Ligand B boasts a significantly better binding affinity and improved metabolic stability (lower Cl_mic) and longer half-life. While Ligand B's BBB penetration is lower, the stronger binding affinity is a significant advantage for a GPCR target. The slightly higher logP of B is a minor concern, but the substantial improvement in affinity and metabolic stability likely outweighs this.

Output:
1
2025-04-17 07:35:05,644 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (351.491 and 345.447 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (53.09) is significantly better than Ligand B (80.12). For CNS targets, we want TPSA <= 90, and A is comfortably within that range, while B is approaching the upper limit.

**logP:** Both ligands have acceptable logP values (0.916 and 1.621, respectively), falling within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A (0 HBD, 4 HBA) is slightly better than Ligand B (1 HBD, 5 HBA) in terms of balancing solubility and permeability. Both are within acceptable limits.

**QED:** Both ligands have similar and good QED scores (0.759 and 0.795), indicating good drug-like properties.

**DILI:** Ligand A (19.581) has a much lower DILI risk than Ligand B (36.565). This is a significant advantage.

**BBB:** Ligand B (66.654) has a substantially better BBB penetration percentile than Ligand A (44.979). This is a crucial factor for a CNS target like DRD2.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.41 and -4.874), which is unusual and suggests poor permeability. However, these values are on a scale where negative values are possible, and direct comparison is difficult without knowing the scale's specifics.

**Aqueous Solubility:** Both ligands have negative solubility values (-0.782 and -2.665), indicating poor aqueous solubility.

**hERG Inhibition:** Both ligands have very low hERG inhibition liability (0.406 and 0.122), which is excellent.

**Microsomal Clearance:** Ligand A (17.448) has lower microsomal clearance than Ligand B (36.573), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (-8.098) has a longer in vitro half-life than Ligand B (-1.063).

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.053 and 0.068), which is favorable for CNS penetration.

**Binding Affinity:** Ligand A (-9.1 kcal/mol) has a significantly stronger binding affinity than Ligand B (-7.7 kcal/mol). This >1.5 kcal/mol difference is a major advantage, potentially outweighing some ADME drawbacks.

**Overall Assessment:**

While Ligand B has a better BBB score, Ligand A excels in most other critical areas, particularly binding affinity, DILI risk, metabolic stability, and in vitro half-life. The significantly stronger binding affinity of Ligand A is a key factor. The poor Caco-2 and solubility for both are concerning, but can potentially be addressed with formulation strategies. Given the GPCR-specific priorities, the strong affinity and lower toxicity/better metabolic profile of Ligand A make it the more promising candidate.

Output:
1
2025-04-17 07:35:05,644 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (356.388 and 353.438 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (58.2) is better than Ligand B (61.88). Both are below the 90 A^2 threshold for CNS targets, which is good.

**logP:** Ligand A (3.263) is optimal (1-3), while Ligand B (0.562) is quite low, potentially hindering permeation. This is a significant advantage for Ligand A.

**H-Bond Donors/Acceptors:** Ligand A (2 HBD, 2 HBA) and Ligand B (1 HBD, 4 HBA) both fall within acceptable ranges (<=5 HBD, <=10 HBA).

**QED:** Both ligands have similar QED values (0.822 and 0.802), indicating good drug-likeness.

**DILI:** Ligand A (53.47) has a higher DILI risk than Ligand B (16.789). This favors Ligand B.

**BBB:** Ligand A (88.949) has a better BBB penetration percentile than Ligand B (73.129). This is a crucial advantage, given the CNS target.

**Caco-2 Permeability:** Ligand A (-4.406) has a worse Caco-2 permeability than Ligand B (-4.862). Both are negative, indicating poor permeability.

**Aqueous Solubility:** Ligand A (-4.031) has worse solubility than Ligand B (-1.466). This favors Ligand B.

**hERG:** Both ligands have low hERG inhibition liability (0.449 and 0.398).

**Microsomal Clearance:** Ligand A (56.007) has higher microsomal clearance than Ligand B (-6.278). This means Ligand B is more metabolically stable, which is beneficial.

**In vitro Half-Life:** Ligand B (9.535) has a significantly longer in vitro half-life than Ligand A (0.697). This is a major advantage for Ligand B.

**P-gp Efflux:** Ligand A (0.064) has lower P-gp efflux than Ligand B (0.024). Lower P-gp efflux is better for CNS exposure, favoring Ligand A.

**Binding Affinity:** Ligand A (-8.0) has a significantly stronger binding affinity than Ligand B (0.0). This is the most important factor. A difference of 8 kcal/mol is substantial and can outweigh many ADME drawbacks.

**Overall Assessment:**

Ligand A has a much stronger binding affinity, a better BBB score, and lower P-gp efflux. Ligand B has better metabolic stability, lower DILI risk, and solubility. However, the large difference in binding affinity (-8.0 vs 0.0 kcal/mol) is the dominant factor. The improved CNS penetration (BBB) of Ligand A also supports its selection. While Ligand B has better ADME properties in some areas, the potency advantage of Ligand A is too significant to ignore, especially for a GPCR target where achieving sufficient target engagement is critical.

Output:
1
2025-04-17 07:35:05,644 - INFO - Batch 377 complete. Total preferences: 6032
2025-04-17 07:35:05,644 - INFO - Processing batch 378/512...
2025-04-17 07:35:49,614 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (376.375 and 343.431 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (59.06) is excellent, well below the 90 A^2 threshold for CNS targets. Ligand B (80.95) is still reasonable but less optimal.

**logP:** Ligand A (3.241) is within the optimal 1-3 range. Ligand B (1.464) is at the lower end, potentially impacting permeability.

**H-Bond Donors/Acceptors:** Ligand A (HBD=1, HBA=4) and Ligand B (HBD=2, HBA=5) both have acceptable numbers of H-bond donors and acceptors.

**QED:** Both ligands have similar QED values (0.814 and 0.799), indicating good drug-likeness.

**DILI:** Both ligands have acceptable DILI risk (52.772 and 47.732 percentile), below the concerning 60 threshold.

**BBB:** Ligand A (75.843) has a significantly better BBB penetration percentile than Ligand B (65.839). This is a crucial advantage for a CNS target like DRD2.

**Caco-2 Permeability:** Both have negative Caco-2 values (-4.894 and -4.906), which is unusual and problematic. This suggests poor intestinal absorption. However, for a CNS target, this is less critical than BBB penetration.

**Aqueous Solubility:** Both have negative solubility values (-3.907 and -3.035), indicating very poor aqueous solubility. This is a significant drawback for both compounds.

**hERG Inhibition:** Ligand A (0.782) has a lower hERG inhibition risk than Ligand B (0.238).

**Microsomal Clearance:** Ligand A (15.275 mL/min/kg) has a lower microsomal clearance than Ligand B (29.677 mL/min/kg), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (54.884 hours) has a significantly longer half-life than Ligand B (16.966 hours).

**P-gp Efflux:** Ligand A (0.597) has lower P-gp efflux liability than Ligand B (0.102), which is favorable for CNS penetration.

**Binding Affinity:** Both ligands have excellent binding affinities (-9.0 and -8.7 kcal/mol). The difference of 0.3 kcal/mol is not substantial enough to outweigh other ADME differences.

**Overall Assessment:**

Ligand A is the more promising candidate. While both have poor solubility and Caco-2 permeability, Ligand A excels in critical areas for a CNS GPCR target: significantly better BBB penetration, lower P-gp efflux, better metabolic stability (lower Cl_mic and longer t1/2), and lower hERG risk. The slight advantage in binding affinity is not a deciding factor given the other benefits of Ligand A.

Output:
1
2025-04-17 07:35:49,614 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (399.208) is slightly higher than Ligand B (350.419), but both are acceptable.

**TPSA:** Both ligands have TPSA values below 140, suggesting reasonable oral absorption. Importantly, both are also below the 90 threshold desirable for CNS targets. Ligand A (94.18) is slightly higher than Ligand B (90.98), but both are good.

**logP:** Ligand A (1.894) is within the optimal range (1-3). Ligand B (-0.315) is *below* 1, which could hinder permeation. This is a significant drawback for Ligand B.

**H-Bond Donors/Acceptors:** Ligand A (HBD=1, HBA=7) and Ligand B (HBD=2, HBA=4) both fall within acceptable limits.

**QED:** Both ligands have good QED scores (A: 0.556, B: 0.727), indicating drug-like properties. Ligand B is slightly better here.

**DILI:** Ligand A has a high DILI risk (98.527), which is concerning. Ligand B has a much lower DILI risk (43.932), a significant advantage.

**BBB:** Ligand A has a BBB penetration of 49.903, which is below the desirable 70% for CNS targets. Ligand B has a much better BBB penetration (59.325), though still not optimal.

**Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and suggests poor permeability. However, the scale is not specified, so it's hard to interpret.

**Aqueous Solubility:** Both have negative solubility values, again unusual and suggesting poor solubility. The scale is not specified, so it's hard to interpret.

**hERG Inhibition:** Ligand A (0.561) has a slightly higher hERG risk than Ligand B (0.069). Lower is better, so Ligand B is preferable.

**Microsomal Clearance:** Ligand A (36.482) has a higher microsomal clearance than Ligand B (0.436), indicating lower metabolic stability. Ligand B is significantly better here.

**In vitro Half-Life:** Ligand A (36.643) has a longer half-life than Ligand B (11.089). This is a positive for Ligand A.

**P-gp Efflux:** Ligand A (0.536) has lower P-gp efflux than Ligand B (0.007), which is favorable for CNS penetration.

**Binding Affinity:** Ligand A (-10.2 kcal/mol) has a *much* stronger binding affinity than Ligand B (-8.5 kcal/mol). This is a substantial advantage for Ligand A, potentially outweighing some of its ADME drawbacks.

**Overall Assessment:**

Ligand A has a significantly better binding affinity and P-gp efflux, and a longer half-life. However, it suffers from a high DILI risk and suboptimal BBB penetration. Ligand B has better DILI, BBB, metabolic stability, and hERG, but its logP is concerningly low, and its affinity is weaker.

Given the GPCR-specific priorities, BBB penetration is crucial for a CNS target like DRD2. While Ligand B's BBB is not ideal, it is better than Ligand A's. However, the *magnitude* of the affinity difference is very large (1.7 kcal/mol). For a GPCR, a strong binding affinity can often compensate for some ADME liabilities, *especially* if the liabilities are not prohibitive. The DILI risk for Ligand A is high, but not necessarily a complete deal-breaker at this stage. The low logP of Ligand B is a more fundamental issue that will likely limit its ability to cross membranes.

Output:
1
2025-04-17 07:35:49,614 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (348.447 and 378.51 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Both ligands have TPSA values (88.33 and 84.5) below the 90 A^2 threshold for CNS targets, which is excellent.

**3. logP:** Both ligands have logP values (1.712 and 1.754) within the optimal 1-3 range.

**4. H-Bond Donors:** Ligand A (1 HBD) and Ligand B (2 HBDs) are both within the acceptable limit of <=5.

**5. H-Bond Acceptors:** Ligand A (5 HBA) and Ligand B (4 HBA) are both within the acceptable limit of <=10.

**6. QED:** Both ligands have QED values (0.723 and 0.607) above 0.5, indicating good drug-like properties.

**7. DILI:** Both ligands have low DILI risk (29.042 and 34.238 percentiles), which is favorable.

**8. BBB:** Both ligands show excellent BBB penetration (81 and 81.466 percentiles), which is crucial for a CNS target like DRD2.

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.072 and -4.927), which is unusual and suggests poor permeability. However, these values are on a log scale and are likely indicating very low permeability.

**10. Aqueous Solubility:** Both ligands have negative solubility values (-2.145 and -2.535), also unusual and suggesting very low solubility.

**11. hERG Inhibition:** Both ligands have low hERG inhibition risk (0.376 and 0.467 percentiles).

**12. Microsomal Clearance:** Ligand A (47.701 mL/min/kg) has higher microsomal clearance than Ligand B (23.519 mL/min/kg), suggesting lower metabolic stability.

**13. In vitro Half-Life:** Ligand B has a significantly longer in vitro half-life (-19.631 hours) than Ligand A (-5.082 hours), indicating better metabolic stability.

**14. P-gp Efflux:** Both ligands have low P-gp efflux liability (0.08 and 0.086 percentiles).

**15. Binding Affinity:** Ligand A (-8.4 kcal/mol) has a stronger binding affinity than Ligand B (-6.9 kcal/mol). The difference of 1.5 kcal/mol is significant.

**Overall Assessment:**

While both ligands have good overall profiles, Ligand A's significantly stronger binding affinity (-8.4 kcal/mol vs -6.9 kcal/mol) is a major advantage, especially for a GPCR target. The difference in affinity could potentially outweigh the slightly higher microsomal clearance and shorter half-life of Ligand A. The poor permeability and solubility are concerning for both, but these can be addressed with formulation strategies. Given the importance of affinity for GPCRs, and the acceptable BBB penetration of both, Ligand A is the more promising candidate.

Output:
1
2025-04-17 07:35:49,614 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B based on the provided guidelines, prioritizing GPCR-specific properties (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (344.375 and 354.451 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (122.03) is slightly above the optimal <90 for CNS targets, while Ligand B (96.35) is comfortably within. This favors Ligand B.

**logP:** Ligand A (-0.049) is quite low, potentially hindering permeation. Ligand B (-1.92) is better, though still on the lower side of the optimal 1-3 range. Ligand B is favored.

**H-Bond Donors/Acceptors:** Both have 3 HBD and acceptable HBA counts (7 and 6 respectively). No significant difference here.

**QED:** Both ligands have acceptable QED scores (0.606 and 0.515), indicating reasonable drug-likeness.

**DILI:** Ligand A (60.217) has a higher DILI risk than Ligand B (6.863). This is a significant advantage for Ligand B.

**BBB:** This is crucial for a CNS target like DRD2. Ligand A (24.622) has a very poor BBB percentile, while Ligand B (9.965) is also low, but significantly better than A. Ligand B is favored.

**Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and suggests poor permeability.

**Aqueous Solubility:** Both have negative solubility values, indicating very poor solubility.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.1 and 0.12). No significant difference.

**Microsomal Clearance:** Ligand A (15.07) has higher clearance than Ligand B (-8.994, indicating high metabolic stability). This favors Ligand B.

**In vitro Half-Life:** Ligand A (3.479) has a slightly longer half-life than Ligand B (2.125).

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.02 and 0.002). No significant difference.

**Binding Affinity:** Ligand A (-8.6 kcal/mol) has a stronger binding affinity than Ligand B (-7.3 kcal/mol). This is a substantial difference (1.3 kcal/mol), which could outweigh some ADME drawbacks.

**Overall Assessment:**

While Ligand A has superior binding affinity, its extremely poor BBB penetration and higher DILI risk are major concerns for a CNS drug targeting DRD2. Ligand B, despite a slightly weaker affinity, exhibits significantly better predicted CNS penetration (though still not ideal), much lower DILI risk, and better metabolic stability. Given the GPCR-specific priorities, particularly BBB and safety (DILI), Ligand B is the more promising candidate. The affinity difference, while notable, might be overcome with further optimization of Ligand B.

Output:
1
2025-04-17 07:35:49,615 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (340.47 and 353.42 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (58.2) is excellent, well below the 90 A^2 threshold for CNS targets. Ligand B (110.85) is higher, but still potentially acceptable, though less ideal.

**logP:** Ligand A (3.136) is optimal (1-3). Ligand B (-0.965) is significantly lower, which could hinder membrane permeability and CNS penetration.

**H-Bond Donors/Acceptors:** Ligand A (2 HBD, 2 HBA) is well within the acceptable ranges. Ligand B (3 HBD, 4 HBA) is also acceptable, but slightly higher.

**QED:** Ligand A (0.885) has a very strong drug-like profile. Ligand B (0.488) is lower, indicating a less favorable overall drug-likeness.

**DILI:** Ligand A (42.54) has a low DILI risk. Ligand B (29.82) also has a low DILI risk.

**BBB:** Ligand A (62.23) is reasonably good, but could be better for a CNS target. Ligand B (49.48) is lower and concerning for CNS penetration.

**Caco-2:** Ligand A (-4.741) and Ligand B (-5.486) both have negative values, which is unusual and suggests poor Caco-2 permeability. However, these values are on a scale where negative values are possible and don't necessarily indicate a complete lack of permeability.

**Solubility:** Ligand A (-4.312) and Ligand B (-1.16) both have negative solubility values. This is concerning, and could lead to formulation challenges.

**hERG:** Ligand A (0.312) has a very low hERG risk. Ligand B (0.089) also has a very low hERG risk.

**Cl_mic:** Ligand A (21.878) has a moderate clearance. Ligand B (-18.737) has a negative clearance, which is unusual and suggests very high metabolic stability.

**t1/2:** Ligand A (5.206) has a moderate half-life. Ligand B (4.558) has a slightly shorter half-life.

**Pgp:** Ligand A (0.113) has low P-gp efflux liability, which is good for CNS penetration. Ligand B (0.003) has extremely low P-gp efflux, which is even better.

**Binding Affinity:** Ligand A (-9.7 kcal/mol) has a significantly stronger binding affinity than Ligand B (-7.8 kcal/mol). This is a substantial difference.

**Overall Assessment:**

Ligand A is superior due to its better logP, QED, and significantly stronger binding affinity. While its BBB is not ideal, the strong binding and better physicochemical properties outweigh this concern. Ligand B's low logP is a major drawback, likely hindering both permeability and CNS penetration. The negative Caco-2 and solubility values for both are concerning, but the strong affinity of A makes it more likely to be optimized to overcome these issues.

Output:
0
2025-04-17 07:35:49,615 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (350.463 and 356.373 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Both ligands have TPSA values (87.46 and 86.63) below 140, suggesting good oral absorption potential. They are also reasonably close to the 90 threshold for CNS targets, but not ideal.

**3. logP:** Both ligands have logP values (1.483 and 1.238) within the optimal range of 1-3.

**4. H-Bond Donors:** Ligand A has 2 HBD, and Ligand B has 1. Both are acceptable (<=5).

**5. H-Bond Acceptors:** Both ligands have 5 HBA, which is acceptable (<=10).

**6. QED:** Both ligands have QED values (0.743 and 0.829) above 0.5, indicating good drug-like properties.

**7. DILI:** Ligand A (35.285) has a lower DILI risk than Ligand B (49.632), which is preferable. Both are below 60, so the risk is moderate.

**8. BBB:** Ligand B (84.451) has a significantly higher BBB penetration percentile than Ligand A (66.227). This is a *major* advantage for a CNS target like DRD2.

**9. Caco-2 Permeability:** Both have negative values (-4.945 and -4.488), which is unusual. This suggests poor permeability. However, the scale isn't specified, so it's hard to interpret.

**10. Aqueous Solubility:** Both have negative values (-1.849 and -2.112), indicating poor solubility. This is a concern.

**11. hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.259 and 0.286).

**12. Microsomal Clearance:** Ligand A (23.124) has a higher microsomal clearance than Ligand B (20.504), suggesting lower metabolic stability.

**13. In vitro Half-Life:** Ligand B (-30.481) has a *much* longer in vitro half-life than Ligand A (-5.478). This is a significant advantage.

**14. P-gp Efflux:** Both ligands have low P-gp efflux liability (0.068 and 0.048).

**15. Binding Affinity:** Ligand A (-7.8 kcal/mol) has a slightly stronger binding affinity than Ligand B (-7.3 kcal/mol). However, the difference is only 0.5 kcal/mol, which isn't huge.

**Overall Assessment:**

While Ligand A has slightly better binding affinity and lower DILI risk, Ligand B is significantly better in terms of BBB penetration and in vitro half-life. For a CNS target like DRD2, BBB penetration is *critical*. The longer half-life of Ligand B is also a substantial benefit. The slightly weaker binding affinity of Ligand B is likely outweighed by its superior pharmacokinetic properties for CNS delivery. The poor solubility and Caco-2 permeability are concerns for both, but can potentially be addressed through formulation strategies.

Output:
1
2025-04-17 07:35:49,615 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (362.59 and 348.447 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (49.41) is excellent, well below the 90 A^2 threshold for CNS targets. Ligand B (87.32) is higher, but still reasonably acceptable, though less ideal.

**logP:** Ligand A (3.568) is optimal. Ligand B (1.902) is at the lower end of the optimal range, potentially impacting permeability.

**H-Bond Donors/Acceptors:** Ligand A (HBD=1, HBA=2) and Ligand B (HBD=2, HBA=4) both have acceptable numbers of H-bond donors and acceptors.

**QED:** Ligand A (0.777) has a better QED score than Ligand B (0.555), indicating better overall drug-likeness.

**DILI:** Ligand A (20.628) has a significantly lower DILI risk than Ligand B (35.789), which is a substantial advantage.

**BBB:** Ligand A (76.851) has a much better BBB penetration score than Ligand B (55.021). This is *critical* for a CNS target like DRD2.

**Caco-2 Permeability:** Ligand A (-4.811) and Ligand B (-5.647) both have negative Caco-2 values, which is unusual. It's difficult to interpret without knowing the scale, but it suggests poor permeability.

**Aqueous Solubility:** Ligand A (-4.758) and Ligand B (-2.144) both have negative solubility values, again making interpretation difficult without knowing the scale.

**hERG:** Both ligands have very low hERG inhibition liability (0.499 and 0.253, respectively), which is excellent.

**Microsomal Clearance:** Ligand B (-18.116) has a more negative value (indicating lower clearance/better metabolic stability) than Ligand A (54.704).

**In vitro Half-Life:** Ligand B (-7.164) has a more negative value (indicating longer half-life) than Ligand A (-18.799).

**P-gp Efflux:** Both ligands show very low P-gp efflux liability (0.415 and 0.037, respectively).

**Binding Affinity:** Ligand B (-8.7 kcal/mol) has a significantly stronger binding affinity than Ligand A (0.0 kcal/mol). This is a *major* advantage, potentially outweighing some of the ADME drawbacks.

**Overall Assessment:**

Ligand B has a much stronger binding affinity, which is paramount for GPCR targeting. However, Ligand A has superior BBB penetration, lower DILI risk, and better QED. The lower logP of Ligand B is a concern for permeability. While Ligand B's metabolic stability and half-life are better, the substantial difference in binding affinity is the deciding factor. For a CNS target, the binding affinity advantage of Ligand B is likely to be more impactful than the slightly less favorable ADME properties, especially given the low hERG risk for both.

Output:
1
2025-04-17 07:35:49,615 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (341.415 and 355.869 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (90.98) is excellent for CNS penetration, being below the 90 threshold. Ligand B (46.09) is also very good.

**logP:** Ligand A (1.733) is within the optimal 1-3 range. Ligand B (4.193) is slightly higher, potentially causing solubility issues or off-target interactions, but still within a reasonable range.

**H-Bond Donors/Acceptors:** Ligand A has 2 HBD and 4 HBA, which is acceptable. Ligand B has 0 HBD and 3 HBA, also acceptable.

**QED:** Both ligands have QED values above 0.7, indicating good drug-likeness.

**DILI:** Both ligands have DILI risk around the 50-55 percentile, indicating moderate risk. This isn't a major differentiating factor.

**BBB:** Ligand B (69.213) has a significantly better BBB penetration score than Ligand A (46.336). This is a crucial advantage for a CNS target like DRD2.

**Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and suggests a potential issue with the data or modeling. However, we can still compare them relatively. Ligand B (-4.671) is slightly better than Ligand A (-5).

**Aqueous Solubility:** Both have negative solubility values, which is also unusual. Ligand A (-2.69) is slightly better than Ligand B (-4.635).

**hERG Inhibition:** Ligand A (0.087) has a very low hERG risk, which is excellent. Ligand B (0.596) is slightly higher, but still relatively low.

**Microsomal Clearance:** Ligand A (12.833) has lower microsomal clearance than Ligand B (87.502), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (-5.702) has a negative half-life, which is problematic. Ligand B (20.032) has a much more reasonable half-life.

**P-gp Efflux:** Ligand A (0.011) has very low P-gp efflux, which is highly desirable for CNS penetration. Ligand B (0.356) is slightly higher, but still relatively low.

**Binding Affinity:** Both ligands have very similar binding affinities (-7.9 and -7.7 kcal/mol), which are both excellent and well below the -7.0 threshold. The difference of 0.2 kcal/mol is unlikely to be decisive.

**Overall Assessment:**

Ligand B is more promising due to its significantly better BBB penetration (69.213 vs 46.336) and a reasonable in vitro half-life (20.032 vs -5.702). While Ligand A has better metabolic stability (lower Cl_mic) and lower P-gp efflux, the BBB is a critical factor for CNS targets, and Ligand B excels in this area. The slight difference in logP is not a major concern, and both ligands have good binding affinities. The unusual negative values for Caco-2 and solubility are concerning, but the relative comparison still points towards Ligand B.

Output:
1
2025-04-17 07:35:49,615 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (364.471 and 350.459 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (97.27) is slightly higher than Ligand B (89.87). Both are below the 140 threshold for oral absorption and reasonably close to the 90 target for CNS penetration, but B is preferable.

**logP:** Ligand A (1.748) and Ligand B (0.829) are both within the optimal 1-3 range. Ligand A is slightly better.

**H-Bond Donors/Acceptors:** Ligand A has 1 HBD and 5 HBA, while Ligand B has 3 HBD and 4 HBA. Both are within acceptable limits (<=5 HBD and <=10 HBA).

**QED:** Ligand A (0.88) has a better QED score than Ligand B (0.655), indicating higher drug-likeness.

**DILI:** Ligand B (8.918) has a significantly lower DILI risk than Ligand A (46.917), which is a major advantage.

**BBB:** Ligand B (52.617) has a considerably better BBB penetration percentile than Ligand A (45.366). This is crucial for a CNS target like DRD2.

**Caco-2 Permeability:** Ligand A (-4.784) has a worse Caco-2 permeability than Ligand B (-5.04). Lower values indicate poorer permeability.

**Aqueous Solubility:** Ligand A (-2.6) is slightly better than Ligand B (-1.387), but both are quite poor.

**hERG Inhibition:** Ligand A (0.331) has a lower hERG inhibition liability than Ligand B (0.175), which is preferable.

**Microsomal Clearance:** Ligand A (-20.871) has a much lower (better) microsomal clearance than Ligand B (-0.986), indicating greater metabolic stability.

**In vitro Half-Life:** Ligand A (10.028) has a longer half-life than Ligand B (-3.966).

**P-gp Efflux:** Ligand A (0.069) has a lower P-gp efflux liability than Ligand B (0.03), which is better for CNS exposure.

**Binding Affinity:** Ligand B (-7.7 kcal/mol) has a slightly better binding affinity than Ligand A (-7.2 kcal/mol). While the difference is not huge, it's enough to consider.

**Overall Assessment:**

Ligand B excels in the most critical areas for a CNS-targeting GPCR ligand: BBB penetration and DILI risk. Its slightly better affinity is also a plus. While Ligand A has advantages in metabolic stability, half-life, and P-gp efflux, the superior CNS penetration and safety profile of Ligand B outweigh these benefits. The solubility of both is poor, but this can be addressed with formulation strategies.

Output:
1
2025-04-17 07:35:49,615 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 drug candidates, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (342.443 and 347.415 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Both ligands have TPSA values (85.23 and 86.88) below the 90 A^2 threshold for CNS targets, which is good.

**3. logP:** Both ligands have logP values (1.577 and 1.386) within the optimal range of 1-3.

**4. H-Bond Donors:** Ligand A (2) and Ligand B (1) both meet the HBD criteria of <=5.

**5. H-Bond Acceptors:** Ligand A (4) and Ligand B (5) both meet the HBA criteria of <=10.

**6. QED:** Both ligands have QED values above 0.5 (0.667 and 0.84), indicating good drug-likeness.

**7. DILI:** Ligand A (23.032) has a significantly lower DILI risk than Ligand B (50.136). This is a substantial advantage.

**8. BBB:** Ligand B (68.67) has a better BBB penetration percentile than Ligand A (41.218). This is a key consideration for a CNS target like DRD2.

**9. Caco-2 Permeability:** Ligand A (-5.143) has worse Caco-2 permeability than Ligand B (-4.589), but both are poor.

**10. Aqueous Solubility:** Ligand A (-2.287) has slightly better aqueous solubility than Ligand B (-2.68), but both are poor.

**11. hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.275 and 0.166).

**12. Microsomal Clearance:** Ligand B (21.14) has lower microsomal clearance than Ligand A (28.232), suggesting better metabolic stability.

**13. In vitro Half-Life:** Ligand B (13.029) has a longer in vitro half-life than Ligand A (10.787).

**14. P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.009 and 0.304).

**15. Binding Affinity:** Ligand B (-7.9 kcal/mol) has a slightly better binding affinity than Ligand A (-7.6 kcal/mol). While the difference is not huge, it's a positive factor.

**Overall Assessment:**

Ligand B is superior in terms of BBB penetration, metabolic stability (lower Cl_mic, longer t1/2), and binding affinity. However, Ligand A has a significantly lower DILI risk. Given the CNS target, BBB is critical. The slight improvement in affinity with Ligand B, combined with its better BBB, outweighs the DILI concern, especially since Ligand A's DILI risk is still relatively low. The Caco-2 and solubility are poor for both, but can be addressed with formulation strategies.

Output:
1
2025-04-17 07:35:49,615 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (356.438 and 380.495 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (78.87) is significantly better than Ligand B (94.56). For CNS targets, we want TPSA <= 90, and A is closer to this threshold.

**logP:** Both ligands have good logP values (1.187 and 1.027), falling within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A (HBD=2, HBA=4) is preferable to Ligand B (HBD=3, HBA=7) as it has fewer H-bonds, potentially improving permeability. Both are within acceptable limits.

**QED:** Both ligands have similar QED values (0.64 and 0.664), indicating good drug-likeness.

**DILI:** Ligand A (13.3) has a much lower DILI risk than Ligand B (73.982). This is a significant advantage for A.

**BBB:** Ligand A (72.354) has a much better BBB penetration percentile than Ligand B (39.24). This is *critical* for a CNS target like DRD2.

**Caco-2 Permeability:** Ligand A (-4.694) has a more negative Caco-2 value than Ligand B (-5.499), suggesting slightly *worse* intestinal absorption. However, for a CNS target, intestinal absorption is less critical than BBB penetration.

**Aqueous Solubility:** Ligand A (-1.796) has a slightly better solubility than Ligand B (-2.933).

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.279 and 0.367).

**Microsomal Clearance:** Ligand A (23.301) has a lower microsomal clearance than Ligand B (64.112), indicating better metabolic stability.

**In vitro Half-Life:** Ligand A (-11.294) has a shorter half-life than Ligand B (27.981). This is a drawback for A, but potentially mitigated by its lower clearance.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.047 and 0.273).

**Binding Affinity:** Ligand B (-8.5 kcal/mol) has a stronger binding affinity than Ligand A (-7.3 kcal/mol). This is a 1.2 kcal/mol difference, which is significant.

**Overall Assessment:**

While Ligand B has a better binding affinity, Ligand A is significantly better across multiple crucial ADME properties, especially for a CNS target. The superior BBB penetration (72.354 vs 39.24), lower DILI risk (13.3 vs 73.982), and lower microsomal clearance (23.301 vs 64.112) of Ligand A outweigh the slightly weaker binding affinity. The TPSA is also more favorable for CNS penetration. The difference in affinity, while notable, may be overcome with further optimization of Ligand A.



Output:
0
2025-04-17 07:35:49,616 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (355.503 and 347.371 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (38.33) is significantly better than Ligand B (105.67). For CNS targets, we want TPSA <= 90, and A is well within that, while B is considerably above. This is a major advantage for A.

**logP:** Ligand A (4.289) is slightly higher than the optimal 1-3 range, potentially leading to solubility issues, but still manageable. Ligand B (1.805) is at the lower end, which could hinder permeation.

**H-Bond Donors/Acceptors:** Both have acceptable HBD counts (1). Ligand B has a higher HBA count (8) compared to A (3), but both are within the acceptable limit of 10.

**QED:** Ligand A (0.813) has a significantly higher QED score than Ligand B (0.573), indicating better overall drug-likeness.

**DILI:** Ligand B (76.115) has a higher DILI risk than Ligand A (46.801). Lower is better, so A is preferable.

**BBB:** Ligand B (75.572) has a better BBB penetration percentile than Ligand A (63.784), but both are reasonably good for a CNS target.

**Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and suggests issues with the prediction method or the molecules themselves. We'll proceed with caution regarding these values.

**Aqueous Solubility:** Both have negative solubility values, again suggesting prediction issues.

**hERG Inhibition:** Both have low hERG inhibition liability (0.8 and 0.578), which is good.

**Microsomal Clearance:** Ligand A (117.764) has a higher microsomal clearance than Ligand B (81.679), meaning it's likely to be metabolized more quickly. This is a disadvantage for A.

**In vitro Half-Life:** Ligand B (-31.751) has a negative half-life, which is unrealistic and indicates a problem with the prediction. Ligand A (26.868) has a reasonable half-life.

**P-gp Efflux:** Ligand A (0.706) has lower P-gp efflux liability than Ligand B (0.373), which is favorable for CNS penetration.

**Binding Affinity:** Ligand B (-7.3 kcal/mol) has a slightly better binding affinity than Ligand A (-9.1 kcal/mol). However, the difference is not substantial enough to overcome the other significant advantages of Ligand A.

**Overall Assessment:**

Ligand A is the stronger candidate. It has a much better TPSA, QED, and DILI profile. While its logP is slightly higher and clearance is higher, its superior TPSA and QED, coupled with acceptable BBB and P-gp efflux, make it more likely to be a viable drug candidate for a CNS target like DRD2. The issues with Caco-2 and solubility predictions for both compounds are concerning, but the other factors strongly favor A. The slightly better affinity of B is not enough to offset A's advantages.

Output:
1
2025-04-17 07:35:49,616 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (360.483 and 350.459 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (67.23) is significantly better than Ligand B (78.87). For CNS targets, we want TPSA <= 90, and A is comfortably within that range, while B is approaching the upper limit.

**logP:** Ligand A (3.407) is optimal (1-3), while Ligand B (1.241) is on the lower side. Lower logP can hinder permeation, and is a negative for GPCRs.

**H-Bond Donors/Acceptors:** Ligand A (HBD=1, HBA=5) and Ligand B (HBD=2, HBA=4) both have acceptable numbers of H-bond donors and acceptors.

**QED:** Ligand A (0.858) has a much better QED score than Ligand B (0.353), indicating a more drug-like profile.

**DILI:** Ligand A (56.223) has a moderate DILI risk, while Ligand B (6.669) has a very low DILI risk. This favors B.

**BBB:** Ligand A (80.574) has a good BBB penetration percentile, exceeding the desirable >70% threshold for CNS targets. Ligand B (54.478) is significantly lower and less favorable.

**Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and hard to interpret without knowing the scale. However, the magnitude of the negative value is similar.

**Aqueous Solubility:** Both have negative solubility values, again unusual. The magnitude is similar.

**hERG:** Ligand A (0.651) has a lower hERG inhibition liability than Ligand B (0.248), indicating a lower risk of cardiotoxicity.

**Microsomal Clearance:** Ligand A (38.468) has a higher microsomal clearance than Ligand B (2.501), suggesting lower metabolic stability. This favors B.

**In vitro Half-Life:** Ligand A (22.082) has a longer half-life than Ligand B (-13.382). The negative value for B is concerning and suggests very rapid degradation.

**P-gp Efflux:** Ligand A (0.477) has lower P-gp efflux liability than Ligand B (0.052), which is favorable for CNS exposure.

**Binding Affinity:** Ligand A (-8.4 kcal/mol) has a slightly better binding affinity than Ligand B (-7.4 kcal/mol). While both are good, the 1.0 kcal/mol difference is significant and can outweigh some ADME drawbacks.

**Overall Assessment:**

Ligand A excels in crucial areas for a CNS-targeting GPCR ligand: TPSA, logP, BBB penetration, P-gp efflux, and binding affinity. While its DILI risk is moderate and clearance is higher, the superior BBB, logP, and binding affinity are critical. Ligand B has better DILI and clearance, but suffers from poor logP, lower BBB penetration, and a very concerning negative in vitro half-life. The significantly better binding affinity of A, combined with its superior CNS penetration properties, makes it the more promising candidate.

Output:
1
2025-04-17 07:35:49,616 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (354.411 and 347.503 Da) fall within the ideal range of 200-500 Da.

**TPSA:** Ligand A (110.61) is higher than the preferred <90 for CNS targets, while Ligand B (43.86) is excellent. This is a significant advantage for Ligand B.

**logP:** Ligand A (-0.049) is slightly below the optimal 1-3 range, potentially hindering permeability. Ligand B (2.3) is within the optimal range.

**H-Bond Donors/Acceptors:** Ligand A has 2 HBD and 7 HBA, which are acceptable. Ligand B has 0 HBD and 3 HBA, also acceptable.

**QED:** Both ligands have reasonable QED scores (0.633 and 0.524), indicating good drug-like properties.

**DILI:** Ligand A (60.566) is approaching a moderate risk for DILI, while Ligand B (14.23) shows very low risk. This is a strong advantage for Ligand B.

**BBB:** Both ligands have good BBB penetration (75.107 and 71.888), exceeding the >70 threshold for CNS targets.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.852 and -4.745), which is unusual and concerning. This suggests poor intestinal absorption, but could be an artifact of the prediction method.

**Aqueous Solubility:** Both ligands have negative solubility values (-0.962 and -1.51), which is also concerning and suggests poor aqueous solubility. This could be a formulation challenge.

**hERG:** Both ligands have low hERG inhibition liability (0.056 and 0.542), which is positive.

**Microsomal Clearance:** Ligand A (21.789) has lower microsomal clearance than Ligand B (37.22), indicating better metabolic stability.

**In vitro Half-Life:** Ligand A (12.277) has a longer in vitro half-life than Ligand B (-10.607), which is desirable.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.01 and 0.103), which is good for CNS exposure.

**Binding Affinity:** Both ligands have the same excellent binding affinity (-7.5 kcal/mol).

**Overall Assessment:**

Ligand B is superior due to its significantly lower TPSA (43.86 vs 110.61), lower DILI risk (14.23 vs 60.566), and more favorable logP (2.3 vs -0.049). While Ligand A has better metabolic stability and half-life, the advantages of Ligand B in TPSA, DILI, and logP are more critical for a CNS-targeting GPCR ligand. The negative Caco-2 and solubility values are concerning for both, but the other advantages of Ligand B outweigh these drawbacks.

Output:
1
2025-04-17 07:35:49,616 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (374.507 and 347.419 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (91.93) is slightly above the optimal <90 for CNS targets, while Ligand B (87.54) is within the desired range. This gives a slight edge to Ligand B.

**logP:** Ligand A (1.165) is within the optimal 1-3 range. Ligand B (0.161) is a bit low, potentially hindering permeation. Ligand A is favored here.

**H-Bond Donors/Acceptors:** Ligand A has 3 HBD and 5 HBA, which are acceptable. Ligand B has 1 HBD and 5 HBA, also acceptable. No clear advantage.

**QED:** Ligand B (0.769) has a significantly better QED score than Ligand A (0.386), indicating a more drug-like profile.

**DILI:** Both ligands have low DILI risk (37.069 and 36.177 percentile), which is good.

**BBB:** Ligand A (63.784) has a moderate BBB penetration, while Ligand B (56.34) is lower. While both are not ideal (>70), Ligand A is better.

**Caco-2 Permeability:** Ligand A (-4.753) and Ligand B (-4.806) both have negative Caco-2 values, which is unusual and suggests poor permeability.

**Aqueous Solubility:** Ligand A (-2.801) and Ligand B (-1.088) both have negative solubility values, indicating poor solubility. Ligand B is slightly better.

**hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.342 and 0.031), which is excellent.

**Microsomal Clearance:** Ligand A (19.08 mL/min/kg) has higher clearance than Ligand B (-1.872 mL/min/kg), suggesting lower metabolic stability. Ligand B is favored.

**In vitro Half-Life:** Ligand A (12.941 hours) has a longer half-life than Ligand B (-2.97 hours). Ligand A is favored.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.023 and 0.007), which is excellent for CNS penetration.

**Binding Affinity:** Ligand B (-8.1 kcal/mol) has a slightly better binding affinity than Ligand A (-7.9 kcal/mol). While the difference is small, it's within the range where it can outweigh minor ADME drawbacks.

**Overall Assessment:**

Ligand B has a better QED score, lower clearance (better metabolic stability), and slightly better binding affinity. Ligand A has better BBB penetration and a longer half-life. However, the slightly stronger binding affinity of Ligand B, combined with its superior QED and metabolic stability, makes it the more promising candidate, despite its lower BBB and logP. The TPSA is also more favorable for Ligand B.

Output:
1
2025-04-17 07:35:49,616 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (342.399 and 377.503 Da) fall within the ideal 200-500 Da range.

**TPSA:** Both ligands have TPSA values (88.32 and 82.14) below the 90 A^2 threshold desirable for CNS targets, which is excellent.

**logP:** Both ligands have logP values (0.943 and 1.011) within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A has 1 HBD and 6 HBA, while Ligand B has 0 HBD and 6 HBA. Both are acceptable, staying within the guidelines of <=5 HBD and <=10 HBA.

**QED:** Ligand A (0.897) has a better QED score than Ligand B (0.727), indicating a more drug-like profile.

**DILI:** Ligand A (60.644) has a higher DILI risk than Ligand B (35.479). This is a negative for Ligand A.

**BBB:** Ligand B (81.388) has a significantly better BBB penetration percentile than Ligand A (66.925). This is a crucial advantage for a CNS target like DRD2.

**Caco-2 Permeability:** Both have negative values, which is unusual. However, the magnitude for Ligand A (-4.877) is worse than Ligand B (-4.428), suggesting lower intestinal absorption for Ligand A.

**Aqueous Solubility:** Ligand B (-1.227) has better solubility than Ligand A (-3.038).

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.21 and 0.291).

**Microsomal Clearance:** Ligand B (-1.792) has a much lower (better) microsomal clearance than Ligand A (25.149), indicating greater metabolic stability.

**In vitro Half-Life:** Ligand B (15.782 hours) has a significantly longer half-life than Ligand A (-13.662 hours).

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.22 and 0.064). Ligand B is slightly better.

**Binding Affinity:** Ligand A (-9.6 kcal/mol) has a significantly stronger binding affinity than Ligand B (-6.2 kcal/mol). This is a substantial advantage, potentially outweighing some of the ADME drawbacks. The difference is >1.5 kcal/mol.

**Overall Assessment:**

Ligand A has a much better binding affinity, which is paramount. However, Ligand B excels in ADME properties critical for CNS penetration and metabolic stability: significantly better BBB, lower DILI, lower clearance, and a longer half-life. While the affinity difference is substantial, the improved ADME profile of Ligand B, especially its BBB penetration, makes it a more promising candidate for a CNS-targeting drug like a DRD2 ligand. The stronger binding of Ligand A might be overcome with formulation strategies, but the inherent permeability and metabolic advantages of Ligand B are harder to engineer.

Output:
1
2025-04-17 07:35:49,617 - INFO - Batch 378 complete. Total preferences: 6048
2025-04-17 07:35:49,617 - INFO - Processing batch 379/512...
2025-04-17 07:36:31,671 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B based on the provided guidelines, prioritizing GPCR-specific properties (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (350.419 and 368.478 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (126.46) is slightly above the optimal <90 for CNS targets, but still reasonable. Ligand B (97.11) is excellent, well below 90. This favors Ligand B.

**logP:** Both ligands have good logP values (1.212 and 2.052), falling within the 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A has 4 HBD and 4 HBA, while Ligand B has 3 HBD and 5 HBA. Both are within acceptable limits (<=5 HBD and <=10 HBA).

**QED:** Both ligands have good QED scores (0.526 and 0.686), indicating drug-like properties. Ligand B is slightly better.

**DILI:** Ligand A (36.797) has a lower DILI risk than Ligand B (53.354), which is favorable.

**BBB:** This is a crucial parameter for CNS targets. Ligand B (76.58) has a significantly better BBB percentile than Ligand A (55.138). This is a major advantage for Ligand B.

**Caco-2 Permeability:** Both have negative values, which is unusual. Assuming these are logP values, they indicate poor permeability.

**Aqueous Solubility:** Both have negative values, which is unusual. Assuming these are logS values, they indicate poor solubility.

**hERG:** Both ligands have very low hERG inhibition liability (0.086 and 0.475), which is excellent.

**Microsomal Clearance:** Both have similar microsomal clearance values (21.952 and 21.368), suggesting comparable metabolic stability.

**In vitro Half-Life:** Ligand A (27.836) has a slightly longer half-life than Ligand B (19.367), which is a minor advantage.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.007 and 0.227), which is excellent.

**Binding Affinity:** Ligand B (-8.3 kcal/mol) has a stronger binding affinity than Ligand A (-7.6 kcal/mol). This is a significant advantage, exceeding the 1.5 kcal/mol threshold.

**Overall Assessment:**

Ligand B is the more promising candidate. While Ligand A has a slightly lower DILI risk and longer half-life, Ligand B excels in the most critical parameters for a CNS-targeting GPCR ligand: TPSA, BBB penetration, and binding affinity. The stronger binding affinity of Ligand B (-8.3 vs -7.6 kcal/mol) is particularly important and can compensate for any minor drawbacks.

Output:
1
2025-04-17 07:36:31,671 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (343.391 and 350.419 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (89.15) is excellent, falling below the 90 A^2 threshold for CNS targets. Ligand B (97.76) is still reasonable, but less optimal.

**logP:** Ligand A (-0.206) is a bit low, potentially hindering permeability. Ligand B (1.627) is within the optimal 1-3 range. This is a significant advantage for Ligand B.

**H-Bond Donors/Acceptors:** Ligand A (0 HBD, 7 HBA) is good. Ligand B (3 HBD, 8 HBA) is also acceptable, though slightly higher.

**QED:** Both ligands have similar QED values (0.77 and 0.651), indicating good drug-likeness.

**DILI:** Both ligands have similar DILI risk (60.915 and 57.697), placing them in a moderate risk category.

**BBB:** Ligand A (46.375) has a lower BBB penetration percentile than Ligand B (54.246). While neither are >70, Ligand B is better.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.928 and -5.22), which is unusual and suggests poor permeability. This is a concern for both.

**Aqueous Solubility:** Both ligands have negative solubility values (-1.138 and -2.645), also unusual and concerning.

**hERG:** Both ligands have low hERG inhibition liability (0.195 and 0.69), which is positive.

**Microsomal Clearance:** Ligand B (51.844) has a slightly lower (better) microsomal clearance than Ligand A (42.469).

**In vitro Half-Life:** Ligand B (54.325) has a significantly longer in vitro half-life than Ligand A (-4.614). This is a substantial advantage.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.064 and 0.051), which is favorable for CNS penetration.

**Binding Affinity:** Both ligands have very similar and excellent binding affinities (-7.9 and -7.8 kcal/mol). The difference is negligible.

**Overall Assessment:**

Ligand B is the more promising candidate. While both have issues with Caco-2 and solubility, Ligand B has a more favorable logP, better BBB penetration, and a significantly longer half-life. The slightly lower clearance is also a benefit. The binding affinity is comparable. Given the GPCR target and the need for CNS penetration, the improvements in logP, BBB, and half-life outweigh the slight differences in other parameters.

Output:
1
2025-04-17 07:36:31,671 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight (MW):** Both ligands (353.463 and 357.483 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (110.52) is higher than the preferred <90 for CNS targets, but still potentially acceptable. Ligand B (74.86) is excellent, well below 90.

**3. logP:** Ligand A (0.858) is a bit low, potentially hindering permeation. Ligand B (4.172) is high, approaching the upper limit where solubility and off-target effects become concerns.

**4. H-Bond Donors (HBD):** Both ligands have 3 HBD, which is within the acceptable limit of <=5.

**5. H-Bond Acceptors (HBA):** Ligand A has 4 HBA, and Ligand B has 6 HBA, both within the acceptable limit of <=10.

**6. QED:** Both ligands have similar QED values (0.615 and 0.592), indicating reasonable drug-likeness.

**7. DILI:** Ligand A (20.744) has a much lower DILI risk than Ligand B (78.131). This is a significant advantage for Ligand A.

**8. BBB:** Ligand A (55.913) has a moderate BBB penetration, while Ligand B (68.631) is better, but still not ideal (>70 is preferred).

**9. Caco-2:** Both ligands have negative Caco-2 values (-5.695 and -5.262), which is unusual and suggests poor permeability. This is a significant concern for both.

**10. Solubility:** Both ligands have negative solubility values (-2.127 and -4.194), indicating very poor aqueous solubility. This is a major drawback for both.

**11. hERG:** Ligand A (0.097) has a very low hERG risk, while Ligand B (0.812) has a moderate risk.

**12. Cl_mic:** Ligand A (7.026) has a lower microsomal clearance than Ligand B (52.868), suggesting better metabolic stability.

**13. t1/2:** Ligand B (57.191) has a much longer in vitro half-life than Ligand A (-1.716). This is a significant advantage for Ligand B.

**14. Pgp:** Ligand A (0.012) has very low P-gp efflux liability, which is excellent for CNS penetration. Ligand B (0.151) has slightly higher Pgp efflux.

**15. Binding Affinity:** Ligand B (-8.6 kcal/mol) has a significantly stronger binding affinity than Ligand A (0.0 kcal/mol). This is a substantial advantage, potentially outweighing some of its ADME drawbacks.

**Overall Assessment:**

Ligand B has a much stronger binding affinity, a longer half-life, and better BBB penetration than Ligand A. However, it suffers from higher DILI risk, higher logP, and a moderate hERG risk. Ligand A has a much better safety profile (DILI, hERG) and Pgp efflux, but its binding affinity is very weak, and its solubility and Caco-2 permeability are very poor.

Given the importance of binding affinity for GPCR ligands, and the fact that the difference in affinity is so large (8.6 vs 0.0 kcal/mol), I would prioritize Ligand B despite its ADME liabilities. The strong binding could potentially be optimized through further structural modifications, while the ADME properties might be more challenging to improve significantly.

Output:
1
2025-04-17 07:36:31,671 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (348.531 and 347.419 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (49.41) is excellent, well below the 90 A^2 threshold for CNS targets. Ligand B (92.77) is higher, but still potentially acceptable, though less ideal.

**logP:** Ligand A (3.624) is within the optimal 1-3 range. Ligand B (-0.376) is significantly lower, which is a concern for permeability and CNS penetration.

**H-Bond Donors/Acceptors:** Ligand A (HBD=1, HBA=2) is favorable. Ligand B (HBD=2, HBA=5) is also acceptable, but slightly higher HBA could impact permeability.

**QED:** Both ligands have good QED scores (A: 0.647, B: 0.728), indicating good drug-like properties.

**DILI:** Ligand A (15.936) has a very low DILI risk. Ligand B (37.185) is higher, but still within a reasonable range.

**BBB:** This is critical for a CNS target like DRD2. Ligand A scores very well (85.033), indicating high predicted BBB penetration. Ligand B (11.555) is very poor, suggesting limited CNS exposure.

**Caco-2 Permeability:** Ligand A (-4.495) is concerningly low. Ligand B (-5.263) is also low, but slightly worse.

**Aqueous Solubility:** Ligand A (-3.871) is poor, while Ligand B (-0.734) is also poor. Solubility is a concern for both, but less critical than BBB for a CNS target.

**hERG Inhibition:** Ligand A (0.643) has a low hERG risk. Ligand B (0.165) is even lower, indicating very low cardiotoxicity potential.

**Microsomal Clearance:** Ligand A (81.906) has moderate clearance. Ligand B (-11.521) has negative clearance, which is not physically possible and indicates a potential data error or unusual metabolic profile. This is a significant red flag.

**In vitro Half-Life:** Ligand A (32.896 hours) is good. Ligand B (-28.472 hours) is also not physically possible and a major concern.

**P-gp Efflux:** Ligand A (0.295) has low P-gp efflux, which is favorable for CNS penetration. Ligand B (0.033) is even lower, which is excellent.

**Binding Affinity:** Ligand A (-7.6 kcal/mol) has slightly better binding affinity than Ligand B (-8.3 kcal/mol). While the difference isn't huge, it's a positive for Ligand A.

**Overall Assessment:**

Ligand A is significantly more promising despite its poor Caco-2 and solubility. Its excellent BBB penetration, low DILI risk, favorable logP, and good affinity make it a much stronger candidate for a CNS-targeting drug like a DRD2 modulator. Ligand B's extremely poor BBB penetration is a deal-breaker, and the negative values for clearance and half-life are highly suspect and indicative of data quality issues or a fundamentally problematic molecule.

Output:
0
2025-04-17 07:36:31,671 - INFO - Reasoning:

Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (354.491 and 377.505 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (78.87) is better than Ligand B (64.86). Both are below the 90 A^2 threshold desirable for CNS targets, but A is closer to the ideal.

**logP:** Both ligands have good logP values (1.848 and 2.701), falling within the optimal 1-3 range. Ligand B is slightly higher, which could potentially cause issues, but is still acceptable.

**H-Bond Donors/Acceptors:** Ligand A has 2 HBD and 4 HBA, while Ligand B has 1 HBD and 7 HBA. Both are within acceptable limits (<=5 HBD and <=10 HBA).

**QED:** Both ligands have similar QED values (0.697 and 0.676), indicating good drug-like properties.

**DILI:** Ligand A (6.592) has a significantly lower DILI risk than Ligand B (57.658). This is a major advantage for Ligand A.

**BBB:** Ligand B (80.419) has a much better BBB penetration percentile than Ligand A (40.093). This is a critical factor for a CNS target like DRD2.

**Caco-2 Permeability:** Ligand A (-4.576) has better Caco-2 permeability than Ligand B (-5.248).

**Aqueous Solubility:** Ligand A (-1.17) has better aqueous solubility than Ligand B (-3.417).

**hERG Inhibition:** Both ligands have low hERG inhibition liability (0.243 and 0.393).

**Microsomal Clearance:** Ligand A (19.334) has lower microsomal clearance than Ligand B (40.164), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (8.822) has a longer in vitro half-life than Ligand B (-4.194).

**P-gp Efflux:** Ligand A (0.022) has significantly lower P-gp efflux liability than Ligand B (0.23). This is beneficial for CNS penetration.

**Binding Affinity:** Ligand A (-7.2) has a slightly better binding affinity than Ligand B (-6.0). While both are good, the 1.2 kcal/mol difference is significant.

**Overall Assessment:**

Ligand A excels in several key areas: DILI risk, metabolic stability (Cl_mic and t1/2), P-gp efflux, solubility, and binding affinity. While Ligand B has a superior BBB score, the other advantages of Ligand A, particularly the significantly lower DILI and P-gp efflux, combined with its better affinity, outweigh the BBB difference. A good CNS drug needs to *reach* the brain, but also needs to be safe and have a reasonable duration of action. Ligand A is more likely to achieve this balance.

Output:
1
2025-04-17 07:36:31,671 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 drug candidates, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (367.833 and 358.507 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (95.67) is higher than the preferred <90 for CNS targets, but not drastically so. Ligand B (46.34) is excellent, well below the threshold.

**logP:** Ligand A (1.744) is within the optimal 1-3 range. Ligand B (4.822) is slightly high, potentially leading to solubility issues or off-target interactions.

**H-Bond Donors/Acceptors:** Ligand A has 2 HBD and 5 HBA, both acceptable. Ligand B has 0 HBD and 4 HBA, also acceptable.

**QED:** Both ligands have reasonable QED scores (0.845 and 0.743), indicating good drug-like properties.

**DILI:** Ligand A (49.67) has a slightly higher DILI risk than Ligand B (37.069), but both are below the concerning threshold of 60.

**BBB:** This is a critical parameter for a CNS target like DRD2. Ligand B (80.031) has a significantly better BBB penetration percentile than Ligand A (62.97). This is a major advantage for Ligand B.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.904 and -4.897), which is unusual and suggests poor permeability. This is a significant concern for both.

**Aqueous Solubility:** Both ligands have very poor aqueous solubility (-3.1 and -4.748). This is a major drawback for both, potentially hindering bioavailability.

**hERG Inhibition:** Ligand A (0.143) has a lower hERG inhibition risk than Ligand B (0.557), which is preferable.

**Microsomal Clearance:** Ligand A (-5.128) has a lower (better) microsomal clearance than Ligand B (75.491), indicating greater metabolic stability.

**In vitro Half-Life:** Ligand B (41.091) has a longer in vitro half-life than Ligand A (14.745), which is generally desirable.

**P-gp Efflux:** Ligand A (0.091) has lower P-gp efflux liability than Ligand B (0.774), which is beneficial for CNS penetration.

**Binding Affinity:** Both ligands have excellent binding affinities (-9.0 and -8.3 kcal/mol). Ligand A is slightly better (-9.0 kcal/mol) but the difference is less than 1.5 kcal/mol.

**Overall Assessment:**

Ligand B stands out primarily due to its superior BBB penetration (80.031 vs 62.97). While its logP is a bit high and P-gp efflux is higher, the BBB advantage is crucial for a CNS target. Ligand A has better metabolic stability and lower hERG risk, but the significantly lower BBB penetration is a major drawback. Both ligands have poor solubility and permeability, which would need to be addressed through formulation strategies. Given the importance of CNS penetration for DRD2, Ligand B is the more promising candidate.

Output:
1
2025-04-17 07:36:31,672 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (347.415 and 356.423 Da) fall within the ideal range of 200-500 Da.

**TPSA:** Ligand A (80.76) is excellent, well below the 90 A^2 threshold for CNS targets. Ligand B (116.84) is higher, but still potentially acceptable, though less ideal.

**logP:** Ligand A (1.115) is within the optimal range (1-3). Ligand B (-0.246) is slightly below 1, which could indicate permeability issues.

**H-Bond Donors/Acceptors:** Ligand A (HBD=1, HBA=5) and Ligand B (HBD=3, HBA=5) both have reasonable numbers of H-bond donors and acceptors, well within the guidelines.

**QED:** Ligand A (0.807) has a very good QED score, indicating high drug-likeness. Ligand B (0.519) is acceptable, but less optimal.

**DILI:** Both ligands have low DILI risk (Ligand A: 30.593, Ligand B: 29.934), which is positive.

**BBB:** Ligand A (60.876) has a moderate BBB penetration score. Ligand B (59.946) is similar. Both are below the desirable >70 for CNS targets, but not disqualifying.

**Caco-2 Permeability:** Ligand A (-4.604) has poor Caco-2 permeability. Ligand B (-5.218) is also poor.

**Aqueous Solubility:** Both ligands have poor aqueous solubility (Ligand A: -1.952, Ligand B: -0.828).

**hERG Inhibition:** Both ligands show very low hERG inhibition risk (Ligand A: 0.307, Ligand B: 0.061).

**Microsomal Clearance:** Ligand A (27.159) has a moderate microsomal clearance. Ligand B (16.253) has lower clearance, suggesting better metabolic stability, which is a plus.

**In vitro Half-Life:** Ligand A (6.066) has a moderate half-life. Ligand B (-14.319) has a very short (and negative!) half-life, which is a significant concern.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (Ligand A: 0.014, Ligand B: 0.003).

**Binding Affinity:** Ligand A (-8.8 kcal/mol) has a significantly stronger binding affinity than Ligand B (-7 kcal/mol). This is a crucial advantage. The difference of 1.8 kcal/mol is substantial.

**Overall Assessment:**

Ligand A is superior despite the moderate BBB and poor Caco-2 permeability and solubility. The substantially stronger binding affinity (-8.8 vs -7 kcal/mol) is the most important factor, and outweighs the ADME drawbacks. The better QED score also favors Ligand A. Ligand B's extremely short in vitro half-life is a major red flag.

Output:
0
2025-04-17 07:36:31,672 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (342.439 and 363.527 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (49.85) is significantly better than Ligand B (62.3). For CNS targets, we want TPSA <= 90, and ideally closer to 60. Ligand A is much closer to the ideal range.

**3. logP:** Both ligands have good logP values (2.481 and 2.865), falling within the optimal 1-3 range.

**4. H-Bond Donors:** Ligand A (0) is preferable to Ligand B (1). Fewer H-bond donors generally improve membrane permeability.

**5. H-Bond Acceptors:** Ligand A (3) is preferable to Ligand B (4). Fewer H-bond acceptors also generally improve membrane permeability.

**6. QED:** Both ligands have good QED values (0.773 and 0.845), indicating good drug-like properties.

**7. DILI:** Both ligands have acceptable DILI risk (21.055 and 26.057), well below the concerning threshold of 60.

**8. BBB:** Ligand A (97.751) is *much* better than Ligand B (71.966). This is a critical factor for a CNS target like DRD2. A value >70 is highly desirable.

**9. Caco-2 Permeability:** Ligand A (-4.272) is better than Ligand B (-4.792), indicating better intestinal absorption.

**10. Aqueous Solubility:** Both ligands have poor aqueous solubility (-2.456 and -2.694). This could pose formulation challenges, but is less critical than BBB penetration for a CNS target.

**11. hERG Inhibition:** Both ligands have low hERG inhibition risk (0.556 and 0.307), which is good.

**12. Microsomal Clearance:** Ligand A (46.5) has lower clearance than Ligand B (59.09), suggesting better metabolic stability.

**13. In vitro Half-Life:** Ligand A (-6.632) has a longer half-life than Ligand B (18.822).

**14. P-gp Efflux:** Ligand A (0.124) is better than Ligand B (0.233), indicating lower P-gp efflux and improved CNS exposure.

**15. Binding Affinity:** Ligand B (-7.9) has a slightly better binding affinity than Ligand A (-8.3). While affinity is important, the difference of 0.4 kcal/mol is not substantial enough to outweigh the significant advantages of Ligand A in other key parameters.

**Overall Assessment:**

Ligand A is significantly superior to Ligand B, particularly regarding BBB penetration, TPSA, and P-gp efflux. These are crucial for CNS drug development. While Ligand B has slightly better binding affinity, the other ADME properties of Ligand A make it a much more promising drug candidate for targeting DRD2.

Output:
1
2025-04-17 07:36:31,672 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (341.455 and 346.391 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (56.41) is excellent, well below the 90 A^2 threshold for CNS targets. Ligand B (95.26) is higher, but still potentially acceptable, though less ideal.

**logP:** Ligand A (2.22) is optimal (1-3). Ligand B (0.295) is quite low, potentially hindering membrane permeability and CNS penetration.

**H-Bond Donors/Acceptors:** Ligand A (1 HBD, 2 HBA) is excellent. Ligand B (0 HBD, 9 HBA) is acceptable, though the higher HBA count could slightly affect permeability.

**QED:** Ligand A (0.835) is very good, indicating high drug-likeness. Ligand B (0.689) is still reasonable, but lower.

**DILI:** Ligand A (16.169) has a very low DILI risk. Ligand B (60.915) is higher, indicating a moderate risk of liver injury.

**BBB:** Ligand A (76.619) has good BBB penetration. Ligand B (72.741) is also reasonable, but lower than Ligand A.

**Caco-2 Permeability:** Both have negative values (-5.014 and -4.885), which is unusual and requires further investigation. However, for comparison, we'll consider the magnitude; Ligand A's value is slightly more negative.

**Aqueous Solubility:** Both have negative values (-2.166 and -1.046), again unusual. Ligand A is slightly less soluble.

**hERG:** Both ligands have very low hERG inhibition liability (0.374 and 0.144).

**Microsomal Clearance:** Both have similar microsomal clearance values (31.256 and 31.175 mL/min/kg), suggesting similar metabolic stability.

**In vitro Half-Life:** Ligand A (-38.361) has a significantly longer in vitro half-life than Ligand B (-6.712).

**P-gp Efflux:** Both have very low P-gp efflux liability (0.197 and 0.006).

**Binding Affinity:** Ligand A (-8.9 kcal/mol) has a significantly stronger binding affinity than Ligand B (-7.6 kcal/mol). This is a >1.3 kcal/mol difference, which is substantial.

**Conclusion:**

Considering all factors, particularly the GPCR-specific priorities, Ligand A is the more promising candidate. It has a better logP, TPSA, QED, DILI risk, BBB penetration, and significantly stronger binding affinity. The longer half-life is also a major advantage. While both have unusual solubility and Caco-2 permeability values, the overall profile of Ligand A is superior for CNS drug development.

Output:
1
2025-04-17 07:36:31,672 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (363.483 and 349.431 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (62.74) is excellent, well below the 90 A^2 threshold for CNS targets. Ligand B (104.46) is higher, but still potentially acceptable, though less ideal.

**logP:** Both ligands have good logP values (1.441 and 1.155), falling within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A (0 HBD, 5 HBA) is favorable. Ligand B (3 HBD, 5 HBA) is also reasonable, though the 3 HBDs are slightly higher.

**QED:** Both ligands have acceptable QED values (0.81 and 0.715), indicating good drug-likeness.

**DILI:** Ligand A (46.103) has a slightly higher DILI risk than Ligand B (34.82), but both are below the concerning threshold of 60.

**BBB:** This is a crucial parameter for a CNS target like DRD2. Ligand A exhibits a significantly better BBB penetration percentile (70.803) compared to Ligand B (38.077). This is a major advantage for Ligand A.

**Caco-2 Permeability:** Ligand A (-4.662) shows better Caco-2 permeability than Ligand B (-5.383), though both are negative values which is unusual and requires further investigation.

**Aqueous Solubility:** Ligand A (-2.272) has slightly better solubility than Ligand B (-1.285), both are negative values which is unusual and requires further investigation.

**hERG Inhibition:** Both ligands show very low hERG inhibition liability (0.246 and 0.048), indicating a low risk of cardiotoxicity.

**Microsomal Clearance:** Ligand B (20.225) has a lower microsomal clearance than Ligand A (27.29), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand B (-8.683) has a longer in vitro half-life than Ligand A (7.25), which is a positive attribute.

**P-gp Efflux:** Ligand A (0.12) has lower P-gp efflux liability than Ligand B (0.038), which is favorable for CNS penetration.

**Binding Affinity:** Both ligands have excellent binding affinities (-7.7 and -8.7 kcal/mol). Ligand B is slightly better (-8.7 kcal/mol) but the difference is relatively small.

**Overall Assessment:**

Ligand A excels in BBB penetration and TPSA, critical for CNS GPCR targets. While Ligand B has slightly better metabolic stability and half-life, the significant advantage of Ligand A in BBB penetration outweighs these factors. The similar binding affinities make the ADME properties the deciding factor.

Output:
1
2025-04-17 07:36:31,672 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (341.455 and 353.463 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (52.65) is excellent, well below the 90 A^2 threshold for CNS targets. Ligand B (98.74) is higher, but still potentially acceptable, though less ideal.

**logP:** Ligand A (2.736) is optimal (1-3). Ligand B (0.561) is low, which could hinder permeability and CNS penetration.

**H-Bond Donors/Acceptors:** Ligand A (HBD=1, HBA=3) is well within the desired ranges. Ligand B (HBD=3, HBA=4) is also acceptable.

**QED:** Ligand A (0.916) is excellent, indicating high drug-likeness. Ligand B (0.594) is acceptable, but lower.

**DILI:** Ligand A (22.838) has a very low DILI risk. Ligand B (11.361) also has a low DILI risk, but slightly higher than A.

**BBB:** This is crucial for a CNS target. Ligand A (92.09) has excellent BBB penetration potential. Ligand B (34.858) has poor predicted BBB penetration.

**Caco-2 Permeability:** Ligand A (-4.764) is negative, which is unusual and suggests poor permeability. Ligand B (-5.062) is also negative, indicating poor permeability.

**Aqueous Solubility:** Both ligands have negative solubility values (-2.259 and -0.924), which is concerning. This suggests poor solubility.

**hERG Inhibition:** Ligand A (0.798) has a low hERG risk. Ligand B (0.057) has a very low hERG risk.

**Microsomal Clearance:** Ligand A (0.949) has low clearance, indicating good metabolic stability. Ligand B (14.762) has higher clearance, suggesting faster metabolism.

**In vitro Half-Life:** Ligand A (52.876) has a good in vitro half-life. Ligand B (-8.971) has a negative half-life, which is not physically possible and indicates a significant issue with the prediction or the molecule itself.

**P-gp Efflux:** Ligand A (0.084) has low P-gp efflux, which is favorable for CNS penetration. Ligand B (0.011) also has very low P-gp efflux.

**Binding Affinity:** Both ligands have very strong binding affinities (-9.5 and -8.3 kcal/mol). Ligand A is slightly better (-9.5 kcal/mol).

**Overall Assessment:**

Ligand A is significantly better. While both have poor predicted solubility and Caco-2 permeability, Ligand A excels in BBB penetration (92.09 vs 34.858), has a better QED score, and slightly better binding affinity. The negative half-life for ligand B is a major red flag. Ligand B's low logP is also a significant concern for CNS penetration. The combination of these factors makes Ligand A the more promising candidate.

Output:
0
2025-04-17 07:36:31,672 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (344.405 and 358.551 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Both ligands have a TPSA of 32.34, which is excellent for CNS penetration (well below the 90 A^2 threshold).

**3. logP:** Ligand A (3.911) is within the optimal range (1-3), while Ligand B (4.579) is slightly above, potentially hinting at solubility issues or off-target interactions.

**4. H-Bond Donors:** Both ligands have 1 HBD, which is acceptable.

**5. H-Bond Acceptors:** Ligand A has 2 HBA, and Ligand B has 3 HBA, both within the acceptable limit of 10.

**6. QED:** Ligand A (0.862) has a significantly better QED score than Ligand B (0.631), indicating a more drug-like profile.

**7. DILI:** Ligand A (55.487) has a higher DILI risk than Ligand B (21.055). This is a concern for Ligand A.

**8. BBB:** Ligand A (86.002) has a good BBB penetration percentile, while Ligand B (70.027) is also acceptable, but lower. Both are above the 70% threshold for CNS targets.

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.792 and -5.212), which is unusual and suggests poor permeability. This is a significant drawback for both.

**10. Aqueous Solubility:** Both ligands have negative solubility values (-4.827 and -2.711), indicating very poor aqueous solubility. This is a major concern for both.

**11. hERG Inhibition:** Both ligands have low hERG inhibition risk (0.973 and 0.953).

**12. Microsomal Clearance:** Ligand B (78.901) has a higher microsomal clearance than Ligand A (67.089), suggesting lower metabolic stability.

**13. In vitro Half-Life:** Ligand B (49.547 hours) has a significantly longer half-life than Ligand A (5.794 hours), which is a substantial advantage.

**14. P-gp Efflux:** Both ligands have low P-gp efflux liability (0.681 and 0.785), which is good for CNS exposure.

**15. Binding Affinity:** Ligand A (-9.6 kcal/mol) has a slightly better binding affinity than Ligand B (-8.8 kcal/mol). This 0.8 kcal/mol difference is meaningful, but not overwhelmingly so.

**Overall Assessment:**

Despite Ligand A's better affinity and QED, its higher DILI risk and significantly shorter half-life are major drawbacks. Both ligands suffer from poor solubility and permeability. However, Ligand B's substantially improved half-life and lower DILI risk, combined with acceptable BBB penetration, make it a more promising candidate, despite the slightly weaker binding affinity. The longer half-life could compensate for the slightly weaker binding, and the lower DILI risk is critical.

Output:
1
2025-04-17 07:36:31,673 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (373.475 and 348.491 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (100.99) is higher than Ligand B (55.89). For a CNS target like DRD2, TPSA should ideally be <= 90. Ligand B is significantly better in this regard.

**3. logP:** Both ligands have good logP values (0.904 and 0.851), falling within the 1-3 range.

**4. H-Bond Donors:** Ligand A (2) and Ligand B (1) are both acceptable, being <= 5.

**5. H-Bond Acceptors:** Ligand A (7) and Ligand B (4) are both acceptable, being <= 10.

**6. QED:** Both ligands have good QED scores (0.632 and 0.723), indicating good drug-like properties.

**7. DILI:** Ligand A (50.291) has a slightly higher DILI risk than Ligand B (8.375), but both are below the concerning threshold of 60.

**8. BBB:** This is a crucial parameter for CNS targets. Ligand B (61.729) has a significantly higher BBB penetration percentile than Ligand A (18.108). This is a major advantage for Ligand B.

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.172 and -5.095), which is unusual and suggests poor permeability. This is a concern for both.

**10. Aqueous Solubility:** Both ligands have negative solubility values (-1.422 and -0.153), which is also concerning and suggests poor solubility.

**11. hERG Inhibition:** Both ligands show low hERG inhibition liability (0.23 and 0.202), which is good.

**12. Microsomal Clearance:** Ligand A (28.623) has a higher microsomal clearance than Ligand B (3.023), indicating lower metabolic stability.

**13. In vitro Half-Life:** Ligand B (-14.1) has a significantly longer in vitro half-life than Ligand A (8.204). This is a significant advantage.

**14. P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.074 and 0.005), which is favorable for CNS penetration.

**15. Binding Affinity:** Ligand B (-7.7 kcal/mol) has a stronger binding affinity than Ligand A (-6.2 kcal/mol). This is a 1.5 kcal/mol difference, which is substantial and can outweigh some ADME drawbacks.

**Overall Assessment:**

Ligand B is the superior candidate. While both have issues with Caco-2 and solubility, Ligand B excels in the critical areas for a CNS GPCR target: significantly better BBB penetration (61.729 vs 18.108), a longer half-life, and a substantially stronger binding affinity (-7.7 vs -6.2 kcal/mol). The lower TPSA of Ligand B is also beneficial. The lower DILI risk is also a plus.

Output:
1
2025-04-17 07:36:31,673 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (359.4 and 366.8 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (99.18) is slightly higher than Ligand B (88.32). Both are below the 140 threshold for oral absorption, but ideally, for a CNS target like DRD2, we want <90. Ligand B is closer to this target.

**logP:** Ligand A (-1.081) is lower than the optimal 1-3 range, potentially hindering permeation. Ligand B (1.684) is within the optimal range. This is a significant advantage for Ligand B.

**H-Bond Donors/Acceptors:** Both ligands have 2 HBD and a reasonable number of HBA (5 and 4 respectively), satisfying the guidelines.

**QED:** Both ligands have good QED scores (0.574 and 0.629), indicating drug-like properties.

**DILI:** Ligand A (28.383) has a much lower DILI risk than Ligand B (58.86). This is a positive for Ligand A.

**BBB:** Ligand B (80.031) has a significantly better BBB penetration score than Ligand A (62.699). For a CNS target, >70 is desirable, and Ligand B is closer to this threshold.

**Caco-2 Permeability:** Both have negative Caco-2 values (-5.029 and -5.454) which is unusual and suggests poor permeability.

**Aqueous Solubility:** Both have negative solubility values (-0.34 and -3.698), suggesting poor solubility.

**hERG:** Ligand A (0.224) has a lower hERG inhibition liability than Ligand B (0.551), which is preferable.

**Microsomal Clearance:** Ligand A (-10.937) has a much lower (better) microsomal clearance than Ligand B (0.512), indicating greater metabolic stability.

**In vitro Half-Life:** Both have negative half-life values (-17.507 and -17.208), which is unusual and suggests rapid degradation.

**P-gp Efflux:** Ligand A (0.009) has a much lower P-gp efflux liability than Ligand B (0.034), which is beneficial for CNS exposure.

**Binding Affinity:** Ligand B (-9.2 kcal/mol) has a better binding affinity than Ligand A (-7.0 kcal/mol). This is a substantial advantage, potentially outweighing some of the ADME drawbacks. The difference is >1.5 kcal/mol.

**Overall Assessment:**

Ligand B excels in binding affinity and BBB penetration, critical for a CNS GPCR target. Its logP is also within the optimal range. However, it has a higher DILI risk, P-gp efflux, and hERG liability compared to Ligand A. Ligand A has better metabolic stability and lower P-gp efflux, but suffers from a lower logP and BBB score. Considering the importance of affinity and CNS penetration for DRD2, the stronger binding and better BBB of Ligand B are more compelling, despite the slightly higher risks in other areas.

Output:
1
2025-04-17 07:36:31,673 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (352.431 and 356.413 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (81.01) is slightly higher than Ligand B (75.27), but both are below the 90 A^2 threshold desirable for CNS targets.

**logP:** Ligand A (2.729) and Ligand B (1.559) are both within the optimal 1-3 range, but Ligand B is closer to the lower bound.

**H-Bond Donors/Acceptors:** Ligand A has 1 HBD and 5 HBA, while Ligand B has 2 HBD and 3 HBA. Both are within acceptable limits (<=5 HBD and <=10 HBA).

**QED:** Ligand A (0.851) has a significantly better QED score than Ligand B (0.624), indicating a more drug-like profile.

**DILI:** Ligand A (38.969) has a slightly higher DILI risk than Ligand B (15.626), but both are below the concerning threshold of 60.

**BBB:** Ligand B (87.476) has a substantially higher BBB penetration percentile than Ligand A (65.529). This is a *critical* advantage for a CNS target like DRD2.

**Caco-2 Permeability:** Ligand A (-4.453) and Ligand B (-5.047) both have negative Caco-2 values, indicating poor permeability.

**Aqueous Solubility:** Both ligands have very poor aqueous solubility (-2.64 and -2.528). This is a significant drawback.

**hERG Inhibition:** Both ligands show very low hERG inhibition risk (0.138 and 0.183).

**Microsomal Clearance:** Ligand B (8.162) has a much lower microsomal clearance than Ligand A (48.657), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand B (26.766) has a slightly longer in vitro half-life than Ligand A (29.038).

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.013 and 0.014).

**Binding Affinity:** Ligand B (-8.4 kcal/mol) has a significantly stronger binding affinity than Ligand A (-7.1 kcal/mol). This is a substantial advantage, potentially outweighing some ADME concerns.

**Overall Assessment:**

Ligand B is the stronger candidate. While both have poor solubility and Caco-2 permeability, Ligand B's superior BBB penetration, significantly stronger binding affinity, and better metabolic stability (lower Cl_mic) outweigh Ligand A's slightly better QED and lower DILI risk. The higher affinity of Ligand B is particularly important for a GPCR target. The improved BBB penetration is also crucial for CNS efficacy.

Output:
1
2025-04-17 07:36:31,673 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (341.411 and 347.459 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (80.32) is excellent, well below the 90 A^2 threshold for CNS targets. Ligand B (91.32) is slightly higher but still acceptable.

**3. logP:** Ligand A (1.575) is optimal. Ligand B (2.537) is also good, within the 1-3 range.

**4. H-Bond Donors:** Ligand A (2) and Ligand B (3) are both acceptable, below the 5 threshold.

**5. H-Bond Acceptors:** Both ligands (A: 4, B: 4) are well below the 10 threshold.

**6. QED:** Ligand A (0.726) is better than Ligand B (0.599), indicating a more drug-like profile.

**7. DILI:** Ligand A (49.399) has a slightly higher DILI risk than Ligand B (23.226), but both are below the concerning 60 percentile.

**8. BBB:** This is critical for a CNS target like DRD2. Ligand A (57.154) is better than Ligand B (26.638). While 57.154 isn't *high* (>70), it's significantly better than 26.638.

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.963 and -5.163). This is unusual and suggests poor permeability. However, these values are on a scale where negative values are possible and don't necessarily disqualify a compound.

**10. Aqueous Solubility:** Both ligands have negative solubility values (-2.665 and -2.742). Similar to Caco-2, these values are on a scale where negatives are possible.

**11. hERG Inhibition:** Both ligands show very low hERG inhibition risk (0.48 and 0.093).

**12. Microsomal Clearance:** Both ligands have similar microsomal clearance (32.017 and 30.553), indicating comparable metabolic stability.

**13. In vitro Half-Life:** Ligand A (11.21) has a positive half-life, while Ligand B (-13.671) has a negative half-life. This is a significant difference. A negative half-life is not physically meaningful and suggests a major issue with the in vitro assay or the molecule's stability.

**14. P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.066 and 0.014), which is excellent for CNS penetration.

**15. Binding Affinity:** Ligand A (-8.6 kcal/mol) has a stronger binding affinity than Ligand B (-7.8 kcal/mol). The difference of 0.8 kcal/mol is significant and could outweigh some ADME drawbacks.

**Overall Assessment:**

Ligand A is the stronger candidate. It has a better QED score, a significantly better BBB penetration percentile, a positive in vitro half-life, and a superior binding affinity. While Ligand B has a lower DILI risk, the substantial difference in BBB and the negative half-life for Ligand B are major concerns. The negative Caco-2 and solubility values are concerning for both, but the stronger affinity and better CNS properties of Ligand A make it the more promising candidate.

Output:
0
2025-04-17 07:36:31,674 - INFO - Batch 379 complete. Total preferences: 6064
2025-04-17 07:36:31,674 - INFO - Processing batch 380/512...
2025-04-17 07:37:13,040 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (349.475 and 336.395 Da) fall comfortably within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (92.5) is slightly higher than Ligand B (78.09). Both are below the 90 A^2 threshold desirable for CNS targets, but B is preferable.

**3. logP:** Both ligands have good logP values (1.742 and 1.556), falling within the optimal 1-3 range.

**4. H-Bond Donors:** Both have 2 HBD, which is acceptable.

**5. H-Bond Acceptors:** Both have 3 HBA, which is acceptable.

**6. QED:** Ligand B (0.813) has a significantly better QED score than Ligand A (0.585), indicating a more drug-like profile.

**7. DILI:** Ligand A (12.059) has a much lower DILI risk than Ligand B (60.915). This is a significant advantage for Ligand A.

**8. BBB:** Ligand A (68.282) has a substantially better BBB penetration percentile than Ligand B (31.02). This is *critical* for a CNS target like DRD2.

**9. Caco-2 Permeability:** Ligand A (-5.266) has worse Caco-2 permeability than Ligand B (-4.731), but both are negative values, indicating poor permeability.

**10. Aqueous Solubility:** Both ligands have poor aqueous solubility (-2.807 and -3.257).

**11. hERG Inhibition:** Both ligands have low hERG inhibition risk (0.119 and 0.332).

**12. Microsomal Clearance:** Ligand B (24.123) has higher microsomal clearance than Ligand A (12.663), suggesting faster metabolism and lower metabolic stability.

**13. In vitro Half-Life:** Ligand A (-24.48) has a much longer in vitro half-life than Ligand B (8.341).

**14. P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.016 and 0.03).

**15. Binding Affinity:** Both ligands have identical binding affinity (-8.0 kcal/mol), which is excellent.

**Overall Assessment:**

While Ligand B has a better QED and slightly better Caco-2 permeability, Ligand A is significantly superior due to its much better BBB penetration (68.282 vs 31.02), lower DILI risk (12.059 vs 60.915), and longer in vitro half-life (-24.48 vs 8.341). For a CNS target like DRD2, BBB penetration is paramount. The lower DILI and improved metabolic stability (longer half-life) further strengthen Ligand A's profile. The similar binding affinity means the ADME properties are the deciding factors.

Output:
1
2025-04-17 07:37:13,040 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (367.471 and 359.901 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (78.95) is higher than Ligand B (47.34). For a CNS target like DRD2, TPSA should ideally be below 90. Ligand B is significantly better in this regard.

**3. logP:** Ligand A (1.046) is within the optimal range (1-3), while Ligand B (3.87) is approaching the upper limit. Both are acceptable, but Ligand A is slightly preferred.

**4. H-Bond Donors:** Ligand A has 1 HBD, and Ligand B has 0. Both are within the acceptable limit of <=5.

**5. H-Bond Acceptors:** Ligand A has 5 HBA, and Ligand B has 3. Both are within the acceptable limit of <=10.

**6. QED:** Both ligands have similar QED values (0.787 and 0.694), indicating good drug-likeness.

**7. DILI:** Ligand A has a DILI risk of 71.694, while Ligand B has 13.61. Ligand B is *much* better here, indicating a significantly lower risk of liver injury.

**8. BBB:** Ligand A has a BBB penetration of 68.786, and Ligand B has 78.092. Ligand B is better, although both are somewhat below the desirable >70 for CNS targets.

**9. Caco-2 Permeability:** Ligand A (-4.866) and Ligand B (-4.632) both have negative Caco-2 values, which is unusual and suggests poor permeability. This is a concern for both.

**10. Aqueous Solubility:** Both ligands have very poor aqueous solubility (-3.391 and -3.684 respectively). This is a significant drawback for both.

**11. hERG Inhibition:** Both ligands have low hERG inhibition risk (0.692 and 0.834).

**12. Microsomal Clearance:** Ligand A (68.63) has a higher microsomal clearance than Ligand B (37.903), suggesting lower metabolic stability. Ligand B is preferred.

**13. In vitro Half-Life:** Ligand A (21.766) has a longer half-life than Ligand B (9.941). This is a positive for Ligand A.

**14. P-gp Efflux:** Ligand A (0.21) has lower P-gp efflux than Ligand B (0.335), which is preferable for CNS penetration.

**15. Binding Affinity:** Both ligands have very similar and excellent binding affinities (-8.3 and -8.4 kcal/mol). The difference is negligible.

**Overall Assessment:**

Ligand B is the better candidate. While both have poor solubility and Caco-2 permeability, Ligand B excels in key areas for a CNS GPCR target: lower DILI risk, better TPSA, better BBB penetration, and better metabolic stability (lower Cl_mic). The slightly longer half-life of Ligand A is outweighed by these advantages.

Output:
1
2025-04-17 07:37:13,040 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (395.874 Da) is slightly higher than Ligand B (344.459 Da), but both are acceptable.

**TPSA:** Ligand A (49.33) is significantly better than Ligand B (59.65). For CNS targets, we want TPSA <= 90, and ideally lower. Ligand A is much closer to the ideal range.

**logP:** Ligand A (4.725) is higher than the optimal range (1-3), potentially leading to solubility issues. Ligand B (1.504) is within the optimal range. However, for a GPCR, a slightly higher logP can be tolerated if other properties are favorable.

**H-Bond Donors/Acceptors:** Ligand A has 2 HBD and 3 HBA, while Ligand B has 1 HBD and 3 HBA. Both are within acceptable limits (<=5 HBD and <=10 HBA).

**QED:** Both ligands have good QED scores (Ligand A: 0.709, Ligand B: 0.824), indicating good drug-like properties.

**DILI:** Ligand A (36.216) has a slightly higher DILI risk than Ligand B (12.485), but both are below the concerning threshold of 60.

**BBB:** Ligand A (76.231) has a significantly better BBB penetration score than Ligand B (66.925). This is a crucial factor for a CNS target like DRD2.

**Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and suggests poor permeability. However, the scale is not clearly defined, so it's difficult to interpret.

**Aqueous Solubility:** Both have negative solubility values, which is also unusual. Again, the scale is unclear, but suggests poor solubility.

**hERG:** Both ligands have low hERG inhibition liability (Ligand A: 0.72, Ligand B: 0.407), which is good.

**Microsomal Clearance:** Ligand B (-7.234) has a negative clearance, which is not physically possible. This is likely an error in the data. Ligand A (33.757) has a reasonable clearance.

**In vitro Half-Life:** Ligand B (-10.066) has a negative half-life, also an error. Ligand A (14.799) has a reasonable half-life.

**P-gp Efflux:** Ligand A (0.259) has lower P-gp efflux liability than Ligand B (0.032), which is favorable for CNS penetration.

**Binding Affinity:** Both ligands have very similar and excellent binding affinities (-8.4 kcal/mol for Ligand A and -8.3 kcal/mol for Ligand B). The difference is negligible.

**Conclusion:**

Considering all factors, **Ligand A is the more promising drug candidate**. While its logP is slightly higher, its superior BBB penetration, more reasonable ADME properties (clearance and half-life are not errors), and lower P-gp efflux outweigh this drawback. The errors in Ligand B's data (negative clearance and half-life) are also concerning. The similar binding affinities mean that the ADME properties become the deciding factor.

Output:
1
2025-04-17 07:37:13,040 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B based on the provided guidelines, prioritizing GPCR-specific properties (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (342.37 and 373.875 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (49.85) is significantly better than Ligand B (38.13), both being well below the 90 A^2 threshold for CNS targets.

**logP:** Ligand A (2.922) is optimal (1-3), while Ligand B (4.446) is slightly higher, potentially raising concerns about solubility and off-target effects.

**H-Bond Donors/Acceptors:** Both ligands have 0 HBD and 3 HBA, which are within acceptable limits.

**QED:** Ligand A (0.858) has a higher QED score than Ligand B (0.523), indicating a more drug-like profile.

**DILI:** Ligand A (77.123) has a higher DILI risk than Ligand B (19.698). This is a significant drawback for Ligand A.

**BBB:** Both ligands have excellent BBB penetration (Ligand A: 89.492, Ligand B: 87.864), exceeding the desirable >70 threshold for CNS targets.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values, which is unusual. Assuming these are percentile scores, both are very poor.

**Aqueous Solubility:** Both ligands have very poor aqueous solubility (-2.945 and -5.561). This is a major concern for both.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.708 and 0.511).

**Microsomal Clearance:** Ligand B (72.131) has higher microsomal clearance than Ligand A (33.385), indicating lower metabolic stability.

**In vitro Half-Life:** Ligand A (-23.973) has a significantly longer in vitro half-life than Ligand B (-1.625).

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.369 and 0.314).

**Binding Affinity:** Ligand A (-8.8 kcal/mol) has a slightly better binding affinity than Ligand B (-8.3 kcal/mol). However, the difference is not substantial enough to overcome other significant drawbacks.

**Overall Assessment:**

Ligand A has a better QED, TPSA, half-life, and binding affinity, but suffers from a significantly higher DILI risk and poor solubility. Ligand B has a lower DILI risk, but has a higher logP, lower QED, and poorer metabolic stability. Given the CNS target, BBB is excellent for both. Solubility is a major issue for both.

Considering the GPCR-specific priorities, the lower DILI risk of Ligand B is a crucial advantage. While the binding affinity of Ligand A is slightly better, the higher DILI risk is a major concern for clinical development. The solubility issues for both are concerning, but could potentially be addressed with formulation strategies.

Output:
1
2025-04-17 07:37:13,041 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (354.451 and 359.352 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (99.77) is slightly higher than Ligand B (97.64), but both are below the 140 threshold for good oral absorption and reasonably close to the 90 target for CNS penetration.

**3. logP:** Ligand A (1.906) is within the optimal 1-3 range. Ligand B (2.534) is also acceptable, leaning towards the higher end.

**4. H-Bond Donors:** Both ligands have 3 HBD, which is within the acceptable limit of <=5.

**5. H-Bond Acceptors:** Ligand A has 4 HBA, and Ligand B has 3. Both are below the limit of <=10.

**6. QED:** Both ligands have good QED scores (0.657 and 0.708, respectively), indicating drug-like properties.

**7. DILI:** Both ligands have similar DILI risk (47.421 and 48.468), both being good (below 60).

**8. BBB:** This is a critical parameter for a CNS target like DRD2. Ligand A has a significantly higher BBB penetration percentile (70.997) compared to Ligand B (53.393). This is a major advantage for Ligand A.

**9. Caco-2 Permeability:** Ligand A (-4.449) and Ligand B (-5.124) both have negative values, indicating poor permeability. However, the scale is not specified, so the absolute difference is hard to interpret.

**10. Aqueous Solubility:** Ligand A (-3.347) and Ligand B (-2.944) both have negative values, indicating poor solubility. Again, the scale is not specified.

**11. hERG Inhibition:** Ligand A (0.198) has a lower hERG inhibition liability than Ligand B (0.579), which is preferable.

**12. Microsomal Clearance:** Ligand A (40.431) has higher microsomal clearance than Ligand B (-3.59). This suggests Ligand B is more metabolically stable.

**13. In vitro Half-Life:** Ligand B (-20.121) has a significantly longer in vitro half-life compared to Ligand A (4.393). This is a substantial advantage for Ligand B.

**14. P-gp Efflux:** Ligand A (0.021) has much lower P-gp efflux liability than Ligand B (0.128), which is beneficial for CNS exposure.

**15. Binding Affinity:** Both ligands have excellent binding affinities (-7.7 and -7.4 kcal/mol). The difference of 0.3 kcal/mol is not substantial enough to outweigh other significant differences.

**Overall Assessment:**

While Ligand B has better metabolic stability (lower Cl_mic, longer t1/2), Ligand A is superior due to its significantly better BBB penetration (71% vs 53%), lower P-gp efflux, and lower hERG inhibition. Given that DRD2 is a CNS target, BBB penetration is paramount. The slightly better metabolic stability of Ligand B is less crucial than the improved CNS exposure profile of Ligand A.

Output:
0
2025-04-17 07:37:13,041 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (351.447 and 336.355 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (84.67) is excellent, being below the 90 A^2 threshold for CNS targets. Ligand B (86.86) is also good, but slightly higher.

**logP:** Ligand A (3.175) is optimal. Ligand B (1.342) is a bit low, potentially hindering membrane permeability, but still within an acceptable range.

**H-Bond Donors:** Both ligands have 1 HBD, which is within the acceptable limit of <=5.

**H-Bond Acceptors:** Ligand A has 5 HBAs, and Ligand B has 7. Both are within the acceptable limit of <=10.

**QED:** Ligand A (0.9) is excellent, indicating high drug-likeness. Ligand B (0.727) is still good, but slightly lower.

**DILI:** Ligand A (44.009) has a better DILI score than Ligand B (83.017), indicating lower liver injury risk.

**BBB:** This is crucial for a CNS target like DRD2. Ligand A (85.111) has a significantly better BBB percentile than Ligand B (35.867).

**Caco-2 Permeability:** Ligand A (-4.334) shows better Caco-2 permeability than Ligand B (-5.059).

**Aqueous Solubility:** Ligand A (-3.859) is better than Ligand B (-2.732).

**hERG:** Both ligands have similar, low hERG inhibition liability (0.554 and 0.549).

**Microsomal Clearance:** Ligand A (57.75) has higher clearance than Ligand B (41.614), suggesting lower metabolic stability.

**In vitro Half-Life:** Ligand B (-27.626) has a much longer in vitro half-life than Ligand A (-14.307).

**P-gp Efflux:** Ligand A (0.092) has lower P-gp efflux liability than Ligand B (0.068), which is favorable for CNS penetration.

**Binding Affinity:** Ligand B (-9.5 kcal/mol) has a significantly stronger binding affinity than Ligand A (-8.2 kcal/mol). This is a substantial advantage.

**Overall Assessment:**

Ligand B has a much stronger binding affinity, and a longer half-life. However, its BBB penetration is poor, and DILI risk is higher. Ligand A has excellent BBB penetration, good solubility, lower DILI risk, and better Caco-2 permeability, but its binding affinity is weaker and clearance is higher.

Given the importance of BBB penetration for a CNS target like DRD2, and the substantial difference in binding affinity, the stronger affinity of Ligand B is likely to outweigh its drawbacks. While the poor BBB is a concern, it might be addressable through prodrug strategies or formulation approaches. The difference of 1.3 kcal/mol in binding affinity is significant.

Output:
1
2025-04-17 07:37:13,041 - INFO - Reasoning:

Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (340.423 and 337.379 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (82.19) is slightly higher than Ligand B (70.27). Both are below the 90 A^2 threshold desirable for CNS targets, but B is preferable.

**3. logP:** Both ligands have good logP values (3.27 and 3.604), falling within the optimal 1-3 range. Ligand B is slightly higher, which could be a minor concern for solubility, but not a major issue.

**4. H-Bond Donors:** Ligand A has 3 HBD, and Ligand B has 0. Both are within the acceptable limit of <=5. Ligand B is preferable as fewer HBDs generally improve membrane permeability.

**5. H-Bond Acceptors:** Ligand A has 2 HBA, and Ligand B has 6. Both are within the acceptable limit of <=10.

**6. QED:** Both ligands have reasonable QED scores (0.755 and 0.614), indicating good drug-like properties. Ligand A is slightly better.

**7. DILI:** Both ligands have similar DILI risk (76.735 and 76.037), indicating moderate risk. This isn't a major differentiator.

**8. BBB:** This is a critical parameter for a CNS target like DRD2. Ligand B (68.941) has a significantly better BBB percentile than Ligand A (46.724). This is a major advantage for Ligand B.

**9. Caco-2:** Ligand A (-5.54) and Ligand B (-4.761) both have negative Caco-2 values, which is unusual and suggests poor permeability. However, these values are on a scale where negative values are possible, and the difference isn't massive.

**10. Solubility:** Both ligands have poor aqueous solubility (-3.941 and -4.841). This is a concern, but can potentially be addressed through formulation.

**11. hERG:** Both ligands show low hERG inhibition liability (0.085 and 0.556), which is good.

**12. Cl_mic:** Ligand A (4.114) has a lower microsomal clearance than Ligand B (51.545), suggesting better metabolic stability. This is a positive for Ligand A.

**13. t1/2:** Ligand B (-9.485) has a longer in vitro half-life than Ligand A (-1.33), which is preferable.

**14. Pgp:** Ligand A (0.135) has lower P-gp efflux liability than Ligand B (0.444), which is desirable for CNS penetration.

**15. Binding Affinity:** Both ligands have excellent binding affinities (-8.9 and -8.5 kcal/mol). Ligand A is slightly better, but the difference is small.

**Overall Assessment:**

While Ligand A has slightly better affinity and metabolic stability, Ligand B significantly outperforms it in BBB penetration (68.941 vs 46.724) and has a longer half-life. Given that this is a CNS target (DRD2), BBB penetration is paramount. The lower Pgp efflux for ligand A is also a positive, but the substantial difference in BBB outweighs this. The similar DILI and hERG profiles, and acceptable logP/TPSA values for both, make the BBB difference the deciding factor.

Output:
1
2025-04-17 07:37:13,041 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (370.841 and 381.571 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (122.47) is slightly above the optimal <90 for CNS targets, but still reasonable. Ligand B (62.31) is excellent, well below 90. This favors Ligand B.

**3. logP:** Both ligands have good logP values (1.802 and 2.176), falling within the 1-3 range.

**4. H-Bond Donors:** Ligand A (3) and Ligand B (2) are both within the acceptable limit of <=5.

**5. H-Bond Acceptors:** Ligand A (7) and Ligand B (8) are both within the acceptable limit of <=10.

**6. QED:** Both ligands have good QED scores (0.547 and 0.665), indicating drug-like properties. Ligand B is slightly better.

**7. DILI:** Ligand A (68.166) has a higher DILI risk than Ligand B (55.952), though both are acceptable (<60 is good). This favors Ligand B.

**8. BBB:** Both ligands show good BBB penetration (71.656 and 79.721), exceeding the 70% threshold for CNS targets. Ligand B is better.

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.026 and -5.351). This is unusual and suggests poor permeability. However, these values are on a log scale and should be interpreted cautiously.

**10. Aqueous Solubility:** Both ligands have negative solubility values (-4.063 and -2.704), indicating poor aqueous solubility.

**11. hERG Inhibition:** Ligand A (0.183) has a slightly lower hERG inhibition risk than Ligand B (0.861). This favors Ligand A.

**12. Microsomal Clearance:** Ligand B (55.858) has a lower microsomal clearance than Ligand A (17.933), indicating better metabolic stability. This strongly favors Ligand B.

**13. In vitro Half-Life:** Ligand B (41.06) has a significantly longer in vitro half-life than Ligand A (-4.383), suggesting slower metabolism and potentially less frequent dosing. This strongly favors Ligand B.

**14. P-gp Efflux:** Ligand A (0.024) has a much lower P-gp efflux liability than Ligand B (0.148), suggesting better CNS exposure. This favors Ligand A.

**15. Binding Affinity:** Ligand A (-8.8 kcal/mol) has a significantly stronger binding affinity than Ligand B (-7.0 kcal/mol). This is a substantial advantage, potentially outweighing some ADME drawbacks.

**Overall Assessment:**

While Ligand A has a better binding affinity and lower P-gp efflux, Ligand B demonstrates superior ADME properties, particularly in terms of BBB penetration, metabolic stability (lower Cl_mic), longer half-life, and lower DILI risk. Given the GPCR-specific priorities for CNS targets (BBB, logP, Pgp, TPSA, and affinity), the improvements in ADME properties for Ligand B are crucial. The 1.8 kcal/mol difference in binding affinity, while significant, might be overcome with further optimization of Ligand B. The poor solubility and permeability of both compounds are concerning, but can be addressed with formulation strategies.

Output:
1
2025-04-17 07:37:13,041 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (335.451 Da) is slightly lower, which could be beneficial for permeability.

**2. TPSA:** Ligand A (46.92) is excellent for CNS penetration, well below the 90 A^2 threshold. Ligand B (52.23) is still reasonable, but less optimal.

**3. logP:** Both ligands have good logP values (A: 3.534, B: 3.125), falling within the 1-3 range.

**4. H-Bond Donors:** Both have 1 HBD, which is acceptable.

**5. H-Bond Acceptors:** Ligand A has 3 HBAs, and Ligand B has 4. Both are within the acceptable limit of 10.

**6. QED:** Both ligands have similar QED values (A: 0.648, B: 0.675), indicating good drug-likeness.

**7. DILI:** Ligand A (45.87) has a slightly higher DILI risk than Ligand B (20.822), but both are below the concerning threshold of 60.

**8. BBB:** Ligand B (89.608) has a significantly better BBB penetration score than Ligand A (64.599). This is a crucial advantage for a CNS target like DRD2.

**9. Caco-2 Permeability:** Ligand A (-4.803) has poorer Caco-2 permeability than Ligand B (-5.205), suggesting lower intestinal absorption.

**10. Aqueous Solubility:** Ligand B (-3.087) has better aqueous solubility than Ligand A (-4.844).

**11. hERG Inhibition:** Ligand A (0.53) has a slightly better hERG profile than Ligand B (0.932).

**12. Microsomal Clearance:** Ligand B (24.396) has significantly lower microsomal clearance than Ligand A (86.072), indicating better metabolic stability.

**13. In vitro Half-Life:** Ligand B (-13.633) has a much longer in vitro half-life than Ligand A (7.301).

**14. P-gp Efflux:** Ligand A (0.502) has lower P-gp efflux than Ligand B (0.248), which is favorable for CNS exposure.

**15. Binding Affinity:** Ligand A (-8.7 kcal/mol) has a significantly stronger binding affinity than Ligand B (-7.5 kcal/mol). This is a substantial advantage.

**Overall Assessment:**

While Ligand A has a better binding affinity and lower P-gp efflux, Ligand B excels in several critical ADME properties for a CNS-targeting GPCR. Specifically, its superior BBB penetration, lower microsomal clearance, and longer half-life are highly desirable. The difference in binding affinity (1.2 kcal/mol) is significant, but the improved ADME profile of Ligand B, especially the BBB score, outweighs this difference. The better solubility and lower DILI risk also contribute to its favorability.

Output:
1
2025-04-17 07:37:13,041 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (339.355 Da) is slightly preferred as it's closer to the lower end, potentially aiding permeability.

**TPSA:** Ligand B (79.21) is significantly better than Ligand A (109.48). For CNS targets, we want TPSA <= 90, and Ligand B comfortably meets this, while Ligand A is pushing the limit.

**logP:** Both ligands have acceptable logP values (Ligand A: 1.687, Ligand B: 3.12), falling within the optimal 1-3 range. Ligand B is closer to the upper end, which could slightly impact solubility, but is still acceptable.

**H-Bond Donors/Acceptors:** Both ligands have reasonable HBD (2 & 1 respectively) and HBA (6 each) counts, falling within the guidelines.

**QED:** Both ligands have good QED scores (Ligand A: 0.732, Ligand B: 0.804), indicating good drug-like properties.

**DILI:** Ligand B (63.978) has a significantly lower DILI risk than Ligand A (96.782). This is a substantial advantage for Ligand B.

**BBB:** Ligand B (74.641) has a much better BBB penetration score than Ligand A (32.183). This is *critical* for a CNS target like DRD2.

**Caco-2 Permeability:** Ligand A (-5.585) has a worse (more negative) Caco-2 permeability than Ligand B (-4.568).

**Aqueous Solubility:** Ligand A (-2.977) has slightly better solubility than Ligand B (-5.168). However, solubility is less critical than BBB for CNS targets.

**hERG Inhibition:** Both ligands have very low hERG inhibition risk (Ligand A: 0.011, Ligand B: 0.376), which is excellent.

**Microsomal Clearance:** Ligand A (2.528) has a much lower microsomal clearance than Ligand B (69.414), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (1.003) has a shorter half-life than Ligand B (-25.95).

**P-gp Efflux:** Ligand A (0.021) has a much lower P-gp efflux liability than Ligand B (0.242), which is favorable for CNS penetration.

**Binding Affinity:** Ligand A (-9.2 kcal/mol) has a significantly stronger binding affinity than Ligand B (-7.5 kcal/mol). This is a substantial advantage.

**Overall Assessment:**

While Ligand A has a better binding affinity and lower P-gp efflux, the substantial advantages of Ligand B in terms of BBB penetration, lower DILI risk, and a much more favorable TPSA outweigh these benefits. The difference in binding affinity (-1.7 kcal/mol) is significant, but not insurmountable, especially if further optimization can improve Ligand B's affinity. The poor BBB penetration of Ligand A is a major concern for a CNS target. The higher metabolic clearance of Ligand B is a drawback, but potentially addressable through structural modifications.

Output:
1
2025-04-17 07:37:13,041 - INFO - Reasoning:

Let's analyze Ligand A and Ligand B against the provided guidelines, prioritizing GPCR-specific properties (BBB, logP, Pgp, TPSA, and affinity).

**Ligand A:**

*   **MW:** 344.375 Da - Good (within 200-500 range)
*   **TPSA:** 122.03 - Marginal. Slightly above the ideal <90 for CNS targets, but not drastically so.
*   **logP:** 0.24 - Low. This is a significant concern, potentially hindering membrane permeability and CNS penetration.
*   **HBD:** 3 - Acceptable.
*   **HBA:** 7 - Acceptable.
*   **QED:** 0.69 - Good.
*   **DILI:** 68.825 - Moderate risk. Not ideal, but manageable.
*   **BBB:** 35.052 - Poor. This is a major drawback for a CNS target like DRD2.
*   **Caco-2:** -5.154 - Very poor permeability. Consistent with the low logP.
*   **Solubility:** -2.511 - Poor.
*   **hERG:** 0.059 - Very low risk. Excellent.
*   **Cl_mic:** 9.455 - Relatively low, suggesting reasonable metabolic stability.
*   **t1/2:** -3.268 - Short half-life.
*   **Pgp:** 0.005 - Very low efflux. Excellent.
*   **Affinity:** -7.5 kcal/mol - Excellent.

**Ligand B:**

*   **MW:** 368.371 Da - Good (within 200-500 range)
*   **TPSA:** 49.85 - Excellent. Well below the 90 threshold for CNS targets.
*   **logP:** 2.848 - Excellent. Within the optimal 1-3 range.
*   **HBD:** 0 - Acceptable.
*   **HBA:** 3 - Acceptable.
*   **QED:** 0.717 - Good.
*   **DILI:** 20.279 - Very low risk. Excellent.
*   **BBB:** 91.857 - Excellent. Highly desirable for a CNS target.
*   **Caco-2:** -4.287 - Moderate permeability.
*   **Solubility:** -2.926 - Poor.
*   **hERG:** 0.55 - Low risk. Good.
*   **Cl_mic:** 27.852 - Moderate clearance.
*   **t1/2:** -14.669 - Very short half-life.
*   **Pgp:** 0.087 - Very low efflux. Excellent.
*   **Affinity:** -8.5 kcal/mol - Excellent. Even stronger than Ligand A.

**Comparison and Decision:**

While Ligand A has a slightly better affinity (-7.5 vs -8.5 kcal/mol), the differences are overshadowed by Ligand B's superior ADME properties, particularly for a CNS target. Ligand A's very low logP and poor BBB penetration are critical liabilities. Ligand B excels in logP, TPSA, BBB, DILI, and Pgp efflux, making it much more likely to reach the target in the brain. The solubility and clearance are less ideal for Ligand B, but these can be addressed through formulation strategies or further chemical modifications. The affinity difference, while present, is unlikely to overcome the permeability issues of Ligand A.

Output:
1
2025-04-17 07:37:13,042 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (348.451 and 354.426 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (90.54) is slightly above the optimal <90 for CNS targets, but still reasonable. Ligand B (69.48) is excellent, well below the threshold.

**logP:** Ligand A (0.664) is a bit low, potentially hindering permeability. Ligand B (1.694) is better, falling within the 1-3 optimal range.

**H-Bond Donors/Acceptors:** Ligand A (2 HBD, 8 HBA) is good. Ligand B (0 HBD, 6 HBA) is also acceptable.

**QED:** Ligand A (0.724) is good, indicating a drug-like profile. Ligand B (0.472) is lower, suggesting a less favorable drug-like profile.

**DILI:** Both ligands have low DILI risk (49.399 and 41.14), which is positive.

**BBB:** Ligand A (58.123) is below the desirable >70 for CNS targets, a significant drawback. Ligand B (91.508) is excellent, strongly favoring its potential.

**Caco-2 Permeability:** Ligand A (-5.232) is very poor, indicating very low intestinal absorption. Ligand B (-4.517) is also poor, but slightly better than A.

**Aqueous Solubility:** Both ligands have poor aqueous solubility (-0.971 and -1.277).

**hERG:** Both ligands show low hERG inhibition risk (0.892 and 0.273).

**Microsomal Clearance:** Ligand A (23.555) has moderate clearance, while Ligand B (31.716) has higher clearance, suggesting lower metabolic stability.

**In vitro Half-Life:** Ligand A (36.793) has a reasonable half-life. Ligand B (-3.49) has a very short half-life, a major concern.

**P-gp Efflux:** Ligand A (0.125) has low P-gp efflux, which is good for CNS penetration. Ligand B (0.165) also has low P-gp efflux.

**Binding Affinity:** Ligand A (-7.1) has a slightly better binding affinity than Ligand B (-6.6). However, the difference is less than 1.5 kcal/mol.

**Overall Assessment:**

Ligand B is the stronger candidate. While its QED and half-life are concerning, its *excellent* BBB penetration and better logP outweigh the slightly weaker affinity and solubility issues. Ligand A's poor BBB penetration and Caco-2 permeability are significant liabilities for a CNS-targeted drug. The affinity difference is not large enough to overcome these ADME deficiencies.

Output:
1
2025-04-17 07:37:13,042 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 drug candidates, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight (MW):** Both ligands are within the ideal range (200-500 Da). Ligand A (348.487 Da) is slightly lower, which is generally favorable for permeability.

**2. TPSA:** Ligand A (49.85) is significantly better than Ligand B (55.35). For CNS targets, we want TPSA <= 90, and ideally lower. Ligand A is much closer to the ideal range.

**3. logP:** Both ligands have logP values within the optimal range (1-3), but Ligand B (4.809) is higher. This could lead to solubility issues and off-target interactions. Ligand A (2.894) is preferable.

**4. H-Bond Donors (HBD):** Both are acceptable (Ligand A: 0, Ligand B: 2).

**5. H-Bond Acceptors (HBA):** Both are acceptable (Ligand A: 3, Ligand B: 4).

**6. QED:** Ligand A (0.768) has a better QED score than Ligand B (0.481), indicating a more drug-like profile.

**7. DILI:** Ligand A (26.095) has a significantly lower DILI risk than Ligand B (67.429). This is a major advantage for Ligand A.

**8. BBB:** Ligand A (86.39) has a much higher BBB penetration percentile than Ligand B (55.874). This is *crucial* for a CNS target like DRD2.

**9. Caco-2 Permeability:** Ligand A (-4.405) has better Caco-2 permeability than Ligand B (-4.993).

**10. Aqueous Solubility:** Ligand A (-2.434) has better aqueous solubility than Ligand B (-4.45).

**11. hERG Inhibition:** Both ligands have low hERG inhibition risk (Ligand A: 0.266, Ligand B: 0.884), but Ligand A is slightly better.

**12. Microsomal Clearance:** Ligand B (41.581) has a lower microsomal clearance than Ligand A (47.903), suggesting better metabolic stability.

**13. In vitro Half-Life:** Ligand B (127.948) has a significantly longer in vitro half-life than Ligand A (10.864). This is a positive for Ligand B.

**14. P-gp Efflux:** Ligand A (0.324) has lower P-gp efflux liability than Ligand B (0.92). Lower P-gp efflux is desirable for CNS penetration.

**15. Binding Affinity:** Both ligands have similar binding affinities (-8.8 kcal/mol and -8.5 kcal/mol). The difference is not substantial enough to outweigh the other significant advantages of Ligand A.

**Overall Assessment:**

Ligand A is clearly the more promising candidate. It excels in key properties for a CNS-targeting GPCR, including TPSA, BBB penetration, DILI risk, solubility, and P-gp efflux. While Ligand B has a longer half-life and slightly better metabolic stability, the superior CNS penetration and safety profile of Ligand A are far more important for DRD2.

Output:
1
2025-04-17 07:37:13,042 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (348.443) is slightly better, being closer to the lower end which can aid permeability.

**TPSA:** Ligand B (55.21) is significantly better than Ligand A (81.47). For CNS targets, TPSA should be <= 90, and Ligand B is comfortably within that range, while Ligand A is approaching the upper limit.

**logP:** Both ligands have acceptable logP values (Ligand A: 3.8, Ligand B: 2.122), falling within the optimal 1-3 range. Ligand B is slightly preferred here, being closer to the center of the range.

**H-Bond Donors:** Both ligands have 1 HBD, which is good.

**H-Bond Acceptors:** Ligand A has 4 HBA, and Ligand B has 7. Both are acceptable (<=10), but Ligand A is slightly better.

**QED:** Both ligands have good QED values (Ligand A: 0.44, Ligand B: 0.627), indicating drug-like properties. Ligand B is better.

**DILI:** Ligand B (19.426) has a much lower DILI risk than Ligand A (44.591). This is a significant advantage for Ligand B.

**BBB:** Both ligands have excellent BBB penetration (Ligand A: 82.047, Ligand B: 83.986). Both exceed the desirable >70 threshold for CNS targets.

**Caco-2 Permeability:** Ligand A (-4.517) shows poor Caco-2 permeability, while Ligand B (-5.222) is also poor, but slightly better.

**Aqueous Solubility:** Ligand A (-4.401) has slightly better aqueous solubility than Ligand B (-2.065), but both are poor.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (Ligand A: 0.672, Ligand B: 0.712).

**Microsomal Clearance:** Ligand B (-15.789) has significantly lower (better) microsomal clearance than Ligand A (64.384), indicating better metabolic stability.

**In vitro Half-Life:** Ligand B (-0.902) has a slightly better in vitro half-life than Ligand A (3.369).

**P-gp Efflux:** Ligand A (0.444) has better P-gp efflux profile than Ligand B (0.068), meaning less efflux and potentially better CNS exposure.

**Binding Affinity:** Ligand A (-9.0) has a significantly stronger binding affinity than Ligand B (-6.7). This is a substantial advantage for Ligand A, potentially outweighing some of its ADME drawbacks.

**Overall Assessment:**

Ligand B has a superior ADME profile overall, with lower DILI, better metabolic stability (lower Cl_mic), and a better TPSA. However, Ligand A boasts a significantly stronger binding affinity (-9.0 vs -6.7 kcal/mol). For a GPCR target like DRD2, strong affinity is crucial. While Ligand A's Caco-2 and solubility are poor, these can potentially be addressed through formulation strategies. The strong binding affinity is a major driver for success.

Output:
1
2025-04-17 07:37:13,042 - INFO - Reasoning:

Let's analyze Ligand A and Ligand B against the provided guidelines, prioritizing GPCR-specific properties (BBB, logP, Pgp, TPSA, and affinity) for DRD2.

**Molecular Weight:** Both ligands (353.438 and 350.503 Da) fall comfortably within the ideal 200-500 Da range.

**TPSA:** Ligand A (61.88) is slightly higher than Ligand B (58.64). Both are below the 90 A^2 threshold desirable for CNS targets, which is good.

**logP:** Ligand A (0.562) is quite low, potentially hindering membrane permeability. Ligand B (2.594) is within the optimal 1-3 range. This is a significant advantage for Ligand B.

**H-Bond Donors/Acceptors:** Both have 1 HBD, which is acceptable. Ligand A has 4 HBA, and Ligand B has 3 HBA. Both are within the acceptable limit of <=10.

**QED:** Both ligands have reasonable QED scores (0.802 and 0.695), indicating good drug-like properties.

**DILI:** Ligand A (16.789) has a higher DILI risk than Ligand B (5.894). Lower is better, so Ligand B is preferable.

**BBB:** Both ligands have good BBB penetration (Ligand A: 73.129, Ligand B: 78.79). Ligand B is slightly better, exceeding 70%.

**Caco-2 Permeability:** Ligand A (-4.862) has poor Caco-2 permeability, while Ligand B (-4.608) is slightly better, but still poor.

**Aqueous Solubility:** Both ligands have negative solubility values (-1.466 and -2.519), indicating poor aqueous solubility. This is a concern for both.

**hERG Inhibition:** Ligand A (0.398) has a lower hERG inhibition risk than Ligand B (0.53). Lower is better.

**Microsomal Clearance:** Ligand A (-6.278) has a much lower (better) microsomal clearance than Ligand B (76.154), suggesting greater metabolic stability.

**In vitro Half-Life:** Ligand A (9.535) has a shorter half-life than Ligand B (-11.771), which is undesirable.

**P-gp Efflux:** Ligand A (0.024) shows very low P-gp efflux, which is excellent for CNS penetration. Ligand B (0.082) is also low, but higher than Ligand A.

**Binding Affinity:** Ligand B (-8.0) has a significantly stronger binding affinity than Ligand A (-0.0). This is a crucial advantage, as a >1.5 kcal/mol difference can outweigh other drawbacks.

**Overall Assessment:**

Ligand B is the stronger candidate. While both have solubility issues, Ligand B's superior logP, significantly better binding affinity, lower DILI risk, and slightly better BBB penetration outweigh Ligand A's advantages in P-gp efflux and microsomal clearance. The strong binding affinity of Ligand B is a critical factor, especially for a GPCR target. The poor Caco-2 permeability is a concern for both, but less critical for a CNS target where direct brain exposure is the goal.

Output:
1
2025-04-17 07:37:13,042 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (360.445 and 363.483 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (58.64) is significantly better than Ligand B (84.23). For CNS targets, we want TPSA <= 90, and ideally closer to 60. Ligand A is much closer to this ideal.

**logP:** Both ligands have good logP values (2.448 and 2.925), falling within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A (HBD=1, HBA=3) is preferable to Ligand B (HBD=2, HBA=5). Lower values generally improve permeability.

**QED:** Both ligands have acceptable QED scores (0.643 and 0.755), indicating good drug-like properties.

**DILI:** Ligand B (63.978) has a higher DILI risk than Ligand A (20.861). Lower DILI is preferred.

**BBB:** This is a critical parameter for CNS targets. Ligand A (94.106) has a *much* higher BBB penetration percentile than Ligand B (42.032). This is a major advantage for Ligand A.

**Caco-2 Permeability:** Ligand A (-4.696) has a more negative Caco-2 value, which is unusual. Caco-2 values are typically positive or near zero, indicating permeability. Ligand B (-5.224) is also negative, but slightly more negative. This is a potential concern for both, but the negative values suggest poor permeability.

**Aqueous Solubility:** Both ligands have very poor aqueous solubility (-2.8 and -2.863). This could be a significant formulation challenge.

**hERG:** Both ligands have low hERG inhibition liability (0.69 and 0.291), which is good.

**Microsomal Clearance:** Ligand B (67.971) has higher microsomal clearance than Ligand A (62.083), suggesting faster metabolism and potentially lower in vivo exposure.

**In vitro Half-Life:** Ligand B (37.492) has a longer half-life than Ligand A (-1.116). This is a positive for Ligand B, but the negative value for Ligand A is concerning.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.091 and 0.148). This is good, as it suggests better CNS exposure.

**Binding Affinity:** Ligand B (-8.5) has a slightly better binding affinity than Ligand A (-8.1). However, the difference is only 0.4 kcal/mol, which is not substantial enough to overcome the significant ADME advantages of Ligand A.

**Overall Assessment:**

Ligand A is the stronger candidate. Its significantly better BBB penetration (94.1% vs 42.0%), lower DILI risk, and more favorable TPSA outweigh the slightly weaker binding affinity and negative Caco-2 value. The negative Caco-2 values for both are concerning, but the superior CNS penetration profile of Ligand A is critical for a DRD2 ligand. The longer half-life of Ligand B is a benefit, but not enough to overcome the other deficiencies.

Output:
0
2025-04-17 07:37:13,043 - INFO - Batch 380 complete. Total preferences: 6080
2025-04-17 07:37:13,043 - INFO - Processing batch 381/512...
2025-04-17 07:37:52,703 - INFO - Reasoning:

Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight (MW):** Both ligands (386.543 and 350.459 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (101.05) is slightly higher than the preferred <90 for CNS targets, while Ligand B (75.71) is well within the range. This favors Ligand B.

**3. logP:** Both ligands have good logP values (1.482 and 1.727), falling within the optimal 1-3 range.

**4. H-Bond Donors (HBD):** Both are acceptable (2 and 1 respectively), below the threshold of 5.

**5. H-Bond Acceptors (HBA):** Both are acceptable (7 and 4 respectively), below the threshold of 10.

**6. QED:** Both ligands have reasonable QED scores (0.795 and 0.677), indicating good drug-like properties.

**7. DILI:** Ligand A (66.382) has a higher DILI risk than Ligand B (26.444). This favors Ligand B.

**8. BBB:** Both ligands have acceptable BBB penetration (70.803 and 65.452), but Ligand A is slightly better, being just above 70.

**9. Caco-2:** Both have negative Caco-2 values, which is unusual and suggests poor permeability. However, the scale is not specified, so it's hard to interpret.

**10. Solubility:** Both have negative solubility values, which is also unusual. Again, the scale is not specified.

**11. hERG:** Both ligands have very low hERG inhibition risk (0.256 and 0.273).

**12. Cl_mic:** Ligand A (3.16) has significantly lower microsomal clearance than Ligand B (63.473), indicating better metabolic stability. This favors Ligand A.

**13. t1/2:** Ligand A (25.948) has a much longer in vitro half-life than Ligand B (-11.343). This is a significant advantage for Ligand A.

**14. Pgp:** Both ligands have low P-gp efflux liability (0.118 and 0.18).

**15. Binding Affinity:** Ligand A (-8.5 kcal/mol) has a stronger binding affinity than Ligand B (-7.3 kcal/mol). This is a substantial advantage for Ligand A (a 1.2 kcal/mol difference).

**Overall Assessment:**

While Ligand B has advantages in TPSA and DILI, Ligand A excels in crucial areas for a CNS-targeting GPCR ligand: significantly better metabolic stability (lower Cl_mic, longer t1/2), a substantially stronger binding affinity, and slightly better BBB penetration. The affinity difference is large enough to outweigh the slightly higher TPSA and DILI risk of Ligand A. The negative values for Caco-2 and solubility are concerning but require knowing the scale to properly assess.

Output:
1
2025-04-17 07:37:52,703 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (354.491 and 361.427 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (67.87) is significantly better than Ligand B (100.35). For CNS targets, we want TPSA <= 90, so Ligand A is preferable.

**logP:** Ligand A (2.116) is within the optimal 1-3 range. Ligand B (0.6) is a bit low, potentially hindering permeability.

**H-Bond Donors/Acceptors:** Ligand A (HBD=1, HBA=4) and Ligand B (HBD=2, HBA=7) both have reasonable numbers of H-bond donors and acceptors.

**QED:** Both ligands have good QED scores (A: 0.678, B: 0.812), indicating drug-like properties.

**DILI:** Both ligands have acceptable DILI risk (A: 21.908, B: 62.389), but Ligand A is significantly lower, suggesting a better safety profile.

**BBB:** This is crucial for a CNS target. Ligand A has a BBB percentile of 63.629, which is decent but not excellent. Ligand B has a very low BBB percentile of 21.791, making it less likely to reach the target in the brain.

**Caco-2 Permeability:** Ligand A (-4.708) and Ligand B (-5.094) both have negative values, indicating poor permeability.

**Aqueous Solubility:** Both ligands have poor aqueous solubility (-1.721 and -2.464 respectively).

**hERG Inhibition:** Both ligands have low hERG inhibition liability (A: 0.493, B: 0.127), which is good.

**Microsomal Clearance:** Ligand A (26.728) has higher clearance than Ligand B (4.56), suggesting Ligand B is more metabolically stable.

**In vitro Half-Life:** Ligand A (10.534) has a longer half-life than Ligand B (-7.126).

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (A: 0.158, B: 0.027), which is favorable for CNS penetration.

**Binding Affinity:** Ligand B (-7.6 kcal/mol) has a significantly stronger binding affinity than Ligand A (-0.0 kcal/mol). This is a major advantage.

**Overall Assessment:**

While Ligand A has better TPSA, DILI, and BBB penetration, the significantly stronger binding affinity of Ligand B (-7.6 vs -0.0 kcal/mol) is a decisive factor. The difference in affinity is substantial enough to potentially overcome the lower BBB and logP values, especially with further optimization. The improved metabolic stability (lower Cl_mic) of Ligand B is also a plus. Although both have poor solubility and Caco-2 permeability, these can be addressed during lead optimization.

Output:
1
2025-04-17 07:37:52,703 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B based on the provided guidelines, prioritizing GPCR-specific properties (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (357.435 and 370.515 Da) fall within the ideal 200-500 Da range.

**TPSA:** Both ligands (79.79 and 78.87) are below the 90 A^2 threshold desirable for CNS targets, which is excellent.

**logP:** Ligand A (2.824) is optimal, while Ligand B (1.189) is slightly low, potentially hindering permeation.

**H-Bond Donors/Acceptors:** Both ligands have 2 HBD and 5 HBA, which are within acceptable limits.

**QED:** Ligand A (0.834) has a significantly better QED score than Ligand B (0.496), indicating a more drug-like profile.

**DILI:** Ligand A (69.988) has a higher DILI risk than Ligand B (31.059), but both are reasonably acceptable.

**BBB:** Ligand A (70.958) has a good BBB penetration percentile, exceeding the 70% threshold for CNS targets. Ligand B (46.336) is significantly lower, which is a major concern for a CNS target like DRD2.

**Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and suggests potential issues with the data or modeling. However, we'll proceed assuming these represent low permeability.

**Aqueous Solubility:** Both ligands have negative solubility values, which is also concerning.

**hERG Inhibition:** Both ligands have low hERG inhibition liability, which is good.

**Microsomal Clearance:** Both ligands have similar microsomal clearance values (51.458 and 52.054 mL/min/kg), suggesting comparable metabolic stability.

**In vitro Half-Life:** Ligand A (68.977 hours) has a much longer half-life than Ligand B (-13.108 hours). The negative value for B is problematic and suggests rapid degradation.

**P-gp Efflux:** Ligand A (0.757) has a lower P-gp efflux liability than Ligand B (0.074), which is favorable for CNS penetration.

**Binding Affinity:** Ligand A (-8.8 kcal/mol) has a significantly stronger binding affinity than Ligand B (-7.0 kcal/mol). This >1.5 kcal/mol difference is substantial and can outweigh minor ADME drawbacks.

**Conclusion:**

Considering all factors, especially the GPCR-specific priorities, **Ligand A is the more promising drug candidate.** It has a superior QED score, better BBB penetration, longer half-life, lower P-gp efflux, and significantly stronger binding affinity. While its DILI risk is slightly higher than Ligand B, the substantial advantages in CNS penetration and potency outweigh this concern. Ligand B's poor BBB penetration and negative half-life are major red flags for a CNS-targeted drug.

Output:
1
2025-04-17 07:37:52,703 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (368.287 Da and 355.438 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (105.49) is slightly above the optimal <90 for CNS targets, but still reasonable. Ligand B (54.88) is excellent, well below 90.

**logP:** Ligand A (1.317) is within the optimal 1-3 range. Ligand B (4.589) is a bit high, potentially leading to solubility issues and off-target interactions.

**H-Bond Donors/Acceptors:** Ligand A (HBD=3, HBA=6) and Ligand B (HBD=1, HBA=4) both have acceptable numbers of H-bond donors and acceptors.

**QED:** Both ligands have good QED scores (0.627 and 0.745, respectively), indicating drug-like properties.

**DILI:** Ligand A (61.691) has a moderate DILI risk, while Ligand B (78.325) has a higher risk.

**BBB:** Both ligands show good BBB penetration (77.898% and 78.48%), which is crucial for a CNS target like DRD2.

**Caco-2 Permeability:** Both have negative Caco-2 values which is unusual and likely indicates a problem with the data.

**Aqueous Solubility:** Both ligands have poor aqueous solubility (-2.681 and -4.843).

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.237 and 0.423).

**Microsomal Clearance:** Both have similar microsomal clearance values (40.252 and 41.96).

**In vitro Half-Life:** Ligand A has a negative half-life (-46.746), which is not possible. Ligand B has a half-life of 43.947.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.015 and 0.3).

**Binding Affinity:** Ligand B (-9.1 kcal/mol) has significantly better binding affinity than Ligand A (-8.1 kcal/mol), exceeding the >1.5 kcal/mol advantage threshold.

**Overall Assessment:**

Ligand B is the more promising candidate. While its logP is slightly elevated, its significantly stronger binding affinity (-9.1 vs -8.1 kcal/mol) is a major advantage, especially for a GPCR target. The better TPSA and comparable BBB penetration also favor Ligand B. The DILI risk is higher for Ligand B, but this could be addressed through structural modifications. The negative half-life for Ligand A is a major red flag, indicating a data issue or a highly unstable compound. The negative Caco-2 permeability for both is concerning and needs investigation.

Output:
1
2025-04-17 07:37:52,704 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (362.417 and 343.387 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (81.08) is significantly better than Ligand B (101.22). For CNS targets, we want TPSA <= 90, and A is comfortably within that range, while B is slightly above.

**3. logP:** Both ligands have similar logP values (1.147 and 1.364), both falling within the optimal 1-3 range.

**4. H-Bond Donors:** Ligand A (2) is slightly higher than Ligand B (1), but both are acceptable (<=5).

**5. H-Bond Acceptors:** Ligand B (6) is higher than Ligand A (4), but both are within the acceptable range (<=10).

**6. QED:** Both ligands have good QED scores (0.695 and 0.814), indicating good drug-like properties.

**7. DILI:** Ligand A (22.024) has a much lower DILI risk than Ligand B (60.605). This is a significant advantage for A.

**8. BBB:** Both ligands have good BBB penetration (76.347 and 74.37), both being >70, which is desirable for CNS targets. The difference is minimal.

**9. Caco-2 Permeability:** Both ligands have very poor Caco-2 permeability (-4.78). This is a concern for both, but doesn't immediately disqualify either.

**10. Aqueous Solubility:** Both ligands have poor aqueous solubility (-1.413 and -2.047). This is a potential formulation challenge for both.

**11. hERG Inhibition:** Ligand A (0.682) has a lower hERG inhibition liability than Ligand B (0.258), which is preferable.

**12. Microsomal Clearance:** Ligand A (8.514) has lower microsomal clearance than Ligand B (56.445), suggesting better metabolic stability.

**13. In vitro Half-Life:** Ligand A (-7.689) has a much longer in vitro half-life than Ligand B (-21.792). This is a significant advantage for A.

**14. P-gp Efflux:** Ligand A (0.302) has lower P-gp efflux liability than Ligand B (0.053), which is a positive for CNS exposure.

**15. Binding Affinity:** Both ligands have the same binding affinity (-7.9 kcal/mol), which is excellent.

**Overall Assessment:**

Ligand A is significantly better than Ligand B. While both have good affinity and BBB penetration, Ligand A excels in ADME properties. Specifically, it has a much lower DILI risk, better metabolic stability (lower Cl_mic and longer t1/2), lower P-gp efflux, and lower hERG inhibition. Its TPSA is also more favorable. The Caco-2 and solubility are poor for both, but the ADME advantages of A outweigh these concerns.

Output:
1
2025-04-17 07:37:52,704 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (409.284 Da) is slightly higher, but acceptable. Ligand B (352.435 Da) is also good.

**TPSA:** Both ligands have TPSA values below 140, indicating good oral absorption potential. Ligand A (102.3) is slightly higher than Ligand B (93.19), but both are reasonably good for CNS penetration, though ideally below 90.

**logP:** Ligand A (1.878) is within the optimal range (1-3). Ligand B (-1.217) is below 1, which could hinder permeation. This is a significant drawback for Ligand B.

**H-Bond Donors/Acceptors:** Both ligands have acceptable HBD (2) and HBA (4/5) counts, balancing solubility and permeability.

**QED:** Both ligands have QED values above 0.5 (0.725 and 0.662), indicating good drug-like properties.

**DILI:** Ligand A (64.676) has a higher DILI risk than Ligand B (17.836). This is a negative for Ligand A.

**BBB:** Ligand A (51.066) shows moderate BBB penetration, while Ligand B (25.94) is quite low. For a CNS target like DRD2, a higher BBB score is crucial. This is a major advantage for Ligand A.

**Caco-2 Permeability:** Ligand A (-4.81) and Ligand B (-5.041) both have negative Caco-2 values, which is unusual and suggests poor permeability. However, these values are on a scale where negative values are possible and don't necessarily disqualify a compound.

**Aqueous Solubility:** Ligand A (-3.934) and Ligand B (-0.969) both have negative solubility values, which is also unusual. This suggests limited solubility, which could be a formulation challenge.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.511 and 0.13).

**Microsomal Clearance:** Ligand B (-8.161) has a negative clearance, which is also unusual and suggests very high metabolic stability. Ligand A (42.751) has a moderate clearance.

**In vitro Half-Life:** Ligand B (-4.348) has a negative half-life, which is also unusual and suggests very high stability. Ligand A (57.175) has a reasonable half-life.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.088 and 0.002), which is favorable for CNS exposure.

**Binding Affinity:** Ligand A (-7.9 kcal/mol) has a slightly better binding affinity than Ligand B (-7.0 kcal/mol). While both are good, the 0.9 kcal/mol difference is significant.

**Overall Assessment:**

Ligand A is the better candidate. While it has a higher DILI risk, its significantly better BBB penetration, acceptable logP, and slightly improved binding affinity outweigh this concern for a CNS target like DRD2. Ligand B's low logP and poor BBB penetration are major drawbacks. The unusual negative values for Caco-2, solubility, clearance and half-life for Ligand B are also concerning.

Output:
1
2025-04-17 07:37:52,704 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (349.479 Da) is slightly preferred as it's closer to the lower end, potentially aiding permeability.

**TPSA:** Both ligands have TPSA values below 90, which is good for CNS penetration. Ligand A (83.29) is slightly better than Ligand B (88.41).

**logP:** Both ligands have logP values within the optimal range (1-3). Ligand A (2.962) is slightly higher, which could be beneficial for membrane permeability, but both are acceptable.

**H-Bond Donors/Acceptors:** Both ligands have 2 HBD and 5/4 HBA, respectively, which are within acceptable limits.

**QED:** Both ligands have QED scores above 0.7, indicating good drug-likeness.

**DILI:** Ligand A (26.018) has a significantly lower DILI risk than Ligand B (80.031). This is a major advantage for Ligand A.

**BBB:** Ligand A (85.498) has a much higher BBB penetration percentile than Ligand B (71.772). This is crucial for a CNS target like DRD2.

**Caco-2 Permeability:** Ligand A (-5.074) has slightly better Caco-2 permeability than Ligand B (-4.851).

**Aqueous Solubility:** Both ligands have poor aqueous solubility (-2.288 and -3.747 respectively). This could pose formulation challenges, but is less critical than BBB penetration for a CNS target.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.34 and 0.533 respectively).

**Microsomal Clearance:** Ligand A (15.565) has a lower microsomal clearance than Ligand B (42.881), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand B (76.365) has a longer in vitro half-life than Ligand A (20.392). This is a positive for Ligand B, but the difference may be offset by other factors.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.076 and 0.35 respectively).

**Binding Affinity:** Ligand B (-9.2 kcal/mol) has a significantly stronger binding affinity than Ligand A (-7.8 kcal/mol). This is a substantial advantage for Ligand B, potentially outweighing some of its ADME drawbacks. A 1.4 kcal/mol difference is significant.

**Overall Assessment:**

While Ligand B boasts a superior binding affinity, Ligand A has a much more favorable ADME profile, particularly regarding BBB penetration and DILI risk. For a CNS target like DRD2, achieving sufficient brain exposure is paramount. The significantly higher BBB percentile and lower DILI risk of Ligand A make it a more promising candidate, despite the slightly weaker binding affinity. The difference in affinity, while substantial, may be overcome with further optimization.

Output:
0
2025-04-17 07:37:52,704 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (359.392 Da) is slightly lower, which can be advantageous for permeability.

**TPSA:** Ligand A (47.36) is excellent for CNS penetration, well below the 90 A^2 threshold. Ligand B (75.11) is higher but still reasonable, though less ideal for CNS targets.

**logP:** Both ligands have logP values within the optimal range (1-3), with Ligand A (3.294) being slightly better positioned. Ligand B (4.375) is approaching the upper limit and could potentially have solubility issues.

**H-Bond Donors/Acceptors:** Ligand A (0 HBD, 4 HBA) and Ligand B (2 HBD, 5 HBA) both fall within acceptable ranges.

**QED:** Both ligands have good QED scores (Ligand A: 0.732, Ligand B: 0.628), indicating drug-like properties.

**DILI:** Ligand A (19.504) has a significantly lower DILI risk than Ligand B (75.456), which is a major advantage.

**BBB:** This is crucial for a CNS target. Ligand A boasts an excellent BBB percentile (97.131), while Ligand B's BBB percentile (47.809) is considerably lower and less desirable.

**Caco-2 Permeability:** Ligand A (-4.272) shows poor Caco-2 permeability, which is a concern. Ligand B (-5.276) is even worse.

**Aqueous Solubility:** Both ligands have negative solubility values, suggesting poor aqueous solubility. Ligand A (-3.044) is slightly better than Ligand B (-4.686).

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.531 and 0.521, respectively).

**Microsomal Clearance:** Ligand B (70.079) has a higher microsomal clearance than Ligand A (27.001), indicating lower metabolic stability.

**In vitro Half-Life:** Ligand B (16.241) has a longer in vitro half-life than Ligand A (-12.328), which is a positive attribute.

**P-gp Efflux:** Both ligands show low P-gp efflux liability (0.243 and 0.616, respectively).

**Binding Affinity:** Both ligands have strong binding affinities (-8 kcal/mol and -10 kcal/mol, respectively). Ligand B is slightly more potent.

**Overall Assessment:**

While Ligand B has a slightly better binding affinity and in vitro half-life, Ligand A is significantly better in several critical areas for a CNS-targeting GPCR drug. Specifically, its much lower DILI risk and significantly higher BBB penetration are major advantages. The poor Caco-2 permeability of both is a concern, but can potentially be addressed through formulation strategies. The slightly better logP and solubility of Ligand A are also beneficial. Given the GPCR-specific priorities, the superior BBB and safety profile of Ligand A outweigh the slightly better potency and half-life of Ligand B.

Output:
0
2025-04-17 07:37:52,705 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 drug candidates, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (341.39 and 354.49 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (47.48) is excellent, well below the 90 A^2 target for CNS drugs. Ligand B (59.08) is still reasonable but less optimal.

**logP:** Ligand A (3.601) is at the upper end of the optimal range (1-3), while Ligand B (1.781) is at the lower end. While both are within range, a slightly higher logP can be beneficial for GPCRs.

**H-Bond Donors/Acceptors:** Both ligands have a low number of HBDs (0) and reasonable HBAs (5 and 4 respectively), which is favorable for permeability.

**QED:** Both ligands have similar QED values (0.685 and 0.633), indicating good drug-like properties.

**DILI:** Ligand A (70.88) has a higher DILI risk than Ligand B (9.926). This is a significant drawback for Ligand A.

**BBB:** Ligand B (88.135) has a substantially better BBB penetration score than Ligand A (77.2). This is a critical advantage for a CNS target like DRD2.

**Caco-2 Permeability:** Ligand A (-4.409) has a lower Caco-2 permeability score than Ligand B (-4.271), suggesting slightly poorer intestinal absorption.

**Aqueous Solubility:** Ligand A (-4.203) has a lower solubility score than Ligand B (-0.763).

**hERG Inhibition:** Ligand A (0.921) has a slightly higher hERG inhibition risk than Ligand B (0.337), but both are relatively low.

**Microsomal Clearance:** Ligand B (52.051) has a lower microsomal clearance than Ligand A (75.62), indicating better metabolic stability.

**In vitro Half-Life:** Ligand B (-5.606) has a negative half-life, which is unusual and suggests very rapid metabolism or issues with the assay. Ligand A (28.621) has a more reasonable half-life.

**P-gp Efflux:** Ligand A (0.564) has lower P-gp efflux liability than Ligand B (0.068), which is favorable for CNS exposure.

**Binding Affinity:** Ligand A (-8.5 kcal/mol) has a slightly better binding affinity than Ligand B (-7.4 kcal/mol). This 1.1 kcal/mol difference is significant and could outweigh some ADME drawbacks.

**Overall Assessment:**

Ligand A has a better binding affinity and P-gp efflux profile, but suffers from higher DILI risk, lower BBB penetration, lower solubility, and higher metabolic clearance. Ligand B excels in BBB penetration, DILI risk, metabolic stability, and solubility, but has slightly weaker binding affinity.

Given the CNS target and the importance of BBB penetration, the lower DILI risk, and better metabolic stability, Ligand B is the more promising candidate despite the slightly weaker binding affinity. The 1.1 kcal/mol difference in binding affinity can potentially be addressed through further optimization, while mitigating the ADME liabilities of Ligand A would be more challenging.

Output:
1
2025-04-17 07:37:52,705 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B against the provided guidelines, prioritizing GPCR-specific properties (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (344.455 and 358.423 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (62.55) is excellent, well below the 90 A^2 threshold for CNS targets. Ligand B (84.42) is still reasonable but less optimal, approaching the 90 A^2 limit.

**logP:** Ligand A (3.395) is within the optimal 1-3 range. Ligand B (1.508) is at the lower end, potentially impacting permeability.

**H-Bond Donors/Acceptors:** Both ligands have acceptable HBD counts (1). Ligand A has 3 HBA, while Ligand B has 6. Both are within the acceptable limit of 10, but Ligand A is preferable.

**QED:** Both ligands have good QED scores (0.609 and 0.895), indicating drug-like properties.

**DILI:** Ligand A (45.328) has a lower DILI risk than Ligand B (77.278), which is a significant advantage.

**BBB:** Ligand A (64.482) has a moderate BBB penetration, while Ligand B (70.531) is better, exceeding the 70% threshold for CNS targets. This is a key advantage for Ligand B.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.711 and -5.004), which is unusual and suggests poor permeability. However, these values are on a scale where negative values are possible, and the absolute magnitude isn't directly comparable without knowing the scale's specifics.

**Aqueous Solubility:** Both ligands have negative solubility values (-3.486 and -3.743), indicating poor aqueous solubility. This could be a formulation challenge.

**hERG:** Ligand A (0.681) has a slightly higher hERG risk than Ligand B (0.312), which is preferable.

**Microsomal Clearance:** Ligand A (79.926) has higher microsomal clearance than Ligand B (40.674), suggesting lower metabolic stability.

**In vitro Half-Life:** Ligand B (13.009) has a longer in vitro half-life than Ligand A (40.012), which is advantageous.

**P-gp Efflux:** Ligand A (0.764) has a higher P-gp efflux liability than Ligand B (0.322), meaning less CNS exposure is expected for Ligand A.

**Binding Affinity:** Ligand B (-9.5 kcal/mol) has a significantly stronger binding affinity than Ligand A (-8.5 kcal/mol). This 1 kcal/mol difference is substantial and can outweigh some ADME drawbacks.

**Overall Assessment:**

Ligand B is superior due to its significantly stronger binding affinity, better BBB penetration, lower DILI risk, longer half-life, and lower P-gp efflux. While Ligand A has a better TPSA and slightly lower hERG risk, the advantages of Ligand B in affinity and CNS penetration are more critical for a DRD2 target. The poor solubility and permeability of both compounds are concerns, but can potentially be addressed through formulation strategies.

Output:
1
2025-04-17 07:37:52,705 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (349.362) is slightly better, being closer to the lower end which can aid permeability.

**TPSA:** Ligand B (76.46) is significantly better than Ligand A (99.6). For CNS targets, TPSA < 90 is preferred, and Ligand B is comfortably within this range, while Ligand A is approaching the upper limit.

**logP:** Both ligands have acceptable logP values (Ligand A: 0.822, Ligand B: 1.177), falling within the optimal 1-3 range. Ligand B is slightly more favorable.

**H-Bond Donors/Acceptors:** Ligand A has 2 HBD and 5 HBA, while Ligand B has 1 HBD and 6 HBA. Both are within acceptable limits (HBD <= 5, HBA <= 10).

**QED:** Ligand A (0.82) has a better QED score than Ligand B (0.669), indicating a more drug-like profile.

**DILI:** Ligand B (30.632) has a much lower DILI risk than Ligand A (49.283). This is a significant advantage for Ligand B.

**BBB:** Ligand A (65.801) has a better BBB penetration score than Ligand B (38.891). This is a crucial factor for CNS targets like DRD2, and gives Ligand A a substantial edge.

**Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and suggests a potential issue with the data or a very poor permeability. However, the scale is not specified, so it's hard to interpret.

**Aqueous Solubility:** Both ligands have negative solubility values, which is also unusual and suggests a potential issue with the data.

**hERG Inhibition:** Both ligands have very low hERG inhibition risk (Ligand A: 0.051, Ligand B: 0.058).

**Microsomal Clearance:** Ligand A (-6.088) has significantly lower (better) microsomal clearance than Ligand B (65.797), indicating better metabolic stability.

**In vitro Half-Life:** Ligand B (28.598) has a much longer in vitro half-life than Ligand A (-0.814). This is a significant advantage for Ligand B.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (Ligand A: 0.009, Ligand B: 0.029).

**Binding Affinity:** Ligand A (-8.0) has a slightly better binding affinity than Ligand B (-6.4). This is a 1.6 kcal/mol difference, which is significant and can outweigh some ADME drawbacks.

**Overall Assessment:**

While Ligand A has better binding affinity and BBB penetration, Ligand B excels in DILI risk, in vitro half-life, and TPSA. The lower TPSA and DILI of Ligand B are very attractive, and the longer half-life is also beneficial. The difference in binding affinity (1.6 kcal/mol) is not large enough to overcome the significant advantages of Ligand B in ADME properties, especially considering the importance of BBB penetration for a CNS target. The negative solubility and Caco-2 values are concerning for both, but the other properties of Ligand B are more favorable overall.

Output:
1
2025-04-17 07:37:52,706 - INFO - Reasoning:

Let's analyze Ligand A and Ligand B based on the provided guidelines, prioritizing GPCR-specific properties (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (355.825 and 365.499 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (81.99) is slightly higher than Ligand B (78.51), but both are below the 90 A^2 threshold desirable for CNS targets.

**logP:** Ligand A (3.244) is within the optimal 1-3 range, while Ligand B (1.94) is at the lower end, potentially impacting permeability.

**H-Bond Donors/Acceptors:** Both have acceptable HBD counts (2). Ligand B has a slightly higher HBA count (4 vs 3 for A), but both are below the 10 threshold.

**QED:** Both ligands have reasonable QED scores (0.863 and 0.691), indicating good drug-like properties.

**DILI:** Ligand A (63.862) has a higher DILI risk than Ligand B (33.501). This is a significant negative for Ligand A.

**BBB:** Ligand A (56.844) and Ligand B (62.97) both have reasonable BBB penetration, but Ligand B is slightly better. A value >70 is highly desirable for CNS targets, and neither quite reaches that.

**Caco-2 Permeability:** Ligand A (-4.573) has poor Caco-2 permeability, while Ligand B (-5.179) is also poor. Both are negative values, indicating low permeability.

**Aqueous Solubility:** Ligand A (-5.36) has worse solubility than Ligand B (-2.178).

**hERG:** Both ligands have low hERG inhibition liability (0.584 and 0.391), which is good.

**Microsomal Clearance:** Ligand A (51.763) has higher microsomal clearance than Ligand B (36.809), indicating lower metabolic stability.

**In vitro Half-Life:** Ligand B (15.574 hours) has a longer half-life than Ligand A (30.747 hours). This is a positive for Ligand B.

**P-gp Efflux:** Ligand A (0.092) has lower P-gp efflux than Ligand B (0.149), which is beneficial for CNS penetration.

**Binding Affinity:** Ligand B (-7.4 kcal/mol) has significantly better binding affinity than Ligand A (-9.4 kcal/mol). This is a crucial advantage, exceeding the 1.5 kcal/mol difference threshold.

**Overall Assessment:**

Ligand B is the more promising candidate. While both have some drawbacks, Ligand B's superior binding affinity, lower DILI risk, better half-life, and acceptable BBB penetration outweigh its slightly lower logP and higher P-gp efflux. Ligand A's poor Caco-2 permeability and higher DILI risk are significant concerns. The substantial affinity difference makes Ligand B the clear choice despite the other factors.

Output:
1
2025-04-17 07:37:52,706 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (364.511 and 355.463 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (58.64) is significantly better than Ligand B (69.12). For CNS targets, we want TPSA <= 90, and ideally closer to 60. Ligand A is much closer to this ideal.

**3. logP:** Both ligands have good logP values (2.84 and 3.215), falling within the optimal 1-3 range.

**4. H-Bond Donors:** Both have 1 HBD, which is acceptable.

**5. H-Bond Acceptors:** Both have 4 HBA, which is acceptable.

**6. QED:** Ligand A (0.874) has a better QED score than Ligand B (0.555), indicating better overall drug-likeness.

**7. DILI:** Ligand A (26.406) has a much lower DILI risk than Ligand B (39.201). Both are below the 40 threshold, but A is preferable.

**8. BBB:** This is a critical parameter for a CNS target like DRD2. Ligand A (75.107) has a significantly higher BBB percentile than Ligand B (46.258). A value >70 is desirable, and A is much closer to this.

**9. Caco-2:** Both have negative values, which is unusual and suggests poor permeability. However, the scale isn't specified, so it's hard to interpret.

**10. Solubility:** Both have negative values, suggesting poor solubility. Again, the scale is unspecified.

**11. hERG:** Both ligands have low hERG inhibition liability (0.576 and 0.795), which is good.

**12. Cl_mic:** Ligand A (30.027) has a lower microsomal clearance than Ligand B (65.384), indicating better metabolic stability.

**13. t1/2:** Ligand A (11.478) has a shorter half-life than Ligand B (25.593), but both are reasonable.

**14. Pgp:** Ligand A (0.383) has lower P-gp efflux liability than Ligand B (0.444), which is favorable for CNS penetration.

**15. Binding Affinity:** Ligand B (-7.3 kcal/mol) has a slightly better binding affinity than Ligand A (-8.1 kcal/mol). While affinity is crucial, the difference of 0.8 kcal/mol is not substantial enough to outweigh the significant advantages of Ligand A in other key ADME properties, especially BBB penetration and DILI risk.

**Overall Assessment:**

Ligand A is significantly better overall. It has a better QED score, lower DILI risk, much better BBB penetration, lower P-gp efflux, and better metabolic stability. While Ligand B has slightly better binding affinity, the other advantages of Ligand A make it a more promising drug candidate for a CNS target like DRD2.

Output:
1
2025-04-17 07:37:52,706 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (361.32) is slightly higher than Ligand B (338.455), but both are acceptable.

**TPSA:** Ligand A (88.69) is better than Ligand B (58.95) as it is closer to the ideal range for CNS targets (<90). Ligand B is quite low, which *could* indicate reduced hydrogen bonding and potentially lower specificity.

**logP:** Both ligands have good logP values (Ligand A: 1.682, Ligand B: 1.988), falling within the optimal range of 1-3.

**H-Bond Donors/Acceptors:** Ligand A has 3 HBD and 4 HBA, while Ligand B has 2 HBD and 4 HBA. Both are within acceptable limits (HBD <= 5, HBA <= 10).

**QED:** Both ligands have good QED scores (Ligand A: 0.697, Ligand B: 0.847), indicating good drug-like properties. Ligand B is slightly better.

**DILI:** Ligand A has a DILI risk of 75.029, which is concerning (approaching the high-risk threshold of >60). Ligand B has a much lower DILI risk of 13.3, which is excellent.

**BBB:** Both ligands have excellent BBB penetration (Ligand A: 77.705, Ligand B: 77.007), exceeding the desirable threshold of >70 for CNS targets.

**Caco-2 Permeability:** Ligand A (-4.859) has poor Caco-2 permeability, while Ligand B (-5.533) is also poor. Both are negative values, suggesting limited intestinal absorption. This is less critical for a CNS target where direct delivery is possible.

**Aqueous Solubility:** Ligand A (-3.247) has poor aqueous solubility, while Ligand B (-1.185) is also poor. Solubility is not a major concern given the BBB penetration.

**hERG Inhibition:** Both ligands have very low hERG inhibition risk (Ligand A: 0.254, Ligand B: 0.686), which is excellent.

**Microsomal Clearance:** Ligand A (2.848) has lower microsomal clearance than Ligand B (3.597), indicating better metabolic stability.

**In vitro Half-Life:** Ligand A (11.558) has a longer in vitro half-life than Ligand B (-1.544), which is a significant advantage.

**P-gp Efflux:** Ligand A (0.02) has very low P-gp efflux, which is excellent for CNS penetration. Ligand B (0.224) is also low, but higher than Ligand A.

**Binding Affinity:** Both ligands have very similar and excellent binding affinities (Ligand A: -9.5 kcal/mol, Ligand B: -9.4 kcal/mol). The difference is negligible.

**Overall Assessment:**

Ligand B is preferable due to its significantly lower DILI risk. While Ligand A has a slightly better metabolic stability and P-gp efflux profile, the DILI risk is a major concern. Both have good BBB penetration and binding affinity. The slightly better QED score of Ligand B also contributes to its favorability.

Output:
1
2025-04-17 07:37:52,706 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (361.829 and 368.499 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (71.53) is significantly better than Ligand B (78.87). For CNS targets, we want TPSA <= 90, and A is closer to the optimal <= 60 range. B is pushing the upper limit.

**3. logP:** Ligand A (3.233) is within the optimal 1-3 range. Ligand B (1.433) is a bit low, potentially hindering membrane permeability.

**4. H-Bond Donors:** Ligand A (1) is good. Ligand B (2) is acceptable.

**5. H-Bond Acceptors:** Ligand A (4) is good. Ligand B (5) is acceptable.

**6. QED:** Both ligands have reasonable QED values (0.857 and 0.728), indicating good drug-like properties.

**7. DILI:** Ligand A (77.588) has a higher DILI risk than Ligand B (23.342). This is a significant drawback for Ligand A.

**8. BBB:** Ligand A (53.276) has a lower BBB penetration percentile than Ligand B (43.311). While neither is ideal (>70), B is slightly better.

**9. Caco-2 Permeability:** Ligand A (-4.572) has *much* better Caco-2 permeability than Ligand B (-5.016). This suggests better intestinal absorption for A.

**10. Aqueous Solubility:** Ligand A (-3.97) has slightly better solubility than Ligand B (-1.382).

**11. hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.34 and 0.304).

**12. Microsomal Clearance:** Ligand A (78.046) has higher microsomal clearance than Ligand B (33.628), indicating lower metabolic stability.

**13. In vitro Half-Life:** Ligand A (38.959) has a longer half-life than Ligand B (15.185).

**14. P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.086 and 0.098).

**15. Binding Affinity:** Both ligands have excellent binding affinity (-8.9 and -8.0 kcal/mol). The difference of 0.9 kcal/mol is not substantial enough to outweigh other factors.

**Overall Assessment:**

Ligand A has better TPSA, Caco-2 permeability, solubility, and half-life. However, it suffers from significantly higher DILI risk and lower BBB penetration, and higher microsomal clearance. Ligand B has a lower DILI risk, slightly better BBB, and lower clearance, but weaker Caco-2 permeability and a slightly lower logP.

Given the GPCR-specific priorities, and particularly the importance of BBB penetration for a CNS target like DRD2, Ligand B is the more promising candidate. While its logP is a bit low, the significantly lower DILI risk and slightly better BBB penetration outweigh the benefits of A's permeability. The affinity difference is not large enough to change this conclusion.

Output:
1
2025-04-17 07:37:52,706 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (346.471 Da) is slightly lower, which could be beneficial for permeability.

**TPSA:** Ligand A (78.43) is better than Ligand B (43.78) as it is closer to the ideal range for CNS targets (<=90). Ligand B is excellent.

**logP:** Both ligands have good logP values (Ligand A: 1.593, Ligand B: 2.334), falling within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A has 3 HBD and 3 HBA, while Ligand B has 1 HBD and 3 HBA. Both are within acceptable limits.

**QED:** Both ligands have similar QED values (Ligand A: 0.683, Ligand B: 0.693), indicating good drug-likeness.

**DILI:** Ligand A (23.032) has a significantly lower DILI risk than Ligand B (8.569), which is a strong advantage.

**BBB:** Ligand B (83.404) has a much higher BBB penetration percentile than Ligand A (61.807). This is a critical factor for a CNS target like DRD2.

**Caco-2 Permeability:** Ligand A (-4.885) has a lower Caco-2 permeability than Ligand B (-4.488), suggesting potentially poorer intestinal absorption.

**Aqueous Solubility:** Ligand A (-3.375) has lower aqueous solubility than Ligand B (-2.293).

**hERG Inhibition:** Ligand A (0.133) has a lower hERG inhibition liability than Ligand B (0.723), which is a positive sign for cardiac safety.

**Microsomal Clearance:** Ligand A (14.563) has a higher microsomal clearance than Ligand B (8.668), suggesting lower metabolic stability.

**In vitro Half-Life:** Ligand B (25.253) has a significantly longer in vitro half-life than Ligand A (-3.314), which is desirable.

**P-gp Efflux:** Ligand A (0.04) shows lower P-gp efflux liability than Ligand B (0.154), which is beneficial for CNS exposure.

**Binding Affinity:** Ligand A (-8.7 kcal/mol) has a slightly better binding affinity than Ligand B (-6.9 kcal/mol). This 1.8 kcal/mol difference is substantial and could outweigh some ADME drawbacks.

**Overall Assessment:**

Ligand A has advantages in binding affinity, DILI risk, and P-gp efflux. However, Ligand B excels in BBB penetration, in vitro half-life, and has a better Caco-2 permeability and solubility. The superior BBB penetration of Ligand B is crucial for a CNS target. While Ligand A's affinity is better, the difference might be overcome with further optimization of Ligand B. The better metabolic stability (lower Cl_mic, longer t1/2) of Ligand B is also a significant advantage.

Output:
1
2025-04-17 07:37:52,706 - INFO - Batch 381 complete. Total preferences: 6096
2025-04-17 07:37:52,706 - INFO - Processing batch 382/512...
2025-04-17 07:38:38,252 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (356.5) is slightly lower, which could be beneficial for permeability. Ligand B (364.5) is also good.

**TPSA:** Ligand A (81.1) is better than Ligand B (25.4) for CNS penetration, being closer to the <90 A^2 target for CNS targets. Ligand B is exceptionally low, which might raise concerns about solubility.

**logP:** Ligand A (1.64) is within the optimal range (1-3). Ligand B (4.53) is higher, potentially leading to solubility issues and off-target interactions.

**H-Bond Donors:** Ligand A (2) is good. Ligand B (0) is also acceptable, but a lack of HBDs can sometimes hinder solubility.

**H-Bond Acceptors:** Both ligands have 4 HBAs, which is within the acceptable limit of <=10.

**QED:** Both ligands have good QED values (A: 0.658, B: 0.753), indicating drug-like properties.

**DILI:** Ligand A (5.97) has a much lower DILI risk than Ligand B (23.73). This is a significant advantage for Ligand A.

**BBB:** Ligand B (95.58) has a significantly higher BBB penetration score than Ligand A (61.23). This is a major advantage for Ligand B, crucial for a CNS target like DRD2.

**Caco-2 Permeability:** Ligand A (-4.66) has a very poor Caco-2 permeability, which is a major drawback. Ligand B (-4.58) also has poor Caco-2 permeability, but is slightly better than Ligand A.

**Aqueous Solubility:** Ligand A (-1.16) has slightly better solubility than Ligand B (-4.30).

**hERG Inhibition:** Ligand A (0.54) has a lower hERG risk than Ligand B (0.89).

**Microsomal Clearance:** Ligand A (28.26) has lower microsomal clearance, indicating better metabolic stability, than Ligand B (55.07).

**In vitro Half-Life:** Ligand A (-14.01) has a negative half-life, which is not possible. This is a major red flag. Ligand B (2.71) has a short half-life, but is still a plausible value.

**P-gp Efflux:** Ligand A (0.11) has lower P-gp efflux, which is favorable for CNS exposure, than Ligand B (0.67).

**Binding Affinity:** Ligand B (-8.2) has a significantly stronger binding affinity than Ligand A (-7.0). This is a substantial advantage for Ligand B, potentially outweighing some of its ADME drawbacks.

**Overall Assessment:**

Ligand B excels in BBB penetration and binding affinity, which are paramount for a CNS GPCR target. While its logP is a bit high and its half-life is short, the strong affinity could compensate. Ligand A has a better safety profile (lower DILI, hERG) and better metabolic stability, but its extremely poor Caco-2 permeability and impossible half-life are dealbreakers. The significantly stronger binding affinity of Ligand B is a key factor.

Output:
1
2025-04-17 07:38:38,252 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 drug candidates, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (342.395 Da) is slightly lower, which is generally favorable for permeability.

**TPSA:** Ligand A (64.8) is excellent for CNS penetration, well below the 90 A^2 threshold. Ligand B (96.97) is higher, but still potentially acceptable, though less ideal.

**logP:** Ligand A (3.331) is optimal. Ligand B (-0.307) is significantly lower, which is a major concern as it may hinder membrane permeability and reduce brain exposure.

**H-Bond Donors/Acceptors:** Ligand A (0 HBD, 5 HBA) and Ligand B (2 HBD, 5 HBA) are both within acceptable ranges.

**QED:** Both ligands have reasonable QED scores (A: 0.837, B: 0.614), indicating good drug-like properties.

**DILI:** Ligand A (63.513) has a higher DILI risk than Ligand B (35.789), which is a negative.

**BBB:** Ligand A (84.141) has a significantly better BBB percentile than Ligand B (48.895). This is crucial for a CNS target like DRD2.

**Caco-2 Permeability:** Ligand A (-4.492) has poor Caco-2 permeability, while Ligand B (-5.323) is also poor.

**Aqueous Solubility:** Ligand A (-4.799) has poor aqueous solubility, while Ligand B (-1.413) is also poor.

**hERG Inhibition:** Ligand A (0.627) has a lower hERG inhibition risk than Ligand B (0.096), which is a positive.

**Microsomal Clearance:** Ligand A (90.199) has higher microsomal clearance, indicating faster metabolism, than Ligand B (-5.143) which is a negative.

**In vitro Half-Life:** Ligand A (-10.587) has a shorter half-life than Ligand B (-12.63), which is a negative.

**P-gp Efflux:** Ligand A (0.547) has lower P-gp efflux than Ligand B (0.022), which is a positive.

**Binding Affinity:** Both ligands have very similar binding affinities (-8.9 kcal/mol and -9.3 kcal/mol), with Ligand B being slightly better. This difference is unlikely to overcome the significant ADME deficiencies of Ligand B.

**Overall Assessment:**

Ligand A, despite the higher DILI risk and poor solubility/permeability, is the more promising candidate. Its significantly better BBB penetration, optimal logP, and lower P-gp efflux are critical for CNS drug development. While Ligand B has a slightly better binding affinity and lower DILI, its very poor logP and BBB penetration are major drawbacks that are unlikely to be overcome. The poor Caco-2 and solubility of Ligand A could be addressed with formulation strategies.

Output:
1
2025-04-17 07:38:38,252 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 drug candidates, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (363.849 Da) is slightly higher than Ligand B (348.531 Da), but both are acceptable.

**TPSA:** Ligand A (82.23) is better than Ligand B (49.41). For CNS targets, TPSA should be <=90, both are within this range, but A is closer to the upper limit.

**logP:** Ligand A (1.686) is within the optimal range (1-3), while Ligand B (3.914) is approaching the upper limit. Higher logP can lead to off-target effects and solubility issues.

**H-Bond Donors/Acceptors:** Ligand A (0 HBD, 5 HBA) and Ligand B (1 HBD, 2 HBA) both have reasonable numbers of H-bond donors and acceptors, well within the guidelines.

**QED:** Both ligands have acceptable QED values (Ligand A: 0.815, Ligand B: 0.709), indicating good drug-like properties.

**DILI:** Ligand A (48.662) has a slightly higher DILI risk than Ligand B (13.3), but both are below the concerning threshold of 60.

**BBB:** Ligand B (87.01) has a significantly better BBB penetration score than Ligand A (74.758). This is a crucial factor for CNS targets like DRD2.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values, which is unusual and suggests poor permeability. This is a significant drawback for both.

**Aqueous Solubility:** Both ligands have negative solubility values, indicating poor aqueous solubility. This is also a significant drawback for both.

**hERG Inhibition:** Ligand A (0.231) has a lower hERG inhibition liability than Ligand B (0.663), which is preferable.

**Microsomal Clearance:** Ligand B (67.125) has a higher microsomal clearance than Ligand A (40.156), meaning it's metabolized faster. Lower clearance is desirable for longer duration of action.

**In vitro Half-Life:** Ligand A (15.693 hours) has a much longer in vitro half-life than Ligand B (-10.655 hours). This is a significant advantage for Ligand A.

**P-gp Efflux:** Ligand A (0.052) has lower P-gp efflux liability than Ligand B (0.133), which is better for CNS exposure.

**Binding Affinity:** Ligand B (-8.0 kcal/mol) has a stronger binding affinity than Ligand A (-6.6 kcal/mol). This is a substantial difference (1.4 kcal/mol), and can often outweigh other drawbacks.

**Overall Assessment:**

Ligand B has a significantly better binding affinity and BBB penetration, which are critical for a CNS GPCR target. However, it has poorer metabolic stability (higher Cl_mic, shorter t1/2) and higher P-gp efflux. Ligand A has better metabolic stability, P-gp efflux, and hERG profile, but weaker binding affinity and lower BBB penetration.

The stronger binding affinity of Ligand B is a major advantage, and the difference is large enough to potentially overcome the metabolic and efflux liabilities, especially if those can be addressed through further optimization. The BBB score is also excellent. The poor Caco-2 and solubility are concerning for both, but are less critical for a CNS-focused drug.

Output:
1
2025-04-17 07:38:38,252 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (348.443 and 362.499 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (66.92) is slightly higher than Ligand B (64.16), but both are below the 90 A^2 threshold desirable for CNS targets.

**3. logP:** Ligand A (1.581) is within the optimal range (1-3), while Ligand B (3.237) is at the higher end. While still acceptable, higher logP can sometimes lead to off-target effects.

**4. H-Bond Donors:** Both ligands have 0 HBD, which is good.

**5. H-Bond Acceptors:** Ligand A has 4 HBA, and Ligand B has 6. Both are within the acceptable limit of 10.

**6. QED:** Both ligands have good QED scores (0.54 and 0.721, respectively), indicating drug-like properties. Ligand B is slightly better.

**7. DILI:** Both ligands have acceptable DILI risk (Ligand A: 49.903, Ligand B: 43.66), below the 60 threshold. Ligand B is marginally better.

**8. BBB:** Both ligands have excellent BBB penetration (Ligand A: 76.968, Ligand B: 78.558), exceeding the 70% threshold for CNS targets. Ligand B is slightly better.

**9. Caco-2:** Both ligands have negative Caco-2 values (-3.992 and -5.096). This is unusual and suggests poor permeability. However, Caco-2 values can be unreliable and are often used as a general indicator.

**10. Solubility:** Both ligands have negative solubility values (-2.705 and -2.826). This suggests poor aqueous solubility, which could be a significant issue for bioavailability.

**11. hERG:** Both ligands have very low hERG inhibition risk (0.136 and 0.215).

**12. Cl_mic:** Ligand A (94.699) has a higher microsomal clearance than Ligand B (89.818), suggesting lower metabolic stability.

**13. t1/2:** Ligand A has a much longer in vitro half-life (-21.491 hours) than Ligand B (-1.159 hours). This is a significant advantage for Ligand A.

**14. Pgp:** Both ligands have low P-gp efflux liability (0.116 and 0.273).

**15. Binding Affinity:** Ligand B (-7.2 kcal/mol) has a significantly stronger binding affinity than Ligand A (-6.7 kcal/mol). This 0.5 kcal/mol difference is substantial and can outweigh some ADME drawbacks.

**Overall Assessment:**

While Ligand A has a better half-life, Ligand B excels in several key areas: slightly better BBB penetration, lower DILI risk, a significantly stronger binding affinity, and a better QED score. The poor solubility and Caco-2 values are concerning for both, but the superior affinity of Ligand B is a major advantage for a GPCR target like DRD2. The stronger binding is likely to drive efficacy and could compensate for permeability issues, especially if formulation strategies can address the solubility concerns.

Output:
1
2025-04-17 07:38:38,252 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 drug candidates, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (353.419 and 352.479 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (104.9) is slightly above the preferred <90 for CNS targets, but still reasonable. Ligand B (81.75) is well within the desired range. This favors Ligand B.

**3. logP:** Ligand A (1.091) is at the lower end of optimal, potentially impacting permeability. Ligand B (0.349) is quite low, raising concerns about membrane permeability.

**4. H-Bond Donors:** Both ligands have 2 HBD, which is acceptable.

**5. H-Bond Acceptors:** Ligand A has 6 HBA, within the acceptable range. Ligand B has 4 HBA, also good.

**6. QED:** Both ligands have similar QED values (0.689 and 0.676), indicating good drug-like properties.

**7. DILI:** Ligand A (55.448) has a higher DILI risk than Ligand B (11.283). This is a significant advantage for Ligand B.

**8. BBB:** Both ligands have similar BBB penetration (50.523 and 52.889). While not exceptional (>70), they are acceptable.

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.932 and -4.914), which is unusual and suggests poor permeability. This is a concern for both.

**10. Aqueous Solubility:** Both ligands have negative solubility values (-2.055 and -1.24), indicating poor aqueous solubility. This is a drawback for both.

**11. hERG:** Both ligands have very low hERG inhibition risk (0.142 and 0.122).

**12. Microsomal Clearance:** Ligand A (17.211) has a higher microsomal clearance than Ligand B (0.455), suggesting lower metabolic stability. Ligand B is significantly better here.

**13. In vitro Half-Life:** Ligand A (26.094) has a longer half-life than Ligand B (1.541). This is a positive for Ligand A.

**14. P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.121 and 0.002).

**15. Binding Affinity:** Ligand B (-8.0 kcal/mol) has a significantly stronger binding affinity than Ligand A (-7.3 kcal/mol). This >1.5 kcal/mol difference is a major advantage for Ligand B, potentially outweighing some of its ADME drawbacks.

**Overall Assessment:**

Ligand B is the better candidate. While both have issues with Caco-2 permeability and solubility, Ligand B boasts a significantly stronger binding affinity, a much lower DILI risk, and better metabolic stability (lower Cl_mic). The slightly lower TPSA of Ligand B is also favorable for CNS penetration. The longer half-life of Ligand A is a benefit, but the superior affinity and safety profile of Ligand B are more critical for a GPCR target like DRD2.

Output:
1
2025-04-17 07:38:38,253 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (366.418 and 346.431 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (85.25) is better than Ligand B (67.67) as both are below the 90 A^2 threshold for CNS targets.

**logP:** Both ligands have good logP values (1.244 and 1.484), falling within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A has 2 HBD and 6 HBA, while Ligand B has 0 HBD and 5 HBA. Both are within acceptable limits.

**QED:** Both ligands have reasonable QED scores (0.806 and 0.758), indicating good drug-likeness.

**DILI:** Ligand A (76.464) has a higher DILI risk than Ligand B (38.116). This is a significant drawback for Ligand A.

**BBB:** Both ligands have similar and acceptable BBB penetration (66.576 and 66.615).

**Caco-2 Permeability:** Both ligands have negative Caco-2 values which is unusual.

**Aqueous Solubility:** Both ligands have negative solubility values, which is also unusual.

**hERG:** Both ligands have low hERG inhibition liability (0.183 and 0.252).

**Microsomal Clearance:** Both ligands have similar microsomal clearance values (16.832 and 17.859).

**In vitro Half-Life:** Ligand B (9.751) has a significantly longer in vitro half-life than Ligand A (45.104).

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.037 and 0.041).

**Binding Affinity:** Ligand B (-8.2 kcal/mol) has a stronger binding affinity than Ligand A (-7.2 kcal/mol). The difference of 1.0 kcal/mol is significant.

**Overall Assessment:**

Ligand B is the more promising candidate. While both meet many of the basic criteria, Ligand B has a significantly lower DILI risk and a stronger binding affinity. The longer half-life is also a benefit. The negative Caco-2 and solubility values are concerning for both, but the stronger binding and lower toxicity of Ligand B outweigh these concerns.

Output:
1
2025-04-17 07:38:38,253 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (345.389 Da) is slightly lower, which can be favorable for permeability. Ligand B (385.917 Da) is also acceptable.

**TPSA:** Ligand A (38.33) is excellent, well below the 90 A^2 threshold for CNS targets. Ligand B (80.32) is higher, but still potentially acceptable, though less ideal for brain penetration.

**logP:** Ligand A (3.823) is at the higher end of the optimal range (1-3), but still acceptable. Ligand B (2.272) is well within the optimal range.

**H-Bond Donors/Acceptors:** Ligand A (HBD=1, HBA=2) is very favorable. Ligand B (HBD=2, HBA=5) is also reasonable, but has more HBA which could slightly hinder permeability.

**QED:** Ligand A (0.915) has a very high drug-likeness score. Ligand B (0.752) is still good, but lower than Ligand A.

**DILI:** Both ligands have DILI risks above the preferred <40, with Ligand A at 61.691 and Ligand B at 67.507. This is a concern for both, but not a deciding factor at this stage.

**BBB:** Ligand A (94.106) has excellent predicted BBB penetration, exceeding the 70% threshold. Ligand B (51.881) is significantly lower, suggesting poor brain penetration. This is a *critical* difference for a CNS target like DRD2.

**Caco-2 Permeability:** Ligand A (-4.545) has poor Caco-2 permeability. Ligand B (-5.372) is also poor.

**Aqueous Solubility:** Ligand A (-4.508) has poor aqueous solubility. Ligand B (-3.296) is slightly better, but still poor.

**hERG Inhibition:** Ligand A (0.885) has a moderate hERG risk. Ligand B (0.241) has a very low hERG risk, which is a significant advantage.

**Microsomal Clearance:** Ligand A (41.802) has moderate clearance. Ligand B (27.126) has lower clearance, indicating better metabolic stability.

**In vitro Half-Life:** Ligand A (13.263) has a relatively short half-life. Ligand B (41.049) has a much longer half-life, which is preferable.

**P-gp Efflux:** Ligand A (0.716) has moderate P-gp efflux. Ligand B (0.056) has very low P-gp efflux, which is a significant advantage for CNS penetration.

**Binding Affinity:** Ligand A (-9.8 kcal/mol) has a significantly stronger binding affinity than Ligand B (-7.6 kcal/mol). This is a substantial advantage, potentially outweighing some of the ADME drawbacks.

**Overall Assessment:**

Despite Ligand A's superior binding affinity, Ligand B is the more promising candidate. The key factors driving this decision are:

*   **BBB Penetration:** Ligand A's excellent affinity is overshadowed by its significantly better BBB penetration (94.106% vs 51.881%). For a CNS target, this is paramount.
*   **P-gp Efflux:** Ligand B has much lower P-gp efflux, further enhancing its potential to reach the brain.
*   **Metabolic Stability & Half-Life:** Ligand B's lower clearance and longer half-life are favorable.
*   **hERG Risk:** Ligand B has a much lower hERG risk.

While Ligand A has a better affinity, the ADME properties of Ligand B are much more favorable for a CNS-active drug. The 2.2 kcal/mol difference in affinity can potentially be optimized in subsequent iterations of drug design, while improving BBB penetration is often more challenging.

Output:
1
2025-04-17 07:38:38,253 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (341.43 and 347.463 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (45.23) is significantly better than Ligand B (99.77). For CNS targets, TPSA should be <= 90, and A is comfortably within that range, while B is above. This is a major advantage for A.

**logP:** Ligand A (4.13) is slightly higher than the optimal 1-3 range, but still acceptable. Ligand B (1.742) is a bit low, potentially hindering permeation.

**H-Bond Donors/Acceptors:** Ligand A (HBD=1, HBA=2) is preferable to Ligand B (HBD=3, HBA=4). Both are within acceptable limits, but fewer H-bonds generally improve permeability.

**QED:** Ligand A (0.889) has a much better QED score than Ligand B (0.561), indicating a more drug-like profile.

**DILI:** Ligand A (29.546) has a lower DILI risk than Ligand B (22.8), making it safer.

**BBB:** Ligand A (89.57) has a significantly higher BBB penetration percentile than Ligand B (64.017). This is *critical* for a CNS target like DRD2.

**Caco-2 Permeability:** Ligand A (-4.447) is better than Ligand B (-5.417), indicating better intestinal absorption.

**Aqueous Solubility:** Ligand A (-4.075) is better than Ligand B (-2.38), suggesting better formulation potential.

**hERG Inhibition:** Ligand A (0.656) has a lower hERG inhibition liability than Ligand B (0.046), reducing cardiotoxicity risk.

**Microsomal Clearance:** Ligand A (50.516) has a higher microsomal clearance than Ligand B (27.571), meaning it's less metabolically stable. This is a drawback for A.

**In vitro Half-Life:** Ligand A (4.429) has a shorter half-life than Ligand B (-19.949), which is a negative for A.

**P-gp Efflux:** Ligand A (0.157) has lower P-gp efflux liability than Ligand B (0.008), which is beneficial for CNS exposure.

**Binding Affinity:** Ligand A (-9.5 kcal/mol) has a slightly better binding affinity than Ligand B (-8.2 kcal/mol). While both are good, the 1.3 kcal/mol difference is significant.

**Overall Assessment:**

Ligand A is clearly superior. Its excellent TPSA, QED, BBB, solubility, and hERG profile, combined with its slightly better affinity, outweigh its drawbacks in clearance and half-life. The high BBB penetration is particularly important for a CNS target. Ligand B's higher TPSA and lower BBB are significant liabilities.

Output:
1
2025-04-17 07:38:38,253 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (350.459 and 366.487 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (67.87) is significantly better than Ligand B (85.25). For CNS targets, we want TPSA <= 90, and A is comfortably within that range, while B is approaching the upper limit.

**3. logP:** Both ligands have good logP values (1.335 and 1.192), falling within the optimal 1-3 range.

**4. H-Bond Donors:** Ligand A (1) is preferable to Ligand B (2). Lower HBD generally improves permeability.

**5. H-Bond Acceptors:** Ligand A (4) is preferable to Ligand B (6). Lower HBA generally improves permeability.

**6. QED:** Both ligands have acceptable QED values (0.812 and 0.765), indicating good drug-like properties.

**7. DILI:** Ligand A (20.9) has a much lower DILI risk than Ligand B (73.013). This is a significant advantage for A.

**8. BBB:** Ligand A (63.164) has a better BBB percentile than Ligand B (44.668). While >70 is desirable, A is still reasonably good, and significantly better than B. This is crucial for a CNS target like DRD2.

**9. Caco-2 Permeability:** Ligand A (-4.846) is better than Ligand B (-5.35), indicating better intestinal absorption, although both are negative values which is not ideal.

**10. Aqueous Solubility:** Ligand A (-1.469) is better than Ligand B (-3.169).

**11. hERG Inhibition:** Both ligands have low hERG inhibition liability (0.189 and 0.111), which is good.

**12. Microsomal Clearance:** Ligand A (9.74) has a lower microsomal clearance than Ligand B (29.687), suggesting better metabolic stability.

**13. In vitro Half-Life:** Ligand B (9.83) has a slightly longer half-life than Ligand A (8.589), but the difference is not substantial.

**14. P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.041 and 0.078), which is excellent.

**15. Binding Affinity:** Ligand A (-8.4 kcal/mol) has a slightly better binding affinity than Ligand B (-7.9 kcal/mol). While both are good, the 0.5 kcal/mol difference is meaningful.

**Overall Assessment:**

Ligand A consistently outperforms Ligand B across most critical parameters, especially those prioritized for GPCRs targeting the CNS. It has a lower TPSA, lower DILI risk, better BBB penetration, better solubility, lower clearance, and slightly better binding affinity. While Ligand B has a slightly longer half-life, the other advantages of Ligand A outweigh this minor difference.

Output:
1
2025-04-17 07:38:38,253 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (348.451 and 370.471 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (82.5) is better than Ligand B (88.85). Both are below the 90 A^2 threshold desirable for CNS targets, but A is closer to the optimal range.

**logP:** Both ligands have good logP values (2.267 and 1.612), falling within the 1-3 optimal range. Ligand A is slightly higher, potentially aiding membrane permeability.

**H-Bond Donors/Acceptors:** Ligand A (2 HBD, 4 HBA) and Ligand B (1 HBD, 5 HBA) both have acceptable numbers of H-bond donors and acceptors.

**QED:** Both ligands have reasonable QED scores (0.879 and 0.788), indicating good drug-like properties.

**DILI:** Ligand A (60.489) has a higher DILI risk than Ligand B (44.048). This is a negative for Ligand A.

**BBB:** Ligand B (82.513) has a significantly better BBB penetration percentile than Ligand A (68.941). This is a critical advantage for a CNS target like DRD2.

**Caco-2 Permeability:** Both ligands have negative Caco-2 permeability values (-4.864 and -4.819), which is unusual and suggests a potential issue with the model or data. However, the values are very similar.

**Aqueous Solubility:** Both ligands have negative solubility values (-3.247 and -3.235), again suggesting a potential issue with the model or data. The values are very similar.

**hERG Inhibition:** Ligand A (0.34) has a slightly lower hERG inhibition liability than Ligand B (0.548), which is preferable.

**Microsomal Clearance:** Ligand B (36.834) has a higher microsomal clearance than Ligand A (26.08), indicating faster metabolism and potentially lower *in vivo* exposure.

**In vitro Half-Life:** Ligand A (12.682) has a longer in vitro half-life than Ligand B (1.291), which is a positive.

**P-gp Efflux:** Ligand A (0.04) has a much lower P-gp efflux liability than Ligand B (0.066), which is beneficial for CNS penetration.

**Binding Affinity:** Ligand B (-8.1 kcal/mol) has a slightly better binding affinity than Ligand A (-9.0 kcal/mol). While A is better, the difference is small and may not be decisive.

**Overall Assessment:**

Ligand B is the stronger candidate. While Ligand A has a slightly better binding affinity and metabolic stability, Ligand B's significantly higher BBB penetration (82.513 vs. 68.941) and lower DILI risk are crucial advantages for a CNS-targeting drug like a DRD2 ligand. The lower P-gp efflux for Ligand A is also positive, but the BBB difference is more impactful.

Output:
1
2025-04-17 07:38:38,253 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B based on the provided guidelines, prioritizing GPCR-specific properties (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (345.483 Da) is slightly lower, which *could* be beneficial for permeability, but both are acceptable.

**TPSA:** Both ligands have TPSA values above the optimal 90 A^2 for CNS targets. Ligand A (47.56 A^2) is better than Ligand B (49.41 A^2), but both are reasonably close and not disqualifying.

**logP:** Both ligands have logP values within the optimal range (1-3). Ligand A (4.248) is slightly higher, potentially raising concerns about solubility and off-target effects, but still within an acceptable range. Ligand B (3.773) is better.

**H-Bond Donors/Acceptors:** Both have acceptable HBD (1) and HBA (4 for A, 3 for B) counts.

**QED:** Both ligands have good QED scores (0.783 and 0.84), indicating good drug-like properties.

**DILI:** Ligand A (20.706) has a significantly lower DILI risk than Ligand B (62.893). This is a major advantage for Ligand A.

**BBB:** Ligand B (89.492) has a much higher BBB penetration percentile than Ligand A (50.872). This is a critical advantage for a CNS target like DRD2.

**Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and potentially indicates issues with the prediction method or the compounds themselves. It's hard to draw conclusions from this.

**Aqueous Solubility:** Both ligands have very poor predicted aqueous solubility (-4.518 and -4.949). This is a concern for both, but might be mitigated by formulation strategies.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.67 and 0.409).

**Microsomal Clearance:** Ligand B (80.582) has a higher microsomal clearance than Ligand A (52.355), indicating faster metabolism and potentially lower in vivo exposure.

**In vitro Half-Life:** Ligand B (28.182 hours) has a significantly longer half-life than Ligand A (3.044 hours). This is a substantial advantage for Ligand B.

**P-gp Efflux:** Ligand A (0.463) has lower P-gp efflux liability than Ligand B (0.318), which is favorable for CNS penetration.

**Binding Affinity:** Ligand B (-9.1 kcal/mol) has a slightly better binding affinity than Ligand A (-8.7 kcal/mol). This difference is significant, as a >1.5 kcal/mol advantage can outweigh other drawbacks.

**Overall Assessment:**

While Ligand A has a much better safety profile (lower DILI, lower P-gp efflux), Ligand B excels in key GPCR-specific properties for CNS targets: significantly higher BBB penetration, longer half-life, and slightly better binding affinity. The higher DILI risk for Ligand B is a concern, but the superior BBB and affinity are crucial for DRD2 targeting. The solubility issues are present in both, but can potentially be addressed during formulation.

Output:
1
2025-04-17 07:38:38,253 - INFO - Reasoning:

Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (361.389 and 368.543 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (87.74) is better than Ligand B (58.64). Both are below the 90 A^2 threshold for CNS targets, but A is closer to the upper limit.

**3. logP:** Ligand B (2.462) is optimal (1-3), while Ligand A (0.433) is quite low, potentially hindering membrane permeability. This is a significant drawback for A.

**4. H-Bond Donors:** Ligand A (2) and Ligand B (1) are both acceptable (<=5).

**5. H-Bond Acceptors:** Both ligands (A: 4, B: 4) are within the acceptable range (<=10).

**6. QED:** Both ligands have good QED values (A: 0.718, B: 0.669), indicating drug-like properties.

**7. DILI:** Both ligands have acceptable DILI risk (A: 30.361, B: 36.409), below the 40% threshold.

**8. BBB:** Ligand A (73.943) has a better BBB percentile than Ligand B (64.211). While both are reasonably good, A is closer to the desirable >70% for CNS targets.

**9. Caco-2:** Both have negative Caco-2 values, which is unusual and suggests poor permeability. However, the scale is not specified, so it is hard to interpret.

**10. Solubility:** Both have negative solubility values, which is also unusual.

**11. hERG:** Both ligands have low hERG inhibition liability (A: 0.131, B: 0.443), which is favorable.

**12. Cl_mic:** Ligand A (0.005) has *much* lower microsomal clearance than Ligand B (59.764), indicating significantly better metabolic stability. This is a major advantage for A.

**13. t1/2:** Ligand A (-8.295) has a very negative in vitro half-life, which is problematic. Ligand B (-1.986) is also negative, but less so.

**14. Pgp:** Ligand A (0.014) has significantly lower P-gp efflux liability than Ligand B (0.171), which is crucial for CNS penetration.

**15. Binding Affinity:** Ligand B (-7.8 kcal/mol) has slightly better binding affinity than Ligand A (-7.5 kcal/mol). While the difference is not huge, it's a factor.

**Overall Assessment:**

Despite the slightly better affinity of Ligand B, Ligand A is the more promising candidate. The critical advantages of Ligand A are its significantly lower P-gp efflux, much lower microsomal clearance (better metabolic stability), and better BBB penetration. While its logP is low, the improved CNS penetration properties outweigh this drawback for a CNS target like DRD2. The negative half-life for A is concerning, but could potentially be addressed with structural modifications. The unusual negative values for Caco-2 and solubility are also concerning and need further investigation.

Output:
1
2025-04-17 07:38:38,254 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (346.471 and 378.925 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (49.85) is better than Ligand B (40.62). Both are below the 90 A^2 threshold desirable for CNS targets.

**3. logP:** Both ligands have good logP values (2.841 and 3.511), falling within the optimal 1-3 range. Ligand B is slightly higher, which could potentially lead to some off-target effects, but it's not a major concern.

**4. H-Bond Donors:** Both ligands have 0 HBD, which is acceptable.

**5. H-Bond Acceptors:** Ligand A has 4 HBA, and Ligand B has 3. Both are within the acceptable limit of 10.

**6. QED:** Both ligands have good QED scores (0.713 and 0.804), indicating good drug-like properties.

**7. DILI:** Ligand A (13.339) has a significantly better DILI score than Ligand B (37.301). This is a major advantage for Ligand A.

**8. BBB:** Both ligands have excellent BBB penetration (86.274 and 88.135), exceeding the >70% threshold for CNS targets. Ligand B is slightly better.

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.041 and -4.998). This is unusual and suggests poor permeability. However, these values are on a strange scale and might not be directly comparable.

**10. Aqueous Solubility:** Both ligands have very poor aqueous solubility (-2.491 and -4.492). This is a significant drawback for both.

**11. hERG Inhibition:** Both ligands show low hERG inhibition risk (0.571 and 0.659).

**12. Microsomal Clearance:** Ligand A has a high microsomal clearance (98.882), indicating poor metabolic stability. Ligand B has a much lower clearance (43.994), which is a significant advantage.

**13. In vitro Half-Life:** Ligand A has a very short in vitro half-life (1.191 hours), while Ligand B has an even shorter one (0.223 hours). Both are poor.

**14. P-gp Efflux:** Both ligands have low P-gp efflux liability (0.056 and 0.584), which is good for CNS exposure. Ligand A is better.

**15. Binding Affinity:** Ligand B (-8.3 kcal/mol) has a significantly stronger binding affinity than Ligand A (-6.9 kcal/mol). This is a substantial advantage, potentially outweighing some of the ADME drawbacks.

**Overall Assessment:**

Ligand B has a significantly better binding affinity and metabolic stability (lower Cl_mic). Ligand A has a better DILI score and P-gp efflux. Both have poor solubility and short half-lives. Given the GPCR-specific priorities, the strong binding affinity of Ligand B is the most critical factor. While the solubility and half-life are concerning, these can be addressed through formulation or further medicinal chemistry optimization. The DILI risk of Ligand A is good, but the weaker binding makes it less likely to be effective.

Output:
1
2025-04-17 07:38:38,254 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 drug candidates, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (336.395 and 346.515 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (83.12) is better than Ligand B (49.41). For CNS targets, TPSA should be <= 90, both are within this range, but A is closer to the upper limit.

**3. logP:** Both ligands have good logP values (2.487 and 3.355), falling within the optimal 1-3 range. Ligand B is slightly higher, which could potentially lead to solubility issues, but is still acceptable.

**4. H-Bond Donors:** Ligand A has 3 HBD, and Ligand B has 1. Both are within the acceptable limit of <=5.

**5. H-Bond Acceptors:** Ligand A has 3 HBA, and Ligand B has 2. Both are within the acceptable limit of <=10.

**6. QED:** Both ligands have similar QED values (0.802 and 0.768), indicating good drug-like properties.

**7. DILI:** Ligand A has a DILI risk of 63.668, while Ligand B has 23.653. Ligand B is significantly better here, falling well below the 40 threshold for low risk. Ligand A is approaching the higher risk zone.

**8. BBB:** Both ligands have excellent BBB penetration (70.415 and 73.827), exceeding the desirable >70 threshold for CNS targets. Ligand B is slightly better.

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.981 and -4.63). These values are unusual and difficult to interpret without further context. However, they suggest poor permeability.

**10. Aqueous Solubility:** Both ligands have negative solubility values (-4.301 and -3.868). Similar to Caco-2, these are unusual and suggest very poor solubility.

**11. hERG Inhibition:** Both ligands have low hERG inhibition risk (0.361 and 0.487).

**12. Microsomal Clearance:** Ligand A has a lower Cl_mic (21.4) than Ligand B (57.594), indicating better metabolic stability.

**13. In vitro Half-Life:** Ligand A has a longer half-life (56.831) than Ligand B (-2.164). The negative value for Ligand B is concerning and likely an error or indicates very rapid degradation.

**14. P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.03 and 0.299), which is favorable for CNS penetration.

**15. Binding Affinity:** Ligand B has a significantly better binding affinity (-8.2 kcal/mol) than Ligand A (-10.5 kcal/mol). This is a substantial difference, and a >1.5 kcal/mol advantage often outweighs other drawbacks.

**Overall Assessment:**

While Ligand A has better metabolic stability and half-life, Ligand B is superior in several critical areas. Its significantly better binding affinity (-8.2 vs -10.5 kcal/mol) is a major advantage. It also has a much lower DILI risk (23.653 vs 63.668) and slightly better BBB penetration. The negative values for Caco-2 and solubility are concerning for both, but the strong binding affinity of Ligand B makes it more likely to be optimized to address these issues.

Output:
1
2025-04-17 07:38:38,254 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (348.531 and 346.483 Da) fall comfortably within the ideal 200-500 Da range.

**TPSA:** Ligand A (49.41) is significantly better than Ligand B (86.34). For CNS targets, we want TPSA <= 90, and A is much closer to the ideal <=60. B is pushing the upper limit and could have permeability issues.

**logP:** Both ligands have good logP values (3.601 and 2.523), falling within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Both have 1 HBD, which is good. Ligand A has 2 HBA, while Ligand B has 8.  Ligand A is better here; high HBA can sometimes hinder permeability.

**QED:** Both ligands have similar QED values (0.797 and 0.79), indicating good drug-like properties.

**DILI:** Ligand A (21.908) has a much lower DILI risk than Ligand B (43.738). This is a significant advantage for A.

**BBB:** Both ligands have good BBB penetration (77.86% and 71.811%), exceeding the 70% threshold for CNS targets. Ligand A is slightly better.

**Caco-2 Permeability:** Ligand A (-4.772) has a worse Caco-2 permeability than Ligand B (-5.38), indicating lower intestinal absorption. However, for a CNS target, intestinal absorption is less critical than BBB penetration.

**Aqueous Solubility:** Ligand A (-4.601) has a worse aqueous solubility than Ligand B (-2.748). This could pose formulation challenges, but is less critical for a CNS drug that can cross the BBB.

**hERG Inhibition:** Ligand A (0.534) has a lower hERG inhibition liability than Ligand B (0.095), which is a significant safety advantage.

**Microsomal Clearance:** Ligand A (60.274) has a higher microsomal clearance than Ligand B (28.216), indicating lower metabolic stability. This is a drawback for A.

**In vitro Half-Life:** Ligand A (4.41) has a shorter half-life than Ligand B (-3.417), which is a negative for A.

**P-gp Efflux:** Ligand A (0.239) has lower P-gp efflux liability than Ligand B (0.077), which is beneficial for CNS exposure.

**Binding Affinity:** Ligand A (-8.5 kcal/mol) has a slightly better binding affinity than Ligand B (-7.8 kcal/mol). This 1.5 kcal/mol difference is substantial and can outweigh some ADME drawbacks.

**Overall Assessment:**

Ligand A is superior despite some ADME liabilities. The key advantages are its significantly lower DILI risk, lower hERG inhibition, better TPSA, and slightly better binding affinity. While its metabolic stability and half-life are less favorable, the strong binding affinity and favorable CNS penetration profile make it a more promising candidate. Ligand B's higher HBA and worse DILI/hERG profiles are concerning.

Output:
1
2025-04-17 07:38:38,254 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (356.308 and 347.419 Da) fall within the ideal 200-500 Da range.

**TPSA:** Both ligands have TPSA values (96.18 and 96.33) slightly above the optimal <90 for CNS targets, but still reasonable.

**logP:** Ligand A (2.405) is within the optimal 1-3 range. Ligand B (-0.041) is slightly below 1, which could potentially hinder permeation.

**H-Bond Donors/Acceptors:** Both have 2 HBD and are within the acceptable range. Ligand A has 6 HBA, while Ligand B has 5. Both are acceptable.

**QED:** Both ligands have reasonable QED scores (0.873 and 0.731), indicating good drug-like properties.

**DILI:** Ligand A (73.245) has a higher DILI risk than Ligand B (45.25), which is preferable.

**BBB:** Ligand A (71.229) has a better BBB penetration score than Ligand B (59.364). This is a critical factor for a CNS target like DRD2.

**Caco-2 Permeability:** Ligand A (-4.979) has a worse Caco-2 permeability than Ligand B (-5.167), but both are negative values, indicating poor permeability.

**Aqueous Solubility:** Ligand A (-3.825) has slightly worse solubility than Ligand B (-2.232), but both are negative values, indicating poor solubility.

**hERG:** Both ligands have very low hERG inhibition liability (0.164 and 0.067), which is excellent.

**Microsomal Clearance:** Ligand A (21.802) has lower microsomal clearance than Ligand B (30.826), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (15.877 hours) has a significantly longer half-life than Ligand B (3.11 hours), which is a major advantage.

**P-gp Efflux:** Both ligands show very low P-gp efflux liability (0.025 and 0.024).

**Binding Affinity:** Ligand A (-9.4 kcal/mol) has a stronger binding affinity than Ligand B (-8.4 kcal/mol). This 1 kcal/mol difference is substantial and can outweigh some of the ADME drawbacks.

**Overall Assessment:**

Ligand A is superior due to its significantly stronger binding affinity, better BBB penetration, lower DILI risk, and longer half-life. While its Caco-2 permeability and solubility are slightly worse than Ligand B, the substantial improvement in affinity and CNS penetration makes it the more promising candidate for a DRD2-targeting drug. The slightly higher DILI risk is a concern, but manageable with further optimization. Ligand B's low logP is a significant drawback.

Output:
1
2025-04-17 07:38:38,254 - INFO - Batch 382 complete. Total preferences: 6112
2025-04-17 07:38:38,254 - INFO - Processing batch 383/512...
2025-04-17 07:39:20,886 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (349.431 and 350.419 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (91.5) is better than Ligand B (107.55). For CNS targets, we want TPSA <= 90, so Ligand A is closer to this threshold.

**3. logP:** Ligand A (1.077) is within the optimal 1-3 range. Ligand B (0.121) is quite low, potentially hindering permeation.

**4. H-Bond Donors:** Ligand A (2) and Ligand B (3) are both acceptable, being <= 5.

**5. H-Bond Acceptors:** Ligand A (4) and Ligand B (5) are both acceptable, being <= 10.

**6. QED:** Ligand A (0.804) is better than Ligand B (0.675), indicating a more drug-like profile.

**7. DILI:** Ligand B (52.113) has a slightly higher DILI risk than Ligand A (30.787), but both are below the concerning threshold of 60.

**8. BBB:** Ligand A (53.083) has a significantly better BBB penetration percentile than Ligand B (36.371). This is *critical* for a CNS target like DRD2.

**9. Caco-2 Permeability:** Ligand A (-4.781) is better than Ligand B (-5.737), indicating better intestinal absorption.

**10. Aqueous Solubility:** Ligand A (-2.268) is better than Ligand B (-1.614), indicating better solubility.

**11. hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.237 and 0.177).

**12. Microsomal Clearance:** Ligand A (-5.109) has a lower (better) microsomal clearance than Ligand B (2.877), suggesting greater metabolic stability.

**13. In vitro Half-Life:** Ligand A (-13.4) has a longer half-life than Ligand B (25.748).

**14. P-gp Efflux:** Ligand A (0.031) has a much lower P-gp efflux liability than Ligand B (0.015), which is beneficial for CNS exposure.

**15. Binding Affinity:** Ligand B (-8.4 kcal/mol) has a slightly better binding affinity than Ligand A (-7.6 kcal/mol). While a 0.8 kcal/mol difference is noticeable, the ADME properties of Ligand A are significantly superior.

**Overall Assessment:**

Ligand A consistently outperforms Ligand B across most crucial ADME properties, particularly BBB penetration, logP, P-gp efflux, and metabolic stability. While Ligand B has a slightly better binding affinity, the superior ADME profile of Ligand A, especially its BBB score, makes it a much more promising drug candidate for a CNS target like DRD2. The difference in affinity is unlikely to overcome the significant ADME advantages of Ligand A.

Output:
1
2025-04-17 07:39:20,887 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (347.423 Da) is slightly lower, which could be beneficial for permeability, while Ligand B (370.446 Da) is also well within range.

**TPSA:** Ligand A (116.11) is higher than Ligand B (70.08). For CNS targets, TPSA < 90 is preferred. Ligand B is significantly better in this regard, suggesting better CNS penetration potential.

**logP:** Both ligands have good logP values (Ligand A: 2.295, Ligand B: 1.221), falling within the optimal 1-3 range. Ligand A is slightly higher, which might lead to some off-target interactions, but both are acceptable.

**H-Bond Donors/Acceptors:** Both ligands have 1 HBD and a reasonable number of HBAs (Ligand A: 6, Ligand B: 5). Both satisfy the criteria of <=5 HBD and <=10 HBA.

**QED:** Ligand B (0.865) has a significantly higher QED score than Ligand A (0.498), indicating a more drug-like profile.

**DILI:** Both ligands have low DILI risk (Ligand A: 38.736, Ligand B: 37.767), both below the 40 threshold.

**BBB:** Ligand B (80.07) has a much higher BBB percentile than Ligand A (44.591). This is a crucial advantage for a CNS target like DRD2, as it suggests better brain penetration.

**Caco-2 Permeability:** Ligand A (-5.011) has a negative Caco-2 value, which is unusual and suggests poor permeability. Ligand B (-4.478) is also negative, but less so.

**Aqueous Solubility:** Both ligands have poor aqueous solubility (Ligand A: -1.11, Ligand B: -2.128). This could pose formulation challenges.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (Ligand A: 0.355, Ligand B: 0.469).

**Microsomal Clearance:** Ligand A (-1.301) has a negative clearance, which is not physically possible and suggests an issue with the data. Ligand B (22.045) has a higher clearance, indicating faster metabolism.

**In vitro Half-Life:** Ligand B (16.691 hours) has a significantly longer half-life than Ligand A (2.467 hours), which is desirable for less frequent dosing.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (Ligand A: 0.009, Ligand B: 0.229), which is favorable for CNS exposure.

**Binding Affinity:** Ligand A (-7.5 kcal/mol) has a slightly better binding affinity than Ligand B (-7.2 kcal/mol), although the difference is relatively small (0.3 kcal/mol).

**Overall Assessment:**

Despite the slightly better affinity of Ligand A, Ligand B is the superior candidate. The significantly better BBB penetration (80.07 vs 44.591), higher QED (0.865 vs 0.498), longer half-life (16.691 vs 2.467), and lower TPSA (70.08 vs 116.11) outweigh the small affinity advantage of Ligand A. The negative Caco-2 and clearance values for Ligand A are also concerning. For a CNS GPCR target, BBB penetration and metabolic stability are paramount, making Ligand B the more promising drug candidate.

Output:
1
2025-04-17 07:39:20,887 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands fall within the ideal range (200-500 Da). Ligand A (339.439 Da) is slightly lower, which could be beneficial for permeability.

**2. TPSA:** Ligand A (64.41) is significantly better than Ligand B (82.89). For CNS targets, TPSA < 90 is preferred, and A is closer to the optimal <60 range.

**3. logP:** Both ligands have good logP values (A: 2.328, B: 1.812) within the optimal 1-3 range.

**4. H-Bond Donors:** Ligand A (0) is preferable to Ligand B (2). Fewer HBDs generally improve permeability.

**5. H-Bond Acceptors:** Ligand A (3) is better than Ligand B (6). Lower HBA is generally preferred for CNS penetration.

**6. QED:** Both ligands have acceptable QED values (A: 0.846, B: 0.717), indicating good drug-like properties.

**7. DILI:** Both ligands have low DILI risk (A: 30.787, B: 27.608), which is good.

**8. BBB:** Both ligands have excellent BBB penetration (A: 73.827, B: 80.419), exceeding the desirable >70 threshold for CNS targets. B is slightly better here.

**9. Caco-2 Permeability:** Both have negative values, which is unusual and suggests a potential issue with the data. However, the magnitude is similar.

**10. Aqueous Solubility:** Both have negative values, also unusual.

**11. hERG Inhibition:** Both ligands show low hERG inhibition risk (A: 0.489, B: 0.453).

**12. Microsomal Clearance:** Ligand B (35.093) has a lower (better) microsomal clearance than Ligand A (47.062), indicating greater metabolic stability.

**13. In vitro Half-Life:** Ligand B (-32.23) has a much longer in vitro half-life than Ligand A (-9.694). This is a significant advantage.

**14. P-gp Efflux:** Both ligands have low P-gp efflux liability (A: 0.093, B: 0.077), which is good for CNS exposure.

**15. Binding Affinity:** Ligand A (-7.3) has a slightly better binding affinity than Ligand B (-6.1). While both are good, the 1.2 kcal/mol difference is notable.

**Overall Assessment:**

Ligand A excels in TPSA, H-bond donors/acceptors, and binding affinity. However, Ligand B demonstrates superior metabolic stability (lower Cl_mic, longer t1/2) and slightly better BBB penetration. Given the importance of metabolic stability and duration of action for CNS drugs, and the relatively small difference in affinity, Ligand B appears to be the more promising candidate. The slightly better affinity of A is outweighed by B's superior ADME properties.

Output:
1
2025-04-17 07:39:20,887 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (362.832 and 348.495 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (46.34) is excellent, well below the 90 A^2 threshold for CNS targets. Ligand B (77.15) is higher but still potentially acceptable, though less ideal.

**logP:** Ligand A (4.742) is slightly high, potentially leading to solubility issues or off-target interactions. Ligand B (1.631) is within the optimal range of 1-3.

**H-Bond Donors/Acceptors:** Ligand A (0 HBD, 3 HBA) is favorable. Ligand B (2 HBD, 5 HBA) is also acceptable.

**QED:** Both ligands have good QED scores (0.697 and 0.817), indicating drug-like properties.

**DILI:** Ligand A (42.497) has a low DILI risk. Ligand B (8.414) has a very low DILI risk, which is excellent.

**BBB:** Ligand A (91.857) has excellent BBB penetration, highly desirable for a CNS target. Ligand B (58.278) has significantly lower BBB penetration, a major drawback.

**Caco-2 Permeability:** Ligand A (-4.718) has poor Caco-2 permeability. Ligand B (-5.522) also has poor Caco-2 permeability.

**Aqueous Solubility:** Ligand A (-4.644) has poor aqueous solubility. Ligand B (-1.324) has slightly better aqueous solubility, but still not ideal.

**hERG Inhibition:** Ligand A (0.733) has a low hERG risk. Ligand B (0.33) also has a very low hERG risk.

**Microsomal Clearance:** Ligand A (81.635) has relatively high microsomal clearance, suggesting lower metabolic stability. Ligand B (-8.728) has negative clearance, which is not physically possible and likely an error in the data, but suggests very high metabolic stability.

**In vitro Half-Life:** Ligand A (24.269 hours) has a reasonable half-life. Ligand B (-0.487 hours) has a very short half-life, which is a significant negative.

**P-gp Efflux:** Ligand A (0.727) has moderate P-gp efflux. Ligand B (0.02) has very low P-gp efflux, which is favorable for CNS penetration.

**Binding Affinity:** Both ligands have very similar and strong binding affinities (-8.4 and -8.3 kcal/mol). The difference is negligible.

**Overall Assessment:**

Ligand A excels in BBB penetration and has a low DILI risk. However, it suffers from high logP, poor Caco-2 permeability, and relatively high microsomal clearance.

Ligand B has a very low DILI risk, low P-gp efflux, and a low hERG risk. However, its BBB penetration is significantly lower than Ligand A, and its in vitro half-life is extremely short. The negative clearance is also a red flag.

Considering the GPCR-specific priorities, **BBB penetration is crucial for CNS targets like DRD2**. While Ligand B has better ADME properties in some areas, the significantly lower BBB penetration of Ligand B compared to Ligand A is a critical disadvantage. The strong binding affinity is similar for both, so the better CNS exposure profile of Ligand A makes it the more promising candidate.

Output:
0
2025-04-17 07:39:20,887 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 drug candidates, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (338.367 Da) is slightly lower, which could be beneficial for permeability.

**TPSA:** Both ligands have TPSA values below the 90 A^2 threshold desirable for CNS targets. Ligand B (61 A^2) is significantly lower than Ligand A (82.18 A^2), which is a strong advantage for brain penetration.

**logP:** Both ligands have logP values within the optimal range (1-3). Ligand A (1.946) and Ligand B (2.051) are very similar.

**H-Bond Donors/Acceptors:** Ligand A has 1 HBD and 6 HBA, while Ligand B has 0 HBD and 7 HBA. Both are within acceptable limits.

**QED:** Both ligands have similar QED values (0.786 and 0.762), indicating good drug-likeness.

**DILI:** Ligand A (74.331) has a higher DILI risk than Ligand B (39.201). This is a significant negative for Ligand A.

**BBB:** Ligand B (85.615) has a much higher BBB percentile than Ligand A (71.501). This is crucial for a CNS target like DRD2, making Ligand B more promising.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values, which is unusual and suggests poor permeability. However, these values are on a log scale and can be difficult to interpret without knowing the base.

**Aqueous Solubility:** Both ligands have negative solubility values, also unusual, and suggest poor solubility.

**hERG:** Both ligands have low hERG inhibition liability, which is good. Ligand A (0.591) is slightly higher than Ligand B (0.32).

**Microsomal Clearance:** Ligand A (57.899) has a higher microsomal clearance than Ligand B (41.423), indicating lower metabolic stability.

**In vitro Half-Life:** Ligand B (-1.163) has a negative half-life, which is impossible. This is a major red flag. Ligand A (6.94) has a reasonable half-life.

**P-gp Efflux:** Ligand A (0.306) has lower P-gp efflux liability than Ligand B (0.238), which is favorable for CNS penetration.

**Binding Affinity:** Ligand B (-7.8 kcal/mol) has a significantly stronger binding affinity than Ligand A (-10 kcal/mol). This is a substantial advantage, potentially outweighing some ADME concerns.

**Overall Assessment:**

Despite the unusual negative values for Caco-2 and solubility, the key factors for a CNS GPCR target heavily favor Ligand B. The significantly better BBB penetration, lower DILI risk, and *much* stronger binding affinity are decisive. The negative half-life for Ligand B is a critical issue, but the superior binding affinity suggests it might be optimized. Ligand A's higher DILI risk and lower affinity make it less attractive.



Output:
1
2025-04-17 07:39:20,887 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (366.805 and 349.387 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (105.49) is better than Ligand B (109.78). Both are reasonably close to the 90 A^2 threshold for CNS targets, but A is preferable.

**3. logP:** Ligand A (2.334) is optimal (1-3), while Ligand B (0.816) is slightly low, potentially hindering membrane permeability.

**4. H-Bond Donors:** Both ligands have 3 HBD, which is within the acceptable limit of <=5.

**5. H-Bond Acceptors:** Ligand A has 5 HBA, while Ligand B has 6. Both are within the acceptable limit of <=10.

**6. QED:** Both ligands have similar QED values (0.652 and 0.629), indicating good drug-likeness.

**7. DILI:** Ligand A (80.574) has a higher DILI risk than Ligand B (49.709). This is a significant drawback for Ligand A.

**8. BBB:** Ligand A (76.309) has a better BBB percentile than Ligand B (63.203). This is crucial for a CNS target like DRD2.

**9. Caco-2:** Ligand A (-4.906) has a worse Caco-2 permeability than Ligand B (-5.186). Lower values are less favorable.

**10. Solubility:** Ligand A (-4.148) has a worse solubility than Ligand B (-2.571).

**11. hERG:** Both ligands have low hERG risk (0.282 and 0.217).

**12. Cl_mic:** Ligand B (15.318) has significantly lower microsomal clearance than Ligand A (47.216), indicating better metabolic stability.

**13. t1/2:** Ligand B (-7.021) has a negative in vitro half-life, which is concerning. Ligand A (36.247) has a more reasonable half-life.

**14. Pgp:** Ligand A (0.111) has lower P-gp efflux liability than Ligand B (0.008), which is favorable for CNS penetration.

**15. Binding Affinity:** Both ligands have excellent binding affinities (-8.8 and -8.3 kcal/mol). Ligand A is slightly better (-8.8 vs -8.3), but the difference is not substantial enough to overcome other issues.

**Overall Assessment:**

Ligand A has a better BBB penetration and Pgp efflux profile, and slightly better binding affinity, which are important for a CNS GPCR target. However, it has significantly higher DILI risk, worse solubility, and higher metabolic clearance. Ligand B has a better safety profile (lower DILI), better metabolic stability, and better solubility, but its BBB penetration is lower and logP is suboptimal.

Considering the balance, the lower DILI risk and improved metabolic stability of Ligand B are more important than the slightly better BBB and affinity of Ligand A. The solubility difference is also a factor. While the negative half-life is a concern for Ligand B, it might be addressable through structural modifications.

Output:
1
2025-04-17 07:39:20,887 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (352.391 and 384.487 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (115.46) is slightly above the optimal <90 for CNS targets, but still reasonable. Ligand B (110.08) is also slightly above, but similar to A.

**logP:** Ligand A (0.92) is a bit low, potentially hindering permeation. Ligand B (0.491) is even lower, raising more concern about permeability.

**H-Bond Donors/Acceptors:** Ligand A (HBD=2, HBA=7) and Ligand B (HBD=1, HBA=8) both have acceptable numbers of H-bond donors and acceptors, within the guidelines.

**QED:** Both ligands have good QED scores (0.814 and 0.776), indicating good drug-like properties.

**DILI:** Ligand A (56.068) has a lower DILI risk than Ligand B (77.2), which is a significant advantage.

**BBB:** Ligand A (72.237) has a better BBB penetration score than Ligand B (52.307). This is crucial for a CNS target like DRD2.

**Caco-2 Permeability:** Ligand A (-4.481) shows better Caco-2 permeability than Ligand B (-5.333), suggesting better intestinal absorption.

**Aqueous Solubility:** Ligand A (-3.185) has better aqueous solubility than Ligand B (-2.586).

**hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.058 and 0.112).

**Microsomal Clearance:** Ligand A (39.245) has a higher (worse) microsomal clearance than Ligand B (18.158), indicating lower metabolic stability.

**In vitro Half-Life:** Ligand B (7.584) has a longer in vitro half-life than Ligand A (-16.064), which is a positive.

**P-gp Efflux:** Ligand A (0.018) has significantly lower P-gp efflux liability than Ligand B (0.148), which is very favorable for CNS penetration.

**Binding Affinity:** Ligand B (-7.3) has a slightly better binding affinity than Ligand A (-8.0). However, the difference is not substantial enough to overcome the other significant drawbacks of Ligand B.

**Overall Assessment:**

Ligand A is the more promising candidate. While its logP is a bit low and its clearance is higher, it excels in crucial areas for a CNS-targeting GPCR ligand: better BBB penetration, lower DILI risk, better Caco-2 permeability, better aqueous solubility, and significantly lower P-gp efflux. The slightly weaker binding affinity of Ligand A is likely outweighed by its superior ADME properties, especially its improved CNS penetration profile. Ligand B's lower logP and higher P-gp efflux are major concerns for brain exposure.

Output:
0
2025-04-17 07:39:20,888 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (353.482 and 346.343 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (61.44) is significantly better than Ligand B (132.64). For CNS targets, TPSA should be <= 90, and A is comfortably within this range, while B exceeds it. This is a major advantage for A.

**3. logP:** Ligand A (2.01) is optimal (1-3), while Ligand B (-0.554) is below 1, which could hinder permeation. A is clearly better here.

**4. H-Bond Donors:** Both have acceptable HBD counts (2 and 3, respectively).

**5. H-Bond Acceptors:** Both have acceptable HBA counts (3 and 6, respectively).

**6. QED:** Both have good QED scores (0.736 and 0.655), indicating drug-like properties.

**7. DILI:** Ligand A (9.383) has a much lower DILI risk than Ligand B (75.029). This is a significant advantage for A.

**8. BBB:** Ligand A (81.698) has a very good BBB penetration percentile, exceeding the desirable >70 threshold for CNS targets. Ligand B (46.336) is considerably lower and less favorable. This is a critical advantage for A.

**9. Caco-2:** Both have negative Caco-2 values, which is unusual and difficult to interpret without knowing the scale. However, the values are similar.

**10. Solubility:** Both have negative solubility values, also unusual. Again, the values are similar.

**11. hERG:** Both ligands show low hERG inhibition liability (0.522 and 0.131), which is good.

**12. Cl_mic:** Ligand A (7.769) has a slightly higher microsomal clearance than Ligand B (4.054), suggesting slightly lower metabolic stability, but the difference isn't huge.

**13. t1/2:** Ligand A (-0.551) has a slightly worse in vitro half-life than Ligand B (0.272), but both are negative values, making comparison difficult.

**14. Pgp:** Ligand A (0.023) has a much lower P-gp efflux liability than Ligand B (0.026), which is beneficial for CNS exposure.

**15. Binding Affinity:** Both ligands have very similar and excellent binding affinities (-8.9 and -8.7 kcal/mol). The difference of 0.2 kcal/mol is unlikely to outweigh the significant ADME advantages of Ligand A.

**Overall Assessment:**

Ligand A is significantly superior to Ligand B. It has better TPSA, logP, DILI risk, and, crucially, a much higher predicted BBB penetration. While Ligand B has slightly better metabolic stability and in vitro half-life, the differences are small compared to the substantial advantages of Ligand A in properties critical for CNS drug development. The similar binding affinities further solidify the choice of Ligand A.

Output:
1
2025-04-17 07:39:20,888 - INFO - Reasoning:

Let's analyze Ligand A and Ligand B based on the provided guidelines, prioritizing GPCR-specific properties (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (356.495 & 371.547 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (48.47) is excellent, well below the 90 A^2 threshold for CNS targets. Ligand B (78.51) is still reasonable but less optimal, approaching the 140 A^2 limit for oral absorption.

**logP:** Ligand A (3.97) is at the upper end of the optimal range (1-3), but acceptable. Ligand B (1.618) is lower, which could hinder permeability.

**H-Bond Donors/Acceptors:** Both ligands have acceptable HBD (1 & 2) and HBA (4 & 4) counts.

**QED:** Both ligands have good QED scores (0.886 & 0.604), indicating drug-likeness.

**DILI:** Ligand A (72.392) has a higher DILI risk than Ligand B (19.271), which is a significant concern.

**BBB:** Ligand A (70.57) has a good BBB penetration percentile, desirable for a CNS target. Ligand B (62.699) is lower, potentially limiting CNS exposure.

**Caco-2 Permeability:** Ligand A (-4.647) has poor Caco-2 permeability, suggesting poor intestinal absorption. Ligand B (-5.478) is also poor, but slightly worse.

**Aqueous Solubility:** Ligand A (-4.026) has poor solubility, while Ligand B (-2.118) is also poor, but slightly better.

**hERG Inhibition:** Both ligands show low hERG inhibition risk (0.591 & 0.638).

**Microsomal Clearance:** Ligand A (52.681) has moderate clearance, while Ligand B (24.196) has lower clearance, indicating better metabolic stability.

**In vitro Half-Life:** Ligand A (43.413) has a reasonable half-life. Ligand B (-31.835) has a *negative* half-life, which is not physically possible and likely represents an outlier or error in the data. This is a major red flag.

**P-gp Efflux:** Both ligands show low P-gp efflux liability (0.353 & 0.071), which is good for CNS penetration.

**Binding Affinity:** Both ligands have excellent binding affinities (-9.9 & -8.5 kcal/mol), with Ligand A being slightly stronger. The 1.4 kcal/mol difference is significant.

**Overall Assessment:**

Ligand A has a better TPSA, BBB, and binding affinity. However, its DILI risk is considerably higher, and its Caco-2 permeability is poor. Ligand B has a better DILI profile and metabolic stability, but suffers from lower BBB penetration and a significantly worse (and physically impossible) in vitro half-life. The negative half-life for Ligand B is a critical issue, suggesting a data error or a fundamentally unstable molecule.

Despite the slightly higher DILI risk, Ligand A's superior binding affinity and acceptable BBB penetration make it the more promising candidate, *assuming* the DILI risk can be mitigated through structural modifications. The negative half-life of Ligand B is a dealbreaker.

Output:
0
2025-04-17 07:39:20,888 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (351.403 and 351.447 Da) fall comfortably within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (117.52) is slightly above the preferred <90 for CNS targets, but still reasonable. Ligand B (87.74) is excellent, well below 90. This favors Ligand B.

**3. logP:** Ligand A (0.067) is quite low, potentially hindering permeability. Ligand B (0.433) is also low, but better than A. Both are below the optimal 1-3 range. This is a concern for both, but more so for A.

**4. H-Bond Donors:** Both ligands have 2 HBD, which is within the acceptable limit of <=5.

**5. H-Bond Acceptors:** Ligand A has 6 HBA, and Ligand B has 4. Both are within the acceptable limit of <=10.

**6. QED:** Both ligands have good QED scores (0.568 and 0.727, respectively), indicating drug-like properties. Ligand B is slightly better.

**7. DILI:** Ligand A (32.028) has a slightly higher DILI risk than Ligand B (25.785), but both are below the concerning threshold of 60.

**8. BBB:** Ligand A (55.603) has a moderate BBB penetration, while Ligand B (60.876) is slightly better. Both are below the desirable >70 for CNS targets, but Ligand B is closer.

**9. Caco-2:** Both ligands have negative Caco-2 values (-5.212 and -4.934). This is unusual and suggests poor permeability.

**10. Solubility:** Both ligands have negative solubility values (-1.538 and -1.617). This is also unusual and suggests poor aqueous solubility.

**11. hERG:** Both ligands have very low hERG inhibition risk (0.132 and 0.122).

**12. Cl_mic:** Ligand A (4.906) has a lower microsomal clearance than Ligand B (10.669), indicating better metabolic stability. This favors Ligand A.

**13. t1/2:** Ligand A (-10.565) has a negative in vitro half-life, which is not possible. Ligand B (11.514) has a reasonable half-life. This is a major red flag for Ligand A.

**14. Pgp:** Both ligands have very low P-gp efflux liability (0.011 and 0.015).

**15. Binding Affinity:** Ligand A (-7.5) has a significantly better binding affinity than Ligand B (-0.0). This is a substantial advantage.

**Overall Assessment:**

Despite Ligand A's superior binding affinity, its negative in vitro half-life is a critical flaw. A negative half-life is not physically possible and indicates a serious issue with the data or the molecule's stability. While Ligand B has a weaker binding affinity, its overall profile is more reasonable, with a positive half-life, better TPSA, and acceptable DILI and BBB scores. The low logP values for both are concerning, but the significant affinity advantage of A isn't enough to overcome the impossible half-life.

Output:
1
2025-04-17 07:39:20,888 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (361.881 and 343.475 Da) fall within the ideal 200-500 Da range.

**TPSA:** Both ligands have TPSA values (71.76 and 70.15) below 90, which is favorable for CNS penetration.

**logP:** Both ligands have logP values (2.887 and 2.666) within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A has 1 HBD and 7 HBA, while Ligand B has 2 HBD and 5 HBA. Both are within acceptable limits (<=5 HBD and <=10 HBA).

**QED:** Both ligands have good QED scores (0.882 and 0.831), indicating drug-like properties.

**DILI:** Ligand A has a DILI risk of 69.872, which is approaching the higher risk threshold (>60). Ligand B has a significantly lower DILI risk of 26.483, which is excellent.

**BBB:** Ligand A has a BBB penetration of 77.472, which is good, but Ligand B has a superior BBB penetration of 90.772. This is a crucial factor for a CNS target like DRD2.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.184 and -5.114). This is unusual and suggests poor permeability. However, the scale isn't specified, so it's hard to interpret.

**Aqueous Solubility:** Both ligands have negative solubility values (-3.963 and -2.601). Similar to Caco-2, the scale is unknown, making interpretation difficult.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.495 and 0.723).

**Microsomal Clearance:** Ligand A has a higher microsomal clearance (86.306) than Ligand B (44.682), indicating lower metabolic stability.

**In vitro Half-Life:** Ligand B has a longer in vitro half-life (25.737 hours) than Ligand A (11.362 hours).

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.126 and 0.136).

**Binding Affinity:** Both ligands have very similar and excellent binding affinities (-9.3 and -9.2 kcal/mol). The difference is minimal.

**Conclusion:**

While both ligands exhibit good binding affinity and generally acceptable physicochemical properties, Ligand B is the more promising candidate. Its significantly lower DILI risk, superior BBB penetration, and longer half-life outweigh the slight difference in binding affinity and the potentially concerning (but scale-unknown) Caco-2 and solubility values. The improved ADME profile of Ligand B makes it a more viable drug candidate for a CNS target like DRD2.

Output:
1
2025-04-17 07:39:20,888 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (368.503 and 360.439 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (76.46) is significantly better than Ligand B (98.58). For CNS targets, we want TPSA <= 90, and A is comfortably within this range, while B is slightly above.

**3. logP:** Both ligands have acceptable logP values (1.29 and 1.929), falling within the optimal 1-3 range.

**4. H-Bond Donors:** Ligand A (1) is preferable to Ligand B (3). Fewer HBDs generally improve permeability.

**5. H-Bond Acceptors:** Ligand A (6) is preferable to Ligand B (7). Fewer HBAs generally improve permeability.

**6. QED:** Both ligands have similar QED values (0.734 and 0.705), indicating good drug-likeness.

**7. DILI:** Ligand A (35.285) has a much lower DILI risk than Ligand B (61.342). This is a significant advantage for A.

**8. BBB:** Ligand A (56.65) is better than Ligand B (17.332), although neither is above the desirable >70 threshold for CNS targets. However, A is considerably closer.

**9. Caco-2 Permeability:** Ligand A (-5.107) is better than Ligand B (-5.597), indicating slightly better intestinal absorption.

**10. Aqueous Solubility:** Ligand A (-1.392) is better than Ligand B (-3.278), indicating better solubility.

**11. hERG Inhibition:** Both ligands have low hERG inhibition risk (0.158 and 0.268).

**12. Microsomal Clearance:** Both ligands have similar microsomal clearance (55.223 and 54.092).

**13. In vitro Half-Life:** Ligand A (-3.446) is significantly better than Ligand B (-14.783), suggesting a much longer half-life.

**14. P-gp Efflux:** Both ligands have low P-gp efflux liability (0.094 and 0.153).

**15. Binding Affinity:** Ligand B (-9.1) has a stronger binding affinity than Ligand A (-7.0). This is a 2.1 kcal/mol difference, which is substantial and could potentially outweigh some ADME drawbacks.

**Overall Assessment:**

While Ligand B boasts a significantly better binding affinity, Ligand A demonstrates superior ADME properties, particularly regarding BBB penetration, DILI risk, solubility, and in vitro half-life. Given the CNS target (DRD2), BBB penetration is crucial, and Ligand A is significantly better in this regard. The lower DILI risk and better half-life are also major advantages. The 2.1 kcal/mol difference in binding affinity is important, but not insurmountable, and can potentially be optimized in future iterations of Ligand A.

Output:
0
2025-04-17 07:39:20,889 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (337.383 and 346.471 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (107.87) is better than Ligand B (67.43). Both are below the 140 A^2 threshold for oral absorption, and Ligand B is especially good for CNS penetration (<90 A^2).

**logP:** Both ligands (2.01 and 2.336) are within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A has 3 HBD and 3 HBA, while Ligand B has 2 HBD and 3 HBA. Both are within acceptable limits.

**QED:** Ligand A (0.68) is slightly better than Ligand B (0.549), indicating a more drug-like profile.

**DILI:** Ligand A (66.421) has a significantly higher DILI risk than Ligand B (28.926). This is a major drawback for Ligand A.

**BBB:** Ligand B (68.282) has a better BBB penetration percentile than Ligand A (59.984). While both are not ideal (>70), Ligand B is closer.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.558 and -5.118), which is unusual and suggests poor permeability. This is a concern for both.

**Aqueous Solubility:** Both ligands have negative solubility values (-3.828 and -3.195), indicating very poor aqueous solubility. This is a significant issue for both.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.491 and 0.225).

**Microsomal Clearance:** Ligand A (-14.092) has a much lower (better) microsomal clearance than Ligand B (56.595), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (13.78 hours) has a longer half-life than Ligand B (-11.324 hours).

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.061 and 0.103), which is favorable for CNS penetration.

**Binding Affinity:** Both ligands have very similar and strong binding affinities (-9.8 and -8.9 kcal/mol). The difference of 0.9 kcal/mol is not substantial enough to override other factors.

**Conclusion:**

Considering the GPCR-specific priorities, Ligand B is the more promising candidate. While both have poor solubility and permeability, Ligand B has a significantly lower DILI risk and a better (though still suboptimal) BBB penetration percentile. The slightly better metabolic stability and half-life of Ligand A are outweighed by the higher DILI risk and lower BBB penetration. The binding affinity difference is not large enough to be decisive.

Output:
1
2025-04-17 07:39:20,889 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (374.849 Da) is slightly higher than Ligand B (342.447 Da), but both are acceptable.

**TPSA:** Ligand A (51.54) is significantly better than Ligand B (88.49). For CNS targets, we want TPSA <= 90, and ideally lower. Ligand A is well within this range, while Ligand B is approaching the upper limit.

**logP:** Both ligands have acceptable logP values (Ligand A: 3.531, Ligand B: 2.618), falling within the optimal 1-3 range. Ligand A is slightly higher, which could potentially lead to off-target effects, but is not a major concern.

**H-Bond Donors/Acceptors:** Ligand A (HBD=0, HBA=5) and Ligand B (HBD=2, HBA=5) both have reasonable numbers of H-bond donors and acceptors.

**QED:** Both ligands have good QED values (Ligand A: 0.689, Ligand B: 0.757), indicating good drug-like properties.

**DILI:** Ligand A (84.102) has a higher DILI risk than Ligand B (47.305). This is a significant drawback for Ligand A.

**BBB:** Ligand A (73.866) has a better BBB penetration percentile than Ligand B (51.493). This is crucial for a CNS target like DRD2.

**Caco-2 Permeability:** Ligand A (-4.398) has a worse Caco-2 permeability than Ligand B (-5.267), indicating lower intestinal absorption.

**Aqueous Solubility:** Ligand A (-5.085) has worse aqueous solubility than Ligand B (-3.141).

**hERG Inhibition:** Both ligands have low hERG inhibition risk (Ligand A: 0.435, Ligand B: 0.181).

**Microsomal Clearance:** Ligand A (67.927) has higher microsomal clearance than Ligand B (12.167), meaning it's less metabolically stable.

**In vitro Half-Life:** Ligand B (-8.747) has a longer in vitro half-life than Ligand A (28.887).

**P-gp Efflux:** Ligand A (0.755) has higher P-gp efflux than Ligand B (0.215). Lower P-gp efflux is better for CNS penetration.

**Binding Affinity:** Both ligands have the same binding affinity (-8.4 kcal/mol), which is excellent.

**Overall Assessment:**

Ligand A has a better BBB score and comparable binding affinity, but suffers from higher DILI risk, lower solubility, higher clearance, and higher P-gp efflux. Ligand B, while having a slightly higher TPSA, demonstrates a significantly better safety profile (lower DILI), better metabolic stability (lower Cl_mic, longer t1/2), and lower P-gp efflux, which is crucial for CNS penetration. Considering the GPCR-specific priorities, the improved ADME properties of Ligand B outweigh the slightly higher TPSA.

Output:
1
2025-04-17 07:39:20,889 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (370.343 and 369.491 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (78.87) is significantly better than Ligand B (100.35). For CNS targets, we want TPSA <= 90, so Ligand A is preferable.

**3. logP:** Ligand A (0.783) is slightly better than Ligand B (0.278), both are a bit low, but still within acceptable range. Lower logP can sometimes hinder permeability.

**4. H-Bond Donors:** Both ligands have 2 HBD, which is within the ideal range of <= 5.

**5. H-Bond Acceptors:** Ligand A (4) is better than Ligand B (7), both are within the ideal range of <= 10.

**6. QED:** Both ligands have good QED scores (0.513 and 0.648, respectively), indicating drug-like properties.

**7. DILI:** Ligand A (19.426) has a much lower DILI risk than Ligand B (43.389). This is a significant advantage for Ligand A.

**8. BBB:** Ligand A (79.488) has a substantially higher BBB penetration score than Ligand B (13.726). This is *critical* for a CNS target like DRD2.

**9. Caco-2 Permeability:** Ligand A (-4.881) and Ligand B (-5.734) both have negative values, indicating poor permeability.

**10. Aqueous Solubility:** Ligand A (-1.493) and Ligand B (-1.01) both have negative values, indicating poor solubility.

**11. hERG Inhibition:** Both ligands have low hERG inhibition risk (0.441 and 0.08, respectively).

**12. Microsomal Clearance:** Ligand A (-10.355) has a much lower (better) microsomal clearance than Ligand B (8.395), indicating greater metabolic stability.

**13. In vitro Half-Life:** Ligand A (-5.841) has a longer in vitro half-life than Ligand B (6.952).

**14. P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.022 and 0.027, respectively).

**15. Binding Affinity:** Ligand A (-7.4 kcal/mol) has a slightly better binding affinity than Ligand B (-6.7 kcal/mol). While both are good, the 0.7 kcal/mol difference is noticeable.

**Overall Assessment:**

Ligand A is clearly superior. Its significantly better BBB penetration, lower DILI risk, lower microsomal clearance, longer half-life, and slightly better binding affinity outweigh the slightly lower logP and Caco-2 permeability. For a CNS target like DRD2, BBB penetration is paramount, and Ligand A excels in this area. The lower DILI and improved metabolic stability are also important factors.

Output:
1
2025-04-17 07:39:20,889 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (346.45 and 345.443 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (38.82) is excellent, well below the 90 Angstroms threshold for CNS targets. Ligand B (71.53) is higher, but still potentially acceptable, though less ideal.

**3. logP:** Ligand A (1.324) is within the optimal 1-3 range. Ligand B (2.535) is also within range, but approaching the upper limit.

**4. H-Bond Donors:** Both ligands have 1 HBD, which is good.

**5. H-Bond Acceptors:** Both ligands have 4 HBA, which is good.

**6. QED:** Both ligands have good QED scores (0.835 and 0.91), indicating drug-like properties.

**7. DILI:** Ligand A (35.052) has a lower DILI risk than Ligand B (49.632), which is preferable.

**8. BBB:** This is a critical parameter for a CNS target like DRD2. Ligand A has a significantly better BBB penetration percentile (70.26) than Ligand B (60.45).  Ligand A is desirable (>70), while B is less so.

**9. Caco-2 Permeability:** Both have negative values, which is unusual and suggests a potential issue with the data. However, the magnitude is similar.

**10. Aqueous Solubility:** Both ligands have negative solubility values, which is also unusual. Again, the magnitude is similar.

**11. hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.8 and 0.256), which is excellent.

**12. Microsomal Clearance:** Ligand A (4.56) has a much lower microsomal clearance than Ligand B (33.223), suggesting better metabolic stability.

**13. In vitro Half-Life:** Ligand A (-7.233) has a significantly longer in vitro half-life than Ligand B (-6.46), indicating slower metabolism.

**14. P-gp Efflux:** Both ligands have a Pgp efflux liability of 0, which is ideal.

**15. Binding Affinity:** Ligand A (-7.233) has a slightly better binding affinity than Ligand B (-6.46). While both are good, the 0.773 kcal/mol difference is meaningful.

**Overall Assessment:**

Ligand A is the superior candidate. It excels in crucial areas for a CNS-targeting GPCR ligand: TPSA, BBB penetration, metabolic stability (lower Cl_mic and longer t1/2), DILI risk, and binding affinity. While both have issues with reported solubility and Caco-2 permeability, Ligand A's other properties are significantly more favorable. The difference in binding affinity, while not enormous, further supports choosing Ligand A.

Output:
1
2025-04-17 07:39:20,890 - INFO - Batch 383 complete. Total preferences: 6128
2025-04-17 07:39:20,890 - INFO - Processing batch 384/512...
2025-04-17 07:40:09,638 - INFO - Reasoning:

Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (368.415 and 385.892 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (109.86) is higher than the preferred <90 for CNS targets, but not drastically so. Ligand B (71.09) is excellent, well below the 90 threshold.

**3. logP:** Ligand A (0.369) is quite low, potentially hindering membrane permeability. Ligand B (4.124) is slightly high, but still within an acceptable range, though approaching the upper limit where solubility issues could arise.

**4. H-Bond Donors:** Both ligands have 2 HBD, which is within the acceptable limit of <=5.

**5. H-Bond Acceptors:** Ligand A has 7 HBA, acceptable. Ligand B has 4 HBA, also acceptable.

**6. QED:** Both ligands have good QED scores (0.751 and 0.812), indicating good drug-like properties.

**7. DILI:** Both ligands have relatively high DILI risk (84.606 and 77.007), which is a concern, but not a dealbreaker at this stage.

**8. BBB:** This is a critical parameter for a CNS target like DRD2. Ligand A has a BBB percentile of 51.105, which is not ideal (below the desirable >70). Ligand B has a BBB percentile of 31.989, even lower. Both are suboptimal.

**9. Caco-2:** Both ligands have negative Caco-2 values (-5.127 and -4.915) which is unusual and suggests poor permeability.

**10. Solubility:** Both ligands have negative solubility values (-2.659 and -4.25), which is also unusual and suggests poor aqueous solubility.

**11. hERG:** Both ligands have low hERG inhibition liability (0.095 and 0.466), which is favorable.

**12. Cl_mic:** Ligand A (-14.831) has a much lower (better) microsomal clearance than Ligand B (33.32). This suggests better metabolic stability for Ligand A.

**13. t1/2:** Ligand A (-15.246) has a negative half-life, which is not physically possible. Ligand B (78.469) has a good in vitro half-life.

**14. Pgp:** Both ligands have low P-gp efflux liability (0.021 and 0.141), which is good for CNS penetration.

**15. Binding Affinity:** Ligand B (-9.4 kcal/mol) has a significantly stronger binding affinity than Ligand A (-7.8 kcal/mol). This is a substantial advantage.

**Overall Assessment:**

Ligand B has a significantly better binding affinity and a more favorable logP, and a better half-life. However, its BBB penetration is very poor. Ligand A has a better metabolic stability profile (lower Cl_mic) but suffers from a very low logP and a poor BBB score. The negative values for Caco-2 and Solubility for both are concerning.

Despite the poor BBB scores, the much stronger binding affinity of Ligand B is a significant advantage for a GPCR target. Optimization efforts could focus on improving its BBB penetration through structural modifications. The negative values for Caco-2 and Solubility are concerning for both, and would require further investigation.

Output:
1
2025-04-17 07:40:09,638 - INFO - Reasoning:

Let's analyze Ligand A and Ligand B against the provided guidelines, prioritizing GPCR-specific properties (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (352.425 and 351.491 Da) fall within the ideal range of 200-500 Da.

**TPSA:** Ligand A (58.2) is excellent for CNS penetration, well below the 90 A^2 threshold. Ligand B (92.5) is higher, but still potentially acceptable, though less ideal.

**logP:** Ligand A (3.546) is at the upper end of the optimal range (1-3), while Ligand B (1.82) is at the lower end. For a CNS target like DRD2, a slightly higher logP is generally preferred for better brain penetration, but both are within acceptable limits.

**H-Bond Donors/Acceptors:** Both ligands have 2 HBD and a reasonable number of HBA (2 for A, 3 for B), satisfying the <5 HBD and <10 HBA guidelines.

**QED:** Both ligands have similar QED values (0.871 and 0.809), indicating good drug-likeness.

**DILI:** Ligand A (51.028) has a higher DILI risk than Ligand B (24.777). This is a significant negative for Ligand A.

**BBB:** Ligand A (82.474) has a better BBB percentile than Ligand B (72.664), which is crucial for a CNS target.

**Caco-2 Permeability:** Ligand A (-4.534) has poor Caco-2 permeability, while Ligand B (-5.053) is also poor. This suggests potential absorption issues for both, but A is slightly better.

**Aqueous Solubility:** Ligand A (-4.866) has poor solubility, while Ligand B (-3.62) is slightly better.

**hERG Inhibition:** Ligand A (0.758) shows slightly higher hERG inhibition liability than Ligand B (0.142). This is a concern for Ligand A.

**Microsomal Clearance:** Both ligands have similar microsomal clearance (40.523 and 51.009), indicating moderate metabolic stability.

**In vitro Half-Life:** Ligand A (24.521) has a significantly longer half-life than Ligand B (1.043), which is a positive for Ligand A.

**P-gp Efflux:** Ligand A (0.071) has lower P-gp efflux liability than Ligand B (0.028), which is favorable for CNS penetration.

**Binding Affinity:** Ligand B (-7.6 kcal/mol) has a significantly stronger binding affinity than Ligand A (-9.7 kcal/mol). This is a substantial advantage for Ligand B, potentially outweighing some of its ADME drawbacks.

**Overall Assessment:**

While Ligand A has better BBB penetration, longer half-life, and lower P-gp efflux, its higher DILI risk, poorer solubility, higher hERG inhibition, and significantly weaker binding affinity are major drawbacks. Ligand B, despite slightly lower BBB and half-life, has a much better safety profile (lower DILI, hERG) and, critically, a substantially stronger binding affinity. The affinity difference is significant enough to likely overcome the slightly less favorable BBB and half-life.

Output:
1
2025-04-17 07:40:09,639 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B based on the provided guidelines, prioritizing GPCR-specific properties (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (372.435 and 349.431 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (105.72) is slightly above the optimal <90 for CNS targets, but acceptable. Ligand B (80.76) is well within the desired range.

**logP:** Ligand A (2.335) is within the optimal 1-3 range. Ligand B (0.884) is a bit low, potentially hindering permeation.

**H-Bond Donors/Acceptors:** Both ligands have 1 HBD, which is good. Ligand A has 9 HBA, acceptable. Ligand B has 5 HBA, also good.

**QED:** Both ligands have similar QED scores (0.662 and 0.67), indicating good drug-likeness.

**DILI:** Ligand A (96.084) has a high DILI risk, which is concerning. Ligand B (31.524) has a low DILI risk, a significant advantage.

**BBB:** Ligand A (48.197) has a moderate BBB penetration, while Ligand B (69.407) is better, though still not ideal (>70 is preferred).

**Caco-2 Permeability:** Ligand A (-5.191) shows poor Caco-2 permeability. Ligand B (-4.571) is also poor, but slightly better than A.

**Aqueous Solubility:** Both ligands have very poor aqueous solubility (-4.785 and -1.432). This could pose formulation challenges.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.315 and 0.395).

**Microsomal Clearance:** Ligand A (88.147) has higher microsomal clearance, suggesting lower metabolic stability. Ligand B (10.65) has much lower clearance, indicating better metabolic stability.

**In vitro Half-Life:** Ligand A (0.257) has a very short half-life. Ligand B (10.713) has a significantly longer half-life.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.35 and 0.041), which is favorable for CNS penetration.

**Binding Affinity:** Ligand A (-8.2 kcal/mol) has a slightly better binding affinity than Ligand B (-7.7 kcal/mol). However, the difference is not substantial enough to overcome the significant ADME liabilities of Ligand A.

**Overall Assessment:**

Ligand A has a better binding affinity, but suffers from a high DILI risk, poor Caco-2 permeability, high microsomal clearance, and a short half-life. Ligand B, while having slightly lower affinity, demonstrates a much more favorable ADME profile, with lower DILI risk, better metabolic stability (lower Cl_mic, longer t1/2), and better BBB penetration. Given the GPCR target and the need for CNS penetration, the ADME properties are crucial. The slightly better affinity of Ligand A is not enough to compensate for its significant drawbacks.

Output:
1
2025-04-17 07:40:09,639 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 drug candidates, considering the provided guidelines and GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight (MW):**
* Ligand A: 404.304 Da - Within the ideal range (200-500 Da).
* Ligand B: 348.441 Da - Also within the ideal range.
* *No clear advantage here.*

**2. Topological Polar Surface Area (TPSA):**
* Ligand A: 55.4  - Good for CNS penetration (below 90).
* Ligand B: 41.05 - Excellent for CNS penetration.
* *Ligand B has a slight advantage.*

**3. Lipophilicity (logP):**
* Ligand A: 3.843 - Optimal (1-3).
* Ligand B: 4.179 - Slightly above optimal, but still acceptable.
* *Ligand A is slightly better.*

**4. H-Bond Donors (HBD):**
* Ligand A: 1 - Meets the criteria (<=5).
* Ligand B: 1 - Meets the criteria (<=5).
* *No clear advantage.*

**5. H-Bond Acceptors (HBA):**
* Ligand A: 3 - Meets the criteria (<=10).
* Ligand B: 4 - Meets the criteria (<=10).
* *No clear advantage.*

**6. Quantitative Estimate of Drug-likeness (QED):**
* Ligand A: 0.714 - Good drug-like properties.
* Ligand B: 0.811 - Slightly better drug-like properties.
* *Ligand B has a slight advantage.*

**7. DILI risk (DILI):**
* Ligand A: 64.366 - Moderate risk.
* Ligand B: 43.622 - Lower risk, desirable.
* *Ligand B is significantly better.*

**8. Blood-Brain Barrier penetration (BBB):**
* Ligand A: 52.734 - Below the desirable threshold (>70) for CNS targets.
* Ligand B: 96.743 - Excellent BBB penetration.
* *Ligand B has a major advantage.*

**9. Caco-2 permeability:**
* Ligand A: -4.83 - Poor permeability.
* Ligand B: -4.922 - Also poor permeability.
* *Similar, both are poor.*

**10. Aqueous Solubility:**
* Ligand A: -4.545 - Poor solubility.
* Ligand B: -4.66 - Poor solubility.
* *Similar, both are poor.*

**11. hERG inhibition liability:**
* Ligand A: 0.707 - Moderate risk.
* Ligand B: 0.898 - Higher risk.
* *Ligand A is slightly better.*

**12. Microsomal Clearance (Cl_mic):**
* Ligand A: 86.857 - High clearance, less metabolic stability.
* Ligand B: 66.745 - Lower clearance, better metabolic stability.
* *Ligand B is better.*

**13. In vitro Half-Life (t1/2):**
* Ligand A: 24.865 - Moderate half-life.
* Ligand B: 13.344 - Shorter half-life.
* *Ligand A is better.*

**14. P-gp efflux liability:**
* Ligand A: 0.283 - Low efflux, good.
* Ligand B: 0.522 - Higher efflux, less desirable.
* *Ligand A is better.*

**15. Binding Affinity (kcal/mol):**
* Ligand A: -9.5 - Excellent affinity.
* Ligand B: -9.2 - Very good affinity, but slightly weaker.
* *Ligand A has a significant advantage.*

**Overall Assessment:**

While Ligand A has a better binding affinity and P-gp efflux, Ligand B demonstrates a significantly superior profile for CNS penetration (BBB) and lower DILI risk. For a DRD2 target (CNS GPCR), BBB penetration is paramount. The lower DILI risk is also a major advantage. Although Ligand A has a better affinity, the difference of 0.3 kcal/mol is unlikely to outweigh the substantial benefits of Ligand B's ADME properties, especially its BBB penetration. The slightly better metabolic stability of Ligand B is also a positive.

Output:
1
2025-04-17 07:40:09,639 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (363.531 and 354.441 Da) fall within the ideal range of 200-500 Da.

**TPSA:** Ligand A (63.05) is better than Ligand B (41.57). Both are below the 90 A^2 threshold for CNS targets, but Ligand B is significantly lower and more favorable.

**logP:** Ligand A (3.777) is slightly higher than Ligand B (2.835), both are within the optimal 1-3 range.

**H-Bond Donors:** Both ligands have 1 HBD, which is good.

**H-Bond Acceptors:** Ligand A has 6 HBA, and Ligand B has 3. Both are below the 10 threshold.

**QED:** Both ligands have similar QED values (0.698 and 0.657), indicating good drug-likeness.

**DILI:** Ligand A (55.487) has a higher DILI risk than Ligand B (13.3). Ligand B is much more favorable here.

**BBB:** Ligand B (96.355) has a substantially better BBB penetration score than Ligand A (76.58). This is a critical factor for a CNS target like DRD2.

**Caco-2 Permeability:** Ligand A (-5.023) has worse Caco-2 permeability than Ligand B (-4.29). Higher values are better, so ligand B is preferable.

**Aqueous Solubility:** Ligand A (-3.611) has worse aqueous solubility than Ligand B (-3.128). Higher values are better, so ligand B is preferable.

**hERG Inhibition:** Both ligands have similar, low hERG inhibition liabilities (0.877 and 0.852).

**Microsomal Clearance:** Ligand A (98.452) has a higher microsomal clearance than Ligand B (62.162), indicating lower metabolic stability. Ligand B is preferable.

**In vitro Half-Life:** Ligand B (22.347) has a longer in vitro half-life than Ligand A (75.715). This is a positive for Ligand B.

**P-gp Efflux:** Ligand A (0.772) has higher P-gp efflux than Ligand B (0.211). Lower efflux is better, especially for CNS targets, making Ligand B preferable.

**Binding Affinity:** Ligand B (-7.2 kcal/mol) has a slightly better binding affinity than Ligand A (-6.9 kcal/mol). While the difference is not huge, it's enough to be considered.

**Overall Assessment:**

Ligand B consistently outperforms Ligand A across several critical ADME properties, particularly BBB penetration, DILI risk, metabolic stability, and P-gp efflux. The slightly better binding affinity of Ligand B further solidifies its advantage. While Ligand A has a slightly better TPSA, the other factors overwhelmingly favor Ligand B.

Output:
1
2025-04-17 07:40:09,639 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B based on the provided guidelines, prioritizing GPCR-specific properties (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (361.873 and 350.503 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (56.15) is significantly better than Ligand B (69.64). For CNS targets, we want TPSA <= 90, and ideally closer to 60. Ligand A is much closer to this ideal.

**logP:** Ligand A (3.771) is slightly higher than Ligand B (2.495), both are within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A (HBD=1, HBA=5) and Ligand B (HBD=2, HBA=3) both have acceptable numbers of H-bond donors and acceptors.

**QED:** Both ligands have good QED scores (0.602 and 0.749, respectively), indicating good drug-like properties.

**DILI:** Ligand A (42.458) has a slightly higher DILI risk than Ligand B (10.585), but both are below the concerning threshold of 60.

**BBB:** Ligand A (62.233) and Ligand B (66.809) both have reasonable BBB penetration, but neither exceeds the desirable >70 percentile for CNS targets.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.778 and -4.589), which is unusual and suggests poor permeability. This is a significant drawback for both.

**Aqueous Solubility:** Both ligands have negative solubility values (-3.924 and -3.014), indicating very poor aqueous solubility. This is a major concern for bioavailability.

**hERG Inhibition:** Both ligands have low hERG inhibition liability (0.508 and 0.385), which is good.

**Microsomal Clearance:** Ligand A (87.09) has a higher microsomal clearance than Ligand B (38.602), suggesting lower metabolic stability.

**In vitro Half-Life:** Ligand B (-4.935) has a negative in vitro half-life, which is concerning and likely indicates rapid degradation. Ligand A (19.851) is much better.

**P-gp Efflux:** Ligand A (0.366) has lower P-gp efflux than Ligand B (0.078), which is favorable for CNS penetration.

**Binding Affinity:** Both ligands have very strong binding affinities (-8.8 and -8.0 kcal/mol). Ligand A is slightly better, but the difference is relatively small.

**Overall Assessment:**

While both ligands have strong binding affinities, Ligand A is the better candidate. Its lower TPSA, better P-gp efflux, and significantly better in vitro half-life are crucial advantages, especially for a CNS target. Although its DILI risk is slightly higher and its clearance is higher, these are less critical than the permeability and metabolic stability issues with Ligand B. The negative Caco-2 and solubility values are concerning for both, but Ligand A's other properties give it a slight edge.

Output:
1
2025-04-17 07:40:09,640 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B based on the provided guidelines, prioritizing GPCR-specific properties (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (343.427 Da) is slightly lower, which could be beneficial for permeability.

**TPSA:** Ligand A (78.51) is significantly better than Ligand B (137.36). For CNS targets, TPSA should be <= 90, and Ligand A comfortably meets this, while Ligand B is close to the upper limit and less desirable.

**logP:** Both ligands have acceptable logP values (Ligand A: 1.617, Ligand B: 0.861), falling within the optimal range of 1-3.

**H-Bond Donors/Acceptors:** Ligand A (HBD=2, HBA=3) is better than Ligand B (HBD=4, HBA=5) in terms of balancing solubility and permeability.

**QED:** Ligand A (0.583) has a better QED score than Ligand B (0.399), indicating a more drug-like profile.

**DILI:** Ligand A (21.52) has a much lower DILI risk than Ligand B (67.003). This is a significant advantage for Ligand A.

**BBB:** Ligand A (60.876) has a significantly better BBB penetration percentile than Ligand B (35.828). For a CNS target like DRD2, BBB penetration is crucial, making Ligand A more promising.

**Caco-2 Permeability:** Ligand A (-4.852) has better Caco-2 permeability than Ligand B (-5.429).

**Aqueous Solubility:** Both ligands have poor aqueous solubility (-2.851 and -2.682 respectively).

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.386 and 0.466 respectively).

**Microsomal Clearance:** Ligand A (12.148) has a higher (worse) microsomal clearance than Ligand B (0.26). This suggests Ligand B is more metabolically stable.

**In vitro Half-Life:** Ligand B (-16.769) has a much longer in vitro half-life than Ligand A (1.649). This is a significant advantage for Ligand B.

**P-gp Efflux:** Ligand A (0.032) has much lower P-gp efflux liability than Ligand B (0.053). Lower P-gp efflux is desirable for CNS exposure.

**Binding Affinity:** Both ligands have very similar and strong binding affinities (-8.3 kcal/mol and -8.0 kcal/mol). The difference is not substantial enough to outweigh other factors.

**Overall Assessment:**

Ligand A is superior due to its significantly better BBB penetration, lower DILI risk, lower P-gp efflux, better TPSA, and better QED score. While Ligand B has better metabolic stability (lower Cl_mic) and a longer half-life, the CNS target requires good brain penetration, which Ligand A provides. The similar binding affinities mean that the ADME properties are the deciding factors.

Output:
0
2025-04-17 07:40:09,640 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 drug candidates, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight (MW):** Both ligands (363.405 and 375.466 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (98.74) is better than Ligand B (100.78), both are below the 140 threshold for oral absorption, and reasonably close to the 90 threshold for CNS targets.

**3. logP:** Ligand B (0.91) is slightly better than Ligand A (0.272). Ligand A is a bit low, potentially hindering permeation. Ligand B is within the optimal 1-3 range.

**4. H-Bond Donors (HBD):** Ligand A (3) is higher than Ligand B (1), but both are within the acceptable limit of <=5.

**5. H-Bond Acceptors (HBA):** Both ligands have 4 HBA, which is within the acceptable limit of <=10.

**6. QED:** Ligand B (0.697) has a better QED score than Ligand A (0.512), indicating a more drug-like profile.

**7. DILI:** Ligand A (33.424) has a significantly lower DILI risk than Ligand B (45.056), which is preferable.

**8. BBB:** Ligand B (79.217) has a much better BBB penetration percentile than Ligand A (60.295). This is *critical* for a CNS target like DRD2.

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.846 and -4.896), which is unusual and suggests poor permeability. This is a significant concern for both.

**10. Aqueous Solubility:** Ligand A (-0.75) is better than Ligand B (-2.148), indicating better solubility.

**11. hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.245 and 0.258).

**12. Microsomal Clearance (Cl_mic):** Ligand B (-2.024) has a lower (better) Cl_mic than Ligand A (9.172), indicating greater metabolic stability.

**13. In vitro Half-Life:** Ligand B (-19.53) has a longer half-life than Ligand A (-27.856), which is desirable.

**14. P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.012 and 0.096).

**15. Binding Affinity:** Ligand B (-7.6 kcal/mol) has a slightly better binding affinity than Ligand A (-7.2 kcal/mol). While the difference is not huge, it's enough to be considered.

**Overall Assessment:**

Ligand B is the stronger candidate. While Ligand A has a lower DILI risk and better solubility, Ligand B excels in the most important parameters for a CNS GPCR target: BBB penetration, metabolic stability (Cl_mic and t1/2), and binding affinity. The slightly better logP of Ligand B is also a plus. The poor Caco-2 permeability is a concern for both, but can be addressed through formulation strategies. The improved BBB penetration of Ligand B is the deciding factor.

Output:
1
2025-04-17 07:40:09,640 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (335.451 and 350.459 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (45.23) is excellent, well below the 90 Angstroms threshold for CNS targets. Ligand B (87.66) is higher but still potentially acceptable, though less ideal.

**3. logP:** Ligand A (3.289) is optimal (1-3). Ligand B (1.26) is a bit low, potentially hindering permeability.

**4. H-Bond Donors:** Ligand A (1) is good. Ligand B (3) is acceptable, but approaching the upper limit.

**5. H-Bond Acceptors:** Ligand A (2) is good. Ligand B (4) is also acceptable.

**6. QED:** Both ligands (0.789 and 0.615) have good drug-likeness scores (>0.5).

**7. DILI:** Ligand A (32.571) has a lower DILI risk than Ligand B (21.946), indicating a safer profile.

**8. BBB:** Ligand A (71.733) has a significantly better BBB penetration percentile than Ligand B (44.203). This is *critical* for a CNS target like DRD2.

**9. Caco-2 Permeability:** Ligand A (-4.483) has worse Caco-2 permeability than Ligand B (-5.375).

**10. Aqueous Solubility:** Ligand A (-3.534) has better aqueous solubility than Ligand B (-2.426).

**11. hERG Inhibition:** Both ligands (0.619 and 0.222) show low hERG inhibition risk.

**12. Microsomal Clearance:** Ligand A (36.666) has higher microsomal clearance than Ligand B (4.911), suggesting lower metabolic stability.

**13. In vitro Half-Life:** Ligand B (31.323) has a longer in vitro half-life than Ligand A (24.977).

**14. P-gp Efflux:** Ligand A (0.085) has lower P-gp efflux liability than Ligand B (0.058), which is favorable for CNS penetration.

**15. Binding Affinity:** Ligand B (-9.1) has a slightly better binding affinity than Ligand A (-8.4). The difference is 0.7 kcal/mol, which is meaningful.

**Overall Assessment:**

While Ligand B has a slightly better binding affinity and half-life, Ligand A is significantly better in several crucial areas for a CNS-targeting GPCR. Specifically, its superior BBB penetration (71.733 vs 44.203), lower P-gp efflux, better DILI score, and acceptable TPSA and logP make it a more promising candidate. The slightly lower affinity of Ligand A can potentially be optimized in subsequent iterations, but improving BBB penetration is often more challenging. The lower metabolic stability of Ligand A is a concern, but not insurmountable.

Output:
1
2025-04-17 07:40:09,640 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 drug candidates, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (343.427 and 351.422 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (82.27) is slightly higher than Ligand B (75.44), but both are below the 90 Angstroms threshold desirable for CNS targets.

**3. logP:** Both ligands have good logP values (1.423 and 2.139), falling within the optimal 1-3 range. Ligand B is slightly more lipophilic, which could be beneficial for membrane permeability.

**4. H-Bond Donors:** Ligand A has 2 HBD, and Ligand B has 1. Both are within the acceptable limit of <=5.

**5. H-Bond Acceptors:** Ligand A has 3 HBA, and Ligand B has 4. Both are within the acceptable limit of <=10.

**6. QED:** Ligand B (0.852) has a significantly better QED score than Ligand A (0.553), indicating a more drug-like profile.

**7. DILI:** Ligand A (16.44) has a much lower DILI risk than Ligand B (25.785), suggesting better potential for avoiding liver toxicity.

**8. BBB:** Ligand B (89.531) has a significantly higher BBB penetration percentile than Ligand A (42.807). This is a *critical* advantage for a CNS target like DRD2.

**9. Caco-2 Permeability:** Ligand A (-5.199) has worse Caco-2 permeability than Ligand B (-4.591).

**10. Aqueous Solubility:** Ligand A (-1.685) has better aqueous solubility than Ligand B (-2.449).

**11. hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.206 and 0.4), which is excellent.

**12. Microsomal Clearance:** Ligand A (-21.524) has significantly lower microsomal clearance than Ligand B (23.55), indicating better metabolic stability.

**13. In vitro Half-Life:** Ligand A (-11.477) has a longer in vitro half-life than Ligand B (8.399).

**14. P-gp Efflux:** Both ligands have low P-gp efflux liability (0.087 and 0.097).

**15. Binding Affinity:** Both ligands have comparable and strong binding affinities (-8.3 and -8.5 kcal/mol). The difference is negligible.

**Overall Assessment:**

While Ligand A has advantages in DILI, metabolic stability, and solubility, Ligand B's *significantly* higher BBB penetration (89.531 vs. 42.807) is the deciding factor for a CNS-targeting drug. This is a GPCR, and CNS penetration is paramount. The better QED score for Ligand B also contributes to its favorability. The slight differences in Caco-2 and solubility are less critical given the importance of BBB for this target.

Output:
1
2025-04-17 07:40:09,640 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (348.403) is slightly better positioned within the range than Ligand B (367.471).

**TPSA:** Ligand B (82.97) is significantly better than Ligand A (113.18). For CNS targets, TPSA should be <=90, and Ligand B comfortably meets this criterion while Ligand A is close to the upper limit.

**logP:** Both ligands have acceptable logP values (Ligand A: 0.82, Ligand B: 0.532), falling within the 1-3 range. Ligand A is slightly more lipophilic, which could be beneficial for membrane permeability, but both are reasonable.

**H-Bond Donors/Acceptors:** Ligand A has 3 HBD and 5 HBA, while Ligand B has 1 HBD and 6 HBA. Both are within acceptable limits (<=5 HBD and <=10 HBA).

**QED:** Both ligands have good QED scores (Ligand A: 0.602, Ligand B: 0.793), indicating drug-like properties. Ligand B is better here.

**DILI:** Ligand B (33.773) has a significantly lower DILI risk than Ligand A (53.858). This is a substantial advantage for Ligand B.

**BBB:** Ligand A (48.313) has a better BBB percentile than Ligand B (27.491). This is a critical factor for CNS targets like DRD2. However, a value of 48.313 is not *great* and could be a limitation.

**Caco-2 Permeability:** Ligand A (-5.308) has a more negative Caco-2 value, indicating *lower* permeability compared to Ligand B (-4.726).

**Aqueous Solubility:** Ligand A (-2.04) has slightly better aqueous solubility than Ligand B (-0.445), but both are quite poor.

**hERG:** Both ligands have very low hERG inhibition risk (Ligand A: 0.095, Ligand B: 0.202).

**Microsomal Clearance:** Ligand B (16.171) has significantly lower microsomal clearance than Ligand A (33.102), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand B (4.094) has a longer in vitro half-life than Ligand A (-22.019). This is a significant advantage.

**P-gp Efflux:** Ligand A (0.017) has a much lower P-gp efflux liability than Ligand B (0.083), meaning it's less likely to be pumped out of the brain.

**Binding Affinity:** Ligand A (-8.1 kcal/mol) has a significantly stronger binding affinity than Ligand B (-6.8 kcal/mol). This is a substantial advantage, potentially outweighing some ADME drawbacks.

**Overall Assessment:**

While Ligand A has a superior binding affinity and lower P-gp efflux, Ligand B demonstrates a more favorable ADME profile overall. Specifically, its lower DILI risk, better TPSA, better metabolic stability (lower Cl_mic, longer t1/2), and better QED are highly desirable. The difference in binding affinity is significant (1.3 kcal/mol), but the improved ADME properties of Ligand B, especially the lower DILI and better CNS penetration potential (despite not being stellar), make it the more promising candidate. The slightly lower BBB of Ligand B is a concern, but the other improvements are more impactful.

Output:
1
2025-04-17 07:40:09,641 - INFO - Reasoning:

Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (347.415 and 344.459 Da) fall comfortably within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (79.9) is slightly higher than Ligand B (75.19). Both are below the 90 A^2 threshold desirable for CNS targets, but Ligand B is preferable.

**3. logP:** Ligand A (1.067) is within the optimal 1-3 range, while Ligand B (2.271) is also acceptable.

**4. H-Bond Donors:** Ligand A has 2 HBD, and Ligand B has 1. Both are below the threshold of 5.

**5. H-Bond Acceptors:** Ligand A has 5 HBA, and Ligand B has 4. Both are below the threshold of 10.

**6. QED:** Both ligands have good QED scores (0.771 and 0.823 respectively), indicating good drug-like properties.

**7. DILI:** Ligand A (41.45) has a better DILI score than Ligand B (15.394), indicating lower potential for liver injury.

**8. BBB:** This is a crucial parameter for a CNS target like DRD2. Ligand B (89.104) has a significantly higher BBB percentile than Ligand A (72.431). This is a major advantage for Ligand B.

**9. Caco-2 Permeability:** Ligand A (-5.034) and Ligand B (-4.917) both have negative values, indicating poor permeability.

**10. Aqueous Solubility:** Both ligands have negative solubility values (-2.091 and -3.613 respectively), indicating poor solubility.

**11. hERG Inhibition:** Ligand A (0.282) has a lower hERG inhibition risk than Ligand B (0.646).

**12. Microsomal Clearance:** Ligand B (56.583) has a lower microsomal clearance than Ligand A (14.483), suggesting better metabolic stability.

**13. In vitro Half-Life:** Ligand A (0.183) has a very short half-life, while Ligand B (-4.369) has a negative value, which is unusual and suggests a very long half-life or an issue with the assay.

**14. P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.025 and 0.02 respectively).

**15. Binding Affinity:** Both ligands have very similar and strong binding affinities (-8.4 and -8.5 kcal/mol). The difference is negligible.

**Overall Assessment:**

While Ligand A has a better DILI score and lower hERG risk, Ligand B significantly outperforms it in BBB penetration (89.104 vs 72.431) and has better metabolic stability (lower Cl_mic). Given the CNS target, BBB is paramount. The slightly better metabolic stability of Ligand B is also a significant advantage. The unusual half-life value for Ligand B warrants further investigation, but the other factors strongly favor it.

Output:
1
2025-04-17 07:40:09,641 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (341.411 and 347.459 Da) fall comfortably within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (82.43) is slightly higher than Ligand B (73.74). Both are below the 90 Angstrom threshold desirable for CNS targets, but B is better.

**3. logP:** Both ligands (2.485 and 2.216) are within the optimal 1-3 range.

**4. H-Bond Donors:** Both have 1 HBD, which is acceptable.

**5. H-Bond Acceptors:** Both have 4 HBA, which is acceptable.

**6. QED:** Both have good QED scores (0.912 and 0.821), indicating drug-like properties.

**7. DILI:** Ligand B (35.479) has a significantly lower DILI risk than Ligand A (44.668). This is a substantial advantage.

**8. BBB:** Ligand A (76.464) has a better BBB penetration score than Ligand B (51.221). This is a *critical* factor for a CNS target like DRD2.

**9. Caco-2 Permeability:** Ligand A (-4.363) has better Caco-2 permeability than Ligand B (-4.743).

**10. Aqueous Solubility:** Ligand B (-1.884) has better aqueous solubility than Ligand A (-3.925).

**11. hERG Inhibition:** Both ligands have low hERG inhibition liability (0.69 and 0.374).

**12. Microsomal Clearance:** Both have similar microsomal clearance rates (45.584 and 47.327).

**13. In vitro Half-Life:** Both have similar in vitro half-lives (8.061 and 8.817).

**14. P-gp Efflux:** Both ligands have low P-gp efflux liability (0.115 and 0.09).

**15. Binding Affinity:** Both ligands have identical binding affinities (-7.9 kcal/mol), which is excellent.

**Overall Assessment:**

The key differentiating factors are BBB penetration and DILI risk. Ligand A has a significantly better BBB score (76.5%) which is paramount for a CNS drug. Ligand B has a lower DILI risk, which is also important. Since DRD2 is a CNS target, the BBB score is the more critical factor. The slightly better Caco-2 permeability and solubility of Ligand B are beneficial but are outweighed by the superior BBB penetration of Ligand A.

Output:
1
2025-04-17 07:40:09,641 - INFO - Reasoning:

Let's analyze Ligand A and Ligand B based on the provided guidelines, prioritizing GPCR-specific properties (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (339.435 Da) is slightly lower, which could be beneficial for permeability, while Ligand B (367.475 Da) is still well within the acceptable range.

**TPSA:** Ligand A (38.77) is excellent, well below the 90 A^2 threshold for CNS targets. Ligand B (102.57) is higher, but still reasonably acceptable, though less ideal for CNS penetration.

**logP:** Ligand A (3.616) is at the upper end of the optimal range (1-3), potentially raising concerns about solubility and off-target effects. Ligand B (1.311) is towards the lower end, which could hinder permeation.

**H-Bond Donors/Acceptors:** Ligand A (0 HBD, 4 HBA) has a favorable profile. Ligand B (4 HBD, 4 HBA) is also acceptable, but the 4 HBDs are slightly higher than ideal.

**QED:** Both ligands have reasonable QED scores (Ligand A: 0.754, Ligand B: 0.63), indicating good drug-like properties.

**DILI:** Ligand A (34.665) has a significantly lower DILI risk than Ligand B (45.56), suggesting a better safety profile.

**BBB:** This is a critical parameter for CNS targets like DRD2. Ligand A (78.868) has a good BBB percentile, exceeding the 70% threshold. Ligand B (61.38) is lower, indicating reduced brain penetration.

**Caco-2 Permeability:** Ligand A (-4.53) and Ligand B (-5.607) both have negative values, which is unusual and suggests poor permeability. However, these values are on a scale that is not fully defined, so the absolute magnitude is difficult to interpret.

**Aqueous Solubility:** Both ligands have poor aqueous solubility (Ligand A: -4.591, Ligand B: -2.645). This could pose formulation challenges.

**hERG Inhibition:** Both ligands show low hERG inhibition risk (Ligand A: 0.915, Ligand B: 0.566).

**Microsomal Clearance:** Ligand B (-39.173) has a much lower (better) microsomal clearance than Ligand A (87.794), indicating greater metabolic stability.

**In vitro Half-Life:** Ligand B (90.869) has a significantly longer in vitro half-life than Ligand A (-5.272), which is highly desirable.

**P-gp Efflux:** Ligand A (0.653) has lower P-gp efflux liability than Ligand B (0.016), suggesting better CNS exposure.

**Binding Affinity:** Both ligands have excellent binding affinity (Ligand A: -8.1 kcal/mol, Ligand B: -9.1 kcal/mol). Ligand B is slightly more potent, with a 1 kcal/mol advantage.

**Overall Assessment:**

Ligand B has a significantly better metabolic stability profile (lower Cl_mic, longer t1/2) and slightly better binding affinity. However, Ligand A excels in BBB penetration and has a lower DILI risk. Given the CNS target (DRD2), BBB penetration is paramount. While Ligand B's affinity is slightly better, the substantial difference in BBB (78.87 vs 61.38) and the lower DILI risk of Ligand A make it the more promising candidate. The poor solubility and Caco-2 permeability are concerns for both, but can be addressed with formulation strategies.

Output:
0
2025-04-17 07:40:09,641 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (346.431 Da) is slightly better, being closer to the middle of the range.

**TPSA:** Ligand A (78.67) is significantly better than Ligand B (111.55). For CNS targets, we want TPSA <= 90, and Ligand A comfortably meets this, while Ligand B is pushing the limit.

**logP:** Both ligands have acceptable logP values (0.698 and 0.799), falling within the 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A (HBD=1, HBA=5) is preferable to Ligand B (HBD=4, HBA=6) as it has fewer H-bond donors, potentially improving permeability. Both are within acceptable ranges.

**QED:** Ligand A (0.737) has a better QED score than Ligand B (0.588), indicating a more drug-like profile.

**DILI:** Ligand A (32.261) has a much lower DILI risk than Ligand B (60.14). This is a significant advantage for Ligand A.

**BBB:** Ligand A (58.007) has a better BBB penetration percentile than Ligand B (44.591), although neither are above the desirable >70 for CNS targets. However, given the other factors, Ligand A's higher BBB is a plus.

**Caco-2 Permeability:** Ligand A (-4.823) has a worse Caco-2 permeability than Ligand B (-5.129). Lower values are worse.

**Aqueous Solubility:** Ligand A (-0.76) has better aqueous solubility than Ligand B (-2.686).

**hERG Inhibition:** Ligand A (0.132) has a much lower hERG inhibition liability than Ligand B (0.368), indicating a lower risk of cardiotoxicity.

**Microsomal Clearance:** Ligand A (37.568) has a higher microsomal clearance than Ligand B (8.789), meaning it's metabolized faster. This is a disadvantage for Ligand A.

**In vitro Half-Life:** Ligand B (-7.978) has a longer in vitro half-life than Ligand A (10.48). This is a significant advantage for Ligand B.

**P-gp Efflux:** Ligand A (0.014) has significantly lower P-gp efflux liability than Ligand B (0.031), which is crucial for CNS penetration.

**Binding Affinity:** Ligand B (-8.4) has a slightly better binding affinity than Ligand A (-7.0). While a 1.4 kcal/mol difference is good, the other ADME properties are more concerning.

**Overall Assessment:**

Ligand A is the stronger candidate. While Ligand B has slightly better affinity and half-life, Ligand A excels in critical areas for a CNS-targeting GPCR ligand: TPSA, DILI, BBB, hERG, and P-gp efflux. Ligand A's lower TPSA and P-gp efflux are particularly important for brain penetration. The better solubility and lower DILI risk also contribute to its improved profile. The higher clearance of Ligand A is a concern, but could potentially be addressed through structural modifications.



Output:
0
2025-04-17 07:40:09,642 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B against the provided guidelines, prioritizing GPCR-specific properties (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (349.435 Da) is slightly lower, which *could* be beneficial for permeability, but both are acceptable.

**TPSA:** Ligand A (98.02) is better than Ligand B (60.77). For CNS targets, TPSA < 90 is preferred, and Ligand A is closer to this threshold. This favors Ligand A.

**logP:** Ligand A (0.376) is quite low, potentially hindering permeation. Ligand B (4.047) is higher, falling within the optimal range of 1-3, and is therefore preferable.

**H-Bond Donors/Acceptors:** Both have 2 HBDs, which is good. Ligand A has 6 HBAs, while Ligand B has 3. Lower HBA is generally preferred for better permeability, favoring Ligand B.

**QED:** Both ligands have similar QED values (0.695 and 0.652), indicating reasonable drug-likeness.

**DILI:** Ligand A (49.011) has a higher DILI risk than Ligand B (10.237). This is a significant advantage for Ligand B.

**BBB:** Ligand A (67.197) has a better BBB percentile than Ligand B (56.34). This is a crucial factor for CNS targets like DRD2, and strongly favors Ligand A.

**Caco-2 Permeability:** Ligand A (-5.141) has a very poor Caco-2 permeability, while Ligand B (-4.823) is also poor, but slightly better.

**Aqueous Solubility:** Both ligands have very poor aqueous solubility (-1.477 and -3.611 respectively).

**hERG:** Ligand A (0.037) has a much lower hERG risk than Ligand B (0.867). This is a significant safety advantage for Ligand A.

**Microsomal Clearance:** Ligand B (84.008) has a much higher microsomal clearance than Ligand A (15.762), indicating lower metabolic stability. This is a clear advantage for Ligand A.

**In vitro Half-Life:** Ligand B (44.684) has a longer in vitro half-life than Ligand A (-13.242). This is a positive for Ligand B.

**P-gp Efflux:** Ligand A (0.05) has significantly lower P-gp efflux liability than Ligand B (0.472). Lower P-gp efflux is crucial for CNS penetration, favoring Ligand A.

**Binding Affinity:** Ligand A (-8.3 kcal/mol) has a stronger binding affinity than Ligand B (-6.8 kcal/mol). The difference of 1.5 kcal/mol is substantial and can outweigh some ADME drawbacks.

**Overall Assessment:**

Ligand A excels in BBB penetration, binding affinity, hERG risk, P-gp efflux, and metabolic stability. However, it suffers from very low logP and Caco-2 permeability. Ligand B has a better logP, lower DILI risk, and a longer half-life, but its BBB penetration is significantly worse, and it has higher P-gp efflux and metabolic clearance.

Given the CNS target (DRD2), BBB penetration is paramount. The superior binding affinity of Ligand A, combined with its better BBB and lower P-gp efflux, outweigh its lower logP and permeability concerns, especially considering optimization strategies could potentially address these issues. The lower DILI risk of Ligand B is attractive, but less critical than CNS exposure.

Output:
0
2025-04-17 07:40:09,642 - INFO - Batch 384 complete. Total preferences: 6144
2025-04-17 07:40:09,642 - INFO - Processing batch 385/512...
2025-04-17 07:41:03,362 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (350.419 Da and 361.433 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (116.48) is higher than the ideal <90 for CNS targets, while Ligand B (70.67) is well within the desired range. This is a significant advantage for Ligand B.

**logP:** Ligand A (-0.49) is a bit low, potentially hindering membrane permeability. Ligand B (0.806) is closer to the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A has 4 HBD and 6 HBA, which are acceptable. Ligand B has 2 HBD and 4 HBA, also acceptable.

**QED:** Both ligands have reasonable QED scores (0.495 and 0.671), indicating drug-like properties. Ligand B is slightly better.

**DILI:** Ligand A (23.769) has a lower DILI risk than Ligand B (11.632), which is favorable.

**BBB:** This is crucial for a CNS target like DRD2. Ligand A (28.81) has a very low BBB penetration percentile, making it unlikely to reach the target in the brain. Ligand B (81.466) exhibits excellent predicted BBB penetration. This is a decisive advantage for Ligand B.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values, which is unusual and suggests poor permeability. However, these values are on a different scale and difficult to directly compare without knowing the scale's specifics.

**Aqueous Solubility:** Both ligands have negative solubility values, again, difficult to interpret without knowing the scale.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.106 and 0.271).

**Microsomal Clearance:** Ligand A (12.119) has a higher microsomal clearance than Ligand B (1.883), indicating faster metabolism and potentially lower exposure.

**In vitro Half-Life:** Ligand A (-19.505) has a negative half-life, which is not physically possible and suggests an issue with the prediction. Ligand B (-2.562) is also negative, but less extreme.

**P-gp Efflux:** Both ligands show low P-gp efflux liability (0.012 and 0.008), which is good for CNS penetration.

**Binding Affinity:** Ligand A (-8.4 kcal/mol) has a slightly better binding affinity than Ligand B (-7.5 kcal/mol). However, the difference is less than 1.5 kcal/mol and can be outweighed by other factors.

**Overall Assessment:**

Ligand B is significantly more promising due to its excellent BBB penetration (81.466), favorable TPSA (70.67), and acceptable logP (0.806). While Ligand A has slightly better binding affinity, the poor BBB penetration makes it unlikely to be effective *in vivo* for a CNS target. The issues with negative half-life values for both compounds are concerning and would require further investigation, but the difference in BBB penetration is the most critical factor here.

Output:
1
2025-04-17 07:41:03,362 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (352.391 and 367.475 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (116.93) is slightly above the optimal <90 for CNS targets, but still reasonable. Ligand B (89.35) is excellent, well below 90.

**logP:** Ligand A (-1.328) is a bit low, potentially hindering permeability. Ligand B (1.411) is within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A has 3 HBD and 7 HBA, which are acceptable. Ligand B has 1 HBD and 7 HBA, also acceptable.

**QED:** Both ligands have good QED scores (0.601 and 0.784), indicating drug-like properties.

**DILI:** Ligand A (29.197) has a very favorable DILI score, indicating low liver injury risk. Ligand B (63.513) is higher, suggesting a moderate risk, but still not alarmingly high.

**BBB:** This is critical for a CNS target. Ligand A (12.33) has a very poor BBB percentile, suggesting limited brain penetration. Ligand B (45.677) is significantly better, although still not ideal (we want >70).

**Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and suggests poor permeability. However, the scale is not specified, so it's difficult to interpret.

**Aqueous Solubility:** Both have negative solubility values, which is also unusual. Again, the scale is unclear.

**hERG:** Both ligands have very low hERG inhibition liability (0.037 and 0.068), which is excellent.

**Microsomal Clearance:** Ligand A (-27.467) has a negative clearance, which is impossible. This is likely an error in the data. Ligand B (40.213) has moderate clearance.

**In vitro Half-Life:** Ligand A (15.803) has a reasonable half-life. Ligand B (-12.192) has a negative half-life, which is impossible. This is likely an error in the data.

**P-gp Efflux:** Both have very low P-gp efflux liability (0.006 and 0.062), which is favorable for CNS penetration.

**Binding Affinity:** Ligand A (-7.3) has a slightly better binding affinity than Ligand B (-6.6), but the difference is not huge (0.7 kcal/mol).

**Overall Assessment:**

Ligand A has a better binding affinity and DILI score, but suffers from a very poor BBB percentile and questionable clearance/half-life data. Its logP is also suboptimal. Ligand B has a better logP, TPSA, and a significantly better BBB percentile, but its binding affinity is slightly weaker and its DILI score is higher. The negative values for Caco-2, solubility, and half-life for Ligand B are concerning and suggest data errors.

Given the importance of BBB penetration for a CNS target like DRD2, and considering the questionable data for Ligand B, **Ligand A is the more promising candidate despite its flaws**. The affinity difference is not large enough to outweigh the significant BBB advantage that would be needed for Ligand B to be viable. However, the negative clearance and half-life values for Ligand A *must* be investigated and corrected.

Output:
0
2025-04-17 07:41:03,363 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (335.411 and 348.531 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (72.7) is better than Ligand B (41.57). For CNS targets, we want TPSA <= 90, both are well within this range, but A is closer to the upper limit.

**logP:** Both ligands have good logP values (2.966 and 3.373), falling within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Both have 1 HBD, which is good. Ligand A has 5 HBA, while Ligand B has 3. Both are acceptable (<=10).

**QED:** Both ligands have acceptable QED scores (0.532 and 0.748), indicating good drug-like properties. Ligand B is better here.

**DILI:** Ligand A (69.911) has a higher DILI risk than Ligand B (9.694). This is a significant advantage for Ligand B.

**BBB:** Ligand B (87.476) has a substantially better BBB penetration score than Ligand A (65.529). This is *critical* for a CNS target like DRD2.

**Caco-2 Permeability:** Both have negative values, which is unusual. Assuming these are logP-like scales, lower values indicate poorer permeability. Ligand A (-5.26) is worse than Ligand B (-4.794).

**Aqueous Solubility:** Both have negative values, which is also unusual. Lower values indicate poorer solubility. Ligand A (-3.188) is worse than Ligand B (-3.075).

**hERG:** Both have low hERG inhibition risk (0.499 and 0.628), which is good.

**Microsomal Clearance:** Ligand A (93.005) has higher microsomal clearance than Ligand B (57.087), suggesting lower metabolic stability. Ligand B is preferred.

**In vitro Half-Life:** Ligand B (-4.449) has a slightly better (less negative) in vitro half-life than Ligand A (-34.681).

**P-gp Efflux:** Ligand A (0.427) has lower P-gp efflux liability than Ligand B (0.136), which is favorable for CNS penetration.

**Binding Affinity:** Ligand B (-7.2 kcal/mol) has a slightly better binding affinity than Ligand A (-8.9 kcal/mol). While A is better, the difference is not substantial enough to overcome the other ADME deficiencies.

**Overall Assessment:**

Ligand B is significantly better overall. The most important factor for a CNS GPCR target is BBB penetration, and Ligand B has a much higher score (87.476 vs 65.529). It also has a much lower DILI risk, better metabolic stability (lower Cl_mic), and a better half-life. While Ligand A has slightly better affinity and P-gp efflux, these are outweighed by the superior ADME profile of Ligand B.

Output:
1
2025-04-17 07:41:03,363 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (368.455 and 361.519 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (112.57) is slightly above the optimal <90 for CNS targets, but still reasonable. Ligand B (73.45) is excellent, well below 90. This favors Ligand B.

**3. logP:** Both ligands (1.811 and 1.977) are within the optimal 1-3 range.

**4. H-Bond Donors:** Ligand A (3) is acceptable. Ligand B (1) is also good, potentially improving permeability.

**5. H-Bond Acceptors:** Ligand A (4) is good. Ligand B (8) is higher, but still within the acceptable limit of 10.

**6. QED:** Both ligands (0.648 and 0.725) have good drug-like properties, exceeding the 0.5 threshold.

**7. DILI:** Ligand A (63.862) has a higher DILI risk than Ligand B (52.152), though both are reasonably low. This favors Ligand B.

**8. BBB:** Ligand B (59.131) has a significantly better BBB penetration percentile than Ligand A (47.111). This is a *critical* advantage for a CNS target like DRD2.

**9. Caco-2 Permeability:** Both are negative, indicating poor permeability. However, the scale is not specified, so it is hard to compare.

**10. Aqueous Solubility:** Both are negative, indicating poor solubility. However, the scale is not specified, so it is hard to compare.

**11. hERG Inhibition:** Both ligands (0.051 and 0.102) show very low hERG inhibition risk, which is excellent.

**12. Microsomal Clearance:** Ligand B (46.809) has a considerably lower microsomal clearance than Ligand A (11.202), suggesting better metabolic stability. This favors Ligand B.

**13. In vitro Half-Life:** Ligand B (-5.245) has a longer in vitro half-life than Ligand A (-35.163). This is a significant advantage.

**14. P-gp Efflux:** Both are very low (0.009 and 0.177), indicating minimal P-gp efflux.

**15. Binding Affinity:** Ligand B (-7.2 kcal/mol) has a slightly better binding affinity than Ligand A (-8.3 kcal/mol). While A is better, the difference is not substantial enough to outweigh the other advantages of B.

**Overall:**

Ligand B consistently outperforms Ligand A in key areas for a CNS-targeting GPCR ligand: BBB penetration, metabolic stability (lower Cl_mic, longer t1/2), and DILI risk. While Ligand A has a slightly better binding affinity, the other ADME/Tox properties of Ligand B make it a more promising drug candidate.

Output:
1
2025-04-17 07:41:03,363 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (346.383 and 352.523 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (95.94) is slightly above the ideal <90 for CNS targets, but still reasonable. Ligand B (55.89) is excellent, well below 90.

**logP:** Both ligands (1.272 and 1.31) are within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A has 2 HBD and 5 HBA, while Ligand B has 1 HBD and 4 HBA. Both are within acceptable limits (<=5 HBD and <=10 HBA).

**QED:** Both ligands have reasonable QED scores (0.756 and 0.68), indicating good drug-like properties.

**DILI:** Ligand A has a DILI risk of 65.374, which is moderately high. Ligand B has a much lower DILI risk of 3.955, which is excellent.

**BBB:** Ligand A has a BBB penetration percentile of 56.611, which is below the desirable >70 for CNS targets. Ligand B has a much better BBB penetration percentile of 70.648, exceeding the threshold.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.07 and -5.148), which is unusual and suggests poor permeability. This is a significant concern for both.

**Aqueous Solubility:** Both ligands have negative solubility values (-3.572 and -0.948), indicating very poor aqueous solubility. This is a major drawback.

**hERG Inhibition:** Ligand A (0.154) has a slightly higher hERG inhibition liability than Ligand B (0.442), but both are relatively low risk.

**Microsomal Clearance:** Ligand A (-11.455) has a lower (better) microsomal clearance than Ligand B (-2.816), suggesting better metabolic stability.

**In vitro Half-Life:** Both ligands have very long in vitro half-lives (11.104 and -11.863 hours), which is positive.

**P-gp Efflux:** Ligand A (0.061) has a lower P-gp efflux liability than Ligand B (0.007), which is favorable for CNS penetration.

**Binding Affinity:** Ligand A (-9.8 kcal/mol) has a significantly stronger binding affinity than Ligand B (-7.4 kcal/mol). This is a substantial advantage.

**Overall Assessment:**

Despite the strong affinity of Ligand A, its higher DILI risk, lower BBB penetration, and higher P-gp efflux are significant concerns for a CNS drug. Ligand B, while having a weaker affinity, presents a much more favorable ADME profile, especially regarding BBB penetration and DILI risk. The poor Caco-2 and solubility for both are concerning, but can potentially be addressed with formulation strategies. The stronger affinity of Ligand A is a compelling factor, but the ADME liabilities are too substantial to ignore, especially for a CNS target.

Output:
1
2025-04-17 07:41:03,363 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (356.419 and 348.531 Da) fall within the ideal range of 200-500 Da.

**TPSA:** Ligand A (105.17) is borderline for CNS penetration, slightly above the preferred <90, but still acceptable. Ligand B (49.41) is excellent, well below the threshold.

**logP:** Ligand A (-0.167) is quite low, potentially hindering membrane permeability. Ligand B (3.748) is optimal.

**H-Bond Donors/Acceptors:** Ligand A (2 HBD, 6 HBA) is good. Ligand B (1 HBD, 2 HBA) is also excellent. Both are within acceptable limits.

**QED:** Both ligands have good QED scores (0.416 and 0.795), indicating drug-like properties. Ligand B is significantly better.

**DILI:** Ligand A (17.642) has a low DILI risk, which is excellent. Ligand B (8.104) is also very low risk.

**BBB:** Both ligands have good BBB penetration (70.57% and 79.488%), exceeding the 70% threshold for CNS targets. Ligand B is slightly better.

**Caco-2 Permeability:** Ligand A (-5.094) has poor Caco-2 permeability, which is concerning. Ligand B (-4.52) is also poor, but slightly better than A.

**Aqueous Solubility:** Both ligands have poor aqueous solubility (-1.374 and -3.715). This could pose formulation challenges.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.162 and 0.657).

**Microsomal Clearance:** Ligand A (33.998) has lower microsomal clearance, suggesting better metabolic stability than Ligand B (82.534).

**In vitro Half-Life:** Ligand A (-15.332) has a negative half-life, which is not possible and suggests an issue with the data or prediction. Ligand B (0.78) has a very short half-life.

**P-gp Efflux:** Ligand A (0.027) has very low P-gp efflux, which is highly desirable for CNS penetration. Ligand B (0.138) also has low P-gp efflux.

**Binding Affinity:** Ligand B (-8.5 kcal/mol) has a significantly stronger binding affinity than Ligand A (-6.1 kcal/mol). This >1.5 kcal/mol difference is substantial and can outweigh other drawbacks.

**Overall Assessment:**

Ligand B is the stronger candidate. While both have poor solubility and Caco-2 permeability, Ligand B's superior logP, significantly higher binding affinity, and better QED score are crucial advantages for a GPCR target like DRD2. The slightly better BBB penetration also contributes. Ligand A's negative in vitro half-life is a major red flag. Although Ligand A has lower clearance, the negative half-life makes it unreliable.

Output:
1
2025-04-17 07:41:03,363 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (377.491 Da) is slightly higher than Ligand B (344.455 Da), but both are acceptable.

**TPSA:** Both ligands have TPSA values below the 90 A^2 threshold desirable for CNS targets. Ligand A (72.36 A^2) is slightly higher than Ligand B (69.64 A^2), but both are good.

**logP:** Ligand A (3.976) is at the upper end of the optimal range (1-3), while Ligand B (1.828) is towards the lower end. While Ligand A's logP isn't alarming, Ligand B's lower value *could* hinder permeability.

**H-Bond Donors/Acceptors:** Both ligands have acceptable HBD (2) and HBA (6 for A, 3 for B) counts, well within the guidelines.

**QED:** Both ligands have good QED scores (0.59 for A, 0.774 for B), indicating good drug-like properties. Ligand B is slightly better here.

**DILI:** Ligand A has a significantly higher DILI risk (83.249%) than Ligand B (11.632%). This is a major red flag for Ligand A.

**BBB:** Ligand A (76.541%) has a good BBB penetration score, exceeding the 70% threshold. Ligand B (40.403%) is considerably lower and less desirable for a CNS target like DRD2.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values, which is unusual and suggests poor permeability. However, the scale is not specified, so it's difficult to interpret.

**Aqueous Solubility:** Both ligands have negative solubility values, also unusual. Again, the scale is not specified, making interpretation difficult.

**hERG:** Both ligands have low hERG inhibition liability (0.266 for A, 0.342 for B), which is good.

**Microsomal Clearance:** Ligand A has a higher microsomal clearance (97.091 mL/min/kg) than Ligand B (14.621 mL/min/kg), indicating lower metabolic stability.

**In vitro Half-Life:** Ligand B has a negative half-life (-15.173 hours), which is impossible and indicates a problem with the data. Ligand A has a reasonable half-life (33.653 hours).

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.231 for A, 0.144 for B), which is favorable for CNS penetration.

**Binding Affinity:** Ligand B (-9.0 kcal/mol) has a significantly stronger binding affinity than Ligand A (-7.8 kcal/mol). This is a substantial difference.

**Overall Assessment:**

Ligand A has good BBB penetration and a reasonable half-life, but suffers from a high DILI risk and higher metabolic clearance. Its logP is borderline.

Ligand B has a much better binding affinity, lower DILI risk, and lower metabolic clearance. However, its BBB penetration is poor, and its half-life data is suspect (negative value).

Given the GPCR-specific priorities, and the importance of CNS penetration for DRD2, the poor BBB score of Ligand B is a significant drawback. However, the *extremely* strong binding affinity of Ligand B (-9.0 kcal/mol vs -7.8 kcal/mol) and the much lower DILI risk are compelling. The negative half-life is a data issue that needs investigation, but even if it's zero, the binding affinity advantage is substantial. I'd prioritize optimizing Ligand B to improve its BBB penetration.

Output:
1
2025-04-17 07:41:03,364 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (338.363 and 362.865 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (102.42) is slightly above the optimal <90 for CNS targets, but still reasonable. Ligand B (84.73) is well within the desired range. This favors Ligand B.

**3. logP:** Both ligands have good logP values (2.78 and 1.996), falling within the 1-3 optimal range.

**4. H-Bond Donors:** Ligand A (4) and Ligand B (2) are both acceptable, being less than 5.

**5. H-Bond Acceptors:** Ligand A (3) and Ligand B (6) are both acceptable, being less than 10.

**6. QED:** Both ligands have good QED scores (0.574 and 0.768), indicating good drug-like properties.

**7. DILI:** Ligand A (78.054) has a higher DILI risk than Ligand B (61.38), though both are acceptable. This favors Ligand B.

**8. BBB:** Ligand B (80.574) has a significantly better BBB penetration percentile than Ligand A (19.93). This is a *critical* advantage for a CNS target like DRD2.

**9. Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and suggests poor permeability. However, the scale isn't specified, so it's hard to interpret.

**10. Aqueous Solubility:** Both have negative solubility values, which is also unusual. Again, difficult to interpret without knowing the scale.

**11. hERG Inhibition:** Both ligands have low hERG inhibition liability (0.204 and 0.521), which is good.

**12. Microsomal Clearance:** Ligand A (11.292) has lower microsomal clearance than Ligand B (19.977), suggesting better metabolic stability. This favors Ligand A.

**13. In vitro Half-Life:** Ligand A (-22.709) has a very negative half-life, which is concerning and likely indicates a very short half-life. Ligand B (36.238) has a more reasonable half-life. This strongly favors Ligand B.

**14. P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.046 and 0.11), which is beneficial for CNS penetration.

**15. Binding Affinity:** Both ligands have excellent binding affinities (-9.6 and -8.6 kcal/mol). Ligand A is slightly better (-9.6 kcal/mol), but the difference is less than 1.5 kcal/mol, so it doesn't overwhelmingly outweigh other factors.

**Overall Assessment:**

Ligand B is the more promising candidate. While Ligand A has slightly better affinity and metabolic stability, Ligand B's significantly superior BBB penetration (80.574 vs 19.93) and lower DILI risk are critical advantages for a CNS-targeting drug. The more reasonable in vitro half-life of Ligand B also contributes to its favorability. The unusual negative values for Caco-2 and solubility are concerning for both, but the BBB advantage of Ligand B is too significant to ignore.

Output:
1
2025-04-17 07:41:03,364 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 drug candidates, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (348.403 Da) is slightly lower, which could be beneficial for permeability, but both are acceptable.

**TPSA:** Ligand A (104.39) is better than Ligand B (61.92) as it is closer to the ideal range for CNS targets (<=90). Ligand B is quite low, which might indicate reduced hydrogen bonding and potentially lower solubility.

**logP:** Ligand A (1.297) is within the optimal range (1-3). Ligand B (3.471) is at the higher end, potentially leading to solubility issues or off-target interactions, but still acceptable.

**H-Bond Donors/Acceptors:** Ligand A has 2 HBD and 5 HBA, while Ligand B has 0 HBD and 4 HBA. Both are within acceptable limits (<=5 HBD, <=10 HBA).

**QED:** Both ligands have reasonable QED values (A: 0.398, B: 0.699), with Ligand B being significantly better.

**DILI:** Both ligands have relatively high DILI risk, but Ligand B (55.797) is lower than Ligand A (67.468), indicating a slightly better safety profile.

**BBB:** Both ligands have similar BBB penetration (A: 56.689, B: 54.595). Neither is ideal (>70), but acceptable given the binding affinity.

**Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and suggests a potential issue with the data or a very poor permeability.

**Aqueous Solubility:** Both ligands have negative solubility values, which is also unusual and suggests a potential issue with the data or very poor solubility.

**hERG Inhibition:** Ligand A (0.288) has a lower hERG inhibition liability than Ligand B (0.909), which is a significant advantage.

**Microsomal Clearance:** Ligand A (92.561) has higher microsomal clearance than Ligand B (73.793), suggesting lower metabolic stability.

**In vitro Half-Life:** Ligand B (10.987) has a significantly longer half-life than Ligand A (-26.92), which is a major advantage.

**P-gp Efflux:** Ligand A (0.153) has lower P-gp efflux liability than Ligand B (0.551), which is favorable for CNS penetration.

**Binding Affinity:** Both ligands have excellent binding affinity (-7.2 kcal/mol for A and -7.0 kcal/mol for B). Ligand A is slightly better.

**Overall Assessment:**

Ligand A has a slightly better binding affinity and lower P-gp efflux, but suffers from higher DILI risk, higher microsomal clearance (lower metabolic stability), and a significantly shorter half-life. Ligand B has a better QED, lower DILI, longer half-life, and lower hERG risk. Considering the GPCR-specific priorities, BBB penetration is similar for both, but the longer half-life and better safety profile of Ligand B are more important. The slightly higher logP of Ligand B is a minor concern, but the overall balance of properties favors Ligand B.

Output:
1
2025-04-17 07:41:03,364 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (350.463 and 346.402 Da) fall within the ideal range of 200-500 Da.

**TPSA:** Ligand A (98.32) is slightly above the optimal <90 for CNS targets, but still reasonable. Ligand B (67.43) is well within the desired range.

**logP:** Both ligands have acceptable logP values (1.623 and 2.528), falling within the 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A has 3 HBD and 4 HBA, while Ligand B has 2 HBD and 3 HBA. Both are within the recommended limits.

**QED:** Both ligands have good QED scores (0.63 and 0.746), indicating drug-like properties.

**DILI:** Ligand A (24.506) has a significantly lower DILI risk than Ligand B (38.891), which is a substantial advantage.

**BBB:** Ligand B (85.343) has a much higher BBB penetration score than Ligand A (27.801). This is a *critical* factor for a CNS target like DRD2.

**Caco-2 Permeability:** Ligand A (-5.408) has poorer Caco-2 permeability than Ligand B (-4.324), suggesting lower intestinal absorption.

**Aqueous Solubility:** Both ligands have poor aqueous solubility (-1.841 and -4.073). This could pose formulation challenges, but is less critical than BBB for a CNS target.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.357 and 0.455).

**Microsomal Clearance:** Ligand A (5.683) has a lower microsomal clearance than Ligand B (64.172), indicating better metabolic stability.

**In vitro Half-Life:** Ligand A (-6.89) has a significantly longer in vitro half-life than Ligand B (-21.788). This is a major advantage.

**P-gp Efflux:** Ligand A (0.042) has much lower P-gp efflux liability than Ligand B (0.16), which is beneficial for CNS exposure.

**Binding Affinity:** Ligand B (-8.1) has a slightly stronger binding affinity than Ligand A (-7.5), a difference of 0.6 kcal/mol. While affinity is important, the other factors are more decisive here.

**Overall Assessment:**

Ligand B excels in BBB penetration and has slightly better binding affinity. However, Ligand A demonstrates superior metabolic stability (lower Cl_mic, longer t1/2), lower DILI risk, and lower P-gp efflux. The significantly better BBB score for Ligand B is a strong point in its favor, given the CNS target. However, the combination of lower DILI, better metabolic stability, and lower P-gp efflux for Ligand A makes it a more promising candidate overall, especially considering the relatively small affinity difference. The poor solubility of both compounds would need to be addressed during formulation.

Output:
1
2025-04-17 07:41:03,364 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (337.463 Da) is slightly lower, which could be advantageous for permeability.

**TPSA:** Ligand A (29.54) is excellent for CNS penetration, well below the 90 A^2 threshold. Ligand B (117.51) is higher, potentially hindering BBB penetration, but still within a reasonable range.

**logP:** Ligand A (4.048) is at the upper end of the optimal range, potentially leading to solubility issues or off-target effects. Ligand B (1.096) is a bit low, which might reduce its ability to cross cell membranes.

**H-Bond Donors/Acceptors:** Ligand A (0 HBD, 3 HBA) is favorable. Ligand B (2 HBD, 8 HBA) is acceptable, but higher HBA could slightly impact permeability.

**QED:** Both ligands have reasonable QED scores (A: 0.771, B: 0.506), suggesting acceptable drug-like properties.

**DILI:** Ligand A (17.138) has a significantly lower DILI risk than Ligand B (87.127), a major advantage.

**BBB:** Ligand A (97.48) exhibits excellent BBB penetration, crucial for a CNS target like DRD2. Ligand B (49.05) is considerably lower, raising concerns about reaching the target in the brain.

**Caco-2 Permeability:** Both have negative values, which is unusual and suggests a problem with the data. However, we can still compare their relative values. Ligand A (-4.678) is better than Ligand B (-4.922).

**Aqueous Solubility:** Both have negative values, which is unusual. Ligand A (-3.969) is slightly better than Ligand B (-2.902).

**hERG Inhibition:** Ligand A (0.951) shows lower hERG inhibition risk than Ligand B (0.134), which is positive.

**Microsomal Clearance:** Ligand A (50.772) has a higher clearance than Ligand B (-0.345), indicating lower metabolic stability. This is a drawback for Ligand A.

**In vitro Half-Life:** Ligand A (-5.772) has a shorter half-life than Ligand B (0.638), further supporting the lower metabolic stability of Ligand A.

**P-gp Efflux:** Ligand A (0.488) has lower P-gp efflux liability than Ligand B (0.058), which is favorable for CNS penetration.

**Binding Affinity:** Both ligands have very similar and strong binding affinities (-8.7 and -8.8 kcal/mol). The difference is negligible.

**Overall Assessment:**

Considering the GPCR-specific priorities, Ligand A is the more promising candidate. Its superior BBB penetration, significantly lower DILI risk, and lower P-gp efflux outweigh its slightly higher logP and poorer metabolic stability. The similar binding affinities mean potency is not a differentiating factor. The unusual negative values for Caco-2 and solubility are concerning, but the relative comparison still favors A.

Output:
0
2025-04-17 07:41:03,365 - INFO - Okay, let's analyze these two ligands for their potential as DRD2 drug candidates. DRD2 is a GPCR in the CNS, so BBB penetration, logP, Pgp efflux, TPSA, and binding affinity are paramount.

**Ligand A: [343.387, 112.91 ,   1.574,   3.   ,   5.   ,   0.63 ,  67.507,  42.497, -5.379,  -3.15 ,   0.05 ,  28.358, -34.999,   0.045,  -8.8  ]**

*   **MW:** 343.387 Da - Good, within the 200-500 range.
*   **TPSA:** 112.91  - Acceptable, but approaching the upper limit for CNS targets (ideally <90).
*   **logP:** 1.574 - Good, within the optimal 1-3 range.
*   **HBD:** 3 - Good, within the acceptable limit.
*   **HBA:** 5 - Good, within the acceptable limit.
*   **QED:** 0.63 - Good, above the 0.5 threshold.
*   **DILI:** 67.507 - Moderate risk, but not alarmingly high.
*   **BBB:** 42.497 - Poor. Significantly below the desirable >70 for CNS targets. A major drawback.
*   **Caco-2:** -5.379 - Very poor permeability.
*   **Solubility:** -3.15 - Very poor solubility.
*   **hERG:** 0.05 - Excellent, very low risk of hERG inhibition.
*   **Cl_mic:** 28.358 mL/min/kg - Moderate clearance. Not ideal, but not terrible.
*   **t1/2:** -34.999 hours - Very short half-life. A significant issue.
*   **Pgp:** 0.045 - Excellent, low P-gp efflux.
*   **Affinity:** -8.8 kcal/mol - Excellent, very strong binding.

**Ligand B: [351.378,  96.62 ,   1.837,   3.   ,   6.   ,   0.597,  69.717,  76.774, -4.814,  -3.202,   0.69 ,  70.   ,  58.949,   0.306,  -7.7  ]**

*   **MW:** 351.378 Da - Good, within the 200-500 range.
*   **TPSA:** 96.62 - Acceptable, closer to the upper limit for CNS targets, but still reasonable.
*   **logP:** 1.837 - Good, within the optimal 1-3 range.
*   **HBD:** 3 - Good, within the acceptable limit.
*   **HBA:** 6 - Acceptable, slightly higher but still reasonable.
*   **QED:** 0.597 - Good, above the 0.5 threshold.
*   **DILI:** 69.717 - Moderate risk, similar to Ligand A.
*   **BBB:** 76.774 - Excellent. Well above the >70 threshold for CNS targets. A major advantage.
*   **Caco-2:** -4.814 - Poor permeability, but better than Ligand A.
*   **Solubility:** -3.202 - Poor solubility, similar to Ligand A.
*   **hERG:** 0.69 - Moderate risk, higher than Ligand A.
*   **Cl_mic:** 70 mL/min/kg - High clearance. A significant drawback.
*   **t1/2:** 58.949 hours - Good, long half-life.
*   **Pgp:** 0.306 - Moderate P-gp efflux, higher than Ligand A.
*   **Affinity:** -7.7 kcal/mol - Good, strong binding, but 1.1 kcal/mol weaker than Ligand A.

**Comparison and Decision:**

While Ligand A boasts a superior binding affinity (-8.8 kcal/mol vs -7.7 kcal/mol), its extremely poor BBB penetration (42.5%) and short half-life are critical liabilities for a CNS-targeting drug. Ligand B, despite slightly weaker binding, has excellent BBB penetration (76.8%) and a good half-life (58.9 hours). The difference in binding affinity (1.1 kcal/mol) is not large enough to overcome the significant pharmacokinetic deficiencies of Ligand A, especially given the CNS target. Ligand B's moderate hERG risk and higher clearance are concerns that could be addressed through further optimization, but the BBB penetration is a major hurdle for Ligand A that is less likely to be overcome.

Therefore, **Ligand B** is the more viable drug candidate.

1
2025-04-17 07:41:03,365 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B based on the provided guidelines, prioritizing GPCR-specific properties (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (410.312 Da) is slightly higher than Ligand B (389.989 Da), but both are acceptable.

**TPSA:** Ligand A (68.8) is better than Ligand B (60.77) for CNS penetration, being closer to the <90 target.

**logP:** Ligand A (2.215) is within the optimal range (1-3), while Ligand B (4.387) is higher. While not drastically high, Ligand B's logP could potentially lead to solubility issues or off-target interactions.

**H-Bond Donors/Acceptors:** Both ligands have 2 HBD and 4-5 HBA, which are within acceptable limits.

**QED:** Both ligands have QED values above 0.6, indicating good drug-likeness.

**DILI:** Ligand A (41.411) has a slightly higher DILI risk than Ligand B (13.61), but both are below the concerning threshold of 60.

**BBB:** Ligand A (53.083) and Ligand B (62.117) both have reasonable BBB penetration, but Ligand B is better, exceeding 60%. A value >70 is desirable for CNS targets, and Ligand B is closer.

**Caco-2 Permeability:** Ligand A (-5.104) has poor Caco-2 permeability, while Ligand B (-4.655) is also poor, but slightly better.

**Aqueous Solubility:** Both ligands have poor aqueous solubility (-2.479 and -3.84 respectively).

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.947 and 0.777 respectively).

**Microsomal Clearance:** Ligand B (83.811) has significantly higher microsomal clearance than Ligand A (50.918), indicating lower metabolic stability.

**In vitro Half-Life:** Ligand B (66.075) has a much longer in vitro half-life than Ligand A (24.462), which is a significant advantage.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.391 and 0.71 respectively).

**Binding Affinity:** Ligand A (-7.8 kcal/mol) has a significantly stronger binding affinity than Ligand B (-6.7 kcal/mol). This ~1.1 kcal/mol difference is substantial and can outweigh some ADME drawbacks.

**Overall Assessment:**

Ligand A has a superior binding affinity, which is crucial for GPCR targets. However, it suffers from poor Caco-2 permeability and lower metabolic stability. Ligand B has better BBB penetration, a longer half-life, and lower DILI risk, but its logP is higher and its binding affinity is weaker.

Considering the GPCR-specific priorities, the strong binding affinity of Ligand A is the most important factor. While its ADME properties aren't ideal, they might be optimized through further medicinal chemistry efforts. The difference in binding affinity is substantial enough to prioritize Ligand A.

Output:
1
2025-04-17 07:41:03,365 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 drug candidates, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (346.427 Da) is slightly better, being closer to the lower end which can aid permeability.

**TPSA:** Ligand A (75.71) is significantly better than Ligand B (47.36). For CNS targets, we want TPSA <= 90, and ideally lower. Ligand A is well within this range, while Ligand B is also acceptable but less optimal.

**logP:** Both ligands have acceptable logP values (Ligand A: 1.923, Ligand B: 3.456), falling within the 1-3 range. Ligand B is slightly higher, which *could* pose some solubility issues, but isn't a major concern.

**H-Bond Donors/Acceptors:** Ligand A (HBD=1, HBA=4) is slightly better than Ligand B (HBD=0, HBA=5) in terms of balancing solubility and permeability.

**QED:** Ligand A (0.799) has a much better QED score than Ligand B (0.477), indicating a more drug-like profile.

**DILI:** Both have relatively low DILI risk, with Ligand A (41.295) being slightly better than Ligand B (35.75).

**BBB:** Ligand B (92.555) has a significantly higher BBB penetration percentile than Ligand A (64.017). This is a *critical* advantage for a CNS target like DRD2.

**Caco-2 Permeability:** Both have negative Caco-2 values (-4.433 and -4.365), which is unusual and requires further investigation. It suggests poor permeability *in vitro*. However, the scale is not clearly defined, so it's difficult to interpret.

**Aqueous Solubility:** Both have negative solubility values (-2.023 and -4.768), which is also concerning. This suggests poor aqueous solubility.

**hERG Inhibition:** Both ligands show low hERG inhibition liability (Ligand A: 0.144, Ligand B: 0.472).

**Microsomal Clearance:** Ligand B (97.103) has a higher microsomal clearance than Ligand A (67.137), indicating faster metabolism and potentially lower *in vivo* exposure.

**In vitro Half-Life:** Ligand B (10.239 hours) has a significantly longer half-life than Ligand A (3.674 hours), which is desirable.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (Ligand A: 0.041, Ligand B: 0.489).

**Binding Affinity:** Ligand A (-7.5 kcal/mol) has a stronger binding affinity than Ligand B (-6.1 kcal/mol). This is a substantial difference (1.4 kcal/mol), and a strong affinity can often outweigh minor ADME drawbacks.

**Overall Assessment:**

Ligand A has a better overall drug-like profile (higher QED, better TPSA, better H-bond characteristics) and significantly stronger binding affinity. However, Ligand B has a *much* better BBB penetration score and a longer half-life. Given that DRD2 is a CNS target, BBB penetration is paramount. While Ligand A's affinity is excellent, the lower BBB score is a significant drawback. The poor solubility and permeability for both are concerning, but could potentially be addressed with formulation strategies.

Despite the affinity advantage of Ligand A, the superior BBB penetration of Ligand B makes it the more promising candidate.

Output:
1
2025-04-17 07:41:03,365 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight (MW):** Both ligands (352.519 and 362.367 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Both ligands have TPSA values (58.64 and 58.2) below the 90 A^2 threshold desirable for CNS targets, indicating good potential for brain penetration.

**3. logP:** Both ligands have logP values (3.291 and 3.299) within the optimal range of 1-3.

**4. H-Bond Donors (HBD):** Ligand A (1 HBD) and Ligand B (2 HBD) are both within the acceptable limit of <=5.

**5. H-Bond Acceptors (HBA):** Ligand A (3 HBA) and Ligand B (2 HBA) are both within the acceptable limit of <=10.

**6. QED:** Both ligands have good QED scores (0.614 and 0.763), indicating a drug-like profile. Ligand B is slightly better.

**7. DILI:** Ligand A (11.322) has a lower DILI risk than Ligand B (52.772), which is a significant advantage.

**8. BBB:** Both ligands have excellent BBB penetration (77.2% and 76.3%), exceeding the desirable threshold of >70% for CNS targets.

**9. Caco-2 Permeability:** Both have negative Caco-2 values which is unusual and likely indicates poor permeability.

**10. Aqueous Solubility:** Both ligands have negative solubility values, which is also unusual and indicates poor solubility.

**11. hERG Inhibition:** Both ligands have low hERG inhibition liability (0.657 and 0.774), which is good.

**12. Microsomal Clearance:** Ligand A (36.711 mL/min/kg) has a lower microsomal clearance than Ligand B (40.595 mL/min/kg), suggesting better metabolic stability.

**13. In vitro Half-Life:** Ligand B (9.847 hours) has a significantly longer in vitro half-life than Ligand A (2.993 hours), which is a major advantage.

**14. P-gp Efflux:** Both ligands have low P-gp efflux liability (0.165 and 0.242), which is favorable for CNS exposure.

**15. Binding Affinity:** Ligand B (-9.4 kcal/mol) has a substantially stronger binding affinity than Ligand A (-7.0 kcal/mol). This difference of 2.4 kcal/mol is significant and can outweigh some of the other drawbacks.

**Overall Assessment:**

Ligand B is the stronger binder, which is paramount for GPCR targets. While Ligand A has a better DILI score and lower clearance, the substantial difference in binding affinity (-9.4 vs -7.0 kcal/mol) makes Ligand B the more promising candidate. The longer half-life of Ligand B is also a significant benefit. The poor solubility and permeability of both compounds would need to be addressed in further optimization.

Output:
1
2025-04-17 07:41:03,366 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (349.5 and 361.9 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (52.65) is significantly better than Ligand B (71.96). For CNS targets, we want TPSA <= 90, and ideally closer to 60. Ligand A is much closer to the ideal range.

**logP:** Both ligands have acceptable logP values (2.26 and 3.82), falling within the 1-3 range. Ligand B is slightly higher, which *could* lead to some solubility issues, but isn't a major concern.

**H-Bond Donors/Acceptors:** Ligand A (HBD=1, HBA=3) is preferable to Ligand B (HBD=2, HBA=6). Lower HBD/HBA generally improves permeability.

**QED:** Both ligands have similar and good QED values (0.767 and 0.781), indicating good drug-like properties.

**DILI:** Ligand A (7.06) has a much lower DILI risk than Ligand B (68.83). This is a significant advantage for Ligand A.

**BBB:** Ligand A (82.9) has a substantially better BBB penetration percentile than Ligand B (66.58). This is *critical* for a CNS target like DRD2.

**Caco-2 Permeability:** Ligand A (-4.797) has better Caco-2 permeability than Ligand B (-5.138).

**Aqueous Solubility:** Ligand A (-2.442) has better aqueous solubility than Ligand B (-4.517).

**hERG:** Both ligands have similar and low hERG inhibition liability (0.675 and 0.636).

**Microsomal Clearance:** Ligand B (73.67) has a higher microsomal clearance than Ligand A (44.33), suggesting lower metabolic stability.

**In vitro Half-Life:** Ligand B (61.42) has a longer in vitro half-life than Ligand A (-14.96). While longer half-life is generally good, the negative value for Ligand A is concerning and suggests a very short half-life.

**P-gp Efflux:** Both ligands have similar P-gp efflux liability (0.086 and 0.202).

**Binding Affinity:** Ligand B (-9.3) has a slightly better binding affinity than Ligand A (-8.2). This is a 1.1 kcal/mol difference, which is significant, but needs to be weighed against the other ADME properties.

**Overall Assessment:**

Ligand A is significantly better overall. While Ligand B has a slightly better binding affinity, Ligand A excels in crucial ADME properties for a CNS-targeting GPCR: TPSA, BBB penetration, DILI risk, solubility, and Caco-2 permeability. The negative in vitro half-life for Ligand A is a concern, but the other advantages are substantial enough to outweigh this. The lower TPSA and higher BBB of Ligand A are particularly important for CNS penetration.



Output:
0
2025-04-17 07:41:03,366 - INFO - Batch 385 complete. Total preferences: 6160
2025-04-17 07:41:03,366 - INFO - Processing batch 386/512...
2025-04-17 07:41:44,842 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (352.475 and 368.543 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (76.66) is slightly higher than Ligand B (67.43). Both are below the 90 A^2 threshold desirable for CNS targets, but Ligand B is better.

**3. logP:** Both ligands have good logP values (2.614 and 2.49), falling within the optimal 1-3 range.

**4. H-Bond Donors:** Both have 2 HBD, which is acceptable.

**5. H-Bond Acceptors:** Both have 4 HBA, which is acceptable.

**6. QED:** Both ligands have similar QED values (0.691 and 0.646), indicating good drug-likeness.

**7. DILI:** Ligand A (36.603) has a slightly higher DILI risk than Ligand B (26.25), but both are below the concerning threshold of 60.

**8. BBB:** Ligand B (74.758) has a significantly better BBB penetration percentile than Ligand A (63.668). This is a crucial advantage for a CNS target like DRD2.

**9. Caco-2 Permeability:** Ligand A (-4.604) has a worse Caco-2 permeability than Ligand B (-5.128). Lower values indicate lower permeability.

**10. Aqueous Solubility:** Both have negative solubility values, indicating poor solubility. Ligand A (-2.979) is slightly better than Ligand B (-3.171).

**11. hERG Inhibition:** Both ligands have low hERG inhibition liability (0.294 and 0.463).

**12. Microsomal Clearance:** Ligand B (67.284) has a higher microsomal clearance than Ligand A (34.814), indicating faster metabolism and potentially lower *in vivo* exposure.

**13. In vitro Half-Life:** Ligand A (4.406) has a shorter half-life than Ligand B (19.55).

**14. P-gp Efflux:** Ligand A (0.053) has lower P-gp efflux liability than Ligand B (0.145), which is favorable for CNS penetration.

**15. Binding Affinity:** Ligand A (-7.7 kcal/mol) has a slightly better binding affinity than Ligand B (-7.2 kcal/mol). This is a 0.5 kcal/mol difference, which is significant but not overwhelming.

**Overall Assessment:**

Ligand B is the more promising candidate. While Ligand A has a slightly better binding affinity and lower P-gp efflux, Ligand B's significantly improved BBB penetration (74.758 vs 63.668) and lower DILI risk outweigh these minor advantages. The better TPSA and Caco-2 permeability also contribute to its favorability. The longer half-life of Ligand B is also a plus. For a CNS target like DRD2, BBB penetration is paramount, making Ligand B the preferred choice.

Output:
1
2025-04-17 07:41:44,843 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (352.435 and 354.439 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (105.48) is slightly above the preferred <90 for CNS targets, but still reasonable. Ligand B (94.8) is better, falling comfortably under 90.

**3. logP:** Both ligands (2.068 and 2.158) are within the optimal 1-3 range.

**4. H-Bond Donors:** Ligand A (3) is acceptable. Ligand B (1) is also good, potentially offering better permeability.

**5. H-Bond Acceptors:** Ligand A (6) is acceptable. Ligand B (7) is also within the limit of 10.

**6. QED:** Both ligands have good QED scores (0.752 and 0.907), indicating drug-like properties. Ligand B is slightly better.

**7. DILI:** Ligand A (48.623) has a lower DILI risk than Ligand B (80.07). This is a significant advantage for Ligand A.

**8. BBB:** Ligand A (78.558) has a better BBB penetration percentile than Ligand B (62.97). This is crucial for a CNS target like DRD2.

**9. Caco-2 Permeability:** Ligand A (-4.466) has a worse Caco-2 permeability than Ligand B (-5.27). Lower values are less favorable.

**10. Aqueous Solubility:** Ligand A (-2.925) has better solubility than Ligand B (-4.625).

**11. hERG Inhibition:** Ligand A (0.118) has a lower hERG inhibition liability than Ligand B (0.787), indicating a lower risk of cardiotoxicity.

**12. Microsomal Clearance:** Ligand A (44.697) has a higher microsomal clearance than Ligand B (32.769), suggesting lower metabolic stability. Ligand B is preferable here.

**13. In vitro Half-Life:** Ligand A (-10.841) has a shorter in vitro half-life than Ligand B (17.962). Ligand B is preferable.

**14. P-gp Efflux:** Ligand A (0.023) exhibits significantly lower P-gp efflux liability than Ligand B (0.121), which is highly desirable for CNS penetration.

**15. Binding Affinity:** Ligand A (-8.5 kcal/mol) has a significantly stronger binding affinity than Ligand B (0.0 kcal/mol). This is a major advantage for Ligand A, potentially outweighing some of its ADME drawbacks.

**Overall Assessment:**

Ligand A has a much stronger binding affinity and better BBB penetration, lower DILI risk, and lower P-gp efflux. While it has a higher microsomal clearance and slightly worse Caco-2 permeability, the strong affinity and CNS-relevant properties are paramount for a DRD2 ligand. Ligand B has better metabolic stability and half-life, but its significantly weaker binding affinity and lower BBB penetration make it a less promising candidate.

Output:
1
2025-04-17 07:41:44,843 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (378.563 and 354.491 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (42.43) is excellent, well below the 90 A^2 threshold for CNS targets. Ligand B (81.08) is higher, but still potentially acceptable, though less ideal.

**logP:** Ligand A (4.633) is slightly high, potentially leading to solubility issues or off-target interactions. Ligand B (1.394) is quite low, which might hinder membrane permeability.

**H-Bond Donors/Acceptors:** Ligand A (0 HBD, 6 HBA) is favorable. Ligand B (2 HBD, 4 HBA) is also acceptable.

**QED:** Both ligands have good QED scores (0.47 and 0.755), indicating reasonable drug-likeness.

**DILI:** Ligand A (52.889) has a moderate DILI risk. Ligand B (14.541) has a very low DILI risk, a significant advantage.

**BBB:** Ligand A (69.988) has a good BBB penetration percentile. Ligand B (57.619) is lower, which is a concern for a CNS target like DRD2.

**Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and suggests potential issues with the data or modeling. However, we can still compare them relative to each other. Ligand A (-4.935) is worse than Ligand B (-4.634).

**Aqueous Solubility:** Both have negative solubility values, also unusual. Ligand A (-5.68) is worse than Ligand B (-1.728).

**hERG Inhibition:** Ligand A (0.736) has a slightly higher hERG risk than Ligand B (0.279).

**Microsomal Clearance:** Ligand A (151.37) has higher clearance, indicating lower metabolic stability, than Ligand B (18.949).

**In vitro Half-Life:** Ligand A (32.053) has a longer half-life than Ligand B (-0.999).

**P-gp Efflux:** Ligand A (0.73) has a higher P-gp efflux liability than Ligand B (0.074), which is unfavorable for CNS penetration.

**Binding Affinity:** Ligand B (-8.0 kcal/mol) has a significantly stronger binding affinity than Ligand A (-7.2 kcal/mol), exceeding the 1.5 kcal/mol advantage threshold.

**Overall Assessment:**

While Ligand A has better BBB penetration and in vitro half-life, Ligand B is superior in most other crucial aspects. The significantly stronger binding affinity (-8.0 vs -7.2 kcal/mol) of Ligand B is a major advantage, especially for a GPCR target. Furthermore, Ligand B exhibits a much lower DILI risk, lower P-gp efflux, and better metabolic stability (lower Cl_mic). Although Ligand B's logP is low, the strong affinity might compensate for this. The TPSA is a bit high, but not prohibitive. The unusual negative Caco-2 and solubility values are concerning, but the relative comparison still favors Ligand B.

Output:
1
2025-04-17 07:41:44,843 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (351.435 and 356.419 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (71.87) is excellent, well below the 90 A^2 threshold for CNS targets. Ligand B (94.17) is still reasonable but closer to the upper limit.

**logP:** Ligand A (3.048) is optimal (1-3). Ligand B (0.242) is significantly low, potentially hindering membrane permeability and CNS penetration.

**H-Bond Donors/Acceptors:** Ligand A (0 HBD, 6 HBA) and Ligand B (1 HBD, 6 HBA) both have acceptable numbers of H-bond donors and acceptors.

**QED:** Both ligands have similar QED values (0.682 and 0.657), indicating good drug-likeness.

**DILI:** Ligand A (68.166) has a slightly higher DILI risk than Ligand B (41.373), but both are acceptable.

**BBB:** Ligand A (70.143) has a good BBB percentile, while Ligand B (68.282) is slightly lower. Both are reasonably good for CNS penetration, but A is better.

**Caco-2 Permeability:** Ligand A (-5.036) has poor Caco-2 permeability, while Ligand B (-4.769) is also poor, but slightly better.

**Aqueous Solubility:** Both ligands have very poor aqueous solubility (-3.201 and -0.916 respectively). This could pose formulation challenges.

**hERG Inhibition:** Ligand A (0.338) has a very low hERG risk, while Ligand B (0.069) is even lower. Both are excellent.

**Microsomal Clearance:** Ligand A (40.857) has lower microsomal clearance than Ligand B (53.747), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (3.548) has a slightly longer half-life than Ligand B (-0.227).

**P-gp Efflux:** Ligand A (0.121) has lower P-gp efflux than Ligand B (0.018), which is favorable for CNS exposure.

**Binding Affinity:** Ligand A (-7.2 kcal/mol) has a significantly stronger binding affinity than Ligand B (0.0 kcal/mol). This is a crucial advantage.

**Overall Assessment:**

Considering the GPCR-specific priorities, Ligand A is the stronger candidate. Its superior binding affinity, better BBB penetration, lower P-gp efflux, and lower microsomal clearance outweigh its slightly higher DILI risk and poorer Caco-2 permeability. Ligand B's extremely low logP is a major drawback, likely severely limiting its ability to cross the blood-brain barrier despite a slightly better Caco-2 value. The significantly stronger binding affinity of Ligand A also provides a buffer for any minor ADME deficiencies.

Output:
1
2025-04-17 07:41:44,843 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 drug candidates, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (360.483 Da) and Ligand B (338.411 Da) are both acceptable.

**2. TPSA:** Both ligands have TPSA values below the 90 A^2 threshold desirable for CNS targets. Ligand A (79.53 A^2) is better than Ligand B (63.42 A^2).

**3. logP:** Ligand A (1.478) is within the optimal range (1-3). Ligand B (3.621) is at the higher end of the optimal range, potentially increasing off-target effects, but still acceptable.

**4. H-Bond Donors:** Both ligands have 1 HBD, which is within the acceptable limit of <=5.

**5. H-Bond Acceptors:** Ligand A has 5 HBAs, and Ligand B has 6 HBAs, both are within the acceptable limit of <=10.

**6. QED:** Both ligands have QED values above 0.5, indicating good drug-like properties. Ligand A (0.88) is slightly better than Ligand B (0.766).

**7. DILI:** Ligand A (57.27%) has a lower DILI risk than Ligand B (77.549%). This is a significant advantage for Ligand A.

**8. BBB:** Both ligands have good BBB penetration (>70%). Ligand A (73.129%) and Ligand B (70.764%) are both acceptable.

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 values, which is unusual and suggests poor permeability. However, the scale is not specified, so it's difficult to interpret.

**10. Aqueous Solubility:** Both ligands have negative solubility values, which is also unusual and suggests poor solubility. Again, the scale is not specified.

**11. hERG Inhibition:** Both ligands have low hERG inhibition risk, with Ligand A (0.278) being slightly lower than Ligand B (0.936).

**12. Microsomal Clearance:** Ligand A (8.574 mL/min/kg) has lower microsomal clearance than Ligand B (85.203 mL/min/kg), indicating better metabolic stability.

**13. In vitro Half-Life:** Ligand A (-10.219 hours) has a negative half-life, which is impossible. This is a major red flag. Ligand B (74.72 hours) has a good in vitro half-life.

**14. P-gp Efflux:** Ligand A (0.041) has lower P-gp efflux than Ligand B (0.189), which is favorable for CNS penetration.

**15. Binding Affinity:** Ligand B (-8.6 kcal/mol) has a significantly stronger binding affinity than Ligand A (-7.2 kcal/mol). This is a substantial advantage, potentially outweighing some of the ADME drawbacks.

**Overall Assessment:**

Ligand A has better TPSA, DILI, P-gp efflux, and microsomal clearance. However, it has a nonsensical negative half-life, which is a critical flaw. Ligand B has a significantly better binding affinity and a good half-life, despite having a slightly higher logP and DILI risk. Considering the GPCR-specific priorities, the strong binding affinity of Ligand B is the most important factor. While its DILI risk is higher, it's not excessively high, and the other properties are acceptable. The negative half-life of Ligand A is a dealbreaker.

Output:
1
2025-04-17 07:41:44,844 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (348.491 and 338.415 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (78.09) is significantly better than Ligand B (106.75). For CNS targets, we want TPSA <= 90, and A is comfortably within that, while B is pushing the limit.

**logP:** Both ligands have good logP values (2.666 and 2.436), falling within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A (HBD=2, HBA=3) is preferable to Ligand B (HBD=3, HBA=7). Lower HBA is generally better for CNS penetration.

**QED:** Both ligands have acceptable QED values (0.709 and 0.635), indicating good drug-like properties.

**DILI:** Ligand A (25.087) has a much lower DILI risk than Ligand B (59.907). This is a significant advantage.

**BBB:** Ligand A (69.213) has a better BBB percentile than Ligand B (59.519), though both are below the desirable >70 for CNS targets. However, A is closer.

**Caco-2 Permeability:** Both have negative Caco-2 values (-5.127 and -5.386), which is unusual and suggests poor permeability. This is a concern for both.

**Aqueous Solubility:** Both have negative solubility values (-2.336 and -3.138), also unusual and concerning.

**hERG:** Both ligands have low hERG inhibition liability (0.401 and 0.828), which is good.

**Microsomal Clearance:** Ligand B (67.033) has a higher microsomal clearance than Ligand A (33.962), indicating lower metabolic stability.

**In vitro Half-Life:** Ligand A (-11.066) has a longer in vitro half-life than Ligand B (13.368). This is a positive for A.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.182 and 0.089), which is good for CNS penetration.

**Binding Affinity:** Both ligands have very similar and strong binding affinities (-8.1 and -8.3 kcal/mol). The difference is negligible.

**Overall Assessment:**

Considering the GPCR-specific priorities, Ligand A is the better candidate. It has a significantly lower DILI risk, better TPSA, better BBB penetration, and improved metabolic stability (lower Cl_mic and longer t1/2). While both have issues with Caco-2 and solubility, the other advantages of Ligand A outweigh these concerns, especially given the similar binding affinities.

Output:
1
2025-04-17 07:41:44,844 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (356.463 and 360.483 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (99.1) is higher than the preferred <90 for CNS targets, while Ligand B (75.19) is comfortably below. This favors Ligand B.

**logP:** Ligand A (0.432) is quite low, potentially hindering membrane permeability. Ligand B (1.865) is within the optimal 1-3 range. This is a significant advantage for Ligand B.

**H-Bond Donors/Acceptors:** Ligand A has 3 HBD and 5 HBA, acceptable values. Ligand B has 1 HBD and 5 HBA, also acceptable.

**QED:** Both ligands have good QED scores (0.575 and 0.84), indicating good drug-like properties.

**DILI:** Ligand A (9.926) has a very low DILI risk, which is excellent. Ligand B (31.601) is also low, but higher than Ligand A.

**BBB:** Ligand A (52.036) has a moderate BBB penetration, but is below the desirable >70 for CNS targets. Ligand B (71.501) is much better, exceeding the 70% threshold. This is a critical advantage for Ligand B.

**Caco-2 Permeability:** Ligand A (-4.896) has poor Caco-2 permeability, suggesting poor intestinal absorption. Ligand B (-5.14) is also poor, but slightly better than A.

**Aqueous Solubility:** Ligand A (-0.953) has poor aqueous solubility. Ligand B (-2.527) is even worse. This could pose formulation challenges for both, but is more concerning for B.

**hERG Inhibition:** Both ligands show very low hERG inhibition risk (0.251 and 0.163), which is positive.

**Microsomal Clearance:** Ligand A (6.922) has lower microsomal clearance than Ligand B (49.791), suggesting better metabolic stability. This favors Ligand A.

**In vitro Half-Life:** Ligand A (-9.693) has a very long in vitro half-life, which is highly desirable. Ligand B (5.384) is shorter, but still reasonable.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.023 and 0.162), which is excellent for CNS penetration.

**Binding Affinity:** Ligand B (-8.7 kcal/mol) has a significantly stronger binding affinity than Ligand A (-5.9 kcal/mol). This >2.8 kcal/mol difference is substantial and can outweigh some ADME drawbacks.

**Overall Assessment:**

Ligand B is the stronger candidate. While its solubility is a concern, its superior BBB penetration, optimal logP, and significantly higher binding affinity are crucial for a CNS-targeting GPCR like DRD2. Ligand A has better metabolic stability and DILI risk, but its poor logP and BBB penetration are major drawbacks. The strong binding affinity of Ligand B is a decisive factor.

Output:
1
2025-04-17 07:41:44,844 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (349.435 and 360.414 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (89.35) is slightly higher than Ligand B (83.98), but both are below the 90 A^2 threshold desirable for CNS targets.

**3. logP:** Ligand A (1.673) is within the optimal 1-3 range. Ligand B (2.978) is also within range, but approaching the upper limit.

**4. H-Bond Donors:** Ligand A (1) and Ligand B (2) are both acceptable, being less than 5.

**5. H-Bond Acceptors:** Ligand A (6) and Ligand B (5) are both acceptable, being less than 10.

**6. QED:** Both ligands have good QED scores (0.685 and 0.776, respectively), indicating drug-like properties.

**7. DILI:** Ligand A (66.693) has a lower DILI risk than Ligand B (83.482). This is a significant advantage.

**8. BBB:** Both ligands have excellent BBB penetration (Ligand A: 79.488, Ligand B: 74.137), exceeding the 70% threshold for CNS targets. Ligand A is slightly better.

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.378 and -4.875), which is unusual and suggests poor permeability. However, these values are on a log scale and the negative values are likely artifacts of the prediction method.

**10. Aqueous Solubility:** Both ligands have negative solubility values (-2.376 and -3.681), which is also unusual and suggests poor solubility. Again, these values are likely artifacts of the prediction method.

**11. hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.325 and 0.224).

**12. Microsomal Clearance:** Ligand A (40.526) has lower microsomal clearance than Ligand B (46.092), suggesting better metabolic stability.

**13. In vitro Half-Life:** Ligand B (39.751) has a significantly longer in vitro half-life than Ligand A (2.455). This is a major advantage for dosing convenience.

**14. P-gp Efflux:** Both ligands have low P-gp efflux liability (0.093 and 0.113).

**15. Binding Affinity:** Ligand B (-8.6 kcal/mol) has a significantly stronger binding affinity than Ligand A (-7.6 kcal/mol). This difference of 1.0 kcal/mol is substantial and can outweigh some ADME drawbacks.

**Overall Assessment:**

Ligand B has a much stronger binding affinity, and a significantly longer half-life. While Ligand A has a slightly better BBB score and lower DILI risk, the affinity difference is critical for a GPCR target. The slightly higher DILI risk of Ligand B is a concern, but potentially manageable with further optimization. The negative solubility and permeability values are concerning, but likely artifacts of the prediction method.

Output:
1
2025-04-17 07:41:44,844 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (348.403 and 367.833 Da) fall within the ideal 200-500 Da range.

**TPSA:** Both ligands (92.79 and 92.51) are slightly above the optimal <90 for CNS targets, but still reasonably acceptable.

**logP:** Both ligands (0.949 and 1.077) are within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A has 2 HBD and 6 HBA, while Ligand B has 1 HBD and 5 HBA. Both are within acceptable limits (<=5 HBD and <=10 HBA).

**QED:** Ligand B (0.728) has a better QED score than Ligand A (0.392), indicating a more drug-like profile.

**DILI:** Ligand B (36.797) has a significantly lower DILI risk than Ligand A (57.076), which is a major advantage.

**BBB:** Both ligands have similar BBB penetration (67.468 and 65.452). While not exceeding the desirable >70, they are acceptable.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.987 and -5.18), which is unusual and suggests poor permeability. This is a significant concern.

**Aqueous Solubility:** Both ligands have negative solubility values (-2.168 and -2.16), which is also a concern.

**hERG Inhibition:** Ligand B (0.05) has a much lower hERG inhibition liability than Ligand A (0.339), indicating a lower risk of cardiotoxicity.

**Microsomal Clearance:** Ligand A (53.909) has lower microsomal clearance than Ligand B (6.221), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand B (-11.987) has a negative half-life, which is not physically possible and suggests a problem with the data or the molecule itself. Ligand A (0.143) has a very short half-life.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.017 and 0.067), which is favorable for CNS penetration.

**Binding Affinity:** Ligand B (-8.5 kcal/mol) has a stronger binding affinity than Ligand A (-7.8 kcal/mol). This difference of 0.7 kcal/mol is substantial and can outweigh some ADME drawbacks.

**Overall Assessment:**

Ligand B is the better candidate despite the negative Caco-2 and solubility values. Its superior binding affinity, lower DILI risk, and lower hERG inhibition liability are significant advantages. The negative half-life is a major red flag, but could be a data error. Ligand A's better metabolic stability is offset by its higher DILI risk and weaker binding. The poor permeability and solubility of both compounds need to be addressed through structural modifications, but Ligand B provides a better starting point due to its potency and safety profile.

Output:
1
2025-04-17 07:41:44,844 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (368.434 and 356.419 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (107.08) is slightly above the optimal <90 for CNS targets, but still reasonable. Ligand B (94.17) is better, falling comfortably under 90.

**logP:** Ligand A (2.014) is within the optimal 1-3 range. Ligand B (-0.046) is slightly below 1, which *could* indicate permeability issues, but isn't a hard disqualifier.

**H-Bond Donors/Acceptors:** Ligand A (2 HBD, 5 HBA) and Ligand B (1 HBD, 6 HBA) both have acceptable numbers of H-bond donors and acceptors.

**QED:** Both ligands have similar QED values (0.695 and 0.643), indicating good drug-like properties.

**DILI:** Ligand A (65.491) has a higher DILI risk than Ligand B (38.62), which is preferable.

**BBB:** This is crucial for a CNS target. Ligand A (68.786) is borderline, while Ligand B (51.415) is lower. Both are less than the desirable >70, but A is closer.

**Caco-2 Permeability:** Ligand A (-5.236) and Ligand B (-4.643) both have negative Caco-2 values, which is unusual. This suggests poor permeability.

**Aqueous Solubility:** Both have negative solubility values (-2.173 and -1.528), which is also unusual and suggests poor solubility.

**hERG:** Both ligands have low hERG inhibition liability (0.629 and 0.164), which is good.

**Microsomal Clearance:** Ligand A (14.102) has significantly lower microsomal clearance than Ligand B (28.969), indicating better metabolic stability.

**In vitro Half-Life:** Ligand A (-6.977) has a longer in vitro half-life than Ligand B (-14.163), which is favorable.

**P-gp Efflux:** Ligand A (0.196) has lower P-gp efflux than Ligand B (0.021), which is better for CNS penetration.

**Binding Affinity:** Ligand A (-7.7 kcal/mol) has a slightly better binding affinity than Ligand B (-7.2 kcal/mol). While the difference is not huge, it is greater than 1.5 kcal/mol, and therefore significant.

**Overall Assessment:**

Considering the GPCR-specific priorities, Ligand A is the better candidate. It has a slightly better affinity, lower DILI risk, lower P-gp efflux, better metabolic stability (lower Cl_mic, longer t1/2), and a slightly better BBB score. While both have poor Caco-2 and solubility, the affinity advantage of A, combined with its better ADME properties, outweigh the slightly higher TPSA. The negative Caco-2 and solubility values are concerning for both, and would require further investigation (e.g., salt formation, formulation strategies).

Output:
1
2025-04-17 07:41:44,845 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (398.304) is slightly higher than Ligand B (344.346), but both are acceptable.

**2. TPSA:** Ligand A (47.04) is much better than Ligand B (69.91). For CNS targets, TPSA should be <= 90, and ideally lower. Ligand A is significantly closer to the ideal range.

**3. logP:** Ligand A (4.672) is a bit high, potentially leading to solubility issues or off-target interactions. Ligand B (2.363) is within the optimal range (1-3).

**4. H-Bond Donors:** Both ligands have 1 HBD, which is good.

**5. H-Bond Acceptors:** Ligand A has 4 HBAs, while Ligand B has 7. Both are within the acceptable limit of <=10, but Ligand A is preferable.

**6. QED:** Both ligands have good QED scores (A: 0.588, B: 0.766), indicating drug-like properties. Ligand B is slightly better.

**7. DILI:** Ligand A (54.944) has a moderate DILI risk, while Ligand B (95.463) has a very high DILI risk. This is a significant drawback for Ligand B.

**8. BBB:** Ligand A (53.16) has a moderate BBB penetration, while Ligand B (71.539) has good BBB penetration (>70). This favors Ligand B, given DRD2 is a CNS target.

**9. Caco-2 Permeability:** Both have negative values, indicating poor permeability. Ligand A (-5.26) is slightly better than Ligand B (-4.42), but both are concerning.

**10. Aqueous Solubility:** Both have negative values, indicating poor solubility. Ligand A (-3.91) is slightly better than Ligand B (-3.749), but both are concerning.

**11. hERG Inhibition:** Both ligands have low hERG inhibition risk (A: 0.954, B: 0.85).

**12. Microsomal Clearance:** Ligand A (41.483) has moderate clearance, while Ligand B (29.622) has lower clearance, indicating better metabolic stability.

**13. In vitro Half-Life:** Ligand A (14.218) has a longer half-life than Ligand B (4.008), which is desirable.

**14. P-gp Efflux:** Both ligands have low P-gp efflux liability (A: 0.675, B: 0.398). Ligand B is slightly better.

**15. Binding Affinity:** Ligand A (-8.6 kcal/mol) has a significantly stronger binding affinity than Ligand B (-7.4 kcal/mol). This is a substantial advantage for Ligand A.

**Overall Assessment:**

Ligand A has a significantly better binding affinity and a more favorable TPSA. While its logP is slightly high, the strong affinity could compensate. Its DILI risk is moderate, which is acceptable. Ligand B has better BBB penetration and metabolic stability, but its very high DILI risk and weaker binding affinity are major concerns. Considering the GPCR-specific priorities, the strong affinity of Ligand A outweighs its slightly higher logP and moderate DILI risk.

Output:
1
2025-04-17 07:41:44,845 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (338.419 and 340.383 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (95.51) is better than Ligand B (98.39). Both are below the 140 A^2 threshold for oral absorption, and reasonably close to the 90 A^2 target for CNS penetration, but A is preferable.

**3. logP:** Both ligands (2.095 and 2.25) are within the optimal 1-3 range.

**4. H-Bond Donors:** Ligand A (2) is slightly higher than Ligand B (1), but both are within the acceptable limit of <=5.

**5. H-Bond Acceptors:** Ligand A (7) is higher than Ligand B (6), but both are within the acceptable limit of <=10.

**6. QED:** Both ligands have similar QED values (0.752 and 0.675), indicating good drug-like properties.

**7. DILI:** Ligand B (51.028) has a significantly lower DILI risk than Ligand A (75.339). This is a substantial advantage for Ligand B.

**8. BBB:** Both ligands have good BBB penetration (64.948 and 65.374), but are slightly below the desirable >70% for CNS targets. They are comparable here.

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.644 and -5.255), which is unusual and suggests poor permeability. This is a concern for both.

**10. Aqueous Solubility:** Both ligands have negative solubility values (-2.723 and -1.649), indicating very poor aqueous solubility. This is a significant drawback for both.

**11. hERG Inhibition:** Both ligands have low hERG inhibition risk (0.492 and 0.591).

**12. Microsomal Clearance:** Ligand B (26.983) has lower microsomal clearance than Ligand A (34.642), suggesting better metabolic stability.

**13. In vitro Half-Life:** Ligand B (40.694) has a longer in vitro half-life than Ligand A (27.136). This is a significant advantage for Ligand B.

**14. P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.027 and 0.175), which is good for CNS exposure.

**15. Binding Affinity:** Ligand A (-9.3 kcal/mol) has a slightly better binding affinity than Ligand B (-8.5 kcal/mol). This 0.8 kcal/mol difference is meaningful, but not overwhelming.

**Overall Assessment:**

While Ligand A has a slightly better binding affinity, Ligand B demonstrates a significantly better safety profile (lower DILI), improved metabolic stability (lower Cl_mic, longer t1/2), and comparable BBB penetration. The poor Caco-2 and solubility are concerning for both, but can potentially be addressed through formulation strategies. Considering the GPCR-specific priorities, the improved ADME properties of Ligand B outweigh the modest difference in binding affinity.

Output:
1
2025-04-17 07:41:44,845 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (348.487 and 365.543 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (49.85) is significantly better than Ligand B (53.51). For CNS targets, we want TPSA <= 90, and ideally closer to 60. Both are acceptable, but A is preferred.

**3. logP:** Both ligands have good logP values (3.938 and 3.271), falling within the optimal 1-3 range.

**4. H-Bond Donors:** Both have 0 HBD, which is acceptable.

**5. H-Bond Acceptors:** Ligand A has 3 HBA, and Ligand B has 4. Both are within the acceptable limit of <=10.

**6. QED:** Both ligands have similar QED values (0.773 and 0.71), indicating good drug-likeness.

**7. DILI:** Ligand A (43.195) has a much lower DILI risk than Ligand B (16.014). This is a significant advantage for Ligand A.

**8. BBB:** Both ligands have excellent BBB penetration (90.074 and 83.366), exceeding the desirable >70 threshold for CNS targets. Ligand A is slightly better.

**9. Caco-2 Permeability:** Both have negative Caco-2 values (-4.265 and -4.788). These values are unusual and suggest poor permeability. However, given the GPCR target and focus on CNS penetration, this is less critical than BBB.

**10. Aqueous Solubility:** Both have negative solubility values (-4.443 and -2.059). This is a concern, but can be addressed with formulation strategies.

**11. hERG Inhibition:** Both ligands show low hERG inhibition risk (0.503 and 0.56).

**12. Microsomal Clearance:** Ligand A (73.019) has higher microsomal clearance than Ligand B (55.6), suggesting lower metabolic stability. This is a drawback for Ligand A.

**13. In vitro Half-Life:** Ligand B (3.866) has a longer in vitro half-life than Ligand A (-5.05). This is a significant advantage for Ligand B.

**14. P-gp Efflux:** Both ligands have low P-gp efflux liability (0.307 and 0.325), which is good for CNS exposure.

**15. Binding Affinity:** Ligand A (-7.5 kcal/mol) has a slightly better binding affinity than Ligand B (-7.2 kcal/mol). While the difference is not huge, it is within the range where it can outweigh some ADME drawbacks.

**Overall Assessment:**

Ligand A has a better TPSA, DILI score, and binding affinity. Ligand B has better metabolic stability (lower Cl_mic, longer t1/2). Both have good logP and BBB penetration. The negative Caco-2 and solubility values are concerning for both, but less critical for a CNS target with good BBB penetration. Considering the GPCR-specific priorities, the slightly better affinity and significantly lower DILI risk of Ligand A, combined with its slightly better TPSA and BBB, make it the more promising candidate.

Output:
1
2025-04-17 07:41:44,846 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 drug candidates, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (367.515 and 362.539 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (91.32) is slightly above the preferred <90 for CNS targets, while Ligand B (40.62) is well within the optimal range. This favors Ligand B.

**logP:** Both ligands have acceptable logP values (1.741 and 3.342), falling within the 1-3 range. Ligand B is slightly higher, potentially aiding membrane permeability.

**H-Bond Donors/Acceptors:** Ligand A has 3 HBD and 5 HBA, which are reasonable. Ligand B has 0 HBD and 3 HBA, also acceptable.

**QED:** Both ligands have good QED scores (0.653 and 0.806), indicating good drug-like properties.

**DILI:** Ligand A (33.812) has a slightly higher DILI risk than Ligand B (24.234), but both are below the concerning threshold of 60.

**BBB:** This is a critical parameter for CNS targets. Ligand A has a BBB percentile of 30.981, which is quite low. Ligand B has a significantly higher BBB percentile of 86.351, making it much more likely to reach the target in the brain. This is a major advantage for Ligand B.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.177 and -4.917), which is unusual and suggests poor permeability. However, these values are on a log scale and difficult to interpret without knowing the base. We'll need to consider other factors.

**Aqueous Solubility:** Both ligands have very poor aqueous solubility (-1.94 and -3.187). This is a significant drawback for both, potentially hindering formulation and bioavailability.

**hERG Inhibition:** Ligand A (0.079) has a very low hERG risk, which is excellent. Ligand B (0.749) has a slightly higher, but still relatively low, hERG risk.

**Microsomal Clearance:** Ligand A (17.895) has a lower microsomal clearance than Ligand B (66.937), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (9.961) has a longer half-life than Ligand B (0.354), which is desirable.

**P-gp Efflux:** Ligand A (0.028) has very low P-gp efflux, which is favorable for CNS penetration. Ligand B (0.631) has a higher P-gp efflux, potentially limiting brain exposure.

**Binding Affinity:** Ligand B (-9.4 kcal/mol) has a significantly stronger binding affinity than Ligand A (-8.0 kcal/mol). This >1.5 kcal/mol difference is substantial and can outweigh some of the ADME drawbacks.

**Overall Assessment:**

Ligand B is the stronger candidate. While both have poor solubility and Caco-2 permeability, Ligand B's superior BBB penetration (86.351 vs 30.981), significantly stronger binding affinity (-9.4 vs -8.0 kcal/mol), and lower P-gp efflux outweigh Ligand A's better metabolic stability and lower hERG risk. For a CNS target like DRD2, getting the drug *into* the brain is paramount, and Ligand B excels in this regard. The higher affinity also increases the likelihood of efficacy.

Output:
1
2025-04-17 07:41:44,846 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (356.419 and 345.403 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (110.8) is slightly higher than Ligand B (102.05). Both are below the 140 A^2 threshold for oral absorption, but closer to the 90 A^2 ideal for CNS targets. Ligand B is preferable here.

**3. logP:** Ligand A (0.682) is below the optimal 1-3 range, potentially hindering permeation. Ligand B (1.028) is closer to the optimal range. Ligand B is preferable.

**4. H-Bond Donors:** Both ligands have 2 HBD, which is within the acceptable limit of <=5.

**5. H-Bond Acceptors:** Both ligands have 6 HBA, also within the acceptable limit of <=10.

**6. QED:** Ligand B (0.661) has a better QED score than Ligand A (0.464), indicating a more drug-like profile.

**7. DILI:** Ligand A (46.219) has a lower DILI risk than Ligand B (57.619), which is preferable.

**8. BBB:** Ligand B (51.725) has a significantly better BBB penetration percentile than Ligand A (27.491). This is *critical* for a CNS target like DRD2.

**9. Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and suggests poor permeability. Ligand A (-5.191) is slightly better than Ligand B (-5.634), but both are concerning.

**10. Aqueous Solubility:** Both have negative solubility values, which is also unusual and suggests poor solubility. Ligand A (-1.921) is slightly better than Ligand B (-1.423).

**11. hERG Inhibition:** Both ligands have very low hERG inhibition liability (0.071 and 0.088), which is excellent.

**12. Microsomal Clearance:** Ligand A (18.581) has a lower (better) microsomal clearance than Ligand B (38.739), suggesting greater metabolic stability.

**13. In vitro Half-Life:** Ligand B (-5.845) has a longer in vitro half-life than Ligand A (-2.51), which is preferable.

**14. P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.035 and 0.029), which is excellent for CNS penetration.

**15. Binding Affinity:** Both ligands have very similar and strong binding affinities (-7.3 and -7.4 kcal/mol). The difference is negligible.

**Overall Assessment:**

While Ligand A has slightly better DILI and clearance, Ligand B significantly outperforms it in BBB penetration (51.725 vs. 27.491) and has a better QED score. For a CNS target like DRD2, BBB penetration is paramount. The slightly better metabolic stability of Ligand A is outweighed by the superior BBB score of Ligand B. The similar affinity values make the ADME properties the deciding factor.

Output:
1
2025-04-17 07:41:44,846 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (361.511 Da) is slightly higher than Ligand B (348.399 Da), but both are acceptable.

**TPSA:** Ligand A (62.3) is excellent for CNS penetration, being well below 90. Ligand B (103.01) is higher, but still potentially acceptable, though less ideal.

**logP:** Ligand A (2.773) is optimal. Ligand B (0.583) is quite low, potentially hindering membrane permeability and CNS entry.

**H-Bond Donors/Acceptors:** Ligand A (HBD=1, HBA=4) and Ligand B (HBD=3, HBA=5) both fall within acceptable limits.

**QED:** Both ligands have good QED scores (A: 0.839, B: 0.739), indicating drug-like properties.

**DILI:** Ligand A (45.25) has a slightly higher DILI risk than Ligand B (34.161), but both are below the concerning threshold of 60.

**BBB:** This is a critical parameter for a CNS target like DRD2. Ligand A (78.054) has a good BBB percentile, while Ligand B (25.785) is significantly lower and problematic.

**Caco-2 Permeability:** Ligand A (-4.818) and Ligand B (-5.221) both have negative values, which is unusual and suggests poor permeability. However, the scale isn't specified, so it's hard to interpret.

**Aqueous Solubility:** Both ligands have negative solubility values (-2.952 and -1.232), which is also unusual and suggests poor solubility.

**hERG:** Both ligands have very low hERG inhibition liability (A: 0.299, B: 0.135), which is excellent.

**Microsomal Clearance:** Ligand A (63.201) has a higher microsomal clearance than Ligand B (-14.313), suggesting lower metabolic stability.

**In vitro Half-Life:** Ligand B (20.684) has a significantly longer in vitro half-life than Ligand A (-14.428), which is a positive attribute.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (A: 0.173, B: 0.036), which is favorable for CNS penetration.

**Binding Affinity:** Both ligands have very similar and strong binding affinities (A: -8.4 kcal/mol, B: -8.7 kcal/mol). The difference is minimal.

**Overall Assessment:**

Ligand A is superior due to its significantly better BBB penetration (78.054 vs. 25.785) and optimal logP (2.773 vs. 0.583). While Ligand B has a slightly better half-life and lower DILI, the poor BBB penetration and low logP are major drawbacks for a CNS-targeting drug. The similar binding affinities mean that the ADME properties are the deciding factors.

Output:
1
2025-04-17 07:41:44,846 - INFO - Batch 386 complete. Total preferences: 6176
2025-04-17 07:41:44,846 - INFO - Processing batch 387/512...
2025-04-17 07:42:25,947 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (358.467 and 348.447 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (67.35) is significantly better than Ligand B (98.32). For CNS targets, we want TPSA <= 90, so Ligand A is much more favorable.

**3. logP:** Ligand A (3.89) is optimal (1-3), while Ligand B (1.318) is on the lower side, potentially hindering permeation.

**4. H-Bond Donors:** Ligand A (1) is better than Ligand B (3). Lower is generally preferred.

**5. H-Bond Acceptors:** Ligand A (6) is better than Ligand B (4). Both are acceptable, but lower is preferred.

**6. QED:** Ligand A (0.901) is excellent, indicating high drug-likeness. Ligand B (0.747) is still reasonable, but not as strong.

**7. DILI:** Ligand A (58.395) has a moderate DILI risk, while Ligand B (33.191) has a lower risk. Both are acceptable, but B is preferable.

**8. BBB:** Ligand A (84.684) has excellent BBB penetration, exceeding the desirable >70 threshold for CNS targets. Ligand B (52.423) is considerably lower and less favorable. This is a critical difference.

**9. Caco-2:** Ligand A (-4.713) and Ligand B (-5.015) both have negative values, which is unusual and difficult to interpret without knowing the scale. However, lower values are generally less favorable.

**10. Solubility:** Ligand A (-4.948) and Ligand B (-2.544) both have negative values, indicating poor solubility. Ligand B is slightly better.

**11. hERG:** Ligand A (0.254) has a very low hERG risk, which is excellent. Ligand B (0.502) is slightly higher, but still relatively low.

**12. Cl_mic:** Ligand A (88.484) has a higher microsomal clearance, suggesting faster metabolism. Ligand B (3.329) has much lower clearance, indicating better metabolic stability.

**13. t1/2:** Ligand A (3.082) has a short in vitro half-life. Ligand B (-38.318) has a very long (and potentially unrealistic) half-life.

**14. Pgp:** Ligand A (0.089) has low P-gp efflux, which is favorable for CNS penetration. Ligand B (0.036) has even lower P-gp efflux, which is excellent.

**15. Binding Affinity:** Both ligands have the same binding affinity (-7.9 kcal/mol), which is excellent and strong enough to potentially overcome minor ADME issues.

**Overall Assessment:**

Ligand A excels in TPSA, logP, QED, and especially BBB penetration, making it highly suitable for a CNS target like DRD2. While its metabolic stability (Cl_mic) and half-life are less ideal, its strong affinity and excellent BBB properties are significant advantages. Ligand B has better DILI, Pgp efflux, and metabolic stability, but its higher TPSA and lower logP are concerning for CNS penetration.

Given the GPCR-specific priorities, particularly the need for good BBB penetration, **Ligand A is the more promising drug candidate.**

Output:
0
2025-04-17 07:42:25,947 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (374.503 and 353.507 Da) fall within the ideal 200-500 Da range.

**TPSA:** Both ligands (84.94 and 81.67) are below the 90 A^2 threshold desirable for CNS targets, which is excellent.

**logP:** Both ligands (1.203 and 1.446) are within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A (1 HBD, 6 HBA) and Ligand B (3 HBD, 4 HBA) both meet the criteria of <=5 HBD and <=10 HBA.

**QED:** Both ligands have acceptable QED scores (0.457 and 0.519), with Ligand B slightly better.

**DILI:** Ligand A (38.813) has a slightly higher DILI risk than Ligand B (5.312), but both are below the concerning threshold of 60.

**BBB:** Ligand A (52.036) and Ligand B (50.523) are both below the 70 percentile, which is less ideal for a CNS target. However, this is not a dealbreaker, as other properties can compensate.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.116 and -5.153), which is unusual and suggests poor permeability. This is a significant concern.

**Aqueous Solubility:** Both ligands have negative solubility values (-2.178 and -1.57), indicating very poor aqueous solubility. This is a major drawback.

**hERG Inhibition:** Both ligands show low hERG inhibition liability (0.28 and 0.472), which is good.

**Microsomal Clearance:** Ligand A (61.874) has higher microsomal clearance than Ligand B (2.08), indicating lower metabolic stability. This is a negative for Ligand A.

**In vitro Half-Life:** Ligand A (-6.012) has a negative half-life, which is not physically possible and indicates a problem with the data or the molecule. Ligand B (2.814) has a short half-life, but it is at least a positive value.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.034 and 0.032), which is favorable for CNS penetration.

**Binding Affinity:** Ligand B (-7.8 kcal/mol) has a significantly stronger binding affinity than Ligand A (-6.4 kcal/mol). This 1.4 kcal/mol difference is substantial and can outweigh some ADME drawbacks.

**Conclusion:**

Considering all factors, **Ligand B** is the more promising drug candidate. While both ligands have poor solubility and permeability, Ligand B has a significantly better binding affinity, lower DILI risk, and a more reasonable (though still short) in vitro half-life. The negative half-life for Ligand A is a critical flaw. The slightly better QED score of Ligand B also contributes to its favorability. The BBB values are suboptimal for both, but the stronger affinity of Ligand B suggests it might still achieve sufficient brain exposure.

Output:
1
2025-04-17 07:42:25,948 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (349.435 Da) is slightly lower, which could be beneficial for permeability. Ligand B (376.479 Da) is also good.

**TPSA:** Ligand A (109.0) is better than Ligand B (139.62). For CNS targets, we want TPSA <= 90, so both are above this ideal, but A is closer.

**logP:** Ligand A (1.025) is within the optimal range (1-3), while Ligand B (-1.004) is below 1, which could hinder permeation. This is a significant advantage for Ligand A.

**H-Bond Donors/Acceptors:** Both have reasonable HBD (3/4) and HBA (5/5) counts, falling within acceptable limits.

**QED:** Ligand A (0.617) has a better QED score than Ligand B (0.43), indicating a more drug-like profile.

**DILI:** Both ligands have low DILI risk (A: 39.705, B: 35.014), which is good.

**BBB:** Ligand A (61.846) has a better BBB percentile than Ligand B (55.176), which is important for CNS targets. While both are not >70, A is closer.

**Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and suggests poor permeability. However, the scale is not specified, so it's hard to interpret.

**Aqueous Solubility:** Both have negative solubility values, which is also unusual. Again, the scale is not specified.

**hERG:** Both ligands have very low hERG inhibition liability (A: 0.251, B: 0.089), which is excellent.

**Microsomal Clearance:** Ligand A (30.97) has a higher microsomal clearance than Ligand B (26.095), suggesting lower metabolic stability.

**In vitro Half-Life:** Ligand A (9.376) has a longer half-life than Ligand B (3.262), which is desirable.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (A: 0.056, B: 0.004), which is good for CNS exposure.

**Binding Affinity:** Ligand B (-7.8 kcal/mol) has a significantly stronger binding affinity than Ligand A (-8.2 kcal/mol). This is a substantial advantage, potentially outweighing some of the ADME drawbacks.

**Overall Assessment:**

Ligand A has better physicochemical properties (logP, TPSA, QED, BBB), while Ligand B has a significantly higher binding affinity. Given the GPCR target and the importance of CNS penetration, the slightly better BBB and logP of Ligand A are valuable. However, the 0.4 kcal/mol difference in binding affinity is substantial. For a GPCR, a strong binding affinity is often critical, and can sometimes compensate for less-than-ideal ADME properties, especially if those properties are still within a reasonable range.

Output:
1
2025-04-17 07:42:25,948 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (359.417 and 385.512 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (67.59) is better than Ligand B (69.64) as both are below the 90 A^2 threshold for CNS targets, but lower is preferred.

**3. logP:** Both ligands have good logP values (2.725 and 2.088), falling within the optimal 1-3 range. Ligand A is slightly higher, which could be beneficial for membrane permeability.

**4. H-Bond Donors:** Ligand A (1) is better than Ligand B (0) as it provides a slight benefit to solubility.

**5. H-Bond Acceptors:** Ligand B (6) is slightly better than Ligand A (5) but both are within the acceptable limit of 10.

**6. QED:** Ligand A (0.775) has a significantly better QED score than Ligand B (0.552), indicating a more drug-like profile.

**7. DILI:** Ligand B (29.895) has a lower DILI risk than Ligand A (39.046), which is a positive attribute.

**8. BBB:** Ligand B (96.006) has a substantially higher BBB penetration percentile than Ligand A (87.01), which is crucial for a CNS target like DRD2. This is a major advantage for Ligand B.

**9. Caco-2 Permeability:** Ligand A (-4.6) has a slightly better Caco-2 permeability than Ligand B (-4.974), but both are negative, indicating poor permeability.

**10. Aqueous Solubility:** Ligand A (-2.028) has a slightly better aqueous solubility than Ligand B (-2.333), but both are negative, indicating poor solubility.

**11. hERG Inhibition:** Ligand A (0.358) has a lower hERG inhibition liability than Ligand B (0.819), which is favorable.

**12. Microsomal Clearance:** Ligand B (53.495) has a higher microsomal clearance than Ligand A (33.548), suggesting faster metabolism and lower metabolic stability.

**13. In vitro Half-Life:** Ligand A (-15.282) has a significantly longer in vitro half-life than Ligand B (-53.647), which is a major advantage.

**14. P-gp Efflux:** Ligand A (0.089) has a lower P-gp efflux liability than Ligand B (0.185), which is beneficial for CNS exposure.

**15. Binding Affinity:** Ligand B (-9.3 kcal/mol) has a significantly stronger binding affinity than Ligand A (-7.2 kcal/mol). This is a substantial advantage, potentially outweighing some of the ADME drawbacks.

**Overall Assessment:**

While Ligand A has better QED, hERG, half-life, and P-gp properties, Ligand B excels in BBB penetration and, critically, binding affinity. The higher binding affinity of Ligand B (-9.3 kcal/mol vs -7.2 kcal/mol) is a significant advantage for a GPCR target. The superior BBB penetration (96.006%) is also crucial for CNS activity. Although Ligand B has a slightly higher DILI risk and lower half-life, the strong binding affinity and BBB penetration are likely to be more important for initial success as a DRD2 ligand.

Output:
1
2025-04-17 07:42:25,948 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (368.5 and 346.4 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (76.66) is slightly above the preferred <90 for CNS targets, but still reasonable. Ligand B (66.92) is excellent, well below 90.

**3. logP:** Both ligands have good logP values (2.337 and 1.494), falling within the optimal 1-3 range.

**4. H-Bond Donors:** Ligand A has 2 HBD, which is acceptable. Ligand B has 0, also acceptable.

**5. H-Bond Acceptors:** Ligand A has 5 HBA, within the limit of 10. Ligand B has 4, also within the limit.

**6. QED:** Both ligands have similar QED values (0.622 and 0.574), indicating good drug-like properties.

**7. DILI:** Ligand A (38.5%) has a slightly higher DILI risk than Ligand B (27.2%), but both are below the concerning threshold of 60%.

**8. BBB:** Ligand B (84.9%) has a significantly better BBB penetration score than Ligand A (70.6%). This is a crucial advantage for a CNS target like DRD2.

**9. Caco-2 Permeability:** Ligand A (-5.149) has poor Caco-2 permeability. Ligand B (-4.554) is also poor, but slightly better.

**10. Aqueous Solubility:** Both ligands have poor aqueous solubility (-2.223 and -3.191). This could pose formulation challenges.

**11. hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.594 and 0.142).

**12. Microsomal Clearance:** Ligand A (32.3) has a lower microsomal clearance than Ligand B (54.2), suggesting better metabolic stability.

**13. In vitro Half-Life:** Ligand A (15.024) has a positive in vitro half-life, while Ligand B (-15.194) has a negative value, which is concerning.

**14. P-gp Efflux:** Both ligands have low P-gp efflux liability (0.185 and 0.215).

**15. Binding Affinity:** Both ligands have excellent binding affinity (-7.5 and -7.6 kcal/mol), with Ligand B being slightly better. The affinity difference is minimal and unlikely to outweigh other factors.

**Overall Assessment:**

Ligand B is the more promising candidate. While both have good affinity and acceptable safety profiles, Ligand B's significantly higher BBB penetration (84.9% vs 70.6%) is a major advantage for a CNS-targeting drug. It also has a lower DILI risk and a slightly better logP. Although Ligand A has better metabolic stability (lower Cl_mic) and a positive in vitro half-life, the BBB score is paramount for DRD2. The poor Caco-2 and solubility for both are drawbacks that would need to be addressed during optimization, but are less critical than CNS penetration at this stage.

Output:
1
2025-04-17 07:42:25,948 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the acceptable range (200-500 Da). Ligand A (363.361 Da) is slightly preferred as it's closer to the lower end, potentially aiding permeability.

**TPSA:** Ligand B (68.02) is significantly better than Ligand A (107.97). For CNS targets, TPSA < 90 is desirable, and Ligand B comfortably meets this, while Ligand A is pushing the limit.

**logP:** Ligand A (-1.269) is too low, potentially hindering membrane permeability. Ligand B (4.258) is high, potentially causing solubility/off-target issues, but within a range that can be tolerated if other properties are favorable.

**H-Bond Donors/Acceptors:** Ligand A has 3 HBD and 5 HBA, a reasonable balance. Ligand B has 1 HBD and 5 HBA, also acceptable.

**QED:** Both ligands have good QED scores (Ligand A: 0.523, Ligand B: 0.634), indicating drug-like properties.

**DILI:** Ligand A (28.461) has a much lower DILI risk than Ligand B (90.733), a significant advantage.

**BBB:** Ligand B (70.997) has a good BBB percentile, exceeding the desirable >70 threshold for CNS targets. Ligand A (53.858) is below this threshold, which is a major drawback for a CNS target like DRD2.

**Caco-2 Permeability:** Ligand A (-5.166) has poor Caco-2 permeability. Ligand B (-4.468) is also poor, but slightly better.

**Aqueous Solubility:** Ligand A (-1.417) has poor solubility. Ligand B (-5.355) is even worse.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (Ligand A: 0.165, Ligand B: 0.393).

**Microsomal Clearance:** Ligand A (-19.059) has a much lower (better) microsomal clearance than Ligand B (35.624), indicating better metabolic stability.

**In vitro Half-Life:** Ligand B (12.191 hours) has a longer half-life than Ligand A (4.367 hours), which is generally preferred.

**P-gp Efflux:** Ligand A (0.004) shows very low P-gp efflux, which is excellent for CNS penetration. Ligand B (0.345) has moderate P-gp efflux, which is less desirable.

**Binding Affinity:** Ligand B (-9.2 kcal/mol) has a significantly stronger binding affinity than Ligand A (-7.8 kcal/mol). This >1.5 kcal/mol difference is substantial and can outweigh some ADME drawbacks.

**Overall Assessment:**

Ligand B's strong binding affinity and good BBB penetration are highly attractive for a CNS-targeting GPCR like DRD2. While its logP is high and solubility is poor, these issues might be addressed through formulation strategies. The higher DILI risk is a concern, but potentially manageable. Ligand A has better metabolic stability and lower DILI, but its poor BBB penetration and weak affinity are significant liabilities for a CNS drug. The strong affinity of Ligand B is the deciding factor.

Output:
1
2025-04-17 07:42:25,948 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (363.571 and 343.427 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (44.37) is excellent, well below the 90 A^2 threshold for CNS targets. Ligand B (74.59) is higher but still acceptable, although less optimal.

**logP:** Ligand A (4.156) is slightly high, potentially leading to solubility issues or off-target interactions. Ligand B (1.814) is within the optimal 1-3 range.

**H-Bond Donors & Acceptors:** Ligand A (2 HBD, 3 HBA) is good. Ligand B (1 HBD, 5 HBA) is also acceptable.

**QED:** Both ligands have good QED scores (0.564 and 0.779), indicating drug-like properties.

**DILI:** Ligand A (23.071) has a very low DILI risk, significantly better than Ligand B (33.618).

**BBB:** This is crucial for a CNS target like DRD2. Ligand A (90.5) has excellent BBB penetration, exceeding the desirable >70 percentile. Ligand B (46.064) is considerably lower and a significant drawback.

**Caco-2 Permeability:** Both are negative, indicating poor permeability. This is a concern for oral bioavailability, but less critical for a CNS target where direct delivery or other routes might be considered.

**Aqueous Solubility:** Both ligands have negative solubility values, indicating poor solubility. This is a concern, but can be addressed with formulation strategies.

**hERG:** Ligand A (0.894) has a slightly higher hERG risk than Ligand B (0.448), but both are relatively low.

**Microsomal Clearance:** Ligand A (78.348) has higher clearance than Ligand B (53.815), suggesting lower metabolic stability.

**In vitro Half-Life:** Ligand A (48.381) has a longer half-life than Ligand B (32.132), which is favorable.

**P-gp Efflux:** Ligand A (0.718) has moderate P-gp efflux, while Ligand B (0.047) has very low efflux. Lower P-gp efflux is preferred for CNS penetration.

**Binding Affinity:** Ligand A (0.0) has a significantly weaker binding affinity than Ligand B (-6.9 kcal/mol). This is a major difference. A >1.5 kcal/mol advantage in binding is considered significant.

**Overall Assessment:**

Ligand B has a superior binding affinity and lower P-gp efflux. However, Ligand A has a much better BBB score, lower DILI risk, and a longer half-life. The strong affinity of Ligand B is a significant advantage. The higher logP of Ligand A is a concern, but the excellent BBB penetration somewhat mitigates this. Given the importance of affinity for GPCRs, and the substantial difference in binding energy (-6.9 vs 0.0), Ligand B is the more promising candidate despite its lower BBB score. Formulation strategies could be explored to improve its CNS penetration.

Output:
1
2025-04-17 07:42:25,949 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (370.471 Da) is slightly higher than Ligand B (344.499 Da), but both are acceptable.

**TPSA:** Ligand A (94.59) is closer to the upper limit for CNS targets (<=90), while Ligand B (49.41) is excellent, well below the threshold. This favors Ligand B.

**logP:** Both ligands have good logP values (Ligand A: 1.938, Ligand B: 3.275), falling within the optimal range of 1-3. Ligand B is slightly higher, which could be beneficial for membrane permeability but needs to be considered alongside other factors.

**H-Bond Donors/Acceptors:** Both ligands have acceptable HBD (1) and HBA (Ligand A: 6, Ligand B: 2) counts.

**QED:** Both ligands have similar and good QED values (Ligand A: 0.769, Ligand B: 0.778), indicating good drug-like properties.

**DILI:** Ligand A (43.622) has a slightly higher DILI risk than Ligand B (24.234), which is preferable.

**BBB:** Ligand B (76.619) has a better BBB percentile than Ligand A (67.468), making it more likely to cross the blood-brain barrier, a crucial factor for a DRD2 ligand targeting CNS disorders.

**Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and requires further investigation. However, the magnitude of negativity is similar.

**Aqueous Solubility:** Both have negative solubility values, which is also unusual and requires further investigation. Again, the values are similar.

**hERG Inhibition:** Both ligands show low hERG inhibition liability (Ligand A: 0.222, Ligand B: 0.303), which is good.

**Microsomal Clearance:** Ligand A (91.716) has a higher microsomal clearance than Ligand B (38.965), indicating lower metabolic stability. This favors Ligand B.

**In vitro Half-Life:** Ligand B (-8.258) has a slightly better (less negative) in vitro half-life than Ligand A (-76.812).

**P-gp Efflux:** Both ligands have low P-gp efflux liability (Ligand A: 0.049, Ligand B: 0.28).

**Binding Affinity:** Ligand B (-8.9 kcal/mol) has a slightly better binding affinity than Ligand A (-8.1 kcal/mol). While both are good, the 0.8 kcal/mol difference is significant and can outweigh minor ADME drawbacks.

**Overall Assessment:**

Ligand B consistently outperforms Ligand A in key areas for a CNS-targeting GPCR ligand: TPSA, BBB, DILI, microsomal clearance, and binding affinity. While both have unusual solubility and Caco-2 permeability values that would need to be investigated, the superior ADME and binding profile of Ligand B make it the more promising candidate.

Output:
1
2025-04-17 07:42:25,949 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (349.351 and 350.379 Da) fall comfortably within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (128.27) is better than Ligand B (131.52). Both are reasonably close to the 140 A^2 threshold for oral absorption, but for a CNS target like DRD2, we ideally want <90 A^2. Ligand A is closer to this target.

**3. logP:** Ligand A (0.167) is significantly lower than the optimal 1-3 range and is quite hydrophilic. Ligand B (-1.709) is also low, but less so than Ligand A. This is a concern for both, potentially hindering membrane permeability.

**4. H-Bond Donors:** Ligand A (1) is good. Ligand B (3) is acceptable but less ideal.

**5. H-Bond Acceptors:** Ligand A (9) is good. Ligand B (6) is also good.

**6. QED:** Ligand A (0.731) is better than Ligand B (0.579), indicating a more drug-like profile.

**7. DILI:** Ligand A (85.576) has a higher DILI risk than Ligand B (63.086). This is a negative for Ligand A.

**8. BBB:** This is crucial for a CNS target. Ligand A (74.06) is good, exceeding the 70% threshold. Ligand B (16.363) is very poor, suggesting limited CNS penetration.

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.04 and -5.48), which is unusual and suggests poor permeability.

**10. Aqueous Solubility:** Both ligands have negative solubility values (-1.631 and -2.129), which is also unusual and indicates very low solubility.

**11. hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.047 and 0.089).

**12. Microsomal Clearance:** Ligand A (34.954) has higher clearance than Ligand B (15.944), suggesting lower metabolic stability.

**13. In vitro Half-Life:** Ligand A (-3.201) has a shorter half-life than Ligand B (-4.292), indicating faster metabolism.

**14. P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.009 and 0.036).

**15. Binding Affinity:** Both ligands have excellent binding affinity (-8.2 and -8.6 kcal/mol). The difference is minor.

**Overall Assessment:**

Despite the unusual negative values for Caco-2 and solubility, the most significant difference lies in BBB penetration. Ligand A has a BBB percentile of 74.06, while Ligand B is only at 16.363. For a CNS target like DRD2, this is a critical factor. While Ligand A has a slightly higher DILI risk and lower metabolic stability, the superior BBB penetration outweighs these concerns. The similar binding affinities mean that the differences in ADME properties become the deciding factor.

Output:
0
2025-04-17 07:42:25,949 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B based on the provided guidelines, prioritizing GPCR-specific properties (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (357.801) is slightly lower, which can be favorable for permeability.

**TPSA:** Ligand A (71.76) is better than Ligand B (57.69) as it is closer to the ideal range for CNS targets (<=90).

**logP:** Both ligands have good logP values (A: 2.472, B: 3.076), falling within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A (HBD=1, HBA=6) is slightly better than Ligand B (HBD=0, HBA=4) in terms of balancing solubility and permeability.

**QED:** Both ligands have similar, good QED values (A: 0.779, B: 0.792), indicating drug-likeness.

**DILI:** Ligand A (97.674) has a significantly higher DILI risk than Ligand B (84.529). This is a major concern.

**BBB:** Ligand B (74.99) has a considerably better BBB penetration percentile than Ligand A (53.587). This is crucial for a CNS target like DRD2.

**Caco-2 Permeability:** Ligand A (-4.567) has a slightly better Caco-2 permeability than Ligand B (-4.633), but both are negative values, indicating poor permeability.

**Aqueous Solubility:** Ligand A (-3.961) has slightly better solubility than Ligand B (-5.043), but both are very poor.

**hERG Inhibition:** Ligand A (0.318) has a lower hERG inhibition liability than Ligand B (0.704), which is preferable.

**Microsomal Clearance:** Ligand B (52.154) has a lower microsomal clearance than Ligand A (17.558), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (31.809) has a longer in vitro half-life than Ligand B (-32.378). This is a positive attribute.

**P-gp Efflux:** Ligand A (0.114) has lower P-gp efflux liability than Ligand B (0.421), which is favorable for CNS exposure.

**Binding Affinity:** Both ligands have excellent binding affinities (A: -9.4 kcal/mol, B: -8.7 kcal/mol). Ligand A is slightly more potent.

**Overall Assessment:**

Despite Ligand A's slightly better affinity and P-gp efflux, the significantly higher DILI risk and lower BBB penetration are major drawbacks. For a CNS target, BBB penetration is paramount. Ligand B, while having slightly lower affinity, presents a much more favorable safety profile (lower DILI) and better BBB penetration. The improved metabolic stability (lower Cl_mic) of Ligand B also contributes to its potential for better *in vivo* performance. Although both have poor solubility and Caco-2 permeability, these can potentially be addressed with formulation strategies.

Output:
1
2025-04-17 07:42:25,949 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B based on the provided guidelines, prioritizing GPCR-specific properties (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (366.483 Da) is slightly higher than Ligand B (349.347 Da), but both are acceptable.

**TPSA:** Ligand A (75.71) is significantly better than Ligand B (126.13). For CNS targets, we want TPSA <= 90, and Ligand A is comfortably within this range, while Ligand B exceeds it.

**logP:** Ligand A (1.846) is optimal (1-3), while Ligand B (-1.173) is below 1, potentially hindering permeation.

**H-Bond Donors/Acceptors:** Ligand A (HBD=1, HBA=4) and Ligand B (HBD=2, HBA=7) both fall within acceptable ranges.

**QED:** Both ligands have similar QED values (A: 0.747, B: 0.69), indicating good drug-likeness.

**DILI:** Ligand A (37.146) has a much lower DILI risk than Ligand B (60.915). Both are below 60, but A is preferable.

**BBB:** Ligand A (81.698) has a significantly higher BBB penetration percentile than Ligand B (45.909). This is *critical* for a CNS target like DRD2.

**Caco-2 Permeability:** Ligand A (-4.65) and Ligand B (-5.502) both have negative values, which is unusual and suggests poor permeability. However, the scale isn't defined, so it's hard to interpret.

**Aqueous Solubility:** Ligand A (-1.979) and Ligand B (-1.628) both have negative solubility values, indicating poor solubility.

**hERG Inhibition:** Ligand A (0.547) has a lower hERG inhibition risk than Ligand B (0.045).

**Microsomal Clearance:** Ligand B (-12.06) has a lower (better) microsomal clearance than Ligand A (32.42). This suggests better metabolic stability for Ligand B.

**In vitro Half-Life:** Ligand A (-7.872) has a longer (better) in vitro half-life than Ligand B (33.161).

**P-gp Efflux:** Ligand A (0.399) has lower P-gp efflux liability than Ligand B (0.017), which is favorable for CNS penetration.

**Binding Affinity:** Ligand A (-8.9 kcal/mol) has a significantly stronger binding affinity than Ligand B (0.0 kcal/mol). This is a major advantage.

**Overall Assessment:**

Ligand A is clearly superior. It has a better TPSA, logP, BBB, DILI, hERG, P-gp efflux, and *much* stronger binding affinity. While Ligand B has better metabolic stability (lower Cl_mic) and half-life, the critical factors for a CNS GPCR target (BBB, affinity, TPSA, logP) overwhelmingly favor Ligand A. The substantial difference in binding affinity (-8.9 vs 0.0 kcal/mol) is a decisive factor, and can compensate for the slightly higher Cl_mic.



Output:
1
2025-04-17 07:42:25,950 - INFO - Reasoning:

Let's analyze Ligand A and Ligand B based on the provided guidelines, prioritizing GPCR-specific properties (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (349.435 and 345.443 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (100.35) is higher than Ligand B (75.44). For CNS targets, TPSA should be <= 90, so both are acceptable, but B is better.

**logP:** Ligand A (0.497) is quite low, potentially hindering permeation. Ligand B (2.703) is within the optimal 1-3 range. This is a significant advantage for B.

**H-Bond Donors/Acceptors:** Ligand A has 2 HBD and 6 HBA, while Ligand B has 1 HBD and 4 HBA. Both are within acceptable limits.

**QED:** Both ligands have good QED scores (0.746 and 0.771), indicating good drug-like properties.

**DILI:** Ligand A (36.758) has a lower DILI risk than Ligand B (47.654), which is preferable.

**BBB:** This is a crucial parameter for CNS targets. Ligand B (84.374) has a significantly higher BBB percentile than Ligand A (35.285). This is a major advantage for B.

**Caco-2 Permeability:** Ligand A (-5.484) has poor Caco-2 permeability, while Ligand B (-4.95) is slightly better, but both are quite low.

**Aqueous Solubility:** Ligand A (-1.143) has slightly better solubility than Ligand B (-3.067).

**hERG Inhibition:** Ligand A (0.073) has a lower hERG risk than Ligand B (0.339), which is preferable.

**Microsomal Clearance:** Ligand A (-4.72) has lower (better) microsomal clearance than Ligand B (60.167). This suggests better metabolic stability for A.

**In vitro Half-Life:** Ligand A (5.761) has a shorter half-life than Ligand B (-19.711). The negative value for B is unusual and likely indicates a very long half-life, which is positive.

**P-gp Efflux:** Ligand A (0.004) has very low P-gp efflux, which is excellent. Ligand B (0.294) is higher, but still reasonably low.

**Binding Affinity:** Both ligands have similar and good binding affinities (-7.8 and -7.6 kcal/mol). The difference is less than the 1.5 kcal/mol threshold.

**Overall Assessment:**

Ligand B is the stronger candidate. While Ligand A has advantages in DILI, hERG, and microsomal clearance, Ligand B's significantly better BBB penetration and logP outweigh these benefits for a CNS-targeting GPCR. The better TPSA of B also contributes. Although Caco-2 permeability is low for both, the BBB is the critical factor here. The unusually long half-life of B is also a positive.



Output:
1
2025-04-17 07:42:25,950 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (357.361 and 348.491 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (100.35) is higher than the preferred <90 for CNS targets, while Ligand B (58.44) is well within the range. This favors Ligand B.

**logP:** Ligand A (0.035) is quite low, potentially hindering permeability. Ligand B (2.719) is nearly ideal. This strongly favors Ligand B.

**H-Bond Donors:** Ligand A (2) is acceptable. Ligand B (0) is also good.

**H-Bond Acceptors:** Ligand A (6) is acceptable. Ligand B (4) is also good.

**QED:** Both ligands have reasonable QED scores (0.748 and 0.645), indicating good drug-like properties.

**DILI:** Ligand A (54.866) has a moderate DILI risk, while Ligand B (29.624) has a lower risk. This favors Ligand B.

**BBB:** Ligand A (68.903) is below the desirable >70 for CNS targets, while Ligand B (81.543) is excellent. This is a significant advantage for Ligand B.

**Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and suggests poor permeability. However, the scale is not specified, so it's difficult to interpret.

**Aqueous Solubility:** Both ligands have negative solubility values, which is also unusual and suggests poor solubility. Again, the scale is not specified.

**hERG:** Ligand A (0.119) has a very low hERG risk, while Ligand B (0.772) has a slightly higher, but still acceptable, risk.

**Microsomal Clearance:** Ligand A (-15.393) has a negative clearance, which is not physically possible and indicates an issue with the data. Ligand B (87.781) has a high clearance, suggesting rapid metabolism. This favors Ligand A, assuming the negative value is an error.

**In vitro Half-Life:** Ligand A (4.975) has a short half-life. Ligand B (25.214) has a much longer half-life. This favors Ligand B.

**P-gp Efflux:** Ligand A (0.09) has low P-gp efflux, which is good for CNS penetration. Ligand B (0.588) has moderate P-gp efflux. This favors Ligand A.

**Binding Affinity:** Ligand A (-8.0) has a slightly better binding affinity than Ligand B (-6.9). However, the difference is less than 1.5 kcal/mol, so it's not a decisive factor.

**Overall Assessment:**

Ligand B consistently outperforms Ligand A in key GPCR-relevant properties: TPSA, logP, BBB, and half-life. While Ligand A has a slightly better affinity and lower P-gp efflux, the significant advantages of Ligand B in terms of CNS penetration (BBB) and drug-like properties (logP, TPSA) outweigh these minor benefits. The negative clearance for Ligand A is also concerning.

Output:
1
2025-04-17 07:42:25,950 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 drug candidates, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (348.443 and 380.539 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (71.78) is slightly higher than Ligand B (68.21), but both are below the 90 A^2 threshold desirable for CNS targets.

**3. logP:** Both ligands have good logP values (2.402 and 3.081), falling within the optimal 1-3 range. Ligand B is slightly more lipophilic.

**4. H-Bond Donors:** Ligand A (1) is preferable to Ligand B (0) as having at least one HBD can improve solubility.

**5. H-Bond Acceptors:** Ligand A (4) is preferable to Ligand B (7). Lower HBA is generally preferred for better permeability.

**6. QED:** Ligand A (0.783) has a significantly better QED score than Ligand B (0.593), indicating a more drug-like profile.

**7. DILI:** Both ligands have low DILI risk (21.404 and 23.769), which is good.

**8. BBB:** Both ligands show excellent BBB penetration (74.486 and 78.868), exceeding the desirable >70% threshold for CNS targets. Ligand B is slightly better.

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.888 and -5.048). This is unusual and suggests poor permeability. However, these values are on a log scale and are likely representing very low permeability.

**10. Aqueous Solubility:** Both ligands have poor aqueous solubility (-1.837 and -2.069). This is a concern for bioavailability.

**11. hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.299 and 0.477).

**12. Microsomal Clearance:** Ligand A (44.516) has lower microsomal clearance than Ligand B (72.291), suggesting better metabolic stability.

**13. In vitro Half-Life:** Ligand A (41.295) has a significantly longer in vitro half-life than Ligand B (1.369), which is a major advantage.

**14. P-gp Efflux:** Both ligands have low P-gp efflux liability (0.061 and 0.291), which is good for CNS exposure. Ligand A is slightly better.

**15. Binding Affinity:** Ligand A (-8.8 kcal/mol) has a significantly stronger binding affinity than Ligand B (-6.2 kcal/mol). This >1.5 kcal/mol difference is substantial and can outweigh minor ADME drawbacks.

**Overall Assessment:**

Ligand A is the superior candidate. While both have good BBB penetration and low DILI/hERG risk, Ligand A excels in crucial areas: significantly stronger binding affinity, better QED, lower microsomal clearance, and a much longer in vitro half-life. The slightly better H-bonding characteristics and lower HBA count also contribute to its favorability. The poor Caco-2 and solubility are concerns for both, but the strong affinity of Ligand A makes it more likely to achieve sufficient target engagement *in vivo* despite these limitations.

Output:
1
2025-04-17 07:42:25,950 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (337.47 & 351.45 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (38.13) is excellent, well below the 90 A^2 threshold for CNS targets. Ligand B (99.61) is higher, but still potentially acceptable, although less ideal.

**logP:** Ligand A (3.47) is optimal (1-3). Ligand B (1.622) is on the lower side, potentially hindering permeability.

**H-Bond Donors/Acceptors:** Ligand A (0 HBD, 4 HBA) is favorable. Ligand B (3 HBD, 7 HBA) is also acceptable, though slightly higher counts.

**QED:** Ligand A (0.838) is very good, indicating high drug-likeness. Ligand B (0.612) is still reasonable, but less optimal.

**DILI:** Both ligands have acceptable DILI risk (Ligand A: 30.012, Ligand B: 39.473), both below the 40 threshold.

**BBB:** Ligand A (96.045) has excellent BBB penetration potential, exceeding the 70% threshold. Ligand B (72.547) is still good, but significantly lower than Ligand A. This is a crucial factor for a CNS target like DRD2.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.842 and -4.982). This is unusual and requires further investigation, but doesn't immediately disqualify either.

**Aqueous Solubility:** Both ligands have negative solubility values (-2.797 and -2.685), which is also unusual and needs further investigation.

**hERG:** Both ligands have low hERG risk (0.935 and 0.806).

**Microsomal Clearance:** Ligand A (12.588) has lower clearance, indicating better metabolic stability than Ligand B (36.855).

**In vitro Half-Life:** Ligand A (8.153) has a longer half-life than Ligand B (2.091).

**P-gp Efflux:** Ligand A (0.473) has lower P-gp efflux, which is beneficial for CNS exposure. Ligand B (0.069) has even lower efflux, which is excellent.

**Binding Affinity:** Ligand A (-8.8 kcal/mol) has a slightly better binding affinity than Ligand B (-7.9 kcal/mol). While both are good, the 0.9 kcal/mol difference is significant.

**Overall Assessment:**

Ligand A is clearly superior. It excels in key areas for a CNS-targeting GPCR ligand: high BBB penetration, excellent QED, better metabolic stability (lower Cl_mic, longer t1/2), lower P-gp efflux, and slightly better binding affinity. While both have unusual solubility and Caco-2 values, the other advantages of Ligand A outweigh these concerns. Ligand B's lower logP and BBB penetration are significant drawbacks.

Output:
1
2025-04-17 07:42:25,951 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (348.531 and 350.467 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (49.41) is excellent, well below the 90 A^2 threshold for CNS targets. Ligand B (92.15) is higher, but still potentially acceptable, though less ideal.

**logP:** Ligand A (3.887) is optimal. Ligand B (0.56) is quite low, potentially hindering membrane permeability and CNS penetration.

**H-Bond Donors/Acceptors:** Ligand A (HBD=1, HBA=2) is favorable. Ligand B (HBD=2, HBA=6) is acceptable, but the higher HBA count could slightly impact permeability.

**QED:** Both ligands have reasonable QED values (A: 0.838, B: 0.679), indicating good drug-like properties.

**DILI:** Ligand A (14.889) has a very low DILI risk. Ligand B (24.583) also has a low DILI risk, but is higher than ligand A.

**BBB:** Ligand A (93.098) has excellent BBB penetration potential. Ligand B (60.45) is significantly lower, raising concerns about reaching the target in the CNS.

**Caco-2 Permeability:** Ligand A (-4.626) is poor. Ligand B (-5.355) is also poor.

**Aqueous Solubility:** Both ligands have poor aqueous solubility (-4.659 and -1.211 respectively).

**hERG:** Both ligands have low hERG inhibition risk (0.533 and 0.283 respectively).

**Microsomal Clearance:** Ligand A (44.74) is moderate. Ligand B (-1.269) is very low, suggesting good metabolic stability.

**In vitro Half-Life:** Ligand A (1.161) is short. Ligand B (9.034) is much longer, a significant advantage.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.233 and 0.023 respectively).

**Binding Affinity:** Ligand B (-8.2 kcal/mol) has a slightly better binding affinity than Ligand A (-7.8 kcal/mol). This 0.4 kcal/mol difference is notable, but not overwhelmingly large.

**Overall Assessment:**

Considering the GPCR-specific priorities, Ligand A is the better candidate. While Ligand B has a slightly better binding affinity and metabolic stability, Ligand A's significantly better BBB penetration (93.098 vs 60.45) and logP (3.887 vs 0.56) are crucial for a CNS-targeting drug. The poor Caco-2 permeability and solubility of both compounds are drawbacks that would need to be addressed during optimization, but are less critical than CNS penetration for this target. The lower DILI risk of Ligand A is also a plus.



Output:
1
2025-04-17 07:42:25,951 - INFO - Batch 387 complete. Total preferences: 6192
2025-04-17 07:42:25,951 - INFO - Processing batch 388/512...
2025-04-17 07:43:05,851 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B against the provided guidelines, prioritizing GPCR-specific properties (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (354.397 and 345.418 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (49.85) is better than Ligand B (53.51) as it is closer to the <90 target for CNS penetration.

**logP:** Both ligands have acceptable logP values (1.519 and 2.472), falling within the 1-3 range. Ligand B is slightly higher, which could potentially lead to some solubility issues, but is still within an acceptable range.

**H-Bond Donors/Acceptors:** Both have 0 HBD and 3 HBA, which are within the recommended limits.

**QED:** Both ligands have good QED scores (0.722 and 0.796), indicating good drug-like properties.

**DILI:** Ligand A (21.753) has a significantly lower DILI risk than Ligand B (26.134), which is a major advantage.

**BBB:** Both ligands have excellent BBB penetration (88.29% and 90.074%), exceeding the desirable >70% threshold for CNS targets. Ligand B is marginally better.

**Caco-2 Permeability:** Both have negative Caco-2 values (-4.287 and -4.221). This is unusual and suggests poor permeability. However, the scale is not clearly defined, so it's difficult to interpret.

**Aqueous Solubility:** Both have negative solubility values (-2.536 and -2.805). Similar to Caco-2, the scale is unclear, but negative values suggest poor solubility.

**hERG:** Both ligands have low hERG inhibition liability (0.337 and 0.305), which is good.

**Microsomal Clearance:** Ligand A (-7.411) has *much* lower microsomal clearance than Ligand B (37.583). This indicates significantly better metabolic stability for Ligand A.

**In vitro Half-Life:** Ligand A (-9.929) has a longer in vitro half-life than Ligand B (14.556).

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.048 and 0.043).

**Binding Affinity:** Ligand B (-8.0 kcal/mol) has a slightly better binding affinity than Ligand A (-7.3 kcal/mol). This is a 0.7 kcal/mol difference, which is significant but not overwhelming.

**Overall Assessment:**

Ligand A is the more promising candidate. While Ligand B has a slightly better binding affinity and BBB penetration, Ligand A excels in crucial ADME properties: significantly lower DILI risk, much better metabolic stability (lower Cl_mic and longer t1/2), and better TPSA. The affinity difference is not large enough to outweigh these substantial advantages, especially for a CNS target where metabolic stability and minimizing off-target effects (DILI) are paramount. The poor Caco-2 and solubility values are concerning for both, but these could potentially be addressed with formulation strategies.

Output:
0
2025-04-17 07:43:05,851 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (349.479 and 367.427 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (83.29) is significantly better than Ligand B (101.21). For CNS targets, we want TPSA <= 90, so Ligand A is preferable.

**3. logP:** Both ligands have acceptable logP values (2.962 and 1.19). Ligand A is slightly better, being closer to the optimal 1-3 range. Ligand B is at the lower end, which *could* indicate permeability issues.

**4. H-Bond Donors:** Both are acceptable (2 and 1 respectively), well below the threshold of 5.

**5. H-Bond Acceptors:** Both are acceptable (5 and 6 respectively), below the threshold of 10.

**6. QED:** Both ligands have similar, good QED values (0.791 and 0.788), indicating good drug-like properties.

**7. DILI:** Ligand A (26.018) has a much lower DILI risk than Ligand B (61.07). This is a significant advantage for Ligand A.

**8. BBB:** Ligand A (85.498) has a significantly higher BBB penetration percentile than Ligand B (46.336). This is *critical* for a CNS target like DRD2. A value >70 is desirable, and Ligand A is closer to that.

**9. Caco-2 Permeability:** Ligand A (-5.074) has a worse Caco-2 permeability compared to Ligand B (-4.834). However, this is less important than BBB for a CNS target.

**10. Aqueous Solubility:** Both have poor aqueous solubility (-2.288 and -2.477). This could pose formulation challenges, but is not a dealbreaker.

**11. hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.34 and 0.276).

**12. Microsomal Clearance:** Ligand A (15.565) has a lower microsomal clearance than Ligand B (44.303), indicating better metabolic stability.

**13. In vitro Half-Life:** Ligand A (20.392) has a longer in vitro half-life than Ligand B (14.818).

**14. P-gp Efflux:** Ligand A (0.076) has lower P-gp efflux liability than Ligand B (0.106), which is desirable for CNS penetration.

**15. Binding Affinity:** Ligand B (-9.0) has a significantly stronger binding affinity than Ligand A (-7.8). This is a substantial advantage for Ligand B. A difference of >1.5 kcal/mol can often outweigh other issues.

**Overall Assessment:**

While Ligand B has a superior binding affinity, Ligand A is significantly better in almost all ADME-Tox properties crucial for CNS drug development, particularly BBB penetration and DILI risk. The difference in binding affinity (-1.2 kcal/mol) is substantial, but the combination of excellent BBB, low DILI, better metabolic stability, and lower P-gp efflux for Ligand A makes it the more promising candidate. The better TPSA also contributes to its favorability.

Output:
0
2025-04-17 07:43:05,851 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (362.86 and 349.48 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (70.59) is significantly better than Ligand B (84.23). For CNS targets, TPSA should be <= 90, and A is closer to the optimal <= 60-70 range. B is pushing the upper limit and could face permeability issues.

**3. logP:** Both ligands have good logP values (3.23 and 3.06), falling within the 1-3 range.

**4. H-Bond Donors:** Ligand A (3) is slightly higher than Ligand B (2), but both are acceptable (<=5).

**5. H-Bond Acceptors:** Ligand A (3) and Ligand B (4) are both within the acceptable range (<=10).

**6. QED:** Ligand A (0.708) has a substantially better QED score than Ligand B (0.502), indicating better overall drug-likeness.

**7. DILI:** Ligand A (52.15) has a higher DILI risk than Ligand B (27.03), but both are below the concerning threshold of 60.

**8. BBB:** Ligand A (56.22) has a significantly better BBB penetration score than Ligand B (44.75). While both are not ideal (>70), A is closer. This is *critical* for a CNS target like DRD2.

**9. Caco-2:** Ligand A (-4.682) and Ligand B (-5.131) both have negative Caco-2 values, which is unusual and suggests very poor permeability. This is a significant concern for both.

**10. Solubility:** Ligand A (-3.505) and Ligand B (-2.795) both have negative solubility values, indicating poor aqueous solubility. This could lead to formulation challenges.

**11. hERG:** Ligand A (0.802) has a slightly higher hERG risk than Ligand B (0.27), but both are relatively low.

**12. Cl_mic:** Ligand A (69.31) has a higher microsomal clearance than Ligand B (57.72), suggesting faster metabolism and lower metabolic stability.

**13. t1/2:** Ligand A (19.79) has a longer in vitro half-life than Ligand B (12.87), which is favorable.

**14. Pgp:** Ligand A (0.561) has a lower P-gp efflux liability than Ligand B (0.18), meaning it is less likely to be pumped out of the brain, which is crucial for CNS penetration.

**15. Binding Affinity:** Ligand A (-9.5 kcal/mol) has a significantly stronger binding affinity than Ligand B (-8.0 kcal/mol). This is a substantial advantage (>1.5 kcal/mol difference).

**Overall Assessment:**

Despite both ligands having issues with Caco-2 and solubility, Ligand A is the stronger candidate. Its superior BBB penetration, significantly better binding affinity, lower P-gp efflux, better QED, and longer half-life outweigh its slightly higher DILI and Cl_mic. The strong binding affinity is a major driver, and the improved CNS penetration properties are critical for a DRD2 target.

Output:
1
2025-04-17 07:43:05,851 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (384.929 Da) is slightly higher than Ligand B (356.394 Da), but both are acceptable.

**TPSA:** Ligand A (58.64) is excellent for CNS penetration, well below the 90 A^2 threshold. Ligand B (84.94) is still reasonable, but less optimal.

**logP:** Ligand A (2.957) is within the optimal range (1-3). Ligand B (0.279) is quite low, potentially hindering membrane permeability and CNS entry.

**H-Bond Donors/Acceptors:** Both ligands have 1 HBD and 4-5 HBA, which are within acceptable limits.

**QED:** Both ligands have good QED scores (0.605 and 0.663), indicating drug-like properties.

**DILI:** Ligand A (54.75) has a moderate DILI risk, while Ligand B (29.43) has a very low risk. This favors Ligand B.

**BBB:** Ligand A (62.156) has a reasonable BBB penetration, but Ligand B (87.67) is significantly better, exceeding the desirable >70 threshold for CNS targets.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.957 and -4.768) which is unusual and suggests poor permeability.

**Aqueous Solubility:** Both ligands have negative solubility values (-4.796 and -1.427) which is also unusual and suggests poor solubility.

**hERG:** Ligand A (0.567) has a low hERG risk, while Ligand B (0.226) has an even lower risk.

**Microsomal Clearance:** Ligand A (82.042) has a higher microsomal clearance, suggesting faster metabolism. Ligand B (19.662) has a much lower clearance, indicating better metabolic stability.

**In vitro Half-Life:** Ligand A (28.361) has a moderate half-life, while Ligand B (-8.786) has a very short half-life.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.568 and 0.019), which is good for CNS exposure.

**Binding Affinity:** Ligand B (-7.6 kcal/mol) has a significantly stronger binding affinity than Ligand A (-0.0 kcal/mol). This is a major advantage.

**Overall Assessment:**

Ligand B is the stronger candidate. While Ligand A has a slightly better DILI score, Ligand B excels in the most critical areas for a CNS-targeting GPCR ligand: BBB penetration, binding affinity, and metabolic stability. The significantly stronger binding affinity of Ligand B (-7.6 kcal/mol vs -0.0 kcal/mol) is a decisive factor, potentially outweighing the slightly higher DILI risk. The low logP of Ligand B is a concern, but the excellent BBB penetration suggests it can still reach the target.

Output:
1
2025-04-17 07:43:05,851 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 drug candidates, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (345.315 Da) is slightly lower, which could be beneficial for permeability, while Ligand B (368.503 Da) is also well within range.

**TPSA:** Ligand A (128.78) is borderline for CNS penetration, being slightly above the ideal <90. Ligand B (94.56) is excellent, falling well within the desired range for CNS targets.

**logP:** Ligand A (-0.211) is quite low, potentially hindering membrane permeability and bioavailability. Ligand B (1.003) is within the optimal range (1-3).

**H-Bond Donors/Acceptors:** Both ligands have acceptable HBD (2/3) and HBA (6/6) counts, unlikely to cause significant issues.

**QED:** Both ligands have good QED scores (0.561 and 0.636), indicating generally drug-like properties.

**DILI:** Ligand A (85.653) has a higher DILI risk than Ligand B (33.23), which is a significant concern.

**BBB:** Ligand A (64.909) has a moderate BBB penetration, while Ligand B (33.579) is quite low. This is a critical disadvantage for a CNS target like DRD2.

**Caco-2 Permeability:** Both show poor Caco-2 permeability (-4.945 and -5.55).

**Aqueous Solubility:** Both have very poor aqueous solubility (-3.584 and -1.003).

**hERG:** Both ligands have very low hERG inhibition risk (0.047 and 0.174).

**Microsomal Clearance:** Ligand A (-5.851) has lower (better) microsomal clearance than Ligand B (-29.142), suggesting better metabolic stability.

**In vitro Half-Life:** Both have similar in vitro half-lives (22.239 and 24.156 hours).

**P-gp Efflux:** Both have very low P-gp efflux liability (0.002 and 0.039).

**Binding Affinity:** Ligand B (-7.8 kcal/mol) has a slightly better binding affinity than Ligand A (-8.5 kcal/mol). While the difference is not huge, it's still a factor.

**Overall Assessment:**

Ligand B is the more promising candidate despite its lower BBB penetration. The key advantages are its better logP, significantly lower DILI risk, and slightly better binding affinity. Ligand A's low logP is a major drawback, and its higher DILI risk is unacceptable. While Ligand A has better metabolic stability, the other factors outweigh this benefit. The poor Caco-2 and solubility for both ligands would require formulation strategies, but are addressable. The lower BBB for Ligand B is a concern, but potentially mitigable through structural modifications.

Output:
1
2025-04-17 07:43:05,852 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (363.361 and 367.965 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (120.25) is better than Ligand B (38.13). For CNS targets, TPSA should be <=90. Ligand A is close to the upper limit, while Ligand B is well within.

**logP:** Ligand A (-0.461) is suboptimal, being below the preferred 1-3 range and potentially hindering permeation. Ligand B (4.767) is high, potentially causing solubility and off-target issues.

**H-Bond Donors/Acceptors:** Ligand A (4 HBD, 6 HBA) is reasonable. Ligand B (0 HBD, 3 HBA) is also acceptable.

**QED:** Both ligands have good QED scores (0.488 and 0.663, respectively), indicating drug-like properties.

**DILI:** Ligand A (36.681) has a slightly higher DILI risk than Ligand B (21.908), but both are below the concerning threshold of 60.

**BBB:** This is crucial for a CNS target like DRD2. Ligand B (87.321) has a significantly higher BBB penetration percentile than Ligand A (48.74). This is a major advantage for Ligand B.

**Caco-2 Permeability:** Ligand A (-5.26) shows poor permeability, while Ligand B (-4.726) is also low, but slightly better.

**Aqueous Solubility:** Ligand A (-1.251) has poor solubility, while Ligand B (-4.31) is even worse.

**hERG Inhibition:** Ligand A (0.204) has a slightly higher hERG risk than Ligand B (0.693), but both are relatively low.

**Microsomal Clearance:** Ligand A (2.815) has lower microsomal clearance, suggesting better metabolic stability, compared to Ligand B (96.364).

**In vitro Half-Life:** Ligand A (-29.345) has a very short half-life, while Ligand B (20.147) is better, but still not ideal.

**P-gp Efflux:** Ligand A (0.01) has very low P-gp efflux, which is highly desirable for CNS penetration. Ligand B (0.787) has moderate P-gp efflux.

**Binding Affinity:** Ligand A (-8.2 kcal/mol) has a significantly stronger binding affinity than Ligand B (-7.0 kcal/mol). This is a substantial advantage for Ligand A.

**Overall Assessment:**

Ligand A has a much stronger binding affinity and better metabolic stability (lower Cl_mic, lower Pgp efflux). However, it suffers from poor logP, poor solubility, and a lower BBB percentile. Ligand B has a much better BBB penetration, and a more favorable TPSA, but its affinity is weaker, solubility is poor, and it has high metabolic clearance.

Given the importance of CNS penetration for a DRD2 ligand, and the significant difference in BBB values, Ligand B is more promising despite its weaker affinity. The affinity difference (1.2 kcal/mol) *could* potentially be overcome with further optimization, while improving BBB penetration is often more challenging. The poor solubility of both compounds is a concern, but formulation strategies can sometimes mitigate this.

Output:
1
2025-04-17 07:43:05,852 - INFO - Reasoning:

Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (360.772 and 359.495 Da) fall comfortably within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (82.45) is higher than Ligand B (57.51). For a CNS target like DRD2, TPSA should be <= 90, so both are acceptable, but B is preferable.

**3. logP:** Both ligands have good logP values (4.604 and 3.896), falling within the optimal 1-3 range, though A is slightly higher.

**4. H-Bond Donors:** Ligand A (3) and B (2) are both acceptable, being less than 5.

**5. H-Bond Acceptors:** Both ligands have 4 H-bond acceptors, which is within the acceptable range of <= 10.

**6. QED:** Both ligands have good QED scores (0.633 and 0.768), indicating good drug-like properties.

**7. DILI:** Ligand A (91.431) has a significantly higher DILI risk than Ligand B (67.507). This is a major concern for Ligand A.

**8. BBB:** Ligand B (68.127) has a better BBB penetration percentile than Ligand A (11.632). This is *critical* for a CNS target like DRD2.

**9. Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and suggests poor permeability. However, the values are similar (-5.136 and -5.252).

**10. Aqueous Solubility:** Both ligands have very poor aqueous solubility (-4.781 and -4.134). This could pose formulation challenges.

**11. hERG Inhibition:** Ligand A (0.176) has a slightly lower hERG inhibition risk than Ligand B (0.817), which is favorable.

**12. Microsomal Clearance:** Ligand B (64.731) has a higher microsomal clearance than Ligand A (31.315), meaning A is more metabolically stable.

**13. In vitro Half-Life:** Ligand B (68.805) has a much longer in vitro half-life than Ligand A (18.886). This is a significant advantage for B.

**14. P-gp Efflux:** Ligand A (0.062) has lower P-gp efflux than Ligand B (0.438), which is favorable for CNS penetration.

**15. Binding Affinity:** Both ligands have excellent binding affinities (-8.6 and -8.8 kcal/mol). The difference is minimal.

**Overall Assessment:**

While Ligand A has slightly better hERG and P-gp profiles and better metabolic stability, the significantly higher DILI risk and *extremely* poor BBB penetration make it a much less desirable candidate. Ligand B, despite the slightly higher P-gp efflux and hERG risk, has a much better BBB score, a lower DILI risk, and a longer half-life. For a CNS target, BBB penetration and safety (DILI) are paramount. The small differences in other parameters are outweighed by these critical factors.

Output:
1
2025-04-17 07:43:05,852 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (342.311 and 360.523 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (120.35) is better than Ligand B (49.41). For CNS targets, we want TPSA <= 90, so Ligand B is significantly better in this regard.

**logP:** Ligand A (1.831) is within the optimal 1-3 range. Ligand B (3.815) is at the higher end but still acceptable.

**H-Bond Donors:** Both have 1 HBD, which is good.

**H-Bond Acceptors:** Ligand A has 8 HBA, which is acceptable. Ligand B has 3 HBA, which is also good.

**QED:** Both ligands have good QED scores (0.674 and 0.838), indicating drug-like properties.

**DILI:** Ligand A (94.843) has a high DILI risk, while Ligand B (36.06) has a low DILI risk. This is a significant advantage for Ligand B.

**BBB:** Ligand A (61.962) has a moderate BBB penetration, while Ligand B (80.419) has a good BBB penetration. Since this is a CNS target, BBB is critical, favoring Ligand B.

**Caco-2 Permeability:** Ligand A (-4.772) has poor Caco-2 permeability, while Ligand B (-5.013) also has poor Caco-2 permeability.

**Aqueous Solubility:** Ligand A (-3.079) and Ligand B (-4.114) both have poor aqueous solubility.

**hERG Inhibition:** Ligand A (0.123) has a very low hERG inhibition risk, while Ligand B (0.511) has a slightly higher, but still acceptable, risk.

**Microsomal Clearance:** Ligand A (83.909) has a higher microsomal clearance, indicating lower metabolic stability, while Ligand B (43.184) has lower clearance and better metabolic stability.

**In vitro Half-Life:** Ligand A (-7.897) has a longer half-life than Ligand B (2.015).

**P-gp Efflux:** Ligand A (0.061) has low P-gp efflux, which is good for CNS penetration. Ligand B (0.341) has slightly higher P-gp efflux, which is less desirable.

**Binding Affinity:** Ligand A (-8.7 kcal/mol) has a significantly stronger binding affinity than Ligand B (-7.2 kcal/mol). This is a substantial advantage for Ligand A.

**Overall Assessment:**

Ligand A has a much stronger binding affinity and better P-gp efflux. However, it suffers from a high DILI risk and poor Caco-2 permeability. Ligand B has a better safety profile (lower DILI), better BBB penetration, and better metabolic stability. The difference in binding affinity is 1.5 kcal/mol, which is significant, but the improved ADME properties of Ligand B, particularly the lower DILI and better BBB, are crucial for a CNS-targeting drug. Given the GPCR-specific priorities, the better ADME profile of Ligand B outweighs the slightly weaker binding affinity.

Output:
1
2025-04-17 07:43:05,852 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (354.491 and 360.426 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (84.5) is better than Ligand B (88.1), both are below the 90 A^2 threshold for CNS targets, which is good.

**3. logP:** Ligand A (2.555) is optimal, while Ligand B (0.254) is quite low, potentially hindering membrane permeability.

**4. H-Bond Donors:** Both ligands have 2 HBD, which is within the acceptable limit of <=5.

**5. H-Bond Acceptors:** Ligand A has 4 HBA, and Ligand B has 5 HBA. Both are within the acceptable limit of <=10.

**6. QED:** Ligand B (0.709) has a better QED score than Ligand A (0.492), indicating a more drug-like profile.

**7. DILI:** Ligand A (21.869) has a significantly lower DILI risk than Ligand B (35.285), which is a major advantage.

**8. BBB:** Ligand A (70.492) has a better BBB penetration percentile than Ligand B (60.876). Both are reasonably good, but A is preferable for a CNS target.

**9. Caco-2 Permeability:** Both have negative values (-4.78 and -4.799), which is unusual and suggests poor permeability. This is a concern for both.

**10. Aqueous Solubility:** Both have negative values (-2.311 and -0.739), indicating poor aqueous solubility. This is a concern for both.

**11. hERG Inhibition:** Both ligands have low hERG inhibition risk (0.367 and 0.309).

**12. Microsomal Clearance:** Ligand B (-5.393) has a more negative value, suggesting lower clearance and thus better metabolic stability than Ligand A (55.23).

**13. In vitro Half-Life:** Ligand B (-1.862) has a more negative value, suggesting a longer half-life than Ligand A (-10.169).

**14. P-gp Efflux:** Both ligands have low P-gp efflux liability (0.148 and 0.031).

**15. Binding Affinity:** Ligand B (-8.1 kcal/mol) has a significantly stronger binding affinity than Ligand A (-7.3 kcal/mol). This is a substantial advantage.

**Overall Assessment:**

Ligand B has a stronger binding affinity and better metabolic stability (lower Cl_mic, longer t1/2) and QED. However, Ligand A has a better logP, lower DILI risk, and better BBB penetration. The low logP of Ligand B is a significant concern for CNS penetration, despite its better BBB percentile. The significantly better affinity of Ligand B (-8.1 vs -7.3) is a major factor that could potentially overcome some of its ADME liabilities. Considering the GPCR-specific priorities, the affinity advantage of Ligand B is substantial enough to outweigh its slightly lower BBB and logP values, especially given that both ligands have poor solubility and permeability.

Output:
1
2025-04-17 07:43:05,852 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (341.415 Da) is slightly lower, which could be beneficial for permeability, but both are acceptable.

**TPSA:** Both ligands have TPSA values below 90 (Ligand A: 88.91, Ligand B: 80.76), which is excellent for CNS penetration. Ligand B is slightly better here.

**logP:** Both ligands have logP values within the optimal range (1-3). Ligand A (1.135) is slightly lower, while Ligand B (1.86) is closer to the center of the range.

**H-Bond Donors/Acceptors:** Ligand A (HBD=2, HBA=5) and Ligand B (HBD=1, HBA=6) both fall within acceptable limits (HBD <= 5, HBA <= 10).

**QED:** Both ligands have good QED scores (Ligand A: 0.824, Ligand B: 0.853), indicating good drug-like properties.

**DILI:** Ligand A (35.634) has a lower DILI risk than Ligand B (56.766), which is a significant advantage.

**BBB:** Ligand B (75.649) has a significantly better BBB percentile than Ligand A (61.846). This is a crucial factor for a CNS target like DRD2.

**Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and suggests poor permeability. However, the scale is not specified, so we cannot definitively say if this is a major issue.

**Aqueous Solubility:** Both have negative solubility values, again unusual. This suggests poor solubility, which could hinder bioavailability.

**hERG Inhibition:** Both ligands have low hERG inhibition liability (Ligand A: 0.218, Ligand B: 0.574), which is favorable.

**Microsomal Clearance:** Ligand A (18.337) has a lower microsomal clearance than Ligand B (39.548), indicating better metabolic stability.

**In vitro Half-Life:** Ligand A (-20.294) has a more negative in vitro half-life, which is not ideal. Ligand B (-2.708) is better.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (Ligand A: 0.018, Ligand B: 0.062), which is excellent for CNS exposure.

**Binding Affinity:** Ligand B (-7.9 kcal/mol) has a slightly better binding affinity than Ligand A (-7.7 kcal/mol), although the difference is small.

**Overall Assessment:**

Ligand B is superior due to its significantly better BBB penetration (75.6% vs. 61.8%), slightly better binding affinity (-7.9 vs -7.7 kcal/mol), and better in vitro half-life. While Ligand A has a lower DILI risk and better metabolic stability, the BBB is paramount for a CNS target. The solubility and Caco-2 values are concerning for both, but the difference in BBB is decisive.

Output:
1
2025-04-17 07:43:05,852 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (366.443 and 373.475 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (102.32) is better than Ligand B (106.5). Both are reasonably close to the 90 A^2 threshold for CNS targets, but A is preferable.

**3. logP:** Both ligands have good logP values (2.27 and 1.771), falling within the optimal 1-3 range.

**4. H-Bond Donors:** Both have 2 HBD, which is within the acceptable limit of <=5.

**5. H-Bond Acceptors:** Both have 6 HBA, also within the acceptable limit of <=10.

**6. QED:** Both ligands have acceptable QED values (0.845 and 0.79), indicating good drug-like properties.

**7. DILI:** Ligand A (94.804) has a higher DILI risk than Ligand B (66.111). This is a significant drawback for Ligand A.

**8. BBB:** Ligand A (48.662) has a lower BBB penetration percentile than Ligand B (51.958). While neither is *excellent* (>70), B is better. This is critical for a CNS target like DRD2.

**9. Caco-2 Permeability:** Both have negative Caco-2 values (-4.826 and -4.891). This is unusual and suggests poor permeability. However, these values are on a log scale and are likely representing very low permeability.

**10. Aqueous Solubility:** Both have negative solubility values (-3.933 and -2.88). Similar to Caco-2, these values suggest poor solubility.

**11. hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.352 and 0.1).

**12. Microsomal Clearance:** Ligand B (44.957) has a lower (better) microsomal clearance than Ligand A (23.817), indicating greater metabolic stability.

**13. In vitro Half-Life:** Ligand B (6.52) has a longer half-life than Ligand A (-14.91). This is a significant advantage.

**14. P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.102 and 0.034).

**15. Binding Affinity:** Both ligands have very similar and excellent binding affinities (-8.1 and -8.0 kcal/mol). The difference is negligible.

**Overall Assessment:**

Ligand B is the better candidate. While both have poor Caco-2 and solubility values, Ligand B demonstrates superior ADME properties in key areas for a CNS GPCR target: lower DILI risk, better BBB penetration, lower microsomal clearance, and a longer half-life. The binding affinity is comparable between the two. The slightly better BBB penetration and lower DILI risk of Ligand B outweigh the slightly better TPSA of Ligand A.

Output:
1
2025-04-17 07:43:05,853 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (338.407) is slightly lower, which is generally favorable for permeability.

**TPSA:** Ligand A (62.55) is excellent for CNS penetration, well below the 90 A^2 threshold. Ligand B (90.38) is approaching the upper limit for CNS targets but still potentially acceptable.

**logP:** Ligand A (3.182) is optimal. Ligand B (0.956) is a bit low, potentially hindering membrane permeability.

**H-Bond Donors/Acceptors:** Ligand A (HBD=1, HBA=3) is good. Ligand B (HBD=3, HBA=6) is also acceptable, but slightly higher counts could impact permeability.

**QED:** Both ligands have reasonable QED scores (A: 0.935, B: 0.676), indicating good drug-like properties.

**DILI:** Ligand A (59.907) has a moderate DILI risk, while Ligand B (10.237) has a very low risk. This is a significant advantage for Ligand B.

**BBB:** Both ligands show good BBB penetration (A: 61.923, B: 74.176), but Ligand B is better.

**Caco-2 Permeability:** Ligand A (-4.751) has poor Caco-2 permeability, indicating poor intestinal absorption. Ligand B (-5.431) is also poor, but slightly better than A.

**Aqueous Solubility:** Ligand A (-3.789) has poor aqueous solubility. Ligand B (-1.074) is also poor, but better than A.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (A: 0.547, B: 0.425).

**Microsomal Clearance:** Ligand A (54.01) has moderate clearance, while Ligand B (-30.062) has a negative clearance, which is excellent, indicating high metabolic stability.

**In vitro Half-Life:** Ligand A (74.797) has a good half-life. Ligand B (12.906) has a short half-life, which is a drawback.

**P-gp Efflux:** Both ligands have low P-gp efflux (A: 0.259, B: 0.014), which is favorable for CNS exposure. Ligand B is significantly better.

**Binding Affinity:** Ligand A (-10.6) has significantly stronger binding affinity than Ligand B (-7.8). This is a substantial advantage for Ligand A.

**Overall Assessment:**

While Ligand B has better safety (DILI), BBB, metabolic stability (Cl_mic), and P-gp efflux, Ligand A's significantly stronger binding affinity (-10.6 vs -7.8 kcal/mol) is a critical factor for a GPCR target. The 2.8 kcal/mol difference in binding is large enough to potentially overcome the moderate DILI risk and poorer solubility/permeability of Ligand A. The TPSA is also much better for CNS penetration. The poor Caco-2 and solubility of Ligand A could be addressed with formulation strategies.

Output:
0
2025-04-17 07:43:05,853 - INFO - Reasoning:

Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (361.32 and 348.49 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (105.64) is higher than Ligand B (67.43). For a CNS target like DRD2, TPSA should ideally be <= 90. Ligand B is much closer to this threshold, giving it an advantage.

**3. logP:** Both ligands have good logP values (1.298 and 2.714), falling within the optimal 1-3 range. Ligand B is slightly better positioned.

**4. H-Bond Donors:** Both have 2 HBD, which is within the acceptable limit of <=5.

**5. H-Bond Acceptors:** Ligand A has 4 HBA, and Ligand B has 3. Both are within the acceptable limit of <=10.

**6. QED:** Ligand A (0.824) has a significantly better QED score than Ligand B (0.63), indicating a more drug-like profile overall.

**7. DILI:** Ligand A (52.70) has a lower DILI risk than Ligand B (22.64), which is favorable.

**8. BBB:** Ligand A (77.71) has a substantially higher BBB percentile than Ligand B (57.19). This is *critical* for a CNS target like DRD2.

**9. Caco-2 Permeability:** Both have negative values, suggesting poor permeability. Ligand A (-5.102) is slightly worse than Ligand B (-4.972).

**10. Aqueous Solubility:** Both have negative values, indicating poor solubility. Ligand A (-3.516) is slightly worse than Ligand B (-2.583).

**11. hERG Inhibition:** Both ligands show low hERG inhibition liability (0.369 and 0.21), which is good.

**12. Microsomal Clearance:** Ligand A (-10.368) has a significantly lower (better) microsomal clearance than Ligand B (41.309), suggesting better metabolic stability.

**13. In vitro Half-Life:** Ligand A (-9.964) has a longer in vitro half-life than Ligand B (-11.294), which is desirable.

**14. P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.041 and 0.1), which is excellent for CNS penetration.

**15. Binding Affinity:** Ligand A (-8.9 kcal/mol) has a slightly better binding affinity than Ligand B (-7.8 kcal/mol). This 1.1 kcal/mol difference is significant and can outweigh some ADME drawbacks.

**Overall Assessment:**

While Ligand A has issues with Caco-2 permeability and solubility, its superior BBB penetration, lower DILI risk, better metabolic stability (lower Cl_mic and longer t1/2), and slightly better binding affinity make it the more promising candidate. The high BBB value is particularly important for a CNS target. The QED score also favors Ligand A. Ligand B's lower TPSA is a plus, but the substantial difference in BBB is a deciding factor.

Output:
1
2025-04-17 07:43:05,853 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (367.511 and 364.511 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (74.68) is slightly higher than Ligand B (69.64). Both are below the 90 A^2 threshold desirable for CNS targets, but B is closer to optimal.

**3. logP:** Both ligands have excellent logP values (2.803 and 2.719) within the optimal 1-3 range.

**4. H-Bond Donors:** Ligand A (1) is better than Ligand B (2), as fewer HBDs generally improve permeability.

**5. H-Bond Acceptors:** Both ligands have 4 HBA, which is acceptable (<=10).

**6. QED:** Both ligands have good QED scores (0.804 and 0.863), indicating drug-like properties. Ligand B is slightly better.

**7. DILI:** Ligand A (37.301) has a higher DILI risk than Ligand B (24.661). This is a significant advantage for Ligand B.

**8. BBB:** Ligand A (73.633) has a better BBB penetration percentile than Ligand B (57.929). This is a crucial factor for a CNS target like DRD2.

**9. Caco-2 Permeability:** Ligand A (-4.425) has better Caco-2 permeability than Ligand B (-5.077).

**10. Aqueous Solubility:** Ligand A (-2.969) has better aqueous solubility than Ligand B (-2.226).

**11. hERG Inhibition:** Both ligands have low hERG inhibition liability (0.544 and 0.432), which is good.

**12. Microsomal Clearance:** Ligand A (62.928) has higher microsomal clearance than Ligand B (-0.049). This means Ligand B is more metabolically stable.

**13. In vitro Half-Life:** Ligand A (31.501) has a longer in vitro half-life than Ligand B (-1.072).

**14. P-gp Efflux:** Ligand A (0.753) has higher P-gp efflux liability than Ligand B (0.285). Lower P-gp efflux is preferred, giving an advantage to Ligand B.

**15. Binding Affinity:** Ligand B (-9.5 kcal/mol) has significantly stronger binding affinity than Ligand A (-8.1 kcal/mol). This >1.5 kcal/mol difference is substantial and can outweigh minor ADME drawbacks.

**Overall Assessment:**

While Ligand A has better BBB penetration and half-life, Ligand B excels in several critical areas: significantly better binding affinity, lower DILI risk, lower P-gp efflux, and better metabolic stability. The strong affinity of Ligand B is a major advantage for a GPCR target. The lower DILI and P-gp efflux are also highly desirable. The slightly lower BBB is a concern, but the superior binding affinity and improved safety/ADME profile likely compensate for this.

Output:
1
2025-04-17 07:43:05,853 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 drug candidates, considering the provided guidelines and GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight (MW):** Both ligands (352.519 and 348.491 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (78.43) is better than Ligand B (86.88). Both are below the 90 A^2 threshold for CNS targets, but A is closer to the ideal.

**3. logP:** Both ligands (2.787 and 2.812) are within the optimal 1-3 range.

**4. H-Bond Donors (HBD):** Both ligands have 3 HBD, which is acceptable (<=5).

**5. H-Bond Acceptors (HBA):** Both ligands have 3 HBA, which is acceptable (<=10).

**6. QED:** Ligand B (0.739) has a slightly better QED score than Ligand A (0.588), indicating a more drug-like profile.

**7. DILI:** Ligand A (24.506) has a significantly lower DILI risk than Ligand B (43.66). This is a substantial advantage for Ligand A.

**8. BBB:** Both ligands have reasonable BBB penetration (Ligand A: 53.858, Ligand B: 55.913). However, both are below the desirable >70 percentile for CNS targets.

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.68 and -4.923), which is unusual. This suggests poor intestinal absorption.

**10. Aqueous Solubility:** Both ligands have negative solubility values (-3.365 and -4.133), indicating very poor aqueous solubility. This is a major concern.

**11. hERG Inhibition:** Both ligands show low hERG inhibition liability (0.415 and 0.174), which is good.

**12. Microsomal Clearance:** Ligand B (39.769) has lower microsomal clearance than Ligand A (57.453), suggesting better metabolic stability.

**13. In vitro Half-Life:** Ligand B (-4.482) has a negative half-life, which is not physically possible and indicates a very short half-life. Ligand A (17.374) has a more reasonable half-life.

**14. P-gp Efflux:** Both ligands show low P-gp efflux liability (0.256 and 0.088), which is favorable for CNS penetration.

**15. Binding Affinity:** Ligand B (-8.3 kcal/mol) has a significantly stronger binding affinity than Ligand A (-7.2 kcal/mol). This is a >1 kcal/mol difference, which is a substantial advantage.

**Overall Assessment:**

While Ligand B boasts a superior binding affinity and better metabolic stability, its extremely poor in vitro half-life and higher DILI risk are major drawbacks. Ligand A, despite a slightly weaker affinity, has a more reasonable half-life, significantly lower DILI risk, and a better TPSA value. Both compounds have poor solubility and Caco-2 permeability, which would require formulation strategies to address.

Considering the GPCR-specific priorities, the stronger binding affinity of Ligand B is attractive. However, the DILI and half-life issues are significant enough to outweigh this benefit. A compound with a high DILI risk is unlikely to progress through development.

Output:
0
2025-04-17 07:43:05,854 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (370.494 and 357.451 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (67.23) is significantly better than Ligand B (91.34). For CNS targets, we want TPSA <= 90, so Ligand A is preferable.

**logP:** Ligand A (1.815) is within the optimal 1-3 range. Ligand B (-0.788) is below 1, which could hinder permeation. This favors Ligand A.

**H-Bond Donors/Acceptors:** Ligand A (HBD=1, HBA=5) and Ligand B (HBD=2, HBA=6) both have reasonable numbers of H-bond donors and acceptors, falling within the guidelines.

**QED:** Both ligands have acceptable QED values (0.795 and 0.648, both >0.5).

**DILI:** Ligand A (39.201) has a lower DILI risk than Ligand B (13.416), indicating a safer profile.

**BBB:** Ligand A (76.309) has a much better BBB penetration percentile than Ligand B (27.608). This is *critical* for a CNS target like DRD2, making Ligand A strongly favored.

**Caco-2 Permeability:** Both are negative, indicating poor permeability. However, the scale is not specified, so it's hard to interpret.

**Aqueous Solubility:** Both are negative, indicating poor solubility. Again, the scale is not specified.

**hERG:** Both ligands have very low hERG inhibition liability (0.229 and 0.045), which is excellent.

**Microsomal Clearance:** Ligand B (-7.646) has a *negative* microsomal clearance, which is not physically possible. This is a major red flag and likely an error in the data. Ligand A (34.299) has a reasonable clearance.

**In vitro Half-Life:** Ligand B (-9.996) also has a negative half-life, another impossible value and a significant data quality issue. Ligand A (-1.154) is also negative, but less concerning given the issues with Ligand B.

**P-gp Efflux:** Both have very low P-gp efflux liability (0.065 and 0.002), which is favorable for CNS exposure.

**Binding Affinity:** Ligand A (-7.5 kcal/mol) has a slightly better binding affinity than Ligand B (-6.4 kcal/mol). While both are good, the 1.1 kcal/mol difference is meaningful.

**Overall:** Ligand A is clearly superior. It has better TPSA, logP, BBB penetration, DILI risk, and binding affinity. Critically, the data for Ligand B contains impossible values for microsomal clearance and half-life, making it an unreliable candidate. Even ignoring those issues, Ligand A is better across most key parameters for a CNS-targeting GPCR.

Output:
1
2025-04-17 07:43:05,854 - INFO - Batch 388 complete. Total preferences: 6208
2025-04-17 07:43:05,854 - INFO - Processing batch 389/512...
2025-04-17 07:43:46,848 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (359.495 Da) is slightly lower, which *could* be beneficial for permeability, but both are acceptable.

**TPSA:** Both ligands have TPSA values below 90, which is good for CNS penetration. Ligand A (66.06) is slightly better than Ligand B (62.3).

**logP:** Both ligands have logP values between 1-3 (Ligand A: 2.506, Ligand B: 3.713), which is optimal. Ligand B is a bit higher, potentially increasing off-target interactions, but still within a reasonable range.

**H-Bond Donors/Acceptors:** Both have 1 HBD, which is good. Ligand A has 4 HBA, and Ligand B has 5. Both are acceptable, being below the threshold of 10.

**QED:** Both ligands have good QED scores (A: 0.911, B: 0.809), indicating drug-like properties.

**DILI:** Ligand A (41.024) has a significantly lower DILI risk than Ligand B (67.817). This is a major advantage for Ligand A.

**BBB:** Ligand A (76.231) has a better BBB penetration percentile than Ligand B (68.088). This is crucial for a CNS target like DRD2.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values, indicating poor permeability. Ligand A (-5.095) is slightly better than Ligand B (-5.193), but both are concerning.

**Aqueous Solubility:** Both ligands have negative solubility values, indicating poor solubility. Ligand A (-2.781) is slightly better than Ligand B (-4.692).

**hERG Inhibition:** Both ligands have low hERG inhibition risk (A: 0.792, B: 0.335). Ligand B is slightly better.

**Microsomal Clearance:** Ligand B (71.893) has a higher microsomal clearance than Ligand A (16.353), indicating lower metabolic stability. This is a significant drawback for Ligand B.

**In vitro Half-Life:** Ligand A (-23.425) has a negative half-life, which is concerning. Ligand B (14.983) is positive and better.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (A: 0.386, B: 0.411).

**Binding Affinity:** Ligand B (-7.7 kcal/mol) has a significantly stronger binding affinity than Ligand A (-10.0 kcal/mol). This is a substantial advantage for Ligand B.

**Overall Assessment:**

While Ligand B boasts a superior binding affinity, Ligand A demonstrates a much more favorable ADME profile, particularly regarding DILI risk and BBB penetration. The significantly better BBB score for Ligand A is critical for a CNS target. The lower DILI risk is also a major advantage. The negative half-life for Ligand A is a concern, but could potentially be addressed through structural modifications. The poor Caco-2 and solubility for both are problematic, but the stronger affinity of Ligand B might allow for lower dosing to compensate. However, the higher clearance of Ligand B is a significant drawback.

Given the GPCR-specific priorities, the better BBB, lower DILI, and acceptable, though not ideal, ADME properties of Ligand A outweigh the stronger binding affinity of Ligand B.

Output:
0
2025-04-17 07:43:46,848 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 drug candidates, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (390.795 Da) is slightly higher than Ligand B (345.443 Da), but both are acceptable.

**TPSA:** Ligand A (88.52) is closer to the ideal TPSA for CNS targets (<=90) than Ligand B (75.44). Both are good.

**logP:** Ligand A (3.607) is within the optimal range (1-3), while Ligand B (2.394) is towards the lower end, but still acceptable.

**H-Bond Donors/Acceptors:** Ligand A has 2 HBD and 5 HBA, while Ligand B has 1 HBD and 4 HBA. Both are within the acceptable limits (<=5 HBD, <=10 HBA).

**QED:** Both ligands have good QED scores (Ligand A: 0.786, Ligand B: 0.889), indicating drug-like properties.

**DILI:** Ligand A has a significantly higher DILI risk (93.525%) compared to Ligand B (31.64%). This is a major concern for Ligand A.

**BBB:** Ligand B has a much better BBB penetration score (82.551%) than Ligand A (36.293%). This is crucial for a CNS target like DRD2.

**Caco-2 Permeability:** Both have negative values, which is unusual. However, the magnitude is similar, and both suggest poor permeability.

**Aqueous Solubility:** Both have negative values, indicating poor solubility.

**hERG Inhibition:** Ligand A (0.053) has a very low hERG inhibition liability, which is excellent. Ligand B (0.393) is slightly higher, but still relatively low.

**Microsomal Clearance:** Ligand B has a much higher microsomal clearance (48.652) than Ligand A (0.719), indicating faster metabolism and potentially lower in vivo exposure.

**In vitro Half-Life:** Ligand A has a very negative half-life (-23.968), which is not physically meaningful and suggests instability. Ligand B has a short half-life (1.343 hours), but is more reasonable.

**P-gp Efflux:** Ligand A (0.159) has lower P-gp efflux liability than Ligand B (0.267), which is favorable for CNS penetration.

**Binding Affinity:** Ligand B (-9.0 kcal/mol) has a significantly stronger binding affinity than Ligand A (-8.4 kcal/mol). This 1.6 kcal/mol difference is substantial and can outweigh some ADME drawbacks.

**Overall Assessment:**

Ligand B is the stronger candidate. While it has a slightly lower logP and a higher P-gp efflux, its significantly better BBB penetration, much lower DILI risk, and substantially stronger binding affinity are decisive advantages. Ligand A's extremely high DILI risk and poor BBB penetration are major red flags. The negative half-life for Ligand A is also concerning. Although Ligand B has a relatively high microsomal clearance, the strong affinity might compensate for that.

Output:
1
2025-04-17 07:43:46,848 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (368.302 and 349.475 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (51.66) is significantly better than Ligand B (75.44). For CNS targets, we want TPSA <= 90, and ideally closer to 60. Ligand A is much closer to this ideal.

**3. logP:** Both ligands have good logP values (3.143 and 2.888), falling within the optimal 1-3 range.

**4. H-Bond Donors:** Ligand A (0) is preferable to Ligand B (1). Fewer HBDs generally improve permeability.

**5. H-Bond Acceptors:** Ligand A (5) is slightly better than Ligand B (4), both are within acceptable limits.

**6. QED:** Ligand B (0.857) has a slightly higher QED score than Ligand A (0.57), suggesting a more drug-like profile overall. However, this is less critical than other factors for CNS penetration.

**7. DILI:** Both ligands have low DILI risk (39.434 and 34.548), both are good.

**8. BBB:** Both ligands have excellent BBB penetration (85.731), which is crucial for a CNS target like DRD2.

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.507 and -4.698). These values are unusual and suggest poor permeability. However, given the focus on BBB penetration for a CNS target, this is less critical than it would be for a peripherally acting drug.

**10. Aqueous Solubility:** Both ligands have negative solubility values (-3.819 and -2.575). This is a concern, but can be mitigated through formulation strategies.

**11. hERG Inhibition:** Both ligands show low hERG inhibition risk (0.561 and 0.464).

**12. Microsomal Clearance:** Ligand A (53.576) has lower microsomal clearance than Ligand B (66.707), indicating better metabolic stability.

**13. In vitro Half-Life:** Ligand B (-28.023) has a longer in vitro half-life than Ligand A (-16.802).

**14. P-gp Efflux:** Both ligands have low P-gp efflux liability (0.131 and 0.287).

**15. Binding Affinity:** Both ligands have similar binding affinities (-8.0 and -8.1 kcal/mol), both are excellent.

**Overall Assessment:**

Ligand A is slightly favored due to its lower TPSA and HBD, and better metabolic stability (lower Cl_mic). While Ligand B has a slightly better QED and half-life, the TPSA value is a significant drawback for CNS penetration. The similar binding affinities make the ADME properties the deciding factor.

Output:
0
2025-04-17 07:43:46,848 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight (MW):** Both ligands (341.43 and 351.437 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (48.99) is better than Ligand B (29.54). Both are well below the 90 A^2 threshold for CNS targets, indicating good potential for brain penetration.

**3. logP:** Both ligands have good logP values (3.988 and 4.132), falling within the optimal 1-3 range.

**4. H-Bond Donors (HBD):** Both ligands are acceptable (1 and 0, respectively), staying below the 5 limit.

**5. H-Bond Acceptors (HBA):** Both ligands are acceptable (2 each), staying below the 10 limit.

**6. QED:** Ligand A (0.898) has a significantly better QED score than Ligand B (0.691), suggesting a more drug-like profile.

**7. DILI:** Ligand A (33.773) has a lower DILI risk than Ligand B (43.893), which is preferable. Both are below the 60 threshold.

**8. BBB:** Both ligands have excellent BBB penetration (96.937 and 92.051), exceeding the desirable >70% for CNS targets.

**9. Caco-2 Permeability:** Ligand A (-5.104) has a worse Caco-2 permeability than Ligand B (-4.603).

**10. Aqueous Solubility:** Ligand A (-3.418) has a worse aqueous solubility than Ligand B (-4.227).

**11. hERG Inhibition:** Both ligands have low hERG inhibition risk (0.929 and 0.803).

**12. Microsomal Clearance (Cl_mic):** Ligand A (30.402) has a lower Cl_mic than Ligand B (84.062), indicating better metabolic stability.

**13. In vitro Half-Life:** Ligand A (-23.55) has a worse in vitro half-life than Ligand B (-7.29).

**14. P-gp Efflux:** Both ligands have good P-gp efflux profiles (0.661 and 0.596).

**15. Binding Affinity:** Ligand B (-8.1 kcal/mol) has a significantly stronger binding affinity than Ligand A (-10.4 kcal/mol). This is a crucial advantage, potentially outweighing some of the ADME drawbacks.

**Overall Assessment:**

Ligand B has a significantly better binding affinity, which is paramount for GPCR targets. While Ligand A has better QED, DILI, and metabolic stability, the substantial difference in binding affinity (-8.1 vs -10.4 kcal/mol) is a decisive factor. The slight differences in solubility and permeability are less critical given the excellent BBB penetration of both compounds.

Output:
1
2025-04-17 07:43:46,848 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (350.419 and 355.479 Da) fall comfortably within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (94.48) is slightly higher than Ligand B (90.9). Both are below the 140 A^2 threshold for oral absorption and reasonably close to the 90 A^2 target for CNS penetration. Ligand B is marginally better.

**3. logP:** Ligand A (0.11) is quite low, potentially hindering membrane permeability. Ligand B (0.269) is also low, but slightly better. Both are below the optimal 1-3 range. This is a concern for both, but more so for A.

**4. H-Bond Donors:** Ligand A (2) is better than Ligand B (3). Lower HBD generally improves permeability.

**5. H-Bond Acceptors:** Ligand A (6) is better than Ligand B (5). Lower HBA generally improves permeability.

**6. QED:** Both ligands have acceptable QED values (0.617 and 0.552, respectively), indicating reasonable drug-likeness.

**7. DILI:** Ligand A (41.218) has a slightly higher DILI risk than Ligand B (5.894), but both are below the concerning threshold of 60.

**8. BBB:** This is a critical parameter for a CNS target like DRD2. Ligand A (43.583) has a significantly better BBB percentile than Ligand B (27.375).

**9. Caco-2 Permeability:** Both have negative Caco-2 values (-5.33 and -5.313) which is unusual and suggests poor permeability.

**10. Aqueous Solubility:** Ligand A (-1.137) has slightly better solubility than Ligand B (0.048).

**11. hERG Inhibition:** Both ligands show very low hERG inhibition risk (0.279 and 0.076, respectively).

**12. Microsomal Clearance:** Ligand A (0.613) has significantly lower microsomal clearance than Ligand B (-12.405), indicating better metabolic stability.

**13. In vitro Half-Life:** Ligand A (10.378) has a much longer in vitro half-life than Ligand B (1.832).

**14. P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.019 and 0.007, respectively).

**15. Binding Affinity:** Both ligands have very similar and excellent binding affinities (-7.4 and -7.3 kcal/mol). The difference is negligible.

**Overall Assessment:**

While Ligand B has a slightly better TPSA and is marginally better in logP, Ligand A is superior in several key areas crucial for CNS drug development: significantly better BBB penetration, much improved metabolic stability (lower Cl_mic and longer t1/2), and slightly better solubility. The similar binding affinities mean that the ADME advantages of Ligand A outweigh the minor differences in other properties. The low logP values for both are a concern, but the superior CNS penetration profile of A makes it the more promising candidate.

Output:
1
2025-04-17 07:43:46,848 - INFO - Reasoning:

Let's analyze Ligand A and Ligand B based on the provided guidelines, prioritizing GPCR-specific properties (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (354.491 Da) is slightly lower, which is generally favorable for permeability.

**TPSA:** Both ligands have TPSA values around 78-79, which is acceptable for general oral absorption but a bit high for optimal CNS penetration (ideally <90, striving for <60).

**logP:** Ligand A (1.563) is within the optimal range (1-3). Ligand B (3.495) is towards the higher end, potentially leading to solubility issues or off-target interactions, but still acceptable.

**H-Bond Donors/Acceptors:** Ligand A (HBD=2, HBA=4) and Ligand B (HBD=3, HBA=5) both have reasonable H-bond counts, balancing solubility and permeability.

**QED:** Ligand A (0.759) has a better QED score than Ligand B (0.568), indicating a more drug-like profile.

**DILI:** Both ligands have relatively low DILI risk (Ligand A: 7.794, Ligand B: 71.772), with Ligand A being significantly lower and thus preferable.

**BBB:** This is a crucial parameter for a CNS target like DRD2. Ligand A has a BBB percentile of 65.801, which is good but not excellent. Ligand B has a significantly lower BBB percentile of 33.85, which is a major drawback.

**Caco-2 Permeability:** Ligand A (-4.542) and Ligand B (-5.357) both have negative Caco-2 values, indicating poor permeability. This is concerning.

**Aqueous Solubility:** Both ligands have poor aqueous solubility (-1.784 and -3.988, respectively), which could hinder formulation and bioavailability. Ligand B is worse.

**hERG Inhibition:** Both ligands show low hERG inhibition risk (Ligand A: 0.304, Ligand B: 0.678), which is positive.

**Microsomal Clearance:** Ligand A (38.932) has lower microsomal clearance than Ligand B (62.39), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (-11.382) has a negative half-life, which is unusual and likely indicates very rapid metabolism. Ligand B (82.609) has a much more favorable, long half-life.

**P-gp Efflux:** Ligand A (0.021) has very low P-gp efflux, which is highly desirable for CNS penetration. Ligand B (0.443) has higher P-gp efflux, which would limit brain exposure.

**Binding Affinity:** Ligand B (-8.1 kcal/mol) has a slightly better binding affinity than Ligand A (-7.6 kcal/mol). While a 0.5 kcal/mol difference is not huge, it's a noticeable advantage.

**Overall Assessment:**

Despite the slightly better affinity of Ligand B, Ligand A is the more promising candidate. The critical factors are the significantly better BBB penetration (65.8 vs 33.8), lower DILI risk, lower P-gp efflux, and better metabolic stability (lower Cl_mic). While both have poor solubility and Caco-2 permeability, the CNS target prioritizes BBB penetration and minimizing efflux, which Ligand A achieves more effectively. The slightly longer half-life of Ligand B is a plus, but the other ADME properties of Ligand A are more favorable for a CNS-active drug.

Output:
0
2025-04-17 07:43:46,849 - INFO - Reasoning:
Let's analyze both ligands against the provided guidelines, prioritizing GPCR-specific properties (BBB, logP, Pgp, TPSA, and affinity).

**Ligand A:**

*   **MW:** 348.443 Da - Good (within 200-500 range).
*   **TPSA:** 81.43 - Acceptable, but pushing the limit for CNS targets (ideally <90).
*   **logP:** 2.962 - Excellent (within 1-3).
*   **HBD:** 1 - Good (<=5).
*   **HBA:** 5 - Good (<=10).
*   **QED:** 0.799 - Excellent (>=0.5).
*   **DILI:** 20.396 - Very good (low risk).
*   **BBB:** 71.694 - Good, but could be better for a CNS target (ideally >70).
*   **Caco-2:** -4.373 - Poor permeability.
*   **Solubility:** -3.634 - Poor solubility.
*   **hERG:** 0.152 - Very low risk.
*   **Cl_mic:** 104.646 - Moderate clearance, not ideal.
*   **t1/2:** -15.93 - Very short half-life.
*   **Pgp:** 0.12 - Low efflux, good.
*   **Affinity:** -8.3 kcal/mol - Excellent.

**Ligand B:**

*   **MW:** 345.399 Da - Good (within 200-500 range).
*   **TPSA:** 70.16 - Excellent for CNS targets (<90).
*   **logP:** 1.041 - Acceptable, but on the lower side (ideally 1-3).
*   **HBD:** 0 - Good (<=5).
*   **HBA:** 5 - Good (<=10).
*   **QED:** 0.602 - Good (>=0.5).
*   **DILI:** 51.997 - Acceptable (moderate risk).
*   **BBB:** 90.927 - Excellent for a CNS target (>70).
*   **Caco-2:** -4.383 - Poor permeability.
*   **Solubility:** -2.397 - Poor solubility.
*   **hERG:** 0.398 - Low risk.
*   **Cl_mic:** 44.085 - Good metabolic stability.
*   **t1/2:** -7.267 - Short half-life, but better than Ligand A.
*   **Pgp:** 0.07 - Very low efflux, excellent.
*   **Affinity:** -8.6 kcal/mol - Excellent, slightly better than Ligand A.

**Comparison & Decision:**

Both ligands have excellent binding affinities. Ligand B has a superior BBB score (90.927 vs 71.694) and lower Pgp efflux (0.07 vs 0.12), both crucial for CNS penetration. Ligand B also has better metabolic stability (lower Cl_mic) and a slightly longer half-life. While both have poor Caco-2 and solubility, these are less critical for a CNS-targeting drug. Ligand A has a slightly better logP, but the advantages of Ligand B in BBB, Pgp, and metabolic stability outweigh this.

Output:
1
2025-04-17 07:43:46,849 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (346.39 and 339.36 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (102.32) is better than Ligand B (118.37). For CNS targets, we want TPSA <= 90, so A is closer to this threshold.

**logP:** Ligand A (0.543) is slightly better than Ligand B (0.173), but both are quite low. A logP between 1-3 is optimal. These low values might hinder membrane permeability.

**H-Bond Donors/Acceptors:** Ligand A (HBD=2, HBA=6) is preferable to Ligand B (HBD=1, HBA=8). Both are within acceptable limits, but A has a better balance.

**QED:** Ligand B (0.72) has a slightly better QED score than Ligand A (0.528), indicating a more drug-like profile.

**DILI:** Ligand A (66.15) has a lower DILI risk than Ligand B (78.25), which is favorable. Both are above the 60 threshold, indicating a higher risk.

**BBB:** Ligand B (50.95) has a better BBB penetration percentile than Ligand A (44.59). However, both are below the desirable >70 for CNS targets.

**Caco-2 Permeability:** Ligand A (-4.762) shows better Caco-2 permeability than Ligand B (-5.554). Higher values are better.

**Aqueous Solubility:** Ligand A (-2.627) is slightly better than Ligand B (-2.144). Both are poor.

**hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.026 and 0.043, respectively).

**Microsomal Clearance:** Ligand B (3.282) has significantly lower microsomal clearance than Ligand A (45.404), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand B (-9.294) has a much longer in vitro half-life than Ligand A (-2.219), which is a significant advantage.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.011 and 0.037, respectively).

**Binding Affinity:** Ligand B (-9.1 kcal/mol) has a significantly stronger binding affinity than Ligand A (-7.3 kcal/mol). This is a crucial factor, as a >1.5 kcal/mol advantage can outweigh other drawbacks.

**Overall Assessment:**

While Ligand A has better TPSA and Caco-2 permeability, Ligand B excels in critical areas: significantly stronger binding affinity, lower microsomal clearance (better metabolic stability), and a longer in vitro half-life. The slightly better BBB penetration of Ligand B is also beneficial for a CNS target. The lower QED and higher DILI risk of Ligand B are concerns, but the substantial affinity advantage likely outweighs these drawbacks. The low logP values for both are a concern, but the stronger binding of Ligand B might compensate for that.

Output:
1
2025-04-17 07:43:46,849 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (356.5 and 357.5 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (67.87) is higher than Ligand B (54.79). For CNS targets, TPSA < 90 is preferred. Both are acceptable, but B is better.

**3. logP:** Ligand A (2.219) is within the optimal 1-3 range. Ligand B (3.746) is slightly higher, bordering on potentially causing solubility issues, but still acceptable.

**4. H-Bond Donors:** Ligand A (1) is good. Ligand B (0) is also good.

**5. H-Bond Acceptors:** Ligand A (4) is good. Ligand B (5) is also good.

**6. QED:** Both ligands have good QED values (0.61 and 0.791, respectively), indicating drug-like properties.

**7. DILI:** Ligand A (10.24) has a much lower DILI risk than Ligand B (54.32). This is a significant advantage for Ligand A.

**8. BBB:** Ligand A (68.21) is close to the desirable >70% threshold for CNS targets. Ligand B (61.42) is lower. This favors Ligand A.

**9. Caco-2:** Both have negative values (-4.533 and -4.598), which is unusual and difficult to interpret without knowing the scale. Assuming these are logP-like values, lower values suggest poorer permeability. They are comparable.

**10. Solubility:** Ligand A (-1.496) has better solubility than Ligand B (-3.547).

**11. hERG:** Both ligands have very low hERG inhibition risk (0.533 and 0.264).

**12. Cl_mic:** Ligand A (36.42) has lower microsomal clearance than Ligand B (53.79), indicating better metabolic stability.

**13. t1/2:** Ligand A (-3.653) has a negative half-life, which is nonsensical. Ligand B (27.13) has a reasonable half-life. This is a major issue for Ligand A.

**14. Pgp:** Ligand A (0.046) has significantly lower P-gp efflux liability than Ligand B (0.358), which is beneficial for CNS penetration.

**15. Binding Affinity:** Both ligands have excellent binding affinity (-7.0 and -7.9 kcal/mol). Ligand B is slightly better, but the difference is small.

**Overall Assessment:**

Despite the slightly better affinity of Ligand B, Ligand A is the more promising candidate. Ligand A has a significantly lower DILI risk, better solubility, lower P-gp efflux, and a more favorable BBB percentile. The negative half-life for Ligand A is a major concern and should be investigated, but the other advantages outweigh this issue. Ligand B's higher DILI risk and P-gp efflux are significant drawbacks.

Output:
0
2025-04-17 07:43:46,849 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (348.355 and 350.419 Da) are within the ideal range of 200-500 Da.

**TPSA:** Ligand A (109.08) is slightly above the optimal <90 for CNS targets, while Ligand B (94.9) is comfortably within the range. This gives a slight edge to Ligand B.

**logP:** Ligand A (0.659) is a bit low, potentially hindering permeability. Ligand B (-0.505) is even lower, raising similar concerns. Both are below the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Both ligands have acceptable HBD (2 and 1 respectively) and HBA (6 each) counts, falling within the recommended limits.

**QED:** Ligand B (0.734) has a better QED score than Ligand A (0.444), indicating a more drug-like profile.

**DILI:** Both ligands have relatively low DILI risk (42.885 and 36.681 respectively), suggesting acceptable hepatic safety.

**BBB:** Ligand B (45.56) has a significantly better BBB percentile than Ligand A (37.301). This is a crucial advantage for a CNS target like DRD2.

**Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and suggests poor permeability. However, the scale is not specified, so it's hard to interpret.

**Aqueous Solubility:** Both ligands have very poor aqueous solubility (-2.229 and -0.716 respectively). This is a significant drawback.

**hERG Inhibition:** Both ligands show very low hERG inhibition liability (0.137 and 0.163), which is positive.

**Microsomal Clearance:** Ligand A (-23.929) has a lower (better) microsomal clearance than Ligand B (-28.989), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand B (30.318) has a significantly longer in vitro half-life than Ligand A (-22.322), which is a substantial advantage.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.042 and 0.01 respectively), which is favorable for CNS penetration.

**Binding Affinity:** Ligand B (-7.2 kcal/mol) has a stronger binding affinity than Ligand A (-8.5 kcal/mol). While A is slightly better, the difference is not substantial enough to overcome other deficiencies.

**Overall Assessment:**

Considering the GPCR-specific priorities, Ligand B is the more promising candidate. Its superior BBB penetration, longer half-life, better QED score, and stronger binding affinity outweigh the slightly worse metabolic stability. While both have poor solubility and logP values, the improved CNS exposure potential of Ligand B is critical for a DRD2 targeting drug.

Output:
1
2025-04-17 07:43:46,850 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B based on the provided guidelines, prioritizing GPCR-specific properties (BBB, logP, Pgp, TPSA, and affinity) for DRD2.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (365.5) is slightly better, being closer to the lower end which can aid permeability.

**TPSA:** Ligand A (61.88) is excellent for CNS penetration, well below the 90 A^2 threshold. Ligand B (117.17) is higher, but still potentially acceptable, though less optimal.

**logP:** Both ligands have good logP values (A: 1.466, B: 1.737), falling within the 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A (HBD=1, HBA=5) is better than Ligand B (HBD=3, HBA=6) regarding the balance of solubility and permeability.

**QED:** Ligand A (0.795) has a significantly better QED score than Ligand B (0.471), indicating a more drug-like profile.

**DILI:** Ligand A (19.43) has a much lower DILI risk than Ligand B (94.77), a major advantage.

**BBB:** This is critical for a CNS target. Ligand A (78.52) has a good BBB percentile, exceeding the 70% threshold. Ligand B (24.08) is very poor, suggesting limited CNS exposure.

**Caco-2 Permeability:** Both have negative values, which is unusual. Assuming these are logP-scale values, lower values indicate poorer permeability. Ligand A (-5.261) is slightly better than Ligand B (-5.774).

**Aqueous Solubility:** Both have negative values, which is also unusual. Assuming these are logS values, lower values indicate poorer solubility. Ligand A (-1.496) is better than Ligand B (-3.676).

**hERG:** Both ligands have low hERG inhibition liability (A: 0.292, B: 0.499), which is good.

**Microsomal Clearance:** Ligand A (21.29) has a higher clearance than Ligand B (13.56), meaning it is less metabolically stable.

**In vitro Half-Life:** Ligand B (34.38) has a significantly longer half-life than Ligand A (8.95).

**P-gp Efflux:** Ligand A (0.034) has very low P-gp efflux liability, which is excellent for CNS penetration. Ligand B (0.094) is also low, but higher than A.

**Binding Affinity:** Ligand B (-9.5 kcal/mol) has a significantly stronger binding affinity than Ligand A (-7.7 kcal/mol). This is a substantial advantage, potentially outweighing some ADME concerns.

**Overall Assessment:**

While Ligand B has a superior binding affinity, the extremely poor BBB penetration (24.08) is a deal-breaker for a CNS target like DRD2. The high DILI risk is also concerning. Ligand A, despite a weaker affinity, has a much more favorable ADME profile, especially its excellent BBB penetration, low DILI risk, and low P-gp efflux. The slightly higher clearance and shorter half-life of Ligand A can be addressed through structural modifications during lead optimization. The combination of good CNS penetration properties and a reasonable drug-like profile makes Ligand A the more promising candidate.

Output:
0
2025-04-17 07:43:46,850 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (381.519 and 348.443 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (72.47) is excellent, well below the 90 A^2 threshold for CNS targets. Ligand B (89.87) is still reasonable, but closer to the upper limit.

**3. logP:** Ligand A (3.438) is optimal. Ligand B (2.293) is acceptable, but slightly lower, potentially impacting membrane permeability.

**4. H-Bond Donors:** Ligand A (1) is good. Ligand B (3) is acceptable, but higher.

**5. H-Bond Acceptors:** Ligand A (5) is good. Ligand B (4) is good.

**6. QED:** Both ligands have acceptable QED values (0.832 and 0.705), indicating good drug-like properties.

**7. DILI:** Ligand A (70.609) is a moderate risk, but acceptable. Ligand B (11.128) is very low risk, a significant advantage.

**8. BBB:** Ligand A (64.482) is reasonable, but could be better for a CNS target. Ligand B (50.872) is lower, which is a concern for CNS penetration.

**9. Caco-2:** Both have negative values, which is unusual and suggests a potential issue with the data. However, we can interpret this as very low permeability.

**10. Solubility:** Both have negative values, again unusual. This suggests very low solubility, which is a major drawback.

**11. hERG:** Both ligands have low hERG inhibition risk (0.606 and 0.397).

**12. Cl_mic:** Ligand A (33.634) has lower microsomal clearance, indicating better metabolic stability. Ligand B (48.637) has higher clearance.

**13. t1/2:** Ligand A (82.011) has a significantly longer in vitro half-life, which is desirable. Ligand B (-14.982) has a negative half-life, which is not possible and indicates a data error.

**14. Pgp:** Ligand A (0.423) has lower P-gp efflux, which is favorable for CNS penetration. Ligand B (0.014) has very low P-gp efflux, which is even better.

**15. Binding Affinity:** Both ligands have strong binding affinities (-8.6 and -8.1 kcal/mol). Ligand A is slightly better (-8.6 vs -8.1), but the difference is not huge.

**Overall Assessment:**

Despite the unusual solubility and Caco-2 values, Ligand A appears more promising. It has a better TPSA, logP, metabolic stability (lower Cl_mic, longer t1/2), and slightly better binding affinity. The DILI risk is higher, but manageable. Ligand B has a much lower DILI risk and Pgp efflux, but suffers from a lower BBB score, higher Cl_mic, and a nonsensical half-life value. The negative solubility and Caco-2 values for both are concerning and would require further investigation, but the other properties of Ligand A make it the slightly better candidate.

Output:
0
2025-04-17 07:43:46,850 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight (MW):** Both ligands are within the ideal range (200-500 Da). Ligand A (349.475) is slightly lower, which could be advantageous for permeability.

**2. TPSA:** Ligand A (70.67) is better than Ligand B (37.38) as it is closer to the desired threshold of 90 for CNS targets. Ligand B is quite low, potentially indicating poor solubility.

**3. logP:** Ligand A (1.89) is optimal, while Ligand B (4.812) is high. High logP can lead to off-target effects and poor solubility.

**4. H-Bond Donors (HBD):** Both ligands are within the acceptable limit of <=5. Ligand A has 2, and Ligand B has 0.

**5. H-Bond Acceptors (HBA):** Both ligands are within the acceptable limit of <=10. Ligand A has 4, and Ligand B has 3.

**6. QED:** Both ligands have acceptable QED scores (A: 0.761, B: 0.625), indicating good drug-like properties.

**7. DILI:** Ligand A (13.183) has a significantly lower DILI risk than Ligand B (35.673). This is a major advantage for Ligand A.

**8. BBB:** Both ligands have good BBB penetration (A: 71.384, B: 73.401), exceeding the 70% threshold for CNS targets. Ligand B is slightly better.

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 values, which is unusual. However, the magnitude of negativity is similar.

**10. Aqueous Solubility:** Both ligands have negative solubility values, which is also unusual. Ligand A (-2.283) is slightly better than Ligand B (-4.514).

**11. hERG Inhibition:** Both ligands show low hERG inhibition risk (A: 0.619, B: 0.666).

**12. Microsomal Clearance:** Ligand A (20.283) has lower microsomal clearance than Ligand B (76.77), suggesting better metabolic stability.

**13. In vitro Half-Life:** Ligand B (60.908) has a significantly longer in vitro half-life than Ligand A (18.334). This is a potential advantage for Ligand B.

**14. P-gp Efflux:** Both ligands have low P-gp efflux liability (A: 0.04, B: 0.811). Ligand A is much better.

**15. Binding Affinity:** Ligand A (-7.8 kcal/mol) has a slightly better binding affinity than Ligand B (-7.2 kcal/mol). While the difference is less than the 1.5 kcal/mol threshold, it's still a positive factor.

**Overall Assessment:**

Considering the GPCR-specific priorities, Ligand A is the more promising candidate. It has a better logP, TPSA, DILI score, P-gp efflux, and slightly better binding affinity. While Ligand B has a longer half-life and slightly better BBB penetration, the higher logP and DILI risk are significant drawbacks. The lower metabolic stability of Ligand A can be addressed through structural modifications during optimization.

Output:
0
2025-04-17 07:43:46,850 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B based on the provided guidelines, prioritizing GPCR-specific properties (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (352.431 and 349.356 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (77.1) is better than Ligand B (45.23). Both are below the 90 A^2 threshold desirable for CNS targets, but Ligand A is closer to the upper limit.

**logP:** Ligand A (1.308) is optimal, while Ligand B (3.372) is approaching the upper limit of the optimal range.

**H-Bond Donors/Acceptors:** Both ligands have acceptable HBD (1) and HBA (Ligand A: 5, Ligand B: 2) counts.

**QED:** Both ligands have good QED scores (A: 0.811, B: 0.864), indicating good drug-likeness.

**DILI:** Ligand A (25.979) has a significantly lower DILI risk than Ligand B (52.385), which is a substantial advantage.

**BBB:** Both ligands exhibit excellent BBB penetration (A: 80.031, B: 88.717), exceeding the 70% threshold for CNS targets. Ligand B is slightly better.

**Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and suggests a potential issue with the data or a very poor permeability. However, since both are similarly affected, this isn't a differentiating factor.

**Aqueous Solubility:** Both have negative solubility values, which is also unusual.

**hERG Inhibition:** Ligand A (0.138) has a much lower hERG inhibition liability than Ligand B (0.636), indicating a lower risk of cardiotoxicity.

**Microsomal Clearance:** Ligand A (23.854) has a lower microsomal clearance than Ligand B (42.508), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (8.137) has a positive half-life, while Ligand B (-18.426) has a negative half-life, which is not physically possible. This is a major red flag for Ligand B.

**P-gp Efflux:** Ligand A (0.01) has very low P-gp efflux liability, which is excellent for CNS penetration. Ligand B (0.129) is also low, but higher than A.

**Binding Affinity:** Ligand B (-10.3 kcal/mol) has a significantly stronger binding affinity than Ligand A (-7.3 kcal/mol). This is a substantial advantage for Ligand B, potentially outweighing some of its ADME drawbacks.

**Overall Assessment:**

Ligand B has a much stronger binding affinity, which is a critical factor for GPCRs. However, it suffers from a negative in vitro half-life, higher DILI risk, and higher hERG inhibition. Ligand A has a more favorable ADME profile (lower DILI, hERG, and clearance, better half-life) and acceptable affinity.

Given the importance of ADME properties for CNS drugs, especially metabolic stability and safety, and the questionable half-life of Ligand B, I would favor Ligand A. While the affinity difference is significant, optimizing Ligand A's affinity may be more achievable than fixing the severe ADME issues of Ligand B.

Output:
0
2025-04-17 07:43:46,850 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (368.543 and 351.447 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (67.43) is significantly better than Ligand B (104.46). For CNS targets, TPSA should be <= 90. Ligand A is within this range, while Ligand B exceeds it, potentially hindering BBB penetration.

**3. logP:** Both ligands have good logP values (2.656 and 1.659), falling within the optimal 1-3 range.

**4. H-Bond Donors:** Ligand A (2) and Ligand B (3) are both acceptable, being <= 5.

**5. H-Bond Acceptors:** Ligand A (4) and Ligand B (5) are both acceptable, being <= 10.

**6. QED:** Both ligands have good QED scores (0.582 and 0.628), indicating drug-like properties.

**7. DILI:** Ligand A (23.885) has a much lower DILI risk than Ligand B (44.591). Both are below the concerning threshold of 60, but A is preferable.

**8. BBB:** This is a critical parameter for CNS targets. Ligand A has a significantly higher BBB percentile (71.772) than Ligand B (56.999). A value >70 is desirable, and Ligand A meets this criterion, while Ligand B does not.

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.977 and -4.9), which is unusual and suggests poor permeability. This is a concern for both.

**10. Aqueous Solubility:** Both ligands have negative solubility values (-3.174 and -1.569), which is also unusual and suggests poor solubility. This is a concern for both.

**11. hERG Inhibition:** Both ligands have low hERG inhibition liability (0.194 and 0.177), which is good.

**12. Microsomal Clearance:** Ligand A (76.35) has higher microsomal clearance than Ligand B (35.308), implying faster metabolism and potentially lower *in vivo* exposure.

**13. In vitro Half-Life:** Ligand B (-29.538) has a negative half-life, which is not physically possible and indicates a data error or issue with the prediction. Ligand A (12.05) is reasonable.

**14. P-gp Efflux:** Both ligands have low P-gp efflux liability (0.106 and 0.164), which is favorable for CNS penetration.

**15. Binding Affinity:** Ligand B (-7.8 kcal/mol) has a slightly better binding affinity than Ligand A (-7.5 kcal/mol). However, the difference is relatively small (0.3 kcal/mol) and may not outweigh the other significant advantages of Ligand A.

**Overall Assessment:**

Ligand A is the more promising candidate. While both have issues with Caco-2 and solubility, Ligand A excels in crucial areas for CNS drug development: TPSA, BBB penetration, and DILI risk. The slightly better affinity of Ligand B is unlikely to compensate for its poorer predicted CNS exposure and higher potential for liver toxicity. The negative half-life for Ligand B is a major red flag.

Output:
0
2025-04-17 07:43:46,850 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B based on the provided guidelines, prioritizing GPCR-specific properties (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (359.451 Da) is slightly lower, which could be beneficial for permeability, but both are acceptable.

**TPSA:** Ligand A (82.43) is better than Ligand B (67.4). Both are below the 90 A^2 threshold desirable for CNS targets, but A is closer to the optimal range.

**logP:** Both ligands have good logP values (A: 1.769, B: 2.319), falling within the 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A has 1 HBD and 5 HBA, while Ligand B has 0 HBD and 6 HBA. Both are within acceptable limits (<=5 HBD, <=10 HBA).

**QED:** Both ligands have similar QED values (A: 0.717, B: 0.731), indicating good drug-likeness.

**DILI:** Ligand A (47.732) has a higher DILI risk than Ligand B (21.171). This is a significant advantage for Ligand B.

**BBB:** Ligand B (72.431) has a considerably better BBB penetration percentile than Ligand A (57.774). This is crucial for a CNS target like DRD2.

**Caco-2 Permeability:** Ligand A (-4.608) has a worse Caco-2 permeability than Ligand B (-5.342). Lower values indicate poorer permeability.

**Aqueous Solubility:** Ligand A (-3.773) has slightly better solubility than Ligand B (-1.59).

**hERG:** Both ligands have very low hERG inhibition risk (A: 0.408, B: 0.376).

**Microsomal Clearance:** Ligand A (45.006) has higher microsomal clearance than Ligand B (7.121), indicating lower metabolic stability.

**In vitro Half-Life:** Ligand B (34.77) has a significantly longer in vitro half-life than Ligand A (14.992).

**P-gp Efflux:** Both ligands have low P-gp efflux liability (A: 0.102, B: 0.064), which is good.

**Binding Affinity:** Ligand B (-7.9 kcal/mol) has a substantially stronger binding affinity than Ligand A (-6.9 kcal/mol). This difference of 1 kcal/mol is significant and can outweigh some ADME drawbacks.

**Conclusion:**

Considering all factors, especially the GPCR-specific priorities, **Ligand B is the more promising drug candidate.** While Ligand A has slightly better solubility, Ligand B excels in crucial areas: significantly better BBB penetration, lower DILI risk, longer half-life, and, most importantly, a much stronger binding affinity. The improved affinity and BBB penetration are particularly important for a CNS target like DRD2.



Output:
1
2025-04-17 07:43:46,850 - INFO - Batch 389 complete. Total preferences: 6224
2025-04-17 07:43:46,850 - INFO - Processing batch 390/512...
2025-04-17 07:44:26,653 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (339.395) is slightly lower, which could be beneficial for permeability, but both are acceptable.

**2. TPSA:** Both ligands have TPSA values below 90 (Ligand A: 75.44, Ligand B: 72.12), which is favorable for CNS penetration.

**3. logP:** Ligand A (2.501) is within the optimal range (1-3). Ligand B (3.891) is approaching the upper limit, potentially raising concerns about solubility and off-target effects, but still acceptable.

**4. H-Bond Donors:** Ligand A has 1 HBD, and Ligand B has 0. Both are within the acceptable limit of <=5.

**5. H-Bond Acceptors:** Ligand A has 4 HBA, and Ligand B has 7. Both are within the acceptable limit of <=10.

**6. QED:** Ligand A (0.849) has a better QED score than Ligand B (0.695), indicating a more drug-like profile.

**7. DILI:** Ligand A (66.693) has a lower DILI risk than Ligand B (78.131), which is preferable.

**8. BBB:** Ligand A (67.546) and Ligand B (74.913) both have reasonably good BBB penetration, but Ligand B is better. For a CNS target like DRD2, this is a crucial factor.

**9. Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and suggests poor permeability. However, these values are on a strange scale and may not be directly comparable.

**10. Aqueous Solubility:** Both ligands have negative solubility values, indicating poor solubility.

**11. hERG Inhibition:** Both ligands show very low hERG inhibition risk (Ligand A: 0.436, Ligand B: 0.307).

**12. Microsomal Clearance:** Ligand A (47.349) and Ligand B (45.021) have similar microsomal clearance values, suggesting comparable metabolic stability.

**13. In vitro Half-Life:** Ligand A (48.859) has a longer in vitro half-life than Ligand B (13.265), which is desirable.

**14. P-gp Efflux:** Both ligands have low P-gp efflux liability (Ligand A: 0.401, Ligand B: 0.626).

**15. Binding Affinity:** Ligand B (-7.6 kcal/mol) has a significantly stronger binding affinity than Ligand A (-9.0 kcal/mol). This is a substantial advantage, potentially outweighing some of the other drawbacks.

**Overall Assessment:**

Ligand B has a significantly better binding affinity, which is the most important factor for GPCRs. It also has a slightly better BBB score. While Ligand A has better QED, DILI, and half-life, the substantial affinity difference of Ligand B is likely to be more impactful. The solubility and Caco-2 permeability are concerning for both, but can be addressed through formulation strategies.

Output:
1
2025-04-17 07:44:26,653 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (348.359 and 347.415 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (134.59) is slightly above the optimal <90 for CNS targets, but still reasonable. Ligand B (82.44) is excellent, well below 90, suggesting good CNS penetration potential.

**logP:** Ligand A (-0.707) is a bit low, potentially hindering membrane permeability. Ligand B (0.682) is better, falling within the 1-3 range, though on the lower end.

**H-Bond Donors/Acceptors:** Ligand A has 3 HBD and 5 HBA, which are acceptable. Ligand B has 1 HBD and 5 HBA, also acceptable.

**QED:** Both ligands have good QED scores (0.604 and 0.745), indicating drug-like properties.

**DILI:** Ligand A (50.911) has a moderate DILI risk. Ligand B (23.769) has a significantly lower DILI risk, which is a major advantage.

**BBB:** Both ligands have similar BBB penetration (56.65% and 57.968%), which is acceptable but not outstanding. Ideally, we'd want >70% for a CNS target.

**Caco-2 Permeability:** Both have negative Caco-2 values (-5.89 and -4.646). This is unusual and suggests poor permeability. However, these values are on a scale where negative values are possible, and the magnitude is important.

**Aqueous Solubility:** Both ligands have negative solubility values (-2.869 and -1.351). This is also unusual and suggests poor solubility.

**hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.055 and 0.077).

**Microsomal Clearance:** Ligand A (-24.773) has significantly lower (better) microsomal clearance than Ligand B (6.813), indicating greater metabolic stability.

**In vitro Half-Life:** Ligand A (-26.135) has a longer half-life than Ligand B (10.852), which is desirable.

**P-gp Efflux:** Both ligands show very low P-gp efflux liability (0.005 and 0.016), which is favorable for CNS penetration.

**Binding Affinity:** Ligand B (-7.5 kcal/mol) has a slightly better binding affinity than Ligand A (-8.1 kcal/mol). While A is better, the difference is not substantial enough to overcome other issues.

**Overall Assessment:**

Ligand B is the more promising candidate. While both have issues with Caco-2 and solubility, Ligand B has a significantly lower DILI risk, a slightly better logP, and a better binding affinity. The lower metabolic clearance and shorter half-life of Ligand B are drawbacks, but the lower DILI risk is a significant advantage. The TPSA of Ligand B is also more favorable for CNS penetration.

Output:
1
2025-04-17 07:44:26,654 - INFO - Reasoning:

Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (365.817 and 360.845 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (100.44) is higher than the preferred <90 for CNS targets, while Ligand B (67.23) is well within the range. This is a significant advantage for Ligand B.

**3. logP:** Both ligands have good logP values (1.392 and 2.498), falling within the optimal 1-3 range.

**4. H-Bond Donors:** Ligand A has 3 HBD, which is acceptable. Ligand B has 1 HBD, also acceptable.

**5. H-Bond Acceptors:** Both ligands have 4 HBA, which is within the acceptable limit of <=10.

**6. QED:** Both ligands have good QED scores (0.702 and 0.91), indicating good drug-like properties.

**7. DILI:** Both ligands have relatively high DILI risk (64.288 and 59.287), but are still below the concerning threshold of 60.

**8. BBB:** Ligand B (68.166) is better than Ligand A (46.801) in terms of BBB penetration, although both are below the desirable >70 for CNS targets. This is a key factor favoring Ligand B.

**9. Caco-2 Permeability:** Ligand A (-5.701) has poor Caco-2 permeability, while Ligand B (-4.954) is slightly better, but still not great.

**10. Aqueous Solubility:** Both ligands have poor aqueous solubility (-2.821 and -3.494). This could pose formulation challenges.

**11. hERG Inhibition:** Ligand A (0.091) has a slightly lower hERG risk than Ligand B (0.329), which is a small advantage.

**12. Microsomal Clearance:** Ligand A (-29.248) has significantly lower microsomal clearance (better metabolic stability) than Ligand B (14.556). This is a substantial advantage for Ligand A.

**13. In vitro Half-Life:** Ligand A (19.751) has a shorter half-life than Ligand B (24.538), but both are reasonable.

**14. P-gp Efflux:** Ligand A (0.071) has lower P-gp efflux than Ligand B (0.179), which is favorable for CNS penetration.

**15. Binding Affinity:** Ligand B (-8.7 kcal/mol) has a significantly stronger binding affinity than Ligand A (0.0 kcal/mol). This is a major advantage for Ligand B, and likely outweighs many of the ADME drawbacks.

**Overall Assessment:**

While Ligand A has better metabolic stability (lower Cl_mic) and P-gp efflux, Ligand B shines with its significantly superior binding affinity and better BBB penetration, both crucial for a CNS-targeting GPCR like DRD2. The lower TPSA of Ligand B is also a plus. The slightly higher hERG risk and moderate DILI risk for Ligand B are manageable, especially given the substantial improvement in binding. The poor Caco-2 and solubility are concerns for both, but can be addressed through formulation strategies.

Output:
1
2025-04-17 07:44:26,654 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (377.457 Da) is slightly higher than Ligand B (350.419 Da), but both are acceptable.

**TPSA:** Ligand A (72.27) is excellent for CNS penetration, well below the 90 A^2 threshold. Ligand B (93.65) is still reasonable, but less optimal for CNS targets.

**logP:** Ligand A (2.763) is within the optimal range (1-3). Ligand B (0.877) is a bit low, potentially hindering membrane permeability.

**H-Bond Donors/Acceptors:** Ligand A (0 HBD, 5 HBA) and Ligand B (1 HBD, 6 HBA) both have acceptable numbers of H-bond donors and acceptors, falling within the guidelines.

**QED:** Both ligands have good QED values (A: 0.732, B: 0.784), indicating drug-like properties.

**DILI:** Ligand A (42.613) has a lower DILI risk than Ligand B (63.397), which is a positive attribute.

**BBB:** This is critical for a CNS target like DRD2. Ligand A (92.168) shows excellent BBB penetration, exceeding the desirable >70% threshold. Ligand B (52.617) is significantly lower, raising concerns about CNS exposure.

**Caco-2 Permeability:** Both have negative values, which is unusual. Assuming these are logP-like scales, lower values indicate lower permeability. Ligand A (-4.617) is slightly better than Ligand B (-4.529), but both are poor.

**Aqueous Solubility:** Both ligands have negative solubility values, which is also unusual. Assuming these are logS-like scales, lower values indicate lower solubility. Ligand A (-3.249) is slightly better than Ligand B (-2.041).

**hERG Inhibition:** Both ligands show low hERG inhibition risk (A: 0.353, B: 0.19), which is favorable.

**Microsomal Clearance:** Ligand A (16.618) has lower microsomal clearance than Ligand B (25.512), indicating better metabolic stability.

**In vitro Half-Life:** Ligand A (3.16 hours) has a shorter half-life than Ligand B (-24.759 hours, which is likely an error or an extremely long half-life).

**P-gp Efflux:** Ligand A (0.304) has lower P-gp efflux than Ligand B (0.031), which is beneficial for CNS penetration.

**Binding Affinity:** Ligand B (-7.5 kcal/mol) has a slightly better binding affinity than Ligand A (-7.1 kcal/mol), but the difference is relatively small (0.4 kcal/mol).

**Overall Assessment:**

Ligand A is significantly better due to its superior BBB penetration (92.168 vs 52.617), lower DILI risk, and better metabolic stability. While Ligand B has a slightly better binding affinity, the difference is not substantial enough to outweigh the significant advantages of Ligand A regarding CNS penetration and safety. The poor Caco-2 and solubility values are concerning for both, but less critical for a CNS-focused drug.

Output:
0
2025-04-17 07:44:26,654 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (340.427 and 346.515 Da) fall comfortably within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (65.54) is higher than Ligand B (49.41). For a CNS target like DRD2, TPSA should ideally be <=90, so both are acceptable, but B is better.

**3. logP:** Ligand A (1.522) is within the optimal 1-3 range. Ligand B (3.668) is slightly higher, but still acceptable.

**4. H-Bond Donors:** Both ligands have 1 HBD, which is well within the acceptable limit of <=5.

**5. H-Bond Acceptors:** Ligand A has 4 HBAs, and Ligand B has 2. Both are below the limit of <=10.

**6. QED:** Both ligands have good QED scores (0.63 and 0.79), indicating good drug-like properties.

**7. DILI:** Ligand A (32.105) has a slightly higher DILI risk than Ligand B (10.585). Both are below 40, indicating low risk, but B is preferable.

**8. BBB:** This is a critical parameter for CNS targets. Ligand B (81.737) has a significantly higher BBB penetration percentile than Ligand A (56.456). This is a major advantage for B.

**9. Caco-2 Permeability:** Both have negative values, which is unusual. This suggests poor permeability. However, the magnitude of the negative value is less important than the other parameters.

**10. Aqueous Solubility:** Both have negative values, indicating poor solubility. This is a concern, but can potentially be addressed through formulation.

**11. hERG Inhibition:** Both ligands have low hERG inhibition risk (0.245 and 0.554).

**12. Microsomal Clearance:** Ligand A (20.717) has a lower microsomal clearance than Ligand B (80.69), suggesting better metabolic stability.

**13. In vitro Half-Life:** Ligand B (-8.852) has a significantly longer in vitro half-life than Ligand A (5.872).

**14. P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.022 and 0.151).

**15. Binding Affinity:** Both ligands have excellent binding affinity (-8.0 and -8.8 kcal/mol). Ligand B is slightly better (-8.8 kcal/mol).

**Overall Assessment:**

Ligand B is the stronger candidate. While Ligand A has better metabolic stability (lower Cl_mic), Ligand B excels in the most critical areas for a CNS GPCR target: significantly higher BBB penetration (81.7% vs 56.5%), slightly better binding affinity, lower DILI risk, and a longer in vitro half-life. The slightly higher logP of Ligand B is not a major concern given its other favorable properties. The poor solubility and Caco-2 permeability are drawbacks for both, but formulation strategies could potentially mitigate these issues.

Output:
1
2025-04-17 07:44:26,654 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (350.459 Da and 341.415 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (84.5) is better than Ligand B (80.12) as both are below the 90 A^2 threshold for CNS targets.

**logP:** Ligand A (1.941) is within the optimal 1-3 range. Ligand B (0.855) is slightly below 1, which *could* indicate permeability issues, but is not a major concern.

**H-Bond Donors/Acceptors:** Ligand A (2 HBD, 4 HBA) and Ligand B (1 HBD, 5 HBA) both have acceptable numbers of H-bond donors and acceptors.

**QED:** Ligand B (0.845) has a significantly better QED score than Ligand A (0.566), indicating better overall drug-likeness.

**DILI:** Ligand B (25.514) has a much lower DILI risk than Ligand A (33.773), which is a significant advantage.

**BBB:** Ligand A (46.84) and Ligand B (42.962) are both below the desirable >70 percentile for CNS targets, but Ligand A is slightly better. This is a critical factor for DRD2, and both are suboptimal.

**Caco-2 Permeability:** Ligand A (-4.712) has better Caco-2 permeability than Ligand B (-5.408), indicating better intestinal absorption.

**Aqueous Solubility:** Ligand A (-2.351) has slightly better aqueous solubility than Ligand B (-0.924).

**hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.096 and 0.179, respectively).

**Microsomal Clearance:** Ligand B (-7.47) has significantly better metabolic stability (lower clearance) than Ligand A (52.021).

**In vitro Half-Life:** Ligand B (-13.706) has a much longer in vitro half-life than Ligand A (-10.957).

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.037 and 0.011, respectively).

**Binding Affinity:** Both ligands have excellent binding affinities (-8.7 kcal/mol and -8.4 kcal/mol). The difference of 0.3 kcal/mol is not substantial enough to outweigh other factors.

**Overall Assessment:**

While Ligand A has slightly better BBB penetration and Caco-2 permeability, Ligand B is superior in almost all other critical ADME properties. Specifically, Ligand B has a much better QED score, significantly lower DILI risk, much better metabolic stability (lower Cl_mic and longer t1/2), and comparable binding affinity. For a CNS target like DRD2, the lower DILI risk and improved metabolic stability of Ligand B are particularly important. The slightly lower BBB value is a concern, but the other advantages outweigh this.

Output:
1
2025-04-17 07:44:26,655 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B based on the provided guidelines, prioritizing GPCR-specific properties (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (369.441 and 354.797 Da) fall within the ideal 200-500 Da range.

**TPSA:** Both ligands (77.04 and 77.92) are reasonably close to the 90 A^2 threshold for CNS targets, but slightly above. This isn't a major concern, but it's a point to consider.

**logP:** Ligand A (2.715) is optimal, while Ligand B (3.98) is approaching the upper limit of the optimal range.

**H-Bond Donors/Acceptors:** Ligand A (HBD=1, HBA=6) and Ligand B (HBD=2, HBA=3) both have acceptable numbers of H-bond donors and acceptors.

**QED:** Ligand A (0.814) has a significantly better QED score than Ligand B (0.569), indicating a more drug-like profile.

**DILI:** Ligand A (41.411) has a much lower DILI risk than Ligand B (77.705). This is a significant advantage for Ligand A.

**BBB:** Ligand A (83.792) has a much better BBB penetration percentile than Ligand B (35.75). This is *critical* for a CNS target like DRD2.

**Caco-2 Permeability:** Ligand A (-4.729) and Ligand B (-5.485) both have negative values, indicating poor permeability. This is a concern for both.

**Aqueous Solubility:** Both ligands have poor aqueous solubility (-3.722 and -4.56 respectively).

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.296 and 0.789).

**Microsomal Clearance:** Ligand B (32.88) has a lower microsomal clearance than Ligand A (37.844), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand B (69.965) has a significantly longer in vitro half-life than Ligand A (-13.899). This is a major advantage for Ligand B.

**P-gp Efflux:** Ligand A (0.071) has a much lower P-gp efflux liability than Ligand B (0.442). Lower P-gp efflux is highly desirable for CNS penetration.

**Binding Affinity:** Ligand B (-8.4 kcal/mol) has a slightly better binding affinity than Ligand A (-7.8 kcal/mol). The difference is 0.6 kcal/mol, which is not a huge advantage but still relevant.

**Overall Assessment:**

Considering the GPCR-specific priorities, Ligand A is the stronger candidate. The superior BBB penetration (83.792 vs 35.75), lower DILI risk (41.411 vs 77.705), and lower P-gp efflux (0.071 vs 0.442) are crucial for a CNS-targeting drug. While Ligand B has a better half-life and slightly better affinity, these are outweighed by the significant advantages of Ligand A in terms of CNS penetration and safety. The solubility and Caco-2 permeability are concerns for both, but can be addressed with formulation strategies.



Output:
0
2025-04-17 07:44:26,655 - INFO - Reasoning:

Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (365.298 and 341.382 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Both ligands have a TPSA of 55.4, which is acceptable for general oral absorption but slightly high for optimal CNS penetration (ideally <90).

**3. logP:** Both ligands have logP values (3.209 and 3.981) within the optimal range of 1-3. Ligand B is slightly higher, which could potentially lead to some off-target interactions, but it's not a major concern.

**4. H-Bond Donors:** Both have 1 HBD, which is good.

**5. H-Bond Acceptors:** Both have 3 HBA, which is also good.

**6. QED:** Both ligands have good QED scores (0.644 and 0.837), indicating good drug-like properties. Ligand B is slightly better.

**7. DILI:** Both ligands have DILI risk above 50%, but Ligand A (57.348%) is lower than Ligand B (69.794%), indicating a slightly lower risk of liver injury.

**8. BBB:** This is a critical parameter for a CNS target like DRD2. Ligand B (90.074%) has a significantly higher BBB penetration percentile than Ligand A (84.141%). This is a major advantage for Ligand B.

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 values, which is unusual and suggests poor permeability. This is a potential issue for both.

**10. Aqueous Solubility:** Both ligands have negative solubility values, which is also unusual and suggests poor solubility. This is a potential issue for both.

**11. hERG Inhibition:** Both ligands have low hERG inhibition liability (0.6 and 0.531), which is good.

**12. Microsomal Clearance:** Ligand B (114.555) has a significantly higher microsomal clearance than Ligand A (70.277), indicating faster metabolism and potentially lower exposure. This is a disadvantage for Ligand B.

**13. In vitro Half-Life:** Ligand A (-18.341) has a negative half-life, which is not physically possible and indicates a data error or a very rapidly degrading compound. Ligand B (6.343) has a reasonable half-life.

**14. P-gp Efflux:** Both ligands have low P-gp efflux liability (0.15 and 0.359), which is good for CNS penetration.

**15. Binding Affinity:** Both ligands have very similar and strong binding affinities (-9.2 and -9.3 kcal/mol). The difference is negligible.

**Overall Assessment:**

While Ligand A has a slightly lower DILI risk and a more reasonable (though still problematic) in vitro half-life, Ligand B clearly wins due to its significantly better BBB penetration (90.074% vs 84.141%) and a reasonable half-life. The higher metabolic clearance of Ligand B is a concern, but the superior BBB penetration is a critical advantage for a CNS-targeting drug. The negative Caco-2 and solubility values are concerning for both, and would require further investigation. However, given the priority for CNS penetration with DRD2, Ligand B is the more promising candidate.

Output:
1
2025-04-17 07:44:26,655 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B based on the provided guidelines, prioritizing GPCR-specific properties (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (358.383 and 368.587 Da) fall within the ideal range of 200-500 Da.

**TPSA:** Ligand A (113.58) is better than Ligand B (40.62). For CNS targets, TPSA should be <=90, and both meet this criterion, but A is closer to the upper limit.

**logP:** Ligand A (1.299) is within the optimal range (1-3), while Ligand B (3.792) is approaching the higher end. This is a slight advantage for A.

**H-Bond Donors/Acceptors:** Ligand A has 1 HBD and 8 HBA, while Ligand B has 0 HBD and 3 HBA. Both are within acceptable limits.

**QED:** Ligand A (0.75) is better than Ligand B (0.612), indicating a more drug-like profile.

**DILI:** Ligand A (93.835) has a significantly higher DILI risk than Ligand B (35.169). This is a major drawback for Ligand A.

**BBB:** Ligand B (77.821) has a much better BBB penetration percentile than Ligand A (33.307). This is *critical* for a CNS target like DRD2.

**Caco-2 Permeability:** Ligand A (-5.437) has poor Caco-2 permeability, while Ligand B (-4.9) is slightly better. Both are negative, indicating poor permeability.

**Aqueous Solubility:** Ligand A (-2.533) has slightly better solubility than Ligand B (-4.082).

**hERG:** Ligand A (0.011) has a very low hERG risk, while Ligand B (0.763) has a moderate risk. This is a significant advantage for A.

**Microsomal Clearance:** Ligand B (88.64) has a much higher microsomal clearance than Ligand A (6.192), indicating lower metabolic stability. This is a major drawback for Ligand B.

**In vitro Half-Life:** Ligand A (2.33) has a shorter half-life than Ligand B (-2.976).

**P-gp Efflux:** Ligand A (0.044) has much lower P-gp efflux than Ligand B (0.692). This is a positive for A, improving CNS exposure.

**Binding Affinity:** Ligand A (-9.3 kcal/mol) has a significantly stronger binding affinity than Ligand B (-7.0 kcal/mol). This is a substantial advantage for A, potentially outweighing some ADME concerns.

**Overall Assessment:**

Despite Ligand A's strong binding affinity and favorable P-gp efflux and hERG profiles, its high DILI risk and poor BBB penetration are major concerns. Ligand B, while having a weaker affinity, exhibits a much better safety profile (lower DILI) and significantly improved BBB penetration, which is crucial for a CNS drug targeting DRD2. The better metabolic stability (lower Cl_mic) of Ligand A is a plus, but the BBB and safety concerns with A are too significant. The affinity difference, while substantial, might be overcome with further optimization of Ligand B.

Output:
1
2025-04-17 07:44:26,655 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (342.355 and 346.471 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (110.11) is higher than the preferred <90 for CNS targets, while Ligand B (49.85) is excellent, well below the threshold. This is a significant advantage for Ligand B.

**3. logP:** Both ligands have good logP values (1.384 and 2.054), falling within the optimal 1-3 range.

**4. H-Bond Donors:** Ligand A has 2 HBD, which is acceptable. Ligand B has 0, which is also good.

**5. H-Bond Acceptors:** Ligand A has 6 HBA, acceptable. Ligand B has 3, also good.

**6. QED:** Both ligands have good QED scores (0.628 and 0.716), indicating good drug-like properties.

**7. DILI:** Ligand A has a DILI risk of 87.786, which is high and concerning. Ligand B has a much lower DILI risk of 12.214, which is very favorable.

**8. BBB:** Ligand A has a BBB penetration of 36.371, which is below the desirable >70% for CNS targets. Ligand B has a much better BBB penetration of 76.154, exceeding the threshold.

**9. Caco-2 Permeability:** Ligand A has a negative Caco-2 value (-5.682), which is unusual and suggests poor permeability. Ligand B has a negative value as well (-4.415), but slightly less negative.

**10. Aqueous Solubility:** Both ligands have poor aqueous solubility (-2.59 and -2.138). This could pose formulation challenges, but is less critical than BBB penetration for a CNS target.

**11. hERG Inhibition:** Both ligands have low hERG inhibition risk (0.227 and 0.371).

**12. Microsomal Clearance:** Ligand A has a moderate Cl_mic (57.039), while Ligand B has a lower Cl_mic (37.244), suggesting better metabolic stability.

**13. In vitro Half-Life:** Ligand A has a short half-life (3.814 hours), while Ligand B has a negative half-life (-10.087 hours), which is not physically possible and likely an error or outlier.

**14. P-gp Efflux:** Both ligands have low P-gp efflux liability (0.105 and 0.117), which is good for CNS exposure.

**15. Binding Affinity:** Ligand A has a slightly better binding affinity (-8.2 kcal/mol) compared to Ligand B (-7.9 kcal/mol). While this difference is notable, the other ADME properties are more critical in this case.

**Overall Assessment:**

Ligand B is significantly more promising. It has a much better TPSA, DILI risk, and BBB penetration, all of which are crucial for a CNS-targeting GPCR ligand. While its half-life value is suspect, the other advantages outweigh this concern. Ligand A's high DILI risk and poor BBB penetration are major drawbacks. The slightly better affinity of Ligand A is not enough to compensate for its inferior ADME profile.

Output:
1
2025-04-17 07:44:26,656 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B based on the provided guidelines, prioritizing GPCR-specific properties (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (363.571 and 350.394 Da) fall within the ideal range of 200-500 Da.

**TPSA:** Ligand A (44.37) is excellent for CNS penetration (<90), while Ligand B (84.42) is higher, but still potentially acceptable.

**logP:** Ligand A (4.156) is slightly high, potentially leading to solubility issues or off-target effects, but still within a reasonable range. Ligand B (0.275) is very low, which could severely hinder membrane permeability and CNS penetration.

**H-Bond Donors/Acceptors:** Ligand A (HBD=2, HBA=3) is well within the acceptable ranges. Ligand B (HBD=1, HBA=5) is also acceptable.

**QED:** Both ligands have good QED scores (A: 0.564, B: 0.796), indicating good drug-like properties.

**DILI:** Ligand A (23.071) has a very low DILI risk, which is excellent. Ligand B (46.219) is higher, but still relatively low risk.

**BBB:** Ligand A (90.5) has excellent BBB penetration, highly desirable for a CNS target. Ligand B (81.117) is good, but less favorable than Ligand A.

**Caco-2 Permeability:** Ligand A (-5.048) has poor Caco-2 permeability. Ligand B (-4.779) also has poor Caco-2 permeability.

**Aqueous Solubility:** Both ligands have poor aqueous solubility (-3.407 and -1.194 respectively).

**hERG Inhibition:** Ligand A (0.894) has a low hERG risk, which is good. Ligand B (0.118) has a very low hERG risk, which is excellent.

**Microsomal Clearance:** Ligand A (78.348) has moderate clearance. Ligand B (-3.292) has negative clearance, which is not possible and likely indicates an error or outlier in the data.

**In vitro Half-Life:** Ligand A (48.381) has a reasonable half-life. Ligand B (-4.911) has a negative half-life, which is not possible and likely indicates an error or outlier in the data.

**P-gp Efflux:** Ligand A (0.718) has moderate P-gp efflux. Ligand B (0.019) has very low P-gp efflux, which is highly desirable for CNS penetration.

**Binding Affinity:** Ligand B (-8.2 kcal/mol) has significantly stronger binding affinity than Ligand A (0.0 kcal/mol). This is a substantial advantage.

**Overall Assessment:**

Despite the slightly higher logP of Ligand A, its superior BBB penetration and significantly better metabolic properties (clearance and half-life) make it a more promising candidate. However, the negative values for clearance and half-life of Ligand B are concerning and likely indicate data errors. The much stronger binding affinity of Ligand B is a significant advantage, but the low logP is a major drawback for CNS penetration. The P-gp efflux is also very low for ligand B.

Considering the GPCR-specific priorities, and the fact that the data for Ligand B appears flawed, I would choose Ligand A.

Output:
0
2025-04-17 07:44:26,656 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight (MW):** Both ligands (353.369 and 367.427 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (73.74) is significantly better than Ligand B (99.93). For CNS targets, we want TPSA <= 90, and A is comfortably within this range, while B is close to the upper limit.

**3. logP:** Ligand A (1.98) is optimal, while Ligand B (0.088) is quite low. A logP below 1 can hinder permeation. This is a significant advantage for Ligand A.

**4. H-Bond Donors (HBD):** Both have 1 HBD, which is acceptable.

**5. H-Bond Acceptors (HBA):** Ligand A has 4 HBA, and Ligand B has 5. Both are within the acceptable limit of <= 10.

**6. QED:** Both ligands have similar QED values (0.84 and 0.816), indicating good drug-likeness.

**7. DILI:** Ligand A (48.468) has a lower DILI risk than Ligand B (62.35), which is preferable.

**8. BBB:** Ligand A (88.135) has a much higher BBB penetration percentile than Ligand B (35.324). This is *critical* for a CNS target like DRD2.

**9. Caco-2 Permeability:** Ligand A (-4.407) is better than Ligand B (-4.866), suggesting slightly better intestinal absorption.

**10. Aqueous Solubility:** Ligand A (-2.212) is better than Ligand B (-2.437), indicating better solubility.

**11. hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.267 and 0.237).

**12. Microsomal Clearance (Cl_mic):** Ligand A (25.839) has a lower Cl_mic than Ligand B (38.54), suggesting better metabolic stability.

**13. In vitro Half-Life:** Ligand A (-43.475) has a much longer half-life than Ligand B (11.206).

**14. P-gp Efflux:** Both ligands have low P-gp efflux liability (0.05 and 0.039).

**15. Binding Affinity:** Both ligands have the same binding affinity (-8.4 kcal/mol), which is excellent.

**Overall Assessment:**

Ligand A is significantly better than Ligand B. While both have excellent binding affinity, Ligand A excels in crucial ADME properties for a CNS-targeting GPCR. Specifically, its superior TPSA, logP, BBB penetration, metabolic stability (lower Cl_mic and longer half-life), and lower DILI risk make it a much more promising drug candidate. Ligand B's low logP and poor BBB penetration are major drawbacks.

Output:
1
2025-04-17 07:44:26,656 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (341.367 and 346.471 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (94.75) is slightly above the optimal <90 for CNS targets, but still reasonable. Ligand B (53.76) is excellent, well below the 90 threshold.

**3. logP:** Ligand A (1.396) is within the optimal 1-3 range. Ligand B (3.479) is at the higher end of the optimal range, but still acceptable.

**4. H-Bond Donors:** Ligand A (1) and Ligand B (0) are both good, meeting the <=5 criteria.

**5. H-Bond Acceptors:** Ligand A (5) and Ligand B (3) are both good, meeting the <=10 criteria.

**6. QED:** Both ligands have good QED scores (0.907 and 0.842), indicating drug-likeness.

**7. DILI:** Ligand A (72.509) has a higher DILI risk than Ligand B (31.601), which is a significant concern.

**8. BBB:** Both ligands have good BBB penetration (67.197 and 71.888), exceeding the 70% threshold. Ligand B is slightly better.

**9. Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and suggests a potential issue with the data or modeling. However, we'll proceed assuming these represent low permeability.

**10. Aqueous Solubility:** Both have negative solubility values, again suggesting a potential data issue. Assuming these represent low solubility.

**11. hERG Inhibition:** Ligand A (0.202) has a very low hERG risk, which is excellent. Ligand B (0.704) is higher, but still relatively low.

**12. Microsomal Clearance:** Ligand A (36.765) has lower clearance than Ligand B (52.272), indicating better metabolic stability.

**13. In vitro Half-Life:** Ligand A (-21.502) has a negative half-life, which is impossible and indicates a data issue. Ligand B (30.377) is good.

**14. P-gp Efflux:** Ligand A (0.114) has lower P-gp efflux than Ligand B (0.65), which is favorable for CNS penetration.

**15. Binding Affinity:** Ligand A (-9.0) has significantly stronger binding affinity than Ligand B (-0.0). This is a substantial advantage.

**Overall Assessment:**

Despite some data inconsistencies (negative Caco-2 and solubility, negative half-life for Ligand A), the binding affinity of Ligand A is *much* stronger. This strong affinity could potentially outweigh the concerns regarding DILI risk and the questionable half-life. The lower P-gp efflux is also a positive. Ligand B has better TPSA and DILI, but its binding affinity is very weak. Given the importance of affinity for GPCRs, and the fact that both ligands have acceptable BBB penetration, Ligand A is the more promising candidate.

Output:
1
2025-04-17 07:44:26,656 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (328.415 Da) is slightly better, being closer to the lower end which can aid permeability.

**TPSA:** Ligand A (41.99) is excellent for CNS penetration, well below the 90 A^2 threshold. Ligand B (81.67) is higher, but still potentially acceptable, though less ideal.

**logP:** Ligand A (4.742) is slightly high, potentially leading to solubility issues or off-target interactions. Ligand B (1.279) is quite low, which could hinder membrane permeability and CNS entry.

**H-Bond Donors/Acceptors:** Ligand A (HBD=1, HBA=2) is favorable. Ligand B (HBD=3, HBA=4) is also acceptable, but slightly higher.

**QED:** Ligand A (0.703) has a better drug-likeness score than Ligand B (0.546).

**DILI:** Ligand A (72.043) has a higher DILI risk than Ligand B (5.584), which is a significant concern.

**BBB:** Ligand A (78.247) has a good BBB penetration percentile, exceeding the 70% threshold. Ligand B (67.197) is lower, making CNS exposure less likely.

**Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and problematic. This suggests poor intestinal absorption. However, for a CNS target, intestinal absorption is less critical than BBB penetration.

**Aqueous Solubility:** Both ligands have very poor aqueous solubility (-5.164 and -1.395 respectively). This is a major drawback.

**hERG Inhibition:** Ligand A (0.812) has a slightly higher hERG risk than Ligand B (0.394).

**Microsomal Clearance:** Ligand A (92.293) has higher microsomal clearance, indicating lower metabolic stability. Ligand B (15.877) has much lower clearance, a significant advantage.

**In vitro Half-Life:** Ligand B (-24.534) has a very negative half-life, which is concerning. Ligand A (8.951) is reasonable.

**P-gp Efflux:** Ligand A (0.68) has lower P-gp efflux liability than Ligand B (0.009), which is beneficial for CNS penetration.

**Binding Affinity:** Ligand A (-10.3 kcal/mol) has significantly stronger binding affinity than Ligand B (-7.3 kcal/mol). This is a substantial advantage, potentially outweighing some of the ADME drawbacks.

**Overall Assessment:**

Ligand A has a superior binding affinity and better BBB penetration and P-gp efflux, crucial for a CNS target like DRD2. However, it has a higher DILI risk and higher metabolic clearance, and poor solubility. Ligand B has a better safety profile (DILI, hERG) and metabolic stability, but suffers from significantly weaker binding affinity and lower BBB penetration.

The strong binding affinity of Ligand A is the deciding factor. While the ADME properties are not ideal, optimization efforts could focus on improving solubility, reducing DILI risk, and enhancing metabolic stability *starting* from this potent scaffold. The weaker affinity of Ligand B makes it a less promising starting point, even with its better ADME profile.

Output:
1
2025-04-17 07:44:26,656 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (347.415 Da) is slightly lower, which *could* be beneficial for permeability, but both are acceptable.

**TPSA:** Ligand A (82.97) is better than Ligand B (42.43). For CNS targets, we want TPSA <= 90, and ideally lower. Ligand B is significantly better here.

**logP:** Ligand A (0.38) is quite low, potentially hindering membrane permeability. Ligand B (4.011) is at the upper end of the optimal range (1-3), but still acceptable. This is a significant advantage for Ligand B.

**H-Bond Donors/Acceptors:** Ligand A has 1 HBD and 5 HBA, while Ligand B has 0 HBD and 3 HBA. Both are within acceptable limits (<=5 HBD, <=10 HBA).

**QED:** Both ligands have reasonable QED values (Ligand A: 0.855, Ligand B: 0.72), indicating good drug-like properties.

**DILI:** Both have low DILI risk (Ligand A: 39.201, Ligand B: 31.989), which is good.

**BBB:** Ligand B (77.743) is significantly better than Ligand A (46.336) regarding BBB penetration, crucial for a CNS target like DRD2.

**Caco-2 Permeability:** Ligand A (-4.602) has very poor Caco-2 permeability, while Ligand B (-4.896) is also poor, but slightly better.

**Aqueous Solubility:** Ligand A (-0.984) has poor solubility, while Ligand B (-3.946) is even worse. This could pose formulation challenges for both.

**hERG Inhibition:** Ligand A (0.125) has very low hERG inhibition risk, which is excellent. Ligand B (0.71) is slightly higher, but still relatively low.

**Microsomal Clearance:** Ligand A (0.779) has lower clearance, suggesting better metabolic stability than Ligand B (69.287).

**In vitro Half-Life:** Ligand A (12.778 hours) has a better in vitro half-life than Ligand B (2.517 hours).

**P-gp Efflux:** Ligand A (0.027) has very low P-gp efflux, which is highly desirable for CNS penetration. Ligand B (0.422) has moderate P-gp efflux.

**Binding Affinity:** Ligand B (-7.6 kcal/mol) has a significantly stronger binding affinity than Ligand A (0.0 kcal/mol). This is a major advantage, potentially outweighing some of the ADME drawbacks.

**Overall Assessment:**

Ligand B is the stronger candidate. While it has poorer solubility and higher clearance than Ligand A, its significantly better BBB penetration, substantially higher binding affinity, and acceptable logP outweigh these concerns. The strong binding affinity is particularly important for a GPCR target. Ligand A's very low logP and poor Caco-2 permeability are major drawbacks.

Output:
1
2025-04-17 07:44:26,657 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (341.411 and 347.459 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Both ligands have TPSA values (84.22 and 82.43) below the 90 A^2 threshold desirable for CNS targets, which is excellent.

**3. logP:** Both ligands have logP values (2.604 and 1.991) within the optimal 1-3 range. Ligand B is slightly lower, which could be beneficial for solubility.

**4. H-Bond Donors:** Ligand A has 2 HBD, and Ligand B has 1. Both are within the acceptable limit of <=5.

**5. H-Bond Acceptors:** Both ligands have 4 HBA, well below the 10 limit.

**6. QED:** Both ligands have high QED scores (0.837 and 0.843), indicating good drug-like properties.

**7. DILI:** Ligand A has a DILI risk of 78.325, which is concerning (approaching the high-risk threshold of >60). Ligand B has a much lower DILI risk of 24.157, a significant advantage.

**8. BBB:** Ligand A has a BBB penetration of 54.44%, which is below the desirable >70% for CNS targets. Ligand B has a significantly better BBB penetration of 61.923%, making it more likely to reach the target in the brain.

**9. Caco-2 Permeability:** Both have negative values (-5.026 and -4.844). This is unusual and suggests poor permeability. However, the scale is not specified, making interpretation difficult.

**10. Aqueous Solubility:** Both ligands have negative solubility values (-3.708 and -1.906), also unusual. Again, the scale is not specified, but suggests poor solubility.

**11. hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.117 and 0.156).

**12. Microsomal Clearance:** Ligand A has a higher microsomal clearance (29.496 mL/min/kg) than Ligand B (6.646 mL/min/kg), meaning Ligand B is likely more metabolically stable.

**13. In vitro Half-Life:** Both ligands have similar in vitro half-lives (30.636 and 30.42 hours).

**14. P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.228 and 0.028). Ligand B is slightly better.

**15. Binding Affinity:** Ligand B has a significantly stronger binding affinity (-8.9 kcal/mol) compared to Ligand A (-0.0 kcal/mol). This is a major advantage, potentially outweighing some of the ADME concerns.

**Overall Assessment:**

Ligand B is the superior candidate. While both have issues with Caco-2 and solubility, Ligand B has a much better safety profile (lower DILI), improved BBB penetration, better metabolic stability (lower Cl_mic), and, crucially, a *significantly* higher binding affinity. The strong binding affinity of Ligand B is a critical factor for a GPCR target and is likely to drive efficacy. The lower DILI and better BBB penetration also contribute to a more favorable overall profile.



Output:
1
2025-04-17 07:44:26,657 - INFO - Batch 390 complete. Total preferences: 6240
2025-04-17 07:44:26,657 - INFO - Processing batch 391/512...
2025-04-17 07:45:11,129 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (368.459 and 347.375 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Both ligands (115.39 and 116.42) are slightly above the optimal <90 for CNS targets, but still reasonable.

**3. logP:** Ligand A (-0.709) is a bit low, potentially hindering permeability. Ligand B (-0.207) is better, falling closer to the optimal 1-3 range.

**4. H-Bond Donors:** Both have 3 HBD, which is within the acceptable limit of <=5.

**5. H-Bond Acceptors:** Both have 5 HBA, also within the acceptable limit of <=10.

**6. QED:** Ligand A (0.588) is good, indicating drug-likeness. Ligand B (0.7) is even better.

**7. DILI:** Ligand A (35.595) has a much lower DILI risk than Ligand B (54.75). This is a significant advantage for Ligand A.

**8. BBB:** Ligand B (55.874) has a considerably better BBB penetration percentile than Ligand A (16.324). This is a *critical* advantage for a CNS target like DRD2.

**9. Caco-2 Permeability:** Both show poor Caco-2 permeability (-5.394 and -5.033).

**10. Aqueous Solubility:** Both have poor aqueous solubility (-2.462 and -2.63).

**11. hERG Inhibition:** Both have low hERG inhibition risk (0.11 and 0.257).

**12. Microsomal Clearance:** Ligand B (-37.481) has significantly lower (better) microsomal clearance than Ligand A (4.302), indicating greater metabolic stability.

**13. In vitro Half-Life:** Ligand B (-36.196) has a much longer in vitro half-life than Ligand A (-12.806).

**14. P-gp Efflux:** Both have very low P-gp efflux liability (0.007 and 0.012).

**15. Binding Affinity:** Both have excellent binding affinities (-8.2 and -9.2 kcal/mol). Ligand B is slightly better, with a 1.0 kcal/mol advantage.

**Overall Assessment:**

While Ligand A has a better safety profile (lower DILI), Ligand B is significantly better regarding key GPCR properties for CNS targets. The substantial improvement in BBB penetration (55.874 vs 16.324), coupled with improved metabolic stability (lower Cl_mic and longer t1/2) and slightly better binding affinity, outweighs the higher DILI risk. The poor Caco-2 and solubility are concerns for both, but can be addressed through formulation strategies. Given the importance of CNS penetration for DRD2, Ligand B is the more promising candidate.

Output:
1
2025-04-17 07:45:11,129 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (364.324 and 344.375 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (97.55) is better than Ligand B (110.17). For CNS targets, we want TPSA <= 90, so A is closer to this threshold.

**logP:** Both ligands have acceptable logP values (0.759 and 1.513), falling within the 1-3 range. Ligand B is slightly better.

**H-Bond Donors/Acceptors:** Ligand A (HBD=1, HBA=7) is preferable to Ligand B (HBD=3, HBA=6) as it has fewer HBDs, which can improve permeability. Both are within acceptable limits.

**QED:** Both ligands have similar QED values (0.775 and 0.761), indicating good drug-likeness.

**DILI:** Ligand A (56.34) has a significantly lower DILI risk than Ligand B (90.617). This is a major advantage for Ligand A.

**BBB:** Ligand A (76.037) has a much better BBB penetration score than Ligand B (59.325).  For a CNS target like DRD2, BBB penetration >70 is highly desirable, and A is closer.

**Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual. However, the magnitude is similar (-4.437 vs -4.892).

**Aqueous Solubility:** Both have negative solubility values, which is also unusual. The magnitude is similar (-2.543 vs -3.894).

**hERG:** Both ligands have low hERG inhibition liability (0.172 and 0.261), which is good.

**Microsomal Clearance:** Ligand A (37.357) has lower microsomal clearance than Ligand B (45.465), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (-23.536) has a much longer in vitro half-life than Ligand B (6.262). This is a significant advantage for dosing considerations.

**P-gp Efflux:** Both have low P-gp efflux liability (0.117 and 0.09), which is good for CNS penetration.

**Binding Affinity:** Ligand B (-9.0 kcal/mol) has a significantly stronger binding affinity than Ligand A (-7.8 kcal/mol). This is a substantial advantage, potentially outweighing some of the ADME drawbacks of Ligand B. A difference of >1.5 kcal/mol is considered significant.

**Overall Assessment:**

While Ligand B boasts a superior binding affinity, Ligand A presents a much more favorable ADME profile, particularly regarding BBB penetration, DILI risk, and metabolic stability (clearance and half-life). Given the CNS target (DRD2), BBB penetration is crucial. The substantial difference in DILI risk also favors Ligand A. The affinity difference, while significant, might be overcome with further optimization of Ligand A.

Output:
0
2025-04-17 07:45:11,129 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (355.435 and 349.391 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (91.34) is better than Ligand B (118.11). For CNS targets, we want TPSA <= 90, so Ligand A is closer to this threshold.

**logP:** Both ligands (-1.036 and -0.988) are slightly below the optimal 1-3 range, but not drastically so. This could potentially impact permeability, but isn't a dealbreaker.

**H-Bond Donors/Acceptors:** Ligand A (2 HBD, 6 HBA) and Ligand B (3 HBD, 6 HBA) both fall within acceptable limits (<=5 HBD and <=10 HBA).

**QED:** Ligand A (0.567) has a better QED score than Ligand B (0.391), indicating a more drug-like profile.

**DILI:** Ligand B (40.403) has a slightly better DILI score than Ligand A (11.206), indicating lower potential for liver injury. However, both are reasonably low risk.

**BBB:** Ligand A (44.203) has a slightly better BBB score than Ligand B (43.893), but both are relatively low. This is a concern for a CNS target like DRD2, where >70 is desirable.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.118 and -5.29), which is unusual and suggests very poor permeability. This is a significant drawback.

**Aqueous Solubility:** Ligand A (0.092) has slightly better solubility than Ligand B (-2.237), but both are very poor.

**hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.215 and 0.031).

**Microsomal Clearance:** Ligand B (-2.775) has a *negative* microsomal clearance, which is impossible and indicates a data error or outlier. Ligand A (12.36) has a reasonable clearance.

**In vitro Half-Life:** Ligand B (-35.057) has a negative half-life, which is also impossible and indicates a data error. Ligand A (26.113) has a reasonable half-life.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.005 and 0.01).

**Binding Affinity:** Ligand B (-7.4 kcal/mol) has a significantly better binding affinity than Ligand A (-6.6 kcal/mol). This is a substantial advantage, potentially outweighing some ADME concerns.

**Overall Assessment:**

Ligand B has a much stronger binding affinity, which is the most critical factor. However, the negative values for microsomal clearance and half-life are red flags suggesting data issues. Ligand A, while having weaker affinity, has more reasonable ADME properties. Given the data quality concerns with Ligand B, and the importance of reasonable ADME properties for *in vivo* efficacy, I would cautiously favor Ligand A. The low BBB and Caco-2 values for both are concerning and would require further investigation/optimization.

Output:
0
2025-04-17 07:45:11,129 - INFO - Reasoning:

Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (350.463 and 352.435 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (96.25) is better than Ligand B (107.61). For CNS targets, we want TPSA <= 90, so both are slightly above, but A is closer.

**3. logP:** Ligand A (1.081) is within the optimal 1-3 range. Ligand B (0.23) is a bit low, potentially hindering permeation.

**4. H-Bond Donors:** Both ligands have 3 HBD, which is acceptable.

**5. H-Bond Acceptors:** Ligand A has 5 HBA, and Ligand B has 4. Both are within the acceptable limit of <= 10.

**6. QED:** Both ligands have similar QED values (0.621 and 0.636), indicating good drug-likeness.

**7. DILI:** Ligand A (29.236) has a significantly lower DILI risk than Ligand B (47.344). This is a substantial advantage.

**8. BBB:** Ligand B (75.921) has a much better BBB penetration percentile than Ligand A (51.377). This is critical for a CNS target like DRD2.

**9. Caco-2 Permeability:** Both have negative Caco-2 values (-5.092 and -5.144), which is unusual and suggests poor permeability. This is a concern for both.

**10. Aqueous Solubility:** Both have negative solubility values (-1.916 and -2.584), which is also concerning and suggests poor solubility.

**11. hERG:** Both ligands have very low hERG inhibition liability (0.052 and 0.053), which is excellent.

**12. Microsomal Clearance:** Ligand B (19.938) has lower microsomal clearance than Ligand A (23.094), indicating better metabolic stability.

**13. In vitro Half-Life:** Ligand B (-10.066) has a significantly longer in vitro half-life than Ligand A (-0.463). This is a major advantage.

**14. P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.016 and 0.008), which is favorable for CNS penetration.

**15. Binding Affinity:** Ligand B (-8.7 kcal/mol) has a stronger binding affinity than Ligand A (-7.8 kcal/mol). This 0.9 kcal/mol difference is substantial and could outweigh some ADME drawbacks.

**Overall Assessment:**

Ligand B is stronger in terms of BBB penetration, metabolic stability (lower Cl_mic, longer t1/2), and binding affinity. However, Ligand A has a significantly lower DILI risk. Both have poor Caco-2 and solubility. Given the GPCR-specific priorities, BBB and affinity are paramount for CNS targets. The stronger affinity of Ligand B, combined with its superior BBB penetration, makes it the more promising candidate despite the slightly higher DILI risk. The difference in affinity is large enough to potentially overcome the DILI concern with further optimization.

Output:
1
2025-04-17 07:45:11,129 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (344.455 and 358.389 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (60.45) is significantly better than Ligand B (87.46). For CNS targets, TPSA should be <= 90, which both meet, but A is closer to the optimal <=60 range.

**logP:** Ligand A (3.972) is optimal, while Ligand B (0.774) is quite low. Low logP can hinder membrane permeability, a significant concern for CNS penetration.

**H-Bond Donors/Acceptors:** Ligand A (HBD=1, HBA=4) and Ligand B (HBD=2, HBA=5) both have acceptable numbers of H-bond donors and acceptors.

**QED:** Both ligands have similar QED values (0.61 and 0.672), indicating good drug-likeness.

**DILI:** Ligand A (54.401) has a higher DILI risk than Ligand B (20.706). This is a negative for Ligand A.

**BBB:** Ligand A (82.9) has a better BBB percentile than Ligand B (67.235). Both are reasonably good, but A is preferable for a CNS target.

**Caco-2 Permeability:** Ligand A (-4.912) is worse than Ligand B (-4.61), indicating lower intestinal absorption.

**Aqueous Solubility:** Ligand A (-3.319) is worse than Ligand B (-1.004).

**hERG:** Ligand A (0.898) has a slightly higher hERG risk than Ligand B (0.267).

**Microsomal Clearance:** Ligand A (50.729) has higher clearance than Ligand B (7.776), meaning it is less metabolically stable.

**In vitro Half-Life:** Ligand A (62.48) has a better half-life than Ligand B (-33.446).

**P-gp Efflux:** Ligand A (0.389) has lower P-gp efflux than Ligand B (0.031), which is favorable for CNS penetration.

**Binding Affinity:** Ligand A (-8.1 kcal/mol) has a significantly better binding affinity than Ligand B (-7.4 kcal/mol). This 1.7 kcal/mol difference is substantial and can outweigh some of the ADME drawbacks.

**Overall Assessment:**

Ligand A has a superior binding affinity and better BBB penetration and P-gp efflux, which are crucial for a CNS-targeting GPCR like DRD2. While it has some drawbacks (higher DILI, lower solubility, and higher clearance), the strong binding affinity and favorable CNS properties are likely to be more important. Ligand B has better DILI, solubility, and clearance, but its significantly lower logP and weaker binding affinity are major concerns. The affinity difference is large enough to compensate for the other issues.

Output:
1
2025-04-17 07:45:11,129 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (349.475 and 351.531 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (70.67) is higher than the preferred <90 for CNS targets, but still reasonable. Ligand B (30.93) is excellent, well below the threshold.

**3. logP:** Ligand A (1.792) is within the optimal range of 1-3. Ligand B (3.345) is slightly higher, but still acceptable.

**4. H-Bond Donors:** Ligand A (2) is good. Ligand B (0) is also good.

**5. H-Bond Acceptors:** Both ligands (4) are within the acceptable limit of 10.

**6. QED:** Both ligands (0.656 and 0.671) have good drug-likeness scores, exceeding the 0.5 threshold.

**7. DILI:** Ligand A (14.23) has a much lower DILI risk than Ligand B (8.181), indicating a safer profile. Both are below the 40 threshold.

**8. BBB:** Ligand B (88.833) has a significantly higher BBB penetration score than Ligand A (57.619). This is a *critical* advantage for a CNS target like DRD2.

**9. Caco-2 Permeability:** Ligand A (-5.469) has poor Caco-2 permeability, suggesting poor intestinal absorption. Ligand B (-4.808) is also poor, but slightly better than A.

**10. Aqueous Solubility:** Ligand A (-1.694) has poor aqueous solubility. Ligand B (-3.006) is even worse.

**11. hERG Inhibition:** Ligand A (0.124) shows very low hERG inhibition risk, which is excellent. Ligand B (0.868) is slightly higher, but still relatively low.

**12. Microsomal Clearance:** Ligand A (-8.264) has very low microsomal clearance, suggesting good metabolic stability. Ligand B (35.536) has much higher clearance, indicating faster metabolism.

**13. In vitro Half-Life:** Ligand A (2.235) has a shorter half-life than Ligand B (31.757).

**14. P-gp Efflux:** Ligand A (0.013) has very low P-gp efflux, which is excellent. Ligand B (0.333) is higher, suggesting more efflux.

**15. Binding Affinity:** Both ligands (-7.8 kcal/mol) have identical and excellent binding affinities.

**Overall Assessment:**

Ligand B is strongly favored due to its significantly higher BBB penetration (88.833 vs 57.619). While Ligand A has advantages in DILI risk, metabolic stability, and P-gp efflux, the BBB score is paramount for a CNS-targeting drug. The slightly better logP of Ligand B also contributes to its favorability. The solubility and Caco-2 permeability are poor for both, but can be addressed with formulation strategies.

Output:
1
2025-04-17 07:45:11,129 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (346.43 & 353.50 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (62.99) is better than Ligand B (48), both are below the 90 A^2 threshold for CNS targets.

**logP:** Ligand A (1.698) is within the optimal 1-3 range. Ligand B (2.875) is also within range, but closer to the upper limit.

**H-Bond Donors:** Both have 0 HBD, which is acceptable.

**H-Bond Acceptors:** Both have 4 HBA, which is acceptable.

**QED:** Ligand A (0.836) is better than Ligand B (0.706), both are above the 0.5 threshold.

**DILI:** Both ligands have very low DILI risk (14.62 & 14.42 percentile), which is excellent.

**BBB:** Ligand B (82.47%) significantly outperforms Ligand A (53.04%) in BBB penetration, a critical factor for CNS targets like DRD2.

**Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and suggests poor permeability. However, the scale is not specified, so it is hard to interpret.

**Aqueous Solubility:** Both have negative solubility values, which is also unusual and suggests poor solubility.

**hERG Inhibition:** Ligand A (0.173) has a much lower hERG inhibition risk than Ligand B (0.657). This is a significant advantage.

**Microsomal Clearance:** Ligand A (30.39 mL/min/kg) has a lower clearance than Ligand B (81.49 mL/min/kg), indicating better metabolic stability.

**In vitro Half-Life:** Ligand A (28.48 hr) has a longer half-life than Ligand B (13.11 hr).

**P-gp Efflux:** Ligand A (0.018) has significantly lower P-gp efflux liability than Ligand B (0.34). Lower P-gp efflux is crucial for CNS penetration.

**Binding Affinity:** Ligand A (-8.1 kcal/mol) has a significantly stronger binding affinity than Ligand B (-0.0 kcal/mol). This is a decisive advantage.

**Overall Assessment:**

While Ligand B has a superior BBB score, Ligand A is significantly better in almost every other critical parameter, especially binding affinity (-8.1 vs -0.0 kcal/mol). The substantial difference in affinity outweighs the BBB advantage of Ligand B. Ligand A also has better metabolic stability, lower hERG risk, and lower P-gp efflux, all crucial for drug development. The negative Caco-2 and solubility values are concerning for both, but the strong affinity of Ligand A suggests it might overcome these issues.

Output:
1
2025-04-17 07:45:11,130 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (348.403 and 352.475 Da) fall within the ideal range of 200-500 Da.

**TPSA:** Ligand A (113.44) is slightly above the preferred <90 for CNS targets, but still reasonable. Ligand B (89.87) is excellent, well within the desired range.

**logP:** Ligand A (-0.262) is quite low, potentially hindering membrane permeability. Ligand B (1.194) is within the optimal 1-3 range. This is a significant advantage for Ligand B.

**H-Bond Donors/Acceptors:** Both ligands have 3 HBDs, which is acceptable. Ligand A has 6 HBAs, and Ligand B has 4 HBAs, both are within the acceptable limit of <=10.

**QED:** Both ligands have good QED scores (0.53 and 0.693), indicating drug-like properties.

**DILI:** Ligand A (47.964) has a moderate DILI risk, while Ligand B (16.014) has a very low risk.

**BBB:** Ligand A (63.707) has a moderate BBB penetration, while Ligand B (22.606) has poor BBB penetration. This is a major drawback for Ligand B, given DRD2 is a CNS target.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.333 and -5.065), indicating poor permeability. This is concerning for both.

**Aqueous Solubility:** Both ligands have negative solubility values (-1.015 and -1.77), indicating poor solubility. This is concerning for both.

**hERG Inhibition:** Both ligands show very low hERG inhibition risk (0.028 and 0.102).

**Microsomal Clearance:** Ligand A (15.482) has moderate clearance, while Ligand B (-1.741) has negative clearance, which is unusual and suggests very high metabolic stability.

**In vitro Half-Life:** Ligand A (0.384) has a very short half-life, while Ligand B (10.281) has a longer, more desirable half-life.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.006 and 0.035).

**Binding Affinity:** Both ligands have very similar and strong binding affinities (-8.1 and -8.3 kcal/mol). The difference is negligible.

**Overall Assessment:**

Ligand B has several advantages: better logP, lower DILI risk, and a longer half-life. However, its BBB penetration is significantly lower than Ligand A. Ligand A's primary weakness is its low logP. Given the importance of BBB penetration for a CNS target like DRD2, Ligand A is the better candidate *despite* its lower logP. The slightly better metabolic stability of Ligand B isn't enough to overcome the BBB issue. Further optimization of Ligand A to improve its logP would be a priority.

Output:
0
2025-04-17 07:45:11,130 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (355.391 and 348.447 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (108.41) is higher than Ligand B (67.67). For CNS targets, TPSA should be <=90. Ligand B is significantly better in this regard.

**logP:** Ligand A (-0.894) is below the optimal 1-3 range and could indicate permeability issues. Ligand B (1.104) is within the optimal range.

**H-Bond Donors/Acceptors:** Ligand A has 2 HBD and 6 HBA, which are acceptable. Ligand B has 0 HBD and 5 HBA, also acceptable.

**QED:** Both ligands have good QED scores (0.574 and 0.799), indicating drug-like properties.

**DILI:** Ligand A (36.487) has a slightly higher DILI risk than Ligand B (28.306), but both are below the concerning threshold of 60.

**BBB:** This is a critical parameter for a CNS target like DRD2. Ligand B (59.364) is significantly better than Ligand A (19.232), though ideally, we'd want >70.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.967 and -4.621), which is unusual and suggests poor permeability. However, these values are on a log scale, so the absolute difference is less important than the overall trend.

**Aqueous Solubility:** Both ligands have negative solubility values (-0.46 and -1.128), indicating poor aqueous solubility.

**hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.05 and 0.161).

**Microsomal Clearance:** Ligand A (-14.437) has a much lower (better) microsomal clearance than Ligand B (20.619), suggesting greater metabolic stability.

**In vitro Half-Life:** Ligand B (14.792) has a significantly longer half-life than Ligand A (-7.232).

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.009 and 0.026).

**Binding Affinity:** Ligand B (-7.4 kcal/mol) has a slightly better binding affinity than Ligand A (-6.9 kcal/mol). While the difference is less than the 1.5 kcal/mol threshold, it's still a positive factor.

**Overall Assessment:**

Ligand B is the more promising candidate. While both have solubility and Caco-2 permeability concerns, Ligand B excels in crucial areas for CNS penetration: significantly better TPSA, a much higher BBB percentile, and a longer half-life. Its logP is also within the optimal range, unlike Ligand A. Although Ligand A has better metabolic stability (lower Cl_mic), the CNS penetration advantages of Ligand B outweigh this benefit for a DRD2 target.

Output:
1
2025-04-17 07:45:11,130 - INFO - Okay, let's analyze these two ligands for their potential as DRD2 drug candidates. DRD2 is a GPCR in the CNS, so BBB penetration, logP, Pgp efflux, TPSA, and binding affinity are paramount.

**Ligand A:** [368.449, 46.38, 4.59, 0, 4, 0.232, 36.216, 86.196, -4.592, -5.26, 0.881, 49.644, -1.37, 0.394, -8.1]
**Ligand B:** [345.447, 99.81, 1.547, 2, 5, 0.817, 38.969, 57.619, -4.832, -2.923, 0.197, 25.318, 10.762, 0.025, -8.5]

**Step-by-step comparison:**

1. **MW:** Both are within the ideal range (200-500 Da). A (368.449) is slightly higher than B (345.447), but both are acceptable.
2. **TPSA:** A (46.38) is excellent for CNS penetration (well below 90). B (99.81) is higher, but still potentially acceptable, though less ideal.
3. **logP:** A (4.59) is a bit high, potentially leading to solubility issues or off-target effects. B (1.547) is very good, within the optimal range.
4. **HBD:** A (0) is low, which is fine. B (2) is also acceptable.
5. **HBA:** A (4) is good. B (5) is also acceptable.
6. **QED:** A (0.232) is quite low, indicating a less drug-like profile. B (0.817) is excellent.
7. **DILI:** Both have low DILI risk (A: 36.216, B: 38.969), both below the 40 threshold.
8. **BBB:** A (86.196) is very good, exceeding the 70% threshold for CNS targets. B (57.619) is significantly lower, which is a major concern for a CNS target like DRD2.
9. **Caco-2:** Both are negative, indicating poor permeability. This is a weakness for both, but less critical for CNS drugs relying on BBB penetration.
10. **Solubility:** Both have negative solubility values, indicating very poor aqueous solubility. A (-5.26) is worse than B (-2.923).
11. **hERG:** Both have low hERG risk (A: 0.881, B: 0.197).
12. **Cl_mic:** A (49.644) is higher than B (25.318), indicating faster metabolism and lower metabolic stability.
13. **t1/2:** B (10.762) has a much longer in vitro half-life than A (-1.37), which is a significant advantage.
14. **Pgp:** A (0.394) has lower P-gp efflux liability than B (0.025), which is favorable for CNS penetration.
15. **Affinity:** B (-8.5) has a slightly stronger binding affinity than A (-8.1), though the difference is relatively small.

**Overall Assessment:**

Ligand B is the stronger candidate despite its slightly higher TPSA and lower Pgp. The key advantages of B are its significantly better QED score, much longer half-life, and better logP. The biggest drawback of A is its poor QED and lower BBB penetration. While A has better Pgp efflux, the superior overall profile of B, particularly its BBB penetration and drug-likeness, makes it the more promising candidate. The slightly better affinity of B is a bonus.

Output:
1
2025-04-17 07:45:11,130 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (343.43 and 344.37 Da) fall comfortably within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (70.67) is significantly better than Ligand B (89.6). For CNS targets, we want TPSA <= 90, and A is closer to the optimal <= 60 range. B is pushing the upper limit.

**3. logP:** Both ligands have acceptable logP values (1.93 and 0.69), falling within the 1-3 range. Ligand A is slightly preferred due to being closer to the optimal range.

**4. H-Bond Donors:** Both ligands have reasonable HBD counts (2 and 1).

**5. H-Bond Acceptors:** Ligand A (3) is better than Ligand B (6). Lower HBA is generally preferred for better permeability.

**6. QED:** Both ligands have good QED values (0.858 and 0.881), indicating good drug-like properties.

**7. DILI:** Ligand A (26.44) has a much lower DILI risk than Ligand B (68.24). This is a significant advantage for A.

**8. BBB:** Ligand A (60.14) has a better BBB percentile than Ligand B (56.38), though both are below the desirable >70 for CNS targets. However, A is closer.

**9. Caco-2:** Both have negative Caco-2 values, which is unusual and suggests poor permeability. However, the magnitude of negativity is similar.

**10. Solubility:** Both have negative solubility values, also unusual. Again, the magnitude is similar.

**11. hERG:** Both ligands have low hERG inhibition risk (0.305 and 0.208).

**12. Cl_mic:** Ligand A (-9.63) has a *much* lower (better) microsomal clearance than Ligand B (5.27). This indicates significantly better metabolic stability for Ligand A.

**13. t1/2:** Ligand A (25.09) has a shorter half-life than Ligand B (45.08), but this is less critical than metabolic stability.

**14. Pgp:** Ligand A (0.022) has a much lower Pgp efflux liability than Ligand B (0.105). This is a major advantage, especially for CNS penetration.

**15. Binding Affinity:** Ligand B (-7.9) has a significantly stronger binding affinity than Ligand A (-9.5). This is a substantial advantage for B, potentially outweighing some ADME drawbacks.

**Overall Assessment:**

While Ligand B boasts a superior binding affinity, Ligand A demonstrates a markedly better ADME profile, particularly regarding DILI risk, metabolic stability (Cl_mic), and P-gp efflux. Given the CNS target (DRD2), BBB penetration is crucial, and while neither ligand is ideal, A is better. The combination of lower DILI, better metabolic stability, and lower P-gp efflux for Ligand A makes it a more promising candidate despite the slightly weaker binding affinity. The 1.5 kcal/mol difference in binding affinity can often be overcome with further optimization, but fixing poor ADME properties is far more challenging.

Output:
0
2025-04-17 07:45:11,130 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (421.646 Da) is at the higher end, while Ligand B (350.467 Da) is more optimal.

**TPSA:** Ligand A (113.41) is slightly above the preferred <90 for CNS targets, but still reasonable. Ligand B (82.62) is well within the desired range.

**logP:** Ligand A (2.412) is within the optimal 1-3 range. Ligand B (0.492) is a bit low, potentially hindering permeation.

**H-Bond Donors/Acceptors:** Both ligands have acceptable HBD (3 and 2 respectively) and HBA (7 each) counts.

**QED:** Both ligands have acceptable QED values (0.438 and 0.627 respectively), suggesting reasonable drug-likeness. Ligand B is better here.

**DILI:** Ligand A has a very high DILI risk (99.341), a major concern. Ligand B has a much lower and acceptable DILI risk (36.487).

**BBB:** Ligand A (40.791) has poor predicted BBB penetration, which is critical for a CNS target like DRD2. Ligand B (71.966) has significantly better BBB penetration, exceeding the desirable >70 threshold.

**Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and suggests a potential issue with the prediction method or the molecules themselves.

**Aqueous Solubility:** Both have negative solubility values, which is also unusual.

**hERG Inhibition:** Ligand A (0.396) shows some hERG inhibition liability, while Ligand B (0.694) shows more.

**Microsomal Clearance:** Ligand A (2.602) has lower clearance, indicating better metabolic stability than Ligand B (23.895).

**In vitro Half-Life:** Ligand A (108.187) has a significantly longer half-life than Ligand B (1.499), which is highly desirable.

**P-gp Efflux:** Ligand A (0.222) has lower P-gp efflux, which is beneficial for CNS exposure. Ligand B (0.012) has very low P-gp efflux, which is even better.

**Binding Affinity:** Ligand A (-10.3 kcal/mol) has a much stronger binding affinity than Ligand B (0.0 kcal/mol). This is a substantial advantage.

**Overall Assessment:**

Despite Ligand A's superior binding affinity and metabolic stability, its extremely high DILI risk and poor BBB penetration are deal-breakers for a CNS drug candidate. Ligand B, while having weaker binding affinity, exhibits a much more favorable safety profile (low DILI), excellent BBB penetration, and good P-gp efflux properties. The difference in binding affinity, while significant, might be overcome with further optimization of Ligand B. Given the GPCR-specific priorities, Ligand B is the more promising candidate.

Output:
1
2025-04-17 07:45:11,130 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (366.33 Da) is slightly higher than Ligand B (341.411 Da), but this isn't a major concern.

**TPSA:** Ligand A (41.57) is significantly better than Ligand B (54.78). For CNS targets, we want TPSA <= 90, and ideally lower. Ligand A is well within this range, while Ligand B is approaching the upper limit.

**logP:** Ligand A (3.664) is optimal, while Ligand B (0.853) is a bit low. A logP between 1-3 is preferred, and Ligand B's value might hinder permeation.

**H-Bond Donors/Acceptors:** Ligand A (HBD=1, HBA=2) is better than Ligand B (HBD=0, HBA=4). Both are within acceptable limits, but higher HBA can sometimes reduce permeability.

**QED:** Ligand A (0.808) has a higher QED score than Ligand B (0.589), indicating a more drug-like profile.

**DILI:** Both ligands have acceptable DILI risk (Ligand A: 42.148, Ligand B: 38.813), below the 60 threshold.

**BBB:** Ligand A (85.033) has a significantly better BBB penetration score than Ligand B (56.805). For a CNS target like DRD2, >70 is desirable, and Ligand A is closer to that goal.

**Caco-2:** Both have negative Caco-2 values, which is unusual and suggests a potential issue with the data or modeling.

**Solubility:** Both have negative solubility values, which is also unusual.

**hERG:** Ligand A (0.749) has a slightly higher hERG risk than Ligand B (0.232), but both are relatively low.

**Cl_mic:** Ligand B (9.406) has significantly lower microsomal clearance than Ligand A (37.568), suggesting better metabolic stability.

**t1/2:** Ligand B (3.666) has a longer in vitro half-life than Ligand A (-25.273), which is a positive attribute.

**Pgp:** Ligand A (0.169) has lower P-gp efflux liability than Ligand B (0.062), which is beneficial for CNS exposure.

**Binding Affinity:** Ligand A (-9.1 kcal/mol) has a significantly stronger binding affinity than Ligand B (-7.5 kcal/mol). This is a crucial advantage, as a >1.5 kcal/mol difference can outweigh other drawbacks.

**Overall Assessment:**

Ligand A excels in key areas for a CNS-targeting GPCR ligand: TPSA, logP, BBB penetration, and, most importantly, binding affinity. While Ligand B has better metabolic stability (lower Cl_mic) and half-life, the substantial difference in binding affinity and the superior BBB score of Ligand A make it the more promising candidate. The negative Caco-2 and solubility values are concerning for both, but the strong affinity of Ligand A suggests it might overcome these issues.

Output:
1
2025-04-17 07:45:11,130 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (369.403 and 352.431 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (122.75) is slightly above the optimal <90 for CNS targets, but still reasonable. Ligand B (84.94) is excellent, well below 90.

**logP:** Ligand A (-0.904) is a bit low, potentially hindering permeation. Ligand B (1.004) is much better, falling within the 1-3 optimal range.

**H-Bond Donors/Acceptors:** Ligand A (2 HBD, 8 HBA) is acceptable. Ligand B (1 HBD, 5 HBA) is also good, with lower counts generally favoring permeability.

**QED:** Both ligands have good QED scores (0.689 and 0.746), indicating drug-like properties.

**DILI:** Ligand A (83.133) has a higher DILI risk than Ligand B (41.838). This is a significant concern.

**BBB:** Ligand B (54.634) has a better BBB percentile than Ligand A (43.117), although both are below the desirable >70 for CNS targets.

**Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and suggests poor permeability. However, the scale is not defined, so it's hard to interpret.

**Aqueous Solubility:** Both ligands have negative solubility values, which is also unusual.

**hERG:** Both ligands have very low hERG inhibition liability (0.054 and 0.112), which is positive.

**Microsomal Clearance:** Ligand A (-12.514) has a much lower (better) microsomal clearance than Ligand B (19.806), indicating better metabolic stability.

**In vitro Half-Life:** Ligand A (26.972) has a longer half-life than Ligand B (17.56), which is favorable.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.016 and 0.027), which is good for CNS penetration.

**Binding Affinity:** Ligand B (-8.9 kcal/mol) has a slightly better binding affinity than Ligand A (-8.2 kcal/mol). While the difference is not huge, it is meaningful.

**Overall Assessment:**

Ligand B is the stronger candidate. While its BBB penetration isn't ideal, it excels in several key areas: logP, TPSA, DILI risk, and binding affinity. Ligand A's low logP and higher DILI risk are significant drawbacks. The improved metabolic stability and half-life of Ligand A are positives, but are outweighed by the other factors.

Output:
1
2025-04-17 07:45:11,130 - INFO - Reasoning:

Let's analyze Ligand A and Ligand B based on the provided guidelines, prioritizing GPCR-specific properties (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (408.292 Da) is slightly higher than Ligand B (348.407 Da), but both are acceptable.

**TPSA:** Ligand A (70.0) is excellent for CNS penetration, well below the 90 A^2 threshold. Ligand B (109.22) is higher, but still potentially acceptable, though less ideal.

**logP:** Ligand A (2.733) is optimal. Ligand B (-0.548) is significantly lower, which could hinder membrane permeability and CNS penetration.

**H-Bond Donors/Acceptors:** Both ligands have 2 HBD and 5/6 HBA, which are within acceptable limits.

**QED:** Both ligands have good QED scores (0.658 and 0.742), indicating drug-like properties.

**DILI:** Both ligands have relatively high DILI risk (13.843 and 51.687), but Ligand A is significantly lower, suggesting a better safety profile.

**BBB:** Ligand A (23.536) has a low BBB percentile, which is a major concern for a CNS target. Ligand B (64.87) is much better, exceeding the desirable >70 threshold.

**Caco-2 Permeability:** Both have negative Caco-2 values (-5.353 and -5.198), which is unusual and suggests poor permeability. However, these values are on a log scale, so small differences can be significant.

**Aqueous Solubility:** Both ligands have negative solubility values (-3.176 and -2.494), indicating poor aqueous solubility, which could impact bioavailability.

**hERG Inhibition:** Ligand A (0.835) has a slightly higher hERG risk than Ligand B (0.079), but both are relatively low.

**Microsomal Clearance:** Ligand A (51.684) has a higher microsomal clearance than Ligand B (16.155), indicating lower metabolic stability.

**In vitro Half-Life:** Ligand B (-4.132) has a negative half-life, which is not physically possible and indicates a very short half-life. Ligand A (32.271) has a reasonable half-life.

**P-gp Efflux:** Ligand A (0.539) has lower P-gp efflux than Ligand B (0.021), which is favorable for CNS penetration.

**Binding Affinity:** Ligand A (-8.5 kcal/mol) has a significantly stronger binding affinity than Ligand B (-7.8 kcal/mol). This 1.5 kcal/mol difference is substantial and could outweigh some of the ADME drawbacks.

**Overall Assessment:**

Ligand A has a much stronger binding affinity and a better DILI profile, but suffers from poor BBB penetration and higher metabolic clearance. Ligand B has excellent BBB penetration and lower P-gp efflux, but a weaker binding affinity and a problematic negative in vitro half-life.

Given the importance of BBB penetration for a CNS target like DRD2, Ligand B initially appears more promising. However, the negative half-life is a critical flaw. A negative half-life is not realistic and suggests a significant issue with the experimental data or the molecule's inherent instability. Furthermore, the substantial affinity difference of 0.7 kcal/mol in favor of Ligand A is significant. While Ligand A's BBB is suboptimal, it might be improved through structural modifications. The poor half-life of Ligand B is a more fundamental issue that is harder to fix.

Therefore, despite the BBB concern, Ligand A is the more viable candidate due to its superior affinity and more reasonable ADME profile (excluding BBB).

Output:
1
2025-04-17 07:45:11,131 - INFO - Reasoning:

Let's analyze Ligand A and Ligand B against the provided guidelines, prioritizing GPCR-specific properties (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (368.543 and 372.466 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (66.48) is significantly better than Ligand B (104.21). For CNS targets, TPSA should be <= 90, and A is comfortably within this range, while B exceeds it. This is a substantial advantage for A.

**logP:** Both ligands have good logP values (2.49 and 2.177), falling within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A (HBD=1, HBA=4) is preferable to Ligand B (HBD=3, HBA=6) as it has fewer hydrogen bond donors and acceptors, potentially improving permeability.

**QED:** Both ligands have acceptable QED values (0.75 and 0.649), indicating reasonable drug-likeness.

**DILI:** Ligand A (21.132) has a much lower DILI risk than Ligand B (61.342). This is a significant advantage for A.

**BBB:** Ligand A (54.827) has a lower BBB penetration percentile than Ligand B (65.529). While both are below the desirable >70 for CNS targets, B is better.

**Caco-2 Permeability:** Ligand A (-5.212) has a worse Caco-2 value than Ligand B (-4.876). Higher values are better, so B is slightly preferable.

**Aqueous Solubility:** Ligand A (-3.029) has a slightly better solubility than Ligand B (-4.363). Higher values are better.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.235 and 0.311).

**Microsomal Clearance:** Ligand A (36.282) has lower microsomal clearance than Ligand B (66.233), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (-19.318) has a worse in vitro half-life than Ligand B (-28.196). Higher values are better.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.134 and 0.331).

**Binding Affinity:** Both ligands have very similar and excellent binding affinities (-8.3 and -8.2 kcal/mol). The difference is negligible.

**Overall Assessment:**

Ligand A is significantly better overall. While Ligand B has a slightly better BBB and Caco-2 permeability, Ligand A excels in TPSA, DILI risk, and metabolic stability (Cl_mic). The lower TPSA and DILI risk are particularly important, and the similar binding affinities make these ADME properties the deciding factors. The CNS target prioritization reinforces the importance of TPSA and BBB, and A is better on TPSA.

Output:
0
2025-04-17 07:45:11,131 - INFO - Batch 391 complete. Total preferences: 6256
2025-04-17 07:45:11,131 - INFO - Processing batch 392/512...
2025-04-17 07:45:53,978 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (359.5 and 354.4 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (82.7) is better than Ligand B (85.7). Both are below the 90 A^2 threshold for CNS targets, but A is closer to the optimal range.

**3. logP:** Ligand A (2.532) is within the optimal 1-3 range. Ligand B (-0.109) is significantly lower, potentially hindering membrane permeability.

**4. H-Bond Donors:** Ligand A (3) is acceptable, while Ligand B (1) is also good.

**5. H-Bond Acceptors:** Ligand A (5) is acceptable, and Ligand B (6) is also within the limit.

**6. QED:** Both ligands have similar QED values (0.733 and 0.704), indicating good drug-like properties.

**7. DILI:** Ligand A (64.8%) has a higher DILI risk than Ligand B (48.3%). This is a negative for Ligand A.

**8. BBB:** Ligand B (83.8%) has a significantly higher BBB penetration percentile than Ligand A (68.3%). This is a crucial advantage for a CNS target like DRD2.

**9. Caco-2 Permeability:** Ligand A (-5.859) has poor Caco-2 permeability, while Ligand B (-4.493) is also poor, but slightly better.

**10. Aqueous Solubility:** Ligand A (-2.202) has poor aqueous solubility, while Ligand B (-1.76) is also poor.

**11. hERG Inhibition:** Ligand A (0.547) has a slightly higher hERG inhibition liability than Ligand B (0.151). This is a negative for Ligand A.

**12. Microsomal Clearance:** Ligand A (0.268) has a much lower microsomal clearance than Ligand B (3.259), indicating better metabolic stability.

**13. In vitro Half-Life:** Ligand A (16.0) has a longer half-life than Ligand B (-19.6). This is a positive for Ligand A.

**14. P-gp Efflux:** Ligand A (0.362) has lower P-gp efflux liability than Ligand B (0.031), which is favorable for CNS penetration.

**15. Binding Affinity:** Ligand B (-8.3 kcal/mol) has a significantly stronger binding affinity than Ligand A (-0.0 kcal/mol). This is a major advantage for Ligand B.

**Overall Assessment:**

While Ligand A has better metabolic stability (lower Cl_mic) and P-gp efflux, Ligand B excels in the most critical areas for a CNS GPCR target: **BBB penetration and binding affinity**. The significantly stronger binding affinity of Ligand B (-8.3 kcal/mol vs -0.0 kcal/mol) is a decisive factor, even considering its slightly higher DILI risk. The superior BBB penetration (83.8% vs 68.3%) further strengthens the case for Ligand B. The logP value for Ligand A is also concerning.

Output:
1
2025-04-17 07:45:53,978 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (372.284 and 358.404 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (32.34) is significantly better than Ligand B (49.41). For CNS targets, we want TPSA <= 90, and ideally closer to 60. Ligand A is much closer to this ideal.

**3. logP:** Both ligands have good logP values (3.601 and 2.44), falling within the optimal 1-3 range.

**4. H-Bond Donors:** Both have 1 HBD, which is acceptable.

**5. H-Bond Acceptors:** Both have 2 HBA, which is acceptable.

**6. QED:** Both ligands have similar QED values (0.823 and 0.793), indicating good drug-likeness.

**7. DILI:** Both ligands have low DILI risk (30.167 and 27.491), which is favorable.

**8. BBB:** Ligand A (92.827) has a significantly higher BBB percentile than Ligand B (87.01).  For a CNS target like DRD2, >70 is desirable, and A is closer to 100.

**9. Caco-2 Permeability:** Both have negative Caco-2 values (-4.784 and -4.615). This is unusual and suggests poor permeability. However, the values are very similar.

**10. Aqueous Solubility:** Both have negative solubility values (-3.452 and -3.676). This is also unusual and suggests poor solubility. Again, the values are very similar.

**11. hERG:** Both ligands have low hERG risk (0.932 and 0.45), which is good.

**12. Microsomal Clearance:** Ligand A (-15.687) has *much* lower (better) microsomal clearance than Ligand B (19.383). Lower clearance indicates greater metabolic stability.

**13. In vitro Half-Life:** Ligand A (4.125) has a lower half-life than Ligand B (11.549). This is a drawback for Ligand A.

**14. P-gp Efflux:** Both ligands have low P-gp efflux liability (0.2 and 0.172), which is good for CNS penetration.

**15. Binding Affinity:** Ligand A (-9.1) has a slightly better binding affinity than Ligand B (-8.3). While both are good, a 0.8 kcal/mol difference is noticeable.

**Overall Assessment:**

Ligand A is superior due to its significantly better TPSA, BBB penetration, and microsomal clearance. While its half-life is shorter, the improved CNS penetration and metabolic stability are more crucial for a DRD2 ligand. The slight advantage in binding affinity further supports choosing Ligand A. The similar poor solubility and Caco-2 permeability are concerns for both, but can be addressed with formulation strategies.

Output:
1
2025-04-17 07:45:53,979 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (366.571 and 352.431 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (58.2) is excellent, well below the 90 A^2 threshold for CNS targets. Ligand B (81.01) is still reasonable but higher, potentially impacting BBB penetration.

**logP:** Ligand A (3.81) is at the upper end of the optimal range (1-3), but acceptable. Ligand B (1.785) is a bit low, potentially hindering membrane permeability.

**H-Bond Donors/Acceptors:** Ligand A (2 HBD, 3 HBA) and Ligand B (1 HBD, 5 HBA) both have acceptable numbers of H-bond donors and acceptors.

**QED:** Both ligands have good QED scores (0.642 and 0.771), indicating drug-like properties.

**DILI:** Ligand A (19.271) has a significantly lower DILI risk than Ligand B (40.869). This is a substantial advantage.

**BBB:** Ligand A (70.415) has a better BBB percentile than Ligand B (65.452), though both are reasonably good.

**Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and suggests a potential issue with the data or modeling. However, the values are similar.

**Aqueous Solubility:** Both have negative solubility values, which is also unusual. Again, the values are similar.

**hERG:** Both ligands have very low hERG risk (0.379 and 0.232).

**Microsomal Clearance:** Ligand A (82.533) has higher microsomal clearance than Ligand B (24.962), indicating faster metabolism and potentially lower *in vivo* exposure.

**In vitro Half-Life:** Ligand B (19.874) has a longer half-life than Ligand A (10.375).

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.146 and 0.065).

**Binding Affinity:** Ligand A (-7.5 kcal/mol) has a slightly better binding affinity than Ligand B (-6.9 kcal/mol). While the difference is less than the 1.5 kcal/mol threshold, it's still a positive factor.

**Overall Assessment:**

Ligand A is the better candidate. It has a significantly lower DILI risk, a better TPSA, and slightly better binding affinity. While its microsomal clearance is higher, the other advantages, particularly the lower DILI and better BBB, outweigh this drawback. Both ligands have unusual solubility and Caco-2 permeability values that would require further investigation, but the relative ranking remains clear.

Output:
1
2025-04-17 07:45:53,979 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (353.419 Da) is slightly lower, which is generally favorable for permeability. Ligand B (399.292 Da) is still acceptable.

**TPSA:** Ligand A (104.81) is better than Ligand B (61.88) as it is closer to the threshold for CNS targets (<90). Ligand B is quite low, which might suggest a lack of necessary interactions.

**logP:** Ligand A (-0.183) is suboptimal, being below the preferred range of 1-3. This could hinder membrane permeability. Ligand B (4.207) is high, potentially leading to solubility issues and off-target interactions, but is within the acceptable range.

**H-Bond Donors/Acceptors:** Ligand A has 2 HBD and 5 HBA, which are reasonable. Ligand B has 1 HBD and 3 HBA, also acceptable.

**QED:** Both ligands have good QED scores (Ligand A: 0.509, Ligand B: 0.676), indicating drug-like properties.

**DILI:** Ligand A (36.758) has a lower DILI risk than Ligand B (64.172), which is a significant advantage.

**BBB:** Ligand A (36.603) has a low BBB penetration percentile, which is a major drawback for a CNS target like DRD2. Ligand B (65.723) is better, but still not ideal (aim for >70).

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.013 and -5.416) which is unusual and suggests poor permeability.

**Aqueous Solubility:** Both ligands have negative solubility values (-1.721 and -3.604) which is also unusual and suggests poor solubility.

**hERG Inhibition:** Ligand A (0.058) has a very low hERG risk, which is excellent. Ligand B (0.845) has a higher, but still moderate, hERG risk.

**Microsomal Clearance:** Ligand A (32.488) has lower microsomal clearance than Ligand B (66.826), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (-3.357) has a negative half-life, which is not possible. Ligand B (72.503) has a long half-life, which is a positive attribute.

**P-gp Efflux:** Ligand A (0.018) has very low P-gp efflux, which is beneficial for CNS penetration. Ligand B (0.436) has moderate P-gp efflux.

**Binding Affinity:** Ligand B (-7.9 kcal/mol) has a significantly stronger binding affinity than Ligand A (-7.1 kcal/mol). This 1.8 kcal/mol difference is substantial and could outweigh some of the ADME drawbacks.

**Overall Assessment:**

Ligand A has better safety profiles (DILI, hERG) and metabolic stability, and P-gp efflux. However, its low logP and very poor BBB penetration are critical issues for a CNS target. The negative half-life is also a major concern.

Ligand B has a much stronger binding affinity, better BBB penetration (though still not optimal), and a longer half-life. While its logP is high and DILI risk is elevated, the strong affinity is a significant advantage.

Considering the GPCR-specific priorities, the binding affinity is paramount. The stronger affinity of Ligand B, combined with its better (though not perfect) BBB penetration, makes it the more promising candidate, despite its other drawbacks. Further optimization could address the logP and DILI concerns.

Output:
1
2025-04-17 07:45:53,979 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 drug candidates, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (377.46 and 359.54 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (78.51) is significantly better than Ligand B (38.13). For CNS targets, TPSA should be <= 90, and lower is preferred. Ligand B is borderline, while A is well within the desired range.

**logP:** Ligand A (1.174) is optimal (1-3), while Ligand B (4.793) is high. High logP can lead to solubility issues and off-target interactions.

**H-Bond Donors/Acceptors:** Ligand A (HBD=2, HBA=4) and Ligand B (HBD=0, HBA=4) both have acceptable numbers of H-bond donors and acceptors.

**QED:** Both ligands have good QED scores (A: 0.561, B: 0.72), indicating good drug-like properties.

**DILI:** Both have low DILI risk (A: 35.05, B: 29.24), which is positive.

**BBB:** Ligand B (83.37) has a considerably better BBB penetration percentile than Ligand A (69.79). A value >70 is desirable for CNS targets.

**Caco-2 Permeability:** Ligand A (-5.322) has poor Caco-2 permeability, while Ligand B (-4.781) is also poor, but slightly better.

**Aqueous Solubility:** Ligand A (-2.04) has better aqueous solubility than Ligand B (-4.671).

**hERG Inhibition:** Ligand A (0.246) has a much lower hERG inhibition liability than Ligand B (0.809), which is a significant advantage.

**Microsomal Clearance:** Ligand B (89.75) has a much higher microsomal clearance than Ligand A (22.56), indicating lower metabolic stability.

**In vitro Half-Life:** Ligand B (24.65) has a longer in vitro half-life than Ligand A (-6.521).

**P-gp Efflux:** Ligand A (0.029) exhibits significantly lower P-gp efflux than Ligand B (0.778), which is crucial for CNS penetration.

**Binding Affinity:** Ligand A (-7.4) has a slightly better binding affinity than Ligand B (-0.0). This is a substantial difference.

**Overall Assessment:**

While Ligand B has superior BBB penetration and a longer half-life, Ligand A is significantly better in most other critical parameters for a CNS-targeting GPCR drug. Specifically, Ligand A has a much better logP, lower hERG risk, lower P-gp efflux, better solubility, and a superior binding affinity. The lower TPSA of Ligand A is also favorable. The poor Caco-2 permeability of both is a concern, but can potentially be addressed with formulation strategies. The difference in binding affinity (-7.4 vs -0.0) is a major advantage for Ligand A and likely outweighs the slightly lower BBB score.

Output:
1
2025-04-17 07:45:53,979 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight (MW):** Both ligands (347.463 and 365.861 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (79.38) is better than Ligand B (81.67). Both are below the 90 A^2 threshold desirable for CNS targets, but A is closer to the optimal range.

**3. logP:** Both ligands have good logP values (1.666 and 1.151), falling within the 1-3 range.

**4. H-Bond Donors (HBD):** Both ligands are acceptable (2 and 3 respectively), being less than 5.

**5. H-Bond Acceptors (HBA):** Both ligands are acceptable (6 and 4 respectively), being less than 10.

**6. QED:** Both ligands have similar and good QED values (0.745 and 0.706), indicating good drug-like properties.

**7. DILI:** Both ligands have low DILI risk (42.575 and 41.877 percentiles), which is favorable.

**8. BBB:** This is a crucial parameter for a CNS target like DRD2. Ligand A has a significantly better BBB penetration percentile (82.823) compared to Ligand B (46.646). This is a major advantage for Ligand A.

**9. Caco-2 Permeability:** Both have negative values, indicating poor permeability. Ligand A (-5.028) is slightly better than Ligand B (-5.206).

**10. Aqueous Solubility:** Both have negative values, indicating poor solubility. Ligand A (-2.269) is slightly better than Ligand B (-2.711).

**11. hERG Inhibition:** Both ligands have low hERG inhibition liability (0.713 and 0.208), which is good.

**12. Microsomal Clearance (Cl_mic):** Ligand B (19.136) has a significantly lower Cl_mic than Ligand A (43.037), suggesting better metabolic stability.

**13. In vitro Half-Life (t1/2):** Ligand B (25.685) has a longer half-life than Ligand A (13.319), which is desirable.

**14. P-gp Efflux:** Both ligands have low P-gp efflux liability (0.06 and 0.066), which is favorable for CNS penetration.

**15. Binding Affinity:** Ligand A (-7.9 kcal/mol) has a slightly better binding affinity than Ligand B (-7.5 kcal/mol). While both are excellent, the 0.4 kcal/mol difference is noteworthy.

**Overall Assessment:**

Ligand A is the better candidate. The significantly higher BBB penetration (82.823 vs 46.646) is critical for a CNS-targeting drug. While Ligand B has better metabolic stability (lower Cl_mic and longer t1/2), the superior BBB score and slightly better binding affinity of Ligand A outweigh these advantages. The TPSA is also slightly better for Ligand A.

Output:
1
2025-04-17 07:45:53,979 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (403.28 Da) is slightly higher than Ligand B (334.423 Da), but both are acceptable.

**2. TPSA:** Both ligands have TPSA values below 90, which is favorable for CNS penetration. Ligand A (64.16) is higher than Ligand B (58.43), but both are good.

**3. logP:** Both ligands have logP values within the optimal range (1-3). Ligand A (3.571) is slightly higher than Ligand B (3.131), which could potentially lead to slightly reduced solubility, but it's not a major concern.

**4. H-Bond Donors:** Ligand A has 0 HBD, while Ligand B has 2. Both are within the acceptable limit of <=5.

**5. H-Bond Acceptors:** Ligand A has 5 HBA, while Ligand B has 3. Both are within the acceptable limit of <=10.

**6. QED:** Both ligands have good QED values (A: 0.654, B: 0.77), indicating good drug-like properties. Ligand B is slightly better.

**7. DILI:** Both ligands have acceptable DILI risk (A: 56.689, B: 53.276), below the 60 threshold.

**8. BBB:** Both ligands have excellent BBB penetration (A: 71.384, B: 76.154), exceeding the desirable >70 threshold. Ligand B is slightly better.

**9. Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and suggests poor permeability. However, the scale is not specified, so it's hard to interpret.

**10. Aqueous Solubility:** Both have negative solubility values, which is also unusual. Again, the scale is not specified, making interpretation difficult.

**11. hERG Inhibition:** Both ligands have low hERG inhibition risk (A: 0.724, B: 0.737), which is good.

**12. Microsomal Clearance:** Ligand A has higher microsomal clearance (86.659) than Ligand B (44.532), indicating lower metabolic stability. This is a significant drawback for Ligand A.

**13. In vitro Half-Life:** Ligand B has a significantly longer in vitro half-life (9.938 hours) compared to Ligand A (-10.32 hours). The negative value for A is concerning.

**14. P-gp Efflux:** Both ligands have low P-gp efflux liability (A: 0.532, B: 0.334), which is favorable for CNS exposure. Ligand B is slightly better.

**15. Binding Affinity:** Ligand B has a significantly stronger binding affinity (-11.1 kcal/mol) than Ligand A (-8.4 kcal/mol). This >1.5 kcal/mol difference in affinity is a major advantage for Ligand B, potentially outweighing any minor ADME drawbacks.

**Overall Assessment:**

Ligand B is the superior candidate. While both have acceptable properties regarding MW, TPSA, logP, DILI, BBB, and hERG, Ligand B demonstrates significantly better metabolic stability (lower Cl_mic, longer t1/2), P-gp efflux, and, most importantly, a much stronger binding affinity. The negative values for Caco-2 and solubility are concerning for both, but the substantial affinity advantage of Ligand B, combined with its better ADME profile, makes it the more promising drug candidate.

Output:
1
2025-04-17 07:45:53,980 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (345.443 and 356.813 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (61.88) is better than Ligand B (67.23) as both are below the 90 A^2 threshold for CNS targets, but lower is preferred.

**3. logP:** Ligand A (1.17) is within the optimal 1-3 range, while Ligand B (2.937) is closer to the upper limit. Both are acceptable, but A is slightly favored.

**4. H-Bond Donors:** Both ligands have 1 HBD, which is within the acceptable limit of <=5.

**5. H-Bond Acceptors:** Ligand A has 5 HBAs, and Ligand B has 4. Both are below the acceptable limit of <=10.

**6. QED:** Both ligands have good QED scores (0.594 and 0.781), indicating drug-like properties. Ligand B is slightly better.

**7. DILI:** Ligand A (26.095) has a significantly lower DILI risk than Ligand B (89.608). This is a major advantage for Ligand A.

**8. BBB:** Ligand B (78.79) has a better BBB penetration percentile than Ligand A (67.08). While both are reasonably good, B is preferable for a CNS target like DRD2.

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.88 and -4.879). This is unusual and suggests poor permeability.

**10. Aqueous Solubility:** Ligand A (-0.706) has slightly better solubility than Ligand B (-4.2).

**11. hERG Inhibition:** Both ligands have low hERG inhibition risk (0.521 and 0.547).

**12. Microsomal Clearance:** Ligand A (42.169) has lower microsomal clearance than Ligand B (70.94), indicating better metabolic stability.

**13. In vitro Half-Life:** Ligand B (112.977) has a significantly longer in vitro half-life than Ligand A (-25.995). This is a substantial advantage for Ligand B.

**14. P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.02 and 0.616).

**15. Binding Affinity:** Ligand B (-9.3) has a significantly stronger binding affinity than Ligand A (-8). This is a crucial factor.

**Overall Assessment:**

Ligand B has a stronger binding affinity and a longer half-life, which are highly desirable. It also exhibits better BBB penetration. However, it has a significantly higher DILI risk. Ligand A has a much lower DILI risk and better metabolic stability, but its binding affinity is weaker and BBB penetration is lower.

Given the importance of binding affinity for GPCRs, and the fact that the difference in affinity (-9.3 vs -8) is substantial (>1.5 kcal/mol), I believe Ligand B is the more promising candidate *despite* the higher DILI risk. The DILI risk could potentially be mitigated through structural modifications during lead optimization. The stronger binding is more difficult to achieve through later-stage modifications.

Output:
1
2025-04-17 07:45:53,980 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B based on the provided guidelines, prioritizing GPCR-specific properties (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (361.433 and 359.535 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (64.09) is significantly better than Ligand B (29.54). For CNS targets, TPSA should be <=90, both are well within this range, but A is closer to the optimal range.

**logP:** Ligand A (0.794) is slightly below the optimal 1-3 range, but still acceptable. Ligand B (4.284) is high, potentially leading to solubility issues and off-target interactions.

**H-Bond Donors/Acceptors:** Ligand A has 1 HBD and 4 HBA, while Ligand B has 0 HBD and 3 HBA. Both are within acceptable limits.

**QED:** Ligand A (0.787) has a better QED score than Ligand B (0.681), indicating better overall drug-likeness.

**DILI:** Ligand A (10.857) has a much lower DILI risk than Ligand B (26.638). This is a significant advantage for Ligand A.

**BBB:** Ligand A (72.16) is good, but Ligand B (83.831) is excellent, exceeding the desirable >70 threshold for CNS targets. This is a strong point for Ligand B.

**Caco-2 Permeability:** Ligand A (-4.64) is poor, while Ligand B (-5.172) is also poor. Both are negative, indicating low permeability.

**Aqueous Solubility:** Ligand A (-0.384) is slightly better than Ligand B (-4.863), but both are poor.

**hERG Inhibition:** Ligand A (0.598) has a slightly higher hERG risk than Ligand B (0.767), but both are relatively low.

**Microsomal Clearance:** Ligand A (-7.139) indicates very low clearance and high metabolic stability, a major advantage. Ligand B (125.288) has high clearance, suggesting rapid metabolism.

**In vitro Half-Life:** Ligand A (-20.961) suggests a very long half-life, which is desirable. Ligand B (4.025) has a short half-life.

**P-gp Efflux:** Ligand A (0.029) has very low P-gp efflux, which is favorable for CNS penetration. Ligand B (0.736) has moderate P-gp efflux.

**Binding Affinity:** Ligand B (-8.2 kcal/mol) has a significantly stronger binding affinity than Ligand A (-7.1 kcal/mol). This is a substantial advantage for Ligand B, potentially outweighing some ADME drawbacks.

**Overall Assessment:**

Ligand A excels in metabolic stability (low Cl_mic, long t1/2), low DILI risk, and low P-gp efflux. However, it suffers from poor Caco-2 permeability and a weaker binding affinity.

Ligand B has excellent BBB penetration and a much stronger binding affinity, but it has a high logP, higher DILI risk, and rapid metabolism.

Given the GPCR target and the importance of CNS penetration, the stronger binding affinity of Ligand B and its excellent BBB penetration are crucial. While the higher logP and DILI risk are concerns, the significant affinity advantage (-1.1 kcal/mol difference) is likely to outweigh these drawbacks, especially if further optimization can address the logP and DILI issues.

Output:
1
2025-04-17 07:45:53,980 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B against the provided guidelines, prioritizing GPCR-specific properties (BBB, logP, Pgp, TPSA, and affinity) for DRD2.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (427.32 Da) is higher, but still acceptable. Ligand B (344.375 Da) is slightly lower, potentially aiding permeability.

**TPSA:** Ligand A (74.45) is excellent for CNS penetration, well below the 90 A^2 threshold. Ligand B (106.15) is higher, but still reasonable.

**logP:** Ligand A (3.726) is optimal. Ligand B (0.777) is low, potentially hindering membrane permeability and CNS entry.

**H-Bond Donors/Acceptors:** Both ligands have acceptable HBD (0/1) and HBA (7/7) counts.

**QED:** Both ligands have good QED scores (0.624 and 0.776), indicating drug-likeness.

**DILI:** Both ligands have relatively high DILI risk (77.588 and 72.354), but are not dramatically concerning.

**BBB:** Ligand A (76.231) has a very good BBB percentile, highly desirable for a CNS target like DRD2. Ligand B (47.654) is significantly lower, raising concerns about CNS exposure.

**Caco-2 Permeability:** Both have negative Caco-2 values which is unusual and likely indicates a data error. Assuming these are percentile scores, we can assume they are low permeability.

**Aqueous Solubility:** Both have negative solubility values which is also unusual and likely indicates a data error.

**hERG Inhibition:** Ligand A (0.257) shows very low hERG inhibition risk, excellent. Ligand B (0.029) is also very low.

**Microsomal Clearance:** Ligand A (87.948) has higher clearance, suggesting lower metabolic stability. Ligand B (19.53) has much lower clearance, indicating better metabolic stability.

**In vitro Half-Life:** Ligand A (8.589) has a moderate half-life. Ligand B (-16.897) has a very short (and likely erroneous) half-life.

**P-gp Efflux:** Ligand A (0.53) has moderate P-gp efflux liability. Ligand B (0.016) has very low P-gp efflux, which is favorable for CNS penetration.

**Binding Affinity:** Both ligands have excellent binding affinity (-8.3 and -8.2 kcal/mol), with a negligible difference.

**Overall Assessment:**

Considering the GPCR-specific priorities, Ligand A is significantly more promising. Its superior BBB penetration, optimal logP, and low hERG risk outweigh its slightly higher molecular weight and clearance. While Ligand B has better metabolic stability and lower P-gp efflux, its poor logP and significantly lower BBB penetration are major drawbacks for a CNS-targeted drug. The negative values for Caco-2 and Solubility are concerning and suggest potential data quality issues, but don't dramatically alter the overall assessment given the strong differences in BBB and logP.

Output:
1
2025-04-17 07:45:53,980 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (356.451 and 361.389 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (83.98) is excellent, well below the 90 A^2 threshold for CNS targets. Ligand B (112.73) is still reasonable but less optimal, exceeding the preferred range.

**logP:** Ligand A (3.65) is within the optimal 1-3 range. Ligand B (0.177) is significantly low, which could hinder membrane permeability and potentially reduce CNS penetration despite a good BBB score.

**H-Bond Donors/Acceptors:** Ligand A has 2 HBD and 5 HBA, both acceptable. Ligand B has 3 HBD and 4 HBA, also acceptable.

**QED:** Ligand A (0.879) has a very strong drug-like profile. Ligand B (0.535) is acceptable, but less ideal than Ligand A.

**DILI:** Ligand A (81.311) has a moderate DILI risk, but still acceptable. Ligand B (34.82) has a very low DILI risk, which is a significant advantage.

**BBB:** Ligand A (82.513) has good BBB penetration. Ligand B (57.076) is lower, but still potentially acceptable, though less desirable for a CNS target.

**Caco-2:** Both ligands have negative Caco-2 values (-5.09 and -5.228), which is unusual and suggests poor permeability. This is a concern for both.

**Solubility:** Both ligands have negative solubility values (-4.501 and -2.163), indicating very poor aqueous solubility. This is a significant drawback for both.

**hERG:** Both ligands have low hERG inhibition liability (0.276 and 0.31), which is positive.

**Microsomal Clearance:** Ligand A (48.005) has moderate clearance, while Ligand B (17.033) has low clearance, suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (52.731) has a reasonable half-life. Ligand B (-17.592) has a negative half-life, which is impossible and indicates a problem with the data or the molecule's stability.

**Pgp Efflux:** Both ligands have very low Pgp efflux liability (0.358 and 0.042), which is favorable for CNS penetration.

**Binding Affinity:** Ligand B (-7.6 kcal/mol) has a significantly stronger binding affinity than Ligand A (0.0 kcal/mol). This is a substantial advantage.

**Overall Assessment:**

Ligand B has a much stronger binding affinity, lower DILI risk, and better metabolic stability. However, it suffers from a very low logP and a nonsensical negative in vitro half-life. Ligand A has a better overall ADME profile (better TPSA, QED, and a reasonable half-life), but its binding affinity is extremely weak.

Given the importance of affinity for GPCR ligands, and the fact that a >1.5 kcal/mol advantage can outweigh ADME drawbacks, Ligand B is the more promising candidate *if* the negative half-life can be resolved (likely a data error). The low logP is a concern, but could potentially be addressed through structural modifications. The poor solubility and Caco-2 values are concerning for both, but solubility can sometimes be improved with formulation strategies.

Output:
1
2025-04-17 07:45:53,981 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (336.355 Da) is slightly lower, which could be beneficial for permeability.

**TPSA:** Ligand A (101.28) is better than Ligand B (67.87) as it is closer to the ideal range for CNS targets (<=90). Ligand B is quite low, which might suggest a lack of necessary interactions.

**logP:** Ligand B (2.219) is optimal, while Ligand A (0.617) is below the preferred range. This could hinder membrane permeability for Ligand A.

**H-Bond Donors/Acceptors:** Ligand A has 2 HBD and 6 HBA, while Ligand B has 1 HBD and 4 HBA. Both are within acceptable limits.

**QED:** Both ligands have similar QED values (0.683 and 0.61), indicating reasonable drug-likeness.

**DILI:** Ligand A (85.072) has a higher DILI risk than Ligand B (10.237). This is a significant drawback for Ligand A.

**BBB:** Ligand B (68.205) has a better BBB percentile than Ligand A (39.473). For a CNS target like DRD2, this is crucial.

**Caco-2 Permeability:** Ligand A (-5.322) has poor Caco-2 permeability, while Ligand B (-4.533) is slightly better.

**Aqueous Solubility:** Ligand A (-2.687) has poor aqueous solubility, while Ligand B (-1.496) is slightly better.

**hERG Inhibition:** Ligand A (0.124) has a lower hERG inhibition risk than Ligand B (0.533), which is a positive.

**Microsomal Clearance:** Ligand B (36.421) has a lower microsomal clearance than Ligand A (9.187), indicating better metabolic stability.

**In vitro Half-Life:** Ligand A (9.273) has a longer in vitro half-life than Ligand B (-3.653).

**P-gp Efflux:** Ligand A (0.078) has lower P-gp efflux than Ligand B (0.046), which is favorable for CNS penetration.

**Binding Affinity:** Ligand A (-10.6 kcal/mol) has significantly stronger binding affinity than Ligand B (-7.0 kcal/mol). This is a substantial advantage.

**Overall Assessment:**

Ligand A has a much stronger binding affinity and better P-gp efflux, but suffers from poor solubility, permeability, and a higher DILI risk. Its BBB penetration is also concerningly low. Ligand B, while having weaker affinity, exhibits a much more favorable ADME profile, particularly regarding BBB penetration, DILI risk, and metabolic stability.

Given the GPCR-specific priorities, BBB penetration is critical for CNS targets. The significantly better BBB value of Ligand B, combined with its lower DILI risk and better metabolic stability, outweighs the affinity difference. While the affinity of Ligand A is excellent, its poor ADME properties make it less likely to succeed as a drug candidate.

Output:
1
2025-04-17 07:45:53,981 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (348.539 and 362.583 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (88.75) is excellent for CNS penetration, being well below the 90 A^2 threshold. Ligand B (23.55) is even better, indicating potentially improved BBB penetration.

**3. logP:** Both ligands (4.32 and 4.84) are slightly above the optimal 1-3 range, but still acceptable. Ligand B is a bit higher, which could slightly increase off-target interactions, but isn't a major concern.

**4. H-Bond Donors:** Ligand A has 3 HBDs, which is good. Ligand B has 0, which is also acceptable.

**5. H-Bond Acceptors:** Ligand A has 6 HBAs, within the acceptable limit. Ligand B has 3 HBAs, also good.

**6. QED:** Both ligands have good QED scores (0.583 and 0.693), indicating drug-like properties.

**7. DILI:** Ligand A (36.448) has a slightly higher DILI risk than Ligand B (11.128), which is a significant advantage for Ligand B.

**8. BBB:** Both ligands have excellent BBB penetration (92.168 and 94.261), exceeding the desirable >70 threshold. Ligand B is marginally better.

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.935 and -5.058). This is unusual and suggests poor permeability. However, these values are on a log scale, and negative values aren't necessarily disqualifying, especially if other properties are favorable.

**10. Aqueous Solubility:** Both ligands have very poor aqueous solubility (-5.669 and -3.857). This is a significant drawback for both, potentially hindering formulation and bioavailability.

**11. hERG Inhibition:** Both ligands have low hERG inhibition risk (0.781 and 0.925).

**12. Microsomal Clearance:** Both ligands have similar microsomal clearance values (80.34 and 82.298), indicating similar metabolic stability.

**13. In vitro Half-Life:** Ligand A (34.98) has a longer half-life than Ligand B (11.313). This is a positive for Ligand A.

**14. P-gp Efflux:** Both ligands have low P-gp efflux liability (0.139 and 0.837), which is good for CNS exposure. Ligand A is better.

**15. Binding Affinity:** Ligand B (-7.5 kcal/mol) has a significantly stronger binding affinity than Ligand A (-8.2 kcal/mol). This is a crucial advantage, as a >1.5 kcal/mol difference can outweigh other concerns.

**Overall Assessment:**

While both ligands have issues with solubility and Caco-2 permeability, Ligand B stands out due to its significantly stronger binding affinity (-7.5 vs -8.2 kcal/mol) and lower DILI risk. The slightly better BBB penetration and acceptable logP also contribute to its favorability. The longer half-life of Ligand A is a plus, but the affinity difference is substantial. Given the GPCR target and the importance of potency, Ligand B is the more promising candidate.

Output:
1
2025-04-17 07:45:53,981 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (361.511 and 352.475 Da) fall within the ideal range of 200-500 Da.

**TPSA:** Ligand A (54.34) is significantly better than Ligand B (67.87). For CNS targets, we want TPSA <= 90, and ideally closer to 60. Ligand A is much closer to this ideal.

**logP:** Both ligands have acceptable logP values (2.929 and 1.441), falling within the 1-3 range. Ligand A is slightly better.

**H-Bond Donors/Acceptors:** Both have 1 HBD and a reasonable number of HBAs (3 and 4 respectively), satisfying the <=5 and <=10 rules.

**QED:** Ligand A (0.894) has a much higher QED score than Ligand B (0.504), indicating better overall drug-likeness.

**DILI:** Ligand A (47.15) has a higher DILI risk than Ligand B (29.74), but both are below the concerning threshold of 60.

**BBB:** This is crucial for a CNS target like DRD2. Ligand A (93.37) has excellent BBB penetration, while Ligand B (54.634) is considerably lower.

**Caco-2 Permeability:** Both have negative values, which is unusual and likely indicates a scale where lower values represent lower permeability. However, the magnitude of the negative value for Ligand A (-4.585) is worse than for Ligand B (-4.402).

**Aqueous Solubility:** Both have negative values, again likely representing a scale where lower values mean lower solubility. Ligand A (-3.098) is slightly worse than Ligand B (-1.737).

**hERG:** Ligand A (0.728) has a slightly higher hERG risk than Ligand B (0.397), but both are relatively low.

**Microsomal Clearance:** Ligand B (13.282) has significantly lower microsomal clearance than Ligand A (59.537), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand B (-3.623) has a negative half-life, which is impossible. This is a significant red flag. Ligand A (22.202) has a reasonable half-life.

**P-gp Efflux:** Ligand A (0.431) has a lower P-gp efflux liability than Ligand B (0.089), which is favorable for CNS penetration.

**Binding Affinity:** Ligand B (-7.5 kcal/mol) has a significantly stronger binding affinity than Ligand A (0.0 kcal/mol). This is a substantial advantage.

**Overall Assessment:**

Ligand A excels in BBB penetration, QED, and P-gp efflux, all critical for CNS GPCR targeting. However, its metabolic stability (high Cl_mic) is a concern, and its binding affinity is very weak.

Ligand B has a much stronger binding affinity, better metabolic stability, and lower DILI risk. However, its BBB penetration is poor, and its QED is only marginally acceptable. The negative half-life is a major issue.

Despite the superior binding affinity of Ligand B, the negative half-life is a showstopper. It suggests a potential issue with the data or a highly unstable compound. Ligand A, while having weaker binding, has a much more favorable ADME profile, particularly its excellent BBB penetration, which is essential for a CNS drug.

Output:
1
2025-04-17 07:45:53,981 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (348.418 and 342.399 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (69.64) is excellent, well below the 90 A^2 threshold for CNS targets. Ligand B (95.73) is still reasonable, but closer to the 140 A^2 limit for oral absorption and slightly less favorable for CNS penetration.

**logP:** Ligand A (2.018) is optimal. Ligand B (0.874) is a bit low, potentially hindering membrane permeability.

**H-Bond Donors/Acceptors:** Ligand A (2 HBD, 3 HBA) and Ligand B (3 HBD, 5 HBA) both have acceptable numbers of hydrogen bond donors and acceptors.

**QED:** Both ligands have good QED values (0.855 and 0.751), indicating drug-like properties.

**DILI:** Ligand A (29.973) has a significantly lower DILI risk than Ligand B (47.421), which is a clear advantage.

**BBB:** Ligand A (80.574) has a much better BBB penetration percentile than Ligand B (41.14). This is *critical* for a CNS target like DRD2.

**Caco-2 Permeability:** Ligand A (-4.581) has poor Caco-2 permeability, while Ligand B (-5.23) is also poor. This is a concern for oral bioavailability, but less critical given the CNS target.

**Aqueous Solubility:** Ligand A (-2.204) and Ligand B (-1.983) both have poor aqueous solubility.

**hERG Inhibition:** Both ligands show low hERG inhibition liability (0.661 and 0.314), which is good.

**Microsomal Clearance:** Ligand A (-13.298) has a lower (better) microsomal clearance than Ligand B (-24.957), suggesting greater metabolic stability.

**In vitro Half-Life:** Ligand B (18.153 hours) has a significantly longer half-life than Ligand A (7.71 hours), which is a positive.

**P-gp Efflux:** Ligand A (0.121) has lower P-gp efflux than Ligand B (0.022), which is favorable for CNS exposure.

**Binding Affinity:** Both ligands have strong binding affinities (-8.4 and -9.4 kcal/mol). Ligand B is slightly better (-9.4 kcal/mol), but the difference is less than 1.5 kcal/mol and can be overcome by other factors.

**Overall Assessment:**

Ligand A is the stronger candidate. While Ligand B has a slightly better binding affinity and longer half-life, Ligand A excels in crucial areas for a CNS-targeting GPCR: significantly better BBB penetration, lower DILI risk, lower P-gp efflux, and a more favorable TPSA. The poor Caco-2 permeability and solubility are less concerning given the CNS focus. The better metabolic stability (lower Cl_mic) is also a plus.



Output:
0
2025-04-17 07:45:53,982 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (369.491 and 362.392 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (107.45) is higher than the preferred <90 for CNS targets, while Ligand B (78.43) is comfortably below. This favors Ligand B.

**logP:** Ligand A (0.397) is quite low, potentially hindering membrane permeability. Ligand B (1.915) is better, falling within the optimal 1-3 range. This is a significant advantage for Ligand B.

**H-Bond Donors/Acceptors:** Both have 3 HBD and are within acceptable limits. Ligand A has 7 HBA, while Ligand B has 3. Ligand B is preferable.

**QED:** Both ligands have similar QED values (0.573 and 0.577), indicating good drug-likeness.

**DILI:** Ligand A (38.736) has a slightly better DILI score than Ligand B (18.651), indicating lower potential for liver injury.

**BBB:** This is crucial for a CNS target. Ligand B (79.488) has a much higher BBB penetration percentile than Ligand A (14.192). This is a major advantage for Ligand B.

**Caco-2 Permeability:** Ligand A (-5.602) has poor Caco-2 permeability, while Ligand B (-4.916) is slightly better, but still not great.

**Aqueous Solubility:** Both have poor aqueous solubility (-1.224 and -2.527).

**hERG Inhibition:** Ligand A (0.048) has a very low hERG risk, which is excellent. Ligand B (0.336) is slightly higher, but still relatively low.

**Microsomal Clearance:** Ligand A (18.618) has lower microsomal clearance, suggesting better metabolic stability than Ligand B (24.424).

**In vitro Half-Life:** Ligand B (-8.933) has a longer in vitro half-life than Ligand A (-0.713), which is desirable.

**P-gp Efflux:** Ligand A (0.036) has lower P-gp efflux, which is beneficial for CNS penetration, while Ligand B (0.076) is slightly higher.

**Binding Affinity:** Ligand B (-8.7 kcal/mol) has a significantly stronger binding affinity than Ligand A (-6.6 kcal/mol). This >1.5 kcal/mol difference is substantial and can outweigh some ADME drawbacks.

**Overall Assessment:**

Ligand B is the stronger candidate. While Ligand A has a slightly better DILI and lower P-gp efflux, Ligand B excels in the most critical areas for a CNS GPCR target: BBB penetration, logP, and, most importantly, binding affinity. The superior affinity of Ligand B is a key driver, and its better TPSA and logP also contribute to its improved potential for brain exposure.



Output:
1
2025-04-17 07:45:53,982 - INFO - Batch 392 complete. Total preferences: 6272
2025-04-17 07:45:53,982 - INFO - Processing batch 393/512...
2025-04-17 07:46:41,992 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (337.47 and 343.35 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (42.99) is significantly better than Ligand B (78.79). For CNS targets, TPSA should be <= 90, and A is much closer to the optimal <=60 range. B is pushing the upper limit and may have reduced brain penetration.

**logP:** Ligand A (4.796) is a bit high, potentially leading to solubility issues or off-target interactions. Ligand B (2.329) is within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A (1 HBD, 4 HBA) is preferable to Ligand B (3 HBD, 4 HBA). Both are within acceptable limits, but fewer H-bonds generally improve permeability.

**QED:** Both ligands have good QED scores (0.571 and 0.641), indicating good drug-like properties.

**DILI:** Both ligands have acceptable DILI risk (49.13 and 44.63), below the 60% threshold.

**BBB:** Ligand A (40.48%) has a significantly lower BBB penetration percentile than Ligand B (29.12%). This is a critical disadvantage for a CNS target like DRD2.

**Caco-2 Permeability:** Both have negative Caco-2 values (-5.506 and -5.31). This is unusual and suggests potential issues with intestinal absorption, but the values are relatively similar.

**Aqueous Solubility:** Both ligands have very poor aqueous solubility (-3.686 and -2.913). This is a concern, but formulation strategies might mitigate it.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.935 and 0.408).

**Microsomal Clearance:** Ligand A (42.67) has a higher microsomal clearance than Ligand B (8.688), indicating faster metabolism and potentially lower in vivo exposure.

**In vitro Half-Life:** Ligand A (66.55 hours) has a significantly longer half-life than Ligand B (-5.49 hours). This is a major advantage for Ligand A.

**P-gp Efflux:** Ligand A (0.922) has a slightly higher P-gp efflux liability than Ligand B (0.068). Lower P-gp is preferred for CNS penetration, favoring Ligand B.

**Binding Affinity:** Both ligands have excellent binding affinities (-8.9 and -8.3 kcal/mol). Ligand A is slightly better (-8.9 vs -8.3), but the difference is less than the 1.5 kcal/mol threshold that would decisively favor it.

**Overall Assessment:**

Despite Ligand A's slightly better affinity and longer half-life, Ligand B is the more promising candidate. The critical factor is the significantly better BBB penetration (29.12% vs 40.48%) and lower P-gp efflux liability. While both have poor solubility and Caco-2 permeability, these can potentially be addressed with formulation strategies. Ligand A's higher logP and clearance are also less desirable. For a CNS GPCR target, brain penetration is paramount, making Ligand B the better choice.

Output:
1
2025-04-17 07:46:41,992 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 drug candidates, considering the provided guidelines and GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (347.394 and 347.39 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (98.17) is slightly above the optimal <90 for CNS targets, but still reasonable. Ligand B (71.53) is well within the desired range. This favors Ligand B.

**3. logP:** Both ligands have good logP values (2.823 and 1.146), falling within the 1-3 range. Ligand A is slightly better.

**4. H-Bond Donors:** Both have 1 HBD, which is acceptable (<=5).

**5. H-Bond Acceptors:** Ligand A has 3 HBAs, and Ligand B has 4. Both are within the acceptable limit of <=10.

**6. QED:** Ligand B (0.83) has a significantly better QED score than Ligand A (0.466), indicating a more drug-like profile.

**7. DILI:** Ligand A (35.828) has a lower DILI risk than Ligand B (58.085), which is preferable.

**8. BBB:** Both ligands have excellent BBB penetration (71.539% and 74.758%), exceeding the 70% threshold for CNS targets. Ligand B is slightly better.

**9. Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and suggests poor permeability. This is a significant concern for both.

**10. Aqueous Solubility:** Both ligands have negative solubility values, indicating very poor aqueous solubility. This is a major drawback for both.

**11. hERG Inhibition:** Both ligands have low hERG inhibition risk (0.549 and 0.456), which is good.

**12. Microsomal Clearance:** Ligand A (7.974) has significantly lower microsomal clearance than Ligand B (24.987), suggesting better metabolic stability. This is a significant advantage for Ligand A.

**13. In vitro Half-Life:** Ligand A (-0.908) has a negative half-life, which is not possible. Ligand B (-16.206) also has a negative half-life, which is also not possible. Both are problematic.

**14. P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.021 and 0.084), which is highly desirable for CNS penetration.

**15. Binding Affinity:** Ligand A (-8.6 kcal/mol) has a significantly stronger binding affinity than Ligand B (-7.2 kcal/mol). This >1.5 kcal/mol difference is a major advantage for Ligand A, potentially outweighing some of its ADME drawbacks.

**Overall Assessment:**

While both ligands have issues with Caco-2 permeability and solubility, Ligand A is the stronger candidate. Its significantly better binding affinity (-8.6 vs -7.2 kcal/mol) and lower microsomal clearance (7.974 vs 24.987) are crucial advantages, especially for a GPCR target. The slightly better BBB and TPSA of Ligand B are not enough to offset these factors. The negative half-life values are concerning for both, but the binding affinity difference is substantial.

Output:
0
2025-04-17 07:46:41,993 - INFO - Reasoning:

Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (340.39 and 383.54 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Both ligands have TPSA values (97.87 and 92.93) below the 140 A^2 threshold for good oral absorption, and reasonably close to the 90 A^2 target for CNS penetration. Ligand B is slightly better here.

**3. logP:** Both ligands have logP values (1.97 and 1.79) within the optimal 1-3 range.

**4. H-Bond Donors:** Both have 2 HBD, which is acceptable.

**5. H-Bond Acceptors:** Ligand A has 6 HBA, while Ligand B has 8. Both are acceptable, but Ligand A is slightly better.

**6. QED:** Both ligands have QED values (0.74 and 0.61) above the 0.5 threshold, indicating good drug-likeness.

**7. DILI:** Ligand A (75.03%) has a higher DILI risk than Ligand B (65.49%). This is a negative for Ligand A.

**8. BBB:** This is a critical parameter for a CNS target like DRD2. Ligand A has a BBB percentile of 79.72%, which is excellent (>70). Ligand B has a significantly lower BBB percentile of 16.01%, making CNS penetration less likely.

**9. Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and suggests poor permeability. However, the scale is not specified, so it's difficult to interpret.

**10. Aqueous Solubility:** Both have negative solubility values, indicating poor solubility. Again, the scale is unclear.

**11. hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.169 and 0.154).

**12. Microsomal Clearance:** Ligand A (24.82 mL/min/kg) has lower microsomal clearance than Ligand B (31.95 mL/min/kg), suggesting better metabolic stability.

**13. In vitro Half-Life:** Ligand A (12.02 hours) has a longer half-life than Ligand B (-0.85 hours). This is a significant advantage for Ligand A.

**14. P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.121 and 0.067).

**15. Binding Affinity:** Ligand A (-9.9 kcal/mol) has a significantly stronger binding affinity than Ligand B (-7.4 kcal/mol). This is a >1.5 kcal/mol advantage, which can outweigh some ADME drawbacks.

**Overall Assessment:**

While Ligand A has a higher DILI risk, its significantly superior BBB penetration, longer half-life, and *much* stronger binding affinity outweigh this concern. The strong binding affinity is a major advantage, and the good BBB value is crucial for a CNS target. Ligand B's poor BBB penetration is a deal-breaker.

Output:
1
2025-04-17 07:46:41,993 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (347.463 and 344.459 Da) fall comfortably within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (77.37) is excellent, well below the 90 A^2 threshold for CNS targets. Ligand B (86.88) is still reasonable, but less optimal.

**3. logP:** Ligand A (1.562) is within the optimal 1-3 range. Ligand B (2.201) is also acceptable, though trending slightly higher.

**4. H-Bond Donors:** Ligand A (1) is good. Ligand B (3) is also acceptable, but higher.

**5. H-Bond Acceptors:** Ligand A (5) is good. Ligand B (3) is also good.

**6. QED:** Ligand A (0.784) is excellent, indicating a highly drug-like profile. Ligand B (0.663) is still good, but less so.

**7. DILI:** Ligand A (20.047) has a very low DILI risk, which is highly desirable. Ligand B (44.048) is higher, but still within an acceptable range.

**8. BBB:** This is critical for a CNS target like DRD2. Ligand A (68.282) is good, but could be better. Ligand B (57.619) is significantly lower, indicating poorer predicted BBB penetration.

**9. Caco-2 Permeability:** Ligand A (-4.986) and Ligand B (-5.156) both have negative values, which is unusual. This suggests poor permeability.

**10. Aqueous Solubility:** Ligand A (-1.768) and Ligand B (-3.857) both have negative values, indicating poor solubility.

**11. hERG Inhibition:** Both ligands (0.104 and 0.204) show low hERG inhibition risk, which is positive.

**12. Microsomal Clearance:** Ligand A (-2.172) has a negative clearance, which is excellent (indicating high metabolic stability). Ligand B (50.831) has a high clearance, suggesting rapid metabolism.

**13. In vitro Half-Life:** Ligand A (2.52) is reasonable, but could be better. Ligand B (-15.849) is very poor, consistent with the high clearance.

**14. P-gp Efflux:** Both ligands (0.008 and 0.086) show very low P-gp efflux, which is favorable for CNS penetration.

**15. Binding Affinity:** Both ligands have excellent binding affinities (-7 and -9 kcal/mol). Ligand B is slightly better (-9 kcal/mol), but the difference is likely not enough to overcome its other weaknesses.

**Overall Assessment:**

Ligand A is superior due to its significantly better TPSA, QED, DILI, BBB, and especially its metabolic stability (Cl_mic and t1/2). While Ligand B has a slightly better binding affinity, the other ADME properties of Ligand A are much more favorable for a CNS-targeting drug. The lower BBB penetration and high metabolic clearance of Ligand B are major drawbacks.

Output:
0
2025-04-17 07:46:41,993 - INFO - Reasoning:

Let's analyze Ligand A and Ligand B against the provided guidelines, prioritizing GPCR-specific properties (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (357.443 and 351.447 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (135.6) is borderline, but acceptable for CNS targets, while Ligand B (98.74) is excellent, well below the 90 threshold. This favors Ligand B.

**logP:** Ligand A (2.174) is optimal. Ligand B (0.195) is quite low, potentially hindering membrane permeability and CNS penetration. This heavily favors Ligand A.

**H-Bond Donors/Acceptors:** Ligand A has 4 HBD and 7 HBA, both within acceptable limits. Ligand B has 3 HBD and 4 HBA, also within limits. No strong differentiation here.

**QED:** Ligand A (0.534) is good, indicating drug-likeness. Ligand B (0.297) is significantly lower, suggesting a less drug-like profile. This favors Ligand A.

**DILI:** Ligand A (86.468) has a higher DILI risk than Ligand B (15.161). This favors Ligand B.

**BBB:** Ligand A (35.014) has a poor BBB percentile, which is a major concern for a CNS target like DRD2. Ligand B (62.078) is better, though still not ideal (aim for >70). This *strongly* favors Ligand B.

**Caco-2 Permeability:** Both are negative, indicating poor permeability. This is a weakness for both.

**Aqueous Solubility:** Both are negative, indicating poor solubility. This is a weakness for both.

**hERG:** Ligand A (0.684) has a slightly higher hERG risk than Ligand B (0.279), favoring Ligand B.

**Microsomal Clearance:** Ligand A (-9.779) has a much lower (better) microsomal clearance than Ligand B (16.342), indicating better metabolic stability. This favors Ligand A.

**In vitro Half-Life:** Ligand A (47.802) has a better in vitro half-life than Ligand B (-2.419). This favors Ligand A.

**P-gp Efflux:** Ligand A (0.328) has lower P-gp efflux than Ligand B (0.032), which is desirable for CNS penetration. This favors Ligand A.

**Binding Affinity:** Ligand A (-8.5 kcal/mol) has a slightly better binding affinity than Ligand B (-7.1 kcal/mol). While both are good, the difference is not substantial enough to overcome other significant drawbacks.

**Overall Assessment:**

Ligand B has a significantly better BBB percentile and lower DILI risk, which are crucial for a CNS GPCR target. However, its low logP is a major concern. Ligand A has a better logP, QED, metabolic stability, half-life, and P-gp efflux, but suffers from a poor BBB score and higher DILI risk.

Considering the critical importance of BBB penetration for a DRD2 ligand, and the fact that the affinity difference is not huge, Ligand B is the more promising candidate *despite* its low logP. The low logP could potentially be addressed with further optimization, while improving BBB penetration is often more challenging.

Output:
1
2025-04-17 07:46:41,993 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (383.941 Da) is slightly higher than Ligand B (368.865 Da), but both are acceptable.

**TPSA:** Ligand A (46.61) is excellent for CNS penetration, well below the 90 A^2 threshold. Ligand B (76.46) is higher, but still reasonably good, though less optimal for CNS targets.

**logP:** Ligand A (4.543) is a bit high, potentially leading to solubility issues or off-target interactions. Ligand B (1.583) is closer to the optimal range (1-3) and is preferable.

**H-Bond Donors/Acceptors:** Ligand A (0 HBD, 4 HBA) and Ligand B (1 HBD, 5 HBA) both fall within acceptable ranges.

**QED:** Both ligands have good QED values (Ligand A: 0.553, Ligand B: 0.8), indicating drug-like properties. Ligand B is slightly better.

**DILI:** Both ligands have acceptable DILI risk (Ligand A: 44.397, Ligand B: 47.421), below the 60 threshold.

**BBB:** Ligand A (50.058) is moderate, while Ligand B (62.854) is better, though still not ideal (>70 is preferred for CNS targets). This is a key consideration for DRD2.

**Caco-2 Permeability:** Both have negative Caco-2 values (-4.711 and -4.886), which is unusual and suggests poor permeability. This is a significant drawback for both.

**Aqueous Solubility:** Both have very poor aqueous solubility (-5.183 and -2.326). This is a major concern for *in vivo* efficacy.

**hERG Inhibition:** Both ligands show low hERG inhibition risk (Ligand A: 0.347, Ligand B: 0.273).

**Microsomal Clearance:** Ligand A has very high microsomal clearance (100.03), indicating poor metabolic stability. Ligand B (12.282) has much better metabolic stability.

**In vitro Half-Life:** Ligand A has a moderate half-life (19.801 hours), while Ligand B has a very short half-life (-0.948 hours).

**P-gp Efflux:** Both ligands show low P-gp efflux (Ligand A: 0.337, Ligand B: 0.03).

**Binding Affinity:** Ligand B (-8.2 kcal/mol) has a slightly better binding affinity than Ligand A (-7.9 kcal/mol), although the difference is relatively small.

**Overall Assessment:**

Ligand B is the better candidate despite the poor Caco-2 and solubility. Its superior logP, metabolic stability (lower Cl_mic), and slightly better binding affinity outweigh the moderate BBB penetration and the slightly shorter half-life. Ligand A's high metabolic clearance is a significant concern. The poor solubility and permeability of both compounds are serious issues that would need to be addressed through formulation or further chemical modification. However, given the choice between the two, Ligand B is more promising.

Output:
1
2025-04-17 07:46:41,994 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (344.415 and 354.491 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (83.56) is better than Ligand B (89.87). Both are below the 90 A^2 threshold desirable for CNS targets, but A is closer to the ideal.

**3. logP:** Both ligands (1.212 and 1.443) are within the optimal 1-3 range.

**4. H-Bond Donors:** Ligand A (2) is preferable to Ligand B (3), as fewer HBDs generally improve permeability.

**5. H-Bond Acceptors:** Ligand A (5) is preferable to Ligand B (4), as fewer HBAs generally improve permeability.

**6. QED:** Ligand B (0.645) has a better QED score than Ligand A (0.441), indicating a more drug-like profile.

**7. DILI:** Ligand A (30.826) has a significantly lower DILI risk than Ligand B (9.151), which is a major advantage.

**8. BBB:** Ligand A (81.272) has a much better BBB penetration score than Ligand B (67.352). This is *critical* for a CNS target like DRD2.

**9. Caco-2 Permeability:** Ligand A (-5.403) and Ligand B (-4.8) both have negative values, suggesting poor permeability.

**10. Aqueous Solubility:** Both ligands have negative solubility values (-1.875 and -1.675), indicating poor solubility.

**11. hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.365 and 0.368).

**12. Microsomal Clearance:** Ligand A (-2.138) has a lower (better) microsomal clearance than Ligand B (13.905), suggesting greater metabolic stability.

**13. In vitro Half-Life:** Ligand A (-24.291) has a longer half-life than Ligand B (-26.666).

**14. P-gp Efflux:** Ligand A (0.008) has a much lower P-gp efflux liability than Ligand B (0.069), which is crucial for CNS penetration.

**15. Binding Affinity:** Ligand B (-7.8) has a slightly better binding affinity than Ligand A (-8.4). However, the difference is not substantial enough to outweigh the significant ADME advantages of Ligand A.

**Overall Assessment:**

Ligand A is the stronger candidate. While Ligand B has slightly better affinity and QED, Ligand A excels in critical ADME properties for a CNS-targeting GPCR: significantly better BBB penetration, lower DILI risk, lower P-gp efflux, and better metabolic stability. The slightly weaker binding affinity of Ligand A can likely be optimized in subsequent iterations of drug design. The poor solubility and Caco-2 permeability are concerns for both, but can be addressed with formulation strategies.

Output:
0
2025-04-17 07:46:41,994 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (354.451 and 373.503 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (99.77) is slightly above the preferred <90 for CNS targets, but still reasonable. Ligand B (76.29) is well within the ideal range.

**3. logP:** Both ligands have good logP values (1.906 and 2.776), falling within the optimal 1-3 range.

**4. H-Bond Donors:** Ligand A (3) and Ligand B (1) both meet the HBD criteria of <=5.

**5. H-Bond Acceptors:** Ligand A (4) and Ligand B (6) both meet the HBA criteria of <=10.

**6. QED:** Both ligands have acceptable QED values (0.657 and 0.715), indicating good drug-like properties.

**7. DILI:** Ligand A (47.421) has a lower DILI risk than Ligand B (81.466), making it more favorable.

**8. BBB:** Both ligands show good BBB penetration (70.997 and 74.796), exceeding the 70% threshold for CNS targets.

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.449 and -4.881), which is unusual and suggests poor permeability. However, these values are on a log scale, and the negative values indicate very low permeability.

**10. Aqueous Solubility:** Both ligands have negative solubility values (-3.347 and -3.131), indicating poor aqueous solubility.

**11. hERG Inhibition:** Ligand A (0.198) has a much lower hERG inhibition risk than Ligand B (0.748).

**12. Microsomal Clearance:** Ligand A (40.431) has a higher microsomal clearance than Ligand B (13.645), suggesting lower metabolic stability.

**13. In vitro Half-Life:** Ligand B (-10.502) has a negative half-life, which is not physically possible. This is a significant red flag. Ligand A (4.393) has a reasonable half-life.

**14. P-gp Efflux:** Ligand A (0.021) has a much lower P-gp efflux liability than Ligand B (0.324), which is favorable for CNS penetration.

**15. Binding Affinity:** Ligand B (-9.3 kcal/mol) has a slightly better binding affinity than Ligand A (-7.7 kcal/mol). However, the difference (1.6 kcal/mol) isn't substantial enough to outweigh the other significant drawbacks of Ligand B.

**Overall Assessment:**

Ligand B has a better binding affinity, but its negative in vitro half-life is a critical flaw. The higher DILI risk, higher P-gp efflux, and higher hERG inhibition also detract from its viability. Ligand A, while having slightly lower affinity, presents a much more balanced profile with acceptable ADME properties, lower toxicity risk, and a reasonable half-life. The poor Caco-2 and solubility are concerning, but potentially addressable through formulation strategies.

Output:
0
2025-04-17 07:46:41,994 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 drug candidates, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (342.399 Da) is slightly lower, which could be advantageous for permeability. Ligand B (364.417 Da) is also good.

**TPSA:** Ligand A (93.09) is excellent for CNS penetration, being well below the 90 A^2 threshold. Ligand B (53.33) is even better, further supporting CNS penetration.

**logP:** Ligand A (0.375) is quite low, potentially hindering membrane permeability and absorption. Ligand B (4.123) is higher, approaching the upper limit of the optimal range, but still acceptable.

**H-Bond Donors/Acceptors:** Ligand A has 2 HBD and 5 HBA, which are reasonable. Ligand B has 0 HBD and 5 HBA, also reasonable.

**QED:** Both ligands have good QED scores (A: 0.577, B: 0.661), indicating drug-like properties.

**DILI:** Both ligands have acceptable DILI risk (A: 56.185, B: 47.654), below the concerning threshold of 60.

**BBB:** Ligand B (80.574) has a significantly better BBB percentile than Ligand A (54.246). This is a crucial advantage for a CNS target like DRD2.

**Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and difficult to interpret without further context. However, the magnitude suggests Ligand A (-4.813) might have slightly better permeability than Ligand B (-4.508).

**Aqueous Solubility:** Both have negative solubility values, again unusual. Ligand A (-2.95) appears slightly better than Ligand B (-4.462).

**hERG Inhibition:** Ligand A (0.05) shows very low hERG inhibition liability, a significant safety advantage. Ligand B (0.885) has a higher, though still relatively low, hERG risk.

**Microsomal Clearance:** Ligand A (12.2 mL/min/kg) has lower clearance than Ligand B (105.97 mL/min/kg), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (-24.614 hours) has a negative half-life, which is not physically possible and indicates an issue with the data. Ligand B (5.715 hours) is a reasonable half-life.

**P-gp Efflux:** Ligand A (0.019) has very low P-gp efflux, which is excellent for CNS penetration and bioavailability. Ligand B (0.361) has a higher, but still moderate, P-gp efflux.

**Binding Affinity:** Ligand B (-7.7 kcal/mol) has a slightly better binding affinity than Ligand A (-8.1 kcal/mol). While the difference is small, it's still a positive factor.

**Overall Assessment:**

Ligand B excels in BBB penetration and has a better binding affinity. However, Ligand A has a significantly better metabolic profile (lower Cl_mic, lower P-gp efflux, and lower hERG risk). The negative values for Caco-2 and solubility are concerning for both, but the other properties suggest Ligand A might be slightly better absorbed. The negative half-life for Ligand A is a major red flag, indicating a data error or significant instability. Considering the importance of BBB penetration for a CNS target, and the slightly better affinity of Ligand B, I would lean towards Ligand B, *assuming the half-life data is accurate*.

Output:
1
2025-04-17 07:46:41,994 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (341.415 and 345.487 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (91.02) is slightly above the preferred <90 for CNS targets, but still reasonable. Ligand B (52.65) is excellent, well below 90.

**logP:** Both ligands (1.411 and 1.488) are within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Both have 1 HBD, which is good. Ligand A has 5 HBA, while Ligand B has 3. Both are within acceptable limits (<=10).

**QED:** Ligand A (0.876) has a significantly better QED score than Ligand B (0.678), indicating a more drug-like profile.

**DILI:** Ligand A (36.06) has a much lower DILI risk than Ligand B (6.282), a significant advantage.

**BBB:** Both ligands have similar BBB penetration (54.052 and 53.005), both are acceptable but not outstanding. Ideally, >70 is desired for CNS targets.

**Caco-2 Permeability:** Ligand A (-5.137) and Ligand B (-4.837) both have negative values, indicating poor permeability.

**Aqueous Solubility:** Both ligands have poor aqueous solubility (-1.895 and -1.512).

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.259 and 0.491).

**Microsomal Clearance:** Ligand A (-14.625) has a significantly lower (better) microsomal clearance than Ligand B (-16.921), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (3.769) has a longer half-life than Ligand B (-5.665), which is preferable.

**P-gp Efflux:** Both ligands have very low P-gp efflux (0.025 and 0.011), which is excellent for CNS penetration.

**Binding Affinity:** Ligand B (-7.2 kcal/mol) has a slightly better binding affinity than Ligand A (-8.6 kcal/mol). However, the difference is not substantial enough to outweigh the other significant advantages of Ligand A.

**Overall Assessment:**

Ligand A is the stronger candidate. While Ligand B has a slightly better binding affinity, Ligand A excels in crucial ADME properties: significantly lower DILI risk, better QED, lower microsomal clearance, and longer half-life. Both have acceptable logP and P-gp efflux. The TPSA of Ligand A is slightly higher, but still within a reasonable range. The similar BBB values are not decisive. The poor Caco-2 and solubility are drawbacks for both, but can be addressed with formulation strategies.

Output:
0
2025-04-17 07:46:41,995 - INFO - Reasoning:

Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (339.435 and 375.456 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (38.77) is slightly higher than Ligand B (29.54). Both are below the 90 Angstrom threshold desirable for CNS targets, but Ligand B is better.

**3. logP:** Both ligands have good logP values (3.616 and 4.184), falling within the optimal 1-3 range. Ligand B is slightly higher, potentially increasing permeability but also raising the possibility of off-target interactions.

**4. H-Bond Donors:** Both have 0 HBD, which is good.

**5. H-Bond Acceptors:** Ligand A has 4 HBA, and Ligand B has 3. Both are below the threshold of 10.

**6. QED:** Both ligands have QED values above 0.5 (0.754 and 0.639), indicating good drug-like properties.

**7. DILI:** Ligand A (34.665) has a slightly higher DILI risk than Ligand B (23.187), but both are below the concerning threshold of 60.

**8. BBB:** This is a critical parameter for CNS targets. Ligand B (96.355) has a significantly higher BBB penetration percentile than Ligand A (78.868). This is a major advantage for Ligand B.

**9. Caco-2 Permeability:** Both have negative values which is unusual. Assuming these are logP values, they are both poor.

**10. Aqueous Solubility:** Both have negative values which is unusual. Assuming these are logS values, they are both poor.

**11. hERG:** Both ligands have very low hERG inhibition liability (0.915 and 0.935), which is excellent.

**12. Microsomal Clearance:** Ligand A (87.794) has lower microsomal clearance than Ligand B (94.384), suggesting better metabolic stability.

**13. In vitro Half-Life:** Ligand B has a much longer in vitro half-life (7.342 hours) than Ligand A (-5.272 hours). This is a significant advantage for Ligand B.

**14. P-gp Efflux:** Both ligands have low P-gp efflux liability (0.653 and 0.611).

**15. Binding Affinity:** Ligand B (-7.7 kcal/mol) has a slightly better binding affinity than Ligand A (-8.1 kcal/mol). While the difference is small, it's still favorable.

**Overall Assessment:**

Ligand B is the more promising candidate. Its significantly higher BBB penetration, longer half-life, and slightly better binding affinity outweigh the slightly higher logP and lower metabolic stability compared to Ligand A. The TPSA is also more favorable for CNS penetration. While both ligands have acceptable profiles, Ligand B's superior CNS-related properties make it the preferred choice for targeting DRD2.

Output:
1
2025-04-17 07:46:41,995 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (352.406 and 344.459 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (76.66) is better than Ligand B (69.3), both are below the 90 A^2 threshold for CNS targets, which is excellent.

**3. logP:** Ligand A (1.183) is within the optimal range (1-3), while Ligand B (1.985) is also acceptable.

**4. H-Bond Donors:** Ligand A (2) and Ligand B (1) are both within the acceptable limit of <=5.

**5. H-Bond Acceptors:** Ligand A (5) and Ligand B (3) are both within the acceptable limit of <=10.

**6. QED:** Both ligands have good QED scores (0.752 and 0.849, respectively), indicating good drug-like properties.

**7. DILI:** Ligand A (40.132) has a slightly higher DILI risk than Ligand B (23.187), but both are below the concerning threshold of 60.

**8. BBB:** This is a critical parameter for a CNS target like DRD2. Ligand A (65.607) is better than Ligand B (51.183), but both are below the desirable >70 percentile.

**9. Caco-2 Permeability:** Ligand A (-4.755) and Ligand B (-5.01) both have negative Caco-2 permeability values, which is unusual and suggests poor intestinal absorption. This is a concern, but less critical for a CNS target where direct delivery is possible.

**10. Aqueous Solubility:** Both ligands have negative solubility values (-1.528 and -1.836), indicating poor aqueous solubility. This could pose formulation challenges.

**11. hERG Inhibition:** Both ligands have very low hERG inhibition liability (0.338 and 0.182), which is excellent.

**12. Microsomal Clearance:** Ligand A (20.527) has lower microsomal clearance than Ligand B (30.424), suggesting better metabolic stability.

**13. In vitro Half-Life:** Ligand A (-4.983) has a longer in vitro half-life than Ligand B (-8.979), which is favorable.

**14. P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.025 and 0.037), which is beneficial for CNS penetration.

**15. Binding Affinity:** Ligand A (-8.2 kcal/mol) has a significantly stronger binding affinity than Ligand B (-7.1 kcal/mol). This 1.1 kcal/mol difference is substantial and can outweigh minor ADME drawbacks.

**Overall Assessment:**

Ligand A is the better candidate. While both have issues with solubility and Caco-2 permeability, Ligand A has a significantly stronger binding affinity, better BBB penetration, lower DILI risk, and improved metabolic stability (lower Cl_mic and longer t1/2). The stronger affinity is particularly important for a GPCR target, and the slightly better BBB penetration is crucial for CNS activity.

Output:
1
2025-04-17 07:46:41,995 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (346.421 Da) is slightly lower, which could be beneficial for permeability.

**TPSA:** Ligand A (24.5) is excellent for CNS penetration, well below the 90 A^2 threshold. Ligand B (87.15) is higher, potentially hindering BBB penetration, but still within a reasonable range.

**logP:** Ligand A (3.728) is optimal. Ligand B (0.498) is quite low, potentially leading to poor membrane permeability and bioavailability.

**H-Bond Donors/Acceptors:** Both have acceptable HBD counts (1). Ligand A has 3 HBA, while Ligand B has 5. Both are within the preferred range of <=10.

**QED:** Both ligands have reasonable QED scores (A: 0.863, B: 0.699), indicating drug-like properties.

**DILI:** Ligand A (9.965) has a very low DILI risk. Ligand B (32.726) is higher, but still relatively low.

**BBB:** This is crucial for a CNS target. Ligand A (93.098) is excellent, exceeding the 70% threshold. Ligand B (59.791) is significantly lower, raising concerns about CNS exposure.

**Caco-2 Permeability:** Both have negative values, which is unusual and requires careful interpretation. Generally, a more negative value suggests lower permeability.

**Aqueous Solubility:** Both have negative values, which is also unusual.

**hERG Inhibition:** Both ligands show low hERG inhibition risk (A: 0.987, B: 0.453).

**Microsomal Clearance:** Ligand A (17.018) has lower clearance, suggesting better metabolic stability. Ligand B (25.394) has higher clearance.

**In vitro Half-Life:** Ligand B (-9.926) has a negative half-life, which is not physically possible and indicates an issue with the data. Ligand A (0.787) has a very short half-life, but is at least a plausible value.

**P-gp Efflux:** Ligand A (0.438) has lower P-gp efflux, which is favorable for CNS penetration. Ligand B (0.104) has very low P-gp efflux.

**Binding Affinity:** Ligand A (-9.0) has a significantly stronger binding affinity than Ligand B (-7.5). This >1.5 kcal/mol difference is substantial.

**Overall Assessment:**

Ligand A is clearly superior. It excels in key GPCR properties: excellent BBB penetration, optimal logP, lower P-gp efflux, and significantly stronger binding affinity. While its half-life is short, the strong affinity could compensate. Ligand B suffers from a low logP, poor BBB penetration, and a questionable half-life value. The stronger affinity of Ligand A outweighs any minor drawbacks.

Output:
1
2025-04-17 07:46:41,995 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (360.36 and 352.48 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (76.15) is excellent, well below the 90 A^2 threshold for CNS targets. Ligand B (81.08) is still acceptable, but less optimal.

**logP:** Ligand A (0.591) is a bit low, potentially hindering permeability. Ligand B (1.151) is better, falling within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A (0 HBD, 5 HBA) is favorable. Ligand B (2 HBD, 4 HBA) is also good, within the recommended limits.

**QED:** Both ligands have good QED scores (0.648 and 0.778, respectively), indicating drug-like properties.

**DILI:** Ligand A (37.263) has a slightly higher DILI risk than Ligand B (15.626), but both are below the concerning 60 percentile.

**BBB:** This is a critical parameter for a CNS target like DRD2. Ligand A shines with a BBB percentile of 89.608, significantly better than Ligand B's 66.072.

**Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and suggests poor permeability. However, the scale is not specified, so it's difficult to interpret.

**Aqueous Solubility:** Both ligands have negative solubility values, indicating poor aqueous solubility. This is a concern for formulation.

**hERG:** Both ligands have low hERG inhibition liability (0.27 and 0.364), which is positive.

**Microsomal Clearance:** Ligand A (27.117) has lower microsomal clearance than Ligand B (42.739), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (-8.719) has a more negative in vitro half-life, which is not ideal. Ligand B (-2.477) is better, but still not great.

**P-gp Efflux:** Both ligands show low P-gp efflux liability (0.051 and 0.054), which is favorable for CNS penetration.

**Binding Affinity:** Both ligands have excellent binding affinities (-7.7 and -7.0 kcal/mol). Ligand A is slightly better, but the difference is less than the 1.5 kcal/mol threshold.

**Overall Assessment:**

Ligand A is superior due to its significantly better BBB penetration (89.6% vs 66.1%), lower microsomal clearance (better metabolic stability), and slightly better binding affinity. While its logP is a bit low and solubility is poor, the strong BBB score outweighs these concerns for a CNS-targeted GPCR. Ligand B has a better logP, but its lower BBB penetration is a significant drawback.

Output:
1
2025-04-17 07:46:41,996 - INFO - Okay, let's analyze these two ligands for their potential as DRD2 drug candidates.

**Ligand A:** [348.29 , 124.2  ,   1.196,   1.   ,   7.   ,   0.475,  96.976,  59.519, -4.612,  -3.694,   0.124,  42.077,  16.519,   0.177,  -8.8  ]
**Ligand B:** [350.459,  67.87 ,   1.501,   1.   ,   4.   ,   0.737,  21.636,  65.801, -4.662,  -1.925,   0.129,  45.253,  24.288,   0.03 ,  -7.   ]

**Step-by-step comparison:**

1. **MW:** Both are within the ideal range (200-500 Da). A: 348.29, B: 350.459. No clear advantage.
2. **TPSA:** Ligand A (124.2) is higher than the ideal for CNS targets (<90), but still potentially acceptable. Ligand B (67.87) is excellent, well below the threshold. *Advantage: B*
3. **logP:** Both are within the optimal range (1-3). A: 1.196, B: 1.501. No significant difference.
4. **HBD:** Both have 1 HBD, which is good. No difference.
5. **HBA:** A has 7, B has 4. Both are acceptable (<=10), but B is better. *Advantage: B*
6. **QED:** A (0.475) is below the desirable threshold of 0.5. B (0.737) is above, indicating a better drug-like profile. *Advantage: B*
7. **DILI:** A (96.976) has a very high DILI risk. B (21.636) has a low DILI risk. *Significant Advantage: B*
8. **BBB:** A (59.519) is below the desirable threshold (>70) for CNS targets. B (65.801) is closer, but still below the ideal. *Advantage: B*
9. **Caco-2:** Both are negative, which is unusual and suggests poor permeability. The scale isn't specified, so it's hard to interpret.
10. **Solubility:** Both are negative, again unusual. The scale isn't specified, so it's hard to interpret.
11. **hERG:** Both are very low (0.124 and 0.129), indicating low cardiotoxicity risk. No difference.
12. **Cl_mic:** A (42.077) and B (45.253) are similar, suggesting comparable metabolic stability. No clear advantage.
13. **t1/2:** B (24.288) has a longer half-life than A (16.519), which is generally desirable. *Advantage: B*
14. **Pgp:** Both are very low (0.177 and 0.03), indicating low P-gp efflux. B is slightly better. *Advantage: B*
15. **Binding Affinity:** A (-8.8 kcal/mol) has a significantly stronger binding affinity than B (-7.0 kcal/mol). *Significant Advantage: A*

**Overall Assessment:**

While Ligand A boasts a superior binding affinity, its extremely high DILI risk and suboptimal BBB penetration are major concerns. Ligand B, despite a slightly weaker binding affinity, presents a much more favorable ADMET profile: lower DILI risk, better QED, slightly better BBB, and a longer half-life. For a CNS target like DRD2, minimizing toxicity and ensuring sufficient brain penetration are crucial. The 1.8 kcal/mol difference in binding affinity, while substantial, might be overcome with further optimization of Ligand B, whereas mitigating the DILI risk of Ligand A would likely require significant structural changes that could also impact potency.

Considering the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity) and the overall balance of properties, Ligand B is the more promising drug candidate.

1
2025-04-17 07:46:41,996 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 drug candidates, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (337.379 and 346.519 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (76.38) is slightly above the optimal <90 for CNS targets, but still reasonable. Ligand B (59.07) is excellent, well below 90.

**3. logP:** Both ligands have good logP values (3.076 and 4.04), falling within the 1-3 range, though Ligand B is pushing the upper limit.

**4. H-Bond Donors:** Both have 2 HBD, which is acceptable.

**5. H-Bond Acceptors:** Both have 5 HBA, also acceptable.

**6. QED:** Both ligands have similar, good QED values (0.75 and 0.78).

**7. DILI:** Ligand A (73.982) has a higher DILI risk than Ligand B (34.858). Ligand B is preferred here.

**8. BBB:** This is a critical parameter for a CNS target like DRD2. Ligand B (92.71) has a significantly higher BBB percentile than Ligand A (35.052). This is a major advantage for Ligand B.

**9. Caco-2 Permeability:** Ligand A (-5.228) has poor Caco-2 permeability, indicating poor intestinal absorption. Ligand B (-4.611) is also poor, but slightly better than A.

**10. Aqueous Solubility:** Both ligands have very poor aqueous solubility (-3.924 and -4.6). This is a concern for both, but might be manageable with formulation strategies.

**11. hERG Inhibition:** Both ligands have low hERG inhibition risk (0.565 and 0.867).

**12. Microsomal Clearance:** Ligand A (65.877) has lower microsomal clearance, suggesting better metabolic stability than Ligand B (79.155).

**13. In vitro Half-Life:** Ligand B (50.426) has a significantly longer in vitro half-life than Ligand A (-29.39). This is a strong advantage for Ligand B.

**14. P-gp Efflux:** Both ligands have low P-gp efflux liability (0.336 and 0.342).

**15. Binding Affinity:** Ligand A (-9.7 kcal/mol) has a significantly stronger binding affinity than Ligand B (-8.1 kcal/mol). This is a substantial advantage for Ligand A.

**Overall Assessment:**

While Ligand A has a superior binding affinity, the significant advantages of Ligand B in BBB penetration, lower DILI risk, and longer half-life outweigh the affinity difference. The poor Caco-2 permeability is a concern for both, but the strong CNS target engagement requirement for DRD2 makes BBB the most critical factor. Ligand A's poor BBB penetration is a major drawback.

Output:
1
2025-04-17 07:46:41,996 - INFO - Batch 393 complete. Total preferences: 6288
2025-04-17 07:46:41,996 - INFO - Processing batch 394/512...
2025-04-17 07:47:22,432 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (350.463 and 345.359 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (69.89) is excellent, well below the 90 A^2 threshold for CNS targets. Ligand B (132.13) is higher, but still potentially acceptable, though less ideal.

**logP:** Ligand A (1.746) is optimal. Ligand B (-0.18) is below 1, which could hinder permeation.

**H-Bond Donors/Acceptors:** Ligand A (0 HBD, 5 HBA) is favorable. Ligand B (5 HBD, 5 HBA) is also acceptable, but the higher HBD count could slightly impact permeability.

**QED:** Ligand A (0.714) is excellent, indicating strong drug-likeness. Ligand B (0.524) is acceptable, but less optimal.

**DILI:** Both ligands have relatively high DILI risk (7.057 and 79.915), but Ligand B is significantly higher, raising a concern.

**BBB:** Ligand A (77.2) is very good, exceeding the 70 percentile threshold for CNS targets. Ligand B (25.979) is poor, indicating limited brain penetration. This is a major drawback for a DRD2 ligand.

**Caco-2 Permeability:** Both have negative values (-5.133 and -5.651), which is unusual and suggests poor permeability. However, these values are on a scale where negative values are possible and don't necessarily preclude activity.

**Aqueous Solubility:** Both have negative values (-0.121 and -3.166), indicating poor solubility. This could pose formulation challenges.

**hERG Inhibition:** Both ligands have very low hERG risk (0.308 and 0.124).

**Microsomal Clearance:** Ligand A (11.982) is better (lower clearance) than Ligand B (-19.769), suggesting greater metabolic stability.

**In vitro Half-Life:** Ligand A (-13.945) is better (longer half-life) than Ligand B (35.907).

**P-gp Efflux:** Ligand A (0.038) has very low P-gp efflux, which is excellent for CNS exposure. Ligand B (0.014) also has low P-gp efflux, but slightly higher than A.

**Binding Affinity:** Ligand A (-7.3 kcal/mol) has a slightly better binding affinity than Ligand B (-9.3 kcal/mol). While both are good, the difference is significant.

**Overall Assessment:**

Ligand A is significantly more promising. It excels in key GPCR properties like BBB penetration, TPSA, logP, and P-gp efflux. It also has better metabolic stability (lower Cl_mic) and a longer half-life. While both have DILI concerns, Ligand B's is much higher. The slightly better affinity of Ligand A further strengthens its position. Ligand B's poor BBB penetration is a critical flaw for a CNS target like DRD2.

Output:
0
2025-04-17 07:47:22,433 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (347.443 and 349.435 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (54.88) is significantly better than Ligand B (87.66). For CNS targets, TPSA should be <= 90, and A is comfortably within this range, while B is approaching the upper limit. This favors A.

**3. logP:** Ligand A (4.364) is higher than the optimal range (1-3) but still potentially acceptable. Ligand B (0.687) is quite low, potentially hindering membrane permeability and CNS penetration. This strongly favors A.

**4. H-Bond Donors:** Both ligands have 1 HBD, which is within the acceptable limit of <=5.

**5. H-Bond Acceptors:** Ligand A has 4 HBAs, and Ligand B has 6. Both are within the acceptable limit of <=10.

**6. QED:** Both ligands have good QED scores (0.716 and 0.841), indicating drug-like properties.

**7. DILI:** Ligand A (83.521) has a higher DILI risk than Ligand B (56.65). This favors B, but the difference isn't massive.

**8. BBB:** Ligand A (57.774) has a lower BBB penetration percentile than Ligand B (76.27). This is a significant advantage for B, given DRD2 is a CNS target.

**9. Caco-2:** Both have negative Caco-2 values, which is unusual and difficult to interpret without knowing the scale. However, it suggests poor permeability for both.

**10. Solubility:** Both have negative solubility values, indicating poor aqueous solubility.

**11. hERG:** Ligand A (0.533) has a slightly higher hERG risk than Ligand B (0.202). This favors B.

**12. Cl_mic:** Ligand A (50.725) has a higher microsomal clearance than Ligand B (24.07). Lower clearance is better for metabolic stability, favoring B.

**13. t1/2:** Ligand A (62.674) has a longer in vitro half-life than Ligand B (-9.315). This favors A.

**14. Pgp:** Ligand A (0.658) has higher P-gp efflux liability than Ligand B (0.046). Lower efflux is preferred, especially for CNS targets, strongly favoring B.

**15. Binding Affinity:** Ligand A (-10.4 kcal/mol) has a significantly stronger binding affinity than Ligand B (-7.8 kcal/mol). This is a substantial advantage for A, potentially outweighing some of its ADME drawbacks. A difference of >1.5 kcal/mol is considered significant.

**Overall Assessment:**

While Ligand B has better BBB penetration, lower Pgp efflux, lower DILI, and better metabolic stability, Ligand A's *much* stronger binding affinity (-10.4 vs -7.8 kcal/mol) is a critical advantage, especially for a GPCR target. The lower TPSA and longer half-life also contribute positively. The higher logP of A is a concern, but the affinity difference is substantial enough to potentially overcome that. The negative solubility and Caco-2 values are concerning for both, but can be addressed with formulation strategies.

Output:
1
2025-04-17 07:47:22,433 - INFO - Reasoning:

Let's analyze Ligand A and Ligand B based on the provided guidelines, prioritizing GPCR-specific properties (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (443.084 Da) is towards the higher end, while Ligand B (348.447 Da) is more optimal.

**TPSA:** Both ligands have TPSA values around 84-85, which is slightly above the ideal <90 for CNS targets but not drastically so.

**logP:** Ligand A (4.032) is at the upper limit of the optimal range, potentially raising concerns about solubility and off-target effects. Ligand B (1.405) is lower, but still acceptable.

**H-Bond Donors/Acceptors:** Both have 2 HBD and are within acceptable limits. Ligand B has 5 HBA, while Ligand A has 4. Both are acceptable.

**QED:** Both ligands have QED values above 0.5, indicating good drug-likeness.

**DILI:** Ligand A (90.151) has a significantly higher DILI risk than Ligand B (38.154). This is a major concern for Ligand A.

**BBB:** Ligand B (73.401) has a much better BBB penetration percentile than Ligand A (21.52). This is *critical* for a CNS target like DRD2.

**Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and suggests poor permeability. However, the scale is not specified, so it's hard to interpret.

**Aqueous Solubility:** Both have negative solubility values, indicating poor aqueous solubility.

**hERG Inhibition:** Both ligands have very low hERG inhibition risk.

**Microsomal Clearance:** Ligand B (37.594) has a considerably higher microsomal clearance than Ligand A (7.203), suggesting lower metabolic stability.

**In vitro Half-Life:** Ligand A (24.192) has a slightly longer half-life than Ligand B (20.428).

**P-gp Efflux:** Ligand A (0.085) shows lower P-gp efflux liability than Ligand B (0.105), which is favorable for CNS penetration.

**Binding Affinity:** Ligand B (-7.1 kcal/mol) has a slightly better binding affinity than Ligand A (-9.2 kcal/mol). While A is stronger, the difference is not large enough to overcome the other significant drawbacks.

**Overall Assessment:**

Ligand B is significantly more promising. Its superior BBB penetration, lower DILI risk, and comparable binding affinity outweigh its slightly higher P-gp efflux and microsomal clearance. Ligand A's high DILI risk and poor BBB penetration are major red flags for CNS drug development. While Ligand A has a slightly better binding affinity, the other ADME/Tox properties of Ligand B make it a much more viable candidate.

Output:
1
2025-04-17 07:47:22,433 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (350.503 and 366.527 Da) fall within the ideal 200-500 Da range.

**TPSA:** Both ligands have TPSA values (70.59 and 72.63) below the 90 A^2 threshold desirable for CNS targets, which is good.

**logP:** Both ligands have logP values (2.678 and 2.967) within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A has 3 HBD and 3 HBA, while Ligand B has 1 HBD and 4 HBA. Both are within acceptable limits (<=5 HBD and <=10 HBA).

**QED:** Both ligands have QED values (0.69 and 0.754) above 0.5, indicating good drug-likeness.

**DILI:** Ligand A (19.465) has a slightly higher DILI risk than Ligand B (16.712), but both are well below the concerning threshold of 60.

**BBB:** Both ligands have excellent BBB penetration (78.868 and 74.758), exceeding the desirable >70 threshold for CNS targets.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.791 and -4.991). This is unusual and suggests poor permeability. However, these values are on a log scale, so the negative values are not directly comparable without knowing the scale.

**Aqueous Solubility:** Both ligands have negative solubility values (-3.074 and -3.302). Similar to Caco-2, these values are on a log scale and suggest poor solubility.

**hERG:** Both ligands have very low hERG inhibition risk (0.499 and 0.492).

**Microsomal Clearance:** Ligand B (82.365) has a significantly higher microsomal clearance than Ligand A (37.877), indicating lower metabolic stability.

**In vitro Half-Life:** Ligand A (22.627) has a longer in vitro half-life than Ligand B (13.025).

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.217 and 0.238), which is favorable for CNS penetration.

**Binding Affinity:** Ligand A (-8.4 kcal/mol) has a substantially stronger binding affinity than Ligand B (-6.8 kcal/mol). This is a difference of 1.6 kcal/mol, which is significant enough to potentially outweigh minor ADME drawbacks.

**Conclusion:**

Despite the unusual negative Caco-2 and solubility values for both compounds, Ligand A is the more promising candidate. Its significantly stronger binding affinity (-8.4 vs -6.8 kcal/mol) is a major advantage, especially for a GPCR target. Additionally, it has better metabolic stability (lower Cl_mic) and a longer half-life than Ligand B. While both have good BBB penetration, the superior affinity of Ligand A makes it the preferred choice. The poor solubility and permeability would need to be addressed in further optimization, but the strong binding provides a solid foundation.

Output:
0
2025-04-17 07:47:22,433 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (348.491 and 353.438 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (78.09) is slightly higher than Ligand B (64.09). Both are below the 90 A^2 threshold desirable for CNS targets, but Ligand B is better.

**3. logP:** Ligand A (2.666) is optimal, while Ligand B (0.249) is quite low. Low logP can hinder membrane permeability. This is a significant advantage for Ligand A.

**4. H-Bond Donors:** Ligand A (2) and Ligand B (1) are both within the acceptable range (<=5).

**5. H-Bond Acceptors:** Ligand A (3) and Ligand B (4) are both within the acceptable range (<=10).

**6. QED:** Both ligands have good QED scores (0.709 and 0.787, respectively), indicating drug-like properties.

**7. DILI:** Ligand A (25.087) has a much lower DILI risk than Ligand B (8.143). This is a substantial advantage for Ligand A.

**8. BBB:** Both ligands have good BBB penetration (69.213 and 68.36, respectively), but are slightly below the ideal >70 for CNS targets.

**9. Caco-2 Permeability:** Ligand A (-5.127) has worse Caco-2 permeability than Ligand B (-4.819), but both are negative values, indicating poor permeability.

**10. Aqueous Solubility:** Ligand A (-2.336) has worse aqueous solubility than Ligand B (-0.823).

**11. hERG Inhibition:** Both ligands have similar, low hERG inhibition risk (0.401 and 0.521).

**12. Microsomal Clearance:** Ligand A (33.962) has higher microsomal clearance than Ligand B (7.647), indicating lower metabolic stability. This favors Ligand B.

**13. In vitro Half-Life:** Ligand A (-11.066) has a negative half-life, which is not physically possible and indicates a problem with the prediction or the molecule. Ligand B (3.542) has a short half-life, but it is at least a plausible value.

**14. P-gp Efflux:** Both ligands have low P-gp efflux liability (0.182 and 0.031).

**15. Binding Affinity:** Ligand A (-8.1 kcal/mol) has a slightly better binding affinity than Ligand B (-7.8 kcal/mol). While the difference is not huge, it's a positive for Ligand A.

**Overall Assessment:**

Ligand A has a better logP, significantly lower DILI risk, and slightly better binding affinity. However, it has worse Caco-2 permeability, aqueous solubility, and a problematic negative in vitro half-life. Ligand B has better metabolic stability (lower Cl_mic), a plausible half-life, and better solubility. Given the importance of BBB penetration for CNS targets, and the fact that both ligands are reasonably close on this metric, the combination of better metabolic stability and a plausible half-life for Ligand B, along with the significant DILI concern with Ligand A, makes Ligand B the more promising candidate. The negative half-life for Ligand A is a major red flag.

Output:
1
2025-04-17 07:47:22,434 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (358.454 and 344.367 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (59.08) is excellent, well below the 90 A^2 threshold for CNS targets. Ligand B (92.78) is higher, but still potentially acceptable, though less optimal.

**logP:** Ligand A (1.768) is within the optimal 1-3 range. Ligand B (-0.193) is slightly below 1, which could indicate permeability issues.

**H-Bond Donors/Acceptors:** Ligand A (0 HBD, 4 HBA) is favorable. Ligand B (1 HBD, 5 HBA) is also acceptable.

**QED:** Ligand A (0.663) is good, indicating strong drug-like properties. Ligand B (0.433) is lower, suggesting a less ideal overall profile.

**DILI:** Ligand A (23.885) has a very low DILI risk. Ligand B (46.801) is higher, but still within an acceptable range.

**BBB:** Ligand A (85.111) has excellent BBB penetration potential. Ligand B (38.232) is significantly lower, a major drawback for a CNS target like DRD2.

**Caco-2 Permeability:** Ligand A (-4.336) is concerningly low, suggesting poor intestinal absorption. Ligand B (-4.8) is similarly poor.

**Aqueous Solubility:** Ligand A (-1.034) is low, but potentially manageable. Ligand B (-2.043) is even lower, raising formulation concerns.

**hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.431 and 0.025).

**Microsomal Clearance:** Ligand A (27.645) has moderate clearance. Ligand B (-7.515) has negative clearance, which is not physically possible and likely an error in the data. This is a significant red flag.

**In vitro Half-Life:** Ligand A (10.335 hours) is reasonable. Ligand B (-11.9 hours) is also not physically possible and further indicates data issues.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.147 and 0.015).

**Binding Affinity:** Ligand B (-9.0 kcal/mol) has a significantly stronger binding affinity than Ligand A (-7.4 kcal/mol). This is a substantial advantage.

**Overall Assessment:**

Despite the superior binding affinity of Ligand B, the negative values for microsomal clearance and in vitro half-life are highly problematic and suggest data errors or an unstable compound. The poor BBB penetration of Ligand B is also a serious concern for a CNS target. Ligand A, while having a weaker binding affinity, presents a much more reasonable ADME-Tox profile, with good BBB penetration, acceptable DILI risk, and plausible metabolic stability. The low Caco-2 permeability and solubility are concerns, but potentially addressable through formulation strategies.

Output:
1
2025-04-17 07:47:22,434 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (344.459 and 364.511 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (70.25) is better than Ligand B (67.43), both are below the 90 A^2 threshold for CNS targets.

**3. logP:** Both ligands have good logP values (3.552 and 3.308), falling within the optimal 1-3 range.

**4. H-Bond Donors:** Both ligands have 2 HBD, which is acceptable.

**5. H-Bond Acceptors:** Ligand A has 3 HBA, while Ligand B has 4. Both are below the 10 threshold.

**6. QED:** Both ligands have similar QED values (0.787 and 0.743), indicating good drug-likeness.

**7. DILI:** Ligand A (43.66) has a slightly higher DILI risk than Ligand B (38.852), but both are below the concerning 60 threshold.

**8. BBB:** Ligand A (77.007) has a significantly better BBB penetration percentile than Ligand B (68.67). This is a crucial factor for a CNS target like DRD2.

**9. Caco-2 Permeability:** Ligand A (-4.849) has better Caco-2 permeability than Ligand B (-4.638).

**10. Aqueous Solubility:** Ligand A (-3.78) has better aqueous solubility than Ligand B (-4.125).

**11. hERG Inhibition:** Ligand A (0.841) has a slightly higher hERG inhibition risk than Ligand B (0.463), but both are relatively low.

**12. Microsomal Clearance:** Ligand B (77.172) has a higher microsomal clearance than Ligand A (42.689), suggesting lower metabolic stability.

**13. In vitro Half-Life:** Ligand B (20.643) has a significantly longer in vitro half-life than Ligand A (-14.904).

**14. P-gp Efflux:** Ligand A (0.272) has lower P-gp efflux liability than Ligand B (0.145), which is favorable for CNS penetration.

**15. Binding Affinity:** Both ligands have very similar and strong binding affinities (-9.2 and -8.1 kcal/mol). The difference of 1.1 kcal/mol is not substantial enough to override other ADME differences.

**Overall Assessment:**

Considering the GPCR-specific priorities, Ligand A is the more promising candidate. While Ligand B has a longer half-life, Ligand A excels in BBB penetration, Caco-2 permeability, solubility, and P-gp efflux. The slightly higher DILI and hERG risk for Ligand A are not concerning given the overall profile. The strong binding affinity is comparable for both. The better BBB penetration and lower efflux of Ligand A are critical for CNS drug development.

Output:
0
2025-04-17 07:47:22,434 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 drug candidates, considering the provided guidelines and GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (363.571 and 351.451 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (44.37) is excellent, well below the 90 A^2 threshold for CNS targets. Ligand B (120) is higher but still within an acceptable range, though less optimal.

**3. logP:** Ligand A (4.156) is slightly high, potentially leading to solubility issues or off-target interactions. Ligand B (0.923) is quite low, which could hinder membrane permeability.

**4. H-Bond Donors:** Ligand A (2) is good. Ligand B (4) is acceptable, but approaching the upper limit.

**5. H-Bond Acceptors:** Ligand A (3) is good. Ligand B (5) is acceptable.

**6. QED:** Both ligands have good QED scores (0.564 and 0.607), indicating drug-like properties.

**7. DILI:** Ligand A (23.071) has a very favorable DILI score. Ligand B (56.146) is higher, indicating a moderate risk of liver injury.

**8. BBB:** Ligand A (90.5) has excellent BBB penetration potential, exceeding the desirable >70% threshold. Ligand B (36.371) has poor predicted BBB penetration. This is a critical disadvantage for a CNS target like DRD2.

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 values, which is unusual and suggests a potential issue with the prediction method or the molecules themselves. However, we can interpret this as very low permeability.

**10. Aqueous Solubility:** Both ligands have negative solubility values, indicating poor aqueous solubility. This is a concern, especially for Ligand A with its higher logP.

**11. hERG Inhibition:** Ligand A (0.894) has a low hERG risk. Ligand B (0.06) also has a very low hERG risk.

**12. Microsomal Clearance:** Ligand A (78.348) has moderate clearance. Ligand B (16.629) has very low clearance, suggesting good metabolic stability.

**13. In vitro Half-Life:** Ligand A (48.381) has a reasonable half-life. Ligand B (-15.387) has a negative half-life, which is not physically possible and indicates a problem with the prediction.

**14. P-gp Efflux:** Ligand A (0.718) has moderate P-gp efflux. Ligand B (0.037) has very low P-gp efflux, which is beneficial for CNS penetration.

**15. Binding Affinity:** Ligand B (-7.5 kcal/mol) has significantly stronger binding affinity than Ligand A (0.0 kcal/mol). This is a substantial advantage.

**Overall Assessment:**

Despite Ligand B's superior binding affinity, its extremely poor BBB penetration (36.371%) and problematic half-life prediction (-15.387) are major drawbacks for a CNS-targeted GPCR like DRD2. Ligand A, while having a slightly higher logP and moderate clearance, exhibits excellent BBB penetration (90.5%), a favorable DILI score, and acceptable overall properties. The significant difference in binding affinity is a concern, but the ADME properties of Ligand A are far more suitable for CNS drug development.

Output:
1
2025-04-17 07:47:22,434 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 drug candidates, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the acceptable range (200-500 Da). Ligand A (354.403 Da) is slightly preferred as it's closer to the ideal range.

**TPSA:** Ligand A (117.87) is better than Ligand B (69.64). For CNS targets, TPSA should be <=90, so Ligand B is much better in this regard.

**logP:** Both ligands have good logP values (A: 1.128, B: 2.83), falling within the optimal 1-3 range. Ligand B is slightly better.

**H-Bond Donors/Acceptors:** Ligand A has 3 HBD and 6 HBA, while Ligand B has 2 HBD and 5 HBA. Both are within acceptable limits.

**QED:** Both ligands have good QED scores (A: 0.572, B: 0.724), indicating good drug-like properties. Ligand B is better.

**DILI:** Ligand A (47.421) has a lower DILI risk than Ligand B (66.693), which is a significant advantage.

**BBB:** Ligand B (39.822) has a significantly better BBB penetration percentile than Ligand A (24.195). This is *critical* for a CNS target like DRD2.

**Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and suggests poor permeability.

**Aqueous Solubility:** Both have negative solubility values, which is also unusual and suggests poor solubility.

**hERG:** Ligand A (0.136) has a much lower hERG inhibition liability than Ligand B (0.767), indicating a lower risk of cardiotoxicity.

**Microsomal Clearance:** Ligand A (38.452) has lower microsomal clearance than Ligand B (64.983), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (24.133) has a longer in vitro half-life than Ligand B (9.362).

**P-gp Efflux:** Ligand A (0.072) has lower P-gp efflux liability than Ligand B (0.389), which is favorable for CNS penetration.

**Binding Affinity:** Ligand B (-8.4 kcal/mol) has a significantly stronger binding affinity than Ligand A (-7.1 kcal/mol). This is a substantial advantage, potentially outweighing some ADME drawbacks.

**Overall Assessment:**

Ligand B excels in binding affinity and BBB penetration, which are paramount for a CNS GPCR target. While it has some drawbacks in DILI and hERG, the strong binding affinity could compensate for these. Ligand A has better ADME properties (DILI, hERG, clearance, half-life, P-gp efflux) but significantly weaker binding affinity. Given the importance of potency for GPCRs, and the substantial difference in affinity (-8.4 vs -7.1 kcal/mol), Ligand B is the more promising candidate despite its slightly worse ADME profile.

Output:
1
2025-04-17 07:47:22,435 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (352.406 and 374.457 Da) fall within the ideal 200-500 Da range.

**TPSA:** Both ligands have TPSA values (78.87 and 76.14) below the 90 A^2 threshold for CNS targets, which is excellent.

**logP:** Ligand A (1.925) is optimal, while Ligand B (3.011) is at the higher end of the optimal range. Both are acceptable.

**H-Bond Donors/Acceptors:** Both ligands have 2 HBDs, which is good. Ligand A has 4 HBAs, and Ligand B has 6 HBAs. Both are within the acceptable limit of 10.

**QED:** Ligand A (0.849) has a significantly better QED score than Ligand B (0.65), indicating a more drug-like profile.

**DILI:** Ligand A (34.781) has a lower DILI risk than Ligand B (59.442), suggesting a safer profile. Both are below the 60 threshold, but A is preferable.

**BBB:** Ligand B (85.692) has a substantially better BBB penetration percentile than Ligand A (71.19). This is a critical factor for a CNS target like DRD2.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.744 and -4.664), which is unusual and suggests poor permeability. This is a significant drawback for both.

**Aqueous Solubility:** Both ligands have negative solubility values (-2.964 and -3.984), indicating very poor aqueous solubility. This is a major concern for bioavailability.

**hERG Inhibition:** Both ligands have low hERG inhibition liability (0.49 and 0.279), which is positive.

**Microsomal Clearance:** Ligand A (22.071) has lower microsomal clearance than Ligand B (62.192), indicating better metabolic stability.

**In vitro Half-Life:** Ligand B (-7.152) has a longer in vitro half-life than Ligand A (-2.297), which is desirable.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.119 and 0.168), which is good for CNS penetration.

**Binding Affinity:** Both ligands have excellent binding affinities (-8.7 and -8.1 kcal/mol). Ligand A is slightly better (-8.7 kcal/mol), but the difference is relatively small.

**Overall Assessment:**

Ligand A has advantages in QED, DILI, and metabolic stability (Cl_mic). However, Ligand B shines with its significantly higher BBB penetration (85.692 vs 71.19). Given DRD2 is a CNS target, BBB penetration is paramount. While both have poor solubility and Caco-2 permeability, the superior BBB score of Ligand B outweighs the other advantages of Ligand A.

Output:
1
2025-04-17 07:47:22,435 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B based on the provided guidelines, prioritizing GPCR-specific properties (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (372.515 and 358.36 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (50.36) is better than Ligand B (58.64). Both are below the 90 A^2 threshold desirable for CNS targets, but A is closer to optimal.

**logP:** Ligand B (2.535) is better than Ligand A (4.321). Ligand A is a bit high, potentially leading to solubility issues or off-target interactions. Ligand B is within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A has 2 HBD and 4 HBA, while Ligand B has 1 HBD and 4 HBA. Both are within acceptable limits.

**QED:** Both ligands have good QED scores (0.621 and 0.761, respectively), indicating drug-like properties. Ligand B is slightly better.

**DILI:** Ligand B (38.658) is significantly better than Ligand A (74.99). Ligand A is approaching a concerning DILI risk.

**BBB:** Ligand B (83.986) is better than Ligand A (71.966). Both are above the 70% threshold for CNS targets, but B is superior.

**Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and suggests poor permeability. However, the magnitude is similar, so this isn't a major differentiator.

**Aqueous Solubility:** Both have negative solubility values, also unusual. Ligand B (-2.886) is slightly better than Ligand A (-5.262).

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.588 and 0.533).

**Microsomal Clearance:** Ligand B (52.864) is significantly better than Ligand A (93.147). Lower clearance means better metabolic stability.

**In vitro Half-Life:** Ligand B (-13.289) is significantly better than Ligand A (87.7). A negative half-life is unusual, but relative to A, it is much more favorable.

**P-gp Efflux:** Ligand B (0.06) is much better than Ligand A (0.66). Lower P-gp efflux is crucial for CNS penetration.

**Binding Affinity:** Ligand A (-8.1 kcal/mol) has a 0.6 kcal/mol advantage over Ligand B (-7.5 kcal/mol). This is a substantial difference in potency.

**Overall Assessment:**

While Ligand A has a better binding affinity, Ligand B demonstrates superior ADME properties, particularly regarding safety (DILI), CNS penetration (BBB, P-gp), and metabolic stability (Cl_mic, t1/2). The affinity difference, while significant, can potentially be optimized in later stages of drug development. The poor ADME profile of Ligand A, especially the DILI risk and higher P-gp efflux, makes it a less viable candidate. For a CNS target like DRD2, good brain penetration and safety are paramount.

Output:
1
2025-04-17 07:47:22,435 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B against the provided guidelines, prioritizing GPCR-specific properties (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (348.531 and 346.387 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (58.2) is excellent for CNS penetration, well below the 90 A^2 threshold. Ligand B (117.25) is higher, but still potentially acceptable, though less ideal.

**logP:** Ligand A (3.508) is at the upper end of the optimal range (1-3), but still acceptable. Ligand B (0.678) is quite low, potentially hindering permeability.

**H-Bond Donors/Acceptors:** Both have 2 HBD, which is good. Ligand A has 2 HBA, also good. Ligand B has 6 HBA, which is higher, potentially affecting permeability.

**QED:** Both ligands have good QED scores (0.705 and 0.782), indicating drug-like properties.

**DILI:** Ligand A (12.602) has a much lower DILI risk than Ligand B (56.572), which is a significant advantage.

**BBB:** Ligand A (78.945) has a very good BBB percentile, exceeding the 70% threshold for CNS targets. Ligand B (63.901) is lower, and less favorable for CNS penetration.

**Caco-2:** Both have negative Caco-2 values, which is unusual and suggests potential issues with intestinal absorption. However, the scale is not well-defined here, so it's difficult to interpret.

**Solubility:** Both have negative solubility values, again suggesting potential formulation challenges.

**hERG:** Both ligands have very low hERG inhibition liability (0.62 and 0.103), which is excellent.

**Microsomal Clearance:** Ligand A (82.306) has higher microsomal clearance, suggesting faster metabolism. Ligand B (13.191) has much lower clearance, indicating better metabolic stability.

**In vitro Half-Life:** Both have negative half-life values, which is not meaningful.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.142 and 0.025), which is favorable for CNS exposure.

**Binding Affinity:** Ligand A (-8.5 kcal/mol) has a slightly better binding affinity than Ligand B (-7.8 kcal/mol). While the difference is not huge (1.7 kcal/mol), it's enough to be considered, especially given the other favorable properties of Ligand A.

**Overall Assessment:**

Ligand A is significantly better suited as a CNS drug candidate targeting DRD2. It has a superior BBB score, lower DILI risk, and slightly better binding affinity. While Ligand B has better metabolic stability, the poor logP and lower BBB penetration are major drawbacks for a CNS-targeted GPCR. The negative values for Caco-2 and solubility are concerning for both, but the other advantages of Ligand A outweigh this.

Output:
1
2025-04-17 07:47:22,435 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (350.438 Da) is slightly lower, which is generally favorable for permeability. Ligand B (381.402 Da) is also acceptable.

**TPSA:** Ligand A (83.98) is excellent, falling well below the 90 A^2 threshold for CNS targets. Ligand B (107.97) is still reasonable but less optimal, being above 100.

**logP:** Ligand A (3.056) is optimal. Ligand B (0.284) is significantly lower, which raises concerns about membrane permeability and potentially reduced binding affinity.

**H-Bond Donors/Acceptors:** Ligand A (HBD=2, HBA=4) is well within acceptable limits. Ligand B (HBD=1, HBA=8) is also acceptable, though the higher HBA count could slightly impact permeability.

**QED:** Both ligands have reasonable QED scores (A: 0.772, B: 0.581), indicating good drug-like properties.

**DILI:** Ligand A (48.119) has a lower DILI risk than Ligand B (87.902), which is a significant advantage.

**BBB:** Ligand A (78.48) has a much better BBB penetration score than Ligand B (46.336). This is *critical* for a CNS target like DRD2.

**Caco-2 Permeability:** Ligand A (-4.505) has better Caco-2 permeability than Ligand B (-5.765).

**Aqueous Solubility:** Ligand A (-3.634) has better aqueous solubility than Ligand B (-2.821).

**hERG:** Both ligands have very low hERG inhibition liability (A: 0.174, B: 0.154), which is excellent.

**Microsomal Clearance:** Ligand B (28.952) has lower microsomal clearance than Ligand A (35.781), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand B (-17.302) has a longer in vitro half-life than Ligand A (-3.916). This is a positive attribute.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (A: 0.033, B: 0.035).

**Binding Affinity:** Both ligands have the same binding affinity (-7.8 kcal/mol), which is excellent.

**Overall Assessment:**

Ligand A is significantly more promising. While Ligand B has slightly better metabolic stability and half-life, Ligand A excels in crucial areas for CNS drug development: TPSA, logP, BBB penetration, and DILI risk. The lower logP of Ligand B is a major concern, potentially hindering its ability to cross the blood-brain barrier and reach the DRD2 receptor effectively. The superior BBB score of Ligand A is a decisive factor.

Output:
0
2025-04-17 07:47:22,436 - INFO - Reasoning:

Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (343.435 and 350.415 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Both ligands have TPSA values (87.97 and 85.89) below the 90 A^2 threshold for CNS targets, which is excellent.

**3. logP:** Both ligands have logP values (1.207 and 1.889) within the optimal 1-3 range. Ligand B is slightly more lipophilic, which could be beneficial for membrane permeability.

**4. H-Bond Donors:** Both ligands have 2 HBD, which is within the acceptable limit of <=5.

**5. H-Bond Acceptors:** Ligand A has 7 HBA, and Ligand B has 5 HBA, both within the acceptable limit of <=10.

**6. QED:** Ligand A (0.848) has a significantly higher QED score than Ligand B (0.664), indicating better overall drug-likeness.

**7. DILI:** Ligand A (56.689) has a lower DILI risk than Ligand B (61.264), suggesting a safer profile.

**8. BBB:** Ligand A (73.827) has a better BBB penetration percentile than Ligand B (65.839). This is a critical factor for a CNS target like DRD2.

**9. Caco-2 Permeability:** Both have negative Caco-2 values which is unusual and suggests poor permeability. Ligand A (-5.249) is slightly better than Ligand B (-4.703)

**10. Aqueous Solubility:** Both ligands have very poor aqueous solubility (-2.291 and -2.251). This is a significant concern for both compounds.

**11. hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.577 and 0.192).

**12. Microsomal Clearance:** Ligand A (15.11 mL/min/kg) has a lower microsomal clearance than Ligand B (28.308 mL/min/kg), indicating better metabolic stability.

**13. In vitro Half-Life:** Ligand A (33.832 hours) has a much longer in vitro half-life than Ligand B (2.973 hours), which is highly desirable.

**14. P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.02 and 0.084).

**15. Binding Affinity:** Both ligands have excellent binding affinities (-8.5 and -8.1 kcal/mol). Ligand A has a slightly better affinity.

**Overall Assessment:**

While both compounds show good binding affinity and acceptable physicochemical properties, Ligand A is the superior candidate. Its higher QED, lower DILI risk, better BBB penetration, lower microsomal clearance, and longer half-life outweigh the slightly better logP of Ligand B. The poor solubility of both compounds is a concern that would need to be addressed during lead optimization, but the other advantages of Ligand A make it the more promising starting point.

Output:
1
2025-04-17 07:47:22,436 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (354.51 and 350.459 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (58.2) is excellent, well below the 90 A^2 threshold for CNS targets. Ligand B (89.87) is higher, but still acceptable, though less optimal for CNS penetration.

**3. logP:** Ligand A (3.6) is within the optimal range (1-3). Ligand B (0.828) is a bit low, potentially hindering membrane permeability.

**4. H-Bond Donors:** Ligand A (2) and Ligand B (3) are both acceptable (<=5).

**5. H-Bond Acceptors:** Ligand A (2) and Ligand B (4) are both acceptable (<=10).

**6. QED:** Both ligands have similar QED values (0.734 and 0.619), indicating good drug-like properties.

**7. DILI:** Both ligands have low DILI risk (13.92 and 12.369), which is favorable.

**8. BBB:** Ligand A (80.264) has a significantly better BBB percentile than Ligand B (47.344). This is *critical* for a CNS target like DRD2.

**9. Caco-2:** Ligand A (-4.616) and Ligand B (-5.07) both have negative Caco-2 values, which is unusual and suggests poor permeability. This is a concern for both, but the negative value for B is worse.

**10. Solubility:** Ligand A (-3.867) and Ligand B (-1.97) both have negative solubility values, which is also unusual and suggests poor solubility.

**11. hERG:** Both ligands have low hERG risk (0.672 and 0.173).

**12. Cl_mic:** Ligand A (53.219) has a higher microsomal clearance than Ligand B (16.113), suggesting faster metabolism and potentially lower exposure.

**13. t1/2:** Ligand A (-9.269) has a negative in vitro half-life, which is unusual. Ligand B (-6.54) is also negative, but less so.

**14. Pgp:** Ligand A (0.249) has lower P-gp efflux liability than Ligand B (0.063), meaning it's less likely to be pumped out of the brain.

**15. Binding Affinity:** Ligand A (-8.6 kcal/mol) has a slightly better binding affinity than Ligand B (-7.5 kcal/mol), although both are quite good.

**Overall Assessment:**

Ligand A is the stronger candidate. While both have issues with Caco-2 and solubility, Ligand A's superior BBB penetration, lower P-gp efflux, and slightly better binding affinity are decisive advantages for a CNS-targeting GPCR. The lower microsomal clearance of Ligand B is a plus, but is outweighed by the other factors. The unusual negative half-life values for both are concerning and would require further investigation, but are less critical than the BBB and Pgp properties.

Output:
1
2025-04-17 07:47:22,436 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (350.507 and 368.503 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (47.1) is excellent, well below the 90 A^2 threshold for CNS targets. Ligand B (97.55) is higher, but still potentially acceptable, though less ideal.

**logP:** Both ligands have good logP values (1.016 and 1.817), falling within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A (0 HBD, 4 HBA) is very favorable. Ligand B (2 HBD, 6 HBA) is also acceptable, though slightly higher.

**QED:** Both ligands have similar and good QED scores (0.759 and 0.765), indicating good drug-like properties.

**DILI:** Ligand A (8.647) has a significantly lower DILI risk than Ligand B (45.25). This is a major advantage for Ligand A.

**BBB:** Ligand B (78.558) has a better BBB penetration score than Ligand A (64.482), which is important for a CNS target like DRD2.

**Caco-2 Permeability:** Both show negative values, which is unusual and suggests poor permeability. However, the scale is not specified, so we can't interpret this definitively.

**Aqueous Solubility:** Both ligands have negative solubility values, which is also unusual. This suggests poor solubility.

**hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.592 and 0.536).

**Microsomal Clearance:** Ligand A (1.692) has much lower microsomal clearance than Ligand B (15.697), indicating better metabolic stability.

**In vitro Half-Life:** Ligand B (8.569) has a significantly longer in vitro half-life than Ligand A (-1.088).

**P-gp Efflux:** Both have very low P-gp efflux liability (0.026 and 0.206).

**Binding Affinity:** Ligand B (-7.5 kcal/mol) has a considerably stronger binding affinity than Ligand A (-0.0 kcal/mol). This is a substantial advantage, potentially outweighing some ADME concerns.

**Overall Assessment:**

Ligand B has a significantly better binding affinity and a better BBB score, which are crucial for a CNS GPCR target. However, it has a higher DILI risk, higher microsomal clearance, and a lower solubility. Ligand A has a much better safety profile (DILI, metabolic stability), but its binding affinity is very weak.

Given the strong preference for potency in GPCR drug discovery, and the substantial difference in binding affinity (-7.5 vs -0.0 kcal/mol), Ligand B is the more promising candidate *despite* its less favorable ADME properties. The difference in affinity is so large that optimization efforts could likely address the ADME liabilities of Ligand B.



Output:
1
2025-04-17 07:47:22,436 - INFO - Batch 394 complete. Total preferences: 6304
2025-04-17 07:47:22,436 - INFO - Processing batch 395/512...
2025-04-17 07:48:05,176 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (348.422 and 352.475 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (67.23) is slightly higher than Ligand B (59.08). Both are below the 90 A^2 threshold for CNS targets, which is good. Ligand B is preferable here.

**3. logP:** Both ligands have good logP values (1.568 and 1.681), falling within the optimal 1-3 range.

**4. H-Bond Donors:** Ligand A has 1 HBD, while Ligand B has 0. Both are acceptable (<=5).

**5. H-Bond Acceptors:** Both ligands have 4 HBAs, well within the acceptable limit of <=10.

**6. QED:** Ligand A (0.822) has a significantly better QED score than Ligand B (0.443), indicating a more drug-like profile.

**7. DILI:** Ligand A (51.648) has a higher DILI risk than Ligand B (12.641). Ligand B is significantly better here.

**8. BBB:** Ligand A (82.435) has a slightly better BBB penetration percentile than Ligand B (79.488), but both are good (>70).

**9. Caco-2 Permeability:** Ligand A (-4.761) has worse Caco-2 permeability than Ligand B (-4.275). Higher values are better, so Ligand B is preferable.

**10. Aqueous Solubility:** Ligand A (-2.581) has worse aqueous solubility than Ligand B (-1.049). Higher values are better, so Ligand B is preferable.

**11. hERG Inhibition:** Both ligands have similar, low hERG inhibition liability (0.41 and 0.526).

**12. Microsomal Clearance:** Ligand A (22.258) has higher microsomal clearance than Ligand B (13.027). Lower clearance is better for metabolic stability, so Ligand B is preferable.

**13. In vitro Half-Life:** Ligand A (-7.667) and Ligand B (-7.592) have similar in vitro half-lives.

**14. P-gp Efflux:** Ligand A (0.128) has lower P-gp efflux liability than Ligand B (0.071). Lower efflux is better for CNS exposure, so Ligand A is preferable.

**15. Binding Affinity:** Ligand A (-7.7 kcal/mol) has a slightly better binding affinity than Ligand B (-6.6 kcal/mol). This 1.1 kcal/mol difference is significant and can outweigh some ADME drawbacks.

**Overall Assessment:**

Ligand A has a better binding affinity, QED, and P-gp efflux, while Ligand B excels in DILI risk, Caco-2 permeability, solubility, and microsomal clearance. Considering the GPCR-specific priorities, BBB is good for both. The affinity difference is substantial. The lower DILI risk of Ligand B is attractive, but the improved binding affinity of Ligand A is a strong advantage for a CNS target. The slightly better BBB of Ligand A also tips the scales.

Output:
1
2025-04-17 07:48:05,177 - INFO - Reasoning:

Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (376.519 and 341.455 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (101.57) is higher than the preferred <90 for CNS targets, while Ligand B (73.2) is well within the range. This is a significant advantage for Ligand B.

**3. logP:** Ligand A (0.885) is a bit low, potentially hindering permeability. Ligand B (2.881) is closer to the optimal 1-3 range.

**4. H-Bond Donors:** Ligand A (2) and Ligand B (1) are both acceptable, being less than 5.

**5. H-Bond Acceptors:** Ligand A (5) and Ligand B (3) are both acceptable, being less than 10.

**6. QED:** Both ligands have good QED scores (0.589 and 0.829), indicating drug-like properties.

**7. DILI:** Both ligands have low DILI risk (40.054 and 38.077), which is positive.

**8. BBB:** Ligand B (72.935) has a much better BBB percentile than Ligand A (55.874). This is crucial for a CNS target like DRD2.

**9. Caco-2 Permeability:** Ligand A (-5.275) has poor Caco-2 permeability, suggesting poor absorption. Ligand B (-4.223) is also not great, but slightly better than A.

**10. Aqueous Solubility:** Ligand A (-1.957) and Ligand B (-3.604) both have poor aqueous solubility.

**11. hERG Inhibition:** Both ligands have low hERG inhibition risk (0.235 and 0.542).

**12. Microsomal Clearance:** Ligand A (26.743) has lower microsomal clearance than Ligand B (65.354), suggesting better metabolic stability.

**13. In vitro Half-Life:** Ligand B (26.541) has a longer in vitro half-life than Ligand A (13.66), which is preferable.

**14. P-gp Efflux:** Ligand A (0.041) has significantly lower P-gp efflux liability than Ligand B (0.121). Lower P-gp efflux is beneficial for CNS exposure.

**15. Binding Affinity:** Ligand B (-8.3 kcal/mol) has a slightly better binding affinity than Ligand A (-7.6 kcal/mol). While both are good, the 0.7 kcal/mol difference is noteworthy.

**Overall Assessment:**

Ligand B is the more promising candidate. While both have acceptable MW, QED, and DILI, Ligand B excels in critical areas for a CNS GPCR target: significantly better BBB penetration (72.9% vs 55.9%), a more optimal logP, and a slightly improved binding affinity. Ligand A has better metabolic stability (lower Cl_mic) and lower P-gp efflux, but the BBB and logP issues are more critical for CNS penetration and overall drug-like properties in this context. The slightly longer half-life of Ligand B is also a plus.

Output:
1
2025-04-17 07:48:05,177 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (428.766 Da) is slightly higher, but acceptable. Ligand B (354.451 Da) is also good.

**TPSA:** Ligand A (76.1) is excellent, falling well below the 90 A^2 threshold for CNS targets. Ligand B (110.77) is higher, but still potentially acceptable, though less ideal for CNS penetration.

**logP:** Ligand A (1.256) is within the optimal range (1-3). Ligand B (-0.18) is slightly below 1, which could hinder permeation, but is not a complete dealbreaker given the high affinity.

**H-Bond Donors/Acceptors:** Ligand A (1 HBD, 7 HBA) is good. Ligand B (4 HBD, 4 HBA) is also acceptable.

**QED:** Both ligands have reasonable QED values (A: 0.669, B: 0.508), indicating good drug-like properties.

**DILI:** Ligand A (33.773) has a lower DILI risk than Ligand B (20.279), which is preferable.

**BBB:** Ligand A (47.848) has a better BBB percentile than Ligand B (40.132), which is critical for a CNS target like DRD2.

**Caco-2 Permeability:** Both have negative Caco-2 values (-5.648 and -5.309), which is unusual and suggests poor permeability. This is a significant concern for both.

**Aqueous Solubility:** Both have negative solubility values (-1.693 and -0.905), suggesting poor solubility. This is also a concern for both.

**hERG:** Both ligands show very low hERG inhibition liability (A: 0.586, B: 0.089), which is excellent.

**Microsomal Clearance:** Ligand A (-9.508) has significantly lower (better) microsomal clearance than Ligand B (-4.937), indicating better metabolic stability.

**In vitro Half-Life:** Ligand A (-2.688) has a longer half-life than Ligand B (12.201), which is desirable.

**P-gp Efflux:** Both ligands show very low P-gp efflux liability (A: 0.016, B: 0.003), which is excellent for CNS penetration.

**Binding Affinity:** Both ligands have very similar and strong binding affinities (-8.3 kcal/mol and -8.2 kcal/mol). The difference is minimal.

**Overall Assessment:**

Ligand A is superior to Ligand B. While both have issues with Caco-2 permeability and aqueous solubility, Ligand A demonstrates better BBB penetration, lower DILI risk, significantly improved metabolic stability (lower Cl_mic and longer half-life), and a slightly better TPSA. The binding affinity is comparable. Given the importance of BBB penetration for a CNS target like DRD2, and the better ADME profile overall, Ligand A is the more promising candidate.

Output:
1
2025-04-17 07:48:05,177 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (365.43 and 347.459 Da) fall within the ideal range of 200-500 Da.

**TPSA:** Ligand A (69.85) is better than Ligand B (75.44). Both are below the 90 A^2 threshold for CNS targets, but A is closer to optimal.

**logP:** Both ligands have good logP values (2.959 and 3.206), falling within the 1-3 range.

**H-Bond Donors/Acceptors:** Both have 1 HBD, which is good. Ligand A has 6 HBA, while Ligand B has 4. Both are acceptable (<=10).

**QED:** Both ligands have good QED scores (0.652 and 0.802), indicating good drug-likeness.

**DILI:** Ligand A (56.727) has a slightly higher DILI risk than Ligand B (33.346), but both are below the concerning threshold of 60.

**BBB:** Ligand A (82.784) has a significantly better BBB penetration percentile than Ligand B (70.609). This is a crucial factor for a CNS target like DRD2.

**Caco-2 Permeability:** Ligand A (-4.903) has worse Caco-2 permeability than Ligand B (-4.424). Lower values indicate lower permeability.

**Aqueous Solubility:** Ligand A (-3.673) has worse aqueous solubility than Ligand B (-3.002). Lower values indicate lower solubility.

**hERG:** Ligand A (0.958) has a slightly higher hERG risk than Ligand B (0.056). Lower is better.

**Microsomal Clearance:** Ligand B (68.963) has a higher microsomal clearance than Ligand A (37.798), indicating faster metabolism and lower metabolic stability.

**In vitro Half-Life:** Ligand A (17.191) has a longer in vitro half-life than Ligand B (9.55).

**P-gp Efflux:** Ligand A (0.774) has lower P-gp efflux than Ligand B (0.076), which is favorable for CNS penetration.

**Binding Affinity:** Both ligands have the same binding affinity (-8.1 kcal/mol), which is excellent.

**Overall Assessment:**

While Ligand B has slightly better Caco-2 permeability, solubility, and a lower hERG risk, Ligand A is superior due to its significantly better BBB penetration (82.8% vs 70.6%), lower P-gp efflux, and longer half-life. Considering DRD2 is a CNS target, BBB penetration is paramount. The slightly higher DILI and hERG risk for Ligand A are less concerning given the excellent affinity and superior CNS penetration properties. The better metabolic stability (lower Cl_mic) of Ligand A is also a plus.

Output:
1
2025-04-17 07:48:05,178 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B based on the provided guidelines, prioritizing GPCR-specific properties (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (348.431 and 346.391 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (59.81) is excellent, well below the 90 A^2 threshold for CNS targets. Ligand B (114.94) is higher, but still potentially acceptable, though less ideal.

**logP:** Ligand A (3.972) is at the upper end of the optimal range (1-3), but still acceptable. Ligand B (0.428) is quite low, potentially hindering membrane permeability and CNS penetration.

**H-Bond Donors/Acceptors:** Ligand A (HBD=1, HBA=5) is favorable. Ligand B (HBD=2, HBA=7) is also reasonable, but slightly higher HBA might affect permeability.

**QED:** Both ligands have good QED scores (A: 0.607, B: 0.716), indicating good drug-like properties.

**DILI:** Ligand A (87.747) has a higher DILI risk than Ligand B (54.556), which is a concern.

**BBB:** Both ligands have good BBB penetration (A: 70.919, B: 72.16), exceeding the 70% threshold for CNS targets.

**Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and problematic. This suggests poor intestinal absorption, but the scale is unclear.

**Aqueous Solubility:** Both ligands have very poor aqueous solubility (-4.364 and -2.165). This is a significant drawback for both.

**hERG Inhibition:** Ligand A (0.619) has a slightly higher hERG risk than Ligand B (0.017), but both are relatively low.

**Microsomal Clearance:** Ligand A (108.322) has higher microsomal clearance, indicating faster metabolism and potentially lower bioavailability. Ligand B (11.718) has much lower clearance, suggesting better metabolic stability.

**In vitro Half-Life:** Ligand B (16.949 hours) has a longer half-life than Ligand A (13.794 hours).

**P-gp Efflux:** Ligand A (0.653) has lower P-gp efflux, which is favorable for CNS penetration. Ligand B (0.011) has very low P-gp efflux, which is even better.

**Binding Affinity:** Ligand B (-7.2 kcal/mol) has a significantly stronger binding affinity than Ligand A (-10.1 kcal/mol). This is a substantial advantage, potentially outweighing some of the ADME drawbacks.

**Overall Assessment:**

While Ligand A has better TPSA and P-gp efflux, Ligand B has a much stronger binding affinity, better metabolic stability (lower Cl_mic, longer t1/2), lower DILI risk, and a slightly better BBB score. The biggest concerns for both are the poor aqueous solubility and negative Caco-2 values. However, the significantly improved binding affinity of Ligand B, coupled with its more favorable metabolic profile, makes it the more promising candidate, especially considering the GPCR target class where potency is crucial. The lower logP of Ligand B is a concern, but the strong binding affinity might compensate.

Output:
1
2025-04-17 07:48:05,178 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (345.443 and 345.451 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (74.43) is significantly better than Ligand B (110.75). For CNS targets, TPSA should be <= 90, and A is comfortably within this range, while B is pushing the limit.

**3. logP:** Both ligands have acceptable logP values (1.574 and 1.951), falling within the optimal 1-3 range.

**4. H-Bond Donors:** Ligand A (2) is preferable to Ligand B (3), though both are within the acceptable limit of <=5.

**5. H-Bond Acceptors:** Ligand B (7) is higher than Ligand A (3). Ideally, this should be <=10, and both are within this range, but A is better.

**6. QED:** Ligand A (0.851) has a better QED score than Ligand B (0.568), indicating a more drug-like profile.

**7. DILI:** Ligand A (35.285) has a significantly lower DILI risk than Ligand B (55.758). Both are below the concerning threshold of 60, but A is much better.

**8. BBB:** Ligand B (89.298) has a substantially better BBB penetration percentile than Ligand A (72.586). This is a critical factor for a CNS target like DRD2, and B has a clear advantage here.

**9. Caco-2 Permeability:** Ligand A (-4.781) has worse Caco-2 permeability than Ligand B (-5.438). Lower values here indicate poorer permeability.

**10. Aqueous Solubility:** Ligand A (-3.119) has slightly better aqueous solubility than Ligand B (-2.809).

**11. hERG Inhibition:** Ligand A (0.488) has a lower hERG inhibition liability than Ligand B (0.745), which is favorable.

**12. Microsomal Clearance:** Ligand B (66.013) has higher microsomal clearance than Ligand A (39.423), suggesting faster metabolism and potentially lower *in vivo* exposure.

**13. In vitro Half-Life:** Ligand B (15.099) has a longer in vitro half-life than Ligand A (-13.755). This is a positive attribute.

**14. P-gp Efflux:** Ligand A (0.185) has lower P-gp efflux liability than Ligand B (0.259), which is beneficial for CNS penetration.

**15. Binding Affinity:** Ligand B (-7.5) has a slightly better binding affinity than Ligand A (-8.3). While A is already very good, B's affinity is marginally better.

**Overall Assessment:**

Ligand B excels in BBB penetration and has a slightly better binding affinity and half-life. However, Ligand A demonstrates superior drug-likeness (QED), lower DILI risk, lower hERG risk, lower P-gp efflux, and better TPSA. Given the GPCR-specific priorities, the improved BBB of Ligand B is significant, but the combination of better ADME properties (lower DILI, hERG, P-gp, and TPSA) in Ligand A, along with its good affinity, makes it a more promising candidate. The slightly better affinity of B is unlikely to overcome the ADME advantages of A.

Output:
0
2025-04-17 07:48:05,178 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (350.503 and 368.543 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Both ligands have TPSA values (63.45 and 62.66) below the 90 A^2 threshold for CNS targets, which is excellent.

**3. logP:** Ligand A (4.421) is slightly above the optimal 1-3 range, while Ligand B (3.632) is within the optimal range. This gives a slight edge to Ligand B.

**4. H-Bond Donors:** Ligand A (0) and Ligand B (1) are both acceptable.

**5. H-Bond Acceptors:** Ligand A (3) and Ligand B (5) are both acceptable.

**6. QED:** Both ligands have good QED scores (0.481 and 0.761), indicating reasonable drug-likeness. Ligand B is better here.

**7. DILI:** Ligand A (16.44) has a significantly lower DILI risk than Ligand B (33.579). This is a substantial advantage for Ligand A.

**8. BBB:** Ligand A (77.2) has a better BBB percentile than Ligand B (62.737). This is critical for a CNS target like DRD2, giving a significant advantage to Ligand A.

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 values, which is unusual and suggests poor permeability. However, the scale is not specified, so we can't draw strong conclusions.

**10. Aqueous Solubility:** Both ligands have negative solubility values, which is also unusual and suggests poor solubility. Again, the scale is not specified.

**11. hERG Inhibition:** Ligand A (0.784) has a slightly higher hERG risk than Ligand B (0.519), but both are relatively low.

**12. Microsomal Clearance:** Ligand A (88.164) has higher microsomal clearance than Ligand B (85.83), suggesting lower metabolic stability. This favors Ligand B.

**13. In vitro Half-Life:** Ligand A (6.297) has a shorter half-life than Ligand B (-19.831). The negative value for ligand B is concerning and likely an error. This favors Ligand A.

**14. P-gp Efflux:** Ligand A (0.791) has higher P-gp efflux than Ligand B (0.565). This is unfavorable for CNS penetration, favoring Ligand B.

**15. Binding Affinity:** Ligand B (-7.0) has a significantly stronger binding affinity than Ligand A (0.0). This is a major advantage for Ligand B, potentially outweighing some ADME drawbacks.

**Overall Assessment:**

Ligand B has a superior binding affinity and falls within the optimal logP range. However, it has a higher DILI risk and lower BBB penetration. Ligand A has better BBB penetration, lower DILI risk, and a more reasonable half-life, but its binding affinity is much weaker and its logP is slightly high.

Given the importance of BBB penetration and low toxicity for a CNS-targeting drug, and the substantial difference in binding affinity, the stronger binding affinity of Ligand B is likely to be the deciding factor. While the ADME properties of Ligand B are not ideal, they could potentially be improved through further optimization. The very weak binding of Ligand A makes it unlikely to be a viable candidate, even with better ADME properties.

Output:
1
2025-04-17 07:48:05,178 - INFO - Reasoning:

Let's analyze Ligand A and Ligand B based on the provided guidelines, prioritizing GPCR-specific properties (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (348.49 and 350.42 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (67.43) is significantly better than Ligand B (105.34). For CNS targets, TPSA should be <= 90, and A is comfortably within this range, while B exceeds it.

**logP:** Ligand A (3.369) is optimal (1-3), while Ligand B (0.157) is quite low, potentially hindering permeation.

**H-Bond Donors/Acceptors:** Ligand A (2 HBD, 3 HBA) and Ligand B (3 HBD, 5 HBA) both are within acceptable ranges.

**QED:** Both ligands have reasonable QED scores (0.743 and 0.619), indicating good drug-like properties.

**DILI:** Ligand A (38.503) has a lower DILI risk than Ligand B (51.338), both are acceptable but A is preferable.

**BBB:** Ligand A (42.187) has a low BBB penetration, while Ligand B (52.23) is also low. Both are below the desirable >70 for CNS targets. This is a significant drawback for both, but less critical if other properties are strongly favorable.

**Caco-2 Permeability:** Ligand A (-4.471) has poor Caco-2 permeability, while Ligand B (-5.533) is even worse.

**Aqueous Solubility:** Ligand A (-3.875) has poor solubility, while Ligand B (-1.893) is slightly better, but still poor.

**hERG:** Ligand A (0.481) has a very low hERG risk, while Ligand B (0.116) is also low.

**Microsomal Clearance:** Ligand A (91.009) has higher clearance, indicating lower metabolic stability, while Ligand B (-8.929) has negative clearance, which is unusual and suggests very high stability.

**In vitro Half-Life:** Ligand A (16.009) has a moderate half-life, while Ligand B (-5.76) has a negative half-life, which is not physically possible and indicates a potential issue with the data.

**P-gp Efflux:** Ligand A (0.168) has low P-gp efflux, which is good for CNS penetration. Ligand B (0.014) has very low P-gp efflux, which is even better.

**Binding Affinity:** Ligand A (-8.7 kcal/mol) has a significantly stronger binding affinity than Ligand B (-7.5 kcal/mol). This >1.5 kcal/mol difference is a major advantage for Ligand A.

**Overall Assessment:**

Despite both ligands having issues with BBB and solubility, Ligand A is the superior candidate. Its significantly better TPSA, logP, binding affinity, and lower DILI risk outweigh the slightly higher clearance and lower BBB. The negative half-life for Ligand B is a major red flag, suggesting a data error or a fundamentally problematic molecule. The stronger binding affinity of Ligand A is particularly crucial for a GPCR target like DRD2.

Output:
1
2025-04-17 07:48:05,179 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (346.471 and 347.459 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (49.85) is significantly better than Ligand B (75.44). For CNS targets, we want TPSA <= 90, and ideally closer to 60. Ligand A is much closer to this ideal.

**3. logP:** Both ligands have good logP values (2.732 and 2.689), falling within the optimal 1-3 range.

**4. H-Bond Donors:** Ligand A (0) is preferable to Ligand B (1). Fewer HBDs generally improve permeability.

**5. H-Bond Acceptors:** Ligand A (3) is preferable to Ligand B (4). Fewer HBAs generally improve permeability.

**6. QED:** Ligand A (0.723) has a higher QED than Ligand B (0.55), indicating a more drug-like profile.

**7. DILI:** Ligand A (35.13) has a slightly higher DILI risk than Ligand B (26.871), but both are below the 40 threshold and considered good.

**8. BBB:** Ligand B (75.533) has a slightly better BBB penetration percentile than Ligand A (67.623), but both are above the desirable 70% threshold for CNS targets.

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.613 and -4.731) which is unusual and suggests poor permeability. However, these values are on a scale where negative values aren't directly interpretable without knowing the scale's origin. We'll need to consider this cautiously.

**10. Aqueous Solubility:** Both ligands have negative solubility values (-2.981 and -1.828) which is also unusual and suggests poor solubility. Similar to Caco-2, the scale is unknown.

**11. hERG Inhibition:** Both ligands have low hERG inhibition liability (0.489 and 0.254), which is good.

**12. Microsomal Clearance:** Ligand B (66.333) has slightly lower microsomal clearance than Ligand A (61.363), suggesting better metabolic stability.

**13. In vitro Half-Life:** Ligand A (-4.89) has a significantly worse in vitro half-life than Ligand B (3.371). This is a major drawback for Ligand A.

**14. P-gp Efflux:** Both ligands have low P-gp efflux liability (0.398 and 0.335), which is good for CNS exposure.

**15. Binding Affinity:** Both ligands have very similar and strong binding affinities (-8.3 and -8.1 kcal/mol). The difference is negligible.

**Overall Assessment:**

Considering the GPCR-specific priorities, Ligand B is slightly more favorable. While Ligand A has a better TPSA and QED, Ligand B has a significantly better in vitro half-life, slightly better BBB penetration, and slightly better metabolic stability. The negative Caco-2 and solubility values are concerning for both, but the overall profile of Ligand B is more promising, especially given the importance of metabolic stability and CNS penetration for a DRD2 ligand.

Output:
1
2025-04-17 07:48:05,179 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (348.403 and 356.511 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (84.74) is excellent, well below the 90 A^2 threshold for CNS targets. Ligand B (73.91) is also very good, even lower.

**logP:** Ligand A (1.694) is optimal. Ligand B (0.45) is a bit low, potentially hindering membrane permeability.

**H-Bond Donors/Acceptors:** Ligand A (0 HBD, 6 HBA) is favorable. Ligand B (2 HBD, 5 HBA) is also acceptable.

**QED:** Both ligands have reasonable QED scores (0.611 and 0.556), indicating good drug-like properties.

**DILI:** Ligand A (78.945) has a higher DILI risk than Ligand B (9.461). This is a significant drawback for Ligand A.

**BBB:** Ligand A (95.192) has excellent BBB penetration, highly desirable for a CNS target. Ligand B (40.52) has poor BBB penetration, a major concern.

**Caco-2 Permeability:** Ligand A (-4.274) has poor Caco-2 permeability. Ligand B (-5.268) is also poor.

**Aqueous Solubility:** Ligand A (-3.305) has poor aqueous solubility. Ligand B (-0.309) is also poor.

**hERG:** Both ligands have very low hERG inhibition risk (0.061 and 0.356).

**Microsomal Clearance:** Ligand A (64.076) has moderate clearance. Ligand B (14.657) has low clearance, indicating better metabolic stability.

**In vitro Half-Life:** Ligand A (14.38 hours) has a moderate half-life. Ligand B (10.168 hours) has a shorter half-life.

**P-gp Efflux:** Ligand A (0.058) has very low P-gp efflux, which is excellent for CNS penetration. Ligand B (0.008) also has very low P-gp efflux.

**Binding Affinity:** Ligand A (-7.5 kcal/mol) has a significantly stronger binding affinity than Ligand B (0.0 kcal/mol). This is a substantial advantage.

**Overall Assessment:**

Ligand A excels in binding affinity and BBB penetration, and has low P-gp efflux. However, it suffers from poor Caco-2 permeability, poor aqueous solubility, and a higher DILI risk. Ligand B has a much better safety profile (lower DILI) and better metabolic stability (lower Cl_mic), but its binding affinity is extremely weak and it has poor BBB penetration.

Given the importance of BBB penetration for a CNS target like DRD2, and the substantial difference in binding affinity, Ligand A is the more promising candidate *despite* its drawbacks. The strong binding affinity could potentially outweigh the ADME issues, and further optimization could address the solubility and permeability concerns. The poor affinity of Ligand B is a more difficult hurdle to overcome.

Output:
1
2025-04-17 07:48:05,179 - INFO - Reasoning:

Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (426.742 Da) is higher, but still acceptable. Ligand B (348.359 Da) is slightly preferable.

**2. TPSA:** Ligand A (72.36) is excellent, well below the 90 Angstroms threshold for CNS targets. Ligand B (128.53) is higher, but still within a reasonable range, though less optimal for CNS penetration.

**3. logP:** Ligand A (3.614) is within the optimal range (1-3). Ligand B (-0.191) is significantly below 1, which is a concern for permeability.

**4. H-Bond Donors:** Ligand A (1) and Ligand B (3) are both acceptable, below the threshold of 5.

**5. H-Bond Acceptors:** Ligand A (4) and Ligand B (6) are both acceptable, below the threshold of 10.

**6. QED:** Both ligands have similar QED values (A: 0.792, B: 0.664), both above the 0.5 threshold, indicating good drug-like properties.

**7. DILI:** Ligand A (33.773) has a much lower DILI risk than Ligand B (69.756). This is a significant advantage for Ligand A.

**8. BBB:** Ligand A (80.884) has a good BBB percentile, exceeding the desirable 70% for CNS targets. Ligand B (8.181) has a very low BBB percentile, indicating poor brain penetration. This is a critical disadvantage for a DRD2 ligand.

**9. Caco-2:** Both have negative values, which is unusual. Assuming these represent permeability ratios, lower values suggest lower permeability.

**10. Solubility:** Both ligands have negative solubility values, which is also unusual.

**11. hERG:** Ligand A (0.807) has a lower hERG risk than Ligand B (0.135).

**12. Cl_mic:** Ligand A (14.06) and Ligand B (16.49) have similar microsomal clearance values.

**13. t1/2:** Ligand A (18.449) has a longer in vitro half-life than Ligand B (11.153).

**14. Pgp:** Ligand A (0.638) has lower P-gp efflux liability than Ligand B (0.019). Lower Pgp is beneficial for CNS exposure.

**15. Binding Affinity:** Ligand B (-7.9 kcal/mol) has a slightly better binding affinity than Ligand A (-8.1 kcal/mol). While a difference of 0.2 kcal/mol is not huge, it's a positive for Ligand B.

**Overall Assessment:**

Despite the slightly better affinity of Ligand B, Ligand A is the superior candidate. The critical factors driving this decision are:

*   **BBB Penetration:** Ligand A's high BBB percentile (80.884) is crucial for a DRD2 ligand targeting CNS disorders, while Ligand B's is extremely low (8.181).
*   **logP:** Ligand A's logP (3.614) is optimal, while Ligand B's is very low (-0.191), suggesting poor membrane permeability.
*   **DILI Risk:** Ligand A has a significantly lower DILI risk.
*   **Pgp Efflux:** Ligand A has lower P-gp efflux, improving CNS exposure.

The slightly better affinity of Ligand B is outweighed by these substantial ADME/PK deficiencies.

Output:
1
2025-04-17 07:48:05,179 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (346.431 Da) is slightly lower, which could be beneficial for permeability, but both are acceptable.

**TPSA:** Ligand A (59.71) is significantly better than Ligand B (29.54) for CNS penetration, falling well below the 90 A^2 threshold. Ligand B is excellent.

**logP:** Ligand A (0.519) is quite low, potentially hindering membrane permeability. Ligand B (4.004) is at the upper end of the optimal range, which could lead to solubility issues but is generally acceptable.

**H-Bond Donors/Acceptors:** Ligand A has 0 HBD and 6 HBA, which is reasonable. Ligand B has 0 HBD and 2 HBA, also good.

**QED:** Both ligands have acceptable QED values (A: 0.81, B: 0.552), indicating good drug-like properties.

**DILI:** Both ligands have similar and acceptable DILI risk (A: 35.363, B: 37.999), below the 40 threshold.

**BBB:** Both ligands exhibit excellent BBB penetration (A: 82.009, B: 88.406), which is crucial for CNS targets. Ligand B is slightly better.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values, which is unusual and suggests a potential issue with the data or modeling. However, we'll proceed assuming these are relative values.

**Aqueous Solubility:** Ligand A has very poor aqueous solubility (0.071), which is a significant concern. Ligand B has very poor aqueous solubility (-4.61), which is also a significant concern.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (A: 0.633, B: 0.653).

**Microsomal Clearance:** Ligand A has moderate clearance (35.107 mL/min/kg). Ligand B has very high clearance (88.615 mL/min/kg), indicating poor metabolic stability.

**In vitro Half-Life:** Ligand A has a reasonable half-life (9.764 hours). Ligand B has a very short half-life (-25.752 hours), which is a major drawback.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (A: 0.17, B: 0.233).

**Binding Affinity:** Ligand B (-7.8 kcal/mol) has significantly stronger binding affinity than Ligand A (0 kcal/mol). This is a substantial advantage.

**Overall Assessment:**

Ligand B is the stronger candidate despite its higher logP and poor solubility. The significantly improved binding affinity (-7.8 kcal/mol vs 0 kcal/mol) outweighs the potential drawbacks. The better BBB penetration and lower clearance also contribute to its favorability. Ligand A's extremely low logP and poor solubility are major concerns, and its lack of binding affinity is a deal-breaker.

Output:
1
2025-04-17 07:48:05,180 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (352.519 and 344.455 Da) fall within the ideal 200-500 Da range.

**TPSA:** Both ligands have a TPSA of 78.43, which is acceptable for general oral absorption but slightly high for optimal CNS penetration (ideally <90, but closer to 70 is better).

**logP:** Both ligands have logP values (2.621 and 2.812) within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Both have 3 HBD and 3 HBA, which is within acceptable limits.

**QED:** Ligand A (0.659) has a slightly better QED score than Ligand B (0.571), indicating a more drug-like profile.

**DILI:** Ligand A (17.371) has a significantly lower DILI risk than Ligand B (37.611), which is a major advantage.

**BBB:** Ligand A (44.397) has a better BBB percentile than Ligand B (38.038), although both are below the desirable >70 threshold for CNS targets. This is a critical factor for DRD2, given its role in CNS disorders.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.595 and -4.721), which is unusual and suggests poor intestinal absorption. This is a significant concern.

**Aqueous Solubility:** Both ligands have negative solubility values (-2.919 and -3.404), indicating very poor aqueous solubility. This is a major drawback for bioavailability.

**hERG Inhibition:** Ligand A (0.23) has a lower hERG inhibition liability than Ligand B (0.444), which is preferable.

**Microsomal Clearance:** Ligand A (41.656) has a slightly higher microsomal clearance than Ligand B (38.584), suggesting slightly lower metabolic stability.

**In vitro Half-Life:** Ligand B (45.999) has a significantly longer in vitro half-life than Ligand A (-0.385), which is a positive attribute.

**P-gp Efflux:** Ligand A (0.09) has a lower P-gp efflux liability than Ligand B (0.267), which is beneficial for CNS exposure.

**Binding Affinity:** Both ligands have very similar binding affinities (-8.5 and -8.3 kcal/mol), with Ligand A being slightly more potent. The difference is less than the 1.5 kcal/mol threshold where affinity strongly outweighs other factors.

**Overall Assessment:**

Considering the GPCR-specific priorities, Ligand A is the more promising candidate. While both have poor solubility and Caco-2 permeability, Ligand A has a significantly lower DILI risk, better BBB penetration, lower hERG inhibition, and lower P-gp efflux. The slightly better QED and binding affinity also contribute to its favorability. The longer half-life of Ligand B is a plus, but the higher DILI and P-gp efflux are concerning.

Output:
0
2025-04-17 07:48:05,180 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (333.435 and 357.435 Da) fall within the ideal range of 200-500 Da.

**TPSA:** Ligand A (56.13) is significantly better than Ligand B (95.13). For CNS targets, we want TPSA <= 90, so Ligand A is much more favorable.

**logP:** Both ligands have acceptable logP values (3.55 and 2.994), falling within the optimal range of 1-3.

**H-Bond Donors/Acceptors:** Ligand A (HBD=1, HBA=3) is preferable to Ligand B (HBD=2, HBA=5) as lower values generally improve permeability. Both are within acceptable limits.

**QED:** Both ligands have good QED scores (0.843 and 0.86), indicating good drug-like properties.

**DILI:** Ligand A (34.161) has a lower DILI risk than Ligand B (70.105). Both are below 60, but A is significantly better.

**BBB:** Ligand A (83.521) has a much higher BBB penetration percentile than Ligand B (42.536). This is *critical* for a CNS target like DRD2, and gives a significant advantage to Ligand A.

**Caco-2 Permeability:** Ligand A (-4.612) and Ligand B (-4.854) are both very poor. This is a concern for oral bioavailability, but less critical for a CNS target where direct delivery or other routes might be considered.

**Aqueous Solubility:** Both ligands have very poor aqueous solubility (-4.326 and -4.835). This could pose formulation challenges.

**hERG:** Both ligands have low hERG inhibition liability (0.892 and 0.45).

**Microsomal Clearance:** Ligand B (42.313) has a higher microsomal clearance than Ligand A (34.367), indicating faster metabolism and potentially lower exposure.

**In vitro Half-Life:** Ligand B (62.148) has a longer in vitro half-life than Ligand A (38.796).

**P-gp Efflux:** Ligand A (0.226) has lower P-gp efflux liability than Ligand B (0.279), which is beneficial for CNS penetration.

**Binding Affinity:** Ligand B (-7.4 kcal/mol) has a significantly stronger binding affinity than Ligand A (-9.2 kcal/mol). This is a substantial advantage, potentially outweighing some of the ADME drawbacks.

**Overall Assessment:**

While Ligand B boasts a superior binding affinity, Ligand A is significantly better in terms of BBB penetration, TPSA, and DILI risk, all of which are crucial for a CNS-targeting GPCR. The difference in binding affinity (-7.4 vs -9.2) is substantial, but the poor ADME properties of Ligand B, particularly the low BBB, are concerning. Ligand A, despite a slightly weaker affinity, has a more balanced profile and is more likely to achieve sufficient brain exposure.

Output:
0
2025-04-17 07:48:05,180 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B based on the provided guidelines, prioritizing GPCR-specific properties (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands fall within the ideal range (200-500 Da). Ligand A (444.738 Da) is higher, but still acceptable. Ligand B (356.535 Da) is slightly better.

**TPSA:** Ligand A (71.53) is higher than the ideal <90 for CNS targets, but still potentially acceptable. Ligand B (36.36) is excellent, well below the threshold.

**logP:** Both ligands have logP values within the optimal range (1-3). Ligand A (3.406) is slightly higher, potentially increasing off-target effects, while Ligand B (4.481) is a bit above the optimal range.

**H-Bond Donors/Acceptors:** Both ligands have acceptable HBD (1) and HBA (5/4) counts.

**QED:** Both ligands have good QED scores (>0.5), indicating drug-likeness. Ligand B (0.743) is slightly better than Ligand A (0.569).

**DILI:** Ligand A (85.227) has a significantly higher DILI risk than Ligand B (11.09). This is a major concern for Ligand A.

**BBB:** Both ligands have similar and good BBB penetration (Ligand A: 69.252, Ligand B: 69.407). Both are just below the desirable >70, but acceptable.

**Caco-2 Permeability:** Ligand A (-4.793) has poor Caco-2 permeability, while Ligand B (-5.111) is also poor, but slightly better.

**Aqueous Solubility:** Both ligands have poor aqueous solubility (-4.45 and -3.243 respectively).

**hERG Inhibition:** Ligand A (0.21) has a slightly lower hERG risk than Ligand B (0.938).

**Microsomal Clearance:** Both ligands have similar microsomal clearance values (Ligand A: 43.997, Ligand B: 41.485), indicating similar metabolic stability.

**In vitro Half-Life:** Ligand B (32.559 hours) has a significantly longer half-life than Ligand A (16.302 hours).

**P-gp Efflux:** Ligand A (0.231) has lower P-gp efflux liability than Ligand B (0.692), which is favorable for CNS penetration.

**Binding Affinity:** Ligand B (-7.6 kcal/mol) has a significantly stronger binding affinity than Ligand A (-9.2 kcal/mol). This is a substantial advantage.

**Overall Assessment:**

Ligand B is the more promising candidate. While both have poor solubility and Caco-2 permeability, Ligand B has a significantly better binding affinity, lower DILI risk, and longer half-life. The slightly higher logP of Ligand B is less concerning than the high DILI risk of Ligand A. The lower P-gp efflux of Ligand A is a plus, but is outweighed by the other factors.

Output:
1
2025-04-17 07:48:05,180 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (352.391 and 345.443 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (113.02) is slightly above the preferred <90 for CNS targets, but still reasonable. Ligand B (73.83) is excellent, well below 90. This favors Ligand B.

**3. logP:** Both ligands have good logP values (1.654 and 1.197), within the optimal 1-3 range.

**4. H-Bond Donors:** Both have 3 HBD, which is acceptable.

**5. H-Bond Acceptors:** Ligand A has 6 HBA, and Ligand B has 4 HBA, both within the acceptable limit of <=10.

**6. QED:** Both ligands have similar and good QED values (0.759 and 0.77), indicating good drug-like properties.

**7. DILI:** Ligand A (47.732) has a moderate DILI risk, while Ligand B (13.843) has a very low risk. This strongly favors Ligand B.

**8. BBB:** Ligand A (52.074) has a moderate BBB penetration, while Ligand B (67.39) is better, though still not ideal (>70 is preferred). However, given the other factors, this is less critical.

**9. Caco-2:** Ligand A (-4.408) and Ligand B (-5.088) both have negative Caco-2 values, which is unusual and suggests poor permeability. This is a significant concern for both.

**10. Solubility:** Ligand A (-2.375) and Ligand B (-1.549) both have poor aqueous solubility. This is a drawback for both.

**11. hERG:** Both ligands have low hERG risk (0.333 and 0.511), which is good.

**12. Cl_mic:** Ligand A (15.56) has a higher microsomal clearance than Ligand B (-17.78). A negative value for Ligand B indicates *higher* metabolic stability, which is a significant advantage.

**13. t1/2:** Ligand A (-9.171) has a very short in vitro half-life, while Ligand B (13.973) has a longer half-life. This favors Ligand B.

**14. Pgp:** Both ligands have very low P-gp efflux liability (0.031 and 0.041), which is excellent for CNS penetration.

**15. Binding Affinity:** Ligand B (-8.7 kcal/mol) has a slightly better binding affinity than Ligand A (-7.9 kcal/mol). While the difference is less than the 1.5 kcal/mol threshold, it contributes to the overall preference for Ligand B.

**Overall Assessment:**

Ligand B consistently outperforms Ligand A in key ADME properties crucial for a CNS-targeting GPCR ligand. Specifically, it has a significantly lower DILI risk, better metabolic stability (negative Cl_mic), a longer half-life, and a slightly better binding affinity. While both have poor Caco-2 and solubility, the superior safety and PK profile of Ligand B outweigh these concerns. The lower TPSA is also a benefit.

Output:
1
2025-04-17 07:48:05,180 - INFO - Batch 395 complete. Total preferences: 6320
2025-04-17 07:48:05,181 - INFO - Processing batch 396/512...
2025-04-17 07:48:46,597 - INFO - Reasoning:

Let's analyze Ligand A and Ligand B based on the provided guidelines, prioritizing GPCR-specific properties (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (355.47 and 356.41 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (88.73) is better than Ligand B (66.48) as it is closer to the ideal range for CNS targets (<=90).

**logP:** Both ligands (2.665 and 2.168) are within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A has 3 HBD and 5 HBA, while Ligand B has 1 HBD and 3 HBA. Both are acceptable.

**QED:** Both ligands have similar QED values (0.635 and 0.562), indicating good drug-likeness.

**DILI:** Ligand A (57.774) has a higher DILI risk than Ligand B (31.136). This favors Ligand B.

**BBB:** Ligand B (95.618) significantly outperforms Ligand A (53.432) in BBB penetration, a critical factor for CNS targets like DRD2.

**Caco-2 Permeability:** Ligand A (-5.935) shows poor Caco-2 permeability, while Ligand B (-4.613) is slightly better.

**Aqueous Solubility:** Both ligands have very poor aqueous solubility (-2.976 and -2.628). This is a concern for both, but not a deciding factor.

**hERG Inhibition:** Ligand A (0.58) has a slightly higher hERG inhibition risk than Ligand B (0.374), favoring Ligand B.

**Microsomal Clearance:** Ligand A (19.136) has a higher microsomal clearance than Ligand B (14.668), indicating lower metabolic stability. Ligand B is preferred.

**In vitro Half-Life:** Ligand B (-44.493) has a significantly longer in vitro half-life than Ligand A (20.118). This is a major advantage for Ligand B.

**P-gp Efflux:** Ligand A (0.145) has a higher P-gp efflux liability than Ligand B (0.047), meaning Ligand B will likely have better CNS exposure.

**Binding Affinity:** Ligand A (-8.9 kcal/mol) has a slightly better binding affinity than Ligand B (-7.6 kcal/mol). However, the difference is less than 1.5 kcal/mol, and can be outweighed by other factors.

**Overall Assessment:**

Ligand B is the superior candidate. While Ligand A has slightly better binding affinity, Ligand B excels in crucial ADME properties for a CNS-targeting GPCR, particularly BBB penetration (95.6% vs 53.4%), P-gp efflux (lower liability), in vitro half-life, and DILI risk. The better BBB and lower P-gp efflux will likely translate to higher brain exposure, which is paramount for DRD2. The improved metabolic stability (lower Cl_mic, longer t1/2) is also a significant advantage.

Output:
1
2025-04-17 07:48:46,598 - INFO - Reasoning:

Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight (MW):** Both ligands (374.453 and 371.493 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (78.43) is higher than Ligand B (40.54). For CNS targets, we prefer TPSA <= 90, so both are acceptable, but B is significantly better.

**3. logP:** Ligand A (2.598) and Ligand B (4.453) are both within the optimal range of 1-3, but B is pushing the upper limit. Higher logP can sometimes lead to off-target effects, but isn't a dealbreaker.

**4. H-Bond Donors (HBD):** Ligand A (3) and Ligand B (1) are both acceptable (<=5).

**5. H-Bond Acceptors (HBA):** Ligand A (4) and Ligand B (3) are both acceptable (<=10).

**6. QED:** Both ligands have good QED scores (0.621 and 0.769, respectively), indicating good drug-like properties.

**7. DILI:** Ligand A (36.06) has a slightly higher DILI risk than Ligand B (13.959), but both are below the concerning threshold of 60.

**8. BBB:** This is crucial for a CNS target like DRD2. Ligand B (89.841) has a significantly higher BBB penetration percentile than Ligand A (48.003). This is a major advantage for B.

**9. Caco-2 Permeability:** Ligand A (-5.681) and Ligand B (-4.689) both have negative values, which is unusual. Lower (more negative) values suggest poor permeability. However, the scale isn't fully defined here, so it's hard to interpret this definitively.

**10. Aqueous Solubility:** Both ligands have poor aqueous solubility (-3.35 and -3.624). This could pose formulation challenges, but isn't a primary concern at this stage.

**11. hERG Inhibition:** Ligand A (0.464) and Ligand B (0.753) both show relatively low hERG inhibition risk.

**12. Microsomal Clearance:** Ligand A (89.06) has a higher microsomal clearance than Ligand B (36.977), suggesting lower metabolic stability.

**13. In vitro Half-Life:** Ligand B (21.834) has a significantly longer in vitro half-life than Ligand A (-13.638). This is a substantial advantage.

**14. P-gp Efflux:** Ligand A (0.083) has lower P-gp efflux than Ligand B (0.55), which is preferable for CNS penetration.

**15. Binding Affinity:** Ligand B (-7.1 kcal/mol) has a slightly better binding affinity than Ligand A (-8.1 kcal/mol). While A is better, the difference is not substantial enough to overcome the other ADME advantages of B.

**Overall Assessment:**

Ligand B is the more promising candidate. It has significantly better BBB penetration, a longer half-life, lower microsomal clearance, and a slightly better binding affinity. While its logP is a bit higher, and P-gp efflux is slightly higher, these are outweighed by the advantages in CNS penetration and metabolic stability. Ligand A has better P-gp efflux and binding affinity, but the substantial advantage of B in BBB penetration makes it the stronger candidate for a CNS-targeting drug.

Output:
1
2025-04-17 07:48:46,598 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 drug candidates, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (363.405 and 361.398 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (79.9) is significantly better than Ligand B (91.32). For CNS targets, we want TPSA <= 90, so Ligand A is preferable.

**3. logP:** Ligand A (0.142) is quite low, potentially hindering permeation. Ligand B (2.609) is within the optimal 1-3 range. This favors Ligand B.

**4. H-Bond Donors:** Ligand A (2) and Ligand B (3) are both acceptable (<=5).

**5. H-Bond Acceptors:** Both ligands (5) are within the acceptable range (<=10).

**6. QED:** Ligand A (0.702) has a better QED score than Ligand B (0.577), suggesting a more drug-like profile.

**7. DILI:** Ligand A (30.477) has a much lower DILI risk than Ligand B (75.456). This is a significant advantage for Ligand A.

**8. BBB:** Ligand A (71.307) has a much better BBB penetration percentile than Ligand B (43.583).  This is critical for a CNS target like DRD2, and strongly favors Ligand A.

**9. Caco-2 Permeability:** Ligand A (-4.971) and Ligand B (-5.399) both have negative values, indicating poor permeability.

**10. Aqueous Solubility:** Ligand A (-1.001) and Ligand B (-4.116) both have negative values, indicating poor solubility.

**11. hERG Inhibition:** Ligand A (0.194) has a lower hERG inhibition liability than Ligand B (0.435), which is preferable.

**12. Microsomal Clearance:** Ligand A (-22.408) has a much lower (better) microsomal clearance than Ligand B (34.802), indicating greater metabolic stability.

**13. In vitro Half-Life:** Ligand A (-2.92) and Ligand B (-7.14) both have negative values, indicating short half-lives.

**14. P-gp Efflux:** Ligand A (0.015) has a much lower P-gp efflux liability than Ligand B (0.149), which is crucial for CNS penetration.

**15. Binding Affinity:** Ligand B (-9.8) has a significantly stronger binding affinity than Ligand A (-8.0). This is a substantial advantage for Ligand B, potentially outweighing some of its ADME drawbacks.

**Overall Assessment:**

While Ligand B has a superior binding affinity, Ligand A demonstrates a much more favorable ADME profile, particularly regarding BBB penetration (71.3% vs 43.6%), DILI risk (30.5% vs 75.5%), P-gp efflux (0.015 vs 0.149), and microsomal clearance (-22.4 vs 34.8). The lower logP of Ligand A is a concern, but the strong BBB penetration suggests it can still reach the target. The superior ADME properties of Ligand A, combined with its acceptable affinity, make it the more promising drug candidate for a CNS target like DRD2.

Output:
0
2025-04-17 07:48:46,598 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (332.363 and 346.446 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (90.94) is slightly above the preferred <90 for CNS targets, while Ligand B (58.2) is well within the range. This favors Ligand B.

**3. logP:** Both ligands have a logP around 3.3, which is optimal.

**4. H-Bond Donors:** Both have 2 HBD, which is acceptable.

**5. H-Bond Acceptors:** Ligand A has 5 HBA, and Ligand B has 2. Both are within the acceptable limit of 10.

**6. QED:** Both ligands have QED values > 0.7, indicating good drug-likeness.

**7. DILI:** Ligand A (90.268) has a significantly higher DILI risk than Ligand B (23.885). This is a major drawback for Ligand A.

**8. BBB:** Ligand B (81.698) has a much better BBB penetration percentile than Ligand A (20.512). This is critical for a CNS target like DRD2 and strongly favors Ligand B.

**9. Caco-2 Permeability:** Ligand A (-5.164) has worse Caco-2 permeability than Ligand B (-4.565), though both are negative, indicating poor permeability.

**10. Aqueous Solubility:** Ligand A (-5.66) has worse aqueous solubility than Ligand B (-3.852), though both are negative.

**11. hERG Inhibition:** Both ligands have similar, low hERG inhibition risk (0.606 and 0.635).

**12. Microsomal Clearance:** Ligand B (77.967) has a slightly higher microsomal clearance than Ligand A (67.503), suggesting slightly lower metabolic stability.

**13. In vitro Half-Life:** Ligand B (17.424) has a significantly longer in vitro half-life than Ligand A (-4.847). This is a significant advantage for Ligand B.

**14. P-gp Efflux:** Both ligands have similar, low P-gp efflux liability (0.278 and 0.254).

**15. Binding Affinity:** Both ligands have very similar and excellent binding affinity (-9.6 and -9.2 kcal/mol). The difference is negligible.

**Overall Assessment:**

Ligand B is significantly better. While both have good affinity and drug-like properties, Ligand B excels in crucial areas for a CNS-targeting GPCR ligand: BBB penetration, lower DILI risk, and longer half-life. Ligand A's poor BBB penetration and high DILI risk are major liabilities. The slightly worse Caco-2 and solubility of Ligand B are less concerning given the strong CNS target engagement and safety profile.

Output:
1
2025-04-17 07:48:46,598 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (365.857 and 363.414 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (55.84) is significantly better than Ligand B (80.32). For CNS targets, we want TPSA <= 90, and A is comfortably within that, while B is approaching the upper limit.

**3. logP:** Ligand A (3.69) is optimal, while Ligand B (2.385) is a bit low, potentially hindering permeation.

**4. H-Bond Donors:** Ligand A (0) is preferable to Ligand B (2). Fewer HBDs generally improve permeability.

**5. H-Bond Acceptors:** Ligand A (4) is better than Ligand B (5).

**6. QED:** Both ligands have acceptable QED values (0.75 and 0.608, respectively), indicating good drug-likeness.

**7. DILI:** Ligand A (60.45) is better than Ligand B (81.117). Both are above the preferred threshold of <40, but A is closer.

**8. BBB:** Ligand A (69.407) is better than Ligand B (64.056), although both are reasonably good. A is closer to the desirable >70 for CNS targets.

**9. Caco-2 Permeability:** Ligand A (-4.115) is better than Ligand B (-4.777). Higher values are better.

**10. Aqueous Solubility:** Ligand A (-4.084) is better than Ligand B (-3.935). Higher values are better.

**11. hERG Inhibition:** Both ligands have very low hERG risk (0.278 and 0.263).

**12. Microsomal Clearance:** Ligand B (52.827) has lower clearance than Ligand A (77.754), suggesting better metabolic stability.

**13. In vitro Half-Life:** Ligand B (44.486) has a significantly longer half-life than Ligand A (-5.161). This is a major advantage.

**14. P-gp Efflux:** Ligand A (0.151) is better than Ligand B (0.099). Lower efflux is preferred for CNS exposure.

**15. Binding Affinity:** Ligand B (-8.2) has a slightly better binding affinity than Ligand A (-7.8). This is a 0.4 kcal/mol difference, which is significant, but needs to be weighed against other factors.

**Overall Assessment:**

Ligand B has a superior binding affinity and metabolic stability (lower Cl_mic, longer t1/2). However, Ligand A excels in TPSA, logP, BBB, and P-gp efflux, all critical for CNS penetration and GPCR targeting. The slightly better affinity of Ligand B is attractive, but the improved CNS properties of Ligand A are more crucial for a DRD2 ligand. The DILI risk is also lower for Ligand A.

Output:
1
2025-04-17 07:48:46,598 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (377.347 and 366.506 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (62.3) is better than Ligand B (54.18). Both are below the 90 A^2 threshold desirable for CNS targets, indicating good potential for brain penetration.

**3. logP:** Both ligands have good logP values (2.804 and 3.078), falling within the optimal 1-3 range.

**4. H-Bond Donors:** Both have 1 HBD, which is within the acceptable limit of <=5.

**5. H-Bond Acceptors:** Ligand A has 4 HBAs, and Ligand B has 6. Both are below the 10 HBA limit.

**6. QED:** Both ligands have similar and good QED values (0.802 and 0.818), indicating a strong drug-like profile.

**7. DILI:** Ligand A (12.563) has a significantly lower DILI risk than Ligand B (8.104). This is a substantial advantage.

**8. BBB:** Both ligands exhibit good BBB penetration (77.472 and 71.345), exceeding the 70% threshold for CNS targets. Ligand A is slightly better.

**9. Caco-2 Permeability:** Both have negative Caco-2 values (-5.016 and -4.883). This is unusual and suggests poor permeability. However, these values are on a log scale, and the negative values indicate very low permeability.

**10. Aqueous Solubility:** Both have negative solubility values (-2.311 and -2.677), indicating poor aqueous solubility. This is a concern for bioavailability.

**11. hERG Inhibition:** Both ligands show low hERG inhibition risk (0.633 and 0.77), which is good.

**12. Microsomal Clearance:** Ligand A (-10.024) has a much lower (better) microsomal clearance than Ligand B (15.043). Lower clearance indicates greater metabolic stability.

**13. In vitro Half-Life:** Ligand A (-5.62) has a slightly longer in vitro half-life than Ligand B (-6.93).

**14. P-gp Efflux:** Both ligands have low P-gp efflux liability (0.077 and 0.309), which is favorable for CNS penetration. Ligand A is better.

**15. Binding Affinity:** Ligand A (-9.6 kcal/mol) has a slightly better binding affinity than Ligand B (-8.3 kcal/mol). This 1.3 kcal/mol difference is significant and can outweigh minor ADME drawbacks.

**Overall Assessment:**

Ligand A is superior to Ligand B. It has a lower DILI risk, better metabolic stability (lower Cl_mic), slightly better BBB penetration, better P-gp efflux, and a significantly better binding affinity. While both have poor Caco-2 permeability and solubility, the stronger binding affinity and improved safety/PK profile of Ligand A make it the more promising candidate.

Output:
1
2025-04-17 07:48:46,598 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (357.4 and 363.5 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (106.2) is better than Ligand B (38.77) as it is closer to the ideal <90 for CNS targets. Ligand B is quite high, potentially hindering BBB penetration.

**logP:** Ligand A (-1.484) is a bit low, potentially impacting permeability. Ligand B (3.65) is within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A (2 HBD, 6 HBA) is preferable to Ligand B (0 HBD, 4 HBA) as it provides a better balance for solubility.

**QED:** Both ligands have acceptable QED scores (0.575 and 0.47), indicating reasonable drug-likeness.

**DILI:** Ligand A (35.673) has a significantly lower DILI risk than Ligand B (16.712), which is a major advantage.

**BBB:** Ligand B (88.29) has a much higher BBB penetration score than Ligand A (35.401). This is a critical factor for a CNS target like DRD2.

**Caco-2 Permeability:** Ligand A (-5.192) and Ligand B (-4.999) are both very poor, indicating very low intestinal absorption. This isn't a dealbreaker for a CNS drug, but not ideal.

**Aqueous Solubility:** Ligand A (-0.978) is slightly better than Ligand B (-3.152), but both are poor.

**hERG:** Ligand A (0.034) has a very low hERG risk, while Ligand B (0.758) has a moderate risk.

**Microsomal Clearance:** Ligand A (-4.439) has a lower (better) microsomal clearance than Ligand B (92.546), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand B (9.323) has a longer half-life than Ligand A (2.299), which is a positive.

**P-gp Efflux:** Ligand A (0.007) has a much lower P-gp efflux liability than Ligand B (0.72), which is crucial for CNS penetration.

**Binding Affinity:** Ligand B (-7.4 kcal/mol) has a significantly stronger binding affinity than Ligand A (-6.6 kcal/mol). This 1.5 kcal/mol difference is substantial and can outweigh some ADME drawbacks.

**Overall Assessment:**

Ligand B excels in binding affinity and BBB penetration, which are paramount for a CNS GPCR target. While its logP is good, its TPSA is high, DILI risk is elevated, and P-gp efflux is concerning. Ligand A has better ADME properties (lower DILI, better P-gp, lower clearance, lower hERG) but significantly weaker binding affinity and poor BBB penetration.

Given the importance of affinity and BBB for DRD2, and the substantial difference in binding affinity, **Ligand B is the more promising candidate despite its ADME liabilities**. Optimization efforts could then focus on improving its TPSA, DILI, and P-gp efflux while maintaining its strong affinity.

Output:
1
2025-04-17 07:48:46,598 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (346.43 and 338.46 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (80.57) is better than Ligand B (66.83). Both are below the 90 A^2 threshold for CNS targets, which is excellent.

**3. logP:** Ligand A (2.263) is within the optimal 1-3 range. Ligand B (3.429) is slightly higher, but still acceptable.

**4. H-Bond Donors:** Ligand A (2) and Ligand B (1) are both good, well below the 5 threshold.

**5. H-Bond Acceptors:** Ligand A (4) and Ligand B (6) are both acceptable, below the 10 threshold.

**6. QED:** Both ligands have good QED scores (0.708 and 0.921), indicating good drug-like properties.

**7. DILI:** Ligand A (39.98%) has a lower DILI risk than Ligand B (56.81%), which is preferable. Both are below the concerning 60% threshold.

**8. BBB:** Ligand A (65.57%) and Ligand B (69.79%) are both reasonably good for BBB penetration, but Ligand B is slightly better. A value >70% is desirable, but these are acceptable starting points.

**9. Caco-2 Permeability:** Ligand A (-4.706) and Ligand B (-5.157) both have negative values, which is unusual. A higher value is better, indicating better intestinal absorption. It's difficult to interpret these negative values without knowing the scale, but they suggest poor permeability.

**10. Aqueous Solubility:** Ligand A (-2.87) and Ligand B (-4.3) both have negative solubility values, suggesting poor aqueous solubility. This is a concern for formulation and bioavailability.

**11. hERG Inhibition:** Ligand A (0.185) has a much lower hERG inhibition liability than Ligand B (0.838), which is a significant advantage.

**12. Microsomal Clearance:** Ligand A (40.18) has lower microsomal clearance than Ligand B (77.25), suggesting better metabolic stability.

**13. In vitro Half-Life:** Ligand A (39.41) has a longer in vitro half-life than Ligand B (-3.288), which is desirable.

**14. P-gp Efflux:** Ligand A (0.129) has lower P-gp efflux liability than Ligand B (0.103), which is preferable for CNS exposure.

**15. Binding Affinity:** Ligand B (-0.0 kcal/mol) has a significantly better binding affinity than Ligand A (-6.9 kcal/mol). This is a substantial advantage, potentially outweighing some of the ADME drawbacks.

**Overall Assessment:**

Ligand B has a much stronger binding affinity (-0.0 kcal/mol vs -6.9 kcal/mol). While Ligand A has better DILI, hERG, clearance, and half-life, the difference in binding affinity is substantial. For a GPCR target, affinity is paramount. The slightly better BBB penetration of Ligand B is also a plus. The ADME properties of Ligand B are not ideal (higher DILI, hERG, clearance, and lower solubility), but these can be addressed through further optimization. The poor Caco-2 and solubility for both are concerning and would need to be addressed.

Output:
1
2025-04-17 07:48:46,598 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (373.519 and 368.415 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (98.74) is higher than the preferred <90 for CNS targets, but not drastically so. Ligand B (49.41) is excellent, well below the threshold.

**logP:** Ligand A (0.227) is quite low, potentially hindering permeability. Ligand B (3.745) is nearly ideal.

**H-Bond Donors/Acceptors:** Ligand A has 3 HBD and 5 HBA, which are acceptable. Ligand B has 1 HBD and 2 HBA, also acceptable.

**QED:** Both ligands have similar QED values (0.476 and 0.472), indicating moderate drug-likeness.

**DILI:** Ligand A (22.644) has a much lower DILI risk than Ligand B (39.977), which is a significant advantage.

**BBB:** Ligand B (85.459) has a significantly higher BBB penetration percentile than Ligand A (23.071). This is a *critical* advantage for a CNS target like DRD2.

**Caco-2 Permeability:** Ligand A (-5.496) shows poor permeability, while Ligand B (-4.673) is slightly better, but still not great.

**Aqueous Solubility:** Ligand A (-1.985) has poor solubility, while Ligand B (-4.375) is also poor.

**hERG:** Ligand A (0.32) has a lower hERG risk than Ligand B (0.734), which is favorable.

**Microsomal Clearance:** Ligand B (43.974) has a much higher microsomal clearance than Ligand A (11.069), indicating faster metabolism and potentially lower *in vivo* exposure.

**In vitro Half-Life:** Ligand A (-7.759) has a negative half-life, which is concerning and likely an error or indicates very rapid degradation. Ligand B (6.725) has a reasonable half-life.

**P-gp Efflux:** Ligand A (0.038) has very low P-gp efflux, which is excellent. Ligand B (0.372) has moderate P-gp efflux.

**Binding Affinity:** Ligand B (-8.1 kcal/mol) has a stronger binding affinity than Ligand A (-7.1 kcal/mol). This is a significant advantage, exceeding the 1.5 kcal/mol threshold.

**Overall Assessment:**

Ligand B is the stronger candidate despite some drawbacks. The superior BBB penetration and binding affinity are crucial for a CNS GPCR target. While its DILI risk and Caco-2 permeability are not ideal, the strong affinity could potentially compensate. Ligand A suffers from extremely poor BBB penetration, poor solubility, very poor Caco-2 permeability, and a questionable half-life, making it a less attractive candidate. The lower DILI risk of Ligand A is overshadowed by its other deficiencies.

Output:
1
2025-04-17 07:48:46,598 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (348.378 and 366.527 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (71.58) is slightly higher than Ligand B (66.48), but both are below the 90 A^2 threshold desirable for CNS targets.

**3. logP:** Ligand A (1.533) and Ligand B (2.242) are both within the optimal 1-3 range.

**4. H-Bond Donors:** Ligand A (0) is better than Ligand B (1). Fewer HBDs generally improve permeability.

**5. H-Bond Acceptors:** Ligand A (5) is slightly higher than Ligand B (4), but both are below the 10 threshold.

**6. QED:** Ligand A (0.84) has a significantly better QED score than Ligand B (0.636), indicating a more drug-like profile.

**7. DILI:** Ligand A (53.276) has a higher DILI risk than Ligand B (21.171). This is a concern for Ligand A.

**8. BBB:** Ligand A (71.733) has a slightly better BBB penetration percentile than Ligand B (69.756), but both are reasonably good for a CNS target.

**9. Caco-2 Permeability:** Ligand A (-4.644) has a worse Caco-2 permeability than Ligand B (-5.378). Lower values indicate poorer permeability.

**10. Aqueous Solubility:** Ligand A (-1.572) has better aqueous solubility than Ligand B (-2.561).

**11. hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.194 and 0.247, respectively).

**12. Microsomal Clearance:** Ligand A (14.823) has a significantly lower microsomal clearance than Ligand B (30.301), suggesting better metabolic stability.

**13. In vitro Half-Life:** Ligand A (15.513) has a longer in vitro half-life than Ligand B (-3.323), which is highly desirable.

**14. P-gp Efflux:** Both ligands show low P-gp efflux liability (0.057 and 0.179, respectively).

**15. Binding Affinity:** Ligand B (-7.7 kcal/mol) has a slightly better binding affinity than Ligand A (-8.0 kcal/mol). While the difference is small, it's still a factor.

**Overall Assessment:**

Ligand A has a better QED, solubility, metabolic stability (lower Cl_mic), and longer half-life. However, it has a higher DILI risk and slightly worse Caco-2 permeability. Ligand B has a better binding affinity and lower DILI risk. Given the GPCR-specific priorities, BBB is important, and both are acceptable. LogP is good for both. Pgp is low for both. The slightly better affinity of Ligand B is a plus, but the significant advantages of Ligand A in terms of metabolic stability and half-life, combined with its better QED and solubility, outweigh the slightly higher DILI risk and lower Caco-2 permeability.

Output:
1
2025-04-17 07:48:46,599 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B based on the provided guidelines, prioritizing GPCR-specific properties (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (354.4 and 345.4 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (119.05) is borderline for CNS targets, slightly above the preferred <90, while Ligand B (80.56) is well within the ideal range. This favors Ligand B.

**logP:** Ligand A (-1.933) is quite low, potentially hindering permeation. Ligand B (0.082) is closer to the optimal 1-3 range. This strongly favors Ligand B.

**H-Bond Donors/Acceptors:** Ligand A has 3 HBD and 5 HBA, acceptable values. Ligand B has 0 HBD and 6 HBA, also acceptable.

**QED:** Both ligands have reasonable QED scores (0.497 and 0.758), indicating drug-like properties, with Ligand B being better.

**DILI:** Ligand A (31.524) has a lower DILI risk than Ligand B (50.33), which is preferable.

**BBB:** This is crucial for a CNS target like DRD2. Ligand A has a BBB percentile of 16.945, which is poor. Ligand B has a much higher BBB percentile of 65.995, a significant advantage.

**Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and suggests poor permeability. However, these are on a scale where negative values are possible, and direct comparison is difficult without knowing the scale's specifics.

**Aqueous Solubility:** Both ligands have negative solubility values, indicating poor solubility. Again, the scale is unknown.

**hERG:** Both ligands have very low hERG inhibition liability (0.024 and 0.187), which is excellent.

**Microsomal Clearance:** Ligand A (-2.506) has a negative clearance, which is unusual and suggests high metabolic stability. Ligand B (26.296) has a higher clearance, indicating faster metabolism. This favors Ligand A.

**In vitro Half-Life:** Ligand A (-11.532) has a negative half-life, which is unusual. Ligand B (8.246) has a more reasonable half-life.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.003 and 0.104), which is good.

**Binding Affinity:** Ligand B (-8.7 kcal/mol) has a significantly stronger binding affinity than Ligand A (-7.3 kcal/mol). This is a substantial advantage, potentially outweighing some ADME drawbacks.

**Overall Assessment:**

Ligand B is the stronger candidate. While Ligand A has a lower DILI risk and potentially better metabolic stability (negative clearance/half-life, which is unusual and requires further investigation), Ligand B excels in the critical GPCR-specific properties: TPSA, logP, and, most importantly, BBB penetration. The significantly stronger binding affinity of Ligand B (-8.7 vs -7.3 kcal/mol) further solidifies its position as the more promising drug candidate, especially considering the CNS target. The lower logP and higher TPSA of Ligand A are significant drawbacks for CNS penetration.



Output:
1
2025-04-17 07:48:46,599 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (378.42 and 343.471 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (97.11) is higher than the preferred <90 for CNS targets, but still potentially acceptable. Ligand B (45.55) is excellent, well below the threshold.

**logP:** Both ligands (2.956 and 2.524) are within the optimal 1-3 range.

**H-Bond Donors:** Ligand A (3) is acceptable. Ligand B (0) is also good.

**H-Bond Acceptors:** Ligand A (4) is acceptable. Ligand B (3) is also good.

**QED:** Both ligands have good QED scores (0.735 and 0.847), indicating good drug-like properties.

**DILI:** Ligand A (59.829) is borderline, but acceptable. Ligand B (35.518) is excellent, indicating low liver injury risk.

**BBB:** Ligand A (81.698) is good, exceeding the 70% threshold for CNS targets. Ligand B (69.988) is close, but falls slightly short of the desirable >70% for CNS penetration.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.97 and -4.673). This is unusual and suggests poor permeability. However, these values are on a log scale, so even negative values can be meaningful.

**Aqueous Solubility:** Both ligands have negative solubility values (-3.835 and -2.854), indicating poor aqueous solubility. This is a concern for bioavailability.

**hERG Inhibition:** Ligand A (0.087) is very low, indicating minimal hERG risk. Ligand B (0.493) is slightly higher, but still relatively low.

**Microsomal Clearance:** Ligand A (25.96) is relatively low, suggesting better metabolic stability. Ligand B (69.738) is significantly higher, indicating faster metabolism.

**In vitro Half-Life:** Ligand A (-5.619) is a negative value, suggesting a very short half-life. Ligand B (1.467) is a short half-life, but better than Ligand A.

**P-gp Efflux:** Ligand A (0.084) is very low, indicating minimal P-gp efflux. Ligand B (0.582) is slightly higher, but still relatively low.

**Binding Affinity:** Both ligands have excellent binding affinities (-8.0 and -8.4 kcal/mol). Ligand B is slightly better.

**Overall Assessment:**

Both ligands show promising binding affinities. However, Ligand B has a superior profile regarding TPSA, DILI, and slightly better affinity. Ligand A has better BBB penetration and lower microsomal clearance. The biggest concerns for both are the negative Caco-2 and solubility values, which suggest poor absorption. However, the high affinity could potentially overcome these issues. Given the importance of BBB penetration for a CNS target, and the slightly better overall profile of Ligand B (better TPSA, DILI, affinity), I would lean towards Ligand B as the more promising candidate, despite the slightly lower BBB score. The lower metabolic clearance of Ligand A is a positive, but the other factors weigh more heavily.

Output:
1
2025-04-17 07:48:46,599 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (361.486 and 388.917 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (45.23) is significantly better than Ligand B (67.87). For CNS targets, we want TPSA <= 90, and ideally closer to 60. Ligand A is much closer to this ideal.

**logP:** Ligand A (3.801) is slightly higher than Ligand B (2.512), both are within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Both have 1 HBD and are within acceptable limits. Ligand B has 5 HBA, slightly higher than Ligand A's 4, but both are below the 10 threshold.

**QED:** Both ligands have similar, good QED values (0.851 and 0.858).

**DILI:** Ligand A (56.96) has a higher DILI risk than Ligand B (40.054), but both are reasonably acceptable.

**BBB:** Ligand A (91.121) has a significantly better BBB penetration percentile than Ligand B (53.897). This is a *critical* factor for a CNS target like DRD2.

**Caco-2 Permeability:** Ligand A (-4.683) has worse Caco-2 permeability than Ligand B (-5.034), but both are negative and suggest poor permeability.

**Aqueous Solubility:** Ligand A (-3.617) has slightly better solubility than Ligand B (-2.975), but both are quite poor.

**hERG:** Both ligands have low hERG inhibition liability (0.966 and 0.642), which is good.

**Microsomal Clearance:** Ligand A (15.491) has higher microsomal clearance than Ligand B (9.588), indicating lower metabolic stability.

**In vitro Half-Life:** Ligand B (-1.046) has a negative half-life, which is concerning. Ligand A (19.784) has a reasonable half-life.

**P-gp Efflux:** Ligand A (0.741) has lower P-gp efflux than Ligand B (0.161), which is favorable for CNS penetration.

**Binding Affinity:** Ligand A (-9.4 kcal/mol) has a significantly stronger binding affinity than Ligand B (-8.1 kcal/mol). This is a substantial difference (1.3 kcal/mol) and can outweigh some ADME deficiencies.

**Overall Assessment:**

Ligand A is the better candidate. While it has slightly higher DILI and clearance, its *superior* BBB penetration, significantly *stronger* binding affinity, and lower P-gp efflux outweigh these drawbacks. Ligand B's negative in vitro half-life is a major red flag. The strong affinity of Ligand A suggests it could be effective at lower doses, potentially mitigating some of the DILI risk. The TPSA of Ligand A is also much more favorable for CNS penetration.



Output:
1
2025-04-17 07:48:46,599 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (343.427 and 347.463 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (62.62) is significantly better than Ligand B (79.38). For CNS targets, we want TPSA <= 90, and A is comfortably within this range, while B is approaching the upper limit.

**3. logP:** Both ligands have acceptable logP values (1.318 and 1.666), falling within the optimal 1-3 range.

**4. H-Bond Donors:** Ligand A (0) is preferable to Ligand B (2). Fewer HBDs generally improve permeability.

**5. H-Bond Acceptors:** Ligand A (4) is better than Ligand B (6). Similar to HBDs, fewer HBAs are generally preferred for permeability.

**6. QED:** Ligand B (0.745) has a better QED score than Ligand A (0.445), indicating a more drug-like profile. However, QED is less critical than other factors for CNS targets.

**7. DILI:** Both ligands have low DILI risk (37.03 and 42.575), both below the 40% threshold.

**8. BBB:** Ligand B (82.823) has a substantially better BBB penetration score than Ligand A (65.413). This is a *critical* factor for a DRD2 ligand, as it's a CNS target.

**9. Caco-2 Permeability:** Ligand A (-4.407) has better Caco-2 permeability than Ligand B (-5.028).

**10. Aqueous Solubility:** Both ligands have poor aqueous solubility (-2.453 and -2.269). This could pose formulation challenges, but is less critical than BBB penetration for a CNS target.

**11. hERG Inhibition:** Ligand A (0.225) has a lower hERG inhibition liability than Ligand B (0.713), which is desirable.

**12. Microsomal Clearance:** Both ligands have similar microsomal clearance (41.376 and 43.037).

**13. In vitro Half-Life:** Ligand A (-24.348) has a significantly longer in vitro half-life than Ligand B (13.319). This is a positive attribute.

**14. P-gp Efflux:** Ligand A (0.173) has lower P-gp efflux liability than Ligand B (0.06). Lower P-gp efflux is better for CNS exposure.

**15. Binding Affinity:** Ligand B (-7.9) has a slightly better binding affinity than Ligand A (-7.7). While a 0.2 kcal/mol difference isn't huge, it's a positive for Ligand B.

**Overall Assessment:**

Ligand B excels in BBB penetration and binding affinity, which are paramount for a DRD2 ligand. Ligand A has better TPSA, H-bonding characteristics, and in vitro half-life, but the superior BBB penetration of Ligand B outweighs these advantages. The slightly better QED of B is also a plus.

Output:
1
2025-04-17 07:48:46,599 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (362.411 Da) is slightly lower, which could be beneficial for permeability. Ligand B (387.311 Da) is also good.

**TPSA:** Ligand A (102.32) is higher than the preferred <90 for CNS targets, while Ligand B (82.11) is closer to the ideal range. This favors Ligand B.

**logP:** Ligand A (0.399) is quite low, potentially hindering membrane permeability. Ligand B (3.422) is within the optimal 1-3 range. This is a significant advantage for Ligand B.

**H-Bond Donors/Acceptors:** Both ligands have 2 HBDs, which is acceptable. Ligand A has 7 HBAs, while Ligand B has 4. Both are within the acceptable limit of 10, but Ligand B is better.

**QED:** Both ligands have reasonable QED scores (A: 0.774, B: 0.484), indicating good drug-like properties, but Ligand A is better.

**DILI:** Ligand A (79.604) has a higher DILI risk than Ligand B (57.891), which is preferable.

**BBB:** Ligand A (52.617) has a lower BBB penetration percentile than Ligand B (43.544). While neither is ideal (>70), Ligand B is better.

**Caco-2 Permeability:** Ligand A (-4.957) has very poor Caco-2 permeability, while Ligand B (-5.58) is also poor, but slightly better.

**Aqueous Solubility:** Both ligands have very poor aqueous solubility (-3.031 and -3.601 respectively).

**hERG Inhibition:** Ligand A (0.16) has a lower hERG inhibition risk than Ligand B (0.793), which is a positive for Ligand A.

**Microsomal Clearance:** Ligand A (17.89) has a lower microsomal clearance than Ligand B (48.203), suggesting better metabolic stability. This favors Ligand A.

**In vitro Half-Life:** Ligand B (55.653) has a significantly longer in vitro half-life than Ligand A (8.592). This is a substantial advantage for Ligand B.

**P-gp Efflux:** Ligand A (0.06) has lower P-gp efflux liability than Ligand B (0.577), which is beneficial for CNS penetration.

**Binding Affinity:** Ligand A (-8.6 kcal/mol) has a significantly stronger binding affinity than Ligand B (-7.5 kcal/mol). This is a major advantage for Ligand A, potentially outweighing some of its ADME drawbacks.

**Overall Assessment:**

Ligand A has a much better binding affinity and lower P-gp efflux, and better metabolic stability. However, its low logP and poor Caco-2 permeability are major concerns, even for a CNS target. Ligand B has better TPSA, logP, BBB, and a significantly longer half-life, but its affinity is weaker, and it has higher P-gp efflux and hERG risk.

Given the importance of affinity for GPCRs, and the substantial difference in binding energy (-8.6 vs -7.5 kcal/mol), Ligand A is the more promising candidate, despite its ADME liabilities. Optimization efforts could focus on improving its logP and permeability without sacrificing its strong binding affinity.

Output:
0
2025-04-17 07:48:46,600 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (364.917 and 348.487 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (40.62) is significantly better than Ligand B (58.64). For CNS targets, we want TPSA <= 90, and ideally closer to 60. Ligand A is much closer to this ideal.

**logP:** Both ligands have good logP values (3.405 and 2.489), falling within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A (0 HBD, 2 HBA) is slightly better than Ligand B (1 HBD, 3 HBA) in terms of minimizing potential issues with permeability. Both are within acceptable limits.

**QED:** Both ligands have similar QED values (0.75 and 0.719), indicating good drug-like properties.

**DILI:** Both have low DILI risk (12.524 and 13.416), which is good.

**BBB:** Ligand A (91.508) has a significantly higher BBB penetration percentile than Ligand B (72.625). This is a *critical* advantage for a CNS target like DRD2.

**Caco-2 Permeability:** Both have negative Caco-2 values (-4.793 and -4.831). This is unusual and suggests poor permeability. However, the values are very similar.

**Aqueous Solubility:** Both have negative solubility values (-3.946 and -2.442). This is also unusual and suggests poor solubility. Again, the values are similar.

**hERG:** Both ligands have low hERG inhibition liability (0.508 and 0.583), which is favorable.

**Microsomal Clearance:** Ligand B (36.269) has lower microsomal clearance than Ligand A (44.069), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand B (3.616 hours) has a longer in vitro half-life than Ligand A (1.184 hours), which is preferable.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.161 and 0.302), which is good for CNS penetration.

**Binding Affinity:** Both ligands have very similar and excellent binding affinities (-8.6 and -8.5 kcal/mol). The difference is negligible.

**Overall Assessment:**

Given the GPCR-specific priorities, the most important factors are BBB penetration and affinity. Ligand A has a substantially higher BBB percentile (91.508 vs 72.625) and a similar binding affinity to Ligand B. While Ligand B has slightly better metabolic stability and half-life, the superior BBB penetration of Ligand A is a decisive advantage for a CNS-targeting drug. The TPSA value of Ligand A is also more favorable. The unusual negative values for Caco-2 and solubility are concerning for both, but the difference in BBB is the most impactful factor.

Output:
1
2025-04-17 07:48:46,600 - INFO - Batch 396 complete. Total preferences: 6336
2025-04-17 07:48:46,600 - INFO - Processing batch 397/512...
2025-04-17 07:49:27,637 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (338.367 Da) is slightly lower, which could be beneficial for permeability. Ligand B (375.881 Da) is also good.

**TPSA:** Ligand A (89.01) is excellent, falling well below the 90 A^2 threshold for CNS targets. Ligand B (55.2) is even better, indicating potentially improved brain penetration.

**logP:** Both ligands have good logP values (A: 1.227, B: 2.955), falling within the optimal 1-3 range. Ligand B is closer to the upper end, which could be slightly concerning for solubility, but not critically so.

**H-Bond Donors/Acceptors:** Ligand A has 2 HBD and 5 HBA, while Ligand B has 0 HBD and 5 HBA. Both are within acceptable limits (<=5 HBD and <=10 HBA).

**QED:** Both ligands have similar, good QED values (A: 0.749, B: 0.755), indicating drug-like properties.

**DILI:** Ligand A (69.678) has a higher DILI risk than Ligand B (42.924). This is a significant negative for Ligand A.

**BBB:** Ligand B (75.301) has a considerably better BBB percentile than Ligand A (35.052). This is a crucial advantage for a CNS target like DRD2.

**Caco-2 Permeability:** Ligand A (-5.538) has a negative Caco-2 value, which is unusual and suggests very poor permeability. Ligand B (-4.493) also has a negative value, but less negative, suggesting slightly better permeability.

**Aqueous Solubility:** Both ligands have poor aqueous solubility (-2.959 and -3.82). This could pose formulation challenges, but is not a dealbreaker if other properties are favorable.

**hERG Inhibition:** Both ligands have very low hERG inhibition risk (A: 0.48, B: 0.073).

**Microsomal Clearance:** Ligand A (-0.33) has a negative clearance, which is not physically possible and indicates an issue with the data. Ligand B (42.446) has a high clearance, suggesting rapid metabolism.

**In vitro Half-Life:** Ligand B (10.94) has a longer half-life than Ligand A (-2.357), which is a positive attribute.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (A: 0.114, B: 0.144).

**Binding Affinity:** Ligand B (-7.3 kcal/mol) has a significantly stronger binding affinity than Ligand A (-10.2 kcal/mol). This is a major advantage, potentially outweighing some of the ADME drawbacks.

**Overall Assessment:**

Ligand B is the stronger candidate. While it has a higher logP and clearance, its significantly better BBB penetration, superior binding affinity, and lower DILI risk outweigh these concerns. Ligand A's extremely poor Caco-2 permeability and the negative clearance value are major red flags. The substantial affinity difference (-7.3 vs -10.2 kcal/mol) is a critical factor favoring Ligand B.

Output:
1
2025-04-17 07:49:27,638 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (350.419 and 351.535 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (106.23) is slightly above the optimal <90 for CNS targets, but still reasonable. Ligand B (52.65) is excellent, well below 90. This favors Ligand B.

**3. logP:** Ligand A (0.736) is a bit low, potentially hindering permeation. Ligand B (2.818) is within the optimal 1-3 range. This favors Ligand B.

**4. H-Bond Donors:** Ligand A (2) and Ligand B (1) are both acceptable, below the threshold of 5.

**5. H-Bond Acceptors:** Ligand A (6) and Ligand B (3) are both acceptable, below the threshold of 10.

**6. QED:** Both ligands have similar QED values (0.754 and 0.718), indicating good drug-like properties.

**7. DILI:** Ligand A (48.972) has a slightly higher DILI risk than Ligand B (6.437), but both are below the concerning threshold of 60.

**8. BBB:** This is a crucial parameter for a CNS target like DRD2. Ligand A (52.23) is moderate, while Ligand B (79.256) is very good, exceeding the desirable >70 threshold. This is a significant advantage for Ligand B.

**9. Caco-2 Permeability:** Ligand A (-5.083) shows poor permeability. Ligand B (-4.627) also shows poor permeability, but is slightly better than Ligand A.

**10. Aqueous Solubility:** Ligand A (-2.168) and Ligand B (-1.894) both have poor aqueous solubility.

**11. hERG Inhibition:** Ligand A (0.05) and Ligand B (0.614) both show low hERG inhibition risk.

**12. Microsomal Clearance:** Ligand A (17.852) has lower clearance than Ligand B (23.924), suggesting better metabolic stability. This favors Ligand A.

**13. In vitro Half-Life:** Ligand B (-10.998) has a significantly longer half-life than Ligand A (-7.948). This favors Ligand B.

**14. P-gp Efflux:** Ligand A (0.056) has lower P-gp efflux than Ligand B (0.034), which is better for CNS exposure. This favors Ligand A.

**15. Binding Affinity:** Ligand A (-8.9 kcal/mol) has a stronger binding affinity than Ligand B (-7.2 kcal/mol). This is a substantial advantage for Ligand A, potentially outweighing some of its ADME drawbacks. The difference is >1.5 kcal/mol.

**Overall Assessment:**

While Ligand A has superior binding affinity and slightly better metabolic stability and P-gp efflux, Ligand B excels in key GPCR-specific properties: TPSA, logP, and, most importantly, BBB penetration. The significantly better BBB score for Ligand B is crucial for a CNS target. The longer half-life of Ligand B is also a significant benefit. The affinity difference, while substantial, may be overcome with further optimization of Ligand B.

Output:
1
2025-04-17 07:49:27,638 - INFO - Reasoning:

Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (370.515 and 383.905 Da) fall comfortably within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (76.66) is significantly better than Ligand B (93.25). For CNS targets, we want TPSA <= 90, so Ligand A is preferable.

**3. logP:** Both ligands have good logP values (2.833 and 2.501), falling within the optimal 1-3 range.

**4. H-Bond Donors:** Both have 2 HBD, which is acceptable.

**5. H-Bond Acceptors:** Both have 5 HBA, which is acceptable.

**6. QED:** Both ligands have good QED scores (0.664 and 0.733), indicating good drug-like properties.

**7. DILI:** Both have acceptable DILI risk (41.373 and 46.452), below the concerning threshold of 60.

**8. BBB:** Ligand B (68.554) has a significantly better BBB penetration percentile than Ligand A (54.634). This is a *critical* factor for a CNS target like DRD2.

**9. Caco-2 Permeability:** Ligand A (-4.899) has a slightly better (less negative) Caco-2 permeability than Ligand B (-5.205). However, both are quite poor, suggesting limited intestinal absorption. This is less critical for a CNS target where direct delivery is possible.

**10. Aqueous Solubility:** Both ligands have poor aqueous solubility (-2.132 and -2.41). This could pose formulation challenges.

**11. hERG Inhibition:** Both ligands show very low hERG inhibition liability (0.471 and 0.193), which is excellent.

**12. Microsomal Clearance:** Ligand B (36.669) exhibits lower microsomal clearance than Ligand A (47.623), suggesting better metabolic stability.

**13. In vitro Half-Life:** Both have similar in vitro half-lives (14.087 and 13.994 hours).

**14. P-gp Efflux:** Both ligands show very low P-gp efflux liability (0.163 and 0.044), which is highly desirable for CNS penetration.

**15. Binding Affinity:** Ligand A (-7.1 kcal/mol) has a slightly better binding affinity than Ligand B (-7.0 kcal/mol), although the difference is small.

**Overall Assessment:**

While Ligand A has a better TPSA and slightly better affinity, Ligand B's significantly improved BBB penetration (68.554 vs 54.634) is the deciding factor for a CNS target like DRD2. The slightly better metabolic stability (lower Cl_mic) of Ligand B is also a plus. The poor Caco-2 permeability and solubility are less concerning given the CNS focus. The small affinity difference is outweighed by the BBB advantage.

Output:
1
2025-04-17 07:49:27,638 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (349.475 and 367.515 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (72.88) is significantly better than Ligand B (78.51). For CNS targets, we want TPSA <= 90, and A is closer to the optimal <= 60 range.

**logP:** Ligand A (0.6) is a bit low, potentially hindering permeation. Ligand B (1.006) is better, falling within the 1-3 optimal range.

**H-Bond Donors/Acceptors:** Both have 2 HBD and 4 HBA, which are acceptable.

**QED:** Both ligands have good QED scores (0.689 and 0.711), indicating drug-like properties.

**DILI:** Ligand A (4.692) has a much lower DILI risk than Ligand B (31.02). This is a significant advantage.

**BBB:** Ligand B (62.233) has a substantially better BBB penetration score than Ligand A (29.275). This is a *critical* factor for a CNS target like DRD2.

**Caco-2 Permeability:** Both have negative Caco-2 values (-5.056 and -5.245), which is unusual and suggests poor permeability. However, these values are on a scale where negative values are possible, and direct comparison is difficult without knowing the scale's specifics.

**Aqueous Solubility:** Both have negative solubility values (-0.408 and -3.371), also unusual. Again, direct comparison is difficult.

**hERG:** Both have very low hERG inhibition liability (0.365 and 0.182), which is excellent.

**Microsomal Clearance:** Ligand A (-25.518) has *much* lower (better) microsomal clearance than Ligand B (31.064), indicating greater metabolic stability.

**In vitro Half-Life:** Ligand A (-9.877) has a longer (better) in vitro half-life than Ligand B (6.156).

**P-gp Efflux:** Both have very low P-gp efflux liability (0.033 and 0.016), which is favorable for CNS penetration.

**Binding Affinity:** Ligand B (-7.5 kcal/mol) has a slightly better binding affinity than Ligand A (-7.2 kcal/mol). While a 0.3 kcal/mol difference isn't huge, it's noticeable.

**Overall Assessment:**

Ligand A excels in metabolic stability (Cl_mic, t1/2), DILI risk, and TPSA. Ligand B's primary advantage is its significantly better BBB penetration and slightly better binding affinity. Given that DRD2 is a CNS target, BBB penetration is paramount. While Ligand A has better ADME properties overall, the poor BBB score is a major drawback. The slightly better affinity of Ligand B, combined with its superior BBB score, outweighs the advantages of Ligand A.

Output:
1
2025-04-17 07:49:27,639 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (368.396 and 356.432 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (67.87) is higher than Ligand B (33.2). For CNS targets, we prefer TPSA <= 90, so both are acceptable, but B is significantly better.

**logP:** Ligand A (1.874) is within the optimal 1-3 range. Ligand B (4.895) is slightly high, potentially leading to solubility issues and off-target interactions.

**H-Bond Donors/Acceptors:** Ligand A has 1 HBD and 4 HBA, while Ligand B has 0 HBD and 2 HBA. Both are within acceptable limits (<=5 HBD and <=10 HBA).

**QED:** Both ligands have reasonable QED values (0.745 and 0.664), indicating good drug-like properties.

**DILI:** Ligand A (35.324) has a slightly higher DILI risk than Ligand B (19.698), but both are below the 40 threshold, indicating low risk.

**BBB:** Ligand B (94.223) has a significantly higher BBB penetration percentile than Ligand A (78.945). This is a crucial advantage for a CNS target like DRD2.

**Caco-2 Permeability:** Both have negative Caco-2 values (-4.569 and -4.415), which is unusual and suggests poor permeability. This is a significant concern for both.

**Aqueous Solubility:** Both ligands have very poor aqueous solubility (-1.851 and -5.246). This could hinder formulation and bioavailability.

**hERG Inhibition:** Ligand A (0.416) has a slightly higher hERG inhibition liability than Ligand B (0.7), but both are relatively low risk.

**Microsomal Clearance:** Ligand B (80.345) has a much higher microsomal clearance than Ligand A (15.39). This suggests Ligand A is more metabolically stable.

**In vitro Half-Life:** Ligand A (-16.119) has a negative half-life, which is not physically possible and indicates a data error or a very rapidly metabolized compound. Ligand B (1.754) has a short half-life, but it's a realistic value.

**P-gp Efflux:** Ligand A (0.049) has much lower P-gp efflux liability than Ligand B (0.616), which is beneficial for CNS exposure.

**Binding Affinity:** Ligand A (-8.1 kcal/mol) has a slightly better binding affinity than Ligand B (-7.8 kcal/mol). While the difference is small, it's potentially significant.

**Overall Assessment:**

Ligand B excels in BBB penetration, a critical factor for DRD2. However, it suffers from a higher logP, higher P-gp efflux, and significantly higher microsomal clearance. Ligand A has better metabolic stability (lower Cl_mic), lower P-gp efflux, and slightly better binding affinity. The negative half-life for Ligand A is a major red flag. Despite the solubility issues for both, Ligand A's superior metabolic stability and P-gp profile, combined with slightly better affinity, make it the more promising candidate, *assuming the half-life data is an error*. If the half-life is accurate, Ligand B is the better choice despite its drawbacks. Given the data as presented, I will assume the half-life for A is an error.

Output:
1
2025-04-17 07:49:27,639 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (344.411 Da) is slightly lower, which could be beneficial for permeability.

**2. TPSA:** Both ligands have TPSA values below 140, suggesting reasonable oral absorption. Ligand B (83.63) is better than Ligand A (98.66) and closer to the <90 target for CNS penetration.

**3. logP:** Ligand A (0.622) is a bit low, potentially hindering permeation. Ligand B (2.961) is within the optimal range (1-3).

**4. H-Bond Donors:** Ligand A (4) is slightly higher than ideal, but acceptable. Ligand B (2) is good.

**5. H-Bond Acceptors:** Both ligands are within the acceptable range (<=10).

**6. QED:** Both ligands have good QED scores (>0.5), indicating drug-like properties. Ligand B (0.706) is slightly better.

**7. DILI:** Both ligands have acceptable DILI risk, but Ligand A (26.095) is significantly lower than Ligand B (36.681).

**8. BBB:** Ligand B (61.923) has a better BBB percentile than Ligand A (50.679), but both are below the desirable >70 for CNS targets.

**9. Caco-2 Permeability:** Both have negative values, which is unusual and suggests poor permeability. However, the scale is not specified, so it's hard to interpret.

**10. Aqueous Solubility:** Both have negative values, which is unusual and suggests poor solubility. However, the scale is not specified, so it's hard to interpret.

**11. hERG Inhibition:** Both ligands show low hERG inhibition risk.

**12. Microsomal Clearance:** Ligand A (12.32) has a lower clearance than Ligand B (50.614), indicating better metabolic stability.

**13. In vitro Half-Life:** Ligand A (-14.32) has a negative half-life, which is impossible. Ligand B (-8.222) also has a negative half-life, which is impossible. This is a major red flag for both compounds.

**14. P-gp Efflux:** Ligand A (0.037) has much lower P-gp efflux liability than Ligand B (0.393), which is favorable for CNS exposure.

**15. Binding Affinity:** Ligand A (-8.8 kcal/mol) has a significantly stronger binding affinity than Ligand B (-7.5 kcal/mol). This is a substantial advantage.

**Overall Assessment:**

Despite the issues with the half-life values, Ligand A is the more promising candidate. The significantly stronger binding affinity (-8.8 vs -7.5 kcal/mol) is a major advantage that can outweigh some of its drawbacks.  Ligand A also has lower DILI risk and P-gp efflux, and better metabolic stability. While Ligand B has a better logP and TPSA, the affinity difference is too large to ignore. The negative half-life values are concerning for both, but the superior binding of A makes it the better starting point for optimization.

Output:
0
2025-04-17 07:49:27,639 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (373.519 and 370.475 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (108.29) is better than Ligand B (113.18). For CNS targets, we want TPSA <= 90, so both are slightly above the ideal, but A is closer.

**3. logP:** Ligand A (1.554) is better than Ligand B (0.932). Both are within the optimal 1-3 range, but A is more favorable.

**4. H-Bond Donors:** Ligand A (2) is better than Ligand B (3). Lower is generally preferred.

**5. H-Bond Acceptors:** Both ligands have 5 H-bond acceptors, which is acceptable (<=10).

**6. QED:** Ligand A (0.704) is better than Ligand B (0.598). A higher QED suggests better drug-likeness.

**7. DILI:** Both ligands have similar DILI risk (44.436 vs 45.25), and are both below the concerning threshold of 60.

**8. BBB:** Ligand B (50.058) is significantly better than Ligand A (38.542). For a CNS target like DRD2, BBB penetration is crucial. A value >70 is desirable, but 50 is considerably better than 38.

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.114 and -5.28), which is unusual and suggests poor permeability. This is a significant drawback for both.

**10. Aqueous Solubility:** Both ligands have negative solubility values (-3.414 and -2.19), indicating very poor aqueous solubility. This is a major concern for bioavailability.

**11. hERG Inhibition:** Both ligands show low hERG inhibition risk (0.468 and 0.263), which is good.

**12. Microsomal Clearance:** Ligand B (12.225) has a much lower microsomal clearance than Ligand A (40.251), indicating better metabolic stability.

**13. In vitro Half-Life:** Ligand B (-41.522) has a longer in vitro half-life than Ligand A (-27.065), which is favorable.

**14. P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.026 and 0.04), which is good for CNS penetration.

**15. Binding Affinity:** Both ligands have the same binding affinity (-7.7 kcal/mol), which is excellent.

**Overall Assessment:**

While Ligand A has slightly better physicochemical properties (TPSA, logP, HBD, QED), Ligand B has a significantly better BBB penetration score and superior metabolic stability (lower Cl_mic) and longer half-life. The equal binding affinity is a tiebreaker. Given the importance of BBB penetration for a CNS target like DRD2, and the better metabolic profile of Ligand B, it is the more promising candidate. The poor Caco-2 and solubility are concerning for both, but can potentially be addressed through formulation strategies.

Output:
1
2025-04-17 07:49:27,639 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (348.487 and 343.427 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (49.85) is significantly better than Ligand B (66.65). For CNS targets, we want TPSA <= 90, and ideally closer to 60. Ligand A is much closer to this ideal.

**3. logP:** Both ligands have good logP values (2.463 and 1.64), falling within the optimal range of 1-3.

**4. H-Bond Donors:** Both have 0 HBD, which is acceptable.

**5. H-Bond Acceptors:** Ligand A has 3 HBA, and Ligand B has 4. Both are within the acceptable limit of <= 10.

**6. QED:** Ligand B (0.834) has a higher QED score than Ligand A (0.525), suggesting a more generally drug-like profile. However, this is less critical than CNS penetration for a CNS target.

**7. DILI:** Ligand A (13.106) has a significantly lower DILI risk than Ligand B (16.596). Lower is better.

**8. BBB:** Ligand A (84.025) has a much better BBB penetration percentile than Ligand B (68.67). A value >70 is desirable for CNS targets, and Ligand A is closer.

**9. Caco-2 Permeability:** Both have negative values (-4.583 and -4.764), which is unusual and difficult to interpret without knowing the scale. However, the values are similar.

**10. Aqueous Solubility:** Both have negative values (-1.965 and -2.035), again, difficult to interpret without the scale. Similar values.

**11. hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.403 and 0.143).

**12. Microsomal Clearance:** Ligand A (44.385) has lower microsomal clearance than Ligand B (62.799), indicating better metabolic stability.

**13. In vitro Half-Life:** Ligand A (7.157) has a longer in vitro half-life than Ligand B (2.168).

**14. P-gp Efflux:** Ligand A (0.307) has lower P-gp efflux than Ligand B (0.022), suggesting better CNS exposure.

**15. Binding Affinity:** Ligand B (-9.1 kcal/mol) has a significantly stronger binding affinity than Ligand A (-7.6 kcal/mol). This is a substantial difference (>1.5 kcal/mol) and a major advantage.

**Overall Assessment:**

While Ligand B has a better QED and significantly stronger binding affinity, Ligand A excels in properties crucial for CNS penetration: TPSA, BBB, P-gp efflux, and metabolic stability (lower Cl_mic and longer t1/2). The difference in binding affinity is significant, but the improved CNS properties of Ligand A are likely to translate to better *in vivo* efficacy for a CNS target like DRD2. The lower DILI risk for Ligand A is also a positive factor.

Output:
0
2025-04-17 07:49:27,640 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (346.431 and 344.39 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Both ligands (77.41 and 78.09) are slightly above the optimal <90 for CNS targets, but still reasonably acceptable.

**3. logP:** Ligand A (1.782) is within the optimal 1-3 range. Ligand B (2.799) is also within the optimal range, leaning towards the higher end, but still acceptable.

**4. H-Bond Donors:** Both ligands have 2 HBD, which is within the desirable limit of <=5.

**5. H-Bond Acceptors:** Ligand A has 5 HBA, and Ligand B has 3 HBA, both within the desirable limit of <=10.

**6. QED:** Both ligands have good QED scores (0.726 and 0.819), indicating good drug-like properties.

**7. DILI:** Ligand A (32.765) has a lower DILI risk than Ligand B (55.913), which is a significant advantage.

**8. BBB:** Ligand B (77.898) has a significantly better BBB penetration percentile than Ligand A (60.644). This is a crucial factor for a CNS target like DRD2.

**9. Caco-2 Permeability:** Both have negative values (-4.928 and -4.749), indicating poor permeability. This is a concern for both.

**10. Aqueous Solubility:** Both have negative values (-2.128 and -3.95), indicating poor solubility. This is a concern for both.

**11. hERG Inhibition:** Both ligands have low hERG inhibition risk (0.288 and 0.412).

**12. Microsomal Clearance:** Ligand A (28.977) has lower microsomal clearance than Ligand B (43.035), suggesting better metabolic stability.

**13. In vitro Half-Life:** Ligand A (41.038) has a longer half-life than Ligand B (-23.982), which is a clear advantage.

**14. P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.019 and 0.022), which is favorable for CNS penetration.

**15. Binding Affinity:** Both ligands have excellent binding affinities (-8.0 and -9.0 kcal/mol). Ligand B is slightly better (-9.0 kcal/mol).

**Overall Assessment:**

Ligand B has a significantly better BBB score and slightly better binding affinity, which are critical for a CNS GPCR target. However, Ligand A has a lower DILI risk, better metabolic stability (lower Cl_mic), and a longer half-life. The difference in binding affinity is relatively small (1 kcal/mol), and the improved ADME properties of Ligand A, particularly the lower DILI risk and better metabolic stability, are valuable. The poor Caco-2 and solubility are concerns for both, but can be addressed with formulation strategies.

Considering the balance of properties, and the importance of BBB penetration for a CNS target, Ligand B is slightly more promising.

Output:
1
2025-04-17 07:49:27,640 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (342.399 and 354.466 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (78.53) is better than Ligand B (58.64). Both are below the 90 A^2 threshold desirable for CNS targets, but Ligand B is closer to the optimal range.

**logP:** Ligand A (1.391) is within the optimal 1-3 range. Ligand B (2.44) is also within range, but slightly higher.

**H-Bond Donors/Acceptors:** Both ligands have 1 HBD and a reasonable number of HBAs (4 for A, 3 for B), satisfying the criteria of <=5 HBD and <=10 HBA.

**QED:** Ligand A (0.824) has a better QED score than Ligand B (0.681), indicating a more drug-like profile.

**DILI:** Ligand A (68.088) has a higher DILI risk than Ligand B (10.469). This is a significant drawback for Ligand A.

**BBB:** Ligand B (94.455) has a significantly higher BBB penetration percentile than Ligand A (65.413). This is *critical* for a CNS target like DRD2.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.9 and -4.656), which is unusual and suggests poor permeability. However, these values are on a logarithmic scale, and the absolute value is more important. They are fairly similar, and both indicate a permeability issue.

**Aqueous Solubility:** Both ligands have negative solubility values (-3.301 and -2.331), indicating poor aqueous solubility. This is a concern for both, but Ligand B is slightly better.

**hERG Inhibition:** Ligand A (0.279) has a slightly lower hERG inhibition liability than Ligand B (0.678), which is favorable.

**Microsomal Clearance:** Ligand B (32.814) has significantly lower microsomal clearance than Ligand A (59.315), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand B (-7.276) has a longer in vitro half-life than Ligand A (-13.926), which is desirable.

**P-gp Efflux:** Both ligands show low P-gp efflux liability (0.11 and 0.275).

**Binding Affinity:** Ligand B (-7.8 kcal/mol) has a significantly stronger binding affinity than Ligand A (-0.0 kcal/mol). This is a major advantage for Ligand B, and a difference of 7.8 kcal/mol is substantial enough to outweigh many other concerns.

**Overall Assessment:**

Ligand B is the superior candidate. While both have issues with Caco-2 and solubility, Ligand B excels in the most critical areas for a CNS-targeting GPCR: BBB penetration and binding affinity. Its lower DILI risk and improved metabolic stability (lower Cl_mic and longer t1/2) further strengthen its profile. Ligand A's high DILI risk and very weak binding affinity are major drawbacks.

Output:
1
2025-04-17 07:49:27,640 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (350.407 and 346.435 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (103.59) is higher than Ligand B (84.22). For CNS targets, TPSA should be <=90. Ligand B is preferable here.

**3. logP:** Ligand A (2.512) is within the optimal 1-3 range. Ligand B (0.725) is slightly below 1, which could potentially hinder permeability. Ligand A is preferable.

**4. H-Bond Donors:** Ligand A (2) and Ligand B (0) are both acceptable (<=5).

**5. H-Bond Acceptors:** Ligand A (7) and Ligand B (6) are both acceptable (<=10).

**6. QED:** Both ligands have good QED values (0.704 and 0.75), indicating drug-like properties.

**7. DILI:** Ligand A (97.674) has a very high DILI risk, which is a significant concern. Ligand B (38.969) has a much lower, and acceptable, DILI risk. This is a major advantage for Ligand B.

**8. BBB:** Ligand A (48.391) has a moderate BBB penetration, but is below the desirable >70% for CNS targets. Ligand B (71.656) has good BBB penetration, exceeding the 70% threshold. Ligand B is preferable.

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.135 and -5.001), which is unusual and suggests poor permeability. This is a drawback for both, but doesn't differentiate them.

**10. Aqueous Solubility:** Both ligands have negative solubility values (-5.176 and -1.575), also unusual and indicating poor solubility. Again, this is a drawback for both.

**11. hERG Inhibition:** Both ligands have low hERG inhibition risk (0.565 and 0.075). Ligand B is slightly better.

**12. Microsomal Clearance:** Ligand A (21.195) and Ligand B (26.787) have moderate clearance. Lower is better, so Ligand A is slightly preferable.

**13. In vitro Half-Life:** Ligand A (57.902) has a better in vitro half-life than Ligand B (-8.49). This is a significant advantage for Ligand A.

**14. P-gp Efflux:** Ligand A (0.187) has lower P-gp efflux than Ligand B (0.087), which is preferable for CNS exposure.

**15. Binding Affinity:** Both ligands have excellent binding affinities (-9.2 and -8.2 kcal/mol). Ligand A is 1 kcal/mol stronger, which is a substantial advantage, potentially outweighing some of its ADME drawbacks.

**Overall Assessment:**

While Ligand A has a superior binding affinity and better half-life, its extremely high DILI risk and suboptimal BBB penetration are major concerns. Ligand B, despite slightly weaker affinity, exhibits a much more favorable safety profile (low DILI) and good BBB penetration, which are critical for a CNS-targeting drug. The lower logP of Ligand B is a minor concern, but the other advantages are more impactful.

Output:
1
2025-04-17 07:49:27,640 - INFO - Reasoning:

Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (352.494 and 353.421 Da) fall comfortably within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (49.41) is significantly better than Ligand B (64.66). For CNS targets, we want TPSA <= 90, and ideally closer to 60. Ligand A is much closer to this ideal.

**3. logP:** Both ligands have good logP values (3.614 and 2.505), falling within the optimal 1-3 range.

**4. H-Bond Donors:** Ligand A has 1 HBD, while Ligand B has 0. Both are acceptable (<=5).

**5. H-Bond Acceptors:** Ligand A has 2 HBA, and Ligand B has 7. Ligand A is preferable as it is closer to the ideal of <=10.

**6. QED:** Both ligands have good QED scores (0.742 and 0.845), indicating good drug-like properties.

**7. DILI:** Ligand A (15.898) has a much lower DILI risk than Ligand B (42.536). This is a significant advantage for Ligand A.

**8. BBB:** Both ligands show excellent BBB penetration (91.663 and 93.486). Both exceed the desirable >70 threshold for CNS targets.

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.74 and -4.889). This is unusual and suggests poor permeability. However, these are relative values and could be within an acceptable range depending on the assay.

**10. Aqueous Solubility:** Both ligands have negative solubility values (-3.138 and -2.605). This is concerning, as poor solubility can hinder bioavailability.

**11. hERG Inhibition:** Both ligands show low hERG inhibition risk (0.594 and 0.436).

**12. Microsomal Clearance:** Ligand A (24.629) has a higher (worse) microsomal clearance than Ligand B (-0.2). Lower clearance is preferred for metabolic stability.

**13. In vitro Half-Life:** Ligand A has a negative half-life (-16.672) which is unusual and likely indicates rapid metabolism. Ligand B has a negative half-life as well (-0.25), but is slightly better.

**14. P-gp Efflux:** Ligand A (0.304) has lower P-gp efflux than Ligand B (0.18). Lower efflux is better for CNS exposure.

**15. Binding Affinity:** Ligand B (-7.8 kcal/mol) has a significantly better binding affinity than Ligand A (-8.5 kcal/mol). This is a substantial advantage, potentially outweighing some of the ADME drawbacks.

**Overall Assessment:**

While Ligand B has a superior binding affinity, Ligand A demonstrates a more favorable ADME profile, particularly regarding DILI risk, TPSA, and HBA. The negative solubility and Caco-2 values are concerning for both, but the lower TPSA and DILI of Ligand A are more appealing for a CNS-targeting GPCR. The difference in binding affinity is 0.7 kcal/mol, which is significant, but not insurmountable if the ADME properties of Ligand A can be improved through further optimization. Given the importance of CNS penetration and minimizing off-target effects (DILI) for a DRD2 ligand, I would initially favor Ligand A.

Output:
0
2025-04-17 07:49:27,641 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 drug candidates, considering the provided guidelines and GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (346.387 and 341.415 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (120.42) is slightly above the preferred <90 for CNS targets, but still reasonable. Ligand B (72.58) is excellent, well below 90, indicating better potential for brain penetration.

**logP:** Ligand A (0.167) is quite low, potentially hindering membrane permeability. Ligand B (0.275) is also low, but slightly better than A. Both are below the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A has 4 HBD and 5 HBA. Ligand B has 0 HBD and 5 HBA. Both are within acceptable limits.

**QED:** Ligand B (0.791) has a significantly better QED score than Ligand A (0.566), indicating a more drug-like profile.

**DILI:** Ligand B (30.787) has a much lower DILI risk than Ligand A (56.572), a significant advantage.

**BBB:** Ligand B (49.826) has a slightly better BBB percentile than Ligand A (45.754), although both are below the desirable >70 for CNS targets.

**Caco-2 Permeability:** Ligand A (-5.513) has poor Caco-2 permeability, while Ligand B (-4.784) is slightly better, but still poor.

**Aqueous Solubility:** Both ligands have very poor aqueous solubility (-2.376 and -1.817 respectively). This could pose formulation challenges.

**hERG Inhibition:** Both ligands show very low hERG inhibition risk (0.092 and 0.473 respectively).

**Microsomal Clearance:** Ligand A (-5.672) has a negative clearance, which is unusual and likely an error or indicates very high metabolic stability. Ligand B (21.7) has a moderate clearance.

**In vitro Half-Life:** Ligand B (17.902) has a longer in vitro half-life than Ligand A (-21.375), which is a positive attribute.

**P-gp Efflux:** Both ligands show very low P-gp efflux liability (0.01).

**Binding Affinity:** Ligand B (-8.2 kcal/mol) has a significantly stronger binding affinity than Ligand A (-9.0 kcal/mol). This is a crucial advantage, exceeding the 1.5 kcal/mol difference threshold.

**Overall Assessment:**

Considering the GPCR-specific priorities, Ligand B is the superior candidate. While both have poor logP and solubility, Ligand B's significantly better binding affinity, lower DILI risk, better QED, and longer half-life outweigh the drawbacks. The slightly better BBB and Caco-2 permeability also contribute to its favorability. The negative microsomal clearance for Ligand A is suspect and warrants further investigation.

Output:
1
2025-04-17 07:49:27,641 - INFO - Reasoning:

Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (351.407 and 350.463 Da) fall comfortably within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (90.22) is slightly above the preferred <90 for CNS targets, but still reasonable. Ligand B (87.47) is excellent, well below 90.

**3. logP:** Both ligands have good logP values (1.181 and 1.592), falling within the optimal 1-3 range.

**4. H-Bond Donors:** Ligand A (1) is good. Ligand B (2) is also acceptable, both are below the threshold of 5.

**5. H-Bond Acceptors:** Ligand A (7) is good. Ligand B (5) is also good, both are below the threshold of 10.

**6. QED:** Both ligands have good QED scores (0.647 and 0.743), indicating good drug-like properties.

**7. DILI:** Ligand A (67.468) has a moderate DILI risk, while Ligand B (17.604) has a very low DILI risk, a significant advantage.

**8. BBB:** Both ligands have excellent BBB penetration (90.772 and 67.662), but Ligand A is superior, exceeding the desirable >70 threshold.

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.746 and -4.98), which is unusual and suggests poor permeability. This is a concern for both.

**10. Aqueous Solubility:** Both ligands have negative solubility values (-1.317 and -1.117), indicating very poor aqueous solubility. This is a significant drawback for both.

**11. hERG Inhibition:** Both ligands show low hERG inhibition risk (0.646 and 0.204).

**12. Microsomal Clearance:** Ligand A (63.978) has moderate clearance, while Ligand B (-0.217) has very low clearance, indicating better metabolic stability.

**13. In vitro Half-Life:** Ligand A (50.608) has a reasonable half-life, while Ligand B (14.041) has a shorter half-life.

**14. P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.068 and 0.012), which is excellent for CNS penetration.

**15. Binding Affinity:** Ligand B (-8.0) has a significantly stronger binding affinity than Ligand A (-6.7), a difference of 1.3 kcal/mol. This is a substantial advantage that can outweigh some ADME concerns.

**Overall Assessment:**

While both ligands have issues with Caco-2 permeability and aqueous solubility, Ligand B clearly stands out due to its superior binding affinity (-8.0 vs -6.7 kcal/mol) and significantly lower DILI risk (17.6 vs 67.5). The lower microsomal clearance of Ligand B is also favorable. Although Ligand A has a slightly better BBB score, the substantial affinity advantage of Ligand B, coupled with the lower toxicity risk, makes it the more promising candidate.

Output:
1
2025-04-17 07:49:27,641 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (366.38 and 346.471 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (75.71) is slightly higher than Ligand B (58.64). For a CNS target like DRD2, we ideally want TPSA <= 90, so both are acceptable, but B is better.

**3. logP:** Both ligands have good logP values (1.675 and 1.96), falling within the optimal 1-3 range.

**4. H-Bond Donors:** Both have 1 HBD, which is within the acceptable limit of <=5.

**5. H-Bond Acceptors:** Ligand A has 4 HBAs, and Ligand B has 3. Both are below the acceptable limit of <=10.

**6. QED:** Both ligands have good QED scores (0.751 and 0.795), indicating good drug-like properties.

**7. DILI:** Both ligands have acceptable DILI risk, with Ligand B (32.377) being slightly better than Ligand A (40.558). Both are well below the concerning threshold of 60.

**8. BBB:** Both ligands exhibit excellent BBB penetration (73.401 and 71.694 percentile), which is crucial for a CNS target.

**9. Caco-2 Permeability:** Both have negative Caco-2 values (-4.549 and -4.602), which is unusual and suggests poor permeability. This is a significant concern.

**10. Aqueous Solubility:** Both have negative solubility values (-2.694 and -2.652), indicating poor aqueous solubility. This is also a concern.

**11. hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.387 and 0.397).

**12. Microsomal Clearance:** Ligand A (32.988) has lower microsomal clearance than Ligand B (48.697), suggesting better metabolic stability.

**13. In vitro Half-Life:** Ligand A (-25.373) has a significantly longer in vitro half-life than Ligand B (-11.756).

**14. P-gp Efflux:** Ligand A (0.053) has lower P-gp efflux than Ligand B (0.115), which is favorable for CNS penetration.

**15. Binding Affinity:** Ligand A (-7.3 kcal/mol) has a slightly better binding affinity than Ligand B (-0.0 kcal/mol). The difference in affinity is substantial (7.3 kcal/mol), and this is the most important factor.

**Overall Assessment:**

Despite the poor Caco-2 and solubility values for both, Ligand A is the stronger candidate. Its significantly better binding affinity (-7.3 vs -0.0 kcal/mol) outweighs the slightly less favorable TPSA, DILI, and P-gp efflux. The longer half-life and lower clearance also contribute to its superiority. The affinity difference is so large that it suggests a fundamentally better interaction with the DRD2 receptor, which is paramount for a GPCR ligand. The poor permeability and solubility would need to be addressed through formulation or further chemical modifications, but a strong starting point with high affinity is essential.

Output:
1
2025-04-17 07:49:27,641 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (352.475 & 360.483 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (67.87) is significantly better than Ligand B (83.98). For CNS targets, TPSA should be <=90, and A is closer to the optimal <=60 range. B is pushing the upper limit and may have reduced brain penetration.

**3. logP:** Both ligands have acceptable logP values (1.89 & 2.35), falling within the 1-3 range.

**4. H-Bond Donors:** Ligand A (1) is preferable to Ligand B (2). Lower HBD generally improves permeability.

**5. H-Bond Acceptors:** Ligand A (4) is preferable to Ligand B (5). Lower HBA generally improves permeability.

**6. QED:** Both ligands have similar and good QED values (0.741 & 0.757), indicating good drug-like properties.

**7. DILI:** Ligand A (32.377) has a much lower DILI risk than Ligand B (64.017). This is a significant advantage for A.

**8. BBB:** Ligand A (61.38) has a better BBB percentile than Ligand B (42.226), although both are below the desirable >70 for CNS targets. A is closer to the threshold.

**9. Caco-2 Permeability:** Ligand A (-4.587) has better Caco-2 permeability than Ligand B (-5.443). Higher values are better.

**10. Aqueous Solubility:** Ligand A (-1.933) has better aqueous solubility than Ligand B (-2.515). Higher values are better.

**11. hERG Inhibition:** Ligand A (0.18) has a lower hERG inhibition liability than Ligand B (0.448), indicating a lower risk of cardiotoxicity.

**12. Microsomal Clearance:** Ligand A (40.366) has a slightly higher microsomal clearance than Ligand B (38.918), meaning B is more metabolically stable. However, the difference isn't huge.

**13. In vitro Half-Life:** Ligand B (20.692) has a significantly longer in vitro half-life than Ligand A (-0.578). This is a substantial advantage for B.

**14. P-gp Efflux:** Ligand A (0.035) has much lower P-gp efflux liability than Ligand B (0.072), which is crucial for CNS penetration.

**15. Binding Affinity:** Ligand B (-8.8) has a slightly better binding affinity than Ligand A (-8.3). While a 0.5 kcal/mol difference is good, it's not massive enough to outweigh the significant ADME advantages of Ligand A.

**Overall Assessment:**

Ligand A is the stronger candidate. While Ligand B has a slightly better binding affinity and half-life, Ligand A excels in critical ADME properties for a CNS-targeting GPCR ligand: lower TPSA, lower DILI risk, better BBB penetration, better Caco-2 permeability, better solubility, lower hERG inhibition, and significantly lower P-gp efflux. The combination of these factors suggests that Ligand A is more likely to achieve sufficient brain exposure and have a favorable safety profile.

Output:
0
2025-04-17 07:49:27,642 - INFO - Batch 397 complete. Total preferences: 6352
2025-04-17 07:49:27,642 - INFO - Processing batch 398/512...
2025-04-17 07:50:09,495 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 drug candidates, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (347.459 and 377.363 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (62.83) is better than Ligand B (64.11). Both are below the 90 A^2 threshold desirable for CNS targets, but A is closer to optimal.

**3. logP:** Ligand A (2.476) is within the optimal 1-3 range. Ligand B (3.913) is pushing the upper limit, potentially raising concerns about solubility and off-target effects.

**4. H-Bond Donors:** Ligand A (2) and Ligand B (1) are both acceptable, well below the 5 threshold.

**5. H-Bond Acceptors:** Ligand A (4) and Ligand B (5) are both acceptable, below the 10 threshold.

**6. QED:** Both ligands have similar QED values (0.83 and 0.776), indicating good drug-like properties.

**7. DILI:** Ligand A (10.585) has a significantly lower DILI risk than Ligand B (75.533). This is a major advantage for Ligand A.

**8. BBB:** Ligand A (83.249) has a better BBB penetration percentile than Ligand B (75.921). Both are reasonably good, but A is better. This is critical for a CNS target like DRD2.

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.887 and -4.682). These values are unusual and suggest poor permeability. However, the scale isn't specified, so we can't definitively say how bad this is.

**10. Aqueous Solubility:** Ligand A (-1.474) has slightly better solubility than Ligand B (-4.125).

**11. hERG Inhibition:** Both ligands have low hERG inhibition liability (0.62 and 0.406), which is good.

**12. Microsomal Clearance:** Ligand A (-16.529) has significantly lower (better) microsomal clearance than Ligand B (54.694), indicating greater metabolic stability.

**13. In vitro Half-Life:** Ligand A (4.818) has a shorter half-life than Ligand B (-26.798). This is a negative for Ligand A, but the negative value for B is concerning.

**14. P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.012 and 0.181), which is favorable for CNS penetration.

**15. Binding Affinity:** Both ligands have very similar binding affinities (-8.3 and -8.4 kcal/mol). The difference is negligible.

**Overall Assessment:**

Ligand A is the superior candidate. It has a lower DILI risk, better BBB penetration, better metabolic stability (lower Cl_mic), and slightly better solubility. While its half-life is shorter, the other advantages, particularly the DILI and BBB scores, outweigh this drawback. Ligand B's high DILI risk and higher Cl_mic are significant concerns. The similar binding affinities mean that the ADME properties are the deciding factors.

Output:
0
2025-04-17 07:50:09,495 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (350.419 and 364.471 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (113.44) is better than Ligand B (77.53) as it is closer to the ideal range of <90 for CNS targets. Ligand B is quite low, which *could* indicate reduced hydrogen bonding and potentially lower specificity.

**3. logP:** Ligand B (2.216) is within the optimal 1-3 range. Ligand A (0.115) is significantly lower, which is concerning for membrane permeability and CNS penetration.

**4. H-Bond Donors:** Ligand A (3) is acceptable, while Ligand B (2) is also good.

**5. H-Bond Acceptors:** Ligand A (6) is acceptable, while Ligand B (8) is also acceptable.

**6. QED:** Both ligands (0.671 and 0.626) have good drug-likeness scores, exceeding the 0.5 threshold.

**7. DILI:** Ligand A (49.011) has a much lower DILI risk than Ligand B (85.653), which is a significant advantage.

**8. BBB:** Ligand B (64.25) has a better BBB percentile than Ligand A (43.66), but both are below the desirable >70 for CNS targets.

**9. Caco-2 Permeability:** Ligand A (-5.249) has a much lower Caco-2 permeability than Ligand B (-5.033). Both are negative, indicating poor permeability.

**10. Aqueous Solubility:** Ligand A (-1.391) has better solubility than Ligand B (-3.4), which is a positive.

**11. hERG Inhibition:** Ligand A (0.158) has a lower hERG inhibition liability than Ligand B (0.871), indicating a lower risk of cardiotoxicity.

**12. Microsomal Clearance:** Ligand A (-4.236) has a much lower (better) microsomal clearance than Ligand B (86.572), suggesting greater metabolic stability.

**13. In vitro Half-Life:** Ligand B (63.875) has a longer in vitro half-life than Ligand A (26.75), which is preferable.

**14. P-gp Efflux:** Ligand A (0.016) has much lower P-gp efflux liability than Ligand B (0.191), which is a significant advantage for CNS penetration.

**15. Binding Affinity:** Ligand A (-8.9 kcal/mol) has a significantly stronger binding affinity than Ligand B (-6.1 kcal/mol). This >1.5 kcal/mol difference is a major factor.

**Overall Assessment:**

Despite Ligand B having a better BBB score and half-life, Ligand A is the superior candidate. The significantly stronger binding affinity (-8.9 vs -6.1 kcal/mol) of Ligand A is a dominant factor. Additionally, Ligand A exhibits lower DILI risk, lower hERG inhibition, lower P-gp efflux, and better solubility. While its logP is suboptimal, the strong binding affinity and favorable ADME properties (especially metabolic stability and reduced efflux) outweigh this concern. The TPSA is also more favorable for CNS penetration.

Output:
1
2025-04-17 07:50:09,495 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B based on the provided guidelines, prioritizing GPCR-specific properties (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (341.371 Da) is slightly lower, which could be beneficial for permeability.

**TPSA:** Ligand B (96.87) is significantly better than Ligand A (114.35). For CNS targets, TPSA should be <=90, so Ligand B is preferable.

**logP:** Both ligands have acceptable logP values (A: 0.847, B: 2.053), falling within the optimal range of 1-3. Ligand B is closer to the ideal range.

**H-Bond Donors/Acceptors:** Both have 2 HBD and 6 HBA, which are within acceptable limits.

**QED:** Ligand A (0.852) has a slightly better QED score than Ligand B (0.737), indicating a more drug-like profile.

**DILI:** Ligand A (50.33) has a much lower DILI risk than Ligand B (76.154). This is a significant advantage for Ligand A.

**BBB:** Ligand A (86.274) has a substantially higher BBB penetration percentile than Ligand B (44.668). This is *critical* for a CNS target like DRD2, making Ligand A highly favored.

**Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and difficult to interpret without knowing the scale. However, the values are similar.

**Aqueous Solubility:** Both have negative solubility values, again, difficult to interpret without scale. The values are similar.

**hERG Inhibition:** Both ligands have low hERG inhibition liability (A: 0.579, B: 0.449).

**Microsomal Clearance:** Ligand A (-7.701) has a much lower (better) microsomal clearance than Ligand B (23.946), suggesting greater metabolic stability.

**In vitro Half-Life:** Ligand A (-17.935) has a much longer in vitro half-life than Ligand B (17.606), which is desirable.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (A: 0.01, B: 0.035).

**Binding Affinity:** Ligand A (-9.4 kcal/mol) has a slightly better binding affinity than Ligand B (-8.7 kcal/mol). While the difference is not enormous, it's still a positive for Ligand A.

**Overall:**

Ligand A excels in the most important parameters for a CNS-targeting GPCR: BBB penetration, metabolic stability (low Cl_mic and long t1/2), and binding affinity. It also has a lower DILI risk. While Ligand B has a slightly better TPSA, the significant advantages of Ligand A in BBB, metabolic stability, and DILI outweigh this.

Output:
1
2025-04-17 07:50:09,495 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (365.449 and 371.478 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (54.88) is significantly better than Ligand B (78.51). For CNS targets, we want TPSA <= 90, and A is comfortably within that, while B is approaching the upper limit.

**logP:** Ligand A (4.572) is slightly higher than optimal (1-3), but still potentially acceptable. Ligand B (2.308) is within the optimal range. However, for a GPCR, a slightly higher logP can be tolerated if other properties are favorable.

**H-Bond Donors/Acceptors:** Ligand A (HBD=1, HBA=4) and Ligand B (HBD=2, HBA=3) both have reasonable numbers of H-bond donors and acceptors, well within the guidelines.

**QED:** Both ligands have similar QED values (0.816 and 0.805), indicating good drug-like properties.

**DILI:** Ligand A (74.796) has a higher DILI risk than Ligand B (55.68). This is a negative for Ligand A.

**BBB:** Ligand A (86.661) has a significantly better BBB penetration percentile than Ligand B (70.066). This is a major advantage for a CNS target like DRD2.

**Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and suggests poor permeability. However, the scale is not specified, so it's hard to interpret.

**Aqueous Solubility:** Both have negative solubility values, again unusual. This suggests poor solubility.

**hERG:** Both ligands have similar, low hERG inhibition liability (0.504 and 0.621).

**Microsomal Clearance:** Ligand B (38.238) has significantly lower microsomal clearance than Ligand A (61.705), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand B (-16.734) has a negative half-life, which is not possible. This is a major red flag. Ligand A (49.335) has a reasonable half-life.

**P-gp Efflux:** Ligand A (0.621) has slightly lower P-gp efflux liability than Ligand B (0.09). Lower is better, so this favors Ligand A.

**Binding Affinity:** Ligand A (-9.5 kcal/mol) has a significantly stronger binding affinity than Ligand B (-8.6 kcal/mol). This is a substantial advantage, potentially outweighing some of the ADME drawbacks.

**Overall Assessment:**

Ligand A excels in BBB penetration and binding affinity, both critical for a CNS GPCR target. While its DILI risk is higher and logP slightly elevated, the strong affinity and good BBB offset these concerns. Ligand B has better metabolic stability and lower DILI, but its significantly weaker binding affinity and questionable half-life are major drawbacks. The negative half-life for Ligand B is a showstopper.

Output:
1
2025-04-17 07:50:09,495 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (368.411 and 342.395 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (113.01) is better than Ligand B (71.03) as it is closer to the desirable <90 A^2 for CNS targets. Ligand B is still acceptable.

**logP:** Ligand B (2.15) is optimal (1-3), while Ligand A (-0.412) is below 1, potentially hindering permeation. This is a significant drawback for Ligand A.

**H-Bond Donors/Acceptors:** Both ligands have 2 HBD and 5-6 HBA, which are within acceptable limits.

**QED:** Both ligands have good QED scores (0.699 and 0.842), indicating drug-like properties.

**DILI:** Ligand B (42.885) has a lower DILI risk than Ligand A (61.225), making it preferable. Both are acceptable, but B is better.

**BBB:** Ligand A (70.764) has a significantly better BBB penetration percentile than Ligand B (55.176). This is a crucial advantage for a CNS target like DRD2.

**Caco-2 Permeability:** Both ligands have similar, very poor Caco-2 permeability (-4.939 and -4.9). This is a concern for oral bioavailability for both, but doesn't immediately disqualify either.

**Aqueous Solubility:** Both ligands have poor aqueous solubility (-2.511 and -3.106). This could pose formulation challenges.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.2 and 0.841).

**Microsomal Clearance:** Ligand A (31.356) has lower microsomal clearance than Ligand B (51.329), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (-20.117) has a negative half-life, which is not possible. This is a major red flag for Ligand A, indicating a potential data error or extremely rapid degradation. Ligand B (5.292) has a reasonable half-life.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.034 and 0.388), which is good for CNS exposure.

**Binding Affinity:** Ligand B (-8.9 kcal/mol) has a slightly better binding affinity than Ligand A (-8.2 kcal/mol). While the difference is not huge, it's a positive for Ligand B.

**Overall Assessment:**

Ligand A has a better BBB score and lower clearance, but suffers from a very poor logP, a nonsensical half-life value, and a higher DILI risk. Ligand B has a better logP, DILI, and binding affinity, and a reasonable half-life. The negative half-life for Ligand A is a critical issue. Given the GPCR-specific priorities, the better logP and more realistic ADME profile of Ligand B make it the more promising candidate, despite its lower BBB score.

Output:
1
2025-04-17 07:50:09,495 - INFO - Reasoning:

Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (347.375 and 348.487 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (109.44) is higher than the preferred <90 for CNS targets, but not drastically so. Ligand B (67.43) is excellent, well below the 90 threshold. This favors Ligand B.

**3. logP:** Ligand A (0.658) is a bit low, potentially hindering membrane permeability. Ligand B (2.413) is within the optimal 1-3 range. This favors Ligand B.

**4. H-Bond Donors:** Both ligands have 2 HBD, which is acceptable (<=5).

**5. H-Bond Acceptors:** Ligand A has 6 HBA, and Ligand B has 3 HBA, both are within the acceptable range (<=10).

**6. QED:** Both ligands have QED values above 0.5 (0.743 and 0.694), indicating good drug-like properties.

**7. DILI:** Ligand A (69.058) has a higher DILI risk than Ligand B (25.087). This favors Ligand B.

**8. BBB:** Ligand A (25.475) has a very low BBB penetration percentile, making it less suitable for a CNS target like DRD2. Ligand B (62.311) is better, but still not ideal (we want >70). However, it's significantly better than Ligand A. This is a major advantage for Ligand B.

**9. Caco-2:** Both ligands have negative Caco-2 values (-4.956 and -5.116), which is unusual and suggests poor permeability. However, the values are similar, so this doesn't strongly differentiate them.

**10. Solubility:** Both ligands have negative solubility values (-1.872 and -2.888), suggesting poor aqueous solubility. Again, similar and doesn't strongly differentiate.

**11. hERG:** Both ligands have very low hERG inhibition risk (0.032 and 0.15), which is excellent.

**12. Cl_mic:** Ligand A (14.445) has a lower microsomal clearance than Ligand B (31.457), suggesting better metabolic stability. This favors Ligand A.

**13. t1/2:** Ligand A (-9.013) has a more negative in vitro half-life, which is counterintuitive and likely indicates a very short half-life. Ligand B (-3.4) is better, but still not ideal. This favors Ligand B.

**14. Pgp:** Both ligands have very low Pgp efflux liability (0.021 and 0.064), which is good for CNS penetration.

**15. Binding Affinity:** Both ligands have strong binding affinities (-8.2 and -9.2 kcal/mol). Ligand B is slightly better (-9.2 kcal/mol), but the difference is relatively small.

**Overall Assessment:**

Considering the GPCR-specific priorities, Ligand B is the more promising candidate. While its BBB penetration isn't optimal, it's *significantly* better than Ligand A's. Ligand B also has a more favorable logP, lower DILI risk, and slightly better binding affinity. Although Ligand A has better metabolic stability (lower Cl_mic), the poor BBB penetration and lower logP are critical drawbacks for a CNS target. The similar solubility and Caco-2 values don't sway the decision.

Output:
1
2025-04-17 07:50:09,495 - INFO - Reasoning:

Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (370.475 and 346.515 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (75.21) is slightly above the optimal <90 for CNS targets, but still reasonable. Ligand B (49.41) is excellent, well below 90.

**3. logP:** Ligand A (0.401) is quite low, potentially hindering membrane permeability. Ligand B (3.522) is near the upper end of the optimal 1-3 range, which is good.

**4. H-Bond Donors:** Ligand A (0) is ideal. Ligand B (1) is acceptable.

**5. H-Bond Acceptors:** Ligand A (7) is good. Ligand B (2) is excellent.

**6. QED:** Both ligands have good QED scores (0.722 and 0.8), indicating drug-likeness.

**7. DILI:** Ligand A (55.138) is moderate, acceptable but not ideal. Ligand B (15.626) is very good, indicating low DILI risk.

**8. BBB:** Ligand A (57.968) is below the desirable >70 for CNS targets. Ligand B (79.062) is excellent, exceeding the threshold.

**9. Caco-2:** Both ligands have negative Caco-2 values (-4.586 and -4.507), which is unusual and suggests poor permeability. This is a significant concern for both.

**10. Solubility:** Both ligands have negative solubility values (-1.611 and -4.23), indicating very poor aqueous solubility. This is a major drawback.

**11. hERG:** Both ligands have low hERG inhibition risk (0.281 and 0.561).

**12. Cl_mic:** Ligand A (39.332) has a moderate clearance, while Ligand B (86.007) has a high clearance, suggesting faster metabolism.

**13. t1/2:** Ligand A (-16.219) has a negative half-life, which is not physically possible and indicates a problem with the data or model. Ligand B (-0.728) also has a negative half-life, indicating a similar issue.

**14. Pgp:** Both ligands have low Pgp efflux liability (0.061 and 0.236), which is favorable for CNS penetration.

**15. Binding Affinity:** Ligand B (-7.5 kcal/mol) has a slightly better binding affinity than Ligand A (-7.1 kcal/mol), though the difference is not huge.

**Overall Assessment:**

Despite both ligands having issues with Caco-2 and solubility, Ligand B is the more promising candidate. Its superior logP, BBB penetration, lower DILI risk, and slightly better binding affinity outweigh the higher microsomal clearance. The negative half-life values are concerning for both, and would require further investigation. Ligand A's very low logP is a significant disadvantage.

Output:
1
2025-04-17 07:50:09,496 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (387.267 and 361.511 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (76.46) is higher than Ligand B (56.67). For a CNS target like DRD2, we want TPSA <= 90, so both are acceptable, but B is better.

**3. logP:** Ligand A (1.859) is within the optimal 1-3 range. Ligand B (3.253) is at the higher end, but still acceptable.

**4. H-Bond Donors:** Both ligands have 1 HBD, which is within the acceptable limit of <= 5.

**5. H-Bond Acceptors:** Both ligands have 5 HBA, which is within the acceptable limit of <= 10.

**6. QED:** Both ligands have good QED scores (0.783 and 0.858, respectively), indicating good drug-like properties.

**7. DILI:** Ligand A (48.468) has a slightly higher DILI risk than Ligand B (23.769). Lower is better, so B is preferable.

**8. BBB:** Ligand A (65.801) has a better BBB penetration percentile than Ligand B (59.093). For a CNS target, >70 is desirable, but A is closer.

**9. Caco-2:** Both ligands have negative Caco-2 values (-4.749 and -4.797). This is unusual and suggests poor permeability. However, these values are on a scale where negative values are possible, and direct comparison is difficult without knowing the scale's specifics.

**10. Solubility:** Both ligands have negative solubility values (-3.274 and -2.641). Similar to Caco-2, this is unusual and suggests poor solubility.

**11. hERG:** Both ligands have low hERG inhibition liability (0.259 and 0.448), which is good.

**12. Cl_mic:** Ligand A (37.068) has a lower microsomal clearance than Ligand B (78.103), indicating better metabolic stability.

**13. t1/2:** Ligand A (-6.341) has a negative in vitro half-life, which is unusual. Ligand B (12.936) has a more reasonable half-life.

**14. Pgp:** Both ligands have low P-gp efflux liability (0.096 and 0.071), which is good for CNS penetration.

**15. Binding Affinity:** Ligand A (-7.4) has a slightly better binding affinity than Ligand B (-7.2). A difference of 0.2 kcal/mol is not huge, but it's a factor.

**Overall Assessment:**

Considering the GPCR-specific priorities, Ligand A has a better BBB score and binding affinity, and lower Cl_mic. However, Ligand B has a significantly lower DILI risk, and a more reasonable in vitro half-life. The negative Caco-2 and solubility values for both are concerning, but we must assume these are on a scale where negative values are possible. The slightly better affinity of A, combined with its better BBB, outweighs the slightly higher DILI and unusual half-life.

Output:
0
2025-04-17 07:50:09,496 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (412.244 Da) is slightly higher than Ligand B (359.411 Da), but both are acceptable.

**TPSA:** Ligand A (125.69) is pushing the upper limit for CNS targets (<=90), while Ligand B (97.19) is comfortably within the desired range. This favors Ligand B.

**logP:** Ligand A (0.37) is quite low, potentially hindering membrane permeability. Ligand B (0.19) is also low, but slightly better. Both are below the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A has 3 HBD and 6 HBA, which are reasonable. Ligand B has 1 HBD and 7 HBA, also acceptable.

**QED:** Both ligands have good QED scores (A: 0.532, B: 0.844), indicating good drug-like properties. Ligand B is superior here.

**DILI:** Ligand A (65.762) has a higher DILI risk than Ligand B (54.517), indicating a potentially greater risk of liver injury. This favors Ligand B.

**BBB:** Ligand B (68.166) has a significantly better BBB penetration score than Ligand A (45.909). This is a *critical* advantage for a CNS target like DRD2.

**Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and suggests poor permeability. However, the scale isn't specified, so it's difficult to interpret.

**Aqueous Solubility:** Both have negative solubility values, also unusual. Again, the scale is unknown, making interpretation difficult.

**hERG Inhibition:** Both ligands show very low hERG inhibition risk (A: 0.065, B: 0.157), which is excellent.

**Microsomal Clearance:** Ligand B (-8.104) has a *negative* microsomal clearance, which is not physically possible. This is a red flag and suggests an error in the data. Ligand A (9.402) has a reasonable clearance.

**In vitro Half-Life:** Ligand B (-10.142) also has a negative half-life, which is impossible. This further reinforces the data quality concerns for Ligand B. Ligand A (15.444) has a reasonable half-life.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (A: 0.038, B: 0.057), which is favorable for CNS penetration.

**Binding Affinity:** Ligand B (-9.2 kcal/mol) has a significantly stronger binding affinity than Ligand A (-7.9 kcal/mol). This is a substantial advantage, potentially outweighing some of the ADME concerns.

**Overall Assessment:**

Despite the stronger binding affinity of Ligand B, the negative values for microsomal clearance and half-life are highly suspect and indicate a serious data quality issue. These values are physically impossible. While Ligand B has a better BBB score and lower DILI risk, these advantages are overshadowed by the unreliable ADME data. Ligand A, while having a lower affinity and less favorable TPSA and logP, has plausible ADME properties.

Output:
1
2025-04-17 07:50:09,496 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (371.849 Da) is slightly higher than Ligand B (354.451 Da), but both are acceptable.

**TPSA:** Ligand A (62.3) is excellent for CNS penetration, well below the 90 A^2 threshold. Ligand B (103.26) is higher, but still potentially acceptable, though less ideal.

**logP:** Ligand A (4.327) is a bit high, potentially leading to solubility issues or off-target interactions. Ligand B (-0.113) is significantly low, which could hinder membrane permeability and CNS penetration.

**H-Bond Donors/Acceptors:** Ligand A (1 HBD, 4 HBA) is good. Ligand B (3 HBD, 6 HBA) is also reasonable, though slightly higher.

**QED:** Both ligands have acceptable QED values (A: 0.692, B: 0.501), indicating reasonable drug-likeness.

**DILI:** Ligand A (85.886) has a higher DILI risk than Ligand B (12.796), which is a significant concern.

**BBB:** Ligand A (69.213) has a good BBB percentile, desirable for a CNS target. Ligand B (22.606) has a very low BBB percentile, making CNS penetration unlikely.

**Caco-2 Permeability:** Both have negative values, which is unusual. Assuming a scale where negative values indicate poor permeability, both are poor, but Ligand A (-4.595) is slightly better than Ligand B (-5.376).

**Aqueous Solubility:** Both have negative values, suggesting poor solubility. Ligand A (-5.362) is slightly better than Ligand B (-0.131).

**hERG Inhibition:** Ligand A (0.594) has a low hERG risk. Ligand B (0.092) also has a low hERG risk.

**Microsomal Clearance:** Ligand A (64.459) has moderate clearance. Ligand B (-2.539) has negative clearance, which is not physically meaningful and likely indicates a very stable compound *in vitro*.

**In vitro Half-Life:** Ligand A (62.893) has a reasonable half-life. Ligand B (-3.67) has a negative half-life, which is not physically meaningful.

**P-gp Efflux:** Ligand A (0.417) has low P-gp efflux, which is good. Ligand B (0.014) has very low P-gp efflux, which is excellent.

**Binding Affinity:** Ligand A (-9.2 kcal/mol) has significantly stronger binding affinity than Ligand B (-7.2 kcal/mol). This is a substantial difference.

**Overall Assessment:**

Ligand A has a better BBB score, better Caco-2 permeability, and *much* better binding affinity. However, its higher logP and DILI risk are concerning. Ligand B has a very low BBB score and a low logP, which are problematic for CNS penetration. It also has unrealistic negative values for clearance and half-life. The significantly superior binding affinity of Ligand A, combined with its acceptable (though not ideal) BBB and P-gp efflux, outweighs the concerns about logP and DILI, especially given that these can be addressed through further optimization. The negative values for Ligand B's clearance and half-life are red flags suggesting issues with the data or the molecule itself.

Output:
1
2025-04-17 07:50:09,496 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (339.366 Da) is slightly preferred as it's closer to the lower end, potentially aiding permeability.

**TPSA:** Ligand A (48.3) is excellent, well below the 90 A^2 threshold for CNS targets. Ligand B (99.25) is higher, but still potentially acceptable, though less ideal.

**logP:** Ligand A (3.163) is optimal. Ligand B (0.491) is quite low, which could hinder membrane permeability and potentially reduce binding affinity. This is a significant drawback.

**H-Bond Donors/Acceptors:** Ligand A (0 HBD, 4 HBA) is favorable. Ligand B (3 HBD, 7 HBA) is also acceptable, but slightly higher counts could affect permeability.

**QED:** Ligand A (0.671) is good, indicating drug-likeness. Ligand B (0.314) is lower, suggesting a less favorable drug-like profile.

**DILI:** Ligand A (75.184) has a moderate DILI risk. Ligand B (34.277) has a lower, more favorable DILI risk.

**BBB:** Ligand A (82.823) has excellent BBB penetration potential. Ligand B (70.997) is good, but less desirable than Ligand A for a CNS target.

**Caco-2 Permeability:** Ligand A (-4.462) has poor Caco-2 permeability. Ligand B (-5.715) also has poor Caco-2 permeability.

**Aqueous Solubility:** Ligand A (-4.491) has poor aqueous solubility. Ligand B (-1.775) has slightly better aqueous solubility.

**hERG:** Ligand A (0.783) has a low hERG risk. Ligand B (0.209) has a very low hERG risk.

**Microsomal Clearance:** Ligand A (91.215) has high microsomal clearance, indicating poor metabolic stability. Ligand B (68.793) has moderate microsomal clearance, better than Ligand A.

**In vitro Half-Life:** Ligand A (-0.475) has a short in vitro half-life. Ligand B (26.23) has a long in vitro half-life.

**P-gp Efflux:** Ligand A (0.545) has moderate P-gp efflux. Ligand B (0.017) has very low P-gp efflux, which is highly desirable for CNS penetration.

**Binding Affinity:** Ligand A (-9.9 kcal/mol) has significantly stronger binding affinity than Ligand B (-7.0 kcal/mol). The difference of 2.9 kcal/mol is substantial.

**Overall Assessment:**

Despite Ligand B having better DILI, solubility, metabolic stability, P-gp efflux, and in vitro half-life, Ligand A's superior binding affinity (-9.9 vs -7.0 kcal/mol) and excellent BBB penetration (82.823) are critical for a CNS GPCR target like DRD2. The strong binding affinity can potentially overcome some of the ADME drawbacks (poor Caco-2, solubility, and high clearance). The low logP of Ligand B is a significant concern, likely impacting its ability to reach the target in the brain.

Output:
1
2025-04-17 07:50:09,496 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (351.535 and 367.519 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (52.65) is significantly better than Ligand B (80.12). For CNS targets, we want TPSA <= 90, and A is comfortably within that range, while B is approaching the upper limit.

**logP:** Both ligands have acceptable logP values (2.815 and 1.561, respectively), falling within the optimal 1-3 range. Ligand A is slightly better.

**H-Bond Donors/Acceptors:** Both have 1 HBD, which is good. Ligand A has 3 HBA, and Ligand B has 6 HBA. Lower HBA is generally preferred, so Ligand A is slightly better here.

**QED:** Ligand B (0.825) has a significantly higher QED score than Ligand A (0.486), indicating a more drug-like profile overall.

**DILI:** Ligand A (14.618) has a much lower DILI risk than Ligand B (40.364). This is a substantial advantage for Ligand A.

**BBB:** Ligand A (69.678) has a better BBB percentile than Ligand B (61.923), though both are reasonably good. For a CNS target like DRD2, >70 is desirable, but A is closer.

**Caco-2 Permeability:** Ligand A (-4.704) has a worse Caco-2 permeability than Ligand B (-5.238). Lower values indicate lower permeability.

**Aqueous Solubility:** Both ligands have poor aqueous solubility (-2.748 and -2.81, respectively). This could be a formulation challenge for both.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.438 and 0.347, respectively).

**Microsomal Clearance:** Ligand B (40.46) has a slightly lower microsomal clearance than Ligand A (46.091), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (10.313) has a longer in vitro half-life than Ligand B (-12.898). This is a significant advantage for Ligand A.

**P-gp Efflux:** Ligand A (0.108) has lower P-gp efflux than Ligand B (0.056), which is favorable for CNS penetration.

**Binding Affinity:** Ligand B (-7.6 kcal/mol) has a slightly better binding affinity than Ligand A (-6.6 kcal/mol). This 1 kcal/mol difference is significant.

**Overall Assessment:**

While Ligand B has a better QED and slightly better binding affinity, Ligand A has several critical advantages for a CNS-targeting GPCR ligand. Specifically, its lower DILI risk, better BBB penetration, lower P-gp efflux, and longer half-life are all very important. The TPSA is also significantly better for Ligand A. The difference in binding affinity (1 kcal/mol) can potentially be overcome with further optimization, while the ADME properties of Ligand A are more favorable *as is*.

Output:
0
2025-04-17 07:50:09,497 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (336.315 and 344.459 Da) fall within the ideal range of 200-500 Da.

**TPSA:** Ligand A (134.36) is borderline but acceptable for CNS penetration, while Ligand B (67.23) is excellent, well below the 90 A^2 threshold for CNS targets. This is a significant advantage for Ligand B.

**logP:** Both ligands have good logP values (1.399 and 2.134), falling within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A has 3 HBD and 7 HBA, which are reasonable. Ligand B has 1 HBD and 4 HBA, which is even better, suggesting improved permeability.

**QED:** Both ligands have good QED scores (0.512 and 0.804), indicating drug-like properties. Ligand B is better here.

**DILI:** Ligand A has a high DILI risk (98.449), which is concerning. Ligand B has a much lower DILI risk (29.236), a major advantage.

**BBB:** Ligand A has a poor BBB penetration percentile (29.12), making it less likely to reach the target in the CNS. Ligand B has a significantly better BBB percentile (50.523), which is still not ideal (>70 is desirable) but much better than Ligand A.

**Caco-2 Permeability:** Ligand A has a negative Caco-2 value (-5.435), suggesting poor permeability. Ligand B has a negative Caco-2 value (-4.926), also suggesting poor permeability.

**Aqueous Solubility:** Both ligands have negative solubility values (-4.119 and -1.793), indicating poor solubility.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.498 and 0.191).

**Microsomal Clearance:** Ligand A has a lower Cl_mic (9.925) than Ligand B (36.363), indicating better metabolic stability.

**In vitro Half-Life:** Ligand A has a longer half-life (10.995) than Ligand B (-2.582), which is desirable.

**P-gp Efflux:** Ligand A has a very high P-gp efflux liability (0.143), which will hinder CNS penetration. Ligand B has very low P-gp efflux liability (0.054), a significant advantage.

**Binding Affinity:** Ligand A has a much stronger binding affinity (-9.5 kcal/mol) than Ligand B (0.0 kcal/mol). This is a substantial advantage for Ligand A.

**Overall Assessment:**

Despite the significantly stronger binding affinity of Ligand A, its poor BBB penetration, high DILI risk, and high P-gp efflux liability are major drawbacks for a CNS-targeting drug. Ligand B, while having weaker affinity, possesses a much better safety profile (lower DILI), better BBB penetration, and lower P-gp efflux. The TPSA is also significantly better for Ligand B. For a GPCR target in the CNS, these ADME properties are crucial. While the affinity difference is large, it might be possible to optimize Ligand B's affinity through medicinal chemistry efforts, whereas mitigating the severe ADME liabilities of Ligand A would be far more challenging.

Output:
1
2025-04-17 07:50:09,497 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (367.515 and 385.251 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (93.43) is slightly higher than Ligand B (89.16), but both are below the 90 A^2 threshold desirable for CNS targets.

**3. logP:** Ligand A (1.678) is within the optimal 1-3 range. Ligand B (2.861) is also within range, but closer to the upper limit.

**4. H-Bond Donors:** Both ligands have 2 HBD, which is acceptable (<=5).

**5. H-Bond Acceptors:** Both ligands have 5 HBA, which is acceptable (<=10).

**6. QED:** Both ligands have good QED scores (0.771 and 0.8), indicating drug-like properties.

**7. DILI:** Ligand A (23.575) has a significantly lower DILI risk than Ligand B (61.07). This is a major advantage for Ligand A.

**8. BBB:** Ligand A (41.218) has a lower BBB percentile than Ligand B (49.089). While neither is above the desirable >70 threshold, Ligand B is slightly better.

**9. Caco-2:** Both have negative Caco-2 values (-5.108 and -5.068), which is unusual and suggests poor permeability. This is a concern for both.

**10. Solubility:** Both ligands have negative solubility values (-2.152 and -3.37), indicating very poor aqueous solubility. This is a significant drawback for both.

**11. hERG:** Both ligands have very low hERG inhibition liability (0.237).

**12. Cl_mic:** Ligand A (-7.928) has a much lower (and therefore better) microsomal clearance than Ligand B (37.059), indicating greater metabolic stability.

**13. t1/2:** Ligand A (-10.13) has a much longer in vitro half-life than Ligand B (50.844).

**14. Pgp:** Both ligands have very low P-gp efflux liability (0.012 and 0.171).

**15. Binding Affinity:** Ligand B (-8.0) has a slightly better binding affinity than Ligand A (-7.4). However, the difference is less than 1.5 kcal/mol.

**Overall Assessment:**

Despite Ligand B having slightly better affinity and BBB penetration, Ligand A is the more promising candidate. The significantly lower DILI risk, much better metabolic stability (lower Cl_mic, longer t1/2), and comparable TPSA, logP, and Pgp efflux make it a superior choice. The poor Caco-2 and solubility are concerns for both, but can potentially be addressed with formulation strategies. The slightly weaker affinity of Ligand A is less concerning given its superior ADME properties. For a CNS target like DRD2, minimizing toxicity and ensuring sufficient metabolic stability are crucial.

Output:
0
2025-04-17 07:50:09,497 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (346.391 and 342.527 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (116.0) is higher than the preferred <90 for CNS targets, but not drastically so. Ligand B (32.34) is excellent, well below the threshold.

**logP:** Ligand A (-0.164) is quite low, potentially hindering membrane permeability. Ligand B (4.532) is a bit high, potentially leading to solubility issues or off-target interactions, but still within a reasonable range.

**H-Bond Donors/Acceptors:** Ligand A (3 HBD, 5 HBA) is acceptable. Ligand B (1 HBD, 2 HBA) is also good, with lower counts generally favoring permeability.

**QED:** Both ligands have good QED scores (0.695 and 0.77), indicating drug-like properties.

**DILI:** Ligand A (62.233) has a moderate DILI risk, while Ligand B (22.722) has a very low risk, which is a significant advantage.

**BBB:** This is critical for a CNS target. Ligand A (32.377) has a poor BBB percentile. Ligand B (88.135) has an excellent BBB percentile, a major positive.

**Caco-2 Permeability:** Ligand A (-5.537) has poor Caco-2 permeability, consistent with its low logP. Ligand B (-4.676) also shows poor permeability.

**Aqueous Solubility:** Ligand A (-1.349) has poor solubility, likely due to the low logP. Ligand B (-4.674) also has poor solubility.

**hERG:** Ligand A (0.114) has a very low hERG risk. Ligand B (0.78) has a slightly higher, but still acceptable, hERG risk.

**Microsomal Clearance:** Ligand A (-19.179) has low microsomal clearance, suggesting good metabolic stability. Ligand B (89.179) has high clearance, indicating rapid metabolism.

**In vitro Half-Life:** Ligand A (-27.826) has a very short half-life, consistent with the high clearance. Ligand B (42.387) has a longer half-life, but still not ideal.

**P-gp Efflux:** Ligand A (0.006) has very low P-gp efflux, which is favorable for CNS penetration. Ligand B (0.521) has moderate P-gp efflux.

**Binding Affinity:** Ligand A (-8.1) has significantly better binding affinity than Ligand B (0.0). This is a substantial advantage.

**Overall Assessment:**

Ligand A has a superior binding affinity and better metabolic stability (lower Cl_mic) and P-gp efflux. However, its low logP, poor BBB penetration, and poor solubility are significant drawbacks for a CNS-targeting drug.

Ligand B excels in BBB penetration, has a low DILI risk, and acceptable H-bond properties. However, it suffers from high metabolic clearance, lower binding affinity, and poor solubility.

Despite the superior affinity of Ligand A, the *critical* importance of BBB penetration for a CNS GPCR target like DRD2, coupled with the low DILI risk of Ligand B, makes **Ligand B** the more promising candidate. While its affinity is weak, it is a starting point for optimization, and the other ADME properties are more readily improved than fundamentally changing BBB penetration.

Output:
1
2025-04-17 07:50:09,497 - INFO - Reasoning:

Let's analyze Ligand A and Ligand B for their potential as DRD2 drug candidates, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (354.366 and 346.431 Da) fall comfortably within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (86.88) is excellent, well below the 90 A^2 threshold for CNS targets. Ligand B (94.48) is still acceptable but less optimal.

**3. logP:** Ligand A (2.992) is within the optimal 1-3 range. Ligand B (1.754) is on the lower end, potentially impacting permeability.

**4. H-Bond Donors:** Ligand A (3) is acceptable. Ligand B (1) is also good.

**5. H-Bond Acceptors:** Ligand A (4) is acceptable. Ligand B (6) is also acceptable.

**6. QED:** Ligand B (0.896) has a significantly better QED score than Ligand A (0.484), suggesting a more drug-like profile overall.

**7. DILI:** Ligand A (99.341) has a very high DILI risk, a major concern. Ligand B (52.036) has a much lower, acceptable DILI risk.

**8. BBB:** Ligand B (75.262) has a good BBB penetration percentile, exceeding the desirable >70% threshold for CNS targets. Ligand A (56.068) is lower, which is a significant drawback for a CNS target.

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.122 and -5.125), which is unusual and likely indicates a problem with the prediction method or the molecule itself. This is a flag for further investigation, but we'll proceed assuming it's a modeling artifact.

**10. Aqueous Solubility:** Both ligands have negative solubility values (-4.459 and -1.911), which is also concerning and suggests poor solubility. Again, we'll assume this is a modeling artifact.

**11. hERG Inhibition:** Ligand A (0.512) has a slightly higher hERG risk than Ligand B (0.26), but both are relatively low.

**12. Microsomal Clearance:** Ligand B (-4.627) has a negative clearance value, which is not physically possible. This suggests a modeling error. Ligand A (2.539) is a more reasonable value.

**13. In vitro Half-Life:** Ligand B (9.333) has a longer half-life than Ligand A (52.569). This is a positive attribute.

**14. P-gp Efflux:** Ligand A (0.348) has lower P-gp efflux liability than Ligand B (0.072), which is beneficial for CNS penetration.

**15. Binding Affinity:** Ligand A (-10.1 kcal/mol) has a significantly stronger binding affinity than Ligand B (-8.8 kcal/mol). This is a substantial advantage, potentially outweighing some ADME drawbacks.

**Overall Assessment:**

Despite Ligand A's superior binding affinity, its extremely high DILI risk and lower BBB penetration are major concerns. Ligand B, while having a weaker affinity, presents a much more favorable ADME profile, with a good BBB score, acceptable DILI risk, and a longer half-life. Given the GPCR-specific priorities and the importance of CNS penetration and safety, Ligand B is the more promising candidate. The questionable Caco-2 and solubility predictions for both compounds warrant further investigation, but the clear differences in DILI and BBB make Ligand B the better choice.

Output:
1
2025-04-17 07:50:09,497 - INFO - Batch 398 complete. Total preferences: 6368
2025-04-17 07:50:09,498 - INFO - Processing batch 399/512...
2025-04-17 07:50:49,084 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (369.575 and 339.443 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (61.44) is significantly better than Ligand B (77.04). For CNS targets, we want TPSA <= 90, and ideally closer to 60. Ligand A is much closer to this ideal.

**3. logP:** Both ligands have good logP values (2.404 and 2.65), falling within the optimal 1-3 range.

**4. H-Bond Donors:** Ligand A (2) is slightly higher than Ligand B (1), but both are acceptable (<=5).

**5. H-Bond Acceptors:** Ligand A (4) and Ligand B (5) are both within the acceptable range (<=10).

**6. QED:** Both ligands have similar QED values (0.69 and 0.671), indicating good drug-likeness.

**7. DILI:** Ligand A (10.237) has a significantly lower DILI risk than Ligand B (50.291). This is a major advantage for Ligand A.

**8. BBB:** Ligand B (73.556) has a better BBB penetration percentile than Ligand A (59.946). While both are reasonably good, >70 is preferred for CNS targets.

**9. Caco-2 Permeability:** Ligand A (-5.502) has better Caco-2 permeability than Ligand B (-5.095). Higher values are better.

**10. Aqueous Solubility:** Ligand A (-1.537) has better aqueous solubility than Ligand B (-2.24). Higher values are better.

**11. hERG Inhibition:** Both ligands have low hERG inhibition risk (0.293 and 0.394).

**12. Microsomal Clearance:** Ligand A (14.869) has lower microsomal clearance than Ligand B (22.695), suggesting better metabolic stability.

**13. In vitro Half-Life:** Ligand B (-23.981) has a significantly longer in vitro half-life than Ligand A (23.39). This is a positive for Ligand B.

**14. P-gp Efflux:** Ligand A (0.014) has significantly lower P-gp efflux liability than Ligand B (0.257). Lower efflux is crucial for CNS exposure.

**15. Binding Affinity:** Ligand B (-9.2 kcal/mol) has a stronger binding affinity than Ligand A (-7.5 kcal/mol). This is a substantial difference (1.7 kcal/mol), and a strong affinity is a key driver.

**Overall Assessment:**

Ligand B has a stronger binding affinity and a longer half-life, which are both desirable. However, Ligand A excels in several critical ADME properties, particularly DILI risk, P-gp efflux, and TPSA. The lower TPSA and P-gp efflux of Ligand A suggest better CNS penetration despite its slightly lower BBB percentile. The significantly lower DILI risk is a major advantage. While the affinity difference is notable, the improved ADME profile of Ligand A, especially for a CNS target, makes it the more promising candidate.

Output:
0
2025-04-17 07:50:49,084 - INFO - Reasoning:

Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (397.272 and 344.455 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Both ligands have TPSA values (62.22 and 62.55) slightly above the optimal <90 for CNS targets, but still reasonable.

**3. logP:** Both ligands have logP values (3.861 and 3.229) within the optimal 1-3 range. Ligand B is slightly better here.

**4. H-Bond Donors:** Ligand A (2) and Ligand B (1) both meet the HBD criteria of <=5. Ligand B is slightly better.

**5. H-Bond Acceptors:** Both ligands (3) meet the HBA criteria of <=10.

**6. QED:** Both ligands have good QED scores (0.687 and 0.773), indicating drug-like properties. Ligand B is slightly better.

**7. DILI:** Ligand A (69.794) has a higher DILI risk than Ligand B (42.769). This is a significant advantage for Ligand B.

**8. BBB:** Ligand B (66.382) has a considerably better BBB penetration percentile than Ligand A (46.336). This is *critical* for a CNS target like DRD2.

**9. Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and suggests poor permeability. However, the scale isn't specified, so it's hard to interpret.

**10. Aqueous Solubility:** Both have negative solubility values, also unusual. Again, the scale is unknown.

**11. hERG Inhibition:** Both ligands have low hERG inhibition risk (0.652 and 0.423). Ligand B is slightly better.

**12. Microsomal Clearance:** Ligand A (32.151) has lower microsomal clearance than Ligand B (76.416), suggesting better metabolic stability.

**13. In vitro Half-Life:** Ligand B (68.701) has a longer in vitro half-life than Ligand A (53.132).

**14. P-gp Efflux:** Ligand A (0.444) has lower P-gp efflux than Ligand B (0.324), which is favorable for CNS penetration.

**15. Binding Affinity:** Ligand B (-8.5 kcal/mol) has a significantly stronger binding affinity than Ligand A (-10.2 kcal/mol). This is a substantial advantage.

**Overall Assessment:**

While Ligand A has better metabolic stability (lower Cl_mic) and P-gp efflux, Ligand B excels in the most crucial areas for a CNS GPCR target: BBB penetration, DILI risk, and binding affinity. The significantly stronger binding affinity (-8.5 vs -10.2 kcal/mol) of Ligand B is a major advantage that can outweigh minor drawbacks in other parameters. The lower DILI risk and better BBB are also very important.



Output:
1
2025-04-17 07:50:49,085 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (339.41 and 374.497 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (38.33) is better than Ligand B (40.62). Both are below the 90 A^2 threshold desirable for CNS targets, but lower is better.

**logP:** Ligand A (4.017) is slightly higher than Ligand B (3.014). While both are within the optimal 1-3 range, Ligand A is approaching the upper limit where solubility issues might arise.

**H-Bond Donors/Acceptors:** Ligand A (1 HBD, 2 HBA) is preferable to Ligand B (0 HBD, 3 HBA). Both are within acceptable limits.

**QED:** Ligand A (0.917) has a significantly better QED score than Ligand B (0.718), indicating a more drug-like profile.

**DILI:** Ligand B (18.612) has a much lower DILI risk than Ligand A (71.966), which is a significant advantage.

**BBB:** Ligand B (94.378) has a substantially higher BBB penetration percentile than Ligand A (87.088). This is a critical factor for a CNS target like DRD2.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.503 and -4.671), which is unusual and suggests poor permeability. This is a concern for both.

**Aqueous Solubility:** Ligand B (-2.861) has better aqueous solubility than Ligand A (-5.034).

**hERG Inhibition:** Ligand A (0.792) has a slightly higher hERG risk than Ligand B (0.515), but both are relatively low.

**Microsomal Clearance:** Ligand B (38.156) has a higher microsomal clearance than Ligand A (28.729), suggesting faster metabolism and potentially lower *in vivo* exposure.

**In vitro Half-Life:** Ligand A (24.148) has a significantly longer in vitro half-life than Ligand B (1.0). This is a major advantage for Ligand A.

**P-gp Efflux:** Ligand A (0.49) has lower P-gp efflux liability than Ligand B (0.1), meaning it is less likely to be pumped out of the brain.

**Binding Affinity:** Ligand A (-10.6 kcal/mol) has a significantly stronger binding affinity than Ligand B (-8.0 kcal/mol). This is a substantial advantage, potentially outweighing some ADME drawbacks.

**Overall Assessment:**

Ligand A has a superior binding affinity and longer half-life, and better P-gp efflux. However, Ligand B has a much better safety profile (lower DILI) and significantly better BBB penetration. The Caco-2 permeability is poor for both. Considering the GPCR-specific priorities, BBB penetration is crucial for CNS targets. The strong binding affinity of Ligand A is attractive, but the significantly better BBB and DILI of Ligand B make it a more promising candidate, despite the shorter half-life and higher clearance. The difference in binding affinity, while substantial, might be overcome with further optimization.

Output:
1
2025-04-17 07:50:49,085 - INFO - Reasoning:

Let's analyze Ligand A and Ligand B based on the provided guidelines, prioritizing GPCR-specific properties (BBB, logP, Pgp, TPSA, and affinity) for DRD2.

**Molecular Weight:** Both ligands (350.478 and 352.41 Da) fall comfortably within the ideal 200-500 Da range.

**TPSA:** Ligand A (49.41) is excellent, well below the 90 A^2 threshold for CNS targets. Ligand B (84.42) is higher, but still potentially acceptable, though less desirable.

**logP:** Ligand A (3.062) is optimal. Ligand B (1.935) is slightly lower, potentially impacting permeability, but still within a reasonable range.

**H-Bond Donors/Acceptors:** Both ligands have 1 HBD, which is good. Ligand A has 2 HBA, and Ligand B has 5 HBA. Both are within the acceptable limits (<=10).

**QED:** Both ligands have good QED scores (0.775 and 0.811), indicating good drug-like properties.

**DILI:** Both ligands have low DILI risk (25.436 and 29.779 percentiles), which is favorable.

**BBB:** Ligand A (85.421) and Ligand B (92.323) both show excellent BBB penetration, exceeding the desirable >70 percentile for CNS targets. Ligand B is slightly better here.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.301 and -4.36), which is unusual and suggests poor permeability. This is a significant concern for both.

**Aqueous Solubility:** Both ligands have negative solubility values (-3.343 and -2.76), also unusual and indicating very poor aqueous solubility. This is a major drawback for both.

**hERG Inhibition:** Ligand A (0.766) has a slightly higher hERG risk than Ligand B (0.207). Ligand B is much better here.

**Microsomal Clearance:** Ligand B (63.06 mL/min/kg) has higher clearance than Ligand A (41.337 mL/min/kg), indicating lower metabolic stability.

**In vitro Half-Life:** Ligand A (-19.734 hours) has a negative half-life, which is not possible. Ligand B (-26.421 hours) also has a negative half-life, which is also not possible. Both are problematic.

**P-gp Efflux:** Ligand A (0.26) has lower P-gp efflux liability than Ligand B (0.012), which is favorable for CNS penetration.

**Binding Affinity:** Both ligands have very similar and strong binding affinities (-7.2 and -7.1 kcal/mol). The difference is negligible.

**Overall Assessment:**

Despite the similar binding affinities, Ligand B is slightly more promising. It has a better BBB score and significantly lower hERG risk. However, both ligands suffer from extremely poor predicted solubility and permeability (negative Caco-2 and solubility values), and impossible half-life values. The negative values for Caco-2 and solubility are likely errors or indicate significant issues with the prediction model for these compounds. Ligand A has better P-gp efflux. Given the critical importance of CNS penetration for a DRD2 targeting drug, and the slightly better BBB and hERG profile of Ligand B, it is marginally preferred, *assuming* the solubility and permeability predictions are inaccurate.

Output:
1
2025-04-17 07:50:49,085 - INFO - Reasoning:

Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (386.206 Da) is slightly higher than Ligand B (352.425 Da), but both are acceptable.

**TPSA:** Ligand A (75.63) is higher than Ligand B (42.43). For CNS targets, we want TPSA <= 90, so both are within range, but Ligand B is significantly better.

**logP:** Ligand A (4.465) is slightly above the optimal range (1-3), potentially leading to solubility issues. Ligand B (3.716) is within the optimal range. This favors Ligand B.

**H-Bond Donors:** Ligand A (2) and Ligand B (0) are both acceptable (<=5).

**H-Bond Acceptors:** Both ligands have 3 HBA, which is well within the acceptable limit of <=10.

**QED:** Both ligands have reasonable QED values (A: 0.744, B: 0.67), indicating good drug-like properties.

**DILI:** Ligand A (97.325) has a very high DILI risk, which is a major concern. Ligand B (22.489) has a low DILI risk, a significant advantage.

**BBB:** Ligand A (34.936) has poor BBB penetration, making it less suitable for a CNS target like DRD2. Ligand B (91.121) has excellent BBB penetration, a crucial factor for CNS activity.

**Caco-2 Permeability:** Both have negative values, indicating poor permeability. However, the scale is not specified, so it's difficult to interpret.

**Aqueous Solubility:** Both have negative values, indicating poor solubility. Again, the scale is not specified.

**hERG Inhibition:** Ligand A (0.143) and Ligand B (0.548) both have low hERG inhibition risk, which is good.

**Microsomal Clearance:** Ligand A (7.434) has lower clearance than Ligand B (74.939), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand B (14.598) has a significantly longer half-life than Ligand A (6.276), which is desirable.

**P-gp Efflux:** Ligand A (0.102) has lower P-gp efflux than Ligand B (0.136), which is favorable for CNS penetration.

**Binding Affinity:** Ligand A (-8.1 kcal/mol) has a significantly stronger binding affinity than Ligand B (-6.9 kcal/mol). This is a substantial advantage and could potentially outweigh some of the ADME drawbacks of Ligand A.

**Overall Assessment:**

Despite the superior binding affinity of Ligand A, its extremely high DILI risk and poor BBB penetration are major red flags. Ligand B, while having a slightly weaker binding affinity, possesses a much more favorable ADME profile, particularly its excellent BBB penetration, low DILI risk, and longer half-life. For a CNS target like DRD2, BBB penetration and safety (DILI) are paramount. The 1.2 kcal/mol difference in binding affinity, while significant, is less critical than these ADME properties.

Output:
1
2025-04-17 07:50:49,085 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (348.403 and 362.495 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (91.84) is slightly above the preferred <90 for CNS targets, while Ligand B (66.57) is well within the range. This favors Ligand B.

**logP:** Ligand A (-0.174) is quite low, potentially hindering permeability. Ligand B (3.68) is within the optimal 1-3 range. This is a significant advantage for Ligand B.

**H-Bond Donors/Acceptors:** Both have 1 HBD and 5 HBA, which are acceptable.

**QED:** Both ligands have reasonable QED scores (0.545 and 0.851), indicating good drug-like properties. Ligand B is better here.

**DILI:** Ligand A (39.162) has a slightly higher DILI risk than Ligand B (22.838), but both are below the concerning threshold of 60.

**BBB:** Ligand A (59.093) has a moderate BBB penetration, while Ligand B (52.23) is lower. While both are below the desirable >70, Ligand A is slightly better.

**Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and suggests poor permeability. However, the scale is not specified, so it's difficult to interpret.

**Aqueous Solubility:** Both have negative solubility values, which is also unusual. Again, the scale is unspecified.

**hERG:** Both ligands show low hERG inhibition liability (0.27 and 0.362), which is good.

**Microsomal Clearance:** Ligand A (10.179) has a lower (better) microsomal clearance than Ligand B (40.522), indicating greater metabolic stability.

**In vitro Half-Life:** Ligand A (-15.869) has a negative half-life, which is not physically possible. This is a major red flag. Ligand B (46.344) has a reasonable half-life.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.015 and 0.341), which is favorable for CNS penetration.

**Binding Affinity:** Ligand B (-7.6) has a significantly stronger binding affinity than Ligand A (-8.4). This is a substantial advantage, potentially outweighing some ADME concerns.

**Overall Assessment:**

Ligand B is the stronger candidate. It has a better logP, TPSA, QED, DILI, and significantly better binding affinity. The negative values for Caco-2 and solubility are concerning for both, but the scale is unknown. The biggest issue with Ligand A is the negative in vitro half-life, which is impossible and indicates a problem with the data or the molecule itself. While Ligand A has slightly better BBB, the other advantages of Ligand B, especially the much stronger binding affinity and better ADME profile, make it the more promising drug candidate.

Output:
1
2025-04-17 07:50:49,085 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B based on the provided guidelines, prioritizing GPCR-specific properties (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (330.395 and 346.471 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (79.47) is slightly higher than Ligand B (62.55). Both are below the 90 A^2 threshold desirable for CNS targets, but Ligand B is better.

**logP:** Ligand A (4.559) is higher than Ligand B (3.464). While both are within the acceptable range (1-3 is optimal, up to 4 is tolerable), Ligand A's higher logP could lead to solubility issues or off-target interactions.

**H-Bond Donors/Acceptors:** Ligand A (0 HBD, 4 HBA) and Ligand B (1 HBD, 3 HBA) both have acceptable numbers of H-bond donors and acceptors, well below the limits of 5 and 10 respectively.

**QED:** Both ligands have good QED scores (0.377 and 0.858), with Ligand B being significantly better, indicating a more drug-like profile.

**DILI:** Ligand A (64.133) has a higher DILI risk than Ligand B (10.508). This is a significant advantage for Ligand B.

**BBB:** Ligand B (84.141) has a substantially better BBB penetration percentile than Ligand A (78.48). This is critical for a CNS target like DRD2.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.843 and -4.766). This is unusual and suggests poor permeability, but the values are similar.

**Aqueous Solubility:** Both ligands have negative solubility values (-5.57 and -3.565), again suggesting poor solubility. Ligand B is slightly better.

**hERG:** Both ligands have low hERG inhibition liability (0.856 and 0.623).

**Microsomal Clearance:** Ligand B (49.223) has a lower microsomal clearance than Ligand A (21.181), indicating better metabolic stability.

**In vitro Half-Life:** Ligand A (-42.743) has a negative half-life, which is not possible. Ligand B (17.357) has a more reasonable half-life.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.565 and 0.119), which is favorable for CNS penetration. Ligand B is better.

**Binding Affinity:** Both ligands have the same binding affinity (-8 kcal/mol), which is excellent.

**Overall Assessment:**

Ligand B is clearly superior. It has a better QED score, significantly lower DILI risk, substantially better BBB penetration, lower microsomal clearance (better metabolic stability), a more reasonable in vitro half-life, and lower P-gp efflux. While both have poor solubility and permeability (Caco-2), Ligand B is slightly better on these parameters as well. The equal binding affinity removes that as a differentiating factor. Given the GPCR target and the importance of CNS penetration, Ligand B is the more promising candidate.

Output:
1
2025-04-17 07:50:49,085 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (346.431 and 347.379 Da) fall within the ideal range of 200-500 Da.

**TPSA:** Ligand A (67.67) is excellent, well below the 90 A^2 threshold for CNS targets. Ligand B (134.92) is higher, but still potentially acceptable, though less ideal.

**logP:** Ligand A (1.195) is within the optimal range of 1-3. Ligand B (0.293) is a bit low, potentially hindering membrane permeability.

**H-Bond Donors/Acceptors:** Ligand A (0 HBD, 5 HBA) is favorable. Ligand B (3 HBD, 8 HBA) is also acceptable, but slightly higher counts could affect permeability.

**QED:** Ligand A (0.807) has a very good drug-likeness score. Ligand B (0.655) is still reasonable, but lower.

**DILI:** Ligand A (35.324) has a low DILI risk. Ligand B (72.043) has a higher, but still manageable, DILI risk.

**BBB:** This is critical for a CNS target. Ligand A (77.162) shows good BBB penetration. Ligand B (23.924) is very poor, a major drawback.

**Caco-2 Permeability:** Ligand A (-4.71) is concerningly low, suggesting poor intestinal absorption. Ligand B (-5.42) is similarly poor.

**Aqueous Solubility:** Both ligands have negative solubility values (-1.464 and -2.493), indicating very poor aqueous solubility, which is a significant formulation challenge.

**hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.393 and 0.067).

**Microsomal Clearance:** Ligand A (25.528) has moderate clearance. Ligand B (17.527) has lower clearance, suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (9.375 hours) is reasonable. Ligand B (-19.531 hours) is a negative value, which is not physically possible and likely indicates an issue with the data or prediction method.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.091 and 0.01).

**Binding Affinity:** Both ligands have identical and excellent binding affinity (-8.2 kcal/mol).

**Overall Assessment:**

Despite the similar binding affinities, Ligand A is the stronger candidate. Its superior BBB penetration (77.162 vs 23.924) is a crucial advantage for a CNS-targeting drug. While its Caco-2 permeability and aqueous solubility are poor, these can potentially be addressed through formulation strategies. Ligand B's extremely poor BBB penetration is a deal-breaker, and the negative in vitro half-life is also a red flag.

Output:
0
2025-04-17 07:50:49,085 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (374.39 and 351.491 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (102.01) is slightly above the optimal <90 for CNS targets, but still reasonable. Ligand B (72.88) is well within the desired range.

**logP:** Ligand A (0.835) is a bit low, potentially hindering permeation. Ligand B (1.176) is also on the lower side, but slightly better than A. Both are below the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A (1 HBD, 6 HBA) and Ligand B (2 HBD, 4 HBA) both have acceptable numbers of H-bond donors and acceptors, well within the guidelines.

**QED:** Ligand A (0.74) has a better QED score than Ligand B (0.534), indicating a more drug-like profile.

**DILI:** Ligand A (69.833) has a higher DILI risk than Ligand B (5.933). This is a significant advantage for Ligand B.

**BBB:** Ligand A (70.415) has a good BBB penetration percentile, desirable for a CNS target. Ligand B (57.774) is considerably lower, which is a major drawback.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.887 and -4.966). This is unusual and suggests poor permeability, but the scale is not specified, so it's difficult to interpret.

**Aqueous Solubility:** Both ligands have negative solubility values (-2.867 and -0.691). Similar to Caco-2, the scale is unknown, making interpretation difficult.

**hERG:** Both ligands have very low hERG inhibition liability (0.094 and 0.169), which is excellent.

**Microsomal Clearance:** Ligand A (11.461) has a higher microsomal clearance than Ligand B (-1.649). Ligand B is predicted to have better metabolic stability.

**In vitro Half-Life:** Ligand A (47.095) has a longer in vitro half-life than Ligand B (-22.935).

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.054 and 0.005), which is favorable for CNS penetration.

**Binding Affinity:** Both ligands have excellent binding affinities (-7.9 and -7.6 kcal/mol). The difference of 0.3 kcal/mol is not substantial enough to outweigh other factors.

**Overall Assessment:**

Ligand B has a significantly better safety profile (much lower DILI) and better metabolic stability (lower Cl_mic). While its BBB penetration is lower than Ligand A, the lower DILI and better metabolic stability are more critical for a CNS drug candidate. The slightly lower affinity is not a major concern given the already strong binding. The negative Caco-2 and solubility values are concerning for both, but the other advantages of Ligand B make it the more promising candidate.

Output:
1
2025-04-17 07:50:49,086 - INFO - Reasoning:

Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight (MW):** Both ligands (352.337 and 344.415 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (73.59) is significantly better than Ligand B (108.02). For a CNS target like DRD2, TPSA should be <= 90. Ligand A is closer to this threshold and thus preferred.

**3. logP:** Both ligands have good logP values (3.721 and 2.118) within the optimal 1-3 range.

**4. H-Bond Donors (HBD):** Both are acceptable (1 and 2, respectively), well below the limit of 5.

**5. H-Bond Acceptors (HBA):** Both are acceptable (5 each), below the limit of 10.

**6. QED:** Both ligands have good QED scores (0.733 and 0.751), indicating good drug-like properties.

**7. DILI:** Ligand A (77.549) has a higher DILI risk than Ligand B (27.685). This is a significant drawback for Ligand A.

**8. BBB:** Both ligands show good BBB penetration (77.511 and 70.027), exceeding the desirable threshold of >70 for CNS targets.

**9. Caco-2 Permeability:** Both have negative Caco-2 values (-4.597 and -4.759). This is unusual and suggests poor permeability, but the scale is not specified. It's difficult to interpret without knowing the scale.

**10. Aqueous Solubility:** Both have negative solubility values (-5.081 and -3.101). Again, the scale is unknown, making interpretation difficult.

**11. hERG Inhibition:** Both ligands have low hERG inhibition risk (0.447 and 0.333).

**12. Microsomal Clearance (Cl_mic):** Ligand B (32.576) has significantly lower microsomal clearance than Ligand A (79.458), indicating better metabolic stability.

**13. In vitro Half-Life:** Ligand B (-20.282) has a longer in vitro half-life than Ligand A (-14.171).

**14. P-gp Efflux:** Ligand A (0.354) has lower P-gp efflux liability than Ligand B (0.016), which is favorable for CNS penetration.

**15. Binding Affinity:** Ligand A (-8.2 kcal/mol) has a slightly better binding affinity than Ligand B (-7.9 kcal/mol). This 0.3 kcal/mol difference is not substantial enough to overcome other significant drawbacks.

**Overall Assessment:**

While Ligand A has slightly better affinity and P-gp efflux, Ligand B is clearly superior overall. The significantly lower DILI risk and improved metabolic stability (lower Cl_mic and longer half-life) of Ligand B are critical advantages. The TPSA of Ligand A is also a concern, being further from the ideal range for CNS penetration. The negative Caco-2 and solubility values for both are concerning, but without knowing the scale, it's hard to weigh their importance. Given the GPCR-specific priorities, and the importance of safety and metabolic stability, Ligand B is the more promising candidate.

Output:
1
2025-04-17 07:50:49,086 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (374.491 and 354.441 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (67.35) is higher than Ligand B (49.41). For CNS targets, TPSA < 90 is preferred. Both are under this threshold, but B is significantly better.

**3. logP:** Both ligands have good logP values (3.921 and 3.111), falling within the optimal 1-3 range.

**4. H-Bond Donors:** Both have 1 HBD, which is acceptable.

**5. H-Bond Acceptors:** Ligand A has 6 HBAs, and Ligand B has 2. Both are below the 10 threshold.

**6. QED:** Ligand A (0.754) has a better QED score than Ligand B (0.538), indicating better overall drug-likeness.

**7. DILI:** Ligand A (93.796) has a significantly higher DILI risk than Ligand B (18.651). This is a major concern for Ligand A.

**8. BBB:** Both ligands show excellent BBB penetration (81.466 and 86.274, respectively), exceeding the desirable >70 threshold for CNS targets. Ligand B is slightly better.

**9. Caco-2 Permeability:** Both have negative Caco-2 values (-4.727 and -4.495). This is unusual and suggests poor permeability. However, these values are on a scale where negative values are possible and don't necessarily disqualify a compound.

**10. Aqueous Solubility:** Both have negative solubility values (-4.463 and -3.486). Similar to Caco-2, these are on a scale where negative values are possible and don't necessarily disqualify a compound.

**11. hERG Inhibition:** Both ligands have low hERG inhibition risk (0.474 and 0.557).

**12. Microsomal Clearance:** Ligand A (71.593) has higher microsomal clearance than Ligand B (19.962), indicating lower metabolic stability.

**13. In vitro Half-Life:** Ligand B (-16.44) has a negative half-life, which is concerning and likely indicates rapid degradation. Ligand A (37.557) is much better.

**14. P-gp Efflux:** Both ligands have low P-gp efflux liability (0.558 and 0.096), which is favorable for CNS penetration. Ligand B is significantly better.

**15. Binding Affinity:** Both ligands have very similar and strong binding affinities (-8.3 and -8.1 kcal/mol). The difference is negligible.

**Overall Assessment:**

While Ligand A has a better QED and *in vitro* half-life, its significantly higher DILI risk and higher microsomal clearance are major drawbacks. Ligand B, despite a lower QED and a concerning negative half-life, has a much lower DILI risk and better P-gp efflux, which are crucial for a CNS-targeting drug. The slightly better BBB penetration and lower TPSA of Ligand B also contribute to its favorability. The similar binding affinities mean that the ADME properties are the deciding factors.

Output:
1
2025-04-17 07:50:49,086 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (370.465 Da) and Ligand B (349.356 Da) are both acceptable.

**TPSA:** Ligand A (58.2) is excellent for CNS penetration, well below the 90 A^2 threshold. Ligand B (38.56) is also very good.

**logP:** Ligand A (3.635) is optimal. Ligand B (4.894) is slightly higher, potentially increasing off-target effects or decreasing solubility, but still within a reasonable range.

**H-Bond Donors/Acceptors:** Ligand A (2 HBD, 3 HBA) and Ligand B (1 HBD, 4 HBA) both have acceptable numbers of hydrogen bond donors and acceptors.

**QED:** Both ligands have similar QED values (Ligand A: 0.77, Ligand B: 0.712), indicating good drug-like properties.

**DILI:** Ligand A (47.538) has a lower DILI risk than Ligand B (66.576), which is a significant advantage.

**BBB:** Ligand A (88.29) has a much better BBB penetration percentile than Ligand B (67.817). This is crucial for a CNS target like DRD2.

**Caco-2 Permeability:** Both have negative Caco-2 values (-4.758 and -4.61), which is unusual and suggests poor permeability. However, these values are on a scale where negative values are possible, and the absolute magnitude isn't necessarily indicative of a complete block.

**Aqueous Solubility:** Both ligands have negative solubility values (-4.133 and -5.674), which is concerning. Poor solubility can hinder bioavailability.

**hERG Inhibition:** Ligand A (0.599) has a slightly lower hERG inhibition risk than Ligand B (0.905), which is preferable.

**Microsomal Clearance:** Both ligands have similar microsomal clearance values (Ligand A: 43.97, Ligand B: 45.377), suggesting comparable metabolic stability.

**In vitro Half-Life:** Ligand A (45.389) has a significantly longer in vitro half-life than Ligand B (-19.409). This is a major advantage, potentially allowing for less frequent dosing.

**P-gp Efflux:** Ligand A (0.412) has lower P-gp efflux liability than Ligand B (0.808), which is beneficial for CNS exposure.

**Binding Affinity:** Both ligands have very similar and excellent binding affinities (-8.6 kcal/mol and -8.5 kcal/mol). The difference is negligible.

**Overall Assessment:**

Ligand A is superior to Ligand B. While both have good affinity, Ligand A demonstrates significantly better BBB penetration, lower DILI risk, lower P-gp efflux, and a longer half-life. The solubility and Caco-2 values are concerning for both, but the other advantages of Ligand A outweigh these drawbacks, especially for a CNS target.

Output:
1
2025-04-17 07:50:49,086 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (354.332 and 348.462 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (85.23) is better than Ligand B (49.41). For CNS targets, TPSA should be <=90. Both are within this range, but A is closer to the upper limit.

**3. logP:** Both ligands have good logP values (2.889 and 2.692), falling within the optimal 1-3 range.

**4. H-Bond Donors:** Ligand A (2) and Ligand B (1) are both acceptable, being less than 5.

**5. H-Bond Acceptors:** Ligand A (3) and Ligand B (2) are both acceptable, being less than 10.

**6. QED:** Both ligands have good QED values (0.824 and 0.794), indicating a drug-like profile.

**7. DILI:** Ligand A (49.05) has a slightly higher DILI risk than Ligand B (14.889), but both are below the concerning threshold of 60.

**8. BBB:** This is a critical parameter for CNS targets. Ligand B (91.896) has a significantly higher BBB penetration percentile than Ligand A (76.309). This is a major advantage for Ligand B.

**9. Caco-2 Permeability:** Both have negative values (-4.697 and -4.763), which is unusual and suggests poor permeability. However, these values are on a scale where negative values are possible, and direct comparison is difficult without knowing the scale's specifics.

**10. Aqueous Solubility:** Both ligands have negative values (-4.082 and -2.989), indicating poor aqueous solubility.

**11. hERG Inhibition:** Both ligands have low hERG inhibition risk (0.685 and 0.465).

**12. Microsomal Clearance:** Ligand A (1.645) has lower microsomal clearance than Ligand B (2.678), suggesting better metabolic stability.

**13. In vitro Half-Life:** Ligand A (17.495) has a significantly longer in vitro half-life than Ligand B (-0.687). This is a substantial advantage for Ligand A.

**14. P-gp Efflux:** Ligand A (0.04) has lower P-gp efflux liability than Ligand B (0.163), which is beneficial for CNS exposure.

**15. Binding Affinity:** Ligand B (-10.3 kcal/mol) has a significantly stronger binding affinity than Ligand A (-7.7 kcal/mol). This is a substantial advantage, potentially outweighing some ADME drawbacks.

**Overall Assessment:**

While Ligand A has better metabolic stability (lower Cl_mic, longer t1/2) and lower P-gp efflux, Ligand B excels in BBB penetration and, crucially, has a much stronger binding affinity. For a CNS target like DRD2, strong binding and good BBB penetration are paramount. The difference in binding affinity (-10.3 vs -7.7 kcal/mol) is significant. Although both have poor solubility and permeability, the superior affinity and BBB penetration of Ligand B make it the more promising candidate.

Output:
1
2025-04-17 07:50:49,086 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (389.321 and 363.502 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (71.09) is higher than the preferred <90 for CNS targets, but still potentially acceptable. Ligand B (35.58) is excellent, well below the threshold.

**logP:** Ligand A (3.349) is within the optimal 1-3 range. Ligand B (1.965) is slightly lower, but still acceptable.

**H-Bond Donors:** Ligand A (2) and Ligand B (1) are both within the acceptable limit of <=5.

**H-Bond Acceptors:** Both ligands (A: 4, B: 4) are well below the limit of <=10.

**QED:** Both ligands have reasonable QED values (A: 0.776, B: 0.619), indicating good drug-like properties.

**DILI:** Ligand A (68.98) has a higher DILI risk than Ligand B (30.787), which is a significant concern.

**BBB:** Both ligands have very similar and good BBB penetration (A: 71.733, B: 71.85).

**Caco-2 Permeability:** Ligand A (-4.645) has poor Caco-2 permeability, while Ligand B (-4.843) is also poor, but slightly better.

**Aqueous Solubility:** Ligand A (-4.214) and Ligand B (-2.428) both have poor aqueous solubility.

**hERG Inhibition:** Ligand A (0.193) has a slightly higher hERG risk than Ligand B (0.832).

**Microsomal Clearance:** Ligand A (37.554) has a higher microsomal clearance than Ligand B (22.082), suggesting lower metabolic stability.

**In vitro Half-Life:** Ligand B (21.544) has a significantly longer in vitro half-life than Ligand A (-26.596), a major advantage.

**P-gp Efflux:** Ligand A (0.032) shows some P-gp efflux, while Ligand B (0.118) shows slightly more. Both are relatively low.

**Binding Affinity:** Ligand A (-8.8 kcal/mol) has a significantly stronger binding affinity than Ligand B (0.0 kcal/mol). This is a substantial difference.

**Overall Assessment:**

Ligand A has a much stronger binding affinity, which is a critical factor for GPCRs. However, it suffers from poor Caco-2 permeability, higher DILI risk, and lower metabolic stability (higher Cl_mic, shorter t1/2). Ligand B has better ADME properties (lower DILI, better half-life, slightly better permeability) but a significantly weaker binding affinity.

Given the strong affinity advantage of Ligand A, and the importance of BBB penetration which is similar for both, I believe Ligand A is the more promising candidate *despite* its ADME liabilities. The potency difference is large enough that optimization efforts could focus on improving its ADME profile. Ligand B's weak affinity makes it less likely to succeed even with excellent ADME properties.

Output:
1
2025-04-17 07:50:49,087 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (351.491 Da) is slightly lower, which could be beneficial for permeability.

**TPSA:** Ligand A (61.88) is significantly better than Ligand B (111.63). For CNS targets, TPSA should be <=90, and A is comfortably within this range, while B is above. This is a significant advantage for A.

**logP:** Ligand A (1.417) is within the optimal range (1-3). Ligand B (-0.024) is slightly below 1, which might hinder permeation.

**H-Bond Donors/Acceptors:** Ligand A (HBD=1, HBA=4) has a more favorable profile than Ligand B (HBD=3, HBA=6). Both are within acceptable limits, but A is better.

**QED:** Both ligands have similar QED values (A: 0.705, B: 0.676), indicating good drug-likeness.

**DILI:** Ligand A (5.816) has a much lower DILI risk than Ligand B (48.313). This is a substantial advantage for A.

**BBB:** Ligand A (59.325) is better than Ligand B (5.855), but neither is ideal (>70). However, given the other properties, A's BBB is acceptable. B's is very low and would severely limit CNS exposure.

**Caco-2 Permeability:** Ligand A (-4.896) has a negative value, which is unusual and suggests poor permeability. Ligand B (-5.377) is also poor, but similar to A.

**Aqueous Solubility:** Ligand A (-1.145) is slightly better than Ligand B (-0.892), but both are quite poor. This could pose formulation challenges.

**hERG Inhibition:** Ligand A (0.308) shows very low hERG inhibition risk, which is excellent. Ligand B (0.095) is also low, but A is preferable.

**Microsomal Clearance:** Ligand A (1.468) has a lower clearance than Ligand B (-7.33), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (5.442) has a much longer half-life than Ligand B (-14.341), which is a significant advantage.

**P-gp Efflux:** Ligand A (0.008) has very low P-gp efflux liability, which is excellent for CNS penetration. Ligand B (0.028) is also low, but A is much better.

**Binding Affinity:** Both ligands have the same binding affinity (-7.8 kcal/mol), which is excellent.

**Overall Assessment:**

Ligand A is significantly better than Ligand B based on the combined ADME-Tox properties and GPCR-specific priorities. While both have good affinity, Ligand A excels in TPSA, DILI, BBB, metabolic stability (Cl_mic and t1/2), and P-gp efflux. Ligand B suffers from a high DILI risk, poor BBB penetration, and lower metabolic stability. The poor Caco-2 and solubility for both are concerns, but can be addressed with formulation strategies. Given the importance of CNS penetration for a DRD2 ligand, Ligand A is the far more promising candidate.

Output:
1
2025-04-17 07:50:49,087 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B based on the provided guidelines, prioritizing GPCR-specific properties (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (353.438 and 348.487 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (75.44) is higher than Ligand B (50.8). For a CNS target like DRD2, TPSA should be <=90, so both are acceptable, but B is better.

**logP:** Both ligands have good logP values (2.157 and 1.95), falling within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Both have 1 HBD and 4 HBA, which are within acceptable limits.

**QED:** Both ligands have QED values above 0.75, indicating good drug-likeness.

**DILI:** Ligand A (41.954) has a slightly higher DILI risk than Ligand B (14.889), but both are below the concerning threshold of 60.

**BBB:** Ligand A (82.319) has a better BBB penetration percentile than Ligand B (78.558). Both are good, but A is better.

**Caco-2 Permeability:** Ligand A (-4.568) has worse Caco-2 permeability than Ligand B (-5.061). Lower values are less favorable.

**Aqueous Solubility:** Ligand A (-2.777) has slightly better aqueous solubility than Ligand B (-2.355).

**hERG:** Both ligands have low hERG inhibition liability (0.429 and 0.609), indicating low cardiotoxicity risk.

**Microsomal Clearance:** Ligand A (39.656) has a higher microsomal clearance than Ligand B (23.351), suggesting lower metabolic stability.

**In vitro Half-Life:** Ligand B (31.787) has a significantly longer in vitro half-life than Ligand A (-5.127). This is a substantial advantage.

**P-gp Efflux:** Ligand A (0.161) has lower P-gp efflux liability than Ligand B (0.076), which is favorable for CNS penetration.

**Binding Affinity:** Ligand A (-8.4 kcal/mol) has a significantly stronger binding affinity than Ligand B (-7.0 kcal/mol). This is a >1.5 kcal/mol advantage, which can outweigh some ADME drawbacks.

**Overall Assessment:**

Ligand A has a significantly better binding affinity and better BBB penetration, and slightly better solubility. However, it has worse Caco-2 permeability, higher microsomal clearance (lower metabolic stability), and higher P-gp efflux. Ligand B has a longer half-life, lower DILI risk, and better metabolic stability.

Considering the GPCR-specific priorities, the strong binding affinity of Ligand A is a major advantage. The slightly better BBB of A is also beneficial. While the metabolic stability of B is better, the substantial affinity difference of A is likely to be more impactful, especially given the potential for structural modifications to improve its metabolic profile.

Output:
1
2025-04-17 07:50:49,087 - INFO - Batch 399 complete. Total preferences: 6384
2025-04-17 07:50:49,087 - INFO - Processing batch 400/512...
2025-04-17 07:51:39,977 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (360.307 and 351.447 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (58.64) is excellent for CNS penetration, well below the 90 A^2 threshold. Ligand B (87.74) is higher but still reasonable, though less optimal.

**logP:** Ligand A (1.846) is within the optimal 1-3 range. Ligand B (0.577) is slightly low, potentially hindering membrane permeability.

**H-Bond Donors/Acceptors:** Ligand A (HBD=1, HBA=3) and Ligand B (HBD=2, HBA=4) both have acceptable numbers of H-bond donors and acceptors.

**QED:** Both ligands have reasonable QED values (A: 0.479, B: 0.685), suggesting drug-like properties, with B being slightly better.

**DILI:** Ligand A (47.693) has a moderate DILI risk, while Ligand B (14.541) has a very low risk. This favors Ligand B.

**BBB:** Ligand A (47.809) has a moderate BBB penetration, while Ligand B (67.197) has a significantly better BBB penetration, exceeding the desirable >70 threshold. This is a major advantage for Ligand B, given the CNS target.

**Caco-2 Permeability:** Ligand A (-4.599) and Ligand B (-5.144) both have negative Caco-2 values, which is unusual and suggests poor permeability. However, these values are on a scale where negative values are possible and don't necessarily preclude development.

**Aqueous Solubility:** Ligand A (-3.391) and Ligand B (-1.154) both have negative solubility values, indicating poor aqueous solubility. Ligand B is slightly better.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (A: 0.426, B: 0.184), which is favorable.

**Microsomal Clearance:** Ligand A (42.244) has a moderate clearance, while Ligand B (-1.324) has a very low (and favorable) clearance, indicating better metabolic stability.

**In vitro Half-Life:** Ligand A (-7.979) has a very long half-life, while Ligand B (-0.924) has a shorter, but still reasonable half-life.

**P-gp Efflux:** Ligand A (0.077) has low P-gp efflux, which is good. Ligand B (0.016) has even lower P-gp efflux, which is excellent for CNS exposure.

**Binding Affinity:** Both ligands have the same binding affinity (-7.9 kcal/mol), which is excellent and meets the criteria.

**Overall Assessment:**

While Ligand A has a very long half-life, Ligand B demonstrates superior ADME properties crucial for a CNS-targeting GPCR ligand. Specifically, its significantly better BBB penetration, lower DILI risk, lower P-gp efflux, and lower microsomal clearance outweigh the slightly lower logP and solubility. The equal binding affinity removes that as a differentiating factor.

Output:
1
2025-04-17 07:51:39,978 - INFO - Okay, let's analyze these two ligands for their potential as DRD2 drug candidates. DRD2 is a GPCR in the CNS, so BBB penetration, logP, Pgp efflux, TPSA, and binding affinity are paramount.

**Ligand A: [342.483, 58.2, 3.243, 2, 2, 0.728, 34.781, 65.297, -4.917, -4.495, 0.22, 54.117, 21.64, 0.295, -8.3]**

*   **MW:** 342.483 Da - Good, within the ideal range.
*   **TPSA:** 58.2  - Good, below the 90 threshold for CNS targets.
*   **logP:** 3.243 - Excellent, within the optimal 1-3 range.
*   **HBD:** 2 - Acceptable, below the threshold of 5.
*   **HBA:** 2 - Acceptable, below the threshold of 10.
*   **QED:** 0.728 - Excellent, well above the 0.5 threshold.
*   **DILI:** 34.781 - Very good, low risk.
*   **BBB:** 65.297 - Moderate. While not *high*, it's not terrible. Could be a concern.
*   **Caco-2:** -4.917 - Poor. Indicates very low intestinal permeability.
*   **Solubility:** -4.495 - Poor. Indicates very low aqueous solubility.
*   **hERG:** 0.22 - Very good, low risk.
*   **Cl_mic:** 54.117 - Moderate. Not ideal, but not excessively high.
*   **t1/2:** 21.64 - Moderate.
*   **Pgp:** 0.295 - Very good, low efflux.
*   **Affinity:** -8.3 kcal/mol - Excellent, very strong binding.

**Ligand B: [380.583, 43.18, 3.477, 0, 7, 0.631, 10.237, 77.976, -5.193, -2.854, 0.826, 45.644, 4.441, 0.279, -6]**

*   **MW:** 380.583 Da - Good, within the ideal range.
*   **TPSA:** 43.18 - Excellent, well below the 90 threshold for CNS targets.
*   **logP:** 3.477 - Good, slightly above the optimal range but still acceptable.
*   **HBD:** 0 - Acceptable.
*   **HBA:** 7 - Acceptable, below the threshold of 10.
*   **QED:** 0.631 - Good, above the 0.5 threshold.
*   **DILI:** 10.237 - Excellent, very low risk.
*   **BBB:** 77.976 - Excellent, very high probability of CNS penetration.
*   **Caco-2:** -5.193 - Poor. Indicates very low intestinal permeability.
*   **Solubility:** -2.854 - Poor. Indicates very low aqueous solubility.
*   **hERG:** 0.826 - Good, low risk.
*   **Cl_mic:** 45.644 - Good, relatively low clearance.
*   **t1/2:** 4.441 - Poor. Short half-life.
*   **Pgp:** 0.279 - Very good, low efflux.
*   **Affinity:** -6 kcal/mol - Good, strong binding, but not as strong as Ligand A.

**Comparison and Decision:**

Both ligands have poor Caco-2 permeability and aqueous solubility, which would present formulation challenges. However, for a CNS target, these are less critical than BBB penetration and affinity.

Ligand A has a significantly stronger binding affinity (-8.3 kcal/mol vs -6 kcal/mol). While Ligand B has a superior BBB score (77.98% vs 65.30%), the difference in affinity is substantial. A 2.3 kcal/mol difference in binding affinity is a significant advantage, and can often outweigh minor ADME drawbacks, especially for a GPCR where achieving sufficient target engagement is crucial. Ligand A also has a better DILI score.

Considering the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity), and the magnitude of the affinity difference, **Ligand A is the more promising drug candidate.**

1
2025-04-17 07:51:39,978 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (348.349 and 349.391 Da) fall comfortably within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (67.43) is significantly better than Ligand B (92.55). For CNS targets, we want TPSA <= 90, so Ligand A is preferable.

**3. logP:** Ligand A (3.121) is optimal (1-3). Ligand B (-0.115) is quite low, which could hinder membrane permeability and potentially reduce CNS exposure.

**4. H-Bond Donors:** Both ligands have acceptable HBD counts (2 and 1, respectively), well below the threshold of 5.

**5. H-Bond Acceptors:** Ligand A (3) is better than Ligand B (9), but both are within the acceptable limit of 10.

**6. QED:** Both ligands have similar and good QED values (0.843 and 0.805), indicating good drug-like properties.

**7. DILI:** Ligand A (81.427) has a higher DILI risk than Ligand B (68.166), but both are below the concerning threshold of 60.

**8. BBB:** Ligand A (73.362) has a better BBB percentile than Ligand B (61.225). While both are not exceptional, Ligand A is closer to the desirable >70 for CNS targets.

**9. Caco-2 Permeability:** Ligand A (-4.347) is better than Ligand B (-5.475). Higher values indicate better permeability.

**10. Aqueous Solubility:** Ligand A (-4.308) is better than Ligand B (-2.196). Higher values indicate better solubility.

**11. hERG Inhibition:** Ligand A (0.625) is better than Ligand B (0.077). Lower values are preferred to avoid cardiotoxicity.

**12. Microsomal Clearance:** Ligand A (45.19) is significantly better than Ligand B (1.005). Lower clearance suggests better metabolic stability.

**13. In vitro Half-Life:** Ligand A (8.644) is better than Ligand B (31.965). Longer half-life is generally desirable.

**14. P-gp Efflux:** Ligand A (0.181) is better than Ligand B (0.033). Lower efflux is preferred for CNS exposure.

**15. Binding Affinity:** Ligand B (-7.3) has a slightly better binding affinity than Ligand A (-9.2). However, the difference is not substantial enough to outweigh the significant ADME advantages of Ligand A.

**Overall Assessment:**

Ligand A consistently outperforms Ligand B across most critical ADME properties, particularly logP, TPSA, BBB, and metabolic stability. While Ligand B has slightly better binding affinity, the superior ADME profile of Ligand A, especially its better predicted CNS penetration, makes it the more promising drug candidate for a CNS target like DRD2.

Output:
1
2025-04-17 07:51:39,978 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (358.551 and 350.419 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (52.89) is significantly better than Ligand B (130.39). For CNS targets, TPSA should be <= 90, and A is comfortably within that, while B exceeds it. This is a major advantage for A.

**3. logP:** Ligand A (4.806) is higher than the optimal 1-3 range, but still potentially acceptable. Ligand B (0.186) is *much* too low, likely hindering permeability. This is a significant drawback for B.

**4. H-Bond Donors:** Ligand A (1) is good. Ligand B (4) is higher, potentially impacting permeability.

**5. H-Bond Acceptors:** Ligand A (3) is good. Ligand B (4) is acceptable.

**6. QED:** Both ligands have reasonable QED values (0.761 and 0.522), indicating drug-like properties.

**7. DILI:** Ligand A (20.9) has a much lower DILI risk than Ligand B (41.024).

**8. BBB:** Ligand A (61.846) is reasonable, but not ideal (>70 is preferred). Ligand B (87.398) is excellent, a strong positive for B.

**9. Caco-2:** Both have negative values, which is unusual and likely indicates poor permeability in this scale.

**10. Solubility:** Both have negative values, which is unusual and likely indicates poor solubility in this scale.

**11. hERG:** Both ligands have very low hERG inhibition liability (0.652 and 0.06).

**12. Cl_mic:** Ligand A (104.575) has higher microsomal clearance, suggesting faster metabolism. Ligand B (41.189) has lower clearance, indicating better metabolic stability.

**13. t1/2:** Ligand A (-19.562) has a negative in vitro half-life, which is not possible and suggests an issue with the data. Ligand B (-5.112) also has a negative half-life, indicating data issues.

**14. Pgp:** Both ligands have very low Pgp efflux liability (0.34 and 0.023).

**15. Binding Affinity:** Both ligands have the same binding affinity (-9 kcal/mol), which is excellent.

**Overall Assessment:**

Despite Ligand B's superior BBB penetration, Ligand A is the more promising candidate. The critical issues with Ligand B are its very low logP (likely poor permeability) and higher TPSA. Ligand A has a much more favorable TPSA, a reasonable logP, and a lower DILI risk. The negative half-life values are concerning for both, but the other ADME properties of A are more favorable. Given the GPCR-specific priorities, TPSA and logP are crucial, and A performs better in these areas.

Output:
1
2025-04-17 07:51:39,978 - INFO - Reasoning:

Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (343.343 and 364.471 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (110.49) is slightly above the preferred <90 for CNS targets, while Ligand B (84.42) is well within the range. This gives a slight edge to Ligand B.

**3. logP:** Both ligands have good logP values (1.782 and 1.632), falling within the optimal 1-3 range.

**4. H-Bond Donors:** Both ligands have 1 HBD, which is acceptable.

**5. H-Bond Acceptors:** Ligand A has 7 HBAs, and Ligand B has 6. Both are below the threshold of 10.

**6. QED:** Both ligands have good QED scores (0.665 and 0.821), indicating good drug-like properties. Ligand B is slightly better.

**7. DILI:** Ligand A has a DILI risk of 95.774, which is high. Ligand B has a DILI risk of 68.282, which is still elevated but considerably better than Ligand A. This is a significant advantage for Ligand B.

**8. BBB:** Both ligands have acceptable BBB penetration (61.342 and 64.211), but neither exceeds the desirable >70 for CNS targets.

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.706 and -4.882), which is unusual and suggests poor permeability. This is a concern for both.

**10. Aqueous Solubility:** Both ligands have negative solubility values (-3.537 and -2.71), indicating poor aqueous solubility. This is a significant drawback for both.

**11. hERG Inhibition:** Both ligands have low hERG inhibition risk (0.324 and 0.168).

**12. Microsomal Clearance:** Ligand A (33.417) has lower microsomal clearance than Ligand B (46.415), suggesting better metabolic stability.

**13. In vitro Half-Life:** Ligand B (-16.226) has a significantly longer in vitro half-life than Ligand A (-4.917). This is a major advantage for Ligand B.

**14. P-gp Efflux:** Both ligands have low P-gp efflux liability (0.058 and 0.152).

**15. Binding Affinity:** Both ligands have excellent binding affinities (-9.5 and -8.8 kcal/mol), with Ligand A being slightly stronger. However, the difference is likely not enough to overcome its other weaknesses.

**Overall Assessment:**

While Ligand A has slightly better binding affinity and metabolic stability, Ligand B is significantly better overall. The major advantages of Ligand B are its lower DILI risk, better QED score, and substantially longer in vitro half-life. Both have poor solubility and permeability, but the DILI risk associated with Ligand A is a major concern. Considering the GPCR-specific priorities, particularly the need for a favorable safety profile (DILI) and reasonable metabolic stability (half-life), Ligand B is the more promising candidate.

Output:
1
2025-04-17 07:51:39,978 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (354.491 and 352.469 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (59.08) is better than Ligand B (33.2). Both are below the 90 A^2 threshold for CNS targets, but Ligand B is significantly lower, which is advantageous for brain penetration.

**logP:** Ligand A (1.923) is within the optimal 1-3 range. Ligand B (4.57) is slightly above, potentially leading to solubility issues and off-target interactions, though not drastically so.

**H-Bond Donors/Acceptors:** Ligand A has 0 HBD and 4 HBA, while Ligand B has 0 HBD and 2 HBA. Both are within acceptable limits.

**QED:** Both ligands have similar QED values (0.701 and 0.72), indicating good drug-likeness.

**DILI:** Ligand A (28.616) has a lower DILI risk than Ligand B (11.943), which is a significant advantage.

**BBB:** Ligand B (95.463) has a substantially higher BBB penetration percentile than Ligand A (77.239). This is a crucial factor for a CNS target like DRD2.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.111 and -4.279), which is unusual and suggests poor intestinal absorption. This is a concern for both.

**Aqueous Solubility:** Ligand A (-1.44) has better aqueous solubility than Ligand B (-4.393).

**hERG Inhibition:** Ligand A (0.422) has a lower hERG inhibition risk than Ligand B (0.835), which is preferable.

**Microsomal Clearance:** Ligand B (66.065) has a slightly better (lower) microsomal clearance than Ligand A (54.615), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand B (12.957) has a significantly longer in vitro half-life than Ligand A (-10.605), which is a major advantage.

**P-gp Efflux:** Ligand A (0.169) has lower P-gp efflux than Ligand B (0.215), which is favorable for CNS exposure.

**Binding Affinity:** Ligand B (-7.2) has a slightly better binding affinity than Ligand A (-7.8). While both are excellent, the 0.6 kcal/mol difference is noteworthy.

**Overall Assessment:**

Ligand B excels in BBB penetration and in vitro half-life, both critical for CNS drug development. Its binding affinity is also slightly better. However, it has a higher logP, higher DILI risk, and higher P-gp efflux. Ligand A has better solubility, lower DILI and hERG risk, and lower P-gp efflux. The difference in binding affinity is relatively small. Given the importance of BBB penetration for a CNS target, and the longer half-life, Ligand B is the more promising candidate despite its slightly less favorable ADME profile.

Output:
1
2025-04-17 07:51:39,978 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 drug candidates, considering the provided guidelines and GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (335.411 and 352.406 Da) fall within the ideal 200-500 Da range.

**TPSA:** Both ligands have TPSA values (71.84 and 70.08) below 90, which is favorable for CNS penetration.

**logP:** Ligand A (3.848) is optimal, while Ligand B (0.054) is significantly low, potentially hindering permeation. This is a major drawback for Ligand B.

**H-Bond Donors/Acceptors:** Both ligands have acceptable HBD (2 and 1 respectively) and HBA (4 each) counts.

**QED:** Both ligands have good QED scores (0.744 and 0.686), indicating drug-likeness.

**DILI:** Ligand A (77.356) has a higher DILI risk than Ligand B (16.13). This is a negative for Ligand A.

**BBB:** Both ligands exhibit good BBB penetration (64.599 and 74.06), but Ligand B is better.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values, which is unusual and suggests poor permeability. However, the scale is not specified, so it's difficult to interpret.

**Aqueous Solubility:** Both ligands have negative solubility values, which is also unusual. Again, the scale is not specified, making interpretation difficult.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.448 and 0.255).

**Microsomal Clearance:** Ligand A (67.889) has higher microsomal clearance than Ligand B (6.713), suggesting lower metabolic stability.

**In vitro Half-Life:** Ligand A (63.616) has a longer half-life than Ligand B (3.783).

**P-gp Efflux:** Ligand A (0.084) has lower P-gp efflux liability than Ligand B (0.044), which is favorable for CNS exposure.

**Binding Affinity:** Ligand A (-9.1 kcal/mol) has a significantly stronger binding affinity than Ligand B (-7.8 kcal/mol). This is a substantial advantage for Ligand A.

**Overall Assessment:**

Considering the GPCR-specific priorities, Ligand A is more promising despite the higher DILI risk. The significantly stronger binding affinity (-9.1 vs -7.8 kcal/mol) is a major advantage that can potentially outweigh the DILI concern. The optimal logP of Ligand A is also crucial for CNS penetration, while Ligand B's very low logP is a significant liability. While both have unusual Caco-2 and solubility values, the affinity and logP differences are more impactful for a CNS target like DRD2.

Output:
1
2025-04-17 07:51:39,978 - INFO - Reasoning:

Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (342.483 and 345.443 Da) fall comfortably within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (41.57) is significantly better than Ligand B (101.29). For CNS targets, we want TPSA <= 90, and Ligand A is well within this range, while Ligand B exceeds it. This is a major advantage for A.

**3. logP:** Both ligands have good logP values (3.151 and 2.445), falling within the optimal 1-3 range.

**4. H-Bond Donors:** Ligand A (1) is preferable to Ligand B (3), as fewer HBDs generally improve permeability.

**5. H-Bond Acceptors:** Both ligands have the same number of HBA (3), which is acceptable.

**6. QED:** Ligand A (0.894) has a higher QED score than Ligand B (0.674), indicating a more drug-like profile.

**7. DILI:** Both ligands have low DILI risk (32.299 and 31.563), both well below the 40 threshold.

**8. BBB:** Ligand A (88.445) has a significantly higher BBB percentile than Ligand B (78.17). For a CNS target like DRD2, this is a crucial advantage.

**9. Caco-2 Permeability:** Ligand A (-4.553) is better than Ligand B (-5.066), indicating better intestinal absorption.

**10. Aqueous Solubility:** Both ligands have poor aqueous solubility (-3.427 and -3.855). This is a potential issue for both, but not a deciding factor.

**11. hERG Inhibition:** Both ligands have low hERG inhibition risk (0.689 and 0.284).

**12. Microsomal Clearance:** Ligand B (28.184) has lower microsomal clearance than Ligand A (48.813), suggesting better metabolic stability. This is a positive for B.

**13. In vitro Half-Life:** Ligand A (7.814) has a longer half-life than Ligand B (-2.246). This is a positive for A.

**14. P-gp Efflux:** Ligand A (0.292) has lower P-gp efflux than Ligand B (0.041), which is favorable for CNS penetration.

**15. Binding Affinity:** Both ligands have excellent binding affinities (-9.1 and -8.9 kcal/mol). The difference of 0.2 kcal/mol is not substantial enough to outweigh other significant differences.

**Overall Assessment:**

Ligand A is the superior candidate. It excels in key properties for CNS drug development: TPSA, BBB penetration, QED, and P-gp efflux. While Ligand B has better metabolic stability (lower Cl_mic), the advantages of Ligand A in CNS penetration and drug-likeness are more critical for a DRD2 ligand. The slightly longer half-life of Ligand A is also a benefit.

Output:
1
2025-04-17 07:51:39,978 - INFO - Reasoning:

Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (337.339 and 351.422 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Both ligands have TPSA values (95.33 and 93.45) that are acceptable for oral absorption (<140), but slightly higher than the ideal <90 for CNS targets. This is a minor concern, but manageable if other properties are favorable.

**3. logP:** Ligand A (1.149) is closer to the optimal range (1-3) than Ligand B (1.705). Both are acceptable, but A is slightly preferred.

**4. H-Bond Donors:** Ligand A (1) is better than Ligand B (3) as fewer HBDs generally improve permeability.

**5. H-Bond Acceptors:** Ligand A (5) is better than Ligand B (4).

**6. QED:** Ligand A (0.757) has a significantly better QED score than Ligand B (0.466), indicating a more drug-like profile.

**7. DILI:** Ligand A (63.668) has a higher DILI risk than Ligand B (39.977), which is a negative for A.

**8. BBB:** This is a critical parameter for a CNS target like DRD2. Ligand B (83.986) has a much higher BBB percentile than Ligand A (28.344). This is a major advantage for B.

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.283 and -5.005), which is unusual. This suggests poor intestinal absorption.

**10. Aqueous Solubility:** Both have negative solubility values (-3.262 and -2.774), which is also unusual and suggests poor solubility.

**11. hERG Inhibition:** Both ligands show low hERG inhibition liability (0.472 and 0.687), which is good.

**12. Microsomal Clearance:** Ligand B (22.687) has a higher microsomal clearance than Ligand A (14.541), suggesting lower metabolic stability. This is a negative for B.

**13. In vitro Half-Life:** Ligand A (22.267) has a longer in vitro half-life than Ligand B (9.827), which is a positive for A.

**14. P-gp Efflux:** Ligand A (0.005) has significantly lower P-gp efflux liability than Ligand B (0.094), which is crucial for CNS penetration.

**15. Binding Affinity:** Ligand A (-9.2 kcal/mol) has a slightly better binding affinity than Ligand B (-8.0 kcal/mol). This difference is substantial (>1.5 kcal/mol) and can outweigh some ADME drawbacks.

**Overall Assessment:**

While Ligand A has a better QED, affinity, half-life, and P-gp efflux profile, Ligand B excels in BBB penetration and has a lower DILI risk. Given that DRD2 is a CNS target, BBB penetration is paramount. The significantly higher BBB score of Ligand B is a major advantage. The slightly lower affinity of Ligand B is less concerning given the importance of CNS exposure. The lower DILI risk is also a positive.

Output:
1
2025-04-17 07:51:39,979 - INFO - Reasoning:

Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (369.447 and 393.311 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (126.65) is higher than the preferred <90 for CNS targets, while Ligand B (87.66) is within the desirable range. This is a significant advantage for Ligand B.

**3. logP:** Ligand A (0.637) is a bit low, potentially hindering membrane permeability. Ligand B (1.655) is better, falling within the optimal 1-3 range.

**4. H-Bond Donors:** Both ligands have 3 HBD, which is acceptable.

**5. H-Bond Acceptors:** Ligand A has 7 HBA, acceptable. Ligand B has 4 HBA, also acceptable and slightly more favorable.

**6. QED:** Both ligands have similar QED values (0.605 and 0.599), indicating reasonable drug-likeness.

**7. DILI:** Ligand A (64.831) has a higher DILI risk than Ligand B (35.673). This is a clear advantage for Ligand B.

**8. BBB:** Ligand A (64.637) has a moderate BBB penetration, while Ligand B (50.097) is lower. While both are below the desirable >70 for CNS targets, Ligand A is slightly better.

**9. Caco-2:** Both ligands have negative Caco-2 values (-5.343 and -5.385), which is unusual and suggests poor permeability. This is a significant drawback for both.

**10. Solubility:** Both ligands have negative solubility values (-2.704 and -2.529), indicating poor aqueous solubility. This is a concern for both.

**11. hERG:** Both ligands have low hERG inhibition risk (0.301 and 0.272).

**12. Cl_mic:** Ligand A (13.081) has a higher microsomal clearance than Ligand B (-1.825), indicating lower metabolic stability. Ligand B is significantly better.

**13. t1/2:** Ligand A (-11.135) has a negative in vitro half-life, which is problematic. Ligand B (46.361) has a much more favorable half-life.

**14. Pgp:** Both ligands have low P-gp efflux liability (0.072 and 0.184).

**15. Binding Affinity:** Ligand B (-7.4) has a slightly better binding affinity than Ligand A (-7.0). While the difference is small, it's still a positive for Ligand B.

**Overall Assessment:**

Considering the GPCR-specific priorities, Ligand B is the more promising candidate. It has a significantly better TPSA, lower DILI risk, better metabolic stability (lower Cl_mic, higher t1/2), and slightly better binding affinity. While both have issues with Caco-2 permeability and solubility, the advantages of Ligand B in terms of CNS penetration potential (lower TPSA, better metabolic stability) and safety (lower DILI) outweigh the slight advantage of Ligand A in BBB.

Output:
1
2025-04-17 07:51:39,979 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B based on the provided guidelines, prioritizing GPCR-specific properties (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (342.403 and 348.447 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (104.7) is slightly above the optimal <90 for CNS targets, while Ligand B (83.56) is well within the range. This favors Ligand B.

**logP:** Ligand A (0.94) is a bit low, potentially hindering permeation. Ligand B (0.593) is also on the lower side, but still comparable.

**H-Bond Donors/Acceptors:** Ligand A has 3 HBD and 5 HBA, while Ligand B has 2 HBD and 5 HBA. Both are acceptable.

**QED:** Both ligands have similar QED values (0.726 and 0.718), indicating good drug-likeness.

**DILI:** Ligand A (59.907) has a higher DILI risk than Ligand B (14.618). This is a significant advantage for Ligand B.

**BBB:** Ligand B (52.268) has a substantially better BBB penetration percentile than Ligand A (39.667). This is a critical factor for a CNS target like DRD2.

**Caco-2 Permeability:** Ligand A (-5.551) has poor Caco-2 permeability, while Ligand B (-4.996) is slightly better, but still not great.

**Aqueous Solubility:** Ligand A (-2.763) has poor solubility, while Ligand B (-0.883) is slightly better.

**hERG:** Both ligands have low hERG inhibition risk (0.103 and 0.341).

**Microsomal Clearance:** Ligand B (-22.994) has significantly lower (better) microsomal clearance than Ligand A (-4.81). This suggests better metabolic stability for Ligand B.

**In vitro Half-Life:** Ligand A (6.873) has a longer half-life than Ligand B (2.126).

**P-gp Efflux:** Ligand A (0.022) has very low P-gp efflux, which is good. Ligand B (0.012) is even lower, which is even better.

**Binding Affinity:** Ligand A (-9.3 kcal/mol) has a significantly stronger binding affinity than Ligand B (-7.7 kcal/mol). This is a substantial advantage for Ligand A.

**Overall Assessment:**

While Ligand A boasts a superior binding affinity, Ligand B demonstrates a much more favorable ADME profile, particularly regarding BBB penetration, DILI risk, and metabolic stability. For a CNS target like DRD2, good brain penetration and minimal toxicity are paramount. The substantial difference in BBB (52.27 vs 39.67) and DILI (14.62 vs 59.91) are key factors. The slightly longer half-life of Ligand A is a minor benefit that is outweighed by the ADME advantages of Ligand B. The affinity difference, while significant, might be overcome with further optimization of Ligand B.

Output:
1
2025-04-17 07:51:39,979 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (338.451 and 340.379 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (53.43) is significantly better than Ligand B (77.52). For CNS targets, we want TPSA <= 90, and A is comfortably within this range, while B is approaching the upper limit.

**3. logP:** Ligand A (3.564) is slightly higher than Ligand B (1.995). Both are within the optimal 1-3 range, but A is closer to the upper bound.

**4. H-Bond Donors:** Both have 1 HBD, which is good.

**5. H-Bond Acceptors:** Ligand A has 3 HBA, and Ligand B has 5. Both are acceptable (<=10), but A is preferable.

**6. QED:** Both ligands have good QED scores (0.911 and 0.865), indicating good drug-like properties.

**7. DILI:** Ligand A (25.281) has a much lower DILI risk than Ligand B (74.021). This is a significant advantage for A.

**8. BBB:** Ligand A (84.529) has a better BBB penetration percentile than Ligand B (78.79). Both are good (>70), but A is more promising for CNS activity.

**9. Caco-2:** Ligand A (-4.542) and Ligand B (-4.493) are similar and both indicate poor Caco-2 permeability.

**10. Solubility:** Ligand A (-2.606) and Ligand B (-3.546) are similar and both indicate poor solubility.

**11. hERG:** Both ligands have low hERG inhibition liability (0.823 and 0.51), which is favorable.

**12. Cl_mic:** Ligand B (70.87) has a higher microsomal clearance than Ligand A (32.909), suggesting A is more metabolically stable.

**13. t1/2:** Ligand A (24.616) has a longer in vitro half-life than Ligand B (14.986).

**14. Pgp:** Ligand A (0.482) has lower P-gp efflux liability than Ligand B (0.137), which is beneficial for CNS penetration.

**15. Binding Affinity:** Both ligands have the same binding affinity (-9.3 kcal/mol), which is excellent.

**Overall Assessment:**

Ligand A is superior to Ligand B. While both have excellent binding affinity, Ligand A demonstrates significantly better ADME properties, particularly concerning CNS penetration (better BBB, lower Pgp efflux) and safety (lower DILI risk). Ligand A also has better metabolic stability (lower Cl_mic) and a longer half-life. The TPSA is also more favorable for CNS penetration. Although both have poor Caco-2 and solubility, the other advantages of A outweigh this drawback.

Output:
1
2025-04-17 07:51:39,979 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (352.475 and 344.459 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (89.87) is better than Ligand B (69.3), both are below the 90 A^2 threshold for CNS targets.

**3. logP:** Ligand A (1.218) is within the optimal range (1-3), while Ligand B (2.415) is also acceptable.

**4. H-Bond Donors:** Ligand A (3) is higher than Ligand B (1), but both are within the acceptable limit of <=5.

**5. H-Bond Acceptors:** Ligand A (4) and Ligand B (3) are both well within the acceptable limit of <=10.

**6. QED:** Ligand A (0.666) is slightly better than Ligand B (0.582), both are above the 0.5 threshold.

**7. DILI:** Ligand B (38.736) has a significantly lower DILI risk than Ligand A (19.504), indicating better predicted liver safety.

**8. BBB:** Ligand B (60.411) has a better BBB penetration percentile than Ligand A (42.148), but neither are above the desirable 70% for CNS targets.

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 values, which is unusual and suggests poor permeability. Ligand A (-4.82) is slightly better than Ligand B (-4.978).

**10. Aqueous Solubility:** Both ligands have negative solubility values, indicating poor aqueous solubility. Ligand A (-2.201) is slightly better than Ligand B (-2.458).

**11. hERG Inhibition:** Ligand A (0.149) has a lower hERG inhibition risk than Ligand B (0.73).

**12. Microsomal Clearance:** Ligand B (71.844) has much higher microsomal clearance than Ligand A (22.778), suggesting lower metabolic stability.

**13. In vitro Half-Life:** Ligand B (-21.536) has a negative half-life, which is not possible and indicates a significant issue. Ligand A (2.779) has a reasonable half-life.

**14. P-gp Efflux:** Ligand A (0.028) has very low P-gp efflux liability, which is favorable for CNS penetration. Ligand B (0.518) is higher.

**15. Binding Affinity:** Ligand B (-7.0) has a significantly stronger binding affinity than Ligand A (0.0). This is a crucial advantage.

**Overall Assessment:**

While Ligand B has a superior binding affinity, its extremely poor in vitro half-life and higher P-gp efflux are major drawbacks. The negative half-life is a critical issue. Ligand A, while having a weaker binding affinity, has a more reasonable ADME profile, particularly regarding metabolic stability (lower Cl_mic, positive t1/2) and P-gp efflux. The better BBB and lower DILI risk of Ligand B are attractive, but the instability and efflux issues are too significant. Given the GPCR-specific priorities, and the importance of CNS penetration, Ligand A is the more promising candidate despite its lower affinity. Further optimization of Ligand A could focus on improving its binding affinity.

Output:
0
2025-04-17 07:51:39,979 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (341.455 and 354.466 Da) fall within the ideal 200-500 Da range.

**TPSA:** Both ligands (57.5 and 58.64) are below the 90 A^2 threshold desirable for CNS targets, which is excellent.

**logP:** Both ligands (2.218 and 2.439) are within the optimal 1-3 range.

**H-Bond Donors & Acceptors:** Ligand A has 2 HBD and 4 HBA, while Ligand B has 1 HBD and 3 HBA. Both are within acceptable limits (<=5 HBD and <=10 HBA).

**QED:** Ligand A (0.847) has a slightly better QED score than Ligand B (0.764), indicating a more drug-like profile.

**DILI:** Ligand A (24.622) has a significantly lower DILI risk than Ligand B (8.453), which is a major advantage.

**BBB:** Ligand B (92.012) has a much higher BBB penetration percentile than Ligand A (51.997). This is *critical* for a CNS target like DRD2.

**Caco-2 Permeability:** Both have negative values, indicating poor permeability.

**Aqueous Solubility:** Both have negative values, indicating poor solubility.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.844 and 0.578).

**Microsomal Clearance:** Ligand B (25.983) has lower microsomal clearance than Ligand A (31.062), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand B (-2.849) has a negative half-life, which is concerning. Ligand A (68.92) has a good half-life.

**P-gp Efflux:** Ligand B (0.047) has very low P-gp efflux, which is favorable for CNS penetration. Ligand A (0.573) has moderate P-gp efflux.

**Binding Affinity:** Ligand A (-8.4 kcal/mol) has a slightly better binding affinity than Ligand B (-7.8 kcal/mol). While both are good, the 0.6 kcal/mol difference is notable.

**Overall Assessment:**

Ligand B excels in BBB penetration and P-gp efflux, which are paramount for CNS GPCR targets. Its lower microsomal clearance is also beneficial. However, its DILI risk is higher, and its in vitro half-life is concerning. Ligand A has a better QED score, lower DILI, and a better half-life, and slightly better binding affinity, but its BBB penetration is significantly lower.

Given the importance of CNS penetration for a DRD2 ligand, the superior BBB score of Ligand B outweighs the advantages of Ligand A, despite the concerns regarding its DILI and half-life. These issues could potentially be addressed through further optimization.

Output:
1
2025-04-17 07:51:39,980 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (353.394 and 352.479 Da) fall comfortably within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (80.76) is slightly higher than Ligand B (76.46). Both are below the 90 A^2 threshold desirable for CNS targets, which is good.

**3. logP:** Both ligands have optimal logP values (2.359 and 2.103), falling within the 1-3 range.

**4. H-Bond Donors:** Both have 1 HBD, which is within the acceptable limit of <=5.

**5. H-Bond Acceptors:** Both have 5 HBA, also within the acceptable limit of <=10.

**6. QED:** Ligand A (0.841) has a better QED score than Ligand B (0.777), indicating a more drug-like profile.

**7. DILI:** Ligand A (64.172) has a higher DILI risk than Ligand B (37.456). This is a significant negative for Ligand A.

**8. BBB:** Both ligands have good BBB penetration (Ligand A: 59.364, Ligand B: 64.676). While >70 is desirable, both are reasonably high, suggesting decent CNS exposure. Ligand B is slightly better.

**9. Caco-2:** Both have negative Caco-2 values, indicating poor permeability. This is a concern for both.

**10. Solubility:** Ligand B (-1.933) has better solubility than Ligand A (-3.073). Solubility is important for formulation and bioavailability.

**11. hERG:** Ligand A (0.23) has a lower hERG risk than Ligand B (0.556), which is favorable.

**12. Cl_mic:** Ligand B (52.203) has lower microsomal clearance than Ligand A (62.015), suggesting better metabolic stability.

**13. t1/2:** Ligand B (36.226) has a longer in vitro half-life than Ligand A (-28.574). This is a significant advantage for Ligand B.

**14. Pgp:** Ligand A (0.023) has lower P-gp efflux liability than Ligand B (0.109), which is favorable for CNS penetration.

**15. Binding Affinity:** Ligand A (-8.1 kcal/mol) has a significantly stronger binding affinity than Ligand B (-6.7 kcal/mol). This is a substantial advantage that could outweigh some of the ADME drawbacks.

**Overall Assessment:**

Ligand A has a superior binding affinity and lower Pgp efflux, but suffers from higher DILI risk, poorer metabolic stability, and shorter half-life. Ligand B has a better safety profile (lower DILI), better metabolic stability, longer half-life, and improved solubility. The difference in binding affinity is significant (1.4 kcal/mol), and for a GPCR target, this is often a critical factor. Given the importance of affinity for GPCRs, and the relatively acceptable BBB values for both, I believe the stronger binding of Ligand A outweighs its other shortcomings.

Output:
1
2025-04-17 07:51:39,980 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (345.33 Da) is slightly lower, which could be beneficial for permeability.

**2. TPSA:** Ligand A (115.36) is better than Ligand B (78.59) as it is closer to the desired threshold of <=90 for CNS targets.

**3. logP:** Both ligands have good logP values (A: 1.857, B: 2.041), falling within the optimal range of 1-3.

**4. H-Bond Donors:** Both ligands are acceptable (A: 3, B: 2), being less than or equal to 5.

**5. H-Bond Acceptors:** Both ligands are acceptable (A: 5, B: 5), being less than or equal to 10.

**6. QED:** Both ligands have good QED values (A: 0.715, B: 0.785), indicating a drug-like profile.

**7. DILI:** Ligand A (74.021) has a higher DILI risk than Ligand B (34.665). This is a significant drawback for Ligand A.

**8. BBB:** Ligand B (68.36) has a significantly better BBB penetration percentile than Ligand A (22.528). This is *critical* for a CNS target like DRD2.

**9. Caco-2 Permeability:** Ligand A (-4.848) has poorer Caco-2 permeability compared to Ligand B (-4.68).

**10. Aqueous Solubility:** Ligand A (-3.856) has poorer aqueous solubility than Ligand B (-2.824).

**11. hERG Inhibition:** Both ligands have similar, low hERG inhibition liability (A: 0.442, B: 0.409).

**12. Microsomal Clearance:** Ligand B (22.217) has higher microsomal clearance than Ligand A (10.998), meaning A is more metabolically stable.

**13. In vitro Half-Life:** Ligand A (89.733) has a much longer in vitro half-life than Ligand B (6.481).

**14. P-gp Efflux:** Ligand A (0.069) has much lower P-gp efflux liability than Ligand B (0.332). This is beneficial for CNS exposure.

**15. Binding Affinity:** Ligand A (-8.9 kcal/mol) has a significantly stronger binding affinity than Ligand B (-6.6 kcal/mol). This is a substantial advantage.

**Overall Assessment:**

While Ligand A has a superior binding affinity and better metabolic stability (lower Cl_mic, longer t1/2) and P-gp efflux, its poor BBB penetration, higher DILI risk, and lower Caco-2 permeability are major concerns. Ligand B, despite its weaker binding affinity, exhibits a much more favorable profile for CNS penetration (higher BBB, lower Pgp), lower DILI risk, and better solubility. For a CNS target like DRD2, BBB penetration is paramount. The 2.3 kcal/mol difference in binding affinity can potentially be overcome with further optimization of Ligand B, whereas improving the BBB penetration of Ligand A would be far more challenging.

Output:
1
2025-04-17 07:51:39,980 - INFO - Batch 400 complete. Total preferences: 6400
2025-04-17 07:51:39,980 - INFO - Processing batch 401/512...
2025-04-17 07:52:21,489 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (358.36 and 366.483 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (61.8) is significantly better than Ligand B (95.5). For CNS targets, we want TPSA <= 90, so Ligand A is preferable.

**logP:** Ligand A (2.553) is within the optimal 1-3 range. Ligand B (-0.044) is below 1, which could hinder permeation. This favors Ligand A.

**H-Bond Donors:** Both have acceptable HBD counts (2 and 3 respectively), well below the threshold of 5.

**H-Bond Acceptors:** Both have acceptable HBA counts (3 and 4 respectively), well below the threshold of 10.

**QED:** Ligand A (0.87) has a much better QED score than Ligand B (0.415), indicating a more drug-like profile.

**DILI:** Ligand A (35.285) has a lower DILI risk than Ligand B (16.169), which is preferable.

**BBB:** Ligand A (75.843) has a significantly higher BBB penetration percentile than Ligand B (32.92). This is *critical* for a CNS target like DRD2, making Ligand A much more promising.

**Caco-2 Permeability:** Ligand A (-4.491) and Ligand B (-5.191) both have negative values, which is unusual and suggests poor permeability. However, the scale is not specified, so it's difficult to interpret.

**Aqueous Solubility:** Both ligands have negative solubility values (-2.646 and -2.242 respectively), indicating poor aqueous solubility. This could be a formulation challenge.

**hERG:** Ligand A (0.734) has a lower hERG inhibition liability than Ligand B (0.058), which is desirable.

**Microsomal Clearance:** Ligand A (-7.629) has a much lower (better) microsomal clearance than Ligand B (23.159), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (13.538 hours) has a much longer half-life than Ligand B (-13.949 hours).

**P-gp Efflux:** Ligand A (0.124) has lower P-gp efflux liability than Ligand B (0.006), which is favorable for CNS penetration.

**Binding Affinity:** Both ligands have excellent binding affinities (-8.9 and -8.0 kcal/mol). While Ligand A is slightly better, the difference isn't huge enough to completely overshadow the ADME advantages of Ligand A.

**Overall:**

Ligand A consistently outperforms Ligand B across most critical ADME properties, especially BBB penetration, TPSA, logP, QED, DILI, metabolic stability, and P-gp efflux. While both have poor solubility and Caco-2 permeability, the superior CNS penetration profile of Ligand A makes it the more viable drug candidate for targeting DRD2.

Output:
1
2025-04-17 07:52:21,489 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (350.419 and 351.363 Da) are within the ideal range of 200-500 Da.

**TPSA:** Ligand A (108.56) is better than Ligand B (137.25). For CNS targets, we want TPSA <= 90, so Ligand A is closer to this threshold. Ligand B is significantly higher and could hinder BBB penetration.

**logP:** Ligand A (0.955) is within the optimal range (1-3), while Ligand B (-1.394) is below 1, which could impede permeation.

**H-Bond Donors/Acceptors:** Both have similar HBD (2 vs 3) and HBA (6 vs 6) counts, both within acceptable limits.

**QED:** Ligand A (0.837) has a better QED score than Ligand B (0.61), indicating a more drug-like profile.

**DILI:** Ligand A (39.667) has a significantly lower DILI risk than Ligand B (69.678). Both are below 60, but A is preferable.

**BBB:** Ligand A (51.919) has a moderate BBB penetration, while Ligand B (23.73) is quite low. This is a critical factor for a CNS target like DRD2, making Ligand A much more promising.

**Caco-2:** Both have negative Caco-2 values, which is unusual and difficult to interpret without knowing the scale. However, the absolute value is larger for Ligand A (-4.927 vs -5.218), suggesting slightly better permeability.

**Solubility:** Both have negative solubility values, again unusual. Ligand B (-2.614) is slightly worse than Ligand A (-1.542).

**hERG:** Both ligands have very low hERG inhibition risk (0.033 and 0.098), which is excellent.

**Microsomal Clearance:** Ligand B (-16.616) has a much lower (better) microsomal clearance than Ligand A (3.341). This suggests better metabolic stability for Ligand B.

**In vitro Half-Life:** Ligand B (-7.442) has a longer in vitro half-life than Ligand A (6.222), which is desirable.

**P-gp Efflux:** Both have very low P-gp efflux liability (0.015 and 0.005), which is good for CNS penetration.

**Binding Affinity:** Both ligands have very similar and excellent binding affinities (-8.0 and -7.8 kcal/mol). The difference is less than the 1.5 kcal/mol threshold.

**Overall Assessment:**

Ligand A is significantly better due to its superior BBB penetration, TPSA, logP, and QED score. While Ligand B has better metabolic stability (lower Cl_mic) and half-life, the CNS target necessitates prioritizing BBB penetration and appropriate lipophilicity. The slightly better DILI score for Ligand A is also a plus. The similar binding affinities mean that the ADME properties become the deciding factor.

Output:
1
2025-04-17 07:52:21,489 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight (MW):** Both ligands are within the ideal range (200-500 Da). Ligand A (341.415 Da) is slightly lower than Ligand B (371.84 Da).

**2. TPSA:** Ligand A (88.47) is better than Ligand B (65.79) as it is closer to the ideal range for CNS targets (<=90).

**3. logP:** Ligand B (1.942) is optimal (1-3), while Ligand A (0.311) is below 1, potentially hindering permeation. This is a significant drawback for Ligand A.

**4. H-Bond Donors (HBD):** Both are acceptable (<=5). Ligand A has 2, and Ligand B has 1.

**5. H-Bond Acceptors (HBA):** Both are acceptable (<=10). Ligand A has 5, and Ligand B has 4.

**6. QED:** Both have good drug-likeness scores (>=0.5). Ligand B (0.881) is slightly better than Ligand A (0.756).

**7. DILI:** Both have low DILI risk (<40). Ligand A (37.999) is slightly higher than Ligand B (33.889) but both are acceptable.

**8. BBB:** Ligand B (61.846) is better than Ligand A (54.13), but both are below the desirable threshold of >70 for CNS targets. This is a concern for both, but less so for B.

**9. Caco-2 Permeability:** Both have negative values, which is unusual. Assuming these are log values, lower values indicate poorer permeability. Ligand A (-5.006) is slightly worse than Ligand B (-4.965).

**10. Aqueous Solubility:** Both have negative values, indicating poor solubility. Ligand A (-2.278) is slightly worse than Ligand B (-2.744).

**11. hERG Inhibition:** Both have low hERG risk (0.678 and 0.508).

**12. Microsomal Clearance (Cl_mic):** Ligand A (-47.418) has a much lower (better) clearance than Ligand B (-33.345), suggesting better metabolic stability.

**13. In vitro Half-Life:** Ligand A (13.349) has a slightly longer half-life than Ligand B (11.107).

**14. P-gp Efflux:** Both have very low P-gp efflux liability (0.003 and 0.062), which is excellent for CNS penetration.

**15. Binding Affinity:** Ligand A (-9.1 kcal/mol) has significantly stronger binding affinity than Ligand B (-8.0 kcal/mol). This is a substantial advantage.

**Overall Assessment:**

Ligand A has a significantly better binding affinity and metabolic stability (lower Cl_mic, longer t1/2). However, its low logP is a major concern, potentially hindering its ability to cross cell membranes and reach the brain. Ligand B has a more favorable logP and slightly better BBB penetration, but its binding affinity is considerably weaker.

Given the GPCR-specific priorities, the strong affinity of Ligand A is a compelling factor. While the low logP is a drawback, it might be overcome with formulation strategies. The substantial difference in binding affinity (-9.1 vs -8.0 kcal/mol) is likely to outweigh the logP issue, especially considering the relatively low P-gp efflux for both compounds.

Output:
0
2025-04-17 07:52:21,490 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (345.4 & 350.5 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (111.55) is slightly higher than Ligand B (103.01). For CNS targets, we want TPSA <= 90, so both are a bit high, but Ligand B is preferable.

**logP:** Both ligands (0.881 & 0.857) are within the optimal 1-3 range.

**H-Bond Donors:** Ligand A has 4 HBD, and Ligand B has 3. Both are acceptable (<=5).

**H-Bond Acceptors:** Both ligands have 5 HBA, which is acceptable (<=10).

**QED:** Both ligands have good QED scores (0.605 & 0.677), indicating drug-like properties. Ligand B is slightly better.

**DILI:** Ligand A (50.99%) has a slightly higher DILI risk than Ligand B (41.10%). Both are acceptable (<60 is good).

**BBB:** This is crucial for a CNS target. Ligand B (44.75%) is significantly better than Ligand A (25.32%). This is a major advantage for Ligand B.

**Caco-2 Permeability:** Both have negative values (-5.315 & -5.558), which is unusual and suggests poor permeability. However, these are scales and not percentiles, so direct comparison is difficult.

**Aqueous Solubility:** Both have negative values (-2.64 & -2.077), indicating poor solubility.

**hERG Inhibition:** Ligand A (0.042) has a slightly lower hERG risk than Ligand B (0.463), which is preferable.

**Microsomal Clearance:** Ligand A (-8.961) has a much lower (better) microsomal clearance than Ligand B (-6.773), indicating better metabolic stability.

**In vitro Half-Life:** Ligand A (-29.604) has a significantly longer half-life than Ligand B (-5.871). This is a substantial advantage for Ligand A.

**P-gp Efflux:** Ligand A (0.02) has a much lower P-gp efflux liability than Ligand B (0.022), which is preferable for CNS penetration.

**Binding Affinity:** Ligand A (-9.4 kcal/mol) has a stronger binding affinity than Ligand B (-7.7 kcal/mol). The difference of 1.7 kcal/mol is substantial and can outweigh some ADME drawbacks.

**Overall Assessment:**

Ligand A has a significantly better binding affinity, lower P-gp efflux, lower microsomal clearance, and longer half-life. However, Ligand B has a much better BBB penetration score. Considering the GPCR-specific priorities, BBB is critical for CNS targets. While Ligand A's affinity is very strong, the poor BBB penetration is a major concern. Ligand B's moderate affinity, coupled with significantly better BBB penetration, makes it a more promising candidate. The slightly higher hERG risk and lower metabolic stability of Ligand B could be addressed with further optimization.

Output:
1
2025-04-17 07:52:21,490 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (351.535 and 355.454 Da) fall comfortably within the ideal 200-500 Da range.

**TPSA:** Ligand A (44.81) is significantly better than Ligand B (64.09). For CNS targets, we want TPSA <= 90, and ideally lower. Ligand A is well within this range, while Ligand B is approaching the upper limit.

**logP:** Ligand A (3.403) is optimal (1-3). Ligand B (0.498) is quite low, potentially hindering membrane permeability and CNS penetration.

**H-Bond Donors/Acceptors:** Both have 1 HBD and 4 HBA, which are acceptable.

**QED:** Both ligands have good QED scores (0.789 and 0.801), indicating good drug-like properties.

**DILI:** Ligand A (5.351) has a much lower DILI risk than Ligand B (8.414). This is a significant advantage.

**BBB:** Ligand A (80.07) has a substantially better BBB penetration percentile than Ligand B (57.464). This is *critical* for a CNS target like DRD2.

**Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and suggests a potential issue with the data or modeling. However, the magnitude of the negative value is larger for Ligand B (-4.887) than Ligand A (-1.956), indicating potentially worse permeability.

**Aqueous Solubility:** Both have negative solubility values, which is also unusual. Again, the value is worse for Ligand B (-0.642) than Ligand A (-1.956).

**hERG Inhibition:** Both ligands show low hERG inhibition risk (0.818 and 0.505), which is good.

**Microsomal Clearance:** Ligand A (6.215) has a better (lower) microsomal clearance than Ligand B (-40.341). This suggests better metabolic stability for Ligand A.

**In vitro Half-Life:** Ligand A (6.983) has a slightly better in vitro half-life than Ligand B (5.624).

**P-gp Efflux:** Both have low P-gp efflux liability (0.039 and 0.018), which is favorable for CNS penetration.

**Binding Affinity:** Ligand B (-8.5 kcal/mol) has a slightly better binding affinity than Ligand A (-7.2 kcal/mol). However, the difference (1.3 kcal/mol) is not large enough to overcome the significant ADME deficiencies of Ligand B.

**Overall Assessment:**

Ligand A is the superior candidate. While Ligand B has a slightly better binding affinity, Ligand A excels in almost all other crucial ADME properties, especially those prioritized for GPCRs targeting the CNS: TPSA, logP, BBB penetration, and DILI risk. The significantly better BBB score and logP for Ligand A are particularly important for ensuring sufficient brain exposure. The better metabolic stability (lower Cl_mic) and half-life also contribute to its favorability. The unusual negative values for Caco-2 and solubility are concerning for both, but less so for Ligand A.

Output:
1
2025-04-17 07:52:21,490 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (346.43 and 356.41 Da) fall comfortably within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (59.08) is significantly better than Ligand B (69.64). For CNS targets, we want TPSA <= 90, and A is much closer to the ideal <=60 for good brain penetration.

**3. logP:** Both ligands have similar logP values (2.371 and 2.339), both within the optimal 1-3 range.

**4. H-Bond Donors:** Ligand A has 0 HBD, while Ligand B has 2. Lower is generally preferred for BBB penetration, giving a slight edge to A.

**5. H-Bond Acceptors:** Ligand A has 4 HBA, and Ligand B has 3. Both are acceptable (<=10).

**6. QED:** Both ligands have similar, good QED values (0.733 and 0.751), indicating good drug-like properties.

**7. DILI:** Ligand A (53.86%) has a higher DILI risk than Ligand B (34.28%). This favors Ligand B.

**8. BBB:** Ligand A (87.13%) has a significantly higher BBB penetration percentile than Ligand B (53.63%). This is a *critical* advantage for a CNS target like DRD2.

**9. Caco-2:** Both have negative Caco-2 values, which is unusual and difficult to interpret without knowing the scale. However, the values are similar.

**10. Solubility:** Both have negative solubility values, which is also unusual. The values are similar.

**11. hERG:** Both ligands have low hERG inhibition liability (0.418 and 0.538), which is good.

**12. Cl_mic:** Ligand A (88.43 mL/min/kg) has a higher microsomal clearance than Ligand B (24.74 mL/min/kg). This suggests Ligand B is more metabolically stable, which is desirable.

**13. t1/2:** Ligand B (23.77 hours) has a much longer in vitro half-life than Ligand A (-9.01 hours). This is a significant advantage for Ligand B.

**14. Pgp:** Both have very low Pgp efflux liability (0.153 and 0.133), which is good for CNS penetration.

**15. Binding Affinity:** Ligand B (-8.5 kcal/mol) has a slightly better binding affinity than Ligand A (-7.6 kcal/mol). This is a meaningful difference, potentially outweighing some ADME drawbacks.

**Overall Assessment:**

While Ligand B has a better safety profile (lower DILI) and metabolic stability (lower Cl_mic, longer t1/2), Ligand A's *much* higher predicted BBB penetration is a decisive factor for a CNS target. The slightly better affinity of Ligand B is helpful, but not enough to overcome the BBB difference. The TPSA of Ligand A is also more favorable.

Output:
0
2025-04-17 07:52:21,490 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B against the provided guidelines, prioritizing GPCR-specific properties (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (349.475 Da) is slightly better, being closer to the lower end which can aid permeability.

**TPSA:** Ligand A (74.57) is significantly better than Ligand B (101.57). For CNS targets, we want TPSA <= 90, and Ligand A comfortably meets this, while Ligand B is close to the upper limit.

**logP:** Ligand A (1.944) is optimal (1-3), while Ligand B (0.092) is quite low. A logP below 1 can hinder permeation, making Ligand A preferable.

**H-Bond Donors/Acceptors:** Both ligands have 2 HBD and are within the acceptable range. Ligand B has 5 HBA, slightly higher than A's 4, but both are acceptable.

**QED:** Both ligands have similar QED values (0.753 and 0.708), indicating good drug-likeness.

**DILI:** Ligand A (24.467) has a much lower DILI risk than Ligand B (53.625). This is a significant advantage for Ligand A.

**BBB:** Ligand B (70.415) has a better BBB percentile than Ligand A (47.732). While >70 is desirable, 70 is still reasonably good. This is the only area where Ligand B excels.

**Caco-2 Permeability:** Ligand A (-4.737) has better Caco-2 permeability than Ligand B (-5.282). Higher values indicate better absorption.

**Aqueous Solubility:** Ligand A (-1.715) is better than Ligand B (-2.083).

**hERG:** Both ligands have low hERG inhibition liability (0.343 and 0.156), which is good.

**Microsomal Clearance:** Ligand B (-13.695) has significantly lower microsomal clearance than Ligand A (23.067), suggesting better metabolic stability. This is a strong point for Ligand B.

**In vitro Half-Life:** Ligand B (33.43) has a much longer in vitro half-life than Ligand A (4.414), which is a significant advantage.

**P-gp Efflux:** Ligand A (0.164) has lower P-gp efflux than Ligand B (0.024), which is better for CNS exposure.

**Binding Affinity:** Ligand B (-8.9) has a slightly better binding affinity than Ligand A (-8.2), but the difference is only 0.7 kcal/mol.

**Overall Assessment:**

Ligand A has advantages in TPSA, logP, DILI, Caco-2 permeability, solubility, and P-gp efflux. Ligand B excels in BBB, microsomal clearance, and in vitro half-life, and has slightly better affinity. However, the poor logP and higher DILI risk of Ligand B are concerning. The TPSA of Ligand B is also less desirable. Considering the GPCR-specific priorities, the better logP, TPSA, and lower DILI risk of Ligand A outweigh the slightly better BBB and metabolic stability of Ligand B. The affinity difference is not substantial enough to overcome the ADME liabilities of Ligand B.

Output:
0
2025-04-17 07:52:21,490 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (433.368 Da) is higher, but still acceptable. Ligand B (340.467 Da) is slightly preferred here.

**TPSA:** Ligand A (75.71) is higher than Ligand B (49.41). For CNS targets, we want TPSA <= 90, both are within this range, but Ligand B is significantly better.

**logP:** Ligand A (1.84) is within the optimal range (1-3). Ligand B (3.569) is at the higher end, but still acceptable. No clear advantage here.

**H-Bond Donors:** Both ligands have 1 HBD, which is good.

**H-Bond Acceptors:** Ligand A has 5 HBA, and Ligand B has 2. Both are within the acceptable limit of <=10. Ligand B is preferred.

**QED:** Both ligands have good QED scores (A: 0.665, B: 0.736), indicating drug-like properties. Ligand B is slightly better.

**DILI:** Both ligands have low DILI risk (A: 28.306, B: 30.593), both are good.

**BBB:** Ligand B (70.221) is better than Ligand A (57.929) in terms of BBB penetration, which is crucial for CNS targets like DRD2.

**Caco-2 Permeability:** Ligand A (-5.011) and Ligand B (-4.802) have negative values, which is unusual and suggests poor permeability. However, the values are very close, so this isn't a major differentiating factor.

**Aqueous Solubility:** Both ligands have very poor aqueous solubility (-2.742 and -3.797). This is a significant concern for both.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.671 and 0.669).

**Microsomal Clearance:** Ligand B (68.455) has a much higher microsomal clearance than Ligand A (17.813), indicating lower metabolic stability. This is a significant drawback for Ligand B.

**In vitro Half-Life:** Ligand A (7.782) has a longer in vitro half-life than Ligand B (3.728), which is desirable.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.136 and 0.373).

**Binding Affinity:** Ligand B (-8.7 kcal/mol) has a significantly stronger binding affinity than Ligand A (-7.8 kcal/mol). This >1.5 kcal/mol difference is a major advantage.

**Overall Assessment:**

Ligand B has a superior binding affinity and better BBB penetration, both critical for a CNS-targeting GPCR. However, it suffers from higher microsomal clearance and lower in vitro half-life. Ligand A has better metabolic stability and half-life, but weaker affinity and lower BBB penetration. The affinity difference is substantial enough to outweigh the metabolic concerns, especially considering optimization could potentially improve the metabolic profile of Ligand B. The solubility is a concern for both, but can be addressed with formulation strategies.

Output:
1
2025-04-17 07:52:21,490 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (378.889 Da) is slightly higher than Ligand B (344.371 Da), but both are acceptable.

**TPSA:** Ligand A (83.04) is excellent for CNS penetration, falling well below the 90 A^2 threshold. Ligand B (111.63) is still reasonable, but less optimal.

**logP:** Ligand A (3.037) is within the optimal range (1-3). Ligand B (0.099) is quite low, potentially hindering membrane permeability and CNS entry.

**H-Bond Donors/Acceptors:** Ligand A (HBD=2, HBA=6) and Ligand B (HBD=3, HBA=5) both have acceptable numbers of hydrogen bond donors and acceptors.

**QED:** Both ligands have reasonable QED values (A: 0.795, B: 0.673), suggesting good drug-like properties.

**DILI:** Ligand A (77.782) has a higher DILI risk than Ligand B (51.609). While both are below the concerning 60 threshold, B is preferable.

**BBB:** Ligand A (75.107) has a significantly better BBB percentile than Ligand B (58.085). This is a crucial factor for a CNS target like DRD2.

**Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and suggests poor permeability. However, these values are on a log scale and need to be interpreted carefully.

**Aqueous Solubility:** Both ligands have negative solubility values, indicating poor aqueous solubility. This could pose formulation challenges.

**hERG Inhibition:** Ligand A (0.345) shows very low hERG inhibition risk, which is excellent. Ligand B (0.096) also has low risk, but slightly higher than A.

**Microsomal Clearance:** Ligand A (39.535) has a moderate clearance, while Ligand B (-16.468) has a negative clearance, which is not physically meaningful and likely indicates a very stable compound.

**In vitro Half-Life:** Ligand A (31.052) has a reasonable half-life. Ligand B (-21.769) has a negative half-life, which is also not physically meaningful.

**P-gp Efflux:** Ligand A (0.153) has low P-gp efflux, which is favorable for CNS penetration. Ligand B (0.002) has even lower efflux, which is excellent.

**Binding Affinity:** Ligand A (-7.6 kcal/mol) has a significantly stronger binding affinity than Ligand B (-9.0 kcal/mol). This is a major advantage.

**Overall Assessment:**

Ligand A excels in crucial areas for a CNS GPCR target: TPSA, BBB, hERG, and, most importantly, binding affinity. While its DILI risk is slightly higher and solubility is poor, the strong binding affinity and good BBB penetration outweigh these concerns. Ligand B has better DILI and P-gp efflux, but suffers from a very low logP, poor BBB penetration, and a significantly weaker binding affinity. The negative values for clearance and half-life are also concerning and likely indicate issues with the data or model.

Output:
1
2025-04-17 07:52:21,490 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B based on the provided guidelines, prioritizing GPCR-specific properties (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (344.386 and 345.447 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (62.55) is excellent, well below the 90 A^2 threshold for CNS targets. Ligand B (78.43) is still reasonable but less optimal.

**logP:** Ligand A (3.358) is within the optimal 1-3 range. Ligand B (0.795) is below 1, which could hinder permeation.

**H-Bond Donors/Acceptors:** Both ligands have acceptable HBD (1) and HBA (A: 3, B: 5) counts, well within the guidelines.

**QED:** Both ligands have good QED scores (A: 0.925, B: 0.825), indicating drug-like properties.

**DILI:** Ligand A (55.952) has a moderate DILI risk, while Ligand B (23.187) shows a very low risk.

**BBB:** Ligand A (89.531) has a very good BBB penetration percentile, exceeding the desirable >70 threshold. Ligand B (64.056) is lower, which is a significant drawback for a CNS target.

**Caco-2 Permeability:** Ligand A (-4.797) and Ligand B (-5.276) both have negative Caco-2 values, which is unusual and suggests poor permeability. However, the scale is not defined, so it's difficult to interpret.

**Aqueous Solubility:** Both ligands have poor aqueous solubility (-4.001 and -1.079 respectively).

**hERG:** Ligand A (0.666) has a slightly higher hERG risk than Ligand B (0.058), but both are relatively low.

**Microsomal Clearance:** Ligand A (9.261) has lower clearance than Ligand B (12.823), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (58.718) has a significantly longer half-life than Ligand B (0.935).

**P-gp Efflux:** Ligand A (0.166) has lower P-gp efflux liability than Ligand B (0.009), which is favorable for CNS penetration.

**Binding Affinity:** Ligand A (-10.2 kcal/mol) has a substantially stronger binding affinity than Ligand B (-8.6 kcal/mol). This difference of 1.6 kcal/mol is significant and can outweigh some ADME drawbacks.

**Overall Assessment:**

Ligand A is the stronger candidate. While both have solubility issues, Ligand A excels in the critical GPCR-relevant properties: significantly better BBB penetration, lower P-gp efflux, better metabolic stability (lower Cl_mic, longer t1/2), and, most importantly, a much higher binding affinity. The slightly higher DILI risk for Ligand A is less concerning given the strong affinity and CNS penetration. Ligand B's low logP and poor BBB penetration are major liabilities for a CNS-targeting drug.



Output:
1
2025-04-17 07:52:21,490 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (358.429 and 350.459 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (69.64) is significantly better than Ligand B (78.87). For CNS targets, TPSA should be <= 90, both are within this range, but A is closer to the optimal value.

**3. logP:** Ligand A (2.078) is optimal (1-3), while Ligand B (0.951) is slightly low, potentially hindering permeation.

**4. H-Bond Donors:** Both have 2 HBD, which is within the acceptable limit of <= 5.

**5. H-Bond Acceptors:** Ligand A has 3 HBA, and Ligand B has 4. Both are within the acceptable limit of <= 10.

**6. QED:** Both ligands have similar QED values (0.764 and 0.699), indicating good drug-likeness.

**7. DILI:** Ligand A (21.055) has a much lower DILI risk than Ligand B (9.965), indicating a safer profile.

**8. BBB:** This is crucial for a CNS target. Ligand A (89.802) has a very good BBB penetration percentile, while Ligand B (46.336) is significantly lower and less desirable.

**9. Caco-2 Permeability:** Both have negative Caco-2 values (-4.747 and -4.771), which is unusual and suggests poor permeability. This is a concern for both.

**10. Aqueous Solubility:** Both have negative solubility values (-3.337 and -1.279), also unusual and indicating poor solubility. This is a concern for both.

**11. hERG Inhibition:** Both ligands have low hERG inhibition risk (0.662 and 0.147).

**12. Microsomal Clearance:** Ligand A (10.989) has lower microsomal clearance than Ligand B (15.408), suggesting better metabolic stability.

**13. In vitro Half-Life:** Both have similar in vitro half-lives (2.428 and 2.179 hours).

**14. P-gp Efflux:** Both have very low P-gp efflux liability (0.064 and 0.049), which is favorable for CNS penetration.

**15. Binding Affinity:** Both ligands have excellent binding affinity (-8.0 and -8.1 kcal/mol), with Ligand B being slightly better. However, the difference is small and likely not enough to overcome the other deficiencies of Ligand B.

**Overall Assessment:**

Ligand A is significantly better due to its superior BBB penetration, lower DILI risk, and better logP value. While both have issues with Caco-2 permeability and solubility, the BBB penetration is a critical factor for a CNS-targeting drug, and Ligand A excels in this area. The slightly better affinity of Ligand B is outweighed by its poorer ADME properties.

Output:
1
2025-04-17 07:52:21,490 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (433.322 Da) is slightly higher, but still acceptable. Ligand B (353.419 Da) is also good.

**TPSA:** Ligand A (50.28) is better than Ligand B (90.39). For CNS targets, we want TPSA <= 90, so Ligand A is preferable. Ligand B is borderline.

**logP:** Ligand A (4.323) is a bit high, potentially leading to solubility issues or off-target interactions. Ligand B (-0.794) is too low, which could hinder membrane permeability.

**H-Bond Donors/Acceptors:** Both ligands have 1 HBD and a reasonable number of HBAs (6 and 5 respectively). This is acceptable for both.

**QED:** Both ligands have similar QED values (0.736 and 0.699), indicating good drug-like properties.

**DILI:** Ligand A (58.434) has a higher DILI risk than Ligand B (27.336). This favors Ligand B.

**BBB:** Ligand A (83.676) has a significantly better BBB penetration percentile than Ligand B (28.344). This is a crucial advantage for a CNS target like DRD2.

**Caco-2 Permeability:** Ligand A (-4.92) has poor Caco-2 permeability, while Ligand B (-5.041) is also poor. Both are unfavorable.

**Aqueous Solubility:** Ligand A (-3.901) has poor aqueous solubility, while Ligand B (-0.482) is also poor. Both are unfavorable.

**hERG Inhibition:** Ligand A (0.866) has a slightly higher hERG inhibition risk than Ligand B (0.093). This favors Ligand B.

**Microsomal Clearance:** Ligand A (12.752) has a higher microsomal clearance than Ligand B (3.671), meaning it's less metabolically stable. This favors Ligand B.

**In vitro Half-Life:** Ligand B (26.044) has a much longer in vitro half-life than Ligand A (2.073). This is a significant advantage for Ligand B.

**P-gp Efflux:** Ligand A (0.42) has lower P-gp efflux liability than Ligand B (0.013). This is favorable for Ligand A, as it suggests better CNS exposure.

**Binding Affinity:** Ligand B (-7.4 kcal/mol) has a slightly better binding affinity than Ligand A (-8.2 kcal/mol). While both are excellent, the difference is small.

**Overall Assessment:**

Ligand A excels in BBB penetration and P-gp efflux, which are critical for CNS targets. However, it suffers from high logP, poor solubility, and higher DILI risk. Ligand B has better ADME properties overall (lower DILI, better metabolic stability, longer half-life, lower hERG risk), but its BBB penetration is very poor.

Given the importance of CNS penetration for a DRD2 ligand, and the relatively small difference in binding affinity, the better BBB score of Ligand A is a significant advantage. While its other properties are less ideal, medicinal chemistry optimization could address these issues more readily than improving the BBB penetration of Ligand B.

Output:
0
2025-04-17 07:52:21,491 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (350.419 and 364.431 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (121.69) is slightly above the optimal <90 for CNS targets, but still reasonable. Ligand B (104.45) is better, falling comfortably below 90.

**3. logP:** Ligand A (0.776) is a bit low, potentially hindering permeation. Ligand B (-0.207) is even lower and more concerning for permeability. Both are below the optimal 1-3 range.

**4. H-Bond Donors:** Ligand A (3) is within the acceptable limit of <=5. Ligand B (1) is also good.

**5. H-Bond Acceptors:** Ligand A (6) is within the acceptable limit of <=10. Ligand B (8) is also acceptable.

**6. QED:** Both ligands have good QED scores (0.668 and 0.787), indicating drug-like properties.

**7. DILI:** Ligand A (37.03) has a lower DILI risk than Ligand B (47.421), both are acceptable.

**8. BBB:** This is crucial for a CNS target. Ligand A (67.197) is moderately good, but Ligand B (32.92) is quite low, suggesting poor brain penetration.

**9. Caco-2 Permeability:** Both have negative values, which is unusual and suggests poor permeability.

**10. Aqueous Solubility:** Both have negative values, which is also unusual and suggests poor solubility.

**11. hERG Inhibition:** Both ligands show low hERG inhibition liability (0.366 and 0.103), which is favorable.

**12. Microsomal Clearance:** Ligand A (0.143) has significantly lower clearance than Ligand B (9.46), indicating better metabolic stability.

**13. In vitro Half-Life:** Ligand A (-23.437) has a very long half-life, which is excellent. Ligand B (20.927) is reasonable.

**14. P-gp Efflux:** Both ligands have low P-gp efflux liability (0.01 and 0.152), which is good for CNS exposure.

**15. Binding Affinity:** Ligand B (-7.8) has a stronger binding affinity than Ligand A (-8.0). However, the difference is small and may not be enough to overcome other issues.

**Overall Assessment:**

Ligand A is the better candidate. While its logP is slightly low, its significantly better BBB penetration, much lower microsomal clearance, and longer half-life outweigh the slightly weaker binding affinity compared to Ligand B. Ligand B's poor BBB penetration is a major drawback for a CNS-targeting drug. The negative values for Caco-2 and solubility are concerning for both, but can be addressed with formulation strategies.

Output:
0
2025-04-17 07:52:21,491 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (399.822 and 380.79 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (78.51) is higher than Ligand B (55.76). For CNS targets, TPSA should be <=90, so both are acceptable, but B is better.

**logP:** Ligand A (2.213) and Ligand B (3.992) are both within the optimal 1-3 range, but B is closer to the upper limit.

**H-Bond Donors:** Ligand A (2) and Ligand B (1) are both acceptable (<=5).

**H-Bond Acceptors:** Both ligands (A: 4, B: 4) are within the acceptable range (<=10).

**QED:** Both ligands have similar QED values (A: 0.795, B: 0.758), indicating good drug-likeness.

**DILI:** Ligand A (61.264) has a higher DILI risk than Ligand B (32.261). B is preferable here.

**BBB:** This is a critical parameter for CNS targets. Ligand B (75.649) has a significantly better BBB penetration percentile than Ligand A (44.862). This is a major advantage for B.

**Caco-2 Permeability:** Ligand A (-5.155) and Ligand B (-4.39) both have negative values, which is unusual and suggests poor permeability. However, the scale isn't specified, so it's hard to interpret.

**Aqueous Solubility:** Both ligands have very poor aqueous solubility (-3.711 and -4.842 respectively). This is a concern for both.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (A: 0.471, B: 0.651).

**Microsomal Clearance:** Ligand B (43.868) has a substantially higher microsomal clearance than Ligand A (3.278), indicating faster metabolism and lower metabolic stability. A is preferable here.

**In vitro Half-Life:** Ligand A (-9.67) has a significantly longer in vitro half-life than Ligand B (10.35). A is preferable here.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (A: 0.026, B: 0.275).

**Binding Affinity:** Both ligands have excellent binding affinity (A: -8.8 kcal/mol, B: -9.1 kcal/mol). B is slightly better.

**Overall Assessment:**

Ligand B excels in BBB penetration, a crucial factor for a CNS target like DRD2. It also has a lower DILI risk. Ligand A has better metabolic stability (lower Cl_mic) and a longer half-life, but the superior BBB penetration of Ligand B outweighs these advantages. The slightly better binding affinity of B is also a positive. While both have poor solubility, this is a formulation challenge that can be addressed.

Output:
1
2025-04-17 07:52:21,491 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (363.483 and 356.438 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (92.5) is slightly above the optimal <90 for CNS targets, but acceptable. Ligand B (67.87) is well within the desired range.

**logP:** Both ligands have good logP values (1.157 and 1.451), falling within the 1-3 range.

**H-Bond Donors:** Ligand A (2) and Ligand B (1) are both within the acceptable limit of <=5.

**H-Bond Acceptors:** Both ligands have 4 H-bond acceptors, well below the limit of 10.

**QED:** Ligand A (0.679) has a better QED score than Ligand B (0.502), indicating better overall drug-likeness.

**DILI:** Both ligands have relatively low DILI risk (18.922 and 20.279), both below the 40 threshold.

**BBB:** Ligand B (77.2) has a significantly better BBB penetration score than Ligand A (68.941). This is a crucial factor for CNS targets like DRD2.

**Caco-2 Permeability:** Ligand A (-5.725) has slightly better Caco-2 permeability than Ligand B (-4.719), suggesting better intestinal absorption. However, for a CNS target, intestinal absorption is less critical than BBB penetration.

**Aqueous Solubility:** Both ligands have poor aqueous solubility (-1.507 and -1.809). This could pose formulation challenges, but is not a dealbreaker.

**hERG Inhibition:** Both ligands show low hERG inhibition risk (0.269 and 0.381).

**Microsomal Clearance:** Ligand A (3.719) has a much lower microsomal clearance than Ligand B (13.557), indicating better metabolic stability.

**In vitro Half-Life:** Ligand A (-19.85) has a significantly longer in vitro half-life than Ligand B (9.259).

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.08 and 0.076).

**Binding Affinity:** Ligand A (-7.8) has a slightly better binding affinity than Ligand B (-7.0). While both are good, the 0.8 kcal/mol difference is noteworthy.

**Overall Assessment:**

Ligand A has a better binding affinity, QED, metabolic stability, and half-life. However, Ligand B excels in BBB penetration, which is paramount for a DRD2 ligand targeting CNS disorders. The difference in binding affinity is not large enough to overcome the substantial advantage of Ligand B's BBB score. While the solubility is poor for both, this can be addressed with formulation strategies.

Output:
1
2025-04-17 07:52:21,491 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (368.415 and 362.463 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (116.88) is slightly above the optimal <90 for CNS targets, but still reasonable. Ligand B (95.57) is better, falling comfortably under 90.

**3. logP:** Ligand A (1.029) is at the lower end of the optimal 1-3 range, potentially impacting permeability. Ligand B (2.218) is well within the optimal range.

**4. H-Bond Donors:** Both have 1 HBD, which is acceptable.

**5. H-Bond Acceptors:** Ligand A has 7 HBA, acceptable. Ligand B has 10 HBA, approaching the upper limit but still potentially tolerable.

**6. QED:** Both ligands have good QED scores (0.627 and 0.688, respectively), indicating drug-like properties.

**7. DILI:** Ligand A (55.293) has a lower DILI risk than Ligand B (70.803), which is a positive.

**8. BBB:** Ligand A (65.025) has a better BBB percentile than Ligand B (35.75). This is *critical* for a CNS target like DRD2.

**9. Caco-2 Permeability:** Ligand A (-4.848) has a significantly worse Caco-2 permeability than Ligand B (-5.169).

**10. Aqueous Solubility:** Both have poor aqueous solubility (-2.406 and -2.714). This could pose formulation challenges.

**11. hERG Inhibition:** Both have very low hERG inhibition risk (0.076 and 0.234).

**12. Microsomal Clearance:** Ligand A (7.569) has lower microsomal clearance than Ligand B (58.643), suggesting better metabolic stability.

**13. In vitro Half-Life:** Ligand A (2.578) has a shorter half-life than Ligand B (-12.334), which is less desirable.

**14. P-gp Efflux:** Ligand A (0.022) has significantly lower P-gp efflux than Ligand B (0.174), which is beneficial for CNS penetration.

**15. Binding Affinity:** Ligand A (-7.1) has a slightly stronger binding affinity than Ligand B (-5.9). This is a significant advantage.

**Overall Assessment:**

While Ligand B has a better logP and slightly better QED, Ligand A is superior due to its significantly better BBB penetration (65.025 vs 35.75), lower P-gp efflux (0.022 vs 0.174), lower DILI risk, and slightly stronger binding affinity (-7.1 vs -5.9). The slightly lower Caco-2 and shorter half-life of Ligand A are less concerning given the importance of CNS penetration for a DRD2 ligand. The TPSA of Ligand A is a little higher, but still within a reasonable range.



Output:
0
2025-04-17 07:52:21,491 - INFO - Batch 401 complete. Total preferences: 6416
2025-04-17 07:52:21,491 - INFO - Processing batch 402/512...
2025-04-17 07:53:02,433 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the acceptable range (200-500 Da). Ligand A (369.443 Da) is slightly higher than Ligand B (346.471 Da), but this isn't a major concern.

**TPSA:** Ligand A (97.83) is higher than the ideal <90 for CNS targets, while Ligand B (69.64) is well within the desired range. This is a significant advantage for Ligand B.

**logP:** Ligand A (0.369) is quite low, potentially hindering membrane permeability. Ligand B (1.86) is much better, falling within the optimal 1-3 range. This favors Ligand B.

**H-Bond Donors/Acceptors:** Ligand A has 1 HBD and 7 HBA, while Ligand B has 2 HBD and 3 HBA. Both are within acceptable limits.

**QED:** Both ligands have good QED scores (A: 0.665, B: 0.747), indicating good drug-like properties.

**DILI:** Ligand A (72.082) has a higher DILI risk than Ligand B (16.906). This is a significant advantage for Ligand B.

**BBB:** Ligand A (23.187) has very poor predicted BBB penetration, a critical issue for a CNS target like DRD2. Ligand B (55.603) is better, but still not ideal (aim for >70). However, the large difference here strongly favors Ligand B.

**Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and suggests a potential issue with the prediction method or the compounds themselves. However, Ligand B (-4.624) is less negative than Ligand A (-5.061).

**Aqueous Solubility:** Both have negative solubility values, again suggesting a potential issue with the prediction method. Ligand B (-2.592) is slightly better than Ligand A (-1.232).

**hERG Inhibition:** Both ligands have very low hERG inhibition risk (A: 0.024, B: 0.246).

**Microsomal Clearance:** Ligand A (9.186) has lower clearance than Ligand B (11.367), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (4.911) has a positive half-life, while Ligand B (-19.289) has a negative half-life. This is a major concern for Ligand B.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (A: 0.021, B: 0.103).

**Binding Affinity:** Ligand B (-8.2 kcal/mol) has a significantly stronger binding affinity than Ligand A (-6.6 kcal/mol). This >1.5 kcal/mol difference is substantial and can outweigh some ADME drawbacks.

**Overall Assessment:**

Despite the negative half-life prediction for Ligand B, the combination of superior BBB penetration, lower DILI risk, better logP, lower TPSA, and *significantly* stronger binding affinity makes Ligand B the more promising candidate. The poor BBB penetration of Ligand A is a deal-breaker for a CNS target. The negative half-life for Ligand B is concerning, but could be addressed through structural modifications.



Output:
1
2025-04-17 07:53:02,433 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (365.86 & 370.48 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (55.84) is excellent, well below the 90 A^2 threshold for CNS targets. Ligand B (95.75) is higher, but still potentially acceptable, though less ideal.

**3. logP:** Ligand A (3.69) is optimal. Ligand B (0.594) is quite low, which could hinder membrane permeability and CNS penetration.

**4. H-Bond Donors:** Both ligands have acceptable HBD counts (0 for A, 1 for B), well below the 5 threshold.

**5. H-Bond Acceptors:** Ligand A (4) and Ligand B (6) are both within the acceptable limit of 10.

**6. QED:** Both ligands have good QED scores (0.75 and 0.815), indicating drug-like properties.

**7. DILI:** Ligand A (60.45) is approaching a concerning DILI risk, while Ligand B (44.591) has a much lower, more favorable risk profile.

**8. BBB:** Ligand A (69.41) has a good BBB percentile, exceeding the 70% threshold for CNS targets. Ligand B (54.052) is significantly lower, raising concerns about CNS exposure.

**9. Caco-2:** Both have negative Caco-2 values, which is unusual and suggests poor permeability. However, the scale is not specified, so it's difficult to interpret.

**10. Solubility:** Both ligands have negative solubility values, which is also unusual. Again, the scale is not specified, making interpretation difficult.

**11. hERG:** Both ligands have very low hERG inhibition liability (0.278 and 0.145), which is excellent.

**12. Cl_mic:** Ligand A (77.754) has a higher microsomal clearance, suggesting lower metabolic stability. Ligand B (21.692) has much lower clearance, indicating better metabolic stability.

**13. t1/2:** Ligand A (-5.161) has a negative in vitro half-life, which is impossible and indicates a data error. Ligand B (-1.216) also has a negative half-life, also indicating a data error.

**14. Pgp:** Both ligands have very low P-gp efflux liability (0.151 and 0.105), which is favorable for CNS penetration.

**15. Binding Affinity:** Ligand A (-7.8 kcal/mol) has a significantly stronger binding affinity than Ligand B (0.0 kcal/mol). This is a substantial advantage.

**Overall Assessment:**

Despite the questionable solubility and Caco-2 values, the key factors for a CNS-targeting GPCR like DRD2 are BBB penetration, logP, and binding affinity. Ligand A excels in these areas (good BBB, optimal logP, and *much* stronger affinity). Ligand B has a poor logP and lower BBB penetration. While Ligand B has a better DILI score and metabolic stability, the affinity difference is so large that it likely outweighs these benefits. The negative half-life values for both compounds are concerning and suggest data quality issues, but the affinity difference is still the dominant factor.

Output:
1
2025-04-17 07:53:02,433 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (346.471 and 343.391 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (58.64) is excellent, well below the 90 A^2 threshold for CNS targets. Ligand B (119.66) is higher, but still potentially acceptable, though less ideal.

**logP:** Ligand A (2.126) is within the optimal 1-3 range. Ligand B (0.516) is a bit low, potentially hindering membrane permeability.

**H-Bond Donors/Acceptors:** Ligand A (HBD=1, HBA=3) is favorable. Ligand B (HBD=3, HBA=5) is also acceptable, but slightly higher.

**QED:** Both ligands have good QED scores (A: 0.592, B: 0.66), indicating drug-like properties.

**DILI:** Ligand A (19.426) has a much lower DILI risk than Ligand B (56.689), which is a significant advantage.

**BBB:** Ligand A (73.633) has a good BBB percentile, exceeding the desirable >70 threshold for CNS targets. Ligand B (35.828) is considerably lower, raising concerns about CNS penetration.

**Caco-2 Permeability:** Ligand A (-4.423) has poor Caco-2 permeability. Ligand B (-5.723) is even worse.

**Aqueous Solubility:** Ligand A (-2.655) has poor aqueous solubility. Ligand B (-1.832) is slightly better, but still not ideal.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (A: 0.37, B: 0.44).

**Microsomal Clearance:** Ligand A (63.631) has higher microsomal clearance, suggesting faster metabolism. Ligand B (-10.632) has negative clearance, which is not possible and likely an error in the data, but suggests very high metabolic stability.

**In vitro Half-Life:** Ligand A (-14.953) has a negative half-life, which is not possible and likely an error in the data. Ligand B (-20.701) also has a negative half-life.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (A: 0.12, B: 0.068), which is good for CNS penetration.

**Binding Affinity:** Ligand B (-8.2 kcal/mol) has a slightly better binding affinity than Ligand A (-7.1 kcal/mol), a difference of 1.1 kcal/mol.

**Overall Assessment:**

Despite the slightly better affinity of Ligand B, Ligand A is the more promising candidate. The critical factors are the significantly better BBB penetration (73.633 vs 35.828) and lower DILI risk (19.426 vs 56.689) for Ligand A. While both have poor Caco-2 permeability and solubility, these can be addressed through formulation strategies. The negative values for half-life and clearance are concerning for both and likely data errors. The affinity difference, while present, is unlikely to outweigh the substantial advantages of Ligand A in terms of CNS penetration and safety.

Output:
1
2025-04-17 07:53:02,434 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (429.38 Da) is higher, but still acceptable. Ligand B (351.407 Da) is slightly better.

**TPSA:** Ligand A (66.48) is excellent, well below the 90 A^2 threshold for CNS targets. Ligand B (118.37) is higher, but still reasonably good, though less ideal for CNS penetration.

**logP:** Ligand A (3.161) is within the optimal range (1-3). Ligand B (-0.534) is significantly lower, which could hinder membrane permeability and CNS penetration. This is a major drawback for Ligand B.

**H-Bond Donors/Acceptors:** Ligand A (1 HBD, 3 HBA) is favorable. Ligand B (3 HBD, 8 HBA) is slightly higher, but still within acceptable limits.

**QED:** Both ligands have reasonable QED values (A: 0.756, B: 0.589), indicating good drug-like properties.

**DILI:** Both ligands have similar DILI risk (A: 42.148, B: 43.311), both being acceptable.

**BBB:** Ligand A (91.702) has excellent BBB penetration potential, exceeding the desirable threshold of 70. Ligand B (53.432) is significantly lower, raising concerns about CNS exposure.

**Caco-2 Permeability:** Ligand A (-4.795) is concerningly low. Ligand B (-5.311) is also low, but slightly better.

**Aqueous Solubility:** Ligand A (-4.115) and Ligand B (-0.837) both have negative solubility values, which is not ideal.

**hERG Inhibition:** Ligand A (0.706) and Ligand B (0.124) both show low hERG inhibition risk, which is good.

**Microsomal Clearance:** Ligand A (33.498) has a moderate clearance. Ligand B (-11.806) has a negative clearance, which is unusual and potentially indicates very high metabolic stability.

**In vitro Half-Life:** Ligand A (6.379) has a reasonable half-life. Ligand B (8.525) has a slightly longer half-life, which is favorable.

**P-gp Efflux:** Ligand A (0.547) has moderate P-gp efflux liability. Ligand B (0.008) has very low P-gp efflux, which is a significant advantage for CNS penetration.

**Binding Affinity:** Both ligands have very good binding affinity (A: -8.7 kcal/mol, B: -8.0 kcal/mol). Ligand A is slightly better, but the difference is not huge.

**Overall Assessment:**

Ligand A excels in BBB penetration, TPSA, and binding affinity. However, its Caco-2 permeability is a concern. Ligand B has better metabolic stability (indicated by negative Cl_mic) and lower P-gp efflux, but suffers from a poor logP and lower BBB penetration. Given the GPCR-specific priorities, especially for a CNS target like DRD2, **BBB penetration and logP are critical**. Ligand A's superior BBB and acceptable logP outweigh its lower Caco-2 permeability, especially considering the strong binding affinity. The negative Caco-2 value could potentially be addressed through formulation strategies.

Output:
1
2025-04-17 07:53:02,434 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (338.411 and 346.435 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (75.19) is significantly better than Ligand B (104.7). For CNS targets, we want TPSA <= 90, and A is comfortably within that range, while B is pushing the limit.

**logP:** Both ligands have good logP values (1.087 and 0.888), falling within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A (HBD=1, HBA=4) is preferable to Ligand B (HBD=3, HBA=5) as lower values generally improve permeability. Both are within acceptable limits.

**QED:** Ligand A (0.755) has a higher QED score than Ligand B (0.594), indicating better overall drug-likeness.

**DILI:** Both ligands have low DILI risk (41.411 and 38.193), both below the 40 threshold, which is excellent.

**BBB:** Ligand A (63.009) has a moderately good BBB penetration, but Ligand B (32.493) is significantly lower. For a CNS target like DRD2, a BBB percentile >70 is desirable, but A is better than B.

**Caco-2 Permeability:** Ligand A (-4.594) has a worse Caco-2 permeability than Ligand B (-5.775). However, Caco-2 values are often difficult to interpret and less reliable than other parameters.

**Aqueous Solubility:** Ligand A (-2.478) has a slightly better solubility than Ligand B (-1.583).

**hERG Inhibition:** Ligand A (0.12) has a much lower hERG risk than Ligand B (0.547), which is a significant advantage.

**Microsomal Clearance:** Both ligands have similar microsomal clearance values (16.002 and 15.189), indicating comparable metabolic stability.

**In vitro Half-Life:** Ligand A (-8.216) has a much longer in vitro half-life than Ligand B (2.131), which is a major advantage.

**P-gp Efflux:** Ligand A (0.021) exhibits much lower P-gp efflux than Ligand B (0.01), indicating better potential for CNS exposure.

**Binding Affinity:** Ligand B (-7.4 kcal/mol) has a slightly better binding affinity than Ligand A (-8.2 kcal/mol). While affinity is crucial, the difference of 0.8 kcal/mol is not substantial enough to outweigh the significant advantages of Ligand A in other critical ADME properties, particularly for a CNS target.

**Overall:** Considering the GPCR-specific priorities, Ligand A is the more promising candidate. It has a better TPSA, QED, BBB, hERG risk, in vitro half-life, and P-gp efflux. While Ligand B has slightly better affinity, the other advantages of Ligand A, especially its superior BBB penetration and lower efflux, make it more likely to reach the target in the CNS and exhibit better overall drug-like properties.

Output:
0
2025-04-17 07:53:02,434 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B based on the provided guidelines, prioritizing GPCR-specific properties (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (368.459 Da) is slightly higher than Ligand B (346.515 Da), but both are acceptable.

**TPSA:** Ligand A (107.69) is higher than Ligand B (49.41). For CNS targets, TPSA should be <=90. Ligand A is above this threshold, while Ligand B is well within. This is a significant advantage for Ligand B.

**logP:** Ligand A (-0.537) is quite low, potentially hindering membrane permeability. Ligand B (3.832) is excellent, falling within the optimal 1-3 range. This is a major advantage for Ligand B.

**H-Bond Donors/Acceptors:** Ligand A has 3 HBD and 7 HBA, acceptable values. Ligand B has 1 HBD and 2 HBA, also acceptable and potentially better for permeability due to fewer hydrogen bonds.

**QED:** Both ligands have similar QED values (0.659 and 0.621), indicating good drug-likeness.

**DILI:** Ligand A (47.77) has a slightly higher DILI risk than Ligand B (25.436), but both are below the concerning threshold of 60.

**BBB:** Ligand B (77.472) has a significantly better BBB percentile than Ligand A (10.392). This is *critical* for a CNS target like DRD2.

**Caco-2 Permeability:** Ligand A (-5.54) has poor Caco-2 permeability, while Ligand B (-4.702) is slightly better, though still not great.

**Aqueous Solubility:** Both ligands have very poor aqueous solubility (-1.744 and -3.932). This could pose formulation challenges, but is less critical than BBB and permeability for CNS drugs.

**hERG Inhibition:** Ligand A (0.168) has a slightly lower hERG risk than Ligand B (0.472), which is preferable.

**Microsomal Clearance:** Ligand A (-2.062) has a lower (better) microsomal clearance than Ligand B (54.541), indicating greater metabolic stability.

**In vitro Half-Life:** Ligand A (3.814) has a shorter half-life than Ligand B (-19.911). The negative value for ligand B is concerning and likely an error, but even if it were a very high positive value, the other issues with ligand B would likely outweigh this benefit.

**P-gp Efflux:** Ligand A (0.031) has a much lower P-gp efflux liability than Ligand B (0.198), which is beneficial for CNS penetration.

**Binding Affinity:** Ligand B (-9.2 kcal/mol) has a significantly stronger binding affinity than Ligand A (-7.4 kcal/mol). This is a substantial advantage, potentially outweighing some of the ADME drawbacks.

**Overall Assessment:**

Ligand B has a much better profile for a CNS-targeting drug. Its superior BBB penetration, logP, and binding affinity are crucial. While its solubility and Caco-2 permeability are poor, these can potentially be addressed with formulation strategies. Ligand A's low logP and poor BBB penetration are major drawbacks that are harder to overcome. The better metabolic stability of ligand A is a plus, but the affinity difference and BBB penetration of ligand B are more important for this target.

Output:
1
2025-04-17 07:53:02,434 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (370.515 and 349.431 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (67.87) is better than Ligand B (72.8). Both are below the 90 A^2 threshold for CNS targets, but A is closer to the optimal range.

**3. logP:** Both ligands have good logP values (1.288 and 0.799), falling within the 1-3 range.

**4. H-Bond Donors:** Both have 1 HBD, which is acceptable.

**5. H-Bond Acceptors:** Both have 5 HBA, which is acceptable.

**6. QED:** Both ligands have good QED scores (0.714 and 0.79), indicating good drug-likeness.

**7. DILI:** Both ligands have low DILI risk (30.438 and 39.899 percentile), which is favorable.

**8. BBB:** Ligand B (76.464%) has a significantly better BBB penetration score than Ligand A (67.623%). This is a crucial factor for a CNS target like DRD2.

**9. Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and suggests poor permeability. However, the scale is not specified, and negative values might represent a different measurement unit.

**10. Aqueous Solubility:** Both have negative solubility values, again unusual and requires clarification of the scale.

**11. hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.419 and 0.265), which is excellent.

**12. Microsomal Clearance:** Ligand B (32.061) has lower microsomal clearance than Ligand A (40.279), indicating better metabolic stability.

**13. In vitro Half-Life:** Both have similar in vitro half-lives (6.855 and 7.134 hours).

**14. P-gp Efflux:** Ligand B (0.075) has lower P-gp efflux liability than Ligand A (0.065), which is beneficial for CNS penetration.

**15. Binding Affinity:** Ligand A (-6.5 kcal/mol) has a slightly better binding affinity than Ligand B (0.0 kcal/mol). This is a significant advantage.

**Overall Assessment:**

While Ligand A has a slightly better binding affinity, Ligand B excels in key properties for CNS drug development: significantly better BBB penetration, lower P-gp efflux, and lower microsomal clearance. The difference in binding affinity (-6.5 vs 0.0 kcal/mol) is substantial, but the improved ADME properties of Ligand B, particularly the BBB score, are critical for a DRD2 ligand. The unusual negative values for Caco-2 and solubility need further investigation, but the other factors strongly favor Ligand B.

Output:
1
2025-04-17 07:53:02,434 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (347.375 and 364.471 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Both ligands (92.84 and 92.26) are slightly above the optimal <90 for CNS targets, but still reasonable.

**3. logP:** Both ligands (1.986 and 1.254) are within the optimal 1-3 range. Ligand A is slightly better.

**4. H-Bond Donors:** Both have 1 HBD, which is good.

**5. H-Bond Acceptors:** Both have 6 HBA, also good.

**6. QED:** Both have good QED scores (0.916 and 0.82), indicating drug-like properties.

**7. DILI:** Ligand A (80.962) has a higher DILI risk than Ligand B (45.909). This is a significant drawback for Ligand A.

**8. BBB:** Ligand A (74.719) has a better BBB penetration score than Ligand B (62.35). This is crucial for a CNS target like DRD2.

**9. Caco-2:** Ligand A (-4.638) has a worse Caco-2 permeability than Ligand B (-5.279), suggesting lower intestinal absorption.

**10. Solubility:** Ligand A (-2.727) has worse aqueous solubility than Ligand B (-1.881).

**11. hERG:** Both ligands have very low hERG inhibition risk (0.323 and 0.041).

**12. Cl_mic:** Both ligands have similar microsomal clearance (23.806 and 24.871).

**13. t1/2:** Ligand B (-22.53) has a negative in vitro half-life, which is concerning. Ligand A has a positive half-life (18.058).

**14. Pgp:** Both ligands have very low P-gp efflux liability (0.055 and 0.063).

**15. Binding Affinity:** Both ligands have excellent binding affinity (-8.6 and -8.0 kcal/mol). Ligand A is slightly better.

**Overall Assessment:**

Ligand A has a slight edge in binding affinity and BBB penetration, which are important for a CNS GPCR target. However, it has significantly higher DILI risk and worse solubility and Caco-2 permeability. Ligand B has a better safety profile (lower DILI) and better predicted absorption (Caco-2, solubility), but its BBB penetration is lower and its in vitro half-life is negative, which is a major red flag.

Given the importance of safety and absorption for *in vivo* efficacy, and the fact that the affinity difference is relatively small, Ligand B is the more promising candidate despite the negative half-life. The negative half-life could potentially be addressed through structural modifications. The DILI risk associated with Ligand A is a more difficult property to improve.

Output:
1
2025-04-17 07:53:02,434 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (368.455 Da) is slightly higher than Ligand B (343.471 Da), but both are acceptable.

**TPSA:** Ligand A (96.69) is borderline for CNS penetration, being slightly above the preferred <90. Ligand B (53.51) is excellent, well below the threshold. This favors Ligand B.

**logP:** Ligand A (1.134) is within the optimal range. Ligand B (3.116) is also within the optimal range, but closer to the upper limit.

**H-Bond Donors/Acceptors:** Ligand A has 1 HBD and 5 HBA, which are acceptable. Ligand B has 0 HBD and 3 HBA, also acceptable.

**QED:** Both ligands have reasonable QED scores (A: 0.863, B: 0.789), indicating good drug-like properties.

**DILI:** Ligand A (63.862) has a higher DILI risk than Ligand B (47.732), though both are below the concerning 60 percentile. This favors Ligand B.

**BBB:** This is crucial for a CNS target. Ligand A (61.225) is below the desirable >70 threshold. Ligand B (71.384) exceeds this threshold, making it significantly more promising for CNS penetration.

**Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and requires further investigation. However, the magnitude of negativity is similar, so this doesn't strongly differentiate them.

**Aqueous Solubility:** Both ligands have negative solubility values, which is also unusual. Again, the magnitudes are similar.

**hERG:** Ligand A (0.153) has a slightly lower hERG risk than Ligand B (0.581), which is a small advantage.

**Microsomal Clearance:** Ligand A (5.786) has a significantly lower microsomal clearance than Ligand B (74.345), indicating better metabolic stability. This is a strong advantage for Ligand A.

**In vitro Half-Life:** Ligand A (43.558) has a longer half-life than Ligand B (-23.937), which is a significant advantage for dosing convenience.

**P-gp Efflux:** Ligand A (0.076) has much lower P-gp efflux liability than Ligand B (0.325), which is beneficial for CNS exposure.

**Binding Affinity:** Both ligands have very similar and strong binding affinities (-8.4 kcal/mol and -8.1 kcal/mol, respectively). The difference of 0.3 kcal/mol is unlikely to outweigh other significant ADME differences.

**Overall Assessment:**

Ligand B excels in BBB penetration and has a lower DILI risk. However, Ligand A demonstrates superior metabolic stability (lower Cl_mic, longer t1/2), lower P-gp efflux, and a slightly lower hERG risk. Given the importance of CNS penetration for a DRD2 ligand (a GPCR in the CNS), and the substantial advantage Ligand B has in BBB, it is the more promising candidate despite the slightly worse metabolic profile. The affinity is comparable, so the ADME properties become the deciding factor.

Output:
1
2025-04-17 07:53:02,434 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, considering the provided guidelines and GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (370.515 Da and 351.407 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (81.08) is excellent, well below the 90 A^2 threshold for CNS targets. Ligand B (125.35) is still reasonable, but approaching the upper limit for good CNS penetration.

**logP:** Ligand A (0.712) is a bit low, potentially hindering permeation. Ligand B (-0.916) is even lower, raising concerns about membrane permeability.

**H-Bond Donors/Acceptors:** Ligand A (HBD=2, HBA=5) is within acceptable limits. Ligand B (HBD=4, HBA=6) is also acceptable, but slightly higher.

**QED:** Ligand A (0.72) has a good drug-likeness score. Ligand B (0.451) is lower, indicating a less favorable drug-like profile.

**DILI:** Ligand B (39.201) has a slightly higher DILI risk than Ligand A (14.424), but both are below the concerning threshold of 60.

**BBB:** Ligand A (43.117) has a significantly better BBB penetration percentile than Ligand B (24.351). This is a crucial factor for a CNS target like DRD2.

**Caco-2 Permeability:** Both ligands show poor Caco-2 permeability (-5.085 and -5.187). This suggests potential absorption issues.

**Aqueous Solubility:** Both ligands have very poor aqueous solubility (-1.725 and -1.477).

**hERG:** Both ligands have very low hERG inhibition risk (0.299 and 0.075).

**Microsomal Clearance:** Ligand A (33.75) has a higher microsomal clearance than Ligand B (1.256), suggesting lower metabolic stability.

**In vitro Half-Life:** Ligand B (-8.349) has a significantly longer in vitro half-life than Ligand A (-4.576).

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.022 and 0.007).

**Binding Affinity:** Both ligands have excellent binding affinities (-7.3 and -7.6 kcal/mol), with Ligand B being slightly better. The affinity difference is small (0.3 kcal/mol) and likely less important than the ADME differences.

**Overall Assessment:**

Ligand A is superior due to its significantly better BBB penetration (43.117 vs 24.351) and better QED score (0.72 vs 0.451). While its logP is suboptimal, the improved CNS penetration is critical for a DRD2 ligand. Ligand B has a slightly better affinity and half-life, but the poor BBB score and lower QED are significant drawbacks. The poor solubility and Caco-2 permeability are concerning for both, but can be addressed with formulation strategies.

Output:
1
2025-04-17 07:53:02,434 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (370.877) is slightly higher than Ligand B (336.435), but both are acceptable.

**TPSA:** Ligand A (84.5) is better than Ligand B (49.41). For CNS targets, TPSA should be <=90, both meet this, but lower is preferred. Ligand B is significantly lower and thus better.

**logP:** Both ligands have good logP values (Ligand A: 1.542, Ligand B: 2.663), falling within the optimal 1-3 range. Ligand B is slightly more lipophilic, which could be beneficial for membrane permeability.

**H-Bond Donors/Acceptors:** Ligand A has 2 HBD and 4 HBA, while Ligand B has 1 HBD and 2 HBA. Both are within acceptable limits (<=5 HBD and <=10 HBA). Ligand B is slightly better due to fewer H-bonds.

**QED:** Both ligands have similar QED values (Ligand A: 0.603, Ligand B: 0.679), indicating good drug-like properties. Ligand B is slightly better.

**DILI:** Ligand A (29.43) has a lower DILI risk than Ligand B (42.264), which is a significant advantage.

**BBB:** Both ligands have acceptable BBB penetration (Ligand A: 60.644, Ligand B: 63.203), but ideally, we want >70 for CNS targets. Neither is ideal, but they are comparable.

**Caco-2 Permeability:** Ligand A (-5.083) has worse Caco-2 permeability than Ligand B (-4.603). Higher values are better, so Ligand B is better.

**Aqueous Solubility:** Ligand A (-2.335) has slightly better aqueous solubility than Ligand B (-4.153).

**hERG Inhibition:** Both ligands have very low hERG inhibition risk (Ligand A: 0.095, Ligand B: 0.223).

**Microsomal Clearance:** Ligand A (8.042) has significantly lower microsomal clearance than Ligand B (16.808), indicating better metabolic stability.

**In vitro Half-Life:** Both ligands have similar in vitro half-lives (Ligand A: 5.11, Ligand B: 5.396).

**P-gp Efflux:** Both ligands have low P-gp efflux (Ligand A: 0.095, Ligand B: 0.109).

**Binding Affinity:** Ligand B (-8.5) has a slightly better binding affinity than Ligand A (-8.0). While both are excellent, the 0.5 kcal/mol difference is notable.

**Overall Assessment:**

Ligand B has a better balance of properties for a CNS-targeting GPCR ligand. It has a lower TPSA, slightly better logP, better Caco-2 permeability, and a slightly stronger binding affinity. While Ligand A has a lower DILI risk and better solubility, the improvements in permeability and affinity for Ligand B outweigh these factors, especially considering the importance of BBB penetration for CNS drugs. The difference in binding affinity, while small, is also a factor.

Output:
1
2025-04-17 07:53:02,434 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (344.46 and 355.40 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (58.64) is excellent, well below the 90 A^2 threshold for CNS targets. Ligand B (125.71) is higher, but still potentially acceptable, though less optimal.

**logP:** Ligand A (3.785) is within the optimal 1-3 range. Ligand B (-2.463) is significantly outside the optimal range, being quite lipophobic. This is a major concern for CNS penetration.

**H-Bond Donors/Acceptors:** Ligand A (1 HBD, 3 HBA) is favorable. Ligand B (2 HBD, 9 HBA) is acceptable, but the higher HBA count could slightly hinder permeability.

**QED:** Both ligands have reasonable QED values (0.908 and 0.575), indicating good drug-like properties.

**DILI:** Ligand A (35.091) has a lower DILI risk than Ligand B (56.689), which is preferable.

**BBB:** This is critical for a CNS target. Ligand A (87.398) has a very good BBB percentile. Ligand B (32.028) has a poor BBB percentile, raising serious concerns about CNS exposure.

**Caco-2 Permeability:** Ligand A (-4.336) shows poor permeability, which is concerning. Ligand B (-5.265) is even worse.

**Aqueous Solubility:** Ligand A (-4.587) has poor solubility. Ligand B (0.111) is also poor.

**hERG:** Ligand A (0.519) has a low hERG risk. Ligand B (0.014) has a very low hERG risk.

**Microsomal Clearance:** Ligand A (81.756) has a high microsomal clearance, indicating rapid metabolism. Ligand B (-0.253) has very low clearance, suggesting good metabolic stability.

**In vitro Half-Life:** Ligand A (-8.947) has a very short half-life. Ligand B (9.06) has a long half-life, which is favorable.

**P-gp Efflux:** Ligand A (0.159) has low P-gp efflux, which is good. Ligand B (0.019) has very low P-gp efflux, which is excellent.

**Binding Affinity:** Ligand A (-8.7 kcal/mol) has a significantly stronger binding affinity than Ligand B (-6.2 kcal/mol). The 2.5 kcal/mol difference is substantial and can outweigh some ADME drawbacks.

**Overall Assessment:**

Despite Ligand A's poor Caco-2 permeability and solubility, and high metabolic clearance, its *significantly* superior binding affinity (-8.7 vs -6.2 kcal/mol) and excellent BBB penetration (87.4%) make it the more promising candidate. The strong binding is likely to drive sufficient target engagement *in vivo*, and the good BBB penetration is crucial for a CNS-acting drug. Ligand B's poor logP and resulting low BBB penetration are major liabilities that are difficult to overcome. While it has better metabolic stability, the weaker binding affinity is a critical disadvantage.

Output:
0
2025-04-17 07:53:02,435 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (341.419 Da) is slightly lower, which could be beneficial for permeability, while Ligand B (378.529 Da) is a bit higher.

**TPSA:** Ligand A (78.66) is better than Ligand B (52.57) as it is closer to the ideal range for CNS targets (<=90).

**logP:** Ligand B (2.753) is optimal (1-3), while Ligand A (0.037) is quite low, potentially hindering permeation. This is a significant drawback for Ligand A.

**H-Bond Donors/Acceptors:** Ligand A (HBD=1, HBA=7) and Ligand B (HBD=2, HBA=4) both fall within acceptable ranges.

**QED:** Both ligands have reasonable QED values (A: 0.774, B: 0.606), indicating drug-like properties.

**DILI:** Ligand B (14.541) has a much lower DILI risk than Ligand A (69.756), which is a major advantage.

**BBB:** Both ligands have excellent BBB penetration (A: 83.87, B: 88.406), exceeding the desirable threshold of >70.

**Caco-2 Permeability:** Both ligands have negative Caco-2 permeability values, which is unusual and suggests a potential issue with the data or the model used to predict it. However, we can still compare them. A less negative value is better, so Ligand A (-4.969) is slightly better than Ligand B (-5.019).

**Aqueous Solubility:** Both ligands have negative solubility values, which is also unusual. Again, a less negative value is better, so Ligand A (-2.09) is slightly better than Ligand B (-3.242).

**hERG Inhibition:** Ligand A (0.581) has a slightly lower hERG risk than Ligand B (0.941), which is preferable.

**Microsomal Clearance:** Both ligands have similar microsomal clearance values (A: 53.762, B: 55.22).

**In vitro Half-Life:** Ligand B (-20.897) has a significantly longer in vitro half-life than Ligand A (4.097), which is a major advantage.

**P-gp Efflux:** Ligand A (0.055) has much lower P-gp efflux liability than Ligand B (0.572), which is beneficial for CNS exposure.

**Binding Affinity:** Ligand A (-8.1 kcal/mol) has a significantly stronger binding affinity than Ligand B (-6.9 kcal/mol). This is a substantial advantage, potentially outweighing some of the ADME drawbacks.

**Overall Assessment:**

Ligand A has a superior binding affinity and lower P-gp efflux, but suffers from a very low logP and higher DILI risk. Ligand B has a better logP, lower DILI, and longer half-life, but weaker affinity. For a CNS GPCR target like DRD2, strong affinity is crucial. The difference in affinity (1.2 kcal/mol) is significant. While the low logP of Ligand A is a concern, it might be mitigated through formulation strategies. The higher DILI risk of Ligand A is also a concern, but could be investigated further. The better half-life and lower DILI of Ligand B are attractive, but the affinity difference is substantial.

Output:
1
2025-04-17 07:53:02,435 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight (MW):** Both ligands (343.358 and 357.841 Da) fall comfortably within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (75.48) is higher than Ligand B (55.32). For a CNS target like DRD2, TPSA should ideally be <= 90. Both are acceptable, but B is better.

**3. logP:** Both ligands have good logP values (3.133 and 3.507), falling within the optimal 1-3 range.

**4. H-Bond Donors (HBD):** Both ligands are acceptable (1 and 0 respectively), being less than the guideline of 5.

**5. H-Bond Acceptors (HBA):** Both ligands are acceptable (4 each), being less than the guideline of 10.

**6. QED:** Both ligands have good QED scores (0.683 and 0.821), indicating good drug-like properties.

**7. DILI:** Ligand A (78.945) has a higher DILI risk than Ligand B (38.581). This is a significant advantage for Ligand B.

**8. BBB:** Both ligands have excellent BBB penetration (81.582 and 83.288), exceeding the desirable >70% threshold for CNS targets.

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.921 and -4.465). This is unusual and suggests poor permeability. However, these values are on a log scale and negative values are common.

**10. Aqueous Solubility:** Both ligands have negative solubility values (-4.566 and -4.307). Similar to Caco-2, this is on a log scale and indicates poor solubility.

**11. hERG Inhibition:** Both ligands have low hERG inhibition risk (0.785 and 0.553).

**12. Microsomal Clearance (Cl_mic):** Ligand A (14.789) has lower microsomal clearance than Ligand B (92.968), suggesting better metabolic stability.

**13. In vitro Half-Life:** Ligand A (18.308) has a longer in vitro half-life than Ligand B (-23.733). This is a significant advantage for Ligand A.

**14. P-gp Efflux:** Both ligands have low P-gp efflux liability (0.29 and 0.103).

**15. Binding Affinity:** Ligand B (-7.9 kcal/mol) has a slightly better binding affinity than Ligand A (-9.7 kcal/mol). While A is stronger, the difference is not huge.

**Overall Assessment:**

Ligand B is the better candidate. While Ligand A has better metabolic stability and half-life, Ligand B has a significantly lower DILI risk, a slightly better binding affinity, and a lower TPSA. The lower DILI risk is a crucial advantage, and the difference in binding affinity is not substantial enough to outweigh this. Both have good BBB penetration and acceptable logP values. The poor Caco-2 and solubility are concerning for both, but can potentially be addressed through formulation strategies.

Output:
1
2025-04-17 07:53:02,435 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (369.897 and 369.487 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (81.33) is slightly higher than Ligand B (79.81). Both are below the 90 A^2 threshold desirable for CNS targets, which is good.

**3. logP:** Both ligands have excellent logP values (1.763 and 1.856), falling within the optimal 1-3 range.

**4. H-Bond Donors:** Ligand A (2) is better than Ligand B (0). While both are acceptable, having some H-bond donors can improve solubility.

**5. H-Bond Acceptors:** Ligand B (6) is higher than Ligand A (4). Both are within the acceptable limit of 10.

**6. QED:** Ligand A (0.684) has a significantly better QED score than Ligand B (0.464), indicating a more drug-like profile.

**7. DILI:** Ligand A (35.363) has a lower DILI risk than Ligand B (52.423), which is preferable. Both are below the concerning threshold of 60.

**8. BBB:** Both ligands have reasonable BBB penetration (Ligand A: 56.805, Ligand B: 58.821). However, neither exceeds the desirable 70% threshold for CNS targets.

**9. Caco-2 Permeability:** Ligand A (-5.371) has worse Caco-2 permeability than Ligand B (-4.761). Lower (more negative) values indicate poorer permeability.

**10. Aqueous Solubility:** Ligand A (-2.597) has worse aqueous solubility than Ligand B (-1.03). Lower (more negative) values indicate poorer solubility.

**11. hERG Inhibition:** Both ligands have very low hERG inhibition risk (Ligand A: 0.798, Ligand B: 0.179), which is excellent. Ligand B is slightly better.

**12. Microsomal Clearance:** Ligand B (99.672) has significantly higher microsomal clearance than Ligand A (22.761), indicating faster metabolism and lower metabolic stability. This is a major drawback for Ligand B.

**13. In vitro Half-Life:** Ligand A (-4.968) has a longer in vitro half-life than Ligand B (-1.204), which is desirable.

**14. P-gp Efflux:** Both ligands have low P-gp efflux liability (Ligand A: 0.087, Ligand B: 0.107), which is good for CNS penetration.

**15. Binding Affinity:** Ligand A (-8.0) has a significantly stronger binding affinity than Ligand B (-6.5). This is a crucial advantage, as a >1.5 kcal/mol difference can outweigh other drawbacks.

**Overall Assessment:**

Ligand A is the superior candidate. While Ligand B has slightly better Caco-2 permeability, solubility, and hERG inhibition, Ligand A excels in critical areas: significantly stronger binding affinity, better QED, lower DILI risk, and much better metabolic stability (lower Cl_mic and longer t1/2). The stronger affinity of Ligand A is a major advantage for a GPCR target, and the improved metabolic stability is crucial for *in vivo* efficacy. The slightly lower BBB penetration is less concerning given the strong affinity.

Output:
1
2025-04-17 07:53:02,435 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (343.471 and 359.423 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (54.34) is excellent, well below the 90 A^2 threshold for CNS targets. Ligand B (106.2) is higher, but still potentially acceptable, though less ideal.

**logP:** Ligand A (2.232) is optimal (1-3). Ligand B (-1.236) is below 1, which may hinder permeation.

**H-Bond Donors/Acceptors:** Ligand A (HBD=1, HBA=3) is favorable. Ligand B (HBD=2, HBA=6) is also within acceptable limits, but higher HBA might slightly reduce permeability.

**QED:** Ligand A (0.891) has a very strong drug-like profile. Ligand B (0.506) is acceptable, but less optimal.

**DILI:** Ligand A (24.389) has a very low DILI risk. Ligand B (19.426) also has a low DILI risk.

**BBB:** Ligand A (66.499) has a moderate BBB penetration. Ligand B (49.826) has a lower BBB penetration, which is a significant drawback for a CNS target like DRD2.

**Caco-2 Permeability:** Ligand A (-4.891) has poor Caco-2 permeability. Ligand B (-5.261) also has poor Caco-2 permeability.

**Aqueous Solubility:** Both ligands have negative solubility values, indicating poor aqueous solubility. Ligand A (-2.839) is slightly better than Ligand B (-1.235).

**hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.307 and 0.072).

**Microsomal Clearance:** Ligand A (16.685) has a higher microsomal clearance than Ligand B (10.286), suggesting lower metabolic stability.

**In vitro Half-Life:** Ligand A (11.555) has a longer half-life than Ligand B (-3.9).

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.112 and 0.002).

**Binding Affinity:** Ligand A (-9.1 kcal/mol) has a significantly stronger binding affinity than Ligand B (-6.6 kcal/mol). This is a >2.5 kcal/mol difference, which is substantial.

**Overall Assessment:**

Ligand A is superior due to its significantly better binding affinity, excellent TPSA, good logP, high QED, and low DILI risk. While its BBB penetration is not ideal, the strong binding affinity can often compensate for moderate permeability issues. Ligand B suffers from a low logP, lower BBB penetration, and a weaker binding affinity. The poor Caco-2 permeability is a concern for both, but the potency advantage of A is likely to be more impactful.

Output:
1
2025-04-17 07:53:02,435 - INFO - Batch 402 complete. Total preferences: 6432
2025-04-17 07:53:02,435 - INFO - Processing batch 403/512...
2025-04-17 07:53:44,846 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 drug candidates, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (355.538 and 362.583 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (29.54) is significantly better than Ligand B (33.2). Both are below the 90 A^2 threshold for CNS targets, but A is closer to optimal.

**3. logP:** Both ligands have similar logP values (4.842 and 4.729), slightly above the optimal 1-3 range, but still potentially acceptable. The higher logP could present solubility challenges, but is not a dealbreaker.

**4. H-Bond Donors:** Both have 0 HBD, which is good.

**5. H-Bond Acceptors:** Ligand A has 2 HBA, while Ligand B has 3. Both are within the acceptable limit of 10.

**6. QED:** Ligand B (0.733) has a slightly better QED score than Ligand A (0.554), indicating a more drug-like profile.

**7. DILI:** Ligand A (10.585) has a much lower DILI risk than Ligand B (24.661), which is a significant advantage.

**8. BBB:** Ligand A (96.743) has a substantially higher BBB penetration percentile than Ligand B (78.054). This is *critical* for a CNS target like DRD2.

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 values, which is unusual and suggests poor permeability. However, these values can be unreliable and should be interpreted with caution.

**10. Aqueous Solubility:** Both ligands have negative solubility values, indicating poor aqueous solubility. This is a concern, especially given their logP values.

**11. hERG Inhibition:** Both ligands have low hERG inhibition liability (0.892 and 0.694), which is good.

**12. Microsomal Clearance:** Ligand A (110.759) has higher microsomal clearance than Ligand B (100.136), suggesting lower metabolic stability.

**13. In vitro Half-Life:** Ligand B (7.093) has a longer in vitro half-life than Ligand A (18.909), which is preferable.

**14. P-gp Efflux:** Both ligands have low P-gp efflux liability (0.857 and 0.706), which is good for CNS penetration.

**15. Binding Affinity:** Ligand B (-7.3 kcal/mol) has a slightly better binding affinity than Ligand A (-7.0 kcal/mol), but the difference is small.

**Overall Assessment:**

Despite Ligand B's slightly better QED and binding affinity, Ligand A is the more promising candidate. The significantly better BBB penetration (96.743 vs 78.054) and much lower DILI risk (10.585 vs 24.661) are major advantages for a CNS-targeted drug. While both have solubility concerns, the superior CNS exposure potential of Ligand A outweighs the small difference in binding affinity and the slightly better half-life of Ligand B. The higher metabolic clearance of Ligand A is a concern, but could be addressed through structural modifications.

Output:
0
2025-04-17 07:53:44,846 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (352.479 and 368.855 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (95.74) is better than Ligand B (36.36) as it's closer to the ideal range for CNS targets (<=90). Ligand B is quite low, which *could* indicate good BBB penetration, but might also suggest reduced aqueous solubility.

**logP:** Ligand A (1.034) is within the optimal 1-3 range. Ligand B (4.485) is higher, potentially leading to solubility issues and off-target interactions.

**H-Bond Donors/Acceptors:** Both have acceptable HBD (2 and 1 respectively) and HBA (3 each) counts.

**QED:** Both ligands have good QED scores (0.716 and 0.782), indicating generally drug-like properties.

**DILI:** Both have relatively low DILI risk (18.612 and 20.163), which is positive.

**BBB:** Ligand A (75.107) has a slightly better BBB percentile than Ligand B (72.005), though both are above the 70% threshold for CNS targets.

**Caco-2 Permeability:** Ligand A (-5.08) has a worse Caco-2 permeability than Ligand B (-4.591).

**Aqueous Solubility:** Ligand A (-2.076) has a better aqueous solubility than Ligand B (-4.18).

**hERG:** Ligand A (0.349) has a lower hERG risk than Ligand B (0.952), which is preferable.

**Microsomal Clearance:** Ligand A (19.613) has a lower microsomal clearance than Ligand B (58.311), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand B (71.657) has a significantly longer in vitro half-life than Ligand A (-15.33). This is a substantial advantage for Ligand B.

**P-gp Efflux:** Ligand A (0.02) has much lower P-gp efflux liability than Ligand B (0.684), which is crucial for CNS penetration.

**Binding Affinity:** Ligand A (-8.3) has a stronger binding affinity than Ligand B (-6.6). This is a 1.7 kcal/mol difference, which is significant and can outweigh some ADME drawbacks.

**Overall Assessment:**

Ligand A excels in key areas for a CNS-targeting GPCR ligand: strong binding affinity, good BBB penetration, low P-gp efflux, low hERG risk, and better metabolic stability. While its Caco-2 permeability is worse, its superior affinity and CNS-relevant properties outweigh this. Ligand B has a longer half-life, which is good, but its higher logP, higher P-gp efflux, and weaker affinity are significant drawbacks.

Output:
1
2025-04-17 07:53:44,846 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B based on the provided guidelines, prioritizing GPCR-specific properties (BBB, logP, Pgp, TPSA, and affinity) for DRD2.

**Molecular Weight:** Both ligands (351.491 and 354.491 Da) fall within the ideal range of 200-500 Da.

**TPSA:** Ligand A (53.09) is significantly better than Ligand B (78.87). For CNS targets, TPSA should be <=90, and A is much closer to the optimal <=60 for brain penetration. B is approaching a less desirable range.

**logP:** Both ligands have acceptable logP values (1.718 and 1.848), falling within the 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A (0 HBD, 4 HBA) and Ligand B (2 HBD, 4 HBA) both have reasonable numbers of H-bond donors and acceptors, well within the guidelines.

**QED:** Both ligands have acceptable QED scores (0.731 and 0.662), indicating good drug-likeness.

**DILI:** Ligand A (12.214) has a much lower DILI risk than Ligand B (15.587), indicating a safer profile. Both are below the 40 threshold.

**BBB:** This is a critical parameter for DRD2. Ligand A (74.254) has a significantly better BBB percentile than Ligand B (51.532). A value >70 is desirable, and A is much closer.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.507 and -4.372), which is unusual and suggests poor permeability. However, these values are on a scale where higher is better, so the less negative value is better. Ligand A is slightly better here.

**Aqueous Solubility:** Both ligands have negative solubility values (-0.722 and -2.354). Again, higher is better, so Ligand A is slightly better.

**hERG:** Both ligands have low hERG inhibition liability (0.434 and 0.308), indicating a low risk of cardiotoxicity.

**Microsomal Clearance:** Ligand A (17.86) has a lower microsomal clearance than Ligand B (46.291), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (-2.409) has a slightly better (less negative) in vitro half-life than Ligand B (-17.174).

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.024 and 0.195), which is good for CNS penetration.

**Binding Affinity:** Ligand B (-7.6 kcal/mol) has a slightly better binding affinity than Ligand A (-6.1 kcal/mol). This is a 1.5 kcal/mol difference, which is significant.

**Overall Assessment:**

While Ligand B has a slightly better binding affinity, Ligand A is superior in almost all other critical ADME properties, especially those important for CNS penetration (BBB, TPSA). The significantly better BBB, lower DILI, lower Cl_mic, and better TPSA of Ligand A outweigh the slight affinity difference. The negative Caco-2 and solubility values are concerning for both, but the other advantages of A make it the more promising candidate.

Output:
0
2025-04-17 07:53:44,846 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (346.431 and 380.279 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (77.41) is better than Ligand B (55.43) as it is closer to the ideal range for CNS targets (<=90).

**logP:** Ligand A (1.782) is optimal, while Ligand B (3.715) is approaching the upper limit of the optimal range.

**H-Bond Donors:** Ligand A (2) is preferable to Ligand B (0) as it provides some hydrogen bonding capacity, which can be important for target engagement.

**H-Bond Acceptors:** Both ligands have 5 HBA, which is acceptable.

**QED:** Ligand A (0.726) has a significantly better QED score than Ligand B (0.464), indicating a more drug-like profile.

**DILI:** Ligand A (32.765) has a much lower DILI risk than Ligand B (64.754), which is a significant advantage.

**BBB:** Both ligands have acceptable BBB penetration (Ligand A: 60.644, Ligand B: 65.607), but neither exceeds the desirable >70% threshold.

**Caco-2 Permeability:** Ligand A (-4.928) and Ligand B (-5.163) both have negative values, which is unusual. This suggests poor permeability.

**Aqueous Solubility:** Ligand A (-2.128) and Ligand B (-3.553) both have negative values, indicating poor aqueous solubility.

**hERG Inhibition:** Ligand A (0.288) has a lower hERG inhibition liability than Ligand B (0.724), which is favorable.

**Microsomal Clearance:** Ligand B (93.208) has a much higher microsomal clearance than Ligand A (28.977), indicating lower metabolic stability.

**In vitro Half-Life:** Ligand A (41.038) and Ligand B (44.447) have similar in vitro half-lives.

**P-gp Efflux:** Both ligands have very low P-gp efflux (0.019 and 0.512, respectively), which is good for CNS penetration.

**Binding Affinity:** Both ligands have the same binding affinity (-8 kcal/mol), which is excellent.

**Overall Assessment:**

Ligand A is superior to Ligand B. While both have excellent binding affinity, Ligand A has a better balance of properties. It has a better QED score, lower DILI risk, lower hERG risk, and lower microsomal clearance (better metabolic stability). Although both have poor Caco-2 permeability and aqueous solubility, the other advantages of Ligand A make it the more promising candidate.

Output:
1
2025-04-17 07:53:44,846 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (352.435 and 387.527 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (118.55) is slightly above the optimal <90 for CNS targets, but still reasonable. Ligand B (88.6) is excellent, well within the desired range.

**logP:** Ligand A (0.127) is quite low, potentially hindering membrane permeability. Ligand B (1.359) is much better, falling within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A has 4 HBD and 5 HBA, acceptable. Ligand B has 1 HBD and 6 HBA, also acceptable.

**QED:** Both ligands have good QED scores (0.6 and 0.688), indicating good drug-like properties.

**DILI:** Ligand A (36.603) has a low DILI risk, which is favorable. Ligand B (67.739) has a higher DILI risk, though not excessively high.

**BBB:** Ligand A (36.758) has a poor BBB penetration score, a significant drawback for a CNS target. Ligand B (28.383) also has a poor BBB penetration score.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.39 and -5.155), which is unusual and suggests poor permeability. This is a concern for both.

**Aqueous Solubility:** Both ligands have negative solubility values (-1.875 and -3.349), indicating very poor aqueous solubility. This is a major issue for both.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.289 and 0.253), which is good.

**Microsomal Clearance:** Ligand A (-25.446) has a negative clearance, which is not physically meaningful. Ligand B (48.083) has a moderate clearance.

**In vitro Half-Life:** Ligand A (1.365) has a very short half-life. Ligand B (-30.721) has a negative half-life, which is not physically meaningful.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.045 and 0.07), which is favorable for CNS penetration.

**Binding Affinity:** Ligand A (-8.3 kcal/mol) has a significantly better binding affinity than Ligand B (-7.3 kcal/mol). The 1 kcal/mol difference is substantial.

**Overall Assessment:**

Despite the stronger binding affinity of Ligand A, its extremely low logP and poor BBB penetration are major liabilities. The negative values for Caco-2 permeability and solubility are also concerning. Ligand B has a better logP and lower DILI risk, but its BBB penetration is also poor, and its affinity is weaker. The negative clearance and half-life for Ligand B are also problematic.

However, the significantly stronger binding affinity of Ligand A (-8.3 kcal/mol vs -7.3 kcal/mol) *could* potentially overcome some of its ADME issues with further optimization. The low logP and solubility are addressable through structural modifications. The poor BBB is more difficult, but not insurmountable. Ligand B's weaker binding affinity makes it less attractive as a starting point.

Output:
0
2025-04-17 07:53:44,847 - INFO - Reasoning:

Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (356.47 and 350.46 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (101.98) is slightly above the optimal <90 for CNS targets, but still reasonable. Ligand B (89.87) is excellent, well below 90.

**3. logP:** Ligand A (-0.964) is a bit low, potentially hindering permeability. Ligand B (0.521) is better, falling within the 1-3 range, but still on the lower side.

**4. H-Bond Donors:** Both ligands have 3 HBD, which is acceptable.

**5. H-Bond Acceptors:** Ligand A has 5 HBA, acceptable. Ligand B has 4 HBA, also acceptable.

**6. QED:** Both ligands have good QED scores (0.52 and 0.645), indicating drug-like properties.

**7. DILI:** Ligand A (11.44) has a significantly lower DILI risk than Ligand B (14.39), making it safer from a liver toxicity perspective.

**8. BBB:** Ligand B (29.74) has a much better BBB penetration percentile than Ligand A (18.96). This is *critical* for a CNS target like DRD2.

**9. Caco-2:** Ligand A (-5.579) and Ligand B (-4.835) both have negative Caco-2 values, which is unusual and suggests very poor permeability. This is a significant concern for both.

**10. Solubility:** Ligand A (-0.122) has slightly better solubility than Ligand B (-2.028), but both are quite poor.

**11. hERG:** Both ligands have very low hERG risk (0.096 and 0.123).

**12. Cl_mic:** Ligand A (-0.753) has a slightly better (lower) microsomal clearance, indicating better metabolic stability, than Ligand B (3.965).

**13. t1/2:** Both have very short in vitro half-lives (-14.425 and -14.136), which is undesirable.

**14. Pgp:** Both ligands have very low P-gp efflux liability (0.002 and 0.013), which is good for CNS penetration.

**15. Binding Affinity:** Ligand B (-8.0) has a significantly stronger binding affinity than Ligand A (-6.6). This is a substantial advantage.

**Overall Assessment:**

Ligand B is clearly superior due to its significantly better binding affinity (-8.0 vs -6.6 kcal/mol) and much improved BBB penetration (29.74 vs 18.96). While Ligand A has a slightly better DILI score and Cl_mic, the affinity and BBB advantages of Ligand B are far more important for a CNS GPCR target. The poor Caco-2 and solubility for both are concerning, but can potentially be addressed with formulation strategies. The short half-lives are also a drawback, but less critical at this early stage than potency and brain penetration.

Output:
1
2025-04-17 07:53:44,847 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (358.471 and 346.402 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (76.8) is slightly higher than Ligand B (69.64). Both are below the 90 A^2 threshold desirable for CNS targets, but Ligand B is preferable.

**3. logP:** Both ligands have good logP values (3.143 and 2.496), falling within the optimal 1-3 range.

**4. H-Bond Donors:** Ligand A has 0 HBD, while Ligand B has 2. Both are acceptable (<=5).

**5. H-Bond Acceptors:** Ligand A has 7 HBA, and Ligand B has 3. Both are within the acceptable range (<=10), with Ligand B being more favorable.

**6. QED:** Both ligands have good QED scores (0.7 and 0.861), indicating good drug-like properties.

**7. DILI:** Ligand A has a DILI risk of 77.472, which is concerning (high risk). Ligand B has a much lower DILI risk of 26.599 (good). This is a significant advantage for Ligand B.

**8. BBB:** Both ligands have good BBB penetration (61.535 and 70.803), with Ligand B being slightly better. Both are above the 70% threshold.

**9. Caco-2 Permeability:** Both have negative Caco-2 values (-5.269 and -5.005), which is unusual and suggests poor permeability. This is a significant drawback for both.

**10. Aqueous Solubility:** Both have negative solubility values (-3.146 and -3.246), which is also unusual and suggests poor solubility. This is a significant drawback for both.

**11. hERG Inhibition:** Both ligands have low hERG inhibition risk (0.296 and 0.496).

**12. Microsomal Clearance:** Ligand A (71.179) has higher clearance than Ligand B (32.266), indicating lower metabolic stability. Ligand B is preferable.

**13. In vitro Half-Life:** Ligand B (-8.672) has a more negative half-life, which is unusual. Ligand A (32.409) has a more reasonable half-life.

**14. P-gp Efflux:** Both ligands have low P-gp efflux liability (0.446 and 0.059), which is good for CNS penetration. Ligand B is preferable.

**15. Binding Affinity:** Ligand B (-9.4 kcal/mol) has a significantly stronger binding affinity than Ligand A (-8.4 kcal/mol). This difference of 1.0 kcal/mol is substantial and can outweigh some of the ADME drawbacks.

**Overall Assessment:**

Ligand B is the better candidate. While both have issues with Caco-2 permeability and solubility, Ligand B has a much lower DILI risk, better metabolic stability (lower Cl_mic), lower P-gp efflux, and significantly stronger binding affinity. The stronger affinity is particularly important for a GPCR target. The slightly better BBB penetration also favors Ligand B.

Output:
1
2025-04-17 07:53:44,847 - INFO - Reasoning:

Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (366.487 and 364.324 Da) are within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (111.09) is better than Ligand B (107.43), both are below the 140 A^2 threshold for oral absorption and reasonably close to the 90 A^2 target for CNS penetration.

**3. logP:** Ligand A (0.703) is slightly better than Ligand B (-0.672). Both are within the optimal range of 1-3, but ligand B is closer to the lower bound, which could affect permeability.

**4. H-Bond Donors:** Both ligands have 3 HBD, which is within the acceptable limit of <=5.

**5. H-Bond Acceptors:** Ligand A has 5 HBA, and Ligand B has 6. Both are within the acceptable limit of <=10.

**6. QED:** Both ligands have good QED scores (0.548 and 0.657, respectively), indicating drug-like properties. Ligand B is slightly better.

**7. DILI:** Ligand A (18.728%) has a significantly lower DILI risk than Ligand B (72.005%). This is a major advantage for Ligand A.

**8. BBB:** Ligand A (63.28%) has a better BBB penetration score than Ligand B (45.909%). While both are not ideal (>70%), Ligand A is closer to the desired threshold for a CNS target.

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 permeability values (-5.668 and -5.288), which is unusual and suggests poor intestinal absorption. This is a concern for both.

**10. Aqueous Solubility:** Both ligands have negative solubility values (-2.585 and -2.408), which is also unusual and indicates poor aqueous solubility. This is a concern for both.

**11. hERG Inhibition:** Both ligands have low hERG inhibition liability (0.214 and 0.317, respectively), which is good.

**12. Microsomal Clearance:** Ligand A (3.176) has a lower microsomal clearance than Ligand B (-11.16). This indicates better metabolic stability for Ligand A.

**13. In vitro Half-Life:** Ligand A (-10.897) has a longer in vitro half-life than Ligand B (-16.867). This is a significant advantage for Ligand A.

**14. P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.025 and 0.016, respectively), which is favorable for CNS exposure.

**15. Binding Affinity:** Ligand B (-9.4 kcal/mol) has a significantly stronger binding affinity than Ligand A (-6.8 kcal/mol). This is a substantial advantage for Ligand B, potentially outweighing some of its ADME drawbacks.

**Overall Assessment:**

Ligand B has a much stronger binding affinity, which is a critical factor for GPCRs. However, it suffers from significantly higher DILI risk, lower BBB penetration, and poorer metabolic stability. Ligand A has a better safety profile (lower DILI), better BBB penetration, and improved metabolic stability, but its binding affinity is weaker.

Given the importance of CNS penetration for a DRD2 ligand and the substantial difference in DILI risk, I would lean towards **Ligand A** as the more viable drug candidate, despite the lower binding affinity. The affinity difference, while significant, might be addressable through further optimization, whereas mitigating high DILI risk and poor BBB penetration is often far more challenging.

Output:
0
2025-04-17 07:53:44,847 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (359.455 and 353.522 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (100.35) is higher than the preferred <90 for CNS targets, while Ligand B (29.54) is excellent. This is a significant advantage for Ligand B.

**3. logP:** Ligand A (2.511) is within the optimal 1-3 range. Ligand B (4.596) is slightly above, potentially raising concerns about solubility and off-target effects, but not drastically.

**4. H-Bond Donors:** Ligand A (3) is acceptable. Ligand B (0) is also good, potentially improving membrane permeability.

**5. H-Bond Acceptors:** Ligand A (4) is acceptable. Ligand B (2) is also good.

**6. QED:** Ligand A (0.764) is very good, indicating high drug-likeness. Ligand B (0.567) is still acceptable, but less optimal.

**7. DILI:** Ligand A (69.135) has a higher DILI risk than Ligand B (6.514). This is a significant advantage for Ligand B.

**8. BBB:** Ligand A (75.301) is good, but Ligand B (97.712) is excellent, exceeding the >70% threshold for CNS targets. This is a major advantage for Ligand B.

**9. Caco-2 Permeability:** Ligand A (-5.245) is poor, indicating low intestinal absorption. Ligand B (-4.534) is also poor, but slightly better than A.

**10. Aqueous Solubility:** Ligand A (-2.98) is poor, while Ligand B (-4.396) is even worse. Both have solubility concerns.

**11. hERG Inhibition:** Ligand A (0.275) has a slightly higher hERG risk than Ligand B (0.964), but both are relatively low.

**12. Microsomal Clearance:** Ligand A (21.704) has lower clearance, suggesting better metabolic stability than Ligand B (86.472).

**13. In vitro Half-Life:** Ligand A (31.201) has a longer half-life than Ligand B (-4.17), which is a significant advantage.

**14. P-gp Efflux:** Ligand A (0.166) has lower P-gp efflux, which is favorable for CNS penetration, compared to Ligand B (0.874).

**15. Binding Affinity:** Ligand B (-7.2) has a significantly stronger binding affinity than Ligand A (-9.2). This is a substantial advantage, potentially outweighing some of the ADME drawbacks.

**Overall Assessment:**

While Ligand A has better metabolic stability (lower Cl_mic, longer t1/2) and P-gp efflux, Ligand B excels in critical areas for a CNS-targeting GPCR ligand: TPSA, BBB penetration, and, most importantly, binding affinity. The significantly higher binding affinity of Ligand B (-7.2 kcal/mol vs. -9.2 kcal/mol) is a decisive factor. The lower DILI risk is also a significant benefit. The solubility and Caco-2 permeability are poor for both, but these can be addressed with formulation strategies.

Output:
1
2025-04-17 07:53:44,847 - INFO - Reasoning:

Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (358.276 and 344.415 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (103.7) is higher than the preferred <90 for CNS targets, while Ligand B (75.94) is comfortably below. This is a significant advantage for Ligand B.

**3. logP:** Ligand A (0.11) is quite low, potentially hindering membrane permeability. Ligand B (2.034) is within the optimal 1-3 range. This favors Ligand B.

**4. H-Bond Donors:** Both have 1 HBD, which is acceptable.

**5. H-Bond Acceptors:** Both have 5 HBA, which is acceptable.

**6. QED:** Both ligands have good QED scores (0.823 and 0.78), indicating good drug-like properties.

**7. DILI:** Ligand A (67.429) and Ligand B (51.609) both have acceptable DILI risk, though Ligand B is preferable.

**8. BBB:** Ligand A (54.246) has a moderate BBB penetration, while Ligand B (74.292) is much better, exceeding the >70% threshold for CNS targets. This is a major advantage for Ligand B.

**9. Caco-2:** Both have negative Caco-2 values, which is unusual and suggests poor permeability. However, the scale is not defined, so it's difficult to interpret.

**10. Solubility:** Both have negative solubility values, which is also unusual and suggests poor solubility. Again, the scale is undefined.

**11. hERG:** Both ligands have very low hERG inhibition risk (0.041 and 0.306).

**12. Cl_mic:** Ligand A (-18.849) has a much lower (better) microsomal clearance than Ligand B (31.474), suggesting greater metabolic stability.

**13. t1/2:** Ligand A (-25.284) has a very negative in vitro half-life, which is concerning. Ligand B (33.404) is better, but still not ideal.

**14. Pgp:** Both have very low Pgp efflux liability (0.004 and 0.066).

**15. Binding Affinity:** Both ligands have similar, strong binding affinities (-8.3 and -8.1 kcal/mol). The difference is not substantial enough to outweigh other factors.

**Overall Assessment:**

Ligand B is significantly more promising due to its superior TPSA, logP, and BBB penetration. While Ligand A has better metabolic stability (lower Cl_mic), the poor logP and TPSA of Ligand A are major drawbacks for a CNS-targeting GPCR ligand. The slightly better BBB score of Ligand B is critical. The unusual negative values for Caco-2 and Solubility are concerning for both, but the other advantages of Ligand B outweigh this.

Output:
1
2025-04-17 07:53:44,847 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (351.491 and 363.489 Da) fall within the ideal range of 200-500 Da.

**TPSA:** Ligand A (69.72) is better than Ligand B (60.77) as it is closer to the optimal range for CNS targets (<=90). Both are acceptable.

**logP:** Ligand A (1.788) is within the optimal range (1-3). Ligand B (3.455) is at the higher end, potentially leading to solubility issues.

**H-Bond Donors/Acceptors:** Ligand A (HBD=1, HBA=3) and Ligand B (HBD=2, HBA=3) both have reasonable numbers of H-bond donors and acceptors, well within the guidelines.

**QED:** Both ligands have similar QED values (0.711 and 0.694), indicating good drug-likeness.

**DILI:** Both ligands have low DILI risk (10.973 and 11.865 percentiles), which is favorable.

**BBB:** Ligand B (89.104) has a significantly better BBB penetration percentile than Ligand A (79.527). This is a crucial advantage for a CNS target like DRD2.

**Caco-2 Permeability:** Both have negative Caco-2 values (-4.363 and -4.273). This is unusual and suggests poor permeability. However, the values are similar.

**Aqueous Solubility:** Both ligands have negative solubility values (-2.304 and -3.182). This is also unusual and suggests poor solubility. Ligand B is slightly worse.

**hERG Inhibition:** Both ligands have low hERG inhibition liability (0.226 and 0.853), which is good.

**Microsomal Clearance:** Ligand A (39.422) has lower microsomal clearance than Ligand B (44.296), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (-6.876) has a longer in vitro half-life than Ligand B (-4.495), which is desirable.

**P-gp Efflux:** Ligand A (0.02) has much lower P-gp efflux liability than Ligand B (0.223), which is a significant advantage for CNS penetration.

**Binding Affinity:** Both ligands have strong binding affinities (-7.0 and -6.4 kcal/mol). Ligand A is slightly better (-7.0 vs -6.4 kcal/mol).

**Overall Assessment:**

While Ligand A has slightly better affinity, metabolic stability, and P-gp efflux, Ligand B excels in BBB penetration. Given that this is a CNS target, BBB penetration is paramount. The difference in BBB (79.53 vs 89.10) is substantial. The slightly better affinity of Ligand A is unlikely to overcome the significant advantage of Ligand B in BBB penetration. The solubility and permeability issues are concerning for both, but the CNS target prioritizes getting the drug *to* the brain.

Output:
1
2025-04-17 07:53:44,847 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (361.471 and 356.455 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (78.43) is significantly better than Ligand B (102.73). For CNS targets, we want TPSA <= 90, and A is comfortably within this range, while B is pushing the limit.

**logP:** Ligand A (1.149) is within the optimal 1-3 range. Ligand B (2.32) is also acceptable, but slightly higher.

**H-Bond Donors/Acceptors:** Ligand A (HBD=1, HBA=6) is preferable to Ligand B (HBD=3, HBA=7) as lower values generally improve permeability. Both are within acceptable limits.

**QED:** Ligand A (0.87) has a better QED score than Ligand B (0.703), indicating a more drug-like profile.

**DILI:** Ligand B (66.848) has a higher DILI risk than Ligand A (52.423), though both are reasonably acceptable.

**BBB:** Ligand A (62.233) has a slightly better BBB percentile than Ligand B (52.617). While both are below the desirable >70 for CNS targets, A is closer.

**Caco-2 Permeability:** Ligand A (-4.983) has better Caco-2 permeability than Ligand B (-5.226), indicating better intestinal absorption.

**Aqueous Solubility:** Ligand B (-4.493) has better aqueous solubility than Ligand A (-2.508). Solubility is important, but less critical than BBB and permeability for CNS drugs.

**hERG Inhibition:** Ligand A (0.187) has a lower hERG inhibition risk than Ligand B (0.762), which is a significant advantage.

**Microsomal Clearance:** Ligand B (29.951) has lower microsomal clearance than Ligand A (38.015), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand B (35.02) has a longer in vitro half-life than Ligand A (6.331), which is desirable.

**P-gp Efflux:** Ligand A (0.064) has lower P-gp efflux than Ligand B (0.114), which is crucial for CNS penetration.

**Binding Affinity:** Ligand B (-8.2 kcal/mol) has a slightly better binding affinity than Ligand A (-9.5 kcal/mol). This is a significant advantage, but must be weighed against other factors.

**Overall Assessment:**

Ligand A excels in TPSA, QED, hERG, and P-gp efflux, all critical for a CNS-targeting GPCR ligand. It also has a better BBB score and lower DILI risk. While Ligand B has superior binding affinity and metabolic stability, the significantly worse TPSA, higher hERG risk, and higher P-gp efflux are major drawbacks. The affinity difference, while noticeable, is unlikely to outweigh the ADME advantages of Ligand A, especially given the already strong binding of Ligand A.

Output:
0
2025-04-17 07:53:44,848 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (364.515 and 382.291 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (75.19) is slightly higher than Ligand B (71.09), but both are below the 90 A^2 threshold desirable for CNS targets.

**3. logP:** Both ligands have good logP values (2.55 and 2.954), falling within the optimal 1-3 range.

**4. H-Bond Donors:** Ligand A has 1 HBD, and Ligand B has 2. Both are within the acceptable limit of <=5.

**5. H-Bond Acceptors:** Ligand A has 5 HBA, and Ligand B has 3. Both are within the acceptable limit of <=10.

**6. QED:** Both ligands have similar QED values (0.787 and 0.77), indicating good drug-like properties.

**7. DILI:** Ligand A (47.732) has a slightly better DILI score than Ligand B (44.552), both are good.

**8. BBB:** Ligand B (67.623) has a slightly better BBB score than Ligand A (61.807), but both are below the desirable >70 for CNS targets. This is a critical factor.

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.162 and -5.047), which is unusual and suggests poor permeability. This is a significant concern for both.

**10. Aqueous Solubility:** Both ligands have negative solubility values (-2.675 and -4.249), indicating poor aqueous solubility. This is also a concern for both.

**11. hERG Inhibition:** Both ligands have low hERG inhibition risk (0.126 and 0.331).

**12. Microsomal Clearance:** Ligand B (12.496) has a significantly lower microsomal clearance than Ligand A (50.078), suggesting better metabolic stability.

**13. In vitro Half-Life:** Ligand B (13.876) has a much longer in vitro half-life than Ligand A (-1.99), indicating better stability.

**14. P-gp Efflux:** Ligand A (0.283) has a lower P-gp efflux liability than Ligand B (0.083), which is favorable for CNS penetration.

**15. Binding Affinity:** Ligand B (-9.4 kcal/mol) has a significantly stronger binding affinity than Ligand A (-7.2 kcal/mol). This is a substantial advantage.

**Overall Assessment:**

While both ligands have issues with Caco-2 permeability and aqueous solubility, Ligand B stands out due to its significantly stronger binding affinity (-9.4 vs -7.2 kcal/mol) and improved metabolic stability (lower Cl_mic and longer t1/2). The slightly better P-gp efflux for Ligand A is offset by the much stronger binding of Ligand B. The difference in binding affinity is large enough to potentially overcome the permeability and solubility issues with further optimization.

Output:
1
2025-04-17 07:53:44,848 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B against the provided guidelines, prioritizing GPCR-specific properties (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (348.531 Da) is slightly lower, which could be beneficial for permeability.

**TPSA:** Ligand A (58.2) is excellent for CNS penetration, well below the 90 A^2 threshold. Ligand B (91.32) is higher, potentially hindering BBB penetration.

**logP:** Ligand A (3.984) is at the upper end of the optimal range (1-3), but still acceptable. Ligand B (2.116) is lower, potentially reducing permeability.

**H-Bond Donors/Acceptors:** Ligand A (HBD=2, HBA=2) is favorable. Ligand B (HBD=3, HBA=5) is also acceptable, but slightly higher.

**QED:** Both ligands have reasonable QED values (A: 0.463, B: 0.688), with Ligand B being slightly more drug-like.

**DILI:** Ligand A (19.659) has a much lower DILI risk than Ligand B (77.898), a significant advantage.

**BBB:** Ligand A (75.107) has a good BBB percentile, exceeding the 70% threshold for CNS targets. Ligand B (38.271) is considerably lower, raising concerns about CNS exposure.

**Caco-2 Permeability:** Ligand A (-4.595) and Ligand B (-5.281) both have negative values, which is unusual. Assuming these are percentile scores, lower values indicate poorer permeability. Ligand A is slightly better here.

**Aqueous Solubility:** Both ligands have poor aqueous solubility (-4.26 and -3.818, respectively). This could pose formulation challenges.

**hERG Inhibition:** Ligand A (0.451) has a lower hERG risk than Ligand B (0.715).

**Microsomal Clearance:** Ligand A (75.735) has higher microsomal clearance than Ligand B (25.752), indicating lower metabolic stability.

**In vitro Half-Life:** Ligand B (39.113) has a significantly longer in vitro half-life than Ligand A (4.592), which is a substantial advantage.

**P-gp Efflux:** Ligand A (0.122) has a much lower P-gp efflux liability than Ligand B (0.095), which is favorable for CNS penetration.

**Binding Affinity:** Ligand B (-8.7 kcal/mol) has a stronger binding affinity than Ligand A (-7.4 kcal/mol), with a difference of 1.3 kcal/mol. This is a significant advantage that could potentially offset some of its ADME drawbacks.

**Overall Assessment:**

While Ligand B has a superior binding affinity and a longer half-life, Ligand A is significantly better in terms of BBB penetration, DILI risk, and P-gp efflux. Given that this is a CNS target (DRD2), BBB penetration is critical. The lower DILI risk of Ligand A is also a major plus. The difference in binding affinity, while substantial, might be overcome with further optimization of Ligand A. The poor solubility of both compounds is a concern, but can be addressed with formulation strategies.

Output:
0
2025-04-17 07:53:44,848 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 drug candidates, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (413.272 Da) is slightly higher than Ligand B (363.755 Da), but both are acceptable.

**2. TPSA:** Ligand A (103.79) is higher than the preferred <90 for CNS targets, while Ligand B (72.7) is well within the range. This is a significant advantage for Ligand B.

**3. logP:** Ligand A (0.506) is quite low, potentially hindering membrane permeability. Ligand B (3.57) is optimal. This is a major advantage for Ligand B.

**4. H-Bond Donors:** Ligand A (3) is acceptable. Ligand B (1) is also good.

**5. H-Bond Acceptors:** Ligand A (6) is acceptable. Ligand B (5) is also good.

**6. QED:** Both ligands have good QED scores (A: 0.622, B: 0.703), indicating drug-like properties.

**7. DILI:** Ligand A (70.221) is at the upper limit of acceptable, while Ligand B (94.378) is concerningly high. This favors Ligand A.

**8. BBB:** Ligand A (46.84) is below the desirable >70 for CNS targets, but not drastically so. Ligand B (69.678) is closer to the threshold, but still below. Neither is ideal, but Ligand B is better.

**9. Caco-2:** Both have negative Caco-2 values (-4.927 and -4.938), which is unusual and suggests poor permeability. This is a significant drawback for both, but they are similar.

**10. Solubility:** Both have negative solubility values (-2.239 and -4.82), also unusual and suggesting poor solubility. Again, similar for both.

**11. hERG:** Both ligands show low hERG inhibition liability (A: 0.236, B: 0.22), which is good.

**12. Cl_mic:** Ligand A (-12.348) has a much lower (better) microsomal clearance than Ligand B (44.853), indicating better metabolic stability. This is a significant advantage for Ligand A.

**13. t1/2:** Ligand A (18.454) has a longer half-life than Ligand B (2.538), which is desirable. This favors Ligand A.

**14. Pgp:** Both have low P-gp efflux liability (A: 0.012, B: 0.204), which is good for CNS penetration. Ligand A is slightly better.

**15. Binding Affinity:** Ligand B (-9.8 kcal/mol) has a significantly stronger binding affinity than Ligand A (-8.2 kcal/mol). This is a substantial advantage for Ligand B, potentially outweighing some of its ADME drawbacks.

**Overall Assessment:**

Ligand B has a superior logP and TPSA, and a much stronger binding affinity. However, its DILI risk is high. Ligand A has better metabolic stability (Cl_mic, t1/2), a lower DILI risk, and slightly better Pgp efflux. The significantly stronger binding affinity of Ligand B is the most important factor for a GPCR target, and its logP is optimal. While the DILI risk is a concern, it could be addressed through structural modifications. The lower TPSA and better logP of Ligand B are crucial for CNS penetration, and the affinity difference is substantial.

Output:
1
2025-04-17 07:53:44,848 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (366.805 and 361.511 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (108.47) is higher than Ligand B (62.3). For CNS targets, TPSA should be <= 90. Ligand B is significantly better here.

**logP:** Both ligands have acceptable logP values (2.006 and 3.331, respectively), falling within the 1-3 range. Ligand B is slightly higher, which could be beneficial for membrane permeability, but isn't a major concern.

**H-Bond Donors/Acceptors:** Ligand A has 2 HBD and 7 HBA, while Ligand B has 1 HBD and 4 HBA. Both are within acceptable limits (<=5 HBD and <=10 HBA).

**QED:** Both ligands have reasonable QED values (0.757 and 0.646), suggesting good drug-like properties.

**DILI:** Ligand A (87.243) has a higher DILI risk than Ligand B (45.677). This is a significant negative for Ligand A.

**BBB:** Ligand B (70.027) has a much better BBB penetration percentile than Ligand A (57.968). This is crucial for a CNS target like DRD2.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.084 and -5.049). This is unusual and suggests poor permeability, but the scale isn't defined, so it's hard to interpret.

**Aqueous Solubility:** Both ligands have negative solubility values (-4.028 and -4.149). Again, the scale is undefined, making interpretation difficult.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.228 and 0.488).

**Microsomal Clearance:** Ligand B (72.336) has a higher microsomal clearance than Ligand A (47.009), indicating faster metabolism and potentially lower *in vivo* exposure.

**In vitro Half-Life:** Ligand A (-5.925) has a shorter half-life than Ligand B (15.557). This is a negative for Ligand A.

**P-gp Efflux:** Ligand A (0.177) has lower P-gp efflux than Ligand B (0.339), which is favorable for CNS penetration.

**Binding Affinity:** Ligand B (-7.8 kcal/mol) has a slightly better binding affinity than Ligand A (-8.1 kcal/mol). While the difference is small, it's still a positive for Ligand B.

**Overall Assessment:**

Ligand B is the superior candidate. It has a much better BBB score, lower DILI risk, better TPSA, and a slightly better binding affinity. While Ligand A has lower P-gp efflux, the advantages of Ligand B in BBB, DILI, and TPSA outweigh this benefit, especially for a CNS target. The negative Caco-2 and solubility values are concerning for both, but the other factors strongly favor Ligand B.

Output:
1
2025-04-17 07:53:44,848 - INFO - Batch 403 complete. Total preferences: 6448
2025-04-17 07:53:44,848 - INFO - Processing batch 404/512...
2025-04-17 07:54:25,206 - INFO - Reasoning:

Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (341.43 and 342.355 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (48.99) is excellent, well below the 90 A^2 threshold for CNS targets. Ligand B (95.43) is higher, but still potentially acceptable, though less ideal.

**3. logP:** Ligand A (3.988) is near the upper limit of the optimal range (1-3), while Ligand B (1.653) is towards the lower end. Both are within range, but A's higher logP might aid in membrane permeability.

**4. H-Bond Donors:** Both ligands have 1 HBD, which is good.

**5. H-Bond Acceptors:** Ligand A has 2 HBA, and Ligand B has 8. Ligand A is preferable here, as fewer HBAs generally improve permeability.

**6. QED:** Both ligands have reasonable QED values (0.898 and 0.753), indicating good drug-like properties.

**7. DILI:** Ligand A (33.773) has a significantly lower DILI risk than Ligand B (80.186). This is a major advantage for Ligand A.

**8. BBB:** Ligand A (96.937) has excellent BBB penetration, exceeding the desirable >70% threshold. Ligand B (43.699) is considerably lower, a significant drawback for a CNS target like DRD2.

**9. Caco-2:** Both have negative Caco-2 values, which is unusual and suggests a potential issue with the data or modeling. However, we'll proceed assuming these represent permeability, and a less negative value is better. Ligand A (-5.104) is better than Ligand B (-4.909).

**10. Solubility:** Both have negative solubility values, again unusual. Assuming lower values indicate lower solubility, Ligand B (-2.878) is slightly better than Ligand A (-3.418).

**11. hERG:** Both ligands have low hERG risk (0.929 and 0.504).

**12. Cl_mic:** Ligand A (30.402) has slightly lower microsomal clearance than Ligand B (35.347), suggesting better metabolic stability.

**13. t1/2:** Ligand A (-23.55) has a much longer in vitro half-life than Ligand B (7.605). This is a significant advantage.

**14. Pgp:** Ligand A (0.661) has lower P-gp efflux liability than Ligand B (0.203), which is favorable for CNS penetration.

**15. Binding Affinity:** Both ligands have similar binding affinities (-10.4 and -9.0 kcal/mol). While both are strong binders, Ligand A is slightly better.

**Overall Assessment:**

Ligand A is significantly more promising. It excels in crucial areas for a CNS-targeting GPCR ligand: excellent BBB penetration, low DILI risk, favorable Pgp efflux, and a longer half-life. While Ligand B has slightly better solubility, the other advantages of Ligand A outweigh this. The TPSA and logP values of Ligand A are also more favorable.

Output:
1
2025-04-17 07:54:25,206 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (369.29 Da and 350.46 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (74.43) is slightly above the optimal <90 for CNS targets, but still reasonable. Ligand B (71.78) is better, comfortably under 90.

**3. logP:** Ligand A (1.259) is within the optimal 1-3 range. Ligand B (3.394) is at the higher end, but still acceptable.

**4. H-Bond Donors:** Ligand A (2) and Ligand B (1) are both within the acceptable limit of <=5.

**5. H-Bond Acceptors:** Ligand A (3) and Ligand B (4) are both within the acceptable limit of <=10.

**6. QED:** Both ligands have similar QED values (0.768 and 0.702), indicating good drug-likeness.

**7. DILI:** Ligand A (58.434) has a moderate DILI risk, while Ligand B (27.142) has a significantly lower, and preferable, DILI risk.

**8. BBB:** This is a critical parameter for CNS targets. Ligand A (74.292) is acceptable, but Ligand B (86.002) is excellent, exceeding the desirable >70 threshold.

**9. Caco-2 Permeability:** Ligand A (-5.005) has poor Caco-2 permeability. Ligand B (-4.191) is slightly better, but still poor.

**10. Aqueous Solubility:** Both ligands have poor aqueous solubility (-2.624 and -3.43, respectively). This could pose formulation challenges.

**11. hERG Inhibition:** Both ligands have low hERG inhibition risk (0.504 and 0.626).

**12. Microsomal Clearance:** Ligand A (-1.369) has lower (better) microsomal clearance than Ligand B (92.824), indicating better metabolic stability.

**13. In vitro Half-Life:** Ligand A (-22.45) has a very short half-life, which is undesirable. Ligand B (29.518) has a much longer, and preferable, half-life.

**14. P-gp Efflux:** Both ligands have very low P-gp efflux (0.024 and 0.164), which is good for CNS penetration.

**15. Binding Affinity:** Ligand B (-7.8 kcal/mol) has a significantly stronger binding affinity than Ligand A (0 kcal/mol). This is a major advantage.

**Overall Assessment:**

Ligand B is the stronger candidate. While both have solubility issues, Ligand B excels in the most critical areas for a CNS-targeting GPCR ligand: BBB penetration, binding affinity, DILI risk, and in vitro half-life. The significantly better binding affinity of Ligand B (-7.8 vs 0 kcal/mol) is a substantial advantage that outweighs the slightly higher logP and poorer Caco-2 permeability. The lower DILI risk and longer half-life further strengthen its profile. Ligand A's very short half-life and lack of binding affinity are major drawbacks.

Output:
1
2025-04-17 07:54:25,206 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (344.415 Da) is slightly better, being closer to the lower end which can aid permeability.

**TPSA:** Ligand A (71.7) is significantly better than Ligand B (44.81). For CNS targets, we want TPSA <= 90, and ideally lower. Ligand A is well within this range, while Ligand B is pushing the upper limit.

**logP:** Ligand A (1.527) is optimal, falling within the 1-3 range. Ligand B (4.859) is too high, potentially leading to solubility issues and off-target interactions.

**H-Bond Donors/Acceptors:** Ligand A (0 HBD, 6 HBA) is preferable. Ligand B (1 HBD, 4 HBA) is acceptable, but more H-bonds can sometimes hinder permeability.

**QED:** Both ligands have reasonably good QED scores (A: 0.791, B: 0.615), indicating drug-like properties. Ligand A is slightly better.

**DILI:** Ligand A (44.591) has a lower DILI risk than Ligand B (57.115), which is desirable. Both are below the concerning threshold of 60.

**BBB:** Both ligands have good BBB penetration (A: 77.433, B: 70.454), but Ligand A is better, exceeding 70%. This is crucial for a CNS target like DRD2.

**Caco-2 Permeability:** Both have negative Caco-2 values (-4.81 and -4.886). This is unusual and suggests poor permeability. However, these values are on a log scale and should be interpreted cautiously.

**Aqueous Solubility:** Both have negative solubility values (-1.871 and -3.975), indicating poor aqueous solubility.

**hERG Inhibition:** Ligand A (0.422) has a lower hERG risk than Ligand B (0.946), which is a significant advantage.

**Microsomal Clearance:** Ligand B (52.05) has slightly lower microsomal clearance than Ligand A (58.398), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (-8.02) has a longer in vitro half-life than Ligand B (46.998).

**P-gp Efflux:** Ligand A (0.226) has a lower P-gp efflux liability than Ligand B (0.899), which is beneficial for CNS exposure.

**Binding Affinity:** Ligand B (-9.7) has a significantly stronger binding affinity than Ligand A (-8.7). This is a substantial advantage (1.0 kcal/mol difference).

**Overall Assessment:**

While Ligand B has a significantly better binding affinity, Ligand A is superior in almost all other critical ADME properties, especially those prioritized for GPCRs targeting the CNS. Ligand A has better TPSA, logP, BBB penetration, lower DILI and hERG risk, and lower P-gp efflux. The stronger binding affinity of Ligand B might overcome some ADME issues, but the combination of poor logP, higher TPSA, and higher P-gp efflux raises concerns about its ability to reach the target in the brain. The negative solubility and Caco-2 values for both are concerning, but the other advantages of Ligand A make it the more promising candidate.

Output:
0
2025-04-17 07:54:25,206 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (353.419 and 365.414 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (71.55) is better than Ligand B (62.62) as it is closer to the <90 threshold for CNS targets.

**3. logP:** Ligand A (-1.066) is quite low, potentially hindering permeability. Ligand B (2.427) is within the optimal 1-3 range. This is a significant advantage for Ligand B.

**4. H-Bond Donors:** Both have 0 HBD, which is acceptable.

**5. H-Bond Acceptors:** Ligand A has 6 HBA, and Ligand B has 4 HBA, both are within the acceptable range of <=10.

**6. QED:** Both ligands have good QED scores (0.63 and 0.77), indicating good drug-like properties.

**7. DILI:** Both ligands have acceptable DILI risk (34.82 and 42.924, both <40).

**8. BBB:** Ligand B (71.229) is significantly better than Ligand A (53.083) regarding BBB penetration, exceeding the desirable >70% threshold for CNS targets. This is a major advantage for Ligand B.

**9. Caco-2 Permeability:** Both ligands have very negative Caco-2 values (-4.514 and -4.527), which is unusual and suggests a potential issue with the data or a very poor permeability.

**10. Aqueous Solubility:** Both ligands have very negative solubility values (-0.426 and -1.935), which suggests poor solubility.

**11. hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.122 and 0.167).

**12. Microsomal Clearance:** Ligand A (-8.817) has a much lower (better) microsomal clearance than Ligand B (37.126), suggesting greater metabolic stability.

**13. In vitro Half-Life:** Ligand A (7.636) has a longer half-life than Ligand B (-9.437).

**14. P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.009 and 0.153).

**15. Binding Affinity:** Ligand B (-7.8 kcal/mol) has a slightly better binding affinity than Ligand A (-7.3 kcal/mol). While not a huge difference, it's a positive factor.

**Overall Assessment:**

Despite Ligand A's better metabolic stability and half-life, Ligand B is the more promising candidate. The critical factors for a CNS-targeting GPCR like DRD2 are BBB penetration and logP. Ligand B significantly outperforms Ligand A in both of these areas. Although both have poor solubility and permeability, the superior BBB penetration and acceptable logP of Ligand B outweigh the benefits of Ligand A's metabolic properties. The slight improvement in binding affinity also favors Ligand B.

Output:
1
2025-04-17 07:54:25,206 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (365.455 and 354.422 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (93.5) is slightly above the optimal <90 for CNS targets, but still reasonable. Ligand B (70.08) is well within the desired range.

**3. logP:** Ligand A (2.73) is within the optimal 1-3 range. Ligand B (1.239) is at the lower end, potentially impacting permeability.

**4. H-Bond Donors:** Ligand A (2) and Ligand B (1) are both acceptable (<=5).

**5. H-Bond Acceptors:** Ligand A (6) and Ligand B (4) are both acceptable (<=10).

**6. QED:** Both ligands have good QED scores (0.457 and 0.699, respectively), indicating reasonable drug-likeness. Ligand B is better.

**7. DILI:** Ligand A (63.086) has a moderate DILI risk, while Ligand B (32.028) has a lower, more favorable risk.

**8. BBB:** This is critical for a CNS target. Ligand A (61.923) is borderline, while Ligand B (86.739) is excellent, exceeding the >70 desirable threshold.

**9. Caco-2:** Ligand A (-5.311) and Ligand B (-4.156) both have negative values, which is unusual. This suggests poor permeability.

**10. Solubility:** Ligand A (-3.003) and Ligand B (-1.233) both have negative values, indicating poor aqueous solubility.

**11. hERG:** Both ligands have low hERG risk (0.491 and 0.381, respectively).

**12. Cl_mic:** Ligand A (-5.716) has a negative value, implying very low clearance and high metabolic stability, which is excellent. Ligand B (19.922) has a higher clearance, suggesting faster metabolism.

**13. t1/2:** Ligand A (3.778) has a short half-life, while Ligand B (-10.831) has a negative value, which is not physically meaningful and suggests potential issues with the in vitro assay or data quality.

**14. Pgp:** Ligand A (0.187) has low P-gp efflux, which is good for CNS penetration. Ligand B (0.097) is even lower, further enhancing CNS exposure potential.

**15. Binding Affinity:** Ligand B (-8.0 kcal/mol) has a significantly stronger binding affinity than Ligand A (-7.6 kcal/mol). This 0.4 kcal/mol difference is substantial and can outweigh some ADME liabilities.

**Overall Assessment:**

Ligand B is the superior candidate. While Ligand A has excellent metabolic stability, Ligand B excels in the most critical areas for a CNS GPCR target: BBB penetration and binding affinity. The stronger affinity of Ligand B is a significant advantage. The lower DILI risk is also favorable. Although its Caco-2 and solubility are poor, the strong affinity and excellent BBB penetration are likely to compensate. The negative t1/2 value for Ligand B is concerning, but the other factors strongly favor it.

Output:
1
2025-04-17 07:54:25,206 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (357.479 and 386.298 Da) fall within the ideal range of 200-500 Da.

**TPSA:** Ligand A (71.09) is better than Ligand B (41.29). For CNS targets, we want TPSA <= 90, both are well within this range, but A is slightly higher.

**logP:** Both ligands have good logP values (3.056 and 4.491), falling within the optimal 1-3 range. Ligand B is a bit higher, potentially increasing off-target effects, but not drastically.

**H-Bond Donors/Acceptors:** Ligand A has 2 HBD and 4 HBA, while Ligand B has 1 HBD and 4 HBA. Both are within acceptable limits (<=5 HBD and <=10 HBA).

**QED:** Both ligands have similar QED values (0.799 and 0.762), indicating good drug-likeness.

**DILI:** Ligand A (59.287) has a higher DILI risk than Ligand B (18.379). This is a significant advantage for Ligand B.

**BBB:** Ligand A (68.554) and Ligand B (73.827) both have good BBB penetration, but Ligand B is slightly better, exceeding the 70% threshold. This is crucial for a CNS target like DRD2.

**Caco-2 Permeability:** Both have negative Caco-2 values (-4.968 and -4.871), which is unusual and suggests poor permeability. However, these values are on a scale where negative values are possible, and direct comparison is difficult without knowing the scale's specifics.

**Aqueous Solubility:** Both ligands have very poor aqueous solubility (-4.585 and -4.692). This is a concern for bioavailability.

**hERG Inhibition:** Ligand A (0.626) has a slightly higher hERG inhibition risk than Ligand B (0.902), meaning B is better.

**Microsomal Clearance:** Ligand A (65.218) has a lower microsomal clearance than Ligand B (69.744), indicating better metabolic stability.

**In vitro Half-Life:** Ligand A (4.817) has a shorter half-life than Ligand B (-2.827). The negative value for B is unusual and warrants further investigation, but generally, a longer half-life is preferred.

**P-gp Efflux:** Ligand A (0.251) has lower P-gp efflux than Ligand B (0.687), which is beneficial for CNS exposure.

**Binding Affinity:** Ligand B (-7.4 kcal/mol) has a significantly stronger binding affinity than Ligand A (-9.5 kcal/mol). This is a substantial advantage, potentially outweighing some of the ADME drawbacks.

**Overall Assessment:**

Ligand B is the better candidate. While Ligand A has better metabolic stability and P-gp efflux, Ligand B excels in the most critical areas for a CNS-targeting GPCR: significantly stronger binding affinity, better BBB penetration, and a much lower DILI risk. The slightly higher logP of Ligand B is a minor concern compared to these advantages. The unusual negative Caco-2 and half-life values for B would need further investigation, but the affinity difference is substantial.

Output:
1
2025-04-17 07:54:25,206 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (352.435 and 354.422 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (107.69) is higher than the preferred <90 for CNS targets, while Ligand B (75.71) is well within the range. This is a significant advantage for Ligand B.

**logP:** Ligand A (0.002) is very low, potentially hindering membrane permeability. Ligand B (1.227) is within the optimal 1-3 range. This is a clear win for Ligand B.

**H-Bond Donors/Acceptors:** Ligand A has 3 HBD and 6 HBA, acceptable values. Ligand B has 1 HBD and 4 HBA, also acceptable and potentially slightly better for permeability due to fewer hydrogen bonds.

**QED:** Both ligands have good QED scores (0.691 and 0.728), indicating good drug-like properties.

**DILI:** Ligand A (42.807) and Ligand B (35.556) both have low DILI risk, below the 40 threshold.

**BBB:** This is a crucial parameter for CNS targets. Ligand A has a BBB percentile of 21.326, which is poor. Ligand B has a much higher BBB percentile of 90.229, making it far more likely to reach the target in the brain.

**Caco-2 Permeability:** Ligand A (-5.155) has very poor Caco-2 permeability, which is concerning. Ligand B (-4.46) is also not great, but better than A.

**Aqueous Solubility:** Both ligands have poor aqueous solubility (-1.473 and -2.18). This could pose formulation challenges, but is less critical than BBB penetration for a CNS target.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.156 and 0.269).

**Microsomal Clearance:** Ligand A (10.052) has lower clearance than Ligand B (33.238), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand B (-25.414) has a significantly longer half-life than Ligand A (-6.567), which is a major advantage.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.055 and 0.036), which is good.

**Binding Affinity:** Ligand A (-8.0) has a slightly better binding affinity than Ligand B (-7.8), but the difference is less than 1.5 kcal/mol, so it's not a decisive factor.

**Overall:**

Ligand B is significantly better suited as a drug candidate for DRD2. Its superior BBB penetration (90.229 vs 21.326), optimal logP (1.227 vs 0.002), lower TPSA (75.71 vs 107.69), and longer half-life (-25.414 vs -6.567) outweigh the slightly better affinity of Ligand A. The poor logP and BBB of Ligand A are major liabilities for a CNS-targeting drug.



Output:
1
2025-04-17 07:54:25,206 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (354.441 and 352.385 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (40.62) is significantly better than Ligand B (69.3). For CNS targets, we want TPSA <= 90, and ideally closer to 60. Ligand A is much closer to this ideal. Ligand B is pushing the upper limit and could face permeability issues.

**3. logP:** Both ligands have acceptable logP values (2.919 and 1.544), falling within the 1-3 range. Ligand A is slightly better, being closer to the optimal range.

**4. H-Bond Donors:** Both ligands have low HBD counts (0 and 1), which is favorable for permeability.

**5. H-Bond Acceptors:** Both ligands have low HBA counts (2 and 3), also favorable for permeability.

**6. QED:** Both ligands have good QED scores (0.782 and 0.897), indicating good drug-like properties.

**7. DILI:** Ligand A (13.804) has a much lower DILI risk than Ligand B (41.566). This is a significant advantage for Ligand A.

**8. BBB:** Ligand A (93.563) has a substantially better BBB penetration score than Ligand B (80.419). This is *critical* for a CNS target like DRD2.

**9. Caco-2 Permeability:** Ligand A (-4.483) and Ligand B (-4.852) both have negative Caco-2 values, which is unusual and suggests poor permeability. However, the scale is not specified, so it's difficult to interpret.

**10. Aqueous Solubility:** Both ligands have poor aqueous solubility (-3.484 and -2.154). This could pose formulation challenges.

**11. hERG Inhibition:** Both ligands show low hERG inhibition risk (0.674 and 0.42).

**12. Microsomal Clearance:** Ligand B (26.229) has lower microsomal clearance than Ligand A (46.117), suggesting better metabolic stability.

**13. In vitro Half-Life:** Ligand B (-45.633) has a significantly longer in vitro half-life than Ligand A (-23.86), which is desirable.

**14. P-gp Efflux:** Both ligands show low P-gp efflux liability (0.193 and 0.063).

**15. Binding Affinity:** Both ligands have similar binding affinities (-9.0 and -8.2 kcal/mol). While both are good, Ligand A has a slightly better affinity.

**Overall Assessment:**

Ligand A is the stronger candidate. While Ligand B has better metabolic stability and half-life, Ligand A excels in the most critical areas for a CNS GPCR target: TPSA, BBB penetration, and DILI risk. The slightly better affinity of Ligand A further supports this conclusion. The poor solubility and Caco-2 values are concerns for both, but can potentially be addressed with formulation strategies. The substantial advantage in BBB penetration for Ligand A outweighs the benefits of Ligand B's improved metabolic profile in this specific context.

Output:
1
2025-04-17 07:54:25,207 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B based on the provided guidelines, prioritizing GPCR-specific properties (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (345.443 Da) is slightly lower, which *could* be beneficial for permeability, but both are acceptable.

**TPSA:** Both ligands have TPSA values below the 90 A^2 threshold desirable for CNS targets. Ligand B (58.64 A^2) is significantly lower than Ligand A (78.51 A^2), which is a clear advantage for brain penetration.

**logP:** Both ligands have logP values within the optimal range (1-3). Ligand A (1.712) is slightly lower, while Ligand B (2.69) is closer to the upper end, which is acceptable.

**H-Bond Donors/Acceptors:** Ligand A has 2 HBD and 3 HBA, while Ligand B has 1 HBD and 4 HBA. Both are within acceptable limits (<=5 HBD and <=10 HBA).

**QED:** Both ligands have QED values above 0.5, indicating good drug-like properties. Ligand A (0.753) is slightly better than Ligand B (0.678).

**DILI:** Ligand A (42.497) has a lower DILI risk than Ligand B (9.888), which is a significant advantage.

**BBB:** Ligand B (83.56) has a substantially higher BBB percentile than Ligand A (59.946). This is a *critical* factor for a CNS target like DRD2.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values, which is unusual and suggests poor permeability. This is a concern for both.

**Aqueous Solubility:** Both ligands have negative solubility values, indicating very poor aqueous solubility. This is a major drawback for both.

**hERG Inhibition:** Both ligands have low hERG inhibition liability, which is good. Ligand A (0.207) is slightly better than Ligand B (0.551).

**Microsomal Clearance:** Ligand A (-4.434) has a much lower (better) microsomal clearance than Ligand B (50.06). This indicates greater metabolic stability for Ligand A.

**In vitro Half-Life:** Ligand A (7.588 hours) has a longer half-life than Ligand B (-3.887 hours).

**P-gp Efflux:** Ligand A (0.038) has much lower P-gp efflux liability than Ligand B (0.103), which is beneficial for CNS penetration.

**Binding Affinity:** Ligand A (-7.7 kcal/mol) has a slightly better binding affinity than Ligand B (-7.1 kcal/mol). While the difference is not huge (less than 1.5 kcal/mol), it contributes to the overall assessment.

**Overall Assessment:**

Ligand A has advantages in DILI, metabolic stability (Cl_mic), half-life, P-gp efflux, and binding affinity. However, Ligand B *significantly* outperforms Ligand A in BBB penetration and has a lower TPSA. For a CNS target like DRD2, BBB penetration is paramount. While the solubility and Caco-2 values are poor for both, the superior BBB score of Ligand B outweighs the other advantages of Ligand A.

Output:
1
2025-04-17 07:54:25,207 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (360.447 and 367.471 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (104.02) is slightly higher than Ligand B (98.66), but both are below the 140 A^2 threshold for oral absorption and reasonably close to the 90 A^2 target for CNS penetration. Ligand B is preferable here.

**logP:** Ligand A (0.613) is quite low, potentially hindering permeability. Ligand B (1.724) is better, falling within the optimal 1-3 range. This is a significant advantage for Ligand B.

**H-Bond Donors/Acceptors:** Ligand A has 3 HBD and 10 HBA, while Ligand B has 1 HBD and 6 HBA. Both are within acceptable limits, but Ligand B is slightly better with fewer H-bonds, potentially improving permeability.

**QED:** Both ligands have good QED scores (0.563 and 0.632), indicating good drug-like properties.

**DILI:** Ligand A has a DILI risk of 83.753, which is concerning (high risk). Ligand B has a much lower DILI risk of 37.65, which is good. This is a major advantage for Ligand B.

**BBB:** Both ligands have similar BBB penetration (32.416 and 83.172 percentile). Ligand B is significantly better, exceeding the desirable >70% threshold for CNS targets.

**Caco-2 Permeability:** Both have negative Caco-2 values (-5.587 and -5.216). These values are unusual and difficult to interpret without further context, but suggest poor permeability.

**Aqueous Solubility:** Both ligands have very poor aqueous solubility (-2.463 and -2.52). This is a significant drawback for both.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.471 and 0.165).

**Microsomal Clearance:** Ligand A has a lower Cl_mic (20.261) than Ligand B (60.791), suggesting better metabolic stability. This favors Ligand A.

**In vitro Half-Life:** Ligand A has a longer half-life (53.795) than Ligand B (0.867). This is a significant advantage for Ligand A.

**P-gp Efflux:** Ligand A has a very low P-gp efflux liability (0.006), which is excellent for CNS exposure. Ligand B has a higher P-gp efflux liability (0.208). This favors Ligand A.

**Binding Affinity:** Ligand A has a stronger binding affinity (-7.6 kcal/mol) than Ligand B (-6.8 kcal/mol). This is a substantial advantage for Ligand A, potentially outweighing some of its ADME drawbacks.

**Overall Assessment:**

While Ligand A has superior binding affinity, half-life, metabolic stability, and P-gp efflux, its very low logP, high DILI risk, and poor solubility are major concerns. Ligand B has a better logP, significantly lower DILI risk, and excellent BBB penetration, making it more likely to be a viable drug candidate despite its weaker affinity and poorer metabolic stability. The improved ADME properties of Ligand B, particularly the lower DILI and better BBB penetration, are critical for a CNS-targeting GPCR like DRD2.

Output:
1
2025-04-17 07:54:25,207 - INFO - Reasoning:

Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (352.356 and 347.463 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (51.22) is excellent, well below the 90 A^2 threshold for CNS targets. Ligand B (63.49) is still reasonable but less optimal.

**logP:** Ligand A (3.887) is at the upper end of the optimal range (1-3), but acceptable. Ligand B (1.312) is a bit low, potentially hindering membrane permeability.

**H-Bond Donors/Acceptors:** Ligand A has 1 HBD and 4 HBA, both within acceptable limits. Ligand B has 0 HBD and 6 HBA, also acceptable.

**QED:** Both ligands have QED values (0.802 and 0.63) indicating good drug-like properties.

**DILI:** Ligand A (52.772) has a moderate DILI risk, but still below the concerning 60 percentile. Ligand B (23.846) has a very low DILI risk, which is favorable.

**BBB:** Ligand A (73.672) shows good BBB penetration, exceeding the 70% threshold. Ligand B (69.407) is close, but slightly below the desired threshold.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.68 and -4.933), which is unusual and suggests poor permeability. These values are likely errors or indicate a significant issue with intestinal absorption.

**Aqueous Solubility:** Both ligands have negative solubility values (-4.064 and -0.542), indicating very poor aqueous solubility. This is a major concern for bioavailability.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.689 and 0.224).

**Microsomal Clearance:** Ligand A (84.995) has higher microsomal clearance, suggesting faster metabolism and potentially lower in vivo exposure. Ligand B (35.121) has significantly lower clearance, indicating better metabolic stability.

**In vitro Half-Life:** Both have similar in vitro half-lives (10.939 and 10.543 hours).

**P-gp Efflux:** Both ligands show low P-gp efflux liability (0.244 and 0.06), which is good for CNS penetration.

**Binding Affinity:** Ligand A (-9.2 kcal/mol) has a substantially stronger binding affinity than Ligand B (-7.6 kcal/mol). This is a significant advantage, potentially outweighing some of the ADME drawbacks.

**Overall Assessment:**

Despite the concerning Caco-2 and solubility values for both, Ligand A is the more promising candidate. Its significantly stronger binding affinity (-9.2 vs -7.6 kcal/mol) is a major advantage for a GPCR target like DRD2. It also has better TPSA and BBB penetration. While Ligand B has a lower DILI risk and better metabolic stability, the affinity difference is too large to ignore. The poor solubility and permeability of both compounds would need to be addressed through formulation or structural modifications, but the higher potency of Ligand A provides a better starting point.

Output:
1
2025-04-17 07:54:25,207 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 drug candidates, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (360.797 and 349.523 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (79.73) is slightly higher than Ligand B (64.52). Both are below the 90 A^2 threshold desirable for CNS targets, but Ligand B is better.

**logP:** Both ligands have good logP values (2.189 and 2.382), falling within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A has 1 HBD and 6 HBA, while Ligand B has 2 HBD and 6 HBA. Both are within acceptable limits (<=5 HBD and <=10 HBA).

**QED:** Both ligands have good QED scores (0.5 and 0.703), indicating good drug-like properties.

**DILI:** Ligand A has a DILI risk of 78.054, which is concerning (approaching the high-risk threshold of >60). Ligand B has a much lower DILI risk of 10.198, which is excellent.

**BBB:** Ligand B (76.696) has a significantly better BBB penetration score than Ligand A (57.736). This is a critical advantage for a CNS target like DRD2.

**Caco-2 Permeability:** Ligand A (-4.709) has poor Caco-2 permeability, while Ligand B (-5.013) also has poor Caco-2 permeability.

**Aqueous Solubility:** Ligand A (-3.519) has poor aqueous solubility, while Ligand B (-1.153) has slightly better solubility.

**hERG Inhibition:** Ligand A (0.28) shows a lower hERG inhibition liability than Ligand B (0.945), which is favorable.

**Microsomal Clearance:** Ligand A (69.728) has lower microsomal clearance, indicating better metabolic stability, compared to Ligand B (12.304).

**In vitro Half-Life:** Ligand B (45.542) has a significantly longer in vitro half-life than Ligand A (0.865).

**P-gp Efflux:** Ligand A (0.348) has lower P-gp efflux, suggesting better CNS exposure, than Ligand B (0.074).

**Binding Affinity:** Ligand B (-7.1 kcal/mol) has a slightly better binding affinity than Ligand A (-9.1 kcal/mol). While A has better affinity, the difference is not substantial enough to outweigh the other factors.

**Overall Assessment:**

Ligand B is the more promising candidate. While Ligand A has slightly better binding affinity and lower P-gp efflux, Ligand B excels in crucial areas for a CNS-targeting GPCR: significantly better BBB penetration, lower DILI risk, and a longer in vitro half-life. The slightly higher hERG risk for Ligand B is a concern, but potentially mitigable with further optimization. The lower metabolic stability of Ligand B is also a concern, but can also be addressed. The poor Caco-2 permeability for both ligands is a shared issue, but less critical for a CNS target.



Output:
1
2025-04-17 07:54:25,207 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (349.366 Da) is slightly lower, which could be advantageous for permeability. Ligand B (369.443 Da) is also good.

**TPSA:** Ligand B (97.83) is significantly better than Ligand A (120). For CNS targets, we want TPSA <= 90, so Ligand B is closer to this threshold.

**logP:** Both ligands have acceptable logP values. Ligand A (1.605) is optimal (1-3), while Ligand B (0.369) is a bit low, potentially hindering permeation.

**H-Bond Donors/Acceptors:** Ligand A has 4 HBD and 5 HBA, which are reasonable. Ligand B has 1 HBD and 7 HBA, also acceptable, but slightly higher HBA could impact permeability.

**QED:** Both ligands have good QED scores (A: 0.591, B: 0.665), indicating drug-like properties.

**DILI:** Ligand B (72.082) has a higher DILI risk than Ligand A (67.429), but both are reasonably low.

**BBB:** Ligand A (30.748) has a significantly better BBB percentile than Ligand B (23.187). This is a *critical* factor for a CNS target like DRD2.

**Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and suggests poor permeability. However, these values can be unreliable and require experimental validation.

**Aqueous Solubility:** Both have negative solubility values, also unusual. Again, experimental validation is needed.

**hERG:** Both ligands have very low hERG inhibition liability (A: 0.198, B: 0.024), which is excellent.

**Microsomal Clearance:** Ligand B (9.186) has a much lower microsomal clearance than Ligand A (33.114), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand B (4.911) has a slightly better in vitro half-life than Ligand A (-47.84), but the negative value for A is concerning and likely an error.

**P-gp Efflux:** Both have very low P-gp efflux liability (A: 0.052, B: 0.021), which is favorable for CNS penetration.

**Binding Affinity:** Ligand A (-8.7 kcal/mol) has a significantly stronger binding affinity than Ligand B (-6.6 kcal/mol). This is a substantial difference (over 2 kcal/mol), and often outweighs minor ADME concerns.

**Overall Assessment:**

Despite Ligand B having a better TPSA and lower Cl_mic, Ligand A is the stronger candidate. The significantly better BBB penetration and substantially higher binding affinity of Ligand A are crucial for a CNS GPCR target. The slightly lower logP of Ligand B is a concern, and the negative solubility and Caco-2 values for both require experimental verification. The large affinity difference is the deciding factor.

Output:
1
2025-04-17 07:54:25,207 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (353.5 & 368.5 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (61.88) is significantly better than Ligand B (107.89). For CNS targets, we want TPSA <= 90, and A is comfortably within this, while B is above.

**logP:** Ligand A (1.641) is within the optimal 1-3 range. Ligand B (-0.166) is below 1, which could hinder permeation.

**H-Bond Donors/Acceptors:** Ligand A (HBD=1, HBA=4) and Ligand B (HBD=4, HBA=6) both have reasonable counts, within the suggested limits.

**QED:** Both ligands have acceptable QED values (A: 0.684, B: 0.508), indicating good drug-like properties.

**DILI:** Ligand A (8.104) has a much lower DILI risk than Ligand B (42.536), which is a significant advantage.

**BBB:** This is crucial for a CNS target. Ligand A (64.482) is moderately good, but Ligand B (13.726) is very poor, suggesting limited brain penetration.

**Caco-2 Permeability:** Ligand A (-4.805) and Ligand B (-5.993) are both negative, indicating low permeability.

**Aqueous Solubility:** Ligand A (-0.584) is slightly better than Ligand B (-2.054), but both are poor.

**hERG Inhibition:** Both ligands have very low hERG inhibition risk (A: 0.227, B: 0.12).

**Microsomal Clearance:** Ligand A (9.944) has a higher clearance than Ligand B (5.371), indicating lower metabolic stability.

**In vitro Half-Life:** Ligand B (9.022) has a better half-life than Ligand A (-7.356).

**P-gp Efflux:** Ligand A (0.04) has a lower P-gp efflux liability than Ligand B (0.031), which is beneficial for CNS exposure.

**Binding Affinity:** Ligand B (-7.7) has a slightly better binding affinity than Ligand A (-8.5). However, the difference is only 0.8 kcal/mol, and other factors are more critical.

**Overall Assessment:**

Ligand A is the superior candidate. While Ligand B has slightly better affinity and half-life, Ligand A excels in critical areas for a CNS-targeting GPCR: TPSA, logP, BBB penetration, and DILI risk. The significantly better BBB score for Ligand A outweighs the small affinity advantage of Ligand B. The lower TPSA and more favorable logP of Ligand A also suggest better permeability.

Output:
1
2025-04-17 07:54:25,208 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (343.515 and 348.443 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (35.58) is excellent, well below the 90 A^2 threshold for CNS targets. Ligand B (78.87) is higher, but still reasonably acceptable, though less favorable for CNS penetration.

**3. logP:** Ligand A (2.603) is optimal (1-3). Ligand B (1.363) is on the lower end, potentially hindering permeability.

**4. H-Bond Donors:** Ligand A (1) and Ligand B (2) are both within the acceptable limit of <=5.

**5. H-Bond Acceptors:** Ligand A (3) and Ligand B (4) are both within the acceptable limit of <=10.

**6. QED:** Ligand A (0.862) is excellent, indicating high drug-likeness. Ligand B (0.681) is still acceptable, but less optimal.

**7. DILI:** Ligand A (2.637) has a very low DILI risk. Ligand B (17.798) is higher, indicating a moderate risk of liver injury.

**8. BBB:** This is crucial for a CNS target like DRD2. Ligand A (80.962) has a very good BBB penetration percentile. Ligand B (47.15) is significantly lower, suggesting poor brain penetration.

**9. Caco-2 Permeability:** Ligand A (-5.086) and Ligand B (-4.755) are both negative, which is unusual and suggests poor permeability. However, the scale is not specified, so it is difficult to interpret.

**10. Aqueous Solubility:** Both ligands have very poor aqueous solubility (-1.805 and -1.621). This could pose formulation challenges.

**11. hERG Inhibition:** Ligand A (0.923) has a low hERG risk. Ligand B (0.191) also has a low hERG risk.

**12. Microsomal Clearance:** Ligand A (-2.235) suggests good metabolic stability (negative value). Ligand B (27.779) indicates rapid metabolism.

**13. In vitro Half-Life:** Ligand A (-12.896) suggests a very long half-life. Ligand B (-1.946) suggests a short half-life.

**14. P-gp Efflux:** Ligand A (0.118) has low P-gp efflux, which is favorable for CNS exposure. Ligand B (0.038) also has low P-gp efflux.

**15. Binding Affinity:** Ligand A (-9.0) has a significantly stronger binding affinity than Ligand B (-7.8). This is a >1.2 kcal/mol difference, which is substantial.

**Overall Assessment:**

Ligand A is clearly superior. It has a better BBB score, a more optimal logP, better metabolic stability, a longer half-life, a significantly stronger binding affinity, and a lower DILI risk. While both have poor solubility, the other advantages of Ligand A, particularly its BBB penetration and binding affinity, outweigh this drawback. The strong affinity of Ligand A could potentially compensate for the solubility issues through formulation strategies. Ligand B's poor BBB penetration and rapid metabolism are significant liabilities for a CNS-targeted drug.

Output:
1
2025-04-17 07:54:25,208 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (345.403 and 356.535 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (89.78) is excellent, falling below the 90 A^2 threshold for CNS targets. Ligand B (32.34) is also very good, well below the threshold.

**logP:** Ligand A (0.908) is slightly low, potentially hindering permeation, but still within an acceptable range. Ligand B (4.594) is higher, potentially causing solubility issues or off-target interactions, but not drastically so.

**H-Bond Donors/Acceptors:** Ligand A has 2 HBD and 6 HBA, which are reasonable. Ligand B has 1 HBD and 3 HBA, also reasonable. Both are within the guidelines.

**QED:** Both ligands have good QED scores (0.841 and 0.869), indicating good drug-like properties.

**DILI:** Ligand A (61.07) has a higher DILI risk than Ligand B (46.103), but both are still within an acceptable range (<60 is good).

**BBB:** Ligand B (83.986) has a significantly better BBB penetration percentile than Ligand A (77.705). This is a crucial factor for a CNS target like DRD2.

**Caco-2 Permeability:** Ligand A (-4.962) has poor Caco-2 permeability, a significant drawback. Ligand B (-5.236) is also poor, but slightly better than A.

**Aqueous Solubility:** Both ligands have very poor aqueous solubility (-1.793 and -3.031 respectively). This could pose formulation challenges.

**hERG Inhibition:** Ligand A (0.274) has a lower hERG inhibition liability than Ligand B (0.917), which is preferable.

**Microsomal Clearance:** Ligand A (6.316) has lower microsomal clearance than Ligand B (8.446), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand B (46.898) has a longer in vitro half-life than Ligand A (25.975), which is desirable.

**P-gp Efflux:** Ligand A (0.009) exhibits significantly lower P-gp efflux than Ligand B (0.772), which is highly favorable for CNS penetration.

**Binding Affinity:** Ligand B (-9.7 kcal/mol) has a stronger binding affinity than Ligand A (-8.8 kcal/mol). The difference of 0.9 kcal/mol is substantial and can outweigh some of the ADME drawbacks.

**Overall Assessment:**

Ligand B is the better candidate. Its superior binding affinity and significantly improved BBB penetration outweigh the slightly higher logP and P-gp efflux. While both have poor solubility and Caco-2 permeability, the stronger binding and better CNS penetration of Ligand B are critical for a DRD2 ligand. The lower hERG risk of Ligand A is a positive, but the affinity difference is more important.



Output:
1
2025-04-17 07:54:25,208 - INFO - Batch 404 complete. Total preferences: 6464
2025-04-17 07:54:25,208 - INFO - Processing batch 405/512...
2025-04-17 07:55:06,808 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (354.5 & 371.4 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (69.64) is better than Ligand B (62.73). Both are below the 90 A^2 threshold desirable for CNS targets, but A is closer to the ideal.

**3. logP:** Ligand A (2.961) is optimal (1-3), while Ligand B (4.555) is slightly high, potentially leading to solubility issues or off-target interactions.

**4. H-Bond Donors:** Both ligands have 2 HBD, which is within the acceptable limit of <=5.

**5. H-Bond Acceptors:** Ligand A has 3 HBA, and Ligand B has 6. Both are within the acceptable limit of <=10, but Ligand A is preferable.

**6. QED:** Both ligands have similar QED values (0.77 and 0.78), indicating good drug-likeness.

**7. DILI:** Ligand A (12.796) has a significantly lower DILI risk than Ligand B (72.819). This is a major advantage for Ligand A.

**8. BBB:** Ligand B (77.937) has a much better BBB penetration percentile than Ligand A (55.642). This is a critical factor for a CNS target like DRD2.

**9. Caco-2 Permeability:** Both have negative values, which is unusual. It's difficult to interpret without knowing the scale. However, the values are similar.

**10. Aqueous Solubility:** Both have negative values, indicating poor solubility. Ligand A (-3.155) is slightly better than Ligand B (-5.514).

**11. hERG Inhibition:** Both ligands have similar, low hERG inhibition liability (0.489 and 0.486).

**12. Microsomal Clearance:** Ligand A (41.728) has lower microsomal clearance than Ligand B (68.199), suggesting better metabolic stability.

**13. In vitro Half-Life:** Ligand B (31.288) has a significantly longer in vitro half-life than Ligand A (-2.243). This is a positive for Ligand B.

**14. P-gp Efflux:** Both ligands have similar, low P-gp efflux liability (0.155 and 0.137).

**15. Binding Affinity:** Ligand B (-8.4 kcal/mol) has a stronger binding affinity than Ligand A (-7.7 kcal/mol). This is a significant advantage for Ligand B, exceeding the 1.5 kcal/mol threshold.

**Overall Assessment:**

Ligand B excels in BBB penetration and binding affinity, which are crucial for a CNS GPCR target. The longer half-life is also beneficial. However, it has a higher logP and a significantly higher DILI risk. Ligand A has better TPSA, lower DILI, and better metabolic stability.

The difference in binding affinity (0.7 kcal/mol) is substantial enough to outweigh the slightly higher logP and DILI risk of Ligand B, especially considering the importance of strong binding for GPCR ligands. The improved BBB penetration is also a decisive factor.

Output:
1
2025-04-17 07:55:06,809 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (347.365 and 344.455 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (61.44) is significantly better than Ligand B (69.64). For CNS targets, we want TPSA <= 90, and ideally closer to 60. Ligand A is much closer to this ideal.

**3. logP:** Ligand A (3.63) is within the optimal range (1-3), while Ligand B (1.943) is at the lower end. While not terrible, lower logP can sometimes hinder permeability.

**4. H-Bond Donors:** Both have 2 HBD, which is acceptable (<=5).

**5. H-Bond Acceptors:** Ligand A has 2 HBA, while Ligand B has 3. Both are within the acceptable range (<=10).

**6. QED:** Both ligands have reasonable QED values (0.868 and 0.694), indicating good drug-like properties.

**7. DILI:** Ligand A (75.921) has a higher DILI risk than Ligand B (13.416). This is a significant concern for Ligand A.

**8. BBB:** Ligand A (78.054) has a much better BBB penetration percentile than Ligand B (53.587). For a CNS target like DRD2, this is a crucial advantage.

**9. Caco-2 Permeability:** Ligand A (-4.322) has better Caco-2 permeability than Ligand B (-4.617), although both are negative values, suggesting poor permeability.

**10. Aqueous Solubility:** Ligand A (-4.501) has slightly better aqueous solubility than Ligand B (-2.432), although both are negative values, suggesting poor solubility.

**11. hERG Inhibition:** Ligand A (0.623) has a slightly higher hERG inhibition risk than Ligand B (0.152), but both are relatively low.

**12. Microsomal Clearance:** Ligand A (69.552) has higher microsomal clearance than Ligand B (50.327), indicating lower metabolic stability.

**13. In vitro Half-Life:** Ligand B (-28.425) has a much longer in vitro half-life than Ligand A (49.186). This is a significant advantage for Ligand B.

**14. P-gp Efflux:** Ligand A (0.192) has lower P-gp efflux than Ligand B (0.118), which is favorable for CNS penetration.

**15. Binding Affinity:** Ligand A (-9.5 kcal/mol) has a significantly stronger binding affinity than Ligand B (-7.8 kcal/mol). This is a substantial advantage, potentially outweighing some of the ADME drawbacks.

**Overall Assessment:**

Ligand A has a much stronger binding affinity and better BBB penetration, which are critical for a CNS GPCR target. However, it has a significantly higher DILI risk and poorer metabolic stability. Ligand B has a better safety profile (lower DILI) and longer half-life, but weaker affinity and lower BBB penetration.

The difference in binding affinity (-9.5 vs -7.8 kcal/mol) is substantial (1.7 kcal/mol), and this is a major driver in my decision. Given the importance of affinity for GPCRs, and the fact that we can potentially mitigate some of the ADME issues with further optimization, I believe Ligand A is the more promising candidate.

Output:
1
2025-04-17 07:55:06,809 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B based on the provided guidelines, prioritizing GPCR-specific properties (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (352.395 Da) is slightly lower, which could be beneficial for permeability, but both are acceptable.

**TPSA:** Ligand A (118.45) is better than Ligand B (58.64), being closer to the optimal range for CNS targets (<=90). Ligand B is quite low, which might suggest reduced hydrogen bonding and potentially lower solubility.

**logP:** Ligand B (2.295) is within the optimal range (1-3), while Ligand A (-1.127) is below 1, which could hinder permeation. This is a significant drawback for Ligand A.

**H-Bond Donors/Acceptors:** Ligand A (2 HBD, 7 HBA) is slightly higher in both counts than Ligand B (1 HBD, 3 HBA), but both are within acceptable limits.

**QED:** Ligand B (0.787) has a better QED score than Ligand A (0.474), indicating a more drug-like profile.

**DILI:** Ligand B (16.789) has a much lower DILI risk than Ligand A (51.648). This is a substantial advantage for Ligand B.

**BBB:** Ligand B (96.084) has excellent BBB penetration, exceeding the desirable threshold of >70, while Ligand A (40.791) is below this threshold. This is a critical advantage for a CNS target like DRD2.

**Caco-2 Permeability:** Ligand A (-5.497) has a negative Caco-2 value, which is concerning and suggests very poor permeability. Ligand B (-4.363) is also negative but less so.

**Aqueous Solubility:** Ligand A (-0.871) has slightly better solubility than Ligand B (-2.197), but both are poor.

**hERG:** Ligand A (0.028) has a very low hERG risk, while Ligand B (0.661) has a slightly higher, but still acceptable, risk.

**Microsomal Clearance:** Ligand A (-6.852) has a lower (better) microsomal clearance than Ligand B (14.801), indicating greater metabolic stability.

**In vitro Half-Life:** Ligand A (7.09) has a better in vitro half-life than Ligand B (-11.593).

**P-gp Efflux:** Ligand A (0.009) has very low P-gp efflux, which is favorable for CNS exposure. Ligand B (0.033) is also low, but slightly higher.

**Binding Affinity:** Ligand B (-8.2) has a slightly better binding affinity than Ligand A (-7.9), although the difference is relatively small.

**Overall Assessment:**

Ligand B is substantially better overall. While Ligand A has advantages in metabolic stability (Cl_mic) and P-gp efflux, these are outweighed by its poor logP, BBB penetration, Caco-2 permeability, and higher DILI risk. Ligand B excels in crucial GPCR-specific properties like BBB penetration and logP, and also has a better QED score and significantly lower DILI risk. The slightly better affinity of Ligand B further solidifies its position as the more promising candidate.

Output:
1
2025-04-17 07:55:06,809 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (360.885 and 352.435 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (41.57) is significantly better than Ligand B (85.69). For CNS targets, we want TPSA <= 90, and ideally closer to 60. Ligand A is well within this range, while Ligand B is approaching the upper limit and could face permeability issues.

**logP:** Ligand A (3.699) is optimal (1-3), while Ligand B (0.35) is quite low. Low logP can hinder membrane permeability and reduce brain penetration.

**H-Bond Donors & Acceptors:** Both have acceptable HBD counts (1). Ligand B has a higher HBA count (6) compared to Ligand A (3), which is less desirable, potentially impacting permeability.

**QED:** Both ligands have reasonable QED values (0.818 and 0.683), indicating good drug-like properties.

**DILI:** Both ligands have low DILI risk (32.842 and 39.938), which is favorable.

**BBB:** Both ligands have similar BBB penetration (54.75 and 51.687). While neither is above the ideal 70, they are both in a reasonable range, and this isn't a major differentiator here.

**Caco-2 Permeability:** Ligand A (-4.702) has a better (less negative) Caco-2 value than Ligand B (-5.052), suggesting better intestinal absorption.

**Aqueous Solubility:** Ligand A (-4.062) has a better (less negative) solubility value than Ligand B (-0.919).

**hERG Inhibition:** Ligand A (0.77) has a lower hERG risk than Ligand B (0.144), which is a significant advantage.

**Microsomal Clearance:** Ligand A (68.092) has a higher (worse) microsomal clearance than Ligand B (22.05). This suggests Ligand B is more metabolically stable.

**In vitro Half-Life:** Ligand A (52.037) has a longer half-life than Ligand B (-7.776), which is a positive.

**P-gp Efflux:** Ligand A (0.181) has lower P-gp efflux than Ligand B (0.012), which is beneficial for CNS penetration.

**Binding Affinity:** Ligand A (-8.1 kcal/mol) has a slightly better binding affinity than Ligand B (-7.4 kcal/mol). While both are good, the 0.7 kcal/mol difference is meaningful and can compensate for some ADME drawbacks.

**Overall Assessment:**

Ligand A is significantly better overall. Its superior logP, TPSA, solubility, hERG risk, and P-gp efflux, combined with comparable BBB and slightly better affinity, outweigh the higher microsomal clearance. Ligand B's low logP is a major concern for CNS penetration, and its higher HBA count and lower solubility are also unfavorable. The better metabolic stability of Ligand B is a plus, but not enough to overcome the other significant deficiencies.

Output:
1
2025-04-17 07:55:06,809 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (397.86 and 358.87 Da) fall within the ideal range of 200-500 Da.

**TPSA:** Ligand A (105.76) is higher than Ligand B (56.33). For CNS targets, TPSA should be <= 90. Ligand B is significantly better here.

**logP:** Both ligands have good logP values (2.45 and 3.98), falling within the optimal range of 1-3. Ligand B is slightly higher, which could be a minor concern for solubility, but not a dealbreaker.

**H-Bond Donors/Acceptors:** Ligand A has 3 HBD and 5 HBA, while Ligand B has 2 HBD and 2 HBA. Both are within acceptable limits (<=5 HBD and <=10 HBA). Ligand B is preferable due to fewer potential off-target interactions.

**QED:** Ligand B (0.81) has a significantly better QED score than Ligand A (0.415), indicating a more drug-like profile.

**DILI:** Ligand A (84.22) has a higher DILI risk than Ligand B (39.67). Lower DILI is preferred.

**BBB:** Both ligands have reasonable BBB penetration (60.68% and 67.35%). However, >70% is desirable for CNS targets. Ligand B is slightly better.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.99 and -4.99). This is unusual and suggests poor permeability.

**Aqueous Solubility:** Both ligands have negative solubility values (-4.34 and -4.29), indicating very poor aqueous solubility. This is a significant concern.

**hERG Inhibition:** Both ligands show low hERG inhibition risk (0.56 and 0.81).

**Microsomal Clearance:** Ligand B (4.10) has significantly lower microsomal clearance than Ligand A (27.38), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand B (31.21) has a longer in vitro half-life than Ligand A (-24.30), which is desirable.

**P-gp Efflux:** Ligand A (0.2) has lower P-gp efflux than Ligand B (0.37), which is favorable for CNS exposure.

**Binding Affinity:** Ligand B (-9.3 kcal/mol) has a significantly stronger binding affinity than Ligand A (-7.7 kcal/mol). This is a crucial advantage, potentially outweighing some of the ADME drawbacks.

**Overall Assessment:**

Ligand B is the stronger candidate. While both have poor solubility and permeability, Ligand B excels in key areas: significantly better QED, lower DILI risk, better metabolic stability (lower Cl_mic, longer t1/2), and *much* stronger binding affinity. The stronger affinity is particularly important for a GPCR target. The slightly better BBB and lower HBD/HBA counts also contribute to its favorability.

Output:
1
2025-04-17 07:55:06,809 - INFO - Reasoning:

Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (362.47 and 346.431 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (52.57) is excellent, well below the 90 A^2 threshold for CNS targets. Ligand B (96.11) is higher, but still potentially acceptable, though less ideal.

**3. logP:** Ligand A (3.589) is within the optimal 1-3 range. Ligand B (1.095) is on the lower side, potentially hindering permeability.

**4. H-Bond Donors:** Ligand A (2) and Ligand B (3) are both acceptable, being less than 5.

**5. H-Bond Acceptors:** Ligand A (3) and Ligand B (4) are both acceptable, being less than 10.

**6. QED:** Both ligands have similar QED values (0.873 and 0.718), indicating good drug-like properties.

**7. DILI:** Both ligands have low DILI risk (38.852 and 31.369), which is favorable.

**8. BBB:** Ligand A (88.988) has a significantly better BBB penetration percentile than Ligand B (58.24). This is a *critical* advantage for a CNS target like DRD2.

**9. Caco-2 Permeability:** Ligand A (-4.598) has poor Caco-2 permeability. Ligand B (-5.512) is also poor, but slightly worse.

**10. Aqueous Solubility:** Ligand A (-3.831) and Ligand B (-2.152) both have poor aqueous solubility.

**11. hERG Inhibition:** Ligand A (0.763) has a slightly higher hERG risk than Ligand B (0.129), but both are relatively low.

**12. Microsomal Clearance:** Ligand A (20.824) has a higher microsomal clearance than Ligand B (0.24), indicating lower metabolic stability.

**13. In vitro Half-Life:** Ligand A (49.767) has a longer in vitro half-life than Ligand B (5.155), which is a positive.

**14. P-gp Efflux:** Ligand A (0.494) has lower P-gp efflux liability than Ligand B (0.01), which is favorable for CNS penetration.

**15. Binding Affinity:** Ligand B (-8.6 kcal/mol) has a significantly stronger binding affinity than Ligand A (-10.2 kcal/mol). This is a substantial advantage.

**Overall Assessment:**

While Ligand B has a superior binding affinity, Ligand A is the better candidate. The critical factor is the BBB penetration. Ligand A's 88.988% BBB percentile is much more promising for a CNS target than Ligand B's 58.24%. The slightly lower affinity of Ligand A can potentially be optimized in subsequent iterations, but improving BBB penetration is far more challenging. Furthermore, Ligand A has better P-gp efflux and a longer half-life. The lower logP of Ligand B is also a concern.

Output:
1
2025-04-17 07:55:06,810 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (340.373 and 345.447 Da) fall within the ideal range of 200-500 Da.

**TPSA:** Ligand A (41.99) is significantly better than Ligand B (90.98). For CNS targets, TPSA should be <= 90, and A is comfortably within this range, while B is right at the upper limit.

**logP:** Ligand A (4.945) is a bit high, potentially leading to solubility issues, but still within a reasonable range. Ligand B (1.855) is lower, which could hinder permeation. Optimal is 1-3.

**H-Bond Donors/Acceptors:** Ligand A (1 HBD, 2 HBA) and Ligand B (2 HBD, 4 HBA) both have acceptable numbers of H-bond donors and acceptors.

**QED:** Both ligands have similar QED values (0.733 and 0.668), indicating good drug-like properties.

**DILI:** Ligand A (84.18) has a higher DILI risk than Ligand B (45.095). This is a negative for Ligand A.

**BBB:** Ligand A (80.574) has a significantly better BBB penetration percentile than Ligand B (62.117). Given DRD2 is a CNS target, this is a crucial advantage for A.

**Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and suggests potential issues with intestinal absorption. However, for CNS targets, this is less critical than BBB.

**Aqueous Solubility:** Both have negative solubility values, indicating poor aqueous solubility. This is a concern for both, but potentially more so for Ligand A given its higher logP.

**hERG Inhibition:** Ligand A (0.792) has a slightly higher hERG risk than Ligand B (0.052). This is a negative for Ligand A.

**Microsomal Clearance:** Ligand A (58.811) has a higher microsomal clearance than Ligand B (30.311), indicating faster metabolism and potentially lower *in vivo* exposure. This favors Ligand B.

**In vitro Half-Life:** Ligand A (103.736) has a longer half-life than Ligand B (2.271), which is desirable.

**P-gp Efflux:** Ligand A (0.667) has lower P-gp efflux than Ligand B (0.056), which is beneficial for CNS penetration.

**Binding Affinity:** Ligand A (-9.4 kcal/mol) has a significantly stronger binding affinity than Ligand B (-8.2 kcal/mol). This is a substantial advantage for Ligand A, potentially outweighing some of its ADME drawbacks. The difference is >1.5 kcal/mol.

**Overall Assessment:**

Ligand A excels in BBB penetration and binding affinity, which are critical for a CNS-targeting GPCR like DRD2. While it has some drawbacks (higher DILI, hERG, and clearance, lower solubility), the strong affinity and good BBB penetration are likely to be decisive. Ligand B has better DILI, hERG, and clearance, but its weaker affinity and lower BBB penetration make it less promising. The 1.2 kcal/mol difference in binding affinity is significant.

Output:
1
2025-04-17 07:55:06,810 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (338.407) is slightly lower, which could be advantageous for permeability.

**TPSA:** Ligand A (71.34) is significantly better than Ligand B (84.5). For a CNS target like DRD2, TPSA should be <= 90, and A is comfortably within this range, while B is approaching the upper limit.

**logP:** Both ligands have acceptable logP values (A: 3.015, B: 1.561), falling within the optimal 1-3 range. Ligand A is slightly higher, which could potentially lead to off-target effects, but is still reasonable.

**H-Bond Donors/Acceptors:** Both have 2 HBD and a reasonable number of HBA (A: 3, B: 4), satisfying the criteria of <=5 HBD and <=10 HBA.

**QED:** Both ligands have acceptable QED values (A: 0.751, B: 0.616), indicating good drug-like properties.

**DILI:** Ligand A (69.523) has a higher DILI risk than Ligand B (44.668). This is a negative for Ligand A.

**BBB:** Ligand A (47.189) has a significantly lower BBB penetration percentile than Ligand B (52.966). While neither is *ideal* (>70), B is better. This is a critical factor for a CNS target.

**Caco-2 Permeability:** Both have negative Caco-2 values (-4.895 and -4.873). This is unusual and suggests poor permeability. However, these values are on a scale where negative values are possible, and the absolute value is more important. They are very similar.

**Aqueous Solubility:** Both have negative solubility values (-3.652 and -2.992). Similar to Caco-2, these values are on a scale where negative values are possible.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (A: 0.432, B: 0.464).

**Microsomal Clearance:** Ligand A (38.235) has significantly lower microsomal clearance than Ligand B (55.89). This suggests better metabolic stability for Ligand A.

**In vitro Half-Life:** Ligand A (131.898) has a much longer in vitro half-life than Ligand B (-50.957). This is a significant advantage for Ligand A.

**P-gp Efflux:** Ligand A (0.291) has lower P-gp efflux liability than Ligand B (0.074). Lower efflux is better, especially for CNS targets, favoring Ligand A.

**Binding Affinity:** Ligand A (-8.2 kcal/mol) has a significantly stronger binding affinity than Ligand B (-7.7 kcal/mol). This 0.5 kcal/mol difference is substantial and can outweigh some ADME drawbacks.

**Overall Assessment:**

Ligand A has a superior binding affinity, better metabolic stability (lower Cl_mic, longer t1/2), and lower P-gp efflux. However, it has a higher DILI risk and lower BBB penetration than Ligand B. The strong affinity of Ligand A is a major advantage, and the lower P-gp efflux and better metabolic stability are also beneficial. The lower BBB of A is concerning, but the strong binding may compensate. Ligand B's better BBB is its main advantage, but the weaker binding and poorer metabolic stability are significant drawbacks. Given the GPCR-specific priorities, the binding affinity is paramount.

Output:
1
2025-04-17 07:55:06,810 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (344.415 Da) is slightly lower, which could be beneficial for permeability, but both are acceptable.

**TPSA:** Ligand A (83.56) is better than Ligand B (51.55) as it is closer to the ideal range for CNS targets (<=90). Ligand B is quite low, which may indicate reduced hydrogen bonding and potentially lower aqueous solubility.

**logP:** Ligand A (1.212) is optimal, while Ligand B (4.356) is high. High logP can lead to poor solubility and off-target effects. This is a significant drawback for Ligand B.

**H-Bond Donors/Acceptors:** Ligand A has 2 HBD and 5 HBA, which are reasonable. Ligand B has 0 HBD and 5 HBA. While not drastically different, the presence of some HBDs in Ligand A can aid solubility.

**QED:** Both ligands have acceptable QED values (Ligand A: 0.441, Ligand B: 0.509), indicating reasonable drug-likeness.

**DILI:** Ligand A (30.826) has a much lower DILI risk than Ligand B (87.282). This is a major advantage for Ligand A.

**BBB:** Ligand A (81.272) has a significantly better BBB penetration prediction than Ligand B (62.699). This is crucial for a CNS target like DRD2.

**Caco-2 Permeability:** Ligand A (-5.403) has a negative value, which is unusual and suggests very poor permeability. Ligand B (-4.547) is also poor, but slightly better than A.

**Aqueous Solubility:** Ligand A (-1.875) is better than Ligand B (-5.87), indicating better solubility.

**hERG Inhibition:** Both ligands have similar, low hERG inhibition risk (0.365 and 0.366).

**Microsomal Clearance:** Ligand A (-2.138) has a negative clearance, which is not physically possible and likely indicates very high metabolic stability. Ligand B (87.578) has a high clearance, suggesting rapid metabolism. This is a significant drawback for Ligand B.

**In vitro Half-Life:** Ligand A (-24.291) is also an unrealistic value, likely indicating a very long half-life. Ligand B (-19.053) is also long, but more plausible.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.008 and 0.487).

**Binding Affinity:** Ligand A (-8.4 kcal/mol) has a significantly stronger binding affinity than Ligand B (-10.0 kcal/mol). This is a major advantage for Ligand A.

**Overall Assessment:**

Ligand A is the superior candidate. While the Caco-2 and half-life values are unrealistic, the combination of strong binding affinity, good BBB penetration, low DILI risk, optimal logP, and reasonable TPSA outweighs the permeability concerns. Ligand B suffers from a high logP, high DILI risk, poor BBB penetration, and high metabolic clearance. The affinity is good, but not enough to compensate for the ADME/Tox liabilities.



Output:
0
2025-04-17 07:55:06,810 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (348.45 & 370.47 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (106.34) is slightly above the optimal <90 for CNS targets, while Ligand B (90.31) is right at the threshold. This gives a slight edge to Ligand B.

**3. logP:** Ligand A (0.872) is a bit low, potentially hindering permeability. Ligand B (-0.546) is even lower, raising concerns about permeability. Both are suboptimal, but Ligand A is marginally better.

**4. H-Bond Donors:** Both ligands have acceptable HBD counts (3 and 2 respectively), well below the 5 threshold.

**5. H-Bond Acceptors:** Both ligands have acceptable HBA counts (5 and 6 respectively), below the 10 threshold.

**6. QED:** Both ligands have good QED scores (0.614 and 0.69), indicating drug-like properties.

**7. DILI:** Both ligands have low DILI risk (23.34 and 27.57 percentiles), which is favorable.

**8. BBB:** Both ligands exhibit similar BBB penetration (61.54% and 61.85%), which is acceptable but not outstanding for a CNS target. Ideally, we'd want >70%.

**9. Caco-2:** Both have negative Caco-2 values (-4.939 and -4.963) which is unusual and problematic. This suggests very poor intestinal absorption.

**10. Solubility:** Both ligands have very poor aqueous solubility (-1.937 and -2.638). This is a significant drawback.

**11. hERG:** Both have low hERG inhibition liability (0.12 and 0.265), which is good.

**12. Cl_mic:** Ligand B (18.46) has significantly lower microsomal clearance than Ligand A (32.77), indicating better metabolic stability. This is a key advantage.

**13. t1/2:** Ligand B (5.588) has a longer in vitro half-life than Ligand A (-10.493), which is desirable.

**14. Pgp:** Both ligands have very low P-gp efflux liability (0.014 and 0.053), which is excellent for CNS penetration.

**15. Binding Affinity:** Ligand A (-8.1 kcal/mol) has a significantly stronger binding affinity than Ligand B (-6.3 kcal/mol). This is a substantial advantage, potentially outweighing some of the ADME drawbacks.

**Overall Assessment:**

While both compounds have significant ADME liabilities (poor solubility and Caco-2 permeability), Ligand A's substantially stronger binding affinity (-8.1 vs -6.3 kcal/mol) is a major advantage, especially for a GPCR target. The improved metabolic stability and half-life of Ligand B are beneficial, but the affinity difference is likely to be more impactful. The TPSA of Ligand B is slightly better, but the low logP for both is concerning. Given the importance of potency for GPCRs, and the fact that both have similar BBB penetration, Ligand A is the more promising candidate, assuming that solubility issues can be addressed through formulation strategies.

Output:
0
2025-04-17 07:55:06,810 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the acceptable range (200-500 Da). Ligand A (345.487 Da) is slightly preferred as it's closer to the ideal range.

**TPSA:** Ligand A (52.65) is significantly better than Ligand B (103.78). For CNS targets, TPSA should be <= 90, and A is comfortably within that, while B is pushing the limit.

**logP:** Both ligands have acceptable logP values (A: 1.485, B: 1.838) falling within the 1-3 range. No clear advantage here.

**H-Bond Donors/Acceptors:** Both have 1 HBD, which is good. Ligand A has 3 HBA, while Ligand B has 10. The higher HBA count in B could potentially hinder permeability.

**QED:** Ligand A (0.786) has a much better QED score than Ligand B (0.488), indicating a more drug-like profile.

**DILI:** Ligand A (16.673) has a significantly lower DILI risk than Ligand B (75.107). This is a substantial advantage for A.

**BBB:** Ligand A (62.737) has a better BBB penetration percentile than Ligand B (54.827), though neither are above the desirable >70 threshold. However, for a CNS target, even a moderate improvement is valuable.

**Caco-2 Permeability:** Ligand A (-4.679) has a more negative Caco-2 value, which indicates *lower* permeability. Ligand B (-5.707) is even worse. This is a concern for both, but slightly more so for B.

**Aqueous Solubility:** Ligand A (-2.416) has slightly better solubility than Ligand B (-1.44).

**hERG:** Both ligands have very low hERG risk (A: 0.237, B: 0.258).

**Microsomal Clearance:** Both have similar microsomal clearance (A: 30.382, B: 30.087).

**In vitro Half-Life:** Ligand B (31.832) has a significantly longer half-life than Ligand A (0.688). This is a major advantage for B.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (A: 0.046, B: 0.311).

**Binding Affinity:** Ligand A (-7.3 kcal/mol) has a slightly better binding affinity than Ligand B (-6.6 kcal/mol). While both are good, the 0.7 kcal/mol difference is meaningful.

**Overall Assessment:**

Ligand A is the stronger candidate. It excels in crucial areas for a CNS-targeting GPCR ligand: TPSA, QED, DILI risk, and binding affinity. While its Caco-2 permeability is a concern, its superior BBB penetration and overall drug-like properties outweigh this drawback. Ligand B's longer half-life is attractive, but its higher TPSA, DILI risk, and lower QED make it less promising. The affinity difference, while not enormous, favors A.

Output:
0
2025-04-17 07:55:06,810 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (343.47 and 351.49 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (38.77) is excellent, well below the 90 A^2 threshold for CNS targets. Ligand B (61.88) is higher but still acceptable, though less ideal.

**logP:** Ligand A (3.764) is at the upper end of the optimal range (1-3), while Ligand B (1.395) is at the lower end. For a CNS target, a slightly higher logP is generally preferred for BBB penetration, giving a slight edge to Ligand A.

**H-Bond Donors/Acceptors:** Ligand A has 0 HBD and 4 HBA, while Ligand B has 1 HBD and 4 HBA. Both are within acceptable limits.

**QED:** Both ligands have similar QED values (0.763 and 0.704), indicating good drug-like properties.

**DILI:** Ligand A (18.19) has a slightly higher DILI risk than Ligand B (12.80), but both are below the 40 threshold and considered good.

**BBB:** This is a critical parameter for a CNS target. Ligand A has a significantly better BBB penetration percentile (83.25) compared to Ligand B (66.62).

**Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and requires further investigation. However, we'll proceed with the comparison based on the other parameters.

**Aqueous Solubility:** Both have negative solubility values, which is also unusual and indicates poor aqueous solubility.

**hERG Inhibition:** Ligand A (0.906) has a slightly higher hERG risk than Ligand B (0.461), but both are relatively low.

**Microsomal Clearance:** Ligand B (9.63) has a lower microsomal clearance than Ligand A (91.76), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand B (-5.57) has a longer in vitro half-life than Ligand A (-15.66).

**P-gp Efflux:** Ligand A (0.562) has lower P-gp efflux liability than Ligand B (0.076), which is favorable for CNS penetration.

**Binding Affinity:** Ligand A (-8.8 kcal/mol) has a significantly stronger binding affinity than Ligand B (-7.3 kcal/mol). This is a substantial advantage, potentially outweighing some of the ADME drawbacks.

**Overall Assessment:**

Ligand A excels in key areas for a CNS-targeting GPCR: TPSA, BBB penetration, and, most importantly, binding affinity. While its logP is higher and its metabolic stability is lower than Ligand B, the strong binding affinity and good BBB penetration are crucial. The slightly higher DILI and hERG risks are less concerning given the strong affinity. Ligand B has better metabolic stability and lower P-gp efflux, but its weaker binding affinity and lower BBB penetration are significant drawbacks.

Output:
1
2025-04-17 07:55:06,810 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (347.459 and 356.413 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (60.93) is significantly better than Ligand B (75.27). For CNS targets, we want TPSA <= 90, and A is comfortably within that range, while B is approaching the upper limit.

**logP:** Both ligands have acceptable logP values (1.247 and 1.559), falling within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A (0 HBD, 3 HBA) is slightly better than Ligand B (2 HBD, 3 HBA) in terms of balancing solubility and permeability. Both are within acceptable limits.

**QED:** Ligand A (0.752) has a higher QED score than Ligand B (0.624), indicating a more drug-like profile.

**DILI:** Both ligands have similar DILI risk (14.269 and 15.626), and both are below the concerning threshold of 40, indicating low liver injury risk.

**BBB:** Ligand B (87.476) has a substantially higher BBB percentile than Ligand A (70.609). This is a *critical* advantage for a CNS target like DRD2.

**Caco-2 Permeability:** Ligand A (-4.773) has a lower (worse) Caco-2 permeability than Ligand B (-5.047).

**Aqueous Solubility:** Ligand A (-1.114) has better aqueous solubility than Ligand B (-2.528).

**hERG:** Both ligands have very low hERG inhibition liability (0.174 and 0.183).

**Microsomal Clearance:** Ligand A (15.664) has a higher microsomal clearance than Ligand B (8.162), suggesting lower metabolic stability.

**In vitro Half-Life:** Ligand B (26.766) has a significantly longer in vitro half-life than Ligand A (-0.554). This is a major advantage.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.036 and 0.014).

**Binding Affinity:** Both ligands have the same binding affinity (-8.4 kcal/mol), which is excellent.

**Overall Assessment:**

While Ligand A has advantages in TPSA, QED, and solubility, Ligand B excels in BBB penetration and in vitro half-life. For a CNS target like DRD2, BBB penetration is paramount. The significantly higher BBB score of Ligand B (87.476 vs. 70.609) and longer half-life outweigh the slight advantages of Ligand A. The similar binding affinity means potency isn't a differentiating factor.

Output:
1
2025-04-17 07:55:06,810 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (354.397 and 366.49 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (58.64) is excellent, well below the 90 A^2 threshold for CNS targets. Ligand B (108.64) is higher, but still potentially acceptable, though less ideal.

**3. logP:** Both ligands have good logP values (2.042 and 1.554), falling within the optimal 1-3 range.

**4. H-Bond Donors:** Ligand A (1) is good. Ligand B (3) is acceptable, but approaching the upper limit.

**5. H-Bond Acceptors:** Ligand A (3) is good. Ligand B (5) is also acceptable.

**6. QED:** Both ligands have similar and good QED values (0.621 and 0.662), indicating good drug-like properties.

**7. DILI:** Ligand A (31.563) has a significantly lower DILI risk than Ligand B (47.77), placing it in a more favorable range.

**8. BBB:** This is a critical parameter for a CNS target like DRD2. Ligand A has a very high BBB penetration percentile (91.47), which is excellent. Ligand B's BBB penetration (46.219) is considerably lower and less desirable.

**9. Caco-2 Permeability:** Both have negative values which is unusual. Assuming these are logP values, both are poor.

**10. Aqueous Solubility:** Both have negative values which is unusual. Assuming these are logS values, both are poor.

**11. hERG Inhibition:** Both ligands show low hERG inhibition liability (0.367 and 0.139), which is positive.

**12. Microsomal Clearance:** Ligand A (22.188) has lower microsomal clearance than Ligand B (41.674), suggesting better metabolic stability.

**13. In vitro Half-Life:** Ligand A (-17.787) has a negative half-life, which is unusual. Ligand B (-26.129) also has a negative half-life.

**14. P-gp Efflux:** Ligand A (0.04) has very low P-gp efflux, which is excellent for CNS penetration. Ligand B (0.078) is slightly higher, but still relatively low.

**15. Binding Affinity:** Ligand A (-8.9 kcal/mol) has significantly stronger binding affinity than Ligand B (-0.0 kcal/mol). This is a major advantage.

**Overall Assessment:**

Ligand A is clearly the superior candidate. It excels in the most important parameters for a CNS-targeting GPCR ligand: BBB penetration, binding affinity, and DILI risk. It also demonstrates better metabolic stability (lower Cl_mic) and lower P-gp efflux. While both have unusual half-life values, the significantly stronger binding affinity of Ligand A outweighs the other minor drawbacks.

Output:
1
2025-04-17 07:55:06,811 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (348.447 and 349.435 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Both ligands have TPSA values (78.68 and 79.7) that are acceptable for oral absorption (<140), but slightly higher than the preferred <90 for CNS targets. This is a minor concern, and not a major differentiator.

**3. logP:** Ligand A (1.298) is optimal, while Ligand B (-0.047) is slightly below the optimal range. While not drastically low, lower logP can sometimes hinder membrane permeability.

**4. H-Bond Donors:** Both ligands have 1 HBD, which is within the acceptable limit of <=5.

**5. H-Bond Acceptors:** Ligand A has 5 HBA, while Ligand B has 6. Both are within the acceptable limit of <=10.

**6. QED:** Both ligands have similar QED values (0.838 and 0.806), indicating good drug-likeness.

**7. DILI:** Ligand A (18.34%) has a significantly lower DILI risk than Ligand B (29.236%). This is a substantial advantage for Ligand A.

**8. BBB:** Ligand A (66.576%) has a better BBB penetration percentile than Ligand B (60.45%). While neither is *outstanding* (>70), Ligand A is closer. This is important for a CNS target like DRD2.

**9. Caco-2 Permeability:** Ligand A (-5.106) has worse Caco-2 permeability than Ligand B (-4.753). This suggests Ligand B might have slightly better intestinal absorption, but the difference is small.

**10. Aqueous Solubility:** Ligand A (-0.846) has slightly worse solubility than Ligand B (-0.533). Solubility isn't a major concern for either, but better is preferred.

**11. hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.342 and 0.31).

**12. Microsomal Clearance:** Ligand A (-13.499) has significantly lower (better) microsomal clearance than Ligand B (9.273). This indicates better metabolic stability for Ligand A.

**13. In vitro Half-Life:** Ligand A (13.938) has a longer in vitro half-life than Ligand B (9.741). This is a positive attribute for Ligand A.

**14. P-gp Efflux:** Both ligands have similar, low P-gp efflux liability (0.047 and 0.032).

**15. Binding Affinity:** Ligand A (-7.8 kcal/mol) has a slightly better binding affinity than Ligand B (-7.5 kcal/mol). While both are good, the 0.3 kcal/mol difference is potentially significant.

**Overall Assessment:**

Ligand A is the more promising candidate. It demonstrates a better safety profile (lower DILI), improved metabolic stability (lower Cl_mic, longer t1/2), slightly better BBB penetration, and a slightly stronger binding affinity. While Ligand B has marginally better Caco-2 permeability and solubility, the advantages of Ligand A in key ADME/Tox properties and binding outweigh these minor differences, especially considering the CNS target.



Output:
1
2025-04-17 07:55:06,811 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (351.447 and 351.491 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (85.62) is slightly above the optimal <90 for CNS targets, but still reasonable. Ligand B (81.67) is excellent, well below 90.

**3. logP:** Ligand A (2.04) is within the optimal 1-3 range. Ligand B (1.036) is at the lower end, potentially impacting permeability.

**4. H-Bond Donors:** Ligand A (2) is good. Ligand B (3) is acceptable, but slightly higher.

**5. H-Bond Acceptors:** Ligand A (5) is good. Ligand B (4) is also good.

**6. QED:** Ligand A (0.819) is excellent, indicating high drug-likeness. Ligand B (0.61) is still acceptable, above the 0.5 threshold.

**7. DILI:** Ligand A (42.691) has a moderate DILI risk, but is below the concerning 60 threshold. Ligand B (4.382) has a very low DILI risk, which is a significant advantage.

**8. BBB:** Ligand A (89.104) has excellent BBB penetration, exceeding the desirable >70% for CNS targets. Ligand B (68.127) is below this threshold, which is a major drawback for a CNS target like DRD2.

**9. Caco-2 Permeability:** Ligand A (-4.79) and Ligand B (-5.205) both have negative values, which is unusual and suggests low permeability. However, the scale is not specified, so it's hard to interpret.

**10. Aqueous Solubility:** Both ligands have negative solubility values (-2.102 and -1.923), which is concerning. Solubility is important for bioavailability.

**11. hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.39 and 0.34).

**12. Microsomal Clearance:** Ligand A (29.231) has moderate clearance. Ligand B (-3.238) has *negative* clearance, which is impossible and likely an error in the data. This suggests very high metabolic stability, but the value is suspect.

**13. In vitro Half-Life:** Ligand A (51.815) has a good half-life. Ligand B (-15.342) has a negative half-life, which is impossible and further reinforces the data quality concerns.

**14. P-gp Efflux:** Both ligands have very low P-gp efflux (0.105 and 0.008), which is favorable for CNS penetration.

**15. Binding Affinity:** Ligand A (-8.7 kcal/mol) has a slightly better binding affinity than Ligand B (-7.9 kcal/mol), though both are excellent.

**Overall Assessment:**

Ligand A is the stronger candidate despite some drawbacks. Its superior BBB penetration is critical for a CNS target. While its TPSA is slightly higher and solubility is low, the strong binding affinity and acceptable DILI risk outweigh these concerns. Ligand B has a better TPSA and DILI, but its significantly lower BBB penetration is a deal-breaker for DRD2. Furthermore, the negative values for Cl_mic and t1/2 in Ligand B are highly suspect and indicate a data quality issue.

Output:
0
2025-04-17 07:55:06,811 - INFO - Batch 405 complete. Total preferences: 6480
2025-04-17 07:55:06,811 - INFO - Processing batch 406/512...
2025-04-17 07:55:49,859 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B based on the provided guidelines, prioritizing GPCR-specific properties (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (348.531 and 347.415 Da) fall within the ideal range of 200-500 Da.

**TPSA:** Ligand A (49.41) is excellent, well below the 90 A^2 threshold for CNS targets. Ligand B (71.44) is still reasonable, but less optimal, being above 60 A^2.

**logP:** Ligand A (3.746) is at the upper end of the optimal range (1-3), but still acceptable. Ligand B (0.947) is below 1, which is a concern for permeability.

**H-Bond Donors/Acceptors:** Ligand A (1 HBD, 2 HBA) is favorable. Ligand B (0 HBD, 5 HBA) is also reasonable.

**QED:** Both ligands have good QED scores (0.654 and 0.71), indicating good drug-like properties.

**DILI:** Ligand A (14.23) has a very low DILI risk. Ligand B (39.201) is also low, but higher than A.

**BBB:** Ligand A (85.459) has excellent BBB penetration, exceeding the 70% threshold. Ligand B (70.648) is acceptable, but less desirable than A.

**Caco-2 Permeability:** Ligand A (-4.625) and Ligand B (-4.274) both have negative values, indicating poor permeability. However, these values are on a scale where higher is better, so this is not a straightforward comparison.

**Aqueous Solubility:** Ligand A (-3.9) and Ligand B (-1.541) both have negative solubility values, indicating poor solubility. Again, higher is better, so B is slightly better.

**hERG:** Ligand A (0.618) has a low hERG risk. Ligand B (0.086) has a very low hERG risk, slightly better than A.

**Microsomal Clearance:** Ligand A (89.69) has a high microsomal clearance, indicating rapid metabolism. Ligand B (21.566) has a much lower clearance, suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (-1.857) has a short half-life. Ligand B (-23.943) has a very long half-life.

**P-gp Efflux:** Ligand A (0.384) has low P-gp efflux, which is good for CNS penetration. Ligand B (0.03) has very low P-gp efflux, even better.

**Binding Affinity:** Ligand B (-8.0 kcal/mol) has a significantly stronger binding affinity than Ligand A (-7.7 kcal/mol). This 1.3 kcal/mol difference is substantial.

**Overall Assessment:**

Ligand B has a significantly better binding affinity and a much improved metabolic profile (lower Cl_mic, longer t1/2). While its logP is lower, the superior affinity and metabolic stability outweigh this drawback, especially for a GPCR target where maintaining sufficient brain exposure is critical. Ligand A has better TPSA and BBB, but the affinity difference is too large to ignore.

Output:
1
2025-04-17 07:55:49,859 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (346.431 and 348.447 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (84.42) is significantly better than Ligand B (94.56). For CNS targets, TPSA < 90 is preferred, and A is closer to this threshold.

**3. logP:** Both ligands have acceptable logP values (1.207 and 1.337), falling within the optimal 1-3 range.

**4. H-Bond Donors:** Ligand A (1) is better than Ligand B (3). Lower HBD generally improves permeability.

**5. H-Bond Acceptors:** Both ligands have the same number of HBA (5), which is within the acceptable limit of <=10.

**6. QED:** Ligand A (0.866) has a much better QED score than Ligand B (0.462), indicating a more drug-like profile.

**7. DILI:** Both ligands have relatively low DILI risk (34.432 and 37.379 percentiles), suggesting minimal liver injury potential.

**8. BBB:** Ligand A (66.964) has a better BBB percentile than Ligand B (52.268), although both are below the desirable >70 for CNS targets. However, given the other factors, A's higher BBB is a plus.

**9. Caco-2 Permeability:** Ligand A (-5.109) has better Caco-2 permeability than Ligand B (-4.948), indicating better intestinal absorption.

**10. Aqueous Solubility:** Ligand A (-1.009) has better aqueous solubility than Ligand B (-1.585).

**11. hERG Inhibition:** Ligand A (0.076) has a lower hERG inhibition liability than Ligand B (0.51), indicating a lower risk of cardiotoxicity.

**12. Microsomal Clearance:** Ligand A (-1.218) has a lower (better) microsomal clearance than Ligand B (47.472), suggesting greater metabolic stability.

**13. In vitro Half-Life:** Ligand A (7.906) has a lower in vitro half-life than Ligand B (38.877).

**14. P-gp Efflux:** Ligand A (0.008) has a much lower P-gp efflux liability than Ligand B (0.204), which is crucial for CNS penetration.

**15. Binding Affinity:** Ligand B (-7.3 kcal/mol) has a slightly better binding affinity than Ligand A (-8.6 kcal/mol). While a 1.3 kcal/mol difference is notable, the other ADME properties of Ligand A are significantly more favorable.

**Overall Assessment:**

Ligand A is the superior candidate. While Ligand B has slightly better binding affinity, Ligand A excels in almost all other crucial ADME properties, particularly those prioritized for GPCRs targeting the CNS: TPSA, BBB, P-gp efflux, and metabolic stability. The significantly better QED score and lower hERG risk further support choosing Ligand A. The better solubility and permeability also contribute to a more favorable profile.



Output:
0
2025-04-17 07:55:49,859 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (371.547 and 355.429 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (81.67) is slightly above the preferred <90 for CNS targets, but acceptable. Ligand B (58.36) is well within the ideal range.

**3. logP:** Both ligands have good logP values (1.535 and 2.708), falling within the optimal 1-3 range.

**4. H-Bond Donors:** Ligand A has 3 HBD, which is acceptable. Ligand B has 1 HBD, also acceptable.

**5. H-Bond Acceptors:** Ligand A has 5 HBA, within the limit. Ligand B has 4 HBA, also within the limit.

**6. QED:** Both ligands have similar and good QED values (0.632 and 0.693), indicating good drug-like properties.

**7. DILI:** Ligand A (52.423) has a moderate DILI risk, while Ligand B (20.279) has a very low DILI risk. This is a significant advantage for Ligand B.

**8. BBB:** This is a critical parameter for CNS targets. Ligand A has a BBB percentile of 17.449, which is quite low. Ligand B has a BBB percentile of 86.08, which is excellent.

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.5 and -4.219), which is unusual and suggests poor permeability. However, these values are on a scale where negative values are possible, and the absolute magnitude is important.

**10. Aqueous Solubility:** Both ligands have negative solubility values (-2.947 and -3.056), suggesting poor aqueous solubility.

**11. hERG Inhibition:** Ligand A (0.273) has a slightly higher hERG risk than Ligand B (0.549), though both are relatively low.

**12. Microsomal Clearance:** Ligand A (25.922) has lower microsomal clearance than Ligand B (32.53), suggesting better metabolic stability.

**13. In vitro Half-Life:** Ligand A (2.194) has a shorter half-life than Ligand B (0.76), indicating faster metabolism.

**14. P-gp Efflux:** Ligand A (0.036) has very low P-gp efflux, which is desirable for CNS penetration. Ligand B (0.139) has slightly higher P-gp efflux.

**15. Binding Affinity:** Ligand A (-8.0) has a slightly better binding affinity than Ligand B (-7.0), a difference of 1 kcal/mol.

**Overall Assessment:**

While Ligand A has a slightly better binding affinity and lower P-gp efflux, Ligand B is significantly better overall, especially considering the GPCR-specific priorities. The most crucial factor is the much higher BBB penetration (86.08 vs. 17.449) of Ligand B. The lower DILI risk of Ligand B is also a significant advantage. The slightly lower metabolic stability and half-life of Ligand B are less concerning than the poor BBB penetration of Ligand A. The negative Caco-2 and solubility values are concerning for both, but can be addressed with formulation strategies. The 1 kcal/mol difference in affinity is unlikely to outweigh the substantial ADME advantages of Ligand B.

Output:
1
2025-04-17 07:55:49,859 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (367.812 and 343.379 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (90.12) is slightly above the optimal <90 for CNS targets, but still reasonable. Ligand B (84.86) is well within the desired range.

**3. logP:** Both ligands have good logP values (2.206 and 2.796), falling within the optimal 1-3 range.

**4. H-Bond Donors:** Ligand A (3) and Ligand B (2) both meet the HBD criteria of <=5.

**5. H-Bond Acceptors:** Both ligands have 4 HBA, which is well within the acceptable limit of <=10.

**6. QED:** Both ligands have acceptable QED scores (0.699 and 0.731), indicating good drug-like properties.

**7. DILI:** Both ligands have relatively high DILI risk (68.437 and 71.035), but below the concerning threshold of >60. This is a potential area for optimization, but not a dealbreaker at this stage.

**8. BBB:** This is a critical parameter for a CNS target. Ligand A has a BBB percentile of 63.164, which is okay, but not great. Ligand B has a significantly lower BBB percentile of 30.206, which is a major drawback.

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.259 and -5.15), which is unusual and suggests poor permeability. This is concerning for both.

**10. Aqueous Solubility:** Both ligands have negative solubility values (-3.631 and -2.517), indicating very poor aqueous solubility. This is a significant issue for formulation and bioavailability.

**11. hERG Inhibition:** Both ligands show low hERG inhibition liability (0.653 and 0.079), which is positive.

**12. Microsomal Clearance:** Ligand A (19.947) has a higher microsomal clearance than Ligand B (7.199), suggesting lower metabolic stability.

**13. In vitro Half-Life:** Ligand B (-9.819) has a negative half-life, which is not physically possible and indicates a potential data error or a very rapidly metabolized compound. Ligand A (76.874) has a reasonable half-life.

**14. P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.041 and 0.054), which is favorable for CNS penetration.

**15. Binding Affinity:** Both ligands have excellent binding affinities (-8.3 and -8.5 kcal/mol). The difference is minimal.

**Overall Assessment:**

While both ligands have strong binding affinities, Ligand B suffers from a very poor BBB penetration score and an implausible negative in vitro half-life. Ligand A has a better BBB score and a reasonable half-life, despite having a higher microsomal clearance and poor solubility/permeability. The solubility and permeability issues are significant for both, but the severe issues with BBB and half-life for Ligand B make it a much less promising candidate.

Output:
0
2025-04-17 07:55:49,859 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (373.812 and 369.487 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (83.72) is slightly higher than Ligand B (79.81), but both are below the 90 A^2 threshold desirable for CNS targets.

**3. logP:** Both ligands have good logP values (2.098 and 1.856), falling within the optimal 1-3 range.

**4. H-Bond Donors:** Both have 0 HBD, which is acceptable.

**5. H-Bond Acceptors:** Ligand A has 5 HBA, and Ligand B has 6. Both are below the 10 threshold.

**6. QED:** Ligand A (0.73) has a significantly better QED score than Ligand B (0.464), indicating better overall drug-likeness.

**7. DILI:** Ligand A (60.217) has a higher DILI risk than Ligand B (52.423), but both are within an acceptable range (<60 is good, >60 is high risk).

**8. BBB:** This is a critical parameter for a CNS target like DRD2. Ligand A (85.033) has a much better BBB percentile than Ligand B (58.821). A value >70 is desirable, and Ligand A is closer to this target.

**9. Caco-2 Permeability:** Both have negative Caco-2 values which is unusual and suggests poor permeability. However, the absolute value is smaller for Ligand A (-4.478 vs -4.761), suggesting slightly better permeability.

**10. Aqueous Solubility:** Both have negative solubility values, which is also unusual. Ligand B (-1.03) is slightly better than Ligand A (-2.273).

**11. hERG Inhibition:** Both ligands have very low hERG inhibition liability (0.146 and 0.179), which is excellent.

**12. Microsomal Clearance:** Ligand B (99.672) has a significantly higher microsomal clearance than Ligand A (23.154), indicating lower metabolic stability.

**13. In vitro Half-Life:** Ligand A (-0.245) has a slightly better in vitro half-life than Ligand B (-1.204).

**14. P-gp Efflux:** Both have low P-gp efflux liability (0.296 and 0.107).

**15. Binding Affinity:** Ligand A (-7.6 kcal/mol) has a stronger binding affinity than Ligand B (-6.5 kcal/mol). The difference of 1.1 kcal/mol is substantial and can outweigh some ADME drawbacks.

**Overall Assessment:**

Ligand A is the superior candidate. While Ligand B has a slightly better solubility and lower DILI risk, Ligand A excels in the most crucial areas for a CNS-targeting GPCR ligand: significantly better BBB penetration, stronger binding affinity, and better metabolic stability (lower Cl_mic). The higher QED score also supports its drug-likeness. The slight DILI risk is a concern, but manageable given the other advantages.

Output:
1
2025-04-17 07:55:49,860 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (343.431 and 364.515 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (83.28) is better than Ligand B (65.54), both are below the 90 A^2 threshold for CNS targets.

**3. logP:** Both ligands have good logP values (1.75 and 1.523) falling within the optimal 1-3 range.

**4. H-Bond Donors:** Ligand A (2) is slightly higher than Ligand B (1), but both are within the acceptable limit of <=5.

**5. H-Bond Acceptors:** Both ligands have 5 H-bond acceptors, well within the acceptable limit of <=10.

**6. QED:** Both ligands have good QED scores (0.783 and 0.86), indicating a drug-like profile.

**7. DILI:** Ligand A (50.136) has a lower DILI risk than Ligand B (23.769), which is preferable.

**8. BBB:** Ligand A (69.562) has a slightly better BBB penetration percentile than Ligand B (62.854). While both are below the ideal >70, Ligand A is closer.

**9. Caco-2 Permeability:** Ligand A (-5.058) has worse Caco-2 permeability than Ligand B (-4.968).

**10. Aqueous Solubility:** Both have very poor aqueous solubility (-1.632 and -1.527). This is a significant drawback for both.

**11. hERG Inhibition:** Both ligands show very low hERG inhibition liability (0.188 and 0.171), which is excellent.

**12. Microsomal Clearance:** Ligand A (-2.476) has significantly lower (better) microsomal clearance than Ligand B (22.387), indicating better metabolic stability.

**13. In vitro Half-Life:** Ligand A (17.207) has a longer half-life than Ligand B (8.128), which is desirable.

**14. P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.053 and 0.048), which is good for CNS exposure.

**15. Binding Affinity:** Ligand A (-8.6 kcal/mol) has a significantly stronger binding affinity than Ligand B (-7.2 kcal/mol). This >1.5 kcal/mol difference is substantial and can outweigh some ADME drawbacks.

**Overall Assessment:**

Ligand A is the stronger candidate. While both have poor solubility, Ligand A's superior binding affinity (-8.6 vs -7.2 kcal/mol), lower DILI risk, better BBB penetration, and significantly improved metabolic stability (lower Cl_mic and longer t1/2) outweigh Ligand B's slightly better Caco-2 permeability. The strong binding affinity is a critical advantage for a GPCR ligand.

Output:
1
2025-04-17 07:55:49,860 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (352.291 and 346.471 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (59.93) is slightly higher than Ligand B (53.76), but both are below the 90 A^2 threshold desirable for CNS targets.

**logP:** Both ligands have good logP values (3.674 and 3.479), falling within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A has 1 HBD and 5 HBA, while Ligand B has 0 HBD and 3 HBA. Both are within acceptable limits (<=5 HBD, <=10 HBA).

**QED:** Ligand B (0.842) has a significantly better QED score than Ligand A (0.561), indicating a more drug-like profile.

**DILI:** Ligand A has a high DILI risk (91.935 percentile), which is a major concern. Ligand B has a much lower DILI risk (31.601 percentile), a significant advantage.

**BBB:** Both ligands have excellent BBB penetration (73.827 and 71.888 percentile), exceeding the desirable >70% threshold for CNS targets.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.713 and -4.611). This is unusual and suggests poor permeability, but the scale is not clearly defined, so it's hard to interpret.

**Aqueous Solubility:** Both ligands have negative solubility values (-4.58 and -2.945). Again, the scale is unclear, but suggests poor aqueous solubility.

**hERG Inhibition:** Both ligands show low hERG inhibition liability (0.892 and 0.704), which is good.

**Microsomal Clearance:** Ligand A (70.089 mL/min/kg) has higher microsomal clearance than Ligand B (52.272 mL/min/kg), suggesting lower metabolic stability.

**In vitro Half-Life:** Ligand B (30.377 hours) has a substantially longer in vitro half-life than Ligand A (-15.842 hours). This is a significant advantage.

**P-gp Efflux:** Ligand B (0.65) has a slightly higher P-gp efflux liability than Ligand A (0.286), but both are relatively low.

**Binding Affinity:** Ligand A (-9.8 kcal/mol) has a significantly stronger binding affinity than Ligand B (0.0 kcal/mol). This is a major advantage, potentially outweighing some of the ADME drawbacks.

**Overall Assessment:**

Ligand A's primary advantage is its significantly higher binding affinity. However, its very high DILI risk and poor metabolic stability (high Cl_mic, negative half-life) are major liabilities. Ligand B, while having a much weaker binding affinity, has a superior drug-like profile (higher QED), lower DILI risk, better metabolic stability (lower Cl_mic, longer half-life), and comparable BBB penetration.

Given the GPCR-specific priorities, and the significant safety concerns with Ligand A, I would prioritize Ligand B for further optimization. While the affinity is a concern, it's a starting point for medicinal chemistry efforts. The improved ADME properties and safety profile of Ligand B provide a better foundation for developing a viable drug candidate.

Output:
1
2025-04-17 07:55:49,860 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (390.893 and 346.431 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (106.0) is higher than the preferred <90 for CNS targets, while Ligand B (76.46) is well within the range. This gives a slight advantage to Ligand B.

**logP:** Ligand A (-0.199) is quite low, potentially hindering membrane permeability. Ligand B (1.238) is within the optimal 1-3 range. This is a significant advantage for Ligand B.

**H-Bond Donors/Acceptors:** Ligand A has 3 HBD and 7 HBA, which are acceptable. Ligand B has 1 HBD and 5 HBA, also acceptable.

**QED:** Both ligands have similar QED values (0.595 and 0.539), indicating good drug-like properties.

**DILI:** Both ligands have low DILI risk (41.218 and 40.054 percentile), which is favorable.

**BBB:** Ligand A has a BBB penetration of 9.732%, which is very low and problematic for a CNS target. Ligand B has a much better BBB penetration of 60.14%, although ideally >70. This is a major advantage for Ligand B.

**Caco-2 Permeability:** Both have negative Caco-2 values (-5.393 and -4.897), which is unusual and suggests poor permeability. However, these values are on a log scale and can be difficult to interpret directly.

**Aqueous Solubility:** Both have negative solubility values (-0.805 and -1.701), indicating poor aqueous solubility. This could be a formulation challenge.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.118 and 0.202 percentile), which is good.

**Microsomal Clearance:** Ligand A has a lower (better) microsomal clearance (-28.36 mL/min/kg) than Ligand B (23.8 mL/min/kg), suggesting greater metabolic stability.

**In vitro Half-Life:** Ligand A has a longer half-life (16.02 hours) than Ligand B (5.579 hours).

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.05 and 0.043 percentile), which is favorable for CNS penetration.

**Binding Affinity:** Ligand B (-7.7 kcal/mol) has a slightly better binding affinity than Ligand A (-7.1 kcal/mol). While the difference is less than the 1.5 kcal/mol threshold, it's still a positive factor.

**Overall Assessment:**

Ligand B is significantly more promising. Its superior logP, TPSA, and, crucially, BBB penetration outweigh the slightly better metabolic stability and half-life of Ligand A. The binding affinity difference is minor. Ligand A's very poor BBB penetration makes it unlikely to be effective for a CNS target like DRD2. The solubility and Caco-2 issues are concerns for both, but can potentially be addressed through formulation strategies.

Output:
1
2025-04-17 07:55:49,860 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (355.295 Da) is slightly lower, which can be advantageous for permeability.

**2. TPSA:** Ligand A (63.05) is excellent, well below the 90 A^2 threshold for CNS targets. Ligand B (129.89) is higher but still potentially acceptable, though less ideal.

**3. logP:** Ligand A (2.799) is optimal. Ligand B (0.786) is a bit low, potentially hindering permeation.

**4. H-Bond Donors:** Ligand A (1) is good. Ligand B (3) is acceptable, but higher HBD can sometimes reduce permeability.

**5. H-Bond Acceptors:** Ligand A (5) is good. Ligand B (7) is acceptable, but higher HBA can sometimes reduce permeability.

**6. QED:** Ligand A (0.842) is excellent, indicating strong drug-likeness. Ligand B (0.467) is lower, suggesting a less favorable drug-like profile.

**7. DILI:** Ligand A (85.964) has a higher DILI risk, which is a concern. Ligand B (61.419) is better, but still above the preferred <40.

**8. BBB:** Ligand A (83.637) has excellent BBB penetration, crucial for a CNS target. Ligand B (59.248) is significantly lower, making it less likely to reach the target in the brain.

**9. Caco-2 Permeability:** Ligand A (-4.698) is very poor. Ligand B (-6.154) is even worse. Both are problematic, but the lower value for B is worse.

**10. Aqueous Solubility:** Ligand A (-4.343) is poor. Ligand B (-2.985) is better, but still not ideal.

**11. hERG Inhibition:** Both ligands have low hERG inhibition risk (0.504 and 0.691, respectively).

**12. Microsomal Clearance:** Ligand A (50.811) is moderate. Ligand B (33.935) is lower, suggesting better metabolic stability.

**13. In vitro Half-Life:** Ligand A (17.436) is reasonable. Ligand B (-13.892) is very poor, indicating rapid metabolism.

**14. P-gp Efflux:** Ligand A (0.193) has low P-gp efflux, which is favorable for CNS penetration. Ligand B (0.075) has even lower P-gp efflux, which is even more favorable.

**15. Binding Affinity:** Ligand A (-9.9 kcal/mol) has significantly stronger binding affinity than Ligand B (-7.5 kcal/mol). This is a substantial advantage.

**Overall Assessment:**

Despite Ligand A's higher DILI risk and poor Caco-2 permeability, its superior BBB penetration, significantly stronger binding affinity, excellent TPSA and QED, and low P-gp efflux make it the more promising candidate. The strong binding affinity could potentially outweigh the ADME liabilities, especially given the CNS target. Ligand B suffers from a lower logP, poor half-life, and significantly weaker binding affinity, making it less likely to be successful.

Output:
1
2025-04-17 07:55:49,860 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (362.543 and 361.551 Da) fall comfortably within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (51.02) is higher than Ligand B (29.54). For a CNS target like DRD2, TPSA should be <=90, both are within this range, but B is significantly better.

**3. logP:** Ligand A (3.257) is within the optimal 1-3 range. Ligand B (4.638) is slightly higher, potentially edging into territory where solubility could become an issue, but still acceptable.

**4. H-Bond Donors:** Both ligands have 0 HBD, which is good.

**5. H-Bond Acceptors:** Ligand A has 5 HBA, and Ligand B has 3. Both are within the acceptable limit of <=10.

**6. QED:** Both ligands have QED values above 0.5 (0.747 and 0.631), indicating good drug-like properties.

**7. DILI:** Ligand A (22.489) has a slightly higher DILI risk than Ligand B (16.053), but both are below the concerning threshold of 40.

**8. BBB:** Both ligands exhibit excellent BBB penetration (Ligand A: 80.845, Ligand B: 91.586). Ligand B is superior here, which is crucial for a CNS target.

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.108 and -5.163). This is unusual and suggests poor permeability. However, these values are on a scale where negative values are possible and don't necessarily disqualify the compounds.

**10. Aqueous Solubility:** Both ligands have very poor aqueous solubility (-3.581 and -3.996). This is a significant concern, but can sometimes be overcome with formulation strategies.

**11. hERG Inhibition:** Both ligands show low hERG inhibition liability (0.452 and 0.833), which is favorable.

**12. Microsomal Clearance:** Ligand A (90.353) has higher microsomal clearance than Ligand B (100.821), suggesting lower metabolic stability.

**13. In vitro Half-Life:** Ligand B (12.951) has a longer in vitro half-life than Ligand A (23.433), indicating better metabolic stability.

**14. P-gp Efflux:** Ligand A (0.334) has lower P-gp efflux than Ligand B (0.886), which is beneficial for CNS penetration.

**15. Binding Affinity:** Ligand B (-7.5 kcal/mol) has a significantly stronger binding affinity than Ligand A (-6.8 kcal/mol). This 0.7 kcal/mol difference is substantial and can outweigh some of the other drawbacks.

**Overall Assessment:**

Ligand B is the stronger candidate. While both have poor solubility and Caco-2 permeability, Ligand B excels in the most critical areas for a CNS GPCR target: BBB penetration, binding affinity, and metabolic stability (half-life). The stronger binding affinity of Ligand B is a significant advantage. The lower P-gp efflux of Ligand A is a minor benefit, but is outweighed by the other factors.

Output:
1
2025-04-17 07:55:49,860 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (349.391 and 344.375 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (118.11) is slightly higher than Ligand B (115.05), but both are below the 140 A^2 threshold for oral absorption and reasonably close to the 90 A^2 target for CNS penetration.

**logP:** Ligand A (-0.988) is a bit low, potentially hindering permeation. Ligand B (0.116) is better, falling within the optimal 1-3 range, although on the lower end.

**H-Bond Donors/Acceptors:** Ligand A has 3 HBD and 6 HBA, while Ligand B has 2 HBD and 5 HBA. Both are within acceptable limits (<=5 HBD and <=10 HBA).

**QED:** Ligand B (0.82) has a significantly higher QED score than Ligand A (0.391), indicating a more drug-like profile.

**DILI:** Ligand B (54.207) has a higher DILI risk than Ligand A (40.403), but both are reasonably low.

**BBB:** Ligand A (43.893) has a significantly better BBB penetration percentile than Ligand B (23.381). This is a crucial factor for a CNS target like DRD2.

**Caco-2 Permeability:** Both ligands have similarly poor Caco-2 permeability scores (-5.29 and -5.058).

**Aqueous Solubility:** Both ligands have poor aqueous solubility (-2.237 and -2.494).

**hERG Inhibition:** Ligand A (0.031) shows slightly lower hERG inhibition risk than Ligand B (0.311).

**Microsomal Clearance:** Ligand A (-2.775) has a lower (better) microsomal clearance than Ligand B (-17.007), suggesting greater metabolic stability.

**In vitro Half-Life:** Ligand A (-35.057) has a much longer in vitro half-life than Ligand B (0.857), which is a significant advantage.

**P-gp Efflux:** Ligand A (0.01) has a much lower P-gp efflux liability than Ligand B (0.023), which is beneficial for CNS exposure.

**Binding Affinity:** Ligand B (-8.5 kcal/mol) has a slightly better binding affinity than Ligand A (-7.4 kcal/mol). This is a 1.1 kcal/mol difference, which is substantial.

**Overall Assessment:**

While Ligand B has a better QED and slightly better binding affinity, Ligand A is superior in several critical areas for a CNS-targeting GPCR ligand. Specifically, its significantly better BBB penetration, lower P-gp efflux, longer half-life, and lower microsomal clearance outweigh the slight affinity difference. The lower logP of Ligand A is a concern, but the strong ADME properties are more important in this case.

Output:
0
2025-04-17 07:55:49,860 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (344.46 and 344.42 Da) fall comfortably within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (70.39) is better than Ligand B (78.53). For CNS targets, we want TPSA <= 90, both are within this range, but A is closer to the optimal value.

**3. logP:** Both ligands have acceptable logP values (2.61 and 1.06), falling within the 1-3 range. Ligand A is slightly better.

**4. H-Bond Donors:** Ligand A (2) and Ligand B (1) are both good, being <=5.

**5. H-Bond Acceptors:** Both ligands have 4 H-bond acceptors, which is within the acceptable limit of <=10.

**6. QED:** Both ligands have good QED scores (0.72 and 0.83), indicating good drug-like properties.

**7. DILI:** Both ligands have acceptable DILI risk (38.5 and 42.7), well below the 60 threshold.

**8. BBB:** This is a crucial parameter for a CNS target like DRD2. Ligand B (80.4%) is significantly better than Ligand A (54.1%). A BBB percentile >70 is desirable, and B is much closer to that.

**9. Caco-2 Permeability:** Both have negative values (-4.82 and -4.90), indicating poor permeability. This is a concern for both.

**10. Aqueous Solubility:** Both have negative values (-2.23 and -2.13), indicating poor solubility. This is a concern for both.

**11. hERG Inhibition:** Both ligands show low hERG inhibition risk (0.55 and 0.42).

**12. Microsomal Clearance:** Ligand B (25.3) has significantly lower microsomal clearance than Ligand A (38.4), suggesting better metabolic stability. Lower is better.

**13. In vitro Half-Life:** Ligand B (-17.05) has a negative half-life, which is concerning. Ligand A (12.3) is positive, and therefore better.

**14. P-gp Efflux:** Both ligands have low P-gp efflux liability (0.31 and 0.07). Lower is better, so Ligand B is slightly better.

**15. Binding Affinity:** Both ligands have very similar and excellent binding affinities (-8.3 kcal/mol). The difference is negligible.

**Overall Assessment:**

While Ligand A has slightly better TPSA, logP, and in vitro half-life, Ligand B excels in BBB penetration and has better metabolic stability (lower Cl_mic). Given that this is a CNS target (DRD2), BBB penetration is paramount. The significantly higher BBB score of Ligand B outweighs the minor advantages of Ligand A. The negative half-life of Ligand B is a major concern, but could potentially be addressed through structural modifications.

Output:
1
2025-04-17 07:55:49,860 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (343.383 and 350.503 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (91.76) is better than Ligand B (67.43) as it is closer to the ideal <90 for CNS targets.

**logP:** Both ligands have good logP values (1.493 and 2.949 respectively), falling within the optimal 1-3 range. Ligand B is slightly higher, which could be beneficial for membrane permeability but needs to be balanced with solubility.

**H-Bond Donors/Acceptors:** Both have 2 HBD and a reasonable number of HBA (5 and 3 respectively), satisfying the <5 HBD and <10 HBA guidelines.

**QED:** Ligand A (0.829) has a significantly better QED score than Ligand B (0.496), indicating a more drug-like profile.

**DILI:** Ligand A (39.201) has a better DILI score than Ligand B (13.843), suggesting a lower risk of liver injury. Both are below the 40 threshold.

**BBB:** Ligand B (69.058) has a substantially better BBB percentile than Ligand A (27.026). This is a *critical* advantage for a CNS target like DRD2.

**Caco-2 Permeability:** Ligand A (-5.136) and Ligand B (-4.522) both have negative values, which is unusual and suggests poor permeability.

**Aqueous Solubility:** Both have negative solubility values (-2.812 and -3.073), indicating poor aqueous solubility.

**hERG:** Both ligands have very low hERG inhibition liability (0.218 and 0.421 respectively), which is excellent.

**Microsomal Clearance:** Both have relatively high microsomal clearance (61.534 and 66.755 mL/min/kg), suggesting moderate metabolic instability.

**In vitro Half-Life:** Ligand A (-32.822) has a much more negative half-life, indicating very rapid metabolism. Ligand B (-7.171) is better, but still not ideal.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.016 and 0.295 respectively), which is favorable for CNS penetration.

**Binding Affinity:** Both ligands have the same binding affinity (-8.6 kcal/mol), which is excellent and removes this as a differentiating factor.

**Overall Assessment:**

Ligand B is clearly superior due to its significantly higher BBB penetration (69.058 vs 27.026). While Ligand A has better QED, DILI, and TPSA, the BBB is paramount for a CNS-targeting drug. The slightly better logP of Ligand B is also a plus. The solubility and permeability are poor for both, but the strong binding affinity might compensate. The faster metabolism of Ligand A is also a concern.

Output:
1
2025-04-17 07:55:49,860 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 drug candidates, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (352.519 and 350.463 Da) fall comfortably within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (67.43) is significantly better than Ligand B (87.46). For CNS targets, we want TPSA <= 90, and A is much closer to the ideal <=60. B is pushing the upper limit and could have reduced brain penetration.

**3. logP:** Ligand A (3.195) is optimal (1-3), while Ligand B (1.246) is a bit low. Lower logP can hinder permeation, including BBB penetration.

**4. H-Bond Donors:** Both ligands have 2 HBD, which is within the acceptable limit of <=5.

**5. H-Bond Acceptors:** Ligand A has 3 HBA, and Ligand B has 5. Both are within the acceptable limit of <=10.

**6. QED:** Both ligands have good QED values (0.692 and 0.739), indicating good drug-like properties.

**7. DILI:** Both ligands have low DILI risk (29.391 and 32.299), both well below the 40 threshold.

**8. BBB:** Ligand A (60.876) is better than Ligand B (54.634), but both are below the desirable >70 for CNS targets. However, given the other properties, A has a better chance of achieving sufficient brain exposure.

**9. Caco-2:** Both have negative Caco-2 values (-4.794 and -4.724). This is unusual and suggests a potential issue with intestinal absorption. However, these values are close and likely not a major differentiator.

**10. Solubility:** Ligand A (-3.268) is better than Ligand B (-1.183). Higher solubility is generally preferred.

**11. hERG:** Both ligands have very low hERG risk (0.362 and 0.192).

**12. Cl_mic:** Ligand B (12.831) has significantly lower microsomal clearance than Ligand A (63.361), indicating better metabolic stability. This is a significant advantage for B.

**13. t1/2:** Ligand B (12.018) has a slightly longer in vitro half-life than Ligand A (15.512).

**14. Pgp:** Ligand A (0.08) has lower P-gp efflux liability than Ligand B (0.052), which is beneficial for CNS penetration.

**15. Binding Affinity:** Ligand A (-7.9 kcal/mol) has a slightly better binding affinity than Ligand B (-7.7 kcal/mol). While the difference is small (0.2 kcal/mol), it's enough to be considered, especially given the other favorable properties of A.

**Overall Assessment:**

Ligand A is favored despite the higher Cl_mic. The superior TPSA, logP, solubility, and Pgp efflux profile, combined with slightly better affinity, make it more likely to achieve sufficient brain penetration and efficacy for a CNS target like DRD2. While Ligand B has better metabolic stability, the lower logP and higher TPSA are significant drawbacks for a CNS-targeting drug.

Output:
1
2025-04-17 07:55:49,861 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (370.739 Da) and Ligand B (347.463 Da) are both acceptable.

**2. TPSA:** Both ligands are below the 140 A^2 threshold for good oral absorption, but more importantly, are reasonably close to the 90 A^2 target for CNS penetration. Ligand A (77.4 A^2) is better than Ligand B (79.26 A^2), but both are acceptable.

**3. logP:** Ligand A (2.865) is optimal (1-3). Ligand B (0.315) is quite low, potentially hindering permeation. This is a significant drawback for Ligand B.

**4. H-Bond Donors:** Both ligands have acceptable HBD counts (Ligand A: 1, Ligand B: 2), well below the limit of 5.

**5. H-Bond Acceptors:** Both ligands have acceptable HBA counts (Ligand A: 5, Ligand B: 5), well below the limit of 10.

**6. QED:** Both ligands have good QED scores (Ligand A: 0.821, Ligand B: 0.777), indicating drug-like properties.

**7. DILI:** Ligand A (87.01 percentile) has a higher DILI risk than Ligand B (6.049 percentile). This is a negative for Ligand A.

**8. BBB:** Ligand A (68.941 percentile) has a better BBB penetration prediction than Ligand B (64.017 percentile), but both are below the desirable >70% for CNS targets.

**9. Caco-2 Permeability:** Ligand A (-4.723) has better Caco-2 permeability than Ligand B (-5.446).

**10. Aqueous Solubility:** Ligand A (-4.299) has better aqueous solubility than Ligand B (-0.71).

**11. hERG Inhibition:** Both ligands have very low hERG inhibition risk (Ligand A: 0.308, Ligand B: 0.131).

**12. Microsomal Clearance:** Ligand B (-24.681 mL/min/kg) has significantly lower microsomal clearance than Ligand A (45.462 mL/min/kg), suggesting better metabolic stability.

**13. In vitro Half-Life:** Ligand A (48.988 hours) has a much longer in vitro half-life than Ligand B (0.864 hours).

**14. P-gp Efflux:** Both ligands have low P-gp efflux liability (Ligand A: 0.252, Ligand B: 0.004). Ligand B is slightly better.

**15. Binding Affinity:** Both ligands have excellent binding affinity (Ligand A: -8.6 kcal/mol, Ligand B: -8.1 kcal/mol). Ligand A is slightly better.

**Overall Assessment:**

Ligand A has a slight edge in binding affinity, better Caco-2 permeability, solubility, and half-life. However, it has a significantly higher DILI risk and worse metabolic stability. Ligand B has a much better safety profile (DILI, metabolic stability), but suffers from a low logP which could severely limit its ability to cross cell membranes and reach the CNS.

Given the GPCR-specific priorities, BBB penetration is crucial. While neither ligand is ideal in this regard, the combination of Ligand A's slightly better BBB, superior half-life, and only marginally worse DILI risk, coupled with its significantly better logP, makes it the more promising candidate. The lower logP of Ligand B is a major concern for CNS penetration.

Output:
1
2025-04-17 07:55:49,861 - INFO - Reasoning:

Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (368.459 Da and 361.471 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (103.79) is higher than Ligand B (88.91). For CNS targets, TPSA should ideally be <= 90. Ligand B is better here.

**3. logP:** Ligand A (0.444) is quite low, potentially hindering permeability. Ligand B (1.41) is better, falling within the optimal 1-3 range.

**4. H-Bond Donors:** Ligand A (3) is slightly higher than Ligand B (2), but both are acceptable (<=5).

**5. H-Bond Acceptors:** Ligand A (7) is higher than Ligand B (6), but both are within the acceptable range (<=10).

**6. QED:** Both ligands have similar, good QED values (0.713 and 0.707, both >= 0.5).

**7. DILI:** Ligand A (71.694) has a higher DILI risk than Ligand B (40.054). Ligand B is preferable.

**8. BBB:** Ligand A (36.487) has a significantly lower BBB penetration percentile than Ligand B (56.883). This is a critical disadvantage for a CNS target like DRD2.

**9. Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and suggests poor permeability. However, the scale is unclear, so we can't definitively compare.

**10. Aqueous Solubility:** Both have negative solubility values, also unusual. Again, the scale is unclear.

**11. hERG Inhibition:** Both ligands show very low hERG inhibition risk (0.224 and 0.064).

**12. Microsomal Clearance:** Ligand A (-13.794) has a *negative* clearance, which is impossible. This suggests a data error. Ligand B (31.231) has a higher clearance, indicating faster metabolism.

**13. In vitro Half-Life:** Ligand A (17.557) has a shorter half-life than Ligand B (12.114).

**14. P-gp Efflux:** Ligand A (0.021) shows very low P-gp efflux, which is good. Ligand B (0.097) is slightly higher, but still relatively low.

**15. Binding Affinity:** Both ligands have the same binding affinity (-7.9 kcal/mol), which is excellent.

**Overall Assessment:**

Considering the GPCR-specific priorities, Ligand B is significantly more promising. Its lower TPSA, better logP, lower DILI risk, and *much* higher BBB penetration outweigh the slightly higher microsomal clearance. The negative clearance value for Ligand A is a major red flag, indicating a data quality issue. While both have unusual solubility and Caco-2 values, the BBB is the most important factor for a CNS target, and Ligand B clearly wins on that front.

Output:
1
2025-04-17 07:55:49,861 - INFO - Batch 406 complete. Total preferences: 6496
2025-04-17 07:55:49,861 - INFO - Processing batch 407/512...
2025-04-17 07:56:33,404 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 drug candidates, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (348.531 Da) is slightly lower, which could be beneficial for permeability.

**TPSA:** Ligand A (49.41) is significantly better than Ligand B (88.33). For CNS targets, we want TPSA <= 90, and A is comfortably within that range, while B is approaching the upper limit.

**logP:** Both ligands have good logP values (A: 3.626, B: 3.009), falling within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Both have acceptable HBD counts (1). Ligand B has a higher HBA count (7) compared to A (2), which could slightly impact permeability.

**QED:** Both ligands have good QED scores (A: 0.647, B: 0.736), indicating good drug-like properties.

**DILI:** Ligand A (19.775) has a much lower DILI risk than Ligand B (87.166). This is a significant advantage for A.

**BBB:** Ligand A (75.378) has a much better BBB penetration score than Ligand B (27.259). This is critical for a CNS target like DRD2.

**Caco-2 Permeability:** Ligand A (-4.833) shows better Caco-2 permeability than Ligand B (-5.342).

**Aqueous Solubility:** Both ligands have poor aqueous solubility (-3.644 and -4.329 respectively). This is a concern for both, but not a deciding factor.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (A: 0.605, B: 0.336).

**Microsomal Clearance:** Ligand B (54.596) has lower microsomal clearance than Ligand A (63.253), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand B (35.448) has a significantly longer half-life than Ligand A (2.79). This is a substantial advantage for B.

**P-gp Efflux:** Both ligands exhibit low P-gp efflux (A: 0.294, B: 0.149).

**Binding Affinity:** Both ligands have excellent binding affinity (A: -8.0 kcal/mol, B: -9.0 kcal/mol). Ligand B is slightly more potent.

**Overall Assessment:**

While Ligand B has slightly better potency and metabolic stability (lower Cl_mic and longer t1/2), Ligand A is significantly better in several key areas for a CNS-targeting GPCR: TPSA, BBB penetration, and DILI risk. The difference in binding affinity (1 kcal/mol) is unlikely to outweigh the substantial advantages of Ligand A in terms of CNS penetration and safety. The lower TPSA and better BBB of Ligand A are crucial for reaching the target in the brain. The significantly lower DILI risk is also a major benefit.

Output:
0
2025-04-17 07:56:33,405 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (352.391 and 347.459 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (115.45) is higher than the preferred <90 for CNS targets, while Ligand B (72.36) is well within the range. This is a significant advantage for Ligand B.

**logP:** Ligand A (0.673) is a bit low, potentially hindering permeability. Ligand B (1.712) is better, falling within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Both have 2 HBDs, which is good. Ligand A has 6 HBAs, and Ligand B has 4 HBAs, both acceptable.

**QED:** Both ligands have good QED scores (0.55 and 0.789), indicating good drug-like properties.

**DILI:** Both have acceptable DILI risk (33.695 and 39.201, both <40).

**BBB:** Ligand B (69.794) is better than Ligand A (20.783) in terms of predicted BBB penetration, which is crucial for a CNS target like DRD2.

**Caco-2 Permeability:** Both have negative Caco-2 values (-5.127 and -5.013), which is unusual and suggests poor permeability. This is a concern for both.

**Aqueous Solubility:** Both have negative solubility values (-0.691 and -2.517), indicating poor aqueous solubility. This is a significant drawback for both.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.213 and 0.34).

**Microsomal Clearance:** Ligand A (-18.931) has a much lower (better) microsomal clearance than Ligand B (53.761), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (3.521) has a slightly longer half-life than Ligand B (0.944).

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.029 and 0.181), which is good for CNS penetration.

**Binding Affinity:** Ligand B (-7.9 kcal/mol) has a slightly better binding affinity than Ligand A (-7.4 kcal/mol). While the difference is not huge, it's enough to be considered.

**Overall Assessment:**

Ligand B is the more promising candidate. While both have issues with Caco-2 permeability and aqueous solubility, Ligand B excels in TPSA and BBB penetration, which are critical for CNS GPCR targets. The slightly better binding affinity further supports this conclusion. Ligand A has better metabolic stability (lower Cl_mic) and half-life, but these are outweighed by the superior CNS penetration properties of Ligand B.

Output:
1
2025-04-17 07:56:33,405 - INFO - Reasoning:

Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (350.459 and 357.401 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (67.87) is better than Ligand B (69.72). Both are below the 90 A^2 threshold for CNS targets, which is excellent.

**3. logP:** Both ligands have good logP values (1.478 and 1.007), falling within the optimal 1-3 range.

**4. H-Bond Donors:** Both have 1 HBD, which is acceptable.

**5. H-Bond Acceptors:** Ligand A has 4 HBA, and Ligand B has 3. Both are below the 10 threshold.

**6. QED:** Both ligands have good QED scores (0.788 and 0.816), indicating good drug-like properties.

**7. DILI:** Ligand A (15.2) has a significantly lower DILI risk than Ligand B (30.826). This is a major advantage.

**8. BBB:** Ligand A (90.772) has a slightly better BBB penetration percentile than Ligand B (86.041). Both are good, but A is preferable for a CNS target.

**9. Caco-2 Permeability:** Both have negative Caco-2 values (-4.677 and -4.577). This is unusual and suggests poor permeability. However, these values are on a scale where negative values are possible and don't necessarily preclude development.

**10. Aqueous Solubility:** Both have negative solubility values (-2.835 and -2.371). Similar to Caco-2, this is not ideal but doesn't automatically disqualify the compounds.

**11. hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.314 and 0.286).

**12. Microsomal Clearance:** Ligand B (11.953) has lower microsomal clearance than Ligand A (22.137), indicating better metabolic stability.

**13. In vitro Half-Life:** Ligand B (-21.659) has a negative half-life, which is not physically possible. This is a significant red flag and suggests a problem with the data or the compound's stability. Ligand A (17.079) has a reasonable half-life.

**14. P-gp Efflux:** Both have very low P-gp efflux liability (0.032 and 0.022).

**15. Binding Affinity:** Both ligands have excellent binding affinities (-9.1 and -8.3 kcal/mol). Ligand A is slightly better.

**Overall Assessment:**

Ligand A is the stronger candidate. While both have good potency and acceptable physicochemical properties, Ligand A has a significantly lower DILI risk, slightly better BBB penetration, and a realistic in vitro half-life. Ligand B's negative half-life is a major concern. The slightly better metabolic stability of Ligand B is outweighed by these other factors.

Output:
1
2025-04-17 07:56:33,405 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (351.391 and 355.467 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (93.65) is slightly above the optimal <90 for CNS targets, but still reasonable. Ligand B (71.84) is excellent, well below 90.

**logP:** Both ligands have good logP values (3.229 and 4.027), falling within the 1-3 range, though Ligand B is pushing the upper limit.

**H-Bond Donors/Acceptors:** Ligand A has 1 HBD and 7 HBA, while Ligand B has 2 HBD and 6 HBA. Both are within acceptable limits (<=5 HBD and <=10 HBA).

**QED:** Both ligands have good QED scores (0.564 and 0.741), indicating good drug-like properties.

**DILI:** Ligand A (95.618) has a concerningly high DILI risk, being well above the 60 threshold. Ligand B (83.249) is better, but still above 40, suggesting some level of liver injury risk.

**BBB:** Ligand A (56.883) has a moderate BBB penetration, while Ligand B (61.613) is slightly better. Both are below the desirable >70 for CNS targets, but Ligand B is closer.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.159 and -5.129), which is unusual and suggests poor permeability. This is a significant concern for both.

**Aqueous Solubility:** Both ligands have very poor aqueous solubility (-4.343 and -4.085). This is a major drawback for both compounds.

**hERG Inhibition:** Both ligands show low hERG inhibition risk (0.273 and 0.626).

**Microsomal Clearance:** Ligand A has very high microsomal clearance (98.379), indicating poor metabolic stability. Ligand B (39.772) has much lower clearance and better metabolic stability.

**In vitro Half-Life:** Ligand A has a very short in vitro half-life (-2.624), while Ligand B has a much longer half-life (80.965).

**P-gp Efflux:** Both ligands have low P-gp efflux (0.235 and 0.689), which is favorable for CNS penetration.

**Binding Affinity:** Both ligands have excellent binding affinities (-9.3 and -9.7 kcal/mol), with Ligand B being slightly better. The difference in affinity is not substantial enough to override other significant differences.

**Overall Assessment:**

Ligand A suffers from a very high DILI risk and poor metabolic stability (high Cl_mic, short t1/2). While its TPSA is slightly better, the other ADME properties are significantly worse. Ligand B, despite a slightly higher logP and still-problematic solubility, has a much better safety profile (lower DILI), better metabolic stability, and a longer half-life. Both have poor Caco-2 permeability and solubility, but these can potentially be addressed with formulation strategies. Given the GPCR-specific focus on BBB penetration and the overall ADME profile, Ligand B is the more promising candidate.

Output:
1
2025-04-17 07:56:33,405 - INFO - Reasoning:

Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands are within the acceptable range (200-500 Da). Ligand A (364.295 Da) is slightly preferred due to being lower.

**2. TPSA:** Ligand A (67.87) is significantly better than Ligand B (73.86). For a CNS target like DRD2, a TPSA below 90 is desirable, and A is closer to the ideal range for CNS penetration.

**3. logP:** Both ligands have good logP values (A: 2.384, B: 3.091), falling within the optimal 1-3 range. B is slightly higher, which *could* indicate potential off-target effects, but isn't a major concern.

**4. H-Bond Donors:** Both have 1 HBD, which is acceptable.

**5. H-Bond Acceptors:** Ligand A has 4 HBAs, and Ligand B has 5. Both are within the acceptable limit of 10.

**6. QED:** Both ligands have similar QED values (A: 0.755, B: 0.697), indicating good drug-likeness.

**7. DILI:** Both ligands have elevated DILI risk (A: 62.737, B: 72.819), but are still below the concerning >60 threshold. B is slightly higher risk.

**8. BBB:** This is a critical parameter for a CNS target. Ligand A has a much better BBB percentile (78.945) compared to Ligand B (51.881). This is a significant advantage for A.

**9. Caco-2:** Ligand A (-4.483) and Ligand B (-5.035) both have negative Caco-2 values, which is unusual and suggests poor permeability. However, these values are on a scale where negative values are possible and don't necessarily disqualify the compounds.

**10. Solubility:** Both have poor aqueous solubility (A: -3.398, B: -3.883). This could pose formulation challenges.

**11. hERG:** Both ligands have low hERG inhibition risk (A: 0.702, B: 0.749).

**12. Cl_mic:** Ligand A (-1.699) has a significantly lower (better) microsomal clearance than Ligand B (68.602). This indicates better metabolic stability for Ligand A.

**13. t1/2:** Ligand A (-0.286) has a very short in vitro half-life, while Ligand B (10.167) is much better. This is a significant drawback for Ligand A.

**14. Pgp:** Ligand A (0.172) has lower P-gp efflux liability than Ligand B (0.382), which is favorable for CNS penetration.

**15. Binding Affinity:** Ligand B (-7.4 kcal/mol) has a slightly better binding affinity than Ligand A (-8.9 kcal/mol). While A is already very good, the 1.5 kcal/mol difference is notable.

**Overall Assessment:**

Despite Ligand B's slightly better affinity and half-life, Ligand A is the more promising candidate. The superior BBB penetration, lower Pgp efflux, and significantly better metabolic stability (lower Cl_mic) outweigh the minor affinity difference. The poor solubility and Caco-2 values are concerns for both, but can potentially be addressed with formulation strategies. For a CNS target like DRD2, getting the molecule into the brain is paramount, and Ligand A is much better positioned to achieve that.

Output:
0
2025-04-17 07:56:33,406 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (344.375 and 348.403 Da) fall comfortably within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (94.28) is slightly higher than Ligand B (87.91). Both are below the 90 A^2 threshold for CNS targets, which is good. Ligand B is preferable here.

**3. logP:** Ligand A (1.422) is within the optimal 1-3 range. Ligand B (0.552) is slightly below 1, which *could* indicate potential permeability issues, though not drastically. Ligand A is preferable.

**4. H-Bond Donors:** Both ligands have 1 HBD, which is within the acceptable limit of <=5.

**5. H-Bond Acceptors:** Ligand A has 7 HBAs, and Ligand B has 6. Both are below the limit of <=10.

**6. QED:** Both ligands have similar QED values (0.85 and 0.836), indicating good drug-like properties.

**7. DILI:** Ligand A has a DILI risk of 91.431, which is concerningly high (>60). Ligand B has a much lower DILI risk of 39.201, which is excellent. This is a significant advantage for Ligand B.

**8. BBB:** Both ligands have excellent BBB penetration (76.541 and 75.417, respectively), exceeding the desirable >70 threshold for CNS targets.

**9. Caco-2 Permeability:** Both have negative Caco-2 values (-4.783 and -4.658). These values are difficult to interpret without knowing the scale, but the similarity suggests comparable intestinal absorption.

**10. Aqueous Solubility:** Both have negative solubility values (-3.266 and -1.449). Again, the scale is unknown, but the similarity suggests comparable solubility.

**11. hERG Inhibition:** Both ligands show very low hERG inhibition liability (0.05 and 0.098), which is excellent.

**12. Microsomal Clearance:** Ligand A (-2.366) has a slightly more negative value than Ligand B (-0.126), suggesting slower clearance and better metabolic stability.

**13. In vitro Half-Life:** Ligand A (29.902) has a longer half-life than Ligand B (-2.656).

**14. P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.022 and 0.034), which is favorable for CNS exposure.

**15. Binding Affinity:** Ligand A (-8.2 kcal/mol) has a slightly stronger binding affinity than Ligand B (-7.6 kcal/mol). While the difference is less than the 1.5 kcal/mol threshold, it's still a positive for Ligand A.

**Overall Assessment:**

Despite Ligand A's slightly better affinity and metabolic stability, the significantly higher DILI risk (91.431 vs 39.201) makes it a less desirable candidate. DILI is a major concern in drug development, and a high percentile score is a red flag. Ligand B, with its much lower DILI risk, acceptable logP, and good BBB penetration, is the more promising candidate. The slight difference in affinity is outweighed by the safety profile.

Output:
1
2025-04-17 07:56:33,406 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (350.419 and 352.406 Da) fall comfortably within the ideal 200-500 Da range.

**TPSA:** Ligand A (96.69) is slightly above the optimal <90 for CNS targets, but still reasonable. Ligand B (59.08) is excellent, well below 90.

**logP:** Ligand A (0.662) is a bit low, potentially hindering membrane permeability. Ligand B (1.492) is better, falling within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A (2 HBD, 6 HBA) is good. Ligand B (0 HBD, 4 HBA) is also good, potentially offering better permeability due to fewer hydrogen bonds.

**QED:** Both ligands have acceptable QED values (0.832 and 0.746, both > 0.5).

**DILI:** Both ligands have low DILI risk (42.226 and 46.026, both < 40), which is positive.

**BBB:** This is a critical parameter for a CNS target like DRD2. Ligand B (89.531) has a significantly higher BBB percentile than Ligand A (48.856). This is a major advantage for Ligand B.

**Caco-2 Permeability:** Ligand A (-4.592) and Ligand B (-4.27) both have negative values, which is unusual and suggests poor permeability. However, the scale isn't specified, so it's difficult to interpret.

**Aqueous Solubility:** Both ligands have very poor aqueous solubility (-1.899 and -1.464). This could pose formulation challenges.

**hERG Inhibition:** Both ligands show very low hERG inhibition risk (0.051 and 0.354).

**Microsomal Clearance:** Ligand A (19.186) has higher microsomal clearance than Ligand B (12.571), suggesting lower metabolic stability.

**In vitro Half-Life:** Ligand B (4.629) has a slightly longer half-life than Ligand A (-24.706), which is favorable.

**P-gp Efflux:** Both ligands show very low P-gp efflux liability (0.011 and 0.047).

**Binding Affinity:** Both ligands have very similar binding affinities (-7.7 and -7.6 kcal/mol), which are both excellent. The difference is negligible.

**Conclusion:**

While both ligands have good binding affinity and low DILI/hERG risk, **Ligand B is the more promising candidate.** Its superior BBB penetration (89.531 vs 48.856), better logP (1.492 vs 0.662), lower microsomal clearance, and slightly longer half-life outweigh the slightly lower TPSA. The poor aqueous solubility is a concern for both, but can potentially be addressed with formulation strategies. The slightly better permeability profile (based on the limited Caco-2 data) also favors Ligand B.

Output:
1
2025-04-17 07:56:33,406 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (381.479 and 397.85 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (89.55) is excellent, falling below the 90 A^2 threshold for CNS targets. Ligand B (53.51) is also very good, well below the threshold.

**logP:** Ligand A (1.807) is optimal (1-3). Ligand B (3.448) is slightly higher but still acceptable.

**H-Bond Donors/Acceptors:** Ligand A has 2 HBD and 7 HBA, both within acceptable limits. Ligand B has 0 HBD and 4 HBA, also good.

**QED:** Both ligands have QED values above 0.7, indicating good drug-likeness.

**DILI:** Both ligands have DILI risk around 60-70, which is moderately concerning, but not immediately disqualifying.

**BBB:** This is critical for a CNS target. Ligand A has a BBB percentile of 54.866, which is below the desirable >70 threshold. Ligand B has a significantly higher BBB percentile of 89.104, making it much more likely to reach the brain.

**Caco-2 Permeability:** Ligand A (-5.384) has poor Caco-2 permeability, suggesting poor intestinal absorption. Ligand B (-4.583) also has poor Caco-2 permeability.

**Aqueous Solubility:** Both ligands have very poor aqueous solubility (-2.797 and -4.253 respectively). This could pose formulation challenges.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.243 and 0.461 respectively).

**Microsomal Clearance:** Ligand A (31.541) has lower microsomal clearance than Ligand B (40.168), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (16.905) has a longer half-life than Ligand B (-4.469). However, the negative value for Ligand B is concerning and likely indicates a very short half-life.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.082 and 0.402 respectively), which is favorable for CNS penetration.

**Binding Affinity:** Ligand A (-8.0) has a significantly stronger binding affinity than Ligand B (0.0). This is a substantial advantage.

**Overall Assessment:**

While Ligand A boasts superior binding affinity and metabolic stability, Ligand B's significantly better BBB penetration is the deciding factor for a CNS target like DRD2. The affinity difference, while large, can potentially be overcome with further optimization. The poor solubility of both compounds is a concern, but formulation strategies can be explored. Ligand A's poor Caco-2 permeability is also a drawback.

Output:
1
2025-04-17 07:56:33,406 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (370.471 and 347.459 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (77.1) is slightly higher than Ligand B (75.44), but both are below the 90 A^2 threshold desirable for CNS targets.

**3. logP:** Ligand A (1.284) is within the optimal 1-3 range. Ligand B (2.958) is also acceptable, leaning towards the higher end but still within the range.

**4. H-Bond Donors:** Both ligands have 1 HBD, which is acceptable (<=5).

**5. H-Bond Acceptors:** Ligand A has 6 HBAs, and Ligand B has 4. Both are below the 10 threshold.

**6. QED:** Ligand A (0.709) has a better QED score than Ligand B (0.521), indicating a more drug-like profile.

**7. DILI:** Ligand A (52.036) has a slightly higher DILI risk than Ligand B (37.03), but both are below the concerning threshold of 60.

**8. BBB:** Both ligands have good BBB penetration (Ligand A: 59.403, Ligand B: 61.38). While >70 is desirable, both are reasonably good for a CNS target.

**9. Caco-2 Permeability:** Both have negative Caco-2 values (-5.199 and -4.525). This is unusual and suggests poor permeability. However, these values are on a log scale, and negative values are not uncommon.

**10. Aqueous Solubility:** Both have negative solubility values (-1.519 and -3.484). Again, these are likely on a log scale and indicate poor aqueous solubility.

**11. hERG Inhibition:** Ligand A (0.127) has a significantly lower hERG inhibition risk than Ligand B (0.559), which is a substantial advantage.

**12. Microsomal Clearance:** Ligand B (54.907) has a lower microsomal clearance than Ligand A (18.359), suggesting better metabolic stability.

**13. In vitro Half-Life:** Ligand A (12.783) has a longer in vitro half-life than Ligand B (2.573), which is favorable.

**14. P-gp Efflux:** Ligand A (0.078) has lower P-gp efflux liability than Ligand B (0.14), which is beneficial for CNS penetration.

**15. Binding Affinity:** Ligand B (-7.5 kcal/mol) has a slightly better binding affinity than Ligand A (-7.1 kcal/mol). This difference of 0.4 kcal/mol is significant, but needs to be weighed against other factors.

**Overall Assessment:**

Ligand B has a better binding affinity and metabolic stability. However, Ligand A has a better QED score, lower hERG risk, lower P-gp efflux, and a longer half-life. The solubility and permeability are poor for both. Considering the GPCR-specific priorities, the lower hERG risk and P-gp efflux of Ligand A are particularly important for CNS penetration and safety. The slightly weaker binding affinity of Ligand A can potentially be optimized in subsequent iterations.

Output:
0
2025-04-17 07:56:33,406 - INFO - Reasoning:

Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (365.39 and 342.451 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (130.87) is slightly above the optimal <90 for CNS targets, but still reasonable. Ligand B (117.43) is better, falling comfortably under 90.

**logP:** Ligand A (0.56) is quite low, potentially hindering permeability. Ligand B (2.068) is much better, within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A (2 HBD, 7 HBA) and Ligand B (4 HBD, 7 HBA) both have acceptable numbers of H-bond donors and acceptors.

**QED:** Both ligands have reasonable QED values (0.769 and 0.634), indicating good drug-like properties.

**DILI:** Ligand A (79.643) has a higher DILI risk than Ligand B (56.146). Both are acceptable, but B is preferable.

**BBB:** This is crucial for a CNS target. Ligand A (42.109) has a poor BBB percentile, indicating limited brain penetration. Ligand B (56.223) is better, but still not ideal ( >70 is desired).

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.27 and -5.765), which is unusual and suggests poor permeability. This is concerning for both.

**Aqueous Solubility:** Both ligands have negative solubility values (-2.775 and -3.126), which is also unusual and suggests poor solubility. This is concerning for both.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.263 and 0.463).

**Microsomal Clearance:** Ligand A (-12.18) has a more negative value, indicating lower clearance and better metabolic stability than Ligand B (9.72).

**In vitro Half-Life:** Ligand A (22.626 hours) has a longer half-life than Ligand B (-7.249 hours).

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.061 and 0.014).

**Binding Affinity:** Ligand B (-8.5 kcal/mol) has a slightly better binding affinity than Ligand A (-8.2 kcal/mol), although the difference is small.

**Overall Assessment:**

Ligand B is the more promising candidate. While both have issues with Caco-2 and solubility, Ligand B has a significantly better logP, which is crucial for CNS penetration. It also has a better BBB percentile and lower DILI risk. The slightly better affinity of Ligand B is a bonus. The longer half-life and better metabolic stability of Ligand A are beneficial, but are outweighed by the poor logP and BBB penetration.

Output:
1
2025-04-17 07:56:33,406 - INFO - Reasoning:

Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (383.583 Da) is slightly higher than Ligand B (340.435 Da), but both are acceptable.

**2. TPSA:** Ligand A (61.44) is significantly better than Ligand B (86.34). For CNS targets, we want TPSA <= 90, and ideally closer to 60. Ligand A is much closer to the ideal range.

**3. logP:** Both ligands have acceptable logP values (Ligand A: 2.252, Ligand B: 0.889), falling within the 1-3 optimal range. Ligand A is slightly preferred.

**4. H-Bond Donors:** Both ligands have a reasonable number of HBDs (Ligand A: 2, Ligand B: 1), well below the limit of 5.

**5. H-Bond Acceptors:** Ligand A (5) is better than Ligand B (8) as we want HBA <= 10.

**6. QED:** Both ligands have good QED scores (Ligand A: 0.758, Ligand B: 0.814), indicating good drug-like properties.

**7. DILI:** Ligand A (33.695) has a lower DILI risk than Ligand B (49.166), which is preferable. Both are below the concerning threshold of 60.

**8. BBB:** This is crucial for a CNS target. Ligand A (64.482) is better than Ligand B (53.703), but both are below the desirable >70 percentile. However, Ligand A is closer.

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.336 and -5.623). This is unusual and suggests poor permeability. However, these values are on a scale where negative values are possible, and we'll consider the other parameters.

**10. Aqueous Solubility:** Both ligands have negative solubility values (-2.891 and -1.838). Similar to Caco-2, these are on a scale where negative values are possible.

**11. hERG Inhibition:** Both ligands have very low hERG inhibition risk (Ligand A: 0.486, Ligand B: 0.103).

**12. Microsomal Clearance:** Ligand B (-32.183) has significantly lower (better) microsomal clearance than Ligand A (67.384), indicating greater metabolic stability.

**13. In vitro Half-Life:** Ligand B (15.756) has a longer half-life than Ligand A (30.619).

**14. P-gp Efflux:** Ligand A (0.119) has lower P-gp efflux than Ligand B (0.024), which is preferable for CNS penetration.

**15. Binding Affinity:** Both ligands have excellent binding affinity (Ligand A: -7.0 kcal/mol, Ligand B: -7.6 kcal/mol). Ligand B is slightly better, but the difference is relatively small.

**Overall Assessment:**

Ligand B has better metabolic stability (lower Cl_mic, longer t1/2) and slightly better binding affinity. However, Ligand A excels in TPSA, logP, HBA, DILI risk, and P-gp efflux, all of which are critical for CNS GPCR targets. The BBB penetration is better for Ligand A, though both are suboptimal. The negative Caco-2 and solubility values are concerning for both, but we must weigh all parameters. Given the importance of CNS penetration for DRD2, and the superior profile of Ligand A regarding TPSA, logP, DILI, and P-gp efflux, it is the more promising candidate.

Output:
1
2025-04-17 07:56:33,406 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (352.454 and 366.933 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (87.46) is excellent, falling well below the 90 A^2 threshold for CNS targets. Ligand B (43.78) is also very good.

**3. logP:** Ligand A (1.539) is within the optimal 1-3 range. Ligand B (3.644) is slightly higher but still acceptable.

**4. H-Bond Donors:** Ligand A (3) and Ligand B (1) both meet the <=5 criteria.

**5. H-Bond Acceptors:** Ligand A (4) and Ligand B (3) both meet the <=10 criteria.

**6. QED:** Both ligands have good QED values (0.619 and 0.714, respectively), indicating drug-like properties.

**7. DILI:** Ligand A (24.506) has a significantly lower DILI risk than Ligand B (14.036), both are good.

**8. BBB:** This is a critical parameter for a CNS target like DRD2. Ligand A (67.701) has a better BBB percentile than Ligand B (57.154). While both are not ideal (>70), A is closer.

**9. Caco-2 Permeability:** Ligand A (-5.297) has worse Caco-2 permeability than Ligand B (-4.53).

**10. Aqueous Solubility:** Ligand A (-1.97) has better aqueous solubility than Ligand B (-3.544).

**11. hERG Inhibition:** Both ligands show low hERG inhibition liability (0.7 and 0.779).

**12. Microsomal Clearance:** Ligand A (11.295) has a lower microsomal clearance than Ligand B (84.975), suggesting better metabolic stability.

**13. In vitro Half-Life:** Ligand B (73.05) has a significantly longer in vitro half-life than Ligand A (-1.286).

**14. P-gp Efflux:** Ligand A (0.015) has much lower P-gp efflux liability than Ligand B (0.672), which is crucial for CNS penetration.

**15. Binding Affinity:** Ligand A (-8.0) has a slightly better binding affinity than Ligand B (-6.8). The difference is 1.2 kcal/mol, which is significant.

**Overall Assessment:**

Ligand A is the stronger candidate. While Ligand B has a better half-life and Caco-2 permeability, Ligand A excels in the most critical areas for a CNS GPCR target: significantly lower P-gp efflux, better BBB penetration, lower DILI risk, better metabolic stability (lower Cl_mic), and slightly improved binding affinity. The superior binding affinity, combined with the favorable ADME properties related to CNS penetration, outweigh the half-life advantage of Ligand B.

Output:
1
2025-04-17 07:56:33,407 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 drug candidates, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight (MW):** Both ligands (348.443 and 356.467 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (80.57) is excellent, well below the 90 A^2 threshold for CNS targets. Ligand B (90.98) is slightly higher but still acceptable.

**3. logP:** Ligand A (2.964) is optimal (1-3). Ligand B (0.138) is significantly low, potentially hindering membrane permeability.

**4. H-Bond Donors (HBD):** Both ligands have 2 HBD, which is within the acceptable limit of <=5.

**5. H-Bond Acceptors (HBA):** Ligand A has 4 HBA, and Ligand B has 5 HBA, both within the acceptable limit of <=10.

**6. QED:** Ligand A (0.719) has a good drug-like profile. Ligand B (0.429) is lower, indicating a less favorable overall drug-likeness.

**7. DILI:** Ligand A (50.33) has a moderate DILI risk. Ligand B (18.651) has a very low DILI risk, which is a significant advantage.

**8. BBB:** Ligand A (47.15) has a moderate BBB penetration. Ligand B (63.862) has a good BBB penetration, which is crucial for a CNS target like DRD2.

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.017 and -5.173), which is unusual and suggests poor permeability. However, these values are on a log scale, and negative values are not uncommon, indicating low permeability.

**10. Aqueous Solubility:** Both ligands have negative solubility values (-3.269 and -0.851), suggesting poor aqueous solubility.

**11. hERG Inhibition:** Ligand A (0.441) has a very low hERG risk. Ligand B (0.13) also has a very low hERG risk.

**12. Microsomal Clearance:** Ligand A (68.586) has a moderate microsomal clearance. Ligand B (22.737) has a low microsomal clearance, indicating better metabolic stability.

**13. In vitro Half-Life:** Ligand A (18.439) has a moderate in vitro half-life. Ligand B (-4.905) has a very short in vitro half-life, which is a major drawback.

**14. P-gp Efflux:** Ligand A (0.426) has low P-gp efflux, which is favorable. Ligand B (0.002) has very low P-gp efflux, which is even more favorable.

**15. Binding Affinity:** Ligand A (-8.2 kcal/mol) has a significantly stronger binding affinity than Ligand B (-6.9 kcal/mol). This 1.3 kcal/mol difference is substantial and can outweigh some ADME drawbacks.

**Overall Assessment:**

Ligand A has a superior binding affinity and a good TPSA, but suffers from moderate BBB penetration and a moderate microsomal clearance. Ligand B has a better BBB penetration, lower DILI risk, and lower microsomal clearance, but its logP is very low, its QED is lower, and its binding affinity is significantly weaker.

Given the importance of affinity for GPCRs, and the fact that the difference in affinity is substantial, Ligand A is the more promising candidate despite its slightly less favorable ADME profile. The strong binding affinity could potentially be optimized through further structural modifications.

Output:
1
2025-04-17 07:56:33,407 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (352.381 and 348.447 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (59.5) is excellent, well below the 90 threshold for CNS targets. Ligand B (78.67) is still reasonable but less optimal.

**logP:** Ligand A (2.621) is within the optimal 1-3 range. Ligand B (1.299) is slightly lower, potentially impacting permeability, but still acceptable.

**H-Bond Donors/Acceptors:** Ligand A (0 HBD, 4 HBA) and Ligand B (1 HBD, 5 HBA) both have acceptable numbers of H-bond donors and acceptors.

**QED:** Both ligands have good QED scores (0.785 and 0.84), indicating drug-like properties.

**DILI:** Ligand A (38.503) has a much lower DILI risk than Ligand B (25.359), which is a significant advantage.

**BBB:** Ligand A (97.945) shows excellent BBB penetration, exceeding the desirable >70 threshold. Ligand B (73.401) is still good, but not as promising. This is a crucial factor for a CNS target like DRD2.

**Caco-2 Permeability:** Ligand A (-4.024) and Ligand B (-4.64) both have negative Caco-2 values, which is unusual and suggests poor permeability. However, these values are on a log scale and are difficult to interpret without knowing the units/scale used in the model. We'll consider this a neutral point for now.

**Aqueous Solubility:** Ligand A (-3.431) and Ligand B (-1.443) both have negative solubility values, suggesting poor aqueous solubility. Again, the scale is unknown, making direct comparison difficult.

**hERG:** Both ligands have low hERG risk (0.454 and 0.355), which is positive.

**Microsomal Clearance:** Ligand A (77.29) has higher microsomal clearance than Ligand B (3.611), suggesting lower metabolic stability. This is a drawback for Ligand A.

**In vitro Half-Life:** Ligand B (3.981) has a longer in vitro half-life than Ligand A (-17.611), which is a significant advantage.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.191 and 0.103), which is favorable for CNS penetration.

**Binding Affinity:** Ligand B (-9.0 kcal/mol) has a significantly stronger binding affinity than Ligand A (-8.6 kcal/mol). This >1.5 kcal/mol difference is substantial and can outweigh some ADME drawbacks.

**Overall Assessment:**

Ligand A excels in TPSA, BBB penetration, and DILI risk. However, it suffers from higher microsomal clearance and a weaker binding affinity. Ligand B has a superior binding affinity and better metabolic stability (lower Cl_mic, longer t1/2). While its BBB penetration is slightly lower, it's still acceptable. The lower DILI risk for Ligand A is attractive, but the strong affinity of Ligand B is a major driver for success with GPCR targets. Given the importance of affinity for GPCRs, and the acceptable BBB and ADME properties of Ligand B, it is the more promising candidate.

Output:
1
2025-04-17 07:56:33,407 - INFO - Reasoning:

Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (368.415 and 353.369 Da) fall within the ideal range of 200-500 Da.

**TPSA:** Ligand A (93.85) is slightly above the optimal <90 for CNS targets, but still reasonable. Ligand B (75.44) is well within the desired range.

**logP:** Ligand A (-0.052) is a bit low, potentially hindering membrane permeability. Ligand B (2.304) is within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A has 0 HBD and 7 HBA, which is acceptable. Ligand B has 1 HBD and 4 HBA, also acceptable.

**QED:** Both ligands have good QED scores (0.757 and 0.824), indicating good drug-like properties.

**DILI:** Ligand A (78.325) has a higher DILI risk than Ligand B (55.874), though both are below the concerning >60 threshold.

**BBB:** This is critical for a CNS target like DRD2. Ligand B (91.392) has a significantly higher BBB penetration percentile than Ligand A (65.529). This is a major advantage for Ligand B.

**Caco-2 Permeability:** Both have negative values (-4.666 and -4.735), which is unusual and suggests poor permeability. However, these values are on a scale where negative values are possible and don't necessarily indicate complete lack of permeability.

**Aqueous Solubility:** Both ligands have negative solubility values (-1.888 and -2.935), which is also unusual and suggests poor solubility.

**hERG Inhibition:** Both ligands have low hERG inhibition liability (0.408 and 0.174), which is good.

**Microsomal Clearance:** Ligand B (27.467) has a lower microsomal clearance than Ligand A (56.414), indicating better metabolic stability.

**In vitro Half-Life:** Ligand B (-47.426) has a much longer in vitro half-life than Ligand A (-14.17), which is highly desirable.

**P-gp Efflux:** Both have low P-gp efflux liability (0.101 and 0.109), which is good.

**Binding Affinity:** Both ligands have similar, strong binding affinities (-8.5 and -7.9 kcal/mol). The difference of 0.6 kcal/mol is not substantial enough to outweigh other factors.

**Conclusion:**

Considering the GPCR-specific priorities, Ligand B is the more promising candidate. Its superior BBB penetration, lower DILI risk, better metabolic stability (lower Cl_mic), and longer half-life outweigh the slightly lower binding affinity and potentially problematic solubility/permeability values. Ligand A's low logP is also a concern. While both have issues with solubility and permeability, the CNS target necessitates prioritizing BBB penetration, which Ligand B excels at.

Output:
1
2025-04-17 07:56:33,407 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (399.252 and 363.487 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (87.11) is better than Ligand B (81.07) as it is closer to the <90 A^2 threshold for CNS targets. Both are acceptable.

**3. logP:** Both ligands have good logP values (3.049 and 3.301), falling within the optimal 1-3 range.

**4. H-Bond Donors:** Both have 3 HBD, which is within the acceptable limit of <=5.

**5. H-Bond Acceptors:** Ligand A has 5 HBA, and Ligand B has 6. Both are within the acceptable limit of <=10.

**6. QED:** Both ligands have reasonable QED scores (0.451 and 0.629), with Ligand B being slightly more drug-like.

**7. DILI:** Both have high DILI risk (89.957 and 80.109), which is a concern. However, this is often a later-stage consideration.

**8. BBB:** Ligand A (66.615) has a significantly better BBB percentile than Ligand B (52.423). This is *crucial* for a CNS target like DRD2.

**9. Caco-2:** Both have negative Caco-2 values (-5.681 and -5.121), which is unusual and suggests poor permeability. This is a significant drawback for both.

**10. Solubility:** Both have negative solubility values (-3.439 and -3.231), indicating poor aqueous solubility. This is a concern for bioavailability.

**11. hERG:** Both have low hERG inhibition liability (0.787 and 0.18), which is good.

**12. Cl_mic:** Ligand A (36.283) has a lower microsomal clearance than Ligand B (52.159), suggesting better metabolic stability.

**13. t1/2:** Ligand A (59.379) has a longer in vitro half-life than Ligand B (52.598), which is desirable.

**14. Pgp:** Ligand A (0.623) has a lower P-gp efflux liability than Ligand B (0.277), meaning it is less likely to be pumped out of the brain, which is beneficial for CNS penetration.

**15. Binding Affinity:** Ligand A (-10.7 kcal/mol) has a significantly stronger binding affinity than Ligand B (-8.5 kcal/mol). This is a substantial advantage, potentially outweighing some of the ADME drawbacks.

**Overall Assessment:**

While both compounds have issues with Caco-2 permeability and solubility, Ligand A is the superior candidate. Its significantly stronger binding affinity (-10.7 vs -8.5 kcal/mol) and better BBB penetration (66.6 vs 52.4) are critical for a CNS-targeting GPCR like DRD2. Additionally, Ligand A exhibits better metabolic stability (lower Cl_mic) and lower P-gp efflux, both of which contribute to improved CNS exposure. The slightly better QED of Ligand B is not enough to offset these advantages.

Output:
1
2025-04-17 07:56:33,407 - INFO - Batch 407 complete. Total preferences: 6512
2025-04-17 07:56:33,407 - INFO - Processing batch 408/512...
2025-04-17 07:57:15,046 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (364.47 & 351.84 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (68.82) is higher than Ligand B (56.99). For CNS targets, we want TPSA <= 90, so both are acceptable, but B is better.

**logP:** Ligand A (1.577) is within the optimal 1-3 range. Ligand B (3.857) is approaching the upper limit, potentially raising solubility concerns, but still acceptable.

**H-Bond Donors/Acceptors:** Ligand A has 2 HBD and 6 HBA, while Ligand B has 0 HBD and 3 HBA. Both are within acceptable limits (<=5 HBD and <=10 HBA).

**QED:** Both ligands have reasonable QED scores (0.773 and 0.621, respectively), indicating good drug-like properties.

**DILI:** Ligand A (54.48%) has a lower DILI risk than Ligand B (60.45%), which is preferable.

**BBB:** Both ligands have similar BBB penetration (55.64% and 52.89%). Neither is above the desirable 70% threshold for CNS targets, but they aren't drastically low either.

**Caco-2 Permeability:** Ligand A (-5.433) has worse Caco-2 permeability than Ligand B (-4.738). Higher values are better.

**Aqueous Solubility:** Ligand A (-2.311) has better aqueous solubility than Ligand B (-5.181). Higher values are better.

**hERG Inhibition:** Ligand A (0.208) has a lower hERG inhibition liability than Ligand B (0.562), which is a significant advantage.

**Microsomal Clearance:** Ligand A (27.45 mL/min/kg) has significantly lower microsomal clearance than Ligand B (98.63 mL/min/kg), indicating better metabolic stability.

**In vitro Half-Life:** Ligand A (45.97 hours) has a much longer in vitro half-life than Ligand B (11.34 hours). This is a major advantage.

**P-gp Efflux:** Ligand A (0.088) has lower P-gp efflux than Ligand B (0.363), which is crucial for CNS penetration.

**Binding Affinity:** Ligand B (-7.9 kcal/mol) has a significantly stronger binding affinity than Ligand A (0.0 kcal/mol). This is a substantial advantage, potentially outweighing some of the ADME drawbacks.

**Overall Assessment:**

While Ligand A exhibits better ADME properties (lower DILI, better solubility, lower hERG, lower clearance, longer half-life, lower P-gp efflux), Ligand B's binding affinity is *much* stronger. The difference in affinity (-7.9 vs 0.0 kcal/mol) is so large that it likely overcomes the ADME liabilities of Ligand B. For a GPCR target, strong binding is paramount, and the other properties can potentially be optimized in subsequent iterations of drug design.

Output:
1
2025-04-17 07:57:15,047 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (340.423 and 345.403 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (62.55) is significantly better than Ligand B (91.16). For CNS targets, we want TPSA <= 90, and A is comfortably within that range, while B is close to the upper limit. This favors A.

**logP:** Ligand A (3.8) is slightly higher than the optimal 1-3 range, but still acceptable. Ligand B (1.987) is towards the lower end, potentially hindering permeation. This favors A.

**H-Bond Donors/Acceptors:** Both have 1 HBD, which is good. Ligand A has 3 HBA, and Ligand B has 8 HBA. Lower HBA is generally preferred, favoring A.

**QED:** Both ligands have reasonable QED values (0.9 and 0.767), indicating good drug-like properties.

**DILI:** Ligand A (38.348) has a much lower DILI risk than Ligand B (78.402). This is a significant advantage for A.

**BBB:** Ligand A (82.164) has a better BBB penetration percentile than Ligand B (75.107). While both are above 70 (desirable for CNS targets), A is better.

**Caco-2 Permeability:** Ligand A (-4.428) and Ligand B (-4.819) both have negative values, which is unusual. It's hard to interpret without knowing the scale, but they are similar.

**Aqueous Solubility:** Ligand A (-4.072) and Ligand B (-3.589) both have negative values, indicating poor solubility. B is slightly better, but both are concerning.

**hERG:** Ligand A (0.598) has a lower hERG risk than Ligand B (0.139), which is preferred.

**Microsomal Clearance:** Ligand B (83.879) has a higher microsomal clearance than Ligand A (54.099), indicating lower metabolic stability. This favors A.

**In vitro Half-Life:** Ligand A (104.95) has a significantly longer half-life than Ligand B (2.055). This is a major advantage for A.

**P-gp Efflux:** Ligand A (0.238) has lower P-gp efflux liability than Ligand B (0.241), which is slightly better for CNS exposure.

**Binding Affinity:** Ligand A (-8.9 kcal/mol) has a significantly stronger binding affinity than Ligand B (-7.7 kcal/mol). This is a substantial advantage, potentially outweighing some of the ADME drawbacks.

**Overall:** Considering all factors, especially the GPCR-specific priorities, Ligand A is the more promising drug candidate. It has better TPSA, logP, DILI, BBB, hERG, metabolic stability (lower Cl_mic, longer t1/2), and significantly stronger binding affinity. While both have poor solubility, the other advantages of A make it the better choice.

Output:
1
2025-04-17 07:57:15,047 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (348.447 Da) is slightly better being closer to the lower end, potentially aiding permeability.

**TPSA:** Both ligands have TPSA values below 140, suggesting reasonable oral absorption. However, for a CNS target like DRD2, we ideally want TPSA < 90. Ligand B (84.67) is significantly better than Ligand A (107.5) in this regard.

**logP:** Ligand A (0.889) is a bit low, potentially hindering membrane permeability. Ligand B (2.359) is within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Both have acceptable HBD (1) and HBA (4/6) counts, not raising major concerns.

**QED:** Both ligands have good QED scores (>0.5), indicating drug-like properties.

**DILI:** Ligand A (17.449) has a much lower DILI risk than Ligand B (78.131). This is a significant advantage for Ligand A.

**BBB:** Both ligands have similar BBB penetration (around 60%), which is not ideal for a CNS target (desirable >70). This is a weakness for both, but not a differentiating factor.

**Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and suggests poor permeability. It is difficult to interpret these values without knowing the scale.

**Aqueous Solubility:** Both have negative solubility values, also unusual and suggesting poor solubility.

**hERG Inhibition:** Both ligands show low hERG inhibition liability, which is good.

**Microsomal Clearance:** Ligand A (4.42 mL/min/kg) has significantly lower microsomal clearance than Ligand B (20.975 mL/min/kg), indicating better metabolic stability.

**In vitro Half-Life:** Ligand B (35.888 hours) has a much longer in vitro half-life than Ligand A (-4.704 hours). This is a major advantage for Ligand B.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability, which is good.

**Binding Affinity:** Ligand B (-8.8 kcal/mol) has a significantly stronger binding affinity than Ligand A (-7.1 kcal/mol). This is a substantial advantage, potentially outweighing some ADME drawbacks.

**Overall Assessment:**

Ligand B's superior binding affinity (-8.8 vs -7.1 kcal/mol) and longer half-life are compelling. While its DILI risk is higher, the difference in binding affinity is significant (>1.5 kcal/mol). Ligand B also has a better TPSA and logP. Ligand A has a better DILI score and lower Cl_mic, but the weaker binding and less favorable logP/TPSA are concerning. Given the GPCR target and the importance of potency, Ligand B is the more promising candidate.

Output:
1
2025-04-17 07:57:15,047 - INFO - Reasoning:

Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (346.43 & 369.57 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (75.71) is better than Ligand B (57.61). For CNS targets, we want TPSA <= 90, both are within this range, but A is closer to the upper limit.

**3. logP:** Ligand A (1.261) is within the optimal 1-3 range. Ligand B (3.657) is higher, approaching the upper limit where solubility issues might arise.

**4. H-Bond Donors:** Both ligands have 1 HBD, which is acceptable (<=5).

**5. H-Bond Acceptors:** Both ligands have 4 HBA, which is acceptable (<=10).

**6. QED:** Both ligands have similar QED values (0.601 and 0.674), indicating good drug-like properties.

**7. DILI:** Ligand A (20.32) has a significantly lower DILI risk than Ligand B (26.76). Both are below the 40 threshold, but A is preferable.

**8. BBB:** Ligand B (76.31) has a substantially better BBB penetration percentile than Ligand A (63.16). This is a critical factor for a CNS target like DRD2.

**9. Caco-2 Permeability:** Both have negative values, indicating poor permeability. This is a concern for both, but the value for Ligand A (-4.903) is worse than Ligand B (-4.879).

**10. Aqueous Solubility:** Both have negative values, indicating poor solubility. Ligand B (-4.088) is slightly better than Ligand A (-2.226).

**11. hERG Inhibition:** Ligand A (0.111) has a lower hERG inhibition liability than Ligand B (0.415), which is preferable.

**12. Microsomal Clearance:** Ligand B (97.073) has a much higher microsomal clearance than Ligand A (5.842), indicating lower metabolic stability. This is a significant drawback for Ligand B.

**13. In vitro Half-Life:** Ligand A (-19.658) has a longer in vitro half-life than Ligand B (-18.821).

**14. P-gp Efflux:** Ligand A (0.046) has a lower P-gp efflux liability than Ligand B (0.774), which is beneficial for CNS penetration.

**15. Binding Affinity:** Ligand A (-8.8 kcal/mol) has a significantly stronger binding affinity than Ligand B (-6.6 kcal/mol). This is a >1.5 kcal/mol difference, which can outweigh some ADME drawbacks.

**Overall Assessment:**

While Ligand B has a better BBB score and slightly better solubility, Ligand A demonstrates a superior overall profile. The significantly stronger binding affinity (-8.8 vs -6.6 kcal/mol) is a major advantage. It also has lower DILI risk, lower hERG inhibition, lower P-gp efflux, and better metabolic stability (lower Cl_mic and longer half-life). The slightly higher TPSA of Ligand A is less concerning than the ADME liabilities of Ligand B. Given the GPCR-specific priorities, the strong affinity and favorable ADME properties of Ligand A make it the more promising drug candidate.

Output:
1
2025-04-17 07:57:15,047 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (367.471 and 347.438 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (93.31) is slightly higher than the ideal <90 for CNS targets, but still reasonable. Ligand B (63.05) is excellent, well below 90.

**3. logP:** Both ligands have good logP values (1.532 and 2.432), falling within the optimal 1-3 range.

**4. H-Bond Donors:** Ligand A (2) and Ligand B (1) are both within the acceptable limit of <=5.

**5. H-Bond Acceptors:** Ligand A (6) and Ligand B (5) are both within the acceptable limit of <=10.

**6. QED:** Both ligands have good QED scores (0.606 and 0.797), indicating good drug-like properties.

**7. DILI:** Ligand A (62.35) is moderately risky, while Ligand B (37.999) is much better, indicating lower liver injury potential.

**8. BBB:** Ligand A (66.382) is acceptable but not great for a CNS target. Ligand B (70.182) is better, exceeding the 70% threshold.

**9. Caco-2:** Both have negative values, which is unusual. Assuming these are logP values, they are very poor.

**10. Solubility:** Both have negative values, which is unusual. Assuming these are logS values, they are very poor.

**11. hERG:** Both ligands have low hERG inhibition liability (0.115 and 0.335), which is favorable.

**12. Cl_mic:** Ligand A (4.142) has a lower microsomal clearance than Ligand B (44.668), suggesting better metabolic stability.

**13. t1/2:** Ligand A (-0.697) has a negative half-life, which is impossible. Ligand B (44.77) has a very long half-life, which is favorable.

**14. Pgp:** Both ligands have low P-gp efflux liability (0.039 and 0.046), which is good for CNS penetration.

**15. Binding Affinity:** Ligand A (-8.8 kcal/mol) has a significantly stronger binding affinity than Ligand B (-6.9 kcal/mol). This is a substantial advantage.

**Overall Assessment:**

Ligand A has a superior binding affinity, lower clearance, and acceptable BBB penetration. However, it has a higher DILI risk and a nonsensical half-life. Ligand B has a better safety profile (lower DILI), better BBB penetration, and a very long half-life, but its binding affinity is considerably weaker.

Given the importance of binding affinity for GPCRs, and the relatively modest difference in other parameters, the stronger binding of Ligand A is a significant advantage. The DILI risk is a concern, but could potentially be mitigated through further structural modifications. The nonsensical half-life is a red flag, but could be a data error.

Output:
1
2025-04-17 07:57:15,047 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (359.451 and 344.415 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (91.32) is slightly above the preferred <90 for CNS targets, while Ligand B (86.37) is closer to the ideal range.

**3. logP:** Both ligands have good logP values (2.11 and 1.108), falling within the optimal 1-3 range.

**4. H-Bond Donors:** Ligand A (3) is acceptable, while Ligand B (1) is even better, minimizing potential permeability issues.

**5. H-Bond Acceptors:** Both ligands (A: 5, B: 4) are within the acceptable limit of <=10.

**6. QED:** Both ligands have good QED scores (A: 0.66, B: 0.832), indicating good drug-like properties. Ligand B is slightly better.

**7. DILI:** Both ligands have similar DILI risk (A: 55.797, B: 51.881), both falling within an acceptable range (<60).

**8. BBB:** Ligand B (49.399) has a significantly better BBB percentile than Ligand A (33.501). This is a crucial factor for a CNS target like DRD2.

**9. Caco-2 Permeability:** Both have negative values, indicating poor permeability. Ligand A (-5.495) is slightly better than Ligand B (-4.862), but both are concerning.

**10. Aqueous Solubility:** Both ligands have poor aqueous solubility (-3.16 and -2.242).

**11. hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.247 and 0.264).

**12. Microsomal Clearance:** Ligand B (30.162) has lower microsomal clearance than Ligand A (39.862), suggesting better metabolic stability.

**13. In vitro Half-Life:** Ligand B (-19.979) has a longer in vitro half-life than Ligand A (-14.991).

**14. P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.067 and 0.088).

**15. Binding Affinity:** Ligand A (-8.3 kcal/mol) has a slightly better binding affinity than Ligand B (-7.9 kcal/mol). However, the difference is less than 1.5 kcal/mol, so it's not a decisive factor.

**Overall Assessment:**

While Ligand A has slightly better binding affinity, Ligand B is significantly better in terms of BBB penetration (49.4% vs 33.5%), metabolic stability (lower Cl_mic), and in vitro half-life. The TPSA of Ligand B is also more favorable. Given the GPCR-specific priorities for CNS targets, the improved BBB and ADME properties of Ligand B outweigh the small difference in binding affinity. Both have poor Caco-2 permeability and solubility, which would need to be addressed in further optimization.

Output:
1
2025-04-17 07:57:15,047 - INFO - Reasoning:

Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight (MW):** Both ligands (356.375 and 371.547 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (103.4) is higher than the preferred <90 for CNS targets, while Ligand B (60.93) is well within the optimal range. This is a significant advantage for Ligand B.

**3. logP:** Ligand A (-0.092) is slightly low, potentially hindering permeation. Ligand B (0.936) is closer to the optimal 1-3 range.

**4. H-Bond Donors (HBD):** Both ligands are acceptable (1 and 0 respectively), falling under the limit of 5.

**5. H-Bond Acceptors (HBA):** Both ligands are acceptable (7 and 4 respectively), falling under the limit of 10.

**6. QED:** Both ligands have good QED scores (0.542 and 0.668), indicating drug-like properties.

**7. DILI:** Ligand A (71.152) has a higher DILI risk than Ligand B (11.516). This is a significant concern for Ligand A.

**8. BBB:** Both ligands have good BBB penetration (55.603 and 71.966), but Ligand B is better. A value >70 is desirable for CNS targets, and Ligand B is closer to this threshold.

**9. Caco-2:** Both ligands have negative Caco-2 values, which is unusual and requires further investigation. However, it doesn't immediately disqualify either.

**10. Solubility:** Both ligands have negative solubility values, which is also unusual and requires further investigation.

**11. hERG:** Both ligands have low hERG inhibition risk (0.079 and 0.456).

**12. Cl_mic:** Ligand B (10.861) has lower microsomal clearance than Ligand A (27.896), suggesting better metabolic stability.

**13. t1/2:** Ligand B (-5.685) has a more negative in vitro half-life, which is unusual and likely indicates a very short half-life. Ligand A (-12.119) is even worse. This is a concern for both.

**14. Pgp:** Both ligands have low P-gp efflux liability (0.039 and 0.058).

**15. Binding Affinity:** Ligand A (-7.9) has a slightly better binding affinity than Ligand B (-7.4). However, the difference is less than 1.5 kcal/mol, so it doesn't necessarily outweigh other factors.

**Overall Assessment:**

Considering the GPCR-specific priorities, Ligand B is the more promising candidate. It has a significantly lower TPSA, better logP, lower DILI risk, and better metabolic stability (lower Cl_mic). While both have unusual solubility and half-life values, the other advantages of Ligand B outweigh the slightly weaker binding affinity. The lower TPSA and improved ADME properties are crucial for CNS penetration and efficacy.

Output:
1
2025-04-17 07:57:15,048 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (351.403 and 366.447 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (99.52) is better than Ligand B (122.03). For CNS targets, we want TPSA <= 90, so Ligand A is closer to this target.

**logP:** Ligand A (1.469) is within the optimal 1-3 range. Ligand B (-0.088) is slightly below 1, which could potentially hinder permeation.

**H-Bond Donors/Acceptors:** Ligand A (1 HBD, 7 HBA) and Ligand B (3 HBD, 8 HBA) both fall within acceptable limits (<=5 HBD and <=10 HBA).

**QED:** Both ligands have reasonable QED scores (0.615 and 0.505), indicating good drug-like properties.

**DILI:** Both ligands have similar DILI risk (60.915 and 62.233), placing them in a moderate risk category. This isn't a major differentiator.

**BBB:** This is crucial for a CNS target like DRD2. Ligand A has a significantly better BBB penetration percentile (68.554) compared to Ligand B (24.389). A value >70 is desirable, but Ligand A is substantially better.

**Caco-2 Permeability:** Ligand A (-4.421) and Ligand B (-6.294) both have negative values, which is unusual. Assuming these are percentile scores, Ligand A is better.

**Aqueous Solubility:** Ligand A (-3.19) is better than Ligand B (-1.101) in terms of solubility.

**hERG Inhibition:** Both ligands show very low hERG inhibition liability (0.156 and 0.064), which is excellent.

**Microsomal Clearance:** Ligand A (51.704) has a higher clearance than Ligand B (15.146), suggesting lower metabolic stability. Ligand B is better here.

**In vitro Half-Life:** Ligand B (10.6 hours) has a longer half-life than Ligand A (3.923 hours), which is preferable.

**P-gp Efflux:** Ligand A (0.13) has lower P-gp efflux liability than Ligand B (0.047), which is favorable for CNS penetration.

**Binding Affinity:** Ligand B (-7.5 kcal/mol) has a slightly better binding affinity than Ligand A (-6.8 kcal/mol). The difference is 0.7 kcal/mol, which is significant.

**Overall Assessment:**

Ligand B has a better binding affinity and *in vitro* half-life, and lower microsomal clearance. However, Ligand A significantly outperforms Ligand B in BBB penetration, TPSA, logP, and P-gp efflux, all of which are critical for a CNS-targeting GPCR. While the affinity difference is notable, the superior ADME properties of Ligand A, particularly its BBB score, make it the more promising candidate. The slightly lower affinity can potentially be optimized in subsequent iterations.

Output:
1
2025-04-17 07:57:15,048 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 drug candidates, considering the provided guidelines and GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (354.407 and 353.507 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (116.92) is higher than the preferred <90 for CNS targets, while Ligand B (61.88) is well within the range. This is a significant advantage for Ligand B.

**3. logP:** Ligand A (-0.63) is slightly low, potentially hindering permeation. Ligand B (1.782) is within the optimal 1-3 range.

**4. H-Bond Donors:** Ligand A (3) is acceptable, while Ligand B (1) is even better.

**5. H-Bond Acceptors:** Ligand A (7) is acceptable, and Ligand B (4) is also good.

**6. QED:** Both ligands have good QED scores (0.586 and 0.837), indicating drug-like properties. Ligand B is slightly better.

**7. DILI:** Ligand A (36.216) has a lower DILI risk than Ligand B (21.675), which is a positive.

**8. BBB:** Ligand A (43.815) has a lower BBB penetration percentile than Ligand B (57.387). While both are not optimal (>70), Ligand B is better suited for a CNS target.

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.291 and -4.584), which is unusual and suggests poor permeability. This is a concern for both.

**10. Aqueous Solubility:** Both ligands have negative solubility values (-1.439 and -1.581), indicating poor aqueous solubility. This is a concern for both.

**11. hERG Inhibition:** Both ligands show low hERG inhibition risk (0.165 and 0.173).

**12. Microsomal Clearance:** Ligand A (-16.813) has a much lower (better) microsomal clearance than Ligand B (17.826), indicating greater metabolic stability.

**13. In vitro Half-Life:** Ligand A (-8.811) has a negative half-life, which is not possible. Ligand B (5.751) has a reasonable half-life. This is a major issue for Ligand A.

**14. P-gp Efflux:** Both ligands have low P-gp efflux liability (0.036 and 0.082), which is favorable for CNS penetration.

**15. Binding Affinity:** Ligand A (-6.8) has a better binding affinity than Ligand B (0.0). This is a significant advantage for Ligand A.

**Overall Assessment:**

Despite Ligand A's superior binding affinity, several critical factors favor Ligand B. Ligand B has a much better TPSA, logP, and BBB penetration, all crucial for a CNS-targeting GPCR. Ligand A has a problematic negative in vitro half-life and a lower BBB value. While Ligand A has better metabolic stability, the poor pharmacokinetic properties and questionable half-life outweigh this benefit. The affinity difference is substantial, but not enough to overcome the other issues with Ligand A.

Output:
1
2025-04-17 07:57:15,048 - INFO - Reasoning:

Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (354.359 Da and 340.423 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (108.17) is better than Ligand B (67.43). Both are below the 90 A^2 threshold for CNS targets, but A is closer to the upper limit.

**3. logP:** Ligand B (3.377) is optimal (1-3), while Ligand A (0.569) is quite low, potentially hindering membrane permeability. This is a significant drawback for A.

**4. H-Bond Donors:** Ligand A (0) is preferable to Ligand B (2). Fewer HBDs generally improve permeability.

**5. H-Bond Acceptors:** Ligand A (8) is higher than Ligand B (3). While both are within the acceptable range (<=10), B is better.

**6. QED:** Both ligands have good QED scores (0.682 and 0.877), indicating drug-like properties.

**7. DILI:** Both ligands have high DILI risk (62.621 and 81.311), but B is worse. This is a concern for both, but slightly less so for A.

**8. BBB:** Ligand A (81.466) has a significantly better BBB percentile than Ligand B (53.199). This is a *critical* advantage for a CNS target like DRD2.

**9. Caco-2 Permeability:** Ligand A (-4.425) is worse than Ligand B (-4.586). Both are very poor.

**10. Aqueous Solubility:** Ligand A (-1.536) is better than Ligand B (-4.882).

**11. hERG:** Both ligands have low hERG inhibition liability (0.114 and 0.698), which is good.

**12. Microsomal Clearance:** Ligand B (70.514) has higher clearance than Ligand A (35.299), indicating lower metabolic stability. A is better here.

**13. In vitro Half-Life:** Ligand A (-18.203) has a shorter half-life than Ligand B (-12.485). B is better here.

**14. P-gp Efflux:** Both ligands have low P-gp efflux liability (0.056 and 0.272), which is good.

**15. Binding Affinity:** Ligand B (-9.8 kcal/mol) has a significantly stronger binding affinity than Ligand A (-8.0 kcal/mol). This is a substantial advantage for B.

**Overall Assessment:**

Despite Ligand A's better BBB penetration and lower clearance, Ligand B is the stronger candidate. The significantly better binding affinity (-9.8 vs -8.0 kcal/mol) of Ligand B outweighs the drawbacks of its lower BBB and higher clearance. The low logP of Ligand A is a major concern, likely hindering its ability to cross cell membranes effectively. While both have high DILI risk, this can be addressed in later optimization stages. The strong binding affinity of B provides a better starting point for further development.

Output:
1
2025-04-17 07:57:15,048 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (356.275 and 340.387 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (79.29) is significantly better than Ligand B (103.87). For CNS targets, we want TPSA <= 90, so Ligand A is preferable.

**3. logP:** Ligand A (2.782) is within the optimal 1-3 range. Ligand B (0.998) is slightly below 1, which *could* indicate permeability issues.

**4. H-Bond Donors:** Both have 2 HBD, which is acceptable (<=5).

**5. H-Bond Acceptors:** Ligand A has 3 HBA, and Ligand B has 5. Both are within the acceptable range (<=10).

**6. QED:** Both ligands have good QED scores (0.78 and 0.864), indicating good drug-like properties.

**7. DILI:** Ligand A (79.643) has a higher DILI risk than Ligand B (64.521), but both are still relatively low and acceptable.

**8. BBB:** Ligand A (58.007) and Ligand B (54.013) both have relatively low BBB penetration. This is a concern for a CNS target like DRD2. However, we need to consider other factors.

**9. Caco-2 Permeability:** Both have negative Caco-2 values (-5.346 and -5.284), which is unusual and suggests poor permeability. This is a significant drawback for both.

**10. Aqueous Solubility:** Both have negative solubility values (-2.874 and -3.182), which is also unusual and indicates very poor solubility.

**11. hERG Inhibition:** Both have very low hERG inhibition risk (0.039 and 0.135).

**12. Microsomal Clearance:** Ligand A (-8.568) has *much* lower (better) microsomal clearance than Ligand B (15.217), indicating greater metabolic stability.

**13. In vitro Half-Life:** Ligand A (-14.605) has a longer (better) in vitro half-life than Ligand B (-10.197).

**14. P-gp Efflux:** Both have very low P-gp efflux liability (0.021 and 0.027).

**15. Binding Affinity:** Both ligands have the same binding affinity (-8.5 kcal/mol), which is excellent.

**Overall Assessment:**

Despite the poor Caco-2 and solubility values for both, Ligand A is the more promising candidate. It has a significantly better TPSA, lower microsomal clearance, and longer half-life. While both have low BBB penetration, the better ADME profile of Ligand A, particularly its metabolic stability, makes it more likely to succeed. The affinity is identical, so we rely on the ADME properties to differentiate.

Output:
1
2025-04-17 07:57:15,048 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (349.5 & 360.4 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (43.86) is significantly better than Ligand B (59.08). For CNS targets, we want TPSA <= 90, and ideally lower. Ligand A is much closer to the optimal range.

**3. logP:** Both ligands have acceptable logP values (2.665 & 1.467), falling within the 1-3 range. Ligand A is slightly better.

**4. H-Bond Donors:** Both have 0 HBD, which is acceptable.

**5. H-Bond Acceptors:** Ligand A (3) is better than Ligand B (5), as lower HBA is generally preferred for BBB penetration.

**6. QED:** Both have good QED values (0.601 & 0.766), indicating drug-like properties.

**7. DILI:** Ligand A (10.585) has a much lower DILI risk than Ligand B (63.086). This is a significant advantage for Ligand A.

**8. BBB:** Ligand A (68.67) is reasonable, but Ligand B (75.727) is better, exceeding the 70% threshold desirable for CNS targets. This is a key advantage for Ligand B.

**9. Caco-2:** Both have negative Caco-2 values (-4.654 & -4.897). These values are unusual and difficult to interpret without further context, but suggest poor permeability.

**10. Solubility:** Both have negative solubility values (-1.56 & -2.947). Again, these are unusual and suggest poor aqueous solubility.

**11. hERG:** Both have low hERG inhibition liability (0.418 & 0.217), which is good.

**12. Cl_mic:** Ligand A (31.277) has a lower microsomal clearance than Ligand B (36.571), indicating better metabolic stability.

**13. t1/2:** Ligand A (19.704) has a longer in vitro half-life than Ligand B (-3.396), which is a significant advantage.

**14. Pgp:** Both have very low Pgp efflux liability (0.06 & 0.112), which is favorable for CNS penetration.

**15. Binding Affinity:** Ligand B (-9.4 kcal/mol) has a significantly stronger binding affinity than Ligand A (-7.7 kcal/mol). This is a substantial advantage for Ligand B, potentially outweighing some of its ADME drawbacks.

**Overall Assessment:**

Ligand B has a significantly better binding affinity and a superior BBB score. However, it has a much higher DILI risk and a negative in vitro half-life. Ligand A has better TPSA, DILI, metabolic stability, and half-life.

Given the GPCR-specific priorities, and the importance of both CNS penetration (BBB) and potency (affinity), the stronger affinity of Ligand B is a compelling factor. While the DILI risk is concerning, it might be mitigated through structural modifications. The negative half-life is also concerning, but could also be addressed. The better ADME profile of Ligand A is appealing, but its weaker binding affinity is a significant drawback for a GPCR target like DRD2.

Output:
1
2025-04-17 07:57:15,049 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (348.403 Da) is slightly lower, which could be beneficial for permeability. Ligand B (372.506 Da) is also acceptable.

**TPSA:** Ligand A (117.67) is better than Ligand B (51.66) as it is closer to the ideal range for CNS targets (<=90). Ligand B's TPSA is quite low, which might suggest good permeability but could also indicate a lack of necessary polar interactions for binding.

**logP:** Ligand A (-0.146) is suboptimal, being below the preferred 1-3 range. This could hinder membrane permeability. Ligand B (3.708) is within the optimal range.

**H-Bond Donors/Acceptors:** Ligand A has 3 HBD and 5 HBA, which are acceptable. Ligand B has 0 HBD and 5 HBA, also acceptable.

**QED:** Both ligands have similar QED values (0.604 and 0.62), indicating good drug-likeness.

**DILI:** Ligand A (15.781) has a significantly lower DILI risk than Ligand B (20.202), which is a substantial advantage.

**BBB:** Ligand B (97.751) has a much higher BBB penetration percentile than Ligand A (62.078). This is a critical advantage for a CNS target like DRD2.

**Caco-2 Permeability:** Ligand A (-6.082) has poor Caco-2 permeability, while Ligand B (-4.397) is slightly better, but still not great.

**Aqueous Solubility:** Both ligands have poor aqueous solubility (-2.361 and -4.234). This could pose formulation challenges.

**hERG Inhibition:** Ligand A (0.185) has a slightly lower hERG inhibition liability than Ligand B (0.425), which is preferable.

**Microsomal Clearance:** Ligand A (-14.61) has a much lower microsomal clearance than Ligand B (99.4), indicating better metabolic stability.

**In vitro Half-Life:** Ligand A (23.508) has a longer in vitro half-life than Ligand B (13.542), which is a positive attribute.

**P-gp Efflux:** Ligand A (0.003) has very low P-gp efflux, while Ligand B (0.285) has moderate P-gp efflux. Lower P-gp efflux is better for CNS penetration.

**Binding Affinity:** Ligand A (-7.8) has a slightly better binding affinity than Ligand B (-6.0). While both are good, the 1.8 kcal/mol difference is significant.

**Overall Assessment:**

Ligand B excels in BBB penetration, which is paramount for a CNS target. However, it suffers from high microsomal clearance, moderate P-gp efflux, and a less favorable logP. Ligand A has a better safety profile (lower DILI, lower hERG), better metabolic stability, lower P-gp efflux, and a slightly stronger binding affinity, despite its suboptimal logP and lower BBB penetration.

Considering the GPCR-specific priorities, the strong BBB penetration of Ligand B is a major advantage. The slightly better affinity of Ligand A is outweighed by the significantly better BBB score of Ligand B.

Output:
1
2025-04-17 07:57:15,049 - INFO - Reasoning:

Let's analyze Ligand A and Ligand B against the provided guidelines, prioritizing GPCR-specific properties (BBB, logP, Pgp, TPSA, and affinity) for DRD2.

**Molecular Weight:** Both ligands (337.463 and 344.459 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (38.33) is significantly better than Ligand B (69.34). For CNS targets, we want TPSA <= 90, and ideally closer to 60. Ligand A is much closer to this ideal.

**logP:** Both ligands have acceptable logP values (3.864 and 2.398, respectively), falling within the 1-3 range. Ligand A is slightly higher, which could be beneficial for membrane permeability but needs to be balanced against solubility.

**H-Bond Donors/Acceptors:** Ligand A (1 HBD, 2 HBA) is preferable to Ligand B (0 HBD, 4 HBA). Lower HBD/HBA generally improves permeability.

**QED:** Both ligands have similar QED values (0.869 and 0.796), indicating good drug-like properties.

**DILI:** Ligand A (32.726) has a lower DILI risk than Ligand B (56.223), which is a significant advantage.

**BBB:** Both ligands have excellent BBB penetration (73.129 and 73.401), exceeding the desirable >70 threshold for CNS targets.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.742 and -4.478). This is unusual and suggests a potential issue with the experimental setup or a highly unusual permeability profile. However, we'll proceed assuming these are relative values and focus on the other parameters.

**Aqueous Solubility:** Both ligands have negative solubility values (-4.43 and -3.394). Similar to Caco-2, this is unusual.

**hERG Inhibition:** Both ligands show low hERG inhibition risk (0.904 and 0.806).

**Microsomal Clearance:** Ligand A (93.296) has higher microsomal clearance than Ligand B (63.306), indicating lower metabolic stability. This is a drawback for Ligand A.

**In vitro Half-Life:** Ligand B (5.286 hours) has a longer in vitro half-life than Ligand A (8.496 hours). This is a positive for Ligand B.

**P-gp Efflux:** Both ligands have similar P-gp efflux liability (0.769 and 0.381). Lower is better, so Ligand B is slightly favored.

**Binding Affinity:** Ligand A (-9.5 kcal/mol) has a significantly stronger binding affinity than Ligand B (-6.8 kcal/mol). This is a substantial advantage, potentially outweighing some of the ADME drawbacks. A difference of 2.7 kcal/mol is very significant.

**Overall Assessment:**

Considering the GPCR-specific priorities, Ligand A is the stronger candidate. Its significantly higher binding affinity (-9.5 vs -6.8 kcal/mol) is a major advantage. While it has higher microsomal clearance, the lower DILI risk and much lower TPSA are also beneficial. The negative Caco-2 and solubility values are concerning but could be artifacts. The strong binding affinity suggests that even with slightly less favorable ADME properties, Ligand A is more likely to be a viable drug candidate.

Output:
1
2025-04-17 07:57:15,049 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (358.825 and 354.422 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (51.66) is significantly better than Ligand B (75.71). For CNS targets, we want TPSA <= 90, and ideally closer to 60. Ligand A is much closer to this ideal.

**logP:** Ligand A (3.514) is optimal (1-3), while Ligand B (1.455) is on the lower side, potentially hindering permeation.

**H-Bond Donors/Acceptors:** Both have acceptable HBD/HBA counts (A: 0/4, B: 1/4), well within the guidelines.

**QED:** Both ligands have reasonable QED values (A: 0.606, B: 0.529), indicating good drug-like properties.

**DILI:** Ligand A (76.076) has a higher DILI risk than Ligand B (15.394). This is a significant drawback for Ligand A.

**BBB:** Ligand B (85.459) has a substantially better BBB penetration percentile than Ligand A (73.168). Both are >70, which is desirable for CNS targets, but B is clearly superior.

**Caco-2 Permeability:** Both have negative Caco-2 values (-4.579 and -4.524), which is unusual and suggests a potential issue with the experimental setup or a very poor permeability. This is not helpful for comparison.

**Aqueous Solubility:** Both have negative solubility values (-4.469 and -1.777), which is also unusual and suggests a potential issue with the experimental setup or very poor solubility. This is not helpful for comparison.

**hERG:** Both ligands have low hERG inhibition liability (A: 0.428, B: 0.244), which is good.

**Microsomal Clearance:** Ligand B (37.945) has a lower microsomal clearance than Ligand A (55.148), indicating better metabolic stability.

**In vitro Half-Life:** Ligand B (-20.014) has a significantly longer in vitro half-life than Ligand A (-7.718).

**P-gp Efflux:** Ligand B (0.018) has much lower P-gp efflux liability than Ligand A (0.382), which is crucial for CNS penetration.

**Binding Affinity:** Both ligands have the same binding affinity (-7.9 kcal/mol), which is excellent.

**Overall Assessment:**

Considering the GPCR-specific priorities, Ligand B is the stronger candidate. While Ligand A has a better TPSA, Ligand B excels in BBB penetration, P-gp efflux, metabolic stability (lower Cl_mic, longer t1/2), and has a significantly lower DILI risk. The similar binding affinity makes these ADME properties the deciding factors. The negative Caco-2 and solubility values are concerning for both but don't differentiate them.

Output:
1
2025-04-17 07:57:15,049 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (353.394 and 361.408 Da) fall comfortably within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (84.67) is better than Ligand B (47.36). Both are below the 90 A^2 threshold for CNS targets, but A is closer to the ideal.

**3. logP:** Both ligands have good logP values (1.422 and 2.899), falling within the optimal 1-3 range. Ligand B is slightly higher, which could be beneficial for membrane permeability, but not dramatically so.

**4. H-Bond Donors:** Ligand A has 1 HBD, and Ligand B has 0. Both are within the acceptable limit of <=5.

**5. H-Bond Acceptors:** Ligand A has 5 HBA, and Ligand B has 4. Both are within the acceptable limit of <=10.

**6. QED:** Ligand A (0.801) has a significantly better QED score than Ligand B (0.679), indicating a more drug-like profile.

**7. DILI:** Ligand A (53.315) has a slightly higher DILI risk than Ligand B (31.524), but both are below the concerning threshold of 60.

**8. BBB:** Both ligands have excellent BBB penetration (Ligand A: 95.269, Ligand B: 91.896), exceeding the desirable >70% threshold for CNS targets.

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.592 and -4.551). This is unusual and suggests a potential issue with intestinal absorption. However, negative values can occur with certain modeling methods and don't necessarily preclude CNS penetration given the high BBB scores.

**10. Aqueous Solubility:** Both ligands have negative solubility values (-3.268 and -2.473), which is also unusual. This suggests poor aqueous solubility, which could be a formulation challenge.

**11. hERG Inhibition:** Ligand A (0.288) has a much lower hERG inhibition risk than Ligand B (0.635), which is a significant advantage.

**12. Microsomal Clearance:** Ligand B (51.206) has a higher microsomal clearance than Ligand A (38.551), indicating faster metabolism and potentially lower in vivo exposure.

**13. In vitro Half-Life:** Ligand A (8.279) has a significantly longer in vitro half-life than Ligand B (0.413), which is a major advantage.

**14. P-gp Efflux:** Ligand A (0.055) has much lower P-gp efflux liability than Ligand B (0.217), which is crucial for CNS penetration.

**15. Binding Affinity:** Ligand A (-7.9 kcal/mol) has a substantially stronger binding affinity than Ligand B (-6.8 kcal/mol). This 1.1 kcal/mol difference is significant and can outweigh minor ADME drawbacks.

**Overall Assessment:**

Ligand A is the superior candidate. It has a better QED score, lower hERG risk, longer half-life, lower P-gp efflux, and significantly stronger binding affinity. While both have unusual Caco-2 and solubility predictions, the strong BBB penetration suggests these might not be insurmountable obstacles. The slightly higher DILI risk for Ligand A is less concerning than the metabolic lability and higher P-gp efflux of Ligand B. The affinity difference is substantial and makes Ligand A the clear choice.

Output:
1
2025-04-17 07:57:15,050 - INFO - Batch 408 complete. Total preferences: 6528
2025-04-17 07:57:15,050 - INFO - Processing batch 409/512...
2025-04-17 07:57:56,167 - INFO - Reasoning:

Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight (MW):** Both ligands (358.785 and 364.383 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (90.06) is borderline but acceptable for CNS targets, while Ligand B (49.41) is excellent, well below the 90 threshold. This favors Ligand B.

**3. logP:** Ligand A (3.46) is at the upper end of the optimal range (1-3), while Ligand B (2.759) is well within it. This slightly favors Ligand B.

**4. H-Bond Donors (HBD):** Both ligands have 1 HBD, which is good.

**5. H-Bond Acceptors (HBA):** Ligand A has 6 HBA, acceptable. Ligand B has 2 HBA, which is also good.

**6. QED:** Ligand B (0.78) has a better QED score than Ligand A (0.414), indicating a more drug-like profile. This favors Ligand B.

**7. DILI:** Ligand A (84.335) has a higher DILI risk than Ligand B (21.946). This strongly favors Ligand B.

**8. BBB:** Both ligands have good BBB penetration (Ligand A: 69.988, Ligand B: 89.725), but Ligand B is significantly better, exceeding the desirable >70 threshold. This is a key advantage for a CNS target like DRD2 and strongly favors Ligand B.

**9. Caco-2 Permeability:** Both have negative values, indicating poor permeability. This is a concern for both, but the scale is unclear, so it's hard to compare.

**10. Aqueous Solubility:** Both have negative values, indicating poor solubility. This is a concern for both, but the scale is unclear, so it's hard to compare.

**11. hERG Inhibition:** Both ligands show low hERG inhibition liability (0.658 and 0.657), which is good.

**12. Microsomal Clearance (Cl_mic):** Ligand B (21.621) has significantly lower microsomal clearance than Ligand A (47.958), suggesting better metabolic stability. This favors Ligand B.

**13. In vitro Half-Life:** Ligand B (13.836 hours) has a longer half-life than Ligand A (78.846 hours). This favors Ligand B.

**14. P-gp Efflux:** Both ligands show low P-gp efflux liability (0.625 and 0.025), which is good. Ligand B is slightly better.

**15. Binding Affinity:** Ligand A (-9.6 kcal/mol) has a slightly better binding affinity than Ligand B (-8.9 kcal/mol). While affinity is crucial, the difference of 0.7 kcal/mol is not substantial enough to overcome the numerous ADME advantages of Ligand B.

**Overall:**

Ligand B consistently outperforms Ligand A across most critical ADME properties, particularly BBB penetration, DILI risk, metabolic stability, and QED. While Ligand A has slightly better binding affinity, the overall profile of Ligand B is much more favorable for development as a CNS-targeting drug.

Output:
1
2025-04-17 07:57:56,168 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B based on the provided guidelines, prioritizing GPCR properties (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (351.382 and 355.429 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (96.33) is better than Ligand B (58.36) as it is closer to the ideal <90 for CNS targets. Ligand B is excellent.

**logP:** Ligand A (-0.246) is suboptimal, being below the preferred 1-3 range. Ligand B (2.708) is within the optimal range. This is a significant advantage for Ligand B.

**H-Bond Donors/Acceptors:** Ligand A (2 HBD, 6 HBA) and Ligand B (1 HBD, 4 HBA) both fall within acceptable limits.

**QED:** Both ligands have similar QED values (0.763 and 0.693), indicating good drug-likeness.

**DILI:** Ligand A (72.741) has a higher DILI risk than Ligand B (20.279). This favors Ligand B.

**BBB:** Ligand B (86.08) has a significantly better BBB penetration percentile than Ligand A (75.262). This is crucial for a CNS target like DRD2 and strongly favors Ligand B.

**Caco-2 Permeability:** Ligand A (-5.055) has poor Caco-2 permeability, while Ligand B (-4.219) is slightly better, but both are poor.

**Aqueous Solubility:** Both ligands have poor aqueous solubility (-2.944 and -3.056).

**hERG Inhibition:** Ligand A (0.349) has a slightly better hERG profile than Ligand B (0.549), but both are acceptable.

**Microsomal Clearance:** Ligand A (-1.532) has a lower (better) microsomal clearance than Ligand B (32.53), indicating better metabolic stability.

**In vitro Half-Life:** Ligand A (6.95 hours) has a longer half-life than Ligand B (0.76 hours). This is a significant advantage for Ligand A.

**P-gp Efflux:** Ligand A (0.032) has much lower P-gp efflux liability than Ligand B (0.139), which is highly desirable for CNS penetration.

**Binding Affinity:** Ligand B (-7.0 kcal/mol) has a slightly better binding affinity than Ligand A (-9.0 kcal/mol). Although A is better, the difference is not substantial enough to overcome the other ADME deficiencies.

**Overall Assessment:**

Ligand B excels in key GPCR properties: logP, BBB penetration, and DILI risk. While Ligand A has better metabolic stability (lower Cl_mic) and P-gp efflux, its poor logP and lower BBB penetration are significant drawbacks for a CNS target. The slightly better affinity of ligand A is not enough to overcome these issues. The poor Caco-2 and solubility of both are concerning, but can be addressed with formulation strategies.

Output:
1
2025-04-17 07:57:56,168 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 drug candidates, considering the provided guidelines and GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (366.49 Da) is slightly better being closer to the lower end, potentially aiding permeability.

**TPSA:** Ligand A (84.42) is significantly better than Ligand B (104.81). For CNS targets, TPSA should be <=90, and A is comfortably within that range, while B is close to the upper limit.

**logP:** Ligand A (1.661) is optimal (1-3), while Ligand B (0.272) is quite low. A logP below 1 can hinder permeation. This is a significant advantage for Ligand A.

**H-Bond Donors/Acceptors:** Ligand A (HBD=1, HBA=6) and Ligand B (HBD=2, HBA=6) are both acceptable, falling within the recommended limits.

**QED:** Ligand A (0.857) has a much higher QED score than Ligand B (0.516), indicating a more drug-like profile.

**DILI:** Ligand A (40.83) has a lower DILI risk than Ligand B (60.954), suggesting better safety.

**BBB:** Ligand A (71.501) has a significantly better BBB penetration percentile than Ligand B (53.703). For a CNS target like DRD2, >70% is desirable, and A is closer to that threshold.

**Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and suggests poor permeability. However, the absolute value is smaller for Ligand A (-5.373 vs -5.571), indicating slightly better permeability.

**Aqueous Solubility:** Both have negative solubility values, which is also unusual. The absolute value is slightly smaller for Ligand A (-2.038 vs -2.865), suggesting slightly better solubility.

**hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.169 and 0.181), which is excellent.

**Microsomal Clearance:** Ligand A (9.6) has a much lower microsomal clearance than Ligand B (64.008), indicating better metabolic stability.

**In vitro Half-Life:** Ligand A (9.388) has a significantly longer in vitro half-life than Ligand B (-30.841), which is a major advantage.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.072 and 0.022).

**Binding Affinity:** Ligand A (-8.3 kcal/mol) has a stronger binding affinity than Ligand B (-6.8 kcal/mol). The difference of 1.5 kcal/mol is substantial and can outweigh minor ADME drawbacks.

**Overall Assessment:**

Ligand A consistently outperforms Ligand B across most critical parameters. It has better TPSA, logP, QED, DILI, BBB, metabolic stability (lower Cl_mic, longer t1/2), and significantly stronger binding affinity. While both have unusual Caco-2 and solubility values, A is slightly better in both cases. Given the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity), Ligand A is the far more promising candidate.

Output:
1
2025-04-17 07:57:56,168 - INFO - Reasoning:

Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (345.4) is slightly better positioned.

**TPSA:** Ligand B (70.16) is significantly better than Ligand A (105.66). For CNS targets, we want TPSA <= 90, and Ligand B is comfortably within that range, while Ligand A is pushing the limit.

**logP:** Ligand A (1.443) is optimal (1-3), while Ligand B (0.083) is a bit low, potentially hindering membrane permeability.

**H-Bond Donors/Acceptors:** Ligand A has 4 HBD and 4 HBA, which is good. Ligand B has 0 HBD and 5 HBA, also acceptable.

**QED:** Both ligands have similar QED values (0.634 and 0.617), indicating good drug-likeness.

**DILI:** Ligand B (19.271) has a much lower DILI risk than Ligand A (42.613), a significant advantage.

**BBB:** Ligand B (70.88) has a much better BBB penetration percentile than Ligand A (14.889). This is *critical* for a CNS target like DRD2.

**Caco-2 Permeability:** Ligand A (-5.872) has better Caco-2 permeability than Ligand B (-4.892), but both are negative values, indicating poor permeability.

**Aqueous Solubility:** Ligand A (-2.972) has slightly better solubility than Ligand B (-0.75), but both are poor.

**hERG:** Ligand A (0.146) has a lower hERG risk than Ligand B (0.666), which is preferable.

**Microsomal Clearance:** Ligand A (-39.468) has significantly lower microsomal clearance than Ligand B (27.582), indicating better metabolic stability.

**In vitro Half-Life:** Ligand A (5.587) has a shorter half-life than Ligand B (-24.303), but the negative value for B is concerning and likely an error.

**P-gp Efflux:** Ligand A (0.008) has a much lower P-gp efflux liability than Ligand B (0.025), which is crucial for CNS penetration.

**Binding Affinity:** Both ligands have very similar binding affinities (-8.4 and -8.1 kcal/mol). The difference is less than 1.5 kcal/mol, so it's not a deciding factor.

**Overall:**

Ligand B excels in BBB penetration and DILI risk, which are highly important for a CNS GPCR target. Its TPSA is also much better. While its logP is lower and Caco-2 permeability is worse, the strong BBB penetration suggests it can overcome these issues. Ligand A has better metabolic stability and lower hERG risk, but the poor BBB penetration is a major drawback. Given the importance of CNS penetration for DRD2, Ligand B is the more promising candidate.

Output:
1
2025-04-17 07:57:56,168 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (354.447 and 351.491 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (88.1) is better than Ligand B (81.67). Both are below the 90 A^2 threshold for CNS targets, which is excellent.

**logP:** Ligand A (0.449) is slightly below the optimal 1-3 range, potentially hindering permeation. Ligand B (0.745) is also on the lower side, but better than A.

**H-Bond Donors/Acceptors:** Ligand A (2 HBD, 5 HBA) and Ligand B (3 HBD, 4 HBA) both have acceptable numbers of H-bond donors and acceptors, well within the guidelines.

**QED:** Both ligands have similar QED values (0.693 and 0.632), indicating good drug-likeness.

**DILI:** Ligand A (13.3) has a significantly lower DILI risk than Ligand B (5.312), which is a major advantage.

**BBB:** Ligand A (62.233) has a much better BBB penetration percentile than Ligand B (32.183). For a CNS target like DRD2, this is a critical factor.

**Caco-2 Permeability:** Ligand A (-4.911) has a worse Caco-2 permeability than Ligand B (-5.303), but both are poor.

**Aqueous Solubility:** Both ligands have very poor aqueous solubility (-0.628 and -0.784).

**hERG Inhibition:** Both ligands show low hERG inhibition risk (0.171 and 0.261).

**Microsomal Clearance:** Ligand A (3.021) has a much lower (better) microsomal clearance than Ligand B (-20.106). This suggests better metabolic stability for Ligand A.

**In vitro Half-Life:** Ligand A (10.448) has a shorter in vitro half-life than Ligand B (23.416).

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.016 and 0.013).

**Binding Affinity:** Both ligands have excellent binding affinity (-8.1 and -7.9 kcal/mol). The difference of 0.2 kcal/mol is not substantial enough to outweigh other factors.

**Overall Assessment:**

Ligand A is superior due to its significantly better BBB penetration, lower DILI risk, and lower microsomal clearance. While its Caco-2 permeability and solubility are poor, the CNS target prioritizes BBB, and the difference in metabolic stability is important. Ligand B's slightly better logP is not enough to compensate for its higher DILI and significantly lower BBB penetration.

Output:
0
2025-04-17 07:57:56,168 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (362.411 and 367.559 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (129.02) is borderline for CNS penetration, being slightly above the preferred <90 threshold. Ligand B (61.44) is well within the ideal range for CNS targets. This is a significant advantage for Ligand B.

**logP:** Ligand A (-0.226) is quite low, potentially hindering membrane permeability. Ligand B (2.767) is within the optimal 1-3 range. This favors Ligand B.

**H-Bond Donors/Acceptors:** Both have 2 HBD and a reasonable number of HBA (6 and 4 respectively). No major concerns here for either.

**QED:** Both ligands have similar QED values (0.745 and 0.705), indicating good drug-like properties.

**DILI:** Ligand A (70.803) has a higher DILI risk than Ligand B (33.501). This is a negative for Ligand A.

**BBB:** Ligand A (48.662) has a low BBB penetration percentile, making it less likely to reach the target in the CNS. Ligand B (54.052) is better, but still not ideal (>70).

**Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and suggests poor permeability. However, the scale is not specified, so it's hard to interpret.

**Aqueous Solubility:** Both have negative solubility values, which is also unusual.

**hERG:** Both ligands have low hERG inhibition liability (0.063 and 0.56), which is good.

**Microsomal Clearance:** Ligand A (-30.35) has a negative clearance, which is not physically possible. This is a red flag and suggests an issue with the data. Ligand B (60.421) has a higher clearance, indicating faster metabolism.

**In vitro Half-Life:** Ligand B (59.068) has a significantly longer half-life than Ligand A (18.945).

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.014 and 0.221), which is favorable for CNS penetration.

**Binding Affinity:** Ligand A (-7.6) has a slightly better binding affinity than Ligand B (-7.4). However, the difference is small (0.2 kcal/mol) and may not be enough to overcome the other significant drawbacks of Ligand A.

**Overall Assessment:**

Ligand B is the more promising candidate. It has a much better logP, TPSA, DILI risk, and in vitro half-life. While its BBB penetration isn't ideal, it's better than Ligand A's. The negative values for Caco-2 and solubility are concerning for both, but the issues with Ligand A's clearance data are a major red flag. The slightly better affinity of Ligand A is unlikely to compensate for its other deficiencies, especially given the importance of CNS penetration for a DRD2 ligand.

Output:
1
2025-04-17 07:57:56,168 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (347.46 and 354.47 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (80.32) is better than Ligand B (49.85) as it is closer to the ideal <90 for CNS targets. Ligand B is excellent.

**3. logP:** Both ligands have a logP around 2.1, which is optimal (1-3).

**4. H-Bond Donors:** Ligand A has 2 HBD, and Ligand B has 0. Both are within the acceptable limit of <=5.

**5. H-Bond Acceptors:** Ligand A has 4 HBA, and Ligand B has 3. Both are within the acceptable limit of <=10.

**6. QED:** Both ligands have reasonable QED scores (0.755 and 0.671), indicating good drug-like properties.

**7. DILI:** Ligand A (31.72%) has a slightly higher DILI risk than Ligand B (17.64%), but both are well below the concerning threshold of 60%.

**8. BBB:** This is a crucial parameter for a CNS target like DRD2. Ligand B (97.25%) significantly outperforms Ligand A (70.92%). This is a major advantage for Ligand B.

**9. Caco-2 Permeability:** Both have negative values, indicating poor permeability. However, the scale is not specified, so it is difficult to interpret these values.

**10. Aqueous Solubility:** Both have negative values, indicating poor solubility. Again, the scale is not specified, making interpretation difficult.

**11. hERG Inhibition:** Both ligands show low hERG inhibition risk (0.49 and 0.698), which is favorable.

**12. Microsomal Clearance:** Ligand A (61.20) has a higher microsomal clearance than Ligand B (50.35), suggesting lower metabolic stability.

**13. In vitro Half-Life:** Ligand B (6.05 hours) has a significantly longer half-life than Ligand A (-12.58 hours). The negative value for Ligand A is concerning and suggests very rapid metabolism or an issue with the assay.

**14. P-gp Efflux:** Both ligands have low P-gp efflux liability (0.167 and 0.219), which is good for CNS penetration.

**15. Binding Affinity:** Ligand B (-7.9 kcal/mol) has a stronger binding affinity than Ligand A (-8.9 kcal/mol). While both are good, the 1 kcal/mol difference is significant and could outweigh minor ADME drawbacks.

**Overall Assessment:**

Ligand B is the superior candidate. While Ligand A has a slightly better TPSA, Ligand B excels in the most critical parameters for a CNS-targeting GPCR: BBB penetration, binding affinity, and in vitro half-life. The lower DILI risk and better metabolic stability (lower Cl_mic) further support choosing Ligand B. The negative half-life for Ligand A is a major red flag.

Output:
1
2025-04-17 07:57:56,168 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (350.459 and 346.515 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (73.99) is higher than Ligand B (49.41). For a CNS target like DRD2, TPSA should be <=90, so both are acceptable, but B is significantly better.

**3. logP:** Ligand A (2.533) and Ligand B (3.832) are both within the optimal 1-3 range. Ligand B is slightly higher, which could be beneficial for membrane permeability, but also increases the risk of off-target interactions.

**4. H-Bond Donors:** Both ligands have 1 HBD, which is within the acceptable limit of <=5.

**5. H-Bond Acceptors:** Ligand A has 4 HBAs, and Ligand B has 2. Both are well within the acceptable limit of <=10.

**6. QED:** Ligand A (0.782) has a better QED score than Ligand B (0.621), indicating a more drug-like profile.

**7. DILI:** Ligand A (20.008) has a lower DILI risk than Ligand B (25.436), which is preferable.

**8. BBB:** This is a critical parameter for CNS targets. Ligand B (77.472) has a significantly higher BBB percentile than Ligand A (47.615). This is a major advantage for Ligand B.

**9. Caco-2 Permeability:** Ligand A (-4.587) and Ligand B (-4.702) both have negative Caco-2 values, which is unusual and suggests poor permeability. However, the scale isn't specified, so it's difficult to interpret.

**10. Aqueous Solubility:** Ligand A (-1.569) and Ligand B (-3.932) both have negative solubility values, indicating poor solubility. This is a concern for both.

**11. hERG Inhibition:** Both ligands have low hERG inhibition liability (0.648 and 0.472 respectively), which is good.

**12. Microsomal Clearance:** Ligand A (36.25) has lower microsomal clearance than Ligand B (54.541), suggesting better metabolic stability.

**13. In vitro Half-Life:** Ligand A (40.513) has a longer in vitro half-life than Ligand B (-19.911). The negative value for B is concerning and likely an outlier or error.

**14. P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.359 and 0.198 respectively), which is favorable for CNS penetration.

**15. Binding Affinity:** Ligand B (-9.2 kcal/mol) has a significantly stronger binding affinity than Ligand A (0.0 kcal/mol). This is a substantial advantage that can outweigh some of the ADME drawbacks.

**Overall Assessment:**

Ligand B excels in the most critical areas for a CNS-targeting GPCR ligand: BBB penetration and binding affinity. While Ligand A has better QED, DILI, metabolic stability, and half-life, the significantly stronger binding affinity and superior BBB penetration of Ligand B are more important for DRD2. The negative half-life for ligand B is a major concern, but the binding affinity is so much higher that it could be optimized. The solubility and permeability are poor for both, but these can be addressed with formulation strategies.

Output:
1
2025-04-17 07:57:56,168 - INFO - Reasoning:

Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (364.47 and 344.46 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (80.68) is slightly above the optimal <90 for CNS targets, but still reasonable. Ligand B (70.25) is excellent, well below 90.

**3. logP:** Both ligands have good logP values (3.315 and 3.552), falling within the 1-3 range.

**4. H-Bond Donors:** Both have 2 HBD, which is within the acceptable limit of <=5.

**5. H-Bond Acceptors:** Ligand A has 7 HBA, while Ligand B has 3. Both are within the acceptable limit of <=10.

**6. QED:** Both ligands have good QED scores (0.665 and 0.787), indicating good drug-like properties.

**7. DILI:** Ligand A (64.87) has a higher DILI risk than Ligand B (43.66). This is a negative for Ligand A.

**8. BBB:** Ligand B (77.007) has a significantly better BBB penetration score than Ligand A (45.715). This is a *critical* advantage for a CNS target like DRD2.

**9. Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and suggests poor permeability. However, the scale is not specified, so the absolute values are difficult to interpret.

**10. Aqueous Solubility:** Both have negative solubility values, also unusual. Again, the scale is unspecified.

**11. hERG Inhibition:** Ligand A (0.398) has a slightly better hERG profile than Ligand B (0.841), indicating lower cardiotoxicity risk.

**12. Microsomal Clearance:** Ligand B (42.689) has significantly lower microsomal clearance than Ligand A (88.867), suggesting better metabolic stability.

**13. In vitro Half-Life:** Ligand B (-14.904) has a much longer in vitro half-life than Ligand A (-4.423). This is a significant advantage.

**14. P-gp Efflux:** Ligand A (0.502) has slightly lower P-gp efflux than Ligand B (0.272), which is favorable for CNS penetration.

**15. Binding Affinity:** Ligand B (-9.2 kcal/mol) has a stronger binding affinity than Ligand A (-7.9 kcal/mol). This is a substantial difference (>1.3 kcal/mol) and a major advantage.

**Overall Assessment:**

Ligand B is the superior candidate. While both meet basic drug-likeness criteria, Ligand B excels in the properties most crucial for a CNS-targeting GPCR ligand: BBB penetration, metabolic stability (lower Cl_mic, longer t1/2), and binding affinity. The lower DILI risk is also a positive. Although Ligand A has a slightly better hERG profile and P-gp efflux, the advantages of Ligand B in BBB, affinity, and metabolic stability outweigh these minor differences. The negative Caco-2 and solubility values are concerning for both, but the other factors strongly favor Ligand B.

Output:
1
2025-04-17 07:57:56,169 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B against the provided guidelines, prioritizing GPCR-specific properties (BBB, logP, Pgp, TPSA, and affinity) for DRD2.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (340.383 Da) is slightly lower, which could be beneficial for permeability, but both are acceptable.

**TPSA:** Ligand A (117.34) is closer to the desirable threshold of 90 for CNS targets than Ligand B (54.18). This is a significant advantage for CNS penetration.

**logP:** Ligand A (0.658) is quite low, potentially hindering membrane permeability. Ligand B (3.755) is within the optimal range (1-3). This is a clear advantage for Ligand B.

**H-Bond Donors/Acceptors:** Ligand A has 4 HBD and 5 HBA, while Ligand B has 1 HBD and 5 HBA. Both are within acceptable limits, but Ligand B's lower HBD count might slightly improve permeability.

**QED:** Both ligands have good QED scores (A: 0.638, B: 0.736), indicating drug-likeness.

**DILI:** Ligand A (61.419) has a higher DILI risk than Ligand B (15.781). This is a significant negative for Ligand A.

**BBB:** Ligand B (52.579) has a substantially higher BBB percentile than Ligand A (23.265). This is crucial for a CNS target like DRD2 and strongly favors Ligand B.

**Caco-2 Permeability:** Both have negative Caco-2 values, indicating poor permeability. However, the scale is not specified, so it's difficult to interpret the magnitude of the difference.

**Aqueous Solubility:** Both have negative solubility values, indicating poor solubility. Again, the scale is unspecified.

**hERG:** Both ligands have low hERG inhibition liability (A: 0.328, B: 0.88), which is good.

**Microsomal Clearance:** Ligand A (-32.821) has a much lower (better) microsomal clearance than Ligand B (25.374), suggesting greater metabolic stability.

**In vitro Half-Life:** Ligand B (65.372) has a significantly longer in vitro half-life than Ligand A (26.708), which is desirable.

**P-gp Efflux:** Ligand A (0.008) has very low P-gp efflux liability, which is excellent for CNS penetration. Ligand B (0.482) is higher, but still relatively low.

**Binding Affinity:** Ligand B (-6.6 kcal/mol) has a better binding affinity than Ligand A (-9.3 kcal/mol). This is a substantial advantage for Ligand B.

**Overall Assessment:**

While Ligand A has better metabolic stability (lower Cl_mic) and lower P-gp efflux, its poor logP, low BBB penetration, and higher DILI risk are major drawbacks for a CNS-targeted GPCR. Ligand B excels in the critical areas for CNS drug development: good logP, significantly higher BBB penetration, better binding affinity, and a lower DILI risk. The longer half-life is also a plus. The lower metabolic stability of Ligand B is a concern, but could potentially be addressed through structural modifications.

Output:
1
2025-04-17 07:57:56,169 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (356.394 and 340.427 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (84.94) is better than Ligand B (78.09) as both are below the 90 A^2 threshold for CNS targets.

**logP:** Ligand B (1.724) is better than Ligand A (0.279). A logP between 1-3 is optimal, and Ligand A is significantly below this range, potentially hindering permeability.

**H-Bond Donors/Acceptors:** Ligand A (1 HBD, 5 HBA) is slightly better than Ligand B (2 HBD, 3 HBA) in terms of maintaining a balance between solubility and permeability. Both are within acceptable limits.

**QED:** Ligand B (0.647) has a better QED score than Ligand A (0.384), indicating a more drug-like profile.

**DILI:** Ligand A (17.798) has a much lower DILI risk than Ligand B (56.844), which is a significant advantage.

**BBB:** Ligand A (92.4) has a substantially higher BBB penetration percentile than Ligand B (68.282). This is a critical factor for a CNS target like DRD2.

**Caco-2 Permeability:** Ligand A (-4.717) has a worse Caco-2 permeability than Ligand B (-4.954).

**Aqueous Solubility:** Ligand A (-2.309) has a worse aqueous solubility than Ligand B (-3.11).

**hERG:** Both ligands have similar hERG inhibition liability (0.43 and 0.434), indicating a similar risk profile.

**Microsomal Clearance:** Ligand B (0.46) has a much lower microsomal clearance than Ligand A (24.404), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand B (-31.02) has a much longer in vitro half-life than Ligand A (-18.489), which is desirable.

**P-gp Efflux:** Both ligands have similar P-gp efflux liability (0.035 and 0.063).

**Binding Affinity:** Ligand B (-7.8 kcal/mol) has a slightly better binding affinity than Ligand A (-7.5 kcal/mol), although the difference is relatively small.

**Overall Assessment:**

Ligand A excels in BBB penetration and DILI risk, which are crucial for a CNS drug. However, its low logP and poor solubility are significant drawbacks. Ligand B has better ADME properties (logP, QED, clearance, half-life) and slightly better affinity, but its higher DILI risk and lower BBB are concerning.

Considering the GPCR-specific priorities, BBB is paramount for CNS targets. Ligand A's significantly higher BBB (92.4 vs 68.282) outweighs the benefits of Ligand B's better ADME profile, especially given the relatively small affinity difference. The lower DILI risk of Ligand A is also a major advantage. While Ligand A's logP is suboptimal, it is not drastically low, and formulation strategies could potentially mitigate this issue.

Output:
0
2025-04-17 07:57:56,169 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (346.43 and 344.42 Da) fall comfortably within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (75.71) is significantly better than Ligand B (91.23). For CNS targets, we want TPSA <= 90, so Ligand A is preferable.

**3. logP:** Both ligands have acceptable logP values (1.83 and 2.22), falling within the optimal 1-3 range.

**4. H-Bond Donors:** Ligand A (1) is better than Ligand B (2). Lower HBD generally improves permeability.

**5. H-Bond Acceptors:** Both ligands have the same HBA count (4), which is well within the acceptable limit of <= 10.

**6. QED:** Both ligands have good QED scores (0.83 and 0.87), indicating good drug-like properties.

**7. DILI:** Ligand A (51.4%) has a slightly better DILI risk profile than Ligand B (60.6%), but both are acceptable.

**8. BBB:** Both ligands have similar BBB penetration (57.6% and 62.0%). While neither exceeds the desirable >70% for CNS targets, they are reasonably close.

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 values, which is unusual and suggests poor permeability. However, the scale is not specified, so it's difficult to interpret.

**10. Aqueous Solubility:** Both ligands have negative solubility values, which is also unusual and suggests poor solubility. Again, the scale is not specified.

**11. hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.33 and 0.19), which is excellent.

**12. Microsomal Clearance:** Ligand B (19.76) has significantly lower microsomal clearance than Ligand A (62.44), indicating better metabolic stability.

**13. In vitro Half-Life:** Ligand B (23.79 hours) has a much longer half-life than Ligand A (-12.87 hours). This is a significant advantage.

**14. P-gp Efflux:** Both ligands have low P-gp efflux liability (0.14 and 0.10), which is good for CNS penetration.

**15. Binding Affinity:** Ligand B (-9.0 kcal/mol) has a significantly stronger binding affinity than Ligand A (-7.8 kcal/mol). This >1.5 kcal/mol difference is a major advantage, potentially outweighing some ADME drawbacks.

**Overall Assessment:**

While Ligand A has a better TPSA, Ligand B wins on several crucial parameters: significantly stronger binding affinity, better metabolic stability (lower Cl_mic), and a longer half-life. The slightly higher TPSA of Ligand B is a minor concern compared to the substantial improvement in potency and PK. Given the GPCR-specific prioritization of affinity, and the fact that both ligands have reasonable BBB penetration, Ligand B is the more promising candidate.

Output:
1
2025-04-17 07:57:56,169 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (347.365 and 357.376 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Both ligands have TPSA values (56.41 and 55.32) below the 90 A^2 threshold desirable for CNS targets, which is excellent.

**3. logP:** Ligand A (2.382) is within the optimal 1-3 range. Ligand B (3.206) is slightly higher but still acceptable.

**4. H-Bond Donors:** Ligand A has 1 HBD, which is good. Ligand B has 0, also good.

**5. H-Bond Acceptors:** Ligand A has 2 HBA, and Ligand B has 4. Both are below the 10 threshold.

**6. QED:** Both ligands have QED values (0.867 and 0.703) above 0.5, indicating good drug-like properties.

**7. DILI:** Ligand A (61.613) has a higher DILI risk than Ligand B (47.732), but both are below the concerning 60 threshold.

**8. BBB:** Both ligands have excellent BBB penetration (87.941 and 85.111), exceeding the 70% threshold for CNS targets.

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.722 and -4.201). This is unusual and suggests poor permeability. However, these values are on a log scale and negative values are not uncommon.

**10. Aqueous Solubility:** Both ligands have very poor aqueous solubility (-3.396 and -3.393). This is a significant drawback.

**11. hERG Inhibition:** Both ligands have low hERG inhibition risk (0.604 and 0.645).

**12. Microsomal Clearance:** Ligand A (11.632) has significantly lower microsomal clearance than Ligand B (65.447), suggesting better metabolic stability.

**13. In vitro Half-Life:** Ligand A (5.047) has a shorter in vitro half-life than Ligand B (-28.159). The negative value for Ligand B is unusual and likely indicates a very long half-life or an issue with the measurement.

**14. P-gp Efflux:** Both ligands have low P-gp efflux liability (0.2 and 0.28).

**15. Binding Affinity:** Ligand A (-8.9 kcal/mol) has a significantly stronger binding affinity than Ligand B (-6.3 kcal/mol). This is a substantial difference (>1.5 kcal/mol advantage).

**Overall Assessment:**

Ligand A is the stronger candidate. While both have poor solubility and questionable Caco-2 permeability, Ligand A's significantly better binding affinity (-8.9 vs -6.3 kcal/mol) and lower microsomal clearance outweigh the slightly higher DILI risk. The superior affinity is critical for a GPCR target, and the improved metabolic stability is a significant advantage. The BBB penetration is excellent for both.

Output:
1
2025-04-17 07:57:56,169 - INFO - Reasoning:
Let's analyze both ligands against the provided guidelines, prioritizing GPCR-specific properties (BBB, logP, Pgp, TPSA, and affinity).

**Ligand A:**

*   **MW:** 465.193 Da - Acceptable, within the 200-500 range.
*   **TPSA:** 36.67 - Excellent, well below the 90 target for CNS drugs.
*   **logP:** 4.138 - Slightly high, potentially leading to solubility issues or off-target interactions, but not drastically so.
*   **HBD:** 0 - Low, could impact solubility.
*   **HBA:** 5 - Acceptable.
*   **QED:** 0.583 - Good, indicates drug-like properties.
*   **DILI:** 67.003 - Moderate risk, needs consideration.
*   **BBB:** 93.563 - Excellent, very high probability of CNS penetration.
*   **Caco-2:** -5.038 - Very poor permeability.
*   **Solubility:** -3.859 - Very poor solubility.
*   **hERG:** 0.977 - Low risk.
*   **Cl_mic:** 55.605 - Moderate clearance, could lead to faster metabolism.
*   **t1/2:** 18.672 - Moderate half-life.
*   **Pgp:** 0.888 - Moderate efflux, could limit CNS exposure.
*   **Affinity:** -8.8 kcal/mol - Excellent, very strong binding.

**Ligand B:**

*   **MW:** 367.471 Da - Acceptable, within the 200-500 range.
*   **TPSA:** 105.23 - Higher than ideal for CNS penetration (above 90), but not prohibitive.
*   **logP:** 1.051 - Low, potentially hindering permeation.
*   **HBD:** 2 - Acceptable.
*   **HBA:** 5 - Acceptable.
*   **QED:** 0.679 - Good, indicates drug-like properties.
*   **DILI:** 58.705 - Acceptable risk.
*   **BBB:** 65.529 - Moderate, lower than desired for a CNS target.
*   **Caco-2:** -5.32 - Very poor permeability.
*   **Solubility:** -2.958 - Poor solubility.
*   **hERG:** 0.122 - Very low risk.
*   **Cl_mic:** 7.437 - Low clearance, suggesting good metabolic stability.
*   **t1/2:** 8.584 - Short half-life.
*   **Pgp:** 0.137 - Low efflux, favorable for CNS exposure.
*   **Affinity:** -7.9 kcal/mol - Very good, strong binding, but 0.9 kcal/mol weaker than Ligand A.

**Comparison & Decision:**

Both ligands have significant drawbacks regarding permeability and solubility. However, for a CNS target like DRD2, BBB penetration is crucial. Ligand A has a significantly higher BBB percentile (93.563) compared to Ligand B (65.529). While Ligand A's logP is higher, its exceptional binding affinity (-8.8 kcal/mol) and excellent BBB penetration outweigh this concern. The DILI risk is moderate, but manageable. Ligand B has better metabolic stability (lower Cl_mic) and lower Pgp efflux, but its weaker affinity and lower BBB penetration are major disadvantages.

Given the GPCR-specific priorities, particularly the need for good CNS penetration and strong binding, **Ligand A** is the more promising drug candidate.

Output:
1
2025-04-17 07:57:56,170 - INFO - Reasoning:

Let's analyze Ligand A and Ligand B based on the provided guidelines, prioritizing GPCR-specific properties (BBB, logP, Pgp, TPSA, and affinity).

**Ligand A:**

*   **MW:** 350.423 Da - Good.
*   **TPSA:** 121.64 - Acceptable, but pushing the limit for CNS targets (ideally <90).
*   **logP:** 0.248 - Low. This is a significant concern as it may hinder membrane permeability.
*   **HBD:** 2 - Good.
*   **HBA:** 5 - Good.
*   **QED:** 0.419 - Below ideal (aim for >0.5), suggesting potential issues.
*   **DILI:** 12.99 - Excellent, very low risk.
*   **BBB:** 30.671 - Poor. This is a major drawback for a CNS target like DRD2.
*   **Caco-2:** -5.428 - Very poor permeability.
*   **Solubility:** -0.775 - Poor solubility.
*   **hERG:** 0.059 - Excellent, very low risk.
*   **Cl_mic:** -12.466 - Excellent, very stable.
*   **t1/2:** 12.777 - Good.
*   **Pgp:** 0.004 - Very low efflux, favorable.
*   **Affinity:** -7.4 kcal/mol - Excellent binding affinity.

**Ligand B:**

*   **MW:** 364.417 Da - Good.
*   **TPSA:** 53.33 - Excellent, well within the ideal range for CNS targets.
*   **logP:** 4.123 - High. Could lead to solubility issues and off-target interactions, but manageable.
*   **HBD:** 0 - Good.
*   **HBA:** 5 - Good.
*   **QED:** 0.661 - Good, indicates a drug-like profile.
*   **DILI:** 47.654 - Acceptable, moderate risk.
*   **BBB:** 80.574 - Excellent, highly desirable for a CNS target.
*   **Caco-2:** -4.508 - Moderate permeability.
*   **Solubility:** -4.462 - Poor solubility.
*   **hERG:** 0.885 - Acceptable risk.
*   **Cl_mic:** 105.97 - High clearance, less metabolically stable.
*   **t1/2:** 5.715 - Moderate half-life.
*   **Pgp:** 0.361 - Moderate efflux.
*   **Affinity:** -7.7 kcal/mol - Excellent, slightly better than Ligand A.

**Comparison & Decision:**

Despite Ligand A having a slightly better affinity (-7.4 vs -7.7 kcal/mol), Ligand B is the far more promising candidate. The critical difference lies in the BBB penetration. Ligand B's BBB score is 80.574, while Ligand A's is only 30.671. For a CNS target like DRD2, this is paramount.

Ligand A's low logP and poor Caco-2 permeability are also significant drawbacks, even with its excellent metabolic stability. Ligand B's higher logP is a concern, but potentially manageable through formulation strategies. While Ligand B has higher clearance and moderate Pgp efflux, these can be addressed through further optimization. The improved TPSA and QED scores also favor Ligand B.

Output:
1
2025-04-17 07:57:56,170 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B based on the provided guidelines, prioritizing GPCR-specific properties (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (349.427 and 346.366 Da) fall within the ideal range of 200-500 Da.

**TPSA:** Ligand A (90.23) is excellent for CNS penetration, being below the 90 A^2 threshold. Ligand B (101.8) is slightly higher but still reasonable.

**logP:** Ligand A (0.786) is a bit low, potentially hindering permeation. Ligand B (0.469) is even lower, raising more concern. Both are below the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A has 3 HBD and 5 HBA, which is acceptable. Ligand B has 2 HBD and 6 HBA, also acceptable.

**QED:** Both ligands have similar QED values (0.731 and 0.723), indicating good drug-likeness.

**DILI:** Ligand A (30.438) has a significantly lower DILI risk than Ligand B (57.697). This is a substantial advantage for Ligand A.

**BBB:** Ligand A (60.644) has a moderate BBB penetration, while Ligand B (71.501) is better, exceeding the 70% threshold desirable for CNS targets. This is a key advantage for Ligand B.

**Caco-2 Permeability:** Both have negative Caco-2 values (-5.014 and -5.285), which is unusual and suggests poor permeability. This is a concern for both.

**Aqueous Solubility:** Both have negative solubility values (-1.84 and -2.732), also unusual and indicating very low solubility. This is a significant drawback for both.

**hERG Inhibition:** Both ligands show low hERG inhibition liability (0.47 and 0.235), which is good.

**Microsomal Clearance:** Ligand A (15.54) has a higher microsomal clearance than Ligand B (4.305), indicating lower metabolic stability. Ligand B is preferable here.

**In vitro Half-Life:** Ligand A (40.627) has a longer half-life than Ligand B (5.857), which is desirable.

**P-gp Efflux:** Ligand A (0.26) has lower P-gp efflux than Ligand B (0.007), which is better for CNS exposure.

**Binding Affinity:** Ligand A (-8.0 kcal/mol) has a slightly better binding affinity than Ligand B (-7.8 kcal/mol), though the difference is small.

**Overall Assessment:**

Ligand B has a better BBB score, lower microsomal clearance, and slightly better P-gp efflux. However, Ligand A has a significantly lower DILI risk, a longer half-life, and slightly better binding affinity. Both have poor solubility and permeability. Given the CNS target and the importance of BBB penetration, Ligand B appears slightly more promising. However, the substantial DILI risk associated with Ligand B is a major concern. The small difference in binding affinity isn't enough to overcome the DILI risk.

Output:
1
2025-04-17 07:57:56,170 - INFO - Batch 409 complete. Total preferences: 6544
2025-04-17 07:57:56,170 - INFO - Processing batch 410/512...
2025-04-17 07:58:41,181 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (367.475 and 374.507 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (113.08) is slightly higher than Ligand B (107.61), but both are below the 140 A^2 threshold for oral absorption and reasonably close to the 90 A^2 target for CNS penetration.

**logP:** Ligand A (0.497) is a bit low, potentially hindering permeation. Ligand B (-0.436) is even lower, raising more concerns about permeability. Both are below the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Both have 3 HBD and similar HBA counts (6 and 5 respectively), which are within acceptable limits.

**QED:** Both ligands have reasonable QED values (0.649 and 0.534), indicating good drug-like properties.

**DILI:** Ligand A (55.138) has a higher DILI risk than Ligand B (30.206). This is a significant negative for Ligand A.

**BBB:** Ligand A (44.203) and Ligand B (40.403) both have relatively low BBB penetration percentiles. This is a concern for a CNS target like DRD2, but not a complete dealbreaker if other properties are strongly favorable.

**Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and suggests poor permeability.

**Aqueous Solubility:** Both have negative solubility values, also unusual and suggesting poor solubility.

**hERG:** Both ligands have very low hERG inhibition liability (0.114 and 0.127), which is excellent.

**Microsomal Clearance:** Ligand A (7.126) has a higher microsomal clearance than Ligand B (6.296), indicating lower metabolic stability.

**In vitro Half-Life:** Ligand B (-38.517) has a *very* negative half-life, which is nonsensical. This is a major red flag. Ligand A (21.847) has a reasonable half-life.

**P-gp Efflux:** Both have very low P-gp efflux liability (0.035 and 0.007), which is favorable for CNS penetration.

**Binding Affinity:** Ligand A (-8.4 kcal/mol) has a significantly stronger binding affinity than Ligand B (-7.3 kcal/mol). This 1.1 kcal/mol difference is substantial and could outweigh some ADME drawbacks.

**Overall Assessment:**

Ligand B has a completely unrealistic negative in vitro half-life, making it immediately unsuitable. While Ligand A has some weaknesses (low logP, moderate DILI, low BBB), its significantly superior binding affinity and reasonable ADME properties (excluding the low logP) make it the more promising candidate. The low logP could potentially be addressed through structural modifications.

Output:
1
2025-04-17 07:58:41,181 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (348.447 and 345.491 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (76.46) is slightly above the optimal <90 for CNS targets, but still reasonable. Ligand B (70.15) is excellent, well below 90.

**3. logP:** Ligand A (1.034) is at the lower end of the optimal 1-3 range, potentially impacting permeability. Ligand B (2.882) is well within the optimal range.

**4. H-Bond Donors:** Ligand A (1) is good. Ligand B (2) is also acceptable.

**5. H-Bond Acceptors:** Both ligands (A: 5, B: 5) are within the acceptable limit of <=10.

**6. QED:** Both ligands have good QED values (A: 0.761, B: 0.859), indicating drug-like properties.

**7. DILI:** Ligand A (18.728) has a significantly lower DILI risk than Ligand B (35.867), which is a substantial advantage.

**8. BBB:** Ligand B (85.072) has a much higher BBB penetration percentile than Ligand A (68.864). This is a critical factor for a CNS target like DRD2.

**9. Caco-2 Permeability:** Ligand A (-4.923) has poor Caco-2 permeability, suggesting poor absorption. Ligand B (-5.084) is also poor, but slightly worse.

**10. Aqueous Solubility:** Ligand A (-1.361) has slightly better solubility than Ligand B (-3.237).

**11. hERG Inhibition:** Both ligands show very low hERG inhibition risk (A: 0.172, B: 0.601).

**12. Microsomal Clearance:** Ligand A (14.325) has significantly lower microsomal clearance, indicating better metabolic stability than Ligand B (62.356).

**13. In vitro Half-Life:** Ligand A (10.976) has a longer half-life than Ligand B (4.853).

**14. P-gp Efflux:** Both ligands show very low P-gp efflux liability (A: 0.016, B: 0.08).

**15. Binding Affinity:** Ligand B (-9.0) has a significantly stronger binding affinity than Ligand A (-7.7). This is a >1.3 kcal/mol advantage, which is substantial.

**Overall Assessment:**

Ligand B excels in BBB penetration and binding affinity, which are paramount for a CNS GPCR target. While Ligand A has advantages in DILI risk, metabolic stability, and half-life, the superior affinity and BBB penetration of Ligand B outweigh these benefits. The slightly higher DILI risk of Ligand B is a concern, but could be addressed with further optimization. The poor Caco-2 permeability of both is a concern, but less critical for a CNS target where direct brain exposure is prioritized.

Output:
1
2025-04-17 07:58:41,182 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (360.443 and 372.49 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (84.22) is better than Ligand B (75.27) as it is closer to the ideal <90 A^2 for CNS targets.

**logP:** Ligand B (3.617) is higher than Ligand A (1.059). While both are within the 1-3 range, Ligand B is approaching the upper limit. Ligand A's lower logP might present solubility challenges, but is generally preferred for CNS penetration.

**H-Bond Donors/Acceptors:** Ligand A (0 HBD, 7 HBA) is preferable to Ligand B (2 HBD, 3 HBA). Fewer H-bonds generally improve BBB penetration.

**QED:** Ligand A (0.817) has a significantly better QED score than Ligand B (0.575), indicating a more drug-like profile.

**DILI:** Ligand B (20.24) has a much lower DILI risk than Ligand A (64.909), which is a significant advantage.

**BBB:** Ligand B (71.811) has a substantially higher BBB percentile than Ligand A (52.268). This is a critical factor for a CNS target like DRD2.

**Caco-2 Permeability:** Both have negative values, which is unusual. Assuming these are logP-like scales, lower values indicate poorer permeability. Ligand A (-5.09) is worse than Ligand B (-4.749).

**Aqueous Solubility:** Ligand A (-1.298) is slightly better than Ligand B (-3.438), indicating better solubility.

**hERG:** Both ligands have very low hERG risk (0.355 and 0.35), which is excellent.

**Microsomal Clearance:** Ligand A (19.987) has lower microsomal clearance than Ligand B (83.521), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (-21.721) has a much longer in vitro half-life than Ligand B (-2.93), which is a significant advantage.

**P-gp Efflux:** Both ligands have very low P-gp efflux (0.118 and 0.183), which is good.

**Binding Affinity:** Ligand A (-8.6 kcal/mol) has a significantly stronger binding affinity than Ligand B (-7.4 kcal/mol). This is a substantial advantage and can potentially offset some of the ADME drawbacks.

**Overall Assessment:**

Ligand A excels in binding affinity, QED, metabolic stability, and half-life. However, its BBB penetration is concerningly low, and it has a higher DILI risk. Ligand B has a much better BBB score and lower DILI, but weaker affinity, lower QED, and poorer metabolic stability.

Given the GPCR-specific priority of BBB penetration for CNS targets, and the substantial difference in binding affinity (-8.6 vs -7.4 kcal/mol), Ligand A is the more promising candidate. The stronger binding affinity is likely to outweigh the lower BBB and higher DILI, as optimization can be performed to improve these parameters.

Output:
0
2025-04-17 07:58:41,182 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B based on the provided guidelines, prioritizing GPCR-specific properties (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (359.451 and 383.539 Da) fall within the ideal 200-500 Da range.

**TPSA:** Both ligands have a TPSA of 80.32, which is acceptable but pushing the upper limit for CNS penetration (ideally <90).

**logP:** Ligand A (3.595) is slightly higher than Ligand B (2.131). Both are within the optimal 1-3 range, but Ligand B is closer to the lower bound, which *could* impact permeability.

**H-Bond Donors/Acceptors:** Both ligands have 2 HBD and 6 HBA, which are within acceptable limits.

**QED:** Both ligands have similar QED scores (0.816 and 0.814), indicating good drug-likeness.

**DILI:** Ligand A (82.241) has a higher DILI risk than Ligand B (65.258). This is a significant negative for Ligand A.

**BBB:** Ligand B (66.382) has a considerably better BBB percentile than Ligand A (55.293). This is a *critical* advantage for a CNS target like DRD2.

**Caco-2 Permeability:** Ligand A (-4.917) shows better Caco-2 permeability than Ligand B (-5.332), suggesting better intestinal absorption. However, for a CNS target, intestinal absorption is less crucial than BBB penetration.

**Aqueous Solubility:** Ligand A (-4.449) has slightly better aqueous solubility than Ligand B (-3.442).

**hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.246 and 0.263).

**Microsomal Clearance:** Ligand B (32.137) has significantly lower microsomal clearance than Ligand A (90.638), indicating better metabolic stability.

**In vitro Half-Life:** Ligand B (23.589) has a longer in vitro half-life than Ligand A (44.166). This is a positive for Ligand B.

**P-gp Efflux:** Both ligands have similar P-gp efflux liability (0.415 and 0.21).

**Binding Affinity:** Ligand A (-8.9 kcal/mol) has a slightly better binding affinity than Ligand B (-8.5 kcal/mol). While a 0.4 kcal/mol difference is noticeable, it's not a massive advantage, and can be overcome by superior ADME properties.

**Overall Assessment:**

Ligand B is the more promising candidate. The significantly better BBB penetration (66.382 vs 55.293), lower DILI risk (65.258 vs 82.241), and improved metabolic stability (lower Cl_mic and longer t1/2) outweigh the slightly weaker binding affinity and lower Caco-2 permeability. For a CNS target, BBB penetration is paramount, and Ligand B excels in this area.

Output:
1
2025-04-17 07:58:41,182 - INFO - Reasoning:

Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (366.483 and 343.427 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Both ligands have TPSA values (87.66 and 82.27) below the 90 A^2 threshold desirable for CNS targets, which is excellent.

**3. logP:** Both ligands have logP values (1.387 and 1.423) within the optimal 1-3 range.

**4. H-Bond Donors:** Ligand A (3) and Ligand B (2) both meet the HBD <= 5 criteria.

**5. H-Bond Acceptors:** Ligand A (5) and Ligand B (3) both meet the HBA <= 10 criteria.

**6. QED:** Both ligands have acceptable QED values (0.68 and 0.553), indicating good drug-like properties.

**7. DILI:** Ligand A (41.218) has a slightly higher DILI risk than Ligand B (16.44), but both are below the concerning threshold of 60.

**8. BBB:** Both ligands have similar BBB penetration percentiles (44.746 and 42.807). These are below the desirable >70 for CNS targets, but not dramatically so.

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.256 and -5.199), which is unusual and suggests poor permeability. This is a significant concern.

**10. Aqueous Solubility:** Both ligands have negative solubility values (-1.961 and -1.685), indicating very poor aqueous solubility. This is a major drawback.

**11. hERG Inhibition:** Both ligands have very low hERG inhibition liability (0.32 and 0.206), which is excellent.

**12. Microsomal Clearance:** Ligand B (-21.524) has significantly lower (better) microsomal clearance than Ligand A (15.749), suggesting better metabolic stability.

**13. In vitro Half-Life:** Ligand B (-11.477) has a shorter in vitro half-life than Ligand A (20.989), which is less desirable.

**14. P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.078 and 0.087), which is favorable for CNS penetration.

**15. Binding Affinity:** Both ligands have very similar and strong binding affinities (-8.6 and -8.3 kcal/mol). The difference of 0.3 kcal/mol is unlikely to be decisive.

**Overall Assessment:**

Both ligands have significant issues with solubility and Caco-2 permeability. However, Ligand B demonstrates superior metabolic stability (lower Cl_mic) and lower DILI risk. While Ligand A has a slightly longer half-life, the benefits of Ligand B's improved metabolic profile and reduced toxicity outweigh this. Given the similar affinities and the critical importance of ADME properties, Ligand B is the slightly more promising candidate. The low BBB values for both are a concern, but could potentially be addressed with prodrug strategies.

Output:
1
2025-04-17 07:58:41,182 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (358.276 and 349.523 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (117.2) is borderline for CNS penetration, being above the preferred <90, but still potentially acceptable. Ligand B (64.86) is excellent, well below the 90 threshold.

**logP:** Both ligands have good logP values (1.252 and 3.499), falling within the optimal 1-3 range. Ligand B is closer to the upper limit, which could raise slight solubility concerns, but isn't a major issue.

**H-Bond Donors/Acceptors:** Ligand A has 3 HBD and 5 HBA, which is acceptable. Ligand B has 1 HBD and 6 HBA, also acceptable.

**QED:** Both ligands have good QED scores (0.757 and 0.816), indicating good drug-like properties.

**DILI:** Ligand A has a DILI risk of 89.066, which is high and concerning. Ligand B has a much lower DILI risk of 22.8, which is very favorable.

**BBB:** Ligand A has a BBB penetration of 64.676, which is below the desirable >70 for CNS targets. Ligand B has a BBB penetration of 82.396, which is excellent.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.528 and -5.405), which is unusual and suggests poor permeability. However, these values are on a log scale and can be difficult to interpret without knowing the original units. We'll consider this a neutral point for now.

**Aqueous Solubility:** Both ligands have negative solubility values (-3.365 and -2.869), indicating poor aqueous solubility. This is a concern, but can sometimes be mitigated with formulation strategies.

**hERG Inhibition:** Ligand A (0.059) has a very low hERG risk, which is excellent. Ligand B (0.407) has a slightly higher, but still relatively low, hERG risk.

**Microsomal Clearance:** Ligand A has a very low (negative) microsomal clearance (-13.895), suggesting high metabolic stability. Ligand B has a higher clearance (28.078), indicating faster metabolism.

**In vitro Half-Life:** Ligand A has a very long half-life (-24.555), consistent with the low clearance. Ligand B has a very short half-life (-0.726).

**P-gp Efflux:** Ligand A has very low P-gp efflux (0.007), which is excellent for CNS penetration. Ligand B has slightly higher P-gp efflux (0.189).

**Binding Affinity:** Ligand A (-8.3 kcal/mol) has a slightly better binding affinity than Ligand B (-7.3 kcal/mol). The difference is 1 kcal/mol, which is significant but not overwhelming.

**Overall Assessment:**

Ligand A has better affinity and metabolic stability (lower Cl_mic, longer t1/2) and P-gp efflux, but suffers from a high DILI risk, poor BBB penetration, and poor solubility. Ligand B has a much better safety profile (low DILI), excellent BBB penetration, and acceptable logP and QED, but has a weaker affinity and poorer metabolic stability.

Given the GPCR target and the need for CNS penetration, BBB is a critical factor. The significantly lower DILI risk of Ligand B is also a major advantage. While Ligand A has slightly better affinity, the 1 kcal/mol difference can be overcome with further optimization. The poor solubility of both compounds is a concern, but is a more tractable problem than a high DILI risk or poor BBB penetration.

Output:
1
2025-04-17 07:58:41,182 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (364.562 and 348.451 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (66.48) is significantly better than Ligand B (89.07). For CNS targets, we want TPSA <= 90, and A is closer to the optimal <=60 range. B is pushing the upper limit.

**3. logP:** Both ligands have good logP values (2.51 and 2.303), falling within the 1-3 range.

**4. H-Bond Donors:** Both have 1 HBD, which is acceptable.

**5. H-Bond Acceptors:** Ligand A has 3 HBA, while Ligand B has 7.  Lower is generally better, and A is preferable here.

**6. QED:** Ligand A (0.78) has a better QED score than Ligand B (0.555), indicating a more drug-like profile.

**7. DILI:** Ligand A (28.887) has a much lower DILI risk than Ligand B (57.425). This is a significant advantage for A.

**8. BBB:** Ligand A (71.772) has a substantially better BBB penetration percentile than Ligand B (57.193). This is *critical* for a CNS target like DRD2.

**9. Caco-2 Permeability:** Ligand A (-4.894) is worse than Ligand B (-5.425). Both are poor, but B is slightly better.

**10. Aqueous Solubility:** Ligand A (-2.802) is slightly better than Ligand B (-2.159), but both are poor.

**11. hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.11 and 0.198).

**12. Microsomal Clearance:** Ligand B (31.024) has lower microsomal clearance than Ligand A (37.289), suggesting better metabolic stability.

**13. In vitro Half-Life:** Ligand B (12.452) has a longer half-life than Ligand A (-16.43). This is a significant advantage for B.

**14. P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.189 and 0.105).

**15. Binding Affinity:** Ligand B (-7.6) has significantly stronger binding affinity than Ligand A (0.0). A difference of >1.5 kcal/mol is a major advantage.

**Overall Assessment:**

While Ligand B has superior binding affinity and metabolic stability (lower Cl_mic, longer t1/2), Ligand A excels in crucial properties for a CNS-targeting GPCR ligand: TPSA, BBB penetration, and DILI risk. The significantly better BBB for Ligand A is a major factor. The higher affinity of Ligand B is attractive, but the poor BBB and higher DILI risk are concerning. Given the importance of CNS penetration for DRD2, and the relatively weak binding of Ligand A, further optimization of Ligand A would be a more promising strategy than trying to improve the CNS properties of Ligand B.

Output:
1
2025-04-17 07:58:41,182 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (365.459 Da) is slightly lower, which can be advantageous for permeability.

**TPSA:** Ligand A (106.84) is better than Ligand B (61.8). For a CNS target like DRD2, a TPSA below 90 is preferred, and Ligand B is significantly better in this regard.

**logP:** Ligand A (0.91) is suboptimal, being slightly below the ideal 1-3 range. Ligand B (4.138) is higher, potentially causing solubility issues and off-target effects, but acceptable.

**H-Bond Donors/Acceptors:** Ligand A (1 HBD, 7 HBA) is better than Ligand B (2 HBD, 4 HBA) in terms of balancing solubility and permeability.

**QED:** Ligand A (0.815) has a higher QED score than Ligand B (0.652), indicating a more drug-like profile.

**DILI:** Ligand B (80.535) has a higher DILI risk than Ligand A (72.276), which is undesirable.

**BBB:** Ligand B (44.552) has a better BBB penetration percentile than Ligand A (38.116), which is crucial for a CNS target.

**Caco-2 Permeability:** Ligand A (-5.417) has a worse Caco-2 permeability than Ligand B (-4.547).

**Aqueous Solubility:** Ligand A (-2.239) has better aqueous solubility than Ligand B (-4.902).

**hERG Inhibition:** Ligand A (0.153) has a lower hERG inhibition liability than Ligand B (0.842), which is preferable.

**Microsomal Clearance:** Ligand A (-12.193) has a lower (better) microsomal clearance than Ligand B (-7.438), indicating greater metabolic stability.

**In vitro Half-Life:** Ligand A (32.858) has a longer in vitro half-life than Ligand B (-24.582).

**P-gp Efflux:** Ligand A (0.031) has a lower P-gp efflux liability than Ligand B (0.32), which is important for CNS exposure.

**Binding Affinity:** Ligand B (-9.3 kcal/mol) has a significantly stronger binding affinity than Ligand A (-7.8 kcal/mol). This is a substantial advantage, potentially outweighing some of the ADME drawbacks.

**Overall Assessment:**

Ligand B has a significantly better binding affinity and a better BBB score, which are critical for a CNS GPCR target. While its logP is higher and DILI risk is greater, the substantial affinity advantage is likely to be decisive. Ligand A has better ADME properties overall, but its weaker binding affinity is a major drawback.

Output:
1
2025-04-17 07:58:41,182 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (354.51 and 361.515 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (49.41) is significantly better than Ligand B (56.07). For CNS targets, we want TPSA <= 90, and ideally closer to 60. Ligand A is much closer to this ideal.

**3. logP:** Both ligands have good logP values (4.006 and 3.278), falling within the optimal 1-3 range.

**4. H-Bond Donors:** Ligand A (1) is preferable to Ligand B (0) as it provides some hydrogen bonding capability.

**5. H-Bond Acceptors:** Ligand B (7) is better than Ligand A (2) in this parameter.

**6. QED:** Ligand B (0.836) has a higher QED score than Ligand A (0.476), indicating a more drug-like profile.

**7. DILI:** Ligand A (17.255) has a much lower DILI risk than Ligand B (49.128). This is a significant advantage for Ligand A.

**8. BBB:** Both ligands have excellent BBB penetration (83.288 and 88.329), exceeding the >70% threshold for CNS targets. Ligand B is slightly better.

**9. Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and suggests a potential issue with intestinal absorption. However, the scale is not specified, so it's hard to interpret.

**10. Aqueous Solubility:** Both ligands have poor aqueous solubility (-3.905 and -3.48). This is a concern, but can sometimes be mitigated with formulation strategies.

**11. hERG Inhibition:** Ligand A (0.83) has a slightly higher hERG risk than Ligand B (0.283). This favors Ligand B.

**12. Microsomal Clearance:** Ligand A (83.843) has a higher microsomal clearance than Ligand B (55.591), meaning it's likely to be metabolized faster. Ligand B is preferable here.

**13. In vitro Half-Life:** Ligand B (-13.582) has a much longer in vitro half-life than Ligand A (7.708). This is a significant advantage for Ligand B.

**14. P-gp Efflux:** Both ligands have low P-gp efflux liability (0.556 and 0.539), which is good for CNS penetration.

**15. Binding Affinity:** Ligand A (-7.7 kcal/mol) has a stronger binding affinity than Ligand B (-6.7 kcal/mol). This is a 1.0 kcal/mol difference, which is substantial and can outweigh some ADME drawbacks.

**Overall Assessment:**

While Ligand B has better QED, half-life, and lower hERG risk, Ligand A's significantly stronger binding affinity (-7.7 vs -6.7 kcal/mol) and much lower DILI risk are critical advantages. The TPSA is also much better for Ligand A. The solubility and Caco-2 permeability are poor for both, but the affinity advantage of A is likely to be more impactful for *in vivo* efficacy. For a GPCR target, strong binding is paramount, and the other issues can potentially be addressed through formulation or further optimization.

Output:
1
2025-04-17 07:58:41,182 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (356.451 and 343.402 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (90.95) is better than Ligand B (54.46) as it is closer to the ideal range for CNS targets (<=90). Ligand B is excellent.

**logP:** Both ligands have good logP values (3.457 and 3.61), falling within the optimal 1-3 range.

**H-Bond Donors:** Ligand A (2) and Ligand B (1) are both within the acceptable limit of <=5. Ligand B is slightly better.

**H-Bond Acceptors:** Both ligands have 5 H-bond acceptors, which is within the acceptable limit of <=10.

**QED:** Both ligands have similar QED values (0.875 and 0.841), indicating good drug-likeness.

**DILI:** Ligand A (72.354) has a slightly higher DILI risk than Ligand B (62.35), but both are below the concerning threshold of 60.

**BBB:** This is a crucial parameter for a CNS target like DRD2. Ligand B (82.086) has a significantly higher BBB percentile than Ligand A (45.909). This is a major advantage for Ligand B.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values, which is unusual. However, the values are similar (-5.182 and -4.582).

**Aqueous Solubility:** Both ligands have negative solubility values, which is also unusual. The values are similar (-4.396 and -4.677).

**hERG Inhibition:** Ligand A (0.219) has a lower hERG inhibition risk than Ligand B (0.774), which is preferable.

**Microsomal Clearance:** Ligand B (86.929) has a higher microsomal clearance than Ligand A (64.468), indicating lower metabolic stability.

**In vitro Half-Life:** Both ligands have similar in vitro half-lives (29.247 and 28.651 hours).

**P-gp Efflux:** Ligand A (0.141) shows lower P-gp efflux liability than Ligand B (0.425), which is favorable for CNS penetration.

**Binding Affinity:** Both ligands have excellent binding affinities (-8.6 and -8.3 kcal/mol), well below the -7.0 kcal/mol threshold. Ligand A has a slightly better affinity.

**Overall Assessment:**

While Ligand A has a slightly better binding affinity and lower hERG/Pgp liabilities, Ligand B's significantly higher BBB penetration (82.086 vs. 45.909) is a decisive advantage for a CNS-targeting drug. The slightly higher DILI and clearance for Ligand B are less concerning given the strong BBB score. The TPSA is also better for Ligand B.

Output:
1
2025-04-17 07:58:41,182 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B based on the provided guidelines, prioritizing GPCR-specific properties (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (349.406 and 332.407 Da) fall within the ideal range of 200-500 Da.

**TPSA:** Ligand A (80.32) is better than Ligand B (66.91). Both are below 90, which is favorable for CNS penetration.

**logP:** Ligand B (3.443) is slightly higher than Ligand A (2.386), edging towards the upper limit of the optimal range (1-3). Ligand A is well within the optimal range.

**H-Bond Donors/Acceptors:** Both ligands have 2 HBD and 4 HBA, which are acceptable.

**QED:** Ligand A (0.818) has a slightly higher QED score than Ligand B (0.751), indicating better overall drug-likeness.

**DILI:** Ligand A (41.838) has a significantly lower DILI risk than Ligand B (79.449). This is a major advantage for Ligand A.

**BBB:** Ligand A (83.288) has a much better BBB penetration score than Ligand B (69.678). This is critical for a CNS target like DRD2.

**Caco-2 Permeability:** Ligand A (-4.303) has a worse Caco-2 permeability than Ligand B (-5.123). Lower (more negative) values indicate lower permeability.

**Aqueous Solubility:** Ligand A (-3.264) has a worse aqueous solubility than Ligand B (-4.186). Lower (more negative) values indicate lower solubility.

**hERG:** Ligand A (0.174) has a lower hERG inhibition liability than Ligand B (0.672), indicating a lower risk of cardiotoxicity.

**Microsomal Clearance:** Ligand B (42.099) has a lower microsomal clearance than Ligand A (47.906), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand B (61.198) has a significantly longer in vitro half-life than Ligand A (-18.334). This is a significant advantage for Ligand B.

**P-gp Efflux:** Ligand A (0.033) exhibits significantly lower P-gp efflux liability than Ligand B (0.272), which is crucial for CNS penetration.

**Binding Affinity:** Ligand B (-10.2 kcal/mol) has a slightly better binding affinity than Ligand A (-9.6 kcal/mol). While both are excellent, the difference is not substantial enough to outweigh other factors.

**Overall Assessment:**

Ligand A is superior due to its significantly better BBB penetration, lower DILI risk, lower hERG liability, and lower P-gp efflux. While Ligand B has better metabolic stability and a slightly better binding affinity, the CNS-specific properties are paramount for a DRD2 ligand. The solubility and permeability of Ligand A are less ideal, but these can potentially be addressed through formulation strategies.

Output:
1
2025-04-17 07:58:41,183 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (340.387 Da) is slightly lower than Ligand B (367.519 Da), which is not a significant difference.

**2. TPSA:** Both ligands have TPSA values below the 90 A^2 threshold for CNS targets. Ligand B (80.12 A^2) is better than Ligand A (93.01 A^2), suggesting potentially better CNS penetration.

**3. logP:** Both ligands have logP values within the optimal range (1-3). Ligand B (1.561) is slightly higher than Ligand A (0.827), which could be beneficial for membrane permeability, but A is still acceptable.

**4. H-Bond Donors:** Both ligands have 1 HBD, which is within the acceptable limit of <=5.

**5. H-Bond Acceptors:** Both ligands have 6 HBA, which is within the acceptable limit of <=10.

**6. QED:** Both ligands have high QED scores (A: 0.89, B: 0.825), indicating good drug-like properties.

**7. DILI:** Ligand B (40.364%) has a significantly lower DILI risk than Ligand A (64.754%). This is a major advantage for Ligand B.

**8. BBB:** Both ligands have similar BBB penetration percentiles (A: 61.535%, B: 61.923%). While not exceptional (>70%), they are both reasonable for a CNS target.

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.144 and -5.238). This is unusual and suggests poor intestinal absorption. However, for a CNS target, intestinal absorption is less critical than BBB penetration.

**10. Aqueous Solubility:** Both ligands have very poor aqueous solubility (-1.655 and -2.81). This is a concern for formulation, but can sometimes be overcome with appropriate formulation strategies.

**11. hERG Inhibition:** Both ligands have low hERG inhibition risk (A: 0.143, B: 0.347).

**12. Microsomal Clearance:** Ligand B (40.46 mL/min/kg) has significantly lower microsomal clearance than Ligand A (11.611 mL/min/kg), indicating better metabolic stability.

**13. In vitro Half-Life:** Ligand B (-12.898 hours) has a much longer in vitro half-life than Ligand A (8.26 hours), which is a substantial advantage.

**14. P-gp Efflux:** Both ligands have very low P-gp efflux liability (A: 0.019, B: 0.056). This is excellent for CNS exposure.

**15. Binding Affinity:** Ligand A (-8.0 kcal/mol) has a slightly better binding affinity than Ligand B (-7.6 kcal/mol). However, the difference is less than 1.5 kcal/mol, so it's not a decisive factor.

**Overall Assessment:**

Ligand B is the more promising candidate. While Ligand A has slightly better binding affinity, Ligand B demonstrates superior ADME properties, particularly lower DILI risk, better metabolic stability (lower Cl_mic, longer t1/2), and a slightly better TPSA. The similar BBB values are acceptable for a CNS target. The poor solubility and Caco-2 values are drawbacks for both, but less critical for a CNS-focused drug.

Output:
1
2025-04-17 07:58:41,183 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (353.463 and 363.483 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (96.53) is slightly above the optimal <90 for CNS targets, but still reasonable. Ligand B (71.53) is well within the desired range. This favors Ligand B.

**3. logP:** Both ligands have good logP values (1.734 and 2.213), falling within the 1-3 range.

**4. H-Bond Donors:** Ligand A has 3 HBD, which is acceptable. Ligand B has 1 HBD, also acceptable.

**5. H-Bond Acceptors:** Ligand A has 4 HBA, and Ligand B has 5 HBA. Both are within the acceptable limit of <=10.

**6. QED:** Both ligands have good QED scores (0.607 and 0.894), indicating drug-like properties. Ligand B is better here.

**7. DILI:** Ligand A (33.307) has a lower DILI risk than Ligand B (55.952), which is preferable.

**8. BBB:** Both ligands exhibit good BBB penetration (70.415 and 77.084), exceeding the 70% threshold for CNS targets. Ligand B is slightly better.

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.869 and -4.819), which is unusual and suggests poor permeability. This is a significant concern for both.

**10. Aqueous Solubility:** Both ligands have negative solubility values (-2.838 and -3.252), indicating poor aqueous solubility. This is a significant drawback for both.

**11. hERG Inhibition:** Ligand A (0.18) has a very low hERG inhibition risk, which is excellent. Ligand B (0.312) is also relatively low, but higher than Ligand A.

**12. Microsomal Clearance:** Ligand A (64.847) has a higher microsomal clearance than Ligand B (31.96), indicating lower metabolic stability. Ligand B is favored here.

**13. In vitro Half-Life:** Ligand A (-23.896) has a negative half-life, which is not physically possible and indicates a potential issue with the data or the molecule's stability. Ligand B (14.629) has a reasonable half-life. This strongly favors Ligand B.

**14. P-gp Efflux:** Ligand A (0.024) has very low P-gp efflux, which is excellent for CNS penetration. Ligand B (0.248) is also relatively low.

**15. Binding Affinity:** Ligand A (-8.1 kcal/mol) has a significantly stronger binding affinity than Ligand B (-0.0 kcal/mol). This is a major advantage for Ligand A, potentially outweighing some of its ADME drawbacks.

**Overall Assessment:**

Despite Ligand A's superior binding affinity, the negative and unrealistic in vitro half-life is a critical flaw. Furthermore, its higher microsomal clearance and slightly higher DILI risk are concerning. Ligand B, while having a significantly weaker binding affinity, presents a much more favorable ADME profile, with better metabolic stability, a reasonable half-life, and acceptable safety parameters. The Caco-2 and solubility issues are shared, but the binding affinity difference is substantial. However, a binding affinity of 0 kcal/mol is extremely weak and unlikely to translate to *in vivo* efficacy.

Considering the GPCR-specific priorities, BBB penetration is good for both, but the other ADME properties of Ligand B are significantly better. Given the extremely poor affinity of Ligand B, and the unrealistic half-life of Ligand A, neither is a strong candidate. However, Ligand A's affinity is so much higher that it could be optimized to improve its ADME properties.

Output:
0
2025-04-17 07:58:41,183 - INFO - Reasoning:
Let's analyze both ligands against the provided guidelines, prioritizing GPCR-specific properties (BBB, logP, Pgp, TPSA, and affinity).

**Ligand A:**

*   **MW:** 351.491 Da - Good (within 200-500 range)
*   **TPSA:** 101.29 - Acceptable, but pushing the limit for CNS targets (ideally <90).
*   **logP:** 1.868 - Good (within 1-3 range)
*   **HBD:** 3 - Good (<=5)
*   **HBA:** 3 - Good (<=10)
*   **QED:** 0.622 - Good (>=0.5)
*   **DILI:** 26.095 - Excellent (low risk)
*   **BBB:** 65.723 - Moderate. Below the desirable >70 for CNS targets.
*   **Caco-2:** -5.241 - Poor permeability.
*   **Solubility:** -3.552 - Poor solubility.
*   **hERG:** 0.138 - Very low risk.
*   **Cl_mic:** 58.284 - Moderate clearance.
*   **t1/2:** -17.542 - Very short half-life.
*   **Pgp:** 0.06 - Low efflux, good for CNS penetration.
*   **Affinity:** -8.1 kcal/mol - Excellent.

**Ligand B:**

*   **MW:** 349.431 Da - Good (within 200-500 range)
*   **TPSA:** 71.97 - Good (<=90, favorable for CNS)
*   **logP:** 2.03 - Good (within 1-3 range)
*   **HBD:** 0 - Good (<=5)
*   **HBA:** 5 - Good (<=10)
*   **QED:** 0.704 - Good (>=0.5)
*   **DILI:** 41.838 - Good (low risk)
*   **BBB:** 72.974 - Very good (above 70, desirable for CNS)
*   **Caco-2:** -4.68 - Poor permeability.
*   **Solubility:** -2.153 - Poor solubility.
*   **hERG:** 0.234 - Very low risk.
*   **Cl_mic:** 15.691 - Low clearance, good metabolic stability.
*   **t1/2:** -17.019 - Very short half-life.
*   **Pgp:** 0.088 - Low efflux, good for CNS penetration.
*   **Affinity:** -8.1 kcal/mol - Excellent (same as Ligand A).

**Comparison & Decision:**

Both ligands have excellent binding affinity. However, Ligand B is superior due to its significantly better BBB penetration (72.974 vs 65.723) and lower microsomal clearance (15.691 vs 58.284). While both have poor Caco-2 and solubility, BBB is a critical factor for CNS targets like DRD2. The lower clearance of Ligand B suggests better metabolic stability, which is also desirable. The TPSA is also more favorable for Ligand B. Both have acceptable DILI and hERG risk. The half-lives are similar and both are quite short, but this is less critical than CNS penetration and metabolic stability at this stage.

Output:
1
2025-04-17 07:58:41,183 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (396.559 and 372.481 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (66.48) is higher than Ligand B (49.41). For a CNS target like DRD2, TPSA should ideally be <=90. Both are acceptable, but B is better.

**3. logP:** Both ligands have similar logP values (2.886 and 2.877), falling within the optimal 1-3 range.

**4. H-Bond Donors:** Both have 1 HBD, which is good.

**5. H-Bond Acceptors:** Ligand A has 6 HBA, and Ligand B has 3. Both are within the acceptable limit of <=10, but B is preferable.

**6. QED:** Both ligands have good QED scores (0.787 and 0.73), indicating good drug-like properties.

**7. DILI:** Ligand A has a significantly higher DILI risk (81.582%) compared to Ligand B (20.396%). This is a major concern for Ligand A.

**8. BBB:** Ligand B (92.943%) has a much higher BBB penetration score than Ligand A (70.997%). This is a critical advantage for a CNS target.

**9. Caco-2:** Both have negative Caco-2 values, suggesting poor permeability. However, the scale is not defined, so it's hard to interpret.

**10. Solubility:** Both have negative solubility values, suggesting poor solubility. Again, the scale is not defined.

**11. hERG:** Ligand A (0.51) has a slightly lower hERG inhibition liability than Ligand B (0.83), which is favorable.

**12. Cl_mic:** Ligand A (35.74) has a lower microsomal clearance than Ligand B (44.845), indicating better metabolic stability.

**13. t1/2:** Ligand B (-1.072) has a negative in vitro half-life, which is concerning. Ligand A (22.717) has a much more reasonable half-life.

**14. Pgp:** Ligand A (0.343) has lower P-gp efflux liability than Ligand B (0.137), which is favorable for CNS penetration.

**15. Binding Affinity:** Ligand B (-7.6 kcal/mol) has a slightly better binding affinity than Ligand A (-8.4 kcal/mol). While A is better, the difference is not substantial enough to outweigh other factors.

**Overall Assessment:**

Ligand B is the more promising candidate. While Ligand A has a slightly better binding affinity and metabolic stability, Ligand B excels in crucial areas for a CNS-targeting GPCR: significantly lower DILI risk, much higher BBB penetration, and lower P-gp efflux. The negative half-life for Ligand B is a concern, but could be addressed with structural modifications. The higher TPSA of Ligand A is also less desirable.

Output:
1
2025-04-17 07:58:41,183 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (348.487 and 354.479 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (69.64) is slightly above the optimal <90 for CNS targets, but still reasonable. Ligand B (50.5) is excellent, well below 90.

**3. logP:** Ligand A (1.938) is within the optimal 1-3 range. Ligand B (3.932) is at the higher end of optimal, but still acceptable.

**4. H-Bond Donors:** Ligand A (2) is within the acceptable limit of <=5. Ligand B (0) is also good.

**5. H-Bond Acceptors:** Ligand A (3) is within the acceptable limit of <=10. Ligand B (5) is also good.

**6. QED:** Both ligands have acceptable QED values (0.771 and 0.674, both >0.5).

**7. DILI:** Ligand A (6.592) has a much lower DILI risk than Ligand B (40.171). This is a significant advantage for Ligand A.

**8. BBB:** Ligand B (84.451) has a significantly higher BBB penetration percentile than Ligand A (69.833). This is a major advantage for Ligand B, given DRD2 is a CNS target.

**9. Caco-2 Permeability:** Ligand A (-4.818) has poor Caco-2 permeability, while Ligand B (-5.029) is also poor. This is not a major concern for CNS targets where direct penetration is favored.

**10. Aqueous Solubility:** Both ligands have poor aqueous solubility (-2.898 and -3.829). This could pose formulation challenges, but is less critical for CNS drugs that can cross the BBB.

**11. hERG Inhibition:** Ligand A (0.316) has a lower hERG inhibition liability than Ligand B (0.88). This is a safety advantage for Ligand A.

**12. Microsomal Clearance:** Ligand B (87) has a higher microsomal clearance than Ligand A (33.765), indicating faster metabolism and potentially lower exposure.

**13. In vitro Half-Life:** Ligand A (4.982) has a longer in vitro half-life than Ligand B (-1.361). This is a positive for Ligand A.

**14. P-gp Efflux:** Ligand A (0.044) has significantly lower P-gp efflux liability than Ligand B (0.526). Lower P-gp efflux is crucial for CNS penetration.

**15. Binding Affinity:** Ligand A (-8.1 kcal/mol) has a slightly better binding affinity than Ligand B (-7.4 kcal/mol). While both are good, the 0.7 kcal/mol difference is noticeable.

**Overall Assessment:**

Ligand B excels in BBB penetration, which is paramount for a DRD2 ligand. However, it suffers from higher DILI risk, higher P-gp efflux, and faster metabolic clearance. Ligand A has a better safety profile (lower DILI, hERG, P-gp), better metabolic stability (lower Cl_mic, longer t1/2), and slightly better affinity. While Ligand A's BBB is lower, its other advantages, particularly the lower efflux, could compensate for this. The affinity difference is not large enough to overcome the ADME/Tox advantages of Ligand A.

Output:
0
2025-04-17 07:58:41,183 - INFO - Batch 410 complete. Total preferences: 6560
2025-04-17 07:58:41,183 - INFO - Processing batch 411/512...
2025-04-17 07:59:21,962 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (350.394 and 353.471 Da) fall comfortably within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (78.67) is significantly better than Ligand B (127.08). For CNS targets, we want TPSA <= 90, and A is well within that, while B exceeds it. This is a substantial advantage for A.

**3. logP:** Ligand A (0.532) is a bit low, potentially hindering permeability. Ligand B (2.237) is within the optimal 1-3 range. While B is better, A isn't drastically outside acceptable limits.

**4. H-Bond Donors:** Ligand A (1) is preferable to Ligand B (4). Fewer HBDs generally improve permeability.

**5. H-Bond Acceptors:** Ligand A (5) is preferable to Ligand B (8). Fewer HBAs generally improve permeability.

**6. QED:** Both ligands have acceptable QED values (0.786 and 0.613, respectively), indicating good drug-like properties.

**7. DILI:** Ligand A (29.081) has a much lower DILI risk than Ligand B (57.425). This is a significant advantage for A.

**8. BBB:** Ligand A (43.583) has a lower BBB penetration percentile than Ligand B (70.997). This is a major advantage for B, given DRD2 is a CNS target.

**9. Caco-2 Permeability:** Ligand A (-4.839) and Ligand B (-5.071) both have negative values, which is unusual and difficult to interpret without knowing the scale. However, they are very similar.

**10. Aqueous Solubility:** Ligand A (-0.571) has slightly better solubility than Ligand B (-4.368).

**11. hERG Inhibition:** Both ligands have low hERG inhibition risk (0.334 and 0.453, respectively).

**12. Microsomal Clearance:** Ligand A (1.474) has significantly lower microsomal clearance than Ligand B (82.372), indicating better metabolic stability. This is a strong advantage for A.

**13. In vitro Half-Life:** Ligand A (-16.51) has a negative half-life, which is not possible. This is a major red flag. Ligand B (1.953) is reasonable.

**14. P-gp Efflux:** Ligand A (0.042) has much lower P-gp efflux liability than Ligand B (0.013), which is advantageous for CNS penetration.

**15. Binding Affinity:** Both ligands have very similar and good binding affinities (-7.7 and -7.6 kcal/mol). The difference is negligible.

**Overall Assessment:**

Ligand A has several advantages: lower TPSA, lower DILI risk, better metabolic stability (lower Cl_mic), and lower P-gp efflux. However, the negative in vitro half-life is a critical flaw. Ligand B excels in BBB penetration, which is crucial for a CNS target like DRD2, and has a reasonable half-life. While Ligand B has a higher TPSA and DILI risk, the BBB penetration is a significant factor.

Considering the importance of BBB penetration for a CNS drug and the fatal flaw of a negative half-life for Ligand A, Ligand B is the more promising candidate.

Output:
1
2025-04-17 07:59:21,963 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (371.363 Da) is slightly higher than Ligand B (348.443 Da), but both are acceptable.

**TPSA:** Both ligands have TPSA values above the optimal 90 A^2 for CNS targets. Ligand A (55.63 A^2) is better than Ligand B (59.08 A^2), but both are reasonably close.

**logP:** Ligand A (4.017) is at the upper end of the optimal range (1-3), potentially raising concerns about solubility and off-target effects. Ligand B (0.919) is below the optimal range, which could hinder permeation.

**H-Bond Donors/Acceptors:** Ligand A has 1 HBD and 6 HBA, while Ligand B has 0 HBD and 4 HBA. Both are within acceptable limits (<=5 HBD and <=10 HBA).

**QED:** Both ligands have similar QED values (0.704 and 0.709), indicating good drug-like properties.

**DILI:** Ligand A has a significantly higher DILI risk (81.543%) than Ligand B (23.149%). This is a major concern for Ligand A.

**BBB:** Ligand A (75.611%) has a better BBB penetration score than Ligand B (68.166%), which is important for a CNS target like DRD2.

**Caco-2 Permeability & Aqueous Solubility:** Both ligands show poor Caco-2 permeability (-4.888 and -4.636) and aqueous solubility (-4.888 and -1.425). These are concerning, but can sometimes be improved with formulation.

**hERG:** Both ligands have low hERG inhibition liability (0.453 and 0.389), which is good.

**Microsomal Clearance & In vitro Half-Life:** Ligand A has a higher microsomal clearance (52.517 mL/min/kg) and shorter half-life (3.388 hours) compared to Ligand B (33.596 mL/min/kg and 5.931 hours). This suggests Ligand B is more metabolically stable.

**P-gp Efflux:** Ligand A (0.61) shows slightly higher P-gp efflux liability than Ligand B (0.098), which is unfavorable for CNS penetration.

**Binding Affinity:** Both ligands have strong binding affinities (-9.6 kcal/mol and -8.6 kcal/mol). Ligand A has a 1 kcal/mol advantage, which is significant.

**Overall Assessment:**

Ligand A has a better binding affinity and BBB penetration, but suffers from a high DILI risk, higher P-gp efflux, and poorer metabolic stability. Ligand B has a lower DILI risk, better metabolic stability, lower P-gp efflux, but a slightly weaker binding affinity and lower BBB penetration.

Given the importance of minimizing toxicity (DILI) and maximizing CNS exposure (BBB, Pgp) for a DRD2 ligand, and considering the relatively small difference in binding affinity (1 kcal/mol), **Ligand B is the more promising candidate.** The better safety profile and pharmacokinetic properties outweigh the slightly weaker binding.

Output:
1
2025-04-17 07:59:21,963 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (387.933 Da) is slightly higher than Ligand B (342.435 Da), but both are acceptable.

**TPSA:** Ligand A (91.32) is borderline for CNS penetration, being slightly above the preferred 90. Ligand B (52.6) is well within the ideal range for CNS targets. This is a significant advantage for Ligand B.

**logP:** Both ligands have good logP values (A: 2.752, B: 3.845), falling within the optimal 1-3 range. Ligand B is slightly higher, which could potentially lead to some solubility issues, but isn't a major concern.

**H-Bond Donors/Acceptors:** Ligand A has 3 HBD and 5 HBA, which are acceptable. Ligand B has 0 HBD and 4 HBA, also acceptable.

**QED:** Both ligands have good QED values (A: 0.654, B: 0.763), indicating good drug-like properties.

**DILI:** Ligand A has a DILI risk of 60.644, which is approaching the higher risk threshold (>60). Ligand B has a much lower DILI risk (24.506), a significant advantage.

**BBB:** Ligand A has a BBB penetration of 55.293, which is below the desirable >70 for CNS targets. Ligand B has a much higher BBB penetration (77.821), a major advantage.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values, which is unusual and requires further investigation. However, the values are on a similar scale, so it doesn't strongly favor one over the other.

**Aqueous Solubility:** Both ligands have negative solubility values, which is also unusual. Again, the values are similar, so it doesn't strongly favor one over the other.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (A: 0.28, B: 0.542).

**Microsomal Clearance:** Ligand A has a moderate microsomal clearance (35.475), while Ligand B has a high clearance (93.144), indicating faster metabolism and potentially lower in vivo exposure. This favors Ligand A.

**In vitro Half-Life:** Ligand A has a half-life of 30.204 hours, while Ligand B has a very short half-life (-2.696 hours - likely an artifact or error). This strongly favors Ligand A.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (A: 0.36, B: 0.371), which is good for CNS penetration.

**Binding Affinity:** Ligand B has a significantly stronger binding affinity (-9.7 kcal/mol) compared to Ligand A (0.0 kcal/mol). This is a substantial advantage for Ligand B and could outweigh some of its ADME drawbacks.

**Overall Assessment:**

While Ligand A has better metabolic stability (lower Cl_mic, longer t1/2), Ligand B excels in key GPCR-specific properties for CNS targets: significantly better BBB penetration, lower DILI risk, and *much* stronger binding affinity. The TPSA is also considerably better for Ligand B. The negative solubility and Caco-2 values are concerning for both, but the affinity difference is so large that it's likely to be the dominant factor.

Output:
1
2025-04-17 07:59:21,963 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (359.495 and 383.499 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (73.2) is excellent, well below the 90 A^2 threshold for CNS targets. Ligand B (106.4) is higher, but still potentially acceptable, though less optimal.

**logP:** Ligand A (3.167) is within the optimal 1-3 range. Ligand B (-0.116) is significantly lower, which is a major concern for CNS penetration as it may struggle to cross cell membranes.

**H-Bond Donors/Acceptors:** Both have acceptable HBD counts (1). Ligand A has 4 HBAs, while Ligand B has 8. While both are within the general guideline of <=10, Ligand A is preferable.

**QED:** Both ligands have good QED values (0.775 and 0.695), indicating drug-like properties.

**DILI:** Both have relatively low DILI risk (43.117 and 72.819), suggesting minimal liver toxicity concerns.

**BBB:** Ligand A has a very good BBB percentile (74.254), exceeding the desirable >70 threshold for CNS targets. Ligand B's BBB percentile (62.233) is considerably lower and less favorable.

**Caco-2 Permeability:** Ligand A (-4.864) and Ligand B (-5.17) both have negative Caco-2 values, which is unusual and suggests poor permeability. This is a concern for both, but the negative values are similar.

**Aqueous Solubility:** Both ligands have poor aqueous solubility (-4.759 and -3.414). This could pose formulation challenges.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.693 and 0.528).

**Microsomal Clearance:** Ligand A (75.365) has moderate clearance, while Ligand B (0.47) has very low clearance, indicating high metabolic stability. This is a significant advantage for Ligand B.

**In vitro Half-Life:** Ligand A (23.173 hours) has a reasonable half-life. Ligand B (-23.136) has a negative half-life, which is not physically possible and indicates a data error or a very rapidly metabolized compound.

**P-gp Efflux:** Ligand A (0.491) has lower P-gp efflux, which is good for CNS exposure. Ligand B (0.036) has very low P-gp efflux, which is even better.

**Binding Affinity:** Ligand A (-7.6 kcal/mol) has a slightly better binding affinity than Ligand B (-6.8 kcal/mol). The difference is 0.8 kcal/mol, which is not huge, but still noticeable.

**Overall Assessment:**

Ligand A excels in BBB penetration, TPSA, and binding affinity. However, Ligand B has superior metabolic stability (very low Cl_mic) and P-gp efflux. The major drawback for Ligand B is its very low logP, which will severely hinder its ability to cross the blood-brain barrier, despite the percentile score. The negative half-life for Ligand B is also a major red flag. While Ligand A has solubility issues, these can often be addressed with formulation strategies. Given the importance of BBB penetration for a CNS target like DRD2, and the questionable half-life of Ligand B, Ligand A is the more promising candidate.

Output:
0
2025-04-17 07:59:21,963 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (371.459 and 351.397 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (96.97) is slightly above the optimal <90 for CNS targets, but still reasonable. Ligand B (54.34) is excellent, well below 90.

**logP:** Both ligands have good logP values (1.1 and 2.092), falling within the 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A has 2 HBD and 5 HBA, which is acceptable. Ligand B has 1 HBD and 3 HBA, also acceptable.

**QED:** Both ligands have good QED scores (0.748 and 0.903), indicating good drug-like properties.

**DILI:** Ligand A has a DILI risk of 60.915, which is borderline high. Ligand B has a significantly lower DILI risk of 22.8, which is excellent.

**BBB:** This is a critical parameter for CNS targets. Ligand A has a BBB penetration of 63.203, which is below the desirable >70. Ligand B has a very high BBB penetration of 95.967, a major advantage.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.995 and -4.677). These values are unusual and difficult to interpret without further context, but suggest poor permeability.

**Aqueous Solubility:** Both ligands have negative solubility values (-2.604 and -2.851). These are also unusual and suggest very poor aqueous solubility.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.284 and 0.397), which is good.

**Microsomal Clearance:** Ligand A has a moderate microsomal clearance (45.529), while Ligand B has a very low clearance (4.128), indicating better metabolic stability.

**In vitro Half-Life:** Ligand A has a negative half-life (-27.62), which is not physically meaningful. Ligand B has a very short half-life (-0.26), also problematic.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.077 and 0.042), which is favorable for CNS penetration.

**Binding Affinity:** Both ligands have very strong binding affinities (-8.4 and -8.7 kcal/mol). The difference of 0.3 kcal/mol is not substantial enough to outweigh other factors.

**Overall Assessment:**

Ligand B is significantly more promising. While both have issues with Caco-2 and solubility, Ligand B excels in crucial areas for a CNS-targeting GPCR ligand: high BBB penetration (95.967 vs 63.203), lower DILI risk (22.8 vs 60.915), and better metabolic stability (lower Cl_mic). The slightly better affinity of Ligand B is a bonus, but the ADME properties are the deciding factors. The negative half-life values are concerning for both, but the other advantages of Ligand B make it the better candidate.

Output:
1
2025-04-17 07:59:21,963 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (380.79 and 343.47 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (55.76) is better than Ligand B (46.61) as it is still below the 90 A^2 threshold for CNS targets.

**3. logP:** Both ligands have good logP values (3.992 and 4.287), falling within the optimal 1-3 range.

**4. H-Bond Donors:** Ligand A has 1 HBD, and Ligand B has 0. Both are acceptable (<=5).

**5. H-Bond Acceptors:** Ligand A has 4 HBA, and Ligand B has 3. Both are acceptable (<=10).

**6. QED:** Both ligands have reasonable QED scores (0.758 and 0.605), indicating good drug-like properties.

**7. DILI:** Ligand A (32.261) has a lower DILI risk than Ligand B (52.385), which is preferable. Both are below the 60 threshold.

**8. BBB:** Both ligands show good BBB penetration (75.649 and 71.656), exceeding the 70% threshold desirable for CNS targets. Ligand A is slightly better.

**9. Caco-2 Permeability:** Both have negative Caco-2 values (-4.39 and -4.5). These values are unusual and suggest poor permeability, but the scale isn't clearly defined. We'll consider this a neutral point for now.

**10. Aqueous Solubility:** Both ligands have negative solubility scores (-4.842 and -5.116). Similar to Caco-2, these are unusual and suggest poor solubility.

**11. hERG Inhibition:** Both ligands have low hERG inhibition risk (0.651 and 0.308).

**12. Microsomal Clearance:** Ligand B (95.521) has significantly higher microsomal clearance than Ligand A (43.868), indicating lower metabolic stability. This is a significant drawback for Ligand B.

**13. In vitro Half-Life:** Ligand A (10.35 hours) has a positive half-life, while Ligand B (-16.985 hours) has a negative half-life, which is concerning.

**14. P-gp Efflux:** Both ligands have low P-gp efflux liability (0.275 and 0.411).

**15. Binding Affinity:** Both ligands have excellent binding affinities (-9.1 and -9.5 kcal/mol). Ligand B is slightly better.

**Overall Assessment:**

While Ligand B has a slightly better binding affinity, Ligand A is the more promising candidate. Ligand A has a lower DILI risk, better metabolic stability (lower Cl_mic and positive t1/2), and a slightly better BBB penetration. The negative solubility and Caco-2 values are concerning for both, but the metabolic stability and safety profile of Ligand A are more favorable for CNS drug development.

Output:
1
2025-04-17 07:59:21,964 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (356.438 and 376.494 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (59.08) is excellent, well below the 90 A^2 threshold for CNS targets. Ligand B (78.87) is still reasonable but less optimal.

**logP:** Ligand A (1.237) is within the optimal 1-3 range. Ligand B (0.974) is slightly below 1, potentially impacting permeability, but not drastically.

**H-Bond Donors/Acceptors:** Ligand A (0 HBD, 4 HBA) is favorable. Ligand B (2 HBD, 5 HBA) is also acceptable, staying within the recommended limits.

**QED:** Both ligands have reasonable QED scores (0.744 and 0.617), suggesting good drug-like properties.

**DILI:** Both ligands have low DILI risk (27.181 and 26.483), which is positive.

**BBB:** This is a critical parameter for a CNS target like DRD2. Ligand A has a very high BBB penetration percentile (93.37), significantly better than Ligand B (64.482).

**Caco-2 Permeability:** Ligand A (-4.268) shows poor Caco-2 permeability, which is a concern. Ligand B (-4.879) is also poor, but slightly worse.

**Aqueous Solubility:** Both ligands have very poor aqueous solubility (-1.203 and -2.274). This could pose formulation challenges.

**hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.318 and 0.488), which is excellent.

**Microsomal Clearance:** Ligand A (35.126) has higher clearance than Ligand B (17.142), suggesting lower metabolic stability.

**In vitro Half-Life:** Ligand B (-9.336) has a negative half-life, which is not physically possible and indicates a data error or an extremely rapid degradation. Ligand A (25.767) has a reasonable half-life.

**P-gp Efflux:** Both ligands show very low P-gp efflux liability (0.048 and 0.056), which is favorable for CNS penetration.

**Binding Affinity:** Ligand B (-7.5 kcal/mol) has a significantly stronger binding affinity than Ligand A (0.0 kcal/mol). This is a substantial advantage.

**Overall Assessment:**

Despite Ligand A's excellent TPSA and BBB penetration, its extremely weak binding affinity (0 kcal/mol) and poor Caco-2 permeability are major drawbacks. The higher microsomal clearance also contributes to concerns about its metabolic stability. Ligand B, while having a slightly higher TPSA and lower BBB, possesses a much stronger binding affinity (-7.5 kcal/mol). The negative half-life for Ligand B is a data issue, but the affinity difference is so large that it outweighs other concerns.

Output:
1
2025-04-17 07:59:21,964 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (385.511 Da) is slightly higher than Ligand B (354.491 Da), but both are acceptable.

**TPSA:** Ligand A (102.76) is above the preferred <90 for CNS targets, while Ligand B (67.87) is well within the range. This is a significant advantage for Ligand B.

**logP:** Both ligands have good logP values (A: 0.96, B: 1.827) falling within the optimal 1-3 range. Ligand B is slightly better.

**H-Bond Donors/Acceptors:** Ligand A has 3 HBD and 7 HBA, which are acceptable. Ligand B has 1 HBD and 4 HBA, also acceptable.

**QED:** Both ligands have similar QED values (A: 0.698, B: 0.686), indicating good drug-likeness.

**DILI:** Ligand A (52.772) has a moderate DILI risk, while Ligand B (15.2) has a very low risk. This is a substantial advantage for Ligand B.

**BBB:** Ligand A (12.175) has a very poor BBB penetration percentile, making it unlikely to effectively reach the target in the CNS. Ligand B (74.37) has excellent BBB penetration, a crucial factor for a DRD2 ligand.

**Caco-2 Permeability:** Ligand A (-5.651) has poor Caco-2 permeability, while Ligand B (-4.435) is slightly better, but still not great.

**Aqueous Solubility:** Both ligands have poor aqueous solubility (A: -3.131, B: -1.656). This could pose formulation challenges.

**hERG Inhibition:** Both ligands have very low hERG inhibition risk (A: 0.066, B: 0.343).

**Microsomal Clearance:** Ligand A (7.286) has lower microsomal clearance than Ligand B (48.392), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (-1.573) has a negative in vitro half-life, which is unusual and likely indicates rapid degradation. Ligand B (1.613) has a short half-life, but it's positive and more reasonable.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (A: 0.053, B: 0.035), which is favorable for CNS penetration.

**Binding Affinity:** Ligand A (-7.5 kcal/mol) has a slightly better binding affinity than Ligand B (-6.9 kcal/mol), but the difference is not substantial enough to overcome the significant ADME deficiencies of Ligand A.

**Overall Assessment:**

Ligand B is significantly more promising. While its solubility and Caco-2 permeability are not ideal, its excellent BBB penetration, low DILI risk, and acceptable logP and TPSA values make it a much better candidate for a CNS-targeting drug like a DRD2 ligand. Ligand A's very poor BBB penetration is a deal-breaker, despite its slightly better affinity and metabolic stability.



Output:
1
2025-04-17 07:59:21,964 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B based on the provided guidelines, prioritizing GPCR-specific properties (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (379.335 Da) is slightly higher than Ligand B (346.435 Da), but both are acceptable.

**TPSA:** Ligand A (22.61) is excellent for CNS penetration, well below the 90 A^2 threshold. Ligand B (78.07) is higher, but still potentially acceptable, though less optimal for CNS targets.

**logP:** Ligand A (4.165) is slightly high, potentially leading to solubility issues or off-target interactions. Ligand B (1.224) is good, falling within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A (0 HBD, 4 HBA) and Ligand B (0 HBD, 7 HBA) both have reasonable numbers of H-bond donors and acceptors, falling within the guidelines.

**QED:** Both ligands have similar QED values (0.796 and 0.786), indicating good drug-likeness.

**DILI:** Ligand A (52.966) has a higher DILI risk than Ligand B (37.301), which is preferable.

**BBB:** Ligand A (89.841) has a significantly better BBB penetration percentile than Ligand B (59.364). This is a *critical* advantage for a CNS target like DRD2.

**Caco-2 Permeability:** Ligand A (-4.72) has poor Caco-2 permeability, suggesting poor intestinal absorption. Ligand B (-5.032) is also poor, but slightly better than A.

**Aqueous Solubility:** Ligand A (-3.916) has very poor aqueous solubility, a concern given its already high logP. Ligand B (-0.453) is also poor, but better than A.

**hERG Inhibition:** Ligand A (0.971) has a slightly higher hERG inhibition risk than Ligand B (0.191), making B safer from a cardiotoxicity perspective.

**Microsomal Clearance:** Ligand A (56.472) has higher microsomal clearance than Ligand B (27.077), indicating lower metabolic stability.

**In vitro Half-Life:** Ligand A (19.378) has a longer half-life than Ligand B (10.341), which is a positive attribute.

**P-gp Efflux:** Ligand A (0.668) has lower P-gp efflux than Ligand B (0.034), which is beneficial for CNS exposure.

**Binding Affinity:** Ligand A (-8.1 kcal/mol) has a significantly stronger binding affinity than Ligand B (-7.7 kcal/mol). This 1.5 kcal/mol difference is substantial and can outweigh some of the ADME drawbacks.

**Overall Assessment:**

Ligand A has a significantly better binding affinity and BBB penetration, which are crucial for a CNS GPCR target. However, it suffers from poor solubility, permeability, and higher DILI risk and clearance. Ligand B has better ADME properties (lower DILI, better solubility, lower hERG, lower clearance, better P-gp efflux), but weaker binding affinity and lower BBB penetration.

Given the importance of strong binding affinity and BBB penetration for CNS GPCR targets, and the substantial difference in affinity (-8.1 vs -7.7), **Ligand A is the more promising candidate**, despite its ADME liabilities. These liabilities could potentially be addressed through further optimization, but a strong starting point with high affinity is essential.

Output:
1
2025-04-17 07:59:21,964 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (373.519 and 339.395 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (118.36) is slightly above the optimal <90 for CNS targets, but still reasonable. Ligand B (82.43) is well within the desired range.

**logP:** Ligand A (0.889) is a bit low, potentially hindering permeability. Ligand B (1.41) is better, falling within the 1-3 optimal range.

**H-Bond Donors/Acceptors:** Ligand A has 3 HBD and 4 HBA, both acceptable. Ligand B has 1 HBD and 4 HBA, also acceptable.

**QED:** Both ligands have QED values above 0.5 (0.556 and 0.483), indicating good drug-like properties.

**DILI:** Ligand A (33.928) has a slightly higher DILI risk than Ligand B (26.793), but both are below the concerning threshold of 60.

**BBB:** Ligand A (55.176) has a moderate BBB penetration, while Ligand B (46.413) is lower. Both are below the desirable >70 for CNS targets, but Ligand A is better.

**Caco-2 Permeability:** Ligand A (-5.346) and Ligand B (-4.987) both have negative values, which is unusual and suggests poor permeability. This is a significant concern.

**Aqueous Solubility:** Both ligands have poor aqueous solubility (-2.933 and -2.6 respectively).

**hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.093 and 0.488).

**Microsomal Clearance:** Ligand A (37.789) has a higher microsomal clearance than Ligand B (-9.596). This suggests Ligand B is more metabolically stable.

**In vitro Half-Life:** Ligand A (-52.772) has a negative half-life, which is not physically possible and suggests a very rapid degradation. Ligand B (0.357) has a very short half-life, but is at least a plausible value.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.038 and 0.046).

**Binding Affinity:** Ligand B (-8.2 kcal/mol) has a slightly better binding affinity than Ligand A (-7.5 kcal/mol). While both are good, the 0.7 kcal/mol difference is notable.

**Overall Assessment:**

Ligand A has a slightly better BBB score, but suffers from a very unrealistic in vitro half-life. Ligand B has better logP, metabolic stability (lower Cl_mic), and a slightly better binding affinity. Both have poor Caco-2 permeability and solubility, but the metabolic stability and binding affinity of Ligand B are more favorable. Given the importance of metabolic stability for CNS drugs and the slightly improved binding affinity, Ligand B is the more promising candidate despite the shared permeability and solubility issues.

Output:
1
2025-04-17 07:59:21,964 - INFO - Reasoning:

Let's analyze Ligand A and Ligand B against the provided guidelines, prioritizing GPCR-specific properties (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (355.435 and 376.435 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (116.76) is better than Ligand B (131.78) as it is closer to the <90 threshold for CNS targets. Ligand B is still acceptable, but A has a clear advantage.

**logP:** Ligand B (-1.673) is lower than ideal (1-3) and could pose absorption challenges. Ligand A (-0.546) is also on the low side, but slightly better.

**H-Bond Donors/Acceptors:** Ligand A (4 HBD, 5 HBA) is slightly better than Ligand B (3 HBD, 8 HBA) in terms of balancing solubility and permeability, though both are acceptable.

**QED:** Both ligands have similar QED values (0.414 and 0.469), indicating moderate drug-likeness.

**DILI:** Ligand B (77.007) has a significantly higher DILI risk than Ligand A (17.449). This is a major concern for Ligand B.

**BBB:** Ligand A (53.548) has a much better BBB percentile than Ligand B (21.404). This is *critical* for a CNS target like DRD2.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.482 and -5.655), which is unusual and suggests poor permeability. This needs further investigation, but the values are similar.

**Aqueous Solubility:** Both ligands have negative solubility values (-1.253 and -1.655), also unusual and indicating poor solubility. Similar issue for both.

**hERG:** Both ligands have very low hERG risk (0.056 and 0.115).

**Microsomal Clearance:** Ligand B (10.028) has a slightly lower (better) microsomal clearance than Ligand A (13.467).

**In vitro Half-Life:** Ligand A (2.138) has a slightly longer half-life than Ligand B (-1.495).

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.003 and 0.012), which is favorable for CNS penetration.

**Binding Affinity:** Ligand A (-7.9 kcal/mol) has a significantly stronger binding affinity than Ligand B (-6.8 kcal/mol). This 1.1 kcal/mol difference is substantial and can outweigh some ADME drawbacks.

**Conclusion:**

Considering all factors, especially the crucial BBB penetration for a CNS target, the significantly lower DILI risk, and the substantially better binding affinity, **Ligand A is the more promising drug candidate.** While both ligands have issues with solubility and permeability, the superior CNS penetration and safety profile of Ligand A outweigh the slightly better metabolic stability of Ligand B. The stronger binding affinity further solidifies this decision.

Output:
1
2025-04-17 07:59:21,964 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (339.391 Da) is slightly lower, which could be beneficial for permeability. Ligand B (368.543 Da) is also well within the range.

**TPSA:** Ligand A (59.75) is excellent, well below the 90 A^2 threshold for CNS targets. Ligand B (67.43) is still acceptable, but less optimal.

**logP:** Both ligands have good logP values (A: 3.16, B: 2.512), falling within the 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A has 0 HBD and 4 HBA, which is favorable. Ligand B has 2 HBD and 4 HBA, also acceptable.

**QED:** Ligand A (0.843) has a significantly better QED score than Ligand B (0.51), indicating a more drug-like profile.

**DILI:** Ligand A (60.682) has a moderate DILI risk, while Ligand B (29.779) has a very low DILI risk. This is a significant advantage for Ligand B.

**BBB:** Ligand A (78.364) has a good BBB penetration percentile, exceeding the 70% threshold for CNS targets. Ligand B (60.411) is below this threshold, which is a major drawback for a CNS target like DRD2.

**Caco-2 Permeability:** Ligand A (-4.207) has poor Caco-2 permeability, which is concerning. Ligand B (-5.254) is also poor, but slightly worse.

**Aqueous Solubility:** Both ligands have very poor aqueous solubility (-3.73 for A, -2.453 for B). This could pose formulation challenges.

**hERG Inhibition:** Ligand A (0.551) has a slightly higher hERG risk than Ligand B (0.325), but both are relatively low.

**Microsomal Clearance:** Ligand A (82.191) has higher microsomal clearance, indicating lower metabolic stability. Ligand B (50.312) has better metabolic stability.

**In vitro Half-Life:** Ligand B (-11.343) has a negative half-life, which is likely an error or indicates very rapid degradation. Ligand A (22.536) has a reasonable half-life.

**P-gp Efflux:** Ligand A (0.659) has moderate P-gp efflux, while Ligand B (0.19) has very low P-gp efflux, which is a significant advantage for CNS penetration.

**Binding Affinity:** Ligand B (-7.4 kcal/mol) has a substantially stronger binding affinity than Ligand A (0.0 kcal/mol). This is a crucial factor, as a >1.5 kcal/mol advantage can outweigh other drawbacks.

**Overall Assessment:**

Ligand B is the stronger candidate despite its lower QED and solubility. The significantly improved binding affinity (-7.4 vs 0 kcal/mol) is a major advantage. The lower DILI risk and P-gp efflux are also beneficial. While the BBB penetration is suboptimal, the strong binding and low efflux might compensate. The negative half-life is a concern, but could be an experimental error. Ligand A's poor Caco-2 permeability and weaker binding affinity are significant drawbacks.



Output:
1
2025-04-17 07:59:21,964 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (350.415 and 344.386 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (107.89) is higher than Ligand B (58.64). For CNS targets, TPSA < 90 is preferred. Ligand B is significantly better here.

**3. logP:** Ligand A (0.518) is quite low, potentially hindering permeability. Ligand B (3.325) is within the optimal 1-3 range. Ligand B is superior.

**4. H-Bond Donors:** Ligand A (4) is acceptable, while Ligand B (1) is even better, potentially improving permeability.

**5. H-Bond Acceptors:** Ligand A (5) is acceptable, and Ligand B (3) is also good.

**6. QED:** Both ligands have good QED scores (0.619 and 0.838), indicating drug-like properties.

**7. DILI:** Ligand A (35.712) has a lower DILI risk than Ligand B (68.244), which is a positive for Ligand A.

**8. BBB:** Both ligands have reasonably good BBB penetration (65.839 and 69.833). However, >70 is desirable for CNS targets. Both are acceptable, but neither is outstanding.

**9. Caco-2:** Both have negative Caco-2 values, which is unusual and difficult to interpret without knowing the scale. However, we can assume they are both relatively low permeability.

**10. Solubility:** Both have negative solubility values, again making direct comparison difficult.

**11. hERG:** Both ligands have low hERG inhibition risk (0.449 and 0.707).

**12. Cl_mic:** Ligand A (34.877) has a lower microsomal clearance than Ligand B (40.26), suggesting better metabolic stability.

**13. t1/2:** Ligand A (-2.137) has a negative in vitro half-life, which is problematic. Ligand B (18.067) has a much more reasonable half-life.

**14. Pgp:** Ligand A (0.081) has significantly lower P-gp efflux liability than Ligand B (0.249), which is crucial for CNS penetration.

**15. Binding Affinity:** Both ligands have excellent binding affinities (-9.5 and -9.9 kcal/mol). The difference of 0.4 kcal/mol is not substantial enough to override other significant differences.

**Overall Assessment:**

Ligand B excels in key GPCR properties like logP and TPSA. While Ligand A has a lower DILI risk and Pgp efflux, its very low logP and negative in vitro half-life are major drawbacks. The superior logP, TPSA, and half-life of Ligand B outweigh the slightly higher DILI risk and Pgp efflux.

Output:
1
2025-04-17 07:59:21,964 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (356.463 and 349.435 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (96.89) is excellent, being below the 90 A^2 threshold for CNS targets. Ligand B (109.14) is still reasonable but less optimal.

**logP:** Ligand A (0.598) is a bit low, potentially hindering permeation. Ligand B (0.115) is even lower, raising concerns about membrane permeability.

**H-Bond Donors/Acceptors:** Both have 3 HBDs, which is good. Ligand A has 5 HBAs, and Ligand B has 6. Both are acceptable, staying within the <10 limit.

**QED:** Both ligands have similar QED values (0.621 and 0.586), indicating good drug-likeness.

**DILI:** Both have low DILI risk (27.181 and 24.544), which is positive.

**BBB:** This is a critical parameter for a CNS target like DRD2. Ligand A has a BBB percentile of 41.838, which is okay, but not great. Ligand B has a significantly better BBB percentile of 54.013.

**Caco-2 Permeability:** Both have negative Caco-2 values (-5.119 and -5.543), which is unusual and suggests poor permeability. This is a significant concern.

**Aqueous Solubility:** Both have negative solubility values (-2.139 and -0.614), indicating very poor aqueous solubility. This could hinder formulation and bioavailability.

**hERG Inhibition:** Both ligands show very low hERG inhibition risk (0.272 and 0.056).

**Microsomal Clearance:** Ligand A (31.882) has a higher clearance than Ligand B (-12.259), suggesting lower metabolic stability.

**In vitro Half-Life:** Ligand B (13.011) has a longer half-life than Ligand A (10.369).

**P-gp Efflux:** Both have very low P-gp efflux liability (0.035 and 0.022), which is favorable for CNS penetration.

**Binding Affinity:** Ligand B (-7.9 kcal/mol) has a slightly better binding affinity than Ligand A (-7.5 kcal/mol). While the difference is not huge, it's enough to consider, especially given the other factors.

**Overall Assessment:**

Ligand B is slightly favored, primarily due to its better BBB penetration, longer half-life, and slightly improved binding affinity. While both ligands suffer from poor Caco-2 permeability and aqueous solubility, the better CNS exposure potential of Ligand B outweighs the marginal affinity difference. The low logP values for both are a concern, but can potentially be addressed with further modifications.

Output:
1
2025-04-17 07:59:21,965 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (345.4 and 346.4 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (84.67) is excellent for CNS penetration, being well below 90. Ligand B (94.56) is still reasonable but less optimal.

**logP:** Both ligands have good logP values (1.142 and 0.928), falling within the 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A has 1 HBD and 5 HBA, while Ligand B has 3 HBD and 5 HBA. Both are within acceptable limits (<=5 HBD and <=10 HBA).

**QED:** Both ligands have good QED scores (0.564 and 0.639), indicating good drug-like properties.

**DILI:** Ligand A (49.13) has a slightly higher DILI risk than Ligand B (31.29), but both are below the concerning threshold of 60.

**BBB:** Ligand A (63.36) has a significantly better BBB penetration percentile than Ligand B (55.64). This is a critical factor for a CNS target like DRD2.

**Caco-2 Permeability:** Ligand A (-4.815) shows poor Caco-2 permeability, while Ligand B (-5.301) is also poor. Both are negative values, indicating low permeability.

**Aqueous Solubility:** Both ligands have very poor aqueous solubility (-1.817 and -1.885). This could pose formulation challenges.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.119 and 0.166).

**Microsomal Clearance:** Ligand A (13.095) has a much lower microsomal clearance than Ligand B (-18.2), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (-0.342) has a negative half-life, which is unusual and likely an artifact of the prediction method. Ligand B (21.779) has a reasonable half-life.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.093 and 0.01).

**Binding Affinity:** Both ligands have very similar and strong binding affinities (-7.9 and -7.7 kcal/mol). The difference is less than the 1.5 kcal/mol threshold.

**Overall Assessment:**

Ligand A is superior due to its significantly better BBB penetration (63.36 vs 55.64) and lower microsomal clearance (13.095 vs -18.2). While its Caco-2 permeability is poor, the BBB is more important for a CNS target. The negative in vitro half-life for ligand A is concerning, but the other advantages outweigh this issue. Ligand B's better half-life is offset by its poorer BBB and higher clearance.

Output:
0
2025-04-17 07:59:21,965 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (348.451 and 356.388 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (97.12) is slightly above the optimal <90 for CNS targets, but still reasonable. Ligand B (49.5) is excellent, well below 90.

**logP:** Ligand A (1.775) is within the optimal 1-3 range. Ligand B (3.997) is at the higher end of optimal, but still acceptable.

**H-Bond Donors/Acceptors:** Ligand A (3 HBD, 8 HBA) is good. Ligand B (1 HBD, 4 HBA) is also very good, with lower counts generally favoring permeability.

**QED:** Both ligands have good QED scores (0.563 and 0.815), indicating drug-like properties.

**DILI:** Ligand A (60.489) is approaching a moderate risk, while Ligand B (13.843) is excellent, indicating very low liver injury risk.

**BBB:** Both ligands have good BBB penetration (75.107 and 79.411), exceeding the 70% threshold for CNS targets. Ligand B is slightly better.

**Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and suggests a potential issue with the data or modeling. However, we'll proceed assuming these represent low permeability.

**Aqueous Solubility:** Both ligands have negative solubility values, which is also unusual. Assuming these represent low solubility, this is a drawback for both.

**hERG:** Both ligands have low hERG inhibition risk (0.885 and 0.945), which is positive.

**Microsomal Clearance:** Both have similar microsomal clearance values (43.611 and 45.179), suggesting moderate metabolic stability.

**In vitro Half-Life:** Ligand A (65.641) has a longer half-life than Ligand B (41.155), which is desirable.

**P-gp Efflux:** Ligand A (0.18) has a significantly lower P-gp efflux liability than Ligand B (0.513), which is crucial for CNS penetration.

**Binding Affinity:** Ligand B (-8.0 kcal/mol) has a slightly better binding affinity than Ligand A (-7.4 kcal/mol). The difference is 0.6 kcal/mol, which is significant but not overwhelming.

**Overall Assessment:**

Ligand B excels in several key areas: lower DILI risk, better TPSA, and slightly better binding affinity and BBB. However, Ligand A has a longer half-life and, crucially, much lower P-gp efflux. Given the CNS target, minimizing P-gp efflux is paramount. The slightly better affinity of Ligand B is helpful, but the lower P-gp efflux of Ligand A could translate to significantly higher brain exposure. The negative Caco-2 and solubility values are concerning for both, but the P-gp advantage of Ligand A is more critical for a CNS target.

Output:
1
2025-04-17 07:59:21,965 - INFO - Batch 411 complete. Total preferences: 6576
2025-04-17 07:59:21,965 - INFO - Processing batch 412/512...
2025-04-17 08:00:02,643 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (368.5 and 357.4 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (76.57) is significantly better than Ligand B (100.55). For CNS targets, we want TPSA <= 90, so Ligand A is closer to this threshold.

**3. logP:** Ligand A (2.745) is optimal (1-3). Ligand B (0.27) is quite low, potentially hindering membrane permeability and CNS penetration.

**4. H-Bond Donors:** Ligand A (0) is preferable to Ligand B (3). Fewer HBDs generally improve permeability.

**5. H-Bond Acceptors:** Both ligands have 5 HBA, which is acceptable (<=10).

**6. QED:** Both ligands have reasonable QED scores (0.747 and 0.62), indicating good drug-like properties.

**7. DILI:** Both ligands have similar, acceptable DILI risk (49.3 and 49.0).

**8. BBB:** Ligand A (61.38) is better than Ligand B (55.603), but both are below the desirable >70% for CNS targets. However, given the other factors, a higher BBB is more critical for Ligand A.

**9. Caco-2:** Ligand A (-4.719) is significantly better than Ligand B (-5.102). Higher values indicate better absorption.

**10. Solubility:** Ligand A (-3.258) is better than Ligand B (-1.583).

**11. hERG:** Both ligands have very low hERG risk (0.573 and 0.14).

**12. Cl_mic:** Ligand A (73.666) is higher than Ligand B (-4.688), indicating faster metabolism and lower stability. This is a negative for Ligand A.

**13. t1/2:** Ligand A (-28.061) is much worse than Ligand B (45.103). A longer half-life is generally preferred.

**14. Pgp:** Both ligands have very low Pgp efflux liability (0.092 and 0.007).

**15. Binding Affinity:** Ligand B (-7.9 kcal/mol) has a *much* stronger binding affinity than Ligand A (0 kcal/mol). This is a decisive advantage, exceeding the 1.5 kcal/mol threshold.

**Overall Assessment:**

While Ligand A has better TPSA, logP, solubility and Caco-2 permeability, Ligand B's significantly superior binding affinity (-7.9 vs 0 kcal/mol) is the most important factor, especially for a GPCR target. The affinity difference is large enough to outweigh the drawbacks of its lower logP and slightly higher TPSA. The longer half-life of Ligand B is also a significant positive. Although both have suboptimal BBB penetration, the stronger binding of Ligand B suggests it may still achieve sufficient target engagement.

Output:
1
2025-04-17 08:00:02,644 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (377.503 and 367.471 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (82.14) is excellent, well below the 90 A^2 threshold for CNS targets. Ligand B (97.39) is still reasonable but less optimal.

**logP:** Both ligands have acceptable logP values (1.011 and 1.816), falling within the 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A has 0 HBD and 6 HBA, fitting well within the guidelines. Ligand B has 2 HBD and 6 HBA, also acceptable.

**QED:** Ligand A (0.727) has a better QED score than Ligand B (0.566), indicating a more drug-like profile.

**DILI:** Ligand A (35.479) has a significantly lower DILI risk than Ligand B (74.952), which is a substantial advantage.

**BBB:** This is critical for a CNS target. Ligand A (81.388) has a very good BBB penetration percentile, exceeding the desirable >70 threshold. Ligand B (51.997) is considerably lower, raising concerns about CNS exposure.

**Caco-2 Permeability:** Ligand A (-4.428) and Ligand B (-5.189) both have negative values, which is unusual and suggests poor permeability. However, the scale isn't defined, so it's hard to interpret.

**Aqueous Solubility:** Both ligands have poor aqueous solubility (-1.227 and -3.128). This could pose formulation challenges.

**hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.291 and 0.072).

**Microsomal Clearance:** Ligand A (-1.792) has a negative clearance, which is unusual and likely indicates high metabolic stability. Ligand B (69.611) has a high clearance, suggesting rapid metabolism.

**In vitro Half-Life:** Ligand A (15.782) has a longer half-life than Ligand B (2.669).

**P-gp Efflux:** Ligand A (0.064) has lower P-gp efflux liability than Ligand B (0.131), which is favorable for CNS penetration.

**Binding Affinity:** Ligand B (-7.6 kcal/mol) has a significantly stronger binding affinity than Ligand A (-6.2 kcal/mol). This is a 1.4 kcal/mol difference, which is substantial.

**Overall Assessment:**

While Ligand B boasts a superior binding affinity, Ligand A is the more promising candidate overall. The significantly better BBB penetration (81.39% vs 51.99%), lower DILI risk (35.48% vs 74.95%), better QED (0.727 vs 0.566), lower P-gp efflux, and longer half-life outweigh the affinity difference. The negative Caco-2 values are concerning for both, but the other ADME properties of Ligand A are much more favorable for CNS drug development. The negative microsomal clearance for Ligand A is also a positive sign.

Output:
0
2025-04-17 08:00:02,644 - INFO - Reasoning:

Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (333.439 and 339.439 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (55.63) is slightly above the preferred <90 for CNS targets, but still reasonable. Ligand B (53.51) is better, comfortably under 90.

**3. logP:** Both ligands have good logP values (3.007 and 2.396), falling within the optimal 1-3 range.

**4. H-Bond Donors:** Ligand A has 1 HBD, which is acceptable. Ligand B has 0, also good.

**5. H-Bond Acceptors:** Ligand A has 5 HBA, within the acceptable limit. Ligand B has 3, also good.

**6. QED:** Both ligands have good QED scores (0.78 and 0.85), indicating good drug-likeness.

**7. DILI:** Ligand A (35.983) has a moderate DILI risk, but is still acceptable. Ligand B (16.44) has a much lower DILI risk, which is a significant advantage.

**8. BBB:** Ligand A (69.833) is borderline for good CNS penetration. Ligand B (89.027) is excellent, exceeding the >70 threshold. This is a critical advantage for a DRD2 ligand.

**9. Caco-2 Permeability:** Both have negative values, indicating poor permeability. However, the scale is not clearly defined, so this is hard to assess.

**10. Aqueous Solubility:** Both ligands have negative solubility values, indicating poor solubility. This is a concern, but can potentially be addressed with formulation strategies.

**11. hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.773 and 0.29).

**12. Microsomal Clearance:** Ligand A (6.342) has a lower (better) microsomal clearance than Ligand B (32.029), suggesting greater metabolic stability.

**13. In vitro Half-Life:** Ligand A (30.323) has a significantly longer half-life than Ligand B (2.376). This is a major advantage.

**14. P-gp Efflux:** Both ligands have low P-gp efflux liability (0.206 and 0.125), which is favorable for CNS penetration.

**15. Binding Affinity:** Ligand B (-7.9 kcal/mol) has a substantially stronger binding affinity than Ligand A (-9.3 kcal/mol). This difference of 1.4 kcal/mol is significant and can outweigh some of the ADME drawbacks of Ligand A.

**Overall Assessment:**

While Ligand A has better metabolic stability and half-life, Ligand B is superior due to its significantly better BBB penetration (89.027 vs 69.833), lower DILI risk (16.44 vs 35.983), and substantially stronger binding affinity (-7.9 vs -9.3 kcal/mol). For a CNS target like DRD2, BBB penetration and affinity are paramount. The lower DILI risk is also a significant benefit.

Output:
1
2025-04-17 08:00:02,644 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (402.292 Da) is slightly higher than Ligand B (348.443 Da), but both are acceptable.

**TPSA:** Ligand A (51.27) is much better than Ligand B (87.66). For CNS targets, we want TPSA <= 90, and ideally lower. Ligand A is well within this range, while Ligand B is approaching the upper limit.

**logP:** Ligand A (4.253) is a bit high, potentially leading to solubility issues or off-target interactions. Ligand B (0.731) is quite low, which could hinder membrane permeability. Optimal is 1-3.

**H-Bond Donors/Acceptors:** Ligand A (0 HBD, 4 HBA) is preferable to Ligand B (3 HBD, 4 HBA). Lower HBDs are generally better for CNS penetration.

**QED:** Both ligands have similar QED values (Ligand A: 0.658, Ligand B: 0.592), indicating reasonable drug-likeness.

**DILI:** Ligand A (62.931) has a higher DILI risk than Ligand B (22.257). Lower is better, so Ligand B is preferable here.

**BBB:** Ligand A (83.133) has a significantly better BBB penetration prediction than Ligand B (46.762). This is *critical* for a CNS target like DRD2.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.004 and -5.109), which is unusual and suggests poor permeability. This is a concern for both.

**Aqueous Solubility:** Both ligands have negative solubility values (-3.498 and -2.015), indicating very poor aqueous solubility. This is a significant drawback for both.

**hERG Inhibition:** Ligand A (0.803) has a slightly higher hERG inhibition risk than Ligand B (0.089). Lower is better, so Ligand B is preferable.

**Microsomal Clearance:** Ligand A (43.414) has a higher microsomal clearance than Ligand B (-5.968). Lower is better, indicating greater metabolic stability, so Ligand B is preferable.

**In vitro Half-Life:** Ligand A (92.084) has a much longer in vitro half-life than Ligand B (9.05). This is a significant advantage for Ligand A.

**P-gp Efflux:** Ligand A (0.771) has a lower P-gp efflux liability than Ligand B (0.022). Lower is better, especially for CNS targets, so Ligand A is preferable.

**Binding Affinity:** Ligand A (-9.4 kcal/mol) has a significantly stronger binding affinity than Ligand B (-7.1 kcal/mol). This is a major advantage for Ligand A. A difference of >1.5 kcal/mol can often outweigh other drawbacks.

**Overall Assessment:**

Despite Ligand A's higher logP and DILI risk, its superior BBB penetration, significantly stronger binding affinity, longer half-life, and lower P-gp efflux liability make it the more promising candidate. The strong binding affinity is a key factor, and the better BBB is crucial for a CNS target. While solubility and Caco-2 permeability are concerns for both, the potency and CNS penetration advantages of Ligand A are more critical for DRD2.

Output:
1
2025-04-17 08:00:02,644 - INFO - Reasoning:

Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (356.4 and 342.5 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (96.7) is slightly above the optimal <90 for CNS targets, but still reasonable. Ligand B (49.41) is excellent, well below 90.

**3. logP:** Ligand A (0.313) is quite low, potentially hindering permeability. Ligand B (3.494) is within the optimal 1-3 range. This is a significant advantage for Ligand B.

**4. H-Bond Donors:** Ligand A (2) and Ligand B (1) are both acceptable, below the threshold of 5.

**5. H-Bond Acceptors:** Ligand A (6) and Ligand B (2) are both acceptable, below the threshold of 10.

**6. QED:** Both ligands have reasonable QED values (0.696 and 0.581), indicating good drug-like properties.

**7. DILI:** Ligand A (28.9%) has a lower DILI risk than Ligand B (38.0%), which is preferable.

**8. BBB:** Ligand A (78.5%) has a significantly better BBB penetration prediction than Ligand B (65.9%). This is a critical factor for a CNS target like DRD2.

**9. Caco-2 Permeability:** Ligand A (-4.872) and Ligand B (-4.613) are both negative, indicating poor permeability.

**10. Aqueous Solubility:** Both ligands have poor aqueous solubility (-2.079 and -3.532).

**11. hERG Inhibition:** Both ligands have low hERG inhibition risk (0.305 and 0.478).

**12. Microsomal Clearance:** Ligand A (6.125) has a lower microsomal clearance than Ligand B (80.136), suggesting better metabolic stability.

**13. In vitro Half-Life:** Ligand A (7.904) has a shorter half-life than Ligand B (26.609).

**14. P-gp Efflux:** Ligand A (0.027) has very low P-gp efflux liability, which is excellent for CNS penetration. Ligand B (0.285) is also low, but higher than Ligand A.

**15. Binding Affinity:** Ligand B (-8.1 kcal/mol) has a stronger binding affinity than Ligand A (-7.5 kcal/mol). The difference of 0.6 kcal/mol is substantial and can outweigh some ADME drawbacks.

**Overall Assessment:**

Ligand B has a superior logP and binding affinity, both crucial for GPCR targeting. While Ligand A has a better BBB prediction and lower DILI, the significantly stronger binding of Ligand B, combined with its acceptable logP, makes it the more promising candidate. The lower BBB of Ligand B is a concern, but the affinity difference is substantial. The metabolic stability of Ligand A is better, but not enough to overcome the affinity difference.

Output:
1
2025-04-17 08:00:02,644 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (342.443 and 346.471 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (66.71) is slightly higher than Ligand B (58.64). Both are below the 90 A^2 threshold desirable for CNS targets, but Ligand B is preferable.

**3. logP:** Both ligands have excellent logP values (2.347 and 2.243), falling within the optimal 1-3 range.

**4. H-Bond Donors:** Both have 1 HBD, which is acceptable.

**5. H-Bond Acceptors:** Ligand A has 4 HBAs, and Ligand B has 3. Both are below the 10 threshold.

**6. QED:** Ligand A (0.907) has a significantly higher QED score than Ligand B (0.593), suggesting better overall drug-likeness.

**7. DILI:** Ligand A (38.891) has a slightly higher DILI risk than Ligand B (11.128), but both are below the concerning 60 percentile.

**8. BBB:** Both ligands have good BBB penetration (61.962% and 64.017%), but are slightly below the >70% target for CNS drugs. Ligand B is slightly better.

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.7 and -4.77), which is unusual and suggests poor permeability. This is a significant concern.

**10. Aqueous Solubility:** Both ligands have negative solubility values (-2.206 and -2.608), indicating very poor aqueous solubility. This is a major drawback.

**11. hERG Inhibition:** Both have low hERG inhibition risk (0.664 and 0.4).

**12. Microsomal Clearance:** Ligand A (39.874) has a higher microsomal clearance than Ligand B (-10.711), indicating lower metabolic stability. Ligand B is preferable here.

**13. In vitro Half-Life:** Ligand A (-8.356) has a negative half-life, which is not possible and indicates an issue with the data. Ligand B (10.908) has a reasonable half-life.

**14. P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.065 and 0.107), which is good for CNS penetration.

**15. Binding Affinity:** Ligand A (-9.0) has a slightly better binding affinity than Ligand B (-7.8). This is a 1.2 kcal/mol difference, which is substantial.

**Overall Assessment:**

Despite the poor Caco-2 and solubility values for both, Ligand A is the slightly better candidate. The significantly stronger binding affinity (-9.0 vs -7.8 kcal/mol) is a major advantage that outweighs the slightly higher DILI risk and lower QED. The negative half-life for Ligand A is a data quality issue and should be investigated. However, the better affinity makes it the more promising starting point, assuming the half-life issue can be resolved.

Output:
0
2025-04-17 08:00:02,644 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (364.467 and 364.515 Da) fall comfortably within the ideal 200-500 Da range.

**2. TPSA:** Both ligands have TPSA values (82.63 and 83.98) slightly above the optimal 90 for CNS targets, but still reasonable.

**3. logP:** Both ligands have logP values (3.065 and 2.452) within the optimal 1-3 range. Ligand B is slightly better here.

**4. H-Bond Donors:** Both have 2 HBD, which is acceptable.

**5. H-Bond Acceptors:** Both have 5 HBA, which is acceptable.

**6. QED:** Both have QED values (0.74 and 0.668) above 0.5, indicating good drug-likeness.

**7. DILI:** Ligand A (56.146) has a higher DILI risk than Ligand B (39.201). Ligand B is preferable here.

**8. BBB:** Ligand B (57.425) has a significantly better BBB penetration percentile than Ligand A (30.283). This is a *critical* advantage for a CNS target like DRD2.

**9. Caco-2 Permeability:** Both have negative Caco-2 values (-5.072 and -5.328), which is unusual and suggests poor permeability. This is a concern for both.

**10. Aqueous Solubility:** Both have negative solubility values (-2.762 and -2.776), indicating very poor aqueous solubility. This is a significant drawback for both.

**11. hERG Inhibition:** Both have low hERG inhibition liability (0.48 and 0.155), which is good. Ligand B is slightly better.

**12. Microsomal Clearance:** Ligand A (68.171) has higher microsomal clearance than Ligand B (38.798), meaning it's less metabolically stable. Ligand B is preferable.

**13. In vitro Half-Life:** Ligand B (12.614) has a longer in vitro half-life than Ligand A (-10.328), which is a significant advantage.

**14. P-gp Efflux:** Both have very low P-gp efflux liability (0.226 and 0.218), which is good.

**15. Binding Affinity:** Both ligands have the same binding affinity (-8.0 kcal/mol), which is excellent.

**Overall Assessment:**

While both ligands have excellent binding affinity, Ligand B is significantly better overall. Its superior BBB penetration, lower DILI risk, lower microsomal clearance (better metabolic stability), and longer half-life outweigh the slightly less optimal logP and solubility. The poor Caco-2 and solubility are concerns for both, but can potentially be addressed with formulation strategies. Given the GPCR-specific focus on BBB penetration for CNS targets, Ligand B is the more promising candidate.

Output:
1
2025-04-17 08:00:02,644 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (341.455 and 367.877 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (47.36) is excellent, well below the 90 A^2 threshold for CNS targets. Ligand B (82.53) is higher, but still acceptable, though less optimal.

**logP:** Ligand A (3.671) is within the optimal 1-3 range. Ligand B (2.171) is also within range, but closer to the lower bound, potentially impacting permeability.

**H-Bond Donors/Acceptors:** Ligand A has 0 HBD and 4 HBA, which is favorable. Ligand B has 2 HBD and 4 HBA, also acceptable.

**QED:** Both ligands have good QED scores (0.805 and 0.835), indicating drug-like properties.

**DILI:** Ligand A (41.024) has a slightly higher DILI risk than Ligand B (34.393), but both are below the concerning threshold of 60.

**BBB:** This is crucial for a CNS target like DRD2. Ligand A has a very high BBB penetration percentile (93.098), which is excellent. Ligand B's BBB penetration (45.638) is significantly lower and less desirable.

**Caco-2 Permeability:** Ligand A (-4.318) has a negative Caco-2 value, which is unusual and suggests poor permeability. Ligand B (-4.812) is also negative and similarly poor. This is a significant concern for both.

**Aqueous Solubility:** Both ligands have negative solubility values (-3.732 and -2.525), indicating very poor aqueous solubility, which could hinder formulation and bioavailability.

**hERG Inhibition:** Ligand A (0.857) has a slightly higher hERG risk than Ligand B (0.249), but both are relatively low.

**Microsomal Clearance:** Ligand B (-6.741) has a negative clearance value, which is unusual and suggests very high metabolic stability. Ligand A (75.15) has a higher, positive clearance, indicating faster metabolism.

**In vitro Half-Life:** Ligand B (9.54) has a shorter half-life than Ligand A (-13.649), which is unusual.

**P-gp Efflux:** Ligand A (0.702) has a lower P-gp efflux liability than Ligand B (0.097), meaning it is less likely to be pumped out of cells, improving CNS exposure.

**Binding Affinity:** Ligand A (-8.1 kcal/mol) has a significantly stronger binding affinity than Ligand B (-7.6 kcal/mol). This 1.5 kcal/mol difference is substantial and can outweigh some ADME drawbacks.

**Overall Assessment:**

Despite the poor Caco-2 and solubility values for both, Ligand A is the more promising candidate. Its significantly higher BBB penetration, lower P-gp efflux, and substantially stronger binding affinity to DRD2 outweigh the slightly higher DILI risk and faster metabolic clearance. The strong affinity is a key advantage for a GPCR target. Ligand B's lower BBB penetration is a major drawback for a CNS-targeted drug.

Output:
0
2025-04-17 08:00:02,644 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (384.42 Da) is slightly higher than Ligand B (351.447 Da), but both are acceptable.

**TPSA:** Ligand A (83.55) is excellent for CNS penetration, being well below 90. Ligand B (110.52) is still reasonable but less optimal, being above 100.

**logP:** Both ligands have good logP values (A: 1.115, B: 0.839), falling within the 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A (HBD=1, HBA=4) and Ligand B (HBD=3, HBA=4) both have acceptable numbers of H-bond donors and acceptors.

**QED:** Both ligands have reasonable QED scores (A: 0.79, B: 0.631), indicating good drug-like properties.

**DILI:** Ligand A (36.681) has a much lower DILI risk than Ligand B (17.216), which is a significant advantage.

**BBB:** Ligand A (93.098) has a very high BBB penetration percentile, which is crucial for a CNS target like DRD2. Ligand B (58.046) is considerably lower, suggesting limited CNS exposure.

**Caco-2 Permeability:** Ligand A (-4.54) and Ligand B (-5.445) both have negative Caco-2 values, which is unusual and suggests poor permeability. However, the scale isn't specified, so it's hard to interpret.

**Aqueous Solubility:** Both ligands have very poor aqueous solubility (-2.541 and -2.49 respectively). This could be a formulation challenge.

**hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.36 and 0.059), which is excellent.

**Microsomal Clearance:** Ligand A (1.984) has significantly lower microsomal clearance than Ligand B (41.722), indicating better metabolic stability.

**In vitro Half-Life:** Ligand A (-30.619) has a longer in vitro half-life than Ligand B (-33.887), which is favorable.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.036 and 0.008), which is good for CNS penetration.

**Binding Affinity:** Both ligands have similar and strong binding affinities (-8.8 kcal/mol and -8.3 kcal/mol). The difference is less than 1.5 kcal/mol, so it doesn't significantly sway the decision.

**Conclusion:**

Considering all factors, **Ligand A** is the more promising drug candidate. Its superior BBB penetration, lower DILI risk, and better metabolic stability (lower Cl_mic and longer t1/2) outweigh the slightly higher molecular weight and similar binding affinity. While both have poor solubility and Caco-2 permeability, the CNS target prioritizes BBB penetration, where Ligand A excels.

Output:
1
2025-04-17 08:00:02,645 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (350.459 and 345.399 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (75.71) is significantly better than Ligand B (95.67). For CNS targets, we want TPSA <= 90, so Ligand A is preferable.

**3. logP:** Both ligands have good logP values (2.191 and 2.74), falling within the optimal 1-3 range.

**4. H-Bond Donors:** Ligand A (1) is better than Ligand B (2). Lower is generally preferred for CNS penetration.

**5. H-Bond Acceptors:** Ligand A (4) is better than Ligand B (5).

**6. QED:** Ligand B (0.785) has a better QED score than Ligand A (0.453), indicating a more drug-like profile.

**7. DILI:** Ligand B (61.962) has a higher DILI risk than Ligand A (52.385), but both are acceptable (<60 is good).

**8. BBB:** Both ligands have similar BBB penetration (38.852 and 39.511). Both are below the desirable >70 for CNS targets, but not drastically so.

**9. Caco-2 Permeability:** Ligand A (-4.796) has slightly better Caco-2 permeability than Ligand B (-5.025).

**10. Aqueous Solubility:** Ligand A (-2.468) has better aqueous solubility than Ligand B (-4.289).

**11. hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.194 and 0.226).

**12. Microsomal Clearance:** Ligand A (42.24) has lower microsomal clearance than Ligand B (72.42), indicating better metabolic stability.

**13. In vitro Half-Life:** Ligand B (-14.303) has a significantly longer in vitro half-life than Ligand A (-7.635). This is a substantial advantage.

**14. P-gp Efflux:** Both ligands have low P-gp efflux liability (0.097 and 0.098).

**15. Binding Affinity:** Ligand B (-8.7 kcal/mol) has a significantly stronger binding affinity than Ligand A (-6.5 kcal/mol). This is a >1.5 kcal/mol advantage, which can outweigh some ADME drawbacks.

**Overall Assessment:**

Ligand B has a significantly better binding affinity and a longer half-life, which are crucial for drug efficacy. While Ligand A has better TPSA and solubility, the substantial affinity advantage of Ligand B, coupled with acceptable ADME properties, makes it the more promising candidate. The slightly higher DILI risk of Ligand B is manageable. The BBB values for both are suboptimal, but not disqualifying.

Output:
1
2025-04-17 08:00:02,645 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight (MW):** Both ligands (346.475 and 359.495 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (76.02) is better than Ligand B (55.32). Both are below the 90 A^2 threshold desirable for CNS targets.

**3. logP:** Ligand A (1.861) is within the optimal 1-3 range. Ligand B (3.614) is at the higher end, potentially raising concerns about solubility and off-target effects, but still acceptable.

**4. H-Bond Donors (HBD):** Both ligands have acceptable HBD counts (2 and 0, respectively), well below the limit of 5.

**5. H-Bond Acceptors (HBA):** Both ligands have acceptable HBA counts (4 and 5, respectively), well below the limit of 10.

**6. QED:** Both ligands have reasonable QED scores (0.854 and 0.758), indicating good drug-like properties.

**7. DILI:** Ligand A (30.593) has a slightly higher DILI risk than Ligand B (21.753), but both are well below the concerning threshold of 60.

**8. BBB:** Ligand B (74.796) has a significantly better BBB penetration score than Ligand A (61.962). This is a critical advantage for a CNS target like DRD2.

**9. Caco-2 Permeability:** Ligand A (-4.985) has better Caco-2 permeability than Ligand B (-4.498), but both are negative values which is unusual.

**10. Aqueous Solubility:** Ligand A (-2.31) has better aqueous solubility than Ligand B (-3.1), which is important for formulation.

**11. hERG Inhibition:** Ligand A (0.088) has a much lower hERG inhibition liability than Ligand B (0.619). This is a significant safety advantage.

**12. Microsomal Clearance (Cl_mic):** Ligand A (15.242) has a lower microsomal clearance than Ligand B (67.184), indicating better metabolic stability.

**13. In vitro Half-Life:** Ligand A (10.825) has a longer in vitro half-life than Ligand B (4.972), which is desirable.

**14. P-gp Efflux:** Ligand A (0.036) has much lower P-gp efflux liability than Ligand B (0.215), which is crucial for CNS penetration.

**15. Binding Affinity:** Ligand A (-8.5 kcal/mol) has a significantly stronger binding affinity than Ligand B (-6.5 kcal/mol). This is a substantial advantage, potentially outweighing some minor ADME drawbacks.

**Overall Assessment:**

While Ligand B has a better BBB score, Ligand A excels in almost every other critical parameter, especially binding affinity, metabolic stability (lower Cl_mic, longer t1/2), safety (lower hERG, lower Pgp efflux), and solubility. The substantial difference in binding affinity (-8.5 vs -6.5 kcal/mol) is a major factor. For a GPCR target, strong binding is paramount, and the other favorable properties of Ligand A suggest it's more likely to translate into a viable drug candidate.

Output:
1
2025-04-17 08:00:02,645 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (346.45 & 361.47 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (58.2) is significantly better than Ligand B (66.65). For a CNS target like DRD2, TPSA < 90 is preferred, and A is closer to the optimal <60 range.

**3. logP:** Both ligands have good logP values (3.795 & 2.872), falling within the 1-3 range.

**4. H-Bond Donors:** Ligand A (2) is reasonable, while Ligand B (0) is also acceptable.

**5. H-Bond Acceptors:** Ligand A (2) is good, while Ligand B (5) is slightly higher but still within the acceptable limit of 10.

**6. QED:** Both ligands have similar, good QED values (0.823 & 0.821), indicating good drug-like properties.

**7. DILI:** Ligand A (25.9%) has a much lower DILI risk than Ligand B (55.4%). This is a significant advantage for A.

**8. BBB:** Ligand A (83.7%) has a considerably higher BBB penetration percentile than Ligand B (71.6%). This is *critical* for a CNS target like DRD2.

**9. Caco-2:** Ligand A (-4.632) is better than Ligand B (-5.008), indicating better intestinal absorption.

**10. Solubility:** Ligand A (-4.03) is better than Ligand B (-2.291), suggesting better aqueous solubility.

**11. hERG:** Ligand A (0.72) has a lower hERG inhibition liability than Ligand B (0.541), which is preferable.

**12. Cl_mic:** Ligand A (56.9) has a lower microsomal clearance than Ligand B (82.9), indicating better metabolic stability.

**13. t1/2:** Ligand B (47.17) has a longer in vitro half-life than Ligand A (26.323). This is a positive for B, but not enough to overcome other deficiencies.

**14. Pgp:** Ligand A (0.315) has lower P-gp efflux liability than Ligand B (0.433). Lower Pgp is favorable for CNS penetration.

**15. Binding Affinity:** Ligand A (-9.5 kcal/mol) has a *much* stronger binding affinity than Ligand B (-0.0 kcal/mol). This is a decisive advantage. A difference of >1.5 kcal/mol can often outweigh minor ADME drawbacks, and here the difference is enormous.

**Overall:**

Ligand A is superior to Ligand B across almost all critical parameters. The significantly better BBB penetration, lower DILI risk, lower Pgp efflux, better solubility, lower hERG risk, better metabolic stability, and *far* superior binding affinity make Ligand A a much more promising drug candidate for targeting DRD2. While Ligand B has a slightly longer half-life, the other advantages of Ligand A are far more important for a CNS GPCR target.

Output:
1
2025-04-17 08:00:02,645 - INFO - Reasoning:

Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (350.35 and 364.563 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (106.2) is better than Ligand B (79.96). For CNS targets, TPSA <= 90 is preferred. Ligand B is well within this range, while Ligand A is slightly above, but still acceptable.

**3. logP:** Both ligands have good logP values (2.422 and 3.701), falling within the optimal 1-3 range. Ligand B is a bit higher, which could potentially lead to off-target effects, but isn't a major concern.

**4. H-Bond Donors:** Both have 2 HBD, which is within the acceptable limit of <=5.

**5. H-Bond Acceptors:** Ligand A has 6 HBA, and Ligand B has 7. Both are within the acceptable limit of <=10.

**6. QED:** Both ligands have similar QED values (0.82 and 0.796), indicating good drug-like properties.

**7. DILI:** Ligand A (88.251) has a higher DILI risk than Ligand B (62.66). Lower DILI is preferred, making Ligand B more favorable.

**8. BBB:** Ligand B (84.141) has a significantly better BBB penetration percentile than Ligand A (64.482). This is *crucial* for a CNS target like DRD2.

**9. Caco-2 Permeability:** Ligand A (-4.421) has a worse Caco-2 permeability than Ligand B (-5.157). Higher values are better, indicating better intestinal absorption.

**10. Aqueous Solubility:** Ligand A (-3.892) has better aqueous solubility than Ligand B (-5.067). Higher values are better.

**11. hERG Inhibition:** Ligand A (0.299) has a lower hERG inhibition liability than Ligand B (0.633). Lower is better, reducing cardiotoxicity risk.

**12. Microsomal Clearance:** Ligand A (77.594) has lower microsomal clearance than Ligand B (84.923). Lower clearance means greater metabolic stability, favoring Ligand A.

**13. In vitro Half-Life:** Ligand A (-20.506) has a longer in vitro half-life than Ligand B (26.511). Longer half-life is generally preferred.

**14. P-gp Efflux:** Ligand A (0.111) has lower P-gp efflux liability than Ligand B (0.162). Lower efflux is better, especially for CNS targets.

**15. Binding Affinity:** Ligand B (-7.5 kcal/mol) has a slightly better binding affinity than Ligand A (-8.6 kcal/mol). While both are excellent, the difference is not substantial enough to outweigh other factors.

**Overall Assessment:**

Ligand B clearly wins out due to its superior BBB penetration (84.141 vs 64.482), lower DILI risk (62.66 vs 88.251), and slightly better binding affinity. While Ligand A has advantages in metabolic stability (Cl_mic, t1/2) and hERG inhibition, the BBB penetration is paramount for a CNS target like DRD2. The better Caco-2 permeability of Ligand B is also a plus.



Output:
1
2025-04-17 08:00:02,645 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (358.435 and 373.475 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (95.12) is better than Ligand B (117.09). For CNS targets, we want TPSA <= 90, so Ligand A is closer to this threshold.

**logP:** Both ligands have low logP values (0.202 and 0.126). While <1 can impede permeation, the very low values here are concerning. However, DRD2 is a GPCR, and some flexibility can be given if other parameters are strong.

**H-Bond Donors/Acceptors:** Ligand A (HBD=2, HBA=6) and Ligand B (HBD=3, HBA=6) are both acceptable.

**QED:** Both ligands have reasonable QED scores (0.579 and 0.523), indicating good drug-like properties.

**DILI:** Ligand A (32.842) has a significantly lower DILI risk than Ligand B (43.66). This is a substantial advantage.

**BBB:** Ligand A (55.021) has a better BBB percentile than Ligand B (43.273). While neither is above the desirable >70, A is closer, which is crucial for a CNS target.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.383 and -5.409), which is unusual and suggests poor permeability.

**Aqueous Solubility:** Both ligands have negative solubility values (-0.849 and -1.83), indicating very poor aqueous solubility.

**hERG:** Both ligands show low hERG inhibition liability (0.151 and 0.379), which is positive.

**Microsomal Clearance:** Ligand A (8.107) has lower microsomal clearance than Ligand B (10.059), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (20.473) has a longer half-life than Ligand B (5.639), which is favorable.

**P-gp Efflux:** Both ligands show very low P-gp efflux liability (0.014 and 0.064), which is good for CNS penetration.

**Binding Affinity:** Ligand B (-7.5 kcal/mol) has a slightly better binding affinity than Ligand A (-7.1 kcal/mol). This 0.4 kcal/mol difference is noticeable, but not overwhelmingly large.

**Overall Assessment:**

Ligand A is the better candidate. While both have issues with logP and solubility, Ligand A demonstrates superior ADME properties: lower DILI risk, better BBB penetration, lower clearance, and a longer half-life. The slightly weaker binding affinity of Ligand A is outweighed by its more favorable ADME profile, particularly for a CNS target like DRD2. The poor Caco-2 and solubility are concerning for both, but can potentially be addressed with formulation strategies.

Output:
0
2025-04-17 08:00:02,645 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (360.523 and 344.455 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (49.41) is significantly better than Ligand B (58.64). For CNS targets, we want TPSA <= 90, and ideally lower. Ligand A is much closer to the ideal range.

**logP:** Ligand A (3.815) is good, within the 1-3 range. Ligand B (2.527) is acceptable but closer to the lower limit, potentially impacting permeability.

**H-Bond Donors/Acceptors:** Both have 1 HBD and 3 HBA, which are within acceptable limits.

**QED:** Both ligands have high QED scores (0.838 and 0.863), indicating good drug-like properties.

**DILI:** Both have acceptable DILI risk (36.06 and 31.563), below the 40 threshold.

**BBB:** Both have excellent BBB penetration (80.419 and 78.751), exceeding the 70% threshold for CNS targets.

**Caco-2 Permeability:** Ligand A (-5.013) and Ligand B (-4.587) both have negative Caco-2 values, which is unusual and suggests poor permeability. However, these values are on a scale where negative values are possible, and the absolute magnitude matters less than the relative difference.

**Aqueous Solubility:** Both ligands have poor aqueous solubility (-4.114 and -2.882). This could pose formulation challenges.

**hERG:** Both ligands have low hERG risk (0.511 and 0.549), which is positive.

**Microsomal Clearance:** Ligand A (43.184) has a better (lower) microsomal clearance than Ligand B (49.696), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (2.015) has a very short half-life, while Ligand B (-21.029) has a long half-life. This is a significant advantage for Ligand B.

**P-gp Efflux:** Both ligands have low P-gp efflux (0.341 and 0.429), which is good for CNS penetration.

**Binding Affinity:** Ligand B (-9.2 kcal/mol) has significantly stronger binding affinity than Ligand A (-7.2 kcal/mol). This is a >1.5 kcal/mol difference, which can outweigh minor ADME drawbacks.

**Overall Assessment:**

While Ligand A has a better TPSA and slightly better metabolic stability, Ligand B's significantly stronger binding affinity (-9.2 vs -7.2 kcal/mol) is the most critical factor for a GPCR target. The longer half-life of Ligand B is also a significant advantage. The slightly lower logP and higher TPSA of Ligand B are less concerning given the strong affinity. Both have acceptable BBB penetration and low DILI/hERG risk.

Output:
1
2025-04-17 08:00:02,645 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (371.503 Da) is slightly higher than Ligand B (340.423 Da), but both are acceptable.

**TPSA:** Ligand A (96.53) is closer to the ideal range for CNS targets (<=90) than Ligand B (62.55), which is excellent.

**logP:** Ligand A (0.29) is quite low, potentially hindering membrane permeability. Ligand B (3.8) is within the optimal range (1-3). This is a significant advantage for Ligand B.

**H-Bond Donors/Acceptors:** Ligand A has 3 HBD and 5 HBA, which are acceptable. Ligand B has 1 HBD and 3 HBA, also acceptable.

**QED:** Both ligands have good QED scores (Ligand A: 0.533, Ligand B: 0.9), indicating good drug-like properties. Ligand B is superior here.

**DILI:** Both have acceptable DILI risk (Ligand A: 56.495, Ligand B: 38.348), with Ligand B being slightly better.

**BBB:** Ligand B (82.164) has a much higher BBB percentile than Ligand A (41.218). This is a critical advantage for a CNS target like DRD2.

**Caco-2 Permeability:** Ligand A (-5.343) has poor Caco-2 permeability, which is concerning. Ligand B (-4.428) is also poor, but slightly better.

**Aqueous Solubility:** Both have poor aqueous solubility (-3.203 and -4.072, respectively). This might pose formulation challenges, but is less critical than permeability for CNS drugs.

**hERG Inhibition:** Both have low hERG inhibition risk (Ligand A: 0.098, Ligand B: 0.598), which is good.

**Microsomal Clearance:** Ligand A (46.898) has lower microsomal clearance than Ligand B (54.099), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand B (104.95) has a significantly longer in vitro half-life than Ligand A (0.379), which is a major advantage.

**P-gp Efflux:** Ligand A (0.02) has very low P-gp efflux, which is excellent for CNS penetration. Ligand B (0.238) is higher, but still acceptable.

**Binding Affinity:** Ligand B (-8.9 kcal/mol) has a significantly stronger binding affinity than Ligand A (-7.2 kcal/mol). This >1.5 kcal/mol difference is substantial and can outweigh some ADME drawbacks.

**Overall:**

Ligand B is the stronger candidate. While both have solubility issues, Ligand B excels in key areas for CNS GPCR targets: BBB penetration, binding affinity, and in vitro half-life. Its logP is also optimal, unlike Ligand A's very low value. The better BBB and affinity of Ligand B are crucial for CNS drug development.

Output:
1
2025-04-17 08:00:02,645 - INFO - Batch 412 complete. Total preferences: 6592
2025-04-17 08:00:02,645 - INFO - Processing batch 413/512...
2025-04-17 08:00:43,567 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (332.407 Da) is slightly lower, which could be advantageous for permeability.

**TPSA:** Both ligands have TPSA values below 90 (Ligand A: 80.9, Ligand B: 87.32), which is good for CNS penetration.

**logP:** Ligand A (3.158) is within the optimal range (1-3), while Ligand B (1.348) is at the lower end. Lower logP can sometimes hinder permeation, but isn't a dealbreaker.

**H-Bond Donors/Acceptors:** Both have 2 HBD and 4 HBA, which are within acceptable limits.

**QED:** Both ligands have similar QED values (A: 0.719, B: 0.744), indicating good drug-like properties.

**DILI:** Ligand B (59.946) has a lower DILI risk than Ligand A (77.782), which is a positive attribute.

**BBB:** Ligand A (71.966) has a slightly better BBB penetration percentile than Ligand B (64.25), which is important for a CNS target like DRD2.

**Caco-2 Permeability:** Ligand A (-5.489) has a significantly *higher* Caco-2 permeability than Ligand B (-4.9). This suggests better intestinal absorption for Ligand A.

**Aqueous Solubility:** Both ligands have negative solubility values, indicating poor aqueous solubility. Ligand B (-2.453) is slightly better than Ligand A (-2.964), but both are problematic.

**hERG Inhibition:** Both ligands have low hERG inhibition liability (A: 0.72, B: 0.412), which is good.

**Microsomal Clearance:** Ligand B (-4.792) has a *much* lower (better) microsomal clearance than Ligand A (61.323), indicating greater metabolic stability.

**In vitro Half-Life:** Ligand B (-26.919) has a *much* longer in vitro half-life than Ligand A (2.939), which is a significant advantage.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (A: 0.414, B: 0.045), which is excellent for CNS exposure. Ligand B is slightly better.

**Binding Affinity:** Ligand A (-10.4 kcal/mol) has a significantly stronger binding affinity than Ligand B (-8.1 kcal/mol). This is a crucial factor, and the 2.3 kcal/mol difference is substantial.

**Overall Assessment:**

Ligand A has a better BBB, Caco-2 permeability, and, most importantly, *much* stronger binding affinity. However, Ligand B exhibits significantly better metabolic stability (lower Cl_mic, longer t1/2) and lower DILI risk. The strong binding affinity of Ligand A is a major advantage that can potentially outweigh its poorer metabolic properties, especially considering the importance of potency for GPCR ligands. The slightly better BBB of Ligand A further supports its selection. While solubility is a concern for both, the binding affinity difference is significant enough to favor Ligand A.

Output:
1
2025-04-17 08:00:43,568 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (362.459 Da and 349.343 Da) fall within the ideal range of 200-500 Da.

**TPSA:** Ligand A (94.31) is significantly better than Ligand B (128.78). For CNS targets, we want TPSA <= 90, and A is closer to that threshold. B is considerably higher, potentially hindering BBB penetration.

**logP:** Both ligands have similar logP values (0.394 and 0.476), which are a bit low. Ideally, we want 1-3. This might slightly impede permeation, but isn't a major concern compared to other factors.

**H-Bond Donors/Acceptors:** Ligand A has 4 HBD and 5 HBA, while Ligand B has 3 HBD and 6 HBA. Both are within acceptable limits (<=5 HBD and <=10 HBA).

**QED:** Ligand B (0.736) has a better QED score than Ligand A (0.347), suggesting a more drug-like profile overall.

**DILI:** Ligand A (66.266) has a lower DILI risk than Ligand B (74.99), which is favorable. Both are acceptable, but A is better.

**BBB:** This is critical for a CNS target. Ligand A (35.014) has a very poor BBB percentile, while Ligand B (13.765) is also low, but slightly better. Both are far from the desirable >70.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.666 and -5.381), which is unusual and suggests poor permeability.

**Aqueous Solubility:** Both ligands have negative solubility values (-2.554 and -2.726), indicating very poor aqueous solubility. This is a significant drawback.

**hERG Inhibition:** Ligand A (0.736) has a slightly higher hERG inhibition risk than Ligand B (0.054), which is unfavorable. B is much better here.

**Microsomal Clearance:** Ligand A (-30.593) has a much lower (better) microsomal clearance than Ligand B (-18.321), indicating greater metabolic stability.

**In vitro Half-Life:** Ligand A (10.73) has a longer half-life than Ligand B (-5.058), which is desirable.

**P-gp Efflux:** Ligand A (0.061) has a lower P-gp efflux liability than Ligand B (0.023), meaning it's less likely to be pumped out of the brain, which is good for CNS penetration.

**Binding Affinity:** Both ligands have very similar and strong binding affinities (-8.4 kcal/mol and -8.6 kcal/mol). The difference is negligible.

**Overall Assessment:**

Despite Ligand B having a better QED and lower hERG risk, Ligand A is the more promising candidate. The critical factor is metabolic stability (Cl_mic and t1/2). Ligand A has significantly better metabolic stability and a longer half-life. While both have poor BBB penetration, the lower P-gp efflux of Ligand A might allow for slightly better CNS exposure. The TPSA of Ligand A is also more favorable. The slight advantage in DILI risk also favors Ligand A. The solubility and Caco-2 permeability are poor for both, but these can be addressed with formulation strategies.

Output:
0
2025-04-17 08:00:43,568 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (357.36 and 356.46 Da) fall comfortably within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (110.52) is higher than the preferred <90 for CNS targets, while Ligand B (49.41) is well within the range. This is a significant advantage for Ligand B.

**3. logP:** Both ligands have good logP values (2.19 and 3.15), falling within the optimal 1-3 range.

**4. H-Bond Donors:** Ligand A has 3 HBD, acceptable. Ligand B has 1 HBD, also acceptable.

**5. H-Bond Acceptors:** Ligand A has 4 HBA, acceptable. Ligand B has 2 HBA, also acceptable.

**6. QED:** Both ligands have good QED scores (0.75 and 0.841), indicating good drug-like properties.

**7. DILI:** Ligand A has a DILI risk of 63.09%, which is moderately high. Ligand B has a much lower DILI risk of 15.32%, a significant advantage.

**8. BBB:** Ligand A has a BBB penetration of 68.40%, which is okay but not ideal for a CNS target. Ligand B has a very good BBB penetration of 89.03%, exceeding the >70% threshold. This is a major advantage for Ligand B.

**9. Caco-2 Permeability:** Both have negative Caco-2 values (-4.98 and -4.56). This is unusual and suggests potential issues with intestinal absorption, but the scale is not clearly defined. It's difficult to draw strong conclusions from this.

**10. Aqueous Solubility:** Both have negative solubility values (-3.74 and -3.88), again suggesting potential formulation challenges. Similar to Caco-2, the scale makes interpretation difficult.

**11. hERG Inhibition:** Both ligands have low hERG inhibition risk (0.533 and 0.68), which is good.

**12. Microsomal Clearance:** Ligand A has a higher microsomal clearance (49.30) than Ligand B (20.08), suggesting lower metabolic stability.

**13. In vitro Half-Life:** Ligand A has a negative half-life (-23.63), which is problematic. Ligand B has a negative half-life (-8.58), also problematic, but less so than Ligand A.

**14. P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.045 and 0.066), which is excellent for CNS penetration.

**15. Binding Affinity:** Both ligands have the same binding affinity (-8.6 kcal/mol), which is excellent.

**Overall Assessment:**

Ligand B is the superior candidate. While both have excellent binding affinity and low P-gp efflux, Ligand B significantly outperforms Ligand A in crucial areas for a CNS-targeting GPCR ligand: lower TPSA, much lower DILI risk, and significantly better BBB penetration. Although both have negative values for Caco-2 and Solubility, the other advantages of Ligand B outweigh these concerns. The lower microsomal clearance and less negative in vitro half-life also favor Ligand B.

Output:
1
2025-04-17 08:00:43,568 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (337.47 & 351.44 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (54.02) is significantly better than Ligand B (77.02). For CNS targets, we want TPSA <= 90, and A is comfortably within that range, while B is approaching the upper limit.

**3. logP:** Ligand A (3.883) is optimal (1-3), while Ligand B (2.146) is on the lower side. While not terrible, lower logP can sometimes hinder permeability.

**4. H-Bond Donors:** Both have 2 HBD, which is within the acceptable limit of <=5.

**5. H-Bond Acceptors:** Ligand A has 2 HBA, while Ligand B has 6.  Ligand A is preferable as it is closer to the ideal of <=10.

**6. QED:** Ligand A (0.87) has a much better QED score than Ligand B (0.664), indicating better overall drug-likeness.

**7. DILI:** Ligand A (38.62) has a lower DILI risk than Ligand B (8.918), which is a significant advantage.

**8. BBB:** Ligand A (80.419) has a substantially higher BBB penetration percentile than Ligand B (63.513). This is *critical* for a CNS target like DRD2.

**9. Caco-2:** Both have negative Caco-2 values, which is unusual and difficult to interpret without context. However, the magnitude of the negative value is similar.

**10. Solubility:** Both have negative solubility values, also unusual. Again, similar magnitudes.

**11. hERG:** Ligand A (0.846) has a slightly higher hERG risk than Ligand B (0.507), but both are relatively low.

**12. Cl_mic:** Ligand A (29.416) has a lower microsomal clearance than Ligand B (64.41), suggesting better metabolic stability.

**13. t1/2:** Ligand A (33.684) has a significantly longer in vitro half-life than Ligand B (-13.794). This is a major advantage.

**14. Pgp:** Ligand A (0.199) has lower P-gp efflux liability than Ligand B (0.152), which is favorable for CNS penetration.

**15. Binding Affinity:** Ligand A (-10.5 kcal/mol) has a *much* stronger binding affinity than Ligand B (-7.7 kcal/mol). This difference of 2.8 kcal/mol is substantial and can outweigh minor ADME drawbacks.

**Overall Assessment:**

Ligand A is clearly superior. It excels in critical areas for CNS GPCR targets: BBB penetration, metabolic stability (lower Cl_mic, longer t1/2), binding affinity, and drug-likeness (QED). While Ligand B has a slightly lower hERG risk, the significant advantages of Ligand A in other key properties make it the more promising drug candidate.

Output:
1
2025-04-17 08:00:43,568 - INFO - Reasoning:

Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (372.774 and 364.829 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (55.17) is significantly better than Ligand B (80.57). For CNS targets, we want TPSA <= 90, and A is comfortably within that, while B is approaching the upper limit.

**3. logP:** Ligand A (4.988) is slightly higher than the optimal 1-3 range, but still potentially acceptable. Ligand B (3.645) is within the optimal range. However, given DRD2 is a CNS target, a slightly higher logP isn't necessarily detrimental if other properties are favorable.

**4. H-Bond Donors:** Ligand A (1) is preferable to Ligand B (2). Fewer HBDs generally improve permeability.

**5. H-Bond Acceptors:** Ligand A (3) is preferable to Ligand B (4). Fewer HBAs generally improve permeability.

**6. QED:** Both ligands have good QED scores (A: 0.574, B: 0.785), indicating good drug-like properties. B is slightly better here.

**7. DILI:** Both have acceptable DILI risk (A: 47.15, B: 63.746), with A being slightly better.

**8. BBB:** Ligand A (65.374) and Ligand B (61.574) are both reasonably good, but below the >70% threshold for strong CNS preference. A is slightly better.

**9. Caco-2:** Both have negative Caco-2 values (-4.939 and -4.768), which is unusual and suggests poor permeability. This is a significant concern for both.

**10. Solubility:** Both have very poor aqueous solubility (-5.018 and -4.652). This is a major drawback for both compounds.

**11. hERG:** Both have low hERG inhibition liability (A: 0.941, B: 0.738), which is good.

**12. Cl_mic:** Ligand A (14.308) has a lower microsomal clearance than Ligand B (55.728), indicating better metabolic stability. This is a significant advantage.

**13. t1/2:** Ligand B (66.428) has a longer in vitro half-life than Ligand A (47.033), which is desirable.

**14. Pgp:** Both have low P-gp efflux liability (A: 0.499, B: 0.5).

**15. Binding Affinity:** Ligand A (-9.7 kcal/mol) has a significantly stronger binding affinity than Ligand B (-8.9 kcal/mol). This is a substantial advantage, potentially outweighing some of the ADME drawbacks.

**Overall Assessment:**

Ligand A is the better candidate despite some ADME concerns. Its significantly stronger binding affinity (-9.7 vs -8.9 kcal/mol) is a major advantage for a GPCR target. It also has a better TPSA, fewer H-bonds, better DILI, and lower Cl_mic. While both have poor solubility and Caco-2 permeability, the stronger binding of A suggests it might still be able to achieve sufficient target engagement *in vivo*. The slightly better BBB for A is also a plus. Ligand B's longer half-life is a benefit, but the weaker binding and higher TPSA are less desirable.

Output:
0
2025-04-17 08:00:43,568 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (354.403 and 345.447 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (81.45) is significantly better than Ligand B (88.91). For CNS targets, we want TPSA <= 90, and A is closer to the ideal <= 60.

**logP:** Ligand A (0.795) is a bit low, potentially hindering permeability, but still within an acceptable range. Ligand B (1.579) is better, falling within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A (0 HBD, 7 HBA) is preferable to Ligand B (2 HBD, 5 HBA). Lower HBD/HBA generally improves permeability. Both are within acceptable limits.

**QED:** Both ligands have similar and good QED values (0.504 and 0.525, respectively), indicating good drug-like properties.

**DILI:** Both ligands have acceptable DILI risk (40.869 and 47.887, both < 60).

**BBB:** This is a critical parameter for a CNS target like DRD2. Ligand A (83.288) has a much higher BBB percentile than Ligand B (58.511). This is a major advantage for A.

**Caco-2 Permeability:** Ligand A (-4.192) is worse than Ligand B (-5.414). Lower values indicate poorer permeability.

**Aqueous Solubility:** Ligand A (-0.899) is better than Ligand B (-1.76). Higher solubility is generally preferred.

**hERG Inhibition:** Ligand A (0.766) is better than Ligand B (0.063), indicating a lower risk of cardiotoxicity.

**Microsomal Clearance:** Ligand B (36.844) has lower microsomal clearance than Ligand A (60.692), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand B (-9.136) has a longer half-life than Ligand A (9.155).

**P-gp Efflux:** Ligand A (0.104) has lower P-gp efflux than Ligand B (0.057), which is favorable for CNS penetration.

**Binding Affinity:** Ligand B (-7.9 kcal/mol) has a slightly better binding affinity than Ligand A (-6.9 kcal/mol). This 1 kcal/mol difference is significant.

**Overall Assessment:**

While Ligand B has slightly better affinity and metabolic stability, Ligand A is superior in several key areas for a CNS-targeting GPCR ligand. Specifically, its significantly higher BBB penetration (83.288 vs 58.511), lower TPSA (81.45 vs 88.91), better hERG profile, and lower P-gp efflux are crucial advantages. The slightly lower affinity of A can potentially be optimized in subsequent iterations, but improving BBB penetration is often more challenging. The logP of A is a minor concern, but not a dealbreaker.

Output:
1
2025-04-17 08:00:43,568 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (362.47 and 351.447 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (52.57) is excellent, well below the 90 A^2 threshold for CNS targets. Ligand B (112.73) is higher, but still potentially acceptable, although less ideal.

**logP:** Ligand A (3.589) is optimal. Ligand B (0.014) is very low, which is a significant concern for membrane permeability and CNS penetration.

**H-Bond Donors/Acceptors:** Ligand A (2 HBD, 3 HBA) is good. Ligand B (3 HBD, 4 HBA) is also reasonable.

**QED:** Ligand A (0.873) is excellent, indicating high drug-likeness. Ligand B (0.626) is still acceptable, but lower.

**DILI:** Ligand A (38.852) has a low DILI risk. Ligand B (14.23) also has a low DILI risk.

**BBB:** Ligand A (88.988) has excellent BBB penetration potential. Ligand B (50.33) is significantly lower, raising concerns about reaching the target in the CNS.

**Caco-2 Permeability:** Ligand A (-4.598) is concerningly low. Ligand B (-5.354) is also low, but slightly better.

**Aqueous Solubility:** Ligand A (-3.831) is poor. Ligand B (-1.944) is also poor.

**hERG Inhibition:** Ligand A (0.763) has a moderate hERG risk. Ligand B (0.091) has a very low hERG risk, which is a significant advantage.

**Microsomal Clearance:** Ligand A (20.824) has moderate clearance. Ligand B (8.737) has lower clearance, indicating better metabolic stability.

**In vitro Half-Life:** Ligand A (49.767) has a reasonable half-life. Ligand B (-2.934) has a very short half-life, which is a major drawback.

**P-gp Efflux:** Ligand A (0.494) has moderate P-gp efflux. Ligand B (0.006) has very low P-gp efflux, which is favorable for CNS penetration.

**Binding Affinity:** Ligand A (-10.2 kcal/mol) has significantly stronger binding affinity than Ligand B (-7.7 kcal/mol). This is a substantial advantage.

**Overall Assessment:**

Ligand A excels in BBB penetration and binding affinity, which are crucial for a CNS GPCR target like DRD2. However, it has poor Caco-2 permeability and aqueous solubility. Ligand B has a better safety profile (lower hERG, lower DILI) and metabolic stability, but suffers from very poor logP, BBB penetration, and a significantly weaker binding affinity. The large difference in binding affinity (-10.2 vs -7.7 kcal/mol) is a major factor. While Ligand A's solubility and permeability are concerns, these can potentially be addressed through formulation strategies. The poor CNS penetration of Ligand B is a more difficult hurdle to overcome.

Output:
1
2025-04-17 08:00:43,568 - INFO - Reasoning:

Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (358.423 and 346.446 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (104.21) is higher than the preferred <90 for CNS targets, while Ligand B (49.41) is excellent. This is a significant advantage for Ligand B.

**3. logP:** Both ligands have good logP values (1.774 and 3.153), falling within the optimal 1-3 range.

**4. H-Bond Donors:** Ligand A (3) is acceptable, while Ligand B (1) is even better, potentially improving permeability.

**5. H-Bond Acceptors:** Ligand A (6) is acceptable, and Ligand B (2) is also good.

**6. QED:** Both ligands have good QED scores (0.756 and 0.89), indicating good drug-like properties.

**7. DILI:** Both ligands have acceptable DILI risk (71.501 and 29.236), below the concerning threshold of 60. Ligand B is preferable.

**8. BBB:** This is critical for a CNS target. Ligand A (28.848) is quite low, indicating poor BBB penetration. Ligand B (96.355) is excellent, exceeding the desirable >70 threshold. This is a major advantage for Ligand B.

**9. Caco-2 Permeability:** Both have negative values, which is unusual and requires careful interpretation. Lower values indicate poorer permeability.

**10. Aqueous Solubility:** Both have negative values, indicating poor solubility.

**11. hERG Inhibition:** Both ligands show low hERG inhibition liability (0.108 and 0.777), which is good.

**12. Microsomal Clearance:** Both have similar microsomal clearance values (37.81 and 36.009), suggesting comparable metabolic stability.

**13. In vitro Half-Life:** Ligand B (-4.913) has a longer half-life than Ligand A (-1.795), which is favorable.

**14. P-gp Efflux:** Both ligands show low P-gp efflux liability (0.035 and 0.34), which is good.

**15. Binding Affinity:** Ligand B (-9.1 kcal/mol) has a slightly better binding affinity than Ligand A (-8.3 kcal/mol). While the difference is not huge, it contributes to the overall preference for Ligand B.

**Overall Assessment:**

Ligand B is significantly better suited as a drug candidate for DRD2. Its superior BBB penetration (96.355 vs. 28.848), lower TPSA (49.41 vs. 104.21), longer half-life, and slightly improved binding affinity outweigh any minor drawbacks. The lower TPSA and higher BBB are particularly important for a CNS GPCR target like DRD2.

Output:
1
2025-04-17 08:00:43,568 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (351.407 and 349.391 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (125.35) is slightly above the optimal <90 for CNS targets, but still reasonable. Ligand B (107.77) is better, falling comfortably below 90.

**3. logP:** Ligand A (-0.916) is a bit low, potentially hindering permeation. Ligand B (-1.264) is also low, but slightly lower than A. Both are below the optimal 1-3 range.

**4. H-Bond Donors:** Ligand A (4) is acceptable. Ligand B (2) is also acceptable and slightly better.

**5. H-Bond Acceptors:** Both ligands (6) are within the acceptable limit of <=10.

**6. QED:** Ligand A (0.451) is below the desirable threshold of 0.5. Ligand B (0.69) is above this threshold, indicating a better drug-like profile.

**7. DILI:** Both ligands have low DILI risk (39.201 and 25.553), both well below the 40 threshold.

**8. BBB:** This is a critical parameter for CNS targets. Ligand A (24.351) has a very low BBB percentile, which is a major drawback. Ligand B (49.011) is significantly better, although still not ideal (aim for >70).

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.187 and -5.197), which is unusual and suggests poor permeability. This is a concern for both.

**10. Aqueous Solubility:** Both ligands have negative solubility values (-1.477 and -0.795), which is also unusual and suggests poor solubility.

**11. hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.075 and 0.204).

**12. Microsomal Clearance:** Ligand A (1.256) has a lower clearance than Ligand B (-8.111), suggesting better metabolic stability.

**13. In vitro Half-Life:** Ligand A (-8.349) has a longer half-life than Ligand B (-3.856).

**14. P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.007 and 0.013).

**15. Binding Affinity:** Ligand B (-8.5 kcal/mol) has a slightly better binding affinity than Ligand A (-7.6 kcal/mol). While both are good, the 0.9 kcal/mol difference is notable.

**Overall Assessment:**

Ligand B is the stronger candidate. While both have issues with Caco-2 and solubility, Ligand B has a significantly better BBB percentile, a better QED score, and a slightly improved binding affinity. The better BBB penetration is crucial for a CNS target like DRD2. Although Ligand A has better metabolic stability and half-life, the poor BBB penetration is a deal-breaker.



Output:
1
2025-04-17 08:00:43,569 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (387.933 and 340.383 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (73.74) is better than Ligand B (79.54). Both are reasonably good for CNS penetration, being below 90, but A is closer to the optimal <60 for CNS targets.

**3. logP:** Both ligands have good logP values (2.513 and 1.753), falling within the 1-3 range. Ligand B is slightly lower, potentially impacting permeability, but both are acceptable.

**4. H-Bond Donors:** Ligand A has 1 HBD, and Ligand B has 0. Both are within the acceptable limit of <=5.

**5. H-Bond Acceptors:** Both ligands have 5 HBAs, which is within the acceptable limit of <=10.

**6. QED:** Both ligands have similar QED values (0.861 and 0.832), indicating good drug-likeness.

**7. DILI:** Ligand A (46.336) has a significantly lower DILI risk than Ligand B (63.668). This is a substantial advantage for Ligand A.

**8. BBB:** Ligand A (53.044) has a better BBB percentile than Ligand B (44.591), although both are below the desirable >70 for CNS targets.

**9. Caco-2:** Both have negative Caco-2 values (-4.648 and -4.879). This is unusual and suggests poor permeability. However, these values are on a scale where negative values are possible, and their relative comparison isn't straightforward.

**10. Solubility:** Ligand A (-3.12) has slightly better solubility than Ligand B (-2.306), although both are poor.

**11. hERG:** Both ligands have very low hERG risk (0.432 and 0.242).

**12. Cl_mic:** Ligand A (32.035) has a slightly lower microsomal clearance than Ligand B (25.622), suggesting better metabolic stability.

**13. t1/2:** Ligand B (29.064) has a longer in vitro half-life than Ligand A (25.547).

**14. Pgp:** Ligand A (0.573) has a lower P-gp efflux liability than Ligand B (0.146), which is favorable for CNS penetration.

**15. Binding Affinity:** Ligand B (-9.1 kcal/mol) has a significantly stronger binding affinity than Ligand A (-7.6 kcal/mol). This is a >1.5 kcal/mol difference, a major advantage.

**Overall Assessment:**

While Ligand A has better DILI, BBB, Pgp, and Cl_mic profiles, the substantially stronger binding affinity of Ligand B (-9.1 vs -7.6 kcal/mol) is the most critical factor for a GPCR ligand. The difference in affinity is significant enough to potentially overcome the slightly higher DILI and lower BBB values of Ligand B, especially considering optimization can address these ADME properties. The poor Caco-2 and solubility are concerning for both, but can be addressed with formulation strategies.

Output:
1
2025-04-17 08:00:43,569 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (396.292 Da) is slightly higher than Ligand B (353.522 Da), but both are acceptable.

**TPSA:** Ligand A (58.53) is higher than Ligand B (29.54). For CNS targets, we prefer TPSA <= 90, so both are within range, but Ligand B is significantly better.

**logP:** Both ligands have logP values around 4 (A: 4.109, B: 4.596). This is slightly high, potentially leading to solubility issues or off-target interactions, but not disqualifying.

**H-Bond Donors/Acceptors:** Ligand A has 2 HBD and 4 HBA, while Ligand B has 0 HBD and 2 HBA. Both are within acceptable limits (<=5 HBD and <=10 HBA).

**QED:** Both ligands have similar QED values (A: 0.534, B: 0.567), indicating good drug-like properties.

**DILI:** Ligand A (72.858) has a higher DILI risk than Ligand B (6.514). This is a significant advantage for Ligand B.

**BBB:** Ligand B (97.712) has a much higher BBB penetration percentile than Ligand A (68.282). This is *critical* for a CNS target like DRD2, making Ligand B highly favored.

**Caco-2 Permeability:** Ligand A (-5.532) has a negative Caco-2 value (scale is unclear, assuming lower is worse), while Ligand B (-4.534) is also negative. Both suggest poor intestinal absorption, but B is slightly better.

**Aqueous Solubility:** Both ligands have very poor aqueous solubility (-4.124 and -4.396). This is a concern, but can sometimes be mitigated with formulation strategies.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (A: 0.848, B: 0.964).

**Microsomal Clearance:** Ligand A (37.816) has lower microsomal clearance than Ligand B (86.472), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (28.953) has a longer in vitro half-life than Ligand B (-4.17). This is a positive for Ligand A.

**P-gp Efflux:** Ligand A (0.667) has lower P-gp efflux than Ligand B (0.874), which is preferable for CNS penetration.

**Binding Affinity:** Ligand B (-7.2 kcal/mol) has a significantly stronger binding affinity than Ligand A (-10.2 kcal/mol). This is a substantial advantage, potentially outweighing some of the ADME drawbacks of Ligand B.

**Overall Assessment:**

Ligand B is the stronger candidate. While both have solubility concerns and moderate logP values, Ligand B excels in the critical areas for a CNS GPCR target: *significantly* better BBB penetration, a much lower DILI risk, and a substantially stronger binding affinity. The better TPSA and slightly better Caco-2 permeability also contribute to its favorability. Although Ligand A has better metabolic stability and half-life, the superior CNS penetration and binding affinity of Ligand B are more important for DRD2 targeting.

Output:
1
2025-04-17 08:00:43,569 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight (MW):** Both ligands (350.5 and 352.4 Da) fall comfortably within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (59.4) is significantly better than Ligand B (84.0). For CNS targets, we want TPSA <= 90, and A is closer to the optimal <=60 range. B is pushing the upper limit.

**3. logP:** Both ligands have good logP values (3.42 and 2.36), falling within the 1-3 optimal range.

**4. H-Bond Donors (HBD):** Both are acceptable (1 and 2, respectively), well below the limit of 5.

**5. H-Bond Acceptors (HBA):** Both are acceptable (4 each), below the limit of 10.

**6. QED:** Both have good QED scores (0.82 and 0.85), indicating drug-like properties.

**7. DILI:** Ligand A (19.5) has a much lower DILI risk than Ligand B (43.8). This is a significant advantage.

**8. BBB:** Both ligands have excellent BBB penetration (90.8% and 87.4%), exceeding the desirable >70% threshold for CNS targets.

**9. Caco-2 Permeability:** Both have negative values (-4.174 and -4.82), which is unusual and likely indicates a scale issue or error in the data. However, the relative values suggest Ligand A may have slightly better permeability.

**10. Aqueous Solubility:** Both have negative values (-3.167 and -3.197), again likely a scale issue. The values are very similar.

**11. hERG Inhibition:** Ligand A (0.42) has a slightly higher hERG risk than Ligand B (0.09), but both are relatively low.

**12. Microsomal Clearance (Cl_mic):** Ligand A (75.5) has significantly higher clearance than Ligand B (24.4), meaning it's less metabolically stable. This is a drawback for Ligand A.

**13. In vitro Half-Life:** Ligand A (19.9) has a longer half-life than Ligand B (-0.99), which is a positive.

**14. P-gp Efflux:** Ligand A (0.15) has lower P-gp efflux than Ligand B (0.01), which is favorable for CNS penetration.

**15. Binding Affinity:** Ligand B (-8.2 kcal/mol) has a slightly better binding affinity than Ligand A (-7.4 kcal/mol). This 1.5 kcal/mol difference is significant and could outweigh some ADME drawbacks.

**Overall Assessment:**

Ligand B has a better binding affinity and lower microsomal clearance, indicating better metabolic stability. However, Ligand A has a significantly lower DILI risk, better TPSA, and lower P-gp efflux. The slightly longer half-life of Ligand A is also a plus. Given the GPCR-specific priorities, the lower TPSA and DILI risk of Ligand A, combined with acceptable BBB and logP values, make it the more promising candidate despite the slightly weaker binding affinity and higher clearance. The difference in binding affinity is not large enough to overcome the ADME advantages of Ligand A.

Output:
0
2025-04-17 08:00:43,569 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 drug candidates, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (340.39 and 345.44 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (106.81) is slightly above the optimal <90 for CNS targets, but still reasonable. Ligand B (66.65) is excellent, well below 90.

**logP:** Both ligands have good logP values (1.51 and 2.83), falling within the 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A has 2 HBDs and 5 HBAs, which is acceptable. Ligand B has 0 HBDs and 4 HBAs, also acceptable.

**QED:** Both ligands have QED values above 0.7, indicating good drug-likeness.

**DILI:** Ligand A (70.92) has a higher DILI risk than Ligand B (56.30), but both are still within a manageable range.

**BBB:** This is a critical parameter for a CNS target like DRD2. Ligand B (85.54) has a significantly higher BBB percentile than Ligand A (50.68). This is a major advantage for Ligand B.

**Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and suggests poor permeability. However, these values are on a different scale and hard to interpret directly.

**Aqueous Solubility:** Both ligands have negative solubility values, which is also unusual and suggests poor solubility.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.49 and 0.30).

**Microsomal Clearance:** Ligand A (2.76) has a much lower microsomal clearance than Ligand B (70.33), indicating better metabolic stability.

**In vitro Half-Life:** Ligand A (10.40 hours) has a significantly longer half-life than Ligand B (-25.21 hours). The negative value for Ligand B is concerning and likely an artifact or error in the data.

**P-gp Efflux:** Ligand A (0.054) has a much lower P-gp efflux liability than Ligand B (0.457), which is favorable for CNS penetration.

**Binding Affinity:** Ligand A (-8.9 kcal/mol) has a slightly better binding affinity than Ligand B (-7.8 kcal/mol), though both are strong binders. The 1.1 kcal/mol difference is significant.

**Overall Assessment:**

Ligand B excels in BBB penetration and TPSA, which are crucial for CNS GPCR targets. However, it suffers from very high microsomal clearance, a negative in vitro half-life, and higher P-gp efflux. Ligand A has a better metabolic profile (lower Cl_mic, longer t1/2, lower Pgp), but its BBB penetration is significantly lower. The affinity difference, while present, is likely outweighed by the ADME advantages of Ligand A.

Considering the importance of CNS penetration for DRD2, and the more favorable ADME profile of Ligand A, I believe Ligand A is the more promising candidate.

Output:
0
2025-04-17 08:00:43,569 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 drug candidates, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (350.547 and 361.515 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (40.62) is excellent, well below the 90 A^2 threshold for CNS targets. Ligand B (74.81) is higher but still potentially acceptable, though less ideal.

**3. logP:** Ligand A (4.088) is at the upper end of the optimal range (1-3), potentially leading to solubility issues. Ligand B (2.759) is well within the optimal range.

**4. H-Bond Donors:** Both ligands have 0 HBDs, which is acceptable.

**5. H-Bond Acceptors:** Ligand A has 2 HBAs, and Ligand B has 6 HBAs. Both are within the acceptable limit of 10.

**6. QED:** Both ligands have good QED scores (0.694 and 0.779), indicating drug-like properties.

**7. DILI:** Ligand A (13.649) has a very low DILI risk, significantly better than Ligand B (32.454).

**8. BBB:** Ligand A (95.657) has excellent BBB penetration, exceeding the desirable >70% threshold. Ligand B (72.896) is good but less favorable. This is a critical factor for a CNS target like DRD2.

**9. Caco-2 Permeability:** Ligand A (-4.451) has poor Caco-2 permeability, which is concerning. Ligand B (-5.21) is also poor, but slightly worse.

**10. Aqueous Solubility:** Ligand A (-4.058) has poor aqueous solubility, consistent with its higher logP. Ligand B (-2.745) is also poor, but better than Ligand A.

**11. hERG Inhibition:** Both ligands have low hERG inhibition risk (0.601 and 0.35).

**12. Microsomal Clearance:** Ligand A (84.488) has higher microsomal clearance, suggesting lower metabolic stability. Ligand B (58.405) has lower clearance and better metabolic stability.

**13. In vitro Half-Life:** Ligand A (3.452) has a short half-life. Ligand B (-15.1) has a very long half-life, which is a significant advantage.

**14. P-gp Efflux:** Both ligands have low P-gp efflux liability (0.391 and 0.236).

**15. Binding Affinity:** Ligand A (-7.3) has a slightly better binding affinity than Ligand B (-6.8), but the difference is not substantial enough to overcome other significant drawbacks.

**Overall Assessment:**

Ligand A excels in BBB penetration, DILI risk, and binding affinity. However, its poor Caco-2 permeability, aqueous solubility, and metabolic stability are major concerns. Ligand B has a more balanced profile, with better metabolic stability (lower Cl_mic, longer t1/2), a more favorable logP, and acceptable BBB penetration. While its affinity is slightly lower, the other improvements outweigh this difference, especially considering the importance of ADME properties for CNS drug development.

Output:
1
2025-04-17 08:00:43,569 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (335.367 Da) is slightly lower, which could be beneficial for permeability.

**2. TPSA:** Both ligands have TPSA values below 140, suggesting reasonable oral absorption. Ligand A (98.81) is closer to the 90 threshold desirable for CNS targets than Ligand B (93.9).

**3. logP:** Both ligands have logP values within the optimal range (1-3). Ligand A (2.751) is slightly higher than Ligand B (1.614), potentially offering better membrane permeability but also a slightly increased risk of off-target interactions.

**4. H-Bond Donors:** Both have 1 HBD, which is acceptable.

**5. H-Bond Acceptors:** Ligand A has 5 HBAs, and Ligand B has 6. Both are within the acceptable limit of 10.

**6. QED:** Both ligands have QED values above 0.5 (0.776 and 0.73), indicating good drug-like properties.

**7. DILI:** Ligand A (82.513) has a higher DILI risk than Ligand B (50.136). This is a significant drawback for Ligand A.

**8. BBB:** Ligand B (81.039) has a significantly better BBB penetration percentile than Ligand A (64.754). This is crucial for a CNS target like DRD2.

**9. Caco-2 Permeability:** Ligand A (-5.148) has worse Caco-2 permeability than Ligand B (-4.678), suggesting lower intestinal absorption.

**10. Aqueous Solubility:** Ligand A (-3.824) has worse solubility than Ligand B (-2.63).

**11. hERG Inhibition:** Both ligands have low hERG inhibition risk (0.453 and 0.263).

**12. Microsomal Clearance:** Both ligands have similar microsomal clearance (25.01 and 25.418).

**13. In vitro Half-Life:** Ligand A (6.391) has a slightly longer half-life than Ligand B (-5.144).

**14. P-gp Efflux:** Both ligands have low P-gp efflux liability (0.189 and 0.168).

**15. Binding Affinity:** Ligand B (-7.7) has a slightly better binding affinity than Ligand A (-7.6). While the difference is small, it's still a positive for Ligand B.

**Overall Assessment:**

Ligand B is the more promising candidate. While the binding affinity difference is small, Ligand B demonstrates significantly better BBB penetration, lower DILI risk, and better solubility and Caco-2 permeability. The slightly lower logP of Ligand B might be preferable given the importance of CNS penetration. Ligand A's higher DILI risk is a major concern. Considering the GPCR-specific priorities, Ligand B is the superior choice.

Output:
1
2025-04-17 08:00:43,569 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (358.364 and 362.459 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (72.09) is better than Ligand B (74.57), both are below the 90 A^2 threshold for CNS targets, which is good.

**logP:** Ligand A (2.908) is optimal (1-3), while Ligand B (0.141) is quite low, potentially hindering membrane permeability. This is a significant drawback for a CNS target.

**H-Bond Donors:** Ligand A (2) is within the acceptable limit of 5. Ligand B (0) is also good.

**H-Bond Acceptors:** Ligand A (4) is within the acceptable limit of 10. Ligand B (7) is also acceptable.

**QED:** Both ligands have similar QED values (0.799 and 0.756), indicating good drug-likeness.

**DILI:** Ligand A (39.046) has a slightly better DILI score than Ligand B (46.375), both are below the concerning threshold of 60.

**BBB:** Ligand A (67.701) has a better BBB percentile than Ligand B (50.95). While 67.7% isn't outstanding, it's considerably better than 50.95% for a CNS target.

**Caco-2 Permeability:** Ligand A (-4.909) has a worse Caco-2 permeability than Ligand B (-5.222). Lower values are less desirable.

**Aqueous Solubility:** Ligand A (-2.79) has better Aqueous Solubility than Ligand B (-0.446).

**hERG:** Ligand A (0.628) has a better hERG score than Ligand B (0.31), indicating lower cardiotoxicity risk.

**Microsomal Clearance:** Ligand A (20.698) and Ligand B (22.38) are similar.

**In vitro Half-Life:** Ligand A (30.089) has a better in vitro half-life than Ligand B (-6.785).

**P-gp Efflux:** Ligand A (0.213) has a better P-gp efflux profile than Ligand B (0.024), which is crucial for CNS penetration.

**Binding Affinity:** Ligand A (-8.4 kcal/mol) has a significantly better binding affinity than Ligand B (-7.4 kcal/mol). This 1.0 kcal/mol difference is substantial and can outweigh some minor ADME drawbacks.

**Conclusion:**

Considering all factors, especially the GPCR-specific priorities, **Ligand A is the more promising drug candidate**. While Ligand B has slightly better Caco-2 permeability, Ligand A excels in crucial areas: logP (optimal vs. very low), BBB penetration (67.7% vs 50.95%), P-gp efflux (better), and, most importantly, binding affinity (-8.4 vs -7.4 kcal/mol). The better binding affinity of Ligand A is a major advantage.

Output:
1
2025-04-17 08:00:43,569 - INFO - Batch 413 complete. Total preferences: 6608
2025-04-17 08:00:43,569 - INFO - Processing batch 414/512...
2025-04-17 08:01:27,110 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (357.435 and 365.499 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (95.13) is slightly higher than Ligand B (80.32). For CNS targets, we ideally want TPSA <= 90, so both are acceptable, but B is better.

**logP:** Both ligands have good logP values (2.766 and 2.168), falling within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Both have 2 HBD and 5 HBA, which are within acceptable limits.

**QED:** Both ligands have good QED scores (0.745 and 0.776), indicating good drug-like properties.

**DILI:** Ligand A (72.199) has a higher DILI risk than Ligand B (43.622). B is preferable here.

**BBB:** This is critical for a CNS target. Ligand B (53.974) has a significantly better BBB penetration percentile than Ligand A (30.593). This is a major advantage for B.

**Caco-2 Permeability:** Both have negative Caco-2 values (-5.204 and -4.818), which is unusual and suggests poor permeability. However, these values are on a scale where negative values are possible and don't necessarily disqualify a compound.

**Aqueous Solubility:** Both have negative solubility values (-4.23 and -2.682), indicating poor aqueous solubility. This could be a formulation challenge, but not a dealbreaker at this stage.

**hERG Inhibition:** Both ligands show low hERG inhibition liability (0.477 and 0.159), which is good.

**Microsomal Clearance:** Ligand B (30.491) has lower microsomal clearance than Ligand A (61.326), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand B (23.411) has a shorter in vitro half-life than Ligand A (48.86). A is better here.

**P-gp Efflux:** Ligand A (0.332) has higher P-gp efflux liability than Ligand B (0.068). B is preferable.

**Binding Affinity:** Both ligands have identical binding affinities (-7.4 kcal/mol), which is excellent.

**Overall Assessment:**

Ligand B is the stronger candidate. While both have excellent binding affinity, Ligand B demonstrates superior ADME properties, particularly regarding BBB penetration (critical for CNS targets), lower DILI risk, and lower P-gp efflux. The lower microsomal clearance is also a benefit. Although Ligand A has a longer half-life, the other advantages of Ligand B outweigh this. The poor Caco-2 and solubility values are concerns for both, but can potentially be addressed with formulation strategies.

Output:
1
2025-04-17 08:01:27,110 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (358.5 and 341.4 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (69.64) is slightly above the ideal <90 for CNS targets, while Ligand B (54.78) is well within the range. This favors Ligand B.

**3. logP:** Ligand A (2.809) is optimal (1-3), while Ligand B (0.853) is a bit low, potentially hindering permeation. This favors Ligand A.

**4. H-Bond Donors:** Ligand A (2) is within the acceptable limit of <=5. Ligand B (0) is also good.

**5. H-Bond Acceptors:** Ligand A (3) is within the acceptable limit of <=10. Ligand B (4) is also good.

**6. QED:** Both ligands have reasonable QED values (0.666 and 0.589), suggesting good drug-like properties.

**7. DILI:** Ligand A (22.26) has a much lower DILI risk than Ligand B (38.81). This is a significant advantage for Ligand A.

**8. BBB:** Ligand A (71.54) has a good BBB penetration percentile, exceeding the desirable >70 threshold for CNS targets. Ligand B (56.81) is lower, which is a concern for CNS penetration. This strongly favors Ligand A.

**9. Caco-2:** Both have negative values which is unusual and not helpful for comparison.

**10. Solubility:** Both ligands have negative solubility values, which is unusual and not helpful for comparison.

**11. hERG:** Ligand A (0.634) and Ligand B (0.232) both have low hERG inhibition liability, which is good. Ligand B is slightly better.

**12. Cl_mic:** Ligand A (27.21) has a higher microsomal clearance than Ligand B (9.41), indicating lower metabolic stability. This favors Ligand B.

**13. t1/2:** Ligand A (5.235) has a slightly longer half-life than Ligand B (3.666), which is generally desirable.

**14. Pgp:** Ligand A (0.375) has higher P-gp efflux liability than Ligand B (0.062). Lower Pgp is better for CNS exposure, favoring Ligand B.

**15. Binding Affinity:** Ligand B (-7.5 kcal/mol) has a significantly stronger binding affinity than Ligand A (-6.8 kcal/mol). This is a substantial advantage for Ligand B, potentially outweighing some of its ADME drawbacks.

**Overall Assessment:**

While Ligand B has superior binding affinity and better Pgp efflux and metabolic stability, Ligand A demonstrates a significantly better BBB penetration, lower DILI risk, and acceptable logP and TPSA. Given that this is a CNS target (DRD2), BBB penetration is paramount. The stronger affinity of Ligand B is attractive, but the compromised BBB and higher DILI risk are significant concerns. The 0.7 kcal/mol difference in binding affinity may be overcome with further optimization of Ligand A.

Output:
1
2025-04-17 08:01:27,110 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (352.312 and 346.387 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (55.61) is excellent, well below the 90 A^2 threshold for CNS targets. Ligand B (95.86) is higher, but still potentially acceptable, though less ideal.

**logP:** Ligand A (4.226) is slightly high, potentially leading to solubility issues or off-target interactions. Ligand B (-0.606) is quite low, which could hinder membrane permeability and CNS penetration.

**H-Bond Donors/Acceptors:** Ligand A (0 HBD, 4 HBA) is favorable. Ligand B (1 HBD, 6 HBA) is also reasonable.

**QED:** Both ligands have good QED scores (0.61 and 0.731), indicating good drug-like properties.

**DILI:** Ligand A (77.394) has a higher DILI risk than Ligand B (60.721), but both are within an acceptable range.

**BBB:** Ligand A (82.629) has a significantly better BBB penetration score than Ligand B (41.295). This is a *critical* advantage for a CNS target like DRD2.

**Caco-2 Permeability:** Both have negative Caco-2 values (-4.819 and -4.881), which is unusual and suggests poor permeability. This is a concern for both.

**Aqueous Solubility:** Both ligands have very poor aqueous solubility (-5.73 and -0.63). This is a significant drawback.

**hERG Inhibition:** Ligand A (0.892) shows a slightly higher hERG risk than Ligand B (0.052), but both are relatively low.

**Microsomal Clearance:** Ligand A (44.792) has moderate clearance, while Ligand B (-0.095) has very low clearance, suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (-8.567) has a very short half-life, while Ligand B (0.052) has a very short half-life. Both are concerning.

**P-gp Efflux:** Ligand A (0.611) has moderate P-gp efflux, while Ligand B (0.006) has very low P-gp efflux, which is beneficial for CNS penetration.

**Binding Affinity:** Ligand B (-7.5 kcal/mol) has a significantly better binding affinity than Ligand A (-10.0 kcal/mol). This is a substantial advantage.

**Overall Assessment:**

While Ligand B has superior binding affinity and lower P-gp efflux, its very low logP and poor BBB penetration are major drawbacks for a CNS target. Ligand A, despite its higher logP and slightly worse affinity, has a much better BBB score. The poor solubility and permeability of both are concerning, but can potentially be addressed with formulation strategies. However, getting a drug into the brain is paramount for DRD2.

Considering the GPCR-specific priorities, particularly BBB penetration, and the significant affinity difference, Ligand B is the more promising candidate. The low logP is a concern, but the strong binding affinity may compensate.

Output:
1
2025-04-17 08:01:27,111 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (376.806 and 362.539 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (37.49) is significantly better than Ligand B (58.2).  For CNS targets, we want TPSA <= 90, and ideally closer to 60. Ligand A is much closer to the ideal range.

**logP:** Both ligands have good logP values (4.434 and 3.755), falling within the optimal 1-3 range. Ligand B is slightly better.

**H-Bond Donors/Acceptors:** Ligand A (HBD=1, HBA=3) and Ligand B (HBD=2, HBA=3) both have acceptable numbers of H-bond donors and acceptors.

**QED:** Both ligands have reasonable QED values (0.838 and 0.776), indicating good drug-like properties.

**DILI:** Ligand A (47.732) has a slightly higher DILI risk than Ligand B (36.603), but both are below the concerning threshold of 60.

**BBB:** This is crucial for a CNS target like DRD2. Ligand A has a significantly better BBB penetration percentile (90.035) compared to Ligand B (70.376).  A value >70 is desirable, and Ligand A exceeds this comfortably.

**Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and difficult to interpret without knowing the scale. However, the values are similar.

**Aqueous Solubility:** Both ligands have negative solubility values, again making direct comparison difficult.

**hERG Inhibition:** Both ligands have low hERG inhibition liability (0.939 and 0.622), which is good.

**Microsomal Clearance:** Ligand A (29.759) has a much lower microsomal clearance than Ligand B (82.547), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (-6.38) has a negative half-life, which is not possible and indicates an issue with the data. Ligand B (40.479) has a reasonable half-life.

**P-gp Efflux:** Ligand A (0.754) has lower P-gp efflux liability than Ligand B (0.451), which is favorable for CNS penetration.

**Binding Affinity:** Both ligands have excellent binding affinities (-8.4 and -8.8 kcal/mol). Ligand B is slightly better, but the difference is small.

**Overall Assessment:**

Ligand A excels in key areas for a CNS-targeting GPCR: TPSA, BBB penetration, P-gp efflux, and metabolic stability (lower Cl_mic). While Ligand B has slightly better logP and binding affinity, the superior CNS penetration profile of Ligand A is more critical. The negative half-life for Ligand A is a major concern, however. Given the importance of CNS penetration for DRD2, and the relatively small difference in binding affinity, Ligand A is the better candidate *if* the half-life data is corrected or re-evaluated.

Output:
1
2025-04-17 08:01:27,111 - INFO - Reasoning:

Let's analyze Ligand A and Ligand B based on the provided guidelines, prioritizing GPCR-specific properties (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (348.443 and 354.491 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (68.82) is significantly better than Ligand B (75.71). For CNS targets, TPSA should be <= 90, both are within this range, but A is preferable.

**logP:** Both ligands (2.389 and 2.652) are within the optimal 1-3 range.

**H-Bond Donors:** Ligand A (2) is slightly higher than Ligand B (1), but both are acceptable (<=5).

**H-Bond Acceptors:** Both ligands (4) are well within the acceptable range (<=10).

**QED:** Ligand A (0.708) has a better QED score than Ligand B (0.483), indicating a more drug-like profile.

**DILI:** Ligand A (33.889) has a slightly higher DILI risk than Ligand B (18.108), but both are below the concerning threshold of 60.

**BBB:** Both ligands have excellent BBB penetration (Ligand A: 73.401, Ligand B: 77.162), exceeding the desirable >70 threshold for CNS targets. Ligand B is slightly better.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values which is unusual. This suggests a potential issue with the data or a very poor permeability.

**Aqueous Solubility:** Both ligands have negative solubility values, which is also unusual. This suggests a potential issue with the data or very poor solubility.

**hERG:** Both ligands have very low hERG inhibition liability (0.465 and 0.459), which is excellent.

**Microsomal Clearance:** Ligand A (32.573) has significantly lower microsomal clearance than Ligand B (92.362), indicating better metabolic stability.

**In vitro Half-Life:** Ligand A (22.552) has a longer half-life than Ligand B (-17.64), which is preferable. The negative value for B is concerning.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.043 and 0.107), which is favorable for CNS penetration.

**Binding Affinity:** Ligand A (-8.3 kcal/mol) has a significantly stronger binding affinity than Ligand B (-7.3 kcal/mol). This 1 kcal/mol difference is substantial and can outweigh minor ADME drawbacks.

**Overall Assessment:**

Ligand A is the superior candidate. While Ligand B has a slightly better BBB score, Ligand A excels in crucial areas: significantly stronger binding affinity, better QED, lower microsomal clearance (better metabolic stability), and a longer in vitro half-life. The unusual negative values for Caco-2 and Solubility are concerning for both, but the overall profile of A is more promising. The substantial affinity advantage of Ligand A makes it the more likely viable drug candidate.

Output:
1
2025-04-17 08:01:27,111 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B based on the provided guidelines, prioritizing GPCR-specific properties (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (340.358 Da) is slightly lower than Ligand B (354.407 Da), but both are acceptable.

**TPSA:** Ligand A (88.0) is excellent for CNS penetration, falling well below the 90 Angstrom threshold. Ligand B (132.7) is higher, potentially hindering BBB penetration, but still within a reasonable range.

**logP:** Ligand A (2.427) is optimal. Ligand B (-0.008) is slightly negative, which could lead to poor membrane permeability.

**H-Bond Donors/Acceptors:** Ligand A (2 HBD, 5 HBA) is well within the acceptable limits. Ligand B (5 HBD, 5 HBA) is at the upper limit for HBD but acceptable.

**QED:** Ligand A (0.745) has a strong drug-like profile. Ligand B (0.403) is lower, suggesting a less ideal overall drug-like profile.

**DILI:** Ligand A (73.245) has a moderate DILI risk. Ligand B (29.624) has a very low DILI risk, which is a significant advantage.

**BBB:** Ligand A (66.576) has a good BBB percentile, but Ligand B (30.787) is quite low, indicating poor brain penetration. This is a critical disadvantage for a CNS target like DRD2.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.161 and -5.602), which is unusual and difficult to interpret. However, it suggests poor permeability.

**Aqueous Solubility:** Both ligands have negative solubility values (-3.591 and -1.093), which is also unusual.

**hERG:** Both ligands have very low hERG inhibition liability (0.519 and 0.113), which is excellent.

**Microsomal Clearance:** Ligand A (62.158) has moderate clearance, while Ligand B (1.888) has very low clearance, indicating better metabolic stability.

**In vitro Half-Life:** Ligand A (-15.735) has a negative half-life, which is not possible. Ligand B (26.947) has a reasonable half-life.

**P-gp Efflux:** Ligand A (0.214) has low P-gp efflux, which is good. Ligand B (0.013) also has very low P-gp efflux, which is even better.

**Binding Affinity:** Ligand B (-7.4 kcal/mol) has significantly stronger binding affinity than Ligand A (-10.4 kcal/mol). This is a substantial advantage.

**Overall Assessment:**

Ligand B has a significantly better binding affinity, lower DILI risk, and better metabolic stability. However, its BBB penetration is poor, and its logP is unfavorable. Ligand A has better BBB penetration and logP, but its binding affinity is weaker and has a non-sensical in vitro half-life.

Given the GPCR-specific priorities, especially for a CNS target like DRD2, BBB penetration is crucial. While Ligand B's affinity is much better, the poor BBB score is a major concern. The negative half-life for Ligand A is a red flag. Considering all factors, the superior binding affinity of Ligand B is likely to outweigh the poor BBB, assuming formulation strategies can be employed to enhance brain delivery.

Output:
1
2025-04-17 08:01:27,111 - INFO - Reasoning:

Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (341.415 and 345.407 Da) fall comfortably within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (90.12) is excellent, falling below the 90 threshold for CNS targets. Ligand B (97.94) is slightly higher but still reasonable.

**3. logP:** Ligand A (1.415) is optimal. Ligand B (0.647) is a bit low, potentially hindering permeability.

**4. H-Bond Donors:** Ligand A (3) is within the acceptable limit. Ligand B (1) is also good.

**5. H-Bond Acceptors:** Ligand A (3) is within the acceptable limit. Ligand B (7) is also within the acceptable limit.

**6. QED:** Both ligands have similar and good QED values (0.768 and 0.794, respectively), indicating good drug-like properties.

**7. DILI:** Ligand A (55.138) has a slightly higher DILI risk than Ligand B (62.001), but both are acceptable (<60 is preferred, but both are under 65).

**8. BBB:** This is crucial for a CNS target. Ligand A (80.419) has a significantly better BBB percentile than Ligand B (71.772). This is a major advantage for Ligand A.

**9. Caco-2:** Both ligands have negative Caco-2 values (-5.154 and -5.171), which is unusual and suggests poor permeability. This is a concern for both.

**10. Solubility:** Both ligands have negative solubility values (-2.99 and -2.38), which is also unusual and suggests poor solubility. This is a concern for both.

**11. hERG:** Both ligands have very low hERG inhibition liability (0.418 and 0.056), which is excellent.

**12. Cl_mic:** Ligand A (-2.118) has a much lower (better) microsomal clearance than Ligand B (21.385). This suggests greater metabolic stability for Ligand A.

**13. t1/2:** Ligand A (-8.829) has a much longer in vitro half-life than Ligand B (-0.516), indicating better persistence.

**14. Pgp:** Both ligands have very low Pgp efflux liability (0.024 and 0.048), which is excellent.

**15. Binding Affinity:** Ligand A (-9.6 kcal/mol) has a slightly better binding affinity than Ligand B (-8.1 kcal/mol). While both are good, the 1.5 kcal/mol difference is significant and can outweigh minor ADME drawbacks.

**Overall Assessment:**

Ligand A is the superior candidate. It has a better BBB score, significantly better metabolic stability (lower Cl_mic and longer t1/2), slightly better binding affinity, and a more optimal logP. While both have issues with Caco-2 and solubility, the improvements in CNS penetration and metabolic stability for Ligand A are critical for a DRD2 ligand.

Output:
1
2025-04-17 08:01:27,112 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (343.43 and 366.49 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (91.32) is slightly above the preferred <90 for CNS targets, while Ligand B (76.58) is well within the range. This gives a slight edge to Ligand B.

**logP:** Both ligands have logP values (2.32 and 2.58) within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A has 3 HBD and 4 HBA, while Ligand B has 1 HBD and 7 HBA. Both are acceptable, staying within the <5 HBD and <10 HBA guidelines.

**QED:** Both ligands have good QED scores (0.63 and 0.72), indicating drug-like properties.

**DILI:** Both ligands have similar DILI risk (39.20 and 60.95), with Ligand A being slightly better. Both are acceptable.

**BBB:** This is a crucial parameter for CNS targets. Ligand B (79.22) has a significantly better BBB percentile than Ligand A (60.68). This is a major advantage for Ligand B.

**Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual. However, the magnitude of negativity is similar (-5.02 and -4.78). This parameter is less informative in this context.

**Aqueous Solubility:** Both ligands have negative solubility values, which is also unusual. Again, the values are similar (-2.78 and -2.36).

**hERG Inhibition:** Ligand A (0.34) shows slightly lower hERG inhibition liability than Ligand B (0.75), which is preferable.

**Microsomal Clearance:** Ligand B (66.95) has a higher microsomal clearance than Ligand A (34.16), suggesting lower metabolic stability. This favors Ligand A.

**In vitro Half-Life:** Ligand B (63.23) has a significantly longer in vitro half-life than Ligand A (25.94), which is a positive for Ligand B.

**P-gp Efflux:** Ligand A (0.13) has lower P-gp efflux liability than Ligand B (0.31), which is beneficial for CNS penetration.

**Binding Affinity:** Ligand B (-7.2 kcal/mol) has a slightly better binding affinity than Ligand A (-8.5 kcal/mol). While A is better, the difference is not substantial enough to outweigh other factors.

**Overall Assessment:**

Ligand B excels in BBB penetration and in vitro half-life, both critical for a CNS-targeting GPCR ligand. Its slightly better binding affinity is also a plus. While Ligand A has a better hERG profile and lower microsomal clearance, the superior BBB penetration of Ligand B is the deciding factor given the target (DRD2). The TPSA of Ligand B is also more favorable.

Output:
1
2025-04-17 08:01:27,112 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (362.905 Da and 354.523 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (57.08) is higher than Ligand B (44.81). For a CNS target like DRD2, we ideally want TPSA <= 90, so both are acceptable, but B is better.

**3. logP:** Ligand A (3.184) and Ligand B (4.236) are both within the optimal 1-3 range, but B is slightly higher. While generally good, a logP >4 can be problematic, so B is approaching that limit.

**4. H-Bond Donors:** Ligand A (2) and Ligand B (1) are both acceptable (<=5).

**5. H-Bond Acceptors:** Both ligands (A: 4, B: 4) are within the acceptable range (<=10).

**6. QED:** Both ligands have similar QED values (A: 0.673, B: 0.625), indicating good drug-like properties.

**7. DILI:** Ligand A (14.541) has a significantly lower DILI risk than Ligand B (42.536). This is a major advantage for Ligand A.

**8. BBB:** Ligand A (32.532) has a lower BBB penetration percentile than Ligand B (55.099). For a CNS target, higher BBB is crucial. This favors Ligand B.

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.122 and -5.656), which is unusual and suggests poor permeability. This is a concern for both.

**10. Aqueous Solubility:** Both ligands have negative solubility values (-3.362 and -3.677), also indicating poor aqueous solubility. This is a concern for both.

**11. hERG Inhibition:** Both ligands have low hERG inhibition risk (A: 0.775, B: 0.853).

**12. Microsomal Clearance:** Ligand A (11.488) has a lower microsomal clearance than Ligand B (54.679), indicating better metabolic stability. This is a significant advantage for Ligand A.

**13. In vitro Half-Life:** Ligand A (85.89) has a much longer in vitro half-life than Ligand B (35.696). This is a substantial benefit for Ligand A.

**14. P-gp Efflux:** Both ligands have relatively low P-gp efflux liability (A: 0.506, B: 0.438).

**15. Binding Affinity:** Ligand B (-8.3 kcal/mol) has a significantly stronger binding affinity than Ligand A (-7.0 kcal/mol). This is a major advantage for Ligand B. The difference of 1.3 kcal/mol is substantial enough to potentially outweigh some ADME drawbacks.

**Overall Assessment:**

Ligand B has a better BBB penetration and significantly stronger binding affinity, which are crucial for a CNS GPCR target. However, Ligand A has a much better safety profile (lower DILI), better metabolic stability (lower Cl_mic, longer t1/2), and is slightly better regarding TPSA. The poor Caco-2 and solubility are concerning for both.

Given the importance of affinity for GPCRs, and the substantial difference in binding affinity (-8.3 vs -7.0 kcal/mol), I believe Ligand B is the more promising candidate, *despite* its higher DILI risk and lower metabolic stability. Optimization efforts could then focus on improving the DILI and Cl_mic of Ligand B.

Output:
1
2025-04-17 08:01:27,112 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (392.861 Da) is slightly higher, but still acceptable. Ligand B (346.406 Da) is also good.

**TPSA:** Ligand A (124.96) is borderline for CNS penetration, being slightly above the preferred <90. Ligand B (78.09) is excellent, well below 90, and favors CNS penetration.

**logP:** Ligand A (0.766) is a bit low, potentially hindering permeability. Ligand B (2.067) is within the optimal range (1-3).

**H-Bond Donors/Acceptors:** Ligand A has 4 HBD and 6 HBA, which are acceptable. Ligand B has 2 HBD and 3 HBA, which is also good.

**QED:** Both ligands have good QED scores (Ligand A: 0.566, Ligand B: 0.806), indicating drug-like properties. Ligand B is better here.

**DILI:** Ligand A (59.403) has a moderate DILI risk. Ligand B (40.287) has a lower, more favorable DILI risk.

**BBB:** Ligand A (48.352) has a poor BBB penetration score, which is a significant drawback for a CNS target. Ligand B (60.838) is better, though still not ideal (aim for >70).

**Caco-2:** Both have negative Caco-2 values which is unusual. I will assume these are percentile scores and higher is better. Ligand A (-5.256) and Ligand B (-4.994) are both very poor.

**Aqueous Solubility:** Both ligands have poor aqueous solubility (-2.182 and -1.532 respectively).

**hERG:** Both ligands have very low hERG risk (0.118 and 0.492 respectively).

**Microsomal Clearance:** Ligand A (-5.383) has a negative clearance, which is not physically possible and likely an error in the data. Ligand B (12.78) has a moderate clearance.

**In vitro Half-Life:** Ligand A (58.036) has a good half-life. Ligand B (-9.08) has a negative half-life, which is not physically possible and likely an error in the data.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.046 and 0.089 respectively).

**Binding Affinity:** Both ligands have very similar and strong binding affinities (-8.4 kcal/mol and -8.9 kcal/mol respectively). Ligand B is slightly better.

**Overall Assessment:**

Ligand B is significantly more promising. While both have poor solubility and Caco-2 permeability, Ligand B excels in TPSA, logP, DILI, and has a slightly better affinity. Most critically, Ligand A has a very poor BBB score and nonsensical clearance and half-life values, making it a less viable candidate. Ligand B's BBB score is still not ideal, but is far superior to Ligand A's. The errors in Ligand A's data are also concerning.

Output:
1
2025-04-17 08:01:27,112 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight (MW):** Both ligands (352.431 and 381.925 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (92.01) is better than Ligand B (49.77). For CNS targets, TPSA < 90 is preferred, and Ligand A is closer to this threshold.

**3. logP:** Ligand A (1.413) is optimal (1-3), while Ligand B (4.664) is high. High logP can lead to solubility issues and off-target interactions.

**4. H-Bond Donors (HBD):** Both ligands have acceptable HBD counts (2 and 1, respectively), well below the threshold of 5.

**5. H-Bond Acceptors (HBA):** Both ligands have acceptable HBA counts (5 and 4, respectively), well below the threshold of 10.

**6. QED:** Both ligands have good QED scores (0.664 and 0.723), indicating drug-like properties.

**7. DILI:** Ligand A (15.083) has a significantly lower DILI risk than Ligand B (36.565). This is a substantial advantage.

**8. BBB:** Ligand A (62.544) has a better BBB percentile than Ligand B (51.687), although both are below the desirable >70 for CNS targets.

**9. Caco-2 Permeability:** Ligand A (-4.561) and Ligand B (-4.9) both have negative values, which is unusual and suggests poor permeability. However, the scale isn't specified, so it's hard to interpret.

**10. Aqueous Solubility:** Ligand A (-1.719) has better aqueous solubility than Ligand B (-4.587).

**11. hERG Inhibition:** Ligand A (0.314) has a lower hERG inhibition liability than Ligand B (0.854), which is favorable.

**12. Microsomal Clearance (Cl_mic):** Ligand A (31.029) has significantly lower microsomal clearance than Ligand B (110.366), indicating better metabolic stability.

**13. In vitro Half-Life:** Ligand A (27.491) has a shorter half-life than Ligand B (44.472), but both are reasonable.

**14. P-gp Efflux:** Ligand A (0.091) has much lower P-gp efflux liability than Ligand B (0.677), which is crucial for CNS penetration.

**15. Binding Affinity:** Ligand A (-7.5) has slightly better binding affinity than Ligand B (-7.3). While the difference is small, it's still a positive factor.

**Overall Assessment:**

Ligand A consistently outperforms Ligand B across most critical ADME-Tox properties, especially DILI, BBB, P-gp efflux, and metabolic stability. While both have issues with Caco-2 permeability, Ligand A's superior profile in other areas, particularly those prioritized for GPCRs targeting the CNS, makes it the more promising candidate. The slightly better binding affinity further supports this conclusion.

Output:
0
2025-04-17 08:01:27,112 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (372.843 Da) is slightly higher than Ligand B (346.435 Da), but both are acceptable.

**TPSA:** Ligand A (51.22) is excellent for CNS penetration, well below the 90 A^2 threshold. Ligand B (89.07) is still reasonable, but less optimal for brain penetration.

**logP:** Ligand A (3.687) is within the optimal range (1-3). Ligand B (1.028) is at the lower end, potentially hindering permeability.

**H-Bond Donors/Acceptors:** Both ligands have 1 HBD, which is good. Ligand A has 3 HBA, and Ligand B has 7 HBA. Both are within the acceptable limit of 10, but Ligand A is preferable.

**QED:** Both ligands have similar QED values (0.877 and 0.809), indicating good drug-likeness.

**DILI:** Ligand A (33.773) has a significantly lower DILI risk than Ligand B (52.385).

**BBB:** This is crucial for a CNS target. Ligand A (90.151) has excellent BBB penetration, exceeding the 70% threshold. Ligand B (55.138) is considerably lower, posing a significant hurdle for CNS efficacy.

**Caco-2 Permeability:** Ligand A (-4.839) and Ligand B (-5.002) both have negative values, which is unusual and suggests poor permeability. However, the scale is not specified, so we can't interpret these values accurately.

**Aqueous Solubility:** Ligand A (-4.054) and Ligand B (-1.402) also have negative values, which is also unusual and suggests poor solubility. Again, the scale is not specified.

**hERG:** Both ligands have low hERG risk (0.392 and 0.244).

**Microsomal Clearance:** Both ligands have similar microsomal clearance values (25.072 and 26.554), indicating comparable metabolic stability.

**In vitro Half-Life:** Ligand A (-0.616) has a slightly better (less negative) in vitro half-life than Ligand B (50.6).

**P-gp Efflux:** Ligand A (0.117) has a lower P-gp efflux liability than Ligand B (0.227), which is favorable for CNS exposure.

**Binding Affinity:** Ligand A (-9.8 kcal/mol) has a significantly stronger binding affinity than Ligand B (-8.1 kcal/mol). This 1.7 kcal/mol difference is substantial and can outweigh minor ADME drawbacks.

**Conclusion:**

Considering all factors, especially the GPCR-specific priorities, **Ligand A is the more promising drug candidate**. It has superior BBB penetration, lower DILI risk, better P-gp efflux, and significantly higher binding affinity. While both have questionable solubility and permeability based on the provided values, the strong affinity and favorable CNS properties of Ligand A make it the better choice.

Output:
1
2025-04-17 08:01:27,113 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (418.316 Da) is slightly higher, but still acceptable. Ligand B (348.399 Da) is also good.

**TPSA:** Ligand A (62.3) is excellent, well below the 90 A^2 threshold for CNS targets. Ligand B (93.73) is approaching the upper limit for CNS penetration, but still potentially acceptable.

**logP:** Ligand A (3.698) is within the optimal range (1-3). Ligand B (1.619) is at the lower end of the optimal range, which *could* impact permeability.

**H-Bond Donors/Acceptors:** Ligand A (1 HBD, 4 HBA) is favorable. Ligand B (2 HBD, 5 HBA) is also acceptable.

**QED:** Both ligands have reasonable QED values (Ligand A: 0.688, Ligand B: 0.577), indicating good drug-like properties.

**DILI:** Both ligands have acceptable DILI risk (Ligand A: 70.105, Ligand B: 62.35), below the concerning threshold of 60.

**BBB:** This is critical for a CNS target. Ligand A has a significantly better BBB penetration percentile (75.882) than Ligand B (48.391). This is a major advantage for Ligand A.

**Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and suggests a potential issue with the data or modeling. However, we'll proceed assuming these represent low permeability.

**Aqueous Solubility:** Both have negative solubility values, again suggesting a potential data issue.

**hERG Inhibition:** Ligand A (0.71) has a slightly higher hERG risk than Ligand B (0.193), but both are relatively low.

**Microsomal Clearance:** Ligand B (-5.24) has a *much* lower (better) microsomal clearance than Ligand A (69.7). This suggests better metabolic stability for Ligand B.

**In vitro Half-Life:** Ligand A (91.813) has a significantly longer half-life than Ligand B (7.735).

**P-gp Efflux:** Ligand A (0.542) has lower P-gp efflux liability than Ligand B (0.037), which is favorable for CNS penetration.

**Binding Affinity:** Both ligands have excellent binding affinities (Ligand A: -9.2 kcal/mol, Ligand B: -8.2 kcal/mol). Ligand A is 1 kcal/mol stronger, which is a substantial difference.

**Overall Assessment:**

Ligand A is the stronger candidate. While Ligand B has better metabolic stability (lower Cl_mic) and lower P-gp efflux, Ligand A's superior BBB penetration, stronger binding affinity, and acceptable ADME properties outweigh these advantages. The slightly higher hERG risk for Ligand A is manageable. The negative Caco-2 and solubility values are concerning, but the overall profile of Ligand A is more promising for CNS drug development.

Output:
1
2025-04-17 08:01:27,113 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (407.264 Da) is slightly higher than Ligand B (352.435 Da), but both are acceptable.

**2. TPSA:** Ligand A (71.89) is better than Ligand B (98.76). For CNS targets, TPSA should be <=90. Ligand A is comfortably within this range, while Ligand B is approaching the upper limit.

**3. logP:** Ligand A (2.604) is optimal (1-3), while Ligand B (0.434) is below 1, which may impede permeation. This is a significant advantage for Ligand A.

**4. H-Bond Donors:** Both ligands have acceptable HBD counts (Ligand A: 1, Ligand B: 2), well below the threshold of 5.

**5. H-Bond Acceptors:** Both ligands have acceptable HBA counts (Ligand A: 6, Ligand B: 5), well below the threshold of 10.

**6. QED:** Both ligands have similar and good QED values (Ligand A: 0.743, Ligand B: 0.742), indicating good drug-like properties.

**7. DILI:** Ligand A (36.293) has a slightly higher DILI risk than Ligand B (20.047), but both are below the concerning threshold of 40.

**8. BBB:** Ligand A (57.852) has a significantly better BBB penetration percentile than Ligand B (44.901). While >70 is desirable, Ligand A is much closer to that target for a CNS drug.

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.724 and -4.895), which is unusual and suggests poor permeability. However, these values are on a scale where negative values are possible and don't necessarily disqualify a compound.

**10. Aqueous Solubility:** Both ligands have negative solubility values (-3.928 and -1.088), also unusual. Similar to Caco-2, these values are on a scale where negative values are possible and don't necessarily disqualify a compound.

**11. hERG Inhibition:** Both ligands have low hERG inhibition risk (Ligand A: 0.75, Ligand B: 0.272).

**12. Microsomal Clearance:** Ligand B (-3.112) has a much lower (better) microsomal clearance than Ligand A (48.882). This suggests greater metabolic stability for Ligand B.

**13. In vitro Half-Life:** Ligand B (-28.714) has a significantly longer in vitro half-life than Ligand A (-12.869).

**14. P-gp Efflux:** Both ligands have very low P-gp efflux liability (Ligand A: 0.299, Ligand B: 0.033). Ligand B is slightly better.

**15. Binding Affinity:** Ligand A (-8.8 kcal/mol) has a significantly stronger binding affinity than Ligand B (-7.2 kcal/mol). This >1.5 kcal/mol difference is substantial and can outweigh some ADME drawbacks.

**Overall Assessment:**

Ligand A has a clear advantage in terms of binding affinity and logP, and a better BBB score. These are critical for a CNS-targeting GPCR like DRD2. While Ligand B has better metabolic stability (lower Cl_mic) and half-life, the stronger binding affinity of Ligand A, coupled with its more favorable logP and BBB, makes it the more promising candidate. The negative Caco-2 and solubility values are concerning for both, but the strong affinity of Ligand A suggests it might overcome these challenges.

Output:
1
2025-04-17 08:01:27,113 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 drug candidates, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (345.403 and 341.411 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (81.39) is better than Ligand B (76.39). Both are below the 90 A^2 threshold desirable for CNS targets, but A is closer to the ideal.

**3. logP:** Ligand A (1.525) is within the optimal range (1-3). Ligand B (2.177) is also within range, but slightly higher.

**4. H-Bond Donors:** Ligand A (1) is better than Ligand B (2). Lower is generally preferred.

**5. H-Bond Acceptors:** Ligand A (6) is better than Ligand B (5). Both are within the acceptable range.

**6. QED:** Both ligands have good QED scores (0.852 and 0.891), indicating good drug-like properties.

**7. DILI:** Ligand A (37.03) has a significantly lower DILI risk than Ligand B (61.574). This is a major advantage for Ligand A.

**8. BBB:** Ligand A (71.888) has a much better BBB penetration percentile than Ligand B (52.579). This is *critical* for a CNS target like DRD2.

**9. Caco-2 Permeability:** Ligand A (-4.694) is better than Ligand B (-5.236). Higher values are better, indicating better intestinal absorption.

**10. Aqueous Solubility:** Ligand A (-1.782) is better than Ligand B (-1.952). Higher values are better.

**11. hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.386 and 0.285).

**12. Microsomal Clearance:** Ligand A (65.016) has higher microsomal clearance than Ligand B (29.722), meaning Ligand B is more metabolically stable.

**13. In vitro Half-Life:** Ligand A (-7.986) has a much longer in vitro half-life than Ligand B (1.683).

**14. P-gp Efflux:** Ligand A (0.065) has lower P-gp efflux than Ligand B (0.113). Lower is better for CNS exposure.

**15. Binding Affinity:** Ligand B (-9.9 kcal/mol) has a significantly stronger binding affinity than Ligand A (-8.2 kcal/mol). This is a substantial advantage.

**Overall Assessment:**

While Ligand B has a superior binding affinity, Ligand A has a much more favorable ADME profile, particularly regarding BBB penetration (71.888 vs 52.579) and DILI risk (37.03 vs 61.574). For a CNS target like DRD2, good BBB penetration is paramount. The difference in binding affinity (1.7 kcal/mol) is significant, but can potentially be overcome with further optimization of Ligand A. The lower DILI risk and better overall ADME profile of Ligand A make it the more promising candidate.

Output:
0
2025-04-17 08:01:27,113 - INFO - Reasoning:

Let's analyze Ligand A and Ligand B for their potential as DRD2 drug candidates, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight (MW):** Both ligands (357.401 and 346.475 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (69.72) is excellent, well below the 90 A^2 threshold for CNS targets. Ligand B (76.02) is still reasonable but less optimal.

**3. logP:** Ligand A (0.802) is a bit low, potentially hindering permeability. Ligand B (2.21) is much better, falling within the optimal 1-3 range.

**4. H-Bond Donors (HBD):** Both ligands have acceptable HBD counts (1 and 2, respectively), well below the 5 threshold.

**5. H-Bond Acceptors (HBA):** Both ligands have acceptable HBA counts (3 and 4, respectively), below the 10 threshold.

**6. QED:** Both ligands have good QED values (0.812 and 0.72), indicating drug-like properties.

**7. DILI:** Ligand A (44.087) has a slightly higher DILI risk than Ligand B (27.336), but both are below the concerning 60 threshold.

**8. BBB:** This is critical for a CNS target. Ligand A (81.233) has a significantly better BBB percentile than Ligand B (68.554).

**9. Caco-2 Permeability:** Ligand A (-4.605) has a very poor Caco-2 permeability, suggesting poor intestinal absorption. Ligand B (-4.982) is also poor, but slightly worse.

**10. Aqueous Solubility:** Both ligands have poor aqueous solubility (-2.449 and -2.85). This could pose formulation challenges.

**11. hERG Inhibition:** Both ligands show very low hERG inhibition risk (0.346 and 0.16).

**12. Microsomal Clearance:** Ligand A (4.914) has lower microsomal clearance than Ligand B (36.664), indicating better metabolic stability.

**13. In vitro Half-Life:** Ligand A (-11.189) has a very poor in vitro half-life, while Ligand B (12.555) is better, but still not ideal.

**14. P-gp Efflux:** Both ligands have low P-gp efflux liability (0.135 and 0.055), which is favorable for CNS penetration.

**15. Binding Affinity:** Both ligands have very similar and excellent binding affinities (-8.9 and -8.4 kcal/mol). The difference is less than the 1.5 kcal/mol threshold.

**Overall Assessment:**

Ligand A excels in TPSA, BBB, and metabolic stability (Cl_mic). However, its poor Caco-2 permeability and extremely short half-life are major drawbacks. Ligand B has a better logP and a more reasonable half-life, but its BBB penetration is lower, and its metabolic clearance is higher.

Given the GPCR-specific priorities, BBB penetration is paramount for a CNS drug. While Ligand A has a superior BBB score, its extremely poor pharmacokinetic properties (Caco-2 and t1/2) are likely insurmountable. Ligand B, despite a slightly lower BBB score, presents a more balanced profile with better permeability characteristics and a more reasonable half-life, making it more likely to be optimized into a viable drug candidate.

Output:
1
2025-04-17 08:01:27,114 - INFO - Batch 414 complete. Total preferences: 6624
2025-04-17 08:01:27,114 - INFO - Processing batch 415/512...
2025-04-17 08:02:08,263 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (347.5) is slightly lower, which could be beneficial for permeability.

**TPSA:** Ligand A (63.13) is better than Ligand B (37.61) as it is closer to the optimal range for CNS targets (<=90). Ligand B is very low, which might indicate issues with solubility.

**logP:** Ligand A (3.175) is within the optimal range (1-3). Ligand B (4.738) is higher, potentially leading to solubility issues and off-target interactions.

**H-Bond Donors/Acceptors:** Ligand A has 2 HBD and 3 HBA, while Ligand B has 0 HBD and 4 HBA. Both are within acceptable limits.

**QED:** Both ligands have similar QED values (0.674 and 0.647), indicating good drug-like properties.

**DILI:** Ligand A (25.204) has a significantly lower DILI risk than Ligand B (43.777), which is a major advantage.

**BBB:** Ligand B (84.451) has a better BBB penetration percentile than Ligand A (70.919), which is crucial for a CNS target like DRD2.

**Caco-2 Permeability:** Both have negative values, indicating poor permeability. Ligand A (-4.758) is slightly better than Ligand B (-4.824).

**Aqueous Solubility:** Both have negative values, indicating poor solubility. Ligand A (-3.218) is slightly better than Ligand B (-4.574).

**hERG Inhibition:** Both ligands show low hERG inhibition liability (0.696 and 0.894), which is good.

**Microsomal Clearance:** Ligand A (48.947) has lower microsomal clearance than Ligand B (75.11), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand B (15.622) has a slightly longer half-life than Ligand A (13.759), but the difference is not substantial.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.394 and 0.646), which is favorable for CNS penetration.

**Binding Affinity:** Ligand A (-7.7 kcal/mol) has a stronger binding affinity than Ligand B (-7.2 kcal/mol). This 0.5 kcal/mol difference is significant and can outweigh some ADME drawbacks.

**Overall Assessment:**

Ligand A is the better candidate. While Ligand B has a slightly better BBB score, Ligand A excels in several critical areas: significantly lower DILI risk, better TPSA, better logP, better metabolic stability (lower Cl_mic), and, most importantly, a stronger binding affinity. The stronger affinity of Ligand A is a substantial advantage for a GPCR target. The slightly lower BBB of Ligand A is less concerning given its other favorable properties.

Output:
1
2025-04-17 08:02:08,263 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (410.199 Da) is slightly higher than Ligand B (385.335 Da), but both are acceptable.

**TPSA:** Ligand A (104.21) is above the optimal 90 for CNS targets, while Ligand B (34.59) is well below. This is a significant advantage for Ligand B.

**logP:** Both ligands have logP values within the optimal range (1-3), with Ligand A at 3.226 and Ligand B at 4.354. Ligand B is slightly higher, potentially increasing off-target effects, but still within acceptable limits.

**H-Bond Donors & Acceptors:** Ligand A has 2 HBD and 5 HBA, while Ligand B has 0 HBD and 4 HBA. Both are within acceptable limits (<=5 HBD and <=10 HBA).

**QED:** Ligand A (0.737) has a better QED score than Ligand B (0.468), indicating a more drug-like profile.

**DILI:** Ligand A (97.867) has a significantly higher DILI risk than Ligand B (11.71). This is a major concern for Ligand A.

**BBB:** Ligand B (87.476) has a much better BBB penetration percentile than Ligand A (40.52). This is crucial for a CNS target like DRD2.

**Caco-2 Permeability:** Ligand A (-4.596) has worse Caco-2 permeability than Ligand B (-4.867), which suggests lower intestinal absorption for both.

**Aqueous Solubility:** Ligand A (-6.293) has worse aqueous solubility than Ligand B (-3.823).

**hERG Inhibition:** Both ligands have relatively low hERG inhibition risk (0.748 and 0.854, respectively).

**Microsomal Clearance:** Both ligands have similar microsomal clearance values (75.37 and 73.34 mL/min/kg).

**In vitro Half-Life:** Ligand A (60.487) has a longer in vitro half-life than Ligand B (34.181).

**P-gp Efflux:** Ligand A (0.224) has lower P-gp efflux liability than Ligand B (0.632), which is favorable for CNS penetration.

**Binding Affinity:** Ligand A (-7.7 kcal/mol) has a slightly better binding affinity than Ligand B (-7.3 kcal/mol). This 0.4 kcal/mol difference is not substantial enough to overcome the significant ADME disadvantages of Ligand A.

**Overall Assessment:**

Ligand B is the more promising candidate. While its QED is lower and logP is slightly higher, its superior BBB penetration, significantly lower DILI risk, and better TPSA outweigh the minor advantage of Ligand A's binding affinity and half-life. The lower TPSA and higher BBB are particularly important for a CNS-targeting GPCR like DRD2. Ligand A's high DILI risk is a major red flag.

Output:
1
2025-04-17 08:02:08,263 - INFO - Reasoning:

Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (357.401 and 364.515 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (69.72) is better than Ligand B (65.54) as it is closer to the optimal range for CNS targets (<=90). Both are acceptable.

**3. logP:** Both ligands have good logP values (1.007 and 1.84), falling within the optimal 1-3 range. Ligand B is slightly better.

**4. H-Bond Donors:** Both have 1 HBD, which is within the acceptable limit of <=5.

**5. H-Bond Acceptors:** Ligand A has 3 HBA, and Ligand B has 5. Both are within the acceptable limit of <=10.

**6. QED:** Both ligands have reasonable QED scores (0.816 and 0.764), indicating good drug-like properties.

**7. DILI:** Ligand A (30.826) has a slightly higher DILI risk than Ligand B (24.544), but both are well below the concerning threshold of 60.

**8. BBB:** This is a crucial parameter for CNS targets. Ligand A has a significantly higher BBB penetration percentile (86.041) than Ligand B (76.309). This is a major advantage for Ligand A.

**9. Caco-2 Permeability:** Ligand A (-4.577) and Ligand B (-5.009) both have negative Caco-2 values, which is unusual and suggests poor permeability. This is a concern for both, but the values are similar.

**10. Aqueous Solubility:** Both ligands have very poor aqueous solubility (-2.371 and -2.109). This is a significant drawback for both compounds.

**11. hERG Inhibition:** Both ligands have low hERG inhibition risk (0.286 and 0.441).

**12. Microsomal Clearance:** Ligand B (33.385) has a significantly higher microsomal clearance than Ligand A (11.953), indicating faster metabolism and potentially lower exposure.

**13. In vitro Half-Life:** Ligand A (-21.659) has a much longer in vitro half-life than Ligand B (14.552). This is a significant advantage for Ligand A.

**14. P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.022 and 0.048), which is favorable for CNS penetration.

**15. Binding Affinity:** Ligand B (-7.7 kcal/mol) has a slightly better binding affinity than Ligand A (-8.3 kcal/mol). While this is a positive for Ligand B, the difference is relatively small.

**Overall Assessment:**

Considering the GPCR-specific priorities, Ligand A is the more promising candidate. Its superior BBB penetration (86.041 vs 76.309), longer half-life, and lower microsomal clearance outweigh the slightly weaker binding affinity. The poor solubility and Caco-2 permeability are concerns for both, but can potentially be addressed through formulation strategies. The slightly higher DILI risk for Ligand A is not a major concern given its low overall score.



Output:
0
2025-04-17 08:02:08,264 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B based on the provided guidelines, prioritizing GPCR-specific properties (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (365.543 and 350.463 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (61.44) is significantly better than Ligand B (107.11). For CNS targets, TPSA should be <= 90, and A is comfortably within this range, while B exceeds it. This is a substantial advantage for A.

**logP:** Both ligands have good logP values (1.793 and 1.297), falling within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A (HBD=2, HBA=4) and Ligand B (HBD=4, HBA=4) are both acceptable, within the recommended limits.

**QED:** Ligand A (0.722) has a higher QED than Ligand B (0.477), indicating a more drug-like profile.

**DILI:** Ligand A (16.44) has a much lower DILI risk than Ligand B (28.887). Both are below 40, but A is preferable.

**BBB:** This is a critical parameter for CNS targets like DRD2. Ligand A (70.415) has a good BBB percentile, exceeding the desirable >70 threshold. Ligand B (13.61) is very poor, indicating limited brain penetration. This is a major disadvantage for B.

**Caco-2 Permeability:** Both have negative values, which is unusual. A (-5.235) is slightly better than B (-5.708).

**Aqueous Solubility:** Both have negative values, which is also unusual. A (-2.939) is slightly better than B (-1.726).

**hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.348 and 0.111).

**Microsomal Clearance:** Ligand A (74.94) has higher clearance than Ligand B (4.289), meaning B is more metabolically stable.

**In vitro Half-Life:** Ligand B (-15.202) has a negative half-life, which is impossible and indicates a data error or unusual experimental result. Ligand A (24.657) has a reasonable half-life.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.1 and 0.035), which is good.

**Binding Affinity:** Ligand A (-8.9 kcal/mol) has a significantly stronger binding affinity than Ligand B (-7.8 kcal/mol). This >1.5 kcal/mol difference is substantial and can outweigh minor ADME drawbacks.

**Overall Assessment:**

Ligand A is clearly superior. It has a better TPSA, QED, DILI risk, and crucially, a much higher BBB penetration. Its binding affinity is also significantly stronger. While Ligand B has better metabolic stability, the poor BBB penetration and lower affinity are major drawbacks for a CNS target like DRD2. The negative half-life for Ligand B is also concerning.

Output:
1
2025-04-17 08:02:08,264 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (350.423 Da) is slightly lower, which is generally favorable for permeability. Ligand B (367.362 Da) is also good.

**TPSA:** Ligand A (110.08) is borderline for CNS penetration, being above the preferred <90. Ligand B (38.13) is excellent, well below the threshold. This is a significant advantage for Ligand B.

**logP:** Ligand A (0.177) is quite low, potentially hindering membrane permeability and CNS penetration. Ligand B (3.835) is within the optimal range (1-3). This is a substantial advantage for Ligand B.

**H-Bond Donors/Acceptors:** Ligand A has 1 HBD and 7 HBA, which are acceptable. Ligand B has 0 HBD and 3 HBA, also acceptable.

**QED:** Both ligands have good QED values (A: 0.636, B: 0.687), indicating drug-like properties.

**DILI:** Ligand A (43.234) has a moderate DILI risk, while Ligand B (14.696) has a very low risk. This favors Ligand B.

**BBB:** Ligand A (63.862) has a moderate BBB penetration, while Ligand B (93.563) has excellent BBB penetration. This is a critical advantage for a CNS target like DRD2, strongly favoring Ligand B.

**Caco-2 Permeability:** Ligand A (-5.32) has poor Caco-2 permeability, suggesting poor intestinal absorption. Ligand B (-4.264) also has poor Caco-2 permeability, but is slightly better than Ligand A.

**Aqueous Solubility:** Ligand A (-0.711) has very poor solubility. Ligand B (-4.569) also has poor solubility, but is slightly better than Ligand A.

**hERG Inhibition:** Ligand A (0.022) has very low hERG inhibition risk, which is excellent. Ligand B (0.711) has a slightly elevated risk, but still relatively low.

**Microsomal Clearance:** Ligand A (35.373) has moderate clearance, while Ligand B (52.664) has higher clearance. This favors Ligand A, suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (-16.449) has a very short half-life, which is a major drawback. Ligand B (-11.161) has a longer half-life, though still not ideal.

**P-gp Efflux:** Ligand A (0.05) has low P-gp efflux, which is favorable for CNS penetration. Ligand B (0.339) has slightly higher P-gp efflux, but still reasonable.

**Binding Affinity:** Both ligands have comparable and strong binding affinities (A: -7.7 kcal/mol, B: -7.0 kcal/mol). Ligand A is slightly better, but the difference is likely not enough to overcome its other deficiencies.

**Overall Assessment:**

Ligand B is significantly more promising. While Ligand A has slightly better affinity and lower clearance, Ligand B excels in key properties for a CNS-targeting GPCR ligand: TPSA, logP, BBB penetration, and DILI risk. The low logP and poor solubility of Ligand A are major concerns, likely leading to poor bioavailability and CNS exposure. The superior BBB penetration of Ligand B is crucial for targeting DRD2.

Output:
1
2025-04-17 08:02:08,264 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (349.391 and 352.41 Da) fall within the ideal range of 200-500 Da.

**TPSA:** Ligand A (137.39) is slightly above the optimal <90 for CNS targets, but still reasonable. Ligand B (84.42) is excellent, well below 90.

**logP:** Ligand A (-0.966) is a bit low, potentially hindering permeability. Ligand B (1.935) is within the optimal 1-3 range.

**H-Bond Donors & Acceptors:** Ligand A (4 HBD, 4 HBA) is good. Ligand B (1 HBD, 5 HBA) is also acceptable.

**QED:** Both ligands have good QED scores (0.525 and 0.811), indicating drug-like properties.

**DILI:** Ligand A (43.66) has a slightly higher DILI risk than Ligand B (29.779), but both are below the concerning threshold of 60.

**BBB:** This is critical for a CNS target. Ligand A (45.599) has a poor BBB penetration percentile, while Ligand B (92.323) is excellent, exceeding the desirable >70 threshold.

**Caco-2 Permeability:** Ligand A (-6.05) shows poor permeability, while Ligand B (-4.36) is better, though still not ideal.

**Aqueous Solubility:** Both ligands have very poor aqueous solubility (-2.46 and -2.76). This could pose formulation challenges.

**hERG Inhibition:** Both ligands show very low hERG inhibition risk (0.057 and 0.207).

**Microsomal Clearance:** Ligand A (-16.975) has a lower (better) microsomal clearance than Ligand B (63.06), suggesting greater metabolic stability.

**In vitro Half-Life:** Ligand B (-26.421) has a significantly longer half-life than Ligand A (-2.33), which is a major advantage.

**P-gp Efflux:** Both ligands show very low P-gp efflux liability (0.009 and 0.012).

**Binding Affinity:** Ligand B (-7.1 kcal/mol) has a slightly better binding affinity than Ligand A (-8.3 kcal/mol). While A is better, the difference is not substantial enough to overcome its other weaknesses.

**Overall Assessment:**

Ligand B is the stronger candidate. Its excellent BBB penetration, good logP, acceptable TPSA, and longer half-life outweigh the slightly lower metabolic stability and solubility compared to Ligand A. Ligand A's poor BBB penetration is a significant drawback for a CNS target like DRD2. While Ligand A has a slightly better affinity, the other ADME properties of Ligand B are more favorable for *in vivo* efficacy.

Output:
1
2025-04-17 08:02:08,264 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (347.459 and 350.503 Da) fall comfortably within the ideal 200-500 Da range.

**TPSA:** Ligand A (81.67) is better than Ligand B (49.85). For CNS targets, we want TPSA <= 90, both meet this, but A is closer to the upper limit.

**logP:** Both ligands have good logP values (1.935 and 3.24), falling within the optimal 1-3 range. Ligand B is slightly higher, which could potentially affect solubility.

**H-Bond Donors/Acceptors:** Ligand A has 3 HBD and 3 HBA, while Ligand B has 0 HBD and 3 HBA. Both are within acceptable limits (<=5 HBD and <=10 HBA).

**QED:** Both ligands have similar QED values (0.735 and 0.632), indicating good drug-like properties.

**DILI:** Ligand A (12.214) has a significantly lower DILI risk than Ligand B (21.908), which is a major advantage.

**BBB:** Ligand B (88.174) has a better BBB penetration percentile than Ligand A (73.75). This is a critical factor for CNS targets like DRD2.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.876 and -4.886). This is unusual and suggests poor permeability. However, these values are on a scale where negative values are possible, and direct comparison is difficult without knowing the scale's specifics.

**Aqueous Solubility:** Both ligands have negative solubility values (-1.609 and -2.97). Similar to Caco-2, this is concerning and suggests poor solubility.

**hERG:** Both ligands have similar, low hERG inhibition liability (0.657 and 0.629).

**Microsomal Clearance:** Ligand A (1.937) has significantly lower microsomal clearance than Ligand B (52.975), indicating better metabolic stability.

**In vitro Half-Life:** Ligand A (-1.568) has a slightly better (less negative) in vitro half-life than Ligand B (-15.03).

**P-gp Efflux:** Ligand A (0.138) has lower P-gp efflux liability than Ligand B (0.227), which is favorable for CNS penetration.

**Binding Affinity:** Ligand A (-8.7 kcal/mol) has a significantly stronger binding affinity than Ligand B (-7.4 kcal/mol). This 1.3 kcal/mol difference is substantial and can outweigh some ADME drawbacks.

**Overall Assessment:**

Ligand A is the stronger candidate. While Ligand B has better BBB penetration, Ligand A's superior binding affinity, lower DILI risk, better metabolic stability (lower Cl_mic), lower P-gp efflux, and slightly better half-life are more compelling advantages, especially considering the negative Caco-2 and solubility values for both. The substantial difference in binding affinity (-8.7 vs -7.4 kcal/mol) is a key factor. The slightly higher TPSA of Ligand A is less concerning than the other benefits it offers.

Output:
1
2025-04-17 08:02:08,264 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (354.451 and 345.447 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (121.6) is slightly above the optimal <90 for CNS targets, but still reasonable. Ligand B (79.26) is excellent, well below 90.

**logP:** Ligand A (-0.234) is quite low, potentially hindering membrane permeability. Ligand B (0.622) is better, falling within the 1-3 range, though on the lower end.

**H-Bond Donors/Acceptors:** Ligand A (3 HBD, 4 HBA) and Ligand B (2 HBD, 5 HBA) both have acceptable numbers of H-bond donors and acceptors.

**QED:** Both ligands have good QED scores (0.584 and 0.82), indicating drug-like properties.

**DILI:** Ligand A (20.047) has a very low DILI risk. Ligand B (31.873) is also low, but slightly higher.

**BBB:** Ligand A (57.619) has a moderate BBB penetration, which is a concern for a CNS target. Ligand B (72.237) is significantly better, exceeding the desirable >70 threshold.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.595 and -5.421), which is unusual and suggests poor permeability. This could be a data error, but we must consider it.

**Aqueous Solubility:** Both ligands have negative solubility values (-1.646 and -1.714), also unusual and suggesting poor solubility. Again, this could be a data error.

**hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.029 and 0.501).

**Microsomal Clearance:** Ligand A (24.821) has moderate clearance, while Ligand B (-1.784) has *negative* clearance, which is impossible and likely a data error.

**In vitro Half-Life:** Ligand A (-20.021) has a negative half-life, which is impossible and a clear data error. Ligand B (20.83) is reasonable.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.006 and 0.032), which is good for CNS penetration.

**Binding Affinity:** Ligand B (-8.4 kcal/mol) has a significantly stronger binding affinity than Ligand A (-7.3 kcal/mol), exceeding the 1.5 kcal/mol advantage threshold.

**Overall Assessment:**

Despite the questionable solubility and permeability data, Ligand B is clearly superior. Its significantly better BBB penetration, stronger binding affinity, and better logP outweigh the slightly higher DILI risk. The negative clearance and half-life values for Ligand A are major red flags, indicating data quality issues. Ligand B, while also having questionable solubility/permeability data, is more likely to be a viable candidate given the other favorable properties.

Output:
1
2025-04-17 08:02:08,265 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (365.455 and 372.531 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (87.65) is better than Ligand B (59.08), both are below the 90 Angstrom threshold for CNS targets.

**logP:** Ligand B (1.632) is within the optimal 1-3 range, while Ligand A (0.392) is slightly below, potentially hindering permeation.

**H-Bond Donors:** Both ligands have 0 HBD, which is acceptable.

**H-Bond Acceptors:** Both ligands have 5 HBA, which is acceptable.

**QED:** Ligand A (0.753) has a slightly better QED score than Ligand B (0.606), indicating better overall drug-likeness.

**DILI:** Ligand A (42.846) has a lower DILI risk than Ligand B (15.51), indicating a safer profile.

**BBB:** Ligand A (83.831) has a significantly better BBB penetration percentile than Ligand B (76.696). This is a crucial factor for a CNS target like DRD2.

**Caco-2:** Ligand A (-4.986) and Ligand B (-4.632) have similar, very low Caco-2 permeability. This is a concern for both.

**Solubility:** Ligand A (-1.549) has slightly better solubility than Ligand B (-2.125), but both are poor.

**hERG:** Ligand A (0.107) has a lower hERG inhibition liability than Ligand B (0.561), suggesting a lower risk of cardiotoxicity.

**Microsomal Clearance:** Ligand A (13.922) has a lower microsomal clearance than Ligand B (50.762), indicating better metabolic stability.

**In vitro Half-Life:** Ligand A (8.854) has a longer in vitro half-life than Ligand B (-3.175), which is desirable.

**P-gp Efflux:** Ligand A (0.05) has a lower P-gp efflux liability than Ligand B (0.072), suggesting better CNS exposure.

**Binding Affinity:** Ligand A (-7.3 kcal/mol) has a slightly better binding affinity than Ligand B (-6.8 kcal/mol). While both are good, the 1.5 kcal/mol difference is significant.

**Overall Assessment:**

Ligand A consistently outperforms Ligand B in most critical parameters for a CNS-targeting GPCR ligand. Specifically, its superior BBB penetration, lower DILI risk, better metabolic stability (lower Cl_mic and longer t1/2), lower P-gp efflux, and slightly better binding affinity make it the more promising candidate. While both have poor Caco-2 permeability and solubility, these can be addressed with formulation strategies. The slightly lower logP of Ligand A is a minor concern, but is outweighed by its other advantages.

Output:
1
2025-04-17 08:02:08,265 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (337.427 and 349.431 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (70.15) is better than Ligand B (75.88). Both are below the 90 A^2 threshold desirable for CNS targets, but A is closer to the optimal range.

**logP:** Ligand A (2.506) is within the optimal 1-3 range. Ligand B (1.544) is at the lower end, potentially impacting permeability.

**H-Bond Donors:** Ligand A (2) is preferable to Ligand B (0). While both are acceptable, a small number of HBDs can aid solubility.

**H-Bond Acceptors:** Both ligands have 5 HBA, which is acceptable.

**QED:** Ligand A (0.9) is significantly better than Ligand B (0.779), indicating a more drug-like profile.

**DILI:** Ligand B (42.807) has a much lower DILI risk than Ligand A (60.76), a significant advantage.

**BBB:** Ligand B (84.257) has a substantially higher BBB penetration percentile than Ligand A (77.2). This is a critical factor for a CNS target like DRD2.

**Caco-2 Permeability:** Ligand A (-4.78) has better Caco-2 permeability than Ligand B (-4.463), suggesting better intestinal absorption.

**Aqueous Solubility:** Ligand B (-0.774) has better aqueous solubility than Ligand A (-3.96).

**hERG Inhibition:** Ligand A (0.718) has a lower hERG inhibition liability than Ligand B (0.159), which is a positive.

**Microsomal Clearance:** Ligand B (47.248) has lower microsomal clearance than Ligand A (58.412), indicating better metabolic stability.

**In vitro Half-Life:** Ligand B (-14.564) has a significantly longer in vitro half-life than Ligand A (7.405), a major advantage.

**P-gp Efflux:** Ligand A (0.122) has lower P-gp efflux liability than Ligand B (0.077), which is favorable for CNS penetration.

**Binding Affinity:** Ligand A (-9.5 kcal/mol) has a significantly stronger binding affinity than Ligand B (-7.8 kcal/mol). This is a substantial advantage, potentially outweighing some of the ADME drawbacks.

**Overall Assessment:**

While Ligand B has superior BBB, lower DILI, better solubility, and improved metabolic stability/half-life, the significantly stronger binding affinity of Ligand A (-9.5 vs -7.8 kcal/mol) is a decisive factor for a GPCR target. The 1.7 kcal/mol difference is substantial and likely to translate to better efficacy. The slightly higher DILI risk and lower BBB of Ligand A are acceptable trade-offs given the potency. Ligand A also has better Caco-2 permeability and P-gp efflux.

Output:
1
2025-04-17 08:02:08,265 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (347.503 and 357.439 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (61.44) is significantly better than Ligand B (73.14). For CNS targets, we want TPSA <= 90, and ideally closer to 60. Ligand A is much closer to this ideal.

**3. logP:** Both ligands have good logP values (2.515 and 2.459), falling within the optimal 1-3 range.

**4. H-Bond Donors:** Ligand A (2) is reasonable, while Ligand B (0) is also acceptable.

**5. H-Bond Acceptors:** Ligand A (3) is good, while Ligand B (7) is slightly higher but still within the acceptable limit of <=10.

**6. QED:** Both ligands have similar and acceptable QED values (0.549 and 0.55).

**7. DILI:** Ligand A (11.361) has a much lower DILI risk than Ligand B (79.953). This is a significant advantage for Ligand A.

**8. BBB:** Ligand A (76.231) has a better BBB penetration percentile than Ligand B (64.25). Both are reasonably good, but Ligand A is closer to the desirable >70 threshold for CNS targets.

**9. Caco-2 Permeability:** Ligand A (-5.219) and Ligand B (-5.154) have similar, and poor, Caco-2 permeability.

**10. Aqueous Solubility:** Both ligands have poor aqueous solubility (-2.187 and -3.114). This could pose formulation challenges.

**11. hERG Inhibition:** Both ligands have low hERG inhibition risk (0.449 and 0.247).

**12. Microsomal Clearance:** Ligand B (96.925) has a much higher microsomal clearance than Ligand A (16.32). This suggests Ligand A is more metabolically stable.

**13. In vitro Half-Life:** Ligand B (-24.739) has a very poor in vitro half-life, while Ligand A (-3.638) is better, though still not ideal.

**14. P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.099 and 0.398), which is good for CNS penetration.

**15. Binding Affinity:** Ligand B (-8.1) has a significantly stronger binding affinity than Ligand A (-0.0). This is a substantial advantage for Ligand B.

**Overall Assessment:**

While Ligand B boasts a much stronger binding affinity, Ligand A has superior ADME properties, particularly regarding DILI risk, BBB penetration, and metabolic stability. The large difference in binding affinity is a major consideration. However, the poor ADME profile of Ligand B, especially the high DILI risk and poor half-life, are significant drawbacks. Ligand A, while having weaker binding, presents a more balanced profile and a lower risk of failure due to ADME issues. Given the GPCR-specific focus on BBB and the importance of avoiding toxicity, Ligand A is the more promising candidate, despite the affinity difference. Further optimization of Ligand A to improve its affinity could yield a highly viable drug candidate.

Output:
0
2025-04-17 08:02:08,265 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (345.443 and 351.447 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (71.53) is excellent for CNS penetration, well below the 90 A^2 threshold. Ligand B (96.53) is still reasonable but less optimal, approaching the 100 A^2 limit.

**logP:** Ligand A (2.389) is within the optimal 1-3 range. Ligand B (0.481) is slightly low, potentially hindering membrane permeability.

**H-Bond Donors/Acceptors:** Ligand A (1 HBD, 4 HBA) and Ligand B (3 HBD, 4 HBA) both have acceptable numbers of H-bond donors and acceptors.

**QED:** Ligand A (0.824) has a higher QED score than Ligand B (0.671), indicating a more drug-like profile.

**DILI:** Ligand A (35.983) has a slightly higher DILI risk than Ligand B (25.514), but both are below the concerning threshold of 60.

**BBB:** This is critical for a CNS target. Ligand A (83.986) has a significantly better BBB percentile than Ligand B (53.625).

**Caco-2 Permeability:** Ligand A (-4.638) has poor Caco-2 permeability. Ligand B (-5.297) is similarly poor.

**Aqueous Solubility:** Both ligands have very poor aqueous solubility (-2.574 and -1.784 respectively). This could pose formulation challenges.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.486 and 0.057).

**Microsomal Clearance:** Ligand A (25.673) has higher microsomal clearance than Ligand B (10.098), suggesting lower metabolic stability.

**In vitro Half-Life:** Ligand B (20.089) has a significantly longer in vitro half-life than Ligand A (-1.996).

**P-gp Efflux:** Both ligands show minimal P-gp efflux liability (0.141 and 0.011).

**Binding Affinity:** Both ligands have excellent binding affinity (-8.0 and -8.5 kcal/mol), with Ligand B being slightly more potent. However, the difference is less than the 1.5 kcal/mol threshold that would strongly favor one over the other.

**Overall Assessment:**

Ligand A excels in TPSA and QED, and has a much better BBB score. However, it suffers from poor Caco-2 permeability and higher metabolic clearance. Ligand B has a slightly better binding affinity and a longer half-life, but its lower logP and significantly worse BBB penetration are major drawbacks for a CNS-targeted drug. Given the importance of BBB penetration for DRD2 (a CNS target), Ligand A is the more promising candidate, despite its other weaknesses. The poor solubility and permeability of both compounds would require significant optimization, but the CNS exposure potential of Ligand A is a key advantage.

Output:
0
2025-04-17 08:02:08,266 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (355.467 and 337.423 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (75.34) is slightly higher than Ligand B (71.09). Both are below the 90 A^2 threshold desirable for CNS targets, but closer to the limit than ideal.

**3. logP:** Both ligands have good logP values (3.206 and 2.705), falling within the optimal 1-3 range.

**4. H-Bond Donors:** Both ligands have 2 HBD, which is within the acceptable limit of <=5.

**5. H-Bond Acceptors:** Ligand A has 7 HBA, and Ligand B has 3 HBA. Both are below the acceptable limit of <=10.

**6. QED:** Both ligands have good QED values (0.752 and 0.83), indicating good drug-like properties.

**7. DILI:** Both ligands have similar DILI risk (59.403 and 56.34), which is acceptable (below 60).

**8. BBB:** Ligand B (59.674) has a better BBB percentile than Ligand A (47.228). While neither is >70, Ligand B is closer. This is a key factor for a CNS target like DRD2.

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.964 and -4.644). These values are unusual and suggest poor permeability. However, these values are on a log scale and can be interpreted as very low permeability.

**10. Aqueous Solubility:** Both ligands have negative solubility values (-3.252 and -3.986). These values are unusual and suggest poor solubility.

**11. hERG Inhibition:** Both ligands have low hERG inhibition risk (0.629 and 0.238).

**12. Microsomal Clearance:** Ligand B (10.924) has significantly lower microsomal clearance than Ligand A (25.376), indicating better metabolic stability.

**13. In vitro Half-Life:** Ligand B (7.554) has a longer in vitro half-life than Ligand A (-24.505). The negative value for Ligand A is concerning and suggests very rapid degradation.

**14. P-gp Efflux:** Ligand A (0.157) has lower P-gp efflux than Ligand B (0.084), which is preferable for CNS penetration.

**15. Binding Affinity:** Ligand B (-9.3 kcal/mol) has a slightly better binding affinity than Ligand A (-10.1 kcal/mol). While both are excellent, the difference is not substantial enough to outweigh other factors.

**Overall Assessment:**

Ligand B is the more promising candidate. While both have issues with Caco-2 and solubility, Ligand B has a better BBB percentile, significantly better metabolic stability (lower Cl_mic and longer t1/2), and a slightly better binding affinity. The lower P-gp efflux for Ligand A is a plus, but the significantly better metabolic properties of Ligand B are more critical for a CNS drug. The negative half-life for Ligand A is a major red flag.

Output:
1
2025-04-17 08:02:08,266 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 drug candidates, considering the provided guidelines and GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight (MW):** Both ligands are within the ideal range (200-500 Da). Ligand A (345.447 Da) is slightly lower, which could be beneficial for permeability.

**2. TPSA:** Ligand A (70.81) is better than Ligand B (47.79) as it is closer to the ideal range for CNS targets (<=90).

**3. logP:** Ligand A (1.942) is optimal (1-3), while Ligand B (4.621) is high and could lead to solubility issues and off-target interactions.

**4. H-Bond Donors (HBD):** Both ligands have acceptable HBD counts (Ligand A: 0, Ligand B: 1), well below the limit of 5.

**5. H-Bond Acceptors (HBA):** Both ligands have acceptable HBA counts (Ligand A: 5, Ligand B: 5), well below the limit of 10.

**6. QED:** Both ligands have good QED scores (Ligand A: 0.769, Ligand B: 0.803), indicating drug-like properties.

**7. DILI:** Ligand A (39.356) has a lower DILI risk than Ligand B (53.354), which is preferable. Both are below the 60 threshold, but A is better.

**8. BBB:** Both ligands have good BBB penetration (Ligand A: 72.237, Ligand B: 77.898), exceeding the 70% threshold for CNS targets. Ligand B is slightly better.

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 values, which is unusual and suggests poor permeability. This is a significant concern for both.

**10. Aqueous Solubility:** Ligand A (-1.488) is better than Ligand B (-4.525), indicating better solubility.

**11. hERG Inhibition:** Both ligands have low hERG inhibition risk (Ligand A: 0.534, Ligand B: 0.91).

**12. Microsomal Clearance (Cl_mic):** Ligand A (56.097) has higher clearance than Ligand B (43.291), meaning Ligand B is more metabolically stable.

**13. In vitro Half-Life (t1/2):** Ligand B (90.867) has a significantly longer half-life than Ligand A (21.147), which is a major advantage.

**14. P-gp Efflux:** Both ligands have low P-gp efflux liability (Ligand A: 0.183, Ligand B: 0.699), which is good for CNS exposure. Ligand A is better.

**15. Binding Affinity:** Ligand B (-7.6 kcal/mol) has a significantly stronger binding affinity than Ligand A (-8.0 kcal/mol). This is a substantial advantage, potentially outweighing some of the ADME drawbacks.

**Overall Assessment:**

While Ligand B has a superior binding affinity and longer half-life, Ligand A demonstrates better physicochemical properties (logP, TPSA, solubility, DILI, P-gp efflux) crucial for CNS penetration and reduced toxicity. The negative Caco-2 values are concerning for both, but the other properties of Ligand A are more favorable for a GPCR targeting the CNS. The affinity difference is not large enough to overcome the ADME advantages of Ligand A.

Output:
1
2025-04-17 08:02:08,266 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (419.235 Da) is higher, but still acceptable. Ligand B (343.431 Da) is slightly preferred.

**TPSA:** Both ligands have TPSA values around 80-81, which is above the optimal <90 for CNS targets, but not drastically so. This isn't a major differentiating factor.

**logP:** Ligand A (4.5) is higher than the optimal range (1-3), potentially leading to solubility issues and off-target interactions. Ligand B (0.989) is slightly below the optimal range, which *could* hinder permeability, but is less concerning than Ligand A's high logP.

**H-Bond Donors/Acceptors:** Both have acceptable HBD (1) and HBA (6/5) counts, well within the guidelines.

**QED:** Both ligands have good QED scores (0.529 and 0.781), indicating drug-like properties. Ligand B is slightly better.

**DILI:** Ligand A has a very high DILI risk (99.729%), which is a major red flag. Ligand B has a much lower and acceptable DILI risk (32.067%).

**BBB:** Ligand B has a significantly better BBB penetration percentile (70.027%) than Ligand A (56.456%). This is crucial for a CNS target like DRD2.

**Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and suggests poor permeability. However, the scale isn't specified, so it's hard to interpret.

**Aqueous Solubility:** Both have negative solubility values, which is also unusual and suggests poor solubility.

**hERG Inhibition:** Ligand A (0.582) has a slightly higher hERG inhibition risk than Ligand B (0.067), which is preferable.

**Microsomal Clearance:** Ligand A (65.522) has a higher microsomal clearance than Ligand B (18.521), indicating lower metabolic stability.

**In vitro Half-Life:** Ligand B has a negative half-life (-2.059 hours), which is concerning and likely an error. Ligand A has a longer half-life (68.227 hours).

**P-gp Efflux:** Ligand A (0.536) has a moderate P-gp efflux liability, while Ligand B (0.036) has very low efflux, which is highly desirable for CNS penetration.

**Binding Affinity:** Ligand B (-9.1 kcal/mol) has a slightly better binding affinity than Ligand A (-10.3 kcal/mol). While the difference isn't huge, it's still a positive for Ligand B.

**Overall Assessment:**

Ligand A has a severe DILI risk, higher logP, higher clearance, and moderate P-gp efflux. While its binding affinity and half-life are better, these are overshadowed by the significant liabilities. Ligand B has a much better safety profile (lower DILI), better BBB penetration, lower P-gp efflux, and slightly better affinity. The negative values for Caco-2 and solubility are concerning for both, but the other factors strongly favor Ligand B.

Output:
1
2025-04-17 08:02:08,266 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (343.43 and 352.30 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (74.69) is significantly better than Ligand B (127.24).  For CNS targets, we want TPSA <= 90, and A is comfortably within this, while B is above.

**logP:** Ligand A (2.027) is optimal (1-3). Ligand B (0.629) is a bit low, potentially hindering membrane permeability.

**H-Bond Donors:** Both have 2 HBD, which is acceptable (<=5).

**H-Bond Acceptors:** Ligand A has 5 HBA, and Ligand B has 7. Both are within the acceptable range of <=10.

**QED:** Both ligands have good QED scores (0.869 and 0.826, both >= 0.5).

**DILI:** Ligand A (45.522) has a much lower DILI risk than Ligand B (84.18).  A score < 40 is good, and A is closer to that than B.

**BBB:** Both have reasonably good BBB penetration (66.654 and 70.997). While >70 is desirable, both are acceptable, but B is slightly better.

**Caco-2:** Ligand A (-4.689) and Ligand B (-5.349) both have negative Caco-2 values, which is unusual and suggests poor permeability. However, the scale isn't specified, so it's difficult to interpret.

**Solubility:** Both have negative solubility values (-2.651 and -3.163), again making interpretation difficult without knowing the scale.

**hERG:** Ligand A (0.807) has a lower hERG risk than Ligand B (0.19). Lower is better.

**Microsomal Clearance:** Ligand A (14.84) has a lower (better) microsomal clearance than Ligand B (-10.235). Lower clearance indicates greater metabolic stability.

**In vitro Half-Life:** Ligand A (15.223) has a significantly longer half-life than Ligand B (-19.177).

**P-gp Efflux:** Ligand A (0.155) has lower P-gp efflux than Ligand B (0.006), meaning it's less likely to be pumped out of the brain, which is crucial for CNS targets.

**Binding Affinity:** Ligand B (-8.6 kcal/mol) has a significantly stronger binding affinity than Ligand A (-7.0 kcal/mol). This is a substantial advantage.

**Overall Assessment:**

Ligand B has a significantly better binding affinity, which is a major plus. However, it suffers from a higher TPSA, lower logP, higher DILI risk, higher P-gp efflux, and significantly worse metabolic stability (higher clearance, shorter half-life). Ligand A has more favorable ADME properties, especially regarding BBB penetration, metabolic stability, and safety (DILI, hERG). The difference in binding affinity (1.6 kcal/mol) is substantial, but the ADME drawbacks of Ligand B are concerning for a CNS target. Given the GPCR-specific priorities, the balance tips towards Ligand A due to its superior predicted CNS exposure and safety profile, despite the weaker binding.

Output:
0
2025-04-17 08:02:08,267 - INFO - Batch 415 complete. Total preferences: 6640
2025-04-17 08:02:08,267 - INFO - Processing batch 416/512...
2025-04-17 08:02:56,944 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (352.395 and 342.443 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (121.61) is slightly above the preferred <90 for CNS targets, while Ligand B (58.44) is well within the range. This favors Ligand B.

**logP:** Ligand A (-0.907) is a bit low, potentially hindering permeability. Ligand B (1.459) is within the optimal 1-3 range. This strongly favors Ligand B.

**H-Bond Donors/Acceptors:** Ligand A has 3 HBD and 7 HBA, acceptable values. Ligand B has 0 HBD and 4 HBA, also acceptable.

**QED:** Both ligands have good QED scores (0.645 and 0.736), indicating good drug-like properties.

**DILI:** Ligand A (62.776) has a higher DILI risk than Ligand B (29.391). This favors Ligand B.

**BBB:** Ligand B (82.668) has a significantly better BBB penetration score than Ligand A (63.862). This is a critical advantage for a CNS target like DRD2.

**Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and suggests poor permeability. However, the scale is not specified, so it's hard to interpret.

**Aqueous Solubility:** Both have negative solubility values, also unusual. Again, the scale is not specified.

**hERG:** Both ligands have very low hERG inhibition risk (0.024 and 0.268).

**Microsomal Clearance:** Ligand A (5.319) has a lower (better) microsomal clearance than Ligand B (29.911), suggesting greater metabolic stability.

**In vitro Half-Life:** Ligand B (-9.933) has a negative half-life, which is not physically possible and indicates a problem with the data. Ligand A (20.314) has a reasonable half-life.

**P-gp Efflux:** Both have very low P-gp efflux liability (0.005 and 0.145).

**Binding Affinity:** Both ligands have similar binding affinities (-8 and -6.6 kcal/mol). Ligand A is significantly more potent.

**Overall Assessment:**

Ligand B excels in key properties for a CNS-targeting GPCR ligand: TPSA, logP, BBB, and DILI. While its microsomal clearance is higher and half-life is problematic (negative value), its superior BBB penetration and favorable logP outweigh these drawbacks. Ligand A has better metabolic stability and a stronger binding affinity, but its poor logP and lower BBB penetration are significant concerns. The negative half-life for Ligand B is a major red flag, but the other properties are so much better that it is still the preferred candidate.

Output:
1
2025-04-17 08:02:56,944 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (349.475 and 350.503 Da) fall comfortably within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (67.6) is significantly better than Ligand B (78.43). For CNS targets, we want TPSA <= 90, and ideally closer to 60. Ligand A is much closer to this ideal.

**3. logP:** Both ligands have good logP values (2.553 and 2.375), falling within the optimal 1-3 range.

**4. H-Bond Donors:** Ligand A (1) is preferable to Ligand B (3). Fewer HBDs generally improve permeability.

**5. H-Bond Acceptors:** Ligand A (6) is better than Ligand B (3). Lower HBA is better for permeability.

**6. QED:** Ligand A (0.763) has a higher QED score than Ligand B (0.629), indicating a more drug-like profile.

**7. DILI:** Ligand A (9.151) has a much lower DILI risk than Ligand B (15.006). This is a significant advantage for Ligand A.

**8. BBB:** Ligand A (72.664) has a better BBB percentile than Ligand B (53.432). While both are not exceptionally high, Ligand A is closer to the desirable >70 threshold for CNS targets.

**9. Caco-2 Permeability:** Ligand A (-4.994) has a better Caco-2 permeability than Ligand B (-4.799).

**10. Aqueous Solubility:** Ligand A (-1.549) has a better Aqueous Solubility than Ligand B (-3.07).

**11. hERG Inhibition:** Ligand A (0.752) has a lower hERG inhibition liability than Ligand B (0.277), which is favorable.

**12. Microsomal Clearance:** Ligand A (49.16) has a slightly better microsomal clearance than Ligand B (50.178).

**13. In vitro Half-Life:** Ligand A (1.362) has a better in vitro half-life than Ligand B (-10.609).

**14. P-gp Efflux:** Ligand A (0.112) has a lower P-gp efflux liability than Ligand B (0.202), which is favorable for CNS penetration.

**15. Binding Affinity:** Ligand B (-8.5 kcal/mol) has a slightly stronger binding affinity than Ligand A (-7.2 kcal/mol). However, the difference is not substantial enough to outweigh the numerous advantages of Ligand A across ADME properties.

**Overall Assessment:**

Ligand A consistently outperforms Ligand B in almost all ADME properties crucial for a CNS-targeting GPCR ligand. While Ligand B has a slightly better binding affinity, Ligand A's superior TPSA, BBB penetration, lower DILI risk, better solubility, and lower P-gp efflux make it the more promising drug candidate. The difference in binding affinity (1.3 kcal/mol) is unlikely to overcome the significant ADME advantages of Ligand A.

Output:
0
2025-04-17 08:02:56,944 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (344.39 and 350.48 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (58.64) is slightly higher than Ligand B (49.41). Both are below the 90 A^2 threshold for CNS targets, which is good.

**logP:** Both ligands have good logP values (3.71 and 3.51), falling within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Both have 1 HBD, which is acceptable. Ligand A has 3 HBA, while Ligand B has 2. Both are within the acceptable limit of <=10.

**QED:** Both ligands have QED values above 0.75, indicating good drug-likeness.

**DILI:** Ligand A has a significantly higher DILI risk (62.89%) compared to Ligand B (20.82%). This is a major concern for Ligand A.

**BBB:** Ligand B (96.16%) has a much higher predicted BBB penetration than Ligand A (82.63%). This is crucial for a CNS target like DRD2.

**Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and difficult to interpret without knowing the scale. However, the values are similar.

**Aqueous Solubility:** Both ligands have negative solubility values, which is also unusual and difficult to interpret. Again, the values are similar.

**hERG:** Both ligands have low hERG inhibition liability (0.83 and 0.64), which is favorable.

**Microsomal Clearance:** Ligand B (31.19 mL/min/kg) has a significantly lower microsomal clearance than Ligand A (76.60 mL/min/kg), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand B (-1.15 hours) has a slightly better (less negative) in vitro half-life than Ligand A (-17.05 hours).

**P-gp Efflux:** Ligand A (0.23) has a slightly lower P-gp efflux liability than Ligand B (0.27), which is slightly favorable for CNS penetration.

**Binding Affinity:** Ligand B (-7.9 kcal/mol) has a significantly stronger binding affinity than Ligand A (-9.5 kcal/mol). This is a substantial advantage.

**Overall Assessment:**

Ligand B is the superior candidate. While both meet general drug-likeness criteria, Ligand B excels in critical areas for a CNS-targeting GPCR ligand: significantly better BBB penetration, lower DILI risk, better metabolic stability (lower Cl_mic), and a much stronger binding affinity. The slightly lower P-gp efflux of Ligand A is a minor advantage that is outweighed by the other benefits of Ligand B.

Output:
1
2025-04-17 08:02:56,945 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (361.389 and 391.43 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (96.53) is excellent, falling well below the 90 A^2 threshold for CNS targets. Ligand B (117.62) is still reasonable, but less optimal.

**3. logP:** Both ligands (1.033 and 0.792) are within the optimal 1-3 range.

**4. H-Bond Donors:** Both ligands have 3 HBD, which is acceptable.

**5. H-Bond Acceptors:** Ligand A has 4 HBA, and Ligand B has 7 HBA. Both are within the acceptable limit of 10, but Ligand A is preferable.

**6. QED:** Both ligands have similar QED values (0.4 and 0.421), indicating moderate drug-likeness.

**7. DILI:** Ligand A (31.563) has a much lower DILI risk than Ligand B (57.154), placing it in the 'good' category while Ligand B is approaching the higher risk threshold.

**8. BBB:** This is a critical parameter for a CNS target like DRD2. Ligand A has a BBB percentile of 80.458, which is excellent (>70). Ligand B has a significantly lower BBB percentile of 32.028, which is a major drawback.

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.524 and -5.746). This is unusual and suggests poor permeability. However, the values are similar.

**10. Aqueous Solubility:** Both ligands have negative solubility values (-2.367 and -1.793), indicating poor aqueous solubility. This is a concern for bioavailability.

**11. hERG Inhibition:** Both ligands have low hERG inhibition liability (0.246 and 0.272), which is good.

**12. Microsomal Clearance:** Ligand A (-8.408) has a much lower (better) microsomal clearance than Ligand B (13.304), suggesting greater metabolic stability.

**13. In vitro Half-Life:** Ligand A (1.279) has a shorter half-life than Ligand B (17.492). This is a negative for Ligand A, but could be addressed with structural modifications.

**14. P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.022 and 0.035), which is favorable for CNS penetration.

**15. Binding Affinity:** Ligand A (-7.6 kcal/mol) has a slightly better binding affinity than Ligand B (-6.9 kcal/mol). While the difference is less than the 1.5 kcal/mol threshold, it contributes to the overall preference for Ligand A.

**Overall Assessment:**

Ligand A is significantly more promising due to its superior BBB penetration, lower DILI risk, and better metabolic stability (lower Cl_mic). While Ligand B has a longer half-life, the poor BBB penetration and higher DILI risk are major concerns for a CNS-targeting drug. The slightly better affinity of Ligand A further supports its selection.

Output:
1
2025-04-17 08:02:56,945 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (362.495 and 368.543 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (62.55) is better than Ligand B (49.85). Both are below the 90 A^2 threshold for CNS targets, which is excellent.

**3. logP:** Both ligands (2.523 and 2.562) are within the optimal 1-3 range.

**4. H-Bond Donors:** Ligand A has 1 HBD, while Ligand B has 0. Both are acceptable (<=5).

**5. H-Bond Acceptors:** Both ligands have 4 HBAs, well within the acceptable limit of <=10.

**6. QED:** Ligand A (0.845) has a significantly higher QED than Ligand B (0.648), indicating a more drug-like profile.

**7. DILI:** Ligand A (23.226) has a slightly higher DILI risk than Ligand B (19.891), but both are well below the concerning threshold of 60.

**8. BBB:** Ligand B (73.943) has a substantially better BBB penetration percentile than Ligand A (64.482). This is a crucial factor for a CNS target like DRD2.

**9. Caco-2 Permeability:** Ligand A (-5.307) has worse Caco-2 permeability than Ligand B (-4.655), suggesting lower intestinal absorption.

**10. Aqueous Solubility:** Ligand A (-2.875) has worse aqueous solubility than Ligand B (-2.544).

**11. hERG Inhibition:** Both ligands have low hERG inhibition risk (0.254 and 0.529, respectively).

**12. Microsomal Clearance:** Ligand A (32.204) has lower microsomal clearance than Ligand B (47.031), suggesting better metabolic stability.

**13. In vitro Half-Life:** Ligand A (31.308) has a longer in vitro half-life than Ligand B (-0.916).

**14. P-gp Efflux:** Ligand A (0.149) has lower P-gp efflux than Ligand B (0.1), which is favorable for CNS penetration.

**15. Binding Affinity:** Ligand A (-7.8 kcal/mol) has a slightly better binding affinity than Ligand B (-7.6 kcal/mol). While the difference is small (0.2 kcal/mol), it's still a positive.

**Overall Assessment:**

Ligand B is superior due to its significantly better BBB penetration (73.943 vs. 64.482) and Caco-2 permeability. While Ligand A has a slightly better binding affinity, longer half-life, and lower clearance, the BBB is the most important factor for a CNS target. The higher QED of Ligand A is also a positive, but the BBB advantage of Ligand B outweighs this.

Output:
1
2025-04-17 08:02:56,945 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B based on the provided guidelines, prioritizing GPCR-specific properties (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (348.443 and 344.346 Da) fall comfortably within the ideal 200-500 Da range.

**TPSA:** Ligand A (67.87) is significantly better than Ligand B (110.25). For CNS targets, we want TPSA <= 90, and A is much closer to this threshold. B is quite high and may hinder BBB penetration.

**logP:** Both ligands have good logP values (1.684 and 1.469), falling within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A (HBD=1, HBA=4) is preferable to Ligand B (HBD=3, HBA=5) as it has fewer hydrogen bond forming groups, which generally improves permeability. Both are within acceptable limits.

**QED:** Ligand A (0.814) has a significantly higher QED score than Ligand B (0.562), indicating a more drug-like profile.

**DILI:** Ligand A (38.503) has a much lower DILI risk than Ligand B (81.311). This is a significant advantage for A.

**BBB:** Ligand A (73.827) has a better BBB percentile than Ligand B (62.156). While both are not exceptionally high, A is closer to the desirable >70 for CNS targets.

**Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and suggests poor permeability. However, the absolute value is smaller for Ligand A (-4.198 vs -4.871), suggesting slightly better permeability.

**Aqueous Solubility:** Both have negative solubility values, indicating poor aqueous solubility. Ligand A (-2.349) is slightly better than Ligand B (-3.564).

**hERG:** Both ligands have very low hERG inhibition liability (0.192 and 0.443), which is excellent.

**Microsomal Clearance:** Ligand A (67.506) has higher microsomal clearance than Ligand B (41.468), meaning it is less metabolically stable. This is a drawback for A.

**In vitro Half-Life:** Ligand B (-18.619) has a much longer in vitro half-life than Ligand A (-3.186). This is a significant advantage for B.

**P-gp Efflux:** Both have very low P-gp efflux liability (0.069 and 0.093).

**Binding Affinity:** Ligand B (-8.9 kcal/mol) has a slightly better binding affinity than Ligand A (-7.7 kcal/mol). The difference is 1.2 kcal/mol, which is significant, but needs to be weighed against other factors.

**Overall Assessment:**

Ligand A excels in TPSA, QED, DILI, and BBB, all crucial for a CNS-targeting GPCR ligand. Its slightly better Caco-2 and solubility are also beneficial. However, its higher microsomal clearance and shorter half-life are concerning.

Ligand B has a better binding affinity and a significantly longer half-life, but suffers from a higher TPSA, lower QED, and higher DILI risk. The higher TPSA is a major concern for CNS penetration.

Considering the GPCR-specific priorities, the balance of properties leans towards Ligand A. The superior BBB, TPSA, and DILI profile outweigh the slightly weaker affinity and poorer metabolic stability, especially given the potential for optimization of metabolic stability.

Output:
0
2025-04-17 08:02:56,945 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (349.475 and 349.406 Da) fall comfortably within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (78.51) is better than Ligand B (85.43). Both are below the 90 A^2 threshold desirable for CNS targets, but A is closer to the optimal range.

**3. logP:** Both ligands (1.612 and 1.734) are within the optimal 1-3 range.

**4. H-Bond Donors:** Ligand A (2) is preferable to Ligand B (3). Lower HBD generally improves permeability.

**5. H-Bond Acceptors:** Both ligands have 3 HBA, which is acceptable.

**6. QED:** Ligand A (0.765) is slightly better than Ligand B (0.708), indicating a more drug-like profile.

**7. DILI:** Ligand A (32.299) has a significantly lower DILI risk than Ligand B (47.77). Both are below the concerning 60 threshold, but A is much safer.

**8. BBB:** Both ligands have similar BBB penetration (63.125 and 63.28). While not exceeding the desirable >70 for CNS targets, they are reasonably good.

**9. Caco-2 Permeability:** Ligand A (-4.748) has better Caco-2 permeability than Ligand B (-5.239).

**10. Aqueous Solubility:** Ligand A (-2.355) has better aqueous solubility than Ligand B (-2.909).

**11. hERG Inhibition:** Ligand A (0.104) has a lower hERG inhibition liability than Ligand B (0.412), reducing cardiotoxicity risk.

**12. Microsomal Clearance:** Ligand A (42.897) has higher microsomal clearance than Ligand B (10.887), indicating lower metabolic stability. This is a negative for A.

**13. In vitro Half-Life:** Ligand A (3.089) has a shorter in vitro half-life than Ligand B (0.051). This is a negative for A.

**14. P-gp Efflux:** Ligand A (0.044) has lower P-gp efflux than Ligand B (0.085), which is favorable for CNS penetration.

**15. Binding Affinity:** Ligand B (-9.1 kcal/mol) has a significantly stronger binding affinity than Ligand A (-8.5 kcal/mol). This is a substantial advantage for B, potentially outweighing some ADME drawbacks. The difference is >1.5 kcal/mol.

**Overall Assessment:**

Ligand A has advantages in several key ADME properties (TPSA, DILI, hERG, Solubility, P-gp efflux, Caco-2 permeability) and QED. However, Ligand B boasts a significantly stronger binding affinity (-9.1 vs -8.5 kcal/mol). For a GPCR target like DRD2, strong binding is paramount. While Ligand A is generally more "drug-like" in terms of ADME, the substantial affinity advantage of Ligand B, coupled with acceptable (though not ideal) ADME properties, makes it the more promising candidate. The slightly higher DILI and P-gp efflux can be addressed with further optimization.

Output:
1
2025-04-17 08:02:56,945 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (341.455 and 356.482 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (73.99) is slightly higher than Ligand B (67.43). Both are below the 90 A^2 threshold desirable for CNS targets, but Ligand B is preferable.

**3. logP:** Both ligands (2.763 and 2.61) are within the optimal 1-3 range.

**4. H-Bond Donors:** Both have 2 HBD, which is acceptable (<=5).

**5. H-Bond Acceptors:** Ligand A has 2 HBA, Ligand B has 3. Both are below the 10 threshold.

**6. QED:** Both ligands have similar QED values (0.636 and 0.591), indicating good drug-likeness.

**7. DILI:** Both ligands have very similar DILI risk (26.173 and 26.871 percentile), both being quite low and acceptable.

**8. BBB:** Ligand B (73.711) has a significantly better BBB penetration percentile than Ligand A (65.374). This is a crucial factor for a CNS target like DRD2.

**9. Caco-2 Permeability:** Ligand A (-5.171) has a worse Caco-2 permeability than Ligand B (-4.762).

**10. Aqueous Solubility:** Both ligands have very poor aqueous solubility (-3.13 and -3.119). This is a potential issue, but can sometimes be mitigated with formulation strategies.

**11. hERG Inhibition:** Both ligands have a low hERG inhibition risk (0.312 and 0.528).

**12. Microsomal Clearance:** Ligand A (23.075) has a lower microsomal clearance than Ligand B (54.349), suggesting better metabolic stability.

**13. In vitro Half-Life:** Ligand A (-20.267) has a significantly longer in vitro half-life than Ligand B (14.937). This is a strong advantage for Ligand A.

**14. P-gp Efflux:** Both ligands have low P-gp efflux liability (0.12 and 0.101).

**15. Binding Affinity:** Ligand A (-8.6 kcal/mol) has a stronger binding affinity than Ligand B (-7.3 kcal/mol). This is a 1.3 kcal/mol difference, which is substantial and can outweigh some ADME drawbacks.

**Overall Assessment:**

While Ligand A has better metabolic stability and half-life, and significantly better binding affinity, Ligand B has a much better BBB penetration. Given that DRD2 is a CNS target, BBB penetration is paramount. The affinity difference is significant, but not so overwhelming that it completely negates the importance of getting the drug into the brain. The slightly better Caco-2 permeability of Ligand B is also a minor plus.

Output:
1
2025-04-17 08:02:56,945 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B based on the provided criteria, prioritizing GPCR-specific properties (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (362.451 Da) is slightly lower than Ligand B (387.571 Da), which is generally favorable for permeability.

**TPSA:** Both ligands are below the 140 A^2 threshold for oral absorption, but only Ligand A (96.1 A^2) is close to the stricter <90 A^2 threshold preferred for CNS targets. Ligand B (101.29 A^2) is a bit higher.

**logP:** Both ligands have optimal logP values (1-3), with Ligand A (1.892) being slightly higher than Ligand B (1.302).

**H-Bond Donors/Acceptors:** Ligand A (HBD=2, HBA=4) is better than Ligand B (HBD=3, HBA=5) in terms of maintaining a balance between solubility and permeability.

**QED:** Ligand A (0.82) has a significantly better QED score than Ligand B (0.491), indicating a more drug-like profile.

**DILI:** Ligand B (25.165) has a much lower DILI risk than Ligand A (66.421), a significant advantage.

**BBB:** Ligand A (61.497) has a better BBB percentile than Ligand B (57.58), but neither are above the desirable >70 threshold.

**Caco-2 Permeability:** Ligand A (-5.256) has better Caco-2 permeability than Ligand B (-5.732).

**Aqueous Solubility:** Both ligands have similar, very poor aqueous solubility (-3.521 and -3.108 respectively).

**hERG:** Both ligands have very low hERG inhibition risk (0.321 and 0.086 respectively).

**Microsomal Clearance:** Ligand A (8.676 mL/min/kg) has significantly lower microsomal clearance than Ligand B (39.016 mL/min/kg), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (27.357 hours) has a much longer in vitro half-life than Ligand B (-18.157 hours).

**P-gp Efflux:** Ligand A (0.11) has lower P-gp efflux liability than Ligand B (0.033), which is favorable for CNS exposure.

**Binding Affinity:** Ligand A (-8.9 kcal/mol) has a significantly stronger binding affinity than Ligand B (-6.9 kcal/mol). This is a substantial advantage, potentially outweighing some of the ADME drawbacks.

**Overall Assessment:**

Ligand A excels in key areas for a CNS-targeting GPCR ligand: significantly better binding affinity, better TPSA, better QED, lower Cl_mic, longer t1/2, and lower Pgp efflux. While Ligand B has a much better DILI score, the substantial improvement in affinity and metabolic stability with Ligand A is more critical for this target class. The slightly better BBB for Ligand A is a bonus. The poor solubility of both compounds is a concern, but can be addressed with formulation strategies.

Output:
1
2025-04-17 08:02:56,945 - INFO - Reasoning:

Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (365.415 and 367.456 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (117.43) is higher than the preferred <90 for CNS targets, while Ligand B (61.44) is well within the desired range. This is a significant advantage for Ligand B.

**3. logP:** Ligand A (0.541) is quite low, potentially hindering membrane permeability. Ligand B (2.562) is within the optimal 1-3 range. This favors Ligand B.

**4. H-Bond Donors:** Both ligands have 2 HBD, which is acceptable.

**5. H-Bond Acceptors:** Ligand A has 7 HBA, acceptable. Ligand B has 3 HBA, also acceptable.

**6. QED:** Both ligands have reasonable QED scores (0.767 and 0.624), indicating good drug-like properties.

**7. DILI:** Ligand A has a high DILI risk (85.576%), which is concerning. Ligand B has a very low DILI risk (14.889%), a major advantage.

**8. BBB:** Both ligands have similar BBB penetration (62.854% and 61.807%). While not exceeding the ideal >70%, they are comparable.

**9. Caco-2 Permeability:** Both have negative Caco-2 values (-5.306 and -5.067), which is unusual and suggests poor permeability. However, these values are on a scale where negative values are possible, and direct comparison is difficult without knowing the scale's specifics.

**10. Aqueous Solubility:** Both have negative solubility values (-3.376 and -2.165), indicating poor aqueous solubility. Again, scale specifics are needed for a proper comparison.

**11. hERG Inhibition:** Ligand A (0.315) has a slightly lower hERG risk than Ligand B (0.685), which is preferable.

**12. Microsomal Clearance:** Ligand A (41.777) has higher microsomal clearance than Ligand B (29.082), indicating lower metabolic stability. Ligand B is favored.

**13. In vitro Half-Life:** Ligand A (29.625) has a slightly longer half-life than Ligand B (20.107).

**14. P-gp Efflux:** Ligand A (0.05) has lower P-gp efflux than Ligand B (0.022), which is better for CNS penetration.

**15. Binding Affinity:** Ligand B (-7.2 kcal/mol) has a significantly stronger binding affinity than Ligand A (-8.5 kcal/mol). This is a substantial advantage, potentially outweighing some of the ADME drawbacks.

**Overall Assessment:**

Considering the GPCR-specific priorities, Ligand B is the more promising candidate. It has a much lower DILI risk, a better logP value, a significantly better TPSA, and a stronger binding affinity. While both have issues with Caco-2 permeability and solubility, the superior ADME profile and binding affinity of Ligand B make it the better choice. The slightly longer half-life of Ligand A is not enough to offset the other disadvantages.

Output:
1
2025-04-17 08:02:56,946 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (364.471 and 359.579 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (84.3) is excellent for CNS penetration, being well below 90. Ligand B (20.31) is even better, extremely low and favorable.

**logP:** Ligand A (1.565) is within the optimal 1-3 range. Ligand B (4.801) is slightly high, potentially leading to solubility issues and off-target interactions, but not drastically so.

**H-Bond Donors/Acceptors:** Ligand A has 1 HBD and 5 HBA, which are acceptable. Ligand B has 0 HBD and 2 HBA, also acceptable.

**QED:** Ligand A (0.835) has a very strong drug-like profile. Ligand B (0.664) is still reasonably good, above the 0.5 threshold.

**DILI:** Ligand A (49.477) has a moderate DILI risk, but still within a reasonable range. Ligand B (16.751) has a very low DILI risk, which is a significant advantage.

**BBB:** Ligand A (85.343) has good BBB penetration. Ligand B (92.361) is even better, exceeding 90% and highly desirable for a CNS target.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.954 and -5.023), which is unusual and indicates poor permeability. This is a major concern for both.

**Aqueous Solubility:** Both ligands have negative solubility values (-1.891 and -4.959), indicating very poor aqueous solubility. This is a significant drawback for both.

**hERG Inhibition:** Ligand A (0.539) has a low hERG risk. Ligand B (0.927) has a slightly higher, but still acceptable, hERG risk.

**Microsomal Clearance:** Ligand A (21.561) has a relatively low clearance, suggesting better metabolic stability. Ligand B (139.207) has a very high clearance, indicating rapid metabolism and a potential issue for maintaining therapeutic concentrations.

**In vitro Half-Life:** Ligand A (22.121) has a reasonable half-life. Ligand B (27.973) has a slightly longer half-life, which is positive.

**P-gp Efflux:** Ligand A (0.169) has low P-gp efflux, which is favorable for CNS exposure. Ligand B (0.789) has moderate P-gp efflux, which could limit CNS penetration.

**Binding Affinity:** Ligand A (0.0) has no binding affinity. Ligand B (-8.2) has a very strong binding affinity. This is a decisive factor.

**Overall Assessment:**

Despite the poor Caco-2 and solubility for both, Ligand B stands out due to its significantly stronger binding affinity (-8.2 kcal/mol vs 0.0 kcal/mol). The better BBB penetration, lower DILI risk, and longer half-life also contribute to its favorability. While the higher logP and P-gp efflux are minor concerns, the substantial affinity advantage outweighs these drawbacks for a GPCR target like DRD2. Ligand A's lack of binding affinity is a deal-breaker.

Output:
1
2025-04-17 08:02:56,946 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (341.411 and 350.34 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (73.1) is better than Ligand B (53.43). For CNS targets, we want TPSA <= 90, both are well within this range, but A is slightly higher.

**3. logP:** Ligand A (2.397) is optimal (1-3). Ligand B (3.78) is pushing the upper limit but still acceptable.

**4. H-Bond Donors:** Both ligands have 1 HBD, which is good.

**5. H-Bond Acceptors:** Ligand A has 5 HBA, and Ligand B has 3. Both are within the acceptable range of <=10.

**6. QED:** Ligand A (0.928) has a significantly better QED score than Ligand B (0.773), indicating a more drug-like profile.

**7. DILI:** Ligand A (64.754) has a higher DILI risk than Ligand B (46.064). This is a negative for Ligand A.

**8. BBB:** Ligand A (75.572) has a better BBB penetration percentile than Ligand B (68.321). This is crucial for a CNS target like DRD2.

**9. Caco-2:** Both have negative values, which is unusual. Assuming these are logP values, they indicate poor permeability.

**10. Solubility:** Both have negative values, indicating poor solubility.

**11. hERG:** Ligand A (0.443) has a lower hERG inhibition liability than Ligand B (0.681), which is favorable.

**12. Cl_mic:** Ligand A (10.426) has a lower microsomal clearance than Ligand B (72.996), suggesting better metabolic stability.

**13. t1/2:** Ligand A (11.631) has a shorter in vitro half-life than Ligand B (-37.661). The negative value for B is concerning and likely an error or outlier.

**14. Pgp:** Ligand A (0.193) has lower P-gp efflux liability than Ligand B (0.264), which is beneficial for CNS penetration.

**15. Binding Affinity:** Ligand A (-8.9 kcal/mol) has a significantly stronger binding affinity than Ligand B (-7.8 kcal/mol). This is a substantial advantage.

**Overall Assessment:**

Ligand A is superior despite the slightly higher DILI risk. The stronger binding affinity (-8.9 vs -7.8 kcal/mol) is a significant advantage, and it's supported by better BBB penetration, lower P-gp efflux, lower hERG inhibition, and better metabolic stability (lower Cl_mic). The QED score is also much better for Ligand A. The negative values for Caco-2 and solubility are concerning for both, but the affinity difference is likely to outweigh these issues.

Output:
1
2025-04-17 08:02:56,946 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (350.415 and 352.475 Da) fall comfortably within the ideal 200-500 Da range.

**TPSA:** Ligand A (88.1) is better than Ligand B (59.08). Both are below the 90 A^2 threshold for CNS targets, but Ligand B is significantly lower, which is favorable for brain penetration.

**logP:** Ligand A (0.489) is a bit low, potentially hindering membrane permeability. Ligand B (1.82) is within the optimal 1-3 range. This is a significant advantage for Ligand B.

**H-Bond Donors/Acceptors:** Ligand A has 2 HBD and 5 HBA, while Ligand B has 0 HBD and 4 HBA. Both are within acceptable limits.

**QED:** Both ligands have similar QED values (0.712 and 0.701), indicating good drug-likeness.

**DILI:** Ligand A (45.328) has a moderate DILI risk, while Ligand B (8.647) has a very low risk. This is a clear advantage for Ligand B.

**BBB:** Ligand B (83.908) is excellent, exceeding the >70% threshold for CNS targets. Ligand A (42.226) is considerably lower, raising concerns about brain penetration. This is a critical advantage for Ligand B.

**Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and suggests poor permeability. However, the scale is not specified, so it's hard to interpret.

**Aqueous Solubility:** Both ligands have negative solubility values, which is also unusual and suggests poor aqueous solubility.

**hERG:** Both ligands have low hERG inhibition liability (0.123 and 0.324), which is good.

**Microsomal Clearance:** Ligand A (-1.214) has a negative clearance, which is not possible and suggests an error in the data. Ligand B (28.218) has a relatively high clearance, indicating faster metabolism.

**In vitro Half-Life:** Ligand A (9.373) has a longer half-life than Ligand B (-0.069), which is a positive.

**P-gp Efflux:** Ligand A (0.087) has lower P-gp efflux liability than Ligand B (0.084), which is slightly favorable.

**Binding Affinity:** Ligand B (-7.8 kcal/mol) has a slightly better binding affinity than Ligand A (-7.4 kcal/mol). While the difference is not huge, it's still a positive for Ligand B.

**Overall:**

Considering the GPCR-specific priorities, Ligand B is the superior candidate. It has a much better BBB score, a more favorable logP, and a significantly lower DILI risk. The slightly better binding affinity and lower logP further strengthen its profile. The negative clearance value for Ligand A is a major red flag. Although both have issues with Caco-2 and solubility, the CNS target profile of DRD2 makes BBB and logP the most important factors here, and Ligand B excels in those areas.

Output:
1
2025-04-17 08:02:56,946 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (345.487 and 343.427 Da) fall comfortably within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (43.86) is significantly better than Ligand B (82.43). For CNS targets, we want TPSA <= 90, and ideally closer to 60. Ligand A is much closer to this ideal, suggesting better BBB penetration potential.

**3. logP:** Both ligands have similar logP values (1.864 and 1.885), falling within the optimal 1-3 range.

**4. H-Bond Donors:** Ligand A (0) is preferable to Ligand B (1). Fewer HBDs generally improve membrane permeability.

**5. H-Bond Acceptors:** Ligand A (3) is preferable to Ligand B (4). Fewer HBAs generally improve membrane permeability.

**6. QED:** Both ligands have good QED scores (0.731 and 0.885), indicating good drug-like properties.

**7. DILI:** Ligand A (10.818) has a significantly lower DILI risk than Ligand B (54.556). This is a major advantage for Ligand A.

**8. BBB:** Ligand A (59.325) has a lower BBB percentile than Ligand B (64.87), but is still reasonable. However, given the importance of BBB penetration for a CNS target like DRD2, Ligand B has a slight edge here.

**9. Caco-2:** Both have negative Caco-2 values (-4.685 and -4.617) which is unusual and suggests poor permeability.

**10. Solubility:** Both have negative solubility values (-2.052 and -3.172) which is also unusual and suggests poor solubility.

**11. hERG:** Both ligands have low hERG inhibition liability (0.381 and 0.568), which is good.

**12. Cl_mic:** Ligand A (10.425) has a much lower microsomal clearance than Ligand B (36.802), indicating better metabolic stability.

**13. t1/2:** Both ligands have similar in vitro half-lives (6.064 and 6.525 hours).

**14. Pgp:** Ligand A (0.047) has significantly lower P-gp efflux liability than Ligand B (0.147), which is crucial for CNS penetration.

**15. Binding Affinity:** Ligand B (-8.1) has a slightly better binding affinity than Ligand A (-7.4), a difference of 0.7 kcal/mol. This is a notable advantage, but needs to be weighed against the ADME properties.

**Overall Assessment:**

While Ligand B has slightly better binding affinity, Ligand A is significantly better across several critical ADME properties, particularly TPSA, DILI, Cl_mic, and Pgp efflux. The lower TPSA, DILI, and Pgp efflux of Ligand A are especially important for a CNS target like DRD2, as they suggest better BBB penetration and reduced toxicity. The better metabolic stability (lower Cl_mic) is also a significant advantage. The difference in binding affinity (0.7 kcal/mol) is not substantial enough to outweigh the substantial ADME advantages of Ligand A.

Output:
0
2025-04-17 08:02:56,946 - INFO - Okay, let's analyze these two ligands for their potential as DRD2 drug candidates. DRD2 is a GPCR in the CNS, so BBB penetration, logP, Pgp efflux, TPSA, and binding affinity are paramount.

**Ligand A:** [350.419, 94.48, 0.11, 2, 6, 0.617, 41.218, 43.583, -5.33, -1.137, 0.279, 0.613, 10.378, 0.019, -7.4]
**Ligand B:** [346.479, 78.1, 2.375, 3, 6, 0.637, 62.001, 78.364, -5.461, -2.639, 0.958, 43.338, 65.242, 0.14, 0.0]

**1. Molecular Weight:** Both ligands are within the ideal range (200-500 Da). A is 350.419, B is 346.479. No significant difference.

**2. TPSA:** Ligand A (94.48) is higher than the preferred <90 for CNS targets, but not drastically so. Ligand B (78.1) is well within the desired range. This favors B.

**3. logP:** Ligand A (0.11) is *very* low, potentially hindering membrane permeability. Ligand B (2.375) is within the optimal 1-3 range. This is a significant advantage for B.

**4. H-Bond Donors:** Ligand A (2) and B (3) are both acceptable (<=5).

**5. H-Bond Acceptors:** Both ligands have 6 HBA, which is acceptable (<=10).

**6. QED:** Both ligands have similar QED values (A: 0.617, B: 0.637), indicating good drug-like properties.

**7. DILI:** Ligand A (41.218) has a lower DILI risk than Ligand B (62.001), which is preferable.

**8. BBB:** Ligand B (78.364) has a significantly higher BBB percentile than Ligand A (43.583). This is a *critical* advantage for a CNS target like DRD2.

**9. Caco-2 Permeability:** Both have negative values, which is unusual. Assuming these are logP-like scales, lower values indicate poorer permeability. They are similar in this regard.

**10. Aqueous Solubility:** Both have negative values, indicating very poor solubility. This is a concern for both, but the scale is not defined, so it's hard to interpret.

**11. hERG Inhibition:** Ligand A (0.279) has a lower hERG risk than Ligand B (0.958). This is preferable.

**12. Microsomal Clearance:** Ligand B (43.338) has a higher clearance than Ligand A (0.613), indicating faster metabolism and potentially lower exposure. This favors A.

**13. In vitro Half-Life:** Ligand B (65.242) has a significantly longer half-life than Ligand A (10.378). This is a significant advantage for B.

**14. P-gp Efflux:** Ligand A (0.019) shows very low P-gp efflux, which is highly desirable for CNS penetration. Ligand B (0.14) is slightly higher, but still relatively low.

**15. Binding Affinity:** Ligand A (-7.4) has a slightly better (more negative) binding affinity than Ligand B (-0.0). This is a substantial advantage for A, and could potentially outweigh some of its ADME liabilities.

**Overall Assessment:**

While Ligand A has a slightly better binding affinity and lower DILI and clearance, Ligand B is significantly better in terms of CNS penetration (BBB, logP, Pgp, and TPSA). The poor logP of Ligand A is a major concern, as it will likely limit its ability to cross the blood-brain barrier despite the low P-gp efflux. The superior BBB penetration and longer half-life of Ligand B are crucial for a CNS-targeting drug. The slightly weaker affinity of B is less concerning than the permeability issues with A.

Therefore, I would select **Ligand B** as the more promising drug candidate.

1
2025-04-17 08:02:56,946 - INFO - Reasoning:

Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight (MW):** Both ligands (343.358 and 346.515 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (67.59) is higher than Ligand B (49.41). For a CNS target like DRD2, we prefer TPSA <= 90, so both are acceptable, but B is better.

**3. logP:** Ligand A (1.666) is within the optimal 1-3 range. Ligand B (3.809) is at the higher end but still acceptable.

**4. H-Bond Donors (HBD):** Both ligands have 1 HBD, which is good.

**5. H-Bond Acceptors (HBA):** Ligand A has 5 HBA, and Ligand B has 2 HBA. Both are below the threshold of 10.

**6. QED:** Ligand A (0.894) has a better QED score than Ligand B (0.795), indicating higher drug-likeness.

**7. DILI:** Ligand B (29.042) has a significantly lower DILI risk than Ligand A (53.432), which is a major advantage.

**8. BBB:** Ligand B (73.362) has a better BBB penetration percentile than Ligand A (65.839). Both are above 70, which is desirable for CNS targets, but B is better.

**9. Caco-2 Permeability:** Ligand A (-4.958) has worse Caco-2 permeability than Ligand B (-4.624). Lower (more negative) values are less desirable.

**10. Aqueous Solubility:** Ligand A (-2.6) has better aqueous solubility than Ligand B (-3.668).

**11. hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.164 and 0.405 respectively).

**12. Microsomal Clearance (Cl_mic):** Ligand B (70.678) has a much higher microsomal clearance than Ligand A (5.58), indicating lower metabolic stability. This is a significant drawback for B.

**13. In vitro Half-Life:** Ligand A (-12.379) has a much longer in vitro half-life than Ligand B (-8.86).

**14. P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.022 and 0.404 respectively).

**15. Binding Affinity:** Both ligands have excellent binding affinity (-9.5 and -9.1 kcal/mol). The difference of 0.4 kcal/mol is not substantial enough to outweigh other factors.

**Overall Assessment:**

Ligand B excels in BBB penetration and DILI risk, which are critical for a CNS GPCR target. However, it suffers from significantly higher microsomal clearance and a shorter half-life. Ligand A has a better QED, solubility, Caco-2 permeability, and *much* better metabolic stability (lower Cl_mic and longer half-life). While Ligand B has a slightly better BBB score, the metabolic liabilities are concerning. The affinity difference is minimal. Given the importance of metabolic stability for *in vivo* efficacy, and the acceptable BBB score of Ligand A, I favor Ligand A.

Output:
0
2025-04-17 08:02:56,947 - INFO - Batch 416 complete. Total preferences: 6656
2025-04-17 08:02:56,947 - INFO - Processing batch 417/512...
2025-04-17 08:03:39,374 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (371.453 Da) is slightly lower, which could be beneficial for permeability.

**2. TPSA:** Ligand A (53.6) is better than Ligand B (46.84). Both are below the 90 A^2 threshold for CNS targets, but A is closer to the ideal range.

**3. logP:** Both ligands have logP values within the optimal range (1-3), with Ligand A (3.207) being slightly better than Ligand B (4.529). Ligand B is approaching the upper limit where solubility issues might arise.

**4. H-Bond Donors:** Ligand A (2) is preferable to Ligand B (0). Having some H-bond donors can improve solubility.

**5. H-Bond Acceptors:** Ligand A (4) is preferable to Ligand B (6).

**6. QED:** Ligand A (0.853) has a significantly higher QED score than Ligand B (0.613), indicating a more drug-like profile.

**7. DILI:** Ligand B (36.138) has a lower DILI risk than Ligand A (74.719), which is a significant advantage.

**8. BBB:** Ligand B (90.074) has a slightly better BBB penetration percentile than Ligand A (86.894), but both are very good (>70).

**9. Caco-2 Permeability:** Ligand A (-4.53) has better Caco-2 permeability than Ligand B (-5.199).

**10. Aqueous Solubility:** Ligand A (-4.007) has better aqueous solubility than Ligand B (-4.41).

**11. hERG Inhibition:** Both ligands have low hERG inhibition risk (0.367 and 0.454 respectively).

**12. Microsomal Clearance:** Ligand A (34.715) has lower microsomal clearance than Ligand B (50.203), suggesting better metabolic stability.

**13. In vitro Half-Life:** Ligand A (37.694) has a longer in vitro half-life than Ligand B (24.959).

**14. P-gp Efflux:** Ligand A (0.092) has lower P-gp efflux liability than Ligand B (0.375), which is crucial for CNS penetration.

**15. Binding Affinity:** Ligand A (-8.1 kcal/mol) has a significantly stronger binding affinity than Ligand B (-6.1 kcal/mol). This is a >1.5 kcal/mol advantage, which can outweigh some ADME drawbacks.

**Overall Assessment:**

Ligand A is superior to Ligand B. While Ligand B has a lower DILI risk and slightly better BBB penetration, Ligand A excels in most other critical parameters, particularly its significantly higher binding affinity, better QED, lower P-gp efflux, and improved metabolic stability. The strong binding affinity of Ligand A is a major advantage for a GPCR target like DRD2, and the other favorable properties suggest it's more likely to translate into a viable drug candidate.

Output:
1
2025-04-17 08:03:39,375 - INFO - Reasoning:

Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (348.443 and 383.857 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (67.87) is significantly better than Ligand B (87.74). For CNS targets, we want TPSA <= 90, and A is comfortably within that range, while B is approaching the upper limit.

**3. logP:** Both ligands have good logP values (1.949 and 1.477), falling within the optimal 1-3 range.

**4. H-Bond Donors:** Ligand A (1) is preferable to Ligand B (2). Lower HBD generally improves permeability.

**5. H-Bond Acceptors:** Ligand A (4) is preferable to Ligand B (5). Lower HBA generally improves permeability.

**6. QED:** Both ligands have good QED scores (0.789 and 0.824), indicating good drug-like properties.

**7. DILI:** Ligand A (45.25) has a much lower DILI risk than Ligand B (75.688).  A score under 60 is desirable, and A is comfortably within that range, while B is approaching a higher risk.

**8. BBB:** Ligand A (71.966) has a significantly better BBB penetration score than Ligand B (55.487). For a CNS target like DRD2, >70 is ideal, but A is much closer than B.

**9. Caco-2 Permeability:** Both have negative Caco-2 values (-5.076 and -4.951). This is unusual and suggests poor permeability. However, the values are very similar.

**10. Aqueous Solubility:** Both have negative solubility values (-2.993 and -3.625). This is also unusual and suggests poor solubility. Again, the values are similar.

**11. hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.246 and 0.186).

**12. Microsomal Clearance:** Ligand A (28.594) has a higher (worse) microsomal clearance than Ligand B (-17.75). Lower clearance is preferred for metabolic stability. This is a significant advantage for B.

**13. In vitro Half-Life:** Ligand A (21.492) has a shorter half-life than Ligand B (-16.557). Longer half-life is generally preferred. This is a significant advantage for B.

**14. P-gp Efflux:** Both have low P-gp efflux liability (0.057 and 0.076).

**15. Binding Affinity:** Ligand A (-8.8 kcal/mol) has a significantly stronger binding affinity than Ligand B (-7.2 kcal/mol). This is a substantial advantage for A, potentially outweighing some ADME drawbacks. The difference is >1.5 kcal/mol.

**Overall Assessment:**

Ligand A excels in key areas for a CNS GPCR target: TPSA, BBB penetration, DILI risk, and *especially* binding affinity. While its clearance and half-life are less favorable than Ligand B, the significantly stronger binding affinity (-8.8 vs -7.2) is a major advantage. The lower TPSA and better BBB are also critical for CNS penetration. The similar poor Caco-2 and solubility are concerning for both, but can potentially be addressed with formulation strategies.

Output:
1
2025-04-17 08:03:39,375 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B based on the provided guidelines, prioritizing GPCR-specific properties (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (361.833 Da) is slightly higher than Ligand B (339.359 Da), but both are acceptable.

**TPSA:** Ligand A (88.08) is excellent for CNS penetration, falling well below 90. Ligand B (107.59) is still reasonable, but less optimal.

**logP:** Ligand A (2.116) is within the optimal range (1-3). Ligand B (0.037) is very low, potentially hindering permeability. This is a significant drawback.

**H-Bond Donors/Acceptors:** Both have acceptable HBD (1) and HBA (5 for A, 8 for B) counts.

**QED:** Both ligands have good QED scores (0.763 and 0.703), indicating drug-likeness.

**DILI:** Ligand A (59.364) has a lower DILI risk than Ligand B (83.715), which is preferable.

**BBB:** Ligand A (46.84) has a substantially better BBB percentile than Ligand B (35.207). This is a critical advantage for a CNS target like DRD2.

**Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and suggests poor permeability. However, the values are similar.

**Aqueous Solubility:** Both have negative solubility values, again unusual. The values are similar.

**hERG:** Both have low hERG inhibition liability (0.488 and 0.092), which is good.

**Microsomal Clearance:** Ligand A (56.353) has higher microsomal clearance than Ligand B (10.321), indicating potentially lower metabolic stability. This is a negative for Ligand A.

**In vitro Half-Life:** Ligand B (-4.997) has a negative half-life, which is not physically possible and suggests an issue with the data. Ligand A (19.086) has a reasonable half-life.

**P-gp Efflux:** Both have very low P-gp efflux liability (0.041 and 0.028), which is favorable for CNS penetration.

**Binding Affinity:** Ligand B (-9.1 kcal/mol) has a significantly stronger binding affinity than Ligand A (-8.2 kcal/mol). This is a substantial advantage, potentially outweighing some ADME concerns.

**Overall Assessment:**

While Ligand B has a superior binding affinity, its extremely low logP and poor BBB penetration are major concerns for a CNS-targeting drug. The negative half-life is also problematic. Ligand A, despite having slightly higher clearance, exhibits much better BBB penetration, a more favorable logP, and a reasonable half-life. The difference in binding affinity (0.9 kcal/mol) is significant, but the ADME profile of Ligand A is far more promising for CNS drug development.

Output:
1
2025-04-17 08:03:39,375 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (357.479 and 362.901 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (62.3) is slightly higher than Ligand B (49.41). Both are below the 90 Angstrom threshold desirable for CNS targets, but Ligand B is preferable.

**logP:** Ligand A (2.8) is within the optimal 1-3 range. Ligand B (4.198) is a bit higher, potentially leading to solubility issues or off-target interactions, but still acceptable.

**H-Bond Donors/Acceptors:** Both have 1 HBD, which is good. Ligand A has 4 HBA, and Ligand B has 2 HBA. Both are within the acceptable limits (<=10).

**QED:** Both ligands have good QED scores (0.829 and 0.853), indicating good drug-like properties.

**DILI:** Both ligands have acceptable DILI risk (54.052 and 47.693), below the 60 threshold.

**BBB:** Ligand B (92.323) has a significantly higher BBB penetration percentile than Ligand A (73.943). This is a *major* advantage for a CNS target like DRD2.

**Caco-2 Permeability:** Both have negative Caco-2 values (-4.994 and -4.448), which is unusual and suggests poor permeability. However, these values are on a scale where negative values are possible, and the absolute magnitude isn't directly comparable without knowing the scale's specifics.

**Aqueous Solubility:** Both have negative solubility values (-2.759 and -5.712), indicating poor aqueous solubility. Ligand B is worse in this regard.

**hERG:** Both ligands have low hERG inhibition liability (0.57 and 0.547), which is good.

**Microsomal Clearance:** Both have similar microsomal clearance values (74.522 and 74.312), suggesting comparable metabolic stability.

**In vitro Half-Life:** Ligand B (66.497) has a longer in vitro half-life than Ligand A (39.648), which is preferable.

**P-gp Efflux:** Both have low P-gp efflux liability (0.392 and 0.37), which is good for CNS penetration.

**Binding Affinity:** Ligand B (-9.1 kcal/mol) has a significantly stronger binding affinity than Ligand A (-8.4 kcal/mol). This >1.5 kcal/mol difference is substantial and can outweigh minor ADME drawbacks.

**Conclusion:**

Considering all factors, especially the GPCR-specific priorities, **Ligand B is the more promising drug candidate.** Its superior BBB penetration and significantly stronger binding affinity are critical advantages. While it has slightly worse solubility, the strong affinity and good BBB penetration are likely to compensate. The longer half-life is also a benefit.

Output:
1
2025-04-17 08:03:39,375 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (350.419 Da) is slightly lower, which is generally favorable for permeability. Ligand B (381.607 Da) is also acceptable.

**TPSA:** Ligand A (85.69) is excellent, falling well below the 90 A^2 threshold for CNS targets. Ligand B (29.54) is even better, indicating potentially superior brain penetration.

**logP:** Ligand A (-0.125) is a bit low, potentially hindering membrane permeability. Ligand B (4.803) is high, potentially causing solubility issues and off-target effects, but acceptable given the CNS target.

**H-Bond Donors/Acceptors:** Ligand A (1 HBD, 6 HBA) is within acceptable limits. Ligand B (0 HBD, 4 HBA) is also good, with fewer hydrogen bonds potentially aiding permeability.

**QED:** Ligand A (0.8) has a better QED score than Ligand B (0.545), suggesting a more drug-like profile overall.

**DILI:** Ligand A (30.128) has a significantly lower DILI risk than Ligand B (19.581), which is a major advantage.

**BBB:** Ligand B (77.084) has a better BBB percentile than Ligand A (68.399), which is crucial for a CNS target like DRD2.

**Caco-2 Permeability:** Ligand A (-4.889) has a negative Caco-2 value, which is concerning. Ligand B (-5.008) is also negative, but similar. Both suggest poor intestinal absorption.

**Aqueous Solubility:** Ligand A (-0.761) has poor aqueous solubility. Ligand B (-4.819) has even worse aqueous solubility.

**hERG Inhibition:** Ligand A (0.17) has a very low hERG risk. Ligand B (0.795) has a slightly higher, but still acceptable, hERG risk.

**Microsomal Clearance:** Ligand A (-18.603) has a negative clearance, which is excellent, indicating high metabolic stability. Ligand B (118.604) has a high clearance, suggesting rapid metabolism.

**In vitro Half-Life:** Ligand A (14.994 hours) has a reasonable half-life. Ligand B (21.65 hours) has a better half-life.

**P-gp Efflux:** Ligand A (0.016) has very low P-gp efflux, which is favorable for CNS penetration. Ligand B (0.774) has higher P-gp efflux, potentially limiting brain exposure.

**Binding Affinity:** Ligand A (-7.1 kcal/mol) has a slightly better binding affinity than Ligand B (-6.4 kcal/mol). While both are good, the 1.5 kcal/mol difference is significant.

**Overall Assessment:**

Ligand A excels in metabolic stability (Cl_mic), DILI risk, hERG risk, and P-gp efflux, and has slightly better binding affinity. However, its logP is low and solubility is poor. Ligand B has a better BBB penetration and in vitro half-life, but suffers from higher DILI risk, higher P-gp efflux, and poorer metabolic stability.

Considering the GPCR-specific priorities, BBB is critical. While Ligand B has a better BBB score, the significantly lower DILI risk, better metabolic stability, and better P-gp efflux of Ligand A are more important. The slightly better affinity of Ligand A also contributes to its favorability. The solubility and logP issues of Ligand A might be addressable through formulation or further structural modifications.

Output:
0
2025-04-17 08:03:39,375 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (373.36 and 386.543 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (80.12) is excellent, well below the 90 A^2 threshold for CNS targets. Ligand B (101.05) is still reasonable but less optimal, exceeding the preferred threshold.

**logP:** Both ligands (1.36 and 1.482) are within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A (1 HBD, 6 HBA) is better than Ligand B (2 HBD, 7 HBA) in terms of balancing solubility and permeability.

**QED:** Ligand A (0.878) has a significantly better QED score than Ligand B (0.795), indicating a more drug-like profile.

**DILI:** Ligand B (66.382) has a lower DILI risk than Ligand A (83.404), which is a positive attribute.

**BBB:** Both ligands have good BBB penetration (Ligand A: 76.309, Ligand B: 70.803), but Ligand A is slightly better. Both are above the 70 percentile desirable for CNS targets.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.057 and -5.635), which is unusual and suggests poor permeability. This is a significant concern for both.

**Aqueous Solubility:** Both ligands have very poor aqueous solubility (-2.668 and -2.769). This is a major drawback.

**hERG Inhibition:** Both ligands have low hERG inhibition liability (0.115 and 0.256), which is good.

**Microsomal Clearance:** Ligand B (3.16 mL/min/kg) has a much lower microsomal clearance than Ligand A (10.474 mL/min/kg), indicating better metabolic stability.

**In vitro Half-Life:** Ligand B (25.948 hours) has a significantly longer in vitro half-life than Ligand A (5.968 hours), which is a major advantage.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.067 and 0.118), which is favorable for CNS exposure.

**Binding Affinity:** Ligand B (-8.5 kcal/mol) has a slightly better binding affinity than Ligand A (-9.1 kcal/mol). While the difference is small, it's still a factor.

**Overall Assessment:**

Despite Ligand A's better TPSA and BBB, Ligand B emerges as the more promising candidate. The significantly improved metabolic stability (lower Cl_mic, longer t1/2), lower DILI risk, and slightly better binding affinity outweigh the minor disadvantages in TPSA and QED. The poor Caco-2 permeability and solubility are concerning for both, but can be addressed with formulation strategies. The affinity difference is small, but in the context of other improved ADME properties, favors Ligand B.

Output:
1
2025-04-17 08:03:39,375 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B based on the provided guidelines, prioritizing GPCR-specific properties (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (336.4 and 349.4 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (88.5) is excellent for CNS penetration, being well below 90. Ligand B (107.1) is still reasonable but less optimal.

**logP:** Ligand A (2.49) is within the optimal 1-3 range. Ligand B (-0.03) is slightly below 1, which *could* indicate permeability issues, though not drastically.

**H-Bond Donors/Acceptors:** Both have 2 HBD and are within the acceptable range. Ligand A has 5 HBA, while Ligand B has 6. Both are acceptable but leaning towards the higher end.

**QED:** Both ligands have similar QED values (0.769 and 0.773), indicating good drug-likeness.

**DILI:** Ligand A (67.6) has a higher DILI risk than Ligand B (41.8), but both are within an acceptable range.

**BBB:** Both ligands have good BBB penetration (Ligand A: 57.5, Ligand B: 55.6). While neither exceeds the desirable >70, they are comparable.

**Caco-2 Permeability:** Ligand A (-5.7) has significantly *better* Caco-2 permeability than Ligand B (-4.8). This suggests better intestinal absorption for Ligand A.

**Aqueous Solubility:** Ligand A (-2.06) has slightly better aqueous solubility than Ligand B (-1.5).

**hERG:** Both ligands have very low hERG inhibition risk (0.65 and 0.10).

**Microsomal Clearance:** Ligand A (-6.9) has much *lower* (better) microsomal clearance than Ligand B (10.6), indicating greater metabolic stability.

**In vitro Half-Life:** Ligand A (4.7) has a better in vitro half-life than Ligand B (-12.2).

**P-gp Efflux:** Ligand A (0.24) has significantly *lower* P-gp efflux than Ligand B (0.012), suggesting better CNS exposure and oral bioavailability.

**Binding Affinity:** Ligand A (-10.7 kcal/mol) has a *much* stronger binding affinity than Ligand B (-7.6 kcal/mol). This is a substantial difference (3.1 kcal/mol), which can outweigh minor ADME drawbacks.

**Overall Assessment:**

Ligand A is superior. While both ligands have acceptable properties, Ligand A excels in critical areas for a CNS-targeting GPCR ligand: significantly better binding affinity, lower P-gp efflux, lower microsomal clearance, better half-life, and better Caco-2 permeability. The slightly higher DILI risk is less concerning given the substantial advantage in potency and predicted CNS exposure. Ligand B's negative logP is a slight concern.

Output:
1
2025-04-17 08:03:39,375 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (360.336 and 349.475 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Both ligands have TPSA values (78.79 and 78.51) below the 90 A^2 threshold desirable for CNS targets, which is excellent.

**3. logP:** Both ligands have logP values (1.579 and 1.59) within the optimal range of 1-3, suggesting good permeability and avoiding solubility issues.

**4. H-Bond Donors:** Ligand A (1 HBD) is better than Ligand B (2 HBDs) in this regard, as fewer HBDs generally improve permeability.

**5. H-Bond Acceptors:** Ligand A (6 HBA) is slightly higher than Ligand B (3 HBA), but both are within the acceptable limit of 10.

**6. QED:** Ligand A (0.863) has a significantly higher QED score than Ligand B (0.621), indicating a more drug-like profile.

**7. DILI:** Ligand A (55.176) has a higher DILI risk than Ligand B (15.355). This is a significant drawback for Ligand A.

**8. BBB:** Ligand A (89.066) has a considerably better BBB penetration percentile than Ligand B (69.407). This is a crucial advantage for a CNS target like DRD2.

**9. Caco-2 Permeability:** Ligand A (-4.438) has a worse Caco-2 permeability than Ligand B (-5.063). Lower (more negative) values indicate poorer permeability.

**10. Aqueous Solubility:** Ligand A (-2.877) has slightly better aqueous solubility than Ligand B (-2.182).

**11. hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.265 and 0.269).

**12. Microsomal Clearance:** Ligand A (40.177 mL/min/kg) has a higher microsomal clearance than Ligand B (29.803 mL/min/kg), meaning it's less metabolically stable.

**13. In vitro Half-Life:** Ligand B (-15.962 hours) has a significantly longer in vitro half-life than Ligand A (-5.613 hours). This is a major advantage for Ligand B.

**14. P-gp Efflux:** Both ligands have similar, low P-gp efflux liability (0.17 and 0.045).

**15. Binding Affinity:** Ligand A (-8.4 kcal/mol) has a slightly better binding affinity than Ligand B (-7.7 kcal/mol). While the difference is not huge, it's still a positive for Ligand A.

**Overall Assessment:**

Ligand A excels in BBB penetration and binding affinity, which are critical for a CNS GPCR target. However, it suffers from higher DILI risk and poorer metabolic stability (higher clearance, shorter half-life). Ligand B has a much better safety profile (lower DILI), better metabolic stability (lower clearance, longer half-life), and acceptable BBB penetration. The slightly weaker binding affinity of Ligand B is less concerning given its superior ADME properties.

Considering the balance of properties, and prioritizing ADME/Tox for a CNS drug, Ligand B appears to be the more viable drug candidate.

Output:
1
2025-04-17 08:03:39,375 - INFO - Reasoning:

Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (347.459 and 351.455 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (75.44) is significantly better than Ligand B (115.3). For CNS targets, TPSA should be <= 90, and A is comfortably within this range, while B exceeds it. This is a substantial advantage for A.

**3. logP:** Both ligands have acceptable logP values (2.928 and 0.908), falling within the optimal 1-3 range. Ligand A is slightly better.

**4. H-Bond Donors:** Ligand A (1) is preferable to Ligand B (4) as lower HBD generally improves permeability.

**5. H-Bond Acceptors:** Ligand A (4) is preferable to Ligand B (7) for similar reasons as HBD.

**6. QED:** Ligand A (0.823) has a better QED score than Ligand B (0.489), indicating a more drug-like profile.

**7. DILI:** Ligand A (21.791) has a much lower DILI risk than Ligand B (47.654), which is a significant advantage.

**8. BBB:** Ligand A (91.392) has a substantially higher BBB penetration percentile than Ligand B (67.352). This is *critical* for a CNS target like DRD2.

**9. Caco-2 Permeability:** Ligand A (-4.899) is better than Ligand B (-5.194), although both are negative, suggesting poor permeability.

**10. Aqueous Solubility:** Both ligands have very poor aqueous solubility (-2.59 and -2.592). This is a concern for both, but can be addressed with formulation strategies.

**11. hERG Inhibition:** Both ligands have low hERG inhibition risk (0.416 and 0.559).

**12. Microsomal Clearance:** Ligand B (31.99) has lower microsomal clearance than Ligand A (54.47), suggesting better metabolic stability.

**13. In vitro Half-Life:** Ligand B (20.803) has a longer in vitro half-life than Ligand A (-29.12). This is a significant advantage for B.

**14. P-gp Efflux:** Ligand A (0.159) has lower P-gp efflux liability than Ligand B (0.011), which is preferable for CNS penetration.

**15. Binding Affinity:** Ligand B (-8.5) has a slightly better binding affinity than Ligand A (-7.7). While a 0.8 kcal/mol difference is noticeable, it's not a massive advantage.

**Overall Assessment:**

Ligand A is significantly better overall, particularly due to its superior TPSA, BBB penetration, lower DILI risk, better QED, and lower P-gp efflux. While Ligand B has a slightly better binding affinity and metabolic stability, the CNS-related properties of Ligand A are far more important for a DRD2 targeting drug. The poor solubility is a concern for both, but can be mitigated.

Output:
1
2025-04-17 08:03:39,376 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (379.869 Da) is slightly higher than Ligand B (352.494 Da), but both are acceptable.

**2. TPSA:** Ligand A (92.18) is above the preferred <90 for CNS targets, while Ligand B (49.41) is well within the range. This is a significant advantage for Ligand B.

**3. logP:** Both ligands have good logP values (A: 2.81, B: 3.304), falling within the optimal 1-3 range.

**4. H-Bond Donors:** Ligand A (2) and Ligand B (1) are both within the acceptable limit of <=5.

**5. H-Bond Acceptors:** Ligand A (5) and Ligand B (2) are both within the acceptable limit of <=10.

**6. QED:** Both ligands have good QED scores (A: 0.514, B: 0.825), indicating drug-like properties. Ligand B is better here.

**7. DILI:** Ligand A (71.539) has a higher DILI risk than Ligand B (20.706). Ligand B is significantly better.

**8. BBB:** This is critical for a CNS target like DRD2. Ligand A (32.765) has a poor BBB percentile, while Ligand B (83.443) is excellent, exceeding the desirable >70 threshold. This is a major advantage for Ligand B.

**9. Caco-2 Permeability:** Ligand A (-5.849) has poor Caco-2 permeability, while Ligand B (-4.617) is slightly better, but still poor.

**10. Aqueous Solubility:** Both ligands have poor aqueous solubility (-3 and -4.181 respectively).

**11. hERG Inhibition:** Both ligands have very low hERG inhibition risk (A: 0.074, B: 0.723).

**12. Microsomal Clearance:** Ligand A (16.139) has lower clearance than Ligand B (52.121), suggesting better metabolic stability.

**13. In vitro Half-Life:** Ligand B (-11.496) has a much longer half-life than Ligand A (-1.961).

**14. P-gp Efflux:** Ligand A (0.054) has lower P-gp efflux than Ligand B (0.345), which is favorable for CNS penetration.

**15. Binding Affinity:** Both ligands have very similar and strong binding affinities (A: -8.1 kcal/mol, B: -8.3 kcal/mol). The difference is negligible.

**Overall Assessment:**

Ligand B is significantly better overall, despite Ligand A having slightly better metabolic stability and P-gp efflux. The critical advantages of Ligand B are its much better BBB penetration (83.443 vs. 32.765), lower DILI risk (20.706 vs. 71.539), lower TPSA (49.41 vs 92.18), and longer half-life. These factors are particularly important for a CNS-targeting GPCR like DRD2. While both have poor solubility and Caco-2 permeability, these can potentially be addressed through formulation strategies. The small difference in binding affinity is not enough to overcome the substantial ADME advantages of Ligand B.

Output:
1
2025-04-17 08:03:39,376 - INFO - Reasoning:

Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (357.435 and 340.423 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (86.45) is better than Ligand B (71.34) as it is closer to the ideal range for CNS targets (<=90). Both are acceptable.

**3. logP:** Both ligands have a logP around 2.7, which is optimal (1-3).

**4. H-Bond Donors:** Ligand A (1) is preferable to Ligand B (2) as lower HBDs are generally better for permeability.

**5. H-Bond Acceptors:** Ligand A (7) is slightly higher than Ligand B (3), but both are within the acceptable limit of <=10.

**6. QED:** Both ligands have similar QED values (0.85 and 0.814), indicating good drug-likeness.

**7. DILI:** Ligand B (38.038) has a significantly lower DILI risk than Ligand A (68.903). This is a substantial advantage for Ligand B.

**8. BBB:** Ligand A (74.758) has a better BBB penetration score than Ligand B (64.482). This is a critical factor for CNS targets like DRD2.

**9. Caco-2 Permeability:** Ligand A (-4.443) has a better Caco-2 permeability than Ligand B (-4.731), indicating better intestinal absorption.

**10. Aqueous Solubility:** Ligand B (-3.31) has better aqueous solubility than Ligand A (-4.556).

**11. hERG Inhibition:** Ligand A (0.699) has a slightly higher hERG inhibition risk than Ligand B (0.389), but both are relatively low.

**12. Microsomal Clearance:** Both ligands have similar microsomal clearance values (56.094 and 59.73), indicating similar metabolic stability.

**13. In vitro Half-Life:** Ligand B (27.675) has a significantly longer in vitro half-life than Ligand A (-11.222). This is a major advantage for Ligand B.

**14. P-gp Efflux:** Ligand A (0.187) has lower P-gp efflux liability than Ligand B (0.206), which is favorable for CNS exposure.

**15. Binding Affinity:** Ligand B (-9.1) has a slightly better binding affinity than Ligand A (-8.7). While both are strong binders, the 0.4 kcal/mol difference is meaningful.

**Overall Assessment:**

While Ligand A has better BBB penetration and slightly better Caco-2 permeability and P-gp efflux, Ligand B demonstrates superior characteristics in several critical areas: significantly lower DILI risk, a longer in vitro half-life, and slightly better binding affinity. For a CNS target like DRD2, minimizing toxicity (DILI) and maximizing duration of action (half-life) are crucial. The slight advantage in binding affinity further supports Ligand B. The TPSA difference is minimal and doesn't outweigh the other benefits.

Output:
1
2025-04-17 08:03:39,376 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (356.451 and 353.369 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (66.37) is significantly better than Ligand B (73.22). For CNS targets, we want TPSA <= 90, and A is closer to the optimal <=60 range.

**3. logP:** Both ligands have good logP values (3.263 and 2.553), falling within the 1-3 optimal range.

**4. H-Bond Donors:** Ligand A (2) is slightly higher than Ligand B (1), but both are acceptable (<=5).

**5. H-Bond Acceptors:** Ligand A (4) and Ligand B (5) are both within the acceptable range (<=10).

**6. QED:** Both ligands have similar QED values (0.753 and 0.74), indicating good drug-likeness.

**7. DILI:** Ligand A (80.962) has a higher DILI risk than Ligand B (59.984), but both are reasonably acceptable.

**8. BBB:** Ligand B (82.435) has a better BBB penetration percentile than Ligand A (65.413). This is a crucial factor for CNS targets like DRD2.

**9. Caco-2 Permeability:** Ligand A (-4.988) has better Caco-2 permeability than Ligand B (-4.292).

**10. Aqueous Solubility:** Ligand A (-4.148) has slightly better aqueous solubility than Ligand B (-2.557).

**11. hERG Inhibition:** Both ligands have low hERG inhibition risk (0.658 and 0.568).

**12. Microsomal Clearance:** Ligand B (89.099) has a higher microsomal clearance than Ligand A (58.006), suggesting lower metabolic stability.

**13. In vitro Half-Life:** Ligand A (89.693) has a much longer in vitro half-life than Ligand B (6.289). This is a significant advantage.

**14. P-gp Efflux:** Both ligands have low P-gp efflux liability (0.344 and 0.391).

**15. Binding Affinity:** Ligand A (-9.5 kcal/mol) has a significantly better binding affinity than Ligand B (-8.6 kcal/mol). This >1.5 kcal/mol difference is substantial and can outweigh some ADME drawbacks.

**Overall Assessment:**

While Ligand B has a better BBB score, Ligand A excels in several critical areas: TPSA, Caco-2 permeability, solubility, metabolic stability (lower Cl_mic and longer t1/2), and, most importantly, significantly stronger binding affinity. The difference in binding affinity is substantial. Given the GPCR-specific priorities, the stronger affinity and better ADME properties (especially metabolic stability and permeability) of Ligand A make it the more promising candidate.

Output:
1
2025-04-17 08:03:39,376 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (366.403 and 351.447 Da) fall within the ideal 200-500 Da range.

**TPSA:** Both ligands (112.74 and 113.66) are slightly above the optimal <90 for CNS targets, but still reasonably acceptable.

**logP:** Ligand A (-0.323) is quite low, potentially hindering permeability. Ligand B (0.555) is better, falling within the 1-3 range, but still on the lower side.

**H-Bond Donors/Acceptors:** Ligand A (0 HBD, 8 HBA) is preferable to Ligand B (3 HBD, 5 HBA) as it has fewer HBDs, which can improve permeability. Both are within acceptable limits.

**QED:** Both ligands have good QED scores (0.723 and 0.647), indicating drug-like properties.

**DILI:** Ligand A (87.864) has a significantly higher DILI risk than Ligand B (12.641). This is a major concern for Ligand A.

**BBB:** Ligand A (65.839) has a moderate BBB penetration, while Ligand B (18.147) is quite low. For a CNS target like DRD2, BBB penetration is crucial. Ligand A is better here, but still not ideal.

**Caco-2 Permeability:** Both have negative Caco-2 values (-4.719 and -5.242), which is unusual and suggests poor permeability. These values are likely errors or indicate very poor absorption.

**Aqueous Solubility:** Both have negative solubility values (-2.922 and -1.626), also unusual and suggesting very poor solubility.

**hERG:** Both ligands have low hERG inhibition liability (0.203 and 0.189), which is good.

**Microsomal Clearance:** Ligand B (-7.505) has significantly lower (better) microsomal clearance than Ligand A (35.26), indicating better metabolic stability.

**In vitro Half-Life:** Ligand B (-2.185) has a slightly better in vitro half-life than Ligand A (-18.978).

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.014 and 0.033), which is favorable for CNS penetration.

**Binding Affinity:** Both ligands have very similar and good binding affinities (-7.5 and -7.4 kcal/mol). The difference is negligible.

**Overall Assessment:**

Ligand A has a better BBB score and fewer HBDs, but suffers from a very high DILI risk and poor metabolic stability. Ligand B has a much lower DILI risk, better metabolic stability, and a slightly better half-life, but its BBB penetration is poor and logP is low. Given the importance of minimizing toxicity (DILI) and achieving reasonable metabolic stability for *in vivo* efficacy, and the fact that the binding affinity is almost identical, **Ligand B is the more promising candidate despite its lower BBB score**. The low logP and BBB can potentially be addressed through further structural modifications, while a high DILI risk is much harder to fix later in development.

Output:
1
2025-04-17 08:03:39,376 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, considering the provided guidelines and GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (373.494 and 354.491 Da) fall within the ideal 200-500 Da range.

**TPSA:** Both ligands have TPSA values (87.3 and 87.66) that are acceptable for oral absorption (<140) but slightly high for optimal CNS penetration (<90). This is a minor concern, but needs consideration.

**logP:** Both ligands have good logP values (2.942 and 2.064), falling within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Both have 3 HBD and 4 HBA, which are within the acceptable limits.

**QED:** Both ligands have QED values above 0.5 (0.621 and 0.524), indicating good drug-like properties.

**DILI:** Ligand A has a DILI risk of 60.876, which is bordering on high risk. Ligand B has a significantly lower DILI risk (30.748), which is a strong advantage.

**BBB:** Ligand A shows a better BBB penetration percentile (59.248) than Ligand B (45.444). However, both are below the desirable threshold of >70 for CNS targets.

**Caco-2 Permeability:** Ligand A (-4.904) has a worse Caco-2 permeability than Ligand B (-5.224), indicating lower intestinal absorption.

**Aqueous Solubility:** Ligand A (-3.461) has slightly worse aqueous solubility than Ligand B (-2.515).

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.646 and 0.243).

**Microsomal Clearance:** Ligand A (37.333) has lower microsomal clearance than Ligand B (44.016), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (46.642) has a significantly longer in vitro half-life than Ligand B (13.613), which is a major advantage.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.183 and 0.165).

**Binding Affinity:** Ligand B (-8.0 kcal/mol) has a slightly better binding affinity than Ligand A (-7.9 kcal/mol). While the difference is small, it's still a factor.

**Overall Assessment:**

Ligand B is the more promising candidate. While Ligand A has a longer half-life and slightly better BBB, Ligand B has a significantly lower DILI risk, better Caco-2 permeability, and slightly better binding affinity. The lower DILI risk is a critical advantage, as liver toxicity is a major concern in drug development. The difference in binding affinity, while small, adds to the benefit. The slightly lower BBB for Ligand B is a concern, but can potentially be addressed through further optimization.

Output:
1
2025-04-17 08:03:39,377 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (338.451 and 352.475 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (75.35) is better than Ligand B (84.5). Both are below the 90 Angstrom threshold desirable for CNS targets, but A is closer to the optimal range.

**3. logP:** Both ligands have good logP values (2.74 and 2.106), falling within the 1-3 range.

**4. H-Bond Donors:** Ligand A (3) is slightly higher than Ligand B (2), but both are acceptable (<=5).

**5. H-Bond Acceptors:** Ligand A (3) is lower than Ligand B (4), both are acceptable (<=10).

**6. QED:** Ligand A (0.758) has a better QED score than Ligand B (0.665), indicating a more drug-like profile.

**7. DILI:** Ligand B (18.418) has a slightly higher DILI risk than Ligand A (15.626), but both are below the concerning threshold of 60.

**8. BBB:** Ligand B (56.34) has a better BBB penetration percentile than Ligand A (49.67), which is a crucial factor for CNS targets like DRD2. However, both are below the desirable >70 threshold.

**9. Caco-2 Permeability:** Ligand A (-4.936) has a better Caco-2 permeability than Ligand B (-4.744).

**10. Aqueous Solubility:** Ligand A (-2.647) has better aqueous solubility than Ligand B (-1.825).

**11. hERG Inhibition:** Ligand A (0.731) has a lower hERG inhibition liability than Ligand B (0.088), which is preferable.

**12. Microsomal Clearance:** Ligand B (24.288) has significantly higher microsomal clearance than Ligand A (3.31), suggesting lower metabolic stability.

**13. In vitro Half-Life:** Ligand A (8.932) has a longer in vitro half-life than Ligand B (8.396).

**14. P-gp Efflux:** Ligand A (0.307) has lower P-gp efflux liability than Ligand B (0.06), which is beneficial for CNS exposure.

**15. Binding Affinity:** Ligand A (-9.5 kcal/mol) has a significantly stronger binding affinity than Ligand B (-8 kcal/mol). This is a substantial difference and can outweigh minor ADME drawbacks.

**Overall Assessment:**

Ligand A is superior to Ligand B. While Ligand B has a slightly better BBB score, Ligand A excels in almost all other critical parameters, especially binding affinity (-9.5 vs -8 kcal/mol), metabolic stability (lower Cl_mic), P-gp efflux, hERG inhibition, and QED. The stronger binding affinity is particularly important for a GPCR target. The better ADME properties of Ligand A suggest a higher probability of successful *in vivo* translation.

Output:
1
2025-04-17 08:03:39,377 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (341.415 and 365.459 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (88.08) is excellent, falling well below the 90 A^2 threshold for CNS targets. Ligand B (92.63) is slightly higher but still acceptable.

**3. logP:** Both ligands (1.553 and 1.627) are within the optimal 1-3 range.

**4. H-Bond Donors:** Ligand A (1) is good. Ligand B (2) is also acceptable.

**5. H-Bond Acceptors:** Ligand A (5) is good. Ligand B (9) is approaching the upper limit but still reasonable.

**6. QED:** Ligand A (0.861) is excellent, indicating strong drug-likeness. Ligand B (0.765) is also good, but slightly lower.

**7. DILI:** Ligand A (57.154) is better than Ligand B (75.184), indicating a lower risk of drug-induced liver injury. Both are below the concerning 60 threshold, but A is preferable.

**8. BBB:** Ligand A (57.736) is better than Ligand B (44.552). While neither is >70, A is significantly closer, which is crucial for a CNS target like DRD2.

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.792 and -4.911), which is unusual and suggests poor permeability. This is a significant drawback for both.

**10. Aqueous Solubility:** Both ligands have negative solubility values (-2.302 and -3.377), indicating very poor aqueous solubility. This is a major concern for bioavailability.

**11. hERG Inhibition:** Ligand A (0.217) has a much lower hERG inhibition liability than Ligand B (0.754), making it safer from a cardiotoxicity perspective.

**12. Microsomal Clearance:** Ligand B (59.248) has a higher microsomal clearance than Ligand A (40.767), suggesting lower metabolic stability.

**13. In vitro Half-Life:** Ligand A (24.672) has a significantly longer in vitro half-life than Ligand B (6.347), which is a positive attribute.

**14. P-gp Efflux:** Ligand A (0.068) has much lower P-gp efflux liability than Ligand B (0.059), which is beneficial for CNS penetration.

**15. Binding Affinity:** Ligand A (-8.6 kcal/mol) has a stronger binding affinity than Ligand B (-7.4 kcal/mol). This 1.2 kcal/mol difference is substantial and can outweigh some of the ADME drawbacks.

**Overall Assessment:**

Ligand A is the superior candidate. While both ligands suffer from poor Caco-2 permeability and solubility, Ligand A demonstrates significantly better BBB penetration, lower DILI risk, lower hERG inhibition, better metabolic stability (lower Cl_mic, longer t1/2), lower P-gp efflux, and, most importantly, a substantially stronger binding affinity for DRD2. The stronger affinity is a critical advantage for a GPCR target.



Output:
0
2025-04-17 08:03:39,377 - INFO - Batch 417 complete. Total preferences: 6672
2025-04-17 08:03:39,377 - INFO - Processing batch 418/512...
2025-04-17 08:04:22,623 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (380.46 and 353.37 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Both ligands have TPSA values (86.71 and 84.23) below the 90 A^2 threshold for CNS targets, which is excellent.

**3. logP:** Ligand A (0.658) is a bit low, potentially hindering permeation. Ligand B (2.045) is within the optimal 1-3 range. This favors Ligand B.

**4. H-Bond Donors:** Both have 2 HBD, which is acceptable.

**5. H-Bond Acceptors:** Both have 4 HBA, also acceptable.

**6. QED:** Both have good QED scores (0.615 and 0.82), indicating drug-like properties. Ligand B is slightly better.

**7. DILI:** Ligand A (24.54%) has a significantly lower DILI risk than Ligand B (36.29%). This is a substantial advantage for Ligand A.

**8. BBB:** Ligand B (89.96%) has a much higher predicted BBB penetration than Ligand A (76.23%). This is *critical* for a CNS target like DRD2 and heavily favors Ligand B.

**9. Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and suggests poor permeability. However, the scale is not specified, so we can't interpret these values definitively.

**10. Aqueous Solubility:** Both have negative solubility values, indicating poor solubility. Again, the scale is unclear.

**11. hERG Inhibition:** Both have low hERG inhibition risk (0.402 and 0.522).

**12. Microsomal Clearance:** Ligand A (17.60 mL/min/kg) has a lower microsomal clearance than Ligand B (38.03 mL/min/kg), suggesting better metabolic stability.

**13. In vitro Half-Life:** Ligand A (-20.14 hours) has a negative half-life, which is impossible. This is a red flag. Ligand B (6.24 hours) is reasonable.

**14. P-gp Efflux:** Both have low P-gp efflux liability (0.107 and 0.063).

**15. Binding Affinity:** Ligand B (-9.6 kcal/mol) has a significantly stronger binding affinity than Ligand A (-7.1 kcal/mol). This is a major advantage for Ligand B, potentially outweighing some of the ADME drawbacks.

**Overall Assessment:**

While Ligand A has a lower DILI risk and better metabolic stability, the negative half-life is a critical flaw. Ligand B excels in the most important areas for a CNS GPCR target: BBB penetration and binding affinity. The slightly higher DILI risk and faster clearance are less concerning given the strong affinity and predicted brain exposure. The logP value for Ligand B is also more favorable.

Output:
1
2025-04-17 08:04:22,623 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (370.49 and 339.487 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (67.43) is better than Ligand B (73.63). Both are below the 90 A^2 threshold desirable for CNS targets, but A is closer to optimal.

**3. logP:** Both ligands have good logP values (3.649 and 4.067), falling within the 1-3 range. Ligand B is slightly higher, which could potentially lead to solubility issues, but is not a major concern.

**4. H-Bond Donors:** Both have 2 HBD, which is within the acceptable limit of <=5.

**5. H-Bond Acceptors:** Ligand A has 4 HBA, and Ligand B has 5. Both are within the acceptable limit of <=10.

**6. QED:** Both ligands have acceptable QED scores (0.769 and 0.699), indicating good drug-like properties.

**7. DILI:** Ligand A (44.242) has a slightly higher DILI risk than Ligand B (36.293), but both are below the concerning threshold of 60.

**8. BBB:** Ligand B (76.696) has a significantly better BBB penetration percentile than Ligand A (57.115). This is a crucial factor for a CNS target like DRD2.

**9. Caco-2 Permeability:** Ligand A (-4.758) has better Caco-2 permeability than Ligand B (-5.047), suggesting better intestinal absorption. However, this is less critical for a CNS target where direct brain penetration is prioritized.

**10. Aqueous Solubility:** Ligand A (-4.321) has slightly better aqueous solubility than Ligand B (-4.614).

**11. hERG Inhibition:** Ligand A (0.565) has a lower hERG inhibition liability than Ligand B (0.901), which is preferable.

**12. Microsomal Clearance:** Ligand B (61.887) has lower microsomal clearance than Ligand A (85.267), indicating better metabolic stability.

**13. In vitro Half-Life:** Ligand B (47.166) has a significantly longer in vitro half-life than Ligand A (8.984). This is a major advantage.

**14. P-gp Efflux:** Ligand A (0.086) has lower P-gp efflux liability than Ligand B (0.441), which is favorable for CNS penetration.

**15. Binding Affinity:** Ligand B (-7.6 kcal/mol) has a slightly better binding affinity than Ligand A (-7.9 kcal/mol). While A is better, the difference is small.

**Overall Assessment:**

Ligand B is the more promising candidate. Its superior BBB penetration (76.7% vs 57.1%), longer half-life (47.2 vs 8.98), and lower P-gp efflux are critical advantages for a CNS-targeting GPCR. While Ligand A has slightly better Caco-2 permeability and hERG inhibition, these are less important considerations for DRD2. The small difference in binding affinity is outweighed by the ADME advantages of Ligand B.

Output:
1
2025-04-17 08:04:22,623 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (351.447 and 352.435 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (78.95) is excellent, well below the 90 A^2 threshold for CNS targets. Ligand B (100.71) is still reasonable but less optimal, approaching the 140 A^2 limit for oral absorption.

**3. logP:** Ligand A (0.387) is a bit low, potentially hindering permeability. Ligand B (-0.022) is even lower, raising concerns about membrane penetration. Both are below the optimal 1-3 range.

**4. H-Bond Donors:** Ligand A (1) is good. Ligand B (2) is acceptable.

**5. H-Bond Acceptors:** Ligand A (5) is good. Ligand B (7) is acceptable.

**6. QED:** Both ligands have good QED scores (0.671 and 0.715), indicating drug-like properties.

**7. DILI:** Ligand A (16.557) has a significantly lower DILI risk than Ligand B (29.314). This is a major advantage for Ligand A.

**8. BBB:** Ligand A (62.97) is moderate, while Ligand B (30.748) is low. For a CNS target like DRD2, a higher BBB penetration is crucial. Ligand A is better here, but ideally, we'd want >70.

**9. Caco-2:** Both ligands have negative Caco-2 values (-4.76 and -4.902). These values are unusual and suggest poor permeability.

**10. Solubility:** Both ligands have negative solubility values (-0.443 and -0.37), which is also unusual and suggests very poor aqueous solubility.

**11. hERG:** Both ligands have very low hERG inhibition risk (0.116 and 0.071).

**12. Cl_mic:** Ligand A (3.737) has a much lower microsomal clearance than Ligand B (-13.315), indicating better metabolic stability.

**13. t1/2:** Ligand B (5.576) has a longer in vitro half-life than Ligand A (0.551).

**14. Pgp:** Both ligands have very low P-gp efflux liability (0.016 and 0.038).

**15. Binding Affinity:** Ligand B (-8.1) has a slightly better binding affinity than Ligand A (-7.7), but the difference is only 0.4 kcal/mol.

**Overall Assessment:**

While Ligand B has slightly better binding affinity and a longer half-life, Ligand A is the more promising candidate. The key advantages of Ligand A are its significantly lower DILI risk, better TPSA, and lower microsomal clearance. The BBB penetration of Ligand A is better than Ligand B, though still not ideal. The poor Caco-2 and solubility values for both are concerning, but can potentially be addressed with formulation strategies. Given the GPCR target and the importance of CNS penetration and safety, Ligand A is the preferred choice.

Output:
0
2025-04-17 08:04:22,624 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (340.43 and 352.45 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (86.88) is better than Ligand B (78.09), both are below the 90 A^2 threshold for CNS targets, which is excellent.

**logP:** Both ligands have good logP values (2.11 and 2.69), falling within the optimal 1-3 range. Ligand B is slightly higher, potentially improving membrane permeability.

**H-Bond Donors/Acceptors:** Ligand A has 3 HBD and 3 HBA, while Ligand B has 2 HBD and 3 HBA. Both are within acceptable limits (<=5 HBD and <=10 HBA).

**QED:** Both ligands have good QED scores (0.779 and 0.826), indicating good drug-like properties.

**DILI:** Ligand A (52.31%) has a higher DILI risk than Ligand B (39.32%), which is preferable.

**BBB:** Ligand B (85.96%) has a significantly better BBB penetration percentile than Ligand A (74.25%). This is a crucial advantage for a CNS target like DRD2.

**Caco-2 Permeability:** Both have negative values (-5.266 and -4.838), which is unusual and suggests poor permeability. This is a concern for both.

**Aqueous Solubility:** Both ligands have very poor aqueous solubility (-3.349 and -3.826). This is a significant drawback, potentially hindering bioavailability.

**hERG:** Both ligands have low hERG inhibition liability (0.751 and 0.765), which is good.

**Microsomal Clearance:** Ligand B (23.39) has significantly lower microsomal clearance than Ligand A (59.17), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand B (-23.08) has a much longer in vitro half-life than Ligand A (-4.12), which is a major advantage.

**P-gp Efflux:** Ligand A (0.415) has lower P-gp efflux liability than Ligand B (0.168). Lower P-gp efflux is favorable for CNS penetration.

**Binding Affinity:** Ligand A (-9.5 kcal/mol) has a significantly stronger binding affinity than Ligand B (-7.2 kcal/mol). This is a substantial advantage, potentially outweighing some of the ADME drawbacks.

**Overall Assessment:**

While Ligand A boasts a superior binding affinity, Ligand B demonstrates a much more favorable ADME profile, particularly regarding BBB penetration (86% vs 74%), metabolic stability (lower Cl_mic), and longer half-life. The large difference in binding affinity is significant, but the poor solubility and Caco-2 permeability of both compounds are concerning. However, for a CNS target, BBB penetration and metabolic stability are paramount. The better BBB and half-life of Ligand B, coupled with acceptable DILI, make it a more promising starting point for optimization. The affinity difference could potentially be addressed through medicinal chemistry efforts.

Output:
1
2025-04-17 08:04:22,624 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (365.5 and 364.4 Da) fall comfortably within the ideal 200-500 Da range.

**TPSA:** Ligand A (61.88) is better than Ligand B (64.8). Both are below the 90 A^2 threshold desirable for CNS targets, but A is closer to the ideal.

**logP:** Ligand A (1.567) is within the optimal range (1-3), while Ligand B (2.714) is approaching the upper limit.

**H-Bond Donors:** Ligand A has 1 HBD, and Ligand B has 0. Both are acceptable (<=5).

**H-Bond Acceptors:** Both ligands have 5 HBAs, which is within the acceptable limit of <=10.

**QED:** Ligand A (0.797) has a better QED score than Ligand B (0.664), indicating a more drug-like profile.

**DILI:** Ligand A (35.7%) has a lower DILI risk than Ligand B (44.1%), both are good.

**BBB:** Ligand B (97.1%) significantly outperforms Ligand A (67.7%) in predicted BBB penetration. This is a *critical* factor for a CNS target like DRD2.

**Caco-2 Permeability:** Ligand A (-4.974) has better Caco-2 permeability than Ligand B (-4.429).

**Aqueous Solubility:** Ligand A (-1.595) has better solubility than Ligand B (-3.017).

**hERG Inhibition:** Both ligands have similar, low hERG inhibition risk (0.404 and 0.571).

**Microsomal Clearance:** Ligand A (21.185) has a lower microsomal clearance than Ligand B (43.736), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (16.661 hours) has a much longer half-life than Ligand B (-11.626 hours).

**P-gp Efflux:** Ligand A (0.117) has lower P-gp efflux than Ligand B (0.412), which is favorable for CNS penetration.

**Binding Affinity:** Both ligands have very similar binding affinities (-8.0 and -7.0 kcal/mol). The difference is less than the 1.5 kcal/mol threshold where other factors become more important.

**Overall Assessment:**

While Ligand A has better physicochemical properties (TPSA, logP, QED, solubility, metabolic stability, half-life, P-gp efflux), Ligand B *strongly* excels in BBB penetration (97.1% vs 67.7%). For a CNS target like DRD2, BBB penetration is paramount. The slightly better ADME profile of Ligand A is outweighed by the substantial difference in predicted brain exposure.

Output:
1
2025-04-17 08:04:22,624 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (346.515 Da) is slightly better positioned.

**TPSA:** Ligand A (40.62) is excellent for CNS penetration, well below 90. Ligand B (79.9) is higher, but still potentially acceptable, though less ideal.

**logP:** Ligand A (3.452) is optimal. Ligand B (0.096) is very low, which is a significant concern for membrane permeability and CNS penetration.

**H-Bond Donors & Acceptors:** Ligand A (0 HBD, 2 HBA) is favorable. Ligand B (2 HBD, 6 HBA) is also acceptable, but slightly higher counts could impact permeability.

**QED:** Both ligands have similar QED values (A: 0.782, B: 0.687), indicating good drug-like properties.

**DILI:** Ligand A (15.277) has a much lower DILI risk than Ligand B (22.489).

**BBB:** This is critical for a CNS target. Ligand A shows excellent BBB penetration (87.476%), while Ligand B is very poor (23.924%).

**Caco-2 Permeability:** Ligand A (-4.742) is concerningly low, indicating poor intestinal absorption. Ligand B (-5.236) is similarly poor.

**Aqueous Solubility:** Ligand A (-3.38) and Ligand B (-0.895) both have poor aqueous solubility.

**hERG Inhibition:** Ligand A (0.624) is a lower risk than Ligand B (0.052).

**Microsomal Clearance:** Ligand A (78.891) has a higher clearance than Ligand B (-1.811), suggesting lower metabolic stability. However, the negative value for Ligand B is unusual and could indicate an *in vitro* to *in vivo* extrapolation issue.

**In vitro Half-Life:** Ligand A (-4.132) is concerningly low, while Ligand B (-3.03) is also low.

**P-gp Efflux:** Ligand A (0.341) has lower P-gp efflux liability than Ligand B (0.005), which is favorable for CNS exposure.

**Binding Affinity:** Ligand A (-9.4 kcal/mol) has a significantly stronger binding affinity than Ligand B (-7.4 kcal/mol). This 1.0 kcal/mol difference is substantial and can outweigh many ADME concerns.

**Overall Assessment:**

Ligand A is clearly the superior candidate. While it has some drawbacks (low Caco-2 permeability, low half-life), its *much* stronger binding affinity, excellent BBB penetration, lower DILI risk, and favorable logP outweigh these concerns. Ligand B's extremely low logP and poor BBB penetration are deal-breakers for a CNS-targeted GPCR. The affinity difference is also significant.

Output:
1
2025-04-17 08:04:22,624 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (344.415 and 347.459 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (92.26) is slightly higher than Ligand B (72.36). Both are below the 90 A^2 threshold desirable for CNS targets, but Ligand B is preferable.

**logP:** Both ligands have good logP values (1.986 and 1.709), falling within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A has 1 HBD and 7 HBA, while Ligand B has 2 HBD and 4 HBA. Both are within acceptable limits (<=5 HBD, <=10 HBA).

**QED:** Both ligands have good QED scores (0.736 and 0.823), indicating drug-like properties.

**DILI:** Ligand A (49.128) has a slightly higher DILI risk than Ligand B (16.673), but both are below the concerning threshold of 60.

**BBB:** Ligand A (63.746) has a better BBB percentile than Ligand B (47.15). This is a critical factor for a CNS target like DRD2.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.287 and -5.107), which is unusual and suggests poor permeability. This is a significant drawback for both.

**Aqueous Solubility:** Both ligands have very poor aqueous solubility (-1.821 and -1.964). This is a major concern for bioavailability.

**hERG Inhibition:** Both ligands show very low hERG inhibition risk (0.186 and 0.097).

**Microsomal Clearance:** Ligand A (17.058) has lower microsomal clearance than Ligand B (26.408), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (-8.587) has a negative half-life, which is not physically possible and indicates an issue with the data. Ligand B (10.209) has a reasonable half-life.

**P-gp Efflux:** Both ligands show very low P-gp efflux liability (0.354 and 0.024).

**Binding Affinity:** Both ligands have the same binding affinity (-8.4 kcal/mol), which is excellent.

**Overall Assessment:**

Despite the similar binding affinity, Ligand B is the more promising candidate. While Ligand A has a slightly better BBB score and lower clearance, the negative half-life is a critical flaw. Ligand B has a better TPSA, lower DILI risk, and a reasonable half-life. Both have poor solubility and Caco-2 permeability, which would need to be addressed through formulation or structural modifications. Given the GPCR-specific priorities, the slightly better TPSA and DILI profile of Ligand B, combined with a valid half-life, make it the preferred choice.

Output:
1
2025-04-17 08:04:22,625 - INFO - Reasoning:
Let's analyze both ligands against the provided guidelines, prioritizing GPCR-specific properties (BBB, logP, Pgp, TPSA, and affinity) for DRD2.

**Ligand A:**

*   **MW:** 339.443 Da - Good (within 200-500 range)
*   **TPSA:** 71.84 - Excellent (well below 90 for CNS targets)
*   **logP:** 3.074 - Excellent (within 1-3 range)
*   **HBD:** 2 - Good (<=5)
*   **HBA:** 4 - Good (<=10)
*   **QED:** 0.826 - Excellent (>=0.5)
*   **DILI:** 66.731 - Moderate risk (slightly above 60, but not drastically)
*   **BBB:** 76.037 - Very Good (above 70, desirable for CNS)
*   **Caco-2:** -5.273 - Poor (negative value suggests very low permeability)
*   **Solubility:** -3.628 - Poor (negative value suggests very low solubility)
*   **hERG:** 0.205 - Very Low Risk
*   **Cl_mic:** 14.881 - Moderate (relatively low, suggesting reasonable metabolic stability)
*   **t1/2:** 55.008 - Good (relatively long half-life)
*   **Pgp:** 0.38 - Low efflux (favorable for CNS penetration)
*   **Affinity:** 0.0 kcal/mol - Very Poor (not binding)

**Ligand B:**

*   **MW:** 358.483 Da - Good (within 200-500 range)
*   **TPSA:** 85.35 - Acceptable (slightly above 90, but potentially tolerable)
*   **logP:** -1.16 - Poor (below 1, may impede permeation)
*   **HBD:** 2 - Good (<=5)
*   **HBA:** 6 - Good (<=10)
*   **QED:** 0.541 - Acceptable (>=0.5)
*   **DILI:** 5.312 - Excellent (very low risk)
*   **BBB:** 22.838 - Poor (well below 70, unfavorable for CNS)
*   **Caco-2:** -5.024 - Poor (negative value suggests very low permeability)
*   **Solubility:** -0.133 - Poor (negative value suggests very low solubility)
*   **hERG:** 0.217 - Very Low Risk
*   **Cl_mic:** 30.271 - Moderate (higher than A, suggesting lower metabolic stability)
*   **t1/2:** -11.341 - Very Poor (negative half-life is not realistic)
*   **Pgp:** 0.004 - Very Low efflux (highly favorable)
*   **Affinity:** -6.5 kcal/mol - Good (strong binding)

**Comparison and Decision:**

Ligand A has a better BBB score and lower DILI risk, but its binding affinity is essentially zero, making it a non-starter. Ligand B has a strong binding affinity (-6.5 kcal/mol), which is a critical factor for GPCRs. While its logP is suboptimal and BBB is poor, the extremely low Pgp efflux is a significant advantage. The negative half-life for Ligand B is a clear indication of an issue with the data, and is likely an error.

Given the importance of binding affinity for DRD2, and the fact that the other issues with Ligand B *might* be addressable through further optimization (e.g., adding lipophilic groups to improve logP and BBB), I would choose Ligand B as the more promising candidate. The poor permeability and solubility of both compounds are concerning, but the binding affinity of Ligand B makes it a better starting point for optimization.

Output:
1
2025-04-17 08:04:22,625 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (360.527 Da) is slightly higher, but acceptable. Ligand B (211.217 Da) is on the lower end, but still within range.

**TPSA:** Ligand A (52.49) is excellent, well below the 90 A^2 threshold for CNS targets. Ligand B (103.78) is higher, but still reasonably good.

**logP:** Ligand A (2.77) is optimal. Ligand B (0.442) is quite low, potentially hindering membrane permeability and CNS penetration.

**H-Bond Donors/Acceptors:** Ligand A (HBD=1, HBA=6) is good. Ligand B (HBD=4, HBA=4) is also acceptable.

**QED:** Both ligands have good QED scores (A: 0.909, B: 0.543), suggesting drug-like properties.

**DILI:** Ligand A (60.45) is borderline, indicating moderate risk. Ligand B (9.461) is very low risk.

**BBB:** This is crucial for a CNS target like DRD2. Ligand A (90.617) is excellent, exceeding the 70% threshold. Ligand B (25.746) is very poor, indicating limited brain penetration.

**Caco-2 Permeability:** Ligand A (-4.914) is concerningly low. Ligand B (-5.982) is also low, but similar to A.

**Aqueous Solubility:** Ligand A (-2.426) is low, but potentially manageable. Ligand B (-0.958) is also low.

**hERG Inhibition:** Ligand A (0.887) is low risk. Ligand B (0.005) is extremely low risk.

**Microsomal Clearance:** Ligand A (14.737) is moderate. Ligand B (-23.473) is very low, suggesting high metabolic stability.

**In vitro Half-Life:** Ligand A (63.04) is good. Ligand B (6.391) is very short, potentially requiring frequent dosing.

**P-gp Efflux:** Ligand A (0.61) is relatively low, indicating less efflux. Ligand B (0.001) is extremely low, suggesting minimal efflux.

**Binding Affinity:** Both ligands have the same excellent binding affinity (-7.4 kcal/mol).

**Overall Assessment:**

Ligand A excels in BBB penetration, which is paramount for a DRD2 ligand. While its Caco-2 permeability and solubility are low, these can potentially be addressed through formulation strategies. The moderate DILI risk is a concern, but the strong binding affinity and favorable logP outweigh these drawbacks.

Ligand B has a very low DILI risk and P-gp efflux, and excellent metabolic stability. However, its extremely poor BBB penetration is a deal-breaker for a CNS target. The low logP and short half-life are also significant disadvantages.

Given the GPCR-specific priorities, especially BBB, Ligand A is the more promising candidate.

Output:
1
2025-04-17 08:04:22,625 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (366.864 and 346.387 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (54.38) is excellent, well below the 90 A^2 threshold for CNS targets. Ligand B (100.51) is higher, but still potentially acceptable, though less ideal.

**logP:** Ligand A (3.701) is optimal. Ligand B (-0.736) is significantly low, which could hinder membrane permeability and brain penetration.

**H-Bond Donors:** Both ligands have 2 HBD, which is within the acceptable limit of <=5.

**H-Bond Acceptors:** Ligand A has 4 HBA, and Ligand B has 5 HBA, both within the acceptable limit of <=10.

**QED:** Both ligands have QED values above 0.6, indicating good drug-like properties.

**DILI:** Ligand A (36.293) has a lower DILI risk than Ligand B (52.617), both being acceptable, but A is preferred.

**BBB:** Ligand A (51.958) has a slightly better BBB percentile than Ligand B (51.105), but both are below the desirable >70 for CNS targets. This is a concern for both, but less so for A.

**Caco-2 Permeability:** Ligand A (-4.798) has poor Caco-2 permeability, which is a significant drawback. Ligand B (-5.153) is similarly poor.

**Aqueous Solubility:** Ligand A (-4.093) has poor aqueous solubility, while Ligand B (-1.4) is also poor, but slightly better.

**hERG Inhibition:** Ligand A (0.81) has a slightly higher hERG risk than Ligand B (0.045), which is a significant advantage for B.

**Microsomal Clearance:** Ligand A (52.142) has higher microsomal clearance, indicating lower metabolic stability. Ligand B (-0.955) suggests excellent metabolic stability.

**In vitro Half-Life:** Ligand A (73.798) has a longer in vitro half-life than Ligand B (2.083), which is a positive attribute.

**P-gp Efflux:** Ligand A (0.77) has lower P-gp efflux than Ligand B (0.017), which is favorable for CNS penetration.

**Binding Affinity:** Both ligands have very similar and excellent binding affinities (-8.6 and -8.7 kcal/mol). The difference is negligible.

**Overall Assessment:**

While both ligands exhibit good binding affinity, Ligand A is superior due to its more favorable logP, lower DILI risk, and lower P-gp efflux. Although its Caco-2 permeability and aqueous solubility are poor, the strong binding affinity and better CNS-related properties (logP, Pgp) outweigh these drawbacks. Ligand B's low logP is a major concern, likely hindering its ability to cross the blood-brain barrier despite its good metabolic stability and low hERG risk.

Output:
1
2025-04-17 08:04:22,625 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 drug candidates, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight (MW):** Both ligands (350.805 and 356.323 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (58.2) is significantly better than Ligand B (69.81). For CNS targets, we want TPSA <= 90, and A is closer to the optimal <=60 range. B is still within the acceptable range, but less desirable.

**3. logP:** Ligand A (4.845) is slightly higher than the optimal 1-3 range, but still potentially acceptable. Ligand B (3.809) is within the optimal range. However, for a GPCR, a slightly higher logP can be tolerated if other properties are favorable.

**4. H-Bond Donors (HBD):** Both ligands have acceptable HBD counts (2 for A, 3 for B), well below the limit of 5.

**5. H-Bond Acceptors (HBA):** Both ligands have acceptable HBA counts (2 for both), well below the limit of 10.

**6. QED:** Both ligands have similar and good QED values (0.707 and 0.732), indicating good drug-likeness.

**7. DILI:** Ligand A (90.733) has a higher DILI risk than Ligand B (64.831). This is a significant negative for Ligand A.

**8. BBB:** Ligand B (78.945) has a substantially better BBB penetration score than Ligand A (61.535). For a CNS target like DRD2, this is a crucial advantage for Ligand B.

**9. Caco-2 Permeability:** Ligand A (-4.746) has a more negative Caco-2 value, indicating *better* permeability than Ligand B (-5.074).

**10. Aqueous Solubility:** Ligand A (-6.472) has better aqueous solubility than Ligand B (-4.62).

**11. hERG Inhibition:** Ligand A (0.632) has a lower hERG inhibition risk than Ligand B (0.88). This is a positive for Ligand A.

**12. Microsomal Clearance:** Ligand A (20.678) has a lower microsomal clearance, indicating better metabolic stability, than Ligand B (7.764).

**13. In vitro Half-Life:** Ligand A (97.933) has a significantly longer in vitro half-life than Ligand B (37.099).

**14. P-gp Efflux:** Ligand A (0.269) has lower P-gp efflux, which is favorable for CNS penetration, compared to Ligand B (0.385).

**15. Binding Affinity:** Ligand B (-10.2 kcal/mol) has a slightly better binding affinity than Ligand A (-9.1 kcal/mol). While both are excellent, the 1.1 kcal/mol difference is noteworthy.

**Overall Assessment:**

Ligand B excels in BBB penetration and binding affinity, which are critical for a CNS GPCR target. While Ligand A has advantages in metabolic stability, solubility, and P-gp efflux, its significantly higher DILI risk and lower BBB penetration are major drawbacks. The slightly better affinity of Ligand B, combined with its superior CNS penetration profile, outweighs the advantages of Ligand A.

Output:
1
2025-04-17 08:04:22,625 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (349.431 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (78.95) is significantly better than Ligand B (93.46). For CNS targets, we want TPSA <= 90, so Ligand A is preferable.

**3. logP:** Both ligands have acceptable logP values (A: 0.98, B: 1.867), falling within the 1-3 range.

**4. H-Bond Donors:** Ligand A (1) is better than Ligand B (2). Lower HBD is generally preferred for better permeability.

**5. H-Bond Acceptors:** Ligand A (4) is better than Ligand B (5). Lower HBA is generally preferred for better permeability.

**6. QED:** Both ligands have similar QED values (A: 0.771, B: 0.747), both above the 0.5 threshold, indicating good drug-likeness.

**7. DILI:** Ligand A (30.399) has a lower DILI risk than Ligand B (41.411), both are good (<40 is preferred).

**8. BBB:** This is a critical parameter for CNS targets. Ligand A (80.419) has a significantly better BBB penetration percentile than Ligand B (55.874). A value >70 is desirable, and A is closer to that target.

**9. Caco-2 Permeability:** Ligand A (-4.587) is better than Ligand B (-5.342), indicating better intestinal absorption.

**10. Aqueous Solubility:** Ligand A (-1.71) is better than Ligand B (-1.174).

**11. hERG Inhibition:** Both ligands have very low hERG inhibition risk (A: 0.242, B: 0.139).

**12. Microsomal Clearance:** Ligand A (45.502) has lower clearance than Ligand B (50.219), suggesting better metabolic stability.

**13. In vitro Half-Life:** Ligand A (-4.7) has a much longer half-life than Ligand B (-22.219).

**14. P-gp Efflux:** Both ligands have very low P-gp efflux liability (A: 0.025, B: 0.137).

**15. Binding Affinity:** Both ligands have similar binding affinities (A: -9.2, B: -8.6). While A is slightly better, the difference isn't huge enough to outweigh other factors if B had a significant advantage elsewhere.

**Overall Assessment:**

Ligand A consistently outperforms Ligand B across most critical ADME properties, particularly TPSA, BBB, and in vitro half-life. While both have acceptable logP and binding affinity, Ligand A's superior CNS penetration (BBB) and drug-like properties make it the more promising candidate for a DRD2-targeting drug.

Output:
0
2025-04-17 08:04:22,626 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (382.595 Da) is slightly higher than Ligand B (352.435 Da), but both are acceptable.

**TPSA:** Ligand A (58.2) is excellent for CNS penetration, well below the 90 A^2 threshold. Ligand B (98.9) is higher, but still potentially acceptable, though less ideal.

**logP:** Ligand A (3.676) is optimal. Ligand B (-0.599) is significantly low, which could hinder membrane permeability and potentially reduce binding affinity.

**H-Bond Donors/Acceptors:** Both ligands have 2 HBD and reasonable HBA counts (4 for A, 6 for B), falling within acceptable limits.

**QED:** Both ligands have similar QED values (0.721 and 0.712), indicating good drug-like properties.

**DILI:** Ligand A (49.283) has a slightly higher DILI risk than Ligand B (31.33), but both are below the concerning threshold of 60.

**BBB:** Ligand A (56.766) has a better BBB percentile than Ligand B (19.581). This is a crucial factor for a CNS target like DRD2.

**Caco-2 Permeability:** Both have negative values (-5.61 and -5.026), which is unusual and difficult to interpret without knowing the scale. However, the values are similar.

**Aqueous Solubility:** Both have negative values (-3.813 and -0.415), indicating poor aqueous solubility. This could pose formulation challenges.

**hERG:** Ligand A (0.395) has a lower hERG risk than Ligand B (0.088), which is preferable.

**Microsomal Clearance:** Ligand A (69.414) has higher microsomal clearance than Ligand B (-2.034). This suggests Ligand B is more metabolically stable.

**In vitro Half-Life:** Ligand A (17.243) has a longer half-life than Ligand B (12.099).

**P-gp Efflux:** Ligand A (0.458) has higher P-gp efflux liability than Ligand B (0.015). Lower P-gp efflux is better for CNS penetration, favoring Ligand B.

**Binding Affinity:** Ligand A (0.0) has significantly weaker binding affinity than Ligand B (-7.4). This is the most critical factor. A difference of >1.5 kcal/mol can outweigh other drawbacks.

**Conclusion:**

Despite Ligand A having a better BBB score and lower hERG risk, the significantly stronger binding affinity of Ligand B (-7.4 kcal/mol vs 0.0 kcal/mol) is the deciding factor. The lower logP and P-gp efflux of Ligand B are also favorable for CNS penetration. While Ligand B has slightly higher DILI and lower metabolic stability, the substantial affinity advantage is likely to outweigh these concerns, especially in early-stage drug discovery.

Output:
1
2025-04-17 08:04:22,626 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (347.38 and 358.825 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (29.1) is excellent, well below the 90 A^2 threshold for CNS targets. Ligand B (68.29) is higher, but still reasonably acceptable, though less ideal.

**logP:** Ligand A (4.403) is slightly high, potentially leading to solubility issues or off-target interactions. Ligand B (2.746) is within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Both ligands have a reasonable number of HBDs (1 each) and Ligand A has 1 HBA, while Ligand B has 4 HBAs, both within acceptable limits.

**QED:** Both ligands have good QED scores (0.816 and 0.916), indicating good drug-like properties.

**DILI:** Ligand A (50.601) has a lower DILI risk than Ligand B (73.362), which is preferable.

**BBB:** This is a critical parameter for a CNS target like DRD2. Ligand A has a very high BBB penetration percentile (91.663), significantly better than Ligand B (79.488).

**Caco-2 Permeability:** Ligand A (-4.503) and Ligand B (-5.051) both have negative values, which is unusual. It's difficult to interpret without knowing the scale, but lower values generally indicate poorer permeability.

**Aqueous Solubility:** Ligand A (-4.897) and Ligand B (-2.999) both have negative values, indicating poor solubility.

**hERG Inhibition:** Ligand A (0.883) has a slightly higher hERG risk than Ligand B (0.299), which is less desirable.

**Microsomal Clearance:** Ligand B (39.973) has lower microsomal clearance than Ligand A (74.413), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (24.337) has a longer half-life than Ligand B (6.515), which is preferable.

**P-gp Efflux:** Ligand A (0.659) has lower P-gp efflux than Ligand B (0.149), which is beneficial for CNS penetration.

**Binding Affinity:** Both ligands have excellent binding affinities (-10.3 and -10.5 kcal/mol), with a very small difference.

**Overall Assessment:**

Ligand A excels in BBB penetration and P-gp efflux, crucial for CNS drug delivery. It also has a lower DILI risk and a longer half-life. While its logP is slightly high and solubility is low, the strong BBB penetration and P-gp efflux properties, combined with excellent affinity, likely outweigh these drawbacks. Ligand B has better metabolic stability (lower Cl_mic) and lower hERG risk, but its significantly lower BBB penetration is a major disadvantage for a CNS target.

Output:
1
2025-04-17 08:04:22,626 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (364.511 Da and 358.471 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (58.64) is significantly better than Ligand B (79.96). For CNS targets, we want TPSA <= 90, and A is comfortably within that range, while B is approaching the upper limit.

**3. logP:** Both ligands have good logP values (2.984 and 1.983), falling within the optimal 1-3 range.

**4. H-Bond Donors:** Both have 1 HBD, which is acceptable.

**5. H-Bond Acceptors:** Ligand A has 4 HBAs, while Ligand B has 8.  Ligand A is preferable, as keeping HBAs lower than 10 is desirable.

**6. QED:** Both ligands have reasonable QED values (0.844 and 0.696), indicating good drug-like properties.

**7. DILI:** Ligand A (35.905) has a lower DILI risk than Ligand B (44.591), which is preferable.

**8. BBB:** Both ligands have good BBB penetration (76.309% and 70.997%), exceeding the 70% threshold for CNS targets. Ligand A is slightly better.

**9. Caco-2 Permeability:** Ligand A (-4.963) shows better Caco-2 permeability than Ligand B (-5.48), though both are negative values which is unusual and requires further investigation.

**10. Aqueous Solubility:** Ligand A (-2.648) has slightly better aqueous solubility than Ligand B (-1.653), though both are negative values which is unusual and requires further investigation.

**11. hERG Inhibition:** Both ligands have low hERG inhibition risk (0.586 and 0.574).

**12. Microsomal Clearance:** Ligand A (24.431) has lower microsomal clearance than Ligand B (29.602), indicating better metabolic stability.

**13. In vitro Half-Life:** Ligand A (24.188 hours) has a longer in vitro half-life than Ligand B (18.104 hours).

**14. P-gp Efflux:** Both ligands have low P-gp efflux liability (0.309 and 0.098), which is good for CNS penetration. Ligand B is slightly better.

**15. Binding Affinity:** Ligand A (-8.8 kcal/mol) has a significantly stronger binding affinity than Ligand B (-7.3 kcal/mol). This 1.5 kcal/mol difference is substantial and can outweigh minor ADME drawbacks.

**Overall Assessment:**

Ligand A is superior to Ligand B. It has a better TPSA, fewer HBA, lower DILI risk, better Caco-2 permeability, better aqueous solubility, lower microsomal clearance, longer half-life, and, most importantly, significantly stronger binding affinity. While Ligand B has slightly better P-gp efflux, the advantages of Ligand A are more impactful, especially the binding affinity.

Output:
1
2025-04-17 08:04:22,626 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (368.4 and 356.5 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (67.87) is higher than Ligand B (49.41). For CNS targets, TPSA should be <= 90, so both are acceptable, but B is better.

**logP:** Ligand A (1.593) is within the optimal 1-3 range. Ligand B (3.215) is at the higher end of optimal, but still acceptable.

**H-Bond Donors/Acceptors:** Both have 1 HBD, which is good. Ligand A has 4 HBA, and Ligand B has 2 HBA. Both are within the acceptable range of <=10, and lower is generally preferred for BBB penetration, making B slightly better.

**QED:** Both ligands have good QED scores (0.636 and 0.743), indicating drug-like properties.

**DILI:** Both have relatively low DILI risk (21.87 and 29.04), which is positive.

**BBB:** Both ligands exhibit excellent BBB penetration (89.84 and 92.48), which is crucial for a CNS target like DRD2. Ligand B is slightly better here.

**Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and suggests poor permeability. This is a significant concern for both.

**Aqueous Solubility:** Both have negative solubility values, indicating very poor solubility. This is a major drawback for both compounds.

**hERG Inhibition:** Both have low hERG inhibition risk (0.534 and 0.661), which is good.

**Microsomal Clearance:** Ligand A (32.33) has lower clearance than Ligand B (50.51), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (-7.781) has a significantly longer half-life than Ligand B (-33.382). This is a major advantage for Ligand A.

**P-gp Efflux:** Both have very low P-gp efflux liability (0.042 and 0.071), which is excellent for CNS penetration.

**Binding Affinity:** Ligand B (-7.5 kcal/mol) has a slightly better binding affinity than Ligand A (-7.3 kcal/mol). While the difference is small, it's still a factor.

**Overall Assessment:**

Ligand A has a better half-life and lower clearance, which are important for *in vivo* efficacy. Ligand B has a slightly better affinity and TPSA, and a marginally better BBB score. However, the poor solubility and Caco-2 permeability are major concerns for both. The slightly better binding affinity of Ligand B, combined with its slightly better BBB and TPSA, and acceptable logP, makes it marginally more promising *despite* the worse metabolic stability.

Output:
1
2025-04-17 08:04:22,627 - INFO - Batch 418 complete. Total preferences: 6688
2025-04-17 08:04:22,627 - INFO - Processing batch 419/512...
2025-04-17 08:05:04,004 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (346.387 and 348.447 Da) are within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (99.77) is slightly above the preferred <90 for CNS targets, while Ligand B (76.46) is well within the range. This favors Ligand B.

**3. logP:** Ligand A (0.303) is quite low, potentially hindering membrane permeability. Ligand B (1.371) is within the optimal 1-3 range. This strongly favors Ligand B.

**4. H-Bond Donors:** Ligand A (3) is acceptable, while Ligand B (1) is even better, potentially improving permeability.

**5. H-Bond Acceptors:** Both ligands (A: 5, B: 5) are within the acceptable limit of <=10.

**6. QED:** Both ligands have good QED scores (A: 0.644, B: 0.755), indicating drug-like properties. Ligand B is slightly better.

**7. DILI:** Ligand A (49.128) has a moderate DILI risk, while Ligand B (30.865) has a lower risk. This favors Ligand B.

**8. BBB:** Both ligands have good BBB penetration (A: 77.821, B: 74.99), both being above the 70% threshold for CNS targets.

**9. Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and suggests either poor permeability or an issue with the prediction method. However, the values are similar.

**10. Aqueous Solubility:** Both have negative solubility values, which is also unusual. Again, the values are similar.

**11. hERG Inhibition:** Ligand A (0.188) has a slightly higher hERG risk than Ligand B (0.549). This favors Ligand B.

**12. Microsomal Clearance:** Ligand A (-9.249) has a much *lower* (better) microsomal clearance than Ligand B (14.377), indicating greater metabolic stability. This favors Ligand A.

**13. In vitro Half-Life:** Ligand A (15.42) has a shorter half-life than Ligand B (-5.745). The negative value for Ligand B is suspect and likely an artifact of the prediction. This favors Ligand A.

**14. P-gp Efflux:** Ligand A (0.007) has very low P-gp efflux, which is excellent for CNS penetration. Ligand B (0.076) is also low, but higher than A. This favors Ligand A.

**15. Binding Affinity:** Ligand A (-8.4) has a slightly better binding affinity than Ligand B (-7.8). While both are good, the 0.6 kcal/mol difference is significant. This favors Ligand A.

**Overall Assessment:**

While Ligand B excels in TPSA, logP, and DILI risk, Ligand A demonstrates superior metabolic stability (Cl_mic), P-gp efflux, and binding affinity. Considering DRD2 is a CNS target, BBB penetration is important for both, but the combination of better affinity, lower efflux, and improved metabolic stability outweighs the slightly higher TPSA and lower logP of Ligand A. The negative solubility and Caco-2 values are concerning for both, but the differences in other key parameters are more decisive.

Output:
0
2025-04-17 08:05:04,004 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 drug candidates, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (348.447 and 368.499 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (87.46) is better than Ligand B (78.87) as it is closer to the ideal <90 for CNS targets.

**3. logP:** Ligand B (0.941) is slightly better than Ligand A (0.644), being closer to the optimal 1-3 range. Ligand A is a bit low, potentially hindering permeation.

**4. H-Bond Donors:** Both have 2 HBD, which is within the acceptable limit of <=5.

**5. H-Bond Acceptors:** Both have 5 HBA, also within the acceptable limit of <=10.

**6. QED:** Both ligands have similar QED values (0.708 and 0.722), indicating good drug-likeness.

**7. DILI:** Ligand A (17.914) has a significantly lower DILI risk than Ligand B (36.293). This is a major advantage for Ligand A.

**8. BBB:** Both ligands have the same BBB penetration (17.914 percentile), which is quite low and a significant drawback for a CNS target like DRD2.

**9. Caco-2 Permeability:** Ligand A (-5.281) shows poorer Caco-2 permeability than Ligand B (-4.965), suggesting lower intestinal absorption.

**10. Aqueous Solubility:** Ligand A (-0.702) has slightly better solubility than Ligand B (-2.559).

**11. hERG Inhibition:** Both ligands show very low hERG inhibition risk (0.254 and 0.162), which is excellent.

**12. Microsomal Clearance:** Ligand A (-5.973) has much lower microsomal clearance than Ligand B (31.599), indicating better metabolic stability. This is a significant advantage.

**13. In vitro Half-Life:** Ligand A (-11.731) has a much longer in vitro half-life than Ligand B (-2.148), which is desirable.

**14. P-gp Efflux:** Ligand A (0.039) has lower P-gp efflux than Ligand B (0.142), which is beneficial for CNS exposure.

**15. Binding Affinity:** Ligand A (-7.6 kcal/mol) has a slightly better binding affinity than Ligand B (-7.3 kcal/mol). While the difference is not huge, it's enough to consider, especially given the other favorable properties of Ligand A.

**Overall Assessment:**

Despite the low BBB penetration for both, Ligand A is the more promising candidate. It has a significantly lower DILI risk, better metabolic stability (lower Cl_mic, longer t1/2), lower P-gp efflux, and slightly better binding affinity. While Ligand B has a slightly better logP and Caco-2 permeability, the advantages of Ligand A in terms of safety (DILI) and pharmacokinetics (Cl_mic, t1/2, P-gp) outweigh these factors, especially for a CNS target where metabolic stability and brain exposure are crucial. The TPSA is also slightly better for Ligand A.

Output:
0
2025-04-17 08:05:04,005 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (385.511 and 362.47 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (87.65) is better than Ligand B (51.22). Both are below the 90 A^2 threshold for CNS targets, but Ligand A is closer to the upper limit.

**logP:** Ligand A (0.954) is slightly lower than optimal (1-3), but acceptable. Ligand B (4.06) is at the higher end of the optimal range, potentially increasing off-target effects or solubility issues.

**H-Bond Donors/Acceptors:** Ligand A (0 HBD, 6 HBA) and Ligand B (1 HBD, 4 HBA) both have reasonable numbers of H-bond donors and acceptors, well within the guidelines.

**QED:** Both ligands have good QED scores (0.77 and 0.843), indicating drug-like properties.

**DILI:** Ligand A (71.229) has a slightly higher DILI risk than Ligand B (63.513), but both are acceptable.

**BBB:** Ligand B (82.396) has a significantly better BBB penetration score than Ligand A (70.105). This is a critical factor for a CNS target like DRD2.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.696 and -4.765), which is unusual and suggests poor permeability. This is a significant concern for both.

**Aqueous Solubility:** Both ligands have negative solubility values (-2.45 and -4.278), which is also concerning and suggests poor solubility.

**hERG Inhibition:** Ligand A (0.216) has a lower hERG inhibition liability than Ligand B (0.686), indicating a lower risk of cardiotoxicity.

**Microsomal Clearance:** Ligand A (14.382) has a lower microsomal clearance than Ligand B (36.52), suggesting better metabolic stability.

**In vitro Half-Life:** Both ligands have similar in vitro half-lives (19.213 and 20.39 hours).

**P-gp Efflux:** Ligand A (0.258) has lower P-gp efflux liability than Ligand B (0.813), which is favorable for CNS penetration.

**Binding Affinity:** Ligand B (-9.4 kcal/mol) has a significantly stronger binding affinity than Ligand A (-7.0 kcal/mol). This is a substantial advantage, potentially outweighing some of the ADME drawbacks.

**Overall Assessment:**

While Ligand A has better metabolic stability, lower hERG risk, and lower P-gp efflux, Ligand B's superior BBB penetration and significantly stronger binding affinity are decisive. The negative Caco-2 and solubility values are concerning for both, but the potency advantage of Ligand B is substantial. For a CNS target like DRD2, strong binding and good BBB penetration are paramount.

Output:
1
2025-04-17 08:05:04,005 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B based on the provided guidelines, prioritizing GPCR-specific properties (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (337.423 Da) is slightly lower, which could be beneficial for permeability. Ligand B (375.313 Da) is also good.

**TPSA:** Ligand A (73.99) is higher than Ligand B (52.65). For a CNS target like DRD2, TPSA should ideally be <=90, so both are acceptable, but Ligand B is better.

**logP:** Ligand A (2.546) is within the optimal range (1-3). Ligand B (1.191) is at the lower end, potentially hindering permeability.

**H-Bond Donors/Acceptors:** Ligand A has 3 HBD and 2 HBA, while Ligand B has 1 HBD and 3 HBA. Both are within acceptable limits.

**QED:** Both ligands have similar QED values (0.758 and 0.735), indicating good drug-likeness.

**DILI:** Both ligands have low DILI risk (39.162 and 37.03), which is favorable.

**BBB:** Ligand B (71.733) has a significantly better BBB percentile than Ligand A (59.403). This is a critical advantage for a CNS target.

**Caco-2 Permeability:** Ligand A (-5.086) has worse Caco-2 permeability than Ligand B (-4.781), suggesting lower intestinal absorption.

**Aqueous Solubility:** Ligand A (-3.702) has worse solubility than Ligand B (-1.698).

**hERG:** Both ligands have low hERG risk (0.405 and 0.479).

**Microsomal Clearance:** Ligand B (-1.583) has better metabolic stability (lower clearance) than Ligand A (27.813).

**In vitro Half-Life:** Ligand B (-15.485) has a much longer in vitro half-life than Ligand A (-3.024).

**P-gp Efflux:** Both ligands have very low P-gp efflux (0.1 and 0.009).

**Binding Affinity:** Both ligands have excellent binding affinity (-9.7 and -9.1 kcal/mol). The difference of 0.6 kcal/mol is not substantial enough to outweigh other significant ADME differences.

**Conclusion:**

Ligand B is the more promising candidate. While Ligand A has a slightly lower molecular weight, Ligand B excels in crucial areas for CNS drug development: significantly better BBB penetration, improved metabolic stability (lower Cl_mic and longer t1/2), better Caco-2 permeability and solubility, and a lower TPSA. The slightly lower logP of Ligand B is a minor concern compared to the substantial advantages in CNS penetration and pharmacokinetic properties.

Output:
1
2025-04-17 08:05:04,005 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (354.43 and 384.57 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (87.46) is better than Ligand B (66.48) as it is closer to the optimal range for CNS targets (<90). Ligand B is also good.

**3. logP:** Ligand A (1.077) is within the optimal range (1-3), while Ligand B (3.464) is at the higher end but still acceptable.

**4. H-Bond Donors:** Both ligands have acceptable HBD counts (2 and 1, respectively), well below the threshold of 5.

**5. H-Bond Acceptors:** Both ligands have acceptable HBA counts (5 and 4, respectively), well below the threshold of 10.

**6. QED:** Ligand A (0.828) has a significantly better QED score than Ligand B (0.663), indicating a more drug-like profile.

**7. DILI:** Both ligands have similar and acceptable DILI risk (46.45 and 49.13, respectively), both below the 60 threshold.

**8. BBB:** Ligand A (77.59%) has a better BBB penetration score than Ligand B (68.67%), which is crucial for a CNS target like DRD2.

**9. Caco-2:** Both ligands have negative Caco-2 permeability values, which is unusual and suggests a potential issue with intestinal absorption. However, these values can be unreliable and require experimental validation.

**10. Solubility:** Both ligands have negative solubility values, which is also unusual and suggests poor aqueous solubility. Again, experimental validation is needed.

**11. hERG:** Both ligands have low hERG inhibition liability (0.382 and 0.495, respectively), which is favorable.

**12. Cl_mic:** Ligand A (23.94) has a much lower microsomal clearance than Ligand B (111.34), suggesting better metabolic stability.

**13. t1/2:** Ligand A (-8.811) has a more negative in vitro half-life than Ligand B (17.924). A more negative value indicates a shorter half-life.

**14. Pgp:** Both ligands have low P-gp efflux liability (0.159 and 0.419, respectively), which is good for CNS penetration.

**15. Binding Affinity:** Both ligands have very similar and strong binding affinities (-8.6 and -8.3 kcal/mol, respectively). The difference of 0.3 kcal/mol is not substantial enough to be a deciding factor.

**Overall Assessment:**

Ligand A is the more promising candidate. It has a better QED score, significantly lower microsomal clearance (better metabolic stability), better BBB penetration, and a more favorable TPSA. While both ligands have similar binding affinities and acceptable safety profiles, the improved ADME properties of Ligand A make it a more likely viable drug candidate for a CNS target like DRD2. The negative Caco-2 and solubility values are concerning for both, but these are less critical than BBB penetration and metabolic stability for a CNS-focused drug.

Output:
1
2025-04-17 08:05:04,005 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (346.515 Da) is slightly better positioned.

**TPSA:** Ligand A (40.62) is excellent for CNS penetration, well below the 90 A^2 threshold. Ligand B (115.11) is higher, but still potentially acceptable, though less ideal.

**logP:** Ligand A (3.618) is within the optimal range (1-3). Ligand B (1.579) is on the lower end, potentially hindering permeability.

**H-Bond Donors/Acceptors:** Ligand A (0 HBD, 2 HBA) is favorable. Ligand B (3 HBD, 6 HBA) is still within acceptable limits, but slightly less optimal.

**QED:** Both ligands have good QED scores (A: 0.661, B: 0.705), indicating good drug-like properties.

**DILI:** Both have acceptable DILI risk (A: 12.641, B: 71.539), but Ligand A is significantly better.

**BBB:** This is critical for a CNS target. Ligand A (89.259) has a very good BBB percentile, while Ligand B (13.532) is poor.

**Caco-2 Permeability:** Ligand A (-4.664) is poor, while Ligand B (-5.127) is also poor. This is a concern for oral bioavailability for both.

**Aqueous Solubility:** Both are very poor (-3.33 and -3.932 respectively). This could pose formulation challenges.

**hERG Inhibition:** Ligand A (0.597) has a lower risk of hERG inhibition than Ligand B (0.289).

**Microsomal Clearance:** Ligand A (72.607) has higher clearance than Ligand B (5.257), indicating lower metabolic stability.

**In vitro Half-Life:** Ligand B (44.897) has a much better in vitro half-life than Ligand A (-10.232).

**P-gp Efflux:** Ligand A (0.341) has lower P-gp efflux than Ligand B (0.06), which is beneficial for CNS exposure.

**Binding Affinity:** Ligand B (-8.0 kcal/mol) has a significantly stronger binding affinity than Ligand A (-0.0 kcal/mol). This is a substantial advantage.

**Overall Assessment:**

Ligand B's significantly stronger binding affinity is a major advantage. However, its poor BBB penetration is a critical drawback for a CNS target like DRD2. Ligand A has excellent BBB penetration and a better safety profile (DILI, hERG), but its binding affinity is very weak. The difference in affinity is >7 kcal/mol, which is substantial enough to potentially overcome some of the ADME deficiencies. Given the importance of CNS penetration for DRD2, and the relatively poor Caco-2 permeability of both, the better BBB score of Ligand A is a strong argument in its favor. However, the binding affinity difference is so large that it is likely Ligand B could be optimized to improve its BBB penetration.

Output:
1
2025-04-17 08:05:04,006 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (374.453 and 339.454 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (75.27) is higher than the preferred <90 for CNS targets, but still reasonable. Ligand B (21.26) is excellent, well below the threshold.

**logP:** Ligand A (3.958) is approaching the upper limit of the optimal range (1-3) but still acceptable. Ligand B (4.781) is slightly above the optimal range, potentially leading to solubility issues or off-target interactions.

**H-Bond Donors/Acceptors:** Ligand A has 2 HBD and 3 HBA, which are both within the acceptable limits. Ligand B has 1 HBD and 2 HBA, also within limits.

**QED:** Both ligands have reasonable QED values (0.784 and 0.552), indicating good drug-like properties.

**DILI:** Ligand A (61.07) has a higher DILI risk than Ligand B (21.598). This is a significant negative for Ligand A.

**BBB:** Ligand A (86.157) has a very good BBB penetration percentile, exceeding the desirable >70 for CNS targets. Ligand B (61.884) is lower, but still not terrible.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.332 and -4.602), which is unusual and suggests poor permeability. This is a concern for both.

**Aqueous Solubility:** Both ligands have negative solubility values (-4.779 and -4.535), indicating very poor solubility. This is a major drawback for both.

**hERG Inhibition:** Ligand A (0.508) has a slightly higher hERG risk than Ligand B (0.966), but both are relatively low.

**Microsomal Clearance:** Ligand A (21.368) has a lower microsomal clearance than Ligand B (53.739), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (44.519) has a longer half-life than Ligand B (3.313), which is desirable.

**P-gp Efflux:** Ligand A (0.246) has lower P-gp efflux liability than Ligand B (0.8), which is beneficial for CNS penetration.

**Binding Affinity:** Ligand B (-8.9 kcal/mol) has a significantly stronger binding affinity than Ligand A (0.0 kcal/mol). This is a crucial advantage, potentially outweighing some of the ADME drawbacks.

**Overall Assessment:**

Ligand B's significantly stronger binding affinity (-8.9 kcal/mol vs 0.0 kcal/mol) is the most important factor. While it has some ADME liabilities (higher logP, Pgp efflux, lower half-life), the substantial improvement in potency is likely to be more impactful, especially for a GPCR target where high affinity is critical. Ligand A has better BBB penetration and metabolic stability, but its very weak binding affinity makes it a less promising candidate. The poor solubility and permeability are concerning for both, but can potentially be addressed with formulation strategies. The DILI risk for Ligand A is also a significant concern.

Output:
1
2025-04-17 08:05:04,006 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (346.471 and 350.419 Da) fall within the ideal range of 200-500 Da.

**TPSA:** Ligand A (49.85) is excellent, well below the 90 A^2 threshold for CNS targets. Ligand B (137.31) is higher, but still potentially acceptable, although less ideal.

**logP:** Ligand A (2.075) is optimal (1-3). Ligand B (0.004) is very low, which is a significant concern for permeability and CNS penetration.

**H-Bond Donors/Acceptors:** Ligand A (0 HBD, 3 HBA) is favorable. Ligand B (5 HBD, 4 HBA) is acceptable, but the 5 HBDs are approaching the upper limit.

**QED:** Ligand A (0.692) is good, indicating drug-likeness. Ligand B (0.406) is lower, suggesting a less drug-like profile.

**DILI:** Ligand A (14.889) has a very low DILI risk. Ligand B (29.159) is also relatively low, but higher than Ligand A.

**BBB:** Ligand A (83.133) has excellent BBB penetration potential. Ligand B (41.528) is poor, a major drawback for a CNS target like DRD2.

**Caco-2 Permeability:** Ligand A (-4.384) is negative, which is unusual and suggests very poor permeability. Ligand B (-5.711) is also poor, but similar to A.

**Aqueous Solubility:** Both ligands have very poor aqueous solubility (-2.416 and -2.929 respectively). This could pose formulation challenges.

**hERG:** Both ligands have very low hERG risk (0.189 and 0.144).

**Microsomal Clearance:** Ligand A (60.753) is moderate. Ligand B (0.912) is very low, indicating good metabolic stability.

**In vitro Half-Life:** Ligand A (6.391) is moderate. Ligand B (-10.792) is very negative, which is problematic and suggests rapid degradation.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.127 and 0.017).

**Binding Affinity:** Ligand A (-9.0) has significantly stronger binding affinity than Ligand B (-7.8). This is a substantial advantage.

**Overall Assessment:**

Ligand A excels in key areas for a CNS GPCR target: TPSA, logP, BBB, and, crucially, binding affinity. While its Caco-2 permeability and solubility are poor, the strong affinity and good BBB penetration are likely to outweigh these issues, especially if formulation strategies can be employed. Ligand B suffers from a very low logP and poor BBB penetration, making it unlikely to reach the target in sufficient concentrations, despite its good metabolic stability. The significantly stronger binding affinity of Ligand A is a decisive factor.

Output:
1
2025-04-17 08:05:04,006 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (370.559 Da) is slightly higher than Ligand B (345.363 Da), but both are acceptable.

**TPSA:** Ligand A (49.85) is excellent for CNS penetration, well below the 90 A^2 threshold. Ligand B (119.04) is higher, but still potentially acceptable, though less ideal.

**logP:** Ligand A (2.784) is optimal. Ligand B (-0.189) is significantly lower, which could hinder membrane permeability and CNS penetration.

**H-Bond Donors/Acceptors:** Ligand A (0 HBD, 4 HBA) is favorable. Ligand B (1 HBD, 8 HBA) is also acceptable, but the higher HBA count could slightly impact permeability.

**QED:** Both ligands have good QED scores (Ligand A: 0.586, Ligand B: 0.721), indicating drug-like properties.

**DILI:** Ligand A (22.451) has a much lower DILI risk than Ligand B (79.333), a significant advantage.

**BBB:** Ligand A (73.711) has a good BBB percentile, exceeding the 70% threshold for CNS targets. Ligand B (53.587) is considerably lower, raising concerns about CNS exposure.

**Caco-2 Permeability:** Ligand A (-4.833) is poor. Ligand B (-5.54) is also poor. This is a weakness for both, but less critical given the focus on BBB for a CNS target.

**Aqueous Solubility:** Ligand A (-2.597) and Ligand B (-1.139) both have poor aqueous solubility. This could pose formulation challenges.

**hERG Inhibition:** Ligand A (0.636) has a low hERG risk. Ligand B (0.029) is even lower, but both are acceptable.

**Microsomal Clearance:** Ligand A (68.102) has higher clearance than Ligand B (42.385), suggesting lower metabolic stability.

**In vitro Half-Life:** Ligand B (-12.782) has a negative half-life, which is not possible. This is a critical error and disqualifies Ligand B. Ligand A (10.342) has a reasonable half-life.

**P-gp Efflux:** Ligand A (0.38) has lower P-gp efflux liability than Ligand B (0.134), which is favorable for CNS penetration.

**Binding Affinity:** Ligand B (-7.6 kcal/mol) has a slightly better binding affinity than Ligand A (-7.1 kcal/mol), but the difference is relatively small (0.5 kcal/mol).

**Overall Assessment:**

Ligand A is significantly better overall. While both have poor Caco-2 and aqueous solubility, Ligand A excels in crucial areas for a CNS-targeting GPCR ligand: BBB penetration, DILI risk, and P-gp efflux. Ligand B's low logP and the impossible half-life are major drawbacks. The slightly better affinity of Ligand B doesn't outweigh these significant liabilities.

Output:
1
2025-04-17 08:05:04,006 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight (MW):** Both ligands (343.427 and 347.415 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Both ligands have TPSA values (75.44 and 75.02) that are acceptable for oral absorption (<140) but slightly high for optimal CNS penetration (<90). This is a minor concern, as other factors are more critical for CNS targets.

**3. logP:** Ligand A (2.17) is optimal, while Ligand B (1.125) is a bit low, potentially hindering membrane permeability.

**4. H-Bond Donors (HBD):** Both ligands have 1 HBD, which is within the acceptable limit of <=5.

**5. H-Bond Acceptors (HBA):** Ligand A has 4 HBA, and Ligand B has 5 HBA, both within the acceptable limit of <=10.

**6. QED:** Both ligands have good QED scores (0.77 and 0.864), indicating drug-like properties.

**7. DILI:** Ligand A (41.411) has a slightly higher DILI risk than Ligand B (30.632), but both are below the concerning threshold of 60.

**8. BBB:** Both ligands have reasonable BBB penetration (61.962% and 65.762%), but ideally, we'd want >70% for a CNS target. Ligand B is slightly better here.

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.834 and -4.955), which is unusual and suggests poor permeability. This is a significant drawback for both.

**10. Aqueous Solubility:** Both ligands have negative solubility values (-3.573 and -1.847), indicating poor aqueous solubility. This is another significant drawback.

**11. hERG Inhibition:** Ligand A (0.142) has a lower hERG inhibition risk than Ligand B (0.497), which is preferable.

**12. Microsomal Clearance (Cl_mic):** Ligand A (58.429) has a higher microsomal clearance than Ligand B (10.169), indicating lower metabolic stability. This is a negative for Ligand A.

**13. In vitro Half-Life:** Ligand A (-11.05) has a negative in vitro half-life, which is impossible and likely an error in the data. Ligand B (59.814) has a good in vitro half-life.

**14. P-gp Efflux:** Ligand A (0.299) has lower P-gp efflux than Ligand B (0.046), which is beneficial for CNS exposure.

**15. Binding Affinity:** Ligand B (-9.2 kcal/mol) has a significantly stronger binding affinity than Ligand A (-8.4 kcal/mol). This is a substantial advantage, potentially outweighing some of the ADME drawbacks.

**Overall Assessment:**

While both ligands have issues with Caco-2 permeability and solubility, Ligand B is the more promising candidate. Its significantly stronger binding affinity (-9.2 vs -8.4 kcal/mol) is a major advantage for a GPCR target.  It also has better metabolic stability (lower Cl_mic, longer t1/2), lower DILI risk, and slightly better BBB penetration. The negative half-life for Ligand A is a dealbreaker. Although Ligand B's logP is slightly lower, the strong affinity and other favorable properties make it the better choice.

Output:
1
2025-04-17 08:05:04,007 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (347.379 and 354.495 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (137.87) is borderline but acceptable for CNS penetration, while Ligand B (56.33) is excellent, well below the 90 A^2 threshold.

**logP:** Ligand A (2.145) is optimal. Ligand B (-0.177) is too low, potentially hindering membrane permeability.

**H-Bond Donors/Acceptors:** Ligand A has 4 HBD and 6 HBA, both within acceptable limits. Ligand B has 0 HBD and 5 HBA, also acceptable.

**QED:** Both ligands have reasonable QED scores (0.483 and 0.575), indicating moderate drug-likeness.

**DILI:** Ligand A (86.39) has a higher DILI risk than Ligand B (5.739). This is a significant drawback for Ligand A.

**BBB:** Ligand B (65.839) has a much better BBB penetration score than Ligand A (48.236). This is crucial for a CNS target like DRD2.

**Caco-2 Permeability:** Ligand A (-5.27) has poor Caco-2 permeability, suggesting poor intestinal absorption. Ligand B (-4.735) is also poor, but slightly better than A.

**Aqueous Solubility:** Ligand A (-4.172) has very poor solubility, which could hinder formulation and bioavailability. Ligand B (-0.01) is also poor, but better than A.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.18 and 0.499).

**Microsomal Clearance:** Ligand A (17.951) has lower microsomal clearance than Ligand B (20.089), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (22.957) has a longer half-life than Ligand B (-12.742). This is a positive attribute for Ligand A.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.032 and 0.003).

**Binding Affinity:** Ligand A (-9.1) has a significantly stronger binding affinity than Ligand B (-6.6). This is a substantial advantage, exceeding the 1.5 kcal/mol threshold.

**Overall Assessment:**

Despite the strong binding affinity of Ligand A, its poor solubility, Caco-2 permeability, and higher DILI risk are major concerns. Ligand B, while having a weaker binding affinity, possesses a much better safety profile (lower DILI), significantly better BBB penetration, and slightly better solubility and permeability. Given the GPCR-specific priorities, especially BBB penetration for a CNS target, and the importance of a favorable safety profile, Ligand B is the more promising candidate. The affinity difference, while significant, *could* potentially be addressed through further optimization of Ligand B, whereas fixing the ADME issues of Ligand A would likely require more substantial structural changes.

Output:
1
2025-04-17 08:05:04,007 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (342.443 and 364.833 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (86.88) is excellent, well below the 90 A^2 threshold for CNS targets. Ligand B (95.42) is still reasonable but slightly higher, potentially impacting BBB penetration.

**logP:** Both ligands have good logP values (1.545 and 1.01), falling within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A has 3 HBD and 3 HBA, which is good. Ligand B has 2 HBD and 5 HBA, also acceptable.

**QED:** Both ligands have good QED scores (0.626 and 0.834), indicating drug-like properties.

**DILI:** Ligand A (37.999) has a significantly lower DILI risk than Ligand B (59.791). This is a major advantage.

**BBB:** Ligand A (39.162) has a lower BBB percentile than Ligand B (45.909), but both are below the desirable >70 for CNS targets. This is a weakness for both, but less so for B.

**Caco-2 Permeability:** Both have negative Caco-2 values (-5.225 and -5.102), which is unusual and suggests poor permeability. This is a significant concern for both.

**Aqueous Solubility:** Both have negative solubility values (-3.362 and -2.859), indicating very poor aqueous solubility. This is a major drawback for both.

**hERG Inhibition:** Both ligands show very low hERG inhibition risk (0.117 and 0.145).

**Microsomal Clearance:** Ligand A (-8.103) has a significantly *lower* (better) microsomal clearance than Ligand B (-14.804), indicating better metabolic stability.

**In vitro Half-Life:** Ligand A (-6.537) has a better (more negative) in vitro half-life than Ligand B (-1.366).

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.066 and 0.012).

**Binding Affinity:** Ligand A (-8.7 kcal/mol) has a slightly better binding affinity than Ligand B (-7.9 kcal/mol). While both are good, the 0.8 kcal/mol difference is meaningful.

**Overall Assessment:**

Ligand A is the better candidate. While both have issues with Caco-2 permeability and solubility, Ligand A excels in several key areas: lower DILI risk, better metabolic stability (lower Cl_mic, better t1/2), and slightly better binding affinity. The TPSA is also more favorable for CNS penetration. Ligand B has a slightly better BBB score, but the other advantages of A outweigh this. The poor permeability and solubility are significant hurdles for both, but can be addressed with formulation strategies.

Output:
0
2025-04-17 08:05:04,007 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (378.826 and 349.475 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (57.26) is better than Ligand B (61.88) as it is closer to the <90 desired for CNS targets. Both are acceptable, but A is preferred.

**3. logP:** Both ligands have good logP values (2.838 and 1.169), falling within the optimal 1-3 range. Ligand A is slightly better.

**4. H-Bond Donors:** Ligand A (2) and Ligand B (1) are both within the acceptable limit of <=5.

**5. H-Bond Acceptors:** Both ligands have 4 H-bond acceptors, which is within the acceptable limit of <=10.

**6. QED:** Both ligands have good QED scores (0.716 and 0.809), indicating good drug-like properties.

**7. DILI:** Ligand A (34.742) has a slightly higher DILI risk than Ligand B (23.575), but both are below the concerning threshold of 60.

**8. BBB:** Ligand A (70.997) has a better BBB penetration percentile than Ligand B (65.839). Both are reasonably good, but A is preferred for a CNS target.

**9. Caco-2 Permeability:** Ligand A (-5.255) has worse Caco-2 permeability than Ligand B (-4.642). This is a negative for Ligand A.

**10. Aqueous Solubility:** Ligand A (-3.42) has worse aqueous solubility than Ligand B (-1.483). This is a negative for Ligand A.

**11. hERG Inhibition:** Ligand A (0.749) has a slightly higher hERG inhibition risk than Ligand B (0.252), but both are relatively low.

**12. Microsomal Clearance:** Ligand B (7.298) has significantly lower microsomal clearance than Ligand A (15.996), indicating better metabolic stability. This is a significant advantage for Ligand B.

**13. In vitro Half-Life:** Ligand A (33.182) has a longer in vitro half-life than Ligand B (15.755). This is a positive for Ligand A.

**14. P-gp Efflux:** Ligand A (0.153) has lower P-gp efflux than Ligand B (0.064), which is favorable for CNS penetration.

**15. Binding Affinity:** Ligand A (-7.9 kcal/mol) has a slightly better binding affinity than Ligand B (-7.3 kcal/mol). This is a significant advantage for Ligand A, potentially outweighing some of its ADME drawbacks.

**Overall Assessment:**

Ligand A has a better binding affinity, TPSA, logP, BBB penetration, and P-gp efflux, which are all important for a CNS-targeting GPCR ligand. However, Ligand B has superior metabolic stability (lower Cl_mic), better Caco-2 permeability and solubility, and lower DILI risk. The difference in binding affinity (0.6 kcal/mol) is substantial enough to potentially overcome the ADME deficiencies of Ligand A, especially considering the importance of potency for GPCR ligands. The better BBB penetration of A is also a significant factor.

Output:
1
2025-04-17 08:05:04,007 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (349.431 and 361.442 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (121.52) is borderline for CNS penetration, being slightly above the preferred <90, while Ligand B (62.3) is excellent.

**logP:** Ligand A (-0.164) is quite low, potentially hindering membrane permeability. Ligand B (2.693) is within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A has 4 HBD and 4 HBA, which are acceptable. Ligand B has 1 HBD and 4 HBA, also acceptable.

**QED:** Both ligands have reasonable QED values (0.477 and 0.86), with Ligand B being significantly better.

**DILI:** Both have low DILI risk (16.712 and 47.964), with Ligand A being slightly better.

**BBB:** Ligand B (82.513) shows excellent BBB penetration, a crucial factor for CNS targets. Ligand A (44.668) is considerably lower, raising concerns about reaching the target in the brain.

**Caco-2 Permeability:** Both have negative Caco-2 values (-5.838 and -4.624), which is unusual and suggests poor permeability. However, the scale is not specified, so it's hard to interpret.

**Aqueous Solubility:** Both have negative solubility values (-2.57 and -3.624), which is also unusual and suggests poor solubility. Again, the scale is not specified.

**hERG:** Both ligands have very low hERG risk (0.082 and 0.15).

**Microsomal Clearance:** Ligand A (5.678) has a lower clearance than Ligand B (41.741), indicating better metabolic stability.

**In vitro Half-Life:** Ligand A (23.124) has a longer half-life than Ligand B (10.747).

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.024 and 0.047).

**Binding Affinity:** Both ligands have strong binding affinities (-8.5 and -9.4 kcal/mol), with Ligand B being slightly better.

**Overall Assessment:**

Ligand B is the stronger candidate. While Ligand A has slightly better DILI and metabolic stability, Ligand B excels in crucial areas for a CNS-targeting GPCR ligand: significantly better BBB penetration (82.513 vs 44.668), a more favorable logP (2.693 vs -0.164), and a slightly better binding affinity (-9.4 vs -8.5). The TPSA of Ligand B is also much more favorable for CNS penetration. The poor Caco-2 and solubility values are concerning for both, but the strong affinity and BBB penetration of Ligand B outweigh these concerns.

Output:
1
2025-04-17 08:05:04,008 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (344.419 and 345.403 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (93.84) is better than Ligand B (103.25). Both are below the 140 A^2 threshold for oral absorption, and Ligand A is closer to the <90 A^2 target for CNS penetration.

**logP:** Ligand A (1.016) is slightly better than Ligand B (0.556), both are within the optimal 1-3 range, but Ligand B is getting close to the lower limit where permeation could be an issue.

**H-Bond Donors/Acceptors:** Ligand A (HBD=2, HBA=6) is slightly preferable to Ligand B (HBD=3, HBA=5) as it has fewer HBDs. Both are within acceptable limits.

**QED:** Both ligands have reasonable QED values (A: 0.733, B: 0.682), indicating good drug-like properties.

**DILI:** Ligand B (40.287) has a lower DILI risk than Ligand A (59.442), which is a significant advantage.

**BBB:** Ligand A (47.111) has a substantially better BBB penetration percentile than Ligand B (17.371). This is *critical* for a CNS target like DRD2.

**Caco-2 Permeability:** Both have negative values, indicating poor permeability. Ligand A (-5.167) is slightly better than Ligand B (-5.517).

**Aqueous Solubility:** Both ligands have negative solubility values, indicating poor aqueous solubility. Ligand B (-1.997) is slightly better than Ligand A (-2.468).

**hERG Inhibition:** Ligand A (0.033) has a lower hERG inhibition risk than Ligand B (0.223), which is desirable.

**Microsomal Clearance:** Ligand B (-10.084) has a significantly lower (better) microsomal clearance than Ligand A (34.267), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand B (-12.706) has a longer in vitro half-life than Ligand A (14.618), which is favorable.

**P-gp Efflux:** Ligand A (0.052) has a lower P-gp efflux liability than Ligand B (0.007), which is beneficial for CNS exposure.

**Binding Affinity:** Both ligands have excellent binding affinities (-8.0 and -8.6 kcal/mol). Ligand B is slightly better (-8.6 kcal/mol), but the difference is small.

**Overall Assessment:**

While Ligand B has advantages in DILI, metabolic stability (Cl_mic), and half-life, Ligand A's significantly better BBB penetration (47.111 vs 17.371) is the deciding factor for a CNS target like DRD2. The slightly better TPSA and lower P-gp efflux also contribute to its favorability. The affinity difference is minimal. The poor Caco-2 and solubility are concerns for both, but less critical for a CNS-focused drug.

Output:
0
2025-04-17 08:05:04,008 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (334.419 and 348.443 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (54.12) is significantly better than Ligand B (59.08). For CNS targets, we want TPSA <= 90, both are well within this range, but A is preferable.

**logP:** Ligand A (3.853) is optimal (1-3), while Ligand B (1.557) is on the lower side. Lower logP can hinder permeation, especially across the BBB. This favors Ligand A.

**H-Bond Donors/Acceptors:** Ligand A (2 HBD, 2 HBA) and Ligand B (0 HBD, 4 HBA) both fall within acceptable ranges (<=5 HBD and <=10 HBA).

**QED:** Both ligands have good QED scores (0.719 and 0.774), indicating drug-like properties.

**DILI:** Ligand A (69.678) has a higher DILI risk than Ligand B (21.171). This is a significant drawback for Ligand A.

**BBB:** Ligand B (64.715) has a better BBB percentile than Ligand A (40.481). For a CNS target like DRD2, BBB penetration is crucial, making Ligand B more promising.

**Caco-2 Permeability:** Ligand A (-4.967) has worse Caco-2 permeability than Ligand B (-4.392).

**Aqueous Solubility:** Ligand A (-6.207) has worse aqueous solubility than Ligand B (-2.069).

**hERG:** Ligand A (0.805) has a slightly higher hERG risk than Ligand B (0.268). Lower is better.

**Microsomal Clearance:** Ligand A (69.351) has higher microsomal clearance than Ligand B (57.924), suggesting faster metabolism and lower metabolic stability.

**In vitro Half-Life:** Ligand B (8.58) has a much longer in vitro half-life than Ligand A (-29.618). This is a major advantage for Ligand B.

**P-gp Efflux:** Ligand A (0.617) has better P-gp efflux profile than Ligand B (0.037). Lower P-gp efflux is better for CNS exposure.

**Binding Affinity:** Ligand B (-7.3 kcal/mol) has significantly stronger binding affinity than Ligand A (-10.6 kcal/mol). A difference of >1.5 kcal/mol is substantial and can outweigh other drawbacks.

**Overall Assessment:**

While Ligand A has a better logP and P-gp efflux, Ligand B excels in almost all other critical parameters for a CNS-targeting GPCR ligand. Specifically, its superior BBB penetration, significantly stronger binding affinity, longer half-life, lower DILI risk, better solubility, and lower hERG risk outweigh the slightly less optimal logP. The substantial difference in binding affinity (-7.3 vs -10.6 kcal/mol) is a key deciding factor.

Output:
1
2025-04-17 08:05:04,008 - INFO - Batch 419 complete. Total preferences: 6704
2025-04-17 08:05:04,008 - INFO - Processing batch 420/512...
2025-04-17 08:05:48,249 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (347.459 and 345.487 Da) fall comfortably within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (61.88) is slightly above the optimal <90 for CNS targets, but still reasonable. Ligand B (52.65) is excellent, well below 90.

**3. logP:** Both ligands have good logP values (1.189 and 1.788), falling within the 1-3 range.

**4. H-Bond Donors:** Both have 1 HBD, which is within the acceptable limit of <=5.

**5. H-Bond Acceptors:** Ligand A has 4 HBAs, and Ligand B has 3. Both are below the acceptable limit of <=10.

**6. QED:** Both ligands have good QED scores (0.599 and 0.773), indicating good drug-likeness.

**7. DILI:** Ligand A (22.761) has a lower DILI risk than Ligand B (9.151), both are quite good.

**8. BBB:** This is a critical parameter for a CNS target like DRD2. Ligand B (83.676) has a significantly higher BBB percentile than Ligand A (67.584). This is a substantial advantage for Ligand B.

**9. Caco-2 Permeability:** Ligand A (-5.212) has worse Caco-2 permeability than Ligand B (-4.99).

**10. Aqueous Solubility:** Ligand A (-1.65) has better aqueous solubility than Ligand B (-2.656).

**11. hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.185 and 0.393).

**12. Microsomal Clearance:** Ligand A (7.73) has significantly lower microsomal clearance than Ligand B (28.763), suggesting better metabolic stability.

**13. In vitro Half-Life:** Ligand B (15.07) has a much longer in vitro half-life than Ligand A (-0.797).

**14. P-gp Efflux:** Both ligands have low P-gp efflux liability (0.045 and 0.065).

**15. Binding Affinity:** Both ligands have excellent binding affinities (-8.4 and -8.2 kcal/mol). The difference of 0.2 kcal/mol is not substantial enough to outweigh other factors.

**Overall Assessment:**

Ligand B is superior due to its significantly better BBB penetration (83.7% vs 67.6%) and longer in vitro half-life (15.07 vs -0.797). While Ligand A has slightly better solubility and lower clearance, the CNS target necessitates prioritizing BBB and metabolic stability. The small difference in affinity is not a deciding factor.

Output:
1
2025-04-17 08:05:48,249 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (357.435 and 346.431 Da) fall within the ideal range of 200-500 Da.

**TPSA:** Ligand A (72.7) is significantly better than Ligand B (99.23). For CNS targets, we want TPSA <= 90, so Ligand A is preferable.

**logP:** Both ligands have good logP values (2.351 and 2.032), falling within the optimal 1-3 range.

**H-Bond Donors & Acceptors:** Both have 1 HBD, which is good. Ligand A has 6 HBA, while Ligand B has 5. Both are acceptable (<=10).

**QED:** Both ligands have good QED scores (0.776 and 0.849), indicating drug-like properties.

**DILI:** Ligand A (61.962) has a higher DILI risk than Ligand B (31.989). This favors Ligand B.

**BBB:** Ligand B (61.535) has a better BBB percentile than Ligand A (49.244). While >70 is desirable, 61.535 is still reasonably good, and a significant improvement over Ligand A. This is a key factor for a CNS target like DRD2.

**Caco-2 Permeability:** Both have negative Caco-2 values (-5.057 and -4.991). This is unusual and suggests poor permeability, but the scale is not specified, so it is hard to interpret.

**Aqueous Solubility:** Both have negative solubility values (-2.814 and -2.491). Again, the scale is not specified, so it is hard to interpret.

**hERG:** Both ligands have low hERG inhibition liability (0.579 and 0.233), which is good.

**Microsomal Clearance:** Ligand A (24.878) has lower microsomal clearance than Ligand B (32.576), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (22.731) has a longer half-life than Ligand B (-19.787). This is a significant advantage.

**P-gp Efflux:** Ligand A (0.278) has lower P-gp efflux than Ligand B (0.077), meaning it is less likely to be pumped out of the brain, and thus better CNS exposure.

**Binding Affinity:** Ligand B (-7.9 kcal/mol) has a stronger binding affinity than Ligand A (-9.2 kcal/mol). This is a substantial difference (>1.5 kcal/mol) and a major advantage.

**Overall Assessment:**

While Ligand A has better TPSA and metabolic stability, Ligand B excels in the most crucial areas for a CNS GPCR target: BBB penetration and binding affinity. The stronger binding affinity of Ligand B is particularly important and can potentially offset some of the drawbacks in other areas. The lower DILI risk for Ligand B is also a positive. The negative Caco-2 and solubility values are concerning for both, but the binding affinity and BBB are the dominating factors.

Output:
1
2025-04-17 08:05:48,249 - INFO - Reasoning:

Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (416.335 Da) is slightly higher than Ligand B (348.403 Da), but both are acceptable.

**2. TPSA:** Ligand A (44.81) is excellent, well below the 90 A^2 threshold for CNS targets. Ligand B (110.26) is higher, but still potentially acceptable, although less desirable.

**3. logP:** Both ligands have good logP values (A: 2.512, B: 2.382), falling within the optimal 1-3 range.

**4. H-Bond Donors:** Both ligands have acceptable HBD counts (A: 1, B: 2), well below the limit of 5.

**5. H-Bond Acceptors:** Ligand A (4) and Ligand B (6) are both below the 10 limit.

**6. QED:** Both ligands have good QED scores (A: 0.742, B: 0.758), indicating good drug-like properties.

**7. DILI:** Ligand A (39.705) has a lower DILI risk than Ligand B (70.686). This is a significant advantage for Ligand A.

**8. BBB:** Ligand A (85.498) has a substantially higher BBB penetration percentile than Ligand B (54.517). This is a *critical* advantage for a CNS target like DRD2.

**9. Caco-2 Permeability:** Both have negative values, which is unusual. Assuming these are logP-like scales, lower values indicate poorer permeability. Ligand A (-4.749) is worse than Ligand B (-5.049), but both are poor.

**10. Aqueous Solubility:** Both have negative values, which is unusual. Assuming these are logS-like scales, lower values indicate poorer solubility. Ligand A (-2.269) is better than Ligand B (-2.9).

**11. hERG Inhibition:** Both ligands show low hERG inhibition liability (A: 0.965, B: 0.203), which is good.

**12. Microsomal Clearance:** Ligand A (10.388) has a lower microsomal clearance than Ligand B (66.417), suggesting better metabolic stability.

**13. In vitro Half-Life:** Ligand A (16.689) has a longer in vitro half-life than Ligand B (-22.619). This is a significant advantage.

**14. P-gp Efflux:** Ligand A (0.242) has lower P-gp efflux liability than Ligand B (0.14), which is favorable.

**15. Binding Affinity:** Ligand A (-8.5 kcal/mol) has a slightly better binding affinity than Ligand B (-7.8 kcal/mol). While both are good, the 0.7 kcal/mol difference is notable.

**Overall Assessment:**

Ligand A is the superior candidate. It excels in key properties for a CNS-targeting GPCR ligand: high BBB penetration, low DILI risk, better metabolic stability (lower Cl_mic, longer t1/2), lower P-gp efflux, and slightly better binding affinity. While Caco-2 and solubility are poor for both, the other advantages of Ligand A outweigh these drawbacks, especially considering the importance of CNS penetration for DRD2.



Output:
1
2025-04-17 08:05:48,249 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight (MW):** Both ligands (350.463 and 360.933 Da) fall comfortably within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (96.25) is slightly above the preferred <90 for CNS targets, but still reasonable. Ligand B (25.99) is excellent, well below the 90 threshold. This favors Ligand B.

**3. logP:** Ligand A (1.923) is within the optimal 1-3 range. Ligand B (4.337) is a bit high, potentially leading to solubility issues and off-target interactions. This favors Ligand A.

**4. H-Bond Donors (HBD):** Ligand A (3) and Ligand B (0) are both acceptable, being less than 5.

**5. H-Bond Acceptors (HBA):** Ligand A (5) and Ligand B (4) are both acceptable, being less than 10.

**6. QED:** Both ligands have similar QED values (0.7 and 0.622), indicating good drug-likeness.

**7. DILI:** Ligand A (48.623) has a moderate DILI risk, but is still acceptable. Ligand B (12.834) has a very low DILI risk, which is a significant advantage. This favors Ligand B.

**8. BBB:** Ligand A (57.968) has a moderate BBB penetration, while Ligand B (66.033) has a good BBB penetration. Since we are targeting a CNS receptor (DRD2), BBB penetration is crucial. This favors Ligand B.

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.914 and -4.796). This is unusual and suggests poor intestinal absorption. However, for a CNS target, intestinal absorption is less critical than BBB penetration.

**10. Aqueous Solubility:** Both ligands have negative solubility values (-3.098 and -4.853). This is concerning, but can potentially be addressed through formulation.

**11. hERG Inhibition:** Ligand A (0.118) has a very low hERG risk, which is excellent. Ligand B (0.889) has a slightly higher, but still acceptable, hERG risk. This favors Ligand A.

**12. Microsomal Clearance:** Ligand A (46.872) and Ligand B (40.354) have similar microsomal clearance values. Lower is better, so Ligand B has a slight advantage.

**13. In vitro Half-Life:** Ligand B (50.821) has a significantly longer in vitro half-life than Ligand A (17.003). This is a substantial advantage, potentially allowing for less frequent dosing. This favors Ligand B.

**14. P-gp Efflux:** Ligand A (0.083) has very low P-gp efflux, which is excellent for CNS exposure. Ligand B (0.458) has moderate P-gp efflux. This favors Ligand A.

**15. Binding Affinity:** Ligand A (-7.7 kcal/mol) has a significantly stronger binding affinity than Ligand B (-6.8 kcal/mol). A 0.9 kcal/mol difference is substantial and can often outweigh minor ADME drawbacks. This strongly favors Ligand A.

**Overall Assessment:**

While Ligand B excels in BBB penetration, DILI risk, and in vitro half-life, Ligand A's significantly stronger binding affinity (-7.7 vs -6.8 kcal/mol) and very low P-gp efflux are critical advantages for a CNS GPCR target like DRD2. The slightly higher TPSA of Ligand A is a minor concern compared to the potency and efflux advantages. The hERG risk is also much lower for Ligand A.

Output:
0
2025-04-17 08:05:48,249 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight (MW):** Both ligands are within the ideal range (200-500 Da). Ligand A (380.417 Da) is slightly higher than Ligand B (346.427 Da), but both are acceptable.

**2. TPSA:** Ligand A (114.18) is borderline for CNS penetration, being above the preferred <90, but still potentially acceptable. Ligand B (73.99) is excellent, well below the 90 threshold. This favors Ligand B.

**3. logP:** Ligand A (0.469) is quite low, potentially hindering membrane permeability. Ligand B (1.799) is within the optimal range (1-3). This strongly favors Ligand B.

**4. H-Bond Donors (HBD):** Both ligands have acceptable HBD counts (Ligand A: 2, Ligand B: 1).

**5. H-Bond Acceptors (HBA):** Both ligands have acceptable HBA counts (Ligand A: 7, Ligand B: 4).

**6. QED:** Both ligands have good QED scores (Ligand A: 0.644, Ligand B: 0.829), indicating drug-like properties. Ligand B is slightly better.

**7. DILI:** Both ligands have acceptable DILI risk (Ligand A: 57.58, Ligand B: 48.895), below the concerning threshold of 60. Ligand B is slightly better.

**8. BBB:** Ligand A (61.535) is below the desirable threshold of 70 for CNS targets. Ligand B (58.511) is also below 70, but the difference isn't huge. This is a weakness for both, but less so for Ligand A given its other issues.

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.988 and -4.575), which is unusual and suggests poor permeability. This is a significant concern for both.

**10. Aqueous Solubility:** Both ligands have negative solubility values (-2.074 and -2.089), which is also unusual and suggests poor solubility. This is a significant concern for both.

**11. hERG Inhibition:** Both ligands have very low hERG inhibition risk (Ligand A: 0.072, Ligand B: 0.309).

**12. Microsomal Clearance (Cl_mic):** Ligand A (-6.287) has a negative clearance, which is impossible and likely indicates an error in the data or a very stable compound. Ligand B (47.328) has a moderate clearance.

**13. In vitro Half-Life:** Ligand A (-8.055) has a negative half-life, which is impossible and likely indicates an error in the data. Ligand B (16.12) has a reasonable half-life.

**14. P-gp Efflux:** Ligand A (0.057) has very low P-gp efflux, which is favorable for CNS penetration. Ligand B (0.252) also has low P-gp efflux.

**15. Binding Affinity:** Ligand A (-7.7) has a slightly better binding affinity than Ligand B (-0.0).

**Overall Assessment:**

Despite Ligand A's slightly better binding affinity, its negative values for Caco-2 permeability, solubility, and half-life, along with its low logP, make it a highly improbable drug candidate. These negative values are likely data errors, but even ignoring them, the low logP is a major issue. Ligand B, while also having negative Caco-2 and solubility values, has a much more reasonable profile overall, with a good logP, acceptable DILI, and a reasonable half-life. The BBB values for both are suboptimal, but Ligand B's other properties make it the more promising candidate.

Output:
1
2025-04-17 08:05:48,249 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (354.378 and 353.407 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (85.89) is better than Ligand B (96.87). For CNS targets, we want TPSA <= 90, so Ligand A is preferable.

**3. logP:** Both ligands have good logP values (1.331 and 1.777), falling within the optimal 1-3 range.

**4. H-Bond Donors:** Both have 2 HBD, which is acceptable.

**5. H-Bond Acceptors:** Ligand A has 5 HBA, and Ligand B has 6. Both are within the acceptable limit of <= 10.

**6. QED:** Both ligands have similar QED values (0.736 and 0.745), indicating good drug-likeness.

**7. DILI:** Ligand A (54.75) has a significantly lower DILI risk than Ligand B (84.025). This is a substantial advantage for Ligand A.

**8. BBB:** Ligand A (72.78) has a better BBB percentile than Ligand B (61.109). While >70 is desirable, Ligand A is closer and more favorable for a CNS target.

**9. Caco-2 Permeability:** Ligand A (-4.82) has better Caco-2 permeability than Ligand B (-5.435), indicating better intestinal absorption.

**10. Aqueous Solubility:** Ligand A (-2.517) has better aqueous solubility than Ligand B (-3.386).

**11. hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.375 and 0.236).

**12. Microsomal Clearance:** Ligand A (21.723) has higher microsomal clearance than Ligand B (4.268), meaning Ligand B is more metabolically stable.

**13. In vitro Half-Life:** Ligand B (50.516) has a significantly longer in vitro half-life than Ligand A (9.295). This is a major advantage for Ligand B.

**14. P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.04 and 0.102).

**15. Binding Affinity:** Both ligands have very similar binding affinities (-8.4 and -8.2 kcal/mol). The difference is minor.

**Overall Assessment:**

Ligand A excels in TPSA, DILI risk, BBB penetration, Caco-2 permeability, and aqueous solubility. Ligand B has a significantly longer half-life and better metabolic stability. Considering the GPCR-specific priorities, BBB penetration is crucial for CNS targets like DRD2. Ligand A's better BBB, coupled with its lower DILI risk and better solubility, outweigh Ligand B's longer half-life, especially given the already strong binding affinity of both compounds. The difference in half-life could potentially be addressed with formulation strategies.

Output:
0
2025-04-17 08:05:48,250 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (350.415 and 347.463 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (77.96) is better than Ligand B (79.26), both are below the 90 A^2 threshold for CNS targets, which is good.

**3. logP:** Ligand A (1.429) is better than Ligand B (0.605), both are within the optimal 1-3 range, but ligand B is closer to the lower limit which could impact permeability.

**4. H-Bond Donors:** Ligand A (0) is better than Ligand B (2). Fewer H-bond donors generally improve permeability.

**5. H-Bond Acceptors:** Ligand A (6) is better than Ligand B (5). Both are within the acceptable limit of 10.

**6. QED:** Both ligands have good QED scores (0.722 and 0.79), indicating good drug-like properties.

**7. DILI:** Ligand A (50.679) is significantly better than Ligand B (14.889). Lower DILI risk is crucial.

**8. BBB:** Ligand A (72.586) is much better than Ligand B (41.218). For a CNS target like DRD2, a high BBB penetration is highly desirable.

**9. Caco-2:** Ligand A (-4.28) is better than Ligand B (-5.478), indicating better intestinal absorption.

**10. Solubility:** Ligand A (-1.134) is better than Ligand B (-0.604). Higher solubility is generally preferred.

**11. hERG:** Both ligands have similar, very low hERG inhibition risk (0.137).

**12. Cl_mic:** Ligand B (-23.733) is better than Ligand A (53.818). Lower microsomal clearance indicates better metabolic stability.

**13. t1/2:** Ligand B (14.369) is better than Ligand A (-25.288). A longer half-life is generally desirable.

**14. Pgp:** Ligand A (0.049) is better than Ligand B (0.008). Lower P-gp efflux is crucial for CNS exposure.

**15. Binding Affinity:** Ligand B (-7.7 kcal/mol) is significantly better than Ligand A (-6.6 kcal/mol). A 1.1 kcal/mol difference in binding affinity is substantial and can outweigh some ADME drawbacks.

**Overall Assessment:**

Ligand B has a significantly better binding affinity, a longer half-life, and better metabolic stability. However, Ligand A excels in BBB penetration, DILI risk, and P-gp efflux. Considering DRD2 is a CNS target, BBB penetration is paramount. While Ligand B's affinity is superior, Ligand A's superior CNS penetration and lower toxicity profile make it a more promising candidate. The difference in affinity, while significant, might be overcome with further optimization of Ligand A.

Output:
0
2025-04-17 08:05:48,250 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (342.53 and 352.41 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (41.13) is excellent, well below the 90 A^2 threshold for CNS targets. Ligand B (76.66) is higher, but still potentially acceptable, though less ideal.

**3. logP:** Ligand A (4.697) is slightly high, potentially leading to solubility issues or off-target interactions. Ligand B (1.183) is quite low, which could hinder membrane permeability.

**4. H-Bond Donors:** Both ligands have 2 HBD, which is within the acceptable limit of <=5.

**5. H-Bond Acceptors:** Ligand A has 1 HBA, and Ligand B has 5 HBA, both are within the acceptable limit of <=10.

**6. QED:** Both ligands have similar QED values (0.748 and 0.752), indicating good drug-like properties.

**7. DILI:** Ligand A (24.932) has a lower DILI risk than Ligand B (40.132), which is preferable.

**8. BBB:** This is critical for a CNS target. Ligand A (91.819) has a very good BBB penetration percentile, significantly better than Ligand B (65.607).

**9. Caco-2 Permeability:** Both have negative values, indicating poor permeability.

**10. Aqueous Solubility:** Both have negative values, indicating poor solubility.

**11. hERG Inhibition:** Ligand A (0.83) has a slightly higher hERG risk than Ligand B (0.338), but both are relatively low.

**12. Microsomal Clearance:** Ligand A (79.903) has a higher clearance than Ligand B (20.527), meaning Ligand B is more metabolically stable.

**13. In vitro Half-Life:** Ligand A (45.557) has a longer half-life than Ligand B (-4.983), which is desirable.

**14. P-gp Efflux:** Ligand A (0.642) has a lower P-gp efflux liability than Ligand B (0.025), meaning Ligand A will likely have better CNS exposure.

**15. Binding Affinity:** Ligand B (-8.2 kcal/mol) has significantly stronger binding affinity than Ligand A (0.0 kcal/mol). This is a major advantage.

**Overall Assessment:**

Ligand B's significantly stronger binding affinity (-8.2 kcal/mol vs 0.0 kcal/mol) is a substantial advantage that could outweigh some of its drawbacks. While its logP is low and BBB penetration is lower than Ligand A, the potency difference is considerable. Ligand B also has better metabolic stability (lower Cl_mic). Ligand A has a better BBB score and lower DILI risk, but the affinity is a critical factor for GPCRs. Given the importance of affinity for GPCRs, and the fact that Ligand B's other properties are not drastically unfavorable, it is the more promising candidate.

Output:
1
2025-04-17 08:05:48,250 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (333.435 and 352.385 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (47.34) is significantly better than Ligand B (83.98). For CNS targets, we want TPSA <= 90, and A is comfortably within that range, while B is approaching the upper limit.

**logP:** Both ligands have acceptable logP values (3.446 and 2.362), falling within the 1-3 optimal range.

**H-Bond Donors/Acceptors:** Ligand A (0 HBD, 3 HBA) is preferable to Ligand B (2 HBD, 4 HBA) as fewer H-bonds generally improve BBB penetration. Both are within acceptable limits.

**QED:** Both ligands have similar and good QED scores (0.846 and 0.852), indicating good drug-like properties.

**DILI:** Ligand A (76.58) has a higher DILI risk than Ligand B (43.777). This is a negative for Ligand A.

**BBB:** Ligand B (87.437) has a better BBB percentile than Ligand A (79.488), although both are above the desirable 70% threshold. This is a significant advantage for Ligand B.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.56 and -4.82). This is unusual and suggests poor permeability. However, these values are on a scale where negative values are possible, and the absolute value is more important. They are very similar.

**Aqueous Solubility:** Both ligands have negative solubility values (-4.994 and -3.197). Similar to Caco-2, these are on a scale where negative values are possible.

**hERG Inhibition:** Ligand A (0.923) has a slightly higher hERG risk than Ligand B (0.089). This favors Ligand B.

**Microsomal Clearance:** Ligand B (24.379) has a significantly lower microsomal clearance than Ligand A (51.942), indicating better metabolic stability.

**In vitro Half-Life:** Ligand A (-8.564) has a longer in vitro half-life than Ligand B (-0.988). This is a positive for Ligand A.

**P-gp Efflux:** Ligand A (0.645) has lower P-gp efflux liability than Ligand B (0.013). Lower P-gp efflux is desirable, particularly for CNS targets, favoring Ligand A.

**Binding Affinity:** Both ligands have very similar and strong binding affinities (-9.0 and -8.2 kcal/mol). The difference of 0.8 kcal/mol is not substantial enough to outweigh other factors.

**Overall Assessment:**

Considering the GPCR-specific priorities, Ligand B appears to be the better candidate. While Ligand A has a slightly longer half-life and lower P-gp efflux, Ligand B excels in crucial areas for CNS penetration: significantly lower DILI risk, better BBB penetration, lower hERG risk, and improved metabolic stability. The TPSA value of Ligand A is also much more favorable. The similar binding affinities make these ADME properties the deciding factors.

Output:
1
2025-04-17 08:05:48,250 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 drug candidates, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (350.459 and 356.417 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (67.87) is significantly better than Ligand B (78.09). For CNS targets, we want TPSA <= 90, and A is closer to the optimal <=60 range. B is approaching the upper limit.

**3. logP:** Both ligands have acceptable logP values (1.335 and 1.844), falling within the 1-3 range.

**4. H-Bond Donors:** Ligand A (1) is preferable to Ligand B (2). Lower HBD generally improves permeability.

**5. H-Bond Acceptors:** Ligand A (4) is preferable to Ligand B (3). Lower HBA generally improves permeability.

**6. QED:** Both ligands have reasonable QED values (0.812 and 0.746), indicating good drug-like properties.

**7. DILI:** Ligand A (20.9) has a much lower DILI risk than Ligand B (44.281). This is a significant advantage for A.

**8. BBB:** Ligand B (68.941) is slightly better than Ligand A (63.164), but both are below the desirable >70 for CNS targets. However, the other properties of A make it more promising.

**9. Caco-2 Permeability:** Ligand A (-4.846) is better than Ligand B (-5.118). Higher values indicate better absorption.

**10. Aqueous Solubility:** Ligand A (-1.469) is better than Ligand B (-2.503). Higher values indicate better solubility.

**11. hERG Inhibition:** Ligand A (0.189) has a lower hERG inhibition risk than Ligand B (0.433), which is a crucial safety consideration.

**12. Microsomal Clearance:** Ligand A (9.74) has lower clearance than Ligand B (18.272), suggesting better metabolic stability.

**13. In vitro Half-Life:** Ligand A (8.589) has a better half-life than Ligand B (-27.876).

**14. P-gp Efflux:** Ligand A (0.041) has a lower P-gp efflux liability than Ligand B (0.11), which is important for CNS penetration.

**15. Binding Affinity:** Both ligands have very similar and excellent binding affinities (-8.4 and -8.3 kcal/mol). The difference is negligible.

**Overall Assessment:**

Ligand A is significantly better across most ADME-Tox properties. It has a lower DILI risk, better solubility, lower hERG inhibition, better metabolic stability, lower P-gp efflux, and a slightly better Caco-2 permeability. While Ligand B has a marginally better BBB score, the substantial advantages of Ligand A in other critical areas, particularly safety (DILI, hERG) and pharmacokinetic properties, make it the more promising drug candidate. The TPSA is also more favorable for CNS penetration.

Output:
1
2025-04-17 08:05:48,250 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B based on the provided guidelines, prioritizing GPCR-specific properties (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (345.359) is slightly lower, which could be beneficial for permeability, but both are acceptable.

**TPSA:** Ligand A (99.44) is better than Ligand B (29.54) for CNS penetration, being closer to the ideal <90 A^2. Ligand B is excellent.

**logP:** Ligand A (0.124) is quite low, potentially hindering membrane permeability. Ligand B (4.591) is higher, approaching the upper limit, but still within an acceptable range. This favors Ligand B.

**H-Bond Donors/Acceptors:** Both have reasonable HBD counts (0 for both). Ligand A has 8 HBA, while Ligand B has 2. Both are within acceptable limits, but Ligand B is better.

**QED:** Both ligands have good QED scores (0.71 and 0.767), indicating drug-likeness.

**DILI:** Ligand A (73.284) has a higher DILI risk than Ligand B (24.157). This is a significant advantage for Ligand B.

**BBB:** Ligand B (91.392) has a significantly better BBB penetration score than Ligand A (63.629). This is crucial for a CNS target like DRD2, making Ligand B much more promising.

**Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and difficult to interpret without further context.

**Aqueous Solubility:** Both have negative solubility values, which is also unusual.

**hERG:** Ligand A (0.03) has a slightly lower hERG risk than Ligand B (0.783), but both are relatively low.

**Microsomal Clearance:** Ligand B (102.754) has a higher microsomal clearance than Ligand A (35.46), indicating lower metabolic stability. This favors Ligand A.

**In vitro Half-Life:** Ligand A (-8.093) has a negative half-life, which is not possible. Ligand B (31.753) has a reasonable half-life.

**P-gp Efflux:** Ligand A (0.037) has lower P-gp efflux liability than Ligand B (0.735), which is favorable for CNS penetration.

**Binding Affinity:** Ligand B (-8.7) has a stronger binding affinity than Ligand A (-7.4), by 1.3 kcal/mol. This is a substantial difference and can outweigh some ADME drawbacks.

**Overall Assessment:**

Ligand B is the stronger candidate. While it has a higher logP and clearance, its significantly better BBB penetration, lower DILI risk, and substantially improved binding affinity outweigh these drawbacks. The negative values for Caco-2 and solubility are concerning and would need investigation, but the other factors strongly favor Ligand B. Ligand A's negative half-life is a critical issue.

Output:
1
2025-04-17 08:05:48,250 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (355.479 and 351.403 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (118.36) is slightly above the preferred <90 for CNS targets, while Ligand B (102.69) is closer to the ideal range. This gives a slight edge to Ligand B.

**logP:** Both ligands have good logP values (1.15 and 1.015), falling within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A has 3 HBD and 4 HBA, which are acceptable. Ligand B has 2 HBD and 6 HBA, also acceptable.

**QED:** Both ligands have good QED scores (0.509 and 0.688), indicating good drug-like properties. Ligand B is slightly better.

**DILI:** Ligand A (27.104) has a significantly lower DILI risk than Ligand B (50.601). This is a substantial advantage for Ligand A.

**BBB:** Ligand B (72.237) has a much better BBB penetration percentile than Ligand A (50.795). This is a critical advantage for a CNS target like DRD2.

**Caco-2 Permeability:** Ligand A (-5.278) has worse Caco-2 permeability than Ligand B (-4.716), but both are quite poor.

**Aqueous Solubility:** Ligand A (-2.856) has slightly better solubility than Ligand B (-1.794), but both are poor.

**hERG:** Both ligands have very low hERG inhibition liability (0.116 and 0.098), which is excellent.

**Microsomal Clearance:** Ligand B (25.574) has significantly lower microsomal clearance than Ligand A (42.959), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand B (-4.911) has a slightly better in vitro half-life than Ligand A (-30.48), but both are negative, which is unusual and requires further investigation.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.006 and 0.052), which is favorable for CNS penetration.

**Binding Affinity:** Ligand A (-7.8 kcal/mol) has a slightly better binding affinity than Ligand B (-7.4 kcal/mol). This 0.4 kcal/mol difference is significant, and can outweigh some ADME drawbacks.

**Overall Assessment:**

Ligand B excels in BBB penetration and metabolic stability, which are crucial for CNS GPCR targets. However, Ligand A has a significantly lower DILI risk and a slightly better binding affinity. The difference in binding affinity is meaningful. Given the importance of CNS penetration for DRD2, and the better BBB score of Ligand B, it is the more promising candidate despite the higher DILI risk. The slightly better affinity of Ligand A is not enough to overcome the superior BBB score of Ligand B.

Output:
1
2025-04-17 08:05:48,250 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (387.364 and 368.459 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (81.18) is excellent, well below the 90 A^2 threshold for CNS targets. Ligand B (113.44) is higher, but still potentially acceptable, though less ideal.

**logP:** Ligand A (3.811) is at the upper end of the optimal range (1-3), but still acceptable. Ligand B (0.542) is quite low, potentially hindering membrane permeability and CNS penetration.

**H-Bond Donors/Acceptors:** Ligand A (1 HBD, 7 HBA) and Ligand B (3 HBD, 7 HBA) both have reasonable numbers of H-bond donors and acceptors, within the guidelines.

**QED:** Both ligands have similar QED values (0.691 and 0.675), indicating good drug-like properties.

**DILI:** Ligand A (96.433) has a high DILI risk, which is a significant concern. Ligand B (47.926) has a much lower, and acceptable, DILI risk.

**BBB:** Ligand A (81.776) has a good BBB percentile, desirable for a CNS target. Ligand B (43.893) has a poor BBB percentile, which is a major drawback.

**Caco-2 Permeability:** Both have negative Caco-2 values which is unusual and suggests a problem with the data or modeling.

**Aqueous Solubility:** Both have negative solubility values which is unusual and suggests a problem with the data or modeling.

**hERG:** Ligand A (0.525) has a low hERG risk, while Ligand B (0.075) also shows low hERG risk.

**Microsomal Clearance:** Ligand A (88.898) has a relatively high microsomal clearance, suggesting faster metabolism. Ligand B (-13.812) has a negative clearance, which is not physically possible and indicates a problem with the data.

**In vitro Half-Life:** Ligand A (59.788) has a moderate in vitro half-life. Ligand B (21.786) has a short in vitro half-life.

**P-gp Efflux:** Ligand A (0.66) shows moderate P-gp efflux, while Ligand B (0.018) shows very low P-gp efflux, which is favorable for CNS penetration.

**Binding Affinity:** Both ligands have the same binding affinity (-8.3 kcal/mol), which is excellent.

**Overall Assessment:**

Despite the equal binding affinity, Ligand A has a very high DILI risk and relatively high metabolic clearance. While its BBB is good, the DILI risk is a major red flag. Ligand B has a much better safety profile (lower DILI) and lower P-gp efflux, but suffers from a poor BBB and a very low logP, which could limit its ability to cross the blood-brain barrier. The negative values for Caco-2 and solubility are also concerning.

Given the importance of BBB penetration for a CNS target like DRD2, and the severe DILI risk associated with Ligand A, Ligand B is the more promising candidate *despite* its lower logP and questionable solubility/permeability data. Further optimization of Ligand B to improve its logP and address the data issues would be a worthwhile pursuit.

Output:
1
2025-04-17 08:05:48,250 - INFO - Reasoning:

Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (364.789 Da and 352.291 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (109.46) is higher than the preferred <90 for CNS targets, but still potentially acceptable. Ligand B (77.81) is well within the desired range. This favors Ligand B.

**logP:** Ligand A (2.378) is within the optimal 1-3 range. Ligand B (3.994) is slightly higher, approaching the upper limit, but still acceptable.

**H-Bond Donors/Acceptors:** Ligand A has 1 HBD and 6 HBA, which are reasonable. Ligand B has 2 HBD and 3 HBA, also reasonable.

**QED:** Both ligands have good QED scores (0.596 and 0.82), indicating drug-like properties.

**DILI:** Both ligands have relatively high DILI risk (79.837 and 73.323), but are not excessively high.

**BBB:** Both ligands show good BBB penetration (65.335 and 69.678), but ideally, we'd want >70 for a CNS target. Ligand B is slightly better.

**Caco-2 Permeability:** Both have negative Caco-2 values (-4.884 and -4.631), which is unusual and suggests poor permeability. This is a significant concern for both.

**Aqueous Solubility:** Both have negative solubility values (-3.097 and -4.935), also concerning. Poor solubility can hinder bioavailability.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.231 and 0.628), which is positive.

**Microsomal Clearance:** Ligand A (47.628) has a higher clearance than Ligand B (21.995), suggesting lower metabolic stability. This favors Ligand B.

**In vitro Half-Life:** Ligand B (53.108) has a significantly longer half-life than Ligand A (-6.805), which is a major advantage.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.175 and 0.173), which is excellent for CNS penetration.

**Binding Affinity:** Ligand B (-9.8 kcal/mol) has a significantly stronger binding affinity than Ligand A (-8.3 kcal/mol). This 1.5 kcal/mol difference is substantial and can outweigh some of the ADME drawbacks.

**Overall Assessment:**

Ligand B is the superior candidate. While both have concerning Caco-2 and solubility values, Ligand B demonstrates better TPSA, metabolic stability (lower Cl_mic, longer t1/2), and, crucially, a significantly stronger binding affinity. The improved BBB penetration and affinity are particularly important for a CNS GPCR target like DRD2. The slightly higher logP is manageable. The DILI risk is similar for both, and the hERG risk is low.



Output:
1
2025-04-17 08:05:48,251 - INFO - Reasoning:

Let's analyze Ligand A and Ligand B based on the provided guidelines, prioritizing GPCR-specific properties (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (346.431 and 359.423 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (86.63) is excellent, well below the 90 A^2 threshold for CNS targets. Ligand B (117.2) is higher, but still potentially acceptable, though less ideal.

**logP:** Ligand A (0.722) is a bit low, potentially hindering permeation. Ligand B (-1.358) is even lower, raising concerns about permeability.

**H-Bond Donors/Acceptors:** Ligand A (HBD=1, HBA=5) is favorable. Ligand B (HBD=3, HBA=7) is also acceptable, but slightly less optimal.

**QED:** Ligand A (0.872) is very good, indicating high drug-likeness. Ligand B (0.38) is poor, suggesting potential issues.

**DILI:** Ligand A (47.034) has a moderate DILI risk, but is acceptable. Ligand B (24.467) has a lower DILI risk, which is favorable.

**BBB:** Ligand A (50.95) is marginal for CNS penetration. Ligand B (17.449) is quite poor, indicating limited brain exposure. This is a significant drawback for a DRD2 ligand.

**Caco-2 Permeability:** Ligand A (-4.726) is very poor. Ligand B (-5.277) is also very poor.

**Aqueous Solubility:** Ligand A (-1.376) is poor. Ligand B (-0.221) is also poor.

**hERG Inhibition:** Both ligands (0.256 and 0.092) show low hERG inhibition risk, which is excellent.

**Microsomal Clearance:** Ligand A (22.363) has moderate clearance. Ligand B (19.409) has lower clearance, suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (-9.477) has a very short half-life. Ligand B (-33.519) has an extremely short half-life, which is a major concern.

**P-gp Efflux:** Both ligands (0.09 and 0.004) show very low P-gp efflux, which is excellent for CNS penetration.

**Binding Affinity:** Ligand A (-8.6 kcal/mol) has significantly stronger binding affinity than Ligand B (-7.3 kcal/mol). This 1.3 kcal/mol difference is substantial and can outweigh some ADME deficiencies.

**Overall Assessment:**

Despite Ligand A's slightly low logP and poor Caco-2 permeability and solubility, its significantly stronger binding affinity (-8.6 vs -7.3 kcal/mol), better BBB penetration (50.95 vs 17.449), and superior QED (0.872 vs 0.38) make it the more promising candidate. Ligand B suffers from very poor BBB penetration, a very short half-life, and a low QED score, making it less likely to succeed as a CNS-active drug. The affinity difference is large enough to compensate for A's other shortcomings.

Output:
1
2025-04-17 08:05:48,251 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 drug candidates, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (370.49 Da and 360.57 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (66.48) is better than Ligand B (44.1). For a CNS target like DRD2, TPSA < 90 is desirable, and both meet this criterion, but A is slightly higher and could potentially hinder BBB penetration more.

**3. logP:** Ligand A (1.39) is optimal (1-3), while Ligand B (4.811) is high. High logP can lead to solubility issues and off-target interactions. This is a significant negative for Ligand B.

**4. H-Bond Donors:** Ligand A (1) is good, while Ligand B (0) is acceptable.

**5. H-Bond Acceptors:** Both ligands have 3 HBA, which is within the acceptable range.

**6. QED:** Ligand A (0.768) is significantly better than Ligand B (0.438), indicating a more drug-like profile.

**7. DILI:** Ligand A (18.883) has a slightly higher DILI risk than Ligand B (10.857), but both are below the concerning threshold of 60.

**8. BBB:** Both ligands have excellent BBB penetration (Ligand A: 85.925%, Ligand B: 83.249%). This is crucial for a CNS target.

**9. Caco-2 Permeability:** Both have negative values, indicating poor permeability. This is a concern for both.

**10. Aqueous Solubility:** Both have negative values, indicating poor solubility. This is a concern for both.

**11. hERG:** Ligand A (0.465) has a lower hERG risk than Ligand B (0.842), which is preferable.

**12. Microsomal Clearance:** Ligand A (18.336) has a lower (better) microsomal clearance than Ligand B (119.85). Lower clearance indicates greater metabolic stability.

**13. In vitro Half-Life:** Ligand A (14.817) has a better half-life than Ligand B (-12.708).

**14. P-gp Efflux:** Ligand A (0.028) has much lower P-gp efflux liability than Ligand B (0.599). Lower P-gp efflux is highly desirable for CNS penetration.

**15. Binding Affinity:** Ligand A (-9.2 kcal/mol) has a significantly stronger binding affinity than Ligand B (-6.7 kcal/mol). This is a substantial advantage, potentially outweighing some ADME drawbacks.

**Overall Assessment:**

Ligand A is clearly the superior candidate. While both have issues with Caco-2 permeability and aqueous solubility, Ligand A excels in critical areas: significantly better binding affinity, a more favorable logP, a better QED score, lower P-gp efflux, lower hERG risk, and improved metabolic stability. The strong binding affinity of Ligand A is a major advantage for a GPCR target, and its other properties are generally more favorable.

Output:
1
2025-04-17 08:05:48,251 - INFO - Batch 420 complete. Total preferences: 6720
2025-04-17 08:05:48,251 - INFO - Processing batch 421/512...
2025-04-17 08:06:32,592 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (353.419 and 350.409 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (105.76) is higher than the preferred <90 for CNS targets, while Ligand B (45.49) is well within the range. This is a significant advantage for Ligand B.

**3. logP:** Ligand A (-0.528) is below the optimal 1-3 range, potentially hindering permeability. Ligand B (3.376) is within the optimal range.

**4. H-Bond Donors:** Ligand A (3) is acceptable, while Ligand B (0) is also good.

**5. H-Bond Acceptors:** Both ligands (A: 5, B: 4) are below the acceptable limit of 10.

**6. QED:** Both ligands have good QED scores (A: 0.595, B: 0.685), indicating drug-like properties.

**7. DILI:** Ligand A (47.266) has a moderate DILI risk, while Ligand B (18.418) has a low DILI risk.

**8. BBB:** This is crucial for a CNS target. Ligand A (46.762) has a poor BBB penetration percentile, while Ligand B (95.269) has excellent BBB penetration. This is a major advantage for Ligand B.

**9. Caco-2 Permeability:** Ligand A (-5.539) has poor Caco-2 permeability, while Ligand B (-4.443) is also poor, but slightly better.

**10. Aqueous Solubility:** Ligand A (-1.652) and Ligand B (-3.111) both have poor aqueous solubility.

**11. hERG Inhibition:** Ligand A (0.075) has very low hERG inhibition risk, while Ligand B (0.962) has slightly increased risk.

**12. Microsomal Clearance:** Ligand A (-9.495) has very low microsomal clearance (highly metabolically stable), while Ligand B (33.196) has higher clearance.

**13. In vitro Half-Life:** Ligand A (19.498) has a moderate half-life, while Ligand B (26.838) has a slightly longer half-life.

**14. P-gp Efflux:** Ligand A (0.009) has very low P-gp efflux, while Ligand B (0.444) has moderate P-gp efflux.

**15. Binding Affinity:** Ligand B (-7.4) has a significantly better binding affinity than Ligand A (-8.0). While -8.0 is better, the difference is not substantial enough to overcome the other deficiencies of Ligand A.

**Overall Assessment:**

Ligand B is significantly more promising. Its superior BBB penetration, optimal logP, lower DILI risk, and better binding affinity outweigh its slightly higher hERG risk and moderate P-gp efflux. Ligand A suffers from poor BBB penetration and a suboptimal logP, making it less likely to reach the target in the CNS. Although Ligand A has better metabolic stability, the other factors are more critical for a CNS GPCR target.

Output:
1
2025-04-17 08:06:32,592 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (350.379 Da) is slightly lower, which is generally favorable for permeability. Ligand B (382.873 Da) is also acceptable.

**TPSA:** Ligand A (118.45) is closer to the ideal range for CNS targets (<=90) than Ligand B (95.42). Both are reasonably good, but A has a slight edge.

**logP:** Ligand A (-0.31) is a bit low, potentially hindering permeation. Ligand B (2.404) is within the optimal range (1-3). This is a significant advantage for Ligand B.

**H-Bond Donors/Acceptors:** Both ligands have 2 HBD and around 6-7 HBA, which are acceptable values.

**QED:** Both ligands have good QED scores (A: 0.703, B: 0.827), indicating good drug-like properties.

**DILI:** Ligand B (78.286) has a higher DILI risk than Ligand A (54.711), which is less desirable.

**BBB:** Ligand A (70.182) has a significantly better BBB penetration percentile than Ligand B (30.438). This is *critical* for a CNS target like DRD2.

**Caco-2 Permeability:** Both have negative Caco-2 values, indicating poor permeability. This is a concern for both, but less critical given the focus on BBB penetration for a CNS target.

**Aqueous Solubility:** Both have negative solubility values, indicating poor solubility. This is a concern for both, but can be addressed with formulation strategies.

**hERG:** Both ligands have very low hERG inhibition risk (A: 0.032, B: 0.138).

**Microsomal Clearance:** Ligand A (28.788) has lower microsomal clearance than Ligand B (34.169), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand B (15.453) has a much longer in vitro half-life than Ligand A (-1.835). This is a significant advantage for Ligand B.

**P-gp Efflux:** Both have very low P-gp efflux liability (A: 0.011, B: 0.084).

**Binding Affinity:** Ligand B (-8.7 kcal/mol) has a slightly better binding affinity than Ligand A (-8.2 kcal/mol). While the difference is not huge, it's still a positive for Ligand B.

**Overall Assessment:**

Ligand B has a better logP and binding affinity and a significantly longer half-life. However, Ligand A has a much better BBB score, lower DILI risk, and better metabolic stability. Given that this is a CNS target (DRD2), BBB penetration is paramount. While Ligand B's affinity is slightly better, the substantial difference in BBB penetration makes Ligand A the more promising candidate. The slightly lower logP of Ligand A is a concern, but can potentially be addressed through structural modifications without sacrificing BBB penetration.

Output:
0
2025-04-17 08:06:32,592 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B based on the provided guidelines, prioritizing GPCR-specific properties (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (352.475 and 346.446 Da) fall within the ideal range of 200-500 Da.

**TPSA:** Ligand A (67.87) is higher than Ligand B (49.41). For CNS targets, TPSA should be <= 90, both are within this range, but B is preferable.

**logP:** Ligand A (1.749) is within the optimal range (1-3), while Ligand B (3.153) is at the upper end. Both are acceptable, but A is slightly better.

**H-Bond Donors/Acceptors:** Both ligands have a reasonable number of HBD (1) and HBA (A: 4, B: 2) within the recommended limits.

**QED:** Ligand B (0.89) has a significantly higher QED score than Ligand A (0.507), indicating better overall drug-likeness.

**DILI:** Ligand A (19.504) has a much lower DILI risk than Ligand B (29.236), suggesting better liver safety.

**BBB:** Ligand B (96.355) has a substantially higher BBB penetration percentile than Ligand A (78.868). This is a critical advantage for a CNS target like DRD2.

**Caco-2 Permeability:** Ligand A (-4.374) has a more negative Caco-2 value than Ligand B (-4.616), suggesting lower intestinal absorption.

**Aqueous Solubility:** Ligand A (-1.075) has better aqueous solubility than Ligand B (-3.46).

**hERG Inhibition:** Ligand A (0.244) has a lower hERG inhibition liability than Ligand B (0.777), indicating a lower risk of cardiotoxicity.

**Microsomal Clearance:** Ligand B (36.009) has lower microsomal clearance than Ligand A (65.353), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand B (-4.913) has a significantly longer in vitro half-life than Ligand A (0.226).

**P-gp Efflux:** Ligand A (0.082) has lower P-gp efflux liability than Ligand B (0.34), which is favorable for CNS penetration.

**Binding Affinity:** Ligand B (-9.1 kcal/mol) has a significantly stronger binding affinity than Ligand A (-7.0 kcal/mol). This is a substantial advantage, potentially outweighing some ADME drawbacks.

**Overall Assessment:**

Ligand B excels in BBB penetration, binding affinity, metabolic stability, and in vitro half-life. These are crucial for a CNS-targeting GPCR. While Ligand A has better DILI and hERG profiles, the superior affinity and BBB penetration of Ligand B are more important for DRD2. The higher QED of Ligand B is also a positive factor. The slightly higher logP of B is acceptable.

Output:
1
2025-04-17 08:06:32,592 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (350.503 and 352.41 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (49.85) is significantly better than Ligand B (96.25). For CNS targets, we want TPSA <= 90, so Ligand A is much more favorable.

**logP:** Ligand A (2.543) is optimal (1-3). Ligand B (0.637) is a bit low, potentially hindering permeation.

**H-Bond Donors/Acceptors:** Ligand A (0 HBD, 3 HBA) is better than Ligand B (3 HBD, 5 HBA) in terms of balancing solubility and permeability. Both are within acceptable limits.

**QED:** Both ligands have similar QED values (0.786 and 0.671), indicating good drug-like properties.

**DILI:** Ligand A (30.05) has a much lower DILI risk than Ligand B (52.695). Both are below the 60 threshold, but A is preferable.

**BBB:** Ligand A (80.574) has a significantly better BBB penetration score than Ligand B (63.94).  >70 is desirable for CNS targets, and A is closer to this threshold.

**Caco-2 Permeability:** Ligand A (-4.223) and Ligand B (-4.995) both have negative values, which is unusual and suggests poor permeability. However, the scale isn't specified, so it's hard to interpret.

**Aqueous Solubility:** Both ligands have similar, very poor aqueous solubility (-2.652 and -2.795). This could pose formulation challenges.

**hERG:** Both ligands have very low hERG inhibition risk (0.383 and 0.125).

**Microsomal Clearance:** Ligand A (48.774) has higher microsomal clearance than Ligand B (10.9), meaning it's less metabolically stable.

**In vitro Half-Life:** Ligand A (-9.947) has a negative half-life, which is not possible, and suggests an error in the data. Ligand B (4.074) has a short half-life.

**P-gp Efflux:** Ligand A (0.247) has lower P-gp efflux than Ligand B (0.044), which is favorable for CNS exposure.

**Binding Affinity:** Ligand B (-7.5) has a slightly better binding affinity than Ligand A (-8.0). However, the difference is less than 1.5 kcal/mol, so it's not a decisive factor.

**Overall:**

Ligand A is superior due to its significantly better TPSA, logP, BBB penetration, and lower DILI risk. While Ligand A has a higher clearance and a problematic half-life value, the CNS-relevant properties are more important for a DRD2 ligand. Ligand B's low logP and BBB are significant drawbacks. The affinity difference is not large enough to overcome these issues.

Output:
1
2025-04-17 08:06:32,592 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (345.443 and 348.403 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (68.4) is significantly better than Ligand B (108.46). For CNS targets, TPSA should be <= 90, and A is comfortably within this range, while B exceeds it.

**3. logP:** Ligand A (3.268) is optimal (1-3), while Ligand B (1.59) is on the lower side, potentially hindering permeability.

**4. H-Bond Donors:** Ligand A (2) and Ligand B (1) are both acceptable (<=5).

**5. H-Bond Acceptors:** Ligand A (5) and Ligand B (6) are both acceptable (<=10).

**6. QED:** Both ligands have good QED scores (0.806 and 0.885), indicating drug-like properties.

**7. DILI:** Ligand A (61.109) has a higher DILI risk than Ligand B (47.654), but both are still acceptable (<60 is good).

**8. BBB:** Ligand A (73.943) has a much better BBB penetration score than Ligand B (48.74). A score >70 is desirable for CNS targets, and A is closer to this threshold.

**9. Caco-2 Permeability:** Ligand A (-5.217) has worse Caco-2 permeability than Ligand B (-4.454). However, both are negative, indicating poor permeability.

**10. Aqueous Solubility:** Ligand A (-2.854) has worse solubility than Ligand B (-3.301). Both are poor, but B is slightly better.

**11. hERG Inhibition:** Ligand A (0.894) has a higher hERG inhibition risk than Ligand B (0.272). Lower is better, making B more favorable.

**12. Microsomal Clearance:** Ligand A (10.867) has lower microsomal clearance (better metabolic stability) than Ligand B (28.218).

**13. In vitro Half-Life:** Ligand A (58.392) has a longer in vitro half-life than Ligand B (-10.139). A longer half-life is generally preferred.

**14. P-gp Efflux:** Ligand A (0.225) has lower P-gp efflux than Ligand B (0.023), which is better for CNS exposure.

**15. Binding Affinity:** Ligand A (-7.6) has a slightly better binding affinity than Ligand B (-7.1). While both are good, the 0.5 kcal/mol difference is notable.

**Overall Assessment:**

Considering the GPCR-specific priorities, Ligand A is the more promising candidate. Its superior TPSA, logP, and BBB penetration are crucial for CNS drug development. While Ligand B has a slightly better hERG profile and solubility, the differences aren't substantial enough to outweigh the advantages of Ligand A in terms of brain penetration and physicochemical properties. The slightly better affinity of Ligand A also contributes to its favorability.

Output:
1
2025-04-17 08:06:32,593 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (346.431 and 347.463 Da) fall comfortably within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (79.63) is significantly better than Ligand B (99.77).  For CNS targets, we want TPSA <= 90, so Ligand A is preferable.

**3. logP:** Both ligands have good logP values (2.402 and 1.742), falling within the optimal 1-3 range. Ligand A is slightly higher, which could be beneficial for membrane permeability.

**4. H-Bond Donors:** Ligand A (2) is better than Ligand B (3). Lower HBD generally improves permeability.

**5. H-Bond Acceptors:** Ligand A (5) is better than Ligand B (4). Lower HBA generally improves permeability.

**6. QED:** Both ligands have acceptable QED values (0.805 and 0.561), with Ligand A being better.

**7. DILI:** Ligand A (36.758) has a slightly higher DILI risk than Ligand B (22.8), but both are below the concerning threshold of 60.

**8. BBB:** Ligand B (64.017) has a slightly better BBB penetration percentile than Ligand A (59.636). However, both are below the desirable >70 for CNS targets.

**9. Caco-2 Permeability:** Ligand A (-4.819) has a worse Caco-2 permeability than Ligand B (-5.417). Lower values indicate poorer permeability.

**10. Aqueous Solubility:** Both ligands have very poor aqueous solubility (-2.023 and -2.38). This is a significant drawback for both.

**11. hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.417 and 0.046).

**12. Microsomal Clearance:** Ligand B (27.571) has lower microsomal clearance than Ligand A (32.722), indicating better metabolic stability.

**13. In vitro Half-Life:** Ligand A (10.749) has a longer in vitro half-life than Ligand B (-19.949). This is a significant advantage for Ligand A.

**14. P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.028 and 0.008).

**15. Binding Affinity:** Both ligands have excellent binding affinities (-8.6 and -8.2 kcal/mol). The difference of 0.4 kcal/mol is not substantial enough to outweigh other factors.

**Overall Assessment:**

Considering the GPCR-specific priorities, Ligand A is slightly more promising. It has a significantly lower TPSA, better HBD/HBA counts, a better QED score, and a longer half-life. While Ligand B has a slightly better BBB and lower clearance, the TPSA advantage of Ligand A is crucial for CNS penetration. The solubility is poor for both, but can be addressed with formulation strategies.

Output:
1
2025-04-17 08:06:32,593 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (359.495 and 360.479 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (54.34) is better than Ligand B (55.57). Both are reasonably good for CNS penetration, being below the 90 A^2 threshold, but closer to the optimal <60 A^2 would be preferable.

**3. logP:** Ligand A (2.487) is optimal (1-3), while Ligand B (4.114) is pushing the upper limit. Higher logP can lead to off-target effects and solubility issues.

**4. H-Bond Donors:** Ligand A (1) is good, while Ligand B (0) is also acceptable.

**5. H-Bond Acceptors:** Ligand A (5) is good, while Ligand B (6) is also acceptable.

**6. QED:** Both ligands have similar QED values (0.737 and 0.726), indicating good drug-likeness.

**7. DILI:** Ligand A (35.789) has a lower DILI risk than Ligand B (46.452), which is preferable. Both are below the concerning threshold of 60.

**8. BBB:** Ligand B (89.608) has a significantly better BBB penetration percentile than Ligand A (61.768). This is a *critical* factor for a CNS target like DRD2.

**9. Caco-2 Permeability:** Ligand A (-5.056) is better than Ligand B (-4.837), indicating better intestinal absorption.

**10. Aqueous Solubility:** Ligand A (-2.349) is better than Ligand B (-5.166), indicating better solubility.

**11. hERG Inhibition:** Both ligands have low hERG inhibition risk (0.776 and 0.569).

**12. Microsomal Clearance:** Ligand A (17.947) has a lower microsomal clearance than Ligand B (101.079), suggesting better metabolic stability.

**13. In vitro Half-Life:** Ligand A (5.269) has a longer in vitro half-life than Ligand B (-2.832).

**14. P-gp Efflux:** Ligand A (0.432) has lower P-gp efflux than Ligand B (0.533), which is favorable for CNS exposure.

**15. Binding Affinity:** Ligand B (-8.7 kcal/mol) has a slightly better binding affinity than Ligand A (-8.2 kcal/mol). While the difference is not huge, it's a positive for Ligand B.

**Overall Assessment:**

Ligand B excels in BBB penetration and binding affinity, which are crucial for a CNS GPCR target. However, it suffers from a higher logP, increased DILI risk, higher microsomal clearance, shorter half-life, and greater P-gp efflux. Ligand A has a more balanced profile with better ADME properties (lower logP, DILI, Cl_mic, better solubility, P-gp efflux, and half-life) but slightly weaker binding affinity.

Given the importance of CNS penetration for DRD2, the superior BBB value of Ligand B is a significant advantage. The slightly better affinity also contributes. While the ADME properties of Ligand B are less ideal, these can potentially be optimized through further medicinal chemistry efforts. The ADME profile of Ligand A is already quite good, but the affinity is less compelling.

Output:
1
2025-04-17 08:06:32,593 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (346.471 Da) is slightly lower, which could be beneficial for permeability.

**2. TPSA:** Both ligands have TPSA values (61.8 and 63.68) that are acceptable for oral absorption but borderline for CNS penetration (ideally <90). Ligand A is slightly better.

**3. logP:** Both ligands have good logP values (2.583 and 3.419), falling within the optimal 1-3 range. Ligand B is slightly higher, potentially increasing off-target interactions.

**4. H-Bond Donors:** Ligand A (2 HBD) is preferable to Ligand B (0 HBD) as it strikes a better balance between solubility and permeability.

**5. H-Bond Acceptors:** Both ligands have the same number of HBA (4), which is within the acceptable range.

**6. QED:** Both ligands have similar QED values (0.831 and 0.736), indicating good drug-likeness.

**7. DILI:** Ligand B (71.113) has a significantly higher DILI risk than Ligand A (19.155). This is a major concern.

**8. BBB:** Ligand A (63.901) has a slightly better BBB penetration percentile than Ligand B (61.342), though both are not ideal.

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 values, which is unusual and suggests poor permeability. Ligand A (-4.557) is slightly better than Ligand B (-4.309).

**10. Aqueous Solubility:** Both ligands have negative solubility values, indicating poor aqueous solubility. Ligand B (-5.163) is worse than Ligand A (-2.68).

**11. hERG Inhibition:** Both ligands have low hERG inhibition liability (0.723 and 0.425), which is good.

**12. Microsomal Clearance:** Ligand B (104.018) has a much higher microsomal clearance than Ligand A (28.778), suggesting lower metabolic stability.

**13. In vitro Half-Life:** Ligand A (-4.354) has a better in vitro half-life than Ligand B (-14.998).

**14. P-gp Efflux:** Both ligands have low P-gp efflux liability (0.437 and 0.37), which is favorable for CNS penetration.

**15. Binding Affinity:** Both ligands have similar and strong binding affinities (-8.9 and -8.0 kcal/mol).

**Overall Assessment:**

Ligand A is significantly better than Ligand B. While both have some ADME liabilities (poor Caco-2 and solubility), Ligand A demonstrates a much lower DILI risk, better metabolic stability (lower Cl_mic, better t1/2), and slightly better BBB penetration. The binding affinities are comparable, so the ADME advantages of Ligand A outweigh any minor differences in potency.

Output:
1
2025-04-17 08:06:32,593 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (348.4 and 342.4 Da) fall comfortably within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (92.01) is slightly higher than Ligand B (84.42). Both are below the 90 A^2 threshold desirable for CNS targets, but Ligand B is closer to the ideal.

**3. logP:** Both ligands have a logP of approximately 1.06, which is within the optimal range of 1-3.

**4. H-Bond Donors:** Ligand A has 2 HBD, and Ligand B has 1. Both are within the acceptable limit of <=5.

**5. H-Bond Acceptors:** Both ligands have 5 HBA, which is within the acceptable limit of <=10.

**6. QED:** Both ligands have high QED scores (0.849 and 0.885), indicating good drug-like properties.

**7. DILI:** Ligand A (45.68%) has a lower DILI risk than Ligand B (52.04%), both are acceptable (<60).

**8. BBB:** This is a crucial parameter for a CNS target like DRD2. Ligand B (79.49%) has a significantly higher BBB penetration percentile than Ligand A (49.83%). This is a major advantage for Ligand B.

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 values which is unusual, and suggests poor permeability. Ligand A (-4.734) is slightly better than Ligand B (-4.803).

**10. Aqueous Solubility:** Both ligands have negative solubility values, indicating poor solubility. Ligand A (-1.589) is slightly better than Ligand B (-1.606).

**11. hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.144 and 0.12), which is excellent.

**12. Microsomal Clearance:** Ligand A (-17.156) has a lower (better) microsomal clearance than Ligand B (23.191), suggesting greater metabolic stability.

**13. In vitro Half-Life:** Ligand A (23.014 hours) has a significantly longer half-life than Ligand B (1.369 hours). This is a substantial advantage for Ligand A.

**14. P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.018 and 0.032), which is excellent.

**15. Binding Affinity:** Both ligands have the same binding affinity (-8.5 kcal/mol), which is very strong and exceeds the desired threshold.

**Overall Assessment:**

While Ligand A has better metabolic stability (lower Cl_mic, longer t1/2) and slightly better solubility and Caco-2 permeability, Ligand B has a significantly higher predicted BBB penetration (79.5% vs. 49.8%). For a CNS target like DRD2, BBB penetration is paramount. The difference in BBB is substantial enough to outweigh the advantages of Ligand A, especially given both ligands have excellent binding affinity and acceptable safety profiles.

Output:
1
2025-04-17 08:06:32,594 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (368.543 and 346.471 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Both ligands have a TPSA of 69.64, which is slightly above the optimal <90 for CNS targets, but still acceptable.

**3. logP:** Both ligands have logP values around 2 (2.2 and 2.001), which is within the optimal 1-3 range.

**4. H-Bond Donors:** Both have 2 HBD, well within the acceptable limit of <=5.

**5. H-Bond Acceptors:** Ligand A has 4 HBA, and Ligand B has 3. Both are below the acceptable limit of <=10.

**6. QED:** Both ligands have good QED scores (0.705 and 0.748), indicating drug-like properties.

**7. DILI:** Ligand A has a DILI risk of 18.418%, while Ligand B has 11.632%. Both are good (below 40), but Ligand B is slightly better.

**8. BBB:** This is a critical parameter for a CNS target like DRD2. Ligand A has a BBB penetration of 39.822%, while Ligand B has 54.478%. Ligand B is significantly better in terms of BBB penetration, exceeding 50%.

**9. Caco-2 Permeability:** Both have negative Caco-2 values (-5.027 and -4.941). This is unusual and suggests poor permeability. However, the scale is not specified, so it's difficult to interpret.

**10. Aqueous Solubility:** Both have negative solubility values (-3.092 and -2.025). Similar to Caco-2, this is difficult to interpret without knowing the scale.

**11. hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.247 and 0.162).

**12. Microsomal Clearance:** Ligand A has a higher microsomal clearance (41.116) than Ligand B (7.353). This indicates Ligand B is more metabolically stable.

**13. In vitro Half-Life:** Ligand B has a longer in vitro half-life (2.769 hours) than Ligand A (-13.59 hours). The negative value for ligand A is concerning and likely an error.

**14. P-gp Efflux:** Both have low P-gp efflux liability (0.175 and 0.074). Ligand B is slightly better.

**15. Binding Affinity:** Ligand B has a significantly stronger binding affinity (-8.8 kcal/mol) compared to Ligand A (-6.6 kcal/mol). This is a substantial difference (>1.5 kcal/mol) and a major advantage.

**Overall Assessment:**

Ligand B is clearly superior. It demonstrates a significantly better binding affinity, improved BBB penetration, lower DILI risk, better metabolic stability (lower Cl_mic and longer t1/2), and lower P-gp efflux. While both have issues with Caco-2 and solubility (difficult to interpret without scale), the substantial advantage in affinity and CNS penetration makes Ligand B the more promising candidate.

Output:
1
2025-04-17 08:06:32,594 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B based on the provided guidelines, prioritizing GPCR-specific properties (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (348.403 Da) is slightly lower, which could be beneficial for permeability, while Ligand B (386.489 Da) is still well within the acceptable range.

**TPSA:** Ligand A (127.32) is borderline for CNS penetration, being slightly above the preferred <90 threshold. Ligand B (42.43) is excellent, well below the threshold, suggesting better CNS penetration potential.

**logP:** Ligand A (0.796) is a bit low, potentially hindering permeation. Ligand B (3.672) is optimal, falling within the 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A has 3 HBD and 5 HBA, which are acceptable. Ligand B has 0 HBD and 5 HBA, also acceptable.

**QED:** Ligand A (0.671) has a good drug-likeness score. Ligand B (0.48) is lower, indicating a less favorable drug-like profile.

**DILI:** Ligand A (36.952) has a low DILI risk, which is excellent. Ligand B (60.411) is higher, indicating a moderate risk of liver injury.

**BBB:** This is a critical parameter for CNS targets. Ligand A (58.434) is moderate, while Ligand B (94.261) is excellent, exceeding the desirable >70 threshold.

**Caco-2 Permeability:** Ligand A (-5.587) has poor Caco-2 permeability, while Ligand B (-4.965) is also poor, but slightly better.

**Aqueous Solubility:** Both ligands have poor aqueous solubility (-2.676 and -4.072 respectively).

**hERG Inhibition:** Ligand A (0.091) has very low hERG inhibition risk, which is excellent. Ligand B (0.848) has a slightly elevated risk.

**Microsomal Clearance:** Ligand A (-6.848) has very low microsomal clearance, suggesting high metabolic stability. Ligand B (74.29) has high clearance, indicating rapid metabolism.

**In vitro Half-Life:** Ligand A (15.027) has a moderate half-life. Ligand B (-20.14) has a very short half-life.

**P-gp Efflux:** Ligand A (0.027) has very low P-gp efflux, which is excellent for CNS penetration. Ligand B (0.612) has moderate P-gp efflux.

**Binding Affinity:** Ligand A (-8.2) has a significantly stronger binding affinity than Ligand B (-6.9). The difference of 1.3 kcal/mol is substantial and can outweigh some ADME drawbacks.

**Overall Assessment:**

While Ligand A has a slightly lower logP and borderline TPSA, its *much* stronger binding affinity (-8.2 vs -6.9 kcal/mol), excellent DILI and hERG profiles, very low P-gp efflux, and low clearance are highly favorable. The better BBB penetration of Ligand B is attractive, but the significantly weaker affinity, higher DILI, faster clearance, and moderate P-gp efflux make it less promising overall. The strong binding affinity of Ligand A is a major advantage for a GPCR target, and the other properties, while not perfect, are acceptable, especially given the potency.

Output:
0
2025-04-17 08:06:32,594 - INFO - Reasoning:

Let's analyze both ligands against the provided guidelines, prioritizing GPCR-specific properties (BBB, logP, Pgp, TPSA, and affinity).

**Ligand A:**

*   **MW:** 348.418 Da - Good (within 200-500 range).
*   **TPSA:** 58.64 A<sup>2</sup> - Excellent (well below 90 A<sup>2</sup> for CNS targets).
*   **logP:** 2.379 - Good (within 1-3 range).
*   **HBD:** 1 - Good (<=5).
*   **HBA:** 3 - Good (<=10).
*   **QED:** 0.853 - Excellent (>=0.5).
*   **DILI:** 43.738 - Good (low risk, <40 is ideal, but <60 is acceptable).
*   **BBB:** 88.135 - Excellent (very high, >70 desirable for CNS).
*   **Caco-2:** -4.514 - Poor (negative value is concerning, indicating very low permeability).
*   **Solubility:** -3.551 - Poor (negative value is concerning, indicating very low solubility).
*   **hERG:** 0.56 - Good (low risk).
*   **Cl_mic:** 46.901 mL/min/kg - Moderate (higher clearance, less metabolic stability).
*   **t1/2:** 17.422 hours - Moderate.
*   **Pgp:** 0.293 - Excellent (low efflux, good for CNS penetration).
*   **Affinity:** -9.2 kcal/mol - Excellent (very strong binding).

**Ligand B:**

*   **MW:** 352.381 Da - Good (within 200-500 range).
*   **TPSA:** 69.64 A<sup>2</sup> - Good (below 90 A<sup>2</sup> for CNS targets).
*   **logP:** 1.847 - Good (within 1-3 range).
*   **HBD:** 2 - Good (<=5).
*   **HBA:** 3 - Good (<=10).
*   **QED:** 0.85 - Excellent (>=0.5).
*   **DILI:** 40.054 - Good (low risk, <40 is ideal, but <60 is acceptable).
*   **BBB:** 63.862 - Moderate (below 70, less desirable for CNS).
*   **Caco-2:** -4.783 - Poor (negative value is concerning, indicating very low permeability).
*   **Solubility:** -2.693 - Poor (negative value is concerning, indicating very low solubility).
*   **hERG:** 0.665 - Good (low risk).
*   **Cl_mic:** 16.033 mL/min/kg - Good (lower clearance, better metabolic stability).
*   **t1/2:** 36.512 hours - Excellent (long half-life).
*   **Pgp:** 0.069 - Excellent (low efflux, good for CNS penetration).
*   **Affinity:** -9.0 kcal/mol - Excellent (strong binding).

**Comparison & Decision:**

Both ligands have excellent affinity, QED, and low DILI/hERG risk. Both also suffer from very poor Caco-2 permeability and aqueous solubility, which is a significant concern. However, Ligand A has a much higher BBB penetration (88.135 vs 63.862) and a slightly better metabolic stability profile (lower Cl_mic). While Ligand B has a longer half-life, the superior BBB penetration of Ligand A is crucial for a CNS-targeting drug like one for DRD2. The slightly better metabolic stability of A also contributes to its favorability. The negative Caco-2 and solubility values are concerning for both, but can be addressed with formulation strategies. Given the GPCR-specific priorities, the higher BBB score of Ligand A is the deciding factor.

Output:
1
2025-04-17 08:06:32,594 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (358.551 and 346.515 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (32.34) is excellent, well below the 90 A^2 threshold for CNS targets. Ligand B (55.56) is still reasonable, but higher and less ideal for CNS penetration.

**3. logP:** Both ligands have good logP values (4.579 and 3.272), falling within the optimal 1-3 range, although Ligand A is slightly higher.

**4. H-Bond Donors:** Both have 1 HBD, which is within the acceptable limit of <=5.

**5. H-Bond Acceptors:** Both have 3 HBA, which is within the acceptable limit of <=10.

**6. QED:** Both ligands have good QED scores (0.631 and 0.86), indicating good drug-like properties.

**7. DILI:** Ligand A (21.055) has a much lower DILI risk than Ligand B (11.206), making it safer from a liver toxicity perspective. Both are below the 40 threshold.

**8. BBB:** Ligand B (83.637) has a significantly better BBB penetration percentile than Ligand A (70.027). This is a critical factor for CNS targets like DRD2.

**9. Caco-2 Permeability:** Ligand A (-5.212) has a worse Caco-2 permeability than Ligand B (-4.522), indicating potentially lower intestinal absorption.

**10. Aqueous Solubility:** Both ligands have very poor aqueous solubility (-2.711 and -2.771). This could pose formulation challenges, but is less critical than BBB for a CNS target.

**11. hERG Inhibition:** Both ligands have low hERG inhibition risk (0.953 and 0.865), which is good.

**12. Microsomal Clearance:** Ligand B (54.503) has lower microsomal clearance than Ligand A (78.901), suggesting better metabolic stability.

**13. In vitro Half-Life:** Ligand A (49.547) has a significantly longer in vitro half-life than Ligand B (2.376), which is a positive attribute.

**14. P-gp Efflux:** Ligand A (0.785) has lower P-gp efflux liability than Ligand B (0.595), which is favorable for CNS exposure.

**15. Binding Affinity:** Both ligands have excellent binding affinities (-8.8 and -8.4 kcal/mol). Ligand A is slightly better (-8.8 kcal/mol).

**Overall Assessment:**

While Ligand B has a superior BBB score and better metabolic stability (lower Cl_mic), Ligand A has a better safety profile (lower DILI), better half-life, lower P-gp efflux, and slightly better binding affinity. The difference in BBB is significant, but the combination of A's other favorable properties, particularly the lower DILI and better affinity, makes it the more promising candidate. The TPSA of Ligand A is also much more favorable for CNS penetration.

Output:
0
2025-04-17 08:06:32,594 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (345.4 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (98.74) is better than Ligand B (100.21). Both are reasonably close to the 90 A^2 threshold for CNS targets, but A is preferable.

**3. logP:** Ligand A (1.029) is within the optimal 1-3 range, while Ligand B (0.039) is quite low, potentially hindering permeability. This is a significant advantage for Ligand A.

**4. H-Bond Donors:** Ligand A (3) and Ligand B (2) are both acceptable, below the 5 threshold.

**5. H-Bond Acceptors:** Ligand A (4) and Ligand B (5) are both acceptable, below the 10 threshold.

**6. QED:** Both ligands have good QED values (A: 0.71, B: 0.802), indicating drug-like properties.

**7. DILI:** Ligand A (72.043) has a higher DILI risk than Ligand B (41.024). This favors Ligand B.

**8. BBB:** Ligand A (60.566) is better than Ligand B (45.095), though both are below the desirable >70 percentile for CNS targets. However, A is significantly better.

**9. Caco-2:** Both have negative Caco-2 values (-5.076 and -5.192), which is unusual and suggests poor permeability. This is a concern for both.

**10. Solubility:** Both have negative solubility values (-2.834 and -2.55), which is also unusual and suggests poor solubility. This is a concern for both.

**11. hERG:** Both ligands have very low hERG inhibition risk (A: 0.063, B: 0.048).

**12. Cl_mic:** Ligand A (-2.442) has a much lower (better) microsomal clearance than Ligand B (19.178), indicating greater metabolic stability.

**13. t1/2:** Ligand A (-4.154) has a more negative in vitro half-life than Ligand B (-1.916), suggesting a longer half-life.

**14. Pgp:** Both ligands have very low Pgp efflux liability (A: 0.022, B: 0.007).

**15. Binding Affinity:** Ligand A (-8.4 kcal/mol) has a stronger binding affinity than Ligand B (-7.7 kcal/mol). This is a substantial difference (0.7 kcal/mol), which can outweigh some ADME drawbacks.

**Overall Assessment:**

Considering the GPCR-specific priorities, Ligand A is the better candidate. While Ligand B has a lower DILI risk, Ligand A has a significantly better logP, BBB penetration, metabolic stability (Cl_mic), in vitro half-life, and, crucially, a stronger binding affinity. The affinity difference is substantial enough to compensate for the slightly higher DILI risk. The poor Caco-2 and solubility for both are concerning, but can be addressed with formulation strategies.

Output:
1
2025-04-17 08:06:32,594 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (348.531 and 346.431 Da) fall comfortably within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (40.62) is significantly better than Ligand B (67.67). For CNS targets, we want TPSA <= 90, and ideally much lower. Ligand A is well within this range, while Ligand B is approaching the upper limit, potentially hindering BBB penetration.

**3. logP:** Ligand A (3.866) is optimal (1-3), while Ligand B (1.031) is on the lower side. While not drastically low, lower logP can sometimes indicate permeability issues.

**4. H-Bond Donors:** Both ligands have 0 HBD, which is acceptable.

**5. H-Bond Acceptors:** Ligand A has 2 HBA, and Ligand B has 5 HBA. Both are within the acceptable limit of <=10.

**6. QED:** Both ligands have good QED scores (0.655 and 0.772), indicating drug-like properties.

**7. DILI:** Both ligands have low DILI risk (24.273 and 26.483), which is favorable.

**8. BBB:** Ligand A (78.907) has a slightly better BBB percentile than Ligand B (76.309), but both are reasonably good for a CNS target.

**9. Caco-2 Permeability:** Ligand A (-4.511) has worse Caco-2 permeability than Ligand B (-4.839). However, both are negative values, indicating poor permeability.

**10. Aqueous Solubility:** Ligand A (-3.5) has better solubility than Ligand B (-0.741). Solubility is important for formulation.

**11. hERG Inhibition:** Ligand A (0.789) has a lower hERG risk than Ligand B (0.23), which is preferable.

**12. Microsomal Clearance:** Ligand A (83.041) has higher microsomal clearance than Ligand B (28.068), indicating lower metabolic stability. This is a negative for Ligand A.

**13. In vitro Half-Life:** Ligand B (10.582) has a significantly longer half-life than Ligand A (4.063), which is a major advantage.

**14. P-gp Efflux:** Ligand A (0.68) has lower P-gp efflux than Ligand B (0.057), which is better for CNS exposure.

**15. Binding Affinity:** Ligand B (-8.0) has a slightly better binding affinity than Ligand A (-7.6). While both are excellent, the 0.4 kcal/mol difference is noticeable.

**Overall Assessment:**

Ligand B has a superior binding affinity and a much longer half-life, which are crucial for *in vivo* efficacy. While Ligand A has better TPSA and P-gp efflux, the significant advantage in half-life and affinity of Ligand B outweigh these benefits. The slightly lower logP of Ligand B is a minor concern, but not a deal-breaker given its strong binding.

Output:
1
2025-04-17 08:06:32,594 - INFO - Reasoning:

Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (346.431 and 371.453 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (83.44) is better than Ligand B (59.23). Both are below the 90 A^2 threshold desirable for CNS targets, but A is closer to the upper limit.

**3. logP:** Ligand A (0.545) is significantly lower than the optimal 1-3 range, potentially hindering membrane permeability. Ligand B (4.702) is high, potentially causing solubility issues and off-target effects.

**4. H-Bond Donors:** Ligand A (2) is acceptable, while Ligand B (0) is also good.

**5. H-Bond Acceptors:** Both ligands (A: 5, B: 5) are within the acceptable limit of 10.

**6. QED:** Both ligands have reasonable QED values (A: 0.755, B: 0.675), indicating good drug-like properties.

**7. DILI:** Ligand A (22.451) has a much lower DILI risk than Ligand B (57.697), which is a significant advantage.

**8. BBB:** Ligand B (89.066) has a significantly higher BBB penetration percentile than Ligand A (58.627). This is a critical factor for a CNS target like DRD2.

**9. Caco-2 Permeability:** Ligand A (-5.274) has very poor Caco-2 permeability, while Ligand B (-4.813) is also poor, but slightly better.

**10. Aqueous Solubility:** Ligand A (-1.093) has poor aqueous solubility, while Ligand B (-4.704) is even worse.

**11. hERG Inhibition:** Ligand A (0.199) has a very low hERG inhibition liability, a major advantage. Ligand B (0.762) is higher, indicating a moderate risk.

**12. Microsomal Clearance:** Ligand A (-17.428) has very low microsomal clearance, suggesting high metabolic stability. Ligand B (77.132) has high clearance, indicating rapid metabolism.

**13. In vitro Half-Life:** Ligand A (-9.456) has a very long in vitro half-life, while Ligand B (23.236) has a moderate half-life.

**14. P-gp Efflux:** Ligand A (0.007) has very low P-gp efflux, which is favorable for CNS penetration. Ligand B (0.714) has moderate P-gp efflux.

**15. Binding Affinity:** Ligand B (-7.7 kcal/mol) has a slightly better binding affinity than Ligand A (-8.5 kcal/mol). While a difference of 0.8 kcal/mol isn't huge, it is noticeable.

**Overall Assessment:**

Ligand A has several significant advantages: lower DILI risk, very low hERG inhibition, very low P-gp efflux, very low microsomal clearance, and a very long half-life. However, its low logP and poor Caco-2 permeability are major concerns. Ligand B excels in BBB penetration and has slightly better binding affinity, but suffers from higher DILI risk, higher hERG inhibition, higher P-gp efflux, and higher metabolic clearance.

Given the GPCR-specific priorities, BBB penetration is crucial for a CNS target. However, the combination of extremely favorable ADME properties (low DILI, hERG, P-gp, Cl_mic, and long t1/2) for Ligand A, despite its lower BBB and logP, makes it a more promising starting point for optimization. The logP and permeability issues could potentially be addressed through structural modifications. The high DILI and hERG risk associated with Ligand B are harder to mitigate.

Output:
0
2025-04-17 08:06:32,594 - INFO - Batch 421 complete. Total preferences: 6736
2025-04-17 08:06:32,595 - INFO - Processing batch 422/512...
2025-04-17 08:07:14,523 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (350.321 and 342.399 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (92.47) is better than Ligand B (96.6) as it is closer to the <90 threshold for CNS targets.

**logP:** Ligand A (2.308) is optimal (1-3), while Ligand B (0.277) is quite low, potentially hindering permeation.

**H-Bond Donors:** Ligand A (2) and Ligand B (1) both meet the <=5 criteria.

**H-Bond Acceptors:** Both ligands (4) are well within the acceptable limit of <=10.

**QED:** Both ligands have good QED scores (0.592 and 0.777, respectively), indicating drug-like properties.

**DILI:** Ligand A (54.556) has a higher DILI risk than Ligand B (32.067), but both are below the concerning threshold of 60.

**BBB:** Ligand B (71.268) significantly outperforms Ligand A (52.579) in BBB penetration, which is crucial for a CNS target like DRD2.

**Caco-2 Permeability:** Ligand A (-4.738) is worse than Ligand B (-5.153), indicating lower intestinal absorption.

**Aqueous Solubility:** Ligand A (-3.398) is better than Ligand B (-1.251), indicating better solubility.

**hERG Inhibition:** Ligand A (0.662) is better than Ligand B (0.044), indicating lower risk of cardiotoxicity.

**Microsomal Clearance:** Ligand B (-7.485) has a significantly lower (better) microsomal clearance than Ligand A (37.009), suggesting greater metabolic stability.

**In vitro Half-Life:** Ligand B (-21.227) has a much longer half-life than Ligand A (18.56), which is desirable.

**P-gp Efflux:** Ligand A (0.297) is better than Ligand B (0.008), indicating lower P-gp efflux and potentially better CNS exposure.

**Binding Affinity:** Both ligands have excellent binding affinities (-9.6 and -8.2 kcal/mol). Ligand A has a 1.4 kcal/mol advantage, which is significant.

**Overall Assessment:**

While Ligand A has a better binding affinity and better solubility, Ligand B excels in crucial areas for CNS penetration: BBB (71.268 vs 52.579), lower microsomal clearance (-7.485 vs 37.009), and longer half-life (-21.227 vs 18.56). The lower logP of Ligand B is a concern, but the substantial advantage in BBB penetration and metabolic stability outweighs this drawback, especially given the strong binding affinity. The P-gp efflux is also significantly better for Ligand A.

Output:
1
2025-04-17 08:07:14,524 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (345.403 Da) and Ligand B (337.471 Da) are comparable.

**TPSA:** Ligand A (104.12) is better than Ligand B (62.73). For CNS targets, TPSA should be <= 90, so Ligand A is borderline, while Ligand B is well within the range.

**logP:** Ligand A (1.363) is optimal, while Ligand B (3.739) is approaching the upper limit. Higher logP can lead to off-target effects and solubility issues.

**H-Bond Donors/Acceptors:** Both have 2 HBDs and 5 HBAs, which are within acceptable limits.

**QED:** Both ligands have similar QED values (0.823 and 0.841), indicating good drug-likeness.

**DILI:** Both ligands have acceptable DILI risk (Ligand A: 41.877, Ligand B: 48.623).

**BBB:** Ligand B (82.047) is significantly better than Ligand A (60.256) in terms of BBB penetration. A value > 70 is desirable for CNS targets, and Ligand B is closer to this threshold.

**Caco-2 Permeability:** Ligand A (-5.381) has a worse Caco-2 permeability than Ligand B (-4.93). Higher values indicate better intestinal absorption.

**Aqueous Solubility:** Ligand A (-1.517) has better aqueous solubility than Ligand B (-4.053).

**hERG:** Ligand A (0.029) has a much lower hERG inhibition liability than Ligand B (0.722), which is a significant advantage.

**Microsomal Clearance:** Ligand A (-6.132) has a much lower (better) microsomal clearance than Ligand B (75.095), indicating greater metabolic stability.

**In vitro Half-Life:** Ligand A (5.163) has a shorter half-life than Ligand B (36.36).

**P-gp Efflux:** Ligand A (0.013) has a much lower P-gp efflux liability than Ligand B (0.171), which is crucial for CNS penetration.

**Binding Affinity:** Ligand B (-8.5) has a slightly better binding affinity than Ligand A (-9.1). However, the difference is relatively small (0.6 kcal/mol).

**Overall Assessment:**

While Ligand B has a slightly better binding affinity and BBB penetration, Ligand A demonstrates superior ADME properties, particularly in terms of hERG inhibition, microsomal clearance, and P-gp efflux. For a CNS target like DRD2, minimizing P-gp efflux and maximizing metabolic stability are critical. The difference in binding affinity (0.6 kcal/mol) is unlikely to outweigh the substantial advantages of Ligand A in ADME. The slightly lower TPSA of Ligand B is also a positive, but not enough to overcome the other factors.

Output:
0
2025-04-17 08:07:14,524 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (368.499 and 392.258 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (81.08) is better than Ligand B (84.23) as both are below the 90 A^2 threshold for CNS targets, but lower is preferred.

**3. logP:** Ligand B (2.62) is more optimal than Ligand A (0.468). A logP between 1-3 is preferred, and Ligand A is significantly below this range, potentially hindering membrane permeability.

**4. H-Bond Donors:** Both ligands have 2 HBD, which is within the acceptable limit of <=5.

**5. H-Bond Acceptors:** Ligand A has 5 HBA, and Ligand B has 4 HBA. Both are within the acceptable limit of <=10.

**6. QED:** Both ligands have acceptable QED values (0.705 and 0.526, respectively), indicating good drug-like properties.

**7. DILI:** Ligand B (43.389) has a lower DILI risk than Ligand A (51.997), which is favorable. Both are below the concerning 60 threshold.

**8. BBB:** This is a crucial parameter for CNS targets. Ligand B (79.139) significantly outperforms Ligand A (26.483). A value >70 is desirable, and Ligand B is much closer to this target.

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.948 and -4.906), which is unusual and indicates very poor permeability. This is a major concern for both.

**10. Aqueous Solubility:** Both ligands have negative solubility values (-2.148 and -3.529), which is also a concern.

**11. hERG Inhibition:** Both ligands have low hERG inhibition risk (0.267 and 0.245).

**12. Microsomal Clearance:** Ligand A (19.078) has lower microsomal clearance than Ligand B (28.48), indicating better metabolic stability.

**13. In vitro Half-Life:** Ligand B (12.381) has a significantly longer half-life than Ligand A (0.171), which is a major advantage.

**14. P-gp Efflux:** Ligand A (0.154) has lower P-gp efflux than Ligand B (0.072), which is favorable for CNS penetration.

**15. Binding Affinity:** Ligand B (-8.2 kcal/mol) has a substantially stronger binding affinity than Ligand A (-6.1 kcal/mol). This >1.5 kcal/mol difference is significant and can outweigh some ADME drawbacks.

**Overall Assessment:**

While both ligands have concerning Caco-2 and solubility values, Ligand B is the stronger candidate. Its superior BBB penetration, significantly better binding affinity, longer half-life, and lower DILI risk outweigh the slightly higher P-gp efflux and lower metabolic stability compared to Ligand A. The low logP of Ligand A is a significant drawback for a CNS target. The strong binding affinity of Ligand B suggests it may be possible to overcome the permeability issues through further optimization.

Output:
1
2025-04-17 08:07:14,524 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (364.471 and 379.448 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (84.3) is better than Ligand B (47.36). Both are below the 90 A^2 threshold for CNS targets, but A is closer to the optimal range.

**logP:** Ligand A (1.565) is within the optimal 1-3 range. Ligand B (3.3) is at the higher end, potentially raising concerns about solubility and off-target effects, but still acceptable.

**H-Bond Donors/Acceptors:** Ligand A has 1 HBD and 5 HBA, while Ligand B has 0 HBD and 5 HBA. Both are within acceptable limits.

**QED:** Ligand A (0.835) has a significantly better QED score than Ligand B (0.729), indicating a more drug-like profile.

**DILI:** Ligand A (49.477) has a slightly higher DILI risk than Ligand B (33.501), but both are below the concerning threshold of 60.

**BBB:** Both ligands have excellent BBB penetration (Ligand A: 85.343, Ligand B: 88.29). This is critical for a CNS target like DRD2.

**Caco-2 Permeability:** Ligand A (-4.954) has a worse Caco-2 permeability than Ligand B (-4.639).

**Aqueous Solubility:** Ligand A (-1.891) has a worse aqueous solubility than Ligand B (-3.111).

**hERG Inhibition:** Both ligands have low hERG inhibition risk (Ligand A: 0.539, Ligand B: 0.689).

**Microsomal Clearance:** Ligand B (49.738) has a higher microsomal clearance than Ligand A (21.561), suggesting lower metabolic stability.

**In vitro Half-Life:** Ligand A (22.121) has a better in vitro half-life than Ligand B (-21.991).

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (Ligand A: 0.169, Ligand B: 0.155).

**Binding Affinity:** Ligand B (-6.9 kcal/mol) has a significantly stronger binding affinity than Ligand A (0.0 kcal/mol). This is a substantial advantage.

**Overall Assessment:**

Ligand B stands out due to its significantly stronger binding affinity (-6.9 kcal/mol vs 0.0 kcal/mol). While Ligand A has better QED, solubility, and metabolic stability, the binding affinity difference is substantial enough to outweigh these minor ADME advantages, especially for a GPCR target where potency is crucial. Both have good BBB penetration and low P-gp efflux, fulfilling key GPCR requirements for CNS targets. The slightly higher DILI risk for Ligand A is not a major concern given the other favorable properties.

Output:
1
2025-04-17 08:07:14,524 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (357.401 and 344.467 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (78.51) is significantly better than Ligand B (86.34). For CNS targets, we want TPSA <= 90, and A is closer to the optimal <= 60 range. B is pushing the upper limit.

**logP:** Both ligands have acceptable logP values (1.22 and 2.075, respectively), falling within the 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A (2 HBD, 3 HBA) is slightly better than Ligand B (1 HBD, 8 HBA). While both are within acceptable limits, fewer H-bonds generally improve permeability.

**QED:** Both ligands have good QED scores (0.702 and 0.789), indicating good drug-like properties.

**DILI:** Ligand A (38.581) has a lower DILI risk than Ligand B (54.401), which is preferable. Both are below the concerning threshold of 60.

**BBB:** Ligand A (78.209) has a significantly better BBB penetration score than Ligand B (63.862). For a CNS target like DRD2, >70 is desirable, and A is closer to that target.

**Caco-2 Permeability:** Ligand A (-4.867) has a worse Caco-2 permeability than Ligand B (-5.702). Lower values suggest lower permeability.

**Aqueous Solubility:** Both ligands have poor aqueous solubility (-2.573 and -2.326). This could be a formulation challenge, but isn't a dealbreaker.

**hERG Inhibition:** Ligand A (0.269) has a much lower hERG inhibition liability than Ligand B (0.098), which is a significant advantage.

**Microsomal Clearance:** Ligand A (-3.154) has a lower (better) microsomal clearance than Ligand B (7.816), indicating better metabolic stability.

**In vitro Half-Life:** Ligand A (-13.391) has a longer in vitro half-life than Ligand B (8.126), which is preferable.

**P-gp Efflux:** Ligand A (0.017) has a much lower P-gp efflux liability than Ligand B (0.096), which is crucial for CNS penetration.

**Binding Affinity:** Ligand A (-8.7 kcal/mol) has a significantly stronger binding affinity than Ligand B (-6.0 kcal/mol). This is a substantial difference (2.7 kcal/mol), and can often outweigh minor ADME drawbacks.

**Overall Assessment:**

Ligand A is clearly superior. It excels in key GPCR-relevant properties: BBB penetration, P-gp efflux, hERG inhibition, metabolic stability, and, most importantly, binding affinity. While both have poor solubility, the substantial affinity advantage of Ligand A, coupled with its better safety profile (lower DILI, hERG) and CNS penetration properties, makes it the much more promising candidate. The slightly worse Caco-2 permeability is less concerning for a CNS target.

Output:
1
2025-04-17 08:07:14,525 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (381.347 Da) is slightly higher than Ligand B (357.407 Da), but both are acceptable.

**TPSA:** Ligand A (32.34) is excellent for CNS penetration, well below the 90 A^2 threshold. Ligand B (119.41) is higher, but still potentially acceptable, though less ideal.

**logP:** Ligand A (4.609) is a bit high, potentially leading to solubility issues and off-target interactions. Ligand B (-2.058) is too low, which could hinder membrane permeability and reduce CNS exposure.

**H-Bond Donors/Acceptors:** Ligand A (HBD=1, HBA=2) is favorable. Ligand B (HBD=3, HBA=6) is also within acceptable limits, but slightly higher.

**QED:** Ligand A (0.812) has a very good drug-likeness score. Ligand B (0.46) is below the 0.5 threshold, indicating a less desirable drug-like profile.

**DILI:** Ligand A (31.059) has a low DILI risk. Ligand B (16.44) also has a low DILI risk.

**BBB:** Ligand A (81.078) has excellent BBB penetration potential. Ligand B (17.138) has very poor BBB penetration potential. This is a critical difference for a CNS target like DRD2.

**Caco-2 Permeability:** Ligand A (-4.945) has poor Caco-2 permeability. Ligand B (-5.411) also has poor Caco-2 permeability.

**Aqueous Solubility:** Ligand A (-4.589) has poor aqueous solubility. Ligand B (-0.962) has slightly better, but still poor aqueous solubility.

**hERG Inhibition:** Ligand A (0.768) has a low hERG inhibition risk. Ligand B (0.026) has a very low hERG inhibition risk.

**Microsomal Clearance:** Ligand A (42.587) has moderate microsomal clearance. Ligand B (-2.72) has negative clearance, which is not physically possible and likely indicates an issue with the data or prediction method.

**In vitro Half-Life:** Ligand A (42.117) has a moderate in vitro half-life. Ligand B (12.294) has a short in vitro half-life.

**P-gp Efflux:** Ligand A (0.588) has moderate P-gp efflux. Ligand B (0.002) has very low P-gp efflux, which is favorable for CNS penetration.

**Binding Affinity:** Ligand A (-7.4 kcal/mol) has slightly better binding affinity than Ligand B (-7.2 kcal/mol). While the difference is small, it's still a factor.

**Overall Assessment:**

Ligand A excels in BBB penetration, DILI risk, and has a good QED score. However, its high logP and poor Caco-2 permeability are concerns. Ligand B has a lower logP and P-gp efflux, but suffers from poor BBB penetration, a low QED score, and a questionable negative microsomal clearance value.

Given the importance of BBB penetration for a CNS target like DRD2, and the slightly better affinity of Ligand A, **Ligand A is the more promising candidate**, despite its drawbacks. The high logP could be addressed through structural modifications, but poor BBB penetration is much harder to fix. The negative clearance value for Ligand B is a red flag.

Output:
0
2025-04-17 08:07:14,525 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (348.447 and 349.435 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (67.67) is excellent, well below the 90 A^2 threshold for CNS targets. Ligand B (115.98) is higher, but still potentially acceptable, though less ideal.

**logP:** Ligand A (1.822) is optimal (1-3). Ligand B (0.27) is low, potentially hindering permeation.

**H-Bond Donors/Acceptors:** Ligand A (0 HBD, 5 HBA) is favorable. Ligand B (4 HBD, 4 HBA) is also acceptable.

**QED:** Ligand A (0.836) is excellent, indicating high drug-likeness. Ligand B (0.485) is below the 0.5 threshold, suggesting a less favorable drug-like profile.

**DILI:** Ligand A (29.779) has a low DILI risk. Ligand B (16.596) also has a low DILI risk.

**BBB:** Ligand A (72.005) has good BBB penetration, exceeding the 70% threshold. Ligand B (45.522) is significantly lower, which is a major concern for a CNS target like DRD2.

**Caco-2 Permeability:** Ligand A (-4.403) is concerningly low, suggesting poor intestinal absorption. Ligand B (-5.683) is even worse.

**Aqueous Solubility:** Both ligands have negative solubility values (-1.741 and -1.501), which is unusual and suggests very poor solubility. This is a potential formulation challenge.

**hERG:** Both ligands have very low hERG inhibition liability (0.252 and 0.112), which is positive.

**Microsomal Clearance:** Ligand A (50.35) is moderate. Ligand B (-1.052) is very low, suggesting high metabolic stability.

**In vitro Half-Life:** Ligand A (-11.29) is very negative, indicating a very short half-life. Ligand B (-30.512) is even shorter.

**P-gp Efflux:** Both ligands show very low P-gp efflux liability (0.028 and 0.005), which is favorable for CNS penetration.

**Binding Affinity:** Ligand A (-8.3 kcal/mol) has significantly better binding affinity than Ligand B (-7.0 kcal/mol). This >1.5 kcal/mol difference is substantial.

**Overall Assessment:**

Ligand A is superior despite its poor Caco-2 permeability and short half-life. Its strong binding affinity, excellent TPSA, good BBB penetration, and favorable DILI/hERG profiles outweigh the drawbacks. Ligand B suffers from a poor logP, significantly lower BBB penetration, and a lower QED score, making it a less attractive candidate. The solubility issues for both are concerning, but can potentially be addressed with formulation strategies. The affinity difference is the deciding factor here, and the CNS target prioritization reinforces the importance of BBB penetration, which Ligand A possesses to a much greater extent.

Output:
0
2025-04-17 08:07:14,525 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 drug candidates, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (352.435 and 348.403 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (91.31) is better than Ligand B (96.55). Both are below the 140 threshold for oral absorption and reasonably close to the 90 threshold for CNS targets, but A is preferable.

**3. logP:** Ligand B (0.719) is slightly better than Ligand A (0.374). Both are a bit low, potentially hindering permeation, but still within an acceptable range.

**4. H-Bond Donors:** Ligand A (1) is better than Ligand B (2). Lower HBD generally improves permeability.

**5. H-Bond Acceptors:** Both ligands have 5 HBA, which is acceptable.

**6. QED:** Ligand A (0.615) has a significantly better QED score than Ligand B (0.41), indicating a more drug-like profile.

**7. DILI:** Ligand A (27.104) has a much lower DILI risk than Ligand B (51.028), a significant advantage.

**8. BBB:** Ligand A (68.864) has a significantly better BBB penetration percentile than Ligand B (42.924). This is *critical* for a CNS target like DRD2.

**9. Caco-2 Permeability:** Ligand A (-4.789) has better Caco-2 permeability than Ligand B (-5.181), though both are negative values.

**10. Aqueous Solubility:** Ligand A (-1.603) has better aqueous solubility than Ligand B (-2.371).

**11. hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.199 and 0.269).

**12. Microsomal Clearance:** Ligand B (-22.881) has lower (better) microsomal clearance than Ligand A (26.214), suggesting greater metabolic stability.

**13. In vitro Half-Life:** Ligand B (-7.838) has a longer in vitro half-life than Ligand A (-14.922).

**14. P-gp Efflux:** Ligand A (0.015) has significantly lower P-gp efflux liability than Ligand B (0.042). Lower P-gp efflux is crucial for CNS penetration.

**15. Binding Affinity:** Ligand B (-8.6) has a slightly better binding affinity than Ligand A (-6.8). This is a 1.8 kcal/mol difference, which is substantial.

**Overall Assessment:**

While Ligand B has a slightly better binding affinity and metabolic stability, Ligand A is significantly better across multiple critical ADME properties, especially for a CNS-targeting GPCR.  The superior BBB penetration (68.864 vs 42.924), lower DILI risk (27.104 vs 51.028), lower P-gp efflux (0.015 vs 0.042), and better QED (0.615 vs 0.41) of Ligand A outweigh the modest affinity difference. The slightly lower logP of Ligand A is a minor concern, but can be addressed through further optimization.

Output:
1
2025-04-17 08:07:14,525 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (385.873) is slightly higher, but still acceptable.

**TPSA:** Both ligands have TPSA values below 140, suggesting reasonable oral absorption. Ligand B (86.6) is better, being closer to the preferred <90 for CNS targets than Ligand A (95.58).

**logP:** Ligand A (1.127) is within the optimal range (1-3). Ligand B (-0.096) is slightly below 1, which *could* indicate permeability issues, but isn't a dealbreaker.

**H-Bond Donors/Acceptors:** Both ligands have acceptable HBD (2 & 3) and HBA (5 & 5) counts.

**QED:** Both ligands have QED values above 0.5, indicating good drug-likeness.

**DILI:** Ligand A (67.313) has a higher DILI risk than Ligand B (16.014). This is a significant negative for Ligand A.

**BBB:** This is crucial for a CNS target like DRD2. Ligand A (60.644) is borderline, while Ligand B (36.177) is quite low. Neither is ideal, but Ligand A is substantially better.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values, which is unusual and suggests poor permeability. This is a concern for both.

**Aqueous Solubility:** Both ligands have negative solubility values, again unusual and concerning.

**hERG Inhibition:** Both ligands show very low hERG inhibition risk, which is positive.

**Microsomal Clearance:** Ligand A (-16.853) has a much lower (better) microsomal clearance than Ligand B (-9.758), indicating improved metabolic stability.

**In vitro Half-Life:** Ligand B (4.744) has a significantly longer half-life than Ligand A (0.135).

**P-gp Efflux:** Both ligands have low P-gp efflux liability, which is favorable.

**Binding Affinity:** Ligand A (-10.1 kcal/mol) has a significantly stronger binding affinity than Ligand B (-8.4 kcal/mol). This is a substantial advantage for Ligand A, potentially outweighing some of its ADME drawbacks.

**Overall Assessment:**

Ligand A has a much better binding affinity and metabolic stability (lower Cl_mic), but suffers from a higher DILI risk and a borderline BBB score. Ligand B has a better BBB score and lower DILI, but significantly weaker binding affinity and poorer metabolic stability.

Given the importance of strong binding for GPCR ligands, and the fact that the affinity difference is substantial (1.7 kcal/mol), I believe Ligand A is the more promising candidate *despite* its higher DILI and lower BBB. The potency advantage is likely to be more impactful than the ADME liabilities, especially if further optimization can address the DILI and BBB concerns.

Output:
1
2025-04-17 08:07:14,526 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (348.49 & 354.42 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (67.43) is better than Ligand B (75.71). For CNS targets, we want TPSA <= 90, both are within this range, but A is closer to the optimal value.

**3. logP:** Both ligands have good logP values (3.59 & 2.11), falling within the 1-3 range. Ligand A is slightly higher, which could be beneficial for membrane permeability, but isn't a major concern for either.

**4. H-Bond Donors:** Ligand A (2) is slightly higher than Ligand B (1), but both are acceptable (<=5).

**5. H-Bond Acceptors:** Ligand A (3) and Ligand B (4) are both within the acceptable range (<=10).

**6. QED:** Ligand A (0.717) has a significantly better QED score than Ligand B (0.313), indicating a more drug-like profile.

**7. DILI:** Ligand A (36.1%) has a lower DILI risk than Ligand B (44.6%), both are good, but A is better.

**8. BBB:** Both ligands show good BBB penetration (Ligand A: 73.8%, Ligand B: 79.6%). Ligand B is slightly better, but both are above the desirable 70% threshold for CNS targets.

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 values, which is unusual and suggests a potential issue with the data or calculation method. However, we can proceed with caution.

**10. Aqueous Solubility:** Both ligands have negative solubility values, again suggesting a potential issue with the data.

**11. hERG Inhibition:** Both ligands have low hERG inhibition risk (0.736 & 0.488).

**12. Microsomal Clearance:** Ligand A (57.94) has a lower microsomal clearance than Ligand B (84.46), suggesting better metabolic stability.

**13. In vitro Half-Life:** Ligand A (25.83) has a longer in vitro half-life than Ligand B (-19.08), which is a significant advantage.

**14. P-gp Efflux:** Both ligands have low P-gp efflux (0.228 & 0.243), which is good for CNS penetration.

**15. Binding Affinity:** Both ligands have excellent binding affinities (-8.8 & -8.0 kcal/mol). Ligand A is 0.8 kcal/mol better, which is a substantial advantage and can outweigh minor ADME drawbacks.

**Overall Assessment:**

Ligand A is the superior candidate. It has a better QED score, lower DILI risk, better metabolic stability (lower Cl_mic, longer t1/2), and a significantly stronger binding affinity. While both ligands have acceptable BBB penetration and logP values, the combination of improved ADME properties and superior binding affinity makes Ligand A the more promising drug candidate. The negative solubility and Caco-2 values are concerning and would require further investigation, but the other factors strongly favor Ligand A.

Output:
1
2025-04-17 08:07:14,526 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (356.47 and 365.46 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (33.2) is excellent, well below the 90 A^2 threshold for CNS targets. Ligand B (87.74) is higher, but still potentially acceptable, though less ideal.

**logP:** Ligand A (4.805) is slightly high, potentially leading to solubility issues or off-target interactions. Ligand B (0.042) is very low, which is problematic for membrane permeability and CNS penetration.

**H-Bond Donors/Acceptors:** Ligand A (0 HBD, 3 HBA) is favorable. Ligand B (2 HBD, 5 HBA) is also acceptable.

**QED:** Ligand A (0.74) is good, indicating a drug-like profile. Ligand B (0.526) is marginally acceptable.

**DILI:** Ligand A (56.883) has a moderate DILI risk. Ligand B (62.737) also has a moderate risk, slightly higher than A.

**BBB:** Ligand A (91.702) has excellent BBB penetration, crucial for a CNS target like DRD2. Ligand B (57.154) is significantly lower, making CNS exposure questionable.

**Caco-2 Permeability:** Ligand A (-4.542) is poor. Ligand B (-5.165) is also poor.

**Aqueous Solubility:** Ligand A (-5.581) is poor. Ligand B (-2.584) is also poor, but better than A.

**hERG Inhibition:** Ligand A (0.75) shows low hERG inhibition risk. Ligand B (0.104) also shows low hERG inhibition risk.

**Microsomal Clearance:** Ligand A (102.08) has moderate clearance. Ligand B (24.21) has low clearance, suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (33.97) has a moderate half-life. Ligand B (-11.637) has a very short half-life, which is a significant drawback.

**P-gp Efflux:** Ligand A (0.631) has moderate P-gp efflux. Ligand B (0.035) has very low P-gp efflux, which is favorable for CNS penetration.

**Binding Affinity:** Both ligands have similar, strong binding affinities (-8.9 and -8.5 kcal/mol). The difference of 0.4 kcal/mol is not substantial enough to override other significant differences.

**Conclusion:**

Considering the GPCR-specific priorities, Ligand A is the more promising candidate. Its excellent BBB penetration (91.7%) is a major advantage for a CNS target. While its logP is slightly high and Caco-2 permeability and solubility are poor, the strong affinity and acceptable DILI/hERG profiles, combined with the crucial BBB score, outweigh these drawbacks. Ligand B's very low logP and poor BBB penetration are significant liabilities that make it less likely to achieve sufficient CNS exposure, despite its better metabolic stability and lower P-gp efflux.

Output:
0
2025-04-17 08:07:14,526 - INFO - Reasoning:

Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (374.794 and 376.551 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (72.94) is better than Ligand B (58.12). Both are below 90, which is favorable for CNS penetration.

**3. logP:** Both ligands have good logP values (3.402 and 3.648), falling within the optimal 1-3 range.

**4. H-Bond Donors:** Ligand A (2) is slightly higher than Ligand B (1), but both are within the acceptable limit of 5.

**5. H-Bond Acceptors:** Ligand A (4) is lower than Ligand B (6), which is slightly better. Both are below the limit of 10.

**6. QED:** Both ligands have similar QED values (0.842 and 0.807), indicating good drug-likeness.

**7. DILI:** Ligand A (54.634) has a lower DILI risk than Ligand B (71.384), which is a significant advantage.

**8. BBB:** Ligand A (80.419) has a better BBB percentile than Ligand B (75.107). Both are above 70, which is desirable for CNS targets.

**9. Caco-2 Permeability:** Ligand A (-4.705) has a worse Caco-2 permeability than Ligand B (-5.186). Lower values indicate lower permeability.

**10. Aqueous Solubility:** Ligand A (-3.468) has a worse aqueous solubility than Ligand B (-4.059). Lower values indicate lower solubility.

**11. hERG Inhibition:** Both ligands have similar, low hERG inhibition liability (0.631 and 0.747).

**12. Microsomal Clearance:** Ligand A (22.478) has a lower microsomal clearance than Ligand B (67.769), indicating better metabolic stability.

**13. In vitro Half-Life:** Ligand A (8.654) has a shorter in vitro half-life than Ligand B (15.958).

**14. P-gp Efflux:** Ligand A (0.357) has lower P-gp efflux liability than Ligand B (0.254), which is better for CNS exposure.

**15. Binding Affinity:** Ligand A (-8.8 kcal/mol) has a significantly stronger binding affinity than Ligand B (-7.7 kcal/mol). This is a >1 kcal/mol advantage, which can outweigh some ADME drawbacks.

**Overall Assessment:**

Ligand A is the better candidate. While Ligand B has slightly better Caco-2 permeability and aqueous solubility, Ligand A excels in critical areas: significantly stronger binding affinity, lower DILI risk, better BBB penetration, lower microsomal clearance (better metabolic stability), and lower P-gp efflux. The stronger binding affinity is particularly important for a GPCR target like DRD2. The lower DILI and better BBB are also crucial for a safe and effective CNS drug.



Output:
1
2025-04-17 08:07:14,526 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (350.503 and 351.401 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (67.43) is significantly better than Ligand B (77.93). For CNS targets, we want TPSA <= 90, and A is closer to the optimal <=60 range. B is pushing the upper limit.

**3. logP:** Both ligands have good logP values (2.662 and 2.307), falling within the 1-3 range.

**4. H-Bond Donors:** Both have 2 HBD, which is acceptable (<=5).

**5. H-Bond Acceptors:** Ligand A has 3 HBA, and Ligand B has 5. Both are within the acceptable range of <=10, but A is preferable.

**6. QED:** Ligand B (0.763) has a better QED score than Ligand A (0.496), indicating a more drug-like profile overall.

**7. DILI:** Ligand A (13.843) has a much lower DILI risk than Ligand B (32.299). This is a significant advantage for A.

**8. BBB:** Ligand B (75.456) has a better BBB penetration percentile than Ligand A (68.554). While both are reasonably good, B is closer to the desirable >70 threshold for CNS targets.

**9. Caco-2 Permeability:** Ligand A (-4.928) has *better* Caco-2 permeability than Ligand B (-5.133). Note that lower values here indicate *higher* permeability.

**10. Aqueous Solubility:** Ligand A (-2.614) has better aqueous solubility than Ligand B (-2.384). Higher values indicate better solubility.

**11. hERG Inhibition:** Both ligands have low hERG inhibition risk (0.444 and 0.636), which is good.

**12. Microsomal Clearance:** Ligand B (9.79) has a lower microsomal clearance than Ligand A (48.609), suggesting better metabolic stability.

**13. In vitro Half-Life:** Ligand B (-17.05) has a significantly longer in vitro half-life than Ligand A (-9.443). This is a major advantage for B.

**14. P-gp Efflux:** Ligand A (0.103) has lower P-gp efflux than Ligand B (0.08). Lower is better, so A is preferable.

**15. Binding Affinity:** Both ligands have very similar binding affinities (-7.7 and -7.5 kcal/mol). The difference is negligible.

**Overall Assessment:**

Ligand B has advantages in BBB, metabolic stability (Cl_mic and t1/2), and QED. However, Ligand A excels in TPSA, DILI risk, Caco-2 permeability, solubility, and P-gp efflux. Given the CNS target (DRD2), TPSA and BBB are critical. While B has a slightly better BBB score, A's significantly lower TPSA and DILI risk, coupled with better permeability and efflux properties, make it the more promising candidate. The small difference in binding affinity is not enough to overcome these ADME advantages.

Output:
0
2025-04-17 08:07:14,526 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 drug candidates, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (342.439 Da) is slightly lower, which could be advantageous for permeability, while Ligand B (399.647 Da) is still well within the acceptable range.

**TPSA:** Ligand A (62.55) is better than Ligand B (40.54) as it is closer to the desired value of <90 for CNS targets.

**logP:** Ligand A (3.068) is optimal (1-3), while Ligand B (4.493) is a bit high, potentially leading to solubility issues and off-target interactions.

**H-Bond Donors/Acceptors:** Both ligands have acceptable HBD (1) and HBA (3 for A, 5 for B) counts, falling within the recommended limits.

**QED:** Ligand A (0.864) has a significantly better QED score than Ligand B (0.686), indicating a more drug-like profile.

**DILI:** Ligand A (25.785) has a much lower DILI risk than Ligand B (42.187), which is a significant advantage.

**BBB:** Both ligands show good BBB penetration (Ligand A: 72.315, Ligand B: 76.541), exceeding the desirable threshold of >70 for CNS targets. Ligand B is slightly better.

**Caco-2 Permeability:** Ligand A (-4.491) has a worse Caco-2 permeability than Ligand B (-5.282).

**Aqueous Solubility:** Ligand A (-3.501) has better aqueous solubility than Ligand B (-4.841).

**hERG Inhibition:** Ligand A (0.319) has a lower hERG inhibition liability than Ligand B (0.772), reducing the risk of cardiotoxicity.

**Microsomal Clearance:** Ligand A (55.99) has a lower microsomal clearance than Ligand B (70.429), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (47.881) has a longer in vitro half-life than Ligand B (14.963), which is desirable for less frequent dosing.

**P-gp Efflux:** Ligand A (0.219) has lower P-gp efflux liability than Ligand B (0.846), improving CNS exposure and oral bioavailability.

**Binding Affinity:** Ligand A (-8.6 kcal/mol) has a significantly stronger binding affinity than Ligand B (-7.3 kcal/mol). This >1.5 kcal/mol difference is a major advantage, potentially outweighing some minor ADME drawbacks.

**Overall Assessment:**

Ligand A is superior to Ligand B. While Ligand B has slightly better BBB penetration and Caco-2 permeability, Ligand A excels in almost all other critical parameters, especially binding affinity, DILI risk, QED, metabolic stability, hERG inhibition, and P-gp efflux. The substantial difference in binding affinity (-8.6 vs -7.3 kcal/mol) is a key factor, and the better ADME profile of Ligand A makes it a more promising drug candidate.

Output:
1
2025-04-17 08:07:14,527 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (347.415 and 350.463 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (92.55) is better than Ligand B (104.21). For CNS targets, we want TPSA <= 90, so Ligand A is closer to this threshold.

**3. logP:** Both ligands have acceptable logP values (1.197 and 1.678, respectively), falling within the optimal 1-3 range.

**4. H-Bond Donors:** Ligand A (1) is better than Ligand B (3). Lower HBD generally improves permeability.

**5. H-Bond Acceptors:** Ligand A (4) is better than Ligand B (5). Lower HBA generally improves permeability.

**6. QED:** Both ligands have similar and good QED values (0.597 and 0.595), indicating good drug-like properties.

**7. DILI:** Ligand A (14.734) has a significantly lower DILI risk than Ligand B (42.303). This is a substantial advantage.

**8. BBB:** Ligand A (51.958) has a much better BBB penetration percentile than Ligand B (30.283). This is *critical* for a CNS target like DRD2. While >70 is desirable, 51.958 is still considerably better than 30.283.

**9. Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and suggests poor permeability. However, the scale is not specified, so it's difficult to interpret.

**10. Aqueous Solubility:** Both have negative solubility values, indicating poor solubility. Again, the scale is not specified.

**11. hERG Inhibition:** Both ligands have low hERG inhibition liability (0.13 and 0.265), which is good.

**12. Microsomal Clearance:** Ligand A (16.583) has lower microsomal clearance than Ligand B (21.168), suggesting better metabolic stability.

**13. In vitro Half-Life:** Ligand B (13.882) has a longer in vitro half-life than Ligand A (0.752). This is a positive for Ligand B.

**14. P-gp Efflux:** Both ligands have low P-gp efflux liability (0.018 and 0.035), which is good for CNS penetration.

**15. Binding Affinity:** Ligand A (-9.5 kcal/mol) has a significantly stronger binding affinity than Ligand B (-7.5 kcal/mol). This difference of 2 kcal/mol is substantial and can outweigh minor ADME drawbacks.

**Overall Assessment:**

Ligand A is clearly superior. It has a better TPSA, lower HBD/HBA, significantly lower DILI risk, much better BBB penetration, lower microsomal clearance, and *much* stronger binding affinity. While Ligand B has a longer half-life, the other advantages of Ligand A, particularly the binding affinity and BBB penetration, are far more important for a CNS-targeting GPCR like DRD2. The poor solubility and permeability are concerns for both, but can be addressed with formulation strategies.

Output:
1
2025-04-17 08:07:14,527 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (345.483 and 355.467 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (57.61) is significantly better than Ligand B (82.77). For CNS targets, we want TPSA <= 90, and A is comfortably within this range, while B is approaching the upper limit.

**3. logP:** Ligand A (4.472) is slightly higher than the optimal 1-3 range, but still reasonable. Ligand B (2.836) is well within the optimal range. However, for a GPCR, a slightly higher logP can be tolerated if other properties are favorable.

**4. H-Bond Donors:** Ligand A (1) is good. Ligand B (0) is also good.

**5. H-Bond Acceptors:** Ligand A (2) is good. Ligand B (6) is higher, but still within the acceptable limit of 10.

**6. QED:** Both ligands have acceptable QED values (0.827 and 0.759, both > 0.5).

**7. DILI:** Ligand A (36.758) has a much lower DILI risk than Ligand B (63.164). This is a significant advantage for Ligand A.

**8. BBB:** Ligand A (51.842) has a lower BBB penetration than Ligand B (64.211). While both are not optimal (>70 desirable), Ligand B is better.

**9. Caco-2:** Both have negative values, which is unusual and likely indicates a problem with the data. However, the magnitude of the negative value is similar for both.

**10. Solubility:** Both have negative values, again indicating a data issue. The values are similar.

**11. hERG:** Ligand A (0.267) has a much lower hERG inhibition liability than Ligand B (0.547). This is a substantial advantage for Ligand A.

**12. Cl_mic:** Ligand A (44.569) has a lower microsomal clearance than Ligand B (87.839), suggesting better metabolic stability.

**13. t1/2:** Ligand A (7.789) has a longer in vitro half-life than Ligand B (4.685).

**14. Pgp:** Ligand A (0.262) has lower P-gp efflux liability than Ligand B (0.171). Lower is better, and A is better.

**15. Binding Affinity:** Ligand A (-7.9 kcal/mol) has a significantly stronger binding affinity than Ligand B (-6.9 kcal/mol). This 1 kcal/mol difference is substantial and can outweigh some ADME drawbacks.

**Overall Assessment:**

Ligand A is superior. While Ligand B has slightly better BBB penetration, Ligand A excels in almost every other crucial parameter: lower DILI risk, lower hERG inhibition, better metabolic stability (lower Cl_mic, longer t1/2), lower Pgp efflux, and *significantly* stronger binding affinity. The TPSA is also much more favorable for CNS penetration. The slightly higher logP of Ligand A is acceptable given its superior binding.



Output:
1
2025-04-17 08:07:14,527 - INFO - Batch 422 complete. Total preferences: 6752
2025-04-17 08:07:14,527 - INFO - Processing batch 423/512...
2025-04-17 08:08:04,723 - INFO - Reasoning:

Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (345.487 and 347.459 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (73.2) is slightly higher than Ligand B (62.21). For CNS targets, we prefer TPSA <= 90, so both are acceptable, but B is better.

**3. logP:** Both ligands have good logP values (3.172 and 2.204), falling within the optimal 1-3 range.

**4. H-Bond Donors:** Ligand A (1) is preferable to Ligand B (0). While both are acceptable, having one HBD can sometimes improve solubility.

**5. H-Bond Acceptors:** Ligand A (3) and Ligand B (4) are both within the acceptable limit of <=10.

**6. QED:** Both ligands have similar QED values (0.752 and 0.716), indicating good drug-like properties.

**7. DILI:** Ligand A (13.416) has a significantly lower DILI risk than Ligand B (23.885). This is a substantial advantage for A.

**8. BBB:** Both ligands have excellent BBB penetration (70.686 and 72.974), exceeding the desirable threshold of >70 for CNS targets.

**9. Caco-2 Permeability:** Both have negative values, which is unusual. Assuming these are logP values, they indicate poor permeability.

**10. Aqueous Solubility:** Both ligands have negative solubility values, which is also unusual.

**11. hERG Inhibition:** Both ligands show low hERG inhibition liability (0.518 and 0.432), which is good.

**12. Microsomal Clearance:** Ligand A (42.027) has lower microsomal clearance than Ligand B (49.77), suggesting better metabolic stability.

**13. In vitro Half-Life:** Ligand A (-18.894) has a much longer in vitro half-life than Ligand B (-1.212). This is a significant advantage.

**14. P-gp Efflux:** Both ligands have low P-gp efflux liability (0.095 and 0.206), which is favorable for CNS penetration.

**15. Binding Affinity:** Ligand B (-8.5 kcal/mol) has a slightly better binding affinity than Ligand A (-7.9 kcal/mol). While a 0.6 kcal/mol difference is noticeable, it might not be enough to overcome other significant advantages of Ligand A.

**Overall Assessment:**

Ligand A demonstrates a more favorable ADMET profile overall. It has significantly lower DILI risk, better metabolic stability (lower Cl_mic, longer t1/2), and comparable BBB penetration and logP values to Ligand B. While Ligand B has slightly better binding affinity, the other advantages of Ligand A, particularly the lower DILI and improved metabolic stability, make it the more promising drug candidate.

Output:
1
2025-04-17 08:08:04,723 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (339.395 and 347.463 Da) fall within the ideal range of 200-500 Da.

**TPSA:** Ligand A (82.43) is better than Ligand B (72.28) as it is closer to the desirable <90 A^2 for CNS targets.

**logP:** Both ligands have good logP values (1.41 and 1.316), falling within the optimal 1-3 range.

**H-Bond Donors:** Both have 1 HBD, which is within the acceptable limit of <=5.

**H-Bond Acceptors:** Ligand A has 4 HBA, while Ligand B has 6. Both are within the acceptable limit of <=10, but A is preferable.

**QED:** Ligand B (0.753) has a significantly better QED score than Ligand A (0.483), suggesting a more drug-like profile.

**DILI:** Ligand A (26.793) has a much lower DILI risk than Ligand B (33.307), indicating a safer profile.

**BBB:** Ligand B (72.043) has a significantly better BBB penetration score than Ligand A (46.413). This is a critical advantage for a CNS target like DRD2.

**Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and suggests poor permeability. However, the absolute value is smaller for Ligand A (-4.987) than for Ligand B (-5.051), suggesting slightly better permeability.

**Aqueous Solubility:** Both ligands have very poor aqueous solubility (-2.6 and -1.252). This is a significant drawback.

**hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.488 and 0.073).

**Microsomal Clearance:** Ligand A (-9.596) has much lower microsomal clearance than Ligand B (32.939), indicating better metabolic stability.

**In vitro Half-Life:** Ligand B (32.573) has a much longer in vitro half-life than Ligand A (0.357). This is a significant advantage.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.046 and 0.067).

**Binding Affinity:** Both ligands have very similar and strong binding affinities (-8.2 and -8.3 kcal/mol). The difference is negligible.

**Overall Assessment:**

Ligand B excels in BBB penetration and in vitro half-life, which are crucial for CNS drug development. Its QED score is also significantly better. However, it has a higher DILI risk and worse metabolic stability. Ligand A has a lower DILI risk and better metabolic stability, but its BBB penetration is poor.

Considering the GPCR-specific priorities, BBB is paramount for CNS targets. The substantial difference in BBB penetration (72.043 vs 46.413) outweighs the advantages of Ligand A in DILI and metabolic stability, especially given the similar binding affinities. While the solubility is poor for both, the longer half-life of ligand B could compensate for this.

Output:
1
2025-04-17 08:08:04,723 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (356.511 and 353.463 Da) fall within the ideal range of 200-500 Da.

**TPSA:** Ligand A (73.91) is significantly better than Ligand B (90.9). For CNS targets, we want TPSA <= 90, so Ligand A is preferable.

**logP:** Ligand A (0.859) is slightly better than Ligand B (-0.121). Both are a bit low, potentially impacting permeability, but Ligand A is closer to the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A (HBD=2, HBA=5) and Ligand B (HBD=3, HBA=5) are both acceptable.

**QED:** Both ligands have similar QED values (0.568 and 0.566), indicating good drug-likeness.

**DILI:** Ligand A (8.453) has a slightly higher DILI risk than Ligand B (6.747), but both are well below the concerning threshold of 60.

**BBB:** This is a critical parameter for a CNS target like DRD2. Ligand A (52.811) has a substantially better BBB percentile than Ligand B (39.55). A value >70 is desirable, and Ligand A is closer.

**Caco-2 Permeability:** Both have negative Caco-2 values (-5.597 and -5.133), which is unusual and suggests poor permeability.

**Aqueous Solubility:** Both have negative solubility values (-0.827 and -0.647), also unusual and suggesting poor solubility.

**hERG:** Both ligands have very low hERG inhibition liability (0.399 and 0.103), which is excellent.

**Microsomal Clearance:** Ligand A (-33.829) has much lower (better) microsomal clearance than Ligand B (7.417), indicating greater metabolic stability.

**In vitro Half-Life:** Ligand A (-4.439) has a negative half-life, which is unusual, but still better than Ligand B (19.352).

**P-gp Efflux:** Both have very low P-gp efflux liability (0.002 and 0.004), which is favorable for CNS penetration.

**Binding Affinity:** Ligand B (-7.9 kcal/mol) has a slightly better binding affinity than Ligand A (-7.3 kcal/mol). This is a 0.6 kcal/mol difference, which is significant but not overwhelming.

**Overall Assessment:**

While Ligand B has a slightly better binding affinity, Ligand A is superior overall, especially considering the GPCR-specific priorities. Ligand A has a significantly better TPSA, BBB, and microsomal clearance. The slightly better affinity of Ligand B is unlikely to overcome the substantial advantages of Ligand A in terms of CNS penetration and metabolic stability. The negative Caco-2 and solubility values are concerning for both, but these can potentially be addressed through formulation strategies.

Output:
1
2025-04-17 08:08:04,723 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (343.427 Da) is slightly lower, which could be beneficial for permeability. Ligand B (370.841 Da) is also acceptable.

**TPSA:** Ligand A (84.08) is excellent, falling well below the 90 A^2 threshold for CNS targets. Ligand B (122.47) is higher, but still potentially acceptable, though less ideal for CNS penetration.

**logP:** Ligand A (3.115) is optimal. Ligand B (1.802) is on the lower side of optimal, potentially hindering permeation.

**H-Bond Donors/Acceptors:** Ligand A (HBD=2, HBA=5) and Ligand B (HBD=3, HBA=7) both fall within acceptable ranges.

**QED:** Both ligands have reasonable QED values (A: 0.815, B: 0.547), suggesting good drug-like properties. Ligand A is superior here.

**DILI:** Ligand B (68.166) has a lower DILI risk than Ligand A (56.572), which is preferable.

**BBB:** Ligand B (71.656) has a better BBB percentile than Ligand A (51.919), which is crucial for a CNS target like DRD2.

**Caco-2 Permeability:** Ligand A (-4.847) has better Caco-2 permeability than Ligand B (-5.026), suggesting better intestinal absorption.

**Aqueous Solubility:** Ligand A (-4.727) has better aqueous solubility than Ligand B (-4.063).

**hERG Inhibition:** Ligand A (0.559) has a lower hERG inhibition liability than Ligand B (0.183), which is a positive safety indicator.

**Microsomal Clearance:** Ligand B (17.933) has significantly lower microsomal clearance than Ligand A (88.37), indicating better metabolic stability.

**In vitro Half-Life:** Ligand A (4.707) has a longer in vitro half-life than Ligand B (-4.383).

**P-gp Efflux:** Ligand A (0.103) has lower P-gp efflux liability than Ligand B (0.024), which is beneficial for CNS exposure.

**Binding Affinity:** Both ligands have excellent binding affinities (A: -9.2 kcal/mol, B: -8.8 kcal/mol). Ligand A is slightly more potent.

**Overall Assessment:**

Ligand A excels in TPSA, logP, QED, solubility, hERG, P-gp efflux, and binding affinity. Ligand B shines in BBB penetration and metabolic stability (lower Cl_mic). While BBB is critical for CNS targets, the substantial difference in binding affinity (-9.2 vs -8.8 kcal/mol) and the favorable ADME profile of Ligand A (especially the lower hERG risk and better solubility) outweigh the slightly lower BBB score. The affinity difference is significant enough to potentially overcome the BBB difference with appropriate formulation strategies.

Output:
1
2025-04-17 08:08:04,723 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (352.431 Da) is slightly lower, which could be beneficial for permeability. Ligand B (381.973 Da) is also acceptable.

**TPSA:** Ligand A (106.94) is better than Ligand B (45.23). For CNS targets, we want TPSA <= 90, and Ligand A is closer to that threshold. Ligand B is excellent.

**logP:** Ligand A (0.154) is quite low, potentially hindering membrane permeability. Ligand B (4.409) is high, potentially causing solubility issues and off-target effects. This is a significant drawback for Ligand B.

**H-Bond Donors/Acceptors:** Ligand A has 3 HBD and 5 HBA, which are acceptable. Ligand B has 1 HBD and 4 HBA, also acceptable.

**QED:** Both ligands have good QED scores (Ligand A: 0.566, Ligand B: 0.821), indicating drug-like properties. Ligand B is better.

**DILI:** Ligand A (22.102) has a much lower DILI risk than Ligand B (47.964). This is a significant advantage for Ligand A.

**BBB:** Ligand B (74.952) has a much better BBB penetration score than Ligand A (27.957). This is a crucial factor for a CNS target like DRD2, and heavily favors Ligand B.

**Caco-2 Permeability:** Both have negative Caco-2 values (-5.174 and -5.219). These values are unusual and suggest poor permeability.

**Aqueous Solubility:** Both have negative solubility values (-0.773 and -4.496), again suggesting poor solubility.

**hERG Inhibition:** Ligand A (0.036) has a very low hERG inhibition risk, while Ligand B (0.498) is slightly higher. Ligand A is preferable.

**Microsomal Clearance:** Ligand B (50.963) has a significantly higher microsomal clearance than Ligand A (3.656), indicating faster metabolism and potentially lower *in vivo* exposure. Ligand A is preferable.

**In vitro Half-Life:** Ligand B (11.989) has a longer half-life than Ligand A (6.936), which is generally desirable.

**P-gp Efflux:** Both ligands have a P-gp efflux liability of 0, which is ideal.

**Binding Affinity:** Ligand A (0) has a weaker binding affinity than Ligand B (0.689). Although both are not strong binders, Ligand B is better.

**Overall Assessment:**

Ligand B excels in BBB penetration and has a longer half-life, which are important for CNS targets. However, its high logP, higher DILI risk, and high microsomal clearance are concerning. Ligand A has a better safety profile (lower DILI, lower hERG, lower Cl_mic) and a more favorable TPSA. The biggest drawback for Ligand A is its low logP and BBB penetration. The negative Caco-2 and solubility values are concerning for both.

Given the GPCR-specific priorities, the BBB score is very important. Although Ligand A has better ADME properties overall, Ligand B's significantly higher BBB score is a major advantage. The binding affinity difference is not large enough to overcome the ADME concerns with Ligand B.

Output:
1
2025-04-17 08:08:04,723 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (349.431 and 352.431 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (111.45) is slightly higher than Ligand B (104.73). Both are below the 140 A^2 threshold for oral absorption, and closer to the 90 A^2 target for CNS penetration, but A is less desirable.

**3. logP:** Both ligands (0.477 and 0.502) are a bit low, potentially hindering permeation. Ideally, we'd like to see values between 1-3.

**4. H-Bond Donors:** Both have 3 HBD, which is within the acceptable limit of <=5.

**5. H-Bond Acceptors:** Both have 5 HBA, also within the acceptable limit of <=10.

**6. QED:** Both ligands have good QED scores (0.59 and 0.604), indicating good drug-like properties.

**7. DILI:** Ligand A (16.906) has a slightly better DILI score than Ligand B (19.232), indicating a lower risk of liver injury. Both are acceptable (<40 is good).

**8. BBB:** Ligand A (32.687) has a slightly better BBB percentile than Ligand B (31.408), but both are quite low. For a CNS target like DRD2, we ideally want >70. This is a significant weakness for both.

**9. Caco-2 Permeability:** Ligand A (-5.125) has worse Caco-2 permeability than Ligand B (-4.985). Lower values indicate poorer intestinal absorption.

**10. Aqueous Solubility:** Ligand A (-1.872) has better aqueous solubility than Ligand B (-2.403), which is a positive attribute.

**11. hERG Inhibition:** Both ligands show very low hERG inhibition liability (0.217 and 0.077), which is excellent.

**12. Microsomal Clearance:** Ligand A (-9.857) has a much lower (better) microsomal clearance than Ligand B (45.852). This suggests better metabolic stability for Ligand A.

**13. In vitro Half-Life:** Ligand A (31.594) has a significantly longer in vitro half-life than Ligand B (-8.3). This is a major advantage for Ligand A.

**14. P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.017 and 0.019), which is favorable for CNS penetration.

**15. Binding Affinity:** Ligand A (-7.2) has a slightly better binding affinity than Ligand B (-8.0). While both are good, the difference is not substantial enough to outweigh other factors.

**Overall Assessment:**

While both ligands have issues with logP and BBB penetration, Ligand A is the more promising candidate. It has better DILI, significantly better metabolic stability (lower Cl_mic and longer half-life), and slightly better binding affinity. The slightly better solubility also helps. The lower TPSA of Ligand B is not enough to compensate for its poor metabolic properties.

Output:
0
2025-04-17 08:08:04,724 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B based on the provided guidelines, prioritizing GPCR-specific properties (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (362.417) is slightly higher than Ligand B (349.431), but both are acceptable.

**TPSA:** Ligand A (59.08) is excellent for CNS penetration, well below the 90 A^2 threshold. Ligand B (104.46) is higher, but still potentially acceptable, though less ideal.

**logP:** Both ligands have good logP values (A: 1.39, B: 1.155), falling within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A (0 HBD, 4 HBA) is better than Ligand B (3 HBD, 5 HBA) in terms of balancing solubility and permeability.

**QED:** Both ligands have good QED scores (A: 0.687, B: 0.715), indicating good drug-like properties.

**DILI:** Ligand A (25.436) has a significantly lower DILI risk than Ligand B (34.82), placing it in a much more favorable range.

**BBB:** This is a crucial parameter for a CNS target like DRD2. Ligand A (85.498) has a very good BBB percentile, exceeding the desirable >70 threshold. Ligand B (38.077) is significantly lower and would likely result in poor CNS exposure.

**Caco-2 Permeability:** Ligand A (-4.269) and Ligand B (-5.383) both have negative Caco-2 values, which is unusual and suggests poor permeability. However, the scale is not specified, so it's difficult to interpret.

**Aqueous Solubility:** Both ligands have poor aqueous solubility (-1.415 and -1.285, respectively). This could present formulation challenges.

**hERG:** Both ligands have very low hERG inhibition risk (A: 0.579, B: 0.048).

**Microsomal Clearance:** Ligand A (24.918) has slightly higher microsomal clearance than Ligand B (20.225), suggesting slightly lower metabolic stability.

**In vitro Half-Life:** Ligand B (-8.683) has a longer in vitro half-life than Ligand A (-0.455), which is a positive attribute.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (A: 0.04, B: 0.038), which is favorable for CNS penetration.

**Binding Affinity:** Both ligands have excellent binding affinity (-8.2 and -8.7 kcal/mol). The difference of 0.5 kcal/mol is not substantial enough to outweigh the other significant differences.

**Conclusion:**

Ligand A is the more promising candidate. Its significantly better BBB penetration (85.5% vs 38.1%), lower DILI risk (25.4% vs 34.8%), and favorable TPSA (59.08 vs 104.46) outweigh the slightly higher microsomal clearance and shorter in vitro half-life. The similar binding affinities make these ADME properties the deciding factors.

Output:
1
2025-04-17 08:08:04,724 - INFO - Reasoning:

Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight (MW):** Both ligands (349.519 and 350.434 Da) fall comfortably within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (52.65) and Ligand B (51.66) are both below the 90 A^2 threshold for CNS targets, which is excellent.

**3. logP:** Both ligands have logP values within the optimal range (Ligand A: 2.548, Ligand B: 2.934, ideal is 1-3).

**4. H-Bond Donors (HBD):** Both ligands are acceptable (Ligand A: 1, Ligand B: 0), being less than or equal to 5.

**5. H-Bond Acceptors (HBA):** Both ligands are acceptable (Ligand A: 3, Ligand B: 4), being less than or equal to 10.

**6. QED:** Both ligands have similar and good QED values (Ligand A: 0.768, Ligand B: 0.759), indicating good drug-like properties.

**7. DILI:** Ligand A (4.653) has a very low DILI risk, significantly better than Ligand B (26.948). This is a substantial advantage.

**8. BBB:** Both ligands have excellent BBB penetration (Ligand A: 79.217, Ligand B: 85.149), exceeding the desirable >70 percentile for CNS targets. Ligand B is slightly better.

**9. Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and suggests poor permeability. However, the scale is not specified, so it's difficult to interpret.

**10. Aqueous Solubility:** Both have negative solubility values, which is also unusual and suggests poor solubility. Again, the scale is not specified.

**11. hERG Inhibition:** Both ligands show low hERG inhibition risk (Ligand A: 0.585, Ligand B: 0.607).

**12. Microsomal Clearance (Cl_mic):** Ligand A (-2.043) has much lower (better) microsomal clearance than Ligand B (41.249), indicating greater metabolic stability.

**13. In vitro Half-Life (t1/2):** Ligand A (-2.044) has a longer half-life than Ligand B (19.95), which is favorable.

**14. P-gp Efflux:** Both ligands have low P-gp efflux liability (Ligand A: 0.035, Ligand B: 0.157), which is good for CNS exposure. Ligand A is slightly better.

**15. Binding Affinity:** Ligand B (-7.2 kcal/mol) has a slightly better binding affinity than Ligand A (-8.2 kcal/mol). While the difference is not huge, it's a noticeable advantage.

**Overall Assessment:**

Ligand A is superior due to its significantly lower DILI risk, better metabolic stability (lower Cl_mic), longer half-life, and slightly lower P-gp efflux. While Ligand B has a slightly better binding affinity and BBB penetration, the ADME properties of Ligand A are much more favorable, especially the DILI score. For a CNS target, minimizing potential liver toxicity is crucial. The slightly stronger binding of Ligand B is unlikely to outweigh the ADME benefits of Ligand A.

Output:
0
2025-04-17 08:08:04,724 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (380.794 and 387.267 Da) are within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (68.29) is excellent, falling well below the 90 A^2 threshold for CNS targets. Ligand B (83.56) is still reasonable but less optimal, approaching the 90 A^2 limit.

**3. logP:** Ligand A (3.85) is at the higher end of the optimal range (1-3), while Ligand B (1.79) is at the lower end. While both are within range, higher logP can sometimes be beneficial for BBB penetration, but needs to be balanced with solubility.

**4. H-Bond Donors:** Ligand A (1) is good. Ligand B (2) is also acceptable.

**5. H-Bond Acceptors:** Ligand A (4) is good. Ligand B (5) is also acceptable.

**6. QED:** Both ligands (0.761 and 0.805) have excellent drug-likeness scores.

**7. DILI:** Ligand A (67.313) has a slightly higher DILI risk than Ligand B (62.466), but both are acceptable (below 60 is preferred, but both are below 70).

**8. BBB:** Ligand A (67.468) and Ligand B (71.035) both have good BBB penetration, but Ligand B is slightly better. For a CNS target like DRD2, this is a crucial factor.

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 values, which is unusual and indicates poor permeability. This is a significant drawback for both.

**10. Aqueous Solubility:** Both ligands have negative solubility values, which is also unusual and indicates poor solubility. This is a significant drawback for both.

**11. hERG Inhibition:** Both ligands have low hERG inhibition risk (0.282 and 0.358).

**12. Microsomal Clearance:** Ligand A (76.342) has a higher microsomal clearance than Ligand B (16.189), indicating lower metabolic stability. This is a significant negative for Ligand A.

**13. In vitro Half-Life:** Ligand B (24.063) has a significantly longer in vitro half-life than Ligand A (11.848). This is a major advantage for Ligand B.

**14. P-gp Efflux:** Ligand A (0.133) has a slightly higher P-gp efflux liability than Ligand B (0.024), but both are low.

**15. Binding Affinity:** Ligand A (-8.1 kcal/mol) has a significantly stronger binding affinity than Ligand B (-0.0 kcal/mol). This is a huge advantage for Ligand A.

**Overall Assessment:**

Despite the poor Caco-2 and solubility values for both, the significantly stronger binding affinity of Ligand A (-8.1 kcal/mol vs -0.0 kcal/mol) is a decisive factor. The affinity difference is so large it likely outweighs the drawbacks of slightly higher DILI and clearance. Ligand B has better BBB and half-life, but the weak binding affinity makes it unlikely to be effective.

Output:
1
2025-04-17 08:08:04,724 - INFO - Reasoning:

Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (374.388 and 347.459 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (83.98) is slightly higher than Ligand B (75.44). Both are below the 90 A^2 threshold desirable for CNS targets, but Ligand B is preferable.

**3. logP:** Both ligands have logP values (2.813 and 2.95) within the optimal 1-3 range.

**4. H-Bond Donors:** Ligand A (2) and Ligand B (1) both meet the HBD <=5 criteria. Ligand B is slightly better here.

**5. H-Bond Acceptors:** Ligand A (6) and Ligand B (4) both meet the HBA <=10 criteria. Ligand B is preferable.

**6. QED:** Both ligands have good QED scores (0.725 and 0.734), indicating drug-like properties.

**7. DILI:** Ligand A (70.88) has a higher DILI risk than Ligand B (43.234). This is a significant advantage for Ligand B.

**8. BBB:** Both ligands have good BBB penetration (63.474 and 71.733). Ligand B is slightly better, exceeding 70% which is desirable for CNS targets.

**9. Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual. However, the magnitude is similar (-5.184 vs -4.837) and doesn't strongly differentiate them.

**10. Aqueous Solubility:** Both have negative solubility values, indicating poor solubility. Ligand B (-2.622) is slightly better than Ligand A (-3.886).

**11. hERG Inhibition:** Both ligands show low hERG inhibition risk (0.767 and 0.386). Ligand B is preferable.

**12. Microsomal Clearance:** Ligand A (11.897) has lower microsomal clearance than Ligand B (71.734), suggesting better metabolic stability. This is a significant advantage for Ligand A.

**13. In vitro Half-Life:** Ligand A (72.126) has a significantly longer half-life than Ligand B (-22.077). This is a major advantage for Ligand A.

**14. P-gp Efflux:** Both ligands have low P-gp efflux liability (0.341 and 0.485).

**15. Binding Affinity:** Both ligands have excellent binding affinities (-8.8 and -8.2 kcal/mol). Ligand A is slightly stronger.

**Overall Assessment:**

While Ligand A has a slightly better binding affinity, longer half-life, and better metabolic stability, Ligand B demonstrates a significantly lower DILI risk and slightly better BBB penetration, TPSA, HBD/HBA, and hERG inhibition. Given the CNS target and the importance of minimizing toxicity (DILI) and maximizing brain exposure (BBB), Ligand B appears to be the more promising candidate. The difference in binding affinity (0.6 kcal/mol) is not large enough to overcome the superior safety and pharmacokinetic profile of Ligand B.

Output:
1
2025-04-17 08:08:04,725 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight (MW):** Both ligands are within the ideal range (200-500 Da). Ligand A (342.443) is slightly lower than Ligand B (369.527), which is generally favorable for permeability.

**2. TPSA:** Both ligands have TPSA values (A: 69.04, B: 72.47) below the 90 A^2 threshold for CNS targets, which is good.

**3. logP:** Both ligands have logP values within the optimal range (1-3), with Ligand A (2.477) being slightly better than Ligand B (3.566). Higher logP can sometimes lead to off-target effects, so A is slightly favored here.

**4. H-Bond Donors (HBD):** Both ligands have 1 HBD, which is within the acceptable limit of 5.

**5. H-Bond Acceptors (HBA):** Ligand A has 5 HBA, and Ligand B has 4 HBA, both are within the acceptable limit of 10.

**6. QED:** Both ligands have QED values above 0.5 (A: 0.8, B: 0.76), indicating good drug-like properties.

**7. DILI:** Ligand A (16.285) has a significantly lower DILI risk than Ligand B (67.39). This is a major advantage for Ligand A.

**8. BBB:** Ligand A (57.852) has a lower BBB penetration percentile than Ligand B (62.854). While both are not ideal (>70), Ligand B is slightly better for CNS penetration.

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.746 and -4.684), which is unusual and suggests poor permeability. However, these values are on the same scale, so it doesn't differentiate the two.

**10. Aqueous Solubility:** Both ligands have negative solubility values (-1.927 and -3.186), suggesting poor aqueous solubility. Again, similar and doesn't differentiate.

**11. hERG Inhibition:** Both ligands have low hERG inhibition risk (A: 0.37, B: 0.513).

**12. Microsomal Clearance:** Ligand A (51.729) has a higher microsomal clearance than Ligand B (39.284), indicating lower metabolic stability. This favors Ligand B.

**13. In vitro Half-Life:** Ligand B (66.22) has a significantly longer in vitro half-life than Ligand A (-10.158), which is a substantial advantage.

**14. P-gp Efflux:** Both ligands have low P-gp efflux liability (A: 0.089, B: 0.328), which is good for CNS exposure. Ligand A is slightly better.

**15. Binding Affinity:** Ligand B (-8.8 kcal/mol) has a slightly better binding affinity than Ligand A (-8.3 kcal/mol), although the difference is relatively small.

**Overall Assessment:**

Considering the GPCR-specific priorities, Ligand A is favored despite the slightly lower binding affinity. The significantly lower DILI risk is a major advantage. While Ligand B has slightly better BBB penetration and in vitro half-life, the DILI risk is concerning. The similar Caco-2 and solubility values don't sway the decision. The small difference in binding affinity is outweighed by the safety profile.

Output:
0
2025-04-17 08:08:04,725 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (345.403 Da) is slightly lower, which could be beneficial for permeability, while Ligand B (364.433 Da) is also well within the range.

**TPSA:** Ligand A (101.22) is slightly above the optimal <90 for CNS targets, but still reasonable. Ligand B (76.66) is excellent, well below 90, suggesting better CNS penetration potential.

**logP:** Both ligands have good logP values (A: 1.414, B: 1.873), falling within the 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A has 1 HBD and 6 HBA, which are acceptable. Ligand B has 2 HBD and 4 HBA, also acceptable.

**QED:** Ligand A (0.849) has a significantly higher QED score than Ligand B (0.655), indicating a more drug-like profile overall.

**DILI:** Both ligands have low DILI risk (A: 49.981, B: 38.736), both well below the 60 threshold. Ligand B is slightly better here.

**BBB:** Ligand B (82.241) has a much higher BBB percentile than Ligand A (58.938). This is a *critical* advantage for a CNS target like DRD2.

**Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and difficult to interpret without knowing the scale. However, we can assume they are both low permeability.

**Aqueous Solubility:** Both have negative solubility values, which is also unusual and suggests poor solubility.

**hERG:** Both ligands have low hERG inhibition liability (A: 0.262, B: 0.436), which is good.

**Microsomal Clearance:** Ligand A (39.496) has higher microsomal clearance than Ligand B (30.075), suggesting lower metabolic stability.

**In vitro Half-Life:** Ligand B (-8.785) has a longer in vitro half-life than Ligand A (5.037), which is preferable.

**P-gp Efflux:** Ligand A (0.017) has very low P-gp efflux liability, which is excellent. Ligand B (0.089) also has low P-gp efflux, but higher than A.

**Binding Affinity:** Ligand A (-8.2 kcal/mol) has slightly weaker binding affinity than Ligand B (-7.5 kcal/mol). However, the difference is less than 0.7 kcal/mol, so this is not a decisive factor.

**Overall Assessment:**

Ligand B is the stronger candidate. While Ligand A has a better QED and slightly lower P-gp efflux, Ligand B's significantly higher BBB penetration (82.241 vs 58.938) is the most important factor for a CNS-targeting drug. The better half-life and lower clearance also contribute to its favorability. The TPSA is also significantly better for Ligand B. The slight difference in binding affinity is less important than the ADME properties.

Output:
1
2025-04-17 08:08:04,725 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (352.391 and 352.469 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (105.92) is better than Ligand B (33.2). For CNS targets, we want TPSA <= 90, and A is closer to this threshold. B is very low, which *could* indicate good BBB penetration, but might also suggest reduced binding affinity due to lack of polar interactions.

**logP:** Ligand A (-1.206) is suboptimal, being below the preferred 1-3 range. Ligand B (4.57) is too high, potentially causing solubility and off-target issues.

**H-Bond Donors/Acceptors:** Ligand A (2 HBD, 7 HBA) is reasonable. Ligand B (0 HBD, 2 HBA) is also acceptable, but the lack of HBDs might impact solubility.

**QED:** Both ligands (0.666 and 0.72) have good drug-likeness scores.

**DILI:** Ligand A (50.291) has a moderate DILI risk, while Ligand B (11.943) has a very low risk. This favors Ligand B.

**BBB:** Ligand B (95.463) is excellent, exceeding the desirable >70% threshold for CNS targets. Ligand A (45.715) is significantly lower and less favorable. This is a major advantage for Ligand B.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.17 and -4.279). This is unusual and suggests poor permeability.

**Aqueous Solubility:** Both ligands have negative solubility values (-0.499 and -4.393). This is also unusual and suggests poor solubility.

**hERG:** Ligand A (0.109) has a very low hERG risk, while Ligand B (0.835) has a slightly elevated risk. This favors Ligand A.

**Microsomal Clearance:** Ligand B (66.065) has a higher clearance than Ligand A (4.263), indicating lower metabolic stability. This favors Ligand A.

**In vitro Half-Life:** Ligand A (36.135) has a longer half-life than Ligand B (12.957). This favors Ligand A.

**P-gp Efflux:** Ligand A (0.031) has very low P-gp efflux, which is good for CNS penetration. Ligand B (0.215) has a slightly higher efflux, which is less desirable. This favors Ligand A.

**Binding Affinity:** Ligand B (-7.2 kcal/mol) has a significantly stronger binding affinity than Ligand A (-8.5 kcal/mol). This is a substantial advantage for Ligand B, potentially outweighing some of its ADME drawbacks.

**Overall Assessment:**

Ligand B excels in BBB penetration and binding affinity, which are critical for a CNS GPCR target like DRD2. However, it suffers from a high logP and higher microsomal clearance. Ligand A has better ADME properties (lower logP, better metabolic stability, lower P-gp efflux, longer half-life) but weaker binding affinity.

The difference in binding affinity (-7.2 vs -8.5 kcal/mol) is significant. A 1.3 kcal/mol advantage can often justify optimizing around ADME liabilities. The excellent BBB penetration of Ligand B is also a major plus. While the high logP is a concern, it might be addressable through structural modifications.

Output:
1
2025-04-17 08:08:04,726 - INFO - Okay, let's analyze these two ligands for their potential as DRD2 drug candidates. DRD2 is a GPCR in the CNS, so BBB penetration, logP, Pgp efflux, TPSA, and binding affinity are paramount.

**Ligand A: [340.427, 67.23, 1.827, 1, 5, 0.902, 61.07, 75.107, -4.983, -3.456, 0.592, 48.176, -6.87, 0.211, -8.7]**

*   **MW:** 340.427 Da - Good, within the ideal range.
*   **TPSA:** 67.23  - Acceptable, but pushing the upper limit for CNS targets (ideally <90).
*   **logP:** 1.827 - Excellent, within the optimal range.
*   **HBD:** 1 - Good.
*   **HBA:** 5 - Good.
*   **QED:** 0.902 - Excellent, very drug-like.
*   **DILI:** 61.07 - Moderate risk, but acceptable.
*   **BBB:** 75.107 - Good, above the 70% threshold for CNS targets.
*   **Caco-2:** -4.983 - Poor permeability.
*   **Solubility:** -3.456 - Poor solubility.
*   **hERG:** 0.592 - Low risk.
*   **Cl_mic:** 48.176 mL/min/kg - Moderate clearance, could be better.
*   **t1/2:** -6.87 hours - Short half-life, a concern.
*   **Pgp:** 0.211 - Low efflux, favorable.
*   **Affinity:** -8.7 kcal/mol - Excellent binding affinity.

**Ligand B: [370.362, 49.41, 2.973, 1, 2, 0.774, 19.62, 93.098, -4.669, -3.129, 0.609, 6.292, -22.928, 0.033, -9.2]**

*   **MW:** 370.362 Da - Good, within the ideal range.
*   **TPSA:** 49.41 - Excellent, well within the ideal range for CNS targets.
*   **logP:** 2.973 - Excellent, within the optimal range.
*   **HBD:** 1 - Good.
*   **HBA:** 2 - Good.
*   **QED:** 0.774 - Good, drug-like.
*   **DILI:** 19.62 - Very low risk.
*   **BBB:** 93.098 - Excellent, very high BBB penetration.
*   **Caco-2:** -4.669 - Poor permeability.
*   **Solubility:** -3.129 - Poor solubility.
*   **hERG:** 0.609 - Low risk.
*   **Cl_mic:** 6.292 mL/min/kg - Very low clearance, excellent metabolic stability.
*   **t1/2:** -22.928 hours - Very long half-life, a significant advantage.
*   **Pgp:** 0.033 - Very low efflux, highly favorable.
*   **Affinity:** -9.2 kcal/mol - Exceptional binding affinity, 0.5 kcal/mol better than Ligand A.

**Comparison and Decision:**

Both ligands have good MW, logP, HBD/HBA counts, and low hERG risk. Ligand B has a significantly better BBB score (93.098 vs 75.107), a much lower DILI risk (19.62 vs 61.07), a drastically improved metabolic stability (Cl_mic of 6.292 vs 48.176) and a significantly longer half-life (-22.928 vs -6.87). Most importantly, Ligand B's binding affinity is 0.5 kcal/mol stronger than Ligand A. While both have poor Caco-2 and solubility, these can potentially be addressed with formulation strategies. Given the CNS target and the importance of BBB penetration and metabolic stability, Ligand B is the superior candidate. The 0.5 kcal/mol difference in binding affinity, combined with the substantial improvements in ADME properties, outweigh the formulation challenges.

Output:
1
2025-04-17 08:08:04,726 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (350.369 and 352.406 Da) fall comfortably within the ideal 200-500 Da range.

**2. TPSA:** Both ligands have TPSA values (67.23 and 67.87) slightly above the optimal <90 for CNS targets, but still reasonable.

**3. logP:** Both ligands have logP values (2.28 and 2.039) within the optimal 1-3 range.

**4. H-Bond Donors:** Both ligands have 1 HBD, which is within the acceptable limit of <=5.

**5. H-Bond Acceptors:** Both ligands have 4 HBA, also within the acceptable limit of <=10.

**6. QED:** Both ligands have QED values (0.9 and 0.842) indicating strong drug-like properties.

**7. DILI:** Both ligands have DILI percentiles (61.07 and 60.217) which are acceptable, being just above the 60 threshold but not dramatically so.

**8. BBB:** This is a critical parameter for a CNS target like DRD2. Ligand A has a BBB percentile of 83.482, while Ligand B has 67.507. Ligand A is significantly better in terms of predicted BBB penetration.

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.442 and -4.349), which is unusual and suggests poor permeability. However, these values are on a log scale, and the absolute difference is small.

**10. Aqueous Solubility:** Both ligands have negative solubility values (-2.812 and -2.063), which is also unusual and suggests poor solubility. Again, the difference is small.

**11. hERG Inhibition:** Both ligands have low hERG inhibition liability (0.587 and 0.217), which is favorable.

**12. Microsomal Clearance:** Both ligands have similar microsomal clearance values (40.1 and 43.937 mL/min/kg), indicating moderate metabolic stability.

**13. In vitro Half-Life:** Ligand A has a longer in vitro half-life (37.623 hours) compared to Ligand B (1.464 hours). This is a significant advantage.

**14. P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.149 and 0.063), which is excellent.

**15. Binding Affinity:** Ligand A has a significantly stronger binding affinity (-8.5 kcal/mol) compared to Ligand B (0.0 kcal/mol). This is a crucial difference.

**Overall Assessment:**

Ligand A is clearly superior. The most important factors are its significantly better BBB penetration (83.482 vs 67.507) and dramatically improved binding affinity (-8.5 vs 0.0 kcal/mol). The longer half-life also contributes positively. While both have some ADME concerns (negative Caco-2 and solubility), the potency and BBB advantages of Ligand A outweigh these concerns, especially for a CNS target.

Output:
1
2025-04-17 08:08:04,726 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (348.447 and 350.434 Da) fall comfortably within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (68.62) is slightly higher than Ligand B (58.64). Both are below the 90 A^2 threshold desirable for CNS targets, but Ligand B is preferable.

**3. logP:** Both ligands have excellent logP values (1.945 and 1.824), falling within the optimal 1-3 range.

**4. H-Bond Donors:** Both have 1 HBD, which is within the acceptable limit of <=5.

**5. H-Bond Acceptors:** Ligand A has 5 HBA, and Ligand B has 3 HBA. Both are below the acceptable limit of <=10.

**6. QED:** Ligand A (0.883) has a better QED score than Ligand B (0.744), indicating a more drug-like profile.

**7. DILI:** Both ligands have low DILI risk (26.057 and 29.159 percentile), which is good.

**8. BBB:** Both ligands exhibit excellent BBB penetration (94.61 and 93.098 percentile), which is critical for a CNS target like DRD2.

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.527 and -4.524). This is unusual and suggests a potential issue with permeability prediction. However, since both are similar, it doesn't differentiate them.

**10. Aqueous Solubility:** Both ligands have negative solubility values (-2.036 and -2.848). Similar to Caco-2, this is unusual and suggests prediction issues, but doesn't differentiate them.

**11. hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.168 and 0.443 percentile), which is excellent.

**12. Microsomal Clearance:** Ligand A (1.196 mL/min/kg) has significantly lower microsomal clearance than Ligand B (39.571 mL/min/kg), indicating better metabolic stability.

**13. In vitro Half-Life:** Ligand A (16.86 hours) has a much longer half-life than Ligand B (-17.455 hours). The negative value for Ligand B is problematic and suggests a very rapid degradation.

**14. P-gp Efflux:** Both ligands have low P-gp efflux liability (0.049 and 0.193 percentile), which is favorable for CNS exposure.

**15. Binding Affinity:** Both ligands have very strong binding affinities (-9.1 and -8.9 kcal/mol). The difference of 0.2 kcal/mol is not substantial enough to outweigh other factors.

**Overall Assessment:**

Ligand A is clearly superior. While both ligands have excellent affinity and BBB penetration, Ligand A has a better QED score, significantly lower microsomal clearance (better metabolic stability), and a much longer in-vitro half-life. The negative values for Caco-2 and solubility are concerning for both, but are similar. The improved metabolic stability and half-life of Ligand A are crucial for *in vivo* efficacy and make it the more promising drug candidate.

Output:
1
2025-04-17 08:08:04,726 - INFO - Batch 423 complete. Total preferences: 6768
2025-04-17 08:08:04,726 - INFO - Processing batch 424/512...
2025-04-17 08:08:48,062 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (348.4 and 345.4 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (99.1) is slightly higher than Ligand B (82.53). For CNS targets, we prefer TPSA <= 90, so Ligand B is better here.

**3. logP:** Ligand A (0.655) is lower than the optimal 1-3 range, potentially hindering permeation. Ligand B (2.419) is within the optimal range. This favors Ligand B.

**4. H-Bond Donors:** Ligand A (3) is acceptable, while Ligand B (2) is even better, being closer to the ideal.

**5. H-Bond Acceptors:** Ligand A (6) is acceptable, and Ligand B (4) is also good.

**6. QED:** Both ligands have good QED scores (0.676 and 0.776, respectively), indicating drug-like properties. Ligand B is slightly better.

**7. DILI:** Ligand A (25.165) has a significantly lower DILI risk than Ligand B (41.915). This is a strong advantage for Ligand A.

**8. BBB:** Ligand A (58.24) and Ligand B (53.742) both have BBB penetration below the desirable 70% threshold for CNS targets. However, Ligand A is slightly better.

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.851 and -4.948), which is unusual and suggests poor permeability. This is a concern for both.

**10. Aqueous Solubility:** Both ligands have negative solubility values (-2.051 and -3.471), indicating very poor aqueous solubility. This is a significant drawback for both.

**11. hERG Inhibition:** Both ligands show low hERG inhibition risk (0.358 and 0.284), which is good.

**12. Microsomal Clearance:** Ligand A (-45.312) has a much lower (better) microsomal clearance than Ligand B (30.332), indicating greater metabolic stability.

**13. In vitro Half-Life:** Ligand B (-28.455) has a longer in vitro half-life than Ligand A (6.652), which is generally desirable.

**14. P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.037 and 0.088), which is favorable for CNS penetration.

**15. Binding Affinity:** Both ligands have excellent binding affinity (-8.4 and -8.7 kcal/mol). Ligand B is slightly better.

**Overall Assessment:**

While Ligand B has better logP, QED, and half-life, Ligand A has a significantly lower DILI risk and better metabolic stability (lower Cl_mic). Both have poor solubility and permeability. Given the importance of metabolic stability and minimizing toxicity (DILI) for a CNS drug, and the similar binding affinities, Ligand A appears to be the more promising candidate. The slightly better BBB penetration of Ligand A also contributes to this decision.

Output:
0
2025-04-17 08:08:48,062 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (342.49 & 363.44 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (48.47) is excellent, well below the 90 A^2 threshold for CNS targets. Ligand B (92.51) is higher, approaching the upper limit for good oral absorption (140) but less ideal for CNS penetration.

**3. logP:** Ligand A (2.7) is within the optimal 1-3 range. Ligand B (1.024) is slightly low, potentially hindering permeation.

**4. H-Bond Donors:** Both ligands have 1 HBD, which is acceptable.

**5. H-Bond Acceptors:** Ligand A has 4 HBA, and Ligand B has 6 HBA, both within the acceptable limit of <=10.

**6. QED:** Both ligands have good QED scores (0.836 and 0.859), indicating good drug-like properties.

**7. DILI:** Both ligands have moderate DILI risk (50.76 and 59.13), but are still below the concerning 60 threshold.

**8. BBB:** This is crucial for a CNS target. Ligand A has a significantly better BBB penetration percentile (84.92) than Ligand B (71.23). Ligand A is well above the 70% desirable threshold.

**9. Caco-2 Permeability:** Ligand A (-4.781) and Ligand B (-5.141) both have negative Caco-2 values, which is unusual and suggests poor permeability. However, the scale isn't specified, so it's hard to interpret.

**10. Aqueous Solubility:** Both ligands have very poor aqueous solubility (-2.232 and -3.497). This is a significant drawback.

**11. hERG Inhibition:** Ligand A (0.852) has a slightly higher hERG risk than Ligand B (0.06), but both are relatively low.

**12. Microsomal Clearance:** Ligand A (36.71) has a higher microsomal clearance than Ligand B (21.98), indicating lower metabolic stability.

**13. In vitro Half-Life:** Ligand B (-19.164) has a very negative half-life, which is concerning and likely indicates rapid degradation. Ligand A (8.589) has a more reasonable half-life.

**14. P-gp Efflux:** Ligand A (0.321) has lower P-gp efflux liability than Ligand B (0.087), which is favorable for CNS exposure.

**15. Binding Affinity:** Ligand A (-9.5 kcal/mol) has a significantly stronger binding affinity than Ligand B (-7.7 kcal/mol). This >1.5 kcal/mol difference is substantial and can outweigh other drawbacks.

**Overall Assessment:**

Ligand A is the stronger candidate. While both have solubility issues, Ligand A excels in the most critical areas for a CNS-targeting GPCR: BBB penetration, binding affinity, and P-gp efflux. Its half-life is also better than Ligand B. The higher TPSA of Ligand B and lower logP are less desirable. The affinity difference is significant enough to overcome Ligand A's slightly higher DILI and clearance.

Output:
1
2025-04-17 08:08:48,062 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the acceptable range (200-500 Da). Ligand A (338.323 Da) is slightly preferred as it's closer to the ideal range.

**TPSA:** Ligand B (89.43) is better than Ligand A (110.15). For CNS targets, TPSA should be <=90, so Ligand B is within the desired range, while Ligand A is slightly above.

**logP:** Both ligands have good logP values (A: 2.796, B: 1.519) falling within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Both ligands have 2 HBD and 5 HBA, which are within acceptable limits.

**QED:** Both ligands have similar QED values (A: 0.563, B: 0.592), indicating good drug-likeness.

**DILI:** Ligand B (77.898) has a significantly lower DILI risk than Ligand A (92.788). This is a substantial advantage for Ligand B.

**BBB:** Ligand A (59.325) has a better BBB penetration percentile than Ligand B (35.401). This is a critical factor for a CNS target like DRD2.

**Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and suggests poor permeability. However, these values are on a different scale and difficult to interpret without further context.

**Aqueous Solubility:** Both have negative solubility values, again unusual and hard to interpret.

**hERG Inhibition:** Both ligands show very low hERG inhibition liability (A: 0.477, B: 0.474), which is excellent.

**Microsomal Clearance:** Ligand B (51.37) has a higher microsomal clearance than Ligand A (37.89), suggesting faster metabolism and potentially lower *in vivo* exposure.

**In vitro Half-Life:** Ligand A (38.355) has a longer in vitro half-life than Ligand B (10.155), which is preferable.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (A: 0.213, B: 0.371), which is good.

**Binding Affinity:** Ligand B (-8.4 kcal/mol) has a significantly stronger binding affinity than Ligand A (-10.1 kcal/mol). This is a major advantage, potentially outweighing some of the ADME drawbacks.

**Overall Assessment:**

While Ligand A has better BBB penetration and a longer half-life, Ligand B's significantly stronger binding affinity (-8.4 vs -10.1 kcal/mol) and lower DILI risk are crucial advantages. The TPSA of Ligand B is also more favorable. The lower BBB and higher clearance of Ligand B are concerns, but the substantial affinity difference is likely to be more impactful for *in vivo* efficacy. For a GPCR target, strong binding is paramount, and the other properties can potentially be optimized in subsequent iterations.

Output:
1
2025-04-17 08:08:48,063 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (358.295 Da and 342.399 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (71.26) is significantly better than Ligand B (78.53). For CNS targets, we want TPSA <= 90, and A is closer to the optimal <=60 range. B is approaching the upper limit.

**3. logP:** Both ligands have good logP values (2.816 and 1.391), falling within the 1-3 range. Ligand A is slightly better.

**4. H-Bond Donors:** Both have 1 HBD, which is acceptable.

**5. H-Bond Acceptors:** Ligand A has 5 HBA, and Ligand B has 4. Both are within the acceptable limit of <=10.

**6. QED:** Both ligands have similar QED values (0.833 and 0.824), indicating good drug-likeness.

**7. DILI:** Ligand A (83.715) has a higher DILI risk than Ligand B (68.088). This is a negative for A.

**8. BBB:** Ligand A (85.459) has a significantly better BBB penetration percentile than Ligand B (65.413). This is a *critical* advantage for a CNS target like DRD2.

**9. Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and suggests poor permeability. However, the scale is not specified, so we can't definitively say which is worse.

**10. Aqueous Solubility:** Both have negative solubility values, suggesting poor solubility. Again, the scale is unspecified.

**11. hERG:** Both ligands have very low hERG inhibition liability (0.296 and 0.279), which is excellent.

**12. Microsomal Clearance:** Ligand B (59.315) has lower microsomal clearance than Ligand A (37.851), indicating better metabolic stability. This is a positive for B.

**13. In vitro Half-Life:** Ligand B (-13.926) has a significantly longer in vitro half-life than Ligand A (1.375). This is a major advantage for B.

**14. P-gp Efflux:** Ligand B (0.11) has lower P-gp efflux liability than Ligand A (0.132), which is preferable for CNS penetration.

**15. Binding Affinity:** Ligand A (-9.6 kcal/mol) has a *much* stronger binding affinity than Ligand B (-0.0 kcal/mol). This is a massive advantage for A. A difference of >1.5 kcal/mol can outweigh other ADME drawbacks.

**Overall Assessment:**

Despite Ligand A's higher DILI risk, its significantly superior binding affinity (-9.6 vs -0.0 kcal/mol) and better BBB penetration (85.459 vs 65.413) are decisive. The strong binding affinity suggests a higher probability of achieving efficacy, and the good BBB penetration is crucial for a CNS target. While Ligand B has better metabolic stability and P-gp efflux, the potency difference is too large to ignore. The TPSA is also better for Ligand A.

Output:
1
2025-04-17 08:08:48,063 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (349.519 Da) is slightly preferred as it's closer to the lower end, potentially aiding permeability.

**TPSA:** Ligand A (52.65) is significantly better than Ligand B (99.6). For CNS targets, TPSA should be <=90, and A is comfortably within this range, while B is approaching the upper limit. This is a substantial advantage for A.

**logP:** Both ligands have acceptable logP values (A: 2.262, B: 1.098), falling within the 1-3 range. B is slightly lower, which *could* indicate a potential issue with membrane permeability, but it's not a major concern.

**H-Bond Donors/Acceptors:** Ligand A (HBD=1, HBA=3) is better than Ligand B (HBD=2, HBA=6) in terms of balancing solubility and permeability. Fewer H-bonds generally improve permeability.

**QED:** Ligand A (0.767) has a much better QED score than Ligand B (0.512), indicating a more drug-like profile.

**DILI:** Ligand A (7.057) has a significantly lower DILI risk than Ligand B (67.507). This is a major advantage for A.

**BBB:** Ligand A (82.9) has a substantially higher BBB penetration percentile than Ligand B (19.736). This is *critical* for a CNS target like DRD2, making A far more promising.

**Caco-2 Permeability:** Ligand A (-4.797) is better than Ligand B (-5.505), indicating better intestinal absorption.

**Aqueous Solubility:** Both ligands have similar, poor aqueous solubility (-2.442 and -2.724 respectively). This could pose formulation challenges for both.

**hERG Inhibition:** Ligand A (0.675) has a slightly lower hERG inhibition liability than Ligand B (0.293), which is preferable.

**Microsomal Clearance:** Ligand A (44.33) has a higher (worse) microsomal clearance than Ligand B (32.711), suggesting faster metabolism.

**In vitro Half-Life:** Ligand A (-14.955) has a much shorter in vitro half-life than Ligand B (-26.239), indicating faster degradation.

**P-gp Efflux:** Ligand A (0.086) has a lower P-gp efflux liability than Ligand B (0.129), which is beneficial for CNS exposure.

**Binding Affinity:** Ligand A (-8.2 kcal/mol) has a slightly better binding affinity than Ligand B (-7.6 kcal/mol). While both are good, the 0.6 kcal/mol difference is noticeable.

**Overall Assessment:**

Ligand A clearly outperforms Ligand B across most critical parameters for a CNS-targeting GPCR. Its superior BBB penetration, lower DILI risk, better TPSA, QED, and slightly better affinity are decisive advantages. While Ligand A has a higher microsomal clearance and shorter half-life, these can potentially be addressed through structural modifications. Ligand B's poor BBB penetration is a significant drawback for a CNS drug.

Output:
1
2025-04-17 08:08:48,063 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 drug candidates, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (351.491 and 358.551 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (78.51) is better than Ligand B (32.34). For CNS targets, we want TPSA <= 90, both meet this, but A is closer to the upper limit while B is much lower. Lower TPSA generally improves BBB penetration.

**3. logP:** Ligand A (1.833) is within the optimal 1-3 range. Ligand B (4.73) is higher, potentially causing solubility issues and off-target interactions.

**4. H-Bond Donors:** Both have acceptable HBD counts (2 and 1, respectively), well below the limit of 5.

**5. H-Bond Acceptors:** Both have acceptable HBA counts (3 each), well below the limit of 10.

**6. QED:** Both ligands have good QED values (0.7 and 0.789), indicating good drug-like properties.

**7. DILI:** Ligand A (15.394) has a significantly lower DILI risk than Ligand B (31.291). This is a substantial advantage.

**8. BBB:** Ligand B (92.361) has a much higher BBB percentile than Ligand A (69.872). This is a critical factor for a CNS target like DRD2.

**9. Caco-2 Permeability:** Both have negative Caco-2 values (-5.134 and -5.412). This is unusual and suggests poor permeability. However, the values are close, so this isn't a major differentiator.

**10. Aqueous Solubility:** Ligand A (-1.938) has better solubility than Ligand B (-4.71). This is important given Ligand B's higher logP.

**11. hERG Inhibition:** Ligand A (0.161) has a lower hERG inhibition risk than Ligand B (0.752).

**12. Microsomal Clearance:** Ligand B (66.539) has lower microsomal clearance than Ligand A (15.263), suggesting better metabolic stability.

**13. In vitro Half-Life:** Ligand B (33.097) has a much longer half-life than Ligand A (3.166). This is a significant advantage.

**14. P-gp Efflux:** Ligand A (0.02) has lower P-gp efflux than Ligand B (0.642), which is favorable for CNS penetration.

**15. Binding Affinity:** Ligand B (-7.9 kcal/mol) has a slightly better binding affinity than Ligand A (-7.3 kcal/mol). This 0.6 kcal/mol difference is noteworthy, but not overwhelming.

**Overall Assessment:**

Ligand B excels in BBB penetration and in vitro half-life, and has slightly better binding affinity. However, it suffers from a higher logP, increased DILI risk, higher P-gp efflux, and worse solubility. Ligand A has a much better safety profile (lower DILI, hERG), better solubility, lower P-gp efflux, and a more favorable TPSA.

Given the GPCR-specific priorities, the improved BBB of Ligand B is attractive. However, the combination of a significantly lower DILI risk, better solubility, and lower P-gp efflux for Ligand A, coupled with a reasonable BBB score, makes it the more promising candidate. The slightly weaker binding affinity of Ligand A can likely be optimized in subsequent iterations.

Output:
0
2025-04-17 08:08:48,063 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (353.419 and 356.535 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (104.9) is better than Ligand B (36.36). For CNS targets, we want TPSA <= 90, so Ligand A is closer to this threshold. Ligand B is quite low, which *could* indicate issues with binding or selectivity, although it's not a hard failure.

**3. logP:** Ligand A (0.515) is suboptimal, being below the preferred 1-3 range. Ligand B (4.481) is too high, potentially leading to solubility issues and off-target interactions.

**4. H-Bond Donors:** Ligand A (2) and Ligand B (1) are both acceptable (<=5).

**5. H-Bond Acceptors:** Ligand A (6) and Ligand B (4) are both acceptable (<=10).

**6. QED:** Both ligands have similar QED values (0.74 and 0.743), indicating good drug-like properties.

**7. DILI:** Ligand A (27.065) has a significantly lower DILI risk than Ligand B (11.09). This is a major advantage for Ligand A.

**8. BBB:** Ligand B (69.407) has a much better BBB penetration percentile than Ligand A (49.011). For a CNS target like DRD2, >70 is desirable, so neither is ideal, but Ligand B is considerably better.

**9. Caco-2 Permeability:** Ligand A (-4.596) has a negative Caco-2 value, which is concerning, indicating poor permeability. Ligand B (-5.111) is also poor, but similar to A.

**10. Aqueous Solubility:** Ligand A (-1.5) and Ligand B (-3.243) both have negative solubility values, indicating poor solubility.

**11. hERG Inhibition:** Ligand A (0.255) has a lower hERG inhibition liability than Ligand B (0.938), which is preferable.

**12. Microsomal Clearance:** Ligand B (41.485) has a slightly lower (better) microsomal clearance than Ligand A (35.09), suggesting better metabolic stability.

**13. In vitro Half-Life:** Ligand B (32.559) has a longer half-life than Ligand A (-6.659), which is desirable.

**14. P-gp Efflux:** Ligand A (0.012) has significantly lower P-gp efflux liability than Ligand B (0.692). This is a crucial advantage for CNS penetration.

**15. Binding Affinity:** Both ligands have the same binding affinity (-7.6 kcal/mol), which is excellent.

**Overall Assessment:**

Ligand B has a better BBB and in vitro half-life, but suffers from a higher logP, higher DILI risk, and higher P-gp efflux. Ligand A has a better TPSA, lower DILI, lower hERG, and significantly lower P-gp efflux, but has a poor logP and Caco-2 permeability.

Given the GPCR-specific priorities, BBB and P-gp efflux are critical. While Ligand B has a better BBB, Ligand A's dramatically lower P-gp efflux is a significant advantage for CNS exposure. The lower DILI risk for Ligand A is also a strong positive. The poor logP of Ligand A could potentially be addressed with medicinal chemistry modifications, whereas the high logP of Ligand B is a more challenging property to improve without impacting binding. The poor Caco-2 permeability of A is a concern, but less critical for a CNS target.

Output:
0
2025-04-17 08:08:48,063 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (368.5 and 366.5 Da) fall comfortably within the ideal 200-500 Da range.

**TPSA:** Ligand A (67.87) is slightly higher than Ligand B (58.2). Both are below the 90 A^2 threshold desirable for CNS targets, but Ligand B is better.

**logP:** Both ligands have good logP values (3.06 and 3.46), falling within the optimal 1-3 range. Ligand B is slightly higher, which could potentially lead to some off-target effects, but is still acceptable.

**H-Bond Donors/Acceptors:** Ligand A has 1 HBD and 6 HBA, while Ligand B has 2 HBD and 3 HBA. Both are within acceptable limits (<=5 HBD and <=10 HBA).

**QED:** Both ligands have good QED scores (0.749 and 0.81), indicating good drug-like properties.

**DILI:** Ligand A (48.3) has a slightly higher DILI risk than Ligand B (37.4), but both are below the concerning threshold of 60.

**BBB:** Both ligands have excellent BBB penetration (82.6% and 82.2%), exceeding the desirable >70% threshold for CNS targets.

**Caco-2 Permeability:** Both have negative Caco-2 values (-4.64 and -4.87), which is unusual and suggests poor permeability. This is a significant concern.

**Aqueous Solubility:** Both ligands have very poor aqueous solubility (-3.27 and -3.91). This is a major drawback.

**hERG Inhibition:** Both ligands show low hERG inhibition risk (0.74 and 0.63), which is good.

**Microsomal Clearance:** Ligand A (93.4) has a higher microsomal clearance than Ligand B (44.1), indicating lower metabolic stability.

**In vitro Half-Life:** Ligand A (18.5) has a longer half-life than Ligand B (14.6), which is preferable.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.20 and 0.47), which is favorable for CNS penetration.

**Binding Affinity:** Ligand B (-9.1 kcal/mol) has a significantly stronger binding affinity than Ligand A (-7.5 kcal/mol). This 1.6 kcal/mol difference is substantial and could outweigh some of the ADME drawbacks.

**Conclusion:**

Despite the poor solubility and Caco-2 permeability for both, Ligand B is the better candidate. The significantly improved binding affinity (-9.1 vs -7.5 kcal/mol) is a major advantage for a GPCR target. While Ligand A has slightly better metabolic stability (lower Cl_mic and longer half-life), the affinity difference is more critical. The similar BBB penetration, acceptable DILI and hERG profiles, and low P-gp efflux for both compounds support prioritizing the higher affinity compound. Addressing the solubility and permeability issues would be crucial in further development, but the potency advantage of Ligand B makes it the more promising starting point.

Output:
1
2025-04-17 08:08:48,064 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (352.431 and 375.42 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (104.73) is higher than Ligand B (71.84). For CNS targets, TPSA should be <=90. Ligand B is preferable here.

**logP:** Ligand A (0.359) is quite low, potentially hindering permeability. Ligand B (3.163) is within the optimal 1-3 range. Ligand B is significantly better.

**H-Bond Donors/Acceptors:** Ligand A has 3 HBD and 5 HBA, while Ligand B has 2 HBD and 6 HBA. Both are acceptable, falling within the guidelines.

**QED:** Both ligands have good QED scores (0.574 and 0.78), indicating drug-likeness.

**DILI:** Ligand A (13.339) has a much lower DILI risk than Ligand B (77.045). This is a significant advantage for Ligand A.

**BBB:** Ligand B (76.425) has a much higher BBB penetration percentile than Ligand A (31.214). This is a critical advantage for a CNS target like DRD2.

**Caco-2 Permeability:** Both have negative values, which is unusual and suggests poor permeability. However, the scale is not specified, so it's hard to interpret.

**Aqueous Solubility:** Both have negative values, again suggesting poor solubility. The scale is not specified, so it's hard to interpret.

**hERG:** Ligand A (0.095) has a lower hERG inhibition liability than Ligand B (0.617), indicating a lower risk of cardiotoxicity.

**Microsomal Clearance:** Ligand A (26.036) has lower microsomal clearance than Ligand B (56.972), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand B (32.043) has a much longer in vitro half-life than Ligand A (-0.879). This is a significant advantage for Ligand B.

**P-gp Efflux:** Ligand A (0.009) has a much lower P-gp efflux liability than Ligand B (0.213). This is a crucial advantage for CNS penetration.

**Binding Affinity:** Ligand B (-8.7 kcal/mol) has a stronger binding affinity than Ligand A (-7.6 kcal/mol). The difference is 1.1 kcal/mol, which is substantial and can outweigh some ADME drawbacks.

**Overall Assessment:**

Ligand B excels in BBB penetration and binding affinity, which are paramount for a CNS GPCR target. It also has a better logP and longer half-life. However, it suffers from higher DILI risk and P-gp efflux. Ligand A has better DILI, hERG, P-gp, and metabolic stability, but its low logP and poor BBB penetration are major drawbacks.

Given the strong emphasis on CNS penetration for DRD2, and the significant affinity advantage of Ligand B, I believe **Ligand B** is the more promising candidate despite its higher DILI and P-gp efflux. These issues can potentially be addressed through further optimization, but the strong binding and BBB penetration are harder to achieve.

Output:
1
2025-04-17 08:08:48,064 - INFO - Reasoning:

Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (349.821 and 371.591 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (46.92) is excellent, well below the 90 A^2 threshold for CNS targets. Ligand B (52.65) is still acceptable but less optimal.

**3. logP:** Ligand A (4.352) is slightly high, potentially leading to solubility issues or off-target interactions. Ligand B (2.603) is within the optimal 1-3 range.

**4. H-Bond Donors:** Both ligands have 1 HBD, which is good.

**5. H-Bond Acceptors:** Both ligands have 4 HBA, which is good.

**6. QED:** Both ligands have QED values above 0.5 (0.598 and 0.677), indicating good drug-like properties.

**7. DILI:** Ligand A (87.243) has a significantly higher DILI risk than Ligand B (19.349). This is a major concern for Ligand A.

**8. BBB:** Both ligands have good BBB penetration (64.482 and 65.064). While both are above 60, higher is better for CNS targets.

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 values, which is unusual and suggests poor permeability. However, the scale is not explicitly defined, so we can't definitively say how problematic this is.

**10. Aqueous Solubility:** Both ligands have negative solubility values, indicating poor aqueous solubility. This is a concern, especially for Ligand A with its higher logP.

**11. hERG Inhibition:** Ligand A (0.707) has a slightly higher hERG risk than Ligand B (0.476), but both are relatively low.

**12. Microsomal Clearance:** Ligand B (80.216) has a higher microsomal clearance than Ligand A (46.524), meaning Ligand A is more metabolically stable.

**13. In vitro Half-Life:** Ligand A (96.511) has a significantly longer half-life than Ligand B (20.337).

**14. P-gp Efflux:** Ligand A (0.749) has a higher P-gp efflux liability than Ligand B (0.072). Lower P-gp efflux is preferred for CNS penetration.

**15. Binding Affinity:** Ligand A (-10.3 kcal/mol) has a *much* stronger binding affinity than Ligand B (-0.0 kcal/mol). This is a substantial advantage.

**Overall Assessment:**

Ligand A has a significantly better binding affinity and metabolic stability (lower Cl_mic, longer t1/2). However, it suffers from a high DILI risk, higher P-gp efflux, and a higher logP which could lead to solubility issues. Ligand B has a better safety profile (lower DILI) and better P-gp efflux, but its binding affinity is extremely weak.

Given the importance of affinity for GPCRs, the substantial difference in binding energy (-10.3 vs -0.0 kcal/mol) is the dominant factor. While the ADME properties of Ligand A are less ideal, the much stronger binding could potentially overcome these issues with further optimization. The high DILI risk is a concern, but could potentially be mitigated through structural modifications. Ligand B's affinity is simply too weak to be a viable starting point.

Output:
1
2025-04-17 08:08:48,064 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (358.379 and 365.495 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (32.34) is excellent, well below the 90 A^2 threshold for CNS targets. Ligand B (55.84) is higher but still reasonable, though less optimal.

**logP:** Both ligands have good logP values (3.667 and 2.869), falling within the 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A (1 HBD, 2 HBA) is better than Ligand B (0 HBD, 4 HBA) in terms of balancing solubility and permeability.

**QED:** Both ligands have acceptable QED scores (0.819 and 0.728), indicating good drug-like properties.

**DILI:** Both ligands have low DILI risk (39.977 and 33.501), which is positive.

**BBB:** This is a critical parameter for a CNS target like DRD2. Ligand A has a significantly higher BBB penetration percentile (91.431) compared to Ligand B (53.742). This is a major advantage for Ligand A.

**Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and suggests a potential issue with the data or modeling. However, the values are similar (-4.621 and -4.532), so this doesn't strongly differentiate them.

**Aqueous Solubility:** Both ligands have negative solubility values (-3.865 and -4.637), which is also unusual. Again, similar values don't provide a clear distinction.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.867 and 0.578).

**Microsomal Clearance:** Ligand A (9.691) has a lower microsomal clearance than Ligand B (65.512), indicating better metabolic stability.

**In vitro Half-Life:** Ligand A (-5.32) has a much longer in vitro half-life than Ligand B (-24.895).

**P-gp Efflux:** Ligand A (0.254) has lower P-gp efflux liability than Ligand B (0.195), which is favorable for CNS penetration.

**Binding Affinity:** Both ligands have excellent binding affinities (-8.5 and -8.1 kcal/mol). The difference of 0.4 kcal/mol is not substantial enough to outweigh the other significant differences.

**Overall Assessment:**

Ligand A is superior due to its significantly better BBB penetration (91.431 vs. 53.742), lower microsomal clearance, longer half-life, and lower P-gp efflux. While both have good affinity, the ADME properties of Ligand A are much more favorable for a CNS-targeting drug. The TPSA and H-bond properties also slightly favor Ligand A.

Output:
1
2025-04-17 08:08:48,064 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (383.901) is slightly higher than Ligand B (352.351), but both are acceptable.

**TPSA:** Ligand A (80.32) is excellent for CNS penetration, being well below 90. Ligand B (139.47) is approaching the upper limit for good oral absorption (140) and is less ideal for CNS targets.

**logP:** Ligand A (2.24) is within the optimal range (1-3). Ligand B (-0.815) is below 1, which could hinder permeation.

**H-Bond Donors/Acceptors:** Both ligands have 2 HBDs, which is good. Ligand A has 5 HBAs, acceptable. Ligand B has 7 HBAs, which is higher but still within the reasonable limit of 10.

**QED:** Ligand A (0.738) has a better QED score than Ligand B (0.39), indicating a more drug-like profile.

**DILI:** Both ligands have similar DILI risk (Ligand A: 54.323, Ligand B: 59.907), and both are acceptable (below 60).

**BBB:** Ligand A (61.691) has a moderate BBB penetration, while Ligand B (59.636) is also moderate. Both are below the desirable >70 for CNS targets, but Ligand A is slightly better.

**Caco-2 Permeability:** Ligand A (-4.614) has poor Caco-2 permeability. Ligand B (-5.19) is even worse.

**Aqueous Solubility:** Ligand A (-4.465) has poor aqueous solubility. Ligand B (-2.27) is better, but still poor.

**hERG Inhibition:** Both ligands have very low hERG inhibition risk (Ligand A: 0.221, Ligand B: 0.161).

**Microsomal Clearance:** Ligand A (23.108) has moderate clearance, while Ligand B (-7.671) has negative clearance, which is unusual and likely an error or indicates very high metabolic stability.

**In vitro Half-Life:** Ligand A (20.692) has a reasonable half-life. Ligand B (-7.717) has a negative half-life, which is also likely an error.

**P-gp Efflux:** Both ligands have very low P-gp efflux (Ligand A: 0.274, Ligand B: 0.019).

**Binding Affinity:** Both ligands have excellent binding affinity (Ligand A: -7.5 kcal/mol, Ligand B: -7.7 kcal/mol). Ligand B is slightly better, but the difference is small.

**Overall Assessment:**

Considering the GPCR-specific priorities, Ligand A is more promising. While both have good affinity, Ligand A has a significantly better TPSA, logP, and QED score. Ligand B's negative values for Caco-2 permeability, microsomal clearance, and half-life are concerning and likely indicate data errors. Although Ligand B has slightly better affinity and P-gp efflux, the other ADME properties of Ligand A make it a more viable starting point for optimization.

Output:
0
2025-04-17 08:08:48,064 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (418.316 Da) is slightly higher than Ligand B (376.356 Da), but both are acceptable.

**TPSA:** Ligand A (62.3) is significantly better than Ligand B (88.41). For CNS targets, we want TPSA <= 90, and ideally closer to 60. Ligand A is much closer to the ideal range.

**logP:** Both ligands have good logP values (A: 3.698, B: 2.99), falling within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Both have reasonable HBD/HBA counts (A: 1/4, B: 2/4), well within the guidelines.

**QED:** Both ligands have good QED scores (A: 0.688, B: 0.811), indicating drug-like properties.

**DILI:** Both ligands have elevated DILI risk (A: 70.105, B: 85.576), but are still within a range that isn't immediately disqualifying.

**BBB:** This is crucial for a CNS target. Ligand A (75.882) has a significantly better BBB percentile than Ligand B (53.432). A value >70 is desirable, and A is closer to that threshold.

**Caco-2 Permeability:** Both have negative Caco-2 values (-4.98 and -5.088), which is unusual and suggests poor permeability. This is a significant concern for both.

**Aqueous Solubility:** Both have very poor aqueous solubility (-3.523 and -3.801). This is a major drawback for both compounds.

**hERG Inhibition:** Both ligands show low hERG inhibition risk (A: 0.71, B: 0.645).

**Microsomal Clearance:** Ligand A (69.7) has a higher clearance than Ligand B (12.694), indicating lower metabolic stability. This is a negative for Ligand A.

**In vitro Half-Life:** Ligand B (49.209) has a shorter half-life than Ligand A (91.813).

**P-gp Efflux:** Both ligands have low P-gp efflux liability (A: 0.542, B: 0.174). Lower is better, so Ligand B is slightly favored here.

**Binding Affinity:** Both ligands have excellent binding affinity (A: -9.2 kcal/mol, B: -9.0 kcal/mol). The difference is minimal.

**Overall Assessment:**

Ligand A is favored due to its significantly better TPSA and BBB penetration, both critical for CNS GPCR targets. While its microsomal clearance is higher, the superior CNS penetration profile outweighs this drawback. Both compounds suffer from poor solubility and permeability, which would require significant medicinal chemistry effort to address. Ligand B has a slightly better P-gp profile and half-life, but the lower BBB penetration is a major disadvantage.

Output:
1
2025-04-17 08:08:48,065 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (358.825 and 350.503 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (68.29) is higher than Ligand B (49.85). For CNS targets, we prefer TPSA <= 90, so both are acceptable, but B is better.

**logP:** Both ligands have a logP around 2.8, which is optimal (1-3).

**H-Bond Donors/Acceptors:** Ligand A has 1 HBD and 4 HBA, while Ligand B has 0 HBD and 3 HBA. Both are within acceptable limits (<=5 HBD and <=10 HBA).

**QED:** Ligand A (0.916) has a significantly higher QED than Ligand B (0.664), indicating better overall drug-likeness.

**DILI:** Ligand A (73.362) has a higher DILI risk than Ligand B (15.238). This is a significant drawback for Ligand A.

**BBB:** Ligand B (92.555) has a much higher BBB penetration percentile than Ligand A (79.488). This is a crucial advantage for a CNS target like DRD2.

**Caco-2 Permeability:** Ligand A (-5.051) and Ligand B (-4.726) both have negative Caco-2 values, which is unusual and suggests poor permeability. However, the scale isn't specified, so it's difficult to interpret.

**Aqueous Solubility:** Both ligands have very low aqueous solubility (-2.999 and -2.345 respectively), which is a concern.

**hERG Inhibition:** Ligand A (0.299) has a slightly lower hERG inhibition risk than Ligand B (0.659), which is favorable.

**Microsomal Clearance:** Ligand A (39.973) has lower microsomal clearance than Ligand B (65.255), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand B (2.697 hours) has a slightly longer half-life than Ligand A (6.515 hours).

**P-gp Efflux:** Ligand A (0.149) shows lower P-gp efflux than Ligand B (0.317), which is beneficial for CNS penetration.

**Binding Affinity:** Ligand B (-7.2 kcal/mol) has a significantly stronger binding affinity than Ligand A (-10.5 kcal/mol). This is a major advantage, potentially outweighing some ADME concerns.

**Overall Assessment:**

Ligand B is the stronger candidate. While Ligand A has a better QED and lower P-gp efflux, Ligand B excels in the most critical areas for a CNS-targeting GPCR: significantly higher BBB penetration, and a substantially stronger binding affinity. The lower DILI risk for Ligand B is also a major positive. The solubility and Caco-2 permeability are concerns for both, but the superior affinity and BBB penetration of Ligand B make it the more promising drug candidate.

Output:
1
2025-04-17 08:08:48,065 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B based on the provided guidelines, prioritizing GPCR-specific properties (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (348.491 and 357.382 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (70.4) is excellent, well below the 90 A^2 threshold for CNS targets. Ligand B (107.97) is higher, but still potentially acceptable, though less ideal.

**logP:** Ligand A (2.991) is optimal (1-3). Ligand B (-0.299) is significantly lower, which is a concern for permeability and CNS penetration.

**H-Bond Donors/Acceptors:** Ligand A (HBD=2, HBA=4) and Ligand B (HBD=3, HBA=5) both have reasonable numbers of H-bond donors and acceptors, staying within the suggested limits.

**QED:** Both ligands have acceptable QED scores (A: 0.829, B: 0.626), indicating good drug-like properties.

**DILI:** Ligand A (12.33) has a much lower DILI risk than Ligand B (35.828), which is a significant advantage.

**BBB:** Ligand A (86.002) has a very good BBB percentile, exceeding the desirable >70% threshold for CNS targets. Ligand B (44.397) is considerably lower, raising concerns about CNS exposure.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.065 and -5.061), which is unusual and suggests poor permeability. However, these values are on the same scale, so don't differentiate the two.

**Aqueous Solubility:** Both ligands have negative solubility values (-1.967 and -1.499), which is also unusual, and suggests poor solubility. Again, these values are similar.

**hERG:** Both ligands have low hERG inhibition liability (A: 0.574, B: 0.184), indicating a low risk of cardiotoxicity.

**Microsomal Clearance:** Ligand A (19.439) has a lower microsomal clearance than Ligand B (-43.723), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (-8.212) has a longer in vitro half-life than Ligand B (-12.507), which is favorable.

**P-gp Efflux:** Ligand A (0.055) has lower P-gp efflux liability than Ligand B (0.018), which is a positive for CNS penetration.

**Binding Affinity:** Both ligands have strong binding affinities (A: -8.3 kcal/mol, B: -8.6 kcal/mol). Ligand B is slightly better, but the difference is small and may not outweigh the other significant drawbacks.

**Overall Assessment:**

Ligand A is significantly better. While both ligands have good binding affinity, Ligand A excels in critical ADME properties for a CNS-targeting GPCR drug. Specifically, its superior BBB penetration, lower DILI risk, better metabolic stability (lower Cl_mic, longer t1/2), and lower P-gp efflux liability are crucial advantages. Ligand B's negative logP value is a major concern, hindering its ability to cross the blood-brain barrier.



Output:
0
2025-04-17 08:08:48,065 - INFO - Reasoning:

Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (358.295 and 337.463 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (60.25) is better than Ligand B (29.54). For CNS targets, we want TPSA <= 90, both are well within this range, but lower is generally preferred.

**3. logP:** Ligand A (1.864) is within the optimal 1-3 range. Ligand B (4.048) is slightly higher, potentially leading to solubility issues and off-target interactions.

**4. H-Bond Donors:** Both ligands have 0 HBD, which is acceptable.

**5. H-Bond Acceptors:** Ligand A has 5 HBA, and Ligand B has 3. Both are below the acceptable limit of 10.

**6. QED:** Both ligands have similar QED values (0.766 and 0.771), indicating good drug-likeness.

**7. DILI:** Ligand A (61.187) has a higher DILI risk than Ligand B (17.138). This is a significant drawback for Ligand A.

**8. BBB:** Both ligands have excellent BBB penetration (92.71 and 97.48), which is crucial for a CNS target like DRD2. Ligand B is slightly better.

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 values, which is unusual and suggests a potential issue with the data or modeling. However, we can still compare them relatively. Ligand A (-4.505) is slightly better than Ligand B (-4.678).

**10. Aqueous Solubility:** Both ligands have very poor aqueous solubility (-3.31 and -3.969). This is a concern for both, but Ligand B is slightly worse.

**11. hERG Inhibition:** Ligand A (0.319) has a slightly lower hERG inhibition risk than Ligand B (0.951).

**12. Microsomal Clearance:** Ligand A (33.171) has lower microsomal clearance than Ligand B (50.772), indicating better metabolic stability.

**13. In vitro Half-Life:** Ligand A (-18.804) has a negative in vitro half-life, which is concerning. Ligand B (-5.772) is also negative, but less so. These values likely indicate issues with the modeling.

**14. P-gp Efflux:** Ligand A (0.206) has lower P-gp efflux than Ligand B (0.488), which is favorable for CNS penetration.

**15. Binding Affinity:** Ligand A (-9.4 kcal/mol) has a significantly stronger binding affinity than Ligand B (-8.7 kcal/mol). This is a substantial advantage, potentially outweighing some of the ADME drawbacks.

**Overall Assessment:**

Ligand A has a significantly better binding affinity and lower P-gp efflux, and better metabolic stability. However, it has a higher DILI risk and a concerningly negative in vitro half-life. Ligand B has a lower DILI risk and slightly better BBB penetration, but a weaker binding affinity and higher P-gp efflux.

Given the importance of binding affinity for GPCRs, and the acceptable BBB penetration of both, I would lean towards **Ligand A** despite its drawbacks. The stronger binding affinity is a significant advantage, and the DILI risk could potentially be mitigated through structural modifications. The negative half-life is concerning, but could also be an artifact of the modeling.



Output:
1
2025-04-17 08:08:48,065 - INFO - Batch 424 complete. Total preferences: 6784
2025-04-17 08:08:48,065 - INFO - Processing batch 425/512...
2025-04-17 08:09:29,808 - INFO - Reasoning:

Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (346.431 and 350.463 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (96.11) is slightly above the optimal <90 for CNS targets, but still reasonable. Ligand B (80.48) is well within the desired range.

**3. logP:** Both ligands have good logP values (1.882 and 1.703), falling within the 1-3 range.

**4. H-Bond Donors:** Ligand A (3) is acceptable. Ligand B (1) is also good, potentially offering better permeability.

**5. H-Bond Acceptors:** Ligand A (4) is acceptable. Ligand B (6) is also within the acceptable range of <=10.

**6. QED:** Both ligands have good QED scores (0.758 and 0.894), indicating good drug-like properties.

**7. DILI:** Ligand A (54.362) is moderately risky, while Ligand B (26.25) is much lower risk. This is a significant advantage for Ligand B.

**8. BBB:** Ligand A (34.626) has a poor BBB percentile, making CNS penetration unlikely. Ligand B (81.582) has an excellent BBB percentile, crucial for a DRD2 ligand.

**9. Caco-2 Permeability:** Ligand A (-5.331) has poor Caco-2 permeability. Ligand B (-4.3) is slightly better, but still not great.

**10. Aqueous Solubility:** Both ligands have poor aqueous solubility (-2.841 and -2.472). This could pose formulation challenges.

**11. hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.207 and 0.199).

**12. Microsomal Clearance:** Ligand A (37.768) has higher clearance than Ligand B (11.924), suggesting lower metabolic stability.

**13. In vitro Half-Life:** Ligand A (-12.578) has a very short half-life, a major drawback. Ligand B (22.439) has a much more reasonable half-life.

**14. P-gp Efflux:** Both ligands have low P-gp efflux liability (0.112 and 0.047).

**15. Binding Affinity:** Ligand B (-7.6) has a slightly better binding affinity than Ligand A (-8.4). While A is stronger, the difference isn't huge enough to overcome the significant ADME deficiencies.

**Overall Assessment:**

Ligand B is the far superior candidate. While both have acceptable MW, logP, QED, and hERG, Ligand B excels in critical areas for a CNS-targeting GPCR ligand: significantly better BBB penetration, lower DILI risk, improved metabolic stability (lower Cl_mic and longer t1/2), and a slightly better binding affinity. Ligand A's poor BBB and short half-life are deal-breakers. The solubility issues are a concern for both, but can be addressed with formulation strategies.

Output:
1
2025-04-17 08:09:29,809 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (351.407 and 360.439 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (109.58) is slightly higher than Ligand B (102.3). Both are above the optimal <90 for CNS targets, but still reasonably acceptable.

**logP:** Ligand A (-0.523) is quite low, potentially hindering membrane permeability. Ligand B (0.867) is better, falling within the 1-3 optimal range. This is a significant advantage for Ligand B.

**H-Bond Donors/Acceptors:** Both have 2 HBDs, which is good. Ligand A has 7 HBAs, while Ligand B has 5. Both are within the acceptable limit of <=10, but Ligand B is preferable.

**QED:** Both ligands have good QED scores (0.713 and 0.753), indicating good drug-like properties.

**DILI:** Both have moderately high DILI risk (61.497 and 59.558), but are still within a range that isn't immediately disqualifying.

**BBB:** Ligand B (49.864) has a significantly better BBB percentile than Ligand A (39.395). This is crucial for a CNS target like DRD2.

**Caco-2 Permeability:** Both have negative Caco-2 values (-4.92 and -5.388), which is unusual and suggests poor permeability. However, these values are on a log scale and can be misleading without knowing the base.

**Aqueous Solubility:** Both have negative solubility values (-1.332 and -2.99), indicating poor aqueous solubility. This could pose formulation challenges.

**hERG Inhibition:** Both have low hERG inhibition liability (0.106 and 0.447), which is positive.

**Microsomal Clearance:** Ligand B (-21.129) has a much lower (better) microsomal clearance than Ligand A (25.544), suggesting greater metabolic stability.

**In vitro Half-Life:** Ligand B (3.697) has a longer half-life than Ligand A (-8.872). This is a positive attribute.

**P-gp Efflux:** Both have very low P-gp efflux liability (0.019 and 0.059), which is favorable for CNS penetration.

**Binding Affinity:** Both ligands have excellent binding affinity (-7.5 and -8.6 kcal/mol). Ligand B is slightly better. The difference of 1.1 kcal/mol is significant and could outweigh some of the ADME drawbacks of Ligand A.

**Overall Assessment:**

Ligand B is the superior candidate. While both have some ADME concerns (low solubility, potentially poor Caco-2 permeability), Ligand B has a significantly better logP, BBB penetration, microsomal clearance, and in vitro half-life. The slightly better binding affinity further strengthens its position. The lower logP of Ligand A is a major concern for CNS penetration.

Output:
1
2025-04-17 08:09:29,809 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (384.267 Da) is slightly higher than Ligand B (353.413 Da), but both are acceptable.

**TPSA:** Ligand A (90.98) is borderline for CNS targets (<=90), while Ligand B (54.34) is well within the desired range. This favors Ligand B.

**logP:** Ligand A (0.899) is a bit low, potentially hindering permeability. Ligand B (2.52) is closer to the optimal range of 1-3. This favors Ligand B.

**H-Bond Donors/Acceptors:** Ligand A has 2 HBD and 4 HBA, which are acceptable. Ligand B has 1 HBD and 3 HBA, also acceptable. No clear advantage here.

**QED:** Both ligands have good QED scores (Ligand A: 0.583, Ligand B: 0.854), indicating good drug-like properties. Ligand B is slightly better.

**DILI:** Both ligands have low DILI risk (Ligand A: 38.503, Ligand B: 34.82), both below the 40% threshold. No significant difference.

**BBB:** Ligand A (61.691) is below the desirable threshold of 70% for CNS targets. Ligand B (93.059) is excellent, exceeding 70%. This is a *major* advantage for Ligand B.

**Caco-2 Permeability:** Ligand A (-5.356) and Ligand B (-4.612) both have negative values, which is unusual and suggests very poor permeability. However, the scale is not specified, so it's difficult to interpret these values precisely.

**Aqueous Solubility:** Both ligands have poor aqueous solubility (-2.885 and -2.87, respectively). This could pose formulation challenges, but is not a deciding factor.

**hERG Inhibition:** Both ligands have very low hERG inhibition risk (Ligand A: 0.09, Ligand B: 0.559), which is excellent.

**Microsomal Clearance:** Ligand A (-30.392) has a significantly lower (better) microsomal clearance than Ligand B (17.81). This suggests better metabolic stability for Ligand A.

**In vitro Half-Life:** Ligand A (-9.893) has a lower in vitro half-life than Ligand B (-8.8), but both are negative values, which is unusual.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (Ligand A: 0.015, Ligand B: 0.093), which is favorable for CNS penetration.

**Binding Affinity:** Both ligands have very similar binding affinities (Ligand A: -7.9 kcal/mol, Ligand B: -7.8 kcal/mol). The difference is negligible.

**Overall Assessment:**

Ligand B is clearly superior due to its significantly better BBB penetration (93.059% vs. 61.691%) and more favorable TPSA and logP values. While Ligand A has better metabolic stability (lower Cl_mic), the CNS target necessitates prioritizing BBB penetration. The similar binding affinities make the ADME properties the deciding factor.

Output:
1
2025-04-17 08:09:29,809 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (360.426 and 359.417 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (90.31) is better than Ligand B (56.59) as it is closer to the ideal range for CNS targets (<=90). Ligand B is excellent.

**logP:** Ligand A (-0.055) is slightly low, potentially hindering permeation. Ligand B (1.944) is within the optimal 1-3 range. This is a significant advantage for Ligand B.

**H-Bond Donors:** Ligand A (2) is acceptable. Ligand B (0) is also good, potentially improving permeability.

**H-Bond Acceptors:** Both ligands (5) are within the acceptable limit of <=10.

**QED:** Both ligands have good QED scores (0.592 and 0.633), indicating good drug-like properties.

**DILI:** Ligand A (12.524) has a much lower DILI risk than Ligand B (23.691). This is a positive for Ligand A.

**BBB:** Ligand B (96.084) has a significantly higher BBB penetration percentile than Ligand A (73.943). This is a crucial advantage for a CNS target like DRD2.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values, which is unusual and requires further investigation. However, we can compare the magnitude of the negative values. Ligand A (-4.711) is slightly worse than Ligand B (-4.415).

**Aqueous Solubility:** Both ligands have negative solubility values, which is also unusual. Ligand A (-0.016) is slightly better than Ligand B (-1.472).

**hERG:** Both ligands have low hERG inhibition liability (0.348 and 0.732), indicating a low risk of cardiotoxicity.

**Microsomal Clearance:** Ligand A (3.812) has significantly lower microsomal clearance than Ligand B (44.619), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (4.007) has a shorter in vitro half-life than Ligand B (11.004).

**P-gp Efflux:** Ligand A (0.039) has much lower P-gp efflux liability than Ligand B (0.259), which is beneficial for CNS exposure.

**Binding Affinity:** Ligand A (-7.2) has a slightly stronger binding affinity than Ligand B (-6.4). This 0.8 kcal/mol difference is substantial and could outweigh some ADME drawbacks.

**Overall Assessment:**

Ligand B excels in BBB penetration and has a good logP value. However, it suffers from higher DILI risk, higher P-gp efflux, and higher microsomal clearance. Ligand A has a slightly better binding affinity, lower DILI, lower P-gp efflux, and lower microsomal clearance, indicating better metabolic stability. While Ligand A's logP is suboptimal, the superior binding affinity and favorable ADME properties (particularly BBB and P-gp) make it the more promising candidate.

Output:
0
2025-04-17 08:09:29,809 - INFO - Reasoning:

Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (349.356 and 361.877 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (45.23) is significantly better than Ligand B (64.86). For CNS targets, we want TPSA <= 90, and ideally closer to 60. Ligand A is much closer to this ideal.

**3. logP:** Both ligands have good logP values (3.372 and 3.122), falling within the optimal range of 1-3.

**4. H-Bond Donors:** Both have 1 HBD, which is acceptable.

**5. H-Bond Acceptors:** Ligand A has 2 HBA, while Ligand B has 6.  Ligand A is preferable, as higher HBA can sometimes hinder permeability.

**6. QED:** Both ligands have reasonable QED values (0.864 and 0.767), indicating good drug-like properties.

**7. DILI:** Both have acceptable DILI risk (52.385 and 47.383), below the 60 threshold.

**8. BBB:** Ligand A (88.717) has a significantly higher BBB percentile than Ligand B (76.231). This is *critical* for a CNS target like DRD2.

**9. Caco-2 Permeability:** Both have negative Caco-2 values, indicating poor permeability. This is a concern for both, but less critical than BBB for a CNS target.

**10. Aqueous Solubility:** Both have negative solubility values, indicating poor solubility. This is a concern for both, but can be addressed with formulation strategies.

**11. hERG Inhibition:** Both have low hERG inhibition risk (0.636 and 0.139), which is good.

**12. Microsomal Clearance:** Both have similar microsomal clearance values (42.508 and 48.982), indicating moderate metabolic liability.

**13. In vitro Half-Life:** Both have negative in vitro half-life values, which is concerning.

**14. P-gp Efflux:** Ligand A (0.129) has lower P-gp efflux liability than Ligand B (0.247). Lower P-gp efflux is desirable, especially for CNS penetration.

**15. Binding Affinity:** Ligand A (-10.3 kcal/mol) has a significantly stronger binding affinity than Ligand B (-7.0 kcal/mol). This is a substantial advantage. A difference of >1.5 kcal/mol can often outweigh minor ADME drawbacks.

**Overall Assessment:**

Ligand A is the superior candidate. Its significantly better BBB penetration, lower TPSA, lower P-gp efflux, and *much* stronger binding affinity outweigh the similar metabolic properties and poor permeability/solubility profiles (which are concerns for both). The strong affinity of Ligand A suggests it might be able to achieve efficacy at lower doses, potentially mitigating some of the permeability/solubility issues. Given the GPCR target and CNS focus, BBB and affinity are paramount, and Ligand A excels in both.

Output:
1
2025-04-17 08:09:29,809 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (350.503 and 355.391 Da) fall within the ideal range of 200-500 Da.

**TPSA:** Ligand A (58.64) is excellent, well below the 90 A^2 threshold for CNS targets. Ligand B (92.12) is higher, but still potentially acceptable, though less ideal.

**logP:** Ligand A (2.757) is optimal (1-3). Ligand B (0.238) is low, potentially hindering permeability and CNS penetration.

**H-Bond Donors/Acceptors:** Ligand A (HBD=1, HBA=3) is favorable. Ligand B (HBD=0, HBA=9) is also acceptable, but the higher HBA count could slightly impact permeability.

**QED:** Both ligands have reasonable QED values (0.718 and 0.642), indicating good drug-like properties.

**DILI:** Ligand A (13.532) has a much lower DILI risk than Ligand B (61.109), which is a significant advantage.

**BBB:** Ligand A (84.064) shows excellent BBB penetration potential. Ligand B (70.027) is acceptable, but lower.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.454 and -4.313), which is unusual and suggests poor permeability. However, these values are on a log scale and negative values are common. We'll need to consider other factors.

**Aqueous Solubility:** Both ligands have negative solubility values (-2.928 and -1.338), also on a log scale, indicating poor solubility.

**hERG:** Both ligands have low hERG inhibition liability (0.343 and 0.218), which is positive.

**Microsomal Clearance:** Ligand A (52.385) has lower microsomal clearance than Ligand B (70.083), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (-15.253) has a more negative half-life, which is unusual and suggests a very short half-life. Ligand B (-39.303) is even worse.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.093 and 0.067), which is favorable for CNS penetration.

**Binding Affinity:** Ligand B (-6.9 kcal/mol) has a slightly better binding affinity than Ligand A (-6.5 kcal/mol), but the difference is relatively small.

**Overall Assessment:**

Considering the GPCR-specific priorities, Ligand A is the more promising candidate. While both have issues with solubility and half-life, Ligand A has a significantly better BBB score, lower DILI risk, and better metabolic stability. The slightly weaker binding affinity of Ligand A is likely outweighed by its superior ADME properties, especially for a CNS target. Ligand B's low logP is a major concern, as it will likely limit its ability to cross the blood-brain barrier despite the P-gp efflux liability being low.

Output:
1
2025-04-17 08:09:29,809 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (354.447 and 344.503 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (99.1) is higher than the preferred <90 for CNS targets, while Ligand B (48.47) is excellent. This is a significant advantage for Ligand B.

**3. logP:** Ligand A (0.042) is quite low, potentially hindering membrane permeability. Ligand B (2.757) is within the optimal 1-3 range. This favors Ligand B.

**4. H-Bond Donors:** Ligand A (3) is acceptable, while Ligand B (1) is even better, potentially improving permeability.

**5. H-Bond Acceptors:** Both ligands (A: 5, B: 4) are within the acceptable limit of 10.

**6. QED:** Both ligands have good QED scores (A: 0.648, B: 0.773), suggesting good drug-like properties.

**7. DILI:** Both ligands have similar, low DILI risk (A: 25.165, B: 25.359).

**8. BBB:** Ligand A (34.044) has a very poor BBB percentile, making CNS penetration unlikely. Ligand B (89.957) is excellent, exceeding the desirable >70 threshold. This is a critical advantage for Ligand B given the CNS target.

**9. Caco-2 Permeability:** Ligand A (-4.978) has poor Caco-2 permeability, consistent with its low logP. Ligand B (-4.722) is also not great, but slightly better than A.

**10. Aqueous Solubility:** Both ligands have poor aqueous solubility (A: -1.226, B: -2.322). This might present formulation challenges, but is less critical than BBB penetration for a CNS target.

**11. hERG Inhibition:** Both ligands show low hERG inhibition risk (A: 0.098, B: 0.779).

**12. Microsomal Clearance:** Ligand A (4.738) has lower clearance than Ligand B (91.428), suggesting better metabolic stability. This is a positive for Ligand A.

**13. In vitro Half-Life:** Ligand B (80.359) has a significantly longer half-life than Ligand A (3.138), which is highly desirable.

**14. P-gp Efflux:** Ligand A (0.018) shows very low P-gp efflux, which is good. Ligand B (0.221) is slightly higher but still acceptable.

**15. Binding Affinity:** Ligand B (-7.5 kcal/mol) has a significantly stronger binding affinity than Ligand A (-9.3 kcal/mol). This is a substantial advantage, potentially outweighing some of the ADME drawbacks.

**Overall Assessment:**

Ligand B is the far superior candidate. While Ligand A has slightly better metabolic stability and P-gp efflux, Ligand B excels in the critical areas for a CNS-targeting GPCR ligand: TPSA, logP, and, most importantly, BBB penetration. The significantly stronger binding affinity of Ligand B further solidifies its position as the more promising drug candidate. The poor solubility of both is a concern, but can be addressed with formulation strategies.



Output:
1
2025-04-17 08:09:29,809 - INFO - Reasoning:

Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (346.427 Da) is slightly lower, which could be beneficial for permeability, but both are acceptable.

**TPSA:** Ligand A (62.99) is much better than Ligand B (49.58) for CNS penetration, being closer to the ideal <90 A^2. Ligand B is quite low, which is good, but A is better.

**logP:** Both ligands have good logP values (A: 2.163, B: 3.416) falling within the optimal 1-3 range. Ligand B is a bit higher, which *could* indicate potential off-target effects, but isn't a major concern.

**H-Bond Donors/Acceptors:** Both have acceptable HBD (0) and HBA (A: 4, B: 5) counts.

**QED:** Ligand A (0.741) has a better QED score than Ligand B (0.479), indicating a more drug-like profile.

**DILI:** Both ligands have low DILI risk (A: 36.293, B: 37.418), both well below the 40% threshold.

**BBB:** Ligand A (73.866) has a significantly better BBB percentile than Ligand B (69.639). This is a *critical* advantage for a CNS target like DRD2.

**Caco-2 Permeability:** Ligand A (-4.076) has a worse Caco-2 permeability than Ligand B (-5.134). Lower values are less desirable.

**Aqueous Solubility:** Both have very poor aqueous solubility (A: -2.983, B: -2.674). This is a concern for both, but might be mitigated by formulation strategies.

**hERG Inhibition:** Both ligands show low hERG inhibition liability (A: 0.417, B: 0.811), which is good.

**Microsomal Clearance:** Ligand B (99.497) has a much higher microsomal clearance than Ligand A (44.687), indicating faster metabolism and potentially lower *in vivo* exposure. This is a significant drawback for Ligand B.

**In vitro Half-Life:** Ligand B (108.556) has a much longer in vitro half-life than Ligand A (8.114). This is a positive for Ligand B, but may not fully compensate for the high clearance.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (A: 0.254, B: 0.203).

**Binding Affinity:** Ligand B (-6.5 kcal/mol) has a significantly better binding affinity than Ligand A (-0.0 kcal/mol). This is a *major* advantage, exceeding the 1.5 kcal/mol threshold.

**Overall Assessment:**

While Ligand A has better TPSA, BBB, QED, and lower clearance, the significantly superior binding affinity of Ligand B (-6.5 vs -0.0 kcal/mol) is the most important factor. The higher affinity is likely to outweigh the drawbacks of slightly higher logP, lower BBB, and higher clearance. The poor solubility is a concern for both, but can be addressed during formulation. The longer half-life of Ligand B is also beneficial. Given the GPCR-specific priorities, the strong binding affinity of Ligand B makes it the more promising candidate.

Output:
1
2025-04-17 08:09:29,810 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (362.47 and 359.495 Da) fall comfortably within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (49.41) is better than Ligand B (53.51). Both are below the 90 A^2 threshold for CNS targets, which is good.

**3. logP:** Both ligands have good logP values (3.295 and 2.929), within the optimal 1-3 range.

**4. H-Bond Donors:** Ligand A (1) is preferable to Ligand B (0) as a single HBD can aid solubility without significantly impacting permeability.

**5. H-Bond Acceptors:** Ligand A (3) and Ligand B (4) are both acceptable.

**6. QED:** Both ligands have similar QED values (0.893 and 0.834), indicating good drug-likeness.

**7. DILI:** Ligand B (35.983) has a significantly lower DILI risk than Ligand A (43.389), making it more favorable from a safety perspective.

**8. BBB:** Ligand A (86.894) has a much better BBB penetration percentile than Ligand B (74.641). This is a *critical* factor for a CNS target like DRD2.

**9. Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and suggests poor permeability. This is a concern for both, but the values are very close.

**10. Aqueous Solubility:** Both have negative solubility values, which is also unusual and suggests poor solubility. Again, values are close.

**11. hERG Inhibition:** Both ligands have low hERG inhibition risk (0.575 and 0.47), which is good.

**12. Microsomal Clearance:** Ligand B (45.081) has a slightly lower microsomal clearance than Ligand A (49.803), indicating potentially better metabolic stability.

**13. In vitro Half-Life:** Ligand A (0.034) has a very short half-life, while Ligand B (-4.343) is also low, but less so. This is a significant drawback for both, but more pronounced for Ligand A.

**14. P-gp Efflux:** Ligand A (0.22) has lower P-gp efflux than Ligand B (0.245), which is favorable for CNS penetration.

**15. Binding Affinity:** Ligand A (-9.5 kcal/mol) has a *much* stronger binding affinity than Ligand B (0.0 kcal/mol). This is a decisive advantage. A difference of 9.5 kcal/mol is substantial and can outweigh many ADME concerns.

**Overall Assessment:**

While Ligand B has a better safety profile (lower DILI) and slightly better metabolic stability, Ligand A's significantly superior binding affinity (-9.5 vs 0.0 kcal/mol) and better BBB penetration (86.894 vs 74.641) are crucial for a CNS GPCR target. The poor permeability and solubility are concerns for both, but a strong binding affinity can sometimes compensate for these issues, especially with strategies to improve formulation. The very short half-life of Ligand A is a concern, but could be addressed through structural modifications.

Output:
1
2025-04-17 08:09:29,810 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (349.308 Da) is slightly preferred due to being closer to the lower end, potentially aiding permeability.

**TPSA:** Ligand A (51.47) is significantly better than Ligand B (57.95). For CNS targets, we want TPSA <= 90, and ideally closer to 60. Ligand A is much closer to this ideal.

**logP:** Both ligands have logP values around 4 (A: 4.146, B: 4.75). This is a bit high, potentially leading to solubility issues and off-target interactions, but acceptable given the strong affinity.

**H-Bond Donors/Acceptors:** Both have 1 HBD and a reasonable number of HBAs (A: 3, B: 4). This is within acceptable limits.

**QED:** Both ligands have good QED values (A: 0.727, B: 0.751), indicating drug-like properties.

**DILI:** Ligand A (86.429) has a significantly higher DILI risk than Ligand B (25.436). This is a major concern for Ligand A.

**BBB:** Ligand A (90.772) has excellent BBB penetration, while Ligand B (77.2) is good, but not as high. This is a critical factor for a CNS target like DRD2.

**Caco-2 Permeability:** Ligand A (-4.342) shows poor Caco-2 permeability, while Ligand B (-5.314) is also poor. Both are negative values, indicating low permeability.

**Aqueous Solubility:** Ligand A (-5.872) has very poor aqueous solubility, and Ligand B (-3.758) is also poor, but better than A.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (A: 0.94, B: 0.848).

**Microsomal Clearance:** Ligand A (69.995) has a higher microsomal clearance than Ligand B (38.263), indicating lower metabolic stability.

**In vitro Half-Life:** Ligand A (91.336) has a longer half-life than Ligand B (38.958).

**P-gp Efflux:** Ligand A (0.703) has lower P-gp efflux than Ligand B (0.539), which is favorable for CNS penetration.

**Binding Affinity:** Ligand A (-9.6 kcal/mol) has a significantly stronger binding affinity than Ligand B (-8.1 kcal/mol). This is a substantial difference (1.5 kcal/mol advantage) and can outweigh some ADME drawbacks.

**Overall Assessment:**

Ligand A has a much stronger binding affinity and better BBB penetration and P-gp efflux, which are crucial for a CNS GPCR target. However, it suffers from significantly higher DILI risk, poorer solubility, and lower Caco-2 permeability. Ligand B has a better safety profile (lower DILI) and slightly better solubility, but weaker affinity and lower BBB penetration.

The strong affinity of Ligand A is a significant advantage. While the DILI risk is concerning, it might be mitigated through structural modifications during lead optimization. The poor solubility and permeability could also be addressed with formulation strategies or prodrug approaches. The superior BBB penetration is a key factor for CNS activity.

Output:
1
2025-04-17 08:09:29,810 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (336.395 Da) is slightly lower, which is generally favorable for permeability.

**TPSA:** Both ligands have TPSA values around 87, which is acceptable for general oral absorption but slightly high for a CNS target (ideally <90).

**logP:** Ligand A (2.806) is within the optimal range (1-3). Ligand B (-0.213) is significantly below this range, which could hinder membrane permeability and reduce brain exposure.

**H-Bond Donors/Acceptors:** Both ligands have acceptable HBD (3 & 1) and HBA (4 & 4) counts.

**QED:** Both ligands have good QED scores (0.625 and 0.746), indicating good drug-like properties.

**DILI:** Ligand A (75.533) has a higher DILI risk than Ligand B (38.348). This is a concern for Ligand A, but not a disqualifier at this stage.

**BBB:** Ligand B (68.282) has a significantly better BBB percentile than Ligand A (43.505). This is a *critical* advantage for a CNS target like DRD2.

**Caco-2 Permeability:** Ligand A (-5.303) shows poor Caco-2 permeability, while Ligand B (-4.769) is also low but relatively better.

**Aqueous Solubility:** Ligand A (-4.462) and Ligand B (-2.447) both have poor aqueous solubility.

**hERG Inhibition:** Both ligands show very low hERG inhibition risk (0.68 and 0.064).

**Microsomal Clearance:** Ligand A (-5.968) has a lower (better) microsomal clearance than Ligand B (13.226), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (40.056 hours) has a much longer half-life than Ligand B (-35.252 hours). This is a significant advantage.

**P-gp Efflux:** Ligand A (0.08) has a lower P-gp efflux liability than Ligand B (0.006), which is favorable for CNS penetration.

**Binding Affinity:** Ligand A (-9.9 kcal/mol) has a substantially stronger binding affinity than Ligand B (-7.8 kcal/mol). This is a major advantage, potentially outweighing some of the ADME drawbacks.

**Overall Assessment:**

Ligand A has a significantly better binding affinity and metabolic stability (lower Cl_mic, longer t1/2), and lower P-gp efflux. However, it has poorer BBB penetration, Caco-2 permeability, and a higher DILI risk. Ligand B excels in BBB penetration and has a lower DILI risk, but its logP is problematic, and its binding affinity is weaker.

Given the GPCR-specific priorities, BBB penetration is crucial for CNS targets. However, the substantial difference in binding affinity (-9.9 vs -7.8 kcal/mol) is a very strong factor. A 2.1 kcal/mol difference is significant and likely to overcome the moderate BBB disadvantage of Ligand A, especially considering its lower P-gp efflux. The poor Caco-2 permeability of both compounds is a concern, but can be addressed with formulation strategies.

Output:
1
2025-04-17 08:09:29,810 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B against the provided guidelines, prioritizing GPCR-specific properties (BBB, logP, Pgp, TPSA, and affinity) for DRD2.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (344.455 Da) is slightly lower, which could be beneficial for permeability.

**TPSA:** Ligand A (59.59) is significantly better than Ligand B (74.09). For a CNS target like DRD2, TPSA should be <= 90, and ideally lower. Ligand A is much closer to the optimal range for CNS penetration.

**logP:** Both ligands have good logP values (A: 2.178, B: 2.692), falling within the 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A (HBD=2, HBA=4) is slightly better than Ligand B (HBD=1, HBA=7) in terms of balancing solubility and permeability, though both are acceptable.

**QED:** Both ligands have similar and good QED values (A: 0.745, B: 0.797), indicating good drug-like properties.

**DILI:** Ligand A (29.042) has a much lower DILI risk than Ligand B (52.772). This is a significant advantage.

**BBB:** Ligand A (69.523) is good, but Ligand B (83.249) is excellent, exceeding the desirable >70 threshold for CNS targets. This is a major point in favor of Ligand B.

**Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and suggests poor permeability. However, the scale is not specified, so it is difficult to interpret.

**Aqueous Solubility:** Both have negative solubility values, again indicating poor solubility. The scale is not specified, so it is difficult to interpret.

**hERG:** Both ligands have low hERG risk (A: 0.474, B: 0.12). Ligand B is slightly better.

**Microsomal Clearance:** Ligand A (39.684) has a higher microsomal clearance than Ligand B (10.862), suggesting lower metabolic stability. Ligand B is significantly better here.

**In vitro Half-Life:** Ligand A (22.944) has a longer half-life than Ligand B (7.82), which is generally desirable.

**P-gp Efflux:** Ligand A (0.115) has lower P-gp efflux than Ligand B (0.099), which is better for CNS exposure.

**Binding Affinity:** Ligand A (-8.4 kcal/mol) has a significantly stronger binding affinity than Ligand B (0.0 kcal/mol). This is a crucial advantage, potentially outweighing some of the ADME drawbacks.

**Overall Assessment:**

Ligand A has a significantly better binding affinity and lower DILI risk, and better P-gp efflux. However, Ligand B has superior BBB penetration and metabolic stability (lower Cl_mic). Given the CNS target (DRD2), BBB penetration is critical. The substantial difference in binding affinity (-8.4 vs 0.0 kcal/mol) for Ligand A is a major factor. While Ligand B's BBB is excellent, the lack of binding affinity makes it unlikely to be a viable candidate. The negative Caco-2 and solubility values are concerning for both, but can potentially be addressed with formulation strategies.

Output:
1
2025-04-17 08:09:29,810 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands are within the acceptable range (200-500 Da). Ligand A (364.408 Da) is slightly lower, which is generally favorable for permeability.

**2. TPSA:** Ligand A (78.43) is significantly better than Ligand B (33.2). For a CNS target like DRD2, a TPSA <= 90 is preferred, and Ligand A is comfortably within this range, while Ligand B is excellent.

**3. logP:** Ligand A (2.305) is within the optimal range (1-3). Ligand B (4.665) is higher, potentially leading to solubility issues and off-target interactions.

**4. H-Bond Donors:** Ligand A (3) is acceptable. Ligand B (0) is also acceptable, but a lack of HBDs can sometimes hinder solubility.

**5. H-Bond Acceptors:** Ligand A (3) is acceptable. Ligand B (5) is also acceptable.

**6. QED:** Both ligands have similar QED values (0.579 and 0.566), indicating good drug-like properties.

**7. DILI:** Ligand A (18.883) has a much lower DILI risk than Ligand B (29.042), which is a significant advantage.

**8. BBB:** Both ligands have good BBB penetration (Ligand A: 77.239, Ligand B: 70.066), but Ligand A is slightly better. A value >70 is desirable for CNS targets.

**9. Caco-2 Permeability:** Ligand A (-4.745) is better than Ligand B (-5.125). Higher values indicate better intestinal absorption.

**10. Aqueous Solubility:** Ligand A (-2.943) is better than Ligand B (-4.376). Higher values are better for formulation and bioavailability.

**11. hERG Inhibition:** Ligand A (0.362) has a lower hERG inhibition liability than Ligand B (0.777), reducing the risk of cardiotoxicity.

**12. Microsomal Clearance:** Ligand A (36.091) has a lower microsomal clearance than Ligand B (122.564), suggesting better metabolic stability.

**13. In vitro Half-Life:** Ligand A (-24.655) has a longer in vitro half-life than Ligand B (18.202).

**14. P-gp Efflux:** Ligand A (0.11) has lower P-gp efflux liability than Ligand B (0.766), which is crucial for CNS exposure.

**15. Binding Affinity:** Ligand A (-7.9 kcal/mol) has a slightly better binding affinity than Ligand B (-6.8 kcal/mol). While both are good, the 1.1 kcal/mol difference is significant.

**Overall Assessment:**

Ligand A consistently outperforms Ligand B across most critical ADME-Tox properties, including DILI, BBB, solubility, hERG, metabolic stability, and P-gp efflux. While Ligand B has a very low TPSA, the other drawbacks outweigh this benefit. The slightly better binding affinity of Ligand A further solidifies its position as the more promising candidate.

Output:
0
2025-04-17 08:09:29,811 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B based on the provided guidelines, prioritizing GPCR-specific properties (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (349.475 Da) is slightly lower, which could be advantageous for permeability, but both are acceptable.

**TPSA:** Both ligands have TPSA values below 90 (A: 61.88, B: 58.2), which is excellent for CNS penetration.

**logP:** Ligand A (1.171) is optimal, while Ligand B (4.121) is approaching the upper limit. Higher logP can sometimes lead to off-target effects and solubility issues.

**H-Bond Donors/Acceptors:** Ligand A (HBD=1, HBA=4) and Ligand B (HBD=2, HBA=3) both have reasonable numbers of H-bond donors and acceptors, falling within the acceptable ranges.

**QED:** Both ligands have good QED scores (A: 0.701, B: 0.717), indicating drug-like properties.

**DILI:** Ligand A (10.198) has a significantly lower DILI risk than Ligand B (30.748). This is a major advantage for Ligand A.

**BBB:** Both ligands have good BBB penetration (A: 68.864, B: 63.746), but Ligand A is slightly better. While both are below the ideal >70, they are reasonably close.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.859 and -4.903), which is unusual and suggests poor permeability. This is a concern for both.

**Aqueous Solubility:** Both ligands have negative solubility values (-1.351 and -3.41), which is also concerning and suggests poor solubility. Ligand B appears to have worse solubility.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (A: 0.241, B: 0.401), which is good.

**Microsomal Clearance:** Ligand A (20.137 mL/min/kg) has significantly lower microsomal clearance than Ligand B (61.361 mL/min/kg), indicating better metabolic stability.

**In vitro Half-Life:** Ligand A (16.647 hours) has a shorter half-life than Ligand B (23.289 hours), but both are reasonable.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (A: 0.026, B: 0.257). This is excellent for CNS exposure.

**Binding Affinity:** Ligand B (-9.2 kcal/mol) has a significantly stronger binding affinity than Ligand A (-7.7 kcal/mol). This is a substantial advantage for Ligand B, potentially outweighing some of its ADME drawbacks. The difference is >1.5 kcal/mol.

**Overall Assessment:**

Ligand B has a much better binding affinity, which is the most critical factor. While it has some ADME liabilities (higher logP, higher DILI, higher Cl_mic, worse solubility), the strong binding affinity is likely to be a significant driver of efficacy. The slightly worse ADME properties might be manageable through further optimization. Ligand A has better ADME properties overall, but the weaker binding affinity is a significant drawback. Given the GPCR target and the importance of potency, the stronger affinity of Ligand B is decisive.

Output:
1
2025-04-17 08:09:29,811 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (342.439 and 358.869 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (49.85) is significantly better than Ligand B (66.56). For CNS targets, we want TPSA <= 90, and ideally closer to 60. Ligand A is much closer to this ideal.

**3. logP:** Ligand A (2.155) is optimal (1-3). Ligand B (4.235) is pushing the upper limit and could potentially lead to solubility issues or off-target interactions.

**4. H-Bond Donors:** Both have acceptable HBD counts (0 for A, 2 for B, both <=5).

**5. H-Bond Acceptors:** Both have acceptable HBA counts (3 for A and B, both <=10).

**6. QED:** Both ligands have good QED values (0.827 and 0.786, both >= 0.5).

**7. DILI:** Ligand B (32.842) has a significantly lower DILI risk than Ligand A (49.283), which is a strong advantage.

**8. BBB:** Ligand A (73.943) has a better BBB penetration percentile than Ligand B (64.87). Both are reasonably good, but A is preferable for a CNS target.

**9. Caco-2 Permeability:** Ligand A (-4.373) has better Caco-2 permeability than Ligand B (-4.922).

**10. Aqueous Solubility:** Ligand A (-2.08) has better aqueous solubility than Ligand B (-5.138).

**11. hERG Inhibition:** Ligand B (0.883) has a slightly higher hERG inhibition risk than Ligand A (0.514), but both are reasonably low.

**12. Microsomal Clearance:** Ligand B (76.145) has higher microsomal clearance than Ligand A (44.136), indicating lower metabolic stability.

**13. In vitro Half-Life:** Ligand A (5.113) has a longer in vitro half-life than Ligand B (-0.86).

**14. P-gp Efflux:** Ligand A (0.298) has lower P-gp efflux than Ligand B (0.389), which is beneficial for CNS exposure.

**15. Binding Affinity:** Ligand A (-8.8 kcal/mol) has a slightly better binding affinity than Ligand B (-8.2 kcal/mol). While the difference is not huge, it's still a positive factor.

**Overall Assessment:**

Ligand A is superior. It has a more favorable TPSA, logP, solubility, BBB, Caco-2 permeability, metabolic stability (lower Cl_mic, longer t1/2), and P-gp efflux. Although Ligand B has a lower DILI risk, the other ADME properties of Ligand A are more critical for a CNS-targeting GPCR ligand. The slightly better binding affinity of Ligand A further supports its selection.

Output:
1
2025-04-17 08:09:29,811 - INFO - Reasoning:

Let's analyze Ligand A and Ligand B based on the provided guidelines, prioritizing GPCR-specific properties (BBB, logP, Pgp, TPSA, and affinity).

**Ligand A:**

*   **MW:** 345.443 Da - Within the ideal range (200-500).
*   **TPSA:** 66.65 - Good for CNS targets (<90).
*   **logP:** 2.512 - Optimal (1-3).
*   **HBD:** 0 - Acceptable, though some H-bond donors can aid solubility.
*   **HBA:** 4 - Acceptable (<10).
*   **QED:** 0.787 - Excellent, highly drug-like.
*   **DILI:** 32.803 - Low risk, very good.
*   **BBB:** 81.776 - Excellent, highly desirable for a CNS target.
*   **Caco-2:** -4.572 - This is a concerningly low value, suggesting poor intestinal absorption.
*   **Solubility:** -3.799 - Also concerningly low, potentially hindering formulation.
*   **hERG:** 0.375 - Low risk, good.
*   **Cl_mic:** 66.249 - Moderate clearance, not ideal but not terrible.
*   **t1/2:** -4.986 - Negative half-life is not physically possible and indicates an issue with the data.
*   **Pgp:** 0.486 - Low efflux, favorable for CNS penetration.
*   **Affinity:** -7.8 kcal/mol - Excellent binding affinity.

**Ligand B:**

*   **MW:** 361.427 Da - Within the ideal range (200-500).
*   **TPSA:** 100.35 - Borderline; acceptable but less ideal for CNS targets.
*   **logP:** 0.6 - Low, potentially hindering permeation.
*   **HBD:** 2 - Acceptable.
*   **HBA:** 7 - Acceptable.
*   **QED:** 0.812 - Excellent, highly drug-like.
*   **DILI:** 62.389 - Moderate risk, higher than Ligand A.
*   **BBB:** 21.791 - Poor, a major drawback for a CNS target.
*   **Caco-2:** -5.094 - Very poor intestinal absorption.
*   **Solubility:** -2.464 - Low, but not as low as Ligand A.
*   **hERG:** 0.127 - Low risk, good.
*   **Cl_mic:** 4.56 - Very low clearance, excellent metabolic stability.
*   **t1/2:** -7.126 - Negative half-life, indicates a data issue.
*   **Pgp:** 0.027 - Very low efflux, highly favorable.
*   **Affinity:** -7.6 kcal/mol - Excellent binding affinity, slightly better than Ligand A.

**Comparison and Decision:**

Both ligands have excellent binding affinity and good QED scores. However, Ligand A significantly outperforms Ligand B in crucial areas for a CNS-targeting GPCR: BBB penetration (81.8% vs 21.8%) and DILI risk (32.8% vs 62.4%). While Ligand A has concerningly low Caco-2 and solubility values, these are less critical for a CNS drug where direct absorption into the brain is prioritized. Ligand B's poor BBB penetration is a deal-breaker. The negative half-life values for both compounds are concerning and suggest data quality issues, but the other parameters are sufficient to make a decision.

Therefore, Ligand A is the more promising drug candidate.

Output:
0
2025-04-17 08:09:29,811 - INFO - Batch 425 complete. Total preferences: 6800
2025-04-17 08:09:29,811 - INFO - Processing batch 426/512...
2025-04-17 08:10:12,529 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (371.453 and 348.447 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (62.3) is excellent, well below the 90 A^2 threshold for CNS targets. Ligand B (76.46) is still reasonable but less optimal.

**logP:** Both ligands have good logP values (2.854 and 1.346), falling within the 1-3 range. Ligand A is slightly preferred here.

**H-Bond Donors/Acceptors:** Both have 1 HBD, which is good. Ligand A has 4 HBA, and Ligand B has 5. Both are acceptable, being under the 10 HBA threshold.

**QED:** Both ligands have similar QED values (0.885 and 0.807), indicating good drug-likeness.

**DILI:** Ligand A (49.787) has a slightly higher DILI risk than Ligand B (34.471), but both are below the concerning 60 threshold.

**BBB:** This is critical for a CNS target. Ligand A has a significantly higher BBB penetration percentile (90.229) compared to Ligand B (73.866). This is a major advantage for Ligand A.

**Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and suggests poor permeability. However, these values are on a scale where negative values are possible, and direct comparison is difficult without knowing the scale's specifics.

**Aqueous Solubility:** Both have negative solubility values, again indicating poor solubility. Similar to Caco-2, the scale is unknown.

**hERG:** Both ligands show low hERG inhibition liability (0.421 and 0.352), which is good.

**Microsomal Clearance:** Ligand A (31.992) has a higher microsomal clearance than Ligand B (25.866), meaning it's likely to be metabolized faster. This is a negative for Ligand A.

**In vitro Half-Life:** Ligand B (17.147 hours) has a significantly longer in vitro half-life than Ligand A (-24.354 hours - a negative value suggests very rapid degradation). This is a substantial advantage for Ligand B.

**P-gp Efflux:** Ligand A (0.179) shows very low P-gp efflux, which is excellent for CNS penetration. Ligand B (0.025) is even lower, which is also excellent.

**Binding Affinity:** Ligand B (-8.5 kcal/mol) has a significantly stronger binding affinity than Ligand A (0.0 kcal/mol). This is a major advantage for Ligand B, potentially outweighing some of its ADME drawbacks.

**Overall Assessment:**

While Ligand A excels in BBB penetration and P-gp efflux, Ligand B's significantly stronger binding affinity and longer half-life are crucial for a GPCR drug candidate. The slightly higher DILI risk for Ligand A and its faster clearance are concerning. The negative solubility and Caco-2 values are problematic for both, but the affinity difference is substantial. Given the importance of affinity for GPCRs, and the relatively good (though not perfect) ADME profile of Ligand B, it is the more promising candidate.

Output:
1
2025-04-17 08:10:12,529 - INFO - Reasoning:

Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (373.475 and 357.357 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (107.78) is slightly above the preferred <90 for CNS targets, but still reasonable. Ligand B (80.76) is well within the ideal range. This favors Ligand B.

**3. logP:** Ligand A (0.455) is quite low, potentially hindering permeability. Ligand B (1.183) is better, falling within the optimal 1-3 range. This favors Ligand B.

**4. H-Bond Donors:** Both have acceptable HBD counts (0 for A, 1 for B), well below the limit of 5.

**5. H-Bond Acceptors:** Both have acceptable HBA counts (6 for A, 5 for B), below the limit of 10.

**6. QED:** Both ligands have good QED scores (0.515 and 0.756), indicating drug-like properties. Ligand B is slightly better.

**7. DILI:** Both have similar, acceptable DILI risk (around 39%).

**8. BBB:** Both ligands have good BBB penetration (74.952% and 78.48%), exceeding the desirable >70% threshold for CNS targets. Ligand B is slightly better.

**9. Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual. It suggests poor permeability.

**10. Aqueous Solubility:** Both have negative solubility values, which is also unusual. It suggests poor solubility.

**11. hERG Inhibition:** Both ligands show low hERG inhibition liability (0.34 and 0.29), which is good.

**12. Microsomal Clearance:** Ligand A (93.548) has a higher clearance than Ligand B (16.754), indicating lower metabolic stability. This strongly favors Ligand B.

**13. In vitro Half-Life:** Ligand B (-17.563) has a significantly longer half-life than Ligand A (-59.916). This is a major advantage for Ligand B.

**14. P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.033 and 0.016), which is excellent for CNS penetration.

**15. Binding Affinity:** Both ligands have identical binding affinities (-6.9 kcal/mol), which is good.

**Overall Assessment:**

While both ligands have good binding affinity and acceptable DILI/hERG profiles, Ligand B is significantly better overall. It has a more favorable logP, lower microsomal clearance (better metabolic stability), a longer half-life, and a slightly better TPSA. The negative Caco-2 and solubility values are concerning for both, but the other advantages of Ligand B outweigh this. Given the GPCR-specific priorities, the improved ADME properties of Ligand B make it the more promising drug candidate.

Output:
1
2025-04-17 08:10:12,530 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (362.37 and 363.58 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (125.88) is slightly above the optimal <90 for CNS targets, but still reasonable. Ligand B (56.41) is excellent, well below 90. This favors Ligand B.

**3. logP:** Ligand A (0.742) is a bit low, potentially hindering permeability. Ligand B (3.21) is within the optimal 1-3 range. This strongly favors Ligand B.

**4. H-Bond Donors:** Both have 1 HBD, which is acceptable.

**5. H-Bond Acceptors:** Ligand A has 8 HBA, which is acceptable. Ligand B has 2 HBA, which is also acceptable.

**6. QED:** Both ligands have good QED scores (0.663 and 0.817), indicating good drug-like properties.

**7. DILI:** Ligand A has a high DILI risk (98.76%), which is a significant concern. Ligand B has a much lower DILI risk (25.48%), making it much safer. This is a major advantage for Ligand B.

**8. BBB:** Ligand A has a BBB penetration of 47.62%, which is below the desirable >70% for CNS targets. Ligand B has a much better BBB penetration of 67.47%, although still not ideal, it is considerably better than Ligand A. This favors Ligand B.

**9. Caco-2 Permeability:** Ligand A has a negative Caco-2 value (-5.019), which is concerning. Ligand B has a negative Caco-2 value (-4.665), also concerning.

**10. Aqueous Solubility:** Both ligands have negative solubility values (-3.226 and -4.116), indicating poor aqueous solubility.

**11. hERG Inhibition:** Ligand A has a very low hERG risk (0.128). Ligand B has a moderate hERG risk (0.744). This favors Ligand A, but the difference isn't huge.

**12. Microsomal Clearance:** Ligand A has a moderate Cl_mic (57.007). Ligand B has a higher Cl_mic (65.648), suggesting faster metabolism. This favors Ligand A.

**13. In vitro Half-Life:** Ligand A has a negative half-life (-2.929), which is not a meaningful value. Ligand B has a positive half-life (1.898), which is better.

**14. P-gp Efflux:** Ligand A has very low P-gp efflux (0.17), which is excellent for CNS penetration. Ligand B has a moderate P-gp efflux (0.261), which is less favorable. This favors Ligand A.

**15. Binding Affinity:** Ligand A has a significantly better binding affinity (-8.2 kcal/mol) than Ligand B (-0.0 kcal/mol). This is a substantial advantage for Ligand A, and could potentially outweigh some of its ADME drawbacks.

**Overall Assessment:**

Despite Ligand A's superior binding affinity, its extremely high DILI risk and poor BBB penetration are major red flags. While its P-gp efflux is low, the other ADME properties are concerning. Ligand B, while having weaker affinity, presents a much more favorable ADME profile, with lower DILI risk, better BBB penetration, and acceptable logP and TPSA values. For a CNS target like DRD2, a balance between affinity and ADME properties is crucial. The significant safety concerns with Ligand A outweigh its binding advantage.

Output:
1
2025-04-17 08:10:12,530 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (361.869 and 340.467 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (58.56) is slightly above the ideal <90 for CNS targets, but still reasonable. Ligand B (50.36) is excellent, well below 90.

**3. logP:** Ligand A (3.852) is at the upper end of the optimal range (1-3), while Ligand B (4.405) is slightly above, potentially raising concerns about solubility and off-target effects.

**4. H-Bond Donors:** Both ligands have 2 HBD, which is within the acceptable limit of <=5.

**5. H-Bond Acceptors:** Ligand A has 3 HBA, and Ligand B has 2. Both are well within the acceptable limit of <=10.

**6. QED:** Both ligands have good QED scores (0.713 and 0.847), indicating drug-like properties.

**7. DILI:** Both ligands have similar, acceptable DILI risk (47.034 and 47.383 percentile).

**8. BBB:** This is a critical parameter for a CNS target like DRD2. Ligand B (89.066) has a significantly higher BBB penetration score than Ligand A (33.424). This is a major advantage for Ligand B.

**9. Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and suggests poor permeability. However, these values are on a strange scale, and likely represent logP-scaled permeability. Given the logP values, this is not unexpected.

**10. Aqueous Solubility:** Both ligands have negative solubility values, which is also unusual.

**11. hERG Inhibition:** Both ligands have low hERG inhibition risk (0.783 and 0.88).

**12. Microsomal Clearance:** Ligand B (36.339) has a lower microsomal clearance than Ligand A (66.733), indicating better metabolic stability.

**13. In vitro Half-Life:** Ligand B (47.782) has a significantly longer in vitro half-life than Ligand A (30.447).

**14. P-gp Efflux:** Ligand A (0.837) has slightly higher P-gp efflux liability than Ligand B (0.474), meaning Ligand B is less likely to be pumped out of the brain.

**15. Binding Affinity:** Ligand B (-9.7 kcal/mol) has a substantially stronger binding affinity than Ligand A (-8.7 kcal/mol). This difference of 1 kcal/mol is significant and can outweigh some ADME drawbacks.

**Overall Assessment:**

Ligand B is the superior candidate. While both ligands are within the acceptable MW and QED ranges, Ligand B excels in the critical parameters for a CNS-targeting GPCR: significantly higher BBB penetration, lower P-gp efflux, better metabolic stability (lower Cl_mic and longer t1/2), and a considerably stronger binding affinity. Although Ligand B's logP is slightly higher, the substantial benefits in other areas make it the more promising drug candidate.

Output:
1
2025-04-17 08:10:12,530 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (339.483 Da) is slightly lower, which could be advantageous for permeability. Ligand B (368.543 Da) is also good.

**TPSA:** Ligand A (48.13) is excellent, well below the 90 A^2 threshold for CNS targets. Ligand B (58.64) is still reasonable, but less optimal.

**logP:** Ligand A (4.247) is a bit high, potentially leading to solubility issues or off-target interactions. Ligand B (2.3) is within the optimal range (1-3).

**H-Bond Donors/Acceptors:** Ligand A (2 HBD, 1 HBA) is favorable. Ligand B (1 HBD, 4 HBA) is also acceptable.

**QED:** Ligand A (0.812) has a very strong drug-like profile. Ligand B (0.678) is still acceptable, but less so.

**DILI:** Ligand A (40.054) has a low DILI risk. Ligand B (8.918) has a very low DILI risk, which is excellent.

**BBB:** Ligand A (96.084) has excellent BBB penetration, highly desirable for a CNS target. Ligand B (71.501) also shows good BBB penetration, but is lower than Ligand A.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values, which is unusual and suggests a potential issue with the prediction method or the compounds themselves. We'll have to consider this cautiously.

**Aqueous Solubility:** Both ligands have negative solubility values, which is also unusual. This suggests poor aqueous solubility for both compounds.

**hERG Inhibition:** Ligand A (0.9) shows a slightly higher risk of hERG inhibition than Ligand B (0.462).

**Microsomal Clearance:** Ligand A (60.497) has a moderate microsomal clearance, suggesting moderate metabolic stability. Ligand B (57.15) also has moderate clearance.

**In vitro Half-Life:** Ligand A (4.108 hours) has a relatively short half-life. Ligand B (-4.239 hours) is even shorter, and the negative value is suspect.

**P-gp Efflux:** Ligand A (0.711) has moderate P-gp efflux, which could limit CNS exposure. Ligand B (0.095) has very low P-gp efflux, a significant advantage.

**Binding Affinity:** Ligand A (-9.3 kcal/mol) has a significantly stronger binding affinity than Ligand B (-7.4 kcal/mol). This is a substantial difference.

**Overall Assessment:**

Ligand A excels in BBB penetration, QED, and, crucially, binding affinity. However, its higher logP and moderate P-gp efflux are concerns. Ligand B has better logP, lower DILI, and significantly lower P-gp efflux, but its binding affinity is weaker.

Given the importance of binding affinity for GPCRs, and the fact that Ligand A's affinity is >1.5 kcal/mol better, I would prioritize Ligand A despite its drawbacks. The strong binding could potentially compensate for the slightly higher logP and moderate P-gp efflux. The excellent BBB penetration is also a major plus. The negative Caco-2 and solubility values are concerning and would require further investigation, but the binding affinity is a strong driver.

Output:
0
2025-04-17 08:10:12,530 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (377.482 and 370.515 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (100.78) is higher than the preferred <90 for CNS targets, while Ligand B (66.92) is well within the range. This is a significant advantage for Ligand B.

**3. logP:** Ligand A (0.499) is quite low, potentially hindering membrane permeability. Ligand B (1.02) is better, falling within the optimal 1-3 range.

**4. H-Bond Donors:** Ligand A (1) and Ligand B (0) are both acceptable.

**5. H-Bond Acceptors:** Both ligands have 4 HBA, which is acceptable.

**6. QED:** Both ligands have similar QED values (0.754 and 0.7), indicating good drug-like properties.

**7. DILI:** Ligand A (28.693) has a slightly higher DILI risk than Ligand B (12.33), but both are below the concerning threshold of 60.

**8. BBB:** Ligand B (82.047) has a better BBB penetration percentile than Ligand A (77.705), which is important for a CNS target like DRD2.

**9. Caco-2 Permeability:** Ligand A (-4.933) has worse Caco-2 permeability than Ligand B (-4.481).

**10. Aqueous Solubility:** Both ligands have similar, poor aqueous solubility (-1.784 and -1.533). This could pose formulation challenges.

**11. hERG Inhibition:** Both ligands have low hERG inhibition risk (0.178 and 0.238).

**12. Microsomal Clearance:** Ligand A (11.749) has lower microsomal clearance than Ligand B (31.763), suggesting better metabolic stability.

**13. In vitro Half-Life:** Ligand A (-32.959) has a significantly longer in vitro half-life than Ligand B (-10.286). This is a major advantage for Ligand A.

**14. P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.019 and 0.045).

**15. Binding Affinity:** Both ligands have similar binding affinities (-8 and -7.5 kcal/mol), both of which are excellent.

**Overall Assessment:**

Ligand B excels in TPSA and BBB, crucial for CNS penetration. Its logP is also more favorable. However, Ligand A demonstrates superior metabolic stability (lower Cl_mic) and a much longer half-life. The difference in half-life is substantial. While Ligand A's logP and TPSA are less ideal, the strong binding affinity and significantly improved half-life outweigh these drawbacks, especially considering the potential for further optimization of logP/TPSA.

Output:
1
2025-04-17 08:10:12,530 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (349.479 and 344.415 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (78.43) is significantly better than Ligand B (95.16). For CNS targets, we want TPSA <= 90, so Ligand A is preferable.

**3. logP:** Both ligands have good logP values (1.479 and 1.235), falling within the optimal 1-3 range.

**4. H-Bond Donors:** Ligand A (1) is better than Ligand B (2). Lower HBD generally improves permeability.

**5. H-Bond Acceptors:** Ligand A (5) is better than Ligand B (4). Lower HBA generally improves permeability.

**6. QED:** Both ligands have similar and acceptable QED values (0.769 and 0.786), indicating good drug-likeness.

**7. DILI:** Ligand A (17.138) has a much lower DILI risk than Ligand B (54.75). This is a significant advantage for Ligand A.

**8. BBB:** Ligand A (49.515) is lower than Ligand B (57.968), but both are below the desirable >70 for CNS targets. However, given the other properties, this is less critical.

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.015 and -5.165), which is unusual and suggests poor permeability. This is a concern for both.

**10. Aqueous Solubility:** Ligand A (-0.254) is better than Ligand B (-3.392). Higher solubility is generally preferred.

**11. hERG Inhibition:** Ligand A (0.089) has a much lower hERG risk than Ligand B (0.217). This is a significant advantage.

**12. Microsomal Clearance:** Ligand A (22.695) has higher clearance than Ligand B (10.528), indicating lower metabolic stability. This is a disadvantage for Ligand A.

**13. In vitro Half-Life:** Ligand B (-22.434) has a much longer half-life than Ligand A (20.164). This is a significant advantage for Ligand B.

**14. P-gp Efflux:** Ligand A (0.001) has very low P-gp efflux liability, which is excellent for CNS penetration. Ligand B (0.019) is also low, but not as favorable.

**15. Binding Affinity:** Ligand B (-7.6) has slightly better binding affinity than Ligand A (-7.4). While a 1.5 kcal/mol advantage is often significant, the other factors are more compelling here.

**Overall Assessment:**

Ligand A is superior due to its significantly better TPSA, DILI risk, hERG risk, solubility, and P-gp efflux liability. While Ligand B has a slightly better affinity and half-life, the lower TPSA and safety profiles of Ligand A are more crucial for a CNS-targeting GPCR ligand. The Caco-2 permeability is a concern for both, but the other advantages of Ligand A outweigh this drawback.

Output:
0
2025-04-17 08:10:12,530 - INFO - Reasoning:

Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (404.308 Da) is slightly higher than Ligand B (340.467 Da), but both are acceptable.

**2. TPSA:** Ligand A (70.23) is higher than Ligand B (49.41). For CNS targets, we prefer TPSA <= 90, so both are within range, but Ligand B is significantly better.

**3. logP:** Both ligands have good logP values (A: 3.429, B: 3.188), falling within the optimal 1-3 range.

**4. H-Bond Donors:** Ligand A has 3 HBD, and Ligand B has 1. Both are acceptable (<=5).

**5. H-Bond Acceptors:** Ligand A has 3 HBA, and Ligand B has 2. Both are acceptable (<=10).

**6. QED:** Both ligands have good QED values (A: 0.62, B: 0.829), indicating good drug-like properties. Ligand B is slightly better.

**7. DILI:** Ligand A (65.762) has a higher DILI risk than Ligand B (25.785). Ligand B is well below the 40% threshold, indicating low risk. Ligand A is above, suggesting moderate risk.

**8. BBB:** Ligand B (77.2) has a better BBB penetration percentile than Ligand A (67.352). Both are reasonably good for a CNS target, but Ligand B is preferable.

**9. Caco-2 Permeability:** Both have negative values, which is unusual and potentially problematic. However, the magnitude of the negative value for Ligand A (-5.056) is larger than Ligand B (-4.624), suggesting potentially lower intestinal absorption for Ligand A.

**10. Aqueous Solubility:** Both have negative values, indicating poor solubility. Ligand A (-4.713) is slightly worse than Ligand B (-3.675).

**11. hERG Inhibition:** Both ligands have low hERG inhibition risk (A: 0.811, B: 0.737).

**12. Microsomal Clearance:** Ligand A (30.818) has lower microsomal clearance than Ligand B (59.471), suggesting better metabolic stability.

**13. In vitro Half-Life:** Ligand A (86.427) has a significantly longer in vitro half-life than Ligand B (-4.505). This is a major advantage for Ligand A.

**14. P-gp Efflux:** Ligand A (0.282) has lower P-gp efflux than Ligand B (0.417), meaning better CNS exposure.

**15. Binding Affinity:** Ligand B (-9.7 kcal/mol) has a slightly better binding affinity than Ligand A (-9.1 kcal/mol). While the difference is not huge, it's still a factor.

**Overall Assessment:**

Ligand B excels in key areas for CNS GPCR targets: lower TPSA, better BBB penetration, lower DILI risk, and slightly better binding affinity. Ligand A has advantages in metabolic stability (lower Cl_mic) and longer half-life, and lower P-gp efflux. However, the better BBB, lower DILI, and slightly better affinity of Ligand B outweigh the advantages of Ligand A. The negative Caco-2 and solubility values are concerning for both, but can be addressed with formulation strategies.

Output:
1
2025-04-17 08:10:12,530 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (348.403 and 353.463 Da) fall comfortably within the ideal 200-500 Da range.

**TPSA:** Ligand A (104.65) is slightly higher than Ligand B (87.74). For CNS targets, we ideally want TPSA <= 90. Ligand B is better here.

**logP:** Ligand A (-0.098) is slightly negative, which could hinder permeability. Ligand B (0.54) is within the optimal 1-3 range. Ligand B is significantly better.

**H-Bond Donors/Acceptors:** Both have 2 HBDs, which is good. Ligand A has 6 HBAs, and Ligand B has 4. Both are acceptable (<=10), but Ligand B is slightly preferable.

**QED:** Both ligands have good QED scores (0.744 and 0.699, both > 0.5).

**DILI:** Ligand A (37.922) has a lower DILI risk than Ligand B (8.104), which is favorable.

**BBB:** Ligand A (64.056) has a better BBB penetration percentile than Ligand B (59.636). This is a crucial factor for a CNS target like DRD2.

**Caco-2 Permeability:** Both have negative Caco-2 values (-4.986 and -4.857), which is unusual and suggests poor permeability. This is a significant concern for both.

**Aqueous Solubility:** Both have negative solubility values (-1.319 and -1.712), also unusual and concerning.

**hERG Inhibition:** Both have very low hERG inhibition liability (0.181 and 0.158), which is excellent.

**Microsomal Clearance:** Ligand A (-3.086) has a lower (better) microsomal clearance than Ligand B (8.788), indicating better metabolic stability.

**In vitro Half-Life:** Ligand A (8.057) has a longer half-life than Ligand B (-4.83). This is a positive attribute.

**P-gp Efflux:** Both have very low P-gp efflux liability (0.006 and 0.004), which is good for CNS penetration.

**Binding Affinity:** Ligand A (-7.8 kcal/mol) has a slightly better binding affinity than Ligand B (-7.4 kcal/mol). This 0.4 kcal/mol difference is significant.

**Overall Assessment:**

While Ligand A has better BBB penetration, metabolic stability, and binding affinity, Ligand B has a better logP and TPSA, which are important for GPCRs. Both ligands have concerningly poor predicted Caco-2 permeability and aqueous solubility. However, the slightly better affinity of Ligand A, combined with its superior BBB and metabolic stability, outweighs the slightly better logP/TPSA of Ligand B. The difference in binding affinity is also substantial enough to compensate for the slightly less ideal logP.

Output:
1
2025-04-17 08:10:12,530 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (347.503 and 347.39 Da) fall comfortably within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (61.44) is significantly better than Ligand B (84.23). For CNS targets, we want TPSA <= 90, and A is much closer to the ideal <=60 range. B is pushing the upper limit and could face permeability issues.

**3. logP:** Both ligands have a logP of around 2, which is optimal (1-3).

**4. H-Bond Donors:** Both have 2 HBD, which is within the acceptable limit of <=5.

**5. H-Bond Acceptors:** Ligand A has 3 HBA, and Ligand B has 4. Both are within the acceptable limit of <=10.

**6. QED:** Ligand B (0.765) has a slightly better QED than Ligand A (0.521), indicating a more drug-like profile. However, QED is less critical than other factors here.

**7. DILI:** Ligand A (10.896) has a much lower DILI risk than Ligand B (35.789). This is a significant advantage for A.

**8. BBB:** Ligand A (51.105) has a better BBB penetration percentile than Ligand B (46.724), although both are not ideal. A score >70 is desirable for CNS targets. However, A is closer.

**9. Caco-2 Permeability:** Ligand A (-4.814) has a worse Caco-2 permeability than Ligand B (-5.034). Lower values indicate lower permeability.

**10. Aqueous Solubility:** Both ligands have very poor aqueous solubility (-2.24 and -2.243). This is a concern for both, but can be addressed with formulation strategies.

**11. hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.196 and 0.25).

**12. Microsomal Clearance:** Ligand A (22.091) has a lower microsomal clearance than Ligand B (26.651), suggesting better metabolic stability.

**13. In vitro Half-Life:** Ligand B (36.357) has a significantly longer in vitro half-life than Ligand A (7.517). This is a strong advantage for B.

**14. P-gp Efflux:** Both ligands have low P-gp efflux liability (0.027 and 0.036).

**15. Binding Affinity:** Ligand B (-9.0 kcal/mol) has a significantly stronger binding affinity than Ligand A (-7.3 kcal/mol). This is a substantial advantage, exceeding the 1.5 kcal/mol threshold.

**Overall Assessment:**

Ligand B has a significantly better binding affinity and a longer half-life, which are crucial for efficacy and dosing. However, Ligand A has a much better TPSA, lower DILI risk, and slightly better BBB penetration. The affinity difference is substantial enough to outweigh the drawbacks of Ligand B, especially considering formulation strategies can potentially address the solubility issues. The lower TPSA of Ligand A is beneficial for CNS penetration, but the difference isn't large enough to overcome the significant affinity advantage of Ligand B.

Output:
1
2025-04-17 08:10:12,530 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (347.415 and 359.407 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (83.76) is significantly better than Ligand B (96.85). For CNS targets, we want TPSA <= 90, so Ligand A is preferable.

**3. logP:** Both ligands have good logP values (1.315 and 1.488), falling within the optimal 1-3 range.

**4. H-Bond Donors:** Ligand A (0) is slightly better than Ligand B (1), as fewer HBDs generally improve permeability.

**5. H-Bond Acceptors:** Ligand A (4) is better than Ligand B (5). Lower HBA is generally preferred.

**6. QED:** Ligand B (0.898) has a substantially better QED score than Ligand A (0.438), indicating a more drug-like profile.

**7. DILI:** Ligand A (34.161) has a much lower DILI risk than Ligand B (70.686). This is a significant advantage for Ligand A.

**8. BBB:** Ligand A (71.384) has a better BBB penetration percentile than Ligand B (60.644). Both are reasonably good, but Ligand A is closer to the desirable >70 threshold for CNS targets.

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 values, which is unusual and requires further investigation. However, the magnitude is similar (-4.813 vs -5.056).

**10. Aqueous Solubility:** Both ligands have negative solubility values, again unusual and requiring further investigation. The magnitude is similar (-2.861 vs -3.543).

**11. hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.18 and 0.196).

**12. Microsomal Clearance:** Ligand A (57.36) has a higher microsomal clearance than Ligand B (19.876), suggesting faster metabolism and potentially lower *in vivo* exposure. This favors Ligand B.

**13. In vitro Half-Life:** Ligand B (19.762) has a significantly longer in vitro half-life than Ligand A (-14.453), which is a major advantage.

**14. P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.171 and 0.203).

**15. Binding Affinity:** Ligand B (-8.4) has a slightly better binding affinity than Ligand A (-8.0). While the difference is not huge, it is still a positive for Ligand B.

**Overall Assessment:**

Ligand A excels in TPSA, BBB, and DILI risk. However, Ligand B has a superior QED score, longer half-life, better binding affinity, and lower microsomal clearance. Given the GPCR-specific priorities, BBB penetration is crucial, and Ligand A has a better score. However, the substantial difference in half-life and QED, coupled with the slightly better affinity, makes Ligand B more promising. The lower DILI risk of Ligand A is attractive, but can potentially be addressed through structural modifications.

Output:
1
2025-04-17 08:10:12,531 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (346.387 and 346.391 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (114.62) is slightly higher than Ligand B (113.24), but both are below the 140 A^2 threshold for good oral absorption and reasonably close to the 90 A^2 target for CNS penetration.

**3. logP:** Ligand A (-0.01) is slightly lower than the optimal 1-3 range, potentially hindering permeability. Ligand B (0.953) is closer to the ideal range.

**4. H-Bond Donors:** Both ligands have 2 HBD, which is within the acceptable limit of <=5.

**5. H-Bond Acceptors:** Ligand A has 5 HBA, while Ligand B has 7. Both are within the acceptable limit of <=10, but Ligand A is preferable.

**6. QED:** Both ligands have good QED scores (0.674 and 0.772, respectively), indicating drug-like properties.

**7. DILI:** Ligand A (38.969) has a lower DILI risk than Ligand B (55.603), which is a significant advantage.

**8. BBB:** This is a critical parameter for CNS targets. Ligand A (60.915) has a better BBB percentile than Ligand B (35.518). This is a major point in favor of Ligand A.

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.459 and -5.691), which is unusual and suggests poor permeability. However, the values are very similar.

**10. Aqueous Solubility:** Both ligands have negative solubility values (-1.631 and -2.588), indicating poor aqueous solubility. Ligand B is slightly worse.

**11. hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.05 and 0.082, respectively).

**12. Microsomal Clearance:** Ligand A (-2.398) has a lower (better) microsomal clearance than Ligand B (39.091), indicating greater metabolic stability.

**13. In vitro Half-Life:** Ligand A (7.175) has a longer half-life than Ligand B (-10.011), which is desirable.

**14. P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.013 and 0.023, respectively).

**15. Binding Affinity:** Both ligands have very similar binding affinities (-8.4 and -8.3 kcal/mol). The difference is negligible.

**Overall Assessment:**

Considering the GPCR-specific priorities, Ligand A is the more promising candidate. It has a significantly better BBB penetration score, lower DILI risk, better metabolic stability (lower Cl_mic), and a longer half-life. While both have poor solubility and permeability, the other advantages of Ligand A outweigh this drawback. The similar binding affinities mean that the ADME properties are the deciding factors.

Output:
0
2025-04-17 08:10:12,531 - INFO - Reasoning:

Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (348.447 and 344.415 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (106.34) is slightly above the optimal <90 for CNS targets, but still reasonable. Ligand B (98.22) is better, falling comfortably under 100.

**3. logP:** Both ligands have good logP values (1.556 and 1.444), within the optimal 1-3 range.

**4. H-Bond Donors:** Ligand A (3) and Ligand B (2) are both acceptable, below the threshold of 5.

**5. H-Bond Acceptors:** Ligand A (5) and Ligand B (4) are both acceptable, below the threshold of 10.

**6. QED:** Both ligands have good QED scores (0.661 and 0.763), indicating good drug-like properties.

**7. DILI:** Both ligands have low DILI risk (45.095 and 43.66), well below the concerning threshold of 60.

**8. BBB:** This is a critical parameter for a CNS target like DRD2. Ligand A has a BBB percentile of 70.027, which is desirable (>70). Ligand B has a significantly lower BBB percentile of 56.029, which is less favorable.

**9. Caco-2 Permeability:** Both have negative values, which is unusual. The scale is not specified, but lower values generally indicate poorer permeability. Ligand A (-5.241) is slightly better than Ligand B (-4.781).

**10. Aqueous Solubility:** Both ligands have negative solubility values, which is also unusual. Lower values indicate poorer solubility. Ligand B (-3.907) is slightly better than Ligand A (-2.296).

**11. hERG Inhibition:** Both ligands have low hERG inhibition risk (0.238 and 0.333).

**12. Microsomal Clearance:** Ligand A (25.946) has higher clearance than Ligand B (-11.523). This suggests Ligand B is more metabolically stable.

**13. In vitro Half-Life:** Ligand B (12.912) has a significantly longer half-life than Ligand A (-1.398).

**14. P-gp Efflux:** Both ligands have low P-gp efflux liability (0.031 and 0.102).

**15. Binding Affinity:** Ligand A (-8.6 kcal/mol) has a slightly better binding affinity than Ligand B (-7.9 kcal/mol). This is a 0.7 kcal/mol difference, which is significant.

**Overall Assessment:**

While Ligand B has better metabolic stability (lower Cl_mic, longer t1/2) and solubility, Ligand A has a substantially better BBB penetration (70% vs 56%), and a slightly better binding affinity (-8.6 vs -7.9 kcal/mol). Given that this is a CNS target, BBB penetration is paramount. The slightly better affinity of Ligand A further strengthens its position. The small differences in solubility and metabolic stability are less critical than the BBB and affinity advantages.

Output:
1
2025-04-17 08:10:12,531 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (349.479 and 348.407 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (98.17) is excellent, falling well below the 90 A^2 threshold for CNS targets. Ligand B (121.93) is still reasonable, but less optimal, being above 90 A^2.

**logP:** Ligand A (3.256) is within the optimal 1-3 range. Ligand B (-0.313) is significantly below 1, which could hinder membrane permeability and CNS penetration.

**H-Bond Donors/Acceptors:** Ligand A (HBD=1, HBA=3) is favorable. Ligand B (HBD=2, HBA=7) is acceptable, but the higher HBA count could slightly impact permeability.

**QED:** Ligand B (0.697) has a better QED score than Ligand A (0.372), indicating a more drug-like profile overall.

**DILI:** Ligand A (22.838) has a much lower DILI risk than Ligand B (57.891), which is a significant advantage.

**BBB:** Ligand A (64.715) has a better BBB percentile than Ligand B (37.146), which is critical for a CNS target like DRD2.

**Caco-2 Permeability:** Ligand A (-4.642) has a worse Caco-2 permeability than Ligand B (-5.395), but both are very poor.

**Aqueous Solubility:** Ligand A (-2.432) has better aqueous solubility than Ligand B (-1.646), though both are poor.

**hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.287 and 0.049 respectively).

**Microsomal Clearance:** Ligand B (-15.254) exhibits significantly lower microsomal clearance than Ligand A (36.773), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand B (20.789) has a longer in vitro half-life than Ligand A (11.551), which is desirable.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.042 and 0.014 respectively).

**Binding Affinity:** Ligand B (-7.6 kcal/mol) has a slightly better binding affinity than Ligand A (-6.8 kcal/mol). This 0.8 kcal/mol difference is substantial and could outweigh some of the ADME drawbacks of Ligand B.

**Overall Assessment:**

Ligand A excels in TPSA, BBB, and DILI risk, which are crucial for CNS GPCR targets. However, its Caco-2 and solubility are poor. Ligand B has a better QED, metabolic stability (lower Cl_mic, longer t1/2), and a slightly stronger binding affinity. Its main weaknesses are the lower BBB penetration and higher DILI risk, and poor logP.

Given the importance of CNS penetration for a DRD2 ligand, and the significant difference in BBB percentile, Ligand A is the more promising candidate despite its slightly weaker affinity. The better TPSA and lower DILI risk further support this conclusion. The affinity difference is not large enough to overcome the permeability concerns of Ligand B.

Output:
0
2025-04-17 08:10:12,531 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (346.431 Da) is slightly lower, which could be beneficial for permeability.

**TPSA:** Ligand A (75.63) is better than Ligand B (56.67) regarding TPSA, being closer to the desirable <90 for CNS targets. Ligand B is quite low, which is good, but A is still acceptable.

**logP:** Both ligands have good logP values (A: 1.441, B: 2.989), falling within the optimal 1-3 range. Ligand B is closer to the upper end, which could potentially lead to solubility issues, but is still acceptable.

**H-Bond Donors/Acceptors:** Both ligands have reasonable HBD/HBA counts (A: 0/5, B: 1/5), well within the guidelines.

**QED:** Both ligands have good QED scores (A: 0.575, B: 0.682), indicating drug-like properties. Ligand B is slightly better.

**DILI:** Ligand A (38.736) has a slightly higher DILI risk than Ligand B (13.416), but both are below the concerning threshold of 60.

**BBB:** This is a critical parameter for CNS targets. Ligand A (83.288) has a significantly better BBB penetration percentile than Ligand B (65.374). This is a major advantage for Ligand A.

**Caco-2 Permeability:** Ligand A (-4.605) and Ligand B (-5.044) both have negative Caco-2 values. This is unusual, and indicates poor permeability.

**Aqueous Solubility:** Both ligands have poor aqueous solubility (A: -1.237, B: -2.913). This could be a formulation challenge.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (A: 0.184, B: 0.664), which is favorable.

**Microsomal Clearance:** Ligand A (32.789) has a lower microsomal clearance than Ligand B (80.769), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (-5.371) has a longer in vitro half-life than Ligand B (-4.922), which is desirable.

**P-gp Efflux:** Ligand A (0.089) has much lower P-gp efflux liability than Ligand B (0.183), which is crucial for CNS exposure.

**Binding Affinity:** Ligand A (-7.7 kcal/mol) has a slightly better binding affinity than Ligand B (-6.5 kcal/mol). This difference of 1.2 kcal/mol is substantial and can outweigh some ADME drawbacks.

**Overall Assessment:**

Ligand A is the stronger candidate. While both have poor solubility and Caco-2 permeability, Ligand A excels in the most important parameters for a CNS-targeting GPCR ligand: BBB penetration, P-gp efflux, metabolic stability (lower Cl_mic, longer t1/2), and binding affinity. The slightly higher DILI risk is less concerning than the significant advantages in CNS penetration and potency.

Output:
0
2025-04-17 08:10:12,531 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (343.43 and 357.40 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (61.88) is excellent, well below the 90 A^2 threshold for CNS targets. Ligand B (128.68) is higher, but still potentially acceptable, though less ideal.

**logP:** Ligand A (1.405) is within the optimal 1-3 range. Ligand B (0.394) is slightly below 1, which *could* indicate permeability issues, but isn't a dealbreaker.

**H-Bond Donors/Acceptors:** Ligand A (1 HBD, 4 HBA) and Ligand B (2 HBD, 8 HBA) both have reasonable numbers of H-bond donors and acceptors, well within the guidelines.

**QED:** Both ligands have good QED scores (0.901 and 0.629), indicating good drug-like properties.

**DILI:** Both ligands have elevated DILI risk (53.94 and 75.18), but are below the concerning >60 threshold.

**BBB:** This is a critical parameter for a CNS target like DRD2. Ligand A has a very good BBB penetration percentile (73.52), while Ligand B is significantly lower (36.14).

**Caco-2 Permeability:** Ligand A (-4.627) has poor Caco-2 permeability, while Ligand B (-5.841) is also poor. This is a concern, but can be mitigated by other factors.

**Aqueous Solubility:** Both ligands have very poor aqueous solubility (-3.047 and -1.707). This will likely require formulation strategies.

**hERG:** Both ligands have very low hERG inhibition liability (0.389 and 0.032).

**Microsomal Clearance:** Ligand A (-20.942) has a lower (better) microsomal clearance than Ligand B (-13.50). This suggests better metabolic stability for Ligand A.

**In vitro Half-Life:** Ligand A (7.876 hours) has a longer half-life than Ligand B (2.578 hours).

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.018 and 0.017).

**Binding Affinity:** Both ligands have excellent binding affinities (-9.4 and -8.0 kcal/mol). Ligand A is slightly stronger.

**Overall Assessment:**

Ligand A is superior due to its significantly better BBB penetration (73.52% vs. 36.14%), longer half-life, and lower microsomal clearance, despite having poorer Caco-2 permeability. The slightly stronger binding affinity of Ligand A is an additional benefit. While both have poor solubility, this is a formulation challenge. The DILI risk is moderate for both, but manageable. For a CNS target, BBB penetration is paramount, and Ligand A clearly wins in this regard.

Output:
0
2025-04-17 08:10:12,532 - INFO - Batch 426 complete. Total preferences: 6816
2025-04-17 08:10:12,532 - INFO - Processing batch 427/512...
2025-04-17 08:10:53,350 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (341.39 and 350.46 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (61.44) is excellent, well below the 90 A^2 threshold for CNS targets. Ligand B (90.54) is at the upper limit, and could potentially suffer from reduced BBB penetration.

**logP:** Ligand A (2.257) is optimal (1-3). Ligand B (0.293) is quite low, potentially hindering membrane permeability and CNS penetration.

**H-Bond Donors/Acceptors:** Ligand A (2 HBD, 2 HBA) is favorable. Ligand B (3 HBD, 4 HBA) is acceptable, but slightly higher counts could impact permeability.

**QED:** Ligand A (0.82) is very good, indicating high drug-likeness. Ligand B (0.642) is still acceptable, but lower than A.

**DILI:** Ligand A (54.323) has a moderate DILI risk, but is acceptable. Ligand B (16.44) has a very low DILI risk, which is excellent.

**BBB:** Ligand A (88.29) has excellent BBB penetration potential. Ligand B (37.65) has poor BBB penetration, a significant drawback for a CNS target.

**Caco-2 Permeability:** Ligand A (-4.811) is concerningly low, suggesting poor intestinal absorption. Ligand B (-5.664) is also low, but slightly better than A.

**Aqueous Solubility:** Ligand A (-3.868) is poor. Ligand B (-1.489) is also poor, but slightly better than A.

**hERG Inhibition:** Ligand A (0.857) has a moderate hERG risk. Ligand B (0.059) has a very low hERG risk, which is excellent.

**Microsomal Clearance:** Ligand A (38.686) has moderate clearance. Ligand B (-13.315) has negative clearance, indicating very high metabolic stability, which is a significant advantage.

**In vitro Half-Life:** Both ligands (8.979 and 8.988 hours) have comparable in vitro half-lives.

**P-gp Efflux:** Ligand A (0.213) has low P-gp efflux, which is good for CNS exposure. Ligand B (0.005) has very low P-gp efflux, which is excellent.

**Binding Affinity:** Ligand A (-10.5 kcal/mol) has significantly stronger binding affinity than Ligand B (-9.4 kcal/mol). This 1.1 kcal/mol difference is substantial and can outweigh some ADME drawbacks.

**Overall Assessment:**

Ligand A excels in binding affinity and BBB penetration, but suffers from poor Caco-2 permeability and solubility. Ligand B has excellent metabolic stability, low DILI and hERG risk, and very low P-gp efflux, but its low logP and poor BBB penetration are major concerns for a CNS target.

Given the importance of BBB penetration for a DRD2 ligand (CNS target), and the substantial affinity advantage of Ligand A, I would prioritize Ligand A despite its ADME liabilities. The strong binding affinity might compensate for the lower permeability and solubility, and formulation strategies could be explored to address those issues. The poor BBB penetration of Ligand B is a critical flaw.

Output:
0
2025-04-17 08:10:53,351 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (350.459 and 360.841 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (76.66) is better than Ligand B (51.66) as it is closer to the optimal range for CNS targets (<=90). Ligand B is excellent.

**3. logP:** Both ligands have good logP values (1.385 and 2.983), falling within the 1-3 range.

**4. H-Bond Donors:** Ligand A has 2 HBD, which is acceptable. Ligand B has 0, also acceptable.

**5. H-Bond Acceptors:** Both ligands have 4 HBA, which is within the acceptable limit of <=10.

**6. QED:** Both ligands have good QED scores (0.512 and 0.794), indicating good drug-like properties.

**7. DILI:** Ligand A (18.651) has a significantly lower DILI risk than Ligand B (36.409). This is a major advantage for Ligand A.

**8. BBB:** Ligand B (80.535) has a substantially better BBB penetration score than Ligand A (50.872). This is critical for a CNS target like DRD2.

**9. Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and suggests poor permeability. However, the scale is not specified, so it's hard to interpret.

**10. Aqueous Solubility:** Both have negative solubility values, which is also unusual and suggests poor solubility. Again, the scale is not specified.

**11. hERG Inhibition:** Both ligands have low hERG inhibition risk (0.23 and 0.5).

**12. Microsomal Clearance:** Ligand A (13.303) has significantly lower microsomal clearance than Ligand B (63.953), indicating better metabolic stability.

**13. In vitro Half-Life:** Ligand B (51.549) has a much longer in vitro half-life than Ligand A (9.407). This is a positive for Ligand B.

**14. P-gp Efflux:** Ligand A (0.04) has much lower P-gp efflux liability than Ligand B (0.255), which is beneficial for CNS penetration.

**15. Binding Affinity:** Ligand B (-7.7) has a slightly better binding affinity than Ligand A (-7.5), but the difference is small (0.2 kcal/mol).

**Overall Assessment:**

Ligand B excels in BBB penetration and has a longer half-life, which are important for CNS drug development. However, it has a higher DILI risk, higher P-gp efflux, and higher microsomal clearance. Ligand A has a much better safety profile (lower DILI) and better metabolic stability (lower Cl_mic), and lower P-gp efflux. The difference in binding affinity is minimal. Given the GPCR-specific priorities, the superior BBB of Ligand B is compelling. However, the significantly lower DILI risk and P-gp efflux of Ligand A are also important considerations. Considering the balance, the slightly better affinity of Ligand B, combined with its superior BBB, outweighs the slightly worse ADME properties.

Output:
1
2025-04-17 08:10:53,351 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (343.427 and 349.475 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Both ligands (74.59 and 75.44) are below the 90 A^2 threshold for CNS targets, which is excellent.

**3. logP:** Ligand A (2.013) is optimal, while Ligand B (3.105) is at the higher end of the optimal range. Both are acceptable.

**4. H-Bond Donors:** Both ligands have 1 HBD, which is within the acceptable limit of <=5.

**5. H-Bond Acceptors:** Ligand A has 5 HBA, and Ligand B has 4. Both are below the acceptable limit of <=10.

**6. QED:** Ligand A (0.885) has a better QED score than Ligand B (0.704), indicating a more drug-like profile.

**7. DILI:** Ligand A (28.306) has a slightly higher DILI risk than Ligand B (16.479), but both are well below the 40% threshold, indicating low risk.

**8. BBB:** Both ligands have excellent BBB penetration (Ligand A: 83.986%, Ligand B: 88.833%), exceeding the desirable >70% threshold for CNS targets. Ligand B is slightly better.

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.562 and -4.534). This is unusual and suggests poor permeability. However, these values are on a scale where negative values are possible and don't necessarily disqualify the compounds.

**10. Aqueous Solubility:** Both ligands have negative solubility values (-3.277 and -3.327). Similar to Caco-2, these values are on a scale where negative values are possible and don't necessarily disqualify the compounds.

**11. hERG Inhibition:** Both ligands have low hERG inhibition risk (Ligand A: 0.876%, Ligand B: 0.672%).

**12. Microsomal Clearance:** Ligand A (24.371) has significantly lower microsomal clearance than Ligand B (75.978), indicating better metabolic stability.

**13. In vitro Half-Life:** Ligand A (33.697) has a longer in vitro half-life than Ligand B (11.044), which is desirable.

**14. P-gp Efflux:** Both ligands have very low P-gp efflux liability (Ligand A: 0.042, Ligand B: 0.172), which is excellent for CNS exposure.

**15. Binding Affinity:** Ligand B (-8.2 kcal/mol) has a slightly stronger binding affinity than Ligand A (-7.8 kcal/mol). This difference of 0.4 kcal/mol is significant, potentially outweighing some of the ADME drawbacks of Ligand B.

**Overall Assessment:**

Ligand B has a slightly better binding affinity and BBB penetration, which are key for a CNS GPCR target like DRD2. However, Ligand A has a better QED score, lower microsomal clearance, and a longer half-life, suggesting better overall drug-like properties and metabolic stability. The Caco-2 and solubility values are concerning for both, but not necessarily disqualifying. Considering the slightly better affinity of Ligand B and its excellent BBB penetration, it appears to be the more promising candidate.

Output:
1
2025-04-17 08:10:53,351 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (404.26 Da) is slightly higher than Ligand B (353.379 Da), but both are acceptable.

**TPSA:** Ligand A (59.0) is excellent for CNS penetration, well below the 90 Angstrom threshold. Ligand B (139.78) is approaching the upper limit for good oral absorption (140), but is less ideal for CNS targets.

**logP:** Ligand A (3.053) is optimal. Ligand B (-2.602) is significantly below the optimal range, potentially hindering membrane permeability and CNS penetration.

**H-Bond Donors/Acceptors:** Ligand A (HBD=1, HBA=4) is within acceptable limits. Ligand B (HBD=3, HBA=7) is also acceptable, but slightly higher, potentially impacting permeability.

**QED:** Ligand A (0.836) has a very good drug-likeness score. Ligand B (0.491) is below the 0.5 threshold, indicating a less favorable drug-like profile.

**DILI:** Both ligands have acceptable DILI risk (Ligand A: 55.293, Ligand B: 39.511).

**BBB:** Ligand A (66.305) has a good BBB percentile, though ideally >70. Ligand B (28.383) has a low BBB percentile, making CNS penetration less likely.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values, which is unusual and suggests potential issues with the prediction method or the compounds themselves. However, we must proceed with the available data.

**Aqueous Solubility:** Both ligands have negative solubility values, which is also unusual.

**hERG:** Ligand A (0.773) has a low hERG risk. Ligand B (0.032) also has a very low hERG risk.

**Microsomal Clearance:** Ligand A (81.022) has a relatively high microsomal clearance, suggesting faster metabolism. Ligand B (-12.241) has a negative clearance, which is not physically realistic and suggests a problem with the data.

**In vitro Half-Life:** Ligand A (40.65) has a moderate half-life. Ligand B (12.311) has a short half-life.

**P-gp Efflux:** Ligand A (0.702) has moderate P-gp efflux liability. Ligand B (0.004) has very low P-gp efflux liability, which is favorable for CNS penetration.

**Binding Affinity:** Ligand A (0.0) has a weak binding affinity. Ligand B (-7.1) has a strong binding affinity.

**Overall Assessment:**

Ligand B has a significantly stronger binding affinity (-7.1 kcal/mol vs 0.0 kcal/mol). While its logP is suboptimal and QED is lower, the large affinity difference is the most important factor, especially for a GPCR target. The low P-gp efflux is also a major advantage for CNS penetration. The negative values for Caco-2 and solubility are concerning but are outweighed by the strong binding affinity. Ligand A's better TPSA and QED are offset by its weaker binding and higher clearance.

Output:
1
2025-04-17 08:10:53,351 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight (MW):** Both ligands (344.5 and 345.5 Da) fall comfortably within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (49.41) is significantly better than Ligand B (69.21). For CNS targets, TPSA should be <= 90, and ideally lower. Ligand A is much closer to the optimal range for CNS penetration.

**3. logP:** Both ligands have good logP values (3.276 and 2.188), falling within the 1-3 range. Ligand A is slightly higher, which could be beneficial for membrane permeability.

**4. H-Bond Donors (HBD):** Both are acceptable (1 and 2, respectively), well below the threshold of 5.

**5. H-Bond Acceptors (HBA):** Both are acceptable (2 and 7, respectively), well below the threshold of 10.

**6. QED:** Both ligands have good QED scores (0.804 and 0.848), indicating good drug-like properties.

**7. DILI:** Ligand A (16.712) has a considerably lower DILI risk than Ligand B (52.423). This is a significant advantage.

**8. BBB:** Both ligands have excellent BBB penetration (78.209 and 83.288), exceeding the desirable >70 threshold for CNS targets. Ligand B is slightly better here.

**9. Caco-2 Permeability:** Both have negative values, which is unusual and suggests poor permeability. However, the scale is not specified, so it's hard to interpret.

**10. Aqueous Solubility:** Both have negative values, suggesting poor solubility. Again, scale is unspecified.

**11. hERG Inhibition:** Ligand A (0.404) has a lower hERG inhibition risk than Ligand B (0.85). Lower is better.

**12. Microsomal Clearance (Cl_mic):** Ligand A (87.038) has a higher (worse) microsomal clearance than Ligand B (36.803). Lower clearance indicates better metabolic stability.

**13. In vitro Half-Life:** Ligand B (5.579) has a longer half-life than Ligand A (33.946). Longer half-life is generally preferred.

**14. P-gp Efflux:** Ligand A (0.342) has lower P-gp efflux liability than Ligand B (0.022). Lower efflux is better for CNS exposure.

**15. Binding Affinity:** Ligand B (-9.0) has a significantly stronger binding affinity than Ligand A (-8.3). A 0.7 kcal/mol difference is substantial and can outweigh some ADME drawbacks.

**Overall Assessment:**

Ligand B has a significantly better binding affinity and longer half-life. However, Ligand A excels in TPSA, DILI risk, hERG inhibition, and P-gp efflux, all critical for CNS drug development. The lower DILI risk and better TPSA of Ligand A are particularly attractive. While Ligand B's affinity is stronger, the other properties of Ligand A make it a more balanced and potentially viable drug candidate, especially considering the GPCR-specific priorities.

Output:
1
2025-04-17 08:10:53,351 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (364.555 and 366.483 Da) fall within the ideal range of 200-500 Da.

**TPSA:** Ligand A (49.41) is significantly better than Ligand B (84.5). For CNS targets, we want TPSA <= 90, and A is comfortably within this range, while B is approaching the upper limit.

**logP:** Ligand A (4.246) is slightly higher than the optimal 1-3 range, but still potentially acceptable. Ligand B (2.096) is within the ideal range. However, for a GPCR, a slightly higher logP can be tolerated if other parameters are favorable.

**H-Bond Donors/Acceptors:** Ligand A (HBD=1, HBA=3) and Ligand B (HBD=2, HBA=5) both have reasonable numbers of H-bond donors and acceptors.

**QED:** Both ligands have similar QED values (0.712 and 0.656), indicating good drug-like properties.

**DILI:** Ligand A (34.781) has a significantly lower DILI risk than Ligand B (62.466). This is a substantial advantage for A.

**BBB:** Ligand A (73.711) has a much better BBB penetration percentile than Ligand B (47.383). This is *critical* for a CNS target like DRD2.

**Caco-2 Permeability:** Ligand A (-4.782) shows poor Caco-2 permeability, while Ligand B (-5.288) is also poor, but slightly better.

**Aqueous Solubility:** Ligand A (-4.003) is better than Ligand B (-2.972), meaning it is more soluble.

**hERG:** Both ligands have very low hERG inhibition liability (0.676 and 0.13), which is excellent.

**Microsomal Clearance:** Ligand A (78.338) has higher microsomal clearance than Ligand B (34.18), indicating lower metabolic stability. This is a negative for A.

**In vitro Half-Life:** Ligand A (50.168) has a longer in vitro half-life than Ligand B (15.499), which is a positive for A.

**P-gp Efflux:** Ligand A (0.468) has lower P-gp efflux liability than Ligand B (0.189), which is favorable for CNS penetration.

**Binding Affinity:** Ligand B (-7.6) has a slightly better binding affinity than Ligand A (-7.4), but the difference is relatively small (0.2 kcal/mol).

**Overall Assessment:**

Ligand A is superior despite slightly worse metabolic stability. The key advantages of Ligand A are its significantly better BBB penetration, lower DILI risk, and lower P-gp efflux. These are crucial for a CNS-targeting GPCR ligand. While Ligand B has slightly better affinity and Caco-2 permeability, the BBB and safety profiles of Ligand A are far more important in this context. The difference in affinity is not substantial enough to overcome the significant ADME/Tox advantages of Ligand A.



Output:
0
2025-04-17 08:10:53,351 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (354.447) is slightly lower, which is generally favorable for permeability. Ligand B (372.531) is also good.

**TPSA:** Ligand A (110.1) is borderline for CNS penetration, being above the ideal <90. Ligand B (67.87) is excellent, well below 90, indicating better potential for CNS penetration.

**logP:** Ligand A (-0.224) is quite low, potentially hindering membrane permeability and bioavailability. Ligand B (1.538) is within the optimal range (1-3).

**H-Bond Donors/Acceptors:** Ligand A has 4 HBD and 5 HBA, acceptable values. Ligand B has 1 HBD and 5 HBA, also acceptable.

**QED:** Both ligands have good QED scores (A: 0.545, B: 0.665), indicating drug-like properties.

**DILI:** Ligand A (22.024) has a very low DILI risk, which is excellent. Ligand B (15.936) also has a low DILI risk.

**BBB:** Ligand A (10.392) has poor BBB penetration, a significant drawback for a CNS target. Ligand B (61.38) has moderate BBB penetration, which is substantially better.

**Caco-2 Permeability:** Both have negative Caco-2 values (-5.372 and -4.848). This is unusual and suggests poor permeability. However, these values are on a log scale, and the negative values are likely indicating very low permeability.

**Aqueous Solubility:** Both ligands have very poor aqueous solubility (-1.785 and -1.92). This could pose formulation challenges.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (A: 0.101, B: 0.337).

**Microsomal Clearance:** Ligand A (-13.162) has very low microsomal clearance, suggesting high metabolic stability. Ligand B (37.693) has higher clearance, indicating faster metabolism.

**In vitro Half-Life:** Ligand A (20.571) has a moderate half-life. Ligand B (9.455) has a shorter half-life.

**P-gp Efflux:** Both ligands have very low P-gp efflux (A: 0.02, B: 0.038), which is favorable for CNS exposure.

**Binding Affinity:** Ligand A (-8.1) has significantly stronger binding affinity than Ligand B (-6.3). This is a substantial advantage (1.8 kcal/mol difference).

**Overall Assessment:**

While Ligand A boasts a superior binding affinity, its extremely low logP and poor BBB penetration are major concerns for a CNS-targeted GPCR. The low logP will likely severely limit its ability to cross cell membranes, including the blood-brain barrier, despite the low P-gp efflux. Ligand B, while having a weaker affinity, exhibits much better physicochemical properties for CNS penetration (better logP, significantly better TPSA, and improved BBB). The higher metabolic clearance and shorter half-life of Ligand B are less concerning than the permeability issues of Ligand A, and can be addressed through structural modifications.

Considering the GPCR-specific priorities, especially BBB and logP, Ligand B is the more promising candidate. The affinity difference, while significant, can potentially be optimized in subsequent iterations of drug design.

Output:
1
2025-04-17 08:10:53,351 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B based on the provided guidelines, prioritizing GPCR-specific properties (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (339.4) is slightly lower, which is generally favorable for permeability.

**TPSA:** Ligand A (90.98) is excellent for CNS penetration, being below the 90 threshold. Ligand B (56.41) is also very good.

**logP:** Ligand A (1.211) is within the optimal range. Ligand B (3.21) is also acceptable, but approaching the upper limit.

**H-Bond Donors/Acceptors:** Ligand A has 2 HBD and 4 HBA, which are both reasonable. Ligand B has 1 HBD and 2 HBA, also acceptable.

**QED:** Both ligands have good QED scores (A: 0.774, B: 0.817), indicating drug-like properties.

**DILI:** Ligand A (55.719) has a moderate DILI risk, while Ligand B (25.475) has a low DILI risk. This favors Ligand B.

**BBB:** Ligand A (35.673) has a poor BBB penetration score, which is a major drawback for a CNS target like DRD2. Ligand B (67.468) has a good BBB score, exceeding the 70% threshold.

**Caco-2 Permeability:** Ligand A (-5.721) shows poor Caco-2 permeability. Ligand B (-4.665) is also poor, but slightly better than A.

**Aqueous Solubility:** Both ligands have very poor aqueous solubility (-2.281 and -4.116 respectively). This could pose formulation challenges.

**hERG Inhibition:** Ligand A (0.106) has a very low hERG risk, which is excellent. Ligand B (0.744) has a slightly elevated, but still acceptable, hERG risk.

**Microsomal Clearance:** Ligand A (-10.977) has very low microsomal clearance, indicating high metabolic stability. Ligand B (65.648) has high clearance, suggesting rapid metabolism.

**In vitro Half-Life:** Ligand A (-23.063) has a very long in vitro half-life, consistent with low clearance. Ligand B (1.898) has a short half-life.

**P-gp Efflux:** Ligand A (0.018) has very low P-gp efflux, which is highly desirable for CNS penetration. Ligand B (0.261) has slightly higher efflux, but still relatively low.

**Binding Affinity:** Ligand A (-8.2) has significantly stronger binding affinity than Ligand B (0.0). This is a substantial advantage.

**Overall Assessment:**

Despite Ligand A's superior binding affinity, its extremely poor BBB penetration is a critical flaw for a CNS-targeting drug. The poor Caco-2 permeability and solubility are also concerning. Ligand B, while having weaker affinity, possesses a good BBB score, lower DILI risk, and acceptable P-gp efflux. The metabolic instability (high Cl_mic and short half-life) of Ligand B could be addressed through structural modifications, but the poor BBB penetration of Ligand A is a more fundamental issue. Given the GPCR-specific prioritization of BBB, Ligand B is the more promising candidate.

Output:
1
2025-04-17 08:10:53,352 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (354.466 and 344.43 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (58.64) is slightly higher than Ligand B (49.41). Both are below the 90 A^2 threshold desirable for CNS targets, but B is better.

**3. logP:** Both ligands have good logP values (2.749 and 2.981), falling within the optimal 1-3 range.

**4. H-Bond Donors:** Both ligands have 1 HBD, which is acceptable.

**5. H-Bond Acceptors:** Ligand A has 3 HBAs, while Ligand B has 2. Both are within the acceptable limit of 10.

**6. QED:** Ligand B (0.913) has a significantly higher QED score than Ligand A (0.565), indicating a more drug-like profile.

**7. DILI:** Ligand A (22.024) has a lower DILI risk than Ligand B (37.999), which is preferable.

**8. BBB:** Both ligands have excellent BBB penetration (88.135 and 87.553), exceeding the >70% threshold for CNS targets.

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 values, which is unusual and suggests poor permeability. However, the scale is not specified, so it's difficult to interpret.

**10. Aqueous Solubility:** Both ligands have negative solubility values, which is also unusual and suggests poor solubility. Again, the scale is not specified.

**11. hERG Inhibition:** Ligand A (0.383) has a lower hERG inhibition liability than Ligand B (0.593), which is better.

**12. Microsomal Clearance:** Ligand B (26.352) has significantly lower microsomal clearance than Ligand A (45.043), indicating better metabolic stability.

**13. In vitro Half-Life:** Ligand B (-14.779) has a much longer in vitro half-life than Ligand A (-3.827), which is highly desirable.

**14. P-gp Efflux:** Ligand A (0.218) has lower P-gp efflux liability than Ligand B (0.253), which is preferable for CNS penetration.

**15. Binding Affinity:** Ligand B (-9.5 kcal/mol) has a *much* stronger binding affinity than Ligand A (-0.0 kcal/mol). This is a decisive advantage.

**Overall Assessment:**

While Ligand A has slightly better DILI and P-gp efflux profiles, Ligand B overwhelmingly outperforms it in critical areas. The significantly stronger binding affinity (-9.5 vs -0.0 kcal/mol) is a major advantage. Furthermore, Ligand B has a much higher QED score, better metabolic stability (lower Cl_mic), and a longer in vitro half-life. Both have good BBB penetration and acceptable logP values. The negative values for Caco-2 and solubility are concerning, but the substantial affinity difference makes Ligand B the more promising candidate.

Output:
1
2025-04-17 08:10:53,352 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (355.385 and 350.459 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (82.27) is better than Ligand B (76.66), both are below the 90 A^2 threshold for CNS targets, which is excellent.

**3. logP:** Both ligands have good logP values (1.317 and 1.668), falling within the optimal 1-3 range.

**4. H-Bond Donors:** Both have 2 HBD, which is acceptable.

**5. H-Bond Acceptors:** Ligand A has 3 HBA, and Ligand B has 4 HBA. Both are within the acceptable limit of <=10.

**6. QED:** Both ligands have reasonable QED scores (0.807 and 0.732), indicating good drug-like properties.

**7. DILI:** Ligand A (29.43) has a lower DILI risk than Ligand B (31.679), both are below the 40 threshold, which is good.

**8. BBB:** This is a crucial parameter for a CNS target like DRD2. Ligand A has a significantly higher BBB penetration percentile (74.176) compared to Ligand B (40.558). This is a major advantage for Ligand A.

**9. Caco-2 Permeability:** Ligand A (-4.866) is better than Ligand B (-5.096), both are negative values.

**10. Aqueous Solubility:** Ligand A (-2.365) is better than Ligand B (-2.196), both are negative values.

**11. hERG Inhibition:** Both ligands show low hERG inhibition liability (0.378 and 0.226), which is desirable.

**12. Microsomal Clearance:** Ligand A (-29.744) has a much lower (better) microsomal clearance than Ligand B (3.692). This suggests better metabolic stability for Ligand A.

**13. In vitro Half-Life:** Ligand A (-27.676) has a much longer half-life than Ligand B (19.562).

**14. P-gp Efflux:** Both ligands show low P-gp efflux liability (0.024 and 0.033).

**15. Binding Affinity:** Both ligands have very similar binding affinities (-8.6 and -8.4 kcal/mol). The difference is minimal and unlikely to be decisive.

**Overall Assessment:**

Ligand A is significantly better than Ligand B due to its superior BBB penetration (74.176 vs 40.558), lower microsomal clearance (-29.744 vs 3.692), and longer in vitro half-life (-27.676 vs 19.562). While both ligands have acceptable properties across most parameters, the improved CNS penetration and metabolic stability of Ligand A make it the more promising drug candidate for targeting DRD2. The binding affinity is almost identical, so the ADME improvements of Ligand A are decisive.

Output:
1
2025-04-17 08:10:53,352 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B based on the provided guidelines, prioritizing GPCR-specific properties (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (353.419 and 353.413 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (96.97) is better than Ligand B (62.13). For CNS targets, TPSA should be <=90, and both meet this criterion, but A is closer to the upper limit.

**logP:** Ligand B (4.205) is significantly higher than Ligand A (-0.72). While 1-3 is optimal, B is pushing the upper limit and could cause solubility issues. A is below 1, which is not ideal for permeation.

**H-Bond Donors/Acceptors:** Ligand A (2 HBD, 5 HBA) is slightly higher in both counts than Ligand B (1 HBD, 3 HBA), but both are within acceptable limits.

**QED:** Both ligands have similar and good QED values (0.657 and 0.735, respectively), indicating good drug-like properties.

**DILI:** Ligand A (26.173) has a much lower DILI risk than Ligand B (53.47). This is a significant advantage for A.

**BBB:** Ligand B (73.827) has a substantially better BBB penetration percentile than Ligand A (46.026). This is *critical* for a CNS target like DRD2.

**Caco-2 Permeability:** Both have negative values (-5.326 and -4.889), which is unusual and suggests poor permeability. This is a concern for both.

**Aqueous Solubility:** Both have negative values (-1.062 and -3.907), indicating poor solubility. This is a concern for both, and B is worse.

**hERG:** Ligand A (0.086) has a much lower hERG inhibition liability than Ligand B (0.715), indicating a lower risk of cardiotoxicity.

**Microsomal Clearance:** Ligand A (-10.797) has a much lower (better) microsomal clearance than Ligand B (76.32), suggesting greater metabolic stability.

**In vitro Half-Life:** Ligand A (14.846 hours) has a better in vitro half-life than Ligand B (-13.423 hours).

**P-gp Efflux:** Ligand A (0.006) has significantly lower P-gp efflux liability than Ligand B (0.387), which is beneficial for CNS penetration.

**Binding Affinity:** Ligand B (-7.2 kcal/mol) has a slightly better binding affinity than Ligand A (-7.5 kcal/mol). While the difference is small, it's a factor.

**Overall Assessment:**

Ligand A excels in safety (DILI, hERG), metabolic stability (Cl_mic, t1/2), and efflux (Pgp). Ligand B's main strength is its significantly better BBB penetration. However, its higher logP, DILI, hERG, and Pgp efflux are concerning. The slight affinity advantage of B is not enough to overcome these drawbacks, especially considering the importance of CNS penetration *and* safety for a DRD2 targeting drug. The poor Caco-2 and solubility for both are concerning but could potentially be addressed with formulation strategies.

Output:
0
2025-04-17 08:10:53,352 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (373.381 and 370.837 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (89.77) is excellent, falling below the 90 A^2 threshold for CNS targets. Ligand B (104.65) is slightly higher, but still acceptable.

**logP:** Ligand A (1.853) is optimal. Ligand B (0.557) is a bit low, potentially hindering permeability.

**H-Bond Donors/Acceptors:** Ligand A (HBD=1, HBA=7) and Ligand B (HBD=2, HBA=6) both have reasonable H-bond characteristics, well within the acceptable limits.

**QED:** Both ligands have similar and good QED values (0.748 and 0.758, respectively).

**DILI:** Ligand A (81.815) has a higher DILI risk than Ligand B (51.493), which is preferable.

**BBB:** Ligand A (74.06) has a good BBB penetration percentile, while Ligand B (51.609) is significantly lower. This is a crucial factor for a CNS target like DRD2.

**Caco-2 Permeability:** Both have negative Caco-2 values (-4.584 and -4.754), which is unusual and suggests poor permeability. However, these values are on a scale where negative values are possible, and the absolute magnitude isn't directly comparable without knowing the scale's specifics.

**Aqueous Solubility:** Both have negative solubility values (-3.264 and -1.801), which is also unusual and suggests poor solubility. Similar to Caco-2, the scale is unknown.

**hERG:** Both ligands have very low hERG inhibition liability (0.283 and 0.171), which is excellent.

**Microsomal Clearance:** Ligand A (69.554) has a higher microsomal clearance than Ligand B (11.551), indicating lower metabolic stability.

**In vitro Half-Life:** Ligand B (4.149 hours) has a lower half-life than Ligand A (12.68 hours).

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.173 and 0.017), which is favorable for CNS penetration.

**Binding Affinity:** Ligand A (-7.9 kcal/mol) has a slightly better binding affinity than Ligand B (-7.3 kcal/mol). While the difference isn't huge, it's enough to potentially outweigh some ADME drawbacks.

**Overall Assessment:**

Ligand A has a better BBB score, slightly better binding affinity, and lower DILI risk. Ligand B has better metabolic stability (lower Cl_mic) and a slightly longer half-life, but its significantly lower BBB penetration is a major drawback for a CNS target. The slightly lower logP of Ligand B is also a concern. Considering the GPCR-specific priorities, especially BBB penetration, Ligand A is the more promising candidate.

Output:
1
2025-04-17 08:10:53,352 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (361.389 and 378.42 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (78.95) is better than Ligand B (71.25). Both are below the 90 A^2 threshold desirable for CNS targets, which is excellent.

**logP:** Ligand B (1.3) is better than Ligand A (0.039). A logP between 1-3 is optimal, and Ligand A is quite low, potentially hindering membrane permeability.

**H-Bond Donors:** Both ligands have 1 HBD, which is within the acceptable limit of <=5.

**H-Bond Acceptors:** Ligand B (6) is slightly higher than Ligand A (4), but both are comfortably below the 10 limit.

**QED:** Both ligands have good QED scores (0.725 and 0.808, respectively), indicating good drug-like properties.

**DILI:** Both ligands have low DILI risk (37.301 and 39.046, respectively), which is favorable.

**BBB:** Ligand B (82.009) is significantly better than Ligand A (75.378) in terms of BBB penetration. For a CNS target like DRD2, >70 is desirable, and Ligand B is closer to this threshold.

**Caco-2 Permeability:** Both have negative Caco-2 values (-4.82 and -4.799). This is unusual and requires further investigation, but it doesn't immediately disqualify either.

**Aqueous Solubility:** Both ligands have very poor aqueous solubility (-0.814 and -3.138). This is a concern, but can sometimes be overcome with formulation strategies.

**hERG Inhibition:** Both ligands show very low hERG inhibition risk (0.245 and 0.217, respectively).

**Microsomal Clearance:** Ligand A (-3.357) has a slightly better (lower) microsomal clearance than Ligand B (-5.029), suggesting better metabolic stability.

**In vitro Half-Life:** Both have very short in vitro half-lives (-19.317 and -19.052). This is a significant drawback for both, potentially requiring frequent dosing.

**P-gp Efflux:** Both ligands show very low P-gp efflux liability (0.015 and 0.105, respectively), which is good for CNS exposure.

**Binding Affinity:** Ligand B (-8.0 kcal/mol) has a slightly better binding affinity than Ligand A (-7.8 kcal/mol), although the difference is small.

**Overall Assessment:**

Ligand B is the better candidate. While both have poor solubility and short half-lives, Ligand B has a more favorable logP, significantly better BBB penetration, and slightly better binding affinity. The BBB penetration is a crucial factor for a CNS target like DRD2, making Ligand B the more promising option. The slightly better metabolic stability of Ligand A is outweighed by the other advantages of Ligand B.

Output:
1
2025-04-17 08:10:53,353 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (348.407 and 356.344 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (100.43) is slightly above the preferred <90 for CNS targets, while Ligand B (78.43) is well within the range. This favors Ligand B.

**logP:** Ligand A (-0.552) is quite low, potentially hindering membrane permeability. Ligand B (1.994) is within the optimal 1-3 range. This is a significant advantage for Ligand B.

**H-Bond Donors/Acceptors:** Ligand A has 1 HBD and 6 HBA, which are acceptable. Ligand B has 3 HBD and 3 HBA, also acceptable.

**QED:** Both ligands have similar QED values (0.739 and 0.729), indicating good drug-likeness.

**DILI:** Both ligands have low DILI risk (43.117 and 42.148), which is positive.

**BBB:** Ligand B (70.88) is better than Ligand A (60.101) in terms of BBB penetration, although both are reasonably good. For a CNS target like DRD2, higher BBB is preferred.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.1 and -5.097), which is unusual and suggests poor permeability. This is a concern for both.

**Aqueous Solubility:** Both ligands have negative solubility values (-1.331 and -2.369), indicating poor aqueous solubility. This is a significant drawback for both.

**hERG Inhibition:** Ligand A (0.025) has a slightly lower hERG risk than Ligand B (0.312), which is favorable.

**Microsomal Clearance:** Ligand A (5.911) has a lower microsomal clearance than Ligand B (25.23), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (6.299) has a slightly longer half-life than Ligand B (-6.525), which is a minor advantage.

**P-gp Efflux:** Ligand A (0.025) has a lower P-gp efflux liability than Ligand B (0.097), which is better for CNS exposure.

**Binding Affinity:** Both ligands have excellent binding affinities (-9.2 and -8.4 kcal/mol). Ligand A has a 0.8 kcal/mol advantage, which is substantial and could outweigh some of its ADME drawbacks.

**Overall Assessment:**

Ligand B has better physicochemical properties regarding TPSA and logP, and superior BBB penetration. However, Ligand A has a significantly better binding affinity, lower P-gp efflux, and lower microsomal clearance. The low logP and poor solubility of Ligand A are concerning, but the strong binding affinity is a major advantage for a GPCR target. Considering the GPCR-specific priorities, the binding affinity is paramount.

Output:
0
2025-04-17 08:10:53,353 - INFO - Reasoning:

Let's analyze Ligand A and Ligand B based on the provided guidelines, prioritizing GPCR-specific properties (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (371.459 Da) is slightly higher than Ligand B (349.435 Da), but both are acceptable.

**TPSA:** Both ligands have TPSA values around 96-98 A^2, which is borderline for CNS penetration. Ideally, we want <90 A^2, but it's not a disqualifier.

**logP:** Ligand A (0.307) is quite low, potentially hindering membrane permeability. Ligand B (0.666) is better, but still on the lower side of the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A has 1 HBD and 6 HBA, while Ligand B has 2 HBD and 4 HBA. Both are within acceptable limits.

**QED:** Both ligands have good QED scores (A: 0.496, B: 0.674), indicating reasonable drug-likeness. Ligand B is slightly better.

**DILI:** Ligand A has a DILI risk of 65.491, which is concerning (high risk). Ligand B has a much lower DILI risk of 25.204, which is excellent.

**BBB:** This is crucial for a CNS target like DRD2. Ligand A has a BBB percentile of 83.792, which is very good. Ligand B has a BBB percentile of 51.842, which is significantly lower and less desirable.

**Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and suggests poor permeability. However, these values are on a different scale and hard to interpret without context.

**Aqueous Solubility:** Both have negative solubility values, also unusual and difficult to interpret.

**hERG Inhibition:** Both ligands have low hERG inhibition liability (A: 0.535, B: 0.093), which is positive. Ligand B is slightly better.

**Microsomal Clearance:** Ligand A has a higher Cl_mic (79.899) than Ligand B (4.703), indicating faster metabolism and lower metabolic stability.

**In vitro Half-Life:** Ligand B has a significantly longer in vitro half-life (-11.706 hours) compared to Ligand A (-64.379 hours).

**P-gp Efflux:** Both have very low P-gp efflux liability (A: 0.085, B: 0.008), which is favorable for CNS penetration.

**Binding Affinity:** Both ligands have the same binding affinity (-7.5 kcal/mol), which is excellent.

**Overall Assessment:**

While Ligand A has a better BBB score, Ligand B is superior in almost every other critical ADME property. Specifically, the significantly lower DILI risk and much better metabolic stability (lower Cl_mic, longer half-life) of Ligand B are major advantages. The slightly lower BBB score of Ligand B is a concern, but the other improvements likely outweigh this. The low logP of Ligand A is also a significant disadvantage.

Output:
1
2025-04-17 08:10:53,353 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (344.415 and 358.483 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (111.11) is slightly above the preferred <90 for CNS targets, but acceptable. Ligand B (85.35) is excellent, well below 90.

**logP:** Ligand A (2.281) is within the optimal 1-3 range. Ligand B (-1.16) is below 1, which could hinder permeability.

**H-Bond Donors/Acceptors:** Both have 2 HBD and reasonable HBA counts (5 and 6 respectively). This is good for balancing solubility and permeability.

**QED:** Both ligands have acceptable QED scores (0.725 and 0.541), indicating drug-like properties.

**DILI:** Both have low DILI risk (51.144 and 5.312 percentile), which is favorable.

**BBB:** Ligand A has a significantly better BBB penetration score (74.835%) than Ligand B (22.838%). This is a *critical* advantage for a CNS target like DRD2.

**Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and suggests poor permeability. However, the scale is not specified, so it's difficult to interpret.

**Aqueous Solubility:** Both have negative solubility values, suggesting poor solubility. Again, the scale is not specified.

**hERG:** Both ligands show low hERG inhibition liability (0.393 and 0.217), which is good.

**Microsomal Clearance:** Ligand A (44.878) has higher microsomal clearance than Ligand B (30.271), suggesting lower metabolic stability.

**In vitro Half-Life:** Ligand B has a substantially longer in vitro half-life (-11.341) than Ligand A (-5.498), which is a significant advantage.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.111 and 0.004), which is good for CNS penetration.

**Binding Affinity:** Ligand A (-9.1 kcal/mol) has a significantly stronger binding affinity than Ligand B (-6.5 kcal/mol). This is a major advantage, potentially outweighing some ADME drawbacks. The difference of 2.6 kcal/mol is substantial.

**Overall Assessment:**

Ligand A excels in binding affinity and BBB penetration, which are paramount for a CNS GPCR target. While its TPSA is slightly higher and clearance is higher, the strong affinity and good BBB offset these concerns. Ligand B has better TPSA, half-life, and lower clearance, but its poor logP and very low BBB penetration are major drawbacks for a CNS drug. The substantial difference in binding affinity further favors Ligand A.

Output:
1
2025-04-17 08:10:53,353 - INFO - Batch 427 complete. Total preferences: 6832
2025-04-17 08:10:53,353 - INFO - Processing batch 428/512...
2025-04-17 08:11:40,182 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (374.893 Da) is slightly higher than Ligand B (349.475 Da), but both are acceptable.

**TPSA:** Ligand A (49.41) is excellent for CNS penetration, well below the 90 A^2 threshold. Ligand B (64.09) is still reasonable, but less optimal.

**logP:** Ligand A (3.674) is within the optimal range (1-3). Ligand B (0.404) is quite low, potentially hindering membrane permeability and CNS entry.

**H-Bond Donors/Acceptors:** Both ligands have acceptable HBD (1) and HBA (3 for A, 4 for B) counts.

**QED:** Both ligands have good QED scores (0.868 and 0.781), indicating good drug-like properties.

**DILI:** Ligand A (61.807) has a moderate DILI risk, while Ligand B (4.731) has a very low risk. This favors Ligand B.

**BBB:** Ligand A (68.205) has a good BBB percentile, but Ligand B (73.362) is even better, exceeding the 70% threshold more comfortably. This is crucial for a CNS target like DRD2.

**Caco-2 Permeability:** Ligand A (-5.034) has poor Caco-2 permeability, suggesting poor intestinal absorption. Ligand B (-4.741) is also poor, but slightly better than A.

**Aqueous Solubility:** Both ligands have very poor aqueous solubility (-4.212 and -0.874 respectively). This could pose formulation challenges.

**hERG:** Both ligands have low hERG inhibition liability (0.373 and 0.302), which is positive.

**Microsomal Clearance:** Ligand A (52.844) has moderate clearance, while Ligand B (-2.231) has *negative* clearance, indicating exceptional metabolic stability. This is a significant advantage for Ligand B.

**In vitro Half-Life:** Ligand A (-0.921) has a short half-life, while Ligand B (14.014) has a long half-life. This strongly favors Ligand B.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.443 and 0.013), which is good for CNS penetration. Ligand B is better.

**Binding Affinity:** Ligand A (-7.8 kcal/mol) has slightly better binding affinity than Ligand B (-7.5 kcal/mol), but the difference is relatively small (0.3 kcal/mol).

**Overall Assessment:**

While Ligand A has slightly better binding affinity, Ligand B significantly outperforms it in crucial ADME properties for a CNS-targeting GPCR. Specifically, its superior BBB penetration, exceptional metabolic stability (negative Cl_mic, long half-life), and lower P-gp efflux are highly desirable. The lower DILI risk is also a plus. The slightly lower logP of Ligand B is a concern, but the other advantages outweigh this drawback.

Output:
1
2025-04-17 08:11:40,182 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 drug candidates, considering the provided guidelines and GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight (MW):**
* Ligand A: 362.832 Da - Within the ideal range (200-500 Da).
* Ligand B: 340.427 Da - Also within the ideal range.
* *Both are acceptable.*

**2. Topological Polar Surface Area (TPSA):**
* Ligand A: 41.57  -  Good for CNS targets (<90).
* Ligand B: 67.35 - Still reasonable for CNS, but less optimal than A.
* *Ligand A is preferred.*

**3. Lipophilicity (logP):**
* Ligand A: 4.317 - Slightly high, potential for off-target effects, but not drastically.
* Ligand B: 3.342 - Optimal range (1-3).
* *Ligand B is preferred.*

**4. H-Bond Donors (HBD):**
* Ligand A: 1 - Acceptable.
* Ligand B: 1 - Acceptable.
* *Equal.*

**5. H-Bond Acceptors (HBA):**
* Ligand A: 2 - Acceptable.
* Ligand B: 4 - Acceptable.
* *Equal.*

**6. QED:**
* Ligand A: 0.883 - Excellent drug-likeness.
* Ligand B: 0.906 - Excellent drug-likeness.
* *Ligand B is slightly preferred.*

**7. DILI Risk:**
* Ligand A: 62.04 - Moderate risk.
* Ligand B: 50.523 - Lower risk.
* *Ligand B is preferred.*

**8. BBB Penetration:**
* Ligand A: 76.347 - Good, but could be better for a CNS target.
* Ligand B: 91.392 - Excellent for CNS penetration.
* *Ligand B is strongly preferred.*

**9. Caco-2 Permeability:**
* Ligand A: -4.623 - Poor permeability.
* Ligand B: -4.562 - Also poor permeability.
* *Equal, and both are concerning.*

**10. Aqueous Solubility:**
* Ligand A: -5.14 - Very poor solubility.
* Ligand B: -3.356 - Poor solubility, but better than A.
* *Ligand B is preferred.*

**11. hERG Inhibition:**
* Ligand A: 0.777 - Acceptable risk.
* Ligand B: 0.763 - Acceptable risk.
* *Equal.*

**12. Microsomal Clearance:**
* Ligand A: 65.704 - High clearance, lower metabolic stability.
* Ligand B: 38.647 - Lower clearance, better metabolic stability.
* *Ligand B is preferred.*

**13. In vitro Half-Life:**
* Ligand A: 19.255 - Moderate half-life.
* Ligand B: 5.785 - Short half-life.
* *Ligand A is preferred.*

**14. P-gp Efflux:**
* Ligand A: 0.434 - Moderate efflux.
* Ligand B: 0.181 - Low efflux, better for CNS exposure.
* *Ligand B is strongly preferred.*

**15. Binding Affinity:**
* Ligand A: -8.2 kcal/mol - Excellent affinity.
* Ligand B: -9.1 kcal/mol - Even better affinity.
* *Ligand B is strongly preferred.*

**Overall Assessment:**

Ligand B consistently outperforms Ligand A in most critical parameters for a CNS-targeting GPCR drug. While both have poor Caco-2 permeability and solubility, Ligand B's superior BBB penetration, lower DILI risk, better metabolic stability (lower Cl_mic), lower P-gp efflux, and significantly better binding affinity outweigh the drawbacks. The higher logP of Ligand A is a concern, and its lower BBB penetration is a significant disadvantage for a CNS target. The affinity difference of 0.9 kcal/mol is substantial and can overcome minor ADME issues.

Output:
1
2025-04-17 08:11:40,182 - INFO - Reasoning:

Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (359.369 and 370.559 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (68.23) is higher than Ligand B (49.85). For a CNS target like DRD2, we ideally want TPSA <= 90, so both are acceptable, but B is better.

**3. logP:** Both ligands have good logP values (1.759 and 2.496), falling within the optimal 1-3 range.

**4. H-Bond Donors:** Ligand A has 1 HBD, while Ligand B has 0. Both are acceptable (<=5).

**5. H-Bond Acceptors:** Ligand A has 5 HBA, and Ligand B has 4. Both are within the acceptable range (<=10).

**6. QED:** Ligand A (0.804) has a higher QED than Ligand B (0.616), indicating a more drug-like profile.

**7. DILI:** Ligand B (27.181) has a significantly lower DILI risk than Ligand A (39.434). This is a strong advantage for Ligand B.

**8. BBB:** Both ligands have excellent BBB penetration (Ligand A: 83.172, Ligand B: 87.553). Ligand B is slightly better, exceeding 85%. This is crucial for a CNS target.

**9. Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and suggests poor permeability. However, the scale isn't defined, so it's hard to interpret.

**10. Aqueous Solubility:** Both ligands have negative solubility values, suggesting poor aqueous solubility. This is a potential issue for formulation.

**11. hERG Inhibition:** Both ligands have low hERG inhibition risk (0.455 and 0.641).

**12. Microsomal Clearance:** Ligand B (83.657) has a much higher microsomal clearance than Ligand A (6.469), meaning it's metabolized faster. This is a significant drawback for Ligand B.

**13. In vitro Half-Life:** Ligand A (-11.86) has a slightly better in vitro half-life than Ligand B (-11.494), though both are negative and hard to interpret without knowing the scale.

**14. P-gp Efflux:** Ligand A (0.173) has lower P-gp efflux than Ligand B (0.314), which is favorable for CNS exposure.

**15. Binding Affinity:** Ligand A (-8.1 kcal/mol) has a significantly stronger binding affinity than Ligand B (-6.7 kcal/mol). This is a substantial advantage, potentially outweighing some ADME concerns.

**Overall Assessment:**

While Ligand B shows advantages in terms of lower DILI risk and slightly better BBB penetration, Ligand A's significantly stronger binding affinity (-8.1 vs -6.7 kcal/mol) is a major factor. The difference of 1.4 kcal/mol is substantial.  The lower P-gp efflux and better (though still negative) half-life also favor Ligand A. The higher clearance of Ligand B is a significant concern. Given the GPCR target and the importance of potency, Ligand A is the more promising candidate.

Output:
1
2025-04-17 08:11:40,182 - INFO - Reasoning:

Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (344.375 and 344.438 Da) fall comfortably within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (95.14) is slightly above the preferred <90 for CNS targets, but still reasonable. Ligand B (79.42) is well within the desired range. This favors Ligand B.

**3. logP:** Ligand A (0.783) is a bit low, potentially hindering membrane permeability. Ligand B (3.364) is near the upper end of optimal (1-3), but still acceptable. This favors Ligand B.

**4. H-Bond Donors:** Ligand A (0) is excellent. Ligand B (1) is also acceptable.

**5. H-Bond Acceptors:** Ligand A (8) is good. Ligand B (6) is also good.

**6. QED:** Both ligands have similar and good QED values (0.744 and 0.754, respectively).

**7. DILI:** Ligand A (73.517) has a higher DILI risk than Ligand B (47.421). This favors Ligand B.

**8. BBB:** Ligand A (67.197) is below the desirable >70 for CNS targets, which is a significant drawback. Ligand B (76.037) is good and exceeds the threshold. This strongly favors Ligand B.

**9. Caco-2 Permeability:** Ligand A (-4.625) has poor Caco-2 permeability. Ligand B (-5.195) also has poor Caco-2 permeability. This is a negative for both, but doesn't differentiate them.

**10. Aqueous Solubility:** Both have very poor solubility (-2.299 and -3.413). This is a concern for both, but not a deciding factor.

**11. hERG Inhibition:** Ligand A (0.052) has very low hERG risk, which is excellent. Ligand B (0.595) has a slightly higher, but still relatively low, hERG risk. This favors Ligand A.

**12. Microsomal Clearance:** Ligand A (40.018) has higher clearance than Ligand B (19.033), indicating lower metabolic stability. This favors Ligand B.

**13. In vitro Half-Life:** Ligand A (-7.467) has a very short half-life, which is a major drawback. Ligand B (3.309) has a reasonable half-life. This strongly favors Ligand B.

**14. P-gp Efflux:** Ligand A (0.041) has very low P-gp efflux, which is excellent. Ligand B (0.36) has moderate P-gp efflux. This favors Ligand A.

**15. Binding Affinity:** Ligand A (-8.7 kcal/mol) has a significantly stronger binding affinity than Ligand B (-7.2 kcal/mol) - a difference of 1.5 kcal/mol. This is a substantial advantage for Ligand A.

**Overall Assessment:**

While Ligand A boasts a superior binding affinity and better P-gp and hERG profiles, its poor BBB penetration, short half-life, and higher DILI risk are major concerns for a CNS-targeting drug. Ligand B, despite slightly weaker affinity, demonstrates significantly better predicted CNS penetration (BBB), lower DILI risk, better metabolic stability (lower Cl_mic, longer t1/2), and acceptable TPSA and logP values. For a GPCR in the CNS, BBB penetration is paramount. The affinity difference, while notable, can potentially be addressed through further optimization, whereas fixing poor CNS penetration is often much more challenging.

Output:
1
2025-04-17 08:11:40,182 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (353.507 Da) is slightly lower, which could be beneficial for permeability, while Ligand B (388.877 Da) is still well within the range.

**TPSA:** Ligand A (72.88) is significantly better than Ligand B (101.91). For CNS targets, TPSA should be <= 90, so Ligand A is preferable.

**logP:** Both ligands have good logP values (A: 1.378, B: 1.143), falling within the optimal range of 1-3.

**H-Bond Donors/Acceptors:** Both have acceptable HBD counts (2). Ligand B has a higher HBA count (7) compared to Ligand A (4), which is less ideal, but still within the acceptable limit of 10.

**QED:** Both ligands have reasonable QED values (A: 0.691, B: 0.585), indicating good drug-like properties.

**DILI:** Ligand B (62.544) has a considerably higher DILI risk than Ligand A (8.996). This is a significant drawback for Ligand B.

**BBB:** Ligand A (42.226) has a slightly better BBB percentile than Ligand B (38.581), though both are below the desirable >70 for CNS targets. However, given the other factors, this difference is less critical.

**Caco-2 Permeability:** Ligand A (-4.953) has a much better (more positive) Caco-2 permeability than Ligand B (-5.333).

**Aqueous Solubility:** Both have very poor aqueous solubility (-1.662 and -1.586 respectively). This could pose formulation challenges, but is not a deciding factor.

**hERG Inhibition:** Both ligands show low hERG inhibition risk (A: 0.508, B: 0.165).

**Microsomal Clearance:** Ligand A (18.633) has a higher microsomal clearance than Ligand B (11.414), suggesting lower metabolic stability.

**In vitro Half-Life:** Ligand B (21.969) has a significantly longer in vitro half-life than Ligand A (-1.161). This is a major advantage for Ligand B.

**P-gp Efflux:** Both ligands show very low P-gp efflux liability (A: 0.088, B: 0.12).

**Binding Affinity:** Ligand B (-7.6 kcal/mol) has a substantially stronger binding affinity than Ligand A (0.0 kcal/mol). This is a critical advantage, as a >1.5 kcal/mol difference can outweigh other drawbacks.

**Overall Assessment:**

Ligand B has a significantly better binding affinity and a longer half-life. However, it has a higher DILI risk and a higher TPSA. Ligand A has better TPSA, Caco-2 permeability, and lower DILI risk, but a much weaker binding affinity and shorter half-life.

Considering the GPCR-specific priorities, binding affinity is paramount. The 7.6 kcal/mol difference in binding affinity is substantial. While the higher DILI risk of Ligand B is concerning, it might be mitigated through structural modifications in later stages of optimization. The TPSA of Ligand B is less than ideal, but not prohibitive. The longer half-life is also a significant advantage.

Output:
1
2025-04-17 08:11:40,182 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B based on the provided guidelines, prioritizing GPCR-specific properties (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (379.222 Da) is slightly higher than Ligand B (344.411 Da), but both are acceptable.

**TPSA:** Ligand A (59.81) is excellent for CNS penetration, well below the 90 A^2 threshold. Ligand B (91.57) is higher, but still potentially acceptable, though less ideal.

**logP:** Ligand A (4.333) is slightly high, potentially leading to solubility issues and off-target effects, but still within a manageable range. Ligand B (3.07) is optimal.

**H-Bond Donors/Acceptors:** Ligand A (HBD=1, HBA=4) and Ligand B (HBD=3, HBA=4) both have acceptable numbers of H-bond donors and acceptors.

**QED:** Both ligands have similar, good QED values (A: 0.734, B: 0.72).

**DILI:** Ligand A (88.019) has a higher DILI risk than Ligand B (36.991), which is a significant concern.

**BBB:** Ligand A (73.827) has a good BBB percentile, desirable for a CNS target. Ligand B (21.908) has a very poor BBB percentile, making CNS penetration unlikely. This is a major disadvantage.

**Caco-2 Permeability:** Ligand A (-4.652) and Ligand B (-5.278) both have negative values, indicating poor permeability.

**Aqueous Solubility:** Both ligands have poor aqueous solubility (A: -5.99, B: -3.406).

**hERG Inhibition:** Ligand A (0.523) has a slightly higher hERG risk than Ligand B (0.295), but both are relatively low.

**Microsomal Clearance:** Ligand A (72.129) has higher microsomal clearance than Ligand B (36.828), indicating lower metabolic stability.

**In vitro Half-Life:** Ligand A (31.671) has a longer half-life than Ligand B (6.931), which is desirable.

**P-gp Efflux:** Ligand A (0.495) has lower P-gp efflux than Ligand B (0.106), suggesting better CNS exposure.

**Binding Affinity:** Both ligands have excellent binding affinities (A: -10.1 kcal/mol, B: -9.0 kcal/mol). Ligand A is slightly more potent.

**Overall Assessment:**

Ligand A has a better binding affinity, BBB penetration, P-gp efflux, and in vitro half-life. However, it has a significantly higher DILI risk and higher microsomal clearance. Ligand B has a much better safety profile (lower DILI) and metabolic stability, but suffers from extremely poor BBB penetration, making it unlikely to reach the target in the CNS.

Given the target is a CNS GPCR (DRD2), BBB penetration is crucial. While Ligand A has a higher DILI risk, this can potentially be mitigated through further structural modifications. The poor BBB penetration of Ligand B is a more fundamental issue that is harder to overcome. The slightly better affinity of Ligand A also contributes to its favorability.

Output:
1
2025-04-17 08:11:40,182 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (336.395 Da) is slightly better as it's closer to the lower end, potentially aiding permeability.

**TPSA:** Ligand A (71.11) is significantly better than Ligand B (112.73). For CNS targets, we want TPSA <= 90, and Ligand A comfortably meets this, while Ligand B exceeds it.

**logP:** Ligand A (2.868) is optimal (1-3), while Ligand B (0.177) is quite low. A low logP can hinder membrane permeability. This is a significant advantage for Ligand A.

**H-Bond Donors/Acceptors:** Ligand A (HBD=1, HBA=4) and Ligand B (HBD=3, HBA=4) are both acceptable.

**QED:** Ligand A (0.798) is better than Ligand B (0.535), indicating a more drug-like profile.

**DILI:** Ligand A (72.043) has a higher DILI risk than Ligand B (34.82). This favors Ligand B, but the difference isn't massive.

**BBB:** Ligand A (43.505) is lower than Ligand B (57.076). For a CNS target like DRD2, we want >70, and both are below this threshold. However, Ligand B is better in this regard.

**Caco-2:** Both have negative Caco-2 values, which is unusual and suggests poor permeability. This is a concern for both.

**Solubility:** Both have negative solubility values, which is also unusual and suggests poor solubility. This is a concern for both.

**hERG:** Both ligands have low hERG inhibition liability, which is good.

**Microsomal Clearance:** Ligand A (26.806) has a higher microsomal clearance than Ligand B (17.033), indicating lower metabolic stability. This favors Ligand B.

**In vitro Half-Life:** Ligand B (-17.592) has a significantly longer in vitro half-life than Ligand A (-4.849). This is a substantial advantage for Ligand B.

**P-gp Efflux:** Ligand A (0.205) has lower P-gp efflux liability than Ligand B (0.042), which is favorable for CNS penetration.

**Binding Affinity:** Ligand A (-8.9 kcal/mol) has a significantly stronger binding affinity than Ligand B (-7.6 kcal/mol). This is a major advantage for Ligand A, potentially outweighing some of its ADME drawbacks. The difference of 1.3 kcal/mol is substantial.

**Overall Assessment:**

Despite Ligand B having better BBB penetration, lower DILI risk, better metabolic stability and a longer half-life, Ligand A's substantially superior binding affinity (-8.9 vs -7.6 kcal/mol) and better logP and TPSA values are critical for a GPCR target in the CNS. The stronger binding is likely to compensate for the slightly higher DILI risk and lower BBB. The lower TPSA and optimal logP will likely improve CNS penetration despite the lower BBB percentile.

Output:
1
2025-04-17 08:11:40,183 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 drug candidates, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (347.361 Da) is slightly lower, which could be advantageous for permeability.

**2. TPSA:** Ligand A (66.4) is significantly better than Ligand B (137.36). For CNS targets, TPSA < 90 is preferred, and A is well within this range, while B is approaching the upper limit.

**3. logP:** Ligand A (3.447) is optimal (1-3). Ligand B (0.861) is a bit low, potentially hindering permeation.

**4. H-Bond Donors:** Ligand A (2) and Ligand B (4) are both acceptable (<=5), but A is preferable.

**5. H-Bond Acceptors:** Ligand A (2) and Ligand B (5) are both acceptable (<=10), but A is preferable.

**6. QED:** Ligand A (0.871) is excellent, indicating high drug-likeness. Ligand B (0.399) is considerably lower, suggesting a less favorable drug-like profile.

**7. DILI:** Ligand A (79.953) is better than Ligand B (67.003), both are acceptable, but lower is better.

**8. BBB:** Ligand A (30.206) is lower than Ligand B (35.828), but both are not ideal. For CNS targets, >70 is desirable.

**9. Caco-2:** Ligand A (-4.669) and Ligand B (-5.429) are both negative, indicating poor permeability.

**10. Solubility:** Ligand A (-3.9) is better than Ligand B (-2.682), both are poor.

**11. hERG:** Ligand A (0.175) is much better than Ligand B (0.466), indicating lower cardiotoxicity risk.

**12. Cl_mic:** Ligand A (29.915) is better than Ligand B (0.26), indicating better metabolic stability.

**13. t1/2:** Ligand A (11.326) is better than Ligand B (-16.769), indicating better in vitro half-life.

**14. Pgp:** Ligand A (0.061) is much better than Ligand B (0.053), indicating lower P-gp efflux.

**15. Binding Affinity:** Ligand A (-9.5) is significantly stronger than Ligand B (-8.0). A difference of >1.5 kcal/mol is highly significant and can often outweigh minor ADME drawbacks.

**Overall Assessment:**

Ligand A is clearly superior. It has a better TPSA, logP, QED, DILI, hERG, Cl_mic, t1/2, Pgp, and, crucially, a much stronger binding affinity. While both have poor Caco-2 and solubility, the superior binding affinity and more favorable ADME properties of Ligand A make it a much more promising drug candidate. The lower TPSA and better logP of Ligand A are particularly important for CNS penetration, even though BBB is not ideal for either.

Output:
1
2025-04-17 08:11:40,183 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (344.459 Da and 359.363 Da) fall within the ideal range of 200-500 Da.

**TPSA:** Ligand A (76.02) is significantly better than Ligand B (40.54), both being below the 90 A^2 threshold for CNS targets. Ligand B is exceptionally good.

**logP:** Ligand A (2.266) is within the optimal range (1-3). Ligand B (4.252) is slightly higher, potentially raising concerns about solubility and off-target effects, but still acceptable.

**H-Bond Donors/Acceptors:** Ligand A (2 HBD, 4 HBA) and Ligand B (1 HBD, 2 HBA) both have favorable counts, well within the recommended limits.

**QED:** Ligand A (0.745) has a better QED score than Ligand B (0.428), indicating a more drug-like profile.

**DILI:** Ligand A (46.646) has a slightly higher DILI risk than Ligand B (16.479), but both are below the concerning threshold of 60.

**BBB:** Both ligands have good BBB penetration (Ligand A: 67.895, Ligand B: 66.188), but neither exceeds the desirable 70% threshold.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values, which is unusual and suggests a potential issue with intestinal absorption. However, these values are on a log scale, and the negative values are not directly comparable without knowing the scale.

**Aqueous Solubility:** Both ligands have negative solubility values, which is also unusual and suggests poor aqueous solubility.

**hERG Inhibition:** Ligand A (0.215) shows a lower hERG inhibition liability than Ligand B (0.915), which is preferable.

**Microsomal Clearance:** Ligand B (65.014) has a lower microsomal clearance than Ligand A (46.753), suggesting better metabolic stability.

**In vitro Half-Life:** Both ligands have similar in vitro half-lives (Ligand A: 14.789, Ligand B: 13.564).

**P-gp Efflux:** Ligand A (0.135) has a lower P-gp efflux liability than Ligand B (0.415), which is beneficial for CNS exposure.

**Binding Affinity:** Ligand A (-8.3 kcal/mol) has a significantly stronger binding affinity than Ligand B (-7.5 kcal/mol). This >1.5 kcal/mol difference is a major advantage.

**Overall Assessment:**

Ligand A is the stronger candidate. While Ligand B has better metabolic stability (lower Cl_mic) and a slightly lower DILI risk, Ligand A's significantly higher binding affinity (-8.3 vs -7.5 kcal/mol) outweighs these minor advantages. The lower P-gp efflux and hERG inhibition liabilities of Ligand A are also positive factors. The TPSA of Ligand B is excellent, but the superior binding affinity of Ligand A is the deciding factor for a GPCR target. The negative Caco-2 and solubility values are concerning for both, but can be addressed during lead optimization.

Output:
0
2025-04-17 08:11:40,183 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (345.4 & 354.4 Da) fall comfortably within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (80.76) is better than Ligand B (85.38). Both are below the 90 A^2 threshold for CNS targets, which is good.

**3. logP:** Ligand A (1.587) is within the optimal 1-3 range. Ligand B (-0.17) is below 1, potentially hindering permeation. This is a significant drawback for B.

**4. H-Bond Donors:** Ligand A (1) is good. Ligand B (0) is also acceptable.

**5. H-Bond Acceptors:** Ligand A (5) is good. Ligand B (6) is also acceptable.

**6. QED:** Ligand A (0.847) is excellent, indicating high drug-likeness. Ligand B (0.422) is below the 0.5 threshold, suggesting a less favorable drug-like profile.

**7. DILI:** Ligand A (41.411) has a slightly higher DILI risk than Ligand B (32.222), but both are below the 40 threshold and considered good.

**8. BBB:** Ligand A (77.898) has a significantly better BBB penetration percentile than Ligand B (61.613). This is crucial for a CNS target like DRD2.

**9. Caco-2:** Both ligands have negative Caco-2 values (-4.645 and -4.529), which is unusual and likely indicates poor permeability. This is a concern for both.

**10. Solubility:** Both ligands have negative solubility values (-3.344 and -1.048), which is also unusual and indicates very poor aqueous solubility. This is a major issue for both.

**11. hERG:** Both ligands have very low hERG inhibition liability (0.24 and 0.077), which is excellent.

**12. Cl_mic:** Ligand A (15.383) has a lower microsomal clearance than Ligand B (24.977), suggesting better metabolic stability.

**13. t1/2:** Ligand A (-7.559) has a more negative in vitro half-life, which is better than Ligand B (-3.099).

**14. Pgp:** Both ligands have very low P-gp efflux liability (0.024 and 0.014), which is favorable for CNS penetration.

**15. Binding Affinity:** Ligand A (-8.1 kcal/mol) has a significantly stronger binding affinity than Ligand B (-6.7 kcal/mol). This >1.5 kcal/mol difference is a substantial advantage.

**Overall Assessment:**

Ligand A is clearly superior. While both compounds have issues with Caco-2 permeability and solubility, Ligand A excels in the most critical areas for a CNS-targeting GPCR ligand: BBB penetration, logP, metabolic stability, and, most importantly, binding affinity. The stronger affinity of Ligand A can potentially compensate for the permeability/solubility issues, whereas Ligand B's poor logP and lower affinity make it a less promising candidate.

Output:
1
2025-04-17 08:11:40,183 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (368.463 and 356.417 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (102.24) is higher than the preferred <90 for CNS targets, while Ligand B (76.14) is well within the range. This is a significant advantage for Ligand B.

**logP:** Ligand A (-0.351) is below the optimal 1-3 range and could indicate poor membrane permeability. Ligand B (2.863) is within the optimal range.

**H-Bond Donors/Acceptors:** Ligand A has 1 HBD and 8 HBA, both acceptable. Ligand B has 2 HBD and 5 HBA, also acceptable.

**QED:** Both ligands have good QED scores (0.626 and 0.674), indicating drug-like properties.

**DILI:** Ligand A (58.627) has a moderate DILI risk, while Ligand B (41.915) has a lower risk.

**BBB:** Ligand B (89.027) has a significantly better BBB percentile than Ligand A (66.537). This is crucial for a CNS target like DRD2.

**Caco-2 Permeability:** Both have negative values, indicating low permeability. However, the scale is not specified, making direct comparison difficult.

**Aqueous Solubility:** Both have negative values, indicating low solubility. Again, the scale is unspecified.

**hERG Inhibition:** Ligand A (0.053) shows very low hERG inhibition risk, which is excellent. Ligand B (0.481) is slightly higher, but still relatively low.

**Microsomal Clearance:** Ligand A (19.412) has lower clearance, suggesting better metabolic stability than Ligand B (79.398).

**In vitro Half-Life:** Ligand A (-19.278) has a negative half-life, which is not possible and likely indicates an issue with the data. Ligand B (-33.047) also has a negative half-life, indicating data issues.

**P-gp Efflux:** Ligand A (0.016) shows very low P-gp efflux, which is favorable for CNS penetration. Ligand B (0.078) is slightly higher, but still low.

**Binding Affinity:** Both ligands have very similar and strong binding affinities (-7.5 and -7.6 kcal/mol). The difference is negligible.

**Overall Assessment:**

Ligand B is the stronger candidate. While Ligand A has a slightly better hERG profile and lower clearance, Ligand B excels in key areas for a CNS-targeting GPCR: TPSA, logP, and especially BBB penetration. The negative half-life values for both are concerning and would require further investigation, but the other properties strongly favor Ligand B. The lower TPSA and optimal logP of Ligand B suggest better permeability and CNS exposure, which are critical for DRD2.

Output:
1
2025-04-17 08:11:40,183 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (368.302 and 349.406 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (72.8) is better than Ligand B (77.25). Both are below the 90 A^2 threshold desirable for CNS targets, but A is closer to the ideal.

**3. logP:** Both ligands have good logP values (2.69 and 2.929), falling within the optimal 1-3 range.

**4. H-Bond Donors:** Ligand A (3) is slightly higher than Ligand B (1), but both are within the acceptable limit of 5.

**5. H-Bond Acceptors:** Ligand A (3) is lower than Ligand B (5), both are within the acceptable limit of 10.

**6. QED:** Both ligands have similar QED values (0.716 and 0.667), indicating good drug-like properties.

**7. DILI:** Ligand A (47.421) has a lower DILI risk than Ligand B (60.062), which is preferable. Both are below the concerning 60 threshold.

**8. BBB:** Ligand B (89.686) has a significantly better BBB penetration score than Ligand A (64.211). This is a *critical* advantage for a CNS target like DRD2.

**9. Caco-2 Permeability:** Both ligands have identical, very poor Caco-2 permeability (-4.889). This is a significant concern for oral bioavailability.

**10. Aqueous Solubility:** Both ligands have poor aqueous solubility (-3.19 and -2.702). This could pose formulation challenges.

**11. hERG Inhibition:** Both ligands have low hERG inhibition risk (0.577 and 0.668).

**12. Microsomal Clearance:** Ligand A (-6.423) has a lower (better) microsomal clearance than Ligand B (55.088), indicating better metabolic stability.

**13. In vitro Half-Life:** Ligand B (22.074) has a slightly longer in vitro half-life than Ligand A (21.432).

**14. P-gp Efflux:** Ligand A (0.102) has lower P-gp efflux liability than Ligand B (0.558), which is favorable for CNS penetration.

**15. Binding Affinity:** Both ligands have excellent binding affinities (-8.9 and -8.4 kcal/mol). Ligand A is slightly better (-8.9 kcal/mol).

**Overall Assessment:**

While Ligand A has advantages in TPSA, DILI, metabolic stability (Cl_mic), and P-gp efflux, the *substantial* difference in BBB penetration (89.7% vs 64.2%) heavily favors Ligand B. For a CNS target like DRD2, achieving good brain exposure is paramount. The slightly better affinity of Ligand A is unlikely to overcome the significantly lower predicted BBB penetration. The poor Caco-2 and solubility are concerns for both, but can be addressed with formulation strategies.

Output:
1
2025-04-17 08:11:40,183 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B based on the provided guidelines, prioritizing GPCR-specific properties (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (350.5 and 367.5 Da) fall within the ideal range of 200-500 Da.

**TPSA:** Ligand A (59.39) is better than Ligand B (61.88), both are below the 90 A^2 threshold for CNS targets.

**logP:** Ligand A (3.418) is slightly higher than Ligand B (1.954). Both are within the optimal range of 1-3, but Ligand A is closer to the upper limit.

**H-Bond Donors/Acceptors:** Both have 1 HBD, which is good. Ligand A has 4 HBA, and Ligand B has 5. Both are acceptable (<=10).

**QED:** Both ligands have good QED scores (0.82 and 0.864, respectively), indicating good drug-like properties.

**DILI:** Ligand A (19.465) has a significantly lower DILI risk than Ligand B (30.826). This is a substantial advantage.

**BBB:** Ligand A (90.772) has a much higher BBB penetration percentile than Ligand B (55.642). This is *critical* for a CNS target like DRD2.

**Caco-2 Permeability:** Ligand A (-4.174) is better than Ligand B (-4.799), indicating better intestinal absorption.

**Aqueous Solubility:** Ligand A (-3.167) is better than Ligand B (-1.044), indicating better solubility.

**hERG:** Both ligands have very low hERG inhibition liability (0.424 and 0.194), which is excellent.

**Microsomal Clearance:** Ligand A (75.49) has higher clearance than Ligand B (12.524), meaning Ligand B is more metabolically stable.

**In vitro Half-Life:** Ligand A (19.875) has a slightly longer half-life than Ligand B (18.398).

**P-gp Efflux:** Ligand A (0.146) has lower P-gp efflux than Ligand B (0.02), which is better.

**Binding Affinity:** Ligand B (-8.1 kcal/mol) has a slightly better binding affinity than Ligand A (-7.4 kcal/mol). While a 0.7 kcal/mol difference is noticeable, it's not a huge advantage, and can be overcome by better ADME properties.

**Overall Assessment:**

Ligand A is the superior candidate. Its significantly better BBB penetration, lower DILI risk, better solubility, and lower P-gp efflux outweigh the slightly weaker binding affinity and higher clearance. For a CNS-targeting GPCR like DRD2, BBB penetration is paramount, and Ligand A excels in this area. The improved ADME profile of Ligand A suggests it will have better *in vivo* exposure and potentially better efficacy.

Output:
1
2025-04-17 08:11:40,184 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (341.415 and 351.382 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (111.25) is slightly above the optimal <90 for CNS targets, but still reasonable. Ligand B (90.44) is excellent, falling right within the desired range.

**logP:** Ligand A (1.469) is within the optimal 1-3 range. Ligand B (0.311) is a bit low, potentially hindering permeability.

**H-Bond Donors/Acceptors:** Ligand A has 3 HBD and 4 HBA, which are both acceptable. Ligand B has 2 HBD and 5 HBA, also acceptable.

**QED:** Both ligands have good QED scores (0.77 and 0.802), indicating good drug-like properties.

**DILI:** Ligand A (34.626) has a lower DILI risk than Ligand B (60.062), which is approaching a higher risk category.

**BBB:** Both ligands have good BBB penetration (70.027% and 72.005%), exceeding the 70% threshold for CNS targets.

**Caco-2 Permeability:** Ligand A (-5.355) has poor Caco-2 permeability. Ligand B (-4.956) also has poor Caco-2 permeability, but is slightly better than A.

**Aqueous Solubility:** Both ligands have very poor aqueous solubility (-3.169 and -2.812). This is a significant concern for both.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.573 and 0.267).

**Microsomal Clearance:** Ligand A (-16.987) has significantly lower (better) microsomal clearance than Ligand B (-32.769), indicating better metabolic stability.

**In vitro Half-Life:** Ligand A (19.987 hours) has a much longer half-life than Ligand B (9.382 hours).

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.008 and 0.029), which is excellent for CNS penetration.

**Binding Affinity:** Both ligands have similar binding affinities (-8.6 and -8.7 kcal/mol), which are both very good.

**Overall Assessment:**

While both ligands have good affinity and BBB penetration, Ligand A is more favorable. Its lower DILI risk, significantly better metabolic stability (lower Cl_mic, longer t1/2), and slightly better Caco-2 permeability outweigh the slightly higher TPSA. The poor solubility is a concern for both, but can potentially be addressed through formulation strategies. Ligand B's lower logP and higher DILI risk are more problematic.

Output:
1
2025-04-17 08:11:40,184 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 drug candidates, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (363.805 and 362.373 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (100.35) is slightly above the optimal <90 for CNS targets, while Ligand B (93.73) is closer to the threshold and thus preferable.

**3. logP:** Ligand A (0.918) is a bit low, potentially hindering permeability. Ligand B (0.622) is even lower, presenting a similar concern. Both are below the optimal 1-3 range.

**4. H-Bond Donors:** Both ligands have 2 HBD, which is within the acceptable limit of <=5.

**5. H-Bond Acceptors:** Ligand A has 6 HBA, and Ligand B has 5. Both are within the acceptable limit of <=10.

**6. QED:** Ligand A (0.844) has a better QED score than Ligand B (0.676), indicating a more drug-like profile.

**7. DILI:** Ligand A (59.791) has a slightly higher DILI risk than Ligand B (49.128), but both are below the concerning threshold of 60.

**8. BBB:** This is a crucial parameter for CNS targets. Ligand B (74.796) has a significantly higher BBB penetration percentile than Ligand A (17.681). This is a major advantage for Ligand B.

**9. Caco-2 Permeability:** Ligand A (-5.299) and Ligand B (-4.982) both have negative Caco-2 values, which is unusual and suggests poor permeability.

**10. Aqueous Solubility:** Both ligands have very poor aqueous solubility (-2.069 and -1.981 respectively). This is a significant drawback.

**11. hERG Inhibition:** Both ligands show low hERG inhibition risk (0.13 and 0.236 respectively).

**12. Microsomal Clearance:** Ligand A (-19) has a lower (better) microsomal clearance than Ligand B (23.208), suggesting greater metabolic stability.

**13. In vitro Half-Life:** Ligand A (-25.372) has a longer in vitro half-life than Ligand B (3.189), which is favorable.

**14. P-gp Efflux:** Both ligands show very low P-gp efflux liability (0.036 and 0.021 respectively), which is good.

**15. Binding Affinity:** Both ligands have comparable and strong binding affinities (-8.0 and -8.3 kcal/mol). The difference is negligible.

**Overall Assessment:**

While Ligand A has a better QED, longer half-life, and better metabolic stability, Ligand B significantly outperforms it in BBB penetration (74.8% vs 17.7%). Given that DRD2 is a CNS target, BBB penetration is paramount. The slightly lower TPSA of Ligand B is also advantageous. The solubility and Caco-2 permeability are poor for both, but the superior BBB score of Ligand B outweighs the other minor advantages of Ligand A.

Output:
1
2025-04-17 08:11:40,184 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (370.316 and 352.435 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (105.56) is better than Ligand B (116.48). For CNS targets, we want TPSA <= 90, so both are a bit high, but A is closer.

**logP:** Ligand A (1.361) is within the optimal 1-3 range. Ligand B (-0.127) is below 1, which could hinder permeation. This is a significant advantage for A.

**H-Bond Donors/Acceptors:** Ligand A (HBD=2, HBA=7) and Ligand B (HBD=4, HBA=6) are both within acceptable limits (<=5 HBD and <=10 HBA).

**QED:** Ligand A (0.721) has a better QED score than Ligand B (0.52), indicating a more drug-like profile.

**DILI:** Ligand A (96.161) has a higher DILI risk than Ligand B (35.479). This is a concern for A.

**BBB:** Ligand A (40.016) has a very low BBB penetration percentile, while Ligand B (20.822) is also low, but better than A. Both are far from the desirable >70 for CNS targets.

**Caco-2 Permeability:** Ligand A (-5.148) and Ligand B (-5.308) both have negative values, indicating poor permeability.

**Aqueous Solubility:** Ligand A (-3.446) and Ligand B (-1.316) both have negative solubility values, indicating poor solubility.

**hERG:** Both ligands have very low hERG inhibition liability (0.143 and 0.026, respectively), which is good.

**Microsomal Clearance:** Ligand A (6.557) has a higher microsomal clearance than Ligand B (2.483), indicating lower metabolic stability.

**In vitro Half-Life:** Ligand A (-31.201) has a negative in vitro half-life, which is a major red flag. Ligand B (19.64) is better, but still not ideal.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.096 and 0.006, respectively), which is good.

**Binding Affinity:** Ligand A (-8.7 kcal/mol) has a significantly stronger binding affinity than Ligand B (-7.5 kcal/mol). This is a substantial advantage for A, potentially outweighing some of its ADME drawbacks.

**Overall Assessment:**

Despite Ligand A's higher DILI risk and poor BBB penetration, its significantly stronger binding affinity (-8.7 vs -7.5 kcal/mol) and better logP value are crucial for a GPCR target like DRD2. The affinity difference is substantial. While both have poor solubility and permeability, the affinity advantage of A is likely to be more impactful in driving efficacy. Ligand B has better DILI and slightly better BBB, but the lower affinity is a major disadvantage.

Output:
1
2025-04-17 08:11:40,184 - INFO - Batch 428 complete. Total preferences: 6848
2025-04-17 08:11:40,184 - INFO - Processing batch 429/512...
2025-04-17 08:12:29,170 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (381.929 and 370.515 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (73.2) is better than Ligand B (75.71). Both are reasonably good for CNS penetration, being below the 90 A^2 threshold, but closer to the ideal range for CNS targets is preferred.

**3. logP:** Ligand A (3.842) is slightly higher than Ligand B (1.656). While both are within the optimal 1-3 range, Ligand A is approaching the upper limit. Ligand B is closer to the lower limit, which *could* indicate permeability issues, but is generally preferable to a high logP.

**4. H-Bond Donors:** Both ligands have 1 HBD, which is within the acceptable limit of <=5.

**5. H-Bond Acceptors:** Both ligands have 4 HBA, which is within the acceptable limit of <=10.

**6. QED:** Both ligands have good QED scores (0.779 and 0.817), indicating drug-like properties.

**7. DILI:** Ligand A (39.201) has a slightly higher DILI risk than Ligand B (12.834). Ligand B is significantly better here, falling well below the 40% threshold.

**8. BBB:** Both ligands have good BBB penetration (Ligand A: 75.378, Ligand B: 70.415), exceeding the 70% threshold for CNS targets. Ligand A is slightly better.

**9. Caco-2:** Both have negative Caco-2 values which is unusual and likely indicates a problem with the data.

**10. Solubility:** Both have negative solubility values which is unusual and likely indicates a problem with the data.

**11. hERG:** Ligand A (0.78) has a slightly higher hERG risk than Ligand B (0.468). Lower is better, so Ligand B is preferable.

**12. Cl_mic:** Ligand A (36.251) has a lower microsomal clearance than Ligand B (21.645), indicating better metabolic stability. This is a significant advantage for Ligand A.

**13. t1/2:** Ligand A (9.738) has a significantly longer in vitro half-life than Ligand B (-17.786). A negative half-life is impossible, indicating a data issue with Ligand B. This is a major advantage for Ligand A.

**14. Pgp:** Ligand A (0.397) has lower P-gp efflux liability than Ligand B (0.024), which is favorable for CNS exposure.

**15. Binding Affinity:** Ligand B (-8.2 kcal/mol) has a slightly better binding affinity than Ligand A (-7.6 kcal/mol). This is a 1.6 kcal/mol difference, which is substantial and could outweigh some ADME drawbacks.

**Overall Assessment:**

Despite Ligand B's slightly better affinity, Ligand A is the more promising candidate. Ligand B has a negative in vitro half-life, which is a critical flaw. It also has a higher Pgp efflux liability and a higher DILI risk. Ligand A has better metabolic stability (lower Cl_mic, positive half-life), lower Pgp efflux, and lower DILI risk. The affinity difference, while notable, is less critical than these ADME properties, especially for a CNS target where maintaining adequate brain exposure is crucial. The questionable Caco-2 and solubility data for both compounds is concerning, but the other factors strongly favor Ligand A.

Output:
1
2025-04-17 08:12:29,171 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (345.487 and 348.447 Da) fall comfortably within the ideal 200-500 Da range.

**TPSA:** Ligand A (81.99) is better than Ligand B (87.46). Both are below the 90 A^2 threshold desirable for CNS targets, but A is closer to the ideal.

**logP:** Ligand A (3.053) is optimal (1-3), while Ligand B (1.17) is on the lower side. A logP below 1 can hinder permeation, making Ligand A more favorable.

**H-Bond Donors/Acceptors:** Both ligands have 2 HBD and a reasonable number of HBA (3 for A, 5 for B). This is acceptable.

**QED:** Ligand A (0.696) has a better QED score than Ligand B (0.518), indicating a more drug-like profile.

**DILI:** Both ligands have similar, low DILI risk (21.753 and 21.055 percentile), which is good.

**BBB:** Ligand A (66.886) has a better BBB percentile than Ligand B (55.332). While >70 is desirable, A is closer, and this is a critical factor for a CNS target like DRD2.

**Caco-2 Permeability:** Both have negative Caco-2 values (-4.885 and -4.985), which is unusual and suggests poor permeability. This is a concern for both.

**Aqueous Solubility:** Both have negative solubility values (-3.723 and -1.102), indicating very poor aqueous solubility. This is a significant drawback for both.

**hERG Inhibition:** Both ligands show low hERG inhibition liability (0.648 and 0.663), which is positive.

**Microsomal Clearance:** Ligand A (54.508) has higher microsomal clearance than Ligand B (39.618), meaning it is less metabolically stable. This favors Ligand B.

**In vitro Half-Life:** Ligand B (-10.254) has a significantly longer in vitro half-life than Ligand A (3.4). This is a major advantage for Ligand B.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.123 and 0.243), which is favorable for CNS penetration.

**Binding Affinity:** Both ligands have excellent binding affinity (-8.8 and -8.2 kcal/mol). Ligand A is slightly better (-8.8 kcal/mol), but the difference is less than 1.5 kcal/mol, so it's not a decisive factor.

**Overall Assessment:**

Considering the GPCR-specific priorities, Ligand A excels in TPSA, logP, and BBB penetration, while Ligand B has better metabolic stability (lower Cl_mic) and a longer half-life. The poor solubility and Caco-2 permeability are concerning for both. However, for a CNS target, BBB penetration is paramount. Ligand A's higher BBB percentile (66.886 vs 55.332) and better logP make it more likely to reach the target in the brain, despite its slightly higher clearance. The affinity difference is minimal.

Output:
0
2025-04-17 08:12:29,171 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B based on the provided guidelines, prioritizing GPCR-specific properties (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (348.447 and 347.434 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (82.7) is better than Ligand B (62.3). For CNS targets, TPSA should be <=90, both are within this range, but A is closer to the upper limit.

**logP:** Ligand B (3.451) is higher than Ligand A (0.713). While both are within the 1-3 range, B is closer to the upper limit, potentially causing solubility issues. A is quite low, which could hinder permeation.

**H-Bond Donors/Acceptors:** Ligand A has 3 HBD and 4 HBA, while Ligand B has 1 HBD and 3 HBA. Both are within acceptable limits (<=5 HBD and <=10 HBA).

**QED:** Ligand A (0.614) has a slightly better QED score than Ligand B (0.487), indicating a more drug-like profile.

**DILI:** Ligand A (12.02) has a significantly lower DILI risk than Ligand B (37.456), a major advantage.

**BBB:** Ligand B (82.047) has a better BBB penetration percentile than Ligand A (71.733). This is a critical factor for CNS targets like DRD2.

**Caco-2 Permeability:** Ligand A (-5.185) has a lower Caco-2 permeability than Ligand B (-4.747), suggesting poorer intestinal absorption.

**Aqueous Solubility:** Ligand A (-1) has better aqueous solubility than Ligand B (-3.244).

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.385 and 0.487, respectively).

**Microsomal Clearance:** Ligand A (-8.816) has a much lower microsomal clearance than Ligand B (50.317), indicating better metabolic stability.

**In vitro Half-Life:** Ligand A (-1.508) has a shorter in vitro half-life than Ligand B (-11.599).

**P-gp Efflux:** Ligand A (0.004) has lower P-gp efflux liability than Ligand B (0.219), which is beneficial for CNS exposure.

**Binding Affinity:** Both ligands have similar binding affinities (-8.2 and -8.4 kcal/mol). The difference is negligible.

**Overall Assessment:**

Ligand B excels in BBB penetration, a crucial factor for a DRD2 ligand. However, it suffers from a higher DILI risk, higher P-gp efflux, and significantly worse metabolic stability (higher Cl_mic and shorter half-life). Ligand A has a better safety profile (DILI), better metabolic stability, and lower P-gp efflux, but its BBB penetration and Caco-2 permeability are lower. Given the importance of metabolic stability and safety for chronic CNS therapies, and the relatively small difference in binding affinity, Ligand A appears to be the more promising candidate.

Output:
0
2025-04-17 08:12:29,171 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (347.423 and 349.431 Da) fall comfortably within the ideal 200-500 Da range.

**TPSA:** Ligand A (101.53) is slightly above the optimal <90 for CNS targets, while Ligand B (84.67) is well within. This gives a slight edge to Ligand B.

**logP:** Both ligands have logP values (0.823 and 1.403) within the optimal 1-3 range. Ligand B is slightly better, being closer to the center of the range.

**H-Bond Donors/Acceptors:** Both have 1 HBD, which is good. Ligand A has 7 HBA, while Ligand B has 5. Both are acceptable (<=10), but Ligand B is slightly preferred due to fewer HBA.

**QED:** Both ligands have good QED scores (0.864 and 0.839), indicating good drug-like properties.

**DILI:** Ligand A (24.622) has a significantly lower DILI risk than Ligand B (32.648), which is a substantial advantage.

**BBB:** Ligand A (75.223) has a better BBB penetration score than Ligand B (69.794). This is crucial for a CNS target like DRD2.

**Caco-2 Permeability:** Both have negative Caco-2 values (-4.865 and -4.545), indicating poor permeability. This is a significant concern for both.

**Aqueous Solubility:** Both have negative solubility values (-1.966 and -1.697), indicating poor solubility. This is also a concern for both.

**hERG Inhibition:** Both ligands have very low hERG inhibition liability (0.78 and 0.146), which is excellent.

**Microsomal Clearance:** Ligand A (-25.612) has a much lower (better) microsomal clearance than Ligand B (26.598), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (15.487 hours) has a longer half-life than Ligand B (7.375 hours), which is desirable.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.006 and 0.039), which is excellent for CNS penetration.

**Binding Affinity:** Both ligands have very similar and strong binding affinities (-7.8 and -7.7 kcal/mol). The difference is negligible.

**Overall Assessment:**

Ligand A excels in BBB penetration, DILI risk, metabolic stability (lower Cl_mic), and in vitro half-life. Ligand B has slightly better TPSA and logP, and fewer HBA. However, the superior CNS properties of Ligand A (BBB, metabolic stability, half-life) and its lower DILI risk outweigh the minor advantages of Ligand B, especially considering DRD2 is a CNS target. The poor Caco-2 and solubility are concerns for both, but can be addressed with formulation strategies.

Output:
1
2025-04-17 08:12:29,171 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (338.407 Da) is slightly lower, which is generally favorable for permeability.

**TPSA:** Ligand A (71.35) is significantly better than Ligand B (93.37). For CNS targets, TPSA should be <= 90, so Ligand A is preferable.

**logP:** Ligand A (2.637) is optimal, while Ligand B (0.876) is a bit low, potentially hindering membrane permeability.

**H-Bond Donors/Acceptors:** Both have 1 HBD, which is good. Ligand A has 4 HBA, while Ligand B has 8.  Lower HBA is generally preferred for better permeability, giving an edge to Ligand A.

**QED:** Both ligands have acceptable QED scores (A: 0.714, B: 0.67), indicating reasonable drug-likeness.

**DILI:** Ligand A (36.06) has a lower DILI risk than Ligand B (49.283), which is a positive attribute. Both are below the concerning threshold of 60.

**BBB:** Ligand A (35.207) has a lower BBB penetration percentile than Ligand B (46.258). While both are below the desirable 70% for CNS targets, B is better.

**Caco-2 Permeability:** Ligand A (-4.689) has worse Caco-2 permeability than Ligand B (-5.005). Lower values suggest poorer absorption.

**Aqueous Solubility:** Ligand A (-3.522) has better aqueous solubility than Ligand B (-0.861).

**hERG:** Ligand A (0.818) has a lower hERG risk than Ligand B (0.194), which is favorable.

**Microsomal Clearance:** Ligand A (62.694) has higher microsomal clearance than Ligand B (47.72), meaning faster metabolism and potentially lower exposure.

**In vitro Half-Life:** Ligand B (-13.34) has a significantly longer in vitro half-life than Ligand A (4.926). This is a major advantage for Ligand B.

**P-gp Efflux:** Ligand A (0.28) has lower P-gp efflux than Ligand B (0.161), suggesting better CNS exposure.

**Binding Affinity:** Ligand A (-8.7 kcal/mol) has a significantly stronger binding affinity than Ligand B (-6.9 kcal/mol). This is a substantial advantage, potentially outweighing some of the ADME drawbacks.

**Overall Assessment:**

Ligand A excels in TPSA, logP, HBA, DILI, hERG, solubility, and crucially, binding affinity. However, it suffers from lower BBB penetration, worse Caco-2 permeability, and higher metabolic clearance. Ligand B has better BBB penetration and a much longer half-life, but its TPSA is higher, logP is lower, and its binding affinity is weaker.

Given the GPCR target and the importance of CNS penetration, the stronger binding affinity of Ligand A is a significant driver. While its BBB is not ideal, the lower TPSA and better logP may still allow for sufficient CNS exposure, especially given the strong binding. The longer half-life of Ligand B is attractive, but the weaker binding may limit its efficacy.

Output:
1
2025-04-17 08:12:29,171 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (364.559 and 358.511 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (66.91) is slightly higher than Ligand B (57.95). Both are below the 90 A^2 threshold desirable for CNS targets, but Ligand B is preferable.

**logP:** Both ligands have logP values (4.014 and 4.259) that are slightly above the optimal 1-3 range, but still acceptable. The higher logP could potentially lead to off-target effects, but isn't a major concern at this stage.

**H-Bond Donors & Acceptors:** Ligand A has 2 HBD and 5 HBA, while Ligand B has 1 HBD and 5 HBA. Both are within acceptable limits (<=5 HBD and <=10 HBA).

**QED:** Both ligands have similar QED values (0.616 and 0.549), indicating good drug-like properties.

**DILI:** Ligand A (35.673) has a slightly lower DILI risk than Ligand B (46.336), which is favorable.

**BBB:** Ligand A (77.162) has a significantly better BBB penetration percentile than Ligand B (68.399). This is a crucial factor for a CNS target like DRD2.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.202 and -5.874), which is unusual and suggests poor permeability. This is a significant drawback for both.

**Aqueous Solubility:** Both ligands have very poor aqueous solubility (-3.85 and -3.546). This could present formulation challenges.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.725 and 0.95).

**Microsomal Clearance:** Ligand A (74.946) has slightly higher microsomal clearance than Ligand B (72.663), indicating potentially lower metabolic stability.

**In vitro Half-Life:** Ligand B (95.514) has a significantly longer in vitro half-life than Ligand A (35.404), which is a major advantage.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.556 and 0.676).

**Binding Affinity:** Ligand A (-8.2 kcal/mol) has a stronger binding affinity than Ligand B (-7.2 kcal/mol). This is a substantial difference (1 kcal/mol), and a significant advantage for Ligand A.

**Overall Assessment:**

While Ligand B has a better half-life and slightly lower TPSA, Ligand A is the stronger candidate. The significantly better BBB penetration (77.162 vs 68.399) and substantially improved binding affinity (-8.2 vs -7.2 kcal/mol) outweigh the slightly higher DILI and clearance. The poor Caco-2 and solubility are concerning for both, but can potentially be addressed with formulation strategies. For a CNS target, BBB penetration and affinity are paramount.

Output:
0
2025-04-17 08:12:29,171 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (364.519 and 371.428 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (72.87) is higher than Ligand B (46.09). For a CNS target like DRD2, TPSA should be <= 90, so both are acceptable, but B is significantly better.

**3. logP:** Ligand A (2.753) is within the optimal 1-3 range. Ligand B (4.646) is higher, potentially leading to solubility issues and off-target interactions.

**4. H-Bond Donors:** Both have 0 HBD, which is acceptable.

**5. H-Bond Acceptors:** Ligand A has 8 HBA, while Ligand B has 4. Both are within the acceptable limit of <=10.

**6. QED:** Ligand A (0.826) has a better QED score than Ligand B (0.712), indicating a more drug-like profile.

**7. DILI:** Ligand A (55.68) has a slightly higher DILI risk than Ligand B (49.477), but both are below the concerning threshold of 60.

**8. BBB:** Ligand B (87.088) has a significantly better BBB penetration percentile than Ligand A (66.499). This is *crucial* for a CNS target.

**9. Caco-2 Permeability:** Both have negative values (-5.456 and -4.662), which is unusual and suggests poor permeability. However, the scale is not specified, so it's difficult to interpret.

**10. Aqueous Solubility:** Both have negative values (-4.044 and -4.177), suggesting poor solubility.

**11. hERG Inhibition:** Ligand A (0.277) has a lower hERG inhibition liability than Ligand B (0.678), which is preferable.

**12. Microsomal Clearance:** Ligand B (62.162) has lower microsomal clearance than Ligand A (75.719), suggesting better metabolic stability.

**13. In vitro Half-Life:** Ligand B (16.834) has a significantly longer in vitro half-life than Ligand A (0.951).

**14. P-gp Efflux:** Both have low P-gp efflux liability (0.348 and 0.389), which is good.

**15. Binding Affinity:** Ligand B (-7.3 kcal/mol) has a *much* stronger binding affinity than Ligand A (-0.0 kcal/mol). This is a decisive factor.

**Overall Assessment:**

While Ligand A has a slightly better QED and lower hERG risk, Ligand B is significantly superior due to its:

*   **Much stronger binding affinity:** -7.3 kcal/mol vs -0.0 kcal/mol. This is the most important factor.
*   **Significantly better BBB penetration:** 87.088% vs 66.499%. Critical for a CNS target.
*   **Better metabolic stability:** Lower Cl_mic.
*   **Longer half-life:** 16.834 hours vs 0.951 hours.
*   **Lower TPSA:** More favorable for CNS penetration.

The slightly higher logP of Ligand B is a potential concern, but the substantial advantages in affinity and BBB penetration outweigh this drawback.

Output:
1
2025-04-17 08:12:29,171 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (352.391 and 346.427 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (122.55) is slightly above the optimal <90 for CNS targets, but still reasonable. Ligand B (73.99) is excellent, well below 90.

**logP:** Ligand A (-0.502) is a bit low, potentially hindering permeability. Ligand B (2.034) is within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A has 3 HBD and 7 HBA, both acceptable. Ligand B has 1 HBD and 4 HBA, also acceptable.

**QED:** Both ligands have good QED scores (0.569 and 0.606), indicating drug-like properties.

**DILI:** Ligand A (54.517) has a moderate DILI risk, while Ligand B (26.173) has a significantly lower risk.

**BBB:** Both ligands have similar BBB penetration (48.081 and 48.236), which is not ideal (>70 desirable), but not disqualifying.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.28 and -4.942). This is unusual and suggests poor permeability, but the scale isn't specified, so it's hard to interpret.

**Aqueous Solubility:** Both ligands have negative solubility values (-2.107 and -1.119). Again, the scale is unclear, but suggests poor solubility.

**hERG Inhibition:** Ligand A (0.037) has very low hERG risk, which is excellent. Ligand B (0.421) has a slightly higher, but still acceptable, hERG risk.

**Microsomal Clearance:** Ligand A (-0.244) has very low (negative) microsomal clearance, suggesting high metabolic stability. Ligand B (57.064) has a high clearance, indicating rapid metabolism.

**In vitro Half-Life:** Ligand A (-5.823) has a negative half-life, which is not physically possible and indicates a problem with the data. Ligand B (18.957) has a reasonable half-life.

**P-gp Efflux:** Ligand A (0.013) has very low P-gp efflux, which is favorable for CNS penetration. Ligand B (0.391) has a slightly higher efflux, but still acceptable.

**Binding Affinity:** Both ligands have comparable and strong binding affinities (-8.2 and -8.4 kcal/mol).

**Overall Assessment:**

Ligand B is the better candidate. While both have similar affinity, Ligand B has a more favorable logP, lower DILI risk, and a reasonable in vitro half-life. Ligand A's low logP and negative half-life are significant concerns. The negative Caco-2 and solubility values for both are concerning, but the other properties of Ligand B make it the stronger candidate.

Output:
1
2025-04-17 08:12:29,171 - INFO - Okay, let's analyze these two ligands for their potential as DRD2 drug candidates.

**Ligand A:** [364.433, 87.66, 1.609, 3, 4, 0.55, 29.779, 76.619, -4.641, -2.169, 0.381, 38.247, -16.833, 0.045, -7.6]
**Ligand B:** [348.403, 113.33, 0.522, 3, 5, 0.734, 56.572, 37.456, -5.416, -2.335, 0.051, -1.761, 15.458, 0.02, -8]

**Step-by-step comparison:**

1. **MW:** Both are within the ideal range (200-500 Da). A (364.433) is slightly higher than B (348.403), but both are acceptable.
2. **TPSA:** A (87.66) is excellent for CNS penetration, well below the 90 threshold. B (113.33) is higher, but still potentially acceptable, though less ideal.
3. **logP:** A (1.609) is optimal. B (0.522) is a bit low, potentially hindering permeability.
4. **HBD:** Both have 3 HBD, which is good.
5. **HBA:** A has 4 HBA, B has 5. Both are within the acceptable range of <=10.
6. **QED:** A (0.55) is good, but B (0.734) is better, suggesting a more drug-like profile.
7. **DILI:** A (29.779) has a significantly lower DILI risk than B (56.572), which is a major advantage.
8. **BBB:** A (76.619) is very good, exceeding the 70% threshold for CNS targets. B (37.456) is poor, indicating limited brain penetration. This is a critical disadvantage for a DRD2 targeting drug.
9. **Caco-2:** Both have negative values, indicating poor permeability. A (-4.641) is worse than B (-5.416).
10. **Solubility:** Both have negative values, indicating poor solubility. A (-2.169) is better than B (-2.335).
11. **hERG:** Both are very low, indicating minimal hERG inhibition risk.
12. **Cl_mic:** A (38.247) is higher than B (-1.761), suggesting lower metabolic stability.
13. **t1/2:** A (-16.833) is significantly worse than B (15.458), indicating a very short half-life.
14. **Pgp:** A (0.045) is lower than B (0.02), suggesting less P-gp efflux.
15. **Affinity:** B (-8) has a slightly better binding affinity than A (-7.6), but the difference is not substantial.

**GPCR-Specific Priorities:**

For DRD2 (a CNS GPCR), BBB, logP, Pgp, TPSA, and affinity are paramount.

*   **BBB:** Ligand A is significantly better (76.6%) than Ligand B (37.5%).
*   **logP:** Ligand A (1.609) is optimal, while Ligand B (0.522) is suboptimal.
*   **Pgp:** Ligand A (0.045) is slightly better than Ligand B (0.02).
*   **TPSA:** Ligand A (87.66) is better than Ligand B (113.33).
*   **Affinity:** Ligand B is slightly better, but not enough to outweigh the other factors.

**Conclusion:**

Despite Ligand B having a slightly better QED and binding affinity, Ligand A is the more promising candidate due to its significantly better BBB penetration, optimal logP, and lower DILI risk. The poor Caco-2 and solubility of both compounds are concerns, but can potentially be addressed through formulation strategies. The short half-life of A is a concern, but could be improved through structural modifications. The poor BBB penetration of B is a more difficult problem to solve.

Output:
1
2025-04-17 08:12:29,171 - INFO - Reasoning:

Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (343.39 & 370.47 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (91.42) is better than Ligand B (95.94). Both are below the 140 A^2 threshold for oral absorption, and reasonably close to the 90 A^2 target for CNS penetration, but A is preferable.

**3. logP:** Both ligands have similar logP values (0.667 and 0.525), which are slightly below the optimal 1-3 range. This could potentially impact permeability, but isn't a major concern.

**4. H-Bond Donors:** Ligand A (1) is better than Ligand B (2). Lower HBD generally improves permeability.

**5. H-Bond Acceptors:** Both ligands have the same number of HBA (5), which is acceptable (<=10).

**6. QED:** Ligand A (0.881) has a significantly better QED score than Ligand B (0.73), indicating a more drug-like profile.

**7. DILI:** Both ligands have acceptable DILI risk (60.22 & 46.80), below the concerning threshold of 60.

**8. BBB:** Ligand A (45.64%) has a better BBB percentile than Ligand B (34.16%). While both are below the desirable >70% for CNS targets, A is closer.

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.819 and -4.955). This is unusual and suggests poor permeability. However, the values are very similar.

**10. Aqueous Solubility:** Both ligands have negative solubility values (-2.437 and -1.973). This is also unusual and suggests poor solubility. Again, the values are similar.

**11. hERG Inhibition:** Both ligands have low hERG inhibition risk (0.264 and 0.414).

**12. Microsomal Clearance:** Ligand A (6.916) has a lower Cl_mic than Ligand B (40.467), indicating better metabolic stability.

**13. In vitro Half-Life:** Ligand A (8.653) has a better in vitro half-life than Ligand B (-51.677).

**14. P-gp Efflux:** Both ligands have low P-gp efflux liability (0.025 and 0.108).

**15. Binding Affinity:** Ligand A (-8.6 kcal/mol) has a slightly better binding affinity than Ligand B (-7.7 kcal/mol). While both are good, the 0.9 kcal/mol difference is significant and can outweigh some ADME drawbacks.

**Overall Assessment:**

Ligand A is significantly better than Ligand B. It has a better QED score, better BBB penetration, lower microsomal clearance, longer in vitro half-life, and slightly better binding affinity. While both have issues with Caco-2 permeability and solubility, these are less critical given the focus on CNS penetration and the relatively small difference between the two. The superior ADME profile and slightly improved affinity of Ligand A make it the more promising drug candidate.

Output:
1
2025-04-17 08:12:29,171 - INFO - Reasoning:

Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (368.503 and 360.443 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (88.18) is better than Ligand B (93.44). Both are below the 90 A^2 threshold desirable for CNS targets, but A is closer to the optimal range.

**3. logP:** Both ligands have good logP values (2.557 and 1.743), falling within the 1-3 range. Ligand A is slightly higher, which could be beneficial for membrane permeability.

**4. H-Bond Donors:** Both have 2 HBD, which is within the acceptable limit of <=5.

**5. H-Bond Acceptors:** Ligand A has 6 HBA, while Ligand B has 8. Both are below the 10 limit, but A is more favorable.

**6. QED:** Both ligands have reasonable QED values (0.439 and 0.565), with B being slightly better and above the 0.5 threshold.

**7. DILI:** Ligand A (59.364) has a lower DILI risk than Ligand B (78.247). Both are acceptable, but A is preferable.

**8. BBB:** Both ligands have similar BBB penetration (51.066 and 58.278). Neither are particularly high, but both are reasonable for a starting point.

**9. Caco-2 Permeability:** Both have negative Caco-2 values (-5.116 and -5.455), which is unusual and suggests poor permeability. This is a significant concern for both.

**10. Aqueous Solubility:** Both have negative solubility values (-2.702 and -1.937), indicating very poor aqueous solubility. This is a major drawback for both compounds.

**11. hERG Inhibition:** Ligand A (0.213) has a much lower hERG risk than Ligand B (0.779). This is a significant advantage for A.

**12. Microsomal Clearance:** Both have similar microsomal clearance values (57.584 and 56.32), indicating moderate metabolic liability.

**13. In vitro Half-Life:** Ligand A has a negative half-life (-3.214), which is not physically meaningful. Ligand B has a half-life of 12.484 hours, which is good.

**14. P-gp Efflux:** Ligand A (0.214) has lower P-gp efflux liability than Ligand B (0.121). Lower is better, so A is preferable.

**15. Binding Affinity:** Ligand B (-7.9 kcal/mol) has a slightly better binding affinity than Ligand A (-7.2 kcal/mol). This is a 0.7 kcal/mol difference, which is noticeable but not overwhelming.

**Overall Assessment:**

While Ligand B has a slightly better binding affinity and *in vitro* half-life, Ligand A is superior in most other critical ADME properties. Specifically, Ligand A has a significantly lower hERG risk, lower DILI risk, and lower P-gp efflux. The TPSA is also more favorable. The negative Caco-2 and solubility values are concerning for both, but the other advantages of Ligand A make it a more promising starting point for optimization. The questionable half-life of Ligand A is also a concern.

Output:
0
2025-04-17 08:12:29,172 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (354.491 and 360.889 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (59.08) is better than Ligand B (50.28). Both are below the 90 A^2 threshold for CNS targets, which is excellent.

**3. logP:** Ligand A (1.923) is within the optimal range (1-3), while Ligand B (3.708) is approaching the upper limit.

**4. H-Bond Donors:** Ligand A (0) is preferable to Ligand B (1). Fewer HBDs generally improve permeability.

**5. H-Bond Acceptors:** Ligand A (4) is better than Ligand B (5). Lower HBA also favors permeability.

**6. QED:** Both ligands have good QED values (0.701 and 0.88), indicating good drug-like properties.

**7. DILI:** Ligand A (28.616) has a significantly lower DILI risk than Ligand B (62.466). This is a major advantage for Ligand A.

**8. BBB:** Both ligands have excellent BBB penetration (77.239 and 79.721), exceeding the desirable >70 threshold for CNS targets.

**9. Caco-2 Permeability:** Ligand A (-4.111) is better than Ligand B (-4.989), indicating better intestinal absorption.

**10. Aqueous Solubility:** Ligand A (-1.44) is better than Ligand B (-4.504).

**11. hERG Inhibition:** Ligand A (0.422) has a lower hERG risk than Ligand B (0.864).

**12. Microsomal Clearance:** Ligand B (95.191) has higher clearance than Ligand A (54.615), suggesting lower metabolic stability.

**13. In vitro Half-Life:** Ligand B (63.348) has a longer half-life than Ligand A (-10.605).

**14. P-gp Efflux:** Ligand A (0.169) has lower P-gp efflux than Ligand B (0.564), which is favorable for CNS exposure.

**15. Binding Affinity:** Ligand B (-0.0) has a better binding affinity than Ligand A (-7.8).

**Overall Assessment:**

While Ligand B has a better binding affinity, Ligand A is superior in almost all other critical ADME properties. Specifically, Ligand A has a much lower DILI risk, better solubility, lower hERG risk, lower P-gp efflux, and better Caco-2 permeability. The difference in binding affinity (-7.8 kcal/mol vs 0 kcal/mol) is significant, but the substantial improvements in safety and ADME for Ligand A outweigh this difference. The improved ADME profile of Ligand A will likely translate to better *in vivo* exposure and efficacy.

Output:
0
2025-04-17 08:12:29,172 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (347.459 and 339.508 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (78.51) is better than Ligand B (9.72). For CNS targets, we want TPSA <= 90, both meet this, but A is closer to the ideal.

**3. logP:** Ligand A (1.222) is within the optimal 1-3 range. Ligand B (3.927) is at the higher end, potentially raising concerns about solubility and off-target effects, but still acceptable.

**4. H-Bond Donors:** Ligand A (2) is good. Ligand B (0) is also acceptable.

**5. H-Bond Acceptors:** Ligand A (3) is good. Ligand B (4) is also acceptable.

**6. QED:** Ligand B (0.835) has a significantly better QED score than Ligand A (0.486), indicating a more drug-like profile.

**7. DILI:** Ligand A (21.675) has a much lower DILI risk than Ligand B (49.166), which is a significant advantage.

**8. BBB:** Ligand B (99.031) has excellent BBB penetration, while Ligand A (54.672) is moderate. This is a *critical* factor for a CNS target like DRD2.

**9. Caco-2:** Both ligands have negative Caco-2 values (-4.961 and -4.405), which is unusual and suggests poor permeability. This is a concern for both.

**10. Solubility:** Both ligands have negative solubility values (-2.078 and -3.404), which is also unusual and suggests poor aqueous solubility. This is a concern for both.

**11. hERG:** Ligand A (0.247) has a lower hERG risk than Ligand B (0.984), which is preferable.

**12. Cl_mic:** Ligand B (-1.279) has a *much* lower microsomal clearance than Ligand A (37.067), indicating better metabolic stability.

**13. t1/2:** Ligand B (-8.056) has a slightly better (less negative) in vitro half-life than Ligand A (-12.966).

**14. Pgp:** Both ligands have very low Pgp efflux liability (0.089 and 0.471).

**15. Binding Affinity:** Ligand B (-8.6) has a slightly better binding affinity than Ligand A (-8.0). While both are strong binders, the 0.6 kcal/mol difference is noticeable.

**Overall Assessment:**

Ligand B excels in BBB penetration, metabolic stability (Cl_mic), QED, and binding affinity. These are the most important factors for a CNS GPCR target. While Ligand A has a lower DILI risk and hERG liability, the superior CNS penetration and metabolic stability of Ligand B outweigh these benefits. The negative Caco-2 and solubility values are concerning for both, but can potentially be addressed through formulation strategies. The slightly better binding affinity of B also helps.

Output:
1
2025-04-17 08:12:29,172 - INFO - Reasoning:

Let's analyze Ligand A and Ligand B based on the provided guidelines, prioritizing GPCR-specific properties (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (349.5 and 366.3 Da) fall within the ideal 200-500 Da range.

**TPSA:** Both ligands (61.4 and 60.9 A<sup>2</sup>) are below the 90 A<sup>2</sup> threshold desirable for CNS targets, which is excellent.

**logP:** Ligand A (2.62) is optimal, while Ligand B (1.56) is slightly lower but still acceptable.

**H-Bond Donors/Acceptors:** Ligand A has 2 HBD and 3 HBA, while Ligand B has 1 HBD and 3 HBA. Both are within the acceptable limits.

**QED:** Both ligands have good QED scores (0.66 and 0.81), indicating drug-like properties.

**DILI:** Ligand A (8.9%) has a significantly lower DILI risk than Ligand B (58.6%). This is a substantial advantage.

**BBB:** Both ligands have excellent BBB penetration (76.6% and 74.2%), exceeding the 70% threshold for CNS targets.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values, which is unusual and suggests poor permeability. However, the scale is not specified, so it's hard to interpret.

**Aqueous Solubility:** Both ligands have negative solubility values, which is also unusual and suggests poor solubility. Again, the scale is not specified, making interpretation difficult.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.39 and 0.59).

**Microsomal Clearance:** Ligand A (36.9 mL/min/kg) has higher clearance than Ligand B (20.4 mL/min/kg), indicating lower metabolic stability.

**In vitro Half-Life:** Ligand B (-39.9 hours) has a significantly longer half-life than Ligand A (-3.8 hours). This is a major advantage for dosing convenience.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.014 and 0.144).

**Binding Affinity:** Both ligands have excellent binding affinities (-7.9 and -8.1 kcal/mol), with Ligand B being slightly more potent. The difference is less than 1.5 kcal/mol, so it's not a decisive factor.

**Overall Assessment:**

Ligand B is superior due to its significantly longer half-life and lower DILI risk. While Ligand A has a slightly better logP, the benefits of improved metabolic stability and reduced toxicity outweigh this minor difference. The negative Caco-2 and solubility values are concerning for both, but we'll assume these are scale issues and not absolute values. Given the importance of BBB penetration for CNS targets, and both ligands meeting that criteria, the other ADME properties become more critical.

Output:
1
2025-04-17 08:12:29,172 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (416.272 Da) is slightly higher than Ligand B (364.471 Da), but both are acceptable.

**TPSA:** Both ligands have TPSA values below 140 (Ligand A: 103.12, Ligand B: 99.33), which is good for oral absorption. More importantly, they are both below the 90 threshold desirable for CNS targets.

**logP:** Ligand A (0.644) is a bit low, potentially hindering permeation. Ligand B (1.9) is within the optimal range (1-3). This is a significant advantage for Ligand B.

**H-Bond Donors/Acceptors:** Ligand A (HBD=2, HBA=6) and Ligand B (HBD=5, HBA=4) both fall within acceptable limits.

**QED:** Both ligands have reasonable QED values (Ligand A: 0.66, Ligand B: 0.408), indicating drug-like properties, although Ligand A is better.

**DILI:** Both ligands have relatively high DILI risk (Ligand A: 68.011, Ligand B: 69.484), suggesting potential liver toxicity concerns. This is a drawback for both, but not a decisive factor at this stage.

**BBB:** Ligand A (66.305) and Ligand B (62.931) both have BBB penetration percentiles below the desirable 70% threshold for CNS targets. Ligand A is slightly better.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.094 and -5.022), which is unusual and suggests poor intestinal absorption. This is a significant concern for both.

**Aqueous Solubility:** Both ligands have very poor aqueous solubility (-2.436 and -3.274). This will likely cause formulation challenges.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (Ligand A: 0.361, Ligand B: 0.417), which is positive.

**Microsomal Clearance:** Ligand A has a much lower microsomal clearance (1.741 mL/min/kg) than Ligand B (19.26 mL/min/kg), indicating better metabolic stability.

**In vitro Half-Life:** Ligand A has a much longer in vitro half-life (-36.954 hours) than Ligand B (67.523 hours). This is a significant advantage for Ligand A.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (Ligand A: 0.017, Ligand B: 0.035), which is good for CNS exposure.

**Binding Affinity:** Ligand B (-8.6 kcal/mol) has a significantly stronger binding affinity than Ligand A (-6.9 kcal/mol). This >1.5 kcal/mol advantage is substantial and can outweigh some ADME drawbacks.

**Overall Assessment:**

Ligand B has a superior binding affinity and a more optimal logP value. However, Ligand A has better metabolic stability (lower Cl_mic, longer t1/2) and a slightly better BBB score. Both have poor solubility and Caco-2 permeability. Given the importance of binding affinity for GPCRs, and the fact that the difference in affinity is substantial, Ligand B is the more promising candidate despite its higher Cl_mic. The poor solubility and permeability would need to be addressed through formulation strategies.

Output:
1
2025-04-17 08:12:29,172 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (348.403 and 351.466 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (99.77) is higher than the preferred <90 for CNS targets, while Ligand B (43.86) is well within the range. This is a significant advantage for Ligand B.

**logP:** Ligand A (2.387) is within the optimal 1-3 range. Ligand B (1.526) is slightly lower, but still acceptable.

**H-Bond Donors/Acceptors:** Ligand A has 3 HBD and 4 HBA, which are reasonable. Ligand B has 0 HBD and 3 HBA, also acceptable.

**QED:** Both ligands have similar QED values (0.711 and 0.729), indicating good drug-likeness.

**DILI:** Ligand A (56.96) has a moderate DILI risk, while Ligand B (13.571) has a very low risk. This favors Ligand B.

**BBB:** Ligand A (69.523) is below the desirable >70 for CNS targets, but not drastically so. Ligand B (87.476) is excellent, exceeding the threshold. This is a major advantage for Ligand B.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.9 and -4.631). These values are unusual and difficult to interpret without further context. However, they suggest poor permeability.

**Aqueous Solubility:** Both ligands have negative solubility values (-3.131 and -1.574), suggesting poor aqueous solubility.

**hERG Inhibition:** Ligand A (0.38) has a slightly higher hERG risk than Ligand B (0.538), but both are relatively low.

**Microsomal Clearance:** Ligand A (8.5 mL/min/kg) has lower clearance, indicating better metabolic stability than Ligand B (15.463 mL/min/kg).

**In vitro Half-Life:** Both ligands have similar negative half-lives (-0.679 and -0.55), which is unusual and suggests rapid degradation.

**P-gp Efflux:** Ligand A (0.024) has very low P-gp efflux, which is favorable for CNS penetration. Ligand B (0.107) has slightly higher efflux, but still relatively low.

**Binding Affinity:** Ligand A (-9.0 kcal/mol) has a significantly stronger binding affinity than Ligand B (-7.6 kcal/mol). This is a substantial advantage for Ligand A. The 1.4 kcal/mol difference is large enough to potentially offset some ADME liabilities.

**Overall Assessment:**

Ligand B excels in properties crucial for CNS penetration (low TPSA, high BBB, low DILI, low P-gp efflux). However, Ligand A boasts a considerably stronger binding affinity. The negative Caco-2 and solubility values are concerning for both, but the affinity difference for Ligand A is substantial. Given the importance of affinity for GPCR ligands, and the fact that Ligand A's other properties are not dramatically worse than Ligand B's, I would prioritize Ligand A for further investigation, with a focus on improving its solubility and permeability.

Output:
0
2025-04-17 08:12:29,172 - INFO - Batch 429 complete. Total preferences: 6864
2025-04-17 08:12:29,172 - INFO - Processing batch 430/512...
2025-04-17 08:13:13,145 - INFO - Reasoning:

Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (358.41 and 351.447 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (87.15) is excellent, falling well below the 90 A^2 threshold for CNS targets. Ligand B (110.52) is higher, but still potentially acceptable, though less ideal.

**3. logP:** Ligand A (0.498) is a bit low, potentially hindering permeability. Ligand B (1.021) is better, falling within the optimal 1-3 range.

**4. H-Bond Donors:** Ligand A (1) is good. Ligand B (3) is acceptable, but approaching the upper limit.

**5. H-Bond Acceptors:** Ligand A (5) is good. Ligand B (4) is also good.

**6. QED:** Both ligands have reasonable QED values (0.699 and 0.539), indicating good drug-like properties.

**7. DILI:** Both have low DILI risk (32.726 and 37.456), which is favorable.

**8. BBB:** Both ligands have acceptable BBB penetration (59.791 and 61.497). While >70 is desirable, these are not disqualifying, and further optimization could improve this.

**9. Caco-2 Permeability:** Ligand A (-4.475) shows poor Caco-2 permeability. Ligand B (-5.706) is even worse. Both are problematic.

**10. Aqueous Solubility:** Ligand A (-1.165) and Ligand B (-3.454) both have poor aqueous solubility.

**11. hERG Inhibition:** Both ligands show very low hERG inhibition risk (0.453 and 0.182).

**12. Microsomal Clearance:** Ligand A (25.394) has a higher microsomal clearance than Ligand B (19.738), suggesting lower metabolic stability.

**13. In vitro Half-Life:** Ligand B (-15.473) has a longer in vitro half-life than Ligand A (-9.926).

**14. P-gp Efflux:** Both ligands show low P-gp efflux liability (0.104 and 0.102).

**15. Binding Affinity:** Both ligands have very similar and strong binding affinities (-7.5 and -7.3 kcal/mol). The difference of 0.2 kcal/mol is not significant enough to be a deciding factor.

**Overall Assessment:**

Ligand A has a better TPSA, but suffers from very poor Caco-2 permeability and lower in vitro half-life. Ligand B has a better logP and half-life, but a slightly higher TPSA and worse Caco-2 permeability. Given the importance of permeability for CNS penetration, and the fact that both have similarly poor Caco-2 values, the slightly better logP and half-life of Ligand B, combined with acceptable TPSA, makes it marginally more promising. The solubility of both is a concern, but can be addressed through formulation strategies.

Output:
1
2025-04-17 08:13:13,146 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (352.391 and 372.506 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (113.77) is better than Ligand B (51.66). Both are below the 90 A^2 threshold for CNS targets, but A is closer to the ideal.

**logP:** Ligand A (-0.422) is suboptimal, being below the preferred 1-3 range, potentially hindering permeation. Ligand B (3.708) is excellent, falling squarely within the optimal range.

**H-Bond Donors/Acceptors:** Ligand A (2 HBD, 6 HBA) is slightly better than Ligand B (0 HBD, 5 HBA) in terms of balance, but both are acceptable.

**QED:** Both ligands have similar QED values (0.657 and 0.62), indicating good drug-likeness.

**DILI:** Ligand A (54.207) has a moderate DILI risk, while Ligand B (20.202) has a very low risk. This is a significant advantage for Ligand B.

**BBB:** Ligand B (97.751) is *much* better than Ligand A (62.04). For a CNS target like DRD2, high BBB penetration is critical, making Ligand B strongly favored.

**Caco-2 Permeability:** Ligand A (-5.041) shows poor permeability, while Ligand B (-4.397) is slightly better, but still not great.

**Aqueous Solubility:** Ligand A (-1.584) has poor solubility, while Ligand B (-4.234) is also poor.

**hERG Inhibition:** Ligand A (0.166) has a slightly better hERG profile than Ligand B (0.425), but both are relatively low risk.

**Microsomal Clearance:** Ligand A (4.106) has a lower clearance, indicating better metabolic stability, than Ligand B (99.4). This is a significant advantage for Ligand A.

**In vitro Half-Life:** Ligand A (9.039) has a shorter half-life than Ligand B (13.542).

**P-gp Efflux:** Ligand A (0.027) has much lower P-gp efflux liability than Ligand B (0.285), which is crucial for CNS penetration.

**Binding Affinity:** Ligand A (-7.6) has a significantly stronger binding affinity than Ligand B (-6.0). This is a substantial advantage for Ligand A, potentially outweighing some of its ADME drawbacks.

**Overall Assessment:**

While Ligand A has superior binding affinity and metabolic stability, Ligand B excels in crucial properties for a CNS-targeting GPCR ligand: BBB penetration, DILI risk, and P-gp efflux. The significantly better BBB penetration of Ligand B is a major factor, as it directly impacts drug exposure in the brain. The lower DILI risk is also very important. The affinity difference, while substantial, might be overcome with further optimization of Ligand B. The poor solubility and Caco-2 permeability of both compounds are concerns, but can be addressed with formulation strategies.

Output:
1
2025-04-17 08:13:13,147 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (364.471 and 366.487 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (76.46) is better than Ligand B (86.95). For CNS targets, we want TPSA <= 90, and both are within this range, but A is closer to the optimal value.

**3. logP:** Ligand A (2.172) is optimal (1-3), while Ligand B (0.862) is slightly low, potentially hindering permeation.

**4. H-Bond Donors:** Both have 1 HBD, which is within the acceptable limit of <= 5.

**5. H-Bond Acceptors:** Ligand A has 6 HBA, and Ligand B has 5. Both are within the acceptable limit of <= 10.

**6. QED:** Both ligands have similar QED values (0.817 and 0.809), indicating good drug-like properties.

**7. DILI:** Ligand A (65.413) has a higher DILI risk than Ligand B (20.396). This is a significant drawback for Ligand A.

**8. BBB:** Ligand B (71.772) has a significantly better BBB penetration percentile than Ligand A (46.491). This is crucial for a CNS target like DRD2.

**9. Caco-2 Permeability:** Ligand A (-4.77) has worse Caco-2 permeability than Ligand B (-5.244). Both are quite poor, but B is slightly better.

**10. Aqueous Solubility:** Ligand A (-2.784) has worse aqueous solubility than Ligand B (-1.408).

**11. hERG Inhibition:** Both ligands have similar, low hERG inhibition risk (0.306 and 0.303).

**12. Microsomal Clearance:** Ligand B (-10.033) has significantly lower (better) microsomal clearance than Ligand A (55.108), indicating greater metabolic stability.

**13. In vitro Half-Life:** Ligand B (4.071) has a slightly better in vitro half-life than Ligand A (26.966).

**14. P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.175 and 0.019).

**15. Binding Affinity:** Both ligands have very similar and strong binding affinities (-7.4 and -7.3 kcal/mol). The difference is negligible.

**Overall Assessment:**

Ligand B is the superior candidate. While both have good affinity and drug-like properties, Ligand B excels in critical areas for a CNS-targeting GPCR: significantly better BBB penetration, lower DILI risk, and improved metabolic stability (lower Cl_mic). Ligand A's higher DILI risk and lower BBB penetration are major concerns. The slightly lower logP of Ligand B is a minor drawback that could potentially be addressed with further optimization, but the benefits of its superior ADME profile outweigh this.

Output:
1
2025-04-17 08:13:13,147 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (347.455 and 345.403 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (64.63) is significantly better than Ligand B (101.16). For CNS targets, we want TPSA <= 90, so Ligand A is much closer to this threshold. Ligand B is considerably above.

**3. logP:** Ligand A (3.454) is within the optimal 1-3 range. Ligand B (0.154) is very low, potentially hindering membrane permeability.

**4. H-Bond Donors:** Ligand A (1) and Ligand B (3) are both acceptable, being <= 5.

**5. H-Bond Acceptors:** Ligand A (4) and Ligand B (6) are both acceptable, being <= 10.

**6. QED:** Both ligands have similar QED values (0.801 and 0.729), indicating good drug-like properties.

**7. DILI:** Ligand A (53.974) has a slightly higher DILI risk than Ligand B (43.66), but both are below the concerning threshold of 60.

**8. BBB:** Ligand A (64.831) has a much better BBB percentile than Ligand B (31.834). For a CNS target like DRD2, >70 is desirable, and Ligand A is closer, while Ligand B is quite low.

**9. Caco-2:** Ligand A (-4.457) and Ligand B (-5.697) both have negative Caco-2 values, which is unusual. It's difficult to interpret without knowing the scale, but generally, higher values are preferred.

**10. Solubility:** Ligand A (-5.264) and Ligand B (-1.579) both have negative solubility values, again making interpretation difficult. Higher values are preferred.

**11. hERG:** Ligand A (0.735) has a lower hERG risk than Ligand B (0.145), which is preferable.

**12. Cl_mic:** Ligand A (108.65) has a higher microsomal clearance than Ligand B (-25.255).  A negative value for Ligand B suggests very high metabolic stability, which is good. However, a very high clearance for Ligand A is concerning.

**13. t1/2:** Ligand A (9.2) has a shorter in vitro half-life than Ligand B (29.14). Longer half-life is generally preferred.

**14. Pgp:** Ligand A (0.647) has a lower P-gp efflux liability than Ligand B (0.006), which is beneficial for CNS penetration.

**15. Binding Affinity:** Ligand A (-7.9) has a significantly better binding affinity than Ligand B (-9.9). A difference of 2 kcal/mol is substantial and can outweigh some ADME drawbacks.

**Overall Assessment:**

Ligand A excels in key areas for a CNS-targeting GPCR ligand: TPSA, logP, BBB, and, most importantly, binding affinity. While its DILI and Cl_mic are slightly concerning, the strong binding affinity and better BBB penetration are likely to be more critical for efficacy. Ligand B's low logP and poor BBB penetration are major drawbacks, despite its better metabolic stability and lower DILI. The affinity difference is also significant.

Output:
1
2025-04-17 08:13:13,147 - INFO - Reasoning:

Let's analyze Ligand A and Ligand B for their potential as DRD2 drug candidates, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (377.941 and 355.498 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (26.79) is excellent, well below the 90 A^2 threshold for CNS targets. Ligand B (61.44) is higher, but still potentially acceptable, though less ideal.

**3. logP:** Ligand A (3.52) is optimal. Ligand B (2.258) is a bit low, potentially hindering membrane permeability.

**4. H-Bond Donors:** Ligand A (0) is good. Ligand B (2) is acceptable.

**5. H-Bond Acceptors:** Ligand A (4) is good. Ligand B (3) is good.

**6. QED:** Ligand A (0.815) is excellent. Ligand B (0.667) is good, but not as high.

**7. DILI:** Ligand A (35.285) has a very low DILI risk. Ligand B (5.777) also has a low DILI risk.

**8. BBB:** Ligand A (88.135) has excellent BBB penetration potential. Ligand B (75.107) is still good, but less favorable. This is a critical factor for a CNS target like DRD2.

**9. Caco-2:** Ligand A (-4.912) is very poor. Ligand B (-5.02) is also very poor. This suggests potential absorption issues for both.

**10. Solubility:** Ligand A (-3.517) is poor. Ligand B (-1.733) is also poor, but slightly better than A.

**11. hERG:** Ligand A (0.857) has a low hERG risk. Ligand B (0.472) has a very low hERG risk.

**12. Cl_mic:** Ligand A (50.885) has moderate clearance. Ligand B (-4.863) has negative clearance, which is unusual and suggests very high metabolic stability.

**13. t1/2:** Ligand A (-0.144) has a very short half-life. Ligand B (-16.427) has an extremely long half-life.

**14. Pgp:** Ligand A (0.617) has moderate P-gp efflux. Ligand B (0.019) has very low P-gp efflux, which is highly desirable for CNS penetration.

**15. Affinity:** Both ligands have very similar and excellent binding affinities (-7.2 and -7.1 kcal/mol). The difference is negligible.

**Overall Assessment:**

Ligand A excels in TPSA, QED, BBB, and has a low DILI risk. However, it suffers from poor Caco-2 permeability, poor solubility, moderate clearance, and a very short half-life.

Ligand B has a slightly lower logP and QED, but it shines with exceptionally low P-gp efflux, extremely high metabolic stability (negative clearance, long half-life), and a slightly better solubility profile. While Caco-2 is also poor for B, the other ADME properties are significantly more favorable.

Given the GPCR-specific priorities, especially BBB penetration and minimizing efflux (Pgp), and the importance of metabolic stability, **Ligand B is the more promising candidate**. The extremely long half-life and low P-gp efflux suggest better CNS exposure, which is crucial for DRD2 targeting. The slight reduction in logP is a manageable concern compared to the significant advantages in ADME properties.

Output:
1
2025-04-17 08:13:13,147 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (340.354 and 350.459 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (82.19) is slightly higher than Ligand B (71.78). Both are below the 90 A^2 threshold desirable for CNS targets, but Ligand B is preferable.

**3. logP:** Both ligands have good logP values (3.286 and 3.142), falling within the optimal 1-3 range.

**4. H-Bond Donors:** Ligand A (3) is higher than Ligand B (1). Lower is generally better for CNS penetration, making Ligand B preferable.

**5. H-Bond Acceptors:** Ligand A (2) is lower than Ligand B (5). Ligand A is preferable here.

**6. QED:** Both ligands have good QED scores (0.666 and 0.765), indicating good drug-like properties. Ligand B is slightly better.

**7. DILI:** Ligand A (95.58) has a significantly higher DILI risk than Ligand B (37.069). This is a major concern for Ligand A.

**8. BBB:** Ligand B (67.197) has a much better BBB percentile than Ligand A (34.161). This is critical for a CNS target like DRD2, making Ligand B strongly favored.

**9. Caco-2:** Ligand A (-5.157) has a worse Caco-2 permeability than Ligand B (-4.234).

**10. Solubility:** Ligand A (-5.035) has a worse solubility than Ligand B (-3.551).

**11. hERG:** Both ligands have similar, low hERG inhibition liability (0.273 and 0.277).

**12. Cl_mic:** Ligand A (14.754) has a lower microsomal clearance than Ligand B (92.41), suggesting better metabolic stability. This is a positive for Ligand A.

**13. t1/2:** Ligand B (36.079) has a significantly longer in vitro half-life than Ligand A (6.137). This is a major advantage for Ligand B.

**14. Pgp:** Both ligands have low P-gp efflux liability (0.135 and 0.137).

**15. Binding Affinity:** Ligand A (-10.2 kcal/mol) has a significantly stronger binding affinity than Ligand B (-6.6 kcal/mol). This is a substantial advantage for Ligand A.

**Overall Assessment:**

While Ligand A boasts a superior binding affinity, its significantly higher DILI risk and poor BBB penetration are major drawbacks for a CNS drug candidate. Ligand B, although with a weaker binding affinity, presents a much more favorable ADME-Tox profile, particularly its better BBB penetration, lower DILI risk, and longer half-life. The difference in binding affinity (3.6 kcal/mol) is substantial, but the ADME/Tox advantages of Ligand B are more critical for a CNS-targeted GPCR.

Output:
1
2025-04-17 08:13:13,147 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (339.439 and 343.479 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (43.86) is significantly better than Ligand B (71.76). For CNS targets, TPSA should be <= 90, and A is comfortably within that range, while B is approaching the upper limit.

**logP:** Both ligands have acceptable logP values (1.355 and 2.223), falling within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A (0 HBD, 3 HBA) is preferable to Ligand B (1 HBD, 7 HBA). Lower HBD/HBA generally improves permeability.

**QED:** Both ligands have good QED scores (0.778 and 0.867), indicating good drug-like properties.

**DILI:** Ligand A (19.426) has a much lower DILI risk than Ligand B (52.423). This is a significant advantage for A.

**BBB:** Both ligands have similar BBB penetration (61.691 and 63.901). While both are above 60%, they are below the desirable >70% threshold for CNS targets.

**Caco-2 Permeability:** Ligand A (-4.421) has worse Caco-2 permeability than Ligand B (-5.232), but both are quite poor.

**Aqueous Solubility:** Ligand A (-1.331) has better aqueous solubility than Ligand B (-2.295).

**hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.319 and 0.404).

**Microsomal Clearance:** Ligand A (4.425) has significantly lower microsomal clearance than Ligand B (17.906), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand B (33.74) has a much longer in vitro half-life than Ligand A (4.73). This is a positive for B.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.045 and 0.058).

**Binding Affinity:** Both ligands have excellent binding affinity (-9.0 and -9.1 kcal/mol). The difference is negligible.

**Overall Assessment:**

Ligand A is superior due to its lower TPSA, lower DILI risk, better solubility, and significantly improved metabolic stability (lower Cl_mic). While Ligand B has a longer half-life, the other advantages of Ligand A outweigh this benefit, especially considering the GPCR-specific focus on BBB, logP, and minimizing off-target effects (DILI). The similar BBB values and binding affinities make the ADME properties the deciding factor.

Output:
0
2025-04-17 08:13:13,147 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (344.459 and 349.519 Da) fall comfortably within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (69.3) is slightly higher than Ligand B (52.65). Both are below the 90 A^2 threshold desirable for CNS targets, but Ligand B is preferable.

**3. logP:** Both ligands have excellent logP values (2.351 and 2.284), falling within the optimal 1-3 range.

**4. H-Bond Donors:** Both have 1 HBD, which is good.

**5. H-Bond Acceptors:** Both have 3 HBA, which is good.

**6. QED:** Ligand A (0.772) has a slightly better QED score than Ligand B (0.684), indicating a more drug-like profile.

**7. DILI:** Ligand A (13.649) has a significantly lower DILI risk than Ligand B (11.012), suggesting a better safety profile.

**8. BBB:** This is a crucial parameter for a CNS target like DRD2. Ligand A (82.164) has a substantially higher BBB percentile than Ligand B (54.44). This is a major advantage for Ligand A.

**9. Caco-2 Permeability:** Ligand A (-4.946) and Ligand B (-4.778) both have negative values, indicating poor permeability.

**10. Aqueous Solubility:** Both have very poor aqueous solubility (-2.181 and -2.15). This is a concern for both, but can potentially be addressed with formulation strategies.

**11. hERG Inhibition:** Both ligands have low hERG inhibition risk (0.284 and 0.39).

**12. Microsomal Clearance:** Ligand A (26.797) has lower microsomal clearance than Ligand B (33.509), indicating better metabolic stability.

**13. In vitro Half-Life:** Ligand A (-23.912) has a much longer in vitro half-life than Ligand B (10.339), which is a significant advantage.

**14. P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.041 and 0.025), which is good.

**15. Binding Affinity:** Ligand B (-8.3 kcal/mol) has a slightly better binding affinity than Ligand A (-7.3 kcal/mol). The difference is 1 kcal/mol, which is significant, but needs to be weighed against other factors.

**Overall Assessment:**

While Ligand B has a slightly better binding affinity, Ligand A is the superior candidate. The significantly better BBB penetration (82.164 vs 54.44), lower DILI risk, better metabolic stability (lower Cl_mic and longer t1/2), and slightly better QED outweigh the small difference in binding affinity. For a CNS target like DRD2, BBB penetration is paramount, and Ligand A excels in this area. The poor solubility and Caco-2 permeability are concerns for both, but are secondary to the critical CNS penetration issue.

Output:
0
2025-04-17 08:13:13,148 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (350.415 and 348.447 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (93.73) is slightly above the optimal <90 for CNS targets, while Ligand B (88.76) is comfortably below. This gives a slight edge to Ligand B.

**logP:** Ligand A (0.547) is quite low, potentially hindering membrane permeability. Ligand B (1.399) is better, falling within the 1-3 optimal range. This is a significant advantage for Ligand B.

**H-Bond Donors/Acceptors:** Ligand A has 2 HBD and 5 HBA, while Ligand B has 1 HBD and 5 HBA. Both are within acceptable limits.

**QED:** Ligand B (0.869) has a much higher QED score than Ligand A (0.274), indicating a more drug-like profile.

**DILI:** Ligand A (51.725) has a slightly higher DILI risk than Ligand B (38.852), though both are reasonably low.

**BBB:** Ligand B (78.209) has a significantly better BBB penetration percentile than Ligand A (58.434). This is *critical* for a CNS target like DRD2.

**Caco-2 Permeability:** Ligand A (-4.699) and Ligand B (-4.926) both have negative Caco-2 values, which is unusual and suggests poor permeability. However, the scale isn't specified, so it's hard to interpret.

**Aqueous Solubility:** Ligand A (-2.436) and Ligand B (-0.708) both have negative solubility values, which is also unusual.

**hERG:** Both ligands have low hERG inhibition liability (0.141 and 0.396 respectively), which is good.

**Microsomal Clearance:** Ligand B (0.917) has significantly lower microsomal clearance than Ligand A (59.189), indicating better metabolic stability.

**In vitro Half-Life:** Ligand A (-41.497) has a negative half-life, which is impossible. Ligand B (12.775) has a reasonable half-life. This is a major red flag for Ligand A.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.111 and 0.015 respectively), which is favorable for CNS penetration.

**Binding Affinity:** Ligand B (-8.1 kcal/mol) has a stronger binding affinity than Ligand A (-7.1 kcal/mol). The difference is >1.5 kcal/mol, which is a substantial advantage.

**Overall:**

Ligand B is clearly superior. It has better logP, QED, BBB penetration, metabolic stability, half-life, and binding affinity. While both have issues with Caco-2 and solubility, the negative half-life for Ligand A is a dealbreaker. Ligand B's profile aligns much better with the requirements for a CNS-active GPCR ligand.

Output:
1
2025-04-17 08:13:13,148 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (351.357 and 347.415 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (102.88) is better than Ligand B (111.55). Both are below the 140 A^2 threshold for oral absorption, and importantly, below the 90 A^2 target for CNS penetration.

**logP:** Ligand A (3.13) is optimal (1-3), while Ligand B (0.963) is slightly low, potentially hindering permeation.

**H-Bond Donors/Acceptors:** Ligand A (HBD=2, HBA=3) is preferable to Ligand B (HBD=4, HBA=5) as it has fewer hydrogen bonding groups, which can improve permeability. Both are within acceptable limits.

**QED:** Ligand B (0.56) has a slightly better QED score than Ligand A (0.314), indicating a more drug-like profile.

**DILI:** Ligand B (36.293) has a significantly lower DILI risk than Ligand A (60.644), which is a substantial advantage.

**BBB:** Ligand A (81.466) has a much better BBB penetration score than Ligand B (34.587). This is *critical* for a CNS target like DRD2.

**Caco-2 Permeability:** Ligand A (-4.95) has a better Caco-2 permeability than Ligand B (-5.151), indicating better intestinal absorption.

**Aqueous Solubility:** Ligand B (-3.154) has better aqueous solubility than Ligand A (-2.677).

**hERG Inhibition:** Ligand B (0.1) has a much lower hERG inhibition liability than Ligand A (0.855), reducing cardiotoxicity concerns.

**Microsomal Clearance:** Ligand B (12.379) has a significantly lower microsomal clearance than Ligand A (38.054), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (42.799) has a longer in vitro half-life than Ligand B (-23.976), which is generally desirable.

**P-gp Efflux:** Ligand A (0.33) has lower P-gp efflux liability than Ligand B (0.025), which is good for CNS exposure.

**Binding Affinity:** Ligand B (-8.6 kcal/mol) has a slightly stronger binding affinity than Ligand A (-7.8 kcal/mol). This difference of 0.8 kcal/mol is significant.

**Overall Assessment:**

Ligand B excels in safety (DILI, hERG) and metabolic stability (Cl_mic), and has a slightly better binding affinity. However, Ligand A has a significantly better BBB score, which is paramount for a CNS target. While Ligand B's lower logP is a minor concern, the substantial improvement in safety and metabolic stability, coupled with the slightly better affinity, outweigh the BBB advantage of Ligand A.

Output:
1
2025-04-17 08:13:13,148 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (356.323 and 347.39 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (69.81) is excellent for CNS penetration, well below 90. Ligand B (80.32) is still reasonable, but less optimal.

**logP:** Ligand A (3.809) is at the higher end of the optimal range (1-3), potentially raising solubility concerns. Ligand B (0.814) is quite low, which could hinder membrane permeability and potentially binding affinity.

**H-Bond Donors/Acceptors:** Ligand A (3 HBD, 2 HBA) is good. Ligand B (2 HBD, 4 HBA) is also acceptable.

**QED:** Both ligands have similar QED values (0.732 and 0.682), indicating good drug-likeness.

**DILI:** Ligand A (64.831) has a slightly higher DILI risk than Ligand B (54.478), but both are below the concerning threshold of 60.

**BBB:** Both ligands have excellent BBB penetration (78.945 and 79.411), exceeding the desirable >70% threshold for CNS targets.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values, which is unusual and potentially indicates issues with the prediction method or the compounds themselves. However, we can still compare them relatively. Ligand A (-5.074) appears slightly better than Ligand B (-4.338).

**Aqueous Solubility:** Both have negative solubility values, again suggesting a potential issue with the prediction. Ligand B (-2.337) is slightly better than Ligand A (-4.62).

**hERG Inhibition:** Ligand A (0.88) has a higher hERG risk than Ligand B (0.206), which is a significant advantage for Ligand B.

**Microsomal Clearance:** Ligand B (30.678) has significantly lower microsomal clearance than Ligand A (7.764), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand B (-12.234) has a much longer in vitro half-life than Ligand A (37.099), which is highly desirable.

**P-gp Efflux:** Ligand A (0.385) has lower P-gp efflux than Ligand B (0.037), which is favorable for CNS exposure.

**Binding Affinity:** Ligand A (-10.2 kcal/mol) has a substantially stronger binding affinity than Ligand B (-7.7 kcal/mol). This is a significant advantage, potentially outweighing some of the ADME concerns. The difference is >1.5 kcal/mol.

**Overall Assessment:**

Ligand A excels in binding affinity and P-gp efflux, crucial for CNS GPCR targeting. However, it has a higher logP, potentially leading to solubility issues, and a higher hERG risk. Ligand B has better ADME properties (lower clearance, longer half-life, lower hERG) but significantly weaker binding affinity.

Given the strong emphasis on affinity for GPCRs, and the substantial difference in binding energy (-10.2 vs -7.7 kcal/mol), Ligand A is the more promising candidate, despite its slightly less ideal ADME profile. The strong binding could potentially be optimized through further medicinal chemistry efforts to address the logP and hERG concerns.

Output:
1
2025-04-17 08:13:13,148 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (349.431 and 360.426 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (72.8) is significantly better than Ligand B (88.1). For CNS targets, we want TPSA <= 90, and A is comfortably within that range, while B is approaching the upper limit.

**logP:** Both ligands have acceptable logP values (1.839 and 0.949), falling within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Both have reasonable HBD (1 & 2) and HBA (5 & 5) counts, well within the guidelines.

**QED:** Ligand A (0.842) has a significantly higher QED score than Ligand B (0.567), indicating better overall drug-likeness.

**DILI:** Both have relatively low DILI risk (47.693 and 35.983), both below the 40 threshold. Ligand B is slightly better.

**BBB:** Ligand A (88.755) has a much higher BBB percentile than Ligand B (74.758). This is *critical* for a CNS target like DRD2.

**Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and suggests poor permeability. However, the scale is not specified, so it's difficult to interpret.

**Aqueous Solubility:** Both have negative solubility values, which is also unusual. This suggests poor solubility.

**hERG:** Both ligands show very low hERG inhibition liability (0.364 and 0.447), which is excellent.

**Microsomal Clearance:** Ligand A (57.875) has a higher microsomal clearance than Ligand B (17.403), meaning it's likely to be metabolized faster. This is a negative for A.

**In vitro Half-Life:** Ligand B (-17.91) has a negative half-life, which is not physically possible and suggests an issue with the data or a very rapid degradation. Ligand A (29.961) is reasonable.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.084 and 0.091), which is favorable for CNS penetration.

**Binding Affinity:** Ligand A (-8.5 kcal/mol) has a significantly stronger binding affinity than Ligand B (-6.9 kcal/mol). This is a substantial advantage (1.6 kcal/mol difference).

**Overall Assessment:**

Ligand A is significantly better overall. Its superior BBB penetration, higher QED, and *much* stronger binding affinity outweigh its higher microsomal clearance. The negative Caco-2 and solubility values are concerning, but the strong affinity and BBB penetration are crucial for a CNS-targeting GPCR. Ligand B's negative half-life is a major red flag, indicating instability or a data error.

Output:
1
2025-04-17 08:13:13,148 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (356.463 and 344.459 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (99.1) is higher than the preferred <90 for CNS targets, while Ligand B (67.23) is comfortably below. This favors Ligand B.

**logP:** Ligand A (0.432) is quite low, potentially hindering membrane permeability. Ligand B (2.081) is within the optimal 1-3 range. This is a significant advantage for Ligand B.

**H-Bond Donors/Acceptors:** Ligand A has 3 HBD and 5 HBA, acceptable values. Ligand B has 1 HBD and 4 HBA, also acceptable.

**QED:** Both ligands have good QED scores (0.575 and 0.832), indicating drug-like properties.

**DILI:** Ligand A (9.926) has a very low DILI risk, which is excellent. Ligand B (19.426) is still reasonably low, but higher than Ligand A.

**BBB:** Ligand B (67.08) is better than Ligand A (52.036), but both are below the desirable >70 for CNS targets. However, given that DRD2 is a CNS target, this is a crucial factor.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.896 and -4.912), which is unusual and suggests poor permeability. This is a concern for both.

**Aqueous Solubility:** Both ligands have negative solubility values (-0.953 and -1.491), also unusual and suggesting poor solubility. This is a concern for both.

**hERG Inhibition:** Both ligands show low hERG inhibition liability (0.251 and 0.218), which is positive.

**Microsomal Clearance:** Ligand A (6.922) has significantly lower microsomal clearance than Ligand B (27.991), indicating better metabolic stability.

**In vitro Half-Life:** Ligand B (-13.175) has a longer in vitro half-life than Ligand A (-9.693).

**P-gp Efflux:** Both ligands show very low P-gp efflux liability (0.023 and 0.049), which is favorable for CNS penetration.

**Binding Affinity:** Ligand B (-8.2 kcal/mol) has a substantially stronger binding affinity than Ligand A (-5.9 kcal/mol). This is a major advantage, potentially outweighing some of the ADME drawbacks.

**Overall Assessment:**

Ligand B is the more promising candidate. While its BBB penetration isn't ideal, it's better than Ligand A's. Critically, it has a much better logP, significantly stronger binding affinity, and a longer half-life. Ligand A has a slightly better DILI score and lower Cl_mic, but the affinity difference is substantial. The poor Caco-2 and solubility for both are concerning, but can potentially be addressed through formulation strategies. For a GPCR target like DRD2, strong affinity and reasonable CNS exposure (even if not optimal) are paramount.

Output:
1
2025-04-17 08:13:13,149 - INFO - Reasoning:
Let's analyze both ligands against the provided guidelines, prioritizing GPCR-specific properties (BBB, logP, Pgp, TPSA, and affinity).

**Ligand A:**

*   **MW:** 344.415 Da - Good (within 200-500 range)
*   **TPSA:** 67.67 A<sup>2</sup> - Excellent (well below 90 A<sup>2</sup> for CNS targets)
*   **logP:** 1.068 - Acceptable (within 1-3 range)
*   **HBD:** 0 - Acceptable (<=5)
*   **HBA:** 5 - Acceptable (<=10)
*   **QED:** 0.766 - Excellent (>=0.5)
*   **DILI:** 42.071 - Good (low risk, <40)
*   **BBB:** 75.301 - Very Good (desirable >70 for CNS)
*   **Caco-2:** -4.35 - Poor (negative value suggests very low permeability)
*   **Solubility:** -2.334 - Poor (negative value suggests very low solubility)
*   **hERG:** 0.121 - Excellent (very low risk)
*   **Cl_mic:** 63.492 - Moderate (relatively high, suggesting moderate metabolic clearance)
*   **t1/2:** -23.594 - Very Poor (negative value suggests very short half-life)
*   **Pgp:** 0.134 - Excellent (low efflux)
*   **Affinity:** -8.4 kcal/mol - Excellent (strong binding)

**Ligand B:**

*   **MW:** 344.459 Da - Good (within 200-500 range)
*   **TPSA:** 67.23 A<sup>2</sup> - Excellent (well below 90 A<sup>2</sup> for CNS targets)
*   **logP:** 2.709 - Good (within 1-3 range)
*   **HBD:** 1 - Acceptable (<=5)
*   **HBA:** 4 - Acceptable (<=10)
*   **QED:** 0.66 - Good (>=0.5)
*   **DILI:** 41.024 - Good (low risk, <40)
*   **BBB:** 69.794 - Acceptable (slightly below the desirable >70, but not a major concern)
*   **Caco-2:** -4.836 - Poor (negative value suggests very low permeability)
*   **Solubility:** -2.745 - Poor (negative value suggests very low solubility)
*   **hERG:** 0.255 - Excellent (very low risk)
*   **Cl_mic:** 39.648 - Good (lower clearance, better metabolic stability)
*   **t1/2:** -0.647 - Very Poor (negative value suggests very short half-life)
*   **Pgp:** 0.09 - Excellent (low efflux)
*   **Affinity:** -8.7 kcal/mol - Excellent (slightly stronger binding than Ligand A)

**Comparison & Decision:**

Both ligands have excellent TPSA, acceptable logP, good QED, low DILI risk, low hERG risk, and low Pgp efflux. Both also have very poor Caco-2 permeability and solubility, and very short in vitro half-lives. The key differences lie in BBB, Cl_mic, and affinity.

Ligand A has a slightly better BBB score (75.3 vs 69.8), but Ligand B has significantly better metabolic stability (lower Cl_mic) and a slightly stronger binding affinity (-8.7 vs -8.4 kcal/mol). For a CNS target like DRD2, the slightly better affinity and metabolic stability of Ligand B are more important than the small difference in BBB. The poor permeability and solubility are significant drawbacks for both, but these can be addressed with formulation strategies.

Therefore, Ligand B is the more promising candidate.

Output:
1
2025-04-17 08:13:13,149 - INFO - Reasoning:

Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (344.415 and 351.451 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (118.01) is slightly higher than Ligand B (109). Both are below the 140 A^2 threshold for good oral absorption and reasonably close to the 90 A^2 target for CNS penetration, but Ligand B is better.

**3. logP:** Both ligands have similar logP values (1.062 and 1.054), falling within the optimal 1-3 range.

**4. H-Bond Donors:** Ligand A has 4 HBD, while Ligand B has 3. Both are acceptable (<=5).

**5. H-Bond Acceptors:** Ligand A has 4 HBA, Ligand B has 5. Both are acceptable (<=10).

**6. QED:** Both ligands have very similar QED values (0.617 and 0.616), indicating good drug-like properties.

**7. DILI:** Ligand A (44.009) has a slightly higher DILI risk than Ligand B (38.62), but both are below the concerning threshold of 60.

**8. BBB:** This is a critical parameter for a CNS target like DRD2. Ligand B (58.085) has a significantly better BBB percentile than Ligand A (40.52). This is a major advantage for Ligand B.

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.122 and -5.047), which is unusual and suggests poor permeability. However, these values are on a scale where negative values are possible and don't necessarily disqualify a compound.

**10. Aqueous Solubility:** Both ligands have negative solubility values (-3.59 and -2.218), which is also unusual. Similar to Caco-2, negative values are possible and don't automatically disqualify a compound.

**11. hERG Inhibition:** Ligand A (0.421) has a slightly higher hERG inhibition risk than Ligand B (0.175), but both are relatively low.

**12. Microsomal Clearance:** Ligand A (-1.619) has a lower (better) microsomal clearance than Ligand B (18.967), indicating greater metabolic stability.

**13. In vitro Half-Life:** Ligand A (-27.289) has a much longer in vitro half-life than Ligand B (4.688), which is a significant advantage.

**14. P-gp Efflux:** Ligand A (0.028) has a much lower P-gp efflux liability than Ligand B (0.055), meaning it's less likely to be pumped out of the brain, improving CNS exposure.

**15. Binding Affinity:** Ligand B (-7.3 kcal/mol) has a slightly better binding affinity than Ligand A (-8.6 kcal/mol). While both are excellent, the 1.3 kcal/mol difference is substantial and could outweigh some ADME drawbacks.

**Overall Assessment:**

Ligand B excels in BBB penetration and binding affinity, which are the most critical factors for a CNS-targeting GPCR like DRD2. While Ligand A has better metabolic stability (lower Cl_mic, longer t1/2) and lower P-gp efflux, the superior BBB and binding affinity of Ligand B are more important in this context. The slightly higher DILI risk of Ligand A is also a minor concern.

Output:
1
2025-04-17 08:13:13,149 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (350.419 Da) is slightly lower, which could be beneficial for permeability. Ligand B (384.929 Da) is also good.

**TPSA:** Ligand A (112.58) is better than Ligand B (66.48) as it is closer to the ideal range for CNS targets (<=90). Ligand B is excellent.

**logP:** Ligand B (3.404) is optimal (1-3), while Ligand A (0.145) is significantly low, potentially hindering permeation. This is a major drawback for Ligand A.

**H-Bond Donors/Acceptors:** Ligand A has 4 HBD and 6 HBA, which are acceptable. Ligand B has 1 HBD and 4 HBA, also acceptable.

**QED:** Both ligands have reasonable QED values (Ligand A: 0.478, Ligand B: 0.732), suggesting decent drug-likeness. Ligand B is better.

**DILI:** Both ligands have low DILI risk (Ligand A: 41.838, Ligand B: 37.34), below the 40 threshold.

**BBB:** Ligand B (70.88) is significantly better than Ligand A (53.819) in terms of BBB penetration, which is crucial for a CNS target like DRD2.

**Caco-2 Permeability:** Ligand A (-4.982) is very poor, suggesting very low intestinal absorption. Ligand B (-5.013) is also poor, but slightly better than A.

**Aqueous Solubility:** Both ligands have poor aqueous solubility (-2.323 and -3.938 respectively).

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.235 and 0.265 respectively).

**Microsomal Clearance:** Ligand A (9.184) has lower clearance than Ligand B (58.054), indicating better metabolic stability. This is a positive for Ligand A.

**In vitro Half-Life:** Ligand B (20.583) has a longer half-life than Ligand A (15.98), which is generally preferred.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.011 and 0.397 respectively).

**Binding Affinity:** Both ligands have very similar and excellent binding affinities (-7.2 and -7.3 kcal/mol). The difference is negligible.

**Overall Assessment:**

Ligand B is significantly better overall. While Ligand A has slightly better metabolic stability, Ligand B excels in crucial areas for a CNS-targeting GPCR ligand: logP, BBB penetration, and QED. The low logP of Ligand A is a major concern, likely hindering its ability to cross cell membranes and reach the target in the brain. The better BBB score of Ligand B is a decisive advantage.

Output:
1
2025-04-17 08:13:13,149 - INFO - Batch 430 complete. Total preferences: 6880
2025-04-17 08:13:13,150 - INFO - Processing batch 431/512...
2025-04-17 08:13:55,439 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (363.502 and 357.363 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (36.44) is excellent, well below the 90 A^2 target for CNS drugs. Ligand B (106.64) is higher, but still potentially acceptable, though less optimal.

**logP:** Ligand A (3.685) is within the optimal 1-3 range. Ligand B (-1.804) is significantly lower, which could hinder membrane permeability and CNS penetration.

**H-Bond Donors/Acceptors:** Ligand A (0 HBD, 4 HBA) is favorable. Ligand B (1 HBD, 7 HBA) is also reasonable, but slightly higher counts could impact permeability.

**QED:** Both ligands have acceptable QED scores (0.718 and 0.597, respectively), indicating good drug-like properties.

**DILI:** Ligand A (36.293) has a lower DILI risk than Ligand B (50.174), which is preferable.

**BBB:** Ligand A (87.553) has a much higher BBB penetration percentile than Ligand B (52.423). This is a *critical* advantage for a CNS target like DRD2.

**Caco-2 Permeability:** Ligand A (-4.403) has poor Caco-2 permeability, which is a concern. Ligand B (-4.961) is also poor, but slightly worse.

**Aqueous Solubility:** Both ligands have very poor aqueous solubility (-3.048 and -0.696 respectively). This could present formulation challenges.

**hERG Inhibition:** Ligand A (0.91) has a slightly higher hERG risk than Ligand B (0.09), but both are relatively low.

**Microsomal Clearance:** Ligand A (43.873) has a higher microsomal clearance than Ligand B (-34.513), indicating lower metabolic stability. Ligand B looks much better here.

**In vitro Half-Life:** Ligand A (55.17) has a better in vitro half-life than Ligand B (-16.501).

**P-gp Efflux:** Ligand A (0.665) has lower P-gp efflux liability than Ligand B (0.002), which is favorable for CNS penetration.

**Binding Affinity:** Ligand A (-7.7 kcal/mol) has a significantly stronger binding affinity than Ligand B (-6.9 kcal/mol). This 1.8 kcal/mol difference is substantial and can outweigh some ADME concerns.

**Overall Assessment:**

Ligand A is the stronger candidate despite its poor Caco-2 permeability and higher clearance. Its superior BBB penetration, significantly better binding affinity, and lower DILI risk are crucial advantages for a CNS-targeting GPCR. The lower logP of Ligand B is a major drawback, likely hindering its ability to cross the blood-brain barrier effectively. While Ligand B has better metabolic stability, the affinity difference and BBB score are too significant to ignore.

Output:
1
2025-04-17 08:13:55,439 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (350.503 and 365.821 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (58.64) is excellent, well below the 90 A^2 threshold for CNS targets. Ligand B (87.54) is still reasonable but closer to the upper limit, potentially impacting BBB penetration.

**3. logP:** Ligand A (3.047) is optimal (1-3). Ligand B (0.025) is very low, which is a significant concern. Low logP typically translates to poor membrane permeability and reduced CNS exposure.

**4. H-Bond Donors:** Both ligands have 1 HBD, which is within the acceptable limit of <=5.

**5. H-Bond Acceptors:** Ligand A has 3 HBAs, and Ligand B has 5. Both are within the acceptable limit of <=10.

**6. QED:** Both ligands have good QED scores (0.65 and 0.818), indicating generally drug-like properties.

**7. DILI:** Ligand A (9.19) has a very low DILI risk. Ligand B (56.146) is higher, indicating a moderate risk, but not a dealbreaker on its own.

**8. BBB:** Ligand A (81.233) has a good BBB percentile, exceeding the desirable >70% for CNS targets. Ligand B (68.903) is lower, which is concerning for a CNS-targeted drug.

**9. Caco-2:** Ligand A (-4.359) and Ligand B (-5.078) have negative values, which is unusual. Assuming these are log scale values, lower values indicate poor permeability.

**10. Solubility:** Both ligands have poor aqueous solubility (-2.178 and -2.708). This could pose formulation challenges.

**11. hERG:** Both ligands have low hERG inhibition risk (0.387 and 0.119).

**12. Cl_mic:** Ligand A (70.712) has moderate clearance. Ligand B (-0.85) has very low clearance, suggesting high metabolic stability, which is a positive.

**13. t1/2:** Ligand A (-1.548) has a short in vitro half-life. Ligand B (15.604) has a long in vitro half-life, which is a significant advantage.

**14. Pgp:** Ligand A (0.116) has low P-gp efflux, which is good for CNS exposure. Ligand B (0.035) has even lower P-gp efflux, which is excellent.

**15. Binding Affinity:** Both ligands have very similar and strong binding affinities (-7.8 and -7.9 kcal/mol). The difference is negligible.

**Overall Assessment:**

Ligand A excels in TPSA and BBB, crucial for CNS penetration. However, its solubility and half-life are concerning. Ligand B, while having a slightly higher TPSA, demonstrates superior metabolic stability (very low Cl_mic, long t1/2) and extremely low P-gp efflux. The biggest drawback of Ligand B is its very low logP, which will likely severely limit its ability to cross the blood-brain barrier despite the favorable BBB percentile.

Given the GPCR-specific priorities, and the importance of CNS penetration for a DRD2 ligand, Ligand A is the better candidate despite its weaknesses. The lower TPSA and higher BBB score are more critical than the slightly better metabolic stability of Ligand B, especially considering the similar binding affinities. The solubility issues of Ligand A can potentially be addressed through formulation strategies.

Output:
0
2025-04-17 08:13:55,439 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B against the provided guidelines, prioritizing GPCR-specific properties (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands fall within the ideal range (200-500 Da). Ligand A (405.933 Da) is slightly higher than Ligand B (345.426 Da), but both are acceptable.

**TPSA:** Ligand A (97.19) is higher than Ligand B (73.45). For CNS targets, we want TPSA <= 90. Ligand A is marginally above this, while Ligand B is well within the range. This favors Ligand B.

**logP:** Both ligands have good logP values (Ligand A: 1.684, Ligand B: 1.777), falling within the optimal 1-3 range. No significant difference here.

**H-Bond Donors/Acceptors:** Both have 1 HBD and 7 HBA, which are within acceptable limits.

**QED:** Both ligands have similar QED values (Ligand A: 0.755, Ligand B: 0.701), indicating good drug-likeness.

**DILI:** Ligand A (86.855) has a higher DILI risk than Ligand B (37.999). This is a significant advantage for Ligand B.

**BBB:** Ligand B (85.731) has a much better BBB penetration percentile than Ligand A (39.24). This is *critical* for a CNS target like DRD2.

**Caco-2 Permeability:** Both have negative Caco-2 values (-5.24 and -5.282), which is unusual and likely indicates a problem with the prediction method or the molecule itself. However, the values are very similar.

**Aqueous Solubility:** Both have negative solubility values (-3.139 and -2.116), also unusual. Again, similar values.

**hERG:** Both ligands have low hERG inhibition liability (Ligand A: 0.216, Ligand B: 0.263).

**Microsomal Clearance:** Ligand A (54.731) has significantly higher microsomal clearance than Ligand B (11.869), suggesting lower metabolic stability. This favors Ligand B.

**In vitro Half-Life:** Ligand B (-6.563) has a longer (less negative) in vitro half-life than Ligand A (-13.099), indicating better stability. This favors Ligand B.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (Ligand A: 0.106, Ligand B: 0.178).

**Binding Affinity:** Ligand B (-7.2 kcal/mol) has a slightly better binding affinity than Ligand A (-8.5 kcal/mol). While Ligand A is stronger, the difference is not substantial enough to overcome the significant ADME advantages of Ligand B.

**Overall Assessment:**

Ligand B is the superior candidate. It has a lower TPSA, significantly lower DILI risk, substantially better BBB penetration, lower microsomal clearance, longer in vitro half-life, and slightly better binding affinity. While Ligand A has a stronger binding affinity, the ADME properties of Ligand B are far more favorable for a CNS-targeting drug, especially considering the importance of BBB penetration for DRD2.

Output:
1
2025-04-17 08:13:55,440 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (349.391 and 344.415 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (117.37) is slightly above the optimal <90 for CNS targets, but still reasonable. Ligand B (83.44) is well within the desired range. This favors Ligand B.

**logP:** Ligand A (0.595) is a bit low, potentially hindering permeability. Ligand B (0.128) is even lower, raising concerns about membrane penetration. Both are suboptimal, but Ligand A is slightly better.

**H-Bond Donors/Acceptors:** Ligand A has 4 HBD and 5 HBA, acceptable. Ligand B has 2 HBD and 4 HBA, also acceptable. No clear advantage here.

**QED:** Both ligands have good QED scores (0.596 and 0.762), indicating good drug-like properties.

**DILI:** Ligand A (73.052) has a higher DILI risk than Ligand B (31.524). This favors Ligand B.

**BBB:** Ligand A (71.772) has a good BBB penetration percentile, while Ligand B (67.158) is lower, but still acceptable. Ligand A is better here, but both are reasonably good.

**Caco-2 Permeability:** Both have negative Caco-2 values (-5.059 and -4.98), which is unusual and suggests poor permeability. This is a significant concern for both.

**Aqueous Solubility:** Both have negative solubility values (-3.122 and -2.288), which is also unusual and suggests poor solubility. This is a significant concern for both.

**hERG:** Both ligands have very low hERG inhibition liability (0.172 and 0.148), which is excellent.

**Microsomal Clearance:** Ligand A (-19.65) has a much lower (better) microsomal clearance than Ligand B (2.479), indicating better metabolic stability. This is a significant advantage for Ligand A.

**In vitro Half-Life:** Ligand A (49.518) has a longer half-life than Ligand B (10.42). This is a significant advantage for Ligand A.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.007 and 0.012), which is excellent.

**Binding Affinity:** Both ligands have strong binding affinities (-9.7 and -8.4 kcal/mol). Ligand A is 1.3 kcal/mol more potent, which is a substantial advantage and can often outweigh minor ADME drawbacks.

**Overall Assessment:**

While both ligands have issues with Caco-2 permeability and solubility, Ligand A has a significantly stronger binding affinity, better metabolic stability (lower Cl_mic, longer t1/2), and slightly better BBB penetration. The lower DILI risk of Ligand B is a plus, but the affinity difference is substantial. Given the GPCR target and the importance of potency, the stronger binding of Ligand A is the deciding factor.

Output:
1
2025-04-17 08:13:55,440 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (355.391 and 349.45 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (108.41) is higher than Ligand B (52.65). For CNS targets, TPSA should be <= 90. Ligand B is significantly better in this regard.

**logP:** Ligand A (-0.894) is below the optimal 1-3 range, potentially hindering permeability. Ligand B (1.348) is within the optimal range. This favors Ligand B.

**H-Bond Donors/Acceptors:** Ligand A has 2 HBD and 6 HBA, while Ligand B has 1 HBD and 3 HBA. Both are within acceptable limits (<=5 HBD and <=10 HBA).

**QED:** Both ligands have good QED scores (0.574 and 0.737, respectively), indicating drug-like properties.

**DILI:** Ligand A (36.487) has a moderate DILI risk, while Ligand B (11.439) has a very low DILI risk. This strongly favors Ligand B.

**BBB:** Ligand A (19.232) has a very poor BBB penetration percentile, making it unlikely to reach the target in the CNS. Ligand B (90.074) has excellent BBB penetration, a crucial factor for a DRD2 ligand.

**Caco-2 Permeability:** Both have negative values (-4.967 and -4.907), which is unusual and difficult to interpret without knowing the scale. However, the values are similar.

**Aqueous Solubility:** Both have negative values (-0.46 and -1.797), also unusual. Again, the values are similar.

**hERG Inhibition:** Ligand A (0.05) has a very low hERG inhibition risk, while Ligand B (0.59) has a slightly higher, but still acceptable, risk.

**Microsomal Clearance:** Ligand A (-14.437) suggests very low clearance and high metabolic stability. Ligand B (3.124) indicates faster clearance. This favors Ligand A.

**In vitro Half-Life:** Ligand A (-7.232) suggests a very long half-life. Ligand B (7.181) has a reasonable half-life.

**P-gp Efflux:** Ligand A (0.009) has very low P-gp efflux, which is good for CNS penetration. Ligand B (0.054) also has low P-gp efflux.

**Binding Affinity:** Ligand B (-8.0 kcal/mol) has a significantly stronger binding affinity than Ligand A (-6.9 kcal/mol). This is a substantial advantage.

**Overall Assessment:**

Ligand B is the superior candidate. Its excellent BBB penetration, favorable logP, low DILI risk, and significantly stronger binding affinity outweigh the slightly higher hERG risk and faster clearance. Ligand A's primary advantage is its metabolic stability and very low P-gp efflux, but its poor BBB penetration is a critical drawback for a CNS target like DRD2. The TPSA of Ligand B is also much more favorable.

Output:
1
2025-04-17 08:13:55,440 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (355.331 and 352.435 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (38.33) is excellent, well below the 90 A^2 threshold for CNS targets. Ligand B (96.55) is higher, but still potentially acceptable, though less ideal.

**3. logP:** Ligand A (4.318) is slightly high, potentially leading to solubility issues or off-target interactions. Ligand B (0.881) is quite low, which might hinder membrane permeability and CNS penetration.

**4. H-Bond Donors:** Both ligands have acceptable HBD counts (1 and 2, respectively), well within the limit of 5.

**5. H-Bond Acceptors:** Both ligands have acceptable HBA counts (2 and 5, respectively), within the limit of 10.

**6. QED:** Both ligands have similar and acceptable QED values (0.812 and 0.759), indicating good drug-like properties.

**7. DILI:** Both ligands have similar and acceptable DILI risk (52.191 and 52.695 percentile), below the 60% threshold.

**8. BBB:** This is a critical parameter for a CNS target like DRD2. Ligand A has a significantly higher BBB penetration percentile (74.758) compared to Ligand B (45.56). This is a major advantage for Ligand A.

**9. Caco-2 Permeability:** Ligand A (-4.324) shows poor Caco-2 permeability, while Ligand B (-5.033) is also poor.

**10. Aqueous Solubility:** Ligand A (-5.047) has very poor aqueous solubility, which is concerning. Ligand B (-1.554) is also poor, but slightly better than A.

**11. hERG Inhibition:** Both ligands have low hERG inhibition risk (0.768 and 0.226, respectively).

**12. Microsomal Clearance:** Ligand A (65.678) has higher microsomal clearance, indicating faster metabolism, which is less desirable. Ligand B (3.612) has very low clearance, suggesting good metabolic stability.

**13. In vitro Half-Life:** Ligand B (-14.673) has a much longer in vitro half-life compared to Ligand A (-5.886).

**14. P-gp Efflux:** Both ligands have low P-gp efflux liability (0.208 and 0.012, respectively).

**15. Binding Affinity:** Ligand A (-9.4 kcal/mol) has a significantly stronger binding affinity than Ligand B (-8.1 kcal/mol). This is a substantial advantage, potentially outweighing some of its ADME drawbacks.

**Overall Assessment:**

Ligand A has a superior binding affinity and better BBB penetration, which are crucial for a CNS GPCR target. However, it suffers from poor solubility, higher metabolic clearance, and poor Caco-2 permeability. Ligand B has better metabolic stability, slightly better solubility, and a longer half-life, but its significantly weaker binding affinity and poor BBB penetration are major drawbacks.

Given the importance of binding affinity and BBB penetration for CNS GPCR targets, and the substantial difference in affinity (-9.4 vs -8.1 kcal/mol), Ligand A is the more promising candidate *despite* its ADME liabilities. These liabilities could potentially be addressed through further structural modifications.

Output:
1
2025-04-17 08:13:55,440 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, considering the provided guidelines and GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (350.419 and 353.463 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (102.32) is slightly above the optimal <90 for CNS targets, but acceptable. Ligand B (62.32) is well within the desired range. This favors Ligand B.

**logP:** Ligand A (0.933) is at the lower end of the optimal 1-3 range, potentially hindering permeability. Ligand B (0.051) is *below* 1, which is a significant concern for membrane permeability. This favors Ligand A.

**H-Bond Donors/Acceptors:** Ligand A has 2 HBD and 6 HBA, both within acceptable limits. Ligand B has 0 HBD and 5 HBA, also acceptable.

**QED:** Both ligands have good QED scores (0.51 and 0.699, respectively), indicating drug-like properties.

**DILI:** Ligand A (41.877) has a slightly higher DILI risk than Ligand B (13.106), but both are below the concerning threshold of 60. This favors Ligand B.

**BBB:** Ligand A (68.166) is reasonably good, but Ligand B (62.737) is slightly lower. Both are below the desirable >70 for CNS targets, but not dramatically so.

**Caco-2 Permeability:** Ligand A (-4.982) and Ligand B (-4.423) both have negative Caco-2 values, which is unusual and suggests poor permeability. This is a concern for both.

**Aqueous Solubility:** Both ligands have very poor aqueous solubility (-1.996 and -0.044 respectively). This is a significant drawback for both.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.172 and 0.283), which is positive.

**Microsomal Clearance:** Ligand A (53.414) has higher microsomal clearance than Ligand B (9.658), indicating lower metabolic stability. This favors Ligand B.

**In vitro Half-Life:** Ligand A (-13.698) has a negative half-life, which is not physically possible and indicates a problem with the data or the molecule itself. Ligand B (13.325) has a reasonable half-life. This *strongly* favors Ligand B.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.042 and 0.021), which is favorable for CNS penetration.

**Binding Affinity:** Ligand A (-7.8 kcal/mol) has a slightly better binding affinity than Ligand B (-7.2 kcal/mol). The difference is 0.6 kcal/mol, which is not huge, but noticeable.

**Overall Assessment:**

Despite Ligand A's slightly better affinity, Ligand B is the more promising candidate. Ligand A has a problematic negative in vitro half-life, higher DILI risk, and higher microsomal clearance. Ligand B has a better TPSA, lower DILI, lower clearance, and a reasonable half-life. While both have poor solubility and Caco-2 permeability, the other factors weigh heavily in favor of Ligand B. The slightly lower logP of Ligand B is a concern, but the other advantages are more significant for a CNS target like DRD2.



Output:
1
2025-04-17 08:13:55,440 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (359.312 and 345.443 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (106.85) is slightly above the optimal <90 for CNS targets, but still reasonable. Ligand B (75.44) is excellent, well below 90.

**logP:** Both ligands have good logP values (1.3 and 2.458), falling within the 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A (2 HBD, 7 HBA) and Ligand B (1 HBD, 4 HBA) both meet the criteria of <=5 HBD and <=10 HBA.

**QED:** Both ligands have good QED scores (0.722 and 0.859), indicating good drug-like properties.

**DILI:** Ligand A (72.043) has a higher DILI risk than Ligand B (23.885). This is a significant negative for Ligand A.

**BBB:** Ligand A (83.715) has a better BBB penetration percentile than Ligand B (68.166), which is a key consideration for a CNS target like DRD2.

**Caco-2 Permeability:** Ligand A (-5.183) has worse Caco-2 permeability than Ligand B (-4.842). Both are negative values, indicating low permeability, but B is slightly better.

**Aqueous Solubility:** Both ligands have very poor aqueous solubility (-2.19 and -2.534). This could pose formulation challenges.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.115 and 0.367).

**Microsomal Clearance:** Ligand A (26.632) has lower microsomal clearance than Ligand B (41.638), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (-10.423) has a shorter in vitro half-life than Ligand B (13.043).

**P-gp Efflux:** Ligand A (0.124) has lower P-gp efflux than Ligand B (0.049), which is favorable for CNS penetration.

**Binding Affinity:** Ligand B (-7.9 kcal/mol) has a slightly better binding affinity than Ligand A (-8.2 kcal/mol). While the difference is small, it's still a positive for Ligand B.

**Overall Assessment:**

Ligand B is the better candidate. While Ligand A has a slightly better BBB score and lower P-gp efflux, Ligand B compensates with a significantly lower DILI risk, better Caco-2 permeability, better in vitro half-life, and a slightly better binding affinity. The lower DILI risk is a major advantage, as liver toxicity is a common reason for drug attrition. The improved half-life is also beneficial. The slightly lower BBB score for Ligand B is less concerning given its other favorable properties.

Output:
1
2025-04-17 08:13:55,440 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight (MW):** Both ligands (347.423 and 351.451 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (117.59) is slightly above the optimal <90 for CNS targets, but still reasonable. Ligand B (88.49) is excellent, well below 90.

**3. logP:** Ligand A (1.045) is at the lower end of the optimal 1-3 range, potentially impacting permeability. Ligand B (0.596) is even lower, raising more concern for permeability.

**4. H-Bond Donors (HBD):** Both ligands have acceptable HBD counts (3 and 2, respectively), well below the limit of 5.

**5. H-Bond Acceptors (HBA):** Both ligands have acceptable HBA counts (6 each), below the limit of 10.

**6. QED:** Both ligands have similar and acceptable QED values (0.626 and 0.68), indicating good drug-like properties.

**7. DILI:** Ligand A (60.411) is borderline, indicating moderate risk. Ligand B (34.432) is much better, with a low DILI risk.

**8. BBB:** This is crucial for a CNS target like DRD2. Ligand A (30.206) has a low BBB percentile, which is a significant drawback. Ligand B (63.086) is much better, though still not ideal (>70 is preferred).

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.825 and -5.061). This is unusual and suggests poor permeability, but the scale is not defined.

**10. Aqueous Solubility:** Both ligands have negative solubility values (-1.915 and -1.294), also unusual and suggesting poor solubility.

**11. hERG Inhibition:** Both ligands have low hERG inhibition risk (0.122 and 0.224).

**12. Microsomal Clearance:** Ligand A (4.323) has lower clearance, suggesting better metabolic stability than Ligand B (17.175).

**13. In vitro Half-Life:** Ligand A (15.668) has a slightly longer half-life than Ligand B (14.433).

**14. P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.04 and 0.017), which is favorable for CNS penetration.

**15. Binding Affinity:** Ligand A (-7.8 kcal/mol) has a slightly better binding affinity than Ligand B (-7.4 kcal/mol). This 0.4 kcal/mol difference is significant, but needs to be weighed against other factors.

**Overall Assessment:**

Ligand B is the better candidate. While both have issues with predicted permeability and solubility, Ligand B has a significantly better BBB percentile and a lower DILI risk. The slightly weaker affinity of Ligand B is outweighed by its superior ADME properties, particularly the improved BBB penetration, which is critical for a CNS target. Ligand A's poor BBB score is a major concern.

Output:
1
2025-04-17 08:13:55,440 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (357.41 and 362.499 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (64.11) is significantly better than Ligand B (69.3). For CNS targets, we want TPSA <= 90, both are within this range, but A is preferable.

**logP:** Ligand A (4.107) is higher than the optimal 1-3 range, potentially causing solubility issues. Ligand B (1.999) is within the optimal range. This favors B.

**H-Bond Donors:** Both have 1 HBD, which is acceptable.

**H-Bond Acceptors:** Ligand A has 6 HBA, and Ligand B has 4. Both are within the acceptable limit of <=10.

**QED:** Both ligands have good QED scores (0.696 and 0.832), indicating good drug-like properties.

**DILI:** Ligand A (85.227) has a higher DILI risk than Ligand B (48.662). This is a significant advantage for B.

**BBB:** Ligand A (81) has a better BBB penetration percentile than Ligand B (60.566). This is a crucial factor for a CNS target like DRD2, favoring A.

**Caco-2 Permeability:** Ligand A (-4.504) has worse Caco-2 permeability than Ligand B (-5.341). Lower values are less favorable.

**Aqueous Solubility:** Ligand A (-5.966) has significantly worse aqueous solubility than Ligand B (-2.832). This is a concern for A, given its already high logP.

**hERG:** Both ligands have low hERG inhibition liability (0.443 and 0.356), which is good.

**Microsomal Clearance:** Ligand A (120.694) has higher microsomal clearance than Ligand B (47.358), indicating lower metabolic stability. This favors B.

**In vitro Half-Life:** Ligand B (-19.604) has a significantly longer in vitro half-life than Ligand A (28.621). This is a strong advantage for B.

**P-gp Efflux:** Ligand A (0.269) has higher P-gp efflux liability than Ligand B (0.16). Lower P-gp efflux is preferred for CNS penetration, favoring B.

**Binding Affinity:** Ligand A (-9.6 kcal/mol) has a significantly stronger binding affinity than Ligand B (0.0 kcal/mol). This is a major advantage for A, potentially outweighing some of its ADME drawbacks.

**Overall Assessment:**

While Ligand A has a superior binding affinity, Ligand B demonstrates a much better ADME profile, particularly regarding BBB penetration, DILI risk, metabolic stability, solubility, and P-gp efflux. The substantial difference in binding affinity (-9.6 vs 0.0) is compelling. Given the importance of CNS penetration for a DRD2 ligand, and the relatively large affinity difference, I believe Ligand A is the more promising candidate.

Output:
1
2025-04-17 08:13:55,440 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (336.395) is slightly better, being closer to the lower end which can aid permeability.

**TPSA:** Ligand A (85.01) is excellent for CNS penetration, well below the 90 A^2 threshold. Ligand B (49.41) is also very good.

**logP:** Both ligands have optimal logP values (around 3), suggesting good permeability and reasonable solubility.

**H-Bond Donors/Acceptors:** Ligand A has 3 HBD and 3 HBA, while Ligand B has 1 HBD and 3 HBA. Both are within acceptable limits.

**QED:** Both ligands have good QED scores (A: 0.683, B: 0.833), indicating drug-likeness.

**DILI:** Both have low DILI risk (A: 44.09, B: 40.05), which is favorable.

**BBB:** This is a crucial parameter for CNS targets. Ligand B (74.564) significantly outperforms Ligand A (26.987) in BBB penetration, making it much more likely to reach the target in the brain.

**Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and suggests poor permeability. However, the scale is not specified, so this is hard to interpret.

**Aqueous Solubility:** Both have negative solubility values, indicating poor solubility. This is a concern, but can potentially be addressed with formulation strategies.

**hERG Inhibition:** Both have low hERG inhibition risk (A: 0.289, B: 0.421).

**Microsomal Clearance:** Ligand A (-4.358) has a much lower (better) microsomal clearance than Ligand B (87.229), indicating better metabolic stability.

**In vitro Half-Life:** Ligand A (-14.636) has a much longer half-life than Ligand B (-0.389), which is a significant advantage.

**P-gp Efflux:** Ligand A (0.03) has very low P-gp efflux, which is excellent for CNS penetration. Ligand B (0.345) is also relatively low.

**Binding Affinity:** Ligand B (0.0) has a slightly better binding affinity than Ligand A (-8.9 kcal/mol), but the difference is not substantial enough to outweigh the other factors.

**Overall:**

Ligand B excels in BBB penetration, which is paramount for a CNS target like DRD2. While Ligand A has better metabolic stability (lower Cl_mic and longer t1/2), the significantly lower BBB score is a major drawback. The slightly better affinity of Ligand B is a bonus. Given the GPCR-specific priorities, BBB is the deciding factor here.

Output:
1
2025-04-17 08:13:55,441 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (353.394 and 348.403 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (82.97) is significantly better than Ligand B (96.55). For CNS targets, we want TPSA <= 90, and A is comfortably within that, while B is close to the upper limit.

**3. logP:** Ligand B (0.71) is slightly better than Ligand A (0.218), being closer to the optimal 1-3 range. A is quite low, potentially hindering permeation.

**4. H-Bond Donors:** Ligand A (1) is preferable to Ligand B (2). Lower HBD generally improves permeability.

**5. H-Bond Acceptors:** Both ligands have 5 HBA, which is acceptable (<=10).

**6. QED:** Both ligands have very similar QED values (0.791 and 0.789), indicating good drug-like properties.

**7. DILI:** Both ligands have low DILI risk (31.291 and 29.857), both well below the 40 threshold.

**8. BBB:** Both ligands have similar BBB penetration (53.587 and 56.301). While not ideal (>70), they are comparable. This is a critical factor for a CNS target like DRD2.

**9. Caco-2 Permeability:** Ligand A (-4.322) shows better Caco-2 permeability than Ligand B (-4.827), suggesting better intestinal absorption.

**10. Aqueous Solubility:** Ligand A (-0.216) has better aqueous solubility than Ligand B (-2.246).

**11. hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.118 and 0.18), which is excellent.

**12. Microsomal Clearance:** Ligand B (-5.783) has significantly lower (better) microsomal clearance than Ligand A (1.097), indicating greater metabolic stability.

**13. In vitro Half-Life:** Ligand B (-8.458) has a much longer in vitro half-life than Ligand A (12.878), which is a significant advantage.

**14. P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.027 and 0.014), which is favorable for CNS penetration.

**15. Binding Affinity:** Ligand B (-7.8 kcal/mol) has slightly better binding affinity than Ligand A (-7.2 kcal/mol). While the difference is less than the 1.5 kcal/mol threshold that would overwhelmingly favor one ligand, it's still a positive for B.

**Overall Assessment:**

Ligand B has a clear advantage in metabolic stability (lower Cl_mic, longer t1/2) and slightly better binding affinity. Ligand A has better TPSA and solubility. However, the lower logP of Ligand A is a concern for CNS penetration, and the higher TPSA of Ligand B is less desirable. Considering the GPCR-specific priorities, the improved metabolic stability and binding affinity of Ligand B, coupled with acceptable TPSA and BBB, make it the more promising candidate.

Output:
1
2025-04-17 08:13:55,441 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 drug candidates, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the acceptable range (200-500 Da). Ligand A (335.407 Da) is slightly better, being closer to the ideal range.

**TPSA:** Ligand A (65.36) is significantly better than Ligand B (93.01). For CNS targets, we want TPSA <= 90, and Ligand A is comfortably within this range, while Ligand B is slightly above.

**logP:** Ligand A (3.942) is good, within the optimal 1-3 range. Ligand B (1.236) is on the lower side, potentially hindering permeation.

**H-Bond Donors/Acceptors:** Both have acceptable HBD counts (1). Ligand B has a higher HBA count (8) compared to Ligand A (3), which is less ideal, but still within the acceptable limit of 10.

**QED:** Ligand A (0.924) has a much better QED score than Ligand B (0.719), indicating a more drug-like profile.

**DILI:** Both ligands have similar DILI risk (around 57), which is acceptable.

**BBB:** Ligand A (82.125) has a significantly higher BBB penetration percentile than Ligand B (25.01). This is a *critical* advantage for a CNS target like DRD2.

**Caco-2 Permeability:** Ligand A (-4.499) shows better Caco-2 permeability than Ligand B (-5.371).

**Aqueous Solubility:** Ligand B (-0.983) has slightly better aqueous solubility than Ligand A (-5.106). However, solubility is less critical than BBB penetration for CNS drugs.

**hERG Inhibition:** Ligand A (0.856) has a slightly higher hERG risk than Ligand B (0.02), but both are relatively low.

**Microsomal Clearance:** Ligand A (50.943) has a higher microsomal clearance than Ligand B (36.138), meaning it's metabolized faster. This is a drawback for Ligand A.

**In vitro Half-Life:** Ligand B (3.205) has a slightly longer in vitro half-life than Ligand A (20.212), which is preferable.

**P-gp Efflux:** Ligand A (0.329) has a lower P-gp efflux liability than Ligand B (0.043), which is a positive for CNS penetration.

**Binding Affinity:** Ligand B (-7.5 kcal/mol) has a significantly stronger binding affinity than Ligand A (-10.4 kcal/mol). This is a substantial advantage, potentially outweighing some of the ADME drawbacks.

**Overall Assessment:**

Ligand A excels in properties crucial for CNS penetration (BBB, TPSA, Pgp) and has a good drug-like profile (QED). However, its metabolic clearance is higher, and its binding affinity is weaker. Ligand B has superior binding affinity and a longer half-life, but suffers from poor BBB penetration and a higher TPSA.

Given the importance of CNS penetration for a DRD2 ligand, and the substantial difference in BBB scores, Ligand A is the more promising candidate *despite* the weaker binding affinity. The difference in affinity (-7.5 vs -10.4) is not as impactful as the difference in BBB penetration (82.125 vs 25.01). Further optimization of Ligand A could potentially improve its affinity while maintaining its favorable CNS properties.

Output:
0
2025-04-17 08:13:55,441 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (353.304 Da) is slightly lower, which could be beneficial for permeability, but both are acceptable.

**TPSA:** Ligand A (84.04) is excellent for CNS penetration, being well below 90. Ligand B (25.36) is even better, indicating potentially improved BBB penetration.

**logP:** Ligand A (1.92) is optimal. Ligand B (4.842) is a bit high, potentially leading to solubility issues and off-target interactions, but not drastically so.

**H-Bond Donors/Acceptors:** Ligand A (0 HBD, 6 HBA) and Ligand B (0 HBD, 4 HBA) both have favorable numbers of H-bond donors and acceptors, balancing solubility and permeability.

**QED:** Both ligands have reasonable QED values (A: 0.838, B: 0.721), suggesting good drug-like properties.

**DILI:** Ligand A (72.703) has a moderate DILI risk, while Ligand B (14.618) has a very low risk, which is a significant advantage.

**BBB:** Ligand A (83.443) has good BBB penetration, but Ligand B (93.292) is excellent, exceeding the >70% threshold for CNS targets. This is a key advantage for DRD2.

**Caco-2 Permeability:** Ligand A (-4.118) and Ligand B (-5.241) both have negative values, which is unusual and suggests poor permeability. This is a concern for both, but B is slightly worse.

**Aqueous Solubility:** Both ligands have poor aqueous solubility (-3.531 and -3.946 respectively). This could pose formulation challenges.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.201 and 0.824 respectively).

**Microsomal Clearance:** Ligand A (63.809) has higher clearance than Ligand B (52.504), suggesting lower metabolic stability.

**In vitro Half-Life:** Ligand A (-6.238) has a longer half-life than Ligand B (-4.789).

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.374 and 0.582 respectively), which is favorable for CNS exposure.

**Binding Affinity:** Both ligands have the same binding affinity (-8.2 kcal/mol), which is excellent.

**Overall Assessment:**

While Ligand A has a slightly better half-life, Ligand B clearly stands out due to its superior BBB penetration (93.292 vs 83.443), significantly lower DILI risk (14.618 vs 72.703), and comparable binding affinity. The higher logP of Ligand B is a minor concern, but the benefits of improved CNS penetration and reduced toxicity outweigh this drawback, especially for a CNS target like DRD2. The Caco-2 permeability is a concern for both, but can potentially be addressed with formulation strategies.

Output:
1
2025-04-17 08:13:55,441 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (356.46 & 346.47 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (40.62) is significantly better than Ligand B (49.85). For CNS targets, we want TPSA <= 90, and ideally closer to 60. Ligand A is much closer to this ideal.

**3. logP:** Both ligands have good logP values (3.47 & 2.51), falling within the optimal 1-3 range.

**4. H-Bond Donors:** Both have 0 HBD, which is acceptable.

**5. H-Bond Acceptors:** Ligand A has 2 HBA, Ligand B has 3. Both are within the acceptable limit of <=10.

**6. QED:** Both ligands have good QED scores (0.655 & 0.738), indicating good drug-like properties.

**7. DILI:** Ligand A (25.13) has a lower DILI risk than Ligand B (18.96), which is preferable.

**8. BBB:** Ligand A (84.41) has a significantly better BBB penetration percentile than Ligand B (72.24). This is a *critical* factor for a CNS target like DRD2.

**9. Caco-2 Permeability:** Ligand A (-4.33) and Ligand B (-4.56) both have negative values, which is not ideal. Higher values are better.

**10. Aqueous Solubility:** Ligand A (-4.03) and Ligand B (-2.84) both have negative values, indicating poor solubility.

**11. hERG Inhibition:** Ligand A (0.69) has a slightly higher hERG risk than Ligand B (0.26), but both are relatively low.

**12. Microsomal Clearance:** Ligand B (59.67) has a lower microsomal clearance than Ligand A (47.93), indicating better metabolic stability.

**13. In vitro Half-Life:** Ligand B (9.96) has a significantly longer in vitro half-life than Ligand A (-0.88). This is a substantial advantage.

**14. P-gp Efflux:** Ligand A (0.24) has a lower P-gp efflux liability than Ligand B (0.12), which is favorable for CNS penetration.

**15. Binding Affinity:** Both ligands have very similar and excellent binding affinities (-8.4 and -8.2 kcal/mol). The difference is negligible.

**Overall Assessment:**

Ligand A is superior due to its significantly better BBB penetration (84.41 vs 72.24) and lower DILI risk (25.13 vs 18.96). While Ligand B has better metabolic stability (lower Cl_mic and longer t1/2), the BBB is paramount for a CNS target. The slightly higher P-gp efflux of Ligand B is also a negative. The similar affinities make the ADME properties the deciding factor.

Output:
1
2025-04-17 08:13:55,442 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B based on the provided guidelines, prioritizing GPCR-specific properties (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (347.503 and 349.435 Da) fall within the ideal range of 200-500 Da.

**TPSA:** Ligand A (43.86) is excellent, well below the 90 A^2 threshold for CNS targets. Ligand B (115.98) is higher, but still potentially acceptable, although less desirable.

**logP:** Ligand A (1.968) is optimal. Ligand B (0.27) is quite low, potentially hindering membrane permeability and CNS penetration.

**H-Bond Donors/Acceptors:** Ligand A (0 HBD, 3 HBA) is favorable. Ligand B (4 HBD, 4 HBA) is acceptable, but slightly higher.

**QED:** Ligand A (0.784) is good, indicating strong drug-likeness. Ligand B (0.485) is lower, suggesting a less favorable drug-like profile.

**DILI:** Ligand A (5.894) has a very low DILI risk. Ligand B (16.596) is higher, indicating a moderate risk.

**BBB:** This is critical for a DRD2 ligand. Ligand A (84.064) shows excellent BBB penetration. Ligand B (45.522) is significantly lower, raising concerns about CNS exposure.

**Caco-2 Permeability:** Ligand A (-4.694) is poor, while Ligand B (-5.683) is also poor. This is not ideal, but less critical than BBB for a CNS target.

**Aqueous Solubility:** Both ligands have poor aqueous solubility (-1.331 and -1.501, respectively). This could pose formulation challenges.

**hERG Inhibition:** Ligand A (0.662) has a low hERG risk. Ligand B (0.112) also has a very low hERG risk.

**Microsomal Clearance:** Ligand A (24.356) shows moderate clearance. Ligand B (-1.052) suggests very slow clearance and high metabolic stability, which is a positive.

**In vitro Half-Life:** Ligand A (-2.405) suggests a short half-life. Ligand B (-30.512) suggests a very long half-life, which is highly desirable.

**P-gp Efflux:** Ligand A (0.075) has low P-gp efflux, which is good. Ligand B (0.005) has very low P-gp efflux, even better.

**Binding Affinity:** Ligand A (0.0) has a weak binding affinity. Ligand B (-7.0) has a very strong binding affinity. This is a significant advantage for Ligand B.

**Overall Assessment:**

Ligand B has a significantly stronger binding affinity (-7.0 kcal/mol vs 0.0 kcal/mol), a much longer half-life, and better metabolic stability. While its TPSA is higher and logP is lower than Ligand A, the substantial advantage in binding affinity and metabolic properties, coupled with acceptable (though not ideal) TPSA and Pgp efflux, outweigh these drawbacks. The lower BBB score for Ligand B is a concern, but the strong binding affinity may compensate for reduced brain entry. Ligand A has a better BBB score, but its weak binding affinity is a major limitation.

Output:
1
2025-04-17 08:13:55,442 - INFO - Batch 431 complete. Total preferences: 6896
2025-04-17 08:13:55,442 - INFO - Processing batch 432/512...
2025-04-17 08:14:36,163 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (353.4 and 351.4 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (89.35) is excellent, well below the 90 threshold for CNS targets. Ligand B (115.21) is higher, but still potentially acceptable, though less ideal.

**3. logP:** Ligand A (0.84) is a bit low, potentially hindering permeability. Ligand B (-0.338) is even lower, raising concerns about membrane penetration.

**4. H-Bond Donors:** Ligand A (1) is good. Ligand B (2) is also acceptable.

**5. H-Bond Acceptors:** Ligand A (6) is good. Ligand B (7) is also acceptable.

**6. QED:** Ligand A (0.81) is excellent, indicating strong drug-likeness. Ligand B (0.465) is lower, suggesting a less favorable drug-like profile.

**7. DILI:** Ligand A (55.913) has a moderate DILI risk. Ligand B (38.232) has a lower, more favorable DILI risk.

**8. BBB:** Ligand A (84.141) has excellent BBB penetration, highly desirable for a CNS target like DRD2. Ligand B (52.423) has significantly lower BBB penetration, a major drawback.

**9. Caco-2 Permeability:** Ligand A (-4.869) is poor. Ligand B (-5.073) is also poor. Both are problematic.

**10. Aqueous Solubility:** Both ligands have very poor aqueous solubility (-1.511 and -1.134 respectively). This could pose formulation challenges.

**11. hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.096 and 0.038).

**12. Microsomal Clearance:** Ligand A (35.394) has lower clearance, suggesting better metabolic stability than Ligand B (43.046).

**13. In vitro Half-Life:** Ligand A (5.138 hours) has a better half-life than Ligand B (-11.318 hours - negative value is unusual and suggests very rapid clearance).

**14. P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.103 and 0.023).

**15. Binding Affinity:** Ligand A (-9.0 kcal/mol) has significantly stronger binding affinity than Ligand B (-7.9 kcal/mol). This is a substantial advantage.

**Overall Assessment:**

Despite the poor Caco-2 permeability and solubility of both, Ligand A is the superior candidate. Its significantly stronger binding affinity (-9.0 vs -7.9 kcal/mol) and excellent BBB penetration (84.141 vs 52.423) are crucial for a CNS-targeting GPCR like DRD2. The better QED, lower clearance and longer half-life also contribute to its favorability. While Ligand B has a slightly lower DILI risk, the affinity and BBB differences outweigh this benefit.

Output:
1
2025-04-17 08:14:36,164 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (342.414 and 356.457 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (42.43) is significantly better than Ligand B (49.41). Both are below the 90 A^2 threshold for CNS targets, but A is closer to optimal.

**logP:** Both ligands have good logP values (3.703 and 3.031), falling within the 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A (0 HBD, 3 HBA) is preferable to Ligand B (1 HBD, 2 HBA) as lower HBD/HBA generally improves BBB penetration. Both are within acceptable limits.

**QED:** Both ligands have similar QED values (0.851 and 0.744), indicating good drug-likeness.

**DILI:** Both ligands have low DILI risk (30.865 and 29.042), which is excellent.

**BBB:** Ligand B (96.084) has a substantially higher BBB percentile than Ligand A (85.576). This is a crucial advantage for a CNS target like DRD2.

**Caco-2 Permeability:** Both have negative Caco-2 values (-4.609 and -4.505), which is unusual and suggests poor permeability. However, these values are on a scale where negative values are possible, and the absolute values are similar.

**Aqueous Solubility:** Both ligands have very poor aqueous solubility (-3.274 and -3.281). This is a significant drawback.

**hERG Inhibition:** Both ligands have low hERG inhibition liability (0.772 and 0.729).

**Microsomal Clearance:** Ligand B (18.571) has a significantly lower microsomal clearance than Ligand A (53.109), indicating better metabolic stability.

**In vitro Half-Life:** Ligand B (-13.016) has a longer in vitro half-life than Ligand A (-8.984), which is desirable.

**P-gp Efflux:** Ligand B (0.314) has a lower P-gp efflux liability than Ligand A (0.462), which is beneficial for CNS penetration.

**Binding Affinity:** Ligand A (-9.7 kcal/mol) has a significantly stronger binding affinity than Ligand B (-0.0 kcal/mol). This is a *major* advantage, potentially outweighing some of the ADME drawbacks.

**Overall Assessment:**

While Ligand B has superior BBB penetration, metabolic stability, half-life, and P-gp efflux, the *massive* difference in binding affinity (9.7 kcal/mol vs 0.0 kcal/mol) makes Ligand A the much more promising candidate. A strong binding affinity is paramount for GPCR ligands, and this difference is large enough to compensate for the poorer BBB and metabolic properties. The solubility is a concern for both, but formulation strategies can be explored to address this.

Output:
1
2025-04-17 08:14:36,164 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (345.487 and 378.485 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (62.3) is slightly above the optimal <90 for CNS targets, but still reasonable. Ligand B (49.85) is excellent, well below 90.

**3. logP:** Both ligands (2.956 and 2.107) are within the optimal 1-3 range.

**4. H-Bond Donors:** Ligand A has 1 HBD, which is good. Ligand B has 0, also good.

**5. H-Bond Acceptors:** Ligand A has 3 HBA, and Ligand B has 4. Both are within the acceptable limit of <=10.

**6. QED:** Ligand A (0.912) has a superior QED score compared to Ligand B (0.71), indicating better overall drug-likeness.

**7. DILI:** Both ligands have low DILI risk (36.332 and 31.485), both well below the 40 threshold.

**8. BBB:** This is a critical parameter for a CNS target like DRD2. Ligand B (85.731) has a significantly higher BBB percentile than Ligand A (61.38). This is a major advantage for Ligand B.

**9. Caco-2 Permeability:** Both have negative values, which is unusual and suggests a potential issue with the data or calculation method. We'll proceed cautiously.

**10. Aqueous Solubility:** Both have negative values, again suggesting a potential issue with the data or calculation method.

**11. hERG Inhibition:** Both ligands show low hERG inhibition liability (0.513 and 0.643), which is good.

**12. Microsomal Clearance:** Ligand A (30.307) has a lower microsomal clearance than Ligand B (39.309), suggesting better metabolic stability.

**13. In vitro Half-Life:** Ligand A (5.672) has a shorter half-life than Ligand B (-6.872). The negative value for Ligand B is suspect and likely an error.

**14. P-gp Efflux:** Both ligands have low P-gp efflux liability (0.163 and 0.191), which is favorable for CNS penetration.

**15. Binding Affinity:** Ligand A (-7.8 kcal/mol) has a slightly better binding affinity than Ligand B (-6.9 kcal/mol). This 0.9 kcal/mol difference is significant, but not overwhelming.

**Overall Assessment:**

Ligand B excels in BBB penetration (85.731 vs 61.38), which is paramount for a CNS target. While Ligand A has a slightly better binding affinity and metabolic stability, the superior BBB score of Ligand B outweighs these advantages. The negative values for Caco-2 and Solubility are concerning for both, but the difference in BBB is substantial.

Output:
1
2025-04-17 08:14:36,164 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (342.403 and 348.382 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (87.12) is better than Ligand B (93.96). Both are below the 90 A^2 threshold for CNS targets, but A is closer to the optimal range.

**3. logP:** Both ligands have good logP values (1.36 and 1.489), falling within the 1-3 range.

**4. H-Bond Donors:** Ligand A (1) is preferable to Ligand B (2). Lower HBD generally improves permeability.

**5. H-Bond Acceptors:** Ligand A (5) is preferable to Ligand B (7). Lower HBA generally improves permeability.

**6. QED:** Both ligands have similar QED values (0.859 and 0.821), indicating good drug-likeness.

**7. DILI:** Ligand A (59.907) has a significantly lower DILI risk than Ligand B (76.425). This is a substantial advantage.

**8. BBB:** Ligand B (60.45) has a slightly better BBB penetration than Ligand A (51.415), but both are below the desirable >70 percentile for CNS targets.

**9. Caco-2 Permeability:** Ligand A (-5.303) has better Caco-2 permeability than Ligand B (-5.041).

**10. Aqueous Solubility:** Ligand A (-1.986) has better aqueous solubility than Ligand B (-2.587).

**11. hERG Inhibition:** Ligand A (0.507) has a lower hERG inhibition liability than Ligand B (0.063). This is a significant advantage.

**12. Microsomal Clearance:** Ligand A (18.732) has a higher microsomal clearance than Ligand B (14.79), meaning it's less metabolically stable. Ligand B is preferable here.

**13. In vitro Half-Life:** Ligand A (-24.777) has a much shorter in vitro half-life than Ligand B (-5.271). Ligand B is preferable.

**14. P-gp Efflux:** Ligand A (0.04) has lower P-gp efflux liability than Ligand B (0.088). This is a slight advantage for A.

**15. Binding Affinity:** Both ligands have the same binding affinity (-7.9 kcal/mol), which is excellent.

**Overall Assessment:**

Ligand A has a clear advantage in several key ADME properties: lower DILI risk, lower hERG inhibition, better Caco-2 permeability, and better aqueous solubility. While Ligand B has slightly better BBB penetration and metabolic stability, the lower toxicity and permeability advantages of Ligand A are more critical for a CNS-targeting GPCR ligand. The equal binding affinity removes that as a differentiating factor.

Output:
0
2025-04-17 08:14:36,164 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (365.382 and 376.791 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (82.56) is excellent, well below the 90 A^2 threshold for CNS targets. Ligand B (95.42) is still reasonable, but closer to the 90 A^2 limit.

**logP:** Both ligands have good logP values (1.858 and 1.028), falling within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A (0 HBD, 6 HBA) is slightly better than Ligand B (2 HBD, 5 HBA) in terms of balancing solubility and permeability, though both are acceptable.

**QED:** Both ligands have similar QED scores (0.769 and 0.723), indicating good drug-like properties.

**DILI:** Ligand A (91.043) has a considerably higher DILI risk than Ligand B (40.054). This is a significant drawback for Ligand A.

**BBB:** Ligand A (82.009) has a much better BBB penetration score than Ligand B (65.801). This is a critical advantage for a CNS target like DRD2.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.41 and -4.893), which is unusual and suggests poor permeability. However, these values are on a log scale and can be interpreted as very low permeability.

**Aqueous Solubility:** Both ligands have negative solubility values (-3.592 and -2.664), indicating very poor aqueous solubility. This is a concern for both.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.38 and 0.217).

**Microsomal Clearance:** Ligand A (42.806) has a higher microsomal clearance than Ligand B (1.47), indicating lower metabolic stability.

**In vitro Half-Life:** Ligand B (-12.733) has a significantly longer in vitro half-life than Ligand A (-0.731). This is a major advantage for Ligand B.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.154 and 0.012), which is favorable for CNS penetration.

**Binding Affinity:** Ligand A (-9.4 kcal/mol) has a significantly stronger binding affinity than Ligand B (-7.4 kcal/mol). This is a substantial advantage, potentially outweighing some ADME concerns.

**Overall Assessment:**

Ligand A has a significantly better binding affinity and BBB penetration, which are crucial for a CNS GPCR target. However, it suffers from higher DILI risk and lower metabolic stability. Ligand B has a better safety profile (lower DILI) and longer half-life, but weaker binding affinity and lower BBB penetration.

Given the importance of potency and CNS penetration for DRD2, and the significant difference in binding affinity (-9.4 vs -7.4 kcal/mol), I believe Ligand A is the more promising candidate, *despite* its higher DILI risk and lower metabolic stability. The strong binding affinity could allow for a lower dose, potentially mitigating the DILI risk. Further optimization could focus on improving the metabolic stability and reducing the DILI risk of Ligand A.

Output:
0
2025-04-17 08:14:36,164 - INFO - Reasoning:

Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (400.28 Da) is slightly higher than Ligand B (351.422 Da), but both are acceptable.

**2. TPSA:** Ligand A (63.91) is better than Ligand B (93.45). For CNS targets, we want TPSA <= 90. Ligand A is within this range, while Ligand B is slightly above. This favors Ligand A.

**3. logP:** Both ligands have acceptable logP values (Ligand A: 3.146, Ligand B: 1.848), falling within the optimal 1-3 range.

**4. H-Bond Donors:** Ligand A (0) is preferable to Ligand B (3). Fewer H-bond donors generally improve permeability.

**5. H-Bond Acceptors:** Ligand A (5) is preferable to Ligand B (4). Both are within the acceptable range of <=10.

**6. QED:** Both ligands have similar QED values (Ligand A: 0.663, Ligand B: 0.623), indicating good drug-like properties.

**7. DILI:** Ligand A (76.386) has a higher DILI risk than Ligand B (47.15). This favors Ligand B.

**8. BBB:** Ligand A (92.323) has a significantly better BBB penetration score than Ligand B (81.815). This is a *critical* factor for a CNS target like DRD2, strongly favoring Ligand A.

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 values, which is unusual and suggests poor permeability. However, the scale isn't defined, so it's hard to interpret.

**10. Aqueous Solubility:** Both ligands have negative solubility values, which is also unusual.

**11. hERG Inhibition:** Both ligands have low hERG inhibition risk (Ligand A: 0.69, Ligand B: 0.469).

**12. Microsomal Clearance:** Both ligands have similar microsomal clearance values (Ligand A: 27.945, Ligand B: 26.791).

**13. In vitro Half-Life:** Ligand A (20.969) has a significantly longer half-life than Ligand B (5.262), which is desirable.

**14. P-gp Efflux:** Ligand A (0.663) has slightly higher P-gp efflux than Ligand B (0.07). Lower is better, so this favors Ligand B.

**15. Binding Affinity:** Ligand A (-9.5 kcal/mol) has a stronger binding affinity than Ligand B (-8.3 kcal/mol). This difference of 1.2 kcal/mol is substantial and can outweigh some ADME drawbacks.

**Overall Assessment:**

Ligand A is the stronger candidate. While it has a slightly higher DILI risk and P-gp efflux, its superior BBB penetration, TPSA, half-life, and *significantly* better binding affinity outweigh these concerns. The strong affinity is particularly important for a GPCR target, and the good BBB penetration is crucial for CNS activity. The negative solubility and Caco-2 values are concerning, but could be addressed through formulation strategies.



Output:
1
2025-04-17 08:14:36,164 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (351.403 and 350.423 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (91.34) is significantly better than Ligand B (128.69). For CNS targets, we want TPSA <= 90, so Ligand A is closer to this threshold and more favorable.

**3. logP:** Both ligands have acceptable logP values (0.767 and 0.689), falling within the optimal range of 1-3.

**4. H-Bond Donors:** Ligand A (2) is preferable to Ligand B (4). Fewer HBDs generally improve permeability.

**5. H-Bond Acceptors:** Ligand A (5) is preferable to Ligand B (6). Fewer HBAs generally improve permeability.

**6. QED:** Ligand A (0.818) has a much better QED score than Ligand B (0.469), indicating a more drug-like profile.

**7. DILI:** Ligand A (66.731) has a higher DILI risk than Ligand B (54.556), but both are within an acceptable range (<60 is good).

**8. BBB:** This is a critical parameter for CNS targets. Ligand A (54.866) has a considerably higher BBB percentile than Ligand B (9.616). This is a major advantage for Ligand A.

**9. Caco-2 Permeability:** Ligand A (-4.632) has a slightly better Caco-2 permeability than Ligand B (-5.645), though both are negative values which is unusual and suggests poor permeability.

**10. Aqueous Solubility:** Ligand A (-0.705) is slightly better than Ligand B (-2.178), but both are negative, suggesting poor solubility.

**11. hERG Inhibition:** Both ligands have low hERG inhibition risk (0.214 and 0.337).

**12. Microsomal Clearance:** Ligand A (-19.076) has a lower (better) microsomal clearance than Ligand B (-10.681), indicating greater metabolic stability.

**13. In vitro Half-Life:** Ligand A (-17.49) has a longer in vitro half-life than Ligand B (-7.274).

**14. P-gp Efflux:** Ligand A (0.018) has a much lower P-gp efflux liability than Ligand B (0.131), which is crucial for CNS penetration.

**15. Binding Affinity:** Both ligands have excellent binding affinities (-7.5 and -8.0 kcal/mol). Ligand B is slightly better, but the difference is likely not enough to overcome the significant ADME advantages of Ligand A.

**Overall Assessment:**

Ligand A is significantly more promising. It has a better TPSA, QED, BBB, P-gp efflux, microsomal clearance, and in vitro half-life. While Ligand B has slightly better binding affinity and a lower DILI risk, the superior ADME properties of Ligand A, particularly its much higher BBB penetration and lower P-gp efflux, make it the more likely candidate to reach the brain and exert a therapeutic effect.

Output:
1
2025-04-17 08:14:36,164 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (361.785 and 371.825 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (113.68) is better than Ligand B (130.41). For CNS targets, TPSA should be <=90, so Ligand A is closer to this threshold.

**logP:** Ligand A (2.301) is within the optimal 1-3 range. Ligand B (0.907) is slightly below 1, which *could* indicate permeability issues.

**H-Bond Donors/Acceptors:** Ligand A has 4 HBD and 4 HBA, while Ligand B has 3 HBD and 5 HBA. Both are within acceptable limits (<=5 HBD and <=10 HBA).

**QED:** Both ligands have similar QED values (0.669 and 0.613), indicating good drug-likeness.

**DILI:** Ligand A (79.062) has a higher DILI risk than Ligand B (52.152). This is a negative for Ligand A.

**BBB:** Ligand B (71.268) has a significantly better BBB penetration percentile than Ligand A (63.048). This is a critical advantage for a CNS target like DRD2.

**Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and difficult to interpret without further context. However, the magnitude of negativity is similar.

**Aqueous Solubility:** Both have negative solubility values, again unusual. The values are similar in magnitude.

**hERG:** Both ligands have low hERG inhibition liability (0.352 and 0.523), which is good.

**Microsomal Clearance:** Ligand A (-22.983) has a lower (better) microsomal clearance than Ligand B (-9.476), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (53.463) has a longer in vitro half-life than Ligand B (-20.936), which is favorable.

**P-gp Efflux:** Ligand A (0.065) has significantly lower P-gp efflux liability than Ligand B (0.045). Lower P-gp efflux is crucial for CNS penetration.

**Binding Affinity:** Ligand A (-9.7 kcal/mol) has a stronger binding affinity than Ligand B (-7.6 kcal/mol). This is a substantial difference (over 2 kcal/mol), and is a major positive for Ligand A.

**Overall Assessment:**

While Ligand A has a higher DILI risk, its significantly stronger binding affinity (-9.7 vs -7.6 kcal/mol), lower P-gp efflux, better metabolic stability (lower Cl_mic), and longer half-life outweigh the DILI concern. The better TPSA of Ligand A is also beneficial. Ligand B's main advantage is its better BBB penetration, but the affinity difference is substantial. Given the strong binding affinity of Ligand A, it is more likely to be a viable drug candidate, even with the slightly elevated DILI risk, which can be addressed in further optimization.

Output:
1
2025-04-17 08:14:36,164 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (361.511 and 345.399 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (71.09) is excellent, well below the 90 A^2 threshold for CNS targets. Ligand B (92.55) is still reasonable, but closer to the 140 A^2 limit for oral absorption and less ideal for CNS penetration.

**logP:** Ligand A (3.055) is within the optimal 1-3 range. Ligand B (0.974) is a bit low, potentially hindering permeation, although not drastically.

**H-Bond Donors/Acceptors:** Ligand A (2 HBD, 4 HBA) and Ligand B (1 HBD, 4 HBA) both have acceptable numbers of H-bond donors and acceptors.

**QED:** Ligand A (0.818) has a much better QED score than Ligand B (0.356), indicating a more drug-like profile.

**DILI:** Ligand A (41.218) has a slightly higher DILI risk than Ligand B (17.449), but both are below the concerning 60 percentile.

**BBB:** Both ligands have similar BBB penetration (Ligand A: 55.293, Ligand B: 56.65). While not exceptional (>70), they are acceptable considering other factors.

**Caco-2 Permeability:** Ligand A (-4.946) has poor Caco-2 permeability, while Ligand B (-5.054) is also poor. This is a concern for oral bioavailability.

**Aqueous Solubility:** Ligand A (-3.86) and Ligand B (-2.413) both have poor aqueous solubility.

**hERG Inhibition:** Ligand A (0.341) has a lower hERG risk than Ligand B (0.069), which is preferable.

**Microsomal Clearance:** Ligand B (-18.347) has significantly lower microsomal clearance than Ligand A (47.088), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand B (-13.171) has a longer in vitro half-life than Ligand A (25.764), which is desirable.

**P-gp Efflux:** Ligand A (0.162) has lower P-gp efflux than Ligand B (0.026), which is better for CNS exposure.

**Binding Affinity:** Both ligands have very similar and strong binding affinities (-8.7 kcal/mol and -8.4 kcal/mol). The difference is less than 1.5 kcal/mol, so this won't be the deciding factor.

**Overall Assessment:**

Ligand A has a superior QED score, better TPSA, and lower P-gp efflux. However, Ligand B has significantly better metabolic stability (lower Cl_mic, longer t1/2) and a lower DILI risk. While both have poor Caco-2 permeability and solubility, the metabolic stability and safety profile of Ligand B are more compelling for a CNS target. Given the importance of metabolic stability for CNS drugs, and the relatively small difference in binding affinity, Ligand B is the more promising candidate.

Output:
1
2025-04-17 08:14:36,165 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 drug candidates, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (366.889 and 348.378 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (78.43) is significantly better than Ligand B (98.22). For CNS targets, we want TPSA <= 90, so Ligand A is preferable.

**3. logP:** Ligand A (3.361) is within the optimal 1-3 range. Ligand B (0.9) is a bit low, potentially hindering permeation.

**4. H-Bond Donors:** Both ligands have acceptable HBD counts (3 and 2, respectively), well below the threshold of 5.

**5. H-Bond Acceptors:** Both ligands have acceptable HBA counts (3 and 4, respectively), well below the threshold of 10.

**6. QED:** Both ligands have good QED values (0.722 and 0.845), indicating good drug-like properties.

**7. DILI:** Ligand A (35.828) has a much lower DILI risk than Ligand B (62.893). This is a significant advantage for Ligand A.

**8. BBB:** Ligand A (67.623) has a better BBB percentile than Ligand B (53.083). While both are below the desirable >70 for CNS targets, A is closer.

**9. Caco-2:** Both ligands have negative Caco-2 values (-4.762 and -4.905), which is unusual and difficult to interpret without more context. It suggests very poor permeability.

**10. Solubility:** Both ligands have negative solubility values (-4.052 and -3.126), also unusual and suggesting poor aqueous solubility.

**11. hERG:** Both ligands have low hERG inhibition liability (0.35 and 0.516), which is good.

**12. Cl_mic:** Ligand B (-28.704) has a much lower (better) microsomal clearance than Ligand A (32.911), indicating greater metabolic stability.

**13. t1/2:** Ligand B (-1.504) has a negative in vitro half-life, which is concerning. Ligand A (44.435) has a much more reasonable half-life.

**14. Pgp:** Both ligands have very low Pgp efflux liability (0.092 and 0.031), which is favorable for CNS penetration.

**15. Binding Affinity:** Ligand A (-9.0) has a significantly stronger binding affinity than Ligand B (-7.8). A difference of 1.2 kcal/mol is substantial and can outweigh some ADME drawbacks.

**Overall Assessment:**

Ligand A is the stronger candidate. While Ligand B has better metabolic stability (lower Cl_mic) and slightly better Pgp efflux, Ligand A excels in crucial areas for a CNS-targeting GPCR: significantly better TPSA, better BBB penetration, substantially lower DILI risk, and *much* stronger binding affinity. The negative Caco-2 and solubility values are concerning for both, but the superior affinity and CNS-relevant properties of Ligand A make it the more promising starting point for optimization.

Output:
1
2025-04-17 08:14:36,165 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (344.455 Da) is slightly lower, which is generally favorable for permeability.

**TPSA:** Ligand A (60.45) is significantly better than Ligand B (74.41). For CNS targets, we want TPSA <= 90, and ideally lower. Ligand A is much closer to the optimal range.

**logP:** Both ligands have acceptable logP values (A: 3.972, B: 2.846), falling within the 1-3 range. Ligand A is slightly higher, which *could* present a minor solubility issue, but is still acceptable.

**H-Bond Donors/Acceptors:** Ligand A (HBD=1, HBA=4) is better than Ligand B (HBD=2, HBA=7). Lower counts are generally preferred for better permeability.

**QED:** Both ligands have similar and acceptable QED values (A: 0.61, B: 0.667), indicating good drug-like properties.

**DILI:** Ligand A (54.401) has a higher DILI risk than Ligand B (19.93). This is a significant drawback for Ligand A.

**BBB:** Ligand A (82.9) has a substantially higher BBB penetration percentile than Ligand B (32.92). This is a *critical* advantage for a CNS target like DRD2.

**Caco-2 Permeability:** Ligand A (-4.912) has a worse Caco-2 permeability than Ligand B (-5.406), but both are negative, so the difference isn't hugely significant.

**Aqueous Solubility:** Ligand A (-3.319) has slightly worse solubility than Ligand B (-2.858), but both are poor.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (A: 0.898, B: 0.632).

**Microsomal Clearance:** Ligand A (50.729) has higher microsomal clearance than Ligand B (36.242), meaning faster metabolism and potentially lower exposure.

**In vitro Half-Life:** Ligand B (23.716) has a longer in vitro half-life than Ligand A (62.48), which is desirable.

**P-gp Efflux:** Ligand A (0.389) has lower P-gp efflux than Ligand B (0.233), which is favorable for CNS penetration.

**Binding Affinity:** Ligand A (-8.1 kcal/mol) has a significantly stronger binding affinity than Ligand B (-6.9 kcal/mol). This is a substantial advantage, potentially outweighing some of the ADME drawbacks. The difference is >1.5 kcal/mol.

**Overall Assessment:**

Ligand A has a much better binding affinity and BBB penetration, which are crucial for a CNS GPCR target. While it has a higher DILI risk and faster clearance, the strong affinity and good BBB are likely to be more important. Ligand B has better DILI and clearance, but its significantly weaker binding affinity and poor BBB penetration make it a less attractive candidate. The strong binding of A is likely to be a major driver of efficacy, and the better BBB will improve CNS exposure.

Output:
1
2025-04-17 08:14:36,165 - INFO - Reasoning:

Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (345.447 and 370.358 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (71.64) is significantly better than Ligand B (121.72). For CNS targets, we want TPSA <= 90, and A is comfortably within this range, while B is above. This is a significant advantage for A.

**3. logP:** Both ligands have acceptable logP values (1.305 and 1.574), falling within the optimal 1-3 range.

**4. H-Bond Donors:** Both have 1 HBD, which is good.

**5. H-Bond Acceptors:** Ligand A has 6 HBAs, and Ligand B has 7. Both are acceptable (<=10).

**6. QED:** Both ligands have good QED scores (0.768 and 0.793), indicating drug-like properties.

**7. DILI:** Ligand A (25.553) has a much lower DILI risk than Ligand B (94.804). This is a major advantage for A.

**8. BBB:** Ligand A (79.721) has a good BBB percentile, while Ligand B (83.87) is slightly better. Both are above the desirable 70% threshold for CNS targets.

**9. Caco-2:** Ligand A (-5.391) and Ligand B (-4.589) both have negative values, which is unusual and suggests poor permeability. However, the scale isn't defined, so it's hard to interpret.

**10. Solubility:** Ligand A (-0.931) has slightly better solubility than Ligand B (-3.301).

**11. hERG:** Ligand A (0.759) has a lower hERG risk than Ligand B (0.133), which is preferable.

**12. Cl_mic:** Ligand A (-4.752) has a lower (better) microsomal clearance than Ligand B (-8.459), indicating better metabolic stability.

**13. t1/2:** Both ligands have similar in vitro half-lives (22.424 and 21.887 hours).

**14. Pgp:** Ligand A (0.055) has significantly lower P-gp efflux liability than Ligand B (0.104), which is crucial for CNS penetration.

**15. Binding Affinity:** Ligand B (-9.3 kcal/mol) has a slightly better binding affinity than Ligand A (-8.2 kcal/mol). This is a 1.1 kcal/mol difference, which is significant but needs to be weighed against other factors.

**Overall Assessment:**

While Ligand B has a slightly better binding affinity, Ligand A is superior overall. It has a much lower DILI risk, better TPSA, better Pgp efflux liability, better metabolic stability, and a lower hERG risk. The TPSA and DILI differences are particularly important. For a CNS target like DRD2, good BBB penetration (both are acceptable), low Pgp efflux, and a favorable safety profile (low DILI) are critical. Ligand A excels in these areas, making it the more promising drug candidate despite the slightly weaker binding affinity.

Output:
0
2025-04-17 08:14:36,165 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (378.877 Da) and Ligand B (351.447 Da) are both acceptable.

**TPSA:** Ligand A (60.44) is excellent, falling well below the 90 A^2 threshold for CNS targets. Ligand B (80.23) is still reasonable, but less optimal.

**logP:** Ligand A (3.989) is at the higher end of the optimal range (1-3), but still acceptable. Ligand B (1.464) is on the lower end, which *could* indicate permeability issues, but isn't a dealbreaker.

**H-Bond Donors/Acceptors:** Ligand A (0 HBD, 4 HBA) is favorable. Ligand B (1 HBD, 5 HBA) is also acceptable, though slightly higher.

**QED:** Both ligands have good QED scores (A: 0.755, B: 0.835), indicating good drug-like properties.

**DILI:** Ligand A (84.917) has a higher DILI risk than Ligand B (41.605). This is a significant concern for Ligand A.

**BBB:** Both ligands have good BBB penetration (A: 61.962, B: 67.468), but ideally, we'd want >70% for a CNS target. Ligand B is slightly better here.

**Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual. Assuming these are logP-like scales, lower values indicate poorer permeability. They are similarly poor.

**Aqueous Solubility:** Both ligands have very poor aqueous solubility (-5.065 and -1.95). This could pose formulation challenges.

**hERG Inhibition:** Ligand A (0.351) has a slightly higher hERG risk than Ligand B (0.119), but both are relatively low.

**Microsomal Clearance:** Ligand A (49.217) has higher clearance than Ligand B (26.271), suggesting lower metabolic stability.

**In vitro Half-Life:** Ligand B (17.653 hours) has a longer half-life than Ligand A (14.111 hours).

**P-gp Efflux:** Ligand A (0.353) has a higher P-gp efflux liability than Ligand B (0.066), which is undesirable for CNS penetration.

**Binding Affinity:** Ligand A (-9.4 kcal/mol) has *significantly* stronger binding affinity than Ligand B (-0.0 kcal/mol). This is a massive difference.

**Overall Assessment:**

Despite the strong binding affinity of Ligand A, its high DILI risk, higher P-gp efflux, and higher microsomal clearance are major drawbacks. Ligand B, while having a much weaker binding affinity, presents a significantly better ADME-Tox profile, with lower DILI, P-gp efflux, and clearance, and a longer half-life. The affinity difference is so large that it's worth considering Ligand A despite the ADME issues, *however*, the DILI risk is a substantial concern. For a CNS target, a good BBB is important, and both are reasonably good. Given the significant difference in binding affinity, and the fact that the ADME properties of Ligand B are not terrible, I'd still lean towards Ligand A as the better starting point, *with the caveat that the DILI risk needs to be addressed through structural modifications*.

Output:
1
2025-04-17 08:14:36,165 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (364.475 and 389.327 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (87.24) is better than Ligand B (67.23), both are below the 90 A^2 threshold for CNS targets.

**logP:** Ligand A (1.04) is within the optimal range (1-3), while Ligand B (2.759) is also acceptable, leaning towards the higher end.

**H-Bond Donors/Acceptors:** Both ligands have 1 HBD, which is good. Ligand A has 7 HBA, while Ligand B has 4. Both are within acceptable limits (<=10).

**QED:** Both ligands have similar QED values (0.753 and 0.73), indicating good drug-likeness.

**DILI:** Ligand A (51.493) has a slightly higher DILI risk than Ligand B (19.736), but both are below the concerning threshold of 60.

**BBB:** Ligand B (59.791) has a significantly better BBB penetration percentile than Ligand A (47.111). This is a crucial advantage for a CNS target like DRD2.

**Caco-2 Permeability:** Ligand A (-5.274) has worse Caco-2 permeability than Ligand B (-4.833), indicating potentially lower intestinal absorption.

**Aqueous Solubility:** Ligand A (-0.98) has slightly better aqueous solubility than Ligand B (-2.601).

**hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.219 and 0.342).

**Microsomal Clearance:** Ligand A (1.86 mL/min/kg) has significantly lower microsomal clearance than Ligand B (37.353 mL/min/kg), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (10.112 hours) has a longer in vitro half-life than Ligand B (-7.226 hours).

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.043 and 0.039).

**Binding Affinity:** Ligand B (-7.4 kcal/mol) has a slightly better binding affinity than Ligand A (-7.0 kcal/mol). While the difference is small, it's within the range where it could outweigh minor ADME drawbacks.

**Overall Assessment:**

Ligand B is the more promising candidate. While Ligand A has better metabolic stability and solubility, Ligand B's significantly improved BBB penetration is paramount for a CNS target like DRD2. The slightly better binding affinity of Ligand B further strengthens its position. The difference in Caco-2 permeability is not a major concern given the focus on CNS penetration.

Output:
1
2025-04-17 08:14:36,166 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (346.431 and 349.391 Da) fall comfortably within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (68.62) is significantly better than Ligand B (110.37). For CNS targets, we want TPSA <= 90, and Ligand A is closer to this threshold. Ligand B is above this preferred range.

**3. logP:** Both ligands have good logP values (2.396 and 1.239), falling within the optimal 1-3 range. Ligand B is slightly lower, which *could* indicate slightly better solubility but potentially reduced permeability.

**4. H-Bond Donors:** Both have 1 HBD, which is acceptable.

**5. H-Bond Acceptors:** Ligand A has 5 HBA, and Ligand B has 6. Both are within the acceptable limit of <= 10.

**6. QED:** Ligand A (0.872) has a substantially better QED score than Ligand B (0.613), indicating a more drug-like profile.

**7. DILI:** Both have acceptable DILI risk (52.966 and 47.421), below the 60 threshold.

**8. BBB:** Ligand B (87.476) has a significantly better BBB percentile than Ligand A (73.905). This is a crucial factor for a CNS target like DRD2.

**9. Caco-2:** Both have negative Caco-2 values, which is unusual and hard to interpret without knowing the scale. However, we can assume they represent low permeability.

**10. Solubility:** Both have negative solubility values, again, unusual and hard to interpret.

**11. hERG:** Both have low hERG inhibition risk (0.448 and 0.352).

**12. Cl_mic:** Ligand A has a higher microsomal clearance (69.68) than Ligand B (9.966), indicating faster metabolism and potentially lower *in vivo* exposure. This is a significant drawback for Ligand A.

**13. t1/2:** Ligand B has a much longer in vitro half-life (-24.469 hours) than Ligand A (-6.473 hours). This is a major advantage for Ligand B.

**14. Pgp:** Both have very low Pgp efflux liability (0.04 and 0.091).

**15. Binding Affinity:** Ligand B (-7.8 kcal/mol) has a slightly better binding affinity than Ligand A (-7.5 kcal/mol), but the difference is relatively small (0.3 kcal/mol).

**Overall Assessment:**

While Ligand A has a better TPSA and QED, Ligand B excels in the critical areas for a CNS GPCR target: BBB penetration, metabolic stability (lower Cl_mic and longer t1/2), and slightly better binding affinity. The lower TPSA of Ligand A is beneficial, but the significantly better BBB and pharmacokinetic properties of Ligand B outweigh this advantage. The negative values for Caco-2 and solubility are concerning for both, but the other factors strongly favor Ligand B.

Output:
1
2025-04-17 08:14:36,166 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (346.431 and 353.419 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (83.56) is excellent, well below the 90 A^2 threshold for CNS targets. Ligand B (115.9) is higher, but still potentially acceptable, though less ideal.

**3. logP:** Ligand A (1.692) is within the optimal range (1-3). Ligand B (0.248) is quite low, potentially hindering membrane permeability and CNS penetration.

**4. H-Bond Donors:** Ligand A (2) and Ligand B (3) are both acceptable, below the 5 threshold.

**5. H-Bond Acceptors:** Ligand A (4) and Ligand B (6) are both acceptable, below the 10 threshold.

**6. QED:** Ligand A (0.872) is very good, indicating high drug-likeness. Ligand B (0.675) is still acceptable, but less favorable.

**7. DILI:** Ligand A (46.297) and Ligand B (39.201) both have low DILI risk, below the 40 threshold.

**8. BBB:** This is critical for a CNS target. Ligand A (56.456) shows moderate BBB penetration, while Ligand B (25.785) is significantly lower, a major concern.

**9. Caco-2 Permeability:** Ligand A (-4.99) and Ligand B (-5.107) both have negative values, indicating poor permeability.

**10. Aqueous Solubility:** Ligand A (-1.482) and Ligand B (-0.798) both have negative values, indicating poor solubility.

**11. hERG Inhibition:** Ligand A (0.095) has a very low risk of hERG inhibition. Ligand B (0.254) is slightly higher, but still relatively low.

**12. Microsomal Clearance:** Ligand A (-13.028) has very low clearance, indicating high metabolic stability. Ligand B (13.315) has a positive value, indicating faster clearance and lower metabolic stability.

**13. In vitro Half-Life:** Ligand A (3.238) has a short half-life, while Ligand B (-20.617) has a very long half-life.

**14. P-gp Efflux:** Ligand A (0.01) has very low P-gp efflux, which is favorable for CNS penetration. Ligand B (0.089) has slightly higher P-gp efflux, but still relatively low.

**15. Binding Affinity:** Ligand B (-8.3) has a significantly stronger binding affinity than Ligand A (0.0). This is a substantial advantage.

**Overall Assessment:**

While Ligand B boasts a much stronger binding affinity, its significantly lower logP and BBB penetration are major drawbacks for a CNS-targeting drug. The poor logP will hinder its ability to cross cell membranes, including the blood-brain barrier. Ligand A, despite its weaker binding, has a much better logP, TPSA, and a more reasonable BBB score, along with superior metabolic stability. The difference in binding affinity is substantial, but the ADME properties of Ligand B are too unfavorable for CNS drug development. Ligand A, while not perfect, presents a more balanced profile and a higher likelihood of reaching the target in the brain.

Output:
0
2025-04-17 08:14:36,166 - INFO - Batch 432 complete. Total preferences: 6912
2025-04-17 08:14:36,166 - INFO - Processing batch 433/512...
2025-04-17 08:15:19,075 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 drug candidates, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (363.487 and 345.447 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (98.17) is slightly above the preferred <90 for CNS targets, while Ligand B (83.4) is comfortably below. This gives a slight edge to Ligand B.

**logP:** Both ligands have good logP values (3.184 and 2.072), falling within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A (HBD=1, HBA=4) and Ligand B (HBD=2, HBA=7) both have reasonable numbers of H-bond donors and acceptors, staying within the guidelines.

**QED:** Both ligands have acceptable QED values (0.457 and 0.758), with Ligand B being significantly better.

**DILI:** Ligand A (43.079) has a lower DILI risk than Ligand B (59.713), which is favorable.

**BBB:** Ligand B (71.772) has a significantly better BBB penetration percentile than Ligand A (41.218). This is a *critical* advantage for a CNS target like DRD2.

**Caco-2 Permeability:** Both are negative, indicating poor permeability.

**Aqueous Solubility:** Both are negative, indicating poor solubility.

**hERG:** Both ligands have low hERG inhibition liability (0.226 and 0.895), which is good.

**Microsomal Clearance:** Ligand A (32.921) has a lower microsomal clearance than Ligand B (59.138), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand B (72.198) has a significantly longer in vitro half-life than Ligand A (14.855).

**P-gp Efflux:** Both ligands exhibit low P-gp efflux liability (0.133 and 0.118).

**Binding Affinity:** Ligand B (-7.7 kcal/mol) has a slightly better binding affinity than Ligand A (-7.1 kcal/mol). While the difference is not huge (0.6 kcal/mol), it is still a positive factor.

**Overall Assessment:**

Ligand B is the stronger candidate. The key advantages are its significantly better BBB penetration (71.772 vs 41.218) and longer in vitro half-life (72.198 vs 14.855), both crucial for CNS drug development. While Ligand A has a lower DILI risk and better metabolic stability, the BBB penetration of Ligand B is a more important factor for DRD2 targeting. The slightly improved binding affinity of Ligand B further supports this conclusion.

Output:
1
2025-04-17 08:15:19,075 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (358.36 and 360.401 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (58.64) is better than Ligand B (67.87). Both are below the 90 A^2 threshold desirable for CNS targets, but A is closer to optimal.

**3. logP:** Ligand A (4.273) is higher than the optimal range of 1-3, while Ligand B (1.358) is at the lower end. High logP can cause solubility issues, but for a GPCR, some lipophilicity is beneficial for membrane permeability.

**4. H-Bond Donors:** Both have 1 HBD, which is within the acceptable limit of <=5.

**5. H-Bond Acceptors:** Ligand A has 3 HBAs, and Ligand B has 4. Both are within the acceptable limit of <=10.

**6. QED:** Ligand A (0.878) has a significantly better QED score than Ligand B (0.696), indicating a more drug-like profile.

**7. DILI:** Ligand A (56.223) has a higher DILI risk than Ligand B (29.779). This is a significant drawback for Ligand A.

**8. BBB:** Both ligands have excellent BBB penetration (Ligand A: 96.006, Ligand B: 91.663), exceeding the desirable >70 percentile for CNS targets.

**9. Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and suggests poor permeability. However, the scale is not specified so it is hard to interpret.

**10. Aqueous Solubility:** Both have negative solubility values, which is also unusual and suggests poor solubility.

**11. hERG Inhibition:** Both ligands have low hERG inhibition risk (Ligand A: 0.387, Ligand B: 0.309).

**12. Microsomal Clearance:** Ligand A (58.439) has a higher microsomal clearance than Ligand B (17.971), indicating lower metabolic stability.

**13. In vitro Half-Life:** Ligand B (3.486) has a longer in vitro half-life than Ligand A (-10.058).

**14. P-gp Efflux:** Both have very low P-gp efflux liability (Ligand A: 0.115, Ligand B: 0.036), which is favorable for CNS exposure.

**15. Binding Affinity:** Ligand A (-7.9 kcal/mol) has a slightly better binding affinity than Ligand B (-7.5 kcal/mol). This 0.4 kcal/mol difference is not huge, but could be significant.

**Overall Assessment:**

Ligand A has better affinity and QED, and comparable BBB penetration and P-gp efflux. However, it suffers from higher DILI risk, higher microsomal clearance (lower metabolic stability), and a less favorable logP. Ligand B has a lower DILI risk, better metabolic stability, and a more reasonable logP, but its QED is lower and affinity is slightly weaker.

Given the GPCR-specific priorities, the BBB penetration is already excellent for both. The slightly better affinity of Ligand A is appealing, but the significantly higher DILI risk and lower metabolic stability are major concerns. The lower logP of Ligand B, while not ideal, is less problematic than the DILI risk.

Output:
1
2025-04-17 08:15:19,075 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight (MW):** Both ligands (341.415 and 340.467 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (94.46) is slightly above the optimal <90 for CNS targets, but still reasonable. Ligand B (40.62) is excellent, well below 90, suggesting good BBB penetration potential.

**3. logP:** Both ligands have good logP values (A: 1.967, B: 2.433), falling within the 1-3 range.

**4. H-Bond Donors (HBD):** Ligand A has 3 HBD, which is acceptable. Ligand B has 0, which is also acceptable.

**5. H-Bond Acceptors (HBA):** Ligand A has 3 HBA, acceptable. Ligand B has 2 HBA, also acceptable.

**6. QED:** Both ligands have similar QED values (A: 0.779, B: 0.721), indicating good drug-like properties.

**7. DILI:** Ligand A has a DILI risk of 58.589, which is approaching the higher risk threshold (>60). Ligand B has a much lower DILI risk (10.392), a significant advantage.

**8. BBB:** Both ligands have good BBB penetration (A: 77.782, B: 76.658), exceeding the desirable >70 threshold for CNS targets.

**9. Caco-2 Permeability:** Ligand A has a negative Caco-2 value (-5.132), which is unusual and concerning, suggesting poor permeability. Ligand B also has a negative value (-4.482), also concerning.

**10. Aqueous Solubility:** Both ligands have negative solubility values (A: -3.575, B: -2.448), which is concerning.

**11. hERG Inhibition:** Both ligands have low hERG inhibition risk (A: 0.697, B: 0.328), which is good.

**12. Microsomal Clearance:** Ligand A has a very low (negative) microsomal clearance (-31.795), indicating high metabolic stability. Ligand B has a clearance of 24.83, which is moderate.

**13. In vitro Half-Life:** Ligand A has a half-life of 5.367 hours, while Ligand B has a half-life of -3.074 hours. The negative half-life for ligand B is concerning.

**14. P-gp Efflux:** Both ligands have very low P-gp efflux (A: 0.022, B: 0.085), which is favorable for CNS penetration.

**15. Binding Affinity:** Ligand A has a binding affinity of -9.1 kcal/mol, which is excellent. Ligand B has a binding affinity of -7.6 kcal/mol, also good, but 1.5 kcal/mol weaker than Ligand A.

**Overall Assessment:**

Ligand A has a significantly stronger binding affinity (-9.1 vs -7.6 kcal/mol). However, it has a concerning negative Caco-2 permeability and a DILI risk approaching the higher threshold. Ligand B has a better safety profile (lower DILI) and a more favorable TPSA, but its binding affinity is weaker and it has a negative half-life.

Given the importance of binding affinity for GPCRs, and the relatively close BBB values, the stronger binding of Ligand A is a significant advantage. While the negative Caco-2 and approaching-high DILI are drawbacks, these can potentially be addressed through further optimization. The negative half-life of Ligand B is a more fundamental issue.

Output:
1
2025-04-17 08:15:19,075 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (340.47 and 353.46 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (33.73) is excellent, well below the 90 A^2 threshold for CNS targets. Ligand B (82.11) is higher, but still potentially acceptable, though less ideal.

**logP:** Ligand A (4.423) is slightly high, potentially leading to solubility issues or off-target interactions, but still within a manageable range. Ligand B (-0.31) is too low, which could hinder membrane permeability and CNS penetration.

**H-Bond Donors/Acceptors:** Ligand A (1 HBD, 4 HBA) is good. Ligand B (2 HBD, 5 HBA) is also acceptable.

**QED:** Both ligands (0.771 and 0.709) have good drug-likeness scores.

**DILI:** Ligand A (54.87) has a moderate DILI risk, while Ligand B (3.41) has a very low risk.

**BBB:** Ligand A (74.37) has a good BBB penetration percentile, desirable for a CNS target. Ligand B (35.05) has a poor BBB percentile, a significant drawback.

**Caco-2 Permeability:** Ligand A (-4.582) has poor Caco-2 permeability. Ligand B (-5.133) also has poor Caco-2 permeability.

**Aqueous Solubility:** Ligand A (-4.85) has poor aqueous solubility. Ligand B (-0.527) has slightly better solubility, but still poor.

**hERG Inhibition:** Ligand A (0.965) has a low hERG risk. Ligand B (0.178) also has a low hERG risk.

**Microsomal Clearance:** Ligand A (90.66) has high microsomal clearance, indicating poor metabolic stability. Ligand B (-23.26) has negative clearance, which is not physically possible and likely an error in the data, but suggests very high stability.

**In vitro Half-Life:** Ligand A (4.594) has a short half-life. Ligand B (-0.583) has a very short, and likely erroneous, half-life.

**P-gp Efflux:** Ligand A (0.745) has moderate P-gp efflux. Ligand B (0.003) has very low P-gp efflux, which is favorable for CNS penetration.

**Binding Affinity:** Ligand B (-8.3 kcal/mol) has significantly stronger binding affinity than Ligand A (-7.5 kcal/mol). This 1.8 kcal/mol difference is substantial.

**Overall Assessment:**

Ligand B has a significantly better binding affinity, very low DILI risk, and low P-gp efflux. However, its low logP and poor BBB penetration are major concerns for a CNS target. Ligand A has a better logP and acceptable BBB penetration, but suffers from poor solubility, high metabolic clearance, and a weaker binding affinity.

Despite the issues with BBB for Ligand B, the significantly improved binding affinity (-8.3 vs -7.5 kcal/mol) is a crucial advantage for a GPCR target. The lower P-gp efflux also helps mitigate the BBB issue. While the negative clearance and half-life values are suspect, the other properties suggest Ligand B is more promising *if* those values are corrected or represent a unique metabolic profile. The poor solubility and metabolic stability of Ligand A are harder to overcome.

Output:
1
2025-04-17 08:15:19,076 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B based on the provided guidelines, prioritizing GPCR characteristics (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (366.53 and 351.40 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (49.85) is excellent, well below the 90 A^2 threshold for CNS targets. Ligand B (113.69) is higher, but still potentially acceptable, though less ideal.

**logP:** Ligand A (2.494) is optimal (1-3). Ligand B (0.945) is slightly low, potentially hindering permeation.

**H-Bond Donors/Acceptors:** Ligand A (0 HBD, 4 HBA) is very good. Ligand B (3 HBD, 6 HBA) is also acceptable, but slightly higher counts could impact permeability.

**QED:** Both ligands have similar QED values (0.77 and 0.601), indicating good drug-like properties.

**DILI:** Ligand A (38.66) has a lower DILI risk than Ligand B (54.21), which is preferable.

**BBB:** This is a critical parameter for a CNS target like DRD2. Ligand A (71.23) has a good BBB percentile, exceeding the desirable >70 threshold. Ligand B (41.22) is significantly lower, raising concerns about CNS exposure.

**Caco-2 Permeability:** Ligand A (-4.65) has a negative value, which is unusual and suggests very poor permeability. Ligand B (-5.236) is also poor.

**Aqueous Solubility:** Both ligands have negative solubility values (-3.895 and -2.187), which is concerning.

**hERG Inhibition:** Both ligands show low hERG inhibition risk (0.364 and 0.134).

**Microsomal Clearance:** Ligand A (72.77) has a higher clearance than Ligand B (5.669), indicating lower metabolic stability.

**In vitro Half-Life:** Ligand B (45.437 hours) has a significantly longer half-life than Ligand A (1.709 hours).

**P-gp Efflux:** Ligand A (0.215) has lower P-gp efflux liability than Ligand B (0.169), which is favorable for CNS penetration.

**Binding Affinity:** Ligand B (-8.4 kcal/mol) has a substantially stronger binding affinity than Ligand A (-7.1 kcal/mol). This is a significant advantage, potentially outweighing some ADME drawbacks.

**Overall Assessment:**

Despite the stronger binding affinity of Ligand B, the poor Caco-2 permeability and significantly lower BBB penetration are major drawbacks for a CNS-targeting drug. Ligand A has a much better BBB score and acceptable TPSA, making it more likely to reach the target in the brain. While the Caco-2 permeability and solubility are poor for both, the difference in BBB is decisive. The longer half-life of Ligand B is a plus, but the affinity advantage isn't enough to overcome the poor CNS penetration.

Output:
0
2025-04-17 08:15:19,076 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 drug candidates, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (386.319 and 352.507 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (49.77) is better than Ligand B (33.43) as it is closer to the optimal range for CNS targets (<=90). Both are acceptable.

**3. logP:** Both ligands have good logP values (3.072 and 4.637), falling within the 1-3 range, with Ligand A being slightly more optimal. Ligand B is approaching the upper limit, potentially raising solubility concerns.

**4. H-Bond Donors:** Ligand A (1) is preferable to Ligand B (0) as it provides a slight benefit to solubility.

**5. H-Bond Acceptors:** Ligand A (4) and Ligand B (5) are both acceptable, falling under the 10 threshold.

**6. QED:** Ligand A (0.817) has a significantly better QED score than Ligand B (0.554), indicating a more drug-like profile.

**7. DILI:** Ligand A (13.067) has a much lower DILI risk than Ligand B (47.266), which is a substantial advantage.

**8. BBB:** Ligand A (76.735) and Ligand B (83.443) both have good BBB penetration, exceeding the 70% threshold for CNS targets. Ligand B is slightly better.

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.73 and -4.95). This is unusual and suggests poor permeability. However, these values are on a different scale and may not be directly comparable.

**10. Aqueous Solubility:** Both ligands have negative solubility values (-3.682 and -4.194), indicating poor aqueous solubility. This is a concern.

**11. hERG Inhibition:** Both ligands have low hERG inhibition risk (0.862 and 0.712), which is good.

**12. Microsomal Clearance:** Ligand A (19.685) has lower microsomal clearance than Ligand B (75.811), suggesting better metabolic stability.

**13. In vitro Half-Life:** Ligand A (34.006) has a significantly longer in vitro half-life than Ligand B (-18.819), which is a major advantage.

**14. P-gp Efflux:** Both ligands have low P-gp efflux liability (0.832 and 0.56), which is good for CNS exposure.

**15. Binding Affinity:** Ligand A (-8.5 kcal/mol) has a slightly better binding affinity than Ligand B (-7.5 kcal/mol). While both are good, the 1 kcal/mol difference is meaningful.

**Overall Assessment:**

Ligand A is the stronger candidate. It excels in key areas: QED, DILI risk, metabolic stability (lower Cl_mic, longer t1/2), and binding affinity. While both have poor solubility and permeability (Caco-2), Ligand A's superior overall profile, particularly its lower toxicity risk and better pharmacokinetic properties, make it the more promising drug candidate. The slightly better BBB penetration of Ligand B is outweighed by the other advantages of Ligand A.

Output:
1
2025-04-17 08:15:19,076 - INFO - Reasoning:

Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight (MW):** Both ligands (370.471 and 349.431 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (94.59) is slightly higher than Ligand B (86.88). Both are below the 90 A^2 threshold desirable for CNS targets, making both favorable.

**3. logP:** Both ligands have good logP values (1.938 and 1.545 respectively), falling within the optimal 1-3 range.

**4. H-Bond Donors (HBD):** Both have 1 HBD, which is well within the acceptable limit of <=5.

**5. H-Bond Acceptors (HBA):** Ligand A has 6 HBA, and Ligand B has 5. Both are below the acceptable limit of <=10.

**6. QED:** Both ligands have similar QED values (0.769 and 0.72), indicating good drug-like properties.

**7. DILI:** Both ligands have similar DILI risk (43.622 and 44.591 percentile), indicating low risk.

**8. BBB:** Ligand A (67.468%) has a better BBB penetration score than Ligand B (60.644%). While both are not ideal (>70%), A is closer. This is a crucial factor for a CNS target like DRD2.

**9. Caco-2 Permeability:** Ligand A (-4.283) has slightly better Caco-2 permeability than Ligand B (-4.434). Both are negative values, which is unusual and requires further investigation, but the difference is minor.

**10. Aqueous Solubility:** Ligand A (-3.723) has slightly better aqueous solubility than Ligand B (-1.404). Both are negative, indicating poor solubility, which could be a concern.

**11. hERG Inhibition:** Both ligands show very low hERG inhibition liability (0.222 and 0.135), which is excellent.

**12. Microsomal Clearance (Cl_mic):** Ligand B (38.794 mL/min/kg) has significantly lower microsomal clearance than Ligand A (91.716 mL/min/kg), suggesting better metabolic stability.

**13. In vitro Half-Life:** Ligand B (-30.852 hours) has a much longer in vitro half-life than Ligand A (-76.812 hours). This is a significant advantage for Ligand B.

**14. P-gp Efflux:** Ligand A (0.049) has lower P-gp efflux liability than Ligand B (0.194), which is favorable for CNS penetration.

**15. Binding Affinity:** Ligand A (-8.1 kcal/mol) has a slightly better binding affinity than Ligand B (-7.9 kcal/mol). While the difference is small (0.2 kcal/mol), it's within the range where it could be a deciding factor.

**Overall Assessment:**

Ligand A has a slight edge in binding affinity and BBB penetration, and lower P-gp efflux. However, Ligand B exhibits significantly better metabolic stability (lower Cl_mic) and a longer in vitro half-life. Given the importance of metabolic stability for *in vivo* efficacy, and the fact that both ligands have acceptable (though not ideal) BBB penetration, Ligand B appears to be the more promising candidate. The small difference in binding affinity is likely outweighed by the improved pharmacokinetic properties of Ligand B.

Output:
1
2025-04-17 08:15:19,076 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 drug candidates, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (360.797 and 347.419 Da) fall comfortably within the ideal 200-500 Da range.

**TPSA:** Ligand A (88.52) is better than Ligand B (80.56), both are below the 90 A^2 threshold for CNS targets.

**logP:** Ligand A (2.764) is optimal, while Ligand B (0.704) is a bit low, potentially hindering membrane permeability.

**H-Bond Donors/Acceptors:** Ligand A (2 HBD, 4 HBA) and Ligand B (0 HBD, 6 HBA) both have acceptable numbers of H-bond donors and acceptors.

**QED:** Both ligands have similar QED values (0.855 and 0.708), indicating good drug-likeness.

**DILI:** Ligand A (97.867) has a very high DILI risk, which is a significant concern. Ligand B (56.572) is much better, falling within the acceptable range.

**BBB:** Ligand B (72.005) has a much better BBB penetration percentile than Ligand A (37.185), which is crucial for a CNS target like DRD2.

**Caco-2 Permeability:** Ligand A (-5.431) and Ligand B (-4.134) both have negative values, which is unusual and suggests very poor permeability.

**Aqueous Solubility:** Ligand A (-3.718) and Ligand B (-1.827) both have poor solubility.

**hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.015 and 0.047).

**Microsomal Clearance:** Ligand A (-18.278) has a significantly lower (better) microsomal clearance than Ligand B (31.42). This suggests better metabolic stability for Ligand A.

**In vitro Half-Life:** Ligand A (-10.809) has a negative half-life, which is not possible. Ligand B (-1.53) is also very low.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.017 and 0.047).

**Binding Affinity:** Ligand A (-10.2 kcal/mol) has a significantly stronger binding affinity than Ligand B (-8.1 kcal/mol). This is a substantial advantage.

**Overall Assessment:**

Despite the strong binding affinity of Ligand A, its extremely high DILI risk and poor BBB penetration are major drawbacks. The negative half-life is also concerning. Ligand B, while having a weaker affinity, exhibits a much more favorable safety profile (lower DILI) and better BBB penetration, which are critical for a CNS drug. The lower logP of Ligand B is a concern, but the significantly better ADME properties outweigh this drawback, especially considering the substantial affinity difference.

Output:
1
2025-04-17 08:15:19,077 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (336.326 Da) is slightly lower, which could be beneficial for permeability, but both are acceptable.

**TPSA:** Both ligands have TPSA values below 90 (Ligand A: 76.97, Ligand B: 78.51), which is good for CNS penetration.

**logP:** Ligand A (3.493) is optimal, while Ligand B (1.618) is at the lower end of the optimal range. A logP too low can hinder permeation, so Ligand A has an advantage here.

**H-Bond Donors/Acceptors:** Ligand A (HBD=1, HBA=6) and Ligand B (HBD=2, HBA=4) both fall within acceptable limits.

**QED:** Both ligands have similar QED values (A: 0.617, B: 0.604), indicating good drug-like properties.

**DILI:** Ligand A (91.857) has a significantly higher DILI risk than Ligand B (19.271). This is a major concern for Ligand A.

**BBB:** Ligand B (62.699) has a much better BBB percentile than Ligand A (33.579). For a CNS target like DRD2, this is a critical advantage.

**Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and suggests poor permeability. However, the scale is not specified, so it's difficult to interpret.

**Aqueous Solubility:** Both ligands have negative solubility values, which is also unusual. This suggests poor solubility.

**hERG:** Both ligands have low hERG inhibition liability (A: 0.527, B: 0.638), which is good.

**Microsomal Clearance:** Ligand B (24.196) has a lower microsomal clearance than Ligand A (77.077), indicating better metabolic stability.

**In vitro Half-Life:** Ligand B (-31.835) has a longer in vitro half-life than Ligand A (-60.697).

**P-gp Efflux:** Both ligands have low P-gp efflux liability (A: 0.304, B: 0.071), which is favorable for CNS penetration. Ligand B is better here.

**Binding Affinity:** Both ligands have similar binding affinities (A: -10.3 kcal/mol, B: -8.5 kcal/mol). Ligand A has a 1.8 kcal/mol advantage, which is significant and could outweigh some of its ADME drawbacks.

**Overall Assessment:**

Ligand A has a better binding affinity and logP, but suffers from a high DILI risk and poor BBB penetration. Ligand B has a much better safety profile (lower DILI), significantly better BBB penetration, and improved metabolic stability and half-life. While its binding affinity is slightly weaker, the difference might be acceptable given the improved ADME properties, especially for a CNS target. Considering the GPCR-specific priorities and the importance of CNS penetration and safety for DRD2, Ligand B is the more promising candidate.

Output:
1
2025-04-17 08:15:19,077 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (347.375 and 345.359 Da) fall comfortably within the ideal 200-500 Da range.

**TPSA:** Ligand A (123.18) is slightly above the preferred <90 for CNS targets, while Ligand B (112.4) is closer to the ideal range.

**logP:** Ligand A (1.379) is within the optimal 1-3 range. Ligand B (0.443) is a bit low, potentially hindering permeability.

**H-Bond Donors/Acceptors:** Ligand A has 2 HBD and 8 HBA, which are acceptable. Ligand B has 1 HBD and 6 HBA, also acceptable.

**QED:** Ligand B (0.845) has a significantly better QED score than Ligand A (0.491), indicating a more drug-like profile.

**DILI:** Ligand A (60.217) is borderline, indicating moderate risk. Ligand B (79.449) has a higher DILI risk, which is concerning.

**BBB:** Both ligands have similar, relatively low BBB penetration (34.626 and 34.975, respectively). This is a significant drawback for a CNS target like DRD2.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.367 and -5.181), which is unusual and suggests poor permeability.

**Aqueous Solubility:** Both ligands have negative solubility values (-2.539 and -2.238), also unusual and suggesting poor solubility.

**hERG Inhibition:** Both ligands show very low hERG inhibition risk (0.086 and 0.142).

**Microsomal Clearance:** Ligand A (17.901) has a higher microsomal clearance than Ligand B (10.204), suggesting lower metabolic stability.

**In vitro Half-Life:** Ligand B (-22.483) has a significantly longer in vitro half-life than Ligand A (-6.506).

**P-gp Efflux:** Ligand A (0.175) has slightly higher P-gp efflux liability than Ligand B (0.047), meaning B might have better CNS exposure.

**Binding Affinity:** Ligand A (-7.9 kcal/mol) has a substantially stronger binding affinity than Ligand B (0.0 kcal/mol). This is a major advantage, potentially outweighing some of the ADME drawbacks.

**Overall Assessment:**

The primary goal for a DRD2 ligand is strong binding affinity and good CNS penetration. While both ligands struggle with BBB penetration and solubility, Ligand A's significantly superior binding affinity (-7.9 kcal/mol vs 0.0 kcal/mol) is a decisive factor. The difference in affinity is substantial (>1.5 kcal/mol advantage). Although Ligand B has a better QED and half-life, the binding affinity is paramount. The moderate DILI risk for Ligand A is manageable, especially given the strong binding.

Output:
1
2025-04-17 08:15:19,077 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B based on the provided guidelines, prioritizing GPCR-specific properties (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (362.813 Da) is slightly higher than Ligand B (345.363 Da), but both are acceptable.

**TPSA:** Ligand A (71.78) is excellent for CNS penetration, well below the 90 A^2 threshold. Ligand B (123.92) is higher, but still potentially acceptable, though less ideal.

**logP:** Ligand A (4.008) is at the upper end of the optimal range, potentially raising concerns about solubility and off-target effects. Ligand B (-0.83) is significantly lower, which could hinder membrane permeability and CNS penetration.

**H-Bond Donors/Acceptors:** Ligand A (1 HBD, 4 HBA) is favorable. Ligand B (2 HBD, 8 HBA) is also acceptable, but the higher HBA count might slightly impact permeability.

**QED:** Both ligands have similar QED values (A: 0.819, B: 0.7), indicating good drug-likeness.

**DILI:** Both have relatively high DILI risk (A: 79.992, B: 82.435), but are not drastically concerning.

**BBB:** Ligand A (73.129) has a good BBB percentile, exceeding the 70% threshold for CNS targets. Ligand B (50.679) is significantly lower, suggesting poor brain penetration. This is a major drawback for a DRD2 ligand.

**Caco-2 Permeability:** Ligand A (-4.528) has poor Caco-2 permeability, which is concerning. Ligand B (-5.36) is similarly poor.

**Aqueous Solubility:** Both have very poor solubility (A: -5.742, B: -1.94). This will likely pose formulation challenges.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (A: 0.474, B: 0.174).

**Microsomal Clearance:** Ligand A (111.834) has a higher clearance than Ligand B (16.862), indicating lower metabolic stability.

**In vitro Half-Life:** Ligand A (71.001) has a longer half-life than Ligand B (23.75), which is desirable.

**P-gp Efflux:** Ligand A (0.342) has lower P-gp efflux than Ligand B (0.009), suggesting better CNS exposure.

**Binding Affinity:** Ligand B (-8.0) has a significantly stronger binding affinity than Ligand A (0.0). This is a substantial advantage.

**Overall Assessment:**

Despite the superior binding affinity of Ligand B, its poor BBB penetration is a critical flaw for a DRD2 ligand targeting CNS disorders. Ligand A, while having a weaker affinity, exhibits much better BBB penetration and P-gp efflux properties, making it more likely to reach the target in the brain. The poor solubility and Caco-2 permeability of both are concerns, but can potentially be addressed through formulation strategies. The higher clearance of Ligand A is also a drawback, but the substantial affinity difference of Ligand B is not enough to overcome the poor CNS penetration.

Output:
1
2025-04-17 08:15:19,077 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (403.255 Da) is slightly higher than Ligand B (356.413 Da), but both are acceptable.

**2. TPSA:** Ligand A (61.88) is higher than Ligand B (50.8). For CNS targets, we want TPSA <= 90, so both are acceptable, but B is better.

**3. logP:** Both ligands have good logP values (A: 3.69, B: 3.25), falling within the optimal range of 1-3.

**4. H-Bond Donors:** Both have 1 HBD, which is within the acceptable limit of <=5.

**5. H-Bond Acceptors:** Ligand A has 3 HBAs, and Ligand B has 4. Both are within the acceptable limit of <=10.

**6. QED:** Both ligands have good QED scores (A: 0.664, B: 0.9), indicating good drug-like properties. Ligand B is better here.

**7. DILI:** Ligand A has a DILI risk of 70.492, which is approaching the higher risk threshold (>60). Ligand B has a much lower DILI risk (23.032), making it significantly safer.

**8. BBB:** This is crucial for a CNS target like DRD2. Ligand A has a BBB penetration of 71.85%, which is good, but Ligand B is significantly better at 84.8%.

**9. Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and suggests poor permeability. However, the scale is not specified, so it's hard to interpret.

**10. Aqueous Solubility:** Both have negative solubility values, which is also unusual and suggests poor solubility. Again, the scale is not specified.

**11. hERG Inhibition:** Both ligands have low hERG inhibition risk (A: 0.852, B: 0.837).

**12. Microsomal Clearance:** Both have similar microsomal clearance values (A: 48.239, B: 44.841), indicating similar metabolic stability.

**13. In vitro Half-Life:** Ligand A has a longer half-life (22.983 hours) than Ligand B (8.031 hours), which is generally desirable.

**14. P-gp Efflux:** Both have low P-gp efflux liability (A: 0.62, B: 0.094). Ligand B is significantly better here.

**15. Binding Affinity:** Ligand A has a stronger binding affinity (-9.5 kcal/mol) than Ligand B (-8.0 kcal/mol). This is a substantial difference (>1.5 kcal/mol).

**Overall Assessment:**

While Ligand A has a better binding affinity and longer half-life, Ligand B is superior in several critical ADME properties for a CNS drug targeting a GPCR. Specifically, Ligand B has a much lower DILI risk, significantly better BBB penetration, and lower P-gp efflux. The difference in binding affinity, while substantial, can potentially be overcome with further optimization, while poor ADME properties are harder to fix. The better BBB and lower P-gp efflux of Ligand B are particularly important for CNS exposure.

Output:
1
2025-04-17 08:15:19,077 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (366.502 and 368.459 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (40.62) is significantly better than Ligand B (92.58). For CNS targets, we want TPSA <= 90, so Ligand A is much more favorable.

**logP:** Ligand A (2.185) is optimal (1-3), while Ligand B (-0.276) is below 1, potentially hindering permeation.

**H-Bond Donors/Acceptors:** Ligand A (0 HBD, 3 HBA) and Ligand B (0 HBD, 6 HBA) both have reasonable numbers, within the guidelines.

**QED:** Both ligands have similar QED values (0.769 and 0.689), indicating good drug-likeness.

**DILI:** Ligand A (36.603) has a lower DILI risk than Ligand B (45.638), both are acceptable but A is preferred.

**BBB:** Ligand A (90.617) has a better BBB penetration percentile than Ligand B (86.351). While both are reasonably good, A is better.

**Caco-2 Permeability:** Ligand A (-4.86) and Ligand B (-5.017) both have negative values, which is unusual and suggests poor permeability. This is a concern for both.

**Aqueous Solubility:** Ligand A (-3.602) and Ligand B (-1.244) both have negative solubility values, indicating poor solubility. B is slightly better.

**hERG Inhibition:** Ligand A (0.699) has a lower hERG inhibition liability than Ligand B (0.282), making it safer from a cardiotoxicity perspective.

**Microsomal Clearance:** Ligand A (45.449) has a higher microsomal clearance than Ligand B (2.542), indicating lower metabolic stability. This is a significant drawback for Ligand A.

**In vitro Half-Life:** Ligand A (-14.848) has a very short in vitro half-life, while Ligand B (9.214) is better, but still not ideal.

**P-gp Efflux:** Ligand A (0.374) has lower P-gp efflux liability than Ligand B (0.058), which is favorable for CNS exposure.

**Binding Affinity:** Ligand B (-7.8 kcal/mol) has a significantly stronger binding affinity than Ligand A (-9.3 kcal/mol). This is a substantial advantage for Ligand B, potentially outweighing some of its ADME drawbacks.

**Overall Assessment:**

Ligand A excels in TPSA, logP, BBB, and P-gp efflux. However, it suffers from poor metabolic stability (high Cl_mic, short half-life) and a weaker binding affinity. Ligand B has a much stronger binding affinity, which is crucial for GPCR targets. While its logP is suboptimal and TPSA is high, the strong binding affinity and better half-life are compelling. The slightly better solubility of B is also a plus. Given the GPCR-specific priorities, the superior binding affinity of Ligand B is the deciding factor.

Output:
1
2025-04-17 08:15:19,078 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (343.471 and 349.406 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Both ligands have TPSA values (84.22 and 83.22) below the 90 A^2 threshold desirable for CNS targets, which is excellent.

**3. logP:** Both ligands have logP values (2.919 and 2.048) within the optimal 1-3 range. Ligand A is slightly higher, which could be beneficial for membrane permeability, but both are acceptable.

**4. H-Bond Donors:** Both have 3 HBD, which is within the acceptable limit of <=5.

**5. H-Bond Acceptors:** Both have 3 HBA, which is within the acceptable limit of <=10.

**6. QED:** Both ligands have QED values (0.712 and 0.704) above 0.5, indicating good drug-like properties.

**7. DILI:** Ligand A (47.344) has a slightly higher DILI risk than Ligand B (51.26), but both are below the concerning threshold of 60.

**8. BBB:** This is a critical parameter for a CNS target. Ligand A has a BBB penetration percentile of 85.111, significantly higher than Ligand B's 79.294. This is a major advantage for Ligand A.

**9. Caco-2 Permeability:** Both have negative Caco-2 values (-4.977 and -4.695), which is unusual and suggests poor permeability. This is a significant concern for both compounds.

**10. Aqueous Solubility:** Both have negative solubility values (-4.491 and -3.195), indicating very poor aqueous solubility. This is a major drawback for both.

**11. hERG Inhibition:** Both ligands have low hERG inhibition liability (0.472 and 0.419), which is good.

**12. Microsomal Clearance:** Ligand A (57.946) has a higher microsomal clearance than Ligand B (20.783), suggesting lower metabolic stability. This is a drawback for Ligand A.

**13. In vitro Half-Life:** Ligand B (13.63 hours) has a significantly longer in vitro half-life than Ligand A (4.88 hours), indicating better metabolic stability.

**14. P-gp Efflux:** Both have very low P-gp efflux liability (0.209 and 0.071), which is favorable for CNS penetration.

**15. Binding Affinity:** Both ligands have excellent binding affinities (-9.1 and -8.8 kcal/mol). Ligand A is slightly better (-9.1 kcal/mol), but the difference is relatively small.

**Overall Assessment:**

Despite both compounds having issues with solubility and Caco-2 permeability, Ligand A is the better candidate. The primary driver is its significantly higher predicted BBB penetration (85.111 vs 79.294). For a CNS target like DRD2, this is paramount. While Ligand A has a higher Cl_mic and shorter t1/2, the superior BBB penetration outweighs this drawback. The affinity difference is minimal. The solubility and permeability issues would need to be addressed through formulation or structural modifications, but the starting point with better CNS exposure is crucial.

Output:
1
2025-04-17 08:15:19,078 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (354.491 and 344.459 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (87.66) is better than Ligand B (58.44). Both are below the 90 A^2 threshold for CNS targets, but Ligand B is significantly lower, which is advantageous for brain penetration.

**3. logP:** Both ligands have good logP values (2.884 and 1.797), falling within the optimal 1-3 range. Ligand B is slightly lower, potentially improving solubility.

**4. H-Bond Donors:** Ligand A has 3 HBD, which is acceptable. Ligand B has 0, which is also acceptable.

**5. H-Bond Acceptors:** Both ligands have 4 HBA, which is within the acceptable limit of 10.

**6. QED:** Both ligands have good QED scores (0.556 and 0.758), indicating good drug-like properties. Ligand B is better.

**7. DILI:** Ligand A (10.896) has a much lower DILI risk than Ligand B (17.1). This is a significant advantage for Ligand A.

**8. BBB:** Ligand B (77.007) has a better BBB penetration percentile than Ligand A (69.678), though both are reasonably good. This is a key factor for a CNS target like DRD2.

**9. Caco-2 Permeability:** Ligand A (-4.551) has worse Caco-2 permeability than Ligand B (-4.927). Lower values indicate poorer permeability.

**10. Aqueous Solubility:** Ligand A (-2.761) has worse solubility than Ligand B (-1.529).

**11. hERG Inhibition:** Both ligands have low hERG inhibition risk (0.636 and 0.32).

**12. Microsomal Clearance:** Ligand A (56.999) has higher microsomal clearance than Ligand B (37.753), indicating lower metabolic stability. Ligand B is preferred.

**13. In vitro Half-Life:** Ligand B (-13.417) has a negative half-life, which is not possible. This is a significant red flag. Ligand A (13.767) has a reasonable half-life.

**14. P-gp Efflux:** Both ligands have low P-gp efflux liability (0.229 and 0.106).

**15. Binding Affinity:** Ligand B (-8.7 kcal/mol) has a significantly stronger binding affinity than Ligand A (-7.3 kcal/mol). This is a substantial advantage, potentially outweighing some ADME drawbacks.

**Overall Assessment:**

Ligand B has a superior binding affinity and better BBB penetration, which are critical for a CNS GPCR target. However, it has a concerning negative in vitro half-life, which is a major issue. Ligand A has a more reasonable half-life and lower DILI risk, but its affinity and BBB penetration are not as good as Ligand B. Given the importance of affinity for GPCRs, and the fact that a negative half-life is a showstopper, I would still lean towards Ligand B *if* the half-life value is a data error. If the half-life is correct, Ligand A is the better candidate.

Output:
1
2025-04-17 08:15:19,078 - INFO - Reasoning:

Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (356.463 and 359.398 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (88.1) is excellent, falling well below the 90 A^2 threshold for CNS targets. Ligand B (96.97) is still acceptable but less optimal.

**3. logP:** Ligand A (1.044) is within the optimal range of 1-3. Ligand B (-0.628) is slightly below 1, which *could* indicate permeability issues, but isn't a dealbreaker.

**4. H-Bond Donors:** Both ligands have 2 HBD, which is within the acceptable limit of <=5.

**5. H-Bond Acceptors:** Both ligands have 5 HBA, also within the acceptable limit of <=10.

**6. QED:** Both ligands have similar QED values (0.603 and 0.631), indicating good drug-like properties.

**7. DILI:** Ligand A (7.29) has a very low DILI risk, significantly better than Ligand B (35.634).

**8. BBB:** Both ligands have good BBB penetration (73.866 and 78.519), exceeding the desirable threshold of >70 for CNS targets. Ligand B is slightly better.

**9. Caco-2 Permeability:** Both have negative values (-4.92 and -5.077). This is unusual and suggests a problem with the data or a very poor permeability. However, since both are similarly poor, it doesn't differentiate them.

**10. Aqueous Solubility:** Both have negative values (-1.012 and -1.597). Again, this is unusual and suggests poor solubility. Similar to Caco-2, it doesn't differentiate the ligands.

**11. hERG Inhibition:** Both ligands have very low hERG risk (0.263 and 0.206).

**12. Microsomal Clearance:** Ligand A (-4.795) has a negative clearance, which is impossible. This is a data error. Ligand B (-14.419) also has a negative clearance, indicating a data error.

**13. In vitro Half-Life:** Ligand A (18.738 hours) has a better half-life than Ligand B (4.337 hours).

**14. P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.049 and 0.015), which is excellent for CNS penetration.

**15. Binding Affinity:** Both ligands have very similar and strong binding affinities (-7.4 and -7.5 kcal/mol). The difference is negligible.

**Overall Assessment:**

Despite the questionable Caco-2 and solubility data, and the impossible clearance values, Ligand A is slightly favored. Its significantly lower DILI risk is a major advantage. The slightly better TPSA and half-life also contribute. The binding affinities are essentially identical. The negative clearance values are concerning and would require further investigation, but given the overall profile, Ligand A appears marginally more promising.

Output:
1
2025-04-17 08:15:19,078 - INFO - Batch 433 complete. Total preferences: 6928
2025-04-17 08:15:19,078 - INFO - Processing batch 434/512...
2025-04-17 08:16:01,936 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (347.375 and 345.443 Da) fall comfortably within the ideal 200-500 Da range.

**TPSA:** Ligand A (124.52) is slightly above the optimal <90 for CNS targets, but still reasonable. Ligand B (62.74) is excellent, well below the threshold.

**logP:** Ligand A (-0.422) is a bit low, potentially hindering permeability. Ligand B (2.257) is within the optimal 1-3 range. This is a significant advantage for Ligand B.

**H-Bond Donors/Acceptors:** Ligand A has 3 HBD and 6 HBA, which are acceptable. Ligand B has 0 HBD and 4 HBA, also acceptable.

**QED:** Both ligands have good QED scores (0.454 and 0.509), indicating drug-like properties.

**DILI:** Ligand A (59.519) is approaching a moderate risk level, while Ligand B (31.989) has a low DILI risk.

**BBB:** Ligand A (53.742) has a moderate BBB penetration, not ideal for a CNS target. Ligand B (75.301) shows excellent BBB penetration, a major advantage.

**Caco-2 Permeability:** Ligand A (-6.015) has poor Caco-2 permeability, suggesting poor absorption. Ligand B (-4.371) is also not great, but better than A.

**Aqueous Solubility:** Both ligands have poor aqueous solubility (-1.185 and -1.707). This could pose formulation challenges.

**hERG Inhibition:** Ligand A (0.022) has very low hERG inhibition risk, which is excellent. Ligand B (0.368) has a slightly elevated risk, but still relatively low.

**Microsomal Clearance:** Ligand A (-5.876) suggests very slow clearance and high metabolic stability, which is excellent. Ligand B (39.578) has a much higher clearance, indicating faster metabolism.

**In vitro Half-Life:** Ligand A (16.773 hours) has a reasonable half-life. Ligand B (12.419 hours) is acceptable, but less desirable than A.

**P-gp Efflux:** Ligand A (0.003) has very low P-gp efflux, which is excellent for CNS penetration. Ligand B (0.134) has slightly higher efflux, but still reasonable.

**Binding Affinity:** Ligand B (-7.7 kcal/mol) has a significantly stronger binding affinity than Ligand A (-8.5 kcal/mol). This difference of 0.8 kcal/mol is substantial and can outweigh some ADME drawbacks.

**Overall Assessment:**

Ligand B is the stronger candidate. While Ligand A has better metabolic stability and lower P-gp efflux, Ligand B excels in key areas for a CNS-targeting GPCR: significantly better BBB penetration, a more optimal logP, and a substantially higher binding affinity. The slightly higher DILI and faster clearance of Ligand B are less concerning given the strong affinity and good BBB penetration. The lower TPSA of Ligand B is also beneficial.

Output:
1
2025-04-17 08:16:01,936 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (339.439 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (53.51) is better than Ligand B (62.3). Both are below the 90 A^2 threshold for CNS targets, but A is closer to the ideal.

**3. logP:** Both ligands (A: 2.396, B: 2.467) are within the optimal 1-3 range.

**4. H-Bond Donors:** Ligand A (0) is preferable to Ligand B (1). Fewer HBDs generally improve permeability.

**5. H-Bond Acceptors:** Both ligands have 3 HBA, which is acceptable.

**6. QED:** Both ligands have similar QED values (A: 0.85, B: 0.857), indicating good drug-likeness.

**7. DILI:** Ligand A (16.44) has a significantly lower DILI risk than Ligand B (23.885). This is a substantial advantage.

**8. BBB:** Ligand A (89.027) has a better BBB penetration percentile than Ligand B (79.062). Both are good, but A is better for a CNS target.

**9. Caco-2 Permeability:** Ligand A (-4.563) is better than Ligand B (-4.905), indicating better intestinal absorption.

**10. Aqueous Solubility:** Ligand A (-2.197) is better than Ligand B (-2.486), indicating better solubility.

**11. hERG Inhibition:** Both ligands have low hERG inhibition risk (A: 0.29, B: 0.316).

**12. Microsomal Clearance:** Ligand A (32.029) has a higher (worse) microsomal clearance than Ligand B (26.819). This suggests Ligand B is more metabolically stable.

**13. In vitro Half-Life:** Ligand B (-12.726) has a much longer in vitro half-life than Ligand A (2.376). This is a significant advantage.

**14. P-gp Efflux:** Both ligands have similar P-gp efflux liability (A: 0.125, B: 0.103).

**15. Binding Affinity:** Ligand B (-9.6 kcal/mol) has a significantly stronger binding affinity than Ligand A (-7.9 kcal/mol). This is a substantial advantage, potentially outweighing some ADME drawbacks.

**Overall Assessment:**

Ligand B has a significantly better binding affinity and a longer half-life, which are crucial for a GPCR ligand. While Ligand A has better DILI, BBB, solubility, and Caco-2 permeability, the difference in affinity is substantial (>1.5 kcal/mol). The improved metabolic stability (lower Cl_mic, longer t1/2) of Ligand B is also a significant benefit. Given the GPCR-specific priorities, the stronger binding affinity of Ligand B is the most important factor.

Output:
1
2025-04-17 08:16:01,936 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (350.419 and 350.503 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (93.19) is slightly above the optimal <90 for CNS targets, but still reasonable. Ligand B (60.85) is excellent, well below 90.

**logP:** Ligand A (-1.585) is quite low, potentially hindering membrane permeability. Ligand B (2.567) is within the optimal 1-3 range. This is a significant advantage for Ligand B.

**H-Bond Donors/Acceptors:** Ligand A (2 HBD, 5 HBA) is acceptable. Ligand B (1 HBD, 3 HBA) is also good, potentially slightly better due to fewer hydrogen bond interactions.

**QED:** Both ligands have reasonable QED values (0.471 and 0.801). Ligand B is significantly better, indicating a more drug-like profile.

**DILI:** Ligand A (14.773) has a very low DILI risk, which is excellent. Ligand B (21.714) is also low, but higher than Ligand A.

**BBB:** Ligand A (8.181) has a very poor BBB penetration score, making it unlikely to effectively target DRD2 in the CNS. Ligand B (63.746) has a good BBB penetration score, which is crucial for a CNS target.

**Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and suggests issues with the prediction method or the molecules themselves. However, the magnitude is similar.

**Aqueous Solubility:** Both have negative solubility values, again suggesting issues with the prediction method. The magnitude is similar.

**hERG Inhibition:** Ligand A (0.083) has a very low hERG risk, which is excellent. Ligand B (0.552) is slightly higher, but still relatively low.

**Microsomal Clearance:** Ligand A (-16.73) has a negative clearance, which is not physically possible and indicates a problem with the prediction. Ligand B (52.564) has a relatively high clearance, suggesting faster metabolism.

**In vitro Half-Life:** Ligand A (-3.497) has a negative half-life, which is not physically possible and indicates a problem with the prediction. Ligand B (3.099) has a short half-life.

**P-gp Efflux:** Ligand A (0.006) has very low P-gp efflux, which is favorable for CNS penetration. Ligand B (0.539) has moderate P-gp efflux, which could limit CNS exposure.

**Binding Affinity:** Ligand A (-7.4) has a slightly better binding affinity than Ligand B (-0.0). This is a significant advantage for Ligand A, but can be overcome by other factors.

**Overall Assessment:**

Despite Ligand A's slightly better binding affinity and lower DILI/hERG risk, its extremely poor BBB penetration and problematic clearance/half-life predictions make it a very unlikely drug candidate. The negative values for clearance and half-life are red flags. Ligand B, while having a weaker binding affinity, excels in crucial areas for a CNS GPCR target: good logP, excellent TPSA, good BBB penetration, and a more reasonable (though not ideal) metabolic profile. The QED score is also much higher for Ligand B.

Output:
1
2025-04-17 08:16:01,936 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (336.395 and 345.443 Da) fall comfortably within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (80.05) is slightly higher than Ligand B (75.44), but both are below the 90 A^2 threshold desirable for CNS targets.

**3. logP:** Ligand A (3.34) is slightly higher than Ligand B (2.709), both are within the optimal 1-3 range.

**4. H-Bond Donors:** Ligand A (2) is slightly higher than Ligand B (1), but both are within the acceptable limit of <=5.

**5. H-Bond Acceptors:** Both ligands have 4 H-bond acceptors, which is well within the acceptable limit of <=10.

**6. QED:** Both ligands have good QED scores (0.723 and 0.824, respectively), indicating good drug-like properties.

**7. DILI:** Ligand A (64.521) has a slightly higher DILI risk than Ligand B (54.207), but both are below the concerning threshold of 60.

**8. BBB:** This is a critical parameter for a CNS target like DRD2. Ligand B (85.731) significantly outperforms Ligand A (50.679) in predicted BBB penetration. This is a major advantage for Ligand B.

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.994 and -4.974). This is unusual and suggests poor permeability, however, these values are on a log scale and close to zero, so the impact is likely small.

**10. Aqueous Solubility:** Both ligands have negative solubility values (-2.971 and -3.486). Similar to Caco-2, these values are on a log scale and close to zero, so the impact is likely small.

**11. hERG Inhibition:** Both ligands have low hERG inhibition risk (0.425 and 0.376).

**12. Microsomal Clearance:** Ligand B (75.641) has a higher microsomal clearance than Ligand A (34.23), indicating faster metabolism and potentially lower *in vivo* exposure.

**13. In vitro Half-Life:** Ligand A (43.995) has a longer in vitro half-life than Ligand B (-4.457), suggesting better metabolic stability.

**14. P-gp Efflux:** Ligand A (0.042) shows lower P-gp efflux than Ligand B (0.254), which is favorable for CNS penetration.

**15. Binding Affinity:** Ligand A (-9.9 kcal/mol) has a significantly stronger binding affinity than Ligand B (-7.8 kcal/mol). This is a substantial difference (2.1 kcal/mol), and a strong affinity can often outweigh minor ADME deficiencies.

**Overall Assessment:**

While Ligand A has a superior binding affinity and better P-gp efflux, Ligand B's significantly better BBB penetration is the deciding factor for a CNS target like DRD2. The difference in BBB penetration (85.731 vs 50.679) is substantial. The slightly worse metabolic stability of Ligand B is less concerning than the limited CNS exposure expected with Ligand A. The affinity difference, while notable, might be overcome with further optimization of Ligand B.

Output:
1
2025-04-17 08:16:01,936 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (349.307 Da) is slightly lower, which could be beneficial for permeability. Ligand B (369.575 Da) is also good.

**TPSA:** Ligand A (138.28) is close to the upper limit for good oral absorption and acceptable for CNS targets, but not ideal. Ligand B (47.36) is *excellent* for CNS penetration, well below the 90 A^2 threshold.

**logP:** Ligand A (0.24) is quite low, potentially hindering membrane permeability and CNS penetration. Ligand B (3.747) is within the optimal range (1-3), suggesting good permeability.

**H-Bond Donors/Acceptors:** Ligand A has 0 HBD and 10 HBA, which is acceptable. Ligand B has 0 HBD and 5 HBA, also acceptable.

**QED:** Both ligands have reasonable QED values (A: 0.425, B: 0.589), suggesting acceptable drug-likeness. Ligand B is better.

**DILI:** Ligand A has a high DILI risk (96.51), which is a significant concern. Ligand B has a much lower DILI risk (27.608), a major advantage.

**BBB:** Ligand A has a good BBB penetration score (82.047), but Ligand B is also good (70.725).

**Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and suggests potential issues with the prediction method or the compounds themselves. However, the values are close enough to not be a major differentiator.

**Aqueous Solubility:** Both have negative solubility values, again suggesting potential issues with the prediction method.

**hERG Inhibition:** Ligand A (0.177) has a very low hERG risk, which is excellent. Ligand B (0.762) has a slightly higher, but still relatively low, hERG risk.

**Microsomal Clearance:** Ligand A has a high microsomal clearance (101.797), indicating poor metabolic stability. Ligand B has a higher clearance (130.425) but is still acceptable.

**In vitro Half-Life:** Ligand A has a very short in vitro half-life (-10.837), a major drawback. Ligand B has a longer half-life (4.384), which is better.

**P-gp Efflux:** Ligand A has low P-gp efflux (0.255), which is good for CNS penetration. Ligand B has moderate P-gp efflux (0.519).

**Binding Affinity:** Ligand A has a stronger binding affinity (-7.2 kcal/mol) than Ligand B (-6.3 kcal/mol). This is a substantial difference.

**Overall Assessment:**

Despite Ligand A's superior binding affinity, its high DILI risk, poor metabolic stability (high Cl_mic, short t1/2), and low logP are significant liabilities. Ligand B, while having slightly weaker affinity, presents a much more favorable ADME-Tox profile, particularly with its lower DILI risk, better logP, and improved metabolic stability. For a CNS target like DRD2, the combination of acceptable BBB penetration, good logP, and a manageable safety profile (low DILI, reasonable hERG) is crucial. The affinity difference, while noticeable, might be overcome with further optimization of Ligand B.

Output:
1
2025-04-17 08:16:01,936 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (368.455 and 355.341 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (115.56) is slightly above the optimal <90 for CNS targets, while Ligand B (87.74) is well within the desired range. This is a point in favor of Ligand B.

**3. logP:** Both ligands have good logP values (1.498 and 1.321), falling within the optimal 1-3 range.

**4. H-Bond Donors:** Both have 2 HBD, which is acceptable.

**5. H-Bond Acceptors:** Ligand A has 5 HBA, and Ligand B has 4. Both are within the acceptable limit of <=10.

**6. QED:** Both ligands have good QED scores (0.738 and 0.798), indicating good drug-like properties.

**7. DILI:** Ligand A (57.697) has a lower DILI risk than Ligand B (64.172), which is preferable.

**8. BBB:** Ligand B (72.082) has a significantly better BBB penetration score than Ligand A (56.495). This is a crucial advantage for a CNS target like DRD2.

**9. Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and suggests poor permeability. However, the scale is not specified, so it's hard to interpret.

**10. Aqueous Solubility:** Both have negative solubility values, also unusual. Again, the scale is not specified.

**11. hERG Inhibition:** Both ligands show very low hERG inhibition risk (0.197 and 0.163), which is excellent.

**12. Microsomal Clearance:** Ligand A (31.626) has a lower microsomal clearance than Ligand B (44.117), indicating better metabolic stability.

**13. In vitro Half-Life:** Ligand A (-38.252) has a significantly longer in vitro half-life than Ligand B (10.648). This is a substantial advantage.

**14. P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.062 and 0.026), which is desirable for CNS penetration.

**15. Binding Affinity:** Both ligands have the same binding affinity (-8.9 kcal/mol), which is excellent and strong.

**Overall Assessment:**

While Ligand A has advantages in DILI risk, metabolic stability (lower Cl_mic), and in vitro half-life, Ligand B excels in BBB penetration and has a more favorable TPSA. Given that DRD2 is a CNS target, BBB penetration is paramount. The slightly higher DILI risk and lower metabolic stability of Ligand B are less concerning than the poor BBB score of Ligand A. The equal binding affinity removes that as a differentiating factor.

Output:
1
2025-04-17 08:16:01,936 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (353.447 Da) is slightly lower, which could be advantageous for permeability. Ligand B (371.503 Da) is also acceptable.

**TPSA:** Ligand A (54.34) is significantly better than Ligand B (95.58). For CNS targets, we want TPSA <= 90, so Ligand A is much closer to this threshold. Ligand B's TPSA is a concern for brain penetration.

**logP:** Ligand A (2.862) is optimal (1-3). Ligand B (-0.085) is below 1, which is suboptimal and could hinder permeation.

**H-Bond Donors/Acceptors:** Ligand A (HBD=1, HBA=4) and Ligand B (HBD=2, HBA=5) both fall within acceptable ranges.

**QED:** Both ligands have reasonable QED values (A: 0.77, B: 0.652), indicating good drug-like properties.

**DILI:** Ligand A (87.049) has a higher DILI risk than Ligand B (18.922). This is a significant drawback for Ligand A.

**BBB:** Ligand A (57.736) is better than Ligand B (51.105), but both are below the desirable threshold of >70 for CNS targets. However, given the other factors, BBB is less critical here.

**Caco-2 Permeability:** Ligand A (-4.996) is very poor, indicating very low intestinal absorption. Ligand B (-5.639) is also poor, but slightly better.

**Aqueous Solubility:** Ligand A (-3.997) is poor, while Ligand B (-1.887) is also poor, but better than A.

**hERG Inhibition:** Both ligands have very low hERG inhibition risk (A: 0.394, B: 0.156).

**Microsomal Clearance:** Ligand A (54.023) has higher clearance than Ligand B (-7.276). This suggests Ligand B is more metabolically stable.

**In vitro Half-Life:** Ligand A (26.411) has a shorter half-life than Ligand B (21.513).

**P-gp Efflux:** Ligand A (0.423) has lower P-gp efflux than Ligand B (0.015), which is favorable for CNS penetration.

**Binding Affinity:** Both ligands have excellent binding affinities (A: -8.4 kcal/mol, B: -7.8 kcal/mol). Ligand A is slightly better (-8.4 vs -7.8), but the difference is less than 1.5 kcal/mol, so it doesn't completely outweigh other issues.

**Overall Assessment:**

Ligand A has superior binding affinity and lower P-gp efflux, but suffers from poor Caco-2 permeability, poor solubility, higher DILI risk, and a TPSA that is less ideal for CNS penetration. Ligand B, while having slightly weaker affinity, exhibits better predicted metabolic stability (lower Cl_mic, longer t1/2), lower DILI risk, and a slightly better solubility profile. The biggest drawback for Ligand B is its low logP and higher TPSA.

Considering the GPCR-specific priorities, the balance of properties favors Ligand B. While BBB is not ideal for either, Ligand B's better ADME profile (lower DILI, better metabolic stability, slightly better solubility) makes it the more promising candidate, despite the weaker affinity. The poor permeability of Ligand A is a major concern.

Output:
1
2025-04-17 08:16:01,936 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (348.49 and 352.44 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (67.43) is significantly better than Ligand B (98.76). For CNS targets, TPSA should be <= 90, and A is comfortably within this range, while B is pushing the limit.

**logP:** Ligand A (2.714) is optimal (1-3), while Ligand B (0.343) is quite low, potentially hindering permeation.

**H-Bond Donors/Acceptors:** Both have 2 HBDs, which is good. Ligand A has 3 HBAs, and Ligand B has 5. Both are acceptable, but lower is generally preferred.

**QED:** Both ligands have good QED scores (0.63 and 0.769), indicating drug-like properties.

**DILI:** Ligand A (22.644) has a lower DILI risk than Ligand B (31.601), which is desirable.

**BBB:** This is crucial for a CNS target like DRD2. Ligand A (57.193) is moderate, while Ligand B (20.512) is poor. A higher BBB percentile is strongly favored.

**Caco-2 Permeability:** Both have negative Caco-2 values (-4.972 and -4.857) which is unusual and suggests poor permeability. This is a concern for both, but doesn't differentiate them.

**Aqueous Solubility:** Both have negative solubility values (-2.583 and -0.318) which is also unusual.

**hERG:** Both ligands show low hERG inhibition liability (0.21 and 0.41), which is good.

**Microsomal Clearance:** Ligand A (41.309) has higher clearance than Ligand B (-2.455). Lower clearance is preferred for better metabolic stability, giving a slight edge to Ligand B.

**In vitro Half-Life:** Ligand B (-17.186) has a longer half-life than Ligand A (-11.294), which is favorable.

**P-gp Efflux:** Both have low P-gp efflux liability (0.1 and 0.126), which is good.

**Binding Affinity:** Ligand B (-8.1) has a slightly better binding affinity than Ligand A (-7.8), but the difference is not huge.

**Overall Assessment:**

Ligand A is superior due to its significantly better TPSA and logP values, which are critical for CNS penetration. While Ligand B has slightly better metabolic stability and half-life, the poor logP and BBB penetration are major drawbacks for a DRD2 ligand. The slightly better affinity of Ligand B is unlikely to overcome these ADME deficiencies.

Output:
1
2025-04-17 08:16:01,937 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 drug candidates, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (406.28 Da) is slightly higher than Ligand B (348.487 Da), but both are acceptable.

**TPSA:** Both ligands have TPSA values below the 90 A^2 threshold desirable for CNS targets. Ligand A (79.46 A^2) is a bit higher than Ligand B (69.64 A^2), making Ligand B slightly more favorable for brain penetration.

**logP:** Both ligands have logP values within the optimal range (1-3). Ligand A (3.746) is at the higher end, potentially raising concerns about solubility and off-target effects, while Ligand B (2.679) is well within the optimal range.

**H-Bond Donors/Acceptors:** Ligand A has 3 HBD and 3 HBA, while Ligand B has 2 HBD and 3 HBA. Both are within acceptable limits (<=5 HBD and <=10 HBA).

**QED:** Both ligands have good QED scores (Ligand A: 0.656, Ligand B: 0.796), indicating a generally drug-like profile. Ligand B has a slightly better QED score.

**DILI:** Ligand A has a DILI risk of 71.772%, which is considered high risk. Ligand B has a much lower DILI risk of 21.791%, which is excellent. This is a significant advantage for Ligand B.

**BBB:** Ligand A has a BBB penetration of 77.821%, which is good, but Ligand B has a BBB penetration of 43.117%, which is less desirable for a CNS target.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values, which is unusual and suggests a potential issue with the data or a very poor permeability.

**Aqueous Solubility:** Both ligands have negative solubility values, which is also unusual and suggests a potential issue with the data or very poor solubility.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (Ligand A: 0.694, Ligand B: 0.771).

**Microsomal Clearance:** Ligand A has a lower microsomal clearance (40.769 mL/min/kg) than Ligand B (64.161 mL/min/kg), indicating better metabolic stability.

**In vitro Half-Life:** Ligand A has a longer in vitro half-life (75.308 hours) than Ligand B (22.727 hours), which is favorable.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (Ligand A: 0.21, Ligand B: 0.36), which is good for CNS penetration.

**Binding Affinity:** Ligand A has a significantly stronger binding affinity (-9.5 kcal/mol) than Ligand B (-8.0 kcal/mol). This is a substantial advantage for Ligand A, potentially outweighing some of its ADME drawbacks.

**Overall Assessment:**

While Ligand A has a superior binding affinity and better metabolic stability and half-life, its high DILI risk is a major concern. Ligand B has a much better safety profile (lower DILI) and a more optimal logP. The BBB penetration for Ligand B is lower, but the strong affinity of Ligand A might compensate for that. However, the significantly higher DILI risk for Ligand A makes it a less attractive candidate. The negative solubility and Caco-2 values for both compounds are concerning and would require further investigation.

Considering the GPCR-specific priorities and the overall profile, Ligand B is the more promising candidate due to its significantly lower DILI risk and acceptable ADME properties, despite its slightly weaker binding affinity.

Output:
1
2025-04-17 08:16:01,937 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B based on the provided guidelines, prioritizing GPCR-specific properties (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (351.447 & 352.454 Da) fall within the ideal range of 200-500 Da.

**TPSA:** Ligand A (113.66) is better than Ligand B (76.14), both are below the 90 A^2 threshold for CNS targets.

**logP:** Ligand B (3.147) is optimal (1-3), while Ligand A (0.581) is low, potentially hindering permeation. This is a significant advantage for Ligand B.

**H-Bond Donors:** Ligand A (3) is slightly higher than Ligand B (2), but both are within the acceptable limit of 5.

**H-Bond Acceptors:** Both ligands have 5 HBA, which is within the acceptable limit of 10.

**QED:** Ligand B (0.714) has a better QED score than Ligand A (0.498), indicating a more drug-like profile.

**DILI:** Ligand A (10.508) has a much lower DILI risk than Ligand B (51.338), a significant advantage.

**BBB:** Ligand B (87.088) has a much higher BBB penetration percentile than Ligand A (27.142). This is a critical advantage for a CNS target like DRD2.

**Caco-2 Permeability:** Ligand A (-5.114) has a worse Caco-2 permeability than Ligand B (-4.306), but both are negative, indicating poor permeability.

**Aqueous Solubility:** Ligand A (-1.246) has slightly better aqueous solubility than Ligand B (-3.91), but both are poor.

**hERG Inhibition:** Ligand A (0.188) has a lower hERG inhibition liability than Ligand B (0.52), which is preferable.

**Microsomal Clearance:** Ligand A (2.327) has a much lower microsomal clearance than Ligand B (84.457), indicating better metabolic stability.

**In vitro Half-Life:** Ligand A (11.681) has a better in vitro half-life than Ligand B (-4.708).

**P-gp Efflux:** Ligand A (0.006) has significantly lower P-gp efflux liability than Ligand B (0.21), which is highly desirable for CNS penetration.

**Binding Affinity:** Ligand B (-8.2 kcal/mol) has a significantly stronger binding affinity than Ligand A (-7.2 kcal/mol). This is a substantial advantage, potentially outweighing some ADME drawbacks.

**Overall Assessment:**

Ligand B excels in BBB penetration and binding affinity, both crucial for a CNS GPCR target. However, it has considerably higher DILI risk and P-gp efflux. Ligand A has better safety (DILI, hERG, P-gp) and metabolic stability, but suffers from poor logP and BBB penetration. The significantly stronger binding affinity of Ligand B (-8.2 vs -7.2) is a substantial advantage, and the higher BBB is also critical. While the DILI risk is a concern, it might be mitigated through structural modifications. The poor logP of Ligand A is a more difficult issue to address without significantly altering the binding pose.

Output:
1
2025-04-17 08:16:01,937 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 drug candidates, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (388.559 and 377.853 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (82.61) is better than Ligand B (86.29). Both are below the 90 A^2 threshold for CNS targets, but A is closer to the ideal.

**logP:** Ligand A (1.517) is within the optimal 1-3 range. Ligand B (2.72) is also acceptable, but slightly higher.

**H-Bond Donors/Acceptors:** Ligand A (HBD=1, HBA=6) and Ligand B (HBD=2, HBA=5) both have reasonable numbers of H-bond donors and acceptors, well within the guidelines.

**QED:** Both ligands have similar QED values (0.766 and 0.715), indicating good drug-likeness.

**DILI:** Ligand A (69.639) has a lower DILI risk than Ligand B (81.427), which is preferable.

**BBB:** This is a critical parameter for a CNS target like DRD2. Ligand A (67.352) has a significantly better BBB penetration percentile than Ligand B (30.554). This is a major advantage for Ligand A.

**Caco-2 Permeability:** Ligand A (-4.832) and Ligand B (-5.475) both have negative Caco-2 values, which is unusual. This suggests poor permeability. However, the values are similar.

**Aqueous Solubility:** Both ligands have very poor aqueous solubility (-3.243 and -3.477). This is a concern for both, but not a deciding factor.

**hERG Inhibition:** Both ligands show low hERG inhibition risk (0.461 and 0.358), which is good.

**Microsomal Clearance:** Ligand B (6.753) has significantly lower microsomal clearance than Ligand A (69.967), indicating better metabolic stability.

**In vitro Half-Life:** Ligand B (99.955) has a much longer in vitro half-life than Ligand A (-34.064). This is a significant advantage for Ligand B.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.21 and 0.223), which is good for CNS penetration.

**Binding Affinity:** Ligand B (-8.7 kcal/mol) has a significantly stronger binding affinity than Ligand A (-7.0 kcal/mol). This is a substantial advantage, potentially outweighing some ADME drawbacks.

**Overall Assessment:**

Ligand B has a much stronger binding affinity and better metabolic stability (lower Cl_mic, longer t1/2). However, Ligand A has a significantly better BBB penetration and lower DILI risk. The difference in binding affinity (1.7 kcal/mol) is substantial, and for a GPCR, strong binding is paramount. While the poor solubility and Caco-2 values are concerns for both, the superior BBB of Ligand A is crucial for CNS targets. However, the binding affinity difference is significant enough to overcome the BBB advantage of Ligand A.

Output:
1
2025-04-17 08:16:01,937 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (369.849 Da) is slightly higher than Ligand B (341.455 Da), but both are acceptable.

**TPSA:** Ligand A (95.26) is higher than Ligand B (52.65). For CNS targets, we ideally want TPSA <= 90. Ligand A is slightly above this, while Ligand B is well within the range. This favors Ligand B.

**logP:** Both ligands have good logP values (Ligand A: 1.66, Ligand B: 2.328), falling within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A has 2 HBD and 5 HBA, while Ligand B has 1 HBD and 3 HBA. Both are within acceptable limits (<=5 HBD and <=10 HBA).

**QED:** Both ligands have similar QED values (Ligand A: 0.79, Ligand B: 0.739), indicating good drug-like properties.

**DILI:** Ligand A (42.924) has a slightly higher DILI risk than Ligand B (19.698). Both are below the 60 threshold, but lower is better. This favors Ligand B.

**BBB:** This is a crucial parameter for CNS targets. Ligand B (70.609) has a significantly better BBB penetration percentile than Ligand A (43.311). This is a major advantage for Ligand B.

**Caco-2 Permeability:** Both have negative values, which is unusual. Assuming these are logP-like scales, lower values indicate poorer permeability. Ligand A (-4.785) appears to have worse permeability than Ligand B (-4.46).

**Aqueous Solubility:** Both ligands have negative solubility values, which is also unusual. Lower values indicate poorer solubility. Ligand A (-3.738) appears to have worse solubility than Ligand B (-2.838).

**hERG:** Both ligands have low hERG inhibition liability (Ligand A: 0.391, Ligand B: 0.492), which is good.

**Microsomal Clearance:** Ligand A (33.135) has a slightly higher microsomal clearance than Ligand B (28.86), suggesting lower metabolic stability. This favors Ligand B.

**In vitro Half-Life:** Ligand B (35.711) has a significantly longer in vitro half-life than Ligand A (-4.365). This is a significant advantage for Ligand B.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (Ligand A: 0.077, Ligand B: 0.027).

**Binding Affinity:** Both ligands have excellent binding affinities (Ligand A: -7.7 kcal/mol, Ligand B: -7.5 kcal/mol). The difference of 0.2 kcal/mol is not substantial enough to outweigh other factors.

**Overall:** Ligand B consistently outperforms Ligand A in key properties for a CNS-targeting GPCR ligand: TPSA, BBB penetration, DILI risk, microsomal clearance, and in vitro half-life. While both have good affinity and acceptable logP, Ligand B's superior ADME profile makes it the more promising drug candidate.

Output:
1
2025-04-17 08:16:01,937 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (345.458 Da) is slightly lower, which could be beneficial for permeability. Ligand B (368.463 Da) is also acceptable.

**TPSA:** Ligand A (38.33) is excellent, well below the 90 A^2 threshold for CNS targets. Ligand B (112.12) is higher, but still potentially acceptable, though less ideal for CNS penetration.

**logP:** Ligand A (4.451) is a bit high, potentially leading to solubility issues or off-target interactions, but still within a reasonable range. Ligand B (-1.226) is significantly low, which is a major concern for CNS penetration as it may struggle to cross cell membranes.

**H-Bond Donors/Acceptors:** Ligand A (1 HBD, 2 HBA) is optimal. Ligand B (3 HBD, 7 HBA) is acceptable, but higher values can sometimes negatively impact permeability.

**QED:** Ligand A (0.875) has a very good drug-likeness score. Ligand B (0.556) is acceptable, but lower than Ligand A.

**DILI:** Both ligands have similar, low DILI risk (Ligand A: 36.952, Ligand B: 36.099), indicating a low potential for liver injury.

**BBB:** Ligand A shows excellent BBB penetration (91.857%), highly desirable for a CNS target like DRD2. Ligand B has very poor predicted BBB penetration (20.628%), a critical drawback.

**Caco-2 Permeability:** Ligand A (-4.347) shows poor permeability, which is concerning. Ligand B (-6.116) shows even worse permeability.

**Aqueous Solubility:** Ligand A (-5.094) shows poor solubility. Ligand B (-2.017) shows slightly better solubility, but is still poor.

**hERG Inhibition:** Ligand A (0.763) has a low risk of hERG inhibition. Ligand B (0.049) also shows a low risk.

**Microsomal Clearance:** Ligand A (55.201) has moderate clearance, while Ligand B (-14.61) suggests very low clearance and high metabolic stability, which is advantageous.

**In vitro Half-Life:** Ligand A (36.411) has a reasonable half-life. Ligand B (-7.069) has a very short half-life, which is a significant disadvantage.

**P-gp Efflux:** Ligand A (0.538) shows moderate P-gp efflux, while Ligand B (0.002) shows very low P-gp efflux, which is favorable for CNS exposure.

**Binding Affinity:** Ligand A (-8.7 kcal/mol) has a significantly stronger binding affinity than Ligand B (-7.0 kcal/mol). The 1.7 kcal/mol difference is substantial and can outweigh some ADME drawbacks.

**Overall Assessment:**

Despite Ligand A's poor Caco-2 and solubility, its superior BBB penetration, significantly stronger binding affinity, and good QED make it the more promising candidate. Ligand B's extremely poor BBB penetration and short half-life are major liabilities that are difficult to overcome, even with its better metabolic stability and lower P-gp efflux. The strong binding affinity of Ligand A is a key advantage for a GPCR target.

Output:
0
2025-04-17 08:16:01,937 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (385.266 Da) is slightly higher than Ligand B (360.841 Da), but both are acceptable.

**TPSA:** Both ligands have TPSA values above the ideal 90 A^2 for CNS targets. Ligand A (50.36 A^2) is better than Ligand B (53.76 A^2), but both are reasonably close and not a major concern.

**logP:** Both ligands have logP values within the optimal range (1-3). Ligand A (4.821) is a bit high, potentially leading to solubility issues or off-target interactions. Ligand B (3.556) is closer to the ideal range.

**H-Bond Donors/Acceptors:** Ligand A has 2 HBD and 3 HBA, while Ligand B has 0 HBD and 3 HBA. Both are within acceptable limits (<=5 HBD and <=10 HBA).

**QED:** Both ligands have good QED scores (Ligand A: 0.672, Ligand B: 0.841), indicating drug-like properties. Ligand B is slightly better.

**DILI:** Ligand A has a DILI risk of 68.321%, which is moderately high. Ligand B has a lower DILI risk of 47.964%, which is much more favorable.

**BBB:** This is critical for a CNS target like DRD2. Ligand A has a BBB penetration of 62.97%, which is below the desirable threshold of 70%. Ligand B has a significantly better BBB penetration of 75.572%.

**Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and suggests poor permeability. However, these values are on a scale where negative values are possible.

**Aqueous Solubility:** Both ligands have very poor aqueous solubility (-5.105 and -4.376 respectively). This is a significant concern, especially given Ligand A's higher logP.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.695 and 0.569 respectively).

**Microsomal Clearance:** Ligand A has a higher microsomal clearance (66.051 mL/min/kg) than Ligand B (30.282 mL/min/kg), indicating faster metabolism and potentially lower in vivo exposure.

**In vitro Half-Life:** Ligand A has a longer in vitro half-life (97.012 hours) than Ligand B (47.851 hours), which is a positive attribute.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.496 and 0.454 respectively), which is favorable for CNS penetration.

**Binding Affinity:** Ligand A (-9.2 kcal/mol) has a slightly better binding affinity than Ligand B (-8.4 kcal/mol). However, the difference is not substantial enough to outweigh the significant ADME drawbacks of Ligand A.

**Overall Assessment:**

Ligand B is the more promising candidate. While both have solubility issues, Ligand B has a significantly better BBB penetration, lower DILI risk, lower microsomal clearance, and a more favorable logP. The slightly weaker binding affinity of Ligand B is less concerning than the ADME liabilities of Ligand A, especially for a CNS target.

Output:
1
2025-04-17 08:16:01,937 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (345.443 and 346.431 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (54.04) is significantly better than Ligand B (95.42). For CNS targets, TPSA should be <= 90, and A is comfortably within this range, while B is pushing the limit.

**logP:** Both ligands have acceptable logP values (0.752 and 1.649, respectively), falling within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A has 1 HBD and 5 HBA, while Ligand B has 2 HBD and 5 HBA. Both are within acceptable limits (<=5 HBD and <=10 HBA).

**QED:** Both ligands have good QED scores (0.876 and 0.845), indicating good drug-like properties.

**DILI:** Ligand A (10.237) has a much lower DILI risk than Ligand B (45.25). This is a significant advantage.

**BBB:** Ligand A (72.237) has a better BBB penetration percentile than Ligand B (62.97). While both are reasonably good, A is closer to the desirable >70 threshold for CNS targets.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.67 and -4.837). These values are unusual and suggest poor permeability. However, the scale isn't specified, so it's hard to interpret.

**Aqueous Solubility:** Ligand A (-0.952) is better than Ligand B (-3.018), indicating slightly better solubility.

**hERG Inhibition:** Ligand A (0.709) has a lower hERG inhibition liability than Ligand B (0.228), which is preferable.

**Microsomal Clearance:** Ligand A (11.11) has a significantly lower microsomal clearance than Ligand B (33.17), indicating better metabolic stability.

**In vitro Half-Life:** Ligand A (10.458) has a positive half-life, while Ligand B (-16.633) has a negative half-life, which is nonsensical. This is a major red flag for Ligand B.

**P-gp Efflux:** Ligand A (0.042) has lower P-gp efflux liability than Ligand B (0.031), which is better for CNS exposure.

**Binding Affinity:** Ligand B (-9.7 kcal/mol) has a significantly stronger binding affinity than Ligand A (-7.5 kcal/mol). This is a substantial advantage for Ligand B.

**Overall Assessment:**

While Ligand B has a better binding affinity, Ligand A is superior in almost all other crucial ADME-Tox properties, especially for a CNS target. Ligand A has better TPSA, DILI, BBB, solubility, hERG, metabolic stability, and a reasonable half-life. Ligand B's negative half-life is a critical flaw. The difference in binding affinity (-9.7 vs -7.5) is significant, but the overall profile of Ligand A is more balanced and suggests a higher probability of success as a drug candidate. Considering the GPCR-specific priorities, the better BBB penetration, lower TPSA, and improved ADME properties of Ligand A outweigh the affinity difference.

Output:
0
2025-04-17 08:16:01,937 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (355.364 and 356.256 Da) fall comfortably within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (62.53) is significantly better than Ligand B (87.61). For CNS targets, TPSA should be <= 90, and A is much closer to the optimal <=60 range. B is approaching a less desirable range.

**3. logP:** Both ligands (2.271 and 2.424) are within the optimal 1-3 range.

**4. H-Bond Donors:** Ligand A (1) is preferable to Ligand B (0), as having some HBD can improve solubility.

**5. H-Bond Acceptors:** Ligand B (7) is better than Ligand A (5).

**6. QED:** Ligand A (0.918) is significantly better than Ligand B (0.76), indicating a more drug-like profile.

**7. DILI:** Ligand A (49.05) has a lower DILI risk than Ligand B (88.794), which is a significant advantage.

**8. BBB:** Ligand A (97.208) has excellent BBB penetration, while Ligand B (76.347) is good but less optimal. This is a *critical* factor for a CNS target like DRD2.

**9. Caco-2 Permeability:** Ligand A (-4.707) is better than Ligand B (-4.263), indicating better intestinal absorption.

**10. Aqueous Solubility:** Ligand A (-2.168) is better than Ligand B (-4.218).

**11. hERG Inhibition:** Ligand A (0.853) has a lower hERG risk than Ligand B (0.283).

**12. Microsomal Clearance:** Ligand A (-1.563) has a lower (better) microsomal clearance than Ligand B (84.228), suggesting better metabolic stability.

**13. In vitro Half-Life:** Ligand A (3.339) has a better in vitro half-life than Ligand B (-27.05).

**14. P-gp Efflux:** Ligand A (0.293) has lower P-gp efflux than Ligand B (0.194), which is favorable for CNS penetration.

**15. Binding Affinity:** Both ligands have very similar binding affinities (-8.7 and -8.4 kcal/mol). The difference is not substantial enough to outweigh the numerous ADME advantages of Ligand A.

**Overall Assessment:**

Ligand A consistently outperforms Ligand B across most crucial ADME properties, especially those prioritized for GPCRs targeting the CNS (BBB, TPSA, Pgp). The significantly better BBB penetration, lower DILI risk, better QED, and improved metabolic stability of Ligand A make it the far more promising drug candidate, despite the similar binding affinities.

Output:
0
2025-04-17 08:16:01,938 - INFO - Batch 434 complete. Total preferences: 6944
2025-04-17 08:16:01,938 - INFO - Processing batch 435/512...
2025-04-17 08:16:43,438 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the acceptable range (200-500 Da). Ligand A (367.431 Da) is preferable as it's closer to the optimal range.

**TPSA:** Ligand A (116.42) is better than Ligand B (69.21). For CNS targets, we want TPSA <= 90, and Ligand B is well within this range, while Ligand A is slightly above. However, the difference isn't massive.

**logP:** Ligand B (3.13) is optimal (1-3), while Ligand A (0.023) is quite low and may hinder permeation. This is a significant drawback for Ligand A.

**H-Bond Donors/Acceptors:** Ligand A has 3 HBD and 5 HBA, which are acceptable. Ligand B has 0 HBD and 8 HBA, also acceptable.

**QED:** Both ligands have reasonable QED values (A: 0.689, B: 0.55), indicating good drug-like properties.

**DILI:** Both ligands have similar DILI risk (A: 75.378, B: 74.719), and are within an acceptable range (< 40 is good, >60 is high risk).

**BBB:** Ligand B (74.486) has a significantly better BBB percentile than Ligand A (52.85). This is crucial for a CNS target like DRD2.

**Caco-2 Permeability:** Both have negative Caco-2 values (-5.346 and -5.294), which is unusual and suggests poor permeability. This is a concern for both.

**Aqueous Solubility:** Both have negative solubility values (-2.523 and -3.985), again unusual and suggesting poor solubility.

**hERG:** Ligand A (0.139) has a lower hERG inhibition liability than Ligand B (0.406), which is preferable.

**Microsomal Clearance:** Ligand A (-5.935) has a much lower (better) microsomal clearance than Ligand B (49.122), indicating greater metabolic stability.

**In vitro Half-Life:** Ligand A (-49.152) has a much longer half-life than Ligand B (39.696).

**P-gp Efflux:** Ligand A (0.004) has a much lower P-gp efflux liability than Ligand B (0.464), which is very favorable for CNS penetration.

**Binding Affinity:** Ligand B (-6.3 kcal/mol) has a slightly better binding affinity than Ligand A (-8.5 kcal/mol). However, the difference is not substantial enough to overcome the significant ADME disadvantages of Ligand B.

**Overall Assessment:**

Ligand A has significant advantages in BBB penetration, P-gp efflux, metabolic stability (Cl_mic), and in vitro half-life. While its logP is a concern, its superior CNS penetration properties and metabolic stability, combined with a good binding affinity, make it a more promising candidate. Ligand B's better affinity is outweighed by its poor BBB, higher P-gp efflux, and faster clearance.

Output:
0
2025-04-17 08:16:43,440 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B based on the provided guidelines, prioritizing GPCR-specific properties (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (344.419 Da) is slightly lower, which could be beneficial for permeability, but both are acceptable.

**TPSA:** Ligand A (94.82) is better than Ligand B (50.28) as it is closer to the optimal range for CNS targets (<=90). Ligand B is excellent.

**logP:** Both ligands have good logP values (Ligand A: 2.001, Ligand B: 3.354), falling within the 1-3 range. Ligand B is slightly better.

**H-Bond Donors/Acceptors:** Both have acceptable HBD (1) and Ligand A has 7 HBA and Ligand B has 5 HBA, both are within the recommended limits.

**QED:** Both ligands have good QED scores (Ligand A: 0.861, Ligand B: 0.903), indicating good drug-like properties. Ligand B is slightly better.

**DILI:** Both ligands have acceptable DILI risk (Ligand A: 57.619, Ligand B: 50.911), below the 60 threshold. Ligand B is slightly better.

**BBB:** This is a critical parameter for CNS targets. Ligand B (90.074) is significantly better than Ligand A (61.846), exceeding the desirable >70 threshold.

**Caco-2 Permeability:** Both have negative values, indicating poor permeability.

**Aqueous Solubility:** Both ligands have negative solubility values, indicating poor solubility.

**hERG:** Both ligands have low hERG inhibition liability (Ligand A: 0.19, Ligand B: 0.874), which is favorable.

**Microsomal Clearance:** Both ligands have similar microsomal clearance values (Ligand A: 61.692, Ligand B: 61.861).

**In vitro Half-Life:** Ligand B (27.874) has a significantly longer half-life than Ligand A (-26.776), which is a major advantage.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (Ligand A: 0.056, Ligand B: 0.393), which is good.

**Binding Affinity:** Ligand B (-9.8 kcal/mol) has a significantly stronger binding affinity than Ligand A (-8.5 kcal/mol). This >1.5 kcal/mol difference is substantial and can outweigh minor ADME drawbacks.

**Conclusion:**

Considering the GPCR-specific priorities, Ligand B is the superior candidate. Its significantly better BBB penetration, longer half-life, and stronger binding affinity outweigh the slightly better TPSA of Ligand A. While both have issues with solubility and Caco-2 permeability, the improved CNS exposure potential of Ligand B is crucial for a DRD2 target.

Output:
1
2025-04-17 08:16:43,440 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (407.312 Da) is higher, but still acceptable. Ligand B (343.427 Da) is slightly better.

**TPSA:** Both ligands have TPSA values above the optimal 90 A^2 for CNS targets. Ligand A (79.9 A^2) is better than Ligand B (82.27 A^2), being closer to the desired threshold.

**logP:** Both ligands have good logP values (1-3). Ligand A (3.346) is slightly higher, which *could* indicate potential off-target effects, but is still within range. Ligand B (1.423) is lower, potentially impacting permeability.

**H-Bond Donors/Acceptors:** Both have 2 HBD and are within the acceptable limits. Ligand A has 4 HBA, while Ligand B has 3. Both are acceptable.

**QED:** Both ligands have acceptable QED values (>0.5). Ligand A (0.77) is slightly better than Ligand B (0.553).

**DILI:** Ligand A (53.432) has a moderate DILI risk, while Ligand B (16.44) has a very low DILI risk. This is a significant advantage for Ligand B.

**BBB:** Ligand A (74.952) has a good BBB penetration percentile, exceeding the 70% threshold. Ligand B (42.807) is significantly lower, which is a major drawback for a CNS target like DRD2.

**Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and suggests poor permeability. Ligand A (-4.936) is slightly better than Ligand B (-5.199).

**Aqueous Solubility:** Both have negative solubility values, again unusual. Ligand A (-5.187) is slightly better than Ligand B (-1.685).

**hERG Inhibition:** Both have low hERG inhibition liability, which is good. Ligand A (0.541) is slightly higher than Ligand B (0.206).

**Microsomal Clearance:** Ligand A (61.149) has moderate clearance, while Ligand B (-21.524) has negative clearance, which is not possible and suggests a data error or unusual metabolic behavior.

**In vitro Half-Life:** Ligand A (22.184 hours) has a reasonable half-life. Ligand B (-11.477 hours) has a negative half-life, which is not possible and suggests a data error.

**P-gp Efflux:** Ligand A (0.559) has moderate P-gp efflux liability. Ligand B (0.087) has very low P-gp efflux liability, which is a significant advantage for CNS penetration.

**Binding Affinity:** Ligand B (-8.3 kcal/mol) has a slightly better binding affinity than Ligand A (-7.9 kcal/mol). While the difference is not huge, it's a positive factor.

**Overall Assessment:**

Ligand B has a significantly better safety profile (lower DILI, lower P-gp efflux). It also has a slightly better binding affinity. However, the negative values for Caco-2 permeability, solubility, microsomal clearance and half-life are concerning and likely indicate data issues. Ligand A, while having a higher DILI risk and slightly lower affinity, has more plausible ADME properties. Given the importance of BBB penetration for a CNS target and Ligand A's acceptable BBB value, it is the more viable candidate despite its drawbacks.

Output:
0
2025-04-17 08:16:43,440 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B based on the provided guidelines, prioritizing GPCR-specific properties (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (344.371 and 358.41 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (101.47) is slightly above the optimal <90 for CNS targets, but still reasonable. Ligand B (77.1) is excellent, well below 90.

**logP:** Ligand A (1.536) is within the optimal 1-3 range. Ligand B (0.415) is a bit low, potentially hindering permeation.

**H-Bond Donors/Acceptors:** Both ligands have acceptable HBD (1) and HBA (6/5) counts, within the guidelines.

**QED:** Both ligands have good QED scores (0.903 and 0.788), indicating drug-likeness.

**DILI:** Ligand A (63.513) has a higher DILI risk than Ligand B (49.011), but both are acceptable (<60 is good).

**BBB:** This is crucial for a CNS target like DRD2. Ligand B (83.404) has a significantly better BBB percentile than Ligand A (65.374).

**Caco-2 Permeability:** Ligand A (-5.128) shows poor Caco-2 permeability, while Ligand B (-4.489) is slightly better, but still not great.

**Aqueous Solubility:** Both ligands have very poor aqueous solubility (-2.344 and -1.633). This could pose formulation challenges.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.136 and 0.249).

**Microsomal Clearance:** Ligand B (2.057) has much lower microsomal clearance than Ligand A (31.041), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand B (0.469) has a very short half-life, while Ligand A (-18.198) has a negative value which is unusual and likely indicates a very rapid degradation.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.076 and 0.056), which is good for CNS penetration.

**Binding Affinity:** Ligand B (-7.9 kcal/mol) has a significantly stronger binding affinity than Ligand A (-9.1 kcal/mol). While A is stronger, the difference isn't large enough to overcome the other deficiencies.

**Overall Assessment:**

Ligand B is the more promising candidate. Its superior BBB penetration, lower DILI risk, much better metabolic stability (lower Cl_mic), and significantly stronger binding affinity outweigh its slightly lower logP and poor solubility. Ligand A's poor Caco-2 permeability and very rapid degradation (negative half-life) are major drawbacks. While both have solubility issues, this can be addressed with formulation strategies. The combination of CNS penetration and metabolic stability makes Ligand B the better choice.

Output:
1
2025-04-17 08:16:43,441 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (341.382 Da) is slightly lower, which could be beneficial for permeability. Ligand B (350.459 Da) is also good.

**TPSA:** Ligand A (55.4) is excellent, well below the 90 A^2 threshold for CNS targets. Ligand B (78.87) is still reasonable but less optimal, potentially hindering BBB penetration.

**logP:** Ligand A (4.072) is at the higher end of the optimal range, potentially causing solubility issues or off-target interactions. Ligand B (0.79) is quite low, which could significantly limit its ability to cross cell membranes, including the BBB.

**H-Bond Donors/Acceptors:** Ligand A (HBD=1, HBA=3) is favorable. Ligand B (HBD=2, HBA=4) is also acceptable.

**QED:** Ligand A (0.806) has a strong drug-like profile. Ligand B (0.635) is still reasonable, but less ideal.

**DILI:** Ligand A (76.115) has a higher DILI risk than Ligand B (12.369). This is a concern for Ligand A.

**BBB:** Ligand A (79.721) exhibits excellent BBB penetration potential. Ligand B (46.84) is significantly lower, a major drawback for a CNS target like DRD2.

**Caco-2 Permeability:** Ligand A (-4.326) has poor Caco-2 permeability. Ligand B (-4.783) is also poor.

**Aqueous Solubility:** Ligand A (-5.229) has poor solubility. Ligand B (-1.397) is also poor.

**hERG:** Both ligands show very low hERG inhibition liability (0.255 and 0.205, respectively).

**Microsomal Clearance:** Ligand A (69.679) has moderate clearance. Ligand B (14.475) has very low clearance, indicating better metabolic stability.

**In vitro Half-Life:** Ligand B (12.562 hours) has a longer half-life than Ligand A (7.812 hours).

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.396 and 0.017, respectively). Ligand B is better.

**Binding Affinity:** Ligand B (-7.7 kcal/mol) has a significantly stronger binding affinity than Ligand A (-9.0 kcal/mol). This is a substantial advantage.

**Overall Assessment:**

While Ligand A has better TPSA and BBB penetration, its high logP, poor solubility, poor Caco-2 permeability, and higher DILI risk are significant concerns. Ligand B, despite its lower BBB penetration, has a much stronger binding affinity, better metabolic stability (lower Cl_mic, longer t1/2), lower DILI risk, and lower P-gp efflux. The significantly improved binding affinity of Ligand B (-7.7 vs -9.0 kcal/mol) is a major advantage that can potentially outweigh its lower BBB score, especially with further optimization. Given the GPCR-specific priorities, the stronger affinity and improved ADME properties (lower DILI, better metabolic stability) make Ligand B the more promising candidate.

Output:
1
2025-04-17 08:16:43,441 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (354.447 and 346.387 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (88.1) is excellent, falling well below the 90 Angstroms threshold for CNS targets. Ligand B (101.46) is still reasonable but less optimal.

**logP:** Ligand A (0.511) is a bit low, potentially hindering permeability. Ligand B (1.198) is better, falling within the 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A (2 HBD, 5 HBA) is good. Ligand B (1 HBD, 7 HBA) is also acceptable.

**QED:** Both ligands have good QED scores (0.696 and 0.843), indicating drug-like properties.

**DILI:** Ligand A (13.61) has a significantly lower DILI risk than Ligand B (58.046), a major advantage.

**BBB:** Ligand A (70.686) has a good BBB penetration percentile, exceeding the 70% threshold for CNS targets. Ligand B (47.111) is considerably lower and less desirable.

**Caco-2 Permeability:** Both have negative Caco-2 values (-4.82 and -4.813), which is unusual and suggests poor permeability. This is a concern for both.

**Aqueous Solubility:** Both have negative solubility values (-1.167 and -2.485), which is also unusual and suggests poor solubility. This is a concern for both.

**hERG Inhibition:** Both ligands show very low hERG inhibition risk (0.188 and 0.041).

**Microsomal Clearance:** Ligand A (15.281) has a higher microsomal clearance than Ligand B (0.185), meaning it's likely to be metabolized faster. Ligand B appears to have excellent metabolic stability.

**In vitro Half-Life:** Ligand A (19.414 hours) has a reasonable half-life. Ligand B (-4.916 hours) is problematic, indicating very rapid degradation.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.042 and 0.053), which is favorable for CNS penetration.

**Binding Affinity:** Ligand B (-8.5 kcal/mol) has a slightly better binding affinity than Ligand A (-8.1 kcal/mol), but the difference is not substantial enough to overcome other significant drawbacks.

**Overall Assessment:**

Ligand A is the better candidate. While its logP is slightly low, it excels in crucial areas for a CNS-targeting GPCR ligand: excellent TPSA, good BBB penetration, and a significantly lower DILI risk. Ligand B, despite its slightly better affinity, suffers from poor BBB penetration, a higher DILI risk, and a very short in vitro half-life. The negative Caco-2 and solubility values are concerning for both, but can be addressed with formulation strategies.

Output:
1
2025-04-17 08:16:43,441 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B based on the provided guidelines, prioritizing GPCR-specific properties (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (352.519 Da) is slightly lower, which could be beneficial for permeability.

**TPSA:** Ligand A (67.43) is significantly better than Ligand B (120.85). For CNS targets, TPSA should be <=90, and Ligand A is comfortably within this range, while Ligand B exceeds it. This is a major advantage for Ligand A.

**logP:** Ligand A (3.171) is optimal (1-3), while Ligand B (-0.261) is quite low, potentially hindering permeation. This is a significant drawback for Ligand B.

**H-Bond Donors/Acceptors:** Both have acceptable HBD counts (2). Ligand B has a higher HBA count (6 vs 3), but both are within reasonable limits.

**QED:** Both ligands have similar QED values (0.626 and 0.552), indicating reasonable drug-likeness.

**DILI:** Ligand A (16.169) has a much lower DILI risk than Ligand B (55.758). This is a substantial advantage for Ligand A.

**BBB:** Ligand A (72.586) has a good BBB percentile, exceeding the 70% threshold for CNS targets. Ligand B (41.76) is significantly lower, making CNS penetration less likely. This is a critical advantage for Ligand A.

**Caco-2 Permeability:** Ligand A (-4.504) has a negative value, which is unusual and suggests poor permeability. Ligand B (-5.36) is also poor, but slightly worse.

**Aqueous Solubility:** Ligand A (-2.996) and Ligand B (-1.75) both have negative solubility values, indicating poor solubility.

**hERG:** Both ligands have low hERG inhibition liability (0.554 and 0.125), which is good.

**Microsomal Clearance:** Ligand A (41.151) has a slightly higher clearance than Ligand B (34.298), suggesting lower metabolic stability.

**In vitro Half-Life:** Ligand B (-8.297) has a longer half-life than Ligand A (-5.42), which is preferable.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.16 and 0.087), which is good for CNS exposure.

**Binding Affinity:** Ligand A (-7.9) has a slightly better binding affinity than Ligand B (-7.0). While both are good, the 0.9 kcal/mol difference is meaningful.

**Overall Assessment:**

Ligand A is significantly better suited as a drug candidate for DRD2, a CNS target. Its superior TPSA, logP, BBB penetration, and lower DILI risk are crucial advantages. While its Caco-2 permeability and aqueous solubility are poor, these can potentially be addressed with formulation strategies. The slightly better binding affinity also contributes to its favorability. Ligand B's low logP and poor BBB penetration are major drawbacks for a CNS-targeting drug.



Output:
1
2025-04-17 08:16:43,441 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (352.431 and 351.363 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (76.15) is excellent, well below the 90 A^2 threshold for CNS targets. Ligand B (130.6) is higher, but still potentially acceptable, though less ideal.

**logP:** Ligand A (0.673) is a bit low, potentially hindering permeability. Ligand B (-0.014) is even lower, raising concerns about membrane penetration.

**H-Bond Donors/Acceptors:** Ligand A (0 HBD, 5 HBA) is favorable. Ligand B (2 HBD, 7 HBA) is also reasonable, though slightly higher.

**QED:** Ligand A (0.68) is good, indicating drug-likeness. Ligand B (0.421) is lower, suggesting a less optimal drug-like profile.

**DILI:** Ligand A (25.475) has a very low DILI risk. Ligand B (64.366) is higher, indicating a moderate risk of liver injury.

**BBB:** Ligand A (69.562) is reasonably good for BBB penetration, close to the desirable >70% threshold. Ligand B (57.968) is lower, which is a significant drawback for a CNS target like DRD2.

**Caco-2 Permeability:** Ligand A (-4.479) has poor Caco-2 permeability. Ligand B (-5.006) is even worse.

**Aqueous Solubility:** Ligand A (-1.859) has poor solubility. Ligand B (-2.592) is even worse.

**hERG:** Both ligands (0.345 and 0.118) show low hERG inhibition liability, which is positive.

**Microsomal Clearance:** Ligand A (67.792) has moderate clearance. Ligand B (13.626) has very low clearance, indicating better metabolic stability.

**In vitro Half-Life:** Ligand A (-1.592) has a short half-life. Ligand B (3.724) has a longer half-life, which is preferable.

**P-gp Efflux:** Both ligands (0.039 and 0.116) show low P-gp efflux, which is good for CNS penetration.

**Binding Affinity:** Ligand B (-8.2 kcal/mol) has significantly stronger binding affinity than Ligand A (-6.8 kcal/mol). This is a substantial advantage, potentially outweighing some of its ADME shortcomings.

**Overall Assessment:**

Ligand B has a much stronger binding affinity, which is paramount for GPCR targets. While its logP is low and Caco-2 permeability and solubility are poor, the superior affinity and lower clearance/longer half-life are compelling. Ligand A has better TPSA and DILI, but its weaker affinity and poor permeability are significant drawbacks. The BBB penetration of Ligand A is better than B, but the affinity difference is substantial. Given the CNS target, the stronger affinity of Ligand B is likely to translate to greater efficacy, even with less favorable permeability.

Output:
1
2025-04-17 08:16:43,442 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 drug candidates, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (369.511 and 368.365 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (37.38) is excellent, well below the 90 A^2 threshold for CNS targets. Ligand B (95.42) is higher, but still potentially acceptable, though less ideal.

**logP:** Ligand A (4.688) is slightly high, potentially leading to solubility issues or off-target effects. Ligand B (0.822) is quite low, which could hinder membrane permeability and CNS penetration.

**H-Bond Donors/Acceptors:** Ligand A (0 HBD, 3 HBA) is favorable. Ligand B (2 HBD, 6 HBA) is also acceptable.

**QED:** Both ligands have good QED scores (0.672 and 0.833), indicating good drug-like properties.

**DILI:** Both ligands have acceptable DILI risk (79.682 and 74.098), below the concerning threshold of 60.

**BBB:** Ligand A has a very high BBB penetration score (78.907), which is excellent for a CNS target like DRD2. Ligand B's BBB score (43.854) is significantly lower and less desirable.

**Caco-2 Permeability:** Both have negative Caco-2 values (-5.096 and -4.904), which is unusual and suggests poor permeability. However, these values are on a log scale, and negative values are not uncommon, indicating low permeability.

**Aqueous Solubility:** Both ligands have very poor aqueous solubility (-6.238 and -2.451). This is a significant drawback.

**hERG Inhibition:** Ligand A (0.831) has a slightly higher hERG risk than Ligand B (0.285), but both are relatively low.

**Microsomal Clearance:** Ligand B (-15.681) has a much lower (better) microsomal clearance than Ligand A (68.287), indicating greater metabolic stability.

**In vitro Half-Life:** Ligand A (34.372) has a longer half-life than Ligand B (14.148).

**P-gp Efflux:** Ligand A (0.73) has a higher P-gp efflux liability than Ligand B (0.169), which is unfavorable for CNS penetration.

**Binding Affinity:** Both ligands have excellent binding affinities (-9.5 and -8.9 kcal/mol). The difference of 0.6 kcal/mol is not substantial enough to override other significant differences.

**Overall Assessment:**

Ligand A excels in BBB penetration, TPSA, and in vitro half-life. However, its high logP and P-gp efflux liability are concerning. Ligand B has better metabolic stability (lower Cl_mic) and lower P-gp efflux, but suffers from poor BBB penetration and a lower logP which may hinder CNS entry. Given the importance of BBB penetration for a CNS target like DRD2, and the relatively small difference in binding affinity, Ligand A is the more promising candidate despite its drawbacks. Solubility is a concern for both, but can potentially be addressed with formulation strategies.

Output:
0
2025-04-17 08:16:43,442 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 drug candidates, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (381.347 Da) is slightly higher than Ligand B (353.379 Da), but both are acceptable.

**TPSA:** Ligand A (32.34) is excellent for CNS penetration, well below the 90 A^2 threshold. Ligand B (130.68) is higher, approaching the 140 A^2 limit for oral absorption and potentially hindering BBB penetration.

**logP:** Ligand A (4.609) is a bit high, potentially leading to solubility issues or off-target interactions. Ligand B (-0.675) is too low, which could impede membrane permeability and reduce brain exposure.

**H-Bond Donors/Acceptors:** Ligand A (1 HBD, 2 HBA) is optimal. Ligand B (4 HBD, 6 HBA) is acceptable, but higher values can sometimes reduce permeability.

**QED:** Ligand A (0.812) is excellent, indicating strong drug-likeness. Ligand B (0.326) is poor, suggesting potential issues with developability.

**DILI:** Ligand A (31.059) has a low DILI risk. Ligand B (56.727) has a moderate DILI risk, but is still within acceptable limits.

**BBB:** Ligand A (81.078) has good BBB penetration potential. Ligand B (70.919) is acceptable, but less desirable for a CNS target.

**Caco-2:** Both ligands have negative Caco-2 values, which is unusual and difficult to interpret. However, the magnitude suggests Ligand A (-4.945) may have slightly better permeability than Ligand B (-5.538).

**Solubility:** Both ligands have negative solubility values, which is also unusual. Ligand B (-1.333) appears to have slightly better solubility than Ligand A (-4.589).

**hERG:** Ligand A (0.768) has a lower hERG risk than Ligand B (0.14).

**Microsomal Clearance:** Ligand A (42.587) has moderate clearance, while Ligand B (-13.767) has very low (and potentially unrealistic) clearance.

**In vitro Half-Life:** Ligand A (42.117) has a moderate half-life. Ligand B (27.633) has a shorter half-life.

**Pgp Efflux:** Ligand A (0.588) has moderate Pgp efflux, while Ligand B (0.004) has very low Pgp efflux, which is highly desirable for CNS penetration.

**Binding Affinity:** Ligand B (-7.8 kcal/mol) has a slightly better binding affinity than Ligand A (-7.4 kcal/mol). The difference is 1.5 kcal/mol, which is significant.

**Overall Assessment:**

Ligand B has a superior binding affinity and very low Pgp efflux, which are crucial for CNS GPCR targets. However, it suffers from a low logP and a poor QED score. Ligand A has a better logP, QED, and DILI profile, and good BBB penetration, but its affinity is slightly weaker.

Given the emphasis on BBB penetration, logP, Pgp, and affinity for DRD2 (a CNS GPCR), and the significant affinity advantage of Ligand B (1.5 kcal/mol), I would prioritize Ligand B despite its lower QED and logP. The low Pgp efflux is a major advantage. Further optimization could address the logP and QED issues.

Output:
1
2025-04-17 08:16:43,442 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (350.394 and 356.413 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (78.67) is better than Ligand B (49.85). For CNS targets, we want TPSA <= 90, both are within this range, but A is closer to the upper limit.

**logP:** Ligand A (0.532) is lower than the optimal 1-3 range, potentially hindering permeation. Ligand B (2.423) is within the optimal range. This is a significant advantage for Ligand B.

**H-Bond Donors/Acceptors:** Ligand A has 1 HBD and 5 HBA, while Ligand B has 0 HBD and 3 HBA. Both are within acceptable limits (<=5 HBD and <=10 HBA).

**QED:** Both ligands have similar QED values (0.786 and 0.704), indicating good drug-likeness.

**DILI:** Ligand A (29.081) has a slightly higher DILI risk than Ligand B (22.722), but both are below the concerning threshold of 60.

**BBB:** This is crucial for a CNS target like DRD2. Ligand A (43.583) has a poor BBB percentile, while Ligand B (97.131) is excellent, exceeding the desirable >70 threshold. This is a major advantage for Ligand B.

**Caco-2 Permeability:** Ligand A (-4.839) and Ligand B (-4.241) both have negative values, indicating poor permeability.

**Aqueous Solubility:** Ligand A (-0.571) and Ligand B (-2.694) both have negative values, indicating poor solubility.

**hERG Inhibition:** Ligand A (0.334) and Ligand B (0.461) have low hERG inhibition risk, which is good.

**Microsomal Clearance:** Ligand A (1.474) has a much lower microsomal clearance than Ligand B (42.444), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (-16.51) has a negative half-life, which is not possible and likely indicates a very short half-life. Ligand B (-9.142) also has a negative half-life, but is slightly better.

**P-gp Efflux:** Ligand A (0.042) has a much lower P-gp efflux liability than Ligand B (0.124), which is favorable for CNS penetration.

**Binding Affinity:** Ligand A (-7.7) has a slightly better binding affinity than Ligand B (-6.7), a difference of 1 kcal/mol. While a 1.5 kcal/mol difference would be more impactful, this difference is worth considering.

**Overall Assessment:**

Ligand B clearly outperforms Ligand A due to its significantly better BBB penetration (97.131 vs. 43.583) and optimal logP (2.423 vs. 0.532). While Ligand A has slightly better affinity and lower clearance, the BBB and logP are critical for CNS drug development, outweighing these benefits. The negative half-life values are concerning for both, but the overall profile of B is more promising.

Output:
1
2025-04-17 08:16:43,442 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (366.483 and 366.527 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (77.52) is better than Ligand B (78.43). Both are below the 90 A^2 threshold desirable for CNS targets, but closer to the 140 A^2 threshold for oral absorption.

**3. logP:** Both ligands have good logP values (2.57 and 2.685), falling within the optimal 1-3 range.

**4. H-Bond Donors:** Ligand A (1) is preferable to Ligand B (3). Lower HBD generally improves permeability.

**5. H-Bond Acceptors:** Ligand A (6) is preferable to Ligand B (4). Lower HBA generally improves permeability.

**6. QED:** Ligand A (0.829) has a significantly better QED score than Ligand B (0.588), indicating a more drug-like profile.

**7. DILI:** Ligand A (65.452) has a higher DILI risk than Ligand B (23.575). This is a significant drawback for Ligand A.

**8. BBB:** Ligand A (65.064) has a better BBB percentile than Ligand B (50.446), which is crucial for a CNS target like DRD2.

**9. Caco-2 Permeability:** Ligand A (-4.869) has better Caco-2 permeability than Ligand B (-5.066).

**10. Aqueous Solubility:** Ligand A (-3.389) has better aqueous solubility than Ligand B (-2.971).

**11. hERG Inhibition:** Ligand A (0.143) has a lower hERG inhibition risk than Ligand B (0.383).

**12. Microsomal Clearance:** Ligand B (72.952) has lower microsomal clearance than Ligand A (88.536), suggesting better metabolic stability.

**13. In vitro Half-Life:** Ligand B (21.214) has a much longer in vitro half-life than Ligand A (-1.878). This is a significant advantage for Ligand B.

**14. P-gp Efflux:** Ligand A (0.171) has lower P-gp efflux than Ligand B (0.16).

**15. Binding Affinity:** Ligand B (-7.5 kcal/mol) has a slightly better binding affinity than Ligand A (-7.3 kcal/mol). While the difference is small, it's still a factor.

**Overall Assessment:**

Ligand A has advantages in BBB, solubility, hERG, and P-gp efflux, but suffers from higher DILI risk, poorer metabolic stability (higher Cl_mic, shorter t1/2), and a lower QED score. Ligand B has a better safety profile (lower DILI), better metabolic stability, a longer half-life, and slightly better binding affinity. Considering the importance of metabolic stability and safety for a CNS drug, and the relatively small difference in binding affinity, Ligand B appears to be the more promising candidate.

Output:
1
2025-04-17 08:16:43,443 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (348.531 and 348.487 Da) are within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (49.41) is significantly better than Ligand B (69.64). For CNS targets, we want TPSA <= 90, and ideally lower. Ligand A is well within this range, while Ligand B is approaching the upper limit, potentially hindering BBB penetration.

**3. logP:** Ligand A (4.056) is slightly higher than the optimal range (1-3), but still acceptable. Ligand B (2.534) is within the optimal range. However, for a GPCR, some degree of lipophilicity is beneficial for membrane interactions, so A isn't severely penalized here.

**4. H-Bond Donors:** Ligand A (1) is preferable to Ligand B (2). Fewer H-bond donors generally improve permeability.

**5. H-Bond Acceptors:** Ligand A (2) is preferable to Ligand B (3) for the same reason as above.

**6. QED:** Both ligands have similar QED values (0.762 and 0.695), indicating good drug-like properties.

**7. DILI:** Ligand A (22.024) has a much lower DILI risk than Ligand B (12.524). This is a significant advantage.

**8. BBB:** Ligand A (84.529) has a substantially better BBB penetration percentile than Ligand B (68.554). This is *critical* for a CNS target like DRD2.

**9. Caco-2 Permeability:** Ligand A (-4.625) has a slightly better Caco-2 permeability than Ligand B (-4.823), but the difference is minimal.

**10. Aqueous Solubility:** Ligand A (-4.444) has better aqueous solubility than Ligand B (-2.478).

**11. hERG Inhibition:** Both ligands show low hERG inhibition risk (0.505 and 0.298).

**12. Microsomal Clearance:** Ligand B (21.737) has lower microsomal clearance than Ligand A (68.272), suggesting better metabolic stability. This is a point in favor of Ligand B.

**13. In vitro Half-Life:** Ligand B (22.698) has a much longer in vitro half-life than Ligand A (-11.208). This is a significant advantage for Ligand B.

**14. P-gp Efflux:** Ligand A (0.38) shows lower P-gp efflux than Ligand B (0.112), which is favorable for CNS penetration.

**15. Binding Affinity:** Both ligands have excellent binding affinity (-8.7 and -8.0 kcal/mol). The difference of 0.7 kcal/mol is not substantial enough to outweigh the other significant differences.

**Overall Assessment:**

Ligand A is superior due to its significantly better TPSA, BBB penetration, lower DILI risk, better solubility, and lower P-gp efflux. While Ligand B has better metabolic stability (lower Cl_mic and higher t1/2), the CNS target prioritization makes the improved brain penetration of Ligand A more important. The small difference in binding affinity doesn't outweigh the substantial ADME advantages of Ligand A.

Output:
1
2025-04-17 08:16:43,443 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (349.475 Da) is slightly lower, which could be beneficial for permeability.

**TPSA:** Ligand A (53.09) is excellent for CNS penetration, well below the 90 A^2 threshold. Ligand B (93.22) is higher, but still potentially acceptable, though less ideal.

**logP:** Ligand A (0.958) is at the lower end of the optimal range (1-3), potentially impacting permeability. Ligand B (0.085) is quite low, raising concerns about membrane permeability and potentially limiting brain exposure.

**H-Bond Donors/Acceptors:** Both ligands have a reasonable number of HBDs (0) and HBAs (4 for A, 6 for B), falling within acceptable limits.

**QED:** Ligand A (0.759) has a better QED score than Ligand B (0.557), indicating a more drug-like profile.

**DILI:** Ligand A (6.282) has a very low DILI risk, significantly better than Ligand B (35.789).

**BBB:** Both ligands have good BBB penetration (A: 75.184, B: 78.868), exceeding the 70% threshold for CNS targets.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.599 and -4.713), which is unusual and suggests poor permeability. This is a significant concern for both.

**Aqueous Solubility:** Both ligands have negative solubility values (-0.296 and -0.902), which is also concerning. Poor solubility can hinder absorption and bioavailability.

**hERG Inhibition:** Both ligands show low hERG inhibition risk (A: 0.264, B: 0.368).

**Microsomal Clearance:** Ligand A (17.543) has a much lower microsomal clearance than Ligand B (68.788), indicating better metabolic stability.

**In vitro Half-Life:** Ligand A (6.473) has a better in vitro half-life than Ligand B (-35.963).

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (A: 0.014, B: 0.037), which is favorable for CNS exposure.

**Binding Affinity:** Ligand A (-8.5 kcal/mol) has a significantly stronger binding affinity than Ligand B (-6.1 kcal/mol). This is a substantial advantage, potentially outweighing some of the ADME concerns.

**Overall Assessment:**

Ligand A is clearly the better candidate. While both have issues with Caco-2 permeability and solubility, Ligand A's superior binding affinity, lower DILI risk, better metabolic stability (lower Cl_mic, longer t1/2), and higher QED score make it more promising. The slightly lower logP of Ligand A is less concerning than the very low logP of Ligand B. The strong binding affinity of Ligand A suggests it might be able to achieve efficacy even with some permeability limitations.

Output:
1
2025-04-17 08:16:43,443 - INFO - Reasoning:

Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (347.415 and 361.471 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (114.43) is slightly above the optimal <90 for CNS targets, but still reasonable. Ligand B (88.39) is excellent, well below 90. This favors Ligand B.

**3. logP:** Both ligands have good logP values (1.648 and 1.353), falling within the 1-3 range.

**4. H-Bond Donors:** Ligand A has 3 HBD, which is acceptable. Ligand B has 2, also acceptable.

**5. H-Bond Acceptors:** Ligand A has 4 HBA, within the limit. Ligand B has 6, still acceptable but approaching the upper limit.

**6. QED:** Both ligands have reasonable QED scores (0.49 and 0.777), with Ligand B being significantly better, indicating a more drug-like profile.

**7. DILI:** Ligand A (35.905) has a much lower DILI risk than Ligand B (69.717). This is a significant advantage for Ligand A.

**8. BBB:** Ligand A (52.579) has a lower BBB percentile than Ligand B (61.691). While neither is *high* (>70), Ligand B is better for CNS penetration.

**9. Caco-2:** Both have negative Caco-2 values, which is unusual and suggests poor permeability. This is a concern for both.

**10. Solubility:** Both ligands have negative solubility values, indicating poor aqueous solubility. This is a significant drawback for both.

**11. hERG:** Both ligands have very low hERG inhibition liability (0.197 and 0.301), which is excellent.

**12. Cl_mic:** Both ligands have similar microsomal clearance values (33.089 and 36.407), suggesting comparable metabolic stability.

**13. t1/2:** Ligand B has a significantly longer in vitro half-life (11.061 hours) than Ligand A (1.197 hours). This is a major advantage for Ligand B.

**14. Pgp:** Both ligands have very low Pgp efflux liability (0.045 and 0.036), which is good for CNS exposure.

**15. Binding Affinity:** Ligand B (-8.4 kcal/mol) has a slightly better binding affinity than Ligand A (-8.1 kcal/mol). While the difference is small, it's still a positive for Ligand B.

**Overall Assessment:**

Ligand B is preferable. While Ligand A has a better DILI score, Ligand B excels in several key areas for a CNS-targeting GPCR ligand: better TPSA, higher QED, better BBB penetration, and a longer half-life. The slightly stronger binding affinity of Ligand B is also a plus. The poor Caco-2 and solubility are concerning for both, but these can potentially be addressed through formulation strategies. The small advantage in affinity combined with the better ADME properties makes Ligand B the more promising candidate.

Output:
1
2025-04-17 08:16:43,443 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (338.451 Da) is slightly lower, which could be beneficial for permeability.

**TPSA:** Ligand A (53.43) is significantly better than Ligand B (87.22). For CNS targets, we want TPSA <= 90, and A is comfortably within that range, while B is approaching the upper limit.

**logP:** Ligand A (3.564) is optimal (1-3), while Ligand B (0.916) is a bit low. Lower logP can hinder permeation.

**H-Bond Donors/Acceptors:** Ligand A (HBD=1, HBA=3) is better than Ligand B (HBD=2, HBA=5). Both are within acceptable limits, but fewer H-bonds generally favor permeability.

**QED:** Ligand A (0.911) is excellent, indicating high drug-likeness. Ligand B (0.756) is still good, but not as strong.

**DILI:** Ligand A (25.281) has a much lower DILI risk than Ligand B (58.744). This is a significant advantage.

**BBB:** Ligand A (84.529) has a better BBB penetration percentile than Ligand B (79.488). Both are reasonably good, but A is closer to the desirable >70 threshold for CNS targets.

**Caco-2 Permeability:** Both have negative values, which is unusual and suggests poor permeability. However, the scale is not specified, so it's hard to interpret.

**Aqueous Solubility:** Both have negative values, which again is unusual and suggests poor solubility.

**hERG:** Ligand A (0.823) has a lower hERG risk than Ligand B (0.228). Lower is better here.

**Microsomal Clearance:** Both have similar microsomal clearance (around 32 mL/min/kg), indicating comparable metabolic stability.

**In vitro Half-Life:** Ligand A (24.616 hours) has a significantly longer half-life than Ligand B (-15.911 hours). This is a major advantage.

**P-gp Efflux:** Ligand A (0.482) has lower P-gp efflux liability than Ligand B (0.006). Lower is better, especially for CNS targets.

**Binding Affinity:** Ligand A (-9.3 kcal/mol) has a substantially stronger binding affinity than Ligand B (-7.5 kcal/mol). This difference of 1.8 kcal/mol is significant and can outweigh some ADME drawbacks.

**Overall Assessment:**

Ligand A consistently outperforms Ligand B across most critical parameters, especially for a CNS target like DRD2. It has better TPSA, logP, DILI risk, BBB penetration, hERG risk, half-life, P-gp efflux, and *significantly* better binding affinity. While both have issues with Caco-2 and solubility, the superior binding and ADME properties of Ligand A make it a much more promising drug candidate.

Output:
1
2025-04-17 08:16:43,443 - INFO - Batch 435 complete. Total preferences: 6960
2025-04-17 08:16:43,444 - INFO - Processing batch 436/512...
2025-04-17 08:17:22,770 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (348.368 and 348.487 Da) fall comfortably within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (41.99) is significantly better than Ligand B (49.85). For CNS targets, we want TPSA <= 90, and ideally lower. Ligand A is much closer to the optimal range.

**3. logP:** Ligand A (4.88) is slightly higher than the optimal 1-3 range, but still potentially acceptable. Ligand B (3.101) is within the ideal range. However, for a GPCR, a slightly higher logP can be tolerated if other properties are favorable.

**4. H-Bond Donors:** Ligand A (1) is good. Ligand B (0) is also good.

**5. H-Bond Acceptors:** Ligand A (2) is good. Ligand B (3) is also acceptable.

**6. QED:** Both ligands have similar QED values (0.856 and 0.784), indicating good drug-likeness.

**7. DILI:** Ligand A (59.131) has a higher DILI risk than Ligand B (25.165). This is a significant negative for Ligand A.

**8. BBB:** Both ligands have excellent BBB penetration (86.39 and 83.482), exceeding the desirable >70 threshold for CNS targets.

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 values, which is unusual and suggests a potential issue with the data or modeling. However, the values are similar, so this doesn't strongly differentiate them.

**10. Aqueous Solubility:** Both ligands have very poor aqueous solubility (-5.971 and -2.866). This is a concern, but can sometimes be overcome with formulation strategies.

**11. hERG Inhibition:** Both ligands have low hERG inhibition liability (0.719 and 0.372), which is good.

**12. Microsomal Clearance:** Ligand B (83.227) has significantly higher microsomal clearance than Ligand A (55.35). Lower clearance is preferred for better metabolic stability.

**13. In vitro Half-Life:** Ligand A (26.64) has a longer half-life than Ligand B (-7.639). This is a positive for Ligand A.

**14. P-gp Efflux:** Both ligands have low P-gp efflux liability (0.407 and 0.486), which is good for CNS penetration.

**15. Binding Affinity:** Both ligands have very strong binding affinity (-9.9 and -8.9 kcal/mol). Ligand A has a 1 kcal/mol advantage, which is substantial.

**Overall Assessment:**

Ligand A has a better TPSA, longer half-life, and significantly better binding affinity. However, it has a higher DILI risk and slightly higher logP. Ligand B has a better logP, lower DILI risk, and better metabolic stability (lower Cl_mic), but its binding affinity is weaker.

Given the GPCR-specific priorities, the strong binding affinity of Ligand A is a major advantage. The slightly higher logP and DILI risk are potentially manageable with further optimization. The TPSA is also favorable. The longer half-life is also a plus.

Output:
1
2025-04-17 08:17:22,770 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (331.375 Da) is slightly better than Ligand B (365.459 Da) as it is closer to the lower end of the range.

**TPSA:** Ligand A (74.89) is excellent, well below the 90 A^2 threshold for CNS targets. Ligand B (115.24) is higher, but still potentially acceptable, though less ideal.

**logP:** Ligand A (3.129) is optimal. Ligand B (1.647) is on the lower side of the optimal range, potentially leading to permeability issues.

**H-Bond Donors/Acceptors:** Both ligands have acceptable HBD (1) and HBA (4/5) counts.

**QED:** Ligand A (0.801) has a very good drug-likeness score. Ligand B (0.453) is below the desirable threshold of 0.5.

**DILI:** Ligand A (84.994) has a higher DILI risk than Ligand B (44.824). This is a concern for Ligand A.

**BBB:** Ligand A (68.786) has a moderate BBB penetration, while Ligand B (28.228) is quite low. For a CNS target like DRD2, BBB penetration is crucial, making Ligand A more favorable.

**Caco-2 Permeability:** Ligand A (-4.846) and Ligand B (-5.334) both have negative values, which is unusual and indicates very poor permeability. This is a significant drawback for both.

**Aqueous Solubility:** Ligand A (-5.19) and Ligand B (-2.181) both have negative solubility values, indicating very poor solubility. This is a significant drawback for both.

**hERG Inhibition:** Ligand A (0.817) has a slightly higher hERG risk than Ligand B (0.029). Ligand B is much safer in this regard.

**Microsomal Clearance:** Ligand A (71.398) has a higher clearance than Ligand B (19.473), suggesting lower metabolic stability.

**In vitro Half-Life:** Ligand A (50.363) has a better half-life than Ligand B (-16.047).

**P-gp Efflux:** Ligand A (0.504) has lower P-gp efflux liability than Ligand B (0.042), which is favorable for CNS penetration.

**Binding Affinity:** Ligand B (-7.8 kcal/mol) has a significantly stronger binding affinity than Ligand A (-9.3 kcal/mol). This is a substantial advantage for Ligand B.

**Overall Assessment:**

While Ligand A has better BBB penetration and P-gp efflux, Ligand B's significantly stronger binding affinity (-7.8 vs -9.3 kcal/mol) is a major advantage that can potentially overcome some of its ADME shortcomings. Ligand B also has a lower DILI risk and hERG inhibition liability. Both compounds have poor Caco-2 permeability and aqueous solubility, which would require formulation strategies. However, the binding affinity difference is substantial enough to favor Ligand B.

Output:
1
2025-04-17 08:17:22,770 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B based on the provided guidelines, prioritizing GPCR-specific properties (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (349.519 and 352.475 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (73.2) is higher than Ligand B (59.08). For CNS targets, TPSA should be <=90, both are within this range, but B is better.

**logP:** Ligand A (3.496) is slightly higher than Ligand B (1.681). Both are within the optimal 1-3 range, but B is closer to the lower end, which could potentially impact permeability.

**H-Bond Donors/Acceptors:** Ligand A has 1 HBD and 3 HBA, while Ligand B has 0 HBD and 4 HBA. Both are within acceptable limits.

**QED:** Ligand A (0.682) has a better QED score than Ligand B (0.443), indicating better overall drug-likeness.

**DILI:** Ligand A (10.469) has a significantly lower DILI risk than Ligand B (12.641), which is a strong advantage.

**BBB:** Both ligands have excellent BBB penetration (Ligand A: 77.239, Ligand B: 79.488), exceeding the desirable >70 threshold for CNS targets. Ligand B is slightly better.

**Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual. Assuming these are logP values, both are poor.

**Aqueous Solubility:** Both ligands have negative solubility values, which is also unusual.

**hERG:** Both ligands have low hERG inhibition liability (Ligand A: 0.729, Ligand B: 0.526), which is good.

**Microsomal Clearance:** Ligand A (60.039) has a higher microsomal clearance than Ligand B (13.027), suggesting lower metabolic stability. This is a significant drawback for A.

**In vitro Half-Life:** Ligand B (-7.592) has a much longer in vitro half-life than Ligand A (0.911), indicating better stability.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (Ligand A: 0.083, Ligand B: 0.071), which is favorable for CNS penetration.

**Binding Affinity:** Ligand A (-7.6 kcal/mol) has a slightly better binding affinity than Ligand B (-6.6 kcal/mol). This 1.0 kcal/mol difference is substantial and could outweigh some ADME concerns.

**Overall Assessment:**

Ligand A has a better binding affinity, QED, and lower DILI risk. However, Ligand B has significantly better metabolic stability (lower Cl_mic, longer t1/2), a slightly better BBB score, and a lower TPSA. The difference in binding affinity is significant, but the metabolic stability of Ligand B is a major advantage for a CNS drug, as it will likely lead to higher brain exposure. The negative solubility and Caco-2 values are concerning for both, but the affinity difference is significant enough to overcome this.

Output:
1
2025-04-17 08:17:22,771 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (359.4) is slightly higher than Ligand B (327.4), but both are acceptable.

**TPSA:** Ligand A (88.18) is excellent for CNS penetration, being well below 90. Ligand B (36.44) is also very good.

**logP:** Ligand A (-0.675) is a bit low, potentially hindering membrane permeability. Ligand B (3.006) is optimal. This is a significant advantage for Ligand B.

**H-Bond Donors/Acceptors:** Ligand A (1 HBD, 6 HBA) and Ligand B (0 HBD, 4 HBA) both fall within acceptable ranges.

**QED:** Both ligands have good QED scores (A: 0.479, B: 0.764), indicating reasonable drug-likeness, with B being better.

**DILI:** Both ligands have similar, acceptable DILI risk (A: 43.39, B: 44.20).

**BBB:** Ligand A (78.87) has good BBB penetration, but Ligand B (90.77) is excellent, exceeding the 70% threshold for CNS targets. This is a major advantage for Ligand B.

**Caco-2 Permeability:** Both have negative values, which is unusual. Assuming these are percentile scores, both have poor Caco-2 permeability.

**Aqueous Solubility:** Both have negative values, indicating poor solubility.

**hERG Inhibition:** Ligand A (0.4) has a very low risk of hERG inhibition, which is excellent. Ligand B (0.956) is slightly higher, but still within an acceptable range.

**Microsomal Clearance:** Ligand A (32.73) has lower clearance than Ligand B (44.88), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (-41.613) has a negative half-life, which is impossible. Ligand B (-24.81) also has a negative half-life, which is impossible.

**P-gp Efflux:** Ligand A (0.018) has very low P-gp efflux, which is excellent for CNS exposure. Ligand B (0.794) is higher, indicating more efflux, which is less desirable.

**Binding Affinity:** Ligand B (-9.5 kcal/mol) has a significantly stronger binding affinity than Ligand A (-7.1 kcal/mol). This >1.5 kcal/mol difference is substantial and can outweigh some ADME drawbacks.

**Overall Assessment:**

Ligand B is the stronger candidate. While Ligand A has better P-gp efflux and lower microsomal clearance, Ligand B excels in crucial areas for a CNS-targeting GPCR ligand: significantly higher binding affinity, excellent BBB penetration, and optimal logP. The slightly higher P-gp efflux and hERG risk for Ligand B are less concerning given its superior potency and brain penetration. The negative half-life values for both are concerning and would require further investigation.

Output:
1
2025-04-17 08:17:22,771 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (376.406 and 359.455 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (121.8) is slightly above the optimal <90 for CNS targets, but still reasonable. Ligand B (109.04) is better, falling comfortably under 140 and closer to the CNS target threshold.

**logP:** Both ligands have good logP values (1.329 and 3.198), within the optimal 1-3 range. Ligand B is slightly higher, potentially offering better membrane permeability.

**H-Bond Donors/Acceptors:** Ligand A has 3 HBD and 6 HBA, which are acceptable. Ligand B has 1 HBD and 7 HBA, also acceptable.

**QED:** Ligand B (0.813) has a significantly better QED score than Ligand A (0.357), indicating a more drug-like profile.

**DILI:** Both ligands have acceptable DILI risk (52.152 and 49.128), below the 60 threshold.

**BBB:** Ligand B (82.513) has a much higher BBB percentile than Ligand A (57.154). This is a *critical* advantage for a CNS target like DRD2.

**Caco-2 Permeability:** Ligand A (-5.372) and Ligand B (-4.971) both have negative Caco-2 permeability values, which is unusual and suggests poor intestinal absorption. However, for a CNS target, this is less critical as BBB penetration is more important.

**Aqueous Solubility:** Both ligands have poor aqueous solubility (-2.841 and -5.134). This could pose formulation challenges.

**hERG:** Both ligands have low hERG risk (0.489 and 0.854).

**Microsomal Clearance:** Ligand B (60.738) has a lower microsomal clearance than Ligand A (68.285), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand B (14.593 hours) has a significantly longer half-life than Ligand A (-16.327 hours). The negative value for Ligand A is concerning.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.114 and 0.21).

**Binding Affinity:** Ligand A (-7.9 kcal/mol) has a slightly better binding affinity than Ligand B (-6.4 kcal/mol). However, the 1.5 kcal/mol difference isn't substantial enough to overcome the significant ADME advantages of Ligand B.

**Overall:** Considering the GPCR-specific priorities, Ligand B is the superior candidate. Its significantly better BBB penetration, QED, metabolic stability, and half-life outweigh the slightly weaker binding affinity. The poor solubility of both compounds is a concern, but can be addressed through formulation strategies.

Output:
1
2025-04-17 08:17:22,771 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (349.35 and 357.38 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (122.75) is slightly above the preferred <90 for CNS targets, but not drastically. Ligand B (56.41) is excellent, well below 90.

**logP:** Ligand A (-1.259) is a bit low, potentially hindering permeability. Ligand B (2.795) is within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A has 2 HBD and 7 HBA, which are acceptable. Ligand B has 1 HBD and 2 HBA, also acceptable.

**QED:** Both ligands have good QED scores (0.615 and 0.885), indicating drug-like properties.

**DILI:** Ligand A (57.35) is moderately risky, while Ligand B (39.40) is much better, indicating lower liver injury potential.

**BBB:** Ligand A (67.58) is borderline for good CNS penetration. Ligand B (87.01) is excellent, exceeding the 70% threshold.

**Caco-2 Permeability:** Both have negative values, which is unusual. Assuming these are percentile scores, Ligand A (-5.013) is very poor, while Ligand B (-4.607) is also poor, but slightly better.

**Aqueous Solubility:** Both have negative values, again assuming percentile scores, indicating poor solubility. Ligand A (-2.177) is slightly better than Ligand B (-3.221).

**hERG:** Ligand A (0.033) has a very low hERG risk, which is excellent. Ligand B (0.59) is slightly elevated, but still relatively low.

**Microsomal Clearance:** Ligand A (-9.79) suggests very slow clearance and high metabolic stability. Ligand B (5.998) indicates faster clearance.

**In vitro Half-Life:** Ligand A (-14.381) suggests a very long half-life, which is favorable. Ligand B (-22.163) also suggests a long half-life, but less so than Ligand A.

**P-gp Efflux:** Ligand A (0.001) has very low P-gp efflux, which is excellent for CNS penetration. Ligand B (0.07) also has low P-gp efflux, but slightly higher.

**Binding Affinity:** Ligand B (-7.4 kcal/mol) has a slightly better binding affinity than Ligand A (-8.1 kcal/mol). While A is better, the difference is not huge.

**Overall Assessment:**

Ligand B is the stronger candidate. While Ligand A has better affinity and metabolic stability, Ligand B excels in crucial areas for a CNS-targeting GPCR ligand: significantly better BBB penetration, a more optimal logP, and lower DILI risk. The slightly lower affinity of Ligand B is outweighed by its superior ADME properties, particularly for CNS delivery. Ligand A's low logP and poor Caco-2 permeability are significant drawbacks.

Output:
1
2025-04-17 08:17:22,772 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (381.219 and 383.945 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (97.12) is higher than the preferred <90 for CNS targets, while Ligand B (43.86) is well within the range. This is a significant advantage for Ligand B.

**logP:** Both ligands (2.52 and 2.805) are within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A has 2 HBD and 5 HBA, which are acceptable. Ligand B has 0 HBD and 4 HBA, also acceptable.

**QED:** Both ligands have similar QED values (0.848 and 0.803), indicating good drug-likeness.

**DILI:** Ligand A (79.604) has a higher DILI risk than Ligand B (16.402). This is a significant negative for Ligand A.

**BBB:** Ligand B (87.553) has a much higher BBB penetration percentile than Ligand A (55.138). This is crucial for a CNS target like DRD2 and heavily favors Ligand B.

**Caco-2 Permeability:** Both have negative Caco-2 values which is unusual, but we can assume they are percentile scores and both are poor.

**Aqueous Solubility:** Both have negative solubility values, indicating poor solubility.

**hERG:** Ligand A (0.167) has a slightly better hERG profile than Ligand B (0.718), but both are relatively low risk.

**Microsomal Clearance:** Ligand A (9.475) has lower microsomal clearance than Ligand B (14.278), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (35.384) has a longer half-life than Ligand B (9.816).

**P-gp Efflux:** Ligand A (0.069) has lower P-gp efflux than Ligand B (0.181), which is favorable for CNS penetration.

**Binding Affinity:** Ligand A (-8.8 kcal/mol) has a slightly stronger binding affinity than Ligand B (-8.2 kcal/mol). While a 0.6 kcal/mol difference is noticeable, it may not be enough to overcome the significant ADME advantages of Ligand B.

**Overall Assessment:**

Ligand B clearly outperforms Ligand A in several critical areas for a CNS-targeting GPCR. Its significantly better BBB penetration, lower DILI risk, and lower TPSA are major advantages. While Ligand A has slightly better metabolic stability, longer half-life, and a slightly stronger binding affinity, these benefits are outweighed by the superior ADME properties of Ligand B, particularly its BBB penetration.

Output:
1
2025-04-17 08:17:22,772 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (348.378 and 347.503 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (104.53) is higher than the preferred <90 for CNS targets, but still reasonable. Ligand B (52.65) is excellent, well below 90.

**logP:** Ligand A (0.706) is a bit low, potentially hindering permeation. Ligand B (1.875) is better, falling within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A has 3 HBD and 3 HBA, which is acceptable. Ligand B has 1 HBD and 3 HBA, also acceptable.

**QED:** Ligand A (0.73) is better than Ligand B (0.565), indicating a more drug-like profile.

**DILI:** Ligand A (38.348) has a lower DILI risk than Ligand B (8.181), which is a significant advantage.

**BBB:** Ligand A (87.67) has a much better BBB penetration percentile than Ligand B (64.211). This is critical for a CNS target like DRD2.

**Caco-2 Permeability:** Ligand A (-5.316) has poor Caco-2 permeability, while Ligand B (-4.608) is slightly better, but still not great.

**Aqueous Solubility:** Ligand A (-2.956) and Ligand B (-1.428) both have poor aqueous solubility.

**hERG:** Ligand A (0.17) has a lower hERG risk than Ligand B (0.517), which is favorable.

**Microsomal Clearance:** Ligand A (7.167) has a lower microsomal clearance than Ligand B (32.118), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (6.596) has a longer half-life than Ligand B (-4.342), which is desirable.

**P-gp Efflux:** Ligand A (0.016) has very low P-gp efflux, which is excellent for CNS penetration. Ligand B (0.034) is also low, but higher than A.

**Binding Affinity:** Ligand B (-7.5 kcal/mol) has a slightly better binding affinity than Ligand A (-8.2 kcal/mol). While A has a slightly better affinity, the difference is not substantial enough to outweigh other factors.

**Overall Assessment:**

Ligand A excels in crucial areas for CNS drug development: BBB penetration, DILI risk, metabolic stability (lower Cl_mic, longer t1/2), P-gp efflux, and hERG risk. While its logP and Caco-2 permeability are concerns, the strong BBB penetration and favorable safety profile are paramount for a DRD2 ligand. Ligand B has better logP and affinity, but suffers from significantly poorer BBB penetration and a higher DILI risk.

Output:
1
2025-04-17 08:17:22,772 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (357.46 and 371.815 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (21.26) is significantly better than Ligand B (62.13). For CNS targets, we want TPSA <= 90, and ideally lower. Ligand A is excellent, while Ligand B is pushing the upper limit and less favorable.

**logP:** Both ligands have good logP values (4.683 and 4.101), falling within the optimal 1-3 range, although slightly high.

**H-Bond Donors/Acceptors:** Both have acceptable HBD (1) and HBA (2 for A, 3 for B) counts, well below the thresholds of 5 and 10 respectively.

**QED:** Both ligands have good QED scores (0.792 and 0.831), indicating good drug-like properties.

**DILI:** Ligand A (13.339) has a much lower DILI risk than Ligand B (53.858). This is a significant advantage for Ligand A.

**BBB:** Ligand A (89.957) has a substantially better BBB penetration percentile than Ligand B (77.976).  For a CNS target like DRD2, >70 is desirable, and Ligand A is closer to this threshold.

**Caco-2 Permeability:** Both have negative Caco-2 values (-4.688 and -4.748), which is unusual and potentially problematic. However, these values are close and don't heavily differentiate the two.

**Aqueous Solubility:** Both have negative solubility values (-4.887 and -4.658), indicating poor aqueous solubility. This is a concern for both, but not a major differentiator.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.792 and 0.392), which is good.

**Microsomal Clearance:** Ligand A (13.068) has a lower microsomal clearance than Ligand B (53.588), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (24.593 hours) has a longer half-life than Ligand B (14.836 hours), which is desirable.

**P-gp Efflux:** Ligand A (0.265) has lower P-gp efflux liability than Ligand B (0.158), meaning it's less likely to be pumped out of the brain, improving CNS exposure.

**Binding Affinity:** Ligand B (-7.6 kcal/mol) has a significantly stronger binding affinity than Ligand A (-9.4 kcal/mol). This is a substantial advantage for Ligand B. A >1.5 kcal/mol advantage often outweighs other drawbacks.

**Overall Assessment:**

While Ligand A excels in ADME properties (DILI, BBB, Cl_mic, t1/2, Pgp), Ligand B has a significantly stronger binding affinity. Given that DRD2 is a GPCR in the CNS, BBB penetration is crucial, and Ligand A is better in this regard. However, the 1.8 kcal/mol difference in binding affinity is substantial. The improved binding of Ligand B is likely to outweigh the ADME drawbacks, especially if further optimization can address the higher DILI and lower BBB.

Output:
1
2025-04-17 08:17:22,773 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (350.415 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (88.1) is slightly higher than Ligand B (83.22), but both are below the 90 A^2 threshold desirable for CNS targets.

**3. logP:** Ligand A (2.146) and Ligand B (1.26) are both within the optimal 1-3 range. Ligand B is a bit lower, which *could* slightly hinder permeability, but isn't a major concern.

**4. H-Bond Donors:** Ligand A (2) and Ligand B (1) are both acceptable, below the 5 limit.

**5. H-Bond Acceptors:** Both ligands (5) are within the acceptable limit of 10.

**6. QED:** Ligand B (0.864) has a significantly better QED score than Ligand A (0.581), indicating a more drug-like profile.

**7. DILI:** Ligand A (21.442) has a much lower DILI risk than Ligand B (35.13). This is a significant advantage for Ligand A.

**8. BBB:** Ligand A (71.229) has a better BBB penetration percentile than Ligand B (50.019). This is crucial for a CNS target like DRD2.

**9. Caco-2 Permeability:** Ligand A (-4.944) has slightly better Caco-2 permeability than Ligand B (-4.416).

**10. Aqueous Solubility:** Ligand A (-3.111) has slightly better aqueous solubility than Ligand B (-1.755).

**11. hERG Inhibition:** Both ligands have low hERG inhibition liability (0.744 and 0.331 respectively), which is good.

**12. Microsomal Clearance:** Ligand B (19.009) has lower microsomal clearance than Ligand A (38.248), suggesting better metabolic stability.

**13. In vitro Half-Life:** Ligand B (23.785) has a longer in vitro half-life than Ligand A (-28.769). This is a significant advantage for Ligand B.

**14. P-gp Efflux:** Ligand A (0.093) has lower P-gp efflux than Ligand B (0.345), which is favorable for CNS exposure.

**15. Binding Affinity:** Ligand A (-8.4 kcal/mol) has a significantly stronger binding affinity than Ligand B (-6.8 kcal/mol). This >1.5 kcal/mol difference is a major advantage, potentially outweighing some ADME drawbacks.

**Overall Assessment:**

Ligand A excels in binding affinity and BBB penetration, which are critical for a CNS GPCR target. It also has lower DILI risk and better P-gp efflux. Ligand B has better QED, metabolic stability (lower Cl_mic), and a longer half-life. However, the substantial difference in binding affinity (-8.4 vs -6.8 kcal/mol) and the better BBB score for Ligand A are decisive. The improved ADME properties of Ligand B are valuable, but can potentially be addressed through further optimization, while improving the binding affinity is often more challenging.

Output:
0
2025-04-17 08:17:22,773 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (364.785 and 367.921 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (81.91) is higher than Ligand B (47.36). For a CNS target like DRD2, TPSA should ideally be below 90. Ligand B is significantly better in this regard.

**3. logP:** Both ligands have good logP values (4.022 and 3.798), falling within the optimal 1-3 range.

**4. H-Bond Donors:** Both have 0 HBD, which is acceptable.

**5. H-Bond Acceptors:** Ligand A has 5 HBA, and Ligand B has 4. Both are within the acceptable limit of 10.

**6. QED:** Both ligands have good QED scores (0.571 and 0.702), indicating drug-like properties. Ligand B is slightly better.

**7. DILI:** Ligand A has a DILI risk of 84.994, which is concerning (high risk). Ligand B has a much lower DILI risk of 16.092, which is excellent.

**8. BBB:** Ligand A has a BBB penetration of 64.482, which is okay but not ideal for a CNS target. Ligand B has a significantly better BBB penetration of 87.631, exceeding the desirable >70 threshold.

**9. Caco-2 Permeability:** Both have negative Caco-2 values (-4.605 and -4.662). This is unusual and suggests poor permeability. However, these values are on a scale where negative values are possible and don't necessarily disqualify a compound.

**10. Aqueous Solubility:** Both have negative solubility values (-4.148 and -2.874). Similar to Caco-2, this suggests poor solubility, but isn't necessarily disqualifying.

**11. hERG Inhibition:** Both have low hERG inhibition risk (0.578 and 0.661).

**12. Microsomal Clearance:** Ligand A (66.62) has lower clearance than Ligand B (77.685), suggesting better metabolic stability.

**13. In vitro Half-Life:** Ligand B has a significantly longer half-life (16.213 hours) than Ligand A (-5.46 hours). This is a major advantage for dosing convenience.

**14. P-gp Efflux:** Ligand A (0.276) has lower P-gp efflux than Ligand B (0.685), which is favorable for CNS exposure.

**15. Binding Affinity:** Ligand A (-8.1 kcal/mol) has a slightly better binding affinity than Ligand B (-7.0 kcal/mol). While the difference is less than the 1.5 kcal/mol threshold, it's still a factor.

**Overall Assessment:**

Ligand B is the more promising candidate. While Ligand A has slightly better binding affinity, Ligand B excels in critical ADME properties for a CNS-targeting GPCR: significantly lower DILI risk, much better BBB penetration, and a substantially longer half-life. The lower TPSA of Ligand B is also beneficial. The slightly higher P-gp efflux of Ligand B is a minor drawback compared to the advantages it offers.



Output:
1
2025-04-17 08:17:22,774 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B based on the provided guidelines, prioritizing GPCR-specific properties (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (345.483 Da) is slightly lower, which could be beneficial for permeability, but both are acceptable.

**TPSA:** Ligand A (66.4) is better than Ligand B (33.2). For CNS targets, TPSA should be <= 90, both are well within this range. Ligand B is significantly lower and may have better CNS penetration.

**logP:** Both ligands have logP values around 4.5-4.8, which is slightly high. While acceptable, it could potentially lead to solubility issues or off-target interactions.

**H-Bond Donors/Acceptors:** Ligand A has 2 HBD and 2 HBA, while Ligand B has 0 HBD and 3 HBA. Both are within acceptable limits (<=5 HBD and <=10 HBA).

**QED:** Both ligands have QED values above 0.7, indicating good drug-likeness.

**DILI:** Ligand A (51.105) has a higher DILI risk than Ligand B (31.214). This is a significant advantage for Ligand B.

**BBB:** Ligand B (84.141) has a much higher BBB penetration percentile than Ligand A (47.809). This is *critical* for a CNS target like DRD2.

**Caco-2 Permeability:** Ligand A (-4.864) has better Caco-2 permeability than Ligand B (-5.179).

**Aqueous Solubility:** Ligand A (-3.829) has better aqueous solubility than Ligand B (-4.127).

**hERG Inhibition:** Ligand A (0.056) has a lower hERG inhibition liability than Ligand B (0.454). This is a safety advantage for Ligand A.

**Microsomal Clearance:** Ligand B (95.573) has a significantly higher microsomal clearance than Ligand A (33.239), indicating faster metabolism and potentially lower *in vivo* exposure.

**In vitro Half-Life:** Ligand A (-16.372) has a longer in vitro half-life than Ligand B (-8.392). This is a positive attribute for Ligand A.

**P-gp Efflux:** Ligand A (0.045) has lower P-gp efflux liability than Ligand B (0.608), which is favorable for CNS penetration.

**Binding Affinity:** Ligand A (-8.9 kcal/mol) has a slightly better binding affinity than Ligand B (-7.6 kcal/mol). This 1.3 kcal/mol difference is substantial and could outweigh some ADME drawbacks.

**Overall Assessment:**

Ligand B excels in BBB penetration and DILI risk, which are crucial for a CNS GPCR target. However, it suffers from higher microsomal clearance, P-gp efflux, and lower solubility. Ligand A has a better safety profile (hERG, DILI), better metabolic stability, and slightly better binding affinity. The difference in binding affinity is significant. Given the importance of CNS penetration for DRD2, and the substantial difference in BBB, Ligand B is the better candidate despite its other shortcomings. The higher affinity of Ligand A is a plus, but the BBB score of Ligand B is a major advantage.

Output:
1
2025-04-17 08:17:22,774 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (355.479 and 366.527 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (82.11) is better than Ligand B (62.55), both are below the 90 A^2 threshold for CNS targets.

**logP:** Ligand B (3.446) is optimal, while Ligand A (0.225) is quite low, potentially hindering permeability. This is a significant drawback for Ligand A.

**H-Bond Donors/Acceptors:** Ligand A (2 HBD, 5 HBA) and Ligand B (1 HBD, 4 HBA) both have acceptable numbers of H-bond donors and acceptors.

**QED:** Both ligands have good QED scores (0.651 and 0.68), indicating drug-like properties.

**DILI:** Ligand A (7.135) has a much lower DILI risk than Ligand B (20.744), which is a positive for Ligand A.

**BBB:** Ligand B (62.544) has a significantly better BBB penetration score than Ligand A (45.909). This is a crucial factor for a CNS target like DRD2.

**Caco-2 Permeability:** Ligand A (-4.977) has poor Caco-2 permeability, while Ligand B (-5.305) is also poor.

**Aqueous Solubility:** Ligand A (-0.595) has slightly better solubility than Ligand B (-3.27).

**hERG Inhibition:** Ligand A (0.277) has a lower hERG inhibition risk than Ligand B (0.629).

**Microsomal Clearance:** Ligand B (55.816) has a much higher microsomal clearance than Ligand A (2.335), indicating lower metabolic stability.

**In vitro Half-Life:** Ligand B (40.155) has a longer in vitro half-life than Ligand A (22.748).

**P-gp Efflux:** Ligand A (0.019) shows very low P-gp efflux, which is excellent for CNS penetration. Ligand B (0.181) is higher, but still relatively low.

**Binding Affinity:** Ligand B (-7.5 kcal/mol) has a significantly stronger binding affinity than Ligand A (0.0 kcal/mol). This is a major advantage for Ligand B. The >1.5 kcal/mol difference in binding affinity can outweigh many ADME drawbacks.

**Overall Assessment:**

While Ligand A has advantages in DILI, P-gp efflux, and slightly better solubility, its extremely low logP and poor Caco-2 permeability are major concerns. The low binding affinity is also a significant issue. Ligand B, despite a higher DILI risk and slightly worse P-gp efflux, has a much better logP, significantly stronger binding affinity, and a reasonable BBB score. The stronger binding affinity is the most important factor, especially for a GPCR target where achieving sufficient occupancy is crucial. The higher clearance of Ligand B could be addressed with structural modifications.

Output:
1
2025-04-17 08:17:22,774 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (385.251 and 376.507 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (89.16) is better than Ligand B (75.19), both are below the 90 A^2 threshold for CNS targets.

**logP:** Both ligands have a logP around 2.9, which is optimal (1-3).

**H-Bond Donors/Acceptors:** Ligand A has 2 HBD and 5 HBA, while Ligand B has 1 HBD and 6 HBA. Both are within acceptable ranges (<=5 HBD and <=10 HBA).

**QED:** Both ligands have good QED scores (0.8 and 0.841), indicating drug-like properties.

**DILI:** Ligand B (72.819) has a higher DILI risk than Ligand A (61.07), but both are moderately risky.

**BBB:** Ligand B (64.095) has a significantly better BBB penetration score than Ligand A (49.089). This is a crucial factor for a CNS target like DRD2.

**Caco-2 Permeability:** Both have negative Caco-2 values which is unusual and suggests poor permeability.

**Aqueous Solubility:** Both have negative solubility values which is also unusual and suggests poor solubility.

**hERG:** Both ligands have low hERG inhibition liability (0.237 and 0.299).

**Microsomal Clearance:** Ligand B (31.465) has lower microsomal clearance than Ligand A (37.059), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (50.844) has a much longer in vitro half-life than Ligand B (10.411).

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.171 and 0.177).

**Binding Affinity:** Ligand B (-8.5 kcal/mol) has a slightly stronger binding affinity than Ligand A (-8.0 kcal/mol). While the difference is not huge, it is still a factor.

**Overall Assessment:**

Given the GPCR-specific priorities, BBB penetration is paramount for a CNS drug. Ligand B has a substantially better BBB score (64.095 vs 49.089). It also has better metabolic stability (lower Cl_mic) and slightly better binding affinity. While Ligand A has a longer half-life, the improved CNS penetration and metabolic stability of Ligand B outweigh this advantage. The negative Caco-2 and solubility values are concerning for both, but can be addressed in later optimization stages.

Output:
1
2025-04-17 08:17:22,774 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (358.385 and 357.445 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (75.71) is higher than Ligand B (61.44). For CNS targets, we prefer TPSA <= 90, so both are acceptable, but B is better.

**3. logP:** Ligand A (1.055) is slightly lower than the optimal 1-3 range, potentially hindering permeability. Ligand B (1.939) is closer to the optimal range.

**4. H-Bond Donors:** Ligand A (1) and Ligand B (2) both meet the <=5 criteria.

**5. H-Bond Acceptors:** Ligand A (4) and Ligand B (3) both meet the <=10 criteria.

**6. QED:** Ligand B (0.685) has a better QED score than Ligand A (0.494), indicating a more drug-like profile.

**7. DILI:** Ligand B (24.661) has a significantly lower DILI risk than Ligand A (30.903), which is a substantial advantage.

**8. BBB:** Ligand B (83.249) has a much higher BBB penetration percentile than Ligand A (73.633). This is *critical* for a CNS target like DRD2.

**9. Caco-2 Permeability:** Both have negative values, indicating low permeability. Ligand A (-4.375) is slightly better than Ligand B (-4.956), but both are poor.

**10. Aqueous Solubility:** Both have negative values, indicating poor solubility. Ligand A (-2.319) is slightly better than Ligand B (-2.373).

**11. hERG Inhibition:** Ligand A (0.315) has a slightly lower hERG inhibition risk than Ligand B (0.539), which is favorable.

**12. Microsomal Clearance:** Ligand A (54.197) has higher microsomal clearance than Ligand B (5.294), suggesting lower metabolic stability. This is a significant disadvantage for A.

**13. In vitro Half-Life:** Ligand B (-13.165) has a much longer in vitro half-life than Ligand A (-47.491). This is a major advantage for B.

**14. P-gp Efflux:** Ligand A (0.028) has lower P-gp efflux than Ligand B (0.038), which is better for CNS exposure.

**15. Binding Affinity:** Ligand B (-8.3 kcal/mol) has a slightly better binding affinity than Ligand A (-7.3 kcal/mol). While both are good, the difference is significant enough to consider.

**Overall Assessment:**

Ligand B is the stronger candidate. It excels in the most important areas for a CNS-targeting GPCR ligand: BBB penetration, DILI risk, metabolic stability (lower Cl_mic, longer t1/2), and binding affinity. While Ligand A has slightly better P-gp efflux and hERG inhibition, these are less critical than the advantages offered by Ligand B. The slightly lower logP of Ligand A is a concern, and the higher TPSA is less ideal.



Output:
1
2025-04-17 08:17:22,775 - INFO - Reasoning:

Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (363.487 and 383.279 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (84.14) is better than Ligand B (67.23) as it is closer to the optimal range for CNS targets (<=90).

**3. logP:** Both ligands have good logP values (1.336 and 1.965), falling within the 1-3 range. Ligand B is slightly higher, which could be marginally beneficial for membrane permeability, but not significantly.

**4. H-Bond Donors:** Both have 1 HBD, which is within the acceptable limit of <=5.

**5. H-Bond Acceptors:** Ligand A has 7 HBAs, and Ligand B has 6. Both are below the 10 threshold.

**6. QED:** Ligand A (0.863) has a significantly better QED score than Ligand B (0.469), indicating a more drug-like profile.

**7. DILI:** Ligand A (42.885) has a lower DILI risk than Ligand B (60.682), making it safer.

**8. BBB:** Ligand B (85.498) has a substantially better BBB penetration percentile than Ligand A (73.517). This is a crucial factor for a CNS target like DRD2.

**9. Caco-2 Permeability:** Both have negative Caco-2 values (-4.976 and -4.917). These values are difficult to interpret without knowing the scale, but the similarity suggests comparable intestinal absorption potential.

**10. Aqueous Solubility:** Ligand A (-2.08) has better aqueous solubility than Ligand B (-4.132).

**11. hERG Inhibition:** Both ligands have low hERG inhibition risk (0.767 and 0.747).

**12. Microsomal Clearance:** Both have similar microsomal clearance values (21.776 and 21.071 mL/min/kg), suggesting comparable metabolic stability.

**13. In vitro Half-Life:** Ligand B (42.553) has a significantly longer in vitro half-life than Ligand A (14.36), which is desirable.

**14. P-gp Efflux:** Both have low P-gp efflux liability (0.081 and 0.536), which is good for CNS penetration.

**15. Binding Affinity:** Both ligands have very strong binding affinities (-8.8 and -8.5 kcal/mol). The difference of 0.3 kcal/mol is not substantial enough to override other significant differences.

**Overall Assessment:**

While Ligand B has a superior BBB score and longer half-life, Ligand A demonstrates a more favorable overall profile. Its better QED, lower DILI risk, and improved solubility are significant advantages. The slightly lower BBB score of Ligand A is a concern, but the strong binding affinity (-8.8 kcal/mol) and other favorable properties outweigh this drawback. For a GPCR target, a good balance of properties is essential, and Ligand A presents a more balanced and promising profile.

Output:
1
2025-04-17 08:17:22,775 - INFO - Batch 436 complete. Total preferences: 6976
2025-04-17 08:17:22,775 - INFO - Processing batch 437/512...
2025-04-17 08:18:09,297 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (383.813 Da) is slightly higher than Ligand B (346.387 Da), but both are acceptable.

**TPSA:** Ligand A (119.27) is borderline for CNS penetration, while Ligand B (94.05) is well within the desirable range (<90 for CNS targets). This favors Ligand B.

**logP:** Ligand A (3.079) is optimal. Ligand B (-0.665) is significantly below the optimal range and could indicate poor membrane permeability. This favors Ligand A.

**H-Bond Donors/Acceptors:** Both ligands have acceptable HBD (1) and HBA (6/5) counts.

**QED:** Both ligands have good QED scores (0.604 and 0.717), indicating good drug-like properties.

**DILI:** Ligand A (96.549) has a high DILI risk, while Ligand B (42.458) has a low DILI risk. This strongly favors Ligand B.

**BBB:** Ligand A (60.954) has a moderate BBB penetration, while Ligand B (32.144) has a low BBB penetration. While both are not ideal, Ligand A is better.

**Caco-2 Permeability:** Ligand A (-4.726) and Ligand B (-4.594) have similar, and poor, Caco-2 permeability.

**Aqueous Solubility:** Ligand A (-5.029) and Ligand B (-0.88) have poor aqueous solubility. Ligand B is slightly better.

**hERG:** Both ligands have very low hERG inhibition risk (0.215 and 0.068).

**Microsomal Clearance:** Ligand A (23.512) has moderate clearance, while Ligand B (-6.581) has negative clearance, which is unusual and suggests high metabolic stability. This favors Ligand B.

**In vitro Half-Life:** Ligand A (111.637 hours) has a long half-life, while Ligand B (17.46 hours) has a shorter half-life. This favors Ligand A.

**P-gp Efflux:** Ligand A (0.272) has moderate P-gp efflux, while Ligand B (0.016) has very low P-gp efflux. This strongly favors Ligand B.

**Binding Affinity:** Ligand A (-8.4 kcal/mol) has a significantly stronger binding affinity than Ligand B (-7.7 kcal/mol). This is a substantial advantage for Ligand A, potentially outweighing some ADME concerns.

**Overall Assessment:**

Ligand B has superior ADME properties (lower DILI, better TPSA, lower P-gp efflux, and better metabolic stability). However, Ligand A has a significantly better binding affinity (-8.4 vs -7.7 kcal/mol). For a GPCR target like DRD2, strong binding affinity is crucial. While Ligand A's DILI risk is a concern, it might be mitigated through structural modifications. The better BBB penetration of Ligand A, coupled with its much stronger binding, makes it the more promising candidate despite the higher DILI risk.

Output:
1
2025-04-17 08:18:09,297 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B based on the provided guidelines, prioritizing GPCR-specific properties (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (360.376 and 346.391 Da) fall within the ideal range of 200-500 Da.

**TPSA:** Ligand A (50.8) is excellent for CNS penetration (<90), while Ligand B (132.47) is approaching the upper limit for good oral absorption (<=140) but is less ideal for CNS targets.

**logP:** Ligand A (2.737) is optimal (1-3). Ligand B (0.543) is quite low, potentially hindering membrane permeability and CNS entry.

**H-Bond Donors/Acceptors:** Both have 1 HBD and 4 HBA, which are within acceptable limits.

**QED:** Ligand A (0.812) has a strong drug-like profile, significantly better than Ligand B (0.452).

**DILI:** Ligand A (20.047) has a much lower DILI risk than Ligand B (27.453). Both are acceptable, but A is preferred.

**BBB:** This is a critical parameter for a CNS target like DRD2. Ligand A (91.198) shows excellent BBB penetration, while Ligand B (39.667) is poor.

**Caco-2 Permeability:** Ligand A (-4.693) and Ligand B (-5.571) both have negative values, suggesting poor permeability. However, the scale isn't explicitly defined, making direct comparison difficult.

**Aqueous Solubility:** Both ligands have similar, poor aqueous solubility (-2.203 and -2.362).

**hERG:** Ligand A (0.791) has a slightly higher hERG risk than Ligand B (0.058), but both are relatively low.

**Microsomal Clearance:** Ligand A (13.735) has a higher clearance than Ligand B (3.742), indicating lower metabolic stability.

**In vitro Half-Life:** Ligand B (1.672) has a very short half-life, while Ligand A (-27.107) has a negative value, which is unusual and may indicate a problem with the assay or data.

**P-gp Efflux:** Ligand A (0.129) shows lower P-gp efflux liability than Ligand B (0.009), which is favorable for CNS exposure.

**Binding Affinity:** Ligand B (-7.9 kcal/mol) has a slightly better binding affinity than Ligand A (-8.4 kcal/mol). However, the difference is small and can be outweighed by other factors.

**Overall Assessment:**

Ligand A is significantly better suited as a drug candidate for DRD2. Its excellent BBB penetration, optimal logP, strong QED, and lower DILI risk are crucial advantages. While its metabolic stability is a concern (higher Cl_mic), the superior CNS penetration and drug-likeness outweigh this drawback. Ligand B's poor logP and BBB penetration are major liabilities for a CNS-targeted drug. The slightly better affinity of Ligand B is not enough to compensate for these significant ADME deficiencies.

Output:
1
2025-04-17 08:18:09,297 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (360.82 and 350.415 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (42.66) is excellent, well below the 90 A^2 threshold for CNS targets. Ligand B (77.1) is higher, but still potentially acceptable, though less ideal.

**3. logP:** Ligand A (4.099) is at the upper end of the optimal range (1-3) and could potentially cause solubility issues. Ligand B (0.758) is quite low, potentially hindering permeation.

**4. H-Bond Donors:** Both have acceptable HBD counts (0 for A, 1 for B), well below the 5 threshold.

**5. H-Bond Acceptors:** Both have acceptable HBA counts (5 for both), below the 10 threshold.

**6. QED:** Ligand A (0.645) has a better QED score than Ligand B (0.542), indicating a more drug-like profile.

**7. DILI:** Ligand A (75.766) has a higher DILI risk than Ligand B (37.03), which is a significant concern.

**8. BBB:** Ligand A (77.007) has a good BBB penetration percentile, exceeding the 70% threshold for CNS targets. Ligand B (43.583) is considerably lower and less favorable for CNS penetration.

**9. Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and suggests poor permeability. However, the scale is not specified, so it's difficult to interpret.

**10. Aqueous Solubility:** Both have negative solubility values, suggesting poor solubility. Again, the scale is not specified, so it's difficult to interpret.

**11. hERG Inhibition:** Ligand A (0.678) has a lower hERG inhibition risk than Ligand B (0.147), which is preferable.

**12. Microsomal Clearance:** Ligand A (75.358) has a higher microsomal clearance than Ligand B (19.645), indicating lower metabolic stability.

**13. In vitro Half-Life:** Ligand B (-13.377) has a negative half-life, which is impossible and indicates a data error. Ligand A (53.764) has a reasonable half-life.

**14. P-gp Efflux:** Ligand A (0.88) has higher P-gp efflux liability than Ligand B (0.028), which is less desirable.

**15. Binding Affinity:** Both ligands have very strong binding affinities (-8.8 and -8.0 kcal/mol), with Ligand A being slightly better. The affinity difference is not large enough to completely overcome other issues.

**Overall Assessment:**

Ligand A has a better BBB score, slightly better affinity, and a better QED score. However, it suffers from higher DILI risk, higher P-gp efflux, and higher microsomal clearance. Ligand B has a lower DILI risk and lower P-gp efflux, but its BBB penetration is significantly worse, and its in vitro half-life is nonsensical.

Given the importance of BBB penetration for a CNS target like DRD2, and the questionable data for Ligand B's half-life, **Ligand A is the more promising candidate despite its drawbacks.** The DILI risk is a concern that would need to be addressed through structural modification, but the better CNS exposure profile is crucial.

Output:
1
2025-04-17 08:18:09,298 - INFO - Reasoning:

Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (350.503 and 364.471 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (69.64) is significantly better than Ligand B (114.18). For CNS targets, we want TPSA <= 90, so Ligand A is much more favorable.

**3. logP:** Both ligands have acceptable logP values (2.781 and 1.368), falling within the 1-3 range. Ligand A is slightly better.

**4. H-Bond Donors:** Both ligands have reasonable HBD counts (2 and 3 respectively), well below the 5 threshold.

**5. H-Bond Acceptors:** Ligand A (3) is better than Ligand B (5), both are below the 10 threshold.

**6. QED:** Both ligands have similar QED values (0.628 and 0.644), indicating good drug-likeness.

**7. DILI:** Ligand A (13.339) has a much lower DILI risk than Ligand B (48.817). This is a significant advantage for Ligand A.

**8. BBB:** Ligand A (68.282) is better than Ligand B (65.607), but both are below the desirable >70 percentile for CNS targets. However, given the other parameters, Ligand A's slightly better BBB is a positive.

**9. Caco-2:** Ligand A (-4.673) and Ligand B (-5.431) are both very poor. This suggests poor intestinal absorption for both.

**10. Solubility:** Ligand A (-2.07) is better than Ligand B (-3.442), although both are poor.

**11. hERG:** Both ligands have very low hERG inhibition liability (0.281 and 0.247), which is excellent.

**12. Cl_mic:** Ligand A (35.038) has a lower microsomal clearance than Ligand B (8.751), indicating better metabolic stability.

**13. t1/2:** Ligand A (-9.751) has a much longer in vitro half-life than Ligand B (18.761). This is a significant advantage.

**14. Pgp:** Both ligands have very low P-gp efflux liability (0.092 and 0.042), which is favorable for CNS penetration.

**15. Binding Affinity:** Ligand A (-7.8) has a slightly better binding affinity than Ligand B (-7.0). While both are good, the 0.8 kcal/mol difference is noticeable.

**Overall Assessment:**

Ligand A is significantly better than Ligand B. It has a lower TPSA, lower DILI risk, better metabolic stability (lower Cl_mic, longer t1/2), slightly better BBB penetration, and slightly better binding affinity. While both have poor Caco-2 and solubility, the CNS target makes these less critical than the other factors. The combination of better ADME properties and comparable affinity makes Ligand A the more promising candidate.

Output:
1
2025-04-17 08:18:09,298 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (339.366) is slightly better positioned.

**TPSA:** Ligand A (55.4) is excellent for CNS penetration, well below the 90 A^2 threshold. Ligand B (114.17) is higher, potentially hindering BBB penetration, but still within a reasonable range.

**logP:** Ligand A (3.701) is optimal. Ligand B (0.109) is significantly low, which could lead to poor membrane permeability and bioavailability.

**H-Bond Donors/Acceptors:** Ligand A (HBD=1, HBA=3) is favorable. Ligand B (HBD=3, HBA=8) is acceptable, but the higher HBA might slightly impact permeability.

**QED:** Both ligands have similar QED values (A: 0.667, B: 0.572), indicating reasonable drug-likeness.

**DILI:** Ligand A (85.77) has a moderate DILI risk, while Ligand B (98.488) has a high DILI risk. This is a significant negative for Ligand B.

**BBB:** Ligand A (73.943) has good BBB penetration potential. Ligand B (22.257) has very poor predicted BBB penetration, a critical drawback for a CNS target like DRD2.

**Caco-2 Permeability:** Ligand A (-4.422) has poor Caco-2 permeability. Ligand B (-5.751) is even worse.

**Aqueous Solubility:** Ligand A (-5.511) has poor solubility. Ligand B (-3.395) is slightly better, but still poor.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (A: 0.551, B: 0.133).

**Microsomal Clearance:** Ligand A (102.147) has moderate clearance. Ligand B (-7.819) has negative clearance, which is not physically possible and likely indicates an error or outlier in the prediction. This is a major red flag for Ligand B.

**In vitro Half-Life:** Both ligands have similar in vitro half-lives (A: 50.318, B: 48.361).

**P-gp Efflux:** Ligand A (0.808) has moderate P-gp efflux liability. Ligand B (0.042) has very low P-gp efflux, which is favorable.

**Binding Affinity:** Both ligands have excellent binding affinities (A: -10 kcal/mol, B: -9.2 kcal/mol). The difference is minimal.

**Overall Assessment:**

Ligand A is significantly more promising. It has a better logP, a much better BBB prediction, and a lower DILI risk. While its Caco-2 permeability and solubility are poor, these can potentially be addressed through formulation strategies. Ligand B suffers from a very low logP, extremely poor BBB penetration, high DILI risk, and an impossible microsomal clearance value. The slightly better P-gp profile of Ligand B is not enough to overcome these significant drawbacks.

Output:
1
2025-04-17 08:18:09,298 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 drug candidates, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (413.268 Da) is slightly higher, but acceptable. Ligand B (352.547 Da) is also good.

**TPSA:** Ligand A (82.81) is borderline for CNS penetration, being above the preferred <90. Ligand B (16.13) is excellent, well below the threshold, suggesting better CNS penetration potential.

**logP:** Ligand A (2.049) is within the optimal range (1-3). Ligand B (4.964) is higher, potentially leading to solubility issues and off-target effects, though not dramatically so.

**H-Bond Donors/Acceptors:** Ligand A has 1 HBD and 7 HBA, which are reasonable. Ligand B has 0 HBD and 3 HBA, also acceptable.

**QED:** Both ligands have similar QED values (0.7 and 0.776), indicating good drug-likeness.

**DILI:** Ligand A (75.572) has a higher DILI risk than Ligand B (24.428). This is a significant concern for Ligand A.

**BBB:** Ligand A (58.86) has a moderate BBB penetration, while Ligand B (96.433) has excellent BBB penetration. This is a crucial advantage for Ligand B as DRD2 is a CNS target.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.116 and -5.172), which is unusual and suggests poor permeability. However, these values are on a log scale and can be misleading.

**Aqueous Solubility:** Both ligands have negative solubility values (-2.562 and -3.612), indicating poor aqueous solubility. This is a concern for both.

**hERG Inhibition:** Ligand A (0.45) has a slightly lower hERG risk than Ligand B (0.928), which is preferable.

**Microsomal Clearance:** Ligand A (49.757) has a higher microsomal clearance than Ligand B (21.784), meaning it's likely to be metabolized faster.

**In vitro Half-Life:** Ligand A (70.821) has a longer in vitro half-life than Ligand B (-19.495). The negative value for Ligand B is concerning and likely an artifact or error.

**P-gp Efflux:** Ligand A (0.375) has lower P-gp efflux liability than Ligand B (0.719), which is beneficial for CNS exposure.

**Binding Affinity:** Ligand B (-9.8 kcal/mol) has a significantly stronger binding affinity than Ligand A (-8.4 kcal/mol). This 1.4 kcal/mol difference is substantial and can outweigh many ADME drawbacks.

**Overall Assessment:**

Ligand B is the more promising candidate. While it has a higher logP and P-gp efflux, its significantly superior BBB penetration and binding affinity are critical for a CNS GPCR target like DRD2. The lower DILI risk is also a major advantage. The negative half-life value for ligand B is a red flag and needs investigation, but the strong binding affinity makes it worth pursuing. Ligand A's higher DILI risk and lower BBB penetration are significant drawbacks.

Output:
1
2025-04-17 08:18:09,299 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (347.415 and 352.391 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (84.67) is excellent, well below the 90 A^2 threshold for CNS targets. Ligand B (117.67) is higher, but still potentially acceptable, though less ideal.

**logP:** Ligand A (1.24) is within the optimal 1-3 range. Ligand B (-0.731) is slightly below 1, which could potentially hinder permeability.

**H-Bond Donors/Acceptors:** Ligand A (HBD=1, HBA=5) is good. Ligand B (HBD=2, HBA=7) is also acceptable.

**QED:** Ligand A (0.866) has a very strong drug-like profile. Ligand B (0.697) is still reasonably good, above the 0.5 threshold.

**DILI:** Ligand A (37.611) has a low DILI risk. Ligand B (44.591) is slightly higher, but still within an acceptable range.

**BBB:** This is critical for a CNS target. Ligand A (78.868) is good, above 70%. Ligand B (25.204) is very poor, indicating limited brain penetration.

**Caco-2 Permeability:** Ligand A (-4.804) is a negative value, which is unusual and requires further investigation, but suggests poor permeability. Ligand B (-5.258) is also poor.

**Aqueous Solubility:** Both ligands have negative solubility values (-2.183 and -1.026), which is concerning. Solubility is generally a desirable property.

**hERG Inhibition:** Both ligands have very low hERG risk (0.243 and 0.034).

**Microsomal Clearance:** Ligand A (30.13) is moderate. Ligand B (-7.095) is negative, which is not physically possible and indicates an error or an unusual calculation.

**In vitro Half-Life:** Ligand A (6.745) is reasonable. Ligand B (-5.018) is negative, which is not physically possible.

**P-gp Efflux:** Both ligands show low P-gp efflux liability (0.123 and 0.008), which is favorable for CNS penetration.

**Binding Affinity:** Ligand A (-9.3 kcal/mol) has significantly stronger binding affinity than Ligand B (-7.9 kcal/mol). The difference of 1.4 kcal/mol is substantial and can outweigh some ADME drawbacks.

**Overall Assessment:**

Ligand A is superior due to its significantly higher binding affinity, better TPSA, and good BBB penetration. While its Caco-2 permeability and solubility are concerning (and require further investigation), the strong binding and favorable BBB outweigh these issues, especially for a CNS target like DRD2. Ligand B's extremely poor BBB penetration is a deal-breaker, even with a reasonable affinity. The negative values for microsomal clearance and half-life for Ligand B are also highly suspect.

Output:
1
2025-04-17 08:18:09,299 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (361.467 Da) is slightly higher than Ligand B (343.479 Da), but both are acceptable.

**TPSA:** Ligand A (72.48) is excellent for CNS penetration, well below the 90 A^2 threshold. Ligand B (81.76) is still reasonable, but less optimal.

**logP:** Ligand A (3.818) is at the higher end of the optimal range (1-3), while Ligand B (2.223) is closer to the lower end. Both are acceptable, but higher logP can sometimes lead to off-target effects.

**H-Bond Donors/Acceptors:** Ligand A (HBD=2, HBA=5) and Ligand B (HBD=3, HBA=6) both have reasonable numbers of H-bond donors and acceptors, falling within the acceptable limits.

**QED:** Both ligands have QED values above 0.5 (Ligand A: 0.786, Ligand B: 0.682), indicating good drug-like properties.

**DILI:** Ligand A (76.968) has a higher DILI risk than Ligand B (23.73). This is a significant drawback for Ligand A.

**BBB:** Ligand A (79.682) has a much better BBB percentile than Ligand B (53.548). This is a critical advantage for a CNS target like DRD2.

**Caco-2 Permeability:** Ligand A (-4.539) shows poor Caco-2 permeability, suggesting poor intestinal absorption. Ligand B (-5.732) is also poor, but slightly worse.

**Aqueous Solubility:** Ligand A (-4.506) has poor aqueous solubility, while Ligand B (-2.145) is slightly better.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (Ligand A: 0.523, Ligand B: 0.852).

**Microsomal Clearance:** Ligand A (76.382) has higher microsomal clearance than Ligand B (0.521), meaning it's metabolized more quickly. This is a negative for Ligand A.

**In vitro Half-Life:** Ligand A (20.468) has a longer half-life than Ligand B (11.183).

**P-gp Efflux:** Both ligands show low P-gp efflux (Ligand A: 0.439, Ligand B: 0.014). Ligand B is slightly better.

**Binding Affinity:** Both ligands have excellent binding affinity (Ligand A: -8.0 kcal/mol, Ligand B: -8.5 kcal/mol). Ligand B is slightly more potent.

**Overall Assessment:**

Ligand A has a strong advantage in BBB penetration and in vitro half-life. However, it suffers from higher DILI risk, poor Caco-2 permeability, and higher microsomal clearance. Ligand B has better DILI, slightly better solubility, and a slightly better binding affinity, but significantly lower BBB penetration.

Given the GPCR-specific priority for BBB penetration in CNS targets, and the fact that the affinity difference is small, the superior BBB score of Ligand A outweighs its other drawbacks. The DILI risk is concerning, but can potentially be addressed through structural modifications. The poor Caco-2 permeability is less critical for a CNS target.

Output:
1
2025-04-17 08:18:09,299 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (357.451 and 348.491 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (113.6) is borderline for CNS targets, slightly above the preferred <90, but acceptable. Ligand B (68.3) is excellent, well below 90.

**3. logP:** Ligand A (0.501) is quite low, potentially hindering membrane permeability. Ligand B (3.241) is optimal.

**4. H-Bond Donors:** Ligand A (3) is within the acceptable limit. Ligand B (2) is also good.

**5. H-Bond Acceptors:** Ligand A (5) is within the acceptable limit. Ligand B (6) is also good.

**6. QED:** Ligand A (0.389) is below the desirable threshold of 0.5. Ligand B (0.668) is above the threshold, indicating better drug-likeness.

**7. DILI:** Ligand A (20.861) has a significantly lower DILI risk than Ligand B (34.665).

**8. BBB:** Ligand A (45.638) has a poor BBB percentile, making CNS penetration unlikely. Ligand B (90.306) has an excellent BBB percentile, highly desirable for a DRD2 ligand.

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.358 and -5.043), which is unusual and suggests poor permeability. However, these values are on a scale where negative values are possible, and the absolute magnitude isn't directly comparable without knowing the scale's specifics.

**10. Aqueous Solubility:** Both ligands have negative solubility values (-1.406 and -3.004), which is also unusual. Similar to Caco-2, the scale is unknown.

**11. hERG Inhibition:** Ligand A (0.123) has a very low hERG risk. Ligand B (0.879) has a moderate hERG risk.

**12. Microsomal Clearance:** Ligand A (45.961) has a moderate clearance, suggesting moderate metabolic stability. Ligand B (75.675) has a higher clearance, indicating lower metabolic stability.

**13. In vitro Half-Life:** Ligand A (-24.204) has a negative half-life, which is not physically possible and suggests an issue with the data. Ligand B (30.048) has a reasonable half-life.

**14. P-gp Efflux:** Ligand A (0.009) has very low P-gp efflux, which is favorable for CNS penetration. Ligand B (0.306) has a moderate P-gp efflux.

**15. Binding Affinity:** Ligand B (-8.5 kcal/mol) has a significantly stronger binding affinity than Ligand A (-7.8 kcal/mol). This 0.7 kcal/mol difference is substantial and could outweigh some ADME drawbacks.

**Overall Assessment:**

Despite Ligand A's lower DILI risk and P-gp efflux, Ligand B is the superior candidate. The critical factors driving this decision are:

*   **BBB:** Ligand B's excellent BBB penetration (90.306) is crucial for a CNS target like DRD2. Ligand A's BBB penetration is very poor.
*   **logP:** Ligand B's optimal logP (3.241) is much better than Ligand A's low logP (0.501).
*   **Affinity:** Ligand B has a significantly stronger binding affinity (-8.5 kcal/mol vs -7.8 kcal/mol).
*   **QED:** Ligand B has a better QED score.

The unusual negative values for Caco-2 and solubility are concerning for both, but the overall profile of Ligand B is much more promising, particularly its BBB penetration and binding affinity. The lower metabolic stability of Ligand B could be addressed through structural modifications.

Output:
1
2025-04-17 08:18:09,299 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (354.328 and 363.483 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (62.55) is significantly better than Ligand B (78.51). For CNS targets, we want TPSA <= 90, and ideally closer to 60. Ligand A is much closer to this ideal.

**3. logP:** Ligand A (4.218) is a bit high, potentially causing solubility issues or off-target interactions. Ligand B (1.93) is within the optimal range (1-3).

**4. H-Bond Donors:** Both have acceptable HBD counts (1 and 2 respectively), well below the threshold of 5.

**5. H-Bond Acceptors:** Both have acceptable HBA counts (3), well below the threshold of 10.

**6. QED:** Both ligands have good QED scores (0.834 and 0.858), indicating good drug-like properties.

**7. DILI:** Ligand A (72.005) has a higher DILI risk than Ligand B (44.552). Ligand B is preferable here.

**8. BBB:** Ligand A (96.161) has excellent BBB penetration, while Ligand B (82.202) is good, but not as high. This is a critical factor for a CNS target like DRD2.

**9. Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and suggests poor permeability. However, the scale is not specified, so it's difficult to interpret.

**10. Aqueous Solubility:** Both have negative solubility values, which is also unusual and suggests poor solubility. Again, the scale is not specified.

**11. hERG Inhibition:** Both ligands have low hERG inhibition risk (0.772 and 0.52).

**12. Microsomal Clearance:** Ligand A (19.731) has lower microsomal clearance than Ligand B (22.188), suggesting better metabolic stability.

**13. In vitro Half-Life:** Ligand A (26.539) has a longer half-life than Ligand B (-9.877). The negative value for B is concerning.

**14. P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.498 and 0.078).

**15. Binding Affinity:** Both ligands have the same binding affinity (-9.5 kcal/mol), which is excellent.

**Overall Assessment:**

Ligand A excels in BBB penetration, TPSA, and metabolic stability (lower Cl_mic and longer half-life). Ligand B has a better logP and lower DILI risk. However, the significantly better BBB penetration of Ligand A is crucial for a CNS target. While Ligand A's logP is slightly elevated, the strong binding affinity (-9.5 kcal/mol) might compensate for this. The negative solubility and Caco-2 values are concerning for both, but the superior CNS penetration profile of Ligand A makes it the more promising candidate.

Output:
1
2025-04-17 08:18:09,300 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (408.267 Da) is slightly higher than Ligand B (350.478 Da), but both are acceptable.

**TPSA:** Ligand A (47.56) is better than Ligand B (49.41) as it is closer to the <90 A^2 threshold for CNS targets. Both are acceptable, but A is preferable.

**logP:** Both ligands have good logP values (A: 4.376, B: 3.201) falling within the optimal range of 1-3. Ligand B is slightly better.

**H-Bond Donors/Acceptors:** Both ligands have acceptable HBD (1) and HBA (A: 3, B: 2) counts, well below the thresholds of 5 and 10, respectively.

**QED:** Both ligands have good QED scores (A: 0.817, B: 0.846), indicating good drug-like properties.

**DILI:** Ligand A (70.26) has a higher DILI risk than Ligand B (16.789). This is a significant drawback for Ligand A.

**BBB:** Ligand B (93.253) has a substantially better BBB penetration score than Ligand A (78.868). This is crucial for a CNS target like DRD2.

**Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual. However, the magnitude of negativity is similar, so this isn't a major differentiator.

**Aqueous Solubility:** Both have negative solubility values, which is also unusual. Again, the magnitude is similar.

**hERG:** Both ligands have low hERG inhibition liability (A: 0.821, B: 0.632), which is good.

**Microsomal Clearance:** Ligand B (36.319) has significantly lower microsomal clearance than Ligand A (76.238), indicating better metabolic stability.

**In vitro Half-Life:** Ligand A (77.311) has a better in vitro half-life than Ligand B (-7.543).

**P-gp Efflux:** Ligand A (0.693) has lower P-gp efflux than Ligand B (0.194), which is favorable for CNS penetration.

**Binding Affinity:** Both ligands have the same binding affinity (-9.6 kcal/mol), which is excellent.

**Overall Assessment:**

Ligand B is the stronger candidate. While Ligand A has a slightly better TPSA and in vitro half-life, Ligand B excels in the critical areas for a CNS GPCR target: significantly better BBB penetration, lower DILI risk, and lower microsomal clearance (better metabolic stability). The P-gp efflux is worse for Ligand B, but the superior BBB penetration likely outweighs this. The similar binding affinity means that the ADME properties are the deciding factors.

Output:
1
2025-04-17 08:18:09,300 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (371.424 and 369.511 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (46.17) is better than Ligand B (37.38) as it is closer to the ideal range of <90 for CNS targets.

**3. logP:** Both ligands have logP values (4.905 and 4.688) that are slightly high, potentially leading to solubility issues or off-target interactions. However, they are not drastically outside the optimal 1-3 range.

**4. H-Bond Donors:** Ligand A (1) is preferable to Ligand B (0) as it is closer to the ideal range of <=5.

**5. H-Bond Acceptors:** Both ligands have 3 HBA, which is within the acceptable limit of <=10.

**6. QED:** Ligand A (0.766) has a slightly better QED score than Ligand B (0.672), indicating a more drug-like profile.

**7. DILI:** Ligand B (79.682) has a significantly lower DILI risk than Ligand A (47.034), which is a major advantage.

**8. BBB:** Ligand A (93.525) has a substantially higher BBB penetration percentile than Ligand B (78.907). This is *critical* for a CNS target like DRD2.

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 values, indicating poor permeability. Ligand A (-4.6) is slightly better than Ligand B (-5.096).

**10. Aqueous Solubility:** Both ligands have very poor aqueous solubility (-5.224 and -6.238). This is a concern, but can sometimes be mitigated with formulation strategies.

**11. hERG Inhibition:** Ligand A (0.411) has a lower hERG inhibition liability than Ligand B (0.831), indicating a lower risk of cardiotoxicity.

**12. Microsomal Clearance:** Ligand B (68.287) has a lower microsomal clearance than Ligand A (50.471), suggesting better metabolic stability.

**13. In vitro Half-Life:** Ligand B (34.372) has a significantly longer in vitro half-life than Ligand A (10.475), which is a positive attribute.

**14. P-gp Efflux:** Ligand A (0.428) has lower P-gp efflux liability than Ligand B (0.73), which is preferable for CNS exposure.

**15. Binding Affinity:** Ligand B (-9.5 kcal/mol) has a significantly stronger binding affinity than Ligand A (-7.8 kcal/mol). This is a substantial advantage, potentially outweighing some of the ADME drawbacks.

**Overall Assessment:**

While Ligand B has better metabolic stability (lower Cl_mic, longer t1/2), lower DILI risk, and *much* stronger binding affinity, Ligand A has a significantly better BBB score and lower P-gp efflux. Given that this is a CNS target (DRD2), BBB penetration is paramount. The strong affinity of Ligand B is very attractive, but the lower BBB and higher P-gp efflux could severely limit its brain exposure. The higher TPSA of Ligand A is also a slight advantage.

Considering the GPCR-specific priorities, the superior BBB penetration of Ligand A, combined with its acceptable TPSA and P-gp efflux, makes it the more promising candidate *despite* the weaker binding affinity. The difference in affinity (1.7 kcal/mol) is significant, but not insurmountable, and could potentially be optimized in subsequent iterations.

Output:
0
2025-04-17 08:18:09,300 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B based on the provided guidelines, prioritizing GPCR-specific properties (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (368.499 and 393.286 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (78.87) is slightly higher than Ligand B (69.64). Both are below the 90 A^2 threshold desirable for CNS targets, but Ligand B is better.

**logP:** Ligand A (0.8) is a bit low, potentially hindering permeability. Ligand B (2.097) is within the optimal 1-3 range. This favors Ligand B.

**H-Bond Donors/Acceptors:** Both have 2 HBDs, which is good. Ligand A has 5 HBAs, while Ligand B has 3. Both are acceptable (<=10), with Ligand B being slightly better.

**QED:** Ligand A (0.767) has a better QED score than Ligand B (0.568), indicating better overall drug-likeness.

**DILI:** Both ligands have low DILI risk (Ligand A: 41.838, Ligand B: 37.767), both well below the 60 threshold.

**BBB:** This is crucial for a DRD2 ligand. Ligand B (72.005) is significantly better than Ligand A (28.306), exceeding the desirable >70 percentile.

**Caco-2 Permeability:** Both have negative values (-4.958 and -5.052). This is unusual and suggests poor permeability. However, the scale isn't specified, so we can't interpret these values definitively.

**Aqueous Solubility:** Both have negative values (-3.061 and -2.985) which is also unusual.

**hERG:** Both ligands have very low hERG inhibition liability (Ligand A: 0.236, Ligand B: 0.42), which is excellent.

**Microsomal Clearance:** Ligand A (46.237) has higher clearance than Ligand B (9.141), meaning Ligand B is more metabolically stable.

**In vitro Half-Life:** Ligand B (-10.897) has a negative half-life, which is not possible. This is a data error. Ligand A (13.404) has a reasonable half-life.

**P-gp Efflux:** Both have low P-gp efflux liability (Ligand A: 0.064, Ligand B: 0.274), which is good for CNS penetration.

**Binding Affinity:** Ligand A (-7.9 kcal/mol) has a slightly better binding affinity than Ligand B (0.0 kcal/mol). This is a significant advantage.

**Overall Assessment:**

Despite Ligand A's slightly better QED and binding affinity, Ligand B is the more promising candidate. The critical factor is the significantly higher BBB penetration (72.005 vs 28.306). The better logP and lower microsomal clearance of Ligand B also contribute to its favorability. The negative half-life for Ligand B is a data error that would need to be investigated. Although both have poor Caco-2 and solubility values, the BBB score for Ligand B is the deciding factor for a CNS target like DRD2.

Output:
1
2025-04-17 08:18:09,300 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (366.531 and 352.431 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (55.89) is excellent, well below the 90 A^2 threshold for CNS targets. Ligand B (88.1) is higher, but still potentially acceptable, though less optimal.

**logP:** Ligand A (2.361) is within the optimal 1-3 range. Ligand B (-0.223) is significantly lower, which is a concern for membrane permeability and CNS penetration.

**H-Bond Donors/Acceptors:** Ligand A (HBD=1, HBA=4) and Ligand B (HBD=2, HBA=5) both have reasonable numbers of H-bond donors and acceptors, staying within the guidelines.

**QED:** Ligand A (0.869) has a very good QED score, indicating high drug-likeness. Ligand B (0.619) is still acceptable, but lower.

**DILI:** Ligand A (56.534) has a moderate DILI risk, but is still within an acceptable range. Ligand B (25.553) has a very low DILI risk, which is favorable.

**BBB:** Ligand A (76.309) has a good BBB percentile, exceeding the 70% threshold for CNS targets. Ligand B (29.003) has a very poor BBB percentile, making CNS penetration unlikely.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.531 and -4.661), which is unusual and suggests poor permeability. However, these values are on a scale where negative values are possible and don't necessarily disqualify a compound.

**Aqueous Solubility:** Both ligands have negative solubility values (-3.542 and -1.698), indicating poor aqueous solubility. This could pose formulation challenges.

**hERG Inhibition:** Ligand A (0.898) has a slightly elevated hERG risk, but not critically high. Ligand B (0.157) has a very low hERG risk, which is a significant advantage.

**Microsomal Clearance:** Ligand A (13.857) has moderate microsomal clearance. Ligand B (-0.067) has very low clearance, indicating high metabolic stability.

**In vitro Half-Life:** Ligand A (11.198) has a moderate in vitro half-life. Ligand B (-3.08) has a very short half-life, which is a major drawback.

**P-gp Efflux:** Ligand A (0.289) has low P-gp efflux, which is good for CNS exposure. Ligand B (0.067) also has low P-gp efflux.

**Binding Affinity:** Ligand A (0.0) has a weak binding affinity. Ligand B (-7.6) has a very strong binding affinity, exceeding the >-7.0 kcal/mol threshold. This is a substantial advantage.

**Overall Assessment:**

Ligand B has a significantly stronger binding affinity, very low DILI and hERG risk, and excellent metabolic stability. However, its low logP and poor BBB penetration are major concerns for a CNS target like DRD2. Ligand A has a better logP and BBB, but weaker affinity, moderate DILI, and a slightly elevated hERG risk.

Despite the strong affinity of Ligand B, the poor BBB penetration is a critical flaw for a CNS drug. While improvements to solubility and permeability might be possible through prodrug strategies or formulation, overcoming a poor BBB prediction is extremely challenging. Ligand A, while not perfect, has a more favorable profile for CNS penetration and a reasonable (though not ideal) affinity.

Output:
1
2025-04-17 08:18:09,301 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (368.503 and 348.447 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (84.3) is better than Ligand B (76.46). Both are below the 90 A^2 threshold for CNS targets, which is excellent.

**logP:** Both ligands have good logP values (2.105 and 1.748), falling within the optimal 1-3 range. Ligand B is slightly lower, which *could* indicate slightly better solubility, but isn't a major difference.

**H-Bond Donors & Acceptors:** Both have 1 HBD and 5 HBA, which are within acceptable limits.

**QED:** Ligand A (0.882) has a significantly higher QED score than Ligand B (0.726), indicating a more drug-like profile.

**DILI:** Ligand A (45.483) has a slightly higher DILI risk than Ligand B (31.989), but both are below the concerning threshold of 60.

**BBB:** Ligand A (81.233) has a better BBB percentile than Ligand B (73.943). While both are reasonably good, Ligand A is closer to the desirable >70 mark for CNS targets.

**Caco-2 Permeability:** Ligand A (-4.812) has a worse Caco-2 permeability than Ligand B (-5.316). Lower values indicate lower permeability, making Ligand B slightly better in this aspect.

**Aqueous Solubility:** Ligand A (-2.914) has worse solubility than Ligand B (-1.78).

**hERG Inhibition:** Ligand A (0.07) has a slightly higher hERG inhibition risk than Ligand B (0.216), but both are very low.

**Microsomal Clearance:** Ligand B (16.157) has a significantly higher microsomal clearance than Ligand A (4.219), meaning Ligand A is more metabolically stable.

**In vitro Half-Life:** Ligand A (12.731) has a longer half-life than Ligand B (-8.713).

**P-gp Efflux:** Ligand A (0.075) has lower P-gp efflux liability than Ligand B (0.054), which is favorable for CNS penetration.

**Binding Affinity:** Ligand A (-8.1 kcal/mol) has slightly better binding affinity than Ligand B (-8.0 kcal/mol). While the difference is small, it's still a positive for Ligand A.

**Overall Assessment:**

Considering the GPCR-specific priorities, Ligand A is the stronger candidate. It has a better BBB score, higher QED, better metabolic stability (lower Cl_mic, longer t1/2), lower P-gp efflux, and slightly better binding affinity. While Ligand B has slightly better Caco-2 permeability and solubility, the CNS target profile of DRD2 makes BBB penetration and metabolic stability more critical. The small difference in binding affinity is less important than the ADME advantages of Ligand A.

Output:
1
2025-04-17 08:18:09,301 - INFO - Okay, let's analyze these two ligands for their potential as DRD2 drug candidates. DRD2 is a GPCR in the CNS, so BBB penetration, logP, Pgp efflux, TPSA, and binding affinity are paramount.

**Ligand A:** [399.292, 59.29, 3.527, 1, 4, 0.683, 72.276, 78.79, -5.273, -4.331, 0.355, 25.886, 39.928, 0.667, -10.1]
**Ligand B:** [366.571, 49.41, 3.475, 1, 3, 0.702, 8.492, 76.89, -4.705, -3.876, 0.607, 89.673, 4.256, 0.057, -7.9]

**Step-by-step comparison:**

1. **MW:** Both are within the ideal 200-500 Da range. A (399.292) is slightly higher than B (366.571), but both are acceptable.
2. **TPSA:** A (59.29) is higher than B (49.41). Both are below the 90 A^2 threshold for CNS targets, but B is preferable.
3. **logP:** Both are in the optimal 1-3 range (A: 3.527, B: 3.475). Very similar, no clear advantage.
4. **HBD:** Both have 1 HBD, which is good.
5. **HBA:** A has 4 HBA, B has 3. Both are acceptable (<=10). B is slightly better.
6. **QED:** Both have good QED scores (A: 0.683, B: 0.702), indicating drug-likeness. B is slightly better.
7. **DILI:** A (72.276) has a higher DILI risk than B (8.492). This is a significant advantage for B.
8. **BBB:** Both have good BBB penetration (A: 78.79, B: 76.89), exceeding the 70% threshold. A is slightly better.
9. **Caco-2:** A (-5.273) and B (-4.705) both have negative values, which is unusual and suggests poor permeability. B is slightly better.
10. **Solubility:** Both have poor solubility (-4.331 for A, -3.876 for B). This is a concern for both, but B is slightly better.
11. **hERG:** Both have low hERG risk (A: 0.355, B: 0.607). B is slightly better.
12. **Cl_mic:** A (25.886) has a lower (better) microsomal clearance than B (89.673), indicating better metabolic stability. This is a significant advantage for A.
13. **t1/2:** A (39.928) has a much longer in vitro half-life than B (4.256). This is a major advantage for A.
14. **Pgp:** A (0.667) has lower P-gp efflux than B (0.057). This is a significant advantage for A, particularly for CNS penetration.
15. **Binding Affinity:** A (-10.1) has a *much* stronger binding affinity than B (-7.9). This is a substantial advantage, potentially outweighing some ADME concerns.

**Overall Assessment:**

While Ligand B has advantages in DILI, TPSA, QED, and hERG, Ligand A's significantly stronger binding affinity (-10.1 vs -7.9 kcal/mol) and superior P-gp efflux profile, coupled with a longer half-life and better metabolic stability, are crucial for a CNS GPCR target like DRD2. The slightly higher DILI risk of A is a concern, but can be addressed in later optimization stages. The binding affinity difference is substantial enough to prioritize A.

Output:
1
2025-04-17 08:18:09,301 - INFO - Batch 437 complete. Total preferences: 6992
2025-04-17 08:18:09,301 - INFO - Processing batch 438/512...
2025-04-17 08:18:51,280 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (341.386 and 345.399 Da) fall comfortably within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (62.3) is significantly better than Ligand B (88.58). For CNS targets, we want TPSA <= 90, and A is much closer to the ideal <=60 range. B is approaching a concerning level.

**3. logP:** Both ligands have good logP values (2.62 and 2.45), falling within the optimal 1-3 range.

**4. H-Bond Donors:** Both have 1 HBD, which is acceptable.

**5. H-Bond Acceptors:** Ligand A has 3 HBA, and Ligand B has 5. Both are within the acceptable limit of <=10, but A is preferable.

**6. QED:** Both ligands have high QED scores (0.93 and 0.899), indicating good drug-like properties.

**7. DILI:** Ligand A (53.354) has a slightly better DILI score than Ligand B (60.644), indicating a lower risk of liver injury. Both are acceptable (<60 is good).

**8. BBB:** Ligand A (81.698) has a significantly better BBB penetration score than Ligand B (70.182). For a CNS target like DRD2, >70 is desirable, and A is closer to this threshold.

**9. Caco-2 Permeability:** Both have negative Caco-2 values (-4.767 and -4.894). This is unusual and suggests poor permeability. However, we must consider this in context with other parameters.

**10. Aqueous Solubility:** Both have negative solubility values (-3.263 and -3.165). This is also concerning, but again, needs to be considered alongside other properties.

**11. hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.334 and 0.13). This is excellent.

**12. Microsomal Clearance:** Ligand A (20.587) has a lower microsomal clearance than Ligand B (40.003), suggesting better metabolic stability.

**13. In vitro Half-Life:** Ligand A (-7.17) has a better (longer) in vitro half-life than Ligand B (-5.273).

**14. P-gp Efflux:** Ligand A (0.137) has a lower P-gp efflux liability than Ligand B (0.055), which is favorable for CNS penetration.

**15. Binding Affinity:** Ligand A (-10.3 kcal/mol) has a significantly stronger binding affinity than Ligand B (-8.3 kcal/mol). This is a substantial advantage (2 kcal/mol difference).

**Overall Assessment:**

Ligand A is clearly superior. It has better TPSA, BBB penetration, metabolic stability (lower Cl_mic, longer t1/2), lower P-gp efflux, and significantly stronger binding affinity. While both ligands have concerningly negative Caco-2 and solubility values, the superior CNS penetration profile and binding affinity of Ligand A outweigh these drawbacks, especially given the GPCR target. The difference in binding affinity is substantial enough to be a key driver in the decision.

Output:
1
2025-04-17 08:18:51,280 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (358.507 and 365.539 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (40.62) is better than Ligand B (38.77), both are below the 90 A^2 threshold for CNS targets.

**3. logP:** Ligand A (3.05) is within the optimal range (1-3). Ligand B (4.078) is slightly higher, potentially increasing off-target effects and decreasing solubility.

**4. H-Bond Donors:** Both ligands have 0 HBD, which is acceptable.

**5. H-Bond Acceptors:** Ligand A has 3 HBA, and Ligand B has 4. Both are below the 10 threshold.

**6. QED:** Ligand A (0.812) has a significantly better QED score than Ligand B (0.73), indicating better overall drug-likeness.

**7. DILI:** Ligand A (21.946) has a much lower DILI risk than Ligand B (36.06), suggesting a safer profile.

**8. BBB:** Ligand A (85.111) has a better BBB penetration percentile than Ligand B (75.921), which is crucial for a CNS target like DRD2.

**9. Caco-2 Permeability:** Ligand A (-5.069) and Ligand B (-4.809) both have negative values, which is unusual and difficult to interpret without knowing the scale. However, they are relatively similar.

**10. Aqueous Solubility:** Ligand A (-3.344) and Ligand B (-4.26) both have negative values, indicating poor solubility. Ligand B is slightly worse.

**11. hERG Inhibition:** Ligand A (0.344) has a lower hERG inhibition liability than Ligand B (0.914), making it safer from a cardiotoxicity perspective.

**12. Microsomal Clearance:** Ligand A (39.234) has a lower microsomal clearance than Ligand B (125.903), indicating better metabolic stability.

**13. In vitro Half-Life:** Ligand A (8.76) has a shorter half-life than Ligand B (43.641). This is a drawback for Ligand A, but can be mitigated with formulation strategies.

**14. P-gp Efflux:** Ligand A (0.348) has lower P-gp efflux liability than Ligand B (0.682), which is beneficial for CNS exposure.

**15. Binding Affinity:** Both ligands have the same binding affinity (-7.5 kcal/mol), which is excellent.

**Overall Assessment:**

Ligand A is superior to Ligand B. While Ligand B has a longer in vitro half-life, Ligand A excels in almost all other critical parameters, especially those prioritized for GPCRs targeting the CNS: BBB penetration, DILI risk, hERG inhibition, P-gp efflux, and QED. The better solubility and metabolic stability of Ligand A are also significant advantages. The similar binding affinity makes the ADME/Tox differences the deciding factor.

Output:
0
2025-04-17 08:18:51,281 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B based on the provided guidelines, prioritizing GPCR-specific properties (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (354.447 and 346.471 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (88.1) is better than Ligand B (50.8), both are below the 90 A^2 threshold for CNS targets.

**logP:** Ligand B (3.144) is optimal (1-3), while Ligand A (0.45) is significantly low, potentially hindering permeation.

**H-Bond Donors/Acceptors:** Ligand A (2 HBD, 5 HBA) and Ligand B (1 HBD, 4 HBA) both meet the criteria of <=5 HBD and <=10 HBA.

**QED:** Both ligands have good QED scores (0.693 and 0.824, respectively), indicating drug-like properties.

**DILI:** Ligand B (15.549) has a much lower DILI risk than Ligand A (28.228), which is a significant advantage.

**BBB:** Ligand B (78.054) is significantly better than Ligand A (55.215) in terms of BBB penetration, crucial for a CNS target like DRD2.

**Caco-2 Permeability:** Ligand A (-4.954) is better than Ligand B (-4.544), but both are negative, indicating poor permeability.

**Aqueous Solubility:** Ligand A (-0.992) is better than Ligand B (-3.261).

**hERG:** Ligand A (0.134) has a lower hERG risk than Ligand B (0.556).

**Microsomal Clearance:** Ligand A (-0.287) has lower clearance and thus better metabolic stability than Ligand B (55.949).

**In vitro Half-Life:** Ligand A (33.552) has a longer half-life than Ligand B (3.209).

**P-gp Efflux:** Ligand A (0.028) has a lower P-gp efflux liability than Ligand B (0.176), which is favorable for CNS penetration.

**Binding Affinity:** Ligand B (-7.5) has slightly better binding affinity than Ligand A (-7.4), but the difference is minimal.

**Overall Assessment:**

While Ligand A has some advantages in metabolic stability, half-life, and P-gp efflux, Ligand B is clearly superior due to its significantly better BBB penetration, lower DILI risk, and optimal logP. The slightly better binding affinity of Ligand B is a bonus. The low logP of Ligand A is a major concern for CNS penetration, outweighing its other benefits. For a GPCR target in the CNS, BBB penetration is paramount, and Ligand B excels in this area.

Output:
1
2025-04-17 08:18:51,281 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (342.483 and 365.905 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (50.36) is significantly better than Ligand B (61.44). For CNS targets, we want TPSA <= 90, and ideally closer to 60. Ligand A is much closer to this ideal.

**3. logP:** Both ligands have good logP values (3.971 and 3.356), falling within the optimal 1-3 range.

**4. H-Bond Donors:** Both have 2 HBD, which is acceptable (<=5).

**5. H-Bond Acceptors:** Ligand A has 2 HBA, and Ligand B has 3. Both are within the acceptable range (<=10).

**6. QED:** Both ligands have similar QED values (0.85 and 0.742), indicating good drug-likeness.

**7. DILI:** Both ligands have low DILI risk (30.632 and 29.081), which is favorable.

**8. BBB:** Ligand A (91.508) has a significantly higher BBB percentile than Ligand B (82.668). This is *critical* for a CNS target like DRD2. A value >70 is desirable, and Ligand A exceeds this more comfortably.

**9. Caco-2 Permeability:** Both have negative Caco-2 values (-4.706 and -4.712). This is unusual and suggests poor permeability. However, these values are on a scale where negative values are possible, and the absolute value is similar for both.

**10. Aqueous Solubility:** Both have negative solubility values (-4.294 and -3.41). Again, this suggests poor solubility. The absolute value is slightly better for Ligand B.

**11. hERG Inhibition:** Both ligands have low hERG inhibition liability (0.733 and 0.447), which is good.

**12. Microsomal Clearance:** Ligand A (44.456) has slightly higher microsomal clearance than Ligand B (39.707), meaning it might be metabolized faster. Lower is better.

**13. In vitro Half-Life:** Ligand B (72.61) has a significantly longer in vitro half-life than Ligand A (20.189). This is a significant advantage.

**14. P-gp Efflux:** Ligand A (0.419) has lower P-gp efflux than Ligand B (0.056), which is beneficial for CNS penetration.

**15. Binding Affinity:** Ligand A (-9.2 kcal/mol) has a *much* stronger binding affinity than Ligand B (-8.1 kcal/mol). This is a difference of 1.1 kcal/mol, which is substantial and can outweigh some ADME drawbacks.

**Overall Assessment:**

Ligand A is the stronger candidate. While Ligand B has a better half-life, Ligand A's superior BBB penetration, significantly higher binding affinity, and lower P-gp efflux are crucial advantages for a CNS-targeting GPCR like DRD2. The slightly higher clearance of Ligand A is a concern, but the strong binding affinity is likely to compensate. The poor Caco-2 and solubility for both are concerning, but can be addressed with formulation strategies.

Output:
1
2025-04-17 08:18:51,281 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 drug candidates, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (347.419 Da and 354.475 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (96.45) is better than Ligand B (58.2). For CNS targets, we want TPSA <= 90, and Ligand A is closer to this threshold.

**3. logP:** Ligand A (0.949) is slightly lower than optimal (1-3), but acceptable. Ligand B (3.73) is closer to the upper end of the optimal range, which could lead to solubility issues.

**4. H-Bond Donors:** Both ligands have 2 HBD, which is within the acceptable limit of <=5.

**5. H-Bond Acceptors:** Ligand A has 5 HBA, and Ligand B has 3 HBA, both within the acceptable limit of <=10.

**6. QED:** Both ligands have good QED scores (0.845 and 0.86), indicating good drug-like properties.

**7. DILI:** Ligand A (47.538) has a lower DILI risk than Ligand B (75.572), which is preferable.

**8. BBB:** Both ligands have excellent BBB penetration (78.48% and 83.831%), exceeding the desirable threshold of >70% for CNS targets.

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 values, which is unusual and suggests poor permeability. However, the scale is not defined, so we cannot interpret these values directly.

**10. Aqueous Solubility:** Both ligands have negative solubility values, which is also unusual. Again, the scale is not defined, so we cannot interpret these values directly.

**11. hERG Inhibition:** Both ligands have low hERG inhibition liability (0.201 and 0.866), which is good.

**12. Microsomal Clearance:** Ligand A (-30.206) has significantly lower (better) microsomal clearance than Ligand B (49.957), indicating greater metabolic stability.

**13. In vitro Half-Life:** Ligand B (28.438) has a slightly longer half-life than Ligand A (24.286), which is generally desirable.

**14. P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.008 and 0.649), which is excellent for CNS penetration.

**15. Binding Affinity:** Both ligands have very similar binding affinities (-9.2 kcal/mol and -9.1 kcal/mol). The difference is negligible.

**Overall Assessment:**

Considering the GPCR-specific priorities, Ligand A is slightly more favorable. It has a lower TPSA, lower DILI risk, and significantly better metabolic stability (lower Cl_mic). While Ligand B has a slightly longer half-life, the other advantages of Ligand A outweigh this. The negative Caco-2 and solubility values are concerning for both, but without knowing the scale, it's difficult to assess their impact.

Output:
0
2025-04-17 08:18:51,281 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (346.471 and 344.375 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (58.64) is excellent, well below the 90 A^2 threshold for CNS targets. Ligand B (116.14) is higher, but still potentially acceptable, though less ideal.

**3. logP:** Ligand A (2.263) is optimal (1-3). Ligand B (0.089) is quite low, potentially hindering permeation.

**4. H-Bond Donors:** Ligand A (1) is good. Ligand B (3) is acceptable, but higher.

**5. H-Bond Acceptors:** Ligand A (3) is good. Ligand B (6) is higher, potentially impacting permeability.

**6. QED:** Both ligands (0.798 and 0.711) have good drug-likeness scores (>0.5).

**7. DILI:** Ligand A (33.928) has a much lower DILI risk than Ligand B (66.421).

**8. BBB:** Ligand A (75.184) has a good BBB penetration score, exceeding the 70% threshold for CNS targets. Ligand B (15.083) is very poor for CNS penetration.

**9. Caco-2 Permeability:** Ligand A (-4.877) is a negative value, which is unusual and requires careful consideration. Ligand B (-5.388) is also negative. These values are difficult to interpret without knowing the scale, but generally, lower values indicate lower permeability.

**10. Aqueous Solubility:** Both ligands have negative solubility values (-3.232 and -2.491), which is also unusual and suggests poor solubility.

**11. hERG:** Both ligands have low hERG inhibition risk (0.205 and 0.211).

**12. Microsomal Clearance:** Ligand A (49.451) has moderate clearance. Ligand B (-12.038) has negative clearance, which is not physically possible and likely indicates an error or unusual data representation.

**13. In vitro Half-Life:** Ligand A (4.863) has a reasonable half-life. Ligand B (-2.728) has a negative half-life, which is not possible.

**14. P-gp Efflux:** Both ligands have low P-gp efflux liability (0.185 and 0.077).

**15. Binding Affinity:** Ligand B (-9.1 kcal/mol) has a slightly better binding affinity than Ligand A (-7.9 kcal/mol). However, the difference is not substantial enough to overcome the significant ADME deficiencies of Ligand B.

**Overall Assessment:**

Ligand A is significantly more promising. It has a favorable TPSA, logP, BBB penetration, and DILI risk. While the Caco-2 and solubility values are concerning, they are less problematic than the extremely poor BBB penetration and questionable clearance/half-life values of Ligand B. The slightly better affinity of Ligand B is outweighed by its poor ADME properties, especially for a CNS target like DRD2. The negative values for clearance and half-life for Ligand B are red flags suggesting data issues.

Output:
1
2025-04-17 08:18:51,282 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (347.455 and 347.354 Da) fall comfortably within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (75.63) is significantly better than Ligand B (125.55). For CNS targets, we want TPSA <= 90, and Ligand A is well within this range, while Ligand B is above. This is a significant advantage for A.

**3. logP:** Ligand A (3.27) is optimal (1-3), while Ligand B (0.55) is quite low, potentially hindering membrane permeability. This is a strong advantage for A.

**4. H-Bond Donors:** Both have acceptable HBD counts (2 and 3, respectively), well below the threshold of 5.

**5. H-Bond Acceptors:** Ligand A (3) is better than Ligand B (6), both are below the 10 threshold, but lower is generally preferred.

**6. QED:** Both ligands have reasonable QED values (0.828 and 0.701), indicating good drug-like properties.

**7. DILI:** Ligand A (52.074) has a lower DILI risk than Ligand B (83.87), which is preferable.

**8. BBB:** Ligand A (46.762) has a lower BBB penetration than Ligand B (65.413). While both are not ideal (>70 desired), Ligand B is significantly better in this regard, which is crucial for a CNS target like DRD2.

**9. Caco-2 Permeability:** Both have negative Caco-2 values (-4.635 and -4.888). This is unusual and suggests poor permeability. However, the values are similar.

**10. Aqueous Solubility:** Both have negative solubility values (-3.346 and -3.329) which is also unusual, and suggests poor solubility. The values are similar.

**11. hERG Inhibition:** Both have very low hERG inhibition risk (0.052 and 0.158).

**12. Microsomal Clearance:** Ligand A (35.811) has higher microsomal clearance than Ligand B (25.757), indicating lower metabolic stability. This favors Ligand B.

**13. In vitro Half-Life:** Ligand A (-22.921) has a shorter half-life than Ligand B (-20.915). This favors Ligand B.

**14. P-gp Efflux:** Both have very low P-gp efflux liability (0.018 and 0.005).

**15. Binding Affinity:** Both have excellent binding affinities (-8.7 and -8.8 kcal/mol). The difference is negligible.

**Overall Assessment:**

Ligand A excels in TPSA, logP, and DILI risk, which are important for GPCRs and CNS penetration. However, Ligand B has a significantly better BBB score, and slightly better metabolic stability (lower Cl_mic) and half-life. The lower logP of Ligand B is a concern, but the superior BBB penetration is a critical advantage for a CNS target. Given the importance of CNS penetration for DRD2, and the similar binding affinities, Ligand B is the more promising candidate.

Output:
1
2025-04-17 08:18:51,282 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (349.435 and 347.503 Da) are within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (96.45) is slightly above the optimal <90 for CNS targets, but still reasonable. Ligand B (52.65) is excellent, well below 90.

**3. logP:** Ligand A (0.459) is quite low, potentially hindering permeability. Ligand B (1.729) is much better, falling within the optimal 1-3 range.

**4. H-Bond Donors:** Ligand A (2) and Ligand B (1) are both acceptable, below the threshold of 5.

**5. H-Bond Acceptors:** Ligand A (6) and Ligand B (3) are both acceptable, below the threshold of 10.

**6. QED:** Ligand B (0.843) has a significantly better QED score than Ligand A (0.523), suggesting a more drug-like profile.

**7. DILI:** Both ligands have low DILI risk (Ligand A: 35.983, Ligand B: 3.994), with Ligand B being preferable.

**8. BBB:** Ligand B (82.164) has a much higher BBB penetration percentile than Ligand A (61.923). This is a *critical* advantage for a CNS target like DRD2.

**9. Caco-2 Permeability:** Ligand A (-5.505) has poor Caco-2 permeability, while Ligand B (-4.898) is slightly better, but still not great.

**10. Aqueous Solubility:** Both have poor aqueous solubility (-0.99 and -1.565). This could pose formulation challenges, but isn't a dealbreaker if other properties are favorable.

**11. hERG Inhibition:** Both ligands show low hERG inhibition risk (0.25 and 0.526).

**12. Microsomal Clearance:** Ligand A (-10.378) has significantly lower (better) microsomal clearance than Ligand B (7.562), indicating better metabolic stability.

**13. In vitro Half-Life:** Ligand A (13.236) has a longer half-life than Ligand B (5.806).

**14. P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.009 and 0.025).

**15. Binding Affinity:** Both ligands have comparable binding affinities (-7.9 and -7.8 kcal/mol). The difference is negligible.

**Overall Assessment:**

Ligand B is the stronger candidate. While Ligand A has better metabolic stability and half-life, Ligand B excels in the most crucial areas for a CNS-targeting GPCR: BBB penetration, logP, and QED. The significantly higher BBB score of Ligand B outweighs the slightly better metabolic profile of Ligand A. The lower TPSA and better logP of Ligand B also contribute to its improved potential for brain exposure.

Output:
1
2025-04-17 08:18:51,282 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (354.422 and 351.403 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (75.71) is excellent, well below the 90 A^2 threshold for CNS targets. Ligand B (117.52) is higher, but still potentially acceptable, though less ideal.

**logP:** Ligand A (1.946) is optimal. Ligand B (0.067) is quite low, potentially hindering membrane permeability and CNS penetration.

**H-Bond Donors/Acceptors:** Ligand A (HBD=1, HBA=4) is favorable. Ligand B (HBD=2, HBA=6) is also reasonable, but slightly higher.

**QED:** Both ligands have acceptable QED values (0.605 and 0.568, respectively), indicating good drug-like properties.

**DILI:** Both ligands have low DILI risk (37.96 and 32.028 percentile), which is good.

**BBB:** This is a critical parameter for a CNS target like DRD2. Ligand A has a very good BBB penetration score (88.445%), significantly better than Ligand B (55.603%).

**Caco-2 Permeability:** Ligand A (-4.158) is poor, while Ligand B (-5.212) is even worse. Both are negative, indicating low permeability.

**Aqueous Solubility:** Ligand A (-2.665) is poor, but Ligand B (-1.538) is slightly better.

**hERG:** Both ligands have very low hERG inhibition liability (0.285 and 0.132), which is excellent.

**Microsomal Clearance:** Ligand A (72.213) has moderate clearance, while Ligand B (4.906) has very low clearance, suggesting better metabolic stability.

**In vitro Half-Life:** Ligand B (-10.565) has a better half-life than Ligand A (-29.277).

**P-gp Efflux:** Both ligands show low P-gp efflux liability (0.064 and 0.011), which is positive for CNS penetration.

**Binding Affinity:** Both ligands have similar, strong binding affinities (-8.0 and -7.5 kcal/mol). The difference is less than the 1.5 kcal/mol threshold.

**Overall Assessment:**

Ligand A excels in TPSA and, crucially, BBB penetration. While its Caco-2 permeability and solubility are poor, the strong BBB score and acceptable logP outweigh these concerns for a CNS target. Ligand B has better metabolic stability and half-life, but its very low logP and significantly poorer BBB penetration are major drawbacks. The affinity difference is not substantial enough to overcome these ADME deficiencies. Considering the GPCR-specific priorities, especially BBB for a CNS target, Ligand A is the more promising candidate.

Output:
1
2025-04-17 08:18:51,282 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (345.527 Da) is slightly lower, which is generally favorable for permeability. Ligand B (373.322 Da) is also good.

**TPSA:** Ligand A (40.54) is excellent, well below the 90 A^2 threshold for CNS targets. Ligand B (81.67) is higher, but still potentially acceptable, though less ideal for brain penetration.

**logP:** Ligand A (4.844) is a bit high, potentially leading to solubility issues or off-target interactions. Ligand B (1.123) is quite low, which could hinder permeation.

**H-Bond Donors/Acceptors:** Ligand A (1 HBD, 2 HBA) is optimal. Ligand B (3 HBD, 4 HBA) is also reasonable, but slightly higher.

**QED:** Ligand A (0.801) is excellent, indicating high drug-likeness. Ligand B (0.462) is below the 0.5 threshold, suggesting a less favorable drug-like profile.

**DILI:** Ligand A (20.861) has a very low DILI risk. Ligand B (48.468) is higher, but still within an acceptable range.

**BBB:** Ligand A (66.344) has a good BBB penetration percentile. Ligand B (50.523) is significantly lower, which is a major concern for a CNS target like DRD2.

**Caco-2 Permeability:** Ligand A (-4.355) has poor Caco-2 permeability. Ligand B (-5.264) is even worse.

**Aqueous Solubility:** Ligand A (-4.849) has poor aqueous solubility. Ligand B (-2.196) is better, but still not ideal.

**hERG Inhibition:** Ligand A (0.777) has a low hERG risk. Ligand B (0.413) also has a low hERG risk.

**Microsomal Clearance:** Ligand A (83.092) has high microsomal clearance, indicating poor metabolic stability. Ligand B (5.289) has very low clearance, suggesting good metabolic stability.

**In vitro Half-Life:** Ligand A (25.731) has a moderate half-life. Ligand B (-13.428) has a very short half-life.

**P-gp Efflux:** Ligand A (0.79) has moderate P-gp efflux. Ligand B (0.016) has very low P-gp efflux, which is highly desirable for CNS penetration.

**Binding Affinity:** Ligand A (-8.9 kcal/mol) has significantly stronger binding affinity than Ligand B (-9.0 kcal/mol).

**Overall Assessment:**

Ligand A excels in binding affinity, DILI, H-bond properties, and QED. However, it suffers from poor Caco-2 permeability, aqueous solubility, and high metabolic clearance. Its logP is also on the higher side.

Ligand B has better metabolic stability (low Cl_mic) and P-gp efflux, but its BBB penetration is a major drawback. It also has a lower QED score and weaker binding affinity.

Given the importance of BBB penetration for a CNS target like DRD2, and the substantial difference in binding affinity, Ligand A is the more promising candidate. While its ADME properties are not ideal, the strong binding affinity could outweigh these concerns, and optimization efforts could focus on improving solubility, permeability, and metabolic stability. The poor BBB of Ligand B is a significant hurdle that is difficult to overcome.

Output:
0
2025-04-17 08:18:51,282 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (344.386 and 353.507 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (81.42) is slightly higher than Ligand B (72.88). Both are below the 90 A^2 threshold desirable for CNS targets, but Ligand B is better.

**logP:** Ligand A (3.744) is at the upper end of the optimal range (1-3), while Ligand B (1.399) is at the lower end. While both are within the range, a logP too low can hinder permeation.

**H-Bond Donors/Acceptors:** Both ligands have 2 HBD and 4 HBA, which are within acceptable limits.

**QED:** Both ligands have good QED scores (0.656 and 0.708), indicating good drug-like properties.

**DILI:** Ligand A has a significantly higher DILI risk (85.653) than Ligand B (13.571). This is a major concern for Ligand A.

**BBB:** Ligand A (55.138) has a moderate BBB penetration, while Ligand B (40.675) is lower. Both are below the desirable >70 for CNS targets, but Ligand A is better.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.506 and -4.771), which is unusual and suggests poor permeability.

**Aqueous Solubility:** Both ligands have negative solubility values (-5.635 and -1.02), indicating very poor solubility. This is a significant drawback.

**hERG Inhibition:** Ligand A (0.777) has a slightly higher hERG inhibition risk than Ligand B (0.279), but both are relatively low.

**Microsomal Clearance:** Ligand A (74.133) has a higher microsomal clearance than Ligand B (38.208), indicating lower metabolic stability.

**In vitro Half-Life:** Ligand A (14.783 hours) has a longer half-life than Ligand B (2.942 hours).

**P-gp Efflux:** Ligand A (0.286) has lower P-gp efflux than Ligand B (0.032), which is favorable for CNS penetration.

**Binding Affinity:** Ligand B (-7.3 kcal/mol) has a significantly stronger binding affinity than Ligand A (-10.4 kcal/mol). This is a substantial advantage.

**Overall Assessment:**

Ligand B is the more promising candidate despite its lower BBB penetration. The significantly stronger binding affinity (-7.3 vs -10.4 kcal/mol) is a major advantage that can potentially outweigh some of the ADME drawbacks. Critically, Ligand B has a much lower DILI risk (13.571 vs 85.653), which is a major safety concern. While both have poor solubility and Caco-2 permeability, the lower DILI and higher affinity of Ligand B make it the better choice for further optimization.

Output:
1
2025-04-17 08:18:51,283 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (356.463 and 351.422 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Both ligands have TPSA values (90.31 and 91.32) close to the upper limit for CNS targets (<=90). Ligand A is slightly better.

**3. logP:** Ligand A (0.386) is a bit low, potentially hindering permeability. Ligand B (1.844) is within the optimal 1-3 range. This favors Ligand B.

**4. H-Bond Donors:** Ligand A (2) and Ligand B (3) are both acceptable, being less than 5.

**5. H-Bond Acceptors:** Ligand A (6) and Ligand B (4) are both acceptable, being less than 10.

**6. QED:** Both ligands have good QED scores (0.693 and 0.755), indicating drug-like properties.

**7. DILI:** Ligand A (10.392) has a significantly lower DILI risk than Ligand B (44.862). This is a substantial advantage for Ligand A.

**8. BBB:** Ligand B (60.45) has a better BBB penetration percentile than Ligand A (46.84), but both are below the desirable >70 for CNS targets.

**9. Caco-2 Permeability:** Both have negative Caco-2 values (-4.607 and -4.72), which is unusual and suggests poor permeability.

**10. Aqueous Solubility:** Both have negative solubility values (-1.267 and -1.898), also unusual and indicating poor solubility.

**11. hERG Inhibition:** Both ligands show low hERG inhibition risk (0.372 and 0.189).

**12. Microsomal Clearance:** Ligand A (38.17) has a higher microsomal clearance than Ligand B (2.851), suggesting lower metabolic stability. Ligand B is favored here.

**13. In vitro Half-Life:** Ligand B (1.431) has a slightly better in vitro half-life than Ligand A (-11.73).

**14. P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.015 and 0.031).

**15. Binding Affinity:** Ligand B (-8.3 kcal/mol) has a significantly stronger binding affinity than Ligand A (-7.0 kcal/mol). This >1.5 kcal/mol difference is a major advantage for Ligand B, potentially outweighing some ADME drawbacks.

**Overall Assessment:**

While Ligand A has a much better DILI profile, Ligand B's superior binding affinity (-8.3 vs -7.0 kcal/mol) and better logP, metabolic stability, and half-life are more critical for a GPCR target, especially considering the relatively poor BBB penetration of both compounds. The stronger binding is likely to translate to greater efficacy. The negative Caco-2 and solubility values are concerning for both, but can potentially be addressed through formulation strategies.

Output:
1
2025-04-17 08:18:51,283 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (356.419 and 348.487 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (116.17) is borderline for CNS penetration, being above the preferred <90, but not drastically so. Ligand B (67.43) is excellent, well below the threshold.

**logP:** Ligand A (-0.574) is quite low, potentially hindering membrane permeability. Ligand B (2.413) is within the optimal 1-3 range. This is a significant advantage for Ligand B.

**H-Bond Donors/Acceptors:** Ligand A (3 HBD, 6 HBA) is acceptable. Ligand B (2 HBD, 3 HBA) is also good, potentially slightly better due to the lower counts.

**QED:** Both ligands have reasonable QED scores (0.415 and 0.694), indicating drug-like properties, with Ligand B being better.

**DILI:** Both ligands have relatively low DILI risk (22.8 and 25.087), suggesting minimal liver injury potential.

**BBB:** Ligand A (24.738) has a very poor BBB penetration score, making CNS activity unlikely. Ligand B (62.311) is better, but still not ideal; a score >70 is preferred.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.01 and -5.116), which is unusual and suggests poor permeability. This is a significant concern for both.

**Aqueous Solubility:** Both ligands have negative solubility values (-1.091 and -2.888), also unusual and concerning.

**hERG Inhibition:** Both ligands show very low hERG inhibition risk (0.084 and 0.15).

**Microsomal Clearance:** Ligand A (20.897) has a lower (better) microsomal clearance than Ligand B (31.457), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (-20.477) has a negative half-life, which is impossible and indicates a data error. Ligand B (-3.4) also has a negative half-life, also indicating a data error.

**P-gp Efflux:** Both ligands show very low P-gp efflux liability (0.012 and 0.064), which is favorable for CNS penetration.

**Binding Affinity:** Ligand B (-9.2 kcal/mol) has a significantly stronger binding affinity than Ligand A (-6.7 kcal/mol). This >1.5 kcal/mol difference is a major advantage for Ligand B.

**Overall Assessment:**

Despite the unusual negative values for Caco-2 and solubility, the key factors for a CNS-targeting GPCR like DRD2 are BBB penetration and binding affinity. Ligand B clearly outperforms Ligand A in both these critical areas. While Ligand B's BBB score isn't ideal, it's far superior to Ligand A's. The significantly stronger binding affinity of Ligand B (-9.2 vs -6.7 kcal/mol) is a substantial advantage that can potentially compensate for other less-than-optimal properties. The better logP of Ligand B also favors its potential for crossing biological membranes. The negative half-life values for both are concerning, but we'll focus on the other parameters for this comparison.

Output:
1
2025-04-17 08:18:51,283 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (363.439 and 344.459 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (86.88) is better than Ligand B (65.54) as it is closer to the <90 threshold for CNS targets.

**logP:** Both ligands have good logP values (2.414 and 1.533), falling within the optimal 1-3 range. Ligand B is slightly lower, which might slightly hinder permeability, but is still acceptable.

**H-Bond Donors/Acceptors:** Both ligands have 1 HBD and a reasonable number of HBAs (6 and 4 respectively), satisfying the <5 HBD and <10 HBA guidelines.

**QED:** Both ligands have high QED scores (0.848 and 0.9), indicating good drug-like properties.

**DILI:** Ligand A (52.385) has a slightly higher DILI risk than Ligand B (14.618), but both are below the concerning threshold of 60.

**BBB:** Both ligands show good BBB penetration (66.615 and 69.213), but Ligand B is slightly better. A value >70 is desirable, but these are both reasonably good for a CNS target.

**Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and indicates poor permeability. However, the scale is not defined, so it is difficult to interpret.

**Aqueous Solubility:** Both ligands have negative solubility values, which is also unusual and indicates poor solubility.

**hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.081 and 0.468).

**Microsomal Clearance:** Ligand A (-14.177) has *much* lower microsomal clearance than Ligand B (4.977), suggesting significantly better metabolic stability. This is a major advantage.

**In vitro Half-Life:** Ligand A (-2.617) has a slightly more negative half-life, which is also unusual, but the difference is small.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.025 and 0.017), which is excellent for CNS penetration.

**Binding Affinity:** Both ligands have similar and excellent binding affinities (-8.3 and -8.2 kcal/mol). The difference is negligible.

**Conclusion:**

Considering all factors, **Ligand A** is the more promising drug candidate. While Ligand B has a slightly better BBB score, Ligand A's significantly improved metabolic stability (lower Cl_mic) and slightly better TPSA outweigh this advantage. Both ligands have similar affinity and acceptable ADME properties, but metabolic stability is crucial for maintaining therapeutic concentrations *in vivo*, especially for a CNS target. The unusual negative values for Caco-2 and solubility are a concern for both, but the difference in Cl_mic is a more decisive factor.

Output:
1
2025-04-17 08:18:51,283 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (354.451 and 360.531 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (121.6) is better than Ligand B (67.66). For CNS targets, we want TPSA <= 90, and Ligand B is well within this range, while Ligand A is slightly above.

**logP:** Ligand B (3.376) is optimal (1-3), while Ligand A (-0.234) is too low, potentially hindering permeation. This is a significant drawback for Ligand A.

**H-Bond Donors/Acceptors:** Ligand A (3 HBD, 4 HBA) and Ligand B (2 HBD, 7 HBA) both fall within acceptable ranges (<=5 HBD and <=10 HBA).

**QED:** Both ligands have good QED scores (0.584 and 0.704, respectively), indicating drug-like properties.

**DILI:** Ligand A (20.047) has a much lower DILI risk than Ligand B (65.723). This is a significant advantage for Ligand A.

**BBB:** Ligand B (88.91) has a much higher BBB penetration percentile than Ligand A (57.619). For a CNS target like DRD2, >70 is desirable, and Ligand B is closer to this threshold.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.595 and -5.399), which is unusual and suggests poor permeability. However, the scale isn't specified, so it's hard to interpret.

**Aqueous Solubility:** Both ligands have negative solubility values (-1.646 and -3.602), which is also unusual.

**hERG:** Ligand A (0.029) has a lower hERG inhibition liability than Ligand B (0.907), indicating a lower risk of cardiotoxicity.

**Microsomal Clearance:** Ligand A (24.821) has a lower microsomal clearance than Ligand B (87.26), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (-20.021) has a negative half-life, which is not physically possible. Ligand B (27.183) has a reasonable half-life.

**P-gp Efflux:** Ligand A (0.006) has a much lower P-gp efflux liability than Ligand B (0.672), which is beneficial for CNS exposure.

**Binding Affinity:** Ligand B (-8.2 kcal/mol) has a slightly better binding affinity than Ligand A (-7.3 kcal/mol). While the difference is not huge, it's a factor.

**Overall Assessment:**

Ligand A has advantages in DILI, hERG, P-gp efflux, and microsomal clearance. However, its significantly lower logP and BBB penetration are major drawbacks for a CNS target. The negative half-life is also concerning. Ligand B, while having a higher DILI risk and P-gp efflux, excels in BBB penetration and has a reasonable half-life and better binding affinity. The logP is also optimal. Given the GPCR-specific priorities, particularly BBB and logP, Ligand B is the more promising candidate despite its higher DILI risk. The affinity difference is not large enough to outweigh the ADME advantages of Ligand B.

Output:
1
2025-04-17 08:18:51,284 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B based on the provided guidelines, prioritizing GPCR-specific properties (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (341.459 and 349.381 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (63.05) is excellent, well below the 90 A^2 threshold for CNS targets. Ligand B (68.06) is still good, but slightly higher.

**logP:** Ligand A (2.182) is optimal (1-3). Ligand B (4.448) is a bit high, potentially leading to solubility issues and off-target interactions, but not drastically so.

**H-Bond Donors/Acceptors:** Both ligands have acceptable HBD (1) and HBA (5/4) counts, well within the guidelines.

**QED:** Ligand A (0.838) has a very strong drug-like profile. Ligand B (0.475) is lower, indicating a less favorable overall drug-likeness.

**DILI:** Ligand A (32.299) has a low DILI risk. Ligand B (53.432) is higher, suggesting a moderate risk of liver injury.

**BBB:** This is crucial for a CNS target like DRD2. Ligand A (70.919) is good, exceeding the 70% threshold. Ligand B (91.276) is excellent, indicating very good brain penetration.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.006 and -4.932), which is unusual and potentially problematic. However, these values are on a logarithmic scale, and negative values simply indicate very low permeability.

**Aqueous Solubility:** Both ligands have negative solubility values (-2.627 and -4.395), indicating very poor aqueous solubility. This is a significant concern for both.

**hERG Inhibition:** Ligand A (0.158) has a very low hERG risk. Ligand B (0.919) has a slightly elevated risk, but still relatively low.

**Microsomal Clearance:** Ligand A (56.535) has a moderate clearance, suggesting moderate metabolic stability. Ligand B (23.202) has a low clearance, indicating good metabolic stability.

**In vitro Half-Life:** Ligand B (33.688 hours) has a significantly longer half-life than Ligand A (8.56 hours), which is a major advantage.

**P-gp Efflux:** Ligand A (0.093) has very low P-gp efflux, which is favorable for CNS penetration. Ligand B (0.459) has a slightly higher efflux, but still relatively low.

**Binding Affinity:** Ligand B (-9.9 kcal/mol) has a substantially stronger binding affinity than Ligand A (-8.5 kcal/mol). This >1.5 kcal/mol difference is a significant advantage and can outweigh some of the ADME drawbacks.

**Overall Assessment:**

Ligand B is the stronger candidate despite some ADME liabilities. The significantly better binding affinity (-9.9 vs -8.5 kcal/mol) and excellent BBB penetration (91.276%) are critical for a CNS GPCR target. The longer half-life is also a major benefit. While the higher logP and DILI risk are concerns, they are less critical than the superior potency and brain penetration. The poor solubility and permeability are shared issues that would need to be addressed through formulation strategies.

Output:
1
2025-04-17 08:18:51,284 - INFO - Batch 438 complete. Total preferences: 7008
2025-04-17 08:18:51,284 - INFO - Processing batch 439/512...
2025-04-17 08:19:31,522 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (367.47 and 373.41 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (72.91) is excellent, well below the 90 A^2 threshold for CNS targets. Ligand B (117.62) is higher, but still potentially acceptable, though less ideal.

**logP:** Ligand A (2.04) is optimal (1-3). Ligand B (-0.042) is slightly below 1, which could hinder permeation.

**H-Bond Donors/Acceptors:** Ligand A (0 HBD, 5 HBA) is favorable. Ligand B (3 HBD, 6 HBA) is also acceptable, though slightly higher.

**QED:** Ligand A (0.745) is strong, indicating good drug-likeness. Ligand B (0.435) is lower, suggesting a less ideal drug-like profile.

**DILI:** Ligand A (57.58) has a moderate DILI risk, acceptable. Ligand B (71.152) is higher, indicating a greater potential for liver injury.

**BBB:** Ligand A (79.992) has excellent BBB penetration potential, exceeding the 70% threshold. Ligand B (52.966) is significantly lower, raising concerns about CNS exposure.

**Caco-2 Permeability:** Ligand A (-4.261) is concerningly low, suggesting poor intestinal absorption. Ligand B (-5.101) is also low, but slightly better than A.

**Aqueous Solubility:** Ligand A (-3.335) is poor. Ligand B (-2.242) is also poor, but slightly better than A.

**hERG Inhibition:** Both ligands (0.37 and 0.314) show low hERG inhibition risk, which is good.

**Microsomal Clearance:** Ligand A (94.515) has high microsomal clearance, suggesting rapid metabolism and lower metabolic stability. Ligand B (28.236) has much lower clearance, indicating better metabolic stability.

**In vitro Half-Life:** Both ligands have negative half-lives (-52.242 and -49.598), which is unusual and likely indicates an issue with the experimental setup or the molecule's stability in the assay. However, the magnitude is similar.

**P-gp Efflux:** Both ligands (0.135 and 0.062) have low P-gp efflux, which is favorable for CNS penetration.

**Binding Affinity:** Ligand B (-8.3 kcal/mol) has a significantly stronger binding affinity than Ligand A (-7.4 kcal/mol). This 0.9 kcal/mol difference is substantial and could outweigh some of the ADME drawbacks of Ligand B.

**Overall Assessment:**

Ligand A has excellent TPSA and BBB penetration, but suffers from poor Caco-2 permeability, solubility, and high metabolic clearance. Ligand B has a superior binding affinity and better metabolic stability, but has a higher TPSA and lower BBB penetration. Given the CNS target and the importance of BBB penetration, Ligand A initially appears more promising. However, the significantly stronger binding affinity of Ligand B (-8.3 vs -7.4 kcal/mol) is a major advantage. While its BBB is lower, the improved affinity could compensate, and further optimization could potentially improve its BBB score. The lower metabolic clearance of Ligand B is also a significant benefit.

Output:
1
2025-04-17 08:19:31,523 - INFO - Reasoning:

Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (353.463 and 362.817 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (96.53) is slightly above the preferred <90 for CNS targets, but still reasonable. Ligand B (89.16) is better, falling comfortably below 90.

**3. logP:** Ligand A (0.729) is a bit low, potentially hindering permeability. Ligand B (2.545) is closer to the optimal 1-3 range.

**4. H-Bond Donors:** Ligand A (3) and Ligand B (2) are both within the acceptable limit of <=5.

**5. H-Bond Acceptors:** Ligand A (4) and Ligand B (5) are both within the acceptable limit of <=10.

**6. QED:** Both ligands have good QED scores (0.629 and 0.855), indicating good drug-like properties.

**7. DILI:** Ligand A (20.822) has a significantly lower DILI risk than Ligand B (67.313). This is a major advantage for Ligand A.

**8. BBB:** Ligand A (45.754) has a lower BBB penetration percentile than Ligand B (51.066). While neither are *high* (>70), Ligand B is slightly better.

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.284 and -5.036), which is unusual and suggests poor permeability. This is a significant concern for both.

**10. Aqueous Solubility:** Both ligands have negative solubility values (-1.574 and -3.301), indicating very poor aqueous solubility. This is a major drawback for both.

**11. hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.116 and 0.106).

**12. Microsomal Clearance:** Ligand A (21.32) has a higher microsomal clearance than Ligand B (2.266), suggesting lower metabolic stability. Ligand B is significantly better here.

**13. In vitro Half-Life:** Ligand B (75.319) has a much longer in vitro half-life than Ligand A (5.135). This is a substantial advantage for Ligand B.

**14. P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.012 and 0.073).

**15. Binding Affinity:** Ligand B (-8.7) has a slightly better binding affinity than Ligand A (-8.3), but the difference is relatively small (0.4 kcal/mol).

**Overall Assessment:**

While Ligand B has a slightly better binding affinity, longer half-life, and better BBB penetration, Ligand A's significantly lower DILI risk is a major advantage. Both compounds suffer from poor predicted solubility and permeability. However, for a CNS target, mitigating toxicity is crucial. The slightly better affinity and metabolic stability of Ligand B are outweighed by the higher DILI risk. The small difference in affinity is unlikely to overcome the significant ADME liabilities of both compounds, but the lower toxicity profile of A makes it slightly more promising as a starting point for optimization.

Output:
0
2025-04-17 08:19:31,523 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (349.475 and 353.413 Da) fall within the ideal range of 200-500 Da.

**TPSA:** Ligand A (70.67) is better than Ligand B (71.09) as both are reasonably close to the 90 A^2 threshold for CNS targets, but lower is preferable.

**logP:** Ligand A (1.073) is within the optimal range (1-3), while Ligand B (3.224) is towards the higher end. This suggests Ligand A might have better solubility and potentially fewer off-target effects.

**H-Bond Donors/Acceptors:** Both ligands have 2 HBD and a reasonable number of HBA (4 and 3 respectively), satisfying the criteria.

**QED:** Both ligands have good QED scores (0.704 and 0.825), indicating good drug-like properties.

**DILI:** Ligand A (15.432) has a significantly lower DILI risk than Ligand B (37.999), which is a major advantage.

**BBB:** Ligand B (84.374) has a much higher BBB penetration percentile than Ligand A (39.007). This is a critical factor for a CNS target like DRD2.

**Caco-2 Permeability:** Ligand A (-5.232) has a worse Caco-2 permeability than Ligand B (-4.597), but both are negative which is not ideal.

**Aqueous Solubility:** Ligand A (-0.97) has better aqueous solubility than Ligand B (-3.587).

**hERG Inhibition:** Ligand A (0.108) has a much lower hERG inhibition liability than Ligand B (0.428), reducing the risk of cardiotoxicity.

**Microsomal Clearance:** Ligand B (28.956) has a higher microsomal clearance than Ligand A (0.73), indicating faster metabolism and potentially lower *in vivo* exposure.

**In vitro Half-Life:** Ligand A (12.534) has a longer half-life than Ligand B (-6.497).

**P-gp Efflux:** Ligand A (0.024) has a significantly lower P-gp efflux liability than Ligand B (0.084), which is crucial for CNS penetration.

**Binding Affinity:** Ligand B (-9.0) has a stronger binding affinity than Ligand A (-8.5), with a difference of 0.5 kcal/mol. While a difference of 1.5 kcal/mol would be more impactful, this difference is still worth considering.

**Overall Assessment:**

Ligand B has a significantly better BBB score and binding affinity, which are highly desirable for a CNS GPCR target. However, it suffers from higher DILI risk, higher P-gp efflux, higher hERG inhibition, and faster metabolic clearance. Ligand A, while having weaker affinity and lower BBB, presents a much safer profile with lower DILI, hERG, and P-gp efflux, and better metabolic stability.

Considering the balance, the stronger affinity of Ligand B is tempting, but the significantly improved safety and pharmacokinetic profile of Ligand A, particularly its lower DILI and P-gp efflux, make it a more promising starting point for drug development. The affinity can be optimized further, while mitigating the safety concerns of Ligand B would be more challenging.

Output:
0
2025-04-17 08:19:31,523 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (350.369 and 346.515 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (68.18) is higher than Ligand B (40.62). For a CNS target like DRD2, TPSA should be <= 90. Both are within this range, but B is significantly better.

**3. logP:** Both ligands have good logP values (2.877 and 3.618), falling within the optimal 1-3 range.

**4. H-Bond Donors:** Ligand A has 2 HBD, and Ligand B has 0. Both are acceptable (<=5).

**5. H-Bond Acceptors:** Ligand A has 4 HBA, and Ligand B has 2. Both are acceptable (<=10).

**6. QED:** Ligand A (0.871) has a better QED score than Ligand B (0.661), indicating a more drug-like profile.

**7. DILI:** Ligand A (73.982) has a higher DILI risk than Ligand B (11.361). This is a significant drawback for Ligand A.

**8. BBB:** Ligand A (90.617) has a slightly better BBB penetration percentile than Ligand B (84.025), but both are very good (>70).

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.78 and -4.698). This is unusual and suggests poor permeability. However, the values are very close.

**10. Aqueous Solubility:** Both ligands have negative solubility values (-4.044 and -3.133). This is also concerning, indicating poor solubility. Again, values are close.

**11. hERG Inhibition:** Both ligands have low hERG inhibition risk (0.451 and 0.495).

**12. Microsomal Clearance:** Ligand A (19.135) has lower microsomal clearance than Ligand B (52.625), suggesting better metabolic stability.

**13. In vitro Half-Life:** Ligand A (52.866) has a longer in vitro half-life than Ligand B (-17.787). This is a significant advantage for Ligand A.

**14. P-gp Efflux:** Ligand A (0.166) has lower P-gp efflux than Ligand B (0.315), which is favorable for CNS penetration.

**15. Binding Affinity:** Ligand A (-9.7 kcal/mol) has a significantly stronger binding affinity than Ligand B (-8.6 kcal/mol). This is a substantial advantage, potentially outweighing some ADME concerns.

**Overall Assessment:**

Ligand A has a superior binding affinity, better metabolic stability (lower Cl_mic), longer half-life, and lower P-gp efflux. However, it has a significantly higher DILI risk. Ligand B has a lower DILI risk and a better TPSA, but weaker binding affinity and poorer metabolic stability.

Given the GPCR-specific priorities, and the importance of CNS penetration for DRD2, the strong binding affinity of Ligand A is a major advantage. While the DILI risk is concerning, it might be mitigated through structural modifications during optimization. The slightly better BBB of A, coupled with the lower P-gp efflux, also supports its potential for CNS exposure.

Output:
1
2025-04-17 08:19:31,523 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (378.523 and 352.385 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (68.09) is excellent, well below the 90 A^2 threshold for CNS targets. Ligand B (78.09) is still reasonable but less optimal.

**logP:** Ligand A (2.268) is within the optimal 1-3 range. Ligand B (1.584) is slightly lower but acceptable.

**H-Bond Donors/Acceptors:** Ligand A has 0 HBD and 7 HBA, fitting well within the guidelines. Ligand B has 2 HBD and 3 HBA, also acceptable.

**QED:** Both ligands have similar and good QED values (0.747 and 0.763), indicating good drug-like properties.

**DILI:** Ligand A (75.766) has a higher DILI risk than Ligand B (56.727). This is a negative for Ligand A.

**BBB:** Ligand B (80.729) has a significantly better BBB penetration score than Ligand A (64.017). This is a crucial advantage for a CNS target like DRD2.

**Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and suggests poor permeability. However, the scale is not provided, so it's hard to interpret.

**Aqueous Solubility:** Both have negative solubility values, which is also unusual. Again, the scale is not provided.

**hERG:** Both ligands have very low hERG inhibition liability (0.324 and 0.247), which is positive.

**Microsomal Clearance:** Ligand A (81.592) has a higher microsomal clearance than Ligand B (21.538), suggesting lower metabolic stability. This is a negative for Ligand A.

**In vitro Half-Life:** Ligand B (-25.087) has a very negative half-life, which is concerning. Ligand A (2.365) is much better.

**P-gp Efflux:** Ligand A (0.425) has a slightly higher P-gp efflux liability than Ligand B (0.066). Lower is better, favoring Ligand B.

**Binding Affinity:** Ligand B (-8.4 kcal/mol) has a slightly better binding affinity than Ligand A (-8.1 kcal/mol), although the difference is small.

**Overall Assessment:**

Considering the GPCR-specific priorities, Ligand B is the stronger candidate. Its significantly better BBB penetration and lower P-gp efflux are critical for CNS drug development. While Ligand A has a better in vitro half-life, the advantages of Ligand B in BBB and P-gp outweigh this. The DILI risk is also lower for Ligand B. The unusual negative values for Caco-2 and solubility are concerning for both, but the other factors push the decision towards Ligand B.

Output:
1
2025-04-17 08:19:31,524 - INFO - Reasoning:

Let's analyze Ligand A and Ligand B against the provided guidelines, prioritizing GPCR-specific properties (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (360.845 and 342.443 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (78.09) is better than Ligand B (69.04) as it is closer to the ideal <90 for CNS targets.

**logP:** Both ligands have good logP values (2.471 and 2.847), falling within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A (HBD=2, HBA=3) is slightly better than Ligand B (HBD=1, HBA=5) in terms of balancing solubility and permeability, though both are acceptable.

**QED:** Both ligands have reasonable QED scores (0.869 and 0.749), indicating good drug-like properties.

**DILI:** Ligand A (56.844) has a slightly higher DILI risk than Ligand B (47.421), but both are below the concerning threshold of 60.

**BBB:** This is a crucial parameter for a CNS target like DRD2. Ligand A (60.372) is significantly better than Ligand B (33.075). A value >70 is desirable, and Ligand A is closer to that goal.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.227 and -4.627), which is unusual and suggests poor permeability. However, these values are on a scale where higher is better, so the less negative value is better. Ligand A (-5.227) is slightly better.

**Aqueous Solubility:** Both ligands have negative solubility values (-3.749 and -4.195), also unusual. Again, the less negative value is better. Ligand A (-3.749) is slightly better.

**hERG:** Both ligands have very low hERG inhibition risk (0.167 and 0.113), which is excellent.

**Microsomal Clearance:** Ligand A (-1.368) has a lower (better) microsomal clearance than Ligand B (80.624), indicating greater metabolic stability.

**In vitro Half-Life:** Ligand A (-38.719) has a longer (better) in vitro half-life than Ligand B (-26.239).

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.09 and 0.099), which is favorable for CNS penetration.

**Binding Affinity:** Ligand B (-8.4 kcal/mol) has a significantly stronger binding affinity than Ligand A (0.0 kcal/mol). This is a substantial advantage, potentially outweighing some of the ADME drawbacks of Ligand B.

**Overall Assessment:**

While Ligand A has better ADME properties (BBB, metabolic stability, half-life, solubility), Ligand B's significantly superior binding affinity (-8.4 vs 0.0 kcal/mol) is a decisive factor. For a GPCR target, strong binding is paramount. The ADME properties of Ligand B, while not ideal, are not catastrophic, and further optimization could address them. The substantial affinity difference suggests Ligand B is more likely to be a viable drug candidate.

Output:
1
2025-04-17 08:19:31,524 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (353.507 and 344.411 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (61.88) is significantly better than Ligand B (75.71). For CNS targets, we want TPSA <= 90, and ideally lower. Ligand A is much closer to the ideal range.

**logP:** Both ligands have acceptable logP values (1.641 and 1.835), falling within the 1-3 range.

**H-Bond Donors/Acceptors:** Both have 1 HBD and 4 HBA, which are within acceptable limits.

**QED:** Ligand A (0.649) has a significantly better QED score than Ligand B (0.354). A QED > 0.5 is desirable.

**DILI:** Both ligands have relatively high DILI risk (4.769 and 63.048), but Ligand A is considerably lower, indicating a better safety profile.

**BBB:** Ligand A (63.784) has a much better BBB penetration percentile than Ligand B (44.785). For a CNS target like DRD2, >70 is highly desirable, but 63.784 is a much better starting point than 44.785.

**Caco-2 Permeability:** Both have negative Caco-2 values (-4.878 and -4.763), which is unusual and suggests poor permeability. This is a significant drawback for both.

**Aqueous Solubility:** Both have negative solubility values (-0.442 and -2.734), indicating poor solubility. Ligand B is worse.

**hERG Inhibition:** Both have low hERG inhibition risk (0.416 and 0.158), which is good.

**Microsomal Clearance:** Ligand A (13.791) has a lower microsomal clearance than Ligand B (61.898), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (-2.911) has a more favorable (less negative) in vitro half-life than Ligand B (-36.595), indicating better stability.

**P-gp Efflux:** Both have very low P-gp efflux liability (0.014 and 0.174), which is good for CNS penetration.

**Binding Affinity:** Ligand B (-8.9 kcal/mol) has a significantly stronger binding affinity than Ligand A (-6.6 kcal/mol). This is a substantial advantage. A difference of >1.5 kcal/mol can often outweigh other drawbacks.

**Overall Assessment:**

While Ligand B boasts a superior binding affinity, Ligand A demonstrates a much more favorable ADME profile, particularly regarding BBB penetration, DILI risk, metabolic stability, and QED. The poor Caco-2 and solubility for both are concerning, but can potentially be addressed with formulation strategies. Given the CNS target, the better BBB penetration of Ligand A is a critical advantage. The stronger affinity of Ligand B is tempting, but the significantly worse ADME properties, especially the low BBB, make it less likely to succeed as a drug candidate.

Output:
0
2025-04-17 08:19:31,524 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (344.386) is slightly lower, which could be beneficial for permeability.

**2. TPSA:** Ligand A (59.59) is better than Ligand B (46.34) as it is closer to the ideal range for CNS targets (<=90).

**3. logP:** Both ligands have good logP values (A: 3.416, B: 4.108), falling within the optimal range of 1-3. Ligand B is slightly higher, which *could* indicate potential off-target effects, but isn't a major concern.

**4. H-Bond Donors:** Ligand A (2) is preferable to Ligand B (0). A small number of HBDs can aid solubility without overly hindering permeability.

**5. H-Bond Acceptors:** Ligand A (3) and Ligand B (4) are both acceptable, being below the 10 threshold.

**6. QED:** Ligand A (0.874) has a significantly better QED score than Ligand B (0.653), indicating a more drug-like profile.

**7. DILI:** Ligand A (59.519) has a higher DILI risk than Ligand B (27.453), which is a negative for Ligand A.

**8. BBB:** Both ligands have excellent BBB penetration (A: 84.141, B: 85.537), exceeding the desirable threshold of 70%. This is crucial for a CNS target like DRD2.

**9. Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and potentially problematic. However, the scale is not specified, so it's difficult to interpret.

**10. Aqueous Solubility:** Both ligands have poor aqueous solubility (-3.917 and -4.417 respectively). This could pose formulation challenges.

**11. hERG Inhibition:** Both ligands show low hERG inhibition risk (A: 0.857, B: 0.531).

**12. Microsomal Clearance:** Ligand A (48.584) has significantly lower microsomal clearance than Ligand B (119.565), suggesting better metabolic stability.

**13. In vitro Half-Life:** Ligand A (24.716) has a longer half-life than Ligand B (10.26), which is favorable.

**14. P-gp Efflux:** Ligand A (0.457) shows lower P-gp efflux than Ligand B (0.707), which is desirable for CNS penetration.

**15. Binding Affinity:** Ligand B (-7.2 kcal/mol) has a significantly stronger binding affinity than Ligand A (-10.8 kcal/mol). This is a substantial advantage, potentially outweighing some of the ADME drawbacks.

**Overall Assessment:**

Ligand B's significantly stronger binding affinity is the most compelling factor. While Ligand A has better QED, metabolic stability, and P-gp efflux, the difference in binding affinity is substantial. The slightly higher logP of Ligand B is not a major concern, and its DILI risk is lower. Both have poor solubility, which will need to be addressed in formulation. Given the GPCR-specific priorities, the strong binding affinity of Ligand B makes it the more promising candidate.

Output:
1
2025-04-17 08:19:31,524 - INFO - Reasoning:

Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (362.5 and 366.6 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (71.25) is higher than Ligand B (33.95). For a CNS target like DRD2, TPSA should be <= 90, so both are acceptable, but Ligand B is significantly better.

**3. logP:** Ligand A (2.476) is within the optimal 1-3 range. Ligand B (4.692) is slightly higher, potentially increasing off-target effects and decreasing solubility, but still within a reasonable range.

**4. H-Bond Donors:** Ligand A (1) is good. Ligand B (0) is also good.

**5. H-Bond Acceptors:** Ligand A (6) is good. Ligand B (5) is also good.

**6. QED:** Both ligands have acceptable QED values (0.783 and 0.611, both > 0.5).

**7. DILI:** Both ligands have low DILI risk (21.06 and 23.77, both < 40).

**8. BBB:** Ligand B (80.42) has a significantly better BBB percentile than Ligand A (71.00). This is *critical* for a CNS target.

**9. Caco-2 Permeability:** Both have negative values, which is unusual and suggests poor permeability. However, the scale is not specified, so it's hard to interpret.

**10. Aqueous Solubility:** Both have negative values, which is also unusual. Again, the scale is unknown, making interpretation difficult.

**11. hERG Inhibition:** Both ligands have low hERG inhibition risk (0.497 and 0.939).

**12. Microsomal Clearance:** Ligand A (65.22) has higher clearance than Ligand B (50.84), suggesting lower metabolic stability.

**13. In vitro Half-Life:** Ligand B (39.22) has a much longer half-life than Ligand A (-1.91). This is a significant advantage.

**14. P-gp Efflux:** Ligand A (0.104) has lower P-gp efflux than Ligand B (0.623), which is desirable for CNS penetration.

**15. Binding Affinity:** Ligand A (-7.5) has a slightly better binding affinity than Ligand B (-6.9). However, the difference is 0.6 kcal/mol, which is not a huge advantage and can be overcome by other factors.

**Overall Assessment:**

Ligand B is the stronger candidate. While Ligand A has slightly better binding affinity, Ligand B excels in critical ADME properties for a CNS-targeting GPCR: significantly better BBB penetration, a longer half-life, and lower P-gp efflux. The lower TPSA of Ligand B is also beneficial. The slightly higher logP of Ligand B is a minor concern, but the substantial advantages in BBB and half-life outweigh this.

Output:
1
2025-04-17 08:19:31,525 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (382.291 and 366.546 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (62.61) is higher than Ligand B (33.2). For a CNS target like DRD2, TPSA should ideally be <= 90, so both are acceptable, but B is significantly better.

**3. logP:** Ligand A (3.066) is within the optimal 1-3 range. Ligand B (4.561) is slightly above, potentially leading to solubility issues or off-target interactions, but not drastically.

**4. H-Bond Donors:** Ligand A (2) is acceptable, while Ligand B (0) is also good.

**5. H-Bond Acceptors:** Both ligands have 3 HBA, which is within the acceptable limit of <=10.

**6. QED:** Both ligands have QED values above 0.5 (0.781 and 0.601), indicating good drug-like properties.

**7. DILI:** Ligand A (47.421) has a higher DILI risk than Ligand B (21.404). Lower is better, so B is preferable.

**8. BBB:** This is crucial for CNS targets. Ligand A (66.499) is okay, but Ligand B (96.161) is *excellent*, exceeding the desirable >70 threshold. This is a major advantage for B.

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.9 and -4.762). This is unusual and suggests poor permeability. However, the scale is not specified, so it's hard to interpret.

**10. Aqueous Solubility:** Both ligands have negative solubility values (-4.175 and -4.088). This is also unusual and suggests poor solubility. Again, the scale is not specified.

**11. hERG Inhibition:** Ligand A (0.365) has a slightly higher hERG risk than Ligand B (0.823). Lower is better.

**12. Microsomal Clearance:** Ligand A (27.474) has a lower (better) microsomal clearance than Ligand B (119.495), indicating greater metabolic stability.

**13. In vitro Half-Life:** Ligand A (33.252) has a longer half-life than Ligand B (16.486).

**14. P-gp Efflux:** Ligand A (0.095) shows lower P-gp efflux than Ligand B (0.726), which is favorable for CNS penetration.

**15. Binding Affinity:** Ligand B (-7.4 kcal/mol) has a significantly stronger binding affinity than Ligand A (-9.7 kcal/mol). This is a substantial advantage, potentially outweighing some of the ADME drawbacks.

**Overall Assessment:**

Ligand B is the stronger candidate. While Ligand A has better metabolic stability and P-gp efflux, Ligand B excels in the most critical areas for a CNS-targeting GPCR: *significantly* better BBB penetration and substantially stronger binding affinity. The slightly higher logP and DILI risk are less concerning given the superior affinity and BBB score. The poor Caco-2 and solubility values are a concern for both, but can be addressed with formulation strategies.

Output:
1
2025-04-17 08:19:31,525 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (348.49 and 367.41 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (67.43) is significantly better than Ligand B (105.04). For CNS targets, we want TPSA <= 90, so Ligand A is preferable.

**logP:** Ligand A (2.908) is optimal (1-3), while Ligand B (0.214) is quite low, potentially hindering membrane permeability.

**H-Bond Donors:** Both ligands have 2 HBD, which is within the acceptable limit of <= 5.

**H-Bond Acceptors:** Ligand A has 3 HBA, and Ligand B has 8 HBA. Both are within the acceptable limit of <= 10, but Ligand A is better.

**QED:** Ligand B (0.801) has a slightly better QED score than Ligand A (0.597), indicating a more drug-like profile overall. However, this is less critical than other factors for a GPCR target.

**DILI:** Ligand A (26.37) has a much lower DILI risk than Ligand B (79.33), indicating better safety.

**BBB:** Ligand A (69.68) has a significantly better BBB penetration percentile than Ligand B (50.68). This is *crucial* for a CNS target like DRD2.

**Caco-2 Permeability:** Both have negative values, which is unusual. However, the magnitude of the negative value is smaller for Ligand A (-4.959 vs -5.091), suggesting slightly better permeability.

**Aqueous Solubility:** Both have negative values, suggesting poor solubility. The values are similar (-3.115 vs -3.227).

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.408 and 0.34).

**Microsomal Clearance:** Ligand B (4.175) has a much lower microsomal clearance than Ligand A (71.886), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand B (28.708 hours) has a significantly longer half-life than Ligand A (-24.091 hours). This is a significant advantage.

**P-gp Efflux:** Ligand A (0.533) has a lower P-gp efflux liability than Ligand B (0.065), which is favorable for CNS penetration.

**Binding Affinity:** Ligand B (-7.7 kcal/mol) has a slightly better binding affinity than Ligand A (-8.3 kcal/mol). While a 1.5 kcal/mol advantage is significant, the other ADME properties of Ligand A are more favorable.



**Overall Assessment:**

Ligand A is considerably better suited as a drug candidate for DRD2. While Ligand B has slightly better affinity and metabolic stability/half-life, Ligand A excels in critical areas for CNS GPCR targets: TPSA, logP, BBB penetration, and DILI risk. The significantly better BBB penetration and lower TPSA of Ligand A outweigh the slightly weaker affinity and higher clearance.

Output:
0
2025-04-17 08:19:31,525 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (392.424 Da) is slightly higher than Ligand B (347.503 Da), but both are acceptable.

**TPSA:** Ligand A (66.48) is higher than Ligand B (43.86). For CNS targets, we ideally want TPSA <= 90. Both are under this threshold, but Ligand B is significantly better.

**logP:** Ligand A (3.546) is within the optimal range (1-3), while Ligand B (2.112) is towards the lower end. While both are acceptable, a slightly higher logP like that of Ligand A is generally preferred for CNS penetration.

**H-Bond Donors/Acceptors:** Ligand A has 1 HBD and 4 HBA, while Ligand B has 0 HBD and 3 HBA. Both are within acceptable limits (<=5 HBD and <=10 HBA).

**QED:** Both ligands have similar QED values (Ligand A: 0.846, Ligand B: 0.782), indicating good drug-like properties.

**DILI:** Ligand A (73.401) has a higher DILI risk than Ligand B (6.747). This is a significant advantage for Ligand B.

**BBB:** Ligand B (86.002) has a significantly higher BBB penetration percentile than Ligand A (74.874). This is *critical* for a CNS target like DRD2.

**Caco-2 Permeability:** Both have negative Caco-2 values (-4.947 and -4.787), which is unusual and suggests poor permeability. This is a concern for both.

**Aqueous Solubility:** Both have negative solubility values (-4.622 and -0.924), which is also concerning. Ligand B is slightly better here.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.811 and 0.653).

**Microsomal Clearance:** Ligand A (58.213) has a higher microsomal clearance than Ligand B (13.206), meaning it's metabolized faster. Lower clearance is preferred.

**In vitro Half-Life:** Ligand B (-11.053) has a negative half-life, which is problematic. Ligand A has a positive half-life (15.502), which is better.

**P-gp Efflux:** Ligand A (0.401) has lower P-gp efflux than Ligand B (0.043), which is favorable for CNS exposure.

**Binding Affinity:** Both ligands have excellent binding affinity (-8.6 kcal/mol and -8.8 kcal/mol), with Ligand B being slightly better. The affinity difference is small and likely less important than the ADME differences.

**Overall Assessment:**

Ligand B excels in BBB penetration and DILI risk, which are crucial for a CNS GPCR target. While its Caco-2 and solubility are concerning, its significantly lower DILI and higher BBB outweigh the slightly lower logP and the negative half-life. Ligand A has a better half-life and P-gp profile, but the higher DILI risk and lower BBB are major drawbacks.

Output:
1
2025-04-17 08:19:31,525 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (337.47 & 365.80 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (57.78) is significantly better than Ligand B (80.12). For a CNS target like DRD2, TPSA should be <= 90, and A is comfortably within this range, while B is approaching the upper limit.

**3. logP:** Ligand A (3.83) is optimal (1-3), while Ligand B (1.54) is at the lower end, potentially hindering permeation.

**4. H-Bond Donors:** Both ligands have acceptable HBD counts (2 and 1 respectively), well below the threshold of 5.

**5. H-Bond Acceptors:** Ligand A (2) is good, while Ligand B (5) is also acceptable, being under the 10 threshold.

**6. QED:** Both ligands have good QED values (0.787 and 0.833), indicating drug-like properties.

**7. DILI:** Ligand A (36.25) has a much lower DILI risk than Ligand B (74.99).  A score below 40 is preferred, and A is closer to this ideal.

**8. BBB:** Ligand A (68.13) and Ligand B (76.77) both have good BBB penetration, but B is slightly better. However, given the other factors, this difference is less crucial.

**9. Caco-2:** Both have negative Caco-2 values, which is unusual and difficult to interpret without knowing the scale. However, it suggests poor permeability.

**10. Solubility:** Both have negative solubility values, again unusual. This suggests poor solubility.

**11. hERG:** Both have low hERG inhibition liability (0.838 and 0.105), which is favorable.

**12. Cl_mic:** Ligand A (43.88) has a higher microsomal clearance than Ligand B (-2.28). Lower clearance is better for metabolic stability, so B is preferable here.

**13. t1/2:** Ligand A (-22.07) has a negative in vitro half-life, which is not possible. Ligand B (-15.03) is also negative. These values are suspect and may indicate issues with the data.

**14. Pgp:** Ligand A (0.783) has a lower P-gp efflux liability than Ligand B (0.095), which is desirable for CNS penetration.

**15. Binding Affinity:** Both ligands have similar strong binding affinities (-9.2 and -9.7 kcal/mol). The difference is minimal.

**Overall Assessment:**

Considering the GPCR-specific priorities, Ligand A is the more promising candidate. Its lower TPSA, optimal logP, lower DILI risk, and lower P-gp efflux liability outweigh the slightly better BBB penetration and lower Cl_mic of Ligand B. The negative half-life values for both are concerning and would require further investigation, but the other ADME properties of A are more favorable.

Output:
1
2025-04-17 08:19:31,526 - INFO - Reasoning:

Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (366.333 and 345.487 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (104.21) is higher than the preferred <90 for CNS targets, while Ligand B (61.44) is well within the range. This is a significant advantage for Ligand B.

**logP:** Both ligands (1.589 and 2.126) are within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A has 3 HBD and 5 HBA, while Ligand B has 2 HBD and 3 HBA. Both are acceptable.

**QED:** Both ligands have similar QED values (0.674 and 0.629), indicating good drug-likeness.

**DILI:** Ligand A (70.027) has a higher DILI risk than Ligand B (11.283). This is a clear advantage for Ligand B.

**BBB:** Ligand B (66.344) has a better BBB percentile than Ligand A (53.587), though both are below the desirable >70 for CNS targets. However, Ligand B is closer.

**Caco-2 Permeability:** Ligand A (-4.988) has worse Caco-2 permeability than Ligand B (-5.25). Both are quite poor.

**Aqueous Solubility:** Ligand A (-3.058) has worse aqueous solubility than Ligand B (-1.946). Both are quite poor.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.328 and 0.421).

**Microsomal Clearance:** Ligand A (27.44) has higher microsomal clearance than Ligand B (2.635), indicating lower metabolic stability. This favors Ligand B.

**In vitro Half-Life:** Ligand A (40.026) has a longer half-life than Ligand B (7.613). This favors Ligand A.

**P-gp Efflux:** Ligand A (0.067) has lower P-gp efflux than Ligand B (0.047), which is favorable for CNS penetration.

**Binding Affinity:** Ligand B (-7.7 kcal/mol) has a significantly stronger binding affinity than Ligand A (-9.6 kcal/mol). This is a substantial advantage for Ligand B, potentially outweighing some of its ADME drawbacks.

**Overall Assessment:**

Ligand B is the better candidate. While neither ligand is perfect, Ligand B excels in key areas for a CNS-targeting GPCR ligand: lower TPSA, significantly better binding affinity, lower DILI risk, better BBB penetration, and improved metabolic stability. The stronger binding affinity of Ligand B is a major advantage. Although Ligand A has a longer half-life and lower P-gp efflux, the other benefits of Ligand B are more critical for this target.



Output:
1
2025-04-17 08:19:31,526 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (373.36 and 357.399 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (80.12) is excellent, well below the 90 A^2 threshold for CNS targets. Ligand B (128.68) is higher, but still potentially acceptable, though less ideal.

**3. logP:** Ligand A (1.36) is optimal. Ligand B (0.394) is a bit low, potentially hindering membrane permeability.

**4. H-Bond Donors:** Ligand A (1) is good. Ligand B (2) is also acceptable.

**5. H-Bond Acceptors:** Ligand A (6) is good. Ligand B (8) is also acceptable.

**6. QED:** Ligand A (0.878) is excellent. Ligand B (0.629) is still reasonable, above the 0.5 threshold.

**7. DILI:** Ligand A (83.404) has a higher DILI risk than Ligand B (75.184), but both are below the concerning 60 percentile.

**8. BBB:** Ligand A (76.309) has a good BBB penetration percentile, desirable for a CNS target. Ligand B (36.138) has poor predicted BBB penetration, a significant drawback.

**9. Caco-2:** Both have negative Caco-2 values, which is unusual and suggests a problem with the prediction method or the molecules themselves. It's hard to interpret this data without more context.

**10. Solubility:** Both have negative solubility values, again suggesting a problem with the prediction method.

**11. hERG:** Both ligands have very low hERG inhibition risk (0.115 and 0.032).

**12. Cl_mic:** Ligand A (10.474) has a lower (better) microsomal clearance than Ligand B (-13.497), indicating better metabolic stability.

**13. t1/2:** Ligand A (5.968) has a longer half-life than Ligand B (2.578).

**14. Pgp:** Ligand A (0.067) has lower P-gp efflux liability than Ligand B (0.017), suggesting better CNS exposure.

**15. Binding Affinity:** Ligand A (-9.1 kcal/mol) has a significantly stronger binding affinity than Ligand B (-8.0 kcal/mol). This is a substantial advantage.

**Overall Assessment:**

Ligand A is clearly superior. It has a better logP, significantly better BBB penetration, better metabolic stability (lower Cl_mic, longer t1/2), lower P-gp efflux, and a much stronger binding affinity. While Ligand A has a slightly higher DILI risk, the substantial advantages in other key ADME/PK properties and binding outweigh this concern. The negative Caco-2 and solubility values are concerning and would require further investigation, but the overall profile of Ligand A is much more promising for CNS drug development.

Output:
1
2025-04-17 08:19:31,526 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (346.431 and 349.45 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (95.42) is slightly above the optimal <90 for CNS targets, but still reasonable. Ligand B (65.2) is excellent, well below the threshold.

**logP:** Ligand A (0.996) is a bit low, potentially hindering permeability. Ligand B (2.818) is within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Both ligands have 2 HBD and 5/2 HBA, respectively, which are acceptable.

**QED:** Both ligands have good QED scores (0.801 and 0.858), indicating drug-like properties.

**DILI:** Ligand A (32.493) has a lower DILI risk than Ligand B (41.024), which is preferable.

**BBB:** This is crucial for a CNS target. Ligand A (53.587) is below the desirable >70, while Ligand B (83.443) is excellent.

**Caco-2 Permeability:** Both have negative values, suggesting poor permeability. However, the scale is not specified, making direct comparison difficult.

**Aqueous Solubility:** Both have negative values, indicating poor solubility. Again, the scale is not specified.

**hERG:** Ligand A (0.176) shows a lower hERG inhibition liability than Ligand B (0.763), which is a significant advantage.

**Microsomal Clearance:** Ligand A (27.916) has lower microsomal clearance, suggesting better metabolic stability than Ligand B (41.206).

**In vitro Half-Life:** Ligand A (-16.454) has a negative half-life, which is concerning and likely indicates a very short half-life. Ligand B (-30.145) is even worse.

**P-gp Efflux:** Ligand A (0.005) has very low P-gp efflux liability, which is highly desirable for CNS penetration. Ligand B (0.409) is higher, but not extremely concerning.

**Binding Affinity:** Ligand B (-8.7 kcal/mol) has a significantly stronger binding affinity than Ligand A (-7.2 kcal/mol). This is a >1.5 kcal/mol advantage, which can outweigh some ADME drawbacks.

**Overall Assessment:**

Ligand B excels in the most critical areas for a CNS-targeting GPCR: BBB penetration and binding affinity. While its DILI and hERG are slightly higher than Ligand A, the substantial improvement in BBB and affinity are paramount. Ligand A has better DILI, hERG, and P-gp efflux, but its poor BBB and weaker affinity are major drawbacks. The negative half-life values for both are concerning, but can be addressed in later optimization stages. Given the importance of CNS penetration and potency for DRD2, Ligand B is the more promising candidate.

Output:
1
2025-04-17 08:19:31,526 - INFO - Batch 439 complete. Total preferences: 7024
2025-04-17 08:19:31,526 - INFO - Processing batch 440/512...
2025-04-17 08:20:19,134 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (347.503 and 346.446 Da) fall comfortably within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (43.86) is significantly better than Ligand B (58.2). For CNS targets, we want TPSA <= 90, and ideally lower. Ligand A is much closer to the optimal range for CNS penetration.

**3. logP:** Ligand A (2.3) is within the optimal 1-3 range. Ligand B (3.644) is slightly higher, but still acceptable.

**4. H-Bond Donors:** Ligand A (0) is preferable to Ligand B (2). Fewer HBDs generally improve permeability.

**5. H-Bond Acceptors:** Ligand A (3) is slightly higher than Ligand B (2), but both are within the acceptable limit of 10.

**6. QED:** Both ligands have good QED scores (0.524 and 0.706), indicating good drug-like properties. Ligand B is slightly better.

**7. DILI:** Ligand A (14.23) has a much lower DILI risk than Ligand B (23.226). This is a significant advantage for Ligand A.

**8. BBB:** Ligand A (71.888) and Ligand B (80.574) both have good BBB penetration, exceeding the 70% threshold for CNS targets. Ligand B is slightly better.

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.745 and -4.668). This is unusual and suggests poor permeability. However, these values are on a log scale, so the absolute difference is not huge.

**10. Aqueous Solubility:** Ligand A (-1.51) has better solubility than Ligand B (-3.489).

**11. hERG Inhibition:** Both ligands show low hERG inhibition risk (0.542 and 0.46).

**12. Microsomal Clearance:** Ligand A (37.22) has lower microsomal clearance than Ligand B (42.126), indicating better metabolic stability.

**13. In vitro Half-Life:** Ligand A (-10.607) has a longer half-life than Ligand B (17.253).

**14. P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.103 and 0.17).

**15. Binding Affinity:** Ligand B (-8.5 kcal/mol) has a significantly stronger binding affinity than Ligand A (-7.5 kcal/mol). This is a 1.0 kcal/mol difference, which is substantial and can outweigh some ADME drawbacks.

**Overall Assessment:**

While Ligand B has a superior binding affinity, Ligand A demonstrates a more favorable ADME profile, particularly regarding TPSA, DILI, solubility, and metabolic stability. Given the GPCR-specific emphasis on BBB penetration, logP, and TPSA, and the importance of minimizing toxicity (DILI), Ligand A appears to be the more promising candidate. The slightly weaker binding affinity of Ligand A can potentially be optimized in subsequent iterations of drug design. The negative Caco-2 values for both are concerning, but the other advantages of Ligand A make it the better choice.

Output:
0
2025-04-17 08:20:19,134 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (389.587 and 360.479 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Both ligands have TPSA values (61.88 and 62.55) slightly above the optimal <90 for CNS targets, but still reasonable.

**3. logP:** Ligand A (1.258) is within the optimal 1-3 range. Ligand B (3.318) is at the higher end of optimal, but still acceptable.

**4. H-Bond Donors:** Both ligands have 1 HBD, which is within the acceptable limit of <=5.

**5. H-Bond Acceptors:** Ligand A has 6 HBAs, and Ligand B has 4. Both are below the acceptable limit of <=10.

**6. QED:** Both ligands have good QED scores (0.599 and 0.824), indicating good drug-like properties.

**7. DILI:** Ligand A (27.142) has a significantly lower DILI risk than Ligand B (54.207), placing it in the 'good' category while B is moderately risky.

**8. BBB:** Ligand B (70.648) has a better BBB penetration score than Ligand A (68.903), although both are above the 70% threshold for CNS targets.

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.193 and -5.115), which is unusual and suggests poor permeability. This is a significant concern.

**10. Aqueous Solubility:** Both ligands have negative solubility values (-1.771 and -3.663), indicating very poor aqueous solubility. This is also a significant concern.

**11. hERG Inhibition:** Both ligands have low hERG inhibition risk (0.458 and 0.739).

**12. Microsomal Clearance:** Ligand A (13.727) has a much lower microsomal clearance than Ligand B (53.768), suggesting better metabolic stability.

**13. In vitro Half-Life:** Ligand B (24.003) has a longer in vitro half-life than Ligand A (9.452).

**14. P-gp Efflux:** Ligand A (0.066) has significantly lower P-gp efflux liability than Ligand B (0.537), which is favorable for CNS penetration.

**15. Binding Affinity:** Ligand B (-8.3 kcal/mol) has a significantly stronger binding affinity than Ligand A (-6.8 kcal/mol). This is a substantial advantage (1.5 kcal/mol difference).

**Overall Assessment:**

While Ligand B boasts a superior binding affinity and BBB penetration, Ligand A has a much better safety profile (lower DILI) and metabolic stability (lower Cl_mic, lower Pgp efflux). Both ligands have concerningly poor predicted solubility and permeability. However, for a CNS target, the stronger affinity of Ligand B is a major advantage, and the slightly better BBB penetration helps offset the other drawbacks. The difference in binding affinity is large enough to potentially overcome the solubility/permeability issues with appropriate formulation strategies.

Output:
1
2025-04-17 08:20:19,134 - INFO - Reasoning:

Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (343.475 and 352.431 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (77.04) is excellent, well below the 90 Angstroms threshold for CNS targets. Ligand B (84.94) is still acceptable, but less optimal.

**3. logP:** Ligand A (2.502) is within the optimal 1-3 range. Ligand B (0.514) is a bit low, potentially hindering membrane permeability.

**4. H-Bond Donors:** Both ligands have 1 HBD, which is good.

**5. H-Bond Acceptors:** Both ligands have 5 HBA, which is good.

**6. QED:** Ligand A (0.909) has a very strong drug-like profile, significantly better than Ligand B (0.753).

**7. DILI:** Ligand A (41.411) has a slightly higher DILI risk than Ligand B (30.012), but both are below the concerning 60 percentile.

**8. BBB:** This is critical for a CNS target. Ligand A (89.957) has excellent BBB penetration, exceeding the desirable 70% threshold. Ligand B (65.413) is significantly lower, raising concerns about CNS exposure.

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 values, which is unusual and difficult to interpret without knowing the scale. However, the values are similar.

**10. Aqueous Solubility:** Both ligands have negative solubility values, which is also unusual. Again, values are similar.

**11. hERG Inhibition:** Ligand A (0.868) has a slightly higher hERG risk than Ligand B (0.066), but both are relatively low.

**12. Microsomal Clearance:** Ligand B (-3.017) has a negative clearance, which is not physically possible. This suggests an error in the data or a very stable compound. Ligand A (11.647) is a reasonable clearance value.

**13. In vitro Half-Life:** Ligand B (-3.997) has a negative half-life, which is not physically possible. This further supports the data quality concerns for Ligand B. Ligand A (5.527) is a reasonable half-life.

**14. P-gp Efflux:** Ligand A (0.407) has lower P-gp efflux than Ligand B (0.015), which is favorable for CNS penetration.

**15. Binding Affinity:** Both ligands have very similar and strong binding affinities (-8.3 and -8.2 kcal/mol). The difference is negligible.

**Overall Assessment:**

Ligand A is significantly more promising. It has superior QED, excellent BBB penetration, and more realistic ADME properties (clearance and half-life). While Ligand B has a slightly lower DILI risk and hERG inhibition, the negative clearance and half-life values are highly suspect and raise serious concerns about its viability. The slightly lower logP of Ligand B is also a disadvantage. The similar binding affinities mean that the superior ADME profile of Ligand A outweighs any minor differences in potency.

Output:
1
2025-04-17 08:20:19,135 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (361.511 and 357.495 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (62.3) is significantly better than Ligand B (96.53). For CNS targets, we want TPSA <= 90, and A is comfortably within this range, while B is close to the upper limit.

**3. logP:** Both ligands have good logP values (3.246 and 2.206), falling within the optimal 1-3 range.

**4. H-Bond Donors:** Ligand A (1) is preferable to Ligand B (3). Lower HBD generally improves permeability.

**5. H-Bond Acceptors:** Both ligands have the same number of HBA (4), which is acceptable (<=10).

**6. QED:** Ligand A (0.758) has a higher QED than Ligand B (0.522), indicating a more drug-like profile.

**7. DILI:** Ligand A (42.148) has a slightly higher DILI risk than Ligand B (21.52), but both are below the concerning threshold of 60.

**8. BBB:** Ligand B (77.2) has a slightly better BBB penetration percentile than Ligand A (68.282). However, both are reasonably good, exceeding the 70% threshold for CNS targets.

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.785 and -4.794), which is unusual and suggests poor permeability. This is a significant concern for both.

**10. Aqueous Solubility:** Both ligands have negative solubility values (-3.801 and -2.57), indicating very poor aqueous solubility. This is a major drawback for both compounds.

**11. hERG Inhibition:** Ligand A (0.379) has a lower hERG inhibition liability than Ligand B (0.613), which is desirable.

**12. Microsomal Clearance:** Ligand B (59.321) has lower microsomal clearance than Ligand A (75.421), suggesting better metabolic stability.

**13. In vitro Half-Life:** Ligand B (-23.98) has a much longer in vitro half-life than Ligand A (-5.444). This is a significant advantage for B.

**14. P-gp Efflux:** Ligand A (0.272) has lower P-gp efflux liability than Ligand B (0.037), which is preferable for CNS penetration.

**15. Binding Affinity:** Ligand A (-7.8) has a slightly better binding affinity than Ligand B (-7.3). While both are good, the 1.5 kcal/mol difference could be significant.

**Overall Assessment:**

Despite both compounds having significant drawbacks (poor solubility and permeability), Ligand A emerges as the slightly better candidate. Its superior TPSA, QED, lower hERG risk, and slightly better binding affinity outweigh the benefits of Ligand B's better BBB, lower clearance, and longer half-life. The lower P-gp efflux for A is also a plus for CNS penetration. The negative Caco-2 and solubility values are concerning for both and would require significant optimization.

Output:
0
2025-04-17 08:20:19,135 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B based on the provided guidelines, prioritizing GPCR-specific properties (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (344.371 Da) is slightly lower, which could be advantageous for permeability, but both are acceptable.

**TPSA:** Ligand A (106.23) is better than Ligand B (49.74) as it is closer to the ideal range for CNS targets (<=90). Ligand B is very low, which could indicate poor interactions with the receptor.

**logP:** Ligand B (3.994) is optimal (1-3), while Ligand A (0.364) is quite low, potentially hindering membrane permeability. This is a significant drawback for Ligand A.

**H-Bond Donors/Acceptors:** Ligand A has 2 HBD and 6 HBA, while Ligand B has 1 HBD and 4 HBA. Both are within acceptable limits.

**QED:** Both ligands have similar QED values (0.787 and 0.734), indicating good drug-likeness.

**DILI:** Ligand B (21.481) has a much lower DILI risk than Ligand A (56.146), which is a significant advantage.

**BBB:** Ligand B (70.997) has a much better BBB penetration percentile than Ligand A (58.356). This is crucial for a CNS target like DRD2.

**Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and suggests poor permeability.

**Aqueous Solubility:** Both have negative solubility values, which is also unusual and suggests poor solubility.

**hERG Inhibition:** Ligand A (0.112) has a lower hERG inhibition liability than Ligand B (0.763), which is preferable.

**Microsomal Clearance:** Ligand B (32.527) has higher microsomal clearance than Ligand A (11.586), suggesting lower metabolic stability.

**In vitro Half-Life:** Ligand B (34.754) has a longer in vitro half-life than Ligand A (-4.273), which is a positive attribute.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.043 and 0.413).

**Binding Affinity:** Ligand B (-8.1 kcal/mol) has a significantly stronger binding affinity than Ligand A (-9.0 kcal/mol). This is a substantial advantage, potentially outweighing some of the ADME concerns.

**Overall Assessment:**

While Ligand A has a slightly better MW and lower hERG risk, Ligand B is superior overall. The critical factors favoring Ligand B are its optimal logP, significantly better BBB penetration, lower DILI risk, and, most importantly, its much stronger binding affinity. The slightly higher clearance of Ligand B is a concern but could be addressed through structural modifications. The poor Caco-2 and solubility values are concerning for both, but the strong affinity of Ligand B makes it a more promising starting point for optimization.

Output:
1
2025-04-17 08:20:19,135 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (334.419 and 346.471 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (55.56) is significantly better than Ligand B (60.85). Both are below the 90 A^2 threshold for CNS targets, but A is closer to optimal.

**logP:** Ligand A (4.366) is higher than the optimal range (1-3) but still potentially manageable. Ligand B (2.249) is within the optimal range. This favors B initially, but high logP can sometimes be tolerated if other properties are excellent.

**H-Bond Donors/Acceptors:** Both have 1 HBD, which is good. Ligand A has 2 HBA, and Ligand B has 3 HBA, both are acceptable.

**QED:** Both ligands have good QED scores (0.681 and 0.889), indicating good drug-like properties.

**DILI:** Ligand A (72.858) has a higher DILI risk than Ligand B (35.556). This is a significant drawback for Ligand A.

**BBB:** Ligand A (82.047) has a much better BBB penetration score than Ligand B (57.193). This is *critical* for a CNS target like DRD2 and heavily favors Ligand A.

**Caco-2 Permeability:** Both have negative Caco-2 values (-4.645 and -4.369) which is unusual and suggests poor permeability. This is concerning for both.

**Aqueous Solubility:** Both ligands have very poor aqueous solubility (-5.047 and -1.868). This is a significant formulation challenge for both.

**hERG:** Both ligands have low hERG inhibition risk (0.906 and 0.687).

**Microsomal Clearance:** Ligand B (65.161) has lower microsomal clearance than Ligand A (78.429), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand B (-5.307) has a longer in vitro half-life than Ligand A (-3.593).

**P-gp Efflux:** Both have low P-gp efflux liability (0.724 and 0.439), which is good for CNS penetration.

**Binding Affinity:** Ligand A (-9.6 kcal/mol) has a significantly stronger binding affinity than Ligand B (-8.5 kcal/mol). This is a substantial advantage for Ligand A, potentially outweighing some of its drawbacks. The difference is >1.5 kcal/mol.

**Overall Assessment:**

Ligand A excels in binding affinity and BBB penetration, which are paramount for a CNS GPCR target. While its logP is higher and DILI risk is elevated, the strong binding and good BBB are compelling. Ligand B has better ADME properties (lower DILI, better metabolic stability, longer half-life) and a more optimal logP, but its significantly weaker binding affinity is a major disadvantage. Given the importance of potency for DRD2, and the fact that the difference in affinity is substantial, the stronger binding of Ligand A outweighs its other weaknesses.



Output:
1
2025-04-17 08:20:19,135 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (366.53 and 347.46 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (58.64) is significantly better than Ligand B (75.44). For CNS targets, we want TPSA <= 90, and ideally closer to 60. Ligand A is much closer to the ideal range.

**3. logP:** Both ligands have good logP values (3.37 and 2.96), falling within the optimal 1-3 range.

**4. H-Bond Donors:** Both have 1 HBD, which is acceptable.

**5. H-Bond Acceptors:** Both have 4 HBA, which is acceptable.

**6. QED:** Ligand A (0.718) has a better QED score than Ligand B (0.521), indicating a more drug-like profile.

**7. DILI:** Both ligands have low DILI risk (35.94 and 37.03 percentile), which is good.

**8. BBB:** Ligand A (76.19%) has a significantly better BBB penetration prediction than Ligand B (61.38%). This is *critical* for a CNS target like DRD2. A value >70 is desirable.

**9. Caco-2 Permeability:** Both have negative Caco-2 values (-4.696 and -4.525), which is unusual and suggests poor permeability. However, these values are on a log scale and are difficult to interpret without knowing the base of the log. We'll consider this a neutral point for now.

**10. Aqueous Solubility:** Both have negative solubility values (-2.917 and -3.484), also on a log scale, suggesting poor aqueous solubility. This is a concern, but can be mitigated with formulation strategies.

**11. hERG Inhibition:** Both ligands have low hERG inhibition risk (0.643 and 0.559 percentile).

**12. Microsomal Clearance:** Ligand A (66.08 mL/min/kg) has a higher clearance than Ligand B (54.91 mL/min/kg), meaning it's likely to be metabolized faster. Lower clearance is preferred.

**13. In vitro Half-Life:** Ligand B (2.57 hours) has a slightly longer half-life than Ligand A (16.35 hours). This is a positive for Ligand B, but the difference isn't huge.

**14. P-gp Efflux:** Both ligands have low P-gp efflux liability (0.473 and 0.14). Lower is better, so Ligand B is slightly better here.

**15. Binding Affinity:** Ligand A (-7.7 kcal/mol) has a slightly better binding affinity than Ligand B (-7.5 kcal/mol). While both are excellent, the 0.2 kcal/mol difference is meaningful and can outweigh some ADME drawbacks.

**Overall Assessment:**

Ligand A is the stronger candidate. Its superior TPSA and BBB penetration are crucial for a CNS-targeting GPCR. The slightly better binding affinity is also a plus. While Ligand B has a slightly better half-life and P-gp efflux, the differences are not substantial enough to overcome Ligand A's advantages in TPSA and BBB. The similar solubility and permeability concerns are present in both, but can be addressed during formulation. The higher clearance of Ligand A is a minor drawback.

Output:
1
2025-04-17 08:20:19,135 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (390.571 and 360.885 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (92.34) is slightly above the optimal <90 for CNS targets, but still reasonable. Ligand B (64.33) is well within the desired range.

**logP:** Ligand A (1.356) is within the optimal 1-3 range. Ligand B (3.854) is approaching the upper limit, potentially raising concerns about solubility and off-target effects, but not critically.

**H-Bond Donors/Acceptors:** Ligand A has 2 HBD and 5 HBA, which are acceptable. Ligand B has 1 HBD and 3 HBA, also acceptable.

**QED:** Both ligands have good QED scores (0.587 and 0.783), indicating good drug-like properties.

**DILI:** Both ligands have low DILI risk (35.014 and 27.142), which is positive.

**BBB:** Ligand A has a better BBB penetration score (65.413) than Ligand B (55.099). While both are not ideal (>70), A is closer.

**Caco-2 Permeability:** Ligand A (-5.619) and Ligand B (-4.427) both have negative Caco-2 values, which is unusual and indicates *low* permeability. This is a significant concern for both.

**Aqueous Solubility:** Both ligands have very poor aqueous solubility (-2.651 and -4.501). This is a major drawback.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.205 and 0.776), which is good.

**Microsomal Clearance:** Ligand A (48.817) has lower microsomal clearance than Ligand B (69.69), suggesting better metabolic stability.

**In vitro Half-Life:** Both ligands have similar in vitro half-lives (21.005 and 20.382 hours), which are acceptable.

**P-gp Efflux:** Ligand A (0.094) has significantly lower P-gp efflux liability than Ligand B (0.453), which is a major advantage for CNS penetration.

**Binding Affinity:** Both ligands have the same binding affinity (-7.2 kcal/mol), which is excellent.

**Overall Assessment:**

Both ligands have excellent binding affinity. However, the poor solubility and Caco-2 permeability are major concerns for both. Considering the GPCR-specific priorities, Ligand A is slightly favored due to its lower P-gp efflux, better BBB penetration, and lower microsomal clearance, despite its slightly higher TPSA. The lower P-gp efflux is particularly important for CNS targets like DRD2. While the solubility is a significant issue for both, the other factors give a slight edge to Ligand A.

Output:
0
2025-04-17 08:20:19,136 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (365.38 and 348.49 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (118.97) is slightly above the optimal <90 for CNS targets, but still reasonable. Ligand B (76.02) is excellent, well below 90.

**logP:** Ligand A (-1.144) is a bit low, potentially hindering permeability. Ligand B (2.858) is nearly ideal.

**H-Bond Donors/Acceptors:** Ligand A has 4 HBD and 5 HBA, acceptable. Ligand B has 2 HBD and 4 HBA, also acceptable.

**QED:** Both ligands have reasonable QED scores (0.39 and 0.674), with Ligand B being better.

**DILI:** Both ligands have similar, low DILI risk (25.82 and 25.28).

**BBB:** This is crucial for a CNS target. Ligand A has a BBB percentile of 43.5, which is not great. Ligand B has a significantly better BBB percentile of 74.2, exceeding the desirable >70 threshold.

**Caco-2 Permeability:** Both have negative Caco-2 values (-5.49 and -4.853), which is unusual and suggests poor permeability. However, these values are on a scale where negative values are possible, and direct comparison is difficult without knowing the scale's specifics.

**Aqueous Solubility:** Both have negative solubility values (-0.434 and -2.655), also unusual and suggesting poor solubility. Again, the scale is unknown.

**hERG:** Both ligands have low hERG inhibition liability (0.267 and 0.716).

**Microsomal Clearance:** Ligand A (-28.5) suggests very low clearance and high metabolic stability, which is good. Ligand B (44.95) suggests moderate clearance.

**In vitro Half-Life:** Ligand A (-5.93) suggests a very long half-life, which is excellent. Ligand B (-2.78) is less favorable.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.005 and 0.398), which is good for CNS penetration.

**Binding Affinity:** Ligand B (-8.1 kcal/mol) has a stronger binding affinity than Ligand A (-7.5 kcal/mol). This 0.6 kcal/mol difference is significant.

**Overall Assessment:**

Ligand B is the stronger candidate. While both have issues with Caco-2 and solubility, Ligand B excels in the most important parameters for a CNS-targeting GPCR: BBB penetration and binding affinity. Its logP is also much more favorable. Ligand A's low logP and poor BBB penetration are significant drawbacks. The superior affinity and BBB of Ligand B outweigh the slightly higher clearance and lower half-life compared to Ligand A.

Output:
1
2025-04-17 08:20:19,136 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (358.438 and 383.279 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (40.62) is significantly better than Ligand B (92.08). For CNS targets, we want TPSA <= 90, so Ligand A is much more favorable.

**logP:** Both ligands have acceptable logP values (3.245 and 2.741), falling within the 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A (0 HBD, 3 HBA) and Ligand B (2 HBD, 3 HBA) both have reasonable numbers of H-bond donors and acceptors, well below the thresholds of 5 and 10, respectively.

**QED:** Ligand A (0.827) has a higher QED score than Ligand B (0.569), indicating a more drug-like profile.

**DILI:** Both ligands have similar and acceptable DILI risk (49.593 and 47.926, both < 60).

**BBB:** Ligand A (87.127) has a substantially better BBB percentile than Ligand B (73.75).  For a CNS target like DRD2, >70 is desirable, and Ligand A is closer to that mark.

**Caco-2 Permeability:** Ligand A (-4.687) has a worse Caco-2 permeability than Ligand B (-5.509). Lower values indicate poorer permeability, but both are quite poor.

**Aqueous Solubility:** Both ligands have poor aqueous solubility (-3.433 and -3.275). This could pose formulation challenges.

**hERG:** Both ligands have low hERG inhibition liability (0.719 and 0.492), which is good.

**Microsomal Clearance:** Ligand A (32.962) has a higher microsomal clearance than Ligand B (16.132), suggesting lower metabolic stability.

**In vitro Half-Life:** Ligand B (-5.237) has a longer in vitro half-life than Ligand A (4.15), which is preferable.

**P-gp Efflux:** Ligand A (0.436) has a lower P-gp efflux liability than Ligand B (0.046), which is favorable for CNS penetration.

**Binding Affinity:** Ligand B (-7.4 kcal/mol) has a significantly stronger binding affinity than Ligand A (-9.3 kcal/mol). This is a substantial advantage, potentially outweighing some ADME drawbacks.

**Overall Assessment:**

Ligand A excels in TPSA and BBB penetration, critical for CNS GPCR targets. It also has better QED and P-gp efflux. However, it suffers from higher microsomal clearance and weaker binding affinity.

Ligand B has a significantly better binding affinity, a longer half-life, and slightly better Caco-2 permeability. Its main drawback is the higher TPSA, which could hinder CNS penetration.

Given the strong emphasis on binding affinity for GPCRs, and the substantial difference (-7.4 vs -9.3 kcal/mol), Ligand B is the more promising candidate despite its higher TPSA. The improved affinity could be optimized further with structural modifications, while reducing TPSA is often more challenging.

Output:
1
2025-04-17 08:20:19,136 - INFO - Reasoning:
Let's analyze both ligands against the provided guidelines, prioritizing GPCR-specific properties (BBB, logP, Pgp, TPSA, and affinity).

**Ligand A:**

*   **MW:** 342.483 Da - Good (within 200-500 range)
*   **TPSA:** 41.57 A<sup>2</sup> - Excellent (well below 90 A<sup>2</sup> for CNS targets)
*   **logP:** 3.959 - Good (close to optimal 1-3 range)
*   **HBD:** 1 - Good (<=5)
*   **HBA:** 3 - Good (<=10)
*   **QED:** 0.851 - Excellent (>=0.5)
*   **DILI:** 14.618 - Excellent (low risk, <40)
*   **BBB:** 89.298 - Excellent (very high, >70)
*   **Caco-2:** -4.488 - Poor (negative value indicates very low permeability)
*   **Solubility:** -3.321 - Poor (negative value indicates very low solubility)
*   **hERG:** 0.88 - Good (low risk)
*   **Cl_mic:** 41.055 mL/min/kg - Moderate (relatively high, suggesting moderate metabolic liability)
*   **t1/2:** 58.764 hours - Good (long half-life)
*   **Pgp:** 0.213 - Excellent (low efflux)
*   **Affinity:** -8.9 kcal/mol - Excellent (very strong binding)

**Ligand B:**

*   **MW:** 349.431 Da - Good (within 200-500 range)
*   **TPSA:** 92.59 A<sup>2</sup> - Moderate (slightly above the ideal 90 A<sup>2</sup> for CNS targets, but not a major concern)
*   **logP:** 0.58 - Poor (below 1, potentially hindering permeation)
*   **HBD:** 3 - Good (<=5)
*   **HBA:** 5 - Good (<=10)
*   **QED:** 0.7 - Good (>=0.5)
*   **DILI:** 39.667 - Good (low risk, <40)
*   **BBB:** 39.86 - Poor (well below 70, undesirable for CNS targets)
*   **Caco-2:** -4.785 - Poor (negative value indicates very low permeability)
*   **Solubility:** -2.004 - Poor (negative value indicates very low solubility)
*   **hERG:** 0.16 - Excellent (very low risk)
*   **Cl_mic:** 24.232 mL/min/kg - Good (low clearance, good metabolic stability)
*   **t1/2:** 17.638 hours - Moderate (shorter half-life)
*   **Pgp:** 0.058 - Excellent (very low efflux)
*   **Affinity:** -7.9 kcal/mol - Good (strong binding, but 1 kcal/mol weaker than Ligand A)

**Comparison & Decision:**

While both ligands have acceptable MW, QED, and DILI scores, Ligand A is significantly superior for a CNS-targeting GPCR like DRD2. The key differences are:

*   **BBB:** Ligand A has a much higher BBB penetration score (89.3%) compared to Ligand B (39.9%). This is *critical* for CNS drug candidates.
*   **logP:** Ligand A's logP (3.96) is within the optimal range, while Ligand B's (0.58) is too low, potentially leading to poor membrane permeability.
*   **Affinity:** Ligand A has a stronger binding affinity (-8.9 kcal/mol) than Ligand B (-7.9 kcal/mol). The 1 kcal/mol difference is significant enough to outweigh some of the minor ADME drawbacks of either compound.
*   **Caco-2 & Solubility:** Both compounds have poor Caco-2 permeability and solubility, but these can be addressed through formulation strategies. The BBB and logP issues with Ligand B are more fundamental.

Ligand A's combination of high BBB penetration, optimal logP, strong binding affinity, and favorable safety profiles makes it the more promising drug candidate.

Output:
1
2025-04-17 08:20:19,136 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 drug candidates, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (352.519 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Both ligands (69.64) are below the 90 A^2 threshold for CNS targets, which is excellent.

**3. logP:** Both ligands (A: 2.574, B: 2.719) are within the optimal range of 1-3.

**4. H-Bond Donors:** Both ligands have 2 HBD, which is acceptable.

**5. H-Bond Acceptors:** Both ligands have 3 HBA, which is acceptable.

**6. QED:** Both ligands have good QED scores (A: 0.67, B: 0.74), indicating drug-like properties.

**7. DILI:** Ligand A (10.237) has a significantly lower DILI risk than Ligand B (15.626). This is a major advantage for Ligand A.

**8. BBB:** Ligand A (70.26) has a better BBB penetration percentile than Ligand B (66.576), although both are reasonably good. For a CNS target like DRD2, maximizing BBB penetration is crucial.

**9. Caco-2 Permeability:** Ligand A (-4.476) has better Caco-2 permeability than Ligand B (-4.701).

**10. Aqueous Solubility:** Both ligands have similar, very poor aqueous solubility (-2.847 and -2.829). This could pose formulation challenges, but is less critical than BBB penetration for a CNS drug.

**11. hERG Inhibition:** Both ligands have low hERG inhibition risk (A: 0.621, B: 0.559).

**12. Microsomal Clearance:** Ligand B (48.822) has significantly lower microsomal clearance than Ligand A (77.884), suggesting better metabolic stability.

**13. In vitro Half-Life:** Ligand B (-10.449) has a negative in vitro half-life, which is concerning and suggests rapid degradation. Ligand A (10.769) has a reasonable half-life.

**14. P-gp Efflux:** Both ligands have low P-gp efflux liability (A: 0.28, B: 0.467).

**15. Binding Affinity:** Ligand B (-8.0 kcal/mol) has a slightly better binding affinity than Ligand A (-7.4 kcal/mol). However, the difference is less than 1.5 kcal/mol, and other factors are more important.

**Overall Assessment:**

Ligand A is the more promising candidate. While Ligand B has slightly better binding affinity and metabolic stability, Ligand A has a significantly lower DILI risk, better BBB penetration, and a more reasonable in vitro half-life. For a CNS GPCR target, the lower DILI and improved BBB are critical advantages that outweigh the small difference in binding affinity. The poor solubility is a concern for both, but can be addressed through formulation strategies.

Output:
0
2025-04-17 08:20:19,137 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (347.443 and 352.479 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (69.54) is better than Ligand B (56.33) as it is closer to the ideal <90 for CNS targets.

**logP:** Ligand A (4.14) is higher than the optimal 1-3 range, potentially causing solubility issues, while Ligand B (-0.139) is significantly *below* the optimal range, which could hinder membrane permeability.

**H-Bond Donors/Acceptors:** Ligand A (1 HBD, 4 HBA) and Ligand B (0 HBD, 5 HBA) both fall within acceptable limits.

**QED:** Both ligands have good QED scores (0.569 and 0.708, respectively), indicating drug-like properties. Ligand B is slightly better.

**DILI:** Ligand A (76.464) has a higher DILI risk than Ligand B (8.026). This is a significant advantage for Ligand B.

**BBB:** Ligand B (65.878) has a significantly better BBB penetration percentile than Ligand A (27.879). This is *critical* for a CNS target like DRD2.

**Caco-2 Permeability:** Ligand A (-5.172) has poor Caco-2 permeability, while Ligand B (-4.637) is also poor, but slightly better.

**Aqueous Solubility:** Ligand A (-6.501) has very poor aqueous solubility, which is a major concern. Ligand B (-0.178) is also poor, but better than Ligand A.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.553 and 0.279, respectively).

**Microsomal Clearance:** Ligand A (43.383) has a moderate clearance, while Ligand B (11.924) has a lower clearance, suggesting better metabolic stability.

**In vitro Half-Life:** Ligand B (-22.546) has a much longer in vitro half-life than Ligand A (-0.731), a significant advantage.

**P-gp Efflux:** Ligand A (0.304) has lower P-gp efflux than Ligand B (0.012), which is favorable for CNS penetration.

**Binding Affinity:** Ligand A (-9.2 kcal/mol) has a significantly stronger binding affinity than Ligand B (-7.2 kcal/mol). This is a substantial advantage, potentially outweighing some of the ADME drawbacks.

**Overall Assessment:**

While Ligand A boasts a superior binding affinity, its extremely poor solubility, low BBB penetration, and moderate clearance are major liabilities. Ligand B, despite a weaker affinity, presents a much more favorable ADME profile, particularly its excellent BBB penetration, low DILI risk, improved metabolic stability (lower Cl_mic and longer t1/2), and better solubility. For a CNS target like DRD2, good brain penetration is paramount. The 1.5 kcal/mol difference in affinity, while notable, is less critical than the substantial improvements in ADME properties offered by Ligand B.

Output:
1
2025-04-17 08:20:19,137 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (347.394 and 366.615 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (91.02) is slightly above the optimal <90 for CNS targets, but still reasonable. Ligand B (32.34) is excellent, well below the threshold.

**logP:** Ligand A (1.254) is within the optimal 1-3 range. Ligand B (4.458) is a bit high, potentially leading to solubility issues and off-target interactions.

**H-Bond Donors/Acceptors:** Both ligands have acceptable HBD (1) and HBA (5 for A, 3 for B) counts, well within the guidelines.

**QED:** Both ligands have similar QED values (0.784 and 0.78), indicating good drug-likeness.

**DILI:** Ligand A (47.732) has a slightly higher DILI risk than Ligand B (32.842), but both are below the concerning threshold of 60.

**BBB:** Ligand B (85.072) has a significantly better BBB penetration percentile than Ligand A (69.019). This is a critical advantage for a CNS target like DRD2.

**Caco-2 Permeability:** Ligand A (-4.832) shows poor Caco-2 permeability, while Ligand B (-5.206) is also poor, but slightly better.

**Aqueous Solubility:** Both ligands have very poor aqueous solubility (-2.702 and -4.773). This is a significant drawback, but can sometimes be mitigated with formulation strategies.

**hERG Inhibition:** Ligand A (0.182) has a lower hERG inhibition risk than Ligand B (0.683), which is preferable.

**Microsomal Clearance:** Ligand A (2.777) has significantly lower microsomal clearance than Ligand B (100.475), indicating better metabolic stability.

**In vitro Half-Life:** Ligand A (-14.983) has a very short in vitro half-life, while Ligand B (14.005) has a longer half-life.

**P-gp Efflux:** Ligand A (0.037) has much lower P-gp efflux liability than Ligand B (0.532), which is favorable for CNS penetration.

**Binding Affinity:** Ligand B (-7.7 kcal/mol) has a slightly better binding affinity than Ligand A (-7.1 kcal/mol), but the difference is relatively small (0.6 kcal/mol).

**Overall Assessment:**

Ligand B excels in BBB penetration and binding affinity, which are crucial for a CNS GPCR target. However, it suffers from a high logP, high P-gp efflux, and very high microsomal clearance. Ligand A has a better safety profile (lower hERG, lower DILI) and better metabolic stability (lower Cl_mic), and lower P-gp efflux, but its BBB penetration is lower and Caco-2 permeability is poor. The difference in binding affinity is not substantial enough to outweigh the ADME advantages of Ligand A.

Considering the GPCR-specific priorities and the overall balance of properties, Ligand A appears to be the more promising candidate, despite its slightly weaker binding affinity. The better BBB penetration and metabolic stability, coupled with lower P-gp efflux, are likely to translate to better *in vivo* exposure at the target site.

Output:
0
2025-04-17 08:20:19,137 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (356.463 and 346.402 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (77.1) is slightly higher than Ligand B (58.64). Both are below the 90 A^2 threshold desirable for CNS targets, but Ligand B is preferable.

**logP:** Ligand A (0.962) is a bit low, potentially hindering permeability. Ligand B (2.9) is within the optimal 1-3 range. This is a significant advantage for Ligand B.

**H-Bond Donors/Acceptors:** Both have 1 HBD, which is good. Ligand A has 5 HBA, while Ligand B has 3. Both are acceptable, but lower HBA is generally preferred for better permeability.

**QED:** Both ligands have similar QED values (0.666 and 0.636), indicating good drug-likeness.

**DILI:** Ligand A (15.859) has a much lower DILI risk than Ligand B (57.658). This is a substantial advantage for Ligand A.

**BBB:** Ligand B (81.776) has a significantly higher BBB penetration percentile than Ligand A (73.129). This is crucial for a CNS target like DRD2 and favors Ligand B.

**Caco-2 Permeability:** Ligand A (-4.462) shows poor Caco-2 permeability, while Ligand B (-4.525) is also poor. This isn't a major deciding factor as both are unfavorable.

**Aqueous Solubility:** Ligand A (-0.634) has slightly better solubility than Ligand B (-3.211).

**hERG Inhibition:** Ligand A (0.204) has a much lower hERG inhibition liability than Ligand B (0.8). This is a significant safety advantage for Ligand A.

**Microsomal Clearance:** Ligand B (65.803) has a higher microsomal clearance than Ligand A (27.836), indicating faster metabolism and lower metabolic stability. Ligand A is preferable here.

**In vitro Half-Life:** Ligand A (-7.666) has a much longer in vitro half-life than Ligand B (2.138). This is a significant advantage for Ligand A.

**P-gp Efflux:** Ligand A (0.01) has very low P-gp efflux liability, while Ligand B (0.438) has moderate efflux. This favors Ligand A for CNS exposure.

**Binding Affinity:** Ligand B (-8.9 kcal/mol) has a significantly stronger binding affinity than Ligand A (-6.9 kcal/mol). This is a substantial advantage for Ligand B, potentially outweighing some of the ADME drawbacks. The difference of 2 kcal/mol is considerable.

**Overall Assessment:**

Ligand B excels in binding affinity and BBB penetration, which are critical for a CNS GPCR target. However, it suffers from higher DILI risk, higher P-gp efflux, faster metabolism, and a less favorable logP. Ligand A has a better safety profile (lower DILI and hERG), better metabolic stability, lower P-gp efflux, and a slightly better solubility. The affinity difference is significant, but the ADME profile of Ligand A is more balanced and potentially more conducive to *in vivo* efficacy and safety. Considering the substantial affinity advantage of Ligand B, it is the more promising candidate.

Output:
1
2025-04-17 08:20:19,137 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (348.45 & 327.40 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (78.67) is better than Ligand B (36.44). Both are below the 90 A^2 threshold for CNS targets, but Ligand A is closer to the ideal.

**logP:** Ligand A (1.051) is within the optimal range (1-3), while Ligand B (3.006) is at the higher end, potentially raising solubility concerns.

**H-Bond Donors/Acceptors:** Ligand A has 1 HBD and 5 HBA, while Ligand B has 0 HBD and 4 HBA. Both are within acceptable limits.

**QED:** Both ligands have good QED scores (0.506 & 0.764), indicating drug-like properties.

**DILI:** Ligand A (28.5%) has a significantly lower DILI risk than Ligand B (44.2%). This is a major advantage for Ligand A.

**BBB:** Ligand B (90.772%) has a much higher BBB penetration score than Ligand A (40.054%). This is a critical advantage for a CNS target like DRD2.

**Caco-2 Permeability:** Ligand A (-5.104) has poorer Caco-2 permeability than Ligand B (-4.781), but both are negative values, indicating low permeability.

**Aqueous Solubility:** Ligand A (-0.319) has slightly better aqueous solubility than Ligand B (-2.338).

**hERG Inhibition:** Ligand A (0.2) has a much lower hERG inhibition liability than Ligand B (0.956). This is a significant safety advantage for Ligand A.

**Microsomal Clearance:** Ligand B (44.875) has a higher microsomal clearance than Ligand A (34.748), meaning Ligand A is more metabolically stable.

**In vitro Half-Life:** Ligand A (22.946 hours) has a significantly longer half-life than Ligand B (-24.809 hours - a negative value suggests very rapid degradation).

**P-gp Efflux:** Ligand A (0.153) has lower P-gp efflux than Ligand B (0.794), which is favorable for CNS penetration.

**Binding Affinity:** Ligand B (-9.5 kcal/mol) has a significantly stronger binding affinity than Ligand A (-7.1 kcal/mol). This is a substantial advantage.

**Overall Assessment:**

Ligand B excels in BBB penetration and binding affinity, which are crucial for a CNS GPCR target. However, it suffers from higher DILI risk, hERG inhibition, and P-gp efflux. Ligand A has a better safety profile (lower DILI and hERG) and improved metabolic stability and P-gp efflux, but its BBB penetration and binding affinity are significantly weaker.

The difference in binding affinity (-9.5 vs -7.1 kcal/mol) is substantial (2.4 kcal/mol), and is likely to outweigh the ADME advantages of Ligand A. A strong binding affinity is paramount for GPCR ligands, and the improved BBB penetration of Ligand B further supports its potential.

Output:
1
2025-04-17 08:20:19,138 - INFO - Batch 440 complete. Total preferences: 7040
2025-04-17 08:20:19,138 - INFO - Processing batch 441/512...
2025-04-17 08:20:58,584 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B based on the provided guidelines, prioritizing GPCR-specific properties (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (352.519 Da) is slightly lower, which could be beneficial for permeability.

**TPSA:** Ligand A (67.43) is better than Ligand B (54.18) as it's closer to the ideal <90 for CNS targets. Ligand B is quite low, potentially indicating poor interactions.

**logP:** Both ligands have good logP values (A: 3.341, B: 3.755), falling within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A (HBD=2, HBA=3) is slightly better than Ligand B (HBD=1, HBA=5) in terms of balancing solubility and permeability.

**QED:** Both ligands have acceptable QED values (A: 0.468, B: 0.736), with Ligand B being significantly better, suggesting a more drug-like profile.

**DILI:** Ligand A (26.871) has a much lower DILI risk than Ligand B (15.781), which is a significant advantage.

**BBB:** Ligand A (73.75) has a substantially better BBB penetration percentile than Ligand B (52.579). This is *critical* for a CNS target like DRD2.

**Caco-2 Permeability:** Ligand A (-4.822) has a worse Caco-2 permeability than Ligand B (-5.108), but both are quite poor.

**Aqueous Solubility:** Ligand A (-3.194) has better aqueous solubility than Ligand B (-2.498).

**hERG Inhibition:** Ligand A (0.583) has a lower hERG inhibition liability than Ligand B (0.88), which is preferable.

**Microsomal Clearance:** Ligand A (67.917) has a higher microsomal clearance than Ligand B (25.374), indicating lower metabolic stability. This is a drawback for Ligand A.

**In vitro Half-Life:** Ligand A (-10.455) has a worse in vitro half-life than Ligand B (65.372).

**P-gp Efflux:** Ligand A (0.395) has lower P-gp efflux liability than Ligand B (0.482), which is beneficial for CNS exposure.

**Binding Affinity:** Ligand A (-7.6 kcal/mol) has a slightly better binding affinity than Ligand B (-6.6 kcal/mol). While both are good, the 1 kcal/mol difference is noteworthy.

**Overall Assessment:**

Ligand A excels in BBB penetration, DILI risk, hERG inhibition, and binding affinity. Ligand B has a better QED and metabolic stability (lower Cl_mic, longer t1/2). However, the significantly better BBB (73.75 vs 52.579) and lower DILI risk of Ligand A are crucial for a CNS-targeting drug. The slightly better binding affinity of Ligand A further supports its selection. The poorer metabolic stability of Ligand A could potentially be addressed through structural modifications during lead optimization.

Output:
0
2025-04-17 08:20:58,585 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (360.435 and 335.403 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (79.73) is slightly above the preferred <90 for CNS targets, but still reasonable. Ligand B (38.77) is excellent, well below the threshold.

**logP:** Ligand A (2.252) is within the optimal 1-3 range. Ligand B (3.706) is at the higher end, but still acceptable.

**H-Bond Donors/Acceptors:** Ligand A has 1 HBD and 6 HBA, fitting the guidelines. Ligand B has 0 HBD and 3 HBA, also fitting the guidelines.

**QED:** Both ligands have good QED scores (0.828 and 0.797), indicating good drug-like properties.

**DILI:** Ligand A (72.664) has a higher DILI risk than Ligand B (49.011), which is preferable.

**BBB:** Ligand B (76.541) has a significantly better BBB penetration percentile than Ligand A (63.048). This is a crucial advantage for a CNS target like DRD2.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.539 and -4.349), which is unusual and suggests poor permeability. However, these values are on a logarithmic scale and are likely representing very low permeability.

**Aqueous Solubility:** Both ligands have negative solubility values (-2.826 and -3.609), again suggesting poor solubility.

**hERG Inhibition:** Both ligands have low hERG inhibition liability (0.295 and 0.516), which is good.

**Microsomal Clearance:** Ligand A (77.792) has higher microsomal clearance than Ligand B (42.471), indicating lower metabolic stability.

**In vitro Half-Life:** Ligand B (22.516) has a significantly longer in vitro half-life than Ligand A (-3.957), which is a major advantage.

**P-gp Efflux:** Ligand A (0.347) has lower P-gp efflux than Ligand B (0.404), which is favorable for CNS penetration.

**Binding Affinity:** Ligand B (-9.0) has a significantly stronger binding affinity than Ligand A (-8.4). This 0.6 kcal/mol difference is substantial and can outweigh some ADME drawbacks.

**Overall Assessment:**

Ligand B is the stronger candidate. While both have issues with predicted permeability and solubility, Ligand B excels in the most critical areas for a CNS-targeting GPCR: BBB penetration, binding affinity, and metabolic stability (half-life). The lower DILI risk is also a plus. The slightly higher logP of Ligand B is not a major concern given its superior affinity.

Output:
1
2025-04-17 08:20:58,585 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (371.825 and 356.457 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (114.35) is better than Ligand B (43.78). For CNS targets, TPSA should be <= 90, and both meet this criterion, but A is closer to the upper limit.

**logP:** Ligand A (-0.539) is suboptimal, being below the preferred 1-3 range. Ligand B (3.661) is excellent. This is a significant advantage for B, as good CNS penetration requires adequate lipophilicity.

**H-Bond Donors/Acceptors:** Ligand A (3 HBD, 6 HBA) is slightly higher in both counts than Ligand B (1 HBD, 3 HBA), but both are within acceptable limits.

**QED:** Both ligands have good QED scores (0.595 and 0.773, respectively), indicating good drug-like properties.

**DILI:** Ligand A (57.348) has a higher DILI risk than Ligand B (13.532). This is a clear advantage for Ligand B.

**BBB:** Ligand B (71.074) has a significantly better BBB percentile than Ligand A (59.984). This is crucial for a CNS target like DRD2, and strongly favors Ligand B.

**Caco-2 Permeability:** Ligand A (-5.448) has a very poor Caco-2 permeability, while Ligand B (-4.621) is also poor, but slightly better.

**Aqueous Solubility:** Both ligands have poor aqueous solubility (-2.764 and -3.143 respectively).

**hERG:** Both ligands have low hERG risk (0.125 and 0.896 respectively).

**Microsomal Clearance:** Ligand A (0.953) has much lower microsomal clearance than Ligand B (83.716), indicating better metabolic stability. This is a positive for A.

**In vitro Half-Life:** Ligand A (24.549 hours) has a much longer half-life than Ligand B (-5.056 hours). This is a significant advantage for A.

**P-gp Efflux:** Ligand A (0.037) has a much lower P-gp efflux liability than Ligand B (0.165), suggesting better CNS exposure. This favors A.

**Binding Affinity:** Ligand A (-7.9 kcal/mol) has a slightly better binding affinity than Ligand B (-6.8 kcal/mol). While both are good, the 1.1 kcal/mol difference is notable.

**Overall Assessment:**

Ligand B excels in key GPCR properties: logP and BBB. Its DILI risk is also much lower. However, Ligand A has better metabolic stability (lower Cl_mic), longer half-life, lower P-gp efflux, and slightly better binding affinity. The poor logP of Ligand A is a major drawback for CNS penetration, and its Caco-2 permeability is very poor. While the affinity difference is present, the significant advantages of Ligand B in terms of BBB, logP, and DILI outweigh the slightly better affinity and metabolic stability of Ligand A.

Output:
1
2025-04-17 08:20:58,585 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (488.249 Da) is higher, but still acceptable. Ligand B (349.475 Da) is preferable.

**TPSA:** Both ligands have TPSA values (71.25 and 78.51) that are above the optimal <90 for CNS targets, but not drastically so. Ligand A is slightly better.

**logP:** Ligand A (4.479) is a bit high, potentially leading to solubility issues and off-target effects. Ligand B (1.612) is within the optimal range (1-3). This favors Ligand B.

**H-Bond Donors/Acceptors:** Both have reasonable HBD (2) and HBA (5/3) counts, falling within acceptable limits.

**QED:** Both ligands have QED values above 0.5, indicating good drug-likeness.

**DILI:** Ligand A (67.313) has a higher DILI risk than Ligand B (22.063), which is a significant concern.

**BBB:** Ligand A (86.041) has a better BBB penetration percentile than Ligand B (70.26), which is crucial for a CNS target like DRD2.

**Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and suggests poor permeability. However, these values are on a scale where negative values are possible, and direct comparison is difficult without knowing the scale's range.

**Aqueous Solubility:** Both ligands have very poor aqueous solubility (-4.599 and -2.226). This is a major drawback for both.

**hERG Inhibition:** Ligand A (0.894) shows some hERG inhibition risk, while Ligand B (0.199) has very low risk. This is a significant advantage for Ligand B.

**Microsomal Clearance:** Ligand A (60.496) has higher microsomal clearance than Ligand B (20.901), implying lower metabolic stability.

**In vitro Half-Life:** Ligand B (-2.824) has a negative half-life, which is not physically possible and indicates a problem with the data or the model. Ligand A (31.217) has a reasonable half-life.

**P-gp Efflux:** Ligand A (0.807) shows some P-gp efflux, while Ligand B (0.046) has very low efflux. This is a significant advantage for Ligand B, as it will improve CNS exposure.

**Binding Affinity:** Ligand A (-9.7 kcal/mol) has a *much* stronger binding affinity than Ligand B (0.0 kcal/mol). This is a substantial advantage for Ligand A, potentially outweighing some of its ADME drawbacks.

**Overall Assessment:**

Ligand B has better ADME properties (lower logP, lower DILI, lower hERG, lower P-gp efflux) but significantly weaker binding affinity. Ligand A has a very strong binding affinity but suffers from higher logP, DILI, hERG, and P-gp efflux, and a higher clearance. The strong binding affinity of Ligand A is a major advantage for a GPCR target. While the ADME properties are suboptimal, they might be addressable through further optimization, especially given the potency. The negative half-life for Ligand B is a showstopper.

Output:
1
2025-04-17 08:20:58,586 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (346.471 and 347.415 Da) fall within the ideal range of 200-500 Da.

**TPSA:** Ligand A (58.64) is significantly better than Ligand B (93.46). For CNS targets, TPSA should be <=90, and A is comfortably within that range, while B is approaching the upper limit.

**logP:** Both ligands have good logP values (1.96 and 1.758), falling within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A (HBD=1, HBA=3) is better than Ligand B (HBD=2, HBA=5) in terms of maintaining a balance between solubility and permeability.

**QED:** Ligand A (0.795) has a higher QED score than Ligand B (0.579), indicating a more drug-like profile.

**DILI:** Ligand A (32.377) has a much lower DILI risk than Ligand B (58.395). Both are below 60, but A is preferable.

**BBB:** Both ligands have good BBB penetration (Ligand A: 71.694, Ligand B: 75.301), exceeding the 70% threshold for CNS targets. B is slightly better.

**Caco-2 Permeability:** Ligand A (-4.602) has worse Caco-2 permeability than Ligand B (-5.141). Lower values are less desirable.

**Aqueous Solubility:** Ligand A (-2.652) has better aqueous solubility than Ligand B (-2.079). Higher values are better.

**hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.397 and 0.251).

**Microsomal Clearance:** Ligand B (43.056) has slightly lower microsomal clearance than Ligand A (48.697), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand B (-17.306) has a significantly longer in vitro half-life than Ligand A (-11.756). This is a major advantage.

**P-gp Efflux:** Both ligands show minimal P-gp efflux liability (0.115 and 0.135).

**Binding Affinity:** Ligand B (-8.7 kcal/mol) has a *much* stronger binding affinity than Ligand A (-0.0 kcal/mol). This is a substantial difference.

**Overall Assessment:**

While Ligand A has better TPSA, QED, DILI risk, and solubility, Ligand B's significantly stronger binding affinity (-8.7 vs -0.0 kcal/mol) and longer half-life are decisive. The affinity difference is large enough to outweigh the minor drawbacks of slightly higher TPSA and lower QED. The BBB penetration is comparable for both. Given the importance of potency for GPCR targets, Ligand B is the more promising candidate.

Output:
1
2025-04-17 08:20:58,586 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (362.5 and 344.5 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (74.33) is slightly higher than Ligand B (69.64). Both are below the 90 A^2 threshold desirable for CNS targets, but Ligand B is preferable.

**3. logP:** Both ligands have good logP values (1.337 and 1.782), falling within the optimal 1-3 range. Ligand B is slightly better.

**4. H-Bond Donors:** Ligand A has 3 HBD, and Ligand B has 2. Both are acceptable (<=5).

**5. H-Bond Acceptors:** Ligand A has 5 HBA, and Ligand B has 3. Both are acceptable (<=10).

**6. QED:** Ligand A (0.61) has a better QED score than Ligand B (0.464), indicating a more drug-like profile.

**7. DILI:** Both ligands have acceptable DILI risk (37.611 and 40.752, both <40).

**8. BBB:** This is crucial for a CNS target like DRD2. Ligand B (70.531) significantly outperforms Ligand A (42.032), exceeding the desirable >70 percentile.

**9. Caco-2:** Both have negative Caco-2 values, which is unusual and suggests poor permeability. However, the scale is not specified, so it's hard to interpret.

**10. Solubility:** Both have negative solubility values, which is also unusual.

**11. hERG:** Both ligands show very low hERG inhibition liability (0.306 and 0.192), which is excellent.

**12. Cl_mic:** Ligand A (-10.446) has significantly lower (better) microsomal clearance than Ligand B (21.902), suggesting better metabolic stability.

**13. t1/2:** Ligand A (31.032) has a better in vitro half-life than Ligand B (-46.538).

**14. Pgp:** Both ligands have very low Pgp efflux liability (0.012 and 0.109), which is favorable for CNS penetration.

**15. Binding Affinity:** Ligand B (-8.3 kcal/mol) has a slightly better binding affinity than Ligand A (-8.0 kcal/mol). While the difference is small, it's still a positive factor.

**Overall Assessment:**

Ligand B is the more promising candidate. The critical advantage is its significantly higher BBB penetration (70.531 vs 42.032). While Ligand A has better QED, metabolic stability (Cl_mic), and in vitro half-life, BBB penetration is paramount for a CNS-targeting drug. The slightly better binding affinity of Ligand B further supports this choice. The unusual negative values for Caco-2 and solubility are concerning for both, but the strong BBB score for Ligand B outweighs these concerns.

Output:
1
2025-04-17 08:20:58,586 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (344.39 and 340.379 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (78.09) is slightly higher than Ligand B (62.99). Both are below the 90 A^2 threshold desirable for CNS targets, but Ligand B is preferable.

**3. logP:** Both ligands have good logP values (2.799 and 2.037), falling within the optimal 1-3 range.

**4. H-Bond Donors:** Ligand A has 2 HBD, and Ligand B has 0. Both are acceptable (<=5).

**5. H-Bond Acceptors:** Ligand A has 3 HBA, and Ligand B has 4. Both are acceptable (<=10).

**6. QED:** Both ligands have high QED scores (0.819 and 0.858), indicating good drug-like properties.

**7. DILI:** Ligand A (55.913) and Ligand B (60.682) both have acceptable DILI risk, below the 60 threshold.

**8. BBB:** Ligand A (77.898) and Ligand B (81.737) both have excellent BBB penetration, exceeding the desirable 70 percentile for CNS targets. Ligand B is slightly better.

**9. Caco-2:** Both ligands have negative Caco-2 values (-4.749 and -4.185). This is unusual and suggests poor permeability. However, these values are on a strange scale and may not be directly comparable.

**10. Solubility:** Both ligands have negative solubility values (-3.95 and -2.647), which is also unusual and suggests poor aqueous solubility. Again, the scale is unclear.

**11. hERG:** Both ligands have very low hERG inhibition liability (0.412 and 0.167), which is excellent.

**12. Cl_mic:** Ligand A (43.035) and Ligand B (39.454) have similar microsomal clearance values. Lower is better, so Ligand B is slightly preferable.

**13. t1/2:** Ligand B (83.968) has a significantly longer in vitro half-life than Ligand A (-23.982). This is a major advantage.

**14. Pgp:** Both ligands have very low P-gp efflux liability (0.022 and 0.089), which is excellent for CNS penetration.

**15. Binding Affinity:** Ligand A (-9.0) has a significantly stronger binding affinity than Ligand B (-8.5). This is a substantial advantage, potentially outweighing some ADME drawbacks.

**Overall Assessment:**

While Ligand B has a better BBB score, longer half-life, and slightly better Cl_mic, the significantly stronger binding affinity of Ligand A (-9.0 kcal/mol vs -8.5 kcal/mol) is a critical factor for a GPCR target. The difference of 0.5 kcal/mol is substantial and likely to translate to greater efficacy. The unusual Caco-2 and solubility values are concerning, but the strong affinity and acceptable other parameters suggest Ligand A is the more promising candidate, assuming these values are not indicative of a severe issue.

Output:
1
2025-04-17 08:20:58,586 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B against the provided guidelines, prioritizing GPCR-specific properties (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (355.438 and 347.503 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (58.64) is slightly higher than Ligand B (52.65), but both are below the 90 A^2 threshold desirable for CNS targets.

**logP:** Ligand A (4.295) is higher than the optimal range of 1-3, potentially leading to solubility issues. Ligand B (2.182) is within the optimal range.

**H-Bond Donors/Acceptors:** Both ligands have 1 HBD and a reasonable number of HBAs (4 and 3 respectively), satisfying the criteria.

**QED:** Both ligands have good QED scores (0.612 and 0.793), indicating drug-like properties.

**DILI:** Ligand A has a significantly higher DILI risk (71.152 percentile) compared to Ligand B (11.361 percentile). This is a major concern for Ligand A.

**BBB:** Both ligands show good BBB penetration (69.523% and 67.546%), but are slightly below the >70% desirable threshold.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values, which is unusual and requires careful interpretation. However, we can assume that lower (more negative) values indicate poorer permeability.

**Aqueous Solubility:** Both ligands have negative solubility values, which is also unusual. Lower values indicate poorer solubility.

**hERG Inhibition:** Ligand A (0.624) has a slightly higher hERG risk than Ligand B (0.471), but both are relatively low.

**Microsomal Clearance:** Ligand A (80.834) has a higher microsomal clearance than Ligand B (7.263), suggesting lower metabolic stability.

**In vitro Half-Life:** Ligand B (11.103 hours) has a significantly longer half-life than Ligand A (0.995 hours).

**P-gp Efflux:** Ligand A (0.885) has a higher P-gp efflux liability than Ligand B (0.088), which is unfavorable for CNS penetration.

**Binding Affinity:** Ligand A (-9.5 kcal/mol) has a significantly stronger binding affinity than Ligand B (-0.0 kcal/mol). This is a substantial advantage.

**Overall Assessment:**

Despite Ligand A's superior binding affinity, its significantly higher DILI risk, higher P-gp efflux, higher microsomal clearance, shorter half-life, and higher logP are major drawbacks. Ligand B, while having weaker affinity, presents a much more favorable ADMET profile, especially regarding safety (DILI) and CNS penetration (P-gp, half-life). The large difference in binding affinity (-9.5 vs -0.0) is substantial, but the ADMET liabilities of Ligand A are too significant to ignore, especially for a CNS target. A small improvement in affinity is unlikely to overcome the poor pharmacokinetic and safety profile.

Output:
1
2025-04-17 08:20:58,586 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (350.503 and 362.543 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (58.64) is better than Ligand B (50.28). Both are below the 90 A^2 threshold for CNS targets, which is excellent.

**3. logP:** Ligand A (2.593) is within the optimal 1-3 range. Ligand B (3.754) is slightly higher, but still acceptable.

**4. H-Bond Donors:** Both ligands have 1 HBD, which is within the acceptable limit of <=5.

**5. H-Bond Acceptors:** Ligand A has 3 HBAs, and Ligand B has 6. Both are below the 10 limit, but Ligand A is preferable.

**6. QED:** Both ligands have good QED scores (0.768 and 0.805), indicating good drug-like properties.

**7. DILI:** Ligand A (8.026) has a significantly lower DILI risk than Ligand B (69.484). This is a major advantage for Ligand A.

**8. BBB:** Ligand A (73.478) and Ligand B (82.086) both have excellent BBB penetration, exceeding the 70% threshold for CNS targets. Ligand B is slightly better.

**9. Caco-2:** Both have negative Caco-2 values, which is unusual and suggests poor permeability. However, the scale is not specified, so it's hard to interpret.

**10. Solubility:** Both ligands have negative solubility values, which is also unusual and suggests poor solubility. Again, the scale is not specified.

**11. hERG:** Ligand A (0.421) has a lower hERG inhibition liability than Ligand B (0.719), indicating a lower risk of cardiotoxicity.

**12. Cl_mic:** Ligand A (46.762) has a lower microsomal clearance than Ligand B (102.003), suggesting better metabolic stability.

**13. t1/2:** Ligand A (-3.613) has a negative in vitro half-life, which is impossible. Ligand B (11.5) has a reasonable half-life. This is a significant issue for Ligand A.

**14. Pgp:** Ligand A (0.046) has much lower P-gp efflux liability than Ligand B (0.408), which is highly desirable for CNS penetration.

**15. Binding Affinity:** Ligand B (-7.4) has a significantly stronger binding affinity than Ligand A (-9.0). This is a substantial advantage for Ligand B, potentially outweighing some ADME drawbacks.

**Overall Assessment:**

Despite Ligand B's superior binding affinity, Ligand A has several critical advantages: much lower DILI risk, lower hERG risk, lower P-gp efflux, and lower microsomal clearance. However, the negative in vitro half-life for Ligand A is a showstopper. The negative values for Caco-2 and Solubility are also concerning, but less critical than the half-life. Ligand B has a reasonable half-life, and while its DILI and Pgp are worse than Ligand A, the significantly better binding affinity is likely to be more important for a GPCR target.

Output:
1
2025-04-17 08:20:58,587 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (356.419 Da) is slightly lower, which could be beneficial for permeability.

**TPSA:** Both ligands have TPSA values below the 90 A^2 threshold desirable for CNS targets. Ligand B (84.5 A^2) is slightly better than Ligand A (96.38 A^2).

**logP:** Ligand A (-0.069) is slightly below the optimal range (1-3), potentially hindering permeation. Ligand B (1.416) is within the optimal range. This is a significant advantage for Ligand B.

**H-Bond Donors/Acceptors:** Ligand A (HBD=1, HBA=6) and Ligand B (HBD=2, HBA=4) both fall within acceptable limits.

**QED:** Both ligands have good QED scores (A: 0.693, B: 0.71), indicating drug-like properties.

**DILI:** Ligand A (20.822) has a much lower DILI risk than Ligand B (47.266), which is a substantial advantage.

**BBB:** Both ligands exhibit good BBB penetration (A: 66.809%, B: 68.941%), but neither exceeds the desirable >70% threshold.

**Caco-2 Permeability:** Both have negative Caco-2 values which is unusual, but we can assume these are percentile scores. Ligand B (-5.22) is slightly better than Ligand A (-4.626).

**Aqueous Solubility:** Both ligands have very poor aqueous solubility (A: -0.51, B: -3.766). This is a concern for both, but more so for Ligand B.

**hERG Inhibition:** Both ligands show low hERG inhibition risk (A: 0.065, B: 0.432).

**Microsomal Clearance:** Ligand A (24.004 mL/min/kg) has significantly lower microsomal clearance than Ligand B (53.465 mL/min/kg), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (-10.427 hours) has a negative half-life, which is not possible. This is likely a percentile score, and a negative value suggests very poor stability. Ligand B (5.36 hours) is better, but still not ideal.

**P-gp Efflux:** Both ligands show low P-gp efflux (A: 0.019, B: 0.067).

**Binding Affinity:** Ligand B (-8.4 kcal/mol) has a significantly stronger binding affinity than Ligand A (-7.1 kcal/mol). This 1.3 kcal/mol difference is substantial and can outweigh some ADME drawbacks.

**Overall Assessment:**

While Ligand A has a better safety profile (lower DILI, better metabolic stability) and slightly better MW, Ligand B has a significantly stronger binding affinity and a more favorable logP value. The stronger binding affinity is a critical advantage for a GPCR ligand, and the logP is within the optimal range. The DILI and metabolic stability concerns with Ligand A are significant. The poor solubility of both is a concern, but can potentially be addressed with formulation strategies.

Output:
1
2025-04-17 08:20:58,587 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B based on the provided guidelines, prioritizing GPCR-specific properties (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (344.386 and 346.475 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (59.59) is excellent, well below the 90 A^2 threshold for CNS targets. Ligand B (86.88) is still reasonable but less optimal, approaching the 90 A^2 limit.

**logP:** Ligand A (3.416) is at the upper end of the optimal range (1-3), while Ligand B (2.346) is within the optimal range.

**H-Bond Donors/Acceptors:** Both ligands have acceptable HBD (2 and 3 respectively) and HBA (3 each) counts.

**QED:** Ligand A (0.874) has a significantly higher QED score than Ligand B (0.449), indicating better overall drug-likeness.

**DILI:** Ligand A (59.519) has a higher DILI risk than Ligand B (23.187), which is a concern.

**BBB:** Ligand A (84.141) demonstrates excellent BBB penetration, exceeding the 70% threshold. Ligand B (46.879) is considerably lower, indicating poor CNS penetration. This is a critical difference for a DRD2 target.

**Caco-2 Permeability:** Ligand A (-4.766) and Ligand B (-5.434) both have negative Caco-2 values, which is unusual and suggests poor permeability. However, the scale is not defined, so it's difficult to interpret.

**Aqueous Solubility:** Both ligands have very poor aqueous solubility (-3.917 and -2.177 respectively). This could pose formulation challenges.

**hERG Inhibition:** Ligand A (0.857) has a slightly higher hERG risk than Ligand B (0.346), but both are relatively low.

**Microsomal Clearance:** Ligand A (48.584) has a higher microsomal clearance than Ligand B (25.137), suggesting lower metabolic stability.

**In vitro Half-Life:** Ligand B (-30.406) has a negative half-life, which is not possible. This is a red flag and suggests a potential data error or a very rapidly metabolized compound. Ligand A (24.716) has a reasonable half-life.

**P-gp Efflux:** Ligand A (0.457) has lower P-gp efflux liability than Ligand B (0.186), which is favorable for CNS exposure.

**Binding Affinity:** Ligand B (-7.9 kcal/mol) has a significantly stronger binding affinity than Ligand A (-10.8 kcal/mol). This is a substantial advantage.

**Overall Assessment:**

Despite Ligand A's better QED, TPSA, and BBB penetration, the significantly stronger binding affinity of Ligand B (-7.9 vs -10.8 kcal/mol) is a major advantage. The problematic negative half-life for Ligand B is a serious concern, but the other properties are generally more favorable. The higher DILI risk for Ligand A and the lower metabolic stability are also drawbacks. The superior affinity of Ligand B can potentially overcome its other deficiencies with further optimization.

Output:
1
2025-04-17 08:20:58,587 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (362.411 and 369.803 Da) are within the ideal 200-500 Da range.

**TPSA:** Ligand A (129.02) is borderline for CNS penetration, being slightly above the preferred <90. Ligand B (64.86) is excellent, well below 90.

**logP:** Ligand A (-0.226) is quite low, potentially hindering membrane permeability. Ligand B (3.256) is optimal.

**H-Bond Donors:** Ligand A (2) and Ligand B (1) are both acceptable, below the threshold of 5.

**H-Bond Acceptors:** Both ligands (A: 6, B: 6) are within the acceptable limit of 10.

**QED:** Both ligands have good QED scores (A: 0.745, B: 0.896), indicating drug-like properties.

**DILI:** Both ligands have relatively high DILI risk (A: 70.803, B: 74.99), but are still within a range that isn't immediately disqualifying.

**BBB:** Ligand A (48.662) has a poor BBB percentile, which is a significant drawback for a CNS target. Ligand B (88.833) is excellent, exceeding the desirable >70 threshold.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.54 and -4.968), which is unusual and suggests poor permeability. However, these values are on a log scale and can be misleading.

**Aqueous Solubility:** Both ligands have very poor solubility scores (-3.008 and -5.362). This is a concern for bioavailability.

**hERG Inhibition:** Both ligands have low hERG risk (A: 0.063, B: 0.143).

**Microsomal Clearance:** Ligand A (-30.35) has a very low (and likely negative) clearance, suggesting excellent metabolic stability. Ligand B (44.892) has moderate clearance.

**In vitro Half-Life:** Ligand A (18.945) has a moderate half-life. Ligand B (0.861) has a very short half-life, which is undesirable.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (A: 0.014, B: 0.185), which is favorable for CNS penetration.

**Binding Affinity:** Ligand B (-8.1 kcal/mol) has a significantly stronger binding affinity than Ligand A (-7.6 kcal/mol). This 0.5 kcal/mol difference is substantial and can outweigh some ADME drawbacks.

**Conclusion:**

Considering the GPCR-specific priorities, Ligand B is the more promising candidate. Its excellent BBB penetration, optimal logP, and significantly stronger binding affinity outweigh its moderate clearance and short half-life. The poor solubility of both compounds is a concern, but could potentially be addressed through formulation strategies. Ligand A's poor BBB penetration is a major disadvantage for a CNS target, despite its excellent metabolic stability.

Output:
1
2025-04-17 08:20:58,587 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B based on the provided guidelines, prioritizing GPCR-specific properties (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (360.307 and 364.515 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (58.64) is significantly better than Ligand B (74.33). For CNS targets, TPSA should be <=90, both are within this range, but A is preferable.

**logP:** Both ligands have good logP values (1.846 and 1.633), falling within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A (HBD=1, HBA=3) is better than Ligand B (HBD=2, HBA=5) in terms of balancing solubility and permeability.

**QED:** Ligand B (0.735) has a higher QED score than Ligand A (0.479), indicating a more drug-like profile.

**DILI:** Ligand B (22.722) has a much lower DILI risk than Ligand A (47.693), a significant advantage.

**BBB:** Ligand A (47.809) has a slightly better BBB percentile than Ligand B (41.644), but both are below the desirable >70 for CNS targets.

**Caco-2 Permeability:** Ligand A (-4.599) has a worse Caco-2 permeability than Ligand B (-5.56). Lower values suggest poorer permeability.

**Aqueous Solubility:** Ligand A (-3.391) has better aqueous solubility than Ligand B (-0.799).

**hERG:** Both ligands have low hERG inhibition liability (0.426 and 0.207).

**Microsomal Clearance:** Ligand B (-17.009) has a significantly lower (better) microsomal clearance than Ligand A (42.244), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand B (6.069) has a longer in vitro half-life than Ligand A (-7.979).

**P-gp Efflux:** Ligand A (0.077) has lower P-gp efflux liability than Ligand B (0.024), which is favorable for CNS penetration.

**Binding Affinity:** Ligand B (-8.5) has a slightly better binding affinity than Ligand A (-7.6). While both are good, the 1.5 kcal/mol difference is noteworthy.

**Overall Assessment:**

Ligand B is superior. While Ligand A has slightly better BBB and P-gp efflux, Ligand B excels in key areas: significantly lower DILI risk, better metabolic stability (lower Cl_mic, longer t1/2), higher QED, and slightly better binding affinity. The lower DILI and improved metabolic properties are crucial for drug development. The slightly lower BBB for Ligand B is a concern, but the other advantages outweigh this drawback.



Output:
1
2025-04-17 08:20:58,588 - INFO - Reasoning:

Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (383.853 and 370.471 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (66.88) is significantly better than Ligand B (88.85). For CNS targets, we want TPSA <= 90, and Ligand A is closer to the optimal range of <=60. Ligand B is pushing the upper limit.

**3. logP:** Ligand A (3.604) is within the optimal range (1-3), while Ligand B (1.612) is at the lower end. While not terrible, lower logP can sometimes hinder permeability.

**4. H-Bond Donors:** Both have acceptable HBD counts (0 for A, 1 for B), well below the threshold of 5.

**5. H-Bond Acceptors:** Both have acceptable HBA counts (7 for A, 5 for B), well below the threshold of 10.

**6. QED:** Both ligands have good QED scores (0.68 and 0.788), indicating good drug-like properties.

**7. DILI:** Ligand A (76.154) has a higher DILI risk than Ligand B (44.048). This is a concern for Ligand A.

**8. BBB:** Ligand B (82.513) has a significantly better BBB penetration score than Ligand A (70.027).  For a CNS target like DRD2, >70 is desirable, and Ligand B is closer to this goal.

**9. Caco-2:** Both have negative Caco-2 values (-4.932 and -4.819), which is unusual and suggests poor permeability. This is a significant drawback for both.

**10. Solubility:** Both have negative solubility values (-4.646 and -3.235), indicating poor aqueous solubility. This is a concern for both.

**11. hERG:** Both have low hERG inhibition liability (0.226 and 0.548), which is good.

**12. Cl_mic:** Ligand B (36.834) has lower microsomal clearance than Ligand A (68.385), suggesting better metabolic stability.

**13. t1/2:** Ligand A (22.818) has a longer in vitro half-life than Ligand B (1.291). This is a positive for Ligand A.

**14. Pgp:** Ligand A (0.329) has lower P-gp efflux liability than Ligand B (0.066), which is favorable for CNS penetration.

**15. Affinity:** Both ligands have the same binding affinity (-8.1 kcal/mol), which is excellent.

**Overall Assessment:**

Despite Ligand A's longer half-life and lower Pgp efflux, Ligand B is the more promising candidate. Ligand B has a significantly better BBB score, lower DILI risk, and lower microsomal clearance. While both have poor Caco-2 and solubility, the CNS target prioritizes BBB penetration. The slightly lower logP of Ligand B is a minor concern compared to the other advantages. The TPSA is also more favorable for Ligand B.



Output:
1
2025-04-17 08:20:58,588 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (344.415 and 346.383 Da) fall comfortably within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (78.27) is significantly better than Ligand B (104.71). For CNS targets, we want TPSA <= 90, and A is much closer to this threshold.

**3. logP:** Both ligands have a logP around 2.1 (2.156 and 2.101), which is optimal (1-3).

**4. H-Bond Donors:** Ligand A (1) is preferable to Ligand B (3). Fewer HBDs generally improve permeability.

**5. H-Bond Acceptors:** Ligand A (6) is preferable to Ligand B (5).

**6. QED:** Ligand A (0.899) has a much better QED score than Ligand B (0.679), indicating a more drug-like profile.

**7. DILI:** Ligand A (73.09) has a higher DILI risk than Ligand B (36.603), but both are reasonably low.

**8. BBB:** Ligand A (77.2) has a significantly better BBB penetration percentile than Ligand B (43.699). This is *critical* for a CNS target like DRD2.

**9. Caco-2 Permeability:** Ligand A (-4.672) is better than Ligand B (-5.001), indicating better intestinal absorption.

**10. Aqueous Solubility:** Ligand A (-3.322) is better than Ligand B (-2.505).

**11. hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.303 and 0.232).

**12. Microsomal Clearance:** Ligand B (13.439) has a lower microsomal clearance than Ligand A (26.593), suggesting better metabolic stability.

**13. In vitro Half-Life:** Ligand B (38.431) has a much longer in vitro half-life than Ligand A (6.988), which is a significant advantage.

**14. P-gp Efflux:** Ligand A (0.129) has a lower P-gp efflux liability than Ligand B (0.049), which is favorable for CNS penetration.

**15. Binding Affinity:** Ligand A (-9.6 kcal/mol) has a slightly better binding affinity than Ligand B (-8.4 kcal/mol). This difference is substantial (1.2 kcal/mol) and can outweigh some ADME drawbacks.

**Overall Assessment:**

Ligand A excels in key properties for a CNS-targeting GPCR ligand: TPSA, BBB, QED, P-gp efflux, and binding affinity. While Ligand B has better metabolic stability (lower Cl_mic, longer t1/2) and lower DILI risk, the superior CNS penetration profile and binding affinity of Ligand A are more critical for DRD2. The difference in binding affinity is also significant enough to compensate for the slightly higher clearance of Ligand A.

Output:
1
2025-04-17 08:20:58,588 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (350.503 and 349.387 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (67.43) is significantly better than Ligand B (123.66). For CNS targets, TPSA should be <=90, and A is comfortably within that, while B is pushing the limit.

**logP:** Ligand A (2.64) is optimal (1-3), while Ligand B (0.386) is quite low, potentially hindering permeation.

**H-Bond Donors/Acceptors:** Ligand A (2 HBD, 3 HBA) and Ligand B (3 HBD, 5 HBA) both fall within acceptable ranges.

**QED:** Both ligands have similar, good QED values (0.672 and 0.685, respectively).

**DILI:** Ligand A (26.095) has a much lower DILI risk than Ligand B (42.458), indicating better potential for liver safety.

**BBB:** Ligand A (70.88) has a good BBB penetration percentile, exceeding the desirable >70 threshold for CNS targets. Ligand B (59.791) is significantly lower, which is a major drawback for a CNS target.

**Caco-2 Permeability:** Ligand A (-5.104) and Ligand B (-5.75) both have negative values, which is unusual and suggests poor permeability. However, the scale isn't defined, so it's hard to interpret.

**Aqueous Solubility:** Both ligands have poor aqueous solubility (-3.171 and -2.554 respectively). This could pose formulation challenges.

**hERG Inhibition:** Ligand A (0.496) has a very low hERG inhibition risk, while Ligand B (0.022) is even lower, but both are acceptable.

**Microsomal Clearance:** Ligand A (61.804) has moderate clearance, while Ligand B (-0.033) has very low clearance, suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (-0.382) has a short half-life, while Ligand B (17.359) has a much longer half-life, which is preferable.

**P-gp Efflux:** Ligand A (0.306) has lower P-gp efflux liability than Ligand B (0.005), which is beneficial for CNS exposure.

**Binding Affinity:** Ligand A (-8.9 kcal/mol) has a significantly stronger binding affinity than Ligand B (-7.8 kcal/mol). This >1.5 kcal/mol difference is substantial and can outweigh some ADME drawbacks.

**Conclusion:**

Considering all factors, especially the GPCR-specific priorities, **Ligand A is the more promising drug candidate.** While both have solubility issues, Ligand A excels in crucial areas for CNS penetration: TPSA, logP, and especially BBB. Its significantly higher binding affinity is also a major advantage. Although Ligand B has better metabolic stability and half-life, the poor BBB penetration and lower affinity are critical drawbacks for a DRD2 target.

Output:
1
2025-04-17 08:20:58,588 - INFO - Batch 441 complete. Total preferences: 7056
2025-04-17 08:20:58,588 - INFO - Processing batch 442/512...
2025-04-17 08:21:39,697 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (428.766 Da) is slightly higher than Ligand B (370.787 Da), but both are acceptable.

**2. TPSA:** Both ligands have TPSA values below the 90 A^2 threshold for CNS targets, which is good. Ligand A (76.1 A^2) is slightly higher than Ligand B (71.25 A^2), but both are favorable.

**3. logP:** Both ligands have logP values within the optimal range (1-3). Ligand A (1.256) is slightly lower, while Ligand B (2.278) is closer to the middle of the range.

**4. H-Bond Donors:** Both ligands have 1 HBD, which is within the acceptable limit of <=5.

**5. H-Bond Acceptors:** Ligand A has 7 HBAs, while Ligand B has 5. Both are within the acceptable limit of <=10.

**6. QED:** Both ligands have QED values above 0.5, indicating good drug-likeness. Ligand B (0.838) has a slightly better QED score than Ligand A (0.669).

**7. DILI:** Ligand A (33.773 percentile) has a significantly lower DILI risk than Ligand B (54.634 percentile). This is a substantial advantage for Ligand A.

**8. BBB:** Both ligands have reasonable BBB penetration, but Ligand A (47.848%) is lower than Ligand B (53.509%). While both are not optimal (>70%), Ligand B is slightly better.

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 values, indicating poor permeability. Ligand A (-5.648) is slightly better (less negative) than Ligand B (-4.447).

**10. Aqueous Solubility:** Both ligands have negative solubility values, indicating poor solubility. Ligand A (-1.693) is slightly better (less negative) than Ligand B (-3.266).

**11. hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.586 and 0.19 respectively), which is excellent.

**12. Microsomal Clearance:** Ligand A (-9.508 mL/min/kg) has a much lower, and therefore better, microsomal clearance than Ligand B (14.977 mL/min/kg). This indicates greater metabolic stability for Ligand A.

**13. In vitro Half-Life:** Ligand A (-2.688 hours) has a slightly better in vitro half-life than Ligand B (-9.445 hours).

**14. P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.016 and 0.109 respectively), which is excellent.

**15. Binding Affinity:** Both ligands have very similar and strong binding affinities (-8.3 and -8.4 kcal/mol). The difference is negligible.

**Overall Assessment:**

Considering the GPCR-specific priorities, Ligand A is the more promising candidate. While Ligand B has slightly better BBB penetration, Ligand A excels in crucial areas: significantly lower DILI risk, much better metabolic stability (lower Cl_mic), and slightly better solubility and permeability. The binding affinities are essentially the same, so the improved ADME properties of Ligand A outweigh the minor difference in BBB.

Output:
0
2025-04-17 08:21:39,697 - INFO - Reasoning:

Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight (MW):** Both ligands (350.296 and 347.419 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (79.29) is better than Ligand B (87.54). Both are below the 90 A^2 threshold desirable for CNS targets, but A is closer to optimal.

**3. logP:** Ligand A (2.884) is within the optimal range (1-3). Ligand B (-0.071) is significantly lower, which could hinder membrane permeability and brain penetration.

**4. H-Bond Donors (HBD):** Both ligands are acceptable (2 and 1, respectively), being less than 5.

**5. H-Bond Acceptors (HBA):** Both ligands are acceptable (3 and 5, respectively), being less than 10.

**6. QED:** Both ligands have reasonable QED scores (0.889 and 0.755), indicating good drug-like properties.

**7. DILI:** Ligand A (90.461) has a higher DILI risk than Ligand B (30.322). This is a significant drawback for Ligand A.

**8. BBB:** Both ligands have similar BBB penetration (57.58% and 57.813%). Neither is above the 70% threshold, but they are comparable.

**9. Caco-2 Permeability:** Both have negative values (-4.966 and -4.994), which is unusual and suggests poor permeability.

**10. Aqueous Solubility:** Both have negative values (-3.593 and -1.747), indicating poor solubility.

**11. hERG Inhibition:** Ligand A (0.053) has a much lower hERG risk than Ligand B (0.279), which is a significant advantage.

**12. Microsomal Clearance (Cl_mic):** Ligand A (-8.171) has a much lower (better) clearance than Ligand B (21.745), indicating better metabolic stability.

**13. In vitro Half-Life:** Ligand A (-43.53) has a much longer half-life than Ligand B (-1.528), which is a significant advantage.

**14. P-gp Efflux:** Ligand A (0.023) has a much lower P-gp efflux liability than Ligand B (0.006), suggesting better CNS exposure.

**15. Binding Affinity:** Both ligands have excellent binding affinities (-9.7 and -8.7 kcal/mol). Ligand A is slightly better (-9.7 kcal/mol).

**Overall Assessment:**

Despite the higher DILI risk, Ligand A is the more promising candidate. Its superior logP, lower hERG risk, significantly better metabolic stability (Cl_mic and t1/2), lower P-gp efflux, and slightly better binding affinity outweigh the DILI concern. The negative Caco-2 and solubility values are concerning for both, but can be addressed with formulation strategies. For a CNS target like DRD2, the logP and P-gp efflux are particularly important, and Ligand A performs much better in these areas.

Output:
1
2025-04-17 08:21:39,697 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (354.401 and 378.42 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Both ligands (74.33 and 71.25) are below the 90 A^2 threshold for CNS targets, which is excellent.

**3. logP:** Both ligands (1.137 and 1.3) are within the optimal 1-3 range.

**4. H-Bond Donors:** Ligand A (2) and Ligand B (1) are both acceptable, being less than 5.

**5. H-Bond Acceptors:** Ligand A (4) and Ligand B (6) are both acceptable, being less than 10.

**6. QED:** Both ligands have good QED scores (0.803 and 0.808), indicating drug-like properties.

**7. DILI:** Ligand A (14.036) has a significantly lower DILI risk than Ligand B (39.046). This is a substantial advantage.

**8. BBB:** Ligand B (82.009) has a better BBB penetration percentile than Ligand A (70.88), which is desirable for a CNS target like DRD2. However, both are above the 70% threshold.

**9. Caco-2 Permeability:** Ligand A (-5.045) has worse Caco-2 permeability than Ligand B (-4.799).

**10. Aqueous Solubility:** Ligand A (-1.481) has better aqueous solubility than Ligand B (-3.138).

**11. hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.425 and 0.217).

**12. Microsomal Clearance:** Ligand A (-43.588) has significantly lower (better) microsomal clearance than Ligand B (-5.029), indicating greater metabolic stability.

**13. In vitro Half-Life:** Ligand A (-10.318) has a longer in vitro half-life than Ligand B (-19.052).

**14. P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.007 and 0.105).

**15. Binding Affinity:** Both ligands have similar and strong binding affinities (-8.5 and -8.0 kcal/mol). The difference of 0.5 kcal/mol is not substantial enough to override other factors.

**Overall Assessment:**

Ligand A is the better candidate. While Ligand B has slightly better BBB penetration and Caco-2 permeability, Ligand A excels in crucial areas like DILI risk, metabolic stability (lower Cl_mic and longer t1/2), and aqueous solubility. The binding affinity is comparable. The lower DILI and improved metabolic properties of Ligand A are particularly important for long-term CNS drug development.

Output:
1
2025-04-17 08:21:39,697 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (352.385 Da) is slightly lower, which is generally favorable for permeability, but both are acceptable.

**TPSA:** Ligand A (75.19) is better than Ligand B (38.13) as it is closer to the ideal range for CNS targets (<=90). Ligand B is quite low, which could potentially indicate poor interactions.

**logP:** Ligand A (1.965) is within the optimal range (1-3), while Ligand B (4.446) is slightly high. Higher logP can lead to solubility issues and off-target effects.

**H-Bond Donors/Acceptors:** Ligand A has 1 HBD and 4 HBA, while Ligand B has 0 HBD and 3 HBA. Both are within acceptable limits (<=5 HBD and <=10 HBA).

**QED:** Ligand A (0.794) has a better QED score than Ligand B (0.523), indicating a more drug-like profile.

**DILI:** Ligand A (52.695) has a slightly higher DILI risk than Ligand B (19.698), but both are below the concerning threshold of 60.

**BBB:** Both ligands have excellent BBB penetration (Ligand A: 87.476, Ligand B: 87.864), exceeding the desirable 70% for CNS targets.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values, which is unusual and suggests a potential issue with the data or modeling. It's difficult to interpret without further information.

**Aqueous Solubility:** Both ligands have negative solubility values, which is also unusual and suggests a potential issue with the data or modeling. It's difficult to interpret without further information.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (Ligand A: 0.412, Ligand B: 0.511).

**Microsomal Clearance:** Ligand B (72.131) has a significantly lower microsomal clearance than Ligand A (10.211), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand B (-1.625) has a slightly better (less negative) in vitro half-life than Ligand A (-15.151), indicating potentially longer duration of action.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (Ligand A: 0.03, Ligand B: 0.314), which is favorable for CNS exposure.

**Binding Affinity:** Ligand A (-8.9 kcal/mol) has a slightly better binding affinity than Ligand B (-8.3 kcal/mol). While the difference is not huge, it's enough to potentially outweigh some of the ADME drawbacks of Ligand A.

**Overall Assessment:**

Considering the GPCR-specific priorities, Ligand A is slightly favored. It has a better TPSA, QED, and binding affinity. While Ligand B has better metabolic stability and a slightly better half-life, the affinity difference is significant. The negative Caco-2 and solubility values are concerning for both, but the overall profile of Ligand A is more promising, especially given the importance of affinity for GPCR ligands.

Output:
1
2025-04-17 08:21:39,698 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (447.28 Da) is higher, but still acceptable. Ligand B (350.419 Da) is slightly lower, potentially aiding permeability.

**TPSA:** Ligand A (75.6) is better than Ligand B (87.76) as it is closer to the <90 A^2 threshold for CNS targets.

**logP:** Ligand A (3.775) is optimal (1-3), while Ligand B (0.713) is low, potentially hindering permeation. This is a significant advantage for Ligand A.

**H-Bond Donors/Acceptors:** Ligand A (HBD=2, HBA=4) and Ligand B (HBD=1, HBA=5) both fall within acceptable ranges.

**QED:** Both ligands have good QED scores (A: 0.601, B: 0.808), indicating good drug-like properties.

**DILI:** Ligand A (78.441) has a higher DILI risk than Ligand B (43.971), which is a concern. However, DILI prediction is not always reliable.

**BBB:** Both ligands have good BBB penetration (A: 62.233, B: 68.554), but Ligand B is slightly better. However, both are below the desired >70 percentile for CNS targets.

**Caco-2 Permeability:** Both have negative Caco-2 values which is unusual and suggests poor permeability. Ligand A (-5.275) is worse than Ligand B (-4.633).

**Aqueous Solubility:** Both have negative solubility values, which is also unusual. Ligand A (-4.454) is worse than Ligand B (-2.107).

**hERG:** Both ligands have low hERG inhibition liability (A: 0.926, B: 0.238), which is favorable.

**Microsomal Clearance:** Ligand A (39.987) has a higher microsomal clearance than Ligand B (13.895), suggesting lower metabolic stability. This is a disadvantage for Ligand A.

**In vitro Half-Life:** Ligand A (47.487) has a longer half-life than Ligand B (-12.188), which is a significant advantage.

**P-gp Efflux:** Ligand A (0.843) has lower P-gp efflux than Ligand B (0.019), which is beneficial for CNS exposure.

**Binding Affinity:** Ligand A (-9.2 kcal/mol) has significantly stronger binding affinity than Ligand B (-8.0 kcal/mol). This is a major advantage, potentially outweighing some of the ADME drawbacks.

**Overall Assessment:**

Ligand A has a much stronger binding affinity, a good logP, and lower P-gp efflux. However, it has a higher DILI risk, higher microsomal clearance, and worse Caco-2 and solubility. Ligand B has better DILI, clearance, and solubility, but a significantly weaker binding affinity and a suboptimal logP. Given the importance of affinity for GPCRs, and the fact that the difference in affinity is substantial (>1.5 kcal/mol), Ligand A is the more promising candidate, despite its ADME liabilities. Optimization efforts could focus on improving its metabolic stability and reducing DILI risk.

Output:
1
2025-04-17 08:21:39,698 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (349.366 and 350.419 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (95.5) is significantly better than Ligand B (116.49). For CNS targets, we want TPSA <= 90, so Ligand A is closer to this threshold.

**logP:** Ligand A (-0.234) is a bit low, potentially hindering permeation. Ligand B (0.892) is better, falling within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A (1 HBD, 5 HBA) is preferable to Ligand B (4 HBD, 6 HBA) as it has fewer potential issues with permeability. Both are within acceptable limits.

**QED:** Ligand A (0.813) has a better QED score than Ligand B (0.605), indicating a more drug-like profile.

**DILI:** Both ligands have acceptable DILI risk (Ligand A: 64.793, Ligand B: 57.038), below the 60 threshold.

**BBB:** Ligand A (60.295) is better than Ligand B (38.891) in terms of BBB penetration, but both are below the desirable >70 percentile for CNS targets. However, given the other properties, this is less of a deciding factor.

**Caco-2 Permeability:** Both have negative Caco-2 values (-4.803 and -5.178), which is unusual and suggests poor permeability. This is a significant concern for both.

**Aqueous Solubility:** Both have negative solubility values (-1.518 and -2.091), also unusual and indicating very poor solubility.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (Ligand A: 0.146, Ligand B: 0.305).

**Microsomal Clearance:** Ligand A (-4.144) has a much lower (better) microsomal clearance than Ligand B (7.65). This suggests better metabolic stability for Ligand A.

**In vitro Half-Life:** Ligand A (-16.551) has a very low half-life, while Ligand B (3.08) is slightly better, but still not ideal.

**P-gp Efflux:** Both have very low P-gp efflux liability (Ligand A: 0.017, Ligand B: 0.018).

**Binding Affinity:** Ligand B (-8.8 kcal/mol) has a significantly better binding affinity than Ligand A (-7.7 kcal/mol). This is a substantial advantage (1.1 kcal/mol difference).

**Overall Assessment:**

Ligand B has a superior binding affinity, which is the most critical factor. While its TPSA and BBB are less favorable, the difference in affinity is substantial enough to potentially overcome these drawbacks, especially if further optimization can improve TPSA and BBB. Ligand A has better TPSA, QED, and metabolic stability, but its lower affinity and poor solubility/permeability are major concerns. The negative solubility and Caco-2 values are red flags for both, but the stronger binding of Ligand B makes it the more promising starting point for optimization.

Output:
1
2025-04-17 08:21:39,698 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B based on the provided guidelines, prioritizing GPCR-specific properties (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (348.45 & 364.38 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (88.33) is excellent for CNS penetration, being well below 90. Ligand B (40.62) is even better.

**logP:** Both ligands (1.71 & 2.77) are within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A has 1 HBD and 5 HBA, while Ligand B has 0 HBD and 2 HBA. Both are acceptable.

**QED:** Both ligands have similar QED values (0.723 and 0.72), indicating good drug-likeness.

**DILI:** Ligand A (29.04) has a lower DILI risk than Ligand B (20.20), which is preferable.

**BBB:** Ligand B (96.39) has significantly better predicted BBB penetration than Ligand A (81), a crucial factor for CNS targets like DRD2.

**Caco-2 Permeability:** Ligand A (-5.072) has slightly better Caco-2 permeability than Ligand B (-4.483).

**Aqueous Solubility:** Both ligands have poor aqueous solubility (-2.145 and -3.214), which could pose formulation challenges.

**hERG Inhibition:** Both ligands show low hERG inhibition liability (0.376 and 0.616).

**Microsomal Clearance:** Ligand B (19.196) has a lower microsomal clearance than Ligand A (47.701), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand B (-2.208) has a better in vitro half-life than Ligand A (-5.082).

**P-gp Efflux:** Ligand A (0.08) has slightly lower P-gp efflux liability than Ligand B (0.127), which is favorable for CNS exposure.

**Binding Affinity:** Ligand A (-8.4 kcal/mol) has a slightly better binding affinity than Ligand B (-7.5 kcal/mol). The difference of 0.9 kcal/mol is significant, but not overwhelming.

**Overall Assessment:**

While Ligand A has a slightly better binding affinity and lower P-gp efflux, Ligand B excels in critical areas for a CNS-targeting GPCR drug. Specifically, its significantly higher BBB penetration (96.39 vs. 81), lower microsomal clearance, and better in vitro half-life are substantial advantages. The slightly lower affinity of Ligand B is likely outweighed by its improved pharmacokinetic properties, especially its ability to cross the blood-brain barrier. The lower DILI risk of Ligand A is a plus, but the BBB advantage of Ligand B is more critical for this target.

Output:
1
2025-04-17 08:21:39,698 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 drug candidates, considering the provided guidelines and GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (370.877 and 348.447 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (80.57) is excellent, well below the 90 A^2 threshold for CNS targets. Ligand B (98.32) is still reasonable but less optimal, nearing the 100 A^2 limit.

**logP:** Ligand A (3.151) is within the optimal 1-3 range. Ligand B (1.098) is slightly low, potentially hindering permeability.

**H-Bond Donors/Acceptors:** Ligand A has 2 HBD and 4 HBA, which are both acceptable. Ligand B has 3 HBD and 4 HBA, also acceptable.

**QED:** Ligand A (0.772) has a strong drug-like profile. Ligand B (0.551) is acceptable, but less ideal than A.

**DILI:** Ligand A (60.644) is approaching a concerning level, but still within a moderate risk range. Ligand B (11.4) has a very low DILI risk, which is a significant advantage.

**BBB:** Ligand A (46.219) is moderate, but not ideal for a CNS target (desirable >70). Ligand B (34.626) is even lower, making CNS penetration a major concern.

**Caco-2 Permeability:** Ligand A (-4.911) is poor. Ligand B (-5.398) is also poor.

**Aqueous Solubility:** Ligand A (-3.577) is poor. Ligand B (-1.51) is also poor.

**hERG Inhibition:** Both ligands (0.169 and 0.158) show very low hERG inhibition liability, which is excellent.

**Microsomal Clearance:** Ligand A (22.497) has moderate clearance. Ligand B (-2.479) has negative clearance, which is unusual and suggests very high metabolic stability.

**In vitro Half-Life:** Ligand A (56.056 hours) has a good half-life. Ligand B (-26.739 hours) has a negative half-life, which is impossible and indicates a data error or a very unusual compound behavior.

**P-gp Efflux:** Both ligands (0.133 and 0.021) show low P-gp efflux, which is favorable for CNS exposure.

**Binding Affinity:** Ligand A (-8.4 kcal/mol) has a significantly stronger binding affinity than Ligand B (-7.7 kcal/mol). This 0.7 kcal/mol difference is substantial and can outweigh some ADME drawbacks.

**Overall Assessment:**

Ligand A has a better overall profile, primarily driven by its significantly superior binding affinity and acceptable TPSA. While its BBB penetration is not ideal, the strong binding may compensate. The DILI risk is a concern, but manageable. Ligand B has a much better DILI profile and metabolic stability, but its lower binding affinity and poor BBB penetration are major drawbacks for a CNS target like DRD2. The negative half-life for ligand B is a data quality issue that makes it less reliable.

Output:
1
2025-04-17 08:21:39,699 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (365.539 and 341.415 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (63.24) is significantly better than Ligand B (110.67). For CNS targets, we want TPSA <= 90, and A is comfortably within that, while B exceeds it.

**3. logP:** Ligand A (3.811) is good, within the 1-3 range. Ligand B (1.804) is on the lower side, potentially hindering permeability.

**4. H-Bond Donors:** Ligand A (1) is preferable to Ligand B (3). Fewer HBDs generally improve permeability.

**5. H-Bond Acceptors:** Ligand A (3) is preferable to Ligand B (4). Fewer HBAs generally improve permeability.

**6. QED:** Both ligands have similar QED values (0.686 and 0.657), indicating reasonable drug-likeness.

**7. DILI:** Ligand A (37.456) has a lower DILI risk than Ligand B (56.96), which is preferable. Both are below the concerning 60 threshold.

**8. BBB:** Ligand A (78.092) has a significantly better BBB penetration score than Ligand B (49.748). This is *critical* for a CNS target like DRD2.

**9. Caco-2 Permeability:** Ligand A (-4.849) and Ligand B (-5.032) both have negative values, which is unusual. This suggests poor permeability. However, the scale isn't specified, so it's difficult to interpret.

**10. Aqueous Solubility:** Both ligands have very poor aqueous solubility (-3.948 and -4.087). This could pose formulation challenges.

**11. hERG Inhibition:** Ligand A (0.607) has a slightly higher hERG risk than Ligand B (0.173), but both are relatively low.

**12. Microsomal Clearance:** Ligand A (62.147) has a higher clearance than Ligand B (14.214), indicating lower metabolic stability. This is a drawback for A.

**13. In vitro Half-Life:** Ligand B (-24.768) has a negative half-life, which is impossible. This is a significant red flag. Ligand A (18.627) has a reasonable half-life.

**14. P-gp Efflux:** Ligand A (0.526) has lower P-gp efflux than Ligand B (0.052), which is desirable for CNS penetration.

**15. Binding Affinity:** Ligand B (-8.5) has a slightly better binding affinity than Ligand A (-8.2), although the difference is small (0.3 kcal/mol).

**Overall Assessment:**

Despite Ligand B's slightly better affinity, Ligand A is the superior candidate. The critical factors are the significantly better BBB penetration, lower DILI risk, more reasonable half-life, and better TPSA. Ligand B's negative half-life is a major concern, and its lower logP and BBB penetration are significant drawbacks for a CNS target. The slightly higher clearance of Ligand A is a manageable issue compared to the problems with Ligand B.

Output:
1
2025-04-17 08:21:39,699 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B based on the provided guidelines, prioritizing GPCR-specific properties (BBB, logP, Pgp, TPSA, and affinity) for DRD2.

**Molecular Weight:** Both ligands (358.463 and 356.369 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (58.64) is significantly better than Ligand B (68.82). For CNS targets, we want TPSA <= 90, and A is closer to the ideal.

**logP:** Both ligands have good logP values (4.095 and 3.174), falling within the 1-3 range. Ligand B is slightly better, being closer to the optimal range.

**H-Bond Donors/Acceptors:** Ligand A (HBD=1, HBA=4) and Ligand B (HBD=2, HBA=4) both have acceptable numbers of H-bond donors and acceptors.

**QED:** Both ligands have good QED scores (0.646 and 0.869), indicating good drug-like properties. Ligand B is better.

**DILI:** Ligand A (78.635) has a higher DILI risk than Ligand B (61.342), but both are acceptable.

**BBB:** This is a critical parameter for a CNS target like DRD2. Ligand B (95.812) has a *much* higher BBB penetration percentile than Ligand A (59.054). This is a major advantage for B.

**Caco-2 Permeability:** Both have negative values (-4.556 and -4.608), which is unusual and likely indicates poor permeability. This is a concern for both.

**Aqueous Solubility:** Both ligands have very poor aqueous solubility (-5.514 and -4.468). This is a significant drawback for both, potentially impacting bioavailability.

**hERG Inhibition:** Ligand A (0.294) has a slightly lower hERG inhibition risk than Ligand B (0.7), which is preferable.

**Microsomal Clearance:** Ligand A (137.698) has a higher microsomal clearance than Ligand B (45.79), indicating lower metabolic stability. Ligand B is better here.

**In vitro Half-Life:** Ligand B (11.701) has a slightly longer in vitro half-life than Ligand A (12.614).

**P-gp Efflux:** Ligand A (0.194) has lower P-gp efflux than Ligand B (0.26), which is better for CNS penetration.

**Binding Affinity:** Ligand A (-8.9 kcal/mol) has a significantly stronger binding affinity than Ligand B (-0.0 kcal/mol). This is a *major* advantage for Ligand A. A difference of >1.5 kcal/mol can often outweigh other drawbacks.

**Overall Assessment:**

While Ligand B excels in BBB penetration, P-gp efflux, and metabolic stability, the *dramatic* difference in binding affinity (8.9 vs 0.0 kcal/mol) heavily favors Ligand A. The poor solubility and Caco-2 permeability are concerns for both, but the strong binding of A suggests it might still be effective *in vivo*, potentially overcoming these limitations. The higher BBB of B is attractive, but the lack of affinity is a dealbreaker.

Output:
1
2025-04-17 08:21:39,699 - INFO - Reasoning:

Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (356.344 and 378.51 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (78.43) is better than Ligand B (84.5). Both are below the 90 A^2 threshold desirable for CNS targets, but A is closer to the optimal range.

**3. logP:** Both ligands (1.994 and 1.754) are within the optimal 1-3 range.

**4. H-Bond Donors:** Ligand A (3) is slightly higher than Ligand B (2), but both are acceptable (<=5).

**5. H-Bond Acceptors:** Ligand A (3) is lower than Ligand B (4), both are acceptable (<=10).

**6. QED:** Ligand A (0.729) is better than Ligand B (0.607), indicating a more drug-like profile.

**7. DILI:** Ligand A (42.148) is slightly higher than Ligand B (34.238), but both are below the concerning threshold of 60, indicating low risk.

**8. BBB:** Ligand B (81.466) has a significantly better BBB penetration percentile than Ligand A (70.88). This is a crucial factor for a CNS target like DRD2.

**9. Caco-2 Permeability:** Ligand A (-5.097) is slightly better than Ligand B (-4.927), indicating better intestinal absorption. However, both are negative values which is unusual and requires further investigation.

**10. Aqueous Solubility:** Both ligands have very poor aqueous solubility (-2.369 and -2.535). This is a significant concern for both compounds.

**11. hERG Inhibition:** Both ligands have low hERG inhibition risk (0.312 and 0.467).

**12. Microsomal Clearance:** Ligand B (23.519) has a lower microsomal clearance than Ligand A (25.23), suggesting better metabolic stability.

**13. In vitro Half-Life:** Ligand A (-6.525) has a significantly longer in vitro half-life than Ligand B (-19.631). This is a major advantage for Ligand A.

**14. P-gp Efflux:** Ligand A (0.097) has lower P-gp efflux liability than Ligand B (0.086), suggesting better CNS exposure.

**15. Binding Affinity:** Ligand B (-6.9 kcal/mol) has a slightly better binding affinity than Ligand A (-8.4 kcal/mol). While A has a better affinity, the difference is not substantial enough to outweigh other factors.

**Overall Assessment:**

While Ligand A has a better QED, half-life, and slightly better Caco-2 permeability, Ligand B excels in BBB penetration, which is paramount for a DRD2 ligand. The slightly better metabolic stability (lower Cl_mic) of Ligand B is also advantageous. The difference in binding affinity is not large enough to overcome the BBB advantage of Ligand B. The poor solubility of both is a concern that would need to be addressed through formulation strategies.

Output:
1
2025-04-17 08:21:39,699 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (374.34 and 346.43 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (90.17) is borderline acceptable for CNS targets (<=90), while Ligand B (62.99) is well within the desired range. This favors Ligand B.

**3. logP:** Ligand A (3.166) is optimal. Ligand B (1.698) is slightly low, potentially impacting permeability, but still within an acceptable range.

**4. H-Bond Donors:** Both ligands have 0 HBD, which is good.

**5. H-Bond Acceptors:** Ligand A has 5 HBA, and Ligand B has 4. Both are acceptable (<=10).

**6. QED:** Both ligands have good QED scores (0.572 and 0.836), indicating drug-like properties. Ligand B is slightly better.

**7. DILI:** Ligand A (69.33) has a moderate DILI risk, while Ligand B (14.62) has a very low risk. This is a significant advantage for Ligand B.

**8. BBB:** Ligand A (81.82) has good BBB penetration, while Ligand B (53.04) is lower. This favors Ligand A.

**9. Caco-2:** Both have negative Caco-2 values, which is unusual and difficult to interpret without knowing the scale. However, it's likely indicating poor permeability for both.

**10. Solubility:** Both have negative solubility values, also unusual. This suggests poor aqueous solubility for both compounds.

**11. hERG:** Both ligands have low hERG inhibition risk (0.728 and 0.173).

**12. Cl_mic:** Both have relatively low microsomal clearance (34.11 and 30.39 mL/min/kg), suggesting reasonable metabolic stability.

**13. t1/2:** Ligand A (47.71) has a better in vitro half-life than Ligand B (28.48).

**14. Pgp:** Ligand A (0.547) has slightly higher P-gp efflux liability than Ligand B (0.018). Lower Pgp is preferred for CNS penetration, favoring Ligand B.

**15. Binding Affinity:** Both ligands have excellent binding affinities (-8.5 and -8.1 kcal/mol). The difference (0.4 kcal/mol) is not substantial enough to outweigh other ADME considerations.

**Overall Assessment:**

Considering the GPCR-specific priorities, Ligand B appears to be the more promising candidate. While Ligand A has better BBB penetration and in vitro half-life, Ligand B has a significantly lower DILI risk, lower Pgp efflux, and a more favorable TPSA. The slightly lower logP of Ligand B is a minor concern, but the substantial advantage in safety (DILI) and CNS penetration (Pgp) outweighs this. The negative values for Caco-2 and solubility are concerning for both, but can be addressed with formulation strategies.



Output:
1
2025-04-17 08:21:39,699 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (360.37 and 365.434 Da) fall comfortably within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (107.08) is slightly higher than Ligand B (90.98). For CNS targets, we prefer TPSA <= 90, so Ligand B is better here.

**3. logP:** Both ligands have good logP values (1.911 and 1.747), falling within the optimal 1-3 range.

**4. H-Bond Donors:** Both have 2 HBD, which is acceptable.

**5. H-Bond Acceptors:** Both have 5 HBA, which is acceptable.

**6. QED:** Both ligands have good QED scores (0.725 and 0.782), indicating good drug-like properties.

**7. DILI:** Ligand A (99.031) has a very high DILI risk, while Ligand B (81.892) is better, but still relatively high. This is a significant concern for Ligand A.

**8. BBB:** Ligand A (59.868) has a moderate BBB penetration, while Ligand B (53.393) is slightly lower. Both are below the desirable >70 for CNS targets, but not drastically so.

**9. Caco-2:** Both have negative Caco-2 values (-5.114 and -5.416), which is unusual and suggests poor permeability. This is a concern for both.

**10. Solubility:** Both have negative solubility values (-3.583 and -3.297), indicating very poor aqueous solubility. This is a major drawback for both.

**11. hERG:** Both ligands have low hERG inhibition risk (0.318 and 0.302).

**12. Cl_mic:** Ligand A (11.657) has a lower microsomal clearance than Ligand B (22.841), suggesting better metabolic stability.

**13. t1/2:** Ligand A (35.467) has a longer in vitro half-life than Ligand B (-3.156), which is a positive.

**14. Pgp:** Both have very low Pgp efflux liability (0.173 and 0.158), which is good for CNS penetration.

**15. Binding Affinity:** Ligand B (-7.5 kcal/mol) has a significantly stronger binding affinity than Ligand A (-9.4 kcal/mol). This is a substantial advantage, potentially outweighing some of the ADME drawbacks.

**Overall Assessment:**

While both ligands have significant ADME issues (poor solubility, Caco-2 permeability, and BBB), Ligand B is the more promising candidate. Its substantially stronger binding affinity (-7.5 vs -9.4 kcal/mol) is a major advantage for a GPCR target. Ligand A's extremely high DILI risk is a deal-breaker. Although Ligand B's DILI is still elevated, it is significantly lower than Ligand A. The better TPSA of Ligand B is also a plus.

Output:
1
2025-04-17 08:21:39,700 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (346.471 and 352.406 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (49.85) is excellent, well below the 90 A^2 threshold for CNS targets. Ligand B (78.87) is higher, but still reasonable, though less optimal for CNS penetration.

**logP:** Ligand A (3.719) is within the optimal 1-3 range. Ligand B (1.334) is on the lower side, potentially hindering permeability.

**H-Bond Donors/Acceptors:** Ligand A (0 HBD, 3 HBA) is very favorable. Ligand B (2 HBD, 4 HBA) is also acceptable.

**QED:** Both ligands have similar QED values (0.82 and 0.776), indicating good drug-likeness.

**DILI:** Ligand A (54.517) has a higher DILI risk than Ligand B (30.438), which is a significant drawback.

**BBB:** Both ligands demonstrate good BBB penetration (Ligand A: 70.609, Ligand B: 76.309), exceeding the 70% threshold. Ligand B is slightly better.

**Caco-2 Permeability:** Both have negative Caco-2 values (-4.168 and -4.319), which is unusual and suggests poor permeability. This is concerning for both.

**Aqueous Solubility:** Both have negative solubility values (-3.412 and -1.76), also concerning.

**hERG Inhibition:** Both ligands show low hERG inhibition risk (0.583 and 0.452).

**Microsomal Clearance:** Ligand A (69.503) has higher microsomal clearance than Ligand B (27.207), suggesting lower metabolic stability.

**In vitro Half-Life:** Ligand B (5.145 hours) has a longer half-life than Ligand A (1.447 hours).

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.375 and 0.087), which is favorable for CNS exposure. Ligand B is better.

**Binding Affinity:** Ligand A (-8.6 kcal/mol) has a significantly stronger binding affinity than Ligand B (-7.7 kcal/mol). This is a substantial advantage.

**Overall Assessment:**

Ligand A has a much stronger binding affinity, which is a critical factor for GPCRs. However, it has a higher DILI risk and poorer metabolic stability (higher Cl_mic, shorter t1/2). Ligand B has a better safety profile (lower DILI) and better metabolic stability, but its binding affinity is weaker and logP is lower. The negative Caco-2 and solubility values are concerning for both.

Given the importance of binding affinity for GPCRs, and the relatively small difference in other ADME properties, the stronger affinity of Ligand A is likely to outweigh its drawbacks, *provided* the DILI risk can be mitigated through further structural modifications. The lower logP of Ligand B is a significant concern for CNS penetration.

Output:
1
2025-04-17 08:21:39,700 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (364.555 and 351.401 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (49.41) is excellent, well below the 90 A^2 threshold for CNS targets. Ligand B (77.93) is still reasonable, but less optimal.

**logP:** Both ligands have good logP values (3.231 and 2.307), falling within the 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A (1 HBD, 3 HBA) is better than Ligand B (2 HBD, 5 HBA) in terms of balancing solubility and permeability.

**QED:** Both ligands have similar, good QED values (0.706 and 0.763), indicating good drug-likeness.

**DILI:** Ligand A (13.532) has a significantly lower DILI risk than Ligand B (32.299), which is a substantial advantage.

**BBB:** Both ligands have very good BBB penetration (77.821 and 75.456), exceeding the 70% threshold for CNS targets.

**Caco-2 Permeability:** Both have negative Caco-2 values (-5.163 and -5.133), which is unusual and suggests poor permeability. This is a concern for both, but doesn't differentiate them.

**Aqueous Solubility:** Both ligands have very poor aqueous solubility (-3.733 and -2.384). This is a significant drawback for both.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.531 and 0.636).

**Microsomal Clearance:** Ligand A (70.636) has higher microsomal clearance than Ligand B (9.79), indicating lower metabolic stability.

**In vitro Half-Life:** Ligand B (-17.05) has a significantly longer in vitro half-life than Ligand A (-10.773), which is a major advantage.

**P-gp Efflux:** Ligand A (0.3) exhibits lower P-gp efflux than Ligand B (0.08), suggesting better CNS exposure.

**Binding Affinity:** Ligand B (-7.5 kcal/mol) has a substantially stronger binding affinity than Ligand A (0.0 kcal/mol). This is a critical factor, as a >1.5 kcal/mol difference can outweigh other drawbacks.

**Overall Assessment:**

While Ligand A has better TPSA, DILI, and P-gp efflux, Ligand B's significantly stronger binding affinity (-7.5 vs 0.0 kcal/mol) and longer half-life are decisive. The poor solubility and Caco-2 permeability are concerns for both, but the potency advantage of Ligand B is substantial enough to overcome these issues, especially for a CNS target where BBB penetration is already good. The lower DILI risk of Ligand A is appealing, but the affinity difference is too large to ignore.

Output:
1
2025-04-17 08:21:39,700 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (358.873 and 351.491 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (62.46) is significantly better than Ligand B (78.51). For CNS targets, we want TPSA <= 90, and ideally closer to 60. Ligand A is much closer to the ideal.

**3. logP:** Both ligands have good logP values (2.664 and 1.692), falling within the optimal 1-3 range. Ligand A is slightly higher, which could be beneficial for membrane permeability.

**4. H-Bond Donors:** Ligand A (1) is better than Ligand B (2). Lower HBD is generally preferred for better permeability.

**5. H-Bond Acceptors:** Ligand A (4) is better than Ligand B (3). Lower HBA is generally preferred for better permeability.

**6. QED:** Ligand A (0.896) has a significantly higher QED score than Ligand B (0.685), indicating a more drug-like profile.

**7. DILI:** Ligand B (12.214) has a much lower DILI risk than Ligand A (59.403), which is a significant advantage.

**8. BBB:** Ligand A (78.48) has a better BBB percentile than Ligand B (56.65), which is crucial for a CNS target like DRD2. Both are reasonably good, but A is better.

**9. Caco-2:** Both ligands have negative Caco-2 values (-5.04 and -5.021), which is unusual and suggests poor permeability. This is a red flag for both.

**10. Solubility:** Both ligands have negative solubility values (-2.36 and -1.389), indicating very poor aqueous solubility. This is a major concern for both compounds.

**11. hERG:** Both ligands have low hERG inhibition liability (0.723 and 0.329), which is good.

**12. Cl_mic:** Ligand B (6.191) has a significantly lower microsomal clearance than Ligand A (15.652), suggesting better metabolic stability.

**13. t1/2:** Ligand A (18.188) has a longer in vitro half-life than Ligand B (-16.57). However, the negative value for B is concerning and likely an error or indicates very rapid degradation.

**14. Pgp:** Ligand A (0.233) has lower P-gp efflux liability than Ligand B (0.057), which is favorable for CNS penetration.

**15. Binding Affinity:** Ligand A (-9.9 kcal/mol) has a significantly stronger binding affinity than Ligand B (-8.2 kcal/mol). This is a substantial advantage, potentially outweighing some of the ADME drawbacks.

**Overall Assessment:**

Ligand A is superior in terms of TPSA, QED, BBB, Pgp, and, most importantly, binding affinity. However, Ligand B has a much better DILI score and lower microsomal clearance. Both have poor solubility and Caco-2 permeability. Given the importance of strong binding affinity for GPCR ligands and the relatively better BBB score of A, I would prioritize Ligand A, but with a strong caveat that solubility and permeability need to be addressed through structural modifications. The large difference in affinity (-9.9 vs -8.2) is a significant advantage that could be difficult to achieve with further optimization of Ligand B.

Output:
1
2025-04-17 08:21:39,700 - INFO - Batch 442 complete. Total preferences: 7072
2025-04-17 08:21:39,700 - INFO - Processing batch 443/512...
2025-04-17 08:22:22,504 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B based on the provided guidelines, prioritizing GPCR-specific properties (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (345.443 and 352.454 Da) fall within the ideal range of 200-500 Da.

**TPSA:** Ligand A (54.78) is significantly better than Ligand B (65.54). For CNS targets, we want TPSA <= 90, both are within this range, but A is closer to the optimal value.

**logP:** Both ligands have good logP values (1.774 and 2.254), falling within the 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A (0 HBD, 4 HBA) and Ligand B (1 HBD, 4 HBA) both have acceptable numbers of H-bond donors and acceptors.

**QED:** Ligand A (0.817) has a better QED score than Ligand B (0.656), indicating a more drug-like profile.

**DILI:** Both ligands have acceptable DILI risk (37.185 and 41.838, both <40).

**BBB:** Ligand B (83.908) has a significantly better BBB percentile than Ligand A (74.758). This is a crucial factor for a CNS target like DRD2.

**Caco-2 Permeability:** Both have negative values, which is unusual. Assuming these are logP-scale values, lower values indicate lower permeability. Ligand A (-4.308) is slightly better than Ligand B (-4.736).

**Aqueous Solubility:** Both ligands have very poor aqueous solubility (-1.686 and -2.42). This is a concern, but can sometimes be mitigated with formulation strategies.

**hERG Inhibition:** Both ligands have low hERG inhibition liability (0.49 and 0.845).

**Microsomal Clearance:** Ligand A (33.15) has a much lower microsomal clearance than Ligand B (67.457), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand B (26.406) has a longer in vitro half-life than Ligand A (11.233).

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.273 and 0.137).

**Binding Affinity:** Ligand B (-7.6 kcal/mol) has a slightly better binding affinity than Ligand A (-8.2 kcal/mol). While A is better, the difference is relatively small.

**Overall Assessment:**

Ligand A excels in TPSA, QED, metabolic stability (Cl_mic), and has a slightly better affinity. However, Ligand B has a significantly better BBB percentile, which is paramount for a CNS drug targeting DRD2. The longer half-life of Ligand B is also a plus. While solubility is poor for both, the superior BBB penetration of Ligand B outweighs the advantages of Ligand A, making it the more promising candidate.

Output:
1
2025-04-17 08:22:22,505 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (355.429 and 351.447 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (58.37) is excellent, well below the 90 A^2 threshold for CNS targets. Ligand B (101.73) is higher, but still potentially acceptable, though less ideal.

**logP:** Ligand A (3.732) is at the upper end of the optimal range (1-3), but still acceptable. Ligand B (0.974) is quite low, potentially hindering permeability.

**H-Bond Donors/Acceptors:** Both ligands have reasonable HBD (1 & 2) and HBA (4 & 4) counts, well within the guidelines.

**QED:** Both ligands have good QED scores (0.722 and 0.77), indicating good drug-like properties.

**DILI:** Ligand A (25.126) has a very low DILI risk, which is excellent. Ligand B (27.026) is also low, but slightly higher.

**BBB:** This is crucial for a CNS target. Ligand A has an excellent BBB penetration percentile (98.061). Ligand B's BBB penetration (62.233) is significantly lower and less desirable.

**Caco-2 Permeability:** Ligand A (-4.69) has poor Caco-2 permeability. Ligand B (-5.744) is even worse.

**Aqueous Solubility:** Both ligands have very poor aqueous solubility (-2.762 and -1.81). This could pose formulation challenges.

**hERG Inhibition:** Ligand A (0.944) has a low hERG risk. Ligand B (0.21) is even lower, which is excellent.

**Microsomal Clearance:** Ligand A (26.052) has moderate clearance, while Ligand B (-8.981) has negative clearance, which is highly unusual and suggests very high metabolic stability.

**In vitro Half-Life:** Ligand A (-17.456) has a negative half-life, which is also unusual and suggests very high stability. Ligand B (-2.292) also has a negative half-life, but less extreme.

**P-gp Efflux:** Ligand A (0.575) has moderate P-gp efflux. Ligand B (0.016) has very low P-gp efflux, which is highly desirable for CNS penetration.

**Binding Affinity:** Ligand A (-8.6 kcal/mol) has significantly better binding affinity than Ligand B (0.0 kcal/mol). This is a substantial advantage.

**Overall Assessment:**

Despite the poor solubility and Caco-2 permeability of both compounds, Ligand A is the stronger candidate. Its significantly better binding affinity (-8.6 vs 0.0 kcal/mol) is a major advantage that can potentially outweigh the ADME liabilities. Furthermore, its excellent BBB penetration (98.061) is critical for a CNS target, while Ligand B's BBB penetration is much lower (62.233). The negative clearance and half-life values for both compounds are concerning and likely indicate issues with the modeling or data, but the large difference in binding affinity still makes Ligand A preferable.

Output:
1
2025-04-17 08:22:22,505 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (367.559 and 347.394 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (61.44) is significantly better than Ligand B (104.11). For CNS targets, we want TPSA <= 90, and A is comfortably within that, while B is above.

**logP:** Both ligands have good logP values (1.728 and 1.638), falling within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A (HBD=2, HBA=4) and Ligand B (HBD=3, HBA=4) are both acceptable, within the guidelines of <=5 HBD and <=10 HBA.

**QED:** Both ligands have good QED scores (0.686 and 0.715), indicating good drug-like properties.

**DILI:** Ligand A (15.083) has a much lower DILI risk than Ligand B (66.615). This is a significant advantage for A.

**BBB:** Ligand A (78.558) has a better BBB penetration percentile than Ligand B (63.668). Both are reasonably good, but A is closer to the desirable >70 threshold for CNS targets.

**Caco-2 Permeability:** Both have negative Caco-2 values (-5.496 and -5.297), which is unusual and suggests poor permeability. However, these values are on a scale where negative values are possible, and direct comparison is difficult without knowing the scale's specifics.

**Aqueous Solubility:** Both have negative solubility values (-3.105 and -2.744), again suggesting poor solubility. Similar to Caco-2, interpretation is limited without knowing the scale.

**hERG:** Both ligands show low hERG inhibition liability (0.466 and 0.567), which is good.

**Microsomal Clearance:** Ligand A (45.397) has higher microsomal clearance than Ligand B (13.997), meaning B is more metabolically stable.

**In vitro Half-Life:** Ligand B (0.964) has a slightly longer half-life than Ligand A (3.14), but both are quite short.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.058 and 0.061).

**Binding Affinity:** Ligand B (-9.1 kcal/mol) has a significantly better binding affinity than Ligand A (-7.9 kcal/mol). This is a substantial advantage (1.2 kcal/mol difference).

**Overall Assessment:**

The key differentiators are binding affinity and metabolic stability. Ligand B binds much more strongly. However, Ligand A has superior TPSA, DILI risk, and BBB penetration. The significantly better affinity of Ligand B is a strong point, potentially outweighing the ADME drawbacks. However, the TPSA of Ligand B is concerning for CNS penetration, and the higher DILI risk is also a negative. Given the GPCR-specific priority for BBB penetration and the relatively close BBB values, the lower TPSA and DILI risk of Ligand A make it a slightly more promising candidate, despite the weaker binding affinity. The difference in affinity is significant, but not insurmountable, and could be addressed with further optimization.

Output:
0
2025-04-17 08:22:22,505 - INFO - Reasoning:

Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the acceptable range (200-500 Da). Ligand A (471.291 Da) is higher, but still reasonable. Ligand B (351.359 Da) is preferable.

**TPSA:** Ligand A (55.4) is excellent for CNS penetration, well below the 90 A^2 threshold. Ligand B (121.71) is higher, but still potentially acceptable, though less ideal.

**logP:** Ligand A (3.941) is near the upper limit of the optimal range (1-3), but still acceptable. Ligand B (0.03) is significantly low, potentially hindering membrane permeability and CNS penetration.

**H-Bond Donors/Acceptors:** Ligand A (HBD=1, HBA=3) is within the ideal ranges. Ligand B (HBD=2, HBA=6) is also acceptable, but slightly higher HBA could pose a minor issue.

**QED:** Both ligands have good QED scores (A: 0.438, B: 0.738), indicating reasonable drug-likeness. Ligand B is better.

**DILI:** Ligand A (89.027) has a higher DILI risk than Ligand B (58.511). Ligand B is preferable.

**BBB:** Ligand A (63.746) has a better BBB percentile than Ligand B (37.495). This is a critical factor for a CNS target like DRD2.

**Caco-2 Permeability:** Both have negative Caco-2 values which is unusual and indicates poor permeability.

**Aqueous Solubility:** Both ligands have negative solubility values which is unusual and indicates poor solubility.

**hERG:** Ligand A (0.885) has a slightly higher hERG risk than Ligand B (0.085). Ligand B is preferable.

**Microsomal Clearance:** Ligand A (82.052) has a higher microsomal clearance than Ligand B (1.606), meaning it's less metabolically stable. Ligand B is preferable.

**In vitro Half-Life:** Ligand A (17.457 hours) has a longer half-life than Ligand B (-25.339 hours). This is a significant advantage for Ligand A.

**P-gp Efflux:** Ligand A (0.676) has lower P-gp efflux than Ligand B (0.01), which is favorable for CNS penetration.

**Binding Affinity:** Ligand A (-9.8 kcal/mol) has a significantly stronger binding affinity than Ligand B (-8.4 kcal/mol). This is a major advantage for Ligand A, potentially outweighing some of its ADME drawbacks.

**Overall Assessment:**

Ligand A excels in binding affinity, BBB penetration, P-gp efflux, and half-life. While its logP is towards the higher end and DILI risk is elevated, the strong binding affinity (-9.8 kcal/mol) is a significant advantage. Ligand B has better solubility and lower DILI/hERG, but its low logP and poor BBB penetration are major drawbacks for a CNS target. The substantial difference in binding affinity (1.4 kcal/mol) is a critical factor.

Output:
1
2025-04-17 08:22:22,505 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B against the provided guidelines, prioritizing GPCR-specific properties (BBB, logP, Pgp, TPSA, and affinity) for DRD2.

**Molecular Weight:** Both ligands (347.419 and 361.368 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (111.21) is slightly above the optimal <90 for CNS targets, while Ligand B (80.12) is well within the desired range. This favors Ligand B.

**logP:** Ligand A (0.421) is quite low, potentially hindering permeability. Ligand B (1.077) is better, falling within the optimal 1-3 range. This favors Ligand B.

**H-Bond Donors/Acceptors:** Ligand A has 3 HBD and 5 HBA, which are acceptable. Ligand B has 1 HBD and 5 HBA, also acceptable. No clear advantage here.

**QED:** Both ligands have good QED scores (0.715 and 0.822), indicating good drug-like properties.

**DILI:** Ligand A (38.503) has a lower DILI risk than Ligand B (43.738), which is favorable.

**BBB:** Ligand B (74.215) has a significantly better BBB percentile than Ligand A (52.579). This is a *major* advantage for a CNS target like DRD2.

**Caco-2 Permeability:** Ligand A (-5.396) has poor Caco-2 permeability, while Ligand B (-4.917) is slightly better, but still poor.

**Aqueous Solubility:** Both ligands have very poor aqueous solubility (-1.875 and -2.158). This is a concern for both, but can be addressed with formulation strategies.

**hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.18 and 0.148), which is excellent.

**Microsomal Clearance:** Ligand A (-33.48) has a much lower (better) microsomal clearance than Ligand B (2.753), indicating greater metabolic stability. This favors Ligand A.

**In vitro Half-Life:** Ligand A (3.666) has a slightly better in vitro half-life than Ligand B (-18.473).

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.022 and 0.026), which is good.

**Binding Affinity:** Ligand B (-8.4) has a slightly better binding affinity than Ligand A (-7.8), although the difference is not huge.

**Overall Assessment:**

Ligand B is clearly favored due to its superior BBB penetration (74.215 vs 52.579) and better logP (1.077 vs 0.421). While Ligand A has better metabolic stability (lower Cl_mic) and a slightly longer half-life, the BBB and logP are critical for CNS penetration with a GPCR target. The slightly better affinity of Ligand B also contributes. The poor solubility of both is a drawback, but formulation strategies could potentially mitigate this.

Output:
1
2025-04-17 08:22:22,505 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (357.435 and 374.575 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (79.79) is better than Ligand B (44.1). For CNS targets, we want TPSA <= 90, both meet this criteria, but A is closer to the upper limit and might have slightly reduced brain penetration.

**logP:** Ligand A (2.824) is within the optimal 1-3 range. Ligand B (4.517) is a bit high, potentially leading to solubility issues and off-target interactions.

**H-Bond Donors/Acceptors:** Ligand A has 2 HBD and 5 HBA, which are acceptable. Ligand B has 0 HBD and 4 HBA, also acceptable.

**QED:** Ligand A (0.834) has a significantly better QED score than Ligand B (0.566), indicating a more drug-like profile.

**DILI:** Ligand A (69.988) has a higher DILI risk than Ligand B (12.757). This is a significant drawback for Ligand A.

**BBB:** Ligand B (84.374) has a much higher BBB percentile than Ligand A (70.958). This is crucial for a CNS target like DRD2, making Ligand B more promising.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.22 and -5.105). These values are unusual and suggest poor permeability. However, the scale isn't specified, so it's hard to interpret.

**Aqueous Solubility:** Both ligands have negative solubility values (-4.111 and -4.486). Again, the scale is unclear, but these suggest poor aqueous solubility.

**hERG:** Both ligands have low hERG inhibition risk (0.72 and 0.877).

**Microsomal Clearance:** Ligand A (51.458) has a lower microsomal clearance than Ligand B (107.225), indicating better metabolic stability.

**In vitro Half-Life:** Ligand A (68.977) has a significantly longer in vitro half-life than Ligand B (-3.773). This is a major advantage for Ligand A.

**P-gp Efflux:** Ligand A (0.757) has lower P-gp efflux liability than Ligand B (0.616), suggesting better CNS exposure.

**Binding Affinity:** Ligand A (-8.8 kcal/mol) has a significantly stronger binding affinity than Ligand B (-6.7 kcal/mol). This is a substantial advantage that could outweigh some of the ADME drawbacks.

**Overall Assessment:**

Ligand A has a significantly better binding affinity and metabolic stability (lower Cl_mic, longer t1/2), and lower P-gp efflux. However, it has a higher DILI risk and slightly lower BBB penetration. Ligand B excels in BBB penetration and has a much lower DILI risk, but suffers from weaker binding affinity, higher metabolic clearance, and a lower QED score.

Given the importance of BBB penetration for a CNS target like DRD2, and the substantial difference in binding affinity, the stronger affinity of Ligand A is likely to be more important. The DILI risk is concerning, but could potentially be mitigated through structural modifications. The difference in binding affinity (>1.5 kcal/mol) is significant enough to prioritize Ligand A despite the other drawbacks.

Output:
1
2025-04-17 08:22:22,506 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (359.455 and 348.447 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (80.12) is significantly better than Ligand B (103.09). For CNS targets, we want TPSA <= 90, so Ligand A is preferable.

**3. logP:** Both ligands have good logP values (1.272 and 1.336), falling within the optimal 1-3 range.

**4. H-Bond Donors:** Ligand A (1) is better than Ligand B (4). Lower HBDs generally improve permeability.

**5. H-Bond Acceptors:** Ligand A (6) is better than Ligand B (3). Lower HBAs generally improve permeability.

**6. QED:** Ligand A (0.872) is significantly better than Ligand B (0.513), indicating a more drug-like profile.

**7. DILI:** Ligand A (60.644) has a higher DILI risk than Ligand B (31.601). This favors Ligand B.

**8. BBB:** Both ligands have similar BBB penetration (Ligand A: 55.138, Ligand B: 57.464). While neither exceeds the desirable >70, they are comparable.

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.178 and -5.256). This is unusual and suggests poor permeability. However, the values are very close.

**10. Aqueous Solubility:** Both ligands have negative solubility values (-1.944 and -2.833), indicating poor solubility. Ligand A is slightly better.

**11. hERG Inhibition:** Ligand A (0.049) has a lower hERG risk than Ligand B (0.134), which is favorable.

**12. Microsomal Clearance:** Ligand A (28.138) has higher clearance than Ligand B (5.178), indicating lower metabolic stability. This favors Ligand B.

**13. In vitro Half-Life:** Ligand A (10.445) has a longer half-life than Ligand B (-9.332). This favors Ligand A.

**14. P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.021 and 0.013).

**15. Binding Affinity:** Ligand A (-8.2 kcal/mol) has a significantly stronger binding affinity than Ligand B (-7.5 kcal/mol). This is a substantial advantage (0.7 kcal/mol difference).

**Overall Assessment:**

Ligand A is superior in terms of TPSA, QED, hERG risk, and, crucially, binding affinity. While Ligand B has a better DILI score and lower clearance, the strong affinity of Ligand A and its better drug-like properties outweigh these drawbacks, especially given the GPCR target class. The affinity difference is significant enough to potentially overcome the slightly higher DILI risk and lower metabolic stability. The permeability issues are concerning for both, but the stronger binding of A may compensate.

Output:
1
2025-04-17 08:22:22,506 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (348.451 and 343.479 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (84.22) is better than Ligand B (71.76) as it is closer to the ideal range for CNS targets (<=90). Both are good.

**3. logP:** Ligand B (2.223) is slightly better than Ligand A (1.115), falling more squarely within the optimal 1-3 range. Ligand A is a bit low, potentially impacting permeability.

**4. H-Bond Donors:** Ligand A (0) is preferable to Ligand B (1). Fewer HBDs generally improve permeability.

**5. H-Bond Acceptors:** Ligand A (6) is preferable to Ligand B (7). Lower HBA is generally better for permeability.

**6. QED:** Both ligands have good QED scores (0.719 and 0.867), indicating good drug-like properties.

**7. DILI:** Ligand A (33.23) has a significantly lower DILI risk than Ligand B (52.423). This is a substantial advantage.

**8. BBB:** Ligand A (73.943) has a better BBB penetration score than Ligand B (63.901). While both are reasonably good, Ligand A is closer to the desirable >70 threshold for CNS targets.

**9. Caco-2:** Both ligands have negative Caco-2 values (-5.005 and -5.232). This is unusual and suggests poor permeability. However, these values are on a scale where negative values are possible, and direct comparison is difficult without knowing the scale's specifics.

**10. Solubility:** Both ligands have negative solubility values (-1.162 and -2.295). Similar to Caco-2, the scale is unclear, and negative values are possible.

**11. hERG:** Both ligands have very low hERG inhibition liability (0.062 and 0.404), which is excellent.

**12. Cl_mic:** Ligand B (17.906) has lower microsomal clearance than Ligand A (22.992), indicating better metabolic stability.

**13. t1/2:** Ligand B (33.74) has a significantly longer in vitro half-life than Ligand A (-10.324). This is a major advantage.

**14. Pgp:** Both ligands have very low P-gp efflux liability (0.039 and 0.058), which is excellent for CNS penetration.

**15. Binding Affinity:** Ligand B (-9.1) has a slightly better binding affinity than Ligand A (-8.0). This difference of 1.1 kcal/mol is significant, and can outweigh some ADME drawbacks.

**Overall Assessment:**

Ligand B has a better binding affinity and a longer half-life. However, Ligand A demonstrates superior properties in terms of DILI risk, BBB penetration, TPSA, and H-bonding characteristics. Given the CNS target (DRD2), BBB penetration and low toxicity (DILI) are crucial. The slightly better affinity of Ligand B is appealing, but the lower DILI and better BBB of Ligand A are more important for a CNS drug. The negative Caco-2 and solubility values are concerning for both, but the other favorable properties of Ligand A make it the slightly more promising candidate.

Output:
0
2025-04-17 08:22:22,506 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (338.411 Da) is slightly lower, which could be beneficial for permeability. Ligand B (370.519 Da) is also good.

**TPSA:** Both ligands have TPSA values below the 90 A^2 threshold desirable for CNS targets. Ligand A (87.04 A^2) is slightly higher than Ligand B (76.46 A^2), giving a slight edge to B.

**logP:** Ligand A (3.762) is at the upper end of the optimal range (1-3), while Ligand B (1.177) is at the lower end. While both are within range, the higher logP of A could potentially lead to off-target effects or solubility issues, but is acceptable.

**H-Bond Donors/Acceptors:** Ligand A has 2 HBD and 4 HBA, while Ligand B has 1 HBD and 6 HBA. Both are within the acceptable limits of <=5 HBD and <=10 HBA.

**QED:** Both ligands have QED values above 0.5 (A: 0.753, B: 0.669), indicating good drug-like properties.

**DILI:** Ligand A (69.911) has a higher DILI risk than Ligand B (30.632). This is a significant advantage for Ligand B.

**BBB:** Ligand A (51.415) has a better BBB percentile than Ligand B (38.891), which is crucial for a CNS target like DRD2.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values, which is unusual and problematic. It suggests poor intestinal absorption. Ligand A (-4.827) is slightly better than Ligand B (-5.108).

**Aqueous Solubility:** Both ligands have very poor aqueous solubility (-5.59 and -1.561 respectively). This is a major concern for both.

**hERG Inhibition:** Ligand A (0.728) has a slightly higher hERG inhibition risk than Ligand B (0.058). This is a significant advantage for Ligand B.

**Microsomal Clearance:** Ligand A (95.637) has higher microsomal clearance than Ligand B (65.797), indicating lower metabolic stability. Ligand B is preferred.

**In vitro Half-Life:** Ligand A (36.882) has a longer half-life than Ligand B (28.598), which is a positive attribute.

**P-gp Efflux:** Ligand A (0.411) has lower P-gp efflux liability than Ligand B (0.029). Lower P-gp efflux is better, especially for CNS targets, giving an edge to A.

**Binding Affinity:** Ligand A (-8.5 kcal/mol) has a significantly stronger binding affinity than Ligand B (-6.4 kcal/mol). This 1.5+ kcal/mol difference is substantial and can outweigh many ADME drawbacks.

**Overall Assessment:**

Ligand A has a significantly better binding affinity and better BBB penetration, and lower P-gp efflux. However, it has higher DILI risk, higher hERG risk, and higher microsomal clearance. Ligand B has better DILI, hERG, and clearance profiles, but significantly weaker binding affinity and lower BBB penetration.

Given the strong emphasis on affinity for GPCRs and the substantial difference in binding energy (-8.5 vs -6.4 kcal/mol), the stronger binding of Ligand A is the most important factor. The other drawbacks of Ligand A, while concerning, might be addressable through further optimization. The weaker affinity of Ligand B is a more difficult hurdle to overcome.

Output:
1
2025-04-17 08:22:22,506 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B based on the provided guidelines, prioritizing GPCR-specific properties (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (352.435 and 344.499 Da) fall within the ideal range of 200-500 Da.

**TPSA:** Ligand A (96.69) is better than Ligand B (49.41). Both are below the 90 A^2 threshold for CNS targets, but A is closer to the upper limit.

**logP:** Ligand B (3.42) is higher than Ligand A (-0.082). While both are within the acceptable range, Ligand B is closer to the optimal 1-3 range, and A is slightly negative which could hinder permeation.

**H-Bond Donors/Acceptors:** Ligand A (2 HBD, 6 HBA) is slightly more favorable than Ligand B (1 HBD, 2 HBA) as it has a higher number of HBA. Both are within acceptable limits.

**QED:** Both ligands have good QED scores (0.682 and 0.795, respectively), indicating good drug-like properties.

**DILI:** Ligand A (24.234) has a significantly lower DILI risk than Ligand B (13.532), which is a major advantage.

**BBB:** Ligand B (76.154) has a much higher BBB penetration percentile than Ligand A (23.11). This is *critical* for a CNS target like DRD2.

**Caco-2 Permeability:** Ligand A (-5.229) has a negative Caco-2 value, which is concerning. Ligand B (-4.82) is also negative, but less so.

**Aqueous Solubility:** Ligand A (-0.647) has slightly better solubility than Ligand B (-3.86).

**hERG Inhibition:** Both ligands have low hERG inhibition liability (0.132 and 0.385, respectively).

**Microsomal Clearance:** Ligand A (6.744) has a much lower microsomal clearance than Ligand B (39.431), indicating better metabolic stability.

**In vitro Half-Life:** Ligand A (3.008) has a positive half-life, while Ligand B (-6.632) has a negative half-life.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.02 and 0.098, respectively).

**Binding Affinity:** Ligand B (-8.9 kcal/mol) has a significantly stronger binding affinity than Ligand A (-7.4 kcal/mol). This is a substantial advantage, exceeding the 1.5 kcal/mol threshold.

**Overall Assessment:**

Ligand B excels in BBB penetration and binding affinity, two crucial factors for a DRD2 ligand. While Ligand A has better DILI and metabolic stability, the superior affinity and BBB of Ligand B outweigh these benefits. The negative Caco-2 values for both are concerning, but the strong binding and CNS penetration potential of Ligand B make it the more promising candidate.

Output:
1
2025-04-17 08:22:22,507 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (352.475 Da) is slightly lower, which could be beneficial for permeability, but both are acceptable.

**2. TPSA:** Ligand A (87.66) is better than Ligand B (62.15) as it is closer to the ideal range for CNS targets (<=90).

**3. logP:** Both ligands have good logP values (Ligand A: 1.386, Ligand B: 3.382), falling within the optimal 1-3 range. Ligand B is slightly higher, which *could* indicate potential off-target effects, but isn't a major concern.

**4. H-Bond Donors:** Ligand A has 3 HBD, which is acceptable. Ligand B has 0, which is also acceptable.

**5. H-Bond Acceptors:** Ligand A has 4 HBA, which is acceptable. Ligand B has 6 HBA, which is also acceptable.

**6. QED:** Both ligands have similar QED values (Ligand A: 0.604, Ligand B: 0.609), indicating good drug-like properties.

**7. DILI:** Ligand B (41.915) has a slightly higher DILI risk than Ligand A (18.922), but both are below the concerning threshold of 60.

**8. BBB:** This is a critical parameter for CNS targets. Ligand B (71.268) has a significantly better BBB percentile than Ligand A (44.203). This is a major advantage for Ligand B.

**9. Caco-2 Permeability:** Both have negative values, indicating poor permeability.

**10. Aqueous Solubility:** Both have negative values, indicating poor solubility.

**11. hERG Inhibition:** Ligand A (0.09) has a lower hERG inhibition liability than Ligand B (0.882), which is preferable.

**12. Microsomal Clearance:** Ligand B (55.847) has higher microsomal clearance than Ligand A (35.882), suggesting lower metabolic stability.

**13. In vitro Half-Life:** Ligand B (50.898) has a much longer in vitro half-life than Ligand A (-6.767). This is a significant advantage for Ligand B.

**14. P-gp Efflux:** Ligand A (0.007) has a lower P-gp efflux liability than Ligand B (0.42), which is preferable for CNS penetration.

**15. Binding Affinity:** Ligand B (-7.4 kcal/mol) has a slightly better binding affinity than Ligand A (-7.1 kcal/mol), although the difference is relatively small.

**Overall Assessment:**

While Ligand A has advantages in TPSA, hERG, and P-gp efflux, Ligand B strongly excels in BBB penetration and in vitro half-life. The improved BBB is *crucial* for a CNS target like DRD2. The slightly better affinity of Ligand B, combined with its longer half-life, further supports its potential. The slightly higher DILI and P-gp efflux of Ligand B are less concerning given the significant advantage in BBB.

Output:
1
2025-04-17 08:22:22,507 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (342.4 and 333.4 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (78.15) is significantly better than Ligand B (105.41). For CNS targets, we want TPSA <= 90, and A is comfortably within that, while B is pushing the limit.

**logP:** Ligand A (0.941) is a bit low, potentially hindering permeability. Ligand B (3.09) is within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A (1 HBD, 6 HBA) is better than Ligand B (2 HBD, 7 HBA). Both are within acceptable ranges, but fewer H-bonds generally improve permeability.

**QED:** Ligand A (0.897) has a better QED score than Ligand B (0.578), indicating a more drug-like profile.

**DILI:** Ligand B (86.39) has a considerably higher DILI risk than Ligand A (62.82). This is a significant negative for B.

**BBB:** Ligand A (73.71) has a much better BBB percentile than Ligand B (29.82). This is *critical* for a CNS target like DRD2.

**Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and difficult to interpret without further context. However, the magnitude of the negative value is similar.

**Aqueous Solubility:** Both have negative solubility values, again unusual. The magnitude is similar.

**hERG:** Ligand A (0.104) has a much lower hERG risk than Ligand B (0.743). This is a significant advantage for A.

**Microsomal Clearance:** Ligand A (40.72) has a higher (worse) microsomal clearance than Ligand B (13.92), suggesting faster metabolism.

**In vitro Half-Life:** Ligand B (-15.56) has a negative half-life, which is impossible. This is a major red flag for B. Ligand A (4.60) is reasonable.

**P-gp Efflux:** Ligand A (0.303) has lower P-gp efflux liability than Ligand B (0.101), which is desirable for CNS penetration.

**Binding Affinity:** Both ligands have very similar and excellent binding affinities (-9.7 and -9.2 kcal/mol). The difference is less than 1.5 kcal/mol, so it's not a deciding factor.

**Overall Assessment:**

Ligand A is significantly better overall. It excels in crucial areas for a CNS-targeting GPCR ligand: TPSA, BBB, DILI, and hERG. While its logP is slightly low and clearance is higher, the substantial advantages in CNS penetration and safety outweigh these drawbacks. Ligand B has a problematic DILI score, poor BBB penetration, a nonsensical half-life, and higher hERG risk.

Output:
0
2025-04-17 08:22:22,507 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (378.881 Da) is slightly higher than Ligand B (349.289 Da), but both are acceptable.

**TPSA:** Ligand A (68.29) is significantly better than Ligand B (78.63). For CNS targets, we want TPSA <= 90, and ideally lower. Ligand A is much closer to the ideal range.

**logP:** Both ligands have good logP values (A: 2.869, B: 2.533), falling within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A (HBD=1, HBA=5) is slightly better than Ligand B (HBD=0, HBA=6) in terms of balancing solubility and permeability.

**QED:** Both have acceptable QED values (A: 0.715, B: 0.623), indicating good drug-like properties.

**DILI:** Ligand A (70.221) has a slightly better DILI score than Ligand B (84.762), indicating lower potential for liver injury. Both are acceptable, but lower is better.

**BBB:** This is a critical parameter for CNS targets. Ligand B (85.731) has a significantly better BBB penetration score than Ligand A (42.924). This is a major advantage for Ligand B.

**Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and suggests poor permeability. However, the scale isn't clearly defined, so it's hard to interpret.

**Aqueous Solubility:** Both have negative solubility values, which is also unusual. Again, the scale is unclear.

**hERG:** Both ligands have low hERG inhibition liability (A: 0.373, B: 0.275), which is good.

**Microsomal Clearance:** Ligand A (91.309) has a lower microsomal clearance than Ligand B (118.049), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (-0.803) has a slightly better in vitro half-life than Ligand B (-34.453).

**P-gp Efflux:** Ligand A (0.135) has lower P-gp efflux liability than Ligand B (0.426), which is favorable for CNS exposure.

**Binding Affinity:** Both ligands have very similar and excellent binding affinities (A: -8.1 kcal/mol, B: -8.2 kcal/mol). The difference is negligible.

**Overall Assessment:**

Ligand B excels in BBB penetration, a crucial factor for a DRD2 ligand targeting CNS disorders. While Ligand A has advantages in TPSA, metabolic stability, and P-gp efflux, the superior BBB score of Ligand B outweighs these benefits. The similar binding affinities make the ADME properties the deciding factor.

Output:
1
2025-04-17 08:22:22,507 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight (MW):** Both ligands (350.478 and 351.466 Da) fall comfortably within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (40.62) is significantly better than Ligand B (58.22). For CNS targets, we want TPSA <= 90, and ideally lower. Ligand A is much closer to the ideal range.

**3. logP:** Both ligands have good logP values (3.344 and 3.713), falling within the optimal 1-3 range.

**4. H-Bond Donors (HBD):** Both ligands are acceptable (0 and 1, respectively), well below the threshold of 5.

**5. H-Bond Acceptors (HBA):** Both ligands are acceptable (2 and 3, respectively), well below the threshold of 10.

**6. QED:** Both ligands have good QED scores (0.689 and 0.738), indicating drug-like properties.

**7. DILI:** Ligand A (19.271) has a slightly higher DILI risk than Ligand B (13.3), but both are below the concerning threshold of 40.

**8. BBB:** Both ligands show excellent BBB penetration (86.972 and 87.864), exceeding the desirable >70 threshold for CNS targets.

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.422 and -4.144). This is unusual and suggests a potential issue with intestinal absorption. However, given the focus on CNS penetration for DRD2, this is less critical than BBB.

**10. Aqueous Solubility:** Both ligands have negative solubility values (-3.548 and -4.324). This is also concerning, but less critical for a CNS target where direct administration or specialized formulations might be considered.

**11. hERG Inhibition:** Both ligands have low hERG inhibition risk (0.587 and 0.689).

**12. Microsomal Clearance (Cl_mic):** Ligand A (54.813) has a significantly lower Cl_mic than Ligand B (86.975), suggesting better metabolic stability.

**13. In vitro Half-Life (t1/2):** Ligand A (5.531) has a better half-life than Ligand B (-35.495). A negative value for ligand B is concerning.

**14. P-gp Efflux:** Both ligands have low P-gp efflux liability (0.154 and 0.137).

**15. Binding Affinity:** Ligand A (-7.8 kcal/mol) has a substantially stronger binding affinity than Ligand B (-6.4 kcal/mol). This difference of 1.4 kcal/mol is significant and can outweigh minor ADME drawbacks.

**Overall Assessment:**

Ligand A is the stronger candidate. While both ligands have acceptable profiles for many parameters, Ligand A excels in TPSA, metabolic stability (Cl_mic), half-life, and, most importantly, binding affinity. The significantly stronger binding affinity of Ligand A (-7.8 vs -6.4 kcal/mol) is a major advantage, especially for a GPCR target. The slightly higher DILI risk is less concerning given the other favorable properties.



Output:
1
2025-04-17 08:22:22,508 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (364.917 and 346.471 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (43.78) is significantly better than Ligand B (58.64). For CNS targets, we want TPSA <= 90, and ideally closer to 60. Ligand A is much closer to this ideal.

**3. logP:** Both ligands have good logP values (3.065 and 2.732), falling within the optimal 1-3 range.

**4. H-Bond Donors:** Both have 1 HBD, which is acceptable.

**5. H-Bond Acceptors:** Both have 3 HBA, which is acceptable.

**6. QED:** Both have reasonable QED scores (0.892 and 0.787), indicating good drug-like properties.

**7. DILI:** Ligand A (13.3) has a much lower DILI risk than Ligand B (29.081). Both are below the 40 threshold, but A is preferable.

**8. BBB:** Ligand B (75.727) has a better BBB penetration percentile than Ligand A (68.282). While both are reasonably good, B is better here. This is a crucial factor for a CNS target like DRD2.

**9. Caco-2 Permeability:** Both have negative Caco-2 values (-4.907 and -4.671), which is unusual and suggests poor permeability. This is a significant concern for both.

**10. Aqueous Solubility:** Both have negative solubility values (-2.38 and -2.771), which is also concerning and suggests poor solubility.

**11. hERG Inhibition:** Both ligands show low hERG inhibition liability (0.869 and 0.714), which is good.

**12. Microsomal Clearance:** Ligand B (70.533) has a higher microsomal clearance than Ligand A (31.147), indicating faster metabolism and lower metabolic stability. A is preferable.

**13. In vitro Half-Life:** Ligand A (25.903) has a longer in vitro half-life than Ligand B (19.253), which is desirable.

**14. P-gp Efflux:** Ligand A (0.598) has lower P-gp efflux than Ligand B (0.206), meaning it's less likely to be pumped out of the brain, improving CNS exposure.

**15. Binding Affinity:** Ligand B (-8.2 kcal/mol) has a slightly better binding affinity than Ligand A (-7.5 kcal/mol). This is a 0.7 kcal/mol difference, which is significant, but not overwhelming.

**Overall Assessment:**

While Ligand B has a slightly better binding affinity and BBB penetration, Ligand A is superior in most other critical ADME properties. Specifically, Ligand A has a much lower DILI risk, better metabolic stability (lower Cl_mic, longer t1/2), and lower P-gp efflux. The poor Caco-2 and solubility for both are concerning, but can be addressed with formulation strategies. Given the GPCR-specific priorities, the improved ADME profile of Ligand A, particularly the lower DILI and better metabolic stability, outweigh the slightly better affinity and BBB of Ligand B.

Output:
1
2025-04-17 08:22:22,508 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (371.463 Da) is slightly higher than Ligand B (340.471 Da), but both are acceptable.

**TPSA:** Ligand A (122.19) is borderline for CNS penetration, being slightly above the preferred <90. Ligand B (51.02) is excellent, well below the threshold.

**logP:** Ligand A (-0.109) is quite low, potentially hindering membrane permeability. Ligand B (3.735) is optimal.

**H-Bond Donors/Acceptors:** Ligand A has 3 HBD and 6 HBA, which are acceptable. Ligand B has 0 HBD and 4 HBA, also acceptable.

**QED:** Both ligands have good QED scores (A: 0.589, B: 0.833), indicating drug-like properties. Ligand B is better.

**DILI:** Ligand A (59.829) has a moderate DILI risk, while Ligand B (31.912) has a low risk.

**BBB:** Ligand A (58.085) has a moderate BBB penetration, while Ligand B (74.564) is very good, exceeding the desirable >70 threshold for CNS targets. This is a significant advantage for Ligand B.

**Caco-2 Permeability:** Both are negative, indicating poor permeability. Ligand A (-5.538) is worse than Ligand B (-4.737).

**Aqueous Solubility:** Both have negative solubility values, indicating poor solubility. Ligand A (-2.097) is slightly better than Ligand B (-4.14).

**hERG:** Both ligands have low hERG risk (A: 0.121, B: 0.358).

**Microsomal Clearance:** Ligand A (8.297) has lower clearance, suggesting better metabolic stability than Ligand B (77.589).

**In vitro Half-Life:** Ligand B (-10.769) has a longer half-life than Ligand A (-6.965).

**P-gp Efflux:** Ligand A (0.016) has very low P-gp efflux, which is highly desirable for CNS penetration. Ligand B (0.331) has moderate P-gp efflux.

**Binding Affinity:** Ligand B (-9.6 kcal/mol) has a significantly stronger binding affinity than Ligand A (-7.8 kcal/mol). This >1.5 kcal/mol difference is substantial and can outweigh some ADME drawbacks.

**Overall Assessment:**

Ligand B is the stronger candidate. While Ligand A has better metabolic stability and P-gp efflux, Ligand B excels in crucial areas for a CNS-targeting GPCR ligand: significantly higher binding affinity, excellent BBB penetration, optimal logP, and lower DILI risk. The superior affinity and BBB penetration are particularly important, outweighing the slightly higher P-gp efflux and lower metabolic stability. The TPSA is also much more favorable for CNS penetration.

Output:
1
2025-04-17 08:22:22,508 - INFO - Batch 443 complete. Total preferences: 7088
2025-04-17 08:22:22,508 - INFO - Processing batch 444/512...
2025-04-17 08:23:03,611 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (352.308 and 359.491 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (44.76) is significantly better than Ligand B (49.77). Both are below the 90 A^2 threshold desirable for CNS targets, but A is closer to optimal.

**3. logP:** Ligand A (4.269) is slightly higher than the optimal range (1-3), but still potentially acceptable. Ligand B (3.679) is within the optimal range.

**4. H-Bond Donors:** Ligand A (0) is preferable to Ligand B (1) as fewer HBDs generally improve permeability.

**5. H-Bond Acceptors:** Both ligands have 4 HBA, which is acceptable (<=10).

**6. QED:** Both ligands have good QED scores (0.771 and 0.856), indicating good drug-like properties.

**7. DILI:** Ligand A (86.623) has a higher DILI risk than Ligand B (46.219). This is a significant drawback for Ligand A.

**8. BBB:** Ligand A (84.529) has a slightly better BBB penetration percentile than Ligand B (70.997). Both are above the 70% threshold for CNS targets, but A is better.

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.296 and -4.8), which is unusual and suggests poor permeability. This is a concern for both.

**10. Aqueous Solubility:** Both ligands have negative solubility values (-5.294 and -3.847), indicating very poor aqueous solubility. This is a major issue for both.

**11. hERG Inhibition:** Both ligands have low hERG inhibition risk (0.634 and 0.776).

**12. Microsomal Clearance:** Ligand B (84.384) has higher microsomal clearance than Ligand A (55.364), suggesting lower metabolic stability.

**13. In vitro Half-Life:** Ligand B (46.45) has a much longer in vitro half-life than Ligand A (-1.255). This is a significant advantage for Ligand B.

**14. P-gp Efflux:** Both ligands have low P-gp efflux liability (0.755 and 0.879).

**15. Binding Affinity:** Ligand A (-9.1 kcal/mol) has a significantly stronger binding affinity than Ligand B (-8.0 kcal/mol). This is a substantial advantage for Ligand A, potentially outweighing some of its other drawbacks.

**Overall Assessment:**

Ligand A has a superior binding affinity and slightly better BBB penetration and TPSA. However, it has a significantly higher DILI risk, poorer metabolic stability (higher Cl_mic, shorter half-life), and negative solubility and Caco-2 values. Ligand B has a lower DILI risk, better metabolic stability, and a longer half-life, but its binding affinity is weaker and TPSA is slightly higher.

Given the GPCR-specific priorities and the substantial difference in binding affinity, the stronger binding of Ligand A is a critical factor. While the DILI risk is concerning, it might be mitigated through structural modifications. The poor solubility and permeability are shared issues that would need to be addressed for either compound. The longer half-life of Ligand B is attractive, but a potent drug with a shorter half-life can often be optimized.

Output:
1
2025-04-17 08:23:03,611 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (340.427 and 361.877 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (50.6) is significantly better than Ligand B (64.86). For CNS targets, we want TPSA <= 90, and A is much closer to the ideal <= 60 range. B is pushing the upper limit.

**3. logP:** Ligand A (1.796) is within the optimal range (1-3). Ligand B (3.122) is at the higher end, potentially leading to solubility issues, but still acceptable.

**4. H-Bond Donors:** Ligand A (0) is preferable to Ligand B (1). Fewer HBDs generally improve permeability.

**5. H-Bond Acceptors:** Ligand A (5) is better than Ligand B (6). Both are within the acceptable limit of <=10.

**6. QED:** Ligand A (0.852) has a better QED score than Ligand B (0.767), indicating a more drug-like profile.

**7. DILI:** Ligand A (29.042) has a significantly lower DILI risk than Ligand B (47.383). Both are below the 60 threshold, but A is much safer.

**8. BBB:** Ligand A (86.274) has a much better BBB penetration prediction than Ligand B (76.231). For a CNS target like DRD2, >70 is desirable, and A is closer.

**9. Caco-2 Permeability:** Ligand A (-4.541) and Ligand B (-4.767) both have negative values, which is unusual and suggests poor permeability. However, the scale isn't specified, so it's hard to interpret.

**10. Aqueous Solubility:** Ligand A (-1.739) has better solubility than Ligand B (-4.102).

**11. hERG Inhibition:** Ligand A (0.92) has a lower hERG inhibition risk than Ligand B (0.139). This is a significant advantage for A.

**12. Microsomal Clearance:** Ligand A (61.433) has higher microsomal clearance than Ligand B (48.982), meaning it's less metabolically stable. B is preferable here.

**13. In vitro Half-Life:** Ligand A (-6.912) has a much longer in vitro half-life than Ligand B (-18.437). This is a major advantage for A.

**14. P-gp Efflux:** Ligand A (0.508) has lower P-gp efflux than Ligand B (0.247), which is good for CNS exposure.

**15. Binding Affinity:** Ligand B (-7.0) has a slightly better binding affinity than Ligand A (-8.5). However, the difference is not substantial enough to outweigh the numerous advantages of Ligand A.

**Overall Assessment:**

Ligand A is the superior candidate. It excels in crucial properties for a CNS-targeting GPCR ligand: TPSA, BBB penetration, DILI risk, hERG inhibition, solubility, QED, and half-life. While Ligand B has slightly better affinity and metabolic stability, the significant advantages of Ligand A in ADME properties, particularly BBB and safety, make it the more promising drug candidate.

Output:
1
2025-04-17 08:23:03,612 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (352.381 and 355.494 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (69.64) is better than Ligand B (46.61). For CNS targets, we want TPSA <= 90, both are well within this range, but lower is generally preferred.

**3. logP:** Ligand A (1.847) is within the optimal 1-3 range. Ligand B (3.835) is pushing the upper limit, potentially leading to solubility issues.

**4. H-Bond Donors:** Ligand A (2) is acceptable. Ligand B (0) is also acceptable, but could potentially impact aqueous solubility.

**5. H-Bond Acceptors:** Both ligands have 3 HBA, which is well within the acceptable limit of <=10.

**6. QED:** Ligand A (0.85) is excellent, indicating high drug-likeness. Ligand B (0.652) is still reasonably good, but lower than A.

**7. DILI:** Ligand A (40.054) is good, indicating low liver injury risk. Ligand B (27.608) is even better.

**8. BBB:** This is critical for a CNS target like DRD2. Ligand A (63.862) is okay, but Ligand B (93.912) is *excellent*, exceeding the desirable >70 threshold. This is a significant advantage for B.

**9. Caco-2 Permeability:** Both have negative values, which is unusual. However, the magnitude of Ligand A (-4.783) is worse than Ligand B (-3.992), suggesting lower intestinal absorption for A.

**10. Aqueous Solubility:** Both have negative values, which is also unusual. Ligand A (-2.693) is worse than Ligand B (-4.392), suggesting lower aqueous solubility for A.

**11. hERG Inhibition:** Both ligands show low hERG inhibition risk (0.665 and 0.68 respectively).

**12. Microsomal Clearance:** Ligand A (16.033) has lower clearance than Ligand B (118.04), indicating better metabolic stability. This is a positive for A.

**13. In vitro Half-Life:** Ligand A (36.512) has a longer half-life than Ligand B (-4.738), which is a positive for A.

**14. P-gp Efflux:** Ligand A (0.069) shows very low P-gp efflux, which is desirable for CNS penetration. Ligand B (0.462) is slightly higher, but still relatively low.

**15. Binding Affinity:** Ligand B (-7.1 kcal/mol) has a significantly stronger binding affinity than Ligand A (-9.0 kcal/mol). This difference of 1.9 kcal/mol is substantial and can outweigh some ADME drawbacks.

**Overall Assessment:**

Ligand B excels in the most critical areas for a CNS-targeting GPCR ligand: **BBB penetration and binding affinity**. While Ligand A has better metabolic stability and half-life, the superior BBB and affinity of Ligand B are more important. The slightly higher logP of B is a minor concern, but the strong affinity and excellent BBB penetration are likely to compensate.

Output:
1
2025-04-17 08:23:03,612 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (339.4) is slightly better, being closer to the lower end which can aid permeability.

**TPSA:** Ligand A (84.83) is excellent, falling well below the 90 A^2 threshold for CNS targets. Ligand B (107.94) is still reasonable but less optimal.

**logP:** Ligand A (2.459) is within the optimal range (1-3). Ligand B (0.209) is quite low, potentially hindering permeability and CNS penetration.

**H-Bond Donors/Acceptors:** Both ligands have 2 HBD and 5-6 HBA, which are acceptable.

**QED:** Both ligands have QED values above 0.6, indicating good drug-likeness.

**DILI:** Ligand A (77.2) has a higher DILI risk than Ligand B (59.9), but both are acceptable.

**BBB:** Ligand A (68.592) is better than Ligand B (61.38), but both are below the desirable >70 percentile for CNS targets. This is a concern for both, but less so for A.

**Caco-2 Permeability:** Ligand A (-5.003) and Ligand B (-5.368) have negative values, suggesting poor permeability. This is a significant drawback for both.

**Aqueous Solubility:** Both ligands have very poor aqueous solubility (-4.655 and -3.075 respectively). This could pose formulation challenges.

**hERG Inhibition:** Both ligands show low hERG inhibition risk (0.595 and 0.157).

**Microsomal Clearance:** Ligand A (25.55) has lower microsomal clearance than Ligand B (33.193), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (1.918) has a slightly better in vitro half-life than Ligand B (-16.241).

**P-gp Efflux:** Ligand A (0.226) has lower P-gp efflux than Ligand B (0.031), which is beneficial for CNS penetration.

**Binding Affinity:** Ligand A (-10.1 kcal/mol) has significantly stronger binding affinity than Ligand B (-7.7 kcal/mol). This is a substantial advantage, potentially outweighing some of the ADME drawbacks. The difference is >1.5 kcal/mol.

**Overall Assessment:**

Ligand A is the better candidate. While both have issues with Caco-2 permeability and solubility, Ligand A's superior binding affinity, better BBB penetration, lower P-gp efflux, and improved metabolic stability make it more likely to succeed. The stronger binding affinity is a key factor, especially for a GPCR target. Ligand B's low logP is a major concern, as it will likely limit its ability to cross the blood-brain barrier effectively.

Output:
1
2025-04-17 08:23:03,612 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (364.511 Da) is slightly preferred due to being lower in weight.

**TPSA:** Both ligands have TPSA values below 140, suggesting reasonable oral absorption. However, for a CNS target like DRD2, we want TPSA < 90. Ligand A (49.85) is significantly better than Ligand B (43.86) in this regard.

**logP:** Both ligands have logP values between 1 and 3 (Ligand A: 2.903, Ligand B: 3.471), which is optimal. No clear preference here.

**H-Bond Donors/Acceptors:** Both ligands have reasonable HBD (0) and HBA (4/5) counts, falling within the acceptable ranges.

**QED:** Both ligands have QED values above 0.5 (A: 0.747, B: 0.604), indicating good drug-like properties. Ligand A is slightly better.

**DILI:** Ligand A (13.571) has a much lower DILI risk than Ligand B (65.801). This is a significant advantage for Ligand A.

**BBB:** Both ligands have high BBB penetration (Ligand A: 87.67, Ligand B: 85.072), which is crucial for CNS targets. Ligand A has a slight edge.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values, which is unusual and indicates poor permeability. However, the values are similar (-4.676 for A, -4.818 for B).

**Aqueous Solubility:** Both ligands have negative solubility values, indicating very poor solubility. This is a significant drawback for both. Ligand B is slightly worse (-4.534 vs -2.604).

**hERG Inhibition:** Both ligands have low hERG inhibition risk (Ligand A: 0.55, Ligand B: 0.952). Ligand A is better.

**Microsomal Clearance:** Ligand A (49.889) has a lower microsomal clearance than Ligand B (52.396), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (26.645 hours) has a significantly longer in vitro half-life than Ligand B (-35.797 hours). This is a major advantage for Ligand A.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (Ligand A: 0.125, Ligand B: 0.566). Ligand A is better.

**Binding Affinity:** Ligand B (-8.8 kcal/mol) has a stronger binding affinity than Ligand A (-6.6 kcal/mol). This is a substantial advantage for Ligand B, potentially outweighing some of its ADME drawbacks. The difference is >1.5 kcal/mol.

**Overall Assessment:**

While Ligand B has a significantly better binding affinity, Ligand A demonstrates superior ADME properties, particularly regarding DILI risk, BBB penetration, metabolic stability (lower Cl_mic, longer t1/2), and P-gp efflux. The poor solubility of both compounds is a concern, but can potentially be addressed with formulation strategies. Given the GPCR-specific priorities, and the substantial difference in DILI risk, I believe the more favorable ADME profile of Ligand A, combined with its acceptable affinity, makes it the more promising drug candidate. The affinity difference, while significant, might be overcome with further optimization of Ligand A.

Output:
0
2025-04-17 08:23:03,612 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (347.434 Da) is slightly lower, which could be beneficial for permeability, but both are acceptable.

**TPSA:** Ligand A (71.09) is significantly better than Ligand B (59). For a CNS target like DRD2, a TPSA below 90 is desirable, and Ligand A is closer to the optimal range of below 60.

**logP:** Ligand A (2.407) is within the optimal range (1-3), while Ligand B (4.004) is pushing the upper limit. Higher logP can lead to solubility issues and off-target interactions.

**H-Bond Donors/Acceptors:** Ligand A (HBD=2, HBA=3) and Ligand B (HBD=1, HBA=4) both have reasonable numbers of H-bond donors and acceptors, falling within the guidelines.

**QED:** Both ligands have acceptable QED values (Ligand A: 0.83, Ligand B: 0.675), indicating good drug-like properties.

**DILI:** Ligand A (35.983) has a much lower DILI risk than Ligand B (16.053), which is a significant advantage.

**BBB:** Ligand A (79.256) has a much better BBB penetration score than Ligand B (50.523). This is *critical* for a CNS target like DRD2.

**Caco-2 Permeability:** Ligand A (-4.743) and Ligand B (-4.896) both have negative Caco-2 permeability values, which is unusual and suggests poor intestinal absorption. However, for a CNS target, intestinal absorption is less critical than BBB penetration.

**Aqueous Solubility:** Ligand A (-2.925) and Ligand B (-3.69) both have poor aqueous solubility.

**hERG Inhibition:** Both ligands show low hERG inhibition risk (Ligand A: 0.473, Ligand B: 0.64).

**Microsomal Clearance:** Ligand B (99.862) has a much higher microsomal clearance than Ligand A (13.824), indicating faster metabolism and potentially lower in vivo exposure.

**In vitro Half-Life:** Ligand B (52.104) has a longer half-life than Ligand A (-1.007), which is generally desirable.

**P-gp Efflux:** Ligand A (0.115) has a lower P-gp efflux liability than Ligand B (0.238), which is beneficial for CNS exposure.

**Binding Affinity:** Ligand A (-9.1 kcal/mol) has a significantly stronger binding affinity than Ligand B (-6.7 kcal/mol). This difference of 2.4 kcal/mol is substantial and can outweigh minor ADME drawbacks.

**Conclusion:**

Considering all factors, especially the GPCR-specific priorities for DRD2 (BBB, logP, Pgp, TPSA, and affinity), **Ligand A is the more promising drug candidate.** Its superior BBB penetration, lower DILI risk, lower P-gp efflux, and significantly stronger binding affinity outweigh its slightly poorer solubility and Caco-2 permeability. The lower metabolic clearance is also a positive attribute.

Output:
0
2025-04-17 08:23:03,613 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (338.411 Da) is slightly lower, which could be beneficial for permeability.

**TPSA:** Ligand A (87.04) is excellent for CNS penetration, being well below 90. Ligand B (104.73) is still reasonable but less optimal.

**logP:** Ligand A (3.762) is within the optimal range (1-3), while Ligand B (0.348) is quite low, potentially hindering membrane permeability and CNS entry.

**H-Bond Donors/Acceptors:** Ligand A (HBD=2, HBA=4) and Ligand B (HBD=3, HBA=5) both have acceptable numbers of H-bond donors and acceptors.

**QED:** Ligand A (0.753) has a better QED score than Ligand B (0.47), indicating a more drug-like profile.

**DILI:** Ligand A (69.911) has a lower DILI risk than Ligand B (22.218), suggesting better hepatotoxicity potential.

**BBB:** Ligand A (51.415) has a moderate BBB penetration, while Ligand B (67.352) is better, exceeding 70%, which is desirable for CNS targets.

**Caco-2 Permeability:** Ligand A (-4.827) has poor Caco-2 permeability, while Ligand B (-5.028) is also poor.

**Aqueous Solubility:** Ligand A (-5.59) and Ligand B (-1.968) both have poor aqueous solubility.

**hERG Inhibition:** Ligand A (0.728) has a lower hERG inhibition risk than Ligand B (0.29), which is preferable.

**Microsomal Clearance:** Ligand A (95.637) has higher microsomal clearance than Ligand B (31.331), suggesting lower metabolic stability.

**In vitro Half-Life:** Ligand B (19.634) has a longer in vitro half-life than Ligand A (36.882).

**P-gp Efflux:** Ligand A (0.411) has lower P-gp efflux liability than Ligand B (0.018), which is beneficial for CNS exposure.

**Binding Affinity:** Ligand B (-7.6 kcal/mol) has a significantly better binding affinity than Ligand A (-8.5 kcal/mol). This is a substantial advantage.

**Overall Assessment:**

Ligand B has a significantly better binding affinity, which is the most crucial factor. While it suffers from a low logP and poor solubility, the strong binding could potentially overcome these issues with appropriate formulation strategies. Ligand A has better TPSA, DILI, hERG, and P-gp efflux, but its weaker binding affinity is a major drawback. Considering the GPCR-specific priorities and the importance of potency, Ligand B is the more promising candidate.

Output:
1
2025-04-17 08:23:03,613 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (360.523 and 344.543 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (53.33) is higher than Ligand B (32.34). For a CNS target like DRD2, TPSA should be <=90, so both are acceptable, but B is significantly better.

**3. logP:** Both ligands have logP values (4.148 and 4.402) slightly above the optimal range of 1-3, but not drastically so. This could potentially lead to some solubility issues, but isn't a dealbreaker.

**4. H-Bond Donors:** Ligand A has 0 HBD, while Ligand B has 1. Both are within the acceptable limit of <=5.

**5. H-Bond Acceptors:** Ligand A has 4 HBA, and Ligand B has 2. Both are within the acceptable limit of <=10.

**6. QED:** Both ligands have similar QED values (0.766 and 0.72), indicating good drug-like properties.

**7. DILI:** Ligand A (20.667) has a much lower DILI risk than Ligand B (12.136), indicating a safer profile.

**8. BBB:** Both ligands have excellent BBB penetration (83.172 and 83.482), exceeding the desirable >70 threshold for CNS targets.

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.878 and -4.495). This is unusual and suggests poor permeability. However, Caco-2 values can be unreliable and are often less predictive than other parameters.

**10. Aqueous Solubility:** Both ligands have negative solubility values (-3.701 and -4.408), indicating very poor aqueous solubility. This is a significant concern.

**11. hERG Inhibition:** Both ligands have low hERG inhibition risk (0.668 and 0.793).

**12. Microsomal Clearance:** Ligand A (77.032) has lower microsomal clearance than Ligand B (110.426), suggesting better metabolic stability.

**13. In vitro Half-Life:** Ligand A (4.665) has a shorter in vitro half-life than Ligand B (39.733), which is less desirable.

**14. P-gp Efflux:** Both ligands have low P-gp efflux liability (0.627 and 0.585), which is good for CNS penetration.

**15. Binding Affinity:** Both ligands have very similar and excellent binding affinities (-7.8 and -7.9 kcal/mol). The difference is negligible.

**Overall Assessment:**

While both ligands have excellent binding affinity and BBB penetration, Ligand A is preferable due to its significantly lower DILI risk and better metabolic stability (lower Cl_mic). Ligand B has a longer half-life, but the DILI risk is a major concern. The poor solubility and Caco-2 permeability are drawbacks for both, but might be addressed with formulation strategies. Considering the GPCR-specific priorities, the lower DILI and better metabolic stability of Ligand A make it the more promising candidate.

Output:
0
2025-04-17 08:23:03,613 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (350.507 and 352.391 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (58.44) is excellent, well below the 90 A^2 threshold for CNS targets. Ligand B (122.41) is higher, but still potentially acceptable, though less ideal.

**logP:** Ligand A (2.425) is optimal (1-3). Ligand B (0.276) is quite low, potentially hindering membrane permeability and CNS penetration.

**H-Bond Donors/Acceptors:** Ligand A (0 HBD, 4 HBA) is favorable. Ligand B (3 HBD, 6 HBA) is also reasonable.

**QED:** Ligand A (0.723) has a strong drug-like profile. Ligand B (0.478) is lower, suggesting a less optimal overall profile.

**DILI:** Ligand A (29.042) has a very low DILI risk. Ligand B (79.643) has a significantly higher DILI risk, which is concerning.

**BBB:** Ligand A (64.986) has a good BBB percentile. Ligand B (50.679) is lower, indicating reduced CNS penetration potential.

**Caco-2 Permeability:** Ligand A (-4.519) is problematic, indicating poor permeability. Ligand B (-5.228) is also poor, but slightly worse.

**Aqueous Solubility:** Ligand A (-1.915) is poor. Ligand B (-3.058) is even worse.

**hERG:** Both ligands have very low hERG risk (0.312 and 0.054).

**Microsomal Clearance:** Ligand A (73.597) has moderate clearance. Ligand B (51.345) has lower clearance, suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (33.856 hours) has a reasonable half-life. Ligand B (-26.864 hours) has a negative half-life, which is not physically possible and indicates a significant issue with the data or the molecule's stability.

**P-gp Efflux:** Ligand A (0.127) has low P-gp efflux, which is good for CNS penetration. Ligand B (0.033) has even lower P-gp efflux, which is also good.

**Binding Affinity:** Ligand B (-8.3 kcal/mol) has a significantly stronger binding affinity than Ligand A (-7.6 kcal/mol). This is a substantial difference.

**Overall Assessment:**

Ligand B has a much stronger binding affinity, which is a major advantage. However, it suffers from a low logP, high DILI risk, poor solubility, and an impossible half-life value. Ligand A has better ADME properties (BBB, DILI, logP, half-life), but its binding affinity is weaker and Caco-2 permeability is poor.

Given the importance of CNS penetration for a DRD2 ligand (targeting CNS disorders), and the significant ADME liabilities of Ligand B, I would favor Ligand A despite its lower affinity. The poor Caco-2 and solubility of Ligand A could potentially be addressed through formulation strategies or further chemical modifications. The issues with Ligand B are more fundamental and harder to overcome.

Output:
0
2025-04-17 08:23:03,613 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (341.459 and 365.88 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (54.26) is significantly better than Ligand B (38.25). For a CNS target like DRD2, a TPSA <= 90 is preferred, and A is much closer to this threshold.

**3. logP:** Ligand A (2.226) is within the optimal 1-3 range. Ligand B (4.587) is higher, potentially leading to solubility issues and off-target interactions.

**4. H-Bond Donors:** Both have 0 HBD, which is acceptable.

**5. H-Bond Acceptors:** Ligand A has 5, and Ligand B has 4, both within the acceptable limit of <=10.

**6. QED:** Ligand A (0.837) has a better QED score than Ligand B (0.651), indicating a more drug-like profile.

**7. DILI:** Ligand A (25.824) has a lower DILI risk than Ligand B (35.983), which is desirable.

**8. BBB:** Ligand B (80.729) has a significantly better BBB penetration percentile than Ligand A (72.005). This is a critical factor for CNS targets.

**9. Caco-2 Permeability:** Ligand A (-4.649) and Ligand B (-4.543) both have negative values, which is unusual. Assuming these are percentile scores, lower values suggest poor permeability.

**10. Aqueous Solubility:** Ligand A (-1.024) has better solubility than Ligand B (-4.609).

**11. hERG Inhibition:** Ligand A (0.399) has a lower hERG inhibition liability than Ligand B (0.931), which is preferable.

**12. Microsomal Clearance:** Ligand A (0.489) has much lower microsomal clearance than Ligand B (100.388), suggesting better metabolic stability.

**13. In vitro Half-Life:** Ligand B (31.809) has a longer in vitro half-life than Ligand A (17.619), which is a positive attribute.

**14. P-gp Efflux:** Ligand A (0.076) has significantly lower P-gp efflux liability than Ligand B (0.612), which is crucial for CNS exposure.

**15. Binding Affinity:** Ligand B (-7.0) has a slightly better binding affinity than Ligand A (-9.0). However, the difference is not substantial enough to outweigh the numerous ADME advantages of Ligand A.

**Overall Assessment:**

While Ligand B has a better BBB score and binding affinity, Ligand A demonstrates superior drug-like properties across most ADME parameters. Specifically, its lower TPSA, better logP, lower DILI, better solubility, lower hERG risk, lower clearance, and lower P-gp efflux are all highly favorable, especially for a CNS-targeting GPCR like DRD2. The slight advantage in binding affinity of Ligand B is unlikely to compensate for the significant ADME liabilities.

Output:
0
2025-04-17 08:23:03,613 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B based on the provided guidelines, prioritizing GPCR-specific properties (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (346.515 and 350.463 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (41.57) is significantly better than Ligand B (87.46). For CNS targets, TPSA should be <= 90, and ideally lower. Ligand A is well within this range, while Ligand B is approaching the upper limit and is less favorable.

**logP:** Ligand A (4.158) is slightly high, potentially leading to solubility issues, but still within a reasonable range. Ligand B (1.246) is quite low, which could hinder membrane permeability and CNS penetration.

**H-Bond Donors/Acceptors:** Ligand A (HBD=1, HBA=3) is preferable to Ligand B (HBD=2, HBA=5) as it has fewer hydrogen bonding groups, potentially improving permeability. Both are within acceptable limits.

**QED:** Both ligands have reasonable QED values (0.87 and 0.739), indicating good drug-like properties.

**DILI:** Ligand A (13.3) has a much lower DILI risk than Ligand B (32.299), making it safer from a liver toxicity perspective.

**BBB:** This is critical for a CNS target like DRD2. Ligand A (93.874) has excellent BBB penetration, exceeding the desirable >70 threshold. Ligand B (54.634) is significantly lower and less favorable.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values, which is unusual and suggests either experimental error or a complex permeability profile. We'll proceed cautiously with this data point.

**Aqueous Solubility:** Both ligands have negative solubility values, which is also unusual.

**hERG Inhibition:** Ligand A (0.934) has a slightly higher hERG risk than Ligand B (0.192), but both are relatively low.

**Microsomal Clearance:** Ligand A (30.693) has a higher microsomal clearance than Ligand B (12.831), indicating faster metabolism and potentially lower exposure.

**In vitro Half-Life:** Ligand B (12.018 hours) has a longer in vitro half-life than Ligand A (6.963 hours), which is generally desirable.

**P-gp Efflux:** Ligand A (0.418) has lower P-gp efflux liability than Ligand B (0.052), which is favorable for CNS penetration.

**Binding Affinity:** Ligand A (-8.7 kcal/mol) has a significantly stronger binding affinity than Ligand B (-7.7 kcal/mol). This 1 kcal/mol difference is substantial and can outweigh some ADME drawbacks.

**Overall Assessment:**

Ligand A is the stronger candidate. While its logP is slightly elevated and clearance is higher, its superior BBB penetration, lower DILI risk, significantly better binding affinity, and favorable TPSA and P-gp efflux profile make it a more promising drug candidate for targeting DRD2. Ligand B's low logP and poor BBB penetration are major drawbacks for a CNS-targeted GPCR.



Output:
1
2025-04-17 08:23:03,614 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B based on the provided guidelines, prioritizing GPCR-specific properties (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (370.362 and 355.454 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (58.2) is excellent for CNS penetration, well below the 90 A^2 threshold. Ligand B (64.09) is still reasonable, but less optimal.

**logP:** Ligand A (3.021) is within the optimal 1-3 range. Ligand B (0.498) is quite low, potentially hindering membrane permeability and CNS entry.

**H-Bond Donors/Acceptors:** Ligand A (2 HBD, 2 HBA) and Ligand B (1 HBD, 4 HBA) both have acceptable numbers of H-bond donors and acceptors.

**QED:** Both ligands have good QED scores (0.731 and 0.801), indicating drug-like properties.

**DILI:** Ligand A (34.471) has a very low DILI risk, significantly better than Ligand B (8.414), which is still acceptable but higher.

**BBB:** Ligand A (88.29) has excellent BBB penetration potential. Ligand B (57.464) is considerably lower, raising concerns about CNS exposure. This is a critical factor for a DRD2 ligand.

**Caco-2 Permeability:** Both have negative Caco-2 values which is unusual and suggests a potential issue with the data. However, we can still compare the relative values. Ligand A (-4.66) is better than Ligand B (-4.887).

**Aqueous Solubility:** Both ligands have negative solubility values, which is also unusual. Ligand A (-3.478) is better than Ligand B (-0.642).

**hERG:** Both ligands have low hERG inhibition liability (0.535 and 0.505).

**Microsomal Clearance:** Ligand A (23.899) has a lower microsomal clearance, indicating better metabolic stability than Ligand B (-40.341).

**In vitro Half-Life:** Ligand A (-19.156) has a longer in vitro half-life than Ligand B (5.624).

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.026 and 0.018).

**Binding Affinity:** Both ligands have similar, strong binding affinities (-9.4 and -8.5 kcal/mol). The difference of 0.9 kcal/mol is not substantial enough to override the ADME differences.

**Conclusion:**

Considering the GPCR-specific priorities, Ligand A is significantly more promising. Its superior BBB penetration, better logP, lower DILI risk, better metabolic stability, and longer half-life outweigh the slightly lower Caco-2 and solubility values. While both have good affinity, the improved ADME profile of Ligand A makes it a more viable drug candidate for targeting DRD2 in the CNS.

Output:
1
2025-04-17 08:23:03,614 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (345.443 and 352.431 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (78.51) is significantly better than Ligand B (104.73). For CNS targets, we want TPSA <= 90, and A is comfortably within that, while B is pushing the limit.

**logP:** Ligand A (1.712) is optimal (1-3), while Ligand B (0.668) is a bit low, potentially hindering permeability.

**H-Bond Donors/Acceptors:** Ligand A (HBD=2, HBA=3) and Ligand B (HBD=3, HBA=5) both have reasonable numbers of H-bond donors and acceptors, well within the guidelines.

**QED:** Ligand A (0.753) has a better QED score than Ligand B (0.44), indicating a more drug-like profile.

**DILI:** Ligand A (42.497) has a lower DILI risk than Ligand B (29.779), both are good, but A is slightly better.

**BBB:** This is crucial for a CNS target like DRD2. Ligand A (59.946) is better than Ligand B (17.022), although ideally we'd like >70. However, A is significantly higher, making it more likely to cross the BBB.

**Caco-2 Permeability:** Both have negative values (-5.003 and -5.341). These are percentile scores, so lower values are worse. Ligand A is slightly better here.

**Aqueous Solubility:** Both have negative values (-2.602 and -1.502). These are percentile scores, so lower values are worse. Ligand B is slightly better here.

**hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.207 and 0.047).

**Microsomal Clearance:** Both have negative clearance values (-4.434 and -4.841), indicating good metabolic stability. Ligand B is slightly better.

**In vitro Half-Life:** Ligand A (7.588) has a longer half-life than Ligand B (1.864), which is desirable.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.038 and 0.022).

**Binding Affinity:** Ligand B (-8.8 kcal/mol) has a stronger binding affinity than Ligand A (-7.7 kcal/mol). This is a significant advantage (1.1 kcal/mol difference).

**Overall Assessment:**

While Ligand B has a superior binding affinity, Ligand A has a much more favorable profile regarding CNS penetration (BBB, TPSA, logP). The stronger binding of Ligand B is attractive, but the poor BBB penetration significantly reduces its potential as a CNS drug. Ligand A strikes a better balance between potency and pharmacokinetic properties crucial for a CNS-active DRD2 ligand.

Output:
0
2025-04-17 08:23:03,614 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (349.431 and 361.442 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (95.67) is better than Ligand B (62.39). For CNS targets, we want TPSA <= 90, so Ligand A is closer to the threshold, but both are acceptable.

**logP:** Ligand A (1.537) is within the optimal 1-3 range. Ligand B (3.357) is at the higher end of optimal, but still acceptable.

**H-Bond Donors/Acceptors:** Ligand A has 2 HBD and 5 HBA, while Ligand B has 1 HBD and 6 HBA. Both are within acceptable limits (<=5 HBD and <=10 HBA).

**QED:** Ligand A (0.812) has a higher QED score than Ligand B (0.667), indicating better overall drug-likeness.

**DILI:** Both ligands have relatively low DILI risk (Ligand A: 44.009, Ligand B: 47.15), both below the 60 threshold.

**BBB:** Ligand A (64.482) has a better BBB penetration percentile than Ligand B (51.415).  For CNS targets, >70 is desirable, but 64.482 is significantly better than 51.415. This is a key advantage for Ligand A.

**Caco-2 Permeability:** Ligand A (-4.673) has a worse Caco-2 permeability than Ligand B (-5.216). Lower values indicate lower permeability.

**Aqueous Solubility:** Both ligands have very poor aqueous solubility (-2.809 and -2.881). This is a concern for both, but not a deciding factor at this stage.

**hERG Inhibition:** Ligand A (0.192) has a lower hERG inhibition risk than Ligand B (0.833). Lower is better.

**Microsomal Clearance:** Ligand A (24.084) has a lower microsomal clearance than Ligand B (45.105), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (11.801) has a shorter in vitro half-life than Ligand B (32.751). Longer is generally preferred.

**P-gp Efflux:** Ligand A (0.039) has significantly lower P-gp efflux liability than Ligand B (0.625). Lower is better, especially for CNS penetration.

**Binding Affinity:** Both ligands have the same binding affinity (-7.8 kcal/mol), which is excellent.

**Overall Assessment:**

Ligand A is superior due to its better BBB penetration, lower P-gp efflux, lower hERG risk, and lower microsomal clearance. While Ligand B has a slightly better in vitro half-life and Caco-2 permeability, the CNS-relevant properties of Ligand A (BBB, P-gp) are more critical for a DRD2 ligand. The higher QED score also favors Ligand A. The solubility is a concern for both, but can be addressed with formulation strategies.

Output:
0
2025-04-17 08:23:03,614 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B based on the provided guidelines, prioritizing GPCR-specific properties (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (362.455 and 369.443 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (93.21) is better than Ligand B (116.67). For CNS targets, TPSA should be <= 90, so Ligand A is closer to the ideal.

**logP:** Ligand A (2.069) is optimal (1-3), while Ligand B (0.184) is quite low, potentially hindering permeation. This is a significant advantage for Ligand A.

**H-Bond Donors/Acceptors:** Both have 2 HBDs and 6 HBAs, which are within acceptable limits.

**QED:** Both ligands have good QED scores (0.709 and 0.765, both > 0.5).

**DILI:** Ligand B (50.136) has a lower DILI risk than Ligand A (73.245), which is favorable.

**BBB:** Ligand A (61.07) is slightly better than Ligand B (57.697), but both are below the desirable >70 for CNS targets. However, given the other factors, this difference is less critical.

**Caco-2 Permeability:** Ligand A (-4.94) is significantly worse than Ligand B (-5.36) indicating lower intestinal absorption.

**Aqueous Solubility:** Ligand A (-3.067) is slightly better than Ligand B (-1.774), which is good.

**hERG:** Both ligands have very low hERG inhibition risk (0.28 and 0.105).

**Microsomal Clearance:** Ligand B (-39.667) has much lower (better) microsomal clearance than Ligand A (8.936), suggesting greater metabolic stability.

**In vitro Half-Life:** Ligand B (20.486) has a significantly longer half-life than Ligand A (-12.743), which is a major advantage.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.015 and 0.021).

**Binding Affinity:** Ligand B (-7.7 kcal/mol) has a slightly better binding affinity than Ligand A (-8.4 kcal/mol). While A is better, the difference is not large enough to overcome the other ADME issues.

**Overall Assessment:**

Ligand A has a better logP and TPSA, which are crucial for CNS penetration. However, Ligand B excels in metabolic stability (Cl_mic, t1/2), has a lower DILI risk, and a comparable binding affinity. The poor logP of Ligand B is a major concern, potentially limiting its ability to cross cell membranes and reach the brain. The Caco-2 permeability is also better for Ligand B. Considering the GPCR-specific priorities, the better metabolic stability and half-life of Ligand B, coupled with its acceptable (though not ideal) BBB score, outweigh the slightly better TPSA and logP of Ligand A.

Output:
1
2025-04-17 08:23:03,615 - INFO - Reasoning:

Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (367.431 and 364.555 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (128.34) is borderline for CNS penetration, being slightly above the preferred <90 threshold, but still potentially acceptable. Ligand B (58.2) is excellent, well below the 90 threshold, suggesting good CNS penetration.

**3. logP:** Ligand A (0.491) is quite low, potentially hindering membrane permeability. Ligand B (4.288) is high, potentially leading to solubility issues and off-target effects, but within the acceptable range.

**4. H-Bond Donors:** Ligand A (3) is acceptable. Ligand B (2) is also acceptable.

**5. H-Bond Acceptors:** Ligand A (7) is acceptable. Ligand B (3) is also acceptable.

**6. QED:** Both ligands (0.611 and 0.687) have good drug-likeness scores, exceeding the 0.5 threshold.

**7. DILI:** Ligand A (83.288) has a higher DILI risk than Ligand B (37.999). This is a significant drawback for Ligand A.

**8. BBB:** Ligand B (78.015) has a significantly better BBB penetration score than Ligand A (50.446). This is crucial for a CNS target like DRD2.

**9. Caco-2 Permeability:** Ligand A (-5.515) has poor Caco-2 permeability, suggesting poor intestinal absorption. Ligand B (-4.859) is also poor, but slightly better than Ligand A.

**10. Aqueous Solubility:** Ligand A (-2.413) has poor aqueous solubility. Ligand B (-4.343) is also poor, but slightly better than Ligand A.

**11. hERG Inhibition:** Both ligands (0.618 and 0.721) have relatively low hERG inhibition risk.

**12. Microsomal Clearance:** Ligand A (-2.253) has lower (better) microsomal clearance than Ligand B (87.837), indicating greater metabolic stability.

**13. In vitro Half-Life:** Ligand B (50.977) has a significantly longer in vitro half-life than Ligand A (-29.197), which is a major advantage.

**14. P-gp Efflux:** Ligand A (0.048) has significantly lower P-gp efflux than Ligand B (0.486), suggesting better CNS exposure.

**15. Binding Affinity:** Ligand B (-7.9 kcal/mol) has a slightly better binding affinity than Ligand A (-8.5 kcal/mol). While the difference is small, it's still a positive for Ligand B.

**Overall Assessment:**

Ligand B is the more promising candidate. While its logP is on the higher side, its superior BBB penetration, longer half-life, lower DILI risk, and slightly better binding affinity outweigh the drawbacks. Ligand A suffers from poor BBB penetration, poor solubility, poor Caco-2 permeability, and a higher DILI risk, making it a less attractive candidate despite its slightly better binding affinity and lower P-gp efflux. The GPCR-specific emphasis on BBB and logP strongly favors Ligand B.

Output:
1
2025-04-17 08:23:03,615 - INFO - Batch 444 complete. Total preferences: 7104
2025-04-17 08:23:03,615 - INFO - Processing batch 445/512...
2025-04-17 08:23:47,111 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B based on the provided guidelines, prioritizing GPCR-specific properties (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (347.415 and 361.385 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (84.67) is better than Ligand B (65.07), both are below the 90 A^2 threshold desirable for CNS targets.

**logP:** Both ligands have acceptable logP values (1.363 and 1.619), falling within the 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A has 1 HBD and 5 HBA, while Ligand B has 0 HBD and 5 HBA. Both are within acceptable limits.

**QED:** Ligand A (0.84) has a higher QED score than Ligand B (0.673), indicating a more drug-like profile.

**DILI:** Ligand A (35.479) has a lower DILI risk than Ligand B (44.591), both are below the 40 threshold.

**BBB:** Ligand B (87.088) has a significantly higher BBB penetration percentile than Ligand A (72.005). This is a crucial advantage for a CNS target like DRD2.

**Caco-2 Permeability:** Ligand A (-4.607) has a lower Caco-2 permeability than Ligand B (-4.491).

**Aqueous Solubility:** Both ligands have similar, poor aqueous solubility (-2.063 and -2.122).

**hERG Inhibition:** Ligand A (0.129) has a lower hERG inhibition liability than Ligand B (0.389).

**Microsomal Clearance:** Ligand A (40.76) has a higher microsomal clearance than Ligand B (13.915), suggesting lower metabolic stability.

**In vitro Half-Life:** Ligand B (13.373) has a longer in vitro half-life than Ligand A (-1.661).

**P-gp Efflux:** Ligand A (0.02) has a lower P-gp efflux liability than Ligand B (0.067), which is favorable for CNS penetration.

**Binding Affinity:** Ligand A (-7.8 kcal/mol) has a slightly better binding affinity than Ligand B (-7.3 kcal/mol). The difference is 0.5 kcal/mol, which is significant.

**Overall Assessment:**

Ligand B excels in BBB penetration and has a longer half-life, which are critical for CNS drug development. While Ligand A has a slightly better affinity and lower P-gp efflux, the superior BBB score of Ligand B outweighs these advantages. The lower metabolic stability of Ligand A is also a concern.

Output:
1
2025-04-17 08:23:47,112 - INFO - Reasoning:

Let's analyze Ligand A and Ligand B based on the provided guidelines, prioritizing GPCR-specific properties (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (363.29 and 368.499 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (62.53) is significantly better than Ligand B (75.71). For CNS targets, we want TPSA <= 90, and A is comfortably within that range, while B is approaching the upper limit.

**logP:** Ligand A (3.257) is optimal (1-3), while Ligand B (1.578) is on the lower side. While not terrible, lower logP can hinder permeation.

**H-Bond Donors/Acceptors:** Both ligands have acceptable HBD (1) and HBA (4 for A, 5 for B) values, well within the recommended limits.

**QED:** Both ligands have reasonable QED values (0.852 and 0.746), indicating good drug-like properties.

**DILI:** Ligand A (67.429) has a higher DILI risk than Ligand B (37.611). This is a concern for A, but not a dealbreaker if other properties are significantly better.

**BBB:** Ligand A (84.141) has a substantially better BBB penetration percentile than Ligand B (71.733). This is *critical* for a CNS target like DRD2.

**Caco-2 Permeability:** Ligand A (-4.634) and Ligand B (-4.802) both have negative Caco-2 values, which is unusual and suggests poor permeability. However, the scale is not clearly defined, so it's hard to interpret.

**Aqueous Solubility:** Both ligands have very poor aqueous solubility (-4.719 and -3.555). This is a significant drawback for both, potentially impacting bioavailability.

**hERG Inhibition:** Ligand A (0.625) has a slightly higher hERG risk than Ligand B (0.242), but both are relatively low.

**Microsomal Clearance:** Ligand B (93.823) has a much higher microsomal clearance than Ligand A (33.592), indicating lower metabolic stability. This is a major disadvantage for B.

**In vitro Half-Life:** Ligand A (-10.011) has a negative half-life, which is not physically possible and likely indicates an issue with the data. Ligand B (3.565) has a short half-life, but a plausible value.

**P-gp Efflux:** Ligand A (0.091) has a lower P-gp efflux liability than Ligand B (0.09). Both are very low, which is favorable for CNS penetration.

**Binding Affinity:** Both ligands have excellent binding affinities (-9 and -7 kcal/mol). Ligand A is slightly better, but the difference is not massive.

**Overall Assessment:**

Ligand A is superior despite the higher DILI risk. Its significantly better BBB penetration, lower microsomal clearance (better metabolic stability), and slightly better binding affinity outweigh the DILI concern. The negative half-life for A is a data quality issue that would need investigation, but assuming it's an error, A is still the preferred candidate. The poor solubility is a concern for both, but can be addressed with formulation strategies. Ligand B's higher clearance and lower BBB penetration are more problematic.

Output:
1
2025-04-17 08:23:47,112 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (344.46 and 347.42 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (58.64) is excellent, well below the 90 A^2 threshold for CNS targets. Ligand B (113.08) is higher, but still potentially acceptable, though less ideal.

**logP:** Ligand A (2.43) is optimal (1-3). Ligand B (0.42) is quite low, potentially hindering permeation.

**H-Bond Donors/Acceptors:** Ligand A (1 HBD, 3 HBA) is favorable. Ligand B (3 HBD, 5 HBA) is also reasonable, but slightly higher.

**QED:** Both ligands have acceptable QED values (0.629 and 0.56), indicating good drug-like properties.

**DILI:** Ligand A (23.85) has a much lower DILI risk than Ligand B (39.55), which is a significant advantage.

**BBB:** Ligand A (82.05) has a significantly better BBB penetration percentile than Ligand B (55.14). This is *critical* for a CNS target like DRD2.

**Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and suggests potential issues with the model or data. However, the magnitude of negativity is similar.

**Aqueous Solubility:** Both have negative solubility values, again unusual. The magnitude of negativity is similar.

**hERG:** Both ligands have very low hERG risk (0.298 and 0.051).

**Microsomal Clearance:** Ligand A (24.40) has a higher microsomal clearance than Ligand B (17.61), indicating potentially lower metabolic stability.

**In vitro Half-Life:** Ligand B (9.72) has a longer half-life than Ligand A (-3.22), which is a positive.

**P-gp Efflux:** Ligand A (0.09) has lower P-gp efflux liability than Ligand B (0.008), which is beneficial for CNS penetration.

**Binding Affinity:** Ligand B (-7.7 kcal/mol) has a significantly stronger binding affinity than Ligand A (-10.6 kcal/mol). This is a substantial advantage, potentially outweighing some ADME concerns.

**Overall Assessment:**

While Ligand B boasts a superior binding affinity, Ligand A presents a much more favorable ADME profile, particularly regarding BBB penetration and DILI risk. Given that DRD2 is a CNS target, BBB penetration is paramount. The significantly lower DILI risk for Ligand A is also a major benefit. The better logP of Ligand A is also a plus. The higher affinity of Ligand B is attractive, but the poor BBB and higher DILI risk are substantial drawbacks.

Output:
0
2025-04-17 08:23:47,112 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B based on the provided guidelines, prioritizing GPCR-specific properties (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (351.422 Da) is slightly lower, which could be beneficial for permeability, but both are acceptable.

**TPSA:** Ligand A (71.53) is excellent for CNS penetration, well below the 90 A^2 threshold. Ligand B (98.14) is higher, but still potentially acceptable, though less ideal.

**logP:** Ligand A (2.065) is optimal. Ligand B (0.978) is a bit low, potentially hindering membrane permeability.

**H-Bond Donors/Acceptors:** Ligand A (HBD=1, HBA=4) and Ligand B (HBD=2, HBA=7) both fall within acceptable ranges.

**QED:** Both ligands have reasonable QED scores (A: 0.778, B: 0.68), suggesting good drug-like properties.

**DILI:** Ligand A (32.842) has a significantly lower DILI risk than Ligand B (63.397), which is a substantial advantage.

**BBB:** Ligand A (91.819) has excellent BBB penetration potential, exceeding the desirable 70% threshold. Ligand B (49.942) is considerably lower, raising concerns about CNS exposure.

**Caco-2 Permeability:** Ligand A (-3.889) has poor Caco-2 permeability. Ligand B (-5.39) is even worse.

**Aqueous Solubility:** Ligand A (-2.258) has poor aqueous solubility. Ligand B (-1.824) is slightly better, but still poor.

**hERG:** Both ligands have low hERG inhibition risk (A: 0.304, B: 0.537).

**Microsomal Clearance:** Ligand A (65.134) has higher microsomal clearance than Ligand B (28.832), indicating lower metabolic stability.

**In vitro Half-Life:** Ligand B (37.425) has a longer in vitro half-life than Ligand A (-23.167).

**P-gp Efflux:** Ligand A (0.055) has very low P-gp efflux, which is highly desirable for CNS penetration. Ligand B (0.184) has slightly higher P-gp efflux, but still relatively low.

**Binding Affinity:** Ligand B (-7.9 kcal/mol) has a slightly better binding affinity than Ligand A (-7.4 kcal/mol), a 0.5 kcal/mol difference.

**Overall Assessment:**

Despite the slightly better affinity of Ligand B, Ligand A is the superior candidate. The critical factors are the significantly better BBB penetration (91.8% vs 49.9%), much lower DILI risk (32.8% vs 63.4%), and very low P-gp efflux. While Ligand A has poorer Caco-2 permeability and aqueous solubility, these can potentially be addressed through formulation strategies. The affinity difference is not large enough to overcome the substantial advantages of Ligand A regarding CNS penetration and safety.

Output:
1
2025-04-17 08:23:47,112 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (364.467 and 344.273 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (95.5) is slightly higher than Ligand B (89.38). Both are below the 140 A^2 threshold for oral absorption, and reasonably close to the 90 A^2 target for CNS penetration. Ligand B is preferable here.

**3. logP:** Ligand A (1.785) and Ligand B (2.653) are both within the optimal 1-3 range. Ligand B is slightly better.

**4. H-Bond Donors:** Ligand A (3) is higher than Ligand B (1). Lower is generally preferred, so Ligand B is better.

**5. H-Bond Acceptors:** Ligand A (4) is lower than Ligand B (6). Ligand A is preferable.

**6. QED:** Both ligands have similar QED values (0.665 and 0.578), both above the 0.5 threshold, indicating good drug-like properties.

**7. DILI:** Ligand A (59.907) has a significantly lower DILI risk than Ligand B (98.992). This is a major advantage for Ligand A.

**8. BBB:** Ligand B (65.607) has a substantially higher BBB penetration percentile than Ligand A (30.826). This is *critical* for a CNS target like DRD2, making Ligand B strongly favored.

**9. Caco-2 Permeability:** Ligand A (-5.335) and Ligand B (-4.277) both have negative values, indicating poor permeability. This is a concern for both, but less so for Ligand B.

**10. Aqueous Solubility:** Both ligands have very poor aqueous solubility (-3.574 and -4.193). This is a significant drawback for both.

**11. hERG Inhibition:** Both ligands have low hERG inhibition risk (0.355 and 0.191).

**12. Microsomal Clearance:** Ligand B (102.531) has a higher microsomal clearance than Ligand A (74.807), indicating lower metabolic stability. Ligand A is better.

**13. In vitro Half-Life:** Ligand A (7.137) has a better in vitro half-life than Ligand B (-28.9). This is a significant advantage for Ligand A.

**14. P-gp Efflux:** Both ligands exhibit high P-gp efflux (0.133 and 0.309). This is a concern for CNS exposure, but less so for Ligand B.

**15. Binding Affinity:** Ligand B (-10.7 kcal/mol) has a significantly stronger binding affinity than Ligand A (-9.0 kcal/mol). This is a major advantage for Ligand B, potentially outweighing some of its ADME drawbacks.

**Overall Assessment:**

Ligand B excels in binding affinity and BBB penetration, which are paramount for a CNS GPCR target. While it has a higher DILI risk and lower metabolic stability, the strong affinity and good BBB penetration are likely to be more impactful for efficacy. Ligand A has better DILI, metabolic stability and half-life but significantly weaker affinity and poor BBB penetration. The difference in binding affinity (1.7 kcal/mol) is substantial enough to favor Ligand B.

Output:
1
2025-04-17 08:23:47,113 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (349.391 and 348.531 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (108.77) is slightly above the preferred <90 for CNS targets, but still reasonable. Ligand B (49.41) is excellent, well below the threshold. This favors Ligand B.

**3. logP:** Ligand A (1.393) is within the optimal 1-3 range. Ligand B (4.033) is slightly high, potentially leading to solubility issues and off-target interactions, but not drastically so. This favors Ligand A.

**4. H-Bond Donors:** Ligand A (3) is acceptable. Ligand B (1) is also good. No clear advantage here.

**5. H-Bond Acceptors:** Ligand A (6) is acceptable. Ligand B (2) is excellent. This favors Ligand B.

**6. QED:** Both ligands have good QED scores (0.548 and 0.684, respectively), indicating drug-like properties. Ligand B is slightly better.

**7. DILI:** Ligand A (62.35) has a moderate DILI risk. Ligand B (12.214) has a very low DILI risk, a significant advantage.

**8. BBB:** Ligand A (59.48) has a moderate BBB penetration, which is concerning for a CNS target. Ligand B (90.772) has excellent BBB penetration, a major advantage.

**9. Caco-2:** Both have negative Caco-2 values, which is unusual and difficult to interpret without further context. However, the magnitude of the negative value for Ligand A (-5.093) is larger than that of Ligand B (-4.86), suggesting potentially lower absorption for Ligand A.

**10. Solubility:** Both have negative solubility values, again unusual. Ligand A (-2.802) is slightly better than Ligand B (-3.893), suggesting slightly better solubility.

**11. hERG:** Both ligands have low hERG inhibition risk (0.432 and 0.667, respectively). No clear advantage.

**12. Cl_mic:** Ligand A (-10.01) has a negative microsomal clearance, which is also unusual. Ligand B (51.662) has a moderate clearance. Negative clearance is not physically possible, so this is a red flag for Ligand A.

**13. t1/2:** Ligand A (25.887) has a reasonable half-life. Ligand B (-16.875) has a negative half-life, which is impossible and a major red flag.

**14. Pgp:** Ligand A (0.018) has very low P-gp efflux, which is excellent for CNS penetration. Ligand B (0.384) has a moderate P-gp efflux. This favors Ligand A.

**15. Affinity:** Ligand A (-9.6 kcal/mol) has a significantly stronger binding affinity than Ligand B (-7.9 kcal/mol), a difference of 1.7 kcal/mol. This is a substantial advantage that can outweigh some ADME concerns.

**Overall Assessment:**

Despite the unusual negative values for Caco-2, solubility, Cl_mic and t1/2, Ligand A has a much stronger binding affinity and very low P-gp efflux. The negative values are concerning and would require further investigation, but the affinity advantage is significant. Ligand B has better TPSA, DILI, and BBB, but its weaker affinity is a major drawback. Given the importance of affinity for GPCR ligands, and the CNS target, Ligand A is the more promising candidate, *assuming the negative values can be explained or are data errors*.

Output:
0
2025-04-17 08:23:47,113 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (347.463 and 348.403 Da) fall comfortably within the ideal 200-500 Da range.

**TPSA:** Ligand A (89.38) is excellent, falling below the 90 A^2 threshold for CNS targets. Ligand B (96.55) is still reasonable but less optimal.

**logP:** Ligand A (2.961) is within the ideal 1-3 range. Ligand B (0.796) is a bit low, potentially hindering membrane permeability.

**H-Bond Donors/Acceptors:** Ligand A (0 HBD, 3 HBA) is good. Ligand B (2 HBD, 5 HBA) is also acceptable.

**QED:** Ligand B (0.842) has a significantly better QED score than Ligand A (0.444), indicating a more drug-like profile.

**DILI:** Ligand A (30.71) has a much lower DILI risk than Ligand B (67.468). This is a significant advantage for Ligand A.

**BBB:** Ligand A (64.017) has a better BBB penetration percentile than Ligand B (53.703), which is crucial for a CNS target like DRD2.

**Caco-2 Permeability:** Ligand A (-4.763) and Ligand B (-5.454) both have negative values, indicating poor Caco-2 permeability. This is a concern for both, but the value is slightly worse for Ligand B.

**Aqueous Solubility:** Both ligands have very poor aqueous solubility (-2.742 and -2.322 respectively). This could pose formulation challenges.

**hERG Inhibition:** Both ligands have a low hERG inhibition risk (0.26).

**Microsomal Clearance:** Ligand B (-0.588) has a significantly *lower* (better) microsomal clearance than Ligand A (56.427), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand B (4.535) has a longer in vitro half-life than Ligand A (-20.171), which is desirable.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.182 and 0.034 respectively).

**Binding Affinity:** Ligand B (-8.9 kcal/mol) has a *much* stronger binding affinity than Ligand A (0.0 kcal/mol). This is a substantial advantage, potentially outweighing some of the ADME concerns.

**Overall Assessment:**

Ligand B has a significantly better binding affinity and metabolic stability (lower Cl_mic, longer t1/2) and a better QED score. However, Ligand A has a much better DILI score and better BBB penetration, both critical for CNS drug development. The poor solubility and Caco-2 permeability are concerns for both. The difference in binding affinity is so large (-8.9 vs 0 kcal/mol) that it is likely to overcome the other drawbacks of Ligand B, especially given the importance of potency for GPCR ligands.

Output:
1
2025-04-17 08:23:47,113 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 drug candidates, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (359.459 and 342.527 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (111.61) is borderline for CNS penetration, being slightly above the preferred <90 threshold, but still potentially acceptable. Ligand B (24.5) is excellent, well below the 90 threshold.

**logP:** Both ligands have good logP values (2.569 and 3.693), falling within the optimal 1-3 range. Ligand B is slightly higher, which could be a minor concern for solubility, but not a dealbreaker.

**H-Bond Donors/Acceptors:** Ligand A has 2 HBD and 8 HBA, which are reasonable. Ligand B has 1 HBD and 3 HBA, also quite good. Both are within acceptable limits.

**QED:** Both ligands have good QED scores (0.727 and 0.853), indicating good drug-like properties.

**DILI:** Ligand A has a DILI risk of 91.431, which is high and concerning. Ligand B has a very low DILI risk of 1.745, a significant advantage.

**BBB:** Ligand A has a BBB penetration of 62.699, which is below the desirable >70 threshold for CNS targets. Ligand B has a much better BBB penetration of 92.594, making it more likely to reach the target in the brain.

**Caco-2 Permeability:** Both have negative Caco-2 values (-5.2 and -4.951), which is unusual and suggests poor permeability. However, these values are on a log scale and can be misleading.

**Aqueous Solubility:** Both ligands have negative solubility values (-3.537 and -2.864), indicating poor aqueous solubility. This could pose formulation challenges.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.595 and 0.947), which is good.

**Microsomal Clearance:** Ligand A has a higher microsomal clearance (31.041) than Ligand B (8.647), suggesting lower metabolic stability.

**In vitro Half-Life:** Ligand B has a slightly longer in vitro half-life (6.258 hours) than Ligand A (44.339 hours). This is a bit counterintuitive given the clearance data, and may be an error in the data.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.16 and 0.126), which is favorable for CNS penetration.

**Binding Affinity:** Both ligands have excellent binding affinities (-8.7 and -8.1 kcal/mol), both well below the -7.0 kcal/mol threshold. Ligand A has a slightly better affinity (-8.7 vs -8.1), but the difference is likely not enough to overcome its other drawbacks.

**Overall Assessment:**

Ligand B is the superior candidate. While both have poor solubility and permeability, Ligand B has a significantly lower DILI risk, much better BBB penetration, lower microsomal clearance, and a slightly longer half-life. The slightly higher logP of Ligand B is a minor concern compared to the significant advantages it offers. The affinity difference is small, and the other ADME properties of Ligand B are far more favorable for CNS drug development.

Output:
1
2025-04-17 08:23:47,113 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (363.439 and 371.503 Da) fall within the ideal 200-500 Da range.

**TPSA:** Both ligands have TPSA values (90.55 and 91.23) close to the upper limit for CNS targets (<=90). Ligand A is slightly better.

**logP:** Both ligands have logP values (0.869 and 1.01) within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A (1 HBD, 5 HBA) is slightly better than Ligand B (2 HBD, 6 HBA) in terms of maintaining a balance between solubility and permeability.

**QED:** Ligand A (0.84) has a significantly better QED score than Ligand B (0.652), indicating a more drug-like profile.

**DILI:** Ligand A (43.622) has a slightly higher DILI risk than Ligand B (16.479), but both are below the concerning threshold of 60.

**BBB:** Ligand A (61.38) has a better BBB percentile than Ligand B (39.667), which is crucial for a CNS target like DRD2. While 61.38 isn't *ideal* (>70), it's considerably better than 39.667.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.921 and -5.174), which is unusual and suggests poor permeability. However, these values are on a scale where more negative values indicate lower permeability.

**Aqueous Solubility:** Both ligands have negative solubility values (-3.117 and -1.935), indicating poor aqueous solubility.

**hERG:** Both ligands have very low hERG inhibition liability (0.115 and 0.313), which is excellent.

**Microsomal Clearance:** Ligand A (-0.707) has a lower (better) microsomal clearance than Ligand B (8.544), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (-27.995) has a lower in vitro half-life than Ligand B (-6.035), which is not ideal.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.035 and 0.036), which is favorable for CNS penetration.

**Binding Affinity:** Both ligands have very similar binding affinities (-8.4 and -8.1 kcal/mol). The difference is less than the 1.5 kcal/mol threshold.

**Overall Assessment:**

Ligand A is superior due to its better QED score, better BBB penetration, and significantly better metabolic stability (lower Cl_mic). While its half-life is worse, the other advantages, especially BBB and metabolic stability, are more critical for a CNS GPCR target. Ligand B's lower DILI risk is a minor advantage, but it's outweighed by the other factors.

Output:
0
2025-04-17 08:23:47,113 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 drug candidates, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (345.418 Da) is slightly lower, which is generally favorable for permeability.

**2. TPSA:** Ligand A (43.86) is excellent for CNS penetration, well below the 90 A^2 threshold. Ligand B (114.19) is higher, but still potentially acceptable, though less ideal.

**3. logP:** Both ligands have acceptable logP values (A: 0.837, B: 1.431), falling within the 1-3 range. Ligand B is slightly better.

**4. H-Bond Donors:** Ligand A (0) is optimal. Ligand B (2) is acceptable.

**5. H-Bond Acceptors:** Ligand A (3) is good. Ligand B (7) is higher, but still within the acceptable limit of 10.

**6. QED:** Both ligands have good QED scores (A: 0.431, B: 0.806). Ligand B is significantly better, indicating a more drug-like profile.

**7. DILI:** Ligand A (21.055) has a much lower DILI risk than Ligand B (60.45). This is a significant advantage for Ligand A.

**8. BBB:** Ligand A (78.79) has a good BBB percentile, desirable for a CNS target. Ligand B (60.644) is lower, which is a concern for CNS penetration.

**9. Caco-2:** Both have negative values, indicating a percentile score. Ligand A (-4.681) is worse than Ligand B (-5.147), suggesting lower intestinal absorption.

**10. Solubility:** Both have negative values, indicating a percentile score. Ligand A (-2.102) is better than Ligand B (-2.502), suggesting better solubility.

**11. hERG:** Both ligands have low hERG risk (A: 0.393, B: 0.098). Ligand B is slightly better.

**12. Cl_mic:** Ligand A (9.639) has a lower microsomal clearance, indicating better metabolic stability, than Ligand B (-15.994).

**13. t1/2:** Ligand A (-30.593) has a much longer in vitro half-life than Ligand B (47.083).

**14. Pgp:** Both ligands have low P-gp efflux liability (A: 0.086, B: 0.065). Ligand B is slightly better.

**15. Binding Affinity:** Ligand B (-8.8 kcal/mol) has a significantly stronger binding affinity than Ligand A (-7.6 kcal/mol). This is a substantial advantage.

**Overall Assessment:**

While Ligand B has a superior binding affinity and QED score, Ligand A exhibits a much better safety profile (lower DILI), better BBB penetration, and improved metabolic stability (lower Cl_mic and longer t1/2). For a CNS target like DRD2, BBB penetration and metabolic stability are crucial. The difference in binding affinity (1.2 kcal/mol) is significant, but not insurmountable, and could potentially be optimized in further iterations. The lower DILI risk of Ligand A is also a major advantage.

Output:
0
2025-04-17 08:23:47,114 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 drug candidates, considering the provided guidelines and GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (364.417 and 351.403 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (49.41) is excellent, well below the 90 A^2 threshold for CNS targets. Ligand B (116.76) is higher, but still potentially acceptable, though less ideal.

**logP:** Ligand A (3.773) is optimal. Ligand B (-1.327) is significantly lower, which raises concerns about permeability and potentially potency.

**H-Bond Donors/Acceptors:** Ligand A (HBD=1, HBA=3) is well within the acceptable ranges. Ligand B (HBD=4, HBA=5) is also acceptable, but slightly higher.

**QED:** Ligand A (0.84) has a very strong drug-like profile. Ligand B (0.443) is lower, indicating a less favorable overall drug-likeness.

**DILI:** Ligand A (62.893) has a moderate DILI risk. Ligand B (21.908) has a very low DILI risk, which is a significant advantage.

**BBB:** Ligand A (89.492) has excellent BBB penetration, crucial for a CNS target like DRD2. Ligand B (35.324) has poor predicted BBB penetration, a major drawback.

**Caco-2 Permeability:** Ligand A (-4.329) has poor Caco-2 permeability, which is concerning. Ligand B (-5.668) is also poor.

**Aqueous Solubility:** Ligand A (-4.949) has poor aqueous solubility. Ligand B (-2.217) is also poor.

**hERG Inhibition:** Ligand A (0.409) has a low hERG risk. Ligand B (0.096) has a very low hERG risk, a positive attribute.

**Microsomal Clearance:** Ligand A (80.582) has relatively high microsomal clearance, suggesting faster metabolism. Ligand B (-1.459) has very low clearance, indicating high metabolic stability.

**In vitro Half-Life:** Ligand A (28.182) has a moderate in vitro half-life. Ligand B (20.994) has a short in vitro half-life.

**P-gp Efflux:** Ligand A (0.318) has low P-gp efflux, which is good for CNS penetration. Ligand B (0.002) has very low P-gp efflux, even better.

**Binding Affinity:** Both ligands have very strong binding affinities (-9.1 and -8.3 kcal/mol). Ligand A has a 0.8 kcal/mol advantage, which is substantial.

**Overall Assessment:**

Ligand A excels in TPSA, logP, BBB penetration, and binding affinity. However, it suffers from poor Caco-2 permeability and aqueous solubility, and moderate DILI risk and metabolic clearance.

Ligand B has a lower logP, lower QED, and poorer BBB penetration. However, it has a significantly lower DILI risk, excellent metabolic stability, very low P-gp efflux, and a very low hERG risk.

Given the GPCR-specific priorities, particularly BBB penetration for a CNS target, Ligand A is more promising *despite* its ADME liabilities. The strong affinity and good BBB penetration outweigh the concerns about solubility and permeability, which can potentially be addressed through formulation strategies. The substantial difference in binding affinity (0.8 kcal/mol) is also a key factor. While Ligand B has better ADME properties overall, its poor BBB penetration makes it less likely to be effective for a CNS target.

Output:
1
2025-04-17 08:23:47,114 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (355.523 and 355.345 Da) fall comfortably within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (101.29) is slightly higher than Ligand B (96.33). Both are below the 140 A^2 threshold for oral absorption, and reasonably close to the 90 A^2 target for CNS penetration. Ligand B is slightly better here.

**3. logP:** Ligand A (2.217) is within the optimal 1-3 range. Ligand B (-0.493) is below 1, which could hinder permeation. This is a significant disadvantage for Ligand B.

**4. H-Bond Donors:** Ligand A (3) and Ligand B (2) are both acceptable, below the 5 threshold.

**5. H-Bond Acceptors:** Ligand A (3) and Ligand B (5) are both acceptable, below the 10 threshold.

**6. QED:** Both ligands have good QED scores (0.591 and 0.765, respectively), indicating good drug-like properties. Ligand B is slightly better.

**7. DILI:** Ligand A (13.843) has a much lower DILI risk than Ligand B (60.682). This is a substantial advantage for Ligand A.

**8. BBB:** Ligand A (62.699) is below the desirable >70 percentile for CNS targets, but Ligand B (73.478) exceeds this threshold. This is a significant advantage for Ligand B.

**9. Caco-2:** Both ligands have negative Caco-2 values (-5.204 and -5.168), which is unusual and suggests poor permeability. This is a concern for both.

**10. Solubility:** Both ligands have negative solubility values (-3.135 and -2.473), which is also unusual and suggests poor aqueous solubility. This is a concern for both.

**11. hERG:** Both ligands have low hERG inhibition liability (0.277 and 0.197), which is good.

**12. Cl_mic:** Ligand A (65.08) has a higher microsomal clearance than Ligand B (-17.191). The negative value for Ligand B suggests very high metabolic stability, which is a significant advantage.

**13. t1/2:** Both ligands have negative in vitro half-life values (-5.109 and -5.753), which is unusual.

**14. Pgp:** Both ligands have very low Pgp efflux liability (0.008 and 0.022), which is good for CNS penetration.

**15. Binding Affinity:** Ligand B (-9.0 kcal/mol) has a significantly stronger binding affinity than Ligand A (-7.0 kcal/mol). This is a substantial advantage for Ligand B.

**Overall Assessment:**

Ligand B has a superior BBB score, significantly better binding affinity, and much better metabolic stability (Cl_mic). However, it has a problematic logP value and a higher DILI risk. Ligand A has a better logP and DILI profile, but weaker binding affinity and poorer metabolic stability.

Given the GPCR-specific priorities, the strong binding affinity and good BBB penetration of Ligand B are crucial. While the low logP is a concern, it might be addressable through structural modifications. The DILI risk is also a concern, but potentially mitigatable. The substantial affinity advantage outweighs the other drawbacks.

Output:
1
2025-04-17 08:23:47,114 - INFO - Reasoning:

Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight (MW):** Both ligands (344.455 and 368.543 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (58.64) is slightly higher than Ligand B (49.85). Both are below the 90 A^2 threshold desirable for CNS targets, making both favorable.

**3. logP:** Both ligands have excellent logP values (2.428 and 2.394), falling within the optimal 1-3 range.

**4. H-Bond Donors (HBD):** Ligand A has 1 HBD, while Ligand B has 0. Both are within the acceptable limit of <=5.

**5. H-Bond Acceptors (HBA):** Ligand A has 3 HBA, and Ligand B has 4. Both are below the acceptable limit of <=10.

**6. QED:** Both ligands have good QED scores (0.629 and 0.692), indicating good drug-like properties.

**7. DILI:** Both ligands have low DILI risk (23.846 and 20.744 percentile), which is favorable.

**8. BBB:** Both ligands have excellent BBB penetration (82.047 and 80.419 percentile), crucial for a CNS target like DRD2.

**9. Caco-2 Permeability:** Both have negative Caco-2 values (-5.199 and -4.898), which is unusual and requires further investigation. However, for comparison purposes, we'll assume similar permeability.

**10. Aqueous Solubility:** Both ligands have very poor aqueous solubility (-3.338 and -2.424). This is a significant drawback.

**11. hERG Inhibition:** Both ligands show low hERG inhibition risk (0.298 and 0.365), which is good.

**12. Microsomal Clearance (Cl_mic):** Ligand B has a significantly higher Cl_mic (74.032 mL/min/kg) than Ligand A (24.399 mL/min/kg). This suggests Ligand A is more metabolically stable.

**13. In vitro Half-Life:** Ligand B has a slightly longer in vitro half-life (1.947 hours) than Ligand A (-3.219 hours). However, the negative value for Ligand A is concerning and likely indicates a very short half-life.

**14. P-gp Efflux:** Both ligands have low P-gp efflux liability (0.09 and 0.149), which is favorable for CNS penetration.

**15. Binding Affinity:** Ligand A has a significantly better binding affinity (-10.6 kcal/mol) than Ligand B (-6.8 kcal/mol). This is a substantial difference.

**Overall Assessment:**

While both ligands have good properties regarding BBB penetration, logP, and DILI risk, Ligand A stands out due to its significantly stronger binding affinity (-10.6 kcal/mol vs -6.8 kcal/mol). The improved metabolic stability (lower Cl_mic) also favors Ligand A. The poor solubility is a concern for both, but the substantially better affinity of Ligand A could potentially outweigh this drawback with appropriate formulation strategies. The negative half-life for Ligand A is a major concern, but the affinity difference is so large that it is still the better candidate.

Output:
1
2025-04-17 08:23:47,114 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (370.362 and 365.543 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (49.41) is significantly better than Ligand B (61.44). For CNS targets, we want TPSA <= 90, and ideally closer to 60. Ligand A is much closer to this ideal.

**3. logP:** Both ligands have good logP values (2.973 and 2.728), falling within the optimal 1-3 range.

**4. H-Bond Donors:** Ligand A (1) is preferable to Ligand B (2). Lower HBD generally improves permeability.

**5. H-Bond Acceptors:** Ligand A (2) is preferable to Ligand B (4). Lower HBA generally improves permeability.

**6. QED:** Both ligands have similar QED values (0.774 and 0.745), indicating good drug-like properties.

**7. DILI:** Ligand A (19.62) has a much lower DILI risk than Ligand B (34.393). This is a significant advantage.

**8. BBB:** Ligand A (93.098) has a substantially better BBB penetration percentile than Ligand B (64.948). This is *critical* for a CNS target like DRD2.

**9. Caco-2 Permeability:** Ligand A (-4.669) is better than Ligand B (-5.297), indicating better intestinal absorption.

**10. Aqueous Solubility:** Ligand A (-3.129) is better than Ligand B (-2.193), indicating better solubility.

**11. hERG Inhibition:** Both ligands have similar hERG inhibition liability (0.609 and 0.664), which is acceptable.

**12. Microsomal Clearance:** Ligand A (6.292) has a lower microsomal clearance than Ligand B (21.558), indicating better metabolic stability.

**13. In vitro Half-Life:** Ligand A (-22.928) has a much longer in vitro half-life than Ligand B (26.038). This is a significant advantage.

**14. P-gp Efflux:** Ligand A (0.033) has a much lower P-gp efflux liability than Ligand B (0.183). Lower efflux is crucial for CNS exposure.

**15. Binding Affinity:** Ligand B (-7.8) has a slightly better binding affinity than Ligand A (-9.2). However, the difference is not substantial enough to outweigh the numerous ADME advantages of Ligand A. A 1.4 kcal/mol difference is not enough to overcome the significant differences in BBB, DILI, metabolic stability, and efflux.

**Overall:**

Ligand A is significantly superior to Ligand B. It exhibits a much better safety profile (lower DILI), superior CNS penetration (higher BBB, lower P-gp efflux), improved ADME properties (lower clearance, longer half-life, better solubility and permeability), and acceptable binding affinity. While Ligand B has slightly better binding affinity, the overall profile of Ligand A makes it a far more promising drug candidate for a CNS target like DRD2.

Output:
0
2025-04-17 08:23:47,115 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (352.291 Da) is slightly lower, which could be beneficial for permeability.

**TPSA:** Ligand A (59.93) is significantly better than Ligand B (105.32). For CNS targets, we want TPSA <= 90, and Ligand A comfortably meets this, while Ligand B exceeds it.

**logP:** Both ligands have acceptable logP values (A: 3.674, B: 2.928), falling within the optimal range of 1-3.

**H-Bond Donors/Acceptors:** Ligand A (HBD=1, HBA=5) is preferable to Ligand B (HBD=2, HBA=6) as lower values generally improve permeability. Both are within acceptable limits.

**QED:** Both ligands have good QED scores (A: 0.561, B: 0.738), indicating drug-like properties. Ligand B is slightly better here.

**DILI:** Both have high DILI risk (A: 91.935, B: 98.371), which is a concern, but not a dealbreaker at this stage.

**BBB:** This is a critical parameter for a CNS target like DRD2. Ligand A has a much better BBB percentile (73.827) than Ligand B (21.946). This is a major advantage for Ligand A.

**Caco-2 Permeability:** Ligand A (-4.713) and Ligand B (-5.09) both have negative Caco-2 values, which is unusual and suggests poor permeability. However, the scale isn't specified, so it's hard to interpret.

**Aqueous Solubility:** Both have poor aqueous solubility (-4.58 and -4.144 respectively).

**hERG Inhibition:** Both ligands show low hERG inhibition risk (A: 0.892, B: 0.634), which is good.

**Microsomal Clearance:** Ligand B (31.098) has significantly lower microsomal clearance than Ligand A (70.089), suggesting better metabolic stability.

**In vitro Half-Life:** Both have negative half-lives (-15.842 and -13.296 respectively), which is also unusual and hard to interpret without knowing the scale.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (A: 0.286, B: 0.232), which is favorable for CNS penetration.

**Binding Affinity:** Both ligands have strong binding affinities (A: -9.8 kcal/mol, B: -10.5 kcal/mol). Ligand B is slightly better in this regard, with a 0.7 kcal/mol advantage.

**Overall Assessment:**

Considering the GPCR-specific priorities, Ligand A is the more promising candidate. The significantly better BBB penetration (73.827 vs. 21.946) and lower TPSA (59.93 vs. 105.32) are crucial for CNS drug development. While Ligand B has slightly better binding affinity and metabolic stability, the poor BBB penetration is a major drawback. The unusual negative values for Caco-2 and half-life are concerning for both, but the difference in BBB is decisive.

Output:
0
2025-04-17 08:23:47,115 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (450.32 Da) is slightly higher, but acceptable. Ligand B (374.463 Da) is also good.

**TPSA:** Ligand A (41.57) is excellent for CNS penetration, well below the 90 A^2 threshold. Ligand B (137.9) is higher, approaching the 140 A^2 limit for oral absorption and potentially hindering BBB penetration.

**logP:** Ligand A (4.813) is a bit high, potentially leading to solubility issues or off-target interactions. Ligand B (-0.212) is too low, likely resulting in poor membrane permeability.

**H-Bond Donors/Acceptors:** Ligand A (1 HBD, 2 HBA) is favorable. Ligand B (4 HBD, 5 HBA) is acceptable, but higher values can sometimes reduce permeability.

**QED:** Both ligands have reasonable QED values (A: 0.68, B: 0.523), indicating good drug-like properties.

**DILI:** Ligand A (41.76) has a slightly higher DILI risk than Ligand B (26.793), but both are below the concerning threshold of 60.

**BBB:** Ligand A (89.725) shows excellent BBB penetration potential. Ligand B (37.301) has very poor predicted BBB penetration, a significant drawback for a CNS target.

**Caco-2:** Ligand A (-4.766) has a negative Caco-2 value, which is unusual and suggests poor permeability. Ligand B (-5.624) also has a negative Caco-2 value, indicating poor permeability.

**Solubility:** Both ligands have very poor predicted aqueous solubility (A: -5.397, B: -1.313).

**hERG:** Ligand A (0.912) has a low hERG risk. Ligand B (0.289) also has a low hERG risk.

**Microsomal Clearance:** Ligand A (58.442) has moderate clearance, while Ligand B (-27.698) has negative clearance, which is not possible. This suggests a potential issue with the prediction for Ligand B.

**In vitro Half-Life:** Ligand A (39.296) has a reasonable half-life. Ligand B (26.899) has a shorter half-life.

**P-gp Efflux:** Ligand A (0.7) has moderate P-gp efflux, while Ligand B (0.008) has very low P-gp efflux, which is favorable for CNS penetration.

**Binding Affinity:** Ligand A (-9.5 kcal/mol) has significantly stronger binding affinity than Ligand B (-8.3 kcal/mol). This 1.2 kcal/mol difference is substantial and could outweigh some of the ADME drawbacks.

**Overall Assessment:**

Ligand A is the better candidate despite its higher logP and moderate P-gp efflux. Its superior BBB penetration, significantly stronger binding affinity, and acceptable DILI risk are crucial for a CNS-targeting GPCR. The negative Caco-2 value is concerning, but the strong affinity might compensate. Ligand B's extremely poor BBB penetration and negative clearance are major liabilities that disqualify it, even with its lower P-gp efflux. The negative Caco-2 value is also concerning.

Output:
1
2025-04-17 08:23:47,115 - INFO - Batch 445 complete. Total preferences: 7120
2025-04-17 08:23:47,115 - INFO - Processing batch 446/512...
2025-04-17 08:24:29,494 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (354.841 and 359.451 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (59.81) is significantly better than Ligand B (82.43). For CNS targets, we want TPSA <= 90, and A is comfortably within this range, while B is approaching the upper limit.

**3. logP:** Ligand A (3.261) is optimal (1-3), while Ligand B (1.769) is on the lower side. While not terrible, lower logP can sometimes hinder permeability.

**4. H-Bond Donors:** Both ligands have 1 HBD, which is within the acceptable limit of <=5.

**5. H-Bond Acceptors:** Ligand A has 4 HBAs, and Ligand B has 5. Both are within the acceptable limit of <=10.

**6. QED:** Both ligands have similar QED values (0.739 and 0.717), indicating good drug-likeness.

**7. DILI:** Ligand A (73.09) has a higher DILI risk than Ligand B (47.732). This is a negative for Ligand A.

**8. BBB:** Ligand A (49.205) has a lower BBB penetration percentile than Ligand B (57.774). While neither is *excellent* (>70), B is better. This is a crucial factor for a CNS target like DRD2.

**9. Caco-2:** Ligand A (-5.138) has a worse Caco-2 permeability than Ligand B (-4.608). Lower values indicate poorer permeability.

**10. Solubility:** Ligand A (-4.288) has slightly worse solubility than Ligand B (-3.773).

**11. hERG:** Both ligands have very low hERG inhibition risk (0.527 and 0.408).

**12. Cl_mic:** Ligand B (45.006) has lower microsomal clearance than Ligand A (68.926), suggesting better metabolic stability.

**13. t1/2:** Ligand B (14.992) has a slightly longer in vitro half-life than Ligand A (17.791).

**14. Pgp:** Ligand A (0.35) has lower P-gp efflux liability than Ligand B (0.102), which is favorable for CNS penetration.

**15. Binding Affinity:** Ligand A (-9.7 kcal/mol) has *significantly* stronger binding affinity than Ligand B (-6.9 kcal/mol). This is a difference of 2.8 kcal/mol, which is substantial and can outweigh many ADME drawbacks.

**Overall Assessment:**

Despite Ligand A having a higher DILI risk and slightly lower BBB, its *much* stronger binding affinity (-9.7 vs -6.9 kcal/mol) is the deciding factor. For a GPCR, potency is paramount, and this difference is large enough to overcome the other minor deficiencies. The lower Pgp efflux for A is also a positive.

Output:
1
2025-04-17 08:24:29,495 - INFO - Reasoning:

Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (349.475 and 345.403 Da) fall comfortably within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (74.57) is significantly better than Ligand B (102.05).  For CNS targets, we want TPSA <= 90, so Ligand A is preferable.

**3. logP:** Both ligands have good logP values (2.026 and 1.374), falling within the optimal 1-3 range.

**4. H-Bond Donors:** Both have 2 HBD, which is acceptable.

**5. H-Bond Acceptors:** Ligand A has 4 HBA, while Ligand B has 6. Both are within the acceptable limit of <=10, but A is slightly better.

**6. QED:** Both ligands have similar QED values (0.791 and 0.789), indicating good drug-like properties.

**7. DILI:** Ligand A (36.642) has a much lower DILI risk than Ligand B (56.262). Both are below 60, but A is clearly safer.

**8. BBB:** Ligand A (35.052) has a significantly lower BBB penetration percentile than Ligand B (55.099). For a CNS target like DRD2, BBB penetration is *critical*. Ligand B is much more favorable here.

**9. Caco-2 Permeability:** Both have negative Caco-2 values (-4.747 and -5.064). This is unusual and suggests poor permeability. However, the values are similar, so this isn't a major differentiator.

**10. Aqueous Solubility:** Both have negative solubility values (-2.569 and -3.028), indicating poor solubility. Similar to Caco-2, this isn't a major differentiator.

**11. hERG Inhibition:** Ligand A (0.398) has a slightly higher hERG risk than Ligand B (0.073). Lower is better, so B is preferable.

**12. Microsomal Clearance:** Ligand A (42.384) has higher microsomal clearance than Ligand B (17.16). Lower clearance is better for metabolic stability, so B is preferable.

**13. In vitro Half-Life:** Ligand A (19.493) has a longer half-life than Ligand B (7.659). Longer half-life is generally desirable, favoring A.

**14. P-gp Efflux:** Ligand A (0.206) has lower P-gp efflux than Ligand B (0.03). Lower efflux is better for CNS exposure, favoring A.

**15. Binding Affinity:** Both ligands have excellent binding affinities (-8.1 and -8.2 kcal/mol). The difference is negligible.

**Overall Assessment:**

While Ligand A has advantages in TPSA, DILI, and P-gp efflux, Ligand B is significantly better in BBB penetration, a crucial factor for a CNS target. It also exhibits lower hERG risk and better metabolic stability (lower Cl_mic). The slightly longer half-life of Ligand A is a minor advantage compared to the substantial benefit of Ligand B's improved BBB penetration. Given the GPCR-specific priorities, the improved BBB penetration of Ligand B outweighs the other minor advantages of Ligand A.

Output:
1
2025-04-17 08:24:29,495 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight (MW):** Both ligands (363.571 and 357.483 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (38.13) is excellent, well below the 90 target for CNS drugs. Ligand B (55.95) is still reasonable but less optimal, exceeding the preferred threshold.

**3. logP:** Ligand A (3.964) is at the upper end of the optimal range (1-3), while Ligand B (2.778) is well within the ideal range.

**4. H-Bond Donors (HBD):** Both ligands have 0 HBD, which is acceptable.

**5. H-Bond Acceptors (HBA):** Ligand A has 4 HBA, and Ligand B has 6 HBA, both within the acceptable limit of <=10.

**6. QED:** Both ligands have similar QED values (0.701 and 0.653), indicating good drug-likeness.

**7. DILI:** Ligand A (13.804) has a significantly lower DILI risk than Ligand B (41.373), which is a substantial advantage.

**8. BBB:** Ligand A (82.862) has a much higher BBB penetration percentile than Ligand B (62.233). This is *critical* for a CNS target like DRD2.

**9. Caco-2 Permeability:** Ligand A (-4.819) and Ligand B (-5.524) both have negative values, suggesting poor Caco-2 permeability. This is a concern, but less critical for a CNS target where BBB penetration is paramount.

**10. Aqueous Solubility:** Ligand A (-3.968) and Ligand B (-1.988) both have negative solubility values, indicating poor solubility. This is a drawback, but can potentially be addressed with formulation strategies.

**11. hERG Inhibition:** Both ligands have low hERG inhibition liability (0.636 and 0.485), which is good.

**12. Microsomal Clearance:** Ligand A (97.021) has higher microsomal clearance than Ligand B (58.546), suggesting lower metabolic stability.

**13. In vitro Half-Life:** Ligand B (9.024) has a longer in vitro half-life than Ligand A (25.234). This is a positive for Ligand B.

**14. P-gp Efflux:** Ligand A (0.505) has lower P-gp efflux than Ligand B (0.268), which is favorable for CNS penetration.

**15. Binding Affinity:** Ligand B (-7.0) has a slightly better binding affinity than Ligand A (-6.7). However, the difference is only 0.3 kcal/mol, which is not a huge advantage.

**Overall Assessment:**

Ligand A is the stronger candidate. While Ligand B has slightly better affinity and half-life, Ligand A excels in critical areas for a CNS GPCR target: significantly lower DILI risk, much higher BBB penetration, and lower P-gp efflux. The TPSA is also considerably better for Ligand A. The solubility and Caco-2 permeability are poor for both, but these are less crucial given the CNS target and the importance of BBB penetration. The higher clearance of Ligand A is a concern, but could potentially be mitigated through structural modifications.

Output:
1
2025-04-17 08:24:29,495 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (371.771 and 350.375 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (83.48) is excellent, well below the 90 A^2 threshold for CNS targets. Ligand B (122.13) is higher, but still potentially acceptable, although less ideal.

**3. logP:** Ligand A (3.265) is optimal (1-3). Ligand B (-0.671) is significantly lower, which could hinder membrane permeability and CNS penetration.

**4. H-Bond Donors:** Both ligands have acceptable HBD counts (3 and 2, respectively), below the threshold of 5.

**5. H-Bond Acceptors:** Ligand A (4) is good. Ligand B (7) is higher, but still within the acceptable range of 10.

**6. QED:** Both ligands have good QED scores (0.704 and 0.722), indicating drug-like properties.

**7. DILI:** Ligand A (83.133) has a higher DILI risk than Ligand B (45.25). This is a concern for Ligand A.

**8. BBB:** Ligand B (70.027) has a significantly better BBB penetration percentile than Ligand A (36.371). This is crucial for a CNS target like DRD2.

**9. Caco-2 Permeability:** Ligand A (-4.781) has poor Caco-2 permeability, indicating poor intestinal absorption. Ligand B (-5.095) is also poor, but slightly better.

**10. Aqueous Solubility:** Ligand A (-4.096) has poor solubility. Ligand B (-0.752) is better, but still not ideal.

**11. hERG Inhibition:** Both ligands show low hERG inhibition risk (0.279 and 0.235).

**12. Microsomal Clearance:** Ligand A (39.065) has a higher microsomal clearance, suggesting faster metabolism. Ligand B (-4.324) has negative clearance, which is unusual and suggests very high metabolic stability.

**13. In vitro Half-Life:** Ligand B (-12.858) has a very long in vitro half-life, which is very favorable. Ligand A (56.736) is reasonable.

**14. P-gp Efflux:** Both ligands show low P-gp efflux liability (0.095 and 0.004).

**15. Binding Affinity:** Both ligands have excellent binding affinities (-7.4 and -7.0 kcal/mol). The difference of 0.4 kcal/mol is not substantial enough to override other significant differences.

**Overall Assessment:**

Ligand B is the more promising candidate. While its TPSA is slightly higher, it excels in crucial areas for CNS drug development: BBB penetration, metabolic stability (indicated by negative Cl_mic and long half-life), and a better logP value. Ligand A has a higher DILI risk and poor Caco-2 permeability and solubility, which are significant drawbacks. The similar binding affinities make the ADME properties the deciding factor.

Output:
1
2025-04-17 08:24:29,495 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (351.403 and 345.378 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (106.62) is slightly higher than Ligand B (96.01). Both are below the 140 A^2 threshold for oral absorption and reasonably close to the 90 A^2 target for CNS penetration, but Ligand B is better.

**3. logP:** Both ligands have good logP values (1.708 and 1.525), falling within the optimal 1-3 range.

**4. H-Bond Donors:** Ligand A (2) is preferable to Ligand B (3).

**5. H-Bond Acceptors:** Ligand A (6) is preferable to Ligand B (4).

**6. QED:** Both ligands have acceptable QED values (0.724 and 0.663), indicating good drug-like properties.

**7. DILI:** Ligand A (52.617) has a lower DILI risk than Ligand B (69.601), which is a significant advantage.

**8. BBB:** Ligand A (62.233) and Ligand B (70.609) both have reasonable BBB penetration, but Ligand B is better, exceeding the 70 percentile threshold.

**9. Caco-2 Permeability:** Ligand A (-4.705) and Ligand B (-5.191) both have negative values, which is unusual. Lower values suggest poor permeability. Ligand A is slightly better.

**10. Aqueous Solubility:** Both ligands have very poor aqueous solubility (-2.719 and -3.177). This is a concern, but can sometimes be mitigated with formulation strategies.

**11. hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.145 and 0.488).

**12. Microsomal Clearance:** Ligand A (72.886) has higher microsomal clearance than Ligand B (20.981), indicating lower metabolic stability. This is a significant disadvantage for Ligand A.

**13. In vitro Half-Life:** Ligand B (23.052) has a much longer in vitro half-life than Ligand A (4.559), which is a substantial advantage.

**14. P-gp Efflux:** Both ligands have low P-gp efflux liability (0.029 and 0.063), which is good for CNS penetration.

**15. Binding Affinity:** Ligand B (-8.5 kcal/mol) has a significantly stronger binding affinity than Ligand A (-7.7 kcal/mol). This >1.5 kcal/mol difference is a major factor.

**Overall Assessment:**

While Ligand A has a better DILI score and slightly better Caco-2 permeability, Ligand B is superior overall. The key advantages of Ligand B are its significantly stronger binding affinity (-8.5 vs -7.7 kcal/mol), better BBB penetration (70.609 vs 62.233), and much improved metabolic stability (lower Cl_mic and longer t1/2). The improved affinity is likely to outweigh the slightly higher DILI risk and poorer solubility. Given the CNS target (DRD2), BBB penetration and metabolic stability are critical.

Output:
1
2025-04-17 08:24:29,495 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (337.467 Da) is slightly lower, which could be beneficial for permeability.

**2. TPSA:** Ligand A (46.92) is excellent for CNS penetration, well below the 90 A^2 threshold. Ligand B (112.58) is higher, but still potentially acceptable, though less optimal.

**3. logP:** Ligand A (4.41) is a bit high, potentially leading to solubility issues or off-target interactions. Ligand B (0.145) is very low, which is a significant concern for membrane permeability and CNS penetration.

**4. H-Bond Donors:** Ligand A (1) is good. Ligand B (4) is acceptable but approaching the upper limit.

**5. H-Bond Acceptors:** Ligand A (3) is good. Ligand B (6) is acceptable.

**6. QED:** Ligand A (0.878) is excellent, indicating strong drug-likeness. Ligand B (0.478) is below the 0.5 threshold, suggesting a less favorable drug-like profile.

**7. DILI:** Ligand A (29.081) has a low DILI risk. Ligand B (41.838) is slightly higher, but still within an acceptable range.

**8. BBB:** Ligand A (73.672) has a good BBB percentile. Ligand B (53.819) is significantly lower, a major drawback for a CNS target like DRD2.

**9. Caco-2:** Both ligands have negative Caco-2 values, which is unusual and could indicate issues with the prediction method or the compounds themselves. However, the values are similar.

**10. Solubility:** Both ligands have negative solubility values, again indicating potential issues with the prediction method. The values are similar.

**11. hERG:** Ligand A (0.794) has a low hERG risk. Ligand B (0.235) also has a low hERG risk.

**12. Cl_mic:** Ligand A (52.305) has moderate clearance. Ligand B (9.184) has very low clearance, suggesting good metabolic stability.

**13. t1/2:** Ligand A (-23.747) has a negative half-life, which is not physically possible and indicates a problem with the prediction. Ligand B (15.98) has a reasonable half-life.

**14. Pgp:** Ligand A (0.475) has low P-gp efflux, which is favorable for CNS penetration. Ligand B (0.011) has very low P-gp efflux, even more favorable.

**15. Binding Affinity:** Ligand B (-7.2 kcal/mol) has significantly better binding affinity than Ligand A (-9.0 kcal/mol). This is a substantial advantage.

**Overall Assessment:**

Despite Ligand B's superior binding affinity, Ligand A is the more promising candidate. The extremely low logP of Ligand B (0.145) is a major red flag, severely hindering its ability to cross cell membranes and reach the CNS.  The poor BBB prediction for Ligand B further supports this. While Ligand A's logP is a bit high, it's not as detrimental as Ligand B's extremely low value. Ligand A also has a much better QED score and a more reasonable (though problematic) predicted half-life. The negative half-life for Ligand A is a concern, but the other factors favor it.

Output:
0
2025-04-17 08:24:29,496 - INFO - Reasoning:

Let's analyze Ligand A and Ligand B based on the provided guidelines, prioritizing GPCR-specific properties (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (408.267 Da) is slightly higher than Ligand B (349.435 Da), but both are acceptable.

**TPSA:** Ligand A (47.56) is excellent for CNS penetration, well below the 90 A^2 threshold. Ligand B (100.21) is higher, but still potentially acceptable, though less ideal.

**logP:** Ligand A (4.376) is a bit high, potentially leading to solubility issues or off-target interactions. Ligand B (1.009) is at the lower end of the optimal range, potentially hindering permeability.

**H-Bond Donors/Acceptors:** Ligand A (HBD=1, HBA=3) is better than Ligand B (HBD=2, HBA=5) in terms of maintaining a balance between solubility and permeability.

**QED:** Both ligands have similar QED values (A: 0.817, B: 0.765), indicating good drug-likeness.

**DILI:** Ligand A (70.26) has a higher DILI risk than Ligand B (33.85), which is a significant concern.

**BBB:** Ligand A (78.868) has a much better BBB penetration percentile than Ligand B (61.923). This is crucial for a CNS target like DRD2.

**Caco-2 Permeability:** Ligand A (-4.474) has poor Caco-2 permeability, while Ligand B (-5.463) is also poor, but slightly worse.

**Aqueous Solubility:** Ligand A (-5.449) has very poor aqueous solubility, which is a major drawback. Ligand B (-1.402) is better, but still not great.

**hERG Inhibition:** Ligand A (0.821) has a higher hERG inhibition risk than Ligand B (0.077). Ligand B is very favorable here.

**Microsomal Clearance:** Ligand A (76.238) has higher microsomal clearance, indicating faster metabolism. Ligand B (-2.67) has negative clearance, which is unusual and could indicate issues with the prediction or a very stable compound.

**In vitro Half-Life:** Ligand A (77.311) has a longer half-life than Ligand B (8.055).

**P-gp Efflux:** Ligand A (0.693) has lower P-gp efflux, which is good for CNS penetration. Ligand B (0.014) has very low P-gp efflux, which is excellent.

**Binding Affinity:** Ligand A (-9.6 kcal/mol) has significantly stronger binding affinity than Ligand B (-7.4 kcal/mol). This is a substantial advantage, potentially outweighing some of its ADME liabilities.

**Overall Assessment:**

Ligand A has a much stronger binding affinity and better BBB penetration, which are critical for a CNS GPCR target. However, it suffers from poor solubility, higher DILI risk, and higher hERG risk. Ligand B has better ADME properties (lower DILI, hERG, P-gp efflux), but weaker binding affinity and lower BBB penetration.

The difference in binding affinity (-9.6 vs -7.4 kcal/mol) is substantial (2.2 kcal/mol). Given the importance of potency for GPCRs, and the potential to mitigate some ADME issues through formulation or structural modifications, Ligand A is the more promising candidate *despite* its drawbacks. The strong binding affinity is the deciding factor.

Output:
1
2025-04-17 08:24:29,496 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (407.769 Da) is slightly higher than Ligand B (350.459 Da), but both are acceptable.

**2. TPSA:** Both ligands have TPSA values (81.7 and 84.5) above the optimal 90 for CNS targets, but not drastically so. This is a minor concern.

**3. logP:** Both ligands have good logP values (2.861 and 1.777), falling within the 1-3 range. Ligand A is slightly higher, which could potentially lead to off-target effects, but is still reasonable.

**4. H-Bond Donors/Acceptors:** Ligand A (HBD=1, HBA=5) and Ligand B (HBD=2, HBA=4) both have acceptable numbers of H-bond donors and acceptors, well below the limits of 5 and 10, respectively.

**5. QED:** Both ligands have reasonable QED scores (0.407 and 0.715), with Ligand B being significantly better. A QED > 0.5 is preferred, so Ligand B has an advantage here.

**6. DILI:** Ligand A has a significantly higher DILI risk (80.962%) compared to Ligand B (31.989%). This is a major concern for Ligand A.

**7. BBB:** Ligand A (60.644%) has a slightly better BBB penetration percentile than Ligand B (56.495%), but neither are above the desirable 70% threshold for CNS targets.

**8. Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.781 and -4.771), which is unusual and suggests poor permeability. This is a significant drawback for both.

**9. Aqueous Solubility:** Both ligands have very poor aqueous solubility (-4.693 and -2.528). This will pose formulation challenges.

**10. hERG Inhibition:** Both ligands show low hERG inhibition risk (0.536 and 0.253).

**11. Microsomal Clearance:** Ligand A (74.073) has a higher microsomal clearance than Ligand B (60.425), indicating lower metabolic stability.

**12. In vitro Half-Life:** Ligand B (-0.763) has a negative half-life, which is concerning and likely an artifact of the prediction method. Ligand A (10.109) has a reasonable half-life.

**13. P-gp Efflux:** Both ligands have low P-gp efflux liability (0.211 and 0.118), which is favorable for CNS penetration.

**14. Binding Affinity:** Ligand B (-8.1 kcal/mol) has a significantly stronger binding affinity than Ligand A (-7.5 kcal/mol). This 0.6 kcal/mol difference is substantial and can outweigh some ADME drawbacks.

**Overall Assessment:**

While both ligands have significant drawbacks (poor solubility, permeability), Ligand B is the more promising candidate. Its significantly stronger binding affinity, lower DILI risk, and better QED score outweigh the slightly lower BBB penetration and the questionable half-life prediction. Ligand A's high DILI risk is a major red flag. The affinity difference is large enough to prioritize Ligand B despite the other issues, as medicinal chemistry efforts could focus on improving solubility and permeability.

Output:
1
2025-04-17 08:24:29,496 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (357.41 and 349.387 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (64.11) is excellent, well below the 90 A^2 threshold for CNS targets. Ligand B (106.08) is still reasonable but less optimal, exceeding the preferred threshold.

**3. logP:** Ligand A (4.147) is slightly high, potentially leading to solubility issues or off-target interactions. Ligand B (0.622) is quite low, which could hinder membrane permeability and CNS penetration.

**4. H-Bond Donors:** Both ligands have 1 HBD, which is within the acceptable limit of <=5.

**5. H-Bond Acceptors:** Both ligands have 5 HBA, also within the acceptable limit of <=10.

**6. QED:** Both ligands have similar, good QED values (0.72 and 0.727).

**7. DILI:** Ligand A (88.251) has a higher DILI risk than Ligand B (33.579), which is a significant drawback.

**8. BBB:** Both ligands have comparable BBB penetration (64.831 and 63.784). While not exceeding the ideal >70, they are both in a reasonable range for CNS targets.

**9. Caco-2:** Both ligands have negative Caco-2 values, which is unusual and potentially indicates issues with the prediction method or the compounds themselves. However, we'll proceed assuming these represent low permeability.

**10. Solubility:** Both ligands have negative solubility values, also unusual, suggesting poor aqueous solubility.

**11. hERG:** Ligand A (0.623) has a slightly higher hERG risk than Ligand B (0.24), but both are relatively low.

**12. Cl_mic:** Ligand A (70.519) has a higher microsomal clearance than Ligand B (-6.313), indicating lower metabolic stability. Ligand B's negative value is unusual and suggests very high stability.

**13. t1/2:** Ligand A (-24.598) has a negative in vitro half-life, which is not physically possible and suggests a prediction error. Ligand B (27.693) has a reasonable half-life.

**14. Pgp:** Ligand A (0.519) has lower P-gp efflux liability than Ligand B (0.023), which is favorable for CNS penetration.

**15. Binding Affinity:** Ligand B (-7.3 kcal/mol) has a significantly better binding affinity than Ligand A (-9.8 kcal/mol). This is a substantial advantage.

**Overall Assessment:**

Ligand B is the more promising candidate despite its low logP. The significantly stronger binding affinity (-7.3 vs -9.8 kcal/mol) is a major advantage for a GPCR ligand, and can often compensate for some ADME deficiencies. Ligand A has concerning issues with DILI risk, metabolic stability (high Cl_mic), and an impossible half-life prediction. While Ligand A has better Pgp properties, the other issues outweigh this benefit. The low logP of Ligand B is a concern, but could potentially be addressed through structural modifications.

Output:
1
2025-04-17 08:24:29,496 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (411.231 Da) is slightly higher, but acceptable. Ligand B (349.431 Da) is also good.

**2. TPSA:** Both ligands have TPSA values (85.25 and 84.67) that are slightly above the optimal <90 for CNS targets, but still reasonable.

**3. logP:** Both ligands have excellent logP values (1.725 and 1.767) falling within the optimal 1-3 range.

**4. H-Bond Donors:** Ligand A has 2 HBD, and Ligand B has 1. Both are within the acceptable limit of <=5.

**5. H-Bond Acceptors:** Both ligands have 5 HBA, which is within the acceptable limit of <=10.

**6. QED:** Both ligands have good QED scores (0.734 and 0.895), indicating good drug-like properties. Ligand B is slightly better.

**7. DILI:** Ligand A has a DILI risk of 89.259, which is high. Ligand B has a much lower DILI risk of 40.83, which is good. This is a significant advantage for Ligand B.

**8. BBB:** Both ligands have acceptable BBB penetration (70.803 and 77.705), exceeding the 70% threshold for CNS targets. Ligand B is slightly better.

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.855 and -4.682). This is unusual and suggests poor permeability. However, these values are on a scale where negative values are possible, and the absolute magnitude isn't directly interpretable without knowing the scale's specifics.

**10. Aqueous Solubility:** Both ligands have negative solubility values (-4.116 and -1.706). Similar to Caco-2, this suggests poor solubility, but the scale is unknown.

**11. hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.61 and 0.231). This is excellent.

**12. Microsomal Clearance:** Ligand A has a Cl_mic of 52.818, while Ligand B has 46.74. Lower is better, so Ligand B is slightly preferable.

**13. In vitro Half-Life:** Ligand A has a half-life of 10.143 hours, while Ligand B has a negative half-life of -25.594 hours. A negative half-life is not physically meaningful and suggests a problem with the data or the assay. This is a major red flag for Ligand B.

**14. P-gp Efflux:** Both ligands have low P-gp efflux liability (0.47 and 0.071), which is good for CNS penetration. Ligand B is significantly better.

**15. Binding Affinity:** Ligand B (-9.3 kcal/mol) has a slightly better binding affinity than Ligand A (-8.9 kcal/mol). While both are good (below -7.0 kcal/mol), the 0.4 kcal/mol difference is potentially significant.

**Overall Assessment:**

Ligand B appears more promising despite the questionable negative half-life value. It has a significantly lower DILI risk, better BBB penetration, lower P-gp efflux, and slightly better binding affinity. Ligand A's high DILI risk is a major concern. The negative half-life for Ligand B is a serious issue that needs investigation, but the other favorable properties make it the better candidate *assuming* the half-life data is an error.

Output:
1
2025-04-17 08:24:29,496 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight (MW):** Both ligands (349.519 and 367.515 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (52.65) is significantly better than Ligand B (80.32). For CNS targets, we want TPSA <= 90, and A is comfortably within that range, while B is approaching the upper limit.

**3. logP:** Both ligands have good logP values (2.118 and 2.67), falling within the optimal 1-3 range.

**4. H-Bond Donors (HBD):** Both ligands are acceptable (1 and 2, respectively), being less than 5.

**5. H-Bond Acceptors (HBA):** Both ligands are acceptable (3 and 5, respectively), being less than 10.

**6. QED:** Both ligands have similar and good QED values (0.846 and 0.838), indicating good drug-like properties.

**7. DILI:** Ligand A (9.616) has a much lower DILI risk than Ligand B (57.076). This is a significant advantage for A.

**8. BBB:** Ligand A (83.56) has a substantially better BBB penetration percentile than Ligand B (62.311).  For a CNS target like DRD2, >70 is desirable, and A is closer to this threshold.

**9. Caco-2 Permeability:** Ligand A (-4.801) has slightly better Caco-2 permeability than Ligand B (-5.169), but both are negative values which is unusual and requires further investigation.

**10. Aqueous Solubility:** Ligand A (-2.17) has slightly better solubility than Ligand B (-3.051), but both are negative values which is unusual and requires further investigation.

**11. hERG Inhibition:** Both ligands have low hERG inhibition risk (0.516 and 0.324).

**12. Microsomal Clearance:** Ligand A (32.588) has slightly lower microsomal clearance than Ligand B (36.573), suggesting better metabolic stability.

**13. In vitro Half-Life:** Ligand A (-10.661) has a significantly longer in vitro half-life than Ligand B (14.442).

**14. P-gp Efflux:** Ligand A (0.057) has a much lower P-gp efflux liability than Ligand B (0.107). Lower P-gp efflux is crucial for CNS penetration.

**15. Binding Affinity:** Both ligands have the same binding affinity (-7.8 kcal/mol), which is excellent.

**Overall Assessment:**

Ligand A is clearly superior. While both have good affinity, Ligand A excels in key ADME properties critical for a CNS-targeting GPCR: TPSA, BBB, DILI, P-gp efflux, and in vitro half-life. Ligand B has a higher TPSA and significantly worse DILI and P-gp efflux profiles, which would likely hinder its ability to reach the brain and could raise safety concerns.

Output:
0
2025-04-17 08:24:29,497 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (385.848 Da) is slightly higher than Ligand B (350.459 Da), but both are acceptable.

**TPSA:** Ligand A (79.37) is better than Ligand B (103.86). For CNS targets, we want TPSA <= 90, so Ligand A is preferable.

**logP:** Both ligands have good logP values (A: 2.939, B: 1.358) falling within the optimal range of 1-3.

**H-Bond Donors/Acceptors:** Ligand A (HBD=1, HBA=4) is better than Ligand B (HBD=3, HBA=4). Lower HBD is generally preferred.

**QED:** Both ligands have acceptable QED values (A: 0.802, B: 0.713), indicating good drug-like properties.

**DILI:** Ligand A (85.576) has a significantly higher DILI risk than Ligand B (19.542). This is a major concern for Ligand A.

**BBB:** Ligand B (67.119) has a better BBB penetration percentile than Ligand A (53.47). While >70 is desirable for CNS targets, 67.119 is still reasonably good.

**Caco-2 Permeability:** Ligand A (-4.683) has worse Caco-2 permeability than Ligand B (-5.378). Lower values are less desirable.

**Aqueous Solubility:** Ligand A (-4.835) has worse solubility than Ligand B (-2.027).

**hERG:** Ligand A (0.422) has a slightly higher hERG risk than Ligand B (0.076).

**Microsomal Clearance:** Ligand B (-16.524) has significantly better metabolic stability (lower clearance) than Ligand A (61.444).

**In vitro Half-Life:** Ligand B (-12.991) has a longer in vitro half-life than Ligand A (45.075).

**P-gp Efflux:** Ligand A (0.251) has lower P-gp efflux than Ligand B (0.004), which is favorable for CNS penetration.

**Binding Affinity:** Ligand A (-8.5 kcal/mol) has a significantly stronger binding affinity than Ligand B (-7.2 kcal/mol). This is a substantial advantage.

**Overall Assessment:**

Ligand A has a much stronger binding affinity, and better TPSA, logP, and P-gp efflux. However, its DILI risk is very high, and its solubility, Caco-2 permeability, and metabolic stability are poor. Ligand B has a better safety profile (lower DILI, hERG), better BBB penetration, and superior ADME properties (solubility, permeability, metabolic stability, half-life). The difference in binding affinity (-8.5 vs -7.2) is 1.3 kcal/mol, which is a significant advantage for Ligand A, but not enough to overcome the substantial safety and ADME concerns. Given the CNS target and the importance of a favorable safety profile, Ligand B is the more promising candidate.

Output:
1
2025-04-17 08:24:29,497 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (347.455 and 355.439 Da) fall within the ideal range of 200-500 Da.

**TPSA:** Ligand A (56.79) is excellent, well below the 90 A^2 threshold for CNS targets. Ligand B (116.63) is higher, but still potentially acceptable, though less ideal.

**logP:** Both ligands have good logP values (2.956 and 2.174), falling within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Both have 1 HBD, which is good. Ligand A has 4 HBA, and Ligand B has 5. Both are within the acceptable limit of <=10.

**QED:** Ligand A (0.804) has a very strong drug-like profile. Ligand B (0.295) is significantly lower, indicating a less desirable overall drug-likeness.

**DILI:** Ligand A (37.379) has a lower DILI risk than Ligand B (43.932), both being acceptable (<40 is good, >60 is high risk).

**BBB:** This is crucial for a CNS target like DRD2. Ligand A (77.433) has a good BBB percentile, exceeding the desirable >70 threshold. Ligand B (55.293) is significantly lower, suggesting poor brain penetration.

**Caco-2 Permeability:** Both have negative Caco-2 values (-4.775 and -4.91), which is unusual and potentially problematic. However, the scale isn't specified, so it's difficult to interpret.

**Aqueous Solubility:** Both ligands have negative solubility values (-3.567 and -1.987), which is also unusual and suggests poor solubility.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.776 and 0.327).

**Microsomal Clearance:** Ligand A (76.434) has a higher microsomal clearance than Ligand B (13.724), meaning it's likely metabolized more quickly. Lower is better here.

**In vitro Half-Life:** Ligand B (13.747) has a slightly longer half-life than Ligand A (16.017), but both are relatively short.

**P-gp Efflux:** Ligand A (0.659) has lower P-gp efflux liability than Ligand B (0.052), which is favorable for CNS penetration.

**Binding Affinity:** Ligand A (-8.5 kcal/mol) has a significantly stronger binding affinity than Ligand B (-6.3 kcal/mol). This is a substantial difference (>1.5 kcal/mol advantage).

**Overall Assessment:**

Ligand A is the superior candidate. It has a better QED score, significantly higher binding affinity, better BBB penetration, and lower P-gp efflux. While its microsomal clearance is higher, the substantial advantage in binding affinity and CNS penetration outweighs this drawback. The negative values for Caco-2 and solubility are concerning, but the other factors strongly favor Ligand A. Ligand B suffers from poor predicted BBB penetration and a weaker binding affinity, making it less likely to be a viable drug candidate.

Output:
0
2025-04-17 08:24:29,497 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (356.375 and 362.402 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (103.4) is slightly above the optimal <90 for CNS targets, while Ligand B (100.21) is closer but still above. This is a minor concern for both.

**logP:** Ligand A (-0.092) is a bit low, potentially hindering permeability. Ligand B (-1.312) is also low, but slightly more problematic. Both are below the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A (HBD=1, HBA=7) is better than Ligand B (HBD=2, HBA=6) in terms of balancing solubility and permeability.

**QED:** Ligand A (0.542) has a better QED score than Ligand B (0.37), indicating a more drug-like profile.

**DILI:** Ligand A (71.152) has a higher DILI risk than Ligand B (29.081), which is a significant negative for Ligand A.

**BBB:** Ligand B (74.68) has a substantially better BBB penetration score than Ligand A (55.603). This is a critical advantage for a CNS target like DRD2.

**Caco-2 Permeability:** Ligand A (-4.867) has poor Caco-2 permeability, indicating poor intestinal absorption. Ligand B (-5.307) is also poor, but similar to A.

**Aqueous Solubility:** Ligand A (-1.345) has slightly better solubility than Ligand B (-0.447).

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.079 and 0.154 respectively).

**Microsomal Clearance:** Ligand B (-1.087) has a significantly lower (better) microsomal clearance than Ligand A (27.896), suggesting greater metabolic stability.

**In vitro Half-Life:** Ligand B (-40.457) has a much longer in vitro half-life than Ligand A (-12.119), which is a major advantage.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.039 and 0.002 respectively).

**Binding Affinity:** Ligand A (-7.9 kcal/mol) has a slightly better binding affinity than Ligand B (-6.2 kcal/mol). While a 1.7 kcal/mol difference is good, it must be weighed against the other ADME properties.

**Overall Assessment:**

Ligand B is the superior candidate. Its significantly better BBB penetration, lower DILI risk, lower microsomal clearance, and longer half-life outweigh the slightly weaker binding affinity and lower logP. The lower logP is a concern for both, but the other advantages of B are more critical for a CNS-targeting GPCR. Ligand A's high DILI risk and poor metabolic stability are major drawbacks.

Output:
1
2025-04-17 08:24:29,497 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (347.419 and 360.42 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (110.44) is higher than the preferred <90 for CNS targets, while Ligand B (40.62) is excellent. This is a significant advantage for Ligand B.

**3. logP:** Ligand A (0.596) is a bit low, potentially hindering permeability. Ligand B (2.519) is within the optimal 1-3 range.

**4. H-Bond Donors:** Ligand A (2) and Ligand B (0) are both acceptable.

**5. H-Bond Acceptors:** Ligand A (6) and Ligand B (2) are both acceptable.

**6. QED:** Both ligands have good QED scores (0.807 and 0.73), indicating drug-like properties.

**7. DILI:** Ligand A (35.479) has a slightly higher DILI risk than Ligand B (23.769), but both are below the concerning threshold of 60.

**8. BBB:** Ligand B (95.618) has a significantly better BBB penetration percentile than Ligand A (89.066). Both are good, but Ligand B is preferable for a CNS target.

**9. Caco-2 Permeability:** Ligand A (-5.26) has a negative value, suggesting poor permeability. Ligand B (-4.457) is also negative, but less so.

**10. Aqueous Solubility:** Both ligands have negative solubility values (-2.253 and -2.94), indicating poor solubility. This is a potential issue for both, but can be addressed with formulation strategies.

**11. hERG Inhibition:** Ligand A (0.359) has a lower hERG risk than Ligand B (0.776), which is favorable.

**12. Microsomal Clearance:** Ligand A (-11.268) has a much lower (better) microsomal clearance than Ligand B (32.203), indicating greater metabolic stability.

**13. In vitro Half-Life:** Ligand B (11.292) has a significantly longer half-life than Ligand A (-0.908).

**14. P-gp Efflux:** Ligand A (0.005) has very low P-gp efflux, which is excellent for CNS penetration. Ligand B (0.155) is also low, but higher than Ligand A.

**15. Binding Affinity:** Both ligands have comparable and strong binding affinities (-8.0 and -6.9 kcal/mol). Ligand A is slightly better, but the difference isn't substantial enough to overcome other deficiencies.

**Overall Assessment:**

Ligand B excels in key GPCR-relevant properties: TPSA, BBB, and half-life. While its solubility and Caco-2 permeability are not ideal, these can potentially be mitigated. Ligand A has better P-gp efflux and microsomal clearance, but its higher TPSA and lower BBB penetration are significant drawbacks for a CNS target. The slightly better affinity of Ligand A is not enough to offset the ADME concerns.

Output:
1
2025-04-17 08:24:29,498 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (370.877 and 350.459 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (76.66) is better than Ligand B (78.87), both are below the 90 A^2 threshold for CNS targets, which is good.

**logP:** Ligand A (2.676) is within the optimal 1-3 range. Ligand B (1.214) is at the lower end, potentially impacting permeability.

**H-Bond Donors/Acceptors:** Both have 2 HBD and are within acceptable limits. Ligand A has 5 HBA, and Ligand B has 4, both are below the 10 limit.

**QED:** Both ligands have good QED scores (0.653 and 0.799, respectively), indicating drug-like properties.

**DILI:** Ligand A (51.493) has a higher DILI risk than Ligand B (12.679). This is a significant drawback for Ligand A.

**BBB:** Ligand B (60.644) has a significantly better BBB penetration score than Ligand A (40.016). This is critical for a CNS target like DRD2.

**Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and suggests poor permeability. However, the scale is not specified, so it's hard to interpret.

**Aqueous Solubility:** Both have negative solubility values, which is also unusual and suggests poor solubility. Again, the scale is not specified.

**hERG:** Both ligands have very low hERG inhibition liability (0.274 and 0.169), which is excellent.

**Microsomal Clearance:** Ligand A (91.839) has higher microsomal clearance than Ligand B (16.757), indicating lower metabolic stability.

**In vitro Half-Life:** Ligand B (13.181) has a longer in vitro half-life than Ligand A (31.678).

**P-gp Efflux:** Both have low P-gp efflux liability (0.067 and 0.023), which is favorable for CNS penetration.

**Binding Affinity:** Ligand B (-8.2 kcal/mol) has a stronger binding affinity than Ligand A (-7.5 kcal/mol). This is a 0.7 kcal/mol difference, which is substantial and can outweigh some ADME drawbacks.

**Conclusion:**

Considering the GPCR-specific priorities, Ligand B is the more promising candidate. While both have issues with Caco-2 and solubility, Ligand B has significantly better BBB penetration, lower DILI risk, better metabolic stability (lower Cl_mic, longer t1/2), and a stronger binding affinity. The higher affinity of Ligand B is a key advantage, and the improved ADME properties make it a more viable drug candidate for a CNS target like DRD2.

Output:
1
2025-04-17 08:24:29,498 - INFO - Batch 446 complete. Total preferences: 7136
2025-04-17 08:24:29,498 - INFO - Processing batch 447/512...
2025-04-17 08:25:16,790 - INFO - Reasoning:

Let's analyze Ligand A and Ligand B against the provided guidelines, prioritizing GPCR-specific properties (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (352.431 and 350.459 Da) fall comfortably within the ideal 200-500 Da range.

**TPSA:** Ligand A (99.1) is higher than the preferred <90 for CNS targets, while Ligand B (70.08) is well within the range. This is a significant advantage for Ligand B.

**logP:** Ligand A (0.105) is quite low, potentially hindering membrane permeability. Ligand B (0.881) is better, but still on the lower side of the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A has 3 HBD and 5 HBA, acceptable values. Ligand B has 1 HBD and 4 HBA, also acceptable.

**QED:** Both ligands have good QED scores (0.669 and 0.772), indicating drug-like properties.

**DILI:** Ligand A (44.397) has a moderate DILI risk, while Ligand B (11.361) has a very low risk. This is a clear advantage for Ligand B.

**BBB:** This is crucial for a CNS target like DRD2. Ligand A has a BBB percentile of 33.579, which is below the desirable >70 threshold. Ligand B has a BBB percentile of 61.535, which is better, though still not optimal.

**Caco-2 Permeability:** Ligand A (-5.222) has poor Caco-2 permeability. Ligand B (-4.466) is also poor, but slightly better than Ligand A.

**Aqueous Solubility:** Both ligands have very poor aqueous solubility (-1.169 and -0.643 respectively). This could pose formulation challenges.

**hERG:** Both ligands show low hERG inhibition liability (0.118 and 0.215), which is favorable.

**Microsomal Clearance:** Ligand A (-4.353) suggests lower clearance and better metabolic stability than Ligand B (4.442).

**In vitro Half-Life:** Ligand A (25.525 hours) has a longer half-life than Ligand B (2.997 hours). This is a significant advantage for Ligand A.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.016 and 0.072), which is good for CNS penetration.

**Binding Affinity:** Ligand B (-7.8 kcal/mol) has a stronger binding affinity than Ligand A (-8.8 kcal/mol). This is a substantial advantage, potentially outweighing some ADME drawbacks.

**Overall Assessment:**

Ligand B is the stronger candidate. While both have solubility issues, Ligand B excels in key GPCR-relevant properties: significantly lower DILI risk, better TPSA, and, most importantly, a stronger binding affinity. Although Ligand A has better metabolic stability and half-life, the superior affinity and safety profile of Ligand B are more critical for a CNS drug candidate. The slightly better BBB penetration of Ligand B also contributes to its favorability.

Output:
1
2025-04-17 08:25:16,791 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (373.475 and 349.475 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (96.97) is slightly higher than Ligand B (74.57). Both are below the 90 A^2 threshold desirable for CNS targets, but Ligand B is significantly better.

**3. logP:** Both ligands have good logP values (1.883 and 1.936), falling within the optimal 1-3 range.

**4. H-Bond Donors:** Both have 2 HBD, which is acceptable.

**5. H-Bond Acceptors:** Ligand A has 5 HBA, and Ligand B has 4. Both are within the acceptable limit of 10.

**6. QED:** Both have similar QED values (0.611 and 0.634), indicating good drug-likeness.

**7. DILI:** Ligand A has a significantly higher DILI risk (63.164%) compared to Ligand B (16.053%). This is a major concern for Ligand A.

**8. BBB:** Ligand A (74.486%) has a better BBB penetration score than Ligand B (55.021%), which is crucial for a CNS target like DRD2.

**9. Caco-2 Permeability:** Ligand A (-5.103) has worse Caco-2 permeability than Ligand B (-4.888).

**10. Aqueous Solubility:** Both have very poor aqueous solubility (-2.057 and -2.1). This is a concern for both, but not a deciding factor.

**11. hERG Inhibition:** Both have low hERG inhibition risk (0.578 and 0.757).

**12. Microsomal Clearance:** Ligand A (20.782) has lower microsomal clearance than Ligand B (45.354), suggesting better metabolic stability.

**13. In vitro Half-Life:** Ligand A (-25.346) has a much shorter in vitro half-life than Ligand B (8.333). This is a significant drawback for Ligand A.

**14. P-gp Efflux:** Ligand A (0.062) has lower P-gp efflux than Ligand B (0.218), which is favorable for CNS penetration.

**15. Binding Affinity:** Ligand B (-7.8 kcal/mol) has a significantly stronger binding affinity than Ligand A (-6.9 kcal/mol). This is a 0.9 kcal/mol difference, which is substantial and can outweigh some ADME drawbacks.

**Overall Assessment:**

While Ligand A has better BBB penetration and lower P-gp efflux, its significantly higher DILI risk, shorter half-life, and weaker binding affinity are major concerns. Ligand B, despite having a lower BBB score, exhibits a much better safety profile (lower DILI), better metabolic stability (lower Cl_mic, longer t1/2), and, most importantly, a significantly stronger binding affinity. The stronger binding affinity is a critical advantage for a GPCR ligand. The difference in BBB is not substantial enough to overcome the other significant advantages of Ligand B.

Output:
1
2025-04-17 08:25:16,791 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B based on the provided guidelines, prioritizing GPCR-specific properties (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (372.55 and 370.877 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (49.41) is significantly better than Ligand B (84.5). For CNS targets, TPSA should be <= 90, and ideally lower. Ligand A is well within this range, while Ligand B is approaching the upper limit and less desirable.

**logP:** Ligand A (3.403) is optimal (1-3), while Ligand B (1.542) is at the lower end of the acceptable range. Lower logP can hinder permeation.

**H-Bond Donors/Acceptors:** Ligand A (HBD=1, HBA=3) and Ligand B (HBD=2, HBA=4) both have reasonable numbers of H-bond donors and acceptors, falling within the recommended limits.

**QED:** Both ligands have similar QED values (0.697 and 0.603), indicating good drug-like properties.

**DILI:** Ligand A (7.29) has a much lower DILI risk than Ligand B (29.43), suggesting better potential for avoiding liver toxicity.

**BBB:** This is crucial for a CNS target like DRD2. Ligand A has an excellent BBB percentile (94.998) compared to Ligand B (60.644). This is a major advantage for Ligand A.

**Caco-2 Permeability:** Ligand A (-4.747) and Ligand B (-5.083) both have negative values, which is unusual. It's difficult to interpret without knowing the scale, but generally, higher values are better.

**Aqueous Solubility:** Ligand A (-3.803) and Ligand B (-2.335) both have negative values, which is unusual. It's difficult to interpret without knowing the scale, but generally, higher values are better.

**hERG Inhibition:** Ligand A (0.844) has a slightly higher hERG risk than Ligand B (0.095), but both are relatively low.

**Microsomal Clearance:** Ligand B (8.042) has significantly lower microsomal clearance than Ligand A (61.194), indicating better metabolic stability.

**In vitro Half-Life:** Ligand B (5.11) has a better in vitro half-life than Ligand A (-12.931).

**P-gp Efflux:** Ligand A (0.172) has lower P-gp efflux than Ligand B (0.095), which is desirable for CNS penetration.

**Binding Affinity:** Ligand B (-8.0 kcal/mol) has a slightly better binding affinity than Ligand A (-7.6 kcal/mol), but the difference is less than 1.5 kcal/mol, and can be overcome by other factors.

**Overall Assessment:**

Ligand A is the stronger candidate. Its significantly better BBB penetration, lower DILI risk, and favorable TPSA outweigh the slightly weaker binding affinity and higher clearance. The logP value is also more optimal. While Ligand B has better metabolic stability and binding affinity, the poor BBB penetration is a major drawback for a CNS-targeted drug.

Output:
1
2025-04-17 08:25:16,791 - INFO - Here's a step-by-step comparison of Ligand A and Ligand B, followed by my final decision:

**1. Molecular Weight (MW):**
*   Ligand A: 340.335 Da - Excellent, within the ideal range.
*   Ligand B: 447.164 Da - Acceptable, but approaching the upper limit.
*   *Advantage: A*

**2. Topological Polar Surface Area (TPSA):**
*   Ligand A: 94.57  - Good for CNS targets, below the 90 threshold.
*   Ligand B: 73.91 - Excellent for CNS targets.
*   *Advantage: B*

**3. Lipophilicity (logP):**
*   Ligand A: 2.58 - Optimal.
*   Ligand B: 4.272 - High, potentially leading to solubility issues and off-target effects.
*   *Advantage: A*

**4. H-Bond Donors (HBD):**
*   Ligand A: 1 - Excellent.
*   Ligand B: 2 - Acceptable.
*   *Advantage: A*

**5. H-Bond Acceptors (HBA):**
*   Ligand A: 6 - Excellent.
*   Ligand B: 3 - Excellent.
*   *No significant advantage*

**6. QED:**
*   Ligand A: 0.693 - Very good, indicating strong drug-like properties.
*   Ligand B: 0.739 - Very good, slightly better than A.
*   *Advantage: B*

**7. DILI Risk:**
*   Ligand A: 85.692 - High risk.
*   Ligand B: 63.125 - Moderate risk, but significantly better than A.
*   *Advantage: B*

**8. BBB Penetration:**
*   Ligand A: 66.111 - Acceptable, but not ideal for a CNS target.
*   Ligand B: 86.661 - Excellent, highly desirable for a CNS target.
*   *Advantage: B*

**9. Caco-2 Permeability:**
*   Ligand A: -4.702 - Poor permeability.
*   Ligand B: -5.269 - Poor permeability.
*   *No significant advantage*

**10. Aqueous Solubility:**
*   Ligand A: -4.581 - Poor solubility.
*   Ligand B: -4.494 - Poor solubility.
*   *No significant advantage*

**11. hERG Inhibition:**
*   Ligand A: 0.275 - Low risk.
*   Ligand B: 0.655 - Moderate risk.
*   *Advantage: A*

**12. Microsomal Clearance:**
*   Ligand A: 77.973 - Moderate clearance.
*   Ligand B: 17.767 - Low clearance, indicating better metabolic stability.
*   *Advantage: B*

**13. In vitro Half-Life:**
*   Ligand A: 26.314 - Moderate half-life.
*   Ligand B: 8.26 - Short half-life.
*   *Advantage: A*

**14. P-gp Efflux:**
*   Ligand A: 0.455 - Moderate efflux.
*   Ligand B: 0.471 - Moderate efflux.
*   *No significant advantage*

**15. Binding Affinity:**
*   Ligand A: -9.3 kcal/mol - Excellent.
*   Ligand B: -9.4 kcal/mol - Excellent, slightly better than A.
*   *Advantage: B*

**Overall Assessment:**

Considering DRD2 is a CNS target (GPCR), BBB penetration, TPSA, logP, and affinity are paramount. Ligand B excels in BBB (86.661 vs 66.111) and has a slightly better affinity (-9.4 vs -9.3). While Ligand A has a better logP, the significantly better BBB and DILI profile of Ligand B outweigh this. Ligand B also demonstrates better metabolic stability (lower Cl_mic). Although both have poor solubility and Caco-2 permeability, these can be addressed with formulation strategies. The higher DILI risk associated with Ligand A is a major concern.

Output:
1
2025-04-17 08:25:16,792 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (346.431 and 345.487 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (94.56) is slightly above the optimal <90 for CNS targets, but still reasonable. Ligand B (52.65) is excellent, well below the threshold.

**logP:** Ligand A (0.928) is a bit low, potentially hindering permeability. Ligand B (2.758) is within the optimal 1-3 range.

**H-Bond Donors & Acceptors:** Ligand A has 3 HBD and 5 HBA, acceptable. Ligand B has 1 HBD and 3 HBA, also acceptable.

**QED:** Both ligands have good QED scores (0.639 and 0.893), indicating drug-like properties.

**DILI:** Ligand A (31.291) has a moderate DILI risk, but is still acceptable. Ligand B (11.594) has a very low DILI risk, which is preferable.

**BBB:** This is crucial for a CNS target. Ligand A (55.642) is below the desirable >70 threshold. Ligand B (86.623) is excellent, exceeding the threshold.

**Caco-2 Permeability:** Ligand A (-5.301) shows poor permeability. Ligand B (-4.643) shows slightly better permeability, but still not great.

**Aqueous Solubility:** Both ligands have negative solubility values (-1.885 and -2.035), which is unusual and suggests poor solubility. This is a concern for both.

**hERG Inhibition:** Ligand A (0.166) has a very low hERG risk. Ligand B (0.804) has a slightly higher, but still acceptable, hERG risk.

**Microsomal Clearance:** Ligand A (-18.2) has very low clearance, indicating good metabolic stability. Ligand B (-3.549) has a slightly higher clearance, but is still acceptable.

**In vitro Half-Life:** Ligand A (21.779) has a reasonable half-life. Ligand B (7.423) has a shorter half-life, which might necessitate more frequent dosing.

**P-gp Efflux:** Ligand A (0.01) has very low P-gp efflux, which is excellent for CNS penetration. Ligand B (0.127) has slightly higher P-gp efflux, but is still acceptable.

**Binding Affinity:** Ligand B (-8.5 kcal/mol) has a significantly stronger binding affinity than Ligand A (-7.7 kcal/mol). This 1.8 kcal/mol difference is substantial and can outweigh some ADME drawbacks.

**Overall Assessment:**

Ligand B is the stronger candidate. While both have solubility issues, Ligand B excels in the critical areas for a CNS-targeting GPCR: BBB penetration (86.623 vs 55.642), logP (2.758 vs 0.928), and, most importantly, binding affinity (-8.5 vs -7.7 kcal/mol). The lower DILI risk and better P-gp efflux of Ligand B further support its selection. The slightly shorter half-life is a minor drawback compared to the significant advantages in other areas.



Output:
1
2025-04-17 08:25:16,792 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (361.511 and 373.425 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Both ligands have TPSA values (71.09 and 71.53) that are acceptable for oral absorption (<140) but slightly high for optimal CNS penetration (<90).

**3. logP:** Ligand A (2.96) is optimal, while Ligand B (1.812) is slightly low, potentially impacting membrane permeability.

**4. H-Bond Donors:** Both ligands have acceptable HBD counts (2 and 1, respectively), well below the threshold of 5.

**5. H-Bond Acceptors:** Both ligands have acceptable HBA counts (4 and 5, respectively), below the threshold of 10.

**6. QED:** Both ligands have similar, good QED values (0.847 and 0.826), indicating drug-like properties.

**7. DILI:** Both ligands have similar, low DILI risk (43.66 and 43.622 percentile), which is favorable.

**8. BBB:** This is a critical parameter for a CNS target. Ligand B (85.498 percentile) significantly outperforms Ligand A (46.336 percentile) in predicted BBB penetration.

**9. Caco-2 Permeability:** Ligand A (-5.077) and Ligand B (-4.8) both have negative values, indicating poor permeability.

**10. Aqueous Solubility:** Both ligands have poor aqueous solubility (-2.755 and -2.322, respectively).

**11. hERG Inhibition:** Both ligands show very low hERG inhibition risk (0.112 and 0.165 percentile), which is excellent.

**12. Microsomal Clearance:** Ligand B (-3.967) has a negative clearance, suggesting very high metabolic stability, while Ligand A (20.789) has a positive clearance, indicating faster metabolism.

**13. In vitro Half-Life:** Ligand B (-1.731) has a negative half-life, suggesting a very long half-life, while Ligand A (9.213) has a shorter half-life.

**14. P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.164 and 0.042 percentile), which is favorable for CNS exposure.

**15. Binding Affinity:** Ligand B (-9.1 kcal/mol) has a slightly better binding affinity than Ligand A (-8.3 kcal/mol). While both are good, the 0.8 kcal/mol difference is noteworthy.

**Overall Assessment:**

Ligand B is the more promising candidate. While both ligands have acceptable MW, QED, DILI, and hERG profiles, Ligand B excels in the key areas for a CNS-targeting GPCR: significantly higher predicted BBB penetration, superior metabolic stability (negative Cl_mic and half-life), and slightly improved binding affinity. The lower logP of Ligand B is a minor concern, but the substantial advantage in BBB penetration and metabolic stability outweighs this drawback.

Output:
1
2025-04-17 08:25:16,792 - INFO - Reasoning:

Let's analyze Ligand A and Ligand B based on the provided guidelines, prioritizing GPCR-specific properties (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (346.431 and 354.51 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (85.25) is significantly better than Ligand B (49.41). For CNS targets, TPSA should be <=90, and ideally lower. Ligand A is closer to the upper limit, while Ligand B is well within the desired range.

**logP:** Ligand A (1.429) is optimal, while Ligand B (4.006) is approaching the upper limit of the optimal range. Higher logP can lead to solubility issues and off-target effects.

**H-Bond Donors/Acceptors:** Ligand A has 2 HBD and 5 HBA, while Ligand B has 1 HBD and 2 HBA. Both are within acceptable limits.

**QED:** Ligand A (0.628) has a better QED score than Ligand B (0.476), indicating a more drug-like profile.

**DILI:** Ligand A (48.313) has a slightly higher DILI risk than Ligand B (17.255), but both are well below the concerning threshold of 60.

**BBB:** Ligand B (83.288) has a significantly higher BBB penetration percentile than Ligand A (59.636). This is *crucial* for a CNS target like DRD2.

**Caco-2 Permeability:** Ligand A (-5.182) has poor Caco-2 permeability, while Ligand B (-4.6) is also poor, but slightly better.

**Aqueous Solubility:** Ligand A (-2.085) has better aqueous solubility than Ligand B (-3.905).

**hERG:** Ligand A (0.366) has a lower hERG inhibition liability than Ligand B (0.83), which is preferable.

**Microsomal Clearance:** Ligand B (83.843) has significantly higher microsomal clearance than Ligand A (40.6), indicating lower metabolic stability.

**In vitro Half-Life:** Ligand B (7.708) has a longer in vitro half-life than Ligand A (-1.774).

**P-gp Efflux:** Ligand A (0.088) has lower P-gp efflux liability than Ligand B (0.556), which is beneficial for CNS penetration.

**Binding Affinity:** Ligand B (-7.7 kcal/mol) has a slightly better binding affinity than Ligand A (-8.0 kcal/mol). While the difference is small, it's still a factor.

**Overall Assessment:**

Ligand B excels in BBB penetration and has a slightly better binding affinity. However, Ligand A has better TPSA, logP, QED, solubility, hERG, P-gp efflux, and metabolic stability. The superior BBB penetration of Ligand B is a significant advantage for a CNS target. The slightly better affinity of Ligand B is also a plus. While Ligand A has a better overall ADME profile, the importance of BBB for DRD2 targeting tips the balance in favor of Ligand B.

Output:
1
2025-04-17 08:25:16,792 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (337.423 and 334.339 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (53.51) is excellent, well below the 90 A^2 threshold for CNS targets. Ligand B (122.8) is higher, but still potentially acceptable, though less ideal.

**logP:** Both ligands have good logP values (2.632 and 3.286), falling within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A (0 HBD, 4 HBA) is preferable to Ligand B (2 HBD, 7 HBA) as it has fewer potential issues with permeability. Both are within acceptable limits.

**QED:** Ligand A (0.805) has a significantly better QED score than Ligand B (0.429), indicating a more drug-like profile.

**DILI:** Ligand A (36.293) has a much lower DILI risk than Ligand B (92.012). This is a significant advantage.

**BBB:** Ligand A (80.38) has a much higher BBB penetration percentile than Ligand B (54.052). This is crucial for a CNS target like DRD2.

**Caco-2 Permeability:** Ligand A (-4.844) has a negative Caco-2 value, which is unusual and suggests very poor permeability. Ligand B (-5.17) is also poor, but similar.

**Aqueous Solubility:** Ligand A (-1.785) and Ligand B (-5.452) both have poor aqueous solubility.

**hERG:** Both ligands have similar hERG inhibition liability (0.698 and 0.763), indicating a moderate risk.

**Microsomal Clearance:** Ligand A (39.604) has a higher microsomal clearance than Ligand B (29.111), suggesting lower metabolic stability.

**In vitro Half-Life:** Ligand B (17.04) has a significantly longer in vitro half-life than Ligand A (0.97).

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.529 and 0.431).

**Binding Affinity:** Ligand B (-9.6 kcal/mol) has a substantially stronger binding affinity than Ligand A (0.0 kcal/mol). This is a very large difference.

**Overall Assessment:**

While Ligand A has better properties in terms of TPSA, logP, QED, DILI, and BBB, the significantly stronger binding affinity of Ligand B (-9.6 kcal/mol vs 0.0 kcal/mol) is a major advantage. The difference in binding affinity is likely to outweigh the drawbacks of Ligand B (higher TPSA, lower QED, higher DILI, lower BBB). The poor Caco-2 and solubility of both are concerning, but can potentially be addressed with formulation strategies. The longer half-life of Ligand B is also a positive.

Output:
1
2025-04-17 08:25:16,793 - INFO - Reasoning:

Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (379.222 and 347.371 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (59.81) is excellent, well below the 90 A^2 threshold for CNS targets. Ligand B (102.69) is higher, but still potentially acceptable, though less optimal.

**logP:** Ligand A (4.333) is slightly high, potentially leading to solubility issues or off-target interactions. Ligand B (2.144) is within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A (1 HBD, 4 HBA) and Ligand B (2 HBD, 6 HBA) both have reasonable numbers of H-bond donors and acceptors, falling within the guidelines.

**QED:** Both ligands have good QED scores (0.734 and 0.795), indicating good drug-like properties.

**DILI:** Both ligands have relatively high DILI risk (88.019 and 73.013), but this isn't a complete dealbreaker at this stage.

**BBB:** Ligand A (73.827) has a better BBB percentile than Ligand B (68.282), which is a significant advantage for a CNS target like DRD2. Both are above 60, but A is closer to the desirable >70.

**Caco-2 Permeability:** Both show poor Caco-2 permeability (-4.652 and -4.854). This suggests potential absorption issues.

**Aqueous Solubility:** Both ligands have very poor aqueous solubility (-5.99 and -3.653). This is a concern, especially given Ligand A's higher logP.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.523 and 0.495).

**Microsomal Clearance:** Ligand B (20.446) has significantly lower microsomal clearance than Ligand A (72.129), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand B (69.331) has a longer in vitro half-life than Ligand A (31.671), which is desirable.

**P-gp Efflux:** Ligand A (0.495) has lower P-gp efflux than Ligand B (0.295), which is beneficial for CNS penetration.

**Binding Affinity:** Ligand A (-10.1 kcal/mol) has a significantly stronger binding affinity than Ligand B (-8.0 kcal/mol). This is a substantial advantage, potentially outweighing some of its ADME drawbacks. The difference is >1.5 kcal/mol.

**Overall Assessment:**

Ligand A has a superior binding affinity and better BBB penetration, which are critical for a CNS GPCR target. However, it suffers from higher logP, poorer solubility, and higher clearance. Ligand B has better ADME properties (lower logP, better clearance, longer half-life) but significantly weaker binding affinity. Given the importance of potency for GPCRs, and the substantial difference in binding affinity, Ligand A is the more promising candidate, *provided* that the solubility and logP issues can be addressed through further optimization. The strong binding affinity could allow for a lower dose, potentially mitigating some of the ADME concerns.

Output:
1
2025-04-17 08:25:16,793 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (342.4) is slightly higher than Ligand B (336.4), but this isn't a major concern.

**TPSA:** Ligand A (78.53) is better than Ligand B (64.59) as it is closer to the optimal range for CNS targets (<=90).

**logP:** Ligand A (1.968) is optimal, while Ligand B (4.28) is higher. While still within the acceptable range, a logP of 4.28 could potentially lead to solubility issues and off-target interactions.

**H-Bond Donors/Acceptors:** Both ligands have 1 HBD, which is good. Ligand A has 4 HBA, and Ligand B has 6. Both are acceptable, but Ligand A is slightly better.

**QED:** Ligand A (0.925) has a significantly better QED score than Ligand B (0.602), indicating a more drug-like profile.

**DILI:** Ligand A (68.244) has a lower DILI risk than Ligand B (93.059), which is a significant advantage.

**BBB:** Ligand A (67.08) has a better BBB penetration score than Ligand B (52.811). While neither is >70, Ligand A is closer, which is crucial for a CNS target like DRD2.

**Caco-2 Permeability:** Ligand A (-5.245) has a more negative Caco-2 value, suggesting lower permeability than Ligand B (-4.644). This is a slight negative for Ligand A.

**Aqueous Solubility:** Ligand A (-2.696) has better solubility than Ligand B (-5.723).

**hERG Inhibition:** Ligand A (0.343) has a much lower hERG inhibition liability than Ligand B (0.938), which is a critical safety advantage.

**Microsomal Clearance:** Ligand A (12.476) has lower microsomal clearance than Ligand B (45.905), indicating better metabolic stability.

**In vitro Half-Life:** Ligand A (-30.338) has a significantly longer in vitro half-life than Ligand B (79.677).

**P-gp Efflux:** Ligand A (0.018) has much lower P-gp efflux liability than Ligand B (0.68), which is highly desirable for CNS penetration.

**Binding Affinity:** Both ligands have similar binding affinities (-9.2 kcal/mol and -8.0 kcal/mol respectively). Ligand A is slightly better, but the difference is not substantial enough to outweigh other significant ADME differences.

**Overall:**

Ligand A consistently outperforms Ligand B across most critical ADME properties, especially those prioritized for GPCRs targeting the CNS (BBB, logP, Pgp, TPSA). It has a better safety profile (lower DILI and hERG), better metabolic stability, and a more drug-like profile (higher QED). While Ligand B has slightly better Caco-2 permeability, this is less important for a CNS target. The binding affinity difference is minimal.

Output:
0
2025-04-17 08:25:16,793 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (348.399 and 361.467 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (90.7) is slightly above the preferred <90 for CNS targets, but still reasonable. Ligand B (69.72) is excellent, well below 90.

**3. logP:** Ligand A (3.069) is optimal. Ligand B (0.876) is a bit low, potentially hindering membrane permeability.

**4. H-Bond Donors:** Both ligands have 1 HBD, which is within the acceptable limit of <=5.

**5. H-Bond Acceptors:** Ligand A has 5 HBA, and Ligand B has 4, both within the acceptable limit of <=10.

**6. QED:** Ligand B (0.813) has a significantly better QED score than Ligand A (0.464), indicating a more drug-like profile.

**7. DILI:** Ligand B (32.299) has a much lower DILI risk than Ligand A (45.328), which is a significant advantage.

**8. BBB:** Both ligands have good BBB penetration (Ligand A: 68.554, Ligand B: 72.043), but Ligand B is slightly better. Both are above the 70% threshold for CNS targets.

**9. Caco-2 Permeability:** Ligand A (-4.478) has poor Caco-2 permeability, while Ligand B (-5.204) is also poor, but slightly worse.

**10. Aqueous Solubility:** Ligand A (-4.062) has poor solubility, while Ligand B (-2.209) has better solubility.

**11. hERG Inhibition:** Ligand A (0.544) has a slightly higher hERG risk than Ligand B (0.184).

**12. Microsomal Clearance:** Ligand B (10.879) has significantly lower microsomal clearance than Ligand A (72.592), suggesting better metabolic stability.

**13. In vitro Half-Life:** Ligand B (6.508) has a longer half-life than Ligand A (-20.664), which is a positive attribute.

**14. P-gp Efflux:** Ligand B (0.038) has very low P-gp efflux, which is excellent for CNS penetration. Ligand A (0.444) has moderate P-gp efflux.

**15. Binding Affinity:** Ligand A (-8.6 kcal/mol) has a significantly stronger binding affinity than Ligand B (0.0 kcal/mol). This is a substantial advantage.

**Overall Assessment:**

While Ligand A boasts a much stronger binding affinity, Ligand B demonstrates superior ADME properties. Specifically, its lower DILI risk, better QED, lower microsomal clearance, longer half-life, and significantly lower P-gp efflux are highly desirable, especially for a CNS target like DRD2. The slightly lower logP of Ligand B is a concern, but the other benefits likely outweigh this drawback. The poor Caco-2 and solubility of both compounds are potential issues that would need to be addressed in further optimization, but the ADME profile of Ligand B is considerably more promising. The substantial difference in binding affinity is a major factor, but the ADME properties of Ligand B are far superior.

Output:
1
2025-04-17 08:25:16,793 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (360.483 and 349.435 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (88.99) is slightly above the optimal <90 for CNS targets, but still reasonable. Ligand B (80.56) is excellent, well below 90.

**logP:** Ligand A (2.303) is within the optimal 1-3 range. Ligand B (0.704) is a bit low, potentially hindering permeability.

**H-Bond Donors/Acceptors:** Ligand A has 2 HBD and 4 HBA, which are acceptable. Ligand B has 0 HBD and 6 HBA, also acceptable.

**QED:** Both ligands have similar QED values (0.807 and 0.782), indicating good drug-likeness.

**DILI:** Ligand A (73.052) has a higher DILI risk than Ligand B (49.942). This is a significant negative for Ligand A.

**BBB:** Ligand B (72.082) has a much better BBB penetration percentile than Ligand A (29.275). This is *critical* for a CNS target like DRD2.

**Caco-2 Permeability:** Ligand A (-5.321) has poor Caco-2 permeability, while Ligand B (-4.704) is slightly better, but still not ideal.

**Aqueous Solubility:** Ligand A (-4.271) has poor aqueous solubility, while Ligand B (-1.57) is better.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.537 and 0.25).

**Microsomal Clearance:** Ligand A (33.826) has higher microsomal clearance than Ligand B (28.05), suggesting lower metabolic stability.

**In vitro Half-Life:** Both ligands have similar, short in vitro half-lives (2.841 and 2.212 hours).

**P-gp Efflux:** Both ligands show low P-gp efflux liability (0.111 and 0.139).

**Binding Affinity:** Both ligands have excellent binding affinities (-8.6 and -8.0 kcal/mol). The difference of 0.6 kcal/mol is not substantial enough to outweigh other factors.

**Conclusion:**

Considering the GPCR-specific priorities, Ligand B is the more promising candidate. Its significantly better BBB penetration (72.082 vs 29.275) is a major advantage for a CNS target. While its logP is slightly low, the superior BBB, lower DILI risk, and better solubility outweigh this drawback. The similar binding affinities make the ADME properties the deciding factor.

Output:
1
2025-04-17 08:25:16,794 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (363.527 and 352.435 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (53.51) is excellent, well below the 90 A^2 threshold for CNS targets. Ligand B (103.53) is higher, but still potentially acceptable, though less ideal.

**logP:** Ligand A (2.985) is optimal (1-3). Ligand B (0.308) is low, which could hinder permeability and CNS penetration.

**H-Bond Donors/Acceptors:** Ligand A (0 HBD, 4 HBA) is favorable. Ligand B (3 HBD, 4 HBA) is also acceptable.

**QED:** Ligand A (0.78) is very good, indicating strong drug-likeness. Ligand B (0.416) is lower, suggesting a less optimal drug-like profile.

**DILI:** Both ligands have acceptable DILI risk (Ligand A: 39.395, Ligand B: 41.024), below the 40 threshold.

**BBB:** Ligand A (76.735) has a good BBB percentile, desirable for a CNS target. Ligand B (42.264) is significantly lower, raising concerns about CNS penetration.

**Caco-2 Permeability:** Ligand A (-4.889) and Ligand B (-5.234) both have negative values, indicating poor permeability.

**Aqueous Solubility:** Both ligands have poor aqueous solubility (-2.572 and -1.543 respectively).

**hERG:** Both ligands show low hERG inhibition liability (Ligand A: 0.483, Ligand B: 0.257).

**Microsomal Clearance:** Ligand A (89.208) has higher clearance than Ligand B (20.519), suggesting lower metabolic stability.

**In vitro Half-Life:** Ligand A (8.639) has a longer half-life than Ligand B (1.814).

**P-gp Efflux:** Both ligands have low P-gp efflux liability (Ligand A: 0.183, Ligand B: 0.062).

**Binding Affinity:** Ligand A (-8.7 kcal/mol) has a significantly stronger binding affinity than Ligand B (-6.4 kcal/mol). This is a substantial difference (>1.5 kcal/mol).

**Conclusion:**

Ligand A is the superior candidate. While both have poor solubility and Caco-2 permeability, Ligand A excels in critical areas for a CNS GPCR target: significantly higher binding affinity, better BBB penetration, better QED, and a longer half-life. The slightly higher microsomal clearance is a concern, but the strong binding affinity likely outweighs this drawback. Ligand B's low logP and poor BBB penetration are major liabilities.

Output:
1
2025-04-17 08:25:16,794 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (352.312 and 341.415 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (70.59) is significantly better than Ligand B (107.77). For CNS targets, TPSA < 90 is preferred, and A is comfortably within this range, while B is approaching the upper limit.

**logP:** Ligand A (3.567) is optimal, while Ligand B (0.888) is quite low. Low logP can hinder membrane permeability, which is a concern for CNS penetration.

**H-Bond Donors/Acceptors:** Ligand A (HBD=3, HBA=4) and Ligand B (HBD=2, HBA=5) are both within acceptable ranges (<=5 HBD and <=10 HBA).

**QED:** Both ligands have similar QED values (0.739 and 0.73), indicating good drug-likeness.

**DILI:** Ligand A (63.086) has a higher DILI risk than Ligand B (41.915), but both are reasonably acceptable.

**BBB:** Ligand A (70.492) has a much better BBB percentile than Ligand B (51.221). A value >70 is desirable for CNS targets, and A is close, while B is significantly lower. This is a major advantage for A.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.168 and -5.22), which is unusual and suggests poor permeability. This is a red flag for both.

**Aqueous Solubility:** Both ligands have negative solubility values (-4.675 and -2.503), also unusual and indicating poor solubility. This is a concern for both.

**hERG Inhibition:** Ligand A (0.842) has a slightly higher hERG risk than Ligand B (0.075). B is much preferred here.

**Microsomal Clearance:** Ligand A (40.6) has higher microsomal clearance than Ligand B (5.206), indicating lower metabolic stability. B is much preferred here.

**In vitro Half-Life:** Ligand A (13.235) has a slightly longer half-life than Ligand B (13.325), but the difference is minimal.

**P-gp Efflux:** Ligand A (0.475) has lower P-gp efflux than Ligand B (0.017), which is beneficial for CNS exposure. A is preferred here.

**Binding Affinity:** Both ligands have very similar and strong binding affinities (-9.4 and -8.4 kcal/mol). The difference of 1 kcal/mol is not substantial enough to override other significant differences.

**Overall Assessment:**

Considering the GPCR-specific priorities, Ligand A is the better candidate. Its significantly better BBB penetration and logP values are crucial for CNS drug development. While it has a slightly higher DILI risk and hERG inhibition, and worse metabolic stability, these are outweighed by the superior CNS penetration properties. The poor Caco-2 and solubility values are concerning for both, but can be addressed with formulation strategies. The slightly better P-gp efflux profile of A is also a plus.



Output:
0
2025-04-17 08:25:16,794 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (357.451 and 344.419 Da) fall within the ideal range of 200-500 Da.

**TPSA:** Ligand A (100.13) is slightly above the optimal <90 for CNS targets, but still reasonable. Ligand B (84.22) is well within the desired range.

**logP:** Ligand A (-1.029) is a bit low, potentially hindering permeability. Ligand B (0.2) is also on the lower side, but slightly better than A. Both could benefit from increased lipophilicity.

**H-Bond Donors/Acceptors:** Ligand A has 3 HBD and 6 HBA, which are acceptable. Ligand B has 0 HBD and 6 HBA, also acceptable.

**QED:** Both ligands have reasonable QED scores (0.462 and 0.689), indicating drug-like properties, with B being better.

**DILI:** Ligand A (6.049) has a very low DILI risk. Ligand B (31.059) is also low, but higher than A.

**BBB:** This is crucial for a CNS target. Ligand A (29.042) has a poor BBB penetration score. Ligand B (76.309) has a significantly better BBB score, exceeding the desirable >70 threshold.

**Caco-2 Permeability:** Both have negative values (-5.109 and -4.918), which is unusual and suggests poor permeability. However, these values are on a scale where negative values are possible.

**Aqueous Solubility:** Both have negative solubility values (-0.077 and -1.225) which is also unusual.

**hERG Inhibition:** Both ligands show very low hERG inhibition risk (0.115 and 0.045).

**Microsomal Clearance:** Ligand A (-0.811) has a more negative value, suggesting lower clearance and better metabolic stability than Ligand B (1.89).

**In vitro Half-Life:** Ligand A (-2.488) has a more negative value, suggesting a longer half-life than Ligand B (-1.227).

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.005 and 0.02).

**Binding Affinity:** Ligand B (-7.7 kcal/mol) has a significantly stronger binding affinity than Ligand A (-6.7 kcal/mol). This 1.0 kcal/mol difference is substantial and can outweigh some ADME drawbacks.

**Overall Assessment:**

While Ligand A has better metabolic stability and lower DILI risk, Ligand B is superior due to its significantly better BBB penetration and substantially stronger binding affinity. The improved BBB penetration is critical for a CNS-targeting drug, and the affinity difference is large enough to compensate for the slightly less favorable metabolic profile. The low logP values for both are a concern, but the strong binding of Ligand B makes it more likely to achieve efficacy even with potentially lower permeability.

Output:
1
2025-04-17 08:25:16,794 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (350.419 Da) is slightly lower, which could be beneficial for permeability. Ligand B (371.463 Da) is also good.

**TPSA:** Ligand A (98.82) is excellent, falling well below the 90 Angstrom threshold for CNS targets. Ligand B (127.39) is higher, but still potentially acceptable, though less ideal.

**logP:** Both ligands have good logP values (-0.736 and -0.522 respectively), falling within the 1-3 range. These suggest reasonable permeability and avoid potential solubility issues.

**H-Bond Donors/Acceptors:** Both have 2 HBDs, which is good. Ligand A has 4 HBAs, and Ligand B has 6. Both are within the acceptable range of <=10, but Ligand A is slightly better.

**QED:** Both ligands have similar QED values (0.638 and 0.635), indicating good drug-like properties.

**DILI:** Ligand A (23.769) has a much lower DILI risk than Ligand B (56.689), which is a significant advantage.

**BBB:** Ligand A (49.942) has a better BBB penetration percentile than Ligand B (32.61). This is *critical* for a CNS target like DRD2.

**Caco-2 Permeability:** Both have negative Caco-2 values (-5.354 and -5.756), which is unusual and suggests poor permeability. This is a concern for both.

**Aqueous Solubility:** Both have negative solubility values (-1.33 and -1.457), which is also unusual and suggests poor solubility. This is a concern for both.

**hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.051 and 0.048).

**Microsomal Clearance:** Ligand A (-27.277) has a much lower (better) microsomal clearance than Ligand B (-9.504), indicating better metabolic stability.

**In vitro Half-Life:** Ligand A (-9.06) has a slightly longer half-life than Ligand B (-5.554).

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.004 and 0.01).

**Binding Affinity:** Ligand A (-8.0) has a slightly better binding affinity than Ligand B (-7.5). While both are good, the 0.5 kcal/mol difference is noticeable.

**Overall Assessment:**

Ligand A is clearly superior. It has a significantly lower DILI risk, better BBB penetration, lower microsomal clearance (better metabolic stability), slightly longer half-life, and slightly better binding affinity. While both have issues with Caco-2 and Solubility, the ADME profile of Ligand A is much more favorable, especially considering the CNS target. The better BBB and lower DILI are crucial advantages.

Output:
1
2025-04-17 08:25:16,795 - INFO - Batch 447 complete. Total preferences: 7152
2025-04-17 08:25:16,795 - INFO - Processing batch 448/512...
2025-04-17 08:26:03,930 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (354.447 and 357.483 Da) fall comfortably within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (68.31) is better than Ligand B (71.87). Both are below the 90 A^2 threshold desirable for CNS targets, but A is closer to optimal.

**3. logP:** Ligand A (0.832) is slightly lower than optimal (1-3), but still acceptable. Ligand B (2.37) is within the optimal range.

**4. H-Bond Donors:** Both ligands have 0 HBD, which is good.

**5. H-Bond Acceptors:** Ligand A (5) and Ligand B (6) are both acceptable, being below the 10 threshold.

**6. QED:** Both ligands have good QED scores (0.604 and 0.686, respectively), indicating drug-like properties.

**7. DILI:** Ligand A (23.342) has a significantly lower DILI risk than Ligand B (50.291). This is a major advantage for Ligand A.

**8. BBB:** Ligand A (83.56) has a better BBB penetration percentile than Ligand B (77.317). Both are reasonably good, but A is preferable for a CNS target like DRD2.

**9. Caco-2 Permeability:** Ligand A (-4.467) has worse Caco-2 permeability than Ligand B (-5.423). Lower values are worse.

**10. Aqueous Solubility:** Ligand A (-1.223) has better aqueous solubility than Ligand B (-2.137).

**11. hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.172 and 0.183).

**12. Microsomal Clearance:** Ligand A (19.745) has a significantly lower microsomal clearance than Ligand B (59.606), indicating better metabolic stability.

**13. In vitro Half-Life:** Ligand A (5.121) has a longer in vitro half-life than Ligand B (-2.845).

**14. P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.056 and 0.069).

**15. Binding Affinity:** Ligand A (-7.3 kcal/mol) has a slightly better binding affinity than Ligand B (-6.7 kcal/mol). While the difference is less than the 1.5 kcal/mol threshold, it contributes to A's overall favorability.

**Overall Assessment:**

Ligand A is the better candidate. While Ligand B has a slightly better logP and Caco-2 permeability, Ligand A excels in crucial areas for a CNS-targeting GPCR ligand: lower DILI risk, better BBB penetration, significantly improved metabolic stability (lower Cl_mic and longer t1/2), and slightly better binding affinity. The TPSA is also more favorable for A. The combination of these factors makes Ligand A the more promising drug candidate.

Output:
1
2025-04-17 08:26:03,931 - INFO - Okay, let's analyze these two ligands for their potential as DRD2 drug candidates. DRD2 is a GPCR in the CNS, so BBB penetration, logP, Pgp efflux, TPSA, and binding affinity are paramount.

**Ligand A: [348.487, 69.64, 1.799, 2, 3, 0.657, 9.926, 46.84, -4.69, -1.781, 0.275, 4.237, 11.86, 0.088, -8.5]**
**Ligand B: [369.481, 56.99, 4.265, 0, 4, 0.721, 32.842, 89.608, -4.376, -4.809, 0.678, 69.909, -12.859, 0.296, -7.2]**

Here's a breakdown, property by property:

1. **MW:** Both are within the ideal range (200-500 Da). A (348.487) is slightly better, being closer to the lower end which can aid permeability.
2. **TPSA:** A (69.64) is better than B (56.99). Both are below 90, which is good for CNS penetration, but A is still higher than ideal.
3. **logP:** A (1.799) is optimal. B (4.265) is high, potentially leading to solubility issues and off-target interactions.
4. **HBD:** A (2) is good. B (0) is also acceptable, but might slightly reduce aqueous solubility.
5. **HBA:** Both A (3) and B (4) are within the acceptable range (<=10).
6. **QED:** Both A (0.657) and B (0.721) are good, indicating drug-like properties. B is slightly better.
7. **DILI:** A (9.926) is *much* better than B (32.842). This is a significant advantage for A.
8. **BBB:** B (89.608) is excellent, exceeding the desirable >70% threshold. A (46.84) is considerably lower and concerning for CNS penetration.
9. **Caco-2:** A (-4.69) and B (-4.376) are both very poor, indicating poor intestinal absorption.
10. **Solubility:** A (-1.781) is better than B (-4.809), although both are poor.
11. **hERG:** A (0.275) is much better than B (0.678), indicating a lower risk of cardiotoxicity.
12. **Cl_mic:** A (4.237) is much better than B (69.909), suggesting better metabolic stability.
13. **t1/2:** A (11.86) is better than B (-12.859) - a negative half-life is concerning.
14. **Pgp:** A (0.088) is much better than B (0.296), indicating lower efflux and better CNS exposure.
15. **Affinity:** A (-8.5) is significantly better than B (-7.2). This 1.3 kcal/mol difference is substantial and can outweigh some ADME drawbacks.

**Overall Assessment:**

Ligand A has a significantly better safety profile (DILI, hERG) and metabolic stability (Cl_mic). It also boasts a much stronger binding affinity. While its BBB penetration is a concern, its superior affinity and other favorable properties might compensate. Ligand B has excellent BBB penetration, but suffers from a high logP, poor metabolic stability, and a higher risk of DILI and hERG inhibition. The negative in vitro half-life is also a major red flag.

Considering the GPCR-specific priorities (BBB, logP, Pgp, TPSA, affinity), and the overall profile, **Ligand A is the more promising drug candidate.** The strong binding affinity and favorable ADME properties (despite the BBB concern) outweigh the benefits of Ligand B's BBB penetration, especially given the significant safety liabilities associated with Ligand B.

Output:
1
2025-04-17 08:26:03,931 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (370.881 and 349.391 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (77.07) is significantly better than Ligand B (122.28). For CNS targets, we want TPSA <= 90, and Ligand A is comfortably within that range, while Ligand B exceeds it. This is a significant advantage for A.

**3. logP:** Both ligands have acceptable logP values (1.18 and 0.71), falling within the optimal 1-3 range.

**4. H-Bond Donors:** Both have 3 HBD, which is acceptable.

**5. H-Bond Acceptors:** Ligand A has 6 HBA, and Ligand B has 7. Both are within the acceptable range of <=10.

**6. QED:** Both ligands have good QED scores (0.596 and 0.645), indicating good drug-like properties.

**7. DILI:** Ligand A (44.63) has a much lower DILI risk than Ligand B (67.778). Lower is better, and A is well below the concerning threshold of 60.

**8. BBB:** Ligand A (45.444) has a significantly better BBB penetration score than Ligand B (20.085). For a CNS target like DRD2, BBB penetration is crucial, and A is much more promising.

**9. Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and suggests poor permeability. However, the magnitude of negativity is similar (-5.007 vs -5.49).

**10. Aqueous Solubility:** Both have negative solubility values, which is also unusual. Again, the magnitude is similar (-2.291 vs -1.837).

**11. hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.886 and 0.064), which is excellent.

**12. Microsomal Clearance:** Ligand A (-5.246) has a much lower (better) microsomal clearance than Ligand B (28.05). Lower clearance indicates greater metabolic stability.

**13. In vitro Half-Life:** Ligand A (18.689) has a longer in vitro half-life than Ligand B (9.46).

**14. P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.058 and 0.055), which is good.

**15. Binding Affinity:** Both ligands have the same binding affinity (-7.6 kcal/mol), which is excellent and meets the criteria of being < -7.0 kcal/mol.

**Overall Assessment:**

While both ligands have excellent binding affinity and low hERG/P-gp liabilities, Ligand A is significantly superior due to its much better TPSA, DILI risk, BBB penetration, microsomal clearance, and in vitro half-life. These factors are particularly important for a CNS-targeting GPCR like DRD2. The similar Caco-2 and solubility values are concerning for both, but the other advantages of Ligand A outweigh these drawbacks.

Output:
1
2025-04-17 08:26:03,931 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (344.43 and 343.391 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (64.35) is significantly better than Ligand B (105.9). For CNS targets, we want TPSA <= 90, so Ligand A is much more favorable.

**3. logP:** Ligand A (3.711) is within the optimal range (1-3). Ligand B (0.186) is quite low, potentially hindering permeation.

**4. H-Bond Donors:** Both ligands are acceptable (2 and 1, respectively), well below the limit of 5.

**5. H-Bond Acceptors:** Ligand A (3) is good, while Ligand B (7) is higher, but still within the acceptable limit of 10.

**6. QED:** Both ligands have good QED values (0.682 and 0.83), indicating good drug-like properties.

**7. DILI:** Ligand A (33.23) has a lower DILI risk than Ligand B (80.07), which is a significant advantage.

**8. BBB:** Ligand A (63.125) is better than Ligand B (41.024), but ideally we want >70 for CNS targets. However, given the other factors, Ligand A's BBB score is more promising.

**9. Caco-2:** Ligand A (-4.707) and Ligand B (-5.502) both have negative Caco-2 values, which is unusual and suggests poor permeability.

**10. Solubility:** Ligand A (-3.533) and Ligand B (-1.509) both have negative solubility values, suggesting poor solubility.

**11. hERG:** Ligand A (0.892) has a lower hERG risk than Ligand B (0.101), which is preferable.

**12. Cl_mic:** Ligand A (54.65) has a higher microsomal clearance than Ligand B (3.343), meaning Ligand B is more metabolically stable.

**13. t1/2:** Ligand B (4.695) has a longer in vitro half-life than Ligand A (3.545), which is a positive.

**14. Pgp:** Ligand A (0.608) has lower P-gp efflux liability than Ligand B (0.009), which is a significant advantage for CNS penetration.

**15. Binding Affinity:** Ligand B (-8.2 kcal/mol) has a significantly stronger binding affinity than Ligand A (-9.0 kcal/mol). This is a substantial advantage.

**Overall Assessment:**

While Ligand B boasts a superior binding affinity and better metabolic stability, Ligand A is significantly better in terms of TPSA, logP, DILI risk, and Pgp efflux. The lower logP of Ligand B is a major concern for CNS penetration, and the higher DILI risk is also unfavorable. Ligand A, despite a slightly weaker affinity, has a more balanced profile that is more conducive to becoming a viable CNS drug candidate. The difference in affinity (1.2 kcal/mol) is not large enough to outweigh the significant ADME advantages of Ligand A, especially considering the importance of BBB penetration for DRD2 targeting.

Output:
1
2025-04-17 08:26:03,932 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (370.718 and 390.774 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (68.52) is significantly better than Ligand B (79.9). For CNS targets, we want TPSA <= 90, and A is comfortably within this range, while B is approaching the upper limit.

**3. logP:** Both ligands have logP values (3.842 and 4.261) within the optimal 1-3 range, but B is slightly higher, which could potentially lead to solubility issues.

**4. H-Bond Donors:** Ligand A (1) is preferable to Ligand B (2). Lower HBD generally improves permeability.

**5. H-Bond Acceptors:** Both ligands have the same number of HBA (5), which is acceptable (<=10).

**6. QED:** Both ligands have similar QED values (0.76 and 0.7), indicating good drug-likeness.

**7. DILI:** Both ligands have high DILI risk (96.51 and 98.643). This is a concern for both, but doesn't immediately disqualify either.

**8. BBB:** Ligand A (65.374) has a better BBB percentile than Ligand B (52.889). This is *critical* for a CNS target like DRD2. A value >70 is desirable, and A is closer to that threshold.

**9. Caco-2:** Both have negative Caco-2 values (-4.627 and -4.733). This is unusual and suggests poor permeability.

**10. Solubility:** Both have negative solubility values (-5.101 and -5.447), indicating very poor aqueous solubility. This is a significant drawback.

**11. hERG:** Both ligands have low hERG inhibition liability (0.598 and 0.778), which is good.

**12. Cl_mic:** Ligand B (41.941) has a lower microsomal clearance than Ligand A (54.366), suggesting better metabolic stability.

**13. t1/2:** Ligand B (20.047) has a significantly longer in vitro half-life than Ligand A (0.438). This is a major advantage for B.

**14. Pgp:** Both have low Pgp efflux liability (0.537 and 0.766), which is favorable for CNS penetration.

**15. Binding Affinity:** Ligand A (-9.4 kcal/mol) has a *much* stronger binding affinity than Ligand B (-8.0 kcal/mol). This is a substantial difference (>1.5 kcal/mol advantage).

**Overall Assessment:**

Despite the poor solubility and Caco-2 permeability for both, Ligand A is the more promising candidate. The significantly stronger binding affinity (-9.4 vs -8.0 kcal/mol) is a major advantage that can potentially overcome some of the ADME liabilities. Furthermore, Ligand A has a better TPSA and BBB percentile, which are crucial for CNS drug development. While Ligand B has better metabolic stability and half-life, the affinity difference is too large to ignore. The poor solubility of both compounds would need to be addressed through formulation strategies.

Output:
0
2025-04-17 08:26:03,932 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (376.513) is slightly higher than Ligand B (337.423), but both are acceptable.

**TPSA:** Ligand A (64.35) is excellent for CNS penetration, being well below 90. Ligand B (73.2) is still reasonable, but less optimal.

**logP:** Both ligands have good logP values (A: 2.804, B: 2.652), falling within the 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A has 2 HBD and 4 HBA, while Ligand B has 1 HBD and 3 HBA. Both are within acceptable limits (<=5 HBD, <=10 HBA).

**QED:** Both ligands have similar and good QED values (A: 0.774, B: 0.777), indicating good drug-like properties.

**DILI:** Ligand A (17.449) has a significantly lower DILI risk than Ligand B (39.705). This is a substantial advantage.

**BBB:** Ligand A (92.904) has a much higher BBB penetration percentile than Ligand B (75.107). This is *critical* for a CNS target like DRD2.

**Caco-2 Permeability:** Both have negative Caco-2 values, indicating poor permeability. However, the absolute value is smaller for Ligand A (-5.298) than for Ligand B (-4.578), suggesting slightly better permeability for A.

**Aqueous Solubility:** Both ligands have negative solubility values, indicating poor aqueous solubility. Ligand B (-4.157) is slightly better than Ligand A (-2.627), but both are problematic.

**hERG Inhibition:** Ligand A (0.732) has a slightly higher hERG inhibition risk than Ligand B (0.355), but both are relatively low.

**Microsomal Clearance:** Ligand B (50.238) has a significantly lower microsomal clearance than Ligand A (17.486), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (20.262) has a longer half-life than Ligand B (-3.511). This is a positive attribute.

**P-gp Efflux:** Ligand A (0.115) has a lower P-gp efflux liability than Ligand B (0.218), which is beneficial for CNS exposure.

**Binding Affinity:** Both ligands have very similar and strong binding affinities (A: -8.5 kcal/mol, B: -8.3 kcal/mol). The difference is less than the 1.5 kcal/mol threshold.

**Overall Assessment:**

Ligand A is significantly better due to its superior BBB penetration (92.9% vs 75.1%), lower DILI risk (17.4% vs 39.7%), and lower P-gp efflux (0.115 vs 0.218). While Ligand B has better metabolic stability, the CNS-related properties of Ligand A are far more important for a DRD2 ligand. The slight difference in binding affinity is not enough to overcome the substantial advantages of Ligand A.

Output:
1
2025-04-17 08:26:03,932 - INFO - Okay, let's analyze these two ligands (A and B) for their potential as DRD2 drug candidates, keeping in mind the provided guidelines and the GPCR-specific priorities.

**Step-by-step comparison:**

1. **MW:** Both ligands (A: 352.45 Da, B: 346.427 Da) fall within the ideal 200-500 Da range. No significant difference here.

2. **TPSA:** Ligand A (60.85) is significantly better than Ligand B (80.57).  For CNS targets, we want TPSA <= 90, and A is comfortably within that range, while B is approaching the upper limit. This is a point in favor of A.

3. **logP:** Both ligands have acceptable logP values (A: 1.614, B: 2.408), falling within the 1-3 range. B is slightly higher, which *could* be a minor concern for solubility, but not a deal-breaker.

4. **HBD:** A (1) is better than B (2). Lower HBD generally improves permeability.

5. **HBA:** A (3) is better than B (4). Similar to HBD, lower HBA is preferred.

6. **QED:** Both are reasonable (A: 0.765, B: 0.673), exceeding the 0.5 threshold. A is slightly better.

7. **DILI:** Ligand A (8.104) has a *much* lower DILI risk than Ligand B (30.671). This is a significant advantage for A.

8. **BBB:** Ligand A (83.56) has a substantially better BBB penetration score than Ligand B (63.784).  For a CNS target like DRD2, >70 is desirable, and A is closer to that mark. This is a critical advantage for A.

9. **Caco-2:** Both are negative (-4.548 and -4.596), indicating poor permeability. This is a concern for both, but doesn't necessarily disqualify either.

10. **Solubility:** Both are negative (-2.335 and -2.762), indicating poor solubility. This is a concern for both, but doesn't necessarily disqualify either.

11. **hERG:** Both have very low hERG inhibition liability (A: 0.433, B: 0.195), which is good.

12. **Cl_mic:** Ligand A (28.256) has significantly lower microsomal clearance than Ligand B (54.535), suggesting better metabolic stability. This is a positive for A.

13. **t1/2:** Ligand B (28.452) has a longer in vitro half-life than Ligand A (-14.932). This is a positive for B, but the negative value for A is concerning.

14. **Pgp:** Ligand A (0.111) has lower P-gp efflux liability than Ligand B (0.082). Lower Pgp is preferred, especially for CNS targets. This is a slight advantage for A.

15. **Binding Affinity:** Ligand B (-7.9) has a slightly better binding affinity than Ligand A (-8.7). While a 1.5 kcal/mol advantage is significant, the other factors are more important in this case.

**Overall Assessment:**

Ligand A consistently outperforms Ligand B across several crucial ADME properties, particularly those prioritized for GPCRs targeting the CNS: TPSA, BBB, DILI, and Cl_mic. While Ligand B has a slightly better binding affinity and in vitro half-life, the superior CNS penetration potential and safety profile of Ligand A make it the more promising drug candidate. The poor Caco-2 and solubility for both compounds would need to be addressed in further optimization.



Output:
1
2025-04-17 08:26:03,932 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (354.411 and 349.475 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (110.61) is higher than Ligand B (78.51). For CNS targets, TPSA should be <= 90. Ligand B is better here.

**logP:** Ligand A (-0.049) is slightly below the optimal 1-3 range, potentially hindering permeability. Ligand B (1.777) is within the optimal range. Ligand B is better.

**H-Bond Donors:** Both ligands have 2 HBD, which is acceptable (<=5).

**H-Bond Acceptors:** Ligand A has 7 HBA, and Ligand B has 3. Both are within the acceptable limit of <=10, but Ligand B is preferable.

**QED:** Both ligands have reasonable QED values (0.633 and 0.543, both >=0.5).

**DILI:** Ligand A (60.566) has a higher DILI risk than Ligand B (27.724). Lower is better, so Ligand B is preferable.

**BBB:** Ligand A (75.107) has a better BBB penetration percentile than Ligand B (53.121). This is a crucial factor for CNS targets like DRD2.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values, which is unusual and suggests poor permeability. However, the scale is not specified, so it's hard to interpret.

**Aqueous Solubility:** Both ligands have negative solubility values, which is also unusual.

**hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.056 and 0.084).

**Microsomal Clearance:** Ligand A (21.789) has lower microsomal clearance than Ligand B (28.504), indicating better metabolic stability.

**In vitro Half-Life:** Ligand A (12.277) has a longer half-life than Ligand B (-1.955).

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.01 and 0.03).

**Binding Affinity:** Ligand B (-7.8 kcal/mol) has a slightly better binding affinity than Ligand A (-7.5 kcal/mol). While the difference is small, it's still a positive for Ligand B.

**Overall Assessment:**

Ligand B has advantages in several key areas: logP, TPSA, DILI, and binding affinity. Ligand A has a better BBB score and slightly better metabolic stability and half-life. However, given the GPCR-specific focus on BBB, logP, and Pgp, and the fact that Ligand B's affinity is slightly better, Ligand B appears to be the more promising candidate. The better logP and TPSA of Ligand B are particularly important for CNS penetration. The DILI risk is also significantly lower for Ligand B.

Output:
1
2025-04-17 08:26:03,932 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (378.215 and 368.543 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (91.24) is slightly above the optimal <90 for CNS targets, but still reasonable. Ligand B (51.66) is well within the desired range, a significant advantage.

**3. logP:** Both ligands have good logP values (4.03 and 3.637), falling within the 1-3 range. Ligand B is slightly better.

**4. H-Bond Donors:** Ligand A has 1 HBD, which is acceptable. Ligand B has 0, also acceptable.

**5. H-Bond Acceptors:** Both ligands have 5 HBA, which is within the acceptable limit of <=10.

**6. QED:** Both ligands have QED values (0.724 and 0.668) above 0.5, indicating good drug-like properties.

**7. DILI:** Ligand A (89.259) has a higher DILI risk than Ligand B (31.834). This is a significant negative for Ligand A.

**8. BBB:** Ligand B (79.449) has a better BBB percentile than Ligand A (68.127). Both are reasonably good, but for a CNS target like DRD2, higher is better.

**9. Caco-2:** Both have negative Caco-2 values, which is unusual and requires careful interpretation. It suggests poor permeability.

**10. Solubility:** Both have negative solubility values, which is also unusual and suggests poor aqueous solubility.

**11. hERG:** Ligand A (0.23) has a slightly better hERG profile than Ligand B (0.781).

**12. Cl_mic:** Ligand A (57.085) has a lower microsomal clearance than Ligand B (80.597), suggesting better metabolic stability.

**13. t1/2:** Ligand B (57.788) has a significantly longer in vitro half-life than Ligand A (1.049). This is a major advantage for Ligand B.

**14. Pgp:** Ligand A (0.411) has lower P-gp efflux liability than Ligand B (0.765), which is favorable for CNS penetration.

**15. Binding Affinity:** Ligand A (-9.8 kcal/mol) has a substantially stronger binding affinity than Ligand B (-7.0 kcal/mol). This is a very significant advantage, potentially outweighing some of the ADME drawbacks.

**Overall Assessment:**

Despite Ligand A's superior binding affinity, Ligand B appears to be the more promising drug candidate. The key factors driving this conclusion are:

*   **Lower DILI risk:** Ligand B's significantly lower DILI risk is crucial for safety.
*   **Better BBB penetration:** Ligand B has a higher BBB percentile, essential for a CNS target.
*   **Longer half-life:** Ligand B's much longer half-life is a significant pharmacokinetic advantage.
*   **Acceptable TPSA:** Ligand B's TPSA is well within the desired range for CNS penetration.

While Ligand A has a stronger binding affinity, the ADME/Tox profile of Ligand B is considerably more favorable, particularly regarding safety and CNS exposure. The difference in affinity, while substantial, might be overcome with further optimization of Ligand B.



Output:
1
2025-04-17 08:26:03,933 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (353.463 and 348.403 Da) fall within the ideal range of 200-500 Da.

**TPSA:** Ligand A (78.95) is excellent, falling well below the 90 A^2 threshold for CNS targets. Ligand B (93.65) is still reasonable but less optimal, being closer to the 90 A^2 limit.

**logP:** Ligand A (0.433) is a bit low, potentially hindering permeation. Ligand B (0.656) is also on the lower side, but slightly better than A. Both are below the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Both have 1 HBD and are within acceptable limits (<=5 HBD, <=10 HBA). Ligand B has 6 HBA, while Ligand A has 5.

**QED:** Both ligands have acceptable QED values (0.455 and 0.759, respectively), with Ligand B being significantly better.

**DILI:** Ligand A (20.163) has a much lower DILI risk than Ligand B (64.521), which is a significant advantage.

**BBB:** Ligand A (74.06) has a good BBB percentile, exceeding the desirable >70 threshold for CNS targets. Ligand B (61.225) is lower and less favorable for CNS penetration.

**Caco-2 Permeability:** Both have negative Caco-2 values (-4.794 and -4.736), which is unusual and suggests poor permeability. This is a concern for both.

**Aqueous Solubility:** Both have negative solubility values (-0.799 and -1.803), indicating very poor aqueous solubility. This is a major drawback for both.

**hERG Inhibition:** Both ligands show low hERG inhibition liability (0.33 and 0.269), which is good.

**Microsomal Clearance:** Ligand A (30.689) has a slightly lower microsomal clearance than Ligand B (33.237), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (-22.836) has a significantly longer in vitro half-life than Ligand B (-13.012), which is a major advantage.

**P-gp Efflux:** Ligand A (0.027) has very low P-gp efflux, which is excellent for CNS exposure. Ligand B (0.018) is also low, but slightly higher.

**Binding Affinity:** Ligand B (-0.0) has a significantly better binding affinity than Ligand A (-6.8). This is a substantial advantage, potentially outweighing some of the ADME drawbacks.

**Overall Assessment:**

Ligand B has a much better binding affinity, which is crucial for GPCR ligands. However, Ligand A has superior BBB penetration, lower DILI risk, better metabolic stability (lower Cl_mic, longer t1/2), and lower P-gp efflux. Both have poor solubility and Caco-2 permeability. Given the CNS target (DRD2), BBB penetration is critical. While the affinity of Ligand B is much better, the superior CNS properties of Ligand A, particularly the BBB and DILI, make it the more promising candidate. The affinity difference is not large enough to overcome the significant ADME advantages of Ligand A.

Output:
1
2025-04-17 08:26:03,933 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (351.451 and 355.385 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (115.98) is slightly above the optimal <90 for CNS targets, but still reasonable. Ligand B (71.51) is excellent, well below 90.

**logP:** Ligand A (0.901) is a bit low, potentially hindering permeability. Ligand B (3.477) is within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A has 4 HBD and 4 HBA, which are acceptable. Ligand B has 1 HBD and 5 HBA, also acceptable.

**QED:** Both ligands have reasonable QED scores (0.469 and 0.785), with Ligand B being better.

**DILI:** Both ligands have similar DILI risk (41.877 and 44.591), both being acceptable (<60).

**BBB:** This is a critical parameter for CNS targets. Ligand A has a BBB percentile of 36.836, which is quite low and concerning. Ligand B has a much higher BBB percentile of 77.278, which is very desirable.

**Caco-2 Permeability:** Ligand A (-5.825) has poor Caco-2 permeability, while Ligand B (-4.63) is slightly better, but still not great.

**Aqueous Solubility:** Both ligands have poor aqueous solubility (-2.347 and -3.1). This could pose formulation challenges.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.291 and 0.523), which is good.

**Microsomal Clearance:** Ligand A (29.724) has lower microsomal clearance than Ligand B (52.069), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (-6.372) has a shorter in vitro half-life than Ligand B (31.909).

**P-gp Efflux:** Ligand A (0.129) has lower P-gp efflux than Ligand B (0.116), which is slightly better for CNS exposure.

**Binding Affinity:** Both ligands have very similar and strong binding affinities (-7.7 and -7.6 kcal/mol). The difference is negligible.

**Conclusion:**

Considering the GPCR-specific priorities, Ligand B is significantly more promising. Its superior BBB penetration (77.278 vs 36.836) is a major advantage for a CNS target like DRD2. While Ligand A has slightly better metabolic stability and P-gp efflux, the poor BBB score and low Caco-2 permeability are significant drawbacks. The similar binding affinities make the ADME properties the deciding factor.

Output:
1
2025-04-17 08:26:03,933 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (362.455 and 348.443 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (93.21) is slightly above the optimal <90 for CNS targets, but still reasonable. Ligand B (82.78) is well within the desired range.

**3. logP:** Both ligands have good logP values (2.069 and 2.405), falling within the 1-3 range.

**4. H-Bond Donors:** Both have 2 HBD, which is acceptable.

**5. H-Bond Acceptors:** Ligand A has 6 HBA, and Ligand B has 4 HBA, both within the acceptable limit of <= 10.

**6. QED:** Ligand A (0.709) has a better QED score than Ligand B (0.53), indicating a more drug-like profile.

**7. DILI:** Ligand A (73.245) has a higher DILI risk than Ligand B (17.836). This is a significant drawback for Ligand A.

**8. BBB:** Ligand A (61.07) has a moderate BBB penetration, while Ligand B (48.003) is lower. Both are below the desirable >70 for CNS targets, but Ligand A is better.

**9. Caco-2 Permeability:** Ligand A (-4.94) has better Caco-2 permeability than Ligand B (-4.663).

**10. Aqueous Solubility:** Ligand A (-3.067) has slightly better aqueous solubility than Ligand B (-1.805).

**11. hERG Inhibition:** Ligand A (0.28) has a lower hERG inhibition liability than Ligand B (0.512), which is favorable.

**12. Microsomal Clearance:** Ligand B (29.924) has significantly lower microsomal clearance than Ligand A (8.936), suggesting better metabolic stability.

**13. In vitro Half-Life:** Ligand B (34.452) has a much longer in vitro half-life than Ligand A (-12.743). This is a major advantage for Ligand B.

**14. P-gp Efflux:** Ligand A (0.015) has significantly lower P-gp efflux liability than Ligand B (0.167), which is crucial for CNS penetration.

**15. Binding Affinity:** Ligand B (-7.9) has a slightly better binding affinity than Ligand A (-8.4). While A is better, the difference is not substantial enough to overcome other issues.

**Overall Assessment:**

Ligand A has advantages in BBB, Caco-2 permeability, solubility, hERG, and P-gp efflux. However, it suffers from a significantly higher DILI risk and poorer metabolic stability (higher Cl_mic, shorter half-life). Ligand B has a better safety profile (lower DILI), better metabolic stability, and a comparable binding affinity. Given the GPCR-specific priorities, particularly the need for good CNS penetration and a favorable safety profile, Ligand B appears to be the more promising candidate despite its slightly lower BBB score. The lower P-gp efflux of Ligand A is attractive, but the high DILI risk is a major concern.

Output:
1
2025-04-17 08:26:03,933 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (354.33 & 363.52 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (51.66) is slightly higher than the ideal <90 for CNS targets, but still reasonable. Ligand B (42.68) is well within the desired range.

**3. logP:** Both ligands have good logP values (3.40 & 4.22), falling within the optimal 1-3 range, though Ligand B is pushing the upper limit.

**4. H-Bond Donors:** Both have 0 HBD, which is acceptable.

**5. H-Bond Acceptors:** Both have 4 HBA, which is acceptable.

**6. QED:** Ligand A (0.746) has a better QED score than Ligand B (0.487), indicating a more drug-like profile.

**7. DILI:** Ligand A (63.09) has a higher DILI risk than Ligand B (27.14), which is a significant drawback.

**8. BBB:** Ligand A (83.25) has a better BBB penetration percentile than Ligand B (77.24), which is crucial for a CNS target like DRD2.

**9. Caco-2 Permeability:** Ligand A (-4.424) has worse Caco-2 permeability than Ligand B (-5.149), indicating lower intestinal absorption.

**10. Aqueous Solubility:** Both have negative solubility values, indicating poor solubility. Ligand A (-3.653) is slightly better than Ligand B (-4.126).

**11. hERG:** Both ligands have low hERG inhibition liability (0.783 and 0.741), which is good.

**12. Microsomal Clearance:** Ligand B (89.61) has significantly higher microsomal clearance than Ligand A (54.09), suggesting lower metabolic stability.

**13. In vitro Half-Life:** Ligand B (44.33) has a much longer in vitro half-life than Ligand A (5.78), which is a major advantage.

**14. P-gp Efflux:** Both ligands have similar P-gp efflux liability (0.408 and 0.75).

**15. Binding Affinity:** Ligand A (-7.9 kcal/mol) has a significantly stronger binding affinity than Ligand B (-6.8 kcal/mol). This is a substantial advantage, potentially outweighing some ADME concerns.

**Overall Assessment:**

Ligand A has a better BBB score, better QED, and significantly better binding affinity. However, it suffers from a higher DILI risk and poorer metabolic stability (higher clearance, shorter half-life) and lower Caco-2 permeability. Ligand B has a lower DILI risk, better metabolic stability, and slightly better Caco-2 permeability, but its binding affinity is considerably weaker.

Given the importance of binding affinity for GPCRs, and the fact that the difference in affinity is substantial (1.1 kcal/mol), I believe Ligand A is the more promising candidate *despite* its higher DILI risk and lower metabolic stability. These ADME properties could be addressed through further optimization, but a strong starting affinity is harder to achieve. The better BBB penetration also supports its potential as a CNS-acting drug.

Output:
0
2025-04-17 08:26:03,934 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (345.414 and 347.331 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (46.61) is excellent, well below the 90 A^2 threshold for CNS targets. Ligand B (127.49) is higher, but still potentially acceptable, though less ideal.

**logP:** Ligand A (3.479) is optimal (1-3). Ligand B (0.353) is quite low, which could hinder membrane permeability and CNS penetration.

**H-Bond Donors/Acceptors:** Ligand A (0 HBD, 3 HBA) is favorable. Ligand B (3 HBD, 7 HBA) is also acceptable, though slightly higher.

**QED:** Both ligands have reasonable QED values (0.771 and 0.541), indicating good drug-like properties.

**DILI:** Ligand A (58.123) has a lower DILI risk than Ligand B (85.576), which is a significant advantage.

**BBB:** Ligand A (92.943) has excellent BBB penetration, highly desirable for a CNS target like DRD2. Ligand B (65.374) is considerably lower, which is a major drawback.

**Caco-2 Permeability:** Ligand A (-4.239) has poor Caco-2 permeability, which is concerning. Ligand B (-5.191) is also poor.

**Aqueous Solubility:** Ligand A (-4.7) has poor solubility. Ligand B (-2.914) has slightly better solubility, but still not ideal.

**hERG Inhibition:** Ligand A (0.53) has a low hERG risk, which is good. Ligand B (0.051) has a very low hERG risk, which is excellent.

**Microsomal Clearance:** Ligand A (43.866) has moderate clearance. Ligand B (28.872) has lower clearance, indicating better metabolic stability.

**In vitro Half-Life:** Ligand B (70.138) has a significantly longer half-life than Ligand A (5.65), which is a major advantage.

**P-gp Efflux:** Ligand A (0.646) has moderate P-gp efflux. Ligand B (0.044) has very low P-gp efflux, which is highly desirable for CNS penetration.

**Binding Affinity:** Ligand B (-8.6) has a slightly stronger binding affinity than Ligand A (-8.1), but the difference is relatively small (0.5 kcal/mol).

**Overall Assessment:**

Ligand A has a superior BBB score and lower DILI risk, but suffers from poor Caco-2 permeability and solubility. Ligand B has better metabolic stability (lower Cl_mic, longer t1/2), lower P-gp efflux, and slightly better affinity, but its BBB penetration is significantly lower and its DILI risk is higher.

Given the GPCR-specific priorities, **BBB penetration is crucial for DRD2**. Ligand A's excellent BBB score (92.943) outweighs its drawbacks, especially considering the relatively small affinity difference. The poor Caco-2 and solubility of Ligand A can be addressed with formulation strategies. The lower BBB penetration of Ligand B is a significant hurdle for a CNS-targeting drug.

Output:
0
2025-04-17 08:26:03,934 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (362.411 and 351.403 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (106.39) is better than Ligand B (132.96). For CNS targets, we want TPSA <= 90, so Ligand A is closer to this threshold, suggesting better CNS penetration potential.

**logP:** Ligand A (4.362) is higher than the optimal range (1-3) but still potentially acceptable. Ligand B (-1.511) is significantly *below* the optimal range, which could hinder membrane permeability and CNS penetration.

**H-Bond Donors/Acceptors:** Ligand A (HBD=2, HBA=6) and Ligand B (HBD=4, HBA=5) both have reasonable numbers of H-bond donors and acceptors.

**QED:** Both ligands have acceptable QED values (A: 0.586, B: 0.489), indicating reasonable drug-likeness.

**DILI:** Ligand A (94.804) has a significantly higher DILI risk than Ligand B (23.071). This is a major concern for Ligand A.

**BBB:** Ligand A (63.746) has a better BBB percentile than Ligand B (22.063), but ideally, we want >70 for CNS targets.

**Caco-2 Permeability:** Ligand A (-4.57) has a negative value, which is unusual and suggests very poor permeability. Ligand B (-6.02) is also poor, but slightly worse.

**Aqueous Solubility:** Ligand A (-5.927) and Ligand B (-1.644) both have poor aqueous solubility.

**hERG Inhibition:** Ligand A (0.247) has a slightly higher hERG risk than Ligand B (0.041), but both are relatively low.

**Microsomal Clearance:** Ligand B (-27.031) has a *much* lower (better) microsomal clearance than Ligand A (77.721), indicating greater metabolic stability.

**In vitro Half-Life:** Ligand A (19.794) has a longer half-life than Ligand B (4.9), which is desirable.

**P-gp Efflux:** Ligand A (0.289) has lower P-gp efflux than Ligand B (0.003), which is favorable for CNS penetration.

**Binding Affinity:** Ligand A (-9.3 kcal/mol) has a significantly stronger binding affinity than Ligand B (-7.9 kcal/mol). This is a substantial advantage, potentially outweighing some of the ADME drawbacks.

**Overall Assessment:**

Ligand A has a much better binding affinity and better BBB penetration and P-gp efflux. However, it has a very high DILI risk, poor Caco-2 permeability, and relatively high metabolic clearance. Ligand B has a much lower DILI risk and better metabolic stability, but significantly weaker binding affinity, poor BBB penetration, and a low logP.

Considering the GPCR-specific priorities, the strong binding affinity of Ligand A is a significant advantage. While the DILI risk is concerning, it might be mitigated through structural modifications. The poor permeability of Ligand A is also a concern, but could potentially be addressed. The very poor logP of Ligand B is a major issue that is harder to fix without significantly altering the binding affinity.

Output:
1
2025-04-17 08:26:03,934 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the acceptable range (200-500 Da). Ligand A (340.379 Da) is slightly better, being closer to the ideal range.

**TPSA:** Ligand A (98.66) is much better than Ligand B (44.12). For CNS targets, we want TPSA <= 90, and Ligand A is closer to this threshold. Ligand B is significantly higher, potentially hindering BBB penetration.

**logP:** Both ligands have acceptable logP values (Ligand A: 1.889, Ligand B: 3.953). Ligand B is a bit higher, which *could* lead to solubility issues, but is still within the generally acceptable range of 1-3.

**H-Bond Donors:** Ligand A (4) is acceptable. Ligand B (0) is also acceptable, but a lack of HBDs can sometimes indicate poor solubility.

**H-Bond Acceptors:** Both ligands have 4 HBA, which is good.

**QED:** Both ligands have similar QED values (Ligand A: 0.645, Ligand B: 0.511), indicating reasonable drug-likeness.

**DILI:** Ligand A (48.623) has a much lower DILI risk than Ligand B (61.07). This is a significant advantage for Ligand A.

**BBB:** Ligand B (96.045) has a *much* higher predicted BBB penetration than Ligand A (31.834). This is a critical factor for a CNS target like DRD2.

**Caco-2 Permeability:** Ligand A (-5.268) has a negative value, which is concerning. Ligand B (-4.496) is also negative, but less so. Both suggest poor intestinal absorption, but Ligand B is slightly better.

**Aqueous Solubility:** Both ligands have poor predicted aqueous solubility (Ligand A: -3.602, Ligand B: -5.279). This could pose formulation challenges.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (Ligand A: 0.505, Ligand B: 0.698).

**Microsomal Clearance:** Ligand A (-2.944) has a lower (better) microsomal clearance than Ligand B (58.565), indicating better metabolic stability.

**In vitro Half-Life:** Ligand A (-15.895) has a negative half-life, which is concerning. Ligand B (29.482) has a reasonable half-life.

**P-gp Efflux:** Ligand A (0.045) has a much lower P-gp efflux liability than Ligand B (0.695), which is favorable for CNS penetration.

**Binding Affinity:** Both ligands have excellent binding affinities (Ligand A: -9.4 kcal/mol, Ligand B: -9.7 kcal/mol). Ligand B is slightly better, but the difference is small.

**Overall Assessment:**

Ligand B excels in BBB penetration and has a better in vitro half-life. However, it has a higher DILI risk, higher P-gp efflux, and a higher TPSA. Ligand A has a more favorable safety profile (lower DILI), better metabolic stability (lower Cl_mic), lower P-gp efflux, and a lower TPSA, all crucial for CNS drug development. While Ligand A has poor Caco-2 permeability and a concerning half-life, the strong binding affinity and favorable ADME properties (especially BBB and P-gp) make it a more promising candidate. The negative Caco-2 and half-life values could be addressed with further structural modifications. The superior BBB and P-gp properties of Ligand A are more critical for a CNS target than the slightly better affinity of Ligand B.

Output:
0
2025-04-17 08:26:03,934 - INFO - Batch 448 complete. Total preferences: 7168
2025-04-17 08:26:03,934 - INFO - Processing batch 449/512...
2025-04-17 08:26:46,335 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (341.346 and 346.431 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (81.93) is better than Ligand B (89.27). Both are below the 90 A^2 threshold for CNS targets, but A is closer to the ideal.

**3. logP:** Both ligands have good logP values (2.679 and 1.921), falling within the optimal 1-3 range.

**4. H-Bond Donors:** Ligand A (1) is better than Ligand B (2). Both are within the acceptable limit of <=5.

**5. H-Bond Acceptors:** Both ligands have the same number of H-bond acceptors (6), which is acceptable (<=10).

**6. QED:** Both ligands have similar QED values (0.789 and 0.724), indicating good drug-likeness (>=0.5).

**7. DILI:** Ligand A (98.565) has a significantly higher DILI risk than Ligand B (45.638). This is a major concern for Ligand A.

**8. BBB:** Ligand A (74.292) has a much better BBB penetration percentile than Ligand B (14.153). This is crucial for a CNS target like DRD2.

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.574 and -4.918), which is unusual and suggests poor permeability. However, these values are on a scale where negative values are possible, and direct comparison is difficult without knowing the scale's specifics.

**10. Aqueous Solubility:** Both ligands have negative solubility values (-3.551 and -2.465), indicating poor aqueous solubility. Again, the scale is unknown.

**11. hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.342 and 0.121).

**12. Microsomal Clearance:** Ligand A (65.719) has higher microsomal clearance than Ligand B (37.248), indicating lower metabolic stability.

**13. In vitro Half-Life:** Ligand B (-4.639) has a longer in vitro half-life than Ligand A (-3.122).

**14. P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.074 and 0.055).

**15. Binding Affinity:** Ligand A (-9.3 kcal/mol) has a significantly stronger binding affinity than Ligand B (-8.2 kcal/mol). This is a substantial advantage.

**Overall Assessment:**

Ligand A has a significantly better binding affinity and BBB penetration, which are critical for a CNS GPCR target. However, it has a very high DILI risk and poorer metabolic stability. Ligand B has a much lower DILI risk and better metabolic stability, but significantly weaker binding affinity and poor BBB penetration.

Given the importance of binding affinity for GPCRs, and the fact that the difference in affinity (-9.3 vs -8.2) is substantial (a >1.1 kcal/mol advantage), I would cautiously favor Ligand A. The high DILI risk is a serious concern, but could potentially be mitigated through structural modifications. The poor solubility and permeability are also drawbacks, but might be addressed through formulation strategies. Ligand B's weak affinity is a more fundamental issue that is harder to overcome.

Output:
1
2025-04-17 08:26:46,336 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (341.419 and 350.503 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (101.96) is better than Ligand B (69.64), both are below the 90 A^2 threshold for CNS targets.

**logP:** Both ligands have acceptable logP values (1.047 and 2.471), falling within the 1-3 range. Ligand B is slightly more lipophilic, which could be beneficial for membrane permeability, but not drastically.

**H-Bond Donors/Acceptors:** Both ligands have 2 HBDs, which is good. Ligand A has 7 HBAs and Ligand B has 3 HBAs. Both are within the acceptable limits (<=10).

**QED:** Both ligands have similar QED scores (0.862 and 0.821), indicating good drug-likeness.

**DILI:** Ligand A (69.058) has a higher DILI risk than Ligand B (5.584). This is a significant drawback for Ligand A.

**BBB:** Ligand A (60.644) has a better BBB penetration percentile than Ligand B (46.84). This is a crucial factor for a CNS target like DRD2.

**Caco-2 Permeability:** Ligand A (-5.46) shows poor Caco-2 permeability, while Ligand B (-4.739) is slightly better.

**Aqueous Solubility:** Both ligands have negative solubility values (-2.11 and -2.534), indicating poor aqueous solubility. This is a concern for both.

**hERG Inhibition:** Both ligands have low hERG inhibition liability (0.65 and 0.23), which is good.

**Microsomal Clearance:** Ligand A (-1.036) has a lower (better) microsomal clearance than Ligand B (15.085), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (36.082) has a longer half-life than Ligand B (4.374).

**P-gp Efflux:** Ligand A (0.045) has lower P-gp efflux liability than Ligand B (0.036), which is favorable for CNS penetration.

**Binding Affinity:** Both ligands have excellent binding affinities (-8.3 and -8.8 kcal/mol). Ligand B is slightly better.

**Overall Assessment:**

Ligand A has a better BBB, lower P-gp efflux, better metabolic stability (lower Cl_mic, longer t1/2), and comparable affinity. However, its significantly higher DILI risk and poor Caco-2 permeability are major concerns. Ligand B has a lower DILI risk, slightly better Caco-2 permeability and affinity, but worse BBB penetration and metabolic stability.

Given the importance of BBB penetration for a CNS target like DRD2, and the substantial difference in DILI risk, I prioritize Ligand A despite its permeability issues. Solubility can be addressed with formulation strategies, and permeability can potentially be improved through structural modifications. The DILI risk associated with Ligand A is a serious concern, but the superior CNS exposure profile makes it a more promising starting point.

Output:
1
2025-04-17 08:26:46,336 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (353.344 and 347.415 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (52.98) is excellent, well below the 90 A^2 threshold for CNS targets. Ligand B (87.74) is higher but still potentially acceptable, though less ideal.

**logP:** Ligand A (2.56) is optimal (1-3). Ligand B (0.804) is a bit low, potentially hindering permeation.

**H-Bond Donors/Acceptors:** Ligand A (0 HBD, 3 HBA) is favorable. Ligand B (2 HBD, 4 HBA) is also acceptable.

**QED:** Both ligands have good QED scores (0.835 and 0.737), indicating good drug-like properties.

**DILI:** Ligand A (53.47) has a moderate DILI risk, while Ligand B (32.338) has a lower, more favorable DILI risk.

**BBB:** Ligand A excels with a BBB percentile of 96.627, highly desirable for a CNS target. Ligand B (68.748) is lower, which is a significant drawback.

**Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and suggests potential issues with the data or modeling. However, we'll proceed assuming these represent low permeability.

**Aqueous Solubility:** Both have negative solubility values, again suggesting potential data issues.

**hERG Inhibition:** Both ligands have very low hERG inhibition liability (0.483 and 0.105), which is excellent.

**Microsomal Clearance:** Ligand A (16.002) has a higher clearance than Ligand B (-4.62), suggesting lower metabolic stability.

**In vitro Half-Life:** Ligand B (-5.507) has a more negative half-life, indicating a longer half-life and better stability.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.107 and 0.016), which is favorable for CNS penetration.

**Binding Affinity:** Both ligands have excellent binding affinities (-10.0 and -8.3 kcal/mol). Ligand A is slightly better (-10.0 vs -8.3).

**Overall Assessment:**

Given the GPCR-specific priorities, BBB penetration is crucial for a CNS target like DRD2. Ligand A has a significantly higher BBB percentile (96.627) compared to Ligand B (68.748). While Ligand B has a slightly better DILI score and in vitro half-life, the superior BBB penetration and slightly better affinity of Ligand A outweigh these advantages. The low logP of Ligand B is also concerning.

Output:
1
2025-04-17 08:26:46,336 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight (MW):** Both ligands (349.475 and 346.431 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (78.51) is significantly better than Ligand B (95.42). For CNS targets, we want TPSA <= 90, so Ligand A is preferable.

**3. logP:** Both ligands (1.614 and 1.649) are within the optimal 1-3 range.

**4. H-Bond Donors (HBD):** Both have 2 HBD, which is acceptable (<=5).

**5. H-Bond Acceptors (HBA):** Ligand A has 3 HBA, and Ligand B has 5 HBA. Both are within the acceptable range (<=10), but Ligand A is slightly better.

**6. QED:** Both ligands have good QED scores (0.715 and 0.845), indicating drug-like properties.

**7. DILI:** Ligand A (15.122) has a much lower DILI risk than Ligand B (45.25). This is a significant advantage for Ligand A.

**8. BBB:** Ligand A (66.344) has a better BBB percentile than Ligand B (62.97), though both are somewhat below the desirable >70 for CNS targets. Still, A is better.

**9. Caco-2 Permeability:** Ligand A (-5.023) has worse Caco-2 permeability than Ligand B (-4.837). This is a slight disadvantage for Ligand A.

**10. Aqueous Solubility:** Ligand A (-1.886) has better aqueous solubility than Ligand B (-3.018).

**11. hERG Inhibition:** Both ligands have low hERG risk (0.24 and 0.228).

**12. Microsomal Clearance (Cl_mic):** Ligand A (-1.179) has significantly lower (better) microsomal clearance than Ligand B (33.17). This suggests better metabolic stability for Ligand A.

**13. In vitro Half-Life:** Ligand A (-2.227) has a better in vitro half-life than Ligand B (-16.633).

**14. P-gp Efflux:** Both ligands have low P-gp efflux liability (0.043 and 0.031).

**15. Binding Affinity:** Ligand B (-9.7) has a slightly better binding affinity than Ligand A (-8.6). This is a 1.1 kcal/mol difference, which is significant.

**Overall Assessment:**

Despite Ligand B having a slightly better binding affinity, Ligand A is the more promising candidate. Ligand A excels in crucial ADME properties like DILI risk, BBB penetration, metabolic stability (Cl_mic and t1/2), and aqueous solubility. The TPSA is also significantly better for CNS penetration. While the Caco-2 permeability is slightly worse for A, the other advantages outweigh this. For a GPCR target in the CNS, minimizing off-target effects (DILI) and maximizing brain exposure (BBB, Pgp, TPSA) are critical. The 1.1 kcal/mol difference in binding affinity can potentially be optimized during lead optimization, whereas poor ADME properties are much harder to fix later.

Output:
0
2025-04-17 08:26:46,336 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B based on the provided guidelines, prioritizing GPCR-specific properties (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (344.455) is slightly lower, which is generally favorable for permeability.

**TPSA:** Ligand A (58.64) is excellent for CNS penetration (<90), while Ligand B (82.11) is still acceptable but less ideal.

**logP:** Ligand A (3.785) is optimal, while Ligand B (1.018) is on the lower side. A logP <1 can hinder permeation, making Ligand A preferable.

**H-Bond Donors/Acceptors:** Ligand A (HBD=1, HBA=3) and Ligand B (HBD=2, HBA=5) both fall within acceptable ranges.

**QED:** Both ligands have good QED scores (A: 0.908, B: 0.634), indicating drug-likeness.

**DILI:** Ligand A (35.091) has a slightly higher DILI risk than Ligand B (23.769), but both are below the concerning threshold of 60.

**BBB:** This is a critical parameter for CNS targets. Ligand A (87.398) has a very good BBB percentile, while Ligand B (30.593) is poor. This is a significant advantage for Ligand A.

**Caco-2 Permeability:** Ligand A (-4.336) and Ligand B (-5.039) both have negative values, which is unusual. Assuming these are percentile scores, lower values indicate lower permeability. Ligand B appears slightly worse here.

**Aqueous Solubility:** Ligand A (-4.587) and Ligand B (-1.577) both have negative values. Again, assuming these are percentile scores, Ligand B is better in this regard.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (A: 0.519, B: 0.265), which is good.

**Microsomal Clearance:** Ligand A (81.756) has higher microsomal clearance than Ligand B (14.197), indicating lower metabolic stability. This is a drawback for Ligand A.

**In vitro Half-Life:** Ligand B (-1.481) has a slightly longer half-life than Ligand A (-8.947).

**P-gp Efflux:** Ligand A (0.159) has lower P-gp efflux than Ligand B (0.021), which is favorable for CNS exposure.

**Binding Affinity:** Ligand A (-8.7 kcal/mol) has a significantly stronger binding affinity than Ligand B (-6.3 kcal/mol). This is a substantial advantage for Ligand A, potentially outweighing some of its ADME drawbacks. The difference of 2.4 kcal/mol is quite large.

**Overall Assessment:**

Ligand A excels in key GPCR properties: TPSA, logP, BBB, and, most importantly, binding affinity. While it has a higher DILI risk and lower metabolic stability (higher Cl_mic), the strong binding affinity and excellent BBB penetration are crucial for a CNS-targeting drug. Ligand B's lower logP and poor BBB penetration are significant drawbacks.

Output:
1
2025-04-17 08:26:46,337 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 drug candidates, considering the provided guidelines and GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (340.427 and 349.459 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (90.01) is excellent for CNS penetration, being below the 90 threshold. Ligand B (36.44) is also very good, well below the threshold.

**logP:** Ligand A (2.201) is within the optimal 1-3 range. Ligand B (4.234) is slightly higher, potentially edging into a range where solubility could become a concern, but still acceptable.

**H-Bond Donors/Acceptors:** Ligand A has 2 HBD and 4 HBA, both within acceptable limits. Ligand B has 0 HBD and 4 HBA, also within limits.

**QED:** Ligand A (0.845) has a very strong drug-like profile. Ligand B (0.694) is still good, above the 0.5 threshold.

**DILI:** Ligand A (50.33) has a low DILI risk. Ligand B (68.282) is higher, indicating a moderate risk, but not excessively concerning.

**BBB:** Both ligands have excellent BBB penetration (Ligand A: 92.4, Ligand B: 93.331), exceeding the desirable >70 threshold for CNS targets.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values, which is unusual and suggests a potential issue with the experimental setup or data quality. However, we'll proceed assuming these represent low permeability.

**Aqueous Solubility:** Both ligands have negative solubility values, which is also unusual. This suggests very low solubility.

**hERG Inhibition:** Both ligands have low hERG inhibition liability (Ligand A: 0.5, Ligand B: 0.812).

**Microsomal Clearance:** Ligand A (58.172) has moderate clearance, while Ligand B (95.056) has high clearance, suggesting lower metabolic stability.

**In vitro Half-Life:** Ligand A (10.959) has a short half-life. Ligand B (47.806) has a much longer half-life, which is preferable.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (Ligand A: 0.526, Ligand B: 0.775).

**Binding Affinity:** Ligand B (-9.4 kcal/mol) has a significantly stronger binding affinity than Ligand A (-10.0 kcal/mol).

**Overall Assessment:**

While Ligand A has a better QED score and slightly better affinity, Ligand B has a significantly longer half-life and a more favorable metabolic stability profile (lower Cl_mic). The solubility and Caco-2 values are concerning for both, but the superior affinity and half-life of Ligand B, combined with acceptable BBB and P-gp properties, outweigh the slightly higher DILI risk. The affinity difference is substantial (>1.5 kcal/mol).

Output:
1
2025-04-17 08:26:46,337 - INFO - Reasoning:

Let's analyze Ligand A and Ligand B based on the provided guidelines, prioritizing GPCR-specific properties (BBB, logP, Pgp, TPSA, and affinity) for DRD2.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (446.147 Da) is higher, but still acceptable. Ligand B (347.503 Da) is lower, potentially favoring permeability.

**TPSA:** Both exceed the optimal <90 for CNS targets, but are reasonably close. Ligand A (41.13) is better than Ligand B (43.86).

**logP:** Ligand A (4.959) is slightly high, potentially leading to solubility issues or off-target interactions. Ligand B (1.968) is excellent, falling squarely within the optimal range.

**H-Bond Donors/Acceptors:** Ligand A (2 HBD, 2 HBA) is preferable to Ligand B (0 HBD, 3 HBA). Both are within acceptable limits.

**QED:** Both ligands have good QED scores (A: 0.698, B: 0.784), indicating drug-like properties.

**DILI:** Ligand A (63.086) has a moderate DILI risk, while Ligand B (5.894) has a very low risk. This is a significant advantage for Ligand B.

**BBB:** Both ligands show excellent BBB penetration (A: 83.521, B: 84.064), exceeding the >70% threshold for CNS targets.

**Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and suggests a potential issue with the data or a non-standard scale. However, the values are similar.

**Aqueous Solubility:** Both have negative solubility values, again suggesting a potential data issue. Ligand B (-1.331) is slightly better than Ligand A (-5.904).

**hERG Inhibition:** Ligand A (0.782) has a slightly higher hERG risk than Ligand B (0.662), but both are relatively low.

**Microsomal Clearance:** Ligand A (34.604) has a higher clearance than Ligand B (24.356), indicating lower metabolic stability.

**In vitro Half-Life:** Ligand A (127.534 hours) has a significantly longer half-life than Ligand B (-2.405 hours). This is a major advantage for Ligand A.

**P-gp Efflux:** Ligand A (0.393) has a higher P-gp efflux liability than Ligand B (0.075), which is unfavorable for CNS penetration.

**Binding Affinity:** Ligand A (-8.4 kcal/mol) has a considerably stronger binding affinity than Ligand B (0.0 kcal/mol). This is a substantial advantage for Ligand A, potentially outweighing some of its ADME drawbacks.

**Overall Assessment:**

Ligand A has a much stronger binding affinity and a longer half-life, which are crucial for DRD2. However, it has a higher logP, higher DILI risk, higher P-gp efflux, and lower metabolic stability. Ligand B has better ADME properties (lower logP, DILI, P-gp, and clearance), but its binding affinity is essentially non-existent.

Given the importance of affinity for GPCRs, and the fact that the affinity difference is so large (8.4 kcal/mol), I believe Ligand A is the more promising candidate *despite* its ADME liabilities. These liabilities could potentially be addressed through further optimization, but a weak binder is unlikely to become a viable drug.

Output:
1
2025-04-17 08:26:46,337 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (346.471 and 351.447 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (60.85) is significantly better than Ligand B (104.46). For CNS targets, we want TPSA <= 90, so Ligand A is much more favorable.

**logP:** Both ligands have acceptable logP values (2.463 and 1.659), falling within the 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A (HBD=1, HBA=3) is better than Ligand B (HBD=3, HBA=5) in terms of maintaining a balance between solubility and permeability.

**QED:** Ligand A (0.891) has a much higher QED score than Ligand B (0.628), indicating a more drug-like profile.

**DILI:** Ligand B (44.591) has a slightly higher DILI risk than Ligand A (31.02), but both are below the concerning threshold of 60.

**BBB:** Both ligands have similar BBB penetration (Ligand A: 57.968, Ligand B: 56.999). While neither exceeds the desirable >70 for CNS targets, they are reasonably comparable.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.385 and -4.9), which is unusual and suggests poor permeability. This is a significant drawback for both.

**Aqueous Solubility:** Both ligands have negative solubility values (-1.924 and -1.569), indicating poor aqueous solubility.

**hERG Inhibition:** Ligand A (0.566) has a lower hERG inhibition risk than Ligand B (0.177), which is preferable.

**Microsomal Clearance:** Ligand B (35.308) has a lower microsomal clearance than Ligand A (41.763), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand B (-29.538) has a much longer in vitro half-life than Ligand A (-2.544), which is a significant advantage.

**P-gp Efflux:** Ligand A (0.684) has lower P-gp efflux liability than Ligand B (0.164), which is favorable for CNS penetration.

**Binding Affinity:** Ligand A (-8.4 kcal/mol) has a significantly stronger binding affinity than Ligand B (-7.8 kcal/mol). This >1.5 kcal/mol difference is substantial and can outweigh some ADME drawbacks.

**Overall Assessment:**

Ligand A is the more promising candidate. While both have poor Caco-2 and solubility, Ligand A excels in crucial areas: TPSA, QED, hERG inhibition, and, most importantly, binding affinity. The stronger binding affinity of Ligand A (-8.4 kcal/mol vs -7.8 kcal/mol) is a major advantage for a GPCR target, and its better TPSA and QED scores contribute to a more favorable drug-like profile. Although Ligand B has better metabolic stability and half-life, the superior affinity and other properties of Ligand A make it the preferred choice.

Output:
0
2025-04-17 08:26:46,337 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (346.475 and 347.419 Da) are within the ideal 200-500 Da range.

**TPSA:** Ligand A (76.02) is excellent for CNS penetration, falling well below the 90 A^2 threshold. Ligand B (94.11) is still reasonable but less optimal.

**logP:** Ligand A (1.862) is within the optimal 1-3 range. Ligand B (-0.687) is slightly below 1, which *could* indicate permeability issues, although not drastically.

**H-Bond Donors/Acceptors:** Both ligands have 2 HBD and 4-5 HBA, satisfying the <5 HBD and <10 HBA guidelines.

**QED:** Ligand A (0.791) has a better QED score than Ligand B (0.596), indicating a more drug-like profile.

**DILI:** Both ligands have low DILI risk (27.608 and 24.855 percentile), which is favorable.

**BBB:** Ligand A (62.233) has a moderate BBB penetration, while Ligand B (28.538) is significantly lower. For a CNS target like DRD2, a higher BBB value is crucial.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.135 and -5.272), which is unusual and suggests potential issues with intestinal absorption. However, these values are on a log scale and can be difficult to interpret without knowing the specific assay details.

**Aqueous Solubility:** Both ligands have negative solubility values (-2.383 and -1.823), suggesting poor aqueous solubility. This could be a formulation challenge.

**hERG Inhibition:** Both ligands have very low hERG risk (0.111 and 0.064), which is excellent.

**Microsomal Clearance:** Ligand B (-21.834) has significantly lower (better) microsomal clearance than Ligand A (30.236), indicating greater metabolic stability.

**In vitro Half-Life:** Ligand B (-6.173) has a negative half-life, which is not physically possible and likely indicates a very rapid degradation or a problem with the assay. Ligand A (12.332) has a reasonable half-life.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.113 and 0.002), which is favorable for CNS penetration.

**Binding Affinity:** Both ligands have strong binding affinities (-8.0 and -7.9 kcal/mol). The difference is minimal.

**Overall Assessment:**

Ligand A excels in TPSA, QED, and has a reasonable half-life. However, its BBB penetration is only moderate. Ligand B has superior metabolic stability (lower Cl_mic) and very low P-gp efflux, but its BBB penetration is poor, and its in vitro half-life is problematic (negative value). Given the importance of BBB penetration for a CNS target like DRD2, and the relatively small difference in binding affinity, Ligand A is the slightly better candidate, despite its moderate BBB score. The negative half-life for Ligand B is a major red flag.

Output:
0
2025-04-17 08:26:46,338 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (348.443 and 370.515 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (84.5) is slightly higher than Ligand B (76.66). Both are below the 90 A^2 threshold desirable for CNS targets, which is good.

**logP:** Both ligands have excellent logP values (1.392 and 1.192) falling within the optimal 1-3 range.

**H-Bond Donors:** Both have 2 HBD, which is within the acceptable limit of <=5.

**H-Bond Acceptors:** Ligand A has 4 HBA, and Ligand B has 5. Both are below the 10 limit.

**QED:** Ligand B (0.671) has a better QED score than Ligand A (0.355), indicating a more drug-like profile.

**DILI:** Ligand A (15.006) has a significantly lower DILI risk than Ligand B (39.55), which is a substantial advantage.

**BBB:** Ligand B (69.446) has a better BBB penetration percentile than Ligand A (55.06). While both are not ideal (>70), Ligand B is closer to the desired threshold for a CNS target.

**Caco-2 Permeability:** Ligand A (-4.651) has worse Caco-2 permeability than Ligand B (-5.302), indicating lower intestinal absorption.

**Aqueous Solubility:** Ligand A (-1.954) has better aqueous solubility than Ligand B (-2.667).

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.182 and 0.281).

**Microsomal Clearance:** Ligand B (31.015) has lower microsomal clearance than Ligand A (40.736), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand B (11.124) has a longer in vitro half-life than Ligand A (-19.832), which is a positive attribute.

**P-gp Efflux:** Both have very low P-gp efflux liability (0.036 and 0.112).

**Binding Affinity:** Ligand B (-7.7 kcal/mol) has a slightly better binding affinity than Ligand A (-7.5 kcal/mol), though the difference is small.

**Overall Assessment:**

Ligand B is better overall. While Ligand A has a lower DILI risk and better solubility, Ligand B excels in critical areas for a CNS-targeting GPCR ligand: better BBB penetration, improved metabolic stability (lower Cl_mic and longer t1/2), and slightly better binding affinity. The QED score is also significantly higher for Ligand B. The small difference in affinity can be outweighed by the superior ADME properties of Ligand B.

Output:
1
2025-04-17 08:26:46,338 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (337.339 Da) is slightly lower, which could be beneficial for permeability. Ligand B (362.455 Da) is also good.

**TPSA:** Ligand A (115.98) is closer to the ideal range for CNS targets (<=90) than Ligand B (84.42), which is excellent.

**logP:** Both ligands have good logP values (Ligand A: 1.5, Ligand B: 1.18), falling within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A (HBD=4, HBA=4) is slightly better balanced than Ligand B (HBD=1, HBA=6). Both are acceptable.

**QED:** Both ligands have good QED scores (Ligand A: 0.51, Ligand B: 0.677), indicating drug-like properties. Ligand B is slightly better.

**DILI:** Ligand A (85.537) has a higher DILI risk than Ligand B (52.423). This is a significant negative for Ligand A.

**BBB:** Ligand B (58.24) has a significantly better BBB penetration percentile than Ligand A (40.558). This is crucial for a CNS target like DRD2.

**Caco-2 Permeability:** Ligand A (-5.835) has worse Caco-2 permeability than Ligand B (-5.405), suggesting lower intestinal absorption.

**Aqueous Solubility:** Ligand A (-4.693) has slightly better aqueous solubility than Ligand B (-0.774).

**hERG Inhibition:** Both ligands have very low hERG inhibition risk (Ligand A: 0.483, Ligand B: 0.141).

**Microsomal Clearance:** Ligand A (-4.185) has a lower (better) microsomal clearance than Ligand B (45.989), indicating better metabolic stability.

**In vitro Half-Life:** Ligand A (66.321) has a much longer in vitro half-life than Ligand B (24.921).

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (Ligand A: 0.03, Ligand B: 0.035).

**Binding Affinity:** Ligand B (-7.1) has a significantly stronger binding affinity than Ligand A (-10). This is a major advantage.

**Overall Assessment:**

Ligand B is the stronger candidate. While Ligand A has better metabolic stability and slightly better solubility, Ligand B excels in the most critical areas for a CNS-targeting GPCR ligand: **BBB penetration and binding affinity**. The significantly lower DILI risk for Ligand B is also a major advantage. The difference in binding affinity (-7.1 vs -10 kcal/mol) is substantial and likely outweighs the minor benefits of Ligand A's metabolic stability.

Output:
1
2025-04-17 08:26:46,338 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (354.841 and 347.463 Da) fall within the ideal 200-500 Da range.

**TPSA:** Both ligands have TPSA values (60.23 and 61.68) slightly above the optimal <90 for CNS targets, but still reasonably acceptable.

**logP:** Ligand A (3.059) is optimal, while Ligand B (0.84) is quite low, potentially hindering membrane permeability and CNS penetration. This is a significant drawback for a CNS target.

**H-Bond Donors/Acceptors:** Both ligands have acceptable HBD (0) and HBA (4 & 5) counts.

**QED:** Ligand A (0.85) has a better QED score than Ligand B (0.516), indicating a more drug-like profile.

**DILI:** Ligand A (71.19) has a higher DILI risk than Ligand B (31.252), which is a concern. However, DILI prediction is not perfect.

**BBB:** Both ligands have good BBB penetration (66.188% and 66.382%), exceeding the desirable >70% threshold, but are close.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.666 and -4.808), which is unusual and suggests poor permeability. This is a major concern.

**Aqueous Solubility:** Both ligands have very poor aqueous solubility (-3.948 and -0.398). This is a significant hurdle for formulation and bioavailability.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.703 and 0.328).

**Microsomal Clearance:** Ligand A (43.216) has lower microsomal clearance than Ligand B (50.196), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand B (-6.574) has a longer in vitro half-life than Ligand A (-3.651), which is favorable.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.276 and 0.093), which is good for CNS exposure.

**Binding Affinity:** Ligand B (-7.6 kcal/mol) has a significantly stronger binding affinity than Ligand A (-9.4 kcal/mol). This is a substantial advantage.

**Overall Assessment:**

While Ligand B has a superior binding affinity and better metabolic stability (longer half-life), its very low logP is a major concern for CNS penetration. Ligand A has a better logP and QED, but suffers from a higher DILI risk and weaker binding. The negative Caco-2 values for both are concerning and suggest potential issues with absorption. However, the affinity difference between Ligand B (-7.6) and Ligand A (-9.4) is 1.8 kcal/mol, which is a substantial difference that could outweigh the logP issue, *if* formulation strategies can overcome the solubility and permeability challenges. Given the importance of affinity for GPCRs, and the relatively similar BBB values, Ligand B is slightly more promising, assuming solubility/permeability can be addressed.

Output:
1
2025-04-17 08:26:46,338 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (352.356 and 346.431 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (51.22) is significantly better than Ligand B (85.25). For CNS targets, we want TPSA <= 90, and ideally closer to 60. Ligand A is much closer to this ideal. Ligand B is quite high and could hinder BBB penetration.

**logP:** Ligand A (3.887) is optimal (1-3), while Ligand B (0.634) is low, potentially causing permeability issues.

**H-Bond Donors/Acceptors:** Ligand A (HBD=1, HBA=4) and Ligand B (HBD=2, HBA=5) are both within acceptable ranges.

**QED:** Both ligands have good QED scores (0.802 and 0.838), indicating good drug-like properties.

**DILI:** Ligand A (52.772) has a slightly higher DILI risk than Ligand B (38.813), but both are below the concerning threshold of 60.

**BBB:** Ligand A (73.672) has a much better BBB percentile than Ligand B (49.787). A value >70 is desirable for CNS targets, and Ligand A is closer to this.

**Caco-2 Permeability:** Ligand A (-4.68) and Ligand B (-5.268) both have negative Caco-2 values, suggesting poor permeability. However, the scale isn't specified, so it's difficult to interpret these values accurately.

**Aqueous Solubility:** Ligand A (-4.064) and Ligand B (-0.824) both have negative solubility values, indicating poor solubility. Again, the scale is unknown.

**hERG:** Ligand A (0.689) has a lower hERG risk than Ligand B (0.192), which is preferable.

**Microsomal Clearance:** Ligand B (8.528) has significantly lower microsomal clearance than Ligand A (84.995), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (10.939) has a longer half-life than Ligand B (4.878), which is generally desirable.

**P-gp Efflux:** Ligand A (0.244) has lower P-gp efflux than Ligand B (0.031), meaning it's less likely to be pumped out of the brain, improving CNS exposure.

**Binding Affinity:** Both ligands have the same binding affinity (-9.2 kcal/mol), which is excellent.

**Overall Assessment:**

Considering the GPCR-specific priorities, Ligand A is the better candidate. While Ligand B has better metabolic stability (lower Cl_mic) and lower P-gp efflux, Ligand A excels in crucial areas for CNS penetration: TPSA, logP, and BBB. The similar affinity means that the ADME advantages of Ligand A outweigh the slight metabolic benefit of Ligand B. The lower hERG risk for Ligand A is also a positive.

Output:
1
2025-04-17 08:26:46,338 - INFO - Reasoning:

Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (375.491 and 353.455 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (127.59) is higher than the preferred <90 for CNS targets, but not drastically so. Ligand B (84.37) is well within the desired range. This favors Ligand B.

**3. logP:** Ligand A (0.541) is quite low, potentially hindering membrane permeability. Ligand B (2.067) is within the optimal 1-3 range. This strongly favors Ligand B.

**4. H-Bond Donors:** Ligand A (3) is acceptable. Ligand B (2) is also acceptable.

**5. H-Bond Acceptors:** Ligand A (5) is acceptable. Ligand B (7) is acceptable, though approaching the upper limit.

**6. QED:** Both ligands have reasonable QED values (0.48 and 0.695), indicating drug-like properties, with Ligand B being slightly better.

**7. DILI:** Ligand A (50.64) has a lower DILI risk than Ligand B (91.314). This favors Ligand A.

**8. BBB:** Ligand A (40.83) has a poor BBB percentile, which is a major concern for a CNS target like DRD2. Ligand B (32.687) is also low, but slightly better than A. Both are suboptimal.

**9. Caco-2:** Both ligands have negative Caco-2 values, which is unusual and suggests a potential issue with the data or modeling. However, we can assume this means poor permeability.

**10. Solubility:** Ligand A (-0.944) has very poor solubility. Ligand B (-3.5) is even worse. Both are problematic.

**11. hERG:** Ligand A (0.133) has a low hERG risk, which is good. Ligand B (0.809) has a higher, but still relatively low, hERG risk. This favors Ligand A.

**12. Cl_mic:** Ligand A (16.754) has lower microsomal clearance, suggesting better metabolic stability, which is preferable. Ligand B (27.129) has higher clearance. This favors Ligand A.

**13. t1/2:** Ligand A (-21.289) has a negative in vitro half-life, which is not physically possible and indicates a data issue. Ligand B (10.749) has a reasonable half-life. This strongly favors Ligand B.

**14. Pgp:** Ligand A (0.06) has very low P-gp efflux, which is excellent for CNS penetration. Ligand B (0.294) has a slightly higher, but still reasonable, Pgp efflux. This favors Ligand A.

**15. Binding Affinity:** Ligand B (-8.8 kcal/mol) has a significantly stronger binding affinity than Ligand A (-7.7 kcal/mol). This is a substantial advantage, potentially outweighing some of the ADME drawbacks.

**Overall Assessment:**

Despite Ligand A having better DILI, hERG, Cl_mic, and Pgp properties, its extremely low logP, poor solubility, and very poor BBB penetration are significant liabilities for a CNS-targeting drug. The negative half-life is also a red flag. Ligand B, while having a higher DILI risk and slightly worse Pgp efflux, possesses a significantly stronger binding affinity and a more favorable logP and TPSA. The better binding affinity is likely to be a decisive factor, and the moderate ADME properties of Ligand B can potentially be improved through further optimization.

Output:
1
2025-04-17 08:26:46,339 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (359.411 Da) is slightly higher than Ligand B (338.447 Da), but both are acceptable.

**TPSA:** Ligand A (90.09) is at the upper limit for CNS targets, while Ligand B (35.53) is excellent, well below the 90 threshold. This favors Ligand B.

**logP:** Ligand A (0.643) is a bit low, potentially hindering membrane permeability. Ligand B (4.373) is higher, potentially causing solubility issues, but still within a reasonable range.

**H-Bond Donors/Acceptors:** Ligand A has 0 HBD and 7 HBA, which is good. Ligand B has 0 HBD and 3 HBA, also good.

**QED:** Both ligands have similar QED values (0.67 and 0.637), indicating good drug-likeness.

**DILI:** Ligand A has a significantly higher DILI risk (85.149%) compared to Ligand B (15.083%). This is a major drawback for Ligand A.

**BBB:** Both ligands have good BBB penetration (69.678% and 68.127%), but neither exceeds the desirable 70% threshold.

**Caco-2 Permeability:** Ligand A (-5.026) shows poor Caco-2 permeability, while Ligand B (-4.408) is slightly better, but still not ideal.

**Aqueous Solubility:** Both ligands have poor aqueous solubility (-3.513 and -5.589). This could pose formulation challenges.

**hERG Inhibition:** Ligand A (0.208) has a slightly lower hERG risk than Ligand B (0.854).

**Microsomal Clearance:** Ligand A (67.096) has a lower microsomal clearance, suggesting better metabolic stability than Ligand B (110.003).

**In vitro Half-Life:** Ligand A (-26.307) has a negative half-life, which is concerning. Ligand B (-8.945) is also negative, but less so. Both are problematic.

**P-gp Efflux:** Ligand A (0.207) has lower P-gp efflux, which is favorable for CNS penetration, compared to Ligand B (0.42).

**Binding Affinity:** Ligand B (-9.0) has a significantly stronger binding affinity than Ligand A (-8.8). This is a crucial advantage.

**Overall Assessment:**

Ligand B is the better candidate. While both have solubility and permeability concerns, Ligand B's superior binding affinity (-9.0 vs -8.8 kcal/mol) and significantly lower DILI risk (15.083% vs 85.149%) outweigh the slightly higher logP and P-gp efflux. The lower TPSA of Ligand B is also beneficial for CNS penetration. Although both have negative in vitro half-lives, the difference is less pronounced for Ligand B.

Output:
1
2025-04-17 08:26:46,339 - INFO - Reasoning:

Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (358.356 and 356.501 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (44.76) is higher than Ligand B (23.55). For a CNS target like DRD2, TPSA should be <=90, so both are acceptable, but B is significantly better.

**3. logP:** Both ligands have good logP values (3.807 and 4.028), falling within the optimal 1-3 range.

**4. H-Bond Donors:** Both have 0 HBD, which is acceptable.

**5. H-Bond Acceptors:** Ligand A has 4 HBA, and Ligand B has 2. Both are below the threshold of 10.

**6. QED:** Both have similar QED values (0.768 and 0.717), indicating good drug-likeness.

**7. DILI:** Ligand A has a DILI risk of 48.817, while Ligand B has 13.532. Ligand B is significantly better here, being well below the 40 threshold.

**8. BBB:** Ligand A has a BBB penetration of 91.702, and Ligand B has 97.635. Both are excellent, exceeding the 70% threshold for CNS targets, but B is slightly better.

**9. Caco-2 Permeability:** Both have negative Caco-2 values (-4.752 and -4.547). These values are unusual and suggest poor permeability. However, since this is a GPCR target, permeability is less critical than BBB penetration.

**10. Aqueous Solubility:** Both have negative solubility values (-4.553 and -3.393), indicating poor solubility. This is a concern, but can be addressed with formulation strategies.

**11. hERG Inhibition:** Ligand A (0.725) has a slightly higher hERG risk than Ligand B (0.963). Lower is better, so Ligand B is preferable.

**12. Microsomal Clearance:** Ligand A (50.133) has a higher microsomal clearance than Ligand B (24.165), indicating lower metabolic stability. Ligand B is better.

**13. In vitro Half-Life:** Ligand A (-0.053) has a very short half-life, while Ligand B (-1.544) is also short, but less so.

**14. P-gp Efflux:** Ligand A (0.237) has lower P-gp efflux than Ligand B (0.632), which is favorable for CNS penetration.

**15. Binding Affinity:** Ligand A (-9.8 kcal/mol) has a significantly stronger binding affinity than Ligand B (-7.5 kcal/mol). This is a substantial advantage (2.3 kcal/mol difference).

**Overall Assessment:**

While Ligand A has a superior binding affinity, Ligand B demonstrates a better overall ADME-Tox profile. Specifically, it has a much lower DILI risk, better metabolic stability (lower Cl_mic), and a slightly better BBB score. The difference in binding affinity is significant, but the ADME advantages of Ligand B are crucial for a CNS drug candidate. The negative Caco-2 and solubility values are concerning for both, but less critical for a GPCR target where BBB penetration is paramount. Given the importance of minimizing off-target effects and maximizing CNS exposure, Ligand B is the more promising candidate.

Output:
1
2025-04-17 08:26:46,339 - INFO - Batch 449 complete. Total preferences: 7184
2025-04-17 08:26:46,339 - INFO - Processing batch 450/512...
2025-04-17 08:27:36,274 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (348.403 and 363.483 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (115.13) is higher than the preferred <90 for CNS targets, while Ligand B (74.57) is well within the range. This is a significant advantage for Ligand B.

**logP:** Ligand A (0.386) is quite low, potentially hindering membrane permeability. Ligand B (0.57) is also on the lower side, but slightly better. Both are below the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A has 3 HBD and 4 HBA, which are acceptable. Ligand B has 2 HBD and 5 HBA, also acceptable.

**QED:** Both ligands have similar QED values (0.645 and 0.662), indicating good drug-likeness.

**DILI:** Ligand A (57.852) has a higher DILI risk than Ligand B (31.097). Lower is better, so Ligand B is preferable.

**BBB:** Ligand A (40.403) has a low BBB penetration percentile, which is a major drawback for a CNS target like DRD2. Ligand B (18.147) is also low, but still better than Ligand A. Both are far from the desirable >70.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.1 and -5.202), which is unusual and suggests poor permeability. This is concerning for both.

**Aqueous Solubility:** Both have negative solubility values (-3.093 and -2.558), indicating very poor aqueous solubility. This is a significant issue for both compounds.

**hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.069 and 0.175), which is positive.

**Microsomal Clearance:** Ligand A (-17.283) has a more negative value, indicating faster clearance and lower metabolic stability compared to Ligand B (-5.664).

**In vitro Half-Life:** Ligand B (7.16 hours) has a significantly longer half-life than Ligand A (-12.69 hours).

**P-gp Efflux:** Both have very low P-gp efflux liability (0.031 and 0.029), which is good.

**Binding Affinity:** Ligand B (-7.2 kcal/mol) has a slightly better binding affinity than Ligand A (-8.1 kcal/mol). While both are good, the difference is significant enough to consider.

**Overall Assessment:**

Ligand B is the better candidate despite both having significant issues. Ligand B has a lower TPSA, lower DILI risk, better BBB penetration (though still low), better metabolic stability, a longer half-life, and slightly better binding affinity. Ligand A's low logP and very poor BBB penetration are major drawbacks for a CNS-targeting drug. The solubility and Caco-2 permeability are problematic for both, but these can potentially be addressed with formulation strategies.

Output:
1
2025-04-17 08:27:36,274 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (362.5 & 347.5 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (76.02) is higher than Ligand B (54.26). For a CNS target like DRD2, TPSA should ideally be <= 90. Both are acceptable, but B is better.

**3. logP:** Both ligands have good logP values (1.91 & 2.68), falling within the optimal 1-3 range. Ligand B is slightly more lipophilic, which could be beneficial for membrane permeability.

**4. H-Bond Donors:** Ligand A has 2 HBD, while Ligand B has 0. Both are within the acceptable limit of <=5.

**5. H-Bond Acceptors:** Both ligands have 5 HBA, which is within the acceptable limit of <=10.

**6. QED:** Both ligands have reasonable QED scores (0.73 & 0.65), indicating good drug-like properties.

**7. DILI:** Both ligands have low DILI risk (37.2 & 33.3), which is favorable.

**8. BBB:** This is a critical parameter for CNS targets. Ligand B (70.6%) is significantly better than Ligand A (53.9%), exceeding the desirable >70% threshold.

**9. Caco-2 Permeability:** Ligand A (-5.49) shows poor Caco-2 permeability, suggesting poor intestinal absorption. Ligand B (-4.83) is better, but still not great.

**10. Aqueous Solubility:** Both ligands have poor aqueous solubility (-2.68 & -1.58). This could pose formulation challenges, but is less critical for CNS drugs that need to cross the BBB.

**11. hERG Inhibition:** Ligand A (0.13) has a slightly lower hERG risk than Ligand B (0.56), which is preferable.

**12. Microsomal Clearance:** Ligand A (19.96) has a lower microsomal clearance than Ligand B (61.54), indicating better metabolic stability.

**13. In vitro Half-Life:** Ligand B (-0.22) has a negative half-life, which is not possible. This is likely an error in the data, and makes this ligand less reliable. Ligand A (1.42) has a reasonable half-life.

**14. P-gp Efflux:** Ligand A (0.057) has lower P-gp efflux than Ligand B (0.152), which is beneficial for CNS penetration.

**15. Binding Affinity:** Ligand A (-8.0) has a slightly better binding affinity than Ligand B (-7.7). While both are good, the 0.3 kcal/mol difference is not huge.

**Overall Assessment:**

Ligand B excels in BBB penetration, a crucial factor for DRD2 targeting. However, it has a questionable half-life value and higher P-gp efflux. Ligand A has better metabolic stability, lower P-gp efflux, and a slightly better binding affinity, but suffers from poor Caco-2 permeability and lower BBB penetration.

Considering the importance of BBB penetration for a CNS target, and the questionable half-life of Ligand B, Ligand A is the more promising candidate despite its permeability issues. The slightly better affinity and metabolic stability also contribute to this decision.

Output:
0
2025-04-17 08:27:36,274 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (342.399 and 352.475 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (80.37) is slightly higher than Ligand B (75.71), but both are below the 90 A^2 threshold desirable for CNS targets.

**logP:** Ligand A (1.202) is within the optimal 1-3 range. Ligand B (1.914) is also within the optimal range, but closer to the upper limit.

**H-Bond Donors/Acceptors:** Both ligands have 1 HBD and a reasonable number of HBAs (5 and 4 respectively), satisfying the <5 HBD and <10 HBA guidelines.

**QED:** Ligand A (0.905) has a significantly better QED score than Ligand B (0.759), indicating a more drug-like profile.

**DILI:** Ligand B (30.05) has a much lower DILI risk than Ligand A (56.805), suggesting better potential for avoiding liver toxicity.

**BBB:** Ligand B (67.197) has a better BBB penetration percentile than Ligand A (55.603), which is crucial for a CNS target like DRD2. While both are not >70, Ligand B is closer.

**Caco-2 Permeability:** Ligand A (-5.256) has a worse Caco-2 permeability than Ligand B (-4.729).

**Aqueous Solubility:** Ligand A (-1.957) has worse aqueous solubility than Ligand B (-1.465).

**hERG Inhibition:** Both ligands have very low hERG inhibition liability (0.138 and 0.1, respectively), which is excellent.

**Microsomal Clearance:** Ligand A (17.974) has a lower microsomal clearance than Ligand B (19.582), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (34.906) has a significantly longer in vitro half-life than Ligand B (0.31), which is a major advantage.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.025 and 0.065, respectively).

**Binding Affinity:** Ligand B (-8.4 kcal/mol) has a significantly stronger binding affinity than Ligand A (-7.7 kcal/mol). This >1.5 kcal/mol difference is substantial and can outweigh some ADME drawbacks.

**Overall Assessment:**

Ligand B is the stronger candidate. While Ligand A has a better QED and half-life, Ligand B's superior binding affinity (-8.4 vs -7.7 kcal/mol) and better BBB penetration (67.2 vs 55.6) are critical for a CNS-targeting GPCR like DRD2. The lower DILI risk for Ligand B is also a significant benefit. The slightly higher metabolic clearance of Ligand B is a minor concern compared to the substantial affinity advantage.

Output:
1
2025-04-17 08:27:36,274 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (351.403 and 350.503 Da) fall comfortably within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (104.9) is higher than the preferred <90 for CNS targets, but not drastically so. Ligand B (49.85) is excellent, well below 90. This favors Ligand B.

**3. logP:** Ligand A (0.521) is quite low, potentially hindering membrane permeability. Ligand B (2.543) is within the optimal 1-3 range. This strongly favors Ligand B.

**4. H-Bond Donors:** Ligand A (2) is acceptable. Ligand B (0) is also good.

**5. H-Bond Acceptors:** Ligand A (6) is acceptable. Ligand B (3) is also good.

**6. QED:** Both ligands have good QED scores (0.662 and 0.709), indicating good drug-like properties.

**7. DILI:** Ligand A (48.275) has a slightly higher DILI risk than Ligand B (11.632), but both are below the concerning threshold of 60.

**8. BBB:** Ligand A (49.554) has a poor BBB penetration percentile. Ligand B (88.329) is excellent, exceeding the desirable >70 for CNS targets. This is a major advantage for Ligand B.

**9. Caco-2 Permeability:** Ligand A (-4.833) has poor Caco-2 permeability. Ligand B (-4.311) is also poor, but slightly better.

**10. Aqueous Solubility:** Both ligands have poor aqueous solubility (-1.863 and -2.609). This could pose formulation challenges.

**11. hERG Inhibition:** Both ligands show very low hERG inhibition risk (0.112 and 0.367).

**12. Microsomal Clearance:** Ligand A (16.975) has lower microsomal clearance than Ligand B (66.738), suggesting better metabolic stability. This favors Ligand A.

**13. In vitro Half-Life:** Both ligands have very short in vitro half-lives (25.863 and 0.062 hours). This is a significant drawback for both, but Ligand A is better.

**14. P-gp Efflux:** Ligand A (0.06) has very low P-gp efflux, which is good for CNS penetration. Ligand B (0.113) is slightly higher, but still relatively low.

**15. Binding Affinity:** Both ligands have excellent binding affinities (-7.1 and -7.0 kcal/mol). The difference is minimal and unlikely to be decisive.

**Overall Assessment:**

Ligand B clearly outperforms Ligand A, particularly regarding crucial GPCR/CNS properties. Its significantly better logP, TPSA, and *especially* BBB penetration make it a much more promising candidate. While Ligand A has better metabolic stability and half-life, the poor BBB penetration is a critical flaw for a CNS target like DRD2. The slightly better Caco-2 permeability of Ligand B is also a minor advantage.



Output:
1
2025-04-17 08:27:36,274 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (349.45 and 351.451 Da) fall within the ideal range of 200-500 Da.

**TPSA:** Ligand A (43.86) is significantly better than Ligand B (91.56). For CNS targets, TPSA should be <= 90, and A is comfortably within this range, while B is close to the upper limit and less desirable.

**logP:** Ligand A (1.654) is optimal, while Ligand B (0.94) is slightly low, potentially hindering permeation.

**H-Bond Donors/Acceptors:** Ligand A (0 HBD, 3 HBA) is preferable to Ligand B (1 HBD, 6 HBA). Both are within acceptable limits, but fewer H-bonds generally improve permeability.

**QED:** Both ligands have good QED scores (0.519 and 0.823), indicating drug-like properties.

**DILI:** Ligand A (14.541) has a much lower DILI risk than Ligand B (55.991), which is a significant advantage.

**BBB:** Ligand A (86.545) has a substantially better BBB penetration score than Ligand B (41.218). This is *critical* for a CNS target like DRD2.

**Caco-2 Permeability:** Ligand A (-4.301) and Ligand B (-4.715) are both negative, indicating poor permeability. However, the scale is not defined, so it's hard to interpret the absolute difference.

**Aqueous Solubility:** Ligand A (-1.459) is better than Ligand B (-2.171), although both are negative, suggesting poor solubility.

**hERG:** Both ligands have low hERG inhibition liability (0.42 and 0.273), which is good.

**Microsomal Clearance:** Ligand A (10.02) has significantly lower microsomal clearance than Ligand B (45.118), indicating better metabolic stability.

**In vitro Half-Life:** Ligand A (-14.031) has a slightly worse in vitro half-life than Ligand B (-13.353).

**P-gp Efflux:** Ligand A (0.058) exhibits lower P-gp efflux than Ligand B (0.134), which is beneficial for CNS exposure.

**Binding Affinity:** Ligand B (-7.8) has a slightly better binding affinity than Ligand A (-7.4), but the difference is less than 1.5 kcal/mol, and can be overcome by the other ADME properties.

**Overall Assessment:**

Ligand A is significantly better overall. Its superior BBB penetration, lower DILI risk, lower microsomal clearance, lower P-gp efflux, and more favorable TPSA and logP values outweigh the slightly weaker binding affinity. For a CNS GPCR target, these ADME properties are paramount. Ligand B's higher affinity is not enough to compensate for its poor predicted CNS penetration and higher potential for toxicity.

Output:
0
2025-04-17 08:27:36,274 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, considering the provided guidelines and GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (338.371 and 344.419 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (93.96) is excellent, falling well below the 90 A^2 threshold for CNS targets. Ligand B (121.34) is higher but still reasonable, though less optimal for CNS penetration.

**logP:** Ligand A (2.549) is within the optimal 1-3 range. Ligand B (-0.086) is slightly negative, which could hinder membrane permeability.

**H-Bond Donors/Acceptors:** Ligand A (HBD=2, HBA=7) and Ligand B (HBD=3, HBA=5) both have acceptable numbers of H-bond donors and acceptors, well within the guidelines.

**QED:** Both ligands have good QED scores (0.687 and 0.7), indicating drug-like properties.

**DILI:** Ligand A (84.606) has a higher DILI risk than Ligand B (44.707). This is a concern for Ligand A.

**BBB:** Ligand A (72.237) has a significantly better BBB percentile than Ligand B (32.183). This is a crucial advantage for a CNS target like DRD2.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.24 and -5.804), which is unusual and suggests poor permeability. However, these values are on a scale where negative values are possible, and direct comparison is difficult without knowing the scale's specifics.

**Aqueous Solubility:** Both ligands have negative solubility values (-3.815 and -1.154), also unusual. Similar to Caco-2, interpretation is limited without knowing the scale.

**hERG:** Both ligands have very low hERG inhibition liability (0.198 and 0.593), which is excellent.

**Microsomal Clearance:** Ligand A (35.897) has a higher microsomal clearance than Ligand B (-23.254). This suggests Ligand B is more metabolically stable.

**In vitro Half-Life:** Ligand A (9.603) has a longer in vitro half-life than Ligand B (-2.185).

**P-gp Efflux:** Ligand A (0.368) has lower P-gp efflux liability than Ligand B (0.006), which is favorable for CNS penetration.

**Binding Affinity:** Both ligands have excellent binding affinities (-9.4 and -8.7 kcal/mol). Ligand A has a slightly better affinity.

**Overall Assessment:**

Considering the GPCR-specific priorities, Ligand A is more promising despite the higher DILI risk. Its superior BBB penetration, lower P-gp efflux, and slightly better binding affinity outweigh the concerns about DILI, especially given the strong binding affinity. The negative Caco-2 and solubility values are concerning for both, but the strong binding affinity suggests these might be mitigated with formulation strategies. Ligand B's poor BBB penetration and negative logP are significant drawbacks for a CNS target.

Output:
0
2025-04-17 08:27:36,274 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (345.4 and 348.5 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (76.83) is higher than Ligand B (49.85). For CNS targets, TPSA < 90 is preferred, both meet this, but B is significantly better.

**logP:** Both ligands have good logP values (2.64 and 2.30), falling within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A has 1 HBD and 6 HBA, while Ligand B has 0 HBD and 3 HBA. Both are within acceptable limits.

**QED:** Ligand A (0.898) has a higher QED than Ligand B (0.766), indicating better overall drug-likeness.

**DILI:** Ligand A (59.5) has a higher DILI risk than Ligand B (13.8), which is a significant advantage for B.

**BBB:** Both ligands have excellent BBB penetration (88.3% and 84.9%), exceeding the desirable >70% threshold for CNS targets.

**Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and potentially problematic. However, the values are close enough to not be a major differentiator.

**Aqueous Solubility:** Both ligands have negative solubility values, which is also unusual. Again, the values are similar.

**hERG:** Both ligands have low hERG inhibition liability (0.66 and 0.452), which is good.

**Microsomal Clearance:** Ligand A has a higher microsomal clearance (83.5) than Ligand B (38.6), suggesting lower metabolic stability for A.

**In vitro Half-Life:** Ligand A has a longer half-life (16.4 hours) than Ligand B (2.2 hours).

**P-gp Efflux:** Ligand A has a Pgp efflux liability of 0.371, while Ligand B is 0.126, indicating lower efflux for B, which is beneficial for CNS exposure.

**Binding Affinity:** Ligand B (-8.0 kcal/mol) has a significantly stronger binding affinity than Ligand A (-0.0 kcal/mol). This is a crucial difference.

**Overall Assessment:**

Ligand B is the superior candidate. While Ligand A has a better QED and longer half-life, Ligand B boasts a significantly stronger binding affinity (-8.0 vs -0.0 kcal/mol), a much lower DILI risk (13.8 vs 59.5), and lower P-gp efflux. The lower TPSA and comparable BBB penetration are also favorable. The difference in affinity is so substantial that it outweighs the advantages of Ligand A.

Output:
1
2025-04-17 08:27:36,275 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (343.435 Da) is slightly lower, which could be beneficial for permeability, but both are acceptable.

**TPSA:** Ligand A (72.08) is significantly better than Ligand B (81.99). For CNS targets, we want TPSA <= 90, and ideally closer to 60. Ligand A is much closer to the ideal range.

**logP:** Ligand A (0.38) is quite low, potentially hindering membrane permeability. Ligand B (3.495) is within the optimal range (1-3). This is a significant advantage for Ligand B.

**H-Bond Donors/Acceptors:** Ligand A (0 HBD, 7 HBA) is better than Ligand B (2 HBD, 4 HBA). While both are within acceptable limits, fewer H-bonds generally improve permeability.

**QED:** Both ligands have reasonable QED scores (A: 0.803, B: 0.756), indicating good drug-like properties.

**DILI:** Ligand A (34.277) has a much lower DILI risk than Ligand B (67.623). This is a substantial advantage for Ligand A.

**BBB:** Both ligands have similar BBB penetration (A: 62.815, B: 62.117). Neither is above the desirable 70% threshold, but they are comparable.

**Caco-2 Permeability:** Ligand A (-5.196) has very poor Caco-2 permeability, while Ligand B (-4.983) is slightly better, but still poor.

**Aqueous Solubility:** Ligand A (-0.709) has poor aqueous solubility, while Ligand B (-5.301) is even worse. This could pose formulation challenges for both.

**hERG Inhibition:** Ligand A (0.103) has a very low hERG risk, which is excellent. Ligand B (0.758) is higher, indicating a moderate risk.

**Microsomal Clearance:** Ligand A (21.818) has lower microsomal clearance (better metabolic stability) than Ligand B (59.517).

**In vitro Half-Life:** Ligand B (34.642) has a significantly longer in vitro half-life than Ligand A (7.668). This is a positive for Ligand B.

**P-gp Efflux:** Ligand A (0.019) has very low P-gp efflux, which is highly desirable for CNS penetration. Ligand B (0.38) has higher P-gp efflux.

**Binding Affinity:** Ligand A (-8.8 kcal/mol) has *much* stronger binding affinity than Ligand B (-0.0 kcal/mol). This is a decisive factor. A difference of >1.5 kcal/mol can outweigh many ADME drawbacks.

**Overall Assessment:**

Despite Ligand B having a better logP and half-life, Ligand A's significantly superior binding affinity (-8.8 vs -0.0 kcal/mol), much lower DILI risk, lower P-gp efflux, and lower hERG risk are compelling advantages. While Ligand A has poor solubility and Caco-2 permeability, the strong binding affinity suggests that these might be less critical, and formulation strategies could potentially address the solubility issue. The TPSA is also more favorable for CNS penetration. Given the GPCR target and the importance of affinity, Ligand A is the more promising candidate.

Output:
1
2025-04-17 08:27:36,275 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (350.463 and 346.402 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (78.68) is higher than Ligand B (49.85). For CNS targets, TPSA should be <=90, so both are acceptable, but B is significantly better.

**logP:** Ligand A (1.424) is within the optimal 1-3 range. Ligand B (3.259) is at the higher end of optimal, but still acceptable.

**H-Bond Donors/Acceptors:** Ligand A has 1 HBD and 5 HBA, while Ligand B has 0 HBD and 3 HBA. Both are within acceptable limits.

**QED:** Ligand A (0.805) has a better QED score than Ligand B (0.679), indicating higher drug-likeness.

**DILI:** Ligand B (54.634) has a lower DILI risk than Ligand A (11.516), which is preferable.

**BBB:** This is a crucial parameter for CNS targets. Ligand B (98.139) has a *much* higher BBB penetration percentile than Ligand A (65.025). This is a significant advantage for B.

**Caco-2 Permeability:** Ligand A (-4.937) and Ligand B (-4.349) both have negative values, which is unusual. However, the scale is not specified, so it's difficult to interpret.

**Aqueous Solubility:** Ligand A (-0.515) has slightly better solubility than Ligand B (-3.863).

**hERG Inhibition:** Ligand A (0.181) has a lower hERG inhibition liability than Ligand B (0.418), which is preferable.

**Microsomal Clearance:** Ligand B (81.17) has a higher microsomal clearance than Ligand A (16.796), indicating lower metabolic stability. This is a drawback for B.

**In vitro Half-Life:** Ligand A (2.95) has a longer half-life than Ligand B (-5.476). This is a significant advantage for A.

**P-gp Efflux:** Ligand A (0.029) has a much lower P-gp efflux liability than Ligand B (0.176), which is highly desirable for CNS penetration.

**Binding Affinity:** Both ligands have very similar, strong binding affinities (-8.2 and -8.3 kcal/mol). The difference is negligible.

**Overall Assessment:**

Ligand B excels in BBB penetration and has a lower DILI risk. However, it suffers from higher P-gp efflux, higher microsomal clearance (lower metabolic stability), and a lower in vitro half-life. Ligand A has better QED, lower P-gp efflux, better metabolic stability, and a longer half-life. The slightly better solubility and lower hERG risk of A are also beneficial. Given the importance of BBB penetration for a CNS target like DRD2, and the relatively small difference in binding affinity, Ligand B appears more promising. However, the metabolic stability and efflux issues with B are concerning. The lower P-gp efflux of A is a significant advantage, potentially overcoming its lower BBB score. Considering all factors, the superior metabolic stability and lower efflux of Ligand A make it the slightly more viable candidate.

Output:
1
2025-04-17 08:27:36,275 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 drug candidates, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (356.482 and 351.403 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (69.64) is excellent, well below the 90 A^2 threshold for CNS targets. Ligand B (109.67) is higher, but still potentially acceptable, though less ideal.

**3. logP:** Ligand A (2.588) is optimal (1-3). Ligand B (0.647) is a bit low, potentially hindering permeation.

**4. H-Bond Donors:** Ligand A (2) and Ligand B (3) are both within the acceptable limit of <=5.

**5. H-Bond Acceptors:** Ligand A (3) and Ligand B (5) are both within the acceptable limit of <=10.

**6. QED:** Both ligands have similar QED values (0.591 and 0.566), indicating good drug-like properties.

**7. DILI:** Ligand A (12.524) has a much lower DILI risk than Ligand B (36.758), which is a significant advantage.

**8. BBB:** Ligand A (64.948) has a better BBB penetration percentile than Ligand B (39.007), although both are below the desirable >70 for CNS targets.

**9. Caco-2 Permeability:** Ligand A (-4.681) shows poor Caco-2 permeability, while Ligand B (-5.618) is even worse.

**10. Aqueous Solubility:** Ligand A (-2.118) shows poor solubility, while Ligand B (-1.41) is slightly better.

**11. hERG Inhibition:** Ligand A (0.521) has a slightly higher hERG risk than Ligand B (0.044), but both are relatively low.

**12. Microsomal Clearance:** Ligand A (19.697) has a higher microsomal clearance than Ligand B (1.319), suggesting lower metabolic stability.

**13. In vitro Half-Life:** Ligand A (24.753) has a longer in vitro half-life than Ligand B (23.446), which is a slight advantage.

**14. P-gp Efflux:** Ligand A (0.094) has lower P-gp efflux liability than Ligand B (0.01), which is favorable for CNS exposure.

**15. Binding Affinity:** Ligand B (-7.0 kcal/mol) has a significantly stronger binding affinity than Ligand A (-6.7 kcal/mol). This is a substantial advantage.

**Overall Assessment:**

While Ligand B has a superior binding affinity, Ligand A has a much better safety profile (lower DILI) and better BBB penetration. Ligand A's lower logP and Caco-2 permeability are concerning, but the significantly lower DILI risk and better BBB are crucial for a CNS target. The difference in binding affinity (0.3 kcal/mol) is not large enough to overcome the safety and CNS penetration advantages of Ligand A.

Output:
1
2025-04-17 08:27:36,275 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (342.483 and 378.51 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (41.57) is significantly better than Ligand B (84.5). For CNS targets, TPSA should be <= 90, and A is comfortably within this range, while B is approaching the upper limit.

**logP:** Ligand A (4.34) is a bit high, potentially causing solubility issues, but still within an acceptable range. Ligand B (1.754) is on the lower side, which might hinder permeability.

**H-Bond Donors/Acceptors:** Ligand A (HBD=1, HBA=2) and Ligand B (HBD=2, HBA=4) both have reasonable numbers of H-bond donors and acceptors, satisfying the <5 and <10 rules respectively.

**QED:** Ligand A (0.884) has a much better QED score than Ligand B (0.607), indicating a more drug-like profile.

**DILI:** Ligand A (24.312) has a significantly lower DILI risk than Ligand B (34.238), which is a major advantage.

**BBB:** Both ligands have good BBB penetration (A: 85.072, B: 81.466), exceeding the 70% threshold for CNS targets.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values, which is unusual and suggests poor permeability. However, these values are on a log scale and the negative values are not directly comparable without knowing the scale.

**Aqueous Solubility:** Both ligands have negative solubility values, which is also unusual. Again, without knowing the scale, it's hard to interpret the difference.

**hERG Inhibition:** Ligand A (0.782) has a slightly higher hERG inhibition risk than Ligand B (0.467), but both are relatively low.

**Microsomal Clearance:** Ligand A (73.301) has a higher microsomal clearance than Ligand B (23.519), meaning it's less metabolically stable.

**In vitro Half-Life:** Ligand A (7.662) has a better in vitro half-life than Ligand B (-19.631). The negative value for B is concerning.

**P-gp Efflux:** Ligand A (0.517) has lower P-gp efflux liability than Ligand B (0.086), which is favorable for CNS exposure.

**Binding Affinity:** Ligand A (-9.9 kcal/mol) has a *much* stronger binding affinity than Ligand B (-6.9 kcal/mol). This is a difference of 3 kcal/mol, which is substantial and can outweigh many ADME drawbacks.

**Overall Assessment:**

Ligand A is the superior candidate. Its significantly stronger binding affinity is the most important factor, especially for a GPCR target. It also has better TPSA, QED, DILI risk, and P-gp efflux. While its logP is slightly higher and clearance is higher, the benefits outweigh these drawbacks. The negative Caco-2 and solubility values are concerning for both, but the large affinity difference makes A the better choice.

Output:
0
2025-04-17 08:27:36,275 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (354.451 and 344.507 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (121.6) is borderline for CNS penetration, being slightly above the preferred <90 threshold. Ligand B (50.08) is excellent, well below 90.

**logP:** Ligand A (-0.234) is quite low, potentially hindering membrane permeability. Ligand B (3.39) is within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A has 3 HBD and 4 HBA, which are acceptable. Ligand B has 0 HBD and 6 HBA, also acceptable.

**QED:** Both ligands have good QED scores (0.584 and 0.804), indicating drug-like properties.

**DILI:** Both ligands have elevated DILI risk (20.047 and 58.395), but Ligand B is considerably higher. This is a concern for both, but more so for B.

**BBB:** Ligand A (57.619) has a moderate BBB penetration, while Ligand B (95.967) is excellent, exceeding the desirable >70 threshold. This is a significant advantage for Ligand B.

**Caco-2 Permeability:** Both have negative Caco-2 values (-5.595 and -4.873), which is unusual and suggests poor permeability. However, these values are on a log scale and the negative values are not directly comparable.

**Aqueous Solubility:** Both ligands have negative solubility values (-1.646 and -4.229), which is also unusual and suggests poor aqueous solubility.

**hERG:** Ligand A (0.029) has very low hERG risk, while Ligand B (0.942) has moderate risk.

**Microsomal Clearance:** Ligand A (24.821) has lower clearance, indicating better metabolic stability, than Ligand B (94.42).

**In vitro Half-Life:** Ligand A (-20.021) has a negative half-life, which is not physically meaningful. Ligand B (33.602) has a reasonable half-life.

**P-gp Efflux:** Ligand A (0.006) has very low P-gp efflux, which is favorable for CNS penetration. Ligand B (0.798) has moderate P-gp efflux.

**Binding Affinity:** Ligand B (-8.0) has a slightly better binding affinity than Ligand A (-7.3). While the difference is less than the 1.5 kcal/mol threshold, it's still a positive factor.

**Overall Assessment:**

Ligand B clearly outperforms Ligand A, particularly regarding BBB penetration, logP, and P-gp efflux. While Ligand B has a higher DILI score, the superior CNS penetration and more favorable logP are critical for a DRD2 ligand. Ligand A's low logP and questionable half-life are significant drawbacks. The negative values for solubility and Caco-2 are concerning for both, but the other properties of B outweigh this.

Output:
1
2025-04-17 08:27:36,275 - INFO - Okay, let's analyze these two ligands for their potential as DRD2 drug candidates. DRD2 is a GPCR in the CNS, so BBB penetration, logP, Pgp efflux, TPSA, and binding affinity are paramount.

**Ligand A:** [349.387, 115.9  ,  -0.156,   3.   ,   6.   ,   0.68 ,  39.201,  60.644, -5.187,  -1.188,   0.092,   3.378,  -4.219,   0.007,  -8.2  ]
**Ligand B:** [349.431, 100.45 ,   0.887,   2.   ,   5.   ,   0.678,  22.761,  64.25 , -5.163,  -1.477,   0.237,  -7.712,  23.658,   0.008,  -6.8  ]

Here's a breakdown of each property:

1. **MW:** Both ligands (349.387 & 349.431 Da) are within the ideal 200-500 Da range.  No significant difference.
2. **TPSA:** Ligand A (115.9) is slightly higher than Ligand B (100.45). Both are *above* the ideal <90 for CNS targets, but Ligand B is closer.
3. **logP:** Ligand A (-0.156) is significantly lower than Ligand B (0.887). Ligand A is below the optimal 1-3 range, which could hinder permeability. Ligand B is within the ideal range.
4. **HBD:** Ligand A (3) is slightly higher than Ligand B (2). Both are acceptable.
5. **HBA:** Ligand A (6) is slightly higher than Ligand B (5). Both are acceptable.
6. **QED:** Both ligands (0.68 & 0.678) have good drug-likeness scores (>0.5). No significant difference.
7. **DILI:** Ligand A (39.201) has a higher DILI risk than Ligand B (22.761). Ligand B is preferable here.
8. **BBB:** Ligand B (64.25) has a slightly better BBB percentile than Ligand A (60.644). While both are not *ideal* (>70), Ligand B is better.
9. **Caco-2:** Both ligands have negative Caco-2 values (-5.187 & -5.163), which is unusual and suggests poor permeability. This is a concern for both, but doesn't differentiate them.
10. **Solubility:** Both ligands have negative solubility values (-1.188 & -1.477), also unusual and concerning. Again, no clear differentiation.
11. **hERG:** Ligand A (0.092) has a slightly lower hERG risk than Ligand B (0.237), but both are very low and unlikely to be a major concern.
12. **Cl_mic:** Ligand B (-7.712) has a *much* lower (better) microsomal clearance than Ligand A (3.378). This suggests better metabolic stability for Ligand B.
13. **t1/2:** Ligand B (23.658) has a significantly longer in vitro half-life than Ligand A (-4.219). This is a major advantage for Ligand B.
14. **Pgp:** Both ligands have very low Pgp efflux liability (0.007 & 0.008), which is good for CNS penetration. No significant difference.
15. **Binding Affinity:** Ligand A (-8.2) has a stronger binding affinity than Ligand B (-6.8). This is a 1.4 kcal/mol difference, which is substantial and could outweigh some ADME drawbacks.

**Overall Assessment:**

While Ligand A has a better binding affinity, Ligand B is superior in almost all ADME properties crucial for a CNS-targeting GPCR drug. Specifically, Ligand B has a better logP, lower DILI risk, slightly better BBB, significantly better metabolic stability (Cl_mic), and a much longer half-life. The improved ADME profile of Ligand B is likely to translate to better *in vivo* exposure and efficacy, despite the slightly weaker binding affinity. The negative Caco-2 and solubility values are concerning for both, but the other advantages of Ligand B are more impactful.

Output:
1
2025-04-17 08:27:36,275 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (358.551 and 356.451 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (32.34) is significantly better than Ligand B (75.5). For CNS targets, TPSA should be <=90, and lower is preferred. Ligand A is well within this range, while Ligand B is approaching the upper limit and less favorable.

**3. logP:** Ligand A (4.579) is slightly higher than the optimal range (1-3), but still potentially acceptable. Ligand B (2.561) is within the optimal range. However, for a GPCR, a slightly higher logP can be tolerated if other properties are favorable.

**4. H-Bond Donors:** Ligand A (1) and Ligand B (2) are both acceptable, being less than 5.

**5. H-Bond Acceptors:** Ligand A (3) and Ligand B (5) are both acceptable, being less than 10.

**6. QED:** Both ligands have good QED scores (0.631 and 0.738, respectively), indicating good drug-like properties.

**7. DILI:** Ligand A (21.055) has a much lower DILI risk than Ligand B (73.013). This is a significant advantage for Ligand A.

**8. BBB:** Ligand A (70.027) has a good BBB penetration percentile, exceeding the desirable threshold of 70% for CNS targets. Ligand B (41.218) is considerably lower, indicating poor brain penetration. This is a critical disadvantage for a DRD2 ligand.

**9. Caco-2:** Both have negative values, which is unusual and difficult to interpret without more context. However, the magnitude is similar.

**10. Solubility:** Both ligands have poor aqueous solubility (-2.711 and -3.501). This could pose formulation challenges, but is less critical than BBB for a CNS target.

**11. hERG:** Both ligands have low hERG inhibition liability (0.953 and 0.726), which is good.

**12. Cl_mic:** Ligand B (46.228) has lower microsomal clearance than Ligand A (78.901), suggesting better metabolic stability.

**13. t1/2:** Ligand A (49.547) has a longer in vitro half-life than Ligand B (35.98), which is favorable.

**14. Pgp:** Ligand A (0.785) has lower P-gp efflux liability than Ligand B (0.47), indicating better potential for CNS exposure.

**15. Binding Affinity:** Ligand B (-9.1 kcal/mol) has a slightly better binding affinity than Ligand A (-8.8 kcal/mol). While a 1.5 kcal/mol advantage is significant, the other ADME properties of Ligand B are significantly worse.

**Overall Assessment:**

Ligand A is the superior candidate. While Ligand B has slightly better binding affinity, Ligand A excels in crucial properties for a CNS-targeting GPCR ligand: significantly lower DILI risk, much better BBB penetration, and lower P-gp efflux. The slightly higher logP of Ligand A is acceptable given its other advantages. The longer half-life of Ligand A is also a plus.



Output:
0
2025-04-17 08:27:36,276 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (348.487 and 344.411 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (67.43) is better than Ligand B (71.78). Both are below the 90 A^2 threshold for CNS targets, but A is closer to optimal.

**3. logP:** Both ligands have good logP values (2.559 and 1.873), falling within the 1-3 range. Ligand A is slightly better.

**4. H-Bond Donors:** Ligand A (2) and Ligand B (1) are both acceptable.

**5. H-Bond Acceptors:** Ligand A (3) and Ligand B (4) are both acceptable.

**6. QED:** Both ligands have good QED scores (0.629 and 0.909), indicating drug-like properties. Ligand B is better here.

**7. DILI:** Ligand A (14.889) has a significantly lower DILI risk than Ligand B (27.724). This is a substantial advantage for Ligand A.

**8. BBB:** Ligand B (76.774) has a much better BBB penetration percentile than Ligand A (56.534). This is a *critical* advantage for a CNS target like DRD2.

**9. Caco-2 Permeability:** Ligand A (-5.111) has worse Caco-2 permeability than Ligand B (-4.674).

**10. Aqueous Solubility:** Both ligands have poor aqueous solubility (-2.486 and -2.494). This could pose formulation challenges, but is less critical than BBB for a CNS target.

**11. hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.252 and 0.232).

**12. Microsomal Clearance:** Ligand B (18.464) has lower microsomal clearance than Ligand A (32.14), suggesting better metabolic stability.

**13. In vitro Half-Life:** Ligand B (42.102) has a much longer in vitro half-life than Ligand A (-15.484). This is a significant advantage.

**14. P-gp Efflux:** Both ligands have low P-gp efflux liability (0.066 and 0.038).

**15. Binding Affinity:** Ligand B (-9.1) has a slightly better binding affinity than Ligand A (-8.3). While A is good, B has a 0.8 kcal/mol advantage.

**Overall Assessment:**

Ligand B excels in the most critical areas for a CNS GPCR target: BBB penetration, metabolic stability (lower Cl_mic, longer t1/2), and binding affinity. While Ligand A has a lower DILI risk, the superior CNS penetration of Ligand B outweighs this benefit. The slightly better affinity of Ligand B further solidifies its position as the more promising candidate.

Output:
1
2025-04-17 08:27:36,276 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (368.949 and 358.404 Da) fall within the ideal range of 200-500 Da.

**TPSA:** Ligand A (33.73) is excellent, well below the 90 A^2 threshold for CNS targets. Ligand B (49.41) is still reasonable but less optimal, exceeding 40 A^2.

**logP:** Ligand A (4.492) is slightly high, potentially leading to solubility issues or off-target interactions. Ligand B (2.32) is within the optimal range of 1-3.

**H-Bond Donors/Acceptors:** Both ligands have acceptable HBD (1) and HBA (A: 4, B: 2) counts.

**QED:** Both ligands have good QED scores (A: 0.617, B: 0.839), indicating drug-likeness.

**DILI:** Ligand A (9.112) has a very low DILI risk, which is excellent. Ligand B (15.355) is also low, but higher than A.

**BBB:** Both ligands have good BBB penetration (A: 80.031, B: 90.074), but Ligand B is superior, exceeding the 70% threshold.

**Caco-2 Permeability:** Both have negative Caco-2 values (-4.777 and -4.916), which is unusual and suggests poor permeability. This is a significant concern for both.

**Aqueous Solubility:** Both ligands have very poor aqueous solubility (-2.727 and -3.179). This is a major drawback.

**hERG Inhibition:** Both ligands show low hERG inhibition liability (A: 0.945, B: 0.492), which is positive.

**Microsomal Clearance:** Ligand A (51.263) has higher microsomal clearance than Ligand B (4.388), suggesting lower metabolic stability.

**In vitro Half-Life:** Ligand B (1.423) has a very short half-life, while Ligand A (41.16) is much better.

**P-gp Efflux:** Both ligands have low P-gp efflux (A: 0.433, B: 0.069), which is favorable for CNS penetration. Ligand B is slightly better.

**Binding Affinity:** Ligand B (-8.7 kcal/mol) has a slightly better binding affinity than Ligand A (-8.0 kcal/mol), although both are excellent.

**Overall Assessment:**

Despite the poor Caco-2 and solubility values for both, Ligand B is the more promising candidate. It has a better logP, superior BBB penetration, lower P-gp efflux, and slightly better binding affinity. While its half-life is very short, this could be addressed through structural modifications. The higher DILI risk is less concerning than the solubility and permeability issues of Ligand A. The slightly better affinity of B, combined with its superior CNS penetration properties, outweigh the slightly higher DILI risk and shorter half-life.

Output:
1
2025-04-17 08:27:36,276 - INFO - Batch 450 complete. Total preferences: 7200
2025-04-17 08:27:36,276 - INFO - Processing batch 451/512...
2025-04-17 08:28:22,472 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (348.447 and 351.393 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (81.75) is slightly above the preferred <90 for CNS targets, but still reasonable. Ligand B (60.77) is excellent, well below 90.

**3. logP:** Ligand A (0.721) is a bit low, potentially hindering permeation. Ligand B (2.415) is within the optimal 1-3 range.

**4. H-Bond Donors:** Both ligands have 2 HBD, which is acceptable.

**5. H-Bond Acceptors:** Both ligands have 3 HBA, which is acceptable.

**6. QED:** Both ligands have similar QED values (0.738 and 0.707), indicating good drug-like properties.

**7. DILI:** Ligand A (29.857) has a lower DILI risk than Ligand B (13.3), indicating a safer profile.

**8. BBB:** This is a critical parameter for a CNS target like DRD2. Ligand A (47.15) is below the desirable >70, while Ligand B (83.249) is excellent.

**9. Caco-2 Permeability:** Ligand A (-4.924) shows poor permeability, while Ligand B (-4.273) is slightly better, but still not ideal.

**10. Aqueous Solubility:** Both ligands have poor aqueous solubility (-1.972 and -2.897). This could pose formulation challenges.

**11. hERG Inhibition:** Ligand A (0.139) has a lower hERG risk than Ligand B (0.8).

**12. Microsomal Clearance:** Ligand A (5.577) has lower clearance, suggesting better metabolic stability than Ligand B (25.54).

**13. In vitro Half-Life:** Ligand A (5.757) has a slightly longer half-life than Ligand B (4.198).

**14. P-gp Efflux:** Ligand A (0.019) has very low P-gp efflux, which is favorable for CNS penetration. Ligand B (0.373) has moderate P-gp efflux.

**15. Binding Affinity:** Ligand A (-7.9) has a significantly stronger binding affinity than Ligand B (-7.4). This is a difference of 0.5 kcal/mol, which is substantial.

**Overall Assessment:**

Ligand B excels in BBB penetration and has a better logP value. However, Ligand A compensates with a significantly stronger binding affinity (-7.9 vs -7.4 kcal/mol), lower DILI risk, lower hERG risk, lower P-gp efflux, and better metabolic stability. The stronger binding affinity of Ligand A is a major advantage, and the lower P-gp efflux will help ensure sufficient CNS exposure despite its lower BBB score. While Ligand A's logP and Caco-2 permeability are not ideal, the strong binding affinity can often overcome these issues.

Output:
1
2025-04-17 08:28:22,472 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (365.876 Da) is slightly lower, which can be advantageous for permeability.

**TPSA:** Ligand A (29.54) is excellent for CNS penetration, well below the 90 A^2 threshold. Ligand B (86.29) is higher, but still potentially acceptable, though less ideal.

**logP:** Ligand A (4.447) is slightly high, potentially leading to solubility issues or off-target interactions. Ligand B (3.653) is within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A (0 HBD, 2 HBA) is favorable. Ligand B (2 HBD, 4 HBA) is also acceptable.

**QED:** Both ligands have reasonable QED scores (A: 0.668, B: 0.596), indicating drug-like properties.

**DILI:** Both ligands have low DILI risk (A: 28.655, B: 36.797), which is good.

**BBB:** This is a critical parameter for a CNS target like DRD2. Ligand A has a very high BBB penetration percentile (96.937), a significant advantage. Ligand B's BBB penetration (32.416) is poor.

**Caco-2 Permeability:** Ligand A (-4.278) shows poor permeability, which is concerning despite the low TPSA. Ligand B (-5.127) is also poor, but not dramatically different.

**Aqueous Solubility:** Ligand A (-5.416) has very poor solubility, likely due to the high logP. Ligand B (-2.882) is better, but still not great.

**hERG Inhibition:** Both ligands show low hERG inhibition risk (A: 0.902, B: 0.567).

**Microsomal Clearance:** Ligand A (104.609) has higher clearance, indicating lower metabolic stability. Ligand B (50.117) has better metabolic stability.

**In vitro Half-Life:** Ligand A (34.401) has a moderate half-life. Ligand B (26.165) has a shorter half-life.

**P-gp Efflux:** Ligand A (0.77) has moderate P-gp efflux, while Ligand B (0.382) has lower efflux. Lower P-gp efflux is preferred for CNS penetration.

**Binding Affinity:** Ligand A (-7.5 kcal/mol) has a significantly stronger binding affinity than Ligand B (-6.7 kcal/mol). This 0.8 kcal/mol difference is substantial and can outweigh some ADME drawbacks.

**Overall Assessment:**

Ligand A has a significantly better binding affinity and excellent BBB penetration, which are crucial for a CNS GPCR target. However, it suffers from poor solubility, poor Caco-2 permeability, and higher metabolic clearance. Ligand B has better solubility and metabolic stability, but its BBB penetration is very poor, and its binding affinity is weaker.

Given the importance of CNS penetration for DRD2, and the substantial affinity advantage of Ligand A, I believe Ligand A is the more promising candidate *despite* its ADME liabilities. The poor solubility and permeability could potentially be addressed through formulation strategies. The strong binding affinity is a major advantage that is harder to improve later in the optimization process.

Output:
0
2025-04-17 08:28:22,473 - INFO - Here's a step-by-step comparison of Ligand A and Ligand B, followed by my final decision:

**1. Molecular Weight (MW):** Both ligands (361.829 Da and 361.389 Da) fall comfortably within the ideal 200-500 Da range. No significant difference.

**2. Topological Polar Surface Area (TPSA):** Ligand A (74.43) is significantly better than Ligand B (87.74). For CNS targets like DRD2, a TPSA below 90 is preferred, and A is closer to the optimal <60 range. B is pushing the upper limit.

**3. Lipophilicity (logP):** Ligand A (2.354) is optimal, while Ligand B (0.926) is slightly low. A logP between 1-3 is ideal, and A falls nicely within this range. B's lower logP *could* hinder permeability.

**4. H-Bond Donors (HBD):** Both ligands have 2 HBD, which is within the acceptable limit of <=5. No difference.

**5. H-Bond Acceptors (HBA):** Ligand A has 3 HBA, and Ligand B has 4. Both are within the acceptable limit of <=10. No significant difference.

**6. QED:** Ligand A (0.877) has a better QED score than Ligand B (0.737), indicating a more drug-like profile. Both are above the 0.5 threshold, but A is superior.

**7. DILI:** Ligand A (67.274) has a higher DILI risk than Ligand B (23.924). This is a significant advantage for B. A DILI score <40 is preferred.

**8. BBB:** Ligand A (64.56) and Ligand B (69.794) are both reasonably good, but B is slightly better. For CNS targets, >70 is desirable, but both are acceptable.

**9. Caco-2 Permeability:** Ligand A (-4.835) and Ligand B (-4.915) are similar and both indicate poor permeability. This is a concern for both.

**10. Aqueous Solubility:** Ligand A (-3.578) and Ligand B (-2.642) are both poor, but B is slightly better.

**11. hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.291 and 0.2, respectively). No significant difference.

**12. Microsomal Clearance (Cl_mic):** Ligand A (0.404) has significantly lower microsomal clearance than Ligand B (-6.215). Lower clearance indicates better metabolic stability, a significant advantage for A.

**13. In vitro Half-Life:** Ligand A (1.145) has a shorter half-life than Ligand B (-29.593). A longer half-life is generally preferred, giving a strong advantage to B.

**14. P-gp Efflux:** Ligand A (0.071) has lower P-gp efflux than Ligand B (0.009). Lower efflux is better for CNS exposure, favoring A.

**15. Binding Affinity:** Ligand B (-7.1 kcal/mol) has a significantly stronger binding affinity than Ligand A (-9.3 kcal/mol). This is a substantial advantage for B, potentially outweighing some of its ADME drawbacks.

**GPCR-Specific Priorities:** For DRD2 (a GPCR), BBB, logP, Pgp, TPSA, and affinity are most important.

*   **BBB:** B is slightly better.
*   **logP:** A is better.
*   **Pgp:** A is better.
*   **TPSA:** A is *much* better.
*   **Affinity:** B is significantly better.

**Overall Assessment:**

While Ligand A has a better TPSA, logP, Pgp efflux, and metabolic stability, Ligand B's significantly stronger binding affinity (-7.1 vs -9.3 kcal/mol) and lower DILI risk are compelling. The affinity difference is substantial and likely to be critical for efficacy. The slightly lower logP of B is a concern, but the strong binding could compensate. The better half-life of B is also a plus.

Therefore, I recommend prioritizing **Ligand B**.

1
2025-04-17 08:28:22,473 - INFO - Reasoning:

Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (368.825 and 350.459 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (124.42) is borderline for CNS penetration, slightly above the preferred <90, while Ligand B (82.78) is well within the optimal range. This is a significant advantage for Ligand B.

**3. logP:** Ligand A (0.327) is quite low, potentially hindering membrane permeability. Ligand B (2.035) is within the optimal 1-3 range. This favors Ligand B.

**4. H-Bond Donors:** Ligand A (3) and Ligand B (2) are both acceptable.

**5. H-Bond Acceptors:** Both ligands have 4 HBA, which is acceptable.

**6. QED:** Both ligands have good QED scores (0.71 and 0.788), indicating drug-like properties.

**7. DILI:** Ligand A (57.348) has a moderate DILI risk, while Ligand B (15.355) has a very low risk. This is a clear advantage for Ligand B.

**8. BBB:** Ligand A (57.193) has a moderate BBB penetration, while Ligand B (41.373) is lower. While both are not ideal (>70), Ligand A is better here.

**9. Caco-2 Permeability:** Ligand A (-5.468) has poor Caco-2 permeability, while Ligand B (-4.952) is also poor, but slightly better.

**10. Aqueous Solubility:** Both ligands have very poor aqueous solubility (-3.3 and -2.006). This could pose formulation challenges.

**11. hERG Inhibition:** Ligand A (0.139) has a very low hERG risk, while Ligand B (0.384) is slightly higher, but still acceptable.

**12. Microsomal Clearance:** Ligand A (-25.392) has very low microsomal clearance (high metabolic stability), while Ligand B (7.765) has moderate clearance. This favors Ligand A.

**13. In vitro Half-Life:** Ligand A (-10.636) has a very long half-life, while Ligand B (24.459) has a moderate half-life. This favors Ligand A.

**14. P-gp Efflux:** Ligand A (0.009) has very low P-gp efflux, which is excellent for CNS penetration. Ligand B (0.216) has moderate P-gp efflux. This is a significant advantage for Ligand A.

**15. Binding Affinity:** Ligand B (-7.8 kcal/mol) has a slightly better binding affinity than Ligand A (-8.5 kcal/mol). While the difference is small, it's a positive for Ligand B.

**Overall Assessment:**

Despite Ligand B's better affinity, Ligand A is the more promising candidate. The key advantages of Ligand A are its significantly lower P-gp efflux, excellent metabolic stability (low Cl_mic and long t1/2), and low hERG risk. While its logP and BBB are less ideal, the combination of favorable ADME properties, particularly the low P-gp efflux, is crucial for CNS drug development. Ligand B's low logP and higher DILI risk are significant drawbacks.

Output:
0
2025-04-17 08:28:22,473 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (352.381 and 359.442 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (61.19) is excellent, well below the 90 A^2 threshold for CNS targets. Ligand B (98.74) is higher, but still potentially acceptable, though less desirable.

**logP:** Ligand A (3.463) is optimal. Ligand B (0.221) is quite low, potentially hindering membrane permeability and CNS penetration.

**H-Bond Donors/Acceptors:** Ligand A (0 HBD, 5 HBA) is favorable. Ligand B (3 HBD, 4 HBA) is also reasonable.

**QED:** Both ligands have acceptable QED scores (0.762 and 0.548, respectively), indicating reasonable drug-likeness.

**DILI:** Both ligands have low DILI risk (30.05 and 29.779), which is good.

**BBB:** Ligand A shines with a very high BBB penetration score (96.472), crucial for a CNS target like DRD2. Ligand B's BBB score (58.976) is significantly lower and concerning.

**Caco-2 Permeability:** Ligand A (-4.178) is poor, suggesting limited intestinal absorption. Ligand B (-5.05) is even worse. This isn't a primary concern for a CNS target where direct delivery or high brain exposure is prioritized.

**Aqueous Solubility:** Ligand A (-3.699) is poor, but not a dealbreaker given the CNS target. Ligand B (-1.278) is also poor.

**hERG:** Both ligands have low hERG inhibition liability (0.598 and 0.214), which is excellent.

**Microsomal Clearance:** Ligand A (56.455) has moderate clearance, while Ligand B (19.811) has low clearance, indicating better metabolic stability.

**In vitro Half-Life:** Ligand A (-19.655) has a negative half-life, which is unusual and suggests rapid metabolism or instability. Ligand B (-27.169) is even lower.

**P-gp Efflux:** Ligand A (0.645) has moderate P-gp efflux, while Ligand B (0.042) has very low efflux, which is highly desirable for CNS penetration.

**Binding Affinity:** Ligand A (-9.3 kcal/mol) has significantly stronger binding affinity than Ligand B (-7.8 kcal/mol). This is a substantial advantage.

**Overall Assessment:**

Ligand A is the stronger candidate despite its poor Caco-2 permeability and negative in vitro half-life. Its exceptional BBB penetration, strong binding affinity, and favorable TPSA and logP values outweigh its drawbacks for a CNS-targeted GPCR. Ligand B's low logP and significantly lower BBB penetration are major concerns, even with its better metabolic stability and lower P-gp efflux. The affinity difference is also substantial.

Output:
1
2025-04-17 08:28:22,473 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (354.407 and 347.39 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (116.84) is higher than Ligand B (80.32). For CNS targets, we prefer TPSA <= 90, so Ligand B is significantly better here.

**logP:** Ligand A (-0.47) is slightly below the optimal 1-3 range, potentially hindering permeability. Ligand B (0.765) is within the optimal range. This favors Ligand B.

**H-Bond Donors:** Ligand A (3) and Ligand B (2) are both acceptable, being <=5.

**H-Bond Acceptors:** Ligand A (5) and Ligand B (4) are both acceptable, being <=10.

**QED:** Both ligands have reasonable QED values (0.362 and 0.681), with Ligand B being better.

**DILI:** Both ligands have low DILI risk (42.807 and 33.695), below the 40 threshold.

**BBB:** Both ligands have good BBB penetration (78.79 and 76.658), although ideally >70. They are comparable here.

**Caco-2 Permeability:** Ligand A (-5.308) and Ligand B (-4.528) are both negative, indicating poor permeability. This is a concern for both, but less so for B.

**Aqueous Solubility:** Both ligands have poor aqueous solubility (-1.595 and -2.279).

**hERG Inhibition:** Both ligands have very low hERG risk (0.054 and 0.093).

**Microsomal Clearance:** Ligand A (16.009) has higher clearance than Ligand B (8.919), suggesting lower metabolic stability. Ligand B is preferred.

**In vitro Half-Life:** Ligand A (2.063) has a shorter half-life than Ligand B (-5.49). This is a significant advantage for Ligand B.

**P-gp Efflux:** Both ligands have very low P-gp efflux (0.006 and 0.008), which is excellent for CNS penetration.

**Binding Affinity:** Ligand A (-7.5) has a slightly better binding affinity than Ligand B (-7.3). However, the difference is only 0.2 kcal/mol, which is not substantial enough to outweigh the ADME advantages of Ligand B.

**Overall:** Considering the GPCR-specific priorities, Ligand B is the better candidate. It has a more favorable logP, lower TPSA, better metabolic stability (lower Cl_mic, longer t1/2), and a comparable BBB score. While Ligand A has slightly better binding affinity, the ADME properties of Ligand B are more promising for a viable drug candidate targeting a CNS target like DRD2.

Output:
1
2025-04-17 08:28:22,473 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (357.479 and 366.439 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (54.46) is significantly better than Ligand B (101.55). For CNS targets, we want TPSA <= 90, so Ligand A is much closer to this threshold. Ligand B is considerably higher, potentially hindering BBB penetration.

**3. logP:** Both ligands have acceptable logP values (3.425 and 2.545), falling within the optimal 1-3 range.

**4. H-Bond Donors:** Ligand A (1) and Ligand B (2) are both within the acceptable limit of <=5.

**5. H-Bond Acceptors:** Ligand A (4) and Ligand B (5) are both within the acceptable limit of <=10.

**6. QED:** Both ligands have reasonable QED values (0.914 and 0.747), indicating good drug-like properties.

**7. DILI:** Ligand A (59.636) is slightly higher than Ligand B (70.919), but both are acceptable. A value < 40 is preferred, but both are below the high-risk threshold of 60.

**8. BBB:** Ligand A (82.047) is significantly better than Ligand B (52.462). For CNS targets, >70 is desirable. Ligand A is much closer to this threshold, suggesting better brain penetration.

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.834 and -4.902), which is unusual and suggests poor permeability. However, these values are on a scale where negative values are possible, and direct comparison is difficult without knowing the scale's specifics.

**10. Aqueous Solubility:** Both ligands have negative solubility values (-4.131 and -2.983), indicating poor aqueous solubility. This is a concern for bioavailability.

**11. hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.629 and 0.266), which is excellent.

**12. Microsomal Clearance:** Ligand A (59.366) is higher than Ligand B (43.868), indicating faster metabolism and potentially lower in vivo exposure.

**13. In vitro Half-Life:** Ligand A (27.569) is slightly longer than Ligand B (22.532).

**14. P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.143 and 0.15), which is favorable for CNS penetration.

**15. Binding Affinity:** Both ligands have very similar and excellent binding affinities (-8.2 and -8.3 kcal/mol). The difference is negligible.

**Overall Assessment:**

Considering the GPCR-specific priorities, Ligand A is the better candidate. Its significantly lower TPSA and higher BBB percentile strongly suggest better CNS penetration. While both have poor solubility and Caco-2 permeability, the improved BBB profile of Ligand A is crucial for a DRD2 ligand targeting CNS disorders. The slightly higher microsomal clearance of Ligand A is a minor drawback, but the substantial advantage in BBB outweighs this.

Output:
0
2025-04-17 08:28:22,474 - INFO - Reasoning:

Let's analyze Ligand A and Ligand B based on the provided guidelines, prioritizing GPCR-specific properties (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (371.825 and 352.41 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (119.28) is slightly above the preferred <90 for CNS targets, but still reasonable. Ligand B (107.11) is better, falling comfortably under 90.

**logP:** Ligand A (3.286) is within the optimal 1-3 range. Ligand B (1.197) is at the lower end, potentially impacting permeability.

**H-Bond Donors/Acceptors:** Ligand A (HBD=2, HBA=7) and Ligand B (HBD=4, HBA=4) both have acceptable numbers of H-bond donors and acceptors.

**QED:** Both ligands have good QED scores (A: 0.473, B: 0.639), indicating reasonable drug-likeness. Ligand B is slightly better.

**DILI:** Both ligands have acceptable DILI risk (A: 75.456, B: 61.691), below the concerning threshold of 60.

**BBB:** Ligand A (67.041) is borderline for good CNS penetration, while Ligand B (53.664) is lower. This is a significant drawback for both, but more so for B.

**Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and suggests poor permeability. Ligand A (-4.803) is slightly better than Ligand B (-5.316).

**Aqueous Solubility:** Both have negative solubility values, indicating very poor solubility. Ligand A (-4.648) is slightly better than Ligand B (-3.142).

**hERG Inhibition:** Both ligands have low hERG inhibition risk (A: 0.091, B: 0.34).

**Microsomal Clearance:** Ligand B (-12.363) has significantly better metabolic stability (lower clearance) than Ligand A (53.631).

**In vitro Half-Life:** Both have negative half-lives, which is not physically meaningful. However, comparing the absolute values, Ligand B (-2.006) appears to have a slightly longer half-life than Ligand A (-2.483).

**P-gp Efflux:** Both ligands have low P-gp efflux liability (A: 0.057, B: 0.06).

**Binding Affinity:** Ligand B (-9.7 kcal/mol) has a significantly stronger binding affinity than Ligand A (-8.2 kcal/mol). This is a >1.5 kcal/mol advantage, which can outweigh other deficiencies.

**Overall Assessment:**

While Ligand A has a slightly better logP and marginally better permeability/solubility metrics, Ligand B's substantially superior binding affinity (-9.7 vs -8.2 kcal/mol) is the most critical factor, especially for a GPCR target. The improved metabolic stability (lower Cl_mic) of Ligand B is also a significant advantage. The lower BBB score is a concern, but the strong affinity suggests it might still be effective with appropriate formulation or structural modifications to improve brain penetration.

Output:
1
2025-04-17 08:28:22,474 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B based on the provided guidelines, prioritizing GPCR-specific properties (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (380.897 and 361.877 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (60.85) is better than Ligand B (47.59). Both are below the 90 A^2 threshold desirable for CNS targets, but A is slightly higher.

**logP:** Ligand B (3.068) is slightly better than Ligand A (2.24), both are within the optimal 1-3 range.

**H-Bond Donors:** Ligand A (1) is better than Ligand B (0). Both are within the acceptable limit of <=5.

**H-Bond Acceptors:** Ligand B (6) is better than Ligand A (4). Both are within the acceptable limit of <=10.

**QED:** Ligand A (0.8) is significantly better than Ligand B (0.578), indicating a more drug-like profile.

**DILI:** Ligand A (25.785) is significantly better than Ligand B (37.728), suggesting a lower risk of drug-induced liver injury.

**BBB:** Ligand B (78.209) is *much* better than Ligand A (56.301). This is a critical advantage for a CNS target like DRD2.

**Caco-2 Permeability:** Ligand A (-4.718) is better than Ligand B (-5.158), indicating better intestinal absorption.

**Aqueous Solubility:** Ligand A (-3.133) is better than Ligand B (-1.854), indicating better solubility.

**hERG Inhibition:** Ligand A (0.51) is better than Ligand B (0.925), suggesting a lower risk of cardiotoxicity.

**Microsomal Clearance:** Ligand A (0.9) is significantly better than Ligand B (58.427), indicating greater metabolic stability.

**In vitro Half-Life:** Ligand B (50.835) is significantly better than Ligand A (-6.169), suggesting a longer half-life.

**P-gp Efflux:** Ligand A (0.266) is significantly better than Ligand B (0.531), indicating lower P-gp efflux and potentially better CNS exposure.

**Binding Affinity:** Ligand B (-7.1) has a significantly stronger binding affinity than Ligand A (-6.169). This is a substantial advantage.

**Overall Assessment:**

Ligand B excels in BBB penetration and binding affinity, which are paramount for a CNS GPCR target. The longer half-life is also a positive. However, it suffers from higher DILI risk, higher P-gp efflux, and lower metabolic stability. Ligand A has a better overall ADME profile (DILI, solubility, metabolic stability, P-gp efflux, hERG) and a good QED score.

The difference in binding affinity (-7.1 vs -6.169) is substantial (1.5 kcal/mol advantage), and for a GPCR, this can often outweigh some ADME liabilities. The improved BBB penetration of Ligand B is also a crucial factor for CNS targets. While Ligand A has a better ADME profile, the stronger binding and better BBB penetration of Ligand B make it the more promising candidate.

Output:
1
2025-04-17 08:28:22,474 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (345.359 and 364.833 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (110.45) is slightly above the preferred <90 for CNS targets, while Ligand B (95.42) is closer to the ideal range. This gives a slight edge to Ligand B.

**logP:** Both ligands have good logP values (1.472 and 1.01), falling within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A has 1 HBD and 7 HBA, while Ligand B has 2 HBD and 5 HBA. Both are within acceptable limits (<=5 HBD and <=10 HBA).

**QED:** Both ligands have good QED scores (0.789 and 0.834), indicating good drug-like properties.

**DILI:** Ligand A (75.107) has a higher DILI risk than Ligand B (59.791). This favors Ligand B.

**BBB:** Ligand A (75.572) has a better BBB percentile than Ligand B (45.909). This is a *significant* advantage for Ligand A, as DRD2 is a CNS target.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.484 and -5.102), which is unusual and suggests poor permeability. However, these values are on a scale where negative values are possible and don't necessarily disqualify the compounds.

**Aqueous Solubility:** Both ligands have negative solubility values (-2.627 and -2.859), indicating poor aqueous solubility. This could pose formulation challenges.

**hERG:** Both ligands have very low hERG inhibition liability (0.116 and 0.145), which is excellent.

**Microsomal Clearance:** Ligand B (-14.804) has significantly lower (better) microsomal clearance than Ligand A (68.322), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand B (-1.366) has a slightly better (longer) in vitro half-life than Ligand A (-13.837).

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.004 and 0.012), which is favorable for CNS penetration.

**Binding Affinity:** Ligand A (-8.1 kcal/mol) has a slightly better binding affinity than Ligand B (-7.9 kcal/mol). While the difference is small, it's within the range where it could outweigh some ADME drawbacks.

**Overall Assessment:**

The key differentiating factors are BBB penetration and metabolic stability. Ligand A has a significantly better BBB score (75.572 vs 45.909), which is crucial for a CNS target like DRD2. Ligand B has better metabolic stability (lower Cl_mic) and a slightly longer half-life, but the BBB advantage of Ligand A is more important in this case. The slightly better affinity of Ligand A further supports its selection. While both have poor solubility and Caco-2 permeability, these can potentially be addressed with formulation strategies. The DILI risk is also lower for Ligand B, but the BBB advantage of Ligand A is more critical.

Output:
0
2025-04-17 08:28:22,474 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (351.422 and 341.415 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (62.21) is significantly better than Ligand B (88.39). For CNS targets, we want TPSA <= 90, and A is comfortably within that range, while B is approaching the upper limit.

**3. logP:** Both ligands have a logP of approximately 1.7, which is optimal (1-3).

**4. H-Bond Donors:** Ligand A (0) is better than Ligand B (2). Fewer HBDs generally improve permeability.

**5. H-Bond Acceptors:** Ligand A (4) is better than Ligand B (5). Fewer HBAs generally improve permeability.

**6. QED:** Both ligands have similar QED values (0.775 and 0.751), indicating good drug-likeness.

**7. DILI:** Ligand A (18.224) has a much lower DILI risk than Ligand B (59.519). This is a significant advantage for A.

**8. BBB:** Ligand A (88.6) has a significantly higher BBB penetration percentile than Ligand B (70.609). This is crucial for a CNS target like DRD2.

**9. Caco-2 Permeability:** Ligand A (-4.38) is better than Ligand B (-5.131), indicating better intestinal absorption.

**10. Aqueous Solubility:** Ligand A (-2.313) is better than Ligand B (-2.608).

**11. hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.386 and 0.3).

**12. Microsomal Clearance:** Ligand A (12.116) has lower microsomal clearance than Ligand B (33.031), suggesting better metabolic stability.

**13. In vitro Half-Life:** Ligand B (-11.625) has a longer in vitro half-life than Ligand A (-8.143). This is a slight advantage for B.

**14. P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.047 and 0.088).

**15. Binding Affinity:** Ligand B (-8.2) has slightly better binding affinity than Ligand A (-7.8). However, the difference is only 0.4 kcal/mol, which is not a huge advantage considering the other factors.

**Overall Assessment:**

Ligand A is significantly better overall. It excels in critical properties for CNS penetration (BBB, TPSA, logP) and has a much lower DILI risk and better metabolic stability. While Ligand B has slightly better affinity and half-life, the advantages of Ligand A in ADME properties, especially BBB penetration, outweigh this small difference in binding. Given the target is a CNS GPCR (DRD2), maximizing brain exposure is paramount.

Output:
0
2025-04-17 08:28:22,474 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (344.459 and 335.415 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (66.4) is significantly better than Ligand B (78.86). For CNS targets, we want TPSA <= 90, and A is closer to the ideal <=60 range. B is pushing the upper limit.

**3. logP:** Both ligands have good logP values (2.286 and 2.557), falling within the optimal 1-3 range.

**4. H-Bond Donors:** Ligand A (0) is preferable to Ligand B (2). Fewer HBDs generally improve permeability.

**5. H-Bond Acceptors:** Ligand A (4) is better than Ligand B (7). Lower HBA counts are generally preferred for better permeability.

**6. QED:** Ligand A (0.825) has a significantly better QED score than Ligand B (0.687), indicating a more drug-like profile.

**7. DILI:** Ligand A (35.789) has a much lower DILI risk than Ligand B (63.086). This is a substantial advantage for A.

**8. BBB:** Ligand A (80.574) has a significantly better BBB penetration prediction than Ligand B (40.675). This is *critical* for a CNS target like DRD2.

**9. Caco-2 Permeability:** Ligand A (-4.692) is better than Ligand B (-5.358), indicating better intestinal absorption.

**10. Aqueous Solubility:** Ligand A (-2.035) is better than Ligand B (-3.062), indicating better solubility.

**11. hERG Inhibition:** Ligand A (0.436) has a lower hERG risk than Ligand B (0.729).

**12. Microsomal Clearance:** Ligand B (67.547) has lower microsomal clearance than Ligand A (39.753), suggesting better metabolic stability. However, the difference isn't huge.

**13. In vitro Half-Life:** Ligand B (45.932) has a much longer in vitro half-life than Ligand A (-0.653). This is a significant advantage for B.

**14. P-gp Efflux:** Ligand A (0.196) has lower P-gp efflux liability than Ligand B (0.014). Lower efflux is better, especially for CNS targets.

**15. Binding Affinity:** Ligand B (-9.0) has a slightly better binding affinity than Ligand A (-8.9). While a difference of 0.1 kcal/mol is not substantial, it is a factor.

**Overall Assessment:**

Ligand A is significantly better overall. Its superior TPSA, QED, DILI, BBB, solubility, hERG, and P-gp efflux properties outweigh the slightly weaker binding affinity and lower half-life compared to Ligand B. The BBB penetration is a particularly important factor for a CNS target like DRD2. While Ligand B has better metabolic stability, the other advantages of Ligand A make it the more promising candidate.

Output:
1
2025-04-17 08:28:22,474 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (383.579 and 390.477 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (49.77) is significantly better than Ligand B (76.13). For CNS targets, we want TPSA <= 90, and A is comfortably within that range, while B is approaching the upper limit.

**logP:** Both ligands have good logP values (3.25 and 2.338), falling within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Both have 1 HBD and 5 HBA, which are acceptable.

**QED:** Both ligands have similar QED values (0.7 and 0.739), indicating good drug-likeness.

**DILI:** Ligand A (36.216) has a much lower DILI risk than Ligand B (62.233). This is a significant advantage for A.

**BBB:** Both ligands have excellent BBB penetration (85.459 and 82.978), exceeding the desirable >70 threshold for CNS targets.

**Caco-2 Permeability:** Ligand A (-5.223) shows poor Caco-2 permeability, while Ligand B (-4.94) is slightly better, but still poor. This is a concern for both, but more so for A.

**Aqueous Solubility:** Both ligands have poor aqueous solubility (-3.515 and -3.015).

**hERG Inhibition:** Ligand A (0.788) has a slightly higher hERG risk than Ligand B (0.203). B is much better here.

**Microsomal Clearance:** Ligand A (94.124) has a higher microsomal clearance than Ligand B (0.574), indicating lower metabolic stability. B is significantly better.

**In vitro Half-Life:** Ligand A (21.527) has a longer half-life than Ligand B (13.559), which is a positive.

**P-gp Efflux:** Ligand A (0.836) has slightly higher P-gp efflux than Ligand B (0.411), which is less desirable for CNS penetration. B is better.

**Binding Affinity:** Ligand B (-8.6 kcal/mol) has a significantly stronger binding affinity than Ligand A (-7.0 kcal/mol). This is a substantial advantage for B, exceeding the >1.5 kcal/mol difference threshold.

**Overall Assessment:**

While Ligand A has a lower DILI risk and a longer half-life, Ligand B is superior in most critical aspects for a CNS-targeting GPCR ligand. The significantly stronger binding affinity (-8.6 vs -7.0 kcal/mol) of Ligand B is a major advantage. It also has better metabolic stability (lower Cl_mic), lower P-gp efflux, and lower hERG risk. The TPSA is slightly higher for B, but still within an acceptable range. Although both have poor Caco-2 permeability and solubility, the potency advantage of B outweighs these drawbacks.

Output:
1
2025-04-17 08:28:22,474 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B based on the provided guidelines, prioritizing GPCR-specific properties (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (344.365 and 346.405 Da) fall within the ideal range of 200-500 Da.

**TPSA:** Ligand A (51.85) is significantly better than Ligand B (105.24). For CNS targets, TPSA should be <= 90, and A is comfortably within this range, while B exceeds it.

**logP:** Both ligands have acceptable logP values (2.926 and 1.431), falling within the 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A (HBD=1, HBA=4) is preferable to Ligand B (HBD=3, HBA=6) as it has fewer hydrogen bond donors and acceptors, generally leading to improved membrane permeability. Both are within acceptable limits.

**QED:** Both ligands have similar QED values (0.774 and 0.634), both above the 0.5 threshold, indicating good drug-likeness.

**DILI:** Ligand A (70.841) has a higher DILI risk than Ligand B (51.493), but both are below the concerning threshold of 60.

**BBB:** Ligand A (85.459) has a substantially better BBB penetration percentile than Ligand B (61.535). This is a *critical* advantage for a CNS target like DRD2, as we want high brain exposure.

**Caco-2 Permeability:** Ligand A (-4.712) has a more positive Caco-2 value than Ligand B (-5.224), indicating better intestinal absorption.

**Aqueous Solubility:** Ligand A (-3.545) has a more positive solubility value than Ligand B (-2.419), indicating better solubility.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.654 and 0.233).

**Microsomal Clearance:** Ligand A (6.43) has a lower microsomal clearance than Ligand B (17.64), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (11.4) has a longer in vitro half-life than Ligand B (-1.681).

**P-gp Efflux:** Ligand A (0.275) has lower P-gp efflux liability than Ligand B (0.013), meaning it is less likely to be pumped out of the brain, improving CNS exposure.

**Binding Affinity:** Ligand A (-10.1 kcal/mol) has a significantly stronger binding affinity than Ligand B (-8.6 kcal/mol). This is a substantial advantage, exceeding the 1.5 kcal/mol difference threshold.

**Conclusion:**

Considering all factors, especially the crucial GPCR-specific properties for CNS targets (BBB, TPSA, Pgp, and affinity), **Ligand A is the superior candidate**. It exhibits better BBB penetration, lower TPSA, lower P-gp efflux, better metabolic stability, longer half-life, and significantly stronger binding affinity. While Ligand B has a slightly lower DILI risk, the advantages of Ligand A outweigh this minor difference.

Output:
1
2025-04-17 08:28:22,474 - INFO - Reasoning:

Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (345.359 and 362.459 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (110.45) is slightly above the optimal <90 for CNS targets, but still reasonable. Ligand B (103.87) is better, falling comfortably below 90.

**3. logP:** Ligand A (1.472) and Ligand B (0.964) are both within the optimal 1-3 range.

**4. H-Bond Donors:** Ligand A (1) and Ligand B (2) are both acceptable, being less than 5.

**5. H-Bond Acceptors:** Ligand A (7) and Ligand B (6) are both acceptable, being less than 10.

**6. QED:** Both ligands have good QED scores (0.789 and 0.797), indicating drug-like properties.

**7. DILI:** Ligand A (75.107) has a higher DILI risk than Ligand B (60.915), but both are still within an acceptable range (below 60 is preferred, but up to 70 is often tolerated).

**8. BBB:** This is a crucial parameter for a CNS target like DRD2. Ligand A (75.572) has a significantly better BBB penetration percentile than Ligand B (33.501).

**9. Caco-2 Permeability:** Ligand A (-4.484) and Ligand B (-5.585) both have negative values, indicating poor permeability. This is a concern, but not a dealbreaker if other properties are strong.

**10. Aqueous Solubility:** Both ligands have very poor aqueous solubility (-2.627 and -2.681). This is a significant drawback and would likely require formulation strategies.

**11. hERG Inhibition:** Both ligands have low hERG inhibition risk (0.116 and 0.417).

**12. Microsomal Clearance:** Ligand A (68.322) has a lower microsomal clearance than Ligand B (11.749), suggesting better metabolic stability.

**13. In vitro Half-Life:** Both ligands have negative half-lives (-13.837 and -12.903), which is unusual and likely indicates rapid degradation *in vitro*. This is a concern.

**14. P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.004 and 0.071), which is positive for CNS penetration.

**15. Binding Affinity:** Both ligands have excellent binding affinities (-8.1 and -8.5 kcal/mol). Ligand B is slightly better, but the difference is small.

**Overall Assessment:**

While both ligands have good binding affinity and acceptable drug-like properties, Ligand A is the more promising candidate. Its significantly better BBB penetration (75.572 vs 33.501) is a major advantage for a CNS-targeted drug. It also has better metabolic stability (lower Cl_mic) despite having a slightly higher DILI risk. The poor solubility and negative half-life are concerns for both, but can potentially be addressed with formulation and structural modifications. The slightly better affinity of Ligand B is not enough to overcome its poor BBB penetration.

Output:
0
2025-04-17 08:28:22,475 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B based on the provided guidelines, prioritizing GPCR-specific properties (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (342.399 and 350.459 Da) fall within the ideal range of 200-500 Da.

**TPSA:** Ligand A (85.25) is better than Ligand B (89.87), both are below the 90 A^2 threshold for CNS targets, but A is closer to the ideal.

**logP:** Ligand A (2.759) is optimal (1-3), while Ligand B (0.829) is slightly low, potentially hindering permeation.

**H-Bond Donors/Acceptors:** Ligand A (HBD=2, HBA=5) and Ligand B (HBD=3, HBA=4) both meet the criteria of <=5 HBD and <=10 HBA.

**QED:** Ligand A (0.818) has a better QED score than Ligand B (0.655), indicating a more drug-like profile.

**DILI:** Ligand A (74.99) has a higher DILI risk than Ligand B (8.918). This is a significant drawback for Ligand A.

**BBB:** Ligand A (79.682) has a much better BBB percentile than Ligand B (52.617). This is a critical advantage for a CNS target like DRD2.

**Caco-2 Permeability:** Both have negative values, which is unusual. However, the magnitude of Ligand A (-5.107) is more negative than Ligand B (-5.04), suggesting potentially worse permeability for A.

**Aqueous Solubility:** Both have negative values, which is unusual. Ligand B (-1.387) is slightly better than Ligand A (-3.631).

**hERG:** Both ligands have very low hERG inhibition liability (0.113 and 0.175), which is good.

**Microsomal Clearance:** Ligand B (-0.986) has a negative clearance, which is unusual and suggests very high metabolic stability. Ligand A (24.433) has a higher clearance, indicating faster metabolism.

**In vitro Half-Life:** Ligand B (-3.966) has a negative half-life, which is unusual and suggests very long half-life. Ligand A (29.15) has a reasonable half-life.

**P-gp Efflux:** Both have low P-gp efflux liability (0.119 and 0.03), which is favorable.

**Binding Affinity:** Ligand A (-9.1 kcal/mol) has a significantly stronger binding affinity than Ligand B (-7.7 kcal/mol). This is a substantial advantage, potentially outweighing some of the ADME drawbacks.

**Overall Assessment:**

Ligand A excels in BBB penetration and binding affinity, which are crucial for a CNS GPCR target. However, it has a higher DILI risk and a higher microsomal clearance. Ligand B has a much better safety profile (lower DILI) and metabolic stability, but suffers from weaker binding affinity and poor BBB penetration.

Given the importance of both potency and CNS penetration for DRD2, the stronger affinity of Ligand A, combined with its acceptable (though not ideal) BBB score, makes it the more promising candidate. The DILI risk is a concern, but could potentially be mitigated through structural modifications. The significantly better affinity of A is likely to outweigh the moderate DILI risk.

Output:
1
2025-04-17 08:28:22,475 - INFO - Batch 451 complete. Total preferences: 7216
2025-04-17 08:28:22,475 - INFO - Processing batch 452/512...
2025-04-17 08:29:04,356 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B based on the provided guidelines, prioritizing GPCR-specific properties (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (364.467 Da) is slightly higher than Ligand B (347.375 Da), but both are acceptable.

**TPSA:** Ligand A (89.87) is excellent for CNS penetration, being well below 90. Ligand B (111.39) is still reasonable but less optimal.

**logP:** Ligand A (1.166) is within the optimal range (1-3). Ligand B (0.454) is a bit low, potentially hindering membrane permeability.

**H-Bond Donors/Acceptors:** Ligand A (HBD=3, HBA=5) and Ligand B (HBD=2, HBA=8) both fall within acceptable limits.

**QED:** Both ligands have good QED scores (A: 0.522, B: 0.7), indicating drug-likeness.

**DILI:** Ligand A (39.977) has a much lower DILI risk than Ligand B (68.903), which is a significant advantage.

**BBB:** Ligand A (29.391) has a slightly better BBB percentile than Ligand B (27.879), although both are relatively low and not ideal for a CNS target.

**Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and suggests poor permeability. This is a concern for both.

**Aqueous Solubility:** Both ligands have negative solubility values, indicating poor aqueous solubility. This is a significant drawback for both.

**hERG Inhibition:** Both ligands show very low hERG inhibition risk (A: 0.256, B: 0.11), which is positive.

**Microsomal Clearance:** Ligand A (16.546) has a lower (better) microsomal clearance than Ligand B (-14.873). This suggests better metabolic stability for Ligand A.

**In vitro Half-Life:** Ligand B (30.357) has a substantially longer in vitro half-life than Ligand A (2.845). This is a significant advantage for Ligand B.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (A: 0.111, B: 0.031), which is favorable for CNS penetration.

**Binding Affinity:** Ligand B (-8.6 kcal/mol) has a slightly better binding affinity than Ligand A (-8.3 kcal/mol), but the difference is small.

**Overall Assessment:**

Considering the GPCR-specific priorities, Ligand A is the more promising candidate. While both have issues with Caco-2 and solubility, Ligand A has a significantly lower DILI risk, better metabolic stability (lower Cl_mic), and a slightly better BBB percentile. The small difference in binding affinity is outweighed by these ADME/Tox advantages. The longer half-life of Ligand B is attractive, but the higher DILI risk is a major concern.

Output:
0
2025-04-17 08:29:04,357 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight (MW):** Both ligands (364.555 and 365.905 Da) are within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (40.62) is significantly better than Ligand B (61.44). For CNS targets, we want TPSA <= 90, and ideally closer to 60. Ligand A is much closer to this ideal.

**3. logP:** Both ligands have good logP values (3.521 and 3.236), falling within the optimal 1-3 range.

**4. H-Bond Donors (HBD):** Both are acceptable (0 and 2 respectively), staying below the 5 threshold.

**5. H-Bond Acceptors (HBA):** Both are acceptable (3 each), staying below the 10 threshold.

**6. QED:** Both ligands have good QED scores (0.709 and 0.761), indicating good drug-like properties.

**7. DILI:** Ligand A (28.073) has a much lower DILI risk than Ligand B (43.738). Both are below the 60 threshold, but A is preferable.

**8. BBB:** Ligand A (89.259) has a significantly better BBB penetration percentile than Ligand B (70.997). For a CNS target like DRD2, >70 is desirable, and A is closer to this.

**9. Caco-2 Permeability:** Both have negative Caco-2 values (-4.814 and -4.781). This is unusual and suggests poor permeability. However, the values are very similar, so this isn't a major differentiator.

**10. Aqueous Solubility:** Both have negative solubility values (-4.553 and -3.722). This is also unusual and indicates poor solubility. Again, the values are similar.

**11. hERG Inhibition:** Both ligands show low hERG inhibition risk (0.929 and 0.533), which is good.

**12. Microsomal Clearance:** Ligand B (52.862) has lower microsomal clearance than Ligand A (72.189), suggesting better metabolic stability.

**13. In vitro Half-Life:** Ligand B (77.955) has a longer in vitro half-life than Ligand A (-41.296). This is a significant advantage.

**14. P-gp Efflux:** Ligand A (0.486) has lower P-gp efflux liability than Ligand B (0.323), which is better for CNS exposure.

**15. Binding Affinity:** Ligand B (-7.8 kcal/mol) has a slightly better binding affinity than Ligand A (-7.3 kcal/mol). This is a 0.5 kcal/mol difference, which is significant.

**Overall Assessment:**

While Ligand B has a slightly better binding affinity and metabolic stability (lower Cl_mic, longer t1/2), Ligand A is superior in several key areas for a CNS-targeting GPCR. Specifically, its lower TPSA and higher BBB penetration are crucial. The lower DILI risk is also a significant advantage. The similar Caco-2 and solubility values are concerning for both, but the other benefits of Ligand A outweigh this. The 0.5 kcal/mol difference in binding affinity is not enough to overcome the superior ADME properties of Ligand A.

Output:
0
2025-04-17 08:29:04,357 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (349.479 Da) is slightly lower, which could be advantageous for permeability. Ligand B (371.413 Da) is also good.

**TPSA:** Both ligands have TPSA values below the 90 A^2 threshold for CNS targets. Ligand A (78.43 A^2) is better than Ligand B (73.14 A^2), suggesting better CNS penetration potential.

**logP:** Both ligands have logP values within the optimal range (1-3). Ligand A (1.479) is slightly lower, while Ligand B (2.507) is closer to the upper end.

**H-Bond Donors/Acceptors:** Ligand A has 1 HBD and 5 HBA, while Ligand B has 0 HBD and 7 HBA. Both are within acceptable limits.

**QED:** Both ligands have similar QED values (0.769 and 0.713), indicating good drug-likeness.

**DILI:** Ligand A (17.138) has a significantly lower DILI risk than Ligand B (41.295), which is a major advantage.

**BBB:** Ligand B (93.486) has a much higher BBB penetration percentile than Ligand A (49.515). This is a critical factor for a CNS target like DRD2.

**Caco-2 Permeability:** Ligand A (-5.015) shows poor Caco-2 permeability, while Ligand B (-4.36) is slightly better, but still not great.

**Aqueous Solubility:** Ligand A (-0.254) has slightly better solubility than Ligand B (-3.922).

**hERG Inhibition:** Ligand A (0.089) has a very low hERG inhibition risk, while Ligand B (0.489) has a slightly higher, but still relatively low, risk.

**Microsomal Clearance:** Ligand B (48.668) has a lower microsomal clearance than Ligand A (22.695), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (20.164) has a longer in vitro half-life than Ligand B (-3.597).

**P-gp Efflux:** Ligand A (0.001) has very low P-gp efflux liability, while Ligand B (0.218) has slightly higher efflux.

**Binding Affinity:** Ligand A (-7.4 kcal/mol) has a slightly better binding affinity than Ligand B (-6.7 kcal/mol). This 0.7 kcal/mol difference is significant.

**Overall Assessment:**

Ligand A excels in binding affinity, DILI risk, hERG inhibition, P-gp efflux, and has a longer half-life. However, its BBB penetration and Caco-2 permeability are poor. Ligand B has superior BBB penetration and slightly better metabolic stability, but suffers from higher DILI risk, worse P-gp efflux, and weaker binding affinity.

Given the GPCR-specific priorities, BBB penetration is crucial for CNS targets. However, the substantial advantage in binding affinity (-0.7 kcal/mol) and the much lower DILI risk of Ligand A, combined with its favorable P-gp efflux, outweigh the lower BBB score. The better TPSA of Ligand A also supports CNS penetration. While the Caco-2 permeability is a concern, it's less critical for a CNS target.

Output:
0
2025-04-17 08:29:04,357 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (371.547 and 344.415 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (72.88) is significantly better than Ligand B (91.4). For CNS targets, we want TPSA <= 90, so Ligand A is preferable.

**3. logP:** Ligand A (1.082) is within the optimal range (1-3), while Ligand B (0.595) is slightly below, potentially hindering permeation.

**4. H-Bond Donors:** Both have 2 HBD, which is acceptable.

**5. H-Bond Acceptors:** Ligand A has 5 HBA, and Ligand B has 4. Both are within the acceptable limit of <= 10.

**6. QED:** Ligand A (0.668) is slightly better than Ligand B (0.56), indicating a more drug-like profile.

**7. DILI:** Ligand A (8.181) has a much lower DILI risk than Ligand B (32.261). This is a significant advantage.

**8. BBB:** Ligand A (23.187) has a very poor BBB penetration percentile, while Ligand B (60.876) is better, but still not ideal (we want >70 for CNS targets). This is a major drawback for Ligand A.

**9. Caco-2:** Both have negative values (-5.498 and -5.398), which is unusual and difficult to interpret without knowing the scale. However, the values are very similar.

**10. Solubility:** Both have negative values (-1.23 and -2.135), indicating poor solubility. Ligand B is slightly worse.

**11. hERG:** Ligand A (0.228) has a lower hERG inhibition liability than Ligand B (0.08), which is preferable.

**12. Cl_mic:** Ligand A (2.928) has a lower microsomal clearance than Ligand B (-5.8), suggesting better metabolic stability.

**13. t1/2:** Ligand A (30.391) has a significantly longer in vitro half-life than Ligand B (-3.209).

**14. Pgp:** Ligand A (0.015) has a much lower P-gp efflux liability than Ligand B (0.018). This is crucial for CNS penetration.

**15. Binding Affinity:** Ligand B (-8.1 kcal/mol) has a slightly better binding affinity than Ligand A (-7.0 kcal/mol). This is a 1.1 kcal/mol difference, which is significant, but needs to be weighed against the ADME properties.

**Overall Assessment:**

Ligand A has superior DILI, Cl_mic, t1/2, and Pgp properties. Its TPSA is also much better. However, its BBB penetration is very poor. Ligand B has better affinity and a better (though still suboptimal) BBB score, but suffers from higher DILI risk, poorer metabolic stability, and higher Pgp efflux.

Given the GPCR-specific priorities, BBB is critical for a CNS target like DRD2. While Ligand A's BBB score is very low, its other favorable ADME properties (especially low DILI, good metabolic stability, and low Pgp efflux) combined with acceptable affinity, make it a slightly more promising starting point for optimization. Improving the BBB penetration of Ligand A through structural modifications would be a key focus. Ligand B's poor ADME profile, despite its slightly better affinity, makes it less attractive.

Output:
0
2025-04-17 08:29:04,357 - INFO - Reasoning:

Let's analyze Ligand A and Ligand B based on the provided guidelines, prioritizing GPCR-specific properties (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (369.422 Da) is slightly higher than Ligand B (345.443 Da), but both are acceptable.

**TPSA:** Ligand A (115.24) is higher than the preferred <90 for CNS targets, while Ligand B (82.53) is comfortably within the range. This favors Ligand B.

**logP:** Both ligands have good logP values (A: 2.283, B: 1.601), falling within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A (HBD=1, HBA=4) and Ligand B (HBD=2, HBA=4) both have reasonable H-bond properties, well within the guidelines.

**QED:** Ligand B (0.849) has a significantly higher QED score than Ligand A (0.487), indicating a more drug-like profile.

**DILI:** Ligand A (63.513) has a higher DILI risk than Ligand B (18.922). This is a significant advantage for Ligand B.

**BBB:** Both ligands have good BBB penetration (A: 51.105, B: 63.746), but Ligand B is slightly better. While both are above 50, >70 is desirable for CNS targets, and neither hits that mark.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.831 and -4.808), which is unusual and suggests poor permeability. This is a concern for both.

**Aqueous Solubility:** Both ligands have negative solubility values (-2.669 and -1.838), indicating very poor aqueous solubility. This is a significant drawback for both.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (A: 0.347, B: 0.412).

**Microsomal Clearance:** Ligand B (-1.144) has a negative clearance, which is not physically possible. This is a red flag and suggests an issue with the data or the prediction method. Ligand A (6.751) has a moderate clearance.

**In vitro Half-Life:** Ligand B (-5.083) has a negative half-life, which is also not physically possible. This reinforces the data quality concerns. Ligand A (-8.736) also has a negative half-life, which is problematic.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (A: 0.063, B: 0.014), which is favorable for CNS penetration.

**Binding Affinity:** Ligand B (-7.8 kcal/mol) has a slightly better binding affinity than Ligand A (-8.5 kcal/mol). While both are excellent, the difference is not substantial enough to overcome other issues.

**Overall Assessment:**

Despite both ligands having issues with Caco-2 permeability and aqueous solubility, Ligand B appears more promising. It has a better QED score, lower DILI risk, slightly better BBB penetration, and better binding affinity. However, the negative values for microsomal clearance and in vitro half-life for Ligand B are major concerns and suggest potential data errors. Ligand A's values are also problematic, but less so. Given the issues with the data, and prioritizing the more favorable ADME properties of B (excluding the erroneous values), I would select Ligand B.

Output:
1
2025-04-17 08:29:04,357 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (367.515 Da) is slightly higher than Ligand B (343.427 Da), but both are acceptable.

**TPSA:** Ligand A (53.09) is significantly better than Ligand B (73.74). For CNS targets, we want TPSA <= 90, and ideally closer to 60. Ligand A is much closer to the ideal range.

**logP:** Ligand A (0.379) is a bit low, potentially impacting permeability. Ligand B (1.44) is better, falling within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A (0 HBD, 5 HBA) is preferable to Ligand B (1 HBD, 4 HBA). Lower HBD/HBA generally improves permeability.

**QED:** Both ligands have similar QED values (0.658 and 0.648), indicating good drug-likeness.

**DILI:** Both ligands have low DILI risk (29.43 and 28.616), which is positive.

**BBB:** This is critical for a CNS target like DRD2. Ligand A has a much better BBB penetration percentile (58.938) than Ligand B (33.424). A value >70 is desirable, but Ligand A is considerably better positioned.

**Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and suggests poor permeability. However, the scale is not specified, so it's hard to interpret.

**Aqueous Solubility:** Both have negative solubility values, again, hard to interpret without knowing the scale.

**hERG:** Both ligands have low hERG inhibition liability (0.265 and 0.292), which is good.

**Microsomal Clearance:** Ligand A (39.312) has a higher microsomal clearance than Ligand B (10.421), meaning it's likely to be metabolized faster. Lower clearance is preferred.

**In vitro Half-Life:** Ligand B (-2.274) has a negative half-life, which is not possible and indicates an issue with the data. Ligand A (1.102) is reasonable.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.049 and 0.086), which is good for CNS penetration.

**Binding Affinity:** Ligand A (-6.5 kcal/mol) has a slightly better binding affinity than Ligand B (0.0 kcal/mol). A difference of 6.5 kcal/mol is significant.

**Overall Assessment:**

Ligand A is the stronger candidate. While its logP is a bit low, its superior TPSA, significantly better BBB penetration, better binding affinity, and reasonable half-life outweigh this drawback. Ligand B has a more optimal logP, but its poor BBB penetration, questionable half-life value, and weaker binding affinity make it less promising. The negative values for Caco-2 and solubility are concerning for both, but the other factors strongly favor Ligand A.

Output:
1
2025-04-17 08:29:04,357 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (362.495 Da) is slightly higher than Ligand B (348.403 Da), but both are acceptable.

**TPSA:** Ligand A (69.64) is significantly better than Ligand B (109.42). For CNS targets, TPSA should be <= 90. Ligand A is well within this range, while Ligand B is pushing the limit and less favorable for brain penetration.

**logP:** Ligand A (2.706) is optimal (1-3). Ligand B (-0.223) is quite low, potentially hindering membrane permeability and reducing CNS exposure.

**H-Bond Donors/Acceptors:** Ligand A (HBD=2, HBA=4) is preferable to Ligand B (HBD=3, HBA=5). Both are within acceptable limits, but fewer H-bonds generally improve permeability.

**QED:** Both ligands have similar QED values (A: 0.791, B: 0.631), indicating good drug-like properties.

**DILI:** Ligand A (33.695) has a lower DILI risk than Ligand B (42.536), which is a positive attribute. Both are below the concerning threshold of 60.

**BBB:** Ligand A (60.76) has a significantly better BBB percentile than Ligand B (43.156). While >70 is desirable, 60.76 is still reasonably good, and a substantial improvement over Ligand B. This is a crucial factor for a CNS target like DRD2.

**Caco-2 Permeability:** Ligand A (-5.027) and Ligand B (-5.365) both have negative values, which is unusual and suggests very poor permeability. However, the scale is not specified, so it's hard to interpret.

**Aqueous Solubility:** Both ligands have poor aqueous solubility (-2.937 and -1.711 respectively). This could pose formulation challenges.

**hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.224 and 0.048 respectively).

**Microsomal Clearance:** Ligand A (12.938) has a higher microsomal clearance than Ligand B (1.745), indicating lower metabolic stability. This is a drawback for Ligand A.

**In vitro Half-Life:** Ligand B (13.993) has a significantly longer in vitro half-life than Ligand A (-4.899). This is a significant advantage for Ligand B.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.07 and 0.006 respectively), which is favorable for CNS penetration.

**Binding Affinity:** Ligand B (-8.7 kcal/mol) has a slightly better binding affinity than Ligand A (-8.2 kcal/mol), although the difference is relatively small.

**Overall Assessment:**

Considering the GPCR-specific priorities, Ligand A is the better candidate. While Ligand B has a slightly better affinity and half-life, Ligand A excels in TPSA and BBB penetration, both critical for CNS drug development. The lower logP of Ligand B is a significant concern, as it will likely limit brain exposure. The DILI score is also better for Ligand A. While the higher clearance of Ligand A is a concern, it is less critical than the poor BBB and logP of Ligand B.



Output:
0
2025-04-17 08:29:04,358 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B based on the provided guidelines, prioritizing GPCR-specific properties (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (361.402 and 353.463 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (106.96) is slightly above the optimal <90 for CNS targets, but still reasonable. Ligand B (87.74) is excellent, well below 90.

**logP:** Ligand A (3.175) is at the upper end of the optimal range (1-3), while Ligand B (1.522) is at the lower end. While both are within range, a logP that is too low can hinder permeation.

**H-Bond Donors/Acceptors:** Both ligands have 2 HBD and 4 HBA, which are within acceptable limits.

**QED:** Ligand B (0.583) has a better QED score than Ligand A (0.326), indicating a more drug-like profile.

**DILI:** Ligand B (22.8) has a significantly lower DILI risk than Ligand A (68.244), which is a major advantage.

**BBB:** Ligand B (82.435) has a much higher BBB penetration percentile than Ligand A (67.778). This is crucial for a CNS target like DRD2.

**Caco-2 Permeability:** Ligand A (-5.152) has a negative Caco-2 value, which is concerning, indicating poor permeability. Ligand B (-4.491) is also negative, but less so.

**Aqueous Solubility:** Both ligands have negative solubility values, indicating poor solubility. This is a potential issue for both, but may be less critical if permeability is good.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.62 and 0.311, respectively).

**Microsomal Clearance:** Ligand A (32.93) has lower microsomal clearance than Ligand B (59.715), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand B (-25.535) has a negative half-life, which is highly problematic. Ligand A (34.041) has a reasonable half-life.

**P-gp Efflux:** Ligand A (0.236) has lower P-gp efflux than Ligand B (0.047), which is favorable for CNS penetration.

**Binding Affinity:** Ligand A (-7.8 kcal/mol) has a significantly stronger binding affinity than Ligand B (-6.9 kcal/mol). This is a substantial advantage, potentially outweighing some of the ADME drawbacks.

**Overall Assessment:**

Ligand A has a superior binding affinity and better metabolic stability (lower Cl_mic, positive t1/2). However, it has a higher DILI risk, lower BBB penetration, and poor Caco-2 permeability. Ligand B has a better QED, lower DILI, and significantly better BBB penetration, but suffers from a very poor in vitro half-life and weaker binding affinity.

Given the importance of BBB penetration for a CNS target, and the substantial difference in binding affinity, Ligand A is the more promising candidate *despite* its drawbacks. The strong binding affinity could potentially be optimized with further modifications to improve ADME properties. The negative half-life of Ligand B is a major red flag.

Output:
0
2025-04-17 08:29:04,358 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 drug candidates, considering the provided guidelines and GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (351.422 and 348.495 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (81.67) is slightly above the optimal <90 for CNS targets, but acceptable. Ligand B (75.94) is well within the desired range.

**3. logP:** Both ligands have good logP values (1.528 and 2.117), falling within the optimal 1-3 range.

**4. H-Bond Donors:** Ligand A (3) is acceptable, while Ligand B (1) is also good.

**5. H-Bond Acceptors:** Ligand A (4) is acceptable, and Ligand B (6) is also within the preferred limit of <=10.

**6. QED:** Both ligands have good QED scores (0.589 and 0.779), indicating good drug-like properties.

**7. DILI:** Ligand A (18.069) has a significantly lower DILI risk than Ligand B (26.91). Both are below the 40 threshold, indicating low risk.

**8. BBB:** Ligand B (89.259) has a much higher BBB penetration percentile than Ligand A (55.603). This is a *critical* advantage for a CNS target like DRD2.

**9. Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and suggests a potential issue with intestinal absorption. However, since we are focusing on CNS targets, this is less critical than BBB.

**10. Aqueous Solubility:** Both ligands have negative solubility values, indicating poor aqueous solubility. This is a potential formulation challenge.

**11. hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.585 and 0.13).

**12. Microsomal Clearance:** Ligand A (8.389) has significantly lower microsomal clearance than Ligand B (27.034), suggesting better metabolic stability.

**13. In vitro Half-Life:** Ligand A (10.579) has a longer half-life than Ligand B (1.022).

**14. P-gp Efflux:** Ligand A (0.046) has much lower P-gp efflux liability than Ligand B (0.103), which is favorable for CNS penetration.

**15. Binding Affinity:** Ligand B (-7.5 kcal/mol) has a stronger binding affinity than Ligand A (-8.1 kcal/mol). While A is better, the difference is not substantial enough to outweigh the other factors.

**Overall Assessment:**

Ligand B excels in BBB penetration and binding affinity, which are the most important factors for a CNS GPCR target. While Ligand A has better metabolic stability (lower Cl_mic, longer t1/2) and lower DILI risk, the significantly higher BBB score of Ligand B is a decisive advantage. The slightly lower P-gp efflux of ligand A is helpful, but not enough to overcome the BBB difference. The solubility and Caco-2 issues are similar for both.

Output:
1
2025-04-17 08:29:04,358 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (350.459 and 347.423 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (75.71) is significantly better than Ligand B (118.06). For CNS targets, we want TPSA <= 90, and A is comfortably within this range, while B is above.

**logP:** Both ligands have good logP values (2.191 and 2.051), falling within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Both have 1 HBD and 4 HBA, which are acceptable.

**QED:** Both ligands have similar QED values (0.453 and 0.482), indicating moderate drug-likeness. Improvement is possible, but not a major differentiator here.

**DILI:** Ligand B (34.587) has a considerably lower DILI risk than Ligand A (52.385), making it safer from a liver toxicity perspective.

**BBB:** Ligand A (38.852) has a slightly better BBB penetration percentile than Ligand B (31.252), but both are below the desirable >70% for CNS targets. This is a weakness for both, but less critical than other factors.

**Caco-2 Permeability:** Ligand A (-4.796) shows better Caco-2 permeability than Ligand B (-5.281), suggesting better intestinal absorption.

**Aqueous Solubility:** Ligand B (-1.588) has slightly better aqueous solubility than Ligand A (-2.468).

**hERG:** Both ligands have very low hERG inhibition liability (0.194 and 0.108), which is excellent.

**Microsomal Clearance:** Ligand B (1.988) has significantly lower microsomal clearance than Ligand A (42.24), indicating better metabolic stability.

**In vitro Half-Life:** Ligand B (3.784) has a longer in vitro half-life than Ligand A (-7.635). This is a substantial advantage for dosing considerations.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.097 and 0.008), which is positive for CNS exposure.

**Binding Affinity:** Ligand B (-6.8 kcal/mol) has a slightly better binding affinity than Ligand A (-6.5 kcal/mol). While the difference is not huge, it's enough to be considered, especially given the other favorable properties of Ligand B.

**Overall Assessment:**

Ligand B is the stronger candidate. While Ligand A has slightly better Caco-2 permeability, Ligand B excels in critical areas for a CNS-targeting GPCR ligand: lower TPSA, significantly lower DILI risk, better metabolic stability (lower Cl_mic and longer t1/2), and slightly improved binding affinity. The lower TPSA and improved metabolic stability are particularly important for CNS penetration and maintaining therapeutic concentrations.

Output:
1
2025-04-17 08:29:04,358 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (349.406 and 352.469 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (72.88) is excellent for CNS penetration, well below the 90 A^2 threshold. Ligand B (33.2) is even better, indicating potentially improved brain exposure.

**logP:** Ligand A (1.455) is optimal. Ligand B (4.57) is a bit high, potentially leading to solubility issues and off-target interactions, though still within a manageable range.

**H-Bond Donors/Acceptors:** Ligand A has 2 HBD and 4 HBA, which is acceptable. Ligand B has 0 HBD and 2 HBA, also acceptable.

**QED:** Both ligands have reasonable QED values (0.866 and 0.72), suggesting good drug-like properties.

**DILI:** Ligand A (41.411) has a slightly higher DILI risk than Ligand B (11.943), but both are below the concerning 60 threshold.

**BBB:** This is a critical parameter for a CNS target. Ligand A (57.154) is moderate, while Ligand B (95.463) is *excellent*, exceeding the desirable >70 threshold. This is a significant advantage for Ligand B.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.801 and -4.279). This is unusual and suggests poor permeability. However, these values are on a log scale and might not be directly comparable.

**Aqueous Solubility:** Both ligands have negative solubility values (-2.022 and -4.393). This is concerning, and formulation could be a challenge.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.679 and 0.835).

**Microsomal Clearance:** Ligand A (-12.092) has a much lower (better) microsomal clearance than Ligand B (66.065), indicating better metabolic stability.

**In vitro Half-Life:** Ligand A (13.66 hours) has a slightly longer half-life than Ligand B (12.957 hours).

**P-gp Efflux:** Ligand A (0.028) has very low P-gp efflux, which is excellent for CNS penetration. Ligand B (0.215) has a slightly higher, but still relatively low, P-gp efflux.

**Binding Affinity:** Ligand A (-8.3 kcal/mol) has a significantly stronger binding affinity than Ligand B (-7.2 kcal/mol). This 1.1 kcal/mol difference is substantial and could outweigh some of the ADME drawbacks of Ligand A.

**Overall Assessment:**

Ligand B excels in BBB penetration and has a lower DILI risk, which are crucial for a CNS-targeted GPCR. However, its higher logP and significantly worse metabolic stability (higher Cl_mic) are concerning. Ligand A has a much stronger binding affinity, better metabolic stability, and lower P-gp efflux, but its BBB penetration is moderate, and DILI risk is slightly higher.

Given the importance of strong binding affinity for GPCR ligands, and the fact that Ligand A's BBB is still reasonable, the superior affinity of Ligand A is the deciding factor. While the solubility and Caco-2 permeability are concerns for both, these can potentially be addressed with formulation strategies.

Output:
0
2025-04-17 08:29:04,358 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight (MW):** Both ligands (356.482 and 360.479 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (78.43) is slightly higher than Ligand B (62.66). Both are below the 90 A^2 threshold desirable for CNS targets, but Ligand B is preferable.

**3. logP:** Both ligands have good logP values (2.324 and 2.989), falling within the optimal 1-3 range. Ligand B is slightly higher, potentially aiding membrane permeability.

**4. H-Bond Donors (HBD):** Ligand A has 3 HBDs, and Ligand B has 1. Both are within the acceptable limit of <=5.

**5. H-Bond Acceptors (HBA):** Ligand A has 3 HBAs, and Ligand B has 5. Both are within the acceptable limit of <=10.

**6. QED:** Both ligands have acceptable QED values (0.624 and 0.581), indicating reasonable drug-likeness.

**7. DILI:** Ligand A (10.043) has a significantly lower DILI risk than Ligand B (38.581). This is a substantial advantage for Ligand A.

**8. BBB:** Both ligands have good BBB penetration (67.39% and 70.919%), but Ligand B is slightly better. Both are above the 70% threshold.

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.791 and -4.846), which is unusual and suggests poor permeability. This is a significant concern for both.

**10. Aqueous Solubility:** Both ligands have negative solubility values (-2.358 and -2.391), indicating very poor aqueous solubility. This is a major drawback for both.

**11. hERG Inhibition:** Both ligands have low hERG inhibition risk (0.324 and 0.625).

**12. Microsomal Clearance (Cl_mic):** Ligand A (22.327) has a significantly lower Cl_mic than Ligand B (51.1), suggesting better metabolic stability.

**13. In vitro Half-Life:** Ligand B (29.003) has a longer in vitro half-life than Ligand A (8.629).

**14. P-gp Efflux:** Ligand A (0.044) has a much lower P-gp efflux liability than Ligand B (0.387), which is crucial for CNS penetration.

**15. Binding Affinity:** Ligand A (-8.5 kcal/mol) has a significantly stronger binding affinity than Ligand B (-6.9 kcal/mol). This is a >1.5 kcal/mol difference, which can outweigh other drawbacks.

**Overall Assessment:**

While both compounds have issues with solubility and Caco-2 permeability, Ligand A is the more promising candidate. Its significantly stronger binding affinity (-8.5 vs -6.9 kcal/mol), lower DILI risk, lower P-gp efflux, and lower microsomal clearance outweigh the slightly better BBB penetration and half-life of Ligand B. The strong affinity suggests that even with permeability issues, sufficient drug can reach the target. The lower DILI and P-gp efflux are critical for a CNS-targeting drug.

Output:
1
2025-04-17 08:29:04,358 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (358.454 Da and 351.447 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (76.66) is better than Ligand B (79.9), both are below the 90 A^2 threshold for CNS targets, which is good.

**3. logP:** Ligand A (2.276) is optimal (1-3), while Ligand B (0.76) is a bit low, potentially hindering permeation.

**4. H-Bond Donors:** Both have 2 HBD, which is within the acceptable limit of <=5.

**5. H-Bond Acceptors:** Ligand A has 4 HBA, and Ligand B has 5 HBA, both are within the acceptable limit of <=10.

**6. QED:** Ligand B (0.764) has a better QED score than Ligand A (0.464), indicating a more drug-like profile.

**7. DILI:** Ligand A (14.036) has a significantly lower DILI risk than Ligand B (17.449). This is a substantial advantage.

**8. BBB:** Ligand A (81.582) has a much higher BBB penetration percentile than Ligand B (54.478). This is *critical* for a CNS target like DRD2.

**9. Caco-2 Permeability:** Ligand A (-4.932) and Ligand B (-5.289) both have negative values, indicating poor permeability. This is a concern for both.

**10. Aqueous Solubility:** Both have negative solubility values, which is concerning.

**11. hERG Inhibition:** Both ligands have low hERG inhibition risk (0.525 and 0.352, respectively).

**12. Microsomal Clearance:** Ligand B (6.708) has lower microsomal clearance than Ligand A (19.013), suggesting better metabolic stability.

**13. In vitro Half-Life:** Ligand B (15.129) has a slightly longer half-life than Ligand A (16.826).

**14. P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.077 and 0.022, respectively).

**15. Binding Affinity:** Both ligands have excellent binding affinity (-8.0 and -8.2 kcal/mol), with Ligand B being slightly better. However, the affinity difference is small and may not outweigh other factors.

**Overall Assessment:**

While Ligand B has a slightly better QED, half-life, and affinity, Ligand A is significantly superior regarding crucial properties for a CNS-targeting GPCR ligand. Specifically, its much higher BBB penetration (81.582 vs. 54.478) and lower DILI risk (14.036 vs. 17.449) are decisive advantages. The slightly lower logP of Ligand B is a concern. The poor Caco-2 and solubility for both are drawbacks that would need to be addressed in further optimization, but are less critical than CNS penetration for this target.

Output:
1
2025-04-17 08:29:04,359 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Ligand A (345.443 Da) is within the ideal range (200-500 Da). Ligand B (153.181 Da) is below the preferred range, potentially impacting potency.

**TPSA:** Ligand A (70.49) is excellent for CNS penetration (below 90). Ligand B (66.48) is also very good.

**logP:** Ligand A (2.489) is optimal (1-3). Ligand B (0.599) is a bit low, potentially hindering membrane permeability.

**H-Bond Donors:** Ligand A (2) and Ligand B (3) are both acceptable (<=5).

**H-Bond Acceptors:** Ligand A (5) and Ligand B (3) are both acceptable (<=10).

**QED:** Ligand A (0.757) is strong, indicating good drug-likeness. Ligand B (0.545) is acceptable, but less optimal.

**DILI:** Both Ligand A (8.181) and Ligand B (8.608) have low DILI risk, which is positive.

**BBB:** Ligand A (79.062) has a good BBB percentile, desirable for a CNS target. Ligand B (18.612) has a very poor BBB percentile, a major drawback.

**Caco-2 Permeability:** Both are negative, indicating poor permeability. This is concerning, but can be mitigated if other properties are favorable.

**Aqueous Solubility:** Both are negative, indicating poor solubility. This is concerning, but can be mitigated if other properties are favorable.

**hERG:** Ligand A (0.904) has a low hERG risk. Ligand B (0.139) also has a low hERG risk.

**Microsomal Clearance:** Ligand A (7.455) is relatively low, suggesting better metabolic stability. Ligand B (-35.062) is very negative, which is not possible and likely an error. Assuming it is a high value, it suggests rapid clearance.

**In vitro Half-Life:** Ligand A (-34.235) is very negative, which is not possible and likely an error. Assuming it is a low value, it suggests a short half-life. Ligand B (-0.194) is also very negative, suggesting a short half-life.

**P-gp Efflux:** Ligand A (0.079) has low P-gp efflux, which is good for CNS penetration. Ligand B (0.012) also has low P-gp efflux.

**Binding Affinity:** Ligand A (-8.7 kcal/mol) has significantly stronger binding affinity than Ligand B (-6.4 kcal/mol). This is a substantial advantage.

**Conclusion:**

Despite the negative values for Caco-2 and Solubility, Ligand A is the far superior candidate. Its optimal logP, excellent BBB penetration, strong binding affinity, and low P-gp efflux outweigh the concerns about permeability and solubility. Ligand B's extremely low BBB penetration is a deal-breaker for a CNS target like DRD2, and its significantly weaker binding affinity further diminishes its potential. The erroneous negative values for clearance and half-life for both compounds are concerning, but the difference in affinity is the most important factor here.

Output:
1
2025-04-17 08:29:04,359 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (384.395 Da) is slightly higher than Ligand B (354.447 Da), but both are acceptable.

**TPSA:** Ligand A (49.85) is excellent for CNS penetration, well below the 90 A^2 threshold. Ligand B (79.31) is higher, but still reasonable.

**logP:** Ligand A (2.021) is optimal (1-3). Ligand B (0.26) is quite low, potentially hindering membrane permeability and CNS entry.

**H-Bond Donors/Acceptors:** Ligand A (0 HBD, 4 HBA) and Ligand B (1 HBD, 5 HBA) both fall within acceptable ranges.

**QED:** Both ligands have similar and good QED values (0.696 and 0.676, respectively).

**DILI:** Ligand A (35.983) has a much lower DILI risk than Ligand B (12.912), suggesting better hepatotoxicity profile.

**BBB:** Ligand A (93.912) shows excellent BBB penetration, exceeding the desirable 70% threshold. Ligand B (63.009) is lower, which is concerning for a CNS target.

**Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and could indicate issues with the prediction method or the compounds themselves. However, the values are similar.

**Aqueous Solubility:** Both have negative solubility values, again unusual. The values are similar.

**hERG:** Ligand A (0.588) has a slightly higher hERG risk than Ligand B (0.213), but both are relatively low.

**Microsomal Clearance:** Ligand A (51.715) has higher microsomal clearance than Ligand B (12.137), indicating lower metabolic stability.

**In vitro Half-Life:** Ligand B (16.887) has a longer in vitro half-life than Ligand A (-26.136), which is preferable.

**P-gp Efflux:** Ligand A (0.054) has a much lower P-gp efflux liability than Ligand B (0.024), meaning it's less likely to be pumped out of the brain.

**Binding Affinity:** Ligand A (-8.7 kcal/mol) has a significantly stronger binding affinity than Ligand B (-6.7 kcal/mol). This is a substantial advantage.

**Overall Assessment:**

Ligand A is significantly better suited as a DRD2 ligand. Its superior BBB penetration, lower DILI risk, and *much* stronger binding affinity outweigh its slightly higher microsomal clearance. Ligand B's low logP is a major drawback for CNS penetration, and its lower affinity is also a concern. The P-gp efflux is also lower for Ligand A, which is beneficial for CNS exposure. While both have unusual solubility and Caco-2 values, the other factors clearly favor Ligand A.

Output:
1
2025-04-17 08:29:04,359 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (353.463 and 355.364 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (87.74) is better than Ligand B (66.07). Both are below the 90 A^2 threshold for CNS targets, but A is closer to the upper limit.

**3. logP:** Ligand B (2.934) is optimal (1-3), while Ligand A (0.683) is below 1, which might hinder permeation. This is a significant advantage for Ligand B.

**4. H-Bond Donors:** Both ligands have 2 HBD, which is within the acceptable limit of <=5.

**5. H-Bond Acceptors:** Ligand A has 4 HBA, and Ligand B has 5. Both are within the acceptable limit of <=10.

**6. QED:** Both ligands have good QED scores (0.705 and 0.883, respectively), indicating good drug-like properties.

**7. DILI:** Ligand A (7.445) has a much lower DILI risk than Ligand B (85.227). This is a major advantage for Ligand A.

**8. BBB:** Both ligands have excellent BBB penetration (76.154 and 78.79), exceeding the 70% threshold for CNS targets.

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.876 and -4.913). This is unusual and suggests poor permeability, but the scale is not specified, so it's difficult to interpret.

**10. Aqueous Solubility:** Both ligands have negative solubility values (-1.344 and -4.65). Again, the scale is unclear, but negative values likely indicate poor solubility.

**11. hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.163 and 0.898).

**12. Microsomal Clearance:** Ligand A (11.121) has significantly lower microsomal clearance than Ligand B (33.723), suggesting better metabolic stability.

**13. In vitro Half-Life:** Ligand A (-13.069) has a negative half-life, which is not possible. Ligand B (28.358) has a reasonable half-life. This is a critical flaw for Ligand A.

**14. P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.012 and 0.09).

**15. Binding Affinity:** Both ligands have comparable and strong binding affinities (-8.3 and -8.4 kcal/mol).

**Overall Assessment:**

Ligand B has a better logP value, which is crucial for GPCR ligands. However, Ligand A has a significantly lower DILI risk, lower microsomal clearance (better metabolic stability), and a more reasonable TPSA. The negative half-life for Ligand A is a fatal flaw. While both have similar affinities and BBB penetration, the DILI and metabolic stability advantages of Ligand A, combined with the better logP of Ligand B, make the decision difficult. However, the negative half-life for Ligand A is a showstopper.

Output:
1
2025-04-17 08:29:04,359 - INFO - Batch 452 complete. Total preferences: 7232
2025-04-17 08:29:04,359 - INFO - Processing batch 453/512...
2025-04-17 08:29:45,498 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B based on the provided guidelines, prioritizing GPCR-specific properties (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (346.358 and 352.431 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (88.52) is excellent for CNS penetration, being below 90. Ligand B (99.1) is still reasonable but less optimal.

**logP:** Ligand A (2.063) is within the optimal 1-3 range. Ligand B (-0.205) is significantly lower, potentially hindering membrane permeability and CNS entry.

**H-Bond Donors/Acceptors:** Both have acceptable HBD (2 and 3 respectively) and HBA (5 each) counts.

**QED:** Both ligands have good QED scores (0.782 and 0.65), indicating drug-like properties.

**DILI:** Ligand A (49.05) has a slightly higher DILI risk than Ligand B (21.869), but both are still considered reasonably safe (<60).

**BBB:** This is a crucial parameter for a CNS target like DRD2. Ligand A (55.215) is better than Ligand B (32.144), though ideally, we'd want >70.

**Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and suggests poor permeability. However, the scale is not clearly defined, so we'll consider this cautiously. Ligand A (-4.44) is slightly better than Ligand B (-4.961).

**Aqueous Solubility:** Both have negative solubility values, again unusual. Ligand A (-3.26) is slightly better than Ligand B (-1.084).

**hERG:** Both ligands have very low hERG inhibition risk (0.165 and 0.108).

**Microsomal Clearance:** Ligand B (-7.273) exhibits significantly *lower* (better) microsomal clearance than Ligand A (58.776), suggesting greater metabolic stability.

**In vitro Half-Life:** Ligand B (37.83) has a much longer half-life than Ligand A (-15.968), which is a significant advantage.

**P-gp Efflux:** Both have very low P-gp efflux liability (0.033 and 0.005).

**Binding Affinity:** Both have excellent binding affinities (-8.2 and -7.7 kcal/mol). The difference of 0.5 kcal/mol is not substantial enough to override other ADME concerns.

**Overall Assessment:**

Ligand A has a better TPSA and BBB, and a slightly better logP, which are crucial for CNS penetration. However, Ligand B excels in metabolic stability (lower Cl_mic) and has a significantly longer half-life. The negative solubility and Caco-2 values are concerning for both, but the difference in BBB and logP is more impactful for a CNS target. Given the importance of CNS penetration for DRD2, and the relatively small difference in binding affinity, Ligand A is the slightly more promising candidate.

Output:
0
2025-04-17 08:29:45,499 - INFO - Reasoning:

Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (348.403 and 347.459 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (97.55) is higher than Ligand B (78.51). For CNS targets, TPSA < 90 is preferred. Ligand B is better here.

**3. logP:** Ligand A (0.259) is quite low, potentially hindering permeability. Ligand B (1.235) is within the optimal 1-3 range. Ligand B is significantly better.

**4. H-Bond Donors:** Ligand A (1) is good. Ligand B (2) is acceptable.

**5. H-Bond Acceptors:** Ligand A (8) is acceptable. Ligand B (3) is excellent.

**6. QED:** Both ligands have similar QED values (0.783 and 0.71), indicating good drug-likeness.

**7. DILI:** Ligand A (55.448) has a moderate DILI risk, while Ligand B (16.053) has a very low DILI risk. Ligand B is much better.

**8. BBB:** Ligand A (85.459) has good BBB penetration, while Ligand B (59.597) is lower. This is a point in favor of Ligand A, but not decisive.

**9. Caco-2:** Ligand A (-4.508) and Ligand B (-5.088) both have negative values, which is unusual and suggests very poor permeability. This is a significant concern for both.

**10. Solubility:** Ligand A (-2.559) and Ligand B (-1.753) both have poor aqueous solubility.

**11. hERG:** Both ligands have low hERG inhibition liability (0.328 and 0.13), which is good.

**12. Cl_mic:** Ligand A (43.267) has higher microsomal clearance than Ligand B (-9.146). Negative clearance is unusual and suggests exceptional metabolic stability, making Ligand B superior.

**13. t1/2:** Ligand A (0.404) has a very short in vitro half-life. Ligand B (-6.736) has a very long in vitro half-life. Ligand B is much better.

**14. Pgp:** Both ligands have very low P-gp efflux liability (0.098 and 0.021), which is good for CNS penetration.

**15. Binding Affinity:** Both ligands have very similar and strong binding affinities (-8.6 and -8.8 kcal/mol). The difference is negligible.

**Overall Assessment:**

Considering the GPCR-specific priorities, Ligand B is significantly better. It has a more favorable logP, lower DILI risk, dramatically better metabolic stability (negative Cl_mic), and a much longer half-life. While Ligand A has slightly better BBB penetration, the other advantages of Ligand B outweigh this. The poor Caco-2 and solubility are concerns for both, but can be addressed with formulation strategies.



Output:
1
2025-04-17 08:29:45,499 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (347.463 and 349.387 Da) fall comfortably within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (100.35) is slightly better than Ligand B (106.08) as both are below the 140 A^2 threshold for oral absorption, but closer to the 90 A^2 target for CNS penetration.

**3. logP:** Ligand A (1.285) is better than Ligand B (0.622). Both are within the optimal 1-3 range, but Ligand B is getting closer to the lower limit which could impact permeability.

**4. H-Bond Donors:** Ligand A (3) is higher than Ligand B (1). While both are acceptable (<=5), lower is generally preferred for better permeability.

**5. H-Bond Acceptors:** Ligand A (4) is lower than Ligand B (5). Both are within the acceptable range (<=10).

**6. QED:** Both ligands have similar QED values (0.764 and 0.727), indicating good drug-like properties.

**7. DILI:** Ligand A (21.946) has a significantly lower DILI risk than Ligand B (33.579). This is a major advantage for Ligand A.

**8. BBB:** Both ligands have similar BBB penetration (64.831 and 63.784). While not ideal (>70), they are comparable.

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.14 and -5.07). This is unusual and suggests poor permeability. However, these values are on a scale where negative values are possible and don't necessarily preclude development.

**10. Aqueous Solubility:** Both ligands have negative solubility values (-1.882 and -2.005), indicating poor aqueous solubility. This could be a formulation challenge.

**11. hERG Inhibition:** Both ligands show low hERG inhibition liability (0.395 and 0.24), which is good.

**12. Microsomal Clearance:** Ligand A (-45.048) has a much lower (better) microsomal clearance than Ligand B (-6.313), indicating greater metabolic stability.

**13. In vitro Half-Life:** Ligand A (21.628) has a longer half-life than Ligand B (27.693).

**14. P-gp Efflux:** Both ligands show low P-gp efflux liability (0.007 and 0.023), which is favorable for CNS exposure.

**15. Binding Affinity:** Ligand A (-8.7 kcal/mol) has a significantly stronger binding affinity than Ligand B (-7.3 kcal/mol). This >1.5 kcal/mol difference is substantial and can outweigh minor ADME drawbacks.

**Overall Assessment:**

Ligand A is the superior candidate. It has a significantly better binding affinity, lower DILI risk, and improved metabolic stability (lower Cl_mic, longer t1/2). While both have poor solubility and permeability (indicated by negative Caco-2 and solubility values), the strong affinity of Ligand A, combined with its improved safety profile, makes it more likely to be a viable drug candidate.

Output:
1
2025-04-17 08:29:45,499 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B against the provided guidelines, keeping in mind DRD2 is a CNS-relevant GPCR, so BBB, logP, Pgp, TPSA, and affinity are paramount.

**Molecular Weight:** Both ligands (347.415 and 346.471 Da) fall comfortably within the ideal 200-500 Da range.

**TPSA:** Ligand A (78.95) is better than Ligand B (62.55) as it is closer to the <90 target for CNS penetration.

**logP:** Ligand B (3.638) is higher than Ligand A (0.761). While 0.761 is low and could hinder permeation, 3.638 is approaching the upper limit and could cause solubility issues.

**H-Bond Donors/Acceptors:** Both have 1 HBD, which is good. Ligand A has 4 HBA, and Ligand B has 3. Both are within the acceptable range of <=10.

**QED:** Ligand A (0.745) has a slightly better QED score than Ligand B (0.52), indicating a more drug-like profile.

**DILI:** Ligand A (40.054) has a slightly higher DILI risk than Ligand B (28.306), but both are below the 40 threshold and considered good.

**BBB:** Ligand A (61.923) is better than Ligand B (53.587), but both are below the desirable >70 for CNS targets.

**Caco-2:** Ligand A (-4.429) and Ligand B (-4.623) are both poor, indicating poor intestinal absorption.

**Solubility:** Ligand A (-1.938) is better than Ligand B (-2.776), indicating better aqueous solubility.

**hERG:** Both ligands have very low hERG risk (0.233 and 0.348, respectively).

**Microsomal Clearance:** Ligand B (82.646) has significantly higher microsomal clearance than Ligand A (24.14), suggesting lower metabolic stability.

**In vitro Half-Life:** Ligand B (73.899) has a significantly longer half-life than Ligand A (-38.901), which is a major advantage.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.025 and 0.177, respectively).

**Binding Affinity:** Both ligands have the same binding affinity (-7.5 kcal/mol), which is excellent.

**Overall Assessment:**

Given the GPCR-specific priorities, BBB is critical. While neither ligand achieves >70, Ligand A is better. TPSA is also important, and Ligand A is better. Ligand B has a better half-life, but a significantly higher clearance. The logP of Ligand B is a concern. Ligand A's slightly better QED and solubility are also beneficial. The equal binding affinities mean that ADME properties become the deciding factor. Considering all factors, Ligand A is the more promising candidate.

Output:
0
2025-04-17 08:29:45,500 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B based on the provided guidelines, prioritizing GPCR-specific properties (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (340.427 Da) is slightly lower, which could be beneficial for permeability.

**TPSA:** Ligand A (68.44) is significantly better than Ligand B (83.98). For CNS targets, we want TPSA <= 90, and A is closer to the ideal <=60.

**logP:** Both ligands have acceptable logP values (A: 1.449, B: 2.721), falling within the 1-3 range. B is slightly higher, which could potentially lead to off-target effects, but is still reasonable.

**H-Bond Donors/Acceptors:** Both have 2 HBDs, which is good. Ligand A has 3 HBAs, while Ligand B has 6. Lower HBA is generally preferred for BBB penetration.

**QED:** Ligand A (0.889) has a substantially better QED score than Ligand B (0.596), indicating a more drug-like profile.

**DILI:** Ligand A (36.448) has a significantly lower DILI risk than Ligand B (72.005). This is a major advantage for A.

**BBB:** Ligand A (63.784) is below the desirable threshold of >70 for CNS targets, but is still reasonable. Ligand B (73.827) is better, exceeding the 70% threshold.

**Caco-2 Permeability:** Both have negative Caco-2 values (-5.08 and -5.074), which is unusual and suggests poor permeability. This is a significant concern for both.

**Aqueous Solubility:** Both have negative solubility values (-2.767 and -3.144), indicating very poor aqueous solubility. This is a major drawback for both.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.612 and 0.651).

**Microsomal Clearance:** Ligand A (-18.611) has a much lower (better) microsomal clearance than Ligand B (49.37), indicating greater metabolic stability.

**In vitro Half-Life:** Ligand B (61.234) has a significantly longer in vitro half-life than Ligand A (-0.239). This is a major advantage for B.

**P-gp Efflux:** Ligand A (0.068) has a much lower P-gp efflux liability than Ligand B (0.316), which is crucial for CNS penetration.

**Binding Affinity:** Ligand A (-9.3 kcal/mol) has a substantially stronger binding affinity than Ligand B (-0.0 kcal/mol). This is the most important factor, and the difference is very large.

**Overall Assessment:**

Despite the poor Caco-2 and solubility for both, Ligand A is the far superior candidate. Its significantly better binding affinity (-9.3 vs -0.0 kcal/mol) outweighs the concerns about permeability and solubility. The lower DILI risk, better QED, lower P-gp efflux, and better metabolic stability also contribute to its superiority. While Ligand B has a better BBB and half-life, these are less critical given the substantial affinity difference. The TPSA is also much better for Ligand A.



Output:
0
2025-04-17 08:29:45,500 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (357.5 and 354.5 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (93.11) is better than Ligand B (98.82). Both are below the 140 threshold for oral absorption and reasonably close to the 90 threshold for CNS targets, but A is preferable.

**3. logP:** Ligand A (0.061) is very low, potentially hindering permeability. Ligand B (-0.269) is also low, but slightly better. Both are below the optimal 1-3 range.

**4. H-Bond Donors:** Ligand A (3) is slightly higher than Ligand B (2), but both are within the acceptable limit of 5.

**5. H-Bond Acceptors:** Ligand A (5) is slightly higher than Ligand B (4), but both are within the acceptable limit of 10.

**6. QED:** Both ligands have good QED scores (0.571 and 0.615), indicating good drug-like properties.

**7. DILI:** Ligand A (9.771) has a significantly lower DILI risk than Ligand B (26.638). This is a major advantage for Ligand A.

**8. BBB:** Ligand B (45.328) has a much higher BBB penetration percentile than Ligand A (12.99). This is a critical factor for a CNS target like DRD2, and strongly favors Ligand B.

**9. Caco-2:** Ligand A (-5.289) and Ligand B (-4.873) both have negative Caco-2 values, which is unusual and suggests poor permeability.

**10. Solubility:** Ligand A (-0.465) and Ligand B (-1.459) both have negative solubility values, which is also unusual and suggests poor aqueous solubility.

**11. hERG:** Both ligands have very low hERG inhibition risk (0.353 and 0.034).

**12. Cl_mic:** Ligand A (19.599) has lower microsomal clearance than Ligand B (29.434), indicating better metabolic stability.

**13. t1/2:** Ligand A (14.65) has a positive in vitro half-life, while Ligand B (-18.77) has a negative value, which is not physically meaningful. This is a significant advantage for Ligand A.

**14. Pgp:** Both ligands have very low P-gp efflux liability (0.016 and 0.004).

**15. Binding Affinity:** Ligand B (-7.5) has a significantly stronger binding affinity than Ligand A (0.0). This is a substantial advantage for Ligand B.

**Overall Assessment:**

Ligand B excels in BBB penetration and binding affinity, which are paramount for a CNS GPCR target. However, it has a higher DILI risk. Ligand A has better metabolic stability, a much lower DILI risk, and a reasonable half-life, but suffers from very poor predicted permeability (low logP, negative Caco-2) and a weak binding affinity.

Despite the low logP values for both, the significantly stronger binding affinity of Ligand B and its much better BBB penetration outweigh the higher DILI risk, especially considering that DILI risk can be further mitigated through structural modifications. The poor affinity of Ligand A makes it unlikely to be a viable starting point, even with its favorable safety profile.

Output:
1
2025-04-17 08:29:45,500 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (361.433 and 344.499 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (92.5) is slightly above the preferred <90 for CNS targets, but still reasonable. Ligand B (58.2) is excellent, well below 90.

**logP:** Ligand A (1.677) is within the optimal 1-3 range. Ligand B (3.762) is at the higher end of optimal, but still acceptable.

**H-Bond Donors/Acceptors:** Both ligands have 2 HBD and 3/2 HBA, respectively, which are within acceptable limits.

**QED:** Both ligands have good QED scores (0.654 and 0.754), indicating drug-like properties.

**DILI:** Ligand A (14.889) has a much lower DILI risk than Ligand B (33.23), which is a significant advantage.

**BBB:** Ligand A (87.127) has a better BBB penetration percentile than Ligand B (73.517), crucial for a CNS target like DRD2.

**Caco-2 Permeability:** Ligand A (-5.323) has poor Caco-2 permeability, while Ligand B (-4.561) is slightly better but still not great.

**Aqueous Solubility:** Ligand A (-2.044) has slightly better solubility than Ligand B (-4.6).

**hERG:** Both ligands have low hERG inhibition liability (0.389 and 0.625).

**Microsomal Clearance:** Ligand A (-11.371) has significantly lower microsomal clearance, suggesting better metabolic stability, than Ligand B (88.554).

**In vitro Half-Life:** Ligand A (-21.342) has a longer in vitro half-life than Ligand B (9.155), which is desirable.

**P-gp Efflux:** Ligand A (0.026) has much lower P-gp efflux liability than Ligand B (0.582), which is highly favorable for CNS penetration.

**Binding Affinity:** Ligand B (-9.5 kcal/mol) has a slightly better binding affinity than Ligand A (-8.2 kcal/mol). However, the difference is not substantial enough to outweigh the other significant advantages of Ligand A.

**Overall:**

Ligand A demonstrates a superior ADMET profile, particularly regarding BBB penetration, DILI risk, metabolic stability, and P-gp efflux. While Ligand B has a slightly better binding affinity, Ligand A's improved pharmacokinetic properties, especially for a CNS target, make it the more promising drug candidate. The difference in binding affinity (1.3 kcal/mol) is unlikely to overcome the substantial benefits of Ligand A's ADME profile.

Output:
0
2025-04-17 08:29:45,500 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (344.459 Da and 370.559 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (82.26) is better than Ligand B (67.43), both are below the 90 A^2 threshold for CNS targets.

**3. logP:** Both ligands have good logP values (1.838 and 2.878, respectively), falling within the optimal 1-3 range. Ligand B is slightly better.

**4. H-Bond Donors:** Ligand A has 4 HBD, and Ligand B has 2. Both are within the acceptable limit of <=5.

**5. H-Bond Acceptors:** Ligand A has 3 HBA, and Ligand B has 4. Both are within the acceptable limit of <=10.

**6. QED:** Both ligands have similar QED values (0.658 and 0.62), indicating good drug-likeness.

**7. DILI:** Ligand A (35.052) has a significantly lower DILI risk than Ligand B (21.908). This is a substantial advantage for Ligand A.

**8. BBB:** Both ligands have good BBB penetration (62.389% and 68.36%), but Ligand B is slightly better. A value >70 is desirable, but both are acceptable.

**9. Caco-2 Permeability:** Ligand A (-5.509) has worse Caco-2 permeability than Ligand B (-4.958).

**10. Aqueous Solubility:** Both ligands have poor aqueous solubility (-2.08 and -3.28). This could be a formulation challenge, but is not a dealbreaker.

**11. hERG Inhibition:** Ligand A (0.23) has a lower hERG inhibition liability than Ligand B (0.434), indicating a lower risk of cardiotoxicity.

**12. Microsomal Clearance:** Ligand A (-0.285) has a lower microsomal clearance than Ligand B (68.256), suggesting better metabolic stability.

**13. In vitro Half-Life:** Ligand A (8.484) has a shorter in vitro half-life than Ligand B (9.433).

**14. P-gp Efflux:** Ligand A (0.041) has lower P-gp efflux liability than Ligand B (0.238). This is a significant advantage for CNS penetration.

**15. Binding Affinity:** Ligand A (-9.9 kcal/mol) has a significantly stronger binding affinity than Ligand B (-7.0 kcal/mol). This is a >1.5 kcal/mol difference, which can outweigh minor ADME drawbacks.

**Overall Assessment:**

Ligand A is the superior candidate. While Ligand B has slightly better BBB penetration and Caco-2 permeability, Ligand A excels in crucial areas: significantly stronger binding affinity, lower DILI risk, lower hERG inhibition, lower P-gp efflux, and better metabolic stability. The strong binding affinity of Ligand A is a major advantage, and the improved safety profile (lower DILI and hERG) is highly desirable. The lower P-gp efflux will also contribute to better CNS exposure.

Output:
1
2025-04-17 08:29:45,500 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (362.455 and 354.447 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (106.34) is slightly higher than Ligand B (99.1). Both are below the 140 threshold for oral absorption and reasonably close to the 90 threshold for CNS targets, but Ligand B is better.

**3. logP:** Ligand A (1.606) is within the optimal range (1-3). Ligand B (0.354) is a bit low, potentially hindering permeation.

**4. H-Bond Donors:** Both ligands have 3 HBD, which is acceptable.

**5. H-Bond Acceptors:** Ligand A has 6 HBA, and Ligand B has 5. Both are within the acceptable limit of 10.

**6. QED:** Both ligands have reasonable QED values (0.661 and 0.584), indicating good drug-like properties.

**7. DILI:** Ligand A (54.285) has a lower DILI risk than Ligand B (16.014), which is a significant advantage.

**8. BBB:** Ligand A (41.722) has a slightly better BBB penetration percentile than Ligand B (33.23), although both are below the desirable >70 for CNS targets.

**9. Caco-2 Permeability:** Ligand A (-5.489) has worse Caco-2 permeability than Ligand B (-5.064).

**10. Aqueous Solubility:** Ligand A (-2.4) has better aqueous solubility than Ligand B (-0.994).

**11. hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.178 and 0.175).

**12. Microsomal Clearance:** Ligand A (13.916) has lower microsomal clearance than Ligand B (17.331), suggesting better metabolic stability.

**13. In vitro Half-Life:** Ligand A (-15.154) has a significantly longer in vitro half-life than Ligand B (7.456), which is a major advantage.

**14. P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.051 and 0.058).

**15. Binding Affinity:** Ligand A (-8.5 kcal/mol) has a significantly stronger binding affinity than Ligand B (0.0 kcal/mol). This is a crucial factor.

**Overall Assessment:**

Ligand A is the stronger candidate. While its BBB penetration isn't ideal, its significantly superior binding affinity (-8.5 vs 0.0 kcal/mol) outweighs the slightly lower BBB and Caco-2 permeability. The better DILI profile, lower clearance, and longer half-life also contribute to its favorability. Ligand B's lower logP is a concern for CNS penetration. The large difference in binding affinity is the deciding factor.

Output:
1
2025-04-17 08:29:45,501 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (348.443 and 382.51 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (89.87) is excellent, falling below the 90 A^2 threshold for CNS targets. Ligand B (49.41) is also very good.

**3. logP:** Ligand A (1.681) is within the optimal 1-3 range. Ligand B (4.509) is slightly high, potentially leading to solubility issues or off-target interactions, but still within a reasonable range.

**4. H-Bond Donors:** Ligand A (3) and Ligand B (1) both meet the <=5 criteria.

**5. H-Bond Acceptors:** Both Ligand A (4) and Ligand B (4) are well below the 10 threshold.

**6. QED:** Both ligands have similar and acceptable QED values (0.755 and 0.763, respectively).

**7. DILI:** Ligand A (24.312) has a lower DILI risk than Ligand B (20.396), suggesting better hepatotoxicity potential.

**8. BBB:** This is a critical parameter for a CNS target like DRD2. Ligand B (86.623) has a significantly higher BBB penetration percentile than Ligand A (43.389). This is a major advantage for Ligand B.

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 values, which is unusual and suggests poor permeability. However, these values are on a log scale, so the magnitude is important. Ligand A (-4.75) is slightly better than Ligand B (-4.908).

**10. Aqueous Solubility:** Both ligands have negative solubility values, indicating poor aqueous solubility. Ligand A (-2.163) is slightly better than Ligand B (-3.71).

**11. hERG Inhibition:** Both ligands have low hERG inhibition risk (0.317 and 0.637, respectively).

**12. Microsomal Clearance:** Ligand A (9.043) has a lower microsomal clearance than Ligand B (55.76), indicating better metabolic stability.

**13. In vitro Half-Life:** Ligand B (17.095) has a longer in vitro half-life than Ligand A (6.724), which is desirable.

**14. P-gp Efflux:** Ligand A (0.06) has a much lower P-gp efflux liability than Ligand B (0.375), which is beneficial for CNS exposure.

**15. Binding Affinity:** Ligand A (-8.2 kcal/mol) has a significantly stronger binding affinity than Ligand B (-6.8 kcal/mol). This is a substantial advantage, potentially outweighing some ADME drawbacks.

**Overall Assessment:**

While Ligand B has a much better BBB penetration and longer half-life, Ligand A's significantly stronger binding affinity (-8.2 vs -6.8 kcal/mol) is a crucial advantage for a GPCR target. The difference of 1.4 kcal/mol is substantial. Additionally, Ligand A has better DILI, Caco-2 permeability, solubility, and P-gp efflux. The slightly higher logP of Ligand B is a concern, but the superior affinity of Ligand A, combined with better ADME properties, makes it the more promising candidate.

Output:
0
2025-04-17 08:29:45,501 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (363.845 and 369.795 Da) fall comfortably within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (77.25) is higher than Ligand B (49.77). For a CNS target like DRD2, TPSA < 90 is preferred, so both are acceptable, but B is significantly better.

**3. logP:** Both ligands have a logP around 4.23, which is slightly above the optimal 1-3 range. This could potentially lead to solubility issues or off-target effects, but is not a dealbreaker.

**4. H-Bond Donors:** Both have 1 HBD, which is within the acceptable limit of <=5.

**5. H-Bond Acceptors:** Ligand A has 5 HBA, and Ligand B has 3. Both are below the acceptable limit of <=10.

**6. QED:** Both ligands have QED values > 0.8, indicating good drug-like properties.

**7. DILI:** Ligand A (70.066) has a higher DILI risk than Ligand B (37.611). Lower DILI is preferred, giving B an advantage.

**8. BBB:** This is a critical parameter for CNS targets. Ligand A has a BBB percentile of 82.745, while Ligand B has 46.879. Ligand A is significantly better here, exceeding the >70 desirable threshold.

**9. Caco-2 Permeability:** Both have negative Caco-2 values (-4.331 and -4.613), which is unusual and suggests poor permeability. This is a concern for both.

**10. Aqueous Solubility:** Both ligands have very poor aqueous solubility (-5.344 and -4.544). This is a significant drawback.

**11. hERG Inhibition:** Ligand A (0.207) has a lower hERG risk than Ligand B (0.885), which is preferable.

**12. Microsomal Clearance:** Ligand B (79.66) has higher microsomal clearance than Ligand A (70.377), indicating lower metabolic stability. A is better here.

**13. In vitro Half-Life:** Ligand A (11.414 hours) has a shorter half-life than Ligand B (22.893 hours). B is preferable.

**14. P-gp Efflux:** Ligand A (0.082) has lower P-gp efflux than Ligand B (0.339), which is better for CNS exposure.

**15. Binding Affinity:** Ligand A (-9.5 kcal/mol) has a significantly stronger binding affinity than Ligand B (-7.7 kcal/mol). This is a substantial advantage, potentially outweighing some of the ADME drawbacks.

**Overall Assessment:**

Ligand A has a superior binding affinity and better BBB penetration, lower P-gp efflux, and lower DILI risk, and better metabolic stability. However, it has poorer solubility and Caco-2 permeability. Ligand B has better TPSA, a longer half-life, and lower DILI risk, but significantly weaker binding affinity and poorer BBB penetration.

Given the importance of strong binding affinity and BBB penetration for a CNS GPCR target like DRD2, and the fact that the affinity difference is substantial (>1.5 kcal/mol), **Ligand A is the more promising candidate**, despite its solubility concerns. Solubility can potentially be addressed through formulation strategies.

Output:
0
2025-04-17 08:29:45,501 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (348.403 and 347.394 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (123.41) is slightly above the optimal <90 for CNS targets, but still reasonable. Ligand B (84.04) is excellent, well below 90. This favors Ligand B.

**3. logP:** Ligand A (0.117) is quite low, potentially hindering membrane permeability. Ligand B (1.548) is within the optimal 1-3 range. This is a significant advantage for Ligand B.

**4. H-Bond Donors:** Ligand A (3) is acceptable. Ligand B (0) is also good, potentially improving permeability.

**5. H-Bond Acceptors:** Both ligands (A: 5, B: 6) are within the acceptable limit of 10.

**6. QED:** Both ligands have good QED scores (A: 0.585, B: 0.825), indicating drug-like properties. Ligand B is better.

**7. DILI:** Ligand A (39.201) has a lower DILI risk than Ligand B (51.221), which is favorable.

**8. BBB:** Ligand A (64.754) has a moderate BBB penetration, while Ligand B (90.655) is excellent, exceeding the desirable >70 threshold for CNS targets. This is a strong advantage for Ligand B.

**9. Caco-2:** Both have negative Caco-2 values which is unusual and likely indicates poor permeability.

**10. Solubility:** Both ligands have negative solubility values, which is also unusual and indicates poor solubility.

**11. hERG:** Both ligands have very low hERG inhibition risk (A: 0.039, B: 0.211).

**12. Cl_mic:** Ligand A (-3.037) has a negative clearance, which is not physically possible and suggests an issue with the data. Ligand B (4.09) is a more reasonable value, indicating faster metabolism.

**13. t1/2:** Ligand B (9.78) has a longer in vitro half-life than Ligand A (5.113), which is desirable.

**14. Pgp:** Both ligands have low P-gp efflux liability (A: 0.01, B: 0.083).

**15. Binding Affinity:** Both ligands have the same binding affinity (-7.8 kcal/mol), which is excellent.

**Overall Assessment:**

Despite Ligand A having a slightly lower DILI risk, Ligand B is the superior candidate. Its significantly better logP, TPSA, and BBB penetration are crucial for a CNS-targeting GPCR like DRD2. The longer half-life and more reasonable metabolic clearance also contribute to its favorability. The negative values for Caco-2 and solubility are concerning for both, but the other advantages of Ligand B outweigh this issue. The negative clearance for Ligand A is a red flag.

Output:
1
2025-04-17 08:29:45,501 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (335.455 and 361.873 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (37.19) is significantly better than Ligand B (53.51). For CNS targets, we want TPSA <= 90, and ideally closer to 60. Ligand A is much closer to this ideal.

**3. logP:** Both ligands have good logP values (3.201 and 3.154), falling within the optimal 1-3 range.

**4. H-Bond Donors:** Both have 0 HBD, which is acceptable.

**5. H-Bond Acceptors:** Ligand A has 5 HBA, and Ligand B has 3. Both are within the acceptable limit of <= 10.

**6. QED:** Both ligands have similar, good QED values (0.717 and 0.757), indicating good drug-like properties.

**7. DILI:** Ligand A (46.375) has a slightly higher DILI risk than Ligand B (39.162), but both are below the concerning threshold of 60.

**8. BBB:** Ligand A (92.71) has a significantly better BBB penetration percentile than Ligand B (82.125). For a CNS target like DRD2, >70 is desirable, and Ligand A is closer to this.

**9. Caco-2 Permeability:** Ligand A (-5.068) has a worse Caco-2 permeability than Ligand B (-4.531). However, the scale is not clear, so this is less informative.

**10. Aqueous Solubility:** Ligand A (-2.699) has worse aqueous solubility than Ligand B (-3.037). Again, the scale is not clear, but lower values are generally worse.

**11. hERG Inhibition:** Ligand A (0.947) has a slightly higher hERG inhibition risk than Ligand B (0.278). Lower is better here.

**12. Microsomal Clearance:** Ligand B (57.068) has a higher microsomal clearance than Ligand A (44.947), meaning it is less metabolically stable. Lower clearance is preferred.

**13. In vitro Half-Life:** Ligand A (3.771) has a longer in vitro half-life than Ligand B (-6.755). This is a significant advantage.

**14. P-gp Efflux:** Ligand A (0.786) has a higher P-gp efflux liability than Ligand B (0.124). Lower is better for CNS exposure.

**15. Binding Affinity:** Ligand A (-8.7 kcal/mol) has a slightly better binding affinity than Ligand B (-8.1 kcal/mol). While both are excellent, the 0.6 kcal/mol difference is meaningful.

**Overall Assessment:**

Considering the GPCR-specific priorities, Ligand A is the better candidate. Its superior BBB penetration, longer half-life, and slightly better binding affinity outweigh its slightly higher DILI and P-gp efflux. The TPSA is also significantly better for CNS penetration. While Ligand B has a slightly better hERG profile and lower DILI, the CNS-related properties of Ligand A are more critical for a DRD2 target.

Output:
1
2025-04-17 08:29:45,502 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 drug candidates, considering the provided guidelines and GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (367.471 and 361.551 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (97.39) is borderline, but acceptable for a CNS target, while Ligand B (25.61) is excellent, well below the 90 threshold. This favors Ligand B.

**logP:** Ligand A (2.044) is optimal. Ligand B (4.832) is high, potentially leading to solubility issues and off-target effects, although not drastically so. This favors Ligand A.

**H-Bond Donors/Acceptors:** Ligand A has 2 HBD and 5 HBA, which are within acceptable limits. Ligand B has 0 HBD and 4 HBA, also acceptable.

**QED:** Ligand A (0.849) has a very good drug-likeness score, while Ligand B (0.465) is lower, suggesting a less favorable overall profile. This strongly favors Ligand A.

**DILI:** Ligand A (56.921) has a moderate DILI risk, while Ligand B (16.092) has a very low risk. This favors Ligand B.

**BBB:** Ligand A (71.035) has a good BBB penetration percentile, while Ligand B (88.174) is excellent. This strongly favors Ligand B, as CNS penetration is crucial for DRD2 targeting.

**Caco-2 Permeability:** Ligand A (-4.817) and Ligand B (-5.422) both have negative values, indicating poor permeability. This is a concern for both, but the difference is minimal.

**Aqueous Solubility:** Both ligands have very poor aqueous solubility (-2.943 and -4.256). This is a significant drawback for both.

**hERG Inhibition:** Ligand A (0.216) has a very low hERG risk, while Ligand B (0.919) has a slightly elevated risk. This favors Ligand A.

**Microsomal Clearance:** Ligand A (54.041) and Ligand B (59.398) have similar moderate clearance values.

**In vitro Half-Life:** Ligand A (-39.207) has a very short half-life, while Ligand B (78.276) has a long half-life. This strongly favors Ligand B.

**P-gp Efflux:** Ligand A (0.043) has very low P-gp efflux, which is excellent for CNS penetration. Ligand B (0.834) has moderate P-gp efflux. This strongly favors Ligand A.

**Binding Affinity:** Ligand A (-8.4 kcal/mol) has a significantly stronger binding affinity than Ligand B (-7.8 kcal/mol). This is a major advantage for Ligand A, potentially outweighing some of its ADME drawbacks.

**Overall Assessment:**

Ligand B excels in BBB penetration, Pgp efflux, and in vitro half-life, which are critical for CNS GPCR targets. However, it suffers from a higher logP, lower QED, and a slightly higher hERG risk. Ligand A, on the other hand, has a superior binding affinity, excellent P-gp efflux, low hERG risk, and a better QED score. While its BBB is lower than Ligand B, it is still acceptable. The significantly stronger binding affinity of Ligand A, combined with its better drug-like properties and safety profile, makes it the more promising candidate despite its solubility and permeability concerns.

Output:
0
2025-04-17 08:29:45,502 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (341.411 and 347.419 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (78.34) is significantly better than Ligand B (105.98). For CNS targets, we want TPSA <= 90, and A is comfortably within that range, while B is pushing the limit.

**logP:** Ligand A (2.617) is optimal (1-3). Ligand B (0.523) is a bit low, potentially hindering permeability.

**H-Bond Donors:** Both have 2 HBD, which is acceptable.

**H-Bond Acceptors:** Ligand A has 3 HBA, and Ligand B has 6. Both are within the acceptable limit of <=10, but A is preferable.

**QED:** Ligand A (0.897) is excellent, indicating high drug-likeness. Ligand B (0.6) is still acceptable, but less favorable.

**DILI:** Both ligands have acceptable DILI risk (39.899 and 47.693, both < 40).

**BBB:** Both ligands have similar BBB penetration (48.003 and 46.336). While neither is *high* (>70), they are comparable and not a major differentiating factor.

**Caco-2 Permeability:** Both have negative Caco-2 values (-5.093 and -5.432). This is unusual and suggests poor permeability in this *in vitro* assay. However, the absolute values are similar.

**Aqueous Solubility:** Both have negative solubility values (-3.317 and -1.5). This is also unusual, and suggests poor aqueous solubility. Ligand B is slightly better.

**hERG Inhibition:** Both have very low hERG risk (0.378 and 0.017).

**Microsomal Clearance:** Ligand A (20.364) has slightly higher clearance than Ligand B (16.582), meaning B is more metabolically stable.

**In vitro Half-Life:** Ligand A (15.972 hours) has a positive half-life, while Ligand B (-17.141 hours) has a negative half-life. This is a significant difference, indicating that Ligand A is more stable *in vitro*.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.037 and 0.033).

**Binding Affinity:** Both ligands have very similar and excellent binding affinities (-8.3 and -8.0 kcal/mol). The difference is less than 0.3 kcal/mol, so it's not a major deciding factor.

**Overall Assessment:**

Ligand A is superior due to its lower TPSA, optimal logP, higher QED, and positive *in vitro* half-life. While both have issues with Caco-2 and solubility, A's other properties are more favorable for a CNS-targeting GPCR ligand. Ligand B's lower logP and negative half-life are concerning.

Output:
1
2025-04-17 08:29:45,502 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (355.434 and 359.817 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (37.38) is significantly better than Ligand B (81.07). For CNS targets, we want TPSA <= 90, and ideally closer to 60. Ligand A is well within this range, while Ligand B is approaching the upper limit and could present permeability challenges.

**logP:** Ligand A (4.256) is slightly higher than the optimal 1-3 range, but still potentially acceptable. Ligand B (2.995) is within the optimal range. However, for a GPCR, a slightly higher logP isn't necessarily detrimental if other properties are favorable.

**H-Bond Donors/Acceptors:** Ligand A (0 HBD, 2 HBA) is more favorable than Ligand B (2 HBD, 5 HBA). Lower numbers are generally preferred for better permeability.

**QED:** Both ligands have similar, acceptable QED values (0.701 and 0.733, both > 0.5).

**DILI:** Both ligands have high DILI risk (77.627 and 87.631), which is a concern. However, this is often a later-stage optimization parameter.

**BBB:** Ligand A (83.133) has a significantly better BBB percentile than Ligand B (70.182). This is a *critical* factor for a CNS target like DRD2.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.988 and -4.882), which is unusual and suggests poor permeability. This is concerning, but could be an artifact of the prediction method.

**Aqueous Solubility:** Both ligands have very poor predicted aqueous solubility (-5.508 and -4.485). This is a significant drawback.

**hERG Inhibition:** Both ligands show low hERG inhibition risk (0.936 and 0.589).

**Microsomal Clearance:** Ligand B (76.012) has a higher microsomal clearance than Ligand A (63.527), indicating faster metabolism and potentially lower *in vivo* exposure.

**In vitro Half-Life:** Ligand A (-30.692) has a much longer predicted half-life than Ligand B (61.918). This is a substantial advantage.

**P-gp Efflux:** Ligand A (0.436) has lower P-gp efflux than Ligand B (0.342), which is beneficial for CNS penetration.

**Binding Affinity:** Ligand A (-11.3 kcal/mol) has a significantly stronger binding affinity than Ligand B (-9.1 kcal/mol). This is a major advantage, and a difference of 2.2 kcal/mol is substantial enough to potentially overcome some ADME liabilities.

**Overall Assessment:**

Ligand A is the better candidate. While both have poor solubility and DILI risk, Ligand A excels in the critical areas for a CNS GPCR target: BBB penetration, binding affinity, and P-gp efflux. Its lower TPSA and longer half-life also contribute to its favorability. The higher logP is less concerning given the strong affinity and BBB prediction. The negative Caco-2 values are a red flag, but the strong binding affinity suggests that the molecule is still effectively interacting with the target.



Output:
0
2025-04-17 08:29:45,502 - INFO - Batch 453 complete. Total preferences: 7248
2025-04-17 08:29:45,502 - INFO - Processing batch 454/512...
2025-04-17 08:30:25,364 - INFO - Reasoning:

Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (360.53 and 348.49 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (68.16) is slightly above the optimal <90 for CNS targets, but still reasonable. Ligand B (58.64) is excellent, well below 90.

**logP:** Ligand A (4.094) is at the upper end of the optimal range (1-3), potentially raising concerns about solubility and off-target effects. Ligand B (2.513) is ideal.

**H-Bond Donors/Acceptors:** Ligand A (2 HBD, 4 HBA) and Ligand B (1 HBD, 3 HBA) both have acceptable numbers of H-bond donors and acceptors.

**QED:** Both ligands have reasonable QED scores (0.849 and 0.769), indicating good drug-like properties.

**DILI:** Ligand A (35.673) has a slightly higher DILI risk than Ligand B (25.436), but both are below the 40 threshold, indicating low risk.

**BBB:** Ligand A (88.29) has a good BBB penetration percentile, while Ligand B (79.992) is also good, but less so. This is a critical factor for CNS targets like DRD2.

**Caco-2 Permeability:** Ligand A (-5.074) and Ligand B (-4.619) have negative values, which is unusual and suggests very poor permeability. This is a significant concern for both.

**Aqueous Solubility:** Both ligands have poor aqueous solubility (-4.169 and -2.403 respectively). This could pose formulation challenges.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.917 and 0.416).

**Microsomal Clearance:** Ligand A (17.764) has a lower microsomal clearance than Ligand B (75.839), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand B (-8.757) has a negative half-life, which is impossible and indicates an issue with the data. Ligand A (41.135) has a reasonable half-life.

**P-gp Efflux:** Ligand A (0.485) has lower P-gp efflux than Ligand B (0.26), which is favorable for CNS penetration.

**Binding Affinity:** Both ligands have the same binding affinity (-8.4 kcal/mol), which is excellent.

**Overall Assessment:**

While both ligands have excellent binding affinity, Ligand A is preferable due to its better BBB penetration (88.29 vs 79.992), lower P-gp efflux (0.485 vs 0.26), and more reasonable in vitro half-life (41.135 vs an impossible -8.757). The slightly higher logP of Ligand A is a concern, but the benefits in CNS penetration and metabolic stability outweigh this drawback. The poor Caco-2 permeability and solubility are concerns for both, but can potentially be addressed with formulation strategies.



Output:
1
2025-04-17 08:30:25,364 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (376.821 Da) is slightly higher than Ligand B (347.503 Da), but both are acceptable.

**TPSA:** Ligand A (78.38) is higher than Ligand B (52.65). For CNS targets, we ideally want TPSA <= 90. Both are under this threshold, but B is significantly better.

**logP:** Ligand A (3.417) is slightly higher than Ligand B (2.35). Both are within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A has 0 HBD and 7 HBA, while Ligand B has 1 HBD and 3 HBA. Both are within acceptable limits (<=5 HBD and <=10 HBA).

**QED:** Both ligands have similar QED values (0.635 and 0.593), indicating good drug-like properties.

**DILI:** Ligand A (90.617) has a significantly higher DILI risk than Ligand B (8.414). This is a major concern for Ligand A.

**BBB:** Ligand B (73.013) has a better BBB penetration percentile than Ligand A (64.599). While both are reasonably good, >70 is preferred for CNS targets, and B is closer.

**Caco-2 Permeability:** Ligand A (-4.479) has better Caco-2 permeability than Ligand B (-4.856), but both are negative values which is not ideal.

**Aqueous Solubility:** Ligand B (-1.704) has better aqueous solubility than Ligand A (-4.451).

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.213 and 0.473).

**Microsomal Clearance:** Ligand A (102.552) has higher microsomal clearance than Ligand B (11.826), suggesting lower metabolic stability.

**In vitro Half-Life:** Ligand B (-14.316) has a significantly longer in vitro half-life than Ligand A (7.111).

**P-gp Efflux:** Ligand A (0.407) has lower P-gp efflux liability than Ligand B (0.057), which is favorable for CNS penetration.

**Binding Affinity:** Both ligands have very similar and strong binding affinities (-8.9 and -8.3 kcal/mol). The difference of 0.6 kcal/mol is not substantial enough to override other significant differences.

**Overall Assessment:**

Ligand B is the more promising candidate. While Ligand A has slightly better Caco-2 permeability and P-gp efflux, its significantly higher DILI risk, lower BBB penetration, and poorer metabolic stability (higher Cl_mic, shorter t1/2) are major drawbacks. Ligand B's superior safety profile (DILI), better BBB penetration, and improved metabolic stability outweigh the minor advantages of Ligand A. The binding affinities are comparable. Considering the GPCR-specific priorities, Ligand B is the better choice.

Output:
1
2025-04-17 08:30:25,364 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B based on the provided guidelines, prioritizing GPCR-specific properties (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (363.845 and 359.491 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (56.07) is better than Ligand B (49.77) as it is closer to the ideal range of <90 for CNS targets.

**logP:** Both ligands have good logP values (2.674 and 3.76), falling within the optimal 1-3 range. Ligand B is slightly higher, which could potentially lead to off-target effects, but is not a major concern.

**H-Bond Donors/Acceptors:** Ligand A (0 HBD, 5 HBA) and Ligand B (1 HBD, 4 HBA) both have acceptable numbers of H-bond donors and acceptors, well below the thresholds of 5 and 10, respectively.

**QED:** Both ligands have reasonable QED values (0.841 and 0.694), indicating good drug-like properties.

**DILI:** Ligand A (64.599) has a higher DILI risk than Ligand B (44.436). This is a significant drawback for Ligand A.

**BBB:** Both ligands exhibit excellent BBB penetration (70.648 and 73.129), exceeding the desirable threshold of >70 for CNS targets. Ligand B is slightly better.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.697), which is unusual and indicates very poor permeability. This is a major issue for both compounds, but doesn't differentiate them.

**Aqueous Solubility:** Both ligands have negative solubility values (-2.075 and -4.348), indicating poor aqueous solubility. Ligand B is worse.

**hERG Inhibition:** Both ligands have low hERG inhibition liability (0.451 and 0.794), which is favorable.

**Microsomal Clearance:** Ligand A (32.952) has significantly lower microsomal clearance than Ligand B (107.153), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (57.084) has a shorter half-life than Ligand B (67.744), but both are reasonable.

**P-gp Efflux:** Ligand A (0.227) has much lower P-gp efflux liability than Ligand B (0.832), which is highly desirable for CNS penetration.

**Binding Affinity:** Ligand B (-7.1 kcal/mol) has a significantly stronger binding affinity than Ligand A (-8.9 kcal/mol). This is a substantial advantage, potentially outweighing some ADME drawbacks.

**Overall Assessment:**

While Ligand A has better metabolic stability (lower Cl_mic) and lower P-gp efflux, the significantly higher DILI risk and weaker binding affinity are major concerns. Ligand B, despite slightly higher logP and P-gp efflux, has a much lower DILI risk and a substantially stronger binding affinity. The affinity difference is >1.5 kcal/mol, which, as per the guidelines, can outweigh minor ADME concerns. The BBB penetration is excellent for both. The poor Caco-2 and solubility are concerning for both, but can potentially be addressed with formulation strategies.

Output:
1
2025-04-17 08:30:25,365 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B based on the provided guidelines, prioritizing GPCR-specific properties (BBB, logP, Pgp, TPSA, and affinity) for DRD2.

**Molecular Weight:** Both ligands (341.382 and 344.455 Da) fall comfortably within the ideal 200-500 Da range.

**TPSA:** Ligand A (55.4) is excellent, well below the 90 A^2 threshold for CNS targets. Ligand B (78.43) is still reasonable but less optimal.

**logP:** Ligand A (3.619) is at the higher end of the optimal range (1-3), but still acceptable. Ligand B (2.011) is lower, potentially impacting permeability.

**H-Bond Donors/Acceptors:** Ligand A (HBD=1, HBA=3) and Ligand B (HBD=3, HBA=3) both have acceptable numbers of hydrogen bond donors and acceptors.

**QED:** Ligand A (0.845) has a very good drug-likeness score. Ligand B (0.449) is below the 0.5 threshold, indicating a less favorable drug-like profile.

**DILI:** Ligand A (67.429) has a moderate DILI risk, while Ligand B (23.691) has a very low risk.

**BBB:** This is critical for a CNS target like DRD2. Ligand A (84.141) has a very good BBB penetration percentile. Ligand B (31.214) has poor predicted BBB penetration.

**Caco-2 Permeability:** Both have negative values, which is unusual. Assuming these are logP-scale values, lower values indicate poorer permeability. Both are poor, but Ligand A (-4.454) is slightly better than Ligand B (-4.692).

**Aqueous Solubility:** Both have negative values, indicating poor solubility. Ligand B (-2.411) is slightly better than Ligand A (-5.19).

**hERG:** Both ligands have low hERG risk (0.577 and 0.654).

**Microsomal Clearance:** Ligand A (73.849) has a higher clearance than Ligand B (-2.336). This suggests Ligand B is more metabolically stable.

**In vitro Half-Life:** Ligand A (-10.107) has a negative half-life, which is not possible. This is likely an error or outlier. Ligand B (15.486) has a reasonable half-life.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.242 and 0.215).

**Binding Affinity:** Ligand A (-8.8 kcal/mol) has a significantly stronger binding affinity than Ligand B (-7.8 kcal/mol). This 1.0 kcal/mol difference is substantial.

**Overall Assessment:**

Ligand A excels in key areas for a CNS-targeting GPCR: TPSA, BBB penetration, and, most importantly, binding affinity. While its DILI risk is moderate and solubility is poor, the strong binding affinity and good BBB penetration are likely to outweigh these drawbacks. The negative half-life is concerning, but could be an experimental error. Ligand B has a better safety profile (lower DILI) and metabolic stability, but its poor BBB penetration and significantly weaker binding affinity make it a less promising candidate.

Output:
1
2025-04-17 08:30:25,365 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (374.467 and 374.478 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (119.81) is slightly above the optimal <90 for CNS targets, but still reasonable. Ligand B (92.34) is well within the desired range. This favors Ligand B.

**3. logP:** Ligand A (-0.747) is a bit low, potentially hindering permeation. Ligand B (1.786) is within the optimal 1-3 range. This strongly favors Ligand B.

**4. H-Bond Donors:** Ligand A (3) is acceptable. Ligand B (2) is also acceptable.

**5. H-Bond Acceptors:** Ligand A (6) is acceptable. Ligand B (4) is also acceptable.

**6. QED:** Both ligands (0.515 and 0.5) have good drug-like profiles, being above 0.5.

**7. DILI:** Ligand A (37.611) has a lower DILI risk than Ligand B (57.348), which is preferable.

**8. BBB:** Ligand B (75.805) has a significantly better BBB penetration percentile than Ligand A (63.746). This is a critical advantage for a CNS target like DRD2.

**9. Caco-2 Permeability:** Both have negative values, indicating a scale rather than percentile. Ligand A (-5.503) is slightly better than Ligand B (-4.703).

**10. Aqueous Solubility:** Both have negative values, indicating a scale rather than percentile. Ligand A (-0.654) is slightly better than Ligand B (-2.54).

**11. hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.244 and 0.215).

**12. Microsomal Clearance:** Ligand A (-10.377) has much lower (better) microsomal clearance than Ligand B (30.955), indicating greater metabolic stability.

**13. In vitro Half-Life:** Ligand B (25.44) has a significantly longer half-life than Ligand A (-5.77). This is a significant advantage.

**14. P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.007 and 0.151).

**15. Binding Affinity:** Ligand B (-8.1 kcal/mol) has a significantly stronger binding affinity than Ligand A (-6.7 kcal/mol). This is a substantial advantage, potentially outweighing some ADME drawbacks.

**Overall Assessment:**

Ligand B is the stronger candidate. While Ligand A has a slightly better DILI score and solubility, Ligand B excels in the key GPCR-relevant properties: logP, BBB penetration, and, most importantly, binding affinity. The significantly stronger binding affinity (-8.1 vs -6.7 kcal/mol) is a major advantage. The longer half-life of Ligand B is also a positive. The TPSA is also better for Ligand B.

Output:
1
2025-04-17 08:30:25,365 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (344.459 and 336.435 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (67.23) is slightly higher than the ideal <90 for CNS targets, but still reasonable. Ligand B (49.41) is excellent, well below 90.

**3. logP:** Both ligands have good logP values (1.965 and 2.71), falling within the optimal 1-3 range.

**4. H-Bond Donors:** Both have 1 HBD, which is within the acceptable limit of <=5.

**5. H-Bond Acceptors:** Ligand A has 4 HBAs, and Ligand B has 2. Both are below the acceptable limit of <=10.

**6. QED:** Both ligands have high QED scores (0.831 and 0.841), indicating good drug-like properties.

**7. DILI:** Ligand A (15.2) has a much lower DILI risk than Ligand B (42.807). This is a significant advantage for Ligand A.

**8. BBB:** Ligand A (66.886) has a lower BBB penetration percentile than Ligand B (62.97), but both are below the desirable >70 for CNS targets.

**9. Caco-2 Permeability:** Ligand A (-4.834) has a lower Caco-2 permeability than Ligand B (-4.931). Both are poor.

**10. Aqueous Solubility:** Ligand A (-1.092) has better aqueous solubility than Ligand B (-3.83).

**11. hERG Inhibition:** Ligand A (0.17) has a lower hERG inhibition liability than Ligand B (0.313), which is preferable.

**12. Microsomal Clearance:** Ligand A (22.265) has a lower microsomal clearance than Ligand B (39.92), suggesting better metabolic stability.

**13. In vitro Half-Life:** Ligand A (-18.017) has a significantly longer in vitro half-life than Ligand B (-5.185).

**14. P-gp Efflux:** Ligand A (0.042) has much lower P-gp efflux liability than Ligand B (0.22), which is crucial for CNS penetration.

**15. Binding Affinity:** Ligand A (-8.7 kcal/mol) has a slightly better binding affinity than Ligand B (-8.1 kcal/mol). While the difference is not huge, it's a positive for Ligand A.

**Overall Assessment:**

Ligand A is the better candidate. While both have acceptable MW, logP, QED, and H-bond properties, Ligand A demonstrates significant advantages in key ADME-Tox parameters relevant for a CNS-targeting GPCR. Specifically, its lower DILI risk, lower P-gp efflux, lower microsomal clearance, longer half-life, and lower hERG inhibition are all highly desirable. The slightly better binding affinity further supports this conclusion. Ligand B's slightly better TPSA is outweighed by its poorer ADME profile.

Output:
1
2025-04-17 08:30:25,365 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B based on the provided guidelines, prioritizing GPCR-specific properties (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (393.227 Da) is slightly higher than Ligand B (348.487 Da), but both are acceptable.

**TPSA:** Ligand A (117.57) is borderline for CNS targets (<=90 is preferred) but still reasonable. Ligand B (58.64) is excellent, well below the 90 threshold. This favors Ligand B.

**logP:** Ligand A (1.32) is within the optimal range. Ligand B (3.352) is at the higher end of optimal, but still acceptable.

**H-Bond Donors/Acceptors:** Ligand A has 2 HBD and 5 HBA, which is good. Ligand B has 1 HBD and 3 HBA, also good.

**QED:** Both ligands have acceptable QED values (Ligand A: 0.392, Ligand B: 0.567). Ligand B is slightly better.

**DILI:** Ligand A (64.909) has a moderate DILI risk. Ligand B (21.093) has a very low DILI risk, a significant advantage.

**BBB:** Both ligands have excellent BBB penetration (Ligand A: 70.841, Ligand B: 70.609). This is crucial for a CNS target like DRD2, and they are comparable.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.301 and -5.121), which is unusual and suggests poor permeability. This is a concern for both.

**Aqueous Solubility:** Both ligands have negative solubility values (-3.002 and -3.141) which is also unusual and suggests very poor solubility. This is a concern for both.

**hERG Inhibition:** Both ligands have low hERG inhibition liability (Ligand A: 0.486, Ligand B: 0.309), which is good. Ligand B is slightly better.

**Microsomal Clearance:** Ligand A (-10.775) has a much lower (better) microsomal clearance than Ligand B (40.718), indicating greater metabolic stability. This is a significant advantage for Ligand A.

**In vitro Half-Life:** Ligand A (2.639) has a shorter half-life than Ligand B (-15.79), which is a disadvantage for Ligand A. Note the negative value for Ligand B is unusual.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (Ligand A: 0.099, Ligand B: 0.131), which is excellent for CNS penetration.

**Binding Affinity:** Both ligands have strong binding affinity (Ligand A: -8.0 kcal/mol, Ligand B: -8.8 kcal/mol). Ligand B is slightly more potent.

**Overall Assessment:**

Ligand B has several advantages: lower DILI risk, better TPSA, slightly better QED, slightly better affinity, and slightly better hERG inhibition. However, Ligand A has a significantly better microsomal clearance, suggesting improved metabolic stability and potentially a longer duration of action. The negative Caco-2 and solubility values are concerning for both, but the difference in clearance is substantial. Given the importance of metabolic stability for CNS drugs, and the relatively small difference in affinity, the improved clearance of Ligand A outweighs the other advantages of Ligand B.

Output:
0
2025-04-17 08:30:25,365 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B based on the provided guidelines, prioritizing GPCR-specific properties (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (340.43 & 348.45 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (76.02) is significantly better than Ligand B (97.12). For CNS targets, TPSA should be <= 90, and A is comfortably within that range, while B is approaching the upper limit.

**logP:** Both ligands have acceptable logP values (1.024 and 1.775, respectively), falling within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A (HBD=2, HBA=4) is preferable to Ligand B (HBD=3, HBA=8) as it has fewer hydrogen bond acceptors, which can improve permeability. Both are within acceptable limits.

**QED:** Both ligands have similar QED values (0.575 and 0.563), indicating good drug-likeness.

**DILI:** Ligand A (37.46%) has a much lower DILI risk than Ligand B (60.49%). This is a significant advantage for A.

**BBB:** Ligand B (75.11%) has a substantially better BBB penetration score than Ligand A (48.31%). This is a critical factor for a CNS target like DRD2.

**Caco-2 Permeability:** Both have negative Caco-2 values which is unusual and suggests a potential issue with the data. However, the magnitude of the negative value is similar.

**Aqueous Solubility:** Both ligands have negative solubility values which is also unusual and suggests a potential issue with the data. However, the magnitude of the negative value is similar.

**hERG:** Ligand A (0.086) has a much lower hERG inhibition liability than Ligand B (0.885), indicating a lower risk of cardiotoxicity.

**Microsomal Clearance:** Ligand A (6.104 mL/min/kg) has a significantly lower microsomal clearance than Ligand B (43.611 mL/min/kg), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand B (65.641 hours) has a much longer in vitro half-life than Ligand A (-7.355 hours). This is a major advantage for B.

**P-gp Efflux:** Ligand A (0.039) has a much lower P-gp efflux liability than Ligand B (0.18), which is beneficial for CNS penetration.

**Binding Affinity:** Ligand B (-7.4 kcal/mol) has a slightly better binding affinity than Ligand A (-8.2 kcal/mol). While A is better, the difference is relatively small.

**Overall Assessment:**

Ligand A excels in TPSA, DILI, hERG, microsomal clearance, and P-gp efflux. Ligand B shines in BBB penetration and in vitro half-life, and has slightly better binding affinity. Given the CNS target (DRD2), BBB penetration is paramount. The improved metabolic stability of A is valuable, but the significantly lower BBB score is a major drawback. The lower DILI and hERG risks for A are also positive. However, the substantial difference in BBB outweighs the other advantages of Ligand A.

Output:
1
2025-04-17 08:30:25,366 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (346.377 and 347.415 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (32.78) is excellent, well below the 90 A^2 threshold for CNS targets. Ligand B (100.29) is higher, but still potentially acceptable, though less ideal.

**3. logP:** Ligand A (3.303) is optimal. Ligand B (1.502) is a bit low, potentially hindering permeability.

**4. H-Bond Donors:** Ligand A (0) is good. Ligand B (3) is acceptable.

**5. H-Bond Acceptors:** Ligand A (3) is good. Ligand B (4) is acceptable.

**6. QED:** Ligand A (0.805) is excellent. Ligand B (0.651) is good, but slightly lower.

**7. DILI:** Ligand A (54.401) is good, indicating low liver injury risk. Ligand B (35.091) is also very good.

**8. BBB:** Ligand A (95.037) is *excellent*, exceeding the desirable >70% threshold for CNS targets. Ligand B (58.821) is significantly lower, raising concerns about brain penetration. This is a critical difference for DRD2.

**9. Caco-2 Permeability:** Ligand A (-4.474) is poor. Ligand B (-5.001) is also poor. Both are negative values, suggesting low permeability.

**10. Aqueous Solubility:** Ligand A (-3.867) is poor. Ligand B (-3.241) is also poor.

**11. hERG Inhibition:** Ligand A (0.874) is low risk. Ligand B (0.218) is very low risk. Both are good.

**12. Microsomal Clearance:** Ligand A (53.503) is moderate. Ligand B (41.12) is lower, suggesting better metabolic stability.

**13. In vitro Half-Life:** Ligand A (2.237) is short. Ligand B (-10.665) is very long, a significant advantage.

**14. P-gp Efflux:** Ligand A (0.422) is low efflux, favorable for CNS exposure. Ligand B (0.111) is even lower, even more favorable.

**15. Binding Affinity:** Ligand A (-8.9) is slightly better than Ligand B (-8.3), though both are excellent. The 1.5 kcal/mol difference is significant enough to consider.

**Overall Assessment:**

While Ligand B has better metabolic stability (lower Cl_mic, longer t1/2) and lower P-gp efflux, the *critical* factor for a CNS target like DRD2 is brain penetration. Ligand A's BBB percentile of 95.037 is far superior to Ligand B's 58.821.  The slightly better affinity of Ligand A further supports its selection. The poor Caco-2 and solubility for both are drawbacks, but can be addressed with formulation strategies. The superior BBB penetration of Ligand A outweighs the benefits of Ligand B's improved metabolic properties in this context.

Output:
1
2025-04-17 08:30:25,366 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B based on the provided guidelines, prioritizing GPCR-specific properties (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (344.459 and 339.443 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (56.84) is significantly better than Ligand B (63.05), both are below the 90 A^2 threshold for CNS targets, but A is closer to optimal.

**logP:** Both ligands (2.535 and 2.463) are within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A (HBD=2, HBA=4) and Ligand B (HBD=1, HBA=5) both meet the criteria of <=5 HBD and <=10 HBA.

**QED:** Both ligands have good QED scores (0.806 and 0.909), indicating good drug-likeness.

**DILI:** Ligand A (54.556) has a higher DILI risk than Ligand B (24.816). This is a significant drawback for Ligand A.

**BBB:** Ligand B (90.151) has a substantially better BBB penetration score than Ligand A (78.558). This is a critical advantage for a CNS target like DRD2.

**Caco-2 Permeability:** Both have negative Caco-2 values which is unusual and suggests poor permeability. However, the values are similar (-4.764 and -4.933).

**Aqueous Solubility:** Both have negative solubility values which is also unusual. However, the values are similar (-2.107 and -2.843).

**hERG:** Both ligands have low hERG inhibition liability (0.737 and 0.47).

**Microsomal Clearance:** Ligand A (14.694) has a lower microsomal clearance than Ligand B (32.139), indicating better metabolic stability.

**In vitro Half-Life:** Ligand B (11.524) has a slightly longer half-life than Ligand A (9.634).

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.083 and 0.08).

**Binding Affinity:** Ligand B (-7.9 kcal/mol) has a slightly better binding affinity than Ligand A (-8.8 kcal/mol). While A is better, the difference is less than the 1.5 kcal/mol threshold.

**Overall Assessment:**

Ligand B is the more promising candidate. Its significantly better BBB penetration (90.151 vs 78.558) and lower DILI risk (24.816 vs 54.556) are crucial advantages for a CNS-targeting drug. While Ligand A has slightly better affinity and metabolic stability, the BBB and DILI scores of Ligand B outweigh these benefits. The Caco-2 and solubility values are concerning for both, but are similar.

Output:
1
2025-04-17 08:30:25,366 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (346.431 and 343.471 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (84.72) is better than Ligand B (52.65). Both are below the 90 A^2 threshold for CNS targets, but Ligand B is significantly lower, which is favorable for brain penetration.

**logP:** Ligand A (0.608) is slightly below the optimal 1-3 range, potentially hindering permeability. Ligand B (1.712) is within the optimal range. This favors Ligand B.

**H-Bond Donors/Acceptors:** Ligand A has 0 HBD and 4 HBA, while Ligand B has 1 HBD and 3 HBA. Both are within acceptable limits (<=5 HBD and <=10 HBA).

**QED:** Both ligands have similar QED values (0.749 and 0.773), indicating good drug-likeness.

**DILI:** Ligand A (23.575) has a slightly higher DILI risk than Ligand B (18.108), but both are well below the concerning threshold of 60.

**BBB:** Ligand B (75.921) has a significantly higher BBB percentile than Ligand A (48.817). This is a crucial advantage for a CNS target like DRD2.

**Caco-2 Permeability:** Both have negative values (-4.617 and -4.726), which is unusual and suggests poor permeability. However, the scale is not defined, so it's hard to interpret.

**Aqueous Solubility:** Both ligands have negative solubility values (-2.077 and -1.925). Again, the scale is undefined, making interpretation difficult.

**hERG:** Both ligands have low hERG inhibition liability (0.18 and 0.397), which is good.

**Microsomal Clearance:** Ligand A (19.58) has a lower microsomal clearance than Ligand B (44.802), indicating better metabolic stability.

**In vitro Half-Life:** Ligand A (12.521) has a longer half-life than Ligand B (6.813). This is a positive attribute.

**P-gp Efflux:** Ligand A (0.003) has very low P-gp efflux liability, while Ligand B (0.145) has slightly higher efflux. Lower P-gp efflux is preferred for CNS penetration, favoring Ligand A.

**Binding Affinity:** Ligand B (-8.1 kcal/mol) has a stronger binding affinity than Ligand A (-7.4 kcal/mol). The difference is 0.7 kcal/mol, which is a significant advantage and can outweigh some ADME drawbacks.

**Overall Assessment:**

Ligand B is stronger in the most important parameters for a CNS GPCR target: BBB penetration and binding affinity. While Ligand A has better metabolic stability (lower Cl_mic) and lower P-gp efflux, the substantial improvement in BBB and binding affinity of Ligand B outweigh these benefits. The slightly suboptimal logP of Ligand A is also a concern.

Output:
1
2025-04-17 08:30:25,366 - INFO - Reasoning:

Let's analyze Ligand A and Ligand B based on the provided guidelines, prioritizing GPCR-specific properties (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (341.459 and 348.403 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (76.18) is significantly better than Ligand B (124.34). For CNS targets, TPSA should be <=90, and A is comfortably within this range, while B is pushing the limit.

**logP:** Ligand A (2.223) is optimal (1-3), while Ligand B (0.835) is slightly low, potentially hindering permeation.

**H-Bond Donors/Acceptors:** Ligand A (HBD=2, HBA=5) and Ligand B (HBD=3, HBA=6) both have acceptable numbers of H-bond donors and acceptors.

**QED:** Ligand A (0.894) has a much better QED score than Ligand B (0.654), indicating a more drug-like profile.

**DILI:** Both ligands have similar DILI risk (A: 52.734, B: 54.827), both being acceptable (<60).

**BBB:** Ligand A (61.535) has a moderate BBB penetration, while Ligand B (20.861) is quite poor. This is a critical difference for a CNS target like DRD2.

**Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and suggests a potential issue with the data or prediction method. However, the values are similar.

**Aqueous Solubility:** Both ligands have negative solubility values, which is also unusual and suggests a potential issue with the data or prediction method. The values are similar.

**hERG:** Ligand A (0.806) has a slightly higher hERG risk than Ligand B (0.266), but both are relatively low.

**Microsomal Clearance:** Ligand A (-24.288) has significantly better metabolic stability (lower clearance) than Ligand B (2.313).

**In vitro Half-Life:** Ligand A (22.506 hours) has a much longer half-life than Ligand B (7.855 hours).

**P-gp Efflux:** Ligand A (0.099) has lower P-gp efflux than Ligand B (0.067), which is favorable for CNS exposure.

**Binding Affinity:** Ligand A (-9.1 kcal/mol) has a significantly stronger binding affinity than Ligand B (-7.7 kcal/mol). This difference of 1.4 kcal/mol is substantial and can outweigh some ADME drawbacks.

**Conclusion:**

Considering all factors, particularly the GPCR-specific priorities, **Ligand A is the superior candidate**. It has a better TPSA, logP, QED, BBB penetration, metabolic stability, half-life, P-gp efflux, and, most importantly, significantly higher binding affinity. While Ligand B has a slightly lower hERG risk, the advantages of Ligand A across multiple critical parameters, especially its superior CNS penetration and binding affinity, make it the more promising drug candidate for targeting DRD2.

Output:
1
2025-04-17 08:30:25,366 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (365.415 and 345.399 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (133.31) is slightly above the optimal <90 for CNS targets, but still reasonable. Ligand B (95.67) is well within the desired range.

**logP:** Both ligands have a logP around 1.7-1.8, which is optimal.

**H-Bond Donors/Acceptors:** Ligand A has 4 HBD and 6 HBA, while Ligand B has 2 HBD and 5 HBA. Both are within acceptable limits.

**QED:** Both ligands have good QED scores (0.597 and 0.76), indicating good drug-likeness.

**DILI:** Ligand A (82.435) has a higher DILI risk than Ligand B (28.965). This is a significant negative for Ligand A.

**BBB:** Ligand A (32.028) has a very poor BBB penetration percentile. Ligand B (28.616) is also low, but slightly better. Both are far from the desirable >70 for CNS targets.

**Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and suggests poor permeability.

**Aqueous Solubility:** Both have negative solubility values, indicating poor solubility.

**hERG:** Both ligands have very low hERG inhibition risk (0.15 and 0.1).

**Microsomal Clearance:** Ligand B (59.74) has a lower microsomal clearance than Ligand A (34.765), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand B (-25.977) has a significantly longer in vitro half-life than Ligand A (-13.851).

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.014 and 0.032).

**Binding Affinity:** Ligand A (-9.1 kcal/mol) has a slightly better binding affinity than Ligand B (-8.6 kcal/mol), a difference of 0.5 kcal/mol.

**Overall Assessment:**

While Ligand A has a slightly better binding affinity, its significantly higher DILI risk and *extremely* poor BBB penetration are major drawbacks for a CNS target. Ligand B, despite its also low BBB penetration, has a much better safety profile (lower DILI) and improved metabolic stability (lower Cl_mic, longer t1/2). The small difference in binding affinity (0.5 kcal/mol) is unlikely to outweigh the substantial ADME/Tox advantages of Ligand B. Given the GPCR-specific priority of BBB penetration, even though both are poor, the other favorable characteristics of Ligand B make it the more promising candidate.

Output:
1
2025-04-17 08:30:25,367 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (364.471 and 357.439 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (95.16) is better than Ligand B (106.91). Both are below the 140 A^2 threshold for oral absorption, and importantly, below the 90 A^2 target for CNS penetration.

**logP:** Both ligands have acceptable logP values (1.022 and 1.753), falling within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A (HBD=2, HBA=5) is slightly better than Ligand B (HBD=3, HBA=6) in terms of maintaining a balance between solubility and permeability. Both are within acceptable limits.

**QED:** Both ligands have similar QED values (0.786 and 0.73), indicating good drug-likeness.

**DILI:** Ligand A (65.568) has a slightly better DILI score than Ligand B (77.2), indicating a lower risk of liver injury. Both are above the preferred <40, but Ligand A is closer.

**BBB:** Ligand B (61.109) has a significantly better BBB penetration percentile than Ligand A (48.391). This is a critical factor for a CNS target like DRD2.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.55 and -5.332). This is unusual and suggests poor intestinal absorption. However, for a CNS drug, intestinal absorption is less critical than BBB penetration.

**Aqueous Solubility:** Both ligands have similarly poor aqueous solubility (-3.568 and -3.592). This could pose formulation challenges.

**hERG Inhibition:** Ligand A (0.276) has a much lower hERG inhibition liability than Ligand B (0.619), which is a significant advantage.

**Microsomal Clearance:** Ligand A (29.079) has a lower microsomal clearance than Ligand B (11.616), indicating better metabolic stability.

**In vitro Half-Life:** Ligand A (-18.265) has a longer in vitro half-life than Ligand B (52.295), which is desirable.

**P-gp Efflux:** Ligand A (0.08) has a lower P-gp efflux liability than Ligand B (0.101), which is beneficial for CNS exposure.

**Binding Affinity:** Ligand B (-9.2 kcal/mol) has a significantly stronger binding affinity than Ligand A (-7.8 kcal/mol). This >1.5 kcal/mol difference is substantial and can outweigh some ADME drawbacks.

**Overall Assessment:**

While Ligand A has advantages in several ADME properties (DILI, hERG, Cl_mic, t1/2, Pgp), Ligand B's superior BBB penetration and significantly stronger binding affinity are decisive for a CNS GPCR target. The improved affinity is likely to overcome the slightly worse ADME profile of Ligand B.

Output:
1
2025-04-17 08:30:25,367 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B based on the provided guidelines, prioritizing GPCR-specific properties (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (346.431 and 354.407 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (89.53) is excellent for CNS penetration, being well below 90. Ligand B (121.73) is still reasonable but less optimal.

**logP:** Ligand A (0.42) is a bit low, potentially hindering permeation. Ligand B (0.835) is better, but still on the lower side of the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Both have 2 HBDs, which is good. Ligand A has 4 HBAs, and Ligand B has 7 HBAs. Both are acceptable, but Ligand A is slightly better.

**QED:** Ligand A (0.781) has a better QED score than Ligand B (0.5), indicating better overall drug-likeness.

**DILI:** Ligand A (35.324) has a significantly lower DILI risk than Ligand B (44.901).

**BBB:** This is crucial for a CNS target. Ligand A (33.656) is poor, while Ligand B (68.515) is considerably better, although still not ideal (>70 is preferred).

**Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and suggests poor permeability. However, the scale is not specified, so it's difficult to interpret.

**Aqueous Solubility:** Both have negative solubility values, which is also unusual and suggests poor solubility. Again, the scale is not specified.

**hERG:** Both ligands have very low hERG inhibition risk (0.165 and 0.279 respectively).

**Microsomal Clearance:** Ligand A (-17.846) has much lower (better) microsomal clearance than Ligand B (8.096), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (-5.895) has a negative half-life, which is impossible. Ligand B (-25.824) also has a negative half-life. This is a major red flag for both.

**P-gp Efflux:** Both have very low P-gp efflux liability (0.015 and 0.109 respectively), which is good for CNS penetration.

**Binding Affinity:** Ligand B (-7.1 kcal/mol) has a slightly better binding affinity than Ligand A (-7.8 kcal/mol). While the difference is small, it's potentially significant.

**Overall Assessment:**

Ligand A has better drug-like properties (QED, DILI, Cl_mic, Pgp) and a more favorable TPSA. However, its BBB penetration is very poor, and its logP is low. The negative half-life is a critical flaw. Ligand B has a better BBB score and slightly better affinity, but suffers from higher DILI risk, worse metabolic stability, and also has a negative half-life.

Given the negative half-life values for both, they are both highly suspect. However, considering the GPCR-specific priorities, the *slightly* better affinity and significantly better BBB penetration of Ligand B make it marginally more promising, *if* the half-life data is corrected or can be explained. The lower metabolic stability of Ligand B is a concern, but could potentially be addressed through structural modifications.

Output:
1
2025-04-17 08:30:25,367 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (336.395) is slightly lower, which is generally favorable for permeability. Ligand B (353.507) is also good.

**TPSA:** Both ligands have TPSA values below 90, which is good for CNS penetration. Ligand B (70.67) is better than Ligand A (80.05).

**logP:** Ligand A (3.487) is within the optimal range (1-3), while Ligand B (1.256) is at the lower end. While not terrible, lower logP can sometimes hinder permeation.

**H-Bond Donors/Acceptors:** Both ligands have acceptable HBD (2) and HBA (5/4) counts, falling within the recommended limits.

**QED:** Both ligands have QED values above 0.5, indicating good drug-likeness. Ligand A (0.72) is slightly better than Ligand B (0.58).

**DILI:** Ligand A (79.449) has a higher DILI risk than Ligand B (19.698). This is a significant drawback for Ligand A.

**BBB:** Ligand A (47.189) has a moderate BBB penetration, while Ligand B (29.003) has poor BBB penetration. This is a critical factor for a CNS target like DRD2.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values, which is unusual and suggests poor permeability.

**Aqueous Solubility:** Both ligands have negative solubility values, which is also unusual and suggests poor solubility.

**hERG:** Both ligands have low hERG inhibition liability, which is good. Ligand A (0.513) is slightly higher than Ligand B (0.208).

**Microsomal Clearance:** Ligand B (35.925) has lower microsomal clearance than Ligand A (41.808), indicating better metabolic stability.

**In vitro Half-Life:** Ligand B (-5.864) has a negative half-life, which is concerning, while Ligand A (63.278) has a good half-life.

**P-gp Efflux:** Ligand A (0.408) has lower P-gp efflux liability than Ligand B (0.033), which is favorable for CNS exposure.

**Binding Affinity:** Ligand A (-9.5 kcal/mol) has significantly better binding affinity than Ligand B (-6.4 kcal/mol). This is a substantial advantage.

**Overall Assessment:**

Ligand A has a much stronger binding affinity and better P-gp efflux, but suffers from higher DILI risk and moderate BBB penetration. Ligand B has better metabolic stability, lower DILI, and a slightly better TPSA, but its binding affinity is significantly weaker and has poor BBB penetration.

Given the importance of BBB penetration for a CNS target like DRD2, Ligand A's superior binding affinity and better P-gp efflux, despite its higher DILI risk and moderate BBB, make it the more promising candidate. The affinity difference is substantial (>3 kcal/mol), which can often outweigh other ADME concerns, especially if the DILI risk can be mitigated through structural modifications.

Output:
1
2025-04-17 08:30:25,367 - INFO - Batch 454 complete. Total preferences: 7264
2025-04-17 08:30:25,368 - INFO - Processing batch 455/512...
2025-04-17 08:31:09,648 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (338.37 and 366.44 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (100.02) is better than Ligand B (109.25). For CNS targets, we want TPSA <= 90, so both are slightly above the ideal, but A is closer.

**3. logP:** Both ligands have good logP values (2.79 and 1.81), falling within the optimal 1-3 range.

**4. H-Bond Donors:** Both have 3 HBD, which is acceptable.

**5. H-Bond Acceptors:** Ligand A has 4 HBA, and Ligand B has 6. Both are within the acceptable limit of <=10, but A is preferable.

**6. QED:** Both ligands have similar QED values (0.666 and 0.657), indicating good drug-likeness.

**7. DILI:** Ligand A (79.64) has a slightly higher DILI risk than Ligand B (74.68), but both are reasonably low.

**8. BBB:** This is a critical parameter for a CNS target like DRD2. Ligand A has a BBB percentile of 49.52, while Ligand B is significantly lower at 27.41. Ligand A is much more likely to cross the blood-brain barrier.

**9. Caco-2 Permeability:** Both have negative Caco-2 values (-5.33 and -5.46), which is unusual and suggests poor permeability. This is a concern for both.

**10. Aqueous Solubility:** Both have negative solubility values (-4.27 and -3.71), suggesting poor aqueous solubility. This is a concern for both.

**11. hERG Inhibition:** Both ligands show very low hERG inhibition risk (0.53 and 0.25).

**12. Microsomal Clearance:** Ligand B (47.19) has a significantly higher microsomal clearance than Ligand A (16.78), indicating faster metabolism and lower metabolic stability.

**13. In vitro Half-Life:** Ligand A (35.10) has a much longer in vitro half-life than Ligand B (6.78).

**14. P-gp Efflux:** Both have very low P-gp efflux liability (0.09 and 0.05), which is favorable for CNS penetration.

**15. Binding Affinity:** Ligand A (-9.5 kcal/mol) has a significantly stronger binding affinity than Ligand B (-7.5 kcal/mol). This is a substantial advantage, exceeding the 1.5 kcal/mol threshold.

**Overall Assessment:**

Ligand A is the superior candidate. While both have issues with Caco-2 permeability and aqueous solubility, Ligand A's significantly better BBB penetration, metabolic stability (lower Cl_mic, longer t1/2), and *much* stronger binding affinity outweigh its slightly higher DILI risk. The strong binding affinity is particularly important for a GPCR target. The better TPSA and HBA also contribute to its favorability.

Output:
1
2025-04-17 08:31:09,649 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (352.479 and 372.342 Da) fall within the ideal 200-500 Da range.

**TPSA:** Both ligands have TPSA values (90.54 and 89.19) below the 90 threshold for CNS targets, which is excellent.

**logP:** Ligand A (0.422) is a bit low, potentially hindering permeability. Ligand B (2.17) is within the optimal 1-3 range. This is a significant advantage for Ligand B.

**H-Bond Donors/Acceptors:** Ligand A has 3 HBD and 4 HBA, which are acceptable. Ligand B has 2 HBD and 7 HBA, also acceptable, though slightly higher HBA could be a minor concern.

**QED:** Both ligands have reasonable QED scores (0.497 and 0.676), indicating drug-like properties, with Ligand B being slightly better.

**DILI:** Ligand A (24.622) has a much lower DILI risk than Ligand B (56.844). This is a substantial advantage for Ligand A.

**BBB:** Ligand B (83.87) has a significantly higher BBB penetration percentile than Ligand A (54.983). This is a critical advantage for a CNS target like DRD2.

**Caco-2 Permeability:** Ligand A (-5.255) has poor Caco-2 permeability, while Ligand B (-4.809) is slightly better, but still not ideal.

**Aqueous Solubility:** Ligand A (-1.568) has poor aqueous solubility, while Ligand B (-4.634) is even worse. This could pose formulation challenges for both.

**hERG Inhibition:** Ligand A (0.224) shows lower hERG inhibition risk than Ligand B (0.644). This is a positive for Ligand A.

**Microsomal Clearance:** Ligand A (25.328) has lower microsomal clearance than Ligand B (55.99), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (-0.992) has a slightly longer in vitro half-life than Ligand B (-2.124).

**P-gp Efflux:** Ligand A (0.009) has very low P-gp efflux, which is excellent for CNS penetration. Ligand B (0.052) is also low, but higher than Ligand A.

**Binding Affinity:** Ligand B (-8.4 kcal/mol) has a significantly stronger binding affinity than Ligand A (-7.6 kcal/mol). This >1.5 kcal/mol difference is a major factor.

**Overall Assessment:**

Ligand B excels in BBB penetration and binding affinity, both crucial for a CNS GPCR target. While it has a higher DILI risk and slightly worse solubility, the strong affinity and good BBB offset these concerns. Ligand A has better safety profiles (DILI, hERG) and metabolic stability, but its poor logP, Caco-2 permeability, and significantly weaker binding affinity are major drawbacks. The affinity difference is substantial enough to outweigh the ADME concerns of Ligand B, especially given the importance of target engagement for GPCRs.

Output:
1
2025-04-17 08:31:09,649 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (358.36 and 359.495 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (49.85) is significantly better than Ligand B (71.09). For CNS targets, we want TPSA <= 90, and ideally closer to 60. Ligand A is much closer to this ideal.

**3. logP:** Both ligands have acceptable logP values (1.733 and 2.09), falling within the optimal range of 1-3.

**4. H-Bond Donors:** Ligand A (0) is preferable to Ligand B (2). Fewer HBDs generally improve permeability.

**5. H-Bond Acceptors:** Ligand A (3) is preferable to Ligand B (4). Fewer HBAs generally improve permeability.

**6. QED:** Both ligands have good QED scores (0.707 and 0.864), indicating good drug-like properties.

**7. DILI:** Ligand A (38.309) has a considerably lower DILI risk than Ligand B (57.619). Both are below the 60 threshold, but A is better.

**8. BBB:** This is a critical parameter for CNS targets. Ligand A (97.363) has excellent BBB penetration, while Ligand B (54.478) is significantly lower.

**9. Caco-2 Permeability:** Ligand A (-4.24) is better than Ligand B (-5.521). Higher values are preferred.

**10. Aqueous Solubility:** Both ligands have very poor aqueous solubility (-2.886 and -2.625). This is a concern, but can sometimes be mitigated with formulation strategies.

**11. hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.365 and 0.228).

**12. Microsomal Clearance:** Ligand B (11.327) has lower microsomal clearance than Ligand A (23.3), indicating better metabolic stability.

**13. In vitro Half-Life:** Ligand B (29.31) has a longer in vitro half-life than Ligand A (-21.386). This is a significant advantage.

**14. P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.089 and 0.101).

**15. Binding Affinity:** Both ligands have the same binding affinity (-8.8 kcal/mol), which is excellent.

**Overall Assessment:**

Ligand A excels in TPSA, BBB penetration, HBD/HBA counts, and DILI risk. These are all crucial for a CNS-targeting GPCR ligand. While Ligand B has better metabolic stability and half-life, the superior CNS penetration and lower TPSA of Ligand A are more important in this context. The equal binding affinity makes the ADME properties the deciding factor.

Output:
1
2025-04-17 08:31:09,649 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B based on the provided guidelines, prioritizing GPCR-specific properties (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (344.419 and 355.511 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (103.91) is better than Ligand B (53.94). For CNS targets, TPSA should be <= 90, so both are acceptable, but A is closer to the upper limit and B is well within.

**logP:** Ligand A (1.03) is within the optimal 1-3 range. Ligand B (3.735) is approaching the upper limit, potentially raising concerns about solubility and off-target effects, but still acceptable.

**H-Bond Donors/Acceptors:** Both ligands have 1 HBD and 6 HBA, which are within acceptable limits (<=5 and <=10, respectively).

**QED:** Both ligands have similar QED values (0.758 and 0.764), indicating good drug-likeness.

**DILI:** Ligand A (38.387) has a significantly lower DILI risk than Ligand B (77.549). This is a substantial advantage for Ligand A.

**BBB:** Ligand A (56.029) has a lower BBB penetration than Ligand B (85.149). For a CNS target like DRD2, BBB penetration >70 is desirable. Ligand B is much closer to this threshold.

**Caco-2 Permeability:** Both have negative Caco-2 values (-5.12 and -5.166). This is unusual and suggests poor permeability. However, the values are very similar.

**Aqueous Solubility:** Both have negative solubility values (-2.139 and -4.249). This is also concerning, but again, similar between the two.

**hERG Inhibition:** Ligand A (0.115) has a lower hERG inhibition liability than Ligand B (0.695), indicating a lower risk of cardiotoxicity.

**Microsomal Clearance:** Ligand A (3.197) has a significantly lower microsomal clearance than Ligand B (78.095), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (5.508) has a shorter half-life than Ligand B (22.035). This is a drawback for Ligand A.

**P-gp Efflux:** Ligand A (0.013) has much lower P-gp efflux liability than Ligand B (0.398), which is crucial for CNS penetration.

**Binding Affinity:** Ligand B (-8.0) has a slightly better binding affinity than Ligand A (-7.6), but the difference is less than 1.5 kcal/mol.

**Overall Assessment:**

Ligand B excels in BBB penetration and binding affinity, which are critical for a CNS GPCR target. However, it suffers from significantly higher DILI risk, higher P-gp efflux, and much higher microsomal clearance. Ligand A has a much better safety profile (lower DILI, hERG, P-gp) and better metabolic stability, despite slightly lower BBB penetration and binding affinity. Given the importance of minimizing off-target effects and achieving sufficient CNS exposure, the improved ADME properties of Ligand A outweigh the slightly weaker binding affinity.

Output:
0
2025-04-17 08:31:09,649 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (352.435 and 357.382 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (90.98) is excellent, falling below the 90 A^2 threshold for CNS targets. Ligand B (104.81) is still reasonable but slightly higher, potentially impacting BBB penetration.

**logP:** Ligand A (0.098) is very low, which is a significant concern. It may struggle with membrane permeability. Ligand B (-0.338) is also low, but slightly better than A. Both are below the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Both ligands have 2 HBD and 5 HBA, which are within acceptable limits.

**QED:** Both ligands have acceptable QED values (0.634 and 0.517, respectively), indicating reasonable drug-likeness.

**DILI:** Both ligands have similar, low DILI risk (35.944 and 36.758 percentile), which is positive.

**BBB:** Ligand B (65.452) has a significantly better BBB percentile than Ligand A (38.426). This is a crucial advantage for a CNS target like DRD2.

**Caco-2 Permeability:** Ligand A (-5.156) shows poor Caco-2 permeability, consistent with its low logP. Ligand B (-4.967) is also poor, but slightly better.

**Aqueous Solubility:** Both ligands have very poor aqueous solubility (-0.402 and -2.141). This could pose formulation challenges.

**hERG Inhibition:** Both ligands show very low hERG inhibition risk (0.061 and 0.161).

**Microsomal Clearance:** Ligand A (-22.927) has a much lower (better) microsomal clearance than Ligand B (13.965), suggesting greater metabolic stability.

**In vitro Half-Life:** Ligand A (-7.097) has a longer in vitro half-life than Ligand B (-28.34), which is desirable.

**P-gp Efflux:** Both ligands show very low P-gp efflux liability (0.003 and 0.014).

**Binding Affinity:** Both ligands have excellent binding affinities (-7.6 and -8.0 kcal/mol). Ligand B is slightly better, but the difference is relatively small.

**Overall Assessment:**

While both ligands have good binding affinity and acceptable safety profiles (DILI, hERG), Ligand A suffers from a very low logP and poor Caco-2 permeability, which will likely hinder its ability to cross cell membranes and reach the brain. Ligand B has a significantly better BBB percentile, which is critical for a CNS target. Despite its slightly higher TPSA and lower metabolic stability, the improved BBB penetration of Ligand B outweighs these drawbacks.

Output:
1
2025-04-17 08:31:09,650 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 drug candidates, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (346.45 & 364.52 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (58.2) is significantly better than Ligand B (67.23). For CNS targets, we want TPSA <= 90, and A is closer to the ideal <=60.

**logP:** Ligand A (3.33) is optimal (1-3), while Ligand B (1.60) is on the lower end, potentially hindering permeability.

**H-Bond Donors/Acceptors:** Ligand A (2 HBD, 2 HBA) and Ligand B (1 HBD, 5 HBA) are both acceptable, within the recommended limits.

**QED:** Both ligands have good QED scores (0.71 and 0.83), indicating good drug-like properties.

**DILI:** Ligand A (22.76) has a lower DILI risk than Ligand B (28.23), both are acceptable.

**BBB:** This is crucial for a CNS target like DRD2. Ligand A (81.7%) is excellent, exceeding the desirable >70% threshold. Ligand B (51.5%) is considerably lower and concerning.

**Caco-2 Permeability:** Ligand A (-4.54) is better than Ligand B (-5.42), indicating better intestinal absorption.

**Aqueous Solubility:** Ligand A (-3.98) is better than Ligand B (-2.09), indicating better solubility.

**hERG:** Both ligands have low hERG inhibition liability (0.62 and 0.11 respectively), which is favorable.

**Microsomal Clearance:** Ligand A (64.51) has higher clearance than Ligand B (28.09), suggesting lower metabolic stability.

**In vitro Half-Life:** Ligand A (5.82) has a longer half-life than Ligand B (1.48), which is preferable.

**P-gp Efflux:** Ligand A (0.13) has lower P-gp efflux than Ligand B (0.06), indicating better CNS exposure.

**Binding Affinity:** Ligand B (-8.1 kcal/mol) has slightly better binding affinity than Ligand A (-8.6 kcal/mol). However, the difference is small and can be overcome by other favorable ADME properties.

**Overall Assessment:**

Ligand A is significantly better overall. Its superior BBB penetration, TPSA, logP, solubility, Caco-2 permeability, and P-gp efflux properties outweigh the slightly weaker binding affinity compared to Ligand B. The better metabolic stability (longer half-life) is also a significant advantage. Ligand B's low BBB penetration is a major drawback for a CNS-targeting drug.

Output:
1
2025-04-17 08:31:09,650 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (353.507 and 353.463 Da) fall within the ideal range of 200-500 Da.

**TPSA:** Ligand A (53.09) is significantly better than Ligand B (73.32). For CNS targets, we want TPSA <= 90, and ideally closer to 60. Ligand A is much closer to this ideal.

**logP:** Ligand A (1.593) is within the optimal range (1-3). Ligand B (-0.071) is slightly below 1, which *could* indicate permeability issues, though not drastically.

**H-Bond Donors/Acceptors:** Ligand A (0 HBD, 4 HBA) is preferable to Ligand B (1 HBD, 5 HBA). Lower values are generally better for BBB penetration.

**QED:** Both ligands have similar QED values (0.728 and 0.724), indicating good drug-likeness.

**DILI:** Ligand A (11.206) has a significantly lower DILI risk than Ligand B (6.941), which is a substantial advantage.

**BBB:** Ligand A (81.582) has a much higher BBB penetration percentile than Ligand B (60.644). This is *critical* for a CNS target like DRD2. A value >70 is desirable, and Ligand A is closer to that threshold.

**Caco-2 Permeability:** Both are negative, indicating poor permeability. However, the scale is not specified, so it is hard to compare.

**Aqueous Solubility:** Both are negative, indicating poor solubility. However, the scale is not specified, so it is hard to compare.

**hERG:** Both ligands have very low hERG inhibition liability (0.414 and 0.222), which is excellent.

**Microsomal Clearance:** Ligand A (33.526) has a higher microsomal clearance than Ligand B (6.165), meaning it's likely to be metabolized faster. Ligand B is preferable here.

**In vitro Half-Life:** Ligand A (-17.99) has a negative half-life, which is not possible. This is likely an error in the data. Ligand B (0.256) is very short, but at least plausible.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.052 and 0.015), which is good for CNS penetration.

**Binding Affinity:** Both ligands have the same binding affinity (-7.5 kcal/mol), which is excellent and meets the criteria of < -7.0 kcal/mol.

**Overall Assessment:**

Despite the similar binding affinity, Ligand A is the far superior candidate. Its significantly better TPSA, BBB penetration, and lower DILI risk outweigh the slightly higher microsomal clearance and the erroneous half-life value. Ligand B's low logP and lower BBB penetration are significant drawbacks for a CNS-targeting drug. The negative half-life for ligand A is concerning and would need investigation, but the other factors strongly favor A.

Output:
1
2025-04-17 08:31:09,650 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (363.483 and 347.459 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Both ligands have TPSA values (95.08 and 91.32) that are acceptable for oral absorption (<140), but slightly higher than the ideal <90 for CNS targets. This is a minor concern, but needs consideration.

**3. logP:** Both ligands have logP values (2.222 and 2.537) within the optimal 1-3 range.

**4. H-Bond Donors:** Both have 3 HBD, which is within the acceptable limit of <=5.

**5. H-Bond Acceptors:** Ligand A has 5 HBA, and Ligand B has 4 HBA, both are within the acceptable limit of <=10.

**6. QED:** Both ligands have QED values (0.703 and 0.599) above 0.5, indicating good drug-like properties.

**7. DILI:** Ligand A (54.207) has a higher DILI risk than Ligand B (23.226). This is a significant drawback for Ligand A.

**8. BBB:** Ligand A (52.889) and Ligand B (26.638) both have BBB penetration percentiles. Ligand A is significantly better, being closer to the desirable >70 for CNS targets. Ligand B is quite low.

**9. Caco-2:** Both have negative Caco-2 values (-5.573 and -5.163), which is unusual and suggests poor permeability. This is a concern for both.

**10. Solubility:** Both have negative solubility values (-2.882 and -2.742), indicating poor aqueous solubility. This is a concern for both.

**11. hERG:** Both ligands have low hERG inhibition liability (0.557 and 0.093), which is good.

**12. Cl_mic:** Ligand A (21.727) has a lower microsomal clearance than Ligand B (30.553), suggesting better metabolic stability.

**13. t1/2:** Ligand A (26.179) has a longer in vitro half-life than Ligand B (-13.671). The negative value for ligand B is concerning and likely indicates very rapid metabolism.

**14. Pgp:** Ligand A (0.402) has lower P-gp efflux liability than Ligand B (0.014), which is favorable for CNS penetration.

**15. Binding Affinity:** Ligand A (-9.4 kcal/mol) has a significantly stronger binding affinity than Ligand B (-7.8 kcal/mol). This is a substantial advantage.

**Overall Assessment:**

Ligand A is superior despite the slightly higher TPSA and DILI. The significantly higher binding affinity (-9.4 vs -7.8 kcal/mol) is a major advantage that can potentially outweigh some of the ADME drawbacks. Furthermore, Ligand A has a better BBB percentile, lower Pgp efflux, and better metabolic stability (lower Cl_mic and longer t1/2). Ligand B has a lower DILI risk, but its very poor in vitro half-life and low BBB penetration are major liabilities for a CNS-targeting drug. The negative Caco-2 and solubility values are concerning for both, but can potentially be addressed through formulation strategies.

Output:
1
2025-04-17 08:31:09,650 - INFO - Reasoning:

Let's analyze Ligand A and Ligand B based on the provided guidelines, prioritizing GPCR-specific properties (BBB, logP, Pgp, TPSA, and affinity).

**Ligand A:**

*   **MW:** 384.929 Da - Within the ideal range (200-500).
*   **TPSA:** 49.85 - Excellent, well below the 90 target for CNS drugs.
*   **logP:** 3.169 - Optimal (1-3).
*   **HBD:** 0 - Acceptable, low.
*   **HBA:** 5 - Acceptable, within the limit.
*   **QED:** 0.731 - Good, above the 0.5 threshold.
*   **DILI:** 37.03 - Low risk, good.
*   **BBB:** 82.862 - Very good, exceeding the 70% threshold for CNS targets.
*   **Caco-2:** -4.603 - Poor, suggests poor intestinal absorption.
*   **Solubility:** -3.573 - Poor, could pose formulation challenges.
*   **hERG:** 0.678 - Low risk, good.
*   **Cl_mic:** 98.981 - High, suggesting rapid metabolism.
*   **t1/2:** -4.992 - Very short half-life, a significant drawback.
*   **Pgp:** 0.355 - Low efflux, favorable for CNS penetration.
*   **Affinity:** -7.2 kcal/mol - Excellent binding affinity.

**Ligand B:**

*   **MW:** 354.363 Da - Within the ideal range (200-500).
*   **TPSA:** 133.99 - Borderline; slightly above the 90 target for CNS drugs, but could still be acceptable.
*   **logP:** -1.961 - Suboptimal, potentially hindering permeation.
*   **HBD:** 3 - Acceptable.
*   **HBA:** 8 - Acceptable.
*   **QED:** 0.484 - Below the 0.5 threshold, suggesting a less drug-like profile.
*   **DILI:** 39.705 - Low risk, good.
*   **BBB:** 36.06 - Poor, significantly below the 70% threshold for CNS targets.
*   **Caco-2:** -5.258 - Poor, suggests poor intestinal absorption.
*   **Solubility:** -0.112 - Poor, could pose formulation challenges.
*   **hERG:** 0.151 - Low risk, good.
*   **Cl_mic:** -3.685 - Very low, suggesting high metabolic stability.
*   **t1/2:** 9.779 - Good, long half-life.
*   **Pgp:** 0.043 - Very low efflux, highly favorable for CNS penetration.
*   **Affinity:** -7.6 kcal/mol - Excellent binding affinity, slightly better than Ligand A.

**Comparison and Decision:**

Both ligands have excellent binding affinities. However, Ligand A has a significantly better BBB score (82.862 vs. 36.06) and a more optimal logP (3.169 vs -1.961). While Ligand A has poor Caco-2 permeability, solubility and a high Cl_mic/short half-life, these can potentially be addressed through formulation strategies or structural modifications. Ligand B's poor BBB penetration is a major concern for a CNS target, and its lower logP is also unfavorable. Ligand B's better metabolic stability and half-life are positives, but are outweighed by the BBB and logP issues.

Given the GPCR-specific priorities, particularly BBB penetration for a CNS target like DRD2, and the slightly better logP of Ligand A, **Ligand A is the more promising candidate despite its ADME liabilities**. The ADME issues with Ligand A are more readily addressable through medicinal chemistry optimization than the fundamental BBB problem with Ligand B.

Output:
1
2025-04-17 08:31:09,651 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (343.471 and 368.518 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (73.99) is better than Ligand B (42.43). For CNS targets, we want TPSA <= 90, both are within this range, but A is closer to the upper limit.

**3. logP:** Both ligands have good logP values (3.062 and 4.007), falling within the optimal range of 1-3, although B is slightly higher.

**4. H-Bond Donors:** Ligand A has 3 HBD, which is acceptable. Ligand B has 0, which is also acceptable.

**5. H-Bond Acceptors:** Ligand A has 2 HBA, and Ligand B has 4. Both are within the acceptable limit of <= 10.

**6. QED:** Both ligands have similar QED values (0.743 and 0.695), indicating good drug-likeness.

**7. DILI:** Ligand A (29.779) has a significantly lower DILI risk than Ligand B (18.728). This is a major advantage for Ligand A.

**8. BBB:** Ligand B (93.563) has a much higher BBB penetration percentile than Ligand A (71.656). This is a critical advantage for a CNS target like DRD2.

**9. Caco-2 Permeability:** Ligand A (-5.088) has a worse Caco-2 permeability than Ligand B (-4.276).

**10. Aqueous Solubility:** Ligand A (-3.941) has a worse aqueous solubility than Ligand B (-4.544).

**11. hERG Inhibition:** Both ligands have similar, low hERG inhibition liability (0.601 and 0.703).

**12. Microsomal Clearance:** Ligand A (49.115) has a lower microsomal clearance than Ligand B (110.828), indicating better metabolic stability.

**13. In vitro Half-Life:** Ligand A (1.348) has a shorter in vitro half-life than Ligand B (-10.897).

**14. P-gp Efflux:** Ligand A (0.255) has a lower P-gp efflux liability than Ligand B (0.353), which is favorable for CNS penetration.

**15. Binding Affinity:** Ligand A (-9.0) has a slightly better binding affinity than Ligand B (-6.8). This is a significant advantage.

**Overall Assessment:**

Ligand B excels in BBB penetration, a crucial factor for a CNS target. However, Ligand A demonstrates a better safety profile (lower DILI), better metabolic stability (lower Cl_mic), and a stronger binding affinity. The difference in binding affinity (-9.0 vs -6.8 kcal/mol) is substantial and can often outweigh minor ADME drawbacks. While Ligand B has better BBB and Caco-2 permeability, Ligand A's lower P-gp efflux liability also contributes to improved CNS exposure. Considering the balance of these factors, and prioritizing affinity and safety for initial lead selection, Ligand A appears to be the more promising candidate.

Output:
0
2025-04-17 08:31:09,651 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B based on the provided guidelines, prioritizing GPCR-specific properties (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (354.378 and 345.447 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (99.1) is slightly higher than the ideal <90 for CNS targets, while Ligand B (71.33) is well within the desired range. This favors Ligand B.

**logP:** Both ligands have good logP values (2.798 and 1.482), falling within the optimal 1-3 range. Ligand B is a bit lower, which could slightly improve solubility but might compromise permeability.

**H-Bond Donors/Acceptors:** Ligand A has 3 HBD and 5 HBA, which are acceptable. Ligand B has 0 HBD and 5 HBA, also acceptable.

**QED:** Both ligands have similar QED values (0.769 and 0.775), indicating good drug-like properties.

**DILI:** Ligand A (47.693) has a slightly higher DILI risk than Ligand B (33.075), but both are below the concerning threshold of 60.

**BBB:** This is a critical parameter for a CNS target like DRD2. Ligand B (71.035) has a significantly better BBB percentile than Ligand A (50.679), exceeding the desirable >70 threshold. This is a major advantage for Ligand B.

**Caco-2 Permeability:** Ligand A (-5.113) shows poor Caco-2 permeability, while Ligand B (-4.674) is also poor, but slightly better.

**Aqueous Solubility:** Ligand A (-3.457) has slightly better solubility than Ligand B (-1.554).

**hERG Inhibition:** Both ligands show low hERG inhibition risk (0.111 and 0.277).

**Microsomal Clearance:** Ligand A (25.407) has lower microsomal clearance than Ligand B (36.838), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand B (-7.276) has a longer in vitro half-life than Ligand A (-2.334).

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.01 and 0.081).

**Binding Affinity:** Ligand B (-9.0 kcal/mol) has a significantly stronger binding affinity than Ligand A (-7.7 kcal/mol). This >1.5 kcal/mol difference is a substantial advantage, potentially outweighing minor ADME drawbacks.

**Overall Assessment:**

Ligand B is the more promising candidate. While Ligand A has slightly better solubility and metabolic stability, Ligand B excels in the most critical areas for a CNS-targeting GPCR: significantly better BBB penetration and substantially stronger binding affinity. The lower TPSA of Ligand B is also beneficial. The slightly lower solubility and higher clearance of Ligand B are less concerning given the strength of its other properties.



Output:
1
2025-04-17 08:31:09,651 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (368.415 Da) and Ligand B (351.491 Da) are comparable.

**2. TPSA:** Ligand A (93.85) is slightly higher than Ligand B (61.88). For CNS targets, we want TPSA <= 90, so Ligand A is marginally less desirable. Ligand B is well within the optimal range.

**3. logP:** Ligand A (-0.052) is a bit low, potentially hindering permeability. Ligand B (1.417) is within the optimal 1-3 range. This favors Ligand B.

**4. H-Bond Donors:** Both have acceptable HBD counts (Ligand A: 0, Ligand B: 1).

**5. H-Bond Acceptors:** Both have acceptable HBA counts (Ligand A: 7, Ligand B: 4).

**6. QED:** Both ligands have similar and good QED scores (Ligand A: 0.757, Ligand B: 0.753).

**7. DILI:** Ligand A (78.325) has a higher DILI risk than Ligand B (21.869). This is a significant advantage for Ligand B.

**8. BBB:** Both ligands have comparable and good BBB penetration (Ligand A: 65.529, Ligand B: 65.607). While not exceeding 70, they are acceptable.

**9. Caco-2:** Both ligands have similar negative Caco-2 values, suggesting poor permeability. This is a concern for both.

**10. Solubility:** Both ligands have similar negative solubility values, indicating poor aqueous solubility. This is a concern for both.

**11. hERG:** Both ligands have low hERG inhibition liability (Ligand A: 0.408, Ligand B: 0.451).

**12. Cl_mic:** Ligand B (27.532) has a lower microsomal clearance than Ligand A (56.414), indicating better metabolic stability.

**13. t1/2:** Ligand B (19.02) has a longer in vitro half-life than Ligand A (-14.17).

**14. Pgp:** Both ligands have low P-gp efflux liability (Ligand A: 0.101, Ligand B: 0.032). Ligand B is slightly better.

**15. Binding Affinity:** Ligand B (-7.7 kcal/mol) has a slightly better binding affinity than Ligand A (-8.5 kcal/mol). While A is better, the difference is not huge.

**Overall Assessment:**

Ligand B is the more promising candidate. It has a better logP, lower DILI risk, lower microsomal clearance, longer half-life, and slightly better Pgp efflux and affinity. While both have issues with Caco-2 and solubility, Ligand B's superior ADME properties, particularly the lower DILI and better metabolic stability, outweigh the slightly better affinity of Ligand A. The TPSA of Ligand B is also more favorable for CNS penetration.

Output:
1
2025-04-17 08:31:09,651 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (347.459 and 353.419 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (65.79) is significantly better than Ligand B (113.17). For CNS targets, we want TPSA <= 90, and A is comfortably within this range, while B exceeds it.

**logP:** Ligand A (2.183) is optimal (1-3). Ligand B (-0.735) is below 1, which could hinder permeation.

**H-Bond Donors/Acceptors:** Ligand A (HBD=1, HBA=4) and Ligand B (HBD=2, HBA=5) both have reasonable counts, within the guidelines.

**QED:** Both ligands have good QED scores (A=0.907, B=0.632), indicating good drug-like properties.

**DILI:** Ligand A (15.626) has a much lower DILI risk than Ligand B (22.451). Both are below 40, which is good.

**BBB:** Ligand A (69.407) is better than Ligand B (63.474), although both are reasonably good. A score >70 is desirable for CNS targets, but these are acceptable.

**Caco-2 Permeability:** Both have negative Caco-2 values (-4.977 and -4.897), which is unusual and suggests poor permeability. However, these values are on a scale where negative values are possible, and direct comparison is difficult without knowing the scale's specifics.

**Aqueous Solubility:** Both have negative solubility values (-1.6 and -1.176), also unusual. Similar to Caco-2, direct comparison is difficult.

**hERG Inhibition:** Ligand A (0.615) has a lower hERG risk than Ligand B (0.178), which is preferable.

**Microsomal Clearance:** Ligand A (0.977) has a lower (better) microsomal clearance than Ligand B (-0.583). This indicates better metabolic stability.

**In vitro Half-Life:** Ligand A (20.731) has a significantly longer half-life than Ligand B (-25.607).

**P-gp Efflux:** Ligand A (0.075) has lower P-gp efflux than Ligand B (0.029), which is desirable for CNS penetration.

**Binding Affinity:** Both ligands have very similar and strong binding affinities (-8.0 and -7.9 kcal/mol). The difference is negligible.

**Overall Assessment:**

Ligand A is clearly superior. It has a better TPSA, logP, DILI score, BBB penetration, microsomal clearance, in vitro half-life, and P-gp efflux. While both have unusual Caco-2 and solubility values, the other advantages of Ligand A, particularly its favorable TPSA and logP for CNS penetration, make it the more promising candidate. The slightly lower hERG risk is also a bonus. The binding affinity is essentially the same for both.

Output:
1
2025-04-17 08:31:09,651 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (349.475 and 351.403 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (69.72) is excellent, well below the 90 A^2 threshold for CNS targets. Ligand B (100.99) is still reasonable but less optimal, nearing the 140 A^2 threshold for oral absorption.

**logP:** Ligand A (1.852) is within the optimal 1-3 range. Ligand B (0.097) is quite low, potentially hindering membrane permeability and CNS penetration.

**H-Bond Donors/Acceptors:** Ligand A (1 HBD, 3 HBA) is favorable. Ligand B (2 HBD, 6 HBA) is also acceptable, but the higher HBA count could slightly impact permeability.

**QED:** Both ligands have good QED scores (0.713 and 0.754), indicating drug-like properties.

**DILI:** Both ligands have low DILI risk (26.871 and 23.226), which is positive.

**BBB:** Ligand A excels with a BBB percentile of 73.672, highly desirable for a CNS target like DRD2. Ligand B's BBB percentile is significantly lower at 48.236, raising concerns about CNS exposure.

**Caco-2 Permeability:** Ligand A (-4.887) has poor Caco-2 permeability. Ligand B (-5.177) also has poor Caco-2 permeability.

**Aqueous Solubility:** Both ligands have poor aqueous solubility (-1.843 and -1.342).

**hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.157 and 0.036).

**Microsomal Clearance:** Ligand A (53.04 mL/min/kg) has moderate clearance. Ligand B shows excellent metabolic stability with a negative clearance (-13.599 mL/min/kg).

**In vitro Half-Life:** Ligand A (15.371 hours) has a reasonable half-life. Ligand B has a very short half-life (-12.992 hours).

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.037 and 0.003), which is favorable for CNS penetration.

**Binding Affinity:** Ligand B (-8.1 kcal/mol) has a significantly stronger binding affinity than Ligand A (-0 kcal/mol). This is a substantial advantage.

**Overall Assessment:**

While Ligand B boasts a much stronger binding affinity, its low logP and poor Caco-2 permeability are major drawbacks, especially considering the need for BBB penetration. The low BBB percentile further reinforces this concern. Ligand A, despite its weak binding affinity, has a much more favorable profile for CNS penetration (excellent BBB, reasonable logP, low P-gp efflux). The poor Caco-2 permeability and solubility are concerning, but these can often be addressed with formulation strategies. The weak binding affinity of Ligand A is a significant issue, but it could potentially be improved through further optimization.

Given the GPCR-specific priorities and the importance of CNS penetration for DRD2, Ligand A is the more promising candidate *at this stage*. The binding affinity is the biggest weakness, but the other properties are more conducive to achieving brain exposure.

Output:
0
2025-04-17 08:31:09,652 - INFO - Reasoning:

Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (343.471 and 350.419 Da) fall comfortably within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (62.3) is excellent, well below the 90 Angstroms threshold for CNS targets. Ligand B (93.65) is higher but still potentially acceptable, though less ideal.

**3. logP:** Ligand A (3.166) is optimal. Ligand B (0.877) is a bit low, potentially hindering membrane permeability.

**4. H-Bond Donors:** Both ligands have 1 HBD, which is within the acceptable limit of 5.

**5. H-Bond Acceptors:** Ligand A has 3 HBAs, and Ligand B has 6. Both are within the acceptable limit of 10, but Ligand A is preferable.

**6. QED:** Both ligands have good QED scores (0.582 and 0.784), indicating drug-like properties.

**7. DILI:** Ligand A (31.33) has a significantly lower DILI risk than Ligand B (63.397). This is a substantial advantage.

**8. BBB:** Ligand A (76.813) has a much better BBB penetration percentile than Ligand B (52.617). This is critical for a CNS target like DRD2.

**9. Caco-2 Permeability:** Both have negative values, indicating poor permeability. However, the scale is not specified, so it's difficult to interpret.

**10. Aqueous Solubility:** Both have negative values, indicating poor solubility. Again, the scale is not specified.

**11. hERG Inhibition:** Ligand A (0.717) has a lower hERG inhibition risk than Ligand B (0.19).

**12. Microsomal Clearance:** Ligand A (72.216) has higher microsomal clearance than Ligand B (25.512), indicating lower metabolic stability. This is a drawback for Ligand A.

**13. In vitro Half-Life:** Ligand B (-24.759) has a significantly longer in vitro half-life than Ligand A (-2.775). This is a major advantage for Ligand B.

**14. P-gp Efflux:** Ligand A (0.381) has lower P-gp efflux liability than Ligand B (0.031), which is favorable for CNS penetration.

**15. Binding Affinity:** Ligand A (-8.5 kcal/mol) has a slightly better binding affinity than Ligand B (-7.5 kcal/mol). This 1 kcal/mol difference is significant and can outweigh some ADME drawbacks.

**Overall Assessment:**

Ligand A is superior due to its excellent TPSA, optimal logP, significantly lower DILI risk, and better BBB penetration. The slightly better binding affinity further supports its selection. While Ligand A has higher microsomal clearance, the benefits in other key areas, particularly BBB and safety (DILI, hERG), are more critical for a CNS-targeting GPCR. Ligand B's longer half-life is a plus, but the poor logP and higher DILI/lower BBB are significant concerns.



Output:
1
2025-04-17 08:31:09,652 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (348.403 and 345.451 Da) fall comfortably within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (84.86) and Ligand B (82.68) are both below the 90 A^2 threshold desirable for CNS targets, which is excellent.

**3. logP:** Ligand A (0.669) is a bit low, potentially hindering permeation. Ligand B (1.354) is better, falling within the optimal 1-3 range.

**4. H-Bond Donors:** Ligand A (0) and Ligand B (1) are both acceptable, well below the 5 limit.

**5. H-Bond Acceptors:** Ligand A (6) and Ligand B (8) are both below the 10 limit.

**6. QED:** Both ligands have similar QED values (0.703 and 0.655), indicating good drug-likeness.

**7. DILI:** Ligand A (63.629) has a higher DILI risk than Ligand B (34.393). This is a significant drawback for Ligand A.

**8. BBB:** Both ligands have good BBB penetration (Ligand A: 72.354, Ligand B: 70.919), exceeding the 70 percentile threshold for CNS targets.

**9. Caco-2 Permeability:** Ligand A (-4.344) has poor Caco-2 permeability, while Ligand B (-5.547) is also poor, but slightly worse.

**10. Aqueous Solubility:** Both ligands have very poor aqueous solubility (-0.967 and -1.233). This is a concern for both, but not a deciding factor given the CNS target.

**11. hERG Inhibition:** Ligand A (0.087) has a very low hERG risk, which is excellent. Ligand B (0.201) is slightly higher, but still relatively low.

**12. Microsomal Clearance:** Ligand A (34.664) has higher microsomal clearance than Ligand B (17.61), suggesting lower metabolic stability.

**13. In vitro Half-Life:** Ligand A (-26.475) has a very short in vitro half-life, a significant negative. Ligand B (2.892) is better, but still not ideal.

**14. P-gp Efflux:** Both ligands have very low P-gp efflux (0.011 and 0.17), which is favorable for CNS penetration.

**15. Binding Affinity:** Ligand A (-7.5) has a slightly stronger binding affinity than Ligand B (-7.1). However, the difference is only 0.4 kcal/mol, which may not be enough to overcome other weaknesses.

**Overall Assessment:**

Ligand B is the more promising candidate. While both have poor solubility and Caco-2 permeability (less concerning for a CNS target), Ligand B has a significantly lower DILI risk, better metabolic stability (lower Cl_mic, longer t1/2), and a more favorable logP value. The slightly weaker binding affinity of Ligand B is likely outweighed by its superior ADME properties and safety profile. Ligand A's very short half-life and higher DILI risk are major concerns.

Output:
1
2025-04-17 08:31:09,652 - INFO - Batch 455 complete. Total preferences: 7280
2025-04-17 08:31:09,652 - INFO - Processing batch 456/512...
2025-04-17 08:31:52,988 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (352.479 and 360.439 Da) are within the ideal range of 200-500 Da.

**2. TPSA:** Both ligands (95.74 and 96.11) are below the 140 A^2 threshold for good oral absorption, but slightly above the stricter <90 A^2 for CNS targets. This is not a major concern, but something to note.

**3. logP:** Ligand A (0.191) is quite low, potentially hindering permeation. Ligand B (2.182) is within the optimal 1-3 range. This is a significant advantage for Ligand B.

**4. H-Bond Donors:** Ligand A (2) and Ligand B (3) are both acceptable, within the limit of 5.

**5. H-Bond Acceptors:** Ligand A (4) and Ligand B (5) are both acceptable, within the limit of 10.

**6. QED:** Both ligands have good QED values (0.684 and 0.703), suggesting good drug-like properties.

**7. DILI:** Ligand A (10.314) has a very favorable DILI score, indicating low liver injury risk. Ligand B (72.896) has a significantly higher DILI score, raising a potential concern.

**8. BBB:** Ligand A (53.47) has a moderate BBB penetration score, while Ligand B (48.391) is lower. Both are below the desirable >70 for CNS targets, but Ligand A is slightly better.

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.517 and -5.161). This is unusual and suggests poor permeability. However, these values are on a log scale and should be interpreted cautiously.

**10. Aqueous Solubility:** Both ligands have negative solubility values (-1.526 and -4.427), indicating poor aqueous solubility. This could pose formulation challenges.

**11. hERG Inhibition:** Both ligands have low hERG inhibition risk (0.139 and 0.309).

**12. Microsomal Clearance:** Ligand A (15.565) has a lower microsomal clearance than Ligand B (42.111), suggesting better metabolic stability.

**13. In vitro Half-Life:** Ligand A (-7.884) has a significantly longer in vitro half-life than Ligand B (-16.396).

**14. P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.003 and 0.034), which is favorable for CNS exposure.

**15. Binding Affinity:** Ligand B (-8.2 kcal/mol) has a slightly better binding affinity than Ligand A (-7.0 kcal/mol). This difference of 1.2 kcal/mol is substantial and could outweigh some of the ADME drawbacks.

**Overall Assessment:**

Ligand B has a significantly better binding affinity, which is paramount for GPCR targets. While its DILI score is higher and its logP is better than Ligand A, the affinity difference is substantial. Ligand A has better metabolic stability and lower DILI, but the lower logP and weaker binding are concerning. Considering the GPCR-specific priorities, the binding affinity is the most important factor here.

Output:
1
2025-04-17 08:31:52,988 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (349.431 and 355.366 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (84.67) is excellent, well below the 90 A^2 threshold for CNS targets. Ligand B (108.73) is still reasonable, but less optimal, being above 90.

**logP:** Ligand A (1.978) is within the optimal 1-3 range. Ligand B (-0.077) is slightly below 1, which could potentially hinder permeation.

**H-Bond Donors/Acceptors:** Both ligands have 1 HBD and 5/6 HBA, respectively, which are within acceptable limits.

**QED:** Both ligands have QED values above 0.6, indicating good drug-likeness.

**DILI:** Ligand A (28.306) has a lower DILI risk than Ligand B (36.487), both are acceptable.

**BBB:** Ligand A (76.58) and Ligand B (84.025) both have good BBB penetration, exceeding the 70% threshold. Ligand B is slightly better.

**Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and suggests a potential issue with the data or modeling. However, we'll proceed assuming these represent permeability scores and higher is better. Ligand A (-4.223) is worse than Ligand B (-4.777).

**Aqueous Solubility:** Both have negative solubility values, which is also unusual. Ligand A (-2.747) is slightly better than Ligand B (-2.002).

**hERG Inhibition:** Both ligands show low hERG inhibition liability (0.17 and 0.248), which is favorable.

**Microsomal Clearance:** Ligand A (53.474) has a higher microsomal clearance than Ligand B (2.226), indicating lower metabolic stability.

**In vitro Half-Life:** Ligand B (-4.717) has a significantly longer in vitro half-life than Ligand A (11.56).

**P-gp Efflux:** Both ligands show very low P-gp efflux liability (0.066 and 0.022), which is excellent for CNS penetration.

**Binding Affinity:** Ligand B (-7.2 kcal/mol) has a slightly better binding affinity than Ligand A (-8.0 kcal/mol). While A is better, the difference is not substantial enough to outweigh other factors.

**Overall Assessment:**

Ligand A has better TPSA and a slightly better affinity, but Ligand B excels in BBB penetration, has a much longer half-life, lower microsomal clearance, and a slightly better binding affinity. The logP of Ligand B is a concern, but the excellent BBB penetration and longer half-life are critical for a CNS-targeting GPCR like DRD2. The negative solubility and Caco-2 values are concerning for both, but the other properties of Ligand B are more favorable overall.

Output:
1
2025-04-17 08:31:52,988 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, considering the provided guidelines and GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (404.895 Da) is slightly higher than Ligand B (345.407 Da), but both are acceptable.

**TPSA:** Ligand A (51.02) is excellent for CNS penetration, well below the 90 A^2 threshold. Ligand B (124.78) is higher, but still potentially acceptable, though less ideal for CNS targets.

**logP:** Ligand A (3.222) is optimal. Ligand B (0.984) is a bit low, potentially hindering membrane permeability.

**H-Bond Donors/Acceptors:** Ligand A (0 HBD, 6 HBA) is favorable. Ligand B (2 HBD, 5 HBA) is also acceptable.

**QED:** Ligand A (0.663) is good, indicating drug-likeness. Ligand B (0.316) is lower, suggesting a less drug-like profile.

**DILI:** Ligand A (77.666) has a moderate DILI risk. Ligand B (41.14) has a lower DILI risk, which is preferable.

**BBB:** Ligand A (88.29) has excellent BBB penetration potential. Ligand B (31.718) has poor BBB penetration, a significant drawback for a CNS target like DRD2.

**Caco-2 Permeability:** Ligand A (-4.933) has poor Caco-2 permeability. Ligand B (-5.311) also has poor Caco-2 permeability.

**Aqueous Solubility:** Ligand A (-4.136) has poor aqueous solubility. Ligand B (-1.509) has slightly better, but still poor aqueous solubility.

**hERG Inhibition:** Ligand A (0.297) has very low hERG inhibition risk. Ligand B (0.062) also has very low hERG inhibition risk.

**Microsomal Clearance:** Ligand A (48.072) has moderate clearance. Ligand B (18.601) has lower clearance, indicating better metabolic stability, which is beneficial.

**In vitro Half-Life:** Ligand A (-27.432) has a very long in vitro half-life. Ligand B (1.295) has a very short in vitro half-life.

**P-gp Efflux:** Ligand A (0.523) has moderate P-gp efflux. Ligand B (0.007) has very low P-gp efflux, which is highly desirable for CNS penetration.

**Binding Affinity:** Ligand A (-8.1 kcal/mol) has significantly better binding affinity than Ligand B (-7.5 kcal/mol). The 1.6 kcal/mol difference in affinity is substantial and can outweigh some ADME concerns.

**Overall Assessment:**

Ligand A excels in binding affinity and BBB penetration, crucial for a CNS-targeting GPCR. While its Caco-2 permeability and aqueous solubility are poor, the strong affinity and good BBB offset these concerns. Ligand B has better metabolic stability and lower DILI risk, but its significantly lower affinity and poor BBB penetration make it a less attractive candidate for DRD2. The affinity difference is large enough to overcome the ADME liabilities of Ligand A.

Output:
1
2025-04-17 08:31:52,988 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (360.361 and 348.443 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (110.56) is slightly above the preferred <90 for CNS targets, but still reasonable. Ligand B (84.5) is well within the optimal range. This favors Ligand B.

**3. logP:** Ligand A (-0.671) is a bit low, potentially hindering membrane permeability. Ligand B (1.534) is within the optimal 1-3 range. This strongly favors Ligand B.

**4. H-Bond Donors:** Both ligands have 2 HBD, which is acceptable (<=5).

**5. H-Bond Acceptors:** Ligand A has 8 HBA, which is acceptable (<=10). Ligand B has 4 HBA, which is also acceptable and slightly better.

**6. QED:** Ligand A (0.689) has a good drug-likeness score. Ligand B (0.376) is below the 0.5 threshold, indicating a less drug-like profile. This favors Ligand A.

**7. DILI:** Ligand A (55.68) has a moderate DILI risk. Ligand B (22.8) has a low DILI risk, which is highly desirable. This favors Ligand B.

**8. BBB:** Ligand A (78.364) has a good BBB penetration percentile. Ligand B (54.905) is lower, which is a significant drawback for a CNS target like DRD2. This favors Ligand A.

**9. Caco-2:** Both have negative values, which is unusual. Assuming these are percentile scores, both are poor.

**10. Solubility:** Both have negative values, indicating poor solubility.

**11. hERG:** Both ligands have low hERG inhibition liability (0.45 and 0.091, respectively), which is good.

**12. Cl_mic:** Ligand A (-7.839) suggests very low clearance and high metabolic stability. Ligand B (55.404) indicates higher clearance and lower metabolic stability. This favors Ligand A.

**13. t1/2:** Ligand A (-28.204) suggests a very long half-life. Ligand B (-21.16) has a shorter half-life. This favors Ligand A.

**14. Pgp:** Both ligands have very low Pgp efflux liability (0.128 and 0.024, respectively), which is excellent.

**15. Binding Affinity:** Both ligands have strong binding affinities (-7.7 and -7.5 kcal/mol). Ligand A is slightly better (-7.7 kcal/mol).

**Overall Assessment:**

While Ligand A has a slightly better binding affinity and significantly better metabolic stability (Cl_mic, t1/2) and BBB penetration, Ligand B excels in TPSA, logP, and DILI risk. The critical factors for a CNS GPCR target are BBB penetration, logP, and affinity. Ligand A's superior BBB (78.364 vs 54.905) and slightly better affinity, combined with its excellent metabolic stability, outweigh the slightly lower logP and QED. The lower DILI risk of Ligand B is attractive, but can be addressed during further optimization.

Output:
0
2025-04-17 08:31:52,988 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (343.479 and 341.371 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (72.97) is excellent, well below the 90 A^2 threshold for CNS targets. Ligand B (88.01) is still reasonable, but less optimal.

**logP:** Both ligands have good logP values (2.165 and 2.389), falling within the 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A has 2 HBD and 6 HBA, which is a good balance. Ligand B has 0 HBD and 7 HBA. While both are within acceptable limits, the presence of some HBDs in Ligand A could be beneficial for solubility.

**QED:** Ligand A (0.751) has a significantly better QED score than Ligand B (0.464), indicating a more drug-like profile.

**DILI:** Ligand A (25.087) has a much lower DILI risk than Ligand B (77.2), which is a major advantage.

**BBB:** Ligand A (69.756) has a better BBB percentile than Ligand B (63.474), though both are somewhat below the ideal >70 for CNS targets.

**Caco-2 Permeability:** Ligand A (-5.453) has worse Caco-2 permeability than Ligand B (-4.995), but both are negative values, indicating poor permeability.

**Aqueous Solubility:** Ligand A (-1.798) has better aqueous solubility than Ligand B (-2.992).

**hERG:** Ligand A (0.934) has a lower hERG risk than Ligand B (0.473), which is preferable.

**Microsomal Clearance:** Ligand A (26.577) has significantly lower microsomal clearance than Ligand B (51.147), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (0.988) has a better in vitro half-life than Ligand B (-27.634).

**P-gp Efflux:** Ligand A (0.067) has a much lower P-gp efflux liability than Ligand B (0.538), which is crucial for CNS penetration.

**Binding Affinity:** Ligand B (-8.7 kcal/mol) has a significantly stronger binding affinity than Ligand A (-7.2 kcal/mol). This is a substantial advantage, exceeding the 1.5 kcal/mol threshold.

**Overall Assessment:**

While Ligand B boasts a superior binding affinity, Ligand A demonstrates a much more favorable ADME-Tox profile. Specifically, the lower DILI risk, better BBB penetration, lower P-gp efflux, improved metabolic stability (lower Cl_mic and better t1/2), and better QED score are compelling advantages. The slightly worse Caco-2 permeability of Ligand A is a concern, but the other benefits, particularly the lower P-gp efflux and better BBB, are critical for a CNS-targeting drug. The affinity difference, while significant, might be overcome with further optimization of Ligand A, whereas improving the ADME properties of Ligand B would likely be more challenging.

Output:
0
2025-04-17 08:31:52,988 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (348.487 and 358.429 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (69.64) is slightly higher than Ligand B (67.43), but both are below the 90 A^2 threshold desirable for CNS targets.

**3. logP:** Both ligands have good logP values (2.249 and 2.417), falling within the optimal 1-3 range.

**4. H-Bond Donors:** Both ligands have 2 HBD, which is within the acceptable limit of <=5.

**5. H-Bond Acceptors:** Both ligands have 3 HBA, also within the acceptable limit of <=10.

**6. QED:** Both ligands have QED values above 0.6 (0.693 and 0.622), indicating good drug-likeness.

**7. DILI:** Ligand A (6.941) has a significantly lower DILI risk than Ligand B (29.042). This is a substantial advantage.

**8. BBB:** Ligand B (89.066) has a much higher BBB penetration percentile than Ligand A (66.111). This is a critical advantage for a CNS target like DRD2.

**9. Caco-2 Permeability:** Ligand A (-4.646) has a lower Caco-2 permeability than Ligand B (-4.861), suggesting potentially poorer intestinal absorption. However, for a CNS target, intestinal absorption is less critical than BBB penetration.

**10. Aqueous Solubility:** Both ligands have negative solubility values (-2.264 and -2.691), indicating poor aqueous solubility. This could be a formulation challenge, but not a deal-breaker if other properties are favorable.

**11. hERG Inhibition:** Both ligands have low hERG inhibition liability (0.217 and 0.419), which is good.

**12. Microsomal Clearance:** Ligand A (32.98) has a higher microsomal clearance than Ligand B (24.161), indicating lower metabolic stability.

**13. In vitro Half-Life:** Ligand B (2.168) has a longer in vitro half-life than Ligand A (-4.308), suggesting better stability.

**14. P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.014 and 0.03), which is excellent for CNS penetration.

**15. Binding Affinity:** Both ligands have very similar binding affinities (-7.9 and -7.8 kcal/mol). The difference is negligible.

**Overall Assessment:**

Ligand B is superior due to its significantly better BBB penetration (89.066 vs 66.111), longer half-life, and lower DILI risk. While Ligand A has slightly better Caco-2 permeability, this is less important for a CNS target. The similar binding affinities make the ADME properties the deciding factor.

Output:
1
2025-04-17 08:31:52,988 - INFO - Reasoning:

Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands fall within the ideal range (200-500 Da). Ligand A (426.332 Da) is slightly higher, but still acceptable. Ligand B (348.443 Da) is a bit lower, but not concerning.

**2. TPSA:** Ligand A (55.84) is excellent, well below the 90 Angstroms threshold for CNS targets. Ligand B (76.66) is higher, but still reasonably good, though less optimal for CNS penetration.

**3. logP:** Ligand A (3.603) is within the optimal range (1-3). Ligand B (1.307) is on the lower side, potentially hindering permeability.

**4. H-Bond Donors:** Ligand A (0) is ideal. Ligand B (2) is acceptable.

**5. H-Bond Acceptors:** Both ligands have 4 H-bond acceptors, which is within the acceptable limit of 10.

**6. QED:** Ligand A (0.709) has a good drug-likeness score. Ligand B (0.374) is significantly lower, indicating a less drug-like profile.

**7. DILI:** Ligand A (70.841) has a higher DILI risk, but is still below the concerning 60 percentile threshold. Ligand B (36.603) has a much lower, and preferable, DILI risk.

**8. BBB:** Ligand A (52.191) has moderate BBB penetration. Ligand B (58.085) is also moderate. Both are below the desirable >70% for CNS targets, but not disqualifying.

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.814 and -5.009), which is unusual and suggests poor permeability. This is a significant concern for both.

**10. Aqueous Solubility:** Both ligands have negative solubility values (-5.722 and -2.396), indicating very poor aqueous solubility. This is a major drawback for both.

**11. hERG Inhibition:** Ligand A (0.753) has a slightly higher hERG risk than Ligand B (0.292).

**12. Microsomal Clearance:** Ligand A (106.457) has higher microsomal clearance, suggesting lower metabolic stability. Ligand B (16.968) has much lower clearance, indicating better metabolic stability.

**13. In vitro Half-Life:** Ligand A (19.242) has a longer half-life than Ligand B (-4.566).

**14. P-gp Efflux:** Ligand A (0.555) has lower P-gp efflux, which is favorable for CNS penetration. Ligand B (0.167) has even lower P-gp efflux, which is even more favorable.

**15. Binding Affinity:** Ligand A (-8.1 kcal/mol) has a slightly better binding affinity than Ligand B (-7.9 kcal/mol). This 1.5 kcal/mol difference is significant and could outweigh some ADME drawbacks.

**Overall Assessment:**

Despite both compounds having significant issues with solubility and Caco-2 permeability, Ligand A appears to be the better candidate. Its superior binding affinity (-8.1 vs -7.9 kcal/mol) is a crucial advantage for a GPCR target. It also has a better QED score and a longer half-life. While Ligand A has a higher DILI risk and clearance, these are less critical than the binding affinity and drug-likeness. The lower P-gp efflux for both is a positive. The poor solubility and permeability would need to be addressed through formulation strategies or further chemical modifications, but the stronger binding affinity of Ligand A makes it a more promising starting point.

Output:
1
2025-04-17 08:31:52,989 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 drug candidates, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (381.977 Da) is slightly higher than Ligand B (347.419 Da), but both are acceptable.

**TPSA:** Ligand A (45.98) is excellent for CNS penetration, well below the 90 A^2 threshold. Ligand B (91.3) is higher, potentially hindering BBB penetration, though not drastically.

**logP:** Ligand A (4.422) is a bit high, potentially leading to solubility issues or off-target interactions. Ligand B (0.377) is quite low, which could impede membrane permeability and reduce CNS exposure.

**H-Bond Donors/Acceptors:** Both ligands have acceptable HBD (1) and HBA (6/5) counts, falling within the recommended ranges.

**QED:** Both ligands have good QED scores (0.851 and 0.78), indicating good drug-like properties.

**DILI:** Ligand A (53.974) has a moderate DILI risk, while Ligand B (41.76) has a lower risk. This favors Ligand B.

**BBB:** Ligand A (83.908) has a very good BBB percentile, highly desirable for a CNS target. Ligand B (55.176) is considerably lower, a significant drawback.

**Caco-2 Permeability:** Ligand A (-4.941) shows poor Caco-2 permeability, which is concerning. Ligand B (-5.053) is similarly poor.

**Aqueous Solubility:** Both ligands have poor aqueous solubility (-4.296 and -2.123). This is a potential issue, but can sometimes be mitigated with formulation strategies.

**hERG Inhibition:** Both ligands show very low hERG inhibition risk (0.767 and 0.095), which is excellent.

**Microsomal Clearance:** Ligand A (52.497) has moderate clearance, while Ligand B (13.605) has very low clearance, suggesting better metabolic stability. This favors Ligand B.

**In vitro Half-Life:** Ligand A (66.275) has a reasonable half-life, while Ligand B (-22.698) has a very short half-life, which is a major concern.

**P-gp Efflux:** Both ligands show low P-gp efflux liability (0.702 and 0.028), which is favorable for CNS penetration.

**Binding Affinity:** Both ligands have the same binding affinity (-8.3 kcal/mol), which is excellent and removes this as a differentiating factor.

**Overall Assessment:**

Ligand A excels in BBB penetration and has a reasonable half-life, but suffers from high logP, poor Caco-2 permeability, and moderate DILI risk. Ligand B has lower DILI risk and significantly better metabolic stability (lower Cl_mic), but its BBB penetration is poor, and its half-life is very short.

Given the GPCR-specific priorities, BBB penetration is crucial for a CNS target like DRD2. While Ligand A's logP is a concern, the significantly better BBB penetration outweighs this drawback. The poor half-life of Ligand B is a major issue that would likely require significant medicinal chemistry efforts to address.

Output:
0
2025-04-17 08:31:52,989 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (357.303 and 357.445 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (48.42) is significantly better than Ligand B (61.44). For CNS targets, we want TPSA <= 90, and ideally closer to 60. Ligand A is much closer to this ideal.

**3. logP:** Ligand A (4.497) is slightly higher than optimal (1-3), but still potentially acceptable. Ligand B (2.085) is within the optimal range. However, for a GPCR, some lipophilicity is beneficial for membrane interactions, and the difference isn't drastic enough to immediately disqualify A.

**4. H-Bond Donors:** Ligand A (0) is preferable to Ligand B (2). Fewer H-bond donors generally improve membrane permeability.

**5. H-Bond Acceptors:** Ligand A (4) is slightly better than Ligand B (3). Both are within the acceptable range of <= 10.

**6. QED:** Both ligands have good QED scores (0.564 and 0.621), indicating good drug-like properties.

**7. DILI:** Ligand A (60.954) has a moderate DILI risk, while Ligand B (13.61) has a very low DILI risk. This is a significant advantage for Ligand B.

**8. BBB:** Ligand A (73.478) has a good BBB penetration score, while Ligand B (84.684) is excellent. This is a major advantage for Ligand B, given the CNS target.

**9. Caco-2 Permeability:** Both have negative Caco-2 values which is unusual and likely indicates a problem with the prediction method. However, the magnitude of the negative value is less for Ligand B (-4.948) than Ligand A (-4.368).

**10. Aqueous Solubility:** Both have negative solubility values, again likely a prediction issue. The magnitude is less negative for Ligand B (-2.226) than Ligand A (-5.213).

**11. hERG Inhibition:** Both ligands have low hERG inhibition risk (0.736 and 0.576).

**12. Microsomal Clearance:** Ligand A (75.52) has higher clearance than Ligand B (3.09), indicating lower metabolic stability. This is a significant advantage for Ligand B.

**13. In vitro Half-Life:** Ligand B (-12.29) has a much longer predicted half-life than Ligand A (-8.1). This is a major advantage for Ligand B.

**14. P-gp Efflux:** Ligand A (0.489) has lower P-gp efflux than Ligand B (0.019), which is favorable for CNS penetration.

**15. Binding Affinity:** Ligand A (-9.4 kcal/mol) has a significantly stronger binding affinity than Ligand B (-8.0 kcal/mol). This is a substantial advantage for Ligand A, potentially outweighing some of its ADME drawbacks.

**Overall Assessment:**

While Ligand A boasts a superior binding affinity, Ligand B has a much better ADME profile, particularly regarding BBB penetration, DILI risk, metabolic stability, and half-life. The strong affinity of Ligand A is tempting, but the combination of better safety (DILI), CNS penetration (BBB), and pharmacokinetic properties (Cl_mic, t1/2) makes Ligand B the more promising drug candidate. The slightly higher logP of Ligand A is less concerning than the significant ADME advantages of Ligand B.

Output:
1
2025-04-17 08:31:52,989 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight (MW):** Both ligands (345.447 and 349.475 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (70.47) is significantly better than Ligand B (91.22). For CNS targets, we want TPSA <= 90, so Ligand A is preferable.

**3. logP:** Ligand A (0.625) is a bit low, potentially hindering permeation. Ligand B (2.144) is within the optimal 1-3 range. This favors Ligand B.

**4. H-Bond Donors (HBD):** Both ligands have acceptable HBD counts (1 and 2, respectively), well below the threshold of 5.

**5. H-Bond Acceptors (HBA):** Both ligands have acceptable HBA counts (5 and 4, respectively), well below the threshold of 10.

**6. QED:** Both ligands have good QED scores (0.85 and 0.632), indicating good drug-like properties.

**7. DILI:** Ligand A (24.273) has a much lower DILI risk than Ligand B (6.282), which is a significant advantage.

**8. BBB:** Both ligands have good BBB penetration (67.817 and 68.941). While both are below the ideal >70, they are comparable.

**9. Caco-2 Permeability:** Ligand A (-5.047) shows poor Caco-2 permeability, while Ligand B (-4.665) is slightly better, but still poor.

**10. Aqueous Solubility:** Both ligands have poor aqueous solubility (-1.385 and -1.845).

**11. hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.436 and 0.371).

**12. Microsomal Clearance:** Ligand A (5.764) has lower microsomal clearance than Ligand B (19.944), suggesting better metabolic stability.

**13. In vitro Half-Life:** Ligand A (39.763) has a much longer in vitro half-life than Ligand B (10.966), which is a significant advantage.

**14. P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.008 and 0.007).

**15. Binding Affinity:** Ligand B (-7.5) has a slightly better binding affinity than Ligand A (-7.0), a 0.5 kcal/mol advantage.

**Overall Assessment:**

Ligand A excels in TPSA, DILI, metabolic stability (Cl_mic and t1/2), and has comparable BBB penetration. However, it suffers from low logP and poor Caco-2 permeability. Ligand B has a slightly better logP and binding affinity, but has a higher DILI risk, worse metabolic stability, and a shorter half-life.

Given the GPCR-specific priorities, the lower TPSA and significantly better safety profile (DILI) and metabolic stability of Ligand A outweigh the slightly lower logP and binding affinity. The improved metabolic stability and half-life are also crucial for CNS drug development. While the logP is suboptimal, it's not drastically outside the acceptable range, and could potentially be addressed with further optimization.

Output:
0
2025-04-17 08:31:52,989 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands are within the acceptable range (200-500 Da). Ligand A (352.519 Da) is slightly preferred as it's lower.

**2. TPSA:** Ligand A (78.43) is excellent for CNS penetration, well below 90. Ligand B (60.77) is also good, but slightly higher.

**3. logP:** Ligand A (2.19) is optimal. Ligand B (4.15) is pushing the upper limit and could potentially cause solubility issues or off-target interactions.

**4. H-Bond Donors:** Both ligands have acceptable HBD counts (Ligand A: 3, Ligand B: 2).

**5. H-Bond Acceptors:** Both ligands have acceptable HBA counts (Ligand A: 3, Ligand B: 4).

**6. QED:** Both ligands have similar QED values (Ligand A: 0.626, Ligand B: 0.578), indicating reasonable drug-likeness.

**7. DILI:** Both ligands have low DILI risk (Ligand A: 20.24, Ligand B: 23.032).

**8. BBB:** Ligand B (67.08) has a better BBB percentile than Ligand A (58.085), which is a significant advantage for a CNS target.

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.725 and -4.743), which is unusual and suggests poor permeability. This is a major concern for both.

**10. Aqueous Solubility:** Both ligands have very poor aqueous solubility (-3.319 and -5.238). This is a significant drawback.

**11. hERG Inhibition:** Ligand A (0.35) has a lower hERG risk than Ligand B (0.783), which is preferable.

**12. Microsomal Clearance:** Both ligands have similar microsomal clearance (Ligand A: 54.82, Ligand B: 57.529).

**13. In vitro Half-Life:** Ligand A (-13.125) has a significantly worse in vitro half-life than Ligand B (43.383). This is a major disadvantage for Ligand A.

**14. P-gp Efflux:** Ligand A (0.173) has lower P-gp efflux liability than Ligand B (0.8), which is favorable for CNS penetration.

**15. Binding Affinity:** Ligand B (-6.8 kcal/mol) has a significantly stronger binding affinity than Ligand A (-8.0 kcal/mol). This is a substantial advantage, potentially outweighing some of the ADME drawbacks.

**Overall Assessment:**

Ligand B has a stronger binding affinity and better BBB penetration, which are critical for a CNS GPCR target like DRD2. However, it has a higher logP and P-gp efflux, and worse solubility. Ligand A has better logP, P-gp, and hERG, but significantly worse half-life and a weaker binding affinity. The poor Caco-2 and solubility for both are concerning, but the binding affinity difference is substantial. Given the importance of affinity for GPCRs, and the relatively better BBB for Ligand B, it is the more promising candidate, *assuming* the solubility and permeability issues can be addressed through formulation or structural modification.

Output:
1
2025-04-17 08:31:52,989 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 drug candidates, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (356.813 and 348.422 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (64.16) is slightly above the optimal <90 for CNS targets, but still reasonable. Ligand B (58.44) is well within the desired range.

**logP:** Ligand A (3.452) is at the upper end of the optimal 1-3 range, while Ligand B (1.283) is at the lower end. While Ligand B's logP is acceptable, a slightly higher value is generally preferred for GPCRs to facilitate membrane permeability.

**H-Bond Donors/Acceptors:** Both ligands have a low number of HBDs (0) and acceptable HBAs (5 and 4 respectively), which is good for permeability.

**QED:** Both ligands have good QED scores (0.721 and 0.824), indicating drug-like properties.

**DILI:** Ligand A (84.219) has a higher DILI risk than Ligand B (23.187). This is a significant negative for Ligand A.

**BBB:** Ligand B (85.459) has a significantly better BBB penetration percentile than Ligand A (68.166). This is crucial for a CNS target like DRD2.

**Caco-2 Permeability:** Both have negative Caco-2 values which is unusual and suggests a potential issue with the data or modeling. However, we will proceed with the other parameters.

**Aqueous Solubility:** Both ligands have very poor aqueous solubility (-3.903 and -1.764). This is a concern for both, but may be less critical if BBB penetration is high.

**hERG:** Both ligands have low hERG inhibition liability (0.33 and 0.283), which is positive.

**Microsomal Clearance:** Ligand B (12.318) has a lower microsomal clearance than Ligand A (46.255), indicating better metabolic stability.

**In vitro Half-Life:** Both have negative in vitro half-life values (-9.797 and -7.509) which is unusual and suggests a potential issue with the data or modeling.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.277 and 0.033), which is favorable for CNS penetration.

**Binding Affinity:** Ligand B (-8.4 kcal/mol) has a slightly better binding affinity than Ligand A (-9.7 kcal/mol). While both are strong binders, the difference is notable.

**Overall Assessment:**

Ligand B is the stronger candidate. It has a significantly better BBB score, lower DILI risk, better metabolic stability (lower Cl_mic), and slightly better binding affinity. While its logP is a bit lower, the other advantages, particularly the superior BBB penetration and reduced toxicity risk, outweigh this drawback for a CNS-targeting GPCR. The solubility issues are a concern for both, but may be addressed through formulation strategies. The negative values for Caco-2 and half-life are concerning and would require further investigation, but do not outweigh the other benefits of Ligand B.

Output:
1
2025-04-17 08:31:52,989 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (348.531 and 346.431 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (49.41) is excellent, well below the 90 A^2 threshold for CNS targets. Ligand B (107.11) is higher, but still potentially acceptable, though less ideal.

**logP:** Ligand A (3.912) is at the upper end of the optimal range (1-3), but still acceptable. Ligand B (1.253) is a bit low, potentially hindering permeability.

**H-Bond Donors/Acceptors:** Ligand A (HBD=1, HBA=2) is favorable. Ligand B (HBD=4, HBA=4) is also acceptable, but higher HBD count could slightly impact permeability.

**QED:** Ligand A (0.676) is good, indicating strong drug-likeness. Ligand B (0.339) is significantly lower, suggesting a less drug-like profile.

**DILI:** Ligand A (25.785) has a very low DILI risk. Ligand B (50.136) is higher, but still within a reasonable range.

**BBB:** Ligand A (80.574) has excellent BBB penetration potential, exceeding the 70% threshold. Ligand B (22.412) is very poor, a major drawback for a CNS target.

**Caco-2 Permeability:** Ligand A (-4.795) and Ligand B (-5.244) have negative values, which is unusual and suggests poor permeability. The scale is not specified, so it's difficult to interpret, but both are likely low.

**Aqueous Solubility:** Ligand A (-3.756) and Ligand B (-2.98) have negative values, indicating low solubility.

**hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.465 and 0.247 respectively).

**Microsomal Clearance:** Ligand A (74.539) has moderate clearance. Ligand B (-8.229) has negative clearance, which is not physically possible and likely indicates an issue with the data.

**In vitro Half-Life:** Ligand A (-22.571) has a negative half-life, which is not possible and indicates a data issue. Ligand B (-9.525) also has a negative half-life.

**P-gp Efflux:** Ligand A (0.396) has low P-gp efflux, which is favorable. Ligand B (0.084) also has low P-gp efflux.

**Binding Affinity:** Ligand A (-8.1 kcal/mol) has significantly stronger binding affinity than Ligand B (0.0 kcal/mol). This is a crucial advantage.

**Overall Assessment:**

Ligand A is clearly superior. It has a better QED score, significantly better BBB penetration, and a much stronger binding affinity. While both have issues with solubility and Caco-2 permeability, the strong affinity and BBB penetration of Ligand A outweigh these concerns. The negative values for clearance and half-life for both compounds are concerning and suggest data quality issues, but the large difference in binding affinity is still decisive. Ligand B's extremely poor BBB penetration makes it a very unlikely candidate for a CNS-targeting drug.

Output:
1
2025-04-17 08:31:52,989 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (347.459 and 343.427 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (63.57) is significantly better than Ligand B (78.6). For a CNS target like DRD2, TPSA < 90 is preferred, and A is closer to the optimal <60 range. B is pushing the upper limit.

**3. logP:** Both ligands have acceptable logP values (1.725 and 2.757, respectively), falling within the 1-3 range.

**4. H-Bond Donors:** Both are acceptable (1 and 2, respectively), well below the limit of 5.

**5. H-Bond Acceptors:** Both are acceptable (4 and 5, respectively), well below the limit of 10.

**6. QED:** Both have similar, good QED values (0.852 and 0.808), indicating good drug-like properties.

**7. DILI:** Ligand A (28.926) has a much lower DILI risk than Ligand B (46.219). This is a significant advantage.

**8. BBB:** Ligand A (81.388) has a better BBB penetration percentile than Ligand B (71.384). While both are reasonably good, A is closer to the desirable >70 threshold for CNS targets.

**9. Caco-2 Permeability:** Both have negative Caco-2 values (-4.662 and -4.977), which is unusual and suggests poor permeability. This is a concern for both, but the values are similar.

**10. Aqueous Solubility:** Both have negative solubility values (-2.296 and -2.481) which is also unusual and suggests poor solubility. This is a concern for both, and the values are similar.

**11. hERG Inhibition:** Both ligands have low hERG inhibition risk (0.6 and 0.776, respectively).

**12. Microsomal Clearance:** Ligand A (14.094) has significantly lower microsomal clearance than Ligand B (26.781), suggesting better metabolic stability.

**13. In vitro Half-Life:** Ligand A (18.25) has a longer in vitro half-life than Ligand B (4.497), which is desirable.

**14. P-gp Efflux:** Both have low P-gp efflux liability (0.082 and 0.554, respectively), which is good for CNS penetration.

**15. Binding Affinity:** Ligand B (-7.7 kcal/mol) has a slightly better binding affinity than Ligand A (-8.3 kcal/mol). However, the difference is relatively small (0.6 kcal/mol), and other factors are more important.

**Overall Assessment:**

Ligand A is the superior candidate. While Ligand B has slightly better binding affinity, Ligand A excels in critical ADME properties for a CNS-targeting GPCR: lower DILI risk, better BBB penetration, lower microsomal clearance, and a longer half-life. The TPSA value is also significantly better for A. The negative Caco-2 and solubility values are concerning for both, but the other advantages of A outweigh the small affinity difference.

Output:
1
2025-04-17 08:31:52,990 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (367.486 and 348.403 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (54.45) is excellent, well below the 90 A^2 threshold for CNS targets. Ligand B (91.93) is slightly above, but still potentially acceptable.

**logP:** Ligand A (2.82) is optimal (1-3). Ligand B (1.316) is at the lower end of optimal, potentially impacting permeability.

**H-Bond Donors/Acceptors:** Ligand A (0 HBD, 3 HBA) is very favorable. Ligand B (3 HBD, 4 HBA) is also acceptable, though slightly higher.

**QED:** Both ligands have good QED scores (0.822 and 0.765), indicating good drug-like properties.

**DILI:** Ligand A (34.665) has a much lower DILI risk than Ligand B (60.682), which is approaching a higher risk category.

**BBB:** Ligand A (92.749) has excellent BBB penetration, exceeding the desirable >70% threshold. Ligand B (76.309) is good, but less favorable.

**Caco-2 Permeability:** Ligand A (-4.651) has poor Caco-2 permeability, which is a concern. Ligand B (-5.135) is similarly poor.

**Aqueous Solubility:** Both ligands have very poor aqueous solubility (-3.374 and -2.392). This could pose formulation challenges.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.562 and 0.368).

**Microsomal Clearance:** Ligand A (34.17) has moderate clearance, while Ligand B (3.538) has very low clearance, suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (0.656 hours) has a very short half-life. Ligand B (43.365 hours) has a very long half-life, a significant advantage.

**P-gp Efflux:** Both ligands show low P-gp efflux liability (0.308 and 0.015), which is good for CNS exposure.

**Binding Affinity:** Ligand B (-8.8 kcal/mol) has a slightly better binding affinity than Ligand A (-8.2 kcal/mol), but the difference is not huge.

**Overall Assessment:**

Ligand A excels in TPSA, DILI, and BBB penetration, crucial for a CNS-targeting GPCR. However, its poor Caco-2 permeability and very short half-life are major drawbacks.

Ligand B has better metabolic stability (lower Cl_mic, longer t1/2) and slightly better binding affinity. Its DILI risk is higher, and BBB penetration is good but not as high as Ligand A. The logP is lower, which could affect permeability.

Given the importance of CNS penetration for DRD2, and the relatively small difference in binding affinity, Ligand A is the more promising candidate *despite* its permeability and half-life issues. These could potentially be addressed through formulation strategies or prodrug approaches. The lower DILI risk is also a significant advantage.

Output:
0
2025-04-17 08:31:52,990 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands fall within the ideal range (200-500 Da). Ligand A (340.427 Da) is slightly preferred due to being lower in weight.

**2. TPSA:** Ligand A (50.6) is excellent, well below the 90 Angstroms threshold for CNS targets. Ligand B (84.3) is higher, but still acceptable, though less optimal for brain penetration.

**3. logP:** Both ligands have good logP values (A: 2.108, B: 2.485), falling within the 1-3 range.

**4. H-Bond Donors:** Ligand A (0) is preferable to Ligand B (1). Fewer H-bond donors generally improve permeability.

**5. H-Bond Acceptors:** Ligand A (4) is better than Ligand B (5), again favoring permeability.

**6. QED:** Both ligands have similar and acceptable QED values (A: 0.86, B: 0.816).

**7. DILI:** Ligand A (25.785) has a significantly lower DILI risk than Ligand B (70.725). This is a major advantage for Ligand A.

**8. BBB:** Ligand A (91.857) has a much higher predicted BBB penetration than Ligand B (72.547). This is critical for a CNS target like DRD2.

**9. Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and suggests a potential issue with the prediction method. However, the values are similar (-4.48 for A, -4.776 for B).

**10. Aqueous Solubility:** Ligand A (-1.744) is better than Ligand B (-3.39), indicating better solubility.

**11. hERG Inhibition:** Both ligands show low hERG inhibition liability (A: 0.691, B: 0.304), which is good.

**12. Microsomal Clearance:** Ligand B (27.797) has slightly lower microsomal clearance than Ligand A (31.55), suggesting better metabolic stability.

**13. In vitro Half-Life:** Ligand B (99.968) has a much longer in vitro half-life than Ligand A (-10.118). This is a significant advantage for Ligand B.

**14. P-gp Efflux:** Ligand A (0.342) has lower P-gp efflux than Ligand B (0.255), which is favorable for CNS exposure.

**15. Binding Affinity:** Both ligands have excellent binding affinities (A: -10.1 kcal/mol, B: -9.0 kcal/mol). Ligand A has a 1.1 kcal/mol advantage, which is substantial and can outweigh some ADME drawbacks.

**Overall Assessment:**

Ligand A is clearly the more promising candidate. While Ligand B has a better half-life, Ligand A excels in critical areas for a CNS-targeting GPCR ligand: significantly lower DILI risk, much higher predicted BBB penetration, better TPSA, solubility, and a stronger binding affinity. The lower HBD/HBA counts also contribute to better predicted permeability. The slight difference in metabolic stability is less concerning than the substantial advantages of Ligand A in other key parameters.

Output:
1
2025-04-17 08:31:52,990 - INFO - Batch 456 complete. Total preferences: 7296
2025-04-17 08:31:52,990 - INFO - Processing batch 457/512...
2025-04-17 08:32:34,973 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (351.447 and 368.459 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (89.95) is excellent, falling well below the 90 A^2 threshold for CNS targets. Ligand B (127.32) is still reasonable, but less optimal, being above 90.

**logP:** Both ligands (0.267 and 0.286) are quite low. While not terrible, logP values between 1-3 are preferred. This could indicate potential permeability issues.

**H-Bond Donors/Acceptors:** Ligand A (2 HBD, 4 HBA) is better than Ligand B (3 HBD, 6 HBA) in terms of balancing solubility and permeability.

**QED:** Both ligands have similar QED values (0.657 and 0.605), indicating good drug-like properties.

**DILI:** Ligand A (10.392) has a significantly lower DILI risk than Ligand B (43.622), which is a substantial advantage.

**BBB:** Ligand A (53.47) has a lower BBB penetration percentile than Ligand B (55.448). Both are below the desirable >70% for CNS targets, but Ligand B is slightly better.

**Caco-2 Permeability:** Ligand A (-4.989) has a worse Caco-2 permeability than Ligand B (-5.893).

**Aqueous Solubility:** Ligand A (-0.957) has better aqueous solubility than Ligand B (-2.752).

**hERG Inhibition:** Both ligands show very low hERG inhibition risk (0.118 and 0.029).

**Microsomal Clearance:** Ligand A (-5.543) has much lower microsomal clearance than Ligand B (21.061), indicating better metabolic stability.

**In vitro Half-Life:** Ligand A (5.421) has a shorter half-life than Ligand B (17.764).

**P-gp Efflux:** Both ligands show very low P-gp efflux liability (0.009 and 0.015).

**Binding Affinity:** Ligand B (-7.8 kcal/mol) has a slightly better binding affinity than Ligand A (-8.0 kcal/mol). However, the difference is small.

**Overall Assessment:**

Considering the GPCR-specific priorities, Ligand A is the more promising candidate. While both have low logP values, Ligand A's significantly lower DILI risk, better metabolic stability (lower Cl_mic), and better solubility are crucial advantages. The slightly lower BBB penetration is a concern, but the other ADME properties outweigh this. The affinity difference is minimal. Ligand B's higher DILI and clearance are significant drawbacks.

Output:
0
2025-04-17 08:32:34,973 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (341.451 Da) is slightly lower, which could be beneficial for permeability, while Ligand B (375.416 Da) is still well within acceptable limits.

**2. TPSA:** Ligand A (55.4) is significantly better than Ligand B (62.3). For CNS targets, TPSA should be <= 90, and lower is preferable. Ligand A is closer to the ideal range for CNS penetration.

**3. logP:** Both ligands have good logP values (A: 3.202, B: 2.27), falling within the optimal 1-3 range. Ligand A is slightly higher, which could potentially lead to off-target effects, but is still acceptable.

**4. H-Bond Donors:** Both have 1 HBD, which is within the acceptable limit of <= 5.

**5. H-Bond Acceptors:** Ligand A has 3 HBAs, and Ligand B has 4. Both are within the acceptable limit of <= 10.

**6. QED:** Both ligands have reasonable QED values (A: 0.856, B: 0.757), indicating good drug-like properties. Ligand A is slightly better.

**7. DILI:** Ligand A (30.748) has a significantly lower DILI risk than Ligand B (56.572). This is a major advantage for Ligand A.

**8. BBB:** Ligand A (67.468) and Ligand B (76.735) both have good BBB penetration, but Ligand B is better, exceeding 70%. However, the difference isn't massive.

**9. Caco-2 Permeability:** Ligand A (-4.329) has a worse Caco-2 permeability than Ligand B (-5.004). Lower values suggest lower permeability.

**10. Aqueous Solubility:** Ligand A (-4.625) has worse solubility than Ligand B (-2.893).

**11. hERG Inhibition:** Both ligands have very low hERG inhibition risk (A: 0.464, B: 0.272), which is excellent.

**12. Microsomal Clearance:** Ligand A (82.633) has a higher microsomal clearance than Ligand B (5.826), indicating faster metabolism and lower metabolic stability. This is a significant drawback for Ligand A.

**13. In vitro Half-Life:** Ligand A (-0.943) has a shorter half-life than Ligand B (-1.83).

**14. P-gp Efflux:** Ligand A (0.265) has lower P-gp efflux than Ligand B (0.047), which is favorable for CNS exposure.

**15. Binding Affinity:** Both ligands have excellent binding affinity (A: -8.2 kcal/mol, B: -8.4 kcal/mol). Ligand B is slightly better, but the difference is small.

**Overall Assessment:**

Ligand A excels in TPSA, DILI, and P-gp efflux. However, it suffers from poorer Caco-2 permeability, aqueous solubility, and significantly higher microsomal clearance and shorter half-life. Ligand B has better BBB penetration, solubility, metabolic stability, and half-life, but has a higher DILI risk and slightly worse TPSA.

Considering the GPCR-specific priorities, BBB is important, but metabolic stability (Cl_mic and t1/2) is crucial for CNS drugs. The significantly better metabolic profile of Ligand B outweighs its slightly higher DILI risk and slightly worse TPSA. The affinity difference is minimal.

Output:
1
2025-04-17 08:32:34,973 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (361.511 and 388.515 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (75.43) is excellent, well below the 90 A^2 threshold for CNS targets. Ligand B (121.18) is higher, but still potentially acceptable, though less ideal.

**logP:** Ligand A (2.621) is optimal (1-3). Ligand B (1.655) is slightly lower, but still within an acceptable range.

**H-Bond Donors/Acceptors:** Both ligands have 2 HBDs, which is good. Ligand A has 4 HBAs, and Ligand B has 7 HBAs. Both are within the acceptable range of <=10, but Ligand B is getting closer to the upper limit.

**QED:** Ligand A (0.817) has a superior QED score compared to Ligand B (0.629), indicating a more drug-like profile.

**DILI:** Ligand A (22.063) has a much lower DILI risk than Ligand B (58.395), which is a significant advantage.

**BBB:** This is crucial for a CNS target like DRD2. Ligand A (89.686) has a very good BBB percentile, exceeding the desirable >70 threshold. Ligand B (38.038) is significantly lower, indicating poor brain penetration.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.455 and -5.447), which is unusual and suggests poor permeability. This is a concern for both, but doesn't necessarily disqualify them.

**Aqueous Solubility:** Both ligands have negative solubility values (-3.774 and -2.594), suggesting poor aqueous solubility. This could pose formulation challenges.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.495 and 0.284).

**Microsomal Clearance:** Ligand A (12.905) has a lower microsomal clearance than Ligand B (41.793), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (-5.629) has a more negative (longer) half-life than Ligand B (12.488).

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.115 and 0.105).

**Binding Affinity:** Ligand A (-8.8 kcal/mol) has a significantly stronger binding affinity than Ligand B (-7.1 kcal/mol). This >1.5 kcal/mol difference is substantial and can outweigh some ADME drawbacks.

**Overall Assessment:**

Ligand A is clearly superior. It excels in critical areas for a CNS-targeting GPCR ligand: high BBB penetration, strong binding affinity, low DILI risk, and good metabolic stability. While both have issues with Caco-2 permeability and aqueous solubility, the superior profile of Ligand A, particularly its BBB and affinity, makes it the more promising candidate.

Output:
1
2025-04-17 08:32:34,973 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (349.471 and 366.864 Da) fall within the ideal 200-500 Da range.

**TPSA:** Both ligands (59.0 and 58.2) are below the 90 A^2 threshold for CNS targets, which is excellent.

**logP:** Both ligands have logP values within the optimal range (2.857 and 3.397). Ligand B is slightly higher, which could be a minor concern for solubility, but it's still acceptable.

**H-Bond Donors/Acceptors:** Ligand A (1 HBD, 4 HBA) and Ligand B (2 HBD, 2 HBA) both have reasonable H-bond characteristics, well within the recommended limits.

**QED:** Both ligands have high QED scores (0.822 and 0.81), indicating good drug-like properties.

**DILI:** Both ligands show low DILI risk (18.224 and 39.511 percentile), which is favorable.

**BBB:** This is a crucial parameter for a CNS target like DRD2. Ligand B (83.637%) significantly outperforms Ligand A (41.528%). This is a major advantage for Ligand B.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.422 and -4.563). These values are unusual and suggest poor permeability. However, these are likely reported as logP values and are therefore negative. In this case, lower (more negative) values indicate lower permeability.

**Aqueous Solubility:** Both ligands have negative solubility values (-2.676 and -4.455). Similar to Caco-2, these are likely logS values and therefore negative. Lower values indicate lower solubility.

**hERG:** Both ligands have low hERG inhibition liability (0.749 and 0.666), which is good.

**Microsomal Clearance:** Ligand A (70.92) has a higher microsomal clearance than Ligand B (50.412), suggesting Ligand B is more metabolically stable.

**In vitro Half-Life:** Ligand B (23.333 hours) has a significantly longer in vitro half-life than Ligand A (15.195 hours). This is a positive attribute for Ligand B.

**P-gp Efflux:** Both ligands show low P-gp efflux (0.497 and 0.31), which is beneficial for CNS penetration. Ligand B is slightly better here.

**Binding Affinity:** Ligand B (-9.4 kcal/mol) has a substantially stronger binding affinity than Ligand A (-7.4 kcal/mol). This difference of 2 kcal/mol is significant and can outweigh some minor ADME drawbacks.

**Overall Assessment:**

Ligand B is the superior candidate. While both ligands have acceptable physicochemical properties, Ligand B excels in the critical areas for a CNS-targeting GPCR: significantly better BBB penetration, stronger binding affinity, and improved metabolic stability (lower Cl_mic and longer t1/2). The slightly higher logP of Ligand B is a minor concern compared to these advantages.

Output:
1
2025-04-17 08:32:34,973 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (357.841 and 337.379 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (62.3) is significantly better than Ligand B (83.48). For CNS targets, TPSA should be <= 90, and lower is preferred. Ligand A is much closer to the ideal <60 range.

**3. logP:** Both ligands have good logP values (3.678 and 3.099), falling within the optimal 1-3 range.

**4. H-Bond Donors:** Ligand A (1) is better than Ligand B (3). Lower HBDs generally improve permeability.

**5. H-Bond Acceptors:** Ligand A (3) is better than Ligand B (4). Lower HBAs generally improve permeability.

**6. QED:** Both ligands have acceptable QED values (0.83 and 0.668), indicating good drug-like properties.

**7. DILI:** Ligand A (62.117) is better than Ligand B (83.133). Both are above the 60 threshold, indicating a higher risk of DILI, but A is preferable.

**8. BBB:** Ligand A (71.966) is significantly better than Ligand B (41.722). For a CNS target like DRD2, a BBB percentile >70 is highly desirable. Ligand A is close, while B is considerably lower.

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.819 and -4.93). This is unusual and suggests very poor permeability. However, these values are on a strange scale and might not be directly comparable.

**10. Aqueous Solubility:** Both ligands have negative solubility values (-4.146 and -4.038). Similar to Caco-2, this is unusual and suggests poor solubility.

**11. hERG Inhibition:** Both ligands have low hERG inhibition risk (0.329 and 0.622).

**12. Microsomal Clearance:** Both ligands have similar microsomal clearance values (29.743 and 28.071 mL/min/kg), suggesting comparable metabolic stability.

**13. In vitro Half-Life:** Ligand B (44.92) has a longer half-life than Ligand A (32.524), which is generally desirable.

**14. P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.14 and 0.114), which is good for CNS penetration.

**15. Binding Affinity:** Both ligands have very similar and excellent binding affinities (-9.6 and -9.4 kcal/mol). The difference is negligible.

**Overall Assessment:**

Considering the GPCR-specific priorities, Ligand A is the better candidate. Its significantly better TPSA and BBB penetration are crucial for a CNS-targeting drug. While Ligand B has a slightly longer half-life, the superior CNS penetration profile of Ligand A outweighs this benefit. The negative values for Caco-2 and solubility are concerning for both, but the other properties of A are more favorable.

Output:
0
2025-04-17 08:32:34,973 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (368.455 Da and 380.897 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (85.89) is better than Ligand B (67.43), both are below the 90 A^2 threshold for CNS targets.

**logP:** Both ligands have good logP values (2.491 and 2.902), falling within the optimal 1-3 range.

**H-Bond Donors:** Both have 2 HBD, which is acceptable.

**H-Bond Acceptors:** Ligand A has 6 HBA, while Ligand B has 4. Both are below the 10 threshold.

**QED:** Both ligands have good QED scores (0.517 and 0.789), indicating drug-likeness.

**DILI:** Ligand A (65.103) has a slightly better DILI risk profile than Ligand B (73.09), but both are above the preferred <40.

**BBB:** Ligand A (65.452) has a better BBB percentile than Ligand B (57.697). While neither is >70, A is closer and more favorable for a CNS target.

**Caco-2 Permeability:** Ligand A (-4.811) has a worse Caco-2 permeability than Ligand B (-5.338), indicating lower intestinal absorption.

**Aqueous Solubility:** Ligand A (-3.095) is better than Ligand B (-4.179).

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.662 and 0.331).

**Microsomal Clearance:** Ligand A (51.936) has a significantly lower microsomal clearance than Ligand B (13.908), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand B (20.717) has a much longer in vitro half-life than Ligand A (5.325).

**P-gp Efflux:** Ligand A (0.158) has a lower P-gp efflux liability than Ligand B (0.246), which is favorable for CNS penetration.

**Binding Affinity:** Ligand B (-9.3 kcal/mol) has a significantly stronger binding affinity than Ligand A (-7.1 kcal/mol). The difference of 2.2 kcal/mol is substantial and can outweigh some ADME drawbacks.

**Overall Assessment:**

Ligand B has a much stronger binding affinity, a longer half-life, and slightly better Caco-2 permeability. However, it has a higher DILI risk and P-gp efflux. Ligand A has better BBB penetration, lower clearance, and lower P-gp efflux, but weaker binding affinity and shorter half-life.

Given the GPCR-specific priorities, the strong binding affinity of Ligand B is the most critical factor. The 2.2 kcal/mol advantage is significant. While the slightly higher DILI and P-gp efflux are concerns, they might be addressable through further optimization. The longer half-life is also a major benefit.

Output:
1
2025-04-17 08:32:34,974 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (340.467 Da) is slightly lower, which could be beneficial for permeability.

**TPSA:** Ligand A (45.48) is significantly better than Ligand B (78.51). For CNS targets, we want TPSA <= 90, and ideally closer to 60. Ligand A is well within this range, while Ligand B is approaching the upper limit and may have reduced brain penetration.

**logP:** Ligand A (3.809) is optimal, while Ligand B (1.942) is a bit low. A logP between 1-3 is preferred, and Ligand B's value might hinder permeation.

**H-Bond Donors/Acceptors:** Ligand A (HBD=1, HBA=3) is better than Ligand B (HBD=2, HBA=4). Both are within acceptable limits, but lower values generally improve permeability.

**QED:** Both ligands have similar QED values (0.9 and 0.857), indicating good drug-likeness.

**DILI:** Ligand A (14.851) has a much lower DILI risk than Ligand B (54.323). This is a significant advantage for Ligand A.

**BBB:** Ligand A (89.531) has a considerably higher BBB penetration percentile than Ligand B (65.452). This is crucial for a CNS target like DRD2 and strongly favors Ligand A.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.03 and -5.143), which is unusual and suggests poor permeability. However, these values are on a log scale and difficult to interpret without further context.

**Aqueous Solubility:** Both ligands have negative solubility values (-2.332 and -3.443), again unusual and suggesting poor solubility.

**hERG Inhibition:** Ligand A (0.929) has a slightly higher hERG risk than Ligand B (0.459), but both are relatively low.

**Microsomal Clearance:** Ligand A (29.195) has a higher microsomal clearance than Ligand B (24.507), indicating faster metabolism. This is a negative for Ligand A.

**In vitro Half-Life:** Ligand A (69.289) has a significantly longer half-life than Ligand B (-3.371). This is a major advantage for Ligand A.

**P-gp Efflux:** Ligand A (0.4) has lower P-gp efflux liability than Ligand B (0.056), meaning it's less likely to be pumped out of the brain, which is beneficial for CNS penetration.

**Binding Affinity:** Both ligands have very similar and strong binding affinities (-9.9 kcal/mol and -9.1 kcal/mol). The difference of 0.8 kcal/mol is not substantial enough to outweigh the other ADME differences.

**Overall:** Considering all factors, especially the GPCR-specific priorities, Ligand A is the more promising candidate. It has better TPSA, logP, DILI risk, BBB penetration, P-gp efflux, and in vitro half-life. While its microsomal clearance is slightly higher, the other advantages are more significant for a CNS-targeting drug.

Output:
1
2025-04-17 08:32:34,974 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B against the provided guidelines, prioritizing GPCR-specific properties (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (349.475 and 351.451 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (65.79) is excellent, well below the 90 A^2 threshold for CNS targets. Ligand B (128.32) is higher, but still potentially acceptable, though less ideal.

**logP:** Ligand A (2.356) is optimal (1-3). Ligand B (0.73) is slightly low, potentially hindering permeation.

**H-Bond Donors/Acceptors:** Ligand A (1 HBD, 4 HBA) is favorable. Ligand B (3 HBD, 4 HBA) is also acceptable.

**QED:** Ligand A (0.821) is excellent, indicating strong drug-likeness. Ligand B (0.557) is acceptable, but lower.

**DILI:** Ligand A (15.743) has a very low DILI risk. Ligand B (29.081) is higher, but still relatively low.

**BBB:** Ligand A (70.105) is good, exceeding the 70% threshold for CNS targets. Ligand B (68.127) is close, but slightly below the desirable threshold.

**Caco-2 Permeability:** Ligand A (-4.668) is poor. Ligand B (-5.304) is also poor. Both are negative values, suggesting very low permeability.

**Aqueous Solubility:** Both ligands have very poor aqueous solubility (-1.221 and -1.982 respectively).

**hERG:** Both ligands have low hERG inhibition liability (0.357 and 0.473 respectively).

**Microsomal Clearance:** Ligand A (24.749) has moderate clearance. Ligand B (-9.502) has negative clearance, which is not physically possible and suggests an error or outlier in the data. This is a major red flag.

**In vitro Half-Life:** Ligand A (39.508 hours) is good. Ligand B (4.523 hours) is short, which is undesirable.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.039 and 0.018 respectively), which is favorable for CNS penetration.

**Binding Affinity:** Ligand A (-7.8 kcal/mol) has significantly stronger binding affinity than Ligand B (0.0 kcal/mol). This is a crucial advantage.

**Overall Assessment:**

Ligand A is clearly superior. It has better TPSA, logP, QED, BBB, in vitro half-life, and *significantly* better binding affinity. While both have poor Caco-2 permeability and solubility, the strong affinity of Ligand A and its favorable CNS properties outweigh these drawbacks, especially for a CNS target like DRD2. The negative clearance value for Ligand B is a critical flaw, indicating a data issue or a fundamentally problematic compound.

Output:
1
2025-04-17 08:32:34,974 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (360.483 and 349.387 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (78.66) is significantly better than Ligand B (93.9), falling well below the 90 Angstroms threshold for CNS targets. Ligand B is approaching the 140 Angstroms limit for oral absorption, which is less ideal.

**logP:** Both ligands have acceptable logP values (2.443 and 1.1), within the optimal 1-3 range. Ligand B is on the lower end, which *could* indicate permeability issues, but isn't a major concern.

**H-Bond Donors/Acceptors:** Ligand A has 3 HBD and 5 HBA, while Ligand B has 1 HBD and 6 HBA. Both are within acceptable limits (<=5 HBD and <=10 HBA).

**QED:** Both ligands have similar QED values (0.787 and 0.707), indicating good drug-like properties.

**DILI:** Ligand A (46.297) has a lower DILI risk than Ligand B (62.35), which is preferable.

**BBB:** Both ligands have reasonably good BBB penetration (57.619 and 60.954). However, neither exceeds the desirable >70 percentile for CNS targets.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.885 and -4.658), which is unusual and suggests poor permeability. This is a significant concern for both.

**Aqueous Solubility:** Both ligands have negative solubility values (-2.771 and -2.227), indicating very poor aqueous solubility. This is a significant drawback for both.

**hERG Inhibition:** Both ligands show low hERG inhibition liability (0.443 and 0.08), which is good.

**Microsomal Clearance:** Ligand A (-10.522) has significantly lower (better) microsomal clearance than Ligand B (21.864), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (37.163) has a much longer in vitro half-life than Ligand B (-21.539). This is a major advantage.

**P-gp Efflux:** Ligand A (0.235) has lower P-gp efflux than Ligand B (0.024), which is preferable for CNS penetration.

**Binding Affinity:** Ligand A (-9.2 kcal/mol) has a significantly stronger binding affinity than Ligand B (-7.4 kcal/mol). This >1.5 kcal/mol difference is substantial and can outweigh some ADME drawbacks.

**Overall Assessment:**

Ligand A is clearly superior. While both ligands suffer from poor Caco-2 permeability and aqueous solubility, Ligand A has a much stronger binding affinity, better metabolic stability (lower Cl_mic, longer t1/2), lower DILI risk, and lower P-gp efflux. Its TPSA is also more favorable. The stronger affinity is a critical advantage for a GPCR target, and the better ADME properties further support its selection.

Output:
1
2025-04-17 08:32:34,974 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (335.371 and 365.499 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (87.45) is slightly above the optimal <90 for CNS targets, while Ligand B (71.53) is well within the desired range. This favors Ligand B.

**3. logP:** Both ligands have good logP values (2.455 and 1.916), falling within the 1-3 range.

**4. H-Bond Donors:** Ligand A has 0 HBD, which is good. Ligand B has 1 HBD, also acceptable.

**5. H-Bond Acceptors:** Ligand A has 8 HBA, and Ligand B has 5 HBA. Both are within the acceptable limit of <=10.

**6. QED:** Both ligands have QED values above 0.5 (0.538 and 0.679), indicating good drug-like properties. Ligand B is slightly better.

**7. DILI:** Ligand A has a DILI risk of 76.037, which is concerning (high risk). Ligand B has a much lower DILI risk of 27.259, which is excellent. This is a significant advantage for Ligand B.

**8. BBB:** Ligand A has a BBB penetration of 43.699, which is below the desirable >70 for CNS targets. Ligand B has a BBB penetration of 80.264, which is excellent. This is a major advantage for Ligand B.

**9. Caco-2:** Both have negative values, indicating poor permeability. This is not ideal, but we need to consider other factors.

**10. Solubility:** Both have negative solubility values, indicating poor solubility. This is a concern for both.

**11. hERG:** Both ligands have low hERG inhibition liability (0.816 and 0.431), which is good.

**12. Cl_mic:** Ligand A has a lower microsomal clearance (19.155) than Ligand B (44.006), suggesting better metabolic stability. This favors Ligand A.

**13. t1/2:** Ligand A has a negative in vitro half-life (-30.753), which is unusual and suggests rapid degradation. Ligand B has a positive half-life (10.355), indicating better stability. This is a strong advantage for Ligand B.

**14. Pgp:** Both ligands have low P-gp efflux liability (0.109 and 0.058), which is good for CNS penetration.

**15. Binding Affinity:** Ligand A has a binding affinity of -9.1 kcal/mol, which is significantly stronger than Ligand B's -6.9 kcal/mol. This is a substantial advantage for Ligand A.

**Overall Assessment:**

While Ligand A has a superior binding affinity, the significant drawbacks of high DILI risk, poor BBB penetration, and a negative in vitro half-life are major concerns. Ligand B, despite having a slightly weaker affinity, presents a much more favorable ADME-Tox profile, with low DILI risk, excellent BBB penetration, and a reasonable half-life. For a CNS target like DRD2, achieving adequate brain exposure is crucial, making the superior BBB penetration of Ligand B a decisive factor. The difference in affinity, while substantial, may be overcome with further optimization of Ligand B.

Output:
1
2025-04-17 08:32:34,974 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 drug candidates, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (341.411 Da) is slightly better, being closer to the lower end which can aid permeability.

**TPSA:** Ligand A (80.32) is excellent, well below the 90 A^2 threshold for CNS targets. Ligand B (101.05) is still reasonable but less optimal.

**logP:** Both ligands have good logP values (A: 3.758, B: 3.179), falling within the 1-3 range.

**H-Bond Donors & Acceptors:** Both have 2 HBD, which is good. Ligand A has 4 HBA, and Ligand B has 6 HBA. Both are acceptable, but lower is generally preferred.

**QED:** Ligand A (0.812) has a significantly better QED score than Ligand B (0.648), indicating a more drug-like profile.

**DILI:** Ligand B (95.192) has a considerably higher DILI risk than Ligand A (75.611). This is a significant drawback for Ligand B.

**BBB:** Both ligands have good BBB penetration (A: 60.915, B: 70.803). Ligand B is slightly better, exceeding 70%, which is desirable for CNS targets.

**Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and suggests poor permeability. Ligand A (-4.604) is slightly better than Ligand B (-5.15).

**Aqueous Solubility:** Both have negative solubility values, indicating very poor solubility. Ligand A (-4.567) is slightly better than Ligand B (-4.085).

**hERG:** Both have low hERG inhibition liability (A: 0.314, B: 0.338), which is good.

**Microsomal Clearance:** Ligand B (29.97) has significantly lower microsomal clearance than Ligand A (92.307), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand B (141.393) has a much longer in vitro half-life than Ligand A (15.295), which is a major advantage.

**P-gp Efflux:** Both have very low P-gp efflux liability (A: 0.095, B: 0.353), which is favorable for CNS penetration.

**Binding Affinity:** Both ligands have excellent binding affinity (A: -9.3 kcal/mol, B: -9.0 kcal/mol). Ligand A is slightly better, but the difference is small.

**Overall Assessment:**

Ligand A has a better QED, lower DILI risk, and slightly better affinity. However, Ligand B has superior BBB penetration, significantly better metabolic stability (lower Cl_mic and longer t1/2), and is only marginally weaker in binding. Given the importance of metabolic stability and BBB penetration for CNS GPCR targets, and the relatively small difference in binding affinity, Ligand B appears to be the more promising candidate despite its higher DILI risk. The poor solubility and permeability of both compounds are concerning and would require addressing during lead optimization.

Output:
1
2025-04-17 08:32:34,975 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (346.36 and 349.39 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (86.71) is excellent, falling well below the 90 A^2 threshold for CNS targets. Ligand B (109.78) is still reasonable but less optimal.

**logP:** Ligand A (1.611) is within the optimal 1-3 range. Ligand B (0.482) is slightly low, potentially hindering permeation.

**H-Bond Donors/Acceptors:** Ligand A (2 HBD, 3 HBA) and Ligand B (3 HBD, 6 HBA) both meet the criteria of <=5 HBD and <=10 HBA.

**QED:** Ligand A (0.867) has a significantly better QED score than Ligand B (0.442), indicating a more drug-like profile.

**DILI:** Ligand A (61.07) has a higher DILI risk than Ligand B (37.224), but both are acceptable.

**BBB:** Ligand A (61.962) has a better BBB percentile than Ligand B (23.149). This is a critical factor for a CNS target like DRD2.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values, which is unusual and suggests poor permeability. However, the scale is not defined, so it's hard to interpret.

**Aqueous Solubility:** Both ligands have negative solubility values, which is also unusual.

**hERG:** Both ligands have very low hERG inhibition liability, which is excellent.

**Microsomal Clearance:** Ligand A (0.373) has significantly lower microsomal clearance than Ligand B (2.89), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (3.489) has a longer half-life than Ligand B (-15.599), which is a positive attribute.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability, which is good.

**Binding Affinity:** Ligand A (-9.8 kcal/mol) has a *much* stronger binding affinity than Ligand B (-6.7 kcal/mol). This is a substantial difference and a major advantage.

**Overall Assessment:**

Ligand A is clearly superior. It has a better TPSA, logP, QED, BBB penetration, metabolic stability (lower Cl_mic, longer t1/2), and, crucially, a significantly stronger binding affinity. While Ligand A has a slightly higher DILI risk, the substantial benefits in other key areas, particularly affinity and CNS penetration, outweigh this concern. Ligand B's low logP and poor BBB penetration are significant drawbacks for a CNS-targeting drug.

Output:
1
2025-04-17 08:32:34,975 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (342.399 Da and 368.909 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (95.16) is slightly above the preferred <90 for CNS targets, but still reasonable. Ligand B (74.33) is well within the ideal range. This favors Ligand B.

**3. logP:** Ligand A (0.847) is a bit low, potentially hindering permeability. Ligand B (2.222) is closer to the optimal 1-3 range. This favors Ligand B.

**4. H-Bond Donors:** Both ligands have 2 HBD, which is within the acceptable limit of <=5.

**5. H-Bond Acceptors:** Both ligands have 4 HBA, also within the acceptable limit of <=10.

**6. QED:** Ligand A (0.796) has a better QED score than Ligand B (0.655), indicating a more drug-like profile. This favors Ligand A.

**7. DILI:** Ligand A (54.789) has a slightly higher DILI risk than Ligand B (25.514). This favors Ligand B.

**8. BBB:** Ligand B (51.415) has a significantly better BBB penetration score than Ligand A (40.946). This is *critical* for a CNS target like DRD2 and strongly favors Ligand B.

**9. Caco-2 Permeability:** Ligand A (-4.995) has poor Caco-2 permeability, while Ligand B (-5.319) is also poor, but slightly better.

**10. Aqueous Solubility:** Ligand A (-3.53) has slightly better solubility than Ligand B (-1.753).

**11. hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.279 and 0.21, respectively).

**12. Microsomal Clearance:** Ligand B (17.277) has lower microsomal clearance than Ligand A (23.004), suggesting better metabolic stability. This favors Ligand B.

**13. In vitro Half-Life:** Ligand B (65.62) has a much longer in vitro half-life than Ligand A (-22.366). This is a significant advantage for Ligand B.

**14. P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.038 and 0.02, respectively).

**15. Binding Affinity:** Ligand B (-7.7 kcal/mol) has a slightly better binding affinity than Ligand A (-8.2 kcal/mol). While the difference is small, it is still a positive for Ligand B.

**Overall Assessment:**

Ligand B consistently outperforms Ligand A in the most critical parameters for a CNS-targeting GPCR: BBB penetration, logP, metabolic stability (Cl_mic and t1/2), and binding affinity. While Ligand A has a slightly better QED and solubility, these are outweighed by the superior CNS penetration and pharmacokinetic properties of Ligand B. The TPSA of Ligand B is also more favorable.

Output:
1
2025-04-17 08:32:34,975 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (363.443 and 361.442 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (110.32) is higher than the preferred <90 for CNS targets, while Ligand B (62.3) is well within the range. This is a significant advantage for Ligand B.

**logP:** Ligand A (0.78) is a bit low, potentially hindering permeability. Ligand B (2.693) is within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A has 2 HBD and 6 HBA, which are acceptable. Ligand B has 1 HBD and 4 HBA, also acceptable.

**QED:** Both ligands have high QED scores (0.834 and 0.86), indicating good drug-like properties.

**DILI:** Ligand A (68.282) and Ligand B (47.964) both have acceptable DILI risk, but Ligand B is notably lower.

**BBB:** Ligand A (68.282) is borderline for good CNS penetration, while Ligand B (82.513) is excellent, exceeding the >70 threshold. This is a major advantage for Ligand B.

**Caco-2 Permeability:** Ligand A (-5.443) and Ligand B (-4.624) both have negative Caco-2 values, indicating poor permeability.

**Aqueous Solubility:** Both ligands have very poor aqueous solubility (-3.043 and -3.624). This is a concern for both, but might be mitigated by formulation strategies.

**hERG Inhibition:** Both ligands show very low hERG inhibition risk (0.298 and 0.15).

**Microsomal Clearance:** Ligand A (38.081) and Ligand B (41.741) have similar, moderate microsomal clearance values.

**In vitro Half-Life:** Ligand A (16.529) and Ligand B (10.747) have moderate in vitro half-lives.

**P-gp Efflux:** Both ligands show very low P-gp efflux liability (0.071 and 0.047).

**Binding Affinity:** Both ligands have excellent binding affinity (-9.0 and -9.4 kcal/mol), with Ligand B being slightly better. The difference in affinity is not substantial enough to overcome the other ADME differences.

**Overall:**

Ligand B is significantly better due to its superior TPSA, logP, and BBB values. While both have poor solubility and Caco-2 permeability, the CNS-focused nature of this target makes BBB penetration paramount. Ligand B's higher BBB score and more favorable logP outweigh the slight advantage in binding affinity of Ligand A.

Output:
1
2025-04-17 08:32:34,975 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (352.322 and 361.389 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (118.73) is better than Ligand B (78.95) as it is closer to the optimal range for CNS targets (<=90).

**logP:** Ligand B (0.101) is slightly better than Ligand A (-0.355) as it is closer to the optimal range of 1-3. However, both are a bit low, potentially impacting permeability.

**H-Bond Donors/Acceptors:** Ligand A has 3 HBD and 8 HBA, while Ligand B has 1 HBD and 5 HBA. Both are within acceptable limits (<=5 HBD and <=10 HBA).

**QED:** Ligand A (0.623) has a better QED score than Ligand B (0.441), indicating a more drug-like profile.

**DILI:** Ligand B (23.808) has a significantly lower DILI risk than Ligand A (81.078). This is a major advantage for Ligand B.

**BBB:** Ligand B (66.072) has a much better BBB penetration percentile than Ligand A (41.838). This is critical for a CNS target like DRD2.

**Caco-2 Permeability:** Ligand A (-5.169) has a worse Caco-2 permeability than Ligand B (-4.859).

**Aqueous Solubility:** Ligand A (-2.093) has a worse solubility than Ligand B (-0.817).

**hERG:** Ligand A (0.085) has a slightly better hERG profile than Ligand B (0.253).

**Microsomal Clearance:** Ligand A (-6.099) has a much lower (better) microsomal clearance than Ligand B (27.502), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (23.503) has a better in vitro half-life than Ligand B (-27.274).

**P-gp Efflux:** Ligand A (0.02) has a much lower P-gp efflux liability than Ligand B (0.009), which is favorable for CNS penetration.

**Binding Affinity:** Ligand A (-7.7 kcal/mol) has a slightly better binding affinity than Ligand B (-6.9 kcal/mol). This is a significant advantage, but needs to be weighed against other factors.

**Overall Assessment:**

While Ligand A has slightly better binding affinity and metabolic stability, Ligand B excels in crucial areas for a CNS-targeting GPCR ligand: BBB penetration, lower DILI risk, and better solubility. The difference in binding affinity (0.8 kcal/mol) is not substantial enough to outweigh the significant advantages of Ligand B in terms of safety (DILI) and brain exposure (BBB). The lower P-gp efflux for ligand A is a positive, but the higher BBB for ligand B is more important.

Output:
1
2025-04-17 08:32:34,975 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (342.443 and 358.467 Da) fall within the ideal range of 200-500 Da.

**TPSA:** Ligand A (76.44) is better than Ligand B (78.09), both are below the 90 A^2 threshold for CNS targets, but closer to the 90 A^2 limit.

**logP:** Ligand A (1.539) is within the optimal range (1-3), while Ligand B (2.414) is also acceptable, but trending higher.

**H-Bond Donors:** Ligand A (1) is preferable to Ligand B (2). Fewer HBDs generally improve permeability.

**H-Bond Acceptors:** Both ligands have 4 HBA, which is acceptable (<=10).

**QED:** Ligand A (0.904) has a significantly better QED score than Ligand B (0.805), indicating a more drug-like profile.

**DILI:** Ligand A (41.179) has a much lower DILI risk than Ligand B (54.983), both are acceptable (<60).

**BBB:** Ligand A (43.815) has a lower BBB penetration percentile than Ligand B (58.938). This is a critical factor for a CNS target like DRD2, making Ligand B more favorable.

**Caco-2 Permeability:** Ligand A (-4.932) has better Caco-2 permeability than Ligand B (-5.374), although both are negative values.

**Aqueous Solubility:** Ligand A (-1.455) has better aqueous solubility than Ligand B (-3.842).

**hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.564 and 0.519 respectively).

**Microsomal Clearance:** Ligand A (-4.566) exhibits better metabolic stability (lower clearance) than Ligand B (6.758).

**In vitro Half-Life:** Ligand A (29.583) has a shorter half-life than Ligand B (-8.97). A negative value for half-life is unusual and suggests a very long half-life, which is favorable.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.049 and 0.214 respectively).

**Binding Affinity:** Ligand B (-8.3 kcal/mol) has a significantly stronger binding affinity than Ligand A (-0.0 kcal/mol). This is the most important factor. A difference of >1.5 kcal/mol is considered substantial.

**Overall Assessment:**

While Ligand A has better QED, DILI, solubility, and metabolic stability, Ligand B's superior binding affinity (-8.3 kcal/mol vs -0.0 kcal/mol) and better BBB penetration (58.938 vs 43.815) are decisive. The strong binding affinity outweighs the minor ADME drawbacks of Ligand B. The longer half-life of Ligand B is also a significant advantage.

Output:
1
2025-04-17 08:32:34,975 - INFO - Batch 457 complete. Total preferences: 7312
2025-04-17 08:32:34,975 - INFO - Processing batch 458/512...
2025-04-17 08:33:16,550 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (368.349 and 358.439 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (85.25) is excellent, being well below the 90 A^2 threshold for CNS targets. Ligand B (111.21) is still reasonable, but less optimal, being above 100 A^2.

**logP:** Ligand A (2.491) is within the optimal 1-3 range. Ligand B (-1.831) is significantly lower, potentially hindering membrane permeability and CNS penetration.

**H-Bond Donors/Acceptors:** Ligand A (HBD=2, HBA=5) and Ligand B (HBD=3, HBA=6) both have acceptable numbers of H-bond donors and acceptors.

**QED:** Ligand A (0.581) has a better QED score than Ligand B (0.447), indicating a more drug-like profile.

**DILI:** Ligand A (68.244) has a higher DILI risk than Ligand B (24.234). This is a concern for Ligand A.

**BBB:** Ligand A (63.203) shows moderate BBB penetration, while Ligand B (41.799) is considerably lower. While both are below the desirable >70 for CNS targets, Ligand A is better.

**Caco-2 Permeability:** Ligand A (-4.972) has poor Caco-2 permeability, a significant drawback. Ligand B (-5.173) is also poor, but similar to A.

**Aqueous Solubility:** Ligand A (-2.944) has poor aqueous solubility. Ligand B (-0.511) is slightly better, but still poor.

**hERG Inhibition:** Ligand A (0.335) has a very low hERG risk, which is excellent. Ligand B (0.082) is also very low risk.

**Microsomal Clearance:** Ligand A (58.803) has moderate clearance, while Ligand B (13.738) has very low clearance, suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (29.802) has a moderate half-life. Ligand B (-10.695) has a negative half-life, which is not physically possible and indicates a problem with the data or the molecule's stability.

**P-gp Efflux:** Ligand A (0.26) has low P-gp efflux, which is good for CNS penetration. Ligand B (0.004) has very low P-gp efflux, even better.

**Binding Affinity:** Ligand A (-8.2 kcal/mol) has a significantly stronger binding affinity than Ligand B (-6.3 kcal/mol). This is a substantial advantage.

**Overall Assessment:**

Despite Ligand A's higher DILI risk and poor Caco-2 permeability/solubility, its *much* stronger binding affinity (-8.2 vs -6.3 kcal/mol) and better BBB penetration, coupled with low hERG and P-gp efflux, make it the more promising candidate. The affinity difference is large enough to potentially overcome the ADME liabilities, especially considering the target is a CNS GPCR where brain exposure is critical. Ligand B's negative in vitro half-life is a major red flag and disqualifies it.

Output:
1
2025-04-17 08:33:16,550 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (365.539 and 361.551 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (46.61) is significantly higher than Ligand B (25.61). For CNS targets, TPSA should be <= 90, both meet this, but B is much better.

**logP:** Both ligands (4.021 and 4.832) are slightly above the optimal 1-3 range, but still acceptable. Ligand B is a bit higher, potentially increasing off-target interactions or decreasing solubility.

**H-Bond Donors/Acceptors:** Ligand A has 0 HBD and 3 HBA, while Ligand B has 0 HBD and 4 HBA. Both are within acceptable limits.

**QED:** Ligand A (0.686) has a better QED score than Ligand B (0.465), indicating a more drug-like profile.

**DILI:** Ligand A (32.338) has a slightly higher DILI risk than Ligand B (16.092), but both are below the concerning threshold of 60.

**BBB:** Ligand B (88.174) has a significantly higher BBB penetration percentile than Ligand A (71.772). This is a crucial advantage for a CNS target like DRD2.

**Caco-2 Permeability:** Ligand A (-4.664) has worse Caco-2 permeability than Ligand B (-5.422). Lower values indicate poorer permeability.

**Aqueous Solubility:** Ligand A (-5.298) has slightly better aqueous solubility than Ligand B (-4.256).

**hERG Inhibition:** Ligand A (0.791) has a slightly higher hERG inhibition risk than Ligand B (0.919), though both are relatively low.

**Microsomal Clearance:** Ligand B (59.398) has a lower microsomal clearance than Ligand A (79.575), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand B (78.276) has a significantly longer in vitro half-life than Ligand A (-27.49). This is a major advantage.

**P-gp Efflux:** Ligand A (0.495) has lower P-gp efflux than Ligand B (0.834), which is favorable for CNS penetration.

**Binding Affinity:** Ligand B (-7.8) has a substantially stronger binding affinity than Ligand A (-8.3). A difference of >1.5 kcal/mol is significant.

**Overall Assessment:**

While Ligand A has a better QED and slightly better solubility, Ligand B excels in the most critical areas for a CNS-targeting GPCR ligand: **BBB penetration, metabolic stability (lower Cl_mic, longer t1/2), and, most importantly, binding affinity.** The stronger binding affinity of Ligand B (-7.8 kcal/mol vs -8.3 kcal/mol) is a significant advantage that outweighs the slightly higher logP and P-gp efflux. The superior BBB penetration (88.174 vs 71.772) is also a key factor.

Output:
1
2025-04-17 08:33:16,550 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (353.463 and 349.431 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (78.95) is significantly better than Ligand B (92.59). For CNS targets, we want TPSA <= 90, so Ligand A is preferable.

**3. logP:** Both ligands have acceptable logP values (0.492 and 0.58), falling within the 1-3 range.

**4. H-Bond Donors:** Ligand A (1) is better than Ligand B (3). Lower HBD generally improves permeability.

**5. H-Bond Acceptors:** Both ligands have 5 HBA, which is acceptable (<=10).

**6. QED:** Both ligands have good QED scores (0.643 and 0.7), indicating drug-like properties.

**7. DILI:** Ligand A (12.214) has a much lower DILI risk than Ligand B (39.667). This is a significant advantage for Ligand A.

**8. BBB:** Ligand A (44.668) has a slightly better BBB penetration percentile than Ligand B (39.86), but both are below the desirable >70 for CNS targets. However, given the other factors, this is less critical.

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 values which is unusual and problematic. It suggests poor permeability. Ligand A (-5) is slightly better than Ligand B (-4.785).

**10. Aqueous Solubility:** Both ligands have negative solubility values, which is also problematic. Ligand A (-0.48) is slightly better than Ligand B (-2.004).

**11. hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.201 and 0.16).

**12. Microsomal Clearance:** Ligand A (-13.842) has significantly lower (better) microsomal clearance than Ligand B (24.232), indicating greater metabolic stability.

**13. In vitro Half-Life:** Ligand A (-10.542) has a better in vitro half-life than Ligand B (17.638).

**14. P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.01 and 0.058).

**15. Binding Affinity:** Ligand B (-7.9) has a slightly better binding affinity than Ligand A (-7.7). While a 0.2 kcal/mol difference isn't huge, it's a positive for Ligand B.

**Overall Assessment:**

Despite the slightly better binding affinity of Ligand B, Ligand A is the more promising candidate. Ligand A excels in critical ADME properties: lower DILI risk, better TPSA, lower HBD, better metabolic stability (lower Cl_mic and better half-life), and slightly better BBB. The negative Caco-2 and solubility values are concerning for both, but Ligand A is still preferable. The small advantage in binding affinity for Ligand B is outweighed by the superior ADME profile of Ligand A, especially considering the CNS target.

Output:
1
2025-04-17 08:33:16,550 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (355.479 Da) is slightly lower, which could be beneficial for permeability. Ligand B (383.945 Da) is also acceptable.

**TPSA:** Ligand A (93.11) is closer to the desirable threshold of 90 for CNS targets than Ligand B (71.09). This suggests potentially better CNS penetration for Ligand A.

**logP:** Ligand A (-0.187) is a bit low, potentially hindering membrane permeability. Ligand B (2.822) is within the optimal range (1-3). This is a significant advantage for Ligand B.

**H-Bond Donors/Acceptors:** Ligand A has 3 HBD and 5 HBA, while Ligand B has 2 HBD and 4 HBA. Both are within acceptable limits.

**QED:** Both ligands have good QED scores (A: 0.636, B: 0.724), indicating drug-like properties.

**DILI:** Ligand A (7.871) has a very low DILI risk, significantly better than Ligand B (40.287).

**BBB:** Ligand A (11.012) has poor BBB penetration, a major drawback for a CNS target. Ligand B (54.323) is better, but still not ideal (aim for >70).

**Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and suggests poor permeability. However, the scale is not specified, so it's difficult to interpret.

**Aqueous Solubility:** Both have negative solubility values, which is also unusual and suggests poor solubility.

**hERG:** Both ligands have low hERG inhibition risk (A: 0.321, B: 0.314).

**Microsomal Clearance:** Ligand A (-2.28) has a negative clearance, which is not physically possible. This is likely an error in the data. Ligand B (30.51) has a relatively high clearance, suggesting faster metabolism.

**In vitro Half-Life:** Ligand A (-2.638) has a negative half-life, which is not physically possible and suggests an error in the data. Ligand B (8.526) has a reasonable half-life.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (A: 0.019, B: 0.146), which is favorable for CNS penetration.

**Binding Affinity:** Ligand B (-8.5 kcal/mol) has a significantly stronger binding affinity than Ligand A (-7.2 kcal/mol). This 1.3 kcal/mol difference is substantial and can outweigh some ADME drawbacks.

**Overall Assessment:**

Ligand A has a better TPSA and DILI profile, but suffers from very poor BBB penetration, and impossible values for clearance and half-life. Ligand B has a superior logP, significantly stronger binding affinity, and a more reasonable (though still not ideal) BBB score. The negative values for solubility and Caco-2 permeability are concerning for both, but the affinity difference is a major deciding factor. Given the importance of affinity for GPCRs, and the relatively better BBB score of Ligand B, it is the more promising candidate. The erroneous values for Ligand A are also a concern.

Output:
1
2025-04-17 08:33:16,551 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (349.475 Da) is slightly lower, which could be beneficial for permeability.

**TPSA:** Ligand A (63.57) is significantly better than Ligand B (88.24). For CNS targets, we want TPSA <= 90, and A is comfortably within this range, while B is approaching the upper limit.

**logP:** Both ligands have a logP of 2.051, which is optimal.

**H-Bond Donors/Acceptors:** Both have 1 HBD, which is good. Ligand A has 4 HBA, while Ligand B has 7. Lower HBA is generally preferred, making Ligand A slightly better.

**QED:** Ligand A (0.658) and Ligand B (0.862) both have good drug-likeness scores, exceeding the 0.5 threshold.

**DILI:** Ligand A (31.563) has a much lower DILI risk than Ligand B (75.766). This is a significant advantage for A.

**BBB:** Ligand A (56.805) is below the desirable threshold of >70 for CNS targets, but Ligand B (84.606) is excellent. This is a major point in favor of Ligand B.

**Caco-2 Permeability:** Both have negative Caco-2 values, indicating poor permeability. However, Ligand A (-4.568) is slightly better than Ligand B (-4.887).

**Aqueous Solubility:** Both have negative solubility values, indicating poor solubility. Ligand A (-1.639) is slightly better than Ligand B (-2.918).

**hERG Inhibition:** Both have low hERG inhibition risk (0.293 and 0.305).

**Microsomal Clearance:** Ligand A (59.623) has lower clearance than Ligand B (65.918), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (14.323) has a positive half-life, while Ligand B (-11.551) has a negative half-life. This is a significant advantage for A.

**P-gp Efflux:** Both have low P-gp efflux liability (0.125 and 0.042).

**Binding Affinity:** Ligand B (-8.4 kcal/mol) has a significantly stronger binding affinity than Ligand A (-7.5 kcal/mol). This is a >1.5 kcal/mol advantage, which can outweigh some ADME drawbacks.

**Overall Assessment:**

Ligand B excels in BBB penetration and binding affinity, crucial for a CNS GPCR target. However, it suffers from higher DILI risk, poorer TPSA, and a negative in vitro half-life. Ligand A has a better safety profile (lower DILI), better TPSA, and better metabolic stability (lower Cl_mic, positive half-life). The difference in binding affinity is significant, but the other advantages of Ligand A, particularly the improved safety and pharmacokinetic properties, make it a more promising starting point for optimization. The poor BBB of Ligand A could be addressed through structural modifications.

Output:
0
2025-04-17 08:33:16,551 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (390.33 and 367.921 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (35.58) is excellent, well below the 90 A^2 threshold for CNS targets. Ligand B (52.65) is still reasonable, but less optimal.

**logP:** Both ligands have good logP values (3.207 and 2.357), falling within the 1-3 range.

**H-Bond Donors/Acceptors:** Both have 1 HBD and 3 HBA, which is acceptable.

**QED:** Both ligands have similar QED values (0.785 and 0.751), indicating good drug-likeness.

**DILI:** Ligand A (31.252) has a significantly lower DILI risk than Ligand B (8.298), which is a major advantage.

**BBB:** Both ligands have excellent BBB penetration (85.498 and 85.459), exceeding the desirable >70 percentile.

**Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and potentially problematic. However, these values are on a strange scale, so it's hard to interpret.

**Aqueous Solubility:** Both ligands have very poor aqueous solubility (-3.311 and -2.032). This is a significant drawback, potentially hindering formulation and bioavailability.

**hERG Inhibition:** Both ligands show low hERG inhibition risk (0.925 and 0.561).

**Microsomal Clearance:** Both have similar, relatively low microsomal clearance (22.365 and 21.177 mL/min/kg), suggesting reasonable metabolic stability.

**In vitro Half-Life:** Ligand B has a longer in vitro half-life (20.217 hours) than Ligand A (14.76 hours), which is a positive.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.169 and 0.038), which is excellent for CNS penetration.

**Binding Affinity:** Ligand B (-7.6 kcal/mol) has a slightly better binding affinity than Ligand A (-8.4 kcal/mol). However, the difference is relatively small.

**Overall Assessment:**

While Ligand B has a slightly better binding affinity and half-life, Ligand A is the more promising candidate. The significantly lower DILI risk for Ligand A is a crucial advantage. Both have excellent BBB penetration and low P-gp efflux. The poor solubility is a concern for both, but the lower DILI risk outweighs the slightly better affinity and half-life of Ligand B. Given the GPCR-specific priorities, the combination of good CNS penetration properties and reduced toxicity risk makes Ligand A a more viable starting point for further optimization.

Output:
0
2025-04-17 08:33:16,551 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (356.423 and 358.435 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (111.21) is slightly above the preferred <90 for CNS targets, while Ligand B (106.12) is closer, but still marginally above. This is a minor concern for both.

**3. logP:** Ligand A (-2.08) is a bit low, potentially hindering permeability. Ligand B (-0.269) is better, falling within the 1-3 range, though still on the lower end.

**4. H-Bond Donors:** Both ligands have 3 HBD, which is acceptable (<=5).

**5. H-Bond Acceptors:** Both ligands have 6 HBA, also acceptable (<=10).

**6. QED:** Both ligands have good QED scores (0.504 and 0.579, respectively), indicating drug-like properties.

**7. DILI:** Ligand A (14.967) has a significantly lower DILI risk than Ligand B (42.458). This is a major advantage for Ligand A.

**8. BBB:** Ligand A (19.659) has a very poor BBB percentile, making CNS penetration unlikely. Ligand B (48.391) is better, but still not ideal (>70 is desired).

**9. Caco-2:** Both ligands have negative Caco-2 values (-5.518 and -5.315), which is unusual and suggests poor permeability.

**10. Solubility:** Both ligands have negative solubility values (-0.493 and -0.906), also unusual and suggesting poor aqueous solubility.

**11. hERG:** Both ligands have very low hERG inhibition risk (0.047 and 0.063).

**12. Cl_mic:** Ligand A (-42.488) has a much lower (better) microsomal clearance than Ligand B (2.968), indicating greater metabolic stability.

**13. t1/2:** Ligand A (-1.705) has a negative in vitro half-life, which is not possible. Ligand B (12.322) has a reasonable half-life.

**14. Pgp:** Both ligands have very low Pgp efflux liability (0.002 and 0.028).

**15. Binding Affinity:** Ligand B (-7.4 kcal/mol) has a significantly stronger binding affinity than Ligand A (-6.5 kcal/mol). This is a substantial advantage, potentially outweighing some ADME concerns.

**Overall Assessment:**

Ligand A has a better safety profile (DILI, hERG) and metabolic stability (Cl_mic), but suffers from extremely poor BBB penetration and a questionable half-life. Ligand B has a significantly better binding affinity and a reasonable half-life, but has a higher DILI risk and a less favorable BBB percentile.

Given the target is DRD2 (a CNS GPCR), BBB penetration is crucial. While Ligand B's BBB is not ideal, it's far superior to Ligand A's. The stronger binding affinity of Ligand B (-7.4 kcal/mol vs -6.5 kcal/mol) is also a significant advantage. The DILI risk of Ligand B is a concern, but could potentially be mitigated through further structural modifications. The negative solubility and Caco-2 values for both are concerning and need to be addressed, but are less critical than BBB and affinity for initial prioritization.

Output:
1
2025-04-17 08:33:16,551 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (345.403 Da) is slightly lower, which could be beneficial for permeability, but both are acceptable.

**TPSA:** Ligand A (104.12) is better than Ligand B (61.38) as it is closer to the ideal range for CNS targets (<=90). Ligand B is quite low, which might indicate a lack of necessary interactions.

**logP:** Ligand A (1.363) is within the optimal range (1-3). Ligand B (3.462) is at the higher end of the optimal range, potentially increasing off-target effects or solubility issues, but still acceptable.

**H-Bond Donors/Acceptors:** Both ligands have 2 HBDs and 5/4 HBAs respectively, which are within acceptable limits.

**QED:** Both ligands have QED values above 0.7, indicating good drug-likeness.

**DILI:** Both ligands have low DILI risk (Ligand A: 41.877, Ligand B: 37.922), which is positive.

**BBB:** Both ligands have acceptable BBB penetration (Ligand A: 60.256, Ligand B: 63.164), but neither is above the desirable threshold of 70%.

**Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and suggests a potential issue with the data or modeling. However, we'll proceed assuming this represents low permeability.

**Aqueous Solubility:** Both ligands have negative solubility values, which is also unusual and suggests poor aqueous solubility.

**hERG Inhibition:** Ligand A (0.029) has a very low hERG risk, which is excellent. Ligand B (0.91) has a moderate hERG risk, which is a concern.

**Microsomal Clearance:** Ligand A (-6.132) has a very low (negative) microsomal clearance, indicating high metabolic stability. Ligand B (30.274) has a higher clearance, suggesting faster metabolism.

**In vitro Half-Life:** Ligand A (5.163 hours) has a moderate half-life. Ligand B (109.046 hours) has a very long half-life, which is a significant advantage.

**P-gp Efflux:** Ligand A (0.013) has very low P-gp efflux, which is highly desirable for CNS penetration. Ligand B (0.771) has moderate P-gp efflux, which could limit CNS exposure.

**Binding Affinity:** Ligand B (-7.6 kcal/mol) has a significantly stronger binding affinity than Ligand A (-9.1 kcal/mol). This is a substantial advantage, potentially outweighing some of the ADME drawbacks.

**Overall Assessment:**

Ligand B has a much stronger binding affinity, a very long half-life, and acceptable DILI and BBB. However, it has a higher logP, moderate P-gp efflux, and moderate hERG risk. Ligand A has better TPSA, lower hERG risk, and very low P-gp efflux, but its binding affinity is weaker.

Given the GPCR-specific priorities, the strong binding affinity of Ligand B is the most critical factor. While its other properties are not ideal, the substantial affinity advantage, coupled with acceptable BBB penetration, makes it the more promising candidate. The longer half-life is also a significant benefit.

Output:
1
2025-04-17 08:33:16,551 - INFO - Reasoning:

Let's analyze Ligand A and Ligand B based on the provided guidelines, prioritizing GPCR-specific properties (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands fall within the ideal range (200-500 Da). Ligand A (345.403 Da) is slightly lower, which could be advantageous for permeability.

**TPSA:** Ligand A (106.1) is better than Ligand B (75.94). Both are below the 140 A^2 threshold for oral absorption, and importantly, Ligand A is closer to the <90 A^2 target for CNS penetration.

**logP:** Both ligands have acceptable logP values (A: 1.074, B: 2.058) within the 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A has 2 HBD and 6 HBA, while Ligand B has 1 HBD and 6 HBA. Both are within the acceptable limits.

**QED:** Both ligands have reasonable QED scores (A: 0.741, B: 0.642), indicating good drug-like properties.

**DILI:** Ligand A (74.564) has a higher DILI risk than Ligand B (49.244). This is a negative for Ligand A.

**BBB:** Ligand A (61.962) has a slightly better BBB percentile than Ligand B (56.611), but neither are above the desirable >70 threshold.

**Caco-2 Permeability:** Ligand A (-5.198) has a worse Caco-2 permeability than Ligand B (-5.34). Lower values indicate poorer permeability.

**Aqueous Solubility:** Ligand A (-2.877) has a worse aqueous solubility than Ligand B (-1.662).

**hERG Inhibition:** Both ligands have low hERG inhibition risk (A: 0.322, B: 0.54).

**Microsomal Clearance:** Ligand A (46.448) has a higher microsomal clearance than Ligand B (18.619), indicating lower metabolic stability.

**In vitro Half-Life:** Ligand B (58.234) has a significantly longer in vitro half-life than Ligand A (23.614).

**P-gp Efflux:** Ligand A (0.046) has a lower P-gp efflux liability than Ligand B (0.134), which is favorable for CNS penetration.

**Binding Affinity:** Both ligands have the same binding affinity (-7.8 kcal/mol), which is excellent.

**Overall Assessment:**

Considering the GPCR-specific priorities, Ligand A has a better TPSA, and P-gp efflux liability, but suffers from higher DILI risk, lower solubility, and faster clearance. Ligand B has a better DILI profile, solubility, and half-life. While Ligand A has a slight edge in BBB, it's not substantial enough to overcome its other weaknesses. Given the importance of metabolic stability and safety (DILI) for a CNS drug, and the equal binding affinity, Ligand B appears to be the more promising candidate.

Output:
1
2025-04-17 08:33:16,551 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 drug candidates, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (342.403 and 344.455 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (84.22) is better than Ligand B (62.55), both are below the 90 A^2 threshold for CNS targets.

**3. logP:** Ligand A (0.913) is slightly lower than optimal (1-3), but still acceptable. Ligand B (2.612) is within the optimal range.

**4. H-Bond Donors:** Ligand A (0) is ideal, while Ligand B (1) is acceptable.

**5. H-Bond Acceptors:** Ligand A (6) is good, while Ligand B (3) is also good.

**6. QED:** Both ligands have good QED scores (0.806 and 0.863, respectively), indicating drug-likeness.

**7. DILI:** Ligand A (50.679) has a slightly higher DILI risk than Ligand B (14.696), but both are below the concerning threshold of 60.

**8. BBB:** Both ligands have good BBB penetration (67.352 and 68.903, respectively), exceeding the 70% threshold.

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.976 and -4.923). This is unusual and suggests poor permeability.

**10. Aqueous Solubility:** Ligand A (-0.634) has slightly better solubility than Ligand B (-3).

**11. hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.326 and 0.266).

**12. Microsomal Clearance:** Ligand A (48.12) has higher clearance than Ligand B (31.883), indicating lower metabolic stability.

**13. In vitro Half-Life:** Ligand B (9.979) has a longer half-life than Ligand A (7.444).

**14. P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.028 and 0.139).

**15. Binding Affinity:** Both ligands have excellent binding affinity (-8.4 and -8.5 kcal/mol). The difference is negligible.

**Overall Assessment:**

Both ligands are very similar in terms of affinity and BBB penetration, which are crucial for a CNS GPCR target like DRD2. However, Ligand B demonstrates advantages in several key areas: lower DILI risk, better metabolic stability (lower Cl_mic, longer t1/2), and slightly better logP. While Ligand A has slightly better solubility, the other advantages of Ligand B outweigh this. The negative Caco-2 values are concerning for both, but the other properties suggest that this might be an artifact of the prediction method rather than a fundamental issue.

Output:
1
2025-04-17 08:33:16,551 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (356.394 and 347.419 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (84.94) is better than Ligand B (89.35). Both are below the 90 A^2 threshold desirable for CNS targets, but A is closer to the optimal range.

**3. logP:** Ligand A (0.421) is slightly lower than Ligand B (0.615). Both are a bit low, potentially hindering permeation, but not drastically.

**4. H-Bond Donors:** Both have 1 HBD, which is acceptable.

**5. H-Bond Acceptors:** Ligand A has 5 HBA, while Ligand B has 6. Both are within the acceptable limit of 10.

**6. QED:** Ligand B (0.843) has a significantly better QED score than Ligand A (0.57), indicating a more drug-like profile.

**7. DILI:** Ligand A (27.685) has a much lower DILI risk than Ligand B (59.752). This is a significant advantage for Ligand A.

**8. BBB:** Ligand A (75.998) has a slightly better BBB penetration percentile than Ligand B (70.803). Both are reasonably good for a CNS target, but A is preferable.

**9. Caco-2 Permeability:** Ligand A (-4.511) and Ligand B (-4.864) both have negative values, which is unusual and suggests poor permeability.

**10. Aqueous Solubility:** Both ligands have very poor aqueous solubility (-1.844 and -2.181 respectively).

**11. hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.349 and 0.113 respectively).

**12. Microsomal Clearance:** Ligand A (31.844) has a higher microsomal clearance than Ligand B (14.227), suggesting lower metabolic stability. This favors Ligand B.

**13. In vitro Half-Life:** Ligand B (-3.095) has a slightly better in vitro half-life than Ligand A (-24.61).

**14. P-gp Efflux:** Both ligands show very low P-gp efflux liability (0.023 and 0.04 respectively).

**15. Binding Affinity:** Ligand B (-8.6 kcal/mol) has a slightly better binding affinity than Ligand A (-8.1 kcal/mol). While the difference is not huge, it's enough to consider.

**Overall Assessment:**

Ligand A excels in DILI risk and BBB penetration, and has a slightly better TPSA. However, Ligand B has a better QED score, binding affinity, metabolic stability (lower Cl_mic), and in vitro half-life. The slightly better affinity of Ligand B, combined with its improved metabolic properties, outweigh the advantages of Ligand A. Both have poor solubility and Caco-2 permeability, which would need to be addressed in further optimization. Given the GPCR-specific focus on BBB, logP, Pgp, TPSA and affinity, and considering the relatively small difference in affinity, Ligand B is the more promising candidate.

Output:
1
2025-04-17 08:33:16,551 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight (MW):** Both ligands (360.376 and 365.543 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (59.59) is better than Ligand B (62.3). Both are below the 90 A^2 threshold for CNS targets, which is good.

**3. logP:** Both ligands (3.037 and 3.111) are within the optimal 1-3 range.

**4. H-Bond Donors (HBD):** Ligand A (2) is slightly higher than Ligand B (1), both are within the acceptable limit of <=5.

**5. H-Bond Acceptors (HBA):** Ligand A (3) is lower than Ligand B (4), both are within the acceptable limit of <=10.

**6. QED:** Both ligands have good QED scores (0.735 and 0.842), indicating good drug-like properties.

**7. DILI:** Ligand A (29.042) has a significantly lower DILI risk than Ligand B (39.201). Both are below the 40 threshold, but A is preferable.

**8. BBB:** Ligand A (94.029) has a much higher BBB penetration percentile than Ligand B (53.587). This is *critical* for a CNS target like DRD2.

**9. Caco-2 Permeability:** Ligand A (-4.486) is better than Ligand B (-4.895), indicating better intestinal absorption.

**10. Aqueous Solubility:** Both ligands have poor aqueous solubility (-2.91 and -2.797). This is a potential concern, but can be addressed with formulation strategies.

**11. hERG Inhibition:** Ligand A (0.794) has a slightly higher hERG risk than Ligand B (0.406). This is a minor drawback for Ligand A.

**12. Microsomal Clearance (Cl_mic):** Ligand A (59.832) has higher clearance than Ligand B (43.985), meaning it is less metabolically stable.

**13. In vitro Half-Life:** Ligand B (-0.95) has a longer half-life than Ligand A (2.195).

**14. P-gp Efflux:** Ligand A (0.299) has lower P-gp efflux liability than Ligand B (0.319), which is favorable for CNS penetration.

**15. Binding Affinity:** Ligand A (-8.6 kcal/mol) has a significantly stronger binding affinity than Ligand B (-0.0 kcal/mol). This is a major advantage.

**Overall Assessment:**

Ligand A is the superior candidate. While it has slightly higher hERG risk and lower metabolic stability, its *significantly* better BBB penetration and *much* stronger binding affinity outweigh these drawbacks. The lower DILI risk is also a positive. For a CNS GPCR target, BBB penetration and affinity are paramount, and Ligand A excels in both.

Output:
1
2025-04-17 08:33:16,551 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (330.431 and 343.362 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (45.05) is excellent, well below the 90 A^2 threshold for CNS targets. Ligand B (71.33) is higher, but still potentially acceptable, though less ideal.

**logP:** Ligand A (4.019) is at the upper end of the optimal range (1-3), potentially raising concerns about solubility and off-target effects. Ligand B (0.798) is quite low, potentially hindering membrane permeability.

**H-Bond Donors/Acceptors:** Ligand A (1 HBD, 3 HBA) is good. Ligand B (0 HBD, 5 HBA) is also acceptable.

**QED:** Both ligands have similar and good QED values (0.842 and 0.826).

**DILI:** Ligand A (26.444) has a much lower DILI risk than Ligand B (60.682), which is considered high risk.

**BBB:** Ligand A (43.699) has a lower BBB penetration percentile than Ligand B (71.307). However, for a CNS target like DRD2, >70% is desirable, and Ligand B is closer to this threshold.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.732 and -4.624). These values are unusual and suggest poor permeability.

**Aqueous Solubility:** Both ligands have negative solubility values (-4.583 and -1.509), indicating very poor aqueous solubility.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.8 and 0.369).

**Microsomal Clearance:** Ligand A (10.599) has higher microsomal clearance than Ligand B (5.018), suggesting lower metabolic stability.

**In vitro Half-Life:** Ligand B (-6.036) has a negative half-life, which is not possible. This indicates a significant issue with the data or the molecule's stability. Ligand A (11.708) has a reasonable half-life.

**P-gp Efflux:** Ligand A (0.344) has lower P-gp efflux than Ligand B (0.052), which is beneficial for CNS penetration.

**Binding Affinity:** Both ligands have strong binding affinities (-9.2 and -8.4 kcal/mol). Ligand A is slightly better (-9.2 kcal/mol).

**Overall Assessment:**

Ligand B has a better BBB score and lower P-gp efflux, which are crucial for CNS targets. However, its high DILI risk, negative in vitro half-life, and low logP are major drawbacks. The negative half-life is a critical issue, suggesting instability. Ligand A, while having a higher logP and lower BBB, has a much better safety profile (lower DILI), a reasonable half-life, and slightly better affinity. The poor Caco-2 and solubility for both are concerning, but can potentially be addressed with formulation strategies.

Considering the GPCR-specific priorities and the severe issues with Ligand B's stability (negative half-life) and safety (high DILI), Ligand A is the more viable drug candidate despite its slightly less optimal logP and BBB.

Output:
0
2025-04-17 08:33:16,551 - INFO - Reasoning:

Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (343.391 and 361.389 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (105.04) is slightly above the preferred <90 for CNS targets, but still reasonable. Ligand B (87.74) is well within the desired range. This favors Ligand B.

**3. logP:** Ligand A (0.059) is quite low, potentially hindering membrane permeability. Ligand B (0.149) is also low, but slightly better. Both are below the optimal 1-3 range. This is a concern for both, but more so for A.

**4. H-Bond Donors:** Both ligands have 2 HBD, which is within the acceptable limit of <=5.

**5. H-Bond Acceptors:** Ligand A has 7 HBA, acceptable. Ligand B has 4 HBA, also acceptable.

**6. QED:** Ligand A (0.761) has a good drug-likeness score, while Ligand B (0.428) is below the 0.5 threshold, indicating a less favorable overall drug-like profile. This favors Ligand A.

**7. DILI:** Ligand A (64.831) has a higher DILI risk than Ligand B (33.695). This favors Ligand B.

**8. BBB:** Ligand B (87.476) has a significantly higher BBB penetration percentile than Ligand A (59.131). This is a *critical* advantage for a CNS target like DRD2.

**9. Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and suggests poor permeability. However, the scale isn't specified, so it's hard to interpret.

**10. Aqueous Solubility:** Both have negative solubility values, which is also unusual and suggests poor solubility. Again, the scale isn't specified.

**11. hERG:** Both ligands have very low hERG inhibition liability (0.222 and 0.402), which is excellent.

**12. Microsomal Clearance:** Ligand A (-45.013) has a very high negative clearance, which is not physically possible. This is likely an error in the data. Ligand B (-1.101) has a low clearance, indicating better metabolic stability. This strongly favors Ligand B.

**13. In vitro Half-Life:** Ligand B (-9.479) has a very negative half-life, which is also not physically possible. Ligand A (24.009) has a reasonable half-life. This favors Ligand A.

**14. P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.013 and 0.025), which is good.

**15. Binding Affinity:** Both ligands have very similar and strong binding affinities (-7.3 and -7.2 kcal/mol). The difference is negligible.

**Overall Assessment:**

Despite Ligand A having a better QED and a more reasonable half-life, Ligand B is the superior candidate. The significantly higher BBB penetration (87.476 vs 59.131) is paramount for a CNS target.  Ligand B also has a lower DILI risk and better metabolic stability (lower Cl_mic). The unusual negative values for Caco-2 and Solubility are concerning for both, but the other advantages of Ligand B outweigh these issues. The negative clearance and half-life for Ligand B are likely data errors.

Output:
1
2025-04-17 08:33:16,552 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (346.431 and 350.459 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (87.32) is slightly higher than Ligand B (78.87). Both are below the 90 A^2 threshold desirable for CNS targets, but Ligand B is preferable.

**3. logP:** Both ligands have similar logP values (1.641 and 1.753), falling within the optimal range of 1-3.

**4. H-Bond Donors:** Both have 2 HBD, which is acceptable.

**5. H-Bond Acceptors:** Both have 4 HBA, which is acceptable.

**6. QED:** Ligand A (0.794) has a slightly better QED score than Ligand B (0.686), indicating a more drug-like profile.

**7. DILI:** Ligand A (40.287) has a slightly higher DILI risk than Ligand B (22.024), but both are below the 40% threshold considered good. Ligand B is preferable.

**8. BBB:** Both ligands have similar BBB penetration (52.966% and 51.997%), which is acceptable but not ideal (>70% is preferred for CNS targets).

**9. Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and suggests poor permeability. This is a significant concern for both.

**10. Aqueous Solubility:** Both have negative solubility values, indicating very poor aqueous solubility. This is a major drawback for both compounds.

**11. hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.254 and 0.174).

**12. Microsomal Clearance:** Ligand A (-10.973) has significantly *lower* (better) microsomal clearance than Ligand B (41.234), suggesting better metabolic stability.

**13. In vitro Half-Life:** Ligand A (-20.561) has a significantly *longer* (better) in vitro half-life than Ligand B (-7.528).

**14. P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.034 and 0.022), which is favorable for CNS penetration.

**15. Binding Affinity:** Both ligands have the same binding affinity (-7.5 kcal/mol), which is good.

**Overall Assessment:**

While both compounds have similar binding affinity, Ligand A is preferable due to its significantly better metabolic stability (lower Cl_mic, longer t1/2) and slightly better QED score. Ligand B has a lower DILI risk, but the difference isn't substantial enough to outweigh the ADME advantages of Ligand A. The poor Caco-2 permeability and aqueous solubility are concerning for both, and would need to be addressed through further optimization. However, considering the GPCR-specific priorities, the improved metabolic stability of Ligand A is crucial for CNS drug development.

Output:
1
2025-04-17 08:33:16,552 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (360.361 and 358.551 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (94.48) is borderline, but acceptable for CNS penetration, while Ligand B (23.55) is excellent, well below the 90 A^2 threshold. This favors Ligand B.

**logP:** Ligand A (0.564) is quite low, potentially hindering membrane permeability. Ligand B (4.76) is high, potentially causing solubility issues and off-target effects. This is a concern for both, but more so for Ligand B.

**H-Bond Donors/Acceptors:** Ligand A (2 HBD, 6 HBA) and Ligand B (0 HBD, 3 HBA) both fall within acceptable ranges.

**QED:** Both ligands have similar QED values (0.707 and 0.712), indicating good drug-likeness.

**DILI:** Ligand A (61.07) has a higher DILI risk than Ligand B (15.2), which is a significant advantage for Ligand B.

**BBB:** Ligand B (96.355) has excellent BBB penetration, exceeding the desirable >70% threshold. Ligand A (74.292) is also good, but not as high. This strongly favors Ligand B.

**Caco-2 Permeability:** Ligand A (-4.96) has poor Caco-2 permeability, while Ligand B (-4.512) is slightly better, but still not great.

**Aqueous Solubility:** Ligand A (-2.491) has poor aqueous solubility, and Ligand B (-4.073) is even worse. This is a concern for both, but more so for Ligand B.

**hERG Inhibition:** Ligand A (0.244) has a lower hERG risk than Ligand B (0.809), which is a positive for Ligand A.

**Microsomal Clearance:** Ligand B (83.543) has significantly higher microsomal clearance than Ligand A (5.243), indicating lower metabolic stability. This is a major advantage for Ligand A.

**In vitro Half-Life:** Ligand B (43.384) has a longer half-life than Ligand A (17.818), which is preferable.

**P-gp Efflux:** Ligand A (0.031) has very low P-gp efflux, which is excellent for CNS penetration. Ligand B (0.439) has moderate P-gp efflux. This favors Ligand A.

**Binding Affinity:** Both ligands have the same binding affinity (-7.3 kcal/mol), which is excellent.

**Overall Assessment:**

Ligand B excels in BBB penetration and has a lower DILI risk, but suffers from high logP, poor solubility, high microsomal clearance, and moderate P-gp efflux. Ligand A has better metabolic stability, lower P-gp efflux, and lower hERG risk, but has a low logP and poor Caco-2 permeability.

Considering the GPCR-specific priorities, BBB penetration is crucial for a CNS target like DRD2. Ligand B's significantly higher BBB score (96.355 vs 74.292) is a major advantage. However, the poor solubility and high clearance of Ligand B are concerning. Ligand A's lower logP and solubility are also problematic, but its better metabolic stability and lower P-gp efflux are beneficial.

Despite the drawbacks, the superior BBB penetration of Ligand B outweighs its other issues, making it the more promising candidate.

Output:
1
2025-04-17 08:33:16,552 - INFO - Batch 458 complete. Total preferences: 7328
2025-04-17 08:33:16,552 - INFO - Processing batch 459/512...
2025-04-17 08:33:59,388 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (345.374 and 353.379 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (69.72) is excellent, well below the 90 A^2 threshold for CNS targets. Ligand B (122.63) is higher, but still potentially acceptable, though less ideal.

**3. logP:** Ligand A (1.227) is within the optimal range (1-3). Ligand B (-1.046) is slightly below 1, which *could* indicate permeability issues, but isn't a hard disqualifier.

**4. H-Bond Donors:** Ligand A (1) is good. Ligand B (2) is also acceptable.

**5. H-Bond Acceptors:** Ligand A (3) is good. Ligand B (7) is higher, but still within the acceptable limit of 10.

**6. QED:** Ligand A (0.662) is better than Ligand B (0.584), indicating a more drug-like profile.

**7. DILI:** Ligand A (67.39) is higher risk than Ligand B (48.623), which is preferable.

**8. BBB:** Ligand A (84.878) has a significantly better BBB penetration percentile than Ligand B (69.794). This is *critical* for a CNS target like DRD2.

**9. Caco-2 Permeability:** Ligand A (-4.613) has poor Caco-2 permeability. Ligand B (-5.17) is also poor, but slightly worse.

**10. Aqueous Solubility:** Ligand A (-3.33) has poor solubility. Ligand B (-0.349) is better, but still not ideal.

**11. hERG Inhibition:** Ligand A (0.39) has a very low hERG risk, which is excellent. Ligand B (0.026) is even lower, also excellent.

**12. Microsomal Clearance:** Both ligands have similar microsomal clearance values (Ligand A: 30.642, Ligand B: 32.718), suggesting comparable metabolic stability.

**13. In vitro Half-Life:** Ligand A (-16.903) has a very short half-life, which is a significant drawback. Ligand B (-24.805) is even shorter, a larger drawback.

**14. P-gp Efflux:** Ligand A (0.157) has lower P-gp efflux liability than Ligand B (0.005), which is preferable for CNS penetration.

**15. Binding Affinity:** Ligand A (-9.4 kcal/mol) has a significantly stronger binding affinity than Ligand B (-7.3 kcal/mol). This is a substantial advantage, potentially outweighing some ADME concerns.

**Overall Assessment:**

Despite the poor Caco-2 and solubility of Ligand A, its *much* stronger binding affinity (-9.4 vs -7.3 kcal/mol) and significantly better BBB penetration (84.88% vs 69.79%) are decisive advantages for a CNS GPCR target. The lower DILI risk is also a plus. While Ligand B has a slightly better hERG profile, the affinity and BBB differences are far more important in this context. The poor half-life of both is a concern, but can be addressed through structural modifications.

Output:
1
2025-04-17 08:33:59,388 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (381.929 and 361.877 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (73.2) is slightly higher than Ligand B (64.86). Both are below the 90 A^2 threshold for CNS targets, which is good. Ligand B is preferable here.

**3. logP:** Both ligands have a logP around 3.8, which is optimal.

**4. H-Bond Donors:** Both have 1 HBD, which is within the acceptable limit of <=5.

**5. H-Bond Acceptors:** Ligand A has 4 HBA, and Ligand B has 6. Both are within the acceptable limit of <=10.

**6. QED:** Both ligands have good QED scores (0.779 and 0.897), indicating drug-like properties. Ligand B is slightly better.

**7. DILI:** Ligand A (39.201) has a lower DILI risk than Ligand B (62.35). This is a significant advantage for Ligand A.

**8. BBB:** Ligand A (75.378) and Ligand B (83.986) both have good BBB penetration, exceeding the 70% threshold. Ligand B is slightly better.

**9. Caco-2 Permeability:** Both have negative Caco-2 values (-4.946 and -5.152), which is unusual and suggests poor permeability. This is a concern for both.

**10. Aqueous Solubility:** Both have negative solubility values (-4.503 and -4.556), indicating very poor aqueous solubility. This is a major drawback for both.

**11. hERG Inhibition:** Both ligands have low hERG inhibition risk (0.78 and 0.261). Ligand B is preferable.

**12. Microsomal Clearance:** Ligand A (36.251) has lower microsomal clearance than Ligand B (45.11), suggesting better metabolic stability.

**13. In vitro Half-Life:** Ligand A (9.738) has a slightly longer half-life than Ligand B (7.162).

**14. P-gp Efflux:** Both ligands have low P-gp efflux liability (0.397 and 0.459), which is good for CNS penetration.

**15. Binding Affinity:** Both ligands have the same binding affinity (-7.6 kcal/mol), which is excellent.

**Overall Assessment:**

Both ligands have excellent binding affinity, which is the most crucial factor. However, they both suffer from poor solubility and permeability. Ligand B has a better BBB score, QED, and hERG profile, but a higher DILI risk. Ligand A has a lower DILI risk and better metabolic stability (lower Cl_mic, longer t1/2). Given the importance of minimizing toxicity (DILI) and maintaining metabolic stability for a CNS drug, and the similar affinities, Ligand A is slightly more promising. The poor solubility and permeability are significant hurdles for both, but formulation strategies might be explored to address these issues.

Output:
0
2025-04-17 08:33:59,388 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (367.881 and 350.459 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (90.12) is borderline acceptable for CNS targets, while Ligand B (59.08) is well within the desirable range (<=90). This favors Ligand B.

**3. logP:** Both ligands have good logP values (1.42 and 1.74), falling within the optimal 1-3 range.

**4. H-Bond Donors:** Ligand A has 3 HBD, which is acceptable. Ligand B has 0, which is also good.

**5. H-Bond Acceptors:** Both ligands have 4 HBA, which is within the acceptable limit of <=10.

**6. QED:** Both ligands have similar QED values (0.734 and 0.685), indicating good drug-like properties.

**7. DILI:** Ligand A (29.314) and Ligand B (21.326) both have low DILI risk, well below the 40 threshold.

**8. BBB:** Ligand B (83.288) has a significantly better BBB percentile than Ligand A (64.172). This is a crucial advantage for a CNS target like DRD2.

**9. Caco-2 Permeability:** Ligand A (-5.549) has poor Caco-2 permeability, while Ligand B (-4.528) is slightly better, but still not great.

**10. Aqueous Solubility:** Both ligands have poor aqueous solubility (-2.716 and -1.548). This could pose formulation challenges.

**11. hERG Inhibition:** Both ligands have low hERG inhibition risk (0.491 and 0.361).

**12. Microsomal Clearance:** Ligand A (-23.302) has a much lower (better) microsomal clearance than Ligand B (46.083), suggesting greater metabolic stability.

**13. In vitro Half-Life:** Ligand A (-14.451) has a longer in vitro half-life than Ligand B (-11.356), which is favorable.

**14. P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.069 and 0.095), which is good for CNS penetration.

**15. Binding Affinity:** Ligand B (-7.2) has a slightly better binding affinity than Ligand A (-9.0). However, the difference is not substantial enough to outweigh other factors.

**Overall Assessment:**

Ligand B is the more promising candidate. Its superior BBB penetration is a significant advantage for a CNS target. While Ligand A has better metabolic stability and half-life, the BBB is a critical factor for DRD2. The slightly better affinity of Ligand B is a bonus. Both have solubility issues that would need to be addressed during development.

Output:
1
2025-04-17 08:33:59,388 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (348.443 Da) is slightly preferred due to being closer to the lower end, potentially aiding permeability.

**TPSA:** Ligand A (84.5) is better than Ligand B (67.4), both are below the 90 A^2 threshold for CNS targets, but A is closer to the ideal range.

**logP:** Both ligands have good logP values (A: 1.392, B: 2.319) falling within the optimal 1-3 range. Ligand B is slightly higher, which could potentially lead to off-target effects, but is still acceptable.

**H-Bond Donors/Acceptors:** Ligand A (HBD=2, HBA=4) and Ligand B (HBD=0, HBA=6) both fall within acceptable limits.

**QED:** Both ligands have reasonable QED values (A: 0.355, B: 0.731). Ligand B is significantly better, indicating a more drug-like profile.

**DILI:** Ligand A (15.006) has a much lower DILI risk than Ligand B (21.171), a significant advantage.

**BBB:** Ligand B (72.431) has a substantially better BBB penetration percentile than Ligand A (55.06). This is a critical factor for a CNS target like DRD2.

**Caco-2 Permeability:** Ligand A (-4.651) has worse Caco-2 permeability than Ligand B (-5.342), indicating poorer intestinal absorption.

**Aqueous Solubility:** Ligand A (-1.954) has worse solubility than Ligand B (-1.59).

**hERG:** Both ligands have low hERG inhibition risk (A: 0.182, B: 0.376).

**Microsomal Clearance:** Ligand A (40.736) has higher microsomal clearance than Ligand B (7.121), suggesting lower metabolic stability.

**In vitro Half-Life:** Ligand B (34.77) has a significantly longer in vitro half-life than Ligand A (-19.832).

**P-gp Efflux:** Both ligands have low P-gp efflux liability (A: 0.036, B: 0.064).

**Binding Affinity:** Ligand B (-7.9 kcal/mol) has a slightly better binding affinity than Ligand A (-7.5 kcal/mol), a 0.4 kcal/mol difference.

**Overall Assessment:**

Ligand B is superior due to its significantly better BBB penetration, longer half-life, lower DILI risk, and better QED score. While Ligand A has a slightly better TPSA and lower molecular weight, the advantages of Ligand B in key ADME/PK properties, particularly BBB and half-life, outweigh these minor differences. The slightly better affinity of Ligand B is also a plus. For a CNS target like DRD2, BBB penetration is paramount.

Output:
1
2025-04-17 08:33:59,388 - INFO - Reasoning:

Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (368.371 and 348.403 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (69.64) is excellent, well below the 90 A^2 threshold for CNS targets. Ligand B (104.54) is still reasonable but higher, potentially impacting BBB penetration.

**3. logP:** Ligand A (1.794) is optimal. Ligand B (0.619) is a bit low, potentially hindering membrane permeability.

**4. H-Bond Donors:** Both ligands have 2 HBD, which is within the acceptable limit of <=5.

**5. H-Bond Acceptors:** Ligand A has 3 HBA, and Ligand B has 5 HBA. Both are within the acceptable limit of <=10.

**6. QED:** Both ligands have good QED scores (0.507 and 0.833, respectively), indicating good drug-like properties.

**7. DILI:** Ligand A (16.053) has a significantly lower DILI risk than Ligand B (51.028). This is a major advantage for Ligand A.

**8. BBB:** Ligand A (94.029) has excellent BBB penetration, exceeding the desirable >70% threshold. Ligand B (49.748) is considerably lower, which is a significant drawback for a CNS target like DRD2.

**9. Caco-2 Permeability:** Both have negative values (-5.079 and -5.114), which is unusual and difficult to interpret without knowing the scale. However, the values are very similar.

**10. Aqueous Solubility:** Both have negative values (-2.444 and -2.32), which is also unusual and hard to interpret. Again, the values are similar.

**11. hERG Inhibition:** Both ligands show very low hERG inhibition risk (0.78 and 0.089).

**12. Microsomal Clearance:** Ligand A (17.961) has a moderate clearance, while Ligand B (-20.863) has a *negative* clearance, which is not physically possible and likely indicates an issue with the data or model. This is a major red flag for Ligand B.

**13. In vitro Half-Life:** Ligand A (-6.157) has a negative half-life, which is not physically possible and suggests a data issue. Ligand B (5.884) has a reasonable half-life.

**14. P-gp Efflux:** Ligand A (0.135) has very low P-gp efflux, which is favorable for CNS penetration. Ligand B (0.012) also has very low P-gp efflux.

**15. Binding Affinity:** Both ligands have very similar and strong binding affinities (-8.6 and -8.5 kcal/mol). The difference is negligible.

**Overall Assessment:**

Ligand A is significantly more promising. It has superior BBB penetration, a much lower DILI risk, and acceptable physicochemical properties. While the negative half-life is concerning, the other advantages, especially the high BBB penetration for a CNS target, outweigh this issue. Ligand B has a problematic negative clearance and significantly lower BBB penetration. The negative half-life and solubility/permeability values are also concerning.

Output:
1
2025-04-17 08:33:59,389 - INFO - Reasoning:

Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (450.244 Da) is higher, but still acceptable. Ligand B (343.423 Da) is lower, potentially aiding permeability.

**2. TPSA:** Ligand A (104.62) is higher than the optimal <90 for CNS targets, while Ligand B (51.91) is well within the desirable range. This is a significant advantage for Ligand B regarding BBB penetration.

**3. logP:** Ligand A (1.639) is within the optimal 1-3 range. Ligand B (3.729) is at the upper end, potentially leading to solubility issues, but still acceptable.

**4. H-Bond Donors:** Ligand A (2) and Ligand B (0) both fall within the acceptable limit of <=5.

**5. H-Bond Acceptors:** Ligand A (6) and Ligand B (4) are both within the acceptable limit of <=10.

**6. QED:** Both ligands have good QED scores (A: 0.591, B: 0.685), indicating drug-like properties.

**7. DILI:** Ligand A (84.994) has a higher DILI risk than Ligand B (52.423). Lower is better, so Ligand B is preferable.

**8. BBB:** Ligand A (43.117) has a low BBB penetration percentile, which is a major drawback for a CNS target like DRD2. Ligand B (66.615) is better, but still not optimal (>70 is desirable).

**9. Caco-2 Permeability:** Ligand A (-5.529) has poor Caco-2 permeability, while Ligand B (-4.636) is slightly better, but both are negative and indicate poor intestinal absorption.

**10. Aqueous Solubility:** Both ligands have poor aqueous solubility (-3.874 and -4.086 respectively).

**11. hERG Inhibition:** Ligand A (0.347) has a lower hERG inhibition risk than Ligand B (0.745), which is preferable.

**12. Microsomal Clearance:** Ligand A (31.978) has lower microsomal clearance, indicating better metabolic stability, than Ligand B (58.702).

**13. In vitro Half-Life:** Ligand B (45.048) has a significantly longer in vitro half-life than Ligand A (-1.787), which is a major advantage.

**14. P-gp Efflux:** Ligand A (0.037) has lower P-gp efflux, which is better for CNS penetration, than Ligand B (0.527).

**15. Binding Affinity:** Ligand A (-9.5 kcal/mol) has a slightly better binding affinity than Ligand B (-8.3 kcal/mol). This 1.2 kcal/mol difference is significant and could potentially outweigh some of the ADME drawbacks of Ligand A.

**Overall Assessment:**

Despite the slightly better binding affinity of Ligand A, Ligand B is the more promising candidate. The primary concern for a CNS target is BBB penetration, and Ligand B has a significantly better BBB percentile (66.615 vs 43.117) and lower TPSA (51.91 vs 104.62). Additionally, Ligand B has a lower DILI risk and a much longer in vitro half-life. While both have poor solubility and Caco-2 permeability, the improved CNS properties of Ligand B are crucial for a DRD2 ligand. The slightly higher P-gp efflux and hERG risk of Ligand B can be addressed through further optimization.

Output:
1
2025-04-17 08:33:59,389 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (345.443 and 368.499 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (82.53) is better than Ligand B (87.66). Both are below the 90 A^2 threshold desirable for CNS targets, but A is closer to the optimal range.

**3. logP:** Both ligands have similar logP values (1.383 and 1.398), falling within the optimal 1-3 range.

**4. H-Bond Donors:** Ligand A (2) is preferable to Ligand B (3). Lower HBD generally improves permeability.

**5. H-Bond Acceptors:** Ligand A (4) is preferable to Ligand B (5). Lower HBA generally improves permeability.

**6. QED:** Ligand A (0.845) has a significantly better QED score than Ligand B (0.647), indicating a more drug-like profile.

**7. DILI:** Both ligands have low DILI risk (33.695 and 35.595 percentiles), which is good.

**8. BBB:** Ligand A (52.772) has a better BBB percentile than Ligand B (40.403), although neither is above the desirable >70 threshold. This is a critical factor for a CNS target like DRD2.

**9. Caco-2 Permeability:** Ligand A (-4.746) has a higher (less negative) Caco-2 value than Ligand B (-5.288), suggesting better intestinal absorption.

**10. Aqueous Solubility:** Ligand A (-2.328) has a slightly better solubility value than Ligand B (-1.953).

**11. hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.209 and 0.266).

**12. Microsomal Clearance:** Ligand A (20.724) has a lower microsomal clearance than Ligand B (34.074), suggesting better metabolic stability.

**13. In vitro Half-Life:** Ligand B (29.749) has a significantly longer in vitro half-life than Ligand A (2.634). This is a positive for B.

**14. P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.022 and 0.105).

**15. Binding Affinity:** Ligand B (-8.3) has a slightly better binding affinity than Ligand A (-7.8). A difference of 0.5 kcal/mol is significant, and can sometimes outweigh other ADME drawbacks.

**Overall Assessment:**

While Ligand B has a slightly better binding affinity and a longer half-life, Ligand A is superior in almost all other crucial ADME properties, especially those prioritized for GPCRs targeting the CNS. Ligand A has a better QED, lower TPSA, better BBB penetration (though still not ideal), better Caco-2 permeability, and lower microsomal clearance. The difference in binding affinity (0.5 kcal/mol) is not substantial enough to overcome the significant advantages of Ligand A in terms of drug-likeness and predicted CNS exposure.

Output:
0
2025-04-17 08:33:59,389 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 drug candidates, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (384.929 Da) is slightly higher than Ligand B (354.539 Da), but both are acceptable.

**TPSA:** Ligand A (50.8) is better than Ligand B (55.89). Both are below the 90 A^2 threshold for CNS targets, but A is closer to the ideal.

**logP:** Ligand A (3.334) is optimal, while Ligand B (1.554) is on the lower side. Lower logP can hinder permeation, particularly across the BBB.

**H-Bond Donors/Acceptors:** Both ligands have 1 HBD and 4 HBA, which are within acceptable limits.

**QED:** Ligand A (0.868) has a significantly better QED score than Ligand B (0.647), indicating better overall drug-likeness.

**DILI:** Ligand A (60.644) has a higher DILI risk than Ligand B (3.18). This is a significant drawback for Ligand A.

**BBB:** Ligand A (75.533) has a better BBB penetration percentile than Ligand B (57.115). This is crucial for a CNS target like DRD2.

**Caco-2 Permeability:** Ligand A (-4.817) has a worse Caco-2 permeability than Ligand B (-5.246). Lower values suggest poorer intestinal absorption.

**Aqueous Solubility:** Ligand A (-4.213) has a worse aqueous solubility than Ligand B (0.17). This could pose formulation challenges.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.466 and 0.436 respectively), which is good.

**Microsomal Clearance:** Ligand B (-20.611) has significantly lower microsomal clearance than Ligand A (51.744), indicating better metabolic stability.

**In vitro Half-Life:** Ligand B (-2.036) has a longer in vitro half-life than Ligand A (38.195), which is desirable.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.178 and 0.003 respectively), which is excellent for CNS penetration.

**Binding Affinity:** Ligand A (-8.4 kcal/mol) has a slightly better binding affinity than Ligand B (-7.4 kcal/mol). This 1 kcal/mol difference is meaningful and could potentially outweigh some of the ADME drawbacks.

**Overall Assessment:**

Ligand A has a better binding affinity and BBB penetration, which are critical for a CNS GPCR target. However, it suffers from higher DILI risk, poorer solubility, and higher metabolic clearance. Ligand B has a significantly better safety profile (DILI), metabolic stability, and solubility, but its lower logP and BBB penetration are concerning.

Considering the balance, the slightly stronger binding affinity of Ligand A, combined with its acceptable BBB penetration, makes it the more promising candidate *despite* the higher DILI risk. The DILI risk could potentially be mitigated through structural modifications in later stages of optimization. The lower logP of Ligand B is a more difficult property to improve significantly.

Output:
1
2025-04-17 08:33:59,389 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (353.419 and 358.473 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (104.81) is slightly above the optimal <90 for CNS targets, but still reasonable. Ligand B (40.62) is excellent, well below 90.

**logP:** Ligand A (-0.183) is quite low, potentially hindering membrane permeability. Ligand B (3.347) is within the optimal 1-3 range. This is a significant advantage for Ligand B.

**H-Bond Donors/Acceptors:** Ligand A has 2 HBD and 5 HBA, acceptable values. Ligand B has 0 HBD and 2 HBA, also acceptable, and potentially better for permeability due to fewer hydrogen bonds.

**QED:** Both ligands have good QED scores (0.509 and 0.655), indicating drug-like properties.

**DILI:** Ligand A (36.758) has a slightly higher DILI risk than Ligand B (25.359), but both are below the concerning threshold of 60.

**BBB:** Ligand A (36.603) has a low BBB penetration percentile, which is a major drawback for a CNS target like DRD2. Ligand B (94.3) has excellent BBB penetration, a crucial advantage.

**Caco-2 Permeability:** Ligand A (-5.013) shows poor permeability. Ligand B (-4.283) is also poor, but slightly better.

**Aqueous Solubility:** Both ligands have negative solubility values, indicating poor aqueous solubility. This could be problematic for formulation.

**hERG Inhibition:** Ligand A (0.058) has very low hERG inhibition risk. Ligand B (0.917) has a slightly higher risk, but still relatively low.

**Microsomal Clearance:** Ligand A (32.488) has lower microsomal clearance, suggesting better metabolic stability. Ligand B (45.979) has higher clearance.

**In vitro Half-Life:** Ligand A (-3.357) has a negative half-life, which is unusual and likely an artifact of the prediction method. Ligand B (3.049) has a reasonable half-life.

**P-gp Efflux:** Ligand A (0.018) has very low P-gp efflux, which is favorable for CNS exposure. Ligand B (0.62) has moderate P-gp efflux.

**Binding Affinity:** Both ligands have excellent binding affinities (-7.1 and -7.2 kcal/mol). The difference is minimal.

**Overall Assessment:**

Ligand B is significantly more promising due to its excellent BBB penetration (94.3), optimal logP (3.347), and acceptable P-gp efflux. While its solubility and Caco-2 permeability are not ideal, the strong BBB penetration is a major advantage for a CNS target. Ligand A's poor BBB penetration (36.603) and low logP are significant liabilities. Although Ligand A has slightly better metabolic stability and lower P-gp efflux, the CNS penetration is paramount for DRD2.

Output:
1
2025-04-17 08:33:59,389 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 drug candidates, considering the provided guidelines and GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (334.419 and 349.431 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (43.6) is excellent, well below the 90 A^2 threshold for CNS targets. Ligand B (94.66) is higher, but still potentially acceptable, though less ideal.

**logP:** Ligand A (3.597) is optimal. Ligand B (0.75) is low, potentially hindering permeation and CNS entry.

**H-Bond Donors/Acceptors:** Ligand A (0 HBD, 4 HBA) is favorable. Ligand B (3 HBD, 4 HBA) is also acceptable.

**QED:** Both ligands have good QED scores (0.479 and 0.748), indicating reasonable drug-likeness.

**DILI:** Ligand A (50.136) has a slightly higher DILI risk than Ligand B (37.418), but both are below the concerning 60 threshold.

**BBB:** This is critical for a CNS target. Ligand A (62.699) is moderately good, while Ligand B (22.644) is poor, significantly hindering its potential to reach the brain.

**Caco-2 Permeability:** Ligand A (-4.674) has poor Caco-2 permeability. Ligand B (-5.025) is also poor.

**Aqueous Solubility:** Ligand A (-4.458) and Ligand B (-2.307) both have poor aqueous solubility.

**hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.414 and 0.281).

**Microsomal Clearance:** Ligand A (76.98) has higher clearance than Ligand B (7.361), suggesting lower metabolic stability.

**In vitro Half-Life:** Ligand B (-6.518) has a longer half-life than Ligand A (-32.146).

**P-gp Efflux:** Both ligands show low P-gp efflux liability (0.407 and 0.047).

**Binding Affinity:** Both ligands have similar and strong binding affinities (-8.9 and -8.5 kcal/mol). The difference is less than the 1.5 kcal/mol threshold.

**Conclusion:**

Considering the GPCR-specific priorities, Ligand A is the better candidate. While its Caco-2 permeability and solubility are poor, its significantly better BBB penetration (62.7% vs 22.6%) is crucial for a CNS-targeting drug. The slightly higher DILI and clearance are less concerning than the poor BBB score of Ligand B. The similar binding affinities make the ADME properties the deciding factor.

Output:
0
2025-04-17 08:33:59,389 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (352.406 and 347.419 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (76.66) is excellent, well below the 90 A^2 threshold for CNS targets. Ligand B (98.14) is still reasonable, but closer to the 140 A^2 limit for oral absorption and less ideal for CNS penetration.

**logP:** Ligand A (2.085) is optimal (1-3). Ligand B (0.146) is significantly low, potentially hindering membrane permeability and CNS entry.

**H-Bond Donors/Acceptors:** Both ligands have 2 HBD and are within the acceptable range. Ligand B has 6 HBA, slightly higher but still acceptable. Ligand A has 4 HBA, which is better.

**QED:** Both ligands have good QED scores (0.632 and 0.684), indicating drug-like properties.

**DILI:** Ligand A (40.946) is better than Ligand B (64.172), indicating a lower risk of drug-induced liver injury.

**BBB:** Ligand A (88.29) shows excellent BBB penetration potential, exceeding the 70% threshold. Ligand B (46.336) is significantly lower and less favorable for a CNS target.

**Caco-2 Permeability:** Ligand A (-4.76) is very poor, while Ligand B (-5.242) is also poor. This is a concern for both, but less critical given the focus on CNS penetration.

**Aqueous Solubility:** Ligand A (-2.764) and Ligand B (-1.534) are both poor, but Ligand B is slightly better.

**hERG Inhibition:** Both ligands show very low hERG inhibition risk (0.422 and 0.1), which is excellent.

**Microsomal Clearance:** Ligand A (28.219) has a moderate clearance, while Ligand B (9.701) has a very low clearance, suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (11.273) has a moderate half-life, while Ligand B (6.726) has a shorter half-life.

**P-gp Efflux:** Both ligands show low P-gp efflux (0.107 and 0.019), which is favorable for CNS penetration. Ligand B is slightly better.

**Binding Affinity:** Ligand A (-8.7 kcal/mol) has a significantly stronger binding affinity than Ligand B (-7.7 kcal/mol). This 1.0 kcal/mol difference is substantial and can outweigh some ADME drawbacks.

**Conclusion:**

Considering all factors, especially the GPCR-specific priorities for a CNS target, **Ligand A is the more promising candidate.** Its superior BBB penetration, significantly stronger binding affinity, and lower DILI risk outweigh its slightly poorer Caco-2 permeability and moderate metabolic clearance. Ligand B's low logP is a major concern, severely limiting its potential for CNS entry.

Output:
1
2025-04-17 08:33:59,389 - INFO - Reasoning:

Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (387.433 and 350.459 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (101.29) is slightly above the preferred <90 for CNS targets, but still reasonable. Ligand B (81.08) is well within the desired range.

**3. logP:** Both ligands (1.177 and 1.092) are within the optimal 1-3 range.

**4. H-Bond Donors:** Ligand A (3) and Ligand B (2) are both acceptable, below the limit of 5.

**5. H-Bond Acceptors:** Ligand A (5) and Ligand B (4) are both acceptable, below the limit of 10.

**6. QED:** Both ligands (0.733 and 0.703) have good drug-likeness scores, exceeding 0.5.

**7. DILI:** Ligand A (75.572) has a higher DILI risk than Ligand B (13.339). This is a significant concern.

**8. BBB:** Ligand A (68.864) and Ligand B (60.876) are both below the desirable >70 for CNS targets, but Ligand A is better.

**9. Caco-2 Permeability:** Ligand A (-5.707) and Ligand B (-4.689) both have negative values, which is unusual and suggests poor permeability.

**10. Aqueous Solubility:** Both ligands have negative solubility values (-2.075 and -1.628) which is concerning.

**11. hERG Inhibition:** Both ligands have low hERG inhibition risk (0.44 and 0.279).

**12. Microsomal Clearance:** Ligand A (5.984) has lower clearance than Ligand B (15.938), suggesting better metabolic stability.

**13. In vitro Half-Life:** Ligand A (33.354) has a longer half-life than Ligand B (-11.504). The negative value for Ligand B is problematic.

**14. P-gp Efflux:** Ligand A (0.239) has lower P-gp efflux than Ligand B (0.135), which is favorable for CNS penetration.

**15. Binding Affinity:** Ligand A (-9.2 kcal/mol) has a significantly stronger binding affinity than Ligand B (-7.6 kcal/mol). This is a >1.5 kcal/mol difference, which can outweigh some ADME drawbacks.

**Overall Assessment:**

Ligand A has a much better binding affinity, better metabolic stability (lower Cl_mic, longer t1/2), and lower P-gp efflux. However, it has a significantly higher DILI risk. Ligand B has a much better safety profile (lower DILI), but its binding affinity is weaker, and it has a negative in vitro half-life.

Given the importance of CNS penetration for a DRD2 ligand, and the substantial affinity advantage of Ligand A, I would prioritize Ligand A despite the DILI risk. The DILI risk could potentially be mitigated through structural modifications during lead optimization. The poor solubility and permeability of both compounds would also need to be addressed.

Output:
1
2025-04-17 08:33:59,389 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (359.373 and 380.945 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (95.67) is slightly above the optimal <90 for CNS targets, but still reasonable. Ligand B (43.18) is excellent, well below 90. This favors Ligand B.

**3. logP:** Ligand A (1.568) is within the optimal 1-3 range. Ligand B (4.287) is slightly high, potentially leading to solubility issues and off-target interactions. This favors Ligand A.

**4. H-Bond Donors:** Ligand A (2) and Ligand B (0) are both acceptable (<=5).

**5. H-Bond Acceptors:** Ligand A (5) and Ligand B (6) are both acceptable (<=10).

**6. QED:** Both ligands have similar QED values (0.77 and 0.641), indicating good drug-likeness.

**7. DILI:** Both ligands have low DILI risk (43.234 and 37.999 percentile), which is good.

**8. BBB:** Both ligands show good BBB penetration (75.572 and 71.462 percentile), but Ligand A is slightly better. This is a crucial factor for a CNS target like DRD2.

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.595 and -4.954), which is unusual and suggests poor permeability. However, these values are on a scale where negative values are possible and don't necessarily preclude development.

**10. Aqueous Solubility:** Both ligands have negative solubility values (-2.485 and -4.285), which is also unusual and suggests poor solubility.

**11. hERG Inhibition:** Both ligands have low hERG inhibition risk (0.261 and 0.838 percentile), which is excellent.

**12. Microsomal Clearance:** Ligand A (33.281) has lower clearance than Ligand B (82.208), indicating better metabolic stability. This favors Ligand A.

**13. In vitro Half-Life:** Ligand A (-38.058) has a negative half-life, which is unusual and likely indicates rapid metabolism. Ligand B (-7.209) is also negative, but less so.

**14. P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.028 and 0.73 percentile), which is excellent for CNS penetration.

**15. Binding Affinity:** Both ligands have very similar binding affinities (-7.6 and -7.2 kcal/mol). The difference of 0.4 kcal/mol is not substantial enough to outweigh other factors.

**Overall Assessment:**

While Ligand B has a better TPSA and a slightly better logP, Ligand A has better BBB penetration, lower microsomal clearance, and a slightly better DILI score. The negative Caco-2 and solubility values are concerning for both, but not necessarily disqualifying. Considering the GPCR-specific priorities, the slightly better BBB penetration and metabolic stability of Ligand A make it the more promising candidate.

Output:
0
2025-04-17 08:33:59,390 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (346.475 and 348.403 Da) fall comfortably within the ideal 200-500 Da range.

**TPSA:** Ligand A (64.68) is excellent, well below the 90 A^2 threshold for CNS targets. Ligand B (93.53) is higher, but still potentially acceptable, though less ideal.

**logP:** Ligand A (2.911) is optimal (1-3). Ligand B (0.503) is low, potentially hindering permeability and CNS penetration.

**H-Bond Donors/Acceptors:** Ligand A (2 HBD, 3 HBA) is good. Ligand B (1 HBD, 6 HBA) is also reasonable, but the higher HBA count could slightly impact permeability.

**QED:** Both ligands have acceptable QED values (0.884 and 0.782), indicating good drug-like properties.

**DILI:** Ligand A (19.581) has a very low DILI risk. Ligand B (38.038) is higher, but still within a reasonably acceptable range.

**BBB:** This is critical for a CNS target like DRD2. Ligand A (72.547) has a good BBB percentile. Ligand B (53.276) is significantly lower, raising concerns about CNS exposure.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.628 and -4.874), which is unusual and suggests poor permeability. However, these values may be experimental artifacts or represent a specific assay limitation.

**Aqueous Solubility:** Both ligands have negative solubility values (-2.854 and -1.03), which is also unusual. Similar to Caco-2, these may not be reliable.

**hERG:** Both ligands have low hERG inhibition liability (0.608 and 0.145), which is positive.

**Microsomal Clearance:** Ligand A (-18.441) has a much lower (better) microsomal clearance than Ligand B (11.331), suggesting greater metabolic stability.

**In vitro Half-Life:** Ligand A (5.901) has a better in vitro half-life than Ligand B (-11.216).

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.01 and 0.019), which is favorable for CNS penetration.

**Binding Affinity:** Both ligands have strong binding affinities (-8.2 and -8.6 kcal/mol). Ligand B is slightly better (-8.6 vs -8.2), but the difference is small.

**Overall Assessment:**

Ligand A is significantly better overall, primarily due to its superior BBB penetration, lower DILI risk, better metabolic stability (lower Cl_mic, longer t1/2), and optimal logP. While both ligands have similar binding affinities, the ADME properties of Ligand A make it a much more promising drug candidate for a CNS target like DRD2. The negative Caco-2 and solubility values are concerning for both, but the other advantages of Ligand A outweigh these potential issues.

Output:
1
2025-04-17 08:33:59,390 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (364.47) is slightly better being closer to the lower end, potentially aiding permeability.

**TPSA:** Ligand A (66.92) is significantly better than Ligand B (106.61). For CNS targets, we want TPSA <= 90, and Ligand A is comfortably within this range, while Ligand B is above.

**logP:** Both ligands have acceptable logP values (A: 1.994, B: 1.304), falling within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A (HBD=0, HBA=4) is preferable to Ligand B (HBD=1, HBA=6) as fewer hydrogen bonds generally improve membrane permeability. Both are within acceptable limits.

**QED:** Both have reasonable QED scores (A: 0.819, B: 0.663), indicating good drug-like properties. Ligand A is slightly better.

**DILI:** Both have relatively high DILI risk (A: 38.58, B: 71.85), but Ligand B is considerably worse. Lower is better, and ideally below 40.

**BBB:** Ligand A (71.58) is significantly better than Ligand B (57.12). A BBB percentile >70 is desirable for CNS targets, and Ligand A is closer to this threshold.

**Caco-2 Permeability:** Both have negative Caco-2 values (-4.551 and -4.645), which is unusual and suggests poor permeability. However, these values are on a scale where negative values are possible, and direct comparison is difficult without knowing the scale's specifics.

**Aqueous Solubility:** Both have negative solubility values (-3.365 and -4.179), again suggesting poor solubility. Similar to Caco-2, the scale is unknown.

**hERG:** Both ligands have low hERG risk (A: 0.421, B: 0.346), which is good.

**Microsomal Clearance:** Ligand B (38.04) has a lower microsomal clearance than Ligand A (69.68), indicating better metabolic stability.

**In vitro Half-Life:** Ligand A (-52.55) has a negative half-life, which is concerning. Ligand B has a very short half-life (4.97). Both are poor.

**P-gp Efflux:** Both have low P-gp efflux liability (A: 0.2, B: 0.074), which is favorable for CNS penetration.

**Binding Affinity:** Both have excellent binding affinities (A: -8.9 kcal/mol, B: -8.1 kcal/mol). Ligand A has a 0.8 kcal/mol advantage, which is significant.

**Overall Assessment:**

Ligand A is significantly better overall. It has a superior TPSA, better BBB penetration, a slightly better QED, and a significantly better binding affinity. While both have issues with solubility and Caco-2 permeability, the strong affinity and improved CNS-relevant properties of Ligand A outweigh these concerns. Ligand B's higher DILI risk and lower BBB penetration are major drawbacks. The negative half-life for Ligand A is a concern, but could potentially be addressed through structural modifications.



Output:
1
2025-04-17 08:33:59,390 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (346.515 and 349.362 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (41.57) is significantly better than Ligand B (93.46). For CNS targets, TPSA should be <=90, and A is comfortably within that range, while B is close to the upper limit. This is a significant advantage for A.

**3. logP:** Ligand A (3.946) is optimal, while Ligand B (1.826) is a bit low, potentially hindering membrane permeability.

**4. H-Bond Donors:** Ligand A (1) is preferred over Ligand B (2). Lower HBD generally improves permeability.

**5. H-Bond Acceptors:** Ligand A (3) is better than Ligand B (5).

**6. QED:** Ligand A (0.767) is better than Ligand B (0.532), indicating a more drug-like profile.

**7. DILI:** Ligand A (6.669) has a much lower DILI risk than Ligand B (56.417). This is a major advantage for A.

**8. BBB:** Ligand A (83.443) has a significantly better BBB penetration percentile than Ligand B (63.784). Both are reasonably good, but A is closer to the desirable >70 threshold for CNS targets.

**9. Caco-2 Permeability:** Ligand A (-4.659) is worse than Ligand B (-5.109). Lower values indicate lower permeability, but both are poor.

**10. Aqueous Solubility:** Ligand A (-3.525) is better than Ligand B (-2.45).

**11. hERG Inhibition:** Ligand A (0.753) is better than Ligand B (0.407). Lower hERG inhibition is preferred.

**12. Microsomal Clearance:** Ligand A (18.11) has a much lower microsomal clearance than Ligand B (45.447), indicating better metabolic stability.

**13. In vitro Half-Life:** Ligand A (14.276) has a better in vitro half-life than Ligand B (46.877).

**14. P-gp Efflux:** Ligand A (0.121) is better than Ligand B (0.055). Lower P-gp efflux is preferred for CNS exposure.

**15. Binding Affinity:** Ligand B (-8.5) has a slightly better binding affinity than Ligand A (-8.1), but the difference is small (0.4 kcal/mol). This difference is unlikely to outweigh the significant ADME advantages of Ligand A.

**Overall Assessment:**

Ligand A consistently outperforms Ligand B across most critical ADME properties, particularly TPSA, logP, DILI, BBB, metabolic stability, and P-gp efflux. While Ligand B has a marginally better binding affinity, the superior ADME profile of Ligand A, especially its favorable BBB penetration and lower toxicity risk, makes it the more promising drug candidate for a CNS target like DRD2.

Output:
1
2025-04-17 08:33:59,390 - INFO - Batch 459 complete. Total preferences: 7344
2025-04-17 08:33:59,390 - INFO - Processing batch 460/512...
2025-04-17 08:34:41,278 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (354.357 and 340.427 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (90.62) is at the upper limit for CNS targets, while Ligand B (67.23) is well below the 90 threshold and therefore more favorable for CNS penetration.

**3. logP:** Both ligands have good logP values (2.386 and 1.334), falling within the optimal 1-3 range.

**4. H-Bond Donors:** Ligand A (3) is acceptable, while Ligand B (1) is even better, potentially improving permeability.

**5. H-Bond Acceptors:** Both ligands have acceptable HBA counts (5 and 4, respectively).

**6. QED:** Both ligands have good QED scores (0.772 and 0.826), indicating good drug-like properties.

**7. DILI:** Both ligands have acceptable DILI risk (69.678 and 54.556), below the concerning threshold of 60.

**8. BBB:** Ligand B (62.35) is better than Ligand A (58.085), but both are below the desirable >70 for CNS targets. This is a critical factor for DRD2.

**9. Caco-2 Permeability:** Both have negative values, which is unusual. Assuming these are logP values, both are very poor.

**10. Aqueous Solubility:** Both have negative values, which is unusual. Assuming these are logS values, both are very poor.

**11. hERG Inhibition:** Both ligands show low hERG inhibition liability (0.722 and 0.258), which is favorable.

**12. Microsomal Clearance:** Ligand A (-2.078) has a negative clearance, which is impossible. Ligand B (24.702) has a higher clearance, indicating faster metabolism, which is less desirable.

**13. In vitro Half-Life:** Ligand A (4.427) has a better half-life than Ligand B (-4.32).

**14. P-gp Efflux:** Both ligands show very low P-gp efflux (0.08 and 0.127), which is excellent for CNS penetration.

**15. Binding Affinity:** Ligand B (-8.1 kcal/mol) has a significantly stronger binding affinity than Ligand A (-0.0 kcal/mol). This is a major advantage, potentially outweighing some ADME drawbacks.

**Overall Assessment:**

Ligand B is the more promising candidate. While both have acceptable physicochemical properties, Ligand B has a much stronger binding affinity, lower P-gp efflux, and a better TPSA. The lower clearance of Ligand A is concerning. The negative values for Caco-2 and Solubility are concerning for both, but the significantly better binding affinity of Ligand B makes it the preferred choice.

Output:
1
2025-04-17 08:34:41,279 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (356.438 and 357.47 Da) fall comfortably within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (76.66) is slightly higher than Ligand B (72.88). Both are below the 90 Angstroms threshold desirable for CNS targets, which is good.

**3. logP:** Ligand A (1.331) and Ligand B (0.792) are both within the optimal 1-3 range. Ligand A is slightly better.

**4. H-Bond Donors:** Both ligands have 2 HBD, which is within the acceptable limit of <=5.

**5. H-Bond Acceptors:** Both ligands have 4 HBA, also within the acceptable limit of <=10.

**6. QED:** Both ligands have QED values above 0.7, indicating good drug-like properties. Ligand A (0.753) is slightly better than Ligand B (0.707).

**7. DILI:** Ligand A (30.361) has a significantly lower DILI risk than Ligand B (5.584). This is a major advantage for Ligand A.

**8. BBB:** Ligand A (82.435) has a better BBB penetration percentile than Ligand B (71.966).  Since DRD2 is a CNS target, this is a critical advantage for Ligand A.

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 values, indicating poor permeability. Ligand A (-4.945) is slightly less negative than Ligand B (-4.955), suggesting marginally better permeability, but both are concerning.

**10. Aqueous Solubility:** Both ligands have negative solubility values, indicating poor solubility. Ligand A (-2.053) is slightly better than Ligand B (-0.957).

**11. hERG Inhibition:** Both ligands show low hERG inhibition liability (0.434 and 0.419), which is good.

**12. Microsomal Clearance:** Ligand B (-10.63) has significantly lower (better) microsomal clearance than Ligand A (15.075). This suggests better metabolic stability for Ligand B.

**13. In vitro Half-Life:** Ligand B (-2.698) has a slightly longer in vitro half-life than Ligand A (26.298).

**14. P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.043 and 0.013), which is favorable for CNS penetration.

**15. Binding Affinity:** Ligand A (-8.7 kcal/mol) has a significantly stronger binding affinity than Ligand B (-7.4 kcal/mol). This is a substantial advantage for Ligand A, potentially outweighing some of its ADME drawbacks.

**Overall Assessment:**

While Ligand B has better metabolic stability and half-life, Ligand A is significantly better in several crucial areas for a CNS-targeting GPCR ligand: DILI risk, BBB penetration, and, most importantly, binding affinity. The 1.3 kcal/mol difference in binding affinity is substantial. Although both have poor Caco-2 and solubility, the superior affinity and safety profile of Ligand A make it the more promising candidate.

Output:
1
2025-04-17 08:34:41,279 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (352.435 and 368.543 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (91.31) is slightly above the optimal <90 for CNS targets, but still reasonable. Ligand B (69.64) is well within the desired range. This favors Ligand B.

**logP:** Ligand A (0.374) is quite low, potentially hindering membrane permeability. Ligand B (2.224) is within the optimal 1-3 range. This is a significant advantage for Ligand B.

**H-Bond Donors/Acceptors:** Ligand A has 1 HBD and 5 HBA, which are acceptable. Ligand B has 2 HBD and 4 HBA, also acceptable. No clear advantage here.

**QED:** Ligand A (0.615) has a better QED score than Ligand B (0.484), indicating a more drug-like profile.

**DILI:** Both ligands have similar, low DILI risk (27.104 and 27.142 percentile).

**BBB:** Ligand A shows a better BBB penetration (68.864%) than Ligand B (54.634%), but both are below the desirable >70% for CNS targets.

**Caco-2 Permeability:** Ligand A (-4.789) has worse Caco-2 permeability than Ligand B (-5.212), indicating lower intestinal absorption.

**Aqueous Solubility:** Ligand A (-1.603) has better aqueous solubility than Ligand B (-2.671).

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.199 and 0.303 percentile).

**Microsomal Clearance:** Ligand B (33.83) has a higher microsomal clearance than Ligand A (26.214), suggesting faster metabolism and potentially lower *in vivo* exposure.

**In vitro Half-Life:** Ligand A (-14.922) has a worse in vitro half-life than Ligand B (-8.652).

**P-gp Efflux:** Both ligands show very low P-gp efflux liability (0.015 and 0.113 percentile).

**Binding Affinity:** Both ligands have the same binding affinity (-6.8 kcal/mol), which is good.

**Overall Assessment:**

Ligand B is favored due to its better logP, TPSA, and Caco-2 permeability. While Ligand A has a better QED and slightly better BBB, the poor logP of Ligand A is a major concern for CNS penetration. The slightly better metabolic stability of Ligand A is outweighed by the permeability issues. The similar affinity means this isn't a deciding factor. Given the GPCR-specific priorities, optimizing for BBB, logP, and permeability is crucial.

Output:
1
2025-04-17 08:34:41,279 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (352.431 and 341.415 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (101.57) is slightly above the optimal <90 for CNS targets, but still reasonable. Ligand B (80.12) is well within the desired range. This favors Ligand B.

**3. logP:** Both ligands have logP values around 1 (0.956 and 1.01), which is optimal.

**4. H-Bond Donors:** Ligand A has 2 HBD, and Ligand B has 1. Both are within the acceptable limit of <=5.

**5. H-Bond Acceptors:** Both ligands have 5 HBA, which is within the acceptable limit of <=10.

**6. QED:** Both ligands have acceptable QED values (0.634 and 0.593), indicating good drug-like properties.

**7. DILI:** Ligand A (35.479) has a lower DILI risk than Ligand B (48.623), which is preferable.

**8. BBB:** Ligand B (58.821) has a significantly better BBB penetration percentile than Ligand A (46.491). This is a crucial factor for a CNS target like DRD2.

**9. Caco-2 Permeability:** Both have negative Caco-2 values (-4.94 and -4.723), which is unusual and suggests poor permeability. However, these values are on a difficult-to-interpret scale, and we must consider other factors.

**10. Aqueous Solubility:** Both have negative solubility values (-1.633 and -2.304), which is also unusual and suggests poor solubility. Again, the scale is difficult to interpret.

**11. hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.045 and 0.113).

**12. Microsomal Clearance:** Ligand B (26.031) has lower microsomal clearance than Ligand A (39.719), indicating better metabolic stability.

**13. In vitro Half-Life:** Ligand B (-17.128) has a longer in vitro half-life than Ligand A (-22.589), which is preferable.

**14. P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.033 and 0.067).

**15. Binding Affinity:** Both ligands have very similar and excellent binding affinities (-7.8 and -7.9 kcal/mol). The difference is negligible.

**Overall Assessment:**

While Ligand A has a slightly better DILI score, Ligand B is superior in several key areas for a CNS-targeting GPCR ligand: significantly better BBB penetration, lower microsomal clearance (better metabolic stability), and a longer in vitro half-life. The TPSA is also more favorable for Ligand B. The similar binding affinities make these ADME properties the deciding factors.

Output:
1
2025-04-17 08:34:41,280 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (339.395 Da) is slightly lower, which could be beneficial for permeability. Ligand B (381.263 Da) is also good.

**TPSA:** Ligand A (54.78) is excellent, well below the 90 A^2 threshold for CNS targets. Ligand B (67.23) is still reasonable, but less optimal.

**logP:** Ligand A (0.65) is a bit low, potentially hindering membrane permeability. Ligand B (1.83) is better, falling within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Both ligands have acceptable HBD (0/1) and HBA (4/4) counts, well within the recommended limits.

**QED:** Both ligands have good QED scores (0.74 and 0.81), indicating good drug-like properties.

**DILI:** Ligand A (32.842) has a significantly lower DILI risk than Ligand B (53.354), which is a substantial advantage.

**BBB:** Ligand B (82.862) has a much better BBB penetration score than Ligand A (62.97). This is a critical factor for a CNS target like DRD2.

**Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and suggests a potential issue with the prediction method. However, the magnitude is worse for Ligand B (-4.797 vs -4.341).

**Aqueous Solubility:** Both have negative solubility values, again suggesting a potential issue with the prediction method. The magnitude is worse for Ligand B (-4.377 vs -2.404).

**hERG:** Both ligands have low hERG inhibition liability (0.102 and 0.272), which is good.

**Microsomal Clearance:** Ligand A (10.347) has a lower microsomal clearance, indicating better metabolic stability than Ligand B (14.139).

**In vitro Half-Life:** Ligand A (8.157) has a slightly longer in vitro half-life than Ligand B (0.886).

**P-gp Efflux:** Ligand A (0.025) has significantly lower P-gp efflux liability than Ligand B (0.166), which is crucial for CNS penetration.

**Binding Affinity:** Ligand A (-8.0 kcal/mol) has a significantly stronger binding affinity than Ligand B (-6.8 kcal/mol). This 1.2 kcal/mol difference is substantial and can outweigh some ADME drawbacks.

**Overall Assessment:**

Ligand A excels in binding affinity, DILI risk, metabolic stability, P-gp efflux, and TPSA. While its logP and BBB are less favorable than Ligand B, the superior affinity and safety profile are compelling. The strong binding affinity could compensate for the slightly lower logP and BBB. Ligand B's main advantage is its BBB penetration, but it is offset by higher DILI, P-gp efflux, and weaker binding. Given the GPCR-specific priorities, the strong affinity and favorable safety profile of Ligand A make it the more promising candidate.

Output:
0
2025-04-17 08:34:41,280 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (374.809 and 346.475 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (105.07) is slightly above the optimal <90 for CNS targets, but still reasonable. Ligand B (66.37) is well within the desired range.

**logP:** Ligand A (2.882) is optimal. Ligand B (1.205) is a bit low, potentially hindering membrane permeability.

**H-Bond Donors/Acceptors:** Both ligands have 2 HBD and a reasonable number of HBA (6 for A, 4 for B), satisfying the <5 HBD and <10 HBA guidelines.

**QED:** Both ligands have good QED scores (0.711 and 0.78), indicating drug-like properties.

**DILI:** Ligand A has a very high DILI risk (99.341), which is a major red flag. Ligand B has a low DILI risk (10.702), a significant advantage.

**BBB:** Ligand A has a moderate BBB penetration (12.99), which is concerning for a CNS target. Ligand B has a much better BBB penetration (59.131), but still not ideal (>70 is preferred).

**Caco-2 Permeability:** Both have negative Caco-2 values (-5.338 and -5.409), which is unusual and suggests poor permeability. This is a potential issue for both, but the negative values are hard to interpret without knowing the scale.

**Aqueous Solubility:** Both have negative solubility values (-3.297 and -0.761), also unusual and suggesting poor solubility. This is a potential issue for both, but the negative values are hard to interpret without knowing the scale.

**hERG Inhibition:** Both ligands show very low hERG inhibition risk (0.026 and 0.219), which is excellent.

**Microsomal Clearance:** Ligand A has a negative clearance (-5.856), which is also unusual and hard to interpret. Ligand B has a high clearance (-12.011), indicating poor metabolic stability.

**In vitro Half-Life:** Ligand B has a positive half-life (5.963), while Ligand A has a negative half-life (-5.264), which is unusual.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.034 and 0.033), which is favorable for CNS penetration.

**Binding Affinity:** Ligand A (-9.4 kcal/mol) has a significantly stronger binding affinity than Ligand B (-8.6 kcal/mol). This 0.8 kcal/mol difference is substantial and could potentially outweigh some ADME drawbacks.

**Overall Assessment:**

Despite the stronger binding affinity of Ligand A, its extremely high DILI risk and poor BBB penetration are major concerns. The negative values for Caco-2 permeability, solubility, and clearance are also problematic. Ligand B, while having a slightly weaker affinity and lower logP, presents a much more favorable ADME profile, particularly the low DILI risk and better (though still not optimal) BBB penetration. The higher metabolic clearance is a concern, but could potentially be addressed through structural modifications.

Given the GPCR-specific priorities and the critical importance of minimizing toxicity (DILI) and maximizing CNS exposure (BBB) for a DRD2 target, Ligand B is the more promising candidate.

Output:
1
2025-04-17 08:34:41,280 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (344.375 and 374.535 Da) are within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (116.14) is better than Ligand B (61.92). For CNS targets, TPSA should be <=90. Ligand B is well within this range, while Ligand A is slightly above, but still potentially acceptable.

**3. logP:** Ligand B (3.788) is closer to the optimal 1-3 range than Ligand A (0.089). Ligand A's low logP is a significant concern, potentially hindering membrane permeability and CNS penetration.

**4. H-Bond Donors:** Ligand A (3) is acceptable, while Ligand B (0) is also good.

**5. H-Bond Acceptors:** Both ligands have 6 HBA, which is within the acceptable range of <=10.

**6. QED:** Ligand A (0.711) has a significantly better QED score than Ligand B (0.469), indicating a more drug-like profile.

**7. DILI:** Both ligands have acceptable DILI risk (Ligand A: 66.421, Ligand B: 57.193), with Ligand B being slightly better.

**8. BBB:** Ligand B (61.729) has a much better BBB percentile than Ligand A (15.083). This is a critical factor for a CNS target like DRD2.

**9. Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and difficult to interpret without knowing the scale. However, the magnitude is similar.

**10. Aqueous Solubility:** Both have negative solubility values, again making direct comparison difficult.

**11. hERG Inhibition:** Ligand A (0.211) has a lower hERG inhibition risk than Ligand B (0.791), which is favorable.

**12. Microsomal Clearance:** Ligand A (-12.038) has a much lower (better) microsomal clearance than Ligand B (106.78). This suggests better metabolic stability for Ligand A.

**13. In vitro Half-Life:** Ligand B (36.012) has a significantly longer in vitro half-life than Ligand A (-2.728).

**14. P-gp Efflux:** Ligand A (0.077) has a lower P-gp efflux liability than Ligand B (0.755), which is beneficial for CNS penetration.

**15. Binding Affinity:** Ligand A (-9.1 kcal/mol) has a significantly stronger binding affinity than Ligand B (-6.8 kcal/mol). This is a substantial advantage, potentially outweighing some ADME drawbacks.

**Overall Assessment:**

Ligand A has superior binding affinity, a better QED score, lower hERG risk, lower microsomal clearance, and lower P-gp efflux. However, it suffers from a very low logP and a less favorable BBB percentile. Ligand B has a better logP and a significantly better BBB percentile, along with a longer half-life, but its binding affinity is weaker, QED is lower, and it has higher P-gp efflux.

Given the GPCR-specific priorities, the strong binding affinity of Ligand A is a major advantage. While the low logP is a concern, it might be addressable through structural modifications. The poor BBB penetration is also a concern, but the strong binding could potentially compensate for lower brain exposure. The better metabolic stability (lower Cl_mic) of Ligand A is also a plus.

Output:
1
2025-04-17 08:34:41,280 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (370.471 and 344.459 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (90.31) is slightly above the optimal <90 for CNS targets, but still reasonable. Ligand B (66.4) is excellent, well below the threshold.

**logP:** Ligand A (-0.828) is a bit low, potentially hindering membrane permeability. Ligand B (2.14) is within the optimal 1-3 range. This is a significant advantage for Ligand B.

**H-Bond Donors/Acceptors:** Ligand A (2 HBD, 6 HBA) and Ligand B (0 HBD, 4 HBA) both fall within acceptable ranges.

**QED:** Both ligands have good QED scores (0.594 and 0.842), indicating good drug-like properties.

**DILI:** Both ligands have similar, acceptable DILI risk (43.079 and 46.297).

**BBB:** This is a critical parameter for a CNS target like DRD2. Ligand A has a BBB percentile of 19.504, which is quite low and concerning. Ligand B has a much higher BBB percentile of 73.827, which is very desirable.

**Caco-2 Permeability:** Both ligands have similar, poor Caco-2 permeability (-4.653 and -4.697). This suggests potential absorption issues for both.

**Aqueous Solubility:** Both ligands have poor aqueous solubility (-1.927 and -2.06).

**hERG Inhibition:** Ligand A (0.114) has a slightly lower hERG risk than Ligand B (0.451), which is preferable.

**Microsomal Clearance:** Ligand A (22.515) has a lower microsomal clearance than Ligand B (46.793), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (-17.567) has a negative half-life, which is not physically possible and indicates a potential data error or very rapid degradation. Ligand B (0.401) has a very short half-life, which is also not ideal.

**P-gp Efflux:** Ligand A (0.052) has very low P-gp efflux, which is excellent for CNS penetration. Ligand B (0.181) has slightly higher, but still relatively low, P-gp efflux.

**Binding Affinity:** Ligand B (-8.8 kcal/mol) has significantly stronger binding affinity than Ligand A (-6.3 kcal/mol). This is a substantial advantage, potentially outweighing some of the ADME drawbacks.

**Overall Assessment:**

Ligand B is the stronger candidate. While both have solubility and Caco-2 permeability issues, Ligand B excels in the critical areas for a CNS GPCR target: significantly better BBB penetration, and a much stronger binding affinity. The logP value is also more favorable for Ligand B. The lower half-life of Ligand B is a concern, but could potentially be addressed through structural modifications. Ligand A's extremely low BBB penetration and questionable half-life are major drawbacks.



Output:
1
2025-04-17 08:34:41,281 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (381.519 and 377.457 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (72.47) is excellent, well below the 90 A^2 threshold for CNS targets. Ligand B (87.3) is still acceptable, but less optimal.

**logP:** Ligand A (3.438) is within the optimal 1-3 range. Ligand B (1.078) is on the lower side, potentially hindering permeability.

**H-Bond Donors/Acceptors:** Ligand A (HBD=1, HBA=5) is good. Ligand B (HBD=3, HBA=4) is also acceptable.

**QED:** Ligand A (0.832) has a very strong drug-like profile. Ligand B (0.436) is below the 0.5 threshold, indicating a less favorable drug-like profile.

**DILI:** Ligand A (70.609) is moderately risky. Ligand B (44.281) has a lower, more favorable DILI risk.

**BBB:** Ligand A (64.482) is acceptable but not ideal for a CNS target. Ligand B (72.664) is better, exceeding the 70% threshold.

**Caco-2 Permeability:** Both are negative, indicating poor permeability. Ligand A (-4.96) is slightly better than Ligand B (-5.262).

**Aqueous Solubility:** Both are negative, indicating poor solubility. Ligand A (-3.655) is slightly better than Ligand B (-2.824).

**hERG Inhibition:** Ligand A (0.606) has a low risk of hERG inhibition. Ligand B (0.271) has an even lower risk.

**Microsomal Clearance:** Ligand A (33.634) has moderate clearance. Ligand B (20.021) has lower clearance, suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (82.011) has a good half-life. Ligand B (-11.617) has a very short half-life, which is a significant drawback.

**P-gp Efflux:** Ligand A (0.423) has moderate P-gp efflux. Ligand B (0.021) has very low P-gp efflux, which is highly desirable for CNS penetration.

**Binding Affinity:** Ligand A (-8.6 kcal/mol) has a significantly stronger binding affinity than Ligand B (-7.3 kcal/mol). The 1.3 kcal/mol difference is substantial and can outweigh some ADME concerns.

**Overall Assessment:**

While Ligand B has better BBB penetration, lower DILI risk, lower P-gp efflux, and better metabolic stability, Ligand A's significantly stronger binding affinity (-8.6 vs -7.3 kcal/mol) and superior QED score are crucial for a GPCR target. The TPSA is also much better for Ligand A. The slightly higher DILI risk and lower BBB for Ligand A are acceptable trade-offs given the potency advantage. The poor Caco-2 and solubility for both are concerning but can be addressed with formulation strategies.

Output:
1
2025-04-17 08:34:41,281 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (352.366 and 348.531 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (104.39) is higher than the preferred <90 for CNS targets, while Ligand B (40.62) is excellent. This is a significant advantage for Ligand B.

**3. logP:** Ligand A (0.34) is quite low, potentially hindering membrane permeability. Ligand B (3.987) is near the upper limit of optimal (1-3) but still acceptable.

**4. H-Bond Donors:** Ligand A (2) and Ligand B (0) are both within the acceptable limit of <=5.

**5. H-Bond Acceptors:** Ligand A (5) and Ligand B (2) are both within the acceptable limit of <=10.

**6. QED:** Both ligands have good QED scores (0.744 and 0.754), indicating generally drug-like properties.

**7. DILI:** Ligand A (63.862) has a higher DILI risk than Ligand B (31.563). Lower is better, so Ligand B is favored.

**8. BBB:** Ligand B (90.733) has a significantly higher BBB penetration percentile than Ligand A (68.282). This is *crucial* for a CNS target like DRD2, making Ligand B much more promising.

**9. Caco-2 Permeability:** Ligand A (-4.911) has poor Caco-2 permeability, while Ligand B (-4.588) is slightly better, but both are quite low.

**10. Aqueous Solubility:** Both ligands have very poor aqueous solubility (-2.566 and -3.5). This is a concern for both, but could be addressed with formulation strategies.

**11. hERG Inhibition:** Ligand A (0.215) has a slightly lower hERG risk than Ligand B (0.733), but both are relatively low.

**12. Microsomal Clearance:** Ligand A (16.78) has lower microsomal clearance than Ligand B (89.977), suggesting better metabolic stability.

**13. In vitro Half-Life:** Ligand A (-27.417) has a negative half-life, which is not physically possible and indicates a significant issue with the data. Ligand B (-19.952) is also negative, indicating a data problem.

**14. P-gp Efflux:** Ligand A (0.016) has very low P-gp efflux, which is excellent for CNS penetration. Ligand B (0.554) has moderate P-gp efflux.

**15. Binding Affinity:** Ligand B (-7.8 kcal/mol) has a slightly better binding affinity than Ligand A (-7.1 kcal/mol), although both are good.

**Overall Assessment:**

Despite the issues with the half-life data for both compounds, Ligand B is clearly the more promising candidate. Its superior BBB penetration, lower DILI risk, and better TPSA profile are critical advantages for a CNS-targeting GPCR. While Ligand A has better metabolic stability and P-gp efflux, the BBB and TPSA differences are more impactful. The slightly better binding affinity of Ligand B further supports this conclusion. The low logP of Ligand A is a significant drawback.

Output:
1
2025-04-17 08:34:41,281 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 drug candidates, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (410.283 Da) is slightly higher than Ligand B (350.415 Da), but both are acceptable.

**TPSA:** Ligand A (47.56) is excellent for CNS penetration, falling well below the 90 A^2 threshold. Ligand B (79.31) is higher, but still potentially acceptable, though less ideal.

**logP:** Ligand A (4.242) is at the upper end of the optimal range (1-3), potentially raising concerns about solubility and off-target effects. Ligand B (-0.232) is significantly lower than ideal, which could hinder permeability and potentially binding.

**H-Bond Donors/Acceptors:** Both ligands have acceptable HBD (1) and HBA (3 for A, 5 for B) counts, within the recommended limits.

**QED:** Both ligands have similar and acceptable QED values (0.663 and 0.661).

**DILI:** Ligand A (55.525) has a slightly higher DILI risk than Ligand B (42.303), but both are below the concerning threshold of 60.

**BBB:** Ligand A (77.162) has a significantly better BBB percentile than Ligand B (32.532). This is a crucial advantage for a CNS target like DRD2.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values, which is unusual and suggests poor permeability. However, the scale isn't specified, so it's difficult to interpret.

**Aqueous Solubility:** Both ligands have negative solubility values, suggesting poor aqueous solubility. This is a concern, but can sometimes be overcome with formulation strategies.

**hERG Inhibition:** Ligand A (0.909) has a slightly higher hERG risk than Ligand B (0.179), but both are relatively low.

**Microsomal Clearance:** Ligand B (-7.262) has a negative clearance, which is not physically possible and indicates an issue with the data. Ligand A (63.717) has a moderate clearance.

**In vitro Half-Life:** Ligand B (-23.701) also has a negative half-life, indicating a data issue. Ligand A (46.568) has a reasonable half-life.

**P-gp Efflux:** Ligand A (0.651) has a moderate P-gp efflux liability, while Ligand B (0.081) has very low efflux. Lower P-gp efflux is favorable for CNS penetration.

**Binding Affinity:** Both ligands have excellent binding affinities (-8.5 kcal/mol and -8.0 kcal/mol). The difference of 0.5 kcal/mol is not substantial enough to outweigh other factors.

**Overall Assessment:**

Ligand A is the stronger candidate. While its logP is slightly high, its significantly better BBB penetration, reasonable metabolic stability (Cl_mic and t1/2), and acceptable P-gp efflux outweigh the slightly higher DILI and hERG risk. Ligand B has problematic negative values for clearance and half-life, and a very poor BBB score, making it a less viable option despite its lower logP and P-gp efflux.

Output:
1
2025-04-17 08:34:41,281 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (355.356 and 347.371 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (57.61) is significantly better than Ligand B (103.89). For CNS targets, we want TPSA <= 90, and A is comfortably within that, while B is above. This is a significant advantage for A.

**3. logP:** Ligand A (4.009) is slightly higher than the optimal 1-3 range, but still acceptable. Ligand B (1.456) is a bit low, potentially hindering permeability.

**4. H-Bond Donors:** Ligand A (1) is preferable to Ligand B (3). Fewer HBDs generally improve permeability.

**5. H-Bond Acceptors:** Ligand A (2) is preferable to Ligand B (5). Fewer HBAs generally improve permeability.

**6. QED:** Both ligands have similar QED values (0.785 and 0.671), indicating reasonable drug-likeness.

**7. DILI:** Both ligands have similar DILI risk (50.33 and 52.074), both being acceptable (<60).

**8. BBB:** Ligand A (71.927) has a much better BBB percentile than Ligand B (47.577). This is *critical* for a CNS target like DRD2.

**9. Caco-2:** Ligand A (-4.796) and Ligand B (-5.581) both have negative values, which is unusual and suggests poor permeability. However, the scale is not specified, so it's difficult to interpret.

**10. Solubility:** Both ligands have similar and poor aqueous solubility (-3.299 and -3.155). This could pose formulation challenges.

**11. hERG:** Both ligands have low hERG inhibition risk (0.284 and 0.456).

**12. Cl_mic:** Ligand B (22.552) has slightly lower microsomal clearance than Ligand A (24.431), suggesting better metabolic stability.

**13. t1/2:** Ligand B (-32.819) has a significantly longer in vitro half-life than Ligand A (-5.963). This is a major advantage for B.

**14. Pgp:** Ligand A (0.17) has much lower P-gp efflux liability than Ligand B (0.043). Lower Pgp efflux is desirable for CNS penetration.

**15. Binding Affinity:** Ligand A (-9.3 kcal/mol) has a significantly stronger binding affinity than Ligand B (-7.4 kcal/mol). This is a substantial advantage, potentially outweighing some of the ADME drawbacks. A difference of 1.9 kcal/mol is significant.

**Overall Assessment:**

Ligand A excels in key areas for a CNS GPCR target: TPSA, BBB, Pgp efflux, and, most importantly, binding affinity. While its logP is slightly high and solubility is poor, the strong binding affinity (-9.3 kcal/mol) and good BBB penetration (71.9%) are compelling. Ligand B has a better half-life and slightly better metabolic stability, but its higher TPSA, lower BBB, and weaker affinity are significant drawbacks.

Output:
1
2025-04-17 08:34:41,282 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (353.463 and 352.519 Da) fall comfortably within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (87.74) is better than Ligand B (49.85). For CNS targets, TPSA < 90 is preferred, and both meet this criterion. Ligand A is closer to the upper limit, but still acceptable.

**3. logP:** Ligand B (2.589) is better than Ligand A (0.681). The optimal range is 1-3, and Ligand B falls squarely within it. Ligand A is below 1, which could hinder permeation.

**4. H-Bond Donors:** Ligand A (2) is better than Ligand B (0). While both are acceptable (<=5), a small number of HBDs can aid permeability.

**5. H-Bond Acceptors:** Both ligands have 4 HBA, which is within the acceptable range (<=10).

**6. QED:** Both ligands have similar QED values (0.705 and 0.606), both above the 0.5 threshold, indicating good drug-like properties.

**7. DILI:** Ligand B (2.171) is significantly better than Ligand A (14.967). Ligand B has a very low DILI risk, while Ligand A is moderate.

**8. BBB:** Ligand B (86.468) is substantially better than Ligand A (57.929). For a CNS target like DRD2, >70% BBB penetration is desirable. Ligand B is approaching this, while Ligand A is considerably lower.

**9. Caco-2 Permeability:** Ligand A (-5.166) is better than Ligand B (-4.47). Higher values indicate better permeability.

**10. Aqueous Solubility:** Ligand A (-0.977) is better than Ligand B (-0.963). Both are similarly poor.

**11. hERG Inhibition:** Ligand A (0.155) is better than Ligand B (0.614). Lower is better, indicating less cardiotoxicity risk.

**12. Microsomal Clearance:** Ligand A (11.193) is better than Ligand B (17.672). Lower clearance suggests better metabolic stability.

**13. In vitro Half-Life:** Ligand B (-9.277) is better than Ligand A (-5.528). Longer half-life is generally preferred.

**14. P-gp Efflux:** Ligand A (0.011) is significantly better than Ligand B (0.041). Lower efflux is crucial for CNS exposure.

**15. Binding Affinity:** Ligand A (-7.9 kcal/mol) is better than Ligand B (-6.8 kcal/mol). This is a 1.1 kcal/mol difference, which is substantial and can outweigh some ADME drawbacks.

**Overall Assessment:**

Ligand A has a superior binding affinity and better P-gp efflux, microsomal clearance, and hERG inhibition. However, Ligand B excels in BBB penetration, DILI risk, and in vitro half-life. The most critical factors for a CNS GPCR target are BBB penetration and affinity. While Ligand A's affinity is significantly better, Ligand B's BBB is much higher, and its DILI risk is very low. The logP of Ligand A is a concern. Considering the balance, the stronger affinity of Ligand A, coupled with its better P-gp efflux and clearance, likely outweighs the lower BBB and slightly concerning logP.

Output:
0
2025-04-17 08:34:41,282 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (382.595 and 364.837 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (49.41) is excellent, well below the 90 A^2 threshold for CNS targets. Ligand B (112.66) is higher, but still potentially acceptable, though less optimal.

**logP:** Ligand A (2.974) is within the optimal 1-3 range. Ligand B (1.357) is on the lower side, which *could* hinder permeability, but isn't a dealbreaker.

**H-Bond Donors/Acceptors:** Ligand A (1 HBD, 4 HBA) is favorable. Ligand B (3 HBD, 5 HBA) is also acceptable, though slightly higher.

**QED:** Both ligands have reasonable QED values (0.794 and 0.654), indicating good drug-like properties.

**DILI:** Ligand A (18.651) has a significantly lower DILI risk than Ligand B (64.831). This is a major advantage for Ligand A.

**BBB:** Ligand A (80.845) has a very good BBB penetration percentile, exceeding the 70% threshold for CNS targets. Ligand B (20.512) is poor, suggesting limited CNS exposure. This is a critical disadvantage for Ligand B.

**Caco-2 Permeability:** Ligand A (-5.065) and Ligand B (-5.743) both have negative values, which is unusual and requires further investigation. However, the scale is not specified, so it's hard to interpret.

**Aqueous Solubility:** Both ligands have poor aqueous solubility (-4.364 and -2.064). This might pose formulation challenges, but can be addressed.

**hERG Inhibition:** Both ligands show low hERG inhibition liability (0.476 and 0.379), which is good.

**Microsomal Clearance:** Ligand A (56.263) has higher microsomal clearance than Ligand B (3.195), suggesting lower metabolic stability. Ligand B is much more stable.

**In vitro Half-Life:** Ligand A (-18.044) has a negative half-life, which is not possible. This is likely an error in the data. Ligand B (-1.893) is also negative, indicating a data issue.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.068 and 0.045), which is favorable for CNS penetration.

**Binding Affinity:** Ligand B (-8.3 kcal/mol) has a slightly better binding affinity than Ligand A (-7.5 kcal/mol). This 0.8 kcal/mol difference is significant, but not overwhelming.

**Overall Assessment:**

Despite Ligand B's slightly better binding affinity, Ligand A is the more promising candidate. The critical factor is the vastly superior BBB penetration (80.845% vs 20.512%). For a CNS target like DRD2, achieving sufficient brain exposure is paramount. Additionally, Ligand A has a much lower DILI risk. The issues with half-life values for both compounds are concerning and require further investigation, but don't immediately disqualify Ligand A given the other advantages. The slightly higher clearance of Ligand A is less concerning than the poor BBB penetration of Ligand B.

Output:
1
2025-04-17 08:34:41,282 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B based on the provided guidelines, prioritizing GPCR-specific properties (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (347.463 and 344.459 Da) fall comfortably within the ideal 200-500 Da range.

**TPSA:** Ligand A (72.54) is better than Ligand B (76.02). Both are below the 90 A^2 threshold desirable for CNS targets, but A is closer to the optimal range.

**logP:** Ligand A (0.743) is slightly lower than optimal (1-3), but still acceptable. Ligand B (2.031) is within the optimal range.

**H-Bond Donors/Acceptors:** Ligand A has 1 HBD and 4 HBA, while Ligand B has 2 HBD and 4 HBA. Both are within acceptable limits (<=5 HBD, <=10 HBA).

**QED:** Ligand A (0.79) is slightly better than Ligand B (0.673), both are above the 0.5 threshold.

**DILI:** Ligand A (16.092) has a significantly lower DILI risk than Ligand B (39.667). This is a major advantage for Ligand A.

**BBB:** Ligand A (68.205) is better than Ligand B (63.746), but both are below the desirable >70 percentile for CNS targets. However, since DRD2 is a CNS target, this is a critical factor.

**Caco-2 Permeability:** Ligand A (-5.175) is worse than Ligand B (-4.956), indicating lower intestinal absorption.

**Aqueous Solubility:** Ligand A (-0.948) is better than Ligand B (-3.044), indicating better solubility.

**hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.212 and 0.116, respectively).

**Microsomal Clearance:** Ligand A (-3.681) has significantly lower (better) microsomal clearance than Ligand B (54.803), indicating better metabolic stability.

**In vitro Half-Life:** Ligand A (-15.57) has a lower half-life than Ligand B (-8.719).

**P-gp Efflux:** Ligand A (0.008) has much lower P-gp efflux liability than Ligand B (0.173), which is crucial for CNS penetration.

**Binding Affinity:** Both ligands have very similar and strong binding affinities (-7.7 and -8.3 kcal/mol). The difference is negligible.

**Overall Assessment:**

Ligand A is superior due to its significantly lower DILI risk, lower P-gp efflux, and lower microsomal clearance, despite slightly worse Caco-2 permeability and BBB penetration. The lower P-gp efflux and clearance are particularly important for a CNS target like DRD2, as they will improve brain exposure and drug duration. While both have acceptable affinities, the ADME properties of Ligand A make it a more promising drug candidate.

Output:
1
2025-04-17 08:34:41,282 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 drug candidates, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight (MW):** Both ligands (363.439 and 386.539 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Both ligands have TPSA values (83.81 and 84.5) below the 90 A^2 threshold for CNS targets, which is favorable.

**3. logP:** Both ligands have logP values (1.714 and 2.07) within the optimal 1-3 range.

**4. H-Bond Donors (HBD):** Both ligands have 2 HBD, which is within the acceptable limit of <=5.

**5. H-Bond Acceptors (HBA):** Ligand A has 6 HBA, and Ligand B has 5 HBA, both below the acceptable limit of <=10.

**6. QED:** Ligand A (0.816) has a significantly better QED score than Ligand B (0.603), indicating a more drug-like profile.

**7. DILI:** Ligand A (59.093) has a slightly higher DILI risk than Ligand B (41.915), but both are below the concerning threshold of 60.

**8. BBB:** Ligand B (63.164) has a significantly better BBB penetration percentile than Ligand A (42.148). This is a *critical* factor for a CNS target like DRD2.

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.192 and -5.273), which is unusual and suggests poor permeability. However, these values are on a scale where negative values are possible and don't necessarily disqualify the compounds.

**10. Aqueous Solubility:** Both ligands have negative solubility values (-2.552 and -2.793), which is also unusual and suggests poor solubility. Similar to Caco-2, these values are on a scale where negative values are possible.

**11. hERG Inhibition:** Both ligands have very low hERG inhibition liability (0.288 and 0.297), which is excellent.

**12. Microsomal Clearance (Cl_mic):** Ligand A (-21.559) has a much lower (better) microsomal clearance than Ligand B (69.827), indicating greater metabolic stability.

**13. In vitro Half-Life:** Ligand A (46.472) has a significantly longer in vitro half-life than Ligand B (-6.244), which is highly desirable.

**14. P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.075 and 0.23).

**15. Binding Affinity:** Ligand A (-7.9 kcal/mol) has a slightly better binding affinity than Ligand B (-7.6 kcal/mol), although the difference is relatively small.

**Overall Assessment:**

While Ligand A has a better QED, metabolic stability (Cl_mic), and half-life, the *significant* advantage of Ligand B in BBB penetration is decisive for a CNS target like DRD2. The slightly better affinity of Ligand A is outweighed by the importance of getting the drug into the brain. The poor Caco-2 and solubility values are concerning for both, but can potentially be addressed through formulation strategies.

Output:
1
2025-04-17 08:34:41,283 - INFO - Batch 460 complete. Total preferences: 7360
2025-04-17 08:34:41,283 - INFO - Processing batch 461/512...
2025-04-17 08:35:23,363 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (415.288 Da) is slightly higher, but still acceptable. Ligand B (351.491 Da) is preferable.

**2. TPSA:** Both ligands have TPSA values below the 90 A^2 threshold for CNS targets. Ligand A (84 A^2) is slightly higher than Ligand B (78.51 A^2), making B more favorable for brain penetration.

**3. logP:** Both ligands have optimal logP values (between 1 and 3). Ligand A (1.737) and Ligand B (1.69) are very similar and both good.

**4. H-Bond Donors:** Ligand A (1 HBD) is better than Ligand B (2 HBDs). Fewer HBDs generally improve permeability.

**5. H-Bond Acceptors:** Ligand A (5 HBA) is better than Ligand B (3 HBA). Fewer HBAs generally improve permeability.

**6. QED:** Both ligands have QED values above 0.5, indicating good drug-like properties. Ligand A (0.81) is slightly better than Ligand B (0.764).

**7. DILI:** Ligand A (73.052 percentile) has a higher DILI risk than Ligand B (25.824 percentile). This is a significant advantage for Ligand B.

**8. BBB:** Both ligands have good BBB penetration (Ligand A: 68.67%, Ligand B: 70.803%). Ligand B is slightly better, but both are reasonably good.

**9. Caco-2 Permeability:** Ligand A (-4.399) has worse Caco-2 permeability than Ligand B (-5.02). Lower values are less favorable.

**10. Aqueous Solubility:** Both ligands have poor aqueous solubility (-2.453 and -2.467 respectively). This is a concern for both, but not a deciding factor.

**11. hERG Inhibition:** Both ligands have low hERG inhibition risk (0.295 and 0.13 respectively), which is good. Ligand B is slightly better.

**12. Microsomal Clearance:** Ligand A (28.646 mL/min/kg) has lower microsomal clearance than Ligand B (38.539 mL/min/kg), suggesting better metabolic stability.

**13. In vitro Half-Life:** Ligand A (-13.954 hours) has a longer in vitro half-life than Ligand B (-1.671 hours). This is a significant advantage for Ligand A.

**14. P-gp Efflux:** Ligand A (0.039) has lower P-gp efflux than Ligand B (0.024), indicating better CNS exposure.

**15. Binding Affinity:** Ligand A (-7.7 kcal/mol) has significantly better binding affinity than Ligand B (-0.0 kcal/mol). This is the most important factor, and the 7.7 kcal/mol advantage is substantial.

**Overall Assessment:**

While Ligand B has advantages in DILI, TPSA, and P-gp efflux, the overwhelmingly stronger binding affinity of Ligand A (-7.7 kcal/mol vs -0.0 kcal/mol) is the deciding factor. The improved half-life is also a significant benefit. The slightly higher TPSA and DILI risk of Ligand A are likely outweighed by the much stronger binding. Given the GPCR target and the importance of affinity, Ligand A is the more promising candidate.

Output:
1
2025-04-17 08:35:23,364 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B based on the provided guidelines, prioritizing GPCR-specific properties (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (414.296 Da) is slightly higher than Ligand B (374.507 Da), but both are acceptable.

**TPSA:** Ligand A (81.7) is much better than Ligand B (101.98). For CNS targets, we want TPSA <= 90. Ligand A is within this range, while Ligand B exceeds it. This is a significant advantage for A.

**logP:** Ligand A (3.932) is optimal (1-3), while Ligand B (-0.913) is below 1, which may impede permeation. This is a substantial advantage for Ligand A.

**H-Bond Donors/Acceptors:** Ligand A (HBD=1, HBA=5) and Ligand B (HBD=3, HBA=6) are both within acceptable limits.

**QED:** Both ligands have reasonable QED values (A: 0.714, B: 0.508), indicating good drug-like properties.

**DILI:** Ligand A (64.521) has a higher DILI risk than Ligand B (21.908). This favors Ligand B.

**BBB:** Ligand A (68.941) has a better BBB percentile than Ligand B (10.779). Given this is a CNS target (DRD2), this is a critical advantage for Ligand A.

**Caco-2 Permeability:** Ligand A (-4.467) is worse than Ligand B (-5.686), however, these values are negative and difficult to interpret without knowing the scale.

**Aqueous Solubility:** Ligand A (-4.935) is worse than Ligand B (-1.105), again, these values are negative and difficult to interpret without knowing the scale.

**hERG Inhibition:** Ligand A (0.505) has a lower hERG inhibition liability than Ligand B (0.034), which is favorable.

**Microsomal Clearance:** Ligand A (102.18) has higher microsomal clearance than Ligand B (22.155), indicating lower metabolic stability. This favors Ligand B.

**In vitro Half-Life:** Ligand A (37.394) has a longer half-life than Ligand B (-9.959), which is favorable.

**P-gp Efflux:** Ligand A (0.14) has lower P-gp efflux liability than Ligand B (0.007), which is favorable for CNS penetration.

**Binding Affinity:** Ligand A (-7.8 kcal/mol) has a slightly better binding affinity than Ligand B (-7.0 kcal/mol). While both are good, the 0.8 kcal/mol difference is significant and can outweigh some ADME drawbacks.

**Overall Assessment:**

Ligand A excels in key GPCR properties: TPSA, logP, BBB, P-gp efflux, and binding affinity. While it has a higher DILI risk and clearance, its superior CNS penetration (BBB, P-gp) and binding affinity are crucial for a DRD2 target. Ligand B has a better DILI and clearance profile, but its poor logP and BBB make it less likely to effectively reach the target in the brain. The affinity difference, while not huge, adds to A's advantage.

Output:
1
2025-04-17 08:35:23,364 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (346.515 and 340.339 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (43.38) is significantly better than Ligand B (100.08). For CNS targets, we want TPSA <= 90, so Ligand A is much more favorable.

**3. logP:** Ligand A (4.48) is slightly high but acceptable. Ligand B (0.674) is quite low, potentially hindering membrane permeability and CNS penetration.

**4. H-Bond Donors:** Ligand A (1) is good. Ligand B (2) is also acceptable.

**5. H-Bond Acceptors:** Ligand A (4) is good. Ligand B (6) is also acceptable.

**6. QED:** Both ligands have similar QED values (0.754 and 0.727), indicating good drug-like properties.

**7. DILI:** Both ligands have similar DILI risk (13.222 and 70.182), suggesting a low risk of liver injury.

**8. BBB:** Ligand A (70.027) is good, exceeding the 70% threshold for CNS targets. Ligand B (12.912) is very poor, indicating limited brain penetration. This is a critical disadvantage for a DRD2 ligand.

**9. Caco-2 Permeability:** Ligand A (-4.589) and Ligand B (-5.22) are both negative, indicating poor permeability.

**10. Aqueous Solubility:** Ligand A (-3.956) and Ligand B (-2.537) are both negative, indicating poor solubility.

**11. hERG Inhibition:** Ligand A (0.761) is better than Ligand B (0.292), suggesting a lower risk of cardiotoxicity.

**12. Microsomal Clearance:** Ligand A (71.447) is higher than Ligand B (-2.857), indicating faster metabolism and lower metabolic stability.

**13. In vitro Half-Life:** Ligand A (1.427) is much lower than Ligand B (21.595), indicating a shorter half-life.

**14. P-gp Efflux:** Ligand A (0.453) is better than Ligand B (0.049), suggesting lower P-gp efflux and better CNS exposure.

**15. Binding Affinity:** Ligand B (-9.1) has a significantly stronger binding affinity than Ligand A (-8.2). This is a 0.9 kcal/mol difference, which is substantial and could outweigh some ADME drawbacks.

**Overall Assessment:**

While Ligand B has a superior binding affinity, its extremely poor BBB penetration (12.912%) is a major drawback for a CNS target like DRD2. Ligand A, despite having a slightly weaker affinity, possesses a much more favorable BBB score (70.027%), a better TPSA, and better P-gp efflux liability. The lower metabolic stability and shorter half-life of Ligand A could be addressed through further medicinal chemistry optimization. The low logP of Ligand B is also concerning.

Given the GPCR-specific priorities and the importance of CNS penetration for DRD2, Ligand A is the more promising candidate.

Output:
0
2025-04-17 08:35:23,364 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (360.401 and 361.562 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (81.08) is slightly above the optimal <90 for CNS targets, but still reasonable. Ligand B (65.2) is excellent, well below 90.

**3. logP:** Ligand A (0.265) is quite low, potentially hindering permeation. Ligand B (3.029) is within the optimal 1-3 range. This is a significant advantage for Ligand B.

**4. H-Bond Donors:** Both ligands have 2 HBD, which is acceptable.

**5. H-Bond Acceptors:** Ligand A has 4 HBA, acceptable. Ligand B has 2 HBA, also acceptable.

**6. QED:** Both ligands have good QED scores (0.757 and 0.813), indicating drug-like properties.

**7. DILI:** Ligand A (20.202) has a lower DILI risk than Ligand B (42.226), which is good.

**8. BBB:** Ligand B (72.354) has a much better BBB percentile than Ligand A (44.746). This is crucial for a CNS target like DRD2.

**9. Caco-2:** Both have negative Caco-2 values, which is unusual and suggests poor permeability. However, the scale is not specified, so it's difficult to interpret.

**10. Solubility:** Both have negative solubility values, also unusual and suggesting poor solubility. Again, the scale is unspecified.

**11. hERG:** Ligand A (0.263) has a lower hERG risk than Ligand B (0.518), which is preferable.

**12. Cl_mic:** Ligand A (-8.695) has a *much* lower (better) microsomal clearance than Ligand B (54.858), suggesting greater metabolic stability.

**13. t1/2:** Ligand A (-1.194) has a negative in vitro half-life, which is not possible. Ligand B (-20.537) also has a negative half-life, which is also not possible. This suggests there may be an error in the data.

**14. Pgp:** Ligand A (0.049) has very low P-gp efflux liability, which is excellent. Ligand B (0.324) has slightly higher, but still reasonable, P-gp efflux.

**15. Binding Affinity:** Ligand A (-8.1) has a slightly better binding affinity than Ligand B (-0.0). This is a significant advantage.

**Overall Assessment:**

Despite the questionable half-life values, the key differences lie in logP and BBB. Ligand B has a much better logP, which is essential for CNS penetration. It also has a significantly higher BBB percentile. While Ligand A has better metabolic stability (Cl_mic) and slightly better binding affinity, the poor logP and lower BBB are major drawbacks for a CNS-targeting drug. The binding affinity difference, while present, is not large enough to overcome the ADME deficiencies of Ligand A.

Output:
1
2025-04-17 08:35:23,364 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B based on the provided guidelines, prioritizing GPCR-specific properties (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (398.985 Da) is slightly higher than Ligand B (345.399 Da), but both are acceptable.

**TPSA:** Ligand A (66.91) is significantly better than Ligand B (111.55). For CNS targets, we want TPSA <= 90, and Ligand A is comfortably within this range, while Ligand B exceeds it. This is a significant advantage for Ligand A.

**logP:** Ligand A (4.826) is higher than the optimal range (1-3), potentially leading to solubility issues. Ligand B (0.881) is lower than optimal, which could hinder permeation. However, for a GPCR, a slightly higher logP is often tolerated if other properties are favorable.

**H-Bond Donors/Acceptors:** Ligand A (HBD=2, HBA=5) and Ligand B (HBD=4, HBA=5) are both within acceptable limits.

**QED:** Both ligands have similar QED values (A: 0.655, B: 0.605), indicating good drug-like properties.

**DILI:** Ligand A (72.354) has a higher DILI risk than Ligand B (50.989). While both are below the concerning threshold of 60, Ligand B is preferable here.

**BBB:** Ligand A (70.57) has a significantly better BBB penetration score than Ligand B (25.32). This is *crucial* for a CNS target like DRD2, making Ligand A much more promising.

**Caco-2 Permeability:** Both have negative values (-5.124 and -5.315) which is unusual and hard to interpret.

**Aqueous Solubility:** Both have negative values (-5.781 and -2.64) which is unusual and hard to interpret.

**hERG:** Ligand A (0.438) has a slightly higher hERG risk than Ligand B (0.042), but both are relatively low.

**Microsomal Clearance:** Ligand B (-8.961) has a *much* lower (better) microsomal clearance than Ligand A (85.286), indicating greater metabolic stability. This is a significant advantage for Ligand B.

**In vitro Half-Life:** Ligand B (-29.604) has a much longer half-life than Ligand A (70.052), again favoring Ligand B.

**P-gp Efflux:** Ligand A (0.375) has lower P-gp efflux than Ligand B (0.02), which is preferable for CNS penetration.

**Binding Affinity:** Ligand B (-9.4 kcal/mol) has a slightly better binding affinity than Ligand A (-8.3 kcal/mol). While both are excellent, the 1.1 kcal/mol difference is notable.

**Overall Assessment:**

Ligand A excels in TPSA and BBB, which are critical for CNS GPCR targets. However, it suffers from higher DILI risk, higher microsomal clearance, shorter half-life, and higher P-gp efflux. Ligand B has superior metabolic stability (lower Cl_mic, longer t1/2), lower DILI, and slightly better binding affinity. The significantly better BBB of Ligand A is a major advantage, but the metabolic liabilities of Ligand A are concerning. Considering the balance, the superior BBB penetration of Ligand A outweighs its other drawbacks, especially given the importance of CNS exposure for DRD2.

Output:
1
2025-04-17 08:35:23,365 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B based on the provided guidelines, prioritizing GPCR-specific properties (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (373.274 and 348.491 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (66.02) is excellent, well below the 90 A^2 threshold for CNS targets. Ligand B (76.02) is still reasonable but less optimal.

**logP:** Both ligands (2.578 and 2.858) are within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A (1 HBD, 5 HBA) and Ligand B (2 HBD, 4 HBA) both meet the criteria of <=5 HBD and <=10 HBA.

**QED:** Both ligands have the same QED score of 0.674, indicating good drug-likeness.

**DILI:** Ligand A (59.131) has a higher DILI risk than Ligand B (25.281), which is a significant negative.

**BBB:** Both ligands have very good BBB penetration (76.347% and 74.176%), exceeding the desirable >70% threshold for CNS targets.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values which is unusual. Assuming these are percentile scores, both are very poor.

**Aqueous Solubility:** Both ligands have negative solubility values, which is unusual. Assuming these are percentile scores, both are very poor.

**hERG:** Both ligands have low hERG inhibition risk (0.687 and 0.716).

**Microsomal Clearance:** Ligand A (31.011) has lower microsomal clearance than Ligand B (44.952), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand B (-2.78) has a longer in vitro half-life than Ligand A (-1.821).

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.17 and 0.398), which is favorable for CNS penetration.

**Binding Affinity:** Ligand B (-8.1 kcal/mol) has a significantly stronger binding affinity than Ligand A (-7.2 kcal/mol), exceeding the 1.5 kcal/mol advantage threshold.

**Overall Assessment:**

While Ligand A has better TPSA and metabolic stability, Ligand B wins out due to its significantly improved binding affinity (-8.1 vs -7.2 kcal/mol) and substantially lower DILI risk. The stronger binding is a major advantage for a GPCR target, and the reduced liver toxicity is a critical factor for drug development. The poor Caco-2 and solubility scores are a concern for both, but can be addressed with formulation strategies.

Output:
1
2025-04-17 08:35:23,365 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (348.374 and 347.463 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (91.57) is slightly above the preferred <90 for CNS targets, but still reasonable. Ligand B (79.26) is well within the desired range.

**3. logP:** Ligand A (2.981) is optimal. Ligand B (1.183) is a bit low, potentially hindering permeability.

**4. H-Bond Donors:** Ligand A (3) and Ligand B (2) are both acceptable, below the limit of 5.

**5. H-Bond Acceptors:** Ligand A (4) and Ligand B (5) are both acceptable, below the limit of 10.

**6. QED:** Both ligands have good QED scores (0.684 and 0.776), indicating drug-like properties.

**7. DILI:** Both ligands have low DILI risk (47.926 and 33.424), which is favorable.

**8. BBB:** This is a critical parameter for a CNS target like DRD2. Ligand B (68.282) has a significantly better BBB percentile than Ligand A (31.834).

**9. Caco-2 Permeability:** Ligand A (-5.314) and Ligand B (-4.914) both have negative values, indicating poor permeability.

**10. Aqueous Solubility:** Both ligands have very poor aqueous solubility (-3.677 and -2.505). This is a concern for both, but might be mitigated with formulation strategies.

**11. hERG Inhibition:** Both ligands have low hERG inhibition risk (0.472 and 0.362).

**12. Microsomal Clearance:** Ligand A (28.386) has lower clearance than Ligand B (33.636), suggesting better metabolic stability.

**13. In vitro Half-Life:** Ligand A (37.698) has a longer half-life than Ligand B (17.927), which is desirable.

**14. P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.09 and 0.043), which is good for CNS penetration.

**15. Binding Affinity:** Ligand A (-8.8 kcal/mol) has a slightly better binding affinity than Ligand B (-7.9 kcal/mol). The difference is 0.9 kcal/mol, which is substantial.

**Overall Assessment:**

While Ligand A has better affinity and metabolic stability, Ligand B's significantly higher BBB penetration (68.282 vs 31.834) is a major advantage for a CNS-targeting drug. The slightly lower affinity of Ligand B can potentially be optimized in subsequent iterations. The poor solubility and Caco-2 permeability are concerns for both, but can be addressed during formulation. Given the GPCR-specific priorities, the superior BBB score of Ligand B outweighs the slightly better affinity and metabolic stability of Ligand A.

Output:
1
2025-04-17 08:35:23,365 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (346.515 Da) is slightly lower, which could be advantageous for permeability. Ligand B (354.407 Da) is also good.

**TPSA:** Ligand A (58.2) is excellent, well below the 90 A^2 threshold for CNS targets. Ligand B (117.17) is higher, but still potentially acceptable, though less ideal.

**logP:** Ligand A (3.592) is within the optimal range (1-3). Ligand B (-0.195) is significantly lower, which is a major concern for CNS penetration as it may struggle to cross the blood-brain barrier.

**H-Bond Donors/Acceptors:** Both ligands have 2 HBDs, which is good. Ligand A has 2 HBAs, while Ligand B has 6. Higher HBA counts can sometimes hinder permeability.

**QED:** Both ligands have acceptable QED values (A: 0.521, B: 0.586), indicating reasonable drug-likeness.

**DILI:** Ligand A (37.728) has a lower DILI risk than Ligand B (56.96), indicating a better safety profile.

**BBB:** Ligand A (60.915) has a moderate BBB penetration, while Ligand B (49.205) is lower. While both are below the desirable >70% for CNS targets, A is better.

**Caco-2 Permeability:** Ligand A (-4.865) and Ligand B (-5.204) both have negative values, which is unusual and suggests very poor permeability. However, these values are on a scale where negative values are possible and don't necessarily mean zero permeability.

**Aqueous Solubility:** Ligand A (-4.874) and Ligand B (-2.24) both have negative solubility values, suggesting poor solubility.

**hERG Inhibition:** Both ligands have very low hERG risk (A: 0.253, B: 0.201).

**Microsomal Clearance:** Ligand B (35.429) has a lower microsomal clearance than Ligand A (81.91), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand B (-1.729) has a negative half-life, which is not possible. This is a significant red flag. Ligand A (3.682) has a reasonable half-life.

**P-gp Efflux:** Both have very low P-gp efflux (A: 0.452, B: 0.015).

**Binding Affinity:** Ligand B (-8.0) has a significantly stronger binding affinity than Ligand A (-0.0). This is a substantial advantage.

**Overall Assessment:**

Despite Ligand B's superior binding affinity, its extremely low logP, negative in vitro half-life, and lower BBB penetration are major drawbacks for a CNS-targeting drug. The negative half-life is a critical issue. Ligand A, while having a weaker binding affinity, possesses more favorable ADME properties, including a better logP, a reasonable BBB score, and a plausible half-life. The TPSA is also significantly better for CNS penetration.

Considering the GPCR-specific priorities, and the critical need for BBB penetration for a CNS target like DRD2, Ligand A is the more promising candidate despite its weaker binding. The affinity difference could potentially be addressed through further optimization, but the ADME issues with Ligand B are more difficult to resolve.

Output:
0
2025-04-17 08:35:23,365 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (429.292 Da) is higher, but still acceptable. Ligand B (348.487 Da) is slightly better.

**TPSA:** Both ligands have TPSA values below the 90 A^2 threshold for CNS targets. Ligand A (89.71 A^2) is excellent, while Ligand B (67.43 A^2) is also very good.

**logP:** Both ligands have logP values within the optimal range (1-3). Ligand A (2.009) and Ligand B (2.701) are both favorable.

**H-Bond Donors/Acceptors:** Ligand A has 0 HBD and 6 HBA, which is good. Ligand B has 2 HBD and 3 HBA, also acceptable.

**QED:** Both ligands have QED values above 0.5, indicating good drug-likeness (Ligand A: 0.726, Ligand B: 0.695).

**DILI:** Ligand A has a DILI risk of 84.645, which is concerning (high risk). Ligand B has a much lower DILI risk of 34.277, which is good. This is a significant advantage for Ligand B.

**BBB:** Ligand A has a BBB penetration percentile of 79.915, which is good for a CNS target. Ligand B has a BBB penetration percentile of 62.233, which is less desirable but not disqualifying.

**Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and suggests poor permeability. Ligand A (-4.592) is slightly better than Ligand B (-5.164).

**Aqueous Solubility:** Both ligands have very poor aqueous solubility (-2.975 and -3.281 respectively). This is a significant drawback for both.

**hERG Inhibition:** Both ligands show low hERG inhibition liability (0.395 and 0.203 respectively), which is good.

**Microsomal Clearance:** Ligand A has a lower microsomal clearance (27.14 mL/min/kg) than Ligand B (45.873 mL/min/kg), indicating better metabolic stability.

**In vitro Half-Life:** Ligand A has a much longer in vitro half-life (78.505 hours) than Ligand B (7.403 hours). This is a major advantage for Ligand A.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.105 and 0.121 respectively), which is good for CNS penetration.

**Binding Affinity:** Ligand B has a slightly better binding affinity (-8.4 kcal/mol) than Ligand A (-7.9 kcal/mol). This is a 0.5 kcal/mol difference, which is significant.

**Overall Assessment:**

Ligand B has a substantially better safety profile (DILI) and a slightly better binding affinity. However, Ligand A has a significantly longer half-life and better metabolic stability. The BBB penetration of Ligand A is also better. The solubility is poor for both, but the DILI risk for Ligand A is a major concern. Given the GPCR-specific priorities, the improved safety profile and binding affinity of Ligand B, despite its shorter half-life, make it the more promising candidate. The difference in binding affinity (0.5 kcal/mol) is enough to outweigh the longer half-life of Ligand A, especially considering the high DILI risk associated with Ligand A.

Output:
1
2025-04-17 08:35:23,366 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the acceptable range (200-500 Da). Ligand A (369.491 Da) is slightly preferred as it's closer to the ideal range.

**TPSA:** Ligand A (89.35) is excellent for CNS penetration, being well below 90. Ligand B (69.38) is also good, but slightly higher.

**logP:** Ligand A (0.552) is a bit low, potentially hindering membrane permeability. Ligand B (3.583) is within the optimal range (1-3). This is a significant advantage for Ligand B.

**H-Bond Donors/Acceptors:** Ligand A (1 HBD, 7 HBA) and Ligand B (0 HBD, 6 HBA) both have reasonable counts, falling within the guidelines.

**QED:** Ligand A (0.72) has a better QED score than Ligand B (0.439), indicating a more drug-like profile.

**DILI:** Ligand A (60.566) is borderline, but acceptable. Ligand B (74.254) is higher, indicating a greater potential for liver injury.

**BBB:** Ligand A (53.044) is moderate, while Ligand B (67.895) is better, but still not ideal (>70 is preferred for CNS targets).

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.258 and -5.3), which is unusual and suggests poor permeability. This is a significant concern for both.

**Aqueous Solubility:** Both ligands have negative solubility values (-2.068 and -4.418), which is also unusual and suggests poor solubility. This is a significant concern for both.

**hERG Inhibition:** Both ligands show low hERG inhibition liability (0.135 and 0.366), which is positive.

**Microsomal Clearance:** Ligand A (34.257) has lower clearance than Ligand B (75.064), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand B (46.795) has a longer half-life than Ligand A (14.933), which is desirable.

**P-gp Efflux:** Both ligands show low P-gp efflux liability (0.052 and 0.682), which is positive for CNS penetration.

**Binding Affinity:** Ligand B (-9.5 kcal/mol) has a significantly stronger binding affinity than Ligand A (-6.8 kcal/mol). This >1.5 kcal/mol difference is a major advantage, potentially outweighing some ADME drawbacks.

**Overall Assessment:**

While Ligand A has a better QED, lower clearance, and slightly better TPSA, Ligand B's significantly stronger binding affinity (-9.5 vs -6.8 kcal/mol) and acceptable logP are crucial for a GPCR target like DRD2. The higher DILI risk for Ligand B is a concern, but the potency advantage is substantial. The poor Caco-2 and solubility for both are concerning and would need to be addressed in further optimization. However, for initial selection, potency is paramount.

Output:
1
2025-04-17 08:35:23,366 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (348.403 and 365.499 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (84.74) is better than Ligand B (71), both are below the 90 A^2 threshold for CNS targets.

**logP:** Both ligands (1.694 and 1.792) are within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A (0 HBD, 6 HBA) and Ligand B (1 HBD, 5 HBA) both have acceptable numbers of H-bond donors and acceptors, well below the thresholds of 5 and 10 respectively.

**QED:** Both ligands have good QED scores (0.611 and 0.825), indicating good drug-like properties.

**DILI:** Ligand A (78.945) has a higher DILI risk than Ligand B (28.267). This is a significant drawback for Ligand A.

**BBB:** Ligand A (95.192) has a *much* better BBB penetration score than Ligand B (59.403). This is a critical advantage for a CNS target like DRD2.

**Caco-2 Permeability:** Ligand A (-4.274) has worse Caco-2 permeability than Ligand B (-5.127), but both are quite poor.

**Aqueous Solubility:** Ligand A (-3.305) has slightly better solubility than Ligand B (-2.906), but both are quite poor.

**hERG:** Both ligands have very low hERG inhibition risk (0.061 and 0.152).

**Microsomal Clearance:** Ligand A (64.076) has higher microsomal clearance than Ligand B (30.727), indicating lower metabolic stability.

**In vitro Half-Life:** Ligand B (-8.595) has a longer in vitro half-life than Ligand A (14.38), which is preferable.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.058 and 0.07).

**Binding Affinity:** Ligand B (-8.8 kcal/mol) has a slightly better binding affinity than Ligand A (-7.5 kcal/mol). While both are good, the 1.3 kcal/mol difference is noteworthy.

**Overall Assessment:**

Ligand A excels in BBB penetration, which is paramount for a CNS GPCR target. However, it suffers from higher DILI risk and lower metabolic stability. Ligand B has a better safety profile (lower DILI), better half-life, and slightly better binding affinity, but its BBB penetration is significantly lower.

Given the importance of BBB penetration for DRD2, and the relatively small advantage in binding affinity for Ligand B, I would prioritize Ligand A. The DILI risk could potentially be mitigated through structural modifications, but poor CNS penetration is much harder to fix.

Output:
1
2025-04-17 08:35:23,366 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (365.43 and 340.423 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (81.06) is slightly higher than Ligand B (71.34). Both are below the 90 A^2 threshold desirable for CNS targets, but Ligand B is better.

**3. logP:** Ligand A (1.911) is within the optimal 1-3 range. Ligand B (3.253) is at the upper end, but still acceptable.

**4. H-Bond Donors:** Ligand A (1) and Ligand B (2) are both acceptable, being less than 5.

**5. H-Bond Acceptors:** Ligand A (5) and Ligand B (3) are both acceptable, being less than 10.

**6. QED:** Both ligands have good QED scores (0.897 and 0.515), indicating drug-like properties. Ligand A is significantly better.

**7. DILI:** Ligand A (71.772) has a higher DILI risk than Ligand B (54.517), but both are below the concerning 60 percentile.

**8. BBB:** Ligand A (79.062) has a better BBB penetration score than Ligand B (61.729). Both are reasonably good, but for a CNS target like DRD2, higher is preferred.

**9. Caco-2 Permeability:** Ligand A (-4.716) and Ligand B (-4.959) have negative values, which is unusual and suggests poor permeability. This is a significant drawback for both.

**10. Aqueous Solubility:** Both ligands have very poor aqueous solubility (-3.293 and -3.517). This is a major concern for bioavailability.

**11. hERG Inhibition:** Both ligands have low hERG inhibition risk (0.401 and 0.828).

**12. Microsomal Clearance:** Ligand A (15.257) and Ligand B (17.02) have similar, relatively low, microsomal clearance, suggesting reasonable metabolic stability.

**13. In vitro Half-Life:** Both ligands have similar in vitro half-lives (66.987 and 71.668 hours), which is good.

**14. P-gp Efflux:** Both ligands have low P-gp efflux liability (0.336 and 0.412), which is favorable for CNS penetration.

**15. Binding Affinity:** Both ligands have identical binding affinities (-8.3 kcal/mol), which is excellent.

**Overall Assessment:**

While both ligands have excellent binding affinity, Ligand A is slightly more favorable. It has a better QED score and a significantly better BBB penetration score, which are crucial for a CNS-targeting drug. Ligand B has a slightly better TPSA and lower DILI risk, but these are less critical given the excellent affinity and the importance of CNS penetration. The poor Caco-2 permeability and aqueous solubility are concerning for both, but can potentially be addressed through formulation strategies.

Output:
1
2025-04-17 08:35:23,366 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 drug candidates, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (340.43 and 352.40 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (50.6) is significantly better than Ligand B (109.66). For CNS targets, we want TPSA <= 90, and A is comfortably within that range, while B is considerably above.

**logP:** Ligand A (2.11) is optimal (1-3), while Ligand B (-1.27) is below 1, potentially hindering permeation.

**H-Bond Donors/Acceptors:** Ligand A (0 HBD, 4 HBA) is preferable. Ligand B has 1 HBD and 7 HBA, which is less ideal, potentially impacting permeability.

**QED:** Both ligands have similar QED values (0.86 and 0.68), indicating good drug-likeness.

**DILI:** Ligand A (25.79) has a much lower DILI risk than Ligand B (64.37). This is a significant advantage.

**BBB:** Ligand A (91.86) has excellent BBB penetration, exceeding the desirable >70% threshold. Ligand B (49.13) is considerably lower, a major drawback for a CNS target.

**Caco-2 Permeability:** Both have negative values, indicating poor permeability. However, the scale is not specified, making direct comparison difficult.

**Aqueous Solubility:** Both have negative values, indicating poor solubility. Again, the scale is not specified.

**hERG:** Ligand A (0.69) has a slightly higher hERG risk than Ligand B (0.06), but both are relatively low.

**Microsomal Clearance:** Ligand A (31.55) has a higher clearance than Ligand B (11.59), indicating lower metabolic stability.

**In vitro Half-Life:** Ligand A (-10.12) has a negative half-life, which is unusual and likely indicates a very short half-life. Ligand B (2.13) is better, but still relatively short.

**P-gp Efflux:** Ligand A (0.34) has lower P-gp efflux liability than Ligand B (0.014), which is beneficial for CNS exposure.

**Binding Affinity:** Ligand B (-7.5 kcal/mol) has a significantly stronger binding affinity than Ligand A (-10.1 kcal/mol). This is a substantial advantage.

**Overall Assessment:**

Despite the stronger binding affinity of Ligand B, Ligand A is the more promising candidate. The critical factors for a CNS GPCR target are BBB penetration, TPSA, and logP. Ligand A excels in these areas, with a high BBB score, low TPSA, and optimal logP. Ligand B's poor BBB penetration and low logP are major concerns. Although Ligand A has a higher clearance and a potentially very short half-life, these can be addressed through structural modifications. The significantly lower DILI risk for Ligand A is also a positive factor. The affinity difference, while notable, can potentially be overcome with further optimization of Ligand A.

Output:
0
2025-04-17 08:35:23,367 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (346.431 and 346.515 Da) fall comfortably within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (94.56) is higher than the preferred <90 for CNS targets, but not drastically so. Ligand B (40.62) is excellent, well below the threshold. This favors Ligand B.

**3. logP:** Ligand A (0.816) is a bit low, potentially hindering permeability. Ligand B (3.166) is within the optimal 1-3 range. This favors Ligand B.

**4. H-Bond Donors:** Ligand A (3) is acceptable. Ligand B (0) is also good, potentially improving permeability.

**5. H-Bond Acceptors:** Ligand A (5) is acceptable. Ligand B (2) is also good.

**6. QED:** Both ligands have good QED scores (0.734 and 0.767, respectively), indicating drug-like properties.

**7. DILI:** Both ligands have relatively low DILI risk (23.11 and 27.065), which is good.

**8. BBB:** This is crucial for a CNS target like DRD2. Ligand A (49.36) is concerningly low. Ligand B (81.698) is very good, exceeding the >70 desirable threshold. This is a major advantage for Ligand B.

**9. Caco-2 Permeability:** Ligand A (-5.29) is poor, suggesting poor intestinal absorption. Ligand B (-4.796) is also poor, but slightly better than A.

**10. Aqueous Solubility:** Ligand A (-1.842) and Ligand B (-3.101) both have poor aqueous solubility.

**11. hERG Inhibition:** Both ligands have low hERG inhibition risk (0.402 and 0.627), which is positive.

**12. Microsomal Clearance:** Ligand A (0.466) has lower clearance, suggesting better metabolic stability than Ligand B (84.512). This favors Ligand A.

**13. In vitro Half-Life:** Ligand A (8.837) has a better half-life than Ligand B (-5.612). This favors Ligand A.

**14. P-gp Efflux:** Ligand A (0.009) has very low P-gp efflux, which is excellent for CNS penetration. Ligand B (0.544) is also relatively low.

**15. Binding Affinity:** Ligand A (-8.4) has significantly better binding affinity than Ligand B (0). A difference of >1.5 kcal/mol is considered substantial.

**Overall Assessment:**

While Ligand A has superior binding affinity and metabolic stability, Ligand B excels in critical properties for a CNS-targeting GPCR ligand: TPSA, logP, and, most importantly, BBB penetration. The significantly better BBB score of Ligand B outweighs the affinity advantage of Ligand A. The poor solubility of both is a concern, but can be addressed with formulation strategies. The slightly better Caco-2 permeability of B is also a minor plus.

Output:
1
2025-04-17 08:35:23,367 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (357.479 and 360.435 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (75.11) is better than Ligand B (84.5). Both are below the 90 A^2 threshold for CNS targets, but A is closer to the ideal range.

**3. logP:** Ligand A (4.283) is slightly higher than the optimal 1-3 range, while Ligand B (2.157) is well within the range. High logP can cause issues, but isn't a dealbreaker if other properties are favorable.

**4. H-Bond Donors:** Both ligands have 2 HBD, which is within the acceptable limit of <=5.

**5. H-Bond Acceptors:** Ligand A has 5 HBA, and Ligand B has 4 HBA, both are within the acceptable limit of <=10.

**6. QED:** Ligand B (0.875) has a significantly better QED score than Ligand A (0.593), indicating a more drug-like profile.

**7. DILI:** Both ligands have similar DILI risk (80.651 and 79.876), and are relatively high, but not excessively so.

**8. BBB:** Ligand A (49.011) has a slightly better BBB percentile than Ligand B (45.909), but both are below the desirable >70 for CNS targets. This is a concern for both.

**9. Caco-2:** Both ligands have negative Caco-2 values (-5.183 and -5.018), which is unusual and suggests poor permeability. This is a significant drawback for both.

**10. Solubility:** Both ligands have negative solubility values (-5.167 and -3.484), indicating very poor aqueous solubility. This is a major issue for both.

**11. hERG:** Both ligands have very low hERG inhibition risk (0.082 and 0.41), which is excellent.

**12. Cl_mic:** Ligand B (49.103) has lower microsomal clearance than Ligand A (61.272), suggesting better metabolic stability.

**13. t1/2:** Ligand B (-2.283) has a slightly better (less negative) in vitro half-life than Ligand A (-3.21), suggesting better stability.

**14. Pgp:** Ligand A (0.122) has lower P-gp efflux liability than Ligand B (0.261), which is favorable for CNS penetration.

**15. Binding Affinity:** Ligand B (-9.5 kcal/mol) has a significantly stronger binding affinity than Ligand A (-8.3 kcal/mol). This is a substantial advantage.

**Overall Assessment:**

While both ligands have significant drawbacks (poor solubility and permeability), Ligand B is the more promising candidate. Its superior binding affinity (-9.5 vs -8.3 kcal/mol) is a major advantage, and it also exhibits better QED, metabolic stability (lower Cl_mic), and in vitro half-life. The slightly lower Pgp efflux is less important given the already poor permeability. The BBB values are suboptimal for both, but the stronger binding of Ligand B might allow for efficacy at lower concentrations, potentially mitigating the BBB issue.

Output:
1
2025-04-17 08:35:23,367 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (354.445 and 356.398 Da) are within the ideal 200-500 Da range.

**TPSA:** Ligand A (58.95) is excellent, well below the 90 A^2 threshold for CNS targets. Ligand B (96.69) is higher, but still acceptable, though less desirable.

**logP:** Ligand A (4.202) is at the upper end of the optimal range (1-3) and could potentially cause solubility issues. Ligand B (-0.065) is too low, potentially hindering membrane permeability.

**H-Bond Donors/Acceptors:** Both ligands have 2 HBDs, which is good. Ligand A has 3 HBAs, and Ligand B has 6 HBAs. Both are within the acceptable limit of 10, but Ligand B is closer to the upper bound.

**QED:** Both ligands have reasonable QED values (0.854 and 0.713), indicating good drug-like properties.

**DILI:** Both ligands have low DILI risk (38.581 and 39.899), which is positive.

**BBB:** Ligand A has a very high BBB penetration percentile (90.772), making it highly favorable for a CNS target. Ligand B's BBB penetration (65.413) is considerably lower, though not terrible.

**Caco-2 Permeability:** Ligand A (-4.347) has poor Caco-2 permeability, which is a concern. Ligand B (-5.004) is also poor, but slightly worse.

**Aqueous Solubility:** Ligand A (-4.988) has poor aqueous solubility, consistent with its high logP. Ligand B (-0.941) has slightly better solubility, but it is still poor.

**hERG:** Ligand A (0.583) has a low hERG risk, which is good. Ligand B (0.24) is even lower, indicating a very low risk of cardiotoxicity.

**Microsomal Clearance:** Ligand A (40.334) has moderate microsomal clearance. Ligand B (-4.89) has *negative* clearance, which is not physically possible and likely an artifact of the prediction method. This is a major red flag.

**In vitro Half-Life:** Ligand A (39.834) has a moderate in vitro half-life. Ligand B (10.648) has a very short in vitro half-life.

**P-gp Efflux:** Ligand A (0.108) has low P-gp efflux, which is desirable for CNS penetration. Ligand B (0.03) has very low P-gp efflux, which is even better.

**Binding Affinity:** Ligand A (-9.3 kcal/mol) has significantly stronger binding affinity than Ligand B (-7.9 kcal/mol). This is a substantial difference (1.4 kcal/mol), and can often outweigh other drawbacks.

**Overall Assessment:**

Ligand A excels in BBB penetration and binding affinity, both crucial for a CNS GPCR target like DRD2. However, it suffers from poor Caco-2 permeability and aqueous solubility, and moderate clearance. Ligand B has a better hERG profile and lower P-gp efflux, but its low logP, poor BBB penetration, very short half-life, and *impossible* negative clearance are major liabilities. The significantly stronger binding affinity of Ligand A, combined with its excellent BBB penetration, makes it the more promising candidate despite its ADME shortcomings. The solubility and permeability issues could potentially be addressed through formulation strategies or further chemical modifications. The negative clearance of Ligand B is a showstopper.

Output:
0
2025-04-17 08:35:23,367 - INFO - Batch 461 complete. Total preferences: 7376
2025-04-17 08:35:23,367 - INFO - Processing batch 462/512...
2025-04-17 08:36:07,339 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (368.459 Da and 353.463 Da) fall within the ideal range of 200-500 Da.

**TPSA:** Ligand A (102.84) is slightly above the optimal <90 for CNS targets, but still reasonable. Ligand B (71.11) is well within the desired range.

**logP:** Ligand A (-0.451) is a bit low, potentially hindering membrane permeability. Ligand B (0.238) is also on the lower side, but slightly better than A. Both are below the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A has 2 HBD and 6 HBA, which are acceptable. Ligand B has 1 HBD and 5 HBA, also acceptable.

**QED:** Both ligands have good QED scores (0.701 and 0.741), indicating drug-like properties.

**DILI:** Ligand A (45.25) has a moderate DILI risk, while Ligand B (28.073) has a lower, more favorable risk.

**BBB:** This is crucial for a CNS target. Ligand A has a BBB percentile of 11.128, which is very poor. Ligand B has a much better BBB percentile of 68.67, though ideally, we'd want >70.

**Caco-2 Permeability:** Both have negative Caco-2 values (-5.17 and -4.543), which is unusual and suggests poor permeability. This is concerning.

**Aqueous Solubility:** Both ligands have poor aqueous solubility (-1.139 and -1.241). This could pose formulation challenges.

**hERG Inhibition:** Both ligands show very low hERG inhibition risk (0.041 and 0.121).

**Microsomal Clearance:** Ligand A (15.823) has lower clearance than Ligand B (44.564), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (-27.459) has a very short half-life, which is unfavorable. Ligand B (-2.394) is slightly better, but still short.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.026 and 0.019), which is good for CNS penetration.

**Binding Affinity:** Ligand A (-7.9 kcal/mol) has a significantly stronger binding affinity than Ligand B (-6.3 kcal/mol). This is a substantial advantage.

**Overall Assessment:**

Despite Ligand A's superior binding affinity, its extremely poor BBB penetration is a major drawback for a CNS target like DRD2. The low logP and poor solubility are also concerns. Ligand B, while having a weaker affinity, possesses a much better BBB percentile, lower DILI risk, and acceptable TPSA. The Caco-2 permeability and solubility are still problematic for both, but the difference in BBB is decisive. The stronger binding of A might overcome some ADME issues, but the poor BBB is a significant hurdle.

Output:
1
2025-04-17 08:36:07,340 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (359.354 and 354.451 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (119.24) is better than Ligand B (121.6). Both are below the 140 threshold for oral absorption and reasonably close to the 90 target for CNS penetration, but A is closer.

**3. logP:** Ligand A (-1.551) is lower than Ligand B (-0.234). While both are within the 1-3 range, A is a bit low and might have permeability issues. B is closer to optimal.

**4. H-Bond Donors:** Ligand A (1) is better than Ligand B (3). Lower HBD generally improves permeability.

**5. H-Bond Acceptors:** Ligand A (6) is better than Ligand B (4). Lower HBA also generally improves permeability.

**6. QED:** Both ligands have acceptable QED values (0.453 and 0.584, respectively), indicating reasonable drug-likeness. Ligand B is slightly better.

**7. DILI:** Ligand A (44.552) has a higher DILI risk than Ligand B (20.047). This is a significant advantage for Ligand B.

**8. BBB:** Ligand A (79.062) has a significantly better BBB penetration percentile than Ligand B (57.619). This is a critical factor for a CNS target like DRD2.

**9. Caco-2 Permeability:** Ligand A (-4.985) has worse Caco-2 permeability than Ligand B (-5.595). Both are negative, which is unusual, but B is slightly better.

**10. Aqueous Solubility:** Both ligands have very poor aqueous solubility (-1.527 and -1.646). This could pose formulation challenges.

**11. hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.171 and 0.029).

**12. Microsomal Clearance:** Ligand A (2.993) has lower microsomal clearance than Ligand B (24.821), indicating better metabolic stability.

**13. In vitro Half-Life:** Ligand A (-34.976) has a much longer in vitro half-life than Ligand B (-20.021). This is a substantial advantage for Ligand A.

**14. P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.026 and 0.006).

**15. Binding Affinity:** Ligand A (-7.7) has a slightly better binding affinity than Ligand B (-7.3). While both are good, the 0.4 kcal/mol difference is noticeable.

**Overall Assessment:**

Ligand A excels in BBB penetration, metabolic stability (lower Cl_mic, longer t1/2), binding affinity, and has fewer H-bonds. Ligand B has a lower DILI risk and a slightly better logP. The critical factors for a CNS GPCR target are BBB, logP, and affinity. Ligand A's superior BBB penetration and affinity outweigh the slightly lower logP and higher DILI risk, especially given the similar solubility and hERG profiles.

Output:
1
2025-04-17 08:36:07,340 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (363.4 and 348.4 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (127.08) is higher than the preferred <90 for CNS targets, while Ligand B (89.27) is closer to the ideal range. This gives a slight edge to Ligand B.

**logP:** Ligand A (0.87) is a bit low, potentially hindering permeation. Ligand B (1.575) is better, falling within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Both have 2 HBD and are within the acceptable limits. Ligand A has 8 HBA, while Ligand B has 6. Both are acceptable (<10).

**QED:** Both ligands have good QED scores (0.699 and 0.781), indicating drug-like properties.

**DILI:** Ligand A (74.021) has a higher DILI risk than Ligand B (26.134). Ligand B is significantly better here.

**BBB:** Ligand A (53.742) has a moderate BBB penetration, while Ligand B (31.834) is quite low. This is a significant drawback for Ligand B, as DRD2 is a CNS target.

**Caco-2 Permeability:** Both have negative Caco-2 values (-5.283 and -5.197), which is unusual and suggests poor permeability. This is a concern for both, but needs further investigation.

**Aqueous Solubility:** Both have negative solubility values (-3.047 and -2.324), also unusual and concerning.

**hERG:** Both have very low hERG inhibition liability (0.024 and 0.08), which is excellent.

**Microsomal Clearance:** Ligand A (37.371) has higher clearance than Ligand B (8.799), suggesting lower metabolic stability. Ligand B is preferable.

**In vitro Half-Life:** Ligand B (9.223) has a significantly longer half-life than Ligand A (2.89). This is a major advantage for Ligand B.

**P-gp Efflux:** Both have low P-gp efflux liability (0.079 and 0.044), which is good for CNS penetration.

**Binding Affinity:** Ligand B (-8.6 kcal/mol) has a slightly better binding affinity than Ligand A (-8.3 kcal/mol). While the difference is small, it's still a positive for Ligand B.

**Overall Assessment:**

Ligand B is the better candidate. While its BBB penetration is low, it excels in several key areas: lower DILI risk, better metabolic stability (lower Cl_mic, longer t1/2), slightly better binding affinity, and a more favorable logP and TPSA. Ligand A's higher BBB score is offset by its higher DILI risk and lower metabolic stability. The unusual solubility and Caco-2 values for both compounds warrant further investigation, but the other factors lean towards Ligand B.

Output:
1
2025-04-17 08:36:07,340 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (358.5 & 363.4 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (40.62) is significantly better than Ligand B (95.67). For CNS targets, TPSA should be <= 90, so Ligand A is much more favorable.

**logP:** Ligand A (3.05) is optimal, while Ligand B (1.58) is a bit low, potentially hindering permeation.

**H-Bond Donors/Acceptors:** Ligand A (0 HBD, 3 HBA) is preferable. Ligand B has 2 HBD and 6 HBA, which is higher and could impact permeability.

**QED:** Both ligands have similar QED values (0.812 and 0.779), indicating good drug-likeness.

**DILI:** Ligand A (21.95) has a much lower DILI risk than Ligand B (57.66), indicating a safer profile.

**BBB:** Ligand A (85.11) has a significantly better BBB penetration score than Ligand B (36.37). This is *critical* for a CNS target like DRD2.

**Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and suggests poor permeability. However, the magnitude is similar.

**Aqueous Solubility:** Both have negative solubility values, which is also unusual. However, the magnitude is similar.

**hERG:** Both ligands have low hERG inhibition liability (0.344 and 0.149), which is good.

**Microsomal Clearance:** Ligand A (39.23) has higher clearance than Ligand B (-1.099). This suggests Ligand B is more metabolically stable.

**In vitro Half-Life:** Ligand B (22 hours) has a significantly longer half-life than Ligand A (8.76 hours).

**P-gp Efflux:** Ligand A (0.348) has lower P-gp efflux liability than Ligand B (0.062), which is favorable for CNS penetration.

**Binding Affinity:** Ligand B (-7.7 kcal/mol) has a slightly better binding affinity than Ligand A (-7.5 kcal/mol), but the difference is small.

**Overall Assessment:**

Ligand A is substantially better overall, particularly due to its superior TPSA, BBB penetration, and lower DILI risk. While Ligand B has a slightly better binding affinity and metabolic stability, the CNS-specific requirements for DRD2 make Ligand A the more promising candidate. The improved BBB penetration and lower TPSA of Ligand A are crucial for reaching the target in the brain. The small difference in binding affinity can likely be optimized during further lead optimization.

Output:
1
2025-04-17 08:36:07,341 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (366.483 and 371.453 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (89.27) is better than Ligand B (71.09). Both are below the 90 A^2 threshold for CNS targets, but A is closer to the upper limit.

**3. logP:** Ligand A (2.511) is within the optimal range (1-3), while Ligand B (3.364) is slightly higher. Both are acceptable, but A is preferable.

**4. H-Bond Donors:** Ligand A (1) is better than Ligand B (2). Lower is generally preferred.

**5. H-Bond Acceptors:** Ligand A (5) is better than Ligand B (4). Both are within the acceptable range.

**6. QED:** Both ligands have similar QED values (0.827 and 0.805), indicating good drug-likeness.

**7. DILI:** Ligand A (52.772) has a lower DILI risk than Ligand B (62.815), which is desirable.

**8. BBB:** Ligand B (85.459) has significantly better BBB penetration than Ligand A (70.919). This is a *critical* factor for a CNS target like DRD2.

**9. Caco-2 Permeability:** Both have negative values, indicating poor permeability. Ligand A (-4.841) is slightly better than Ligand B (-4.944), but both are problematic.

**10. Aqueous Solubility:** Both have negative values, indicating poor solubility. Ligand A (-2.907) is slightly better than Ligand B (-4.431).

**11. hERG Inhibition:** Both ligands have low hERG inhibition liability (0.107 and 0.359), which is good.

**12. Microsomal Clearance:** Ligand B (53.318) has a lower microsomal clearance than Ligand A (17.895), suggesting better metabolic stability.

**13. In vitro Half-Life:** Ligand B (24.965) has a much longer half-life than Ligand A (-1.52). This is a significant advantage.

**14. P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.309 and 0.246), which is good.

**15. Binding Affinity:** Ligand B (-7.5 kcal/mol) has a *much* stronger binding affinity than Ligand A (0.0 kcal/mol). A difference of >1.5 kcal/mol is highly significant and can outweigh other drawbacks.

**Overall Assessment:**

While Ligand A has some advantages in terms of TPSA, logP, DILI, solubility, and H-bonding, Ligand B is clearly superior due to its *significantly* stronger binding affinity (-7.5 vs 0.0 kcal/mol) and much better BBB penetration (85.459 vs 70.919). The longer half-life and lower clearance of Ligand B are also beneficial. The slightly higher logP and DILI risk of Ligand B are less concerning given the substantial improvement in affinity and CNS penetration.

Output:
1
2025-04-17 08:36:07,341 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 drug candidates, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (355.394 and 362.47 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (56.15) is better than Ligand B (58.2), both are below the 90 A^2 threshold for CNS targets.

**3. logP:** Both ligands have a logP around 4.1, which is slightly above the optimal 1-3 range but not drastically so. This could potentially lead to some solubility issues, but is not a dealbreaker.

**4. H-Bond Donors:** Ligand A (1) is preferable to Ligand B (2). Lower HBD generally improves permeability.

**5. H-Bond Acceptors:** Ligand A (5) is preferable to Ligand B (3). Lower HBA generally improves permeability.

**6. QED:** Both ligands have good QED scores (0.6 and 0.811), indicating good drug-like properties.

**7. DILI:** Ligand A (96.898) has a significantly higher DILI risk than Ligand B (65.529). This is a major concern for Ligand A.

**8. BBB:** Ligand B (69.252) has a slightly better BBB penetration percentile than Ligand A (61.342), but both are below the desirable >70% for CNS targets.

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.734 and -4.702), which is unusual and suggests poor permeability.

**10. Aqueous Solubility:** Both ligands have negative solubility values (-4.682 and -4.431), indicating very poor aqueous solubility.

**11. hERG Inhibition:** Both ligands have low hERG inhibition risk (0.828 and 0.756).

**12. Microsomal Clearance:** Both ligands have similar microsomal clearance (75.964 and 75.866), indicating similar metabolic stability.

**13. In vitro Half-Life:** Ligand B (56.79) has a significantly longer in vitro half-life than Ligand A (16.606), which is a major advantage.

**14. P-gp Efflux:** Both ligands have low P-gp efflux liability (0.857 and 0.457).

**15. Binding Affinity:** Both ligands have excellent binding affinity (-9.2 and -9.0 kcal/mol). The difference is minor.

**Overall Assessment:**

Despite similar binding affinities, Ligand B is the more promising candidate. Its significantly lower DILI risk, longer half-life, and slightly better BBB penetration outweigh the minor differences in other properties. While both ligands have poor Caco-2 permeability and aqueous solubility, these can be addressed with formulation strategies. The high DILI risk associated with Ligand A is a major red flag.

Output:
1
2025-04-17 08:36:07,341 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (345.443 Da) is slightly lower, which could be beneficial for permeability, but both are acceptable.

**TPSA:** Both ligands have TPSA values below 90 (Ligand A: 74.59, Ligand B: 69.64), which is excellent for CNS penetration.

**logP:** Both ligands have optimal logP values (Ligand A: 2.487, Ligand B: 2.349), falling within the 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A (HBD=1, HBA=5) and Ligand B (HBD=2, HBA=4) both have reasonable H-bond donor and acceptor counts, well within the guidelines.

**QED:** Both ligands have good QED scores (Ligand A: 0.783, Ligand B: 0.862), indicating good drug-like properties.

**DILI:** Ligand A (15.2) has a significantly lower DILI risk than Ligand B (39.046), which is a major advantage.

**BBB:** Ligand A (83.908) has a substantially higher BBB penetration percentile than Ligand B (48.391). This is *critical* for a CNS target like DRD2.

**Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and suggests poor permeability. However, the scale is not specified, so it's difficult to interpret.

**Aqueous Solubility:** Both have negative solubility values, also unusual. This suggests poor solubility, which could be a formulation challenge.

**hERG Inhibition:** Both ligands show low hERG inhibition liability (Ligand A: 0.668, Ligand B: 0.458), which is good.

**Microsomal Clearance:** Ligand A (57.993) has a higher microsomal clearance than Ligand B (17.274), indicating faster metabolism and potentially lower in vivo exposure.

**In vitro Half-Life:** Ligand B (31.142 hours) has a significantly longer in vitro half-life than Ligand A (13.219 hours), which is desirable.

**P-gp Efflux:** Both ligands show low P-gp efflux liability (Ligand A: 0.04, Ligand B: 0.207), which is favorable for CNS exposure.

**Binding Affinity:** Ligand B (-8.5 kcal/mol) has a slightly better binding affinity than Ligand A (-7.5 kcal/mol). This 1 kcal/mol difference is significant, but must be weighed against other factors.

**Overall Assessment:**

Ligand A is superior due to its significantly better BBB penetration (83.9% vs 48.4%), much lower DILI risk (15.2% vs 39.0%), and acceptable binding affinity. While Ligand B has a slightly better affinity and longer half-life, the substantial improvements in BBB and DILI for Ligand A outweigh these benefits, especially given the CNS target. The poor solubility and permeability (negative Caco-2 and solubility values) are concerns for both, but can potentially be addressed with formulation strategies.

Output:
1
2025-04-17 08:36:07,341 - INFO - Reasoning:

Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (348.443 Da) is slightly lower, which is generally favorable for permeability.

**2. TPSA:** Ligand A (59.08) is significantly better than Ligand B (110.53). For CNS targets, TPSA < 90 is preferred, and A is comfortably within this range, while B is pushing the limit.

**3. logP:** Both ligands have acceptable logP values (A: 1.068, B: 0.604), falling within the optimal 1-3 range.

**4. H-Bond Donors:** Ligand A (0) is better than Ligand B (2). Fewer HBDs generally improve permeability.

**5. H-Bond Acceptors:** Ligand A (4) is better than Ligand B (6). Fewer HBAs generally improve permeability.

**6. QED:** Both ligands have good QED scores (A: 0.532, B: 0.692), indicating drug-like properties. B is slightly better here.

**7. DILI:** Ligand A (23.575) has a much lower DILI risk than Ligand B (51.221). This is a significant advantage for A.

**8. BBB:** Ligand A (66.111) has a better BBB percentile than Ligand B (59.442), although both are not ideal (>70 is desirable). A is closer to the target.

**9. Caco-2 Permeability:** Ligand A (-4.328) has a worse Caco-2 permeability than Ligand B (-5.135). However, Caco-2 values are often difficult to interpret and less reliable than other parameters.

**10. Aqueous Solubility:** Ligand A (-1.048) has a slightly better aqueous solubility than Ligand B (-1.762).

**11. hERG Inhibition:** Both ligands have very low hERG inhibition risk (A: 0.336, B: 0.11).

**12. Microsomal Clearance:** Ligand A (10.119) has lower microsomal clearance than Ligand B (19.001), suggesting better metabolic stability.

**13. In vitro Half-Life:** Ligand A (8.428) has a longer in vitro half-life than Ligand B (1.389). This is a significant advantage for A.

**14. P-gp Efflux:** Ligand A (0.061) has lower P-gp efflux than Ligand B (0.044), meaning better CNS exposure.

**15. Binding Affinity:** Ligand B (-7.7 kcal/mol) has a slightly better binding affinity than Ligand A (-7.1 kcal/mol). While a 1.5 kcal/mol difference is generally significant, the other advantages of Ligand A outweigh this.

**Overall Assessment:**

Ligand A is the superior candidate. It has a better TPSA, lower DILI risk, better BBB penetration, lower clearance, longer half-life, and lower P-gp efflux. While Ligand B has slightly better binding affinity and QED, the ADME properties of Ligand A are significantly more favorable, especially for a CNS target like DRD2. The combination of improved CNS penetration (BBB, TPSA, Pgp) and reduced toxicity (DILI) makes Ligand A the more promising drug candidate.

Output:
0
2025-04-17 08:36:07,341 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (354.372 and 346.402 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (38.5) is excellent, well below the 90 A^2 threshold for CNS targets. Ligand B (69.64) is higher, but still potentially acceptable, though less ideal.

**3. logP:** Ligand A (4.513) is slightly high, potentially leading to solubility issues or off-target interactions. Ligand B (2.496) is within the optimal 1-3 range.

**4. H-Bond Donors:** Ligand A (0) and Ligand B (2) are both acceptable, being less than 5.

**5. H-Bond Acceptors:** Ligand A (4) and Ligand B (3) are both acceptable, being less than 10.

**6. QED:** Both ligands have good QED scores (0.81 and 0.861), indicating good drug-like properties.

**7. DILI:** Ligand A (46.258) has a moderate DILI risk, while Ligand B (26.599) has a lower, more favorable DILI risk.

**8. BBB:** Ligand A (85.731) has a very good BBB penetration percentile, exceeding the 70% threshold for CNS targets. Ligand B (70.803) also meets the threshold, but is less favorable than Ligand A.

**9. Caco-2:** Both ligands have negative Caco-2 values which is unusual and likely indicates a data error. We'll proceed assuming these are percentile scores and higher is better.

**10. Solubility:** Ligand A (-4.721) has poor aqueous solubility, consistent with its higher logP. Ligand B (-3.246) has better, though still poor, solubility.

**11. hERG:** Both ligands have low hERG inhibition liability (0.875 and 0.496), which is good.

**12. Cl_mic:** Ligand A (46.006) has a moderate microsomal clearance, while Ligand B (32.266) has lower clearance, suggesting better metabolic stability.

**13. t1/2:** Ligand A (-33.607) has a negative in vitro half-life, which is impossible. This is likely a data error. Ligand B (-8.672) also has a negative half-life, also likely a data error.

**14. Pgp:** Both ligands have low P-gp efflux liability (0.37 and 0.059), which is favorable for CNS penetration.

**15. Binding Affinity:** Both ligands have excellent binding affinities (-9.0 and -9.4 kcal/mol), with Ligand B being slightly better. The difference in affinity is small and likely less important than the ADME differences.

**Overall Assessment:**

Ligand A has a superior BBB score and a comparable binding affinity. However, its high logP leads to poor solubility and a moderate DILI risk. Ligand B has a better logP, lower DILI, and better metabolic stability, despite a slightly lower affinity. Given the GPCR-specific priorities, the better BBB penetration of Ligand A is a significant advantage. However, the poor solubility and DILI risk are concerning. The negative half-life values for both compounds are suspect and would need to be verified.

Considering the balance of properties, and prioritizing BBB for a CNS target like DRD2, and acknowledging the data errors, Ligand A is slightly more promising.

Output:
1
2025-04-17 08:36:07,342 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (385.823 and 388.877 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (62.39) is excellent, well below the 90 A^2 threshold for CNS targets. Ligand B (101.91) is higher, but still potentially acceptable, though less ideal.

**logP:** Ligand A (3.867) is at the upper end of the optimal 1-3 range, while Ligand B (1.143) is a bit low, potentially impacting permeability.

**H-Bond Donors/Acceptors:** Ligand A has 3 HBD and 3 HBA, which is good. Ligand B has 2 HBD and 7 HBA, also acceptable, but the higher HBA count could slightly hinder permeability.

**QED:** Both ligands have reasonable QED values (0.659 and 0.585), indicating good drug-like properties.

**DILI:** Ligand A (81.078) has a higher DILI risk than Ligand B (62.544). This is a negative for Ligand A.

**BBB:** Ligand A (64.211) has a better BBB penetration percentile than Ligand B (38.581). This is a *significant* advantage for a CNS target like DRD2.

**Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and suggests poor permeability. However, the scale is not specified, so it's hard to interpret.

**Aqueous Solubility:** Both ligands have negative solubility values, which is also unusual. Again, the scale is not specified.

**hERG:** Ligand A (0.663) has a slightly higher hERG risk than Ligand B (0.165). This is a negative for Ligand A.

**Microsomal Clearance:** Ligand A (20.726) has a higher microsomal clearance than Ligand B (11.414), indicating lower metabolic stability.

**In vitro Half-Life:** Ligand B (21.969) has a slightly longer in vitro half-life than Ligand A (65.55).

**P-gp Efflux:** Ligand A (0.366) has lower P-gp efflux liability than Ligand B (0.12), which is favorable for CNS penetration.

**Binding Affinity:** Ligand B (-7.6 kcal/mol) has a significantly stronger binding affinity than Ligand A (-9.3 kcal/mol). This is a major advantage, potentially outweighing some ADME drawbacks.

**Overall Assessment:**

Ligand B has a substantially better binding affinity, which is paramount for GPCR targets. While its BBB penetration is lower than Ligand A, the affinity difference is significant. Ligand A has better BBB and P-gp, but suffers from higher DILI risk, hERG risk, and lower affinity. Given the importance of affinity for GPCRs, and the relatively acceptable BBB value of Ligand B, Ligand B is the more promising candidate.

Output:
1
2025-04-17 08:36:07,342 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (349.475 & 347.459 Da) fall comfortably within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (54.04) is significantly better than Ligand B (75.44). For a CNS target like DRD2, a TPSA <= 90 is preferred, and A is much closer to the optimal <=60 range. B is pushing the upper limit.

**3. logP:** Both ligands have acceptable logP values (2.494 & 3.002), falling within the 1-3 range.

**4. H-Bond Donors:** Both have 1 HBD, which is good.

**5. H-Bond Acceptors:** Both have 4 HBA, which is good.

**6. QED:** Ligand A (0.887) has a higher QED than Ligand B (0.769), indicating better overall drug-likeness.

**7. DILI:** Ligand A (20.008) has a much lower DILI risk than Ligand B (43.66), which is a significant advantage.

**8. BBB:** Ligand A (82.435) has a better BBB penetration percentile than Ligand B (75.921). While both are reasonably good, A is closer to the desirable >70 threshold for CNS targets.

**9. Caco-2 Permeability:** Ligand A (-4.424) has better Caco-2 permeability than Ligand B (-4.743). Both are negative, but A is less negative.

**10. Aqueous Solubility:** Ligand A (-1.129) has better aqueous solubility than Ligand B (-3.704).

**11. hERG Inhibition:** Ligand A (0.654) has a slightly higher hERG inhibition risk than Ligand B (0.359), but both are relatively low.

**12. Microsomal Clearance:** Ligand B (90.64) has a significantly *lower* (better) microsomal clearance than Ligand A (24.75). This suggests B is more metabolically stable.

**13. In vitro Half-Life:** Ligand B (-16.536) has a much longer in vitro half-life than Ligand A (6.979). This is a substantial advantage.

**14. P-gp Efflux:** Ligand B (0.446) has lower P-gp efflux than Ligand A (0.048), which is favorable for CNS penetration.

**15. Binding Affinity:** Ligand A (-7.6) has a slightly better binding affinity than Ligand B (-0.0). This is a very important factor.

**Overall Assessment:**

Ligand A excels in key areas for a CNS GPCR target: TPSA, BBB, DILI risk, solubility, and, critically, binding affinity. Ligand B has better metabolic stability (lower Cl_mic, longer t1/2) and P-gp efflux, but its higher TPSA, DILI risk, and significantly weaker binding affinity are major drawbacks. The difference in binding affinity (-7.6 vs -0.0) is substantial and likely outweighs the benefits of B's improved metabolic properties. For a GPCR, strong initial binding is crucial.

Output:
1
2025-04-17 08:36:07,342 - INFO - Okay, let's analyze these two ligands for their potential as DRD2 drug candidates. DRD2 is a GPCR in the CNS, so BBB penetration, logP, Pgp efflux, TPSA, and binding affinity are paramount.

**Ligand A:** [337.427, 64.74, 3.354, 1, 5, 0.776, 55.68, 58.782, -4.937, -2.837, 0.745, 37.713, 19.3, 0.378, -9.1]
**Ligand B:** [352.45, 58.64, 1.903, 1, 3, 0.841, 23.187, 90.074, -4.586, -2.834, 0.487, 8.743, -1.545, 0.1, -9]

**1. Molecular Weight:** Both are within the ideal range (200-500 Da). A (337.427) is slightly preferred.

**2. TPSA:** A (64.74) is higher than B (58.64), but both are below the 90 A^2 threshold for CNS targets. B is better here.

**3. logP:** A (3.354) is good, within the optimal 1-3 range. B (1.903) is also acceptable, but closer to the lower limit, potentially impacting permeability. A is better.

**4. H-Bond Donors:** Both have 1 HBD, which is good.

**5. H-Bond Acceptors:** A has 5, B has 3. Both are within the acceptable limit of 10. B is slightly better.

**6. QED:** Both have good QED values (A: 0.776, B: 0.841). B is slightly better.

**7. DILI:** A (55.68) is higher than B (23.187), indicating a greater potential for liver injury. B is significantly better.

**8. BBB:** This is *critical* for a CNS target. B (90.074) is excellent (>70), while A (58.782) is moderate. B is *much* better.

**9. Caco-2:** Both are negative, indicating poor permeability. This is a concern for both, but the scale is unclear.

**10. Solubility:** Both are negative, indicating poor solubility. This is a concern for both, but the scale is unclear.

**11. hERG:** Both have low hERG risk (A: 0.745, B: 0.487). B is slightly better.

**12. Cl_mic:** A (37.713) is higher than B (8.743), meaning faster metabolic clearance and potentially lower exposure. B is better.

**13. t1/2:** A (19.3) is much better than B (-1.545). A is better.

**14. Pgp:** A (0.378) is better than B (0.1), indicating less P-gp efflux. A is better.

**15. Binding Affinity:** Both have excellent binding affinity (A: -9.1, B: -9.0). The difference is negligible.

**Overall Assessment:**

While Ligand A has a slightly better MW, logP, t1/2, and Pgp profile, Ligand B *significantly* outperforms it in crucial areas for a CNS-targeting GPCR: **BBB penetration** and **DILI risk**. The superior BBB penetration of Ligand B is a major advantage, and the lower DILI risk is a critical safety factor. The better metabolic stability (lower Cl_mic) of B is also a positive. The slight differences in TPSA, QED, and hERG are less important given the substantial benefits of B in the key CNS-relevant parameters.

Output:
1
2025-04-17 08:36:07,342 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (362.832 Da) is slightly lower, which could be advantageous for permeability.

**TPSA:** Ligand A (54.27) is significantly better than Ligand B (81.86). For CNS targets, we want TPSA <= 90, and A is comfortably within that range, while B is approaching the upper limit.

**logP:** Ligand A (4.481) is higher than the optimal range (1-3), potentially leading to solubility issues and off-target effects. Ligand B (1.903) is within the optimal range.

**H-Bond Donors/Acceptors:** Ligand A (HBD=2, HBA=2) and Ligand B (HBD=1, HBA=5) both fall within acceptable limits.

**QED:** Both ligands have similar QED values (A: 0.842, B: 0.739), indicating good drug-likeness.

**DILI:** Both ligands have similar and acceptable DILI risk (A: 37.185, B: 37.03).

**BBB:** Both ligands exhibit good BBB penetration (A: 78.829, B: 82.745), exceeding the 70% threshold for CNS targets. B is slightly better.

**Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and suggests a potential issue with the data or modeling. However, we can't definitively say which is better without understanding the scale.

**Aqueous Solubility:** Both have negative solubility values, which is also unusual. Again, we can't draw firm conclusions.

**hERG:** Ligand A (0.643) has a slightly higher hERG risk than Ligand B (0.264), which is preferable.

**Microsomal Clearance:** Ligand B (32.998) has significantly lower microsomal clearance than Ligand A (47.924), indicating better metabolic stability.

**In vitro Half-Life:** Ligand A (110.511) has a much longer half-life than Ligand B (10.228), which is generally desirable.

**P-gp Efflux:** Ligand A (0.407) has lower P-gp efflux than Ligand B (0.14), which is better for CNS exposure.

**Binding Affinity:** Ligand B (-7.5 kcal/mol) has a significantly stronger binding affinity than Ligand A (-10.6 kcal/mol). This is a substantial advantage, potentially outweighing some of the ADME drawbacks of Ligand B.

**Overall Assessment:**

Ligand B has a significantly better binding affinity, lower microsomal clearance (better metabolic stability), and lower hERG risk. While Ligand A has a slightly better BBB penetration and longer half-life, the superior affinity of Ligand B is a critical factor for a GPCR target like DRD2. The slightly higher logP of Ligand A is a concern, and the lower TPSA of Ligand A is good, but the affinity difference is substantial. The negative solubility and Caco-2 values are concerning for both, but the overall profile of B is more promising.

Output:
1
2025-04-17 08:36:07,343 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (345.4 and 348.4 Da) fall comfortably within the ideal 200-500 Da range.

**TPSA:** Ligand A (82.97) is excellent for CNS penetration, being well below the 90 A^2 threshold. Ligand B (98.82) is still reasonable, but less optimal.

**logP:** Ligand A (0.296) is a bit low, potentially hindering membrane permeability. Ligand B (-0.163) is even lower, raising concerns about absorption. Both are below the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A (1 HBD, 5 HBA) is good. Ligand B (2 HBD, 4 HBA) is also acceptable.

**QED:** Both ligands have reasonable QED scores (0.83 and 0.515), indicating good drug-like properties.

**DILI:** Ligand A (24.78) has a significantly lower DILI risk than Ligand B (33.62), which is a substantial advantage.

**BBB:** Ligand A (72.66) has better predicted BBB penetration than Ligand B (69.87), although both are reasonably good.

**Caco-2 Permeability:** Ligand A (-4.688) has a worse Caco-2 permeability than Ligand B (-5.05), suggesting lower intestinal absorption.

**Aqueous Solubility:** Ligand A (-1.414) has better aqueous solubility than Ligand B (-2.147).

**hERG Inhibition:** Both ligands show very low hERG inhibition risk (0.409 and 0.033).

**Microsomal Clearance:** Ligand A (5.562) has a much lower microsomal clearance than Ligand B (-27.981), indicating better metabolic stability.

**In vitro Half-Life:** Ligand A (6.963) has a longer in vitro half-life than Ligand B (-22.532).

**P-gp Efflux:** Ligand A (0.025) has lower P-gp efflux liability than Ligand B (0.006), which is favorable for CNS exposure.

**Binding Affinity:** Both ligands have excellent binding affinities (-7.9 and -7.7 kcal/mol), with Ligand A being slightly stronger. The difference is less than the 1.5 kcal/mol threshold where affinity alone would dominate.

**Overall Assessment:**

Considering the GPCR-specific priorities, Ligand A is the better candidate. While its logP is suboptimal, its superior BBB penetration, significantly lower DILI risk, much better metabolic stability (lower Cl_mic and longer t1/2), and lower P-gp efflux outweigh the slightly lower Caco-2 permeability and marginally weaker binding affinity. The lower DILI and improved metabolic properties are crucial for developing a safe and effective drug.

Output:
1
2025-04-17 08:36:07,343 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (376.762 Da) is slightly higher than Ligand B (355.423 Da), but both are acceptable.

**TPSA:** Ligand A (64.21) is significantly better than Ligand B (92.79). For CNS targets, we want TPSA <= 90, so Ligand A is much more favorable.

**logP:** Both ligands have good logP values (A: 4.157, B: 3.375) within the optimal range of 1-3, but Ligand A is a bit high. This could potentially lead to off-target effects, but the high affinity might compensate.

**H-Bond Donors/Acceptors:** Ligand A (HBD=1, HBA=4) is preferable to Ligand B (HBD=2, HBA=6). Lower values are generally better for permeability.

**QED:** Both ligands have similar and acceptable QED values (A: 0.737, B: 0.732).

**DILI:** Ligand A (72.509) is better than Ligand B (92.982) regarding DILI risk, indicating a lower potential for liver injury.

**BBB:** This is a critical parameter for CNS targets. Ligand A (58.007) is significantly better than Ligand B (50.523), although neither exceeds the desirable >70 threshold.

**Caco-2 Permeability:** Ligand A (-4.608) is better than Ligand B (-5.073). Higher values indicate better intestinal absorption.

**Aqueous Solubility:** Ligand A (-4.645) is better than Ligand B (-4.734).

**hERG Inhibition:** Both ligands have low hERG inhibition risk (A: 0.606, B: 0.318), which is good.

**Microsomal Clearance:** Ligand B (40.624) has lower microsomal clearance than Ligand A (71.483), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand B (-2.392) has a longer in vitro half-life than Ligand A (6.394), which is desirable.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (A: 0.507, B: 0.241), which is good for CNS penetration.

**Binding Affinity:** Ligand B (-8.5 kcal/mol) has a slightly better binding affinity than Ligand A (-8.0 kcal/mol). While both are excellent, the 0.5 kcal/mol difference is noteworthy.

**Overall Assessment:**

Ligand A excels in TPSA, DILI, BBB, solubility and Caco-2 permeability, all crucial for CNS penetration and safety. However, its logP is slightly high and its metabolic stability (Cl_mic) is lower.

Ligand B has better metabolic stability and half-life, and slightly better affinity, but suffers from a higher TPSA, higher DILI risk, and lower BBB penetration.

Given the GPCR-specific priorities, particularly BBB and TPSA for CNS targets, **Ligand A is the more promising candidate**. The slightly better BBB and lower TPSA outweigh the slightly higher logP and lower metabolic stability, especially considering the already strong binding affinity.

Output:
1
2025-04-17 08:36:07,343 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (359.344 and 348.443 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (59.0) is significantly better than Ligand B (71.78). For CNS targets, we want TPSA <= 90, and A is closer to the optimal <=60 range. B is still within the acceptable range, but less favorable.

**logP:** Both ligands have acceptable logP values (1.876 and 2.552), falling within the 1-3 range.

**H-Bond Donors/Acceptors:** Both have 1 HBD and 4 HBA, which are within acceptable limits.

**QED:** Both have reasonable QED scores (0.895 and 0.769), indicating good drug-like properties.

**DILI:** Ligand A (38.077) has a lower DILI risk than Ligand B (43.079), which is preferable. Both are below the concerning threshold of 60.

**BBB:** This is a critical parameter for a CNS target like DRD2. Ligand A (81.698) has a significantly higher BBB penetration percentile than Ligand B (65.839). A value >70 is desirable, and A is closer.

**Caco-2 Permeability:** Both have negative Caco-2 values (-4.504 and -4.173) which is unusual and likely indicates a problem with the prediction method or the molecule itself. However, we can't rely on this data point.

**Aqueous Solubility:** Both have negative solubility values (-2.697 and -3.525) which is also unusual and likely indicates a problem with the prediction method or the molecule itself. We can't rely on this data point.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.766 and 0.686), which is good.

**Microsomal Clearance:** Ligand A (14.661) has a lower microsomal clearance than Ligand B (73.384), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (-7.455) has a much longer in vitro half-life than Ligand B (12.541). A negative value here is also unusual, but the *difference* is important.

**P-gp Efflux:** Ligand A (0.325) has lower P-gp efflux liability than Ligand B (0.282), which is favorable for CNS penetration.

**Binding Affinity:** Ligand B (-7.7) has a slightly better binding affinity than Ligand A (-8.6). However, the difference is relatively small (0.9 kcal/mol), and other factors are more important.

**Overall Assessment:**

Ligand A is the stronger candidate. While Ligand B has slightly better binding affinity, Ligand A excels in critical ADME properties for a CNS-targeting GPCR: significantly better BBB penetration, lower DILI risk, better metabolic stability (lower Cl_mic and longer t1/2), and lower P-gp efflux. The TPSA is also more favorable for CNS penetration. The unusual negative values for Caco-2 and solubility are concerning, but the overall profile of A is superior.

Output:
1
2025-04-17 08:36:07,343 - INFO - Batch 462 complete. Total preferences: 7392
2025-04-17 08:36:07,344 - INFO - Processing batch 463/512...
2025-04-17 08:36:49,636 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (396.49 Da) is slightly higher than Ligand B (348.443 Da), but both are acceptable.

**TPSA:** Both ligands have TPSA values below the 90 A^2 threshold desirable for CNS targets. Ligand A (89.26 A^2) is closer to the threshold than Ligand B (73.99 A^2), which is excellent.

**logP:** Both ligands have logP values within the optimal range (1-3). Ligand A (3.167) is at the higher end, while Ligand B (2.17) is closer to 2. Both are acceptable, but Ligand A's higher logP *could* potentially lead to off-target interactions.

**H-Bond Donors/Acceptors:** Ligand A has 2 HBD and 5 HBA, while Ligand B has 1 HBD and 4 HBA. Both are within the acceptable limits (<=5 HBD and <=10 HBA).

**QED:** Both ligands have good QED scores (Ligand A: 0.713, Ligand B: 0.819), indicating drug-like properties. Ligand B is slightly better here.

**DILI:** Ligand A has a significantly higher DILI risk (91.314%) than Ligand B (12.524%). This is a major concern for Ligand A.

**BBB:** Ligand A has a good BBB penetration score (70.609%), meeting the >70% threshold for CNS targets. Ligand B's BBB score (59.674%) is lower, which is a significant drawback for a CNS target.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values, which is unusual and suggests poor permeability. Ligand A (-5.242) is slightly better than Ligand B (-4.594), but both are concerning.

**Aqueous Solubility:** Both ligands have negative solubility values, indicating poor aqueous solubility. Ligand A (-3.736) is slightly worse than Ligand B (-1.145).

**hERG Inhibition:** Both ligands have low hERG inhibition liability (Ligand A: 0.604, Ligand B: 0.228), which is positive. Ligand B is better here.

**Microsomal Clearance:** Ligand A (17.668 mL/min/kg) has a lower clearance than Ligand B (25.493 mL/min/kg), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (42.102 hours) has a longer half-life than Ligand B (47.597 hours).

**P-gp Efflux:** Ligand A (0.387) has lower P-gp efflux than Ligand B (0.081), which is beneficial for CNS penetration.

**Binding Affinity:** Ligand B (-7.7 kcal/mol) has a significantly stronger binding affinity than Ligand A (-9.7 kcal/mol). This is a substantial advantage.

**Overall Assessment:**

Ligand B is the better candidate despite the lower BBB. The significantly stronger binding affinity (-7.7 vs -9.7 kcal/mol) is a major advantage, and the much lower DILI risk (12.524% vs 91.314%) is critical. While the BBB score is suboptimal, it is not a complete deal-breaker, and further optimization could potentially improve it. Ligand A's high DILI risk is a major red flag. The lower P-gp efflux for Ligand A is a minor benefit, but it's outweighed by the other factors.



Output:
1
2025-04-17 08:36:49,637 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (407.268 Da) is slightly higher than Ligand B (353.463 Da), but both are acceptable.

**2. TPSA:** Both ligands have TPSA values around 96, which is slightly above the optimal <90 for CNS targets, but still reasonable.

**3. logP:** Ligand A (2.836) is within the optimal range (1-3). Ligand B (0.729) is a bit low, potentially hindering membrane permeability.

**4. H-Bond Donors:** Both ligands have 3 HBD, which is within the acceptable limit of <=5.

**5. H-Bond Acceptors:** Both ligands have 4 HBA, which is within the acceptable limit of <=10.

**6. QED:** Both ligands have similar QED values (0.665 and 0.629), indicating good drug-likeness.

**7. DILI:** Ligand A (70.182) has a higher DILI risk than Ligand B (20.822). This is a significant drawback for Ligand A.

**8. BBB:** Ligand A (64.172) has a better BBB percentile than Ligand B (45.754). This is crucial for a CNS target like DRD2.

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 values, which is unusual and suggests poor permeability. However, the values are similar.

**10. Aqueous Solubility:** Both ligands have negative solubility values, indicating poor solubility. Again, the values are similar.

**11. hERG Inhibition:** Both ligands have very low hERG inhibition liability (0.474 and 0.116), which is excellent.

**12. Microsomal Clearance:** Ligand A (47.591) has a higher microsomal clearance than Ligand B (21.32), indicating lower metabolic stability.

**13. In vitro Half-Life:** Ligand A (9.417) has a longer half-life than Ligand B (5.135), which is favorable.

**14. P-gp Efflux:** Ligand A (0.223) has lower P-gp efflux than Ligand B (0.012), which is beneficial for CNS penetration.

**15. Binding Affinity:** Ligand A (-8.7 kcal/mol) has a slightly better binding affinity than Ligand B (-8.3 kcal/mol). This 0.4 kcal/mol difference is not huge, but is noticeable.

**Overall Assessment:**

Ligand A has a better binding affinity, BBB penetration, P-gp efflux, and half-life. However, it has a significantly higher DILI risk and higher microsomal clearance. Ligand B has a lower DILI risk and better metabolic stability, but its logP is low and BBB penetration is poor.

Given the importance of minimizing toxicity (DILI) and achieving CNS penetration for a DRD2 ligand, and the relatively small difference in binding affinity, **Ligand B is the more promising candidate**. The lower DILI risk and improved metabolic stability outweigh the slightly weaker affinity and lower BBB penetration, especially considering the potential for further optimization to improve these parameters.

Output:
1
2025-04-17 08:36:49,637 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (405.227 Da) is slightly higher, but acceptable. Ligand B (348.407 Da) is also good.

**TPSA:** Ligand A (64.28) is excellent for CNS penetration, well below the 90 A^2 threshold. Ligand B (109.22) is higher, but still potentially acceptable, though less ideal.

**logP:** Ligand A (3.691) is within the optimal range (1-3). Ligand B (-0.548) is significantly below 1, which is a concern for membrane permeability and CNS penetration.

**H-Bond Donors/Acceptors:** Ligand A (0 HBD, 6 HBA) is favorable. Ligand B (2 HBD, 6 HBA) is also acceptable.

**QED:** Both ligands have good QED values (A: 0.66, B: 0.742), indicating good drug-like properties.

**DILI:** Ligand A (90.733) has a high DILI risk, which is a significant concern. Ligand B (51.687) has a more acceptable DILI risk.

**BBB:** Ligand A (73.556) has a good BBB percentile, desirable for a CNS target. Ligand B (64.87) is lower, indicating reduced CNS penetration.

**Caco-2 Permeability:** Ligand A (-4.757) has poor Caco-2 permeability. Ligand B (-5.198) is also poor.

**Aqueous Solubility:** Both ligands have very poor aqueous solubility (A: -4.993, B: -2.494). This could pose formulation challenges.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (A: 0.522, B: 0.079).

**Microsomal Clearance:** Ligand A (78.615) has higher clearance, suggesting lower metabolic stability. Ligand B (16.155) has much lower clearance, indicating better metabolic stability.

**In vitro Half-Life:** Ligand A (-22.52) has a very short half-life. Ligand B (-4.132) is also short, but better than Ligand A.

**P-gp Efflux:** Both ligands show P-gp efflux (A: 0.335, B: 0.021), but Ligand B has significantly lower efflux, which is beneficial for CNS exposure.

**Binding Affinity:** Ligand B (-7.8 kcal/mol) has a significantly stronger binding affinity than Ligand A (-10.1 kcal/mol). This is a substantial advantage.

**Overall Assessment:**

Ligand B is the more promising candidate despite its lower BBB and solubility. The significantly improved binding affinity (-7.8 vs -10.1 kcal/mol) is a major advantage that can outweigh some of the ADME drawbacks. The lower DILI risk and P-gp efflux, coupled with better metabolic stability (lower Cl_mic) are also favorable. While the logP is suboptimal, the strong binding affinity might compensate. Ligand A's high DILI risk and poor Caco-2 permeability are major drawbacks.

Output:
1
2025-04-17 08:36:49,637 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (379.429 Da) is slightly higher than Ligand B (350.415 Da), but both are acceptable.

**TPSA:** Ligand A (100.55) is higher than Ligand B (79.31). For CNS targets, we ideally want TPSA <= 90. Ligand B is better here.

**logP:** Ligand A (1.524) is within the optimal range (1-3). Ligand B (-0.374) is slightly below 1, which *could* indicate permeability issues, though not severely. Ligand A is preferred.

**H-Bond Donors/Acceptors:** Ligand A has 3 HBD and 6 HBA, while Ligand B has 1 HBD and 5 HBA. Both are within acceptable limits (<=5 HBD and <=10 HBA).

**QED:** Both ligands have similar QED values (0.535 and 0.54), indicating good drug-likeness.

**DILI:** Ligand A (67.158) has a higher DILI risk than Ligand B (25.087). This is a significant advantage for Ligand B.

**BBB:** Ligand B (55.099) has a considerably better BBB penetration percentile than Ligand A (38.193). This is *critical* for a CNS target like DRD2.

**Caco-2 Permeability:** Ligand A (-5.279) has a negative Caco-2 value, which is concerning. Ligand B (-4.511) is also negative, but less so. Both suggest poor intestinal absorption, but A is worse.

**Aqueous Solubility:** Both ligands have negative solubility values (-2.293 and -1.721). This is a weakness for both, but not a dealbreaker if other properties are favorable.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.289 and 0.294).

**Microsomal Clearance:** Ligand B (-5.286) has a negative clearance, which is excellent (indicates very slow clearance/high metabolic stability). Ligand A (20.722) has a positive value, indicating faster clearance.

**In vitro Half-Life:** Ligand B (-5.189) has a negative half-life, which is excellent. Ligand A (-9.532) is also negative, but less so.

**P-gp Efflux:** Both ligands have similar P-gp efflux liability (0.145 and 0.075), indicating relatively low efflux.

**Binding Affinity:** Ligand A (-7.2 kcal/mol) has a slightly better binding affinity than Ligand B (-6.7 kcal/mol). While a 0.5 kcal/mol difference is not huge, it's a positive for Ligand A.

**Overall Assessment:**

Ligand B is clearly superior due to its significantly better BBB penetration (55.099 vs 38.193), lower DILI risk (25.087 vs 67.158), and much better metabolic stability (negative Cl_mic and t1/2). While Ligand A has a slightly better binding affinity and logP, the ADME properties of Ligand B are far more favorable for a CNS-targeting drug. The negative Caco-2 values for both are a concern, but can be addressed with formulation strategies.



Output:
1
2025-04-17 08:36:49,637 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (364.471 and 353.373 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (84.3) is better than Ligand B (77.05). Both are below the 90 A^2 threshold desirable for CNS targets.

**logP:** Ligand B (2.963) is closer to the optimal 1-3 range than Ligand A (1.221). While A is still acceptable, B's logP suggests better membrane permeability.

**H-Bond Donors:** Ligand A (1) is better than Ligand B (0). Lower HBD is generally preferred for BBB penetration.

**H-Bond Acceptors:** Ligand A (5) is better than Ligand B (6). Both are within the acceptable limit of 10.

**QED:** Ligand A (0.884) has a significantly better QED score than Ligand B (0.729), indicating a more drug-like profile.

**DILI:** Ligand B (44.63) has a lower DILI risk than Ligand A (55.68), which is favorable.

**BBB:** Ligand B (94.727) has a much higher BBB penetration percentile than Ligand A (75.339). This is a *critical* advantage for a CNS target like DRD2.

**Caco-2 Permeability:** Ligand A (-4.867) has better Caco-2 permeability than Ligand B (-4.42).

**Aqueous Solubility:** Ligand A (-2.247) has better aqueous solubility than Ligand B (-3.852).

**hERG Inhibition:** Ligand B (0.391) has a lower hERG inhibition liability than Ligand A (0.654), which is a safety advantage.

**Microsomal Clearance:** Ligand A (30.736) has lower microsomal clearance than Ligand B (53.969), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (-26.206) has a significantly longer in vitro half-life than Ligand B (-2.098), which is desirable.

**P-gp Efflux:** Ligand A (0.101) has lower P-gp efflux liability than Ligand B (0.183), which is favorable for CNS exposure.

**Binding Affinity:** Ligand A (-8.9 kcal/mol) has a stronger binding affinity than Ligand B (-7.4 kcal/mol). This is a substantial difference (1.5 kcal/mol), and a strong affinity can often outweigh minor ADME concerns.

**Overall Assessment:**

Ligand B excels in BBB penetration and has a lower DILI and hERG risk. However, Ligand A has a significantly better binding affinity, QED, metabolic stability, half-life, and P-gp efflux. The strong binding affinity of Ligand A, combined with acceptable ADME properties, makes it the more promising candidate despite the slightly higher DILI and hERG risk. The substantial difference in binding affinity is a key factor, and the other parameters are within reasonable ranges.

Output:
1
2025-04-17 08:36:49,638 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (372.491 and 366.571 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (102.32) is higher than the preferred <90 for CNS targets, while Ligand B (53.43) is well within the range. This favors Ligand B.

**logP:** Ligand A (0.663) is a bit low, potentially hindering permeation. Ligand B (4.661) is slightly high, potentially causing solubility issues or off-target effects, but is closer to the optimal 1-3 range than Ligand A.

**H-Bond Donors/Acceptors:** Ligand A has 2 HBD and 6 HBA, while Ligand B has 1 HBD and 4 HBA. Both are within acceptable limits (<=5 HBD and <=10 HBA).

**QED:** Both ligands have similar QED values (0.663 and 0.647), indicating good drug-likeness.

**DILI:** Ligand A (54.944) has a higher DILI risk than Ligand B (24.467). This favors Ligand B.

**BBB:** Ligand B (80.807) has a significantly higher BBB penetration percentile than Ligand A (57.193). This is a crucial advantage for a CNS target like DRD2.

**Caco-2 Permeability:** Ligand A (-5.075) shows poor Caco-2 permeability, while Ligand B (-4.609) is slightly better, but still low.

**Aqueous Solubility:** Ligand A (-1.869) has better aqueous solubility than Ligand B (-4.229).

**hERG Inhibition:** Ligand A (0.318) has a lower hERG inhibition risk than Ligand B (0.859).

**Microsomal Clearance:** Ligand B (96.632) has a much higher microsomal clearance than Ligand A (43.03), indicating lower metabolic stability. This favors Ligand A.

**In vitro Half-Life:** Ligand A (-35.317) has a much shorter in vitro half-life than Ligand B (15.571). This favors Ligand B.

**P-gp Efflux:** Ligand A (0.059) shows lower P-gp efflux liability than Ligand B (0.952). This is a significant advantage for CNS penetration, favoring Ligand A.

**Binding Affinity:** Ligand A (-7.5 kcal/mol) has a slightly better binding affinity than Ligand B (-7.3 kcal/mol), although the difference is small.

**Overall Assessment:**

Ligand B excels in BBB penetration and has a lower DILI risk. However, it suffers from higher P-gp efflux and higher microsomal clearance. Ligand A has better P-gp efflux, lower DILI, and better binding affinity, but its TPSA is higher and its BBB penetration is lower. Considering the importance of BBB penetration for a CNS target like DRD2, and the relatively small difference in binding affinity, Ligand B is the more promising candidate. The slightly higher logP is a concern, but the strong BBB score and lower DILI risk outweigh this.

Output:
1
2025-04-17 08:36:49,638 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (367.877 and 349.479 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (82.53) is better than Ligand B (61.68) as it is closer to the <90 A^2 threshold for CNS targets.

**3. logP:** Ligand A (2.399) is optimal (1-3), while Ligand B (0.61) is slightly low, potentially hindering permeation.

**4. H-Bond Donors:** Ligand A (2) is acceptable, while Ligand B (0) is also good.

**5. H-Bond Acceptors:** Ligand A (4) is acceptable, while Ligand B (5) is also good.

**6. QED:** Both ligands have good QED values (0.656 and 0.724, respectively), indicating drug-like properties.

**7. DILI:** Ligand A (43.738) has a slightly higher DILI risk than Ligand B (16.44), but both are below the concerning threshold of 60.

**8. BBB:** Both ligands have similar BBB penetration (60.644 and 59.209), which is not ideal (>70 desirable), but acceptable given the binding affinity.

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 permeability values, which is unusual and suggests a potential issue with the data or modeling. However, we will proceed with the assumption that these values represent low permeability.

**10. Aqueous Solubility:** Both ligands have negative solubility values, which is also unusual.

**11. hERG Inhibition:** Both ligands show very low hERG inhibition liability (0.341 and 0.239), which is excellent.

**12. Microsomal Clearance:** Ligand B (3.574) has significantly lower microsomal clearance than Ligand A (45.957), indicating better metabolic stability.

**13. In vitro Half-Life:** Ligand A (57.632) has a longer half-life than Ligand B (3.843), which is generally desirable.

**14. P-gp Efflux:** Ligand A (0.151) has lower P-gp efflux than Ligand B (0.018), which is better for CNS exposure.

**15. Binding Affinity:** Ligand A (-7.8 kcal/mol) has a slightly stronger binding affinity than Ligand B (-7.5 kcal/mol). This 0.3 kcal/mol difference, while not huge, is a factor.

**Overall Assessment:**

Ligand A has a better logP and TPSA, and a slightly better binding affinity. However, Ligand B has significantly better metabolic stability (lower Cl_mic) and lower DILI risk. Both have suboptimal BBB penetration and permeability. Given the GPCR-specific priorities, the slightly better affinity and TPSA of Ligand A, combined with acceptable BBB and P-gp efflux, make it a marginally more promising candidate despite the higher Cl_mic. The difference in binding affinity is not large enough to completely outweigh the metabolic stability advantage of Ligand B.

Output:
1
2025-04-17 08:36:49,638 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (347.365 and 342.443 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (61.44) is significantly better than Ligand B (97.11). For CNS targets, we want TPSA <= 90, so Ligand A is preferable.

**3. logP:** Both ligands have good logP values (3.63 and 2.118, respectively) falling within the optimal 1-3 range.

**4. H-Bond Donors:** Ligand A (2) and Ligand B (3) are both acceptable, being less than 5.

**5. H-Bond Acceptors:** Ligand A (2) and Ligand B (4) are both acceptable, being less than 10.

**6. QED:** Both ligands have similar QED values (0.868 and 0.661), indicating good drug-like properties.

**7. DILI:** Ligand A (75.921) has a higher DILI risk than Ligand B (46.297). This favors Ligand B.

**8. BBB:** Both ligands have excellent BBB penetration (78.054 and 73.905, respectively). Both are above the desirable 70% threshold.

**9. Caco-2 Permeability:** Ligand A (-4.322) has a worse Caco-2 permeability than Ligand B (-5.248). Lower values are less desirable.

**10. Aqueous Solubility:** Ligand A (-4.501) has worse aqueous solubility than Ligand B (-2.772). Lower values are less desirable.

**11. hERG Inhibition:** Ligand A (0.623) has a slightly higher hERG inhibition risk than Ligand B (0.144). Lower is better, favoring Ligand B.

**12. Microsomal Clearance:** Ligand A (69.552) has a higher microsomal clearance than Ligand B (15.6). Lower clearance indicates better metabolic stability, favoring Ligand B.

**13. In vitro Half-Life:** Ligand A (49.186) has a better in vitro half-life than Ligand B (-11.919). Longer half-life is preferable, favoring Ligand A.

**14. P-gp Efflux:** Ligand A (0.192) has lower P-gp efflux than Ligand B (0.031). Lower efflux is better, favoring Ligand A.

**15. Binding Affinity:** Ligand A (-9.5 kcal/mol) has a significantly stronger binding affinity than Ligand B (-8.4 kcal/mol). This is a substantial advantage (1.1 kcal/mol difference).

**Overall Assessment:**

While Ligand B has advantages in terms of DILI, hERG, clearance, and solubility, Ligand A's significantly superior binding affinity (-9.5 vs -8.4 kcal/mol) and better TPSA, P-gp efflux, and half-life outweigh these drawbacks, especially for a GPCR target like DRD2 where strong binding is crucial. The TPSA of Ligand A is also more favorable for CNS penetration. The difference in binding affinity is large enough to potentially overcome the slightly higher DILI and hERG risks, which can be further investigated and potentially mitigated through structural modifications.

Output:
1
2025-04-17 08:36:49,638 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (381.929 Da) is slightly higher than Ligand B (347.419 Da), but both are acceptable.

**2. TPSA:** Ligand A (62.3) is excellent, falling well below the 90 A^2 threshold for CNS targets. Ligand B (104.12) is higher, but still potentially acceptable, though less ideal.

**3. logP:** Ligand A (3.347) is optimal. Ligand B (1.617) is on the lower side of optimal, potentially hindering permeability.

**4. H-Bond Donors:** Ligand A (1) is good. Ligand B (2) is also acceptable.

**5. H-Bond Acceptors:** Ligand A (4) is good. Ligand B (5) is also acceptable.

**6. QED:** Both ligands have good QED scores (Ligand A: 0.582, Ligand B: 0.755), indicating drug-like properties. Ligand B is slightly better.

**7. DILI:** Both have acceptable DILI risk (Ligand A: 41.838, Ligand B: 45.522), below the 60 threshold.

**8. BBB:** This is a critical parameter for a CNS target like DRD2. Ligand A (67.158) is reasonably good, but Ligand B (23.032) is poor, suggesting limited brain penetration.

**9. Caco-2 Permeability:** Ligand A (-4.742) is poor, while Ligand B (-5.694) is even worse. Both are very low, indicating poor intestinal absorption.

**10. Aqueous Solubility:** Ligand A (-3.776) is poor, while Ligand B (-1.664) is also poor.

**11. hERG Inhibition:** Both have very low hERG inhibition risk (Ligand A: 0.542, Ligand B: 0.08).

**12. Microsomal Clearance:** Ligand A (36.094) is moderate, while Ligand B (15.835) is lower, indicating better metabolic stability.

**13. In vitro Half-Life:** Ligand A (11.024) is moderate, while Ligand B (25.042) is better, suggesting a longer half-life.

**14. P-gp Efflux:** Ligand A (0.448) is good, indicating low efflux. Ligand B (0.016) is excellent, suggesting very low efflux.

**15. Binding Affinity:** Both have excellent binding affinity (Ligand A: -8.1 kcal/mol, Ligand B: -8.3 kcal/mol). Ligand B is slightly better, but the difference is small.

**Overall Assessment:**

While Ligand B has slightly better QED, metabolic stability, half-life, and P-gp efflux, the critical difference lies in BBB penetration. Ligand A's BBB percentile (67.158) is significantly higher than Ligand B's (23.032). For a CNS target like DRD2, this is paramount. The slightly lower logP of Ligand B is also a concern. Although both have poor Caco-2 and solubility, the BBB is the deciding factor.

Output:
0
2025-04-17 08:36:49,639 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (350.503 and 343.471 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (67.43) is slightly higher than Ligand B (62.3). Both are below the 90 A^2 threshold desirable for CNS targets, but Ligand B is preferable.

**3. logP:** Both ligands have excellent logP values (2.664 and 2.584) within the optimal 1-3 range.

**4. H-Bond Donors:** Ligand A has 2 HBD, and Ligand B has 1. Both are within the acceptable limit of <=5. Ligand B is slightly better.

**5. H-Bond Acceptors:** Both ligands have 3 HBA, well within the acceptable limit of <=10.

**6. QED:** Both ligands have good QED scores (0.724 and 0.863), indicating good drug-like properties. Ligand B is slightly better.

**7. DILI:** Ligand A (14.889) has a lower DILI risk than Ligand B (20.706), which is a significant advantage.

**8. BBB:** Ligand A (80.69) has a higher BBB percentile than Ligand B (74.176). This is crucial for a CNS target like DRD2, making Ligand A more promising.

**9. Caco-2 Permeability:** Ligand A (-4.578) has better Caco-2 permeability than Ligand B (-4.94), suggesting better intestinal absorption.

**10. Aqueous Solubility:** Ligand A (-3.448) has better aqueous solubility than Ligand B (-1.723).

**11. hERG:** Both ligands have similar, low hERG inhibition liability (0.34 and 0.39).

**12. Microsomal Clearance:** Ligand A (79.819) has a higher microsomal clearance than Ligand B (18.796), indicating faster metabolism and potentially lower *in vivo* exposure. Ligand B is preferable.

**13. In vitro Half-Life:** Ligand B (-16.736) has a significantly longer in vitro half-life than Ligand A (-4.858), which is a major advantage.

**14. P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.016 and 0.093).

**15. Binding Affinity:** Ligand B (-8.6) has a slightly better binding affinity than Ligand A (-8.2). While the difference is small, it's still a positive for Ligand B.

**Overall Assessment:**

Ligand A excels in BBB penetration, DILI risk, solubility and Caco-2 permeability. However, Ligand B has a significantly longer half-life and slightly better binding affinity, as well as lower microsomal clearance. Given the importance of metabolic stability and potency for GPCR ligands, and the relatively small difference in binding affinity, the longer half-life of Ligand B is a key advantage. The slightly better BBB of Ligand A is outweighed by the metabolic concerns.

Output:
1
2025-04-17 08:36:49,639 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (373.519 Da) is slightly higher than Ligand B (345.418 Da), but both are acceptable.

**TPSA:** Both ligands have TPSA values below 90, which is good for CNS penetration. Ligand A (70.16) is slightly higher than Ligand B (61.44), but both are favorable.

**logP:** Ligand A (0.083) is quite low, potentially hindering membrane permeability. Ligand B (2.147) is within the optimal range (1-3). This is a significant advantage for Ligand B.

**H-Bond Donors/Acceptors:** Ligand A has 0 HBD and 5 HBA, which is acceptable. Ligand B has 2 HBD and 3 HBA, also acceptable.

**QED:** Both ligands have QED values above 0.5 (Ligand A: 0.617, Ligand B: 0.588), indicating good drug-like properties.

**DILI:** Ligand A (19.271) has a lower DILI risk than Ligand B (39.434), which is a positive attribute.

**BBB:** Both ligands have excellent BBB penetration (Ligand A: 70.88, Ligand B: 70.105), satisfying the key requirement for CNS targets.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values, which is unusual and suggests potential issues with intestinal absorption. However, given the focus on BBB penetration for DRD2, this is less critical.

**Aqueous Solubility:** Both ligands have negative solubility values, which is also unusual. This could present formulation challenges.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (Ligand A: 0.666, Ligand B: 0.747).

**Microsomal Clearance:** Ligand A (27.582) has higher microsomal clearance than Ligand B (18.237), suggesting lower metabolic stability.

**In vitro Half-Life:** Ligand B (-3.77) has a slightly better (less negative) in vitro half-life than Ligand A (-24.303).

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (Ligand A: 0.025, Ligand B: 0.133), which is favorable for CNS penetration.

**Binding Affinity:** Ligand A (-8.1 kcal/mol) has a significantly stronger binding affinity than Ligand B (-6.9 kcal/mol). This is a substantial advantage, potentially outweighing some of the ADME drawbacks.

**Conclusion:**

While Ligand A has a superior binding affinity, Ligand B has a much more favorable logP value, which is crucial for permeability and CNS exposure. The low logP of Ligand A is a significant concern. Although both have unusual solubility and Caco-2 values, the BBB values are acceptable. Considering the GPCR-specific priorities, the better logP and slightly improved metabolic stability of Ligand B, combined with acceptable affinity, make it the more promising candidate despite the affinity difference.

Output:
1
2025-04-17 08:36:49,639 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B based on the provided guidelines, prioritizing GPCR-specific properties (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (367.391 and 353.403 Da) fall within the ideal range of 200-500 Da.

**TPSA:** Ligand A (127.36) is borderline for CNS targets, slightly above the preferred <90, but acceptable. Ligand B (68.46) is excellent, well below the 90 threshold.

**logP:** Ligand A (-0.243) is quite low, potentially hindering permeability. Ligand B (3.861) is within the optimal range of 1-3. This is a significant advantage for Ligand B.

**H-Bond Donors/Acceptors:** Ligand A (0 HBD, 9 HBA) and Ligand B (0 HBD, 7 HBA) both have reasonable H-bond characteristics, within the guidelines.

**QED:** Both ligands have similar QED scores (0.523 and 0.519), indicating good drug-likeness.

**DILI:** Ligand A (87.204) has a moderate DILI risk, while Ligand B (96.316) has a higher risk.

**BBB:** Ligand A (54.634) has a moderate BBB penetration, which is concerning for a CNS target. Ligand B (87.088) exhibits excellent BBB penetration, a major advantage.

**Caco-2 Permeability:** Both have negative Caco-2 values (-5.193 and -4.878), which is unusual and suggests poor permeability. However, these values are on a log scale, and negative values are not directly interpretable without knowing the base of the log. We'll consider this a neutral point for now.

**Aqueous Solubility:** Both have negative solubility values (-2.296 and -5.291), also unusual and suggesting poor solubility. Similar to Caco-2, we'll consider this a neutral point.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.24 and 0.492).

**Microsomal Clearance:** Ligand A (2.509) has lower clearance, suggesting better metabolic stability than Ligand B (113.72).

**In vitro Half-Life:** Ligand A (-23.299) has a negative half-life, which is not physically possible. This is a major red flag. Ligand B (32.963) has a reasonable half-life.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.036 and 0.632).

**Binding Affinity:** Ligand B (-9.8 kcal/mol) has a significantly stronger binding affinity than Ligand A (-7.1 kcal/mol). This >1.5 kcal/mol difference is substantial and can outweigh some ADME drawbacks.

**Overall Assessment:**

Ligand B is the stronger candidate. While its DILI risk is higher, its superior logP, BBB penetration, and *much* stronger binding affinity are critical for a CNS-targeting GPCR ligand. The negative half-life for Ligand A is a fatal flaw. The lower metabolic clearance of Ligand A is a positive, but doesn't compensate for the other issues.

Output:
1
2025-04-17 08:36:49,639 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (390.452) is slightly higher than Ligand B (352.345), but both are acceptable.

**TPSA:** Ligand A (51.22) is much better than Ligand B (96.17). For CNS targets, we want TPSA <= 90, so Ligand A is preferable.

**logP:** Ligand A (4.741) is a bit high, potentially leading to solubility issues and off-target effects. Ligand B (1.588) is good, falling within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A (HBD=1, HBA=5) is better than Ligand B (HBD=2, HBA=6). Both are within acceptable limits, but fewer H-bonds generally improve permeability.

**QED:** Both ligands have good QED values (A: 0.742, B: 0.871), indicating good drug-like properties.

**DILI:** Ligand A (76.425) has a higher DILI risk than Ligand B (58.976), indicating a greater potential for liver injury.

**BBB:** Ligand A (68.864) has a better BBB penetration percentile than Ligand B (48.74). This is *critical* for a CNS target like DRD2.

**Caco-2 Permeability:** Ligand A (-4.795) and Ligand B (-4.807) have similar, very poor Caco-2 permeability.

**Aqueous Solubility:** Ligand A (-4.991) and Ligand B (-2.064) have poor aqueous solubility. Ligand B is slightly better.

**hERG Inhibition:** Both ligands have very low hERG inhibition risk (A: 0.462, B: 0.225).

**Microsomal Clearance:** Ligand A (81.192) has a higher microsomal clearance than Ligand B (-7.174). This suggests Ligand B is more metabolically stable.

**In vitro Half-Life:** Ligand B (-3.628) has a much better in vitro half-life than Ligand A (-15.358).

**P-gp Efflux:** Ligand A (0.572) has better P-gp efflux profile than Ligand B (0.023). Lower P-gp efflux is desirable for CNS penetration.

**Binding Affinity:** Ligand B (-9.0 kcal/mol) has a significantly stronger binding affinity than Ligand A (-7.9 kcal/mol). This is a substantial advantage.

**Overall Assessment:**

While Ligand A has better BBB penetration and P-gp efflux, Ligand B excels in several key areas: significantly stronger binding affinity, better metabolic stability (lower Cl_mic, longer t1/2), lower DILI risk, and a more favorable logP. The large difference in binding affinity (-1.1 kcal/mol) is likely to outweigh the drawbacks of its slightly lower BBB and higher TPSA. The poor Caco-2 and solubility are concerns for both, but less critical for a CNS target where direct oral bioavailability isn't always essential.

Output:
1
2025-04-17 08:36:49,640 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (376.283 Da) is slightly higher than Ligand B (347.427 Da), but both are acceptable.

**TPSA:** Ligand A (52.49) is significantly better than Ligand B (130.04). For CNS targets, we want TPSA <= 90, and A is well within this range, while B is considerably above. This is a major advantage for A.

**logP:** Ligand A (4.462) is higher than the optimal range (1-3) but not drastically so. Ligand B (-0.067) is quite low, potentially hindering permeability. A's higher logP is preferable here, despite being slightly elevated.

**H-Bond Donors/Acceptors:** Ligand A (HBD=3, HBA=3) and Ligand B (HBD=4, HBA=10) are both reasonable, but Ligand B has a higher number of HBA which could impact permeability.

**QED:** Ligand A (0.595) is better than Ligand B (0.466), indicating a more drug-like profile.

**DILI:** Both ligands have similar, acceptable DILI risk (A: 48.623, B: 47.305).

**BBB:** Ligand A (37.34) and Ligand B (39.162) are both low, and not ideal for a CNS target. However, BBB prediction can be unreliable, and a lower BBB doesn't automatically disqualify a compound if other properties are strong.

**Caco-2 Permeability:** Both are negative, indicating poor permeability. This is a concern for both compounds.

**Aqueous Solubility:** Both are negative, indicating poor solubility. This is a concern for both compounds.

**hERG Inhibition:** Ligand A (0.92) is better than Ligand B (0.471), indicating lower cardiotoxicity risk.

**Microsomal Clearance:** Ligand A (12.141) is higher than Ligand B (3.775), meaning faster clearance and lower metabolic stability. This favors Ligand B.

**In vitro Half-Life:** Ligand A (140.185) is much better than Ligand B (1.891), indicating a longer half-life.

**P-gp Efflux:** Ligand A (0.673) is better than Ligand B (0.002), suggesting lower P-gp efflux and better CNS exposure.

**Binding Affinity:** Ligand A (-9.1 kcal/mol) has significantly stronger binding affinity than Ligand B (-6.7 kcal/mol). This is a substantial advantage for A, potentially outweighing some of its ADME drawbacks.

**Overall Assessment:**

Ligand A is the stronger candidate. Its superior TPSA, QED, hERG, P-gp efflux, and *especially* its significantly higher binding affinity outweigh its slightly higher logP and faster clearance. Ligand B's low logP and high TPSA are significant drawbacks for a CNS-targeting GPCR ligand. While both have poor Caco-2 and solubility, the strong binding affinity of A offers a greater opportunity for optimization to address these issues.



Output:
1
2025-04-17 08:36:49,640 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (342.439 and 349.479 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (70.59) is higher than Ligand B (61.68). For a CNS target like DRD2, we ideally want TPSA <= 90, so both are acceptable, but B is preferable.

**3. logP:** Ligand A (4.324) is significantly higher than Ligand B (1.133). While 1-3 is optimal, A is pushing the upper limit and could lead to solubility issues or off-target interactions. B is well within the optimal range.

**4. H-Bond Donors:** Ligand A (3) is acceptable, while Ligand B (0) is also good.

**5. H-Bond Acceptors:** Ligand A (3) and Ligand B (5) are both within the acceptable limit of <=10.

**6. QED:** Both ligands have good QED values (0.669 and 0.8), indicating drug-like properties.

**7. DILI:** Ligand A (55.68) has a higher DILI risk than Ligand B (21.869). B is significantly better here.

**8. BBB:** Ligand B (70.997) has a much better BBB penetration percentile than Ligand A (36.177). This is *critical* for a CNS target like DRD2.

**9. Caco-2 Permeability:** Ligand A (-5.129) has poor Caco-2 permeability, while Ligand B (-4.79) is also poor, but slightly better.

**10. Aqueous Solubility:** Ligand A (-4.724) has poor aqueous solubility, and Ligand B (0.17) is also poor, but better.

**11. hERG Inhibition:** Ligand A (0.745) has a slightly higher hERG inhibition risk than Ligand B (0.647), but both are relatively low.

**12. Microsomal Clearance:** Ligand A (87.522) has a higher microsomal clearance than Ligand B (20.056), indicating lower metabolic stability. B is significantly better.

**13. In vitro Half-Life:** Ligand A (27.352) has a longer half-life than Ligand B (13.958). This is a positive for A.

**14. P-gp Efflux:** Ligand A (0.389) has higher P-gp efflux than Ligand B (0.059). This is a negative for A, as it will reduce CNS exposure. B is much better.

**15. Binding Affinity:** Ligand A (-8.9 kcal/mol) has a *much* stronger binding affinity than Ligand B (-0.0 kcal/mol). This is a significant advantage for A, potentially outweighing some of its ADME drawbacks.

**Overall Assessment:**

While Ligand A has a superior binding affinity, its significantly worse ADME profile, particularly the poor BBB penetration, high DILI risk, high P-gp efflux, and high microsomal clearance, are major concerns. Ligand B, despite its weaker affinity, has a much more favorable ADME profile, including excellent BBB penetration, low DILI risk, and low P-gp efflux. For a CNS target like DRD2, achieving sufficient brain exposure is paramount. The substantial difference in BBB penetration and other ADME properties makes Ligand B the more promising candidate, even with the lower binding affinity. It's more likely to reach the target in the brain.

Output:
1
2025-04-17 08:36:49,640 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (345.4 and 348.4 Da) fall comfortably within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (87.74) is excellent, falling well below the 90 A^2 threshold for CNS targets. Ligand B (99.23) is still reasonable, but closer to the 140 A^2 limit for oral absorption and slightly less desirable for CNS penetration.

**3. logP:** Ligand A (0.695) is a bit low, potentially hindering permeability. Ligand B (1.805) is better, falling within the optimal 1-3 range.

**4. H-Bond Donors:** Ligand A (2) and Ligand B (1) are both acceptable, well below the 5 limit.

**5. H-Bond Acceptors:** Ligand A (4) and Ligand B (5) are both acceptable, below the 10 limit.

**6. QED:** Both ligands have good QED scores (0.789 and 0.875), indicating good drug-like properties.

**7. DILI:** Both ligands have similar, acceptable DILI risk (53.3% and 52.9%), both below the 60% threshold.

**8. BBB:** Ligand A (78.2%) is good, but Ligand B (87.1%) is significantly better, exceeding the desirable >70% threshold for CNS targets. This is a major advantage for Ligand B.

**9. Caco-2 Permeability:** Ligand A (-4.619) and Ligand B (-4.554) are similar and indicate poor permeability.

**10. Aqueous Solubility:** Both ligands have very poor aqueous solubility (-2.145 and -3.515). This is a significant drawback for both.

**11. hERG Inhibition:** Ligand A (0.109) shows very low hERG inhibition risk, which is excellent. Ligand B (0.394) is slightly higher, but still relatively low risk.

**12. Microsomal Clearance:** Ligand A (-5.936) has a very low (and therefore good) microsomal clearance, suggesting high metabolic stability. Ligand B (29.873) has a much higher clearance, indicating faster metabolism and potentially lower *in vivo* exposure.

**13. In vitro Half-Life:** Ligand A (-4.65) has a very short half-life, while Ligand B (-38.491) has a longer half-life.

**14. P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.012 and 0.099), which is favorable for CNS penetration.

**15. Binding Affinity:** Both ligands have excellent binding affinities (-8.6 and -8.2 kcal/mol), well below the -7.0 kcal/mol threshold. The difference of 0.4 kcal/mol is not substantial enough to outweigh other factors.

**Overall Assessment:**

While both ligands have good potency, Ligand B is superior due to its significantly better BBB penetration (87.1% vs 78.2%), longer in vitro half-life, and more favorable logP. Ligand A has better metabolic stability and lower hERG risk, but the BBB and half-life advantages of Ligand B are more critical for a CNS-targeting GPCR like DRD2. The poor solubility of both is a concern that would need to be addressed during formulation.

Output:
1
2025-04-17 08:36:49,640 - INFO - Batch 463 complete. Total preferences: 7408
2025-04-17 08:36:49,640 - INFO - Processing batch 464/512...
2025-04-17 08:37:30,921 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B based on the provided guidelines, prioritizing GPCR-specific properties (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (340.343 and 354.407 Da) fall within the ideal range of 200-500 Da.

**TPSA:** Ligand A (121.93) is slightly above the optimal <90 for CNS targets, but still reasonable. Ligand B (108.13) is better, falling comfortably below 90.

**logP:** Ligand A (0.441) is quite low, potentially hindering permeability. Ligand B (-1.608) is even lower, raising concerns about absorption. Both are below the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Both ligands have 2 HBD and 7 HBA, which are within acceptable limits.

**QED:** Both ligands have reasonable QED scores (0.736 and 0.582), indicating drug-like properties.

**DILI:** Ligand A (78.247) has a higher DILI risk than Ligand B (21.598). This is a significant advantage for Ligand B.

**BBB:** Ligand A (48.391) has a low BBB penetration percentile, which is a major drawback for a CNS target like DRD2. Ligand B (21.326) is also low, but slightly better than A. Both are far from the desirable >70.

**Caco-2 Permeability:** Ligand A (-5.334) and Ligand B (-5.081) both have negative Caco-2 values, suggesting poor intestinal absorption.

**Aqueous Solubility:** Ligand A (-3.879) and Ligand B (0.465) have poor solubility.

**hERG:** Both ligands have very low hERG inhibition liability (0.125 and 0.057), which is good.

**Microsomal Clearance:** Ligand A (-16.441) has a lower (better) microsomal clearance than Ligand B (-13.269), indicating greater metabolic stability.

**In vitro Half-Life:** Ligand A (20.297) has a significantly longer half-life than Ligand B (8.882), which is a positive attribute.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.029 and 0.01), which is favorable for CNS penetration.

**Binding Affinity:** Ligand B (-7.1 kcal/mol) has a slightly better binding affinity than Ligand A (-8.4 kcal/mol). While A is better, the difference is not substantial enough to overcome the other significant issues.

**Overall Assessment:**

Despite Ligand A having a slightly better binding affinity and metabolic stability, its very low BBB penetration and low logP are major concerns for a CNS-targeting drug. Ligand B, while also having a low logP and BBB, exhibits a significantly lower DILI risk, which is crucial. Considering the GPCR-specific priorities, the lower DILI risk of Ligand B, combined with a reasonable affinity, makes it the more promising candidate, even with its limitations.

Output:
1
2025-04-17 08:37:30,921 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (345.4 and 357.3 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (82.97) is significantly better than Ligand B (103.79). For CNS targets, we want TPSA <= 90, so Ligand A is preferable.

**3. logP:** Ligand B (1.426) is better than Ligand A (0.528). Optimal logP is 1-3, and A is a bit low, potentially hindering permeability.

**4. H-Bond Donors:** Ligand A (1) is better than Ligand B (3). Lower HBDs are generally preferred for better permeability.

**5. H-Bond Acceptors:** Both ligands have 5 HBA, which is acceptable (<=10).

**6. QED:** Ligand A (0.861) has a better QED than Ligand B (0.651), indicating a more drug-like profile.

**7. DILI:** Ligand B (72.8%) has a higher DILI risk than Ligand A (35.1%). Lower DILI is preferred.

**8. BBB:** Ligand A (61.7%) is better than Ligand B (47.2%), although both are below the desirable >70% for CNS targets. However, A is closer.

**9. Caco-2:** Both ligands have negative Caco-2 values, which is unusual and difficult to interpret without knowing the scale. We'll proceed cautiously, assuming these indicate poor permeability.

**10. Solubility:** Both ligands have negative solubility values, again unusual. We'll assume this indicates poor solubility.

**11. hERG:** Both ligands have very low hERG inhibition liability (0.163 and 0.131), which is excellent.

**12. Cl_mic:** Ligand A (-4.076) has a lower (better) microsomal clearance than Ligand B (-13.284), suggesting greater metabolic stability.

**13. t1/2:** Ligand A (-26.988) has a longer in vitro half-life than Ligand B (-6.958), which is desirable.

**14. Pgp:** Both ligands have very low Pgp efflux liability (0.022 and 0.154), which is good for CNS penetration.

**15. Binding Affinity:** Both ligands have similar binding affinities (-9.0 and -9.1 kcal/mol), which are excellent and very comparable.

**Overall Assessment:**

Considering the GPCR-specific priorities, Ligand A is the better candidate. It has a significantly lower TPSA, better BBB penetration, lower DILI risk, better metabolic stability (lower Cl_mic, longer t1/2), and a higher QED score. While Ligand B has a slightly better logP, the other advantages of Ligand A outweigh this. The negative values for Caco-2 and solubility are concerning for both, but the other ADME properties of A are more favorable.

Output:
0
2025-04-17 08:37:30,921 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 drug candidates, considering the provided guidelines and GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (366.845 Da) and Ligand B (347.39 Da) are both acceptable.

**TPSA:** Both ligands have TPSA values around 84, which is slightly above the optimal <90 for CNS targets, but still reasonable.

**logP:** Ligand A (3.605) is optimal, while Ligand B (1.881) is on the lower side. A logP below 1 can hinder permeation. This favors Ligand A.

**H-Bond Donors/Acceptors:** Both ligands have 2 HBD and 4 HBA, which are within acceptable limits.

**QED:** Both ligands have similar QED scores (0.779 and 0.77), indicating good drug-likeness.

**DILI:** Ligand A (56.146) has a slightly higher DILI risk than Ligand B (44.591), but both are below the concerning threshold of 60.

**BBB:** Both ligands have excellent BBB penetration (Ligand A: 74.486, Ligand B: 75.107), exceeding the desirable >70 for CNS targets.

**Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and suggests an issue with the data or the model used to predict it. However, we can't definitively say which is better based on this.

**Aqueous Solubility:** Both have negative solubility values, which is also unusual and suggests an issue with the data or the model used to predict it. However, we can't definitively say which is better based on this.

**hERG Inhibition:** Both ligands show very low hERG inhibition liability (0.265 and 0.153), which is excellent.

**Microsomal Clearance:** Ligand A (49.134) has higher microsomal clearance than Ligand B (10.077), indicating lower metabolic stability. This favors Ligand B.

**In vitro Half-Life:** Ligand B (-18.859) has a significantly longer in vitro half-life than Ligand A (31.748), which is a major advantage.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.095 and 0.038), which is favorable for CNS penetration.

**Binding Affinity:** Ligand A (-9.0 kcal/mol) has a slightly better binding affinity than Ligand B (-8.5 kcal/mol). A 0.5 kcal/mol difference is significant, and can outweigh some ADME drawbacks.

**Overall Assessment:**

Considering the GPCR-specific priorities, Ligand A has a better logP and binding affinity, while Ligand B has better metabolic stability (lower Cl_mic, longer t1/2). The affinity difference is more significant than the logP difference. While the higher clearance of Ligand A is a concern, the stronger binding is a significant advantage for a GPCR target. Both have good BBB penetration and low P-gp efflux.

Output:
1
2025-04-17 08:37:30,922 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (365.503 and 367.515 Da) fall comfortably within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (79.26) is better than Ligand B (80.32). Both are reasonably good for CNS penetration, being under the 90 A^2 threshold, but closer to the ideal <60 A^2 would be preferable.

**3. logP:** Ligand B (2.676) is better than Ligand A (0.719).  Ligand A is a bit low, potentially hindering membrane permeability. Ligand B is within the optimal 1-3 range.

**4. H-Bond Donors:** Both ligands have 2 HBD, which is acceptable.

**5. H-Bond Acceptors:** Ligand A has 6 HBA and Ligand B has 5 HBA. Both are within the acceptable limit of 10.

**6. QED:** Both ligands have similar QED values (0.777 and 0.74), indicating good drug-like properties.

**7. DILI:** Ligand A (48.623) is slightly better than Ligand B (52.966), both are good, being under the 60 percentile threshold.

**8. BBB:** Ligand A (48.313) and Ligand B (49.244) are both relatively low. For a CNS target like DRD2, we ideally want >70. Both are suboptimal.

**9. Caco-2 Permeability:** Ligand A (-5.555) is better than Ligand B (-4.851). Higher values are better, indicating better intestinal absorption. However, both are negative, which is concerning.

**10. Aqueous Solubility:** Ligand A (-2.184) is better than Ligand B (-2.761). Both are poor, which could lead to formulation challenges.

**11. hERG Inhibition:** Both ligands show very low hERG inhibition risk (0.19 and 0.173). This is excellent.

**12. Microsomal Clearance:** Ligand A (29.851) is slightly better than Ligand B (30.656), indicating slightly better metabolic stability.

**13. In vitro Half-Life:** Ligand A (25.249) is better than Ligand B (20.222). Longer half-life is generally preferred.

**14. P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.02 and 0.124), which is excellent for CNS penetration.

**15. Binding Affinity:** Ligand B (-7.9 kcal/mol) is significantly better than Ligand A (-7.4 kcal/mol). A 0.5 kcal/mol difference is substantial and can outweigh some ADME drawbacks.

**Overall Assessment:**

While both ligands have issues with BBB penetration and solubility, Ligand B's significantly stronger binding affinity (-7.9 vs -7.4 kcal/mol) is a major advantage for a GPCR target. The slightly better logP of Ligand B also contributes to better permeability. Although Ligand A has slightly better Caco-2 permeability, the difference isn't enough to overcome the affinity gap. The other ADME properties are relatively similar. Given the importance of affinity for GPCRs, and the relatively acceptable ADME profiles of both, Ligand B is the more promising candidate.

Output:
1
2025-04-17 08:37:30,922 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (358.873 and 349.475 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (50.16) is significantly better than Ligand B (83.36). For CNS targets, we want TPSA <= 90, and A is comfortably within this range, while B is approaching the upper limit.

**logP:** Both ligands have acceptable logP values (2.981 and 1.52), falling within the 1-3 optimal range. Ligand A is slightly better.

**H-Bond Donors/Acceptors:** Ligand A (HBD=1, HBA=4) and Ligand B (HBD=3, HBA=4) both have reasonable numbers of H-bond donors and acceptors.

**QED:** Both ligands have good QED scores (0.863 and 0.599), indicating drug-likeness. Ligand A is better.

**DILI:** Ligand A (45.638) has a slightly higher DILI risk than Ligand B (15.626), but both are below the concerning threshold of 60.

**BBB:** This is critical for a CNS target like DRD2. Ligand A (82.435) has a much higher BBB percentile than Ligand B (50.872). A value >70 is desirable, and A is closer to that target.

**Caco-2 Permeability:** Ligand A (-5.208) and Ligand B (-4.997) have similar Caco-2 permeability values.

**Aqueous Solubility:** Both ligands have poor aqueous solubility (-3.269 and -1.277). This could be a formulation challenge, but is less critical than BBB penetration for a CNS target.

**hERG Inhibition:** Ligand A (0.845) has a slightly higher hERG risk than Ligand B (0.121). B is much preferred here.

**Microsomal Clearance:** Ligand A (18.477) has a higher microsomal clearance than Ligand B (15.122), suggesting lower metabolic stability.

**In vitro Half-Life:** Ligand A (33.624 hours) has a significantly longer half-life than Ligand B (12.95 hours). This is a substantial advantage.

**P-gp Efflux:** Ligand A (0.442) has lower P-gp efflux liability than Ligand B (0.032), meaning it's less likely to be pumped out of the brain.

**Binding Affinity:** Ligand A (-9.1 kcal/mol) has a significantly stronger binding affinity than Ligand B (-7.9 kcal/mol). This >1.5 kcal/mol difference is a major advantage and can outweigh some ADME drawbacks.

**Overall Assessment:**

Ligand A is the stronger candidate. While it has a slightly higher DILI risk and hERG inhibition, its superior BBB penetration, longer half-life, lower P-gp efflux, and *much* stronger binding affinity outweigh these concerns. The TPSA is also much better for CNS penetration. Ligand B's lower hERG risk is its main advantage, but the significantly weaker binding and poor BBB penetration are dealbreakers for a CNS-targeted GPCR.

Output:
1
2025-04-17 08:37:30,922 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B based on the provided guidelines, prioritizing GPCR-specific properties (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (370.559 Da and 386.876 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (58.64) is significantly better than Ligand B (69.64). For CNS targets, TPSA should be <= 90, both are within this range, but A is closer to the optimal <60 range.

**logP:** Both ligands have good logP values (2.688 and 1.924), falling within the 1-3 optimal range.

**H-Bond Donors/Acceptors:** Both have acceptable HBD (1 & 2) and HBA (4 & 4) counts, well below the thresholds of 5 and 10 respectively.

**QED:** Both ligands have good QED scores (0.634 and 0.829), indicating good drug-like properties.

**DILI:** Ligand A (31.563) has a much lower DILI risk than Ligand B (52.074), indicating a safer profile. Both are below the 60 threshold.

**BBB:** Ligand A (63.125) has a better BBB penetration percentile than Ligand B (55.293). While >70 is desirable, A is closer and more promising for a CNS target.

**Caco-2 Permeability:** Both have negative Caco-2 values (-5.074 and -4.967). This is unusual and suggests poor permeability. However, the scale isn't specified, so it's difficult to interpret.

**Aqueous Solubility:** Both have negative solubility values (-3.37 and -3.569), again, the scale is unknown, but suggests low solubility.

**hERG:** Both ligands have low hERG inhibition liability (0.613 and 0.488), which is good.

**Microsomal Clearance:** Ligand A (79.999) has higher microsomal clearance than Ligand B (6.984), suggesting lower metabolic stability. Ligand B is significantly better here.

**In vitro Half-Life:** Ligand B (-7.866) has a significantly longer in vitro half-life than Ligand A (16.299). This is a major advantage for dosing considerations.

**P-gp Efflux:** Ligand A (0.313) has lower P-gp efflux liability than Ligand B (0.534), which is favorable for CNS penetration.

**Binding Affinity:** Ligand B (-8.4 kcal/mol) has a significantly stronger binding affinity than Ligand A (-6.8 kcal/mol). This >1.5 kcal/mol difference is substantial and can outweigh some ADME drawbacks.

**Overall Assessment:**

Ligand B has a significantly stronger binding affinity and a much better in vitro half-life. While Ligand A has a better BBB score and lower DILI risk, the affinity difference is crucial for a GPCR target. The lower clearance of Ligand B is also a significant advantage. The negative Caco-2 and solubility values are concerning for both, but the strong binding of B makes it more likely to be optimized to overcome these issues.

Output:
1
2025-04-17 08:37:30,922 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (334.463 and 350.459 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (24.5) is excellent, well below the 90 A^2 threshold for CNS targets. Ligand B (87.66) is higher, but still potentially acceptable, though less desirable.

**logP:** Both ligands have good logP values (3.134 and 2.572), falling within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A (1 HBD, 3 HBA) is better than Ligand B (3 HBD, 4 HBA) in terms of balancing solubility and permeability.

**QED:** Both ligands have reasonable QED scores (0.788 and 0.672), indicating good drug-like properties.

**DILI:** Ligand A (13.3) has a significantly lower DILI risk than Ligand B (37.728). This is a major advantage.

**BBB:** Ligand A (62.466) has a much better BBB percentile than Ligand B (28.848). This is *critical* for a CNS target like DRD2.

**Caco-2 Permeability:** Both have negative Caco-2 values (-4.906 and -4.711). These values are unusual and suggest poor permeability, but the scale isn't specified, so it's hard to interpret.

**Aqueous Solubility:** Both ligands have negative solubility values (-2.761 and -2.828). Similar to Caco-2, the scale is unclear, making interpretation difficult.

**hERG:** Both ligands have low hERG inhibition liability (0.932 and 0.469), which is good.

**Microsomal Clearance:** Ligand A (-11.64) has much lower (better) microsomal clearance than Ligand B (47.92). This indicates better metabolic stability.

**In vitro Half-Life:** Ligand A (15.909) has a longer half-life than Ligand B (-16.828).

**P-gp Efflux:** Ligand A (0.357) has lower P-gp efflux liability than Ligand B (0.112), which is beneficial for CNS exposure.

**Binding Affinity:** Ligand A (-8.9 kcal/mol) has a slightly better binding affinity than Ligand B (-7.8 kcal/mol). While both are good, the 1.1 kcal/mol difference is significant.

**Overall Assessment:**

Ligand A is clearly superior. It excels in critical properties for a CNS-targeting GPCR ligand: TPSA, BBB penetration, DILI risk, metabolic stability (Cl_mic and t1/2), and P-gp efflux. Its binding affinity is also slightly better. While the Caco-2 and solubility values are concerning for both, the other advantages of Ligand A outweigh these potential issues, especially given the importance of CNS penetration for DRD2.

Output:
1
2025-04-17 08:37:30,923 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (358.291 and 359.539 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (70.59) is better than Ligand B (38.25). For CNS targets, we want TPSA <= 90, both are within this range, but A is closer to the upper limit.

**3. logP:** Ligand A (3.075) is optimal (1-3), while Ligand B (4.589) is slightly high, potentially leading to solubility issues and off-target interactions.

**4. H-Bond Donors:** Ligand A (3) is acceptable, while Ligand B (0) is also good.

**5. H-Bond Acceptors:** Ligand A (4) is acceptable, and Ligand B (5) is also acceptable.

**6. QED:** Both ligands have good QED values (A: 0.568, B: 0.622), indicating good drug-like properties.

**7. DILI:** Ligand A (68.592) has a higher DILI risk than Ligand B (20.9). This is a significant drawback for Ligand A.

**8. BBB:** Ligand B (85.498) has a significantly better BBB penetration percentile than Ligand A (66.421). This is *crucial* for a CNS target like DRD2.

**9. Caco-2 Permeability:** Both have negative values, indicating poor permeability. Ligand A (-4.551) is slightly better than Ligand B (-4.822).

**10. Aqueous Solubility:** Both have negative values, indicating poor solubility. Ligand A (-4.27) is slightly better than Ligand B (-4.786).

**11. hERG Inhibition:** Both ligands have low hERG inhibition risk (A: 0.716, B: 0.786).

**12. Microsomal Clearance:** Ligand B (90.89) has a higher microsomal clearance than Ligand A (31.593), suggesting lower metabolic stability.

**13. In vitro Half-Life:** Ligand A (-23.504) has a longer in vitro half-life than Ligand B (-9.667).

**14. P-gp Efflux:** Ligand A (0.168) has lower P-gp efflux liability than Ligand B (0.531), which is favorable for CNS penetration.

**15. Binding Affinity:** Ligand A (-9.9 kcal/mol) has a significantly stronger binding affinity than Ligand B (-7.5 kcal/mol). This is a substantial advantage.

**Overall Assessment:**

Ligand A has a much stronger binding affinity and better P-gp efflux, but suffers from higher DILI risk and lower BBB penetration. Ligand B has a superior BBB penetration, lower DILI risk, and acceptable P-gp efflux, but its binding affinity is considerably weaker.

Given the GPCR-specific priorities, especially for a CNS target, BBB penetration is paramount. While the affinity of Ligand A is very attractive, the significantly better BBB of Ligand B, coupled with the lower DILI risk, outweighs the affinity difference. The slightly higher logP of Ligand B is a concern, but manageable. The longer half-life of Ligand A is also a plus, but not enough to overcome the BBB and DILI issues.

Output:
1
2025-04-17 08:37:30,923 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (361.389 and 348.399 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (112.73) is slightly above the optimal <90 for CNS targets, but still reasonable. Ligand B (81.01) is excellent, well below 90.

**logP:** Ligand A (0.177) is quite low, potentially hindering membrane permeability. Ligand B (1.282) is better, falling within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A has 3 HBD and 4 HBA, which is acceptable. Ligand B has 1 HBD and 5 HBA, also acceptable.

**QED:** Both ligands have good QED scores (0.535 and 0.867), indicating drug-like properties.

**DILI:** Ligand A (34.82) has a lower DILI risk than Ligand B (43.273), both are good.

**BBB:** Ligand A (57.076) has a moderate BBB penetration, while Ligand B (49.748) is lower. Both are below the desirable >70 for CNS targets, but Ligand A is better.

**Caco-2 Permeability:** Ligand A (-5.228) has poor Caco-2 permeability, which is concerning. Ligand B (-4.589) is also poor, but slightly better.

**Aqueous Solubility:** Both ligands have poor aqueous solubility (-2.163 and -1.937).

**hERG:** Both ligands have low hERG inhibition liability (0.31 and 0.239), which is good.

**Microsomal Clearance:** Ligand A (17.033) has lower microsomal clearance than Ligand B (23.902), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand B (30.024) has a significantly longer in vitro half-life than Ligand A (-17.592).

**P-gp Efflux:** Ligand A (0.042) has very low P-gp efflux, which is excellent for CNS penetration. Ligand B (0.035) is also very low, and similar to Ligand A.

**Binding Affinity:** Ligand A (-7.6) has a slightly better binding affinity than Ligand B (0.0).

**Overall Assessment:**

Ligand A has a better binding affinity and lower P-gp efflux, but suffers from very low logP and poor Caco-2 permeability. Its BBB is also only moderately good. Ligand B has better logP, TPSA, and a significantly longer half-life, but its binding affinity is much weaker.

Given the GPCR-specific priorities, BBB penetration and logP are crucial. While both have issues, Ligand B's better logP and TPSA are more favorable for CNS penetration, despite the weaker affinity. The longer half-life is also a significant advantage. The affinity difference, while present, is not large enough to overcome the permeability concerns with Ligand A.

Output:
1
2025-04-17 08:37:30,923 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (350.375 and 369.491 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (116.52) is slightly above the preferred <90 for CNS targets, while Ligand B (98.66) is closer to the ideal range. This gives a slight edge to Ligand B.

**logP:** Ligand A (-0.337) is a bit low, potentially hindering permeability. Ligand B (0.59) is within the optimal 1-3 range. Ligand B is significantly better here.

**H-Bond Donors/Acceptors:** Ligand A has 3 HBD and 5 HBA, which are acceptable. Ligand B has 2 HBD and 7 HBA, also acceptable, but slightly higher HBA could potentially affect permeability.

**QED:** Both ligands have similar QED values (0.687 and 0.661), indicating good drug-like properties.

**DILI:** Ligand A (60.644) is at the upper limit of acceptable DILI risk, while Ligand B (46.103) has a lower, more favorable risk profile.

**BBB:** This is crucial for a CNS target. Ligand A (18.961) has very poor predicted BBB penetration. Ligand B (50.756) is significantly better, although still not ideal (>70 is preferred).

**Caco-2 Permeability:** Both have negative Caco-2 values (-5.118 and -5.358) which is unusual and suggests very poor permeability. This is a significant concern for both.

**Aqueous Solubility:** Both ligands have very poor predicted aqueous solubility (-1.491 and -1.108). This is a major drawback for both.

**hERG Inhibition:** Both ligands show low hERG inhibition risk (0.152 and 0.274).

**Microsomal Clearance:** Ligand A (-3.388) has a more negative value, suggesting lower clearance and better metabolic stability than Ligand B (8.742).

**In vitro Half-Life:** Ligand A (-34.992) has a more negative value, suggesting a longer half-life than Ligand B (9.341).

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.01 and 0.064), which is positive for CNS penetration.

**Binding Affinity:** Ligand B (-7.7 kcal/mol) has a slightly better binding affinity than Ligand A (-8.6 kcal/mol). While the difference is not huge, it's enough to consider, given the other factors.

**Overall Assessment:**

Ligand B is the better candidate despite its poor solubility and Caco-2 permeability. Its significantly better logP and BBB penetration are critical for a CNS-targeting GPCR like DRD2. While Ligand A has better metabolic stability and half-life, the poor BBB penetration is a deal-breaker. The slightly better affinity of Ligand B further supports its selection. The poor solubility and permeability of both ligands would need to be addressed through formulation or structural modifications.

Output:
1
2025-04-17 08:37:30,923 - INFO - Reasoning:

Let's analyze Ligand A and Ligand B for their potential as DRD2 drug candidates, considering the provided guidelines and GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (349.431 and 370.49 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (101.3) is slightly above the preferred <90 for CNS targets, while Ligand B (78.43) is well within the range. This favors Ligand B.

**3. logP:** Both ligands have logP values within the optimal range (1.542 and 2.932). Ligand B is slightly higher, which *could* be beneficial for membrane permeability, but isn't a major concern for either.

**4. H-Bond Donors:** Ligand A (2) and Ligand B (3) are both acceptable, being less than 5.

**5. H-Bond Acceptors:** Ligand A (5) and Ligand B (4) are both acceptable, being less than 10.

**6. QED:** Both ligands have similar, good QED values (0.574 and 0.584), indicating good drug-like properties.

**7. DILI:** Ligand A (43.66) has a slightly higher DILI risk than Ligand B (37.456), but both are below the concerning threshold of 60.

**8. BBB:** Both ligands have reasonably good BBB penetration (63.048% and 61.38%), but neither exceeds the desirable >70% for CNS targets. This is not a decisive factor.

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.755 and -4.934). This is unusual and suggests poor permeability. However, these values are on a scale where negative values are possible and don't necessarily preclude activity.

**10. Aqueous Solubility:** Both ligands have negative solubility values (-2.715 and -3.726) which suggests poor solubility.

**11. hERG Inhibition:** Ligand A (0.084) has a much lower hERG inhibition risk than Ligand B (0.79). This is a significant advantage for Ligand A.

**12. Microsomal Clearance:** Ligand B (61.695) has higher microsomal clearance than Ligand A (47.912), indicating faster metabolism and potentially lower *in vivo* exposure. This favors Ligand A.

**13. In vitro Half-Life:** Ligand B (67.206) has a significantly longer half-life than Ligand A (-18.537). This is a strong advantage for Ligand B.

**14. P-gp Efflux:** Ligand A (0.048) has lower P-gp efflux liability than Ligand B (0.455), which is beneficial for CNS penetration and bioavailability.

**15. Binding Affinity:** Ligand B (-7.6 kcal/mol) has a slightly stronger binding affinity than Ligand A (-8.2 kcal/mol). While the difference is small, it's still a positive for Ligand B.

**Overall Assessment:**

Considering the GPCR-specific priorities, Ligand A is slightly favored. While Ligand B has a longer half-life and slightly better affinity, Ligand A has a significantly lower hERG risk, lower P-gp efflux, and lower microsomal clearance, all of which are crucial for a CNS drug candidate. The TPSA value of Ligand B is also more favorable. The negative Caco-2 and solubility values are concerning for both, but are not necessarily disqualifying. The slightly better affinity of Ligand B is unlikely to overcome the better ADME profile of Ligand A.

Output:
0
2025-04-17 08:37:30,924 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (359.377 and 363.805 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (93.78) is better than Ligand B (103.34). Both are below the 140 threshold for oral absorption, and Ligand A is closer to the desirable <90 for CNS targets.

**logP:** Ligand A (-1.315) is lower than the optimal 1-3 range, potentially hindering permeation. Ligand B (0.594) is also a bit low, but closer to the optimal range.

**H-Bond Donors/Acceptors:** Ligand A has 3 HBD and 5 HBA, which is acceptable. Ligand B has 1 HBD and 6 HBA, also acceptable.

**QED:** Both ligands have good QED scores (0.547 and 0.809), indicating good drug-like properties.

**DILI:** Both ligands have similar DILI risk (50.989 and 60.178), both being acceptable (below 60 is good).

**BBB:** Both ligands have similar BBB penetration (61.807 and 60.838). While not ideal (>70), they are comparable and suggest some CNS exposure is possible.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.252 and -5.021), which is unusual and indicates poor permeability.

**Aqueous Solubility:** Both ligands have negative solubility values (-1.96 and -2.453), which is also unusual and indicates very poor solubility.

**hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.301 and 0.051).

**Microsomal Clearance:** Ligand A (-16.684) has significantly lower (better) microsomal clearance than Ligand B (-4.2), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (-3.992) has a slightly better in vitro half-life than Ligand B (-9.717).

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.005 and 0.053), which is favorable for CNS penetration.

**Binding Affinity:** Both ligands have similar binding affinities (-8.5 and -8.6 kcal/mol), indicating strong binding.

**Overall Assessment:**

Ligand A is slightly favored due to its lower TPSA, better metabolic stability (lower Cl_mic), and slightly better half-life. While its logP is lower, the strong binding affinity (-8.5 kcal/mol) might compensate for this. The poor Caco-2 and solubility are concerning for both, but less critical for a CNS target where direct administration or strategies to bypass the gut are possible. Ligand B's slightly better logP is offset by its worse TPSA and metabolic stability.

Output:
0
2025-04-17 08:37:30,924 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (352.475 and 360.479 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (84.5) is better than Ligand B (62.55). Both are below the 90 A^2 threshold desirable for CNS targets.

**logP:** Ligand B (3.373) is slightly higher than Ligand A (2.189), but both are within the optimal 1-3 range.

**H-Bond Donors:** Ligand A (2) is slightly higher than Ligand B (1), both are within the acceptable limit of 5.

**H-Bond Acceptors:** Both ligands have 4 H-bond acceptors, well within the limit of 10.

**QED:** Ligand B (0.909) has a significantly higher QED score than Ligand A (0.492), indicating better overall drug-likeness.

**DILI:** Ligand A (33.501) has a lower DILI risk than Ligand B (43.932), both are below the 60 threshold.

**BBB:** Both ligands have similar BBB penetration (Ligand A: 60.295, Ligand B: 63.746). Neither exceeds the desirable >70 percentile for CNS targets, but are acceptable.

**Caco-2 Permeability:** Ligand A (-4.672) has a much worse Caco-2 permeability than Ligand B (-5.102). Lower values indicate poorer permeability.

**Aqueous Solubility:** Ligand A (-3.221) has slightly better solubility than Ligand B (-3.561).

**hERG Inhibition:** Ligand A (0.118) has a lower hERG inhibition risk than Ligand B (0.636), which is a significant advantage.

**Microsomal Clearance:** Ligand B (45.296) has a lower microsomal clearance than Ligand A (85.44), indicating better metabolic stability.

**In vitro Half-Life:** Ligand B (36.564) has a significantly longer in vitro half-life than Ligand A (-16.694), which is a major advantage.

**P-gp Efflux:** Ligand A (0.077) has lower P-gp efflux liability than Ligand B (0.434), which is beneficial for CNS penetration.

**Binding Affinity:** Ligand B (-9.0 kcal/mol) has a significantly stronger binding affinity than Ligand A (-7.8 kcal/mol). This >1.5 kcal/mol difference is substantial and can outweigh some ADME drawbacks.

**Overall Assessment:**

While Ligand A has advantages in TPSA, DILI, hERG, and P-gp efflux, Ligand B excels in QED, metabolic stability (Cl_mic and t1/2), and crucially, *binding affinity*. The significantly stronger binding affinity of Ligand B (-9.0 vs -7.8 kcal/mol) is a major driver. Although its Caco-2 permeability and P-gp efflux are less favorable than Ligand A, the strong binding and better metabolic profile are more important for a GPCR target like DRD2.

Output:
1
2025-04-17 08:37:30,924 - INFO - Reasoning:

Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (360.395 and 367.877 Da) fall comfortably within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (107.51) is higher than Ligand B (70.67). For CNS targets, TPSA < 90 is preferred. Ligand B is significantly better in this regard.

**3. logP:** Ligand A (0.622) is lower than the optimal 1-3 range, potentially hindering permeability. Ligand B (2.451) is within the optimal range. This is a significant advantage for Ligand B.

**4. H-Bond Donors:** Ligand A (0) and Ligand B (2) are both acceptable, being less than 5.

**5. H-Bond Acceptors:** Ligand A (6) and Ligand B (4) are both acceptable, being less than 10.

**6. QED:** Both ligands have similar QED values (0.791 and 0.784), indicating good drug-like properties.

**7. DILI:** Ligand A (76.58) and Ligand B (34.277) both have acceptable DILI risk, but Ligand B is substantially lower, indicating a better safety profile.

**8. BBB:** Both ligands show good BBB penetration (Ligand A: 34.548, Ligand B: 76.696). Ligand B is significantly better, exceeding the 70% threshold desirable for CNS targets.

**9. Caco-2 Permeability:** Both have negative Caco-2 values (-4.798 and -4.766). This is unusual and suggests poor permeability. However, these values are close enough that this isn't a major differentiator.

**10. Aqueous Solubility:** Both have negative solubility values (-3.955 and -2.906), indicating poor aqueous solubility. This is a concern for both, but less so for Ligand B.

**11. hERG Inhibition:** Both ligands have low hERG inhibition risk (0.234 and 0.468).

**12. Microsomal Clearance:** Ligand A (24.464) has higher clearance than Ligand B (17.372), suggesting lower metabolic stability.

**13. In vitro Half-Life:** Ligand A (-36.403) has a much lower half-life than Ligand B (24.098), indicating faster metabolism.

**14. P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.062 and 0.034), which is favorable for CNS penetration.

**15. Binding Affinity:** Both ligands have excellent binding affinity (-8.5 and -8.8 kcal/mol). The difference is minor.

**Overall Assessment:**

Ligand B is the superior candidate. While both ligands have good affinity, Ligand B excels in several key areas crucial for CNS drug development: better logP, lower TPSA, significantly lower DILI risk, and substantially improved BBB penetration and metabolic stability (lower Cl_mic and higher t1/2). The slightly better BBB and DILI profiles are particularly important given the target (DRD2) and desired therapeutic area (CNS disorders).



Output:
1
2025-04-17 08:37:30,924 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (355.479 and 342.447 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (62.32) is excellent, well below the 90 A^2 threshold for CNS targets. Ligand B (74.25) is still reasonable, but less optimal.

**logP:** Ligand A (1.424) is within the optimal 1-3 range. Ligand B (2.753) is also within range, but approaching the upper limit.

**H-Bond Donors/Acceptors:** Ligand A (0 HBD, 5 HBA) and Ligand B (1 HBD, 5 HBA) both have acceptable numbers of H-bond donors and acceptors.

**QED:** Both ligands have good QED scores (0.675 and 0.904), indicating good drug-like properties.

**DILI:** Ligand A (10.12) has a very favorable DILI score, indicating low liver injury risk. Ligand B (55.68) is higher, suggesting a moderate risk.

**BBB:** Both ligands have excellent BBB penetration (89.763 and 90.655), exceeding the >70% threshold for CNS targets.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.284 and -4.543), which is unusual and difficult to interpret without additional context. Typically, higher values are better. However, given the other strong properties, this is less concerning.

**Aqueous Solubility:** Both ligands have negative solubility values (-0.333 and -2.799), which is also unusual. This could pose formulation challenges.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.736 and 0.677).

**Microsomal Clearance:** Ligand A (27.799) has a lower microsomal clearance than Ligand B (38), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (-30.566) has a negative half-life, which is not physically possible and suggests an issue with the data. Ligand B (62.84) has a reasonable half-life.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.044 and 0.115), which is excellent for CNS penetration.

**Binding Affinity:** Ligand B (-8.0 kcal/mol) has a slightly better binding affinity than Ligand A (-7.7 kcal/mol). While the difference is not huge, it's enough to consider.

**Overall Assessment:**

Ligand A has a better safety profile (DILI) and metabolic stability (Cl_mic). However, the negative half-life is a major red flag. Ligand B has a slightly better binding affinity and a more reasonable half-life, despite the higher DILI risk. Considering the importance of CNS penetration for a DRD2 target, both ligands exhibit excellent BBB penetration and low P-gp efflux. The unusual solubility and Caco-2 values are concerning for both, but potentially manageable with formulation strategies.

Given the significant issue with Ligand A's half-life, and the slightly better affinity of Ligand B, I would choose Ligand B.

Output:
1
2025-04-17 08:37:30,925 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 drug candidates, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (350.459 and 358.471 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (78.87) is better than Ligand B (79.7), both are reasonably good for CNS penetration, being under 90.

**3. logP:** Ligand A (1.071) is slightly better than Ligand B (2.475), both are within the optimal 1-3 range, but A is closer to 1.

**4. H-Bond Donors:** Ligand A (2) is slightly higher than Ligand B (1), but both are acceptable (<=5).

**5. H-Bond Acceptors:** Ligand A (4) is lower than Ligand B (6), which is preferable.

**6. QED:** Both ligands have similar and good QED values (0.727 and 0.732, respectively), indicating good drug-like properties.

**7. DILI:** Ligand A (20.047) has a significantly lower DILI risk than Ligand B (67.313). This is a major advantage for Ligand A.

**8. BBB:** Ligand A (52.074) has a better BBB penetration percentile than Ligand B (41.334), though both are not ideal (>70). However, for a CNS target, a higher BBB is very important.

**9. Caco-2 Permeability:** Ligand A (-4.453) has a worse Caco-2 permeability than Ligand B (-5.542).

**10. Aqueous Solubility:** Ligand A (-1.487) has better aqueous solubility than Ligand B (-3.059).

**11. hERG Inhibition:** Ligand A (0.125) has a lower hERG inhibition risk than Ligand B (0.524).

**12. Microsomal Clearance:** Ligand A (11.954) has significantly lower microsomal clearance than Ligand B (46.883), suggesting better metabolic stability.

**13. In vitro Half-Life:** Ligand B (49.332) has a much longer in vitro half-life than Ligand A (-10.05).

**14. P-gp Efflux:** Ligand A (0.026) has significantly lower P-gp efflux liability than Ligand B (0.116), which is crucial for CNS penetration.

**15. Binding Affinity:** Ligand B (-7.3) has a slightly better binding affinity than Ligand A (-6.6), a difference of 0.7 kcal/mol.

**Overall Assessment:**

While Ligand B has a slightly better binding affinity and *much* better in vitro half-life, Ligand A is superior in almost all other critical ADME properties, especially those prioritized for GPCRs targeting the CNS. Ligand A has a significantly lower DILI risk, better BBB penetration, lower P-gp efflux, lower hERG inhibition, and better metabolic stability. The 0.7 kcal/mol difference in binding affinity is unlikely to outweigh the substantial advantages of Ligand A in terms of safety and pharmacokinetic properties.

Output:
0
2025-04-17 08:37:30,925 - INFO - Batch 464 complete. Total preferences: 7424
2025-04-17 08:37:30,925 - INFO - Processing batch 465/512...
2025-04-17 08:38:11,036 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (342.4 and 366.5 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (82.7) is better than Ligand B (58.64). Both are below the 90 A^2 threshold for CNS targets, but A is closer to the upper limit.

**3. logP:** Both ligands have good logP values (1.362 and 2.938, respectively), falling within the optimal 1-3 range. Ligand B is slightly higher, which could be beneficial for membrane permeability.

**4. H-Bond Donors:** Both have 1 HBD, which is acceptable.

**5. H-Bond Acceptors:** Ligand A has 6 HBAs, while Ligand B has 4. Both are within the acceptable limit of 10.

**6. QED:** Ligand A (0.903) has a significantly better QED score than Ligand B (0.446), indicating a more drug-like profile.

**7. DILI:** Ligand A (67.623) has a higher DILI risk than Ligand B (41.877), which is less desirable.

**8. BBB:** Ligand B (63.164) has a better BBB percentile than Ligand A (56.999), which is crucial for a CNS target like DRD2.

**9. Caco-2 Permeability:** Ligand A (-4.632) has a much worse Caco-2 permeability than Ligand B (-5.43). Lower values indicate poorer permeability.

**10. Aqueous Solubility:** Ligand A (-1.764) has better aqueous solubility than Ligand B (-3.385).

**11. hERG Inhibition:** Both ligands have low hERG inhibition risk (0.424 and 0.37, respectively).

**12. Microsomal Clearance:** Ligand A (9.906) has a lower microsomal clearance than Ligand B (43.236), suggesting better metabolic stability.

**13. In vitro Half-Life:** Ligand A (10.847) has a longer in vitro half-life than Ligand B (-12.951), which is preferable.

**14. P-gp Efflux:** Ligand A (0.058) has a much lower P-gp efflux liability than Ligand B (0.146), which is very important for CNS penetration.

**15. Binding Affinity:** Ligand A (-8.4 kcal/mol) has a slightly better binding affinity than Ligand B (-7.9 kcal/mol). This 0.5 kcal/mol difference is significant.

**Overall Assessment:**

While Ligand A has a better QED, affinity, metabolic stability, half-life, and P-gp efflux, Ligand B excels in BBB penetration and has a lower DILI risk. Given that this is a CNS target (DRD2), BBB penetration is paramount. The slightly better affinity of Ligand A is helpful, but the significant improvement in BBB for Ligand B outweighs the other advantages of Ligand A. The lower DILI risk of Ligand B is also a significant advantage.

Output:
1
2025-04-17 08:38:11,036 - INFO - Reasoning:

Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (352.519 and 348.531 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (67.43) is slightly higher than Ligand B (58.2). Both are below the 90 A^2 threshold desirable for CNS targets, but Ligand B is preferable.

**3. logP:** Both ligands have good logP values (3.053 and 3.984), falling within the optimal 1-3 range. Ligand B is slightly higher, which could potentially lead to some solubility issues, but is still acceptable.

**4. H-Bond Donors:** Both have 2 HBD, which is within the acceptable limit of <=5.

**5. H-Bond Acceptors:** Ligand A has 3 HBA, and Ligand B has 2. Both are below the acceptable limit of <=10.

**6. QED:** Ligand A (0.594) has a better QED score than Ligand B (0.463), indicating a more drug-like profile.

**7. DILI:** Ligand A (15.471) has a significantly lower DILI risk than Ligand B (19.659), which is a major advantage.

**8. BBB:** Ligand B (75.107) has a better BBB penetration percentile than Ligand A (69.407), which is crucial for a CNS target like DRD2.

**9. Caco-2:** Both have negative Caco-2 values, which is unusual and suggests poor permeability. Ligand A (-4.844) is slightly worse than Ligand B (-4.595).

**10. Solubility:** Both have negative solubility values, indicating very poor aqueous solubility. Ligand A (-3.302) is slightly better than Ligand B (-4.26).

**11. hERG:** Both ligands have very low hERG inhibition liability (0.482 and 0.451), which is excellent.

**12. Cl_mic:** Ligand A (68.721) has lower microsomal clearance than Ligand B (75.735), suggesting better metabolic stability.

**13. t1/2:** Ligand A (18.582) has a significantly longer in vitro half-life than Ligand B (4.592), which is a significant advantage.

**14. Pgp:** Both ligands have very low P-gp efflux liability (0.023 and 0.122), which is favorable for CNS penetration.

**15. Affinity:** Both ligands have the same binding affinity (-7.4 kcal/mol), which is excellent and strong.

**Overall Assessment:**

While Ligand B has a slightly better BBB score, Ligand A demonstrates superior characteristics in several critical areas. It has a better QED score, significantly lower DILI risk, better metabolic stability (lower Cl_mic and longer t1/2), and slightly better solubility. The similar binding affinity means the ADME properties become the deciding factor. Given the importance of minimizing toxicity and maximizing metabolic stability for a CNS drug, Ligand A is the more promising candidate.

Output:
1
2025-04-17 08:38:11,036 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B based on the provided guidelines, prioritizing GPCR-specific properties (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (345.49 and 356.46 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (52.65) is significantly better than Ligand B (107.89). For CNS targets, TPSA should be <= 90, and A is comfortably within this range, while B is above.

**logP:** Ligand A (1.648) is within the optimal 1-3 range. Ligand B (0.501) is slightly below 1, which *could* indicate permeability issues.

**H-Bond Donors/Acceptors:** Ligand A (HBD=1, HBA=3) and Ligand B (HBD=4, HBA=5) both have acceptable numbers of H-bond donors and acceptors.

**QED:** Ligand A (0.745) has a better QED score than Ligand B (0.45), indicating better overall drug-likeness.

**DILI:** Ligand A (4.033) has a very low DILI risk, while Ligand B (11.128) is slightly higher, but still relatively low.

**BBB:** This is a critical parameter for a CNS target like DRD2. Ligand A (72.082) has a good BBB percentile, exceeding the desirable >70 threshold. Ligand B (34.858) is significantly lower, suggesting poor brain penetration.

**Caco-2 Permeability:** Both have negative values, which is unusual. Assuming these are logP-like scales, lower values indicate lower permeability. Both are poor.

**Aqueous Solubility:** Both ligands have very poor aqueous solubility (-1.463 and -1.866). This could pose formulation challenges.

**hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.457 and 0.062).

**Microsomal Clearance:** Ligand A (-14.568) has a much lower (better) microsomal clearance than Ligand B (28.4), indicating greater metabolic stability.

**In vitro Half-Life:** Ligand A (-6.109) has a better in vitro half-life than Ligand B (-13.369).

**P-gp Efflux:** Ligand A (0.011) has a very low P-gp efflux liability, while Ligand B (0.016) is slightly higher. Lower is better for CNS exposure.

**Binding Affinity:** Ligand A (-8.5 kcal/mol) has a stronger binding affinity than Ligand B (-6.9 kcal/mol). The difference of 1.6 kcal/mol is substantial and can outweigh some ADME drawbacks.

**Conclusion:**

Considering all factors, especially the critical GPCR-specific properties (BBB, TPSA, and affinity), **Ligand A is the more promising drug candidate.** It has superior BBB penetration, a lower TPSA, better metabolic stability, a longer half-life, lower P-gp efflux, and significantly stronger binding affinity. While both have poor solubility, the other advantages of Ligand A make it a more viable starting point for optimization.

Output:
1
2025-04-17 08:38:11,036 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (350.415 and 349.475 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (110.1) is higher than the preferred <90 for CNS targets, while Ligand B (64.09) is well within the range. This is a significant advantage for Ligand B.

**logP:** Ligand A (0.411) is quite low, potentially hindering membrane permeability. Ligand B (0.857) is better, but still on the lower side of the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A has 4 HBD and 5 HBA, acceptable values. Ligand B has 1 HBD and 4 HBA, also acceptable.

**QED:** Both ligands have good QED scores (0.615 and 0.765), indicating generally drug-like properties.

**DILI:** Ligand A (14.696) has a slightly higher DILI risk than Ligand B (7.135), but both are below the concerning threshold of 40.

**BBB:** This is a critical parameter for a CNS target. Ligand A (14.036) has a very low BBB penetration percentile, making it unlikely to reach the target in the brain. Ligand B (52.191) is significantly better, although still not ideal (aim for >70).

**Caco-2 Permeability:** Ligand A (-5.533) shows poor permeability, consistent with its low logP. Ligand B (-4.786) is slightly better but still indicates limited permeability.

**Aqueous Solubility:** Both ligands have negative solubility values (-1.755 and -0.771), indicating poor aqueous solubility. This could pose formulation challenges.

**hERG Inhibition:** Both ligands show low hERG inhibition risk (0.27 and 0.363).

**Microsomal Clearance:** Ligand A (-15.344) has a very negative value, indicating very rapid clearance and poor metabolic stability. Ligand B (24.78) is better, but still suggests moderate clearance.

**In vitro Half-Life:** Ligand A (-26.563) has a very short half-life, consistent with its high clearance. Ligand B (-0.526) is better, but still relatively short.

**P-gp Efflux:** Both ligands show low P-gp efflux liability (0.032 and 0.039), which is favorable for CNS penetration.

**Binding Affinity:** Ligand B (-7.6 kcal/mol) has a slightly better binding affinity than Ligand A (-8.1 kcal/mol). While the difference is small, it's still a positive factor.

**Overall Assessment:**

Ligand B is clearly the more promising candidate. Its significantly better TPSA and BBB penetration are crucial for a CNS-targeting GPCR like DRD2. While its logP and Caco-2 permeability are not ideal, they are better than Ligand A's. The slightly better binding affinity of Ligand B further supports its selection. Ligand A's extremely poor BBB penetration and metabolic stability are major drawbacks.

Output:
1
2025-04-17 08:38:11,037 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (448.308 Da) is higher, but still acceptable. Ligand B (366.937 Da) is slightly better.

**2. TPSA:** Both ligands have TPSA values below the 90 A^2 threshold desirable for CNS targets. Ligand A (51.02 A^2) is a bit higher than Ligand B (41.37 A^2), making Ligand B slightly preferable.

**3. logP:** Both ligands have logP values within the optimal range (1-3). Ligand A (4.115) is at the higher end, potentially raising concerns about solubility and off-target effects, while Ligand B (3.241) is better positioned.

**4. H-Bond Donors:** Both have 0 HBD, which is good.

**5. H-Bond Acceptors:** Both have 4 HBA, which is good.

**6. QED:** Both ligands have good QED scores (A: 0.565, B: 0.803). Ligand B is significantly better here, indicating a more drug-like profile.

**7. DILI:** Ligand A (59.17) has a moderate DILI risk, while Ligand B (21.908) has a low DILI risk. This is a significant advantage for Ligand B.

**8. BBB:** Both ligands demonstrate good BBB penetration (A: 79.217, B: 89.337). Ligand B is better, exceeding 85%, which is highly desirable for a CNS target like DRD2.

**9. Caco-2:** Both ligands have negative Caco-2 values, which is unusual and suggests poor permeability. This is a significant concern for both.

**10. Solubility:** Both ligands have negative solubility values, indicating very poor aqueous solubility. This is a major drawback for both.

**11. hERG:** Both ligands have low hERG inhibition liability (A: 0.847, B: 0.589), which is good.

**12. Cl_mic:** Ligand A (98.355) has a higher microsomal clearance than Ligand B (56.837), indicating lower metabolic stability. Ligand B is preferable.

**13. t1/2:** Ligand A (103.49) has a longer in vitro half-life than Ligand B (16.711). This is a positive for Ligand A.

**14. Pgp:** Both ligands have low P-gp efflux liability (A: 0.571, B: 0.573), which is good for CNS penetration.

**15. Binding Affinity:** Ligand A (-7.8 kcal/mol) has a slightly better binding affinity than Ligand B (-7.5 kcal/mol). While a 0.3 kcal/mol difference isn't huge, it's a positive for Ligand A.

**Overall Assessment:**

Despite Ligand A having slightly better affinity and half-life, Ligand B is the more promising candidate. Ligand B excels in key areas for CNS drug development: better QED, significantly lower DILI risk, superior BBB penetration, and lower microsomal clearance. The poor Caco-2 and solubility are concerning for both, but these can potentially be addressed with formulation strategies. The slightly lower affinity of Ligand B is likely outweighed by its improved ADME properties, especially for a CNS target.

Output:
1
2025-04-17 08:38:11,037 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (348.378 and 378.332 Da) fall within the ideal range of 200-500 Da.

**TPSA:** Ligand A (95.37) is better than Ligand B (116.31). For CNS targets, we want TPSA <= 90, so Ligand A is closer to this threshold.

**logP:** Ligand A (3.961) is optimal (1-3), while Ligand B (0.738) is a bit low, potentially hindering membrane permeability.

**H-Bond Donors/Acceptors:** Ligand A (0 HBD, 4 HBA) is better than Ligand B (2 HBD, 6 HBA). Both are within acceptable limits, but fewer H-bonds generally improve permeability.

**QED:** Both ligands have good QED scores (0.358 and 0.769, respectively), with Ligand B being significantly better.

**DILI:** Ligand A (52.772) has a lower DILI risk than Ligand B (90.733), which is a significant advantage.

**BBB:** Ligand A (83.908) has a much better BBB penetration score than Ligand B (65.413). This is *critical* for a CNS target like DRD2.

**Caco-2 Permeability:** Ligand A (-4.274) has a more negative Caco-2 value than Ligand B (-5.133), indicating slightly better permeability.

**Aqueous Solubility:** Both are quite poor (-3.828 and -3.268). Solubility is a concern for both, but not a deciding factor given the other properties.

**hERG:** Both ligands have low hERG inhibition risk (0.613 and 0.153).

**Microsomal Clearance:** Ligand A (34.462) has higher microsomal clearance than Ligand B (2.69), suggesting lower metabolic stability. This is a drawback for Ligand A.

**In vitro Half-Life:** Ligand A (12.393) has a longer half-life than Ligand B (4.377), which is a positive.

**P-gp Efflux:** Ligand A (0.231) has lower P-gp efflux than Ligand B (0.093), which is beneficial for CNS penetration.

**Binding Affinity:** Ligand B (-8.7 kcal/mol) has a slightly better binding affinity than Ligand A (-8.4 kcal/mol), though the difference is small.

**Overall Assessment:**

Ligand A excels in BBB penetration, TPSA, logP, and P-gp efflux, all crucial for CNS GPCR targeting. It also has a lower DILI risk. However, it suffers from higher microsomal clearance. Ligand B has a better QED and slightly better affinity, but its poor BBB penetration and lower logP are significant drawbacks for a CNS target. Considering the GPCR-specific priorities, the superior BBB penetration and favorable logP of Ligand A outweigh its slightly higher clearance and slightly weaker affinity.

Output:
1
2025-04-17 08:38:11,037 - INFO - Reasoning:

Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (349.39 and 367.81 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (110.53) is slightly above the preferred <90 for CNS targets, while Ligand B (93.09) is within the desirable range. This gives a slight edge to Ligand B.

**3. logP:** Ligand A (0.861) is a bit low, potentially hindering permeability. Ligand B (1.768) is better, falling within the optimal 1-3 range. Ligand B is favored.

**4. H-Bond Donors:** Ligand A (2) and Ligand B (1) are both acceptable, being less than 5.

**5. H-Bond Acceptors:** Ligand A (6) and Ligand B (4) are both acceptable, being less than 10.

**6. QED:** Ligand B (0.858) has a significantly better QED score than Ligand A (0.429), indicating a more drug-like profile. This is a substantial advantage for Ligand B.

**7. DILI:** Ligand A (43.51) has a lower DILI risk than Ligand B (55.33), which is preferable.

**8. BBB:** Both ligands have reasonably good BBB penetration (Ligand A: 62.31, Ligand B: 68.13), but Ligand B is slightly better. While both are below the ideal >70, they are acceptable.

**9. Caco-2:** Both have negative Caco-2 values which is unusual and suggests poor permeability.

**10. Solubility:** Both ligands have negative solubility values which is also unusual and suggests poor solubility.

**11. hERG:** Both ligands have very low hERG inhibition risk (Ligand A: 0.036, Ligand B: 0.401). This is good for both.

**12. Cl_mic:** Ligand B (-22.74) has a much lower (better) microsomal clearance than Ligand A (79.27), indicating greater metabolic stability. This is a significant advantage for Ligand B.

**13. t1/2:** Ligand B (-8.38) has a slightly longer in vitro half-life than Ligand A (-11.64), which is preferable.

**14. Pgp:** Both ligands have very low Pgp efflux liability (Ligand A: 0.057, Ligand B: 0.048). This is good for both.

**15. Binding Affinity:** Ligand A (-8.1 kcal/mol) has a slightly better binding affinity than Ligand B (-7.1 kcal/mol). This is a 1.0 kcal/mol difference, which is significant.

**Overall Assessment:**

While Ligand A has a slightly better binding affinity, Ligand B demonstrates a superior ADME profile. Specifically, its better logP, QED, lower Cl_mic, and acceptable TPSA make it a more promising drug candidate. The slightly better BBB and solubility of Ligand B also contribute to its favorability. The difference in binding affinity (1.0 kcal/mol) can potentially be optimized during lead optimization, while the ADME properties are harder to improve significantly later in the drug discovery process. Given the GPCR-specific priorities, Ligand B is the better choice.

Output:
1
2025-04-17 08:38:11,037 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (355.425 and 348.443 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (47.56) is excellent, well below the 90 A^2 threshold for CNS targets. Ligand B (87.66) is higher but still potentially acceptable, though less ideal.

**logP:** Ligand A (3.397) is optimal. Ligand B (0.731) is quite low, potentially hindering membrane permeability and CNS penetration.

**H-Bond Donors/Acceptors:** Ligand A (HBD=1, HBA=3) is good. Ligand B (HBD=3, HBA=4) is also acceptable, though slightly higher.

**QED:** Both ligands have similar QED values (0.623 and 0.592), indicating reasonable drug-likeness.

**DILI:** Ligand A (47.15) has a slightly higher DILI risk than Ligand B (22.257), but both are below the concerning 60 threshold.

**BBB:** Ligand A (90.112) has a significantly better BBB penetration prediction than Ligand B (46.762). This is a *critical* advantage for a CNS target like DRD2.

**Caco-2 Permeability:** Ligand A (-4.623) and Ligand B (-5.109) both have negative values, indicating poor permeability.

**Aqueous Solubility:** Ligand A (-4.722) and Ligand B (-2.015) both have negative values, indicating poor solubility.

**hERG Inhibition:** Ligand A (0.485) shows lower hERG inhibition risk than Ligand B (0.089).

**Microsomal Clearance:** Ligand B (-5.968) has a lower (better) microsomal clearance than Ligand A (11.11). This suggests better metabolic stability for Ligand B.

**In vitro Half-Life:** Ligand A (19.83) has a longer half-life than Ligand B (9.05).

**P-gp Efflux:** Ligand A (0.195) has lower P-gp efflux liability than Ligand B (0.022), which is favorable for CNS penetration.

**Binding Affinity:** Ligand B (-7.1 kcal/mol) has a slightly better binding affinity than Ligand A (-9.0 kcal/mol). While a 1.9 kcal/mol difference is significant, the other ADME properties are more concerning for Ligand B.

**Overall Assessment:**

Ligand A is the more promising candidate. Its superior BBB penetration, better logP, lower P-gp efflux, and acceptable DILI/hERG profiles outweigh the slightly weaker binding affinity and higher clearance compared to Ligand B. The poor Caco-2 and solubility are concerns for both, but can be addressed with formulation strategies. The low logP of Ligand B is a major drawback for CNS penetration, making it less likely to be effective *in vivo*.



Output:
1
2025-04-17 08:38:11,038 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (340.471 and 349.431 Da) fall within the ideal range of 200-500 Da.

**TPSA:** Ligand A (83.8) is better than Ligand B (91.76). Both are below the 90 A^2 threshold desirable for CNS targets, but A is closer to the optimal <60 A^2.

**logP:** Ligand A (3.177) is within the optimal 1-3 range. Ligand B (0.437) is quite low, potentially hindering membrane permeability. This is a significant drawback.

**H-Bond Donors/Acceptors:** Ligand A (HBD=3, HBA=3) and Ligand B (HBD=2, HBA=5) both have reasonable numbers of H-bond donors and acceptors, well within the guidelines.

**QED:** Both ligands have similar QED values (0.69 and 0.675), indicating good drug-likeness.

**DILI:** Ligand A (14.734) has a much lower DILI risk than Ligand B (12.408), which is preferable.

**BBB:** Ligand A (68.282) has a better BBB percentile than Ligand B (53.16), though ideally, we'd want >70 for a CNS target.

**Caco-2 Permeability:** Ligand A (-5.494) has a worse Caco-2 permeability than Ligand B (-4.674), but both are negative values, indicating poor permeability.

**Aqueous Solubility:** Ligand A (-1.823) has better aqueous solubility than Ligand B (-1.263), though both are negative, suggesting poor solubility.

**hERG:** Ligand A (0.723) has a lower hERG risk than Ligand B (0.06), which is a significant advantage.

**Microsomal Clearance:** Ligand A (-11.21) has much lower microsomal clearance than Ligand B (34.79), indicating better metabolic stability.

**In vitro Half-Life:** Ligand A (-7.268) has a longer in vitro half-life than Ligand B (-7.429), which is preferable.

**P-gp Efflux:** Ligand A (0.169) has lower P-gp efflux than Ligand B (0.015), which is a significant advantage for CNS penetration.

**Binding Affinity:** Both ligands have comparable binding affinities (-9.2 and -7.5 kcal/mol). Ligand A is significantly more potent. The 1.7 kcal/mol difference is substantial and can outweigh some ADME drawbacks.

**Conclusion:**

Considering all factors, especially the GPCR-specific priorities, **Ligand A** is the more promising drug candidate. While its Caco-2 and solubility are not ideal, its superior logP, BBB, lower DILI, lower hERG risk, better metabolic stability (lower Cl_mic, longer t1/2), lower P-gp efflux, and significantly stronger binding affinity outweigh the drawbacks. Ligand B's low logP is a major concern for CNS penetration.



Output:
1
2025-04-17 08:38:11,038 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (354.491 and 352.45 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (89.87) is better than Ligand B (66.48) as it is closer to the ideal range for CNS targets (<=90). Ligand B is also good, but A is slightly preferred.

**3. logP:** Both ligands have good logP values (1.44 and 2.405, respectively) within the optimal range of 1-3.

**4. H-Bond Donors:** Ligand A (3) is slightly higher than Ligand B (1), but both are within the acceptable limit of <=5.

**5. H-Bond Acceptors:** Ligand A (4) is slightly higher than Ligand B (3), but both are within the acceptable limit of <=10.

**6. QED:** Both ligands have similar QED values (0.697 and 0.682), indicating good drug-likeness.

**7. DILI:** Both ligands have relatively low DILI risk (16.092 and 17.72), both well below the concerning threshold of 60.

**8. BBB:** This is a crucial parameter for CNS targets. Ligand B (89.531) significantly outperforms Ligand A (60.76). A BBB percentile >70 is desirable, and Ligand B is much closer to that goal.

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.856 and -4.572), which is unusual and suggests poor permeability. It's difficult to interpret these values without knowing the scale, but they are both unfavorable.

**10. Aqueous Solubility:** Both ligands have negative solubility values (-2.707 and -2.615) which is also unusual.

**11. hERG Inhibition:** Both ligands show very low hERG inhibition risk (0.18 and 0.157), which is excellent.

**12. Microsomal Clearance:** Ligand B (23.317) has higher clearance than Ligand A (19.154). Lower clearance is preferred for metabolic stability, so Ligand A is slightly better.

**13. In vitro Half-Life:** Ligand A (-8.445) has a significantly longer half-life than Ligand B (-20.759). This is a major advantage for Ligand A.

**14. P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.05 and 0.048), which is favorable for CNS penetration.

**15. Binding Affinity:** Ligand A (-8.0) has a slightly better binding affinity than Ligand B (-7.6). While both are good, the 0.4 kcal/mol difference is noticeable.

**Overall Assessment:**

Ligand B excels in BBB penetration, a critical factor for a CNS-targeting drug. However, Ligand A has a better half-life, better TPSA, better clearance, and slightly better binding affinity. The negative Caco-2 and solubility values are concerning for both, but the difference in BBB is significant. Given the importance of CNS penetration for DRD2, the superior BBB score of Ligand B outweighs the other advantages of Ligand A.

Output:
1
2025-04-17 08:38:11,038 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (341.455 and 350.467 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (56.41) is significantly better than Ligand B (107.95). For CNS targets, we want TPSA <= 90, and A is well within that, while B is pushing the limit.

**3. logP:** Both ligands have good logP values (2.22 and 1.282), falling within the optimal 1-3 range.

**4. H-Bond Donors:** Both have acceptable HBD counts (1 and 2 respectively), well below the limit of 5.

**5. H-Bond Acceptors:** Ligand A (2) is better than Ligand B (7), keeping in mind the preference for HBA <= 10.

**6. QED:** Both have reasonable QED values (0.835 and 0.767), indicating good drug-like properties.

**7. DILI:** Ligand A (16.169) has a much lower DILI risk than Ligand B (29.934). Both are below the 40 threshold, but A is preferable.

**8. BBB:** Ligand A (76.619) has a slightly better BBB penetration percentile than Ligand B (72.005). Both are above 70, which is good for CNS targets, but A is slightly favored.

**9. Caco-2 Permeability:** Ligand A (-5.014) has a worse Caco-2 permeability than Ligand B (-5.362). Lower values indicate poorer permeability.

**10. Aqueous Solubility:** Ligand A (-2.166) has slightly better solubility than Ligand B (-1.983).

**11. hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.374 and 0.069), which is excellent.

**12. Microsomal Clearance:** Ligand B (21.718) has a lower microsomal clearance than Ligand A (31.256), indicating better metabolic stability.

**13. In vitro Half-Life:** Ligand A (-38.361) has a much longer in vitro half-life than Ligand B (-1.654). This is a significant advantage.

**14. P-gp Efflux:** Ligand A (0.197) has lower P-gp efflux liability than Ligand B (0.029), which is favorable for CNS penetration.

**15. Binding Affinity:** Ligand A (-8.9 kcal/mol) has a significantly stronger binding affinity than Ligand B (-6.8 kcal/mol). This difference of 2.1 kcal/mol is substantial and can outweigh some ADME drawbacks.

**Overall Assessment:**

Considering the GPCR-specific priorities, Ligand A is the stronger candidate. Its superior TPSA, lower DILI risk, slightly better BBB, significantly better binding affinity, and longer half-life outweigh the slightly worse Caco-2 permeability and higher clearance. The strong binding affinity is a key driver, and the favorable TPSA and BBB values are crucial for CNS penetration.

Output:
1
2025-04-17 08:38:11,038 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (460.266) is higher, but still acceptable. Ligand B (348.491) is lower, potentially aiding permeability.

**TPSA:** Ligand A (50.16) is excellent for CNS penetration, well below the 90 A^2 threshold. Ligand B (78.09) is higher, but still reasonable, though less favorable for CNS targets.

**logP:** Ligand A (4.369) is slightly high, potentially leading to solubility issues or off-target interactions. Ligand B (2.666) is optimal.

**H-Bond Donors/Acceptors:** Both ligands have acceptable HBD (1 & 2) and HBA (3 & 3) counts.

**QED:** Both ligands have similar and good QED values (0.69 and 0.709).

**DILI:** Ligand A (52.772) has a moderate DILI risk, while Ligand B (25.087) has a very low risk. This is a significant advantage for Ligand B.

**BBB:** Ligand A (94.261) has excellent BBB penetration, exceeding the desirable 70% threshold. Ligand B (69.213) is below this threshold, which is a major drawback for a CNS target.

**Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and suggests a potential issue with the data or modeling. However, we can proceed with relative comparison.

**Aqueous Solubility:** Both have negative solubility values, again suggesting a potential data issue.

**hERG:** Ligand A (0.854) has a slightly higher hERG risk than Ligand B (0.401), but both are relatively low.

**Microsomal Clearance:** Both have similar microsomal clearance values (31.225 and 33.962), indicating comparable metabolic stability.

**In vitro Half-Life:** Ligand B (-11.066) has a negative half-life, which is not possible. This suggests a significant data issue. Ligand A (3.806) has a short half-life, which is not ideal.

**P-gp Efflux:** Ligand A (0.517) has lower P-gp efflux, which is favorable for CNS exposure. Ligand B (0.182) has very low P-gp efflux, which is even better.

**Binding Affinity:** Ligand A (-10.1) has significantly stronger binding affinity than Ligand B (-8.1). This is a substantial advantage, potentially outweighing some of the ADME drawbacks. A difference of 2 kcal/mol is significant.

**Overall Assessment:**

The key differentiating factors are BBB penetration and binding affinity. Ligand A has excellent BBB penetration and a much stronger binding affinity. However, Ligand B has a significantly lower DILI risk and better P-gp efflux. The negative values for Caco-2 and solubility are concerning for both, but the affinity difference is substantial. For a CNS target like DRD2, strong binding and good BBB penetration are paramount. While Ligand B's lower DILI is attractive, the compromised BBB makes it less likely to reach the target in the brain.

Output:
1
2025-04-17 08:38:11,039 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (347.419 and 363.527 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (96.33) is slightly above the optimal <90 for CNS targets, but still reasonable. Ligand B (53.51) is excellent, well below 90.

**logP:** Ligand A (-0.023) is a bit low, potentially hindering membrane permeability. Ligand B (3.485) is within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A has 2 HBD and 5 HBA, which are acceptable. Ligand B has 0 HBD and 4 HBA, also acceptable.

**QED:** Both ligands have good QED scores (0.732 and 0.777), indicating good drug-like properties.

**DILI:** Ligand A (25.165) has a very low DILI risk, which is excellent. Ligand B (42.924) is also reasonably low.

**BBB:** Ligand A (67.197) is borderline for good CNS penetration. Ligand B (81.698) is excellent, exceeding the 70% threshold. This is a significant advantage for a CNS target like DRD2.

**Caco-2 Permeability:** Both have negative values, indicating poor permeability. However, the scale is not specified, so the absolute values are difficult to interpret.

**Aqueous Solubility:** Both have negative values, indicating poor solubility. Again, the scale is not specified.

**hERG:** Ligand A (0.265) has a very low hERG risk. Ligand B (0.617) is slightly higher, but still relatively low.

**Microsomal Clearance:** Ligand A (-0.816) suggests good metabolic stability (negative value). Ligand B (77.023) indicates high metabolic clearance, which is undesirable.

**In vitro Half-Life:** Ligand A (-1.329) suggests a long half-life (negative value). Ligand B (-17.662) suggests a very short half-life.

**P-gp Efflux:** Ligand A (0.008) has very low P-gp efflux, which is excellent for CNS penetration. Ligand B (0.612) has moderate P-gp efflux.

**Binding Affinity:** Ligand B (-7.2 kcal/mol) has a significantly stronger binding affinity than Ligand A (-8.9 kcal/mol). While both are good, the 1.7 kcal/mol difference is substantial and can outweigh some ADME drawbacks.

**Overall Assessment:**

Ligand B is the stronger candidate. While Ligand A has better DILI, hERG, and metabolic stability, Ligand B excels in critical areas for a CNS GPCR target: BBB penetration, binding affinity, and lower P-gp efflux. The significantly better affinity of Ligand B is a major advantage. The higher metabolic clearance and shorter half-life of Ligand B could be addressed through structural modifications in subsequent optimization rounds. The slightly higher logP of Ligand B is also favorable for CNS penetration.

Output:
1
2025-04-17 08:38:11,039 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B based on the provided guidelines, prioritizing GPCR-specific properties (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (367.324 and 353.507 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (96.97) is better than Ligand B (53.09) as it is closer to the ideal <90 for CNS targets. Ligand B is excellent.

**logP:** Ligand B (1.447) is optimal (1-3), while Ligand A (0.191) is quite low, potentially hindering permeation. This is a significant drawback for Ligand A.

**H-Bond Donors/Acceptors:** Ligand A has 2 HBD and 5 HBA, while Ligand B has 0 HBD and 4 HBA. Both are within acceptable limits.

**QED:** Both ligands have good QED scores (0.654 and 0.768, respectively), indicating drug-likeness.

**DILI:** Ligand B (11.516) has a much lower DILI risk than Ligand A (40.675), making it safer.

**BBB:** Ligand A (64.211) is moderately good, while Ligand B (51.454) is lower. Both are below the desirable >70 for CNS targets, but Ligand A is closer.

**Caco-2 Permeability:** Ligand A (-5.042) is very poor, indicating poor intestinal absorption. Ligand B (-4.442) is also poor, but slightly better.

**Aqueous Solubility:** Ligand A (-1.505) and Ligand B (-0.183) both have poor solubility.

**hERG:** Ligand A (0.155) has a slightly better hERG profile than Ligand B (0.439), indicating lower cardiotoxicity risk.

**Microsomal Clearance:** Ligand B (18.459) has higher clearance than Ligand A (15.856) indicating lower metabolic stability.

**In vitro Half-Life:** Ligand A (-28.457) has a significantly longer half-life than Ligand B (0.818), which is a major advantage.

**P-gp Efflux:** Ligand A (0.008) has very low P-gp efflux, which is excellent for CNS penetration. Ligand B (0.036) is also low.

**Binding Affinity:** Ligand B (-7.9 kcal/mol) has a significantly stronger binding affinity than Ligand A (-6.9 kcal/mol). This 1.0 kcal/mol difference is substantial and can outweigh some ADME drawbacks.

**Overall Assessment:**

While Ligand A has a better BBB score, longer half-life, and lower P-gp efflux, its extremely low logP and poor Caco-2 permeability are major concerns. These properties will severely limit its ability to cross cell membranes and reach the CNS. Ligand B, despite the slightly higher DILI and clearance, has a much better logP, which is crucial for CNS penetration. The significantly stronger binding affinity of Ligand B also tips the balance in its favor.

Output:
1
2025-04-17 08:38:11,039 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (347.459 and 350.419 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (69.72) is significantly better than Ligand B (102.44). For CNS targets, we want TPSA <= 90, and A is comfortably within that range, while B is above.

**3. logP:** Ligand A (0.805) is slightly better than Ligand B (0.379), both are a bit low, but acceptable. Lower logP can sometimes hinder permeability, but isn't a dealbreaker.

**4. H-Bond Donors:** Ligand A (1) is better than Ligand B (2). Lower HBDs generally improve permeability.

**5. H-Bond Acceptors:** Ligand A (4) is better than Ligand B (6). Lower HBAs generally improve permeability.

**6. QED:** Both ligands have acceptable QED values (0.817 and 0.703, both > 0.5).

**7. DILI:** Ligand A (6.049) has a much lower DILI risk than Ligand B (41.838). This is a significant advantage for A.

**8. BBB:** Both ligands have similar BBB penetration (63.086 and 63.009). While not ideal (>70), they are comparable and acceptable.

**9. Caco-2 Permeability:** Ligand A (-5.155) is better than Ligand B (-4.886). Higher values indicate better absorption.

**10. Aqueous Solubility:** Ligand A (-1.116) is better than Ligand B (-1.297).

**11. hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.143 and 0.171).

**12. Microsomal Clearance:** Ligand A (-28.479) has significantly lower (better) microsomal clearance than Ligand B (17.045). This suggests better metabolic stability for Ligand A.

**13. In vitro Half-Life:** Ligand A (-9.74) has a lower half-life than Ligand B (20.451). This is a disadvantage for A, but can be mitigated with formulation.

**14. P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.006 and 0.003).

**15. Binding Affinity:** Ligand B (-7.5) has a slightly better binding affinity than Ligand A (-8.3). However, the difference is less than 1.5 kcal/mol, so the other ADME properties are more important.

**Overall Assessment:**

Ligand A is superior due to its significantly better TPSA, DILI risk, microsomal clearance, and Caco-2 permeability. While Ligand B has slightly better binding affinity and in vitro half-life, the improvements in ADME properties for Ligand A, particularly the TPSA and DILI, are more critical for a CNS-targeting GPCR ligand. The lower TPSA of A will likely translate to better brain penetration, and the lower DILI risk is crucial for safety.

Output:
1
2025-04-17 08:38:11,039 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 drug candidates, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the acceptable range (200-500 Da). Ligand A (354.447 Da) is slightly better, being closer to the ideal range.

**TPSA:** Both ligands have TPSA values below 90, which is good for CNS penetration. Ligand B (66.4) is better than Ligand A (88.1).

**logP:** Ligand A (0.515) is quite low, potentially hindering membrane permeability. Ligand B (2.686) is within the optimal range (1-3). This is a significant advantage for Ligand B.

**H-Bond Donors/Acceptors:** Ligand A has 2 HBD and 5 HBA, while Ligand B has 0 HBD and 6 HBA. Both are within acceptable limits.

**QED:** Both ligands have similar QED values (0.62 and 0.675), indicating good drug-likeness.

**DILI:** Ligand A (32.144) has a lower DILI risk than Ligand B (56.146), which is favorable.

**BBB:** Ligand B (64.017) has a better BBB percentile than Ligand A (50.058). While both are not ideal (>70), Ligand B is closer to the desired threshold for CNS targets.

**Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and suggests poor permeability. However, the scale is not specified, making direct comparison difficult.

**Aqueous Solubility:** Both ligands have negative solubility values, indicating poor solubility. Again, the scale is unspecified.

**hERG:** Both ligands have very low hERG inhibition liability (0.2 and 0.197), which is excellent.

**Microsomal Clearance:** Ligand A (21.002) has a significantly lower microsomal clearance than Ligand B (62.124), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (-8.179) has a negative half-life, which is not possible. Ligand B (21.513) has a reasonable half-life.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.05 and 0.218), which is favorable for CNS penetration.

**Binding Affinity:** Ligand A (-7.5 kcal/mol) has a slightly better binding affinity than Ligand B (-7.3 kcal/mol), although the difference is small.

**Overall Assessment:**

Ligand B is the more promising candidate. While Ligand A has slightly better affinity and lower DILI risk, Ligand B excels in crucial GPCR-specific properties: logP (optimal), BBB (better), and a reasonable in vitro half-life. The low logP of Ligand A is a major concern, potentially leading to poor permeability and bioavailability. The negative half-life for Ligand A is also a red flag. The difference in binding affinity is not substantial enough to outweigh the ADME advantages of Ligand B.

Output:
1
2025-04-17 08:38:11,040 - INFO - Batch 465 complete. Total preferences: 7440
2025-04-17 08:38:11,040 - INFO - Processing batch 466/512...
2025-04-17 08:38:52,834 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (344.419 and 347.459 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (103.01) is higher than Ligand B (75.44). For CNS targets, TPSA < 90 is preferred. Ligand B is better here.

**3. logP:** Ligand A (0.805) is slightly lower than optimal (1-3), potentially hindering permeation. Ligand B (2.459) is well within the optimal range. Ligand B is better.

**4. H-Bond Donors:** Ligand A (3) and Ligand B (1) both meet the HBD <= 5 criteria. Ligand B is preferable.

**5. H-Bond Acceptors:** Ligand A (5) and Ligand B (4) both meet the HBA <= 10 criteria. Ligand B is preferable.

**6. QED:** Both ligands have good QED scores (0.689 and 0.822, respectively), indicating drug-like properties.

**7. DILI:** Ligand A (25.165) has a significantly lower DILI risk than Ligand B (19.891). This is a substantial advantage for Ligand A.

**8. BBB:** Ligand B (78.558) has a much higher BBB penetration percentile than Ligand A (34.548). This is *critical* for a CNS target like DRD2, making Ligand B strongly favored.

**9. Caco-2 Permeability:** Ligand A (-5.806) has a negative Caco-2 value, which is concerning. Ligand B (-4.518) is also negative, but less so. Both suggest poor intestinal absorption, but A is worse.

**10. Aqueous Solubility:** Ligand A (-1.249) and Ligand B (-2.37) both have negative solubility values, which is not ideal.

**11. hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.242 and 0.116, respectively).

**12. Microsomal Clearance:** Ligand A (-20.093) has a much lower (better) microsomal clearance than Ligand B (49.955), indicating greater metabolic stability.

**13. In vitro Half-Life:** Ligand A (11.455) has a shorter half-life than Ligand B (15.896).

**14. P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.01 and 0.048, respectively).

**15. Binding Affinity:** Both ligands have similar and excellent binding affinities (-8.3 and -8.1 kcal/mol). The difference is negligible.

**Overall Assessment:**

While Ligand A has a lower DILI risk and better metabolic stability, Ligand B *significantly* outperforms it in BBB penetration (78.56% vs 34.55%). Given that DRD2 is a CNS target, BBB penetration is paramount. Ligand B also has a more favorable logP and TPSA. The slightly shorter half-life and higher clearance of Ligand B are less concerning than the poor BBB score of Ligand A.

Output:
1
2025-04-17 08:38:52,835 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (348.487 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (69.64) is slightly higher than Ligand B (49.85). For CNS targets, TPSA < 90 is preferred. Both are within this range, but B is better.

**3. logP:** Both ligands (A: 2.247, B: 2.299) are within the optimal 1-3 range.

**4. H-Bond Donors:** Ligand A (2) is slightly higher than Ligand B (0). Both are acceptable (<=5).

**5. H-Bond Acceptors:** Both ligands (3) are within the acceptable range (<=10).

**6. QED:** Both ligands (0.766) have excellent drug-likeness scores.

**7. DILI:** Ligand A (14.541) has a slightly higher DILI risk than Ligand B (13.843), but both are well below the concerning threshold of 60.

**8. BBB:** This is a crucial parameter for CNS targets. Ligand B (84.917) has a significantly higher BBB penetration percentile than Ligand A (65.025). This is a major advantage for B.

**9. Caco-2 Permeability:** Ligand A (-4.673) has slightly better Caco-2 permeability than Ligand B (-4.482), but both are negative values, indicating poor permeability.

**10. Aqueous Solubility:** Ligand A (-2.661) has slightly worse aqueous solubility than Ligand B (-1.935), both are poor.

**11. hERG Inhibition:** Ligand B (0.452) has a lower hERG inhibition risk than Ligand A (0.162), which is preferable.

**12. Microsomal Clearance:** Ligand A (39.607) and Ligand B (38.635) have similar microsomal clearance values.

**13. In vitro Half-Life:** Ligand B (2.153) has a longer in vitro half-life than Ligand A (-7.926). This is a significant advantage for B.

**14. P-gp Efflux:** Ligand A (0.054) has lower P-gp efflux than Ligand B (0.126), which is preferable for CNS penetration.

**15. Binding Affinity:** Both ligands have excellent binding affinities (-8.1 and -8.0 kcal/mol respectively). The difference is minimal.

**Overall Assessment:**

While Ligand A has slightly better Caco-2 permeability and P-gp efflux, Ligand B overwhelmingly wins due to its significantly better BBB penetration (84.917 vs 65.025), longer half-life, and lower hERG risk. For a CNS target like DRD2, BBB penetration is paramount. The small differences in other ADME properties are outweighed by this critical advantage.

Output:
1
2025-04-17 08:38:52,835 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B based on the provided guidelines, prioritizing GPCR-specific properties (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (344.415 and 358.463 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (70.83) is better than Ligand B (58.64). Both are below the 90 A^2 threshold for CNS targets, but A is closer to the upper limit.

**logP:** Ligand A (1.235) is optimal, while Ligand B (4.095) is approaching the upper limit of the optimal range. This is a point in favor of Ligand A.

**H-Bond Donors/Acceptors:** Both have acceptable HBD (1) and HBA (6 for A, 4 for B) counts.

**QED:** Ligand A (0.883) has a significantly better QED score than Ligand B (0.646), indicating better overall drug-likeness.

**DILI:** Ligand A (65.917) has a lower DILI risk than Ligand B (78.635), which is preferable.

**BBB:** Both ligands have reasonable BBB penetration (51.377 and 59.054, respectively), but neither exceeds the desirable >70% threshold. Ligand B is slightly better.

**Caco-2 Permeability:** Both have negative Caco-2 values (-4.535 and -4.556) which is unusual and suggests poor permeability.

**Aqueous Solubility:** Both have negative solubility values (-2.404 and -5.514), indicating poor aqueous solubility. Ligand A is slightly better.

**hERG:** Both ligands have low hERG inhibition liability (0.581 and 0.294), which is good.

**Microsomal Clearance:** Ligand A (34.011) has significantly lower microsomal clearance than Ligand B (137.698), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (7.199) has a shorter half-life than Ligand B (12.614), but both are reasonable.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.177 and 0.194), which is good for CNS penetration.

**Binding Affinity:** Ligand B (-8.9 kcal/mol) has a significantly stronger binding affinity than Ligand A (-7.2 kcal/mol). This is a substantial advantage.

**Overall Assessment:**

While Ligand A has better drug-likeness (QED), lower DILI risk, and better metabolic stability (lower Cl_mic), Ligand B's significantly stronger binding affinity (-8.9 vs -7.2 kcal/mol) is a major advantage, especially for a GPCR target. The difference in affinity is greater than 1.5 kcal/mol, potentially outweighing the ADME drawbacks of Ligand B. The slightly better BBB penetration of Ligand B is also a positive. The poor Caco-2 and solubility are concerning for both, but can be addressed with formulation strategies.

Output:
1
2025-04-17 08:38:52,835 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (344.411 and 350.463 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (91.57) is slightly above the optimal <90 for CNS targets, but still reasonable. Ligand B (76.46) is well within the desired range. This favors Ligand B.

**3. logP:** Ligand A (3.07) is at the upper end of the optimal range (1-3), while Ligand B (1.376) is towards the lower end. While both are acceptable, a slightly higher logP can be beneficial for GPCRs, but needs to be balanced with solubility.

**4. H-Bond Donors:** Ligand A (3) is acceptable. Ligand B (1) is also good.

**5. H-Bond Acceptors:** Ligand A (4) is acceptable. Ligand B (5) is also good.

**6. QED:** Both ligands have good QED scores (0.72 and 0.806, respectively), indicating drug-like properties.

**7. DILI:** Both ligands have low DILI risk (36.991 and 32.842, respectively), which is positive. Ligand B is slightly better.

**8. BBB:** This is critical for a CNS target like DRD2. Ligand B (75.107) is significantly better than Ligand A (21.908), exceeding the desirable >70 threshold. This is a major advantage for Ligand B.

**9. Caco-2:** Both have negative values, which is unusual. However, the magnitude of the negative value for Ligand A (-5.278) is larger than that of Ligand B (-4.524), suggesting potentially lower permeability for Ligand A.

**10. Solubility:** Both have negative solubility values, which is also unusual. Ligand B (-1.921) is slightly better than Ligand A (-3.406).

**11. hERG:** Both ligands have low hERG inhibition risk (0.295 and 0.343, respectively).

**12. Cl_mic:** Both have similar microsomal clearance values (36.828 and 37.385 mL/min/kg).

**13. t1/2:** Ligand B (9.197 hours) has a longer half-life than Ligand A (6.931 hours), which is preferable.

**14. Pgp:** Both have very low P-gp efflux liability (0.106 and 0.048, respectively). Ligand B is slightly better.

**15. Binding Affinity:** Ligand B (-7.1 kcal/mol) has a significantly stronger binding affinity than Ligand A (-9.0 kcal/mol). This is a substantial advantage, potentially outweighing minor ADME drawbacks.

**Overall Assessment:**

Ligand B is the superior candidate. It has a better BBB score, a longer half-life, slightly better solubility, and, crucially, a significantly stronger binding affinity. While Ligand A has a slightly higher logP, the benefits of Ligand B's improved CNS penetration and binding outweigh this difference.

Output:
1
2025-04-17 08:38:52,835 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (348.403 and 346.391 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (128.25) is slightly above the optimal <90 for CNS targets, but still reasonable. Ligand B (117.44) is better, falling comfortably under 90.

**logP:** Ligand A (0.772) is a bit low, potentially hindering permeation. Ligand B (-0.511) is even lower, raising concerns about membrane permeability. Both are below the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Both ligands have 3 HBD and 6 HBA, which are within acceptable limits (<=5 and <=10 respectively).

**QED:** Both ligands have QED values above 0.5 (0.605 and 0.562), indicating good drug-like properties.

**DILI:** Ligand A (47.732) has a lower DILI risk than Ligand B (61.07), which is approaching a higher risk category.

**BBB:** Ligand B (54.362) has a significantly better BBB penetration percentile than Ligand A (35.712). This is a *critical* advantage for a CNS target like DRD2.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.175 and -5.301), which is unusual and suggests poor permeability. This is a significant concern for both.

**Aqueous Solubility:** Both ligands have very poor aqueous solubility (-2.519 and -2.134). This could pose formulation challenges.

**hERG Inhibition:** Both ligands show very low hERG inhibition risk (0.168 and 0.084).

**Microsomal Clearance:** Ligand B (-22.256) has a lower (better) microsomal clearance than Ligand A (19.532), indicating better metabolic stability.

**In vitro Half-Life:** Ligand B (-38.591) has a significantly longer in vitro half-life than Ligand A (-26.756).

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.027 and 0.004), which is favorable for CNS penetration.

**Binding Affinity:** Both ligands have the same binding affinity (-8.1 kcal/mol), which is excellent and strong enough to potentially overcome some ADME deficiencies.

**Overall Assessment:**

While both ligands have excellent binding affinity, Ligand B is the more promising candidate. Its significantly better BBB penetration (54.362 vs 35.712), lower DILI risk (61.07 vs 47.732), lower microsomal clearance (-22.256 vs 19.532), and longer half-life (-38.591 vs -26.756) outweigh the slightly lower TPSA and logP. The poor Caco-2 and solubility are concerning for both, but can potentially be addressed through formulation strategies. The BBB is the most important factor for a CNS target, and Ligand B has a clear advantage here.

Output:
1
2025-04-17 08:38:52,836 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (439.14) is higher, but still acceptable. Ligand B (356.463) is also good.

**TPSA:** Ligand A (37.61) is excellent for CNS penetration, well below the 90 A^2 threshold. Ligand B (93.73) is higher, approaching the upper limit for good oral absorption (140) and less ideal for CNS targets.

**logP:** Ligand A (4.888) is slightly high, potentially leading to solubility issues and off-target interactions. Ligand B (1.546) is quite low, which could hinder membrane permeability.

**H-Bond Donors/Acceptors:** Ligand A (0 HBD, 4 HBA) is favorable. Ligand B (2 HBD, 5 HBA) is also reasonable.

**QED:** Both ligands have good QED scores (A: 0.542, B: 0.611), indicating drug-like properties.

**DILI:** Ligand A (75.378) has a higher DILI risk than Ligand B (25.087), which is a significant concern.

**BBB:** Ligand A (82.978) has excellent BBB penetration, exceeding the 70% threshold. Ligand B (45.095) is considerably lower, which is a major drawback for a CNS target.

**Caco-2 Permeability:** Ligand A (-4.637) shows poor Caco-2 permeability, likely due to its high logP. Ligand B (-5.023) is also poor.

**Aqueous Solubility:** Ligand A (-6.23) has very poor aqueous solubility, consistent with its high logP. Ligand B (-1.582) is slightly better, but still poor.

**hERG Inhibition:** Ligand A (0.72) has a low hERG risk, which is good. Ligand B (0.18) is even lower, excellent.

**Microsomal Clearance:** Ligand A (52.936) and Ligand B (42.028) have comparable microsomal clearance values.

**In vitro Half-Life:** Ligand A (95.303) has a very long in vitro half-life, which is highly desirable. Ligand B (-3.877) has a short half-life, a significant negative.

**P-gp Efflux:** Ligand A (0.798) shows moderate P-gp efflux. Ligand B (0.025) shows very low P-gp efflux, which is a major advantage for CNS penetration.

**Binding Affinity:** Ligand A (-8.7 kcal/mol) has a significantly stronger binding affinity than Ligand B (-6.9 kcal/mol). This 1.8 kcal/mol difference is substantial and can outweigh some ADME drawbacks.

**Overall Assessment:**

Ligand A has a superior binding affinity and excellent BBB penetration and in vitro half-life. However, it suffers from poor solubility, poor Caco-2 permeability, a higher DILI risk, and moderate P-gp efflux. Ligand B has a better safety profile (lower DILI, hERG, Pgp) but significantly weaker affinity and poor BBB penetration.

Given the importance of affinity for GPCRs, and the fact that DRD2 is a CNS target, the stronger binding affinity and good BBB penetration of Ligand A are crucial. While the ADME properties of Ligand A are suboptimal, medicinal chemistry efforts could focus on improving solubility and permeability without sacrificing affinity. The weak affinity of Ligand B makes it less promising, even with its better ADME profile.

Output:
1
2025-04-17 08:38:52,836 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (348.447 and 346.427 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (96.11) is slightly above the preferred <90 for CNS targets, but still reasonable. Ligand B (70.08) is excellent, well below 90.

**3. logP:** Ligand A (1.775) is within the optimal 1-3 range. Ligand B (0.265) is a bit low, potentially hindering permeability.

**4. H-Bond Donors:** Ligand A (3) is acceptable. Ligand B (1) is also good.

**5. H-Bond Acceptors:** Both ligands (A: 4, B: 4) are within the acceptable limit of 10.

**6. QED:** Both ligands have good QED scores (A: 0.683, B: 0.793), indicating drug-like properties.

**7. DILI:** Ligand A (52.423) has a moderate DILI risk, but is still acceptable. Ligand B (34.587) has a lower, more favorable DILI risk.

**8. BBB:** Ligand B (61.535) has a significantly better BBB penetration percentile than Ligand A (50.679). This is a crucial factor for a CNS target like DRD2.

**9. Caco-2 Permeability:** Ligand A (-5.093) has poor Caco-2 permeability, which is concerning. Ligand B (-4.522) is also poor, but slightly better than A.

**10. Aqueous Solubility:** Both ligands have poor aqueous solubility (A: -2.691, B: -1.732). This could pose formulation challenges.

**11. hERG Inhibition:** Both ligands show very low hERG inhibition risk (A: 0.153, B: 0.178).

**12. Microsomal Clearance:** Ligand A (9.063) has lower microsomal clearance, suggesting better metabolic stability than Ligand B (32.703).

**13. In vitro Half-Life:** Ligand A (-10.821) has a negative half-life, which is not physically possible and indicates an issue with the data or the model. Ligand B (13.537) has a reasonable half-life.

**14. P-gp Efflux:** Both ligands have very low P-gp efflux liability (A: 0.044, B: 0.132).

**15. Binding Affinity:** Both ligands have very similar and strong binding affinities (A: -8.1 kcal/mol, B: -8.3 kcal/mol). The difference is negligible.

**Overall Assessment:**

While Ligand A has better metabolic stability (lower Cl_mic), the negative half-life is a major red flag and suggests a data error. Ligand B excels in key GPCR properties: lower TPSA, better BBB penetration, and a slightly better DILI profile. Although both have poor solubility and Caco-2 permeability, the superior BBB penetration of Ligand B is critical for a CNS target. The similar binding affinities make the ADME properties the deciding factor.

Output:
1
2025-04-17 08:38:52,836 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (349.439 and 341.375 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (122.89) is better than Ligand B (126.85). Both are below the 140 A^2 threshold for oral absorption, and closer to the <90 A^2 ideal for CNS targets.

**3. logP:** Both ligands have good logP values (2.782 and 2.439), falling within the optimal 1-3 range.

**4. H-Bond Donors:** Ligand A (1) is better than Ligand B (2). Both are within the acceptable limit of <=5.

**5. H-Bond Acceptors:** Ligand A (5) is better than Ligand B (4). Both are within the acceptable limit of <=10.

**6. QED:** Both ligands have similar QED values (0.431 and 0.492), indicating moderate drug-likeness.

**7. DILI:** Ligand A (42.885) has a significantly lower DILI risk than Ligand B (61.574). This is a substantial advantage.

**8. BBB:** Ligand A (69.407) has a better BBB percentile than Ligand B (56.65). While both are below the ideal >70 for CNS targets, A is closer.

**9. Caco-2:** Ligand A (-4.94) is better than Ligand B (-5.155). Both are negative, indicating poor permeability, but A is slightly better.

**10. Solubility:** Ligand A (-2.805) is better than Ligand B (-4.049). Both are poor, but A is better.

**11. hERG:** Ligand A (0.196) has a lower hERG inhibition liability than Ligand B (0.462). This is a significant safety advantage.

**12. Cl_mic:** Ligand A (37.852) has a higher (worse) microsomal clearance than Ligand B (14.788). This suggests Ligand B is more metabolically stable.

**13. t1/2:** Ligand B (12.934) has a much longer in vitro half-life than Ligand A (0.4). This is a major advantage for dosing convenience.

**14. Pgp:** Ligand A (0.017) has a lower P-gp efflux liability than Ligand B (0.013). This is a slight advantage for CNS exposure.

**15. Binding Affinity:** Ligand B (-9.0) has a significantly stronger binding affinity than Ligand A (-7.3). This is a substantial advantage, potentially outweighing some ADME drawbacks.

**Overall Assessment:**

Ligand B has a much stronger binding affinity and better metabolic stability (lower Cl_mic, longer t1/2). However, Ligand A has a lower DILI risk, better BBB penetration, lower hERG risk, and slightly better solubility and Caco-2 permeability.

Given the GPCR-specific priorities, the stronger binding affinity of Ligand B is a critical factor. While Ligand A has advantages in safety and CNS penetration, the 1.7 kcal/mol difference in binding affinity is substantial. The improved metabolic stability of Ligand B is also very important. The lower BBB of Ligand B is a concern, but can potentially be addressed through further optimization.

Output:
1
2025-04-17 08:38:52,836 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (339.454 and 347.463 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (21.26) is excellent, well below the 90 Angstroms threshold for CNS targets. Ligand B (78.43) is higher, but still potentially acceptable, though less ideal.

**3. logP:** Ligand A (4.781) is slightly high, potentially leading to solubility issues or off-target interactions. Ligand B (1.06) is low, which could hinder membrane permeability.

**4. H-Bond Donors:** Both ligands have 1 HBD, which is within the acceptable limit of 5.

**5. H-Bond Acceptors:** Ligand A has 2 HBAs, and Ligand B has 5. Both are within the acceptable limit of 10.

**6. QED:** Both ligands have good QED scores (0.552 and 0.832), indicating drug-like properties.

**7. DILI:** Ligand A (21.598) has a slightly higher DILI risk than Ligand B (16.13), but both are below the concerning threshold of 60.

**8. BBB:** Both ligands have similar BBB penetration (61.884 and 60.527). Neither reaches the highly desirable >70 percentile, but they are reasonable for a starting point.

**9. Caco-2 Permeability:** Ligand A (-4.602) has poor Caco-2 permeability, while Ligand B (-5.174) is even worse. Both are significantly negative, indicating very low intestinal absorption.

**10. Aqueous Solubility:** Ligand A (-4.535) has poor aqueous solubility, while Ligand B (-1.243) is better, but still not ideal.

**11. hERG Inhibition:** Ligand A (0.966) has a slightly higher hERG risk than Ligand B (0.119).

**12. Microsomal Clearance:** Ligand B (-10.276) has significantly lower (better) microsomal clearance than Ligand A (53.739), suggesting better metabolic stability.

**13. In vitro Half-Life:** Ligand B (-2.853) has a longer half-life than Ligand A (3.313).

**14. P-gp Efflux:** Ligand A (0.8) shows moderate P-gp efflux, while Ligand B (0.006) has very low P-gp efflux. This is a significant advantage for Ligand B, especially for CNS penetration.

**15. Binding Affinity:** Ligand A (-8.9 kcal/mol) has a significantly stronger binding affinity than Ligand B (-7.5 kcal/mol). This is a substantial advantage.

**Overall Assessment:**

Ligand A has a much stronger binding affinity, which is the most critical factor. However, it suffers from poor Caco-2 permeability, poor aqueous solubility, and moderate P-gp efflux. Ligand B has better ADME properties (lower clearance, longer half-life, very low P-gp efflux, better solubility), but its binding affinity is weaker.

Given the GPCR-specific priorities, and the substantial difference in binding affinity, I would prioritize Ligand A despite its ADME liabilities. The strong affinity provides a good starting point for optimization, and the ADME issues can potentially be addressed through structural modifications. The lower TPSA of Ligand A is also favorable for CNS penetration.

Output:
0
2025-04-17 08:38:52,837 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (335.407 and 345.403 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (61.44) is significantly better than Ligand B (115.19). For CNS targets, we want TPSA <= 90, and A is comfortably within that, while B exceeds it.

**3. logP:** Ligand A (2.242) is optimal (1-3), while Ligand B (0.222) is quite low, potentially hindering permeation.

**4. H-Bond Donors:** Both have 2 HBD, which is within the acceptable limit of <= 5.

**5. H-Bond Acceptors:** Ligand A has 3 HBA, and Ligand B has 5. Both are within the acceptable limit of <= 10.

**6. QED:** Both ligands have acceptable QED values (0.904 and 0.733, both >= 0.5).

**7. DILI:** Ligand A (65.917) has a higher DILI risk than Ligand B (42.807). Both are acceptable, but B is preferable.

**8. BBB:** Ligand A (74.292) has a much better BBB penetration percentile than Ligand B (37.65). This is *critical* for a CNS target like DRD2.

**9. Caco-2:** Ligand A (-4.92) and Ligand B (-5.147) both have negative Caco-2 permeability values, which is unusual and suggests poor permeability. However, the scale isn't defined, so this is hard to interpret.

**10. Solubility:** Ligand A (-4.55) and Ligand B (-1.903) both have negative solubility values, which is also unusual and suggests poor solubility. Again, the scale isn't defined.

**11. hERG:** Ligand A (0.755) has a slightly higher hERG risk than Ligand B (0.324), but both are relatively low.

**12. Cl_mic:** Ligand A (30.593) has a higher microsomal clearance than Ligand B (11.737), indicating lower metabolic stability.

**13. t1/2:** Ligand A (67.889) has a longer in vitro half-life than Ligand B (23.129), which is desirable.

**14. Pgp:** Ligand A (0.463) has lower P-gp efflux liability than Ligand B (0.024), which is beneficial for CNS exposure.

**15. Binding Affinity:** Ligand B (-7.8 kcal/mol) has a significantly stronger binding affinity than Ligand A (-10.6 kcal/mol). This is a substantial advantage.

**Overall Assessment:**

While Ligand B has a superior binding affinity, Ligand A is significantly better in terms of BBB penetration and TPSA, both crucial for CNS GPCR targets. Ligand A also has better Pgp efflux liability and a longer half-life. Ligand B's low logP is a major concern, potentially hindering its ability to cross cell membranes. The superior affinity of Ligand B *could* potentially overcome its poor logP, but the combination of better CNS properties in Ligand A makes it the more promising candidate.

Output:
1
2025-04-17 08:38:52,837 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (352.435 and 344.411 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (96.69) is slightly above the ideal <90 for CNS targets, but still reasonable. Ligand B (88.41) is excellent, well below 90.

**logP:** Ligand A (-0.082) is a bit low, potentially hindering membrane permeability. Ligand B (1.89) is within the optimal 1-3 range. This is a significant advantage for Ligand B.

**H-Bond Donors/Acceptors:** Both ligands have 2 HBD and a reasonable number of HBA (6 and 4 respectively). This is acceptable for both.

**QED:** Both ligands have good QED scores (0.682 and 0.854), indicating drug-like properties.

**DILI:** Ligand A (24.234) has a very favorable DILI score, indicating low liver injury risk. Ligand B (42.148) is higher, but still within an acceptable range.

**BBB:** This is crucial for a CNS target. Ligand A (23.11) has a poor BBB penetration percentile. Ligand B (67.584) is much better, though ideally >70.

**Caco-2 Permeability:** Both have negative values, which is unusual and suggests a problem with the data. However, the magnitude of the negative value is less important than the other parameters.

**Aqueous Solubility:** Both have negative values, which is also unusual.

**hERG:** Both ligands have low hERG inhibition liability (0.132 and 0.123), which is positive.

**Microsomal Clearance:** Both have similar, relatively low microsomal clearance (6.744 and 6.673), suggesting reasonable metabolic stability.

**In vitro Half-Life:** Ligand B has a significantly longer half-life (58.999 hours) compared to Ligand A (3.008 hours). This is a major advantage for Ligand B.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.02 and 0.152), which is good for CNS penetration.

**Binding Affinity:** Ligand B (-9.0 kcal/mol) has a substantially stronger binding affinity than Ligand A (-7.4 kcal/mol). This >1.5 kcal/mol difference is very significant and can outweigh some ADME drawbacks.

**Overall Assessment:**

Ligand B is the superior candidate. While Ligand A has a slightly better DILI score, Ligand B excels in the critical areas for a CNS-targeting GPCR: logP, BBB penetration, binding affinity, and *in vitro* half-life. The stronger binding affinity of Ligand B is a decisive factor. The slightly higher DILI score of Ligand B is less concerning given the other advantages.



Output:
1
2025-04-17 08:38:52,837 - INFO - Reasoning:

Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight (MW):** Both ligands (366.336 and 358.463 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (87.15) is better than Ligand B (49.85) as it is closer to the <90 target for CNS penetration. Ligand B is excellent.

**3. logP:** Ligand B (1.702) is better than Ligand A (0.168). A logP between 1-3 is optimal, and Ligand A's value is quite low, potentially hindering membrane permeability.

**4. H-Bond Donors (HBD):** Both ligands are acceptable (1 and 0 respectively), staying under the 5 threshold.

**5. H-Bond Acceptors (HBA):** Both ligands are acceptable (5 and 4 respectively), staying under the 10 threshold.

**6. QED:** Both ligands have reasonable QED values (0.701 and 0.608), indicating good drug-like properties.

**7. DILI:** Both ligands have low DILI risk (34.277 and 39.434), which is favorable.

**8. BBB:** Both ligands have good BBB penetration (76.309 and 74.564). Both are above the 70% threshold.

**9. Caco-2 Permeability:** Ligand A (-4.465) is better than Ligand B (-4.683), indicating slightly better intestinal absorption.

**10. Aqueous Solubility:** Ligand A (-1.052) is better than Ligand B (-2.875), indicating better solubility.

**11. hERG Inhibition:** Both ligands have low hERG inhibition risk (0.253 and 0.58), which is good.

**12. Microsomal Clearance (Cl_mic):** Ligand A (13.717) has a significantly lower Cl_mic than Ligand B (45.493), indicating better metabolic stability.

**13. In vitro Half-Life:** Ligand A (-32.37) has a much longer half-life than Ligand B (0.729), which is a significant advantage.

**14. P-gp Efflux:** Ligand A (0.026) has much lower P-gp efflux than Ligand B (0.486), which is crucial for CNS exposure.

**15. Binding Affinity:** Ligand B (-7.8) has a significantly stronger binding affinity than Ligand A (-8.2). This is a substantial advantage, potentially outweighing some of the ADME concerns with Ligand A.

**Overall Assessment:**

While Ligand A has better ADME properties (lower Cl_mic, longer half-life, lower P-gp efflux, better solubility, and slightly better Caco-2 permeability), Ligand B boasts a significantly stronger binding affinity (-7.8 vs -8.2 kcal/mol). For a GPCR target like DRD2, strong binding is paramount. The slightly less favorable ADME profile of Ligand B can potentially be addressed through further optimization, but improving a weaker binding affinity is often more challenging. The BBB values are comparable for both.

Output:
1
2025-04-17 08:38:52,837 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (370.494 and 354.495 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (64.68) is better than Ligand B (67.33). Both are below the 90 A^2 threshold for CNS targets, which is good.

**3. logP:** Ligand A (0.777) is slightly better than Ligand B (-0.159). Ligand B is a bit low, potentially hindering permeation.

**4. H-Bond Donors:** Ligand A (2) is slightly higher than Ligand B (1), but both are within the acceptable limit of 5.

**5. H-Bond Acceptors:** Both ligands have 5 HBA, which is within the acceptable limit of 10.

**6. QED:** Both ligands have similar QED values (0.775 and 0.718), indicating good drug-likeness.

**7. DILI:** Ligand A (46.064) has a higher DILI risk than Ligand B (6.398). This is a significant advantage for Ligand B.

**8. BBB:** Ligand A (55.176) has a significantly better BBB penetration score than Ligand B (34.238). This is a crucial factor for a CNS target like DRD2.

**9. Caco-2 Permeability:** Ligand A (-5.272) has worse Caco-2 permeability than Ligand B (-4.997), but both are negative, indicating poor permeability.

**10. Aqueous Solubility:** Ligand A (-2.108) has better aqueous solubility than Ligand B (0.087).

**11. hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.681 and 0.161).

**12. Microsomal Clearance:** Ligand A (-10.253) has much lower microsomal clearance (better metabolic stability) than Ligand B (12.994).

**13. In vitro Half-Life:** Ligand A (-20.403) has a much longer in vitro half-life than Ligand B (-2.978).

**14. P-gp Efflux:** Ligand A (0.027) has much lower P-gp efflux than Ligand B (0.007), which is favorable for CNS penetration.

**15. Binding Affinity:** Ligand A (-8.4 kcal/mol) has a better binding affinity than Ligand B (-6.5 kcal/mol). This is a substantial difference (1.9 kcal/mol), and can often outweigh minor ADME drawbacks.

**Overall Assessment:**

Ligand A has a significantly stronger binding affinity, better BBB penetration, lower P-gp efflux, better metabolic stability, and longer half-life. While Ligand B has a lower DILI risk, the affinity difference is substantial, and the BBB score for Ligand A is reasonable. Given the importance of CNS penetration and potency for a DRD2 ligand, the benefits of Ligand A outweigh the slightly higher DILI risk.

Output:
1
2025-04-17 08:38:52,838 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (371.459 Da) is slightly higher than Ligand B (349.435 Da), but both are acceptable.

**TPSA:** Ligand A (106.62) is higher than Ligand B (88.49). For CNS targets, we want TPSA <= 90. Ligand B is better here.

**logP:** Ligand A (1.599) is within the optimal range (1-3). Ligand B (-0.379) is slightly below 1, which *could* hinder permeation. Ligand A is better.

**H-Bond Donors:** Both ligands have 2 HBD, which is within the acceptable limit of <=5.

**H-Bond Acceptors:** Ligand A has 7 HBA, and Ligand B has 6. Both are below the acceptable limit of <=10.

**QED:** Ligand B (0.757) has a significantly better QED score than Ligand A (0.368), indicating a more drug-like profile.

**DILI:** Ligand B (36.797) has a much lower DILI risk than Ligand A (52.346). Both are below 40, which is good.

**BBB:** Ligand A (51.881) and Ligand B (35.518) both have low BBB penetration. This is a significant drawback for a CNS target like DRD2. However, Ligand B is worse.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.384 and -5.183), which is unusual and suggests poor permeability.

**Aqueous Solubility:** Both ligands have negative solubility values (-2.014 and -1.213), indicating very poor solubility.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.34 and 0.149).

**Microsomal Clearance:** Ligand B (-16.842) has a much *lower* (better) microsomal clearance than Ligand A (51.165), suggesting greater metabolic stability.

**In vitro Half-Life:** Ligand B (34.797) has a much longer half-life than Ligand A (-5.993).

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.068 and 0.01).

**Binding Affinity:** Ligand B (-7.8 kcal/mol) has a slightly better binding affinity than Ligand A (-7.3 kcal/mol). This difference (0.5 kcal/mol) is significant.

**Overall Assessment:**

While both compounds have significant issues (poor solubility, permeability, and BBB penetration), Ligand B is the better candidate. It has a better QED score, lower DILI risk, significantly lower microsomal clearance, longer half-life, and slightly better binding affinity. The slightly better affinity, combined with improved ADME properties (lower Cl_mic, longer t1/2, better QED, lower DILI), outweighs the slightly worse TPSA and BBB. The negative Caco-2 and solubility values are concerning for both, but can potentially be addressed with formulation strategies.

Output:
1
2025-04-17 08:38:52,838 - INFO - Reasoning:

Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (434.4 Da) is slightly higher, but acceptable. Ligand B (349.523 Da) is also good.

**TPSA:** Ligand A (82.53) is borderline for CNS penetration, being above the preferred <90 cutoff, but not drastically so. Ligand B (64.86) is well within the desirable range for CNS targets.

**logP:** Both ligands have good logP values (A: 3.085, B: 3.163), falling within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A (HBD=2, HBA=5) and Ligand B (HBD=1, HBA=6) both have reasonable numbers of H-bond donors and acceptors, well within the recommended limits.

**QED:** Both ligands have good QED scores (A: 0.592, B: 0.73), indicating good drug-like properties.

**DILI:** Ligand A (53.781) has a moderate DILI risk, but is still acceptable. Ligand B (23.187) has a very low DILI risk, which is a significant advantage.

**BBB:** Both ligands have good BBB penetration (A: 74.176, B: 72.005), exceeding the 70% threshold for CNS targets.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values, which is unusual and suggests poor permeability. However, these values are on a strange scale and may not be directly comparable.

**Aqueous Solubility:** Both ligands have negative solubility values, also unusual, suggesting poor solubility.

**hERG Inhibition:** Ligand A (0.818) has a slightly higher hERG risk than Ligand B (0.264), which is preferable.

**Microsomal Clearance:** Ligand A (65.542) has a higher microsomal clearance than Ligand B (40.495), indicating lower metabolic stability.

**In vitro Half-Life:** Ligand B (-4.409) has a negative half-life, which is not possible. This is a red flag. Ligand A (32.346) has a reasonable half-life.

**P-gp Efflux:** Ligand A (0.611) has moderate P-gp efflux, while Ligand B (0.043) has very low P-gp efflux, which is highly desirable for CNS penetration.

**Binding Affinity:** Ligand A (-8.1 kcal/mol) has a significantly stronger binding affinity than Ligand B (-6.7 kcal/mol). This is a substantial advantage, potentially outweighing some ADME drawbacks.

**Overall Assessment:**

Ligand A has a stronger binding affinity, which is crucial for GPCR targets. However, Ligand B demonstrates superior ADME properties, particularly lower DILI risk, lower P-gp efflux, and potentially better solubility and permeability (despite the unusual scale). The negative half-life value for Ligand B is a major concern and likely indicates an error in the data. Given the importance of affinity for GPCRs, and the acceptable (though not ideal) ADME profile of Ligand A, it is the more promising candidate.

Output:
1
2025-04-17 08:38:52,838 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B based on the provided guidelines, prioritizing GPCR-specific properties (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (367.83 and 365.40 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (38.13) is excellent, well below the 90 A^2 threshold for CNS targets. Ligand B (70.67) is higher, but still acceptable, though less optimal.

**logP:** Ligand A (4.173) is slightly high, potentially leading to solubility issues or off-target effects. Ligand B (1.411) is within the optimal range of 1-3.

**H-Bond Donors/Acceptors:** Ligand A (0 HBD, 3 HBA) is favorable. Ligand B (2 HBD, 4 HBA) is also acceptable.

**QED:** Both ligands have reasonable QED scores (0.813 and 0.606), indicating good drug-like properties.

**DILI:** Ligand A (58.511) has a moderate DILI risk, while Ligand B (11.865) has a very low risk, which is a significant advantage.

**BBB:** Both ligands have excellent BBB penetration (89.492 and 82.513), exceeding the desirable >70 threshold for CNS targets.

**Caco-2 Permeability:** Ligand A (-4.336) has poor Caco-2 permeability, indicating poor intestinal absorption. Ligand B (-5.102) also has poor Caco-2 permeability.

**Aqueous Solubility:** Ligand A (-4.793) has very poor solubility. Ligand B (-1.617) has poor solubility, but is better than Ligand A.

**hERG:** Both ligands show low hERG inhibition liability (0.707 and 0.667).

**Microsomal Clearance:** Ligand A (60.244) has relatively high microsomal clearance, suggesting faster metabolism. Ligand B (-5.501) has negative clearance, which is unusual and suggests high metabolic stability.

**In vitro Half-Life:** Ligand A (0.519) has a short half-life. Ligand B (4.289) has a longer half-life, which is preferable.

**P-gp Efflux:** Both ligands exhibit low P-gp efflux (0.597 and 0.018), which is good for CNS exposure.

**Binding Affinity:** Ligand A (-8.6 kcal/mol) has a slightly better binding affinity than Ligand B (-7.9 kcal/mol). However, the difference is less than the 1.5 kcal/mol threshold where affinity strongly outweighs other factors.

**Overall Assessment:**

Ligand B is the more promising candidate. While Ligand A has slightly better binding affinity, Ligand B excels in crucial ADME properties: significantly lower DILI risk, better solubility, and much better metabolic stability (indicated by negative Cl_mic and longer half-life). The logP value for Ligand B is also more optimal. The TPSA is slightly higher for Ligand B, but still acceptable for a CNS-targeting drug. The poor Caco-2 permeability for both is a concern, but can be addressed with formulation strategies.

Output:
1
2025-04-17 08:38:52,838 - INFO - Batch 466 complete. Total preferences: 7456
2025-04-17 08:38:52,838 - INFO - Processing batch 467/512...
2025-04-17 08:39:33,760 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (351.403 and 360.357 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (100.46) is slightly above the optimal <90 for CNS targets, while Ligand B (76.15) is well within the desired range. This favors Ligand B.

**logP:** Ligand A (-0.344) is a bit low, potentially hindering membrane permeability. Ligand B (0.591) is better, falling within the 1-3 range, though still on the lower side.

**H-Bond Donors/Acceptors:** Ligand A has 2 HBD and 6 HBA, which are acceptable. Ligand B has 0 HBD and 5 HBA, also acceptable.

**QED:** Both ligands have good QED scores (0.706 and 0.648), indicating good drug-like properties.

**DILI:** Ligand A (26.677) has a lower DILI risk than Ligand B (37.263), which is favorable.

**BBB:** Ligand B (89.608) has a significantly higher BBB penetration percentile than Ligand A (52.617). This is a *major* advantage for a CNS target like DRD2.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.841 and -4.267), which is unusual and suggests poor permeability. However, these values are on a scale where higher is better, so the less negative value is preferable. Ligand B is slightly better here.

**Aqueous Solubility:** Both ligands have negative solubility values (-1.748 and -1.393), indicating poor solubility. Again, the less negative value is preferable, giving a slight edge to Ligand B.

**hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.195 and 0.27), which is excellent.

**Microsomal Clearance:** Ligand A (13.652) has lower microsomal clearance than Ligand B (27.117), suggesting better metabolic stability. This is a positive for Ligand A.

**In vitro Half-Life:** Ligand A (19.356) has a longer in vitro half-life than Ligand B (-8.719), which is a significant advantage.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.043 and 0.051), which is good.

**Binding Affinity:** Ligand A (-7.3 kcal/mol) has a slightly better binding affinity than Ligand B (-7.7 kcal/mol). While the difference is small, it's still a positive for Ligand A.

**Overall Assessment:**

Ligand B excels in BBB penetration and TPSA, both critical for CNS GPCR targets. It also has slightly better Caco-2 and solubility. However, Ligand A has a better DILI score, lower Cl_mic, longer half-life, and slightly better binding affinity. The difference in binding affinity is small, and the BBB penetration advantage of Ligand B is substantial. Considering the importance of CNS penetration for DRD2, and the acceptable (though not ideal) ADME profile of Ligand B, it appears to be the more promising candidate.

Output:
1
2025-04-17 08:39:33,761 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (377.868 and 358.473 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (46.17) is slightly higher than Ligand B (40.62). Both are below the 90 A^2 threshold desirable for CNS targets, which is good.

**logP:** Both ligands have good logP values (3.988 and 3.347), falling within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A has 1 HBD and 3 HBA, while Ligand B has 0 HBD and 2 HBA. Both are within acceptable limits.

**QED:** Both ligands have similar QED values (0.611 and 0.655), indicating good drug-likeness.

**DILI:** Ligand A (54.207) has a higher DILI risk than Ligand B (25.359). This is a significant negative for Ligand A.

**BBB:** Ligand B (94.3) has a substantially better BBB penetration score than Ligand A (85.459). This is a critical advantage for a CNS target like DRD2.

**Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and suggests poor permeability. However, the values are relatively close.

**Aqueous Solubility:** Both have negative solubility values, indicating poor solubility. Again, the values are relatively close.

**hERG Inhibition:** Ligand A (0.412) has a slightly lower hERG inhibition liability than Ligand B (0.917), which is preferable.

**Microsomal Clearance:** Ligand B (45.979) has a lower microsomal clearance than Ligand A (67.606), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand B (3.049) has a longer in vitro half-life than Ligand A (-4.829). This is a positive for Ligand B.

**P-gp Efflux:** Ligand A (0.443) has lower P-gp efflux liability than Ligand B (0.62), which is favorable for CNS penetration.

**Binding Affinity:** Ligand B (-7.2 kcal/mol) has a significantly stronger binding affinity than Ligand A (-9.7 kcal/mol). This is a substantial advantage.

**Overall Assessment:**

Ligand B is the stronger candidate. While both have issues with Caco-2 and solubility, Ligand B excels in the most important parameters for a CNS-targeting GPCR ligand: BBB penetration and binding affinity. It also has lower DILI risk and better metabolic stability. The slightly higher P-gp efflux of Ligand B is less concerning given its superior BBB score. The affinity difference is significant enough to outweigh the slightly higher P-gp efflux and hERG risk.

Output:
1
2025-04-17 08:39:33,761 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (358.438 and 338.371 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (40.62) is excellent, well below the 90 A<sup>2</sup> threshold for CNS targets. Ligand B (114.77) is higher, but still potentially acceptable, though less ideal.

**logP:** Ligand A (3.245) is optimal (1-3). Ligand B (1.004) is a bit low, potentially hindering permeability.

**H-Bond Donors/Acceptors:** Ligand A (0 HBD, 3 HBA) is favorable. Ligand B (2 HBD, 5 HBA) is also acceptable, but slightly higher.

**QED:** Both ligands have similar and good QED values (0.827 and 0.81).

**DILI:** Ligand A (49.593) has a lower DILI risk than Ligand B (65.723), indicating better predicted liver safety.

**BBB:** This is crucial for a CNS target. Ligand A (87.127) has a very good BBB percentile. Ligand B (23.304) is significantly lower, suggesting poor brain penetration.

**Caco-2 Permeability:** Ligand A (-4.687) has poor Caco-2 permeability, which is concerning. Ligand B (-5.166) is also poor, but similar to A.

**Aqueous Solubility:** Both ligands have very poor aqueous solubility (-3.433 and -3.84). This could pose formulation challenges.

**hERG:** Both ligands have low hERG inhibition liability (0.719 and 0.369).

**Microsomal Clearance:** Ligand A (32.962) has moderate clearance, while Ligand B (0.995) has very low clearance, suggesting better metabolic stability.

**In vitro Half-Life:** Ligand B (8.993) has a longer half-life than Ligand A (4.15), which is desirable.

**P-gp Efflux:** Ligand A (0.436) has lower P-gp efflux than Ligand B (0.033), which is favorable for CNS exposure.

**Binding Affinity:** Both ligands have excellent binding affinities (-9.3 and -8.4 kcal/mol). Ligand A is slightly better (-9.3 kcal/mol).

**Overall Assessment:**

Ligand A is superior due to its significantly better BBB penetration (87.127 vs 23.304), lower DILI risk, and slightly better binding affinity. While both have poor solubility and Caco-2 permeability, the BBB is the most critical factor for a CNS target like DRD2. Ligand B's excellent metabolic stability (low Cl_mic and longer t1/2) is a plus, but it's outweighed by the poor BBB score.

Output:
0
2025-04-17 08:39:33,761 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (352.356 and 349.431 Da) are within the ideal 200-500 Da range.

**TPSA:** Ligand A (58.2) is excellent, falling well below the 90 A^2 threshold for CNS targets. Ligand B (104.46) is higher, but still potentially acceptable, though less ideal.

**logP:** Ligand A (2.641) is optimal (1-3). Ligand B (1.585) is a little low, potentially impacting permeability.

**H-Bond Donors/Acceptors:** Ligand A (HBD=2, HBA=2) is good. Ligand B (HBD=3, HBA=5) is slightly higher, but still within reasonable limits.

**QED:** Both ligands have good QED values (A: 0.585, B: 0.628), indicating good drug-like properties.

**DILI:** Ligand A (56.96) is moderately risky, while Ligand B (42.575) shows lower DILI risk, which is a significant advantage.

**BBB:** Both ligands have good BBB penetration (A: 54.905, B: 58.821), but Ligand B is slightly better. Both are above the desirable 70% threshold for CNS targets.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.625 and -4.797), which is unusual and suggests poor permeability. This is a major concern for both.

**Aqueous Solubility:** Both ligands have negative solubility values (-4.121 and -3.234), which is also unusual and suggests poor solubility. This is a major concern for both.

**hERG:** Both ligands have low hERG inhibition liability (A: 0.515, B: 0.166), which is excellent.

**Microsomal Clearance:** Ligand A (22.592) has lower clearance than Ligand B (44.35), indicating better metabolic stability.

**In vitro Half-Life:** Ligand A (22.769) has a longer half-life than Ligand B (-9.9), which is a significant advantage.

**P-gp Efflux:** Both ligands show low P-gp efflux liability (A: 0.113, B: 0.12).

**Binding Affinity:** Both ligands have strong binding affinities (A: -8.7 kcal/mol, B: -8.1 kcal/mol). Ligand A is slightly better (-8.7 vs -8.1).

**Overall Assessment:**

Ligand A has a slight edge in binding affinity and metabolic stability (lower Cl_mic, longer t1/2). However, Ligand B has a lower DILI risk and slightly better BBB penetration. The negative Caco-2 and solubility values are concerning for both. Considering the GPCR-specific priorities, BBB is crucial for CNS targets, and Ligand B has a slightly better value. The lower DILI risk of Ligand B is also a significant advantage. The affinity difference is relatively small (0.6 kcal/mol) and might be overcome with further optimization.

Output:
1
2025-04-17 08:39:33,762 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (341.371 and 358.507 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (120.91) is excellent for CNS penetration, being well below 90. Ligand B (34.47) is also very good, falling well below the threshold.

**logP:** Ligand A (1.419) is within the optimal 1-3 range. Ligand B (4.318) is slightly above, potentially leading to solubility issues and off-target interactions, but not drastically so.

**H-Bond Donors/Acceptors:** Ligand A has 2 HBD and 6 HBA, both acceptable. Ligand B has 0 HBD and 4 HBA, also acceptable.

**QED:** Both ligands have similar QED values (0.819 and 0.771), indicating good drug-likeness.

**DILI:** Ligand A (72.974) has a higher DILI risk than Ligand B (23.11), which is a significant concern.

**BBB:** Ligand B (88.6) has a much better BBB penetration percentile than Ligand A (47.964). This is a crucial factor for a CNS target like DRD2.

**Caco-2 Permeability:** Ligand A (-5.05) has poor Caco-2 permeability, suggesting poor intestinal absorption. Ligand B (-4.496) is also poor, but slightly better than A.

**Aqueous Solubility:** Both ligands have negative solubility values (-3.683 and -4.734), indicating poor aqueous solubility. This is a concern, but can sometimes be mitigated through formulation.

**hERG Inhibition:** Ligand A (0.112) has a very low hERG risk. Ligand B (0.84) has a higher, but still relatively low, hERG risk.

**Microsomal Clearance:** Ligand A (49.23) has a lower microsomal clearance, suggesting better metabolic stability than Ligand B (119.435).

**In vitro Half-Life:** Ligand A (0.648) has a very short in vitro half-life, which is undesirable. Ligand B (16.954) has a much longer half-life.

**P-gp Efflux:** Ligand A (0.058) has very low P-gp efflux, which is favorable for CNS penetration. Ligand B (0.854) has higher P-gp efflux, which could limit CNS exposure.

**Binding Affinity:** Ligand B (-7.6 kcal/mol) has a slightly better binding affinity than Ligand A (-8.7 kcal/mol). While A is better, the difference is not substantial enough to overcome the other drawbacks.

**Overall Assessment:**

Ligand B is the more promising candidate. While its logP is slightly elevated and solubility is poor, its significantly better BBB penetration, longer half-life, and slightly improved binding affinity outweigh the drawbacks. Ligand A's poor BBB penetration, short half-life, and poor Caco-2 permeability are major concerns. The higher DILI risk for Ligand A is also a significant negative.

Output:
1
2025-04-17 08:39:33,762 - INFO - Reasoning:

Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (345.403 and 347.463 Da) fall comfortably within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (100.25) is slightly higher than Ligand B (80.12). For CNS targets, we prefer TPSA <= 90. Ligand B is better here.

**3. logP:** Ligand B (1.354) is within the optimal 1-3 range, while Ligand A (0.46) is a bit low, potentially hindering membrane permeability. Ligand B is better.

**4. H-Bond Donors:** Both have 1 HBD, which is acceptable.

**5. H-Bond Acceptors:** Ligand A has 6 HBA, and Ligand B has 5. Both are within the acceptable limit of <=10.

**6. QED:** Both ligands have similar QED values (0.782 and 0.72), indicating good drug-likeness.

**7. DILI:** Ligand A (71.345) has a higher DILI risk than Ligand B (30.826). Lower is better, so Ligand B is preferable.

**8. BBB:** Both ligands have similar BBB penetration (52.268 and 51.803). While not exceptional (>70 is desirable), they are comparable.

**9. Caco-2:** Ligand A (-4.604) and Ligand B (-4.866) both have negative values, which is unusual. Lower values generally indicate poor permeability. They are similar.

**10. Solubility:** Ligand A (-3.102) and Ligand B (-1.47) both have negative solubility values, which is also unusual. Ligand B is slightly better.

**11. hERG:** Both ligands have very low hERG inhibition risk (0.197 and 0.069).

**12. Cl_mic:** Ligand B (21.44) has a slightly higher microsomal clearance than Ligand A (19.18), indicating potentially lower metabolic stability. Ligand A is slightly better.

**13. t1/2:** Ligand A (-14.391) has a significantly *longer* in vitro half-life than Ligand B (-0.682). This is a major advantage for Ligand A.

**14. Pgp:** Both ligands have very low P-gp efflux liability (0.088 and 0.018).

**15. Binding Affinity:** Ligand A (-7.8) has a slightly better binding affinity than Ligand B (-7.6). While the difference is small, it's within the range where it can outweigh minor ADME drawbacks.

**Overall Assessment:**

Considering the GPCR-specific priorities, Ligand B has advantages in TPSA and logP. However, Ligand A has a significantly longer half-life and slightly better binding affinity, and a lower DILI risk. The longer half-life is particularly important for CNS drugs, as it allows for less frequent dosing. The slightly better affinity also contributes to its potential. The slightly lower logP of Ligand A is a concern, but the other factors outweigh this.

Output:
1
2025-04-17 08:39:33,762 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (357.885 and 359.348 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (39.6) is significantly better than Ligand B (63.69). For CNS targets, we want TPSA <= 90, and ideally closer to 60. Ligand A is much closer to this ideal.

**logP:** Both ligands have good logP values (3.82 and 3.026), falling within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Both have 1 HBD and 4 HBA, which are acceptable.

**QED:** Both ligands have high QED scores (0.906 and 0.882), indicating good drug-likeness.

**DILI:** Both ligands have similar, acceptable DILI risk (43.932 and 43.66). Both are below the 60 threshold.

**BBB:** Ligand B (96.937) has a substantially better BBB penetration score than Ligand A (85.072). This is a critical factor for a CNS target like DRD2.

**Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and requires further investigation. However, the magnitude is similar.

**Aqueous Solubility:** Both have negative solubility values, which is also unusual. Again, the magnitude is similar.

**hERG Inhibition:** Ligand A (0.911) has a slightly higher hERG inhibition risk than Ligand B (0.583), but both are relatively low.

**Microsomal Clearance:** Ligand B (13.469) has significantly lower microsomal clearance than Ligand A (49.32), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand B (-2.011) has a much longer in vitro half-life than Ligand A (61.027). This is a significant advantage.

**P-gp Efflux:** Ligand A (0.767) shows slightly higher P-gp efflux liability compared to Ligand B (0.248), which is unfavorable for CNS penetration.

**Binding Affinity:** Ligand B (-9.3 kcal/mol) has a slightly better binding affinity than Ligand A (-10 kcal/mol). While both are excellent, the difference is small.

**Overall Assessment:**

Ligand B is superior due to its significantly better BBB penetration (96.937 vs 85.072), lower microsomal clearance (13.469 vs 49.32), longer half-life (-2.011 vs 61.027), and lower P-gp efflux (0.248 vs 0.767). While Ligand A has a slightly better binding affinity, the ADME properties of Ligand B are more favorable for a CNS-targeting drug. The lower TPSA of Ligand A is a positive, but the other ADME advantages of Ligand B outweigh this.

Output:
1
2025-04-17 08:39:33,762 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (345.443 and 352.435 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (71.53) is excellent, well below the 90 A^2 threshold for CNS targets. Ligand B (106) is higher but still potentially acceptable, though less ideal.

**logP:** Ligand A (2.258) is optimal (1-3). Ligand B (-0.535) is significantly lower, which could hinder membrane permeability and CNS penetration.

**H-Bond Donors/Acceptors:** Ligand A (1 HBD, 5 HBA) is favorable. Ligand B (3 HBD, 6 HBA) is also acceptable, but slightly higher.

**QED:** Both ligands have reasonable QED values (0.606 and 0.522), indicating good drug-like properties.

**DILI:** Ligand A (33.307) has a very low DILI risk. Ligand B (14.696) also has a low DILI risk.

**BBB:** Ligand A (70.027) has a good BBB percentile, exceeding the desirable >70% for CNS targets. Ligand B (19.077) is very poor, indicating limited brain penetration. This is a critical disadvantage for a DRD2 ligand.

**Caco-2 Permeability:** Ligand A (-4.594) is concerningly low. Ligand B (-5.441) is also low, but slightly better.

**Aqueous Solubility:** Ligand A (-2.184) is low. Ligand B (0.006) is very close to zero, indicating extremely poor solubility.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.342 and 0.21), which is positive.

**Microsomal Clearance:** Ligand A (109.88) is relatively high, suggesting faster metabolism. Ligand B (-14.241) is negative, which is unusual and could indicate issues with the modeling or a very stable compound.

**In vitro Half-Life:** Ligand A (7.35 hours) is reasonable. Ligand B (22.514 hours) is significantly longer, which is a positive attribute.

**P-gp Efflux:** Both ligands show low P-gp efflux liability (0.076 and 0.014), which is beneficial for CNS penetration.

**Binding Affinity:** Ligand A (-7.6 kcal/mol) has a significantly stronger binding affinity than Ligand B (-6.9 kcal/mol). The 0.7 kcal/mol difference is substantial and can outweigh some ADME drawbacks.

**Overall Assessment:**

Ligand A is the better candidate despite its lower Caco-2 permeability and higher microsomal clearance. Its superior BBB penetration, optimal logP, and significantly stronger binding affinity are crucial for a DRD2 ligand targeting CNS disorders. Ligand B's very poor logP and BBB penetration are major drawbacks that are unlikely to be overcome. While Ligand B has a longer half-life, the lack of brain exposure makes it a less viable candidate.

Output:
0
2025-04-17 08:39:33,763 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight (MW):** Both ligands (346.471 and 342.483 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (67.43) is higher than Ligand B (49.41). For CNS targets, we prefer TPSA <= 90, both are within this range, but B is significantly better.

**3. logP:** Both ligands have good logP values (2.169 and 2.891), falling within the optimal 1-3 range.

**4. H-Bond Donors (HBD):** Both ligands have acceptable HBD counts (2 and 1 respectively), well below the threshold of 5.

**5. H-Bond Acceptors (HBA):** Both ligands have acceptable HBA counts (3 and 2 respectively), below the threshold of 10.

**6. QED:** Both ligands have reasonable QED scores (0.724 and 0.633), indicating good drug-like properties.

**7. DILI:** Ligand A (15.394) has a much lower DILI risk than Ligand B (36.603). This is a significant advantage for Ligand A.

**8. BBB:** Ligand B (71.035) has a slightly better BBB penetration percentile than Ligand A (69.019), both are above the desirable 70% threshold for CNS targets.

**9. Caco-2 Permeability:** Ligand A (-5.042) has worse Caco-2 permeability than Ligand B (-4.612). Both are negative, but B is less negative.

**10. Aqueous Solubility:** Ligand A (-2.911) has slightly better aqueous solubility than Ligand B (-3.807).

**11. hERG Inhibition:** Ligand A (0.221) has a lower hERG inhibition liability than Ligand B (0.468), which is preferable.

**12. Microsomal Clearance (Cl_mic):** Ligand B (74.402) has a much higher microsomal clearance than Ligand A (34.32). Lower clearance is better for metabolic stability, favoring Ligand A.

**13. In vitro Half-Life (t1/2):** Ligand A (-0.471) has a longer in vitro half-life than Ligand B (-15.085). This is a significant advantage for Ligand A.

**14. P-gp Efflux:** Ligand A (0.053) has lower P-gp efflux liability than Ligand B (0.326), which is beneficial for CNS penetration.

**15. Binding Affinity:** Ligand B (-8.8) has a slightly better binding affinity than Ligand A (-8.1). While a difference of 0.7 kcal/mol is noticeable, the other ADME properties are more concerning for Ligand B.

**Overall Assessment:**

Considering the GPCR-specific priorities, Ligand A is the more promising candidate. While Ligand B has a slightly better binding affinity and BBB penetration, Ligand A demonstrates significantly better DILI risk, metabolic stability (lower Cl_mic, longer t1/2), lower P-gp efflux, and lower hERG inhibition. The TPSA is also more favorable in Ligand A. The slightly worse Caco-2 permeability of Ligand A is less concerning than the higher DILI and clearance of Ligand B. The small difference in binding affinity can potentially be optimized during lead optimization.

Output:
0
2025-04-17 08:39:33,763 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight (MW):** Both ligands (364.408 and 359.495 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (58.64) is better than Ligand B (55.32). Both are below the 90 A^2 threshold for CNS targets, which is excellent.

**3. logP:** Ligand A (2.295) is within the optimal 1-3 range. Ligand B (3.614) is slightly higher, but still acceptable.

**4. H-Bond Donors (HBD):** Both ligands are acceptable (1 and 0, respectively), being less than 5.

**5. H-Bond Acceptors (HBA):** Both ligands are acceptable (3 and 5, respectively), being less than 10.

**6. QED:** Both ligands are good (0.787 and 0.758), indicating a strong drug-like profile.

**7. DILI:** Ligand A (16.789) has a significantly lower DILI risk than Ligand B (21.753), which is a substantial advantage.

**8. BBB:** Ligand A (96.084) has a much higher BBB penetration percentile than Ligand B (74.796). This is *critical* for a CNS target like DRD2.

**9. Caco-2 Permeability:** Both are negative, indicating poor permeability. Ligand A (-4.363) is slightly better than Ligand B (-4.498).

**10. Aqueous Solubility:** Both are negative, indicating poor solubility. Ligand A (-2.197) is slightly better than Ligand B (-3.1).

**11. hERG Inhibition:** Both ligands have low hERG inhibition risk (0.661 and 0.619).

**12. Microsomal Clearance:** Ligand A (14.801) has a lower microsomal clearance than Ligand B (67.184), suggesting better metabolic stability.

**13. In vitro Half-Life:** Ligand A (-11.593) has a longer *predicted* half-life than Ligand B (4.972).

**14. P-gp Efflux:** Ligand A (0.033) has much lower P-gp efflux liability than Ligand B (0.215), which is beneficial for CNS exposure.

**15. Binding Affinity:** Ligand A (-8.2 kcal/mol) has a significantly stronger binding affinity than Ligand B (-6.5 kcal/mol). This 1.7 kcal/mol difference is very substantial and can outweigh minor ADME drawbacks.

**Overall Assessment:**

Ligand A is clearly superior. It has a significantly better BBB score, lower DILI risk, lower P-gp efflux, better metabolic stability (lower Cl_mic and longer half-life), and a much stronger binding affinity. While both have poor Caco-2 and solubility, the strong affinity and CNS penetration profile of Ligand A make it the far more promising candidate.

Output:
1
2025-04-17 08:39:33,763 - INFO - Reasoning:

Let's analyze Ligand A and Ligand B for their potential as DRD2 drug candidates, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (363.805 and 365.405 Da) fall comfortably within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (107.4) is higher than the preferred <90 for CNS targets, but not drastically so. Ligand B (56.67) is excellent, well below the threshold. This favors Ligand B.

**3. logP:** Both ligands have good logP values (2.668 and 3.313), falling within the optimal 1-3 range.

**4. H-Bond Donors:** Both have 1 HBD, which is acceptable.

**5. H-Bond Acceptors:** Ligand A has 4 HBA, and Ligand B has 5. Both are within the acceptable limit of <=10.

**6. QED:** Ligand B (0.903) has a significantly better QED score than Ligand A (0.376), indicating a more drug-like profile. This is a substantial advantage for Ligand B.

**7. DILI:** Ligand A (59.131) has a slightly higher DILI risk than Ligand B (68.903), but both are reasonably acceptable.

**8. BBB:** Both ligands have excellent BBB penetration (77.898% and 71.85%), exceeding the desirable >70% threshold for CNS targets.

**9. Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and suggests poor permeability. However, these values are on a log scale and the negative values are not directly comparable.

**10. Aqueous Solubility:** Both ligands have very poor aqueous solubility (-3.299 and -4.659). This is a significant drawback for both.

**11. hERG Inhibition:** Both ligands have low hERG inhibition risk (0.353 and 0.361).

**12. Microsomal Clearance:** Ligand A (1.792) has significantly lower microsomal clearance than Ligand B (54.518), suggesting better metabolic stability. This favors Ligand A.

**13. In vitro Half-Life:** Ligand A (7.068) has a better in vitro half-life than Ligand B (-9.204). This is a substantial advantage for Ligand A.

**14. P-gp Efflux:** Both ligands have low P-gp efflux liability (0.1 and 0.239), which is good for CNS exposure.

**15. Binding Affinity:** Ligand B (-9.7 kcal/mol) has a significantly stronger binding affinity than Ligand A (-7.7 kcal/mol). This is a >1.5 kcal/mol advantage, which can outweigh minor ADME drawbacks.

**Overall Assessment:**

Ligand B has a superior QED score and significantly better binding affinity. Its TPSA is also much more favorable for CNS penetration. While Ligand A has better metabolic stability (lower Cl_mic) and half-life, the strong binding affinity of Ligand B, coupled with its good BBB penetration and acceptable ADME properties, makes it the more promising candidate. The solubility issues are a concern for both, but can potentially be addressed through formulation strategies.



Output:
1
2025-04-17 08:39:33,763 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (349.435 and 364.511 Da) fall within the ideal range of 200-500 Da.

**TPSA:** Ligand A (98.4) is slightly above the optimal <90 for CNS targets, but still reasonable. Ligand B (58.64) is excellent, well below 90.

**logP:** Ligand A (0.666) is a bit low, potentially hindering permeability. Ligand B (2.893) is within the optimal 1-3 range.

**H-Bond Donors:** Ligand A (2) and Ligand B (1) are both acceptable, below the threshold of 5.

**H-Bond Acceptors:** Both ligands (A: 4, B: 4) are well below the threshold of 10.

**QED:** Both ligands have similar QED values (A: 0.674, B: 0.65), indicating good drug-like properties.

**DILI:** Ligand A (25.204) has a much lower DILI risk than Ligand B (31.059), both are good.

**BBB:** Ligand B (78.868) has a significantly better BBB penetration percentile than Ligand A (51.842). This is a critical advantage for a CNS target like DRD2.

**Caco-2 Permeability:** Ligand A (-5.566) has poor Caco-2 permeability, while Ligand B (-4.628) is slightly better, but still poor.

**Aqueous Solubility:** Ligand A (-1.455) has slightly better solubility than Ligand B (-3.157).

**hERG Inhibition:** Both ligands have very low hERG inhibition risk (A: 0.093, B: 0.494).

**Microsomal Clearance:** Ligand A (4.703) has a lower microsomal clearance than Ligand B (81.987), indicating better metabolic stability.

**In vitro Half-Life:** Ligand A (-11.706) has a very long in vitro half-life, while Ligand B (17.545) is moderate.

**P-gp Efflux:** Ligand A (0.008) has very low P-gp efflux, which is favorable for CNS penetration. Ligand B (0.288) has slightly higher P-gp efflux.

**Binding Affinity:** Both ligands have the same binding affinity (-7.5 kcal/mol), which is excellent.

**Overall Assessment:**

Ligand B excels in BBB penetration and has a good logP, which are crucial for CNS GPCR targets. However, its higher P-gp efflux and significantly higher microsomal clearance are concerning. Ligand A has a lower logP, but compensates with excellent metabolic stability (low Cl_mic, long t1/2), very low P-gp efflux, and a lower DILI risk. The poor Caco-2 permeability of Ligand A is a drawback, but less critical for a CNS target where direct brain exposure is prioritized. Given the importance of BBB penetration for DRD2, and the similar affinity, Ligand B is slightly favored. However, the metabolic liability of Ligand B is a significant concern.

Output:
1
2025-04-17 08:39:33,764 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 drug candidates, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (344.459 Da and 372.342 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (74.33) is significantly better than Ligand B (89.19). For CNS targets, we want TPSA <= 90, and A is comfortably within that range, while B is approaching the upper limit.

**3. logP:** Both ligands have good logP values (2.759 and 2.17), falling within the optimal 1-3 range.

**4. H-Bond Donors:** Both have 2 HBD, which is acceptable.

**5. H-Bond Acceptors:** Ligand A has 3 HBA, while Ligand B has 7.  Lower HBA is generally preferred for better permeability, giving an edge to Ligand A.

**6. QED:** Ligand A (0.866) has a significantly higher QED than Ligand B (0.676), indicating a more drug-like profile.

**7. DILI:** Ligand A (39.201) has a lower DILI risk than Ligand B (56.844), which is favorable.

**8. BBB:** Both ligands have excellent BBB penetration (82.358% and 83.87%), exceeding the desirable >70% threshold for CNS targets. This is a strong positive for both.

**9. Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and suggests a potential issue with the data or modeling. However, the values are similar (-4.682 and -4.809).

**10. Aqueous Solubility:** Both have negative solubility values, which is also unusual. Again, the values are similar (-3.455 and -4.634).

**11. hERG Inhibition:** Both ligands show low hERG inhibition risk (0.489 and 0.644).

**12. Microsomal Clearance:** Ligand A (38.573) has lower microsomal clearance than Ligand B (55.99), suggesting better metabolic stability.

**13. In vitro Half-Life:** Ligand A (12.005 hours) has a longer half-life than Ligand B (-2.124 hours). A negative half-life is not physically possible, indicating a data issue with Ligand B.

**14. P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.088 and 0.052), which is excellent for CNS exposure.

**15. Binding Affinity:** Ligand B (-8.4 kcal/mol) has a slightly better binding affinity than Ligand A (-9.1 kcal/mol). While a >1.5 kcal/mol advantage is significant, the difference here is relatively small.

**Overall Assessment:**

Ligand A is the stronger candidate. It has a better TPSA, QED, DILI risk, metabolic stability (lower Cl_mic), and a longer half-life. While Ligand B has slightly better binding affinity, the other ADME properties of Ligand A are superior, especially considering the GPCR-specific priorities and the questionable negative half-life for Ligand B. The negative solubility and Caco-2 values are concerning for both, but the overall profile of A is more promising.

Output:
1
2025-04-17 08:39:33,764 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (349.475 and 355.435 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (61.88) is significantly better than Ligand B (93.89). For CNS targets, we want TPSA <= 90, so Ligand A is preferable.

**logP:** Both ligands have similar logP values (0.864 and 0.878), falling within the optimal 1-3 range.

**H-Bond Donors:** Both have 1 HBD, which is acceptable.

**H-Bond Acceptors:** Ligand A has 4 HBA, while Ligand B has 7.  Both are acceptable (<=10), but A is slightly better.

**QED:** Ligand A (0.522) is slightly better than Ligand B (0.495), both being above the 0.5 threshold.

**DILI:** Ligand A (11.09) has a much lower DILI risk than Ligand B (38.62). This is a significant advantage for Ligand A.

**BBB:** Ligand A (66.576) has a better BBB penetration percentile than Ligand B (59.597). While >70 is desirable, A is closer.

**Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and potentially problematic. However, the magnitude of negativity is similar (-4.718 vs -4.543), so this isn't a major differentiator.

**Aqueous Solubility:** Both have negative solubility values, which is also unusual. Again, the values are similar (-1.093 vs -0.58), so this isn't a major differentiator.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.243 and 0.252).

**Microsomal Clearance:** Ligand A (18.671) has a much lower microsomal clearance than Ligand B (77.187), indicating better metabolic stability.

**In vitro Half-Life:** Ligand A (2.93 hours) has a positive half-life, while Ligand B (-22.304 hours) has a negative half-life, which is not physically meaningful. This is a major advantage for Ligand A.

**P-gp Efflux:** Ligand A (0.036) has much lower P-gp efflux liability than Ligand B (0.1). This is crucial for CNS penetration.

**Binding Affinity:** Ligand B (-6.0) has a significantly better binding affinity than Ligand A (0.0). This is a substantial advantage for Ligand B.

**Overall Assessment:**

Despite the significantly better binding affinity of Ligand B, Ligand A has a much more favorable ADME profile. The lower TPSA, DILI, clearance, P-gp efflux, and a positive half-life, combined with reasonable BBB penetration, make Ligand A a more promising drug candidate. The superior affinity of Ligand B is tempting, but the poor ADME properties, particularly the high clearance and P-gp efflux, are likely to translate to poor *in vivo* exposure and efficacy. For a CNS target like DRD2, getting the drug into the brain is paramount, and Ligand A is better positioned to achieve that.

Output:
0
2025-04-17 08:39:33,764 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 drug candidates, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (353.304 and 349.362 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (73.33) is significantly better than Ligand B (93.46). For CNS targets, TPSA should be <= 90, so Ligand A is preferable.

**3. logP:** Both ligands have acceptable logP values (1.327 and 2.377, respectively), falling within the optimal 1-3 range. Ligand B is slightly higher, which could potentially lead to some off-target effects, but it's not a major concern.

**4. H-Bond Donors:** Both ligands have acceptable HBD counts (1 and 2, respectively), well below the threshold of 5.

**5. H-Bond Acceptors:** Both ligands have acceptable HBA counts (6 and 5, respectively), below the threshold of 10.

**6. QED:** Both ligands have similar and good QED values (0.769 and 0.781), indicating good drug-like properties.

**7. DILI:** Ligand A (70.803) has a higher DILI risk than Ligand B (52.346). This is a significant advantage for Ligand B.

**8. BBB:** Both ligands have good BBB penetration (69.407 and 64.211, respectively), but Ligand A is slightly better. A value >70 is desirable, and both are reasonably close.

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.985 and -4.336). This is unusual and suggests poor permeability. However, these values are on a scale where negative values are possible, and the absolute magnitude is important. They are relatively similar.

**10. Aqueous Solubility:** Both ligands have negative solubility values (-2.551 and -3.344). Again, this is unusual and suggests poor solubility. The values are similar.

**11. hERG Inhibition:** Both ligands have low hERG inhibition risk (0.418 and 0.271, respectively). Ligand B is slightly better.

**12. Microsomal Clearance:** Ligand A (10.658) has significantly lower microsomal clearance than Ligand B (84.31). Lower clearance is preferred for better metabolic stability.

**13. In vitro Half-Life:** Ligand A (8.775) has a lower in vitro half-life than Ligand B (52.615). Longer half-life is generally desirable.

**14. P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.235 and 0.031, respectively). Ligand B is significantly better, which is crucial for CNS penetration.

**15. Binding Affinity:** Both ligands have excellent binding affinity (-9.2 and -9.0 kcal/mol, respectively). The difference is minimal.

**Overall Assessment:**

While Ligand A has a slightly better TPSA and BBB, Ligand B has significant advantages in DILI risk, P-gp efflux, microsomal clearance, and in vitro half-life. Given the GPCR-specific priorities, especially BBB and P-gp efflux for CNS targets, Ligand B is the more promising candidate. The lower DILI risk and improved metabolic stability (lower Cl_mic and higher t1/2) further support this conclusion. The slight difference in affinity is negligible given the strong binding of both.

Output:
1
2025-04-17 08:39:33,764 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 drug candidates, considering the provided guidelines and GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight (MW):** Both ligands are within the ideal range (200-500 Da). Ligand A (346.427 Da) is slightly lower, which is generally favorable for permeability. Ligand B (359.905 Da) is also good.

**2. TPSA:** Ligand A (84.5) is excellent, falling well below the 90 Angstroms threshold for CNS targets. Ligand B (46.84) is also very good.

**3. logP:** Ligand A (1.408) is within the optimal range (1-3). Ligand B (3.754) is approaching the upper limit, potentially raising concerns about solubility and off-target effects, but still acceptable.

**4. H-Bond Donors (HBD):** Ligand A (2) and Ligand B (0) both meet the criteria of <=5.

**5. H-Bond Acceptors (HBA):** Ligand A (4) and Ligand B (5) both meet the criteria of <=10.

**6. QED:** Both ligands have good QED scores (Ligand A: 0.671, Ligand B: 0.788), indicating drug-like properties.

**7. DILI:** Ligand A (23.226) has a significantly lower DILI risk than Ligand B (15.82). This is a substantial advantage for Ligand A.

**8. BBB:** Both ligands exhibit good BBB penetration (Ligand A: 71.462, Ligand B: 78.79). Ligand B is slightly better, but both are above the 70% threshold for CNS targets.

**9. Caco-2 Permeability:** Ligand A (-4.746) has poor Caco-2 permeability, while Ligand B (-5.02) is also poor.

**10. Aqueous Solubility:** Ligand A (-2.006) and Ligand B (-3.59) both have poor solubility.

**11. hERG Inhibition:** Ligand A (0.124) has a very low hERG inhibition risk, while Ligand B (0.502) is slightly higher.

**12. Microsomal Clearance:** Ligand A (25.13) has lower microsomal clearance than Ligand B (37.348), suggesting better metabolic stability.

**13. In vitro Half-Life:** Ligand A (-5.172) has a longer in vitro half-life than Ligand B (7.882).

**14. P-gp Efflux:** Ligand A (0.038) has significantly lower P-gp efflux liability than Ligand B (0.23), which is crucial for CNS penetration.

**15. Binding Affinity:** Ligand B (-8.4) has a slightly better binding affinity than Ligand A (-7.8). This is a 1.5 kcal/mol advantage, which is significant.

**Overall Assessment:**

While Ligand B has a slightly better binding affinity, Ligand A demonstrates a superior ADME profile. Specifically, its lower DILI risk, lower P-gp efflux, better metabolic stability (lower Cl_mic and longer t1/2), and lower hERG risk are all highly desirable characteristics for a CNS drug candidate. The slightly lower BBB penetration of Ligand A is less concerning given its other favorable properties. The poor Caco-2 and solubility of both compounds are potential issues, but can be addressed with formulation strategies. Given the GPCR-specific priorities, the improvements in ADME properties outweigh the small difference in binding affinity.

Output:
0
2025-04-17 08:39:33,765 - INFO - Batch 467 complete. Total preferences: 7472
2025-04-17 08:39:33,765 - INFO - Processing batch 468/512...
2025-04-17 08:40:15,061 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (368.865 and 367.471 Da) fall within the ideal range of 200-500 Da.

**TPSA:** Ligand A (89.53) is better than Ligand B (97.39). Both are under the 90 A^2 threshold for CNS targets, but A is closer to the optimal range.

**logP:** Ligand A (1.533) is slightly better than Ligand B (0.773), both are within the optimal 1-3 range.

**H-Bond Donors:** Both ligands have 2 HBD, which is acceptable.

**H-Bond Acceptors:** Ligand A has 4 HBA, and Ligand B has 5. Both are acceptable, under the 10 threshold.

**QED:** Ligand A (0.846) is significantly better than Ligand B (0.596), indicating a more drug-like profile.

**DILI:** Ligand A (59.442) and Ligand B (56.146) are both relatively low risk, below the 60 threshold.

**BBB:** Ligand B (35.052) is considerably better than Ligand A (25.32). This is a critical factor for a CNS target like DRD2.

**Caco-2 Permeability:** Ligand A (-4.997) is better than Ligand B (-4.886), but both are negative values, indicating poor permeability.

**Aqueous Solubility:** Ligand A (-3.183) is better than Ligand B (-2.834), but both are negative values, indicating poor solubility.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.394 and 0.291).

**Microsomal Clearance:** Ligand A (6.389) has lower clearance than Ligand B (10.488), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (-13.147) has a much longer half-life than Ligand B (-28.944), which is a significant advantage.

**P-gp Efflux:** Ligand A (0.326) has lower P-gp efflux than Ligand B (0.049), which is better for CNS exposure.

**Binding Affinity:** Ligand B (-7.2) has a slightly better binding affinity than Ligand A (-8.0). However, the difference is less than 1.5 kcal/mol, and other factors are more important.

**Overall Assessment:**

Ligand A excels in QED, metabolic stability (Cl_mic and t1/2), P-gp efflux, and TPSA. Ligand B's primary advantage is its BBB penetration. However, the superior ADME properties of Ligand A, particularly its longer half-life and lower efflux, combined with acceptable binding affinity, outweigh the BBB advantage of Ligand B. The slightly better affinity of Ligand B is not enough to overcome the other deficiencies.

Output:
1
2025-04-17 08:40:15,061 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B based on the provided guidelines, prioritizing GPCR-specific properties (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (364.515 and 367.471 Da) fall within the ideal range of 200-500 Da.

**TPSA:** Ligand A (75.19) is significantly better than Ligand B (91.76). For CNS targets, TPSA should be <=90, and A is much closer to the ideal.

**logP:** Ligand A (2.55) is optimal (1-3), while Ligand B (0.735) is a bit low, potentially hindering permeation.

**H-Bond Donors/Acceptors:** Ligand A (HBD=1, HBA=5) is better than Ligand B (HBD=3, HBA=6) regarding the balance of solubility and permeability.

**QED:** Both ligands have acceptable QED values (0.787 and 0.645, both >0.5).

**DILI:** Ligand A (47.732) has a lower DILI risk than Ligand B (72.199), which is preferable.

**BBB:** This is a critical parameter for DRD2. Ligand A (61.807) is moderately good, while Ligand B (18.961) is quite poor. A BBB percentile >70 is desirable, and A is closer.

**Caco-2 Permeability:** Both are negative (-5.162 and -5.102), which is unusual and difficult to interpret without knowing the scale. We'll assume lower values indicate poorer permeability.

**Aqueous Solubility:** Both are negative (-2.675 and -1.694), again unusual. Lower values suggest poorer solubility.

**hERG:** Both ligands have very low hERG inhibition risk (0.126 and 0.155).

**Microsomal Clearance:** Ligand A (50.078) has a moderate clearance, while Ligand B (0.102) has extremely low clearance, suggesting high metabolic stability.

**In vitro Half-Life:** Ligand A (-1.99) has a negative half-life, which is impossible. Ligand B (4.656) is reasonable. This is a major red flag for Ligand A.

**P-gp Efflux:** Ligand A (0.283) has lower P-gp efflux, which is good for CNS penetration, compared to Ligand B (0.034).

**Binding Affinity:** Ligand A (-7.2 kcal/mol) has a slightly better binding affinity than Ligand B (-6.5 kcal/mol). While the difference is less than the 1.5 kcal/mol threshold, it's still a positive factor.

**Overall Assessment:**

Ligand A has a better TPSA, logP, H-bond profile, DILI risk, and P-gp efflux. However, the negative in vitro half-life is a critical flaw. Ligand B has excellent metabolic stability (very low Cl_mic) but suffers from poor BBB penetration, a suboptimal logP, and a higher DILI risk.

Despite the slightly better affinity of Ligand A, the impossible half-life makes it a non-starter. A negative half-life indicates a fundamental issue with the data or the molecule's stability. Therefore, Ligand B, while not ideal, is the more viable candidate.

Output:
1
2025-04-17 08:40:15,061 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (361.511 Da) is slightly higher than Ligand B (338.415 Da), but both are acceptable.

**TPSA:** Ligand A (71.09) is excellent for CNS penetration, well below the 90 A^2 threshold. Ligand B (95.59) is still reasonable but less optimal, approaching the 100 A^2 limit.

**logP:** Both ligands have good logP values (A: 3.112, B: 2.205), falling within the 1-3 range. Ligand A is slightly more lipophilic, which *could* be beneficial for membrane permeability, but also raises a slight concern for off-target effects.

**H-Bond Donors/Acceptors:** Ligand A (HBD=2, HBA=4) and Ligand B (HBD=3, HBA=6) both fall within acceptable limits.

**QED:** Both ligands have similar QED values (A: 0.524, B: 0.504), indicating good drug-like properties.

**DILI:** Ligand A (34.238) has a significantly lower DILI risk than Ligand B (69.95). This is a major advantage for Ligand A.

**BBB:** Ligand A (62.078) has a lower BBB penetration than Ligand B (67.313), but both are acceptable for a CNS target. A value >70 is desirable, and both are below that, but Ligand B is closer.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values, which is unusual and suggests a potential issue with permeability prediction. However, the magnitude of the negative value for Ligand A (-4.854) is less extreme than for Ligand B (-5.453).

**Aqueous Solubility:** Both ligands have negative solubility values, also unusual. Again, Ligand A (-3.095) is slightly better than Ligand B (-3.431).

**hERG Inhibition:** Both ligands have low hERG inhibition risk (A: 0.413, B: 0.613).

**Microsomal Clearance:** Ligand A (29.349) has a lower microsomal clearance than Ligand B (57.708), indicating better metabolic stability.

**In vitro Half-Life:** Ligand A (14.093) has a significantly longer in vitro half-life than Ligand B (0.562). This is a substantial advantage.

**P-gp Efflux:** Ligand A (0.275) has a much lower P-gp efflux liability than Ligand B (0.178), which is crucial for CNS penetration.

**Binding Affinity:** Ligand B (-9.3 kcal/mol) has a significantly stronger binding affinity than Ligand A (-7.7 kcal/mol). This is a substantial advantage for Ligand B, exceeding the 1.5 kcal/mol difference threshold.

**Overall Assessment:**

While Ligand A has advantages in terms of DILI, metabolic stability, half-life, and P-gp efflux, the significantly stronger binding affinity of Ligand B (-9.3 vs -7.7 kcal/mol) is a decisive factor. The affinity difference is large enough to outweigh the ADME drawbacks of Ligand B. The slightly lower BBB and higher DILI of Ligand B are concerns, but can potentially be addressed through further optimization. The negative Caco-2 and solubility values are concerning for both, but the affinity advantage of B is too significant to ignore.

Output:
1
2025-04-17 08:40:15,061 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, considering the provided guidelines and GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (341.382 and 349.431 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (55.4) is significantly better than Ligand B (84.67). For CNS targets, TPSA should be <= 90, and A is comfortably within that range, while B is approaching the upper limit.

**3. logP:** Ligand A (3.981) is optimal (1-3), while Ligand B (1.767) is on the lower side. While not terrible, lower logP can sometimes hinder permeability.

**4. H-Bond Donors:** Both ligands have 1 HBD, which is within the acceptable limit of <=5.

**5. H-Bond Acceptors:** Ligand A has 3 HBAs, and Ligand B has 5. Both are within the acceptable limit of <=10.

**6. QED:** Both ligands have good QED scores (0.837 and 0.895), indicating good drug-like properties.

**7. DILI:** Ligand A (69.794) has a higher DILI risk than Ligand B (40.83). This is a negative for Ligand A.

**8. BBB:** Ligand A (90.074) has excellent BBB penetration, exceeding the desirable threshold of >70. Ligand B (77.705) is still reasonable but lower. This is a significant advantage for Ligand A, given the CNS target.

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.203 and -4.682). These values are unusual and difficult to interpret without knowing the scale. However, they suggest poor permeability.

**10. Aqueous Solubility:** Both ligands have negative solubility values (-5.787 and -1.706). Similar to Caco-2, these are unusual and suggest poor solubility.

**11. hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.531 and 0.231).

**12. Microsomal Clearance:** Ligand A (114.555) has higher microsomal clearance than Ligand B (46.74). This suggests lower metabolic stability for Ligand A.

**13. In vitro Half-Life:** Ligand B (-25.594) has a significantly longer in vitro half-life than Ligand A (6.343). This is a major advantage for Ligand B.

**14. P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.359 and 0.071).

**15. Binding Affinity:** Both ligands have the same binding affinity (-9.3 kcal/mol), which is excellent.

**Overall Assessment:**

Ligand A excels in BBB penetration and has a better TPSA. However, it suffers from higher DILI risk and poorer metabolic stability (higher Cl_mic, shorter t1/2). Ligand B has a lower DILI risk, better metabolic stability, and a longer half-life, but its TPSA is higher and BBB penetration is lower. Given the CNS target and the importance of BBB penetration for GPCRs, Ligand A is slightly favored despite its drawbacks. The equal binding affinity makes the ADME properties the deciding factor. The lower TPSA and high BBB of Ligand A are more critical for a CNS-acting GPCR ligand.

Output:
0
2025-04-17 08:40:15,061 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B based on the provided guidelines, prioritizing GPCR-specific properties (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (354.885 Da) is slightly higher than Ligand B (284.428 Da), but both are acceptable.

**TPSA:** Ligand A (33.95) is better than Ligand B (6.48) for CNS penetration, falling well below the 90 A^2 threshold. Ligand B is excellent.

**logP:** Both ligands have similar logP values (A: 4.179, B: 4.241), slightly above the optimal range of 1-3, but not excessively high. This could potentially lead to some solubility issues, but is not a major concern.

**H-Bond Donors/Acceptors:** Both ligands have low HBD counts (0). Ligand A has 4 HBA, and Ligand B has 3. Both are within acceptable limits.

**QED:** Both ligands have good QED scores (A: 0.704, B: 0.829), indicating good drug-like properties.

**DILI:** Ligand A (65.568) has a higher DILI risk than Ligand B (49.166), but both are still below the concerning threshold of 60.

**BBB:** Ligand B (98.914) has a significantly better BBB penetration score than Ligand A (88.329). This is a crucial advantage for a CNS target like DRD2.

**Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and needs further investigation. It suggests poor permeability, but these values can be unreliable.

**Aqueous Solubility:** Both ligands have poor aqueous solubility (A: -3.23, B: -4.438). This could be a formulation challenge.

**hERG Inhibition:** Ligand A (0.724) has a slightly higher hERG risk than Ligand B (0.968), but both are relatively low.

**Microsomal Clearance:** Ligand B (20.903) has significantly lower microsomal clearance than Ligand A (37.759), indicating better metabolic stability.

**In vitro Half-Life:** Ligand A (145.735) has a much longer in vitro half-life than Ligand B (2.008). This is a significant advantage.

**P-gp Efflux:** Ligand A (0.739) has lower P-gp efflux liability than Ligand B (0.512), which is favorable for CNS exposure.

**Binding Affinity:** Ligand B (-7.5 kcal/mol) has a significantly stronger binding affinity than Ligand A (-9.8 kcal/mol). This is a substantial advantage, potentially outweighing some of the ADME drawbacks.

**Overall Assessment:**

While Ligand A has a longer half-life and lower P-gp efflux, Ligand B excels in the most critical areas for a CNS-targeting GPCR: **BBB penetration and binding affinity**. The significantly stronger binding affinity (-7.5 vs -9.8 kcal/mol) is a major driver, and the excellent BBB score (98.914) suggests it will reach the target effectively. The lower metabolic clearance of Ligand B is also a positive. The solubility issues are a concern for both, but can be addressed through formulation strategies.

Output:
1
2025-04-17 08:40:15,061 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (347.463 and 358.439 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (77.57) is significantly better than Ligand B (109). For CNS targets, we want TPSA <= 90, so Ligand A is preferable.

**logP:** Ligand A (0.943) is within the optimal 1-3 range, but on the lower side. Ligand B (-0.678) is below 1, which could hinder permeation. Ligand A is better here.

**H-Bond Donors/Acceptors:** Ligand A (HBD=2, HBA=5) and Ligand B (HBD=3, HBA=5) are both acceptable, falling within the guidelines.

**QED:** Both ligands have reasonable QED values (0.65 and 0.506), indicating good drug-like properties.

**DILI:** Ligand A (13.959) has a much lower DILI risk than Ligand B (19.271), which is a significant advantage.

**BBB:** Both ligands have good BBB penetration (66.227 and 69.523), but neither exceeds the desirable >70 threshold. This isn't a major differentiating factor here.

**Caco-2 Permeability:** Both have negative values (-5.237 and -5.155), indicating poor permeability. This is a concern for both, but doesn't strongly favor one over the other.

**Aqueous Solubility:** Both ligands have negative solubility values (-0.876 and -0.361), indicating poor solubility. This is a concern for both, but doesn't strongly favor one over the other.

**hERG Inhibition:** Ligand A (0.469) has a lower hERG inhibition liability than Ligand B (0.091), which is preferable.

**Microsomal Clearance:** Ligand A (-12.319) has a much lower (better) microsomal clearance than Ligand B (-2.97), suggesting greater metabolic stability.

**In vitro Half-Life:** Ligand A (11.134) has a longer half-life than Ligand B (-1.363), which is desirable.

**P-gp Efflux:** Ligand A (0.01) has a much lower P-gp efflux liability than Ligand B (0.001), which is crucial for CNS penetration.

**Binding Affinity:** Ligand A (-7.3) has a slightly better binding affinity than Ligand B (-6.6), although the difference is less than 1.5 kcal/mol.

**Overall:** Ligand A is significantly better across multiple key ADME properties (DILI, Cl_mic, t1/2, Pgp efflux, hERG) and has a slightly better binding affinity and TPSA. While both have issues with Caco-2 and solubility, Ligand A's superior ADME profile, particularly its lower DILI and P-gp efflux, makes it the more promising candidate for CNS drug development.

Output:
1
2025-04-17 08:40:15,061 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 drug candidates, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (348.374 and 378.826 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (78.87) is better than Ligand B (66.91). Both are below the 90 A^2 threshold desirable for CNS targets, but A is closer to the ideal.

**3. logP:** Ligand A (1.287) is within the optimal range (1-3), while Ligand B (3.805) is approaching the upper limit. This favors Ligand A.

**4. H-Bond Donors:** Both ligands have 2 HBD, which is within the acceptable limit of <=5.

**5. H-Bond Acceptors:** Both ligands have 4 HBA, which is within the acceptable limit of <=10.

**6. QED:** Both ligands have good QED scores (0.575 and 0.757, respectively), indicating good drug-like properties. Ligand B is slightly better.

**7. DILI:** Ligand A (35.324) has a lower DILI risk than Ligand B (47.77), which is preferable.

**8. BBB:** Ligand B (80.264) has a significantly better BBB penetration score than Ligand A (56.611). This is a critical advantage for a CNS target like DRD2.

**9. Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and suggests poor permeability. Ligand A (-4.637) is slightly better than Ligand B (-4.892).

**10. Aqueous Solubility:** Both have negative solubility values, which is also unusual and suggests poor solubility. Ligand A (-2.152) is slightly better than Ligand B (-4.44).

**11. hERG Inhibition:** Both ligands have low hERG inhibition risk (0.411 and 0.613, respectively).

**12. Microsomal Clearance:** Ligand A (-1.527) has a lower (better) microsomal clearance than Ligand B (31.652), indicating greater metabolic stability.

**13. In vitro Half-Life:** Ligand A (18.332) has a longer half-life than Ligand B (4.327), which is desirable.

**14. P-gp Efflux:** Ligand A (0.091) has lower P-gp efflux than Ligand B (0.135), which is preferable for CNS penetration.

**15. Binding Affinity:** Ligand B (-8.7 kcal/mol) has a stronger binding affinity than Ligand A (-7.9 kcal/mol). This is a significant advantage, exceeding the 1.5 kcal/mol threshold.

**Overall Assessment:**

Ligand B excels in BBB penetration and binding affinity, which are paramount for a CNS GPCR target. While Ligand A has advantages in TPSA, DILI, metabolic stability, and P-gp efflux, the superior affinity and BBB score of Ligand B outweigh these benefits. The negative Caco-2 and solubility values are concerning for both, but can be addressed with formulation strategies. The stronger binding affinity of Ligand B is likely to translate to greater efficacy, making it the more promising candidate.

Output:
1
2025-04-17 08:40:15,062 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (392.258 Da and 380.941 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (84.23) is better than Ligand B (34.59) as it is closer to the <90 A^2 threshold for CNS targets. Ligand B is very low, which *could* indicate poor binding, but isn't necessarily a dealbreaker.

**3. logP:** Ligand A (2.62) is within the optimal 1-3 range. Ligand B (4.567) is slightly higher, potentially increasing off-target effects and decreasing solubility, but not drastically.

**4. H-Bond Donors:** Ligand A (2) and Ligand B (0) are both acceptable, below the threshold of 5.

**5. H-Bond Acceptors:** Ligand A (4) and Ligand B (5) are both acceptable, below the threshold of 10.

**6. QED:** Both ligands have good QED scores (0.526 and 0.735, respectively), indicating drug-like properties. Ligand B is slightly better.

**7. DILI:** Ligand A (43.389) has a slightly higher DILI risk than Ligand B (32.571), but both are below the concerning 60 percentile.

**8. BBB:** Both ligands have excellent BBB penetration (Ligand A: 79.139, Ligand B: 83.831), exceeding the >70% target for CNS drugs. Ligand B is slightly better.

**9. Caco-2 Permeability:** Both have negative values, indicating poor permeability. Ligand A (-4.906) is slightly better than Ligand B (-5.044), but both are concerning.

**10. Aqueous Solubility:** Both have negative values, indicating poor solubility. Ligand A (-3.529) is slightly better than Ligand B (-4.601), but both are concerning.

**11. hERG Inhibition:** Ligand A (0.245) has a lower hERG risk than Ligand B (0.797), which is preferable.

**12. Microsomal Clearance:** Ligand A (28.48) has lower clearance than Ligand B (48.199), suggesting better metabolic stability.

**13. In vitro Half-Life:** Ligand A (12.381) has a longer half-life than Ligand B (26.852). This is a positive attribute.

**14. P-gp Efflux:** Ligand A (0.072) has lower P-gp efflux than Ligand B (0.58), which is favorable for CNS penetration.

**15. Binding Affinity:** Ligand B (-7.3 kcal/mol) has a significantly stronger binding affinity than Ligand A (-8.2 kcal/mol). This is a substantial advantage, potentially outweighing some of the ADME drawbacks.

**Overall Assessment:**

While Ligand A has better TPSA, lower hERG, lower clearance, longer half-life, and lower P-gp efflux, the significantly stronger binding affinity of Ligand B (-7.3 vs -8.2 kcal/mol) is a critical factor for a GPCR target. The slightly higher logP of Ligand B is manageable, and its BBB penetration is still excellent. The poor Caco-2 and solubility are concerns for both, but can potentially be addressed with formulation strategies. The difference in binding affinity is large enough to prioritize Ligand B.

Output:
1
2025-04-17 08:40:15,062 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B against the provided guidelines, prioritizing GPCR-specific properties (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (368.474 and 349.387 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (67.43) is significantly better than Ligand B (93.37). For CNS targets, we want TPSA <= 90, so Ligand A is preferable.

**logP:** Ligand A (2.281) is optimal (1-3), while Ligand B (0.667) is a bit low, potentially hindering permeation.

**H-Bond Donors/Acceptors:** Ligand A (2 HBD, 4 HBA) and Ligand B (1 HBD, 6 HBA) both fall within acceptable ranges.

**QED:** Both ligands have similar QED values (0.691 and 0.602), indicating good drug-likeness.

**DILI:** Ligand A (60.799) has a higher DILI risk than Ligand B (46.801), but both are reasonably acceptable.

**BBB:** Ligand A (72.005) has a better BBB penetration percentile than Ligand B (65.297), which is crucial for a CNS target like DRD2.

**Caco-2 Permeability:** Ligand A (-5.142) has a worse Caco-2 permeability than Ligand B (-4.817), but both are negative values, which is not ideal.

**Aqueous Solubility:** Ligand A (-3.175) has worse solubility than Ligand B (-1.027).

**hERG:** Both ligands have low hERG inhibition liability (0.74 and 0.226).

**Microsomal Clearance:** Ligand B (9.806) has significantly lower microsomal clearance than Ligand A (58.312), indicating better metabolic stability.

**In vitro Half-Life:** Ligand B (15.025) has a longer in vitro half-life than Ligand A (11.345).

**P-gp Efflux:** Ligand A (0.297) has lower P-gp efflux liability than Ligand B (0.051), which is favorable for CNS penetration.

**Binding Affinity:** Ligand B (-7.9 kcal/mol) has a slightly better binding affinity than Ligand A (-8.3 kcal/mol). While both are excellent, the difference is relatively small.

**Overall Assessment:**

Considering the GPCR-specific priorities, Ligand A is more promising. Its superior TPSA and BBB penetration are critical for CNS drug development. While Ligand B has better metabolic stability and slightly better binding affinity, the lower TPSA and better BBB of Ligand A outweigh these advantages. The slightly worse solubility and Caco-2 permeability of Ligand A can potentially be addressed through formulation strategies.

Output:
1
2025-04-17 08:40:15,062 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B based on the provided guidelines, prioritizing GPCR-specific properties (BBB, logP, Pgp, TPSA, and affinity) for DRD2.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (343.471 Da) is slightly lower, which could be beneficial for permeability.

**TPSA:** Both ligands have TPSA values below 90, which is good for CNS penetration. Ligand A (73.2) is better than Ligand B (80.57).

**logP:** Both ligands have logP values within the optimal range (1-3). Ligand A (2.946) and Ligand B (3.151) are comparable.

**H-Bond Donors/Acceptors:** Ligand A (HBD=1, HBA=3) is better than Ligand B (HBD=2, HBA=4) in terms of balancing solubility and permeability.

**QED:** Both ligands have similar QED values (A: 0.78, B: 0.772), indicating good drug-likeness.

**DILI:** Ligand A (19.155) has a significantly lower DILI risk than Ligand B (60.644). This is a major advantage for Ligand A.

**BBB:** Ligand A (78.674) has a much better BBB penetration percentile than Ligand B (46.219). This is crucial for a CNS target like DRD2.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values, which is unusual and suggests poor permeability. Ligand A (-4.617) is slightly better than Ligand B (-4.911), but both are problematic.

**Aqueous Solubility:** Both ligands have negative solubility values, indicating poor solubility. Ligand A (-3.362) is slightly better than Ligand B (-3.577).

**hERG Inhibition:** Both ligands have low hERG inhibition risk (A: 0.387, B: 0.169). Ligand B is slightly better.

**Microsomal Clearance:** Ligand A (25.49) has a lower microsomal clearance than Ligand B (22.497), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (-7.938) has a much longer in vitro half-life than Ligand B (56.056). This is a significant advantage for Ligand A.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (A: 0.053, B: 0.133). Ligand A is slightly better.

**Binding Affinity:** Ligand B (-8.4) has a slightly better binding affinity than Ligand A (-8.0). However, the difference is less than 1.5 kcal/mol, so it's not a decisive factor.

**Overall Assessment:**

Ligand A is significantly better overall. It has a much lower DILI risk, better BBB penetration, longer half-life, and slightly better TPSA, H-bond properties, and P-gp efflux. While Ligand B has slightly better binding affinity and hERG inhibition, the advantages of Ligand A in ADME properties, especially BBB and DILI, are more critical for a CNS-targeting drug like a DRD2 ligand. The poor Caco-2 and solubility for both are concerning, but can potentially be addressed with formulation strategies.

Output:
1
2025-04-17 08:40:15,062 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (347.419 and 339.355 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (88.82) is excellent, falling well below the 90 Angstroms threshold for CNS targets. Ligand B (102.92) is still reasonable but less optimal.

**3. logP:** Ligand A (0.256) is quite low, potentially hindering permeability. Ligand B (1.324) is better, falling within the optimal 1-3 range.

**4. H-Bond Donors:** Ligand A (1) is good. Ligand B (0) is also acceptable.

**5. H-Bond Acceptors:** Ligand A (6) is good. Ligand B (8) is also acceptable.

**6. QED:** Both ligands have good QED scores (0.611 and 0.757, respectively), indicating good drug-like properties.

**7. DILI:** Ligand A (39.511) has a lower DILI risk than Ligand B (68.786), which is a significant advantage.

**8. BBB:** Ligand A (76.658) has a better BBB penetration percentile than Ligand B (69.911), which is crucial for a CNS target like DRD2.

**9. Caco-2 Permeability:** Ligand A (-5.134) has poor Caco-2 permeability. Ligand B (-4.734) is also poor, but slightly better.

**10. Aqueous Solubility:** Both ligands have very poor aqueous solubility (-1.929 and -3.94, respectively). This could pose formulation challenges.

**11. hERG Inhibition:** Both ligands have low hERG inhibition risk (0.133 and 0.308, respectively).

**12. Microsomal Clearance:** Ligand A (15.716) has lower microsomal clearance, suggesting better metabolic stability than Ligand B (50.427).

**13. In vitro Half-Life:** Ligand A (8.703) has a shorter half-life than Ligand B (-8.322), but the negative value for B is unusual and could indicate an issue with the data.

**14. P-gp Efflux:** Both ligands have low P-gp efflux liability (0.041 and 0.076, respectively), which is good for CNS penetration.

**15. Binding Affinity:** Ligand B (-8.5 kcal/mol) has a slightly better binding affinity than Ligand A (-7.8 kcal/mol), but the difference is not huge.

**Overall Assessment:**

Ligand A is better overall. While its logP is low and Caco-2 permeability is poor, it excels in crucial areas for a CNS-targeting GPCR ligand: TPSA, BBB penetration, DILI risk, and metabolic stability. Ligand B has a slightly better affinity and logP, but its higher DILI risk and lower BBB penetration are significant drawbacks. The slightly better affinity of Ligand B is unlikely to outweigh the more favorable ADME properties of Ligand A.

Output:
0
2025-04-17 08:40:15,062 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (344.365 and 346.427 Da) fall comfortably within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (51.85) is significantly better than Ligand B (75.71). For CNS targets, TPSA should be <= 90, and A is much closer to the optimal <= 60 range. B is pushing the upper limit.

**3. logP:** Ligand A (4.018) is slightly higher than the optimal 1-3 range, but still acceptable. Ligand B (1.535) is a bit low, potentially hindering permeability.

**4. H-Bond Donors:** Both have 1 HBD, which is good.

**5. H-Bond Acceptors:** Both have 4 HBA, which is good.

**6. QED:** Both are above 0.7, indicating good drug-likeness.

**7. DILI:** Ligand A (78.441) has a higher DILI risk than Ligand B (30.826). This is a significant drawback for A.

**8. BBB:** Ligand A (84.451) has a much better BBB penetration score than Ligand B (70.027). For a CNS target like DRD2, this is *critical*.

**9. Caco-2 Permeability:** Ligand A (-4.813) is worse than Ligand B (-4.182), indicating lower intestinal absorption.

**10. Aqueous Solubility:** Ligand A (-3.914) is worse than Ligand B (-2.045), indicating lower solubility.

**11. hERG Inhibition:** Ligand A (0.798) has a slightly higher hERG risk than Ligand B (0.129).

**12. Microsomal Clearance:** Ligand B (77.21) has a higher microsomal clearance than Ligand A (34.297), indicating lower metabolic stability.

**13. In vitro Half-Life:** Ligand A (27.059) has a better in vitro half-life than Ligand B (-16.325).

**14. P-gp Efflux:** Ligand A (0.519) has lower P-gp efflux than Ligand B (0.048), which is favorable for CNS penetration.

**15. Binding Affinity:** Ligand A (-10.2 kcal/mol) has a significantly stronger binding affinity than Ligand B (-7.7 kcal/mol). This is a substantial advantage, potentially outweighing some of the ADME concerns.

**Overall Assessment:**

Ligand A has a superior binding affinity and better BBB penetration and P-gp efflux, which are crucial for a CNS target. However, it has concerning DILI risk, lower solubility, and lower Caco-2 permeability. Ligand B has a better safety profile (lower DILI, hERG) and better solubility/absorption, but its lower BBB penetration and significantly weaker binding affinity are major drawbacks.

Given the strong emphasis on affinity and BBB for CNS GPCR targets, and the substantial difference in binding affinity (-10.2 vs -7.7 kcal/mol), I believe **Ligand A** is the more promising candidate, *despite* its ADME liabilities. Optimization efforts could focus on mitigating the DILI risk and improving solubility/absorption, but the strong binding and BBB penetration provide a solid foundation.

Output:
1
2025-04-17 08:40:15,062 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (358.291 and 349.475 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Both ligands have TPSA values (70.59 and 69.72) that are above the optimal <90 for CNS targets, but not drastically so. This is a minor concern.

**3. logP:** Ligand A (3.075) is within the optimal range (1-3). Ligand B (0.905) is slightly below, which *could* hinder permeability, but isn't a major red flag.

**4. H-Bond Donors:** Ligand A (3) and Ligand B (1) both meet the HBD criteria of <=5. Ligand B is preferable here.

**5. H-Bond Acceptors:** Both ligands (A: 4, B: 4) are well within the acceptable limit of <=10.

**6. QED:** Both ligands have good QED scores (A: 0.568, B: 0.774), indicating good drug-like properties. Ligand B is better.

**7. DILI:** Ligand A (68.592) has a higher DILI risk than Ligand B (18.922). This is a significant advantage for Ligand B.

**8. BBB:** Both ligands have reasonably good BBB penetration (A: 66.421, B: 61.342). However, for a CNS target like DRD2, higher is better, and A is slightly better.

**9. Caco-2:** Both have negative Caco-2 values which is unusual. This suggests poor permeability.

**10. Solubility:** Both have negative solubility values, which is also unusual and suggests poor solubility.

**11. hERG:** Both ligands have low hERG inhibition risk (A: 0.716, B: 0.095). Ligand B is significantly better.

**12. Cl_mic:** Ligand B (13.281) has a much lower microsomal clearance than Ligand A (31.593), indicating better metabolic stability.

**13. t1/2:** Ligand A (-23.504) has a negative in vitro half-life, which is not possible. Ligand B (0.944) has a very short half-life. Both are problematic.

**14. Pgp:** Ligand A (0.168) has lower P-gp efflux liability than Ligand B (0.032), which is favorable for CNS penetration.

**15. Binding Affinity:** Ligand A (-9.9 kcal/mol) has a significantly stronger binding affinity than Ligand B (-8.0 kcal/mol). This is a substantial advantage for Ligand A.

**Overall Assessment:**

Ligand A has a much stronger binding affinity, which is a critical factor for GPCR ligands. However, it has a higher DILI risk, higher Cl_mic, and a nonsensical half-life. Ligand B has better ADME properties (lower DILI, lower Cl_mic, lower hERG, better QED), but a weaker binding affinity.

Given the importance of binding affinity for GPCRs, and the fact that the difference in affinity is substantial (>1.5 kcal/mol), I would prioritize Ligand A, *assuming the negative half-life is a data error*. The ADME issues, while concerning, might be addressable through further optimization, but a weak binder is unlikely to become a viable drug.

Output:
1
2025-04-17 08:40:15,063 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (378.447 Da) and Ligand B (342.443 Da) are both acceptable.

**TPSA:** Ligand A (133.24) is borderline for CNS penetration, slightly above the preferred <90, but still potentially acceptable. Ligand B (67.23) is excellent, well below the threshold.

**logP:** Ligand A (-1.408) is a bit low, potentially hindering permeability. Ligand B (2.049) is within the optimal range (1-3). This is a significant advantage for Ligand B.

**H-Bond Donors/Acceptors:** Ligand A has 3 HBD and 7 HBA, which are reasonable. Ligand B has 1 HBD and 4 HBA, also reasonable.

**QED:** Both ligands have good QED scores (Ligand A: 0.535, Ligand B: 0.833), indicating drug-like properties. Ligand B is better.

**DILI:** Both ligands have low DILI risk (Ligand A: 41.062, Ligand B: 35.983), below the 40 threshold.

**BBB:** This is crucial for a CNS target. Ligand A has a BBB percentile of 33.967, which is quite low and concerning. Ligand B has a much higher BBB percentile of 83.443, making it significantly more likely to reach the brain.

**Caco-2 Permeability:** Both have negative values which is unusual. Assuming these are logP-scale values, they indicate poor permeability.

**Aqueous Solubility:** Both have negative values which is unusual. Assuming these are logS values, they indicate poor solubility.

**hERG:** Both ligands have low hERG inhibition liability (Ligand A: 0.111, Ligand B: 0.175), which is good.

**Microsomal Clearance:** Ligand A (-21.918) has a negative clearance, which is not possible. This is likely an error in the data. Ligand B (31.164) is higher, indicating faster metabolism, but not excessively so.

**In vitro Half-Life:** Both have similar half-lives (Ligand A: 23.703, Ligand B: 24.6).

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (Ligand A: 0.018, Ligand B: 0.114), which is favorable for CNS penetration.

**Binding Affinity:** Both ligands have the same binding affinity (-7.7 kcal/mol), which is excellent.

**Overall Assessment:**

Ligand B is significantly better due to its superior logP, TPSA, and, most importantly, BBB penetration. While Ligand A has acceptable properties in many areas, its poor BBB score is a major drawback for a CNS-targeting drug. The negative clearance value for Ligand A is also a red flag. The similar binding affinities mean that the ADME properties are the deciding factor.

Output:
1
2025-04-17 08:40:15,063 - INFO - Reasoning:

Let's analyze Ligand A and Ligand B based on the provided guidelines, prioritizing GPCR-specific properties (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (387.391 Da) is slightly higher than Ligand B (344.415 Da), but both are acceptable.

**TPSA:** Ligand A (139.83) is close to the upper limit for good oral absorption and acceptable for CNS targets, while Ligand B (95.16) is excellent for CNS penetration. This favors Ligand B.

**logP:** Both ligands have optimal logP values (A: 1.306, B: 1.157), falling within the 1-3 range.

**H-Bond Donors/Acceptors:** Both have 2 HBDs, which is good. Ligand A has 8 HBAs and Ligand B has 4 HBAs, both within the acceptable limit of 10.

**QED:** Both ligands have similar and good QED scores (A: 0.578, B: 0.573).

**DILI:** Ligand A has a high DILI risk (98.643), which is a significant concern. Ligand B has a much lower DILI risk (36.72), a major advantage.

**BBB:** Ligand A has a very low BBB penetration (9.81), making it unlikely to effectively target a CNS receptor like DRD2. Ligand B has a significantly better BBB penetration (59.597), although still not ideal (>70 is preferred).

**Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and potentially problematic. However, the scale is not clearly defined.

**Aqueous Solubility:** Both have negative solubility values, which is also unusual. Again, the scale is unclear.

**hERG Inhibition:** Both ligands show very low hERG inhibition liability (A: 0.025, B: 0.11), indicating a low risk of cardiotoxicity.

**Microsomal Clearance:** Ligand A has a slower clearance (-12.973) than Ligand B (-9.981), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A has a longer half-life (45.447 hours) than Ligand B (-32.771 hours), which is desirable.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (A: 0.076, B: 0.016), which is favorable for CNS penetration.

**Binding Affinity:** Both ligands have strong binding affinities (A: -8.1 kcal/mol, B: -8.9 kcal/mol). Ligand B has a slightly better affinity, but the difference is not substantial enough to outweigh other factors.

**Overall Assessment:**

Considering the GPCR-specific priorities, Ligand B is the more promising candidate. While Ligand A has a slightly longer half-life and better metabolic stability, its extremely poor BBB penetration and very high DILI risk are major drawbacks. Ligand B has a significantly lower DILI risk and a much better (though not optimal) BBB penetration, making it more likely to reach the target in the CNS. The slightly better affinity of Ligand B is a bonus.



Output:
1
2025-04-17 08:40:15,063 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B based on the provided guidelines, prioritizing GPCR-specific properties (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (379.869 Da) is slightly higher than Ligand B (348.487 Da), but both are acceptable.

**TPSA:** Both ligands have TPSA values around 70, which is acceptable for general oral absorption, but higher than the ideal <90 for CNS targets. However, this is not a major concern as other factors are more critical for CNS penetration.

**logP:** Both ligands have optimal logP values around 2.0, falling within the 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A (0 HBD, 4 HBA) is slightly better than Ligand B (2 HBD, 3 HBA) in terms of balancing solubility and permeability.

**QED:** Both ligands have good QED scores (A: 0.8, B: 0.817), indicating good drug-like properties.

**DILI:** Ligand A (79.798) has a significantly higher DILI risk than Ligand B (12.059). This is a major drawback for Ligand A.

**BBB:** Ligand A (81.621) has a much better BBB penetration percentile than Ligand B (62.466). This is a crucial advantage for a CNS target like DRD2.

**Caco-2 Permeability:** Ligand A (-4.724) has slightly better Caco-2 permeability than Ligand B (-4.848), but both are negative values and not particularly informative.

**Aqueous Solubility:** Ligand A (-4.049) has slightly worse aqueous solubility than Ligand B (-2.476).

**hERG:** Both ligands have low hERG inhibition liability (A: 0.609, B: 0.393), which is good.

**Microsomal Clearance:** Ligand A (67.73) has higher microsomal clearance than Ligand B (10.172), indicating lower metabolic stability.

**In vitro Half-Life:** Ligand B (-5.816) has a significantly longer in vitro half-life than Ligand A (-30.01).

**P-gp Efflux:** Ligand A (0.214) has lower P-gp efflux liability than Ligand B (0.103), which is favorable for CNS penetration.

**Binding Affinity:** Ligand B (-7.5 kcal/mol) has a better binding affinity than Ligand A (-9.4 kcal/mol). This is a substantial difference, and a stronger affinity is highly desirable.

**Overall Assessment:**

Ligand A has a better BBB score and lower P-gp efflux, which are important for CNS penetration. However, its significantly higher DILI risk, lower metabolic stability (higher clearance, shorter half-life), and weaker binding affinity are major concerns. Ligand B, despite having a lower BBB score, exhibits a much more favorable safety profile (lower DILI), better metabolic stability, and significantly stronger binding affinity. The affinity difference is large enough to outweigh the slightly lower BBB.

Output:
1
2025-04-17 08:40:15,063 - INFO - Batch 468 complete. Total preferences: 7488
2025-04-17 08:40:15,063 - INFO - Processing batch 469/512...
2025-04-17 08:40:55,905 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (366.53 and 370.47 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (49.85) is significantly better than Ligand B (92.01). For CNS targets, we want TPSA <= 90, and A is comfortably within this range, while B is slightly above.

**logP:** Ligand A (2.494) is optimal (1-3), while Ligand B (1.367) is at the lower end, potentially hindering permeability.

**H-Bond Donors/Acceptors:** Ligand A (0 HBD, 4 HBA) is preferable to Ligand B (2 HBD, 6 HBA). Both are within acceptable limits, but fewer H-bonds generally improves permeability.

**QED:** Both ligands have similar QED values (0.77 and 0.672), indicating good drug-likeness.

**DILI:** Ligand A (38.66) and Ligand B (41.41) both have low DILI risk, below the 40% threshold.

**BBB:** Ligand A (71.23) is significantly better than Ligand B (37.96). A BBB percentile >70 is desirable for CNS targets, and A is closer to this threshold. This is a critical advantage for DRD2.

**Caco-2 Permeability:** Ligand A (-4.65) and Ligand B (-5.071) both have negative values, which is unusual and requires careful interpretation. Lower values suggest poor permeability.

**Aqueous Solubility:** Ligand A (-3.895) and Ligand B (-2.552) both have negative values, indicating poor solubility.

**hERG:** Both ligands have low hERG risk (0.364 and 0.285).

**Microsomal Clearance:** Ligand A (72.77) has higher clearance than Ligand B (37.52), suggesting lower metabolic stability.

**In vitro Half-Life:** Ligand B (38.47) has a much longer half-life than Ligand A (1.71), which is a significant advantage.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.215 and 0.086).

**Binding Affinity:** Ligand B (-7.2) has slightly better binding affinity than Ligand A (-7.1), but the difference is small (0.1 kcal/mol).

**Overall Assessment:**

Considering the GPCR-specific priorities, Ligand A is the better candidate. Its superior TPSA and BBB penetration are crucial for CNS drug development. While Ligand B has a slightly better affinity and half-life, the significantly better CNS penetration profile of Ligand A outweighs these advantages. The lower logP of Ligand B is also a concern.

Output:
1
2025-04-17 08:40:55,905 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (363.336 and 353.463 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (78.95) is significantly better than Ligand B (96.53). For CNS targets, TPSA should be <= 90, and A is comfortably within this range, while B is approaching the upper limit.

**logP:** Ligand A (-0.097) is slightly lower than ideal (1-3), but still acceptable. Ligand B (1.711) is within the optimal range.

**H-Bond Donors/Acceptors:** Ligand A (HBD=1, HBA=5) and Ligand B (HBD=3, HBA=4) both have reasonable H-bond characteristics.

**QED:** Both ligands have similar QED values (0.694 and 0.677), indicating good drug-likeness.

**DILI:** Ligand A (26.483) has a much lower DILI risk than Ligand B (43.389), which is a significant advantage. Both are below the concerning threshold of 60.

**BBB:** This is a critical parameter for a CNS target like DRD2. Ligand A (72.043) has a good BBB percentile, exceeding the desirable >70 threshold. Ligand B (55.293) is considerably lower and less favorable for CNS penetration.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.859 and -4.986), which is unusual and suggests poor permeability. However, these values are on a scale where negative values are possible, and direct comparison is difficult without knowing the scale's specifics.

**Aqueous Solubility:** Both ligands have negative solubility values (-2.137 and -2.809), again suggesting poor solubility. Similar to Caco-2, the scale is unclear.

**hERG Inhibition:** Both ligands show low hERG inhibition risk (0.447 and 0.096).

**Microsomal Clearance:** Ligand A (4.885) has a much lower microsomal clearance than Ligand B (18.193), indicating better metabolic stability.

**In vitro Half-Life:** Ligand A (-7.157) has a significantly longer in vitro half-life than Ligand B (-27.162).

**P-gp Efflux:** Both ligands show low P-gp efflux liability (0.011 and 0.031).

**Binding Affinity:** Ligand B (-7.9) has a slightly better binding affinity than Ligand A (-7.3), but the difference is only 0.6 kcal/mol.

**Overall Assessment:**

While Ligand B has a slightly better binding affinity, Ligand A is the superior candidate due to its significantly better BBB penetration, lower DILI risk, better metabolic stability (lower Cl_mic and longer t1/2), and more favorable TPSA. The slightly lower logP of Ligand A is less concerning than the poor BBB of Ligand B for a CNS target. The negative solubility and Caco-2 values are concerning for both, but the other advantages of Ligand A outweigh this.



Output:
0
2025-04-17 08:40:55,906 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (354.447 and 366.487 Da) fall within the ideal range of 200-500 Da.

**TPSA:** Ligand A (110.1) is higher than the preferred <90 for CNS targets, while Ligand B (76.58) is well within the range. This is a significant advantage for Ligand B.

**logP:** Ligand A (-0.224) is quite low, potentially hindering membrane permeability. Ligand B (2.576) is within the optimal 1-3 range. This is a major advantage for Ligand B.

**H-Bond Donors/Acceptors:** Ligand A has 4 HBD and 5 HBA, acceptable values. Ligand B has 1 HBD and 7 HBA, also acceptable.

**QED:** Both ligands have good QED scores (0.545 and 0.724), indicating good drug-like properties.

**DILI:** Ligand A (22.024) has a very low DILI risk, significantly better than Ligand B (60.954), which is approaching a concerning level.

**BBB:** Ligand A (10.392) has poor BBB penetration, a critical drawback for a CNS target. Ligand B (79.217) has excellent BBB penetration. This is a decisive advantage for Ligand B.

**Caco-2 Permeability:** Both have negative values, which is unusual. Assuming these are percentile scores, Ligand A (-5.372) is very poor, and Ligand B (-4.782) is also poor, but slightly better.

**Aqueous Solubility:** Both have negative solubility values, which is also unusual. Assuming these are percentile scores, Ligand A (-1.785) is slightly better than Ligand B (-2.355).

**hERG:** Ligand A (0.101) has very low hERG inhibition risk, while Ligand B (0.754) has a moderate risk.

**Microsomal Clearance:** Ligand A (-13.162) has a negative clearance, which is not possible. Assuming this is a percentile score, it suggests very high metabolic stability. Ligand B (66.949) has moderate clearance.

**In vitro Half-Life:** Ligand A (20.571) has a moderate half-life, while Ligand B (63.228) has a long half-life.

**P-gp Efflux:** Ligand A (0.02) has very low P-gp efflux, a positive attribute for CNS penetration. Ligand B (0.314) has moderate P-gp efflux.

**Binding Affinity:** Ligand B (-7.2 kcal/mol) has a slightly better binding affinity than Ligand A (-8.1 kcal/mol). While A is better, the difference is not substantial enough to overcome the other drawbacks.

**Overall Assessment:**

Ligand B is clearly the superior candidate. It excels in key GPCR properties like logP, TPSA, and BBB penetration. While its DILI risk is higher and hERG risk is moderate, these can be addressed during optimization. Ligand A suffers from poor logP and BBB penetration, which are difficult to fix without significantly altering the molecule and potentially losing affinity. Although Ligand A has better DILI and P-gp efflux, the CNS-related properties of Ligand B are far more important for DRD2 targeting.



Output:
1
2025-04-17 08:40:55,906 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (351.451 and 347.371 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (88.49) is excellent, falling well below the 90 A^2 threshold for CNS targets. Ligand B (111.88) is still reasonable, but less optimal.

**logP:** Ligand A (-0.04) is slightly below the optimal 1-3 range, potentially hindering permeation. Ligand B (-0.373) is also on the lower side, but marginally better than A.

**H-Bond Donors/Acceptors:** Ligand A (2 HBD, 6 HBA) and Ligand B (3 HBD, 5 HBA) both have acceptable numbers of hydrogen bond donors and acceptors.

**QED:** Both ligands have similar QED values (0.652 and 0.629), indicating good drug-likeness.

**DILI:** Ligand A (15.2) has a significantly lower DILI risk than Ligand B (51.028). This is a substantial advantage for A.

**BBB:** Ligand A (66.344) has a better BBB percentile than Ligand B (50.33), although ideally, we'd want >70 for a CNS target. A is closer to this threshold.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.192 and -5.566), which is unusual and suggests poor permeability. This is a significant concern for both.

**Aqueous Solubility:** Both ligands have negative solubility values (-1.086 and -1.889), indicating very poor aqueous solubility. This is a major drawback for both.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.093 and 0.234).

**Microsomal Clearance:** Ligand A (19.254) has a lower microsomal clearance than Ligand B (-20.034), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand B (45.273) has a significantly longer in vitro half-life than Ligand A (11.711). This is a positive for B.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.003 and 0.009), which is favorable for CNS penetration.

**Binding Affinity:** Ligand B (-8.6 kcal/mol) has a slightly better binding affinity than Ligand A (-7.8 kcal/mol). This 0.8 kcal/mol difference is significant, and could potentially outweigh some of the ADME drawbacks.

**Overall Assessment:**

While Ligand B has a better binding affinity and longer half-life, Ligand A has a significantly better safety profile (lower DILI) and better BBB penetration. Both compounds suffer from poor solubility and permeability. Considering the GPCR-specific priorities, BBB penetration is crucial for a CNS target like DRD2. The lower DILI risk of Ligand A is also a major advantage. The affinity difference, while notable, may be overcome with further optimization.

Output:
0
2025-04-17 08:40:55,906 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (422.666 Da) is slightly higher than Ligand B (369.422 Da), but both are acceptable.

**2. TPSA:** Ligand A (73.22) is better than Ligand B (95.5). For CNS targets, we want TPSA <= 90. Ligand A is closer to this threshold, suggesting better CNS penetration potential.

**3. logP:** Ligand A (3.46) is optimal (1-3), while Ligand B (0.218) is quite low. Low logP can hinder membrane permeability. This is a significant advantage for Ligand A.

**4. H-Bond Donors:** Both ligands have 1 HBD, which is within the acceptable limit of <=5.

**5. H-Bond Acceptors:** Ligand A has 5 HBAs, and Ligand B has 6. Both are within the acceptable limit of <=10.

**6. QED:** Both ligands have good QED scores (A: 0.699, B: 0.801), indicating good drug-like properties.

**7. DILI:** Ligand A (89.027) has a higher DILI risk than Ligand B (63.358). While both are reasonably low, Ligand B is preferable.

**8. BBB:** Ligand B (69.407) has a better BBB percentile than Ligand A (57.193). However, both are below the desirable >70 for CNS targets.

**9. Caco-2:** Ligand A (-4.81) has a significantly worse Caco-2 permeability than Ligand B (-5.058). Lower values indicate poorer permeability.

**10. Solubility:** Ligand A (-5.272) has worse solubility than Ligand B (-2.611).

**11. hERG:** Ligand A (0.625) has a slightly higher hERG risk than Ligand B (0.139). Lower is better.

**12. Cl_mic:** Ligand B (15.093) has a much lower microsomal clearance than Ligand A (55.56). Lower clearance means greater metabolic stability, which is desirable.

**13. t1/2:** Ligand A (60.02) has a longer in vitro half-life than Ligand B (-6.284). This is a positive for Ligand A.

**14. Pgp:** Ligand A (0.474) has lower P-gp efflux than Ligand B (0.034). Lower efflux is better for CNS exposure.

**15. Binding Affinity:** Ligand A (-9.2 kcal/mol) has a significantly stronger binding affinity than Ligand B (-8.3 kcal/mol). This is a substantial advantage for Ligand A.

**Overall Assessment:**

Despite Ligand A having a better binding affinity and half-life, Ligand B appears to be a more promising candidate. Ligand B has better logP, lower DILI risk, lower microsomal clearance, and lower P-gp efflux. While its BBB is still suboptimal, the combination of these factors outweighs the affinity advantage of Ligand A, especially considering the importance of ADME properties for CNS drugs. The poor Caco-2 and solubility of Ligand A are also concerning.

Output:
1
2025-04-17 08:40:55,906 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (349.479 and 362.495 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (80.12) is significantly better than Ligand B (57.69). Both are below the 90 A^2 threshold desirable for CNS targets, but A is closer to the ideal.

**3. logP:** Both ligands have good logP values (2.051 and 1.615), falling within the optimal 1-3 range.

**4. H-Bond Donors:** Ligand A has 1 HBD, while Ligand B has 0. Both are acceptable.

**5. H-Bond Acceptors:** Ligand A has 5 HBA, and Ligand B has 3. Both are below the 10 threshold.

**6. QED:** Both ligands have good QED scores (0.764 and 0.818), indicating good drug-like properties.

**7. DILI:** Both ligands have acceptable DILI risk (35.324 and 39.473 percentile), below the 40 threshold.

**8. BBB:** Ligand B (82.164%) has a significantly higher BBB penetration score than Ligand A (53.276%). This is a *critical* advantage for a CNS target like DRD2.

**9. Caco-2 Permeability:** Both have negative values, which is unusual. Assuming these are logP values, they indicate poor permeability.

**10. Aqueous Solubility:** Both ligands have poor aqueous solubility (-1.553 and -1.782). This could be a formulation challenge, but is less critical than BBB for a CNS drug.

**11. hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.072 and 0.3).

**12. Microsomal Clearance:** Ligand A (49.413) has lower microsomal clearance than Ligand B (53.92), suggesting better metabolic stability.

**13. In vitro Half-Life:** Ligand B (24.138 hours) has a much longer in vitro half-life than Ligand A (5.457 hours). This is a significant advantage.

**14. P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.02 and 0.267).

**15. Binding Affinity:** Ligand B (-8.0 kcal/mol) has a slightly better binding affinity than Ligand A (-7.6 kcal/mol). While the difference is not huge, it's still a positive for Ligand B.

**Overall Assessment:**

While Ligand A has a slightly better TPSA and Cl_mic, Ligand B is superior due to its significantly higher BBB penetration (82.164% vs 53.276%), longer half-life, and slightly better binding affinity. For a CNS target like DRD2, BBB penetration is paramount. The improved half-life also contributes to a more favorable pharmacokinetic profile. The solubility issues are a concern for both, but can be addressed through formulation strategies.

Output:
1
2025-04-17 08:40:55,907 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (348.447 and 344.371 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (102.3) is better than Ligand B (126.55). For CNS targets, we want TPSA <= 90, so both are a bit high, but A is closer.

**3. logP:** Ligand A (0.95) is within the optimal range (1-3), while Ligand B (-0.725) is slightly below, potentially hindering permeation.

**4. H-Bond Donors:** Ligand A (2) and Ligand B (3) are both acceptable (<=5).

**5. H-Bond Acceptors:** Ligand A (4) and Ligand B (6) are both acceptable (<=10).

**6. QED:** Both ligands have similar QED values (0.669 and 0.647), indicating good drug-like properties.

**7. DILI:** Ligand A (16.208) has a significantly lower DILI risk than Ligand B (34.277). This is a major advantage for Ligand A.

**8. BBB:** Ligand A (53.974) has a much better BBB percentile than Ligand B (21.171). This is *critical* for a CNS target like DRD2.

**9. Caco-2 Permeability:** Both have negative values, which is unusual. Assuming these are logP-scaled permeability values, lower (more negative) values indicate poorer permeability. Ligand A (-5.221) is slightly better than Ligand B (-5.346).

**10. Aqueous Solubility:** Both have negative values, indicating poor solubility. Ligand A (-1.585) is slightly better than Ligand B (-2.339).

**11. hERG:** Both ligands have very low hERG risk (0.406 and 0.157).

**12. Microsomal Clearance:** Ligand A (-19.562) has a lower (better) microsomal clearance than Ligand B (-34.326), indicating greater metabolic stability.

**13. In vitro Half-Life:** Ligand B (17.223) has a significantly longer half-life than Ligand A (-1.939). This is a positive for Ligand B.

**14. P-gp Efflux:** Ligand A (0.021) has a much lower P-gp efflux liability than Ligand B (0.003), which is favorable for CNS penetration.

**15. Binding Affinity:** Ligand B (-8.7 kcal/mol) has a slightly better binding affinity than Ligand A (-7.8 kcal/mol). While a 0.9 kcal/mol difference is noticeable, it's not a huge gap and can be overcome by better ADME properties.

**Overall Assessment:**

Ligand A is the stronger candidate. While Ligand B has slightly better binding affinity and *much* better in vitro half-life, Ligand A excels in crucial areas for a CNS-targeting GPCR ligand: significantly lower DILI risk, much better BBB penetration, lower P-gp efflux, and better metabolic stability. The slightly lower logP of Ligand A is a minor concern compared to the substantial advantages in CNS penetration and safety.

Output:
0
2025-04-17 08:40:55,907 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B against the provided guidelines, prioritizing GPCR-specific properties (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (365.865 and 346.431 Da) fall within the ideal range of 200-500 Da.

**TPSA:** Ligand A (101.21) is slightly higher than Ligand B (82.08). For CNS targets, we want TPSA <= 90, so Ligand B is better here.

**logP:** Ligand A (2.013) is optimal, while Ligand B (0.77) is a bit low, potentially hindering permeation.

**H-Bond Donors/Acceptors:** Ligand A has 2 HBD and 5 HBA, while Ligand B has 1 HBD and 4 HBA. Both are within acceptable limits.

**QED:** Both ligands have similar QED values (0.777 and 0.721), indicating good drug-likeness.

**DILI:** Ligand A (49.864) has a slightly higher DILI risk than Ligand B (32.842), but both are below the concerning threshold of 60.

**BBB:** This is crucial for a CNS target like DRD2. Ligand A has a BBB percentile of 78.364, while Ligand B is significantly lower at 57.736. Ligand A is much more favorable.

**Caco-2 Permeability:** Both have negative values (-5.169 and -5.039), which is unusual. It's difficult to interpret without knowing the scale, but it suggests poor permeability.

**Aqueous Solubility:** Both ligands have very poor aqueous solubility (-3.349 and -2.049). This is a concern for formulation.

**hERG Inhibition:** Ligand A (0.404) has a slightly higher hERG risk than Ligand B (0.102), but both are relatively low.

**Microsomal Clearance:** Ligand A (22.482) has a higher clearance than Ligand B (10.339), indicating lower metabolic stability.

**In vitro Half-Life:** Ligand B (-12.301) has a negative half-life, which is impossible. This is a major red flag and suggests an issue with the data or the compound itself. Ligand A (0.433) is very short, but at least plausible.

**P-gp Efflux:** Ligand A (0.021) has very low P-gp efflux, which is excellent for CNS penetration. Ligand B (0.01) is even lower, but the other issues with B are more significant.

**Binding Affinity:** Ligand B (-8.3 kcal/mol) has a slightly better binding affinity than Ligand A (-7.9 kcal/mol), but the difference is not substantial enough to overcome the other drawbacks.

**Overall Assessment:**

Ligand A is the better candidate despite its slightly higher DILI and clearance. Its significantly better BBB penetration, acceptable logP, and low P-gp efflux are critical for a CNS-targeting GPCR. Ligand B's negative in vitro half-life is a fatal flaw. While its affinity is slightly better, the other ADME properties are less favorable, and the half-life issue is insurmountable.

Output:
1
2025-04-17 08:40:55,907 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight (MW):** Both ligands (349.431 and 360.527 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (104.46) is better than Ligand B (61.28). For CNS targets, we want TPSA <= 90, so Ligand B is preferable.

**3. logP:** Both ligands have acceptable logP values (1.405 and 3.894), falling within the optimal range of 1-3. Ligand B is closer to the upper limit, but still acceptable.

**4. H-Bond Donors (HBD):** Both ligands are within the acceptable limit of <=5 (Ligand A: 3, Ligand B: 2).

**5. H-Bond Acceptors (HBA):** Both ligands are within the acceptable limit of <=10 (Ligand A: 5, Ligand B: 6).

**6. QED:** Ligand A (0.745) has a better QED score than Ligand B (0.497), indicating a more drug-like profile.

**7. DILI:** Ligand A (38.581) has a significantly lower DILI risk than Ligand B (68.709). This is a major advantage for Ligand A.

**8. BBB:** Ligand A (46.646) has a lower BBB penetration percentile than Ligand B (60.45). While both are not ideal (>70 is desirable), Ligand B is better.

**9. Caco-2:** Both have negative values, which is unusual. Assuming these are log scale values, lower values indicate poorer permeability.

**10. Solubility:** Both have negative values, which is unusual. Assuming these are log scale values, lower values indicate poorer solubility.

**11. hERG:** Ligand A (0.127) has a much lower hERG inhibition liability than Ligand B (0.9), a significant safety advantage.

**12. Cl_mic:** Ligand A (12.051) has a lower microsomal clearance than Ligand B (92.647), suggesting better metabolic stability.

**13. t1/2:** Ligand B (108.878) has a significantly longer in vitro half-life than Ligand A (9.08). This is a positive for Ligand B.

**14. Pgp:** Ligand A (0.041) has much lower P-gp efflux liability than Ligand B (0.643), which is crucial for CNS penetration.

**15. Binding Affinity:** Ligand B (-7.2 kcal/mol) has a stronger binding affinity than Ligand A (-8.8 kcal/mol). This is a substantial advantage for Ligand B, potentially outweighing some ADME drawbacks.

**Overall Assessment:**

Ligand B has a better binding affinity and BBB penetration, and longer half-life. However, Ligand A demonstrates a significantly better safety profile (lower DILI and hERG) and better metabolic stability (lower Cl_mic) and P-gp efflux. Considering the CNS target and the importance of BBB penetration, the stronger affinity of Ligand B is a significant advantage. The lower DILI and hERG risk of Ligand A are also important, but the affinity difference is substantial. The lower Pgp efflux of Ligand A is also a positive.

Given the balance, the stronger binding affinity of Ligand B is the most important factor for a GPCR target, and the BBB penetration is reasonable.

Output:
1
2025-04-17 08:40:55,907 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (346.431 and 350.413 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (72.65) is better than Ligand B (61.02). Both are below the 90 A^2 threshold desirable for CNS targets.

**3. logP:** Both ligands have good logP values (2.345 and 3.063), falling within the optimal 1-3 range. Ligand B is slightly higher, which could be a minor advantage.

**4. H-Bond Donors:** Ligand A (1) is better than Ligand B (2). Lower HBD is generally preferred for BBB penetration.

**5. H-Bond Acceptors:** Ligand A (7) is higher than Ligand B (3). Ligand B is better here.

**6. QED:** Both ligands have similar and acceptable QED values (0.708 and 0.731), indicating good drug-like properties.

**7. DILI:** Ligand A (38.193) has a lower DILI risk than Ligand B (47.421), which is a significant advantage.

**8. BBB:** Ligand A (80.962) has a substantially better BBB percentile than Ligand B (71.811). This is *critical* for a CNS target like DRD2.

**9. Caco-2 Permeability:** Both have negative values, which is unusual. It suggests poor permeability. However, the absolute value for Ligand A (-5.073) is less negative than Ligand B (-5.111), suggesting slightly better permeability.

**10. Aqueous Solubility:** Both ligands have negative solubility values, indicating very poor aqueous solubility. Ligand B (-3.268) is slightly worse than Ligand A (-2.104).

**11. hERG Inhibition:** Both ligands have low hERG inhibition risk (0.684 and 0.921), which is good.

**12. Microsomal Clearance:** Ligand A (13.018) has lower microsomal clearance than Ligand B (22.552), suggesting better metabolic stability.

**13. In vitro Half-Life:** Ligand B (8.065) has a slightly longer in vitro half-life than Ligand A (5.276), which is a minor advantage.

**14. P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.092 and 0.142), which is favorable for CNS penetration.

**15. Binding Affinity:** Ligand B (-7.9 kcal/mol) has a slightly better binding affinity than Ligand A (-8.1 kcal/mol). While the difference is small, it's a positive for Ligand B.

**Overall Assessment:**

Ligand A is the stronger candidate. The superior BBB penetration (80.962 vs 71.811), lower DILI risk, and better metabolic stability (lower Cl_mic) outweigh the slightly weaker binding affinity and slightly worse solubility. For a CNS target like DRD2, BBB penetration is paramount, and Ligand A clearly excels in this area. While Ligand B has a slightly better affinity and half-life, these are less critical than the ADME properties favoring Ligand A.

Output:
0
2025-04-17 08:40:55,908 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (342.447 and 340.427 Da) fall comfortably within the ideal 200-500 Da range.

**2. TPSA:** Both ligands have TPSA values (74.22 and 74.33) slightly above the optimal <90 for CNS targets, but still reasonable.

**3. logP:** Both ligands have logP values (1.71 and 1.48) within the optimal 1-3 range.

**4. H-Bond Donors:** Ligand A (3) is slightly higher than Ligand B (2), but both are acceptable (<=5).

**5. H-Bond Acceptors:** Ligand A (5) is slightly higher than Ligand B (4), but both are acceptable (<=10).

**6. QED:** Both ligands have good QED scores (0.723 and 0.865), indicating good drug-like properties. Ligand B is slightly better.

**7. DILI:** Ligand A (25.165) has a significantly lower DILI risk than Ligand B (55.448). This is a major advantage for Ligand A.

**8. BBB:** Ligand A (77.123) has a better BBB penetration percentile than Ligand B (63.862). This is crucial for a CNS target like DRD2.

**9. Caco-2 Permeability:** Both have negative Caco-2 values (-5.154 and -5.029), which is unusual and suggests very poor permeability. This is a significant concern for both.

**10. Aqueous Solubility:** Both ligands have negative solubility values (-2.192 and -2.758), indicating very poor aqueous solubility. This is a significant concern for both.

**11. hERG Inhibition:** Both ligands show low hERG inhibition liability (0.572 and 0.428), which is good.

**12. Microsomal Clearance:** Ligand A (-32.686) has a much lower (better) microsomal clearance than Ligand B (32.957), indicating greater metabolic stability.

**13. In vitro Half-Life:** Ligand A (32.96) has a significantly longer in vitro half-life than Ligand B (5.126).

**14. P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.016 and 0.039), which is favorable for CNS penetration.

**15. Binding Affinity:** Both ligands have similar and strong binding affinities (-9.1 and -8.5 kcal/mol). Ligand A is slightly better.

**Overall Assessment:**

While both ligands have issues with Caco-2 permeability and aqueous solubility, Ligand A is the superior candidate. It demonstrates a significantly lower DILI risk, better BBB penetration, greater metabolic stability (lower Cl_mic, longer t1/2), and slightly better binding affinity. The improvements in safety (DILI) and PK (BBB, Cl_mic, t1/2) outweigh the slight differences in other parameters.

Output:
1
2025-04-17 08:40:55,908 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B against the provided guidelines, prioritizing GPCR-specific properties (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (363.439 and 353.463 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (112.73) is better than Ligand B (62.32). For CNS targets, we want TPSA <= 90, so both are acceptable, but A is closer to the upper limit.

**logP:** Ligand A (1.508) is optimal (1-3). Ligand B (0.051) is quite low, potentially hindering permeation. This is a significant drawback for B.

**H-Bond Donors/Acceptors:** Ligand A (HBD=3, HBA=4) and Ligand B (HBD=0, HBA=5) both fall within acceptable ranges.

**QED:** Both ligands have reasonable QED values (A: 0.767, B: 0.699), indicating good drug-like properties.

**DILI:** Ligand A (49.128) has a slightly higher DILI risk than Ligand B (13.106), but both are below the concerning threshold of 60.

**BBB:** Both ligands have similar BBB penetration (A: 63.358, B: 62.737). While ideally >70 for CNS targets, these are not terrible, and the difference is minimal.

**Caco-2 Permeability:** Ligand A (-5.524) has poor Caco-2 permeability, while Ligand B (-4.423) is also poor, but slightly better. Both are negative values, indicating low permeability.

**Aqueous Solubility:** Ligand A (-3.322) has poor solubility, while Ligand B (-0.044) is slightly better.

**hERG:** Both ligands show low hERG inhibition risk (A: 0.461, B: 0.283).

**Microsomal Clearance:** Ligand A (5.64) has lower (better) microsomal clearance than Ligand B (9.658), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (-33.284) has a very long half-life, while Ligand B (13.325) is shorter.

**P-gp Efflux:** Both ligands show low P-gp efflux (A: 0.025, B: 0.021).

**Binding Affinity:** Ligand A (-9.5 kcal/mol) has significantly stronger binding affinity than Ligand B (-7.2 kcal/mol). This is a >1.5 kcal/mol difference, which is a major advantage.

**Conclusion:**

Considering the GPCR-specific priorities, Ligand A is the more promising candidate. While its TPSA is slightly higher and Caco-2 permeability and solubility are poor, its significantly stronger binding affinity (-9.5 vs -7.2 kcal/mol) and better metabolic stability (lower Cl_mic) outweigh these drawbacks. The low logP of Ligand B is a major concern for CNS penetration, despite its slightly better solubility and lower DILI risk.

Output:
1
2025-04-17 08:40:55,908 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the acceptable range (200-500 Da). Ligand A (359.853 Da) is slightly preferred as it's closer to the ideal range.

**TPSA:** Ligand A (38.77) is excellent for CNS penetration, well below the 90 A^2 threshold. Ligand B (67.01) is higher, but still potentially acceptable, though less ideal.

**logP:** Both ligands have good logP values (A: 4.419, B: 3.109) within the 1-3 range. Ligand B is slightly better here, being closer to the optimal range. However, Ligand A's value is still acceptable.

**H-Bond Donors/Acceptors:** Ligand A (0 HBD, 3 HBA) is better than Ligand B (2 HBD, 3 HBA). Lower HBDs are generally preferred for BBB penetration.

**QED:** Both ligands have good QED values (A: 0.687, B: 0.769), indicating good drug-like properties.

**DILI:** Ligand A (64.56) has a higher DILI risk than Ligand B (43.622). This is a significant drawback for Ligand A.

**BBB:** Ligand B (68.127) has a better BBB percentile than Ligand A (59.093). This is crucial for a CNS target like DRD2.

**Caco-2 Permeability:** Both have negative Caco-2 values which is unusual and suggests a potential issue with the data. However, we can still compare them. Ligand A (-4.565) is slightly better than Ligand B (-5.272).

**Aqueous Solubility:** Both have negative solubility values, which is also unusual. Ligand B (-3.01) is slightly better than Ligand A (-4.672).

**hERG:** Both ligands have low hERG risk (A: 0.569, B: 0.843).

**Microsomal Clearance:** Ligand B (35.031) has significantly lower microsomal clearance than Ligand A (103.098), indicating better metabolic stability.

**In vitro Half-Life:** Ligand B (13.374) has a longer half-life than Ligand A (33.93).

**P-gp Efflux:** Ligand A (0.507) has lower P-gp efflux than Ligand B (0.428), which is favorable for CNS penetration.

**Binding Affinity:** Ligand B (-8.1 kcal/mol) has a slightly better binding affinity than Ligand A (-7.9 kcal/mol). While the difference is small, it's still a positive for Ligand B.

**Overall Assessment:**

Ligand B is the more promising candidate. While Ligand A has a slightly better MW and P-gp efflux, Ligand B excels in critical areas for a CNS GPCR target: BBB penetration, metabolic stability (lower Cl_mic, longer t1/2), lower DILI risk, and slightly better binding affinity. The TPSA is acceptable for Ligand B, and its logP is well within the optimal range. The slightly lower P-gp efflux of Ligand A is outweighed by the other advantages of Ligand B.

Output:
1
2025-04-17 08:40:55,908 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (346.515 and 339.443 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (40.62) is significantly better than Ligand B (64.86). For CNS targets, we want TPSA <= 90, and ideally lower. Ligand A is well within this range, while Ligand B is approaching the upper limit and less favorable.

**logP:** Both ligands have good logP values (3.308 and 3.244), falling within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A (0 HBD, 2 HBA) is better than Ligand B (1 HBD, 6 HBA). Lower values are generally preferred for better permeability, and Ligand B has a higher HBA count.

**QED:** Both ligands have good QED values (0.783 and 0.926), indicating good drug-like properties.

**DILI:** Ligand A (15.781) has a much lower DILI risk than Ligand B (48.313). This is a significant advantage for Ligand A.

**BBB:** Both ligands have excellent BBB penetration (79.721 and 82.513), exceeding the desirable >70 threshold for CNS targets.

**Caco-2 Permeability:** Both have negative Caco-2 values (-4.682 and -4.851). This is unusual and likely indicates a problem with the prediction model or the compounds themselves. It's difficult to interpret without further investigation, but it doesn't immediately disqualify either.

**Aqueous Solubility:** Both have negative solubility values (-3.947 and -4.233), which is also unusual and suggests potential formulation challenges. Similar to Caco-2, this requires further investigation.

**hERG:** Both ligands have low hERG inhibition liability (0.549 and 0.361), which is good.

**Microsomal Clearance:** Ligand A (64.388) has higher microsomal clearance than Ligand B (52.256), meaning it's likely to be metabolized faster. Lower is better here.

**In vitro Half-Life:** Ligand B (-7.68) has a longer in vitro half-life than Ligand A (-5.258), which is preferable.

**P-gp Efflux:** Ligand A (0.44) has lower P-gp efflux than Ligand B (0.397), which is more favorable for CNS penetration.

**Binding Affinity:** Ligand B (-9.0 kcal/mol) has a significantly stronger binding affinity than Ligand A (-8.1 kcal/mol). This is a substantial advantage, potentially outweighing some of the ADME drawbacks. A difference of >1.5 kcal/mol is considered significant.

**Overall Assessment:**

Ligand A has better TPSA, DILI, and P-gp efflux, while Ligand B has better half-life and *significantly* better binding affinity. The negative Caco-2 and solubility values are concerning for both, but the affinity difference is substantial. Given the GPCR-specific priorities, and the strong binding affinity of Ligand B, I would favor Ligand B despite the slightly higher DILI risk and faster clearance. The stronger binding is likely to be more impactful for efficacy.

Output:
1
2025-04-17 08:40:55,908 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (381.929 Da) is slightly higher than Ligand B (348.531 Da), but both are acceptable.

**TPSA:** Ligand A (62.3) is higher than Ligand B (49.41). For CNS targets, we ideally want TPSA <= 90, so both are good, but Ligand B is preferable.

**logP:** Both ligands have good logP values (A: 3.488, B: 3.912), falling within the optimal 1-3 range. Ligand B is slightly higher, which *could* be a minor concern for solubility, but isn't a major issue.

**H-Bond Donors/Acceptors:** Both have 1 HBD, which is good. Ligand A has 4 HBA, while Ligand B has 2. Lower HBA is generally preferred for better permeability, giving a slight edge to Ligand B.

**QED:** Both ligands have acceptable QED values (A: 0.868, B: 0.609), indicating reasonable drug-likeness. Ligand A is better here.

**DILI:** Ligand A (53.044) has a higher DILI risk than Ligand B (17.449). This is a significant advantage for Ligand B.

**BBB:** Both ligands have excellent BBB penetration (A: 73.75, B: 78.945), exceeding the desirable >70 threshold for CNS targets. Ligand B is slightly better.

**Caco-2 Permeability:** Both have negative Caco-2 values (-5.071 and -4.788). This is unusual and suggests poor permeability. However, these values are on a log scale, and the negative values indicate very low permeability.

**Aqueous Solubility:** Both have negative solubility values (-4.193 and -3.238), indicating poor aqueous solubility. This is a concern for both, but Ligand B is slightly better.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (A: 0.405, B: 0.474).

**Microsomal Clearance:** Ligand A (37.175) has lower microsomal clearance than Ligand B (48.081), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (-5.333) has a longer in vitro half-life than Ligand B (-2.287). This is a significant advantage for Ligand A.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (A: 0.529, B: 0.171). Ligand B is significantly better here, which is crucial for CNS penetration.

**Binding Affinity:** Ligand B (-7.5 kcal/mol) has a significantly stronger binding affinity than Ligand A (-9.0 kcal/mol). This is a major advantage for Ligand B, potentially outweighing some of the ADME drawbacks.

**Overall Assessment:**

Ligand B is the stronger candidate. While Ligand A has a better QED and in vitro half-life, Ligand B excels in key areas for a CNS-targeting GPCR ligand: significantly better binding affinity, lower DILI risk, better BBB penetration, and much lower P-gp efflux. The slightly higher logP of Ligand B is a minor concern, but the substantial affinity advantage and improved safety profile make it the more promising candidate. The poor Caco-2 and solubility for both are concerning, but can be addressed with formulation strategies.

Output:
1
2025-04-17 08:40:55,909 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (367.333 Da) is slightly higher than Ligand B (344.415 Da), but both are acceptable.

**TPSA:** Ligand A (29.1) is excellent for CNS penetration, well below the 90 Angstrom threshold. Ligand B (95.42) is higher, potentially hindering BBB penetration, although not drastically.

**logP:** Ligand A (4.666) is a bit high, potentially leading to solubility issues or off-target interactions. Ligand B (0.667) is quite low, which could limit its ability to cross cell membranes.

**H-Bond Donors/Acceptors:** Ligand A (1 HBD, 1 HBA) is optimal. Ligand B (2 HBD, 5 HBA) is still within acceptable limits, but slightly higher.

**QED:** Ligand B (0.84) has a significantly better QED score than Ligand A (0.468), indicating a more drug-like profile overall.

**DILI:** Ligand A (48.895) shows a slightly higher DILI risk than Ligand B (46.53), but both are reasonably low.

**BBB:** Ligand A (90.112) has a very good BBB percentile, which is crucial for a CNS target like DRD2. Ligand B (52.191) is much lower, suggesting poor brain penetration.

**Caco-2 Permeability:** Ligand A (-4.374) has poor Caco-2 permeability, which is concerning. Ligand B (-5.022) is also poor, but slightly worse.

**Aqueous Solubility:** Ligand A (-6.194) has very poor aqueous solubility, which could cause formulation challenges. Ligand B (-1.294) is better, but still low.

**hERG Inhibition:** Ligand A (0.703) shows a low risk of hERG inhibition. Ligand B (0.15) is even lower, indicating a very safe profile.

**Microsomal Clearance:** Ligand A (47.702) has moderate microsomal clearance. Ligand B (2.16) has very low clearance, suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (37.464) has a reasonable in vitro half-life. Ligand B (-9.49) has a very long half-life, which is highly desirable.

**P-gp Efflux:** Ligand A (0.231) has low P-gp efflux, which is good for CNS exposure. Ligand B (0.023) has extremely low P-gp efflux, even better.

**Binding Affinity:** Ligand B (-8.9 kcal/mol) has a significantly stronger binding affinity than Ligand A (0.0 kcal/mol). This is a major advantage, potentially outweighing some of its ADME drawbacks.

**Overall Assessment:**

Ligand B is the stronger candidate despite its lower logP and solubility. The significantly improved binding affinity (-8.9 vs 0.0 kcal/mol) is a dominant factor. The excellent P-gp efflux, very long half-life, and low hERG risk are also highly favorable. While the lower BBB score is a concern, the strong affinity might compensate for reduced permeability. Ligand A's poor solubility and Caco-2 permeability, coupled with its weak binding affinity, make it a less attractive candidate.

Output:
1
2025-04-17 08:40:55,909 - INFO - Batch 469 complete. Total preferences: 7504
2025-04-17 08:40:55,909 - INFO - Processing batch 470/512...
2025-04-17 08:41:36,293 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (346.39 and 334.42 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (105.82) is higher than Ligand B (65.96). For a CNS target like DRD2, TPSA < 90 is preferred. Ligand B is significantly better in this regard.

**3. logP:** Ligand A (1.484) is within the optimal 1-3 range. Ligand B (3.574) is at the higher end, potentially leading to solubility issues, but still acceptable.

**4. H-Bond Donors:** Ligand A (2) and Ligand B (1) both meet the HBD <= 5 criteria.

**5. H-Bond Acceptors:** Ligand A (6) and Ligand B (5) both meet the HBA <= 10 criteria.

**6. QED:** Both ligands have similar QED values (0.812 and 0.741), indicating good drug-likeness.

**7. DILI:** Ligand A (50.14) has a lower DILI risk than Ligand B (62.00), which is preferable.

**8. BBB:** Ligand B (77.39) has a significantly higher BBB penetration percentile than Ligand A (49.79). This is a *critical* advantage for a CNS target like DRD2.

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.144 and -5.059), which is unusual and suggests poor permeability. This is a concern for both.

**10. Aqueous Solubility:** Both ligands have negative solubility values (-2.436 and -3.561), indicating poor aqueous solubility, which could hinder bioavailability.

**11. hERG Inhibition:** Ligand A (0.062) has a much lower hERG inhibition risk than Ligand B (0.863), a significant safety advantage.

**12. Microsomal Clearance:** Ligand A (-14.384) exhibits much lower microsomal clearance, indicating better metabolic stability compared to Ligand B (32.692).

**13. In vitro Half-Life:** Ligand A (25.431) has a shorter half-life than Ligand B (-26.301), but the negative value for B is concerning.

**14. P-gp Efflux:** Ligand A (0.029) has a much lower P-gp efflux liability than Ligand B (0.767), which is beneficial for CNS exposure.

**15. Binding Affinity:** Ligand B (-9.8 kcal/mol) has a slightly better binding affinity than Ligand A (-8.9 kcal/mol). This difference (0.9 kcal/mol) is notable, but not overwhelming.

**Overall Assessment:**

While Ligand B has a slightly better binding affinity and significantly better BBB penetration, Ligand A demonstrates superior ADMET properties. Specifically, Ligand A has lower DILI risk, lower hERG inhibition, lower P-gp efflux, and better metabolic stability (lower Cl_mic). The poor Caco-2 and solubility for both are concerning, but the ADMET advantages of Ligand A, coupled with its acceptable affinity, make it the more promising candidate. The BBB penetration of Ligand B is attractive, but the higher hERG and P-gp efflux, and the DILI risk, are significant drawbacks.

Output:
0
2025-04-17 08:41:36,293 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (386.206) is slightly higher than Ligand B (341.39), but both are acceptable.

**TPSA:** Ligand A (65.49) is better than Ligand B (83.6). For CNS targets, we want TPSA <= 90, and ideally closer to 60. Ligand A is closer to the ideal range.

**logP:** Both ligands have good logP values (A: 3.972, B: 2.38), falling within the optimal 1-3 range. Ligand A is slightly higher, which *could* be a minor concern for solubility, but is still acceptable.

**H-Bond Donors/Acceptors:** Ligand A (HBD=0, HBA=5) is preferable to Ligand B (HBD=1, HBA=5). Lower HBD is generally favored for BBB penetration.

**QED:** Both ligands have good QED scores (A: 0.703, B: 0.874), indicating good drug-like properties. Ligand B is slightly better.

**DILI:** Ligand A (77.743) has a higher DILI risk than Ligand B (56.727). Lower DILI is always preferred.

**BBB:** Both ligands have excellent BBB penetration (A: 78.209, B: 81.039), exceeding the desirable >70 threshold for CNS targets. Ligand B is slightly better.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.357 and -4.685), which is unusual and problematic. This suggests very poor intestinal absorption.

**Aqueous Solubility:** Both ligands have very poor aqueous solubility (-5.29 and -4.121). This is a significant drawback.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (A: 0.451, B: 0.418).

**Microsomal Clearance:** Ligand A (120.974) has significantly higher microsomal clearance than Ligand B (22.004). This means Ligand A will be metabolized more quickly, leading to a shorter duration of action.

**In vitro Half-Life:** Ligand A (36.553) has a shorter half-life than Ligand B (0.014). This is consistent with the higher clearance.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (A: 0.38, B: 0.222), which is good for CNS exposure. Ligand B is slightly better.

**Binding Affinity:** Ligand B (-9.3 kcal/mol) has a significantly stronger binding affinity than Ligand A (-8.4 kcal/mol). This >1.5 kcal/mol difference is substantial and can outweigh minor ADME concerns.

**Overall Assessment:**

While both ligands have issues with Caco-2 permeability and aqueous solubility, Ligand B is significantly better due to its superior binding affinity, lower DILI risk, lower microsomal clearance (longer half-life), and slightly better BBB and P-gp profiles. The stronger binding affinity is the most important factor, especially for a GPCR target. The slightly better BBB and P-gp profiles of Ligand B further support its potential for CNS penetration.

Output:
1
2025-04-17 08:41:36,294 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (392.5) is slightly higher than Ligand B (344.4).

**TPSA:** Both ligands have TPSA values below the 140 A^2 threshold for oral absorption, and importantly, below the 90 A^2 target for CNS penetration. Ligand B (100.86) is slightly better than Ligand A (117.5).

**logP:** Ligand A (-0.771) is a bit low, potentially hindering permeation. Ligand B (0.985) is closer to the optimal 1-3 range. This favors Ligand B.

**H-Bond Donors/Acceptors:** Both ligands have acceptable HBD (1 & 2 respectively) and HBA (8) counts.

**QED:** Both ligands have good QED scores (0.647 and 0.736), indicating drug-likeness.

**DILI:** Both ligands have similar DILI risk (52.889 and 54.478), and are both below the concerning threshold of 60.

**BBB:** Both ligands have moderate BBB penetration (52.811 and 59.984). While neither exceeds the desirable >70% for CNS targets, Ligand B is slightly better.

**Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and suggests poor permeability. This is a significant concern for both.

**Aqueous Solubility:** Both ligands have very poor aqueous solubility (-2.765 and -1.65). This is a major drawback for both.

**hERG Inhibition:** Both ligands show very low hERG inhibition risk (0.25 and 0.068).

**Microsomal Clearance:** Ligand A (5.259) has significantly lower microsomal clearance than Ligand B (9.987), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (-7.018) has a much longer in vitro half-life than Ligand B (32.171). This is a substantial advantage for Ligand A.

**P-gp Efflux:** Both ligands show low P-gp efflux liability (-8 and -8.1).

**Binding Affinity:** Ligand A (-8.0 kcal/mol) has a slightly better binding affinity than Ligand B (-7.0 kcal/mol). The 1.0 kcal/mol difference is significant and can outweigh some ADME drawbacks.

**Overall Assessment:**

Considering the GPCR-specific priorities, the binding affinity is paramount. Ligand A has a significantly better affinity. While Ligand B has a slightly better logP and BBB, Ligand A's superior affinity, lower clearance, and longer half-life are more critical for a CNS-targeting GPCR ligand. The poor solubility and Caco-2 permeability are concerns for both, but can potentially be addressed through formulation strategies.

Output:
1
2025-04-17 08:41:36,294 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (341.415 Da) is slightly preferred as it's closer to the lower end, potentially aiding permeability.

**2. TPSA:** Both ligands have TPSA values below 140, suggesting reasonable oral absorption. Ligand B (84.08) is better than Ligand A (98.17), and closer to the <90 ideal for CNS targets.

**3. logP:** Both ligands have logP values between 1-3 (Ligand A: 3.729, Ligand B: 3.398), which is optimal. Ligand B is slightly better.

**4. H-Bond Donors:** Ligand A (1) is better than Ligand B (2) as fewer HBDs generally improve permeability.

**5. H-Bond Acceptors:** Ligand A (3) is better than Ligand B (4) for the same reason as above.

**6. QED:** Both ligands have good QED scores (A: 0.513, B: 0.6), indicating drug-like properties.

**7. DILI:** Ligand A (47.848) has a significantly lower DILI risk than Ligand B (70.105). This is a substantial advantage for Ligand A.

**8. BBB:** This is a critical parameter for CNS targets. Ligand A (78.79) has a much better BBB percentile than Ligand B (41.411). This is a major advantage for Ligand A.

**9. Caco-2 Permeability:** Ligand A (-4.785) has a worse Caco-2 permeability than Ligand B (-5.502). However, this is less critical than BBB for a CNS target.

**10. Aqueous Solubility:** Both ligands have poor aqueous solubility (-3.809 and -3.41). This could pose formulation challenges, but is not a deciding factor.

**11. hERG Inhibition:** Ligand A (0.49) has a lower hERG inhibition risk than Ligand B (0.741), which is favorable.

**12. Microsomal Clearance:** Ligand A (-14.933) has a much lower (better) microsomal clearance than Ligand B (57.471), indicating better metabolic stability.

**13. In vitro Half-Life:** Ligand A (-1.809) has a slightly worse in vitro half-life than Ligand B (27.676).

**14. P-gp Efflux:** Ligand A (0.063) has a much lower P-gp efflux liability than Ligand B (0.295), which is highly desirable for CNS penetration.

**15. Binding Affinity:** Both ligands have excellent binding affinities (A: -9.1 kcal/mol, B: -8.1 kcal/mol). Ligand A is slightly better, but the difference is less significant than the ADME differences.

**Overall Assessment:**

Ligand A is significantly better overall. While Ligand B has a slightly better TPSA and Caco-2 permeability, Ligand A excels in critical areas for a CNS-targeting GPCR ligand: BBB penetration, DILI risk, P-gp efflux, and metabolic stability (Cl_mic). The slightly better binding affinity of Ligand A further supports its selection. The solubility and half-life are not ideal for either, but can be addressed in later optimization stages.

Output:
1
2025-04-17 08:41:36,294 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (343.446 and 356.413 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (37.39) is excellent, well below the 90 A^2 threshold for CNS targets. Ligand B (83.63) is higher, but still potentially acceptable, though less ideal.

**logP:** Ligand A (4.689) is slightly high, potentially leading to solubility issues or off-target interactions. Ligand B (2.496) is within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A (HBD=1, HBA=4) and Ligand B (HBD=2, HBA=3) both have reasonable numbers of H-bond donors and acceptors, well within the guidelines.

**QED:** Ligand A (0.826) has a very good QED score, indicating high drug-likeness. Ligand B (0.676) is still acceptable, but less optimal.

**DILI:** Ligand A (32.144) has a low DILI risk, which is excellent. Ligand B (17.604) also has a very low DILI risk.

**BBB:** Both ligands have high BBB penetration (Ligand A: 95.89, Ligand B: 78.48), which is crucial for a CNS target like DRD2. Ligand A is slightly better.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.211 and -4.58), which is unusual and suggests poor permeability. This is a significant concern.

**Aqueous Solubility:** Both ligands have negative solubility values (-4.298 and -3.355), indicating very poor aqueous solubility. This is a major drawback.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.876 and 0.853).

**Microsomal Clearance:** Ligand A (77.325) has a higher microsomal clearance than Ligand B (48.278), suggesting lower metabolic stability.

**In vitro Half-Life:** Ligand B (0.3) has a very short in vitro half-life, which is a significant concern. Ligand A (26.993) is much better.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.379 and 0.291), which is favorable for CNS penetration.

**Binding Affinity:** Ligand A (-8.4 kcal/mol) has a significantly stronger binding affinity than Ligand B (-7.4 kcal/mol). This 1.0 kcal/mol difference is substantial and could outweigh some of the ADME drawbacks.

**Overall Assessment:**

Despite the poor solubility and permeability indicated by the negative Caco-2 and solubility values, Ligand A is the more promising candidate. Its significantly higher binding affinity (-8.4 vs -7.4 kcal/mol) is a major advantage for a GPCR target. It also has a better QED score, BBB penetration, and in vitro half-life. While the higher logP and clearance are concerns, the strong binding and favorable CNS penetration make it the better choice. The poor solubility/permeability would need to be addressed through formulation strategies, but the potency advantage is substantial.

Output:
0
2025-04-17 08:41:36,294 - INFO - Reasoning:

Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands are within the acceptable range (200-500 Da). Ligand A (345.443 Da) is slightly lower, which is generally favorable for permeability.

**2. TPSA:** Both ligands are reasonably close to the ideal TPSA for CNS targets (<=90 A^2). Ligand A (91.32 A^2) is slightly higher than Ligand B (95.5 A^2), but both are acceptable.

**3. logP:** Both ligands have logP values within the optimal range (1-3), at 2.124 and 2.275 respectively. This suggests good permeability and reasonable solubility.

**4. H-Bond Donors & Acceptors:** Both ligands have 3 HBDs and 4 HBAs, which are within the acceptable limits.

**5. QED:** Both ligands have QED values above 0.5 (0.706 and 0.671), indicating good drug-like properties.

**6. DILI:** Ligand A (26.599) has a significantly lower DILI risk than Ligand B (67.429). This is a major advantage for Ligand A.

**7. BBB:** Ligand A (53.974) has a better BBB penetration percentile than Ligand B (34.122). While neither is *excellent* (>70), Ligand A is considerably better, which is crucial for a CNS target like DRD2.

**8. Caco-2 Permeability:** Ligand A (-4.966) shows better Caco-2 permeability than Ligand B (-5.205).

**9. Aqueous Solubility:** Both ligands have very poor aqueous solubility (-3.392 and -3.509). This is a concern for both, but might be manageable with formulation strategies.

**10. hERG Inhibition:** Both ligands have low hERG inhibition risk (0.106 and 0.347).

**11. Microsomal Clearance:** Ligand B (23.014) has lower microsomal clearance than Ligand A (47.128), suggesting better metabolic stability. This is a positive for Ligand B.

**12. In vitro Half-Life:** Both ligands have negative in vitro half-life values (-39.714 and -36.902), which is unusual and indicates very rapid degradation. This is a significant drawback for both.

**13. P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.041 and 0.033). This is favorable for CNS penetration.

**14. Binding Affinity:** Ligand B (-9.3 kcal/mol) has a stronger binding affinity than Ligand A (-8.5 kcal/mol). This is a substantial difference (0.8 kcal/mol), and a significant advantage for Ligand B.

**Overall Assessment:**

While Ligand B has a superior binding affinity, Ligand A is the more promising candidate overall. The significantly lower DILI risk and better BBB penetration of Ligand A are critical advantages for a CNS-targeted drug. The slightly better Caco-2 permeability also contributes. The metabolic stability of Ligand B is better, but the difference isn't large enough to overcome the safety and CNS penetration concerns. The poor solubility and short half-life are drawbacks for both, but can potentially be addressed through formulation and structural modifications. Given the GPCR-specific priorities, the improved safety and CNS exposure potential of Ligand A outweigh the binding affinity advantage of Ligand B.

Output:
0
2025-04-17 08:41:36,295 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (363.292 and 376.469 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (106.62) is slightly above the optimal <90 for CNS targets, but still reasonable. Ligand B (67.43) is excellent, well below 90.

**logP:** Both ligands have good logP values (0.983 and 2.097), falling within the 1-3 range.

**H-Bond Donors/Acceptors:** Both have 2 HBDs, which is good. Ligand A has 6 HBAs, while Ligand B has 4. Both are acceptable (<=10).

**QED:** Both ligands have QED values above 0.5 (0.577 and 0.613), indicating good drug-like properties.

**DILI:** Ligand A has a DILI risk of 85.576, which is high. Ligand B has a much lower DILI risk of 26.483, which is very favorable.

**BBB:** Ligand A has a BBB penetration of 68.127, which is borderline for a CNS target. Ligand B has a significantly better BBB penetration of 78.247, making it more promising for CNS activity.

**Caco-2 Permeability:** Ligand A (-4.732) and Ligand B (-5.012) both have negative Caco-2 values, which is unusual and suggests poor permeability. However, these values are on a scale where negative values are possible and don't necessarily disqualify a compound.

**Aqueous Solubility:** Both ligands have very poor aqueous solubility (-3.048 and -2.774). This is a significant drawback.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.204 and 0.389).

**Microsomal Clearance:** Ligand A (33.421) has a higher microsomal clearance than Ligand B (25.288), suggesting lower metabolic stability.

**In vitro Half-Life:** Ligand A (-31.913) has a very poor in vitro half-life, while Ligand B (2.578) is slightly better, but still not ideal.

**P-gp Efflux:** Both ligands show low P-gp efflux liability (0.02 and 0.095), which is good for CNS penetration.

**Binding Affinity:** Ligand B (-7.6 kcal/mol) has a significantly stronger binding affinity than Ligand A (-8.2 kcal/mol). While both are good, the 0.6 kcal/mol difference is substantial and can outweigh some of the ADME drawbacks.

**Overall Assessment:**

Ligand B is the more promising candidate. While both have solubility issues, Ligand B excels in key areas for a CNS-targeting GPCR ligand: significantly lower DILI risk, better BBB penetration, stronger binding affinity, and slightly better metabolic stability. The TPSA is also much more favorable for CNS penetration. The slightly better P-gp efflux of Ligand A is not enough to offset the other advantages of Ligand B.

Output:
1
2025-04-17 08:41:36,295 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (351.403 Da) is slightly preferred as it's closer to the lower end, potentially aiding permeability.

**2. TPSA:** Both ligands have TPSA values below 140 (Ligand A: 106.62, Ligand B: 100.03), which is good for oral absorption. They are also both below the 90 threshold desirable for CNS targets, a significant plus.

**3. logP:** Both ligands have logP values within the optimal range (1-3). Ligand B (2.91) is slightly higher, which could potentially lead to some off-target interactions, but it's still acceptable.

**4. H-Bond Donors:** Ligand A (2) and Ligand B (3) are both within the acceptable limit of 5.

**5. H-Bond Acceptors:** Ligand A (6) and Ligand B (7) are both within the acceptable limit of 10.

**6. QED:** Ligand A (0.758) has a significantly better QED score than Ligand B (0.531), indicating a more drug-like profile.

**7. DILI:** Ligand B (88.639) has a much higher DILI risk than Ligand A (64.366). This is a major concern for Ligand B.

**8. BBB:** Ligand A (64.87) has a considerably better BBB penetration percentile than Ligand B (32.765). This is *critical* for a CNS target like DRD2.

**9. Caco-2 Permeability:** Ligand A (-4.528) shows better Caco-2 permeability than Ligand B (-5.443).

**10. Aqueous Solubility:** Both ligands have very poor aqueous solubility (-3.467 and -3.704 respectively). This is a significant drawback for both, but could be addressed with formulation strategies.

**11. hERG Inhibition:** Ligand A (0.29) has a lower hERG inhibition risk than Ligand B (0.692), which is preferable.

**12. Microsomal Clearance:** Ligand B (43.434) has a lower microsomal clearance than Ligand A (81.736), suggesting better metabolic stability.

**13. In vitro Half-Life:** Ligand A (-17.441) has a negative half-life, which is concerning and likely an error or indicates very rapid degradation. Ligand B (-6.247) is also negative, but less so.

**14. P-gp Efflux:** Ligand A (0.036) has a much lower P-gp efflux liability than Ligand B (0.197), which is beneficial for CNS penetration.

**15. Binding Affinity:** Ligand B (-9.4 kcal/mol) has a stronger binding affinity than Ligand A (-8.0 kcal/mol). This is a substantial advantage.

**Overall Assessment:**

While Ligand B boasts a stronger binding affinity, Ligand A is the more promising candidate overall. The significantly better BBB penetration, lower DILI risk, lower P-gp efflux, and better QED score outweigh the affinity difference. The negative half-life for both is concerning, but the magnitude is less for Ligand B. The solubility is poor for both, but manageable with formulation. Given the GPCR-specific priorities, particularly BBB for a CNS target, Ligand A is the better choice.

Output:
0
2025-04-17 08:41:36,295 - INFO - Reasoning:

Let's analyze Ligand A and Ligand B based on the provided guidelines, prioritizing GPCR-specific properties (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (382.511 Da) is slightly higher than Ligand B (370.519 Da), but both are acceptable.

**TPSA:** Ligand A (118.2) is borderline for CNS penetration, being above the preferred <90. Ligand B (78.67) is well within the ideal range for CNS targets. This is a significant advantage for Ligand B.

**logP:** Both ligands have good logP values (A: 2.145, B: 1.614), falling within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A (HBD=3, HBA=7) is slightly more polar than Ligand B (HBD=1, HBA=6), but both are within acceptable limits.

**QED:** Both ligands have reasonable QED values (A: 0.64, B: 0.5), indicating good drug-like properties.

**DILI:** Ligand A has a significantly higher DILI risk (82.668%) than Ligand B (27.142%). This is a major concern for Ligand A.

**BBB:** Ligand A (64.211%) is moderately good for BBB penetration, but Ligand B (43.583%) is lower. While both could be improved, this isn't a decisive factor given other differences.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values, which is unusual and suggests poor permeability. This is a concern for both, but the values are difficult to interpret without knowing the scale.

**Aqueous Solubility:** Both ligands have negative solubility values, again unusual and indicating poor solubility. This is a concern for both.

**hERG Inhibition:** Ligand A (0.131) has a slightly lower hERG risk than Ligand B (0.546), which is preferable.

**Microsomal Clearance:** Ligand A (17.037 mL/min/kg) has a lower (better) microsomal clearance than Ligand B (44.385 mL/min/kg), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand B (30.601 hours) has a significantly longer in vitro half-life than Ligand A (-14.599 hours). This is a major advantage for Ligand B.

**P-gp Efflux:** Ligand A (0.033) has a much lower P-gp efflux liability than Ligand B (0.463), which is desirable for CNS penetration.

**Binding Affinity:** Ligand B (-7.1 kcal/mol) has a slightly better binding affinity than Ligand A (-8.0 kcal/mol). While A is better, the difference is not substantial enough to outweigh the other issues.

**Overall Assessment:**

Ligand B is the more promising candidate. While it has a lower BBB score and higher P-gp efflux, its significantly lower DILI risk, longer half-life, and acceptable TPSA outweigh these drawbacks. Ligand A's high DILI risk is a major red flag. The slightly better affinity of Ligand A doesn't compensate for its poor safety profile and metabolic stability.

Output:
1
2025-04-17 08:41:36,295 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (357.435 and 356.457 Da) fall comfortably within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (69.72) is higher than Ligand B (49.41). For a CNS target like DRD2, TPSA should be <= 90, so both are acceptable, but B is significantly better.

**3. logP:** Ligand A (1.609) is within the optimal 1-3 range. Ligand B (3.355) is at the higher end, but still acceptable.

**4. H-Bond Donors:** Both ligands have 1 HBD, which is within the acceptable limit of <=5.

**5. H-Bond Acceptors:** Ligand A has 4 HBAs, and Ligand B has 2. Both are within the acceptable limit of <=10.

**6. QED:** Ligand A (0.845) has a better QED score than Ligand B (0.652), indicating a more drug-like profile.

**7. DILI:** Ligand A (65.568) has a higher DILI risk than Ligand B (23.42). This is a significant negative for Ligand A.

**8. BBB:** Ligand B (90.617) has a much higher BBB penetration percentile than Ligand A (68.127). This is *critical* for a CNS target like DRD2.

**9. Caco-2 Permeability:** Ligand A (-4.806) and Ligand B (-4.55) both have negative values, which is unusual. Lower values suggest poor permeability. However, the scale is not specified, so it's difficult to interpret.

**10. Aqueous Solubility:** Both ligands have negative solubility values (-2.953 and -3.462). This is concerning, and suggests poor solubility.

**11. hERG Inhibition:** Ligand A (0.43) has a slightly lower hERG risk than Ligand B (0.763), but both are relatively low.

**12. Microsomal Clearance:** Ligand A (45.061) has a higher microsomal clearance than Ligand B (38.912), indicating lower metabolic stability.

**13. In vitro Half-Life:** Ligand B (-3.18) has a negative half-life, which is not possible. This is a major red flag. Ligand A (42.421) has a reasonable half-life.

**14. P-gp Efflux:** Ligand A (0.147) has a lower P-gp efflux liability than Ligand B (0.277), which is favorable for CNS penetration.

**15. Binding Affinity:** Both ligands have excellent binding affinities (-9.2 and -8.6 kcal/mol). The difference of 0.6 kcal/mol is not substantial enough to override other significant differences.

**Overall Assessment:**

Despite Ligand A's better QED and slightly lower P-gp efflux, Ligand B is the more promising candidate. The significantly higher BBB penetration (90.617 vs 68.127) is crucial for a CNS target. The lower DILI risk of Ligand B is also a major advantage. The negative half-life for Ligand B is a major issue, but could be an error in the data. Considering the GPCR-specific priorities, Ligand B is the better choice.

Output:
1
2025-04-17 08:41:36,295 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 drug candidates, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (349.439 and 357.483 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (110.24) is higher than the preferred <90 for CNS targets, but not drastically so. Ligand B (55.95) is excellent, well below the threshold.

**logP:** Ligand A (-0.002) is slightly below the optimal 1-3 range, potentially hindering permeability. Ligand B (2.778) is within the optimal range.

**H-Bond Donors/Acceptors:** Ligand A has 1 HBD and 7 HBA, which are acceptable. Ligand B has 0 HBD and 6 HBA, also acceptable.

**QED:** Both ligands have reasonable QED scores (0.801 and 0.653), indicating good drug-like properties.

**DILI:** Ligand A (56.844) has a slightly higher DILI risk than Ligand B (41.373), but both are below the concerning 60 threshold.

**BBB:** This is critical for a CNS target. Ligand A has a very good BBB penetration percentile (81.388), while Ligand B (62.233) is lower, though still not terrible.

**Caco-2 Permeability:** Both are very poor (-5.405 and -5.524). This is concerning for oral bioavailability, but less critical for a CNS target where direct delivery or other routes may be considered.

**Aqueous Solubility:** Both ligands have poor aqueous solubility (-1.88 and -1.988). This could pose formulation challenges.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.181 and 0.485).

**Microsomal Clearance:** Ligand A (26.279) has lower clearance than Ligand B (58.546), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (-6.189) has a negative half-life, which is impossible and indicates an issue with the data or the prediction method. Ligand B (9.024) has a reasonable half-life.

**P-gp Efflux:** Both ligands exhibit very low P-gp efflux liability (0.117 and 0.268), which is favorable for CNS penetration.

**Binding Affinity:** Ligand B (-7.0 kcal/mol) has significantly better binding affinity than Ligand A (-0.0 kcal/mol). This is a major advantage.

**Overall Assessment:**

Ligand B is the stronger candidate. While both have poor solubility and Caco-2 permeability, Ligand B excels in the most critical areas for a CNS GPCR target: logP, binding affinity, and acceptable BBB penetration. The significantly better affinity of Ligand B (-7.0 vs -0.0 kcal/mol) is a decisive factor, outweighing the slightly higher DILI risk and lower BBB compared to Ligand A. The problematic negative half-life for Ligand A is a major red flag.



Output:
1
2025-04-17 08:41:36,296 - INFO - Reasoning:

Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (392.859 and 350.507 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (75.19) is slightly above the optimal <90 for CNS targets, but still reasonable. Ligand B (55.89) is excellent, well below 90.

**3. logP:** Both ligands have good logP values (2.095 and 1.617), falling within the 1-3 range.

**4. H-Bond Donors:** Both have 1 HBD, which is within the acceptable limit of <=5.

**5. H-Bond Acceptors:** Ligand A has 5 HBAs, and Ligand B has 3. Both are below the 10 limit.

**6. QED:** Both ligands have good QED scores (0.769 and 0.792), indicating good drug-like properties.

**7. DILI:** Ligand A (56.805) has a moderate DILI risk, while Ligand B (7.871) has a very low DILI risk. This is a significant advantage for Ligand B.

**8. BBB:** Ligand A (68.321) has a reasonable BBB penetration, but Ligand B (81.155) is excellent, exceeding the desirable >70 threshold for CNS targets.

**9. Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and requires further investigation. However, the magnitude is similar, so it doesn't strongly differentiate them.

**10. Aqueous Solubility:** Both have negative solubility values, also unusual. Again, the magnitude is similar.

**11. hERG Inhibition:** Both ligands have low hERG inhibition risk (0.432 and 0.615).

**12. Microsomal Clearance:** Ligand A (32.022) has a moderate clearance, while Ligand B (-7.889) has a *negative* clearance, which is highly unusual and suggests exceptional metabolic stability.

**13. In vitro Half-Life:** Ligand A (-9.775) has a negative half-life, which is impossible. Ligand B (2.586) has a short half-life. The negative value for A is a red flag.

**14. P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.046 and 0.026).

**15. Binding Affinity:** Both ligands have excellent binding affinities (-7.4 and -7.7 kcal/mol). Ligand B is slightly better (-7.7 vs -7.4), but the difference is small.

**Overall Assessment:**

Ligand B is the superior candidate. While both have good affinity and drug-like properties, Ligand B excels in crucial areas for CNS drug development: BBB penetration, DILI risk, and P-gp efflux. The negative clearance and half-life values for Ligand A are concerning and suggest potential issues with the data or the molecule itself. The slightly better affinity of Ligand B further strengthens its position.

Output:
1
2025-04-17 08:41:36,296 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 drug candidates, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (359.333 and 362.539 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (127.42) is borderline for CNS penetration, being above the preferred 90 A^2. Ligand B (40.62) is excellent, well below the 90 A^2 threshold.

**logP:** Ligand A (-0.996) is quite low, potentially hindering membrane permeability. Ligand B (3.342) is optimal, falling within the 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A has 4 HBD and 5 HBA, acceptable values. Ligand B has 0 HBD and 3 HBA, also acceptable.

**QED:** Both ligands have good QED scores (0.502 and 0.806), indicating drug-like properties.

**DILI:** Ligand A (53.47) has a moderate DILI risk, while Ligand B (24.234) has a low DILI risk, which is favorable.

**BBB:** Ligand A (36.371) has poor BBB penetration, a significant drawback for a CNS target. Ligand B (86.351) exhibits excellent BBB penetration, a major advantage.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.461 and -4.917), which is unusual and suggests poor permeability. However, these values are on a log scale, and the negative values are not directly comparable without knowing the scale.

**Aqueous Solubility:** Both ligands have negative solubility values (-1.983 and -3.187), again suggesting poor solubility. Similar to Caco-2, the scale is unknown.

**hERG:** Ligand A (0.233) has a slightly higher hERG risk than Ligand B (0.749), but both are relatively low.

**Microsomal Clearance:** Ligand A (-37.477) has a very low (and negative) microsomal clearance, indicating high metabolic stability. Ligand B (66.937) has a moderate clearance.

**In vitro Half-Life:** Ligand A (-25.591) has a negative half-life, which is not physically possible and suggests an issue with the data. Ligand B (0.354) has a very short half-life.

**P-gp Efflux:** Ligand A (0.011) has very low P-gp efflux, which is excellent. Ligand B (0.631) has moderate P-gp efflux.

**Binding Affinity:** Both ligands have strong binding affinities (-8.6 and -9.4 kcal/mol), with Ligand B being slightly more potent.

**Overall Assessment:**

Ligand B is the superior candidate. While both have issues with Caco-2 and solubility, Ligand B excels in key areas for a CNS GPCR target: excellent BBB penetration, optimal logP, low DILI risk, and slightly higher binding affinity. Ligand A's poor BBB penetration and low logP are significant liabilities. The negative half-life for Ligand A is also concerning and suggests data quality issues. Although Ligand A has better metabolic stability (lower Cl_mic), the other factors outweigh this benefit.

Output:
1
2025-04-17 08:41:36,296 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (354.378 and 346.431 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Both ligands have TPSA values (84.94 and 84.3) below the 90 A^2 threshold for CNS targets, which is good.

**3. logP:** Both ligands have logP values (1.039 and 1.103) within the optimal range of 1-3.

**4. H-Bond Donors:** Both have 1 HBD, well within the acceptable limit of 5.

**5. H-Bond Acceptors:** Both have 5 HBA, also within the acceptable limit of 10.

**6. QED:** Both ligands have good QED scores (0.705 and 0.809), indicating drug-like properties.

**7. DILI:** Both ligands have acceptable DILI risk (41.993 and 39.162), below the 40% threshold.

**8. BBB:** Ligand B (70.182) has a slightly better BBB penetration percentile than Ligand A (66.111). Both are above the 70% desired threshold for CNS targets, but B is preferable.

**9. Caco-2 Permeability:** Ligand A (-4.463) has a slightly better Caco-2 permeability than Ligand B (-4.905).

**10. Aqueous Solubility:** Both ligands have similar and poor aqueous solubility (-1.809 and -1.784). This could be a formulation challenge.

**11. hERG Inhibition:** Both ligands show very low hERG inhibition risk (0.153 and 0.145).

**12. Microsomal Clearance:** Ligand B (14.148) has significantly lower microsomal clearance than Ligand A (61.758), indicating better metabolic stability. This is a significant advantage.

**13. In vitro Half-Life:** Ligand B (-8.357) has a slightly better in vitro half-life than Ligand A (-16.526).

**14. P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.029 and 0.046).

**15. Binding Affinity:** Ligand B (-8.7 kcal/mol) has a slightly better binding affinity than Ligand A (-8.0 kcal/mol). While both are good, the 0.7 kcal/mol difference is notable.

**Overall Assessment:**

Ligand B is the more promising candidate. While both ligands are generally good, Ligand B demonstrates superior BBB penetration, significantly improved metabolic stability (lower Cl_mic and better half-life), and slightly better binding affinity. The slightly better Caco-2 permeability of Ligand A is less important given the CNS target and the other advantages of Ligand B.

Output:
1
2025-04-17 08:41:36,296 - INFO - Reasoning:

Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (340.463 and 351.447 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (46.53) is significantly better than Ligand B (72.8). For CNS targets, we want TPSA <= 90, and A is comfortably within that, while B is approaching the upper limit.

**3. logP:** Ligand A (4.503) is a bit high, potentially leading to solubility issues, but still within a tolerable range. Ligand B (0.954) is quite low, potentially hindering membrane permeability. Optimal is 1-3.

**4. H-Bond Donors:** Both ligands have 1 HBD, which is good.

**5. H-Bond Acceptors:** Ligand A has 3 HBA, and Ligand B has 5. Both are acceptable (<=10).

**6. QED:** Both ligands have good QED scores (0.596 and 0.757), indicating drug-like properties.

**7. DILI:** Both ligands have low DILI risk (24.195 and 28.965), which is positive.

**8. BBB:** This is critical for a CNS target. Ligand A has a BBB percentile of 66.266, which is decent but not excellent. Ligand B is significantly lower at 41.993, making CNS penetration less likely.

**9. Caco-2 Permeability:** Both have negative values, which is unusual. Assuming these are logP-like scales where lower is worse, Ligand A (-4.505) appears to have worse permeability than Ligand B (-4.675).

**10. Aqueous Solubility:** Both have negative values. Again, assuming a scale where lower is worse, Ligand A (-5.591) is slightly better than Ligand B (-1.448).

**11. hERG:** Ligand A (0.822) has a lower hERG risk than Ligand B (0.143), which is preferable.

**12. Microsomal Clearance:** Ligand A (101.222) has higher clearance than Ligand B (29.488), indicating lower metabolic stability.

**13. In vitro Half-Life:** Ligand B (12.052 hours) has a significantly longer half-life than Ligand A (1.823 hours).

**14. P-gp Efflux:** Ligand A (0.848) has lower P-gp efflux than Ligand B (0.03), which is good for CNS exposure.

**15. Binding Affinity:** Ligand A (-9.2 kcal/mol) has a substantially stronger binding affinity than Ligand B (-6.5 kcal/mol). This is a major advantage. A difference of 2.7 kcal/mol is significant and can outweigh some ADME drawbacks.

**Overall Assessment:**

Ligand A is the stronger candidate despite some ADME liabilities. Its significantly better binding affinity (-9.2 vs -6.5 kcal/mol) is a major driver. While its logP is a bit high and clearance is higher, its TPSA is much better, and its BBB penetration is reasonable. The lower P-gp efflux is also beneficial. Ligand B's lower logP and longer half-life are positives, but its poor TPSA and significantly weaker binding affinity are major drawbacks for a GPCR target like DRD2.

Output:
1
2025-04-17 08:41:36,297 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (349.435 and 356.457 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (104.69) is higher than the preferred <90 for CNS targets, while Ligand B (40.62) is excellent. This is a significant advantage for Ligand B.

**logP:** Ligand A (0.225) is quite low, potentially hindering membrane permeability. Ligand B (3.474) is within the optimal 1-3 range. This favors Ligand B.

**H-Bond Donors/Acceptors:** Ligand A has 2 HBD and 6 HBA, which are acceptable. Ligand B has 0 HBD and 2 HBA, also acceptable.

**QED:** Ligand A (0.812) has a better QED score than Ligand B (0.655), suggesting a more drug-like profile overall.

**DILI:** Both ligands have low DILI risk (44.281 and 42.885 percentile), which is good.

**BBB:** Ligand B (96.316%) has a significantly higher BBB penetration score than Ligand A (67.197%). This is a crucial advantage for a CNS target like DRD2.

**Caco-2 Permeability:** Ligand A (-5.216) has very poor Caco-2 permeability, while Ligand B (-4.246) is slightly better, but still poor.

**Aqueous Solubility:** Both ligands have poor aqueous solubility (-1.622 and -3.016). This could pose formulation challenges, but is less critical than BBB penetration for a CNS drug.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.208 and 0.611).

**Microsomal Clearance:** Ligand A (-9.059) exhibits much lower (better) microsomal clearance than Ligand B (52.339), indicating greater metabolic stability.

**In vitro Half-Life:** Ligand A (-2.023) has a slightly better in vitro half-life than Ligand B (-24.123).

**P-gp Efflux:** Ligand A (0.015) has very low P-gp efflux, which is excellent. Ligand B (0.261) is slightly higher, but still relatively low.

**Binding Affinity:** Both ligands have very similar and strong binding affinities (-8.3 and -8.1 kcal/mol). The difference is negligible.

**Overall Assessment:**

Ligand B is the stronger candidate. While Ligand A has a better QED and metabolic stability, Ligand B's superior TPSA and, most importantly, *significantly* higher BBB penetration outweigh these advantages. The low logP of Ligand A is a major concern for CNS penetration. The similar binding affinities mean that the ADME properties become the deciding factor. For a CNS GPCR target, BBB penetration is paramount.

Output:
1
2025-04-17 08:41:36,297 - INFO - Batch 470 complete. Total preferences: 7520
2025-04-17 08:41:36,297 - INFO - Processing batch 471/512...
2025-04-17 08:42:16,745 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight (MW):** Both ligands (362.5 & 370.9 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (65.54) is significantly better than Ligand B (84.5). For CNS targets, we want TPSA <= 90, and A is comfortably within that, while B is approaching the upper limit.

**3. logP:** Both ligands have good logP values (1.88 & 1.54), falling within the optimal 1-3 range.

**4. H-Bond Donors (HBD):** Both ligands are acceptable (1 & 2), well below the threshold of 5.

**5. H-Bond Acceptors (HBA):** Both ligands are acceptable (5 & 4), well below the threshold of 10.

**6. QED:** Ligand A (0.892) has a substantially better QED score than Ligand B (0.603), indicating a more drug-like profile.

**7. DILI:** Ligand A (48.9) has a slightly higher DILI risk than Ligand B (29.4), but both are below the concerning threshold of 60.

**8. BBB:** Ligand A (69.4) is better than Ligand B (60.6), but both are below the desirable >70 for CNS targets. This is a critical factor for DRD2.

**9. Caco-2 Permeability:** Both have negative values (-5.019 & -5.083) which is unusual and suggests poor permeability. This is a significant drawback for both.

**10. Aqueous Solubility:** Both have negative values (-2.811 & -2.335) which is unusual and suggests poor solubility. This is a significant drawback for both.

**11. hERG Inhibition:** Ligand A (0.442) has a slightly higher hERG risk than Ligand B (0.095), but both are relatively low.

**12. Microsomal Clearance:** Ligand A (22.8) has a higher clearance than Ligand B (8.0), indicating lower metabolic stability.

**13. In vitro Half-Life:** Ligand A (35.9) has a longer half-life than Ligand B (5.1), which is desirable.

**14. P-gp Efflux:** Ligand A (0.108) has lower P-gp efflux than Ligand B (0.095), meaning better potential for CNS exposure.

**15. Binding Affinity:** Ligand B (-8.0) has a slightly better binding affinity than Ligand A (-7.8), but the difference is small (0.2 kcal/mol).

**Overall Assessment:**

Despite Ligand B having a slightly better binding affinity, Ligand A is the more promising candidate. Its superior TPSA, QED, BBB, and P-gp efflux, combined with a reasonable half-life, outweigh the slight disadvantage in binding affinity and the higher DILI/clearance. The poor Caco-2 and solubility are concerning for both, but can be addressed with formulation strategies. For a CNS target like DRD2, maximizing BBB penetration and minimizing P-gp efflux are crucial, and Ligand A performs better in these areas.

Output:
1
2025-04-17 08:42:16,745 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (347.415 and 352.435 Da) are within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (73.32) is significantly better than Ligand B (107.7). For CNS targets, we want TPSA <= 90, so Ligand A is preferable.

**3. logP:** Ligand A (0.641) is a bit low, potentially hindering permeation, but Ligand B (0.032) is even lower and more concerning. Optimal is 1-3.

**4. H-Bond Donors:** Ligand A (1) is good. Ligand B (3) is acceptable but less ideal.

**5. H-Bond Acceptors:** Both ligands have 6 HBA, which is within the acceptable limit of <= 10.

**6. QED:** Ligand A (0.809) is better than Ligand B (0.548), indicating a more drug-like profile.

**7. DILI:** Both ligands have relatively low DILI risk (22.722 and 20.085), both well below the 40 threshold.

**8. BBB:** This is crucial for a CNS target like DRD2. Ligand A (64.327) is significantly better than Ligand B (40.132). We want >70, and A is closer.

**9. Caco-2:** Ligand A (-4.877) and Ligand B (-5.142) both have negative values, indicating poor permeability. This is a concern for both.

**10. Solubility:** Both ligands have very poor aqueous solubility (-1.474 and -1.243). This is a significant drawback for both.

**11. hERG:** Both ligands have very low hERG inhibition risk (0.586 and 0.156).

**12. Cl_mic:** Ligand B (-7.228) has a *negative* microsomal clearance, which is unusual and suggests potential instability or issues with the assay. Ligand A (11.705) is more reasonable.

**13. t1/2:** Ligand B (14.889) has a longer in vitro half-life than Ligand A (2.7), which is a positive.

**14. Pgp:** Both ligands have very low P-gp efflux liability (0.016 and 0.019), which is good for CNS penetration.

**15. Binding Affinity:** Ligand A (-8.2 kcal/mol) has a significantly stronger binding affinity than Ligand B (-7.1 kcal/mol). This >1.5 kcal/mol difference is substantial and can outweigh some ADME concerns.

**Overall Assessment:**

Ligand A is the better candidate. While both have solubility and Caco-2 permeability issues, Ligand A excels in crucial areas for a CNS GPCR target: TPSA, BBB penetration, and, most importantly, binding affinity. Ligand B's negative microsomal clearance is a red flag. The stronger binding affinity of Ligand A (-8.2 vs -7.1) is a significant advantage.



Output:
1
2025-04-17 08:42:16,746 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (384.523 Da) is slightly higher than Ligand B (344.434 Da), but both are acceptable.

**TPSA:** Ligand A (83.55) is better than Ligand B (59.07) for CNS penetration, being closer to the <90 A^2 threshold.

**logP:** Ligand A (1.907) is within the optimal range (1-3). Ligand B (3.496) is at the higher end, potentially leading to solubility issues, but still acceptable.

**H-Bond Donors/Acceptors:** Both ligands have reasonable HBD/HBA counts (Ligand A: 1/5, Ligand B: 2/5), falling within the recommended limits.

**QED:** Both ligands have good QED values (Ligand A: 0.786, Ligand B: 0.805), indicating good drug-like properties.

**DILI:** Both ligands have similar DILI risk (Ligand A: 59.48, Ligand B: 57.348), which is acceptable (below 60).

**BBB:** Ligand B (73.943) has a significantly better BBB percentile than Ligand A (55.138). This is a crucial advantage for a CNS target like DRD2.

**Caco-2 Permeability:** Ligand A (-5.382) shows poor permeability, whereas Ligand B (-4.979) is slightly better.

**Aqueous Solubility:** Ligand A (-2.377) has slightly better solubility than Ligand B (-4.463).

**hERG:** Both ligands have low hERG inhibition liability (Ligand A: 0.205, Ligand B: 0.9), which is favorable.

**Microsomal Clearance:** Ligand B (61.186) has a higher clearance than Ligand A (15.753), suggesting lower metabolic stability.

**In vitro Half-Life:** Ligand A (35.388) has a slightly longer half-life than Ligand B (32.646).

**P-gp Efflux:** Ligand A (0.207) has lower P-gp efflux liability than Ligand B (0.397), which is better for CNS exposure.

**Binding Affinity:** Ligand B (-8.5 kcal/mol) has a significantly stronger binding affinity than Ligand A (-7.3 kcal/mol). This >1.5 kcal/mol difference is a major advantage, potentially outweighing some ADME drawbacks.

**Overall Assessment:**

While Ligand A has slightly better solubility and lower P-gp efflux, Ligand B excels in the most critical areas for a CNS-targeting GPCR ligand: **BBB penetration and binding affinity**. The significantly stronger binding affinity of Ligand B (-8.5 vs -7.3 kcal/mol) is a substantial advantage. The better BBB penetration (73.943 vs 55.138) is also a key factor. The slightly higher clearance of Ligand B is a concern, but the potency advantage is likely to be more impactful.

Output:
1
2025-04-17 08:42:16,746 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 drug candidates, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (350.419 Da) and Ligand B (338.411 Da) are both acceptable.

**TPSA:** Ligand A (94.48) is slightly above the preferred <90 for CNS targets, but still reasonable. Ligand B (66.71) is excellent, well below 90, suggesting better CNS penetration potential.

**logP:** Both ligands have good logP values (A: 2.665, B: 1.855), falling within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A (HBD=2, HBA=6) and Ligand B (HBD=1, HBA=4) both have acceptable numbers of H-bond donors and acceptors.

**QED:** Both ligands have high QED scores (A: 0.874, B: 0.925), indicating good drug-like properties.

**DILI:** Ligand A (68.786) has a slightly higher DILI risk than Ligand B (54.634), but both are below the concerning threshold of 60.

**BBB:** Both ligands exhibit good BBB penetration (A: 76.154, B: 73.013), exceeding the desirable >70% for CNS targets.

**Caco-2 Permeability:** Ligand A (-4.53) and Ligand B (-5.071) both have negative Caco-2 values, which is unusual and suggests poor permeability. This is a potential red flag for both.

**Aqueous Solubility:** Both ligands have very poor aqueous solubility (A: -4.28, B: -2.959). This is a significant drawback.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (A: 0.166, B: 0.428).

**Microsomal Clearance:** Ligand B (21.429) has significantly lower microsomal clearance than Ligand A (45.123), indicating better metabolic stability.

**In vitro Half-Life:** Ligand B (-4.049) has a negative in vitro half-life, which is not physically possible and suggests an issue with the data. Ligand A (14.341) has a reasonable half-life.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (A: 0.047, B: 0.073), which is favorable for CNS penetration.

**Binding Affinity:** Both ligands have identical and strong binding affinities (-8.6 kcal/mol).

**Overall Assessment:**

While both ligands have excellent binding affinity and acceptable BBB penetration, Ligand B appears more promising. It has a lower TPSA, lower DILI risk, significantly lower microsomal clearance (better metabolic stability), and lower P-gp efflux. The negative Caco-2 and aqueous solubility values are concerning for both, but the better ADME profile of Ligand B, particularly the lower clearance, makes it the more likely candidate to progress. The negative in vitro half-life for Ligand B is a data quality issue that would need to be resolved, but assuming it's an error, the other properties favor it.

Output:
1
2025-04-17 08:42:16,746 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (348.491 Da) is slightly preferred as it's closer to the lower end, potentially aiding permeability.

**TPSA:** Ligand A (47.1) is excellent, well below the 90 A^2 threshold for CNS targets. Ligand B (83.63) is higher, but still potentially acceptable, though less ideal.

**logP:** Ligand A (0.195) is quite low, which could hinder membrane permeability and brain penetration. Ligand B (2.961) is much better, falling within the optimal 1-3 range.

**H-Bond Donors & Acceptors:** Ligand A (0 HBD, 4 HBA) and Ligand B (2 HBD, 5 HBA) both have reasonable numbers of H-bond donors and acceptors, well within the guidelines.

**QED:** Both ligands have similar QED values (0.712 and 0.706), indicating good drug-likeness.

**DILI:** Ligand A (5.157) has a very low DILI risk, significantly better than Ligand B (36.681).

**BBB:** This is a crucial parameter for a CNS target like DRD2. Ligand A shows excellent BBB penetration (80.07%), while Ligand B is considerably lower (61.923%).

**Caco-2 Permeability:** Ligand A (-4.791) has poor Caco-2 permeability, consistent with its low logP. Ligand B (-5.289) is also poor, but not drastically different.

**Aqueous Solubility:** Ligand A (-0.316) and Ligand B (-2.586) both have poor aqueous solubility.

**hERG Inhibition:** Both ligands show low hERG inhibition liability (0.467 and 0.57), which is good.

**Microsomal Clearance:** Ligand A (-3.726) has a negative value, indicating very low clearance and high metabolic stability. Ligand B (50.614) has a high clearance, suggesting faster metabolism.

**In vitro Half-Life:** Ligand A (-3.211) has a negative value, indicating a very long half-life. Ligand B (-8.222) has a shorter half-life.

**P-gp Efflux:** Ligand A (0.008) shows very low P-gp efflux, which is highly desirable for CNS penetration. Ligand B (0.393) has moderate P-gp efflux.

**Binding Affinity:** Ligand A (-8.6 kcal/mol) has a significantly stronger binding affinity than Ligand B (-7.5 kcal/mol). This 1.1 kcal/mol difference is substantial and can outweigh some ADME drawbacks.

**Overall Assessment:**

While Ligand A has a very strong binding affinity and excellent BBB penetration and metabolic stability, its extremely low logP is a major concern. This will likely result in poor oral absorption and bioavailability. Ligand B, while having a weaker affinity, has a much better logP, which is crucial for permeability and CNS exposure. The better logP, coupled with acceptable BBB, makes it more likely to reach the target in vivo. The difference in affinity is significant, but not insurmountable, and could potentially be improved through further optimization of Ligand B.

Output:
1
2025-04-17 08:42:16,746 - INFO - Reasoning:

Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (367.471 and 357.405 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (110.52) is slightly above the preferred <90 for CNS targets, but acceptable. Ligand B (80.12) is well within the optimal range. This favors Ligand B.

**3. logP:** Both ligands have good logP values (2.12 and 1.873), falling within the 1-3 range.

**4. H-Bond Donors:** Ligand A (3) is acceptable, while Ligand B (1) is even better, minimizing potential permeability issues.

**5. H-Bond Acceptors:** Ligand A (4) and Ligand B (5) are both within the acceptable limit of <=10.

**6. QED:** Both ligands have good QED scores (0.74 and 0.872), indicating good drug-like properties.

**7. DILI:** Ligand A (65.723) has a higher DILI risk than Ligand B (47.732), though both are reasonably acceptable.

**8. BBB:** This is crucial for a CNS target like DRD2. Ligand B (81.97) has a significantly better BBB penetration percentile than Ligand A (65.646). This is a major advantage for Ligand B.

**9. Caco-2 Permeability:** Ligand A (-5.172) has poor Caco-2 permeability. Ligand B (-4.547) is also poor, but slightly better.

**10. Aqueous Solubility:** Both ligands have poor aqueous solubility (-2.91 and -2.826). This could pose formulation challenges, but is not a dealbreaker.

**11. hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.121 and 0.317).

**12. Microsomal Clearance:** Ligand A (10.958) has lower microsomal clearance than Ligand B (21.044), suggesting better metabolic stability.

**13. In vitro Half-Life:** Ligand A (20.404) has a longer half-life than Ligand B (-18.883). This is a positive attribute for Ligand A.

**14. P-gp Efflux:** Ligand A (0.068) has lower P-gp efflux than Ligand B (0.073), meaning it's less likely to be pumped out of the brain, favoring better CNS exposure.

**15. Binding Affinity:** Ligand A (-9.3 kcal/mol) has a significantly stronger binding affinity than Ligand B (0.0 kcal/mol). This is a substantial advantage for Ligand A, potentially outweighing some of its ADME drawbacks.

**Overall Assessment:**

While Ligand A has a superior binding affinity and better metabolic stability (lower Cl_mic, longer t1/2) and P-gp efflux, Ligand B excels in crucial GPCR-specific properties for CNS targets: TPSA and, most importantly, BBB penetration. The substantial difference in binding affinity (-9.3 vs 0.0 kcal/mol) is a major factor. Even with a slightly higher TPSA and worse BBB, the much stronger binding of Ligand A is likely to overcome these issues, especially considering the potential for further optimization. The poor Caco-2 permeability is a concern for both, but less critical for a CNS target.

Output:
1
2025-04-17 08:42:16,746 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (348.29 and 349.475 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (124.2) is slightly above the optimal <90 for CNS targets, but still reasonable. Ligand B (84.64) is excellent, well below 90.

**logP:** Both ligands (1.196 and 1.784) are within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Both have 1 HBD, which is good. Ligand A has 7 HBA, while Ligand B has 4. Both are acceptable (<=10), but Ligand B is preferable.

**QED:** Ligand B (0.792) has a significantly better QED score than Ligand A (0.475), indicating a more drug-like profile.

**DILI:** Ligand A (96.976) has a very high DILI risk, which is a major concern. Ligand B (12.369) has a very low DILI risk, a significant advantage.

**BBB:** Ligand B (66.925) has a better BBB penetration percentile than Ligand A (59.519), though both are below the desirable >70 for CNS targets.

**Caco-2 Permeability:** Ligand A (-4.612) has poor Caco-2 permeability, while Ligand B (-4.52) is slightly better but still poor.

**Aqueous Solubility:** Ligand A (-3.694) has poor aqueous solubility, and Ligand B (-1.779) is also poor, but better than A.

**hERG:** Both ligands have low hERG inhibition risk (0.124 and 0.381).

**Microsomal Clearance:** Ligand A (42.077) has higher microsomal clearance than Ligand B (11.012), suggesting lower metabolic stability.

**In vitro Half-Life:** Ligand B (-0.868) has a negative half-life, which is unusual and likely an error or indicates very rapid degradation. Ligand A (16.519) has a reasonable half-life.

**P-gp Efflux:** Ligand A (0.177) has lower P-gp efflux than Ligand B (0.032), which is preferable for CNS penetration.

**Binding Affinity:** Ligand A (-8.8 kcal/mol) has significantly better binding affinity than Ligand B (-6.8 kcal/mol). This is a substantial advantage.

**Overall Assessment:**

Ligand A has a much better binding affinity, which is crucial for GPCRs. However, its extremely high DILI risk and poor Caco-2 permeability are major drawbacks. Ligand B has a better safety profile (DILI), better QED, and better TPSA, but its binding affinity is significantly weaker. The half-life for Ligand B is also questionable.

Given the GPCR-specific priorities and the severity of the DILI risk for Ligand A, I would prioritize Ligand B despite its weaker affinity. The DILI risk is a showstopper for Ligand A. While the affinity difference is substantial, medicinal chemistry efforts could focus on optimizing Ligand B's affinity while maintaining its favorable ADME properties.

Output:
1
2025-04-17 08:42:16,747 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (342.483 Da) is slightly preferred as it's closer to the lower end, potentially aiding permeability.

**TPSA:** Ligand A (49.41) is significantly better than Ligand B (61.92). For CNS targets, TPSA < 90 is desirable, and A is much closer to the optimal <60 range. B is getting towards the upper limit.

**logP:** Both ligands have good logP values (A: 3.173, B: 3.471), falling within the 1-3 range. No significant difference here.

**H-Bond Donors/Acceptors:** Ligand A (HBD=1, HBA=2) is slightly better than Ligand B (HBD=0, HBA=4). Lower HBD/HBA generally improves permeability.

**QED:** Both ligands have acceptable QED values (A: 0.798, B: 0.699), indicating good drug-like properties. A is slightly better.

**DILI:** Ligand A (19.465) has a much lower DILI risk than Ligand B (55.797). This is a significant advantage for A.

**BBB:** Ligand A (73.943) has a substantially better BBB penetration percentile than Ligand B (54.595). This is *critical* for a CNS target like DRD2.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.945 and -4.803). This is unusual and suggests poor permeability. However, the negative values are very close, so this isn't a major differentiator.

**Aqueous Solubility:** Both ligands have negative solubility values (-4.47 and -3.888). This is also concerning, indicating poor solubility. Again, the difference is small.

**hERG Inhibition:** Ligand A (0.293) has a much lower hERG inhibition liability than Ligand B (0.909). This is a significant safety advantage for A.

**Microsomal Clearance:** Ligand B (73.793) has a higher microsomal clearance than Ligand A (47.904), indicating faster metabolism and potentially lower exposure.

**In vitro Half-Life:** Ligand A (12.177) has a slightly longer in vitro half-life than Ligand B (10.987).

**P-gp Efflux:** Ligand A (0.18) has significantly lower P-gp efflux liability than Ligand B (0.551). This is important for CNS penetration.

**Binding Affinity:** Ligand A (-8.7 kcal/mol) has a substantially stronger binding affinity than Ligand B (-7.0 kcal/mol). This is a major advantage, as a 1.7 kcal/mol difference is significant.

**Overall Assessment:**

Ligand A consistently outperforms Ligand B across most critical parameters, especially for a CNS-targeting GPCR. The superior BBB penetration, lower DILI risk, lower hERG inhibition, lower P-gp efflux, and significantly stronger binding affinity make it a much more promising drug candidate. While both have issues with Caco-2 and solubility, the other advantages of A outweigh these concerns.

Output:
1
2025-04-17 08:42:16,747 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (344.415 and 357.336 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (76.46) is excellent, well below the 90 A^2 threshold for CNS targets. Ligand B (103.79) is still reasonable but less optimal, approaching the 140 A^2 limit for oral absorption.

**3. logP:** Ligand A (0.835) is a bit low, potentially hindering permeation. Ligand B (1.426) is better, falling within the optimal 1-3 range.

**4. H-Bond Donors:** Ligand A (1) is good. Ligand B (3) is acceptable, but higher HBD can sometimes reduce permeability.

**5. H-Bond Acceptors:** Both ligands have 5 HBA, which is within the acceptable limit of <=10.

**6. QED:** Both ligands have good QED scores (0.56 and 0.651), indicating drug-like properties.

**7. DILI:** Ligand A (39.434) has a significantly lower DILI risk than Ligand B (72.819). This is a major advantage for Ligand A.

**8. BBB:** Ligand A (65.452) has a moderate BBB penetration, while Ligand B (47.15) is considerably lower. For a CNS target like DRD2, a higher BBB score is crucial.

**9. Caco-2 Permeability:** Ligand A (-4.652) has poor Caco-2 permeability, suggesting poor intestinal absorption. Ligand B (-5.363) is also poor, but slightly worse than A.

**10. Aqueous Solubility:** Both have negative solubility values, indicating poor aqueous solubility. Ligand A (-2.209) is slightly better than Ligand B (-1.991).

**11. hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.219 and 0.131).

**12. Microsomal Clearance:** Ligand A (0.421) has a much lower microsomal clearance, indicating better metabolic stability, than Ligand B (-13.284).

**13. In vitro Half-Life:** Ligand A (-0.787) has a slightly better in vitro half-life than Ligand B (-6.958).

**14. P-gp Efflux:** Both ligands have low P-gp efflux liability (0.054 and 0.154).

**15. Binding Affinity:** Ligand B (-9.1 kcal/mol) has a significantly stronger binding affinity than Ligand A (-7.7 kcal/mol). This is a substantial advantage, exceeding the 1.5 kcal/mol threshold.

**Overall Assessment:**

While Ligand B boasts a superior binding affinity, Ligand A has several advantages regarding safety (DILI) and CNS penetration (BBB). The lower metabolic clearance and half-life of Ligand A are also favorable. Considering the GPCR-specific priorities, the BBB score is critical for CNS targets. Ligand A's BBB score is acceptable, while Ligand B's is low. The affinity difference is significant, but the other ADME/Tox properties of Ligand A are more favorable for development as a CNS drug.

Output:
0
2025-04-17 08:42:16,747 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (356.348 and 376.519 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (79.18) is slightly higher than Ligand B (76.15), but both are below the 90 A^2 threshold desirable for CNS targets.

**3. logP:** Both ligands have good logP values (1.789 and 1.089), falling within the optimal 1-3 range. Ligand B is slightly lower, which *could* indicate slightly better solubility, but isn't a major concern.

**4. H-Bond Donors:** Ligand A has 3 HBD, which is acceptable. Ligand B has 0, which is also acceptable.

**5. H-Bond Acceptors:** Both ligands have 5 HBA, which is within the acceptable limit of <=10.

**6. QED:** Both ligands have similar QED values (0.714 and 0.694), indicating good drug-like properties.

**7. DILI:** Ligand A (51.493) has a slightly higher DILI risk than Ligand B (38.852). This is a point in favor of Ligand B.

**8. BBB:** Ligand B (82.009) has a significantly better BBB penetration percentile than Ligand A (68.864). This is *crucial* for a CNS target like DRD2.

**9. Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and suggests poor permeability. However, the scale is not specified, so it's difficult to interpret.

**10. Aqueous Solubility:** Both have negative solubility values, again making interpretation difficult.

**11. hERG:** Both ligands have very low hERG inhibition liability (0.512 and 0.507), which is excellent.

**12. Microsomal Clearance:** Ligand A (18.733) has lower microsomal clearance than Ligand B (51.15), suggesting better metabolic stability. This is a positive for Ligand A.

**13. In vitro Half-Life:** Ligand A (5.646) has a longer in vitro half-life than Ligand B (-56.212). The negative value for Ligand B is concerning and likely indicates very rapid degradation.

**14. P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.135 and 0.078), which is favorable for CNS penetration.

**15. Binding Affinity:** Ligand B (-7.2 kcal/mol) has a significantly stronger binding affinity than Ligand A (-9.4 kcal/mol). A 1.5 kcal/mol difference is substantial and can outweigh minor ADME drawbacks.

**Overall Assessment:**

While Ligand A has better metabolic stability (lower Cl_mic, longer t1/2) and slightly lower DILI risk, Ligand B's significantly superior BBB penetration and binding affinity are decisive. For a CNS GPCR target like DRD2, BBB penetration is paramount. The stronger binding affinity of Ligand B also increases the likelihood of efficacy. The negative values for Caco-2 and solubility are concerning for both, but the strong affinity and BBB penetration of Ligand B make it the more promising candidate.

Output:
1
2025-04-17 08:42:16,747 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (352.475 and 368.463 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (67.87) is significantly better than Ligand B (114.42). For CNS targets, we want TPSA <= 90, and A is comfortably within that, while B is above.

**logP:** Ligand A (1.441) is within the optimal 1-3 range. Ligand B (-0.635) is slightly below 1, which *could* hinder permeation.

**H-Bond Donors/Acceptors:** Both have 1 HBD, which is good. Ligand A has 4 HBA, and Ligand B has 7 HBA. Both are acceptable (<=10), but A is preferable.

**QED:** Both ligands have good QED scores (0.504 and 0.62), indicating good drug-like properties.

**DILI:** Ligand A (29.74) has a much lower DILI risk than Ligand B (43.622). Both are below 40, which is good, but A is better.

**BBB:** Both ligands have reasonable BBB penetration (54.634 and 56.572). While >70 is desirable, these are not terrible, and the difference is minor.

**Caco-2 Permeability:** Ligand A (-4.402) has a worse Caco-2 permeability than Ligand B (-5.498). Lower values are less favorable.

**Aqueous Solubility:** Ligand A (-1.737) has better aqueous solubility than Ligand B (-1.223). Higher values are preferred.

**hERG:** Both ligands have very low hERG inhibition risk (0.397 and 0.059).

**Microsomal Clearance:** Ligand A (13.282) has a lower microsomal clearance, indicating better metabolic stability, than Ligand B (15.161).

**In vitro Half-Life:** Ligand A (-3.623) has a much longer in vitro half-life than Ligand B (-16.015). This is a significant advantage.

**P-gp Efflux:** Ligand A (0.089) has lower P-gp efflux liability than Ligand B (0.012), which is better for CNS exposure.

**Binding Affinity:** Ligand A (-7.5) has a slightly better binding affinity than Ligand B (-6.7). While both are good, A has a 0.8 kcal/mol advantage.

**Overall Assessment:**

Ligand A is superior. It has a better TPSA, logP, DILI score, microsomal clearance, in vitro half-life, P-gp efflux, and binding affinity. While Ligand B has slightly better Caco-2 permeability, the other advantages of Ligand A, particularly its lower TPSA and better metabolic stability/half-life, are more important for a CNS-targeting GPCR like DRD2. The 0.8 kcal/mol difference in binding affinity is also a significant factor.

Output:
1
2025-04-17 08:42:16,748 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 drug candidates, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (353.419 Da) is slightly lower, which *could* be advantageous for permeability, but both are acceptable.

**TPSA:** Ligand B (93.96) is better than Ligand A (104.81). For CNS targets, we want TPSA <= 90, so Ligand B is closer to this ideal.

**logP:** Ligand B (0.603) is within the optimal range (1-3), while Ligand A (-0.183) is slightly below 1. This is a significant drawback for Ligand A as it might struggle with membrane permeability.

**H-Bond Donors/Acceptors:** Both have 2 HBDs, which is good. Ligand B has 7 HBAs, while Ligand A has 5. Both are acceptable, staying under the 10 HBA limit.

**QED:** Both ligands have good QED scores (A: 0.509, B: 0.656), indicating a generally drug-like profile.

**DILI:** Ligand B (49.632) has a slightly higher DILI risk than Ligand A (36.758), but both are below the concerning threshold of 60.

**BBB:** This is critical for a CNS target. Ligand B (90.112) is significantly better than Ligand A (36.603). Ligand B exceeds the desirable >70 percentile, while A falls far short.

**Caco-2 Permeability:** Both are negative, indicating poor permeability. This is concerning, but can be mitigated if other properties are favorable.

**Aqueous Solubility:** Both are negative, indicating poor solubility. This is also concerning.

**hERG Inhibition:** Both have very low hERG inhibition risk (A: 0.058, B: 0.144).

**Microsomal Clearance:** Ligand A (32.488) has a lower Cl_mic than Ligand B (14.182), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand B (-5.083) has a slightly longer half-life than Ligand A (-3.357).

**P-gp Efflux:** Both have very low P-gp efflux liability (A: 0.018, B: 0.056).

**Binding Affinity:** Ligand B (-7.5 kcal/mol) has a slightly better binding affinity than Ligand A (-7.1 kcal/mol), though the difference is not huge.

**Overall Assessment:**

Ligand B is the stronger candidate. Its superior BBB penetration is the most critical factor given the CNS target. While Ligand A has better metabolic stability (lower Cl_mic), Ligand B's better logP and TPSA, combined with its excellent BBB score and slightly better affinity, outweigh this advantage. The poor Caco-2 and solubility for both are concerning, but could be addressed with formulation strategies.

Output:
1
2025-04-17 08:42:16,748 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (332.363 and 348.447 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (90.68) is slightly above the preferred <90 for CNS targets, while Ligand B (78.67) is well within the range. This gives a slight edge to Ligand B.

**logP:** Both ligands have good logP values (2.657 and 1.299), falling within the optimal 1-3 range. Ligand A is slightly higher, which could potentially lead to off-target effects, but is still acceptable.

**H-Bond Donors/Acceptors:** Ligand A has 2 HBD and 4 HBA, while Ligand B has 1 HBD and 5 HBA. Both are within acceptable limits (<=5 HBD and <=10 HBA).

**QED:** Both ligands have good QED scores (0.769 and 0.84), indicating good drug-like properties.

**DILI:** Ligand A has a DILI risk of 85.227, which is high and concerning. Ligand B has a much lower DILI risk of 25.359, which is excellent. This is a major advantage for Ligand B.

**BBB:** Ligand A has a BBB penetration of 35.983, which is quite low and unfavorable for a CNS target like DRD2. Ligand B has a much better BBB penetration of 73.401, exceeding the desirable threshold of >70. This is a critical advantage for Ligand B.

**Caco-2 Permeability:** Both have negative Caco-2 values (-5.1 and -4.64), which is unusual and suggests poor permeability. However, these values are on a strange scale and difficult to interpret without more context.

**Aqueous Solubility:** Both have negative solubility values (-5.41 and -1.443) which is also unusual and suggests poor solubility.

**hERG Inhibition:** Both ligands show low hERG inhibition liability (0.67 and 0.355), which is good.

**Microsomal Clearance:** Ligand A has a higher microsomal clearance (14.178) than Ligand B (3.611), indicating lower metabolic stability. This favors Ligand B.

**In vitro Half-Life:** Ligand A has a longer in vitro half-life (33.788) than Ligand B (3.981), which is a positive for Ligand A.

**P-gp Efflux:** Ligand A shows higher P-gp efflux (0.263) than Ligand B (0.103), meaning Ligand B is less likely to be pumped out of the brain, which is beneficial for CNS penetration.

**Binding Affinity:** Both ligands have excellent binding affinities (-9.7 and -9.0 kcal/mol). Ligand A is slightly better (-9.7 vs -9.0), but the difference is not substantial enough to outweigh the significant ADME advantages of Ligand B.

**Overall:** Considering all factors, especially the GPCR-specific priorities, Ligand B is the more promising drug candidate. It has a significantly lower DILI risk, much better BBB penetration, lower P-gp efflux, and better metabolic stability, despite a slightly weaker binding affinity. The poor Caco-2 and solubility values are concerning for both, but the other advantages of Ligand B are more critical for a CNS target.

Output:
1
2025-04-17 08:42:16,748 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B based on the provided guidelines, prioritizing GPCR-specific properties (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (348.403 Da) is slightly lower, which could be beneficial for permeability. Ligand B (367.431 Da) is also acceptable.

**TPSA:** Ligand A (127.32) is closer to the upper limit for good oral absorption (<=140) and still reasonable for a CNS target, but less ideal than Ligand B (107.77), which is well within the desired range for CNS penetration (<=90).

**logP:** Ligand A (0.539) is a bit low, potentially hindering permeation. Ligand B (-0.433) is even lower, raising concerns about membrane permeability. Both are below the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A (HBD=3, HBA=5) is slightly more balanced. Ligand B (HBD=2, HBA=7) has fewer donors but more acceptors. Both are within acceptable limits.

**QED:** Both ligands have good QED scores (A: 0.62, B: 0.699), indicating drug-like properties.

**DILI:** Ligand A (48.313) has a significantly lower DILI risk than Ligand B (69.95), which is approaching a higher risk category.

**BBB:** This is crucial for a CNS target. Ligand A (74.758) has a much better BBB percentile than Ligand B (39.511). This is a major advantage for Ligand A.

**Caco-2 Permeability:** Both have negative Caco-2 values (-5.353 and -5.606), which is unusual and suggests poor permeability. This is a significant concern for both.

**Aqueous Solubility:** Both have negative solubility values (-3.832 and -2.09), also unusual and indicating poor solubility.

**hERG:** Both ligands have very low hERG inhibition liability (A: 0.068, B: 0.134), which is excellent.

**Microsomal Clearance:** Ligand A (34.667) has a higher microsomal clearance than Ligand B (22.276), suggesting lower metabolic stability.

**In vitro Half-Life:** Ligand B (1.451) has a slightly longer in vitro half-life than Ligand A (-7.99), but both are quite poor.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (A: 0.025, B: 0.025).

**Binding Affinity:** Ligand A (-8.3 kcal/mol) has a significantly stronger binding affinity than Ligand B (-7.5 kcal/mol). This >1.5 kcal/mol advantage is substantial and can outweigh some ADME drawbacks.

**Overall Assessment:**

Ligand A is the stronger candidate despite some ADME concerns. Its significantly better BBB penetration (74.758 vs 39.511) and much stronger binding affinity (-8.3 vs -7.5 kcal/mol) are critical advantages for a CNS-targeting GPCR. While its logP is low and solubility/permeability are poor, the affinity difference is substantial. The lower DILI risk is also a positive. Ligand B's lower TPSA is good, but it is offset by the poor BBB penetration, weaker binding, and higher DILI risk. The poor solubility and permeability are concerning for both, but can be addressed with formulation strategies.



Output:
0
2025-04-17 08:42:16,748 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 drug candidates, considering the provided guidelines and GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight (MW):** Both ligands (352.825 and 358.551 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (58.12) is higher than Ligand B (32.34). For a CNS target like DRD2, TPSA should ideally be <=90, so both are acceptable, but B is significantly better.

**3. logP:** Ligand A (3.394) and Ligand B (4.73) are both within the optimal 1-3 range, but B is pushing the upper limit. While acceptable, higher logP can sometimes lead to off-target effects.

**4. H-Bond Donors (HBD):** Both ligands have 1 HBD, which is within the acceptable limit of <=5.

**5. H-Bond Acceptors (HBA):** Ligand A has 4 HBAs, and Ligand B has 3. Both are within the acceptable limit of <=10.

**6. QED:** Both ligands have similar QED values (0.782 and 0.789), indicating good drug-like properties.

**7. DILI:** Ligand A has a DILI risk of 83.986, which is high (>60). Ligand B has a much lower DILI risk of 31.291, which is excellent (<40). This is a significant advantage for Ligand B.

**8. BBB:** Ligand A has a BBB penetration of 84.684, which is good (>70). Ligand B has an even better BBB penetration of 92.361, which is excellent. Both are favorable for a CNS target.

**9. Caco-2 Permeability:** Ligand A (-4.876) and Ligand B (-5.412) both have negative Caco-2 values, which is unusual and suggests poor permeability. However, the scale isn't specified, so it's hard to interpret.

**10. Aqueous Solubility:** Both ligands have poor aqueous solubility (-4.464 and -4.71). This could be a formulation challenge, but not a deal-breaker if other properties are strong.

**11. hERG Inhibition:** Both ligands have low hERG inhibition risk (0.824 and 0.752).

**12. Microsomal Clearance:** Ligand A (83.752) has higher microsomal clearance than Ligand B (66.539), indicating lower metabolic stability.

**13. In vitro Half-Life:** Ligand A (65.651) has a longer in vitro half-life than Ligand B (33.097).

**14. P-gp Efflux:** Both ligands have low P-gp efflux liability (0.623 and 0.642).

**15. Binding Affinity:** Ligand B (-7.9 kcal/mol) has a significantly stronger binding affinity than Ligand A (-10.0 kcal/mol). This is a substantial advantage, potentially outweighing some of the other minor drawbacks.

**Overall Assessment:**

Ligand B is the more promising candidate. While both have some solubility issues, Ligand B excels in key areas for a CNS GPCR target: significantly better DILI risk, superior BBB penetration, and *much* stronger binding affinity. The slightly higher logP is a minor concern, but the substantial affinity advantage likely compensates for it. Ligand A's high DILI risk is a major red flag.

Output:
1
2025-04-17 08:42:16,748 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (352.475 Da) is slightly lower, which is generally favorable for permeability.

**2. TPSA:** Ligand A (86.71) is better than Ligand B (69.64), both are below the 90 A^2 threshold for CNS targets.

**3. logP:** Ligand A (1.365) is within the optimal range (1-3), while Ligand B (3.111) is at the higher end. While still acceptable, higher logP can sometimes lead to off-target effects.

**4. H-Bond Donors:** Both ligands have 2 HBD, which is within the acceptable limit of <=5.

**5. H-Bond Acceptors:** Ligand A has 4 HBA, and Ligand B has 3. Both are within the acceptable limit of <=10.

**6. QED:** Both ligands have similar QED values (0.656 and 0.679), indicating good drug-like properties.

**7. DILI:** Ligand A (9.655) has a significantly lower DILI risk than Ligand B (21.442). This is a major advantage for Ligand A.

**8. BBB:** Ligand B (60.527) has a better BBB penetration percentile than Ligand A (53.16), but both are below the desirable >70 for CNS targets.

**9. Caco-2 Permeability:** Ligand A (-4.942) shows better Caco-2 permeability than Ligand B (-4.569).

**10. Aqueous Solubility:** Ligand A (-0.991) has better aqueous solubility than Ligand B (-3.637).

**11. hERG Inhibition:** Both ligands have low hERG inhibition liability (0.181 and 0.353).

**12. Microsomal Clearance:** Ligand A (10.231) has lower microsomal clearance than Ligand B (63.501), indicating better metabolic stability.

**13. In vitro Half-Life:** Ligand A (-10.89) has a longer in vitro half-life than Ligand B (4.435).

**14. P-gp Efflux:** Ligand A (0.025) has much lower P-gp efflux liability than Ligand B (0.1). This is crucial for CNS penetration.

**15. Binding Affinity:** Ligand B (-7.1) has a slightly better binding affinity than Ligand A (-7.6). However, the difference is only 0.5 kcal/mol, which is not substantial enough to outweigh the significant ADME advantages of Ligand A.

**Overall Assessment:**

Ligand A demonstrates a superior ADME profile compared to Ligand B. It has lower DILI risk, better solubility, better permeability, lower P-gp efflux, and improved metabolic stability (lower Cl_mic and longer t1/2). While Ligand B has slightly better BBB penetration and binding affinity, the ADME advantages of Ligand A are more critical for a CNS-targeting GPCR like DRD2. The small difference in binding affinity can likely be optimized in subsequent iterations of drug design.

Output:
0
2025-04-17 08:42:16,749 - INFO - Batch 471 complete. Total preferences: 7536
2025-04-17 08:42:16,749 - INFO - Processing batch 472/512...
2025-04-17 08:42:57,810 - INFO - Reasoning:

Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (345.403 and 344.375 Da) fall comfortably within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (95.5) is better than Ligand B (112.33). For CNS targets, we want TPSA <= 90, so Ligand A is closer to this threshold.

**3. logP:** Ligand A (0.127) is quite low, potentially hindering permeability. Ligand B (0.684) is better, but still on the lower side of the optimal 1-3 range.

**4. H-Bond Donors:** Both have 1 HBD, which is acceptable.

**5. H-Bond Acceptors:** Both have 5 HBA, also acceptable.

**6. QED:** Ligand A (0.84) has a much better QED score than Ligand B (0.258), indicating a more drug-like profile.

**7. DILI:** Both ligands have acceptable DILI risk (54.285 and 51.338, respectively), well below the 60 threshold.

**8. BBB:** Ligand A (64.095) has a significantly better BBB percentile than Ligand B (46.84). This is *critical* for a CNS target like DRD2.

**9. Caco-2 Permeability:** Ligand A (-5.058) has a worse Caco-2 permeability than Ligand B (-4.793), but both are quite poor.

**10. Aqueous Solubility:** Ligand A (-1.542) is slightly better than Ligand B (-1.128), but both are poor.

**11. hERG Inhibition:** Ligand A (0.073) has a lower hERG inhibition risk than Ligand B (0.178), which is favorable.

**12. Microsomal Clearance:** Ligand A (-1.071) has a better (lower) microsomal clearance than Ligand B (-3.67), indicating better metabolic stability.

**13. In vitro Half-Life:** Ligand A (0.298) has a better (longer) in vitro half-life than Ligand B (-5.159).

**14. P-gp Efflux:** Ligand A (0.007) has a much lower P-gp efflux liability than Ligand B (0.018), which is crucial for CNS penetration.

**15. Binding Affinity:** Ligand A (-8.9 kcal/mol) has a significantly stronger binding affinity than Ligand B (-6.7 kcal/mol). This is a substantial advantage (2.2 kcal/mol difference).

**Overall Assessment:**

Ligand A is the superior candidate. While both have some ADME liabilities, Ligand A excels in the most critical areas for a CNS GPCR target: BBB penetration, P-gp efflux, metabolic stability, in vitro half-life, and, most importantly, binding affinity. The stronger binding affinity of Ligand A can potentially offset some of its permeability issues. Ligand B's lower BBB and higher P-gp efflux are significant drawbacks. The QED score also favors Ligand A.

Output:
1
2025-04-17 08:42:57,810 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (353.463 Da) is slightly lower, which could be beneficial for permeability, but both are acceptable.

**TPSA:** Ligand A (90.9) is excellent for CNS penetration, falling well below the 90 A^2 threshold. Ligand B (29.02) is even better, indicating potentially improved BBB penetration.

**logP:** Ligand A (-0.121) is quite low, potentially hindering membrane permeability and bioavailability. Ligand B (4.948) is high, potentially causing solubility issues and off-target interactions.

**H-Bond Donors/Acceptors:** Ligand A has 3 HBD and 5 HBA, which are within acceptable limits. Ligand B has 0 HBD and 5 HBA, also acceptable.

**QED:** Both ligands have good QED scores (A: 0.566, B: 0.6), indicating drug-like properties.

**DILI:** Both ligands have similar, acceptable DILI risk (A: 6.747, B: 39.201).

**BBB:** Ligand B (93.098) has a significantly higher BBB percentile than Ligand A (39.55). This is a crucial advantage for a CNS target like DRD2.

**Caco-2 Permeability:** Ligand A (-5.133) has poor Caco-2 permeability, which is concerning. Ligand B (-4.9) is also poor, but slightly better than A.

**Aqueous Solubility:** Ligand A (-0.647) has poor aqueous solubility, which could limit bioavailability. Ligand B (-4.984) also has poor aqueous solubility.

**hERG Inhibition:** Ligand A (0.103) has a very low hERG risk, which is excellent. Ligand B (0.877) has a slightly higher, but still acceptable, hERG risk.

**Microsomal Clearance:** Ligand A (7.417) has lower microsomal clearance than Ligand B (43.817), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (19.352) has a longer in vitro half-life than Ligand B (4.231), which is desirable.

**P-gp Efflux:** Ligand A (0.004) has very low P-gp efflux, indicating good potential for CNS exposure. Ligand B (0.506) has moderate P-gp efflux.

**Binding Affinity:** Ligand A (-7.9 kcal/mol) has a slightly better binding affinity than Ligand B (-7.1 kcal/mol). While the difference is not huge (1.8 kcal/mol), it's a positive factor for Ligand A.

**Overall Assessment:**

Ligand A has superior metabolic stability (lower Cl_mic, longer t1/2) and P-gp efflux, and a slightly better binding affinity. However, its low logP and poor Caco-2 permeability are significant drawbacks. Ligand B excels in BBB penetration, which is paramount for a CNS target. While its logP is high and metabolic stability is lower, the strong BBB penetration and acceptable affinity make it a more promising candidate. The poor solubility of both is a concern that would need to be addressed in formulation. Given the importance of CNS penetration for DRD2, and the relatively small affinity difference, Ligand B is the better candidate.

Output:
1
2025-04-17 08:42:57,810 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (351.403 and 342.443 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (100.88) is slightly above the preferred <90 for CNS targets, but still reasonable. Ligand B (70.25) is excellent, well below 90.

**3. logP:** Ligand A (0.348) is quite low, potentially hindering membrane permeability. Ligand B (2.241) is within the optimal 1-3 range. This is a significant advantage for Ligand B.

**4. H-Bond Donors:** Both ligands have 2 HBD, which is acceptable.

**5. H-Bond Acceptors:** Ligand A has 5 HBA, acceptable. Ligand B has 4 HBA, also acceptable.

**6. QED:** Both ligands have good QED scores (0.625 and 0.894), indicating drug-like properties.

**7. DILI:** Ligand A (23.73) has a low DILI risk. Ligand B (11.749) also has a low DILI risk, but slightly higher than A.

**8. BBB:** Ligand A (55.952) has a moderate BBB penetration score, which is not ideal for a CNS target. Ligand B (82.319) has a very good BBB penetration score, exceeding the >70 threshold. This is a major advantage for Ligand B.

**9. Caco-2:** Both have negative Caco-2 values, which is unusual and difficult to interpret without knowing the scale. However, the values are similar and don't strongly differentiate the two.

**10. Solubility:** Both have negative solubility values, also unusual. Again, similar and not a strong differentiator.

**11. hERG:** Ligand A (0.21) has a low hERG risk. Ligand B (0.741) has a slightly higher, but still acceptable, hERG risk.

**12. Cl_mic:** Ligand A (0.397) has a very low microsomal clearance, suggesting good metabolic stability. Ligand B (8.217) has a higher clearance, indicating faster metabolism. This favors Ligand A.

**13. t1/2:** Ligand A (3.018) has a short in vitro half-life. Ligand B (-1.245) has a negative half-life, which is not physically possible and indicates a problem with the data.

**14. Pgp:** Ligand A (0.014) has very low P-gp efflux, which is excellent for CNS penetration. Ligand B (0.026) also has low P-gp efflux, but slightly higher than A.

**15. Binding Affinity:** Ligand B (-9.0) has a significantly stronger binding affinity than Ligand A (-8.3). This 1.7 kcal/mol difference is substantial and can outweigh some ADME drawbacks.

**Overall Assessment:**

Ligand B is the stronger candidate despite the questionable t1/2 value. Its superior logP, BBB penetration, and significantly better binding affinity are critical for a CNS-targeting GPCR ligand. While Ligand A has better metabolic stability (Cl_mic), the weaker affinity and poor logP are significant drawbacks. The negative t1/2 value for Ligand B is concerning, but the strong affinity suggests it may be a data error.

Output:
1
2025-04-17 08:42:57,811 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B based on the provided guidelines, prioritizing GPCR-specific properties (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (339.374) is slightly lower, which could be beneficial for permeability, but both are acceptable.

**TPSA:** Ligand A (72.7) is better than Ligand B (47.36) as it is closer to the ideal range for CNS targets (<=90). Ligand B is excellent.

**logP:** Both ligands have good logP values (Ligand A: 2.184, Ligand B: 3.503), falling within the optimal 1-3 range. Ligand B is slightly higher, which could potentially raise concerns about off-target effects, but is still acceptable.

**H-Bond Donors/Acceptors:** Ligand A has 1 HBD and 5 HBA, while Ligand B has 0 HBD and 4 HBA. Both are within acceptable limits.

**QED:** Both ligands have reasonable QED values (Ligand A: 0.773, Ligand B: 0.674), indicating good drug-like properties.

**DILI:** Ligand A has a DILI risk of 63.397, which is approaching the higher risk threshold (>60). Ligand B has a significantly lower DILI risk (14.541), making it more favorable.

**BBB:** This is a crucial parameter for CNS targets. Ligand B (95.696) has a very high BBB percentile, significantly better than Ligand A (71.268), which is still good but less desirable.

**Caco-2 Permeability:** Both have negative values, which is unusual. Assuming these are logP-scale values, lower values indicate lower permeability. Ligand A (-5.009) has worse permeability than Ligand B (-4.616).

**Aqueous Solubility:** Both have negative values, which is also unusual. Assuming these are logS values, lower values indicate lower solubility. Ligand A (-2.81) has slightly worse solubility than Ligand B (-2.798).

**hERG Inhibition:** Ligand A (0.16) has a slightly lower hERG inhibition risk than Ligand B (0.715), which is preferable.

**Microsomal Clearance:** Ligand B (64.883) has higher clearance than Ligand A (36.586), indicating faster metabolism and potentially lower in vivo exposure.

**In vitro Half-Life:** Ligand A (-23.276) has a negative half-life, which is impossible. Ligand B (3.356) has a short half-life, but is at least a positive value.

**P-gp Efflux:** Ligand A (0.21) has lower P-gp efflux liability than Ligand B (0.458), which is beneficial for CNS penetration.

**Binding Affinity:** Ligand B (-7.0) has a significantly stronger binding affinity than Ligand A (-10.0). This is a substantial advantage, potentially outweighing minor ADME drawbacks.

**Overall Assessment:**

Ligand B is superior due to its significantly better BBB penetration, much lower DILI risk, and substantially stronger binding affinity. While Ligand A has slightly better hERG inhibition and P-gp efflux, the advantages of Ligand B in the critical areas of BBB, DILI, and affinity are decisive. The half-life of Ligand A is also nonsensical.

Output:
1
2025-04-17 08:42:57,811 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (331.423 and 354.447 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (66.53) is excellent, well below the 90 A^2 threshold for CNS targets. Ligand B (87.15) is still reasonable, but closer to the 90 A^2 limit.

**logP:** Ligand A (4.012) is at the higher end of the optimal range (1-3), potentially causing solubility issues. Ligand B (0.593) is quite low, which could hinder membrane permeability and CNS penetration.

**H-Bond Donors/Acceptors:** Both ligands have 1 HBD and 5 HBA, which are within acceptable limits.

**QED:** Both ligands have QED values above 0.5 (0.741 and 0.689), indicating good drug-likeness.

**DILI:** Ligand A (68.941) has a higher DILI risk than Ligand B (24.544). This is a significant negative for Ligand A.

**BBB:** Both ligands have reasonable BBB penetration (Ligand A: 53.974, Ligand B: 55.215). However, for a CNS target like DRD2, >70 is desirable. Neither is ideal, but they are comparable.

**Caco-2:** Both have negative Caco-2 values, which is unusual and suggests poor permeability. This is a concern for both.

**Aqueous Solubility:** Both ligands have very poor aqueous solubility (-5.454 and -0.95). This is a significant drawback, particularly for Ligand A with its higher logP.

**hERG:** Ligand A (0.833) has a slightly higher hERG risk than Ligand B (0.141).

**Microsomal Clearance:** Ligand A (98.418) has a higher microsomal clearance than Ligand B (19.898), indicating lower metabolic stability.

**In vitro Half-Life:** Ligand A (45.564) has a longer half-life than Ligand B (2.407).

**P-gp Efflux:** Ligand A (0.524) has lower P-gp efflux than Ligand B (0.058), which is favorable for CNS penetration.

**Binding Affinity:** Ligand B (-7.6 kcal/mol) has a significantly stronger binding affinity than Ligand A (-9.1 kcal/mol). This is a substantial advantage for Ligand B.

**Overall Assessment:**

Ligand B is the better candidate despite its low logP and Caco-2 value. Its significantly stronger binding affinity (-7.6 vs -9.1 kcal/mol) is a major advantage, and can potentially overcome the permeability issues. It also has a much lower DILI risk and better metabolic stability (lower Cl_mic). While both have poor solubility and BBB penetration, the affinity and safety profile of Ligand B make it more promising. Ligand A's high logP and DILI risk are significant concerns.

Output:
1
2025-04-17 08:42:57,811 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (345.363 and 358.498 Da) fall within the ideal range of 200-500 Da.

**TPSA:** Ligand A (130.04) is borderline for CNS penetration, slightly above the preferred <90, while Ligand B (58.64) is excellent.

**logP:** Ligand A (-0.136) is too low, potentially hindering membrane permeability. Ligand B (2.786) is within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A has 4 HBD and 6 HBA, acceptable values. Ligand B has 1 HBD and 3 HBA, also acceptable and potentially better for permeability.

**QED:** Both ligands have reasonable QED scores (0.453 and 0.726), indicating drug-like properties, with Ligand B being better.

**DILI:** Ligand A (94.649) has a high DILI risk, which is concerning. Ligand B (8.104) has a very low DILI risk, a significant advantage.

**BBB:** Ligand A (40.791) has poor predicted BBB penetration, a major drawback for a CNS target. Ligand B (91.198) has excellent predicted BBB penetration.

**Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and could indicate issues with the prediction method or the molecule itself. However, the values are similar.

**Aqueous Solubility:** Both have negative solubility values, also unusual. Again, the values are similar.

**hERG:** Ligand A (0.098) has a very low hERG risk, while Ligand B (0.727) has a slightly elevated, but still acceptable, risk.

**Microsomal Clearance:** Ligand A (10.662) has lower clearance than Ligand B (56.991), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (48.581) has a better in vitro half-life than Ligand B (-7.508).

**P-gp Efflux:** Ligand A (0.014) has very low P-gp efflux, which is favorable for CNS exposure. Ligand B (0.07) also has low P-gp efflux.

**Binding Affinity:** Ligand A (-9.2 kcal/mol) has significantly better binding affinity than Ligand B (-7.0 kcal/mol). This is a substantial advantage.

**Overall Assessment:**

Despite the superior binding affinity of Ligand A, its poor logP, high DILI risk, and especially its very low BBB penetration are major liabilities for a CNS-targeted GPCR. Ligand B, while having slightly weaker affinity, possesses a much more favorable ADME profile, including excellent BBB penetration, low DILI risk, and a good logP value. The difference in binding affinity (2.2 kcal/mol) is significant, but the ADME advantages of Ligand B are likely to outweigh this difference, particularly for a CNS target where achieving sufficient brain exposure is critical.

Output:
1
2025-04-17 08:42:57,811 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 drug candidates, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (392.327 Da) is slightly higher than Ligand B (370.837 Da), but both are acceptable.

**TPSA:** Ligand A (61.88) is significantly better than Ligand B (113.33). For CNS targets, we want TPSA <= 90, so Ligand A is much more favorable.

**logP:** Both ligands have good logP values (A: 1.627, B: 1.259) falling within the optimal range of 1-3.

**H-Bond Donors/Acceptors:** Ligand A (HBD=1, HBA=4) is better than Ligand B (HBD=3, HBA=5) in terms of balancing solubility and permeability.

**QED:** Both ligands have acceptable QED values (A: 0.682, B: 0.566), indicating reasonable drug-likeness.

**DILI:** Ligand A (10.237) has a much lower DILI risk than Ligand B (45.25), which is a significant advantage.

**BBB:** Both ligands have similar BBB penetration (A: 61.768, B: 61.729). While not ideal (>70 is desirable), they are comparable and suggest some CNS exposure.

**Caco-2 Permeability:** Both have negative Caco-2 values which is unusual. Assuming these are logP values, ligand A (-4.876) is worse than ligand B (-5.454).

**Aqueous Solubility:** Both have negative solubility values, which is also unusual. Ligand A (-1.769) is better than ligand B (-2.402).

**hERG:** Both ligands have low hERG inhibition liability (A: 0.443, B: 0.2), which is good.

**Microsomal Clearance:** Ligand A (10.499) has lower microsomal clearance than Ligand B (5.754), indicating better metabolic stability.

**In vitro Half-Life:** Ligand B (30.341 hours) has a significantly longer half-life than Ligand A (4.245 hours), which is a positive attribute.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (A: 0.021, B: 0.093), which is excellent for CNS penetration.

**Binding Affinity:** Ligand B (-7.8 kcal/mol) has a slightly better binding affinity than Ligand A (-7.1 kcal/mol). This 0.7 kcal/mol difference is significant, and could potentially outweigh some ADME drawbacks.

**Overall Assessment:**

Ligand A excels in TPSA, DILI, and metabolic stability. Ligand B has a better half-life and slightly better binding affinity. Considering the GPCR-specific priorities, TPSA is crucial for CNS penetration, and a lower DILI risk is highly desirable. The better TPSA and DILI profile of Ligand A, combined with acceptable BBB and logP values, makes it a more promising candidate despite the slightly weaker binding affinity and shorter half-life. The binding affinity difference, while notable, is not large enough to overcome the significant advantages of Ligand A in terms of safety and CNS penetration.

Output:
0
2025-04-17 08:42:57,811 - INFO - Reasoning:

Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (346.431 Da) is slightly lower, which could be beneficial for permeability.

**TPSA:** Ligand A (78.67) is significantly better than Ligand B (115.39). For CNS targets, TPSA should be <= 90, and A is comfortably within this range, while B is above. This is a significant advantage for A.

**logP:** Ligand A (0.668) is a bit low, potentially hindering permeation. Ligand B (-0.709) is even lower, raising concerns about membrane permeability. Both are suboptimal, but A is slightly better.

**H-Bond Donors/Acceptors:** Ligand A (HBD=1, HBA=5) is better than Ligand B (HBD=3, HBA=5). Lower HBD counts generally improve CNS penetration.

**QED:** Both have acceptable QED values (A: 0.813, B: 0.588), indicating good drug-like properties. A is better.

**DILI:** Both have similar, relatively low DILI risk (A: 34.277, B: 35.595).

**BBB:** This is crucial for a CNS target like DRD2. Ligand A (66.188) is *much* better than Ligand B (16.324). A percentile >70 is desirable, and A is closer to this threshold.

**Caco-2 Permeability:** Ligand A (-4.77) is better than Ligand B (-5.394), indicating slightly better intestinal absorption, though both are negative and suggest poor permeability.

**Aqueous Solubility:** Ligand A (-1.604) is better than Ligand B (-2.462), but both are quite poor.

**hERG Inhibition:** Both ligands have low hERG risk (A: 0.383, B: 0.11).

**Microsomal Clearance:** Ligand A (22.604) is higher than Ligand B (4.302), meaning faster clearance and lower metabolic stability. This favors B.

**In vitro Half-Life:** Ligand B (-12.806) has a longer half-life than Ligand A (-10.722), which is a positive.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (A: 0.176, B: 0.007), which is excellent for CNS penetration. B is slightly better.

**Binding Affinity:** Both ligands have very similar and strong binding affinities (A: -8.5 kcal/mol, B: -8.2 kcal/mol). The difference is less than 1.5 kcal/mol, so this isn't a deciding factor.

**Overall Assessment:**

Ligand A is significantly superior due to its much better TPSA and BBB penetration, both critical for CNS drug development. While its logP and solubility are suboptimal, the strong affinity and acceptable QED outweigh these concerns. Ligand B's poor TPSA and BBB scores are major drawbacks, despite its slightly better metabolic stability and P-gp efflux profile. The difference in affinity is not substantial enough to overcome the ADME deficiencies of Ligand B.

Output:
1
2025-04-17 08:42:57,811 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B based on the provided guidelines, prioritizing GPCR-specific properties (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (350.459 Da) is slightly lower, which could be advantageous for permeability.

**TPSA:** Ligand A (87.66) is better than Ligand B (49.41) as it is closer to the ideal range for CNS targets (<=90). Ligand B is quite low, which might suggest reduced hydrogen bonding and potentially lower solubility.

**logP:** Both ligands have acceptable logP values (Ligand A: 1.26, Ligand B: 3.245), falling within the optimal 1-3 range. Ligand B is closer to the upper limit, which could raise concerns about off-target effects, but is still acceptable.

**H-Bond Donors/Acceptors:** Ligand A has 3 HBD and 4 HBA, while Ligand B has 1 HBD and 3 HBA. Both are within the acceptable limits (<=5 HBD and <=10 HBA).

**QED:** Both ligands have good QED scores (Ligand A: 0.697, Ligand B: 0.762), indicating drug-like properties.

**DILI:** Both ligands have low DILI risk (Ligand A: 28.616, Ligand B: 27.608), which is favorable.

**BBB:** This is a critical parameter for CNS targets. Ligand B (85.033) significantly outperforms Ligand A (28.81) in BBB penetration, making it much more likely to reach the target in the brain.

**Caco-2 Permeability:** Ligand A (-5.095) has a negative Caco-2 value, which is unusual and suggests poor permeability. Ligand B (-4.626) is also negative, but slightly less so. Both are concerning.

**Aqueous Solubility:** Both ligands have very poor aqueous solubility (-2.783 and -3.215 respectively). This is a significant drawback for both compounds.

**hERG Inhibition:** Ligand A (0.136) has a lower hERG risk than Ligand B (0.669), which is preferable.

**Microsomal Clearance:** Ligand B (62.999) has a higher microsomal clearance than Ligand A (28.402), indicating faster metabolism and potentially lower *in vivo* exposure.

**In vitro Half-Life:** Ligand A (15.624) has a longer half-life than Ligand B (1.264), which is desirable.

**P-gp Efflux:** Ligand A (0.046) shows much lower P-gp efflux than Ligand B (0.243), suggesting better CNS exposure.

**Binding Affinity:** Ligand B (-7.7 kcal/mol) has a slightly better binding affinity than Ligand A (-8.6 kcal/mol). While the difference is small, it's still a positive for Ligand B.

**Overall Assessment:**

Ligand B excels in BBB penetration and has a slightly better binding affinity. However, it has higher P-gp efflux and faster metabolic clearance. Ligand A has better TPSA, lower hERG risk, longer half-life, and lower P-gp efflux. Both have poor solubility and Caco-2 permeability.

Given the importance of BBB penetration for a CNS target like DRD2, and the slightly better affinity of Ligand B, it is the more promising candidate *despite* the drawbacks in metabolic stability and P-gp efflux. These can potentially be addressed through further optimization. The poor solubility of both compounds is a major concern that would need to be tackled early in development.

Output:
1
2025-04-17 08:42:57,811 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (332.407) is slightly lower, which could be beneficial for permeability.

**TPSA:** Both ligands have TPSA values (A: 62.97, B: 67.43) below the 90 A^2 threshold for CNS targets, which is excellent.

**logP:** Both ligands have optimal logP values (A: 3.002, B: 2.043) within the 1-3 range. Ligand A is slightly higher, which might lead to some off-target interactions, but is still acceptable.

**H-Bond Donors/Acceptors:** Both ligands have reasonable HBD (2) and HBA (A: 5, B: 4) counts, well within the guidelines.

**QED:** Both ligands have good QED scores (A: 0.721, B: 0.842), indicating drug-like properties.

**DILI:** Ligand A (79.411) has a higher DILI risk than Ligand B (50.174). This is a significant drawback for Ligand A.

**BBB:** Ligand B (71.384) has a significantly better BBB penetration percentile than Ligand A (31.563). This is *critical* for a CNS target like DRD2.

**Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and likely indicates a problem with the prediction method or the molecule's behavior in the assay. It's difficult to interpret this data.

**Aqueous Solubility:** Both ligands have very poor aqueous solubility (-3.94 and -3.508). This is a concern for formulation and bioavailability, but can sometimes be mitigated.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (A: 0.771, B: 0.478), which is good.

**Microsomal Clearance:** Ligand A (23.687) has a lower microsomal clearance than Ligand B (44.014), suggesting better metabolic stability.

**In vitro Half-Life:** Both have similar in vitro half-lives (A: 17.576, B: 18.084).

**P-gp Efflux:** Ligand A (0.425) has lower P-gp efflux liability than Ligand B (0.299), which is favorable for CNS exposure.

**Binding Affinity:** Ligand B (-7.9 kcal/mol) has a significantly stronger binding affinity than Ligand A (-9.4 kcal/mol). This is a substantial advantage, potentially outweighing some of the ADME drawbacks.

**Overall Assessment:**

Ligand B is the stronger candidate. While both have solubility issues, Ligand B's superior BBB penetration, significantly better binding affinity, and lower DILI risk are decisive. The lower P-gp efflux of Ligand A is a plus, but the large affinity difference and better CNS penetration of Ligand B are more important for a CNS-targeted GPCR.

Output:
1
2025-04-17 08:42:57,812 - INFO - Reasoning:

Let's analyze Ligand A and Ligand B for their potential as DRD2 drug candidates, considering the provided guidelines and GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (349.39 and 380.41 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (96.97) is excellent, falling well below the 90 A^2 threshold for CNS targets. Ligand B (58.2) is also very good, being below the threshold.

**3. logP:** Ligand A (1.229) is within the optimal 1-3 range. Ligand B (3.573) is at the higher end of optimal, but still acceptable.

**4. H-Bond Donors:** Both ligands have 2 HBD, which is within the acceptable limit of <=5.

**5. H-Bond Acceptors:** Ligand A has 5 HBA, and Ligand B has 3 HBA, both within the acceptable limit of <=10.

**6. QED:** Both ligands have similar QED values (0.78 and 0.768), indicating good drug-like properties.

**7. DILI:** Both ligands have relatively similar DILI risk (57.154 and 51.377), and both are below the concerning 60 threshold.

**8. BBB:** This is a critical parameter for a CNS target like DRD2. Ligand B (81.621) has a significantly higher BBB percentile than Ligand A (53.16). This is a major advantage for Ligand B.

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.701 and -4.737). This is unusual and suggests poor permeability. However, the values are very similar.

**10. Aqueous Solubility:** Both ligands have negative solubility values (-2.237 and -4.287), indicating poor aqueous solubility. Ligand B is slightly worse.

**11. hERG Inhibition:** Both ligands have low hERG inhibition risk (0.202 and 0.492).

**12. Microsomal Clearance:** Ligand A (-0.835) has a lower (better) microsomal clearance than Ligand B (40.88). This suggests better metabolic stability for Ligand A.

**13. In vitro Half-Life:** Ligand A (-14.566) has a negative half-life, which is not physically possible. This is a significant red flag. Ligand B (0.584) has a very short half-life, which is also undesirable, but not as problematic as a negative value.

**14. P-gp Efflux:** Ligand A (0.016) has very low P-gp efflux, which is ideal for CNS penetration. Ligand B (0.137) also has low P-gp efflux, but higher than Ligand A.

**15. Binding Affinity:** Ligand B (-9.2 kcal/mol) has a significantly stronger binding affinity than Ligand A (-8.2 kcal/mol). This 1 kcal/mol difference is substantial and can often outweigh minor ADME drawbacks.

**Overall Assessment:**

While Ligand A has better metabolic stability and P-gp efflux, its negative in vitro half-life is a major concern and likely indicates an issue with the data or a highly unstable compound. Ligand B, despite slightly worse metabolic stability and higher P-gp efflux, has a significantly better BBB penetration score and a substantially stronger binding affinity. For a CNS target like DRD2, strong binding affinity and good BBB penetration are paramount.

Output:
1
2025-04-17 08:42:57,812 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (346.471 and 353.507 Da) fall comfortably within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (58.64) is significantly better than Ligand B (72.88). For CNS targets, we want TPSA <= 90, and ideally closer to 60. Ligand A is much closer to the ideal range.

**3. logP:** Both ligands have good logP values (2.267 and 1.399), falling within the optimal 1-3 range. Ligand B is slightly lower, which *could* indicate slightly lower permeability, but it's not a major concern.

**4. H-Bond Donors:** Ligand A (1) is preferable to Ligand B (2). Lower HBD generally improves permeability.

**5. H-Bond Acceptors:** Ligand A (3) is preferable to Ligand B (4). Lower HBA generally improves permeability.

**6. QED:** Both ligands have similar QED values (0.686 and 0.615), both above the 0.5 threshold, indicating good drug-like properties.

**7. DILI:** Ligand A (15.898) has a considerably higher DILI risk than Ligand B (4.382). This is a significant negative for Ligand A.

**8. BBB:** Ligand A (72.896) has a better BBB percentile than Ligand B (54.013). For a CNS target like DRD2, >70 is desirable. Ligand A is closer, but both are not optimal.

**9. Caco-2:** Ligand A (-4.798) and Ligand B (-4.939) have similar, and very poor, Caco-2 permeability values. This suggests poor intestinal absorption for both.

**10. Solubility:** Ligand A (-2.431) has slightly better solubility than Ligand B (-1.23), but both are quite poor.

**11. hERG:** Both ligands have low hERG inhibition liability (0.263 and 0.298), which is good.

**12. Cl_mic:** Ligand B (11.272) has a lower microsomal clearance than Ligand A (51.9), indicating better metabolic stability. This is a significant advantage for Ligand B.

**13. t1/2:** Ligand B (11.969) has a much longer in vitro half-life than Ligand A (-27.981). This is a major advantage for Ligand B.

**14. Pgp:** Both ligands have very low Pgp efflux liability (0.114 and 0.037).

**15. Affinity:** Both ligands have excellent binding affinities (-8 and -6.9 kcal/mol). Ligand A is 1.1 kcal/mol better, which is a substantial advantage.

**Overall Assessment:**

While Ligand A has a better binding affinity and BBB penetration, its significantly higher DILI risk, poorer metabolic stability (higher Cl_mic, shorter t1/2), and higher HBD/HBA counts are major drawbacks. Ligand B, despite slightly lower affinity, presents a much more favorable ADME-Tox profile, particularly with its lower DILI risk and improved metabolic stability. Given the GPCR-specific emphasis on ADME properties for CNS targets, and the substantial difference in DILI risk, Ligand B is the more promising candidate.

Output:
1
2025-04-17 08:42:57,812 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B against the provided guidelines, prioritizing GPCR-specific properties (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (364.345 and 385.917 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (110.8) is slightly above the optimal <90 for CNS targets, but still reasonable. Ligand B (69.72) is excellent, well below 90.

**logP:** Ligand A (0.147) is quite low, potentially hindering permeability. Ligand B (2.085) is within the optimal 1-3 range. This is a significant advantage for Ligand B.

**H-Bond Donors/Acceptors:** Ligand A (HBD=2, HBA=6) is acceptable. Ligand B (HBD=1, HBA=4) is also good, potentially slightly better due to fewer H-bonds.

**QED:** Both ligands have good QED scores (0.564 and 0.78), indicating drug-like properties.

**DILI:** Both have similar, acceptable DILI risk (48.623 and 50.33).

**BBB:** Both ligands show good BBB penetration (79.682 and 71.074), but Ligand A is slightly better, exceeding 70%.

**Caco-2 Permeability:** Both have negative Caco-2 values (-4.764 and -4.788), which is unusual and suggests poor permeability. This is a concern for both, but doesn't differentiate them.

**Aqueous Solubility:** Both have negative solubility values (-2.489 and -3.02), also unusual and indicating poor solubility. This is a concern for both, but doesn't differentiate them.

**hERG Inhibition:** Both have very low hERG risk (0.187 and 0.242).

**Microsomal Clearance:** Ligand A (50.818) has higher clearance than Ligand B (31.95), suggesting lower metabolic stability.

**In vitro Half-Life:** Ligand B (19.471) has a significantly longer half-life than Ligand A (-25.003). This is a major advantage for Ligand B.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.034 and 0.091).

**Binding Affinity:** Ligand B (-8.2 kcal/mol) has a stronger binding affinity than Ligand A (-7.5 kcal/mol). This 0.7 kcal/mol difference is significant, exceeding the 1.5 kcal/mol threshold where affinity can outweigh other drawbacks.

**Overall Assessment:**

Ligand B is the superior candidate. While Ligand A has slightly better BBB penetration, Ligand B excels in several crucial areas: a much better logP, significantly improved metabolic stability (lower Cl_mic and longer t1/2), and a stronger binding affinity. The low logP of Ligand A is a major concern for permeability and CNS exposure. The better affinity of Ligand B is also a key advantage for a GPCR target. The similar DILI and P-gp values, and acceptable H-bond properties, further support choosing Ligand B.

Output:
1
2025-04-17 08:42:57,812 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (352.341 and 341.411 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Both ligands have TPSA values (69.48 and 68.46) below the 90 A^2 threshold desirable for CNS targets, which is excellent.

**3. logP:** Both ligands have logP values (2.027 and 2.331) within the optimal 1-3 range.

**4. H-Bond Donors:** Both have 0 HBD, which is acceptable.

**5. H-Bond Acceptors:** Ligand A has 6 HBA, and Ligand B has 5. Both are below the 10 threshold.

**6. QED:** Both ligands have high QED scores (0.824 and 0.835), indicating good drug-like properties.

**7. DILI:** Both ligands have DILI risk scores (59.325 and 50.485) below 60, indicating acceptable liver injury risk. Ligand B is slightly better here.

**8. BBB:** Both ligands exhibit excellent BBB penetration (89.841 and 92.594), exceeding the >70% threshold for CNS targets. Ligand B is slightly better.

**9. Caco-2 Permeability:** Both have negative Caco-2 values (-4.322 and -4.818). This is unusual and suggests poor permeability. However, these values are on a log scale, and negative values are not uncommon for compounds with specific efflux properties.

**10. Aqueous Solubility:** Both have negative solubility values (-1.942 and -2.324), indicating poor aqueous solubility. This is a potential concern for bioavailability.

**11. hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.111 and 0.156).

**12. Microsomal Clearance:** Ligand A has a lower Cl_mic (37.122) than Ligand B (53.504), suggesting better metabolic stability.

**13. In vitro Half-Life:** Ligand A has a negative half-life (-19.787), which is not physically possible. This is a significant red flag. Ligand B has a half-life of -6.936, also not possible, but less extreme.

**14. P-gp Efflux:** Both ligands have low P-gp efflux liability (0.229 and 0.245), which is favorable for CNS penetration.

**15. Binding Affinity:** Ligand B has a significantly better binding affinity (-9.9 kcal/mol) than Ligand A (-8.5 kcal/mol). This difference of 1.4 kcal/mol is substantial and can outweigh minor ADME drawbacks.

**Overall Assessment:**

Ligand B is the superior candidate. While both have issues with solubility and Caco-2 permeability, Ligand B has a significantly stronger binding affinity, better BBB penetration, a lower DILI score, and a less problematic (though still negative) in vitro half-life compared to Ligand A's impossible half-life value. The stronger binding affinity is the most crucial factor, especially for a GPCR target like DRD2.

Output:
1
2025-04-17 08:42:57,813 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (362.496 Da and 351.491 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (41.13) is excellent, well below the 90 A^2 threshold for CNS targets. Ligand B (72.88) is higher but still potentially acceptable, though less ideal.

**logP:** Ligand A (3.27) is optimal (1-3). Ligand B (0.987) is a bit low, potentially hindering membrane permeability.

**H-Bond Donors/Acceptors:** Both ligands have 2 HBDs, which is good. Ligand A has 1 HBA, while Ligand B has 4 HBAs. Both are within the acceptable limits (<=10).

**QED:** Both ligands have similar QED values (0.761 and 0.748), indicating good drug-likeness.

**DILI:** Ligand A (53.936) has a moderate DILI risk, while Ligand B (5.118) has a very low DILI risk, which is a significant advantage.

**BBB:** Ligand A (70.26) has good BBB penetration, meeting the >70% threshold for CNS targets. Ligand B (30.942) has poor BBB penetration, a major drawback for a CNS target like DRD2.

**Caco-2 Permeability:** Ligand A (-4.59) has poor Caco-2 permeability. Ligand B (-5.017) also has poor Caco-2 permeability.

**Aqueous Solubility:** Ligand A (-5.071) has poor solubility. Ligand B (-1.086) has slightly better, but still poor solubility.

**hERG:** Ligand A (0.902) has a low hERG risk. Ligand B (0.37) also has very low hERG risk.

**Microsomal Clearance:** Ligand A (75.334) has high microsomal clearance, suggesting rapid metabolism. Ligand B (25.251) has lower clearance, indicating better metabolic stability.

**In vitro Half-Life:** Ligand A (60.895) has a reasonable half-life. Ligand B (18.008) has a shorter half-life.

**P-gp Efflux:** Ligand A (0.582) has moderate P-gp efflux. Ligand B (0.028) has very low P-gp efflux, which is highly desirable for CNS penetration.

**Binding Affinity:** Ligand B (-7.6 kcal/mol) has significantly stronger binding affinity than Ligand A (0.0 kcal/mol). This is a substantial advantage.

**Overall Assessment:**

Ligand B is the stronger candidate despite its lower logP and solubility. The significantly improved binding affinity (-7.6 vs 0 kcal/mol) is a major driver. Its low DILI risk and very low P-gp efflux are also highly favorable, especially for a CNS target. While its BBB penetration is suboptimal, the strong binding affinity and low efflux might compensate for this. Ligand A's poor binding affinity is a deal-breaker, even with its better BBB penetration. The poor Caco-2 and solubility of both are concerns but can potentially be addressed with formulation strategies.

Output:
1
2025-04-17 08:42:57,813 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (347.411 and 348.487 Da) fall comfortably within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (76.07) is higher than Ligand B (58.64). For a CNS target like DRD2, we prefer TPSA <= 90, so both are acceptable, but B is better.

**3. logP:** Both ligands have good logP values (2.427 and 2.798), falling within the optimal 1-3 range.

**4. H-Bond Donors:** Both have 1 HBD, which is within the acceptable limit of <=5.

**5. H-Bond Acceptors:** Ligand A has 4 HBAs, and Ligand B has 3. Both are below the limit of <=10.

**6. QED:** Both ligands have reasonably good QED scores (0.8 and 0.777), indicating good drug-like properties.

**7. DILI:** Ligand A (60.915) has a higher DILI risk than Ligand B (33.773). This is a significant drawback for Ligand A.

**8. BBB:** This is crucial for a CNS target. Ligand B (85.537) has a much higher BBB penetration percentile than Ligand A (55.332). This is a major advantage for Ligand B.

**9. Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and suggests poor permeability. However, the values are similar (-4.644 vs -4.363).

**10. Aqueous Solubility:** Both have negative solubility values, indicating poor aqueous solubility. Again, the values are similar (-2.706 vs -3.589).

**11. hERG Inhibition:** Both ligands have low hERG inhibition risk (0.138 and 0.256).

**12. Microsomal Clearance:** Ligand A (9.323) has a lower microsomal clearance than Ligand B (47.552), suggesting better metabolic stability.

**13. In vitro Half-Life:** Ligand B (-14.784) has a negative half-life, which is not realistic and indicates a very short half-life. Ligand A (10.386) has a reasonable half-life.

**14. P-gp Efflux:** Both ligands have low P-gp efflux liability (0.051 and 0.182).

**15. Binding Affinity:** Both ligands have very similar and strong binding affinities (-8.2 and -8.1 kcal/mol). The difference is negligible.

**Overall Assessment:**

Ligand B is significantly better due to its much higher predicted BBB penetration (85.537 vs 55.332) and lower DILI risk (33.773 vs 60.915). While Ligand A has better metabolic stability (lower Cl_mic) and a more reasonable half-life, the CNS target necessitates prioritizing BBB penetration. The similar affinity and other ADME properties make the BBB and DILI differences the deciding factors. The negative half-life for Ligand B is a concern, but the other advantages outweigh this.

Output:
1
2025-04-17 08:42:57,813 - INFO - Batch 472 complete. Total preferences: 7552
2025-04-17 08:42:57,813 - INFO - Processing batch 473/512...
2025-04-17 08:43:39,308 - INFO - Reasoning:

Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (349.431 and 347.459 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (107.53) is higher than Ligand B (72.88). For CNS targets, we prefer TPSA <= 90. Ligand B is significantly better here.

**3. logP:** Both ligands (1.554 and 1.241) are within the optimal range of 1-3.

**4. H-Bond Donors:** Ligand A (4) is slightly higher than Ligand B (2), but both are acceptable (<=5).

**5. H-Bond Acceptors:** Both ligands (4) are well within the acceptable limit of <=10.

**6. QED:** Both ligands have good QED scores (0.571 and 0.705), indicating good drug-like properties. Ligand B is slightly better.

**7. DILI:** Ligand A (29.663) has a higher DILI risk than Ligand B (8.026). Lower is better, and Ligand B is significantly preferred.

**8. BBB:** Ligand B (46.413) has a better BBB penetration percentile than Ligand A (37.069). While both are not ideal (>70 desirable), Ligand B is closer.

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.43 and -5.394). This is unusual and suggests poor permeability. However, the values are very similar.

**10. Aqueous Solubility:** Both ligands have negative solubility values (-3.212 and -1.667). This is also concerning, indicating poor solubility. Ligand B is slightly better.

**11. hERG:** Both ligands have low hERG inhibition liability (0.233 and 0.376), which is good.

**12. Microsomal Clearance:** Ligand A (47.013) has higher microsomal clearance than Ligand B (-0.643). Lower is better for metabolic stability, so Ligand B is preferred.

**13. In vitro Half-Life:** Ligand B (-4.39) has a better in vitro half-life than Ligand A (-14.716).

**14. P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.016 and 0.012), which is excellent.

**15. Binding Affinity:** Both ligands have identical binding affinities (-8.4 kcal/mol), which is very strong and excellent.

**Overall Assessment:**

Ligand B is the better candidate. While both have concerningly low Caco-2 and solubility values, Ligand B demonstrates superior properties in several key areas: lower DILI risk, better BBB penetration, lower microsomal clearance, and better in vitro half-life. The TPSA value is also significantly lower for Ligand B, which is favorable for CNS penetration. The binding affinity is equal for both, so the ADME improvements of Ligand B outweigh any potential drawbacks.

Output:
1
2025-04-17 08:43:39,308 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (348.4 and 377.4 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (90.7) is slightly above the optimal <90 for CNS targets, but still reasonable. Ligand B (71.53) is well within the desired range.

**3. logP:** Both ligands (2.527 and 2.487) have excellent logP values, falling within the optimal 1-3 range.

**4. H-Bond Donors:** Both have 1 HBD, which is within the acceptable limit of <=5.

**5. H-Bond Acceptors:** Both have 5 HBA, which is within the acceptable limit of <=10.

**6. QED:** Both ligands have good QED scores (0.667 and 0.822), indicating good drug-like properties. Ligand B is slightly better.

**7. DILI:** Ligand A (56.8%) has a slightly higher DILI risk than Ligand B (46.5%), but both are below the concerning 60% threshold.

**8. BBB:** Ligand A (74.3%) has a better BBB penetration percentile than Ligand B (68.6%). This is a crucial factor for a CNS target like DRD2.

**9. Caco-2 Permeability:** Both ligands have very poor Caco-2 permeability (-4.71 and -4.713). This is a significant concern for oral bioavailability.

**10. Aqueous Solubility:** Both ligands have very poor aqueous solubility (-3.225 and -3.266). This could pose formulation challenges.

**11. hERG Inhibition:** Both ligands have low hERG inhibition risk (0.567 and 0.274). Ligand B is better here.

**12. Microsomal Clearance:** Ligand A (25.46) has higher microsomal clearance than Ligand B (-2.013), suggesting lower metabolic stability. Ligand B is significantly better.

**13. In vitro Half-Life:** Ligand A (21.4) has a better in vitro half-life than Ligand B (-0.638).

**14. P-gp Efflux:** Ligand A (0.211) has lower P-gp efflux than Ligand B (0.032), which is favorable for CNS penetration.

**15. Binding Affinity:** Both ligands have excellent binding affinities (-9.6 and -9.1 kcal/mol). Ligand A is slightly better.

**Overall Assessment:**

While both ligands show promising binding affinity, Ligand A has a better BBB score and P-gp efflux, which are critical for CNS targets. However, Ligand B demonstrates superior metabolic stability (lower Cl_mic, better half-life) and lower hERG risk. The poor Caco-2 and solubility for both are concerning, but can potentially be addressed with formulation strategies. Considering the balance, the slightly better BBB and P-gp efflux of Ligand A, combined with its slightly better affinity, outweigh the slightly worse metabolic stability and DILI risk.

Output:
0
2025-04-17 08:43:39,309 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (361.873 Da) is slightly higher than Ligand B (346.391 Da), but both are acceptable.

**TPSA:** Ligand A (62.3) is excellent for CNS penetration, well below the 90 A^2 threshold. Ligand B (109.22) is higher, but still potentially acceptable, though less ideal.

**logP:** Ligand A (3.633) is within the optimal range (1-3). Ligand B (-0.772) is significantly lower, which could hinder membrane permeability and CNS penetration.

**H-Bond Donors/Acceptors:** Ligand A (HBD=1, HBA=3) and Ligand B (HBD=2, HBA=6) both fall within reasonable limits.

**QED:** Both ligands have acceptable QED values (A: 0.814, B: 0.681), suggesting good drug-like properties.

**DILI:** Ligand A (48.623) has a lower DILI risk than Ligand B (56.689), indicating a potentially safer profile. Both are below the concerning threshold of 60.

**BBB:** Ligand A (80.031) has a significantly better BBB percentile than Ligand B (58.666). This is a critical advantage for a CNS target like DRD2.

**Caco-2 Permeability:** Ligand A (-4.994) and Ligand B (-5.271) both have negative Caco-2 values, which is unusual and suggests poor permeability. However, these values are on a log scale and are difficult to interpret without knowing the units.

**Aqueous Solubility:** Ligand A (-4.15) and Ligand B (-1.968) both have negative solubility values, which is also unusual and suggests poor solubility.

**hERG Inhibition:** Ligand A (0.59) shows a lower hERG inhibition liability than Ligand B (0.041), which is a positive safety indicator.

**Microsomal Clearance:** Ligand B (-6.464) has a negative clearance, which is not possible. This is likely an error in the data. Ligand A (43.409) has a moderate clearance.

**In vitro Half-Life:** Ligand B (6.556) has a slightly longer half-life than Ligand A (35.767).

**P-gp Efflux:** Ligand A (0.126) has a lower P-gp efflux liability than Ligand B (0.013), which is favorable for CNS penetration.

**Binding Affinity:** Ligand B (-8.3 kcal/mol) has a stronger binding affinity than Ligand A (-7.7 kcal/mol). This is a significant advantage.

**Overall Assessment:**

Despite the stronger binding affinity of Ligand B, several factors favor Ligand A. Ligand A has a significantly better BBB score, a more favorable logP, lower DILI risk, and lower P-gp efflux. The negative values for Caco-2 and solubility are concerning for both, but the other advantages of Ligand A, particularly its BBB penetration, are crucial for a CNS-targeting drug. Ligand B's very low logP is a major drawback, and the negative clearance value is suspect. The 0.6 kcal/mol difference in binding affinity can likely be overcome with further optimization of Ligand A.

Output:
1
2025-04-17 08:43:39,309 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (348.403 and 352.479 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (97.56) is slightly higher than Ligand B (76.46). For CNS targets, we prefer TPSA <= 90. Ligand B is better here.

**3. logP:** Ligand A (1.115) is within the optimal range (1-3), while Ligand B (2.103) is also acceptable.

**4. H-Bond Donors:** Both have 1 HBD, which is good.

**5. H-Bond Acceptors:** Ligand A has 6 HBAs, and Ligand B has 5. Both are below the threshold of 10.

**6. QED:** Ligand A (0.856) has a better QED score than Ligand B (0.777), indicating a more drug-like profile.

**7. DILI:** Ligand A (52.423) has a slightly higher DILI risk than Ligand B (37.456), but both are acceptable (<60).

**8. BBB:** This is crucial for a CNS target like DRD2. Ligand A (83.676) has a significantly better BBB percentile than Ligand B (64.676).

**9. Caco-2 Permeability:** Both have negative values, which is unusual and suggests poor permeability. However, the scale isn't specified, so it's hard to interpret.

**10. Aqueous Solubility:** Both have negative values, which is also unusual. Again, the scale is unknown.

**11. hERG Inhibition:** Ligand A (0.074) has a much lower hERG inhibition liability than Ligand B (0.556), which is a significant advantage.

**12. Microsomal Clearance:** Ligand B (52.203) has a higher microsomal clearance than Ligand A (16.687), indicating lower metabolic stability.

**13. In vitro Half-Life:** Ligand B (36.226) has a much longer in vitro half-life than Ligand A (-1.244). This is a positive for Ligand B.

**14. P-gp Efflux:** Ligand A (0.026) has a much lower P-gp efflux liability than Ligand B (0.109), which is favorable for CNS penetration.

**15. Binding Affinity:** Ligand A (-9.4 kcal/mol) has a significantly stronger binding affinity than Ligand B (-6.7 kcal/mol). This is a substantial advantage, potentially outweighing some ADME drawbacks.

**Overall Assessment:**

Ligand A excels in binding affinity, BBB penetration, hERG inhibition, and P-gp efflux. While Ligand B has a better half-life, the superior affinity and CNS penetration profile of Ligand A are more critical for a DRD2 ligand. The slightly higher DILI risk of Ligand A is acceptable given its other advantages.

Output:
1
2025-04-17 08:43:39,309 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (352.435 and 351.514 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (103.53) is borderline for CNS penetration, being slightly above the preferred <90. Ligand B (55.63) is well within the ideal range for CNS targets. This is a significant advantage for Ligand B.

**logP:** Ligand A (0.308) is quite low, potentially hindering membrane permeability. Ligand B (4.161) is slightly high, but still within an acceptable range, though it could lead to off-target interactions.

**H-Bond Donors/Acceptors:** Ligand A has 3 HBD and 4 HBA, which are reasonable. Ligand B has 1 HBD and 5 HBA, also acceptable.

**QED:** Both ligands have reasonable QED scores (0.416 and 0.679), indicating acceptable drug-likeness. Ligand B is better.

**DILI:** Ligand A (41.024) has a slightly higher DILI risk than Ligand B (35.789), but both are below the concerning threshold of 60.

**BBB:** This is critical for a CNS target. Ligand A has a BBB percentile of 42.264, which is not ideal. Ligand B has a much better BBB percentile of 88.329, exceeding the >70 desirable threshold.

**Caco-2 Permeability:** Ligand A (-5.234) shows poor Caco-2 permeability, which is concerning. Ligand B (-4.926) is also poor, but slightly better than A.

**Aqueous Solubility:** Both ligands have poor aqueous solubility (-1.543 and -4.379). This could pose formulation challenges.

**hERG Inhibition:** Both ligands have low hERG inhibition liability (0.257 and 0.443), which is good.

**Microsomal Clearance:** Ligand A (20.519) has lower microsomal clearance than Ligand B (31.411), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand B (8.392) has a significantly longer in vitro half-life than Ligand A (1.814), which is a major advantage.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.062 and 0.533), which is favorable for CNS penetration.

**Binding Affinity:** Ligand B (-7.2 kcal/mol) has a significantly stronger binding affinity than Ligand A (-6.4 kcal/mol). This 0.8 kcal/mol difference is substantial and can outweigh some of the ADME drawbacks.

**Overall Assessment:**

Ligand B is clearly the more promising candidate. While its logP is slightly elevated and solubility is poor, its significantly improved BBB penetration, substantially stronger binding affinity, and longer half-life outweigh the drawbacks. Ligand A suffers from poor BBB penetration and weak binding. The TPSA of Ligand A is also less favorable. For a CNS target like DRD2, BBB penetration and affinity are paramount.

Output:
1
2025-04-17 08:43:39,309 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (344.415 Da) is slightly lower, which is generally favorable for permeability. Ligand B (373.578 Da) is also good.

**TPSA:** Ligand A (88.32) is excellent, falling well below the 90 A^2 threshold for CNS targets. Ligand B (29.54) is even better, suggesting superior CNS penetration potential.

**logP:** Ligand A (1.397) is within the optimal range (1-3). Ligand B (4.549) is slightly above this range, potentially leading to solubility issues and off-target interactions, but not drastically so.

**H-Bond Donors/Acceptors:** Ligand A has 1 HBD and 6 HBA, both acceptable. Ligand B has 0 HBD and 3 HBA, also acceptable.

**QED:** Ligand A (0.892) has a very strong drug-like profile. Ligand B (0.526) is still acceptable, but less ideal.

**DILI:** Ligand A (47.421) has a moderate DILI risk, but is still acceptable. Ligand B (10.741) has a very low DILI risk, which is a significant advantage.

**BBB:** Ligand A (47.15) has a moderate BBB penetration, which is not ideal for a CNS target. Ligand B (97.402) has *excellent* BBB penetration, a critical factor for DRD2.

**Caco-2 Permeability:** Ligand A (-5.004) has poor Caco-2 permeability. Ligand B (-4.845) also has poor Caco-2 permeability.

**Aqueous Solubility:** Both ligands have very poor aqueous solubility (-1.783 and -4.188 respectively). This is a concern for both, but could be mitigated through formulation.

**hERG Inhibition:** Ligand A (0.02) has very low hERG inhibition risk. Ligand B (0.918) has a slightly higher, but still acceptable, hERG risk.

**Microsomal Clearance:** Ligand A (-0.383) has negative clearance, which is unusual and could indicate issues with the calculation or a very stable compound. Ligand B (103.633) has high microsomal clearance, indicating rapid metabolism.

**In vitro Half-Life:** Ligand A (6.973) has a reasonable half-life. Ligand B (10.527) has a longer half-life, which is preferable.

**P-gp Efflux:** Ligand A (0.031) has very low P-gp efflux, which is excellent for CNS penetration. Ligand B (0.749) has moderate P-gp efflux, which is less desirable.

**Binding Affinity:** Ligand A (-7.4 kcal/mol) and Ligand B (-7.1 kcal/mol) both have excellent binding affinity. Ligand A is slightly better, but the difference is not huge.

**Overall Assessment:**

Ligand B is the stronger candidate. While Ligand A has slightly better affinity and lower P-gp efflux, Ligand B's *exceptional* BBB penetration (97.402) and very low DILI risk (10.741) outweigh these minor differences. The higher half-life of Ligand B is also a plus. The solubility issues are a concern for both, but the CNS target prioritizes BBB penetration and metabolic stability. The high clearance of Ligand B is a drawback, but potentially addressable through structural modifications.

Output:
1
2025-04-17 08:43:39,310 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (341.371 and 346.431 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (106.94) is slightly above the optimal <90 for CNS targets, but still reasonable. Ligand B (96.25) is better, falling comfortably under 90.

**logP:** Ligand A (2.952) is within the optimal 1-3 range. Ligand B (0.751) is a bit low, potentially hindering membrane permeability, although not drastically.

**H-Bond Donors/Acceptors:** Ligand A has 1 HBD and 7 HBA, both acceptable. Ligand B has 3 HBD and 5 HBA, also acceptable.

**QED:** Both ligands have similar QED values (0.704 and 0.605), indicating good drug-like properties.

**DILI:** Ligand A (81.233) has a higher DILI risk than Ligand B (32.571). This is a significant negative for Ligand A.

**BBB:** Ligand A (79.721) has a good BBB percentile, desirable for a CNS target. Ligand B (25.204) has a very low BBB percentile, making it less likely to reach the target in the brain.

**Caco-2:** Both ligands have negative Caco-2 values (-5.207 and -4.928), which is unusual and indicates poor permeability. This is a concern for both.

**Solubility:** Both ligands have negative solubility values (-3.086 and -2.187), also unusual and indicating poor aqueous solubility. This is a concern for both.

**hERG:** Both ligands have very low hERG inhibition liability (0.267 and 0.027), which is excellent.

**Microsomal Clearance:** Ligand A (37.976) has higher microsomal clearance than Ligand B (4.453), suggesting lower metabolic stability.

**In vitro Half-Life:** Ligand B (-4.943) has a negative half-life, which is not physically possible and indicates a potential issue with the data or the molecule's stability. Ligand A (19.507) has a reasonable half-life.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.229 and 0.008), which is favorable for CNS penetration.

**Binding Affinity:** Ligand A (-9.4 kcal/mol) has significantly stronger binding affinity than Ligand B (-8.2 kcal/mol). This 1.2 kcal/mol difference is substantial and can outweigh some ADME drawbacks.

**Overall Assessment:**

Ligand A has a significantly better binding affinity and acceptable BBB penetration, but suffers from higher DILI risk and faster metabolic clearance. Ligand B has a lower DILI risk and better TPSA, but its very poor BBB penetration is a major drawback for a CNS target. The negative Caco-2 and solubility values are concerning for both, but the strong affinity of Ligand A makes it more promising, assuming the solubility issues can be addressed through formulation. The negative half-life for Ligand B is a serious red flag.

Output:
1
2025-04-17 08:43:39,310 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (349.415 and 346.471 Da) fall comfortably within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (71.95) is higher than Ligand B (58.64). For a CNS target like DRD2, TPSA should ideally be <= 90, so both are acceptable, but B is better.

**3. logP:** Ligand A (4.083) is slightly higher than the optimal range (1-3), potentially leading to solubility issues. Ligand B (2.267) is within the optimal range. This favors B.

**4. H-Bond Donors:** Both ligands have 1 HBD, which is within the acceptable limit of <=5.

**5. H-Bond Acceptors:** Ligand A has 5 HBAs, and Ligand B has 3. Both are below the limit of <=10.

**6. QED:** Both ligands have good QED scores (0.703 and 0.777, respectively), indicating good drug-like properties.

**7. DILI:** Ligand A has a significantly higher DILI risk (92.206 percentile) compared to Ligand B (23.187 percentile). This is a major concern for Ligand A.

**8. BBB:** Both ligands have acceptable BBB penetration (62.544 and 69.213 percentile, respectively). Ligand B is slightly better. A value >70 is desirable, but these are still reasonable.

**9. Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and suggests poor permeability. However, the scale is not specified, so it's hard to interpret.

**10. Aqueous Solubility:** Both have negative solubility values, which is also unusual and suggests poor solubility. Again, the scale is not specified.

**11. hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.27 and 0.132 percentile, respectively).

**12. Microsomal Clearance:** Both have similar microsomal clearance values (65.401 and 65.299 mL/min/kg).

**13. In vitro Half-Life:** Ligand B has a significantly longer in vitro half-life (6.134 hours) compared to Ligand A (46.193 hours). This is a major advantage for B.

**14. P-gp Efflux:** Both ligands have low P-gp efflux liability (0.44 and 0.065 percentile, respectively). Ligand B is better.

**15. Binding Affinity:** Ligand A (-9.2 kcal/mol) has a slightly better binding affinity than Ligand B (-8.7 kcal/mol). However, the difference is only 0.5 kcal/mol, which might not be enough to overcome the ADME liabilities of Ligand A.

**Overall Assessment:**

Ligand B is the more promising candidate. While its binding affinity is slightly lower, it exhibits significantly better ADME properties, particularly a much lower DILI risk, better logP, and a longer half-life. The lower TPSA and P-gp efflux also contribute to its favorability. Ligand A's high DILI risk is a significant red flag. Considering the GPCR-specific priorities, Ligand B's better BBB penetration and logP are also beneficial.

Output:
1
2025-04-17 08:43:39,310 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (375.372 and 349.431 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (72.48) is excellent, well below the 90 A^2 threshold for CNS targets. Ligand B (84.67) is still reasonable, but less optimal.

**3. logP:** Ligand A (3.503) is at the upper end of the optimal range (1-3), but acceptable. Ligand B (1.553) is on the lower end, potentially hindering permeability.

**4. H-Bond Donors:** Both ligands have a reasonable number of HBDs (2 and 1, respectively), well within the limit of 5.

**5. H-Bond Acceptors:** Both ligands have 5 HBAs, within the limit of 10.

**6. QED:** Both ligands have similar QED values (0.785 and 0.77), indicating good drug-likeness.

**7. DILI:** Ligand A (89.841) has a higher DILI risk than Ligand B (34.626). This is a significant negative for Ligand A.

**8. BBB:** Ligand A (95.308) has excellent BBB penetration, a crucial factor for a CNS target like DRD2. Ligand B (61.691) is considerably lower, which is a major drawback.

**9. Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and suggests a potential issue with the data or modeling. However, we can still compare them relatively.

**10. Aqueous Solubility:** Both ligands have negative solubility values, which is also unusual.

**11. hERG Inhibition:** Ligand A (0.721) has a slightly higher hERG risk than Ligand B (0.197), but both are relatively low.

**12. Microsomal Clearance:** Ligand A (46.893) and Ligand B (37.299) have similar microsomal clearance values.

**13. In vitro Half-Life:** Ligand A (38.008) has a longer half-life than Ligand B (24.172), which is preferable.

**14. P-gp Efflux:** Ligand A (0.4) has lower P-gp efflux than Ligand B (0.092), which is beneficial for CNS penetration.

**15. Binding Affinity:** Ligand A (-9.1 kcal/mol) has a significantly stronger binding affinity than Ligand B (-8.1 kcal/mol). This 1.0 kcal/mol difference is substantial and can outweigh some ADME drawbacks.

**Overall Assessment:**

Despite the higher DILI risk, Ligand A is the more promising candidate. The significantly stronger binding affinity (-9.1 vs -8.1 kcal/mol) and excellent BBB penetration (95.308) are critical advantages for a CNS-targeting GPCR. The lower P-gp efflux also supports better CNS exposure. While Ligand B has a lower DILI risk, its significantly poorer BBB penetration and weaker affinity make it less likely to succeed. The unusual solubility and Caco-2 values are concerning for both, but the affinity and BBB of A are more compelling.

Output:
1
2025-04-17 08:43:39,310 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (344.46 and 350.46 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (58.44) is significantly better than Ligand B (89.87). For CNS targets, we want TPSA <= 90, and A is comfortably within this range, while B is approaching the upper limit.

**3. logP:** Both ligands have acceptable logP values (1.55 and 0.97), falling within the optimal 1-3 range.

**4. H-Bond Donors:** Ligand A (0) is preferable to Ligand B (3). Lower HBD generally improves permeability.

**5. H-Bond Acceptors:** Both ligands have 4 HBA, which is acceptable.

**6. QED:** Both ligands have similar QED values (0.705 and 0.623), indicating good drug-likeness.

**7. DILI:** Both ligands have the same DILI risk (22.8%), which is low and favorable.

**8. BBB:** Ligand A (63.47%) is significantly better than Ligand B (36.37%). A BBB percentile >70 is highly desirable for CNS targets, and A is closer to that threshold.

**9. Caco-2:** Ligand A (-4.627) is better than Ligand B (-5.01), indicating better intestinal absorption.

**10. Solubility:** Ligand A (-2.032) is better than Ligand B (-2.556), indicating better solubility.

**11. hERG:** Both ligands have similar, low hERG risk (0.18 and 0.195).

**12. Cl_mic:** Ligand B (25.375) has a slightly lower microsomal clearance than Ligand A (32.718), suggesting better metabolic stability. However, the difference isn't huge.

**13. t1/2:** Ligand B (-2.808) has a slightly longer in vitro half-life than Ligand A (-5.671), which is a positive.

**14. Pgp:** Both ligands have similar Pgp efflux liability (0.07 and 0.122), indicating low efflux.

**15. Binding Affinity:** Ligand B (-8.1 kcal/mol) has a significantly stronger binding affinity than Ligand A (-6.9 kcal/mol). This is a >1.2 kcal/mol advantage, which is substantial and can outweigh some ADME drawbacks.

**Overall Assessment:**

While Ligand A excels in properties crucial for BBB penetration (lower TPSA, better BBB percentile, better solubility), Ligand B boasts a considerably stronger binding affinity. For a CNS GPCR target like DRD2, strong affinity is paramount. The slightly lower metabolic stability of Ligand A is a concern, but the superior BBB penetration and other favorable ADME properties are valuable. However, the 1.2 kcal/mol difference in binding affinity is a significant advantage for Ligand B.

Output:
1
2025-04-17 08:43:39,311 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (355.435 and 370.475 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (104.81) is better than Ligand B (113.76). Both are below the 140 A^2 threshold for oral absorption, but closer to the 90 A^2 target for CNS penetration.

**3. logP:** Ligand A (0.35) is slightly better than Ligand B (-0.161), both are a bit low, potentially hindering permeation.

**4. H-Bond Donors:** Ligand A (2) is preferable to Ligand B (3). Lower HBD generally improves permeability.

**5. H-Bond Acceptors:** Both ligands have 5 HBA, which is acceptable.

**6. QED:** Ligand A (0.654) has a slightly better QED score than Ligand B (0.576), indicating a more drug-like profile.

**7. DILI:** Both ligands have acceptable DILI risk (Ligand A: 29.779, Ligand B: 32.959), well below the 60 threshold.

**8. BBB:** Ligand A (70.027) has a significantly better BBB percentile than Ligand B (64.482). This is a crucial factor for a CNS target like DRD2.

**9. Caco-2 Permeability:** Ligand A (-5.221) is better than Ligand B (-5.656), indicating better intestinal absorption.

**10. Aqueous Solubility:** Both ligands have poor aqueous solubility (-2.257 and -2.353). This could pose formulation challenges.

**11. hERG Inhibition:** Both ligands show very low hERG inhibition risk (Ligand A: 0.023, Ligand B: 0.108).

**12. Microsomal Clearance:** Ligand A (11.866) has a better (lower) microsomal clearance than Ligand B (-0.401), suggesting better metabolic stability.

**13. In vitro Half-Life:** Ligand A (-14.422) has a significantly longer in vitro half-life than Ligand B (5.643).

**14. P-gp Efflux:** Both ligands have very low P-gp efflux liability (Ligand A: 0.007, Ligand B: 0.007).

**15. Binding Affinity:** Both ligands have similar and strong binding affinities (-7.8 and -7.7 kcal/mol). The difference is negligible.

**Overall Assessment:**

Ligand A consistently outperforms Ligand B across several critical ADME properties, particularly BBB penetration, metabolic stability (Cl_mic and t1/2), and Caco-2 permeability. While both have similar affinity, Ligand A's superior ADME profile, especially its better BBB score, makes it the more promising candidate for a CNS-targeting drug like a DRD2 ligand. The slightly better QED and lower HBD also contribute to its favorability.

Output:
0
2025-04-17 08:43:39,311 - INFO - Reasoning:

Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (346.435 and 352.475 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (93.84) is slightly above the preferred <90 for CNS targets, while Ligand B (89.87) is comfortably below. This gives a slight edge to Ligand B.

**3. logP:** Both ligands have good logP values (1.331 and 1.053), falling within the optimal 1-3 range.

**4. H-Bond Donors:** Ligand A (2) and Ligand B (3) are both acceptable, being less than 5.

**5. H-Bond Acceptors:** Ligand A (6) and Ligand B (4) are both acceptable, being less than 10.

**6. QED:** Both ligands have similar QED values (0.705 and 0.69), indicating good drug-like properties.

**7. DILI:** Ligand A (38.852) has a lower DILI risk than Ligand B (19.736), which is favorable.

**8. BBB:** Ligand A (62.854) has a better BBB penetration percentile than Ligand B (54.517), which is crucial for a CNS target like DRD2.

**9. Caco-2 Permeability:** Ligand A (-5.396) has a more negative Caco-2 value, suggesting *lower* permeability compared to Ligand B (-4.837). This is a negative for Ligand A.

**10. Aqueous Solubility:** Ligand A (-1.352) has slightly better aqueous solubility than Ligand B (-2.083).

**11. hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.25 and 0.308), which is excellent.

**12. Microsomal Clearance:** Ligand A (17.551) has a higher microsomal clearance than Ligand B (-4.631), indicating lower metabolic stability. This is a negative for Ligand A.

**13. In vitro Half-Life:** Ligand A (31.889) has a longer in vitro half-life than Ligand B (2.931), which is favorable.

**14. P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.016 and 0.056), which is good for CNS penetration.

**15. Binding Affinity:** Both ligands have the same binding affinity (-8.1 kcal/mol), which is excellent and the most important factor.

**Overall Assessment:**

While Ligand A has better DILI, BBB, and in vitro half-life, Ligand B has a lower TPSA, better Caco-2 permeability, and better metabolic stability (lower Cl_mic). Given the importance of BBB penetration for a CNS target like DRD2, and the fact that both ligands have equal binding affinity, the slight advantage in TPSA and permeability of Ligand B, coupled with its improved metabolic stability, makes it the more promising candidate.

Output:
1
2025-04-17 08:43:39,311 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 drug candidates, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (350.419 and 355.389 Da) fall within the ideal range of 200-500 Da.

**TPSA:** Ligand A (96.69) is slightly above the optimal <90 for CNS targets, but still reasonable. Ligand B (70.47) is excellent, well below 90.

**logP:** Ligand A (0.499) is a bit low, potentially hindering permeation. Ligand B (1.092) is better, falling within the 1-3 optimal range.

**H-Bond Donors/Acceptors:** Ligand A has 2 HBD and 6 HBA, which are acceptable. Ligand B has 1 HBD and 5 HBA, also acceptable.

**QED:** Both ligands have good QED scores (0.754 and 0.829), indicating good drug-like properties.

**DILI:** Ligand A (51.493) has a moderate DILI risk, while Ligand B (26.406) has a significantly lower and more desirable DILI risk.

**BBB:** This is a critical parameter for a CNS target like DRD2. Ligand A (36.448) has a poor BBB percentile, suggesting limited brain penetration. Ligand B (80.884) has a very good BBB percentile, indicating excellent potential for CNS exposure.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values, which is unusual and requires further investigation. However, we'll proceed assuming these represent low permeability.

**Aqueous Solubility:** Both ligands have negative solubility values, which is also unusual.

**hERG Inhibition:** Both ligands show very low hERG inhibition risk (0.126 and 0.262).

**Microsomal Clearance:** Ligand A (-5.033) has a negative clearance, which is not physically meaningful. Ligand B (-10.387) also has a negative clearance. These values likely indicate very high *stability* (low clearance).

**In vitro Half-Life:** Ligand A (17.241 hours) is reasonable. Ligand B (-0.883 hours) is not physically meaningful.

**P-gp Efflux:** Both ligands show very low P-gp efflux liability (0.013 and 0.007).

**Binding Affinity:** Ligand B (-8.9 kcal/mol) has a slightly better binding affinity than Ligand A (-7.8 kcal/mol), although both are good (below -7.0). The 1.1 kcal/mol difference is significant.

**Overall Assessment:**

Ligand B is the superior candidate. While both ligands have acceptable MW, QED, and hERG profiles, Ligand B excels in the critical areas for a CNS GPCR target: BBB penetration and DILI risk. Its binding affinity is also slightly better. The negative values for Caco-2, solubility, and clearance are concerning and would require experimental verification, but the significant advantage in BBB and DILI, coupled with better affinity, outweighs these concerns. Ligand A's poor BBB penetration is a major drawback.

Output:
1
2025-04-17 08:43:39,311 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 drug candidates, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (358.395 and 347.375 Da) fall within the ideal 200-500 Da range.

**TPSA:** Both ligands (126.07 and 123.4) are slightly above the optimal <90 for CNS targets, but not drastically so. This is a moderate concern.

**logP:** Ligand A (-1.828) is lower than the optimal 1-3 range, potentially hindering permeation. Ligand B (-0.253) is closer to the ideal range, but still on the lower side.

**H-Bond Donors/Acceptors:** Ligand A (3 HBD, 7 HBA) and Ligand B (4 HBD, 4 HBA) both fall within acceptable limits (<=5 HBD, <=10 HBA).

**QED:** Both ligands have reasonable QED scores (0.238 and 0.363), but are below the preferred 0.5. This suggests room for improvement in drug-likeness.

**DILI:** Ligand A (35.595) has a significantly better DILI score than Ligand B (66.77), indicating a lower risk of liver injury. This is a major advantage for Ligand A.

**BBB:** Ligand B (69.484) has a better BBB percentile than Ligand A (54.207), which is important for CNS targets like DRD2. However, both are below the desirable >70 threshold.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.279 and -5.492), which is unusual and suggests poor intestinal absorption. This is a significant drawback for both.

**Aqueous Solubility:** Both ligands have negative solubility values (-1.407 and -2.807), again suggesting poor solubility.

**hERG Inhibition:** Both ligands have very low hERG inhibition liability (0.14 and 0.057), which is excellent.

**Microsomal Clearance:** Ligand A (21.402) has a higher microsomal clearance than Ligand B (0.019), suggesting faster metabolism and potentially lower in vivo exposure. This favors Ligand B.

**In vitro Half-Life:** Ligand B (-0.884) has a slightly better in vitro half-life than Ligand A (-31.456).

**P-gp Efflux:** Ligand A (0.002) exhibits very low P-gp efflux, which is favorable for CNS penetration. Ligand B (0.01) is slightly higher, but still low.

**Binding Affinity:** Ligand B (-7.8 kcal/mol) has a stronger binding affinity than Ligand A (-7.3 kcal/mol). The difference of 0.5 kcal/mol is substantial and could outweigh some of the ADME drawbacks.

**Overall Assessment:**

Ligand B has a better binding affinity and slightly better metabolic stability (lower Cl_mic, better t1/2) and BBB penetration. However, Ligand A has a significantly better DILI score and lower P-gp efflux. Both ligands have poor Caco-2 permeability and solubility. Given the importance of binding affinity for GPCRs, and the relatively small difference in BBB penetration, the stronger binding affinity of Ligand B is the deciding factor. The lower DILI risk of Ligand A is appealing, but can be addressed during lead optimization.

Output:
1
2025-04-17 08:43:39,312 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (349.362 Da) is slightly lower, which could be advantageous for permeability. Ligand B (372.471 Da) is also good.

**TPSA:** Ligand A (98.74) is closer to the desirable threshold of 90 for CNS targets than Ligand B (72.2). This is a significant advantage for CNS penetration.

**logP:** Both ligands have acceptable logP values (Ligand A: 1.511, Ligand B: 3.872). Ligand B is higher, which *could* lead to solubility issues or off-target interactions, but is still within a reasonable range.

**H-Bond Donors/Acceptors:** Ligand A has 3 HBD and 4 HBA, while Ligand B has 1 HBD and 5 HBA. Both are within acceptable limits (<=5 HBD and <=10 HBA).

**QED:** Ligand A (0.702) has a better QED score than Ligand B (0.577), indicating a more drug-like profile.

**DILI:** Ligand B (89.415) has a considerably higher DILI risk than Ligand A (67.313). This is a significant negative for Ligand B.

**BBB:** Ligand A (76.464) has a better BBB percentile than Ligand B (62.854), although both are reasonably good. For a CNS target like DRD2, maximizing BBB penetration is crucial, giving Ligand A an edge.

**Caco-2 Permeability:** Ligand A (-4.906) shows poor Caco-2 permeability, while Ligand B (-5.495) is also poor. This is a concern for both, but not a deciding factor given the other parameters.

**Aqueous Solubility:** Both ligands have very poor aqueous solubility (-3.194 and -3.988 respectively). This could pose formulation challenges, but might be mitigated by other factors.

**hERG Inhibition:** Ligand A (0.215) has a lower hERG inhibition liability than Ligand B (0.626), which is favorable.

**Microsomal Clearance:** Ligand B (90.751) has a much higher microsomal clearance than Ligand A (1.857). This suggests Ligand B will be metabolized more quickly, leading to lower exposure.

**In vitro Half-Life:** Ligand A (28.771) has a significantly longer in vitro half-life than Ligand B (7.309). This is a major advantage for Ligand A.

**P-gp Efflux:** Ligand A (0.022) has much lower P-gp efflux liability than Ligand B (0.72). Lower P-gp efflux is crucial for CNS penetration.

**Binding Affinity:** Ligand B (-10.3 kcal/mol) has a substantially stronger binding affinity than Ligand A (-8.7 kcal/mol). This is a significant advantage for Ligand B, and could potentially outweigh some of its ADME drawbacks. However, the difference is not so large that it completely overshadows the other factors.

**Overall Assessment:**

Ligand A demonstrates a superior ADME profile, particularly regarding BBB penetration, metabolic stability, and P-gp efflux. It also has a lower DILI risk and better QED. While Ligand B has a stronger binding affinity, the substantial ADME liabilities (high clearance, P-gp efflux, DILI risk, and lower BBB) make it a less attractive candidate. The difference in binding affinity, while significant, is unlikely to overcome these substantial drawbacks for a CNS target.

Output:
0
2025-04-17 08:43:39,312 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (365.455 and 366.38 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (80.23) is better than Ligand B (66.92). Both are below 90, which is favorable for CNS penetration.

**logP:** Ligand A (1.455) and Ligand B (2.12) are both within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A has 1 HBD and 6 HBA, while Ligand B has 0 HBD and 4 HBA. Both are within acceptable limits (<=5 HBD, <=10 HBA).

**QED:** Ligand A (0.857) has a significantly better QED score than Ligand B (0.648), indicating a more drug-like profile.

**DILI:** Ligand B (34.665) has a lower DILI risk than Ligand A (49.128), which is a positive attribute.

**BBB:** Ligand B (97.557) has a *much* higher BBB penetration percentile than Ligand A (68.127). This is a critical advantage for a CNS target like DRD2.

**Caco-2 Permeability:** Ligand A (-4.827) and Ligand B (-4.008) both have negative values, which are difficult to interpret without knowing the scale. However, they are relatively similar.

**Aqueous Solubility:** Ligand A (-2.439) and Ligand B (-2.126) both have negative values, indicating poor solubility. This is a concern, but can sometimes be overcome with formulation strategies.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.244 and 0.381, respectively).

**Microsomal Clearance:** Ligand B (68.614) has a higher microsomal clearance than Ligand A (18.89), suggesting faster metabolism and potentially lower *in vivo* exposure.

**In vitro Half-Life:** Ligand A (36.688) has a much longer *in vitro* half-life than Ligand B (-36.278). This is a significant advantage.

**P-gp Efflux:** Ligand A (0.174) has a lower P-gp efflux liability than Ligand B (0.048), suggesting better CNS exposure.

**Binding Affinity:** Ligand B (-7.5 kcal/mol) has a slightly better binding affinity than Ligand A (-8.0 kcal/mol). While A is better, the difference is small.

**Overall Assessment:**

While Ligand A has a better QED, half-life, and P-gp efflux profile, Ligand B's *significantly* higher BBB penetration (97.557 vs 68.127) is the deciding factor for a CNS target like DRD2. The slightly better affinity of Ligand B is a bonus. The lower DILI risk of Ligand B is also favorable. The faster clearance of Ligand B is a drawback, but could potentially be addressed through structural modifications.

Output:
1
2025-04-17 08:43:39,312 - INFO - Batch 473 complete. Total preferences: 7568
2025-04-17 08:43:39,312 - INFO - Processing batch 474/512...
2025-04-17 08:44:22,628 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight (MW):** Both ligands (348.49 & 363.48 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (61.8) is significantly better than Ligand B (78.51). For CNS targets, we want TPSA <= 90, and A is closer to the ideal <=60. B is pushing the upper limit.

**3. logP:** Both ligands have good logP values (1.84 & 1.69), falling within the optimal 1-3 range.

**4. H-Bond Donors (HBD):** Both have 2 HBD, which is acceptable (<=5).

**5. H-Bond Acceptors (HBA):** Both have 4 HBA, which is acceptable (<=10).

**6. QED:** Both have good QED scores (0.715 & 0.854), indicating drug-like properties.

**7. DILI:** Ligand A (10.62) has a much lower DILI risk than Ligand B (35.79). This is a significant advantage.

**8. BBB:** Ligand B (61.85) has a better BBB penetration percentile than Ligand A (51.99). However, both are below the desirable >70 for CNS targets.

**9. Caco-2 Permeability:** Ligand A (-4.75) has better Caco-2 permeability than Ligand B (-5.09). Higher values are better.

**10. Aqueous Solubility:** Ligand A (-1.81) has better aqueous solubility than Ligand B (-2.56). Higher values are better.

**11. hERG Inhibition:** Ligand A (0.80) has a lower hERG inhibition liability than Ligand B (0.20). Lower is better.

**12. Microsomal Clearance:** Ligand B (2.61) has a much lower microsomal clearance than Ligand A (34.78). Lower clearance indicates better metabolic stability.

**13. In vitro Half-Life:** Ligand B (9.54) has a longer in vitro half-life than Ligand A (5.84). Longer is generally preferred.

**14. P-gp Efflux:** Ligand A (0.34) has lower P-gp efflux liability than Ligand B (0.05). Lower is better, especially for CNS targets.

**15. Binding Affinity:** Ligand B (-8.9 kcal/mol) has a slightly better binding affinity than Ligand A (-8.1 kcal/mol). This is a 1.5 kcal/mol advantage, which is significant.

**Overall Assessment:**

Ligand B has a superior binding affinity and metabolic stability (lower Cl_mic, longer t1/2), and better BBB penetration. However, Ligand A has significantly better DILI risk, solubility, Caco-2 permeability, hERG inhibition, and P-gp efflux. The TPSA for ligand A is also much more favorable. Given the GPCR-specific priorities, the better BBB of ligand B is important, but the substantial advantages of ligand A in safety (DILI, hERG) and permeability (Caco-2, Pgp) outweigh the slightly weaker affinity and slightly worse BBB. The TPSA is also a significant factor favoring ligand A.

Output:
0
2025-04-17 08:44:22,629 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (339.351) is slightly lower, which could be beneficial for permeability, while Ligand B (363.933) is still well within the range.

**TPSA:** Ligand A (97.39) is higher than the optimal <90 for CNS targets, but still potentially acceptable. Ligand B (41.29) is excellent, well below the 90 threshold, suggesting better CNS penetration potential.

**logP:** Ligand A (1.47) is within the optimal range (1-3). Ligand B (3.965) is approaching the upper limit, but still acceptable.

**H-Bond Donors/Acceptors:** Ligand A has 2 HBD and 5 HBA, which are reasonable. Ligand B has 1 HBD and 4 HBA, also reasonable.

**QED:** Both ligands have acceptable QED values (A: 0.825, B: 0.733), indicating good drug-like properties.

**DILI:** Ligand A has a high DILI risk (92.904), which is a significant concern. Ligand B has a very low DILI risk (8.104), a major advantage.

**BBB:** Ligand A has a BBB penetration of 55.099, which is below the desirable >70 for CNS targets. Ligand B has a much better BBB penetration (74.952), exceeding the threshold.

**Caco-2 Permeability:** Both have negative Caco-2 values (-4.788 and -4.89). This is unusual and suggests a potential issue with the experimental data or a very poor permeability.

**Aqueous Solubility:** Both have negative solubility values (-4.143 and -3.901), indicating very poor solubility. This is a significant drawback.

**hERG Inhibition:** Ligand A (0.292) shows a slightly higher hERG inhibition risk than Ligand B (0.947), although both are relatively low.

**Microsomal Clearance:** Both ligands have similar microsomal clearance values (A: 54.712, B: 51.71), suggesting comparable metabolic stability.

**In vitro Half-Life:** Ligand B (97.181) has a significantly longer in vitro half-life than Ligand A (11.923), which is a major advantage.

**P-gp Efflux:** Ligand A (0.037) has very low P-gp efflux, which is good. Ligand B (0.759) has moderate P-gp efflux, which could limit CNS exposure.

**Binding Affinity:** Ligand B (-7.1 kcal/mol) has a significantly stronger binding affinity than Ligand A (-10.2 kcal/mol). This difference in affinity is substantial and could outweigh some of the ADME drawbacks of Ligand B.

**Overall Assessment:**

Ligand B is the more promising candidate. While it has a slightly higher logP and moderate P-gp efflux, its significantly better BBB penetration, much lower DILI risk, substantially longer half-life, and *much* stronger binding affinity outweigh these concerns. Ligand A's high DILI risk and poor BBB penetration are major red flags. The negative solubility and Caco-2 values for both are concerning and would require further investigation, but the superior binding and ADME profile of Ligand B make it the better choice.

Output:
1
2025-04-17 08:44:22,629 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (371.547 and 344.415 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (61.88) is significantly better than Ligand B (83.44). For CNS targets, we want TPSA <= 90, and ideally closer to 60. Ligand A is much closer to the ideal.

**logP:** Ligand A (1.205) is within the optimal 1-3 range. Ligand B (0.128) is quite low, potentially hindering permeation.

**H-Bond Donors/Acceptors:** Ligand A (HBD=1, HBA=5) and Ligand B (HBD=2, HBA=4) both have reasonable H-bond characteristics, well within the guidelines.

**QED:** Both ligands have good QED scores (0.65 and 0.762), indicating good drug-like properties.

**DILI:** Ligand A (20.396) has a much lower DILI risk than Ligand B (31.524). Both are below the 40 threshold, but A is preferable.

**BBB:** Ligand A (60.333) and Ligand B (67.158) are both reasonably good, but below the desirable >70 for CNS targets. Ligand B is slightly better here.

**Caco-2 Permeability:** Ligand A (-5.175) and Ligand B (-4.98) both have negative values, which is unusual and suggests poor permeability. However, the scale isn't specified, so it's difficult to interpret.

**Aqueous Solubility:** Both ligands have very poor aqueous solubility (-1.619 and -2.288). This is a concern, but can sometimes be overcome with formulation strategies.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.403 and 0.148).

**Microsomal Clearance:** Ligand A (33.011) has a higher microsomal clearance than Ligand B (2.479), suggesting lower metabolic stability. This is a significant drawback for Ligand A.

**In vitro Half-Life:** Ligand B (10.42) has a much longer in vitro half-life than Ligand A (3.301), which is a major advantage.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.056 and 0.012). This is good for CNS penetration.

**Binding Affinity:** Ligand B (-8.4 kcal/mol) has a significantly stronger binding affinity than Ligand A (-6.9 kcal/mol). This >1.5 kcal/mol difference is substantial and can outweigh some ADME drawbacks.

**Overall Assessment:**

Ligand B is the stronger candidate. While both have solubility issues and less-than-ideal BBB penetration, Ligand B's superior binding affinity (-8.4 vs -6.9 kcal/mol), longer half-life, and lower DILI risk are compelling. Ligand A has a better TPSA, but the significantly worse clearance and lower affinity are critical drawbacks, especially given the importance of potency for GPCR ligands. The slightly better BBB for ligand B is a bonus.



Output:
1
2025-04-17 08:44:22,629 - INFO - Reasoning:

Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (365.5 & 352.4 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (87.3) is excellent, falling well below the 90 A^2 threshold for CNS targets. Ligand B (124.6) is higher, but still potentially acceptable, though less ideal.

**3. logP:** Ligand A (1.85) is optimal. Ligand B (-0.585) is slightly low, potentially hindering permeability.

**4. H-Bond Donors:** Both ligands (A: 3, B: 2) are within the acceptable limit of <=5.

**5. H-Bond Acceptors:** Ligand A (4) is good. Ligand B (7) is higher, but still within the acceptable limit of <=10.

**6. QED:** Both ligands (A: 0.719, B: 0.73) have excellent drug-likeness scores.

**7. DILI:** Both ligands have similar, acceptable DILI risk (A: 45.4, B: 45.2).

**8. BBB:** Ligand B (77.9%) is significantly better than Ligand A (46.1%) in terms of predicted BBB penetration, a critical factor for CNS targets like DRD2.

**9. Caco-2 Permeability:** Both have negative values, indicating poor permeability. This is unusual and requires further investigation, but the scale is not specified, so it's difficult to interpret.

**10. Aqueous Solubility:** Both ligands have negative values, indicating poor solubility. This is also unusual and requires further investigation.

**11. hERG Inhibition:** Both ligands have very low hERG risk (A: 0.172, B: 0.042).

**12. Microsomal Clearance:** Ligand B (-33.6) has *much* lower (better) microsomal clearance than Ligand A (33.4), suggesting greater metabolic stability.

**13. In vitro Half-Life:** Ligand B (31.2) has a significantly longer half-life than Ligand A (12.7).

**14. P-gp Efflux:** Both ligands have very low P-gp efflux liability (A: 0.095, B: 0.006), which is favorable for CNS penetration.

**15. Binding Affinity:** Ligand A (-7.8 kcal/mol) has a slightly better binding affinity than Ligand B (-7.5 kcal/mol), although the difference is relatively small.

**Overall Assessment:**

While Ligand A has slightly better binding affinity, Ligand B is superior overall, particularly for a CNS target like DRD2. The significantly better BBB penetration (77.9% vs 46.1%), lower microsomal clearance, and longer half-life of Ligand B are crucial advantages. The slightly lower logP of Ligand B is a minor concern, but the other improvements outweigh this. The negative Caco-2 and solubility values are concerning for both, but we'll prioritize the CNS-relevant properties for DRD2.

Output:
1
2025-04-17 08:44:22,630 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (340.427 Da) is slightly better than Ligand B (381.402 Da) as it's closer to the lower end, potentially aiding permeability.

**TPSA:** Ligand A (86.88) is excellent, falling well below the 90 A^2 threshold for CNS targets. Ligand B (107.97) is still reasonable but less optimal.

**logP:** Ligand A (2.111) is within the optimal range (1-3). Ligand B (0.284) is quite low, potentially hindering membrane permeability and CNS penetration.

**H-Bond Donors/Acceptors:** Ligand A (3 HBD, 3 HBA) is well-balanced. Ligand B (1 HBD, 8 HBA) has a higher number of HBA, which could slightly impact permeability.

**QED:** Both ligands have acceptable QED values (A: 0.779, B: 0.581), indicating reasonable drug-likeness.

**DILI:** Ligand A (52.307) has a much lower DILI risk than Ligand B (87.902), which is a significant advantage.

**BBB:** Ligand A (74.254) has a good BBB percentile, exceeding the 70% threshold for CNS targets. Ligand B (46.336) is considerably lower, raising concerns about CNS exposure.

**Caco-2 Permeability:** Both have negative values, which is unusual and suggests poor permeability. However, the scale is not specified, so it's difficult to interpret.

**Aqueous Solubility:** Both ligands have negative solubility values, indicating very poor aqueous solubility. This is a major concern for both.

**hERG Inhibition:** Ligand A (0.751) shows a lower hERG inhibition liability than Ligand B (0.154), which is preferable.

**Microsomal Clearance:** Ligand A (59.173) has a higher clearance than Ligand B (28.952), indicating lower metabolic stability.

**In vitro Half-Life:** Ligand B (-17.302) has a significantly longer half-life than Ligand A (-4.121). This is a positive attribute.

**P-gp Efflux:** Ligand A (0.415) has lower P-gp efflux liability than Ligand B (0.035), which is favorable for CNS penetration.

**Binding Affinity:** Ligand A (-9.5 kcal/mol) has a considerably stronger binding affinity than Ligand B (-7.8 kcal/mol). This is a substantial advantage, potentially outweighing some of the ADME drawbacks.

**Overall Assessment:**

Considering the GPCR-specific priorities, Ligand A is the superior candidate. It has a better BBB score, a more favorable logP, lower DILI risk, lower P-gp efflux, and significantly stronger binding affinity. While Ligand B has a longer half-life, the poor logP and lower BBB penetration are major drawbacks for a CNS target like DRD2. The solubility issues are concerning for both, but the superior binding and CNS penetration potential of Ligand A make it the more promising candidate.

Output:
1
2025-04-17 08:44:22,630 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (345.443 and 347.415 Da) fall comfortably within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (71.53) is excellent, well below the 90 A^2 threshold for CNS targets. Ligand B (115.89) is higher, but still potentially acceptable, though less ideal.

**3. logP:** Ligand A (1.995) is optimal. Ligand B (0.775) is a bit low, potentially hindering permeation.

**4. H-Bond Donors:** Ligand A (1) and Ligand B (4) are both within the acceptable limit of <=5.

**5. H-Bond Acceptors:** Ligand A (4) and Ligand B (5) are both within the acceptable limit of <=10.

**6. QED:** Ligand A (0.886) is very good, indicating high drug-likeness. Ligand B (0.448) is lower, suggesting a less favorable drug-like profile.

**7. DILI:** Both ligands have low DILI risk (26.018 and 27.414), which is positive.

**8. BBB:** This is a critical parameter for a CNS target like DRD2. Ligand A has a very good BBB percentile (84.684). Ligand B's BBB percentile (23.11) is very poor, a significant drawback.

**9. Caco-2 Permeability:** Ligand A (-4.599) is concerningly low, suggesting poor intestinal absorption. Ligand B (-5.705) is also low, but slightly worse.

**10. Aqueous Solubility:** Both ligands have poor aqueous solubility (-2.425 and -2.479). This could pose formulation challenges, but is less critical than BBB penetration for a CNS target.

**11. hERG Inhibition:** Both ligands show low hERG inhibition liability (0.435 and 0.503), which is good.

**12. Microsomal Clearance:** Ligand A (25.133) has moderate clearance, while Ligand B (-3.422) has negative clearance, which is not possible and likely an error in the data. Assuming the negative value is an artifact, it suggests very high metabolic stability, which is a positive.

**13. In vitro Half-Life:** Ligand A (-6.274) is concerningly low. Ligand B (-26.53) is even lower, and also likely an artifact.

**14. P-gp Efflux:** Both ligands show minimal P-gp efflux (0.025 and 0.01), which is favorable for CNS penetration.

**15. Binding Affinity:** Both ligands have excellent binding affinity (-8.0 and -8.8 kcal/mol). Ligand B is slightly better.

**Overall Assessment:**

Despite Ligand B having slightly better binding affinity and potentially better metabolic stability (assuming the negative clearance is an error), Ligand A is the more promising candidate. The overwhelmingly superior BBB penetration (84.684 vs. 23.11) of Ligand A is the deciding factor for a CNS-targeting drug. While Ligand A has lower Caco-2 permeability and a low in vitro half-life, these can potentially be addressed through formulation strategies or structural modifications. The poor BBB penetration of Ligand B is a much more difficult hurdle to overcome.

Output:
0
2025-04-17 08:44:22,630 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (342.443 and 350.507 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (67.35) is slightly higher than Ligand B (50.6). Both are below the 90 A^2 threshold for CNS targets, which is good. Ligand B is preferable here.

**3. logP:** Both ligands have good logP values (2.166 and 2.449), falling within the optimal 1-3 range.

**4. H-Bond Donors:** Ligand A has 1 HBD, and Ligand B has 0. Both are within the acceptable limit of <=5.

**5. H-Bond Acceptors:** Ligand A has 4 HBA, and Ligand B has 5. Both are within the acceptable limit of <=10.

**6. QED:** Ligand A (0.894) has a significantly higher QED score than Ligand B (0.65), indicating better overall drug-likeness.

**7. DILI:** Ligand A (29.546) has a much lower DILI risk than Ligand B (7.755), which is a significant advantage.

**8. BBB:** Both ligands have excellent BBB penetration (90.229 and 90.772), exceeding the desirable >70 threshold for CNS targets.

**9. Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual. However, the magnitude is similar (-4.73 and -4.296). This suggests poor intestinal absorption, but is less critical for a CNS target where direct delivery is possible.

**10. Aqueous Solubility:** Both ligands have negative solubility values (-1.818 and -1.298), indicating poor aqueous solubility. This could pose formulation challenges.

**11. hERG Inhibition:** Both ligands show very low hERG inhibition risk (0.192 and 0.45).

**12. Microsomal Clearance:** Ligand A (13.731) has a significantly lower microsomal clearance than Ligand B (76.548), indicating better metabolic stability.

**13. In vitro Half-Life:** Ligand A (25.693) has a longer in vitro half-life than Ligand B (3.796), which is desirable.

**14. P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.051 and 0.048), which is excellent for CNS penetration.

**15. Binding Affinity:** Ligand A (-9.1 kcal/mol) has a significantly stronger binding affinity than Ligand B (-5.7 kcal/mol). This is a substantial advantage, potentially outweighing some of the ADME drawbacks.

**Overall Assessment:**

Ligand A is clearly superior. While both have good BBB penetration and low P-gp efflux, Ligand A excels in crucial areas: significantly stronger binding affinity, better QED, lower DILI risk, and improved metabolic stability (lower Cl_mic and longer t1/2). The slightly higher TPSA of Ligand A is not a major concern given the CNS target. The poor solubility and Caco-2 permeability are less critical for a CNS drug. The large difference in binding affinity (-9.1 vs -5.7 kcal/mol) is the most important factor.

Output:
1
2025-04-17 08:44:22,630 - INFO - Reasoning:

Let's analyze Ligand A and Ligand B based on the provided guidelines, prioritizing GPCR-specific properties (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (337.471 Da) is slightly lower, which could be advantageous for permeability, but both are acceptable.

**TPSA:** Ligand A (57.74) is significantly better than Ligand B (61.88). For CNS targets, we want TPSA <= 90, and ideally closer to 60. Ligand A is much closer to the ideal range.

**logP:** Ligand A (4.238) is higher than the optimal range (1-3), but still potentially manageable. Ligand B (1.205) is quite low, which could hinder permeability and CNS penetration.

**H-Bond Donors/Acceptors:** Both ligands have reasonable HBD/HBA counts (A: 0/5, B: 1/5), falling within the acceptable limits.

**QED:** Both ligands have similar QED values (A: 0.791, B: 0.65), indicating good drug-likeness.

**DILI:** Ligand A (32.183) has a much lower DILI risk than Ligand B (20.396), which is a significant advantage.

**BBB:** Ligand A (74.292) has a substantially better BBB percentile than Ligand B (60.333). For a CNS target like DRD2, >70 is desirable, and A is closer to this threshold.

**Caco-2 Permeability:** Ligand A (-4.874) has a more negative Caco-2 value, suggesting *lower* permeability than Ligand B (-5.175). However, the absolute values are not directly comparable without knowing the scale.

**Aqueous Solubility:** Ligand A (-4.917) has a more negative solubility value, indicating lower solubility than Ligand B (-1.619).

**hERG Inhibition:** Both ligands have low hERG inhibition risk (A: 0.695, B: 0.403).

**Microsomal Clearance:** Ligand A (56.796) has a higher microsomal clearance than Ligand B (33.011), indicating lower metabolic stability.

**In vitro Half-Life:** Ligand B (3.301) has a longer in vitro half-life than Ligand A (-2.915), which is preferable.

**P-gp Efflux:** Ligand A (0.335) has lower P-gp efflux liability than Ligand B (0.056), which is a significant advantage for CNS penetration.

**Binding Affinity:** Ligand A (-7.9 kcal/mol) has a stronger binding affinity than Ligand B (-6.9 kcal/mol). This 1 kcal/mol difference is substantial and can outweigh some ADME drawbacks.

**Overall Assessment:**

Considering the GPCR-specific priorities, Ligand A is the more promising candidate. Its superior BBB penetration, lower DILI risk, stronger binding affinity, and lower P-gp efflux outweigh its slightly lower solubility, higher clearance, and lower Caco-2 permeability. The higher logP of Ligand A is a concern, but the strong affinity and good BBB suggest it can still achieve sufficient CNS exposure. Ligand B's low logP is a major drawback for a CNS target.

Output:
1
2025-04-17 08:44:22,630 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (344.415 and 344.455 Da) are within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (85.25) is better than Ligand B (47.73). For CNS targets, we want TPSA <= 90, and both meet this criterion, but A is closer to the upper limit, potentially indicating a slightly reduced ability to cross the BBB compared to B.

**3. logP:** Both ligands have good logP values (2.746 and 3.871), falling within the optimal 1-3 range. Ligand B is slightly higher, which *could* be a minor concern for solubility, but it's not a major issue.

**4. H-Bond Donors:** Ligand A has 2 HBD, and Ligand B has 0. Both are within the acceptable limit of <= 5.

**5. H-Bond Acceptors:** Ligand A has 6 HBA, and Ligand B has 5. Both are within the acceptable limit of <= 10.

**6. QED:** Both ligands have similar QED values (0.787 and 0.763), indicating good drug-like properties.

**7. DILI:** Ligand A has a DILI risk of 81.078%, which is high. Ligand B has a much lower DILI risk of 11.71%, making it significantly safer in terms of liver toxicity.

**8. BBB:** Ligand A has a BBB penetration of 65.374%, which is below the desirable >70% for CNS targets. Ligand B has a BBB penetration of 83.366%, which is excellent. This is a crucial difference given the target is DRD2.

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.638 and -4.868). These values are unusual and likely indicate issues with the calculation or data source. However, the values are similar, so this isn't a differentiating factor.

**10. Aqueous Solubility:** Both ligands have negative solubility values (-4.575 and -3.214). Similar to Caco-2, these are problematic values. Again, the values are similar, so this isn't a differentiating factor.

**11. hERG Inhibition:** Ligand A has a hERG inhibition risk of 0.355, and Ligand B has 0.922. Lower is better, so Ligand A is preferable here.

**12. Microsomal Clearance:** Ligand A has a higher microsomal clearance (108.935) than Ligand B (29.622). Lower clearance is better for metabolic stability, favoring Ligand B.

**13. In vitro Half-Life:** Ligand A has a half-life of 16.965 hours, while Ligand B has a very short half-life of 1.381 hours. Ligand A is much more favorable in this regard.

**14. P-gp Efflux:** Ligand A has a P-gp efflux liability of 0.199, while Ligand B has 0.731. Lower is better, favoring Ligand A.

**15. Binding Affinity:** Both ligands have very similar and strong binding affinities (-8.4 and -8.6 kcal/mol). The difference is negligible.

**Overall Assessment:**

Ligand B is significantly better overall, despite the shorter half-life. The key advantages of Ligand B are its much lower DILI risk and substantially better BBB penetration, both critical for a CNS-targeting drug. While Ligand A has a better hERG profile, P-gp efflux, and half-life, the safety and CNS penetration advantages of Ligand B outweigh these factors. The similar affinities mean that the ADME properties are the deciding factors.

Output:
1
2025-04-17 08:44:22,631 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (349.431 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (89.95) is slightly higher than Ligand B (83.66), but both are below the 90 A^2 threshold desirable for CNS targets.

**3. logP:** Ligand A (-0.125) is significantly lower than the optimal 1-3 range, potentially hindering permeability. Ligand B (1.263) is within the optimal range. This is a significant advantage for Ligand B.

**4. H-Bond Donors:** Both ligands have 2 HBD, which is acceptable.

**5. H-Bond Acceptors:** Both ligands have 4 HBA, which is acceptable.

**6. QED:** Both ligands have QED values above 0.6, indicating good drug-like properties.

**7. DILI:** Ligand A (24.351) has a lower DILI risk than Ligand B (42.652), which is favorable.

**8. BBB:** Ligand B (58.434) has a better BBB penetration percentile than Ligand A (42.303), though both are below the desirable >70 for CNS targets.

**9. Caco-2 Permeability:** Ligand A (-4.878) has worse Caco-2 permeability than Ligand B (-5.017). Both are poor.

**10. Aqueous Solubility:** Both ligands have very poor aqueous solubility (-2.121 and -2.288).

**11. hERG Inhibition:** Ligand A (0.088) has a lower hERG inhibition liability than Ligand B (0.389), which is favorable.

**12. Microsomal Clearance:** Ligand A (7.659) has lower microsomal clearance than Ligand B (24.776), suggesting better metabolic stability.

**13. In vitro Half-Life:** Ligand A (-6.043) has a longer in vitro half-life than Ligand B (3.169), which is favorable.

**14. P-gp Efflux:** Ligand A (0.024) has lower P-gp efflux liability than Ligand B (0.07), which is favorable for CNS penetration.

**15. Binding Affinity:** Ligand B (-7.7 kcal/mol) has a slightly better binding affinity than Ligand A (-8.1 kcal/mol). While the difference is small, it's still a positive for Ligand B.

**Overall Assessment:**

Ligand B has a more favorable logP, which is crucial for permeability and CNS penetration. While Ligand A has advantages in DILI, metabolic stability, half-life, P-gp efflux, and a slightly better binding affinity, the significantly lower logP of Ligand A is a major drawback for a CNS target. The slightly better BBB of Ligand B also contributes to its favorability. The affinity difference is small enough that it is outweighed by the logP and BBB considerations.

Output:
1
2025-04-17 08:44:22,631 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B based on the provided guidelines, prioritizing GPCR-specific properties (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (345.418 and 359.857 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (43.86) is significantly better than Ligand B (62.39). For CNS targets, we want TPSA <= 90, and ideally lower. Ligand A is well within this range, while Ligand B is approaching the upper limit.

**logP:** Ligand A (0.837) is within the optimal 1-3 range, but on the lower side. Ligand B (4.63) is too high, potentially causing solubility issues and off-target effects.

**H-Bond Donors/Acceptors:** Ligand A (0 HBD, 3 HBA) is preferable to Ligand B (1 HBD, 5 HBA). Both are within acceptable limits, but fewer H-bonds generally improve permeability.

**QED:** Both ligands have reasonable QED scores (0.431 and 0.666), indicating acceptable drug-likeness. Ligand B is slightly better.

**DILI:** Ligand A (21.055) has a much lower DILI risk than Ligand B (37.34). This is a significant advantage for Ligand A.

**BBB:** Ligand A (78.79) has a better BBB percentile than Ligand B (59.364). For a CNS target like DRD2, >70% is desirable, and Ligand A is closer to that threshold.

**Caco-2 Permeability:** Ligand A (-4.681) has a negative Caco-2 value, which is unusual and suggests very poor permeability. Ligand B (-5.147) is also poor, but similar to A.

**Aqueous Solubility:** Both ligands have negative solubility values (-2.102 and -4.621), indicating poor aqueous solubility. This is a concern, but can sometimes be mitigated with formulation strategies.

**hERG Inhibition:** Ligand A (0.393) has a lower hERG risk than Ligand B (0.939), which is favorable.

**Microsomal Clearance:** Ligand A (9.639) has a lower microsomal clearance than Ligand B (81.451), indicating better metabolic stability.

**In vitro Half-Life:** Ligand A (-30.593) has a negative half-life, which is not possible. This is a major red flag. Ligand B (39.107) has a reasonable half-life.

**P-gp Efflux:** Ligand A (0.086) has much lower P-gp efflux liability than Ligand B (0.606), which is crucial for CNS penetration.

**Binding Affinity:** Ligand B (-8.2 kcal/mol) has a slightly better binding affinity than Ligand A (-7.6 kcal/mol), but the difference is not substantial enough to outweigh the other significant drawbacks of Ligand B.

**Overall Assessment:**

Ligand A has significant advantages in TPSA, DILI, BBB, hERG, and P-gp efflux. However, the negative Caco-2 and half-life values are concerning and potentially invalid data. Ligand B has a better affinity and QED, but suffers from high logP, higher DILI risk, lower BBB penetration, and higher P-gp efflux. Given the importance of BBB penetration for a CNS target and the lower DILI risk, Ligand A is the more promising candidate *if* the Caco-2 and half-life data are corrected. The negative values suggest a data error.

Output:
0
2025-04-17 08:44:22,631 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 drug candidates, considering the provided guidelines and GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (350.434 and 380.863 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (61.8) is slightly higher than Ligand B (58.64), but both are below the 90 A^2 threshold desirable for CNS targets.

**logP:** Both ligands have good logP values (2.218 and 2.911), falling within the optimal 1-3 range. Ligand B is slightly higher, which *could* be a minor concern for solubility, but is not a major drawback.

**H-Bond Donors/Acceptors:** Ligand A has 2 HBD and 4 HBA, while Ligand B has 1 HBD and 3 HBA. Both are within acceptable limits (<=5 HBD and <=10 HBA).

**QED:** Ligand A (0.826) has a better QED score than Ligand B (0.659), indicating a more drug-like profile.

**DILI:** Ligand B (29.391) has a significantly lower DILI risk than Ligand A (18.845), which is a substantial advantage.

**BBB:** Both ligands have excellent BBB penetration (Ligand A: 84.374, Ligand B: 85.847), exceeding the >70% threshold for CNS targets.

**Caco-2 Permeability:** Both show negative Caco-2 values, which is unusual. This suggests a potential issue with intestinal absorption, but the scale is not clear and these values may be relative to a control.

**Aqueous Solubility:** Both ligands have negative solubility values, which is also unusual. This suggests poor aqueous solubility.

**hERG:** Both ligands have very low hERG inhibition liability (0.721 and 0.406), which is excellent.

**Microsomal Clearance:** Ligand A (12.75 mL/min/kg) has a lower microsomal clearance than Ligand B (35.164 mL/min/kg), indicating better metabolic stability.

**In vitro Half-Life:** Ligand A (29.528 hours) has a significantly longer in vitro half-life than Ligand B (6.648 hours), which is a major advantage.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.198 and 0.131), which is favorable for CNS exposure.

**Binding Affinity:** Both ligands have the same binding affinity (-8.6 kcal/mol), which is excellent and meets the < -7.0 kcal/mol criterion.

**Overall Assessment:**

While Ligand A has a better QED, longer half-life, and lower clearance, Ligand B has a significantly lower DILI risk. Given the importance of minimizing toxicity, and the comparable binding affinity and excellent BBB penetration for both, the lower DILI risk of Ligand B is a decisive factor. The negative solubility and Caco-2 values are concerning for both, but can be addressed during lead optimization.

Output:
1
2025-04-17 08:44:22,632 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (346.471 Da) is slightly higher than Ligand B (276.38 Da), but both are acceptable.

**TPSA:** Ligand A (58.64) is better than Ligand B (45.33) as it is closer to the ideal TPSA for CNS targets (<90). Both are well below the 140 threshold for oral absorption.

**logP:** Both ligands have good logP values (Ligand A: 2.577, Ligand B: 1.963), falling within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Both ligands have 1 HBD and 3 HBA, which are within acceptable limits.

**QED:** Both ligands have good QED scores (Ligand A: 0.752, Ligand B: 0.918), indicating drug-like properties. Ligand B is slightly better.

**DILI:** Both ligands have low DILI risk (Ligand A: 22.334, Ligand B: 24.971), both well below the 40 threshold.

**BBB:** Ligand B (93.137) significantly outperforms Ligand A (67.701) in BBB penetration. This is a crucial factor for a CNS target like DRD2.

**Caco-2 Permeability:** Both have negative Caco-2 values which is unusual, and suggests poor permeability. Ligand A (-4.777) is slightly worse than Ligand B (-4.423).

**Aqueous Solubility:** Both have negative solubility values, which is also unusual and suggests poor solubility. Ligand A (-2.331) is slightly worse than Ligand B (-1.308).

**hERG Inhibition:** Both ligands show low hERG inhibition risk (Ligand A: 0.325, Ligand B: 0.619).

**Microsomal Clearance:** Ligand B (9.066) has significantly lower microsomal clearance than Ligand A (42.215), indicating better metabolic stability.

**In vitro Half-Life:** Ligand B (-4.895) has a slightly better (less negative) in vitro half-life than Ligand A (-19.054).

**P-gp Efflux:** Ligand A (0.178) has lower P-gp efflux than Ligand B (0.383), which is favorable for CNS exposure.

**Binding Affinity:** Ligand B (-7.9 kcal/mol) has a slightly better binding affinity than Ligand A (-9.2 kcal/mol). While A is stronger, the difference is not substantial enough to outweigh the other ADME properties.

**Overall Assessment:**

Ligand B is the stronger candidate. While Ligand A has a slightly better binding affinity, Ligand B excels in critical properties for a CNS-targeting GPCR ligand: significantly higher BBB penetration, lower microsomal clearance (better metabolic stability), and a better in vitro half-life. The slightly lower P-gp efflux of Ligand A is a minor advantage compared to the substantial benefits of Ligand B's ADME profile.

Output:
1
2025-04-17 08:44:22,632 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (366.38 and 350.507 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (78.87) is better than Ligand B (55.89). Both are below the 90 A^2 threshold desirable for CNS targets, but A is closer to the upper limit.

**3. logP:** Both ligands have good logP values (1.222 and 0.943), falling within the optimal 1-3 range.

**4. H-Bond Donors:** Ligand A (2) is slightly higher than Ligand B (1), but both are within the acceptable limit of <=5.

**5. H-Bond Acceptors:** Both ligands have the same number of H-bond acceptors (4), which is well below the limit of 10.

**6. QED:** Ligand A (0.71) has a better QED score than Ligand B (0.497), indicating higher drug-likeness.

**7. DILI:** Ligand A (29.236) has a significantly lower DILI risk than Ligand B (4.382), which is a major advantage.

**8. BBB:** Ligand A (78.829) has a substantially higher BBB penetration percentile than Ligand B (62.233). This is *critical* for a CNS target like DRD2.

**9. Caco-2 Permeability:** Ligand A (-4.56) has worse Caco-2 permeability than Ligand B (-5.223). Lower values indicate lower permeability.

**10. Aqueous Solubility:** Ligand A (-1.659) has better aqueous solubility than Ligand B (0.103).

**11. hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.427 and 0.452).

**12. Microsomal Clearance:** Ligand B (-19.859) has a lower (better) microsomal clearance than Ligand A (2.264), indicating greater metabolic stability.

**13. In vitro Half-Life:** Ligand B (-5.788) has a longer in vitro half-life than Ligand A (-17.497).

**14. P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.03 and 0.009).

**15. Binding Affinity:** Ligand A (-8.7 kcal/mol) has a slightly better binding affinity than Ligand B (-7.3 kcal/mol). While both are good, the 1.4 kcal/mol difference is significant.

**Overall Assessment:**

Ligand A is the superior candidate. While Ligand B has better metabolic stability (lower Cl_mic, longer t1/2) and Caco-2 permeability, Ligand A excels in the most crucial areas for a CNS GPCR target: BBB penetration, DILI risk, and binding affinity. The higher BBB value and lower DILI risk of Ligand A are particularly important, outweighing the slightly less favorable metabolic properties. The better QED score also supports its drug-likeness. The difference in binding affinity, while not enormous, further tips the scale in favor of Ligand A.

Output:
1
2025-04-17 08:44:22,632 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (347.459 Da) is slightly lower, which could be beneficial for permeability.

**TPSA:** Ligand A (64.09) is significantly better than Ligand B (102.32). For CNS targets, TPSA should be <=90, and A is comfortably within this range, while B is pushing the limit.

**logP:** Ligand A (0.613) is a bit low, potentially hindering permeation. Ligand B (-0.47) is even lower, raising concerns about absorption. Both are below the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A (HBD=1, HBA=4) is preferable to Ligand B (HBD=2, HBA=7). Lower HBD/HBA generally improves permeability.

**QED:** Both ligands have acceptable QED values (A: 0.76, B: 0.645), indicating reasonable drug-likeness.

**DILI:** Ligand B (67.739) has a higher DILI risk than Ligand A (11.206). This is a significant negative for B.

**BBB:** Ligand A (59.403) has a slightly lower BBB penetration than Ligand B (62.156), but both are below the desirable >70% for CNS targets. However, given the other factors, this difference is less critical.

**Caco-2 Permeability:** Ligand A (-4.519) has a more negative Caco-2 value than Ligand B (-5.599), suggesting better intestinal absorption.

**Aqueous Solubility:** Both have very negative solubility values, indicating poor aqueous solubility. Ligand B (-2.772) is slightly worse than Ligand A (-1.349).

**hERG Inhibition:** Both ligands show very low hERG inhibition risk (A: 0.176, B: 0.056).

**Microsomal Clearance:** Ligand A (33.371) has a higher microsomal clearance than Ligand B (23.237), suggesting lower metabolic stability.

**In vitro Half-Life:** Ligand B (3.421) has a significantly shorter in vitro half-life than Ligand A (26.249). This is a major drawback for B.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (A: 0.006, B: 0.014).

**Binding Affinity:** Both ligands have very similar and strong binding affinities (-7.5 and -7.4 kcal/mol). The difference is negligible.

**Overall Assessment:**

Ligand A is the more promising candidate. While its logP is suboptimal, its superior TPSA, lower DILI risk, better Caco-2 permeability, and significantly longer half-life outweigh the slightly lower BBB penetration. Ligand B's higher DILI risk and short half-life are major concerns. The similar binding affinities make the ADME properties the deciding factor.

Output:
0
2025-04-17 08:44:22,632 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B against the provided guidelines, prioritizing GPCR-specific properties (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (342.46 and 343.43 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (32.34) is excellent, well below the 90 A^2 threshold for CNS targets. Ligand B (87.3) is higher, but still potentially acceptable, though less ideal.

**logP:** Ligand A (3.53) is at the upper end of the optimal range (1-3), while Ligand B (0.64) is quite low, potentially hindering membrane permeability.

**H-Bond Donors/Acceptors:** Ligand A (1 HBD, 2 HBA) is favorable. Ligand B (3 HBD, 3 HBA) is also reasonable.

**QED:** Ligand A (0.835) is excellent, indicating strong drug-likeness. Ligand B (0.376) is significantly lower, suggesting a less drug-like profile.

**DILI:** Ligand A (32.77) has a low DILI risk. Ligand B (27.61) also has a low DILI risk.

**BBB:** This is critical for a DRD2 ligand. Ligand A (79.22) shows good BBB penetration. Ligand B (30.13) is very poor, a major drawback.

**Caco-2 Permeability:** Ligand A (-4.702) is negative, indicating poor permeability. Ligand B (-5.037) is also negative, indicating poor permeability.

**Aqueous Solubility:** Ligand A (-4.153) is negative, indicating poor solubility. Ligand B (-2.972) is also negative, indicating poor solubility.

**hERG Inhibition:** Ligand A (0.946) has a low hERG risk. Ligand B (0.031) has a very low hERG risk.

**Microsomal Clearance:** Ligand A (76.60) has moderate clearance. Ligand B (22.29) has low clearance, suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (43.01 hours) is good. Ligand B (-17.04 hours) is negative, indicating very short half-life.

**P-gp Efflux:** Ligand A (0.457) has moderate P-gp efflux. Ligand B (0.03) has very low P-gp efflux, which is favorable for CNS penetration.

**Binding Affinity:** Both ligands have similar, strong binding affinities (-9.6 and -8.2 kcal/mol). The difference of 1.4 kcal/mol is not enough to overcome the other significant differences.

**Conclusion:**

Considering the GPCR-specific priorities, Ligand A is the better candidate despite its moderate Caco-2 permeability and solubility. Its significantly better BBB penetration (79.22 vs 30.13) and higher QED score (0.835 vs 0.376) are crucial advantages for a CNS-targeting drug. While Ligand B has better metabolic stability and lower P-gp efflux, the poor BBB penetration is a deal-breaker.

Output:
0
2025-04-17 08:44:22,633 - INFO - Batch 474 complete. Total preferences: 7584
2025-04-17 08:44:22,633 - INFO - Processing batch 475/512...
2025-04-17 08:45:02,893 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (353.419 and 346.515 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (105.76) is slightly above the optimal <90 for CNS targets, but still reasonable. Ligand B (49.41) is excellent, well below the threshold.

**logP:** Ligand A (-0.528) is a bit low, potentially hindering membrane permeability. Ligand B (3.38) is within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A has 3 HBD and 5 HBA, acceptable. Ligand B has 1 HBD and 2 HBA, also acceptable.

**QED:** Both ligands have similar QED values (0.595 and 0.541), indicating good drug-likeness.

**DILI:** Ligand A (47.266) has a moderate DILI risk, while Ligand B (16.053) has a very low risk.

**BBB:** Ligand B (60.644) shows significantly better BBB penetration potential than Ligand A (46.762). This is a crucial advantage for a CNS target like DRD2.

**Caco-2 Permeability:** Ligand A (-5.539) has poor Caco-2 permeability, suggesting poor intestinal absorption. Ligand B (-4.648) is also poor, but slightly better than A.

**Aqueous Solubility:** Both ligands have poor aqueous solubility (-1.652 and -4.364). This could pose formulation challenges.

**hERG Inhibition:** Ligand A (0.075) shows very low hERG inhibition risk, which is excellent. Ligand B (0.335) is slightly higher, but still relatively low.

**Microsomal Clearance:** Ligand A (-9.495) has a very low (and thus favorable) microsomal clearance, indicating good metabolic stability. Ligand B (54.55) has a high clearance, suggesting it will be rapidly metabolized.

**In vitro Half-Life:** Ligand A (19.498) has a moderate half-life. Ligand B (9.341) has a short half-life.

**P-gp Efflux:** Ligand A (0.009) has very low P-gp efflux, which is highly desirable for CNS penetration. Ligand B (0.125) has slightly higher efflux, but still relatively low.

**Binding Affinity:** Both ligands have good binding affinity (-8.0 and -6.5 kcal/mol). Ligand A is significantly more potent, with a 1.5 kcal/mol advantage.

**Overall Assessment:**

While Ligand A boasts superior binding affinity and metabolic stability, its poor logP, Caco-2 permeability, and lower BBB penetration are significant drawbacks for a CNS-targeting GPCR. Ligand B, despite its weaker affinity, exhibits a much more favorable profile regarding BBB penetration, logP, and DILI risk. The better BBB penetration and lower DILI risk of Ligand B outweigh the affinity difference, especially considering the potential for further optimization of Ligand B's affinity.

Output:
1
2025-04-17 08:45:02,894 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (345.359 and 368.463 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Both ligands (109.85 and 110.08) are slightly above the optimal <90 for CNS targets, but still reasonable.

**3. logP:** Ligand A (1.175) is within the optimal 1-3 range. Ligand B (-0.025) is slightly below 1, which *could* indicate permeability issues, though not drastically.

**4. H-Bond Donors:** Both have 1 HBD, which is good.

**5. H-Bond Acceptors:** Ligand A has 6 HBA, and Ligand B has 7. Both are acceptable (<=10).

**6. QED:** Both ligands have good QED scores (0.624 and 0.782), indicating drug-like properties.

**7. DILI:** Ligand A (64.327) has a higher DILI risk than Ligand B (59.403), but both are still reasonably low.

**8. BBB:** Ligand A (77.821) has a better BBB percentile than Ligand B (68.36). This is a significant advantage for a CNS target like DRD2.

**9. Caco-2:** Both have negative Caco-2 values (-5.025 and -5.62), which is unusual and suggests poor permeability. This is a concern for both.

**10. Solubility:** Both have negative solubility values (-3.552 and -2.17), also unusual and suggesting poor aqueous solubility.

**11. hERG:** Both ligands have very low hERG inhibition risk (0.195 and 0.048).

**12. Cl_mic:** Ligand B (20.799) has a lower microsomal clearance than Ligand A (34.078), suggesting better metabolic stability.

**13. t1/2:** Ligand B (-17.964) has a negative in vitro half-life, which is not possible and indicates a very short half-life. Ligand A (3.222) has a reasonable half-life.

**14. Pgp:** Both have very low Pgp efflux liability (0.055 and 0.046).

**15. Binding Affinity:** Both ligands have the same binding affinity (-8.8 kcal/mol), which is excellent.

**Overall Assessment:**

Despite the unusual negative values for Caco-2 and solubility, the key differentiator here is the BBB penetration. Ligand A has a significantly higher BBB percentile (77.821) compared to Ligand B (68.36). Given DRD2 is a CNS target, this is a crucial factor. Furthermore, Ligand A has a reasonable in vitro half-life, while Ligand B has an impossible negative value. Although Ligand B has better metabolic stability, the superior BBB penetration and half-life of Ligand A outweigh this benefit.

Output:
1
2025-04-17 08:45:02,894 - INFO - Reasoning:

Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (348.355 Da) is slightly lower, which could be beneficial for permeability.

**2. TPSA:** Ligand A (109.08) is higher than the ideal <90 for CNS targets, while Ligand B (58.64) is well within the range. This is a significant advantage for Ligand B.

**3. logP:** Ligand A (0.659) is a bit low, potentially hindering membrane permeability. Ligand B (1.859) is closer to the optimal 1-3 range.

**4. H-Bond Donors:** Both ligands have acceptable HBD counts (2 for A, 1 for B), well under the limit of 5.

**5. H-Bond Acceptors:** Both ligands have acceptable HBA counts (6 for A, 5 for B), under the limit of 10.

**6. QED:** Ligand B (0.804) has a significantly better QED score than Ligand A (0.444), indicating a more drug-like profile.

**7. DILI:** Both ligands have low DILI risk (A: 42.885, B: 36.681), both below the 40 threshold.

**8. BBB:** Ligand B (65.568) has a much better BBB percentile than Ligand A (37.301). This is *critical* for a CNS target like DRD2.

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.133 and -5.071), which is unusual and suggests poor permeability. However, these values are on a logarithmic scale and may not be directly comparable without knowing the units.

**10. Aqueous Solubility:** Both ligands have negative solubility values (-2.229 and -3.129), again, unusual and potentially problematic.

**11. hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.137 and 0.163).

**12. Microsomal Clearance:** Ligand A (-23.929) has a much lower (better) microsomal clearance than Ligand B (36.31). This suggests better metabolic stability for Ligand A.

**13. In vitro Half-Life:** Ligand A (-22.322) has a lower (better) in vitro half-life than Ligand B (21.1).

**14. P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.042 and 0.028).

**15. Binding Affinity:** Both ligands have similar and strong binding affinities (-8.5 kcal/mol and -8.1 kcal/mol). The difference of 0.4 kcal/mol is not substantial enough to override other significant differences.

**Overall Assessment:**

Ligand B is the stronger candidate. While Ligand A has slightly better metabolic stability and half-life, Ligand B excels in critical areas for a CNS GPCR target: TPSA, BBB penetration, and QED. The lower TPSA and significantly higher BBB percentile of Ligand B are major advantages. The slightly better logP also supports better permeability. The negative Caco-2 and solubility values are concerning for both, but the other advantages of Ligand B outweigh this concern.

Output:
1
2025-04-17 08:45:02,894 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (352.435 Da) is slightly lower than Ligand B (365.414 Da), which is acceptable.

**TPSA:** Ligand A (106.78) is better than Ligand B (62.62) as it is closer to the ideal range for CNS targets (<=90). Ligand B is quite low, which *could* indicate poor interactions.

**logP:** Both ligands have good logP values (A: 1.296, B: 2.427), falling within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A (HBD=2, HBA=6) and Ligand B (HBD=0, HBA=4) both fall within acceptable limits.

**QED:** Both ligands have good QED scores (A: 0.649, B: 0.77), indicating drug-like properties.

**DILI:** Ligand A (58.976) has a slightly higher DILI risk than Ligand B (42.924), but both are below the concerning threshold of 60.

**BBB:** Ligand B (71.229) has a better BBB penetration score than Ligand A (67.546), both are above the desirable 70% threshold for CNS targets.

**Caco-2 Permeability:** Ligand A (-5.114) has a worse Caco-2 permeability than Ligand B (-4.527), indicating potentially lower intestinal absorption.

**Aqueous Solubility:** Both ligands have negative solubility values (A: -2.152, B: -1.935), which is not ideal, but not a dealbreaker.

**hERG Inhibition:** Both ligands have very low hERG inhibition risk (A: 0.327, B: 0.167).

**Microsomal Clearance:** Ligand A (30.413) has a lower microsomal clearance than Ligand B (37.126), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand B (-9.437) has a significantly longer in vitro half-life than Ligand A (5.728).

**P-gp Efflux:** Ligand A (0.034) has a much lower P-gp efflux liability than Ligand B (0.153), suggesting better CNS exposure.

**Binding Affinity:** Ligand B (-7.8 kcal/mol) has a stronger binding affinity than Ligand A (-6.5 kcal/mol), with a difference of 1.3 kcal/mol. This is a significant advantage.

**Overall Assessment:**

Ligand B has a stronger binding affinity and better BBB penetration, and a longer half life. While Ligand A has better TPSA and lower P-gp efflux, the affinity difference and BBB score of Ligand B are more critical for a CNS target like DRD2. The slightly higher DILI risk of Ligand A is also a concern. The better metabolic stability of Ligand A is a plus, but the affinity difference is more important.

Output:
1
2025-04-17 08:45:02,894 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (383.901 and 368.503 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (75.44) is better than Ligand B (87.58). For CNS targets, we want TPSA <= 90, and A is closer to the ideal <60.

**3. logP:** Ligand A (3.367) is optimal (1-3), while Ligand B (1.679) is on the lower side, potentially impacting permeability.

**4. H-Bond Donors:** Ligand A (1) and Ligand B (2) are both acceptable (<=5).

**5. H-Bond Acceptors:** Ligand A (5) and Ligand B (7) are both acceptable (<=10).

**6. QED:** Both ligands have good QED scores (0.758 and 0.794, both >= 0.5).

**7. DILI:** Both ligands have similar, moderately high DILI risk (60.682 and 61.264). This is a concern, but not a deciding factor at this stage.

**8. BBB:** Ligand A (31.136) is significantly worse than Ligand B (57.968). For CNS targets, >70 is desirable. While neither is ideal, B is much better.

**9. Caco-2 Permeability:** Ligand A (-4.993) is worse than Ligand B (-5.02). Both are very poor, but similar.

**10. Aqueous Solubility:** Ligand A (-3.249) is worse than Ligand B (-2.5). Both are poor.

**11. hERG Inhibition:** Ligand A (0.287) is better than Ligand B (0.49), indicating lower cardiotoxicity risk.

**12. Microsomal Clearance:** Ligand A (76.395) is higher than Ligand B (32.63), meaning faster clearance and lower metabolic stability. This is a significant drawback for A.

**13. In vitro Half-Life:** Ligand A (58.569) is better than Ligand B (1.797).

**14. P-gp Efflux:** Ligand A (0.175) is better than Ligand B (0.174), indicating lower efflux and potentially better CNS exposure.

**15. Binding Affinity:** Ligand B (-7.5 kcal/mol) has a slightly better binding affinity than Ligand A (-7.3 kcal/mol). While the difference is small, it's still a factor.

**Overall Assessment:**

Ligand B is the better candidate. While its logP is a bit low, its significantly better BBB penetration (57.968 vs 31.136) and lower microsomal clearance (32.63 vs 76.395) are crucial for a CNS-targeting GPCR like DRD2. The slightly better binding affinity of B further supports this conclusion. Ligand A's higher metabolic clearance is a major concern, and its poor BBB penetration is a significant disadvantage.

Output:
1
2025-04-17 08:45:02,895 - INFO - Reasoning:

Let's analyze Ligand A and Ligand B for their potential as DRD2 drug candidates, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight (MW):** Both ligands (353.325 and 342.483 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (85.61) is slightly above the optimal <90 for CNS targets, but still reasonable. Ligand B (40.62) is excellent, well below 90.

**3. logP:** Ligand A (1.524) is within the optimal 1-3 range. Ligand B (3.123) is at the higher end of optimal, but still acceptable.

**4. H-Bond Donors (HBD):** Both ligands have acceptable HBD counts (2 and 0, respectively), well below the threshold of 5.

**5. H-Bond Acceptors (HBA):** Both ligands have acceptable HBA counts (6 and 2, respectively), below the threshold of 10.

**6. QED:** Both ligands have reasonable QED scores (0.823 and 0.74), indicating good drug-like properties.

**7. DILI:** Ligand A (53.625) has a moderate DILI risk, but is still acceptable. Ligand B (25.281) has a very low DILI risk, a significant advantage.

**8. BBB:** Ligand A (70.803) has a good BBB penetration percentile, meeting the >70 threshold for CNS targets. Ligand B (82.823) has even better BBB penetration.

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.87 and -4.781), which is unusual and suggests poor permeability. This is a concern for both.

**10. Aqueous Solubility:** Both ligands have negative solubility values (-2.656 and -3.915), indicating very poor aqueous solubility. This is a significant drawback for both.

**11. hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.254 and 0.249).

**12. Microsomal Clearance:** Ligand A (10.089) has lower microsomal clearance than Ligand B (43.245), suggesting better metabolic stability.

**13. In vitro Half-Life:** Ligand B (13.81) has a longer in vitro half-life than Ligand A (8.734), which is a positive.

**14. P-gp Efflux:** Both ligands have low P-gp efflux liability (0.163 and 0.276), which is good for CNS exposure.

**15. Binding Affinity:** Ligand A (-9.4 kcal/mol) has a slightly better binding affinity than Ligand B (-8.5 kcal/mol). This 0.9 kcal/mol difference is significant, potentially outweighing some ADME drawbacks.

**Overall Assessment:**

While both ligands have significant solubility and permeability issues, Ligand A has a superior binding affinity and better metabolic stability. However, Ligand B has a much lower DILI risk and better BBB penetration, and a longer half-life. Considering the GPCR-specific priorities, the improved BBB penetration and lower toxicity of Ligand B are more valuable than the slightly better affinity of Ligand A, especially given the similar binding energies. The solubility and permeability issues would need to be addressed through formulation or further chemical modifications for either compound.

Output:
1
2025-04-17 08:45:02,895 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (351.447 and 371.497 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (89.02) is excellent, falling well below the 90 A^2 threshold for CNS targets. Ligand B (45.23) is also very good.

**3. logP:** Ligand A (1.678) is optimal. Ligand B (3.919) is approaching the upper limit, but still acceptable.

**4. H-Bond Donors:** Ligand A (2) and Ligand B (1) are both within the acceptable limit of <=5.

**5. H-Bond Acceptors:** Ligand A (5) and Ligand B (4) are both within the acceptable limit of <=10.

**6. QED:** Both ligands have good QED scores (0.619 and 0.873), indicating drug-like properties.

**7. DILI:** Both ligands have low DILI risk (29.314 and 24.04), which is favorable.

**8. BBB:** This is a critical parameter for a CNS target like DRD2. Ligand A (41.644) is concerningly low, suggesting poor brain penetration. Ligand B (91.314) is excellent, exceeding the desirable >70 threshold.

**9. Caco-2 Permeability:** Both have negative values, which is unusual. However, the magnitude suggests Ligand A (-5.208) has worse permeability than Ligand B (-4.862).

**10. Aqueous Solubility:** Both have negative solubility values, which is also unusual. Ligand A (-1.599) is slightly better than Ligand B (-3.721).

**11. hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.088 and 0.683).

**12. Microsomal Clearance:** Ligand A (11.486) has lower clearance than Ligand B (23.744), suggesting better metabolic stability.

**13. In vitro Half-Life:** Ligand A (15.098) has a longer half-life than Ligand B (-1.619), which is desirable.

**14. P-gp Efflux:** Ligand A (0.029) has significantly lower P-gp efflux liability than Ligand B (0.449), indicating better potential for CNS exposure.

**15. Binding Affinity:** Ligand A (-7.4) has a slightly better binding affinity than Ligand B (-6.9), although both are good. The difference is 0.5 kcal/mol, which is significant.

**Overall Assessment:**

While Ligand A has slightly better affinity, metabolic stability, half-life, and P-gp efflux, its extremely poor BBB penetration (41.644) is a major drawback for a CNS target. Ligand B, despite slightly weaker affinity, exhibits excellent BBB penetration (91.314), which is paramount for DRD2 targeting. The difference in affinity (0.5 kcal/mol) is likely outweighed by the substantial difference in BBB penetration.

Output:
1
2025-04-17 08:45:02,895 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (340.471 and 362.495 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (44.39) is significantly better than Ligand B (58.64). For CNS targets, we want TPSA <= 90, and ideally lower. Ligand A is much closer to the ideal range.

**3. logP:** Both ligands have good logP values (2.763 and 2.214), falling within the optimal 1-3 range.

**4. H-Bond Donors:** Both have 1 HBD, which is acceptable.

**5. H-Bond Acceptors:** Both have 4 HBA, which is acceptable.

**6. QED:** Both ligands have high QED scores (0.929 and 0.874), indicating good drug-like properties.

**7. DILI:** Ligand A (10.857) has a much lower DILI risk than Ligand B (25.553). This is a significant advantage.

**8. BBB:** Both ligands have excellent BBB penetration (77.705 and 80.264), exceeding the desirable >70 threshold for CNS targets.

**9. Caco-2 Permeability:** Both have negative Caco-2 values (-5.181 and -5.201), which is unusual. It suggests poor permeability. However, given the focus on CNS targets, this is less critical than BBB.

**10. Aqueous Solubility:** Both have negative solubility values (-2.219 and -3.434), suggesting poor solubility. This could be a formulation challenge, but is less critical for CNS drugs that can utilize active transport mechanisms.

**11. hERG Inhibition:** Ligand A (0.944) has a slightly higher hERG risk than Ligand B (0.583), but both are relatively low.

**12. Microsomal Clearance:** Ligand A (-2.222) has a much lower (better) microsomal clearance than Ligand B (28.793), indicating greater metabolic stability.

**13. In vitro Half-Life:** Ligand A (-1.696) has a slightly better in vitro half-life than Ligand B (5.359).

**14. P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.107 and 0.157), which is excellent for CNS penetration.

**15. Binding Affinity:** Ligand B (-8.8 kcal/mol) has a significantly stronger binding affinity than Ligand A (0.0 kcal/mol). This is a substantial advantage, potentially outweighing some of the ADME drawbacks of Ligand B.

**Overall Assessment:**

While Ligand A has better ADME properties (lower DILI, better metabolic stability, slightly better half-life, lower TPSA), Ligand B's significantly superior binding affinity (-8.8 vs 0.0 kcal/mol) is a decisive factor for a GPCR target. A strong binding affinity is paramount, and can often be optimized through further medicinal chemistry efforts to improve ADME properties. The BBB penetration is excellent for both, mitigating concerns about CNS exposure.

Output:
1
2025-04-17 08:45:02,895 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (342.403 and 351.403 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (93.01) is better than Ligand B (104.64). Both are under the 90 A^2 threshold for CNS targets, but A is closer.

**3. logP:** Ligand A (1.337) is slightly better than Ligand B (0.894), both are within the optimal 1-3 range.

**4. H-Bond Donors:** Ligand A (1) is better than Ligand B (2). Lower HBD generally favors permeability.

**5. H-Bond Acceptors:** Ligand A (6) is better than Ligand B (5). Both are within the acceptable limit of 10.

**6. QED:** Ligand A (0.908) is significantly better than Ligand B (0.71), indicating a more drug-like profile.

**7. DILI:** Ligand A (60.721) is worse than Ligand B (33.307), suggesting a higher risk of liver injury. This is a significant drawback for Ligand A.

**8. BBB:** Ligand A (75.649) is better than Ligand B (63.784). Both are reasonably good, but A is closer to the desirable >70 threshold for CNS targets.

**9. Caco-2 Permeability:** Ligand A (-4.998) is slightly better than Ligand B (-4.873). Both are negative, which is unusual, but the difference is small.

**10. Aqueous Solubility:** Ligand A (-2.722) is slightly worse than Ligand B (-2.202). Both are quite poor, which could pose formulation challenges.

**11. hERG Inhibition:** Ligand A (0.361) is better than Ligand B (0.219). Both are low, indicating low cardiotoxicity risk.

**12. Microsomal Clearance:** Ligand B (-11.298) is *much* better than Ligand A (17.112). This indicates significantly improved metabolic stability for Ligand B.

**13. In vitro Half-Life:** Ligand B (-40.49) is *much* better than Ligand A (4.43). This suggests a much longer half-life for Ligand B, which is desirable.

**14. P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.023).

**15. Binding Affinity:** Ligand A (-8.7 kcal/mol) is slightly better than Ligand B (-8.2 kcal/mol). This is a meaningful difference, and could potentially outweigh some ADME issues.

**Overall Assessment:**

While Ligand A has a slightly better binding affinity and BBB penetration, Ligand B is superior in almost all ADME properties. The most critical factors for a CNS GPCR drug are BBB penetration, metabolic stability, and a reasonable safety profile. Ligand B excels in metabolic stability (Cl_mic, t1/2) and has a much lower DILI risk. The slightly weaker binding affinity of Ligand B is likely outweighed by its superior pharmacokinetic properties, especially for a CNS target where achieving sufficient brain exposure is crucial. The poor solubility of both compounds is a concern, but can often be addressed through formulation strategies.

Output:
1
2025-04-17 08:45:02,895 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (360.36 and 367.52 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (81.01) is slightly higher than Ligand B (78.51), but both are below the 90 A^2 threshold desirable for CNS targets.

**logP:** Both ligands have good logP values (1.60 and 1.17), falling within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A has 1 HBD and 5 HBA, while Ligand B has 2 HBD and 4 HBA. Both are within acceptable limits (<=5 HBD and <=10 HBA).

**QED:** Both ligands have similar QED values (0.712 and 0.715), indicating good drug-likeness.

**DILI:** Ligand A (31.49%) has a slightly higher DILI risk than Ligand B (27.61%), but both are below the concerning 40% threshold.

**BBB:** This is a crucial parameter for a CNS target like DRD2. Ligand A has a significantly higher BBB penetration percentile (94.46%) compared to Ligand B (33.39%). This is a major advantage for Ligand A.

**Caco-2 Permeability:** Ligand A (-4.676) and Ligand B (-5.242) both have negative values, suggesting poor permeability. However, the scale is not clearly defined, so it's difficult to interpret the absolute difference.

**Aqueous Solubility:** Both ligands have similar, very poor aqueous solubility (-2.39 and -2.351). This could pose formulation challenges.

**hERG Inhibition:** Ligand A (0.689) has a slightly higher hERG inhibition risk than Ligand B (0.065). This is a concern, but Ligand B is significantly better.

**Microsomal Clearance:** Ligand B (19.103) has a much higher microsomal clearance than Ligand A (-1.494), indicating faster metabolism and potentially lower *in vivo* exposure. Ligand A is significantly more metabolically stable.

**In vitro Half-Life:** Ligand A (-9.06) has a longer in vitro half-life than Ligand B (-13.326), consistent with its lower clearance.

**P-gp Efflux:** Ligand A (0.089) has lower P-gp efflux liability than Ligand B (0.017), which is favorable for CNS penetration.

**Binding Affinity:** Ligand B (-8.2 kcal/mol) has a slightly stronger binding affinity than Ligand A (-7.7 kcal/mol). This 0.5 kcal/mol difference is significant, but not overwhelming.

**Overall Assessment:**

While Ligand B has a slightly better binding affinity and lower hERG risk, Ligand A is significantly superior in terms of BBB penetration (94.46% vs 33.39%) and metabolic stability (lower Cl_mic and longer half-life).  For a CNS target, BBB penetration is paramount. The slightly weaker affinity of Ligand A can potentially be optimized in subsequent iterations, but poor BBB penetration is much harder to fix. The lower P-gp efflux of Ligand A also contributes to better CNS exposure.

Output:
0
2025-04-17 08:45:02,896 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (348.491 and 353.495 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (67.23) is slightly higher than Ligand B (62.73), but both are below the 90 A^2 threshold desirable for CNS targets.

**3. logP:** Ligand A (2.584) is optimal (1-3), while Ligand B (4.751) is pushing the upper limit and could potentially cause solubility issues or off-target interactions.

**4. H-Bond Donors:** Ligand A (1) and Ligand B (2) are both within the acceptable limit of <=5.

**5. H-Bond Acceptors:** Ligand A (4) and Ligand B (6) are both within the acceptable limit of <=10.

**6. QED:** Ligand A (0.823) has a significantly better QED score than Ligand B (0.693), indicating a more drug-like profile.

**7. DILI:** Ligand B (77.549) has a higher DILI risk than Ligand A (19.659). This is a significant concern.

**8. BBB:** Ligand A (77.898) has a slightly better BBB penetration percentile than Ligand B (73.866), both are acceptable but A is preferred.

**9. Caco-2 Permeability:** Ligand A (-4.726) has better Caco-2 permeability than Ligand B (-5.255).

**10. Aqueous Solubility:** Ligand A (-2.243) has better aqueous solubility than Ligand B (-4.742).

**11. hERG Inhibition:** Ligand A (0.221) has a lower hERG inhibition liability than Ligand B (0.633), which is a positive.

**12. Microsomal Clearance:** Ligand B (90.875) has higher microsomal clearance than Ligand A (65.25), meaning it's less metabolically stable.

**13. In vitro Half-Life:** Ligand B (59.643) has a longer in vitro half-life than Ligand A (3.845), which is generally desirable.

**14. P-gp Efflux:** Ligand A (0.084) has lower P-gp efflux liability than Ligand B (0.46), which is crucial for CNS penetration.

**15. Binding Affinity:** Ligand B (-8.8) has a slightly better binding affinity than Ligand A (-8.0), but the difference is relatively small (0.8 kcal/mol).

**Overall Assessment:**

Ligand A is the stronger candidate. While Ligand B has slightly better binding affinity and in vitro half-life, Ligand A excels in critical ADME properties. Specifically, its significantly lower DILI risk, better QED, improved solubility, lower hERG inhibition, and lower P-gp efflux are major advantages, especially for a CNS target like DRD2. The slightly better BBB and Caco-2 permeability of Ligand A further support this conclusion. The difference in binding affinity is not substantial enough to outweigh the ADME benefits of Ligand A.

Output:
0
2025-04-17 08:45:02,896 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (385.243 Da) is slightly higher than Ligand B (353.419 Da), but both are acceptable.

**TPSA:** Ligand A (64.99) is excellent for CNS penetration, well below the 90 A^2 threshold. Ligand B (110.96) is higher, but still potentially acceptable, though less ideal.

**logP:** Ligand A (3.737) is within the optimal range (1-3). Ligand B (-1.018) is significantly below this, which is a major concern for permeability and CNS penetration.

**H-Bond Donors/Acceptors:** Ligand A (1 HBD, 5 HBA) and Ligand B (2 HBD, 5 HBA) both have reasonable numbers of H-bond donors and acceptors, falling within the guidelines.

**QED:** Both ligands have acceptable QED scores (A: 0.702, B: 0.657), indicating good drug-like properties.

**DILI:** Ligand A (55.448) has a higher DILI risk than Ligand B (25.94), but both are below the concerning threshold of 60.

**BBB:** Ligand A (29.391) has a low BBB percentile, which is a significant drawback for a CNS target. Ligand B (65.956) has a much better BBB percentile, exceeding 60, and is more favorable.

**Caco-2 Permeability:** Ligand A (-4.564) shows poor Caco-2 permeability, suggesting poor absorption. Ligand B (-5.574) is also poor, but slightly worse.

**Aqueous Solubility:** Ligand A (-4.657) and Ligand B (-1.897) both show poor aqueous solubility.

**hERG Inhibition:** Ligand A (0.728) has a slightly higher hERG risk than Ligand B (0.113), but both are relatively low.

**Microsomal Clearance:** Ligand A (77.412) has a higher microsomal clearance, indicating faster metabolism. Ligand B (19.255) has significantly lower clearance, suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (37.469) has a moderate in vitro half-life. Ligand B (-4.15) has a very short half-life, which is undesirable.

**P-gp Efflux:** Ligand A (0.712) shows moderate P-gp efflux. Ligand B (0.003) shows very low P-gp efflux, which is highly desirable for CNS penetration.

**Binding Affinity:** Ligand A (-8.4 kcal/mol) has a significantly stronger binding affinity than Ligand B (-0.0 kcal/mol). This is a substantial advantage.

**Overall Assessment:**

Despite Ligand A's superior binding affinity, its poor BBB penetration, poor Caco-2 permeability, and higher metabolic clearance are major drawbacks for a CNS-targeting drug. Ligand B, while having a weaker binding affinity, exhibits much better BBB penetration, lower P-gp efflux, and better metabolic stability. The significantly better logP of Ligand A is also a major advantage. For a GPCR in the CNS, BBB penetration and metabolic stability are critical. The difference in binding affinity (-8.4 vs -0.0) is substantial, and could potentially be optimized in future iterations of Ligand B.

Output:
1
2025-04-17 08:45:02,896 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B based on the provided guidelines, prioritizing GPCR-specific properties (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (353.423 and 350.394 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (125.35) is slightly above the optimal <90 for CNS targets, while Ligand B (94.3) is within the desired range. This favors Ligand B.

**logP:** Ligand A (-0.902) is below the optimal 1-3 range, potentially hindering permeation. Ligand B (0.813) is closer to the optimal range, though still on the lower side. This favors Ligand B.

**H-Bond Donors/Acceptors:** Ligand A has 4 HBD and 6 HBA, which are acceptable. Ligand B has 3 HBD and 3 HBA, also acceptable. No clear advantage here.

**QED:** Both ligands have reasonable QED values (0.458 and 0.663), indicating decent drug-likeness. Ligand B is slightly better.

**DILI:** Both ligands have DILI risk below 50, indicating low risk. No clear advantage.

**BBB:** Ligand A (20.822%) has very poor predicted BBB penetration, a major drawback for a CNS target like DRD2. Ligand B (53.083%) has significantly better BBB penetration, although still not ideal (>70). This is a significant advantage for Ligand B.

**Caco-2 Permeability:** Both have negative values (-5.552 and -5.159), which is unusual and difficult to interpret without knowing the scale. However, the negative values suggest poor permeability.

**Aqueous Solubility:** Both have negative values (-1.219 and -2.398), also unusual and suggesting poor solubility.

**hERG Inhibition:** Both ligands show low hERG inhibition risk (0.107 and 0.265). No clear advantage.

**Microsomal Clearance:** Ligand A (12.115) has higher clearance than Ligand B (1.819), suggesting lower metabolic stability. This favors Ligand B.

**In vitro Half-Life:** Ligand A (23.39) has a longer half-life than Ligand B (-8.341). However, the negative value for Ligand B is suspect and likely an error. Assuming a positive value, the longer half-life of Ligand A would be preferable.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.01 and 0.011). No clear advantage.

**Binding Affinity:** Ligand B (-8.5 kcal/mol) has a slightly better binding affinity than Ligand A (-7.7 kcal/mol). While the difference is less than the 1.5 kcal/mol threshold, it contributes to the overall advantage of Ligand B.

**Overall Assessment:**

Considering the GPCR-specific priorities, Ligand B is significantly more promising. Its superior BBB penetration, better logP, lower microsomal clearance, and slightly better binding affinity outweigh the longer half-life of Ligand A. The TPSA value of Ligand B is also more favorable for CNS penetration. The negative values for Caco-2 and solubility are concerning for both, but the other factors strongly favor Ligand B.

Output:
1
2025-04-17 08:45:02,896 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight (MW):** Both ligands (350.478 and 362.901 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (49.41) is significantly better than Ligand B (38.5). Both are below the 90 A^2 threshold for CNS targets, but A is closer to the ideal range.

**3. logP:** Ligand A (3.285) is within the optimal 1-3 range. Ligand B (4.358) is slightly higher, potentially increasing off-target effects and decreasing solubility.

**4. H-Bond Donors (HBD):** Both ligands are acceptable (1 and 0 respectively), falling under the 5 threshold.

**5. H-Bond Acceptors (HBA):** Both ligands are acceptable (2 and 4 respectively), falling under the 10 threshold.

**6. QED:** Both ligands have similar QED values (0.799 and 0.629), indicating good drug-like properties.

**7. DILI:** Both ligands have the same DILI risk (15.2), which is low and favorable.

**8. BBB:** Ligand A (96.045) has a significantly higher BBB penetration percentile than Ligand B (85.033). This is a crucial advantage for a CNS target like DRD2.

**9. Caco-2 Permeability:** Ligand A (-4.572) and Ligand B (-4.786) both have negative Caco-2 values, which is unusual. It's difficult to interpret without knowing the scale, but it suggests poor permeability.

**10. Aqueous Solubility:** Ligand A (-3.877) and Ligand B (-4.606) both have negative solubility values, which is also unusual. It suggests poor solubility.

**11. hERG Inhibition:** Ligand A (0.604) has a lower hERG inhibition liability than Ligand B (0.946), making it safer from a cardiotoxicity perspective.

**12. Microsomal Clearance:** Ligand B (87.092) has a higher microsomal clearance than Ligand A (43.834), indicating faster metabolism and potentially lower exposure.

**13. In vitro Half-Life:** Ligand B (59.945) has a much longer in vitro half-life than Ligand A (-2.493). This is a significant advantage.

**14. P-gp Efflux:** Ligand A (0.105) has lower P-gp efflux liability than Ligand B (0.683), which is favorable for CNS penetration.

**15. Binding Affinity:** Ligand A (-8.7 kcal/mol) has a stronger binding affinity than Ligand B (-7.2 kcal/mol). The difference of 1.5 kcal/mol is substantial and can outweigh some ADME drawbacks.

**Overall Assessment:**

Ligand A is the more promising candidate. While both have issues with Caco-2 and solubility, Ligand A excels in key areas for a CNS GPCR target: significantly better BBB penetration, lower P-gp efflux, stronger binding affinity, and lower hERG risk. The longer half-life of Ligand B is attractive, but the superior CNS penetration and binding of Ligand A are more critical for DRD2.

Output:
1
2025-04-17 08:45:02,897 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (347.375 and 362.499 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (133.14) is slightly above the optimal <90 for CNS targets, but still reasonable. Ligand B (72.21) is excellent, well below 90.

**logP:** Ligand A (0.32) is quite low, potentially hindering permeability. Ligand B (3.731) is near the upper end of the optimal 1-3 range, but acceptable.

**H-Bond Donors/Acceptors:** Ligand A has 4 HBD and 6 HBA, which are acceptable. Ligand B has 2 HBD and 7 HBA, also acceptable.

**QED:** Both ligands have reasonable QED scores (0.615 and 0.493), suggesting drug-like properties.

**DILI:** Both ligands have similar DILI risk (69.019 and 68.437), indicating moderate risk.

**BBB:** This is a critical parameter for a CNS target like DRD2. Ligand A has a BBB percentile of 21.714, which is quite low and a significant drawback. Ligand B has a much higher BBB percentile of 82.823, which is very desirable.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.53 and -5.481), which is unusual and suggests poor permeability. However, these values are on a log scale and can be misleading.

**Aqueous Solubility:** Both ligands have very poor aqueous solubility (-2.227 and -3.993). This is a concern for formulation and bioavailability.

**hERG Inhibition:** Ligand A (0.132) shows very low hERG inhibition risk, which is excellent. Ligand B (0.886) has a higher, but still relatively low, hERG risk.

**Microsomal Clearance:** Ligand A has a negative Cl_mic (-4.033), which is not physically meaningful and likely indicates very high metabolic stability. Ligand B has a high Cl_mic (103.044), suggesting rapid metabolism.

**In vitro Half-Life:** Ligand A has a very short in vitro half-life (-26.525), while Ligand B has a longer half-life (119.981).

**P-gp Efflux:** Ligand A (0.046) shows very low P-gp efflux, which is favorable for CNS penetration. Ligand B (0.582) has moderate P-gp efflux.

**Binding Affinity:** Both ligands have strong binding affinities (-7.9 and -7.5 kcal/mol), with Ligand A being slightly better. However, the 1.5 kcal/mol difference is not enough to overcome the significant ADME deficiencies of Ligand A.

**Conclusion:**

Despite the slightly better binding affinity of Ligand A, Ligand B is the more promising drug candidate. Its significantly better BBB penetration, longer half-life, and acceptable logP outweigh the slightly lower affinity and higher P-gp efflux. Ligand A's extremely low BBB penetration and poor solubility are major liabilities.

Output:
1
2025-04-17 08:45:02,897 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (350.478 and 345.403 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (40.62) is excellent, well below the 90 A^2 threshold for CNS targets. Ligand B (93.26) is higher, exceeding the preferred range for CNS penetration, though not drastically.

**logP:** Ligand A (3.344) is optimal (1-3). Ligand B (1.526) is on the lower side, potentially hindering permeability.

**H-Bond Donors/Acceptors:** Ligand A (0 HBD, 2 HBA) is favorable. Ligand B (1 HBD, 6 HBA) is also acceptable, though slightly higher in HBA count.

**QED:** Both ligands have good QED scores (0.689 and 0.907), indicating drug-like properties.

**DILI:** Ligand A (19.271) has a much lower DILI risk than Ligand B (38.697), which is a significant advantage.

**BBB:** Both ligands have high BBB penetration (86.972% and 84.102%), which is crucial for a CNS target like DRD2. The difference is minimal.

**Caco-2 Permeability:** Ligand A (-4.422) has poor Caco-2 permeability, while Ligand B (-5.018) is also poor. This is a concern for oral bioavailability.

**Aqueous Solubility:** Both ligands have poor aqueous solubility (-3.548 and -2.635). This could pose formulation challenges.

**hERG Inhibition:** Both ligands show low hERG inhibition liability (0.587 and 0.2), which is good.

**Microsomal Clearance:** Ligand A (54.813) has higher microsomal clearance than Ligand B (12.295), suggesting lower metabolic stability. Ligand B is significantly better here.

**In vitro Half-Life:** Ligand B (-0.023) has a very short half-life, which is a major drawback. Ligand A (5.531) has a more reasonable half-life.

**P-gp Efflux:** Both ligands have low P-gp efflux (0.154 and 0.088), which is favorable for CNS exposure.

**Binding Affinity:** Ligand B (-9.0 kcal/mol) has a significantly stronger binding affinity than Ligand A (-7.8 kcal/mol). This is a substantial advantage (1.2 kcal/mol difference).

**Overall Assessment:**

Ligand B has a superior binding affinity and better metabolic stability (lower Cl_mic). However, it has a very short in vitro half-life and lower logP. Ligand A has a better DILI score, a more reasonable half-life, and a better TPSA. The difference in binding affinity is substantial, and for a GPCR, this can often outweigh other ADME concerns, *especially* if the compound can achieve sufficient brain exposure (which both appear to do). The poor Caco-2 and solubility are concerns for both, but can be addressed with formulation strategies. Given the importance of affinity for GPCRs, and the acceptable BBB penetration for both, Ligand B is the more promising candidate.

Output:
1
2025-04-17 08:45:02,897 - INFO - Batch 475 complete. Total preferences: 7600
2025-04-17 08:45:02,897 - INFO - Processing batch 476/512...
2025-04-17 08:45:43,328 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (343.435 and 358.507 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (80.99) is excellent, well below the 90 A^2 threshold for CNS targets. Ligand B (42.43) is also very good.

**3. logP:** Ligand A (1.71) is within the optimal 1-3 range. Ligand B (3.85) is slightly higher, but still acceptable.

**4. H-Bond Donors:** Ligand A (1) is good. Ligand B (0) is also good.

**5. H-Bond Acceptors:** Ligand A (8) is acceptable. Ligand B (5) is also acceptable.

**6. QED:** Ligand A (0.828) is excellent, indicating high drug-likeness. Ligand B (0.671) is still reasonably good.

**7. DILI:** Ligand A (65.064) has a moderate DILI risk, but is acceptable. Ligand B (37.263) has a lower DILI risk, which is preferable.

**8. BBB:** Ligand A (75.107) has good BBB penetration, exceeding the 70% threshold. Ligand B (68.709) is close but slightly below the desirable threshold.

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.033 and -4.892), which is unusual and suggests poor permeability. This is a significant concern for both.

**10. Aqueous Solubility:** Both ligands have negative solubility scores (-2.595 and -4.654), indicating very poor aqueous solubility. This is a major drawback.

**11. hERG Inhibition:** Ligand A (0.4) has a very low hERG risk, which is excellent. Ligand B (0.901) has a slightly higher, but still acceptable, risk.

**12. Microsomal Clearance:** Ligand A (57.966) has moderate clearance. Ligand B (146.69) has high clearance, suggesting poor metabolic stability.

**13. In vitro Half-Life:** Ligand A (9.296) has a reasonable half-life. Ligand B (12.806) has a slightly longer half-life, which is preferable.

**14. P-gp Efflux:** Ligand A (0.019) has very low P-gp efflux, which is excellent for CNS penetration. Ligand B (0.404) has moderate P-gp efflux.

**15. Binding Affinity:** Ligand B (-7.7 kcal/mol) has significantly stronger binding affinity than Ligand A (-0.0 kcal/mol). This is a crucial advantage.

**Overall Assessment:**

Despite both ligands having issues with Caco-2 permeability and aqueous solubility, the significantly stronger binding affinity of Ligand B (-7.7 kcal/mol vs -0.0 kcal/mol) is a decisive factor. The improved half-life of Ligand B is also beneficial. While Ligand A has better BBB penetration and P-gp efflux, the affinity difference is substantial enough to outweigh these advantages, especially for a GPCR target where high affinity is critical. The DILI risk is also lower for Ligand B. The poor solubility and permeability would need to be addressed through formulation strategies, but the potency advantage of Ligand B makes it the more promising candidate.

Output:
1
2025-04-17 08:45:43,328 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, considering the provided guidelines and GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (351.447 and 364.511 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (89.95) is excellent, falling below the 90 A^2 threshold for CNS targets. Ligand B (58.64) is also very good.

**logP:** Ligand A (0.123) is quite low, potentially hindering permeability. Ligand B (1.665) is within the optimal 1-3 range. This is a significant advantage for Ligand B.

**H-Bond Donors:** Ligand A (2) and Ligand B (1) are both acceptable, below the 5 threshold.

**H-Bond Acceptors:** Both ligands (A: 4, B: 4) are below the 10 threshold.

**QED:** Ligand A (0.711) has a better QED score than Ligand B (0.575), indicating a more drug-like profile.

**DILI:** Ligand A (8.026) has a much lower DILI risk than Ligand B (23.187). This is a substantial advantage for Ligand A.

**BBB:** Ligand A (46.491) has a lower BBB penetration percentile than Ligand B (55.642). While both are not ideal (>70), Ligand B is better.

**Caco-2 Permeability:** Ligand A (-5.094) has poor Caco-2 permeability. Ligand B (-4.944) is also poor, but slightly better.

**Aqueous Solubility:** Both ligands have very poor aqueous solubility (-1.171 and -3.351 respectively).

**hERG:** Both ligands have very low hERG inhibition risk (0.144 and 0.251).

**Microsomal Clearance:** Ligand A (-17.845) has significantly lower microsomal clearance (better metabolic stability) than Ligand B (35.669).

**In vitro Half-Life:** Ligand A (5.984) has a slightly better in vitro half-life than Ligand B (-4.825).

**P-gp Efflux:** Ligand A (0.007) has extremely low P-gp efflux, which is excellent for CNS penetration. Ligand B (0.086) is also low, but higher than A.

**Binding Affinity:** Ligand B (-8.0) has a slightly better binding affinity than Ligand A (-7.5). However, the difference is only 0.5 kcal/mol, which may not be enough to overcome other deficiencies.

**Overall Assessment:**

Ligand A has advantages in DILI, metabolic stability (Cl_mic), P-gp efflux, and QED. However, its low logP and poor Caco-2 permeability are major concerns, especially for a CNS target. Ligand B has a better logP and BBB penetration, and slightly better binding affinity, but suffers from higher DILI risk and worse metabolic stability.

Given the GPCR-specific priorities, BBB penetration and logP are crucial. While Ligand A's P-gp efflux is excellent, its low logP severely limits its ability to cross membranes. Ligand B's logP is within the optimal range, and its BBB is better, making it more likely to reach the target in the CNS. The 0.5 kcal/mol difference in binding affinity is not enough to outweigh the significant ADME advantages of Ligand B.

Output:
1
2025-04-17 08:45:43,329 - INFO - Reasoning:

Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (346.39 and 354.40 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (113.44) is slightly above the optimal <90 for CNS targets, while Ligand B (85.38) is well within the desired range. This favors Ligand B.

**3. logP:** Both ligands (-0.222 and -0.17) are a bit low, potentially hindering membrane permeability. However, they are not drastically outside the 1-3 range.

**4. H-Bond Donors:** Ligand A has 3 HBD, acceptable. Ligand B has 0, also acceptable.

**5. H-Bond Acceptors:** Both ligands have 6 HBA, within the acceptable limit of 10.

**6. QED:** Both ligands have similar QED values (0.421 and 0.422), indicating moderate drug-likeness.

**7. DILI:** Ligand A (45.25) has a slightly higher DILI risk than Ligand B (32.22), but both are below the concerning threshold of 60.

**8. BBB:** This is a critical parameter for CNS targets. Ligand B (61.61) has a significantly better BBB percentile than Ligand A (34.74). This is a major advantage for Ligand B.

**9. Caco-2 Permeability:** Both have negative values, indicating poor permeability. This is a concern for both.

**10. Aqueous Solubility:** Both have negative values, indicating poor solubility. This is a concern for both.

**11. hERG Inhibition:** Both ligands show very low hERG inhibition risk (0.049 and 0.077), which is excellent.

**12. Microsomal Clearance:** Ligand A (-2.964) has a lower (better) microsomal clearance than Ligand B (24.977), suggesting better metabolic stability.

**13. In vitro Half-Life:** Ligand A (-19.626) has a longer half-life than Ligand B (-3.099), which is desirable.

**14. P-gp Efflux:** Both ligands show very low P-gp efflux liability (0.006 and 0.014), which is favorable for CNS penetration.

**15. Binding Affinity:** Ligand A (-7.4 kcal/mol) has a slightly better binding affinity than Ligand B (-6.7 kcal/mol). This 0.7 kcal/mol difference is significant, but needs to be weighed against the ADME properties.

**Overall Assessment:**

While Ligand A has better binding affinity and metabolic stability (lower Cl_mic, longer t1/2), Ligand B excels in crucial GPCR-specific properties for CNS targets: significantly better BBB penetration (61.61 vs 34.74) and a lower TPSA (85.38 vs 113.44). The improved BBB is a strong advantage, outweighing the slightly weaker binding affinity. Both compounds have permeability and solubility issues, but the CNS target demands prioritize brain exposure.

Output:
1
2025-04-17 08:45:43,329 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (351.447 and 367.383 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (85.61) is significantly better than Ligand B (134.67). For CNS targets, TPSA should be <= 90, which A meets comfortably, while B is pushing the limit and less favorable.

**logP:** Both ligands have acceptable logP values (1.324 and 0.921, respectively), falling within the 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A has 2 HBD and 6 HBA, while Ligand B has 3 HBD and 7 HBA. Both are within acceptable limits (<=5 HBD and <=10 HBA).

**QED:** Ligand A (0.807) has a substantially higher QED score than Ligand B (0.646), indicating better overall drug-likeness.

**DILI:** Ligand A (33.346) has a much lower DILI risk than Ligand B (81.427). This is a significant advantage for A.

**BBB:** Ligand A (20.318) has a very low BBB penetration percentile, while Ligand B (37.418) is also low, but better than A. Both are far from the desirable >70 for CNS targets. This is a major drawback for both, but less so for B.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.232 and -5.343), which is unusual and suggests poor permeability.

**Aqueous Solubility:** Both ligands have negative solubility values (-0.768 and -3.142), indicating poor aqueous solubility.

**hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.309 and 0.083).

**Microsomal Clearance:** Ligand A (4.485) has a lower microsomal clearance than Ligand B (18.17), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (27.188) has a longer in vitro half-life than Ligand B (6.51).

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.097 and 0.071).

**Binding Affinity:** Both ligands have excellent binding affinities (-8.4 and -8.6 kcal/mol). The difference is minimal.

**Overall Assessment:**

Considering the GPCR-specific priorities, Ligand A is the better candidate. While both have poor BBB penetration and solubility, Ligand A excels in several key areas: significantly lower DILI risk, better TPSA, higher QED, lower microsomal clearance, and longer half-life. The slight advantage in binding affinity for Ligand B is outweighed by the superior ADME properties of Ligand A. The poor Caco-2 and solubility are concerning for both, but can be addressed with formulation strategies.

Output:
0
2025-04-17 08:45:43,329 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 drug candidates, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (365.5 & 376.5 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (71.53) is slightly higher than Ligand B (66.48), but both are below the 90 A^2 threshold desirable for CNS targets.

**3. logP:** Both ligands have good logP values (2.235 & 2.72), falling within the optimal 1-3 range. Ligand B is slightly higher, potentially increasing permeability but also raising concerns about off-target effects.

**4. H-Bond Donors:** Both have 1 HBD, which is within the acceptable limit of <=5.

**5. H-Bond Acceptors:** Ligand A has 5 HBA, and Ligand B has 3 HBA, both within the acceptable limit of <=10.

**6. QED:** Ligand A (0.839) has a better QED score than Ligand B (0.708), indicating a more drug-like profile.

**7. DILI:** Ligand A (22.761) has a significantly lower DILI risk than Ligand B (29.779), which is a major advantage.

**8. BBB:** Ligand B (91.508) has a substantially higher BBB penetration percentile than Ligand A (82.28). This is *critical* for a CNS target like DRD2.

**9. Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and suggests poor permeability. However, the scale is not defined, so it's hard to interpret.

**10. Aqueous Solubility:** Both have negative solubility values, suggesting poor solubility. Again, the scale is undefined, making interpretation difficult.

**11. hERG:** Both ligands have low hERG inhibition liability (0.528 & 0.77), which is good.

**12. Microsomal Clearance:** Ligand A (17.821) has a much lower microsomal clearance than Ligand B (51.052), indicating better metabolic stability.

**13. In vitro Half-Life:** Ligand A (8.174) has a positive half-life, while Ligand B (-48.63) has a negative half-life. This is a significant advantage for Ligand A.

**14. P-gp Efflux:** Both have low P-gp efflux liability (0.101 & 0.214), which is favorable for CNS penetration.

**15. Binding Affinity:** Ligand B (-7.8 kcal/mol) has a slightly better binding affinity than Ligand A (-7.1 kcal/mol). This is a 0.7 kcal/mol difference, which is a good advantage, but not overwhelming.

**Overall Assessment:**

Ligand B's superior BBB penetration and binding affinity are strong positives. However, Ligand A demonstrates a much better safety profile (lower DILI), better metabolic stability (lower Cl_mic, positive t1/2), and a better QED score. The difference in affinity (0.7 kcal/mol) is not large enough to outweigh the significant ADME/Tox advantages of Ligand A. Given the importance of metabolic stability and safety for CNS drugs, and the relatively small difference in binding affinity, Ligand A is the more promising candidate.

Output:
0
2025-04-17 08:45:43,329 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (343.358 Da and 352.519 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (76.24) is better than Ligand B (78.43), both are below the 90 A^2 threshold for CNS targets, which is good.

**3. logP:** Both ligands have good logP values (2.544 and 2.765, respectively), falling within the optimal 1-3 range.

**4. H-Bond Donors:** Ligand A (2) is preferable to Ligand B (3). Lower HBD generally improves permeability.

**5. H-Bond Acceptors:** Ligand A (4) is preferable to Ligand B (3). Lower HBA generally improves permeability.

**6. QED:** Ligand A (0.691) has a slightly better QED score than Ligand B (0.597), indicating a more drug-like profile.

**7. DILI:** Ligand A (76.192) has a significantly higher DILI risk than Ligand B (14.734). This is a major concern for Ligand A.

**8. BBB:** Ligand B (60.527) has a better BBB penetration percentile than Ligand A (53.974), though both are below the desirable >70 for CNS targets.

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.777 and -4.737), which is unusual and suggests poor permeability. This is a significant drawback for both.

**10. Aqueous Solubility:** Both ligands have negative solubility values (-3.983 and -3.773), indicating very poor aqueous solubility. This is a major formulation challenge for both.

**11. hERG Inhibition:** Ligand A (0.834) has a slightly higher hERG inhibition risk than Ligand B (0.293), but both are relatively low.

**12. Microsomal Clearance:** Ligand B (70.447) has a higher microsomal clearance than Ligand A (43.452), suggesting lower metabolic stability.

**13. In vitro Half-Life:** Ligand A (-10.421) has a much longer in vitro half-life than Ligand B (5.173).

**14. P-gp Efflux:** Ligand A (0.414) has a lower P-gp efflux liability than Ligand B (0.152), which is favorable for CNS penetration.

**15. Binding Affinity:** Ligand A (-8.9 kcal/mol) has a significantly stronger binding affinity than Ligand B (-7.3 kcal/mol). This is a substantial advantage.

**Overall Assessment:**

Despite the poor Caco-2 and solubility profiles for both, Ligand A is the more promising candidate. Its significantly higher binding affinity (-8.9 vs -7.3 kcal/mol) is a major advantage, and could potentially overcome some of the ADME liabilities. While Ligand A has a higher DILI risk, the lower P-gp efflux and longer half-life are beneficial. Ligand B's lower DILI is attractive, but the weaker binding affinity is a significant drawback, especially for a GPCR target where potency is crucial.

Output:
0
2025-04-17 08:45:43,330 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight (MW):** Both ligands (342.483 and 350.547 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (40.62) is better than Ligand B (49.41). Both are below the 90 A^2 threshold for CNS targets, but A is closer to the optimal range.

**3. logP:** Both ligands have good logP values (2.984 and 3.706), falling within the 1-3 range. Ligand B is slightly higher, which could potentially lead to off-target effects, but is still acceptable.

**4. H-Bond Donors (HBD):** Both ligands have a low number of HBDs (0 and 1 respectively), which is favorable for permeability.

**5. H-Bond Acceptors (HBA):** Both ligands have a similar number of HBAs (2), which is within the acceptable limit of 10.

**6. QED:** Both ligands have similar and good QED values (0.721 and 0.725), indicating good drug-like properties.

**7. DILI:** Ligand A (27.065) has a slightly higher DILI risk than Ligand B (12.718), but both are below the concerning threshold of 40.

**8. BBB:** Ligand B (83.443) has a significantly better BBB penetration percentile than Ligand A (70.997). This is a crucial advantage for a CNS target like DRD2.

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 values, which is unusual and potentially problematic. However, the values are similar (-4.533 and -4.483).

**10. Aqueous Solubility:** Both ligands have negative solubility values, which is also unusual. Again, the values are similar (-3.536 and -3.909).

**11. hERG Inhibition:** Both ligands have low hERG inhibition risk (0.527 and 0.645).

**12. Microsomal Clearance (Cl_mic):** Ligand B (95.517) has a higher microsomal clearance than Ligand A (42.862), indicating faster metabolism and potentially lower exposure.

**13. In vitro Half-Life (t1/2):** Ligand A (13.108) has a longer half-life than Ligand B (-2.999). This is a significant advantage.

**14. P-gp Efflux:** Both ligands have low P-gp efflux liability (0.34 and 0.216).

**15. Binding Affinity:** Ligand B (-7.8 kcal/mol) has a slightly better binding affinity than Ligand A (-7.0 kcal/mol). While the difference is not huge, it's enough to be considered.

**Overall Assessment:**

Ligand B is the more promising candidate. The significantly better BBB penetration (83.443 vs 70.997) is a major advantage for a CNS target. The slightly improved binding affinity (-7.8 vs -7.0) also contributes. While Ligand B has a higher Cl_mic, the longer half-life of Ligand A is offset by the superior BBB penetration of Ligand B. The similar, and somewhat concerning, Caco-2 and solubility values would need further investigation for both compounds.

Output:
1
2025-04-17 08:45:43,330 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (345.403 and 345.399 Da) fall comfortably within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (89.35) is slightly higher than Ligand B (86.88), but both are below the 90 A^2 threshold desirable for CNS targets.

**3. logP:** Ligand A (-0.166) is significantly lower than the optimal 1-3 range, potentially hindering permeability. Ligand B (2.231) is within the optimal range. This is a significant advantage for Ligand B.

**4. H-Bond Donors:** Both ligands have 1 HBD, which is acceptable.

**5. H-Bond Acceptors:** Ligand A has 6 HBA, and Ligand B has 5. Both are within the acceptable limit of 10.

**6. QED:** Both ligands have good QED scores (0.749 and 0.867), indicating good drug-like properties.

**7. DILI:** Ligand A (57.658) has a higher DILI risk than Ligand B (36.487).  Ligand B is preferred.

**8. BBB:** Ligand A (57.774) has a lower BBB penetration percentile than Ligand B (41.218). While neither is *high* (>70), Ligand B is better. This is a crucial factor for a CNS target like DRD2.

**9. Caco-2 Permeability:** Both have negative values (-5.081 and -4.981) which is unusual and difficult to interpret without knowing the scale. However, the values are very similar.

**10. Aqueous Solubility:** Both have negative values (-1.243 and -2.25) which is also unusual and difficult to interpret without knowing the scale. Ligand B is slightly worse.

**11. hERG Inhibition:** Ligand A (0.059) has a slightly lower hERG inhibition risk than Ligand B (0.416), which is preferable.

**12. Microsomal Clearance:** Ligand A (15.293) has a lower microsomal clearance than Ligand B (56.313), indicating better metabolic stability. This is a significant advantage for Ligand A.

**13. In vitro Half-Life:** Ligand A (16.965) has a shorter half-life than Ligand B (-9.407). The negative value for Ligand B is concerning and likely an error.

**14. P-gp Efflux:** Ligand A (0.044) has a lower P-gp efflux liability than Ligand B (0.074), which is beneficial for CNS penetration.

**15. Binding Affinity:** Both ligands have excellent binding affinities (-9.4 and -8.4 kcal/mol). Ligand A is slightly better (-9.4 kcal/mol), but the difference is less than the 1.5 kcal/mol threshold.

**Overall Assessment:**

Ligand B has a much more favorable logP, which is critical for permeability and CNS penetration. It also has a lower DILI risk and better BBB penetration. While Ligand A has better metabolic stability and slightly better affinity, the poor logP and higher DILI risk are significant drawbacks. The negative half-life for Ligand B is a red flag.

Output:
1
2025-04-17 08:45:43,330 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (352.45 and 350.375 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (69.64) is excellent, well below the 90 A^2 threshold for CNS targets. Ligand B (120.33) is higher, but still potentially acceptable, though less ideal.

**logP:** Ligand A (3.925) is optimal. Ligand B (-1.63) is significantly lower, potentially hindering membrane permeability and CNS penetration.

**H-Bond Donors/Acceptors:** Ligand A (2 HBD, 3 HBA) and Ligand B (3 HBD, 6 HBA) both fall within acceptable ranges.

**QED:** Ligand A (0.627) is good, indicating a drug-like profile. Ligand B (0.476) is lower, suggesting a less favorable drug-like profile.

**DILI:** Ligand A (31.291) has a very low DILI risk. Ligand B (61.574) is higher, indicating a moderate risk.

**BBB:** Ligand A (72.78) has a good BBB penetration percentile, exceeding the 70% threshold for CNS targets. Ligand B (19.038) is very poor for CNS penetration.

**Caco-2 Permeability:** Ligand A (-4.747) is concerningly low. Ligand B (-5.21) is also low, but slightly worse.

**Aqueous Solubility:** Ligand A (-3.855) and Ligand B (-1.508) both have poor aqueous solubility.

**hERG:** Ligand A (0.857) has a low hERG risk. Ligand B (0.16) also has a low hERG risk.

**Microsomal Clearance:** Ligand A (92.211) has high microsomal clearance, suggesting rapid metabolism. Ligand B (-13.716) has negative clearance, which is not physically possible and likely an error in the data, but suggests very high metabolic stability.

**In vitro Half-Life:** Ligand A (4.416) has a relatively short half-life. Ligand B (1.922) has a very short half-life.

**P-gp Efflux:** Ligand A (0.514) has moderate P-gp efflux. Ligand B (0.007) has very low P-gp efflux, which is favorable for CNS penetration.

**Binding Affinity:** Ligand A (-8.2 kcal/mol) has significantly stronger binding affinity than Ligand B (-7.3 kcal/mol). The difference of 0.9 kcal/mol is substantial.

**Overall Assessment:**

Ligand A excels in key areas for a CNS-targeting GPCR ligand: TPSA, logP, BBB, and, crucially, binding affinity. However, its Caco-2 permeability is very poor and its metabolic clearance is high. Ligand B has a better P-gp efflux profile and potentially better metabolic stability (though the negative clearance is suspect), but suffers from a very poor logP and BBB penetration, and a significantly weaker binding affinity.

Given the importance of CNS penetration for a DRD2 ligand (involved in CNS disorders), and the substantial difference in binding affinity, Ligand A is the more promising candidate despite its drawbacks. The strong affinity could potentially compensate for the permeability and metabolic stability issues, and these could be addressed through further optimization.

Output:
1
2025-04-17 08:45:43,330 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (339.483 and 344.499 Da) fall comfortably within the ideal 200-500 Da range.

**2. TPSA:** Both ligands have a TPSA of approximately 58.3-58.2 A^2, well below the 90 A^2 threshold for CNS targets, which is excellent.

**3. logP:** Both ligands have a logP around 3.5, which is within the optimal 1-3 range.

**4. H-Bond Donors:** Both have 2 HBD, well within the acceptable limit of 5.

**5. H-Bond Acceptors:** Both have 2 HBA, well within the acceptable limit of 10.

**6. QED:** Ligand A (0.81) has a slightly better QED than Ligand B (0.75), indicating a more drug-like profile.

**7. DILI:** Both ligands have low DILI risk (29.042 and 26.871 percentile), which is favorable.

**8. BBB:** Ligand A (76.309%) has a significantly better BBB penetration prediction than Ligand B (64.25%). This is a crucial advantage for a CNS target like DRD2.

**9. Caco-2 Permeability:** Both have negative Caco-2 values (-4.777 and -4.785). While unusual, these values suggest poor permeability. However, given the GPCR target and emphasis on CNS penetration, this is less critical than BBB.

**10. Aqueous Solubility:** Both have negative solubility values (-3.328 and -4.204). This is a concern, but can be addressed with formulation strategies.

**11. hERG Inhibition:** Both ligands show very low hERG inhibition liability (0.931 and 0.126), which is excellent.

**12. Microsomal Clearance:** Ligand B (49.391) has a slightly lower microsomal clearance than Ligand A (53.93), suggesting better metabolic stability.

**13. In vitro Half-Life:** Ligand A (37.76 hours) has a much longer in vitro half-life than Ligand B (7.668 hours). This is a significant advantage, potentially allowing for less frequent dosing.

**14. P-gp Efflux:** Both ligands exhibit low P-gp efflux liability (0.341 and 0.153), which is favorable for CNS exposure.

**15. Binding Affinity:** Both ligands have excellent binding affinity (-9.5 and -9.0 kcal/mol). The difference of 0.5 kcal/mol is not substantial enough to outweigh other factors.

**Overall Assessment:**

Ligand A is the better candidate. While Ligand B has slightly better metabolic stability, Ligand A's superior BBB penetration (76.3% vs 64.25%), longer half-life (37.76 vs 7.668 hours), and slightly better QED outweigh the minor difference in clearance. For a CNS GPCR target, BBB penetration is paramount, and Ligand A clearly excels in this area. The negative Caco-2 and solubility values are concerns for both, but are less critical given the CNS focus and can potentially be addressed through formulation.

Output:
1
2025-04-17 08:45:43,331 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (351.451 Da) is slightly better, being closer to the lower end which can aid permeability.

**TPSA:** Ligand A (80.56) is excellent, well below the 90 A^2 threshold for CNS targets. Ligand B (121.6) is higher, but still acceptable, though less favorable for CNS penetration.

**logP:** Ligand A (2.087) is optimal. Ligand B (0.453) is a bit low, potentially hindering membrane permeability.

**H-Bond Donors/Acceptors:** Ligand A (0 HBD, 6 HBA) is very good. Ligand B (3 HBD, 5 HBA) is also acceptable, but the higher number of HBDs could slightly impact permeability.

**QED:** Both ligands have reasonable QED values (A: 0.833, B: 0.695), indicating good drug-like properties.

**DILI:** Both ligands have the same DILI risk (49.632%), which is good (below 60).

**BBB:** Both ligands have similar BBB penetration (A: 65.064%, B: 65.452%), which is acceptable but not outstanding. A higher value is preferred for CNS targets.

**Caco-2 Permeability:** Ligand A (-4.354) has poor Caco-2 permeability, while Ligand B (-5.618) is even worse. Both are problematic.

**Aqueous Solubility:** Ligand A (-1.636) has slightly better solubility than Ligand B (-2.182), but both are quite poor.

**hERG Inhibition:** Both ligands have very low hERG inhibition risk (A: 0.076, B: 0.122).

**Microsomal Clearance:** Ligand A (50.229) has moderate clearance, while Ligand B (-26.99) has negative clearance, which is not possible and likely an error in the data. This is a significant red flag for Ligand B.

**In vitro Half-Life:** Ligand A (-9.624) has negative half-life, which is not possible and likely an error in the data. Ligand B (17.387) has a reasonable half-life.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (A: 0.041, B: 0.025).

**Binding Affinity:** Ligand B (-7.8 kcal/mol) has significantly better binding affinity than Ligand A (0.0 kcal/mol). This is a substantial advantage.

**Overall Assessment:**

Despite Ligand B's superior binding affinity, the negative clearance and half-life values are highly suspect and indicate a data error. The poor Caco-2 permeability of both ligands is a concern. Ligand A has better physicochemical properties (logP, TPSA, HBD/HBA) and, while its affinity is poor, its other parameters are more realistic. Ligand B's affinity is excellent, but the data issues raise serious doubts about its viability.

Output:
0
2025-04-17 08:45:43,331 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (348.443 and 339.439 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (81.86) is slightly higher than Ligand B (62.3). For CNS targets, we ideally want TPSA <= 90, so both are acceptable, but Ligand B is preferable.

**logP:** Both ligands have a logP around 2.45-2.47, which is optimal (1-3).

**H-Bond Donors/Acceptors:** Both have 1 HBD, which is good. Ligand A has 5 HBA, while Ligand B has 3. Both are within the acceptable limit of <=10, but Ligand B's lower HBA count is slightly better for permeability.

**QED:** Both ligands have high QED scores (0.845 and 0.857), indicating good drug-like properties.

**DILI:** Ligand A (48.546) has a higher DILI risk than Ligand B (23.885). This is a significant advantage for Ligand B.

**BBB:** Both ligands have excellent BBB penetration (77.821 and 79.062), exceeding the desirable >70 threshold for CNS targets.

**Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and suggests a potential issue with the data or modeling. However, the values are similar (-4.525 and -4.905).

**Aqueous Solubility:** Both have negative solubility values, which is also unusual and suggests a potential issue with the data or modeling. The values are similar (-3.014 and -2.486).

**hERG Inhibition:** Both ligands show low hERG inhibition risk (0.68 and 0.316). Ligand B is slightly better here.

**Microsomal Clearance:** Ligand A (81.582) has significantly higher microsomal clearance than Ligand B (26.819). This means Ligand B is more metabolically stable.

**In vitro Half-Life:** Ligand B (-12.726) has a much longer in vitro half-life than Ligand A (-4.865). This is a substantial advantage for Ligand B.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.195 and 0.103), which is excellent for CNS exposure. Ligand B is slightly better.

**Binding Affinity:** Ligand B (-9.6 kcal/mol) has a significantly stronger binding affinity than Ligand A (-7.0 kcal/mol). This >1.5 kcal/mol difference is a major advantage, potentially outweighing minor ADME drawbacks.

**Overall Assessment:**

Ligand B consistently outperforms Ligand A in several crucial parameters for a CNS-targeting GPCR ligand. It has a lower DILI risk, better metabolic stability (lower Cl_mic, longer t1/2), slightly better hERG and Pgp profiles, and, most importantly, a significantly stronger binding affinity. While both have acceptable BBB penetration and logP values, the combined advantages of Ligand B make it the more promising drug candidate.

Output:
1
2025-04-17 08:45:43,331 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 drug candidates, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (350.375 and 365.455 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (137.48) is slightly above the preferred <90 for CNS targets, but still reasonable. Ligand B (97.39) is excellent, well within the desired range.

**3. logP:** Both ligands (0.663 and 0.775) are a bit low. While not drastically outside the 1-3 range, they could potentially hinder membrane permeability.

**4. H-Bond Donors:** Ligand A (3) is acceptable. Ligand B (2) is also good.

**5. H-Bond Acceptors:** Ligand A (7) is acceptable. Ligand B (5) is also good.

**6. QED:** Both ligands have reasonable QED scores (0.462 and 0.664), with Ligand B being slightly more drug-like.

**7. DILI:** Both ligands have acceptable DILI risk (54.323 and 47.15), below the 60 threshold.

**8. BBB:** Both ligands have similar BBB penetration (45.25 and 46.413). These are below the desired >70 for CNS targets, which is a concern.

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.273 and -4.951), which is unusual and suggests poor permeability. This is a significant drawback.

**10. Aqueous Solubility:** Both ligands have negative solubility values (-1.942 and -2.553), indicating very poor aqueous solubility. This is a major issue for formulation and bioavailability.

**11. hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.186 and 0.151). This is positive.

**12. Microsomal Clearance:** Ligand A (-0.858) has a lower (better) microsomal clearance than Ligand B (19.263), suggesting better metabolic stability.

**13. In vitro Half-Life:** Ligand A (-9.662) has a significantly longer in vitro half-life than Ligand B (-43.522). This is a strong advantage.

**14. P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.015 and 0.021), which is favorable for CNS penetration.

**15. Binding Affinity:** Ligand B (-8.2 kcal/mol) has a stronger binding affinity than Ligand A (-7.4 kcal/mol). This is a 0.8 kcal/mol difference, which is substantial and can outweigh some ADME drawbacks.

**Overall Assessment:**

Both ligands have significant issues with Caco-2 permeability and aqueous solubility. The BBB penetration is also suboptimal. However, Ligand B has a significantly stronger binding affinity, a better QED score, and better metabolic stability (lower Cl_mic). The stronger binding affinity is a critical advantage for a GPCR target. While the solubility and permeability are concerning, these could potentially be addressed through formulation strategies.

Output:
1
2025-04-17 08:45:43,331 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 drug candidates, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (362.417 Da and 357.519 Da) fall within the ideal range of 200-500 Da.

**TPSA:** Ligand A (78.87) is better than Ligand B (32.7). For CNS targets, TPSA should be <=90, both are well within this range, but the lower TPSA of Ligand B is more favorable for brain penetration.

**logP:** Ligand A (1.318) is within the optimal range (1-3), while Ligand B (3.739) is approaching the upper limit. While not a dealbreaker, higher logP can sometimes lead to off-target effects.

**H-Bond Donors/Acceptors:** Ligand A has 2 HBD and 4 HBA, while Ligand B has 1 HBD and 4 HBA. Both are within acceptable limits.

**QED:** Both ligands have good QED scores (0.67 and 0.781), indicating good drug-like properties.

**DILI:** Ligand A (15.471) has a significantly lower DILI risk than Ligand B (12.33), which is a substantial advantage.

**BBB:** Ligand A (85.498) has a better BBB penetration percentile than Ligand B (77.433). This is critical for a CNS target like DRD2.

**Caco-2 Permeability:** Ligand A (-4.623) has a worse Caco-2 permeability than Ligand B (-5.2). Lower values are less favorable.

**Aqueous Solubility:** Ligand A (-1.309) has better aqueous solubility than Ligand B (-3.788).

**hERG Inhibition:** Ligand A (0.53) has a lower hERG inhibition liability than Ligand B (0.954), which is preferable for cardiac safety.

**Microsomal Clearance:** Ligand A (11.481) has a lower microsomal clearance than Ligand B (44.92), indicating better metabolic stability.

**In vitro Half-Life:** Ligand A (-13.298) has a worse in vitro half-life than Ligand B (21.578). This is a disadvantage for Ligand A.

**P-gp Efflux:** Ligand A (0.051) has much lower P-gp efflux liability than Ligand B (0.732), which is highly desirable for CNS penetration.

**Binding Affinity:** Both ligands have excellent binding affinities (-7.9 kcal/mol and -8.1 kcal/mol). Ligand B is slightly better, but the difference is small.

**Overall Assessment:**

Ligand A is superior due to its significantly lower DILI risk, better BBB penetration, lower hERG inhibition, lower P-gp efflux, and better metabolic stability. While Ligand B has a slightly better half-life and affinity, the ADME properties of Ligand A are much more favorable, especially considering the CNS target. The lower TPSA of Ligand B is a minor benefit, but is outweighed by the other advantages of Ligand A.

Output:
0
2025-04-17 08:45:43,332 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 drug candidates, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (348.487 and 378.826 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Both ligands have TPSA values (67.43 and 66.91) below the 90 A^2 threshold desirable for CNS targets, which is excellent.

**3. logP:** Ligand A (2.413) is within the optimal 1-3 range. Ligand B (3.805) is slightly higher but still acceptable, though approaching the upper limit where solubility issues might arise.

**4. H-Bond Donors:** Both ligands have 2 HBDs, well within the acceptable limit of <=5.

**5. H-Bond Acceptors:** Ligand A has 3 HBAs, and Ligand B has 4. Both are below the 10 limit.

**6. QED:** Both ligands have QED values (0.694 and 0.757) above 0.5, indicating good drug-like properties.

**7. DILI:** Ligand A (25.087 percentile) has a significantly lower DILI risk than Ligand B (47.77 percentile). This is a substantial advantage for Ligand A.

**8. BBB:** Ligand B (80.264 percentile) has a much better predicted BBB penetration than Ligand A (62.311 percentile). This is a critical factor for a CNS target like DRD2.

**9. Caco-2 Permeability:** Ligand A (-5.116) has a worse Caco-2 permeability than Ligand B (-4.892), suggesting lower intestinal absorption.

**10. Aqueous Solubility:** Ligand A (-2.888) has slightly better aqueous solubility than Ligand B (-4.44).

**11. hERG Inhibition:** Both ligands have relatively low hERG inhibition risk (0.15 and 0.613 respectively), which is positive.

**12. Microsomal Clearance:** Both ligands have similar microsomal clearance values (31.457 and 31.652 mL/min/kg), suggesting comparable metabolic stability.

**13. In vitro Half-Life:** Ligand B (4.327 hours) has a longer in vitro half-life than Ligand A (-3.4 hours). This is a positive for Ligand B.

**14. P-gp Efflux:** Both ligands have low P-gp efflux liability (0.064 and 0.135 respectively).

**15. Binding Affinity:** Both ligands show excellent binding affinity (-9.2 and -8.7 kcal/mol). The difference of 0.5 kcal/mol is not substantial enough to override other significant ADME differences.

**Overall Assessment:**

Ligand B excels in BBB penetration and has a longer half-life, both crucial for CNS drug development. However, Ligand A has a significantly lower DILI risk. Considering the GPCR-specific priorities, BBB is paramount for DRD2. While DILI is important, the substantial difference in BBB penetration outweighs the slightly higher DILI risk of Ligand B. The affinity difference is minimal.

Output:
1
2025-04-17 08:45:43,332 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands are within the acceptable range (200-500 Da). Ligand A (362.392 Da) is slightly preferred due to being lower.

**2. TPSA:** Ligand A (49.85) is excellent for CNS penetration, well below the 90 A^2 threshold. Ligand B (64.8) is still reasonable, but less optimal.

**3. logP:** Ligand A (2.061) is within the optimal range (1-3). Ligand B (4.827) is higher, potentially leading to solubility issues and off-target interactions.

**4. H-Bond Donors:** Both have 0 HBD, which is acceptable.

**5. H-Bond Acceptors:** Ligand A (3) is good, Ligand B (6) is acceptable but higher.

**6. QED:** Ligand A (0.722) is excellent, indicating good drug-likeness. Ligand B (0.38) is significantly lower, raising concerns.

**7. DILI:** Both ligands have acceptable DILI risk (Ligand A: 41.877, Ligand B: 46.026).

**8. BBB:** Ligand A (70.454) is good, exceeding the 70% threshold for CNS targets. Ligand B (91.237) is even better, indicating excellent potential for brain penetration.

**9. Caco-2:** Both have negative Caco-2 values, which is unusual and suggests poor permeability. This is a concern for both.

**10. Solubility:** Both have negative solubility values, indicating poor aqueous solubility. This is a significant drawback for both compounds.

**11. hERG:** Both have low hERG inhibition risk (Ligand A: 0.476, Ligand B: 0.969).

**12. Cl_mic:** Ligand A (11.619) has a lower microsomal clearance, suggesting better metabolic stability. Ligand B (47.777) has a significantly higher clearance.

**13. t1/2:** Ligand A (-22.763) has a negative in vitro half-life, which is concerning. Ligand B (-2.861) is also negative, but less so.

**14. Pgp:** Ligand A (0.093) has lower P-gp efflux, which is favorable for CNS exposure. Ligand B (0.983) has higher efflux.

**15. Binding Affinity:** Ligand B (-10.4 kcal/mol) has a significantly stronger binding affinity than Ligand A (-8.1 kcal/mol). This is a substantial advantage.

**Overall Assessment:**

While Ligand B has a superior binding affinity, Ligand A demonstrates better overall ADME properties, particularly regarding TPSA, logP, QED, Cl_mic, and Pgp efflux. The negative Caco-2 and solubility values are concerning for both, but the better metabolic stability and CNS penetration potential of Ligand A, coupled with its superior QED score, make it the more promising candidate. The strong affinity of Ligand B might be able to overcome some ADME issues, but the higher logP and Pgp efflux are significant drawbacks.

Output:
0
2025-04-17 08:45:43,332 - INFO - Batch 476 complete. Total preferences: 7616
2025-04-17 08:45:43,332 - INFO - Processing batch 477/512...
2025-04-17 08:46:24,556 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (351.422 and 360.483 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (62.21) is excellent, well below the 90 A^2 threshold for CNS targets. Ligand B (76.14) is still reasonable but less optimal.

**3. logP:** Ligand A (1.74) is within the optimal 1-3 range. Ligand B (2.757) is also good, leaning towards the higher end but still acceptable.

**4. H-Bond Donors:** Ligand A (0) is good. Ligand B (2) is also acceptable.

**5. H-Bond Acceptors:** Ligand A (4) is good. Ligand B (6) is also acceptable.

**6. QED:** Both ligands have reasonable QED values (0.775 and 0.67), indicating good drug-like properties.

**7. DILI:** Ligand A (18.224) has a significantly lower DILI risk than Ligand B (63.746), which is a substantial advantage.

**8. BBB:** Ligand A (88.6) has a much higher BBB penetration percentile than Ligand B (59.325). This is *critical* for a CNS target like DRD2.

**9. Caco-2 Permeability:** Ligand A (-4.38) has a worse Caco-2 permeability than Ligand B (-5.162). Lower values here indicate lower permeability.

**10. Aqueous Solubility:** Ligand A (-2.313) has better aqueous solubility than Ligand B (-3.746).

**11. hERG Inhibition:** Both ligands have similar, low hERG inhibition risk (0.386 and 0.466).

**12. Microsomal Clearance:** Ligand A (12.116) has lower microsomal clearance than Ligand B (94.451), suggesting better metabolic stability.

**13. In vitro Half-Life:** Ligand A (-8.143) has a much longer in vitro half-life than Ligand B (-1.152), which is a significant advantage.

**14. P-gp Efflux:** Ligand A (0.047) has a much lower P-gp efflux liability than Ligand B (0.185), which is beneficial for CNS penetration.

**15. Binding Affinity:** Both ligands have the same binding affinity (-7.8 kcal/mol), which is excellent.

**Overall Assessment:**

Ligand A is clearly superior. While Ligand B has slightly better Caco-2 permeability, Ligand A excels in almost all other crucial parameters, especially those prioritized for GPCRs targeting the CNS. Specifically, Ligand A has a significantly better BBB score, lower DILI risk, lower P-gp efflux, better metabolic stability (lower Cl_mic, longer t1/2), and better solubility. The equal binding affinity removes that as a differentiating factor. The combination of these factors makes Ligand A a much more promising drug candidate.

Output:
1
2025-04-17 08:46:24,556 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (362.455 and 347.463 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (85.37) is slightly higher than Ligand B (79.26), but both are below the 90 A^2 threshold desirable for CNS targets.

**logP:** Ligand A (3.418) is optimal, while Ligand B (0.727) is quite low. Low logP can hinder membrane permeability, a significant concern for CNS penetration.

**H-Bond Donors/Acceptors:** Both ligands have 2 HBD and around 5-6 HBA, which are within acceptable limits.

**QED:** Both ligands have QED values above 0.7, indicating good drug-likeness.

**DILI:** Ligand A (85.459) has a significantly higher DILI risk than Ligand B (18.379). This is a major drawback for Ligand A.

**BBB:** Ligand A (74.874) has a better BBB percentile than Ligand B (67.352), but both are reasonably good, though ideally >70 for CNS targets.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values, which is unusual and suggests poor permeability. However, the absolute value is more important than the sign here. Ligand A (-5.022) is slightly better than Ligand B (-5.243).

**Aqueous Solubility:** Both ligands have very poor aqueous solubility (-4.329 and -1.918 respectively).

**hERG:** Both ligands have low hERG inhibition liability (0.22 and 0.493 respectively).

**Microsomal Clearance:** Ligand A (76.1) has a higher microsomal clearance than Ligand B (16.254), indicating faster metabolism and potentially lower *in vivo* exposure.

**In vitro Half-Life:** Ligand B (18.05 hours) has a significantly longer half-life than Ligand A (-1.502 hours).

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.229 and 0.02 respectively).

**Binding Affinity:** Both ligands have very similar and excellent binding affinities (-8.5 and -8.3 kcal/mol). The difference is less than the 1.5 kcal/mol threshold.

**Conclusion:**

Despite the similar binding affinities, Ligand B is the more promising candidate. Its significantly lower DILI risk, better metabolic stability (lower Cl_mic, longer t1/2), and acceptable BBB penetration outweigh the slightly lower logP. While both have poor solubility and Caco-2 permeability, these can be addressed with formulation strategies. Ligand A's high DILI risk is a major concern that is difficult to overcome.

Output:
1
2025-04-17 08:46:24,556 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 drug candidates, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (348.328 Da and 353.419 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (61.92) is excellent, well below the 90 A^2 threshold for CNS targets. Ligand B (104.9) is higher, but still potentially acceptable, though less ideal.

**logP:** Ligand A (3.249) is optimal (1-3). Ligand B (0.521) is low, which could hinder membrane permeability and CNS penetration.

**H-Bond Donors/Acceptors:** Ligand A (0 HBD, 4 HBA) is favorable. Ligand B (2 HBD, 6 HBA) is also acceptable.

**QED:** Both ligands (0.795 and 0.706) have good drug-likeness scores (>0.5).

**DILI:** Both ligands have acceptable DILI risk (55.525 and 46.142, both <60).

**BBB:** Ligand A excels with a BBB percentile of 91.702, highly desirable for a CNS target. Ligand B's BBB (53.587) is considerably lower, raising concerns about CNS exposure.

**Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and suggests a problem with the data or modeling. However, we can still compare them relatively. Ligand A (-4.455) is slightly better than Ligand B (-4.883).

**Aqueous Solubility:** Both have negative solubility values, suggesting poor solubility. Ligand A (-5.159) is slightly better than Ligand B (-1.555).

**hERG:** Both ligands have low hERG inhibition liability (0.797 and 0.224), which is good.

**Microsomal Clearance:** Ligand A (45.266) has a slightly higher clearance than Ligand B (38.974), indicating potentially lower metabolic stability.

**In vitro Half-Life:** Ligand A (24.394 hours) has a better half-life than Ligand B (17.704 hours).

**P-gp Efflux:** Ligand A (0.661) has lower P-gp efflux liability than Ligand B (0.094), which is favorable for CNS penetration.

**Binding Affinity:** Ligand A (-8.2 kcal/mol) has a significantly stronger binding affinity than Ligand B (-7.6 kcal/mol). This 0.6 kcal/mol difference is substantial and can outweigh some ADME drawbacks.

**Overall Assessment:**

Ligand A is clearly the superior candidate. It has a much better BBB score, a more optimal logP, lower P-gp efflux, and significantly stronger binding affinity. While both have issues with solubility and Caco-2 permeability, Ligand A's superior CNS-related properties and binding affinity make it the more promising drug candidate for DRD2, a CNS-relevant GPCR.

Output:
1
2025-04-17 08:46:24,557 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (344.46 and 360.44 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (58.44) is significantly better than Ligand B (88.33). For CNS targets, TPSA should be <=90, and A is comfortably within this range, while B is approaching the upper limit.

**logP:** Both ligands have similar logP values (1.79 and 1.89), falling within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A (0 HBD, 4 HBA) is preferable to Ligand B (1 HBD, 6 HBA). Lower HBD/HBA generally improves permeability.

**QED:** Ligand B (0.903) has a higher QED score than Ligand A (0.676), suggesting a more generally drug-like profile. However, this is less critical than CNS penetration for a DRD2 target.

**DILI:** Ligand A (37.61) has a lower DILI risk than Ligand B (66.42), which is a significant advantage.

**BBB:** Both ligands have good BBB penetration (70.80 and 69.76), exceeding the 70% threshold for CNS targets. Ligand A is slightly better.

**Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual. It suggests poor permeability. However, the values are close enough to not be a major differentiator.

**Aqueous Solubility:** Both ligands have negative solubility values, indicating poor solubility.

**hERG:** Both ligands have very low hERG inhibition risk (0.299 and 0.283).

**Microsomal Clearance:** Ligand B (22.17) has a lower microsomal clearance than Ligand A (42.03), indicating better metabolic stability.

**In vitro Half-Life:** Ligand B (-5.73) has a longer in vitro half-life than Ligand A (-13.70). This is a significant advantage.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.14 and 0.166).

**Binding Affinity:** Ligand B (-8.9 kcal/mol) has a significantly stronger binding affinity than Ligand A (-7.3 kcal/mol). This >1.5 kcal/mol difference is a major factor.

**Overall Assessment:**

While Ligand A has advantages in TPSA, DILI, and BBB, the significantly stronger binding affinity of Ligand B (-8.9 vs -7.3 kcal/mol) outweighs these benefits. The longer half-life of Ligand B is also a considerable advantage. The slightly higher TPSA and DILI risk of Ligand B are acceptable given its superior potency and metabolic stability.

Output:
1
2025-04-17 08:46:24,557 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (340.358 Da and 358.389 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (86.02) is excellent, well below the 90 Angstroms threshold for CNS targets. Ligand B (96.25) is still reasonable but less optimal.

**3. logP:** Ligand A (2.988) is within the optimal range of 1-3. Ligand B (1.7) is at the lower end, potentially impacting permeability, but not drastically.

**4. H-Bond Donors:** Ligand A (4) and Ligand B (3) are both acceptable, being less than 5.

**5. H-Bond Acceptors:** Ligand A (2) and Ligand B (5) are both acceptable, being less than 10.

**6. QED:** Both ligands have similar QED values (0.588 and 0.586), indicating good drug-like properties.

**7. DILI:** Ligand A (90.694) has a higher DILI risk than Ligand B (59.131). This is a significant negative for Ligand A.

**8. BBB:** Ligand A (67.313) has a better BBB penetration percentile than Ligand B (52.811). This is a crucial factor for a CNS target like DRD2.

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.148 and -5.124). This is unusual and suggests poor permeability, but the scale is not defined, so it's difficult to interpret.

**10. Aqueous Solubility:** Both ligands have negative solubility values (-4.861 and -2.127). Similar to Caco-2, this is hard to interpret without knowing the scale.

**11. hERG Inhibition:** Ligand A (0.69) shows a lower hERG inhibition liability than Ligand B (0.3), which is favorable.

**12. Microsomal Clearance:** Ligand B (46.174) has a significantly lower microsomal clearance than Ligand A (6.159), indicating better metabolic stability.

**13. In vitro Half-Life:** Ligand A (100.987) has a much longer in vitro half-life than Ligand B (-5.666).

**14. P-gp Efflux:** Ligand A (0.201) has lower P-gp efflux liability than Ligand B (0.107), which is beneficial for CNS penetration.

**15. Binding Affinity:** Ligand B (-7.8 kcal/mol) has a significantly stronger binding affinity than Ligand A (-11.0 kcal/mol). This is a major advantage.

**Overall Assessment:**

Ligand B has a superior binding affinity, better metabolic stability (lower Cl_mic), and a lower DILI risk. While Ligand A has better BBB penetration and P-gp efflux, the significantly stronger binding affinity of Ligand B outweighs these advantages, especially considering the higher DILI risk associated with Ligand A. The negative values for Caco-2 and solubility are concerning for both, but the affinity difference is substantial. Given the GPCR-specific priorities, a strong binding affinity is paramount.

Output:
1
2025-04-17 08:46:24,557 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B based on the provided guidelines, prioritizing GPCR-specific properties (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (360.38 and 366.48 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (67.43) is slightly higher than Ligand B (60.89). Both are below the 90 A^2 threshold desirable for CNS targets, but Ligand B is closer to optimal.

**logP:** Both ligands have good logP values (3.12 and 2.37), falling within the 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A has 2 HBD and 3 HBA, while Ligand B has 0 HBD and 6 HBA. Both are within acceptable limits (<=5 HBD and <=10 HBA).

**QED:** Both ligands have similar QED scores (0.748 and 0.707), indicating good drug-likeness.

**DILI:** Ligand B (36.49) has a significantly lower DILI risk than Ligand A (44.44), suggesting better hepatotoxicity potential.

**BBB:** Ligand A has a better BBB penetration score (85.65) than Ligand B (75.11). This is a crucial factor for CNS targets like DRD2.

**Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and suggests poor permeability. However, the scale is not defined, so it's hard to interpret.

**Aqueous Solubility:** Both have negative solubility values, which is also unusual and suggests poor solubility.

**hERG:** Ligand A (0.786) has a slightly higher hERG risk than Ligand B (0.439), but both are relatively low.

**Microsomal Clearance:** Ligand B (43.41) has a lower microsomal clearance than Ligand A (47.50), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand B (22.75) has a significantly longer in vitro half-life than Ligand A (5.86), which is favorable.

**P-gp Efflux:** Ligand A (0.169) has lower P-gp efflux liability than Ligand B (0.094), which is beneficial for CNS penetration.

**Binding Affinity:** Ligand A (-8.2 kcal/mol) has a significantly stronger binding affinity than Ligand B (-5.9 kcal/mol). This is a substantial advantage, potentially outweighing some ADME drawbacks.

**Overall Assessment:**

The key trade-off is between binding affinity and ADME properties. Ligand A has a much stronger binding affinity, which is paramount for GPCR targets. While Ligand B has better DILI, metabolic stability, and half-life, the difference in binding affinity is substantial (2.3 kcal/mol). The BBB score for Ligand A is also better. Given the CNS target (DRD2), maximizing BBB penetration and binding affinity are critical. The slightly higher DILI risk of Ligand A might be manageable with further optimization.

Output:
1
2025-04-17 08:46:24,557 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (366.487 and 346.446 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (59.31) is better than Ligand B (55.56). Both are below the 90 A^2 threshold desirable for CNS targets, indicating good potential for brain penetration.

**3. logP:** Ligand A (0.845) is slightly lower than the optimal 1-3 range, potentially hindering permeability. Ligand B (2.795) is within the optimal range. This favors Ligand B.

**4. H-Bond Donors:** Ligand A (0) is preferable to Ligand B (1) as fewer HBDs generally improve permeability.

**5. H-Bond Acceptors:** Ligand A (8) is preferable to Ligand B (3), as fewer HBAs generally improve permeability.

**6. QED:** Both ligands have good QED scores (0.646 and 0.912), indicating drug-like properties. Ligand B is slightly better.

**7. DILI:** Ligand A (39.55) has a lower DILI risk than Ligand B (11.128), which is a significant advantage.

**8. BBB:** Both ligands have good BBB penetration (78.402 and 74.098). Ligand A is slightly better.

**9. Caco-2:** Both ligands have negative Caco-2 values, which is unusual. It's difficult to interpret without knowing the scale.

**10. Solubility:** Both ligands have negative solubility values, which is also unusual. It's difficult to interpret without knowing the scale.

**11. hERG:** Both ligands have low hERG inhibition liability (0.881 and 0.761), which is good.

**12. Cl_mic:** Ligand B (23.914) has significantly lower microsomal clearance than Ligand A (39.072), indicating better metabolic stability.

**13. t1/2:** Ligand A (13.335) has a longer in vitro half-life than Ligand B (-10.323). However, the negative value for Ligand B is concerning and likely an error.

**14. Pgp:** Both ligands have low P-gp efflux liability (0.124 and 0.168), which is good for CNS penetration.

**15. Binding Affinity:** Ligand B (-8.9 kcal/mol) has a significantly stronger binding affinity than Ligand A (-7.3 kcal/mol). This >1.5 kcal/mol difference is a major advantage, potentially outweighing some ADME drawbacks.

**Overall Assessment:**

Ligand B has a superior binding affinity and better logP, and lower Cl_mic. While Ligand A has a slightly better BBB and lower DILI, the substantial affinity advantage of Ligand B, combined with acceptable ADME properties, makes it the more promising candidate. The negative values for Caco-2 and solubility are concerning for both, but the strong binding of Ligand B is a key driver.

Output:
1
2025-04-17 08:46:24,557 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (346.475) is slightly lower, which is generally favorable for permeability.

**2. TPSA:** Ligand A (78.09) is better than Ligand B (58.64) as it is closer to the ideal range for CNS targets (<=90). Ligand B is quite low, potentially impacting binding affinity.

**3. logP:** Both ligands have good logP values (A: 2.798, B: 1.685), falling within the optimal range of 1-3.

**4. H-Bond Donors:** Both ligands have acceptable HBD counts (A: 2, B: 1).

**5. H-Bond Acceptors:** Both ligands have acceptable HBA counts (A: 3, B: 4).

**6. QED:** Both ligands have similar and good QED values (A: 0.745, B: 0.719), indicating good drug-like properties.

**7. DILI:** Both ligands have similar and acceptable DILI risk (A: 31.563, B: 31.989), below the 40% threshold.

**8. BBB:** Ligand B (84.878) significantly outperforms Ligand A (67.662) in BBB penetration, which is *critical* for a CNS target like DRD2. This is a major advantage for Ligand B.

**9. Caco-2 Permeability:** Ligand A (-5.228) has a worse Caco-2 permeability than Ligand B (-4.686).

**10. Aqueous Solubility:** Both ligands have poor aqueous solubility (-3.06 and -2.999 respectively). This could pose formulation challenges, but is less critical than BBB for a CNS target.

**11. hERG Inhibition:** Both ligands have low hERG inhibition risk (A: 0.808, B: 0.373), which is good. Ligand B is even better.

**12. Microsomal Clearance:** Ligand A (44.501) has higher microsomal clearance than Ligand B (30.047), suggesting lower metabolic stability.

**13. In vitro Half-Life:** Ligand B (-15.431) has a significantly better in vitro half-life than Ligand A (-30.285).

**14. P-gp Efflux:** Ligand A (0.36) has lower P-gp efflux than Ligand B (0.069), which is favorable for CNS penetration.

**15. Binding Affinity:** Ligand B (-7.9 kcal/mol) has a slightly better binding affinity than Ligand A (-7.5 kcal/mol). While the difference is not huge, it's still a positive factor.

**Overall Assessment:**

While Ligand A has a slightly better MW and P-gp efflux, Ligand B is superior in almost all other crucial parameters for a CNS-targeting GPCR ligand. The significantly better BBB penetration (84.878 vs 67.662), improved in vitro half-life, better hERG profile, and slightly better binding affinity outweigh the minor advantages of Ligand A. The lower TPSA of Ligand B is also a slight concern, but the strong BBB penetration suggests it is still able to bind effectively.

Output:
1
2025-04-17 08:46:24,558 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (365.43 and 353.463 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (69.85) is excellent, well below the 90 A^2 threshold for CNS targets. Ligand B (93.11) is pushing the limit, but still potentially acceptable.

**logP:** Ligand A (2.959) is optimal (1-3). Ligand B (-0.268) is too low, potentially hindering permeation.

**H-Bond Donors/Acceptors:** Ligand A (HBD=1, HBA=6) is favorable. Ligand B (HBD=3, HBA=5) is also reasonable.

**QED:** Ligand A (0.652) is good, indicating drug-likeness. Ligand B (0.548) is acceptable, but less optimal.

**DILI:** Ligand A (56.73) is good (low risk). Ligand B (9.93) is excellent.

**BBB:** Ligand A (82.78) is very good, exceeding the 70% threshold for CNS targets. Ligand B (25.13) is poor, indicating very limited brain penetration. This is a critical disadvantage for a DRD2 ligand.

**Caco-2 Permeability:** Ligand A (-4.903) is poor. Ligand B (-5.196) is also poor.

**Aqueous Solubility:** Ligand A (-3.673) is poor. Ligand B (-0.557) is also poor.

**hERG Inhibition:** Ligand A (0.958) is low risk. Ligand B (0.04) is very low risk.

**Microsomal Clearance:** Ligand A (37.798) is moderate. Ligand B (-7.232) is excellent, indicating high metabolic stability.

**In vitro Half-Life:** Ligand A (17.191) is moderate. Ligand B (-4.89) is poor.

**P-gp Efflux:** Ligand A (0.774) is moderate. Ligand B (0.002) is very low, suggesting minimal efflux.

**Binding Affinity:** Both ligands have excellent binding affinities (-8.1 and -7.3 kcal/mol), with Ligand A being slightly better. The difference is less than 1.5 kcal/mol, so this isn't a decisive factor on its own.

**Overall Assessment:**

Ligand A excels in BBB penetration, TPSA, and has a slightly better binding affinity. While its Caco-2 and Solubility are poor, the strong BBB score is crucial for a CNS target like DRD2. Ligand B has excellent metabolic stability and low P-gp efflux, but its extremely poor BBB penetration is a major drawback. The negative logP is also concerning. Given the GPCR-specific priorities, **Ligand A is the more promising candidate.**

Output:
1
2025-04-17 08:46:24,558 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (348.393 and 357.445 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (50.36) is significantly better than Ligand B (69.22). For CNS targets, we want TPSA <= 90, and A is comfortably within that range, while B is approaching the upper limit.

**3. logP:** Both ligands have good logP values (3.714 and 3.287), falling within the optimal 1-3 range.

**4. H-Bond Donors:** Both have 2 HBD, which is acceptable.

**5. H-Bond Acceptors:** Both have 3 HBA, which is acceptable.

**6. QED:** Both ligands have similar QED values (0.715 and 0.75), indicating good drug-likeness.

**7. DILI:** Ligand A (51.493) has a higher DILI risk than Ligand B (18.263). This is a significant advantage for B.

**8. BBB:** Ligand A (83.831) has a better BBB penetration percentile than Ligand B (68.476). While both are reasonably good, A is preferable for a CNS target.

**9. Caco-2 Permeability:** Ligand A (-4.616) has worse Caco-2 permeability than Ligand B (-4.578). Though both are negative, B is slightly better.

**10. Aqueous Solubility:** Ligand A (-4.432) has worse aqueous solubility than Ligand B (-3.244). B is preferable.

**11. hERG Inhibition:** Ligand A (0.967) has slightly higher hERG inhibition liability than Ligand B (0.794), but both are reasonably low risk.

**12. Microsomal Clearance:** Ligand A (69.969) has higher microsomal clearance than Ligand B (19.011). B is preferable, indicating better metabolic stability.

**13. In vitro Half-Life:** Ligand A (-1.784) has a worse in vitro half-life than Ligand B (-11.256). B is preferable.

**14. P-gp Efflux:** Ligand A (0.566) has lower P-gp efflux liability than Ligand B (0.294). This is a significant advantage for A, as lower efflux is desirable for CNS exposure.

**15. Binding Affinity:** Ligand A (-9.2 kcal/mol) has a significantly stronger binding affinity than Ligand B (-7.3 kcal/mol). This is a substantial advantage for A, exceeding the 1.5 kcal/mol threshold.

**Overall Assessment:**

While Ligand B has advantages in DILI, solubility, metabolic stability, and half-life, Ligand A's significantly stronger binding affinity (-9.2 vs -7.3 kcal/mol) and better BBB penetration outweigh these drawbacks, especially considering this is a CNS target (DRD2). The lower P-gp efflux for Ligand A is also a positive. The TPSA is also much better for Ligand A. The DILI risk for A is a concern, but can potentially be addressed through further optimization.

Output:
1
2025-04-17 08:46:24,558 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (349.431 and 364.808 Da) fall within the ideal range of 200-500 Da.

**TPSA:** Ligand A (80.76) is slightly higher than Ligand B (74.33), but both are below the 90 A^2 threshold desirable for CNS targets.

**logP:** Both ligands have good logP values (2.523 and 1.536), falling within the optimal 1-3 range. Ligand B is slightly lower, which *could* indicate slightly better solubility, but isn't a major concern.

**H-Bond Donors/Acceptors:** Ligand A has 1 HBD and 5 HBA, while Ligand B has 2 HBD and 3 HBA. Both are within acceptable limits (<=5 HBD and <=10 HBA).

**QED:** Ligand A (0.826) has a significantly better QED score than Ligand B (0.586), indicating a more drug-like profile.

**DILI:** Ligand A (38.542) has a much lower DILI risk than Ligand B (59.984). This is a significant advantage for Ligand A.

**BBB:** Both ligands have very similar BBB penetration scores (74.06 and 73.788), both exceeding the 70% threshold desirable for CNS targets.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.723 and -4.719). This is unusual and suggests poor permeability. However, since these are negative values, it's difficult to interpret directly.

**Aqueous Solubility:** Both ligands have negative solubility values (-2.453 and -3.739). Again, this is unusual and suggests very poor aqueous solubility.

**hERG Inhibition:** Both ligands have low hERG inhibition liability (0.345 and 0.232), which is good.

**Microsomal Clearance:** Ligand B (-0.785) has a *negative* microsomal clearance, which is not physically possible. This suggests a data error or a very unusual metabolic profile. Ligand A (20.243) has a reasonable clearance.

**In vitro Half-Life:** Both have negative half-lives (-11.083 and -11.22), which are not physically possible. This suggests data errors.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.032 and 0.078), which is favorable for CNS penetration.

**Binding Affinity:** Both ligands have very similar and strong binding affinities (-8.5 and -8.6 kcal/mol). The difference is negligible.

**Overall Assessment:**

Despite the unusual negative values for Caco-2 and half-life, the most significant difference lies in the DILI risk and QED score. Ligand A has a substantially lower DILI risk and a higher QED, making it a more promising drug candidate. The negative clearance value for Ligand B is a major red flag, suggesting a data quality issue. While both have good BBB penetration and affinity, the improved safety profile and drug-likeness of Ligand A outweigh the minor differences in other parameters.

Output:
1
2025-04-17 08:46:24,558 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands fall within the ideal range (200-500 Da). Ligand A (378.219 Da) is slightly better positioned.

**TPSA:** Ligand A (92.41) is better than Ligand B (112.81). For CNS targets, we want TPSA <= 90, so Ligand A is closer to this threshold.

**logP:** Both ligands have acceptable logP values (Ligand A: 2.813, Ligand B: 0.83). Ligand A is optimal (1-3), while Ligand B is on the lower side, potentially impacting permeability.

**H-Bond Donors/Acceptors:** Both ligands have 2 HBD and acceptable HBA counts (Ligand A: 6, Ligand B: 4).

**QED:** Both ligands have similar, good QED values (Ligand A: 0.731, Ligand B: 0.716).

**DILI:** Ligand A (94.106) has a significantly higher DILI risk than Ligand B (52.152). This is a major concern for Ligand A.

**BBB:** Ligand B (62.117) has a much better BBB penetration percentile than Ligand A (33.036). This is critical for a CNS target like DRD2.

**Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and suggests a potential issue with the prediction method or the molecules themselves. However, the values are similar.

**Aqueous Solubility:** Both have negative solubility values, again suggesting a problem with the prediction. The values are similar.

**hERG:** Both ligands have low hERG inhibition liability (Ligand A: 0.291, Ligand B: 0.204).

**Microsomal Clearance:** Ligand B (1.853) has significantly lower microsomal clearance than Ligand A (26.973), indicating better metabolic stability.

**In vitro Half-Life:** Ligand B (-24.032) has a much longer in vitro half-life than Ligand A (12.893).

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (Ligand A: 0.106, Ligand B: 0.017).

**Binding Affinity:** Both ligands have excellent binding affinities (Ligand A: -10.1 kcal/mol, Ligand B: -9.1 kcal/mol). Ligand A is slightly better, but the difference is likely not enough to overcome other significant drawbacks.

**Overall Assessment:**

Ligand A has a better binding affinity and TPSA, but suffers from a high DILI risk, poor BBB penetration, and higher metabolic clearance. Ligand B, while having slightly lower affinity, exhibits a much more favorable profile regarding BBB penetration, DILI risk, metabolic stability, and half-life. Given the CNS target, BBB penetration is paramount, and the lower DILI risk is also a significant advantage.

Output:
1
2025-04-17 08:46:24,559 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (356.369 and 342.403 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (67.87) is significantly better than Ligand B (122.89). For CNS targets, we want TPSA <= 90, and Ligand A is comfortably within this range, while Ligand B exceeds it. This is a substantial advantage for A.

**logP:** Both ligands have good logP values (1.581 and 1.172), falling within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A (HBD=1, HBA=4) is preferable to Ligand B (HBD=3, HBA=6) as it has fewer potential issues with permeability. Both are within acceptable limits.

**QED:** Ligand A (0.806) has a higher QED score than Ligand B (0.649), indicating a more drug-like profile.

**DILI:** Ligand B (66.964) has a higher DILI risk than Ligand A (41.838). Both are acceptable, but A is better.

**BBB:** Ligand A (88.096) has a significantly higher BBB penetration percentile than Ligand B (50.523). This is *critical* for a CNS target like DRD2.

**Caco-2 Permeability:** Ligand A (-4.644) has a better Caco-2 permeability value than Ligand B (-5.603), suggesting better intestinal absorption.

**Aqueous Solubility:** Ligand A (-1.924) has a better aqueous solubility value than Ligand B (-3.038).

**hERG:** Both ligands have low hERG inhibition liability (0.437 and 0.645), which is good.

**Microsomal Clearance:** Ligand A (29.887) has a higher microsomal clearance than Ligand B (1.159), indicating lower metabolic stability. This is a negative for A.

**In vitro Half-Life:** Ligand B (9.947) has a longer in vitro half-life than Ligand A (19.937), which is a positive for B.

**P-gp Efflux:** Ligand A (0.061) has a lower P-gp efflux liability than Ligand B (0.026), which is favorable for CNS penetration.

**Binding Affinity:** Both ligands have very similar and excellent binding affinities (-8.9 and -8.7 kcal/mol). The difference is negligible.

**Overall Assessment:**

Ligand A is clearly superior. While Ligand B has a slightly better half-life and lower P-gp efflux, Ligand A excels in critical areas for a CNS GPCR target: TPSA, BBB penetration, QED, solubility, and DILI risk. The slightly higher clearance of Ligand A is a concern, but the substantial advantage in BBB penetration and TPSA outweighs this drawback, especially given the strong binding affinity of both compounds.

Output:
1
2025-04-17 08:46:24,559 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (340.423 and 355.366 Da) fall within the ideal range of 200-500 Da.

**TPSA:** Ligand A (82.19) is excellent for CNS penetration, well below the 90 A^2 threshold. Ligand B (108.73) is still reasonable but less optimal.

**logP:** Ligand A (3.27) is within the optimal range (1-3). Ligand B (-0.077) is significantly below this, which could hinder membrane permeability and potentially reduce brain exposure.

**H-Bond Donors/Acceptors:** Ligand A (3 HBD, 2 HBA) and Ligand B (1 HBD, 6 HBA) both have acceptable numbers of H-bond donors and acceptors, falling within the recommended limits.

**QED:** Both ligands have similar QED values (0.755 and 0.668), indicating good drug-like properties.

**DILI:** Ligand A (76.735) has a higher DILI risk than Ligand B (36.487). This is a concern for Ligand A.

**BBB:** Ligand B (84.025) has a significantly higher BBB percentile than Ligand A (46.724). This is a crucial advantage for a CNS target like DRD2.

**Caco-2 Permeability:** Ligand A (-5.54) has very poor Caco-2 permeability. Ligand B (-4.777) is also poor, but slightly better.

**Aqueous Solubility:** Both ligands have poor aqueous solubility (-3.941 and -2.002). This could pose formulation challenges.

**hERG Inhibition:** Ligand A (0.085) has a very low hERG risk, which is excellent. Ligand B (0.248) has a slightly higher, but still acceptable, hERG risk.

**Microsomal Clearance:** Ligand A (4.114) has a higher microsomal clearance than Ligand B (2.226), indicating faster metabolism and potentially lower in vivo exposure.

**In vitro Half-Life:** Ligand B (-4.717) has a longer in vitro half-life than Ligand A (-1.33). This is a positive attribute for Ligand B.

**P-gp Efflux:** Ligand A (0.135) has lower P-gp efflux liability than Ligand B (0.022), which is favorable for CNS penetration.

**Binding Affinity:** Ligand A (-8.9 kcal/mol) has a significantly stronger binding affinity than Ligand B (-7.2 kcal/mol). This is a substantial advantage.

**Overall Assessment:**

Despite the higher DILI risk, Ligand A's significantly stronger binding affinity (-8.9 vs -7.2 kcal/mol) is a major advantage that could potentially outweigh some of its ADME drawbacks. However, the poor Caco-2 permeability and relatively low BBB penetration are serious concerns. Ligand B, while having a weaker affinity, exhibits a much better BBB profile (84.025 vs 46.724), lower DILI risk, and a longer half-life. Given the GPCR-specific emphasis on BBB penetration for CNS targets, and the substantial difference in BBB values, Ligand B is the more promising candidate. The affinity difference, while significant, might be overcome with further optimization of Ligand B.



Output:
1
2025-04-17 08:46:24,559 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (359.392 and 364.348 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (54.46) is significantly better than Ligand B (69.96). For CNS targets, we want TPSA <= 90, and ideally closer to 60. Ligand A is much closer to this ideal.

**logP:** Both ligands have acceptable logP values (2.63 and 3.5), falling within the 1-3 optimal range. Ligand B is slightly higher, which *could* indicate a potential for off-target interactions, but isn't a major concern.

**H-Bond Donors/Acceptors:** Both have 1 HBD and a reasonable number of HBAs (4 and 3, respectively), satisfying the <=5 and <=10 rules.

**QED:** Both ligands have good QED scores (0.775 and 0.844), indicating drug-like properties.

**DILI:** Ligand A (20.822) has a much lower DILI risk than Ligand B (73.982). This is a significant advantage for Ligand A.

**BBB:** This is a critical parameter for a CNS target like DRD2. Ligand A (82.513) has a good BBB percentile, exceeding the desirable >70 threshold. Ligand B (44.281) is considerably lower, suggesting poor brain penetration.

**Caco-2 Permeability:** Both have negative values, indicating poor permeability. However, the scale is not clearly defined, so it's hard to interpret the absolute difference.

**Aqueous Solubility:** Both have negative values, suggesting poor solubility. Again, the scale is unclear.

**hERG Inhibition:** Both ligands show low hERG inhibition liability (0.613 and 0.749), which is good.

**Microsomal Clearance:** Ligand A (25.775) has a higher microsomal clearance than Ligand B (6.951), indicating potentially lower metabolic stability. This is a negative for Ligand A.

**In vitro Half-Life:** Ligand B (-2.998) has a slightly better (less negative) in vitro half-life than Ligand A (-19.234).

**P-gp Efflux:** Ligand A (0.109) has significantly lower P-gp efflux liability than Ligand B (0.374), which is beneficial for CNS exposure.

**Binding Affinity:** Both ligands have excellent binding affinities (-8.4 and -8.8 kcal/mol). The difference is small, and within the range where other factors become more important.

**Overall Assessment:**

Ligand A is significantly better due to its superior BBB penetration (82.5 vs 44.3), much lower DILI risk (20.8 vs 73.9), and lower P-gp efflux (0.109 vs 0.374). While Ligand A has a higher microsomal clearance, the benefits of better CNS penetration and lower toxicity outweigh this drawback, especially considering the similar binding affinities. The TPSA is also much more favorable for Ligand A.

Output:
0
2025-04-17 08:46:24,559 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (354.801 and 347.419 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (85.59) is slightly higher than Ligand B (81.77), but both are below the 90 A^2 threshold desirable for CNS targets.

**3. logP:** Ligand A (2.842) is within the optimal 1-3 range. Ligand B (-0.413) is significantly lower, which could hinder permeability and potentially reduce binding affinity.

**4. H-Bond Donors:** Both ligands have 1 HBD, which is acceptable.

**5. H-Bond Acceptors:** Ligand A has 6 HBA, and Ligand B has 5. Both are within the acceptable limit of 10.

**6. QED:** Both ligands have good QED scores (0.731 and 0.801), indicating good drug-like properties.

**7. DILI:** Ligand A has a high DILI risk (95.502 percentile), which is a significant concern. Ligand B has a much lower DILI risk (36.448 percentile), making it more favorable.

**8. BBB:** Ligand A has a good BBB penetration score (77.007 percentile), while Ligand B has a very low BBB score (36.448 percentile). This is a critical factor for a CNS target like DRD2.

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.898 and -4.895), which is unusual and suggests poor permeability. However, these values are on a scale where negative values are possible, and their relative comparison is less informative.

**10. Aqueous Solubility:** Both ligands have negative solubility values (-3.974 and -0.988), indicating poor aqueous solubility. Ligand B is slightly better in this regard.

**11. hERG Inhibition:** Both ligands show low hERG inhibition liability (0.304 and 0.494), which is positive.

**12. Microsomal Clearance:** Ligand A (64.697 mL/min/kg) has a higher clearance than Ligand B (9.657 mL/min/kg), suggesting lower metabolic stability for Ligand A.

**13. In vitro Half-Life:** Ligand A (31.676 hours) has a longer half-life than Ligand B (-10.83 hours). However, the negative value for Ligand B is concerning and likely indicates a very short half-life.

**14. P-gp Efflux:** Ligand A (0.341) has lower P-gp efflux than Ligand B (0.022), which is favorable for CNS penetration.

**15. Binding Affinity:** Ligand A (-10.3 kcal/mol) has a significantly stronger binding affinity than Ligand B (-7.7 kcal/mol). This is a substantial advantage.

**Overall Assessment:**

Ligand A has a much stronger binding affinity and better BBB penetration and P-gp efflux, which are crucial for a CNS GPCR target. However, its high DILI risk and higher metabolic clearance are significant drawbacks. Ligand B has a lower DILI risk and better metabolic stability, but its weak logP and very poor BBB penetration are major concerns.

Despite the DILI risk, the significantly stronger binding affinity of Ligand A and its acceptable BBB penetration make it the more promising candidate, *assuming* the DILI risk can be mitigated through structural modifications. The affinity difference is large enough to potentially overcome the DILI concern with further optimization.

Output:
1
2025-04-17 08:46:24,560 - INFO - Batch 477 complete. Total preferences: 7632
2025-04-17 08:46:24,560 - INFO - Processing batch 478/512...
2025-04-17 08:47:05,470 - INFO - Reasoning:

Let's analyze Ligand A and Ligand B based on the provided guidelines, prioritizing GPCR-specific properties (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (340.379 Da) is slightly lower, which could be advantageous for permeability.

**TPSA:** Ligand A (75.8) is better than Ligand B (87.3). For CNS targets, we want TPSA <= 90, and both are within this range, but A is closer to the ideal.

**logP:** Both ligands have good logP values (A: 2.392, B: 1.366) within the optimal range of 1-3.

**H-Bond Donors/Acceptors:** Ligand A (HBD=1, HBA=5) is preferable to Ligand B (HBD=3, HBA=4) as lower HBD/HBA generally improves CNS penetration.

**QED:** Ligand A (0.925) has a significantly higher QED score than Ligand B (0.593), indicating a more drug-like profile.

**DILI:** Ligand A (65.568) has a higher DILI risk than Ligand B (18.845). This is a significant drawback for Ligand A.

**BBB:** Ligand A (63.203) has a better BBB percentile than Ligand B (52.423), which is crucial for CNS targets like DRD2. However, ideally, we want >70.

**Caco-2 Permeability:** Ligand A (-4.572) has a worse Caco-2 permeability than Ligand B (-5.462). Lower values are less favorable.

**Aqueous Solubility:** Ligand A (-2.943) has a worse aqueous solubility than Ligand B (-2.456).

**hERG Inhibition:** Ligand A (0.474) has a slightly higher hERG inhibition risk than Ligand B (0.075). Lower is better.

**Microsomal Clearance:** Ligand A (54.031) has a higher microsomal clearance than Ligand B (38.756), suggesting lower metabolic stability.

**In vitro Half-Life:** Ligand B (-6.815) has a much longer in vitro half-life than Ligand A (4.363). This is a significant advantage for Ligand B.

**P-gp Efflux:** Ligand A (0.598) has a slightly higher P-gp efflux liability than Ligand B (0.039). Lower is better, especially for CNS targets.

**Binding Affinity:** Ligand A (-8.5 kcal/mol) has a slightly better binding affinity than Ligand B (-7.8 kcal/mol). This is a 1.5 kcal/mol difference, which is significant.

**Overall Assessment:**

Ligand A has a better binding affinity, TPSA, QED, and BBB penetration. However, it suffers from significantly higher DILI risk, worse solubility, higher hERG risk, higher clearance, higher P-gp efflux, and worse Caco-2 permeability. Ligand B has a much better safety profile (DILI, hERG), better metabolic stability (half-life, clearance), and better permeability (Caco-2, Pgp). The affinity difference, while present, is likely outweighed by the substantial ADME/Tox advantages of Ligand B, especially considering the CNS target.

Output:
1
2025-04-17 08:47:05,470 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (349.391 and 346.435 Da) fall comfortably within the ideal 200-500 Da range.

**TPSA:** Ligand A (126.65) is slightly above the ideal <90 for CNS targets, while Ligand B (101.8) is closer to the threshold. This favors Ligand B.

**logP:** Ligand A (-0.012) is very low, potentially hindering membrane permeability. Ligand B (0.598) is within the optimal 1-3 range. This is a significant advantage for Ligand B.

**H-Bond Donors/Acceptors:** Ligand A has 3 HBD and 6 HBA, while Ligand B has 2 HBD and 6 HBA. Both are within acceptable limits.

**QED:** Both ligands have reasonable QED scores (0.62 and 0.503), indicating good drug-like properties.

**DILI:** Ligand A (50.601) has a slightly higher DILI risk than Ligand B (40.054), but both are below the concerning threshold of 60.

**BBB:** Ligand A (79.488) has a significantly better BBB penetration percentile than Ligand B (52.074). This is a crucial factor for a CNS target like DRD2, strongly favoring Ligand A.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.248 and -5.455), which is unusual and suggests poor permeability. However, these values are on a scale where negative values are possible, and direct comparison is difficult without knowing the scale's specifics.

**Aqueous Solubility:** Both ligands have very poor aqueous solubility (-2.114 and -2.108). This is a concern for both, but can potentially be addressed with formulation strategies.

**hERG Inhibition:** Both ligands show very low hERG inhibition risk (0.417 and 0.014).

**Microsomal Clearance:** Ligand A (-7.553) has much lower (better) microsomal clearance than Ligand B (16.267), indicating better metabolic stability.

**In vitro Half-Life:** Ligand A (-33.185) has a negative half-life, which is not physically possible and indicates an issue with the data or assay. Ligand B (-1.771) is also negative, but less extreme. This is a major red flag for both, but more so for Ligand A.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.006 and 0.03), which is favorable for CNS penetration.

**Binding Affinity:** Ligand B (-8.2 kcal/mol) has a slightly better binding affinity than Ligand A (-7.9 kcal/mol), although the difference is relatively small.

**Overall Assessment:**

Ligand A has a significantly better BBB score and lower microsomal clearance, but suffers from a very low logP and a nonsensical in vitro half-life. Ligand B has a better logP and TPSA, and a slightly better binding affinity, but has a lower BBB score. The low logP of Ligand A is a major concern for CNS penetration, despite the better BBB percentile. The negative half-life values for both are problematic, but the more extreme value for Ligand A is particularly concerning. Considering the importance of BBB penetration for a CNS target, and the more favorable logP and binding affinity of Ligand B, I would select Ligand B.

Output:
1
2025-04-17 08:47:05,471 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (363.351 and 351.407 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (47.56) is excellent, well below the 90 A^2 threshold for CNS targets. Ligand B (109.58) is higher, but still potentially acceptable, though less ideal.

**logP:** Ligand A (3.957) is within the optimal 1-3 range. Ligand B (-0.582) is significantly lower, which could hinder membrane permeability and CNS penetration.

**H-Bond Donors & Acceptors:** Ligand A (HBD=1, HBA=3) is favorable. Ligand B (HBD=2, HBA=7) is also acceptable, but the higher HBA count could slightly impact permeability.

**QED:** Both ligands have reasonable QED values (A: 0.779, B: 0.606), indicating good drug-like properties.

**DILI:** Ligand A (37.456) has a lower DILI risk than Ligand B (50.174), both are acceptable.

**BBB:** Ligand A (92.633) shows excellent BBB penetration, a critical factor for a CNS target like DRD2. Ligand B (54.75) is considerably lower, raising concerns about reaching the target in the brain.

**Caco-2 Permeability:** Ligand A (-4.18) has poor Caco-2 permeability. Ligand B (-5.059) is also poor, but slightly worse.

**Aqueous Solubility:** Ligand A (-3.4) and Ligand B (-1.27) both have poor solubility.

**hERG Inhibition:** Ligand A (0.751) has a lower hERG risk than Ligand B (0.189).

**Microsomal Clearance:** Ligand A (52.737) has higher clearance than Ligand B (34.458), suggesting lower metabolic stability.

**In vitro Half-Life:** Ligand B (12.158 hours) has a significantly longer half-life than Ligand A (-15.045 hours), which is a major advantage.

**P-gp Efflux:** Ligand A (0.217) shows lower P-gp efflux than Ligand B (0.009), which is favorable for CNS penetration.

**Binding Affinity:** Both ligands have good binding affinities (A: -7.7 kcal/mol, B: -6.9 kcal/mol), with Ligand A being slightly stronger. The 0.8 kcal/mol difference is significant.

**Conclusion:**

Considering the GPCR-specific priorities, Ligand A is the more promising candidate. While it has poorer Caco-2 permeability and metabolic stability, its superior BBB penetration, favorable logP, and slightly better binding affinity outweigh these drawbacks. The strong BBB score is crucial for a CNS target. Ligand B's low logP and poor BBB penetration are significant liabilities.

Output:
1
2025-04-17 08:47:05,471 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (351.447 and 349.45 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (87.74) is better than Ligand B (62.3). Both are below the 90 A^2 threshold for CNS targets, but A is closer to the upper limit.

**3. logP:** Ligand B (2.902) is optimal (1-3), while Ligand A (0.293) is quite low, potentially hindering membrane permeability. This is a significant drawback for A.

**4. H-Bond Donors:** Ligand A (2) and Ligand B (1) are both acceptable (<=5).

**5. H-Bond Acceptors:** Ligand A (4) and Ligand B (3) are both acceptable (<=10).

**6. QED:** Both ligands have good QED scores (0.674 and 0.746, respectively), indicating drug-like properties.

**7. DILI:** Ligand B (18.069) has a much lower DILI risk than Ligand A (35.285). This is a clear advantage for B.

**8. BBB:** Ligand B (91.663) exhibits excellent BBB penetration, exceeding the desirable >70% threshold for CNS targets. Ligand A (45.715) is considerably lower, raising concerns about CNS exposure.

**9. Caco-2 Permeability:** Both have negative values which is unusual. Assuming these are logP values, both are poor.

**10. Aqueous Solubility:** Both have negative values which is unusual.

**11. hERG Inhibition:** Ligand A (0.084) shows slightly lower hERG inhibition risk than Ligand B (0.453), but both are relatively low.

**12. Microsomal Clearance:** Ligand A (21.661) has a lower microsomal clearance than Ligand B (62.338), suggesting better metabolic stability.

**13. In vitro Half-Life:** Ligand B (-1.4) has a very short half-life, which is a major concern. Ligand A (-23.969) is also poor.

**14. P-gp Efflux:** Ligand A (0.029) shows very low P-gp efflux, which is favorable for CNS penetration. Ligand B (0.083) is slightly higher but still relatively low.

**15. Binding Affinity:** Ligand B (-8.2 kcal/mol) has a significantly stronger binding affinity than Ligand A (-7.1 kcal/mol). The 1.1 kcal/mol difference is substantial and can outweigh some ADME drawbacks.

**Overall Assessment:**

While Ligand A has better metabolic stability and P-gp efflux, Ligand B is superior overall. The critical factors driving this conclusion are:

*   **BBB Penetration:** Ligand B's high BBB penetration is crucial for a CNS target like DRD2. Ligand A's low BBB is a significant limitation.
*   **logP:** Ligand B's optimal logP value is much better than Ligand A's low value.
*   **Binding Affinity:** Ligand B's stronger binding affinity is a major advantage.
*   **DILI Risk:** Ligand B has a significantly lower risk of drug-induced liver injury.

The poor half-life of Ligand B is a concern, but could potentially be addressed through structural modifications. The low logP of Ligand A is more difficult to fix without significantly altering its binding affinity.

Output:
1
2025-04-17 08:47:05,471 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (358.404 and 364.471 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (58.2) is excellent, well below the 90 A^2 threshold for CNS targets. Ligand B (97.27) is higher, but still potentially acceptable, though less ideal.

**logP:** Ligand A (4.298) is slightly high, potentially leading to solubility issues or off-target interactions. Ligand B (1.748) is within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A (2 HBD, 2 HBA) is good. Ligand B (1 HBD, 5 HBA) is also acceptable.

**QED:** Both ligands have good QED scores (0.764 and 0.88), indicating good drug-like properties.

**DILI:** Ligand A (57.425) has a moderate DILI risk, but is still acceptable. Ligand B (46.917) has a lower, more favorable DILI risk.

**BBB:** Ligand A excels with a BBB percentile of 81.233, very desirable for a CNS target. Ligand B (45.366) is significantly lower, which is a major drawback for DRD2.

**Caco-2 Permeability:** Both have negative Caco-2 values (-4.659 and -4.784), which is unusual and suggests poor permeability. This is a concern for both.

**Aqueous Solubility:** Both ligands have very poor aqueous solubility (-4.839 and -2.6). This is a significant issue, especially given Ligand A's higher logP.

**hERG Inhibition:** Ligand A (0.814) shows some hERG inhibition risk, while Ligand B (0.331) has a lower risk, which is preferable.

**Microsomal Clearance:** Ligand B (-20.871) has a much lower (better) microsomal clearance than Ligand A (50.154), indicating greater metabolic stability.

**In vitro Half-Life:** Ligand A (22.103 hours) has a better in vitro half-life than Ligand B (10.028 hours).

**P-gp Efflux:** Ligand A (0.186) has lower P-gp efflux, which is good for CNS penetration. Ligand B (0.069) has even lower efflux, which is even better.

**Binding Affinity:** Ligand A (-9.6 kcal/mol) has a significantly stronger binding affinity than Ligand B (-7.2 kcal/mol). This is a substantial advantage, potentially outweighing some of its other drawbacks.

**Overall Assessment:**

Ligand A has a much stronger binding affinity and excellent BBB penetration, which are critical for a CNS GPCR target like DRD2. However, it has a higher logP, moderate DILI risk, some hERG risk, and poor solubility. Ligand B has better ADME properties (lower DILI, hERG, Cl_mic, Pgp) and acceptable logP, but its significantly weaker binding affinity and poor BBB penetration are major concerns.

The difference in binding affinity (2.4 kcal/mol) is substantial. For a GPCR, strong binding is often paramount, and can sometimes compensate for less-than-ideal ADME properties, *especially* if BBB penetration is good, as is the case with Ligand A. The poor solubility of Ligand A is a concern that could be addressed with formulation strategies.

Output:
1
2025-04-17 08:47:05,471 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (350.344 and 338.455 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (49.33) is better than Ligand B (51.37). Both are below the 90 A^2 threshold for CNS targets, which is good.

**3. logP:** Both ligands (2.511 and 2.841) are within the optimal 1-3 range.

**4. H-Bond Donors:** Ligand A (0) is preferable to Ligand B (2). Fewer HBDs generally improve permeability.

**5. H-Bond Acceptors:** Ligand A (4) is slightly higher than Ligand B (2), but both are well within the acceptable limit of 10.

**6. QED:** Both ligands have good QED values (0.85 and 0.904), indicating good drug-like properties.

**7. DILI:** Ligand A (45.677) has a lower DILI risk than Ligand B (56.844), making it more favorable. Both are below the concerning 60 threshold.

**8. BBB:** Ligand A (96.045) has significantly better BBB penetration potential than Ligand B (90.112). This is a *critical* factor for a CNS target like DRD2.

**9. Caco-2 Permeability:** Ligand A (-4.503) shows better Caco-2 permeability than Ligand B (-4.864).

**10. Aqueous Solubility:** Ligand A (-2.479) has slightly better aqueous solubility than Ligand B (-3.384).

**11. hERG Inhibition:** Both ligands have low hERG inhibition risk (0.907 and 0.851).

**12. Microsomal Clearance:** Ligand B (16.386) has lower microsomal clearance than Ligand A (23.712), suggesting better metabolic stability.

**13. In vitro Half-Life:** Ligand B (57.549) has a significantly longer in vitro half-life than Ligand A (-19.361). This is a significant advantage.

**14. P-gp Efflux:** Both ligands have low P-gp efflux liability (0.277 and 0.327).

**15. Binding Affinity:** Both ligands have very similar and strong binding affinities (-8.6 and -8.4 kcal/mol). The difference is negligible.

**Overall Assessment:**

Ligand A excels in BBB penetration, TPSA, and DILI risk. Ligand B has better metabolic stability (lower Cl_mic and longer t1/2). However, for a CNS target like DRD2, BBB penetration is paramount. The substantial difference in BBB scores (96.045 vs 90.112) heavily favors Ligand A. The slightly better solubility and permeability of Ligand A further support this conclusion. While Ligand B's metabolic stability is attractive, the improved CNS exposure potential of Ligand A is more critical for DRD2.

Output:
0
2025-04-17 08:47:05,471 - INFO - Reasoning:

Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (364.56 and 351.45 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (40.62) is excellent, well below the 90 A^2 threshold for CNS targets. Ligand B (107.53) is higher, but still potentially acceptable, though less ideal.

**3. logP:** Ligand A (3.52) is optimal (1-3). Ligand B (0.38) is quite low, potentially hindering permeability and CNS penetration.

**4. H-Bond Donors:** Ligand A (0) is good. Ligand B (4) is acceptable, but higher HBD can sometimes reduce permeability.

**5. H-Bond Acceptors:** Ligand A (3) is good. Ligand B (4) is also acceptable.

**6. QED:** Ligand A (0.71) is strong, indicating good drug-likeness. Ligand B (0.50) is at the threshold, indicating acceptable drug-likeness.

**7. DILI:** Both ligands have similar, low DILI risk (28.07 and 28.69 percentile).

**8. BBB:** This is critical for a CNS target. Ligand A excels with 89.26%, suggesting good brain penetration. Ligand B is very low at 29.12%, severely limiting its potential for CNS activity.

**9. Caco-2:** Ligand A (-4.81) is poor, indicating low intestinal absorption. Ligand B (-5.49) is also poor.

**10. Solubility:** Ligand A (-4.55) is poor. Ligand B (-2.18) is also poor.

**11. hERG:** Both ligands have low hERG risk (0.93 and 0.06 percentile).

**12. Cl_mic:** Ligand A (72.19) is moderate. Ligand B (27.27) is lower, suggesting better metabolic stability.

**13. t1/2:** Ligand A (-41.30) is very negative, indicating a short half-life. Ligand B (-0.57) is slightly negative, indicating a short half-life.

**14. Pgp:** Ligand A (0.49) is relatively low, suggesting less efflux. Ligand B (0.04) is very low, suggesting minimal efflux.

**15. Binding Affinity:** Ligand B (-8.6 kcal/mol) has a significantly stronger binding affinity than Ligand A (-7.3 kcal/mol) - a difference of 1.3 kcal/mol. This is a substantial advantage.

**Overall Assessment:**

While Ligand B boasts superior binding affinity, the extremely poor BBB penetration (29.12%) is a major drawback for a CNS target like DRD2. Ligand A, despite a slightly weaker affinity, has a very good BBB penetration (89.26%) and a more optimal logP. The poor Caco-2 and solubility for both are concerns, but can be addressed with formulation strategies. The metabolic stability of Ligand B is better, but the brain exposure issue is paramount.

Given the GPCR-specific priorities, particularly BBB for CNS targets, Ligand A is the more promising candidate. The affinity difference, while significant, can potentially be optimized in subsequent iterations of drug design, whereas improving BBB penetration is significantly more challenging.

Output:
1
2025-04-17 08:47:05,472 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (350.463 and 370.431 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (87.47) is excellent, falling well below the 90 A^2 threshold for CNS targets. Ligand B (132.46) is higher, but still potentially acceptable, though less ideal.

**logP:** Ligand A (1.449) is within the optimal 1-3 range. Ligand B (-0.802) is slightly below 1, which could potentially hinder permeation.

**H-Bond Donors/Acceptors:** Ligand A (HBD=2, HBA=5) and Ligand B (HBD=3, HBA=6) both have reasonable numbers of H-bond donors and acceptors, staying within the guidelines.

**QED:** Ligand A (0.777) has a better QED score than Ligand B (0.575), indicating a more drug-like profile.

**DILI:** Ligand A (29.236) has a significantly lower DILI risk than Ligand B (78.325). This is a major advantage for Ligand A.

**BBB:** Ligand A (58.976) has a better BBB penetration percentile than Ligand B (27.763). While neither is >70, A is significantly better. This is critical for a CNS target like DRD2.

**Caco-2 Permeability:** Ligand A (-5.336) and Ligand B (-5.73) both have negative values, which is unusual and suggests poor permeability. This is a concern for both.

**Aqueous Solubility:** Both ligands have very poor aqueous solubility (-1.327 and -2.196 respectively). This will likely require formulation strategies.

**hERG Inhibition:** Both ligands show low hERG inhibition risk (0.313 and 0.062).

**Microsomal Clearance:** Ligand A (-16.671) has a lower (better) microsomal clearance than Ligand B (-12.316), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (15.96) and Ligand B (14.083) have similar in vitro half-lives.

**P-gp Efflux:** Ligand A (0.073) has a lower P-gp efflux liability than Ligand B (0.012), which is favorable for CNS penetration.

**Binding Affinity:** Ligand A (-8.8 kcal/mol) has a significantly stronger binding affinity than Ligand B (-7.3 kcal/mol). This 1.5 kcal/mol difference is substantial and can outweigh some ADME drawbacks.

**Overall Assessment:**

Ligand A is the superior candidate. It has a better QED score, significantly lower DILI risk, better BBB penetration, lower P-gp efflux, and, most importantly, a substantially stronger binding affinity. While both have poor solubility and Caco-2 permeability, the superior binding and CNS properties of Ligand A make it the more promising drug candidate.

Output:
1
2025-04-17 08:47:05,472 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (338.371 and 343.406 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (114.77) is slightly above the optimal <90 for CNS targets, but still reasonable. Ligand B (84.81) is excellent, well below 90.

**logP:** Both ligands have acceptable logP values (1.004 and 2.505), falling within the 1-3 range. Ligand B is slightly better positioned.

**H-Bond Donors/Acceptors:** Both have 2 HBD and are within the acceptable range of <=5. Ligand A has 5 HBA, while Ligand B has 4. Both are within the acceptable range of <=10.

**QED:** Both ligands have good QED scores (0.81 and 0.757), indicating good drug-like properties.

**DILI:** Ligand A (65.723) has a higher DILI risk than Ligand B (38.62), which is preferable.

**BBB:** This is critical for a CNS target. Ligand B (76.347) has a significantly better BBB percentile than Ligand A (23.304). This is a major advantage for Ligand B.

**Caco-2 Permeability:** Ligand A (-5.166) has poor Caco-2 permeability, while Ligand B (-4.814) is slightly better but still not great.

**Aqueous Solubility:** Both have poor aqueous solubility (-3.84 and -3.625). This could pose formulation challenges, but is less critical than BBB for a CNS target.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.369 and 0.868), which is good.

**Microsomal Clearance:** Ligand A (0.995) has significantly lower microsomal clearance than Ligand B (26.39), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand B (16.231) has a longer half-life than Ligand A (8.993), which is favorable.

**P-gp Efflux:** Ligand A (0.033) has very low P-gp efflux, which is excellent for CNS penetration. Ligand B (0.14) is slightly higher, but still reasonable.

**Binding Affinity:** Ligand B (-7.7 kcal/mol) has a 0.3 kcal/mol better binding affinity than Ligand A (-8.4 kcal/mol). While both are excellent, the difference is significant.

**Overall Assessment:**

Ligand B is the stronger candidate. It has a significantly better BBB percentile (76.347 vs 23.304), which is paramount for a CNS target like DRD2. It also exhibits better binding affinity (-7.7 vs -8.4), a lower DILI risk, and a longer half-life. While Ligand A has better metabolic stability and lower P-gp efflux, the substantial advantage of Ligand B in BBB penetration and affinity outweighs these benefits. The poor Caco-2 and solubility are concerns for both, but are less critical for a CNS-focused drug.

Output:
1
2025-04-17 08:47:05,472 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 drug candidates, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (347.375 Da) is slightly lower, which is generally favorable for permeability. Ligand B (377.941 Da) is also acceptable.

**TPSA:** Ligand A (127.51) is borderline for CNS penetration, being slightly above the preferred <90 threshold. Ligand B (36.44) is excellent, well below the threshold, indicating good potential for CNS penetration.

**logP:** Ligand A (-0.103) is quite low, potentially hindering membrane permeability and absorption. Ligand B (3.881) is very good, falling within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A has 2 HBD and 7 HBA, which are reasonable. Ligand B has 0 HBD and 4 HBA, also acceptable.

**QED:** Both ligands have good QED scores (A: 0.543, B: 0.766), indicating drug-like properties.

**DILI:** Ligand A (75.184) has a higher DILI risk than Ligand B (29.585), which is a significant concern.

**BBB:** Both ligands have good BBB penetration (A: 71.966, B: 70.919), exceeding the 70% threshold, which is crucial for CNS targets.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.273 and -4.851). This is unusual and suggests poor permeability, but the scale is not defined, so it's hard to interpret.

**Aqueous Solubility:** Both ligands have negative solubility values (-2.468 and -2.9), which is also unusual.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (A: 0.094, B: 0.869).

**Microsomal Clearance:** Ligand A (20.873) has lower microsomal clearance than Ligand B (38.874), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (-13.574) has a negative half-life, which is not possible. Ligand B (11.874) has a reasonable half-life.

**P-gp Efflux:** Ligand A (0.013) has very low P-gp efflux, which is favorable for CNS exposure. Ligand B (0.503) has moderate P-gp efflux.

**Binding Affinity:** Ligand B (-7.7 kcal/mol) has a slightly better binding affinity than Ligand A (-7.1 kcal/mol), although both are good. The difference is less than the 1.5 kcal/mol threshold.

**Overall Assessment:**

Ligand B is the more promising candidate. While both have acceptable BBB penetration and binding affinity, Ligand B excels in logP, DILI risk, and has a reasonable half-life. Ligand A's low logP and higher DILI risk are significant drawbacks. The negative values for Caco-2 and solubility are concerning for both, but the other properties of Ligand B make it the better choice.

Output:
1
2025-04-17 08:47:05,472 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (340.39 and 339.44 Da) fall comfortably within the ideal 200-500 Da range.

**TPSA:** Ligand A (98.02) is higher than Ligand B (43.86). For CNS targets, we ideally want TPSA <= 90. Ligand B is significantly better here.

**logP:** Both ligands have acceptable logP values (0.896 and 1.355), falling within the 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A has 1 HBD and 5 HBA, while Ligand B has 0 HBD and 3 HBA. Both are within acceptable limits (<=5 HBD and <=10 HBA).

**QED:** Ligand A (0.894) has a better QED score than Ligand B (0.778), indicating a more drug-like profile.

**DILI:** Ligand B (19.43) has a much lower DILI risk than Ligand A (58.67), which is a significant advantage.

**BBB:** Ligand B (61.69) has a considerably higher BBB penetration percentile than Ligand A (32.14). This is *critical* for a CNS target like DRD2.

**Caco-2 Permeability:** Ligand A (-5.261) has a worse Caco-2 permeability than Ligand B (-4.421). Higher values are better.

**Aqueous Solubility:** Ligand A (-2.547) has a worse solubility than Ligand B (-1.331). Higher values are better.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.374 and 0.319).

**Microsomal Clearance:** Ligand B (4.425) has a lower microsomal clearance than Ligand A (30.361), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand B (4.73) has a longer in vitro half-life than Ligand A (-2.679).

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.047 and 0.045).

**Binding Affinity:** Ligand B (-9.0) has a slightly better binding affinity than Ligand A (-8.3). While both are excellent, the 0.7 kcal/mol difference is notable.

**Overall Assessment:**

Ligand B clearly outperforms Ligand A, primarily due to its significantly better BBB penetration, lower DILI risk, improved metabolic stability (lower Cl_mic, longer t1/2), and slightly better binding affinity. While Ligand A has a better QED score, the ADME properties of Ligand B are far more favorable for a CNS-targeting drug, especially considering the importance of BBB penetration for GPCRs in the brain. The lower TPSA of Ligand B is also a significant advantage.

Output:
1
2025-04-17 08:47:05,472 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (368.459 and 364.433 Da) fall within the ideal range of 200-500 Da.

**TPSA:** Ligand A (91.84) is slightly above the preferred <90 for CNS targets, while Ligand B (60.03) is well within the range. This favors Ligand B.

**logP:** Ligand A (0.498) is quite low, potentially hindering membrane permeability. Ligand B (1.981) is much better, falling within the optimal 1-3 range. This strongly favors Ligand B.

**H-Bond Donors/Acceptors:** Both have acceptable HBD (1) and HBA (6/5) counts, well within the guidelines.

**QED:** Both ligands have reasonable QED scores (0.757 and 0.678), indicating good drug-like properties.

**DILI:** Ligand A (62.001) has a higher DILI risk than Ligand B (19.542), which is a significant advantage for B.

**BBB:** Ligand B (93.641) has a much higher BBB penetration percentile than Ligand A (55.254). This is *critical* for a CNS target like DRD2 and a major advantage for Ligand B.

**Caco-2 Permeability:** Ligand A (-5.117) has a negative Caco-2 value which is unusual and suggests very poor permeability. Ligand B (-4.695) is also poor, but slightly better.

**Aqueous Solubility:** Both have negative solubility values, indicating poor solubility. This is a concern for both, but not a deciding factor.

**hERG:** Both ligands have low hERG inhibition liability (0.153 and 0.563), which is good.

**Microsomal Clearance:** Ligand A (26.821) has lower microsomal clearance than Ligand B (31.412), suggesting better metabolic stability. This favors Ligand A, but the difference isn't huge.

**In vitro Half-Life:** Ligand A (-19.307) has a negative half-life, which is not physically possible and suggests a problem with the data or the molecule. Ligand B (-7.596) is also negative, but less so.

**P-gp Efflux:** Both have very low P-gp efflux liability (0.056 and 0.033), which is favorable for CNS penetration.

**Binding Affinity:** Ligand A (-8.1 kcal/mol) has a slightly better binding affinity than Ligand B (-6.3 kcal/mol). This is a significant difference (1.8 kcal/mol) and could potentially outweigh some of the ADME drawbacks of Ligand A *if* the ADME issues weren't so severe.

**Overall Assessment:**

Despite the slightly better affinity of Ligand A, its extremely poor Caco-2 permeability, negative half-life, lower BBB penetration, and higher DILI risk make it a significantly less viable candidate. Ligand B, while having a slightly weaker affinity, possesses a much more favorable ADME profile, especially its high BBB penetration, lower DILI, and better logP. For a CNS target like DRD2, these factors are paramount. The negative half-life values are concerning for both, but less so for Ligand B given its other advantages.

Output:
1
2025-04-17 08:47:05,473 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (348.451 Da) is slightly preferred as it's closer to the lower end, potentially aiding permeability.

**TPSA:** Ligand A (84.22) is significantly better than Ligand B (66.91). For CNS targets, TPSA < 90 is desired, and A is closer to the optimal range.

**logP:** Ligand A (1.097) is optimal, while Ligand B (3.983) is approaching the upper limit. Higher logP can lead to off-target effects and solubility issues.

**H-Bond Donors/Acceptors:** Ligand A (0 HBD, 6 HBA) is preferable to Ligand B (2 HBD, 5 HBA). Lower HBD/HBA generally improves membrane permeability.

**QED:** Ligand A (0.761) has a better QED score than Ligand B (0.575), indicating a more drug-like profile.

**DILI:** Both ligands have similar DILI risk (A: 53.432, B: 56.146), and both are acceptable (<60).

**BBB:** Ligand A (83.831) has a significantly better BBB penetration percentile than Ligand B (71.035). This is a crucial factor for CNS targets like DRD2.

**Caco-2 Permeability:** Ligand A (-4.983) is better than Ligand B (-5.112), indicating better intestinal absorption.

**Aqueous Solubility:** Ligand A (-1.405) is better than Ligand B (-4.473).

**hERG Inhibition:** Both ligands have very low hERG inhibition liability (A: 0.067, B: 0.268), which is excellent.

**Microsomal Clearance:** Ligand A (25.971) has a lower microsomal clearance than Ligand B (54.432), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (12.684) has a lower half-life than Ligand B (43.945).

**P-gp Efflux:** Ligand A (0.394) has lower P-gp efflux than Ligand B (0.208), which is favorable for CNS penetration.

**Binding Affinity:** Both ligands have very similar and excellent binding affinities (-8.4 kcal/mol and -8.5 kcal/mol respectively). The difference is negligible.

**Overall:** Ligand A consistently outperforms Ligand B across most key ADME properties, particularly TPSA, logP, BBB, solubility, and metabolic stability. While both have excellent binding affinity, the superior ADME profile of Ligand A makes it the more promising drug candidate for targeting DRD2.

Output:
1
2025-04-17 08:47:05,473 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (382.913 and 363.845 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (58.64) is significantly better than Ligand B (82.53). For CNS targets, we want TPSA <= 90, and ideally closer to 60. Ligand A is much closer to this ideal.

**logP:** Both ligands have good logP values (2.652 and 1.334), falling within the 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A (HBD=1, HBA=4) and Ligand B (HBD=2, HBA=4) both have acceptable numbers of H-bond donors and acceptors.

**QED:** Both ligands have reasonable QED scores (0.851 and 0.773), indicating good drug-like properties.

**DILI:** Both ligands have low DILI risk (33.695 and 38.503), below the 40 threshold.

**BBB:** Ligand A (71.229) has a significantly better BBB percentile than Ligand B (24.738). This is *critical* for a CNS target like DRD2. A value >70 is desirable, and Ligand A is much closer.

**Caco-2 Permeability:** Both have negative Caco-2 values (-4.999 and -4.69), which is unusual and suggests poor permeability. However, these values are on a scale where negative values are possible and don't necessarily preclude activity.

**Aqueous Solubility:** Both ligands have negative solubility values (-3.784 and -2.629). This is also unusual, and indicates poor solubility.

**hERG Inhibition:** Both ligands show low hERG inhibition risk (0.447 and 0.188).

**Microsomal Clearance:** Ligand A (30.615) has higher microsomal clearance than Ligand B (-6.337). Lower clearance is preferred for better metabolic stability, so Ligand B is better here.

**In vitro Half-Life:** Ligand B (-1.44) has a negative half-life, which is not possible. This is a red flag. Ligand A (5.86) has a reasonable half-life.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.19 and 0.033), which is good for CNS penetration.

**Binding Affinity:** Ligand A (-8.6 kcal/mol) has a slightly better binding affinity than Ligand B (-7.8 kcal/mol). While both are good (<-7.0), the 0.8 kcal/mol difference is meaningful.

**Overall Assessment:**

Ligand A is significantly better due to its superior BBB penetration, more reasonable half-life, and slightly better binding affinity. While both have poor solubility and permeability (Caco-2), the BBB is paramount for a CNS target. Ligand B's negative half-life is a major concern. The better affinity of Ligand A, combined with its improved CNS penetration profile, makes it the more promising candidate.

Output:
1
2025-04-17 08:47:05,473 - INFO - Reasoning:

Let's analyze Ligand A and Ligand B for their potential as DRD2 drug candidates, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (339.443 and 347.415 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (63.91) is significantly better than Ligand B (75.88). For CNS targets, we want TPSA <= 90, and A is comfortably within that range, while B is approaching the upper limit.

**3. logP:** Both ligands have good logP values (2.032 and 1.36), falling within the optimal 1-3 range.

**4. H-Bond Donors:** Both have 0 HBD, which is acceptable.

**5. H-Bond Acceptors:** Both have 5 HBA, which is acceptable.

**6. QED:** Ligand A (0.855) has a better QED score than Ligand B (0.664), indicating a more drug-like profile.

**7. DILI:** Both ligands have low DILI risk (42.613 and 40.287), both below the 40 threshold.

**8. BBB:** Both ligands exhibit excellent BBB penetration (81.97% and 89.763%), exceeding the desirable >70% threshold for CNS targets. Ligand B is slightly better here.

**9. Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and suggests a potential issue with the data or modeling. However, we'll proceed assuming these represent low permeability.

**10. Aqueous Solubility:** Both have negative solubility values, again unusual. We'll assume this indicates poor solubility.

**11. hERG Inhibition:** Both ligands have low hERG inhibition risk (0.268 and 0.388).

**12. Microsomal Clearance:** Ligand A (32.246) has significantly lower microsomal clearance than Ligand B (62.775), suggesting better metabolic stability.

**13. In vitro Half-Life:** Ligand A (-4.693) has a much longer in vitro half-life than Ligand B (-23.527).

**14. P-gp Efflux:** Both have low P-gp efflux liability (0.07 and 0.274).

**15. Binding Affinity:** Ligand A (-9.1 kcal/mol) has a significantly stronger binding affinity than Ligand B (-6.9 kcal/mol). This >1.5 kcal/mol difference is substantial and outweighs minor ADME drawbacks.

**Overall Assessment:**

Ligand A is the superior candidate. While both have good BBB penetration and low DILI/hERG risk, Ligand A excels in crucial areas: TPSA, QED, metabolic stability (lower Cl_mic, longer t1/2), and, most importantly, binding affinity. The stronger binding affinity of Ligand A is a significant advantage for a GPCR target like DRD2. The negative solubility and Caco-2 values are concerning for both, but the superior potency and pharmacokinetic properties of Ligand A make it the more promising candidate.

Output:
1
2025-04-17 08:47:05,473 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (344.43 and 355.479 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (42.43) is significantly better than Ligand B (82.11). For CNS targets, we want TPSA <= 90, and ideally closer to 60. Ligand A is well within this range, while Ligand B is approaching the upper limit and less favorable.

**logP:** Ligand A (4.24) is a bit high, potentially leading to solubility issues, but still within a reasonable range. Ligand B (0.225) is very low, which is problematic for membrane permeability and CNS penetration. Optimal logP is 1-3.

**H-Bond Donors/Acceptors:** Ligand A (0 HBD, 4 HBA) is better than Ligand B (2 HBD, 5 HBA). Both are acceptable, but fewer H-bonds generally improve permeability.

**QED:** Both ligands have reasonable QED values (0.778 and 0.651), indicating good drug-like properties.

**DILI:** Ligand A (39.938) has a much lower DILI risk than Ligand B (7.135), which is a significant advantage.

**BBB:** Ligand A (96.123) has excellent BBB penetration potential, exceeding the desirable >70% threshold. Ligand B (45.909) is considerably lower, making CNS exposure less likely. This is a critical factor for a DRD2 ligand.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.5 and -4.977). This is unusual and suggests potential issues with the prediction method or the molecules themselves. It's difficult to interpret without further investigation.

**Aqueous Solubility:** Both ligands have negative solubility values (-3.939 and -0.595), which is also concerning and suggests poor solubility.

**hERG Inhibition:** Ligand A (0.908) has a slightly higher hERG risk than Ligand B (0.277), but both are relatively low.

**Microsomal Clearance:** Ligand A (94.873) has a high microsomal clearance, indicating rapid metabolism. Ligand B (2.335) has very low clearance, suggesting good metabolic stability.

**In vitro Half-Life:** Ligand A (29.518) has a moderate half-life. Ligand B (22.748) has a shorter half-life.

**P-gp Efflux:** Ligand A (0.69) has moderate P-gp efflux, while Ligand B (0.019) has very low efflux. Lower P-gp efflux is preferred for CNS penetration.

**Binding Affinity:** Ligand A (-8.2 kcal/mol) has significantly stronger binding affinity than Ligand B (-0.0 kcal/mol). This is a crucial advantage, as a >1.5 kcal/mol difference can outweigh other drawbacks.

**Overall Assessment:**

Ligand A is the superior candidate. Its strong binding affinity, excellent BBB penetration, lower DILI risk, and favorable TPSA outweigh its slightly higher logP and higher microsomal clearance. Ligand B's extremely low logP and poor BBB penetration are major drawbacks, despite its better metabolic stability. The negative solubility and Caco-2 values for both are concerning but might be artifacts of the prediction. The substantial difference in binding affinity (-8.2 vs -0.0) is the most decisive factor.

Output:
1
2025-04-17 08:47:05,474 - INFO - Batch 478 complete. Total preferences: 7648
2025-04-17 08:47:05,474 - INFO - Processing batch 479/512...
2025-04-17 08:47:47,534 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (345.4 and 342.5 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (106.57) is slightly above the optimal <90 for CNS targets, but still reasonable. Ligand B (49.41) is excellent, well below the threshold.

**logP:** Ligand A (1.167) is within the optimal 1-3 range. Ligand B (3.081) is also within range, but approaching the upper limit.

**H-Bond Donors/Acceptors:** Ligand A has 2 HBD and 5 HBA, both acceptable. Ligand B has 1 HBD and 2 HBA, also acceptable.

**QED:** Both ligands have good QED scores (0.833 and 0.789), indicating drug-like properties.

**DILI:** Ligand A (33.7) has a lower DILI risk than Ligand B (17.8), suggesting better hepatotoxicity potential.

**BBB:** Ligand B (81.7%) has a significantly higher BBB penetration score than Ligand A (67.3%). This is a crucial advantage for a CNS target like DRD2.

**Caco-2 Permeability:** Ligand A (-4.819) has worse Caco-2 permeability than Ligand B (-4.558), indicating lower intestinal absorption.

**Aqueous Solubility:** Both ligands have similar, very poor aqueous solubility (-3.396 and -3.135). This could pose formulation challenges.

**hERG Inhibition:** Both ligands have similar, low hERG inhibition risk (0.47 and 0.523).

**Microsomal Clearance:** Ligand A (23.19) has a lower microsomal clearance than Ligand B (78.7), indicating better metabolic stability.

**In vitro Half-Life:** Ligand A (18.5) has a longer in vitro half-life than Ligand B (-17.6), which is a significant advantage.

**P-gp Efflux:** Ligand A (0.028) has much lower P-gp efflux liability than Ligand B (0.295). Lower efflux is highly desirable for CNS penetration.

**Binding Affinity:** Both ligands have excellent binding affinity (-8.2 and -8.7 kcal/mol). Ligand B is slightly better, but the difference is small.

**Overall Assessment:**

Ligand B excels in BBB penetration and has slightly better binding affinity. However, Ligand A has a better safety profile (lower DILI), better metabolic stability (lower Cl_mic, longer t1/2), and significantly lower P-gp efflux. Considering the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity), the improved BBB of Ligand B is a strong point. However, the combination of lower P-gp efflux, better metabolic stability, and lower DILI risk for Ligand A makes it the more promising candidate. The solubility is a concern for both, but can potentially be addressed with formulation strategies.

Output:
1
2025-04-17 08:47:47,534 - INFO - Reasoning:

Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (339.355 and 350.503 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (98.48) is slightly above the preferred <90 for CNS targets, but still reasonable. Ligand B (58.64) is well within the optimal range. This favors Ligand B.

**3. logP:** Both ligands have good logP values (1.925 and 2.879), falling within the 1-3 range.

**4. H-Bond Donors:** Both have 1 HBD, which is acceptable.

**5. H-Bond Acceptors:** Ligand A has 7 HBAs, and Ligand B has 3. Both are within the acceptable limit of <=10.

**6. QED:** Both ligands have good QED scores (0.729 and 0.768), indicating good drug-like properties.

**7. DILI:** Ligand A has a high DILI risk (98.488%), which is a significant concern. Ligand B has a much lower DILI risk (14.696%), making it considerably safer.

**8. BBB:** Ligand A has a BBB penetration of 72.237%, which is acceptable but not outstanding. Ligand B has a significantly better BBB penetration (81.194%), which is highly desirable for a CNS target like DRD2.

**9. Caco-2 Permeability:** Both have negative Caco-2 values (-4.967 and -4.791). These values are unusual and likely represent a logP-scaled permeability, where negative values indicate poor permeability. However, the values are very close, so this isn't a major differentiator.

**10. Aqueous Solubility:** Both have negative solubility values (-3.819 and -2.7). Similar to Caco-2, these are likely scaled values, and negative values suggest poor solubility. Again, the difference isn't substantial.

**11. hERG Inhibition:** Both ligands show low hERG inhibition risk (0.231 and 0.504).

**12. Microsomal Clearance:** Ligand A has a higher microsomal clearance (95.155) than Ligand B (48.321), indicating lower metabolic stability. Ligand B is preferred.

**13. In vitro Half-Life:** Ligand A has a slightly longer half-life (4.219 hours) than Ligand B (3.086 hours), but the difference is not substantial.

**14. P-gp Efflux:** Both ligands have low P-gp efflux liability (0.181 and 0.158).

**15. Binding Affinity:** Ligand A (-9.3 kcal/mol) has a slightly better binding affinity than Ligand B (-8.8 kcal/mol). However, the difference is only 0.5 kcal/mol, which is less significant than the ADME advantages of Ligand B.

**Overall Assessment:**

Ligand B is the superior candidate. While Ligand A has marginally better binding affinity, Ligand B excels in critical ADME properties for a CNS-targeting GPCR. Specifically, its significantly lower DILI risk, better BBB penetration, and improved metabolic stability (lower Cl_mic) outweigh the small difference in binding affinity. The TPSA is also more favorable for CNS penetration.

Output:
1
2025-04-17 08:47:47,534 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (347.415 Da) is slightly lower, which could be beneficial for permeability. Ligand B (360.376 Da) is also good.

**TPSA:** Ligand A (113.68) is better than Ligand B (67.43), being closer to the ideal threshold of 90 for CNS targets. Ligand B is excellent.

**logP:** Ligand A (0.683) is a bit low, potentially hindering membrane permeability. Ligand B (3.123) is within the optimal range (1-3).

**H-Bond Donors/Acceptors:** Ligand A has 4 HBD and 5 HBA, which are acceptable. Ligand B has 2 HBD and 3 HBA, also acceptable.

**QED:** Both ligands have good QED values (Ligand A: 0.64, Ligand B: 0.748), indicating drug-like properties.

**DILI:** Ligand A (31.059) has a lower DILI risk than Ligand B (44.436), which is preferable. Both are below the concerning threshold of 60.

**BBB:** Ligand B (85.653) has a significantly higher BBB penetration percentile than Ligand A (32.92). This is a *major* advantage for a CNS target like DRD2.

**Caco-2 Permeability:** Ligand A (-5.636) has poor Caco-2 permeability, while Ligand B (-4.577) is slightly better, but still not great.

**Aqueous Solubility:** Both ligands have poor aqueous solubility (-3.125 and -3.938).

**hERG Inhibition:** Ligand A (0.138) has a lower hERG inhibition liability than Ligand B (0.786), which is favorable.

**Microsomal Clearance:** Ligand A (11.853) has lower microsomal clearance than Ligand B (47.498), suggesting better metabolic stability.

**In vitro Half-Life:** Both ligands have similar in vitro half-lives (Ligand A: 5.416, Ligand B: 5.859).

**P-gp Efflux:** Ligand A (0.012) has very low P-gp efflux liability, which is excellent for CNS penetration. Ligand B (0.169) is higher, but still relatively low.

**Binding Affinity:** Both ligands have very similar and strong binding affinities (-8.1 and -8.2 kcal/mol). This difference is negligible.

**Overall Assessment:**

Ligand B is superior due to its significantly higher BBB penetration (85.653 vs 32.92). While Ligand A has advantages in DILI, hERG, and metabolic stability, the BBB is paramount for a CNS-targeting drug. Ligand B's logP is also more favorable. The similar binding affinities make the ADME properties the deciding factor.

Output:
1
2025-04-17 08:47:47,535 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 drug candidates, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (336.395 and 344.455 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (92.24) is better than Ligand B (56.92). For CNS targets, TPSA should be <=90, so Ligand A is borderline, while Ligand B is well within the desired range.

**logP:** Ligand A (2.062) is optimal, while Ligand B (3.483) is slightly higher but still acceptable.

**H-Bond Donors/Acceptors:** Both ligands have 1 HBD and 4-5 HBA, which are within acceptable limits.

**QED:** Ligand A (0.922) has a much higher QED score than Ligand B (0.715), indicating better overall drug-likeness.

**DILI:** Ligand A (58.627) has a higher DILI risk than Ligand B (33.307). This is a significant advantage for Ligand B.

**BBB:** Ligand A (70.88) has a good BBB penetration percentile, exceeding the 70% threshold for CNS targets. Ligand B (49.554) is significantly lower, which is a major drawback.

**Caco-2 Permeability:** Ligand A (-4.954) has poor Caco-2 permeability, while Ligand B (-5.067) is also poor, but slightly worse.

**Aqueous Solubility:** Ligand A (-3.856) has poor aqueous solubility, while Ligand B (-1.834) is better.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.824 and 0.768, respectively).

**Microsomal Clearance:** Ligand A (58.29) has a higher microsomal clearance than Ligand B (9.457), indicating lower metabolic stability. Ligand B is significantly better in this regard.

**In vitro Half-Life:** Ligand A (9.341) has a slightly longer half-life than Ligand B (54.01).

**P-gp Efflux:** Ligand A (0.312) has lower P-gp efflux than Ligand B (0.082), which is favorable for CNS penetration.

**Binding Affinity:** Ligand B (-7.8 kcal/mol) has a significantly stronger binding affinity than Ligand A (-9.5 kcal/mol). This is a substantial advantage.

**Overall Assessment:**

Ligand A has better QED, P-gp efflux, and slightly better half-life, and acceptable BBB. However, it suffers from poor Caco-2 permeability, poor aqueous solubility, higher DILI risk, and higher microsomal clearance.

Ligand B has a much stronger binding affinity, lower DILI risk, significantly better metabolic stability (lower Cl_mic), and better aqueous solubility. The lower BBB penetration is a concern, but the significantly improved affinity may compensate for this, especially if further optimization can improve BBB.

Given the GPCR-specific priorities, the stronger binding affinity of Ligand B (-7.8 kcal/mol vs -9.5 kcal/mol) is a decisive factor. A 1.7 kcal/mol difference in binding is substantial and can outweigh the drawbacks of lower BBB and slightly worse Caco-2 permeability.

Output:
1
2025-04-17 08:47:47,535 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 drug candidates, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (352.45 and 347.459 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (58.64) is significantly better than Ligand B (78.51). For CNS targets, we want TPSA <= 90, and A is comfortably within that range, while B is approaching the upper limit.

**3. logP:** Both ligands have good logP values (2.191 and 1.532), falling within the optimal 1-3 range.

**4. H-Bond Donors:** Ligand A (1) is preferable to Ligand B (2). Lower HBD generally improves permeability.

**5. H-Bond Acceptors:** Both ligands have 3 HBA, which is acceptable.

**6. QED:** Ligand A (0.797) has a significantly better QED score than Ligand B (0.49), indicating a more drug-like profile.

**7. DILI:** Both ligands have low DILI risk (18.573 and 16.557), which is good.

**8. BBB:** Ligand A (87.088) has a much better BBB percentile than Ligand B (71.811).  For a CNS target like DRD2, >70 is desirable, and A is closer to that threshold.

**9. Caco-2:** Ligand A (-4.677) has a worse Caco-2 permeability than Ligand B (-5.284). However, Caco-2 is less critical than BBB for CNS targets.

**10. Solubility:** Ligand A (-2.674) has slightly better solubility than Ligand B (-1.685).

**11. hERG:** Both ligands have very low hERG risk (0.582 and 0.147).

**12. Cl_mic:** Ligand B (21.264) has lower microsomal clearance than Ligand A (30.314), suggesting better metabolic stability.

**13. t1/2:** Ligand A (5.602) has a longer in vitro half-life than Ligand B (-14.29). A negative half-life is concerning and suggests rapid degradation.

**14. Pgp:** Ligand A (0.143) has lower P-gp efflux liability than Ligand B (0.034), which is desirable for CNS penetration.

**15. Binding Affinity:** Ligand A (-8.8 kcal/mol) has a significantly stronger binding affinity than Ligand B (-7.6 kcal/mol). This >1.5 kcal/mol difference is substantial and can outweigh minor ADME drawbacks.

**Overall Assessment:**

Ligand A is the stronger candidate. While Ligand B has slightly better metabolic stability, Ligand A excels in crucial areas for a CNS-targeting GPCR: TPSA, BBB penetration, QED, and, most importantly, binding affinity. The significantly stronger binding affinity of Ligand A (-8.8 vs -7.6 kcal/mol) is a major advantage. The longer half-life of Ligand A is also a positive.



Output:
1
2025-04-17 08:47:47,535 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (346.391 and 342.483 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (114.91) is better than Ligand B (49.41). Both are below the 90 A^2 threshold for CNS targets, but A is closer to the upper limit.

**3. logP:** Ligand B (2.888) is optimal (1-3), while Ligand A (0.866) is slightly low, potentially hindering permeation.

**4. H-Bond Donors:** Ligand A (2) is reasonable, while Ligand B (1) is also good.

**5. H-Bond Acceptors:** Ligand A (7) is reasonable, while Ligand B (2) is excellent.

**6. QED:** Both ligands have good QED scores (0.797 and 0.854), indicating drug-like properties.

**7. DILI:** Ligand A (67.546) has a higher DILI risk than Ligand B (13.532). This is a significant negative for Ligand A.

**8. BBB:** Ligand B (70.997) is much better than Ligand A (56.65). Ligand B exceeds the desirable >70 percentile for CNS targets, while A falls short.

**9. Caco-2 Permeability:** Ligand A (-5.426) is significantly worse than Ligand B (-4.865). Both are negative, indicating poor permeability.

**10. Aqueous Solubility:** Ligand A (-1.624) is better than Ligand B (-3.432).

**11. hERG:** Ligand A (0.065) is better than Ligand B (0.344), indicating lower cardiotoxicity risk.

**12. Microsomal Clearance:** Ligand A (-26.488) is much better than Ligand B (49.742), suggesting better metabolic stability.

**13. In vitro Half-Life:** Ligand A (20.352) is better than Ligand B (-10.746).

**14. P-gp Efflux:** Ligand A (0.019) is significantly better than Ligand B (0.097), indicating lower efflux and potentially better CNS exposure.

**15. Binding Affinity:** Ligand B (-9.6 kcal/mol) has a slightly better binding affinity than Ligand A (-7.9 kcal/mol). This 1.7 kcal/mol difference is substantial and can outweigh some ADME drawbacks.

**Overall Assessment:**

While Ligand A has advantages in metabolic stability (Cl_mic, t1/2), P-gp efflux, and hERG, Ligand B excels in critical areas for a CNS-targeting GPCR ligand: BBB penetration and binding affinity. The significantly lower DILI risk for Ligand B is also a major advantage. Ligand A's low logP and poor Caco-2 permeability are concerning. The superior BBB penetration and binding affinity of Ligand B, coupled with its lower DILI risk, make it the more promising candidate despite its slightly higher P-gp efflux and worse metabolic stability.

Output:
1
2025-04-17 08:47:47,535 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (411.231 Da) is slightly higher than Ligand B (366.38 Da), but both are acceptable.

**2. TPSA:** Both ligands have TPSA values below the 90 A^2 threshold for CNS targets. Ligand A (85.25 A^2) is slightly higher than Ligand B (78.87 A^2), but both are good.

**3. logP:** Both ligands have optimal logP values (1-3). Ligand A (1.725) and Ligand B (1.222) are both well within this range.

**4. H-Bond Donors:** Both ligands have 2 HBD, which is within the acceptable limit of <=5.

**5. H-Bond Acceptors:** Ligand A has 5 HBA, and Ligand B has 4 HBA, both within the acceptable limit of <=10.

**6. QED:** Both ligands have similar QED values (0.734 and 0.71), indicating good drug-like properties.

**7. DILI:** Ligand A has a DILI risk of 89.259, which is high. Ligand B has a much lower DILI risk of 29.236, which is excellent. This is a significant advantage for Ligand B.

**8. BBB:** Both ligands have good BBB penetration (Ligand A: 70.803, Ligand B: 78.829). Ligand B is slightly better, exceeding 70% which is desirable for CNS targets.

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 values, which is unusual and suggests poor permeability. However, the scale is not defined, so it's hard to interpret.

**10. Aqueous Solubility:** Both ligands have negative solubility values, which is also unusual and suggests poor solubility. Again, the scale is not defined.

**11. hERG Inhibition:** Both ligands have low hERG inhibition risk (Ligand A: 0.61, Ligand B: 0.427).

**12. Microsomal Clearance:** Ligand A has a moderate Cl_mic (52.818 mL/min/kg), while Ligand B has a very low Cl_mic (2.264 mL/min/kg). This indicates much better metabolic stability for Ligand B.

**13. In vitro Half-Life:** Ligand A has a half-life of 10.143 hours, while Ligand B has a negative half-life (-17.497 hours). The negative value is concerning and likely an error or indicates very rapid degradation.

**14. P-gp Efflux:** Both ligands have low P-gp efflux liability (Ligand A: 0.47, Ligand B: 0.03). Ligand B is significantly better, suggesting better CNS exposure.

**15. Binding Affinity:** Both ligands have very similar and strong binding affinities (-8.9 kcal/mol and -8.7 kcal/mol). The difference is less than 1.5 kcal/mol, so it's not a deciding factor.

**Overall Assessment:**

While both ligands have good affinity and BBB penetration, Ligand B is significantly better overall. Its lower DILI risk, much better metabolic stability (lower Cl_mic), and lower P-gp efflux make it a more promising candidate. The negative values for Caco-2 and solubility are concerning for both, but the other advantages of Ligand B outweigh these issues. The negative half-life for Ligand B is a red flag, but the other properties are so much better that it's still the preferred candidate.

Output:
1
2025-04-17 08:47:47,536 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (343.47 and 361.83 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (38.77) is excellent, well below the 90 A^2 threshold for CNS targets. Ligand B (79.24) is higher, but still reasonably acceptable, though less ideal.

**logP:** Ligand A (3.746) is within the optimal 1-3 range. Ligand B (4.493) is slightly above this, potentially raising concerns about solubility and off-target effects, but not drastically.

**H-Bond Donors/Acceptors:** Ligand A has 0 HBD and 3 HBA, which is good. Ligand B has 1 HBD and 3 HBA, also acceptable.

**QED:** Ligand A (0.765) has a strong drug-like profile. Ligand B (0.325) is significantly lower, indicating a less favorable overall drug-likeness.

**DILI:** Ligand A (25.09) has a very low DILI risk. Ligand B (64.75) is higher, indicating a moderate risk of liver injury.

**BBB:** Ligand A (80.57) has good BBB penetration, exceeding the 70% threshold for CNS targets. Ligand B (64.48) is below this threshold, which is a significant drawback for a CNS target like DRD2.

**Caco-2 Permeability:** Both have negative values, indicating poor permeability. However, the scale is not specified, making direct comparison difficult.

**Aqueous Solubility:** Both have negative values, indicating poor solubility. The scale is not specified, making direct comparison difficult.

**hERG:** Both ligands have low hERG inhibition liability (0.684 and 0.822), which is positive.

**Microsomal Clearance:** Both have similar microsomal clearance values (74.86 and 79.37), indicating similar metabolic stability.

**In vitro Half-Life:** Both have similar in vitro half-lives (12.85 and 11.81 hours).

**P-gp Efflux:** Both have low P-gp efflux liability (0.671 and 0.602), which is favorable for CNS penetration.

**Binding Affinity:** Ligand B (-7.8 kcal/mol) has significantly stronger binding affinity than Ligand A (-0.0 kcal/mol). This is a substantial advantage.

**Overall Assessment:**

Ligand B's significantly higher binding affinity is a major advantage. However, it suffers from lower QED, higher DILI risk, and, critically, poorer BBB penetration compared to Ligand A. For a CNS target like DRD2, BBB penetration is paramount. While the affinity difference is substantial, the poor BBB penetration of Ligand B is a significant hurdle. Ligand A, while having weaker affinity, possesses a much better overall profile, particularly regarding CNS penetration and safety (DILI). The combination of good BBB, low DILI, and acceptable physicochemical properties makes Ligand A a more promising starting point for drug development, even with its weaker binding. Further optimization could focus on improving the affinity of Ligand A while maintaining its favorable ADME properties.

Output:
0
2025-04-17 08:47:47,536 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (343.515 and 343.383 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (36.44) is excellent, well below the 90 A^2 threshold for CNS targets. Ligand B (93.46) is higher, approaching the upper limit for good oral absorption (140) but less desirable for CNS penetration.

**3. logP:** Ligand A (3.231) is within the optimal range of 1-3. Ligand B (1.434) is at the lower end, potentially hindering permeation.

**4. H-Bond Donors:** Ligand A (0) is good. Ligand B (2) is acceptable.

**5. H-Bond Acceptors:** Ligand A (4) is good. Ligand B (5) is acceptable.

**6. QED:** Both ligands (0.762 and 0.756) have good drug-likeness scores, exceeding the 0.5 threshold.

**7. DILI:** Ligand A (1.551) has a very low DILI risk. Ligand B (52.385) has a moderate DILI risk, but is still within acceptable limits.

**8. BBB:** Ligand A (91.586) has excellent BBB penetration, exceeding the 70% threshold. Ligand B (74.292) is good, but not as favorable as Ligand A.

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.989 and -4.891), which is unusual and suggests poor permeability. However, these values are on a log scale and negative values are common.

**10. Aqueous Solubility:** Both ligands have negative solubility values (-1.125 and -2.815), which is also unusual.

**11. hERG Inhibition:** Both ligands have low hERG inhibition risk (0.875 and 0.168).

**12. Microsomal Clearance:** Ligand A (7.028) has a lower microsomal clearance, indicating better metabolic stability. Ligand B (28.624) has a significantly higher clearance.

**13. In vitro Half-Life:** Ligand A (-12.859) has a very long in vitro half-life. Ligand B (-3.393) has a shorter half-life.

**14. P-gp Efflux:** Both ligands have low P-gp efflux liability (0.26 and 0.123).

**15. Binding Affinity:** Ligand B (-9.3 kcal/mol) has a significantly stronger binding affinity than Ligand A (-7.9 kcal/mol), exceeding the 1.5 kcal/mol advantage threshold.

**Overall Assessment:**

Ligand B has a substantially better binding affinity. However, Ligand A has superior ADME properties, particularly regarding BBB penetration, metabolic stability, and lower DILI risk. Given that this is a CNS target (DRD2), BBB penetration is critical. The significantly stronger affinity of Ligand B is a major advantage, but the lower BBB and higher clearance are concerning. The negative solubility and Caco-2 values for both are concerning and would need further investigation. However, the difference in affinity is substantial enough to outweigh the slightly less favorable ADME profile of Ligand B, *assuming* the solubility and permeability issues can be addressed through formulation or further chemical modification.

Output:
1
2025-04-17 08:47:47,536 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (351.378 and 351.451 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (86.79) is significantly better than Ligand B (113.49). For CNS targets, we want TPSA <= 90, and A is comfortably within that range, while B is slightly above.

**3. logP:** Ligand B (0.922) is slightly better than Ligand A (-0.213). Both are within the 1-3 range, but A is a bit low, potentially hindering permeation.

**4. H-Bond Donors:** Ligand A (1) is preferable to Ligand B (3). Lower HBD generally improves permeability.

**5. H-Bond Acceptors:** Ligand A (4) is preferable to Ligand B (6). Lower HBA generally improves permeability.

**6. QED:** Both ligands have acceptable QED values (0.746 and 0.642, both > 0.5).

**7. DILI:** Ligand B (24.855) has a much lower DILI risk than Ligand A (38.348). This is a significant advantage for B.

**8. BBB:** Ligand B (76.735) has a better BBB penetration percentile than Ligand A (68.282). While both are reasonably good, >70 is desirable for CNS targets, and B is closer.

**9. Caco-2 Permeability:** Ligand A (-4.769) has better Caco-2 permeability than Ligand B (-5.238), but both are negative and not particularly informative without knowing the scale.

**10. Aqueous Solubility:** Both ligands have very poor aqueous solubility (-2.447 and -2.58). This is a concern for both, but not a deciding factor.

**11. hERG Inhibition:** Ligand A (0.064) has a slightly lower hERG inhibition liability than Ligand B (0.351), which is preferable.

**12. Microsomal Clearance:** Ligand A (13.226) has a significantly lower microsomal clearance than Ligand B (33.094), indicating better metabolic stability.

**13. In vitro Half-Life:** Ligand A (-35.252) has a much longer in vitro half-life than Ligand B (9.454). This is a major advantage for A.

**14. P-gp Efflux:** Ligand A (0.006) has a much lower P-gp efflux liability than Ligand B (0.013), which is crucial for CNS penetration.

**15. Binding Affinity:** Both ligands have very similar binding affinities (-7.8 and -7.7 kcal/mol). The difference is negligible.

**Overall Assessment:**

Considering the GPCR-specific priorities, Ligand A is slightly favored. While Ligand B has better BBB and lower DILI, Ligand A excels in TPSA, HBD/HBA, metabolic stability (Cl_mic and t1/2), and P-gp efflux. The slightly lower logP of A is a minor concern, but the substantial improvements in TPSA, metabolic stability, and efflux outweigh this. The similar binding affinities mean that the ADME properties become the deciding factor.

Output:
0
2025-04-17 08:47:47,536 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (406.24 Da) is slightly higher than Ligand B (353.463 Da), but both are acceptable.

**TPSA:** Ligand A (101.22) is higher than Ligand B (84.32). For CNS targets, we want TPSA <= 90. Ligand B is preferable here.

**logP:** Ligand A (2.407) is within the optimal range (1-3). Ligand B (-0.34) is *below* 1, which could hinder permeation. This is a significant drawback for Ligand B.

**H-Bond Donors:** Both ligands have 2 HBD, which is within the acceptable limit of <= 5.

**H-Bond Acceptors:** Ligand A has 6 HBA, and Ligand B has 5, both within the acceptable limit of <= 10.

**QED:** Both ligands have good QED scores (A: 0.621, B: 0.706), indicating drug-like properties.

**DILI:** Ligand A (87.631) has a higher DILI risk than Ligand B (10.508). This is a concern for Ligand A.

**BBB:** Ligand A (82.474) has a much better BBB penetration score than Ligand B (35.13). Given that DRD2 is a CNS target, this is a critical advantage for Ligand A.

**Caco-2 Permeability:** Ligand A (-5.109) has poor Caco-2 permeability, while Ligand B (-4.866) is also poor, but slightly better.

**Aqueous Solubility:** Both ligands have very poor aqueous solubility (-4.32 and -0.344 respectively).

**hERG:** Both ligands have very low hERG inhibition liability (0.125 and 0.16 respectively).

**Microsomal Clearance:** Ligand A (29.834) has a higher microsomal clearance than Ligand B (12.12), indicating lower metabolic stability.

**In vitro Half-Life:** Ligand B (4.416) has a longer in vitro half-life than Ligand A (0.86).

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.085 and 0.023 respectively).

**Binding Affinity:** Ligand A (-9.9 kcal/mol) has a significantly stronger binding affinity than Ligand B (-6.5 kcal/mol). This is a substantial advantage for Ligand A, potentially outweighing some of its ADME drawbacks.

**Overall Assessment:**

Ligand A excels in binding affinity and BBB penetration, which are crucial for a CNS GPCR target like DRD2. While it has some ADME liabilities (higher DILI, higher Cl_mic, poor Caco-2), the strong binding and good BBB are significant positives. Ligand B has better TPSA and DILI, but suffers from a poor logP and significantly weaker binding affinity, and very poor BBB penetration. The affinity difference is >3 kcal/mol, which is a large margin.

Output:
1
2025-04-17 08:47:47,536 - INFO - Reasoning:

Let's analyze Ligand A and Ligand B for their potential as DRD2 drug candidates, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (424.32 Da) is slightly higher, but acceptable. Ligand B (356.348 Da) is also good.

**2. TPSA:** Both ligands have TPSA values below 90, which is favorable for CNS penetration. Ligand A (89.02) is slightly higher than Ligand B (78.09), but both are good.

**3. logP:** Both ligands have logP values within the optimal range (1-3). Ligand A (2.993) is closer to the upper limit, while Ligand B (1.667) is closer to the lower limit.

**4. H-Bond Donors:** Ligand A (1) and Ligand B (2) are both within the acceptable limit of 5.

**5. H-Bond Acceptors:** Ligand A (5) and Ligand B (3) are both within the acceptable limit of 10.

**6. QED:** Both ligands have similar QED values (0.797 and 0.788), indicating good drug-like properties.

**7. DILI:** Ligand A (88.251) has a significantly higher DILI risk than Ligand B (38.852). This is a major concern for Ligand A.

**8. BBB:** Ligand B (83.443) has a much better BBB percentile than Ligand A (62.466). This is crucial for a CNS target like DRD2.

**9. Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and suggests poor permeability. However, the scale is not specified, so it's difficult to interpret.

**10. Aqueous Solubility:** Both have negative solubility values, which is also unusual. Again, the scale is not specified.

**11. hERG Inhibition:** Both ligands have low hERG inhibition liability (0.143 and 0.324), which is good.

**12. Microsomal Clearance:** Ligand B (-28.7 mL/min/kg) has a *much* lower (better) microsomal clearance than Ligand A (21.65 mL/min/kg), indicating greater metabolic stability.

**13. In vitro Half-Life:** Ligand B (-29.965 hours) has a *much* longer in vitro half-life than Ligand A (33.428 hours), indicating greater stability.

**14. P-gp Efflux:** Both ligands have low P-gp efflux liability (0.212 and 0.013), which is favorable.

**15. Binding Affinity:** Both ligands have excellent binding affinities (-9.6 and -8.4 kcal/mol). Ligand A is slightly better (-9.6 kcal/mol), but the difference is not substantial enough to overcome its other weaknesses.

**Overall Assessment:**

Ligand B is the more promising candidate. While Ligand A has a slightly better binding affinity, Ligand B excels in critical ADME properties for a CNS-targeting GPCR: significantly lower DILI risk, much better BBB penetration, and superior metabolic stability (lower Cl_mic and longer t1/2). The slight difference in binding affinity is outweighed by these substantial advantages.

Output:
1
2025-04-17 08:47:47,537 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (340.427 and 350.419 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (67.35) is significantly better than Ligand B (85.69). For CNS targets, we want TPSA <= 90, and A is comfortably within that range, while B is approaching the upper limit.

**logP:** Ligand A (2.667) is optimal (1-3), while Ligand B (0.577) is a bit low, potentially hindering membrane permeability.

**H-Bond Donors/Acceptors:** Both have 1 HBD, which is good. Ligand A has 4 HBA, and Ligand B has 6. Both are acceptable (<=10), but A is slightly preferred.

**QED:** Both ligands have reasonable QED scores (0.878 and 0.789), indicating good drug-like properties.

**DILI:** Ligand A (39.667) has a lower DILI risk than Ligand B (51.183), which is preferable. Both are below the concerning threshold of 60.

**BBB:** Ligand A (83.831) has a significantly better BBB penetration score than Ligand B (72.237). For a CNS target like DRD2, a BBB percentile > 70 is highly desirable, and A is closer to this goal.

**Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and suggests poor permeability. However, the magnitude of negativity is important. Ligand A (-4.213) is less negative than Ligand B (-4.715), suggesting slightly better permeability.

**Aqueous Solubility:** Both have negative solubility values, which is also unusual. Ligand A (-2.891) is slightly better than Ligand B (-1.771).

**hERG:** Both ligands have very low hERG inhibition risk (0.306 and 0.21), which is excellent.

**Microsomal Clearance:** Ligand A (73.579) has a higher microsomal clearance than Ligand B (21.483), indicating faster metabolism and potentially lower in vivo exposure. This favors Ligand B.

**In vitro Half-Life:** Ligand B (36.025) has a significantly longer in vitro half-life than Ligand A (-20.249). This is a strong advantage for Ligand B.

**P-gp Efflux:** Both have very low P-gp efflux liability (0.026 and 0.018), which is good for CNS penetration.

**Binding Affinity:** Ligand A (-8.1 kcal/mol) has a substantially stronger binding affinity than Ligand B (-0.0 kcal/mol). This is a major advantage for Ligand A, and a difference of >1.5 kcal/mol can outweigh other drawbacks.

**Overall Assessment:**

Ligand A excels in key areas for a CNS GPCR target: TPSA, logP, BBB penetration, and, crucially, binding affinity. While its microsomal clearance is higher and half-life shorter than Ligand B, the significantly stronger binding affinity (-8.1 vs -0.0 kcal/mol) is a decisive factor. The better TPSA and logP also contribute to improved potential for brain penetration. Ligand B's longer half-life is a positive, but insufficient to overcome the much weaker binding.

Output:
1
2025-04-17 08:47:47,537 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 drug candidates, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight (MW):** Both ligands are within the ideal range (200-500 Da). Ligand A (336.351 Da) is slightly lower, which can be favorable for permeability.

**2. TPSA:** Ligand A (86.97) is excellent for CNS penetration, well below the 90 A^2 threshold. Ligand B (58.2) is even better. Both are highly favorable.

**3. logP:** Both ligands have good logP values (A: 2.285, B: 2.946), falling within the optimal 1-3 range. Ligand B is slightly higher, potentially leading to some solubility concerns, but still acceptable.

**4. H-Bond Donors (HBD):** Ligand A (0) is ideal, while Ligand B (2) is still within the acceptable limit of <=5.

**5. H-Bond Acceptors (HBA):** Ligand A (7) and Ligand B (3) are both within the acceptable limit of <=10.

**6. QED:** Both ligands have good QED scores (A: 0.525, B: 0.854), indicating good drug-like properties. Ligand B is significantly better.

**7. DILI:** Ligand A (92.051) has a higher DILI risk than Ligand B (55.176). This is a significant drawback for Ligand A.

**8. BBB:** Ligand B (87.553) has a much better BBB percentile than Ligand A (50.523). This is a critical advantage for a CNS target like DRD2.

**9. Caco-2 Permeability:** Both have negative Caco-2 values which is unusual and suggests a potential issue with the data or modeling. However, we will proceed with the assumption that lower is worse.

**10. Aqueous Solubility:** Both ligands have negative solubility values, which is also unusual. Again, assuming lower is worse, both are unfavorable.

**11. hERG Inhibition:** Both ligands have low hERG inhibition risk (A: 0.151, B: 0.468).

**12. Microsomal Clearance:** Ligand B (7.327) has a lower microsomal clearance than Ligand A (75.322), suggesting better metabolic stability.

**13. In vitro Half-Life:** Ligand B (23.621) has a longer half-life than Ligand A (11.84), which is desirable.

**14. P-gp Efflux:** Both ligands have very low P-gp efflux liability (A: 0.174, B: 0.26).

**15. Binding Affinity:** Ligand B (-8.7 kcal/mol) has a slightly better binding affinity than Ligand A (-8.0 kcal/mol), although the difference is relatively small.

**Overall Assessment:**

Ligand B is significantly superior to Ligand A. It has a much better BBB score, lower DILI risk, better metabolic stability (lower Cl_mic, longer t1/2), a higher QED score, and slightly better binding affinity. While both have unusual solubility and Caco-2 permeability values, the other advantages of Ligand B outweigh these concerns. The GPCR-specific priorities of BBB and logP are strongly met by Ligand B.

Output:
1
2025-04-17 08:47:47,537 - INFO - Reasoning:

Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (340.47 & 346.48 Da) fall comfortably within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (54.12) is significantly better than Ligand B (67.23). For CNS targets, we want TPSA <= 90, and ideally closer to 60. Ligand A is much closer to this ideal.

**3. logP:** Both ligands have acceptable logP values (3.92 & 2.76), falling within the 1-3 range. Ligand A is slightly higher, which could be beneficial for membrane permeability, but isn't a major concern for either.

**4. H-Bond Donors:** Ligand A (2) and Ligand B (1) are both within the acceptable limit of <=5.

**5. H-Bond Acceptors:** Ligand A (3) and Ligand B (4) are both within the acceptable limit of <=10.

**6. QED:** Both ligands have good QED scores (0.716 & 0.891), indicating good drug-like properties.

**7. DILI:** Ligand A (21.95) has a considerably lower DILI risk than Ligand B (30.32). Both are below the 40% threshold, but lower is always preferred.

**8. BBB:** Both ligands have similar BBB penetration (77.2% & 70.4%). Both are above the desirable 70% threshold for CNS targets.

**9. Caco-2 Permeability:** Ligand A (-4.905) has better Caco-2 permeability than Ligand B (-4.424). Higher values indicate better absorption.

**10. Aqueous Solubility:** Ligand A (-4.411) has better aqueous solubility than Ligand B (-3.244). Higher values are preferred.

**11. hERG Inhibition:** Ligand A (0.836) has a slightly higher hERG risk than Ligand B (0.259). Lower is better, so Ligand B is preferable here.

**12. Microsomal Clearance:** Ligand A (70.48) has higher microsomal clearance than Ligand B (37.50), indicating faster metabolism and lower metabolic stability. Ligand B is significantly better.

**13. In vitro Half-Life:** Ligand A (-11.59) has a negative half-life, which is not physically possible. This is a significant red flag. Ligand B (23.64) has a reasonable half-life.

**14. P-gp Efflux:** Ligand A (0.412) has lower P-gp efflux than Ligand B (0.028). Lower efflux is better for CNS exposure.

**15. Binding Affinity:** Ligand A (-8.3 kcal/mol) has significantly stronger binding affinity than Ligand B (-6.8 kcal/mol). This is a substantial advantage, potentially outweighing some ADME concerns.

**Overall Assessment:**

While Ligand A boasts superior binding affinity and better TPSA, P-gp efflux, solubility and Caco-2 permeability, its extremely poor predicted half-life and higher hERG risk are major drawbacks. The negative half-life is a critical issue. Ligand B, while having slightly weaker affinity, presents a much more balanced profile with better metabolic stability (lower Cl_mic, longer t1/2), lower hERG risk, and acceptable ADME properties overall. Given the importance of metabolic stability and safety (hERG) for a CNS drug, and the problematic half-life of Ligand A, Ligand B is the more promising candidate.

Output:
1
2025-04-17 08:47:47,537 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (365.905 and 366.531 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (61.44) is significantly better than Ligand B (67.23). For CNS targets, we want TPSA <= 90, and ideally closer to 60. Ligand A is closer to this ideal.

**3. logP:** Both ligands have good logP values (3.236 and 2.158), falling within the optimal range of 1-3.

**4. H-Bond Donors:** Ligand A (2) is slightly higher than Ligand B (1), but both are within the acceptable limit of <=5.

**5. H-Bond Acceptors:** Ligand A (3) is lower than Ligand B (5), which is preferable. We want HBA <= 10.

**6. QED:** Both ligands have similar QED values (0.761 and 0.727), indicating good drug-like properties.

**7. DILI:** Ligand A (43.738) has a higher DILI risk than Ligand B (29.624). Lower is better, and Ligand B is clearly preferable here.

**8. BBB:** This is a crucial parameter for CNS targets. Ligand A (70.997) is significantly better than Ligand B (38.038). A value >70 is desirable, and Ligand A meets this criterion, while B does not.

**9. Caco-2 Permeability:** Ligand A (-4.781) is worse than Ligand B (-5.307). Higher values are better, indicating better intestinal absorption. However, for a CNS target, intestinal absorption is less critical than BBB penetration.

**10. Aqueous Solubility:** Ligand A (-3.722) is worse than Ligand B (-1.38). Higher values are better.

**11. hERG Inhibition:** Both ligands have low hERG inhibition risk (0.533 and 0.482).

**12. Microsomal Clearance:** Ligand A (52.862) has higher clearance than Ligand B (25.86). Lower clearance is preferred for better metabolic stability. Ligand B is better here.

**13. In vitro Half-Life:** Ligand A (77.955) has a better half-life than Ligand B (-2.539). Longer half-life is desirable.

**14. P-gp Efflux:** Ligand A (0.323) has lower P-gp efflux than Ligand B (0.061). Lower efflux is preferred for CNS exposure. Ligand A is better here.

**15. Binding Affinity:** Ligand A (-7.8) has a slightly better binding affinity than Ligand B (-7.0). A difference of >1.5 kcal/mol can outweigh other drawbacks.

**Overall Assessment:**

Ligand A excels in BBB penetration, P-gp efflux, and binding affinity, which are critical for a CNS GPCR target like DRD2. While Ligand B has a better DILI score and lower clearance, the superior BBB and binding affinity of Ligand A are more important in this context. The slightly lower solubility and higher DILI of Ligand A are acceptable trade-offs given its strong affinity and CNS penetration potential.

Output:
1
2025-04-17 08:47:47,538 - INFO - Batch 479 complete. Total preferences: 7664
2025-04-17 08:47:47,538 - INFO - Processing batch 480/512...
2025-04-17 08:48:31,380 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (347.463 and 353.413 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (61.68) is slightly higher than Ligand B (58.22), but both are below the 90 A^2 threshold desirable for CNS targets.

**logP:** Ligand A (0.84) is a bit low, potentially hindering permeation. Ligand B (3.609) is within the optimal 1-3 range. This is a significant advantage for Ligand B.

**H-Bond Donors/Acceptors:** Ligand A has 0 HBD and 5 HBA, while Ligand B has 1 HBD and 3 HBA. Both are within acceptable limits.

**QED:** Both ligands have good QED scores (0.516 and 0.664, respectively), indicating drug-like properties.

**DILI:** Both ligands have low DILI risk (31.252 and 38.697 percentiles), which is good.

**BBB:** Ligand B (81.776%) has a significantly better BBB penetration score than Ligand A (66.382%). This is crucial for a CNS target like DRD2.

**Caco-2 Permeability:** Both have negative values (-4.808 and -4.814), which is unusual and requires further investigation. However, the values are very similar.

**Aqueous Solubility:** Ligand A (-0.398) has slightly better aqueous solubility than Ligand B (-3.226), but both are quite poor.

**hERG Inhibition:** Ligand A (0.328) has a lower hERG inhibition liability than Ligand B (0.971), which is preferable.

**Microsomal Clearance:** Both ligands have similar microsomal clearance values (50.196 and 49.113 mL/min/kg).

**In vitro Half-Life:** Ligand B (20.265 hours) has a significantly longer in vitro half-life than Ligand A (-6.574 hours). This is a major advantage for Ligand B.

**P-gp Efflux:** Ligand A (0.093) has lower P-gp efflux liability than Ligand B (0.473), which is favorable for CNS penetration.

**Binding Affinity:** Ligand B (-7.4 kcal/mol) has a slightly better binding affinity than Ligand A (-7.6 kcal/mol). While the difference is small, it's still a positive for Ligand B.

**Overall Assessment:**

Ligand B is the better candidate. While Ligand A has slightly better hERG and P-gp profiles, Ligand B excels in the most critical areas for a CNS-targeting GPCR: BBB penetration, logP, and in vitro half-life. The slightly better affinity of Ligand B further supports this conclusion. The poor solubility of both compounds is a concern that would need to be addressed during optimization, but the other advantages of Ligand B outweigh this drawback.

Output:
1
2025-04-17 08:48:31,381 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (342.443 and 361.467 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (83.12) is better than Ligand B (67.6), both are below the 90 A^2 threshold for CNS targets.

**3. logP:** Both ligands (2.247 and 2.478) are within the optimal 1-3 range.

**4. H-Bond Donors:** Ligand A (3) is slightly higher than Ligand B (1), but both are acceptable (<=5).

**5. H-Bond Acceptors:** Ligand A (4) is lower than Ligand B (6), both are acceptable (<=10).

**6. QED:** Both ligands have good QED scores (0.664 and 0.817), indicating good drug-like properties.

**7. DILI:** Both ligands have acceptable DILI risk (47.421 and 52.423, both <60).

**8. BBB:** Ligand A (65.374) is better than Ligand B (49.942). A BBB percentile >70 is desirable for CNS targets, and Ligand A is closer to this threshold.

**9. Caco-2 Permeability:** Both have negative values (-5.054 and -5.096). These values are difficult to interpret without knowing the scale, but a negative value suggests poor permeability.

**10. Aqueous Solubility:** Both have negative values (-2.919 and -4.151). These values are difficult to interpret without knowing the scale, but a negative value suggests poor solubility.

**11. hERG Inhibition:** Both ligands show low hERG inhibition liability (0.492 and 0.42).

**12. Microsomal Clearance:** Ligand A (12.01) has a lower microsomal clearance than Ligand B (61.544), indicating better metabolic stability.

**13. In vitro Half-Life:** Ligand A (8.214) has a slightly longer half-life than Ligand B (9.163).

**14. P-gp Efflux:** Both ligands show low P-gp efflux liability (0.038 and 0.192).

**15. Binding Affinity:** Ligand A (-8.8 kcal/mol) has a slightly better binding affinity than Ligand B (-8.1 kcal/mol). While both are strong binders, the 0.7 kcal/mol difference is significant.

**Overall Assessment:**

Considering the GPCR-specific priorities, Ligand A is the better candidate. It has a better BBB score, lower microsomal clearance (better metabolic stability), and a slightly better binding affinity. While both have poor Caco-2 and solubility values, the differences in BBB and metabolic stability are more crucial for a CNS-targeting drug like a DRD2 ligand. The slightly better affinity of Ligand A further strengthens its position.

Output:
1
2025-04-17 08:48:31,381 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (342.483 and 350.482 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (49.41) is better than Ligand B (51.02). Both are below the 90 A^2 threshold for CNS targets, which is good.

**3. logP:** Both ligands have good logP values (3.204 and 3.613), falling within the optimal 1-3 range. Ligand B is slightly higher, which *could* be a minor concern for solubility, but is not a major issue.

**4. H-Bond Donors:** Ligand A has 1 HBD, and Ligand B has 0. Both are within the acceptable limit of <=5.

**5. H-Bond Acceptors:** Ligand A has 2 HBA, and Ligand B has 4. Both are within the acceptable limit of <=10.

**6. QED:** Ligand A (0.893) has a significantly better QED score than Ligand B (0.639), indicating a more drug-like profile.

**7. DILI:** Ligand A (26.095) has a much lower DILI risk than Ligand B (16.208), which is a significant advantage.

**8. BBB:** Ligand B (89.066) has a better BBB penetration score than Ligand A (77.2), which is crucial for a CNS target like DRD2. This is a key advantage for Ligand B.

**9. Caco-2 Permeability:** Both have negative values, which is unusual. Assuming these are logP values, they suggest poor permeability. However, the scale is not specified, so it is hard to interpret.

**10. Aqueous Solubility:** Both have negative values, suggesting poor solubility. Again, the scale is not specified.

**11. hERG Inhibition:** Both ligands have low hERG inhibition risk (0.549 and 0.356), which is good.

**12. Microsomal Clearance:** Both have similar microsomal clearance values (63.719 and 62.102), indicating similar metabolic stability.

**13. In vitro Half-Life:** Ligand B (-16.22) has a longer in vitro half-life than Ligand A (-18.312).

**14. P-gp Efflux:** Ligand A (0.344) has lower P-gp efflux liability than Ligand B (0.09), which is favorable for CNS penetration.

**15. Binding Affinity:** Ligand B (-6.7 kcal/mol) has a significantly stronger binding affinity than Ligand A (-10.0 kcal/mol). This is a substantial advantage, potentially outweighing some ADME concerns.

**Overall Assessment:**

Ligand B has a significantly better binding affinity and BBB penetration, which are critical for a CNS GPCR target. While Ligand A has better QED and DILI scores, the improved affinity and BBB of Ligand B are more important in this context. The slightly higher logP of Ligand B is not a major concern, and its longer half-life is also a plus.

Output:
1
2025-04-17 08:48:31,381 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (344.459 and 353.507 Da) fall comfortably within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (69.34) is better than Ligand B (70.67). Both are below the 90 A^2 threshold desirable for CNS targets, but A is closer to the optimal range.

**3. logP:** Both ligands have good logP values (2.123 and 1.4), falling within the 1-3 optimal range. Ligand B is slightly lower, which *could* indicate slightly reduced permeability, but it's not a major concern.

**4. H-Bond Donors:** Ligand A has 0 HBD, while Ligand B has 2. Both are within the acceptable limit of <=5.

**5. H-Bond Acceptors:** Both ligands have 4 HBA, well within the acceptable limit of <=10.

**6. QED:** Both ligands have acceptable QED scores (0.821 and 0.726), indicating good drug-like properties.

**7. DILI:** Ligand A (11.632) has a significantly lower DILI risk than Ligand B (7.484). This is a substantial advantage for Ligand A.

**8. BBB:** Ligand A (65.374) has a slightly better BBB penetration percentile than Ligand B (60.682). While both are below the ideal >70 for CNS targets, A is closer.

**9. Caco-2 Permeability:** Ligand A (-4.614) has worse Caco-2 permeability than Ligand B (-5.02). This suggests B might have slightly better intestinal absorption.

**10. Aqueous Solubility:** Ligand A (-1.751) has slightly better aqueous solubility than Ligand B (-2.05).

**11. hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.438 and 0.455).

**12. Microsomal Clearance:** Ligand A (3.415) has higher microsomal clearance than Ligand B (-0.098). This means Ligand B is more metabolically stable.

**13. In vitro Half-Life:** Both ligands have similar in vitro half-lives (4.326 and 4.497 hours).

**14. P-gp Efflux:** Both ligands have similar P-gp efflux liability (0.035 and 0.037).

**15. Binding Affinity:** Ligand B (-7.3) has a slightly better binding affinity than Ligand A (-7.2). However, the difference is only 0.1 kcal/mol, which is a small advantage.

**Overall Assessment:**

Considering the GPCR-specific priorities, Ligand A is the better candidate. While Ligand B has a slightly better binding affinity and Caco-2 permeability, Ligand A has a significantly lower DILI risk and better BBB penetration. The lower DILI risk is a major advantage, and the slightly better BBB is crucial for a CNS target like DRD2. The slightly higher metabolic stability of Ligand B is a benefit, but not enough to overcome the other advantages of Ligand A.

Output:
1
2025-04-17 08:48:31,381 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 drug candidates, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (357.475 and 350.503 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (53.68) is higher than Ligand B (42.01). For CNS targets, we prefer TPSA <= 90, both are within this range, but B is better.

**3. logP:** Ligand A (3.949) is at the upper end of the optimal range (1-3), while Ligand B (2.356) is well within it. This favors B.

**4. H-Bond Donors:** Ligand A (1) and Ligand B (0) are both acceptable (<=5).

**5. H-Bond Acceptors:** Both ligands (A: 4, B: 4) are within the acceptable range (<=10).

**6. QED:** Ligand A (0.823) has a better QED than Ligand B (0.64), indicating a more drug-like profile.

**7. DILI:** Ligand A (31.214) has a significantly lower DILI risk than Ligand B (13.3), which is a substantial advantage.

**8. BBB:** Ligand B (89.376) has a much higher BBB penetration percentile than Ligand A (70.919). This is a critical factor for a CNS target like DRD2, heavily favoring B.

**9. Caco-2 Permeability:** Ligand A (-5.048) has worse Caco-2 permeability than Ligand B (-4.725). Lower values are less favorable.

**10. Aqueous Solubility:** Ligand A (-3.93) has worse solubility than Ligand B (-2.222). Higher values are preferred.

**11. hERG Inhibition:** Both ligands (A: 0.751, B: 0.722) have similar, relatively low hERG inhibition risk.

**12. Microsomal Clearance:** Ligand A (41.226) has a lower microsomal clearance than Ligand B (61.509), suggesting better metabolic stability.

**13. In vitro Half-Life:** Ligand A (52.487) has a significantly longer in vitro half-life than Ligand B (23.144), which is a major advantage.

**14. P-gp Efflux:** Ligand A (0.565) has lower P-gp efflux than Ligand B (0.369), which is favorable for CNS penetration.

**15. Binding Affinity:** Ligand A (-8.5 kcal/mol) has a significantly stronger binding affinity than Ligand B (-6.3 kcal/mol). This is a substantial advantage, potentially outweighing some ADME drawbacks.

**Overall Assessment:**

Ligand B excels in BBB penetration and has a good logP. However, Ligand A has a significantly stronger binding affinity, better DILI risk, longer half-life, and lower P-gp efflux. The substantial affinity difference (-2.2 kcal/mol) is a key factor. While Ligand B has better BBB, the improved affinity of A, coupled with acceptable BBB (70.919), and better metabolic stability, makes it a more promising candidate. The lower DILI risk is also a significant benefit.

Output:
1
2025-04-17 08:48:31,382 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (351.491 and 348.487 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (69.72) and Ligand B (67.43) are both below the 90 A^2 threshold desirable for CNS targets, which is excellent.

**3. logP:** Ligand A (1.953) is within the optimal 1-3 range. Ligand B (2.925) is also within the optimal range, but closer to the upper limit.

**4. H-Bond Donors:** Ligand A (1) and Ligand B (2) both meet the <=5 criteria.

**5. H-Bond Acceptors:** Ligand A (3) and Ligand B (3) both meet the <=10 criteria.

**6. QED:** Both ligands have good QED values (0.68 and 0.721, respectively), indicating drug-like properties.

**7. DILI:** Ligand A (42.187) has a moderate DILI risk, but is still acceptable. Ligand B (18.651) has a much lower DILI risk, which is a significant advantage.

**8. BBB:** Ligand A (62.466) has a moderate BBB penetration, while Ligand B (55.603) is lower. Both are below the desirable >70 for CNS targets, but Ligand A is better.

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.646 and -4.592), which is unusual and suggests poor permeability. This is a concern for both.

**10. Aqueous Solubility:** Both ligands have negative solubility values (-2.167 and -2.808), indicating very poor aqueous solubility. This is a significant drawback for both.

**11. hERG Inhibition:** Both ligands have low hERG inhibition liability (0.167 and 0.406, respectively), which is good.

**12. Microsomal Clearance:** Ligand A (63.202) has moderate microsomal clearance, while Ligand B (71.153) is higher, indicating faster metabolism and potentially lower exposure.

**13. In vitro Half-Life:** Ligand A (-6.682) has a negative half-life, which is not physically possible and indicates a data issue. Ligand B (7.536) has a reasonable half-life.

**14. P-gp Efflux:** Both ligands have low P-gp efflux liability (0.133 and 0.052, respectively), which is favorable for CNS penetration.

**15. Binding Affinity:** Ligand B (-8.7 kcal/mol) has a significantly stronger binding affinity than Ligand A (-7.1 kcal/mol). This >1.5 kcal/mol difference is substantial and could outweigh some of the ADME concerns.

**Overall Assessment:**

Ligand A has a better BBB score, but its negative in vitro half-life is a major red flag, suggesting a data error or inherent instability. Ligand B has a superior binding affinity, lower DILI risk, and a reasonable half-life. While both have poor solubility and permeability, the stronger binding affinity of Ligand B is a critical advantage for a GPCR target. Given the importance of potency for GPCRs, and the significant difference in binding affinity, Ligand B is the more promising candidate despite its lower BBB penetration.

Output:
1
2025-04-17 08:48:31,382 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (355.435 and 370.318 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (96.97) is better than Ligand B (58.64), both are below the 90 A^2 threshold for CNS targets.

**logP:** Ligand A (0.509) is a bit low, potentially hindering permeability. Ligand B (1.677) is within the optimal 1-3 range. This favors Ligand B.

**H-Bond Donors/Acceptors:** Ligand A has 2 HBD and 5 HBA, while Ligand B has 1 HBD and 3 HBA. Both are within acceptable limits.

**QED:** Both ligands have reasonable QED scores (0.749 and 0.572, respectively), indicating good drug-like properties.

**DILI:** Both ligands have acceptable DILI risk (53.819 and 46.452 percentile), below the 60 threshold.

**BBB:** Ligand B (95.308) significantly outperforms Ligand A (46.568) in BBB penetration, which is crucial for a CNS target like DRD2.

**Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and suggests a potential issue with the data or modeling. However, the magnitude is similar.

**Aqueous Solubility:** Both have negative solubility values, which is also unusual.

**hERG Inhibition:** Both ligands show low hERG inhibition liability (0.123 and 0.272), which is good.

**Microsomal Clearance:** Ligand B (-3.486) has a *negative* microsomal clearance, which is highly unusual and suggests very high metabolic stability. Ligand A (12.281) has a moderate clearance.

**In vitro Half-Life:** Ligand B has a very long half-life (-12.355 hours), again, the negative value is unusual but indicates high stability. Ligand A has a very short half-life (0.247 hours).

**P-gp Efflux:** Both have very low P-gp efflux liability (0.017 and 0.03).

**Binding Affinity:** Ligand B (-8.8 kcal/mol) has a significantly stronger binding affinity than Ligand A (0.0 kcal/mol). This is a substantial advantage.

**Conclusion:**

Ligand B is the superior candidate. Its significantly better BBB penetration, much stronger binding affinity, and exceptionally high metabolic stability (indicated by the negative clearance and long half-life) outweigh the slightly lower logP. While the negative Caco-2 and solubility values are concerning and should be investigated, the other factors strongly favor Ligand B. The substantial difference in binding affinity (>1.5 kcal/mol) is a key driver of this decision.

Output:
1
2025-04-17 08:48:31,382 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (349.519 and 346.431 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (73.2) is excellent, well below the 90 A^2 threshold for CNS targets. Ligand B (116.29) is higher, but still potentially acceptable, although less ideal.

**logP:** Ligand A (3.496) is optimal. Ligand B (0.711) is low, potentially hindering permeation.

**H-Bond Donors/Acceptors:** Ligand A (1 HBD, 3 HBA) is good. Ligand B (2 HBD, 4 HBA) is also acceptable.

**QED:** Both ligands have similar QED values (0.682 and 0.63), indicating good drug-likeness.

**DILI:** Ligand A (10.469) has a very low DILI risk. Ligand B (16.906) is slightly higher, but still relatively low.

**BBB:** This is a critical parameter for a CNS target like DRD2. Ligand A shows excellent BBB penetration (77.239%), while Ligand B is significantly lower (52.966%).

**Caco-2 Permeability:** Ligand A (-4.414) has poor Caco-2 permeability. Ligand B (-5.618) is even worse.

**Aqueous Solubility:** Ligand A (-2.941) has poor solubility. Ligand B (-1.887) is better, but still poor.

**hERG Inhibition:** Ligand A (0.729) has a low hERG risk. Ligand B (0.174) is very low, indicating minimal cardiotoxicity concerns.

**Microsomal Clearance:** Ligand A (60.039) has moderate clearance. Ligand B (-20.109) has negative clearance, which is not physically possible and likely an error in the data. This suggests very high metabolic stability, which is a significant advantage.

**In vitro Half-Life:** Ligand A (0.911) has a very short half-life. Ligand B (-4.744) has a negative half-life, which is not physically possible.

**P-gp Efflux:** Ligand A (0.083) has low P-gp efflux, which is good for CNS penetration. Ligand B (0.008) has even lower efflux, which is even better.

**Binding Affinity:** Both ligands have very similar and strong binding affinities (-7.6 and -7.5 kcal/mol). The difference is negligible.

**Overall Assessment:**

Ligand A has excellent TPSA, logP, DILI, and P-gp efflux. However, it suffers from poor Caco-2 permeability, poor solubility, and a short half-life. Its BBB penetration is good, but not outstanding.

Ligand B has a higher TPSA, lower logP, and poor Caco-2 permeability and solubility. However, it exhibits exceptionally high metabolic stability (indicated by the negative clearance and half-life values, which are likely data errors, but point to a very stable molecule) and very low P-gp efflux.

Given the GPCR-specific priorities, BBB penetration is crucial. Ligand A has better BBB penetration than Ligand B. However, the errors in the data for Ligand B (negative clearance and half-life) suggest a potentially very stable molecule. While these values are impossible, they strongly indicate a favorable metabolic profile. The low logP of Ligand B is a concern, but the strong binding affinity and potentially excellent metabolic stability could outweigh this drawback.

Considering all factors, and acknowledging the data anomalies for Ligand B, I'd lean towards **Ligand A** as the more viable candidate. The BBB penetration and logP are more favorable, and the binding affinity is comparable. The issues with solubility and permeability can be addressed through formulation strategies.

Output:
0
2025-04-17 08:48:31,382 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (345.355 Da) is slightly lower, which could be beneficial for permeability.

**TPSA:** Ligand A (88.18) is excellent for CNS penetration, falling well below the 90 threshold. Ligand B (49.77) is also very good.

**logP:** Ligand A (-0.472) is a bit low, potentially hindering membrane permeability. Ligand B (3.489) is within the optimal range (1-3). This is a significant advantage for Ligand B.

**H-Bond Donors/Acceptors:** Both ligands have 1 HBD and a reasonable number of HBAs (5 and 4 respectively). They both meet the criteria.

**QED:** Both ligands have acceptable QED values (0.783 and 0.698), indicating good drug-like properties.

**DILI:** Ligand A (52.966) has a moderate DILI risk, while Ligand B (9.849) has a very low risk. This favors Ligand B.

**BBB:** Both ligands have excellent BBB penetration (73.478 and 74.292), exceeding the 70% threshold.

**Caco-2 Permeability:** Both have negative values, indicating poor permeability. This is a concern for both, but the lower value for Ligand A (-4.511) is worse than Ligand B (-4.421).

**Aqueous Solubility:** Both have negative values, indicating poor solubility. This is a concern for both.

**hERG Inhibition:** Both ligands show very low hERG inhibition risk (0.071 and 0.705).

**Microsomal Clearance:** Ligand A (-12.778) exhibits much lower microsomal clearance, suggesting better metabolic stability than Ligand B (68.538). This is a significant advantage for Ligand A.

**In vitro Half-Life:** Ligand A (-22.395) has a negative half-life, which is not possible and indicates an issue with the data or prediction. Ligand B (-3.499) is also negative, indicating a problem.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.013 and 0.574), which is favorable for CNS penetration.

**Binding Affinity:** Ligand A (-8.9 kcal/mol) has a significantly stronger binding affinity than Ligand B (-7.0 kcal/mol). This is a substantial advantage for Ligand A, potentially outweighing some of its ADME drawbacks.

**Overall Assessment:**

Ligand A has a much stronger binding affinity and better metabolic stability, but suffers from a lower logP and worse Caco-2 permeability. Ligand B has a more favorable logP and lower DILI risk, but weaker binding affinity. Given the GPCR-specific emphasis on affinity, the substantial difference in binding energy (-8.9 vs -7.0 kcal/mol) is a critical factor. While the logP of Ligand A is suboptimal, the strong binding may compensate for this. The negative half-life values are concerning for both, but the difference in affinity is the most significant factor.

Output:
0
2025-04-17 08:48:31,382 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (356.86 and 346.52 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (50.16) is better than Ligand B (58.2), both are below the 90 A^2 threshold for CNS targets, but A is closer to the ideal.

**logP:** Both ligands have good logP values (3.46 and 3.71), falling within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A (1 HBD, 4 HBA) is slightly better than Ligand B (2 HBD, 2 HBA) in terms of balancing solubility and permeability.

**QED:** Both ligands have acceptable QED scores (0.735 and 0.69), indicating good drug-like properties.

**DILI:** Ligand A (68.79) has a lower DILI risk than Ligand B (22.33), suggesting a better safety profile.

**BBB:** Ligand A (72.32) has a significantly better BBB penetration percentile than Ligand B (65.37). This is a crucial factor for CNS targets like DRD2.

**Caco-2 Permeability:** Ligand A (-5.05) has a worse Caco-2 permeability than Ligand B (-4.77).

**Aqueous Solubility:** Both ligands have poor aqueous solubility (-3.19 and -4.40).

**hERG:** Both ligands have low hERG inhibition liability (0.596 and 0.453).

**Microsomal Clearance:** Ligand A (82.76) has higher microsomal clearance than Ligand B (65.04), indicating lower metabolic stability.

**In vitro Half-Life:** Ligand B (4.04) has a significantly shorter in vitro half-life than Ligand A (144.16).

**P-gp Efflux:** Ligand A (0.445) has lower P-gp efflux than Ligand B (0.435).

**Binding Affinity:** Ligand B (-8.6 kcal/mol) has a slightly better binding affinity than Ligand A (-9.3 kcal/mol). While A is better, the difference is not substantial enough to outweigh other factors.

**Overall Assessment:**

Considering the GPCR-specific priorities, Ligand A is the more promising candidate. The significantly better BBB penetration (72.32 vs. 65.37) and lower DILI risk are major advantages for a CNS-targeting drug. While Ligand B has slightly better binding affinity and Caco-2 permeability, the superior BBB and safety profile of Ligand A are more critical for DRD2, a CNS target. The longer half-life of Ligand A is also a positive attribute.

Output:
1
2025-04-17 08:48:31,383 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (351.451 and 351.535 Da) fall comfortably within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (80.56) is better than Ligand B (52.65). Both are below the 90 A^2 threshold for CNS targets, but Ligand B is significantly lower, which is favorable for brain penetration.

**3. logP:** Both ligands have good logP values (2.087 and 2.672), falling within the optimal 1-3 range. Ligand B is slightly higher, which could potentially lead to some off-target effects, but it's not a major concern.

**4. H-Bond Donors:** Ligand A has 0 HBDs, while Ligand B has 1. Both are acceptable, being less than 5.

**5. H-Bond Acceptors:** Ligand A has 6 HBAs, and Ligand B has 3. Both are below the 10 threshold.

**6. QED:** Ligand A (0.833) has a better QED score than Ligand B (0.684), indicating a more drug-like profile.

**7. DILI:** Ligand A (49.632) has a higher DILI risk than Ligand B (16.324). This is a significant advantage for Ligand B.

**8. BBB:** Ligand B (78.209) has a substantially better BBB percentile than Ligand A (65.064). This is crucial for a CNS target like DRD2.

**9. Caco-2 Permeability:** Ligand A (-4.354) has a worse Caco-2 permeability than Ligand B (-4.64). Lower values are less favorable.

**10. Aqueous Solubility:** Ligand A (-1.636) has better aqueous solubility than Ligand B (-2.962).

**11. hERG Inhibition:** Ligand A (0.076) has a lower hERG inhibition risk than Ligand B (0.508), which is preferable.

**12. Microsomal Clearance:** Ligand B (54.058) has a slightly higher microsomal clearance than Ligand A (50.229), suggesting slightly lower metabolic stability.

**13. In vitro Half-Life:** Ligand A (-9.624) has a much longer in vitro half-life than Ligand B (3.063). This is a significant advantage for Ligand A.

**14. P-gp Efflux:** Ligand A (0.041) has a lower P-gp efflux liability than Ligand B (0.23). Lower efflux is better for CNS exposure.

**15. Binding Affinity:** Ligand B (-8.0) has a significantly stronger binding affinity than Ligand A (-0.0). This is the most important factor, and the 8 kcal/mol difference is substantial.

**Overall Assessment:**

While Ligand A has advantages in QED, solubility, hERG, half-life, and P-gp efflux, Ligand B's superior BBB penetration and *much* stronger binding affinity outweigh these benefits. The lower DILI risk for Ligand B is also a significant plus. For a CNS GPCR target, strong affinity and good brain penetration are paramount. The difference in binding affinity is so large that it's likely to overcome any minor ADME deficiencies in Ligand B.

Output:
1
2025-04-17 08:48:31,383 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 drug candidates, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (363.755 and 364.961 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (72.7) is higher than the preferred <90 for CNS targets, but still reasonable. Ligand B (32.34) is excellent, well below 90. This favors Ligand B.

**3. logP:** Ligand A (3.57) is within the optimal 1-3 range. Ligand B (4.883) is slightly above, potentially raising concerns about solubility and off-target effects, but not drastically.

**4. H-Bond Donors:** Both ligands have 1 HBD, which is acceptable.

**5. H-Bond Acceptors:** Ligand A has 5 HBA, and Ligand B has 2 HBA. Both are within the acceptable limit of <=10.

**6. QED:** Both ligands have similar QED values (0.703 and 0.677), indicating good drug-like properties.

**7. DILI:** Ligand A has a DILI risk of 94.378, which is high. Ligand B has a much lower DILI risk of 21.869, which is very favorable. This is a significant advantage for Ligand B.

**8. BBB:** Ligand A has a BBB penetration of 69.678, which is below the desirable >70 for CNS targets. Ligand B has a BBB penetration of 83.482, which is excellent. This strongly favors Ligand B.

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.938 and -4.621). These values are unusual and suggest poor permeability, but the scale isn't defined, making interpretation difficult.

**10. Aqueous Solubility:** Both ligands have very poor aqueous solubility (-4.82 and -4.638). This is a concern for both, but might be mitigated by formulation strategies.

**11. hERG Inhibition:** Ligand A has a low hERG inhibition risk (0.22). Ligand B has a slightly higher risk (0.804), but still relatively low.

**12. Microsomal Clearance:** Ligand A has a lower Cl_mic (44.853) indicating better metabolic stability than Ligand B (89.699). This favors Ligand A.

**13. In vitro Half-Life:** Ligand B has a significantly longer in vitro half-life (89.727) compared to Ligand A (2.538). This is a major advantage for Ligand B.

**14. P-gp Efflux:** Ligand A has a low P-gp efflux liability (0.204), which is good. Ligand B has a slightly higher efflux liability (0.453), but still reasonable.

**15. Binding Affinity:** Ligand B (-7.4 kcal/mol) has a significantly stronger binding affinity than Ligand A (-9.8 kcal/mol). This is a substantial advantage, potentially outweighing some of the ADME drawbacks.

**Overall Assessment:**

Ligand B is the superior candidate. While both have solubility issues, Ligand B excels in key areas for CNS GPCR targets: significantly better BBB penetration, a much lower DILI risk, and a substantially stronger binding affinity. The longer half-life is also a major benefit. Although Ligand A has better metabolic stability, the other advantages of Ligand B are more critical for success as a DRD2-targeting drug.

Output:
1
2025-04-17 08:48:31,383 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (385.511 and 391.27 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (88.07) is better than Ligand B (53.76) as it is closer to the ideal range for CNS targets (<=90). Ligand B is also good, but A is slightly preferred.

**3. logP:** Ligand B (3.48) is optimal (1-3), while Ligand A (0.289) is quite low, potentially hindering permeation. This is a significant drawback for Ligand A.

**4. H-Bond Donors:** Ligand A (1) is good, while Ligand B (0) is also acceptable.

**5. H-Bond Acceptors:** Ligand A (6) is good, while Ligand B (3) is also acceptable.

**6. QED:** Both ligands have similar and good QED values (0.703 and 0.723).

**7. DILI:** Both ligands have similar DILI risk (56.805 and 53.276), which is acceptable (below 60).

**8. BBB:** Ligand B (85.964) is significantly better than Ligand A (46.026) for CNS penetration. This is a critical advantage for targeting DRD2.

**9. Caco-2 Permeability:** Ligand A (-5.34) is very poor, while Ligand B (-4.423) is also poor, but slightly better.

**10. Aqueous Solubility:** Ligand A (-2.395) is very poor, while Ligand B (-3.617) is also poor.

**11. hERG Inhibition:** Ligand A (0.083) is very low risk, while Ligand B (0.669) is slightly higher, but still acceptable.

**12. Microsomal Clearance:** Ligand B (56.949) has higher clearance than Ligand A (28.428), indicating lower metabolic stability. This is a drawback for Ligand B.

**13. In vitro Half-Life:** Ligand B (32.616) has a much longer half-life than Ligand A (1.131), which is a significant advantage.

**14. P-gp Efflux:** Ligand A (0.104) has lower P-gp efflux liability than Ligand B (0.507), which is beneficial for CNS exposure.

**15. Binding Affinity:** Ligand B (-7.6) has a significantly stronger binding affinity than Ligand A (-9.0). A 1.6 kcal/mol difference is substantial and can outweigh some ADME drawbacks.

**Overall Assessment:**

Despite Ligand A having slightly better TPSA and P-gp efflux, Ligand B is the superior candidate. The critical factors driving this decision are:

*   **BBB:** Ligand B exhibits a much higher BBB penetration score, essential for a CNS target like DRD2.
*   **logP:** Ligand B has an optimal logP, while Ligand A's is too low.
*   **Affinity:** Ligand B has a significantly stronger binding affinity.
*   **Half-Life:** Ligand B has a much longer half-life.

While Ligand B has higher microsomal clearance, the benefits of its superior BBB penetration, logP, binding affinity, and half-life outweigh this drawback. Ligand A's poor logP and Caco-2 permeability are major concerns.

Output:
1
2025-04-17 08:48:31,383 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (339.443 and 371.825 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (73.05) is significantly better than Ligand B (130.41). For CNS targets, we want TPSA <= 90, and Ligand A is comfortably within that range, while Ligand B is pushing the limit and may have reduced brain penetration.

**3. logP:** Both ligands have acceptable logP values (2.503 and 0.907), falling within the 1-3 range. Ligand A is slightly better.

**4. H-Bond Donors:** Both have 3 HBD, which is within the acceptable limit of <=5.

**5. H-Bond Acceptors:** Ligand A has 3 HBA, while Ligand B has 5. Both are within the acceptable limit of <=10, but Ligand A is preferable.

**6. QED:** Both ligands have reasonable QED values (0.801 and 0.613), indicating good drug-like properties. Ligand A is better.

**7. DILI:** Ligand A (32.648) has a much lower DILI risk than Ligand B (52.152). Both are below 60, but Ligand A is significantly safer.

**8. BBB:** Both ligands have excellent BBB penetration (70.105 and 71.268), exceeding the desirable >70 threshold for CNS targets.

**9. Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and suggests a potential issue with intestinal absorption. However, these values are on a different scale and hard to interpret directly.

**10. Aqueous Solubility:** Both have negative solubility values, which is also unusual. Again, difficult to interpret without knowing the scale.

**11. hERG Inhibition:** Both ligands show low hERG inhibition liability (0.769 and 0.523), which is good.

**12. Microsomal Clearance:** Ligand A (-18.364) has a more negative (lower) microsomal clearance than Ligand B (-9.476), indicating better metabolic stability.

**13. In vitro Half-Life:** Ligand A (13.562) has a longer in vitro half-life than Ligand B (-20.936).

**14. P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.071 and 0.045), which is excellent for CNS penetration.

**15. Binding Affinity:** Ligand A (-10.0) has a significantly stronger binding affinity than Ligand B (-7.6). This is a crucial advantage, as a >1.5 kcal/mol difference can outweigh minor ADME drawbacks.

**Overall Assessment:**

Ligand A is superior to Ligand B across most parameters. It has a lower TPSA, lower DILI risk, better metabolic stability (lower Cl_mic, longer t1/2), and, most importantly, a significantly stronger binding affinity. While both have good BBB penetration and low P-gp efflux, the combination of improved ADME properties and substantially better affinity makes Ligand A the more promising drug candidate.

Output:
1
2025-04-17 08:48:31,384 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (356.373 and 361.511 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (75.63) is slightly higher than Ligand B (73.2). Both are below the 90 A^2 threshold desirable for CNS targets, which is good.

**3. logP:** Ligand A (2.496) is within the optimal range (1-3). Ligand B (3.27) is slightly higher, but still acceptable.

**4. H-Bond Donors:** Ligand A (0) is preferable to Ligand B (1). Fewer HBDs generally improve permeability.

**5. H-Bond Acceptors:** Ligand A (5) is slightly higher than Ligand B (4), but both are within the acceptable limit of 10.

**6. QED:** Both ligands have good QED scores (0.832 and 0.845), indicating good drug-like properties.

**7. DILI:** Ligand B (31.563) has a significantly lower DILI risk than Ligand A (53.315). This is a substantial advantage for Ligand B.

**8. BBB:** Ligand A (90.074) has a slightly better BBB penetration percentile than Ligand B (76.774), but both are reasonably good for a CNS target.

**9. Caco-2:** Both have negative Caco-2 values, which is unusual and suggests poor permeability. However, the scale is not specified, so it's hard to interpret.

**10. Solubility:** Ligand B (-4.254) has worse solubility than Ligand A (-2.195). Solubility is important, but can be addressed with formulation.

**11. hERG:** Ligand A (0.202) has a lower hERG inhibition liability than Ligand B (0.672), which is favorable.

**12. Cl_mic:** Ligand A (36.149) has a lower microsomal clearance than Ligand B (71.876), indicating better metabolic stability.

**13. t1/2:** Ligand B (21.417) has a significantly longer in vitro half-life than Ligand A (-11.367). This is a major advantage for Ligand B.

**14. Pgp:** Both ligands have very low Pgp efflux liability (0.058 and 0.183), which is excellent for CNS penetration.

**15. Binding Affinity:** Both ligands have the same binding affinity (-8 kcal/mol), which is excellent.

**Overall Assessment:**

While Ligand A has slightly better BBB penetration and hERG inhibition, Ligand B has a significantly lower DILI risk, a longer half-life, and better metabolic stability. Given the GPCR-specific priorities, the lower DILI and improved metabolic stability of Ligand B are more critical. The slight difference in BBB is less important given both are reasonably good. The longer half-life is also a significant advantage.

Output:
1
2025-04-17 08:48:31,384 - INFO - Reasoning:

Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (374.5) is slightly better positioned.

**TPSA:** Ligand A (113.32) is preferable as it's closer to the <90 threshold for CNS targets, while Ligand B (67.35) is excellent.

**logP:** Ligand A (0.994) is a bit low, potentially hindering permeability. Ligand B (2.757) is within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A (3 HBD, 6 HBA) and Ligand B (1 HBD, 5 HBA) both fall within acceptable limits.

**QED:** Both ligands have good QED scores (A: 0.529, B: 0.589), indicating drug-likeness.

**DILI:** Ligand A (26.948) has a significantly lower DILI risk than Ligand B (43.738), which is a major advantage.

**BBB:** Ligand B (85.537) has a much higher BBB penetration percentile than Ligand A (38.542). This is *critical* for a CNS target like DRD2.

**Caco-2 Permeability:** Ligand A (-5.283) has poor Caco-2 permeability, while Ligand B (-4.932) is also poor, but slightly better.

**Aqueous Solubility:** Both ligands have poor aqueous solubility (-1.265 and -2.556 respectively).

**hERG:** Both ligands have low hERG inhibition risk (0.334 and 0.548 respectively).

**Microsomal Clearance:** Ligand A (0.324) has significantly lower microsomal clearance than Ligand B (61.893), indicating better metabolic stability.

**In vitro Half-Life:** Ligand A (26.426) has a longer in vitro half-life than Ligand B (19.136).

**P-gp Efflux:** Ligand A (0.088) has much lower P-gp efflux liability than Ligand B (0.121), which is favorable for CNS penetration.

**Binding Affinity:** Ligand A (-7.2 kcal/mol) has a slightly better binding affinity than Ligand B (-6.4 kcal/mol). While both are good, the 0.8 kcal/mol difference is noteworthy.

**Overall Assessment:**

Ligand B excels in BBB penetration, a crucial factor for CNS drug development. However, it suffers from higher DILI risk, higher P-gp efflux, and significantly higher microsomal clearance. Ligand A has a better safety profile (DILI, P-gp), better metabolic stability, and slightly better affinity, but its BBB penetration is a significant concern.

Given the importance of CNS penetration for DRD2, and the relatively small difference in binding affinity, Ligand B is the more promising candidate *despite* its drawbacks. The higher BBB value is likely to translate to better in vivo brain exposure, potentially compensating for the other issues. Optimization efforts could then focus on reducing DILI and P-gp efflux.

Output:
1

2025-04-17 08:48:31,384 - INFO - Batch 480 complete. Total preferences: 7680
2025-04-17 08:48:31,384 - INFO - Processing batch 481/512...
2025-04-17 08:49:16,616 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (373.791 and 349.406 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (99.12) is slightly higher than the preferred <90 for CNS targets, but still reasonable. Ligand B (76.64) is well within the desired range.

**3. logP:** Ligand A (4.79) is a bit high, potentially leading to solubility issues and off-target effects. Ligand B (1.522) is optimal.

**4. H-Bond Donors:** Both ligands have 2 HBD, which is acceptable.

**5. H-Bond Acceptors:** Both ligands have 3 HBA, which is acceptable.

**6. QED:** Ligand B (0.85) has a significantly better QED score than Ligand A (0.408), indicating a more drug-like profile.

**7. DILI:** Both ligands have low DILI risk (59.403 and 40.209 percentile), which is good.

**8. BBB:** Ligand A (78.868) has a good BBB percentile, while Ligand B (59.093) is lower, though not terrible. This is a crucial factor for CNS targets like DRD2.

**9. Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and suggests poor permeability. However, these values are on a log scale, and the negative values are not directly comparable without knowing the scale.

**10. Aqueous Solubility:** Both ligands have very poor aqueous solubility (-5.159 and -2.158). This is a significant concern.

**11. hERG Inhibition:** Both ligands show low hERG inhibition risk (0.691 and 0.537).

**12. Microsomal Clearance:** Ligand B (2.647) has significantly lower microsomal clearance than Ligand A (40.583), suggesting better metabolic stability.

**13. In vitro Half-Life:** Ligand B (-2.351) has a negative half-life, which is impossible. This is a data error and a major red flag. Ligand A (30.546) has a reasonable half-life.

**14. P-gp Efflux:** Both ligands show low P-gp efflux liability (0.229 and 0.039), which is favorable for CNS penetration.

**15. Binding Affinity:** Ligand B (-8.8 kcal/mol) has a significantly stronger binding affinity than Ligand A (-7.9 kcal/mol). This is a substantial advantage.

**Overall Assessment:**

Despite the poor solubility and questionable Caco-2 values for both, Ligand B is the more promising candidate. Its superior binding affinity, better logP, higher QED, and lower microsomal clearance outweigh the slightly lower BBB penetration. The negative half-life for Ligand B is a critical data error that would require further investigation, but assuming it's a data issue, the other properties favor it. Ligand A's higher logP and poorer metabolic stability are concerning.

Output:
1
2025-04-17 08:49:16,616 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (345.345 and 357.405 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (46.61) is excellent, well below the 90 A^2 threshold for CNS targets. Ligand B (80.12) is still reasonable but less optimal, approaching the 90 A^2 limit.

**logP:** Ligand A (3.214) is within the optimal 1-3 range. Ligand B (1.871) is at the lower end of the range, potentially impacting permeability.

**H-Bond Donors/Acceptors:** Ligand A (0 HBD, 3 HBA) is favorable. Ligand B (1 HBD, 5 HBA) is also acceptable, though slightly higher.

**QED:** Both ligands have good QED scores (0.597 and 0.77), indicating good drug-like properties.

**DILI:** Ligand A (88.523) has a higher DILI risk than Ligand B (38.891). This is a significant concern for Ligand A.

**BBB:** Both ligands have high BBB penetration (77.898 and 87.398), which is crucial for a CNS target like DRD2. Ligand B is slightly better here.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.009 and -4.362), which is unusual and suggests poor permeability. This is a red flag for both, but the values are similar.

**Aqueous Solubility:** Both ligands have negative solubility values (-4.419 and -3.303), also unusual and suggesting very low solubility. This is a significant issue for both.

**hERG Inhibition:** Ligand A (0.603) has a slightly higher hERG risk than Ligand B (0.182), but both are relatively low.

**Microsomal Clearance:** Ligand A (96.545) has a higher microsomal clearance, indicating lower metabolic stability, than Ligand B (50.647).

**In vitro Half-Life:** Ligand B (-32.69) has a much more negative half-life, indicating very rapid metabolism, compared to Ligand A (-1.404). This is a major drawback for Ligand B.

**P-gp Efflux:** Ligand A (0.335) has lower P-gp efflux liability than Ligand B (0.026), which is favorable for CNS penetration.

**Binding Affinity:** Ligand A (-8.5 kcal/mol) has a slightly better binding affinity than Ligand B (-7.7 kcal/mol). This 0.8 kcal/mol difference is significant.

**Overall Assessment:**

Ligand A has a better binding affinity, TPSA, P-gp efflux, and half-life. However, it has a significantly higher DILI risk and higher microsomal clearance. Ligand B has a lower DILI risk, better metabolic stability, and lower P-gp efflux, but suffers from a weaker binding affinity and a very short half-life.

Considering the GPCR-specific priorities, BBB penetration is good for both. The affinity difference is important, and Ligand A's affinity is substantially better. However, the DILI risk for Ligand A is concerning. The solubility and permeability issues are problematic for both. Given the CNS target, the slightly better affinity and P-gp profile of Ligand A, combined with the acceptable BBB penetration, outweigh the DILI risk *if* the DILI risk can be mitigated through structural modifications. The very short half-life of Ligand B is a more difficult issue to address.

Output:
1
2025-04-17 08:49:16,617 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (353.463 and 351.535 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (79.9) is higher than Ligand B (52.65). For a CNS target like DRD2, we ideally want TPSA <= 90, so both are acceptable, but B is better.

**3. logP:** Ligand A (0.284) is quite low, potentially hindering permeability. Ligand B (2.672) is within the optimal 1-3 range. This is a significant advantage for B.

**4. H-Bond Donors:** Ligand A (2) and Ligand B (1) are both acceptable (<=5).

**5. H-Bond Acceptors:** Ligand A (5) and Ligand B (3) are both acceptable (<=10).

**6. QED:** Both ligands have similar QED values (0.687 and 0.684), indicating good drug-like properties.

**7. DILI:** Ligand A (12.796) has a lower DILI risk than Ligand B (16.324), which is favorable.

**8. BBB:** Ligand B (78.209) has a significantly higher BBB penetration percentile than Ligand A (39.511). This is *critical* for a CNS target like DRD2, making B much more promising.

**9. Caco-2 Permeability:** Ligand A (-5.556) has very poor Caco-2 permeability, while Ligand B (-4.64) is slightly better, but still poor.

**10. Aqueous Solubility:** Ligand A (-0.656) has slightly better solubility than Ligand B (-2.962).

**11. hERG Inhibition:** Both ligands have low hERG inhibition risk (0.245 and 0.508).

**12. Microsomal Clearance:** Ligand A (-8.834) has a much lower (better) microsomal clearance than Ligand B (54.058), suggesting greater metabolic stability.

**13. In vitro Half-Life:** Ligand A (28.757) has a longer half-life than Ligand B (3.063). This is a positive for A.

**14. P-gp Efflux:** Ligand A (0.004) has much lower P-gp efflux liability than Ligand B (0.23), which is highly desirable for CNS penetration.

**15. Binding Affinity:** Both ligands have very similar and strong binding affinities (-8.1 and -8.0 kcal/mol). The difference is negligible.

**Overall Assessment:**

Ligand B excels in BBB penetration and has a better logP value, which are crucial for CNS GPCR targets. However, it suffers from higher P-gp efflux and significantly worse metabolic stability (higher Cl_mic, shorter t1/2). Ligand A has a better metabolic profile, lower P-gp efflux, and slightly better solubility, but its low logP and poor BBB penetration are major drawbacks.

Considering the GPCR-specific priorities, the improved BBB penetration and logP of Ligand B outweigh its metabolic liabilities, especially given the strong binding affinity. While Ligand A's metabolic stability is appealing, its poor CNS penetration makes it less likely to be a viable drug candidate for DRD2.

Output:
1
2025-04-17 08:49:16,617 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (353.432 and 346.515 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (31.06) is significantly better than Ligand B (40.62). For CNS targets, we want TPSA <= 90, both are well within this range, but A is preferable.

**logP:** Ligand A (4.541) is slightly higher than Ligand B (3.739). Both are above the optimal 1-3 range, but still acceptable. The higher logP of A could potentially lead to off-target effects, but it might also aid in BBB penetration.

**H-Bond Donors/Acceptors:** Ligand A has 2 HBD and 2 HBA, while Ligand B has 0 HBD and 2 HBA. Both are within acceptable limits (<=5 HBD and <=10 HBA).

**QED:** Both ligands have similar QED values (0.799 and 0.704), indicating good drug-like properties.

**DILI:** Ligand A (22.257) has a slightly higher DILI risk than Ligand B (15.083), but both are below the 40 threshold and considered good.

**BBB:** Both ligands have excellent BBB penetration (Ligand A: 96.472, Ligand B: 91.392), exceeding the desirable >70 threshold for CNS targets.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.999 and -4.539). This is unusual and suggests poor permeability. However, these values might be from a different scale or represent an issue with the prediction method.

**Aqueous Solubility:** Both ligands have very poor aqueous solubility (-3.809 and -3.901). This is a significant concern for bioavailability.

**hERG Inhibition:** Ligand A (0.986) has a slightly higher hERG risk than Ligand B (0.575), but both are relatively low.

**Microsomal Clearance:** Ligand A (-3.924) has a significantly *lower* (better) microsomal clearance than Ligand B (80.527), indicating greater metabolic stability.

**In vitro Half-Life:** Ligand A (24.502) has a much longer in vitro half-life than Ligand B (1.205), which is highly desirable.

**P-gp Efflux:** Ligand A (0.508) has lower P-gp efflux than Ligand B (0.333), which is better for CNS exposure.

**Binding Affinity:** Ligand A (-9.0) has a significantly stronger binding affinity than Ligand B (-8.5). This is a crucial advantage, potentially outweighing some of the ADME drawbacks. A difference of 0.5 kcal/mol is substantial.

**Conclusion:**

Despite the poor solubility and Caco-2 permeability predictions for both compounds, Ligand A is the more promising candidate. Its superior binding affinity (-9.0 vs -8.5 kcal/mol), lower microsomal clearance, longer half-life, and lower P-gp efflux, combined with acceptable BBB penetration, outweigh its slightly higher logP and DILI risk. The strong binding affinity is a key factor, especially for a GPCR target where achieving sufficient occupancy is critical.

Output:
1
2025-04-17 08:49:16,617 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 drug candidates, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (334.354 Da and 358.32 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (61.4) is significantly better than Ligand B (78.27). For CNS targets, TPSA should be <=90, and lower is preferred. Ligand A is much closer to the optimal range for CNS penetration.

**3. logP:** Both ligands have good logP values (3.184 and 2.388), falling within the optimal 1-3 range.

**4. H-Bond Donors:** Ligand A (0) is better than Ligand B (1). Fewer HBDs generally improve membrane permeability.

**5. H-Bond Acceptors:** Ligand A (4) is better than Ligand B (6). Fewer HBAs also contribute to better permeability.

**6. QED:** Both ligands have acceptable QED values (0.687 and 0.769), indicating good drug-like properties.

**7. DILI:** Both ligands have relatively high DILI risk (72.509 and 62.893), but are still below the concerning >60 threshold. This isn't a major differentiating factor.

**8. BBB:** Both ligands show good BBB penetration (79.217 and 73.362), exceeding the desirable >70 threshold for CNS targets. Ligand A is slightly better.

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.347 and -4.598). This is unusual and suggests poor permeability. However, these values are on a strange scale and may not be directly comparable.

**10. Aqueous Solubility:** Both ligands have negative solubility values (-4.682 and -3.078). Similar to Caco-2, this is unusual and suggests poor solubility.

**11. hERG Inhibition:** Ligand A (0.922) is better than Ligand B (0.351), indicating a lower risk of cardiotoxicity.

**12. Microsomal Clearance:** Ligand B (57.828) has lower microsomal clearance than Ligand A (62.168), suggesting better metabolic stability.

**13. In vitro Half-Life:** Ligand A (20.95) has a significantly longer half-life than Ligand B (-19.014). This is a major advantage.

**14. P-gp Efflux:** Ligand A (0.68) is better than Ligand B (0.335), indicating lower P-gp efflux and potentially better CNS exposure.

**15. Binding Affinity:** Ligand A (-8.8 kcal/mol) has a slightly better binding affinity than Ligand B (-8.3 kcal/mol). While both are good, the 0.5 kcal/mol difference is notable.

**Overall Assessment:**

Considering the GPCR-specific priorities, Ligand A is the more promising candidate. It has a lower TPSA, fewer H-bonds, better hERG inhibition, a longer half-life, lower P-gp efflux, and slightly better binding affinity. While both have issues with Caco-2 and solubility, the other advantages of Ligand A outweigh these concerns. The longer half-life and better CNS penetration properties are particularly important for a DRD2 ligand targeting CNS disorders.

Output:
1
2025-04-17 08:49:16,617 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (355.479 and 341.415 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (90.9) is slightly above the optimal <90 for CNS targets, while Ligand B (80.12) is comfortably within the range.

**logP:** Ligand A (0.127) is quite low, potentially hindering membrane permeability. Ligand B (0.433) is also low, but better than A. Both are below the optimal 1-3 range.

**H-Bond Donors:** Ligand A (3) is acceptable, while Ligand B (1) is even better, being lower.

**H-Bond Acceptors:** Both ligands (A: 5, B: 5) are within the acceptable limit of <=10.

**QED:** Ligand B (0.806) has a significantly higher QED score than Ligand A (0.485), indicating better overall drug-likeness.

**DILI:** Both ligands have similar, reasonably low DILI risk (A: 8.414, B: 36.642).

**BBB:** Ligand B (60.644) has a substantially better BBB percentile than Ligand A (36.332). This is a critical advantage for a CNS target like DRD2.

**Caco-2:** Both have negative Caco-2 values which is unusual and suggests poor permeability.

**Solubility:** Both ligands have negative solubility values, which is also unusual and suggests poor solubility.

**hERG:** Both ligands have low hERG inhibition liability (A: 0.34, B: 0.08), which is favorable.

**Cl_mic:** Ligand B (0.256) has a much lower microsomal clearance than Ligand A (12.953), suggesting better metabolic stability.

**t1/2:** Ligand B (-2.258) has a more negative in vitro half-life, which is not ideal. Ligand A (-13.289) is even worse.

**Pgp:** Ligand A (0.017) has a very low Pgp efflux liability, which is excellent. Ligand B (0.035) is slightly higher, but still good.

**Binding Affinity:** Ligand B (-8.3 kcal/mol) has a slightly better binding affinity than Ligand A (-7.5 kcal/mol). While both are good, the difference is significant enough to consider.

**Overall Assessment:**

Ligand B is the stronger candidate. While both have issues with solubility and Caco-2 permeability, Ligand B excels in the most important areas for a CNS-targeting GPCR: BBB penetration, metabolic stability (lower Cl_mic), and a slightly better binding affinity. Its higher QED score also suggests a more favorable overall drug-like profile. Ligand A's low logP is a significant concern, and its poorer BBB penetration is a major drawback.

Output:
1
2025-04-17 08:49:16,618 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (341.323 Da) is slightly lower, which could be advantageous for permeability.

**TPSA:** Both ligands are below the 140 A^2 threshold for oral absorption. Ligand A (98.66 A^2) is better, being closer to the 90 A^2 target for CNS penetration. Ligand B (105.49 A^2) is still acceptable but less optimal.

**logP:** Ligand A (0.598) is a bit low, potentially hindering permeation. Ligand B (2.334) is within the optimal range (1-3). This is a significant advantage for Ligand B.

**H-Bond Donors/Acceptors:** Ligand A (2 HBD, 6 HBA) and Ligand B (3 HBD, 5 HBA) both fall within acceptable limits.

**QED:** Both ligands have reasonable QED scores (A: 0.78, B: 0.652), indicating good drug-like properties.

**DILI:** Both have relatively high DILI risk, but Ligand A (87.98) is higher than Ligand B (80.574). Lower is better, so Ligand B is preferable.

**BBB:** This is crucial for a CNS target. Ligand A (44.009) has a poor BBB percentile, while Ligand B (76.309) is much better, exceeding the desirable >70 threshold. This is a major advantage for Ligand B.

**Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and suggests potential issues with in vitro permeability assays.

**Aqueous Solubility:** Both have negative solubility values, which is also unusual and suggests potential issues with in vitro solubility assays.

**hERG Inhibition:** Both ligands show very low hERG inhibition risk (A: 0.191, B: 0.282).

**Microsomal Clearance:** Ligand A (0.782 mL/min/kg) has significantly lower clearance than Ligand B (47.216 mL/min/kg), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (6.131 hours) has a better half-life than Ligand B (36.247 hours).

**P-gp Efflux:** Both ligands have low P-gp efflux liability (A: 0.158, B: 0.111), which is good for CNS exposure.

**Binding Affinity:** Ligand B (-8.8 kcal/mol) has a slightly better binding affinity than Ligand A (-9.7 kcal/mol). While the difference is small, it's still a positive for Ligand B.

**Overall Assessment:**

Ligand B is the stronger candidate. While Ligand A has better metabolic stability and half-life, Ligand B excels in key areas for a CNS-targeting GPCR: significantly better BBB penetration, a more favorable logP, and slightly better binding affinity. The higher DILI risk for Ligand A is also a concern. The TPSA is also more favorable for Ligand A, but the BBB advantage of Ligand B outweighs this.

Output:
1
2025-04-17 08:49:16,618 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (347.415 and 355.429 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (114.43) is better than Ligand B (47.36). For CNS targets, TPSA should be <=90. Both are within this range, but A is closer to the upper limit.

**3. logP:** Both ligands have good logP values (1.648 and 2.926), falling within the optimal 1-3 range.

**4. H-Bond Donors:** Ligand A has 3 HBD, which is acceptable. Ligand B has 0, also acceptable.

**5. H-Bond Acceptors:** Both ligands have 4 HBA, which is within the acceptable limit of <=10.

**6. QED:** Ligand B (0.756) has a better QED score than Ligand A (0.49), indicating a more drug-like profile.

**7. DILI:** Both ligands have similar, acceptable DILI risk (35.905 and 35.285 percentile).

**8. BBB:** This is a crucial parameter for a CNS target like DRD2. Ligand B (97.751) significantly outperforms Ligand A (52.579) in BBB penetration. This is a major advantage for Ligand B.

**9. Caco-2 Permeability:** Ligand A (-5.336) shows poor Caco-2 permeability, while Ligand B (-4.58) is slightly better, but still poor.

**10. Aqueous Solubility:** Both ligands have very poor aqueous solubility (-2.703 and -2.705). This could pose formulation challenges.

**11. hERG Inhibition:** Both ligands have low hERG inhibition risk (0.197 and 0.669).

**12. Microsomal Clearance:** Both ligands have similar microsomal clearance (33.089 and 35.896 mL/min/kg).

**13. In vitro Half-Life:** Ligand B (6.95 hours) has a significantly longer half-life than Ligand A (1.197 hours).

**14. P-gp Efflux:** Ligand A (0.045) has much lower P-gp efflux than Ligand B (0.18), which is favorable for CNS penetration.

**15. Binding Affinity:** Ligand B (-7.2 kcal/mol) has a slightly better binding affinity than Ligand A (-8.1 kcal/mol). While A is better, the difference is not substantial enough to overcome the other deficiencies.

**Overall Assessment:**

While Ligand A has a slightly better binding affinity and P-gp efflux, Ligand B is the superior candidate due to its significantly better BBB penetration (97.751 vs 52.579), longer half-life (6.95 vs 1.197), and better QED score (0.756 vs 0.49). The poor Caco-2 permeability and solubility are concerns for both, but the CNS target prioritizes BBB penetration, making Ligand B the more promising candidate.

Output:
1
2025-04-17 08:49:16,618 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (388.511 Da) is slightly higher than Ligand B (347.459 Da), but both are acceptable.

**TPSA:** Ligand A (91.83) is slightly above the optimal <90 for CNS targets, while Ligand B (75.44) is well within the desired range. This favors Ligand B.

**logP:** Ligand A (0.515) is a bit low, potentially hindering membrane permeability. Ligand B (2.958) is nearly ideal. This is a significant advantage for Ligand B.

**H-Bond Donors/Acceptors:** Ligand A has 0 HBD and 5 HBA, which is good. Ligand B has 1 HBD and 4 HBA, also acceptable.

**QED:** Both ligands have similar QED values (0.733 and 0.521), indicating reasonable drug-likeness.

**DILI:** Ligand A (61.807) has a higher DILI risk than Ligand B (37.03). This favors Ligand B.

**BBB:** Both ligands have similar BBB penetration (59.791 and 61.38), which is acceptable but not outstanding for a CNS target. Ideally, we'd want >70.

**Caco-2 Permeability:** Ligand A (-4.854) has poor Caco-2 permeability, while Ligand B (-4.525) is slightly better, but still not great.

**Aqueous Solubility:** Both ligands have very poor aqueous solubility (-2.839 and -3.484). This could pose formulation challenges.

**hERG Inhibition:** Ligand A (0.312) has a slightly lower hERG risk than Ligand B (0.559), which is favorable.

**Microsomal Clearance:** Ligand A (22.62) has significantly lower microsomal clearance than Ligand B (54.907), suggesting better metabolic stability. This is a strong advantage for Ligand A.

**In vitro Half-Life:** Ligand A (-23.464) has a very short in vitro half-life, which is concerning. Ligand B (2.573) is better, but still relatively short.

**P-gp Efflux:** Ligand A (0.119) has lower P-gp efflux than Ligand B (0.14), which is favorable for CNS penetration.

**Binding Affinity:** Ligand B (-7.5 kcal/mol) has a significantly stronger binding affinity than Ligand A (-8.3 kcal/mol). This is a substantial advantage for Ligand B, potentially outweighing some of its ADME drawbacks.

**Overall Assessment:**

While Ligand A has better metabolic stability and lower P-gp efflux, Ligand B excels in crucial areas for a CNS-targeting GPCR ligand: better logP, lower DILI risk, and *significantly* stronger binding affinity. The TPSA is also more favorable for Ligand B. The solubility and Caco-2 permeability are poor for both, but the affinity difference is substantial. Given the importance of binding affinity for GPCRs, and the relatively similar BBB values, Ligand B is the more promising candidate.

Output:
1
2025-04-17 08:49:16,618 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (348.403 and 356.419 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (127.32) is slightly above the preferred <90 for CNS targets, but still reasonable. Ligand B (116.17) is better, falling comfortably under 90.

**logP:** Ligand A (0.539) is a bit low, potentially hindering membrane permeability. Ligand B (-0.574) is even lower, raising concerns about permeability. Both are below the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Both have 3 HBD and acceptable HBA counts (5 and 6 respectively).

**QED:** Both ligands have similar QED values (0.62 and 0.526), indicating good drug-likeness.

**DILI:** Ligand A (48.313) has a higher DILI risk than Ligand B (26.018), which is a significant advantage for B.

**BBB:** Ligand A (74.758) has a significantly better BBB penetration percentile than Ligand B (33.85). This is a *critical* factor for a CNS target like DRD2.

**Caco-2 Permeability:** Ligand A (-5.353) and Ligand B (-5.021) both have negative Caco-2 values, which is unusual and suggests poor permeability.

**Aqueous Solubility:** Both have negative solubility values (-3.832 and -1.149), which is also concerning.

**hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.068 and 0.128).

**Microsomal Clearance:** Ligand B (9.008) has a much lower microsomal clearance than Ligand A (34.667), indicating better metabolic stability.

**In vitro Half-Life:** Ligand B (-16.019) has a significantly longer in vitro half-life than Ligand A (-7.99), which is a major advantage.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.025 and 0.015).

**Binding Affinity:** Ligand A (-8.3 kcal/mol) has a slightly better binding affinity than Ligand B (-7.6 kcal/mol), but the difference is less than 1.5 kcal/mol.

**Overall Assessment:**

While Ligand A has better BBB penetration and slightly better binding affinity, Ligand B excels in several crucial ADME properties. Specifically, the significantly lower DILI risk, lower microsomal clearance, and longer half-life of Ligand B are highly desirable. The lower BBB penetration of Ligand B is a concern, but the other improvements outweigh this drawback, especially considering the relatively modest difference in binding affinity. The poor solubility and Caco-2 permeability are shared concerns that would need to be addressed in further optimization, but are less critical at this stage than the metabolic stability and safety profile.

Output:
1
2025-04-17 08:49:16,618 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (355.341 and 361.511 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (91.76) is slightly above the optimal <90 for CNS targets, but still reasonable. Ligand B (62.3) is well within the desired range.

**logP:** Ligand A (1.744) is within the optimal 1-3 range. Ligand B (3.227) is at the higher end but still acceptable.

**H-Bond Donors/Acceptors:** Ligand A has 2 HBD and 5 HBA, which are acceptable. Ligand B has 1 HBD and 4 HBA, also acceptable.

**QED:** Both ligands have similar QED values (0.8 and 0.791), indicating good drug-likeness.

**DILI:** Ligand A (80.109) has a higher DILI risk than Ligand B (46.375). This is a significant negative for Ligand A.

**BBB:** Ligand B (70.105) has a significantly better BBB penetration score than Ligand A (48.042). This is a crucial advantage for a CNS target like DRD2.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.976 and -4.904), which is unusual and suggests poor permeability. However, these values are on a log scale, and the absolute difference isn't huge.

**Aqueous Solubility:** Both ligands have negative solubility values (-2.451 and -3.58), indicating poor aqueous solubility. This could pose formulation challenges.

**hERG Inhibition:** Both ligands show very low hERG inhibition risk (0.056 and 0.519).

**Microsomal Clearance:** Ligand A (-21.566) has a much lower (better) microsomal clearance than Ligand B (55.119), indicating better metabolic stability.

**In vitro Half-Life:** Ligand A (-30.524) has a much longer in vitro half-life than Ligand B (5.365), which is a significant advantage.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.002 and 0.565).

**Binding Affinity:** Both ligands have comparable binding affinities (-8.6 and -8.1 kcal/mol), both being strong binders. The difference of 0.5 kcal/mol is not substantial enough to override other factors.

**Overall Assessment:**

Ligand B is the more promising candidate. While Ligand A has better metabolic stability and half-life, Ligand B's significantly better BBB penetration (70.105 vs 48.042) and lower DILI risk are critical advantages for a CNS-targeting drug. The slightly higher logP of Ligand B is acceptable, and the affinity difference is minimal. The poor Caco-2 and solubility are concerns for both, but can potentially be addressed with formulation strategies.

Output:
1
2025-04-17 08:49:16,619 - INFO - Reasoning:

Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight (MW):** Both ligands (352.475 and 359.539 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (89.87) is excellent, being below the 90 A^2 threshold for CNS targets. Ligand B (45.23) is also very good.

**3. logP:** Ligand A (1.194) is within the optimal range of 1-3. Ligand B (3.183) is also within the optimal range.

**4. H-Bond Donors (HBD):** Ligand A (3) and Ligand B (1) both meet the <=5 criteria.

**5. H-Bond Acceptors (HBA):** Ligand A (4) and Ligand B (4) both meet the <=10 criteria.

**6. QED:** Both ligands have good QED scores (0.693 and 0.847, respectively), indicating drug-like properties.

**7. DILI:** Both ligands have similar DILI risk (16.014 and 16.208), both being low risk (<40).

**8. BBB:** This is a critical parameter for a CNS target like DRD2. Ligand B (79.566) significantly outperforms Ligand A (22.606), exceeding the desirable >70 percentile.

**9. Caco-2 Permeability:** Both have negative values (-5.065 and -5.258), which is unusual and suggests poor permeability. However, the scale isn't clearly defined, so this is difficult to interpret.

**10. Aqueous Solubility:** Both ligands have poor aqueous solubility (-1.77 and -3.487). This could be a formulation challenge.

**11. hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.102 and 0.57).

**12. Microsomal Clearance (Cl_mic):** Ligand A (-1.741) has a negative clearance, which is unusual and likely indicates high metabolic stability. Ligand B (69.397) has a high clearance, suggesting faster metabolism.

**13. In vitro Half-Life:** Ligand A (10.281) has a reasonable half-life. Ligand B (9.326) is also acceptable.

**14. P-gp Efflux:** Ligand A (0.035) has very low P-gp efflux, which is excellent for CNS penetration. Ligand B (0.219) also has low P-gp efflux.

**15. Binding Affinity:** Ligand B (-7.8 kcal/mol) has a slightly better binding affinity than Ligand A (-8.3 kcal/mol). While the difference is small, it's still a positive factor.

**Overall Assessment:**

Ligand B is the more promising candidate. Its significantly higher BBB penetration (79.566 vs. 22.606) is the most crucial factor for a CNS-targeting drug. While Ligand A has better metabolic stability (negative Cl_mic), the improved BBB penetration of Ligand B outweighs this advantage. Both ligands have acceptable properties in other areas, but the BBB score is the deciding factor for DRD2.

Output:
1
2025-04-17 08:49:16,619 - INFO - Okay, let's analyze these two ligands for their potential as DRD2 drug candidates. DRD2 is a GPCR in the CNS, so BBB penetration, logP, Pgp efflux, TPSA, and binding affinity are key.

**Ligand A:** [346.475, 76.02, 2.354, 2, 4, 0.796, 29.895, 64.172, -4.873, -2.817, 0.488, 41.066, -9.902, 0.169, -8.6]
**Ligand B:** [347.463, 80.12, 1.556, 1, 5, 0.896, 36.952, 48.662, -5.081, -1.374, 0.117, 19.903, 17.272, 0.079, 0]

**1. Molecular Weight:** Both are within the ideal range (200-500 Da).
**2. TPSA:** Ligand A (76.02) is better than Ligand B (80.12), both are below the 90 A^2 threshold for CNS targets, but A is closer to the optimal range.
**3. logP:** Ligand A (2.354) is optimal, while Ligand B (1.556) is a bit low, potentially hindering permeability.
**4. H-Bond Donors:** Ligand A (2) is preferable to Ligand B (1), as it provides a slight advantage in balancing solubility and permeability.
**5. H-Bond Acceptors:** Ligand B (5) is slightly higher than Ligand A (4), but both are within acceptable limits.
**6. QED:** Both have good QED scores (A: 0.796, B: 0.896), indicating drug-like properties. B is slightly better.
**7. DILI:** Ligand A (29.895) has a better DILI score than Ligand B (36.952), indicating lower potential for liver injury.
**8. BBB:** Ligand A (64.172) has a significantly better BBB score than Ligand B (48.662). This is *critical* for a CNS target like DRD2.
**9. Caco-2:** Ligand A (-4.873) is better than Ligand B (-5.081). Higher values indicate better absorption.
**10. Solubility:** Ligand B (-1.374) is better than Ligand A (-2.817).
**11. hERG:** Both have very low hERG inhibition risk (A: 0.488, B: 0.117), which is excellent.
**12. Cl_mic:** Ligand B (19.903) has a significantly lower microsomal clearance than Ligand A (41.066), suggesting better metabolic stability.
**13. t1/2:** Ligand B (17.272) has a longer in vitro half-life than Ligand A (-9.902).
**14. Pgp:** Ligand B (0.079) has lower P-gp efflux than Ligand A (0.169), which is favorable for CNS penetration.
**15. Binding Affinity:** Ligand A (-8.6) has a *much* stronger binding affinity than Ligand B (0). This is a substantial advantage.

**Overall Assessment:**

While Ligand B has some advantages in terms of metabolic stability (Cl_mic, t1/2), Pgp efflux, and solubility, Ligand A is the superior candidate due to its significantly stronger binding affinity (-8.6 vs 0 kcal/mol) and substantially better BBB penetration (64.172 vs 48.662). The strong binding affinity can likely compensate for the slightly higher Cl_mic and lower solubility. For a CNS target, BBB penetration is paramount, and Ligand A clearly wins in that regard. The lower DILI risk is also a positive.

1
2025-04-17 08:49:16,619 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (347.415 and 355.479 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (80.76) is better than Ligand B (87.74). Both are below the 90 A^2 threshold desirable for CNS targets, but A is closer to the optimal range.

**3. logP:** Both ligands have good logP values (1.26 and 1.073), falling within the 1-3 range.

**4. H-Bond Donors:** Ligand A (1) is better than Ligand B (2). Lower HBD is generally preferred for BBB penetration.

**5. H-Bond Acceptors:** Ligand A (5) is better than Ligand B (4). Both are within the acceptable range of <=10.

**6. QED:** Both ligands have good QED scores (0.593 and 0.648), indicating drug-like properties.

**7. DILI:** Ligand A (37.611) has a significantly lower DILI risk than Ligand B (11.128). This is a major advantage for Ligand A.

**8. BBB:** Ligand A (69.407) has a better BBB percentile than Ligand B (62.466). While both are not ideal (>70), A is closer.

**9. Caco-2 Permeability:** Ligand A (-4.603) has a worse Caco-2 permeability than Ligand B (-5.132). Lower values indicate lower permeability.

**10. Aqueous Solubility:** Ligand A (-1.846) has better aqueous solubility than Ligand B (-1.297).

**11. hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.324 and 0.289).

**12. Microsomal Clearance:** Ligand B (-2.055) has a lower (better) microsomal clearance than Ligand A (12.986). This suggests better metabolic stability for Ligand B.

**13. In vitro Half-Life:** Ligand B (-1.33) has a better in vitro half-life than Ligand A (-18.371).

**14. P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.031 and 0.008).

**15. Binding Affinity:** Both ligands have the same binding affinity (-7.7 kcal/mol), which is excellent.

**Overall Assessment:**

Ligand A excels in TPSA, DILI risk, BBB penetration, aqueous solubility and H-bonding characteristics. Ligand B has better metabolic stability (lower Cl_mic) and in vitro half-life, and slightly better Caco-2 permeability. However, the significantly lower DILI risk and better BBB for Ligand A are crucial for a CNS-targeting drug like a DRD2 ligand. The affinity is identical, so the ADME properties become the deciding factor. Given the GPCR-specific priorities, the better BBB and lower DILI risk of Ligand A outweigh the slightly better metabolic stability of Ligand B.

Output:
1
2025-04-17 08:49:16,619 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (380.945 Da) is slightly higher than Ligand B (366.487 Da), but both are acceptable.

**TPSA:** Ligand A (59.81) is significantly better than Ligand B (84.3). For CNS targets, we want TPSA <= 90, and ideally closer to 60. Ligand A is much closer to this ideal.

**logP:** Ligand A (3.669) is within the optimal range (1-3), while Ligand B (0.627) is below 1, which could hinder permeation. This is a significant advantage for Ligand A.

**H-Bond Donors/Acceptors:** Both ligands have 1 HBD and a reasonable number of HBAs (5 and 6 respectively). This is acceptable for both.

**QED:** Both ligands have QED values above 0.5 (0.674 and 0.512), indicating good drug-likeness.

**DILI:** Ligand A (48.313) has a slightly higher DILI risk than Ligand B (29.042), but both are below the concerning threshold of 60.

**BBB:** Ligand A (51.066) has a better BBB percentile than Ligand B (43.893), although both are below the desirable >70 for CNS targets.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.27 and -5.506). This is unusual and suggests poor permeability. However, the scale is not specified, so it's hard to interpret.

**Aqueous Solubility:** Both ligands have negative solubility values (-3.808 and -0.821). Again, the scale is unknown, but this suggests poor aqueous solubility for both.

**hERG:** Both ligands have low hERG inhibition liability (0.39 and 0.333), which is good.

**Microsomal Clearance:** Ligand A (82.748) has a higher microsomal clearance than Ligand B (-6.358). This means Ligand B is likely more metabolically stable, which is a positive.

**In vitro Half-Life:** Ligand A (51.454) has a longer half-life than Ligand B (0.892), which is desirable.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.406 and 0.052), which is good for CNS penetration.

**Binding Affinity:** Ligand A (-8.1 kcal/mol) has a slightly better binding affinity than Ligand B (-7.9 kcal/mol). While the difference is small, it's still a factor.

**Overall Assessment:**

Considering the GPCR-specific priorities, Ligand A is the better candidate. Its superior logP and TPSA values are crucial for CNS penetration. While Ligand B has better metabolic stability (lower Cl_mic) and lower DILI, the significantly better logP and TPSA of Ligand A, coupled with only slightly weaker binding affinity, outweigh these advantages. The negative Caco-2 and solubility values are concerning for both, but can be addressed with formulation strategies.



Output:
1
2025-04-17 08:49:16,620 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (349.387 and 353.419 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (115.9) is slightly above the preferred <90 for CNS targets, but still reasonable. Ligand B (107.97) is better, falling comfortably under 90.

**3. logP:** Ligand A (-0.156) is quite low, potentially hindering membrane permeability. Ligand B (-0.983) is also low, but slightly better than A. Both are below the optimal 1-3 range.

**4. H-Bond Donors:** Both ligands have 3 HBD, which is within the acceptable limit of <=5.

**5. H-Bond Acceptors:** Ligand A has 6 HBA, and Ligand B has 5. Both are within the acceptable limit of <=10.

**6. QED:** Both ligands have similar QED values (0.68 and 0.602), indicating good drug-like properties.

**7. DILI:** Ligand A (39.201) has a slightly higher DILI risk than Ligand B (35.246), but both are below the concerning threshold of 60.

**8. BBB:** This is a critical parameter for CNS targets. Ligand A has a BBB percentile of 60.644, which is not ideal (we want >70). Ligand B has a very low BBB percentile of 20.085, which is a significant drawback.

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.187 and -5.17), which is unusual and suggests poor permeability. These values are difficult to interpret without further context, but generally indicate a problem.

**10. Aqueous Solubility:** Both ligands have negative solubility values (-1.188 and -1.336), also unusual and suggesting poor solubility.

**11. hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.092 and 0.08), which is excellent.

**12. Microsomal Clearance:** Ligand A (3.378) has a lower (better) microsomal clearance than Ligand B (-10.522). This suggests better metabolic stability for Ligand A.

**13. In vitro Half-Life:** Ligand A (-4.219) has a negative half-life, which is impossible. Ligand B (20.118) has a reasonable half-life. The negative value for A is a major red flag.

**14. P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.007 and 0.003), which is favorable for CNS penetration.

**15. Binding Affinity:** Ligand B (-8.7 kcal/mol) has a significantly stronger binding affinity than Ligand A (-8.2 kcal/mol). This 0.5 kcal/mol difference is substantial and could outweigh some of the ADME drawbacks.

**Overall Assessment:**

Despite the stronger affinity of Ligand B, its extremely poor BBB penetration is a major concern for a CNS target like DRD2. Ligand A has a better (though still suboptimal) BBB score, better metabolic stability, and a plausible half-life. The negative solubility and Caco-2 values are concerning for both, but the significant affinity advantage of Ligand B is compelling. However, the negative half-life for Ligand A is a fatal flaw.

Considering the GPCR-specific priorities and the fact that a strong affinity can sometimes compensate for ADME issues, Ligand B is the more promising candidate, *despite* its poor BBB. Further optimization would need to focus on improving its BBB penetration, but the initial binding is strong.

Output:
1
2025-04-17 08:49:16,620 - INFO - Batch 481 complete. Total preferences: 7696
2025-04-17 08:49:16,620 - INFO - Processing batch 482/512...
2025-04-17 08:49:58,455 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (369.531 Da) is slightly higher than Ligand B (346.446 Da), but both are acceptable.

**2. TPSA:** Ligand A (91.32) is borderline for CNS targets (ideally <90), while Ligand B (49.41) is well within the desired range. This is a significant advantage for Ligand B.

**3. logP:** Both ligands have good logP values (Ligand A: 2.05, Ligand B: 3.209), falling within the optimal 1-3 range.

**4. H-Bond Donors:** Ligand A (3) is acceptable, while Ligand B (1) is even better, minimizing potential issues with permeability.

**5. H-Bond Acceptors:** Ligand A (5) is acceptable, and Ligand B (2) is also good.

**6. QED:** Both ligands have good QED scores (Ligand A: 0.621, Ligand B: 0.89), indicating drug-like properties. Ligand B is slightly better.

**7. DILI:** Both ligands have low DILI risk (Ligand A: 34.432, Ligand B: 36.603), both well below the 40% threshold.

**8. BBB:** This is a crucial parameter for CNS targets. Ligand A has a BBB percentile of 21.753, which is quite low. Ligand B has a significantly higher BBB percentile of 89.259, making it much more likely to reach the target in the brain.

**9. Caco-2 Permeability:** Ligand A (-5.267) shows poor permeability, while Ligand B (-4.426) is better, but still not great.

**10. Aqueous Solubility:** Both have negative solubility values, indicating poor solubility. Ligand A (-1.99) is slightly better than Ligand B (-3.723).

**11. hERG Inhibition:** Both ligands have low hERG inhibition risk (Ligand A: 0.162, Ligand B: 0.74).

**12. Microsomal Clearance:** Ligand A (35.48) has lower clearance than Ligand B (56.344), suggesting better metabolic stability.

**13. In vitro Half-Life:** Ligand A (17.78) has a longer half-life than Ligand B (-5.018), which is a positive attribute.

**14. P-gp Efflux:** Ligand A (0.17) has lower P-gp efflux than Ligand B (0.353), which is favorable for CNS penetration.

**15. Binding Affinity:** Ligand B (-10.0) has a significantly stronger binding affinity than Ligand A (-6.8). This is a substantial advantage, potentially outweighing some of the ADME drawbacks.

**Overall Assessment:**

While Ligand A has some advantages in terms of metabolic stability and half-life, Ligand B is clearly superior due to its excellent BBB penetration, significantly higher binding affinity, lower TPSA, and better QED. The strong binding affinity of Ligand B is a major factor, and the improved BBB penetration is critical for a CNS target like DRD2. The slightly worse metabolic stability and half-life of Ligand B can potentially be addressed through further optimization.

Output:
1
2025-04-17 08:49:58,455 - INFO - Reasoning:

Let's analyze Ligand A and Ligand B based on the provided guidelines, prioritizing GPCR-specific properties (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (341.37 & 344.46 Da) fall comfortably within the ideal 200-500 Da range.

**TPSA:** Ligand A (111.55) is better than Ligand B (67.23). Both are below the 90 A^2 threshold desirable for CNS targets, but A is closer to the upper limit.

**logP:** Both ligands have good logP values (1.95 & 2.71), falling within the optimal 1-3 range. Ligand B is slightly higher, potentially offering better membrane permeability.

**H-Bond Donors/Acceptors:** Ligand A has 4 HBD and 5 HBA, while Ligand B has 1 HBD and 4 HBA. Both are within acceptable limits (<=5 HBD and <=10 HBA).

**QED:** Both ligands have similar QED scores (0.664 and 0.66), indicating good drug-likeness.

**DILI:** Ligand A (54.63) has a slightly higher DILI risk than Ligand B (41.02), but both are below the concerning 60 percentile.

**BBB:** This is a crucial parameter for a CNS target like DRD2. Ligand B (69.79) significantly outperforms Ligand A (37.96) in BBB penetration, making it more likely to reach the target in the brain.

**Caco-2 Permeability:** Ligand A (-5.282) has a worse Caco-2 permeability than Ligand B (-4.836), indicating lower intestinal absorption.

**Aqueous Solubility:** Ligand A (-4.242) has slightly worse solubility than Ligand B (-2.745).

**hERG Inhibition:** Both ligands show low hERG inhibition risk (0.316 and 0.255).

**Microsomal Clearance:** Ligand B (39.65) has slightly higher microsomal clearance than Ligand A (32.83), suggesting slightly lower metabolic stability.

**In vitro Half-Life:** Ligand A (-26.82) has a significantly longer in vitro half-life than Ligand B (-0.65).

**P-gp Efflux:** Ligand A (0.011) has a much lower P-gp efflux liability than Ligand B (0.09), which is favorable for CNS penetration.

**Binding Affinity:** Both ligands have excellent binding affinities (-9.1 and -8.7 kcal/mol). Ligand A has a 0.4 kcal/mol advantage.

**Overall Assessment:**

While Ligand A has a slightly better binding affinity and longer half-life, the significant advantage of Ligand B in BBB penetration (69.8% vs 38.0%) is paramount for a CNS-targeting drug. The slightly higher P-gp efflux of Ligand B is a concern, but the superior BBB penetration likely outweighs this drawback. The slightly better solubility of Ligand B is also a plus. The small difference in metabolic stability is not a major concern given the strong affinity and good overall profile of Ligand B.

Output:
1
2025-04-17 08:49:58,455 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (356.423 and 362.396 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (127.84) is borderline for CNS penetration, slightly above the preferred <90, but acceptable. Ligand B (59.39) is excellent, well below 90, indicating good potential for CNS penetration.

**logP:** Ligand A (-0.511) is a bit low, potentially hindering membrane permeability. Ligand B (2.115) is within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A has 4 HBD and 5 HBA, which are reasonable. Ligand B has 1 HBD and 5 HBA, also reasonable.

**QED:** Both ligands have acceptable QED values (0.392 and 0.895), with Ligand B being significantly better.

**DILI:** Ligand A (51.842) has a moderate DILI risk, while Ligand B (38.348) has a lower risk.

**BBB:** Ligand A (52.268) has a poor BBB percentile, which is a major concern for a CNS target. Ligand B (84.413) has excellent BBB penetration potential.

**Caco-2 Permeability:** Ligand A (-5.497) has very poor Caco-2 permeability, suggesting poor absorption. Ligand B (-4.54) is also poor, but slightly better than A.

**Aqueous Solubility:** Both ligands have very poor aqueous solubility (-1.663 and -1.657). This could pose formulation challenges.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.054 and 0.238).

**Microsomal Clearance:** Ligand A (4.615) has lower microsomal clearance, indicating better metabolic stability than Ligand B (17.361).

**In vitro Half-Life:** Ligand A (3.229) has a shorter half-life than Ligand B (-8.478, which is a negative value and likely an error, but indicates a very long half-life).

**P-gp Efflux:** Ligand A (0.008) has very low P-gp efflux, which is favorable for CNS exposure. Ligand B (0.105) has slightly higher P-gp efflux.

**Binding Affinity:** Both ligands have the same excellent binding affinity (-7.1 kcal/mol).

**Conclusion:**

Despite Ligand A's good affinity and metabolic stability, its poor BBB penetration and Caco-2 permeability are major drawbacks for a CNS target like DRD2. Ligand B excels in the critical areas of BBB penetration, logP, and QED, making it a much more promising candidate. While its solubility and Caco-2 permeability are also poor, these can potentially be addressed with formulation strategies. The significantly better BBB and logP outweigh the slightly higher P-gp efflux and worse metabolic stability.

Output:
1
2025-04-17 08:49:58,455 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B based on the provided guidelines, prioritizing GPCR-specific properties (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (388.333 and 384.531 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (49.41) is excellent, well below the 90 A^2 threshold for CNS targets. Ligand B (100.11) is higher, but still potentially acceptable, though less ideal.

**logP:** Ligand A (3.439) is optimal. Ligand B (1.854) is on the lower side of optimal, potentially impacting permeability.

**H-Bond Donors/Acceptors:** Ligand A (HBD=1, HBA=3) is favorable. Ligand B (HBD=2, HBA=8) is acceptable, but the higher HBA count could slightly hinder permeability.

**QED:** Both ligands have similar QED values (0.79 and 0.716), indicating good drug-likeness.

**DILI:** Ligand A (46.491) has a lower DILI risk than Ligand B (65.917), which is a significant advantage.

**BBB:** Ligand A (89.066) has a significantly higher BBB penetration percentile than Ligand B (38.736). This is *critical* for a CNS target like DRD2.

**Caco-2 Permeability:** Ligand A (-4.873) and Ligand B (-5.366) both have negative Caco-2 values, indicating poor permeability.

**Aqueous Solubility:** Both ligands have poor aqueous solubility (-3.593 and -2.537 respectively).

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.514 and 0.31).

**Microsomal Clearance:** Ligand B (47.84) has a higher clearance than Ligand A (9.965), suggesting lower metabolic stability.

**In vitro Half-Life:** Ligand A (-2.04) has a longer half-life than Ligand B (-11.11).

**P-gp Efflux:** Ligand A (0.16) has lower P-gp efflux liability than Ligand B (0.039), which is beneficial for CNS exposure.

**Binding Affinity:** Both ligands have excellent binding affinities (-9.5 and -8.0 kcal/mol). Ligand A is slightly more potent.

**Overall Assessment:**

Ligand A is clearly superior. While both have good affinity, Ligand A excels in crucial areas for a CNS-targeting GPCR: significantly better BBB penetration, lower DILI risk, lower P-gp efflux, and better metabolic stability (lower Cl_mic, longer half-life). The slightly better TPSA and logP values of Ligand A also contribute to its favorability. The poor Caco-2 and solubility are drawbacks for both, but less critical for a CNS target where BBB penetration is paramount.

Output:
1
2025-04-17 08:49:58,456 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (347.423 and 343.427 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (118.06) is higher than the preferred <90 for CNS targets, but not drastically so. Ligand B (73.74) is excellent, well below 90. This favors Ligand B.

**3. logP:** Both ligands have good logP values (2.051 and 1.44), falling within the optimal 1-3 range.

**4. H-Bond Donors:** Both have 1 HBD, which is acceptable.

**5. H-Bond Acceptors:** Both have 4 HBA, which is acceptable.

**6. QED:** Ligand B (0.648) has a better QED score than Ligand A (0.482), indicating a more drug-like profile.

**7. DILI:** Both have low DILI risk (34.587 and 28.616), both below the 40 threshold.

**8. BBB:** Ligand B (33.424) has a slightly better BBB penetration percentile than Ligand A (31.252), but both are relatively low and not ideal for a CNS target.

**9. Caco-2 Permeability:** Ligand A (-5.281) has a negative Caco-2 value, which is concerning. Ligand B (-4.643) is also negative, but less so. Both suggest poor intestinal absorption.

**10. Aqueous Solubility:** Both have poor aqueous solubility (-1.588 and -1.12). This could be a formulation challenge.

**11. hERG Inhibition:** Both have very low hERG inhibition risk (0.108 and 0.292).

**12. Microsomal Clearance:** Ligand B (10.421) has significantly higher microsomal clearance than Ligand A (1.988), suggesting lower metabolic stability. This is a major drawback for Ligand B.

**13. In vitro Half-Life:** Ligand A (3.784) has a longer in vitro half-life than Ligand B (-2.274).

**14. P-gp Efflux:** Ligand B (0.086) has a lower P-gp efflux liability than Ligand A (0.008), which is favorable for CNS penetration.

**15. Binding Affinity:** Ligand A (-6.8) has a significantly better binding affinity than Ligand B (0.0). This is a substantial advantage. A >1.5 kcal/mol difference is considered significant.

**Overall Assessment:**

Despite Ligand B having better TPSA, QED, and P-gp efflux, the significantly superior binding affinity of Ligand A (-6.8 vs 0.0) is the most important factor, especially for a GPCR target. The lower metabolic clearance and longer half-life of Ligand A are also beneficial. While both have poor solubility and Caco-2 permeability, the strong binding affinity of Ligand A makes it more likely to be a viable starting point for optimization. The solubility and permeability issues can be addressed through medicinal chemistry efforts, but a weak binder is much harder to improve.

Output:
1
2025-04-17 08:49:58,456 - INFO - Reasoning:

Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (352.366 and 368.543 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (104.39) is higher than the preferred <90 for CNS targets, but still potentially acceptable. Ligand B (53.76) is excellent, well below the threshold. This favors Ligand B.

**3. logP:** Ligand A (0.34) is quite low, potentially hindering membrane permeability. Ligand B (3.596) is within the optimal 1-3 range. This significantly favors Ligand B.

**4. H-Bond Donors:** Ligand A (2) is acceptable. Ligand B (0) is also good, potentially improving permeability.

**5. H-Bond Acceptors:** Ligand A (5) is acceptable. Ligand B (4) is also good.

**6. QED:** Both ligands have reasonable QED values (0.744 and 0.592), indicating good drug-like properties.

**7. DILI:** Ligand A (63.862) has a higher DILI risk than Ligand B (35.944). This favors Ligand B.

**8. BBB:** Both ligands have good BBB penetration (68.282 and 67.933), but are slightly below the >70 desirable threshold. This is not a major differentiating factor.

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.911 and -4.96), which is unusual and suggests poor permeability. This is a concern for both, but doesn't clearly differentiate them.

**10. Aqueous Solubility:** Both ligands have negative solubility values (-2.566 and -2.627), which is also unusual and suggests poor solubility. This is a concern for both, but doesn't clearly differentiate them.

**11. hERG Inhibition:** Ligand A (0.215) shows a slightly lower hERG risk than Ligand B (0.886).

**12. Microsomal Clearance:** Ligand A (16.78) has a lower clearance, indicating better metabolic stability, compared to Ligand B (92.805). This favors Ligand A.

**13. In vitro Half-Life:** Ligand A (-27.417) has a negative half-life, which is not physically possible and suggests an issue with the data. Ligand B (76.541) has a good half-life. This strongly favors Ligand B.

**14. P-gp Efflux:** Ligand A (0.016) has very low P-gp efflux, which is excellent for CNS penetration. Ligand B (0.62) has moderate P-gp efflux. This favors Ligand A.

**15. Binding Affinity:** Ligand B (-7.3) has a slightly better binding affinity than Ligand A (-7.1), but the difference is small.

**Overall Assessment:**

While Ligand A has advantages in P-gp efflux and metabolic stability, its very low logP and negative half-life are major concerns. Ligand B, despite a slightly higher hERG risk and P-gp efflux, has a much more favorable profile overall, particularly its optimal logP, excellent TPSA, lower DILI risk, and reasonable half-life. The negative values for Caco-2 and solubility are concerning for both, but the other properties of Ligand B make it the more promising candidate.

Output:
1
2025-04-17 08:49:58,456 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (366.418 and 384.567 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (85.25) is better than Ligand B (51.66) as it is closer to the ideal range for CNS targets (<=90). Ligand B is very good.

**logP:** Ligand A (1.244) is within the optimal range (1-3), while Ligand B (3.154) is at the higher end but still acceptable.

**H-Bond Donors:** Ligand A (2) is good, while Ligand B (0) is also acceptable.

**H-Bond Acceptors:** Both ligands have 6 HBA, which is within the acceptable limit of <=10.

**QED:** Ligand A (0.806) has a significantly better QED score than Ligand B (0.612), indicating a more drug-like profile.

**DILI:** Ligand B (43.117) has a lower DILI risk than Ligand A (76.464), which is a significant advantage.

**BBB:** Ligand B (82.551) has a substantially better BBB penetration score than Ligand A (66.576). This is crucial for a CNS target like DRD2.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values, which is unusual and suggests poor permeability. However, the scale is not defined, so it's difficult to interpret.

**Aqueous Solubility:** Both ligands have negative solubility values, which is also unusual and suggests poor solubility.

**hERG:** Both ligands have very low hERG inhibition liability (0.183 and 0.436), which is excellent.

**Microsomal Clearance:** Ligand A (16.832) has lower microsomal clearance than Ligand B (55.209), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (45.104) has a longer in vitro half-life than Ligand B (-2.402), which is a significant advantage.

**P-gp Efflux:** Ligand A (0.037) has much lower P-gp efflux liability than Ligand B (0.243), which is beneficial for CNS exposure.

**Binding Affinity:** Ligand A (-7.2 kcal/mol) has a slightly better binding affinity than Ligand B (-6.8 kcal/mol), although the difference is not huge.

**Overall Assessment:**

Ligand A has advantages in QED, metabolic stability (Cl_mic and t1/2), P-gp efflux, and binding affinity. However, Ligand B excels in BBB penetration and has a lower DILI risk. Given the CNS target (DRD2), BBB penetration is paramount. While Ligand A has slightly better affinity, the substantial difference in BBB (82.551 vs 66.576) and the lower DILI risk of Ligand B outweigh the minor affinity advantage of Ligand A.

Output:
1
2025-04-17 08:49:58,456 - INFO - Reasoning:

Let's analyze Ligand A and Ligand B based on the provided guidelines, prioritizing GPCR-specific properties (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (352.45 and 369.403 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (58.64) is excellent for CNS penetration, well below the 90 A^2 threshold. Ligand B (135.18) is higher, but still potentially acceptable, although less ideal.

**logP:** Ligand A (2.357) is within the optimal 1-3 range. Ligand B (-1.168) is significantly lower, which could hinder membrane permeability and CNS penetration.

**H-Bond Donors/Acceptors:** Ligand A (HBD=1, HBA=3) has favorable H-bonding characteristics. Ligand B (HBD=3, HBA=7) is higher in both, potentially impacting permeability.

**QED:** Both ligands have reasonable QED scores (A: 0.773, B: 0.537), indicating drug-like properties.

**DILI:** Ligand A (24.661) has a much lower DILI risk than Ligand B (76.076), a significant advantage.

**BBB:** Ligand A (89.725) shows excellent BBB penetration, exceeding the desirable >70% threshold. Ligand B (22.606) is very poor for CNS penetration.

**Caco-2 Permeability:** Ligand A (-4.379) is concerningly low, suggesting poor intestinal absorption. Ligand B (-5.782) is even worse.

**Aqueous Solubility:** Both ligands have negative solubility values, indicating very poor aqueous solubility. This is a concern for both, but may be less critical for a CNS target if BBB penetration is good.

**hERG Inhibition:** Both ligands show low hERG inhibition risk (A: 0.453, B: 0.09).

**Microsomal Clearance:** Ligand A (36.247) has a higher (worse) microsomal clearance than Ligand B (9.262), suggesting lower metabolic stability.

**In vitro Half-Life:** Both have negative half-lives, which is unusual and likely indicates a problem with the experimental setup or the molecule's stability.

**P-gp Efflux:** Ligand A (0.122) has lower P-gp efflux liability than Ligand B (0.045), which is favorable for CNS exposure.

**Binding Affinity:** Ligand A (-8.3 kcal/mol) has a significantly stronger binding affinity than Ligand B (-7.7 kcal/mol). This 0.6 kcal/mol difference is substantial and can outweigh some ADME drawbacks.

**Overall Assessment:**

Given the GPCR-specific priorities, Ligand A is the more promising candidate. Its superior BBB penetration, lower DILI risk, and significantly stronger binding affinity are critical advantages. While its Caco-2 permeability and microsomal clearance are not ideal, the strong affinity and good BBB penetration suggest it is more likely to achieve sufficient CNS exposure. Ligand B's poor logP and extremely low BBB penetration are major drawbacks that are difficult to overcome.

Output:
1
2025-04-17 08:49:58,456 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (361.764 and 354.439 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (92.93) is slightly higher than Ligand B (84.73). Both are below the 90 A^2 threshold desirable for CNS targets, but B is better.

**logP:** Ligand A (1.918) and Ligand B (2.924) are both within the optimal 1-3 range. Ligand B is slightly better positioned.

**H-Bond Donors/Acceptors:** Both have 2 HBD and 6 HBA, which are acceptable values.

**QED:** Both ligands have good QED scores (0.724 and 0.754), indicating good drug-like properties.

**DILI:** Both have high DILI risk (89.221 and 85.847), which is a concern. However, this can sometimes be mitigated with structural modifications.

**BBB:** Ligand B (74.292) has a significantly better BBB percentile than Ligand A (46.181). This is a *critical* advantage for a CNS target like DRD2.

**Caco-2 Permeability:** Ligand A (-4.957) and Ligand B (-5.033) have similar, very poor Caco-2 permeability. This is a significant drawback for oral bioavailability.

**Aqueous Solubility:** Both have poor aqueous solubility (-2.94 and -4.269). This could pose formulation challenges.

**hERG:** Both have low hERG inhibition risk (0.681 and 0.343), which is positive. Ligand B is better.

**Microsomal Clearance:** Ligand B (54.416) has a lower microsomal clearance than Ligand A (6.588), suggesting better metabolic stability.

**In vitro Half-Life:** Both have similar in vitro half-lives (21.381 and 21.855 hours).

**P-gp Efflux:** Ligand A (0.235) has lower P-gp efflux than Ligand B (0.306), which is favorable for CNS penetration.

**Binding Affinity:** Ligand B (-10.1 kcal/mol) has a significantly stronger binding affinity than Ligand A (-8.6 kcal/mol). This is a substantial advantage, potentially outweighing some of the ADME concerns. The difference is >1.5 kcal/mol.

**Overall:**

Ligand B is the superior candidate. While both have issues with DILI and Caco-2 permeability, Ligand B's significantly better BBB penetration, stronger binding affinity, and lower microsomal clearance make it more likely to succeed as a DRD2-targeting drug. The stronger binding affinity is a major driver, and the improved BBB is crucial for a CNS target.

Output:
1
2025-04-17 08:49:58,457 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (343.471 and 350.591 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (63.13) is higher than the preferred <90 for CNS targets, but still reasonable. Ligand B (23.55) is excellent, well below 90.

**3. logP:** Ligand A (2.634) is within the optimal 1-3 range. Ligand B (4.954) is slightly high, potentially leading to solubility issues and off-target interactions, but not drastically so.

**4. H-Bond Donors:** Ligand A (2) and Ligand B (0) are both acceptable (<=5).

**5. H-Bond Acceptors:** Ligand A (3) and Ligand B (2) are both acceptable (<=10).

**6. QED:** Both ligands have similar QED values (0.642 and 0.618), indicating good drug-like properties.

**7. DILI:** Ligand A (28.383) has a lower DILI risk than Ligand B (11.594), which is a significant advantage.

**8. BBB:** This is a critical parameter for a CNS target like DRD2. Ligand A (58.976) is moderate, while Ligand B (90.617) is excellent, exceeding the desirable >70 threshold.

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.874 and -4.688), which is unusual and suggests poor permeability. However, these values are on a scale where negative values are possible and don't necessarily preclude *in vivo* absorption.

**10. Aqueous Solubility:** Both ligands have negative solubility values (-2.732 and -4.171), indicating poor aqueous solubility. This is a concern, but can sometimes be overcome with formulation strategies.

**11. hERG Inhibition:** Ligand A (0.127) has a very low hERG risk, while Ligand B (0.937) is higher, though still relatively low.

**12. Microsomal Clearance:** Ligand B (89.346) has a significantly higher microsomal clearance than Ligand A (38.023), indicating faster metabolism and potentially lower *in vivo* exposure.

**13. In vitro Half-Life:** Ligand B (6.612) has a longer half-life than Ligand A (0.124), which is generally desirable. However, the very short half-life of Ligand A is a major drawback.

**14. P-gp Efflux:** Ligand A (0.255) has moderate P-gp efflux, while Ligand B (0.775) has higher efflux. Lower P-gp efflux is preferred for CNS penetration.

**15. Binding Affinity:** Ligand A (-8.0) has a significantly stronger binding affinity than Ligand B (-0.0). This is a substantial advantage, potentially outweighing some of its ADME drawbacks.

**Overall Assessment:**

While Ligand B excels in BBB penetration and has a longer half-life, Ligand A's significantly superior binding affinity (-8.0 vs -0.0 kcal/mol) is the deciding factor. The strong binding is likely to be more impactful than the moderate BBB and solubility concerns, especially given the potential for formulation strategies to address solubility. The lower DILI risk and hERG inhibition for Ligand A are also favorable. The short half-life of Ligand A is a concern, but could be addressed through structural modifications.

Output:
1
2025-04-17 08:49:58,457 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (369.437 and 368.493 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (73.2) is higher than the preferred <90 for CNS targets, but still reasonable. Ligand B (33.2) is excellent, well below 90.

**3. logP:** Ligand A (2.44) is within the optimal range of 1-3. Ligand B (4.541) is slightly above, potentially raising concerns about solubility and off-target effects, but not drastically.

**4. H-Bond Donors:** Ligand A (1) is good. Ligand B (0) is also good.

**5. H-Bond Acceptors:** Ligand A (4) is good. Ligand B (3) is also good.

**6. QED:** Ligand A (0.802) is excellent, indicating high drug-likeness. Ligand B (0.6) is still acceptable, but lower.

**7. DILI:** Ligand A (37.65) has a low DILI risk. Ligand B (24.544) has an even lower DILI risk.

**8. BBB:** Both ligands have excellent BBB penetration (Ligand A: 83.404, Ligand B: 84.917), exceeding the >70 threshold for CNS targets.

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.889 and -4.734). This is unusual and potentially problematic, suggesting poor intestinal absorption. However, for a CNS target, intestinal absorption is less critical than BBB penetration.

**10. Aqueous Solubility:** Both ligands have negative solubility values (-2.749 and -4.611). This is concerning, but can sometimes be overcome with formulation strategies, especially if BBB penetration is high.

**11. hERG Inhibition:** Both ligands have low hERG inhibition risk (0.794 and 0.889).

**12. Microsomal Clearance:** Ligand A (17.759) has lower clearance, suggesting better metabolic stability than Ligand B (80.226).

**13. In vitro Half-Life:** Ligand A (-2.176) has a longer half-life than Ligand B (-4.787).

**14. P-gp Efflux:** Both ligands have low P-gp efflux liability (0.147 and 0.412).

**15. Binding Affinity:** Ligand A (-8.1 kcal/mol) has a significantly stronger binding affinity than Ligand B (-7.0 kcal/mol). This >1.5 kcal/mol difference is a major advantage.

**Overall Assessment:**

While both ligands show good BBB penetration and low DILI/hERG risks, Ligand A is superior due to its significantly stronger binding affinity (-8.1 vs -7.0 kcal/mol), better metabolic stability (lower Cl_mic), and longer half-life. The slightly higher TPSA of Ligand A is less concerning given the CNS target and its excellent BBB penetration. The negative solubility and Caco-2 values are shared concerns, but less critical for a CNS-focused drug. The stronger binding affinity of Ligand A is likely to outweigh the slightly less optimal logP compared to Ligand B.

Output:
1
2025-04-17 08:49:58,457 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (351.407 Da) is slightly lower, which could be beneficial for permeability.

**TPSA:** Ligand A (109.58) is better than Ligand B (49.77) as it is closer to the ideal range for CNS penetration (<=90). Ligand B is quite low, which might indicate a lack of necessary interactions with the receptor.

**logP:** Ligand A (-0.256) is suboptimal, being below the preferred 1-3 range. Ligand B (4.033) is high, potentially leading to solubility issues and off-target effects.

**H-Bond Donors/Acceptors:** Ligand A (HBD=2, HBA=7) and Ligand B (HBD=1, HBA=5) both fall within acceptable ranges.

**QED:** Both ligands have good QED scores (A: 0.635, B: 0.715), indicating generally drug-like properties.

**DILI:** Ligand A (58.395) has a higher DILI risk than Ligand B (26.095), which is a concern.

**BBB:** Both ligands have similar BBB penetration (A: 48.662, B: 47.926), and are below the desirable >70 percentile for CNS targets. This is a significant drawback for both, but not a differentiating factor.

**Caco-2 Permeability:** Both ligands show poor Caco-2 permeability (-5.145 and -5.122 respectively).

**Aqueous Solubility:** Both ligands have poor aqueous solubility (-1.231 and -4.818 respectively).

**hERG Inhibition:** Ligand A (0.153) has a lower hERG risk than Ligand B (0.823), which is a positive.

**Microsomal Clearance:** Ligand A (24.876) has significantly lower microsomal clearance than Ligand B (124.575), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (12.504) has a shorter half-life than Ligand B (17.629), but both are relatively low.

**P-gp Efflux:** Ligand A (0.045) has much lower P-gp efflux than Ligand B (0.441), which is crucial for CNS penetration.

**Binding Affinity:** Ligand A (-7.5 kcal/mol) has a slightly better binding affinity than Ligand B (-6.7 kcal/mol). While both are good, the 0.8 kcal/mol difference is meaningful.

**Overall Assessment:**

Ligand A is better despite the higher DILI risk. Its superior TPSA, lower logP (though still suboptimal), significantly lower P-gp efflux, lower microsomal clearance, and slightly better binding affinity outweigh the DILI concern. The lower P-gp efflux is particularly important for CNS targets like DRD2. Ligand B's high logP and high P-gp efflux are major liabilities. The similar BBB values are not enough to compensate for these issues.

Output:
0
2025-04-17 08:49:58,457 - INFO - Reasoning:

Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (354.422 and 367.41 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (89.87) is excellent, falling below the 90 A^2 threshold for CNS targets. Ligand B (105.04) is still reasonable but less optimal.

**3. logP:** Both ligands have similar logP values (0.218 and 0.214), which are quite low. While not ideal (optimal is 1-3), they aren't drastically outside the acceptable range. The low logP could indicate potential solubility issues, but isn't a dealbreaker.

**4. H-Bond Donors:** Ligand A has 3 HBD, which is good. Ligand B has 2, also good.

**5. H-Bond Acceptors:** Ligand A has 4 HBA, within the acceptable range. Ligand B has 8, which is approaching the upper limit and could potentially affect permeability.

**6. QED:** Both ligands have good QED scores (0.676 and 0.801), indicating drug-like properties.

**7. DILI:** Ligand A (25.591) has a significantly lower DILI risk than Ligand B (79.333). This is a major advantage for Ligand A.

**8. BBB:** Ligand A (71.501) has a good BBB penetration percentile, exceeding the 70% threshold. Ligand B (50.679) is below this threshold, which is a significant drawback for a CNS target like DRD2.

**9. Caco-2:** Both have negative Caco-2 values, which is unusual and suggests poor permeability. This is a concern for both.

**10. Solubility:** Both have negative solubility values, also unusual and concerning.

**11. hERG:** Both ligands have low hERG inhibition liability (0.292 and 0.34), which is positive.

**12. Cl_mic:** Ligand A (-2.021) has a negative and therefore very low microsomal clearance, indicating high metabolic stability. Ligand B (4.175) has a positive clearance, suggesting faster metabolism.

**13. t1/2:** Ligand A (1.095) has a shorter in vitro half-life than Ligand B (28.708). This is a disadvantage for Ligand A.

**14. Pgp:** Both ligands have very low Pgp efflux liability (0.03 and 0.065), which is excellent for CNS penetration.

**15. Binding Affinity:** Ligand B (-7.7 kcal/mol) has a slightly better binding affinity than Ligand A (-8.4 kcal/mol). While the difference is small, it is still a factor.

**Overall Assessment:**

Considering the GPCR-specific priorities, Ligand A is the more promising candidate. Its superior BBB penetration, significantly lower DILI risk, and excellent metabolic stability (low Cl_mic) outweigh the slightly weaker binding affinity and shorter half-life. The low logP and negative Caco-2/Solubility values are concerns for both, but can potentially be addressed through prodrug strategies or formulation techniques. Ligand B's higher DILI risk and poor BBB penetration are more difficult to overcome.

Output:
0
2025-04-17 08:49:58,458 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (364.364 and 350.459 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Both ligands have a TPSA of 78.87, which is acceptable for oral absorption but slightly high for optimal CNS penetration (ideally <90, but closer to 60-70 is better).

**3. logP:** Ligand A (1.14) is within the optimal range (1-3). Ligand B (3.149) is at the higher end of the optimal range, potentially leading to solubility issues but aiding in membrane permeability.

**4. H-Bond Donors:** Both ligands have 2 HBDs, which is within the acceptable limit of <=5.

**5. H-Bond Acceptors:** Both ligands have 4 HBAs, which is within the acceptable limit of <=10.

**6. QED:** Both ligands have good QED scores (0.734 and 0.792), indicating favorable drug-like properties.

**7. DILI:** Ligand A (39.318) has a slightly higher DILI risk than Ligand B (18.922), but both are below the 40 threshold and considered good.

**8. BBB:** Ligand A (69.833) has a better BBB percentile than Ligand B (64.444), which is crucial for a CNS target like DRD2. Although both are not ideal (>70 desirable), A is better.

**9. Caco-2 Permeability:** Ligand A (-4.848) has a negative Caco-2 value, indicating poor permeability. Ligand B (-4.708) also has a negative Caco-2 value, indicating poor permeability.

**10. Aqueous Solubility:** Ligand A (-1.896) has better aqueous solubility than Ligand B (-3.672).

**11. hERG Inhibition:** Ligand A (0.359) has a lower hERG inhibition liability than Ligand B (0.713), making it safer from a cardiotoxicity perspective.

**12. Microsomal Clearance:** Ligand A (8.888) has a lower microsomal clearance than Ligand B (107.093), indicating better metabolic stability.

**13. In vitro Half-Life:** Ligand A (-28.993) has a much longer in vitro half-life than Ligand B (-13.817).

**14. P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.107 and 0.025).

**15. Binding Affinity:** Ligand B (-7.1 kcal/mol) has a significantly stronger binding affinity than Ligand A (-0.0 kcal/mol). This is a substantial advantage.

**Overall Assessment:**

Ligand B has a much stronger binding affinity, which is the most important factor. While Ligand A has better BBB penetration, solubility, metabolic stability, and lower hERG risk, the difference in binding affinity is substantial enough to outweigh these benefits. The slightly higher logP of Ligand B is acceptable, and its other ADME properties, while not ideal, aren't drastically worse than Ligand A. The large difference in binding affinity suggests Ligand B is more likely to be efficacious.

Output:
1
2025-04-17 08:49:58,458 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (359.421 and 346.395 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (79.26) is excellent, falling well below the 90 A^2 threshold for CNS targets. Ligand B (118.79) is higher, but still potentially acceptable, though less ideal.

**logP:** Ligand A (0.767) is a little low, potentially hindering permeability. Ligand B (-0.171) is even lower, raising concerns about membrane penetration.

**H-Bond Donors/Acceptors:** Ligand A (2 HBD, 5 HBA) is well within acceptable limits. Ligand B (1 HBD, 8 HBA) is also reasonable, though the higher HBA count could slightly impact permeability.

**QED:** Both ligands have good QED scores (0.647 and 0.704), indicating drug-like properties.

**DILI:** Ligand A (35.983) has a significantly lower DILI risk than Ligand B (68.631), which is a substantial advantage.

**BBB:** Ligand A (65.413) shows moderate BBB penetration, while Ligand B (51.066) is lower. While both are below the desirable >70 for CNS targets, Ligand A is better.

**Caco-2 Permeability:** Ligand A (-4.998) has poor Caco-2 permeability, which is a concern. Ligand B (-5.476) is similarly poor.

**Aqueous Solubility:** Both ligands have very poor aqueous solubility (-1.542 and -1.188 respectively). This could pose formulation challenges.

**hERG Inhibition:** Both ligands show very low hERG inhibition risk (0.253 and 0.035).

**Microsomal Clearance:** Both have similar microsomal clearance (28.002 and 29.957 mL/min/kg), suggesting comparable metabolic stability.

**In vitro Half-Life:** Ligand A (19.86 hours) has a longer half-life than Ligand B (10.663 hours), which is preferable.

**P-gp Efflux:** Both ligands show very low P-gp efflux liability (0.021 and 0.018).

**Binding Affinity:** Ligand B (-7.8 kcal/mol) has a significantly stronger binding affinity than Ligand A (-6.6 kcal/mol). This 1.2 kcal/mol difference is substantial and could potentially overcome some of the ADME drawbacks.

**Overall Assessment:**

Ligand B has a much stronger binding affinity, which is the most critical factor. However, it suffers from a higher DILI risk and lower BBB penetration. Ligand A has better DILI and BBB, but significantly weaker binding. Considering the GPCR-specific priorities, the binding affinity difference is large enough to outweigh the ADME concerns of Ligand B, *provided* the higher DILI risk can be mitigated through further structural modifications. The poor solubility and Caco-2 permeability of both are significant issues that would need to be addressed in either case.

Output:
1
2025-04-17 08:49:58,458 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (356.491 and 352.475 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (58.2) is significantly better than Ligand B (76.66). For CNS targets, we want TPSA <= 90, and A is much closer to the optimal <=60 range. B is pushing the upper limit.

**3. logP:** Ligand A (4.587) is higher than the optimal 1-3 range, but still potentially acceptable. Ligand B (1.914) is on the lower side, which could hinder permeability.

**4. H-Bond Donors:** Both have 2 HBD, which is within the acceptable limit of <=5.

**5. H-Bond Acceptors:** Ligand A has 3 HBA, and Ligand B has 4. Both are within the acceptable limit of <=10.

**6. QED:** Both ligands have good QED scores (0.646 and 0.766), indicating good drug-like properties.

**7. DILI:** Ligand A (58.627) has a higher DILI risk than Ligand B (15.161). This is a significant drawback for A.

**8. BBB:** Ligand A (85.498) has a much better BBB penetration score than Ligand B (68.825). This is crucial for a CNS target like DRD2.

**9. Caco-2 Permeability:** Ligand A (-5.008) shows poor Caco-2 permeability, while Ligand B (-4.856) is slightly better, but both are very low.

**10. Aqueous Solubility:** Ligand A (-5.015) has very poor aqueous solubility, while Ligand B (-1.98) is better, but still low.

**11. hERG Inhibition:** Ligand A (0.808) has a higher hERG inhibition risk than Ligand B (0.18). B is much preferred here.

**12. Microsomal Clearance:** Ligand A (77.807) has higher microsomal clearance than Ligand B (21.573), meaning it's less metabolically stable.

**13. In vitro Half-Life:** Ligand A (12.446) has a longer half-life than Ligand B (9.371), which is a positive.

**14. P-gp Efflux:** Ligand A (0.688) has lower P-gp efflux than Ligand B (0.026), which is beneficial for CNS exposure.

**15. Binding Affinity:** Ligand A (-9.3 kcal/mol) has a significantly stronger binding affinity than Ligand B (-8.4 kcal/mol). This is a substantial advantage.

**Overall Assessment:**

Ligand A has a much better binding affinity and BBB penetration, and lower P-gp efflux, which are all highly desirable for a CNS-targeting GPCR. However, it suffers from poor solubility, permeability, higher DILI risk, and higher hERG risk. Ligand B has better ADME properties (lower DILI, hERG, better solubility) but weaker binding affinity and lower BBB penetration.

The strong affinity of Ligand A is a significant advantage that *could* outweigh its ADME liabilities, *if* those liabilities can be addressed through further optimization. The difference in affinity (-9.3 vs -8.4) is substantial (a 0.9 kcal/mol difference). Given the GPCR-specific priorities, the strong binding and reasonable BBB penetration of Ligand A make it the more promising starting point, despite the ADME concerns.

Output:
1
2025-04-17 08:49:58,458 - INFO - Batch 482 complete. Total preferences: 7712
2025-04-17 08:49:58,458 - INFO - Processing batch 483/512...
2025-04-17 08:50:48,013 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (368.543 and 372.809 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (78.43) is significantly better than Ligand B (113.76). For CNS targets, we want TPSA <= 90, and A is comfortably within that range, while B is pushing the limit.

**logP:** Ligand A (2.368) is optimal (1-3). Ligand B (-0.434) is below 1, which could hinder permeation.

**H-Bond Donors/Acceptors:** Ligand A (3 HBD, 4 HBA) and Ligand B (2 HBD, 7 HBA) both fall within acceptable ranges (<=5 HBD and <=10 HBA).

**QED:** Both ligands have similar QED values (0.696 and 0.628), indicating good drug-likeness.

**DILI:** Ligand A (36.72) has a much lower DILI risk than Ligand B (60.566). This is a significant advantage for A.

**BBB:** Ligand A (42.342) is better than Ligand B (20.822), but both are below the desirable >70 for CNS targets. However, given the other properties, a higher BBB is less critical if other parameters are favorable.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.352 and -5.253), which is unusual and suggests poor permeability. However, these values are on a log scale, and the negative values are less informative than a comparison of positive values.

**Aqueous Solubility:** Both ligands have negative solubility values (-3.012 and -2.074) which suggest poor aqueous solubility.

**hERG:** Both ligands show very low hERG inhibition liability (0.246 and 0.023).

**Microsomal Clearance:** Ligand A (32.266) has a higher microsomal clearance than Ligand B (15.553), suggesting lower metabolic stability.

**In vitro Half-Life:** Ligand B (9.796) has a longer in vitro half-life than Ligand A (4.592).

**P-gp Efflux:** Ligand A (0.154) has lower P-gp efflux liability than Ligand B (0.02). Lower P-gp efflux is desirable for CNS penetration.

**Binding Affinity:** Ligand B (-7.4 kcal/mol) has a slightly better binding affinity than Ligand A (-8.2 kcal/mol). While a 1.5 kcal/mol advantage is significant, the other ADME properties are more concerning for Ligand B.

**Overall Assessment:**

Ligand A is the better candidate. While its BBB is not ideal, its superior TPSA, logP, DILI, and P-gp efflux properties outweigh the slightly weaker binding affinity and higher clearance. Ligand B's low logP and high DILI risk are major concerns, and its BBB is also quite low. The negative Caco-2 and solubility values for both are concerning, but the other properties of A are more favorable.



Output:
0
2025-04-17 08:50:48,014 - INFO - Reasoning:

Let's analyze Ligand A and Ligand B based on the provided guidelines, prioritizing GPCR-specific properties (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (337.379 and 344.459 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (99.58) is higher than Ligand B (69.3). For CNS targets, TPSA should be <=90. Ligand B is preferable here.

**logP:** Both ligands have good logP values (1.454 and 2.351), falling within the optimal 1-3 range. Ligand B is slightly better.

**H-Bond Donors/Acceptors:** Ligand A has 2 HBD and 5 HBA, while Ligand B has 1 HBD and 3 HBA. Both are within acceptable limits (<=5 HBD and <=10 HBA).

**QED:** Both ligands have similar QED values (0.86 and 0.772), indicating good drug-likeness.

**DILI:** Ligand A (41.024) has a higher DILI risk than Ligand B (13.649). Ligand B is significantly better here.

**BBB:** This is a critical parameter for CNS targets. Ligand B (82.164) has a much higher BBB percentile than Ligand A (24.661). This is a major advantage for Ligand B.

**Caco-2 Permeability:** Both have negative values, which is unusual and potentially problematic. However, the scale is not defined, so we can't interpret these values definitively.

**Aqueous Solubility:** Both have negative values, indicating poor solubility. This is a concern for both, but not a deciding factor between them.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.773 and 0.284). Ligand B is slightly better.

**Microsomal Clearance:** Ligand A (-35.893) has a more negative value, indicating lower clearance and thus better metabolic stability than Ligand B (26.797). This is an advantage for Ligand A.

**In vitro Half-Life:** Ligand A (28.891) has a longer half-life than Ligand B (-23.912). This is a positive for Ligand A.

**P-gp Efflux:** Ligand A (0.144) has lower P-gp efflux liability than Ligand B (0.041). Lower is better, so Ligand A is preferable.

**Binding Affinity:** Ligand B (-7.3 kcal/mol) has a slightly better binding affinity than Ligand A (-9.3 kcal/mol). While A is better, the difference isn't substantial enough to outweigh other factors.

**Overall Assessment:**

Ligand B clearly wins due to its significantly better BBB penetration (82.164 vs 24.661) and lower DILI risk (13.649 vs 41.024). While Ligand A has advantages in metabolic stability (lower Cl_mic, longer t1/2) and P-gp efflux, these are less critical for a GPCR target, especially one in the CNS, compared to BBB and safety. The slightly better affinity of Ligand B is also a benefit. The TPSA of Ligand B is also more favorable.

Output:
1
2025-04-17 08:50:48,014 - INFO - Reasoning:

Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (340.427 and 361.442 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (66.4) is better than Ligand B (62.39). Both are below the 90 A^2 threshold for CNS targets, which is excellent.

**3. logP:** Ligand A (1.709) is within the optimal 1-3 range. Ligand B (3.357) is at the higher end of optimal, but still acceptable.

**4. H-Bond Donors:** Ligand A (0) is preferable to Ligand B (1). Fewer HBDs generally improve permeability.

**5. H-Bond Acceptors:** Ligand A (4) is better than Ligand B (6). Lower HBA is also favorable for permeability.

**6. QED:** Ligand A (0.837) has a significantly better QED score than Ligand B (0.667), indicating a more drug-like profile.

**7. DILI:** Ligand A (33.501) has a much lower DILI risk than Ligand B (47.15). This is a significant advantage for Ligand A.

**8. BBB:** Ligand A (82.202) has a considerably higher BBB penetration percentile than Ligand B (51.415). This is *critical* for a CNS target like DRD2.

**9. Caco-2 Permeability:** Ligand A (-4.789) and Ligand B (-5.216) both have negative values, which is unusual. It's difficult to interpret without knowing the scale, but generally, higher values are preferred.

**10. Aqueous Solubility:** Ligand A (-1.858) and Ligand B (-2.881) both have negative values, which is also unusual and suggests poor solubility.

**11. hERG Inhibition:** Ligand A (0.243) has a much lower hERG inhibition liability than Ligand B (0.833), indicating a lower risk of cardiotoxicity.

**12. Microsomal Clearance:** Ligand A (18.871) has a lower microsomal clearance than Ligand B (45.105), suggesting better metabolic stability.

**13. In vitro Half-Life:** Ligand A (20.183) has a shorter half-life than Ligand B (32.751), but both are reasonable.

**14. P-gp Efflux:** Ligand A (0.076) has a much lower P-gp efflux liability than Ligand B (0.625). This is crucial for CNS penetration, as P-gp actively pumps drugs *out* of the brain.

**15. Binding Affinity:** Ligand B (-7.8 kcal/mol) has a slightly better binding affinity than Ligand A (-8.7 kcal/mol). While affinity is important, the difference of 0.9 kcal/mol is not substantial enough to outweigh the numerous ADME advantages of Ligand A.

**Overall Assessment:**

Ligand A consistently outperforms Ligand B across most critical ADME properties, particularly BBB penetration, DILI risk, hERG inhibition, and P-gp efflux. While Ligand B has slightly better binding affinity, the differences in other parameters, especially for a CNS target, are substantial. Ligand A's superior drug-like properties and lower potential for toxicity make it the more promising candidate.

Output:
0
2025-04-17 08:50:48,014 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (345.359 Da) is slightly lower, which could be beneficial for permeability. Ligand B (363.868 Da) is also good.

**TPSA:** Ligand A (120.32) is borderline for CNS penetration, being slightly above the preferred <90 threshold. Ligand B (55.63) is excellent, well below the 90 threshold, indicating better potential for CNS penetration.

**logP:** Ligand A (-0.294) is quite low, potentially hindering membrane permeability and bioavailability. Ligand B (3.588) is optimal, falling within the 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A has 3 HBD and 6 HBA, which are acceptable. Ligand B has 1 HBD and 5 HBA, also acceptable and potentially better for permeability due to fewer hydrogen bonds.

**QED:** Both ligands have good QED scores (A: 0.703, B: 0.901), indicating generally drug-like properties. Ligand B is superior.

**DILI:** Both have moderate DILI risk (A: 56.146, B: 47.305), but Ligand B is slightly lower, suggesting a marginally reduced risk of liver injury.

**BBB:** This is crucial for a CNS target. Ligand A (19.349) has very poor predicted BBB penetration. Ligand B (88.445) has excellent predicted BBB penetration, exceeding the desirable >70 threshold.

**Caco-2 Permeability:** Both have negative Caco-2 values (-5.408 and -5.055), which is unusual and suggests poor permeability. However, these values are on a log scale and are difficult to interpret directly without knowing the scale used.

**Aqueous Solubility:** Both have negative solubility values (-2.832 and -4.104), which is also unusual and suggests poor solubility. Similar to Caco-2, the scale is unknown.

**hERG Inhibition:** Both ligands show low hERG inhibition risk (A: 0.202, B: 0.337).

**Microsomal Clearance:** Ligand A (-18.016) has a significantly lower (better) microsomal clearance than Ligand B (33.779), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (-35.024) has a very negative half-life, which is concerning and likely indicates rapid metabolism. Ligand B (22.859) is better, but still relatively short.

**P-gp Efflux:** Both have very low P-gp efflux liability (A: 0.013, B: 0.557), which is favorable for CNS exposure.

**Binding Affinity:** Both ligands have similar binding affinities (-8.6 kcal/mol and -8.4 kcal/mol). The difference is minor.

**Overall Assessment:**

Ligand B is significantly better due to its excellent BBB penetration (88.445), optimal logP (3.588), and superior QED (0.901). While Ligand A has better metabolic stability (lower Cl_mic), its extremely poor BBB penetration and low logP are major drawbacks for a CNS-targeting drug. The slightly better DILI risk for Ligand B is also a plus. The negative values for Caco-2 and solubility are concerning for both, but the other factors strongly favor Ligand B.

Output:
1
2025-04-17 08:50:48,014 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (352.356 Da) and Ligand B (346.431 Da) are comparable.

**TPSA:** Ligand A (51.22) is significantly better than Ligand B (96.11). For CNS targets, we want TPSA <= 90, so Ligand A is much more favorable.

**logP:** Ligand A (4.892) is a bit high, potentially leading to solubility issues, but still within a reasonable range. Ligand B (1.501) is on the lower side, which might hinder permeability. Optimal is 1-3.

**H-Bond Donors/Acceptors:** Ligand A (HBD=1, HBA=4) and Ligand B (HBD=3, HBA=4) are both acceptable.

**QED:** Both ligands have similar QED values (A: 0.778, B: 0.727), indicating good drug-likeness.

**DILI:** Ligand A (64.793) has a higher DILI risk than Ligand B (43.971), but both are below the concerning threshold of 60.

**BBB:** Ligand A (71.229) has a significantly better BBB percentile than Ligand B (57.929). This is a critical factor for CNS targets like DRD2, and >70 is desirable.

**Caco-2 Permeability:** Ligand A (-4.693) and Ligand B (-5.102) both have negative values, which is unusual. Lower values indicate poorer permeability.

**Aqueous Solubility:** Ligand A (-6.165) and Ligand B (-4.099) both have negative values, indicating poor solubility.

**hERG Inhibition:** Ligand A (0.769) has a slightly higher hERG risk than Ligand B (0.222), but both are relatively low.

**Microsomal Clearance:** Ligand A (111.543) has a higher microsomal clearance than Ligand B (32.532), suggesting faster metabolism and potentially lower in vivo exposure.

**In vitro Half-Life:** Ligand A (14.139) has a longer half-life than Ligand B (0.338), which is favorable.

**P-gp Efflux:** Ligand A (0.581) has lower P-gp efflux than Ligand B (0.112), meaning it's less likely to be pumped out of the brain, improving CNS exposure.

**Binding Affinity:** Ligand B (-10.1 kcal/mol) has a significantly stronger binding affinity than Ligand A (-8.9 kcal/mol). This is a substantial difference (1.2 kcal/mol), and a strong affinity can often outweigh minor ADME drawbacks.

**Overall Assessment:**

Ligand A excels in TPSA and BBB, crucial for CNS penetration. It also has a better half-life and lower P-gp efflux. However, its logP is higher, solubility is lower, and clearance is faster.

Ligand B has a *much* stronger binding affinity, which is the most important factor. While its TPSA is higher and BBB is lower, the significant affinity advantage likely compensates for these drawbacks, especially considering the potential for further optimization of TPSA and BBB.

Output:
1
2025-04-17 08:50:48,014 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 drug candidates, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (369.29 Da) is slightly higher than Ligand B (338.451 Da), but both are acceptable.

**2. TPSA:** Ligand A (74.43) is higher than Ligand B (49.41). For CNS targets, we prefer TPSA <= 90. Both are below this threshold, but Ligand B is significantly better.

**3. logP:** Ligand A (1.259) is within the optimal range (1-3). Ligand B (3.613) is at the higher end of the optimal range, potentially increasing off-target effects, but still acceptable.

**4. H-Bond Donors:** Ligand A (2) and Ligand B (1) are both within the acceptable limit of <=5.

**5. H-Bond Acceptors:** Ligand A (3) and Ligand B (2) are both within the acceptable limit of <=10.

**6. QED:** Both ligands have good QED values (Ligand A: 0.768, Ligand B: 0.834), indicating good drug-like properties.

**7. DILI:** Ligand A (58.434) has a higher DILI risk than Ligand B (32.842). Both are below the 60% threshold, but Ligand B is preferable.

**8. BBB:** Ligand A (74.292) and Ligand B (87.941) both have good BBB penetration, but Ligand B is significantly better, exceeding 80%. This is crucial for a CNS target like DRD2.

**9. Caco-2 Permeability:** Ligand A (-5.005) has poor Caco-2 permeability, while Ligand B (-4.504) is also poor, but slightly better.

**10. Aqueous Solubility:** Ligand A (-2.624) and Ligand B (-3.913) both have poor aqueous solubility.

**11. hERG Inhibition:** Both ligands have low hERG inhibition risk (Ligand A: 0.504, Ligand B: 0.405).

**12. Microsomal Clearance:** Ligand A (-1.369) has lower (better) microsomal clearance than Ligand B (50.127), indicating better metabolic stability.

**13. In vitro Half-Life:** Ligand A (-22.45) has a very long in vitro half-life, while Ligand B (-5.154) is shorter.

**14. P-gp Efflux:** Ligand A (0.024) has very low P-gp efflux, which is desirable for CNS penetration. Ligand B (0.201) has slightly higher P-gp efflux.

**15. Binding Affinity:** Ligand B (-8.7 kcal/mol) has a significantly stronger binding affinity than Ligand A (0.0 kcal/mol). This >1.5 kcal/mol difference in affinity is a major advantage, potentially outweighing some ADME drawbacks.

**Overall Assessment:**

Ligand B is the stronger candidate. While Ligand A has better metabolic stability and P-gp efflux, Ligand B excels in the most critical areas for a CNS GPCR target: BBB penetration and binding affinity. The significantly stronger binding affinity of Ligand B (-8.7 kcal/mol vs 0.0 kcal/mol) is a decisive factor. Ligand B also has a lower DILI risk and better TPSA. The slightly higher logP of Ligand B is a minor concern, but the benefits outweigh this potential drawback.

Output:
1
2025-04-17 08:50:48,014 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (364.873 and 366.487 Da) are within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (49.85) is excellent, falling well below the 90 Angstroms threshold for CNS targets. Ligand B (95.42) is higher, but still potentially acceptable, though less ideal.

**3. logP:** Ligand A (3.4) is optimal. Ligand B (1.509) is a bit low, potentially hindering membrane permeability.

**4. H-Bond Donors:** Ligand A (0) is good. Ligand B (2) is also acceptable.

**5. H-Bond Acceptors:** Ligand A (3) is good. Ligand B (6) is acceptable, but approaching the upper limit.

**6. QED:** Both ligands have similar QED values (0.767 and 0.691), indicating good drug-like properties.

**7. DILI:** Ligand A (46.956) has a slightly higher DILI risk than Ligand B (37.611), but both are below the concerning threshold of 60.

**8. BBB:** Ligand A (85.072) has a significantly better BBB penetration prediction than Ligand B (56.495). This is *critical* for a CNS target like DRD2.

**9. Caco-2 Permeability:** Ligand A (-4.42) has worse Caco-2 permeability than Ligand B (-5.073), but both are negative and therefore indicate poor permeability.

**10. Aqueous Solubility:** Ligand A (-4.198) has better aqueous solubility than Ligand B (-2.86), which is important for formulation.

**11. hERG Inhibition:** Ligand A (0.593) has a lower hERG inhibition risk than Ligand B (0.167), which is preferable.

**12. Microsomal Clearance:** Ligand A (61.074) has higher microsomal clearance than Ligand B (40.044), indicating lower metabolic stability.

**13. In vitro Half-Life:** Ligand A (-0.506) has a shorter half-life than Ligand B (-5.687).

**14. P-gp Efflux:** Ligand A (0.486) has lower P-gp efflux than Ligand B (0.36), which is beneficial for CNS exposure.

**15. Binding Affinity:** Ligand A (-9.1 kcal/mol) has a significantly stronger binding affinity than Ligand B (-8.0 kcal/mol). This is a substantial difference.

**Overall Assessment:**

Ligand A is the stronger candidate. While Ligand B has slightly better solubility and a lower DILI risk, Ligand A's superior BBB penetration, significantly stronger binding affinity, lower P-gp efflux, and lower hERG risk outweigh these minor drawbacks. The strong affinity of Ligand A is particularly important, and a 1.1 kcal/mol difference is substantial enough to compensate for the slightly higher clearance and lower Caco-2 permeability. The TPSA is also much more favorable for CNS penetration.



Output:
1
2025-04-17 08:50:48,015 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (349.475 and 350.427 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (78.51) is significantly better than Ligand B (130.32). For CNS targets, we want TPSA <= 90, and A is comfortably within that, while B is pushing the limit and may have reduced brain penetration.

**logP:** Ligand A (1.755) is within the optimal 1-3 range. Ligand B (-0.723) is below 1, which could hinder permeation, including BBB penetration.

**H-Bond Donors/Acceptors:** Ligand A (2 HBD, 3 HBA) is preferable to Ligand B (4 HBD, 9 HBA). Lower counts generally improve permeability.

**QED:** Ligand A (0.717) has a better QED score than Ligand B (0.525), indicating a more drug-like profile.

**DILI:** Both ligands have acceptable DILI risk (A: 32.299, B: 37.611), both below the 40 threshold.

**BBB:** Ligand B (72.392) has a significantly better BBB percentile than Ligand A (55.487). This is a crucial factor for a CNS target like DRD2.

**Caco-2 Permeability:** Ligand A (-4.844) has a worse Caco-2 permeability than Ligand B (-5.753), indicating lower intestinal absorption.

**Aqueous Solubility:** Both have poor aqueous solubility (-2.393 and -1.912 respectively), but this is less critical for CNS drugs that can utilize other transport mechanisms.

**hERG Inhibition:** Both ligands show low hERG inhibition risk (A: 0.089, B: 0.228).

**Microsomal Clearance:** Ligand B (7.025) has a lower microsomal clearance than Ligand A (32.449), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand B (1.857) has a slightly better in vitro half-life than Ligand A (-2.615).

**P-gp Efflux:** Ligand A (0.028) has a much lower P-gp efflux liability than Ligand B (0.001), which is favorable for CNS penetration.

**Binding Affinity:** Ligand A (-8.1 kcal/mol) has a slightly better binding affinity than Ligand B (-7.7 kcal/mol), although the difference is relatively small (0.4 kcal/mol).

**Overall Assessment:**

Ligand A excels in TPSA, logP, H-bonding, QED, and P-gp efflux, and has a slightly better binding affinity. These are all important for CNS penetration and overall drug-likeness. However, Ligand B has a significantly better BBB percentile and lower microsomal clearance, which are also critical for CNS drug development. The difference in binding affinity is not substantial enough to outweigh the BBB advantage of Ligand B. Considering the GPCR-specific priorities, the better BBB penetration of Ligand B is the deciding factor.

Output:
1
2025-04-17 08:50:48,015 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (386.43 and 358.43 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (106.38) is higher than the preferred <90 for CNS targets, while Ligand B (58.64) is well within the range. This is a significant advantage for Ligand B.

**logP:** Both ligands (2.68 and 2.34) are within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Both have 1 HBD, which is good. Ligand A has 6 HBA, while Ligand B has 3. Both are acceptable (<=10), but Ligand B is slightly better.

**QED:** Both ligands have good QED scores (0.58 and 0.79), indicating good drug-like properties.

**DILI:** Ligand A (86.66) has a higher DILI risk than Ligand B (26.10). This is a significant negative for Ligand A.

**BBB:** Ligand B (90.62) has excellent BBB penetration, exceeding the desirable >70 threshold, while Ligand A (63.09) is lower. This is a major advantage for Ligand B, given DRD2 is a CNS target.

**Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and requires further investigation. However, the magnitude is similar.

**Aqueous Solubility:** Both have negative solubility values, also unusual. Again, the magnitude is similar.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.34 and 0.49).

**Microsomal Clearance:** Ligand B (5.46) has significantly lower microsomal clearance than Ligand A (13.28), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand B (7.37) has a longer in vitro half-life than Ligand A (26.11).

**P-gp Efflux:** Ligand A (0.395) has slightly lower P-gp efflux than Ligand B (0.052), which is favorable.

**Binding Affinity:** Ligand B (-8.5 kcal/mol) has a slightly better binding affinity than Ligand A (-8.9 kcal/mol). While the difference is small, it's still a positive for Ligand B.

**Overall:**

Ligand B consistently outperforms Ligand A across several critical parameters for a CNS-targeting GPCR ligand. Specifically, its superior BBB penetration, lower DILI risk, better metabolic stability (lower Cl_mic, longer t1/2), and lower TPSA make it a much more promising candidate. While Ligand A has slightly lower P-gp efflux and a slightly better binding affinity, these advantages are outweighed by the significant drawbacks in BBB, DILI, and metabolic stability.

Output:
1
2025-04-17 08:50:48,015 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight (MW):**
   - Ligand A: 425.304 Da - Within the ideal range (200-500 Da).
   - Ligand B: 354.535 Da - Also within the ideal range.
   - *Both are acceptable.*

**2. Topological Polar Surface Area (TPSA):**
   - Ligand A: 76.57  -  Below the 90 A^2 threshold for CNS targets. Good.
   - Ligand B: 69.64 - Below the 90 A^2 threshold for CNS targets. Good.
   - *Both are acceptable.*

**3. Lipophilicity (logP):**
   - Ligand A: 2.289 - Optimal (1-3).
   - Ligand B: 3.251 - Optimal (1-3), but approaching the upper limit.
   - *Both are acceptable, A slightly preferred.*

**4. H-Bond Donors (HBD):**
   - Ligand A: 0 -  Good.
   - Ligand B: 2 - Acceptable, but higher than A.
   - *A is preferred.*

**5. H-Bond Acceptors (HBA):**
   - Ligand A: 5 - Good.
   - Ligand B: 3 - Good.
   - *Both are acceptable.*

**6. QED:**
   - Ligand A: 0.735 - Excellent (>0.5).
   - Ligand B: 0.625 - Good (>0.5).
   - *A is preferred.*

**7. DILI:**
   - Ligand A: 84.296 - High risk (>60). Concerning.
   - Ligand B: 8.957 - Low risk (<40). Excellent.
   - *B is significantly preferred.*

**8. BBB:**
   - Ligand A: 67.003 - Below the desirable >70 for CNS targets.
   - Ligand B: 68.748 - Also below the desirable >70 for CNS targets.
   - *Both are suboptimal, but similar.*

**9. Caco-2 Permeability:**
   - Ligand A: -5.011 - Poor permeability.
   - Ligand B: -4.714 - Poor permeability.
   - *Both are suboptimal, but similar.*

**10. Aqueous Solubility:**
   - Ligand A: -2.899 - Poor solubility.
   - Ligand B: -3.062 - Poor solubility.
   - *Both are suboptimal, but similar.*

**11. hERG Inhibition:**
   - Ligand A: 0.361 - Low risk.
   - Ligand B: 0.729 - Moderate risk.
   - *A is preferred.*

**12. Microsomal Clearance (Cl_mic):**
   - Ligand A: 7.693 - Relatively low, suggesting better metabolic stability.
   - Ligand B: 48.576 - Higher, suggesting faster metabolism.
   - *A is preferred.*

**13. In vitro Half-Life:**
   - Ligand A: 49.97 - Good half-life.
   - Ligand B: 1.642 - Short half-life.
   - *A is significantly preferred.*

**14. P-gp Efflux:**
   - Ligand A: 0.285 - Low efflux, good for CNS exposure.
   - Ligand B: 0.453 - Moderate efflux.
   - *A is preferred.*

**15. Binding Affinity:**
   - Ligand A: -7.4 kcal/mol - Excellent.
   - Ligand B: -7.3 kcal/mol - Excellent, but slightly weaker than A.
   - *A is preferred.*

**Overall Assessment:**

While both ligands have good binding affinity and acceptable TPSA/logP, Ligand A is superior in most critical ADME properties for a CNS-targeting GPCR. Specifically, it has a better QED, lower DILI risk, better metabolic stability (lower Cl_mic, longer t1/2), lower P-gp efflux, and slightly better binding affinity. Ligand B's primary advantage is its significantly lower DILI risk, but this is outweighed by its poorer ADME profile overall. The poor Caco-2 and solubility of both compounds are concerning, but can potentially be addressed through formulation strategies.

Output:
1
2025-04-17 08:50:48,015 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 drug candidates, considering the provided guidelines and GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (360.37 and 348.531 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (97.11) is borderline but acceptable for CNS penetration, while Ligand B (49.41) is excellent, well below the 90 A^2 threshold. This favors Ligand B.

**logP:** Both ligands have good logP values (2.737 and 3.482), falling within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A has 2 HBD and 6 HBA, while Ligand B has 1 HBD and 2 HBA. Both are within acceptable limits (<=5 HBD and <=10 HBA).

**QED:** Both ligands have similar and good QED scores (0.704 and 0.716), indicating good drug-likeness.

**DILI:** Ligand A has a very high DILI risk (99.341 percentile), which is a major concern. Ligand B has a much lower, and acceptable, DILI risk (12.718 percentile). This is a significant advantage for Ligand B.

**BBB:** Ligand A has a poor BBB penetration (22.334 percentile), while Ligand B has a very good BBB penetration (86.274 percentile). Given that DRD2 is a CNS target, this is a crucial advantage for Ligand B.

**Caco-2 Permeability:** Ligand A has a negative Caco-2 value (-5.318), which is unusual and suggests poor permeability. Ligand B also has a negative Caco-2 value (-4.407), but it's slightly less negative. Both are concerning.

**Aqueous Solubility:** Both ligands have poor aqueous solubility (-3.322 and -3.9). This could pose formulation challenges, but is less critical than BBB for a CNS target.

**hERG Inhibition:** Both ligands show very low hERG inhibition risk (0.078 and 0.394 percentile), which is excellent.

**Microsomal Clearance:** Ligand A has a low microsomal clearance (1.783 mL/min/kg), indicating good metabolic stability. Ligand B has a very high clearance (74.079 mL/min/kg), which is a significant drawback.

**In vitro Half-Life:** Ligand A has a negative in vitro half-life (-0.749 hours), which is not realistic and suggests instability or rapid metabolism. Ligand B has a reasonable half-life (16.399 hours).

**P-gp Efflux:** Ligand A has very low P-gp efflux (0.033 percentile), which is favorable for CNS exposure. Ligand B has slightly higher efflux (0.028 percentile), but still very low.

**Binding Affinity:** Ligand A has a stronger binding affinity (-8.9 kcal/mol) compared to Ligand B (-7.4 kcal/mol). This is a 1.5 kcal/mol difference, which is substantial.

**Overall Assessment:**

Despite Ligand A's superior binding affinity, its extremely high DILI risk, poor BBB penetration, negative Caco-2 permeability, and unrealistic half-life make it a very poor candidate. Ligand B, while having a weaker affinity, possesses a much more favorable ADME profile, particularly its excellent BBB penetration and acceptable DILI risk, which are critical for a CNS-targeting drug. The high metabolic clearance of Ligand B is a concern, but could potentially be addressed through structural modifications.

Output:
1
2025-04-17 08:50:48,015 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (345.483 and 340.379 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (47.56) is significantly better than Ligand B (78.87). For CNS targets, we want TPSA <= 90, and A is comfortably within that range, while B is approaching the upper limit.

**3. logP:** Both ligands have acceptable logP values (3.858 and 2.328), falling within the 1-3 range. Ligand A is slightly higher, which could be beneficial for membrane permeability, but isn't a major concern for either.

**4. H-Bond Donors:** Both have reasonable HBD counts (1 and 2 respectively), well below the threshold of 5.

**5. H-Bond Acceptors:** Both have reasonable HBA counts (3 and 4 respectively), well below the threshold of 10.

**6. QED:** Both ligands have good QED scores (0.603 and 0.841), indicating good drug-like properties.

**7. DILI:** Ligand A (18.922) has a considerably lower DILI risk than Ligand B (63.397). This is a significant advantage for A.

**8. BBB:** Both ligands have very good BBB penetration (83.288 and 82.474), exceeding the desirable threshold of 70 for CNS targets. This is a positive for both.

**9. Caco-2 Permeability:** Both have negative Caco-2 values (-4.344 and -4.407). This is unusual and suggests poor permeability. However, these values are on a scale where negative values are possible, and the absolute values are similar.

**10. Aqueous Solubility:** Both have negative solubility values (-4.063 and -3.716). This suggests poor aqueous solubility.

**11. hERG Inhibition:** Both have low hERG inhibition risk (0.605 and 0.728), which is good.

**12. Microsomal Clearance:** Ligand A (68.27) has higher microsomal clearance than Ligand B (17.682), indicating lower metabolic stability. This is a disadvantage for A.

**13. In vitro Half-Life:** Ligand B (3.023) has a longer in vitro half-life than Ligand A (5.651), which is a positive for B.

**14. P-gp Efflux:** Ligand A (0.193) has lower P-gp efflux than Ligand B (0.048), which is beneficial for CNS exposure.

**15. Binding Affinity:** Ligand B (-9.1 kcal/mol) has a slightly better binding affinity than Ligand A (-8.6 kcal/mol). While the difference is not huge, it's a noticeable advantage.

**Overall Assessment:**

Considering the GPCR-specific priorities, Ligand B is slightly more promising. While Ligand A has a significantly lower DILI risk and better TPSA, Ligand B has a slightly better binding affinity, longer half-life, and lower P-gp efflux. The higher DILI risk of Ligand B is a concern, but the affinity difference and metabolic stability are important. The similar BBB values mean that this isn't a differentiating factor. The negative Caco-2 and solubility values are concerning for both, and would need to be addressed during optimization.

Output:
1
2025-04-17 08:50:48,015 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 drug candidates, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (351.357 and 339.439 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (102.88) is better than Ligand B (62.3). Both are below the 90 A^2 threshold desirable for CNS targets, but Ligand B is significantly lower, which is favorable.

**logP:** Both ligands have good logP values (3.13 and 2.403), falling within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A has 2 HBD and 3 HBA, while Ligand B has 1 HBD and 3 HBA. Both are within acceptable limits (<=5 HBD and <=10 HBA).

**QED:** Ligand B (0.896) has a significantly higher QED score than Ligand A (0.314), indicating a more drug-like profile.

**DILI:** Ligand A (60.644) has a higher DILI risk than Ligand B (21.675). Ligand B is well below the 40 threshold, indicating low liver injury risk.

**BBB:** Ligand A (81.466) has a better BBB penetration percentile than Ligand B (71.85), both are good, but A is better. This is a critical factor for a CNS target like DRD2.

**Caco-2 Permeability:** Ligand A (-4.95) has a worse Caco-2 permeability than Ligand B (-4.875).

**Aqueous Solubility:** Ligand A (-2.677) has a worse aqueous solubility than Ligand B (-2.435).

**hERG Inhibition:** Ligand A (0.855) has a slightly higher hERG inhibition liability than Ligand B (0.172). Ligand B is much lower, indicating a lower risk of cardiotoxicity.

**Microsomal Clearance:** Ligand A (38.054) has a higher microsomal clearance than Ligand B (21.618), suggesting lower metabolic stability.

**In vitro Half-Life:** Ligand B (-16.578) has a much longer in vitro half-life than Ligand A (42.799).

**P-gp Efflux:** Ligand A (0.33) has a higher P-gp efflux liability than Ligand B (0.06), which is unfavorable for CNS penetration.

**Binding Affinity:** Ligand B (-9.9 kcal/mol) has a significantly stronger binding affinity than Ligand A (-7.8 kcal/mol). This is a >1.5 kcal/mol advantage, which is substantial.

**Overall Assessment:**

While Ligand A has better BBB penetration, Ligand B excels in almost all other crucial parameters. It has a superior QED score, significantly lower DILI and hERG risk, better metabolic stability (lower Cl_mic, longer t1/2), lower P-gp efflux, and, most importantly, a much stronger binding affinity. The slightly lower BBB of Ligand B is outweighed by its other advantages, especially the significantly improved binding affinity.

Output:
1
2025-04-17 08:50:48,016 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (413.247 Da) is slightly higher than Ligand B (363.531 Da), but both are acceptable.

**TPSA:** Ligand A (109.98) is above the preferred <90 for CNS targets, while Ligand B (70.15) is well within the range. This is a significant advantage for Ligand B.

**logP:** Both ligands have good logP values (A: 2.237, B: 2.739), falling within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A has 3 HBD and 5 HBA, while Ligand B has 2 HBD and 6 HBA. Both are within acceptable limits (<=5 HBD, <=10 HBA).

**QED:** Both ligands have good QED scores (A: 0.714, B: 0.842), indicating good drug-like properties.

**DILI:** Ligand A (79.333) has a higher DILI risk than Ligand B (51.26). Both are below the concerning threshold of 60, but B is preferable.

**BBB:** Ligand B (74.835) has a significantly better BBB penetration percentile than Ligand A (58.821). This is a crucial advantage for a CNS target like DRD2.

**Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and suggests poor permeability. However, the scale isn't specified, so it's hard to interpret.

**Aqueous Solubility:** Both ligands have negative solubility values, which is also unusual. Again, the scale is unspecified.

**hERG:** Both ligands have low hERG inhibition liability (A: 0.664, B: 0.27), which is good.

**Microsomal Clearance:** Ligand A (-3.464) has a *negative* microsomal clearance, which is impossible. This is likely an error in the data. Ligand B (11.626) has a reasonable clearance.

**In vitro Half-Life:** Ligand B (32.629 hours) has a longer half-life than Ligand A (44.943 hours).

**P-gp Efflux:** Ligand A (0.207) has lower P-gp efflux than Ligand B (0.105), which is favorable for CNS penetration.

**Binding Affinity:** Ligand B (-9.2 kcal/mol) has a slightly better binding affinity than Ligand A (-8.6 kcal/mol). While both are strong binders, the difference is significant.

**Overall Assessment:**

Ligand B is the superior candidate. It has a much better TPSA, significantly better BBB penetration, a lower DILI risk, and a slightly better binding affinity. The negative clearance value for Ligand A is a major red flag. While both have issues with Caco-2 and solubility, the CNS-focused properties of TPSA and BBB heavily favor Ligand B for a DRD2 target.

Output:
1
2025-04-17 08:50:48,016 - INFO - Reasoning:

Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (344.455 and 348.403 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (71.34) is significantly better than Ligand B (118.53). For CNS targets, we want TPSA <= 90, and A is comfortably within this range, while B exceeds it. This is a significant advantage for A.

**3. logP:** Ligand A (3.349) is within the optimal 1-3 range. Ligand B (0.64) is below 1, which could hinder permeation. This favors A.

**4. H-Bond Donors:** Both ligands have 2 HBD, which is acceptable (<=5).

**5. H-Bond Acceptors:** Ligand A has 3 HBA, and Ligand B has 5. Both are within the acceptable range (<=10), but A is slightly better.

**6. QED:** Both ligands have similar QED values (0.778 and 0.714), indicating good drug-likeness.

**7. DILI:** Ligand A (35.944) has a slightly better DILI score than Ligand B (44.126), indicating lower potential for liver injury. Both are below the concerning threshold of 60.

**8. BBB:** Both ligands have good BBB penetration (65.878% and 67.08%), but neither exceeds the desirable 70% threshold. This is not a major differentiating factor.

**9. Caco-2 Permeability:** Ligand A (-4.613) has a worse Caco-2 permeability than Ligand B (-5.191). Lower values represent lower permeability.

**10. Aqueous Solubility:** Ligand A (-4.057) has a worse solubility than Ligand B (-2.183). Lower values represent lower solubility.

**11. hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.215 and 0.048), which is excellent.

**12. Microsomal Clearance:** Ligand A (64.251) has a higher microsomal clearance than Ligand B (19.043), indicating faster metabolism and potentially lower *in vivo* exposure. This favors B.

**13. In vitro Half-Life:** Ligand B (-28.357) has a much longer in vitro half-life than Ligand A (40.109), indicating greater metabolic stability. This is a significant advantage for B.

**14. P-gp Efflux:** Ligand A (0.306) has a slightly higher P-gp efflux liability than Ligand B (0.018), meaning B is less likely to be pumped out of the brain. This favors B.

**15. Binding Affinity:** Both ligands have very similar and strong binding affinities (-8.9 and -8.1 kcal/mol). The difference of 0.8 kcal/mol is not substantial enough to outweigh other factors.

**Overall Assessment:**

While Ligand B has better metabolic stability (lower Cl_mic, longer t1/2), lower P-gp efflux, and slightly better solubility, Ligand A has a much more favorable TPSA and logP, which are crucial for CNS penetration and GPCR binding. The TPSA difference is particularly important. Considering the GPCR-specific priorities, the lower TPSA and better logP of Ligand A are more critical for CNS target engagement. Although Ligand B has a slight edge in metabolic stability, the difference isn't large enough to overcome the permeability advantages of Ligand A.

Output:
0
2025-04-17 08:50:48,016 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (356.419 and 353.423 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (116.17) is slightly higher than Ligand B (111.39). Both are below the 140 A^2 threshold for oral absorption, but ideally, for a CNS target like DRD2, we want <90 A^2. Ligand B is closer to this target.

**3. logP:** Ligand A (-0.574) is a bit low, potentially hindering permeability. Ligand B (-0.027) is better, falling within the optimal 1-3 range, though still on the lower end.

**4. H-Bond Donors:** Ligand A (3) is slightly higher than Ligand B (2). Both are acceptable (<=5).

**5. H-Bond Acceptors:** Ligand A (6) is lower than Ligand B (9). Both are acceptable (<=10), but Ligand A is preferable.

**6. QED:** Ligand B (0.658) has a better QED score than Ligand A (0.415), indicating a more drug-like profile.

**7. DILI:** Ligand A (22.8%) has a significantly lower DILI risk than Ligand B (33.501%). This is a substantial advantage for Ligand A.

**8. BBB:** Ligand B (62.737%) has a much higher BBB penetration percentile than Ligand A (24.738%). This is *critical* for a CNS target like DRD2, and a major advantage for Ligand B.

**9. Caco-2:** Both ligands have similar, very poor Caco-2 permeability (-5.01 and -5.165).

**10. Solubility:** Both ligands have similar, very poor aqueous solubility (-1.091 and -1.2).

**11. hERG:** Both ligands have very low hERG inhibition risk (0.084 and 0.07).

**12. Cl_mic:** Ligand B (38.497) has a higher microsomal clearance than Ligand A (20.897), suggesting lower metabolic stability. Ligand A is preferable.

**13. t1/2:** Ligand A (-20.477) has a much longer in vitro half-life than Ligand B (5.343). This is a significant advantage for Ligand A.

**14. Pgp:** Both ligands have very low P-gp efflux liability (0.012 and 0.031).

**15. Binding Affinity:** Ligand A (-6.7 kcal/mol) has a slightly better binding affinity than Ligand B (-6.2 kcal/mol). While the difference is not huge, it's a positive for Ligand A.

**Overall Assessment:**

Ligand B excels in BBB penetration, a crucial factor for DRD2. However, it suffers from higher DILI risk and lower metabolic stability. Ligand A has a better safety profile (lower DILI), better metabolic stability (lower Cl_mic, longer t1/2), and slightly better affinity, but its BBB penetration is poor.

Given the importance of BBB penetration for CNS targets, and the relatively small affinity difference, Ligand B is the more promising candidate *despite* its higher DILI and lower metabolic stability. These ADME properties could potentially be improved through further optimization, but achieving good BBB penetration is often more challenging.

Output:
1
2025-04-17 08:50:48,016 - INFO - Batch 483 complete. Total preferences: 7728
2025-04-17 08:50:48,017 - INFO - Processing batch 484/512...
2025-04-17 08:51:29,468 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (368.396 and 372.853 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (70.08) is significantly better than Ligand B (94.48). For CNS targets, TPSA should be <= 90, and A is comfortably within this range, while B is approaching the upper limit.

**logP:** Both ligands have acceptable logP values (1.217 and 0.75), falling within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A (HBD=1, HBA=4) is preferable to Ligand B (HBD=2, HBA=6) as lower values generally improve permeability. Both are within acceptable limits.

**QED:** Both ligands have good QED scores (0.621 and 0.736), indicating good drug-like properties.

**DILI:** Ligand A (21.132) has a much lower DILI risk than Ligand B (55.487). This is a significant advantage for A.

**BBB:** Ligand A (77.2) has a considerably better BBB penetration score than Ligand B (60.915).  A score >70 is desirable for CNS targets, and A is closer to this threshold.

**Caco-2 Permeability:** Ligand A (-4.306) shows better Caco-2 permeability than Ligand B (-5.107), indicating better intestinal absorption.

**Aqueous Solubility:** Ligand B (-2.446) has slightly better aqueous solubility than Ligand A (-0.439). While solubility is important, it's less critical than BBB for a CNS target.

**hERG Inhibition:** Both ligands have low hERG inhibition liability (0.67 and 0.136), which is good.

**Microsomal Clearance:** Ligand A (19.772) has lower microsomal clearance than Ligand B (29.591), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand B (21.912) has a longer in vitro half-life than Ligand A (-20.965). This is a positive for B, but the negative value for A is concerning and suggests rapid metabolism.

**P-gp Efflux:** Ligand A (0.114) has lower P-gp efflux liability than Ligand B (0.036), which is beneficial for CNS exposure.

**Binding Affinity:** Ligand B (-8.1) has a slightly better binding affinity than Ligand A (-7.4). This is a 0.7 kcal/mol difference, which is not huge, but is noticeable.

**Overall Assessment:**

Considering the GPCR-specific priorities, Ligand A is the more promising candidate. Its superior BBB penetration, lower TPSA, lower DILI risk, and lower P-gp efflux outweigh the slightly weaker binding affinity and shorter half-life. The negative in vitro half-life for A is a concern, but this could potentially be addressed through structural modifications. Ligand B's higher TPSA and DILI risk are significant drawbacks.

Output:
0
2025-04-17 08:51:29,469 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (348.575 and 356.363 Da) are within the ideal range of 200-500 Da.

**TPSA:** Ligand A (32.34) is excellent, well below the 90 A^2 threshold for CNS targets. Ligand B (136.89) is higher, exceeding the preferred threshold for CNS penetration, which is a significant drawback.

**logP:** Ligand A (4.9) is at the upper end of the optimal range (1-3) and could potentially lead to solubility issues or off-target interactions. Ligand B (2.011) is well within the optimal range.

**H-Bond Donors/Acceptors:** Both ligands have a reasonable number of HBD (1) and HBA (Ligand A: 2, Ligand B: 6), falling within acceptable limits.

**QED:** Both ligands have acceptable QED scores (A: 0.74, B: 0.621), indicating reasonable drug-likeness.

**DILI:** Ligand A (13.532) has a much lower DILI risk than Ligand B (89.376), which is a substantial advantage.

**BBB:** Ligand A (79.992) has a good BBB percentile, desirable for a CNS target. Ligand B (38.465) has a poor BBB percentile, a major concern.

**Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and requires further investigation. However, the magnitude of the negative value for Ligand A (-4.883) is smaller than that of Ligand B (-4.888).

**Aqueous Solubility:** Both ligands have similar, very poor aqueous solubility (-4.344 and -4.514).

**hERG Inhibition:** Both ligands have low hERG inhibition risk (A: 0.895, B: 0.629).

**Microsomal Clearance:** Ligand B (34.456) has a lower microsomal clearance than Ligand A (62.387), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (8.915) has a longer half-life than Ligand B (-9.321), which is a positive attribute.

**P-gp Efflux:** Ligand A (0.433) has a lower P-gp efflux liability than Ligand B (0.161), which is beneficial for CNS exposure.

**Binding Affinity:** Ligand B (-8.2 kcal/mol) has a significantly stronger binding affinity than Ligand A (-0.0 kcal/mol). This is a substantial advantage that could potentially overcome some of its ADME drawbacks.

**Overall Assessment:**

Despite Ligand B's superior binding affinity, the combination of its poor BBB penetration, high DILI risk, and higher TPSA makes it a less favorable candidate. Ligand A, while having a weaker binding affinity, possesses a much better safety profile (lower DILI), better BBB penetration, and lower P-gp efflux. For a CNS target like DRD2, BBB penetration and safety are paramount. While the affinity difference is significant, it might be possible to optimize Ligand A's affinity through further medicinal chemistry efforts, whereas improving the BBB penetration of Ligand B would be a much more challenging task.

Output:
0
2025-04-17 08:51:29,469 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (342.395 and 371.905 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (79.2) is better than Ligand B (59.0) as it is closer to the ideal range for CNS targets (<=90).

**logP:** Ligand B (4.004) is higher than Ligand A (2.258). While both are above the optimal 1-3 range, Ligand B is significantly higher and could present solubility challenges.

**H-Bond Donors/Acceptors:** Both have 1 HBD and 4 HBA, which are within acceptable limits.

**QED:** Ligand A (0.914) has a significantly better QED score than Ligand B (0.675), indicating a more drug-like profile.

**DILI:** Ligand A (36.177) has a lower DILI risk than Ligand B (16.053), which is preferable.

**BBB:** Both ligands have similar BBB penetration (Ligand A: 53.587, Ligand B: 50.523). Neither are ideal (>70), but acceptable given the other parameters.

**Caco-2 Permeability:** Both have very negative Caco-2 values (-4.899 and -4.896), indicating poor permeability. This is a significant drawback for both.

**Aqueous Solubility:** Both ligands have very negative solubility values (-2.013 and -3.69), indicating poor solubility.

**hERG Inhibition:** Ligand A (0.016) has a much lower hERG inhibition liability than Ligand B (0.64), which is a major advantage.

**Microsomal Clearance:** Ligand A (-17.481) has a much lower (better) microsomal clearance than Ligand B (99.862), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand B (52.104) has a significantly longer in vitro half-life than Ligand A (4.7). This is a positive for Ligand B.

**P-gp Efflux:** Ligand A (0.019) has a lower P-gp efflux liability than Ligand B (0.238), which is preferable for CNS penetration.

**Binding Affinity:** Ligand B (-6.7 kcal/mol) has a better binding affinity than Ligand A (-9.2 kcal/mol). This is a substantial advantage, potentially outweighing some of the ADME concerns.

**Overall Assessment:**

Ligand B has a superior binding affinity, and a longer half-life. However, it suffers from a high logP, higher DILI risk, and significantly higher microsomal clearance. Ligand A has a much better drug-like profile (QED, DILI, hERG, Pgp, Cl_mic) and a better TPSA. The poor Caco-2 and solubility are concerning for both, but the stronger binding affinity of Ligand B is a significant advantage for a GPCR target. Given the importance of affinity for GPCRs, and the potential to address solubility/permeability issues through formulation, Ligand B is the more promising candidate.

Output:
1
2025-04-17 08:51:29,469 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (350.409 and 348.447 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (58.2) is excellent, well below the 90 A^2 threshold for CNS targets. Ligand B (84.42) is still reasonable but approaching the upper limit for good CNS penetration.

**logP:** Ligand A (3.227) is optimal. Ligand B (1.373) is a bit low, potentially hindering membrane permeability, though not drastically.

**H-Bond Donors/Acceptors:** Ligand A has 2 HBD and 2 HBA, which is ideal. Ligand B has 1 HBD and 5 HBA, still acceptable, but slightly higher HBA could affect permeability.

**QED:** Both ligands have similar QED values (0.823 and 0.804), indicating good drug-likeness.

**DILI:** Ligand A (52.152) has a moderate DILI risk, while Ligand B (34.354) has a lower, more favorable DILI risk.

**BBB:** Ligand A (86.002) has a very good BBB penetration percentile. Ligand B (68.282) is lower, suggesting less efficient CNS exposure. This is a critical factor for a DRD2 ligand.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.422 and -4.762), which is unusual and suggests poor permeability. These values are likely errors or indicate a significant issue with intestinal absorption.

**Aqueous Solubility:** Both ligands have negative solubility values (-4.54 and -1.842), which is also concerning and suggests poor solubility.

**hERG Inhibition:** Ligand A (0.519) has a low hERG inhibition risk. Ligand B (0.181) has even lower risk, which is excellent.

**Microsomal Clearance:** Ligand A (45.587) has moderate clearance, while Ligand B (29.605) has lower clearance, indicating better metabolic stability.

**In vitro Half-Life:** Ligand A (15.156 hours) has a reasonable half-life. Ligand B (-6.03 hours) has a negative half-life, which is impossible and indicates a significant issue with the data.

**P-gp Efflux:** Ligand A (0.335) has low P-gp efflux, which is favorable for CNS penetration. Ligand B (0.023) has very low P-gp efflux, even better.

**Binding Affinity:** Ligand B (-9.0) has significantly stronger binding affinity than Ligand A (-0.0). This is a substantial difference.

**Overall Assessment:**

Despite the concerning negative values for Caco-2 and solubility, the most significant difference is the binding affinity. Ligand B has a much stronger binding affinity (-9.0 kcal/mol) compared to Ligand A (-0.0 kcal/mol). The better metabolic stability (lower Cl_mic) and lower P-gp efflux of Ligand B are also advantageous. While Ligand A has a better BBB score, the large affinity difference of Ligand B outweighs this advantage, especially considering the potential for optimization of BBB penetration. The negative half-life for Ligand B is a major red flag, however.

Given the data, and acknowledging the questionable solubility and permeability data, I would cautiously favor Ligand B *if* the negative half-life can be explained or corrected. The strong binding affinity is a major driver.

Output:
1
2025-04-17 08:51:29,469 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (364.471 Da) is slightly higher than Ligand B (341.415 Da), but both are acceptable.

**TPSA:** Both ligands have TPSA values below 140, suggesting good oral absorption potential. Ligand A (85.67) is better than Ligand B (91.81) and closer to the preferred <90 for CNS targets.

**logP:** Both ligands have logP values within the optimal range (1-3). Ligand A (0.773) is slightly lower, potentially impacting permeability, while Ligand B (1.426) is better positioned.

**H-Bond Donors/Acceptors:** Ligand A (1 HBD, 6 HBA) is preferable to Ligand B (3 HBD, 4 HBA) as it has fewer HBDs, which can improve membrane permeability.

**QED:** Ligand A (0.806) has a significantly better QED score than Ligand B (0.501), indicating a more drug-like profile.

**DILI:** Both ligands have similar DILI risk (Ligand A: 47.693, Ligand B: 49.632), and are both considered low risk (<60).

**BBB:** Both ligands have relatively low BBB penetration (Ligand A: 40.093, Ligand B: 43.699). This is a concern for a CNS target like DRD2. However, we must consider other factors.

**Caco-2 Permeability:** Both ligands have negative Caco-2 permeability values, which is unusual and suggests poor intestinal absorption. Ligand A (-5.021) is slightly better than Ligand B (-5.729).

**Aqueous Solubility:** Both ligands have negative solubility values, which is also unusual. Ligand A (-1.634) is slightly better than Ligand B (-2.39).

**hERG Inhibition:** Both ligands have low hERG inhibition liability (Ligand A: 0.682, Ligand B: 0.47), which is good.

**Microsomal Clearance:** Ligand A (-15.619) has a much lower (better) microsomal clearance than Ligand B (25.589), indicating greater metabolic stability.

**In vitro Half-Life:** Ligand A (27.632 hours) has a significantly longer half-life than Ligand B (-3.805 hours).

**P-gp Efflux:** Both ligands have low P-gp efflux liability (Ligand A: 0.055, Ligand B: 0.152), which is favorable for CNS penetration.

**Binding Affinity:** Ligand B (-7.9 kcal/mol) has a slightly better binding affinity than Ligand A (-7.4 kcal/mol). This 0.5 kcal/mol difference is significant.

**Overall Assessment:**

While both ligands have drawbacks (low BBB, unusual solubility/permeability), Ligand B's superior binding affinity (-7.9 kcal/mol vs -7.4 kcal/mol) is a crucial advantage for a GPCR target. The difference in affinity outweighs the slightly worse ADME properties of Ligand B. Ligand A has better QED and metabolic stability, but the binding affinity is the most important factor here.

Output:
1
2025-04-17 08:51:29,470 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight (MW):** Both ligands (346.435 and 334.387 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (96.17) is better than Ligand B (105.2), both are below the 140 A^2 threshold for oral absorption, and importantly, below the 90 A^2 target for CNS penetration.

**3. logP:** Both ligands have good logP values (1.324 and 1.102), falling within the optimal 1-3 range.

**4. H-Bond Donors (HBD):** Both are acceptable (2 and 1 respectively), well below the 5 limit.

**5. H-Bond Acceptors (HBA):** Both are acceptable (7 and 8 respectively), below the 10 limit.

**6. QED:** Both ligands have good QED scores (0.665 and 0.719), indicating good drug-like properties.

**7. DILI:** Ligand A (59.907) has a slightly better DILI score than Ligand B (69.833), both are acceptable but lower is better.

**8. BBB:** Ligand A (40.946) and Ligand B (46.491) are both below the 70% threshold desirable for CNS targets. This is a critical factor for DRD2, and both are weak here.

**9. Caco-2 Permeability:** Both have negative Caco-2 values (-5.164 and -5.731), which is unusual and suggests poor permeability. This is a significant concern.

**10. Aqueous Solubility:** Both have negative solubility values (-1.345 and -2.469), which is also concerning.

**11. hERG Inhibition:** Both have very low hERG inhibition risk (0.178 and 0.078).

**12. Microsomal Clearance:** Ligand A (-2.176) has a *better* (lower, meaning more stable) microsomal clearance than Ligand B (-5.736).

**13. In vitro Half-Life:** Ligand A (30.197) has a slightly longer half-life than Ligand B (26.73).

**14. P-gp Efflux:** Both have very low P-gp efflux liability (0.045 and 0.046).

**15. Binding Affinity:** Both ligands have identical and excellent binding affinities (-7.9 kcal/mol).

**Overall Assessment:**

The primary differentiating factors are TPSA, DILI, and microsomal clearance. Ligand A is slightly better in all three. While both ligands have poor Caco-2 and solubility, the slightly better ADME profile of Ligand A (lower DILI, better clearance, slightly longer half-life, and lower TPSA) makes it the more promising candidate. The binding affinity is identical, so ADME properties become the deciding factor. The BBB penetration is a concern for both, but can potentially be addressed with formulation strategies.

Output:
0
2025-04-17 08:51:29,470 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (344.5 and 351.5 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (40.62) is significantly better than Ligand B (70.67). For CNS targets, we want TPSA <= 90, and ideally lower. Ligand A is much closer to the ideal range for CNS penetration.

**3. logP:** Ligand A (3.21) is optimal (1-3), while Ligand B (1.15) is on the lower end, potentially hindering permeability.

**4. H-Bond Donors:** Ligand A (0) is preferable to Ligand B (2). Fewer HBDs generally improve permeability.

**5. H-Bond Acceptors:** Ligand A (2) is better than Ligand B (4). Lower HBA is generally better for CNS penetration.

**6. QED:** Both ligands have similar QED values (0.786 and 0.722), indicating good drug-likeness.

**7. DILI:** Ligand A (26.13) has a lower DILI risk than Ligand B (18.42), suggesting a safer profile. Lower is better.

**8. BBB:** Ligand A (85.46) has a slightly better BBB percentile than Ligand B (74.84), although both are reasonably good for a CNS target.

**9. Caco-2:** Both have negative Caco-2 values, which is unusual and difficult to interpret without knowing the scale. However, the magnitude seems similar.

**10. Solubility:** Both have negative solubility values, again making direct comparison difficult.

**11. hERG:** Both ligands have low hERG inhibition liability (0.571 and 0.34), which is good.

**12. Cl_mic:** Ligand B (42.96) has significantly lower microsomal clearance than Ligand A (73.88), indicating better metabolic stability.

**13. t1/2:** Ligand B (-0.64) has a slightly longer in vitro half-life than Ligand A (-15.48), which is preferable.

**14. Pgp:** Ligand B (0.039) has much lower P-gp efflux liability than Ligand A (0.321), which is a significant advantage for CNS exposure.

**15. Binding Affinity:** Ligand A (-8.9 kcal/mol) has *significantly* stronger binding affinity than Ligand B (0.0 kcal/mol). This is a crucial factor. A difference of >1.5 kcal/mol can often outweigh other ADME drawbacks.

**Overall Assessment:**

Ligand A excels in binding affinity and has favorable TPSA, logP, HBD, HBA, and DILI scores. Its BBB is also good. The main drawback is its higher Cl_mic. Ligand B has better metabolic stability (Cl_mic and t1/2) and P-gp efflux, but its significantly weaker binding affinity is a major concern. For a GPCR target like DRD2, strong binding affinity is paramount. The superior affinity of Ligand A, combined with its acceptable ADME properties, makes it the more promising candidate.

Output:
1
2025-04-17 08:51:29,470 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands fall within the ideal range (200-500 Da). Ligand A (402.292 Da) is slightly higher than Ligand B (343.427 Da), but both are acceptable.

**2. TPSA:** Ligand A (51.27) is significantly better than Ligand B (82.62). For CNS targets, we want TPSA <= 90, and ideally closer to 60. Ligand A is much closer to this ideal.

**3. logP:** Ligand A (4.253) is slightly above the optimal range (1-3), while Ligand B (2.984) is within the optimal range. However, for a GPCR, a slightly higher logP isn't necessarily detrimental, as long as solubility isn't severely compromised.

**4. H-Bond Donors:** Ligand A (0) is preferable to Ligand B (4). Fewer H-bond donors generally improve membrane permeability.

**5. H-Bond Acceptors:** Both ligands have 4 H-bond acceptors, which is acceptable (<=10).

**6. QED:** Both ligands have similar QED values (Ligand A: 0.658, Ligand B: 0.594), both above the 0.5 threshold, indicating good drug-like properties.

**7. DILI:** Ligand A (62.931) has a slightly higher DILI risk than Ligand B (54.362), but both are below the concerning threshold of 60.

**8. BBB:** Ligand A (83.133) has a significantly better BBB penetration percentile than Ligand B (47.926). This is *critical* for a CNS target like DRD2.

**9. Caco-2 Permeability:** Ligand A (-5.004) and Ligand B (-4.858) both have negative values, suggesting poor Caco-2 permeability. This is a concern for oral bioavailability, but less critical for a CNS target where direct delivery or other routes may be considered.

**10. Aqueous Solubility:** Ligand A (-3.498) and Ligand B (-3.27) both have poor aqueous solubility. This could pose formulation challenges.

**11. hERG Inhibition:** Both ligands have low hERG inhibition risk (Ligand A: 0.803, Ligand B: 0.786).

**12. Microsomal Clearance:** Ligand B (61.02) has a higher microsomal clearance than Ligand A (43.414), suggesting faster metabolism and potentially lower exposure.

**13. In vitro Half-Life:** Ligand A (92.084) has a much longer in vitro half-life than Ligand B (26.951), which is a significant advantage.

**14. P-gp Efflux:** Both ligands have similar P-gp efflux liability (Ligand A: 0.771, Ligand B: 0.433).

**15. Binding Affinity:** Ligand A (-9.4 kcal/mol) has a significantly stronger binding affinity than Ligand B (-8.1 kcal/mol). This is a substantial difference (1.3 kcal/mol), and can often outweigh minor ADME drawbacks.

**Overall Assessment:**

Ligand A is the superior candidate. While it has a slightly higher logP and DILI risk, its significantly better BBB penetration, longer half-life, and *much* stronger binding affinity outweigh these drawbacks. The lower TPSA and fewer H-bond donors are also beneficial for CNS penetration. Ligand B's lower BBB and weaker affinity are major liabilities.

Output:
1
2025-04-17 08:51:29,470 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (336.351 Da) is slightly lower, which is generally favorable for permeability.

**TPSA:** Ligand A (91.73) is better than Ligand B (118.45). For CNS targets, TPSA should be <= 90, so Ligand A is closer to this threshold.

**logP:** Ligand A (2.649) is optimal (1-3), while Ligand B (-0.483) is below 1, potentially hindering permeation. This is a significant advantage for Ligand A.

**H-Bond Donors/Acceptors:** Ligand A (HBD=1, HBA=5) and Ligand B (HBD=2, HBA=7) both fall within acceptable ranges.

**QED:** Both ligands have reasonable QED values (A: 0.869, B: 0.74), indicating good drug-like properties.

**DILI:** Ligand A (90.733) has a higher DILI risk than Ligand B (64.056), which is a negative for Ligand A.

**BBB:** Both ligands have similar BBB penetration (A: 59.325, B: 58.434). Neither is above the desirable threshold of 70, but this is less critical if other properties are strong.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values, which is unusual and suggests poor permeability. However, these values are on a log scale and negative values are common.

**Aqueous Solubility:** Both ligands have negative solubility values, which is also unusual and suggests poor aqueous solubility.

**hERG Inhibition:** Ligand A (0.259) has a much lower hERG risk than Ligand B (0.047), a significant advantage.

**Microsomal Clearance:** Ligand A (-11.955) has a much *lower* (better) microsomal clearance than Ligand B (-28.981), indicating better metabolic stability.

**In vitro Half-Life:** Ligand A (41.209) has a longer half-life than Ligand B (-15.919), which is desirable.

**P-gp Efflux:** Ligand A (0.162) has lower P-gp efflux than Ligand B (0.007), which is favorable for CNS exposure.

**Binding Affinity:** Ligand A (-10.2 kcal/mol) has a significantly stronger binding affinity than Ligand B (-8.5 kcal/mol). This is a substantial advantage, potentially outweighing some of the ADME drawbacks.

**Overall Assessment:**

Ligand A is the stronger candidate. While it has a higher DILI risk, its superior logP, hERG inhibition profile, metabolic stability, half-life, P-gp efflux, and *especially* its significantly better binding affinity outweigh this concern. The TPSA is also closer to the ideal range for CNS penetration. Ligand B's low logP is a major drawback, and its weaker affinity is difficult to overcome.

Output:
1
2025-04-17 08:51:29,470 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (340.423 and 347.503 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (78.43) is higher than Ligand B (52.65). For CNS targets, TPSA should be <= 90, so both are acceptable, but B is better.

**logP:** Ligand A (3.284) is slightly higher than Ligand B (2.326), both within the optimal 1-3 range.

**H-Bond Donors:** Ligand A has 3 HBD, and Ligand B has 1. Both are within the acceptable limit of <=5.

**H-Bond Acceptors:** Both ligands have 3 HBA, well within the limit of <=10.

**QED:** Ligand B (0.802) has a better QED score than Ligand A (0.677), indicating a more drug-like profile.

**DILI:** Ligand B (7.794) has a significantly lower DILI risk than Ligand A (42.536). This is a major advantage for B.

**BBB:** Ligand B (87.941) has a much higher BBB penetration score than Ligand A (38.775). This is *crucial* for a CNS target like DRD2.

**Caco-2:** Ligand A (-5.103) and Ligand B (-4.714) have negative values, which is unusual and suggests poor permeability. However, the scale isn't specified, so it's difficult to interpret.

**Solubility:** Ligand A (-3.43) and Ligand B (-2.033) both have negative solubility values, indicating poor aqueous solubility.

**hERG:** Both ligands have very low hERG inhibition risk (0.396 and 0.37, respectively).

**Cl_mic:** Ligand B (35.963) has a slightly lower microsomal clearance than Ligand A (38.442), suggesting better metabolic stability.

**t1/2:** Ligand B (-7.101) has a longer in vitro half-life than Ligand A (-5.864).

**Pgp:** Ligand A (0.229) has a lower P-gp efflux liability than Ligand B (0.047), which is favorable for CNS penetration.

**Binding Affinity:** Ligand B (-8.5 kcal/mol) has a slightly better binding affinity than Ligand A (-9.8 kcal/mol). While A is better, the difference is small.

**Overall Assessment:**

Ligand B is the superior candidate. Its significantly higher BBB penetration (87.941 vs. 38.775), lower DILI risk (7.794 vs. 42.536), better QED (0.802 vs. 0.677), and longer half-life outweigh the slight advantage of Ligand A in Pgp efflux and binding affinity. The TPSA is also more favorable for CNS penetration. Although both have poor solubility and Caco-2 permeability, the CNS target prioritizes BBB penetration, which Ligand B excels at.

Output:
1
2025-04-17 08:51:29,471 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (368.478 and 383.587 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (97.11) is higher than Ligand B (63.05). For a CNS target like DRD2, TPSA should be <= 90. Ligand B is preferable here.

**3. logP:** Both ligands have good logP values (2.052 and 2.83), falling within the optimal 1-3 range.

**4. H-Bond Donors:** Ligand A has 3 HBD, while Ligand B has 1. Both are acceptable (<=5).

**5. H-Bond Acceptors:** Ligand A has 5 HBA, and Ligand B has 7. Both are within the acceptable limit of <=10.

**6. QED:** Both ligands have good QED scores (0.686 and 0.844), indicating good drug-like properties.

**7. DILI:** Ligand A (53.354) has a slightly higher DILI risk than Ligand B (42.846), but both are below the concerning threshold of 60.

**8. BBB:** Ligand A (76.58) has significantly better BBB penetration than Ligand B (52.036). This is a *critical* factor for a CNS target like DRD2.

**9. Caco-2 Permeability:** Both have negative Caco-2 values (-5.076 and -5.299). This is unusual and suggests poor permeability. However, the values are similar.

**10. Aqueous Solubility:** Both have negative solubility values (-3.36 and -3.556), indicating poor aqueous solubility. This is a concern, but can sometimes be overcome with formulation strategies.

**11. hERG Inhibition:** Ligand A (0.475) has a slightly higher hERG inhibition risk than Ligand B (0.14), but both are relatively low.

**12. Microsomal Clearance:** Ligand B (81.6) has a much higher microsomal clearance than Ligand A (21.368), indicating faster metabolism and lower metabolic stability.

**13. In vitro Half-Life:** Ligand A (19.367) has a longer in vitro half-life than Ligand B (0.821). This is a significant advantage.

**14. P-gp Efflux:** Ligand A (0.227) has lower P-gp efflux liability than Ligand B (0.085), which is favorable for CNS penetration.

**15. Binding Affinity:** Ligand A (-8.3 kcal/mol) has a *much* stronger binding affinity than Ligand B (-0.0 kcal/mol). This is the most important factor, and a difference of 8.3 kcal/mol is substantial.

**Overall Assessment:**

While Ligand B has a lower TPSA, the significantly stronger binding affinity of Ligand A (-8.3 vs -0.0 kcal/mol), coupled with better BBB penetration (76.58 vs 52.036), longer half-life, and lower P-gp efflux, outweighs its slightly higher TPSA and DILI risk. The affinity difference is so large that it is likely to overcome the other minor drawbacks.

Output:
1
2025-04-17 08:51:29,471 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (344.411 Da) is slightly lower, which can be favorable for permeability.

**TPSA:** Ligand A (71.78) is significantly better than Ligand B (115.9). For CNS targets, TPSA should be <=90. Ligand A comfortably meets this, while Ligand B exceeds it, potentially hindering BBB penetration.

**logP:** Ligand A (1.134) is within the optimal range (1-3). Ligand B (0.406) is a bit low, potentially impacting permeability.

**H-Bond Donors/Acceptors:** Ligand A (HBD=1, HBA=4) is preferable to Ligand B (HBD=3, HBA=7) as it has fewer hydrogen bond forming groups, which generally improves membrane permeability. Both are within acceptable limits.

**QED:** Both ligands have similar QED values (A: 0.786, B: 0.707), indicating good drug-likeness.

**DILI:** Ligand A (29.43) has a much lower DILI risk than Ligand B (70.686). This is a significant advantage for Ligand A.

**BBB:** Ligand A (53.936) has a better, though not ideal, BBB percentile than Ligand B (9.539). For a CNS target like DRD2, BBB penetration is crucial, and Ligand A is much more promising in this regard.

**Caco-2 Permeability:** Ligand A (-4.645) has a more positive Caco-2 value than Ligand B (-5.399), suggesting better intestinal absorption.

**Aqueous Solubility:** Ligand A (-1.208) has better solubility than Ligand B (-2.088).

**hERG Inhibition:** Both ligands have very low hERG inhibition risk (A: 0.161, B: 0.105).

**Microsomal Clearance:** Ligand A (-7.657) has a much lower (better) microsomal clearance than Ligand B (-12.489), indicating greater metabolic stability.

**In vitro Half-Life:** Ligand A (20.732 hours) has a better in vitro half-life than Ligand B (32.876 hours).

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (A: 0.042, B: 0.153).

**Binding Affinity:** Ligand A (-8.4 kcal/mol) has a significantly stronger binding affinity than Ligand B (-7.6 kcal/mol). This 0.8 kcal/mol difference is substantial and can outweigh some minor ADME drawbacks.

**Overall Assessment:**

Ligand A is superior to Ligand B across most critical parameters. It has a better TPSA, logP, DILI risk, BBB penetration, solubility, metabolic stability, half-life, and, most importantly, a significantly stronger binding affinity. While both have acceptable QED and low hERG/P-gp liabilities, the combination of favorable ADME properties and superior potency makes Ligand A the more promising drug candidate for targeting DRD2.

Output:
1
2025-04-17 08:51:29,471 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (344.323 Da and 359.373 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (114.82) is better than Ligand B (93.87), both are below the 90 A^2 threshold for CNS targets.

**logP:** Ligand A (1.921) is within the optimal 1-3 range. Ligand B (0.381) is slightly low, potentially hindering permeation.

**H-Bond Donors:** Ligand A (2) and Ligand B (1) are both acceptable, below the threshold of 5.

**H-Bond Acceptors:** Ligand A (7) and Ligand B (5) are both acceptable, below the threshold of 10.

**QED:** Both ligands have similar QED values (0.814 and 0.74), indicating good drug-likeness.

**DILI:** Ligand A (88.019) has a higher DILI risk than Ligand B (26.677). This is a significant drawback for Ligand A.

**BBB:** Ligand B (57.929) has a significantly better BBB penetration percentile than Ligand A (27.879). This is crucial for a CNS target like DRD2.

**Caco-2 Permeability:** Ligand A (-4.852) and Ligand B (-4.698) both have negative values, which is unusual and suggests poor permeability. However, the scale is not specified, so it's difficult to interpret.

**Aqueous Solubility:** Ligand A (-5.113) and Ligand B (-0.904) both have negative values, suggesting poor solubility. However, the scale is not specified, so it's difficult to interpret.

**hERG Inhibition:** Both ligands have similar, low hERG inhibition liability (0.416 and 0.501).

**Microsomal Clearance:** Ligand B (-8.018) has a negative value, suggesting very slow clearance and high metabolic stability, which is favorable. Ligand A (82.198) has a higher clearance.

**In vitro Half-Life:** Ligand B (-19.347) has a negative value, suggesting a very long half-life, which is favorable. Ligand A (-12.579) has a shorter half-life.

**P-gp Efflux:** Both ligands have similar P-gp efflux liability (0.071 and 0.031).

**Binding Affinity:** Ligand A (-7.8 kcal/mol) has a slightly better binding affinity than Ligand B (-6.3 kcal/mol). The difference is 1.5 kcal/mol, which is significant.

**Overall Assessment:**

While Ligand A has a slightly better binding affinity, Ligand B is the superior candidate. The significantly better BBB penetration, lower DILI risk, and improved metabolic stability (lower Cl_mic, longer t1/2) of Ligand B outweigh the small difference in binding affinity. For a CNS target like DRD2, BBB penetration is paramount, and Ligand B excels in this area. The lower DILI risk is also a major advantage.

Output:
1
2025-04-17 08:51:29,471 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (347.434 and 345.487 Da) fall comfortably within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (61.44) is significantly better than Ligand B (71.09). For CNS targets, we want TPSA <= 90, and ideally closer to 60. Ligand A is much closer to this ideal.

**3. logP:** Both ligands have acceptable logP values (1.746 and 2.793), falling within the 1-3 range. Ligand B is slightly higher, which *could* indicate a potential for off-target interactions, but isn't a major concern.

**4. H-Bond Donors:** Both have 2 HBD, which is within the acceptable limit of <=5.

**5. H-Bond Acceptors:** Both have 3 HBA, also within the acceptable limit of <=10.

**6. QED:** Both ligands have reasonable QED values (0.801 and 0.747), indicating good drug-like properties.

**7. DILI:** Ligand A (32.261) has a lower DILI risk than Ligand B (23.032), indicating a better safety profile. Lower is better.

**8. BBB:** This is a crucial parameter for a CNS target like DRD2. Ligand A (78.596) has a significantly higher BBB penetration percentile than Ligand B (58.821). A value >70 is desirable, and Ligand A is much closer to that threshold.

**9. Caco-2 Permeability:** Both have negative values, which is unusual and potentially problematic. However, the magnitude is similar.

**10. Aqueous Solubility:** Both have negative values, which is also unusual.

**11. hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.54 and 0.221), which is excellent.

**12. Microsomal Clearance:** Ligand A (-6.303) has *much* lower (better) microsomal clearance than Ligand B (52.349). This suggests greater metabolic stability for Ligand A.

**13. In vitro Half-Life:** Ligand A (15.598) has a slightly longer half-life than Ligand B (13.586).

**14. P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.087 and 0.035), which is favorable for CNS penetration.

**15. Binding Affinity:** Both ligands have identical binding affinities (-8.6 kcal/mol), which is excellent and strong.

**Overall Assessment:**

While both ligands have strong binding affinity, Ligand A is clearly superior based on its ADME-Tox profile, particularly its significantly better BBB penetration (78.6% vs 58.8%), lower DILI risk, and much lower microsomal clearance. The TPSA value is also more favorable for CNS penetration. The unusual negative values for Caco-2 and solubility are concerning for both, but the other advantages of Ligand A outweigh this.

Output:
1
2025-04-17 08:51:29,472 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (349.391 and 351.491 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (119.67) is better than Ligand B (69.72) as it is closer to the optimal range for CNS targets (<=90). Ligand B is excellent.

**logP:** Ligand A (-0.394) is suboptimal, being below the preferred 1-3 range. Ligand B (1.441) is within the optimal range. This is a significant advantage for Ligand B.

**H-Bond Donors/Acceptors:** Ligand A (2 HBD, 7 HBA) is acceptable. Ligand B (1 HBD, 4 HBA) is also acceptable and slightly better.

**QED:** Both ligands have good QED scores (0.643 and 0.753, respectively), indicating drug-like properties.

**DILI:** Ligand A (72.043) has a higher DILI risk than Ligand B (9.965). This is a substantial advantage for Ligand B.

**BBB:** Both ligands have reasonably good BBB penetration (63.901 and 68.282, respectively), but neither exceeds the desirable >70 threshold.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.255 and -4.974), which is unusual and suggests poor permeability.

**Aqueous Solubility:** Both ligands have negative solubility values (-1.978 and -1.264), which is also unusual and suggests poor solubility.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.106 and 0.247).

**Microsomal Clearance:** Ligand A (8.064) has significantly lower microsomal clearance than Ligand B (16.981), indicating better metabolic stability.

**In vitro Half-Life:** Ligand A (5.556) has a slightly longer half-life than Ligand B (-4.78).

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.004 and 0.014).

**Binding Affinity:** Ligand B (-7.3 kcal/mol) has a stronger binding affinity than Ligand A (-6.5 kcal/mol). The difference of 0.8 kcal/mol is significant, exceeding the 1.5 kcal/mol threshold where affinity can outweigh other drawbacks.

**Overall Assessment:**

Ligand B is the better candidate. While both have issues with Caco-2 and solubility, Ligand B has a superior logP, a much lower DILI risk, and significantly better binding affinity. The better logP and lower DILI risk are crucial for a CNS-targeting drug. The stronger binding affinity further solidifies its potential. Ligand A's lower clearance and slightly longer half-life are positives, but are outweighed by the other factors.

Output:
1
2025-04-17 08:51:29,472 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (378.313 and 369.843 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (78.43) is excellent for CNS penetration, well below the 90 A^2 threshold. Ligand B (37.61) is even better.

**logP:** Ligand A (2.065) is within the optimal 1-3 range. Ligand B (4.239) is slightly above, which could potentially lead to solubility issues or off-target interactions, but is still acceptable.

**H-Bond Donors & Acceptors:** Ligand A has 3 HBD and 3 HBA, which is good. Ligand B has 0 HBD and 3 HBA, also acceptable.

**QED:** Ligand A (0.447) is a bit low, indicating a less drug-like profile. Ligand B (0.714) is much better, exceeding the 0.5 threshold.

**DILI:** Both ligands have low DILI risk (29.003 and 31.601, respectively), which is positive.

**BBB:** Ligand A (65.452) is decent, but not ideal for a CNS target. Ligand B (96.782) is *excellent*, exceeding the >70% threshold. This is a significant advantage.

**Caco-2 Permeability:** Ligand A (-5.052) and Ligand B (-4.44) are both negative, indicating poor permeability. This is a concern for both.

**Aqueous Solubility:** Both ligands have negative solubility values (-2.881 and -4.217), indicating very poor aqueous solubility. This is a major drawback for both.

**hERG Inhibition:** Both ligands show low hERG inhibition risk (0.551 and 0.848, respectively).

**Microsomal Clearance:** Ligand A (23.262) has lower clearance than Ligand B (51.714), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (0.376) has a very short half-life. Ligand B (4.421) is better, but still relatively short.

**P-gp Efflux:** Ligand A (0.057) shows very low P-gp efflux, which is highly desirable for CNS penetration. Ligand B (0.589) is higher, indicating more efflux.

**Binding Affinity:** Ligand B (-7.7 kcal/mol) has a slightly better binding affinity than Ligand A (-8.1 kcal/mol), although the difference is small.

**Overall Assessment:**

Ligand B is the stronger candidate. While both have poor solubility and Caco-2 permeability, Ligand B's significantly higher BBB penetration (96.8% vs 65.5%) and better QED score are crucial for a CNS-targeted GPCR. The slightly better affinity of Ligand B is a bonus. Ligand A's lower P-gp efflux is good, but the BBB score is the deciding factor here. The solubility and permeability issues would need to be addressed through formulation strategies or further chemical modifications, but the starting point is better with Ligand B.

Output:
1
2025-04-17 08:51:29,472 - INFO - Batch 484 complete. Total preferences: 7744
2025-04-17 08:51:29,472 - INFO - Processing batch 485/512...
2025-04-17 08:52:11,638 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 drug candidates, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (344.379 and 349.431 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (127.93) is slightly above the preferred <90 for CNS targets, but still reasonable. Ligand B (100.55) is better, falling comfortably below 140 and closer to the CNS target.

**logP:** Ligand A (0.02) is very low, potentially hindering membrane permeability. Ligand B (0.88) is better, within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A has 4 HBD and 6 HBA, acceptable values. Ligand B has 3 HBD and 5 HBA, also acceptable.

**QED:** Both ligands have reasonable QED scores (0.605 and 0.545), suggesting generally drug-like properties.

**DILI:** Ligand A has a high DILI risk (80.651), which is concerning. Ligand B has a much lower DILI risk (24.428), a significant advantage.

**BBB:** Ligand A has a BBB penetration of 43.699, which is below the desirable >70 for CNS targets. Ligand B has a BBB penetration of 37.069, also below the desired threshold, but not as low as Ligand A.

**Caco-2 Permeability:** Ligand A has a negative Caco-2 value (-5.664), indicating poor permeability. Ligand B also has a negative Caco-2 value (-4.889), indicating poor permeability.

**Aqueous Solubility:** Both ligands have negative solubility values (-2.389 and -1.769), indicating poor aqueous solubility.

**hERG Inhibition:** Ligand A has a very low hERG risk (0.064), which is excellent. Ligand B has a slightly higher hERG risk (0.266), but still relatively low.

**Microsomal Clearance:** Ligand A has a very low microsomal clearance (-7.093), suggesting high metabolic stability. Ligand B has a significantly higher clearance (21.168), indicating faster metabolism.

**In vitro Half-Life:** Ligand A has a good in vitro half-life (9.262 hours). Ligand B has a negative in vitro half-life (-15.791), which is not possible and likely indicates an issue with the data or prediction method.

**P-gp Efflux:** Ligand A has very low P-gp efflux (0.004), which is favorable for CNS penetration. Ligand B has slightly higher P-gp efflux (0.017), but still relatively low.

**Binding Affinity:** Ligand A has a better binding affinity (-8.8 kcal/mol) than Ligand B (-7.9 kcal/mol), a difference of 0.9 kcal/mol.

**Overall Assessment:**

Despite Ligand A's superior binding affinity, its significantly higher DILI risk, lower BBB penetration, and poor Caco-2 permeability are major drawbacks. The very low logP is also a concern. Ligand B, while having a slightly weaker affinity, presents a much better ADME profile with a lower DILI risk and better logP. The negative half-life for Ligand B is a red flag, but the other properties are more favorable. Given the GPCR-specific emphasis on BBB penetration and the need to minimize toxicity, Ligand B is the more promising candidate, assuming the half-life issue can be resolved.

Output:
1
2025-04-17 08:52:11,639 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B based on the provided guidelines, prioritizing GPCR-specific properties (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (348.531 and 342.483 Da) fall within the ideal range of 200-500 Da.

**TPSA:** Both ligands have a TPSA of 49.41, which is excellent for CNS penetration, being well below the 90 A^2 threshold.

**logP:** Both ligands have logP values within the optimal range (3.914 and 3.029). Ligand B is slightly better here, being closer to the center of the 1-3 range.

**H-Bond Donors/Acceptors:** Both have 1 HBD and 2 HBA, which is acceptable.

**QED:** Ligand B (0.854) has a better QED score than Ligand A (0.609), indicating a more drug-like profile.

**DILI:** Ligand B (40.054) has a significantly lower DILI risk than Ligand A (16.906), which is a major advantage.

**BBB:** Ligand A (85.072) has a substantially better BBB penetration percentile than Ligand B (69.523). This is critical for a CNS target like DRD2.

**Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and suggests poor permeability. However, the scale is not specified, so it's hard to interpret.

**Aqueous Solubility:** Both have negative solubility values, indicating poor solubility. This is a concern, but can potentially be addressed with formulation strategies.

**hERG Inhibition:** Ligand A (0.732) has a slightly higher hERG inhibition liability than Ligand B (0.294), making Ligand B safer from a cardiotoxicity perspective.

**Microsomal Clearance:** Ligand A (99.104) has a very high microsomal clearance, suggesting rapid metabolism. Ligand B (51.015) has a better, lower clearance.

**In vitro Half-Life:** Ligand A (21.89) has a longer half-life than Ligand B (5.24), which is generally desirable.

**P-gp Efflux:** Ligand A (0.689) has lower P-gp efflux liability than Ligand B (0.408), which is favorable for CNS exposure.

**Binding Affinity:** Ligand B (-9.0 kcal/mol) has a significantly stronger binding affinity than Ligand A (-7.6 kcal/mol). This is a substantial advantage, potentially outweighing some of the ADME drawbacks.

**Overall Assessment:**

Ligand B has a better safety profile (lower DILI, lower hERG), better QED, and significantly stronger binding affinity. Ligand A's main advantage is BBB penetration and a longer half-life, and lower P-gp efflux. However, the substantial difference in binding affinity (-9.0 vs -7.6 kcal/mol) and the better safety profile of Ligand B are more important for a GPCR target, especially considering the TPSA is already excellent for CNS penetration. The lower clearance of Ligand B is also a significant benefit. While both have solubility and permeability concerns, the superior potency and safety of Ligand B make it the more promising candidate.

Output:
1
2025-04-17 08:52:11,639 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (374.497 and 387.571 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (40.62) is significantly better than Ligand B (82.53). For CNS targets, TPSA should be <= 90, and ideally lower. Ligand A is well within this range, while Ligand B is approaching the upper limit and less favorable.

**logP:** Both ligands have good logP values (3.014 and 2.417), falling within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A (0 HBD, 3 HBA) is better than Ligand B (2 HBD, 6 HBA). Lower HBD/HBA generally improves permeability.

**QED:** Both ligands have similar QED values (0.718 and 0.699), indicating good drug-likeness.

**DILI:** Ligand A (18.612) has a much lower DILI risk than Ligand B (59.752). This is a significant advantage for Ligand A.

**BBB:** Ligand A (94.378) has excellent BBB penetration potential, exceeding the desirable >70 threshold. Ligand B (47.189) is considerably lower, indicating poor CNS exposure. This is a critical difference for a CNS target like DRD2.

**Caco-2 Permeability:** Ligand A (-4.671) and Ligand B (-5.315) both have negative Caco-2 values, which is unusual and suggests poor permeability. However, the scale isn't specified, so it's hard to interpret.

**Aqueous Solubility:** Both ligands have poor aqueous solubility (-2.861 and -3.901). This could pose formulation challenges.

**hERG:** Both ligands have similar, low hERG risk (0.515 and 0.669).

**Microsomal Clearance:** Ligand A (38.156) has lower microsomal clearance than Ligand B (65.42), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (1 hour) has a shorter half-life than Ligand B (-0.649 hours - this is unusual and may be an error).

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.1 and 0.161), which is favorable for CNS penetration.

**Binding Affinity:** Both ligands have very similar and strong binding affinities (-8.0 and -8.1 kcal/mol). The difference is negligible.

**Conclusion:**

Considering all factors, **Ligand A** is the more promising drug candidate. Its superior BBB penetration (94.378 vs 47.189), lower DILI risk (18.612 vs 59.752), lower microsomal clearance, and better TPSA outweigh the slightly shorter half-life and similar binding affinity. The GPCR-specific priorities heavily favor Ligand A due to its excellent CNS penetration potential.

Output:
1
2025-04-17 08:52:11,639 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (344.415 and 351.447 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (76.46) is significantly better than Ligand B (87.74). For CNS targets, we want TPSA <= 90, and A is comfortably within that, while B is approaching the upper limit.

**logP:** Ligand A (1.628) is within the optimal 1-3 range. Ligand B (0.599) is slightly below 1, which *could* indicate permeability issues, though not drastically.

**H-Bond Donors/Acceptors:** Ligand A has 1 HBD and 6 HBA, while Ligand B has 2 HBD and 4 HBA. Both are within acceptable limits (<=5 HBD, <=10 HBA).

**QED:** Ligand A (0.773) has a better QED score than Ligand B (0.596), indicating a more drug-like profile.

**DILI:** Ligand A (59.984) has a higher DILI risk than Ligand B (21.791). This is a significant advantage for Ligand B.

**BBB:** Ligand A (70.997) has a slightly better BBB penetration percentile than Ligand B (61.535). Both are reasonably good, but >70 is desirable for CNS targets, and A is closer.

**Caco-2 Permeability:** Both have negative Caco-2 values which is unusual and suggests poor permeability.

**Aqueous Solubility:** Both ligands have negative solubility values, which is also unusual and suggests poor solubility.

**hERG:** Ligand A (0.416) has a slightly higher hERG inhibition liability than Ligand B (0.045), meaning B is safer in terms of cardiotoxicity.

**Microsomal Clearance:** Ligand A (67.943) has a higher microsomal clearance than Ligand B (4.29). Lower clearance is preferred for better metabolic stability, so Ligand B is better here.

**In vitro Half-Life:** Ligand A (5.821) has a longer half-life than Ligand B (-0.204). This is a positive for Ligand A.

**P-gp Efflux:** Ligand A (0.061) has lower P-gp efflux liability than Ligand B (0.01). Lower P-gp efflux is desirable for CNS exposure, making Ligand A slightly better.

**Binding Affinity:** Ligand B (-7.2 kcal/mol) has a significantly stronger binding affinity than Ligand A (-8.0 kcal/mol). This is a crucial advantage, as a >1.5 kcal/mol difference can outweigh other drawbacks.

**Overall Assessment:**

Ligand B has a substantially better binding affinity and a much lower DILI risk. While Ligand A has slightly better BBB penetration and in vitro half-life, the affinity difference and lower toxicity of Ligand B are more important for a CNS GPCR target like DRD2. The slightly lower logP of Ligand B is a minor concern, but the strong affinity could compensate.

Output:
1
2025-04-17 08:52:11,639 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B based on the provided guidelines, prioritizing GPCR-specific properties (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (352.475 and 357.485 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (89.87) is excellent for CNS penetration, being under the 90 A^2 threshold. Ligand B (29.54) is even better, significantly below the threshold.

**logP:** Ligand A (1.218) is within the optimal range (1-3). Ligand B (4.502) is slightly above, potentially leading to solubility issues and off-target effects, but not drastically so.

**H-Bond Donors/Acceptors:** Ligand A has 3 HBD and 4 HBA, both acceptable. Ligand B has 0 HBD and 2 HBA, also acceptable.

**QED:** Both ligands have similar QED values (0.666 and 0.671), indicating good drug-likeness.

**DILI:** Ligand A (19.504) has a lower DILI risk than Ligand B (15.238), which is preferable.

**BBB:** This is a crucial parameter for CNS targets. Ligand A has a BBB percentile of 42.148, which is not ideal (below 70). Ligand B excels with a BBB percentile of 95.696, making it highly likely to cross the blood-brain barrier.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.82 and -4.447), which is unusual and suggests poor permeability. However, these values are on a log scale, and the negative values may be artifacts of the modeling or indicate very low permeability.

**Aqueous Solubility:** Both ligands have negative solubility values (-2.201 and -4.147), indicating poor aqueous solubility. This is a concern, but can sometimes be overcome with formulation strategies.

**hERG Inhibition:** Ligand A (0.149) has a slightly lower hERG risk than Ligand B (0.828), which is preferable.

**Microsomal Clearance:** Ligand B (55.653) has a lower microsomal clearance than Ligand A (22.778), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand B (16.887) has a significantly longer in vitro half-life than Ligand A (2.779), which is a major advantage.

**P-gp Efflux:** Ligand A (0.028) shows very low P-gp efflux, which is good. Ligand B (0.465) shows slightly higher P-gp efflux, which could limit CNS exposure.

**Binding Affinity:** Ligand B (-8.0) has a significantly stronger binding affinity than Ligand A (0.0). This is a substantial advantage, potentially outweighing some of the ADME drawbacks.

**Overall Assessment:**

Ligand B is the stronger candidate. Its exceptional BBB penetration, significantly stronger binding affinity, and improved metabolic stability (lower Cl_mic and longer t1/2) are key advantages for a CNS-targeting GPCR. While its logP is slightly elevated and solubility is low, the superior affinity and BBB penetration are likely to be more critical for efficacy. Ligand A's lower DILI and P-gp efflux are positives, but are overshadowed by its poor BBB penetration and weak binding affinity.



Output:
1
2025-04-17 08:52:11,639 - INFO - Reasoning:

Let's analyze Ligand A and Ligand B for their potential as DRD2 drug candidates, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (371.463 and 375.519 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (96.77) is better than Ligand B (58.22) as it is closer to the optimal range for CNS targets (<=90). Ligand B is quite low, which *could* indicate poor interactions.

**3. logP:** Ligand B (4.391) is higher than the optimal range (1-3), potentially leading to solubility issues and off-target effects. Ligand A (0.251) is quite low, which could hinder permeation.

**4. H-Bond Donors:** Both ligands have 1 HBD, which is within the acceptable limit of <=5.

**5. H-Bond Acceptors:** Ligand A has 6 HBAs, and Ligand B has 5, both within the acceptable limit of <=10.

**6. QED:** Ligand A (0.818) has a better QED score than Ligand B (0.666), indicating a more drug-like profile.

**7. DILI:** Both ligands have relatively high DILI risk (65.568 and 75.998), but Ligand A is slightly better.

**8. BBB:** Ligand A (75.921) has significantly better BBB penetration potential than Ligand B (44.785). This is a crucial factor for a CNS target like DRD2.

**9. Caco-2 Permeability:** Ligand A (-4.74) has a worse Caco-2 permeability than Ligand B (-5.309). Both are negative, indicating poor permeability.

**10. Aqueous Solubility:** Ligand A (-2.081) has better aqueous solubility than Ligand B (-4.482).

**11. hERG Inhibition:** Both ligands have low hERG inhibition risk (0.127 and 0.568).

**12. Microsomal Clearance:** Ligand B (113.255) has significantly higher microsomal clearance than Ligand A (10.893), suggesting lower metabolic stability.

**13. In vitro Half-Life:** Ligand A (-38.65) has a much longer in vitro half-life than Ligand B (-15.561).

**14. P-gp Efflux:** Ligand A (0.014) has significantly lower P-gp efflux liability than Ligand B (0.488), which is favorable for CNS exposure.

**15. Binding Affinity:** Ligand B (-7.7) has a slightly better binding affinity than Ligand A (-8.7). However, the difference is less than 1.5 kcal/mol, and other factors are more critical.

**Overall Assessment:**

Ligand A is the more promising candidate. While Ligand B has slightly better binding affinity, Ligand A excels in crucial ADME properties for a CNS-targeting GPCR: significantly better BBB penetration, lower P-gp efflux, longer half-life, lower clearance, and better solubility. The lower logP of Ligand A is a concern, but the substantial advantages in CNS penetration and metabolic stability outweigh this drawback. The TPSA is also better for Ligand A.



Output:
0
2025-04-17 08:52:11,640 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B based on the provided guidelines, prioritizing GPCR-specific properties (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (346.471 and 345.399 Da) fall within the ideal range of 200-500 Da.

**TPSA:** Ligand A (71.34) is excellent for CNS penetration, being well below 90. Ligand B (86.78) is still reasonable but less optimal.

**logP:** Ligand A (3.21) is within the optimal range (1-3). Ligand B (1.581) is at the lower end, potentially impacting permeability.

**H-Bond Donors/Acceptors:** Ligand A (2 HBD, 3 HBA) and Ligand B (0 HBD, 5 HBA) both have acceptable counts, within the guidelines.

**QED:** Both ligands have good QED scores (0.796 and 0.83), indicating drug-like properties.

**DILI:** Ligand A (43.195) has a slightly higher DILI risk than Ligand B (37.03), but both are below the concerning threshold of 60.

**BBB:** Both ligands show excellent BBB penetration (Ligand A: 70.299, Ligand B: 78.907). Ligand B is slightly better.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.538 and -4.256). This is unusual and suggests a potential issue with the data or a very poor permeability. However, since both are similarly poor, it doesn't differentiate them.

**Aqueous Solubility:** Both ligands have negative solubility values (-3.972 and -2.065). This is also unusual and suggests a potential issue with the data.

**hERG:** Both ligands have low hERG inhibition risk (0.312 and 0.521).

**Microsomal Clearance:** Ligand A (49.323) has a higher clearance than Ligand B (-0.132), suggesting lower metabolic stability.

**In vitro Half-Life:** Ligand A (62.362) has a longer half-life than Ligand B (34.184).

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.311 and 0.174), which is favorable for CNS penetration.

**Binding Affinity:** Both ligands have very strong binding affinity (-8.5 and -8.0 kcal/mol). The difference of 0.5 kcal/mol is not substantial enough to be a deciding factor given the other considerations.

**Conclusion:**

Considering the GPCR-specific priorities, Ligand B is slightly more favorable. It has a better BBB score, a more favorable logP, and significantly better metabolic stability (lower Cl_mic, longer half-life). While Ligand A has a slightly lower DILI risk, the differences are small. The negative Caco-2 and solubility values are concerning for both, but since they are similar, they don't differentiate the ligands.

Output:
1
2025-04-17 08:52:11,640 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B based on the provided guidelines, prioritizing GPCR-specific properties (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (365.861 Da) is slightly higher than Ligand B (349.391 Da), but both are acceptable.

**TPSA:** Ligand A (61.88) is significantly better than Ligand B (127.32). For CNS targets, TPSA should be <= 90, and Ligand A is comfortably within this range, while Ligand B exceeds it. This is a significant advantage for Ligand A.

**logP:** Ligand A (2.371) is optimal (1-3), while Ligand B (-0.464) is below 1, potentially hindering permeation. This favors Ligand A.

**H-Bond Donors/Acceptors:** Ligand A (HBD=1, HBA=3) is better than Ligand B (HBD=3, HBA=5) in terms of balancing solubility and permeability.

**QED:** Both ligands have reasonable QED values (A: 0.894, B: 0.52), indicating good drug-like properties. Ligand A is superior.

**DILI:** Ligand A (33.152) has a lower DILI risk than Ligand B (41.024), indicating a safer profile.

**BBB:** Ligand A (77.162) has a significantly higher BBB penetration percentile than Ligand B (31.834). This is *critical* for a CNS target like DRD2, giving a substantial advantage to Ligand A.

**Caco-2 Permeability:** Ligand A (-4.523) and Ligand B (-5.449) both have negative values, which is unusual. Assuming these are logP-like scales, lower values indicate poorer permeability. Ligand A is slightly better.

**Aqueous Solubility:** Ligand A (-2.627) is slightly better than Ligand B (-1.625), but both are quite poor, potentially causing formulation challenges.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (A: 0.581, B: 0.351).

**Microsomal Clearance:** Ligand A (-12.153) has a much lower (better) microsomal clearance than Ligand B (0.735), suggesting greater metabolic stability.

**In vitro Half-Life:** Ligand A (2.39 hours) is better than Ligand B (-5.889 hours).

**P-gp Efflux:** Ligand A (0.082) has lower P-gp efflux liability than Ligand B (0.018), which is favorable for CNS exposure.

**Binding Affinity:** Ligand A (-7.5 kcal/mol) has a slightly better binding affinity than Ligand B (-7.3 kcal/mol), though the difference is small.

**Overall Assessment:**

Ligand A consistently outperforms Ligand B across most critical parameters, especially those prioritized for GPCRs targeting the CNS. Its superior TPSA, logP, BBB penetration, metabolic stability, and slightly better affinity make it a much more promising drug candidate. While solubility is a concern for both, the other advantages of Ligand A outweigh this drawback.

Output:
1
2025-04-17 08:52:11,640 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (345.359 and 349.387 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Both ligands (110.45 and 110.53) are slightly above the optimal <90 for CNS targets, but still reasonably acceptable, especially considering the other parameters.

**3. logP:** Ligand A (0.573) is quite low, potentially hindering permeability. Ligand B (0.861) is also on the lower side, but better than A. Optimal is 1-3.

**4. H-Bond Donors:** Ligand A (1) is good. Ligand B (2) is also acceptable.

**5. H-Bond Acceptors:** Ligand A (7) is good. Ligand B (6) is also good.

**6. QED:** Ligand A (0.781) is excellent, indicating good drug-like properties. Ligand B (0.429) is lower, suggesting a less ideal overall profile.

**7. DILI:** Ligand A (70.143) is acceptable, indicating moderate risk. Ligand B (43.505) is better, with a lower DILI risk.

**8. BBB:** This is critical for a CNS target like DRD2. Ligand A (46.491) is concerningly low, suggesting poor brain penetration. Ligand B (62.311) is better, but still not ideal (aim for >70).

**9. Caco-2 Permeability:** Both ligands have negative values (-5.37 and -4.929), which is unusual and suggests poor permeability. This is a red flag for both.

**10. Aqueous Solubility:** Both ligands have negative values (-0.631 and -2.149), indicating poor aqueous solubility. This is also a concern.

**11. hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.1 and 0.036), which is excellent.

**12. Microsomal Clearance:** Ligand A (-5.846) suggests very low clearance and high metabolic stability, which is good. Ligand B (79.265) indicates high clearance and poor metabolic stability, a significant drawback.

**13. In vitro Half-Life:** Ligand A (3.909) is a moderate half-life. Ligand B (-11.636) is a very short half-life, indicating rapid metabolism.

**14. P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.003 and 0.057), which is favorable for CNS penetration.

**15. Binding Affinity:** Both ligands have the same binding affinity (-8.1 kcal/mol), which is excellent and strong.

**Overall Assessment:**

Despite the equal binding affinity, Ligand A is significantly hampered by its poor BBB penetration (46.491) and low logP (0.573). While it has a better QED and metabolic stability, the inability to cross the blood-brain barrier is a major obstacle for a CNS drug. Ligand B has a better BBB score (62.311) and logP (0.861), but suffers from poor metabolic stability (high clearance, short half-life) and a lower QED.

Considering the GPCR-specific priorities, BBB is paramount for DRD2. While neither ligand is ideal, Ligand B's slightly better BBB penetration, combined with acceptable P-gp efflux, makes it marginally more promising, *assuming* that its metabolic instability can be addressed through structural modifications. The poor Caco-2 and solubility of both are concerning and would need to be improved.

Output:
1
2025-04-17 08:52:11,640 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (351.407 and 344.415 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (122.31) is slightly above the optimal <90 for CNS targets, but still reasonable. Ligand B (87.32) is excellent, well below 90.

**logP:** Both ligands have good logP values (1.308 and 1.566), falling within the 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A has 3 HBD and 6 HBA, both acceptable. Ligand B has 2 HBD and 4 HBA, also acceptable.

**QED:** Both ligands have good QED scores (0.706 and 0.881), indicating good drug-likeness.

**DILI:** Ligand A (72.47) has a slightly higher DILI risk than Ligand B (56.805), but both are below the concerning threshold of 60.

**BBB:** Ligand A (55.215) has a moderate BBB penetration, while Ligand B (49.515) is even lower. Neither are ideal (>70) for a CNS target like DRD2, but this is less critical if other properties are strong.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.597 and -4.906). This is unusual and suggests poor permeability. However, these values are on a log scale, and negative values are common for compounds with very low permeability.

**Aqueous Solubility:** Both ligands have negative solubility values (-2.982 and -2.386), indicating poor aqueous solubility. This could be a formulation challenge.

**hERG:** Ligand A (0.052) has a very low hERG risk, which is excellent. Ligand B (0.611) has a slightly elevated, but still relatively low, hERG risk.

**Microsomal Clearance:** Ligand A (37.987) has a higher microsomal clearance than Ligand B (14.276), suggesting lower metabolic stability.

**In vitro Half-Life:** Ligand B (-7.673) has a significantly longer predicted in vitro half-life than Ligand A (-0.61), which is a major advantage.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.005 and 0.047), which is favorable for CNS penetration.

**Binding Affinity:** Ligand B (-9.1 kcal/mol) has a substantially stronger binding affinity than Ligand A (-8.2 kcal/mol). This 0.9 kcal/mol difference is significant and could outweigh some of the ADME drawbacks.

**Overall Assessment:**

Ligand B is the more promising candidate. While both have poor predicted permeability and solubility, Ligand B's significantly stronger binding affinity (-9.1 vs -8.2 kcal/mol) and longer half-life are crucial advantages for a GPCR target. The lower DILI risk and slightly better hERG profile also contribute to its favorability. The BBB values for both are suboptimal, but the strong binding affinity of Ligand B suggests it might still achieve sufficient brain exposure.

Output:
1
2025-04-17 08:52:11,641 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B based on the provided guidelines, prioritizing GPCR-specific properties (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (346.427 Da) is slightly lower, which could be advantageous for permeability.

**TPSA:** Ligand A (62.99) is significantly better than Ligand B (102.3). For CNS targets, TPSA should be <=90, and A is comfortably within this range, while B is above. This is a significant advantage for A.

**logP:** Both ligands have acceptable logP values (A: 1.698, B: 0.867), falling within the 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A (HBD=0, HBA=4) is better than Ligand B (HBD=2, HBA=5) in terms of minimizing potential permeability issues.

**QED:** Both ligands have good QED scores (A: 0.836, B: 0.753), indicating good drug-like properties.

**DILI:** Ligand A (14.618) has a much lower DILI risk than Ligand B (59.558). This is a substantial advantage for A.

**BBB:** Ligand A (53.044) is better than Ligand B (49.864), although neither are above the desirable 70% threshold for CNS targets. However, given the context of DRD2, a higher BBB is crucial, making A preferable.

**Caco-2 Permeability:** Ligand A (-4.464) is better than Ligand B (-5.388), indicating better intestinal absorption.

**Aqueous Solubility:** Ligand A (-1.62) is better than Ligand B (-2.99), indicating better solubility.

**hERG Inhibition:** Ligand A (0.173) has a lower hERG risk than Ligand B (0.447), which is preferable.

**Microsomal Clearance:** Ligand B (-21.129) has significantly lower microsomal clearance than Ligand A (30.388), suggesting better metabolic stability. This is a strong point in favor of B.

**In vitro Half-Life:** Ligand A (28.482) has a longer half-life than Ligand B (3.697), which is generally desirable.

**P-gp Efflux:** Ligand A (0.018) has much lower P-gp efflux than Ligand B (0.059), which is crucial for CNS penetration.

**Binding Affinity:** Ligand B (-8.6) has a slightly better binding affinity than Ligand A (-8.1), but the difference is less than 1.5 kcal/mol.

**Overall Assessment:**

Ligand A consistently outperforms Ligand B across most critical ADME properties, especially TPSA, DILI, BBB, solubility, hERG, and P-gp efflux. While Ligand B has better metabolic stability (lower Cl_mic) and slightly better binding affinity, the advantages of Ligand A in terms of CNS penetration and safety are more important for a DRD2 target. The slightly better affinity of B is unlikely to overcome the significant ADME deficiencies.

Output:
0
2025-04-17 08:52:11,641 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (418.367 Da) is slightly higher, but acceptable. Ligand B (343.435 Da) is also good.

**TPSA:** Ligand A (46.61) is excellent for CNS penetration, well below the 90 A^2 threshold. Ligand B (80.99) is higher, but still potentially acceptable, though less ideal for CNS targets.

**logP:** Ligand A (4.755) is a bit high, potentially leading to solubility issues and off-target interactions. Ligand B (1.71) is within the optimal range (1-3).

**H-Bond Donors/Acceptors:** Ligand A (0 HBD, 4 HBA) is favorable. Ligand B (1 HBD, 8 HBA) is also reasonable, though slightly higher in HBA count.

**QED:** Both ligands have good QED scores (Ligand A: 0.636, Ligand B: 0.828), indicating drug-like properties. Ligand B is slightly better here.

**DILI:** Both ligands have similar DILI risk (Ligand A: 67.739, Ligand B: 65.064), and are within an acceptable range (<40 is good, >60 is high risk).

**BBB:** Ligand A (52.617) is moderate, while Ligand B (75.107) is much better, exceeding the 70% threshold desirable for CNS targets. This is a significant advantage for Ligand B.

**Caco-2 Permeability:** Both have negative values (-4.801 and -5.033), which is unusual and suggests poor permeability. This is a concern for both.

**Aqueous Solubility:** Both ligands have very poor aqueous solubility (-6.494 and -2.595). This is a major drawback for both.

**hERG Inhibition:** Ligand A (0.644) has a slightly higher hERG risk than Ligand B (0.4).

**Microsomal Clearance:** Ligand A (93.182) has higher clearance than Ligand B (57.966), suggesting lower metabolic stability.

**In vitro Half-Life:** Ligand B (9.296 hours) has a significantly longer half-life than Ligand A (28.305 hours). This is a substantial advantage for Ligand B.

**P-gp Efflux:** Ligand A (0.65) shows moderate P-gp efflux, while Ligand B (0.019) shows very low efflux. Lower P-gp efflux is preferred, especially for CNS targets, giving Ligand B an advantage.

**Binding Affinity:** Ligand A (-8.0 kcal/mol) has a significantly stronger binding affinity than Ligand B (-0.0 kcal/mol). This is a crucial factor, and a >1.5 kcal/mol advantage can outweigh other drawbacks.

**Overall Assessment:**

While Ligand A boasts a much stronger binding affinity, its higher logP, lower BBB penetration, higher microsomal clearance, and moderate P-gp efflux are significant concerns. Ligand B, despite its weaker affinity, has a much better profile regarding CNS penetration (BBB, P-gp, TPSA), metabolic stability, and half-life. The difference in affinity is substantial (-8.0 vs -0.0), but the ADME properties of Ligand B are far more favorable for a CNS-targeting drug. Given the importance of BBB penetration and metabolic stability for CNS drugs, and the fact that the affinity difference is so large, I believe Ligand A is the better candidate.

Output:
1
2025-04-17 08:52:11,641 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (352.316 and 344.459 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (76.02) is excellent, well below the 90 A^2 threshold for CNS targets. Ligand B (83.98) is still reasonable but less optimal.

**3. logP:** Both ligands (2.095 and 2.333) are within the optimal 1-3 range.

**4. H-Bond Donors:** Both have 2 HBD, which is acceptable.

**5. H-Bond Acceptors:** Both have 4 HBA, which is acceptable.

**6. QED:** Ligand A (0.885) has a better QED score than Ligand B (0.532), indicating higher drug-likeness.

**7. DILI:** Ligand A (74.952) has a higher DILI risk than Ligand B (43.001), which is a negative for Ligand A.

**8. BBB:** Ligand A (83.482) has significantly better BBB penetration than Ligand B (56.378). This is a *critical* advantage for a CNS target like DRD2.

**9. Caco-2 Permeability:** Ligand A (-4.896) has lower Caco-2 permeability than Ligand B (-5.187), but both are poor.

**10. Aqueous Solubility:** Ligand A (-3.799) has slightly better solubility than Ligand B (-2.233), but both are poor.

**11. hERG Inhibition:** Ligand A (0.462) has a slightly better hERG profile than Ligand B (0.153).

**12. Microsomal Clearance:** Ligand B (47.641) has higher microsomal clearance than Ligand A (23.275), meaning Ligand A is more metabolically stable.

**13. In vitro Half-Life:** Ligand A (44.002) has a longer in vitro half-life than Ligand B (-4.997), which is a positive.

**14. P-gp Efflux:** Ligand A (0.442) has lower P-gp efflux than Ligand B (0.095), meaning better CNS exposure.

**15. Binding Affinity:** Ligand B (-8.0) has a significantly better binding affinity than Ligand A (-9.6). This is a substantial advantage.

**Overall Assessment:**

While Ligand A has better BBB penetration, P-gp efflux, metabolic stability, and half-life, the significantly stronger binding affinity of Ligand B (-8.0 vs -9.6 kcal/mol) is a major advantage that likely outweighs the drawbacks. The difference in binding affinity is greater than the 1.5 kcal/mol threshold where it can compensate for other issues. The DILI risk for Ligand B is also considerably lower. Although both have poor solubility and Caco-2 permeability, these can potentially be addressed with formulation strategies. Given the GPCR target and the importance of CNS penetration and potency, Ligand B is the more promising candidate.

Output:
1
2025-04-17 08:52:11,641 - INFO - Reasoning:

Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (349.381 and 353.419 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (58.36) is excellent, well below the 90 A^2 threshold for CNS targets. Ligand B (107.97) is higher, but still reasonably acceptable, though less ideal.

**3. logP:** Ligand A (3.088) is optimal (1-3). Ligand B (-0.983) is significantly lower, which could hinder membrane permeability and CNS penetration.

**4. H-Bond Donors:** Ligand A (1) is good. Ligand B (3) is acceptable, but slightly higher.

**5. H-Bond Acceptors:** Ligand A (4) is good. Ligand B (5) is acceptable.

**6. QED:** Ligand A (0.836) is excellent, indicating strong drug-likeness. Ligand B (0.494) is lower, suggesting a less favorable drug-like profile.

**7. DILI:** Ligand A (49.438) has a low DILI risk. Ligand B (11.594) has a very low DILI risk, which is positive.

**8. BBB:** Ligand A (90.074) has excellent BBB penetration potential. Ligand B (40.675) has poor BBB penetration potential. This is a critical difference for a CNS target like DRD2.

**9. Caco-2 permeability:** Ligand A (-4.203) is negative, which is unusual and suggests very poor permeability. Ligand B (-5.292) is also negative and poor permeability.

**10. Aqueous Solubility:** Ligand A (-3.613) is very poor. Ligand B (-0.833) is also poor, but slightly better than A.

**11. hERG inhibition:** Ligand A (0.613) has a low hERG risk. Ligand B (0.05) has a very low hERG risk, which is positive.

**12. Microsomal Clearance:** Ligand A (45.117) is moderate. Ligand B (11.231) is low, indicating better metabolic stability.

**13. In vitro Half-Life:** Ligand A (14.94) is moderate. Ligand B (18.675) is better.

**14. P-gp efflux:** Ligand A (0.442) has moderate P-gp efflux. Ligand B (0.006) has very low P-gp efflux, which is highly desirable for CNS penetration.

**15. Binding Affinity:** Ligand B (-7.9) has a slightly better binding affinity than Ligand A (-7.6), but the difference is relatively small (0.3kcal/mol).

**Overall Assessment:**

Despite Ligand B having slightly better affinity and lower P-gp efflux, the critical factor is BBB penetration. Ligand A has a much higher BBB percentile (90.074) compared to Ligand B (40.675). The poor Caco-2 and solubility of both are concerning, but can potentially be addressed with formulation strategies. However, without adequate BBB penetration, Ligand B is unlikely to be effective for a CNS target like DRD2. Ligand A's superior BBB score, coupled with acceptable logP, TPSA, and DILI, makes it the more promising candidate.

Output:
0
2025-04-17 08:52:11,642 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (345.4 and 350.4 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (82.97) is better than Ligand B (71.34). Both are below the 90 A^2 threshold desirable for CNS targets.

**logP:** Ligand B (3.058) is optimal (1-3), while Ligand A (0.528) is quite low, potentially hindering membrane permeability. This is a significant drawback for Ligand A.

**H-Bond Donors/Acceptors:** Ligand A has 1 HBD and 5 HBA, while Ligand B has 2 HBD and 3 HBA. Both are within acceptable ranges.

**QED:** Both ligands have reasonable QED values (0.861 and 0.794), indicating good drug-like properties.

**DILI:** Both ligands have the same DILI risk (35.0%), which is acceptable (below 40).

**BBB:** Ligand B (83.4%) significantly outperforms Ligand A (61.7%). For a CNS target like DRD2, high BBB penetration is crucial.

**Caco-2 Permeability:** Ligand A (-5.086) is significantly worse than Ligand B (-4.655). While both are negative, indicating poor permeability, A is worse.

**Aqueous Solubility:** Ligand A (-1.292) is better than Ligand B (-4.092).

**hERG Inhibition:** Ligand A (0.163) has a lower hERG risk than Ligand B (0.485), which is preferable.

**Microsomal Clearance:** Ligand A (-4.076) has a lower (better) microsomal clearance than Ligand B (41.293), suggesting greater metabolic stability.

**In vitro Half-Life:** Ligand B (45.527) has a much longer half-life than Ligand A (-26.988), which is a significant advantage.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.022 and 0.191), which is good.

**Binding Affinity:** Both ligands have similar binding affinities (-9.0 and -8.9 kcal/mol), which are both excellent.

**Overall Assessment:**

While Ligand A has better hERG and clearance, its significantly lower logP and BBB penetration are major concerns for a CNS target. Ligand B, despite slightly worse hERG and clearance, has a much better logP and, critically, a significantly higher BBB penetration. The superior BBB penetration and logP of Ligand B outweigh the minor drawbacks in hERG and clearance. The binding affinity is comparable.

Output:
1
2025-04-17 08:52:11,642 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 drug candidates, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (456.284 Da) is higher, but still acceptable. Ligand B (343.402 Da) is lower, potentially aiding permeability.

**TPSA:** Ligand A (99.24) is approaching the upper limit for CNS targets (<=90), while Ligand B (62.3) is well within the desired range. This favors Ligand B.

**logP:** Both ligands have good logP values (A: 2.505, B: 1.697), falling within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A (HBD=2, HBA=5) and Ligand B (HBD=1, HBA=3) both have reasonable numbers of H-bond donors and acceptors, well below the thresholds of 5 and 10 respectively.

**QED:** Both ligands have similar and acceptable QED values (A: 0.626, B: 0.632), indicating good drug-like properties.

**DILI:** Ligand A has a significantly higher DILI risk (65.917%) than Ligand B (29.159%). This is a major concern for Ligand A.

**BBB:** Both ligands have comparable and good BBB penetration (A: 67.468%, B: 67.041%).

**Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and suggests poor permeability. However, the values are similar (-5.165 for A, -4.634 for B).

**Aqueous Solubility:** Both ligands have poor aqueous solubility (-3.78 for A, -2.67 for B). This could pose formulation challenges.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (A: 0.453%, B: 0.176%), which is favorable.

**Microsomal Clearance:** Ligand A has a higher microsomal clearance (52.252) than Ligand B (13.042), suggesting lower metabolic stability for Ligand A.

**In vitro Half-Life:** Ligand B has a negative in vitro half-life (-15.336), which is problematic and suggests rapid degradation. Ligand A has a more reasonable half-life (24.14).

**P-gp Efflux:** Both ligands have low P-gp efflux liability (A: 0.207, B: 0.034), which is good for CNS exposure.

**Binding Affinity:** Ligand B has a slightly better binding affinity (-8.2 kcal/mol) than Ligand A (-7.9 kcal/mol). While the difference is small, it's still a factor.

**Overall Assessment:**

Ligand B is the more promising candidate. While it has a concerning negative in vitro half-life, it excels in several key areas: lower DILI risk, better TPSA, and slightly better binding affinity. Ligand A's higher DILI risk and higher microsomal clearance are significant drawbacks. The similar BBB and logP values don't differentiate them. The negative Caco-2 values are a concern for both, but the other factors favor B.

Output:
1
2025-04-17 08:52:11,642 - INFO - Batch 485 complete. Total preferences: 7760
2025-04-17 08:52:11,642 - INFO - Processing batch 486/512...
2025-04-17 08:52:54,004 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (345.351 and 348.378 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (89.21) is better than Ligand B (90.87), both are below the 90 A^2 threshold desirable for CNS targets, but A is closer.

**3. logP:** Both ligands have good logP values (2.452 and 2.848), falling within the optimal 1-3 range.

**4. H-Bond Donors:** Ligand A (1) is preferable to Ligand B (2), as fewer HBDs generally improve permeability.

**5. H-Bond Acceptors:** Ligand A (6) is preferable to Ligand B (4), as fewer HBAs generally improve permeability.

**6. QED:** Both ligands have acceptable QED values (0.639 and 0.801), indicating good drug-like properties.

**7. DILI:** Ligand B (72.043) has a lower DILI risk than Ligand A (64.831), which is a positive attribute.

**8. BBB:** Ligand B (66.964) has a better BBB penetration score than Ligand A (48.391). This is a *critical* factor for a CNS target like DRD2.

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.899 and -4.904), indicating poor permeability. This is a significant concern for both.

**10. Aqueous Solubility:** Both ligands have negative solubility values (-3.448 and -4.126), indicating poor solubility. This is a concern for both.

**11. hERG Inhibition:** Both ligands have low hERG inhibition risk (0.485 and 0.468).

**12. Microsomal Clearance:** Ligand B (7.62) has significantly lower microsomal clearance than Ligand A (89.784), suggesting better metabolic stability.

**13. In vitro Half-Life:** Ligand B (12.696) has a much longer in vitro half-life than Ligand A (-7.809), which is a major advantage.

**14. P-gp Efflux:** Both ligands have low P-gp efflux liability (0.371 and 0.116). Ligand B is slightly better.

**15. Binding Affinity:** Ligand B (-8.5 kcal/mol) has a significantly stronger binding affinity than Ligand A (-7.8 kcal/mol). This >1.5 kcal/mol difference is a substantial advantage.

**Overall Assessment:**

While Ligand A has slightly better TPSA and H-bonding characteristics, Ligand B is superior in almost every other critical parameter.  The significantly improved BBB penetration, metabolic stability (lower Cl_mic, longer t1/2), and, most importantly, binding affinity of Ligand B outweigh the minor drawbacks in TPSA and H-bonding. The poor Caco-2 and solubility are concerns for both, but can be addressed with formulation strategies. Given the GPCR-specific priorities, the stronger binding affinity and better CNS penetration of Ligand B make it the more promising drug candidate.

Output:
1
2025-04-17 08:52:54,005 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (340.299 and 356.495 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (132.39) is better than Ligand B (57.26). For CNS targets, we want TPSA <= 90, and A is closer to this threshold. B is significantly lower, which *could* be good for BBB penetration, but might also indicate a lack of necessary interactions.

**logP:** Ligand A (1.634) is within the optimal 1-3 range. Ligand B (3.39) is at the higher end but still acceptable.

**H-Bond Donors/Acceptors:** Ligand A has 1 HBD and 8 HBA, while Ligand B has 2 HBD and 5 HBA. Both are within acceptable limits (<=5 HBD and <=10 HBA).

**QED:** Ligand B (0.882) has a significantly better QED score than Ligand A (0.409), indicating a more drug-like profile overall.

**DILI:** Ligand A (97.984) has a higher DILI risk than Ligand B (59.829). B is preferable here, being below the 60% threshold.

**BBB:** Ligand B (94.184) has a much higher BBB percentile than Ligand A (68.282). This is a *critical* advantage for a CNS target like DRD2.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.163 and -5.036), which is unusual and suggests poor permeability. This is a significant concern for both.

**Aqueous Solubility:** Both ligands have negative solubility values (-3.968 and -3.231), indicating very poor aqueous solubility. This is a major drawback for both.

**hERG Inhibition:** Ligand A (0.132) has a slightly lower hERG risk than Ligand B (0.867), which is favorable.

**Microsomal Clearance:** Ligand A (51.473) has a higher microsomal clearance than Ligand B (4.602), meaning it's less metabolically stable. B is much better here.

**In vitro Half-Life:** Ligand B (40.18) has a longer in vitro half-life than Ligand A (29.071), which is desirable.

**P-gp Efflux:** Ligand A (0.128) has lower P-gp efflux liability than Ligand B (0.421), which is good for CNS exposure.

**Binding Affinity:** Both ligands have excellent binding affinities (-9.4 and -8.4 kcal/mol). Ligand A is slightly better (-9.4 kcal/mol), but the difference is less than 1.5 kcal/mol, so it's not a decisive factor.

**Overall Assessment:**

While Ligand A has slightly better affinity and P-gp efflux, Ligand B is significantly better in several crucial areas for a CNS-targeting GPCR: BBB penetration, DILI risk, metabolic stability (lower Cl_mic), and in vitro half-life. The QED score is also much higher for Ligand B. The poor Caco-2 and solubility for both are concerning, but can potentially be addressed with formulation strategies. Given the importance of BBB penetration for DRD2, and the other favorable ADME properties of Ligand B, it is the more promising candidate.

Output:
1
2025-04-17 08:52:54,005 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (355.439 and 360.451 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Both ligands (119.21 and 119.33) are slightly above the optimal <90 for CNS targets, but still reasonably acceptable, especially considering the other properties.

**3. logP:** Ligand A (-1.583) is a bit low, potentially hindering permeability. Ligand B (-0.884) is better, falling within the 1-3 range, but still on the lower side.

**4. H-Bond Donors:** Ligand A (3) and Ligand B (4) are both acceptable, being less than 5.

**5. H-Bond Acceptors:** Ligand A (5) and Ligand B (6) are both acceptable, being less than 10.

**6. QED:** Both ligands have reasonable QED scores (0.531 and 0.468), indicating good drug-like properties.

**7. DILI:** Ligand A (9.228) has a significantly lower DILI risk than Ligand B (11.128), which is a substantial advantage.

**8. BBB:** Ligand A (45.522) has a better BBB penetration percentile than Ligand B (38.581), but both are below the desirable >70 for CNS targets. This is a concern for both, but less so for A.

**9. Caco-2:** Both ligands have negative Caco-2 values (-5.717 and -5.087), which is unusual and suggests poor permeability. This is a significant drawback for both.

**10. Solubility:** Both ligands have negative solubility values (-0.653 and -0.68), indicating poor aqueous solubility. This is a concern for both.

**11. hERG:** Both ligands have very low hERG inhibition liability (0.118 and 0.17), which is excellent.

**12. Cl_mic:** Ligand A (-39.053) has a much lower (better) microsomal clearance than Ligand B (-1.56), suggesting greater metabolic stability.

**13. t1/2:** Ligand A (-19.829) has a slightly worse in vitro half-life than Ligand B (-18.784), but both are quite poor.

**14. Pgp:** Both ligands have very low P-gp efflux liability (0.001 and 0.014), which is favorable for CNS penetration.

**15. Binding Affinity:** Both ligands have comparable and strong binding affinities (-7.8 and -7.9 kcal/mol). The difference is negligible.

**Overall Assessment:**

Considering the GPCR-specific priorities, Ligand A is the more promising candidate. While both have issues with Caco-2 permeability and solubility, Ligand A has a significantly lower DILI risk and better metabolic stability (lower Cl_mic). The slightly better BBB penetration also favors Ligand A. The binding affinities are essentially the same. The lower logP of Ligand A is a minor concern, but the other advantages outweigh this.

Output:
0
2025-04-17 08:52:54,005 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (364.421 and 374.463 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (49.64) is excellent, well below the 90 A^2 threshold for CNS targets. Ligand B (110.6) is higher, but still potentially acceptable, though less ideal.

**3. logP:** Ligand A (3.632) is optimal. Ligand B (0.427) is quite low, potentially hindering membrane permeability and CNS penetration.

**4. H-Bond Donors:** Both ligands have 1 HBD, which is within the acceptable limit of <=5.

**5. H-Bond Acceptors:** Ligand A has 4 HBAs, and Ligand B has 7 HBAs. Both are within the acceptable limit of <=10.

**6. QED:** Both ligands have similar QED values (0.769 and 0.706), indicating good drug-like properties.

**7. DILI:** Ligand A (58.085) has a slightly higher DILI risk than Ligand B (66.615), but both are reasonably acceptable.

**8. BBB:** Ligand A (75.843) has a significantly better BBB penetration percentile than Ligand B (62.233). This is a crucial advantage for a CNS target like DRD2.

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.469 and -4.758), which is unusual and suggests poor permeability. However, these values are on a scale where negative values are possible and don't necessarily disqualify a compound outright.

**10. Aqueous Solubility:** Both ligands have negative solubility values (-3.575 and -1.756), indicating poor aqueous solubility. This could pose formulation challenges.

**11. hERG Inhibition:** Ligand A (0.675) has a slightly higher hERG inhibition risk than Ligand B (0.109). This is a concern, but not a major disqualifier at these levels.

**12. Microsomal Clearance:** Ligand A (51.244) has a higher microsomal clearance than Ligand B (23.1), suggesting lower metabolic stability.

**13. In vitro Half-Life:** Ligand A (25.588) has a longer in vitro half-life than Ligand B (12.604).

**14. P-gp Efflux:** Ligand A (0.534) has lower P-gp efflux liability than Ligand B (0.071), which is beneficial for CNS exposure.

**15. Binding Affinity:** Ligand A (-9.6 kcal/mol) has a significantly stronger binding affinity than Ligand B (-6.8 kcal/mol). This is a substantial advantage.

**Overall Assessment:**

Ligand A is the stronger candidate. While both have issues with Caco-2 permeability and solubility, Ligand A's superior BBB penetration, significantly higher binding affinity, lower P-gp efflux, and longer half-life outweigh its slightly higher DILI and microsomal clearance. Ligand B's low logP is a major drawback for a CNS-targeting drug, as it will likely struggle to cross the blood-brain barrier effectively. The substantial affinity difference (-2.8 kcal/mol) is also a critical factor.

Output:
1
2025-04-17 08:52:54,006 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (356.388 and 353.507 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (41.57) is significantly better than Ligand B (70.67). For CNS targets, we want TPSA <= 90, and ideally closer to 60. Ligand A is much closer to this ideal. Ligand B is higher and may have reduced brain penetration.

**3. logP:** Ligand A (4.188) is a bit high, potentially leading to solubility issues and off-target effects. Ligand B (1.709) is within the optimal 1-3 range.

**4. H-Bond Donors:** Both have acceptable HBD counts (1 and 2 respectively), well below the threshold of 5.

**5. H-Bond Acceptors:** Both have acceptable HBA counts (2 and 4 respectively), well below the threshold of 10.

**6. QED:** Ligand A (0.882) has a much better QED score than Ligand B (0.619), indicating a more drug-like profile.

**7. DILI:** Ligand A (22.683) has a significantly lower DILI risk than Ligand B (14.036), which is a major advantage.

**8. BBB:** Ligand A (89.763) has excellent BBB penetration, exceeding the desirable >70% threshold. Ligand B (49.826) is considerably lower, raising concerns about CNS exposure.

**9. Caco-2:** Both have negative Caco-2 values, which is unusual and difficult to interpret without knowing the scale. However, the values are similar.

**10. Solubility:** Both have negative solubility values, which is also unusual. Again, the values are similar.

**11. hERG:** Ligand A (0.813) has a slightly higher hERG risk than Ligand B (0.35), but both are relatively low.

**12. Cl_mic:** Ligand B (34.094) has lower microsomal clearance than Ligand A (41.647), suggesting better metabolic stability.

**13. t1/2:** Ligand B (13.087) has a longer in vitro half-life than Ligand A (-16.073). The negative value for Ligand A is concerning and suggests rapid degradation.

**14. Pgp:** Ligand A (0.291) has lower P-gp efflux than Ligand B (0.028), which is favorable for CNS penetration.

**15. Binding Affinity:** Ligand A (-9.0) has a significantly stronger binding affinity than Ligand B (-0.0). This is a crucial advantage, as a >1.5 kcal/mol difference can outweigh other drawbacks.

**Overall Assessment:**

Despite Ligand A's slightly higher logP, its significantly superior BBB penetration, much stronger binding affinity, lower DILI risk, and better QED score make it the more promising candidate. The negative in vitro half-life is a concern, but the strong binding affinity might compensate for it, potentially allowing for a lower dose. Ligand B's lower logP and better metabolic stability are positives, but its poor BBB penetration and weak binding affinity are major drawbacks for a CNS target like DRD2.

Output:
1
2025-04-17 08:52:54,006 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (343.471 and 368.499 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (54.34) is significantly better than Ligand B (80.57). For CNS targets, we want TPSA <= 90, and A is comfortably within that range, while B is approaching the upper limit.

**3. logP:** Both ligands have similar and optimal logP values (2.294 and 2.225), falling within the 1-3 range.

**4. H-Bond Donors:** Ligand A (1) is preferable to Ligand B (2). Lower HBD generally improves permeability.

**5. H-Bond Acceptors:** Ligand A (3) is preferable to Ligand B (5) for similar reasons as HBD.

**6. QED:** Ligand A (0.834) has a much better QED score than Ligand B (0.619), indicating a more drug-like profile.

**7. DILI:** Both ligands have low DILI risk (25.94 and 29.197 percentiles), which is good.

**8. BBB:** Ligand A (88.833) has a significantly higher BBB percentile than Ligand B (55.603). This is *critical* for a CNS target like DRD2.

**9. Caco-2:** Ligand A (-4.851) and Ligand B (-5.301) both have negative values, which is unusual. Higher values are better, but the relative difference is not substantial.

**10. Solubility:** Ligand A (-2.679) and Ligand B (-2.463) both have negative solubility values, suggesting poor aqueous solubility. This is a concern, but can be addressed with formulation.

**11. hERG:** Both ligands have low hERG inhibition liability (0.395 and 0.359), which is positive.

**12. Cl_mic:** Both ligands have similar microsomal clearance values (44.795 and 44.315 mL/min/kg), indicating similar metabolic stability.

**13. t1/2:** Ligand A (-14.104) has a worse in vitro half-life than Ligand B (39.564). This is a drawback for Ligand A.

**14. Pgp:** Both ligands have low P-gp efflux liability (0.252 and 0.112), which is good for CNS penetration.

**15. Binding Affinity:** Ligand B (-7.2 kcal/mol) has a significantly stronger binding affinity than Ligand A (-9.0 kcal/mol). This is a substantial advantage.

**Overall Assessment:**

While Ligand B has a superior binding affinity and a better half-life, Ligand A is significantly better in terms of BBB penetration, TPSA, QED, and H-bonding characteristics. Given that DRD2 is a CNS target, BBB penetration is paramount. The stronger binding affinity of Ligand B is a significant plus, but the poor BBB score is a major concern. The improved drug-likeness properties of Ligand A, particularly the higher QED and lower TPSA, also make it more promising. The difference in affinity, while substantial, might be overcome with further optimization of Ligand A.

Output:
0
2025-04-17 08:52:54,006 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (344.43 Da) is slightly higher than Ligand B (336.399 Da), but both are acceptable.

**TPSA:** Ligand A (45.59) is significantly better than Ligand B (101.62). For CNS targets, we want TPSA <= 90, and Ligand A is comfortably within this range, while Ligand B exceeds it. This is a substantial advantage for Ligand A.

**logP:** Both ligands have acceptable logP values (Ligand A: 3.359, Ligand B: 2.32), falling within the optimal range of 1-3.

**H-Bond Donors/Acceptors:** Ligand A (HBD=1, HBA=4) is preferable to Ligand B (HBD=3, HBA=5) as lower values generally improve permeability.

**QED:** Ligand A (0.862) has a better QED score than Ligand B (0.68), indicating a more drug-like profile.

**DILI:** Ligand A (30.942) has a significantly lower DILI risk than Ligand B (68.36), which is a major advantage.

**BBB:** Ligand A (88.135) has a much better BBB penetration score than Ligand B (45.715). This is *critical* for a CNS target like DRD2.

**Caco-2 Permeability:** Ligand A (-4.652) has a worse Caco-2 permeability than Ligand B (-5.621). However, given the strong advantages of Ligand A in other areas, this is less concerning.

**Aqueous Solubility:** Both ligands have very poor aqueous solubility (-2.013 and -3.138 respectively). This could pose formulation challenges, but isn't a deciding factor.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.964 and 0.741 respectively).

**Microsomal Clearance:** Ligand B (-16.902) has a lower (better) microsomal clearance than Ligand A (21.757), indicating better metabolic stability.

**In vitro Half-Life:** Ligand A (53.929) has a longer in vitro half-life than Ligand B (28.896), which is favorable.

**P-gp Efflux:** Both have low P-gp efflux liability (0.776 and 0.132 respectively). Ligand B is slightly better here.

**Binding Affinity:** Both ligands have strong binding affinities (-9.0 and -8.3 kcal/mol respectively). Ligand A is slightly better (-9.0 kcal/mol).

**Overall Assessment:**

Ligand A is significantly better overall, particularly due to its superior TPSA, BBB penetration, DILI risk, QED, and slightly better binding affinity. While Ligand B has better metabolic stability and P-gp efflux, the CNS target necessitates prioritizing BBB penetration, which Ligand A excels at. The lower TPSA of Ligand A also supports better CNS entry. The solubility issue is a concern for both, but can be addressed with formulation strategies.

Output:
1
2025-04-17 08:52:54,006 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (344.5) is slightly lower, which could be beneficial for permeability, but both are acceptable.

**TPSA:** Ligand A (40.62) is significantly better than Ligand B (76.46). For CNS targets, we want TPSA <= 90, and ideally closer to 60. Ligand A is well within the desirable range, while Ligand B is approaching the upper limit and could have reduced brain penetration.

**logP:** Ligand A (3.232) is optimal (1-3), while Ligand B (1.376) is at the lower end. While not terrible, lower logP can sometimes hinder membrane permeability.

**H-Bond Donors/Acceptors:** Ligand A (0 HBD, 2 HBA) is preferable to Ligand B (1 HBD, 5 HBA). Lower numbers generally improve permeability.

**QED:** Both ligands have good QED scores (A: 0.567, B: 0.806), indicating good drug-like properties. Ligand B is slightly better here.

**DILI:** Ligand A (11.283) has a much lower DILI risk than Ligand B (32.842). This is a significant advantage for Ligand A.

**BBB:** Both ligands have good BBB penetration (A: 76.309, B: 75.107), exceeding the 70% threshold for CNS targets. This is comparable.

**Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and requires further investigation. However, we can compare the magnitudes. Ligand A (-4.505) is slightly better than Ligand B (-4.524).

**Aqueous Solubility:** Both have negative solubility values, which is also unusual. Ligand A (-3.546) is slightly better than Ligand B (-1.921).

**hERG:** Both ligands have low hERG inhibition risk (A: 0.452, B: 0.343).

**Microsomal Clearance:** Ligand A (42.029) has a slightly higher clearance than Ligand B (37.385), indicating potentially lower metabolic stability.

**In vitro Half-Life:** Ligand B (9.197) has a significantly longer half-life than Ligand A (-7.607). This is a substantial advantage for Ligand B.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (A: 0.206, B: 0.048). Ligand B is slightly better here.

**Binding Affinity:** Ligand A (-8.1 kcal/mol) has a significantly better binding affinity than Ligand B (-7.1 kcal/mol). This 1.0 kcal/mol difference is substantial and can outweigh many ADME drawbacks.

**Overall Assessment:**

Ligand A excels in TPSA, DILI risk, and crucially, binding affinity. Its logP is optimal. While its clearance is slightly higher and half-life lower than Ligand B, the significantly stronger binding affinity and lower DILI risk are major advantages for a GPCR target, especially in the CNS. Ligand B has a better QED and half-life, but the weaker binding and higher DILI risk are concerning. Given the GPCR-specific priorities, the affinity advantage of Ligand A is decisive.

Output:
1
2025-04-17 08:52:54,006 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (384.27 and 362.50 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (90.98) is better than Ligand B (58.64). Both are below the 90 A^2 threshold for CNS targets, which is favorable.

**logP:** Ligand A (0.899) is slightly lower than ideal (1-3), potentially hindering permeability. Ligand B (2.478) is within the optimal range.

**H-Bond Donors:** Ligand A (2) is acceptable, while Ligand B (1) is also good.

**H-Bond Acceptors:** Both ligands have 4 HBA, which is within the acceptable limit of 10.

**QED:** Both ligands have good QED scores (0.583 and 0.772), indicating drug-like properties.

**DILI:** Ligand A (38.503) has a slightly better DILI score than Ligand B (48.662), indicating a lower risk of liver injury. Both are below the concerning 60 threshold.

**BBB:** Ligand B (71.888) has a significantly better BBB penetration score than Ligand A (61.691). This is a crucial advantage for a CNS target like DRD2.

**Caco-2 Permeability:** Ligand A (-5.356) has a worse Caco-2 permeability than Ligand B (-4.896), suggesting lower intestinal absorption.

**Aqueous Solubility:** Both ligands have poor aqueous solubility (-2.885 and -3.965). This could pose formulation challenges.

**hERG Inhibition:** Ligand A (0.09) has a slightly better hERG inhibition profile than Ligand B (0.556), implying lower cardiotoxicity risk.

**Microsomal Clearance:** Ligand A (-30.392) has a much lower (better) microsomal clearance than Ligand B (78.774), indicating greater metabolic stability.

**In vitro Half-Life:** Ligand A (-9.893) has a worse in vitro half-life than Ligand B (-7.658).

**P-gp Efflux:** Ligand A (0.015) has a much lower P-gp efflux liability than Ligand B (0.183), which is highly desirable for CNS penetration.

**Binding Affinity:** Both ligands have very similar and strong binding affinities (-7.9 and -8.1 kcal/mol). The difference is negligible.

**Overall Assessment:**

Ligand B excels in BBB penetration and has a better logP, making it more likely to reach the CNS target. However, Ligand A has superior metabolic stability (lower Cl_mic), lower P-gp efflux, and slightly better DILI and hERG profiles. The difference in binding affinity is minimal. Given the importance of BBB penetration for a CNS target like DRD2, and the acceptable, though not ideal, ADME properties of Ligand B, it is the more promising candidate. The lower P-gp efflux and better metabolic stability of Ligand A are attractive, but are outweighed by the significant advantage in BBB penetration of Ligand B.

Output:
1
2025-04-17 08:52:54,007 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (349.475 and 357.523 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (53.09) is significantly higher than the preferred <90 for CNS targets, while Ligand B (29.77) is excellent. This is a major advantage for Ligand B.

**logP:** Ligand A (0.814) is a bit low, potentially hindering permeation. Ligand B (3.625) is within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A (0 HBD, 4 HBA) and Ligand B (0 HBD, 5 HBA) both have reasonable H-bond characteristics.

**QED:** Both ligands have acceptable QED values (0.757 and 0.675, respectively), indicating good drug-like properties.

**DILI:** Ligand A (7.871) has a very low DILI risk, significantly better than Ligand B (19.698).

**BBB:** Ligand A (71.888) is acceptable, but Ligand B (88.639) is excellent, exceeding the >70 threshold for CNS targets.

**Caco-2 Permeability:** Ligand A (-4.417) is poor, suggesting poor intestinal absorption. Ligand B (-5.173) is also poor.

**Aqueous Solubility:** Ligand A (-0.887) and Ligand B (-2.773) both have poor aqueous solubility.

**hERG:** Ligand A (0.473) has a low hERG risk, better than Ligand B (0.937).

**Microsomal Clearance:** Ligand A (10.928) has lower clearance than Ligand B (67.257), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (-9.125) has a significantly longer half-life than Ligand B (2.945).

**P-gp Efflux:** Ligand A (0.023) has very low P-gp efflux, which is highly desirable for CNS penetration. Ligand B (0.576) is higher, indicating more efflux.

**Binding Affinity:** Ligand A (-7.8 kcal/mol) and Ligand B (-7.2 kcal/mol) both have good binding affinities. Ligand A is slightly better, with a 0.6 kcal/mol advantage.

**Overall Assessment:**

Ligand B excels in TPSA and BBB penetration, critical for a CNS-targeting GPCR. However, it has higher DILI risk, higher P-gp efflux, and poorer metabolic stability (higher Cl_mic, shorter t1/2) compared to Ligand A. Ligand A has a slight advantage in binding affinity, significantly better DILI, P-gp, and metabolic stability profiles, and acceptable BBB. While Ligand A's logP is a bit low and Caco-2 permeability is poor, the superior CNS properties and safety profile outweigh these concerns. The lower TPSA of Ligand B is a significant advantage, but the other factors favor Ligand A.

Output:
0
2025-04-17 08:52:54,007 - INFO - Reasoning:

Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (344.405 and 346.431 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (32.34) is excellent, well below the 90 A^2 threshold for CNS targets. Ligand B (87.46) is higher, but still potentially acceptable, though less ideal.

**3. logP:** Ligand A (3.911) is at the higher end of the optimal range (1-3), but still acceptable. Ligand B (0.683) is quite low, potentially hindering permeability.

**4. H-Bond Donors:** Both ligands have acceptable HBD counts (1 and 2, respectively), well below the 5 threshold.

**5. H-Bond Acceptors:** Ligand A (2) is good. Ligand B (5) is also acceptable, below the 10 threshold.

**6. QED:** Both ligands have reasonable QED values (0.862 and 0.742), indicating good drug-like properties.

**7. DILI:** Ligand A (55.487) has a moderate DILI risk, but is acceptable. Ligand B (31.718) has a very low DILI risk, which is excellent.

**8. BBB:** This is crucial for a CNS target. Ligand A scores very well (86.002), exceeding the 70% threshold. Ligand B (51.183) is significantly lower, raising concerns about CNS penetration.

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.792 and -4.993). This is unusual and suggests a potential issue with the data or a very poor permeability. However, since both are similarly poor, it doesn't differentiate them.

**10. Aqueous Solubility:** Both ligands have negative solubility values (-4.827 and -1.745). Similar to Caco-2, this is concerning and suggests poor solubility.

**11. hERG Inhibition:** Ligand A (0.973) has a slightly higher hERG risk than Ligand B (0.184), but both are relatively low.

**12. Microsomal Clearance:** Ligand B (-10.675) has a significantly lower (better) microsomal clearance than Ligand A (67.089), indicating greater metabolic stability.

**13. In vitro Half-Life:** Ligand B (-11.9) has a much longer in vitro half-life than Ligand A (5.794), which is highly desirable.

**14. P-gp Efflux:** Ligand A (0.681) has lower P-gp efflux liability than Ligand B (0.065), which is favorable for CNS penetration.

**15. Binding Affinity:** Ligand A (-9.6 kcal/mol) has a significantly stronger binding affinity than Ligand B (-7.6 kcal/mol). This is a substantial advantage, potentially outweighing some of the ADME drawbacks.

**Overall Assessment:**

Ligand A is strongly favored due to its superior BBB penetration and significantly higher binding affinity. While Ligand B has better metabolic stability and lower DILI risk, the critical factor for a CNS-targeting GPCR like DRD2 is the ability to cross the blood-brain barrier and achieve sufficient target engagement. The substantial difference in binding affinity (-9.6 vs -7.6 kcal/mol) further solidifies Ligand A's position as the more promising candidate. The poor solubility and permeability scores are concerning for both, but the strong affinity and BBB penetration of A make it more likely to overcome these issues with formulation strategies.



Output:
1
2025-04-17 08:52:54,007 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (351.447 and 352.362 Da) fall comfortably within the ideal 200-500 Da range.

**TPSA:** Ligand A (100.44) is slightly above the optimal <90 for CNS targets, while Ligand B (90.31) is right at the threshold. This gives a slight edge to Ligand B.

**logP:** Ligand A (1.906) is within the optimal 1-3 range. Ligand B (0.213) is quite low, potentially hindering membrane permeability. This is a significant drawback for Ligand B.

**H-Bond Donors/Acceptors:** Ligand A has 3 HBD and 4 HBA, which are both acceptable. Ligand B has 2 HBD and 5 HBA, also acceptable.

**QED:** Both ligands have good QED scores (0.599 and 0.809), indicating good drug-like properties.

**DILI:** Both ligands have low DILI risk (21.946 and 22.8), which is favorable.

**BBB:** Ligand B (43.311) has a significantly better BBB percentile than Ligand A (32.765). This is a crucial advantage for a CNS target like DRD2.

**Caco-2 Permeability:** Ligand A (-5.279) has a negative Caco-2 value, indicating poor permeability. Ligand B (-4.812) is also negative, but slightly less so. Both are problematic.

**Aqueous Solubility:** Both have negative solubility values, indicating poor solubility.

**hERG:** Both ligands have very low hERG inhibition liability (0.09 and 0.253), which is excellent.

**Microsomal Clearance:** Ligand A (35.441) has moderate clearance, while Ligand B (-8.03) has negative clearance, which is highly favorable, suggesting excellent metabolic stability.

**In vitro Half-Life:** Ligand A (32.058) has a reasonable half-life. Ligand B (-2.288) has a negative half-life, which is not physically possible but suggests extremely high stability.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.006 and 0.018), which is excellent.

**Binding Affinity:** Both ligands have excellent binding affinity (-7.7 and -8.0 kcal/mol). Ligand B is slightly better, but the difference is not huge.

**Overall Assessment:**

Ligand B excels in BBB penetration and metabolic stability, which are critical for a CNS GPCR target. However, its low logP is a major concern, potentially limiting its ability to cross cell membranes. Ligand A has a better logP, but suffers from poor Caco-2 permeability and a lower BBB score. The slightly better affinity of Ligand B is not enough to overcome its permeability issues. Considering the importance of BBB penetration for CNS targets, and the fact that the affinity difference is small, Ligand B is the more promising candidate *if* the logP issue can be addressed through structural modifications. However, the negative Caco-2 values for both are concerning.

Output:
1
2025-04-17 08:52:54,007 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (354.801 and 353.463 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (85.59) is excellent, falling well below the 90 A^2 threshold for CNS targets. Ligand B (101.73) is still reasonable, but less optimal.

**logP:** Ligand A (2.842) is within the optimal 1-3 range. Ligand B (0.954) is slightly below 1, which could potentially hinder permeation, although not drastically.

**H-Bond Donors/Acceptors:** Ligand A (HBD=1, HBA=6) and Ligand B (HBD=2, HBA=4) both have acceptable numbers of H-bond donors and acceptors.

**QED:** Both ligands have reasonable QED values (0.731 and 0.603), indicating good drug-like properties.

**DILI:** Ligand A has a high DILI risk (95.502 percentile), which is a significant concern. Ligand B has a very low DILI risk (12.718 percentile), a major advantage.

**BBB:** Ligand A has a good BBB penetration (77.007 percentile), desirable for a CNS target. Ligand B has a lower BBB penetration (58.24 percentile), which is less favorable.

**Caco-2 Permeability:** Ligand A has a negative Caco-2 value (-4.898), which is unusual and suggests poor permeability. Ligand B also has a negative Caco-2 value (-5.393), indicating poor permeability.

**Aqueous Solubility:** Both ligands have negative solubility values (-3.974 and -1.609), indicating very poor aqueous solubility. This could present formulation challenges.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.304 and 0.226 percentile), which is positive.

**Microsomal Clearance:** Ligand A has a moderate microsomal clearance (64.697 mL/min/kg). Ligand B has a negative clearance (-4.416 mL/min/kg), which is not physically possible and likely indicates an issue with the data or prediction method.

**In vitro Half-Life:** Ligand A has a moderate half-life (31.676 hours). Ligand B has a very short half-life (-12.754 hours), which is problematic.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.341 and 0.022 percentile), which is good for CNS penetration.

**Binding Affinity:** Ligand A (-10.3 kcal/mol) has a significantly stronger binding affinity than Ligand B (-7.9 kcal/mol). This is a substantial advantage, potentially outweighing some ADME drawbacks.

**Overall Assessment:**

Despite Ligand A's superior binding affinity, its extremely high DILI risk and poor Caco-2 permeability are major red flags. The negative Caco-2 and solubility values for both compounds are concerning. Ligand B, while having a weaker affinity, presents a much better safety profile (low DILI) and acceptable P-gp efflux. However, the negative clearance and half-life values for Ligand B are suspect.

Considering the GPCR-specific priorities, the strong binding affinity of Ligand A is very attractive. However, the DILI risk is too high to ignore. Ligand B is less potent, but much safer. Given the choice, and assuming the negative values for Ligand B are data errors, I would cautiously favor Ligand B for further investigation, contingent on resolving the ADME data issues. However, the DILI risk for A is so high that it is unlikely to be a viable candidate.

Output:
1
2025-04-17 08:52:54,008 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (351.407 and 342.443 Da) fall within the ideal range of 200-500 Da.

**TPSA:** Ligand A (139.46) is close to the upper limit for good oral absorption and acceptable for CNS targets, while Ligand B (83.12) is excellent for CNS penetration.

**logP:** Ligand A (-0.672) is slightly below the optimal range, potentially hindering permeation. Ligand B (2.247) is within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A has 4 HBD and 7 HBA, both acceptable. Ligand B has 3 HBD and 4 HBA, also acceptable.

**QED:** Both ligands have reasonable QED scores (0.462 and 0.664), indicating drug-like properties, with Ligand B being slightly better.

**DILI:** Both ligands have similar, acceptable DILI risk (49.477 and 47.421).

**BBB:** Both ligands show good BBB penetration (63.862 and 65.374), but neither exceeds the desirable >70 threshold.

**Caco-2 Permeability:** Both have negative Caco-2 values which is unusual and suggests poor permeability.

**Aqueous Solubility:** Both ligands have very poor aqueous solubility (-1.664 and -2.919). This is a significant concern.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.216 and 0.492).

**Microsomal Clearance:** Ligand A (0.482) has significantly lower microsomal clearance than Ligand B (12.01), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand B (8.214) has a longer in vitro half-life than Ligand A (-5.473).

**P-gp Efflux:** Both ligands have very low P-gp efflux (0.005 and 0.038), which is favorable for CNS exposure.

**Binding Affinity:** Ligand B (-8.8 kcal/mol) has a significantly stronger binding affinity than Ligand A (-7.0 kcal/mol). This is a >1.5 kcal/mol advantage, which is substantial.

**Overall Assessment:**

While both ligands have some drawbacks, Ligand B is the more promising candidate. Its superior binding affinity (-8.8 vs -7.0 kcal/mol) is a major advantage, especially for a GPCR target. The better logP value (2.247 vs -0.672) is also favorable for permeability. Although both have poor solubility, the stronger binding and better logP of Ligand B are likely to outweigh this concern, particularly given the low P-gp efflux. The longer half-life of Ligand B is also a plus.

Output:
1
2025-04-17 08:52:54,008 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (350.503 and 371.88 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (58.64) is better than Ligand B (60.77) as both are below the 90 A^2 threshold for CNS targets.

**3. logP:** Ligand A (2.903) is optimal, while Ligand B (4.209) is pushing the upper limit. Higher logP can lead to off-target effects and solubility issues.

**4. H-Bond Donors:** Ligand A (1) is preferable to Ligand B (2) as lower HBDs generally improve permeability.

**5. H-Bond Acceptors:** Both ligands have 3 HBA, which is within the acceptable range.

**6. QED:** Both ligands have similar QED values (0.685 and 0.606), indicating good drug-like properties.

**7. DILI:** Both ligands have low DILI risk (9.228 and 9.926 percentile), which is good.

**8. BBB:** Both ligands have excellent BBB penetration (77.705 and 75.107 percentile), crucial for a CNS target like DRD2.

**9. Caco-2 Permeability:** Ligand A (-4.636) has better Caco-2 permeability than Ligand B (-4.849).

**10. Aqueous Solubility:** Ligand A (-2.514) has better aqueous solubility than Ligand B (-3.751).

**11. hERG Inhibition:** Ligand A (0.485) has a lower hERG inhibition liability than Ligand B (0.82).

**12. Microsomal Clearance:** Ligand A (44.523) has lower microsomal clearance, indicating better metabolic stability, than Ligand B (62.946).

**13. In vitro Half-Life:** Ligand A (-10.718) has a much longer in vitro half-life than Ligand B (31.053).

**14. P-gp Efflux:** Ligand A (0.125) has lower P-gp efflux liability than Ligand B (0.53), which is favorable for CNS penetration.

**15. Binding Affinity:** Ligand B (-7.2 kcal/mol) has a significantly stronger binding affinity than Ligand A (-9.0 kcal/mol). This is a substantial advantage.

**Overall Assessment:**

While Ligand B has a better binding affinity, Ligand A demonstrates superior ADME properties across the board, including better solubility, permeability, metabolic stability, lower hERG risk, and lower P-gp efflux. The difference in binding affinity (-7.2 vs -9.0) is significant, but the ADME profile of Ligand A is much more promising. Given the GPCR-specific priorities, the improved CNS penetration characteristics (BBB, Pgp, TPSA) and overall ADME profile of Ligand A make it the more viable candidate.

Output:
0
2025-04-17 08:52:54,008 - INFO - Reasoning:

Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight (MW):** Both ligands (382.555 and 364.511 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (83.98) is better than Ligand B (62.55). Both are below the 90 A^2 threshold desirable for CNS targets.

**3. logP:** Ligand A (1.871) is within the optimal 1-3 range. Ligand B (3.088) is at the higher end, but still acceptable.

**4. H-Bond Donors (HBD):** Both ligands have acceptable HBD counts (2 and 1 respectively), well below the 5 limit.

**5. H-Bond Acceptors (HBA):** Both ligands have acceptable HBA counts (6 and 4 respectively), below the 10 limit.

**6. QED:** Both ligands have good QED scores (0.785 and 0.892), indicating good drug-like properties.

**7. DILI:** Both ligands have similar and acceptable DILI risk (49.864 and 47.732 percentile).

**8. BBB:** Ligand B (68.166%) is slightly better than Ligand A (60.954%) in terms of BBB penetration, but both are below the desirable >70% for CNS targets. However, this is less critical if other properties are significantly better.

**9. Caco-2:** Both have negative values, which is unusual. Assuming these are logP-scaled values, lower values indicate lower permeability. Ligand A (-5.717) is worse than Ligand B (-5.181).

**10. Solubility:** Both have negative values, which is unusual. Assuming these are logS values, lower values indicate lower solubility. Ligand A (-2.945) is worse than Ligand B (-3.931).

**11. hERG:** Both ligands have very low hERG inhibition risk (0.088 and 0.55), which is excellent.

**12. Cl_mic:** Ligand A (30.334) has a lower microsomal clearance than Ligand B (53.359), suggesting better metabolic stability.

**13. t1/2:** Ligand B (34.996) has a significantly longer in vitro half-life than Ligand A (4.955). This is a major advantage.

**14. Pgp:** Both ligands have low P-gp efflux liability (0.079 and 0.453).

**15. Binding Affinity:** Both ligands have excellent binding affinities (-8.1 and -8.2 kcal/mol). Ligand B is slightly better, but the difference is minimal.

**Overall Assessment:**

While Ligand B has a slightly better BBB score and a significantly longer half-life, Ligand A has a better TPSA and lower microsomal clearance. The Caco-2 and Solubility values are concerning for both, but the slightly better values for Ligand B give it an edge. The binding affinity is comparable. Considering the GPCR-specific priorities, the longer half-life of Ligand B is a significant advantage for a CNS target, as it suggests potentially less frequent dosing.

Output:
1
2025-04-17 08:52:54,008 - INFO - Batch 486 complete. Total preferences: 7776
2025-04-17 08:52:54,008 - INFO - Processing batch 487/512...
2025-04-17 08:53:35,120 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (358.479 and 354.403 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (99.1) is slightly higher than Ligand B (97.33), but both are below the 140 for good oral absorption and reasonably close to the <90 target for CNS penetration.

**logP:** Ligand A (0.537) is lower than the optimal 1-3 range, potentially hindering permeation. Ligand B (-0.719) is even lower, raising more concern for permeability.

**H-Bond Donors/Acceptors:** Ligand A has 3 HBD and 5 HBA, which are acceptable. Ligand B has 2 HBD and 6 HBA, also acceptable.

**QED:** Ligand B (0.676) has a better QED score than Ligand A (0.495), indicating a more drug-like profile.

**DILI:** Ligand B (38.852) has a significantly lower DILI risk than Ligand A (5.428), which is a substantial advantage.

**BBB:** Ligand A (46.491) has a much better BBB penetration percentile than Ligand B (28.81). This is a crucial factor for a CNS target like DRD2.

**Caco-2 Permeability:** Ligand A (-4.793) has better Caco-2 permeability than Ligand B (-5.036), suggesting better intestinal absorption.

**Aqueous Solubility:** Ligand B (-1.292) has better aqueous solubility than Ligand A (-0.348).

**hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.252 and 0.171, respectively).

**Microsomal Clearance:** Ligand B (25.714) has a higher microsomal clearance than Ligand A (14.877), indicating faster metabolism and potentially lower *in vivo* exposure.

**In vitro Half-Life:** Ligand B (17.522) has a longer in vitro half-life than Ligand A (0.924), which is a positive attribute.

**P-gp Efflux:** Ligand B (0.012) shows slightly lower P-gp efflux than Ligand A (0.014), which is beneficial for CNS exposure.

**Binding Affinity:** Ligand A (-6.5 kcal/mol) has a slightly better binding affinity than Ligand B (-0.0 kcal/mol). This is a significant advantage, as a 1.5 kcal/mol difference can outweigh other drawbacks.

**Overall Assessment:**

While Ligand B has better QED, DILI, solubility, and half-life, Ligand A's superior BBB penetration and, crucially, significantly stronger binding affinity to DRD2 are decisive. The lower logP of both is a concern, but the strong affinity of Ligand A suggests it may overcome this. The difference in binding affinity is substantial enough to prioritize Ligand A despite its other weaknesses.

Output:
1
2025-04-17 08:53:35,120 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B against the provided guidelines, prioritizing GPCR-specific properties (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (338.451 Da) is slightly lower, which could be beneficial for permeability.

**TPSA:** Ligand A (49.41) is excellent for CNS penetration, well below 90. Ligand B (87.3) is higher, potentially hindering BBB penetration, though still not drastically outside acceptable limits.

**logP:** Ligand A (4.259) is a bit high, potentially leading to solubility issues or off-target interactions. Ligand B (0.279) is quite low, which could severely limit its ability to cross cell membranes, including the BBB.

**H-Bond Donors/Acceptors:** Ligand A (HBD=1, HBA=2) and Ligand B (HBD=3, HBA=3) are both within acceptable ranges.

**QED:** Both ligands have reasonable QED scores (A: 0.85, B: 0.598), indicating drug-like properties.

**DILI:** Ligand A (68.864) has a higher DILI risk than Ligand B (36.758). This is a negative for Ligand A.

**BBB:** Ligand A (90.345) has excellent BBB penetration predicted. Ligand B (67.197) is lower, and concerning given the target is a CNS GPCR.

**Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual. This suggests a potential issue with the prediction method or the molecules themselves. However, we can still compare them relatively.

**Aqueous Solubility:** Both ligands have negative solubility values, which is also unusual.

**hERG:** Ligand A (0.66) has a slightly higher hERG risk than Ligand B (0.189), but both are relatively low.

**Microsomal Clearance:** Ligand B (-3.979) has a *negative* microsomal clearance, which is not physically possible and indicates a problem with the data. Ligand A (62.456) is a reasonable value.

**In vitro Half-Life:** Ligand A (50.577) has a better in vitro half-life than Ligand B (-0.898), which is also problematic.

**P-gp Efflux:** Ligand A (0.258) has lower P-gp efflux liability, which is favorable for CNS penetration. Ligand B (0.027) has very low efflux, which is good, but the other ADME properties are concerning.

**Binding Affinity:** Both ligands have the same binding affinity (-8.8 kcal/mol), which is excellent.

**Conclusion:**

Despite Ligand A's higher DILI risk and slightly elevated logP, it is the far more promising candidate. Ligand B has a very low logP, a problematic negative microsomal clearance, a negative half-life, and a significantly lower predicted BBB penetration. The negative values for Caco-2 and solubility are also red flags. Ligand A, while not perfect, has a much more favorable ADME profile, especially regarding BBB penetration, which is critical for a DRD2 ligand. The equal binding affinity makes the ADME properties the deciding factor.

Output:
1
2025-04-17 08:53:35,121 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (349.475 Da) is slightly lower, which could be beneficial for permeability. Ligand B (376.429 Da) is also good.

**TPSA:** Ligand A (67.6) is excellent, well below the 90 A^2 threshold for CNS targets. Ligand B (93.21) is still reasonable, but higher, potentially hindering BBB penetration slightly.

**logP:** Both ligands have good logP values (A: 2.553, B: 1.296) falling within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Both ligands have acceptable HBD (A: 1, B: 2) and HBA (A: 6, B: 6) counts.

**QED:** Both ligands have reasonable QED values (A: 0.763, B: 0.678), indicating good drug-like properties.

**DILI:** Ligand A (9.151) has a significantly lower DILI risk than Ligand B (55.525), which is a major advantage.

**BBB:** Both ligands have good BBB penetration (A: 72.664, B: 71.501), exceeding the 70% threshold for CNS targets.

**Caco-2 Permeability:** Ligand A (-4.994) has a more negative Caco-2 value, indicating lower permeability. Ligand B (-5.462) is also low, but slightly lower than A.

**Aqueous Solubility:** Both ligands have poor aqueous solubility (A: -1.549, B: -1.771). This might pose formulation challenges, but is less critical for CNS drugs that can utilize alternative transport mechanisms.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (A: 0.752, B: 0.154). Ligand B is slightly better here.

**Microsomal Clearance:** Ligand A (49.16) has a higher microsomal clearance than Ligand B (-0.325), suggesting lower metabolic stability. Ligand B has a negative clearance, which is highly desirable.

**In vitro Half-Life:** Ligand A (1.362) has a short in vitro half-life, while Ligand B (0.0) is essentially immediate degradation. This is a significant drawback for both, but worse for B.

**P-gp Efflux:** Ligand A (0.112) has lower P-gp efflux than Ligand B (0.083), which is beneficial for CNS penetration.

**Binding Affinity:** Ligand B (-7.8 kcal/mol) has a significantly stronger binding affinity than Ligand A (-7.2 kcal/mol). This 0.6 kcal/mol difference is substantial and could outweigh some of the ADME drawbacks.

**Overall Assessment:**

Ligand B has a superior binding affinity and better metabolic stability (lower Cl_mic). However, Ligand A has a much lower DILI risk and slightly better P-gp efflux. The solubility and Caco-2 permeability are poor for both. Given the importance of potency for GPCR ligands, and the significant difference in binding affinity, Ligand B is the more promising candidate, *despite* the higher DILI risk. The DILI risk could potentially be mitigated through structural modifications during lead optimization.

Output:
1
2025-04-17 08:53:35,121 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (344.415 Da) is slightly better, being closer to the middle of the range.

**TPSA:** Ligand A (95.16) is excellent for CNS penetration, being well below the 90 A^2 threshold. Ligand B (131.44) is higher, but still potentially acceptable, although less ideal.

**logP:** Ligand A (1.157) is within the optimal range (1-3). Ligand B (-0.615) is slightly below 1, which *could* indicate permeability issues, but isn't a dealbreaker.

**H-Bond Donors/Acceptors:** Ligand A (HBD=2, HBA=4) and Ligand B (HBD=4, HBA=7) both fall within acceptable limits (<=5 HBD and <=10 HBA).

**QED:** Both ligands have reasonable QED scores (A: 0.573, B: 0.448), indicating drug-like properties. Ligand A is slightly better.

**DILI:** Both ligands have acceptable DILI risk (A: 36.72, B: 41.877), well below the 60 threshold.

**BBB:** This is a crucial parameter for a CNS target. Ligand A (59.597) is moderately good, but not excellent. Ligand B (14.541) is quite poor, suggesting limited brain penetration. This is a major drawback.

**Caco-2 Permeability:** Ligand A (-5.353) and Ligand B (-6.223) both have negative Caco-2 values, which is unusual and suggests poor permeability. However, these values are on a scale where negative values are possible, and the absolute magnitude isn't directly comparable to a percentile.

**Aqueous Solubility:** Both ligands have very poor aqueous solubility (-1.881 and -1.657 respectively). This could pose formulation challenges.

**hERG Inhibition:** Both ligands show very low hERG inhibition risk (A: 0.11, B: 0.053).

**Microsomal Clearance:** Both ligands have negative Cl_mic values, which is unusual. This likely indicates very *slow* clearance and high metabolic stability, which is favorable.

**In vitro Half-Life:** Both ligands have very long in vitro half-lives (A: -32.771, B: -11.524), further supporting high metabolic stability.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (A: 0.016, B: 0.01). This is excellent for CNS penetration.

**Binding Affinity:** Ligand A (-8.9 kcal/mol) has a significantly stronger binding affinity than Ligand B (-7.0 kcal/mol). This difference of 1.9 kcal/mol is substantial and could outweigh minor ADME drawbacks.

**Overall Assessment:**

Ligand A is the superior candidate. While both have solubility issues and unusual Caco-2 values, Ligand A's significantly better BBB penetration and much stronger binding affinity are decisive advantages for a CNS-targeting GPCR like DRD2. The slightly better QED and TPSA also contribute to its favorability. Ligand B's very poor BBB score is a major concern.

Output:
0
2025-04-17 08:53:35,121 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (346.431 and 339.439 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (95.74) is slightly higher than Ligand B (75.43). For CNS targets, we ideally want TPSA <= 90. Ligand B is better here.

**logP:** Ligand A (1.055) is within the optimal range (1-3), while Ligand B (3.138) is at the higher end but still acceptable.

**H-Bond Donors:** Both ligands have 2 HBD, which is within the acceptable limit of <=5.

**H-Bond Acceptors:** Ligand A has 4 HBA, and Ligand B has 3. Both are below the threshold of <=10.

**QED:** Both ligands have similar QED values (0.833 and 0.814), indicating good drug-likeness.

**DILI:** Ligand A (23.769) has a significantly lower DILI risk than Ligand B (39.201). This is a major advantage for Ligand A.

**BBB:** Ligand A (79.992) has a better BBB penetration percentile than Ligand B (71.656). Both are reasonably good, but A is preferable for a CNS target.

**Caco-2 Permeability:** Ligand A (-5.337) has worse Caco-2 permeability than Ligand B (-4.977). Higher values are better, so B is slightly favored.

**Aqueous Solubility:** Ligand A (-2.421) has better aqueous solubility than Ligand B (-3.444).

**hERG Inhibition:** Ligand A (0.352) has a lower hERG inhibition liability than Ligand B (0.848), indicating a lower risk of cardiotoxicity.

**Microsomal Clearance:** Ligand A (-36.291) has much lower microsomal clearance than Ligand B (-6.923), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (-7.031) has a much longer in vitro half-life than Ligand B (68.401). This is a significant advantage for Ligand A.

**P-gp Efflux:** Ligand A (0.011) has significantly lower P-gp efflux liability than Ligand B (0.128), which is crucial for CNS penetration.

**Binding Affinity:** Ligand B (-9.2) has a slightly stronger binding affinity than Ligand A (-8.0). However, the difference is not substantial enough to outweigh the numerous advantages of Ligand A.

**Overall Assessment:**

Ligand A consistently outperforms Ligand B in critical ADME properties for a CNS-targeting GPCR, including DILI, BBB, metabolic stability (Cl_mic, t1/2), and P-gp efflux. While Ligand B has a slightly better binding affinity and Caco-2 permeability, the superior safety profile and CNS penetration potential of Ligand A make it the more promising drug candidate.



Output:
0
2025-04-17 08:53:35,121 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B against the provided guidelines, with a strong emphasis on GPCR-specific properties (BBB, logP, Pgp, TPSA, and affinity) for DRD2.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (335.382 Da) is slightly lower, which could be beneficial for permeability. Ligand B (364.475 Da) is also good.

**TPSA:** Ligand A (37.61) is excellent, well below the 90 A^2 threshold for CNS targets. Ligand B (85.91) is higher, but still acceptable, though less ideal for CNS penetration.

**logP:** Ligand A (3.946) is at the upper end of the optimal range (1-3), potentially raising concerns about solubility and off-target effects. Ligand B (0.666) is quite low, which could hinder permeation.

**H-Bond Donors/Acceptors:** Ligand A has 0 HBD and 3 HBA, which is favorable. Ligand B has 0 HBD and 8 HBA, which is acceptable but higher, potentially impacting permeability.

**QED:** Both ligands have good QED scores (A: 0.675, B: 0.718), indicating good drug-like properties.

**DILI:** Both ligands have acceptable DILI risk (A: 68.05, B: 62.893), below the concerning threshold of 60.

**BBB:** Ligand A has a very high BBB penetration score (93.408), excellent for a CNS target like DRD2. Ligand B's BBB score (66.382) is lower, which is a significant disadvantage.

**Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and suggests a potential issue with the data or a very poor permeability. However, we must consider other factors.

**Aqueous Solubility:** Both have negative solubility values, which is also unusual and suggests a potential issue with the data or very poor solubility.

**hERG Inhibition:** Ligand A (0.821) has a slightly higher hERG risk than Ligand B (0.152), but both are relatively low.

**Microsomal Clearance:** Ligand A (90.221) has a higher microsomal clearance, indicating faster metabolism and potentially lower duration of action. Ligand B (33.608) has a significantly lower clearance, suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (39.911) has a moderate half-life. Ligand B (22.617) has a shorter half-life.

**P-gp Efflux:** Ligand A (0.585) has moderate P-gp efflux, while Ligand B (0.158) has low P-gp efflux, which is beneficial for CNS penetration.

**Binding Affinity:** Ligand B (-7.7 kcal/mol) has a significantly stronger binding affinity than Ligand A (-9.4 kcal/mol). This is a substantial advantage, potentially outweighing some of its ADME drawbacks.

**Overall Assessment:**

Considering the GPCR-specific priorities, Ligand A excels in BBB penetration and has a good TPSA. However, Ligand B's significantly stronger binding affinity (-7.7 vs -9.4 kcal/mol) is a major advantage. While Ligand B has a lower BBB score and a lower logP, the strong binding could compensate, especially if formulation strategies can address the solubility and permeability issues. The lower P-gp efflux of Ligand B is also a plus. The improved metabolic stability (lower Cl_mic) of Ligand B is also a benefit.

Output:
1
2025-04-17 08:53:35,121 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B based on the provided guidelines, prioritizing GPCR-specific properties (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (366.531 Da) is slightly higher than Ligand B (340.343 Da), but both are acceptable.

**TPSA:** Ligand A (57.7) is excellent for CNS penetration, well below the 90 A^2 threshold. Ligand B (135.17) is higher, approaching the 140 A^2 limit for oral absorption and less ideal for CNS targets.

**logP:** Both ligands have good logP values (A: 2.395, B: 1.51), falling within the optimal range of 1-3.

**H-Bond Donors/Acceptors:** Ligand A (HBD=1, HBA=6) is better than Ligand B (HBD=4, HBA=6) regarding the number of hydrogen bond donors.

**QED:** Both ligands have acceptable QED values (A: 0.838, B: 0.534), indicating good drug-like properties.

**DILI:** Ligand A (31.679) has a significantly lower DILI risk than Ligand B (94.765), which is a major concern.

**BBB:** Ligand A (80.845) has a very good BBB penetration percentile, exceeding the desirable >70% threshold for CNS targets. Ligand B (44.591) is considerably lower, suggesting poor brain exposure.

**Caco-2 Permeability:** Ligand A (-4.618) and Ligand B (-5.468) both have negative values, which is unusual. However, the magnitude is similar and doesn't strongly differentiate them.

**Aqueous Solubility:** Both ligands have poor aqueous solubility (-2.285 and -4.011 respectively), but Ligand B is worse.

**hERG Inhibition:** Ligand A (0.89) has a slightly higher hERG risk than Ligand B (0.126), but both are relatively low.

**Microsomal Clearance:** Ligand A (22.879) has a lower microsomal clearance than Ligand B (0.554), indicating better metabolic stability.

**In vitro Half-Life:** Ligand B (68.84) has a much longer in vitro half-life than Ligand A (23.814), which is a positive attribute.

**P-gp Efflux:** Ligand A (0.434) has lower P-gp efflux liability than Ligand B (0.004), which is favorable for CNS penetration.

**Binding Affinity:** Ligand B (-9.7 kcal/mol) has a significantly stronger binding affinity than Ligand A (-7.7 kcal/mol). This is a substantial advantage, exceeding the 1.5 kcal/mol difference threshold.

**Overall Assessment:**

While Ligand B boasts a superior binding affinity, Ligand A is a more balanced candidate. The critical factors for a CNS-targeting GPCR drug are BBB penetration, metabolic stability, and safety. Ligand A excels in BBB (80.845), has a much lower DILI risk (31.679 vs 94.765), and better metabolic stability (lower Cl_mic). Ligand B's high DILI risk and poor BBB penetration are major red flags. The affinity difference, while significant, can potentially be addressed through further optimization, whereas fixing the ADME liabilities of Ligand B would be more challenging.

Output:
0
2025-04-17 08:53:35,121 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (343.387 Da) is slightly lower, which could be beneficial for permeability. Ligand B (364.471 Da) is also acceptable.

**TPSA:** Ligand A (105.12) is slightly above the optimal <90 for CNS targets, but still reasonable. Ligand B (83.89) is excellent, falling well within the desired range.

**logP:** Ligand A (0.945) is a bit low, potentially hindering membrane permeability. Ligand B (1.514) is better, falling within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A has 3 HBD and 5 HBA, which are acceptable. Ligand B has 1 HBD and 6 HBA, also acceptable.

**QED:** Both ligands have good QED scores (Ligand A: 0.567, Ligand B: 0.858), suggesting good drug-like properties. Ligand B is significantly better.

**DILI:** Ligand A has a DILI risk of 87.786, which is quite high. Ligand B has a much lower DILI risk of 35.401, a significant advantage.

**BBB:** Ligand A has a BBB penetration of 51.842, which is below the desirable >70 for CNS targets. Ligand B has a BBB penetration of 47.111, also below the desired threshold, but not drastically so.

**Caco-2:** Both ligands have negative Caco-2 values (-5.017 and -5.19), which is unusual and suggests poor permeability. This is a significant concern for both.

**Aqueous Solubility:** Both ligands have very poor aqueous solubility (-4.632 and -1.303). This is a major drawback for both compounds.

**hERG:** Both ligands have very low hERG inhibition liability (0.177 and 0.118), which is excellent.

**Microsomal Clearance:** Ligand A has a clearance of 6.214 mL/min/kg, which is moderate. Ligand B has a negative clearance (-0.379), which is highly unusual and likely indicates very high metabolic stability.

**In vitro Half-Life:** Ligand A has a half-life of 70.236 hours, which is excellent. Ligand B has a half-life of 8.29 hours, which is acceptable but not as good as Ligand A.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.101 and 0.029), which is favorable for CNS penetration.

**Binding Affinity:** Both ligands have excellent binding affinities (-8.9 kcal/mol and -8.1 kcal/mol). Ligand A has a slightly better affinity, but the difference is less than 1.5 kcal/mol.

**Overall Assessment:**

Ligand B is the better candidate despite the poor Caco-2 and solubility. The significantly lower DILI risk, better QED, and excellent metabolic stability (negative Cl_mic) are major advantages. While both have suboptimal BBB penetration, Ligand B's other properties are more favorable. The slightly better affinity of Ligand A is outweighed by its higher DILI risk and lower QED. The negative Caco-2 values for both are concerning and would require investigation, but can potentially be addressed through formulation strategies.

Output:
1
2025-04-17 08:53:35,122 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (344.455 and 349.435 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (50.8) is significantly better than Ligand B (80.56). For CNS targets, we want TPSA <= 90, and A is comfortably within that, while B is approaching the upper limit.

**logP:** Ligand A (2.453) is optimal (1-3). Ligand B (0.676) is a bit low, potentially hindering permeability.

**H-Bond Donors/Acceptors:** Ligand A (1 HBD, 4 HBA) and Ligand B (0 HBD, 6 HBA) both have reasonable numbers, well within the guidelines.

**QED:** Both ligands have similar QED values (0.787 and 0.723), indicating good drug-likeness.

**DILI:** Ligand A (14.192) has a much lower DILI risk than Ligand B (42.575), which is a significant advantage.

**BBB:** Both ligands have excellent BBB penetration (79.721 and 78.364), meeting the >70% threshold for CNS targets.

**Caco-2 Permeability:** Both have negative values, which is unusual. Assuming these are logP-scale values, lower values indicate poorer permeability. Ligand A (-4.695) is slightly better than Ligand B (-4.939).

**Aqueous Solubility:** Both have negative values, suggesting poor solubility. Ligand A (-2.176) is slightly better than Ligand B (-0.931).

**hERG:** Ligand A (0.702) has a slightly higher hERG risk than Ligand B (0.08), but both are relatively low.

**Microsomal Clearance:** Ligand A (51.493) has a higher clearance than Ligand B (41.12), indicating lower metabolic stability.

**In vitro Half-Life:** Ligand B (-4.548) has a significantly longer half-life than Ligand A (18.507).

**P-gp Efflux:** Ligand A (0.247) has lower P-gp efflux than Ligand B (0.075), which is favorable for CNS exposure.

**Binding Affinity:** Ligand A (-8.4 kcal/mol) has a substantially better binding affinity than Ligand B (-0.0 kcal/mol). This is a crucial difference. A >1.5 kcal/mol advantage in affinity can outweigh minor ADME drawbacks.

**Overall Assessment:**

Ligand A is the stronger candidate. While Ligand B has a better half-life and slightly lower hERG risk, Ligand A excels in critical areas: significantly better binding affinity, lower DILI risk, and a more favorable TPSA. The slightly higher clearance of Ligand A is a concern, but the superior affinity is likely to compensate. The lower logP of Ligand B is a significant drawback for a CNS target.

Output:
1
2025-04-17 08:53:35,122 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (344.46 and 365.46 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (88.32) is excellent, falling well below the 90 A^2 threshold for CNS targets. Ligand B (99.5) is still reasonable, but less optimal.

**logP:** Ligand A (2.13) is within the optimal 1-3 range. Ligand B (1.04) is at the lower end, potentially impacting permeability, but still acceptable.

**H-Bond Donors/Acceptors:** Ligand A has 2 HBD and 4 HBA, both within acceptable limits. Ligand B has 1 HBD and 5 HBA, also acceptable.

**QED:** Both ligands have good QED scores (0.876 and 0.812), indicating good drug-like properties.

**DILI:** Ligand A (26.87) has a significantly lower DILI risk than Ligand B (68.17). This is a major advantage.

**BBB:** Ligand A (89.22) has a very good BBB penetration percentile, exceeding the desirable >70% threshold for CNS targets. Ligand B (48.90) is considerably lower, raising concerns about CNS exposure.

**Caco-2 Permeability:** Both have negative Caco-2 values which is unusual and indicates poor permeability.

**Aqueous Solubility:** Both have negative solubility values which is unusual and indicates poor solubility.

**hERG:** Both ligands have similar, low hERG inhibition liability (0.501 and 0.578).

**Microsomal Clearance:** Ligand A (2.44) has much lower microsomal clearance than Ligand B (36.94), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (-18.29) has a negative half-life, which is unusual. Ligand B (-7.99) is also negative, but less so.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.012 and 0.07).

**Binding Affinity:** Ligand B (-8.5 kcal/mol) has a slightly better binding affinity than Ligand A (-7.6 kcal/mol), a difference of 0.9 kcal/mol. While a difference of >1.5 kcal/mol usually outweighs other factors, this is not the case here.

**Overall Assessment:**

Ligand A is the stronger candidate. While Ligand B has slightly better binding affinity, Ligand A excels in crucial ADME properties for a CNS-targeting GPCR ligand: significantly lower DILI risk, much better BBB penetration, and lower microsomal clearance. The negative values for Caco-2 and Solubility are concerning for both, but the other advantages of Ligand A are more compelling.

Output:
1
2025-04-17 08:53:35,122 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (337.375 and 343.427 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (57.53) is excellent, well below the 90 A^2 threshold for CNS targets. Ligand B (86.34) is still reasonable but less optimal, approaching the 90 A^2 limit.

**3. logP:** Ligand A (3.63) is within the optimal 1-3 range. Ligand B (2.36) is also acceptable, though slightly lower, potentially impacting permeability.

**4. H-Bond Donors:** Ligand A (0) is good. Ligand B (1) is also acceptable.

**5. H-Bond Acceptors:** Ligand A (5) is good. Ligand B (4) is also good.

**6. QED:** Both ligands have good QED scores (0.682 and 0.889, respectively), indicating drug-like properties.

**7. DILI:** Ligand A (81.97) has a higher DILI risk than Ligand B (21.869). This is a significant negative for Ligand A.

**8. BBB:** Ligand A (63.901) and Ligand B (71.501) both have reasonable BBB penetration, but Ligand B is better, exceeding 70%, which is desirable for CNS targets.

**9. Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and suggests a potential issue with the data or modeling. However, the values are similar, so it doesn't differentiate the ligands significantly.

**10. Aqueous Solubility:** Both have negative solubility values, again suggesting a potential data/modeling issue. Similar to Caco-2, this doesn't clearly favor one ligand.

**11. hERG Inhibition:** Both ligands have low hERG inhibition risk (0.447 and 0.559).

**12. Microsomal Clearance:** Ligand A (114.561) has higher microsomal clearance than Ligand B (20.517), indicating lower metabolic stability.

**13. In vitro Half-Life:** Ligand B (18.343) has a longer in vitro half-life than Ligand A (10.749).

**14. P-gp Efflux:** Both ligands have low P-gp efflux liability (0.58 and 0.08), which is good for CNS penetration. Ligand B is better.

**15. Binding Affinity:** Both ligands have excellent binding affinities (-9.4 and -8.8 kcal/mol). Ligand A has a slightly better affinity, but the difference (0.6 kcal/mol) is not substantial enough to overcome its other weaknesses.

**Overall Assessment:**

Ligand B is the more promising candidate. While Ligand A has a slightly better binding affinity, Ligand B exhibits significantly better ADME properties, particularly lower DILI risk, better BBB penetration, lower microsomal clearance, and longer half-life. These factors are crucial for a CNS-targeting drug, and outweigh the small difference in binding affinity. The lower Pgp efflux for Ligand B is also a benefit.

Output:
1
2025-04-17 08:53:35,122 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (369.845 and 368.459 Da) fall comfortably within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (84.86) is significantly better than Ligand B (93.65). For CNS targets, we want TPSA <= 90, so Ligand A is preferable.

**3. logP:** Ligand A (2.599) is within the optimal 1-3 range. Ligand B (1.037) is on the lower end, potentially hindering permeation.

**4. H-Bond Donors:** Both have acceptable HBD counts (2 and 1, respectively), well below the threshold of 5.

**5. H-Bond Acceptors:** Ligand A (4) is better than Ligand B (7), keeping within the desirable range of <=10.

**6. QED:** Ligand A (0.735) has a higher QED than Ligand B (0.541), indicating a more drug-like profile.

**7. DILI:** Both ligands have similar DILI risk (57.929 and 56.572), both falling under the 'good' risk category (<60).

**8. BBB:** This is a crucial parameter for a CNS target like DRD2. Ligand B (69.717) has a substantially better BBB percentile than Ligand A (44.591). This is a significant advantage for Ligand B.

**9. Caco-2 Permeability:** Both have negative values (-5.497 and -5.133), which is unusual and suggests poor permeability. However, the scale isn't specified, so it's hard to interpret.

**10. Aqueous Solubility:** Both have negative values (-2.167 and -2.238), suggesting poor solubility. Again, the scale is unclear.

**11. hERG Inhibition:** Both have very low hERG inhibition liability (0.028 and 0.167), which is excellent.

**12. Microsomal Clearance:** Ligand A (-7.306) has significantly lower (better) microsomal clearance than Ligand B (28.685). This suggests better metabolic stability for Ligand A.

**13. In vitro Half-Life:** Ligand A (12.286) has a longer half-life than Ligand B (10.282).

**14. P-gp Efflux:** Both have very low P-gp efflux liability (0.012 and 0.022), which is favorable.

**15. Binding Affinity:** Ligand A (-8.8 kcal/mol) has a significantly stronger binding affinity than Ligand B (-6.9 kcal/mol). This is a substantial advantage (over 1.5 kcal/mol difference).

**Overall Assessment:**

Ligand A excels in TPSA, logP, QED, metabolic stability (Cl_mic), half-life, and, crucially, binding affinity. Ligand B's main advantage is its better BBB penetration. However, the significantly stronger binding affinity of Ligand A (-8.8 vs -6.9 kcal/mol) is a major factor. For a GPCR, strong binding can often compensate for slightly less favorable BBB penetration, especially if other properties are good. The lower TPSA and better logP of Ligand A also contribute to its potential for CNS penetration.

Output:
1
2025-04-17 08:53:35,122 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (357.382 and 354.397 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (104.81) is slightly above the preferred <90 for CNS targets, but still reasonable. Ligand B (50.8) is excellent, well below the threshold.

**logP:** Ligand A (-0.338) is a bit low, potentially hindering permeation. Ligand B (2.404) is within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A has 2 HBD and 5 HBA, acceptable. Ligand B has 1 HBD and 4 HBA, also acceptable.

**QED:** Both ligands have good QED scores (0.517 and 0.882), indicating drug-like properties.

**DILI:** Both ligands have similar, acceptable DILI risk (36.758 and 36.836 percentile).

**BBB:** Ligand B (84.141) has a significantly better BBB penetration score than Ligand A (65.452). This is a crucial advantage for a CNS target like DRD2.

**Caco-2 Permeability:** Both have negative values, indicating poor permeability.

**Aqueous Solubility:** Both have negative values, indicating poor solubility.

**hERG:** Both ligands show low hERG inhibition risk (0.161 and 0.355).

**Microsomal Clearance:** Ligand A (13.965) has a lower (better) microsomal clearance than Ligand B (42.267), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (-28.34) has a negative half-life, which is not possible. Ligand B (-6.693) also has a negative half-life, which is not possible.

**P-gp Efflux:** Both have very low P-gp efflux liability (0.014 and 0.063), which is favorable for CNS penetration.

**Binding Affinity:** Both ligands have similar binding affinities (-8.0 and -7.7 kcal/mol), both of which are excellent. The difference is not substantial enough to outweigh other factors.

**Conclusion:**

Considering the GPCR-specific priorities, Ligand B is the more promising candidate. Its superior BBB penetration (84.141 vs 65.452) and optimal logP (2.404 vs -0.338) are significant advantages for a CNS-targeting drug. While Ligand A has slightly better metabolic stability, the improved CNS exposure potential of Ligand B is more critical for DRD2. The negative half-life values are concerning for both, but do not change the overall ranking.

Output:
1
2025-04-17 08:53:35,123 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 drug candidates, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (369.447 and 350.419 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (119.67) is better than Ligand B (87.9). Both are below the 140 threshold for oral absorption and, importantly, below the 90 threshold desirable for CNS targets.

**3. logP:** Ligand A (-0.25) is slightly lower than optimal (1-3), potentially hindering permeation. Ligand B (0.176) is also on the lower side, but closer to the desired range.

**4. H-Bond Donors:** Ligand A (2) is acceptable, while Ligand B (1) is even better, both being within the limit of 5.

**5. H-Bond Acceptors:** Ligand A (8) is acceptable, while Ligand B (6) is better, both being within the limit of 10.

**6. QED:** Both ligands have good QED scores (0.709 and 0.765, respectively), indicating a generally drug-like profile.

**7. DILI:** Ligand A (63.823) has a higher DILI risk than Ligand B (48.197), which is preferable.

**8. BBB:** Ligand A (83.792) has a significantly better BBB penetration percentile than Ligand B (56.572). This is a *critical* factor for a CNS target like DRD2.

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.045 and -4.529), which is unusual and suggests poor permeability. However, these values are on a scale where negative values are possible and don't necessarily disqualify a compound, especially if other properties are favorable.

**10. Aqueous Solubility:** Both ligands have negative solubility values (-2.779 and -1.056), which is also unusual. Similar to Caco-2, these values don't automatically disqualify the compounds, but solubility is a concern.

**11. hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.211 and 0.137, respectively).

**12. Microsomal Clearance:** Ligand A (10.658) has a lower microsomal clearance than Ligand B (24.381), suggesting better metabolic stability.

**13. In vitro Half-Life:** Ligand A (-13.565) has a negative half-life, which is not physically possible and indicates a potential issue with the data or the model. Ligand B (10.641) has a reasonable half-life.

**14. P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.035 and 0.153, respectively), which is good for CNS penetration.

**15. Binding Affinity:** Both ligands have the same binding affinity (-7.4 kcal/mol), which is excellent.

**Overall Assessment:**

Ligand A has a superior BBB score and lower microsomal clearance, which are highly desirable for a CNS GPCR target. However, the negative in vitro half-life is a major red flag. Ligand B has a more reasonable half-life and slightly better DILI and solubility profiles. Given the equal binding affinity, the significantly better BBB penetration of Ligand A would typically make it the preferred candidate. However, the impossible half-life value for Ligand A raises serious concerns about the reliability of its predicted ADME profile. Therefore, I'm leaning towards Ligand B.

Output:
1
2025-04-17 08:53:35,123 - INFO - Reasoning:

Let's analyze Ligand A and Ligand B against the provided guidelines, prioritizing GPCR-specific properties (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (368.865 and 387.889 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (89.53) is better than Ligand B (78.95), both are below the 90 A^2 threshold for CNS targets.

**logP:** Both ligands have good logP values (1.533 and 1.145), falling within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A has 2 HBD and 4 HBA, while Ligand B has 1 HBD and 5 HBA. Both are within acceptable limits.

**QED:** Both ligands have similar QED scores (0.846 and 0.821), indicating good drug-likeness.

**DILI:** Both ligands have relatively high DILI risk (59.442 and 61.807 percentile). This is a concern, but we'll consider it later in the context of other properties.

**BBB:** Ligand B (61.031 percentile) significantly outperforms Ligand A (25.32 percentile) in BBB penetration, a critical factor for CNS targets like DRD2.

**Caco-2 Permeability:** Ligand A (-4.997) has a worse Caco-2 permeability than Ligand B (-4.675).

**Aqueous Solubility:** Ligand A (-3.183) has a worse aqueous solubility than Ligand B (-2.215).

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.394 and 0.164 percentile).

**Microsomal Clearance:** Ligand A (6.389 mL/min/kg) has a lower microsomal clearance than Ligand B (29.304 mL/min/kg), indicating better metabolic stability.

**In vitro Half-Life:** Ligand A (-13.147 hours) has a negative in vitro half-life, which is concerning and likely an error in the data. Ligand B (11.864 hours) has a reasonable half-life.

**P-gp Efflux:** Ligand A (0.326) has lower P-gp efflux than Ligand B (0.062), which is favorable for CNS penetration.

**Binding Affinity:** Ligand B (-7.1 kcal/mol) has a slightly better binding affinity than Ligand A (-8.0 kcal/mol). While A is better, the difference is not huge.

**Overall Assessment:**

Ligand B is the more promising candidate. Its significantly better BBB penetration (61.031 vs 25.32) is a major advantage for a CNS target. While Ligand A has better metabolic stability and P-gp efflux, the importance of BBB penetration for DRD2 outweighs these benefits. The half-life of Ligand A is also a red flag. The DILI risk is similar for both, and both have acceptable logP, TPSA, and hERG values. The slight difference in binding affinity is not enough to overcome the BBB disadvantage of Ligand A.

Output:
1
2025-04-17 08:53:35,123 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the acceptable range (200-500 Da). Ligand A (361.389 Da) is slightly preferred as it's closer to the ideal range.

**TPSA:** Ligand A (96.53) is excellent for CNS penetration, being well below 90. Ligand B (64.11) is also good.

**logP:** Ligand A (1.033) is within the optimal range. Ligand B (3.832) is approaching the upper limit, potentially raising concerns about solubility and off-target effects, but still acceptable.

**H-Bond Donors/Acceptors:** Ligand A (3 HBD, 4 HBA) and Ligand B (1 HBD, 5 HBA) both have reasonable counts, falling within the guidelines.

**QED:** Both ligands have acceptable QED values (Ligand A: 0.4, Ligand B: 0.766). Ligand B is significantly better.

**DILI:** Ligand A (31.563) has a much lower DILI risk than Ligand B (55.409), which is a significant advantage.

**BBB:** Ligand A (80.458) has a good BBB penetration percentile, exceeding the 70% threshold for CNS targets. Ligand B (58.938) is considerably lower and less desirable for a CNS target like DRD2.

**Caco-2 Permeability:** Both have negative values, which is unusual and suggests poor permeability. However, the scale is not specified, so it's hard to interpret.

**Aqueous Solubility:** Both ligands have negative values, indicating poor solubility. This is a concern, but can sometimes be overcome with formulation strategies.

**hERG Inhibition:** Ligand A (0.246) has a very low hERG risk, which is excellent. Ligand B (0.731) is higher, indicating a greater potential for cardiotoxicity.

**Microsomal Clearance:** Ligand A (-8.408) has a negative clearance, which is not physically possible. This is likely an error in the data. Ligand B (48.108) has a moderate clearance.

**In vitro Half-Life:** Ligand A (1.279 hours) has a short half-life. Ligand B (15.902 hours) has a much longer half-life, which is highly desirable.

**P-gp Efflux:** Ligand A (0.022) has very low P-gp efflux, which is excellent for CNS penetration. Ligand B (0.353) has moderate P-gp efflux.

**Binding Affinity:** Both ligands have the same binding affinity (-8.4 kcal/mol), which is excellent and strong.

**Overall Assessment:**

Despite the questionable values for Caco-2 and solubility, and the impossible clearance value for Ligand A, Ligand A is the better candidate. It has a significantly lower DILI risk, better BBB penetration, and lower P-gp efflux. The strong affinity is equal for both. The longer half-life of Ligand B is a benefit, but the higher DILI risk and lower BBB penetration are major drawbacks for a CNS target. The negative clearance for Ligand A is a red flag, but the other advantages are substantial.

Output:
0
2025-04-17 08:53:35,123 - INFO - Batch 487 complete. Total preferences: 7792
2025-04-17 08:53:35,123 - INFO - Processing batch 488/512...
2025-04-17 08:54:20,253 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (350.419 and 354.479 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (96.55) is slightly above the optimal <90 for CNS targets, but still reasonable. Ligand B (61.92) is excellent, well below 90.

**logP:** Ligand A (0.572) is a bit low, potentially hindering membrane permeability. Ligand B (3.576) is within the optimal 1-3 range.

**H-Bond Donors:** Ligand A (2) and Ligand B (0) are both acceptable, below the limit of 5.

**H-Bond Acceptors:** Both ligands (A: 5, B: 5) are within the acceptable limit of 10.

**QED:** Both ligands have good QED scores (A: 0.782, B: 0.824), indicating drug-like properties.

**DILI:** Ligand A (46.413) has a slightly higher DILI risk than Ligand B (31.989), but both are below the concerning threshold of 60.

**BBB:** This is a critical parameter for a CNS target like DRD2. Ligand A (47.693) has a poor BBB penetration percentile. Ligand B (84.413) has excellent BBB penetration.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.914 and -4.931). This is unusual and suggests potential issues with in vitro permeability assessment or a calculation error. It's difficult to interpret without more information, but it doesn't immediately disqualify either.

**Aqueous Solubility:** Both ligands have very poor aqueous solubility (-2.576 and -5.08). This is a significant concern for bioavailability.

**hERG Inhibition:** Ligand A (0.27) has a lower hERG risk than Ligand B (0.718), which is preferable.

**Microsomal Clearance:** Ligand A (-10.691) has much lower (better) microsomal clearance than Ligand B (67.223), indicating greater metabolic stability.

**In vitro Half-Life:** Ligand A (22.331) has a longer half-life than Ligand B (14.296), which is desirable.

**P-gp Efflux:** Ligand A (0.029) has very low P-gp efflux, while Ligand B (0.626) has moderate efflux. Lower efflux is better for CNS exposure.

**Binding Affinity:** Ligand B (-8.1 kcal/mol) has a significantly stronger binding affinity than Ligand A (-6.8 kcal/mol). This >1.5 kcal/mol difference is substantial and can outweigh some ADME drawbacks.

**Overall Assessment:**

Ligand B clearly wins on the most important criteria for a CNS-targeting GPCR: **BBB penetration and binding affinity**. The stronger binding affinity is a major advantage. While its logP is good, its solubility and P-gp efflux are less ideal than Ligand A, and its hERG risk is higher. However, the superior BBB penetration and affinity are likely to be more impactful for CNS efficacy. Ligand A has better metabolic stability and lower P-gp efflux, but its poor BBB penetration is a deal-breaker for a CNS target. The solubility issues for both are concerning and would require formulation strategies.

Output:
1
2025-04-17 08:54:20,254 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (356.463 and 361.486 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (106.94) is better than Ligand B (29.77). For CNS targets, TPSA should be <= 90, and both meet this criterion, but A is closer to the upper limit and may have permeability issues. B is excellent.

**logP:** Ligand A (0.622) is suboptimal, being below the preferred 1-3 range. Ligand B (4.381) is high, potentially causing solubility and off-target issues.

**H-Bond Donors/Acceptors:** Ligand A has 3 HBD and 5 HBA, which are acceptable. Ligand B has 0 HBD and 5 HBA, also acceptable.

**QED:** Both ligands have good QED values (0.532 and 0.625), suggesting good drug-like properties.

**DILI:** Ligand A (14.114) has a significantly lower DILI risk than Ligand B (46.219), which is a major advantage.

**BBB:** Ligand B (78.402) has a much higher BBB penetration percentile than Ligand A (19.232). This is crucial for a CNS target like DRD2.

**Caco-2 Permeability:** Ligand A (-5.134) has poor Caco-2 permeability, while Ligand B (-4.573) is also poor, but slightly better.

**Aqueous Solubility:** Ligand A (-0.475) has slightly better solubility than Ligand B (-4.177), but both are poor.

**hERG Inhibition:** Ligand A (0.1) has a very low hERG inhibition risk, while Ligand B (0.98) has a moderate risk.

**Microsomal Clearance:** Ligand A (1.226) has much lower microsomal clearance than Ligand B (80.242), indicating better metabolic stability.

**In vitro Half-Life:** Ligand A (-4.668) has a shorter half-life than Ligand B (-3.258), but both are poor.

**P-gp Efflux:** Ligand A (0.029) has very low P-gp efflux, which is excellent for CNS penetration. Ligand B (0.936) has moderate P-gp efflux.

**Binding Affinity:** Ligand B (-7.9 kcal/mol) has a stronger binding affinity than Ligand A (-6.9 kcal/mol). The difference is 1.0 kcal/mol, which is significant.

**Overall Assessment:**

Ligand B has a significantly better binding affinity and BBB penetration, which are critical for a CNS GPCR target. However, it suffers from higher DILI risk, higher logP, higher microsomal clearance, and moderate P-gp efflux. Ligand A has better safety profiles (DILI, hERG, P-gp), better metabolic stability, and a slightly better solubility, but its BBB penetration is very poor, and its logP is suboptimal.

The stronger binding affinity of Ligand B is a substantial advantage. While its ADME properties are less ideal, the 1.0 kcal/mol difference in binding could be enough to overcome these drawbacks, especially if further optimization can address the DILI and logP issues. The poor BBB penetration of Ligand A is a major concern for a CNS target.

Output:
1
2025-04-17 08:54:20,254 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (365.411 and 342.439 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (104.81) is higher than the preferred <90 for CNS targets, while Ligand B (58.64) is well within the range. This is a significant advantage for Ligand B.

**3. logP:** Ligand A (0.108) is quite low, potentially hindering membrane permeability. Ligand B (1.86) is within the optimal 1-3 range. This favors Ligand B.

**4. H-Bond Donors:** Ligand A (2) and Ligand B (1) are both acceptable, being less than 5.

**5. H-Bond Acceptors:** Ligand A (5) and Ligand B (3) are both acceptable, being less than 10.

**6. QED:** Both ligands have good QED scores (0.74 and 0.912), indicating good drug-like properties.

**7. DILI:** Ligand A (64.831) has a higher DILI risk than Ligand B (31.601). Lower is better, so Ligand B is preferable.

**8. BBB:** Ligand B (77.007) has a significantly better BBB penetration score than Ligand A (57.425). This is crucial for a CNS target like DRD2, making Ligand B a stronger candidate.

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.865 and -4.795), which is unusual and suggests poor permeability. However, the scale isn't specified, so it's hard to interpret.

**10. Aqueous Solubility:** Both ligands have negative solubility values (-2.429 and -2.498), which is also unusual and suggests poor solubility.

**11. hERG Inhibition:** Both ligands have low hERG inhibition risk (0.179 and 0.299), which is good.

**12. Microsomal Clearance:** Ligand A (-0.083) has a very low (and potentially problematic) clearance, suggesting very slow metabolism. Ligand B (40.596) has a higher, more typical clearance. While lower clearance is generally better, extremely low clearance can indicate issues with assay artifacts or poor in vivo behavior.

**13. In vitro Half-Life:** Ligand B (2.996) has a longer half-life than Ligand A (0.887). This is favorable.

**14. P-gp Efflux:** Ligand A (0.02) has very low P-gp efflux, which is good. Ligand B (0.17) also has low P-gp efflux, but slightly higher than Ligand A.

**15. Binding Affinity:** Ligand A (-8.3 kcal/mol) has a significantly stronger binding affinity than Ligand B (-0.0 kcal/mol). This is a major advantage for Ligand A.

**Overall Assessment:**

Despite the superior binding affinity of Ligand A, its poor logP, higher TPSA, and lower BBB penetration are significant drawbacks for a CNS-targeting GPCR. Ligand B, while having a much weaker binding affinity, possesses a more favorable ADME profile, particularly regarding TPSA, logP, and BBB penetration. The better BBB score and more reasonable ADME properties of Ligand B outweigh the affinity difference, especially considering the potential for optimization of Ligand B's affinity.

Output:
1
2025-04-17 08:54:20,254 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (348.443 Da) is slightly preferred as it's closer to the lower end, potentially aiding permeability.

**TPSA:** Both ligands have TPSA values below the 90 A^2 threshold desirable for CNS targets. Ligand B (71.68 A^2) is slightly better than Ligand A (84.5 A^2) in this regard.

**logP:** Both ligands have logP values within the optimal range (1-3). Ligand A (1.534) is slightly lower, which could be a minor drawback for permeability, but Ligand B (3.194) is approaching the upper limit and could present solubility issues.

**H-Bond Donors/Acceptors:** Both have 2 HBD and 4 HBA, which are within acceptable limits.

**QED:** Both ligands have reasonable QED scores, but Ligand B (0.605) is better than Ligand A (0.376), indicating a more drug-like profile.

**DILI:** Ligand A (22.8) has a significantly lower DILI risk than Ligand B (32.726). This is a substantial advantage for Ligand A.

**BBB:** Ligand B (90.306) has a much higher BBB penetration percentile than Ligand A (54.905). This is a *critical* advantage for a CNS target like DRD2.

**Caco-2 Permeability:** Ligand A (-4.66) shows poor Caco-2 permeability, while Ligand B (-5.35) is also poor, but slightly better.

**Aqueous Solubility:** Both ligands have negative solubility values, indicating poor aqueous solubility. Ligand A (-2.723) is slightly better than Ligand B (-3.374).

**hERG Inhibition:** Ligand A (0.091) has a very low hERG inhibition liability, a significant advantage. Ligand B (0.926) is higher, indicating a potential cardiotoxicity risk.

**Microsomal Clearance:** Ligand B (28.47 mL/min/kg) has lower microsomal clearance than Ligand A (55.404 mL/min/kg), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand B (1.793 hours) has a slightly longer half-life than Ligand A (-21.16 hours). However, the negative value for ligand A is concerning and likely an error.

**P-gp Efflux:** Ligand A (0.024) has very low P-gp efflux liability, which is excellent for CNS penetration. Ligand B (0.332) is higher, indicating more efflux.

**Binding Affinity:** Ligand B (-8.4 kcal/mol) has a significantly stronger binding affinity than Ligand A (-7.5 kcal/mol). This 1.9 kcal/mol difference is substantial and can outweigh many ADME drawbacks.

**Overall Assessment:**

Ligand B excels in BBB penetration and binding affinity, both crucial for a CNS GPCR target. It also has better metabolic stability and a slightly longer half-life. However, it has a higher DILI risk and P-gp efflux. Ligand A has a much lower DILI and P-gp efflux, and a lower hERG risk, but suffers from poor BBB penetration and weaker binding affinity.

The superior binding affinity and BBB penetration of Ligand B are the deciding factors, despite its slightly higher DILI and P-gp efflux. The strong binding is likely to allow for lower doses, potentially mitigating the DILI risk. The high BBB penetration is essential for CNS activity.

Output:
1
2025-04-17 08:54:20,254 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (368.499 and 373.469 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (87.66) is slightly above the optimal <90 for CNS targets, but still reasonable. Ligand B (56.67) is excellent, well below 90.

**logP:** Both ligands (2.322 and 2.218) are within the optimal 1-3 range.

**H-Bond Donors:** Ligand A has 3 HBDs, which is acceptable. Ligand B has 1 HBD, also acceptable.

**H-Bond Acceptors:** Both ligands have 5 HBAs, which is within the acceptable limit of <=10.

**QED:** Ligand B (0.86) has a significantly better QED score than Ligand A (0.591), indicating a more drug-like profile.

**DILI:** Ligand B (20.706) has a much lower DILI risk than Ligand A (41.799), which is a significant advantage.

**BBB:** Ligand B (91.896) has a very high BBB penetration score, highly desirable for a CNS target like DRD2. Ligand A (43.001) is considerably lower, and while not terrible, it's not ideal.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.74 and -4.673). These values are unusual and difficult to interpret without further context. However, given they are similarly negative, this isn't a major differentiator.

**Aqueous Solubility:** Both ligands have negative solubility values (-3.207 and -1.94). Again, unusual and difficult to interpret. Ligand B is slightly better.

**hERG:** Both ligands have low hERG inhibition liability (0.362 and 0.525), which is good.

**Microsomal Clearance:** Ligand B (8.744) has significantly lower microsomal clearance than Ligand A (61.867), indicating better metabolic stability.

**In vitro Half-Life:** Ligand B (-12.175) has a longer in vitro half-life than Ligand A (-11.423), which is a positive attribute.

**P-gp Efflux:** Ligand B (0.094) has much lower P-gp efflux liability than Ligand A (0.246), which is crucial for CNS penetration.

**Binding Affinity:** Ligand A (-7.6 kcal/mol) has a slightly better binding affinity than Ligand B (-6.9 kcal/mol). While a 0.7 kcal/mol difference is noticeable, it's not a huge gap, and can potentially be overcome with further optimization.

**Overall Assessment:**

Ligand B is the superior candidate. It excels in key areas for CNS GPCR targets: high BBB penetration, low DILI risk, low P-gp efflux, and good metabolic stability (low Cl_mic and longer t1/2). Its QED score is also significantly better. While Ligand A has slightly better binding affinity, the ADME properties of Ligand B are far more favorable, and the affinity difference is likely surmountable through further optimization.

Output:
1
2025-04-17 08:54:20,254 - INFO - Reasoning:
Let's analyze both ligands against the provided guidelines, prioritizing GPCR-specific properties (BBB, logP, Pgp, TPSA, and affinity).

**Ligand A:**

*   **MW:** 358.467 Da - Within the ideal range (200-500).
*   **TPSA:** 61.94 A<sup>2</sup> - Good for CNS penetration, well below the 90 A<sup>2</sup> threshold.
*   **logP:** 3.368 - Optimal, within the 1-3 range.
*   **HBD:** 0 - Acceptable, low.
*   **HBA:** 7 - Acceptable, within the limit of 10.
*   **QED:** 0.333 - Below the desirable 0.5, suggesting a less drug-like profile.
*   **DILI:** 65.607 - Moderate risk, above the preferred <40, but not extremely high.
*   **BBB:** 60.838 - Below the desirable >70 for CNS targets, a significant drawback.
*   **Caco-2:** -5.233 - Very poor permeability.
*   **Solubility:** -2.802 - Very poor solubility.
*   **hERG:** 0.846 - Low risk.
*   **Cl_mic:** 135.832 - High metabolic clearance, indicating poor metabolic stability.
*   **t1/2:** -10.607 - Very short half-life.
*   **Pgp:** 0.84 - Moderate efflux, not ideal.
*   **Affinity:** -7.5 kcal/mol - Excellent binding affinity.

**Ligand B:**

*   **MW:** 343.383 Da - Within the ideal range (200-500).
*   **TPSA:** 111.45 A<sup>2</sup> - Higher than ideal for CNS penetration, exceeding the 90 A<sup>2</sup> threshold.
*   **logP:** 0.194 - Low, potentially hindering permeation.
*   **HBD:** 3 - Acceptable.
*   **HBA:** 5 - Acceptable.
*   **QED:** 0.584 - Good drug-like properties, above 0.5.
*   **DILI:** 33.85 - Low risk, below 40.
*   **BBB:** 14.153 - Very poor CNS penetration.
*   **Caco-2:** -4.918 - Poor permeability.
*   **Solubility:** -2.543 - Poor solubility.
*   **hERG:** 0.27 - Low risk.
*   **Cl_mic:** 4.707 - Low metabolic clearance, indicating good metabolic stability.
*   **t1/2:** -8.417 - Short half-life, but not as bad as Ligand A.
*   **Pgp:** 0.036 - Very low efflux, a significant advantage.
*   **Affinity:** -6.5 kcal/mol - Good binding affinity, but less potent than Ligand A.

**Comparison & Decision:**

Both ligands have significant drawbacks. Ligand A has superior affinity (-7.5 kcal/mol vs -6.5 kcal/mol) but suffers from poor BBB penetration, poor solubility, poor permeability, high metabolic clearance, and a short half-life. Ligand B has better DILI, Pgp, and metabolic stability, but its TPSA is higher, logP is lower, and BBB penetration is very poor.

For a CNS target like DRD2, BBB penetration is critical. While Ligand A's affinity is better, its extremely low BBB score makes it unlikely to reach the target in sufficient concentrations. Ligand B's BBB is also poor, but its other properties are more favorable, and the affinity difference isn't large enough to overcome the BBB issue with Ligand A. The lower Pgp efflux for Ligand B is also a significant advantage.

Therefore, despite its lower affinity, Ligand B is the more promising starting point for optimization, as improvements to its affinity are more likely to yield a viable drug candidate than attempting to drastically improve the BBB penetration of Ligand A.

Output:
1
2025-04-17 08:54:20,254 - INFO - Reasoning:

Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (344.39 Da) is slightly lower, which could be advantageous for permeability.

**2. TPSA:** Ligand A (67.23) is significantly better than Ligand B (96.87).  For CNS targets, we want TPSA <= 90, so Ligand A is much closer to this threshold.

**3. logP:** Both ligands have good logP values (A: 2.535, B: 2.401), falling within the optimal range of 1-3.

**4. H-Bond Donors:** Ligand A (1) is preferable to Ligand B (2). Fewer HBDs generally improve permeability.

**5. H-Bond Acceptors:** Ligand A (4) is better than Ligand B (6). Lower HBA counts are generally favored for CNS penetration.

**6. QED:** Both ligands have good QED scores (A: 0.906, B: 0.831), indicating good drug-like properties.

**7. DILI:** Ligand B (83.676) has a higher DILI risk than Ligand A (53.858). While both are acceptable, A is better.

**8. BBB:** Ligand A (82.086) has a significantly better BBB percentile than Ligand B (57.193). This is *critical* for a CNS target like DRD2.

**9. Caco-2 Permeability:** Ligand A (-4.59) has a better Caco-2 permeability than Ligand B (-5.355).

**10. Aqueous Solubility:** Ligand A (-2.661) is better than Ligand B (-3.206).

**11. hERG Inhibition:** Both ligands have low hERG inhibition liability (A: 0.56, B: 0.276), which is good.

**12. Microsomal Clearance:** Ligand B (1.569) has much lower microsomal clearance than Ligand A (21.113), suggesting better metabolic stability. This is a significant advantage for B.

**13. In vitro Half-Life:** Ligand B (31.397) has a much longer in vitro half-life than Ligand A (-10.977). This is a major advantage for B.

**14. P-gp Efflux:** Ligand A (0.162) has lower P-gp efflux than Ligand B (0.09). Lower efflux is preferable for CNS exposure.

**15. Binding Affinity:** Both ligands have excellent binding affinities (A: -8.7 kcal/mol, B: -8.0 kcal/mol). Ligand A is slightly better, but the difference is not huge.

**Overall Assessment:**

Ligand A excels in properties crucial for CNS penetration (TPSA, BBB, P-gp efflux) and has slightly better affinity. However, Ligand B demonstrates superior metabolic stability (lower Cl_mic, longer t1/2) and a lower DILI risk. Given the importance of metabolic stability and half-life for *in vivo* efficacy, and the acceptable, though lower, BBB score, Ligand B is the more promising candidate. The slight advantage in binding affinity of Ligand A is outweighed by the significant pharmacokinetic benefits of Ligand B.

Output:
1
2025-04-17 08:54:20,254 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (366.483 and 370.49 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (75.71) is higher than Ligand B (58.64). For a CNS target like DRD2, TPSA should be <= 90, so both are acceptable, but B is better.

**3. logP:** Both ligands have good logP values (1.764 and 2.437), falling within the optimal 1-3 range.

**4. H-Bond Donors:** Both have 1 HBD, which is within the acceptable limit of <=5.

**5. H-Bond Acceptors:** Both have 5 and 4 HBAs respectively, well within the acceptable limit of <=10.

**6. QED:** Ligand A (0.882) has a significantly higher QED than Ligand B (0.474), indicating a more drug-like profile.

**7. DILI:** Both have acceptable DILI risk (49.554 and 35.983), both below the threshold of 60. B is slightly better.

**8. BBB:** Both ligands have excellent BBB penetration (83.249 and 81.815), exceeding the desirable >70 threshold for CNS targets.

**9. Caco-2 Permeability:** Both have negative Caco-2 values (-4.625 and -4.689), which is unusual and suggests poor permeability. This is a significant concern for both.

**10. Aqueous Solubility:** Both have negative solubility values (-2.455 and -2.961), indicating very poor aqueous solubility. This is a major drawback for both.

**11. hERG Inhibition:** Both ligands show low hERG inhibition risk (0.595 and 0.486), which is good.

**12. Microsomal Clearance:** Ligand A (32.458) has a lower microsomal clearance than Ligand B (72.584), suggesting better metabolic stability.

**13. In vitro Half-Life:** Ligand A (-4.46) has a longer in vitro half-life than Ligand B (-0.828), which is favorable.

**14. P-gp Efflux:** Both have very low P-gp efflux liability (0.261 and 0.27), which is good for CNS penetration.

**15. Binding Affinity:** Ligand A (-8.6 kcal/mol) has a slightly better binding affinity than Ligand B (-7.9 kcal/mol). While both are good, the 0.7 kcal/mol difference is potentially significant.

**Overall Assessment:**

Both compounds have significant issues with solubility and Caco-2 permeability. However, Ligand A has a better QED, lower Cl_mic, longer half-life, and slightly better binding affinity. The improved metabolic stability and binding affinity of Ligand A outweigh the slightly higher TPSA compared to Ligand B. The BBB penetration is excellent for both.

Output:
1
2025-04-17 08:54:20,255 - INFO - Reasoning:

Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight (MW):** Both ligands (343.36 and 343.47 Da) fall comfortably within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (75.29) is better than Ligand B (81.99). Both are below the 90 A^2 threshold for CNS targets, but A is closer to the optimal range.

**3. logP:** Both ligands have acceptable logP values (2.41 and 3.55), falling within the 1-3 range. Ligand B is slightly higher, potentially increasing off-target interactions, but not dramatically.

**4. H-Bond Donors (HBD):** Both are acceptable (1 and 2 respectively), well below the 5 limit.

**5. H-Bond Acceptors (HBA):** Both are acceptable (4 and 3 respectively), well below the 10 limit.

**6. QED:** Both ligands have good QED scores (0.668 and 0.681), indicating good drug-like properties.

**7. DILI:** Ligand A (72.59) has a higher DILI risk than Ligand B (56.19), which is preferable.

**8. BBB:** Ligand A (67.58) has a better BBB penetration percentile than Ligand B (41.53). This is *critical* for a CNS target like DRD2.

**9. Caco-2 Permeability:** Both have negative values, indicating poor permeability. This is concerning, but we'll consider it in the context of other properties.

**10. Aqueous Solubility:** Both have negative values, indicating poor solubility. This is also concerning.

**11. hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.614 and 0.686).

**12. Microsomal Clearance (Cl_mic):** Ligand A (40.93) has lower clearance than Ligand B (58.99), suggesting better metabolic stability.

**13. In vitro Half-Life (t1/2):** Ligand A (-21.14) has a more negative half-life, which is not good. Ligand B (36.14) is better.

**14. P-gp Efflux:** Both ligands have low P-gp efflux liability (0.156 and 0.226), which is good for CNS penetration.

**15. Binding Affinity:** Both ligands have excellent binding affinity (-7.7 and -7.8 kcal/mol). The difference is negligible.

**Overall Assessment:**

Ligand A is superior due to its significantly better BBB penetration (67.58 vs 41.53), lower DILI risk (72.59 vs 56.19), and better metabolic stability (lower Cl_mic). While Ligand A has a worse in vitro half-life, the improved CNS penetration and reduced toxicity risk are more important for a DRD2 ligand. The poor Caco-2 and solubility values are drawbacks for both, but can potentially be addressed through formulation strategies.

Output:
1
2025-04-17 08:54:20,255 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (365.905 and 381.973 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (47.36) is significantly better than Ligand B (30.29). For CNS targets, we want TPSA <= 90, both meet this, but A is closer to the ideal.

**logP:** Both ligands have logP values (3.718 and 4.616) within the optimal 1-3 range, but Ligand B is slightly higher. While not a major concern, higher logP can sometimes lead to off-target effects.

**H-Bond Donors/Acceptors:** Both have acceptable HBD (0) and HBA (4/5) counts.

**QED:** Both ligands have good QED scores (0.722 and 0.6), indicating good drug-like properties.

**DILI:** Ligand A (23.769) has a much lower DILI risk than Ligand B (33.501), which is a significant advantage.

**BBB:** Ligand A (89.027) has a substantially better BBB penetration percentile than Ligand B (48.895). This is *critical* for a CNS target like DRD2.

**Caco-2 Permeability:** Ligand A (-4.793) and Ligand B (-5.061) both have negative Caco-2 values, which is unusual and suggests poor permeability. This is a concern for both.

**Aqueous Solubility:** Both ligands have very poor aqueous solubility (-3.008 and -4.536). This could pose formulation challenges.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.539 and 0.919).

**Microsomal Clearance:** Ligand B (88.65) has higher microsomal clearance than Ligand A (68.353), suggesting faster metabolism and potentially lower in vivo exposure.

**In vitro Half-Life:** Ligand A (-4.936) has a negative in vitro half-life, which is not possible and indicates a data error or unusual behavior. Ligand B (49.809) has a reasonable half-life.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.301 and 0.792).

**Binding Affinity:** Both ligands have identical binding affinities (-7.3 kcal/mol), which is excellent.

**Overall Assessment:**

Ligand A is significantly better due to its superior BBB penetration (89.027 vs 48.895) and lower DILI risk (23.769 vs 33.501). While both have poor solubility and Caco-2 permeability, the BBB is paramount for a CNS target. The negative in vitro half-life for Ligand A is a major red flag, but the other advantages are substantial enough to still favor it *if* that value is an error. If the half-life is truly negative, then Ligand B would be preferred despite its lower BBB.

Output:
1
2025-04-17 08:54:20,255 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (357.426 and 347.459 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (78.95) is better than Ligand B (57). For CNS targets, we want TPSA <= 90, both are within this range, but lower is preferable. Ligand B is significantly lower.

**3. logP:** Both ligands have good logP values (1.03 and 1.991), falling within the optimal 1-3 range.

**4. H-Bond Donors:** Ligand A has 1 HBD, while Ligand B has 0. Both are acceptable (<=5).

**5. H-Bond Acceptors:** Both ligands have 4 HBAs, which is within the acceptable range (<=10).

**6. QED:** Both ligands have good QED scores (0.72 and 0.836), indicating good drug-like properties.

**7. DILI:** Ligand A (33.773) has a slightly higher DILI risk than Ligand B (20.9), but both are below the concerning threshold of 40.

**8. BBB:** This is a crucial parameter for CNS targets. Ligand A has a BBB percentile of 89.608, which is excellent (>70). Ligand B has a BBB percentile of 59.131, which is considerably lower and less desirable.

**9. Caco-2:** Both have negative values, indicating a percentile. Ligand A (-4.842) is slightly worse than Ligand B (-4.609).

**10. Solubility:** Both have negative values, indicating a percentile. Ligand A (-1.984) is slightly worse than Ligand B (-0.64).

**11. hERG:** Both ligands have low hERG inhibition liability (0.19 and 0.415), which is good.

**12. Cl_mic:** Ligand A (-8.87) has a much lower (better) microsomal clearance than Ligand B (8.452). Lower clearance suggests better metabolic stability.

**13. t1/2:** Ligand A (-12.013) has a much longer (better) in vitro half-life than Ligand B (43.096).

**14. Pgp:** Ligand A (0.011) has significantly lower P-gp efflux liability than Ligand B (0.13). Lower P-gp efflux is highly desirable for CNS penetration.

**15. Binding Affinity:** Both ligands have very similar and strong binding affinities (-7.1 and -7.0 kcal/mol). The difference is negligible.

**Overall Assessment:**

Ligand A is superior due to its significantly better BBB penetration (89.6 vs 59.1), lower P-gp efflux (0.011 vs 0.13), lower microsomal clearance (-8.87 vs 8.452), and longer half-life (-12.013 vs 43.096). While Ligand B has a slightly lower TPSA and DILI, the CNS-specific properties of BBB and P-gp efflux are more critical for a DRD2 ligand, and Ligand A excels in these areas. The comparable binding affinities make the ADME advantages of Ligand A decisive.

Output:
1
2025-04-17 08:54:20,255 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (372.809 Da) is slightly lower, which is generally favorable for permeability.

**2. TPSA:** Both ligands have TPSA values below 140, suggesting reasonable oral absorption. Ligand A (102.88) is closer to the preferred <90 for CNS targets, giving it a slight edge.

**3. logP:** Ligand A (0.273) is quite low, potentially hindering membrane permeability. Ligand B (2.392) is within the optimal 1-3 range. This is a significant advantage for Ligand B.

**4. H-Bond Donors:** Ligand A (1) is good. Ligand B (3) is acceptable but less ideal.

**5. H-Bond Acceptors:** Ligand A (8) is good. Ligand B (6) is also good.

**6. QED:** Both ligands have similar QED values (0.68 and 0.633), indicating good drug-like properties.

**7. DILI:** Ligand A (70.182) has a higher DILI risk than Ligand B (41.993). This favors Ligand B.

**8. BBB:** Both ligands have acceptable BBB penetration (68.748% and 63.009%), but neither exceeds the desirable >70% threshold.

**9. Caco-2 Permeability:** Ligand A (-4.82) shows poor Caco-2 permeability, which is concerning. Ligand B (-5.107) is also poor, but slightly better.

**10. Aqueous Solubility:** Both ligands have very poor aqueous solubility (-2.651 and -3.414). This could pose formulation challenges.

**11. hERG Inhibition:** Ligand A (0.103) has a very low hERG risk, which is excellent. Ligand B (0.598) is higher, but still relatively low.

**12. Microsomal Clearance:** Ligand A (67.119) has higher microsomal clearance than Ligand B (36.265), indicating lower metabolic stability. Ligand B is preferred.

**13. In vitro Half-Life:** Ligand A (12.689) has a longer half-life than Ligand B (5.003). This is a positive for Ligand A.

**14. P-gp Efflux:** Ligand A (0.015) shows very low P-gp efflux, which is excellent for CNS penetration. Ligand B (0.114) is higher, but still relatively low.

**15. Binding Affinity:** Ligand B (-8.0 kcal/mol) has a significantly stronger binding affinity than Ligand A (-6.9 kcal/mol). This is a crucial advantage, exceeding the 1.5 kcal/mol threshold.

**Overall Assessment:**

While Ligand A has some advantages (lower MW, lower TPSA, lower P-gp efflux, longer half-life, and very low hERG risk), its extremely low logP and poor Caco-2 permeability are major drawbacks. Ligand B, despite having a slightly higher DILI risk and lower half-life, has a significantly better logP, stronger binding affinity, and lower microsomal clearance. The stronger binding affinity outweighs the minor ADME concerns, especially given the GPCR target class. The better logP will likely translate to better permeability *in vivo* despite the Caco-2 results.

Output:
1
2025-04-17 08:54:20,255 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (354.447 and 368.378 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (95.94) is better than Ligand B (118.87). For CNS targets, TPSA should be <=90, so Ligand A is closer to the ideal range.

**logP:** Ligand A (0.845) is within the optimal range of 1-3, while Ligand B (0.013) is significantly lower. A low logP can hinder membrane permeability.

**H-Bond Donors/Acceptors:** Both have 2 HBDs, which is good. Ligand A has 5 HBAs, and Ligand B has 7. Both are acceptable, but lower is generally preferred.

**QED:** Both ligands have good QED scores (0.598 and 0.655), indicating drug-like properties.

**DILI:** Ligand A (15.626) has a much lower DILI risk than Ligand B (44.126). This is a significant advantage for Ligand A.

**BBB:** Ligand B (64.482) has a better BBB penetration percentile than Ligand A (52.191), but both are below the desirable >70 for CNS targets.

**Caco-2 Permeability:** Ligand A (-4.704) has a worse Caco-2 permeability than Ligand B (-5.679). Lower values suggest poorer absorption.

**Aqueous Solubility:** Ligand A (-1.217) has slightly better solubility than Ligand B (-0.798).

**hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.191 and 0.018).

**Microsomal Clearance:** Ligand A (51.519) has higher microsomal clearance than Ligand B (12.578), indicating lower metabolic stability.

**In vitro Half-Life:** Ligand B (17.441) has a significantly longer in vitro half-life than Ligand A (-13.899).

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.03 and 0.033).

**Binding Affinity:** Ligand B (-7.1) has a slightly better binding affinity than Ligand A (-7.0). However, the difference is small (0.1 kcal/mol).

**Overall Assessment:**

Considering the GPCR-specific priorities, Ligand A is the better candidate. While Ligand B has slightly better affinity and half-life, Ligand A has a much better logP, lower DILI risk, and a more favorable TPSA. The lower logP of Ligand B is a significant concern for CNS penetration. The DILI risk for Ligand B is also considerably higher. The small affinity difference is unlikely to outweigh these ADME/Tox concerns.

Output:
0
2025-04-17 08:54:20,255 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (356.46 and 353.55 Da) fall comfortably within the ideal 200-500 Da range.

**TPSA:** Ligand A (49.41) is significantly better than Ligand B (61.44). For CNS targets, we want TPSA <= 90, and ideally closer to 60. Ligand A is much closer to the ideal range.

**logP:** Both ligands have good logP values (3.03 and 2.66), falling within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A (HBD=1, HBA=2) is slightly better than Ligand B (HBD=2, HBA=3) in terms of minimizing potential permeability issues. Both are within acceptable limits.

**QED:** Both ligands have reasonable QED scores (0.74 and 0.67), indicating good drug-like properties.

**DILI:** Ligand A (29.04) has a much lower DILI risk than Ligand B (4.34). This is a significant advantage.

**BBB:** Ligand A (96.08) has excellent BBB penetration, exceeding the desirable >70 threshold. Ligand B (62.16) is considerably lower and less favorable for a CNS target.

**Caco-2 Permeability:** Both have negative Caco-2 values which is unusual and likely indicates a problem with the modeling or data. We will have to ignore this parameter.

**Aqueous Solubility:** Both have negative solubility values, which is also unusual and likely indicates a problem with the modeling or data. We will have to ignore this parameter.

**hERG:** Both ligands have low hERG inhibition liability (0.73 and 0.41), which is good.

**Microsomal Clearance:** Ligand A (18.57) has lower microsomal clearance than Ligand B (24.44), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (-13.02) has a negative half-life, which is impossible and likely indicates a problem with the modeling or data. Ligand B (4.36) is positive, but still low.

**P-gp Efflux:** Ligand A (0.31) has much lower P-gp efflux liability than Ligand B (0.006), meaning it's less likely to be pumped out of the brain, improving CNS exposure.

**Binding Affinity:** Ligand B (-8.0) has a significantly stronger binding affinity than Ligand A (-0.0). This is a substantial advantage, potentially outweighing some of the ADME drawbacks of Ligand B.

**Overall Assessment:**

Despite the strong binding affinity of Ligand B, Ligand A is the more promising candidate. The combination of excellent BBB penetration, low DILI risk, lower P-gp efflux, and better metabolic stability (lower Cl_mic) makes it a more viable drug candidate for a CNS target like DRD2. The significantly stronger binding affinity of Ligand B is attractive, but the poor BBB penetration and higher DILI risk are major concerns. The negative values for Caco-2, solubility, and half-life are concerning and suggest issues with the data, but the other parameters strongly favor Ligand A.

Output:
1
2025-04-17 08:54:20,255 - INFO - Reasoning:

Let's analyze Ligand A and Ligand B against the provided guidelines, prioritizing GPCR properties (BBB, logP, Pgp, TPSA, and affinity) for DRD2.

**Molecular Weight:** Both ligands (353.344 and 367.881 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (57.01) is excellent, well below the 90 A^2 target for CNS drugs. Ligand B (61.68) is still reasonable but less optimal.

**logP:** Ligand A (3.698) is within the optimal 1-3 range. Ligand B (1.231) is at the lower end, which *could* hinder permeability, though not drastically.

**H-Bond Donors/Acceptors:** Both have 0 HBD and 5 HBA, which are acceptable.

**QED:** Both ligands have similar QED scores (0.769 and 0.758), indicating good drug-likeness.

**DILI:** Ligand A (72.043) has a higher DILI risk than Ligand B (25.087). This is a significant negative for Ligand A.

**BBB:** Both ligands show good BBB penetration (Ligand A: 87.864, Ligand B: 77.2). Both are above the 70% threshold for CNS targets.

**Caco-2 Permeability:** Ligand A (-4.435) has poor Caco-2 permeability, while Ligand B (-4.9) is also poor, but slightly worse.

**Aqueous Solubility:** Ligand A (-5.106) has poor aqueous solubility, and Ligand B (-1.266) has also poor aqueous solubility.

**hERG:** Both ligands have low hERG inhibition risk (Ligand A: 0.236, Ligand B: 0.343).

**Microsomal Clearance:** Ligand A (75.258) has higher clearance than Ligand B (-1.332), indicating lower metabolic stability.

**In vitro Half-Life:** Ligand A (-22.319) has a very short half-life, while Ligand B (13.281) is better, but still not ideal.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (Ligand A: 0.241, Ligand B: 0.033). Ligand B is slightly better.

**Binding Affinity:** Ligand A (-9.4 kcal/mol) has significantly better binding affinity than Ligand B (-6.5 kcal/mol). This is a >1.5 kcal/mol advantage, which can outweigh some ADME concerns.

**Overall Assessment:**

Ligand A's primary advantage is its significantly stronger binding affinity. However, it suffers from higher DILI risk, poor Caco-2 permeability, poor solubility, and a short half-life. Ligand B has a better safety profile (lower DILI) and slightly better metabolic stability and P-gp efflux, but its binding affinity is considerably weaker.

Given the importance of affinity for GPCRs, and the fact that both ligands have acceptable BBB penetration, the stronger affinity of Ligand A is a major advantage. While the ADME properties of Ligand A are concerning, medicinal chemistry optimization could potentially address these issues without sacrificing potency. The weaker affinity of Ligand B makes it less likely to be a viable starting point, even with better ADME properties.

Output:
1
2025-04-17 08:54:20,256 - INFO - Reasoning:

Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (360.439 and 366.439 Da) are within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (89.27) is excellent, falling well below the 90 A^2 threshold for CNS targets. Ligand B (101.55) is still reasonable but less optimal.

**3. logP:** Ligand A (0.758) is a bit low, potentially hindering permeability. Ligand B (2.545) is closer to the optimal 1-3 range.

**4. H-Bond Donors:** Both ligands have 2 HBD, which is within the acceptable limit of <=5.

**5. H-Bond Acceptors:** Ligand A has 7 HBA, and Ligand B has 5 HBA, both within the acceptable limit of <=10.

**6. QED:** Both ligands have QED values above 0.7, indicating good drug-like properties.

**7. DILI:** Both ligands have DILI risk above 60, indicating a higher risk. Ligand A (67.235) is slightly better than Ligand B (70.919), but both are concerning.

**8. BBB:** Ligand A (43.777) has a lower BBB percentile than Ligand B (52.462). For a CNS target like DRD2, a higher BBB penetration is crucial. Ligand B is better here.

**9. Caco-2 Permeability:** Ligand A (-5.357) has significantly worse Caco-2 permeability than Ligand B (-4.902), suggesting poorer intestinal absorption.

**10. Aqueous Solubility:** Both ligands have very poor aqueous solubility (-2.469 and -2.983 respectively). This is a significant drawback for both, but Ligand A is slightly better.

**11. hERG Inhibition:** Ligand A (0.063) has a lower hERG inhibition risk than Ligand B (0.266), which is favorable.

**12. Microsomal Clearance:** Ligand B (43.868) has a slightly lower microsomal clearance than Ligand A (27.316), suggesting better metabolic stability.

**13. In vitro Half-Life:** Ligand B (22.532) has a longer in vitro half-life than Ligand A (14.254), which is desirable.

**14. P-gp Efflux:** Ligand A (0.081) has lower P-gp efflux liability than Ligand B (0.15), which is beneficial for CNS penetration.

**15. Binding Affinity:** Ligand A (-8.9 kcal/mol) has a slightly stronger binding affinity than Ligand B (-8.3 kcal/mol). This is a significant advantage.

**Overall Assessment:**

While both ligands have drawbacks (particularly solubility and DILI risk), Ligand A's superior binding affinity and lower P-gp efflux are strong advantages. The slightly better TPSA and hERG profile also contribute. Ligand B has a better BBB and metabolic stability, but the difference in binding affinity is substantial. Given the GPCR-specific priorities, the binding affinity is paramount, and the lower P-gp efflux of Ligand A is also critical for CNS penetration.

Output:
0
2025-04-17 08:54:20,256 - INFO - Batch 488 complete. Total preferences: 7808
2025-04-17 08:54:20,256 - INFO - Processing batch 489/512...
2025-04-17 08:55:05,273 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 drug candidates, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (343.515 and 349.41 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (44.37) is significantly better than Ligand B (79.26). For CNS targets, we want TPSA <= 90, and A is comfortably within that, while B is approaching the upper limit.

**logP:** Ligand A (2.687) is optimal (1-3), while Ligand B (0.446) is quite low. Low logP can hinder membrane permeability.

**H-Bond Donors/Acceptors:** Both have 2 HBDs, which is good. Ligand A has 3 HBAs, and Ligand B has 5. Both are acceptable (<=10), but A is slightly preferred.

**QED:** Both ligands have similar QED values (0.8 and 0.731), indicating good drug-likeness.

**DILI:** Ligand A (11.128) has a much lower DILI risk than Ligand B (39.434). This is a significant advantage for A.

**BBB:** Ligand A (86.274) has a better BBB penetration percentile than Ligand B (76.735). Both are reasonably good, but A is closer to the desirable >70 threshold for CNS targets.

**Caco-2 Permeability:** Both have negative Caco-2 values (-4.939 and -4.934), which is unusual and suggests poor permeability. This is a concern for both, but doesn't differentiate them.

**Aqueous Solubility:** Both have negative solubility values (-2.06 and -1.432), indicating poor solubility. This is a concern for both, but doesn't differentiate them.

**hERG Inhibition:** Ligand A (0.846) has a slightly better hERG profile than Ligand B (0.426), indicating lower cardiotoxicity risk.

**Microsomal Clearance:** Ligand A (29.45) has a higher microsomal clearance than Ligand B (3.561), meaning it is less metabolically stable. This is a disadvantage for A.

**In vitro Half-Life:** Ligand B (-11.267) has a longer in vitro half-life than Ligand A (20.558). This is a significant advantage for B.

**P-gp Efflux:** Ligand A (0.073) has a much lower P-gp efflux liability than Ligand B (0.045). Lower P-gp efflux is crucial for CNS penetration, favoring A.

**Binding Affinity:** Both ligands have very similar and strong binding affinities (-8.2 and -8.0 kcal/mol). The difference is negligible.

**Overall Assessment:**

Considering the GPCR-specific priorities, Ligand A is the better candidate. While Ligand B has a better half-life and lower clearance, Ligand A excels in crucial areas for CNS penetration: TPSA, logP, BBB, and P-gp efflux. The lower DILI risk for A is also a significant advantage. The slightly worse metabolic stability of A might be addressable through structural modifications, but the permeability issues of B (low logP) are harder to fix without significantly impacting binding.

Output:
0
2025-04-17 08:55:05,274 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (335.37 & 348.49 Da) fall comfortably within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (88.91) is slightly higher than Ligand B (78.09), but both are below the 90 A^2 threshold desirable for CNS targets.

**3. logP:** Both ligands have good logP values (2.03 & 2.67), falling within the optimal 1-3 range.

**4. H-Bond Donors:** Both have 2 HBD, which is acceptable.

**5. H-Bond Acceptors:** Ligand A has 5 HBA, and Ligand B has 3. Both are below the 10 limit.

**6. QED:** Both ligands have similar QED scores (0.721 and 0.709), indicating good drug-like properties.

**7. DILI:** Ligand A (81.89%) has a significantly higher DILI risk than Ligand B (25.09%). This is a major concern for Ligand A.

**8. BBB:** Ligand A (62.62%) and Ligand B (69.21%) both have acceptable BBB penetration, but Ligand B is better. A value >70 is desirable, but these are reasonable starting points.

**9. Caco-2:** Both have negative Caco-2 values, which is unusual and suggests poor permeability. This is a significant drawback for both.

**10. Solubility:** Both ligands have negative solubility values, indicating very poor aqueous solubility. This is a major formulation challenge for both.

**11. hERG:** Both ligands have very low hERG inhibition risk (0.463 & 0.401).

**12. Cl_mic:** Ligand A (26.66 mL/min/kg) has a lower (better) microsomal clearance than Ligand B (33.96 mL/min/kg), suggesting better metabolic stability.

**13. t1/2:** Ligand A (28.45 hours) has a significantly longer in vitro half-life than Ligand B (-11.07 hours). The negative value for Ligand B is concerning and likely an error or indicates very rapid degradation.

**14. Pgp:** Both ligands have very low P-gp efflux liability (0.033 & 0.182), which is favorable for CNS penetration.

**15. Binding Affinity:** Ligand A (-9.4 kcal/mol) has a significantly stronger binding affinity than Ligand B (-8.1 kcal/mol). This is a substantial advantage.

**Overall Assessment:**

Ligand A has a much stronger binding affinity and better metabolic stability (lower Cl_mic, longer t1/2). However, its significantly higher DILI risk is a major red flag. Ligand B has a lower DILI risk, slightly better BBB penetration, but significantly weaker binding affinity and a concerning negative in vitro half-life.

Given the GPCR-specific priorities, the binding affinity is crucial. While the DILI risk for Ligand A is concerning, it *might* be mitigated through structural modifications. The poor solubility and Caco-2 values are problematic for both, but could potentially be addressed through formulation strategies. The negative half-life for Ligand B is a showstopper.

Therefore, despite the DILI risk, Ligand A is the more promising starting point due to its superior binding affinity.

Output:
0
2025-04-17 08:55:05,274 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the acceptable range (200-500 Da). Ligand A (429.336 Da) is higher, but not excessively so. Ligand B (349.431 Da) is slightly preferred here.

**TPSA:** Ligand A (60.77) is excellent for CNS penetration, well below the 90 A^2 threshold. Ligand B (103.94) is higher, but still potentially acceptable, though less ideal. This favors Ligand A.

**logP:** Ligand A (2.665) is within the optimal range (1-3). Ligand B (-0.283) is significantly below 1, which could hinder membrane permeability. This is a strong advantage for Ligand A.

**H-Bond Donors/Acceptors:** Ligand A (0 HBD, 6 HBA) is favorable. Ligand B (2 HBD, 4 HBA) is also acceptable. No clear advantage here.

**QED:** Both ligands have good QED scores (A: 0.648, B: 0.712), indicating good drug-like properties. Ligand B is slightly better.

**DILI:** Ligand A (44.591) has a moderate DILI risk, while Ligand B (10.857) has a very low risk. This favors Ligand B.

**BBB:** Ligand A (68.748) has a good BBB percentile, exceeding the 70% threshold for CNS targets. Ligand B (45.366) is significantly lower, raising concerns about CNS exposure. This is a major advantage for Ligand A.

**Caco-2 Permeability:** Ligand A (-4.778) and Ligand B (-5.261) both have negative values, which is unusual and suggests poor permeability. However, the scale is not specified, so it's difficult to interpret.

**Aqueous Solubility:** Both ligands have very poor aqueous solubility (-2.583 and -2.104 respectively). This is a concern for both, but might be mitigated by formulation strategies.

**hERG Inhibition:** Both ligands have low hERG inhibition liability (A: 0.557, B: 0.061). Ligand B is slightly better.

**Microsomal Clearance:** Ligand A (96.582) has high microsomal clearance, suggesting rapid metabolism. Ligand B (-11.917) has negative clearance, which is impossible and suggests an error in the data or a very stable compound. This is a major advantage for Ligand B, *assuming the negative value is accurate and not an error*.

**In vitro Half-Life:** Ligand A (30.009 hours) has a reasonable half-life. Ligand B (1.527 hours) has a very short half-life. This favors Ligand A.

**P-gp Efflux:** Ligand A (0.59) has moderate P-gp efflux. Ligand B (0.007) has very low P-gp efflux, which is highly desirable for CNS penetration. This favors Ligand B.

**Binding Affinity:** Both ligands have the same binding affinity (-6.8 kcal/mol), which is excellent. No differentiation here.

**Overall Assessment:**

Ligand A excels in TPSA, logP, BBB, and in vitro half-life, all critical for CNS GPCR targets. However, it has higher DILI risk and higher metabolic clearance. Ligand B has lower DILI, lower P-gp efflux, and potentially very high metabolic stability (if the negative clearance is accurate). Its main drawbacks are lower BBB penetration and a poor logP.

Considering the importance of BBB penetration for a CNS target like DRD2, and the excellent binding affinity shared by both, Ligand A appears to be the more promising candidate *unless* the negative clearance value for Ligand B is a reliable indicator of exceptional metabolic stability. The negative clearance is highly suspect, and would require further investigation. Given the data as presented, the better CNS penetration profile of Ligand A outweighs the slightly higher DILI risk and clearance.

Output:
0
2025-04-17 08:55:05,274 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 drug candidates, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight (MW):** Both ligands are within the ideal range (200-500 Da). Ligand A (365.455 Da) is slightly higher than Ligand B (339.399 Da), but both are acceptable.

**2. TPSA:** Both ligands have TPSA values around 90-95, which is slightly above the optimal <90 for CNS targets, but still reasonable.

**3. logP:** Both ligands have logP values within the optimal range (1-3). Ligand A (1.777) is slightly lower than Ligand B (2.641).

**4. H-Bond Donors (HBD):** Both ligands are within the acceptable limit of <=5. Ligand A has 2, and Ligand B has 3.

**5. H-Bond Acceptors (HBA):** Both ligands are within the acceptable limit of <=10. Ligand A has 4, and Ligand B has 6.

**6. QED:** Both ligands have QED values above 0.5, indicating good drug-likeness. Ligand A (0.764) is slightly better than Ligand B (0.612).

**7. DILI:** Both ligands have DILI risk above 60, indicating a higher risk. Ligand A (64.288) is slightly lower than Ligand B (69.484), making it marginally preferable.

**8. BBB:** This is a critical parameter for CNS targets. Ligand A (77.317) has a significantly higher BBB percentile than Ligand B (29.546). This is a major advantage for Ligand A.

**9. Caco-2 Permeability:** Both have negative values, which is unusual and could indicate issues with the calculation or data quality. However, the magnitude of the negative value is similar, so it doesn't strongly differentiate the two.

**10. Aqueous Solubility:** Both have negative values, which is also unusual. Similar to Caco-2, this doesn't strongly differentiate the two.

**11. hERG Inhibition:** Both ligands have low hERG inhibition risk (0.793 and 0.813).

**12. Microsomal Clearance (Cl_mic):** Ligand A (43.634 mL/min/kg) has lower clearance than Ligand B (54.31 mL/min/kg), suggesting better metabolic stability.

**13. In vitro Half-Life:** Ligand B (52.58 hours) has a significantly longer half-life than Ligand A (6.639 hours). This is a significant advantage for Ligand B.

**14. P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.127 and 0.153).

**15. Binding Affinity:** Both ligands have excellent binding affinity (-9.0 and -9.3 kcal/mol), with Ligand B being slightly more potent.

**Overall Assessment:**

While Ligand B has a longer half-life and slightly better binding affinity, Ligand A is significantly better in terms of BBB penetration (77.317 vs 29.546). For a CNS target like DRD2, BBB penetration is paramount. The slightly better metabolic stability of Ligand A is also a plus. The DILI risk is slightly lower for Ligand A. The unusual negative values for Caco-2 and Solubility are concerning for both, but don't heavily sway the decision given the importance of BBB.

Output:
0
2025-04-17 08:55:05,275 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight (MW):** Both ligands (359.436 and 349.406 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (41.73) is significantly better than Ligand B (71.53). For CNS targets, we want TPSA <= 90, and ideally closer to 60. Ligand A is much closer to this ideal.

**3. logP:** Both ligands have good logP values (2.874 and 1.923), falling within the optimal 1-3 range.

**4. H-Bond Donors (HBD):** Both have 1 HBD, which is acceptable (<=5).

**5. H-Bond Acceptors (HBA):** Both have 4 HBA, also acceptable (<=10).

**6. QED:** Both have good QED scores (0.689 and 0.764), indicating good drug-like properties.

**7. DILI:** Ligand A (8.104) has a much lower DILI risk than Ligand B (42.264). This is a significant advantage.

**8. BBB:** Both ligands show excellent BBB penetration (87.864 and 82.474). Both are above the desirable 70% threshold.

**9. Caco-2 Permeability:** Both have negative Caco-2 values (-4.508 and -4.571). This is unusual and suggests poor permeability. However, these values are on a log scale, and the negative values might indicate very low permeability.

**10. Aqueous Solubility:** Both have negative solubility values (-1.535 and -2.469). This is also concerning, indicating poor aqueous solubility.

**11. hERG Inhibition:** Ligand A (0.992) has a slightly better hERG profile than Ligand B (0.392), but both are relatively low risk.

**12. Microsomal Clearance (Cl_mic):** Ligand A (-5.326) has much lower (better) microsomal clearance than Ligand B (8.517). This indicates greater metabolic stability.

**13. In vitro Half-Life:** Ligand A (-9.532) has a much longer in vitro half-life than Ligand B (2.452). This is a significant advantage.

**14. P-gp Efflux:** Both have very low P-gp efflux (0.313 and 0.038), which is excellent for CNS penetration.

**15. Binding Affinity:** Both ligands have very similar and strong binding affinities (-8.0 and -8.3 kcal/mol). The difference is negligible.

**Overall Assessment:**

Ligand A is superior due to its significantly better DILI risk, lower microsomal clearance, longer half-life, and lower TPSA. While both have poor Caco-2 and solubility, the other ADME properties of Ligand A are much more favorable, especially considering it's a CNS target. The similar binding affinities make the ADME profile the deciding factor.

Output:
1
2025-04-17 08:55:05,275 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (345.403 and 366.487 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (92.52) is slightly above the optimal <90 for CNS targets, but still reasonable. Ligand B (85.77) is excellent, well below 90.

**logP:** Ligand A (1.256) is within the optimal 1-3 range. Ligand B (0.568) is a bit low, potentially hindering permeability.

**H-Bond Donors/Acceptors:** Both ligands have 2 HBD and 6 HBA, which are within acceptable limits (<=5 and <=10 respectively).

**QED:** Both ligands have QED values (0.819 and 0.737) indicating good drug-likeness.

**DILI:** Ligand A (57.425) has a moderate DILI risk, while Ligand B (25.708) has a very low DILI risk, which is a significant advantage.

**BBB:** Ligand A (78.868) has a good BBB penetration percentile, desirable for a CNS target. Ligand B (21.675) has a very poor BBB penetration percentile, a major drawback.

**Caco-2 Permeability:** Ligand A (-4.996) and Ligand B (-5.283) both have negative Caco-2 values, which is unusual and suggests poor permeability. However, the scale isn't defined, so it's hard to interpret.

**Aqueous Solubility:** Both ligands have poor aqueous solubility (-1.586 and -1.048). This could pose formulation challenges.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.521 and 0.446).

**Microsomal Clearance:** Ligand A (2.483) has a relatively low microsomal clearance, suggesting better metabolic stability. Ligand B (-1.259) has negative clearance, which is not physically possible and likely an error or unusual scale.

**In vitro Half-Life:** Ligand A (-3.302) has a negative half-life, which is not physically possible and likely an error or unusual scale. Ligand B (6.879) has a reasonable half-life.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.01 and 0.054), which is good for CNS penetration.

**Binding Affinity:** Ligand B (-8.5 kcal/mol) has a significantly stronger binding affinity than Ligand A (-9.2 kcal/mol). While both are excellent, the 0.7 kcal/mol difference is substantial.

**Overall Assessment:**

Ligand B has a superior binding affinity and a much lower DILI risk. However, its extremely poor BBB penetration is a critical flaw for a CNS target like DRD2. The negative values for clearance and half-life are also concerning. Ligand A has a better BBB score, acceptable clearance, but a weaker binding affinity and a moderate DILI risk. Considering the importance of BBB penetration for CNS targets, and the significant affinity advantage of Ligand B, the affinity difference is likely to outweigh the BBB concern, *assuming* the negative clearance and half-life values are errors.

Output:
1
2025-04-17 08:55:05,275 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (343.387 and 346.435 Da) fall within the ideal range of 200-500 Da.

**TPSA:** Ligand A (110.95) is slightly higher than Ligand B (101.8). Both are below the 140 threshold for oral absorption, but closer to the 90 threshold for CNS targets. Ligand B is preferable here.

**logP:** Ligand A (0.58) is quite low, potentially hindering membrane permeability. Ligand B (0.821) is better, but still on the lower side of the optimal 1-3 range. This is a weakness for both, but more so for A.

**H-Bond Donors/Acceptors:** Ligand A has 3 HBD and 4 HBA, while Ligand B has 2 HBD and 6 HBA. Both are within acceptable limits (<=5 HBD and <=10 HBA).

**QED:** Both ligands have similar QED values (0.737 and 0.712), indicating good drug-like properties.

**DILI:** Both have similar, acceptable DILI risk (50.523 and 48.119 percentile).

**BBB:** This is a critical parameter for a CNS target like DRD2. Ligand B (71.268%) is significantly better than Ligand A (19.814%). This is a major advantage for B.

**Caco-2 Permeability:** Both have negative Caco-2 values (-5.501 and -5.523), which is unusual and suggests poor permeability. This is a significant concern for both.

**Aqueous Solubility:** Both have negative solubility values (-2.318 and -2.136), which is also unusual and suggests poor solubility. This is a significant concern for both.

**hERG Inhibition:** Both ligands show very low hERG inhibition risk (0.087 and 0.022 percentile).

**Microsomal Clearance:** Ligand A (-18.611) has a much lower (better) microsomal clearance than Ligand B (24.077), indicating greater metabolic stability.

**In vitro Half-Life:** Ligand A (-25.237) has a much longer half-life than Ligand B (1.311), which is a significant advantage.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.018 and 0.078 percentile), which is favorable for CNS penetration.

**Binding Affinity:** Ligand A (-8.8 kcal/mol) has a slightly better binding affinity than Ligand B (-8.3 kcal/mol). While the difference is not huge (0.5 kcal/mol), it's a positive for A.

**Overall Assessment:**

Ligand B excels in BBB penetration, a crucial factor for DRD2. However, Ligand A has superior metabolic stability (lower Cl_mic, longer t1/2) and slightly better binding affinity. Both suffer from poor predicted permeability and solubility. The significantly better BBB value of Ligand B outweighs the advantages of Ligand A, especially considering the target is a CNS GPCR. The slightly better affinity of A is not enough to overcome the poor BBB.

Output:
1
2025-04-17 08:55:05,275 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (349.366 and 354.447 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (120.0) is higher than the preferred <90 for CNS targets, while Ligand B (79.31) is well within the range. This is a significant advantage for Ligand B.

**logP:** Ligand A (1.605) is within the optimal 1-3 range. Ligand B (0.117) is quite low, potentially hindering permeation.

**H-Bond Donors/Acceptors:** Ligand A has 4 HBD and 5 HBA, both acceptable. Ligand B has 1 HBD and 5 HBA, also acceptable.

**QED:** Both ligands have good QED scores (0.591 and 0.759, respectively), indicating drug-like properties.

**DILI:** Ligand A (67.429) has a higher DILI risk than Ligand B (13.843). This favors Ligand B.

**BBB:** Ligand B (55.874) has a significantly better BBB penetration score than Ligand A (30.748). This is crucial for a CNS target like DRD2 and strongly favors Ligand B.

**Caco-2 Permeability:** Ligand A (-5.418) has poor Caco-2 permeability, while Ligand B (-4.47) is only slightly better. Both are suboptimal, but Ligand B is preferable.

**Aqueous Solubility:** Ligand A (-3.247) and Ligand B (-1.513) both have poor aqueous solubility.

**hERG Inhibition:** Both ligands show low hERG inhibition risk (0.198 and 0.304, respectively).

**Microsomal Clearance:** Ligand A (33.114) and Ligand B (25.634) have reasonable microsomal clearance values, suggesting moderate metabolic stability. Ligand B is slightly better.

**In vitro Half-Life:** Ligand A (-47.84) has a very short half-life, while Ligand B (2.697) has a slightly longer half-life. This favors Ligand B.

**P-gp Efflux:** Ligand A (0.052) has lower P-gp efflux liability than Ligand B (0.028), which is favorable.

**Binding Affinity:** Ligand A (-8.7 kcal/mol) has a significantly stronger binding affinity than Ligand B (-7.1 kcal/mol). This is a substantial advantage for Ligand A, potentially outweighing some of its ADME drawbacks.

**Overall Assessment:**

While Ligand A boasts a superior binding affinity, Ligand B demonstrates a much more favorable ADME profile, particularly regarding BBB penetration (critical for a CNS target), lower DILI risk, and better TPSA. The significant difference in binding affinity (-8.7 vs -7.1 kcal/mol) is notable, but the poor BBB and higher DILI risk of Ligand A are major concerns. Given the GPCR-specific priorities, the improved ADME properties of Ligand B, especially its BBB score, make it the more promising candidate.



Output:
1
2025-04-17 08:55:05,275 - INFO - Reasoning:

Let's analyze Ligand A and Ligand B against the provided guidelines, prioritizing GPCR-specific properties (BBB, logP, Pgp, TPSA, and affinity) for DRD2.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (370.837 Da) and Ligand B (349.431 Da) are both acceptable.

**TPSA:** Ligand A (104.65) is slightly above the optimal <90 for CNS targets, but still reasonable. Ligand B (84.67) is excellent, well below 90.

**logP:** Ligand A (0.557) is a bit low, potentially hindering permeability. Ligand B (1.767) is within the optimal range (1-3). This is a significant advantage for Ligand B.

**H-Bond Donors/Acceptors:** Ligand A (HBD=2, HBA=6) and Ligand B (HBD=1, HBA=5) both have acceptable numbers of hydrogen bond donors and acceptors.

**QED:** Both ligands have good QED scores (Ligand A: 0.758, Ligand B: 0.895), indicating good drug-like properties.

**DILI:** Ligand A (51.493) has a slightly higher DILI risk than Ligand B (40.83), but both are below the concerning threshold of 60.

**BBB:** Ligand B (77.705) has a significantly better BBB percentile than Ligand A (51.609). This is a crucial advantage for a CNS target like DRD2.

**Caco-2 Permeability:** Both have negative Caco-2 values which is unusual and suggests a potential issue with the data. However, the magnitude is similar.

**Aqueous Solubility:** Both have negative solubility values, again suggesting a potential data issue. The values are similar.

**hERG:** Both ligands have low hERG inhibition liability (Ligand A: 0.171, Ligand B: 0.231), which is positive.

**Microsomal Clearance:** Ligand A (11.551) has a lower (better) microsomal clearance than Ligand B (46.74). This suggests better metabolic stability for Ligand A.

**In vitro Half-Life:** Ligand B (-25.594) has a negative half-life, which is impossible and indicates a data error. Ligand A (4.149) is reasonable.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (Ligand A: 0.017, Ligand B: 0.071), which is favorable.

**Binding Affinity:** Ligand B (-9.3 kcal/mol) has a substantially stronger binding affinity than Ligand A (-7.3 kcal/mol). This difference of 2 kcal/mol is very significant and can outweigh minor ADME drawbacks.

**Overall Assessment:**

Ligand B is the stronger candidate. While Ligand A has better metabolic stability (lower Cl_mic), Ligand B excels in key areas for a CNS GPCR target: significantly better BBB penetration, a more optimal logP, and a much stronger binding affinity. The negative half-life for Ligand B is a red flag, but the substantial affinity advantage makes it worth investigating further to determine if this is a data error. The TPSA for Ligand B is also more favorable. The slightly higher DILI risk for Ligand A is not a major concern.



Output:
1
2025-04-17 08:55:05,276 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (344.371 Da) is slightly lower, which could be beneficial for permeability, but both are acceptable.

**TPSA:** Ligand A (106.35) is better than Ligand B (53.43). For CNS targets, we want TPSA <= 90, so Ligand A is closer to the ideal range.

**logP:** Ligand A (1.163) is within the optimal range (1-3), while Ligand B (3.617) is approaching the upper limit. Higher logP can lead to off-target effects and solubility issues.

**H-Bond Donors/Acceptors:** Ligand A has 2 HBD and 6 HBA, while Ligand B has 1 HBD and 4 HBA. Both are within acceptable limits (<=5 HBD and <=10 HBA).

**QED:** Both ligands have good QED scores (Ligand A: 0.661, Ligand B: 0.814), indicating good drug-like properties.

**DILI:** Ligand A (67.003) has a higher DILI risk than Ligand B (26.406). This is a significant drawback for Ligand A.

**BBB:** Ligand B (74.137) has a significantly better BBB penetration score than Ligand A (62.233). This is crucial for a CNS target like DRD2.

**Caco-2 Permeability:** Both have negative values, which is unusual. However, the magnitude of the negative value for Ligand A (-4.925) is more negative than Ligand B (-4.765), suggesting potentially lower permeability for Ligand A.

**Aqueous Solubility:** Both have negative values, indicating poor solubility. Ligand A (-2.997) is slightly better than Ligand B (-4.377).

**hERG Inhibition:** Ligand A (0.193) has a slightly lower hERG inhibition risk than Ligand B (0.579).

**Microsomal Clearance:** Ligand B (77.604) has a higher microsomal clearance than Ligand A (44.08), meaning Ligand A is more metabolically stable.

**In vitro Half-Life:** Ligand A (-46.264) has a significantly longer in vitro half-life than Ligand B (-19.229).

**P-gp Efflux:** Ligand A (0.047) has lower P-gp efflux liability than Ligand B (0.24), which is favorable for CNS penetration.

**Binding Affinity:** Ligand B (-7.2 kcal/mol) has a slightly better binding affinity than Ligand A (-8.1 kcal/mol). While both are good, the difference is not substantial enough to outweigh other factors.

**Overall Assessment:**

Ligand B is the better candidate. While Ligand A has better metabolic stability and P-gp efflux, Ligand B excels in the critical areas for a CNS GPCR target: BBB penetration and lower DILI risk. The slightly better affinity of Ligand B further supports this conclusion. The TPSA of Ligand B is also much closer to the ideal range for CNS penetration.

Output:
1
2025-04-17 08:55:05,276 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (343.427 and 349.475 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (71.53) is slightly higher than Ligand B (64.09). Both are below the 90 A^2 threshold desirable for CNS targets, but Ligand B is preferable.

**3. logP:** Ligand A (1.987) and Ligand B (0.857) are both within the optimal 1-3 range, but Ligand A is better.

**4. H-Bond Donors:** Both ligands have 1 HBD, which is acceptable.

**5. H-Bond Acceptors:** Both ligands have 4 HBA, which is acceptable.

**6. QED:** Ligand A (0.857) has a better QED score than Ligand B (0.765), indicating a more drug-like profile.

**7. DILI:** Ligand B (7.135) has a significantly lower DILI risk than Ligand A (43.932), which is a major advantage.

**8. BBB:** Ligand A (55.913) and Ligand B (52.191) are both below the 70 percentile desirable for CNS targets. However, this is not a dealbreaker as other properties can compensate.

**9. Caco-2 Permeability:** Ligand A (-4.967) has better Caco-2 permeability than Ligand B (-4.786).

**10. Aqueous Solubility:** Ligand A (-1.954) has better aqueous solubility than Ligand B (-0.771).

**11. hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.286 and 0.363 respectively).

**12. Microsomal Clearance:** Ligand A (23.121) and Ligand B (24.78) have similar microsomal clearance rates.

**13. In vitro Half-Life:** Ligand A (-4.853) has a better in vitro half-life than Ligand B (-0.526).

**14. P-gp Efflux:** Both ligands have low P-gp efflux liability (0.086 and 0.039 respectively).

**15. Binding Affinity:** Ligand B (-7.6 kcal/mol) has a significantly stronger binding affinity than Ligand A (-9.4 kcal/mol). This is a substantial advantage, potentially outweighing some of the ADME drawbacks.

**Overall Assessment:**

Ligand B has a significantly better binding affinity (-7.6 vs -9.4 kcal/mol) and a much lower DILI risk (7.135 vs 43.932). While Ligand A has slightly better TPSA, Caco-2 permeability, solubility, and half-life, the superior affinity and safety profile of Ligand B are more critical for a CNS GPCR target like DRD2. The slightly lower BBB penetration of Ligand B is not a major concern given its strong binding.

Output:
1
2025-04-17 08:55:05,276 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (340.423 Da) is slightly better, being closer to the middle of the range.

**TPSA:** Ligand A (78.43) is significantly better than Ligand B (127.59). For CNS targets, we want TPSA <= 90, and Ligand A comfortably meets this, while Ligand B is pushing the limit and less favorable.

**logP:** Ligand A (3.284) is optimal (1-3), while Ligand B (0.047) is very low, potentially hindering membrane permeability and CNS penetration. This is a significant drawback for Ligand B.

**H-Bond Donors/Acceptors:** Both have 3 HBDs, which is acceptable. Ligand B has 5 HBAs, which is higher than Ligand A's 3, but still within the acceptable limit of <=10.

**QED:** Ligand A (0.677) has a better QED score than Ligand B (0.465), indicating a more drug-like profile.

**DILI:** Both have relatively low DILI risk (Ligand A: 42.536, Ligand B: 40.287), indicating similar safety profiles in this regard.

**BBB:** Ligand A (38.775) has a lower BBB percentile than Ligand B (46.375). While both are not ideal (>70 desirable), Ligand B has a slight advantage here.

**Caco-2 Permeability:** Both have negative Caco-2 values (-5.103 and -5.532), which is unusual and suggests poor permeability. However, the scale isn't specified, so it's hard to interpret.

**Aqueous Solubility:** Both have negative solubility values (-3.43 and -2.057), also unusual and suggesting poor solubility.

**hERG Inhibition:** Ligand A (0.396) has a much lower hERG inhibition risk than Ligand B (0.068), which is a significant advantage.

**Microsomal Clearance:** Ligand B (33.472) has lower microsomal clearance than Ligand A (38.442), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (-5.864) has a longer in vitro half-life than Ligand B (-32.654), which is a significant advantage.

**P-gp Efflux:** Ligand A (0.229) has lower P-gp efflux than Ligand B (0.027), indicating better CNS exposure.

**Binding Affinity:** Ligand A (-9.8 kcal/mol) has a significantly stronger binding affinity than Ligand B (-6.3 kcal/mol). This is a substantial advantage, potentially outweighing some of the ADME drawbacks.

**Overall Assessment:**

Ligand A is the stronger candidate. While its BBB penetration isn't ideal, its superior logP, TPSA, QED, hERG inhibition, in vitro half-life, P-gp efflux, and *especially* its significantly higher binding affinity outweigh the slightly lower BBB score. Ligand B's very low logP is a major concern, likely leading to poor permeability and CNS penetration.

Output:
1
2025-04-17 08:55:05,276 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B based on the provided guidelines, prioritizing GPCR-specific properties (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (347.434 Da) is slightly lower, which could be beneficial for permeability.

**TPSA:** Both ligands have TPSA values below 90, suitable for CNS targets. Ligand A (71.09) is better than Ligand B (78.95).

**logP:** Both ligands have good logP values (1-3). Ligand A (2.212) is slightly higher than Ligand B (1.468), which is generally preferable for CNS penetration.

**H-Bond Donors/Acceptors:** Ligand A (HBD=2, HBA=3) and Ligand B (HBD=1, HBA=5) both fall within acceptable ranges.

**QED:** Both ligands have QED values above 0.5, indicating good drug-likeness. Ligand B (0.765) is slightly better than Ligand A (0.708).

**DILI:** Both ligands have acceptable DILI risk. Ligand A (28.189) is better than Ligand B (36.797).

**BBB:** This is crucial for a CNS target like DRD2. Ligand A (78.984) has a significantly better BBB percentile than Ligand B (66.925).

**Caco-2 Permeability:** Both are negative, indicating poor permeability. Ligand A (-4.865) is slightly better than Ligand B (-4.792).

**Aqueous Solubility:** Both are negative, indicating poor solubility. Ligand A (-2.285) is slightly better than Ligand B (-1.813).

**hERG Inhibition:** Both ligands have low hERG inhibition risk. Ligand A (0.639) is slightly higher than Ligand B (0.137).

**Microsomal Clearance:** Ligand A (24.897) has a significantly lower microsomal clearance than Ligand B (46.123), indicating better metabolic stability.

**In vitro Half-Life:** Ligand A (3.855) has a positive half-life, while Ligand B (-35.791) has a negative half-life, indicating poor stability.

**P-gp Efflux:** Ligand A (0.141) has a lower P-gp efflux liability than Ligand B (0.033), which is favorable for CNS exposure.

**Binding Affinity:** Ligand A (-8.9 kcal/mol) has a significantly stronger binding affinity than Ligand B (-6.4 kcal/mol). This is a major advantage, potentially outweighing some ADME drawbacks.

**Overall Assessment:**

Ligand A is superior to Ligand B. It has a better BBB score, lower DILI risk, lower microsomal clearance (better metabolic stability), lower P-gp efflux, and, most importantly, a significantly stronger binding affinity. While both have issues with Caco-2 permeability and solubility, the strong affinity and improved CNS properties of Ligand A make it the more promising drug candidate for DRD2.

Output:
1
2025-04-17 08:55:05,277 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (338.382 Da) is slightly preferred as it's closer to the lower end, potentially aiding permeability.

**TPSA:** Ligand A (53.17) is excellent for CNS penetration, well below the 90 A^2 threshold. Ligand B (91.06) is pushing the limit, potentially hindering BBB penetration.

**logP:** Ligand A (3.646) is optimal. Ligand B (1.755) is a bit low, potentially impacting membrane permeability.

**H-Bond Donors/Acceptors:** Ligand A (HBD=1, HBA=2) is favorable. Ligand B (HBD=3, HBA=5) is acceptable, but slightly higher counts could affect permeability.

**QED:** Both ligands have similar QED values (A: 0.725, B: 0.648), indicating good drug-likeness.

**DILI:** Both ligands have similar DILI risk (A: 73.052, B: 78.131), indicating moderate risk.

**BBB:** This is a crucial parameter for a CNS target. Ligand A has a very high BBB percentile (91.508), which is excellent. Ligand B's BBB percentile (32.299) is significantly lower and concerning.

**Caco-2 Permeability:** Ligand A (-4.758) shows poor permeability, while Ligand B (-5.677) is also poor.

**Aqueous Solubility:** Ligand A (-5.482) and Ligand B (-3.723) both show poor solubility.

**hERG Inhibition:** Ligand A (0.913) has a slightly higher hERG risk than Ligand B (0.391), but both are relatively low.

**Microsomal Clearance:** Ligand A (9.649) has a lower clearance, suggesting better metabolic stability than Ligand B (16.014).

**In vitro Half-Life:** Ligand A (32.32 hours) has a significantly longer half-life than Ligand B (14.143 hours).

**P-gp Efflux:** Ligand A (0.683) has lower P-gp efflux liability than Ligand B (0.178), which is beneficial for CNS exposure.

**Binding Affinity:** Both ligands have excellent binding affinities (A: -9.6 kcal/mol, B: -10.2 kcal/mol). Ligand B is slightly stronger, but the difference is unlikely to outweigh the significant ADME advantages of Ligand A.

**Overall Assessment:**

Ligand A is the stronger candidate despite the slightly weaker binding affinity. Its superior BBB penetration, lower P-gp efflux, better metabolic stability (lower Cl_mic, longer t1/2), and favorable TPSA and logP values make it much more likely to achieve sufficient CNS exposure. While both have poor solubility and Caco-2 permeability, these can potentially be addressed with formulation strategies. Ligand B's poor BBB penetration is a major drawback for a CNS-targeted drug.

Output:
0
2025-04-17 08:55:05,277 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (338.411) is slightly lower, which could be beneficial for permeability.

**2. TPSA:** Ligand A (86.88) is better than Ligand B (56.15) as it is closer to the optimal range for CNS targets (<=90). Ligand B is quite low, which might indicate a lack of necessary interactions.

**3. logP:** Both ligands have good logP values (A: 2.145, B: 3.851), falling within the 1-3 range. Ligand B is slightly higher, which could potentially lead to solubility issues, but is still acceptable.

**4. H-Bond Donors:** Ligand A (3) is slightly higher than Ligand B (1), but both are within the acceptable limit of <=5.

**5. H-Bond Acceptors:** Ligand A (3) and Ligand B (4) are both within the acceptable limit of <=10.

**6. QED:** Both ligands have similar and good QED values (A: 0.801, B: 0.814), indicating good drug-like properties.

**7. DILI:** Both ligands have acceptable DILI risk (A: 59.442, B: 50.523), below the 60 threshold. Ligand B is slightly better.

**8. BBB:** Ligand B (82.668) has a significantly better BBB penetration percentile than Ligand A (74.176). This is a critical advantage for a CNS target like DRD2.

**9. Caco-2 Permeability:** Ligand A (-5.456) has a worse Caco-2 permeability than Ligand B (-4.519), indicating potentially lower intestinal absorption.

**10. Aqueous Solubility:** Ligand A (-3.088) has a worse aqueous solubility than Ligand B (-4.772).

**11. hERG Inhibition:** Both ligands have similar and low hERG inhibition liability (A: 0.52, B: 0.575).

**12. Microsomal Clearance:** Ligand B (87.716) has a much higher microsomal clearance than Ligand A (5.841), indicating poorer metabolic stability. This is a significant drawback for Ligand B.

**13. In vitro Half-Life:** Ligand A (4.865) has a better in vitro half-life than Ligand B (1.752).

**14. P-gp Efflux:** Ligand A (0.247) has a lower P-gp efflux liability than Ligand B (0.347), which is favorable for CNS exposure.

**15. Binding Affinity:** Both ligands have very similar and excellent binding affinities (A: -9.1, B: -9.2). The difference is negligible.

**Overall Assessment:**

While Ligand B has a superior BBB score and slightly better DILI, Ligand A has a better TPSA, lower P-gp efflux, better metabolic stability (lower Cl_mic and higher t1/2), and better Caco-2 permeability. Given the importance of metabolic stability and permeability for oral bioavailability, and the acceptable BBB score of Ligand A, Ligand A appears to be the more promising candidate. The slight advantage in BBB for Ligand B is outweighed by its poor metabolic properties.

Output:
0
2025-04-17 08:55:05,277 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (412.303 Da) is slightly higher than Ligand B (352.385 Da), but both are acceptable.

**2. TPSA:** Both ligands have TPSA values (70.23 and 67.23 respectively) that are above the optimal <90 for CNS targets, but not drastically so. This is a minor concern.

**3. logP:** Both ligands have good logP values (2.648 and 2.092 respectively), falling within the optimal 1-3 range.

**4. H-Bond Donors:** Ligand A has 3 HBD, which is acceptable. Ligand B has only 1, also acceptable.

**5. H-Bond Acceptors:** Ligand A has 3 HBA, acceptable. Ligand B has 4 HBA, also acceptable.

**6. QED:** Ligand B (0.902) has a significantly better QED score than Ligand A (0.515), indicating a more drug-like profile.

**7. DILI:** Both ligands have low DILI risk (41.877 and 40.83 respectively), which is good.

**8. BBB:** This is a critical parameter for a CNS target like DRD2. Ligand B (92.827) has a *much* higher BBB percentile than Ligand A (49.903). This is a major advantage for Ligand B.

**9. Caco-2 Permeability:** Both have negative values, indicating poor permeability. This is concerning for both, but the values are similar.

**10. Aqueous Solubility:** Both have negative values, indicating poor solubility. This is concerning for both, but the values are similar.

**11. hERG Inhibition:** Both ligands have low hERG inhibition risk (0.639 and 0.458 respectively).

**12. Microsomal Clearance:** Ligand B (-10.61) has a much lower (better) microsomal clearance than Ligand A (15.512), suggesting better metabolic stability.

**13. In vitro Half-Life:** Ligand B (-5.258) has a much longer in vitro half-life than Ligand A (58.497), which is desirable.

**14. P-gp Efflux:** Ligand B (0.062) has significantly lower P-gp efflux liability than Ligand A (0.135), which is a significant advantage for CNS penetration.

**15. Binding Affinity:** Ligand B (-9.0 kcal/mol) has a slightly better binding affinity than Ligand A (-7.9 kcal/mol), exceeding the 1.5 kcal/mol advantage threshold.

**Overall Assessment:**

Ligand B is clearly superior. While both ligands have some ADME liabilities (poor Caco-2 and solubility), Ligand B excels in the critical areas for a CNS GPCR target: BBB penetration, metabolic stability (lower Cl_mic, longer t1/2), P-gp efflux, and binding affinity. The higher QED score also supports its drug-likeness. The 1.1 kcal/mol difference in binding affinity, combined with the substantial improvements in ADME properties, makes Ligand B the more promising candidate.

Output:
1
2025-04-17 08:55:05,277 - INFO - Batch 489 complete. Total preferences: 7824
2025-04-17 08:55:05,278 - INFO - Processing batch 490/512...
2025-04-17 08:55:46,967 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (340.43 and 350.35 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (50.6) is significantly better than Ligand B (81.75). For CNS targets, we want TPSA <= 90, and A is much closer to the ideal <=60. B is pushing the upper limit and could have reduced brain penetration.

**logP:** Both ligands have good logP values (2.11 and 1.52), falling within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Both have acceptable HBD (0) and HBA (4 for A, 6 for B) counts, well within the guidelines.

**QED:** Both have reasonable QED scores (0.86 and 0.78), indicating good drug-like properties.

**DILI:** Ligand A (25.79) has a much lower DILI risk than Ligand B (59.91), which is a significant advantage.

**BBB:** Both ligands show excellent BBB penetration (91.86% and 96.16%), exceeding the desirable >70% threshold.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values, which is unusual and suggests poor permeability. However, the scale is not specified, so it is difficult to interpret.

**Aqueous Solubility:** Both ligands have negative solubility values, which is also unusual and suggests poor solubility.

**hERG:** Both ligands have low hERG inhibition risk (0.69 and 0.32).

**Microsomal Clearance:** Ligand A (31.55) has a lower microsomal clearance than Ligand B (59.40), indicating better metabolic stability.

**In vitro Half-Life:** Ligand A (-10.12) has a longer in vitro half-life than Ligand B (-15.88), which is favorable.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.34 and 0.24), which is good for CNS exposure.

**Binding Affinity:** Ligand B (-8.7 kcal/mol) has a stronger binding affinity than Ligand A (-10.1 kcal/mol). This is a substantial difference (1.4 kcal/mol), and usually a strong affinity can outweigh some ADME drawbacks.

**Overall Assessment:**

While Ligand B has a superior binding affinity, Ligand A demonstrates a significantly better safety profile (lower DILI) and improved ADME properties (lower Cl_mic, longer t1/2, lower TPSA). Given the CNS target, the lower TPSA and DILI risk of Ligand A are particularly important. The slightly weaker affinity of Ligand A is a concern, but the other advantages are compelling. The negative Caco-2 and solubility values are concerning for both, and would need to be investigated further. However, considering all factors, and prioritizing the GPCR-specific properties, Ligand A is the more promising candidate.

Output:
1
2025-04-17 08:55:46,967 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (377.491 Da) is slightly higher than Ligand B (356.432 Da), but both are acceptable.

**TPSA:** Ligand A (79.37) is higher than Ligand B (33.2). For CNS targets, we want TPSA <= 90, so both are within range, but Ligand B is significantly better.

**logP:** Ligand A (2.579) is within the optimal range (1-3). Ligand B (4.895) is above this range, potentially leading to solubility issues and off-target interactions.

**H-Bond Donors/Acceptors:** Ligand A has 1 HBD and 5 HBA, while Ligand B has 0 HBD and 2 HBA. Both are within acceptable limits (<=5 HBD and <=10 HBA).

**QED:** Ligand A (0.869) has a better QED score than Ligand B (0.664), indicating a more drug-like profile.

**DILI:** Ligand A (86.429) has a higher DILI risk than Ligand B (19.698). This is a significant drawback for Ligand A.

**BBB:** Ligand B (94.223) has a much higher BBB penetration percentile than Ligand A (75.882). This is *critical* for a CNS target like DRD2.

**Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and suggests poor permeability. However, the scale is not specified, so it's hard to interpret.

**Aqueous Solubility:** Both have negative solubility values, again, the scale is not specified.

**hERG:** Ligand A (0.127) shows a slightly higher hERG inhibition liability than Ligand B (0.7). Lower is better.

**Microsomal Clearance:** Ligand B (80.345) has a higher microsomal clearance than Ligand A (42.282), meaning Ligand A is more metabolically stable.

**In vitro Half-Life:** Ligand A (14.614 hours) has a longer half-life than Ligand B (1.754 hours). This is a positive for Ligand A.

**P-gp Efflux:** Ligand A (0.242) has lower P-gp efflux liability than Ligand B (0.616), which is favorable for CNS penetration.

**Binding Affinity:** Ligand B (-7.8 kcal/mol) has a significantly stronger binding affinity than Ligand A (-9.4 kcal/mol). This is a substantial advantage for Ligand B. A >1.5 kcal/mol advantage can outweigh other drawbacks.

**Overall Assessment:**

Ligand B excels in key areas for a CNS GPCR target: high BBB penetration (94.223), strong binding affinity (-7.8 kcal/mol), and low DILI risk (19.698). While its logP is slightly high, the strong affinity and excellent BBB penetration are likely to compensate for this. Ligand A has better metabolic stability and a longer half-life, but its higher DILI risk, lower BBB penetration, and weaker binding affinity make it a less attractive candidate. The significantly better affinity of ligand B is a major deciding factor.

Output:
1
2025-04-17 08:55:46,967 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (350.379 and 359.442 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (133.39) is slightly above the optimal <90 for CNS targets, but still reasonable. Ligand B (78.95) is excellent, well below 90.

**logP:** Ligand A (-0.444) is a bit low, potentially hindering permeation. Ligand B (0.725) is within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A has 3 HBD and 7 HBA, which are acceptable. Ligand B has 1 HBD and 4 HBA, also acceptable.

**QED:** Both ligands have good QED scores (0.637 and 0.693), indicating drug-like properties.

**DILI:** Ligand A (62.893) has a moderate DILI risk. Ligand B (19.426) has a very low DILI risk, a significant advantage.

**BBB:** Ligand A (58.278) has a suboptimal BBB penetration. Ligand B (89.027) has excellent BBB penetration, crucial for a CNS target like DRD2.

**Caco-2 Permeability:** Ligand A (-5.516) has poor Caco-2 permeability. Ligand B (-4.481) also has poor Caco-2 permeability, but slightly better than A.

**Aqueous Solubility:** Ligand A (-1.946) has poor aqueous solubility. Ligand B (-0.577) has slightly better aqueous solubility, but still poor.

**hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.042 and 0.223).

**Microsomal Clearance:** Ligand A (-3.288) has good metabolic stability (negative value). Ligand B (44.384) has high microsomal clearance, indicating rapid metabolism.

**In vitro Half-Life:** Ligand A (10.045) has a reasonable half-life. Ligand B (-15.374) has a very short half-life, a major drawback.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.018 and 0.013).

**Binding Affinity:** Both ligands have comparable and strong binding affinities (-9 and -6 kcal/mol). Ligand A has a 3 kcal/mol advantage, which is substantial.

**Overall Assessment:**

Ligand A's main strengths are its strong binding affinity and good metabolic stability. However, its low logP, poor Caco-2 permeability, suboptimal BBB penetration, and moderate DILI risk are significant concerns.

Ligand B excels in BBB penetration and has a very low DILI risk. While its affinity is weaker, its logP is optimal. Its major weaknesses are its high microsomal clearance and very short half-life.

Considering the GPCR-specific priorities, **BBB penetration is paramount for a CNS target**. Ligand B's superior BBB penetration, coupled with its low DILI risk, outweighs the affinity difference. While the metabolic instability is a concern, it could potentially be addressed through structural modifications. The poor solubility and permeability of both compounds are also concerns that would need to be addressed.

Output:
1
2025-04-17 08:55:46,968 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (365.857 and 367.921 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (55.84) is slightly higher than Ligand B (47.36). Both are below the 90 A^2 threshold for CNS targets, which is good. Ligand B is preferable here.

**3. logP:** Both ligands have good logP values (3.69 and 3.573), falling within the optimal 1-3 range.

**4. H-Bond Donors:** Both have 0 HBD, which is acceptable.

**5. H-Bond Acceptors:** Both have 4 HBA, which is acceptable.

**6. QED:** Both ligands have good QED scores (0.75 and 0.772), indicating drug-like properties.

**7. DILI:** Ligand A (60.45) has a higher DILI risk than Ligand B (29.973). This is a significant advantage for Ligand B.

**8. BBB:** Ligand B (88.29) has a substantially better BBB penetration percentile than Ligand A (69.407). This is *critical* for a CNS target like DRD2.

**9. Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and suggests poor permeability. However, the scale is not clearly defined.

**10. Aqueous Solubility:** Both have negative solubility values, which is also unusual and suggests poor solubility.

**11. hERG Inhibition:** Ligand A (0.278) has a slightly lower hERG inhibition liability than Ligand B (0.523), which is preferable.

**12. Microsomal Clearance:** Both have similar microsomal clearance values (77.754 and 76.465), suggesting comparable metabolic stability.

**13. In vitro Half-Life:** Ligand B (29.408) has a significantly longer in vitro half-life than Ligand A (-5.161). This is a major advantage for Ligand B.

**14. P-gp Efflux:** Ligand B (0.615) has a lower P-gp efflux liability than Ligand A (0.151). Lower P-gp efflux is highly desirable for CNS penetration.

**15. Binding Affinity:** Ligand A (-7.8 kcal/mol) has a slightly better binding affinity than Ligand B (-0.0 kcal/mol). While affinity is important, the difference here is not substantial enough to overcome the significant ADME advantages of Ligand B.

**Overall Assessment:**

Ligand B is the superior candidate. Its significantly better BBB penetration, lower DILI risk, longer half-life, and lower P-gp efflux outweigh the slightly better affinity of Ligand A. For a CNS GPCR target like DRD2, maximizing brain exposure is paramount, and Ligand B is clearly positioned to do that better.

Output:
1
2025-04-17 08:55:46,968 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (356.354 and 353.423 Da) fall comfortably within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (119.51) is slightly higher than Ligand B (110.85). Both are below the 140 A^2 threshold for oral absorption and reasonably close to the 90 A^2 target for CNS penetration. Ligand B is preferred here.

**3. logP:** Ligand A (1.401) is within the optimal 1-3 range. Ligand B (-0.965) is slightly below 1, which *could* indicate permeability issues, although not drastically. Ligand A is preferred.

**4. H-Bond Donors:** Ligand A (2) and Ligand B (3) are both acceptable, being less than 5.

**5. H-Bond Acceptors:** Ligand A (7) and Ligand B (4) are both below the 10 threshold.

**6. QED:** Ligand A (0.739) has a better QED score than Ligand B (0.488), indicating a more drug-like profile.

**7. DILI:** Ligand A (73.711) has a significantly higher DILI risk than Ligand B (29.818). This is a major concern for Ligand A.

**8. BBB:** Ligand A (76.076) has a much better BBB penetration percentile than Ligand B (49.477). This is critical for a CNS target like DRD2.

**9. Caco-2 Permeability:** Ligand A (-4.427) has poor Caco-2 permeability, while Ligand B (-5.486) is also poor, but slightly better.

**10. Aqueous Solubility:** Ligand A (-3.052) has better aqueous solubility than Ligand B (-1.16).

**11. hERG Inhibition:** Both ligands (0.166 and 0.089) have very low hERG inhibition risk, which is excellent.

**12. Microsomal Clearance:** Ligand B (-18.737) has significantly lower (better) microsomal clearance than Ligand A (85.2). This suggests better metabolic stability for Ligand B.

**13. In vitro Half-Life:** Ligand B (4.558) has a slightly longer half-life than Ligand A (-25.873).

**14. P-gp Efflux:** Both ligands (0.021 and 0.003) have very low P-gp efflux, which is favorable.

**15. Binding Affinity:** Both ligands have the same binding affinity (-7.8 kcal/mol), which is excellent.

**Overall Assessment:**

Ligand A has a better BBB score, QED, and solubility, but suffers from a significantly higher DILI risk and poor Caco-2 permeability. Ligand B has a lower DILI risk, better metabolic stability (lower Cl_mic and longer half-life), and slightly better Caco-2 permeability, but a lower BBB score and QED.

Given the GPCR-specific priorities, and particularly the importance of BBB penetration for a CNS target, Ligand A initially appears more promising due to its higher BBB score. However, the high DILI risk of Ligand A is a major red flag. While the binding affinity is the same, a high DILI risk often leads to attrition during development. Ligand B, despite its lower BBB, presents a much safer profile with a significantly lower DILI risk and improved metabolic stability. The slightly lower BBB could potentially be addressed through formulation strategies.

Output:
1
2025-04-17 08:55:46,968 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (374.815 Da) is slightly lower, which is generally favorable for permeability. Ligand B (400.975 Da) is also acceptable.

**TPSA:** Ligand A (67.43) is higher than Ligand B (26.71). For CNS targets, TPSA should be <= 90, both are within this range, but Ligand B is significantly better.

**logP:** Both ligands have good logP values (Ligand A: 3.336, Ligand B: 4.236), falling within the optimal 1-3 range. Ligand B is slightly higher, potentially raising concerns about solubility and off-target effects, but still within an acceptable range.

**H-Bond Donors/Acceptors:** Ligand A has 2 HBD and 3 HBA, while Ligand B has 1 HBD and 4 HBA. Both are within the suggested limits of <=5 HBD and <=10 HBA.

**QED:** Both ligands have similar QED values (Ligand A: 0.75, Ligand B: 0.693), indicating good drug-like properties.

**DILI:** Ligand A (57.193) has a slightly higher DILI risk than Ligand B (49.36), but both are below the concerning threshold of 60.

**BBB:** Both ligands exhibit excellent BBB penetration (Ligand A: 87.67, Ligand B: 85.77), exceeding the desirable >70 threshold for CNS targets.

**Caco-2 Permeability:** Ligand A (-4.467) has worse Caco-2 permeability than Ligand B (-5.066). Lower values are less desirable.

**Aqueous Solubility:** Ligand A (-4.545) has worse aqueous solubility than Ligand B (-3.788). Lower values are less desirable.

**hERG Inhibition:** Ligand A (0.639) has a slightly lower hERG inhibition liability than Ligand B (0.984), which is preferable.

**Microsomal Clearance:** Ligand A (47.612) has higher microsomal clearance than Ligand B (17.658), indicating lower metabolic stability. This is a significant drawback for Ligand A.

**In vitro Half-Life:** Ligand A (8.086) has a shorter in vitro half-life than Ligand B (59.566), which is less desirable.

**P-gp Efflux:** Ligand A (0.179) has lower P-gp efflux liability than Ligand B (0.915), which is preferable for CNS penetration.

**Binding Affinity:** Ligand B (-8.8 kcal/mol) has a slightly stronger binding affinity than Ligand A (-8.0 kcal/mol). While both are excellent, the 0.8 kcal/mol difference is noteworthy.

**Overall Assessment:**

Ligand B is the stronger candidate. While Ligand A has better P-gp efflux and slightly lower hERG risk, Ligand B excels in several critical areas: significantly lower microsomal clearance (better metabolic stability), a much longer in vitro half-life, better Caco-2 permeability, better aqueous solubility, and slightly stronger binding affinity. The lower TPSA of Ligand B is also a significant advantage for CNS penetration. The slightly higher logP of Ligand B is a minor concern, but is outweighed by the other benefits.



Output:
1
2025-04-17 08:55:46,968 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (340.431 and 349.351 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (75.94) is excellent, well below the 90 A^2 threshold for CNS targets. Ligand B (139.27) is approaching the upper limit for good oral absorption (140 A^2) and is less desirable for CNS penetration.

**logP:** Ligand A (2.316) is within the optimal 1-3 range. Ligand B (-1.926) is significantly below this, which could hinder membrane permeability and CNS penetration.

**H-Bond Donors/Acceptors:** Ligand A (1 HBD, 5 HBA) and Ligand B (2 HBD, 9 HBA) both have reasonable counts, staying within the guidelines.

**QED:** Ligand A (0.927) has a very strong drug-like profile. Ligand B (0.636) is still acceptable, but less favorable.

**DILI:** Ligand A (33.773) has a low DILI risk. Ligand B (65.568) has a higher, but still moderate, risk.

**BBB:** Ligand A (77.511) has a good BBB percentile, exceeding the 70% threshold for CNS targets. Ligand B (24.002) is very poor for CNS penetration.

**Caco-2 Permeability:** Ligand A (-4.832) is poor, while Ligand B (-5.701) is also poor. This is a concern for both, but less critical given the CNS target.

**Aqueous Solubility:** Both ligands have negative solubility values (-2.01 and -1.205), which is unusual and suggests potential formulation challenges. However, for a CNS target, solubility is less critical than BBB penetration.

**hERG Inhibition:** Ligand A (0.304) has a very low hERG risk. Ligand B (0.031) also has a very low hERG risk.

**Microsomal Clearance:** Ligand A (7.705) has a moderate clearance. Ligand B (6.117) has a lower clearance, suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (-7.404) has a very long half-life, which is excellent. Ligand B (15.073) has a reasonable half-life.

**P-gp Efflux:** Ligand A (0.042) has low P-gp efflux, which is favorable for CNS exposure. Ligand B (0.011) also has very low P-gp efflux.

**Binding Affinity:** Ligand A (-9.1 kcal/mol) has significantly stronger binding affinity than Ligand B (0.0 kcal/mol). This is a decisive advantage.

**Overall:**

Ligand A clearly outperforms Ligand B. Its superior BBB penetration, excellent TPSA, optimal logP, strong binding affinity, and low DILI risk make it a much more promising candidate for a CNS-targeting drug like a DRD2 ligand. While both have poor Caco-2 permeability and negative solubility values, these are less critical for a CNS target. The significantly stronger binding affinity of Ligand A is a major advantage that can compensate for other minor drawbacks.

Output:
1
2025-04-17 08:55:46,969 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (346.431 and 359.442 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (77.41) is significantly better than Ligand B (101.73). For CNS targets, we want TPSA <= 90, so Ligand A is preferable.

**logP:** Both ligands have acceptable logP values (1.782 and 0.757), falling within the 1-3 range. Ligand A is slightly better.

**H-Bond Donors/Acceptors:** Both have 2 HBD and reasonable HBA counts (5 and 4 respectively). This is acceptable for both.

**QED:** Both ligands have good QED scores (0.726 and 0.7), indicating good drug-like properties.

**DILI:** Both have low DILI risk (32.765 and 34.393), below the 40 threshold.

**BBB:** Ligand B (78.829) is significantly better than Ligand A (60.644) in terms of BBB penetration. This is a crucial factor for a CNS target like DRD2, and gives Ligand B a substantial advantage.

**Caco-2 Permeability:** Both have negative Caco-2 values (-4.928 and -5.006) which is unusual and suggests poor permeability.

**Aqueous Solubility:** Both have negative solubility values (-2.128 and -2.762), which is also unusual and suggests poor solubility.

**hERG:** Both ligands have very low hERG risk (0.288 and 0.365).

**Microsomal Clearance:** Ligand B (18.589) has a lower microsomal clearance than Ligand A (28.977), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (41.038) has a longer half-life than Ligand B (-10.746). However, the negative value for Ligand B is concerning and likely indicates a very short half-life.

**P-gp Efflux:** Both have very low P-gp efflux liability (0.019 and 0.065).

**Binding Affinity:** Ligand B (-6.5 kcal/mol) has a slightly better binding affinity than Ligand A (-8.0 kcal/mol). While Ligand A has a stronger binding affinity, the difference is not large enough to overcome Ligand B's superior BBB penetration and metabolic stability.

**Overall:** Considering the GPCR-specific priorities, Ligand B is the more promising candidate. While Ligand A has a slightly better binding affinity and half-life, Ligand B's significantly better BBB penetration and lower microsomal clearance are more critical for a CNS-targeting drug. The negative Caco-2 and solubility values are concerning for both, but can be addressed through formulation strategies.

Output:
1
2025-04-17 08:55:46,969 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (360.483 and 376.389 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (78.66) is significantly better than Ligand B (109.22). For CNS targets, we want TPSA <= 90, so Ligand A is preferable.

**logP:** Ligand A (2.443) is within the optimal 1-3 range. Ligand B (-1.243) is below 1, which could hinder permeation. This favors Ligand A.

**H-Bond Donors/Acceptors:** Ligand A (3 HBD, 5 HBA) and Ligand B (2 HBD, 7 HBA) both have reasonable counts, within the guidelines.

**QED:** Both ligands have acceptable QED values (0.787 and 0.601, both > 0.5).

**DILI:** Ligand A (46.297) has a much lower DILI risk than Ligand B (75.882). This is a significant advantage for Ligand A.

**BBB:** Ligand A (57.619) has a slightly better BBB percentile than Ligand B (54.634), but both are below the desirable >70 for CNS targets.

**Caco-2 Permeability:** Ligand A (-4.885) has a worse Caco-2 permeability than Ligand B (-5.421).

**Aqueous Solubility:** Ligand A (-2.771) has a worse aqueous solubility than Ligand B (-1.744).

**hERG:** Both ligands have very low hERG inhibition liability (0.443 and 0.049).

**Microsomal Clearance:** Ligand A (-10.522) has significantly better metabolic stability (lower clearance) than Ligand B (14.619).

**In vitro Half-Life:** Ligand A (37.163) has a better in vitro half-life than Ligand B (-10.634).

**P-gp Efflux:** Ligand A (0.235) has lower P-gp efflux than Ligand B (0.016), which is favorable for CNS penetration.

**Binding Affinity:** Ligand A (-9.2 kcal/mol) has a significantly stronger binding affinity than Ligand B (-7.4 kcal/mol). This is a >1.5 kcal/mol advantage, which can outweigh minor ADME drawbacks.

**Overall Assessment:**

Ligand A is clearly superior. It has better TPSA, logP, DILI risk, metabolic stability, half-life, P-gp efflux, and, most importantly, significantly better binding affinity. While both have suboptimal BBB penetration, the stronger affinity of Ligand A makes it more likely to achieve sufficient target engagement *in vivo*, even with limited BBB penetration. The slightly worse Caco-2 and solubility of Ligand A are less critical given the CNS target.



Output:
1
2025-04-17 08:55:46,969 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (347.463 and 357.495 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (106.96) is slightly above the ideal <90 for CNS targets, but still reasonable. Ligand B (73.32) is excellent, well below 90.

**logP:** Ligand A (3.224) is at the upper end of the optimal 1-3 range, while Ligand B (0.419) is quite low, potentially hindering membrane permeability.

**H-Bond Donors/Acceptors:** Ligand A has 2 HBD and 3 HBA, which are acceptable. Ligand B has 1 HBD and 5 HBA, also acceptable.

**QED:** Ligand B (0.682) has a better QED score than Ligand A (0.22), indicating a more drug-like profile.

**DILI:** Ligand B (7.135) has a significantly lower DILI risk than Ligand A (19.659), which is a major advantage.

**BBB:** Ligand B (62.156) has a better BBB penetration score than Ligand A (54.634), although both are below the desirable >70 for CNS targets.

**Caco-2 Permeability:** Ligand A (-5.04) has a more negative Caco-2 value, indicating lower permeability. Ligand B (-4.586) is also negative, but less so.

**Aqueous Solubility:** Both ligands have negative solubility values, indicating poor aqueous solubility. Ligand B (-0.351) is slightly better than Ligand A (-2.05).

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.313 and 0.236).

**Microsomal Clearance:** Ligand B (13.178) has slightly lower microsomal clearance than Ligand A (15.219), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (4.533) has a longer in vitro half-life than Ligand B (0.058), which is a positive.

**P-gp Efflux:** Ligand A (0.066) has a lower P-gp efflux liability than Ligand B (0.014), which is favorable for CNS penetration.

**Binding Affinity:** Ligand A (-7.5 kcal/mol) has a significantly stronger binding affinity than Ligand B (-6.6 kcal/mol). This 0.9 kcal/mol difference is substantial and could outweigh some of the ADME drawbacks.

**Overall Assessment:**

While Ligand B has better ADME properties overall (lower DILI, better QED, better BBB, better solubility, lower clearance), Ligand A's significantly stronger binding affinity (-7.5 vs -6.6 kcal/mol) is a critical factor, especially for a GPCR target. The affinity difference is large enough to potentially overcome the less favorable ADME profile, particularly if formulation strategies can address the solubility issues. The P-gp efflux is also favorable for Ligand A.

Output:
1
2025-04-17 08:55:46,969 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (340.427 and 340.423 Da) fall comfortably within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (83.98) is better than Ligand B (62.55). Both are below the 90 A^2 threshold for CNS targets, but A is closer to the upper limit.

**3. logP:** Ligand B (3.965) is higher than Ligand A (1.523). While both are within the 1-3 optimal range, B is approaching the upper limit, which could raise solubility concerns.

**4. H-Bond Donors:** Ligand A (2) is slightly higher than Ligand B (1), both are acceptable.

**5. H-Bond Acceptors:** Ligand A (4) is slightly higher than Ligand B (3), both are acceptable.

**6. QED:** Both ligands have good QED scores (0.769 and 0.857, respectively), indicating drug-like properties.

**7. DILI:** Ligand A (44.552) has a significantly lower DILI risk than Ligand B (60.915). This is a substantial advantage for A.

**8. BBB:** Ligand B (77.239) has a much better BBB penetration score than Ligand A (48.662). This is a critical factor for a CNS target like DRD2.

**9. Caco-2 Permeability:** Ligand A (-4.886) has a worse Caco-2 permeability than Ligand B (-4.648). Both are negative, indicating poor permeability, but B is slightly better.

**10. Aqueous Solubility:** Ligand A (-2.623) has better solubility than Ligand B (-4.905).

**11. hERG Inhibition:** Ligand A (0.155) has a lower hERG inhibition liability than Ligand B (0.645). This is a significant safety advantage for A.

**12. Microsomal Clearance:** Ligand B (50.277) has a lower microsomal clearance than Ligand A (15.243), indicating better metabolic stability.

**13. In vitro Half-Life:** Ligand B (68.208) has a much longer in vitro half-life than Ligand A (-18.296). This is a major advantage for B.

**14. P-gp Efflux:** Ligand A (0.024) has a lower P-gp efflux liability than Ligand B (0.461). This is beneficial for CNS exposure.

**15. Binding Affinity:** Both ligands have very similar and strong binding affinities (-8.1 and -7.9 kcal/mol, respectively). The difference is negligible.

**Overall Assessment:**

Ligand B excels in BBB penetration and metabolic stability (half-life and clearance), which are crucial for a CNS GPCR target. However, it has a higher DILI risk and P-gp efflux. Ligand A has a lower DILI and P-gp efflux, better solubility, and lower hERG risk, but suffers from poorer BBB penetration and metabolic stability.

Considering the balance, the improved BBB penetration of Ligand B is the most important factor for a CNS target like DRD2. The slightly higher DILI risk can be investigated further during optimization.

Output:
1
2025-04-17 08:55:46,970 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (363.527 Da and 352.475 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (53.51) is excellent, well below the 90 A^2 threshold for CNS targets. Ligand B (78.87) is still reasonable, but less optimal.

**logP:** Ligand A (3.061) is within the optimal 1-3 range. Ligand B (1.482) is at the lower end, potentially hindering permeability.

**H-Bond Donors/Acceptors:** Ligand A (0 HBD, 4 HBA) and Ligand B (2 HBD, 4 HBA) both have acceptable numbers of H-bond donors and acceptors.

**QED:** Both ligands have acceptable QED scores (0.826 and 0.649, respectively), indicating good drug-like properties.

**DILI:** Ligand A (61.691) has a moderate DILI risk, while Ligand B (16.673) has a very low DILI risk, which is a significant advantage.

**BBB:** Ligand A (78.247) has a good BBB penetration score, exceeding the 70% threshold for CNS targets. Ligand B (44.94) is considerably lower, which is a major drawback for a CNS target like DRD2.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.712 and -4.464), which is unusual and suggests poor permeability. However, these values are on a log scale and can be interpreted cautiously.

**Aqueous Solubility:** Both ligands have negative solubility values (-3.365 and -1.888), indicating poor aqueous solubility. This could pose formulation challenges.

**hERG Inhibition:** Both ligands have low hERG inhibition liability (0.462 and 0.239), which is positive.

**Microsomal Clearance:** Ligand A (85.862) has higher microsomal clearance than Ligand B (35.619), suggesting lower metabolic stability.

**In vitro Half-Life:** Ligand B (-6.166) has a longer in vitro half-life than Ligand A (-12.399), which is favorable.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.369 and 0.08), which is good for CNS penetration.

**Binding Affinity:** Both ligands have very similar and strong binding affinities (-7.6 kcal/mol and -7.5 kcal/mol). The difference is negligible.

**Overall Assessment:**

Ligand A excels in TPSA and BBB penetration, crucial for CNS targets. However, it has a higher DILI risk and lower metabolic stability. Ligand B has a significantly lower DILI risk, better metabolic stability (lower Cl_mic, longer t1/2), and a slightly better solubility profile, but suffers from poor BBB penetration.

Given the importance of BBB penetration for a DRD2 ligand (CNS target), and the similar binding affinities, Ligand A is the more promising candidate despite its slightly higher DILI risk and lower metabolic stability. The poor BBB penetration of Ligand B is a critical flaw.

Output:
0
2025-04-17 08:55:46,970 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (357.405 and 348.364 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (80.12) is better than Ligand B (26.3). For CNS targets, we want TPSA <= 90, both are well within this range, but lower is generally preferred for better BBB penetration.

**3. logP:** Ligand A (1.871) is optimal (1-3), while Ligand B (4.862) is a bit high, potentially leading to solubility issues and off-target interactions.

**4. H-Bond Donors:** Ligand A (1) is good, while Ligand B (0) is also acceptable.

**5. H-Bond Acceptors:** Ligand A (5) is good, while Ligand B (2) is also acceptable.

**6. QED:** Both ligands have similar QED values (0.77 and 0.74), indicating good drug-like properties.

**7. DILI:** Both ligands have very similar DILI risk (38.891 and 38.852), both are low risk (<40).

**8. BBB:** Both ligands have excellent BBB penetration (87.398 and 87.127), exceeding the desirable >70 threshold for CNS targets.

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.362 and -4.337). This is unusual and suggests a potential issue with the data or modeling. However, since both are similarly affected, it doesn't differentiate them.

**10. Aqueous Solubility:** Ligand A (-3.303) is better than Ligand B (-5.835), indicating better solubility. Solubility is important for formulation and bioavailability.

**11. hERG Inhibition:** Ligand A (0.182) has a much lower hERG inhibition risk than Ligand B (0.869). This is a significant advantage, as hERG inhibition can lead to cardiotoxicity.

**12. Microsomal Clearance:** Ligand A (50.647) has lower clearance than Ligand B (67.336), suggesting better metabolic stability.

**13. In vitro Half-Life:** Ligand A (-32.69) has a much longer half-life than Ligand B (26.106). This is a significant advantage, potentially allowing for less frequent dosing.

**14. P-gp Efflux:** Ligand A (0.026) has significantly lower P-gp efflux liability than Ligand B (0.515). Lower P-gp efflux is crucial for CNS exposure.

**15. Binding Affinity:** Ligand B (-10.2) has a significantly stronger binding affinity than Ligand A (-7.7). This is a substantial advantage, potentially outweighing some of the ADME drawbacks of Ligand B. The difference is >1.5 kcal/mol.

**Overall Assessment:**

While Ligand B boasts a superior binding affinity, Ligand A demonstrates a significantly better ADME profile, particularly regarding solubility, hERG inhibition, metabolic stability, P-gp efflux, and half-life. Given the GPCR-specific priorities, the improved CNS penetration properties of Ligand A (lower P-gp, better solubility, better metabolic stability) are crucial. The difference in affinity, while significant, might be overcome with further optimization of Ligand A, while addressing the ADME issues of Ligand B would likely be more challenging.

Output:
0
2025-04-17 08:55:46,970 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 drug candidates, considering the provided guidelines and GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (376.519 and 344.283 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (96.89) is excellent for CNS penetration, being well below 90. Ligand B (139.6) is approaching the 140 limit for oral absorption, but still potentially acceptable, though less favorable for CNS targets.

**logP:** Both ligands (0.551 and 0.449) are a bit low. While not drastically outside the 1-3 range, they might suffer from permeability issues.

**H-Bond Donors/Acceptors:** Both have 3 HBDs, which is good. Ligand A has 6 HBAs, and Ligand B has 8 HBAs. Both are within the acceptable limit of 10.

**QED:** Both ligands have good QED scores (0.515 and 0.61), indicating drug-like properties.

**DILI:** Ligand A (33.501) has a much lower DILI risk than Ligand B (90.5), which is a significant advantage.

**BBB:** Ligand A (22.334) has a very poor BBB percentile, making CNS penetration unlikely. Ligand B (16.751) also has a poor BBB percentile, but is slightly better than Ligand A.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.357 and -5.398), indicating poor intestinal absorption.

**Aqueous Solubility:** Both ligands have negative solubility values (-1.426 and -3.5), indicating poor aqueous solubility.

**hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.109 and 0.095).

**Microsomal Clearance:** Ligand A (33.573) has higher microsomal clearance than Ligand B (-2.381), suggesting lower metabolic stability.

**In vitro Half-Life:** Ligand B (39.577) has a longer in vitro half-life than Ligand A (4.891), which is desirable.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.021 and 0.047), which is good.

**Binding Affinity:** Ligand B (-8.5 kcal/mol) has a significantly stronger binding affinity than Ligand A (-7.0 kcal/mol). This >1.5 kcal/mol difference is a major advantage, potentially outweighing some ADME drawbacks.

**Conclusion:**

Despite both ligands having issues with logP, Caco-2 permeability and solubility, Ligand B is the more promising candidate. The substantially stronger binding affinity (-8.5 vs -7.0 kcal/mol) is a critical factor for a GPCR target. While the BBB penetration is not ideal for either, the lower DILI risk and longer half-life of Ligand B are also beneficial. The slightly higher HBA count of Ligand B is not a major concern.

Output:
1
2025-04-17 08:55:46,970 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (333.387 and 345.418 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (55.4) is significantly better than Ligand B (62.71). For a CNS target like DRD2, TPSA should be <=90, and lower is preferable. Ligand A is much closer to the optimal range.

**3. logP:** Ligand A (4.368) is higher than the optimal 1-3 range, but still potentially manageable. Ligand B (2.023) is within the optimal range. However, for CNS penetration, a slightly higher logP can be beneficial, provided other properties are favorable.

**4. H-Bond Donors:** Both ligands have 1 HBD, which is within the acceptable limit of <=5.

**5. H-Bond Acceptors:** Ligand A has 3 HBAs, and Ligand B has 4. Both are within the acceptable limit of <=10.

**6. QED:** Both ligands have good QED scores (0.706 and 0.87), indicating good drug-like properties.

**7. DILI:** Ligand A has a high DILI risk (93.37%), which is a significant concern. Ligand B has a much lower DILI risk (16.479%), making it more favorable.

**8. BBB:** Both ligands have good BBB penetration (77.162% and 78.868%), exceeding the desirable threshold of >70% for CNS targets.

**9. Caco-2 Permeability:** Ligand A (-4.725) and Ligand B (-5.124) both have negative Caco-2 values, which is unusual and suggests poor permeability. It's difficult to interpret these values without knowing the scale.

**10. Aqueous Solubility:** Both ligands have very poor aqueous solubility (-6.303 and -1.227). This is a significant drawback, potentially hindering bioavailability.

**11. hERG Inhibition:** Ligand A (0.738) has a slightly higher hERG risk than Ligand B (0.95), but both are relatively low.

**12. Microsomal Clearance:** Ligand A (66.935) has higher microsomal clearance than Ligand B (9.886), indicating lower metabolic stability.

**13. In vitro Half-Life:** Ligand A (33.551) has a longer half-life than Ligand B (10.372).

**14. P-gp Efflux:** Ligand A (0.82) has slightly lower P-gp efflux than Ligand B (0.148), which is favorable for CNS exposure.

**15. Binding Affinity:** Ligand A (-10.1 kcal/mol) has significantly stronger binding affinity than Ligand B (-9.0 kcal/mol). This is a substantial advantage.

**Overall Assessment:**

Despite Ligand A's superior binding affinity and acceptable BBB penetration, its extremely high DILI risk and higher microsomal clearance are major liabilities. The poor solubility of both compounds is also concerning. Ligand B, while having a slightly weaker affinity, presents a much more favorable safety profile (lower DILI) and better metabolic stability. Given the importance of safety and metabolic stability in drug development, and the fact that the affinity difference isn't *massive*, Ligand B is the more promising candidate.

Output:
1
2025-04-17 08:55:46,971 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (359.491 and 345.399 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (53.68) is significantly better than Ligand B (86.47). For CNS targets, we want TPSA <= 90, and A is comfortably within that, while B is approaching the upper limit.

**3. logP:** Ligand A (4.056) is slightly higher than the optimal 1-3 range, but still acceptable. Ligand B (2.425) is well within the optimal range.

**4. H-Bond Donors:** Both ligands have 1 HBD, which is good.

**5. H-Bond Acceptors:** Ligand A has 4 HBA, and Ligand B has 7. Both are acceptable (<=10), but A is preferable.

**6. QED:** Both ligands have similar QED values (0.811 and 0.776), indicating good drug-likeness.

**7. DILI:** Ligand A (26.444) has a much lower DILI risk than Ligand B (50.174). This is a significant advantage for A.

**8. BBB:** Ligand A (67.197) has a better BBB penetration percentile than Ligand B (50.95). While both are not ideal (>70), A is closer. This is crucial for a CNS target like DRD2.

**9. Caco-2:** Both ligands have negative Caco-2 values (-4.773 and -4.469). This is unusual and suggests poor permeability. However, the scale is not defined, so it is hard to interpret.

**10. Solubility:** Both ligands have negative solubility values (-4.078 and -3.239). This is also unusual and suggests poor solubility.

**11. hERG:** Ligand A (0.734) has a slightly higher hERG risk than Ligand B (0.068). B is significantly better here.

**12. Cl_mic:** Ligand A (61.513) has a higher microsomal clearance than Ligand B (35.269), indicating lower metabolic stability. B is preferable here.

**13. t1/2:** Ligand A (59.139) has a much longer in vitro half-life than Ligand B (-35.541). This is a major advantage for A.

**14. Pgp:** Ligand A (0.879) has a lower P-gp efflux liability than Ligand B (0.207). This is beneficial for CNS penetration.

**15. Binding Affinity:** Ligand B (-8.6 kcal/mol) has a stronger binding affinity than Ligand A (-7.7 kcal/mol). This is a significant advantage for B (a 0.9 kcal/mol difference).

**Overall Assessment:**

Ligand B has a significantly better binding affinity and lower hERG risk. However, Ligand A excels in DILI risk, BBB penetration, in vitro half-life, and P-gp efflux. Considering the GPCR-specific priorities for DRD2 (BBB, logP, Pgp, TPSA, and affinity), and the fact that the affinity difference is substantial, Ligand B is the more promising candidate. The better BBB and Pgp values of A are outweighed by the stronger binding of B. The poor solubility and Caco-2 values are concerning for both, but can be addressed in later optimization stages.

Output:
1
2025-04-17 08:55:46,971 - INFO - Batch 490 complete. Total preferences: 7840
2025-04-17 08:55:46,971 - INFO - Processing batch 491/512...
2025-04-17 08:56:27,616 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (351.403 and 354.491 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (93.9) is slightly above the optimal <90 for CNS targets, while Ligand B (87.66) is comfortably below. This gives a slight edge to Ligand B.

**3. logP:** Ligand A (0.619) is a bit low, potentially hindering permeability. Ligand B (1.323) is better, falling within the 1-3 range. Ligand B is favored here.

**4. H-Bond Donors:** Ligand A (1) is good. Ligand B (3) is acceptable, but higher HBD can sometimes reduce permeability.

**5. H-Bond Acceptors:** Ligand A (6) is good. Ligand B (4) is also good.

**6. QED:** Both ligands have reasonable QED values (0.836 and 0.552), indicating drug-like properties. Ligand A is better.

**7. DILI:** Ligand A (58.976) has a higher DILI risk than Ligand B (10.198). Ligand B is significantly better regarding liver toxicity.

**8. BBB:** Both ligands have similar BBB penetration (57.968% and 57.619%). While not exceptional, they are both in a reasonable range for CNS targets, but ideally, we'd want >70%.

**9. Caco-2:** Both have negative Caco-2 values (-4.652 and -4.68), which is unusual and suggests poor permeability. This is a significant drawback for both.

**10. Solubility:** Both have negative solubility values (-1.919 and -2.949), which is also unusual and suggests poor solubility. This is another significant drawback for both.

**11. hERG:** Both ligands have low hERG inhibition risk (0.196 and 0.285).

**12. Cl_mic:** Ligand A (11.186) has lower microsomal clearance than Ligand B (59.627), indicating better metabolic stability. This is a significant advantage for Ligand A.

**13. t1/2:** Ligand A (23.378) has a longer in vitro half-life than Ligand B (7.763). This is a significant advantage for Ligand A.

**14. Pgp:** Both have very low P-gp efflux liability (0.045 and 0.085).

**15. Binding Affinity:** Ligand A (-7.9 kcal/mol) has a stronger binding affinity than Ligand B (-7.2 kcal/mol). This 0.7 kcal/mol difference is substantial and could outweigh some ADME drawbacks.

**Overall Assessment:**

Ligand A has a significantly better binding affinity, lower clearance, and longer half-life. However, Ligand B has a better logP and a much lower DILI risk. Both have poor Caco-2 and solubility. Given the GPCR-specific focus on affinity and the substantial difference in binding energy, and considering the relatively acceptable BBB values for both, the stronger affinity of Ligand A is the deciding factor. The improved metabolic stability (lower Cl_mic and longer t1/2) further strengthens its profile. The DILI risk of Ligand A is a concern, but could be addressed with further optimization.

Output:
1
2025-04-17 08:56:27,616 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (368.503 Da) is slightly lower, which could be beneficial for permeability. Ligand B (396.192 Da) is also good.

**TPSA:** Ligand A (87.58) is better than Ligand B (53.68) as it is closer to the ideal range for CNS targets (<=90). Ligand B is excellent.

**logP:** Ligand A (1.679) is within the optimal range (1-3), while Ligand B (3.871) is approaching the upper limit. While still acceptable, higher logP can sometimes lead to off-target effects.

**H-Bond Donors/Acceptors:** Ligand A has 2 HBD and 7 HBA, while Ligand B has 1 HBD and 3 HBA. Both are within acceptable limits (<=5 HBD and <=10 HBA).

**QED:** Ligand A (0.794) has a better QED score than Ligand B (0.596), indicating a more drug-like profile.

**DILI:** Ligand A (61.264) has a slightly higher DILI risk than Ligand B (48.74), but both are reasonably low.

**BBB:** Ligand B (70.376) has a significantly better BBB penetration score than Ligand A (57.968). This is a crucial advantage for a CNS target like DRD2.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values, which is unusual and suggests a potential issue with intestinal absorption. However, the scale is not defined, so it is difficult to interpret.

**Aqueous Solubility:** Both ligands have negative solubility values, which is also unusual and suggests poor solubility.

**hERG Inhibition:** Ligand A (0.49) has a slightly lower hERG inhibition liability than Ligand B (0.891), which is preferable.

**Microsomal Clearance:** Ligand B (59.473) has a higher microsomal clearance than Ligand A (32.63), indicating faster metabolism and potentially lower *in vivo* exposure.

**In vitro Half-Life:** Ligand B (69.217) has a significantly longer *in vitro* half-life than Ligand A (1.797), which is a major advantage.

**P-gp Efflux:** Ligand A (0.174) has much lower P-gp efflux liability than Ligand B (0.802). Lower P-gp efflux is highly desirable for CNS penetration.

**Binding Affinity:** Ligand B (-8.4 kcal/mol) has a significantly stronger binding affinity than Ligand A (-7.5 kcal/mol). This difference of 0.9 kcal/mol is substantial and can outweigh some ADME drawbacks.

**Overall Assessment:**

Ligand B is the stronger candidate. While Ligand A has a better QED and lower P-gp efflux, Ligand B's superior BBB penetration, significantly stronger binding affinity, and longer half-life are critical for a CNS-targeting GPCR. The slightly higher logP and DILI risk of Ligand B are less concerning given the magnitude of its advantages in key properties. The negative solubility and Caco-2 values are concerning for both, but can be addressed with formulation strategies.

Output:
1
2025-04-17 08:56:27,616 - INFO - Reasoning:

Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (366.359 and 342.399 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (76.02) is significantly better than Ligand B (86.94). For CNS targets, we want TPSA <= 90, and A is closer to the ideal <60 range. B is pushing the upper limit.

**3. logP:** Both ligands have acceptable logP values (2.03 and 0.99), falling within the 1-3 range. Ligand A is slightly preferred.

**4. H-Bond Donors:** Both have 2 HBD, which is good.

**5. H-Bond Acceptors:** Ligand A has 4 HBA, and Ligand B has 5. Both are acceptable, below the 10 limit.

**6. QED:** Both ligands have good QED scores (0.657 and 0.735), indicating drug-likeness.

**7. DILI:** Ligand A (33.773) has a much lower DILI risk than Ligand B (53.276). This is a significant advantage for A.

**8. BBB:** Ligand A (65.607) has a better BBB penetration percentile than Ligand B (35.518). This is *critical* for a CNS target like DRD2.

**9. Caco-2:** Both have negative Caco-2 values, which is unusual and suggests poor permeability. However, the scale is not defined, so it's hard to interpret.

**10. Solubility:** Both have negative solubility values, which is also unusual and suggests poor solubility. Again, the scale is not defined.

**11. hERG:** Both ligands have very low hERG inhibition liability (0.407 and 0.162), which is excellent.

**12. Cl_mic:** Ligand B (15.596) has a lower microsomal clearance than Ligand A (18.544), suggesting better metabolic stability.

**13. t1/2:** Ligand B (-12.144) has a much more negative in vitro half-life, which is not good. Ligand A (-1.753) is better, though still not ideal.

**14. Pgp:** Both ligands have very low Pgp efflux liability (0.025 and 0.017), which is favorable for CNS penetration.

**15. Binding Affinity:** Ligand A (-8.2 kcal/mol) has a slightly better binding affinity than Ligand B (-7.6 kcal/mol). While both are good, the 0.6 kcal/mol difference is noticeable.

**Overall Assessment:**

Considering the GPCR-specific priorities, Ligand A is the superior candidate. The significantly better BBB penetration, lower DILI risk, and slightly better binding affinity outweigh the slightly higher microsomal clearance and potentially problematic solubility/permeability (although the scales are undefined). The TPSA is also much more favorable for CNS penetration.

Output:
1
2025-04-17 08:56:27,616 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (360.523 and 369.571 Da) fall comfortably within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (49.41) is better than Ligand B (38.77). Both are below the 90 A^2 threshold for CNS targets, which is excellent.

**3. logP:** Both ligands have good logP values (3.287 and 3.733), falling within the optimal 1-3 range. Ligand B is slightly higher, which could potentially lead to some off-target effects, but is still acceptable.

**4. H-Bond Donors:** Ligand A has 1 HBD, and Ligand B has 0. Both are within the acceptable limit of <=5.

**5. H-Bond Acceptors:** Ligand A has 3 HBA, and Ligand B has 4. Both are within the acceptable limit of <=10.

**6. QED:** Ligand A (0.846) has a significantly better QED score than Ligand B (0.588), indicating a more drug-like profile.

**7. DILI:** Ligand A (14.889) has a much lower DILI risk than Ligand B (21.869), which is a significant advantage.

**8. BBB:** Ligand B (80.613) has a slightly better BBB penetration percentile than Ligand A (73.556), but both are above the 70% threshold desirable for CNS targets.

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.204 and -5.102). This is unusual and suggests poor permeability. However, these values are on a scale where negative values are possible, and the absolute values are similar.

**10. Aqueous Solubility:** Both ligands have negative solubility values (-2.902 and -3.83). This indicates poor aqueous solubility, which could be a formulation challenge. Ligand B is slightly worse.

**11. hERG Inhibition:** Both ligands have low hERG inhibition risk (0.425 and 0.731).

**12. Microsomal Clearance:** Ligand A (47.95) has lower microsomal clearance than Ligand B (79.7), suggesting better metabolic stability.

**13. In vitro Half-Life:** Ligand A (-9.151) has a significantly longer in vitro half-life than Ligand B (18.824).

**14. P-gp Efflux:** Ligand A (0.249) has lower P-gp efflux liability than Ligand B (0.685), which is beneficial for CNS exposure.

**15. Binding Affinity:** Ligand A (-8.4 kcal/mol) has a stronger binding affinity than Ligand B (-6.9 kcal/mol). The difference of 1.5 kcal/mol is substantial and can outweigh minor ADME drawbacks.

**Overall Assessment:**

Ligand A is the superior candidate. It has a better QED score, significantly lower DILI risk, better metabolic stability (lower Cl_mic and longer t1/2), lower P-gp efflux, and a much stronger binding affinity. While Ligand B has slightly better BBB penetration, the other advantages of Ligand A are more critical, especially the strong binding affinity and favorable safety profile (DILI). The poor Caco-2 and solubility for both are concerning, but can potentially be addressed with formulation strategies.

Output:
1
2025-04-17 08:56:27,617 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B based on the provided guidelines, prioritizing GPCR-specific properties (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (351.475 and 344.455 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (54.88) is slightly higher than Ligand B (53.76), but both are below the 90 A^2 threshold desirable for CNS targets.

**logP:** Ligand A (4.567) is higher than the optimal range (1-3), potentially causing solubility issues or off-target effects. Ligand B (3.016) is within the optimal range.

**H-Bond Donors/Acceptors:** Ligand A has 1 HBD and 4 HBA, while Ligand B has 0 HBD and 3 HBA. Both are within acceptable limits.

**QED:** Both ligands have similar QED values (0.733 and 0.715), indicating good drug-likeness.

**DILI:** Ligand A (69.911) has a higher DILI risk than Ligand B (23.885). Ligand B's DILI risk is very favorable.

**BBB:** Ligand B (67.778) has a better BBB penetration percentile than Ligand A (53.083), though both are below the >70 desirable for CNS targets.

**Caco-2 Permeability:** Ligand A (-5.022) shows poor Caco-2 permeability, while Ligand B (-4.638) is slightly better, but still low.

**Aqueous Solubility:** Ligand A (-5.1) has very poor aqueous solubility, which is a significant concern. Ligand B (-2.249) is also poor, but better than Ligand A.

**hERG Inhibition:** Both ligands show low hERG inhibition risk (0.644 and 0.466).

**Microsomal Clearance:** Ligand A (82.459) has higher microsomal clearance than Ligand B (64.199), indicating lower metabolic stability.

**In vitro Half-Life:** Ligand A (25.577) has a slightly longer half-life than Ligand B (21.462).

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.402 and 0.371).

**Binding Affinity:** Ligand B (-7.9 kcal/mol) has a significantly stronger binding affinity than Ligand A (-9.6 kcal/mol). This difference of 1.7 kcal/mol is substantial and can outweigh minor ADME drawbacks.

**Conclusion:**

Considering all factors, especially the GPCR-specific priorities, **Ligand B is the more promising drug candidate.** While both have issues with Caco-2 permeability and solubility, Ligand B exhibits a significantly stronger binding affinity, lower DILI risk, and better BBB penetration. The logP value is also more favorable for Ligand B. The slightly longer half-life of Ligand A is not enough to compensate for its other weaknesses.

Output:
1
2025-04-17 08:56:27,617 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (362.417 and 355.389 Da) fall within the ideal range of 200-500 Da.

**TPSA:** Ligand A (78.87) is slightly higher than Ligand B (70.47), but both are below the 90 A^2 threshold desirable for CNS targets.

**logP:** Both ligands have good logP values (1.133 and 1.092), falling within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A has 2 HBD and 4 HBA, while Ligand B has 1 HBD and 5 HBA. Both are within acceptable limits (<=5 HBD and <=10 HBA).

**QED:** Ligand B (0.829) has a slightly better QED score than Ligand A (0.603), indicating a more drug-like profile.

**DILI:** Ligand A (16.402) has a significantly lower DILI risk than Ligand B (26.406). This is a substantial advantage.

**BBB:** Ligand B (80.884) has a better BBB penetration percentile than Ligand A (68.282). This is crucial for a CNS target like DRD2.

**Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and suggests poor permeability. Ligand A (-4.517) is slightly better than Ligand B (-4.826).

**Aqueous Solubility:** Both ligands have very poor aqueous solubility (-1.496 and -1.677). This is a significant drawback.

**hERG:** Both ligands show low hERG inhibition liability (0.484 and 0.262), which is good.

**Microsomal Clearance:** Ligand B (-10.387) has a much lower (better) microsomal clearance than Ligand A (19.97). This suggests better metabolic stability for Ligand B.

**In vitro Half-Life:** Ligand B (-0.883) has a slightly better in vitro half-life than Ligand A (-20.486).

**P-gp Efflux:** Ligand A (0.037) has lower P-gp efflux liability than Ligand B (0.007), which is favorable for CNS penetration.

**Binding Affinity:** Ligand B (-8.9 kcal/mol) has a significantly stronger binding affinity than Ligand A (-7.2 kcal/mol). The 1.7 kcal/mol difference is substantial and can outweigh some ADME drawbacks.

**Overall Assessment:**

Ligand B is clearly superior in terms of binding affinity and BBB penetration, which are critical for a CNS GPCR target. It also has better metabolic stability (lower Cl_mic) and a slightly better half-life. However, Ligand A has a significantly lower DILI risk. Both have poor solubility and Caco-2 permeability. The strong affinity of Ligand B, combined with its improved BBB, outweighs the higher DILI risk and solubility concerns, especially considering the potential for structural modifications to address these issues.

Output:
1
2025-04-17 08:56:27,617 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (377.535 and 353.394 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (54.46) is significantly better than Ligand B (110.52). For CNS targets, TPSA should be <= 90, and A is comfortably within this range, while B exceeds it. This is a substantial advantage for A.

**logP:** Ligand A (3.419) is optimal (1-3), while Ligand B (1.348) is on the lower end, potentially hindering permeability.

**H-Bond Donors/Acceptors:** Ligand A (HBD=1, HBA=6) and Ligand B (HBD=3, HBA=4) both have reasonable values, within the guidelines.

**QED:** Both ligands have acceptable QED values (0.75 and 0.613, respectively), indicating good drug-like properties.

**DILI:** Ligand A (69.872) has a higher DILI risk than Ligand B (43.66), but both are below the concerning threshold of 60.

**BBB:** Ligand B (75.572) has a better BBB penetration percentile than Ligand A (62.699). While both are reasonably good, B is preferable for a CNS target.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.105 and -5.091), which is unusual and difficult to interpret without further context. It suggests poor permeability.

**Aqueous Solubility:** Both ligands have negative solubility values (-3.75 and -2.629), also unusual and suggesting poor solubility.

**hERG:** Both ligands have low hERG inhibition liability (0.491 and 0.662), which is good.

**Microsomal Clearance:** Ligand A (53.22) and Ligand B (51.216) have similar microsomal clearance values.

**In vitro Half-Life:** Ligand B (-24.258) has a significantly *longer* in vitro half-life than Ligand A (7.073). This is a major advantage for B.

**P-gp Efflux:** Ligand A (0.469) has lower P-gp efflux liability than Ligand B (0.114), which is favorable for CNS penetration.

**Binding Affinity:** Ligand B (-8.3) has a slightly better binding affinity than Ligand A (-8.1). While the difference is small (0.2 kcal/mol), it's still a positive for B.

**Overall Assessment:**

Considering the GPCR-specific priorities, Ligand A excels in TPSA and P-gp efflux, while Ligand B has better BBB penetration, a longer half-life, and slightly better affinity. The lower logP of Ligand B is a concern, but the stronger binding affinity and significantly improved half-life are compelling. The unusual negative values for Caco-2 and solubility are concerning for both, but the differences in other key parameters outweigh these. Given the importance of CNS penetration for DRD2, the better BBB score and half-life of Ligand B make it the more promising candidate.

Output:
1
2025-04-17 08:56:27,617 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (348.487 and 347.419 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (61.8) is significantly better than Ligand B (78.87). For CNS targets, we want TPSA <= 90, and A is closer to the optimal <=60 range. B is pushing the upper limit.

**logP:** Ligand A (2.575) is optimal (1-3), while Ligand B (0.108) is quite low, potentially hindering membrane permeability.

**H-Bond Donors/Acceptors:** Ligand A (2 HBD, 4 HBA) and Ligand B (0 HBD, 6 HBA) both have acceptable numbers.

**QED:** Both ligands have good QED scores (0.674 and 0.769), indicating good drug-like properties.

**DILI:** Ligand A (2.365) has a much lower DILI risk than Ligand B (45.095). This is a significant advantage.

**BBB:** Both ligands have similar, good BBB penetration (68.941 and 68.282). While >70 is preferred, both are reasonably acceptable.

**Caco-2 Permeability:** Both have negative values, which is unusual. Assuming these are logP-scale values, lower values indicate poorer permeability. Ligand A (-4.667) is worse than Ligand B (-4.503), but both are poor.

**Aqueous Solubility:** Both have negative values, which is also unusual. Assuming these are logS values, lower values indicate poorer solubility. Ligand A (-1.639) is slightly worse than Ligand B (-0.668).

**hERG Inhibition:** Ligand A (0.935) has a slightly higher hERG risk than Ligand B (0.246), but both are relatively low.

**Microsomal Clearance:** Ligand A (17.969) has a higher microsomal clearance than Ligand B (-5.29). A negative value for B suggests very high metabolic stability, which is a major advantage.

**In vitro Half-Life:** Ligand A (-14.091) has a negative half-life, which is impossible. This is a red flag. Ligand B (1.036) has a short half-life, but it's a realistic value.

**P-gp Efflux:** Ligand A (0.495) has lower P-gp efflux than Ligand B (0.021), which is favorable for CNS penetration.

**Binding Affinity:** Ligand B (-7.6 kcal/mol) has a significantly stronger binding affinity than Ligand A (-8.7 kcal/mol). This is a substantial advantage, potentially outweighing some ADME concerns.

**Overall Assessment:**

Ligand B has a much better binding affinity and significantly better metabolic stability (negative Cl_mic). However, it suffers from a low logP and a short half-life. Ligand A has a better TPSA and P-gp efflux, but its negative in vitro half-life is a critical flaw. The DILI risk is also much higher for Ligand B.

Despite Ligand B's low logP, the significantly stronger binding affinity (-7.6 vs -8.7 kcal/mol) is a major advantage for a GPCR target. The improved metabolic stability is also crucial. While the low logP is a concern, it may be addressable through further optimization. The negative half-life for ligand A is a showstopper.

Output:
1
2025-04-17 08:56:27,617 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (360.435) is slightly lower, which could be beneficial for permeability, but both are acceptable.

**TPSA:** Ligand A (85.36) is much better than Ligand B (41.93) regarding TPSA. For CNS targets, we want TPSA <= 90, and ideally lower. Ligand A is closer to this ideal.

**logP:** Ligand A (2.534) is within the optimal range (1-3). Ligand B (4.237) is a bit high, potentially leading to solubility issues and off-target interactions.

**H-Bond Donors/Acceptors:** Both ligands have acceptable HBD (1) and HBA (5 & 6) counts.

**QED:** Ligand A (0.8) has a significantly better QED score than Ligand B (0.625), indicating a more drug-like profile.

**DILI:** Ligand A (76.192) has a higher DILI risk than Ligand B (25.165). This is a concern for Ligand A.

**BBB:** Ligand B (79.294) has a considerably better BBB penetration percentile than Ligand A (55.138). This is a critical factor for a CNS target like DRD2, making Ligand B more promising.

**Caco-2 Permeability:** Ligand A (-4.483) shows poor Caco-2 permeability, while Ligand B (-5.282) is also poor, but slightly better.

**Aqueous Solubility:** Ligand A (-4.252) has slightly better aqueous solubility than Ligand B (-3.041), but both are quite poor.

**hERG:** Ligand A (0.101) has a lower hERG risk than Ligand B (0.89), which is favorable.

**Microsomal Clearance:** Ligand B (62.831) has lower microsomal clearance than Ligand A (82.107), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand B (54.501) has a longer in vitro half-life than Ligand A (-32.065), which is desirable.

**P-gp Efflux:** Ligand A (0.049) has significantly lower P-gp efflux liability than Ligand B (0.749), which is crucial for CNS penetration.

**Binding Affinity:** Ligand B (-6.6 kcal/mol) has a better binding affinity than Ligand A (-9.7 kcal/mol). This is a substantial difference, and a strong binding affinity can often outweigh minor ADME concerns.

**Overall Assessment:**

Ligand B is the stronger candidate. While Ligand A has better TPSA, hERG, and P-gp efflux, Ligand B excels in the most critical areas for a CNS GPCR target: BBB penetration and binding affinity. The better metabolic stability (lower Cl_mic, longer t1/2) and lower DILI risk of Ligand B further support its selection. The higher logP of Ligand B is a slight concern, but the substantial affinity advantage likely compensates for it.



Output:
1
2025-04-17 08:56:27,617 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (338.451 Da) is slightly lower, which is generally favorable for permeability.

**TPSA:** Ligand A (61.36) is significantly better than Ligand B (128.68). For CNS targets, TPSA < 90 is preferred, and Ligand A comfortably meets this, while Ligand B is pushing the limit.

**logP:** Ligand A (3.249) is optimal (1-3), while Ligand B (0.394) is quite low, potentially hindering membrane permeability and CNS penetration.

**H-Bond Donors/Acceptors:** Ligand A (HBD=3, HBA=2) and Ligand B (HBD=2, HBA=8) both fall within acceptable ranges, but Ligand B has a higher number of HBA, which can sometimes impact permeability.

**QED:** Both ligands have similar QED values (0.615 and 0.629), indicating good drug-like properties.

**DILI:** Ligand A (35.169) has a much lower DILI risk than Ligand B (75.184), which is a significant advantage.

**BBB:** Ligand A (57.619) has a better BBB percentile than Ligand B (36.138). While neither is >70, Ligand A is closer, and given the CNS target, this is crucial.

**Caco-2 Permeability:** Ligand A (-4.648) has a more negative Caco-2 value, which is not ideal. Ligand B (-5.841) is even worse. Both suggest poor intestinal absorption, but this is less critical for a CNS target where direct delivery is possible.

**Aqueous Solubility:** Ligand A (-3.645) and Ligand B (-1.707) both have negative solubility values, indicating poor aqueous solubility. This could pose formulation challenges.

**hERG Inhibition:** Ligand A (0.843) has a lower hERG risk than Ligand B (0.032), which is a major safety concern.

**Microsomal Clearance:** Ligand A (43.19) has a higher (worse) microsomal clearance than Ligand B (-13.497). This suggests Ligand B is more metabolically stable.

**In vitro Half-Life:** Ligand A (17.723) has a longer half-life than Ligand B (2.578), which is desirable.

**P-gp Efflux:** Ligand A (0.533) has lower P-gp efflux than Ligand B (0.017), meaning it's less likely to be pumped out of the brain, improving CNS exposure.

**Binding Affinity:** Both ligands have similar and good binding affinities (-9.2 kcal/mol and -8.0 kcal/mol). The difference of 1.2 kcal/mol is not substantial enough to override other significant ADME differences.

**Overall Assessment:**

Ligand A is significantly better overall. It has a more favorable TPSA, logP, DILI risk, BBB penetration, hERG inhibition profile, and P-gp efflux. While its Caco-2 permeability and solubility are not ideal, these are less critical for a CNS target. Ligand B suffers from a low logP, high DILI risk, poor BBB penetration, and a very high risk of hERG inhibition. Although it has better metabolic stability, the other liabilities are too significant to ignore.

Output:
1
2025-04-17 08:56:27,618 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (359.5 & 386.5 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Both ligands (82.7 & 86.71) are below the 90 A^2 threshold desirable for CNS targets, which is good.

**3. logP:** Both ligands (2.532 & 1.919) are within the optimal 1-3 range.

**4. H-Bond Donors:** Ligand A has 3 HBD, and Ligand B has 2. Both are acceptable (<=5).

**5. H-Bond Acceptors:** Both ligands have 5 HBA, which is acceptable (<=10).

**6. QED:** Both ligands have similar QED values (0.733 & 0.75), indicating good drug-likeness.

**7. DILI:** Ligand A (64.793) has a lower DILI risk than Ligand B (59.984), suggesting it's slightly safer regarding liver toxicity.

**8. BBB:** Ligand A (68.282) has a significantly better BBB penetration percentile than Ligand B (51.299). This is a *critical* advantage for a CNS target like DRD2.

**9. Caco-2 Permeability:** Both have negative values (-5.859 & -5.303), which is unusual and hard to interpret without knowing the scale. However, it's likely indicating poor permeability.

**10. Aqueous Solubility:** Both have negative values (-2.202 & -3.295), indicating poor solubility.

**11. hERG Inhibition:** Both ligands have low hERG inhibition risk (0.547 & 0.389).

**12. Microsomal Clearance:** Ligand A (0.268) has significantly lower microsomal clearance than Ligand B (41.212), indicating better metabolic stability.

**13. In vitro Half-Life:** Ligand A (16.012) has a longer in vitro half-life than Ligand B (-45.683). The negative value for Ligand B is concerning and likely indicates very rapid degradation.

**14. P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.362 & 0.2).

**15. Binding Affinity:** Ligand B (-7.4 kcal/mol) has a substantially stronger binding affinity than Ligand A (-0.0 kcal/mol). This is a significant advantage.

**Overall Assessment:**

While Ligand B boasts a much stronger binding affinity, Ligand A has a significantly better BBB penetration, lower DILI risk, better metabolic stability (lower Cl_mic and longer t1/2), and a more reasonable half-life. For a CNS target like DRD2, BBB penetration and metabolic stability are paramount. The affinity difference is substantial, but not insurmountable. Optimization of Ligand A could potentially improve its affinity while retaining its favorable ADME properties. Ligand B's very short half-life and poor metabolic stability are major drawbacks that would be difficult to overcome.

Output:
0
2025-04-17 08:56:27,618 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (347.39 and 356.901 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (82.53) is significantly better than Ligand B (47.71). For CNS targets, TPSA should be <= 90, and both meet this, but A is closer to the upper limit.

**logP:** Ligand A (1.837) is optimal (1-3). Ligand B (4.896) is higher, potentially leading to solubility issues and off-target effects.

**H-Bond Donors/Acceptors:** Both ligands have 2 HBD and a reasonable number of HBA (4 for A, 2 for B), satisfying the criteria of <=5 HBD and <=10 HBA.

**QED:** Ligand A (0.871) has a much better QED score than Ligand B (0.603), indicating better overall drug-likeness.

**DILI:** Ligand A (33.346) has a slightly higher DILI risk than Ligand B (28.81), but both are well below the concerning threshold of 60.

**BBB:** Ligand A (70.609) has a good BBB penetration percentile, exceeding the 70% threshold for CNS targets. Ligand B (55.603) is considerably lower, which is a significant drawback for a CNS target like DRD2.

**Caco-2 Permeability:** Ligand A (-4.69) and Ligand B (-5.444) both have negative values, indicating poor permeability. This is a concern, but less critical than BBB for CNS targets.

**Aqueous Solubility:** Both ligands have very poor aqueous solubility (-3.225 and -4.332 respectively). This could pose formulation challenges.

**hERG Inhibition:** Ligand A (0.157) has a lower hERG inhibition liability than Ligand B (0.931), which is preferable.

**Microsomal Clearance:** Ligand A (15.679) has a lower microsomal clearance than Ligand B (47.804), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (-30.095) has a negative half-life, which is unusual and likely an error or indicates very rapid degradation. Ligand B (65.569) has a reasonable half-life.

**P-gp Efflux:** Ligand A (0.021) shows very low P-gp efflux, which is excellent for CNS penetration. Ligand B (0.59) has moderate P-gp efflux.

**Binding Affinity:** Both ligands have similar, strong binding affinities (-9.7 and -8.8 kcal/mol). The difference is less than the 1.5 kcal/mol threshold.

**Overall Assessment:**

Ligand A is significantly better due to its superior BBB penetration, lower logP, better QED, lower hERG risk, lower microsomal clearance, and very low P-gp efflux. While its in vitro half-life is problematic (likely an error), the other advantages outweigh this concern. Ligand B's higher logP and poor BBB penetration are major drawbacks for a CNS-targeted drug.

Output:
0
2025-04-17 08:56:27,618 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (354.495 and 364.563 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (56.33) is excellent, well below the 90 A^2 threshold for CNS targets. Ligand B (79.96) is still acceptable but less optimal.

**logP:** Ligand A (-0.036) is slightly below the optimal 1-3 range, potentially impacting permeability. Ligand B (3.701) is within the optimal range.

**H-Bond Donors/Acceptors:** Ligand A (0 HBD, 5 HBA) is favorable. Ligand B (2 HBD, 7 HBA) is also acceptable, though slightly higher.

**QED:** Both ligands have good QED scores (0.642 and 0.796), indicating good drug-like properties.

**DILI:** Ligand A (5.467) has a very low DILI risk, significantly better than Ligand B (62.66), which is considered a higher risk.

**BBB:** Ligand A (66.925) is reasonably good, but Ligand B (84.141) is excellent, exceeding the >70 percentile desirable for CNS targets. This is a significant advantage for Ligand B.

**Caco-2 Permeability:** Ligand A (-4.594) is poor, suggesting poor intestinal absorption. Ligand B (-5.157) is also poor, but similar to A.

**Aqueous Solubility:** Ligand A (0.469) is poor, while Ligand B (-5.067) is very poor, both are concerning.

**hERG Inhibition:** Ligand A (0.354) has a low hERG risk, which is good. Ligand B (0.633) is slightly higher, but still acceptable.

**Microsomal Clearance:** Ligand A (29.959) has lower clearance, suggesting better metabolic stability than Ligand B (84.923).

**In vitro Half-Life:** Ligand A (-28.486) has a very long half-life, which is highly desirable. Ligand B (26.511) is shorter, but still reasonable.

**P-gp Efflux:** Ligand A (0.003) has very low P-gp efflux, which is excellent for CNS penetration. Ligand B (0.162) is also low, but not as favorable.

**Binding Affinity:** Ligand B (-7.5 kcal/mol) has a significantly stronger binding affinity than Ligand A (-6.9 kcal/mol). This 1.5 kcal/mol difference is substantial and can outweigh some ADME drawbacks.

**Overall Assessment:**

Ligand B excels in BBB penetration and binding affinity, both critical for a CNS-targeting GPCR like DRD2. While its DILI risk is higher and solubility is poor, the strong affinity and excellent BBB are compelling. Ligand A has a better safety profile (DILI, hERG) and metabolic stability, but its lower affinity and poorer BBB penetration are significant drawbacks for a CNS target. The poor Caco-2 and solubility for both are concerning but might be addressed with formulation strategies.

Output:
1
2025-04-17 08:56:27,618 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (361.368 and 347.459 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Both ligands have TPSA values (80.12 and 78.51) below the 90 A^2 threshold for CNS targets, which is excellent.

**3. logP:** Both ligands have logP values (1.077 and 1.235) within the optimal 1-3 range.

**4. H-Bond Donors:** Ligand A (1 HBD) is better than Ligand B (2 HBDs), but both are acceptable.

**5. H-Bond Acceptors:** Ligand A (5 HBA) is better than Ligand B (3 HBA), but both are acceptable.

**6. QED:** Ligand A (0.822) has a higher QED score than Ligand B (0.71), indicating better overall drug-likeness.

**7. DILI:** Ligand A (43.738 percentile) has a significantly lower DILI risk than Ligand B (16.053 percentile). This is a major advantage for Ligand A.

**8. BBB:** Ligand A (74.215 percentile) has a considerably higher BBB penetration prediction than Ligand B (59.597 percentile). This is critical for a CNS target like DRD2.

**9. Caco-2 Permeability:** Ligand A (-4.917) and Ligand B (-5.088) both have negative values, indicating poor permeability. This is a potential concern for both.

**10. Aqueous Solubility:** Ligand A (-2.158) and Ligand B (-1.753) both have negative values, indicating poor solubility. This is a potential concern for both.

**11. hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.148 and 0.13).

**12. Microsomal Clearance:** Ligand B (-9.146) has a lower (better) microsomal clearance than Ligand A (2.753). This suggests better metabolic stability for Ligand B.

**13. In vitro Half-Life:** Ligand B (-6.736) has a longer half-life than Ligand A (-18.473).

**14. P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.026 and 0.021).

**15. Binding Affinity:** Both ligands have the same binding affinity (-8.8 kcal/mol), which is excellent.

**Overall Assessment:**

Ligand A is the better candidate. While Ligand B has slightly better metabolic stability and half-life, Ligand A significantly outperforms it in crucial areas for a CNS-targeting GPCR: DILI risk and BBB penetration. The higher QED score also favors Ligand A. The similar Caco-2 and solubility values are drawbacks for both, but can be addressed with formulation strategies. The equal binding affinity means this doesn't sway the decision.

Output:
1
2025-04-17 08:56:27,618 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (348.531 and 350.423 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (58.2) is excellent, well below the 90 A^2 threshold for CNS targets. Ligand B (131.26) is higher, but still potentially acceptable, though less ideal.

**3. logP:** Ligand A (3.938) is at the upper end of the optimal range (1-3), while Ligand B (1.009) is slightly below, potentially impacting permeability.

**4. H-Bond Donors:** Ligand A (2) and Ligand B (4) are both within the acceptable limit of <=5.

**5. H-Bond Acceptors:** Ligand A (2) and Ligand B (7) are both within the acceptable limit of <=10.

**6. QED:** Both ligands have similar QED values (0.628 and 0.514), indicating reasonable drug-likeness.

**7. DILI:** Ligand A (20.24) has a significantly lower DILI risk than Ligand B (41.411), which is a substantial advantage.

**8. BBB:** Both ligands have good BBB penetration (75.378 and 77.162), exceeding the 70% threshold for CNS targets.

**9. Caco-2 Permeability:** Ligand A (-4.77) and Ligand B (-5.532) both have negative values, indicating poor permeability. This is a concern for both.

**10. Aqueous Solubility:** Ligand A (-4.747) and Ligand B (-2.5) both have negative solubility values, which is a concern.

**11. hERG Inhibition:** Ligand A (0.577) has a slightly higher hERG risk than Ligand B (0.321), but both are relatively low.

**12. Microsomal Clearance:** Ligand A (81.484) has a higher microsomal clearance than Ligand B (37.849), suggesting lower metabolic stability.

**13. In vitro Half-Life:** Ligand A (0.679) has a shorter half-life than Ligand B (0.778).

**14. P-gp Efflux:** Ligand A (0.542) has lower P-gp efflux liability than Ligand B (0.015), which is favorable for CNS penetration.

**15. Binding Affinity:** Both ligands have very similar and strong binding affinities (-8.2 and -8.1 kcal/mol). The difference is negligible.

**Overall Assessment:**

Considering the GPCR-specific priorities, Ligand A is more promising. While both have similar affinity and BBB penetration, Ligand A has a significantly lower DILI risk, lower P-gp efflux (better CNS exposure), and a more favorable logP. Although Ligand A has higher microsomal clearance, the lower DILI and P-gp efflux are more critical for a CNS-targeting drug. The Caco-2 and Solubility values are concerning for both, but can be addressed through formulation strategies.

Output:
1
2025-04-17 08:56:27,618 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (345.355 Da and 347.459 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (108.66) is higher than Ligand B (75.44). For CNS targets, TPSA should be <=90, so both are acceptable, but Ligand B is significantly better.

**logP:** Ligand A (0.643) is lower than the optimal 1-3 range, potentially hindering permeability. Ligand B (2.858) is within the optimal range. This is a significant advantage for Ligand B.

**H-Bond Donors/Acceptors:** Ligand A has 2 HBD and 6 HBA, while Ligand B has 1 HBD and 4 HBA. Both are within acceptable limits.

**QED:** Both ligands have high QED scores (0.845 and 0.858), indicating good drug-like properties.

**DILI:** Ligand A (67.817) has a higher DILI risk than Ligand B (41.373). Lower is better, so Ligand B is preferable.

**BBB:** This is crucial for a CNS target. Ligand A has a BBB percentile of 20.512, which is quite low. Ligand B has a much higher BBB percentile of 84.606, making it far more likely to reach the brain.

**Caco-2 Permeability:** Ligand A (-4.803) has poor Caco-2 permeability, while Ligand B (-5.013) is also poor, but slightly better.

**Aqueous Solubility:** Both ligands have very poor aqueous solubility (-2.465 and -2.58). This could pose formulation challenges, but is less critical than BBB for CNS targets.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.272 and 0.357).

**Microsomal Clearance:** Ligand A (-12.853) has lower (better) microsomal clearance than Ligand B (47.424), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (-0.863) has a very short half-life, while Ligand B (-19.822) is also short, but less so.

**P-gp Efflux:** Ligand A (0.01) has very low P-gp efflux, which is good. Ligand B (0.282) has slightly higher efflux, but still relatively low.

**Binding Affinity:** Ligand B (-9.4 kcal/mol) has a slightly better binding affinity than Ligand A (-8.8 kcal/mol). While both are good, the difference is not huge, but it is a benefit to Ligand B.

**Overall Assessment:**

Ligand B is significantly better due to its superior BBB penetration, optimal logP, lower DILI risk, and slightly better binding affinity. While Ligand A has better metabolic stability (lower Cl_mic) and lower P-gp efflux, these are less critical than CNS penetration for a DRD2 target. The poor solubility of both is a concern, but can be addressed with formulation strategies.

Output:
1
2025-04-17 08:56:27,619 - INFO - Batch 491 complete. Total preferences: 7856
2025-04-17 08:56:27,619 - INFO - Processing batch 492/512...
2025-04-17 08:57:12,726 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the acceptable range (200-500 Da). Ligand A (335.407 Da) is slightly better, being closer to the ideal range.

**TPSA:** Ligand A (61.44) is significantly better than Ligand B (81.08). For CNS targets, TPSA < 90 is preferred, and A is comfortably within this range, while B is approaching the upper limit.

**logP:** Both ligands have acceptable logP values (A: 2.242, B: 0.712), falling within the 1-3 range. Ligand A is slightly better.

**H-Bond Donors/Acceptors:** Both have 2 HBDs, which is good. Ligand A has 3 HBAs, while Ligand B has 5. Both are acceptable (<=10), but A is slightly preferred.

**QED:** Both ligands have reasonable QED values (A: 0.904, B: 0.72), indicating good drug-like properties. A is better.

**DILI:** Ligand A (65.917) has a higher DILI risk than Ligand B (14.424). This is a significant negative for A.

**BBB:** Ligand A (74.292) has a much better BBB penetration percentile than Ligand B (43.117). This is *crucial* for a CNS target like DRD2.

**Caco-2 Permeability:** Ligand A (-4.92) is better than Ligand B (-5.085), indicating slightly better intestinal absorption.

**Aqueous Solubility:** Ligand A (-4.55) is better than Ligand B (-1.725), suggesting better solubility.

**hERG Inhibition:** Ligand A (0.755) has a slightly higher hERG risk than Ligand B (0.299). B is much better here.

**Microsomal Clearance:** Ligand A (30.593) and Ligand B (33.75) are comparable. Lower is better, but the difference isn't substantial.

**In vitro Half-Life:** Ligand A (67.889) has a significantly longer half-life than Ligand B (-4.576). This is a positive for A.

**P-gp Efflux:** Ligand A (0.463) has a much lower P-gp efflux liability than Ligand B (0.022). This is very important for CNS penetration.

**Binding Affinity:** Ligand B (-7.3) has a significantly stronger binding affinity than Ligand A (-10.6). This is a substantial advantage for B, potentially outweighing some ADME drawbacks.

**Overall Assessment:**

Ligand B has a substantially better binding affinity, which is paramount. However, it suffers from poor BBB penetration, higher P-gp efflux, and a higher hERG risk. Ligand A has a better BBB, lower P-gp efflux, better solubility, and longer half-life, but its affinity is significantly weaker and has a higher DILI risk.

Considering the GPCR-specific priorities for a CNS target, the strong binding affinity of Ligand B is a major advantage. While its ADME properties are less favorable, the potency difference is large enough to potentially overcome these issues with further optimization. The improved BBB and P-gp of A are beneficial, but not enough to compensate for the large affinity gap.

Output:
1
2025-04-17 08:57:12,726 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (338.407 and 344.415 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (82.35) is better than Ligand B (84.42), both are below the 90 A^2 threshold for CNS targets.

**logP:** Ligand A (3.969) is optimal, while Ligand B (1.212) is a bit low, potentially hindering permeability.

**H-Bond Donors:** Ligand A (2) and Ligand B (1) are both within the acceptable limit of <=5.

**H-Bond Acceptors:** Ligand A (4) and Ligand B (5) are both within the acceptable limit of <=10.

**QED:** Both ligands have good QED scores (0.781 and 0.887), indicating drug-like properties.

**DILI:** Ligand A (50.33) has a lower DILI risk than Ligand B (60.682), which is preferable.

**BBB:** Ligand B (60.954) has a significantly better BBB penetration percentile than Ligand A (32.416). This is a crucial factor for a CNS target like DRD2.

**Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and suggests poor permeability. However, the scale is not specified, so it's difficult to interpret.

**Aqueous Solubility:** Both have negative solubility values, which is also unusual.

**hERG:** Both ligands have very low hERG inhibition liability (0.678 and 0.091), which is excellent.

**Microsomal Clearance:** Ligand A (89.114) has a higher microsomal clearance than Ligand B (16.469), suggesting lower metabolic stability.

**In vitro Half-Life:** Ligand B (11.073) has a significantly longer in vitro half-life than Ligand A (0.055), which is a major advantage.

**P-gp Efflux:** Ligand A (0.141) has a lower P-gp efflux liability than Ligand B (0.007), which is preferable for CNS exposure.

**Binding Affinity:** Ligand B (-8.5 kcal/mol) has a stronger binding affinity than Ligand A (-7.7 kcal/mol). The difference of 0.8 kcal/mol is substantial and can outweigh some ADME drawbacks.

**Overall Assessment:**

Ligand B is the better candidate. While Ligand A has better logP and P-gp efflux, Ligand B's superior BBB penetration, significantly longer half-life, and substantially stronger binding affinity are critical advantages for a CNS-targeting GPCR like DRD2. The slightly higher DILI risk for Ligand B is a concern, but potentially manageable. The poor Caco-2 and solubility values are concerning for both, and would require further investigation.

Output:
1
2025-04-17 08:57:12,726 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (346.431 Da) is slightly lower, which could be advantageous for permeability.

**TPSA:** Ligand A (85.25) is better than Ligand B (105.25). Both are below the 140 threshold for oral absorption, and Ligand A is closer to the desirable <90 for CNS targets.

**logP:** Ligand A (1.429) is within the optimal range (1-3), while Ligand B (-1.208) is below 1. This is a significant drawback for Ligand B, potentially hindering membrane permeability and brain penetration.

**H-Bond Donors/Acceptors:** Ligand A (2 HBD, 5 HBA) and Ligand B (1 HBD, 7 HBA) both fall within acceptable ranges.

**QED:** Both ligands have similar QED values (0.628 and 0.594), indicating reasonable drug-likeness.

**DILI:** Both ligands have low DILI risk (48.313 and 43.622), which is positive.

**BBB:** Ligand A (59.636) has a slightly better BBB percentile than Ligand B (56.301), but both are below the desirable >70 for CNS targets. This is a concern for both, but less so for A.

**Caco-2 Permeability:** Ligand A (-5.182) has a worse Caco-2 permeability than Ligand B (-5.299). Both are negative, indicating poor permeability.

**Aqueous Solubility:** Ligand A (-2.085) has worse solubility than Ligand B (-0.936). Both are negative, indicating poor solubility.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.366 and 0.133).

**Microsomal Clearance:** Ligand A (40.6) has a higher clearance than Ligand B (-2.593). This suggests Ligand B is more metabolically stable, which is a positive.

**In vitro Half-Life:** Ligand A (-1.774) has a shorter half-life than Ligand B (0.506). This is a negative for Ligand A.

**P-gp Efflux:** Ligand A (0.088) has lower P-gp efflux than Ligand B (0.008), which is beneficial for CNS penetration.

**Binding Affinity:** Ligand B (-7.3 kcal/mol) has a significantly stronger binding affinity than Ligand A (-8.0 kcal/mol). This is a substantial advantage for Ligand B.

**Overall Assessment:**

While Ligand A has slightly better TPSA and P-gp efflux, Ligand B's superior binding affinity (-7.3 vs -8.0 kcal/mol) and metabolic stability (lower Cl_mic, longer t1/2) are more critical for a GPCR target like DRD2. The lower logP of Ligand B is a concern, but the strong binding affinity could potentially compensate for this. The BBB values for both are suboptimal, but the stronger affinity of Ligand B suggests it might still achieve sufficient brain exposure.

Output:
1
2025-04-17 08:57:12,727 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (337.383 and 347.415 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (71.76) is significantly better than Ligand B (100.45). For CNS targets, TPSA should be <= 90, so Ligand A is preferable.

**3. logP:** Ligand A (1.525) is within the optimal range (1-3). Ligand B (0.639) is slightly low, potentially hindering permeation.

**4. H-Bond Donors:** Ligand A (1) and Ligand B (2) are both acceptable (<=5).

**5. H-Bond Acceptors:** Ligand A (6) and Ligand B (5) are both acceptable (<=10).

**6. QED:** Both ligands have similar, good QED values (0.785 and 0.777, both >= 0.5).

**7. DILI:** Ligand A (69.794) has a higher DILI risk than Ligand B (49.283), but both are still acceptable (<60 is good).

**8. BBB:** Ligand A (62.737) has a lower BBB penetration percentile than Ligand B (56.534). While neither are *great*, Ligand B is better.

**9. Caco-2 Permeability:** Ligand A (-4.653) has a more negative Caco-2 value than Ligand B (-5.22), indicating slightly better intestinal absorption.

**10. Aqueous Solubility:** Ligand A (-2.143) has slightly better solubility than Ligand B (-2.85).

**11. hERG Inhibition:** Ligand A (0.719) has a slightly higher hERG inhibition risk than Ligand B (0.295). Lower is better here, so Ligand B is preferable.

**12. Microsomal Clearance:** Ligand A (33.999) has higher microsomal clearance than Ligand B (6.772), indicating lower metabolic stability. Ligand B is preferable.

**13. In vitro Half-Life:** Ligand A (-3.836) has a more negative in vitro half-life than Ligand B (25.207), suggesting a shorter half-life and faster metabolism. Ligand B is preferable.

**14. P-gp Efflux:** Ligand A (0.062) has a lower P-gp efflux liability than Ligand B (0.036). Lower is better, so Ligand A is preferable.

**15. Binding Affinity:** Both ligands have excellent binding affinities (-7.7 and -7.8 kcal/mol). The difference is negligible.

**Overall Assessment:**

Considering the GPCR-specific priorities, Ligand B is the better candidate. While Ligand A has a better TPSA and P-gp efflux, Ligand B excels in BBB penetration, metabolic stability (lower Cl_mic and longer t1/2), and hERG inhibition. The slightly lower logP of Ligand B is a minor drawback compared to the significant advantages in ADME properties crucial for CNS drug development.

Output:
1
2025-04-17 08:57:12,727 - INFO - Reasoning:

Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (344.371 and 347.463 Da) fall comfortably within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (113.44) is better than Ligand B (79.26) as it is closer to the optimal range for CNS targets (<=90). Ligand B is excellent.

**3. logP:** Ligand A (1.644) is within the optimal 1-3 range. Ligand B (0.407) is slightly low, potentially hindering membrane permeability.

**4. H-Bond Donors:** Ligand A (3) and Ligand B (2) both meet the <=5 criteria.

**5. H-Bond Acceptors:** Ligand A (6) and Ligand B (5) both meet the <=10 criteria.

**6. QED:** Both ligands have good QED scores (0.687 and 0.749), indicating good drug-like properties.

**7. DILI:** Ligand A (61.962) has a higher DILI risk than Ligand B (10.896). This is a significant drawback for Ligand A.

**8. BBB:** Both ligands have reasonable BBB penetration (Ligand A: 53.083, Ligand B: 50.523). However, neither exceeds the desirable >70 percentile for CNS targets.

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 values, which is unusual and suggests poor permeability.

**10. Aqueous Solubility:** Both ligands have negative solubility values, which is also unusual and suggests poor solubility.

**11. hERG Inhibition:** Both ligands show very low hERG inhibition risk (0.186 and 0.163).

**12. Microsomal Clearance:** Ligand B (-18.317) has significantly lower (better) microsomal clearance than Ligand A (74.324), suggesting better metabolic stability.

**13. In vitro Half-Life:** Ligand B (11.843) has a longer half-life than Ligand A (-23.464), which is favorable.

**14. P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.069 and 0.005), which is excellent for CNS penetration.

**15. Binding Affinity:** Ligand A (-9.1 kcal/mol) has a significantly stronger binding affinity than Ligand B (-7.9 kcal/mol). This is a substantial advantage.

**Overall Assessment:**

While Ligand A boasts a superior binding affinity, its significantly higher DILI risk and poorer metabolic stability (higher Cl_mic) are major concerns. Ligand B, despite a slightly lower affinity, presents a much more favorable ADMET profile, with a substantially lower DILI risk, better metabolic stability, and a longer half-life. The negative Caco-2 and solubility values are concerning for both, but the ADMET profile of Ligand B is more promising overall. Given the GPCR-specific emphasis on BBB, logP, Pgp, TPSA, and affinity, and considering the importance of minimizing toxicity (DILI), Ligand B is the more viable candidate.

Output:
1
2025-04-17 08:57:12,727 - INFO - Reasoning:

Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (409.917 Da) is slightly higher than Ligand B (359.411 Da), but both are acceptable.

**2. TPSA:**  Ligand A (126.64) is pushing the upper limit for CNS targets (<=90), while Ligand B (110.32) is better positioned.

**3. logP:** Ligand A (0.288) is quite low, potentially hindering membrane permeability. Ligand B (0.831) is better, but still on the lower side of the optimal 1-3 range.

**4. H-Bond Donors:** Both ligands have 2 HBD, which is within the acceptable limit of <=5.

**5. H-Bond Acceptors:** Ligand A has 5 HBA, and Ligand B has 6. Both are within the acceptable limit of <=10.

**6. QED:** Both ligands have good QED scores (A: 0.669, B: 0.84), indicating good drug-like properties.

**7. DILI:** Ligand A (65.491) has a higher DILI risk than Ligand B (83.986). Both are reasonably acceptable, but lower is always preferred.

**8. BBB:** This is a critical parameter for CNS targets. Ligand A (38.813) has a poor BBB percentile, while Ligand B (57.697) is better, but still not ideal (aim for >70).

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 values, which is unusual and problematic. It suggests poor intestinal absorption.

**10. Aqueous Solubility:** Both ligands have negative solubility values, which is also unusual and problematic.

**11. hERG Inhibition:** Ligand A (0.074) shows very low hERG inhibition risk, while Ligand B (0.274) is slightly higher. Both are acceptable.

**12. Microsomal Clearance:** Ligand A (-8.661) has a much lower (better) microsomal clearance than Ligand B (-5.646), indicating greater metabolic stability.

**13. In vitro Half-Life:** Ligand A (13.462) has a longer half-life than Ligand B (0.083).

**14. P-gp Efflux:** Ligand A (0.061) has lower P-gp efflux liability than Ligand B (0.04), which is favorable for CNS penetration.

**15. Binding Affinity:** Ligand B (-7.6 kcal/mol) has a significantly stronger binding affinity than Ligand A (-8.2 kcal/mol). A difference of 0.6 kcal/mol is substantial and can often outweigh minor ADME drawbacks.

**Overall Assessment:**

Despite the unusual negative values for Caco-2 and solubility, the binding affinity of Ligand B is significantly better. The slightly improved BBB penetration compared to Ligand A, combined with the stronger binding, makes Ligand B the more promising candidate. While Ligand A has better metabolic stability and lower P-gp efflux, the affinity difference is crucial for a GPCR target. The lower logP of Ligand A is a significant concern for CNS penetration.

Output:
1
2025-04-17 08:57:12,727 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight (MW):** Both ligands (364.837 and 367.555 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (87.38) is better than Ligand B (55.4). Both are below 90, which is favorable for CNS penetration.

**3. logP:** Ligand B (3.617) is closer to the optimal range (1-3) than Ligand A (0.518), which is quite low and could hinder membrane permeability.

**4. H-Bond Donors (HBD):** Both ligands have 1 HBD, which is acceptable.

**5. H-Bond Acceptors (HBA):** Ligand A has 7 HBA, while Ligand B has 3. Both are within the acceptable limit of 10.

**6. QED:** Both ligands have reasonable QED scores (0.832 and 0.755), indicating good drug-like properties.

**7. DILI:** Ligand B (35.789) has a significantly lower DILI risk than Ligand A (46.413), making it safer.

**8. BBB:** Ligand B (57.774) has a better BBB percentile than Ligand A (48.74), although both are below the desirable >70 for CNS targets.

**9. Caco-2 Permeability:** Both have negative values (-4.914 and -4.977), which is unusual and suggests poor permeability. This is a significant concern for both.

**10. Aqueous Solubility:** Both have negative values (-1.523 and -5.392), indicating very poor aqueous solubility. This is a major drawback for both compounds.

**11. hERG Inhibition:** Ligand A (0.076) has a slightly lower hERG risk than Ligand B (0.617), which is preferable.

**12. Microsomal Clearance (Cl_mic):** Ligand A (-12.658) has a much lower (better) Cl_mic than Ligand B (53.538), suggesting better metabolic stability.

**13. In vitro Half-Life:** Ligand B (-31.774) has a more negative value, which is unusual and indicates a very short half-life. Ligand A (-13.578) is better, but still not ideal.

**14. P-gp Efflux:** Ligand A (0.078) has a much lower P-gp efflux liability than Ligand B (0.45), which is crucial for CNS penetration.

**15. Binding Affinity:** Ligand A (-8.5 kcal/mol) has significantly better binding affinity than Ligand B (-0.0 kcal/mol). This is a substantial advantage.

**Overall Assessment:**

While both compounds have significant drawbacks (poor solubility and Caco-2 permeability), Ligand A is the more promising candidate. Its substantially stronger binding affinity (-8.5 vs -0.0 kcal/mol) outweighs the slightly higher DILI risk and lower BBB. The lower P-gp efflux is also a major advantage for CNS targeting. The better metabolic stability (lower Cl_mic) is also a positive. Ligand B's very short half-life is a major concern.

Output:
0
2025-04-17 08:57:12,728 - INFO - Reasoning:

Let's analyze Ligand A and Ligand B for their potential as DRD2 drug candidates, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight (MW):** Both ligands (346.431 and 352.475 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Both ligands (83.56 and 81.08) are below the 90 A^2 threshold desirable for CNS targets, which is excellent.

**3. logP:** Ligand A (0.743) is slightly lower than optimal (1-3), potentially hindering permeability. Ligand B (1.314) is within the optimal range.

**4. H-Bond Donors (HBD):** Both ligands have 2 HBD, which is within the acceptable limit of <=5.

**5. H-Bond Acceptors (HBA):** Ligand A has 5 HBA, and Ligand B has 4 HBA, both are within the acceptable limit of <=10.

**6. QED:** Both ligands have good QED scores (0.611 and 0.731), indicating good drug-like properties.

**7. DILI:** Ligand A (27.065) has a slightly higher DILI risk than Ligand B (19.465), but both are below the concerning threshold of 60.

**8. BBB:** Both ligands have acceptable BBB penetration (47.926% and 50.679%), but are below the >70% desired for CNS targets. This is a point where we need to consider other factors.

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.902 and -4.635), which is unusual and suggests poor permeability. This is a significant drawback.

**10. Aqueous Solubility:** Both ligands have negative solubility values (-1.355 and -1.746), indicating very poor aqueous solubility. This is a major issue for formulation and bioavailability.

**11. hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.195 and 0.307).

**12. Microsomal Clearance (Cl_mic):** Ligand A (1.433 mL/min/kg) has much lower clearance than Ligand B (8.537 mL/min/kg), suggesting better metabolic stability.

**13. In vitro Half-Life:** Ligand A (24.782 hours) has a significantly longer half-life than Ligand B (9.079 hours).

**14. P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.009 and 0.195), which is favorable for CNS exposure.

**15. Binding Affinity:** Ligand A (-7.1 kcal/mol) has a slightly better binding affinity than Ligand B (-7.0 kcal/mol), although the difference is small.

**Overall Assessment:**

Both ligands have significant drawbacks (poor Caco-2 and solubility). However, Ligand A has a clear advantage in metabolic stability (lower Cl_mic, longer half-life) and a slightly better binding affinity. While both have suboptimal BBB penetration, the better ADME profile of Ligand A, particularly its metabolic stability, makes it the more promising candidate *despite* the similar affinities and shared solubility/permeability issues. The improved half-life could partially compensate for the permeability issues.

Output:
0
2025-04-17 08:57:12,728 - INFO - Okay, let's analyze these two ligands for their potential as DRD2 drug candidates. DRD2 is a GPCR in the CNS, so BBB penetration, logP, Pgp efflux, TPSA, and binding affinity are paramount.

**Ligand A:** [345.399, 76.83, 2.64, 1, 6, 0.898, 59.519, 88.29, -4.628, -3.875, 0.66, 83.5, 16.395, 0.371, 0]
**Ligand B:** [346.427, 82.78, 1.585, 2, 4, 0.7, 19.504, 46.762, -4.484, -2.463, 0.237, 37.918, -4.95, 0.096, -7.3]

**Step-by-step comparison:**

1. **MW:** Both ligands (345.4 and 346.4 Da) are within the ideal 200-500 Da range.
2. **TPSA:** Ligand A (76.83) is better than Ligand B (82.78). Both are below 140, but for a CNS target, we want <90. Ligand A is closer.
3. **logP:** Ligand A (2.64) is optimal, while Ligand B (1.585) is on the lower side. Lower logP can hinder membrane permeability.
4. **HBD:** Ligand A (1) is better than Ligand B (2). Lower is generally preferred.
5. **HBA:** Ligand A (6) is better than Ligand B (4). Lower is generally preferred.
6. **QED:** Ligand A (0.898) is significantly better than Ligand B (0.7). Higher QED indicates better drug-like properties.
7. **DILI:** Ligand A (59.5%) is higher than Ligand B (19.5%). Ligand B has a much lower DILI risk.
8. **BBB:** Ligand A (88.29%) is excellent, exceeding the 70% threshold. Ligand B (46.762%) is considerably lower and less desirable for a CNS target.
9. **Caco-2:** Both are negative, indicating poor permeability. This is a concern for both.
10. **Solubility:** Both are negative, indicating poor solubility. This is a concern for both.
11. **hERG:** Ligand A (0.66) is higher than Ligand B (0.237), indicating a higher risk of hERG inhibition.
12. **Cl_mic:** Ligand B (37.9) has significantly lower microsomal clearance than Ligand A (83.5), suggesting better metabolic stability.
13. **t1/2:** Ligand B (-4.95) has a longer in vitro half-life than Ligand A (16.4). This is a significant advantage.
14. **Pgp:** Ligand A (0.371) is higher than Ligand B (0.096), suggesting higher P-gp efflux. Lower Pgp is preferred for CNS penetration.
15. **Binding Affinity:** Ligand B (-7.3 kcal/mol) has a *much* stronger binding affinity than Ligand A (0 kcal/mol). This is a substantial advantage, potentially outweighing some ADME concerns.

**Overall Assessment:**

Ligand B has a significantly better binding affinity, lower DILI risk, better metabolic stability (lower Cl_mic, longer t1/2), and lower P-gp efflux. While its BBB penetration is lower than Ligand A, the substantial improvement in binding affinity and metabolic properties, combined with the lower DILI and Pgp, make it a more promising candidate. The lower logP and TPSA are concerns, but the strong binding could compensate. Ligand A's primary advantage is its excellent BBB penetration, but this is overshadowed by its weaker binding, higher DILI risk, and higher Pgp efflux.

Output:
1
2025-04-17 08:57:12,728 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (341.459 and 352.479 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (76.18) is significantly better than Ligand B (87.46). For CNS targets, we want TPSA <= 90, and A is closer to the optimal <= 60 range. B is pushing the upper limit.

**logP:** Both ligands have good logP values (2.223 and 1.031), falling within the 1-3 range. Ligand A is slightly more favorable.

**H-Bond Donors/Acceptors:** Both ligands have 2 HBD and 5 HBA, which are within acceptable limits.

**QED:** Ligand A (0.894) has a higher QED than Ligand B (0.767), indicating a more drug-like profile.

**DILI:** Ligand A (52.734) has a higher DILI risk than Ligand B (21.908). B is significantly better here.

**BBB:** Ligand A (61.535) has a better BBB percentile than Ligand B (30.167). This is *critical* for a CNS target like DRD2. A is still not ideal (>70 desirable), but significantly better than B.

**Caco-2 Permeability:** Both are negative, indicating poor permeability. This is a concern for both, but the scale is not provided, so it's hard to compare.

**Aqueous Solubility:** Both are negative, indicating poor solubility. Again, the scale is not provided.

**hERG:** Ligand A (0.806) has a slightly higher hERG risk than Ligand B (0.155). B is much better here.

**Microsomal Clearance:** Ligand A (-24.288) has *much* lower (better) microsomal clearance than Ligand B (31.822). This suggests better metabolic stability for A.

**In vitro Half-Life:** Ligand A (22.506) has a longer half-life than Ligand B (12.875).

**P-gp Efflux:** Ligand A (0.099) has lower P-gp efflux than Ligand B (0.043), which is favorable for CNS penetration.

**Binding Affinity:** Ligand A (-9.1 kcal/mol) has a significantly stronger binding affinity than Ligand B (-7.9 kcal/mol). This is a substantial advantage, potentially outweighing some of the ADME drawbacks. The difference is >1.5 kcal/mol.

**Overall Assessment:**

Ligand A excels in binding affinity, BBB penetration, metabolic stability (low Cl_mic, long t1/2), and P-gp efflux. While its DILI and hERG are slightly higher, the strong binding affinity and better CNS penetration properties are crucial for a DRD2 ligand. Ligand B has better DILI and hERG, but suffers from significantly worse BBB penetration and weaker binding affinity. Given the GPCR-specific priorities, the stronger affinity and improved BBB of Ligand A are more important.

Output:
1
2025-04-17 08:57:12,728 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (371.459 and 346.475 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (102.67) is higher than Ligand B (67.23). For CNS targets, TPSA should be <=90. Ligand B is better here.

**logP:** Ligand A (-0.354) is quite low, potentially hindering membrane permeability. Ligand B (2.373) is within the optimal 1-3 range. Ligand B is significantly better.

**H-Bond Donors/Acceptors:** Ligand A (2 HBD, 7 HBA) is slightly higher in both counts than Ligand B (1 HBD, 4 HBA), but both are within acceptable limits.

**QED:** Both ligands have good QED scores (0.661 and 0.771, respectively), indicating good drug-like properties.

**DILI:** Both ligands have similar DILI risk (21.791 and 21.946), and are both low risk (<40).

**BBB:** This is critical for a CNS target. Ligand B (74.874) is much better than Ligand A (17.1). Ligand B is desirable (>70), while Ligand A is quite low.

**Caco-2 Permeability:** Both are negative, indicating poor permeability. This is concerning, but less so for a CNS target where BBB penetration is paramount.

**Aqueous Solubility:** Both are negative, indicating poor solubility.

**hERG Inhibition:** Both ligands show very low hERG inhibition liability (0.044 and 0.284), which is excellent.

**Microsomal Clearance:** Ligand B (34.988) has a higher clearance than Ligand A (17.842), indicating potentially lower metabolic stability.

**In vitro Half-Life:** Both have negative half-lives, which is not ideal.

**P-gp Efflux:** Both have very low P-gp efflux liability (0.007 and 0.111), which is good.

**Binding Affinity:** Ligand B (-7.9 kcal/mol) has a significantly stronger binding affinity than Ligand A (-6.7 kcal/mol). This >1.5 kcal/mol difference is substantial and can outweigh some ADME drawbacks.

**Overall Assessment:**

Ligand B is the superior candidate. While both have issues with Caco-2 permeability and aqueous solubility, Ligand B excels in the most critical areas for a CNS-targeting GPCR: logP, BBB penetration, and binding affinity. The stronger binding affinity of Ligand B is a major advantage. The slightly higher microsomal clearance is a minor concern compared to the benefits of better brain penetration and potency. Ligand A's low logP and poor BBB penetration are significant liabilities.

Output:
1
2025-04-17 08:57:12,729 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (349.519 and 342.395 Da) fall comfortably within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (52.65) is significantly better than Ligand B (73.44). For CNS targets, we want TPSA <= 90, and ideally closer to 60. Ligand A is much closer to the ideal range.

**3. logP:** Both ligands have acceptable logP values (2.118 and 3.931), falling within the 1-3 range. Ligand B is slightly higher, potentially increasing off-target interactions, but still within acceptable limits.

**4. H-Bond Donors:** Both have 1 HBD, which is good.

**5. H-Bond Acceptors:** Ligand A has 3 HBAs, and Ligand B has 5. Both are within the acceptable limit of <= 10.

**6. QED:** Both ligands have similar, good QED values (0.846 and 0.852), indicating good drug-like properties.

**7. DILI:** Ligand A (9.616) has a much lower DILI risk than Ligand B (68.399). This is a significant advantage for Ligand A.

**8. BBB:** Ligand A (83.56) has a better BBB penetration percentile than Ligand B (74.952). Both are reasonably good, but Ligand A is closer to the desirable >70 threshold for CNS targets.

**9. Caco-2 Permeability:** Both have negative Caco-2 values (-4.801 and -4.606). This is unusual and suggests poor permeability, but the scale isn't defined. We'll consider this a neutral point.

**10. Aqueous Solubility:** Both have negative solubility values (-2.17 and -5.751). Again, the scale is undefined, but suggests poor solubility. We'll consider this a neutral point.

**11. hERG Inhibition:** Both ligands have low hERG inhibition risk (0.516 and 0.548).

**12. Microsomal Clearance:** Ligand A (32.588) has significantly lower microsomal clearance than Ligand B (83.719), indicating better metabolic stability.

**13. In vitro Half-Life:** Ligand A (-10.661) has a significantly longer in vitro half-life than Ligand B (5.273).

**14. P-gp Efflux:** Both ligands have low P-gp efflux liability (0.057 and 0.553).

**15. Binding Affinity:** Ligand B (-9.2 kcal/mol) has a stronger binding affinity than Ligand A (-7.8 kcal/mol). This is a 1.4 kcal/mol difference, which is substantial.

**Overall Assessment:**

Ligand B has a better binding affinity, which is a key factor. However, Ligand A demonstrates significantly better ADME properties, particularly regarding DILI risk, BBB penetration, metabolic stability (lower Cl_mic and longer t1/2), and TPSA. Given the GPCR-specific emphasis on BBB and the importance of avoiding toxicity (DILI), the superior ADME profile of Ligand A outweighs the slightly weaker binding affinity. The difference in affinity, while notable, isn't so large that it completely negates the benefits of Ligand A's improved pharmacokinetic properties and safety profile.

Output:
0
2025-04-17 08:57:12,729 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (347.5 and 348.5 Da) fall comfortably within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (43.86) is significantly better than Ligand B (49.85). For CNS targets, we want TPSA <= 90, and ideally closer to 60. Ligand A is closer to this ideal.

**3. logP:** Both ligands have acceptable logP values (1.83 and 2.32), falling within the 1-3 range. Ligand B is slightly higher, which could potentially lead to off-target effects, but is still within acceptable limits.

**4. H-Bond Donors:** Both have 0 HBD, which is good.

**5. H-Bond Acceptors:** Both have 3 HBA, which is also good.

**6. QED:** Ligand A (0.689) has a better QED score than Ligand B (0.475). A higher QED suggests better drug-like properties.

**7. DILI:** Ligand A (5.78) has a much lower DILI risk than Ligand B (15.2). This is a significant advantage for Ligand A.

**8. BBB:** Both ligands have similar and good BBB penetration (68.94% and 68.67%). Both are reasonably good, but slightly below the ideal >70% for CNS targets.

**9. Caco-2 Permeability:** Ligand A (-4.562) is better than Ligand B (-4.096), indicating better intestinal absorption.

**10. Aqueous Solubility:** Ligand A (-0.943) is better than Ligand B (-2.006), indicating better aqueous solubility.

**11. hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.559 and 0.306).

**12. Microsomal Clearance:** Ligand A (-4.132) has significantly lower (better) microsomal clearance than Ligand B (43.616). This suggests greater metabolic stability for Ligand A.

**13. In vitro Half-Life:** Ligand A (-5.79) has a better in vitro half-life than Ligand B (11.719).

**14. P-gp Efflux:** Ligand A (0.043) has significantly lower P-gp efflux than Ligand B (0.086). Lower P-gp efflux is crucial for CNS penetration.

**15. Binding Affinity:** Both ligands have very similar and good binding affinities (-7.6 and -7.0 kcal/mol). The difference of 0.6 kcal/mol is not substantial enough to override other significant differences.

**Overall Assessment:**

Ligand A consistently outperforms Ligand B across several critical ADME properties (DILI, Cl_mic, t1/2, P-gp efflux, solubility, Caco-2 permeability) and has a better QED score. While both have acceptable logP and BBB values, Ligand A's superior ADME profile, particularly its lower DILI risk and better metabolic stability, makes it the more promising drug candidate. The slight advantage in TPSA is also beneficial for CNS penetration.

Output:
0
2025-04-17 08:57:12,729 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B based on the provided guidelines, prioritizing GPCR-specific properties (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (385.266 and 361.511 Da) fall within the ideal range of 200-500 Da.

**TPSA:** Ligand A (49.41) is better than Ligand B (51.39), both are reasonably good for CNS penetration being below 90.

**logP:** Both ligands have logP values (3.298 and 4.099) within the optimal range of 1-3, though Ligand B is slightly higher.

**H-Bond Donors/Acceptors:** Ligand A (HBD=1, HBA=2) is slightly better than Ligand B (HBD=0, HBA=6) in terms of balancing solubility and permeability.

**QED:** Both ligands have good QED scores (0.639 and 0.743), indicating drug-likeness.

**DILI:** Ligand A (57.697) has a higher DILI risk than Ligand B (27.918). This is a significant drawback for Ligand A.

**BBB:** Ligand A (86.623) has a significantly better BBB penetration percentile than Ligand B (73.362). This is a crucial advantage for a CNS target like DRD2.

**Caco-2 Permeability:** Ligand A (-4.953) has worse Caco-2 permeability than Ligand B (-5.294). Both are negative, which is not ideal, but B is slightly better.

**Aqueous Solubility:** Ligand A (-4.358) has worse aqueous solubility than Ligand B (-3.182).

**hERG Inhibition:** Both ligands have similar, low hERG inhibition liability (0.554 and 0.557).

**Microsomal Clearance:** Ligand B (65.326) has a higher microsomal clearance than Ligand A (14.968), indicating lower metabolic stability. This is a significant disadvantage for Ligand B.

**In vitro Half-Life:** Ligand A (-17.217) has a longer in vitro half-life than Ligand B (-23.134).

**P-gp Efflux:** Both ligands have similar P-gp efflux liability (0.242 and 0.255).

**Binding Affinity:** Ligand A (-9.5 kcal/mol) has a significantly stronger binding affinity than Ligand B (-7.8 kcal/mol). This is a major advantage for Ligand A, exceeding the 1.5 kcal/mol threshold.

**Overall Assessment:**

Ligand A excels in BBB penetration and binding affinity, both critical for a CNS GPCR target. While it has a higher DILI risk and slightly worse solubility and Caco-2 permeability, the strong affinity and good BBB outweigh these drawbacks. Ligand B has a better safety profile (lower DILI) but suffers from weaker binding affinity and poorer metabolic stability. The substantial affinity difference (-9.5 vs -7.8 kcal/mol) is a decisive factor.

Output:
1
2025-04-17 08:57:12,729 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (346.471 and 339.443 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (62.55) is better than Ligand B (64.86) as it is closer to the optimal <90 for CNS targets. Both are acceptable.

**3. logP:** Ligand A (3.638) is within the optimal 1-3 range, while Ligand B (1.753) is at the lower end. While not terrible, lower logP can sometimes hinder permeability.

**4. H-Bond Donors:** Both ligands have 1 HBD, which is within the acceptable limit of <=5.

**5. H-Bond Acceptors:** Ligand A has 3 HBAs, and Ligand B has 6. Ligand A is preferable here, as lower HBA counts generally improve permeability.

**6. QED:** Ligand B (0.863) has a significantly higher QED score than Ligand A (0.52), suggesting a more drug-like profile overall.

**7. DILI:** Ligand A (28.306) has a lower DILI risk than Ligand B (40.481), indicating a safer profile.

**8. BBB:** Ligand B (79.953) has a substantially better BBB penetration percentile than Ligand A (53.587). This is a *critical* factor for a CNS target like DRD2.

**9. Caco-2 Permeability:** Ligand A (-4.623) has a worse Caco-2 permeability than Ligand B (-5.48). Lower values indicate lower permeability.

**10. Aqueous Solubility:** Ligand A (-2.776) has slightly better aqueous solubility than Ligand B (-2.395).

**11. hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.348 and 0.28, respectively).

**12. Microsomal Clearance:** Ligand B (20.327) has significantly lower microsomal clearance than Ligand A (82.646), indicating better metabolic stability.

**13. In vitro Half-Life:** Ligand A (73.899) has a much longer in vitro half-life than Ligand B (1.513).

**14. P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.177 and 0.177, respectively).

**15. Binding Affinity:** Ligand A (-7.5) has a significantly stronger binding affinity than Ligand B (0.0). This is a major advantage. A difference of 7.5 kcal/mol is substantial.

**Overall Assessment:**

Ligand A excels in binding affinity and has a better DILI profile and solubility. However, Ligand B shines with its BBB penetration and metabolic stability (lower Cl_mic). The strong binding affinity of Ligand A is a significant advantage, and can potentially outweigh some of the ADME drawbacks. The difference in affinity is so large that it is likely to overcome the lower BBB score.

Output:
1
2025-04-17 08:57:12,730 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (344.37 and 349.43 Da) fall within the ideal 200-500 Da range.

**TPSA:** Both ligands (92.78 and 91.5) are below the 140 A^2 threshold for oral absorption, and reasonably close to the 90 A^2 target for CNS penetration.

**logP:** Ligand A (-0.193) is slightly low, potentially hindering permeation. Ligand B (1.158) is within the optimal 1-3 range. This favors Ligand B.

**H-Bond Donors/Acceptors:** Ligand A (1 HBD, 5 HBA) and Ligand B (2 HBD, 4 HBA) both have acceptable numbers of H-bond donors and acceptors, well within the guidelines.

**QED:** Ligand B (0.7) has a better QED score than Ligand A (0.433), indicating a more drug-like profile.

**DILI:** Ligand B (18.3) has a significantly lower DILI risk than Ligand A (46.8). This is a substantial advantage for Ligand B.

**BBB:** Ligand B (61.923) has a much better BBB penetration percentile than Ligand A (38.232). This is *critical* for a CNS target like DRD2, making Ligand B highly favored.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.8 and -4.56), which is unusual and suggests poor permeability. However, these values are on a log scale and difficult to interpret without further context.

**Aqueous Solubility:** Both ligands have negative solubility values (-2.043 and -2.534), also unusual and suggesting poor solubility.

**hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.025 and 0.2), which is excellent.

**Microsomal Clearance:** Ligand A (-7.515) has a much lower (better) microsomal clearance than Ligand B (30.176), suggesting greater metabolic stability. This is a point in favor of Ligand A.

**In vitro Half-Life:** Ligand A (-11.9) has a more negative (worse) in vitro half-life than Ligand B (-23.25), indicating faster metabolism. This favors Ligand B.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.015 and 0.017), which is good.

**Binding Affinity:** Ligand B (-7.8 kcal/mol) has slightly better binding affinity than Ligand A (-9.0 kcal/mol). While A is better, the difference is not substantial enough to outweigh the ADME advantages of B.

**Overall Assessment:**

Ligand B is the stronger candidate. Its superior BBB penetration, lower DILI risk, better QED, and better in vitro half-life are significant advantages for a CNS-targeting GPCR. While Ligand A has better metabolic stability (lower Cl_mic) and slightly better binding affinity, the ADME profile of Ligand B is far more promising. The slightly lower logP of Ligand A is a concern, and the substantial difference in BBB penetration is a decisive factor.

Output:
1
2025-04-17 08:57:12,730 - INFO - Batch 492 complete. Total preferences: 7872
2025-04-17 08:57:12,730 - INFO - Processing batch 493/512...
2025-04-17 08:57:55,941 - INFO - Reasoning:

Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (343.329 and 353.304 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (53.68) is significantly better than Ligand B (84.04). For CNS targets, TPSA should be <= 90, and A is comfortably within this range, while B is approaching the upper limit. This favors A.

**3. logP:** Both ligands have good logP values (2.984 and 1.92), falling within the optimal 1-3 range. B is slightly lower, which *could* indicate slightly better solubility, but isn't a major concern.

**4. H-Bond Donors:** Ligand A has 1 HBD, while Ligand B has 0. Both are acceptable.

**5. H-Bond Acceptors:** Ligand A has 3 HBA, and Ligand B has 6. Both are within the acceptable limit of <=10, but A is preferable.

**6. QED:** Both ligands have similar and good QED values (0.795 and 0.838), indicating good drug-like properties.

**7. DILI:** Ligand B (72.703) has a slightly higher DILI risk than Ligand A (53.819), but both are reasonably acceptable (below 60 is preferred, but both are below 75).

**8. BBB:** Ligand B (83.443) has a better BBB penetration percentile than Ligand A (77.2). This is a crucial factor for a CNS target like DRD2, giving B an advantage.

**9. Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual. This suggests poor permeability. However, the scale is not specified, so we cannot draw firm conclusions.

**10. Aqueous Solubility:** Both have negative solubility values, also unusual. Again, the scale is unknown, so we cannot draw firm conclusions.

**11. hERG Inhibition:** Ligand A (0.85) shows a slightly higher hERG inhibition liability than Ligand B (0.201). B is significantly better here, which is a major safety advantage.

**12. Microsomal Clearance:** Ligand A (37.698) has lower microsomal clearance than Ligand B (63.809), suggesting better metabolic stability. This is a positive for A.

**13. In vitro Half-Life:** Ligand A (38.36) has a significantly longer in vitro half-life than Ligand B (-6.238). This is a substantial advantage for A.

**14. P-gp Efflux:** Ligand A (0.649) has lower P-gp efflux than Ligand B (0.374), meaning more drug will likely reach the brain. This favors A.

**15. Binding Affinity:** Ligand B (-8.3 kcal/mol) has a significantly stronger binding affinity than Ligand A (-10.4 kcal/mol). This is a major advantage for B, and could potentially outweigh some of the ADME drawbacks.

**Overall Assessment:**

While Ligand B has a better BBB score and significantly stronger binding affinity, Ligand A demonstrates superior ADME properties, particularly in terms of metabolic stability (lower Cl_mic, longer t1/2), P-gp efflux, and TPSA. The hERG risk is also lower for Ligand A. The substantial difference in binding affinity (-8.3 vs -10.4 kcal/mol) is a significant factor. Given the importance of affinity for GPCRs, and the fact that the difference is over 1.5 kcal/mol, I believe Ligand B is the more promising candidate, despite its slightly less favorable ADME profile. The better BBB and significantly improved binding affinity are likely to be more impactful for a CNS target.

Output:
1
2025-04-17 08:57:55,942 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (368.415 and 388.475 Da) fall within the ideal range of 200-500 Da.

**TPSA:** Ligand A (40.62) is excellent, well below the 90 A^2 threshold for CNS targets. Ligand B (139.1) is approaching the upper limit for good oral absorption (140 A^2) and is less desirable for CNS penetration.

**logP:** Ligand A (3.205) is optimal (1-3). Ligand B (0.008) is very low, potentially hindering permeation and reducing brain exposure.

**H-Bond Donors/Acceptors:** Ligand A (0 HBD, 2 HBA) is favorable. Ligand B (3 HBD, 9 HBA) is acceptable, but higher values can sometimes impact permeability.

**QED:** Ligand A (0.648) is good, indicating a drug-like profile. Ligand B (0.514) is acceptable, but slightly lower.

**DILI:** Ligand A (30.826) has a very low DILI risk. Ligand B (83.986) has a significantly higher DILI risk, which is concerning.

**BBB:** Ligand A (90.772) has excellent BBB penetration potential. Ligand B (22.528) has very poor predicted BBB penetration. This is a critical disadvantage for a CNS target like DRD2.

**Caco-2 Permeability:** Ligand A (-4.233) suggests poor permeability, which is concerning. Ligand B (-5.751) is even worse.

**Aqueous Solubility:** Both ligands have negative solubility values (-2.758 and -2.373), indicating poor aqueous solubility, which could pose formulation challenges.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.722 and 0.201).

**Microsomal Clearance:** Ligand A (39.432) has moderate clearance. Ligand B (20.513) has lower clearance, suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (13.161 hours) has a reasonable half-life. Ligand B (-27.909 hours) has a negative half-life, which is not physically possible and indicates a problem with the prediction or the molecule itself.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.216 and 0.061).

**Binding Affinity:** Ligand B (-7.9 kcal/mol) has a slightly better binding affinity than Ligand A (-7.5 kcal/mol). However, the difference is not substantial enough to outweigh the significant ADME deficiencies of Ligand B.

**Overall Assessment:**

Ligand A is significantly more promising. While its Caco-2 permeability and solubility are concerning, its excellent TPSA, logP, BBB penetration, and low DILI risk make it a much better candidate for a CNS-targeting drug like a DRD2 ligand. Ligand B's extremely poor BBB penetration, high DILI risk, and problematic half-life prediction are major drawbacks that cannot be easily overlooked, even with slightly better binding affinity.

Output:
0
2025-04-17 08:57:55,942 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (410.308 Da) is slightly higher than Ligand B (343.387 Da), but both are acceptable.

**TPSA:** Ligand A (71.7) is significantly better than Ligand B (99.83). For CNS targets, we want TPSA <= 90, and Ligand A is comfortably within this range, while Ligand B is close to the upper limit.

**logP:** Ligand A (3.691) is optimal (1-3), while Ligand B (0.243) is quite low. Low logP can hinder membrane permeability, especially crucial for CNS penetration.

**H-Bond Donors/Acceptors:** Both ligands have 2 HBDs and 5-6 HBAs, which are within acceptable limits.

**QED:** Both ligands have good QED scores (0.682 and 0.758), indicating drug-like properties.

**DILI:** Ligand A (35.789) has a much lower DILI risk than Ligand B (68.864). This is a significant advantage for Ligand A.

**BBB:** Ligand A (28.344) has a better BBB percentile than Ligand B (16.906). While neither is exceptionally high, Ligand A is more likely to cross the blood-brain barrier, critical for a DRD2 target.

**Caco-2 Permeability:** Ligand A (-4.953) has better Caco-2 permeability than Ligand B (-5.396), though both are negative values and suggest limited permeability.

**Aqueous Solubility:** Ligand A (-4.436) has better solubility than Ligand B (-2.197), though both are negative values and suggest limited solubility.

**hERG Inhibition:** Ligand A (0.763) has a slightly higher hERG risk than Ligand B (0.169). However, both are relatively low, so this is not a major concern.

**Microsomal Clearance:** Ligand A (73.516) has a higher microsomal clearance than Ligand B (0.774), meaning it's metabolized faster. This is a disadvantage for Ligand A.

**In vitro Half-Life:** Ligand A (102.195) has a longer half-life than Ligand B (0.188), which is a positive attribute.

**P-gp Efflux:** Ligand A (0.63) has lower P-gp efflux than Ligand B (0.019). Lower P-gp efflux is desirable for CNS exposure.

**Binding Affinity:** Both ligands have very similar and strong binding affinities (-8.8 and -8.6 kcal/mol). The difference is minimal.

**Overall Assessment:**

Considering the GPCR-specific priorities, Ligand A is significantly better. Its superior TPSA, logP, BBB penetration, lower DILI risk, and lower P-gp efflux outweigh its slightly higher microsomal clearance and hERG risk. While both have good binding affinity, the ADME properties of Ligand A make it a more promising drug candidate for targeting DRD2.

Output:
1
2025-04-17 08:57:55,942 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (364.358 and 361.829 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (33.2) is excellent, well below the 90 A^2 threshold for CNS targets. Ligand B (60.93) is higher, but still acceptable, though less optimal for CNS penetration.

**logP:** Ligand A (4.619) is slightly high, potentially leading to solubility issues or off-target interactions. Ligand B (1.914) is within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Both ligands have a low number of HBDs (0) and acceptable HBAs (2 and 3 respectively), suggesting good permeability.

**QED:** Both ligands have good QED scores (0.731 and 0.808), indicating drug-like properties.

**DILI:** Ligand A (40.713) has a better DILI score than Ligand B (67.313), suggesting a lower risk of liver injury.

**BBB:** This is a critical parameter for a CNS target like DRD2. Ligand A (93.137) has a significantly higher BBB percentile than Ligand B (77.627), making it more likely to reach the target in the brain.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.433 and -4.588), which is unusual and potentially problematic. It suggests poor intestinal absorption, but could be an artifact of the prediction method.

**Aqueous Solubility:** Both ligands have negative solubility values (-4.651 and -3.64), which is also concerning. This could limit bioavailability.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.812 and 0.424).

**Microsomal Clearance:** Both ligands have similar microsomal clearance values (23.869 and 25.291 mL/min/kg), indicating moderate metabolic stability.

**In vitro Half-Life:** Ligand A (0.196) has a very short half-life, which is undesirable. Ligand B (11.511) has a much longer half-life, which is a significant advantage.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.435 and 0.183), which is good for CNS penetration.

**Binding Affinity:** Ligand B (-9.2 kcal/mol) has a slightly better binding affinity than Ligand A (-8.5 kcal/mol). This 0.7 kcal/mol difference is significant, but not overwhelming.

**Overall Assessment:**

Ligand A excels in BBB penetration and DILI risk, but suffers from a very short half-life and a higher logP. Ligand B has a better binding affinity and a significantly longer half-life, but its BBB penetration is lower and DILI risk is higher. Given the importance of CNS penetration for a DRD2 ligand, and the substantial difference in half-life, Ligand B appears to be the more promising candidate, despite the slightly higher DILI risk. The better affinity also contributes to this decision. The solubility and permeability issues are concerning for both, but can potentially be addressed through formulation strategies.

Output:
1
2025-04-17 08:57:55,943 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (337.423 and 345.399 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (71.09) is excellent, well below the 90 A^2 threshold for CNS targets. Ligand B (84.67) is still reasonable but less optimal.

**logP:** Ligand A (3.123) is within the optimal 1-3 range. Ligand B (1.142) is a bit low, potentially hindering membrane permeability.

**H-Bond Donors/Acceptors:** Ligand A has 2 HBD and 3 HBA, both within acceptable limits. Ligand B has 1 HBD and 5 HBA, also acceptable.

**QED:** Ligand A (0.845) has a very strong drug-like profile. Ligand B (0.564) is acceptable but less desirable.

**DILI:** Ligand A (64.754) has a moderate DILI risk, but still acceptable. Ligand B (49.128) has a lower DILI risk, which is favorable.

**BBB:** Ligand A (77.782) shows good BBB penetration, exceeding the 70% threshold. Ligand B (63.358) is lower, which is a significant drawback for a CNS target.

**Caco-2 Permeability:** Both have negative Caco-2 values (-4.403 and -4.815), which is unusual and suggests poor permeability. This is a red flag for both, but the negative values are difficult to interpret directly.

**Aqueous Solubility:** Both ligands have negative solubility values (-4.948 and -1.817), also unusual. This suggests very poor aqueous solubility, which is a major concern.

**hERG Inhibition:** Both ligands show very low hERG inhibition risk (0.256 and 0.119).

**Microsomal Clearance:** Ligand A (75.778) has a higher microsomal clearance, indicating faster metabolism. Ligand B (13.095) has much lower clearance, suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (24.487) has a moderate half-life. Ligand B (-0.342) has a very short half-life, which is unfavorable.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.065 and 0.093), which is good for CNS penetration.

**Binding Affinity:** Ligand B (-7.9 kcal/mol) has a significantly stronger binding affinity than Ligand A (-9.4 kcal/mol). This >1.5 kcal/mol difference is substantial and can outweigh some ADME drawbacks.

**Overall Assessment:**

Despite the unusual solubility and permeability values, Ligand B stands out due to its significantly higher binding affinity (-7.9 vs -9.4 kcal/mol). The lower DILI risk and better metabolic stability (lower Cl_mic) are also positive attributes. While the BBB penetration is lower than Ligand A, the strong affinity may compensate for this, especially if formulation strategies can improve CNS delivery. Ligand A's better BBB is offset by its poorer affinity and faster metabolism. The solubility/permeability issues need to be addressed for either compound, but the potency advantage of B is compelling.

Output:
1
2025-04-17 08:57:55,943 - INFO - Reasoning:

Let's analyze Ligand A and Ligand B based on the provided guidelines, prioritizing GPCR-specific properties (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (341.5 & 353.5 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (53.16) is excellent for CNS penetration, well below the 90 A^2 threshold. Ligand B (81.67) is higher, but still potentially acceptable, though less ideal.

**logP:** Ligand A (3.262) is optimal. Ligand B (1.424) is on the lower side, potentially impacting permeability.

**H-Bond Donors/Acceptors:** Both ligands have 3 HBD and a reasonable number of HBA (3 and 4 respectively), satisfying the <5 HBD and <10 HBA guidelines.

**QED:** Ligand A (0.791) has a better QED score than Ligand B (0.555), indicating a more drug-like profile.

**DILI:** Ligand A (23.614) has a significantly lower DILI risk than Ligand B (5.584), which is a substantial advantage.

**BBB:** Ligand A (80.574) has excellent BBB penetration, exceeding the 70% threshold. Ligand B (31.989) is poor for CNS penetration. This is a critical difference given the target (DRD2).

**Caco-2 Permeability:** Ligand A (-5.307) has poor Caco-2 permeability. Ligand B (-5.54) is also poor.

**Aqueous Solubility:** Both ligands have poor aqueous solubility (-2.192 and -1.228 respectively).

**hERG:** Both ligands have very low hERG inhibition risk (0.785 and 0.469 respectively).

**Microsomal Clearance:** Ligand A (-28.973) has significantly lower (better) microsomal clearance than Ligand B (-4.515), indicating greater metabolic stability.

**In vitro Half-Life:** Ligand A (28.833) has a longer half-life than Ligand B (26.479), which is favorable.

**P-gp Efflux:** Ligand A (0.232) has lower P-gp efflux than Ligand B (0.014), which is better for CNS exposure.

**Binding Affinity:** Ligand B (-7.5 kcal/mol) has a slightly better binding affinity than Ligand A (-10.4 kcal/mol). However, the difference is not substantial enough to outweigh the significant ADME advantages of Ligand A.

**Overall:** Considering the GPCR-specific priorities, Ligand A is significantly more promising. Its superior BBB penetration, lower DILI risk, better metabolic stability (lower Cl_mic), lower P-gp efflux, and better QED outweigh the slightly weaker binding affinity and poor Caco-2 permeability. The poor solubility and Caco-2 permeability of both compounds would need to be addressed in further optimization, but these are less critical than CNS penetration for a DRD2 target.

Output:
1
2025-04-17 08:57:55,943 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (339.435 and 353.507 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (58.56) is better than Ligand B (53.09). Both are below the 90 A^2 threshold for CNS targets, which is good.

**3. logP:** Ligand A (3.527) is optimal (1-3), while Ligand B (1.593) is on the lower end, potentially hindering permeability.

**4. H-Bond Donors:** Ligand A (2) is acceptable, while Ligand B (0) is also good.

**5. H-Bond Acceptors:** Ligand A (3) is acceptable, and Ligand B (4) is also good.

**6. QED:** Both ligands have similar QED values (0.82 and 0.728), indicating good drug-like properties.

**7. DILI:** Ligand A (57.658) has a higher DILI risk than Ligand B (11.206). This is a significant drawback for Ligand A.

**8. BBB:** Ligand B (81.582) has a much better BBB penetration percentile than Ligand A (51.105). This is *critical* for a CNS target like DRD2.

**9. Caco-2 Permeability:** Both have negative values, which is unusual. Without knowing the scale, it's hard to interpret.

**10. Aqueous Solubility:** Both have negative values, which is unusual. Without knowing the scale, it's hard to interpret.

**11. hERG Inhibition:** Both ligands have low hERG inhibition risk (0.615 and 0.414).

**12. Microsomal Clearance:** Ligand B (33.526) has lower microsomal clearance than Ligand A (42.832), suggesting better metabolic stability.

**13. In vitro Half-Life:** Ligand B (-17.99) has a negative half-life, which is impossible. This is a major red flag. Ligand A (24.298) is acceptable.

**14. P-gp Efflux:** Both ligands have low P-gp efflux liability (0.489 and 0.052). Ligand B is significantly better.

**15. Binding Affinity:** Ligand B (-7.5 kcal/mol) has a significantly better binding affinity than Ligand A (-9.0 kcal/mol). This is a substantial advantage.

**Overall Assessment:**

While Ligand A has a better half-life, its higher DILI risk and significantly lower BBB penetration are major concerns for a CNS drug. Ligand B, despite the impossible half-life value, has a superior binding affinity, much better BBB penetration, lower DILI risk, and lower P-gp efflux. The negative half-life is a data issue that would need to be resolved, but the other properties strongly favor Ligand B. The affinity difference is also large enough to potentially overcome other minor drawbacks.

Output:
1
2025-04-17 08:57:55,943 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (367.471 and 350.503 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (70.16) is slightly above the preferred <90 for CNS targets, but still reasonable. Ligand B (58.64) is excellent, well below 90.

**3. logP:** Ligand A (0.495) is a bit low, potentially hindering permeation. Ligand B (2.737) is within the optimal 1-3 range.

**4. H-Bond Donors:** Ligand A (0) is good. Ligand B (1) is also acceptable.

**5. H-Bond Acceptors:** Ligand A (5) is good. Ligand B (3) is also good.

**6. QED:** Both ligands have good QED scores (0.726 and 0.801), indicating drug-like properties.

**7. DILI:** Ligand A (39.201) has a slightly higher DILI risk than Ligand B (21.714), but both are below the concerning threshold of 60.

**8. BBB:** Both ligands have excellent BBB penetration (71.85 and 77.898), exceeding the >70 desirable value for CNS targets.

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 values, which is unusual and suggests a potential issue with the data or modeling. However, we'll proceed assuming these represent poor permeability.

**10. Aqueous Solubility:** Both ligands have negative solubility values, also unusual. Again, assuming these represent poor solubility.

**11. hERG Inhibition:** Both ligands show low hERG inhibition liability (0.314 and 0.437).

**12. Microsomal Clearance:** Ligand A (57.682) has lower microsomal clearance than Ligand B (79.874), suggesting better metabolic stability.

**13. In vitro Half-Life:** Ligand A (-19.505) has a negative half-life, which is not possible and indicates a data issue. Ligand B (-8.733) also has a negative half-life.

**14. P-gp Efflux:** Ligand A (0.038) has very low P-gp efflux, which is highly desirable for CNS penetration. Ligand B (0.32) is also relatively low.

**15. Binding Affinity:** Ligand A (-6.7) has a slightly better binding affinity than Ligand B (-0.0). This is a substantial difference.

**Overall Assessment:**

Despite the questionable Caco-2 and solubility data, and the impossible half-life values, the key factors for a CNS-targeting GPCR ligand are affinity, BBB penetration, logP, and P-gp efflux. Ligand A has a significantly better binding affinity (-6.7 kcal/mol vs -0.0 kcal/mol) and very low P-gp efflux. While its logP is suboptimal, the strong affinity could compensate. Ligand B has a better logP and TPSA, but the extremely weak binding affinity is a major drawback. The negative half-life values are concerning, but the large affinity difference between the two ligands is the most important factor.

Output:
1
2025-04-17 08:57:55,943 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (350.39 and 343.362 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (66.92) is significantly better than Ligand B (95.04). For CNS targets, TPSA should be <= 90, so Ligand A is preferable.

**3. logP:** Both ligands have acceptable logP values (1.238 and 2.373, respectively), falling within the optimal 1-3 range.

**4. H-Bond Donors:** Both are low (0 and 1), which is good.

**5. H-Bond Acceptors:** Ligand A (4) is better than Ligand B (6), but both are acceptable (<=10).

**6. QED:** Both have similar and good QED values (0.694 and 0.642), indicating good drug-like properties.

**7. DILI:** Ligand A (33.812) has a much lower DILI risk than Ligand B (68.825). This is a significant advantage for Ligand A.

**8. BBB:** Both ligands have high BBB penetration (87.166 and 84.374), which is crucial for a CNS target like DRD2. Ligand A is slightly better.

**9. Caco-2 Permeability:** Both have negative values, which is unusual. However, the magnitude of negativity is similar, and this metric is less critical than others for CNS targets.

**10. Aqueous Solubility:** Both have negative values, suggesting poor solubility. Ligand B (-4.095) is worse than Ligand A (-1.64).

**11. hERG Inhibition:** Both have very low hERG inhibition risk (0.432 and 0.398).

**12. Microsomal Clearance:** Ligand A (44.184) has a higher microsomal clearance than Ligand B (15.184), meaning it is less metabolically stable. Ligand B is preferable here.

**13. In vitro Half-Life:** Ligand B (-4.503) has a longer in vitro half-life than Ligand A (-1.441).

**14. P-gp Efflux:** Both have very low P-gp efflux liability (0.055 and 0.216).

**15. Binding Affinity:** Ligand B (-9.0) has a significantly stronger binding affinity than Ligand A (-8.3). This is a 0.7 kcal/mol difference, which is substantial and can outweigh some ADME drawbacks.

**Overall Assessment:**

While Ligand A has advantages in TPSA, DILI risk, and BBB, Ligand B's significantly stronger binding affinity (-9.0 vs -8.3 kcal/mol) is the most important factor for a GPCR target. The slightly worse TPSA and DILI of Ligand B are less concerning given the substantial affinity difference. The better metabolic stability and half-life of Ligand B also contribute to its favorability.

Output:
1
2025-04-17 08:57:55,944 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (337.423 and 356.482 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Both ligands have TPSA values (61.44 and 61.8) that are acceptable for oral absorption (<140) but slightly higher than optimal for CNS penetration (<90).

**3. logP:** Ligand A (4.049) is at the upper end of the optimal range (1-3), while Ligand B (2.865) is well within the optimal range. Ligand A's higher logP *could* lead to solubility issues or off-target interactions, but isn't immediately disqualifying.

**4. H-Bond Donors:** Both ligands have 2 HBD, which is well within the acceptable limit of 5.

**5. H-Bond Acceptors:** Ligand A has 2 HBA, while Ligand B has 3. Both are below the acceptable limit of 10.

**6. QED:** Both ligands have similar QED values (0.827 and 0.817), indicating good drug-like properties.

**7. DILI:** Ligand A has a significantly higher DILI risk (84.025%) compared to Ligand B (8.996%). This is a major concern for Ligand A.

**8. BBB:** Ligand B has a substantially better BBB penetration percentile (88.29%) than Ligand A (71.462%). This is crucial for a CNS target like DRD2.

**9. Caco-2 Permeability:** Both have negative Caco-2 values which is unusual and suggests a potential issue with the data. However, the relative values are similar.

**10. Aqueous Solubility:** Both ligands have poor aqueous solubility (-5.23 and -3.312). This could be a formulation challenge, but is not a dealbreaker if other properties are favorable.

**11. hERG Inhibition:** Ligand A (0.724) has a slightly higher hERG inhibition risk than Ligand B (0.405), but both are relatively low.

**12. Microsomal Clearance:** Ligand A (55.008) has higher microsomal clearance than Ligand B (38.324), suggesting lower metabolic stability.

**13. In vitro Half-Life:** Ligand B has a significantly longer in vitro half-life (6.463 hours) than Ligand A (35.151 hours). This is a significant advantage for Ligand B.

**14. P-gp Efflux:** Ligand A (0.23) has lower P-gp efflux than Ligand B (0.043), which is favorable for CNS exposure.

**15. Binding Affinity:** Ligand B (-7.6 kcal/mol) has a significantly stronger binding affinity than Ligand A (-10.2 kcal/mol). This is a substantial advantage, potentially outweighing some of the minor ADME drawbacks.

**Overall Assessment:**

Ligand B is the superior candidate. While both have some issues with solubility, Ligand B excels in the critical areas for a CNS GPCR target: BBB penetration, binding affinity, and metabolic stability (longer half-life, lower clearance). The significantly lower DILI risk for Ligand B is also a major advantage. The slightly higher P-gp efflux for Ligand B is a minor concern compared to the other benefits. The stronger binding affinity of Ligand B further solidifies its position as the more promising drug candidate.

Output:
1
2025-04-17 08:57:55,944 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (349.341 and 365.547 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (90.98) is excellent, being below the 90 threshold for CNS targets. Ligand B (67.07) is also very good, well below the threshold.

**3. logP:** Ligand A (1.252) is within the optimal 1-3 range. Ligand B (3.321) is at the higher end of optimal, but still acceptable.

**4. H-Bond Donors:** Ligand A (2) and Ligand B (1) both meet the <=5 criteria.

**5. H-Bond Acceptors:** Ligand A (4) and Ligand B (7) both meet the <=10 criteria.

**6. QED:** Both ligands have reasonable QED values (0.85 and 0.777), indicating good drug-like properties.

**7. DILI:** Ligand A (60.062) is borderline, entering the higher risk category. Ligand B (19.349) is excellent, indicating low DILI risk.

**8. BBB:** Ligand A (74.021) is good, exceeding the 70% threshold for CNS targets. Ligand B (48.817) is significantly lower and a concern for CNS penetration.

**9. Caco-2:** Both ligands have negative Caco-2 values (-4.888 and -5.113), which is unusual and suggests poor permeability. This is a significant drawback for both.

**10. Solubility:** Both ligands have negative solubility values (-2.751 and -3.047), also unusual and indicating poor aqueous solubility. This is a significant drawback for both.

**11. hERG:** Both ligands have low hERG risk (0.428 and 0.593).

**12. Cl_mic:** Ligand A (-13.271) has a much lower (better) microsomal clearance than Ligand B (40.882), suggesting better metabolic stability.

**13. t1/2:** Ligand B (35.541) has a significantly longer in vitro half-life than Ligand A (-7.743), which is a positive.

**14. Pgp:** Ligand A (0.077) has very low P-gp efflux liability, which is excellent for CNS penetration. Ligand B (0.116) is slightly higher, but still relatively low.

**15. Binding Affinity:** Ligand A (-9.1) has a substantially stronger binding affinity than Ligand B (-6.8). This is a >2.3 kcal/mol difference, which is a major advantage and can outweigh some ADME drawbacks.

**Overall Assessment:**

Ligand A is stronger in terms of binding affinity, metabolic stability (lower Cl_mic), and P-gp efflux (better CNS penetration). It also has a good BBB score. However, it has a higher DILI risk. Ligand B has a longer half-life and lower DILI risk, but significantly weaker binding affinity and a poor BBB score.

Given the GPCR-specific priorities, particularly the importance of BBB penetration and strong binding affinity for CNS targets, **Ligand A is the more promising candidate despite the slightly elevated DILI risk.** The strong affinity and favorable BBB/Pgp profile are likely to be more critical for efficacy in a CNS disorder. The DILI risk could be investigated further with additional studies and potentially mitigated through structural modifications. The poor Caco-2 and solubility are concerning for both, but could be addressed through formulation strategies.

Output:
0
2025-04-17 08:57:55,944 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 drug candidates, considering the provided guidelines and GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (352.406 and 356.457 Da) fall comfortably within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (75.71) is higher than Ligand B (49.41). For a CNS target like DRD2, TPSA < 90 is preferred, so both are acceptable, but B is significantly better.

**3. logP:** Ligand A (1.003) is within the optimal range (1-3), while Ligand B (3.355) is at the higher end. Both are acceptable, but A is slightly preferred.

**4. H-Bond Donors:** Both ligands have 1 HBD, which is within the acceptable limit of <=5.

**5. H-Bond Acceptors:** Ligand A has 4 HBAs, and Ligand B has 2. Both are within the acceptable limit of <=10.

**6. QED:** Both ligands have good QED scores (0.694 and 0.793, respectively), indicating good drug-like properties.

**7. DILI:** Ligand A (28.616) has a lower DILI risk than Ligand B (10.585), suggesting it's less likely to cause liver injury. This is a significant advantage for A.

**8. BBB:** Ligand A (89.027) and Ligand B (96.743) both have high BBB penetration percentiles, which is crucial for CNS targets. B is slightly better.

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.785 and -4.713). This is unusual and suggests poor intestinal absorption. This is a drawback for both, but doesn't heavily influence the decision given the CNS target.

**10. Aqueous Solubility:** Both ligands have negative solubility values (-2.172 and -3.391), indicating poor aqueous solubility. This is a drawback for both, but less critical for a CNS drug.

**11. hERG Inhibition:** Ligand A (0.121) has a lower hERG inhibition risk than Ligand B (0.687). This is a significant advantage for A.

**12. Microsomal Clearance:** Ligand B (18.625) has a higher microsomal clearance than Ligand A (10.786), indicating lower metabolic stability. A is preferred.

**13. In vitro Half-Life:** Ligand A (-1.375) has a shorter in vitro half-life than Ligand B (-12.667). B is preferred.

**14. P-gp Efflux:** Ligand A (0.022) has significantly lower P-gp efflux liability than Ligand B (0.077). This is a major advantage for A, as it will lead to better CNS exposure.

**15. Binding Affinity:** Ligand B (-8.2) has a slightly stronger binding affinity than Ligand A (-7.8). This is a positive for B, but the difference is relatively small (0.4 kcal/mol).

**Overall Assessment:**

While Ligand B has a slightly better binding affinity and BBB penetration, Ligand A demonstrates a more favorable ADME profile. Specifically, Ligand A has a significantly lower DILI risk, lower hERG inhibition, lower P-gp efflux, and better metabolic stability (lower Cl_mic). Given the GPCR-specific priorities, the lower P-gp efflux and DILI risk of Ligand A are particularly important for CNS penetration and safety. The small difference in binding affinity is outweighed by these ADME advantages.

Output:
0
2025-04-17 08:57:55,944 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (335.5 & 357.5 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (27.3) is significantly better than Ligand B (32.7), both being below the 90 A^2 threshold desirable for CNS targets.

**3. logP:** Both ligands have similar logP values (3.799 & 3.739), falling within the optimal 1-3 range.

**4. H-Bond Donors:** Ligand A (2) is slightly higher than Ligand B (1), both are within the acceptable limit of 5.

**5. H-Bond Acceptors:** Ligand A (3) and Ligand B (4) are both below the 10 limit.

**6. QED:** Both ligands have similar QED values (0.806 & 0.781), indicating good drug-likeness.

**7. DILI:** Ligand A (11.594) has a lower DILI risk than Ligand B (12.33), both are good (<40).

**8. BBB:** Ligand A (97.945) has a substantially higher BBB penetration percentile than Ligand B (77.433). This is a *critical* advantage for a CNS target like DRD2.

**9. Caco-2 Permeability:** Ligand A (-4.918) has a better Caco-2 permeability than Ligand B (-5.2), but both are negative values which is unusual.

**10. Aqueous Solubility:** Ligand A (-3.039) has better solubility than Ligand B (-3.788), both are negative values which is unusual.

**11. hERG:** Both ligands have similar low hERG inhibition liability (0.981 & 0.954).

**12. Microsomal Clearance:** Ligand A (23.766) has a lower microsomal clearance than Ligand B (44.92), indicating better metabolic stability.

**13. In vitro Half-Life:** Ligand A (54.755) has a longer in vitro half-life than Ligand B (21.578).

**14. P-gp Efflux:** Ligand A (0.217) has a lower P-gp efflux liability than Ligand B (0.732), which is beneficial for CNS exposure.

**15. Binding Affinity:** Ligand A (-9.1) has a slightly better binding affinity than Ligand B (-8.1). While both are excellent, the 1 kcal/mol difference is noteworthy.

**Overall Assessment:**

Ligand A consistently outperforms Ligand B across multiple crucial parameters for a CNS-targeting GPCR ligand. The most significant differences are in BBB penetration (97.9% vs 77.4%), microsomal clearance (lower is better for A), P-gp efflux (lower is better for A), and binding affinity (slightly better for A). While both are good candidates, Ligand A's superior predicted CNS exposure and metabolic stability make it the more promising drug candidate.

Output:
1
2025-04-17 08:57:55,944 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (363.443 and 380.279 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (96.67) is slightly above the preferred <90 for CNS targets, but still reasonable. Ligand B (55.43) is excellent, well below the 90 threshold.

**3. logP:** Ligand A (1.693) is within the optimal 1-3 range. Ligand B (3.715) is at the higher end of optimal, but still acceptable.

**4. H-Bond Donors:** Ligand A (1) is good. Ligand B (0) is also good.

**5. H-Bond Acceptors:** Ligand A (6) is good. Ligand B (5) is good.

**6. QED:** Ligand A (0.876) is excellent, indicating high drug-likeness. Ligand B (0.464) is below the 0.5 threshold and suggests a less drug-like profile.

**7. DILI:** Ligand A (80.225) has a higher DILI risk than Ligand B (64.754), but both are below the concerning >60 threshold.

**8. BBB:** Ligand A (83.249) has a good BBB penetration percentile. Ligand B (65.607) is lower, which is a significant drawback for a CNS target like DRD2.

**9. Caco-2:** Both ligands have negative Caco-2 values, which is unusual and suggests potential issues with permeability prediction. This is a flag for further investigation, but difficult to interpret directly.

**10. Solubility:** Both ligands have negative solubility values, indicating poor aqueous solubility. This is also a flag for further investigation.

**11. hERG:** Ligand A (0.203) has a very low hERG risk. Ligand B (0.724) has a moderate hERG risk, but is still acceptable.

**12. Cl_mic:** Ligand A (-4.707) suggests very low metabolic clearance (good). Ligand B (93.208) indicates high metabolic clearance (poor).

**13. t1/2:** Ligand A (45.781) has a reasonable in vitro half-life. Ligand B (44.447) is similar.

**14. Pgp:** Ligand A (0.073) has low P-gp efflux liability (good). Ligand B (0.512) has moderate P-gp efflux liability.

**15. Binding Affinity:** Both ligands have excellent binding affinities (-8.6 and -8.0 kcal/mol). Ligand A is slightly better.

**Overall Assessment:**

Considering the GPCR-specific priorities, Ligand A is the more promising candidate. While its TPSA is slightly higher, it has a significantly better BBB score, lower P-gp efflux, and superior metabolic stability (lower Cl_mic). Its QED score is also much higher, indicating better overall drug-likeness. The slightly better binding affinity is a bonus. Ligand B's lower TPSA is offset by its poorer BBB, higher P-gp efflux, and significantly higher metabolic clearance.

Output:
0
2025-04-17 08:57:55,945 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (350.415 and 364.515 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Both ligands have TPSA values (88.1 and 86.88) below the 90 A^2 threshold desirable for CNS targets, which is excellent.

**3. logP:** Ligand A (0.489) is a bit low, potentially hindering permeation. Ligand B (2.445) is within the optimal 1-3 range. This favors Ligand B.

**4. H-Bond Donors:** Ligand A (2) and Ligand B (3) are both acceptable, being less than 5.

**5. H-Bond Acceptors:** Ligand A (5) and Ligand B (4) are both acceptable, being less than 10.

**6. QED:** Both ligands have decent QED values (0.712 and 0.595), indicating good drug-like properties.

**7. DILI:** Ligand A (45.328) has a slightly higher DILI risk than Ligand B (29.624), but both are below the concerning 60 threshold.

**8. BBB:** This is crucial for a CNS target. Ligand B (53.781) has a significantly better BBB penetration percentile than Ligand A (42.226). This is a major advantage for Ligand B.

**9. Caco-2 Permeability:** Ligand A (-4.889) has poor Caco-2 permeability, while Ligand B (-5.555) is also poor.

**10. Aqueous Solubility:** Ligand A (-0.978) has slightly better solubility than Ligand B (-3.25), but both are quite poor.

**11. hERG Inhibition:** Both ligands show low hERG inhibition risk (0.123 and 0.33).

**12. Microsomal Clearance:** Ligand A (-1.214) has much lower (better) microsomal clearance than Ligand B (24.474), indicating better metabolic stability.

**13. In vitro Half-Life:** Ligand A (9.373) has a significantly longer half-life than Ligand B (2.696). This is a strong advantage for Ligand A.

**14. P-gp Efflux:** Both ligands have low P-gp efflux liability (0.087 and 0.064), which is good.

**15. Binding Affinity:** Ligand B (-7.6) has a slightly better binding affinity than Ligand A (-7.4), although the difference is small (0.2 kcal/mol).

**Overall Assessment:**

While Ligand A has better metabolic stability (lower Cl_mic and longer t1/2) and slightly better solubility, Ligand B excels in the critical areas for a CNS GPCR target: BBB penetration and logP. The modest improvement in binding affinity for Ligand B further supports its selection. The poor Caco-2 permeability is a concern for both, but less critical for a CNS-focused drug. Given the priorities for DRD2 (a CNS GPCR), Ligand B is the more promising candidate.

Output:
1
2025-04-17 08:57:55,945 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (339.435 and 340.387 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (38.77) is excellent, well below the 90 A^2 threshold for CNS targets. Ligand B (113.24) is higher, but still potentially acceptable, though less optimal.

**3. logP:** Ligand A (4.289) is slightly high, potentially leading to solubility issues or off-target interactions. Ligand B (0.443) is quite low, which could hinder membrane permeability and CNS penetration.

**4. H-Bond Donors:** Ligand A (0) is good. Ligand B (3) is acceptable.

**5. H-Bond Acceptors:** Ligand A (3) is good. Ligand B (5) is acceptable.

**6. QED:** Both ligands have reasonable QED values (0.788 and 0.684), suggesting good drug-like properties.

**7. DILI:** Ligand A (39.318) has a lower DILI risk than Ligand B (56.146), which is a positive attribute.

**8. BBB:** Both ligands have similar and good BBB penetration (78.868% and 78.558%), meeting the >70% threshold for CNS targets.

**9. Caco-2 Permeability:** Ligand A (-4.131) is poor. Ligand B (-5.514) is even worse. Both are very low, indicating poor intestinal absorption.

**10. Aqueous Solubility:** Ligand A (-4.807) is poor. Ligand B (-2.637) is also poor, but better than Ligand A.

**11. hERG Inhibition:** Ligand A (0.771) has a lower hERG risk than Ligand B (0.271), which is favorable.

**12. Microsomal Clearance:** Ligand A (100.792) has higher clearance than Ligand B (32.814), suggesting lower metabolic stability.

**13. In vitro Half-Life:** Ligand B (-17.418) has a much longer half-life than Ligand A (-4.964), a significant advantage.

**14. P-gp Efflux:** Ligand A (0.459) has lower P-gp efflux liability than Ligand B (0.006), which is beneficial for CNS exposure.

**15. Binding Affinity:** Ligand B (-9.9 kcal/mol) has a significantly stronger binding affinity than Ligand A (-8.8 kcal/mol). This >1.1 kcal/mol difference is substantial and can outweigh some ADME drawbacks.

**Overall Assessment:**

Ligand B has a much stronger binding affinity, a longer half-life, and a slightly better solubility profile. While its logP is low and Caco-2 permeability is poor, the strong affinity and good BBB penetration are crucial for a CNS GPCR target like DRD2. Ligand A has better logP and P-gp efflux, but its weaker affinity and higher clearance are significant drawbacks. The superior affinity of Ligand B is the deciding factor.

Output:
1
2025-04-17 08:57:55,945 - INFO - Batch 493 complete. Total preferences: 7888
2025-04-17 08:57:55,945 - INFO - Processing batch 494/512...
2025-04-17 08:58:39,045 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (344.455 and 344.415 Da) fall within the ideal range of 200-500 Da.

**TPSA:** Ligand A (62.55) is excellent, well below the 90 A^2 threshold for CNS targets. Ligand B (89.53) is still acceptable but closer to the upper limit.

**logP:** Ligand A (3.589) is optimal. Ligand B (0.72) is quite low, potentially hindering membrane permeability and CNS penetration.

**H-Bond Donors/Acceptors:** Ligand A (HBD=1, HBA=3) and Ligand B (HBD=2, HBA=4) both have reasonable numbers of H-bond donors and acceptors, well within the guidelines.

**QED:** Both ligands have acceptable QED values (A: 0.888, B: 0.774), indicating good drug-like properties.

**DILI:** Both ligands have low DILI risk (A: 44.009, B: 48.623), which is positive.

**BBB:** Ligand A (83.56) has a very good BBB percentile, exceeding the 70% threshold for CNS targets. Ligand B (40.52) is significantly lower, raising concerns about CNS exposure.

**Caco-2 Permeability:** Ligand A (-4.788) has poor Caco-2 permeability. Ligand B (-5.044) also has poor Caco-2 permeability.

**Aqueous Solubility:** Both ligands have poor aqueous solubility (A: -3.597, B: -2.308).

**hERG Inhibition:** Ligand A (0.603) has a slightly higher hERG risk than Ligand B (0.325), but both are relatively low.

**Microsomal Clearance:** Ligand A (59.957) has a higher microsomal clearance than Ligand B (36.251), suggesting lower metabolic stability.

**In vitro Half-Life:** Ligand B (-18.746) has a negative half-life, which is not possible. This is a red flag and indicates a potential issue with the data or the molecule's stability. Ligand A (17.211) has a reasonable half-life.

**P-gp Efflux:** Ligand A (0.666) has moderate P-gp efflux, while Ligand B (0.084) has very low P-gp efflux, which is beneficial for CNS penetration.

**Binding Affinity:** Ligand A (-9.9 kcal/mol) has a significantly stronger binding affinity than Ligand B (-0.0 kcal/mol). This is a substantial advantage.

**Overall Assessment:**

Ligand A is the stronger candidate. Its superior binding affinity, good TPSA, acceptable DILI, and excellent BBB penetration outweigh its moderate P-gp efflux and poor Caco-2 permeability and solubility. Ligand B suffers from a very low logP, poor BBB penetration, and a nonsensical negative in vitro half-life, making it a less viable candidate despite its lower P-gp efflux. The large difference in binding affinity is also a major factor.

Output:
1
2025-04-17 08:58:39,045 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (344.46 and 368.38 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (76.02) is excellent, well below the 90 A^2 threshold for CNS targets. Ligand B (118.87) is higher, but still potentially acceptable, though less ideal.

**logP:** Ligand A (2.12) is optimal (1-3). Ligand B (0.013) is very low, which could significantly hinder membrane permeability and CNS penetration.

**H-Bond Donors/Acceptors:** Both have 2 HBDs, which is good. Ligand A has 4 HBAs, and Ligand B has 7 HBAs. Both are within the acceptable range (<=10), but Ligand B is approaching the upper limit.

**QED:** Both ligands have reasonably good QED scores (0.744 and 0.655), indicating drug-like properties.

**DILI:** Ligand A (25.55) has a much lower DILI risk than Ligand B (44.13), which is a significant advantage.

**BBB:** Ligand A (56.03) is lower than desirable (>70) for a CNS target, but still reasonable. Ligand B (64.48) is also below the 70% threshold, but is slightly better than Ligand A.

**Caco-2 Permeability:** Both have negative Caco-2 values (-5.158 and -5.679), which is unusual and suggests poor permeability. This is a concern for both, but the negative values are similar.

**Aqueous Solubility:** Both have negative solubility values (-2.281 and -0.798), indicating poor aqueous solubility. This is a drawback for both compounds.

**hERG Inhibition:** Both ligands show very low hERG inhibition risk (0.122 and 0.018).

**Microsomal Clearance:** Both have similar, relatively low microsomal clearance values (13.26 and 12.58 mL/min/kg), suggesting reasonable metabolic stability.

**In vitro Half-Life:** Ligand B (17.44) has a significantly longer half-life compared to Ligand A (2.95), which is a positive attribute.

**P-gp Efflux:** Both have very low P-gp efflux liability (0.039 and 0.033), which is favorable for CNS penetration.

**Binding Affinity:** Ligand A (-8.4 kcal/mol) has a significantly stronger binding affinity than Ligand B (-7.1 kcal/mol). This 1.3 kcal/mol difference is substantial and can outweigh some ADME drawbacks.

**Overall Assessment:**

Ligand A is the stronger candidate. Despite having a lower BBB score than Ligand B, its significantly better logP, lower DILI risk, and *much* stronger binding affinity outweigh the slightly lower BBB. The poor Caco-2 and solubility are concerns for both, but can be addressed with formulation strategies. The superior affinity of Ligand A is crucial for a GPCR target, and the lower DILI risk is a major safety advantage.

Output:
1
2025-04-17 08:58:39,045 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (345.447 Da) is slightly lower, which could be advantageous for permeability. Ligand B (360.365 Da) is also good.

**TPSA:** Ligand A (70.47) is excellent, well below the 90 A^2 threshold for CNS targets. Ligand B (126.37) is higher, but still potentially acceptable, though less ideal.

**logP:** Ligand A (0.939) is at the lower end of the optimal range (1-3), potentially impacting permeability. Ligand B (-0.77) is below 1, which is a concern for membrane permeability.

**H-Bond Donors/Acceptors:** Ligand A (1 HBD, 5 HBA) is good. Ligand B (3 HBD, 7 HBA) is also acceptable, but slightly higher counts could impact permeability.

**QED:** Both ligands have reasonable QED values (A: 0.833, B: 0.586), indicating good drug-like properties.

**DILI:** Ligand A (16.285) has a significantly lower DILI risk than Ligand B (43.622), a major advantage.

**BBB:** Ligand A (91.043) has excellent BBB penetration, exceeding the desirable 70% threshold for CNS targets. Ligand B (64.986) is considerably lower, raising concerns about CNS exposure.

**Caco-2 Permeability:** Both have negative values, which is unusual and suggests a problem with the data or a very poor permeability.

**Aqueous Solubility:** Both have negative values, which is unusual and suggests a problem with the data or a very poor solubility.

**hERG:** Ligand A (0.549) has a lower hERG risk than Ligand B (0.089), which is preferable.

**Microsomal Clearance:** Ligand A (22.882) has a higher (worse) microsomal clearance than Ligand B (-6.604). This suggests Ligand B is more metabolically stable.

**In vitro Half-Life:** Ligand B (-12.275) has a negative half-life, which is impossible and indicates a data issue. Ligand A (17.193) is reasonable.

**P-gp Efflux:** Ligand A (0.08) has lower P-gp efflux liability than Ligand B (0.003), which is favorable for CNS penetration.

**Binding Affinity:** Ligand B (-8.6 kcal/mol) has a slightly better binding affinity than Ligand A (-7.8 kcal/mol), but the difference is not substantial enough to overcome the significant ADME deficiencies.

**Overall Assessment:**

Ligand A is the stronger candidate. While its logP is slightly low, its excellent BBB penetration, low DILI risk, favorable hERG profile, and reasonable metabolic stability outweigh the slightly weaker binding affinity. Ligand B has a better affinity, but its poor BBB penetration, higher DILI risk, and questionable half-life make it a less viable candidate. The negative values for Caco-2 and solubility are concerning for both, but the other issues with Ligand B are more critical.

Output:
1
2025-04-17 08:58:39,046 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (407.36 Da) is slightly higher than Ligand B (369.519 Da), but both are acceptable.

**2. TPSA:**  Both ligands have TPSA values that are a bit high for optimal CNS penetration (ideally <90). Ligand A (59.73) is higher than Ligand B (46.32). Ligand B is preferable here.

**3. logP:** Both ligands have logP values within the optimal range (1-3). Ligand A (3.759) and Ligand B (4.067) are both acceptable, but slightly on the higher end, potentially raising concerns about solubility and off-target effects.

**4. H-Bond Donors:** Both have 0 HBD, which is good.

**5. H-Bond Acceptors:** Ligand A has 6 HBA, and Ligand B has 7. Both are within the acceptable limit of <=10.

**6. QED:** Both ligands have acceptable QED scores (Ligand A: 0.73, Ligand B: 0.514), indicating reasonable drug-likeness.

**7. DILI:** Ligand A (29.74) has a significantly lower DILI risk than Ligand B (63.086). This is a substantial advantage for Ligand A.

**8. BBB:** Ligand A (85.072) has a much higher BBB percentile than Ligand B (68.864). This is a critical advantage for a CNS target like DRD2.

**9. Caco-2:** Both have negative Caco-2 values, which is unusual and problematic. It suggests poor permeability.

**10. Solubility:** Both have negative solubility values, which is also problematic.

**11. hERG:** Both ligands have low hERG inhibition liability (Ligand A: 0.484, Ligand B: 0.879), which is good.

**12. Cl_mic:** Ligand A (41.765) has lower microsomal clearance than Ligand B (50.288), suggesting better metabolic stability.

**13. t1/2:** Ligand A (17.701) has a longer in vitro half-life than Ligand B (6.813). This is a significant advantage.

**14. Pgp:** Both ligands have low Pgp efflux liability (Ligand A: 0.484, Ligand B: 0.709), which is good.

**15. Binding Affinity:** Ligand B (-7.9 kcal/mol) has a significantly stronger binding affinity than Ligand A (-6.7 kcal/mol). This is a substantial advantage, potentially outweighing some of the ADME drawbacks.

**Overall Assessment:**

While Ligand B has a superior binding affinity, Ligand A demonstrates a much more favorable ADME profile, particularly regarding BBB penetration (crucial for a CNS target), DILI risk, metabolic stability (Cl_mic and t1/2), and solubility. The difference in binding affinity (-7.9 vs -6.7) is significant, but the ADME advantages of Ligand A are compelling, especially considering the negative Caco-2 and solubility values for both. Given the GPCR-specific priorities, the improved CNS penetration and safety profile of Ligand A are more valuable.

Output:
0
2025-04-17 08:58:39,046 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (367.827 and 344.499 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (38.13) is better than Ligand B (40.62), both are below the 90 A^2 threshold for CNS targets.

**3. logP:** Ligand A (4.173) is slightly higher than the optimal range (1-3) but still acceptable. Ligand B (3.372) is within the optimal range.

**4. H-Bond Donors:** Both have 0 HBD, which is good.

**5. H-Bond Acceptors:** Ligand A has 3 HBA, and Ligand B has 2. Both are within the acceptable limit of 10.

**6. QED:** Both ligands have similar QED values (0.813 and 0.737), indicating good drug-likeness.

**7. DILI:** Ligand A (58.511) has a higher DILI risk than Ligand B (15.2). This is a significant drawback for Ligand A.

**8. BBB:** Both ligands have excellent BBB penetration (Ligand A: 89.492, Ligand B: 91.663), exceeding the desirable >70 threshold for CNS targets.

**9. Caco-2 Permeability:** Both have negative Caco-2 values (-4.336 and -4.644) which is unusual and suggests poor permeability. However, these values are on a scale where negative values are possible, and direct comparison is difficult without knowing the scale's specifics.

**10. Aqueous Solubility:** Both have negative solubility values (-4.793 and -3.21). Similar to Caco-2, this is unusual and requires caution.

**11. hERG Inhibition:** Both ligands show low hERG inhibition liability (0.707 and 0.444), which is favorable.

**12. Microsomal Clearance:** Ligand A (60.244) has a higher microsomal clearance than Ligand B (50.939), indicating lower metabolic stability.

**13. In vitro Half-Life:** Ligand B (2.232) has a longer half-life than Ligand A (0.519), which is preferable.

**14. P-gp Efflux:** Both ligands have low P-gp efflux liability (0.597 and 0.277), which is good for CNS exposure.

**15. Binding Affinity:** Both ligands have very similar and excellent binding affinities (-8.6 and -8.7 kcal/mol). The difference is negligible.

**Overall Assessment:**

Ligand B is the better candidate. While both ligands have excellent binding affinity and BBB penetration, Ligand B has a significantly lower DILI risk, better metabolic stability (lower Cl_mic, longer t1/2), and lower P-gp efflux. The slightly better logP and solubility of Ligand B are also favorable. The negative Caco-2 and solubility values are concerning for both, but the other advantages of Ligand B outweigh this concern.

Output:
1
2025-04-17 08:58:39,046 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (333.355 and 347.375 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (105.41) is better than Ligand B (133.14). For CNS targets, we want TPSA <= 90, so Ligand A is closer to this threshold.

**logP:** Ligand A (3.09) is optimal (1-3). Ligand B (0.753) is a bit low, potentially hindering permeation.

**H-Bond Donors/Acceptors:** Ligand A (HBD=2, HBA=7) and Ligand B (HBD=4, HBA=6) both have reasonable values within the suggested ranges.

**QED:** Both ligands have good QED scores (A: 0.578, B: 0.609), indicating drug-like properties.

**DILI:** Ligand B (71.307) has a lower DILI risk than Ligand A (86.39), which is preferable.

**BBB:** Ligand B (40.597) has a better BBB percentile than Ligand A (29.818), which is crucial for CNS targets. While both are below the desirable >70, B is significantly better.

**Caco-2 Permeability:** Both have negative values (-5.417 and -5.61), which is unusual. It's difficult to interpret without knowing the scale, but it suggests poor permeability.

**Aqueous Solubility:** Both have negative values (-3.709 and -2.58), again, difficult to interpret without the scale, but suggests poor solubility.

**hERG:** Both ligands have very low hERG inhibition liability (0.743 and 0.143), which is excellent.

**Microsomal Clearance:** Ligand B (11.883) has slightly lower clearance than Ligand A (13.92), suggesting better metabolic stability.

**In vitro Half-Life:** Both have negative half-lives (-15.561 and -16.28), which is impossible. This is likely an error in the data, and we cannot rely on this parameter.

**P-gp Efflux:** Ligand A (0.101) has lower P-gp efflux than Ligand B (0.036), which is favorable for CNS exposure.

**Binding Affinity:** Both ligands have excellent binding affinities (-9.2 and -8.2 kcal/mol). Ligand A is slightly better (-9.2 kcal/mol).

**Overall Assessment:**

Considering the GPCR-specific priorities, Ligand A has a better affinity and lower P-gp efflux. However, Ligand B has a much better BBB penetration, lower DILI risk, and slightly better metabolic stability. The lower logP of Ligand B is a concern, but the stronger BBB penetration and lower DILI risk are more important for a CNS target like DRD2. The affinity difference is not large enough to overcome these ADME advantages.

Output:
1
2025-04-17 08:58:39,046 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (366.845 Da) is slightly higher than Ligand B (337.387 Da), but both are acceptable.

**TPSA:** Ligand A (63.94) is significantly better than Ligand B (101.38). For CNS targets, we want TPSA <= 90, and Ligand A is comfortably within this range, while Ligand B exceeds it. This is a significant advantage for Ligand A.

**logP:** Ligand A (3.724) is good, within the optimal 1-3 range. Ligand B (1.432) is on the lower side, potentially hindering permeability.

**H-Bond Donors/Acceptors:** Ligand A (HBD=1, HBA=4) and Ligand B (HBD=2, HBA=6) both fall within acceptable limits (<=5 HBD and <=10 HBA).

**QED:** Both ligands have similar QED values (A: 0.773, B: 0.708), indicating good drug-likeness.

**DILI:** Ligand B (75.766) has a higher DILI risk than Ligand A (52.423). While both are not ideal, Ligand A is preferable.

**BBB:** Ligand A (69.252) has a better BBB percentile than Ligand B (57.193). While ideally >70 for CNS targets, Ligand A is closer to this threshold. This is a crucial advantage for a DRD2 ligand.

**Caco-2 Permeability:** Ligand A (-4.661) has a worse Caco-2 permeability than Ligand B (-5.637). Lower values indicate lower permeability.

**Aqueous Solubility:** Ligand A (-3.963) has a worse aqueous solubility than Ligand B (-2.765). Higher values indicate better solubility.

**hERG Inhibition:** Ligand A (0.686) has a slightly higher hERG risk than Ligand B (0.081). Ligand B is much better here.

**Microsomal Clearance:** Ligand A (77.061) has a higher microsomal clearance than Ligand B (27.188), indicating lower metabolic stability. Ligand B is significantly better.

**In vitro Half-Life:** Ligand A (77.801) has a better in vitro half-life than Ligand B (-27.131).

**P-gp Efflux:** Ligand A (0.375) has a lower P-gp efflux liability than Ligand B (0.095), which is favorable for CNS penetration.

**Binding Affinity:** Ligand B (-9.6 kcal/mol) has a significantly stronger binding affinity than Ligand A (-7.9 kcal/mol). This is a substantial advantage, potentially outweighing some of the ADME drawbacks. The difference is >1.5 kcal/mol.

**Overall Assessment:**

Ligand A excels in TPSA, BBB, and P-gp efflux, which are critical for CNS GPCR targets. However, its solubility and metabolic stability are concerning. Ligand B has a much stronger binding affinity, lower hERG risk, and better metabolic stability, but suffers from higher TPSA and lower BBB penetration.

Despite the superior binding affinity of Ligand B, the combination of a more favorable TPSA and BBB for Ligand A, coupled with acceptable (though not ideal) other parameters, makes it a slightly more promising starting point for optimization. The strong affinity of Ligand B is tempting, but the TPSA and BBB issues are significant hurdles for CNS penetration. Further optimization of Ligand A could address its solubility and metabolic stability, while retaining its favorable CNS properties.

Output:
0
2025-04-17 08:58:39,046 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (336.435 and 361.511 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (61.36) is better than Ligand B (73.2). For CNS targets, we want TPSA <= 90, both are within this range, but A is closer to the optimal value.

**logP:** Both ligands have good logP values (4.065 and 3.416), falling within the 1-3 range. Ligand B is slightly more optimal.

**H-Bond Donors/Acceptors:** Ligand A has 3 HBD and 2 HBA, while Ligand B has 1 HBD and 4 HBA. Both are within acceptable limits (<=5 HBD and <=10 HBA).

**QED:** Both ligands have good QED scores (0.774 and 0.844), indicating good drug-like properties.

**DILI:** Both ligands have similar and acceptable DILI risk (50.291 and 49.011, both <60).

**BBB:** Both ligands have similar BBB penetration (61.846 and 61.38). While not ideal (>70), they are comparable.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.126 and -4.851), which is unusual and suggests poor permeability. This is a significant concern.

**Aqueous Solubility:** Both ligands have negative solubility values (-4.447 and -3.772), indicating poor aqueous solubility. This is also a concern.

**hERG:** Both ligands have low hERG inhibition liability (0.715 and 0.676), which is good.

**Microsomal Clearance:** Ligand B (46.21) has lower microsomal clearance than Ligand A (58.233), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand B (22.45) has a longer half-life than Ligand A (13.802), which is preferable.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.33 and 0.327), which is good for CNS penetration.

**Binding Affinity:** Ligand A (-9.7 kcal/mol) has a significantly stronger binding affinity than Ligand B (-8.0 kcal/mol). This is a substantial advantage (1.7 kcal/mol difference).

**Overall Assessment:**

The most critical factor here is the binding affinity. Ligand A's significantly stronger binding affinity (-9.7 kcal/mol) is a major advantage that can potentially outweigh its slightly less favorable TPSA and metabolic stability. While both ligands have issues with Caco-2 permeability and solubility, the strong binding of Ligand A makes it a more promising starting point for optimization. The similar BBB values are not decisive. The slightly better metabolic stability and half-life of Ligand B are beneficial, but not enough to overcome the substantial affinity difference.

Output:
1
2025-04-17 08:58:39,046 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (350.419 and 352.435 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (113.44) is slightly above the optimal <90 for CNS targets, but still reasonable. Ligand B (82.19) is excellent, well below 90.

**logP:** Ligand A (0.059) is quite low, potentially hindering permeability. Ligand B (-0.379) is also low, but slightly better than A. Both are below the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A (3 HBD, 6 HBA) is within acceptable limits. Ligand B (1 HBD, 5 HBA) is also good.

**QED:** Both ligands have acceptable QED scores (0.641 and 0.521, respectively), indicating reasonable drug-likeness.

**DILI:** Ligand A (46.219) has a moderate DILI risk, but is acceptable. Ligand B (29.624) has a lower, and more favorable DILI risk.

**BBB:** Ligand A (43.156) has a low BBB penetration, which is a significant drawback for a CNS target like DRD2. Ligand B (37.573) is also low, but slightly better than A.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.96 and -4.743), which is unusual and suggests poor permeability. This is concerning.

**Aqueous Solubility:** Both ligands have negative solubility values (-1.323 and -0.663), indicating very poor aqueous solubility. This is a major issue for bioavailability.

**hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.079 and 0.088).

**Microsomal Clearance:** Ligand A (7.427) has a relatively low clearance, suggesting better metabolic stability. Ligand B (-16.844) has a *very* negative clearance, which is not physically possible and likely indicates an error in the data or a very unusual compound behavior.

**In vitro Half-Life:** Both ligands have similar, very long in vitro half-lives (-7.953 and -7.868). Again, the negative values are unusual.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.01 and 0.002), which is favorable for CNS penetration.

**Binding Affinity:** Both ligands have the same binding affinity (-7.8 kcal/mol), which is excellent.

**Overall Assessment:**

Despite the equal binding affinity, Ligand A and Ligand B both have significant issues. The negative Caco-2 and solubility values are red flags. However, considering the GPCR-specific priorities, BBB is crucial for DRD2. While both are low, Ligand B is slightly better. Ligand A has a better metabolic stability (lower Cl_mic), but the poor BBB penetration is a major concern. The negative clearance and half-life for Ligand B are suspect and raise concerns about data quality.

Given the slightly better BBB and lower DILI risk, and acknowledging the questionable Cl_mic value for Ligand B, I would cautiously select **Ligand A** as the more viable candidate, *pending further investigation into the solubility and permeability issues*. The equal binding affinity means these issues are the deciding factors.

Output:
0
2025-04-17 08:58:39,046 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (390.456 and 388.833 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (58.12) is excellent, well below the 90 Angstroms threshold for CNS targets. Ligand B (128.53) is higher, but still potentially acceptable, though less ideal.

**3. logP:** Ligand A (4.853) is slightly high, potentially leading to solubility issues or off-target effects. Ligand B (0.376) is quite low, which could hinder membrane permeability and CNS penetration.

**4. H-Bond Donors:** Ligand A (1) is good. Ligand B (3) is also acceptable, but slightly higher.

**5. H-Bond Acceptors:** Ligand A (5) is good. Ligand B (6) is also acceptable.

**6. QED:** Both ligands have reasonable QED values (0.812 and 0.679), indicating good drug-like properties.

**7. DILI:** Ligand A (68.98) has a moderate DILI risk. Ligand B (77.743) has a higher DILI risk.

**8. BBB:** This is a critical parameter for a CNS target like DRD2. Ligand A (94.843) has excellent BBB penetration potential. Ligand B (6.088) has very poor BBB penetration.

**9. Caco-2 Permeability:** Ligand A (-4.817) has poor Caco-2 permeability, which is concerning. Ligand B (-5.601) is also poor.

**10. Aqueous Solubility:** Ligand A (-4.872) has poor aqueous solubility. Ligand B (-2.58) is also poor.

**11. hERG Inhibition:** Both ligands have low hERG inhibition risk (0.779 and 0.227).

**12. Microsomal Clearance:** Ligand A (35.042) has moderate clearance. Ligand B (-8.577) has negative clearance, which is not physically possible and likely represents an error or extrapolation issue in the prediction. This is a significant red flag.

**13. In vitro Half-Life:** Ligand A (-7.844) has a negative half-life, which is not physically possible and likely represents an error or extrapolation issue in the prediction. Ligand B (-3.4) also has a negative half-life.

**14. P-gp Efflux:** Ligand A (0.581) has moderate P-gp efflux. Ligand B (0.079) has low P-gp efflux, which is favorable.

**15. Binding Affinity:** Both ligands have excellent binding affinity (-9.3 and -8.6 kcal/mol). The difference of 0.7 kcal/mol is not substantial enough to override other significant differences.

**Overall Assessment:**

Ligand A excels in BBB penetration and has acceptable TPSA, HBD, HBA, QED, and hERG. However, it suffers from poor Caco-2 permeability and solubility, and moderate DILI risk. The negative half-life is a major concern.

Ligand B has a lower logP and P-gp efflux, but its extremely poor BBB penetration is a deal-breaker for a CNS target. The higher DILI risk and negative clearance/half-life are also concerning.

Despite the issues with solubility and permeability, Ligand A is the more promising candidate due to its excellent BBB penetration, which is paramount for DRD2 targeting. The negative half-life is a serious issue that would need to be investigated and addressed through structural modifications, but it's a problem that *can* potentially be solved. The poor BBB penetration of Ligand B is a much more difficult hurdle to overcome.

Output:
1
2025-04-17 08:58:39,046 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (349.431 Da) is slightly better, being closer to the lower end which can aid permeability.

**TPSA:** Ligand A (75.01) is excellent for CNS penetration, well below the 90 A^2 threshold. Ligand B (87.3) is still reasonable, but less optimal.

**logP:** Ligand A (0.026) is very low, potentially hindering membrane permeability. Ligand B (2.155) is within the optimal range (1-3). This is a significant advantage for Ligand B.

**H-Bond Donors/Acceptors:** Ligand A (1 HBD, 5 HBA) and Ligand B (3 HBD, 3 HBA) both fall within acceptable limits.

**QED:** Ligand A (0.814) has a superior QED score, indicating better drug-likeness compared to Ligand B (0.608).

**DILI:** Ligand A (17.642) has a much lower DILI risk than Ligand B (24.234).

**BBB:** Ligand B (64.87) has a better BBB percentile than Ligand A (51.183), though both are below the desirable >70% for CNS targets.

**Caco-2 Permeability:** Ligand A (-4.615) has very poor Caco-2 permeability, while Ligand B (-5.606) is also poor, but slightly better.

**Aqueous Solubility:** Ligand A (-0.718) has slightly better solubility than Ligand B (-2.59).

**hERG:** Both ligands have low hERG inhibition liability (0.16 and 0.22 respectively).

**Microsomal Clearance:** Ligand A (4.115) has slightly lower microsomal clearance than Ligand B (3.82), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand B (26.194) has a significantly longer in vitro half-life than Ligand A (14.578).

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.024 and 0.043 respectively).

**Binding Affinity:** Ligand B (-9.2 kcal/mol) has a substantially stronger binding affinity than Ligand A (-7.5 kcal/mol). This is a very important factor, as a 1.7 kcal/mol difference is significant.

**Overall Assessment:**

Ligand B is the stronger candidate despite some drawbacks. The significantly improved binding affinity (-9.2 vs -7.5 kcal/mol) outweighs the slightly higher TPSA and DILI risk. The better logP value of Ligand B is crucial for permeability, addressing a major concern with Ligand A. While Ligand A has a better QED and slightly better solubility, the binding affinity and logP of Ligand B are more critical for a GPCR target in the CNS. The longer half-life of Ligand B is also a bonus.

Output:
1
2025-04-17 08:58:39,047 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (368.459 and 357.445 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (107.69) is higher than Ligand B (61.44). For CNS targets, TPSA should be <= 90. Ligand B is significantly better here.

**logP:** Ligand A (-0.537) is quite low, potentially hindering permeation. Ligand B (1.939) is within the optimal 1-3 range. This is a significant advantage for Ligand B.

**H-Bond Donors/Acceptors:** Ligand A has 3 HBD and 7 HBA, while Ligand B has 2 HBD and 3 HBA. Both are within acceptable limits.

**QED:** Both ligands have similar QED values (0.659 and 0.685), indicating good drug-likeness.

**DILI:** Ligand A (47.77) has a slightly higher DILI risk than Ligand B (24.661), but both are below the concerning threshold of 60.

**BBB:** Ligand B (83.249) has a much higher BBB penetration percentile than Ligand A (10.392). This is *critical* for a CNS target like DRD2.

**Caco-2 Permeability:** Both have negative values, which is unusual. Assuming these are percentile scores, Ligand B (-4.956) is slightly better than Ligand A (-5.54).

**Aqueous Solubility:** Both have negative values, indicating poor solubility. Ligand A (-1.744) is slightly better than Ligand B (-2.373).

**hERG Inhibition:** Ligand A (0.168) has a slightly lower hERG inhibition risk than Ligand B (0.539).

**Microsomal Clearance:** Ligand A (-2.062) has a lower (better) microsomal clearance than Ligand B (5.294), suggesting greater metabolic stability.

**In vitro Half-Life:** Ligand B (-13.165) has a significantly longer half-life than Ligand A (3.814).

**P-gp Efflux:** Ligand A (0.031) has a lower P-gp efflux liability than Ligand B (0.038), which is favorable for CNS penetration.

**Binding Affinity:** Ligand B (-8.3 kcal/mol) has a slightly better binding affinity than Ligand A (-7.4 kcal/mol). While both are good, the difference is substantial enough to be a key factor.

**Overall Assessment:**

Ligand B is the superior candidate. While Ligand A has slightly better metabolic stability and P-gp efflux, Ligand B excels in the most crucial areas for a CNS-targeting GPCR: BBB penetration, logP, and binding affinity. The significantly higher BBB value and optimal logP of Ligand B outweigh the minor advantages of Ligand A. The better affinity of Ligand B further solidifies its position.

Output:
1
2025-04-17 08:58:39,047 - INFO - Reasoning:

Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (364.48 & 373.48 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (58.64) is excellent, well below the 90 A^2 threshold for CNS targets. Ligand B (96.97) is higher, but still potentially acceptable, though less ideal.

**3. logP:** Ligand A (3.084) is optimal (1-3). Ligand B (-0.764) is significantly lower, which could hinder membrane permeability and CNS penetration.

**4. H-Bond Donors:** Ligand A (1) is good. Ligand B (2) is also acceptable.

**5. H-Bond Acceptors:** Ligand A (3) is good. Ligand B (6) is higher, but still within the acceptable range of <=10.

**6. QED:** Ligand A (0.648) is better, indicating a stronger drug-like profile than Ligand B (0.489).

**7. DILI:** Both ligands have low DILI risk (Ligand A: 30.4%, Ligand B: 27.0%), both well below the 40% threshold.

**8. BBB:** This is critical for a CNS target. Ligand A (85.5%) is very good, exceeding the 70% threshold. Ligand B (44.7%) is considerably lower and a significant concern.

**9. Caco-2 Permeability:** Ligand A (-4.31) is poor. Ligand B (-5.59) is also poor. Both values are negative, indicating low permeability.

**10. Aqueous Solubility:** Ligand A (-3.31) is poor. Ligand B (-2.05) is also poor.

**11. hERG Inhibition:** Both ligands show low hERG inhibition risk (Ligand A: 0.83, Ligand B: 0.21).

**12. Microsomal Clearance:** Ligand A (76.88) is relatively high, suggesting faster metabolism. Ligand B (9.52) is very low, indicating good metabolic stability.

**13. In vitro Half-Life:** Ligand A (17.69 hours) is reasonable. Ligand B (-1.60 hours) is extremely short, a major drawback.

**14. P-gp Efflux:** Ligand A (0.22) is low, suggesting minimal P-gp efflux. Ligand B (0.011) is even lower, indicating very little P-gp efflux.

**15. Binding Affinity:** Ligand B (-6.8 kcal/mol) is slightly better than Ligand A (-6.5 kcal/mol), but the difference is small.

**Overall Assessment:**

While Ligand B has slightly better binding affinity and metabolic stability, Ligand A is significantly better overall. The critical factors are the much higher BBB penetration (85.5% vs 44.7%) and the better QED score for Ligand A. The poor Caco-2 and solubility for both are concerns, but can potentially be addressed with formulation strategies. The very short half-life of Ligand B is a major issue. The lower logP of Ligand B is also a significant negative, hindering its ability to cross the blood-brain barrier. Given the GPCR-specific priorities, particularly BBB penetration for a CNS target, Ligand A is the more promising candidate.

Output:
1
2025-04-17 08:58:39,047 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (351.422 and 344.459 Da) fall within the ideal range of 200-500 Da.

**TPSA:** Ligand A (78.51) is better than Ligand B (58.44). Both are below the 90 A^2 threshold for CNS targets, but Ligand B is closer to optimal.

**logP:** Ligand A (0.756) is slightly lower than optimal (1-3), potentially hindering permeation. Ligand B (2.077) is within the optimal range.

**H-Bond Donors/Acceptors:** Ligand A has 2 HBD and 3 HBA, while Ligand B has 0 HBD and 4 HBA. Both are within acceptable limits.

**QED:** Both ligands have similar QED values (0.785 and 0.743), indicating good drug-likeness.

**DILI:** Ligand A (29.43) has a lower DILI risk than Ligand B (32.261), which is preferable.

**BBB:** Ligand A (76.037) has a significantly better BBB penetration percentile than Ligand B (69.174). This is a crucial factor for a CNS target like DRD2.

**Caco-2 Permeability:** Ligand A (-5.076) has worse Caco-2 permeability than Ligand B (-4.848).

**Aqueous Solubility:** Ligand A (-2.455) has worse solubility than Ligand B (-1.564).

**hERG:** Both ligands have very low hERG inhibition liability (0.198 and 0.222), which is excellent.

**Microsomal Clearance:** Ligand A (0.324) has significantly lower microsomal clearance than Ligand B (42.559), indicating better metabolic stability.

**In vitro Half-Life:** Ligand A (6.195) has a shorter half-life than Ligand B (-6.585).

**P-gp Efflux:** Ligand A (0.021) has much lower P-gp efflux liability than Ligand B (0.171), which is highly desirable for CNS penetration.

**Binding Affinity:** Ligand A (-9.2 kcal/mol) has a stronger binding affinity than Ligand B (-7.6 kcal/mol). The difference of 1.6 kcal/mol is substantial and can outweigh some ADME drawbacks.

**Overall Assessment:**

Ligand A excels in binding affinity, BBB penetration, metabolic stability (low Cl_mic), and P-gp efflux. While its logP is slightly suboptimal and Caco-2 permeability and solubility are lower, the strong affinity and excellent CNS penetration properties are paramount for a DRD2 ligand. Ligand B has a better logP and Caco-2 permeability, but its weaker affinity, lower BBB, and higher P-gp efflux are significant drawbacks.

Output:
1
2025-04-17 08:58:39,047 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (344.371 and 367.852 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (106.35) is better than Ligand B (69.22) as it is closer to the ideal range for CNS targets (<=90). Ligand B is quite low, which *could* indicate poor interactions.

**3. logP:** Ligand A (1.163) is within the optimal 1-3 range. Ligand B (3.426) is at the higher end of the optimal range, potentially increasing off-target effects.

**4. H-Bond Donors:** Both ligands have 2 HBD, which is within the acceptable limit of <=5.

**5. H-Bond Acceptors:** Ligand A has 6 HBA, and Ligand B has 3 HBA. Both are within the acceptable limit of <=10.

**6. QED:** Both ligands have good QED scores (0.661 and 0.751, respectively), indicating drug-like properties.

**7. DILI:** Ligand A (67.003) has a higher DILI risk than Ligand B (36.681). This is a significant drawback for Ligand A.

**8. BBB:** Ligand A (62.233) has a slightly better BBB percentile than Ligand B (50.523), but both are below the desirable >70 for CNS targets.

**9. Caco-2:** Both have negative Caco-2 values which is odd. Assuming these are logP values, both are very poor.

**10. Solubility:** Both have negative solubility values which is odd. Assuming these are logS values, both are very poor.

**11. hERG:** Ligand A (0.193) has a slightly better hERG profile than Ligand B (0.88), indicating lower cardiotoxicity risk.

**12. Cl_mic:** Both ligands have similar microsomal clearance values (44.08 and 44.34 mL/min/kg), suggesting comparable metabolic stability.

**13. t1/2:** Ligand A has a very negative in vitro half-life (-46.264), which is problematic. Ligand B (44.309) is reasonable.

**14. Pgp:** Ligand A (0.047) has much lower P-gp efflux liability than Ligand B (0.62), which is favorable for CNS penetration.

**15. Binding Affinity:** Ligand A (-8.1 kcal/mol) has significantly stronger binding affinity than Ligand B (-6.9 kcal/mol). This is a substantial advantage.

**Overall Assessment:**

Despite Ligand A's superior binding affinity and lower P-gp efflux, the combination of its higher DILI risk and *extremely* poor in vitro half-life are major concerns. Ligand B, while having a weaker affinity, presents a much more favorable safety (lower DILI) and pharmacokinetic (better half-life) profile. The BBB penetration for both is suboptimal, but Ligand B is better. Given the GPCR-specific priorities, and the importance of a reasonable ADME profile, Ligand B is the more promising candidate.

Output:
1
2025-04-17 08:58:39,047 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 drug candidates, considering the provided guidelines and GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (408.347 Da) is slightly higher than Ligand B (363.483 Da), but both are acceptable.

**TPSA:** Ligand A (55.84) is significantly better than Ligand B (75.44). For CNS targets, we want TPSA <= 90, and ideally lower. Ligand A is much closer to the ideal range.

**logP:** Both ligands have acceptable logP values (Ligand A: 3.973, Ligand B: 2.096), falling within the 1-3 optimal range. Ligand A is slightly higher, which could potentially lead to off-target effects, but is still reasonable.

**H-Bond Donors/Acceptors:** Ligand A (HBD=0, HBA=4) is better than Ligand B (HBD=1, HBA=5). Lower HBD/HBA generally improves permeability.

**QED:** Both ligands have reasonable QED values (Ligand A: 0.76, Ligand B: 0.593), indicating good drug-like properties. Ligand A is slightly better.

**DILI:** Ligand A (55.176) has a higher DILI risk than Ligand B (37.767). This is a concern for Ligand A, but not disqualifying at this stage.

**BBB:** Ligand B (66.615) has a significantly better BBB penetration percentile than Ligand A (53.742). For a CNS target like DRD2, BBB penetration is *critical*. This is a major advantage for Ligand B.

**Caco-2 Permeability:** Both are negative, indicating poor permeability. This is a concern for both.

**Aqueous Solubility:** Both are negative, indicating poor solubility. This is a concern for both.

**hERG:** Ligand A (0.763) has a slightly higher hERG risk than Ligand B (0.304), but both are relatively low.

**Microsomal Clearance:** Ligand B (52.149) has lower microsomal clearance than Ligand A (71.112), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand B (-13.053) has a negative half-life, which is not possible. This is a major red flag for Ligand B. Ligand A (1.266) has a short half-life, but at least it's a positive value.

**P-gp Efflux:** Ligand A (0.507) has better P-gp efflux properties than Ligand B (0.179). Lower P-gp efflux is preferred for CNS exposure.

**Binding Affinity:** Ligand B (-7.9 kcal/mol) has a *much* stronger binding affinity than Ligand A (-0.0 kcal/mol). This is a decisive advantage for Ligand B. A difference of >1.5 kcal/mol can outweigh other drawbacks.

**Overall Assessment:**

Despite Ligand B's negative half-life, its significantly superior binding affinity (-7.9 vs -0.0 kcal/mol) and better BBB penetration (66.6 vs 53.7) are crucial for a CNS GPCR target. The better metabolic stability (lower Cl_mic) and lower DILI risk are also positives. Ligand A's better TPSA is overshadowed by its poor affinity and BBB penetration. The negative half-life for ligand B is a serious concern, but could potentially be addressed through structural modifications. The affinity difference is so large that it is likely to be the dominant factor.

Output:
1
2025-04-17 08:58:39,047 - INFO - Batch 494 complete. Total preferences: 7904
2025-04-17 08:58:39,047 - INFO - Processing batch 495/512...
2025-04-17 08:59:21,888 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight (MW):** Both ligands (341.375 and 343.471 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (126.85) is borderline for CNS targets, exceeding the preferred <90, but still potentially acceptable. Ligand B (54.34) is excellent, well below the 90 threshold. This favors Ligand B.

**3. logP:** Both ligands have good logP values (2.439 and 2.823), falling within the optimal 1-3 range.

**4. H-Bond Donors (HBD):** Both ligands have acceptable HBD counts (2 and 1, respectively), well below the limit of 5.

**5. H-Bond Acceptors (HBA):** Both ligands have acceptable HBA counts (4 and 3, respectively), below the limit of 10.

**6. QED:** Both ligands have reasonable QED values (0.492 and 0.611), suggesting reasonable drug-likeness. Ligand B is slightly better.

**7. DILI:** Ligand A (61.574) has a higher DILI risk than Ligand B (41.605). This favors Ligand B.

**8. BBB:** Ligand B (67.352) has a significantly better BBB penetration percentile than Ligand A (56.65). This is a crucial advantage for a CNS target like DRD2.

**9. Caco-2 Permeability:** Ligand A (-5.155) has poor Caco-2 permeability, while Ligand B (-4.886) is also poor, but slightly better.

**10. Aqueous Solubility:** Both ligands have poor aqueous solubility (-4.049 and -2.75, respectively). This is a concern, but can be addressed with formulation strategies.

**11. hERG Inhibition:** Both ligands have low hERG inhibition risk (0.462 and 0.394, respectively).

**12. Microsomal Clearance:** Ligand B (45.738) has a higher microsomal clearance than Ligand A (14.788), suggesting lower metabolic stability. This favors Ligand A.

**13. In vitro Half-Life:** Ligand A (12.934) has a longer in vitro half-life than Ligand B (-5.107). This favors Ligand A.

**14. P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.013 and 0.375, respectively).

**15. Binding Affinity:** Both ligands have excellent binding affinities (-9 and -8.6 kcal/mol, respectively). Ligand A is slightly better, but the difference is not substantial.

**Overall Assessment:**

Ligand B is clearly superior due to its significantly better BBB penetration (67.352 vs 56.65) and lower DILI risk (41.605 vs 61.574), both critical for a CNS-targeting drug. While Ligand A has slightly better metabolic stability and half-life, the improved CNS penetration of Ligand B outweighs these advantages. The TPSA of Ligand B is also much more favorable.

Output:
1
2025-04-17 08:59:21,888 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B against the provided guidelines, prioritizing GPCR-specific properties (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (347.419 and 351.403 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (86.71) is slightly higher than Ligand B (82.89), but both are below the 90 A^2 threshold desirable for CNS targets.

**logP:** Ligand A (0.118) is quite low, potentially hindering permeability. Ligand B (0.914) is better, falling within the optimal 1-3 range. This is a significant advantage for Ligand B.

**H-Bond Donors/Acceptors:** Ligand A (0 HBD, 5 HBA) and Ligand B (0 HBD, 7 HBA) both have acceptable numbers of H-bond donors and acceptors.

**QED:** Both ligands have good QED scores (0.709 and 0.734, respectively), indicating drug-like properties.

**DILI:** Ligand B (40.713) has a lower DILI risk than Ligand A (55.758), which is preferable.

**BBB:** Ligand B (66.421) has a significantly better BBB penetration percentile than Ligand A (49.244). This is a crucial advantage for a CNS target like DRD2.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.762 and -4.676), which is unusual and suggests poor permeability. However, the scale isn't fully defined, so it's hard to interpret.

**Aqueous Solubility:** Ligand A (0.095) has very poor solubility, while Ligand B (-1.169) is also poor, but slightly better.

**hERG Inhibition:** Ligand A (0.032) has a slightly lower hERG risk than Ligand B (0.131), which is good.

**Microsomal Clearance:** Ligand B (-9.681) has a *negative* microsomal clearance, which is not physically possible. This is a major red flag and suggests an error in the data or a very unusual metabolic profile. Ligand A (20.241) has a reasonable clearance.

**In vitro Half-Life:** Ligand B (11.722 hours) has a much longer half-life than Ligand A (-0.547 hours). This is a significant advantage, *if* the clearance data is reliable.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.004 and 0.032), which is favorable for CNS penetration.

**Binding Affinity:** Ligand B (-7.5 kcal/mol) has a significantly stronger binding affinity than Ligand A (0.0 kcal/mol). This is a decisive advantage.

**Overall Assessment:**

Despite the poor Caco-2 and solubility values for both, Ligand B is the stronger candidate. Its superior BBB penetration, significantly better binding affinity, lower DILI risk, and longer half-life outweigh the slightly higher hERG risk. However, the negative microsomal clearance for Ligand B is a serious concern and needs to be investigated. It's likely an error, but if accurate, it would disqualify the compound. Assuming the clearance is an error, Ligand B is the better choice.

Output:
1
2025-04-17 08:59:21,888 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (354.451 Da) is slightly preferred as it's closer to the lower end, potentially aiding permeability.

**TPSA:** Ligand A (116.48) is much better than Ligand B (49.84). For CNS targets, TPSA should be <=90. Ligand A is closer to this threshold, suggesting better CNS penetration. Ligand B is significantly higher, which is a concern.

**logP:** Ligand A (-0.03) is suboptimal, being slightly below the ideal range of 1-3. Ligand B (4.887) is too high, potentially leading to solubility issues and off-target interactions.

**H-Bond Donors/Acceptors:** Ligand A (HBD=4, HBA=6) is slightly better than Ligand B (HBD=2, HBA=4) in terms of balancing solubility and permeability, though both are acceptable.

**QED:** Ligand A (0.549) has a better QED score than Ligand B (0.438), indicating a more drug-like profile.

**DILI:** Ligand A (20.163) has a significantly lower DILI risk than Ligand B (37.224), which is a substantial advantage.

**BBB:** Ligand B (83.288) has a much higher BBB percentile than Ligand A (19.426). This is a critical factor for CNS targets like DRD2.

**Caco-2 Permeability:** Both have negative values (-5.529 and -5.354), which is unusual and hard to interpret without knowing the scale. However, we can assume lower values indicate poorer permeability.

**Aqueous Solubility:** Both ligands have negative solubility values (-1.376 and -4.756), again unusual and suggesting poor solubility.

**hERG Inhibition:** Ligand A (0.134) has a lower hERG inhibition liability than Ligand B (0.948), which is preferable.

**Microsomal Clearance:** Ligand B (99.272) has a much higher microsomal clearance than Ligand A (27.372), indicating lower metabolic stability.

**In vitro Half-Life:** Ligand B (72.21) has a significantly longer in vitro half-life than Ligand A (-14.468), which is a positive attribute.

**P-gp Efflux:** Ligand A (0.02) has a much lower P-gp efflux liability than Ligand B (0.823), which is beneficial for CNS exposure.

**Binding Affinity:** Ligand B (-8.8 kcal/mol) has a stronger binding affinity than Ligand A (-6.9 kcal/mol). This is a significant advantage, potentially outweighing some of the ADME drawbacks. A 1.9 kcal/mol difference is substantial.

**Overall Assessment:**

Ligand B excels in BBB penetration and binding affinity, which are crucial for a CNS GPCR target. However, it suffers from high logP, high DILI risk, high P-gp efflux, and high microsomal clearance. Ligand A has better ADME properties (lower DILI, P-gp, Cl_mic, better TPSA and QED), but its BBB penetration and binding affinity are significantly weaker.

Given the importance of CNS penetration for DRD2 and the substantial affinity advantage of Ligand B, I believe **Ligand B** is the more promising candidate *despite* its ADME liabilities. The stronger binding affinity could potentially be optimized through further medicinal chemistry to improve the ADME profile, while it's harder to significantly improve affinity. The high BBB value is a major plus.

Output:
1
2025-04-17 08:59:21,888 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (359.451 and 348.403 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (63.69) is significantly better than Ligand B (92.7). For CNS targets, we want TPSA <= 90, so Ligand A is preferable.

**3. logP:** Both ligands have acceptable logP values (1.942 and 0.739), falling within the 1-3 range. Ligand A is slightly better.

**4. H-Bond Donors:** Ligand A (1) is better than Ligand B (0). While both are acceptable, a single donor can sometimes improve solubility.

**5. H-Bond Acceptors:** Both ligands have 6 HBA, which is within the acceptable limit of <=10.

**6. QED:** Both ligands have QED values (0.884 and 0.704) above 0.5, indicating good drug-like properties. Ligand A is slightly better.

**7. DILI:** Both ligands have relatively high DILI risk (68.476 and 60.876), but are still below the concerning threshold of 60. Ligand B is slightly better.

**8. BBB:** Ligand A (51.454) and Ligand B (55.913) both have BBB penetration percentiles below the desired 70 for CNS targets. However, Ligand A is slightly lower.

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.831 and -4.49), which is unusual and suggests poor permeability.

**10. Aqueous Solubility:** Both ligands have negative solubility values (-2.037 and -0.947), indicating very poor aqueous solubility.

**11. hERG Inhibition:** Both ligands have low hERG inhibition risk (0.403 and 0.085). Ligand B is better.

**12. Microsomal Clearance:** Ligand A (11.973) has a significantly lower (better) microsomal clearance than Ligand B (20.255), suggesting greater metabolic stability.

**13. In vitro Half-Life:** Ligand B (7.006) has a much longer half-life than Ligand A (1.934). This is a significant advantage.

**14. P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.086 and 0.031). Ligand B is slightly better.

**15. Binding Affinity:** Ligand A (-8.0) has a slightly better binding affinity than Ligand B (-7.8). While the difference is small (0.2 kcal/mol), it's still a factor.

**Overall Assessment:**

Considering the GPCR-specific priorities, TPSA is a key factor. Ligand A has a much more favorable TPSA (63.69 vs 92.7). While both have issues with solubility and Caco-2 permeability, the better TPSA, logP, QED, and slightly better affinity of Ligand A, coupled with its lower clearance, make it the more promising candidate. The longer half-life of Ligand B is attractive, but the higher TPSA is a significant drawback for a CNS target.

Output:
1
2025-04-17 08:59:21,888 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (348.531 and 354.447 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (58.2) is excellent, well below the 90 A^2 threshold for CNS targets. Ligand B (77.1) is still reasonable but less optimal.

**logP:** Ligand A (3.793) is within the optimal 1-3 range, while Ligand B (0.741) is slightly low, potentially hindering membrane permeability.

**H-Bond Donors/Acceptors:** Ligand A (2 HBD, 2 HBA) and Ligand B (1 HBD, 5 HBA) both have acceptable numbers of H-bond donors and acceptors.

**QED:** Both ligands have similar QED values (0.688 and 0.618), indicating good drug-like properties.

**DILI:** Ligand A (27.685) has a significantly lower DILI risk than Ligand B (12.214), which is a substantial advantage.

**BBB:** Both ligands show good BBB penetration (Ligand A: 71.539, Ligand B: 69.833), but Ligand A is slightly better.

**Caco-2 Permeability:** Both have negative Caco-2 values (-4.679 and -4.667), which is unusual and suggests poor permeability. This is a significant concern for both.

**Aqueous Solubility:** Both have negative solubility values (-4.778 and -0.722), indicating very poor aqueous solubility. This is a major drawback for both compounds.

**hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.351 and 0.324).

**Microsomal Clearance:** Ligand A (63.466) has higher microsomal clearance than Ligand B (10.182), suggesting lower metabolic stability.

**In vitro Half-Life:** Ligand B (-3.199) has a longer in vitro half-life than Ligand A (-1.624).

**P-gp Efflux:** Both ligands show no P-gp efflux liability (0.018 and 0.0).

**Binding Affinity:** Ligand A (0) has a slightly better binding affinity than Ligand B (0.237).

**Overall Assessment:**

Considering the GPCR-specific priorities, Ligand A is the more promising candidate. While both have poor solubility and Caco-2 permeability, Ligand A has a significantly lower DILI risk, better logP, and slightly better BBB penetration and binding affinity. The lower metabolic stability of Ligand A is a concern, but the improved safety profile and CNS penetration potential outweigh this drawback. The poor solubility and permeability of both compounds would need to be addressed through formulation or structural modifications.

Output:
1
2025-04-17 08:59:21,889 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (362.539 and 340.427 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (58.2) is excellent, well below the 90 A^2 threshold for CNS targets. Ligand B (67.23) is still acceptable, but less optimal.

**logP:** Ligand A (4.347) is slightly high, potentially leading to solubility issues or off-target interactions. Ligand B (1.812) is within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A (2 HBD, 3 HBA) and Ligand B (1 HBD, 4 HBA) both have reasonable numbers of H-bond donors and acceptors, well within the guidelines.

**QED:** Both ligands have good QED values (0.642 and 0.782), indicating generally drug-like properties.

**DILI:** Ligand A (34.277) has a lower DILI risk than Ligand B (43.117), both being acceptable.

**BBB:** Both ligands have good BBB penetration (69.523 and 66.886), but are slightly below the >70% desirable threshold.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.983 and -5.085), which is unusual and suggests poor permeability. This is a significant concern.

**Aqueous Solubility:** Both ligands have negative solubility values (-3.747 and -1.535), indicating very poor aqueous solubility. This is a major drawback.

**hERG Inhibition:** Both ligands show low hERG inhibition liability (0.411 and 0.252).

**Microsomal Clearance:** Ligand A (65.091) has higher microsomal clearance than Ligand B (43.371), suggesting lower metabolic stability.

**In vitro Half-Life:** Ligand B (29.316) has a slightly longer in vitro half-life than Ligand A (24.93).

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.303 and 0.123), which is favorable for CNS penetration.

**Binding Affinity:** Ligand B (-8.4 kcal/mol) has a significantly stronger binding affinity than Ligand A (-7.6 kcal/mol) - a difference of 0.8 kcal/mol. This is a substantial advantage.

**Overall Assessment:**

While both compounds suffer from poor solubility and permeability, Ligand B is the more promising candidate. Its superior binding affinity (-8.4 vs -7.6 kcal/mol) is a significant advantage, and it has better metabolic stability (lower Cl_mic) and a slightly longer half-life. The logP value is also more favorable for Ligand B. Although the BBB values are similar and below the ideal threshold, the stronger binding affinity of Ligand B could potentially compensate for this. The solubility and permeability issues would need to be addressed through formulation or structural modifications, but the starting point is better with Ligand B.

Output:
1
2025-04-17 08:59:21,889 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (353.47 & 365.86 Da) fall within the ideal 200-500 Da range.

**TPSA:** Both ligands (84.99 & 81.67) are below the 90 A^2 threshold for CNS targets, which is excellent.

**logP:** Ligand A (-0.297) is slightly low, potentially hindering permeation. Ligand B (1.151) is within the optimal 1-3 range. This favors Ligand B.

**H-Bond Donors/Acceptors:** Both have 2 HBD and 4 HBA, which are acceptable values.

**QED:** Both ligands have similar QED scores (0.711 and 0.706), indicating good drug-likeness.

**DILI:** Ligand A (14.97) has a significantly lower DILI risk than Ligand B (41.88), which is a substantial advantage.

**BBB:** Ligand A (60.53) has a moderate BBB penetration, while Ligand B (46.65) is lower. While both are below the desirable >70 for CNS targets, Ligand A is better.

**Caco-2 Permeability:** Both ligands have similar, very negative Caco-2 values (-5.232 and -5.206), suggesting poor intestinal absorption. This is a concern for both, but less critical for a CNS target where direct delivery is possible.

**Aqueous Solubility:** Both ligands have negative solubility values (-0.887 and -2.711), indicating poor aqueous solubility. Ligand B is worse.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.106 and 0.208).

**Microsomal Clearance:** Ligand A (-28.237) has a much lower (better) microsomal clearance than Ligand B (19.136), indicating greater metabolic stability.

**In vitro Half-Life:** Ligand A (-5.032) has a negative half-life, which is unusual and suggests very rapid metabolism or instability. Ligand B (25.685) has a reasonable half-life.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.001 and 0.066), which is favorable for CNS penetration.

**Binding Affinity:** Both ligands have very similar and strong binding affinities (-7.7 and -7.5 kcal/mol). The difference is minor.

**Overall Assessment:**

Ligand A excels in DILI risk and microsomal clearance, and has a slightly better BBB score. However, its negative in vitro half-life is a major concern. Ligand B has a better logP and a more reasonable half-life, but suffers from a higher DILI risk and lower BBB penetration.

Considering the GPCR-specific priorities, BBB is crucial. While neither is ideal, Ligand A is slightly better. The significantly lower DILI risk and better metabolic stability (lower Cl_mic) of Ligand A are also compelling. The negative half-life is a red flag, but could potentially be addressed with structural modifications. The slight advantage in binding affinity is negligible.

Output:
0
2025-04-17 08:59:21,889 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (357.479 and 358.511 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (53.51) is better than Ligand B (51.02). Both are reasonably low, but for a CNS target like DRD2, we ideally want TPSA < 90. Ligand A is closer to this threshold.

**3. logP:** Ligand A (2.02) is within the optimal 1-3 range. Ligand B (3.821) is pushing the upper limit, potentially leading to solubility issues and off-target interactions.

**4. H-Bond Donors:** Both ligands have 0 HBD, which is acceptable.

**5. H-Bond Acceptors:** Ligand A has 4 HBA, and Ligand B has 5. Both are within the acceptable limit of <=10.

**6. QED:** Both ligands have similar QED values (0.774 and 0.756), indicating good drug-likeness.

**7. DILI:** Ligand A (48.895) has a slightly better DILI risk profile than Ligand B (55.525), though both are reasonably good (<60).

**8. BBB:** This is a critical parameter for CNS targets. Ligand B (78.558) significantly outperforms Ligand A (59.597) in BBB penetration. A value >70 is desirable, and Ligand B is closer.

**9. Caco-2 Permeability:** Ligand A (-4.758) has poor Caco-2 permeability, suggesting poor intestinal absorption. Ligand B (-5.318) is also poor, but slightly better than A.

**10. Aqueous Solubility:** Both ligands have very poor aqueous solubility (-3.864 and -3.497 respectively). This is a concern, but can sometimes be mitigated with formulation strategies.

**11. hERG Inhibition:** Ligand A (0.284) shows a lower risk of hERG inhibition than Ligand B (0.44).

**12. Microsomal Clearance:** Ligand B (96.015) has a much higher microsomal clearance than Ligand A (50.757), indicating faster metabolism and potentially lower *in vivo* exposure.

**13. In vitro Half-Life:** Ligand A (-12.143) has a negative half-life, which is not physically possible and indicates an issue with the data or the model. Ligand B (3.127) has a short half-life, but is at least a plausible value.

**14. P-gp Efflux:** Ligand A (0.062) shows lower P-gp efflux than Ligand B (0.664), which is favorable for CNS penetration.

**15. Binding Affinity:** Ligand A (-8.0) has a significantly stronger binding affinity than Ligand B (-0.0). This is a major advantage. A difference of >1.5 kcal/mol is considered substantial.

**Overall Assessment:**

Ligand A has a much better binding affinity and lower P-gp efflux, which are crucial for CNS GPCR targets. However, its Caco-2 permeability is very poor, and the reported negative half-life is a red flag. Ligand B has better BBB penetration, but suffers from higher microsomal clearance, a weaker binding affinity, and higher P-gp efflux.

Despite the issues with Ligand A's half-life and permeability, the significantly stronger binding affinity (-8.0 kcal/mol vs -0.0 kcal/mol) is a major driver. The improved affinity could potentially overcome the permeability issues, and the negative half-life is likely an artifact of the prediction. The lower P-gp efflux also favors CNS exposure.

Output:
1
2025-04-17 08:59:21,889 - INFO - Reasoning:

Let's analyze Ligand A and Ligand B against the provided guidelines, prioritizing GPCR-specific properties (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (391.249 Da) is slightly higher than Ligand B (364.471 Da), but both are acceptable.

**TPSA:** Ligand A (105.32) is borderline for CNS targets (ideally <90), while Ligand B (65.98) is well within the desired range. This favors Ligand B.

**logP:** Ligand A (2.251) is optimal. Ligand B (0.675) is a bit low, potentially hindering membrane permeability. This favors Ligand A.

**H-Bond Donors/Acceptors:** Ligand A has 2 HBD and 6 HBA, while Ligand B has 0 HBD and 6 HBA. Both are within acceptable limits.

**QED:** Both ligands have good QED scores (A: 0.612, B: 0.769), indicating good drug-like properties. Ligand B is slightly better.

**DILI:** Ligand A (90.461) has a higher DILI risk than Ligand B (28.383). This strongly favors Ligand B.

**BBB:** Ligand A (33.695) has a poor BBB penetration prediction, which is a major drawback for a CNS target. Ligand B (76.851) shows good predicted BBB penetration. This is a critical advantage for Ligand B.

**Caco-2 Permeability:** Both have negative Caco-2 values (-5.041 and -5.036), which is unusual and suggests poor permeability. However, these values are very close, and the scale isn't defined, making it hard to interpret.

**Aqueous Solubility:** Both ligands have very poor predicted aqueous solubility (-3.434 and -1.121). This could pose formulation challenges.

**hERG Inhibition:** Both ligands show low hERG inhibition risk (0.125 and 0.255).

**Microsomal Clearance:** Ligand A (58.171) has higher predicted clearance than Ligand B (-5.314), suggesting lower metabolic stability. This favors Ligand B.

**In vitro Half-Life:** Ligand A (-43.218) has a very short predicted half-life, while Ligand B (1.776) is slightly better, but still short.

**P-gp Efflux:** Both have low P-gp efflux liability (0.05 and 0.044).

**Binding Affinity:** Ligand A (-9.3 kcal/mol) has a significantly stronger binding affinity than Ligand B (-8.2 kcal/mol). This is a substantial advantage for Ligand A. The 1.1 kcal/mol difference is large enough to potentially offset some ADME liabilities.

**Overall Assessment:**

While Ligand A has superior binding affinity, its poor BBB penetration, high DILI risk, and high microsomal clearance are major concerns for CNS drug development. Ligand B, despite slightly weaker affinity, exhibits a much more favorable ADME profile, particularly its good BBB penetration, low DILI risk, and improved metabolic stability. For a GPCR targeting the CNS, BBB penetration is paramount. The binding affinity difference, while significant, might be overcome with further optimization of Ligand B.

Output:
1
2025-04-17 08:59:21,889 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (376.86 and 351.45 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (78.87) is excellent, well below the 90 A^2 threshold for CNS targets. Ligand B (91.56) is slightly higher but still acceptable, though less optimal.

**logP:** Both ligands have good logP values (0.848 and 0.94), falling within the 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A (2 HBD, 4 HBA) and Ligand B (1 HBD, 6 HBA) both have reasonable numbers of H-bond donors and acceptors, well within the guidelines.

**QED:** Both ligands have good QED scores (0.674 and 0.823), indicating good drug-like properties.

**DILI:** Ligand A (20.78) has a significantly lower DILI risk than Ligand B (55.99). This is a substantial advantage.

**BBB:** Ligand A (81.82) has a much higher BBB penetration percentile than Ligand B (41.22). This is *critical* for a CNS target like DRD2.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.927 and -4.715), which is unusual and suggests poor permeability. However, these values are on a scale where negative values are possible, and the absolute difference is small.

**Aqueous Solubility:** Both ligands have negative solubility values (-1.623 and -2.171) which suggests poor solubility.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.325 and 0.273).

**Microsomal Clearance:** Ligand A (-16.43) has a much lower (better) microsomal clearance than Ligand B (45.12). This suggests better metabolic stability for Ligand A.

**In vitro Half-Life:** Ligand A (5.29 hours) has a shorter half-life than Ligand B (-13.35 hours). However, the negative value for Ligand B is concerning and likely indicates an issue with the data.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.057 and 0.134).

**Binding Affinity:** Both ligands have comparable binding affinities (-8.0 and -7.8 kcal/mol). The difference is less than 1.5 kcal/mol, so it's not a deciding factor.

**Conclusion:**

Considering the GPCR-specific priorities, Ligand A is the far superior candidate. Its significantly better BBB penetration, lower DILI risk, and lower microsomal clearance outweigh the slightly shorter half-life and similar binding affinity. The negative Caco-2 and solubility values are concerning for both, but the other advantages of Ligand A are more impactful for a CNS-targeted GPCR.

Output:
1
2025-04-17 08:59:21,889 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (346.43) is slightly better positioned.

**TPSA:** Ligand A (62.99) is excellent for CNS penetration, well below the 90 A^2 threshold. Ligand B (130.67) is higher, but still potentially acceptable, though less ideal.

**logP:** Ligand A (2.084) is optimal. Ligand B (-0.537) is quite low, potentially hindering membrane permeability and CNS entry.

**H-Bond Donors/Acceptors:** Ligand A (0 HBD, 4 HBA) is favorable. Ligand B (3 HBD, 6 HBA) is also acceptable, but slightly higher counts could impact permeability.

**QED:** Both ligands have reasonable QED scores (A: 0.841, B: 0.522), indicating good drug-like properties.

**DILI:** Ligand A (26.522) has a much lower DILI risk than Ligand B (52.734).

**BBB:** Ligand A (78.829) has a significantly better BBB percentile than Ligand B (67.158). This is a critical advantage for a CNS target like DRD2.

**Caco-2 Permeability:** Ligand A (-4.486) is unfavorable. Ligand B (-5.411) is also unfavorable, but slightly worse.

**Aqueous Solubility:** Both ligands have negative solubility values, indicating poor solubility. Ligand A (-2.252) is slightly better than Ligand B (-1.515).

**hERG Inhibition:** Both ligands have low hERG inhibition risk (A: 0.507, B: 0.055). Ligand B is negligibly better.

**Microsomal Clearance:** Ligand A (24.496) has a higher (worse) microsomal clearance than Ligand B (3.808), suggesting lower metabolic stability.

**In vitro Half-Life:** Ligand A (42.179) has a longer half-life than Ligand B (5.191).

**P-gp Efflux:** Ligand A (0.272) has lower P-gp efflux liability than Ligand B (0.027), meaning it's less likely to be pumped out of the brain.

**Binding Affinity:** Ligand A (-8.4 kcal/mol) has a significantly stronger binding affinity than Ligand B (-7.3 kcal/mol). This 1.1 kcal/mol difference is substantial and can outweigh some ADME drawbacks.

**Overall Assessment:**

Ligand A is the superior candidate. While it has some drawbacks (Caco-2 permeability, moderate clearance), its significantly better BBB penetration, lower DILI risk, substantially stronger binding affinity, and favorable logP and TPSA values outweigh these concerns. Ligand B's low logP is a major issue, likely hindering its ability to cross the blood-brain barrier effectively. The affinity difference is also critical.

Output:
1
2025-04-17 08:59:21,889 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (337.379 and 348.531 Da) are within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (86.45) is better than Ligand B (40.62). Both are below the 90 A^2 threshold for CNS targets, but Ligand B is significantly lower, which is favorable for brain penetration.

**3. logP:** Both ligands have acceptable logP values (2.59 and 3.841), falling within the 1-3 range. Ligand B is slightly higher, potentially leading to some solubility concerns, but still within an acceptable range.

**4. H-Bond Donors:** Ligand A has 1 HBD, while Ligand B has 0. Both are within the acceptable limit of <=5.

**5. H-Bond Acceptors:** Ligand A has 5 HBA, and Ligand B has 2. Both are within the acceptable limit of <=10.

**6. QED:** Both ligands have good QED scores (0.926 and 0.732), indicating good drug-like properties.

**7. DILI:** Ligand A (50.33) has a higher DILI risk than Ligand B (26.173). This is a significant advantage for Ligand B.

**8. BBB:** Ligand B (92.71) has a much higher BBB penetration percentile than Ligand A (46.84). This is *critical* for a CNS target like DRD2, making Ligand B strongly favored.

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.57 and -4.641). This is unusual and suggests poor permeability. However, the values are very similar.

**10. Aqueous Solubility:** Both ligands have negative solubility values (-3.398 and -4.011). This is also concerning, indicating poor aqueous solubility. Again, the values are comparable.

**11. hERG Inhibition:** Both ligands have low hERG inhibition risk (0.718 and 0.524).

**12. Microsomal Clearance:** Ligand A (-5.222) has a *much* lower (better) microsomal clearance than Ligand B (88.465). This suggests better metabolic stability for Ligand A.

**13. In vitro Half-Life:** Ligand A (3.005) has a shorter half-life than Ligand B (28.073). This favors Ligand B.

**14. P-gp Efflux:** Ligand A (0.165) has lower P-gp efflux than Ligand B (0.469), which is favorable for CNS exposure.

**15. Binding Affinity:** Ligand A (-8.9 kcal/mol) has a significantly stronger binding affinity than Ligand B (-7.4 kcal/mol). This is a substantial advantage for Ligand A, potentially outweighing some of its ADME drawbacks.

**Overall Assessment:**

While Ligand A has superior binding affinity and metabolic stability, Ligand B excels in crucial properties for a CNS-targeting GPCR: BBB penetration and lower DILI risk. The difference in binding affinity (1.5 kcal/mol) is significant, but the substantial improvement in BBB (92.71 vs 46.84) and the lower DILI risk of Ligand B are more critical for a CNS drug. The similar poor solubility and permeability are drawbacks for both, but can potentially be addressed with formulation strategies.

Output:
1
2025-04-17 08:59:21,889 - INFO - Reasoning:

Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (391.153 Da) is slightly higher than Ligand B (358.427 Da), but both are acceptable.

**TPSA:** Ligand A (72.83) is excellent for CNS penetration, falling well below the 90 A^2 threshold. Ligand B (84.22) is still reasonable but less optimal.

**logP:** Ligand A (4.121) is a bit high, potentially leading to solubility issues and off-target effects. Ligand B (0.802) is quite low, which could hinder membrane permeability and CNS entry.

**H-Bond Donors/Acceptors:** Ligand A has 1 HBD and 5 HBA, which is good. Ligand B has 0 HBD and 7 HBA, also acceptable.

**QED:** Both ligands have similar QED values (0.794 and 0.758), indicating good drug-likeness.

**DILI:** Ligand A (83.676) has a higher DILI risk than Ligand B (72.043), which is less desirable.

**BBB:** Ligand B (74.098) has a significantly better BBB percentile than Ligand A (34.509). This is a *critical* advantage for a CNS target like DRD2.

**Caco-2 Permeability:** Ligand A (-4.357) shows poor permeability, while Ligand B (-5.16) is also poor, but slightly better.

**Aqueous Solubility:** Ligand A (-6.01) has very poor solubility, a major concern. Ligand B (-2.353) is also poor, but better than A.

**hERG Inhibition:** Both ligands show low hERG inhibition risk (0.47 and 0.144).

**Microsomal Clearance:** Ligand A (110.853) has higher clearance than Ligand B (39.367), indicating lower metabolic stability.

**In vitro Half-Life:** Ligand B (-11.757) has a negative half-life, which is not possible. This is likely an error in the data. Ligand A (37.645) has a reasonable half-life.

**P-gp Efflux:** Ligand A (0.283) has lower P-gp efflux liability than Ligand B (0.2), which is favorable for CNS penetration.

**Binding Affinity:** Ligand A (-9.6 kcal/mol) has a significantly stronger binding affinity than Ligand B (-8.5 kcal/mol). This is a substantial advantage, potentially outweighing some of its ADME drawbacks.

**Overall Assessment:**

Despite Ligand A's superior binding affinity, its poor solubility, low BBB penetration, and higher DILI risk are major concerns. Ligand B, while having a weaker affinity, exhibits a much more favorable ADME profile, especially its significantly better BBB penetration and lower DILI risk. For a CNS target like DRD2, achieving sufficient brain exposure is paramount. The difference in binding affinity (1.1 kcal/mol) might be overcome with further optimization of Ligand B, while fixing Ligand A's solubility and BBB issues would be far more challenging.

Output:
1
2025-04-17 08:59:21,890 - INFO - Reasoning:

Let's analyze Ligand A and Ligand B based on the provided guidelines, prioritizing GPCR-specific properties (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (347.411 and 351.407 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (76.07) is significantly better than Ligand B (133.26). For CNS targets, we want TPSA <= 90, and A is comfortably within that range, while B is approaching the upper limit and could present permeability challenges.

**logP:** Both ligands have acceptable logP values (2.447 and 1.572), falling within the 1-3 range. Ligand A is slightly higher, which is generally favorable for membrane permeability.

**H-Bond Donors/Acceptors:** Ligand A (HBD=1, HBA=4) is better than Ligand B (HBD=2, HBA=5). Both are within acceptable limits, but fewer H-bonds generally improve permeability.

**QED:** Ligand A (0.885) has a much higher QED score than Ligand B (0.312), indicating a more drug-like profile.

**DILI:** Ligand A (41.179) has a slightly higher DILI risk than Ligand B (34.82), but both are below the concerning threshold of 60.

**BBB:** Ligand A (61.535) has a better BBB percentile than Ligand B (48.391). While both are not ideal (>70 desired), A is closer. This is a critical factor for a CNS target like DRD2.

**Caco-2 Permeability:** Both have negative Caco-2 values (-4.578 and -4.962), which is unusual and suggests poor permeability. This is a significant concern for both.

**Aqueous Solubility:** Both have negative solubility values (-1.993 and -1.653), also unusual and indicating very low solubility. This is a significant concern for both.

**hERG Inhibition:** Both ligands have very low hERG inhibition liability (0.012 and 0.075), which is excellent.

**Microsomal Clearance:** Ligand A (13.997) has a lower microsomal clearance than Ligand B (45.03), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (-9.436) has a longer in vitro half-life than Ligand B (-16.643), which is favorable.

**P-gp Efflux:** Both ligands exhibit very low P-gp efflux liability (0.012 and 0.014), which is good.

**Binding Affinity:** Ligand A (-8.5 kcal/mol) has a slightly better binding affinity than Ligand B (-7.7 kcal/mol). While both are good (<-7.0), the difference is noticeable.

**Overall Assessment:**

Ligand A is the superior candidate. It excels in key GPCR properties like TPSA, BBB, QED, metabolic stability (Cl_mic and t1/2), and binding affinity. While both ligands have issues with Caco-2 permeability and aqueous solubility, Ligand A's better overall profile, particularly its superior BBB penetration and drug-likeness, makes it more likely to succeed as a DRD2 drug candidate. The slightly better affinity is a bonus.



Output:
0
2025-04-17 08:59:21,890 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B based on the provided guidelines, prioritizing GPCR-specific properties (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (350.463 and 370.513 Da) fall within the ideal range of 200-500 Da.

**TPSA:** Ligand A (85.25) is significantly better than Ligand B (49.84), falling comfortably below the 90 A^2 threshold for CNS targets. Ligand B is also good, but A is preferable.

**logP:** Ligand A (1.589) is within the optimal range (1-3), while Ligand B (4.576) is slightly high, potentially leading to solubility issues and off-target interactions.

**H-Bond Donors/Acceptors:** Both ligands have 2 HBD and 5 HBA, which are within acceptable limits.

**QED:** Both ligands have similar QED values (0.745 and 0.702), indicating good drug-likeness.

**DILI:** Both ligands have acceptable DILI risk (36.681 and 40.83), below the 40 threshold.

**BBB:** Ligand B (89.686) has a substantially better BBB penetration percentile than Ligand A (70.027). This is a critical advantage for a CNS target like DRD2.

**Caco-2 Permeability:** Ligand A (-4.583) and Ligand B (-4.971) both have negative values, which is unusual and suggests poor permeability. However, the scale isn't specified, so it's hard to interpret.

**Aqueous Solubility:** Ligand A (-2.355) has better solubility than Ligand B (-4.937).

**hERG Inhibition:** Ligand A (0.329) has a lower hERG inhibition liability than Ligand B (0.833), indicating a lower risk of cardiotoxicity.

**Microsomal Clearance:** Ligand B (71.047) has higher microsomal clearance than Ligand A (39.732), suggesting lower metabolic stability.

**In vitro Half-Life:** Ligand B (53.726) has a longer in vitro half-life than Ligand A (-14.887). This is a significant advantage.

**P-gp Efflux:** Ligand A (0.057) has lower P-gp efflux liability than Ligand B (0.592), which is desirable for CNS penetration.

**Binding Affinity:** Ligand B (-8.3 kcal/mol) has a slightly better binding affinity than Ligand A (-7.7 kcal/mol). The difference is 0.6 kcal/mol, which is significant but not overwhelming.

**Overall Assessment:**

Ligand B excels in BBB penetration and in vitro half-life, which are crucial for CNS drug development. Its binding affinity is also slightly better. However, it suffers from a higher logP, potentially leading to solubility issues, and higher P-gp efflux. Ligand A has better TPSA, solubility, lower hERG risk, and lower P-gp efflux.

Considering the GPCR-specific priorities, the superior BBB penetration of Ligand B is a major advantage that outweighs its slightly higher logP and P-gp efflux. The better half-life also contributes to its favorability.

Output:
1
2025-04-17 08:59:21,890 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (427.364 Da) is higher, but still acceptable. Ligand B (350.383 Da) is slightly better.

**TPSA:** Ligand A (61.8) is excellent for CNS penetration, well below the 90 A^2 threshold. Ligand B (139.85) is approaching the upper limit for good oral absorption (140 A^2) and is less ideal for CNS targets.

**logP:** Ligand A (3.511) is within the optimal range (1-3). Ligand B (-1.734) is significantly below this, potentially hindering membrane permeability and CNS penetration.

**H-Bond Donors/Acceptors:** Ligand A (HBD=2, HBA=5) is good. Ligand B (HBD=3, HBA=9) is acceptable, but the higher HBA count could slightly impact permeability.

**QED:** Ligand A (0.767) has a strong drug-like profile. Ligand B (0.488) is lower, suggesting a less favorable overall drug-likeness.

**DILI:** Ligand A (41.877) has a lower DILI risk than Ligand B (64.521), indicating a better safety profile.

**BBB:** Ligand A (81.311) shows excellent BBB penetration potential. Ligand B (19.93) is very poor, a major drawback for a CNS target like DRD2.

**Caco-2 Permeability:** Ligand A (-5.038) is negative, which is unusual and suggests very poor permeability. Ligand B (-5.924) is also negative and similarly poor. This is concerning for both.

**Aqueous Solubility:** Both ligands have negative solubility values (-3.219 and -0.97), which is also unusual and suggests very poor solubility.

**hERG Inhibition:** Ligand A (0.929) has a low hERG risk. Ligand B (0.031) has a very low hERG risk, which is good.

**Microsomal Clearance:** Ligand A (41.084) has moderate clearance. Ligand B (3.694) has very low clearance, suggesting good metabolic stability.

**In vitro Half-Life:** Ligand A (41.405) has a moderate half-life. Ligand B (17.636) has a shorter half-life.

**P-gp Efflux:** Ligand A (0.737) has moderate P-gp efflux. Ligand B (0.021) has very low P-gp efflux, which is highly desirable for CNS penetration.

**Binding Affinity:** Both ligands have strong binding affinities (-7.7 and -7.5 kcal/mol). The difference of 0.2 kcal/mol is not substantial enough to outweigh other significant differences.

**Conclusion:**

Considering the GPCR-specific priorities, Ligand A is the better candidate despite the negative Caco-2 and solubility values. Its superior BBB penetration (81.311 vs 19.93), better logP (3.511 vs -1.734), and lower DILI risk are crucial for a CNS-targeting drug. While Ligand B has better metabolic stability and lower P-gp efflux, the extremely poor BBB penetration is a deal-breaker for DRD2. The negative Caco-2 and solubility values are concerning for both, but can potentially be addressed with formulation strategies.



Output:
0
2025-04-17 08:59:21,890 - INFO - Batch 495 complete. Total preferences: 7920
2025-04-17 08:59:21,890 - INFO - Processing batch 496/512...
2025-04-17 09:00:04,240 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (362.407 and 364.511 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (94.59) is higher than the preferred <90 for CNS targets, but not drastically so. Ligand B (58.64) is well within the desired range. This favors Ligand B.

**3. logP:** Ligand A (1.673) and Ligand B (2.84) are both within the optimal 1-3 range. Ligand B is slightly better positioned.

**4. H-Bond Donors:** Both ligands have 1 HBD, which is acceptable (<=5).

**5. H-Bond Acceptors:** Ligand A has 6 HBA, and Ligand B has 4. Both are below the acceptable limit of 10.

**6. QED:** Both ligands have similar QED values (0.869 and 0.874), indicating good drug-like properties.

**7. DILI:** Ligand A has a DILI risk of 88.639, which is high. Ligand B has a much lower DILI risk of 26.406, which is excellent. This is a significant advantage for Ligand B.

**8. BBB:** Ligand A has a BBB penetration of 40.713, which is below the desirable >70 for CNS targets. Ligand B has a BBB penetration of 75.107, which is very good. This strongly favors Ligand B.

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.014 and -4.903), which is unusual and suggests poor permeability. However, these values are on a somewhat arbitrary scale and may not be directly comparable.

**10. Aqueous Solubility:** Both ligands have negative solubility values (-3.098 and -3.135), also unusual and suggesting poor solubility. Similar to Caco-2, these values are difficult to interpret directly.

**11. hERG Inhibition:** Ligand A (0.042) has a very low hERG risk, which is excellent. Ligand B (0.576) has a slightly elevated hERG risk, but still relatively low.

**12. Microsomal Clearance:** Ligand A (-7.612) has a negative clearance, which is not physically possible and likely indicates a very stable compound. Ligand B (30.027) has a moderate clearance. While negative clearance is ideal, it's suspect.

**13. In vitro Half-Life:** Both ligands have similar in vitro half-lives (11.94 and 11.478 hours).

**14. P-gp Efflux:** Ligand A (0.058) has very low P-gp efflux, which is excellent for CNS penetration. Ligand B (0.383) has a slightly higher, but still relatively low, P-gp efflux.

**15. Binding Affinity:** Ligand B (-8.1 kcal/mol) has a slightly better binding affinity than Ligand A (-9.7 kcal/mol). While both are excellent, the difference is notable.

**Overall Assessment:**

Ligand B is the superior candidate. While Ligand A has a slightly better binding affinity and lower hERG risk, Ligand B significantly outperforms it in crucial areas for a CNS-targeting GPCR ligand: lower DILI risk, much better BBB penetration, and a more favorable TPSA. The slightly better logP of Ligand B is also a plus. The negative values for Caco-2 and solubility are concerning for both, but the other advantages of Ligand B outweigh these issues. The negative clearance for Ligand A is also a red flag.

Output:
1
2025-04-17 09:00:04,241 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (432.34 Da) is slightly higher, but acceptable. Ligand B (364.471 Da) is also good.

**TPSA:** Both ligands are close to the upper limit for CNS targets (90-140 A^2). Ligand A (95.58 A^2) is better than Ligand B (96.6 A^2), but both are reasonably close.

**logP:** Both ligands have optimal logP values (1-3). Ligand A (1.626) and Ligand B (1.108) are both good, with Ligand A being slightly more favorable.

**H-Bond Donors/Acceptors:** Ligand A (2 HBD, 4 HBA) and Ligand B (1 HBD, 5 HBA) both fall within acceptable ranges (<=5 HBD, <=10 HBA).

**QED:** Both ligands have good QED scores (>0.5). Ligand A (0.707) and Ligand B (0.865) are both highly drug-like.

**DILI:** Ligand A (59.48) has a higher DILI risk than Ligand B (41.411), but both are below the concerning threshold of 60.

**BBB:** This is a crucial parameter for CNS targets. Ligand A (74.176) has a significantly better BBB percentile than Ligand B (56.378). This is a major advantage for Ligand A.

**Caco-2 Permeability:** Both have negative values, indicating poor permeability. Ligand A (-4.979) is slightly better than Ligand B (-5.14).

**Aqueous Solubility:** Both have negative values, indicating poor solubility. Ligand A (-3.689) is slightly better than Ligand B (-1.82).

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.468 and 0.139 respectively). Ligand B is slightly better.

**Microsomal Clearance:** Ligand B (-12.528) has a lower (better) microsomal clearance than Ligand A (24.221), suggesting greater metabolic stability.

**In vitro Half-Life:** Ligand B (-6.045) has a longer half-life than Ligand A (-44.66), which is a significant advantage.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.077 and 0.034 respectively). Ligand B is slightly better.

**Binding Affinity:** Ligand B (-8.0 kcal/mol) has a slightly better binding affinity than Ligand A (-7.7 kcal/mol). However, the difference is relatively small.

**Overall Assessment:**

Ligand A excels in BBB penetration, which is paramount for a CNS target like DRD2. While Ligand B has slightly better metabolic stability (lower Cl_mic, longer t1/2), slightly better affinity, and lower P-gp efflux, the substantial difference in BBB penetration (74.18% vs 56.38%) outweighs these minor advantages. The slightly higher DILI risk for Ligand A is not a major concern given that it's still below the 60% threshold.

Output:
1
2025-04-17 09:00:04,241 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (346.519 and 344.499 Da) fall comfortably within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (48.47) is better than Ligand B (40.62). Both are below the 90 A^2 threshold for CNS targets, which is excellent.

**3. logP:** Both ligands have good logP values (3.265 and 3.537), falling within the optimal 1-3 range.

**4. H-Bond Donors:** Ligand A has 1 HBD, and Ligand B has 0. Both are within the acceptable limit of <=5.

**5. H-Bond Acceptors:** Ligand A has 3 HBA, and Ligand B has 2. Both are within the acceptable limit of <=10.

**6. QED:** Both ligands have similar QED values (0.707 and 0.735), indicating good drug-likeness.

**7. DILI:** Ligand A (5.777) has a significantly lower DILI risk than Ligand B (12.175). This is a substantial advantage.

**8. BBB:** Ligand B (93.253) has a superior BBB penetration percentile than Ligand A (84.8). This is crucial for a CNS target like DRD2.

**9. Caco-2 Permeability:** Ligand A (-4.611) has slightly better Caco-2 permeability than Ligand B (-4.587), but both are negative values, which is unusual and requires further investigation.

**10. Aqueous Solubility:** Ligand A (-0.872) has better aqueous solubility than Ligand B (-3.572).

**11. hERG Inhibition:** Ligand A (0.809) has a slightly better hERG profile than Ligand B (0.333). Lower is better.

**12. Microsomal Clearance:** Ligand A (22.676) has a significantly lower microsomal clearance than Ligand B (53.647), suggesting better metabolic stability.

**13. In vitro Half-Life:** Ligand A (74.493) has a much longer in vitro half-life than Ligand B (-11.218). This is a major advantage.

**14. P-gp Efflux:** Ligand A (0.022) has a much lower P-gp efflux liability than Ligand B (0.238), meaning it's less likely to be pumped out of the brain.

**15. Binding Affinity:** Ligand B (-8.1) has a slightly better binding affinity than Ligand A (-7.6). However, the difference is only 0.5 kcal/mol, which may not be enough to overcome the ADME deficiencies of Ligand B.

**Overall Assessment:**

Ligand A demonstrates a more favorable balance of properties, particularly regarding ADME characteristics critical for CNS penetration and safety. While Ligand B has slightly better binding affinity and BBB penetration, Ligand A excels in DILI risk, metabolic stability (lower Cl_mic and longer t1/2), P-gp efflux, and solubility. The combination of these factors, especially the lower DILI and P-gp efflux, makes Ligand A a more promising drug candidate for targeting DRD2. The 0.5 kcal/mol difference in binding affinity is unlikely to outweigh the significant ADME advantages of Ligand A.

Output:
0
2025-04-17 09:00:04,241 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (408.256 Da) is higher, but still acceptable. Ligand B (344.459 Da) is slightly better.

**TPSA:** Ligand A (119.14) is borderline for CNS penetration, being above the ideal <90, but not drastically so. Ligand B (67.35) is excellent, well below the 90 threshold.

**logP:** Both ligands have good logP values (A: 1.86, B: 2.015), falling within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A has 5 HBD and 4 HBA, which is acceptable. Ligand B has 1 HBD and 5 HBA, also acceptable.

**QED:** Ligand B (0.908) has a significantly higher QED score than Ligand A (0.533), indicating a more drug-like profile.

**DILI:** Ligand A (72.703) has a higher DILI risk than Ligand B (26.173). This is a significant advantage for Ligand B.

**BBB:** Ligand B (77.627) has a much better BBB penetration percentile than Ligand A (32.183). This is *critical* for a CNS target like DRD2.

**Caco-2 Permeability:** Ligand A (-5.607) shows poor Caco-2 permeability, which is concerning. Ligand B (-4.947) is also poor, but marginally better.

**Aqueous Solubility:** Both ligands have poor aqueous solubility (-3.791 and -1.33 respectively). This could pose formulation challenges, but is less critical than BBB penetration for a CNS drug.

**hERG Inhibition:** Both ligands show low hERG inhibition risk (A: 0.291, B: 0.326).

**Microsomal Clearance:** Ligand A (-0.328) has better metabolic stability (lower clearance) than Ligand B (11.141).

**In vitro Half-Life:** Ligand B (4.195 hours) has a slightly better half-life than Ligand A (-6.522 hours).

**P-gp Efflux:** Both ligands show very low P-gp efflux (A: 0.018, B: 0.053), which is good for CNS penetration.

**Binding Affinity:** Ligand B (-8.7 kcal/mol) has a significantly stronger binding affinity than Ligand A (-0.0 kcal/mol). This is a decisive factor.

**Overall Assessment:**

Ligand B is clearly the superior candidate. While both have solubility issues, Ligand B excels in the most critical areas for a CNS GPCR target: BBB penetration, binding affinity, and DILI risk. The stronger affinity of Ligand B (-8.7 kcal/mol vs -0.0 kcal/mol) is a substantial advantage that outweighs the slightly worse metabolic stability and Caco-2 permeability. Ligand A's poor BBB penetration and weak binding affinity are major drawbacks.

Output:
1
2025-04-17 09:00:04,241 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 drug candidates, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (386.428 Da) is slightly higher than Ligand B (357.376 Da), but both are acceptable.

**TPSA:** Ligand A (70.59) is borderline for CNS targets (ideally <90), while Ligand B (65.46) is well within the range. This favors Ligand B.

**logP:** Ligand A (3.892) is at the upper end of the optimal range (1-3), potentially raising concerns about solubility and off-target effects. Ligand B (2.793) is well within the optimal range. This favors Ligand B.

**H-Bond Donors/Acceptors:** Ligand A (HBD=1, HBA=7) and Ligand B (HBD=2, HBA=3) both have reasonable numbers of H-bond donors and acceptors, falling within the acceptable limits.

**QED:** Both ligands have good QED scores (Ligand A: 0.689, Ligand B: 0.871), indicating good drug-like properties. Ligand B is slightly better.

**DILI:** Ligand A has a significantly higher DILI risk (91.237%) than Ligand B (15.898%). This is a major concern for Ligand A.

**BBB:** Ligand B (82.009%) has a better BBB penetration score than Ligand A (73.633%), which is crucial for a CNS target like DRD2.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.059 and -4.614), which is unusual and suggests poor permeability. However, the scale isn't defined, so it's hard to interpret.

**Aqueous Solubility:** Both ligands have negative solubility values (-4.743 and -2.815), indicating poor aqueous solubility.

**hERG Inhibition:** Both ligands have low hERG inhibition liability (Ligand A: 0.747, Ligand B: 0.488), which is good.

**Microsomal Clearance:** Ligand B (5.085) has a much lower microsomal clearance than Ligand A (30.98), indicating better metabolic stability.

**In vitro Half-Life:** Ligand B (-0.948) has a slightly better in vitro half-life than Ligand A (-18.724).

**P-gp Efflux:** Ligand A (0.485) has lower P-gp efflux liability than Ligand B (0.106), which is favorable for CNS penetration.

**Binding Affinity:** Ligand B (-9.3 kcal/mol) has a slightly better binding affinity than Ligand A (-8.7 kcal/mol). While the difference is not huge, it's still a positive for Ligand B.

**Overall Assessment:**

Ligand B is significantly better overall. It has a lower DILI risk, better BBB penetration, lower microsomal clearance (better metabolic stability), and a slightly better binding affinity. While both have poor solubility and permeability, the other advantages of Ligand B outweigh this concern, especially given the CNS target. Ligand A's high DILI risk is a major red flag.

Output:
1
2025-04-17 09:00:04,241 - INFO - Reasoning:

Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (364.511 and 348.491 Da) fall within the ideal range of 200-500 Da.

**TPSA:** Ligand A (67.43) is better than Ligand B (69.04), both are reasonably close to the 90 A^2 threshold for CNS targets, but lower is preferred.

**logP:** Both ligands have good logP values (2.754 and 2.893), falling within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A has 2 HBD and 4 HBA, while Ligand B has 1 HBD and 5 HBA. Both are within acceptable limits (<=5 HBD and <=10 HBA).

**QED:** Ligand B (0.888) has a significantly better QED score than Ligand A (0.662), indicating a more drug-like profile.

**DILI:** Both ligands have acceptable DILI risk (Ligand A: 36.448, Ligand B: 39.434), below the 40 threshold.

**BBB:** Ligand B (71.539) has a much better BBB percentile than Ligand A (46.219). This is *critical* for a CNS target like DRD2.

**Caco-2 Permeability:** Ligand A (-4.838) has better Caco-2 permeability than Ligand B (-5.017), but both are negative values which is concerning.

**Aqueous Solubility:** Ligand A (-3.634) has slightly better aqueous solubility than Ligand B (-2.559), but both are negative, indicating poor solubility.

**hERG Inhibition:** Both ligands have very low hERG inhibition liability (Ligand A: 0.472, Ligand B: 0.133), which is excellent.

**Microsomal Clearance:** Ligand B (49.245) has lower microsomal clearance than Ligand A (61.693), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (24.267) has a longer in vitro half-life than Ligand B (-3.656). This is a positive for Ligand A.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (Ligand A: 0.186, Ligand B: 0.167), which is beneficial for CNS penetration.

**Binding Affinity:** Ligand B (-9.0 kcal/mol) has a significantly stronger binding affinity than Ligand A (-7.9 kcal/mol). This is a substantial advantage, exceeding the 1.5 kcal/mol threshold.

**Overall Assessment:**

While Ligand A has slightly better Caco-2 permeability and in vitro half-life, Ligand B is superior overall, especially considering the GPCR-specific priorities. The significantly better BBB penetration (71.539 vs 46.219) and substantially stronger binding affinity (-9.0 vs -7.9 kcal/mol) of Ligand B are decisive factors. The improved QED and lower microsomal clearance further support its selection. The solubility is a concern for both, but can be addressed with formulation strategies.

Output:
1
2025-04-17 09:00:04,241 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (368.5 and 352.5 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (66.92) is significantly better than Ligand B (87.66). For CNS targets, we want TPSA <= 90, and A is closer to the ideal <=60. B is pushing the upper limit and could have reduced brain penetration.

**3. logP:** Ligand A (0.653) is a bit low, potentially hindering membrane permeability. Ligand B (1.531) is better, falling within the optimal 1-3 range.

**4. H-Bond Donors:** Ligand A (0) is preferable to Ligand B (3). Fewer HBDs generally improve permeability.

**5. H-Bond Acceptors:** Both ligands have 4 HBA, which is acceptable.

**6. QED:** Ligand A (0.669) has a slightly better QED score than Ligand B (0.52), indicating a more drug-like profile.

**7. DILI:** Ligand A (30.71) has a much lower DILI risk than Ligand B (6.592), a significant advantage.

**8. BBB:** Ligand A (60.838) has a better BBB percentile than Ligand B (47.732), though neither are above the desirable >70 for CNS targets. A is closer.

**9. Caco-2:** Both have negative Caco-2 values, which is unusual and difficult to interpret without knowing the scale. However, the values are similar.

**10. Solubility:** Both have negative solubility values, again making comparison difficult.

**11. hERG:** Both ligands have very low hERG inhibition liability (0.146 and 0.138), which is excellent.

**12. Cl_mic:** Ligand B (17.893) has a significantly lower microsomal clearance than Ligand A (46.827), suggesting better metabolic stability.

**13. t1/2:** Ligand B (16.1) has a positive in vitro half-life, whereas Ligand A (-16.13) has a negative value, which is concerning.

**14. Pgp:** Both ligands have very low Pgp efflux liability (0.048 and 0.013), which is favorable for CNS penetration.

**15. Binding Affinity:** Both ligands have comparable and strong binding affinities (-7.8 and -7.9 kcal/mol). The difference is negligible.

**Overall Assessment:**

Ligand A excels in TPSA, DILI, and QED, and has a better BBB score. However, Ligand B has a better logP, significantly better metabolic stability (lower Cl_mic, positive t1/2), and comparable affinity. Considering the GPCR-specific priorities, BBB and logP are crucial. While neither ligand has an ideal BBB score, Ligand A is closer. The significantly better metabolic stability of Ligand B is a strong advantage, as is the more favorable logP. The negative in vitro half-life of Ligand A is a major concern.

Output:
1
2025-04-17 09:00:04,241 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (407.533 Da) is slightly higher than Ligand B (332.447 Da), but both are acceptable.

**TPSA:** Ligand A (53.51) is higher than Ligand B (25.36). For CNS targets, we want TPSA <= 90, so both are within range, but Ligand B is significantly better.

**logP:** Both ligands have good logP values (A: 2.865, B: 3.896), falling within the optimal 1-3 range. Ligand B is slightly higher, which could potentially lead to some off-target effects, but it's not a major concern.

**H-Bond Donors/Acceptors:** Both have low HBD (0) and acceptable HBA (A: 6, B: 3).

**QED:** Both ligands have good QED values (A: 0.739, B: 0.777), indicating drug-like properties.

**DILI:** Ligand A has a significantly higher DILI risk (67.429%) than Ligand B (12.369%). This is a major concern for Ligand A.

**BBB:** Ligand A (90.694%) has a better BBB penetration percentile than Ligand B (71.927%), which is important for a CNS target like DRD2.

**Caco-2 Permeability:** Both have negative Caco-2 values (-4.829 and -4.825), which is unusual and suggests poor permeability. This is a significant drawback for both.

**Aqueous Solubility:** Both have negative solubility values (-4.77 and -4.333), indicating very poor aqueous solubility. This is a major formulation challenge for both.

**hERG Inhibition:** Both ligands show low hERG inhibition risk (A: 0.917, B: 0.847).

**Microsomal Clearance:** Ligand A has a higher microsomal clearance (58.4 mL/min/kg) than Ligand B (29.658 mL/min/kg), suggesting lower metabolic stability for Ligand A.

**In vitro Half-Life:** Ligand B has a better in vitro half-life (-21.647 hours) than Ligand A (-31.136 hours).

**P-gp Efflux:** Both ligands show good P-gp efflux profiles (A: 0.553, B: 0.407), indicating lower efflux liability.

**Binding Affinity:** Ligand B has a better binding affinity (-9.4 kcal/mol) than Ligand A (-8.4 kcal/mol). This 1 kcal/mol difference is substantial and can outweigh some ADME drawbacks.

**Overall Assessment:**

Ligand B is the better candidate. While both have poor Caco-2 and solubility, Ligand B has a significantly lower DILI risk, better metabolic stability (lower Cl_mic, longer t1/2), and a substantially stronger binding affinity. The slightly lower BBB of Ligand B is less concerning given the strong affinity and other favorable properties. The higher logP of Ligand B is a minor concern, but the benefits outweigh this potential drawback.



Output:
1
2025-04-17 09:00:04,242 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (346.471 and 367.921 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (67.43) is slightly higher than Ligand B (54.34). Both are below the 90 A^2 threshold desirable for CNS targets, but Ligand B is closer to the optimal range.

**3. logP:** Both ligands have good logP values (3.521 and 3.098), falling within the 1-3 range.

**4. H-Bond Donors:** Ligand A has 2 HBD, and Ligand B has 1. Both are within the acceptable limit of <=5.

**5. H-Bond Acceptors:** Both ligands have 3 HBA, well within the limit of <=10.

**6. QED:** Both ligands have similar QED scores (0.757 and 0.753), indicating good drug-likeness.

**7. DILI:** Ligand A (28.383) has a slightly higher DILI risk than Ligand B (22.257), but both are below the 40 threshold, indicating low risk.

**8. BBB:** Ligand A (76.968) has a significantly better BBB penetration score than Ligand B (69.562). This is a crucial factor for a CNS target like DRD2.

**9. Caco-2 Permeability:** Ligand A (-4.254) shows better Caco-2 permeability than Ligand B (-4.46). Higher values are better, indicating better intestinal absorption.

**10. Aqueous Solubility:** Ligand A (-4.087) has slightly better aqueous solubility than Ligand B (-3.503).

**11. hERG Inhibition:** Both ligands have very low hERG inhibition liability (0.578 and 0.311), which is excellent.

**12. Microsomal Clearance:** Ligand A (85.576) has a higher microsomal clearance than Ligand B (61.687), suggesting lower metabolic stability. This is a negative for Ligand A.

**13. In vitro Half-Life:** Ligand B (37.516) has a much longer in vitro half-life than Ligand A (4.283), indicating better metabolic stability.

**14. P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.128), which is favorable for CNS penetration.

**15. Binding Affinity:** Ligand A (-7.9 kcal/mol) has a slightly better binding affinity than Ligand B (-7.6 kcal/mol). While the difference is not huge, it's a positive for Ligand A.

**Overall Assessment:**

Ligand A has a better binding affinity and BBB penetration, and slightly better solubility and Caco-2 permeability. However, Ligand B has a significantly better metabolic profile (lower Cl_mic and much longer half-life) and a lower DILI risk. Given the importance of metabolic stability for *in vivo* efficacy, and the fact that the affinity difference isn't massive, Ligand B is the more promising candidate. The improved BBB of Ligand A is somewhat offset by its poorer metabolic stability.

Output:
1
2025-04-17 09:00:04,242 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 drug candidates, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (359.363 and 348.443 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (49.33) is excellent, well below the 90 A^2 threshold for CNS targets. Ligand B (78.87) is higher, but still potentially acceptable, though less optimal.

**logP:** Ligand A (3.444) is within the optimal 1-3 range. Ligand B (0.849) is a bit low, potentially hindering membrane permeability.

**H-Bond Donors/Acceptors:** Both ligands have 2 HBD, which is good. Ligand A has 2 HBA, also good. Ligand B has 4 HBA, which is higher but still within the acceptable limit of 10.

**QED:** Ligand A (0.792) has a better QED score than Ligand B (0.551), indicating a more drug-like profile.

**DILI:** Both ligands have relatively low DILI risk (16.324 and 18.728, respectively), which is positive.

**BBB:** This is a critical parameter for a CNS target like DRD2. Ligand A exhibits a very high BBB penetration (84.529%), which is highly desirable. Ligand B's BBB penetration (28.848%) is significantly lower and a major drawback.

**Caco-2 Permeability:** Both have negative values, indicating poor permeability. However, the scale is not specified, so it's difficult to interpret these values directly.

**Aqueous Solubility:** Both ligands have negative solubility values, which is concerning. Again, the scale is unspecified.

**hERG Inhibition:** Ligand A (0.83) has a slightly higher hERG risk than Ligand B (0.098), but both are relatively low.

**Microsomal Clearance:** Ligand A (11.358 mL/min/kg) has a higher clearance than Ligand B (2.18 mL/min/kg), suggesting lower metabolic stability.

**In vitro Half-Life:** Ligand B (-1.53 hours) has a very short half-life, which is undesirable. Ligand A (29.4 hours) has a much better half-life.

**P-gp Efflux:** Ligand A (0.371) has lower P-gp efflux liability than Ligand B (0.037), which is beneficial for CNS exposure.

**Binding Affinity:** Ligand B (-7.8 kcal/mol) has a significantly stronger binding affinity than Ligand A (-10 kcal/mol). This is a substantial advantage.

**Overall Assessment:**

Despite the superior binding affinity of Ligand B, the significantly lower BBB penetration and short half-life are major concerns for a CNS drug targeting DRD2. Ligand A, while having a slightly weaker binding affinity, possesses excellent BBB penetration, a good QED score, a reasonable half-life, and lower P-gp efflux. The TPSA is also much more favorable for CNS penetration. The solubility and Caco-2 permeability are concerning for both, but the BBB and half-life issues with Ligand B are more critical for a CNS target.

Output:
1
2025-04-17 09:00:04,242 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (351.447 and 352.435 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (95.67) is better than Ligand B (99.77), both are below the 140 threshold for oral absorption, and reasonably close to the 90 target for CNS penetration.

**3. logP:** Ligand A (1.958) is optimal (1-3). Ligand B (-0.836) is slightly low, potentially hindering permeation.

**4. H-Bond Donors:** Ligand A (2) and Ligand B (3) are both acceptable (<=5).

**5. H-Bond Acceptors:** Both ligands (5) are within the acceptable range (<=10).

**6. QED:** Ligand A (0.783) is better than Ligand B (0.555), indicating a more drug-like profile.

**7. DILI:** Ligand A (39.434) has a much lower DILI risk than Ligand B (14.773), which is a significant advantage.

**8. BBB:** Both ligands have similar BBB penetration (Ligand A: 44.979, Ligand B: 43.311). While not exceptional, they are both reasonable for a CNS target.

**9. Caco-2 Permeability:** Ligand A (-4.779) is significantly better than Ligand B (-5.887), indicating better intestinal absorption.

**10. Aqueous Solubility:** Ligand A (-2.184) is better than Ligand B (-0.749), suggesting better formulation potential.

**11. hERG Inhibition:** Both ligands have very low hERG inhibition risk (Ligand A: 0.372, Ligand B: 0.051).

**12. Microsomal Clearance:** Ligand B (-25.561) has a much lower (better) microsomal clearance than Ligand A (26.043), suggesting greater metabolic stability.

**13. In vitro Half-Life:** Ligand B (1.908) has a slightly better in vitro half-life than Ligand A (-2.958).

**14. P-gp Efflux:** Ligand A (0.138) has lower P-gp efflux than Ligand B (0.002), which is favorable for CNS exposure.

**15. Binding Affinity:** Both ligands have very similar and strong binding affinities (Ligand A: -7.9 kcal/mol, Ligand B: -7.0 kcal/mol). Ligand A is slightly better.

**Overall Assessment:**

Ligand A is the stronger candidate. While Ligand B has better metabolic stability and half-life, Ligand A excels in crucial areas like DILI risk, solubility, Caco-2 permeability, QED, and slightly better affinity. The logP value for Ligand A is also more optimal. Given the GPCR-specific focus on BBB, logP, Pgp, TPSA, and affinity, Ligand A's superior profile in logP, Pgp, and overall drug-likeness (QED) outweighs the metabolic advantages of Ligand B. The slightly better affinity of Ligand A is also a plus.

Output:
1
2025-04-17 09:00:04,242 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (366.483 and 349.41 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (91.57) is slightly above the optimal <90 for CNS targets, while Ligand B (79.26) is well within the range. This favors Ligand B.

**logP:** Ligand A (2.179) is within the optimal 1-3 range. Ligand B (0.446) is a bit low, potentially hindering permeability. This favors Ligand A.

**H-Bond Donors:** Both ligands have acceptable HBD counts (3 and 2, respectively), well below the threshold of 5.

**H-Bond Acceptors:** Both ligands have the same HBA count (5), which is below the threshold of 10.

**QED:** Both ligands have good QED scores (0.614 and 0.731), indicating good drug-like properties.

**DILI:** Both ligands have similar, acceptable DILI risk (31.563 and 39.434, both <40).

**BBB:** Ligand B (76.735) has a significantly better BBB percentile than Ligand A (62.233). This is a crucial advantage for a CNS target like DRD2.

**Caco-2 Permeability:** Ligand A (-5.082) has a worse Caco-2 permeability than Ligand B (-4.934), indicating potentially lower intestinal absorption.

**Aqueous Solubility:** Ligand A (-3.357) has a worse aqueous solubility than Ligand B (-1.432).

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.239 and 0.426).

**Microsomal Clearance:** Ligand B (3.561) has significantly lower microsomal clearance than Ligand A (39.018), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand B (-11.267) has a much longer in vitro half-life than Ligand A (3.247).

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.075 and 0.045).

**Binding Affinity:** Both ligands have excellent binding affinity (-8.1 and -8.0 kcal/mol), with Ligand A being slightly better. However, the affinity difference is small (0.1 kcal/mol) and may not outweigh other ADME concerns.

**Overall Assessment:**

Ligand B clearly outperforms Ligand A in several critical ADME properties for a CNS-targeting GPCR: BBB penetration, microsomal clearance, and in vitro half-life. While Ligand A has a slightly better logP and binding affinity, the differences are not substantial enough to offset Ligand B's superior pharmacokinetic profile, especially considering the importance of CNS penetration for DRD2. The TPSA of Ligand B is also more favorable.

Output:
1
2025-04-17 09:00:04,242 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (342.443 and 351.437 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (59.39) is better than Ligand B (29.54). For CNS targets, we want TPSA <= 90, both are well within this range, but A is closer to the upper limit, potentially impacting BBB penetration slightly.

**3. logP:** Ligand A (2.997) is optimal (1-3). Ligand B (4.179) is slightly higher, potentially leading to solubility issues or off-target interactions, but still within an acceptable range.

**4. H-Bond Donors:** Ligand A (1) is preferable to Ligand B (0). A single H-bond donor is generally acceptable.

**5. H-Bond Acceptors:** Ligand A (4) is higher than Ligand B (2). Both are within the acceptable limit of <=10.

**6. QED:** Ligand A (0.929) is significantly better than Ligand B (0.796), indicating a more drug-like profile.

**7. DILI:** Ligand A (36.603) has a slightly higher DILI risk than Ligand B (21.442), but both are below the 40 threshold and considered good.

**8. BBB:** Ligand B (96.743) has a much higher BBB penetration percentile than Ligand A (79.682). This is *critical* for a CNS target like DRD2.

**9. Caco-2 Permeability:** Ligand A (-4.637) has worse Caco-2 permeability than Ligand B (-4.214). Both are negative, indicating poor permeability, but B is slightly better.

**10. Aqueous Solubility:** Ligand A (-2.45) is better than Ligand B (-5.125). Solubility is important for formulation and bioavailability.

**11. hERG Inhibition:** Ligand A (0.437) has a lower hERG inhibition liability than Ligand B (0.873), which is preferable.

**12. Microsomal Clearance:** Ligand B (73.39) has a higher microsomal clearance than Ligand A (26.465), meaning A is more metabolically stable.

**13. In vitro Half-Life:** Ligand B (19.794) has a longer in vitro half-life than Ligand A (2.459), which is generally desirable.

**14. P-gp Efflux:** Ligand A (0.18) has significantly lower P-gp efflux liability than Ligand B (0.541). Lower efflux is crucial for CNS exposure.

**15. Binding Affinity:** Both ligands have the same binding affinity (-8.8 kcal/mol), which is excellent.

**Overall Assessment:**

While Ligand A has better QED, solubility, metabolic stability, and lower P-gp efflux and hERG liability, Ligand B *significantly* outperforms it in BBB penetration (96.743 vs. 79.682). For a CNS target like DRD2, BBB penetration is paramount. The slightly higher logP and P-gp efflux of Ligand B are less concerning given its superior BBB score. The longer half-life of Ligand B is also a positive.

Output:
1
2025-04-17 09:00:04,242 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (368.5 and 344.5 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Both ligands have TPSA values around 75, which is above the optimal <90 for CNS targets, but not drastically so.

**3. logP:** Ligand A (1.577) and Ligand B (2.329) both fall within the optimal 1-3 range. Ligand B is slightly more lipophilic, which could be beneficial for membrane permeability.

**4. H-Bond Donors:** Both ligands have 1 HBD, which is within the acceptable limit of <=5.

**5. H-Bond Acceptors:** Ligand A has 5 HBA, and Ligand B has 4. Both are within the acceptable limit of <=10.

**6. QED:** Both ligands have good QED scores (0.721 and 0.824), indicating good drug-like properties.

**7. DILI:** Ligand A (21.9%) has a considerably lower DILI risk than Ligand B (31.6%). This is a significant advantage.

**8. BBB:** Both ligands have excellent BBB penetration (71.5% and 74.3%), exceeding the desirable >70% threshold for CNS targets.

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 values, which is unusual and suggests poor permeability. This is a concern for both.

**10. Aqueous Solubility:** Both ligands have negative solubility values, indicating very poor aqueous solubility. This is a major drawback for both.

**11. hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.23 and 0.146), which is excellent.

**12. Microsomal Clearance:** Ligand A (40.9 mL/min/kg) has a higher microsomal clearance than Ligand B (31.7 mL/min/kg), indicating lower metabolic stability.

**13. In vitro Half-Life:** Both ligands have negative in vitro half-life values, which is unusual.

**14. P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.045 and 0.019), which is favorable for CNS exposure.

**15. Binding Affinity:** Ligand B (-8.5 kcal/mol) has a slightly better binding affinity than Ligand A (-8.0 kcal/mol). While the difference is not huge, it is noticeable.

**Overall Assessment:**

Both compounds have significant drawbacks (poor solubility and Caco-2 permeability). However, Ligand B has a slightly better binding affinity and lower microsomal clearance, while Ligand A has a significantly lower DILI risk. Given the importance of minimizing toxicity, and the fact that the affinity difference isn't substantial, the lower DILI risk of Ligand A is a key advantage. The similar BBB penetration and P-gp efflux profiles are positive for both.

Output:
0
2025-04-17 09:00:04,242 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (351.535 and 347.379 Da) fall within the ideal range of 200-500 Da.

**TPSA:** Ligand A (61.44) is excellent, well below the 90 A^2 threshold for CNS targets. Ligand B (107.17) is higher, but still potentially acceptable, though less ideal.

**logP:** Ligand A (3.539) is optimal. Ligand B (-0.249) is significantly low, potentially hindering membrane permeability and CNS penetration.

**H-Bond Donors/Acceptors:** Ligand A (2 HBD, 2 HBA) is favorable. Ligand B (1 HBD, 8 HBA) is acceptable, but the higher HBA count could slightly impact permeability.

**QED:** Both ligands have similar QED values (0.796 and 0.74), indicating good drug-likeness.

**DILI:** Ligand A (16.557) has a much lower DILI risk than Ligand B (73.982), which is a significant advantage.

**BBB:** Ligand A (91.508) has excellent BBB penetration, exceeding the desirable >70% threshold. Ligand B (70.997) is at the lower end of acceptable, but still reasonable.

**Caco-2 Permeability:** Ligand A (-4.631) is poor, indicating low intestinal absorption. Ligand B (-5.434) is also poor, but slightly worse.

**Aqueous Solubility:** Ligand A (-3.179) is poor, while Ligand B (-1.661) is slightly better, but still not ideal.

**hERG:** Both ligands have low hERG inhibition risk (0.523 and 0.131).

**Microsomal Clearance:** Ligand A (37.279) has moderate clearance, while Ligand B (1.098) has very low clearance, suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (-8.332) has a long half-life, while Ligand B (3.647) has a short half-life.

**P-gp Efflux:** Ligand A (0.152) has low P-gp efflux, which is favorable for CNS penetration. Ligand B (0.021) has very low P-gp efflux, which is even more favorable.

**Binding Affinity:** Both ligands have excellent binding affinity (-8.5 and -8.1 kcal/mol). The difference of 0.4 kcal/mol is not substantial enough to outweigh other factors.

**Overall Assessment:**

Ligand A excels in BBB penetration, DILI risk, and has a long half-life. However, its Caco-2 permeability and aqueous solubility are poor. Ligand B has better metabolic stability (lower Cl_mic) and slightly better solubility, but suffers from a significantly lower logP, higher DILI risk, and lower BBB penetration.

Given the GPCR-specific priorities, particularly for a CNS target like DRD2, **BBB penetration is crucial**. Ligand A's superior BBB score (91.508 vs 70.997) and lower DILI risk make it the more promising candidate, despite its lower Caco-2 permeability and solubility. The affinity difference is minimal.

Output:
0
2025-04-17 09:00:04,242 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (364.43 and 348.42 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (102.58) is higher than Ligand B (75.19). For CNS targets, TPSA should be <=90, so Ligand B is preferable.

**logP:** Ligand A (0.42) is quite low, potentially hindering permeability. Ligand B (2.202) is within the optimal 1-3 range. This is a significant advantage for Ligand B.

**H-Bond Donors:** Ligand A (2) and Ligand B (1) are both acceptable, being <=5.

**H-Bond Acceptors:** Both ligands (A: 4, B: 4) are within the acceptable range of <=10.

**QED:** Both ligands have good QED scores (A: 0.821, B: 0.577), indicating drug-like properties.

**DILI:** Ligand A (70.841) has a higher DILI risk than Ligand B (51.493), although both are reasonably acceptable.

**BBB:** Ligand B (89.027) has a significantly better BBB penetration score than Ligand A (52.811). This is crucial for a CNS target like DRD2.

**Caco-2 Permeability:** Both have negative Caco-2 values (-4.9 and -4.952), which is unusual and suggests poor permeability. This is a red flag for both, but doesn't necessarily disqualify them.

**Aqueous Solubility:** Both have negative solubility values (-3.657 and -2.746), also unusual and suggesting poor solubility.

**hERG Inhibition:** Ligand A (0.389) has a slightly lower hERG risk than Ligand B (0.603), which is preferable.

**Microsomal Clearance:** Ligand A (1.369) has much lower microsomal clearance than Ligand B (45.733), indicating better metabolic stability.

**In vitro Half-Life:** Ligand A (-7.155) has a longer in vitro half-life than Ligand B (-3.8), which is desirable.

**P-gp Efflux:** Ligand A (0.017) has much lower P-gp efflux liability than Ligand B (0.279), which is very favorable for CNS penetration.

**Binding Affinity:** Both ligands have excellent binding affinities (-9.1 and -7.1 kcal/mol). Ligand A is significantly more potent.

**Overall Assessment:**

While Ligand A has superior binding affinity, metabolic stability, half-life, and P-gp efflux, its poor logP and BBB penetration are major drawbacks for a CNS target. Ligand B, despite being less potent, has a much better logP, BBB, and TPSA, making it more likely to reach the target in the brain. The lower P-gp efflux of ligand A is a plus, but the other ADME properties are more critical for CNS penetration. Given the GPCR-specific priorities, and the importance of CNS penetration for DRD2, Ligand B is the more promising candidate.

Output:
1
2025-04-17 09:00:04,243 - INFO - Batch 496 complete. Total preferences: 7936
2025-04-17 09:00:04,243 - INFO - Processing batch 497/512...
2025-04-17 09:00:45,639 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (358.408 and 346.515 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (39.68) is better than Ligand B (24.94) as it is closer to the ideal range of <90 for CNS targets. Ligand B is quite low, which *could* be a concern for binding, but isn't a major issue.

**logP:** Ligand A (1.739) is within the optimal 1-3 range. Ligand B (3.538) is slightly higher, but still acceptable.

**H-Bond Donors/Acceptors:** Both ligands have 0 HBD and 4 HBA, which are within acceptable limits.

**QED:** Both ligands have similar QED values (0.777 and 0.754), indicating good drug-likeness.

**DILI:** Ligand A (14.851) has a significantly lower DILI risk than Ligand B (3.645), which is a substantial advantage.

**BBB:** Both ligands have excellent BBB penetration (86.817 and 83.055), exceeding the desirable >70 threshold for CNS targets.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.625 and -4.738). This is unusual and suggests poor permeability. However, these values are on a log scale, and negative values are not uncommon for compounds with specific efflux properties.

**Aqueous Solubility:** Both ligands have very poor aqueous solubility (-0.489 and -1.814). This is a significant drawback and could hinder formulation and bioavailability.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.774 and 0.955), which is positive.

**Microsomal Clearance:** Ligand A (-5.009) has a *much* lower (better) microsomal clearance than Ligand B (20.475), indicating greater metabolic stability.

**In vitro Half-Life:** Ligand A (-18.429) has a much longer in vitro half-life than Ligand B (-6.647), which is a significant advantage.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.078 and 0.219), which is favorable for CNS penetration.

**Binding Affinity:** Ligand A (-8.6 kcal/mol) has a slightly better binding affinity than Ligand B (-7.2 kcal/mol). The difference is 1.4 kcal/mol, which is significant enough to potentially outweigh some ADME drawbacks.

**Overall Assessment:**

Ligand A is the stronger candidate. While both have good BBB penetration and acceptable logP, Ligand A excels in crucial areas: significantly lower DILI risk, much better metabolic stability (lower Cl_mic, longer t1/2), and slightly better binding affinity. The poor aqueous solubility is a concern for both, but can potentially be addressed through formulation strategies. The negative Caco-2 values are a shared concern, but less critical given the strong BBB penetration.

Output:
1
2025-04-17 09:00:45,640 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (418.332) is slightly higher, but acceptable. Ligand B (342.443) is also good.

**TPSA:** Ligand A (82.45) is borderline for CNS targets (ideally <90). Ligand B (65.54) is excellent for CNS penetration.

**logP:** Both ligands have good logP values (Ligand A: 2.848, Ligand B: 1.069), falling within the optimal 1-3 range. Ligand A is slightly better.

**H-Bond Donors/Acceptors:** Both ligands have acceptable HBD (1) and HBA (Ligand A: 6, Ligand B: 4) counts, well within the guidelines.

**QED:** Both ligands have strong drug-like profiles (Ligand A: 0.719, Ligand B: 0.889), exceeding the 0.5 threshold.

**DILI:** Ligand A (55.797) has a moderate DILI risk, while Ligand B (19.969) has a very low risk. This favors Ligand B.

**BBB:** Ligand B (61.962) has a significantly better BBB percentile than Ligand A (49.864). This is a critical factor for a CNS target like DRD2.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values, which is unusual and problematic. It suggests poor permeability. However, the scale is not specified, so it's hard to interpret.

**Aqueous Solubility:** Both ligands have negative solubility values, which is also problematic. It suggests poor solubility. However, the scale is not specified, so it's hard to interpret.

**hERG Inhibition:** Both ligands have low hERG inhibition liability (Ligand A: 0.128, Ligand B: 0.248), which is positive.

**Microsomal Clearance:** Ligand A (90.473) has a higher microsomal clearance than Ligand B (4.904), indicating lower metabolic stability. Ligand B is significantly better.

**In vitro Half-Life:** Ligand B (11.55) has a slightly longer half-life than Ligand A (9.497).

**P-gp Efflux:** Both ligands have low P-gp efflux liability (Ligand A: 0.082, Ligand B: 0.042), which is good for CNS exposure. Ligand B is slightly better.

**Binding Affinity:** Ligand B (-8.8 kcal/mol) has a substantially stronger binding affinity than Ligand A (-7.1 kcal/mol). This is a significant advantage, potentially outweighing some ADME drawbacks.

**Overall Assessment:**

Ligand B is superior. While both ligands have issues with Caco-2 and solubility, Ligand B excels in the critical areas for a CNS GPCR target: BBB penetration, binding affinity, metabolic stability (lower Cl_mic), lower DILI risk, and slightly better P-gp efflux. The significantly stronger binding affinity of Ligand B (-8.8 vs -7.1 kcal/mol) is a major advantage.



Output:
1
2025-04-17 09:00:45,640 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (345.487 and 348.422 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (43.86) is significantly better than Ligand B (76.02). For CNS targets, TPSA should be <= 90, and lower is preferable. Ligand A is well within this range, while Ligand B is approaching the upper limit.

**3. logP:** Both ligands have acceptable logP values (2.173 and 1.49), falling within the optimal 1-3 range.

**4. H-Bond Donors:** Ligand A (0) is preferable to Ligand B (2). Fewer HBDs generally improve permeability.

**5. H-Bond Acceptors:** Ligand A (3) is preferable to Ligand B (4). Fewer HBAs generally improve permeability.

**6. QED:** Both ligands have good QED values (0.737 and 0.866), indicating good drug-like properties.

**7. DILI:** Ligand A (19.581) has a much lower DILI risk than Ligand B (49.399). This is a significant advantage for Ligand A.

**8. BBB:** Ligand A (86.119) has a better BBB penetration percentile than Ligand B (78.907). While both are reasonably good, exceeding 70 is desirable for CNS targets, and A is closer.

**9. Caco-2 Permeability:** Both have negative Caco-2 values (-4.707 and -4.83), which is unusual and indicates poor permeability. This is a significant drawback for both.

**10. Aqueous Solubility:** Both have negative solubility values (-2.182 and -2.917), also unusual and indicating poor solubility. This is a significant drawback for both.

**11. hERG Inhibition:** Both ligands have low hERG inhibition risk (0.435 and 0.375).

**12. Microsomal Clearance:** Ligand B (-11.729) has a *lower* (better) microsomal clearance than Ligand A (47.237). Lower clearance suggests greater metabolic stability.

**13. In vitro Half-Life:** Ligand B (19.287) has a longer half-life than Ligand A (9.239). This is a positive for Ligand B.

**14. P-gp Efflux:** Ligand A (0.293) has lower P-gp efflux liability than Ligand B (0.061). Lower efflux is better for CNS exposure.

**15. Binding Affinity:** Ligand A (-8.2 kcal/mol) has a slightly better binding affinity than Ligand B (-7.9 kcal/mol). While the difference is small, it's still a positive for Ligand A.

**Overall Assessment:**

Considering the GPCR-specific priorities, Ligand A is the more promising candidate. It has a significantly lower DILI risk, better TPSA, better BBB penetration, lower P-gp efflux, and slightly better binding affinity. While both have poor Caco-2 and solubility, the other advantages of Ligand A outweigh the better metabolic stability and half-life of Ligand B. The small affinity difference is less important than the ADME advantages of A.

Output:
0
2025-04-17 09:00:45,640 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (346.43 and 352.40 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (75.71) is excellent, well below the 90 A^2 threshold for CNS targets. Ligand B (133.79) is higher but still potentially acceptable, though less ideal.

**logP:** Ligand A (1.535) is within the optimal 1-3 range. Ligand B (-1.603) is below 1, which could hinder permeation.

**H-Bond Donors/Acceptors:** Ligand A (HBD=1, HBA=4) and Ligand B (HBD=3, HBA=6) both have reasonable numbers of H-bond donors and acceptors, staying within the guidelines.

**QED:** Ligand A (0.725) has a better QED score than Ligand B (0.587), indicating a more drug-like profile.

**DILI:** Both ligands have low DILI risk (Ligand A: 30.83, Ligand B: 29.08), which is good.

**BBB:** This is a crucial parameter for a CNS target like DRD2. Ligand A has a significantly better BBB penetration percentile (70.03) than Ligand B (22.06).

**Caco-2 Permeability:** Ligand A (-4.182) is poor, while Ligand B (-5.675) is also poor. This is a concern for both, but less critical given the focus on CNS penetration.

**Aqueous Solubility:** Ligand A (-2.045) and Ligand B (-0.035) both have poor solubility.

**hERG Inhibition:** Both ligands show very low hERG inhibition risk (Ligand A: 0.129, Ligand B: 0.024).

**Microsomal Clearance:** Ligand A (77.21 mL/min/kg) has higher clearance than Ligand B (-23.604 mL/min/kg), suggesting lower metabolic stability.

**In vitro Half-Life:** Ligand A (-16.325 hours) has a negative half-life, which is not possible. This is a red flag. Ligand B (0.179 hours) has a very short half-life.

**P-gp Efflux:** Both have very low P-gp efflux liability (Ligand A: 0.048, Ligand B: 0.003).

**Binding Affinity:** Ligand A (-7.7 kcal/mol) has a slightly better binding affinity than Ligand B (-6.8 kcal/mol), although both are good.

**Overall Assessment:**

Ligand A is superior despite some drawbacks. Its significantly better BBB penetration (70% vs 22%), better QED, and slightly better binding affinity outweigh its poorer Caco-2 permeability and higher clearance. The negative half-life for Ligand A is a significant concern and suggests a data error, but even ignoring that, the other properties favor A. Ligand B's low logP and poor BBB penetration are major liabilities for a CNS-targeting drug.

Output:
1
2025-04-17 09:00:45,640 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (355.435 and 369.384 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (96.97) is better than Ligand B (101.9). Both are below the 140 A^2 threshold for oral absorption and reasonably close to the 90 A^2 target for CNS penetration.

**3. logP:** Both ligands (-0.449 and -0.378) are a bit low, potentially hindering permeation. Ideally, we'd like values between 1-3. However, for a GPCR, this isn't a complete dealbreaker if other properties are favorable.

**4. H-Bond Donors:** Ligand A (2) is preferable to Ligand B (4). Lower HBD generally improves permeability.

**5. H-Bond Acceptors:** Both ligands have 5 HBA, which is acceptable.

**6. QED:** Ligand A (0.546) has a better QED score than Ligand B (0.467), indicating a more drug-like profile.

**7. DILI:** Ligand A (20.706) has a significantly lower DILI risk than Ligand B (9.965), which is a major advantage.

**8. BBB:** Ligand A (54.246) has a better BBB percentile than Ligand B (48.119), crucial for a CNS target like DRD2. While neither is >70, A is closer.

**9. Caco-2 Permeability:** Both have negative values (-5.22 and -5.379), indicating poor permeability. This is concerning.

**10. Aqueous Solubility:** Both have negative values (-0.714 and -0.673), indicating poor solubility.

**11. hERG:** Both ligands have very low hERG inhibition risk (0.076 and 0.225).

**12. Microsomal Clearance:** Ligand B (-12.912) has a lower (better) microsomal clearance than Ligand A (32.979), suggesting better metabolic stability.

**13. In vitro Half-Life:** Ligand B (-32.298) has a longer half-life than Ligand A (-21.335).

**14. P-gp Efflux:** Both have very low P-gp efflux liability (0.007 and 0.006).

**15. Binding Affinity:** Both ligands have very similar and excellent binding affinities (-7.4 and -7.0 kcal/mol). The difference of 0.4 kcal/mol is not significant enough to outweigh other factors.

**Overall Assessment:**

Ligand A is the better candidate. Despite both having poor Caco-2 and solubility, Ligand A has a significantly lower DILI risk, a better BBB percentile, a better QED score, and fewer H-bond donors. While Ligand B has better metabolic stability and half-life, the CNS target prioritization makes the improved BBB and reduced toxicity of Ligand A more important. The similar binding affinities make the ADME properties the deciding factor.

Output:
1
2025-04-17 09:00:45,640 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (361.793 and 354.466 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (108.06) is higher than Ligand B (67.43). For CNS targets, TPSA should be <= 90. Ligand B is significantly better in this regard.

**logP:** Both ligands (2.725 and 2.508) are within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A has 3 HBD and 6 HBA, while Ligand B has 2 HBD and 3 HBA. Both are acceptable, staying within the guidelines of <=5 HBD and <=10 HBA.

**QED:** Both ligands have reasonable QED values (0.659 and 0.593), indicating good drug-like properties.

**DILI:** Ligand A has a high DILI risk (98.953 percentile), which is a major concern. Ligand B has a much lower and acceptable DILI risk (22.8 percentile).

**BBB:** Ligand A (51.725 percentile) has a moderate BBB penetration, while Ligand B (87.941 percentile) has excellent predicted BBB penetration. This is a critical advantage for a CNS target like DRD2.

**Caco-2 Permeability:** Ligand A (-5.006) and Ligand B (-4.597) have similar, and poor, Caco-2 permeability.

**Aqueous Solubility:** Ligand A (-5.073) and Ligand B (-3.18) have poor aqueous solubility.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.472 and 0.533).

**Microsomal Clearance:** Ligand A (48.258 mL/min/kg) has lower clearance than Ligand B (55.247 mL/min/kg), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (49.414 hours) has a longer half-life than Ligand B (-4.367 hours). This is a significant advantage.

**P-gp Efflux:** Ligand A (0.056) has very low P-gp efflux, while Ligand B (0.243) has slightly higher efflux. Lower is better for CNS exposure.

**Binding Affinity:** Ligand A (-8.7 kcal/mol) has a significantly stronger binding affinity than Ligand B (-7.8 kcal/mol). This is a substantial advantage, potentially outweighing some ADME drawbacks.

**Overall Assessment:**

While Ligand A boasts a stronger binding affinity and better metabolic stability and P-gp efflux, its extremely high DILI risk and moderate BBB penetration are major red flags. Ligand B, despite slightly weaker affinity, presents a much more favorable ADME profile, particularly its excellent BBB penetration and low DILI risk. For a CNS target like DRD2, good brain penetration and safety are paramount. The 0.9 kcal/mol difference in affinity might be overcome with further optimization of Ligand B, but the safety concerns with Ligand A are harder to address.

Output:
1
2025-04-17 09:00:45,640 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (347.415 and 351.491 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (82.11) is better than Ligand B (69.72). Both are below the 90 A^2 threshold for CNS targets, which is excellent.

**3. logP:** Ligand B (1.787) is optimal (1-3), while Ligand A (-0.233) is below 1, potentially hindering permeation. This is a significant advantage for Ligand B.

**4. H-Bond Donors:** Ligand A (2) is slightly higher than Ligand B (1), but both are within the acceptable limit of <=5.

**5. H-Bond Acceptors:** Ligand A (5) is higher than Ligand B (3), but both are within the acceptable limit of <=10.

**6. QED:** Both ligands have good QED scores (0.743 and 0.768, respectively), indicating good drug-like properties.

**7. DILI:** Ligand B (20.706) has a significantly lower DILI risk than Ligand A (27.453). This is a strong point in favor of Ligand B.

**8. BBB:** Ligand B (73.633) has a much better BBB penetration percentile than Ligand A (29.391). This is *critical* for a CNS target like DRD2, giving Ligand B a substantial advantage.

**9. Caco-2 Permeability:** Both have negative values, which is unusual and difficult to interpret without knowing the scale. However, the absolute value for Ligand A (-4.897) is slightly less negative than Ligand B (-4.406).

**10. Aqueous Solubility:** Both have negative values, indicating poor solubility. Ligand B (-2.26) is slightly better than Ligand A (-1.124).

**11. hERG Inhibition:** Both ligands show low hERG inhibition liability (0.18 and 0.189).

**12. Microsomal Clearance:** Ligand A (9.773) has a lower microsomal clearance than Ligand B (38.017), suggesting better metabolic stability.

**13. In vitro Half-Life:** Ligand A (-15.387) has a longer in vitro half-life than Ligand B (-20.392).

**14. P-gp Efflux:** Both ligands show low P-gp efflux liability (0.048 and 0.045).

**15. Binding Affinity:** Ligand A (-9.1 kcal/mol) has a significantly stronger binding affinity than Ligand B (0.0 kcal/mol). This is a major advantage for Ligand A.

**Overall Assessment:**

While Ligand A has a superior binding affinity, Ligand B excels in crucial ADME properties for a CNS-targeting GPCR. Specifically, the significantly better BBB penetration, lower DILI risk, and more favorable logP of Ligand B are highly desirable. The better affinity of Ligand A might be overcome with further optimization, but the poor logP and lower BBB penetration are more challenging to address. Given the importance of CNS penetration for DRD2, and the substantial difference in BBB values, Ligand B is the more promising candidate.

Output:
1
2025-04-17 09:00:45,640 - INFO - Reasoning:

Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (352.475 and 345.535 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (78.87) is better than Ligand B (55.63). Both are below the 90 A^2 threshold for CNS targets, but A is closer to the upper limit.

**3. logP:** Ligand A (1.317) is within the optimal 1-3 range. Ligand B (4.309) is higher, potentially leading to solubility issues and off-target interactions.

**4. H-Bond Donors:** Ligand A (2) and Ligand B (1) are both acceptable (<=5).

**5. H-Bond Acceptors:** Ligand A (4) and Ligand B (5) are both acceptable (<=10).

**6. QED:** Ligand A (0.724) is better than Ligand B (0.642), indicating a more drug-like profile.

**7. DILI:** Ligand A (9.19) has a significantly lower DILI risk than Ligand B (27.801). This is a major advantage for Ligand A.

**8. BBB:** Ligand B (78.402) has a much better BBB penetration percentile than Ligand A (56.805). This is a critical factor for a CNS target like DRD2.

**9. Caco-2:** Ligand A (-4.664) and Ligand B (-5.155) both have negative values, which is unusual and suggests poor permeability. The values are similar, so this isn't a major differentiator.

**10. Solubility:** Ligand A (-2.235) and Ligand B (-4.303) both have negative solubility values, which is concerning. Ligand B is slightly worse.

**11. hERG:** Both ligands have low hERG risk (0.253 and 0.353, respectively).

**12. Cl_mic:** Ligand A (51.81) has a slightly lower microsomal clearance than Ligand B (43.723), suggesting better metabolic stability.

**13. t1/2:** Ligand B (-10.583) has a significantly longer in vitro half-life than Ligand A (-4.313). This is a positive for Ligand B.

**14. Pgp:** Ligand A (0.042) has a much lower P-gp efflux liability than Ligand B (0.348). Lower Pgp efflux is desirable for CNS exposure.

**15. Binding Affinity:** Ligand A (-8.1 kcal/mol) has a substantially stronger binding affinity than Ligand B (-6.4 kcal/mol). This is a significant advantage, potentially outweighing some of the ADME drawbacks.

**Overall Assessment:**

While Ligand B has a better BBB score and longer half-life, Ligand A is superior overall. The significantly stronger binding affinity (-8.1 vs -6.4 kcal/mol) is a major advantage. Additionally, Ligand A has a much lower DILI risk and Pgp efflux liability, and slightly better metabolic stability. The logP value for Ligand A is also more favorable. Although both have poor solubility and Caco-2 permeability, the strong affinity and better safety profile of Ligand A make it the more promising candidate.

Output:
1
2025-04-17 09:00:45,640 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 drug candidates, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (349.39 & 354.40 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (80.34) is better than Ligand B (69.64), both are below the 90 A^2 threshold for CNS targets.

**logP:** Ligand A (0.739) is a bit low, potentially hindering permeability, while Ligand B (2.791) is within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A (1 HBD, 5 HBA) is slightly better than Ligand B (2 HBD, 3 HBA) in terms of balancing solubility and permeability, but both are acceptable.

**QED:** Both ligands have good QED scores (0.848 and 0.791, respectively), indicating drug-likeness.

**DILI:** Ligand A (60.22%) has a higher DILI risk than Ligand B (23.42%), which is a significant concern.

**BBB:** Ligand A (83.83%) has a slightly better BBB penetration score than Ligand B (74.91%), both are above the 70% threshold, but A is preferable.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values, which is unusual and potentially indicates an issue with the data or the model. However, we can still compare them. Ligand A (-4.605) is slightly better than Ligand B (-4.707).

**Aqueous Solubility:** Both ligands have negative solubility values, which is also unusual and potentially indicates an issue with the data or the model. Ligand A (-1.374) is slightly better than Ligand B (-3.198).

**hERG Inhibition:** Ligand A (0.383) has a lower hERG inhibition liability than Ligand B (0.68), which is favorable.

**Microsomal Clearance:** Ligand A (5.566) has a significantly lower microsomal clearance than Ligand B (21.411), indicating better metabolic stability.

**In vitro Half-Life:** Ligand A (3.825) has a shorter half-life than Ligand B (-3.09), which is less desirable.

**P-gp Efflux:** Ligand A (0.03) has a much lower P-gp efflux liability than Ligand B (0.078), which is crucial for CNS penetration.

**Binding Affinity:** Ligand B (-9.2 kcal/mol) has a significantly stronger binding affinity than Ligand A (-7.4 kcal/mol). This is a substantial advantage, exceeding the 1.5 kcal/mol threshold.

**Overall Assessment:**

Despite Ligand A's better BBB and P-gp efflux, the significantly stronger binding affinity of Ligand B (-9.2 vs -7.4 kcal/mol) is a major advantage that outweighs its slightly lower BBB and higher P-gp efflux. Furthermore, Ligand B has a much lower DILI risk, which is a critical safety concern. While the negative Caco-2 and solubility values are concerning, the overall profile of Ligand B is more promising.

Output:
1
2025-04-17 09:00:45,641 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (337.427 and 345.403 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (55.21) is significantly better than Ligand B (91.61). For CNS targets, we want TPSA <= 90, and A is comfortably within that range, while B is close to the upper limit and less desirable.

**3. logP:** Both ligands have acceptable logP values (2.9 and 1.169, respectively), falling within the 1-3 optimal range. Ligand A is slightly better.

**4. H-Bond Donors:** Both have 1 HBD, which is good.

**5. H-Bond Acceptors:** Both have 6 HBA, which is also good.

**6. QED:** Ligand A (0.776) has a better QED score than Ligand B (0.651), indicating a more drug-like profile.

**7. DILI:** Ligand B (54.168) has a lower DILI risk than Ligand A (66.615), making it slightly more favorable from a toxicity perspective.

**8. BBB:** Both ligands have good BBB penetration (75.921 and 72.586, respectively), exceeding the desirable threshold of >70 for CNS targets. Ligand A is slightly better.

**9. Caco-2:** Both have negative Caco-2 values, which is unusual and suggests poor permeability. However, the scale is not specified, so it's hard to interpret.

**10. Solubility:** Both have negative solubility values, which is also unusual. Again, the scale is not specified, making interpretation difficult.

**11. hERG:** Both ligands have low hERG inhibition liability (0.924 and 0.504, respectively), which is excellent.

**12. Cl_mic:** Ligand B (15.557) has a significantly lower microsomal clearance than Ligand A (56.589), indicating better metabolic stability. This is a significant advantage.

**13. t1/2:** Ligand B (-9.582) has a longer in vitro half-life than Ligand A (17.281), which is also a significant advantage.

**14. Pgp:** Both have very low Pgp efflux liability (0.477 and 0.057, respectively), which is excellent for CNS penetration. Ligand B is better.

**15. Binding Affinity:** Both ligands have the same binding affinity (-9.5 kcal/mol), which is very strong.

**Overall Assessment:**

While Ligand B has advantages in DILI, Cl_mic, t1/2, and Pgp efflux, Ligand A has a better TPSA and QED score. Given the GPCR-specific priorities, TPSA is crucial for CNS penetration, and Ligand A's lower TPSA is a significant advantage. The difference in metabolic stability (Cl_mic and t1/2) is also important, favoring Ligand B, but the strong affinity of both ligands mitigates some of the concern about Ligand A's higher clearance. Ultimately, the slightly better TPSA and QED of Ligand A, combined with comparable BBB and affinity, give it a slight edge.

Output:
1
2025-04-17 09:00:45,641 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (348.418 Da) is slightly lower, which could be beneficial for permeability. Ligand B (353.507 Da) is also good.

**TPSA:** Ligand A (50.8) is excellent, well below the 90 A^2 threshold for CNS targets. Ligand B (61.88) is still reasonable, but less optimal.

**logP:** Both ligands have good logP values (A: 2.335, B: 1.497), falling within the 1-3 range.

**H-Bond Donors/Acceptors:** Both have 1 HBD and 4 HBA, which are within acceptable limits.

**QED:** Ligand A (0.887) has a significantly better QED score than Ligand B (0.682), indicating a more drug-like profile.

**DILI:** Ligand A (13.61) has a much lower DILI risk than Ligand B (5.894), which is a significant advantage.

**BBB:** Ligand A (88.057) has a substantially higher BBB penetration percentile than Ligand B (66.925). This is *critical* for a CNS target like DRD2.

**Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and suggests poor permeability. However, the scale isn't specified, so it's hard to interpret.

**Aqueous Solubility:** Both have negative solubility values, also unusual. Again, the scale is unknown.

**hERG:** Both ligands have low hERG inhibition liability (A: 0.634, B: 0.361), which is good.

**Microsomal Clearance:** Ligand A (41.786) has higher microsomal clearance than Ligand B (-0.864), suggesting lower metabolic stability.

**In vitro Half-Life:** Ligand B (-1.114) has a negative half-life, which is not physically possible and indicates an issue with the data. Ligand A (1.431) is reasonable.

**P-gp Efflux:** Both have low P-gp efflux liability (A: 0.061, B: 0.023), which is favorable for CNS penetration.

**Binding Affinity:** Ligand A (-8.7 kcal/mol) has a significantly stronger binding affinity than Ligand B (-7.6 kcal/mol). This 1.1 kcal/mol difference is substantial and can outweigh some ADME drawbacks.

**Overall Assessment:**

Ligand A is clearly superior. It has a much better BBB score, a significantly higher binding affinity, a better QED score, and a much lower DILI risk. While its microsomal clearance is higher, the substantial advantages in BBB, affinity, and safety outweigh this concern. The negative values for Caco-2 and solubility are concerning, but the overall profile of Ligand A is far more promising for CNS drug development. The negative half-life value for Ligand B is a major red flag.

Output:
1
2025-04-17 09:00:45,641 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (356.348 and 349.37 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (79.18) is significantly better than Ligand B (97.94). For CNS targets, we want TPSA <= 90, so Ligand A is preferable.

**3. logP:** Ligand A (1.789) is within the optimal range (1-3). Ligand B (-0.135) is below 1, which could hinder permeation. This favors Ligand A.

**4. H-Bond Donors:** Ligand A (3) and Ligand B (1) are both acceptable (<=5).

**5. H-Bond Acceptors:** Ligand A (5) and Ligand B (7) are both acceptable (<=10).

**6. QED:** Both ligands have good QED scores (0.714 and 0.751, both >= 0.5).

**7. DILI:** Both ligands have similar DILI risk (51.493 and 53.393, both <60, indicating low risk).

**8. BBB:** Ligand A (68.864) and Ligand B (64.482) are both below the desirable threshold of >70 for CNS targets. However, Ligand A is slightly better.

**9. Caco-2 Permeability:** Both have negative values (-5.071 and -5.163). This is unusual and requires further investigation, but doesn't immediately disqualify either.

**10. Aqueous Solubility:** Both have negative values (-2.806 and -1.45). Again, unusual and requires further investigation.

**11. hERG:** Both ligands have low hERG risk (0.512 and 0.336).

**12. Microsomal Clearance:** Both have similar microsomal clearance (18.733 and 17.431).

**13. In vitro Half-Life:** Ligand A (5.646) has a better half-life than Ligand B (-12.258).

**14. P-gp Efflux:** Ligand A (0.135) has a much lower P-gp efflux liability than Ligand B (0.025), which is crucial for CNS penetration.

**15. Binding Affinity:** Ligand A (-9.4 kcal/mol) has a significantly stronger binding affinity than Ligand B (-8.0 kcal/mol). This >1.5 kcal/mol difference is substantial and can outweigh minor ADME drawbacks.

**Overall Assessment:**

Ligand A is clearly superior. It has better TPSA, logP, P-gp efflux, and significantly better binding affinity. While both have suboptimal BBB penetration and solubility/permeability values, the stronger binding and better ADME properties of Ligand A make it the more promising drug candidate.

Output:
1
2025-04-17 09:00:45,641 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (381.223 Da) is slightly higher than Ligand B (354.451 Da), but both are acceptable.

**TPSA:** Both ligands have TPSA values below 140 (Ligand A: 99.25, Ligand B: 94.47), which is good for oral absorption. More importantly, both are below the 90 threshold desirable for CNS targets.

**logP:** Ligand A (3.059) is optimal, while Ligand B (-0.039) is significantly below the optimal range of 1-3. This is a major disadvantage for Ligand B as it may struggle with membrane permeability.

**H-Bond Donors/Acceptors:** Ligand A (HBD=3, HBA=5) and Ligand B (HBD=2, HBA=6) both fall within acceptable limits.

**QED:** Both ligands have QED values above 0.5 (Ligand A: 0.707, Ligand B: 0.669), indicating good drug-like properties.

**DILI:** Ligand A (97.829) has a high DILI risk, while Ligand B (9.965) has a very low risk. This is a significant concern for Ligand A.

**BBB:** Ligand A (60.876) has a moderate BBB penetration, while Ligand B (32.299) has poor BBB penetration. While >70 is desirable, Ligand A is better than Ligand B in this regard.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values, which is unusual and suggests poor permeability. However, the scale is not specified, so it's difficult to interpret.

**Aqueous Solubility:** Both ligands have negative solubility values, again, the scale is not specified.

**hERG:** Both ligands have very low hERG inhibition liability (Ligand A: 0.116, Ligand B: 0.104), which is good.

**Microsomal Clearance:** Ligand A (10.783) has a moderate clearance, while Ligand B (-4.62) has a negative clearance, which is not physically possible. This suggests an issue with the data for Ligand B.

**In vitro Half-Life:** Ligand A (20.454 hours) has a reasonable half-life, while Ligand B (11.244 hours) is also acceptable.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (Ligand A: 0.033, Ligand B: 0.017), which is favorable for CNS penetration.

**Binding Affinity:** Ligand A (-9.5 kcal/mol) has a significantly stronger binding affinity than Ligand B (-7.1 kcal/mol). This is a substantial advantage for Ligand A. The difference is >1.5 kcal/mol, and could outweigh other drawbacks.

**Overall Assessment:**

Ligand A has a much stronger binding affinity and a better logP value, both crucial for GPCR targeting. However, it has a high DILI risk. Ligand B has a low DILI risk but suffers from a very poor logP, and questionable Caco-2 and solubility data. The poor logP of Ligand B is a major concern for CNS penetration, even with low P-gp efflux. The negative clearance value for Ligand B is also a red flag. While the DILI risk for Ligand A is concerning, it might be mitigated with structural modifications. The significantly better affinity of Ligand A makes it the more promising starting point for optimization.

Output:
1
2025-04-17 09:00:45,641 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 drug candidates, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (344.386 and 352.414 Da) fall within the ideal range of 200-500 Da.

**TPSA:** Ligand A (49.85) is excellent, well below the 90 A^2 threshold for CNS targets. Ligand B (117) is higher, but still potentially acceptable, though less ideal.

**logP:** Ligand A (2.154) is optimal (1-3). Ligand B (0.565) is a bit low, potentially hindering permeation.

**H-Bond Donors/Acceptors:** Ligand A (0 HBD, 3 HBA) is very favorable. Ligand B (3 HBD, 5 HBA) is also reasonable, within the guidelines.

**QED:** Both ligands have similar QED values (0.79 and 0.663), indicating good drug-likeness.

**DILI:** Both ligands have low DILI risk (34.587 and 32.842 percentile), which is good.

**BBB:** Ligand A (86.39%) has a significantly better BBB penetration score than Ligand B (68.554%). This is a crucial advantage for a CNS target like DRD2.

**Caco-2 Permeability:** Ligand A (-4.401) has a negative value, suggesting poor permeability. Ligand B (-5.562) is even worse. This is a concern for both, but less critical for CNS targets where direct brain penetration is prioritized.

**Aqueous Solubility:** Both ligands have negative solubility values (-2.693 and -2.375), indicating poor aqueous solubility. This could pose formulation challenges.

**hERG Inhibition:** Ligand A (0.501) has a lower hERG inhibition risk than Ligand B (0.078). This is a positive for Ligand A.

**Microsomal Clearance:** Ligand A (-0.874) has a lower (better) microsomal clearance than Ligand B (-9.029), indicating greater metabolic stability.

**In vitro Half-Life:** Both ligands have similar, very long in vitro half-lives (-19.811 and -19.92 hours).

**P-gp Efflux:** Ligand A (0.111) has a lower P-gp efflux liability than Ligand B (0.004), which is favorable for CNS penetration.

**Binding Affinity:** Ligand B (-8.6 kcal/mol) has a slightly better binding affinity than Ligand A (-7.5 kcal/mol). However, the difference is less than 1.5 kcal/mol, and can be overcome by other favorable ADME properties.

**Overall Assessment:**

Ligand A is the more promising candidate. While Ligand B has slightly better binding affinity, Ligand A excels in crucial properties for a CNS-targeting GPCR drug: significantly better BBB penetration, lower P-gp efflux, lower hERG risk, and better metabolic stability. The lower logP and Caco-2 permeability of Ligand B are significant drawbacks. The poor solubility of both compounds would need to be addressed during formulation.



Output:
0
2025-04-17 09:00:45,642 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 drug candidates, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (350.459 Da and 362.417 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Both ligands have a TPSA of 78.87, which is acceptable for oral absorption but slightly high for optimal CNS penetration (ideally <90, but closer to 60-70 is preferred).

**3. logP:** Both ligands have logP values around 1.1 (1.095 and 1.172), which is within the optimal range of 1-3.

**4. H-Bond Donors:** Both have 2 HBD, which is within the acceptable limit of <=5.

**5. H-Bond Acceptors:** Both have 4 HBA, also within the acceptable limit of <=10.

**6. QED:** Both ligands have a QED > 0.7, indicating good drug-likeness.

**7. DILI:** Ligand A (14.618) has a significantly lower DILI risk than Ligand B (16.402). This is a substantial advantage.

**8. BBB:** Ligand B (87.67) has a considerably higher BBB penetration percentile than Ligand A (72.819). This is a major advantage for a CNS target like DRD2.

**9. Caco-2 Permeability:** Ligand A (-4.525) has slightly better Caco-2 permeability than Ligand B (-4.754), but both are negative values, suggesting poor permeability.

**10. Aqueous Solubility:** Ligand A (-1.909) has slightly better aqueous solubility than Ligand B (-1.768), but both are negative, indicating poor solubility.

**11. hERG Inhibition:** Ligand A (0.253) has a lower hERG inhibition liability than Ligand B (0.469), which is preferable.

**12. Microsomal Clearance:** Ligand B (-8.685) has a significantly *lower* (better) microsomal clearance than Ligand A (34.442). This suggests better metabolic stability for Ligand B.

**13. In vitro Half-Life:** Ligand B (-24.64) has a much longer in vitro half-life than Ligand A (1.315), indicating greater stability.

**14. P-gp Efflux:** Ligand A (0.04) has slightly lower P-gp efflux liability than Ligand B (0.027), which is favorable.

**15. Binding Affinity:** Both ligands have the same binding affinity (-8.1 kcal/mol), which is excellent.

**Overall Assessment:**

While Ligand A has a lower DILI risk and slightly better Caco-2 permeability and P-gp efflux, Ligand B is superior due to its significantly better BBB penetration (87.67 vs 72.819) and dramatically improved metabolic stability (lower Cl_mic and much longer half-life). For a CNS target like DRD2, BBB penetration and metabolic stability are paramount. The slightly higher DILI risk of Ligand B is a concern but potentially manageable with further optimization. The equal binding affinity removes that as a differentiating factor.

Output:
1
2025-04-17 09:00:45,642 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (356.438 and 355.408 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (76.66) is better than Ligand B (57.7). Both are below the 90 A^2 threshold desirable for CNS targets, but Ligand B is closer to the optimal range.

**3. logP:** Ligand A (1.331) is within the optimal range (1-3). Ligand B (3.965) is at the higher end of the optimal range, potentially edging into a zone where solubility could become an issue.

**4. H-Bond Donors:** Ligand A (2) and Ligand B (1) both satisfy the <=5 rule.

**5. H-Bond Acceptors:** Both ligands (4) are well below the 10 threshold.

**6. QED:** Both ligands have good QED scores (0.753 and 0.779, respectively), indicating good drug-like properties.

**7. DILI:** Both ligands have acceptable DILI risk (30.361 and 35.401 percentile), below the 40% threshold.

**8. BBB:** Ligand A (82.435) has a significantly better BBB penetration score than Ligand B (76.735). This is a critical factor for a CNS target like DRD2.

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 values, which is unusual and suggests a potential issue with in vitro permeability assessment. However, the magnitude of the negative value for Ligand A (-4.945) is less extreme than for Ligand B (-4.986).

**10. Aqueous Solubility:** Both ligands have negative solubility values, which is also unusual. Ligand A (-2.053) is slightly better than Ligand B (-3.744).

**11. hERG Inhibition:** Both ligands have low hERG inhibition risk (0.434 and 0.909, respectively).

**12. Microsomal Clearance:** Ligand B (18.643) has a higher microsomal clearance than Ligand A (15.075), suggesting Ligand A is more metabolically stable.

**13. In vitro Half-Life:** Ligand A (26.298) has a significantly longer in vitro half-life than Ligand B (9.822).

**14. P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.043 and 0.352, respectively).

**15. Binding Affinity:** Ligand A (-8.7 kcal/mol) has a substantially stronger binding affinity than Ligand B (-7.3 kcal/mol). This 1.4 kcal/mol difference is significant and can outweigh minor ADME drawbacks.

**Overall Assessment:**

Ligand A is the superior candidate. While both ligands have acceptable physicochemical properties, Ligand A excels in the most critical areas for a CNS-targeting GPCR: BBB penetration, binding affinity, metabolic stability (lower Cl_mic, longer t1/2), and slightly better solubility. The stronger binding affinity of Ligand A is a major advantage. The negative Caco-2 and solubility values are concerning for both, but the values are less problematic for Ligand A.

Output:
1
2025-04-17 09:00:45,642 - INFO - Batch 497 complete. Total preferences: 7952
2025-04-17 09:00:45,642 - INFO - Processing batch 498/512...
2025-04-17 09:01:27,619 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (364.515 and 362.543 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (66.49) is better than Ligand B (51.02). Both are below the 90 A^2 threshold for CNS targets, which is excellent.

**logP:** Ligand A (1.93) is within the optimal 1-3 range. Ligand B (3.257) is at the higher end of the optimal range, potentially increasing off-target interactions.

**H-Bond Donors:** Ligand A (2) is preferable to Ligand B (0). Having some H-bond donors can aid solubility.

**H-Bond Acceptors:** Both ligands have 5 H-bond acceptors, which is acceptable (<=10).

**QED:** Ligand A (0.838) has a better QED score than Ligand B (0.747), indicating a more drug-like profile.

**DILI:** Both ligands have low DILI risk (21.753 and 22.489, respectively), which is good.

**BBB:** Ligand B (80.845) has a slightly better BBB penetration percentile than Ligand A (77.2), but both are above the desirable 70% threshold for CNS targets.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values, which is unusual and suggests poor permeability. However, the scale is not defined, so it is difficult to interpret.

**Aqueous Solubility:** Both ligands have negative solubility values, which is also unusual and suggests poor solubility. Again, the scale is not defined.

**hERG Inhibition:** Both ligands have low hERG inhibition liability (0.569 and 0.452, respectively), which is good.

**Microsomal Clearance:** Ligand A (-14.647) has a much lower (better) microsomal clearance than Ligand B (90.353), indicating higher metabolic stability.

**In vitro Half-Life:** Ligand A (33.703 hours) has a longer half-life than Ligand B (23.433 hours), which is desirable.

**P-gp Efflux:** Ligand A (0.03) has significantly lower P-gp efflux liability than Ligand B (0.334), which is crucial for CNS penetration.

**Binding Affinity:** Ligand A (-8.9 kcal/mol) has a significantly stronger binding affinity than Ligand B (-6.8 kcal/mol). This is a substantial advantage (over 2 kcal/mol difference).

**Overall Assessment:**

Ligand A is superior. While Ligand B has a slightly better BBB score, Ligand A excels in almost every other critical parameter. Its significantly better affinity, lower P-gp efflux, lower microsomal clearance, longer half-life, better QED, and more favorable HBD count outweigh the slight difference in BBB. The negative Caco-2 and solubility values are concerning for both, but the stronger binding and better ADME properties of Ligand A make it a more promising candidate.

Output:
1
2025-04-17 09:01:27,620 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (348.447 and 367.519 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (97.55) is slightly above the optimal <90 for CNS targets, but still reasonable. Ligand B (61.68) is excellent, well below 90.

**logP:** Ligand A (2.142) is within the optimal 1-3 range. Ligand B (0.696) is a bit low, potentially impacting permeability.

**H-Bond Donors/Acceptors:** Ligand A has 2 HBD and 5 HBA, which are acceptable. Ligand B has 0 HBD and 6 HBA, also acceptable.

**QED:** Both ligands have good QED scores (0.499 and 0.693), indicating reasonable drug-likeness.

**DILI:** Both ligands have low DILI risk (42.885 and 35.789), which is favorable.

**BBB:** Ligand A has a significantly better BBB penetration score (78.596) compared to Ligand B (68.554). This is a critical factor for a CNS target like DRD2.

**Caco-2 Permeability:** Ligand A (-5.229) has a worse Caco-2 permeability score than Ligand B (-4.986), but both are negative and thus indicate poor permeability.

**Aqueous Solubility:** Ligand A (-2.727) has a worse aqueous solubility score than Ligand B (-0.849), but both are negative and thus indicate poor solubility.

**hERG:** Both ligands have low hERG inhibition liability (0.347 and 0.54), which is good.

**Microsomal Clearance:** Ligand A (21.781) has a lower microsomal clearance than Ligand B (28.672), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (-5.198) has a worse in vitro half-life than Ligand B (-3.634), but both are negative and thus indicate poor half-life.

**P-gp Efflux:** Ligand A (0.064) has a lower P-gp efflux liability than Ligand B (0.099), which is favorable for CNS penetration.

**Binding Affinity:** Both ligands have strong binding affinities (-8.0 and -6.8 kcal/mol). Ligand A is significantly more potent (1.2 kcal/mol advantage). This is a substantial difference and can often outweigh minor ADME issues.

**Overall Assessment:**

Ligand A has a significantly better binding affinity and a superior BBB score, both crucial for a CNS-targeting GPCR. While its Caco-2 permeability and aqueous solubility are worse than Ligand B, the strong affinity and good BBB penetration are likely to be more important for *in vivo* efficacy at the DRD2 receptor. Ligand B's lower logP is a concern for permeability. The slightly better metabolic stability of Ligand A is also a plus.

Output:
1
2025-04-17 09:01:27,620 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (420.317 Da) is higher than Ligand B (347.415 Da), but both are acceptable.

**TPSA:** Ligand A (18.51) is excellent, well below the 90 A^2 threshold for CNS targets. Ligand B (93.46) is significantly higher, exceeding the preferred threshold for CNS penetration. This is a major drawback for Ligand B.

**logP:** Ligand A (3.668) is within the optimal range (1-3). Ligand B (1.804) is at the lower end, potentially hindering membrane permeability.

**H-Bond Donors/Acceptors:** Ligand A (HBD=1, HBA=3) and Ligand B (HBD=2, HBA=5) both have reasonable numbers of hydrogen bond donors and acceptors, falling within acceptable limits.

**QED:** Both ligands have similar QED values (A: 0.785, B: 0.734), indicating good drug-likeness.

**DILI:** Ligand A (8.957) has a much lower DILI risk than Ligand B (54.052), which is a significant advantage.

**BBB:** Ligand A (92.943) exhibits excellent BBB penetration, exceeding the desirable 70% threshold. Ligand B (75.223) is lower, but still reasonable, although not as favorable.

**Caco-2 Permeability:** Ligand A (-5.084) has a negative value, which is unusual and suggests poor permeability. Ligand B (-4.931) is also negative, but slightly less so.

**Aqueous Solubility:** Both ligands have negative solubility values (-3.745 and -3.19 respectively), indicating poor aqueous solubility. This could pose formulation challenges.

**hERG Inhibition:** Ligand A (0.985) has a slightly higher hERG risk than Ligand B (0.175), but both are relatively low.

**Microsomal Clearance:** Ligand A (-5.704) has a negative clearance, which is unusual and suggests very high metabolic stability. Ligand B (39.966) has a higher clearance, indicating faster metabolism.

**In vitro Half-Life:** Ligand A (8.856) has a longer half-life than Ligand B (-1.475).

**P-gp Efflux:** Ligand A (0.229) has lower P-gp efflux liability than Ligand B (0.089), which is beneficial for CNS exposure.

**Binding Affinity:** Ligand A (-9.0 kcal/mol) has a significantly stronger binding affinity than Ligand B (-8.1 kcal/mol). This 1.9 kcal/mol difference is substantial and can outweigh some ADME drawbacks.

**Conclusion:**

Considering all factors, especially the GPCR-specific priorities, **Ligand A is the more promising drug candidate**. Its superior BBB penetration, lower DILI risk, significantly stronger binding affinity, and lower P-gp efflux outweigh its slightly lower logP and negative Caco-2 permeability. The negative clearance is also a positive sign, suggesting high metabolic stability. While both ligands have solubility issues, the overall profile of Ligand A is much more favorable for CNS drug development targeting DRD2.

Output:
1
2025-04-17 09:01:27,620 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (365.411 Da) is slightly higher than Ligand B (348.399 Da), but both are acceptable.

**TPSA:** Ligand A (104.81) is higher than Ligand B (79.31). For CNS targets, we prefer TPSA <= 90. Ligand B is better here.

**logP:** Ligand A (0.108) is quite low, potentially hindering permeability. Ligand B (1.072) is within the optimal range (1-3). Ligand B is significantly better.

**H-Bond Donors:** Ligand A (2) and Ligand B (1) are both acceptable (<=5). Ligand B is slightly preferred.

**H-Bond Acceptors:** Both ligands have 5 HBA, which is acceptable (<=10).

**QED:** Both ligands have good QED scores (Ligand A: 0.74, Ligand B: 0.832), indicating good drug-like properties.

**DILI:** Ligand A (64.831) has a higher DILI risk than Ligand B (37.185). Lower is better, so Ligand B is preferred.

**BBB:** Both ligands have reasonable BBB penetration (Ligand A: 57.425, Ligand B: 59.248). However, for a CNS target like DRD2, >70 is desirable. Neither is ideal, but they are comparable.

**Caco-2 Permeability:** Both have negative Caco-2 values (-4.865 and -4.576), which is unusual and suggests poor permeability. This is a concern for both.

**Aqueous Solubility:** Both have negative solubility values (-2.429 and -1.645), also unusual and concerning.

**hERG Inhibition:** Ligand A (0.179) has a slightly lower hERG risk than Ligand B (0.356), which is preferable.

**Microsomal Clearance:** Ligand A (-0.083) has a lower (better) microsomal clearance than Ligand B (11.906). This suggests better metabolic stability for Ligand A.

**In vitro Half-Life:** Ligand A (0.887) has a shorter half-life than Ligand B (-10.61). This is a significant drawback for Ligand A.

**P-gp Efflux:** Ligand A (0.02) has much lower P-gp efflux liability than Ligand B (0.081), which is beneficial for CNS penetration.

**Binding Affinity:** Ligand A (-8.3 kcal/mol) has a slightly better binding affinity than Ligand B (-7.7 kcal/mol). This is a significant advantage.

**Overall Assessment:**

Ligand B has better physicochemical properties (logP, TPSA, DILI) and metabolic stability (Cl_mic). However, Ligand A has a slightly better binding affinity and lower P-gp efflux. The low logP of Ligand A is a major concern, potentially limiting its ability to cross cell membranes. The negative solubility and Caco-2 values are also concerning for both. Considering the GPCR-specific priorities, the better logP and lower DILI risk of Ligand B, combined with its acceptable BBB, outweigh the slightly weaker binding affinity. The improved metabolic stability is also a plus.

Output:
1
2025-04-17 09:01:27,620 - INFO - Reasoning:

Let's analyze Ligand A and Ligand B based on the provided guidelines, prioritizing GPCR-specific properties (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (339.483) is slightly lower, which could be beneficial for permeability, but both are acceptable.

**TPSA:** Ligand A (46.92) is excellent for CNS penetration, well below the 90 A^2 threshold. Ligand B (78.87) is higher, but still reasonably good.

**logP:** Ligand A (4.619) is at the upper end of the optimal range, potentially leading to solubility issues or off-target interactions. Ligand B (1.419) is lower, but still within the acceptable range.

**H-Bond Donors/Acceptors:** Ligand A (HBD=1, HBA=3) and Ligand B (HBD=2, HBA=4) both have reasonable numbers of H-bond donors and acceptors, unlikely to cause significant issues.

**QED:** Ligand A (0.887) has a higher QED score than Ligand B (0.725), indicating a more drug-like profile.

**DILI:** Ligand A (55.021) has a moderate DILI risk, while Ligand B (11.322) has a very low DILI risk. This is a significant advantage for Ligand B.

**BBB:** Ligand A (95.657) has excellent BBB penetration, a crucial factor for a CNS target like DRD2. Ligand B (69.756) is still good, but significantly lower than Ligand A.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values, which is unusual and suggests a potential issue with the data or modeling. However, we'll proceed assuming these represent low permeability.

**Aqueous Solubility:** Both ligands have negative solubility values, again suggesting a potential data issue.

**hERG:** Ligand A (0.883) and Ligand B (0.333) both show low hERG inhibition liability, which is good.

**Microsomal Clearance:** Ligand A (64.366) has a higher microsomal clearance than Ligand B (23.652), indicating lower metabolic stability. Ligand B is preferable here.

**In vitro Half-Life:** Ligand A (86.568) has a longer in vitro half-life than Ligand B (8.037), which is desirable.

**P-gp Efflux:** Ligand A (0.857) has moderate P-gp efflux, while Ligand B (0.048) has very low P-gp efflux. This is a significant advantage for Ligand B, as it will lead to better CNS exposure.

**Binding Affinity:** Ligand A (-8.9 kcal/mol) has a slightly better binding affinity than Ligand B (-8.0 kcal/mol). This 0.9 kcal/mol difference, while noticeable, may not be enough to overcome the ADME liabilities of Ligand A.

**Overall Assessment:**

Ligand A excels in BBB penetration, in vitro half-life, and binding affinity. However, it has a higher logP, higher DILI risk, higher microsomal clearance, and moderate P-gp efflux. Ligand B has a much better safety profile (lower DILI, lower P-gp efflux, lower Cl_mic) and a reasonable BBB score. The slightly weaker binding affinity of Ligand B is likely outweighed by its superior ADME properties, especially for a CNS target where achieving sufficient brain exposure is critical.

Output:
1
2025-04-17 09:01:27,620 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (348.49 and 343.39 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (49.85) is excellent, well below the 90 A^2 threshold for CNS targets. Ligand B (135.78) is higher, but still potentially acceptable, though less ideal.

**3. logP:** Ligand A (2.468) is optimal (1-3). Ligand B (0.372) is low, potentially hindering permeation.

**4. H-Bond Donors:** Ligand A (0) is good. Ligand B (3) is acceptable.

**5. H-Bond Acceptors:** Ligand A (3) is good. Ligand B (7) is acceptable.

**6. QED:** Both ligands have good QED scores (0.475 and 0.689, respectively), indicating reasonable drug-likeness. Ligand B is slightly better.

**7. DILI:** Ligand A (17.26) has a much lower DILI risk than Ligand B (66.42). This is a significant advantage for Ligand A.

**8. BBB:** Ligand A (73.75) has a good BBB penetration percentile, exceeding the 70% threshold. Ligand B (57.74) is lower, which is concerning for a CNS target.

**9. Caco-2 Permeability:** Ligand A (-4.248) is poor, indicating low intestinal absorption. Ligand B (-5.602) is also poor.

**10. Aqueous Solubility:** Both ligands have poor aqueous solubility (-2.548 and -2.629).

**11. hERG Inhibition:** Both ligands show low hERG inhibition risk (0.545 and 0.17).

**12. Microsomal Clearance:** Ligand A (70.26) has higher clearance than Ligand B (26.67), suggesting lower metabolic stability.

**13. In vitro Half-Life:** Ligand B (-10.663) has a negative half-life, which is not possible and indicates a very rapid degradation. Ligand A (6.305) has a reasonable half-life.

**14. P-gp Efflux:** Ligand A (0.154) has lower P-gp efflux liability than Ligand B (0.003), which is favorable for CNS penetration.

**15. Binding Affinity:** Ligand B (-7.7 kcal/mol) has a slightly better binding affinity than Ligand A (-6.7 kcal/mol). However, the difference is not substantial enough to overcome the significant ADME deficiencies of Ligand B.

**Overall Assessment:**

Ligand A is clearly the better candidate. While its Caco-2 permeability and aqueous solubility are poor, its superior BBB penetration, lower DILI risk, more reasonable metabolic stability, and lower P-gp efflux outweigh the slightly weaker binding affinity. Ligand B has a concerningly low BBB penetration, very high DILI risk, and a nonsensical half-life value. The slightly better affinity of Ligand B does not compensate for these critical flaws.

Output:
0
2025-04-17 09:01:27,620 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (371.487 and 355.429 Da) are within the ideal 200-500 Da range.

**TPSA:** Ligand A (64.11) is higher than Ligand B (37.83). For CNS targets, TPSA should be <= 90, both are within this range, but B is significantly better.

**logP:** Ligand A (4.117) is slightly higher than the optimal range (1-3), potentially leading to solubility issues. Ligand B (2.536) is within the optimal range.

**H-Bond Donors/Acceptors:** Ligand A has 1 HBD and 6 HBA, which are acceptable. Ligand B has 0 HBD and 5 HBA, also acceptable.

**QED:** Both ligands have good QED scores (0.661 and 0.759), indicating drug-like properties.

**DILI:** Ligand A has a DILI risk of 88.212, which is high. Ligand B has a very low DILI risk of 5.545, a significant advantage.

**BBB:** Ligand A has a BBB penetration of 46.646, which is below the desirable threshold of >70 for CNS targets. Ligand B has a very high BBB penetration of 97.208, a major advantage.

**Caco-2 Permeability:** Both have negative Caco-2 values (-5.001 and -4.414) which is unusual and suggests poor permeability. However, these values are on a scale where negative values are possible and don't necessarily disqualify the compounds.

**Aqueous Solubility:** Both have negative solubility values (-4.631 and -1.301), indicating poor aqueous solubility. This is a concern, especially for Ligand A with its higher logP.

**hERG Inhibition:** Ligand A (0.551) has a slightly higher hERG risk than Ligand B (0.877), but both are relatively low.

**Microsomal Clearance:** Ligand A (75.952) has a higher microsomal clearance than Ligand B (-9.637), indicating lower metabolic stability. Negative clearance is unusual and very favorable.

**In vitro Half-Life:** Ligand A (3.357) has a shorter half-life than Ligand B (-3.392). Again, negative half-life is unusual and very favorable.

**P-gp Efflux:** Ligand A (0.365) has lower P-gp efflux than Ligand B (0.059), which is favorable for CNS penetration.

**Binding Affinity:** Both ligands have the same binding affinity (-8.2 kcal/mol), which is excellent.

**Conclusion:**

Despite similar binding affinities, Ligand B is significantly more promising. Its superior BBB penetration (97.208 vs 46.646), much lower DILI risk (5.545 vs 88.212), better logP (2.536 vs 4.117), and more favorable metabolic stability (negative Cl_mic and t1/2) outweigh the slightly lower P-gp efflux and TPSA. The negative Caco-2 and solubility values are concerning for both, but the other advantages of Ligand B make it the better candidate.

Output:
1
2025-04-17 09:01:27,620 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 drug candidates, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (370.425 Da) and Ligand B (341.415 Da) are both acceptable.

**TPSA:** Both ligands have TPSA values below the 90 A^2 threshold desirable for CNS targets. Ligand A (86.88 A^2) is better than Ligand B (72.58 A^2).

**logP:** Ligand A (2.932) is optimal (1-3). Ligand B (0.275) is quite low, potentially hindering membrane permeability and CNS penetration.

**H-Bond Donors/Acceptors:** Ligand A has 3 HBD and 4 HBA, which are within acceptable limits. Ligand B has 0 HBD and 5 HBA, also acceptable, but the lack of HBD could impact aqueous solubility.

**QED:** Both ligands have good QED scores (A: 0.668, B: 0.791), indicating good drug-like properties.

**DILI:** Ligand A has a DILI risk of 67.817, which is moderately high. Ligand B has a much lower DILI risk (30.787), a significant advantage.

**BBB:** Ligand A has a BBB penetration of 61.923, which is acceptable, but not ideal. Ligand B has a lower BBB penetration (49.826), which is concerning for a CNS target.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values, which is unusual and suggests poor permeability. Ligand A (-5.468) is slightly better than Ligand B (-4.784).

**Aqueous Solubility:** Both ligands have negative solubility values, indicating poor aqueous solubility. Ligand A (-3.077) is slightly better than Ligand B (-1.817).

**hERG Inhibition:** Both ligands have low hERG inhibition risk (A: 0.592, B: 0.473).

**Microsomal Clearance:** Ligand A has a higher microsomal clearance (36.755 mL/min/kg) than Ligand B (21.7 mL/min/kg), suggesting lower metabolic stability.

**In vitro Half-Life:** Ligand B has a significantly longer in vitro half-life (17.902 hours) than Ligand A (-3.662 hours). This is a major advantage for Ligand B.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (A: 0.153, B: 0.01). Ligand B is slightly better.

**Binding Affinity:** Both ligands have excellent binding affinity (-8.8 kcal/mol and -8.2 kcal/mol). The difference of 0.6 kcal/mol is not substantial enough to outweigh other factors.

**Overall Assessment:**

Ligand B is the better candidate. While Ligand A has a slightly better TPSA and Caco-2 permeability, Ligand B excels in crucial areas for a CNS-targeting GPCR drug: lower DILI risk, significantly longer half-life, and a slightly better P-gp efflux profile. The low logP of Ligand B is a concern, but the strong binding affinity might compensate. The negative solubility and Caco-2 values are concerning for both, but can be addressed with formulation strategies.

Output:
1
2025-04-17 09:01:27,620 - INFO - Reasoning:

Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (355.389 Da) is slightly lower, which is generally favorable for permeability.

**2. TPSA:** Ligand A (110.0) is better than Ligand B (56.49). For CNS targets, we want TPSA <= 90. Ligand A is slightly above, but Ligand B is significantly lower and more desirable.

**3. logP:** Ligand A (1.426) is within the optimal range (1-3). Ligand B (4.36) is higher, potentially leading to solubility issues and off-target interactions.

**4. H-Bond Donors:** Ligand A (3) is acceptable. Ligand B (0) is also acceptable, but a lack of HBDs can sometimes hinder solubility.

**5. H-Bond Acceptors:** Both ligands are within the acceptable range (<=10). Ligand A (5) and Ligand B (6) are both reasonable.

**6. QED:** Ligand A (0.715) is better than Ligand B (0.526), indicating a more drug-like profile.

**7. DILI:** Ligand A (54.44) has a lower DILI risk than Ligand B (85.692), which is a significant advantage.

**8. BBB:** Ligand A (79.294) has a substantially better BBB penetration percentile than Ligand B (48.391). This is *critical* for a CNS target like DRD2.

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 values, which is unusual and suggests poor permeability. However, the scale is not defined, so it is hard to interpret.

**10. Aqueous Solubility:** Both ligands have negative solubility values, which is also unusual.

**11. hERG Inhibition:** Ligand A (0.279) has a much lower hERG inhibition risk than Ligand B (0.539).

**12. Microsomal Clearance:** Ligand A (3.902) has a lower microsomal clearance, suggesting better metabolic stability than Ligand B (34.16).

**13. In vitro Half-Life:** Ligand A (-10.965) has a more negative half-life, which is unusual. Ligand B (-7.941) is also negative.

**14. P-gp Efflux:** Ligand A (0.011) has much lower P-gp efflux liability than Ligand B (0.579), which is crucial for CNS penetration.

**15. Binding Affinity:** Ligand B (-9.9 kcal/mol) has a slightly better binding affinity than Ligand A (-8.3 kcal/mol). This is a 1.6 kcal/mol difference, which is significant.

**Overall Assessment:**

Despite the slightly better affinity of Ligand B, Ligand A is the superior candidate. The significantly better BBB penetration, lower DILI risk, lower hERG inhibition, lower P-gp efflux, and better metabolic stability outweigh the minor difference in binding affinity. The TPSA is also more favorable for CNS penetration. The unusual negative values for Caco-2 and solubility are concerning for both, but the other ADME properties of Ligand A are much more promising.

Output:
1
2025-04-17 09:01:27,621 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (386.901 Da) is slightly higher than Ligand B (342.403 Da), but both are acceptable.

**TPSA:** Ligand A (66.92) is better than Ligand B (103.01). For CNS targets, we want TPSA <= 90. Ligand A is closer to this threshold, suggesting better CNS penetration potential.

**logP:** Ligand A (2.37) is optimal (1-3), while Ligand B (1.028) is at the lower end. Lower logP can hinder permeation. Ligand A has a clear advantage here.

**H-Bond Donors/Acceptors:** Ligand A (0 HBD, 4 HBA) is preferable to Ligand B (3 HBD, 5 HBA). Fewer H-bonds generally improve membrane permeability.

**QED:** Both ligands have similar QED values (Ligand A: 0.796, Ligand B: 0.697), indicating good drug-like properties.

**DILI:** Ligand A (60.954) is slightly higher than Ligand B (55.176), but both are within an acceptable range (<60 is good).

**BBB:** Ligand A (63.746) is significantly better than Ligand B (30.399). A BBB percentile >70 is desirable for CNS targets, and Ligand A is closer to that goal. This is a crucial factor for DRD2.

**Caco-2 Permeability:** Ligand A (-4.411) is worse than Ligand B (-5.633), indicating lower intestinal absorption. However, for a CNS target, intestinal absorption is less critical than BBB penetration.

**Aqueous Solubility:** Ligand A (-3.963) is worse than Ligand B (-2.387). Solubility is important, but can often be addressed with formulation strategies.

**hERG:** Both ligands have similar hERG values (Ligand A: 0.401, Ligand B: 0.607), indicating low cardiotoxicity risk.

**Microsomal Clearance:** Ligand B (-28.31) has a lower (better) microsomal clearance than Ligand A (53.565), suggesting greater metabolic stability.

**In vitro Half-Life:** Ligand B (-6.484) has a longer half-life than Ligand A (-33.435), which is desirable.

**P-gp Efflux:** Ligand A (0.203) has lower P-gp efflux than Ligand B (0.013), which is favorable for CNS exposure.

**Binding Affinity:** Ligand B (-8.5 kcal/mol) has a slightly better binding affinity than Ligand A (-7.6 kcal/mol). A difference of 0.9 kcal/mol is significant, but not overwhelming.

**Overall Assessment:**

Considering the GPCR-specific priorities, Ligand A is the better candidate. Its superior BBB penetration (63.746 vs 30.399), optimal logP (2.37 vs 1.028), and lower P-gp efflux (0.203 vs 0.013) are critical for CNS drug development. While Ligand B has better metabolic stability and slightly higher affinity, the CNS penetration advantages of Ligand A outweigh these benefits. The TPSA of Ligand A is also more favorable.



Output:
0
2025-04-17 09:01:27,621 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (371.702 Da) is slightly higher than Ligand B (343.391 Da), but both are acceptable.

**TPSA:** Ligand A (84.08) is excellent for CNS penetration, falling well below the 90 A^2 threshold. Ligand B (105.04) is still reasonable, but less optimal.

**logP:** Ligand A (3.398) is within the optimal range (1-3). Ligand B (0.059) is significantly low, potentially hindering membrane permeability and CNS entry.

**H-Bond Donors/Acceptors:** Both ligands have 2 HBDs, which is good. Ligand A has 4 HBAs, and Ligand B has 7 HBAs. Both are within acceptable limits (<=10), but Ligand B is closer to the upper bound.

**QED:** Both ligands have good QED scores (A: 0.637, B: 0.761), indicating drug-like properties.

**DILI:** Ligand A (96.51) has a higher DILI risk than Ligand B (64.831), which is concerning.

**BBB:** Both ligands show good BBB penetration (A: 54.246, B: 59.131), but neither exceeds the desirable >70 percentile.

**Caco-2 Permeability:** Ligand A (-4.741) has poor Caco-2 permeability, which is a significant drawback. Ligand B (-5.474) is also poor, but slightly better.

**Aqueous Solubility:** Both ligands have very poor aqueous solubility (A: -5.768, B: -1.436). This could pose formulation challenges.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (A: 0.263, B: 0.222).

**Microsomal Clearance:** Ligand A (9.947) has a lower (better) microsomal clearance than Ligand B (-45.013). This suggests better metabolic stability for Ligand A.

**In vitro Half-Life:** Ligand A (44.236) has a longer half-life than Ligand B (24.009), which is favorable.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (A: 0.286, B: 0.013). Ligand B is slightly better.

**Binding Affinity:** Ligand A (-7.9 kcal/mol) has a slightly better binding affinity than Ligand B (-7.3 kcal/mol). While both are good, the 0.6 kcal/mol difference is noteworthy.

**Overall Assessment:**

Ligand A has a better binding affinity, TPSA, metabolic stability (Cl_mic), and half-life. However, it has a significantly higher DILI risk and poor Caco-2 permeability. Ligand B has a lower DILI risk and slightly better P-gp efflux, but suffers from a very low logP, which is a major concern for CNS penetration, and a significantly higher clearance.

Considering the GPCR-specific priorities, **logP and BBB are crucial for CNS targets**. Ligand B's extremely low logP is a deal-breaker, despite its other advantages. While Ligand A has a higher DILI risk and poor Caco-2 permeability, these issues might be addressable through structural modifications. The better affinity and TPSA of Ligand A, combined with acceptable BBB, make it the more promising starting point.

Output:
0
2025-04-17 09:01:27,621 - INFO - Reasoning:

Let's analyze Ligand A and Ligand B based on the provided guidelines, prioritizing GPCR-specific properties (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (346.387 Da) is slightly higher than Ligand B (299.802 Da), but both are acceptable.

**TPSA:** Ligand A (120.42) is borderline for CNS targets (ideally <90), while Ligand B (67.59) is well within the optimal range for CNS penetration. This is a significant advantage for Ligand B.

**logP:** Ligand A (-0.139) is too low, potentially hindering membrane permeability. Ligand B (2.002) is within the optimal range (1-3). This is a clear advantage for Ligand B.

**H-Bond Donors/Acceptors:** Ligand A has 4 HBD and 5 HBA, which are acceptable. Ligand B has 2 HBD and 4 HBA, also acceptable.

**QED:** Both ligands have reasonable QED values (Ligand A: 0.282, Ligand B: 0.756). Ligand B's value is significantly better, indicating a more drug-like profile.

**DILI:** Both ligands have similar DILI risk (Ligand A: 43.893, Ligand B: 50.446), and both are below the concerning threshold of 60.

**BBB:** Ligand A (19.581) has very poor predicted BBB penetration, a critical drawback for a CNS target like DRD2. Ligand B (87.592) has excellent predicted BBB penetration, a major advantage.

**Caco-2 Permeability:** Both have negative Caco-2 values (-5.374 and -4.877), which is unusual and suggests poor permeability. However, the scale is not specified, so it's hard to interpret.

**Aqueous Solubility:** Both have negative solubility values (-1.989 and -2.705), also unusual and suggesting poor solubility. Again, the scale is unspecified.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (Ligand A: 0.166, Ligand B: 0.827).

**Microsomal Clearance:** Ligand A (5.26) has lower clearance than Ligand B (28.947), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (-30.361) has a very negative half-life, which is concerning. Ligand B (13.569) has a more reasonable half-life.

**P-gp Efflux:** Ligand A (0.019) has very low P-gp efflux, which is good. Ligand B (0.015) also has very low P-gp efflux, similar to Ligand A.

**Binding Affinity:** Ligand A (-7.8) has slightly better binding affinity than Ligand B (-7.0). However, the difference is less than 1.5 kcal/mol and can be outweighed by other factors.

**Overall Assessment:**

Ligand B is significantly more promising. Its superior BBB penetration, optimal logP, better QED, and reasonable half-life outweigh the slightly weaker binding affinity and potentially problematic solubility/permeability values (given the unusual negative scales). Ligand A's poor BBB penetration and low logP are major liabilities for a CNS-targeting drug.

Output:
1
2025-04-17 09:01:27,621 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (348.447) is slightly lower, which could be beneficial for permeability. Ligand B (372.575) is also acceptable.

**TPSA:** Both ligands have TPSA values below the 90 A^2 threshold for CNS targets, which is good. Ligand A (87.32) is slightly higher than Ligand B (78.43), giving a slight edge to B.

**logP:** Both ligands have logP values within the optimal range (1-3). Ligand A (1.122) is on the lower side, potentially impacting permeability. Ligand B (2.716) is closer to the ideal range.

**H-Bond Donors/Acceptors:** Both have reasonable HBD (2 & 3) and HBA (4 & 4) counts, unlikely to cause major issues.

**QED:** Both ligands have QED values above 0.5, indicating good drug-likeness. Ligand A (0.62) is slightly better.

**DILI:** Both ligands have low DILI risk (Ligand A: 26.134, Ligand B: 29.081), which is favorable.

**BBB:** This is a critical parameter for CNS targets. Ligand B (44.397) has a significantly better BBB percentile than Ligand A (25.126). This is a major advantage for Ligand B.

**Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and suggests poor permeability. However, the scale is not specified, so it's difficult to interpret.

**Aqueous Solubility:** Both have negative solubility values, also unusual. Again, the scale is unclear.

**hERG Inhibition:** Both ligands show low hERG inhibition risk (Ligand A: 0.11, Ligand B: 0.341).

**Microsomal Clearance:** Ligand A (-3.294) has a negative clearance, which is not physically possible and indicates an issue with the data. Ligand B (45.498) has a high clearance, suggesting rapid metabolism.

**In vitro Half-Life:** Ligand A (-9.209) has a negative half-life, which is also not physically possible and indicates a data issue. Ligand B (16.095) has a moderate half-life.

**P-gp Efflux:** Both ligands show low P-gp efflux liability (Ligand A: 0.018, Ligand B: 0.1).

**Binding Affinity:** Ligand B (-7.2 kcal/mol) has a slightly better binding affinity than Ligand A (-6.9 kcal/mol). While the difference is not huge, it's within the range where it can outweigh minor ADME drawbacks.

**Overall Assessment:**

Ligand B is the more promising candidate. Its significantly better BBB penetration is crucial for a CNS target like DRD2. While its metabolic clearance is higher, the more potent binding affinity and better TPSA/logP profile, coupled with acceptable DILI and hERG risk, make it preferable. The negative values for clearance and half-life for Ligand A are concerning data quality issues.



Output:
1
2025-04-17 09:01:27,621 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (362.495 and 353.507 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (67.43) is better than Ligand B (70.67). Both are reasonably good for CNS penetration, being below 90, but A is closer to the ideal <60 for CNS targets.

**3. logP:** Both ligands have good logP values (2.726 and 1.829), falling within the optimal 1-3 range. Ligand A is slightly higher, potentially aiding membrane permeability.

**4. H-Bond Donors:** Both have 2 HBD, which is acceptable.

**5. H-Bond Acceptors:** Both have 4 HBA, which is acceptable.

**6. QED:** Ligand A (0.846) has a significantly higher QED score than Ligand B (0.698), indicating better overall drug-likeness.

**7. DILI:** Ligand A (49.128) has a higher DILI risk than Ligand B (11.09). This is a significant drawback for Ligand A.

**8. BBB:** Ligand A (62.35) has a better BBB percentile than Ligand B (54.789), but both are below the desirable >70 for CNS targets.

**9. Caco-2:** Ligand A (-4.966) has a worse Caco-2 permeability than Ligand B (-5.093). Lower values indicate lower permeability.

**10. Solubility:** Ligand A (-2.785) has worse solubility than Ligand B (-1.168).

**11. hERG:** Both ligands have very low hERG inhibition liability (0.326 and 0.212), which is excellent.

**12. Cl_mic:** Ligand B (2.303) has a much lower microsomal clearance than Ligand A (33.677), suggesting better metabolic stability.

**13. t1/2:** Ligand B (18.179) has a longer in vitro half-life than Ligand A (22.978).

**14. Pgp:** Both ligands have very low P-gp efflux liability (0.18 and 0.013), which is good.

**15. Binding Affinity:** Ligand B (-7.6 kcal/mol) has a substantially stronger binding affinity than Ligand A (0.0 kcal/mol). This is a crucial advantage, exceeding the 1.5 kcal/mol threshold.

**Overall Assessment:**

While Ligand A has slightly better TPSA and BBB penetration, Ligand B is significantly superior in several critical areas. The most important factor is the dramatically higher binding affinity of Ligand B. Additionally, Ligand B has a much lower DILI risk, better metabolic stability (lower Cl_mic), and a longer half-life. The slightly lower BBB score of Ligand B is less concerning given its superior binding and ADME properties.

Output:
1
2025-04-17 09:01:27,621 - INFO - Reasoning:

Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (347.375 and 346.387 Da) fall comfortably within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (137.07) is borderline for CNS penetration, slightly above the preferred <90, but acceptable. Ligand B (104.39) is excellent, well below 90.

**3. logP:** Ligand A (0.754) is a bit low, potentially hindering membrane permeability. Ligand B (-0.126) is even lower and concerning for permeability.

**4. H-Bond Donors:** Ligand A (4) is acceptable. Ligand B (2) is also good.

**5. H-Bond Acceptors:** Both ligands (5) are within the acceptable range of <=10.

**6. QED:** Ligand A (0.63) is good, indicating reasonable drug-likeness. Ligand B (0.368) is lower, suggesting a less favorable drug-like profile.

**7. DILI:** Ligand A (77.743) has a higher DILI risk than Ligand B (44.164), but both are below the concerning threshold of 60.

**8. BBB:** Ligand A (11.245) has very poor predicted BBB penetration. Ligand B (23.071) is still low, but significantly better than Ligand A. This is a critical factor for a CNS target like DRD2.

**9. Caco-2:** Ligand A (-6.231) has poor Caco-2 permeability. Ligand B (-5.338) is also poor, but slightly better.

**10. Solubility:** Ligand A (-2.664) shows poor aqueous solubility. Ligand B (-1.686) is also poor, but slightly better.

**11. hERG:** Both ligands (0.01 and 0.14) have very low predicted hERG inhibition risk, which is excellent.

**12. Cl_mic:** Ligand A (-16.081) has a negative clearance, which is unusual and likely indicates very high metabolic stability. Ligand B (-6.742) also shows good metabolic stability.

**13. t1/2:** Ligand A (-3.744) has a negative half-life which is unusual and likely indicates very high stability. Ligand B (-17.741) has a negative half-life which is unusual and likely indicates very high stability.

**14. Pgp:** Both ligands (0.002 and 0.033) show very low P-gp efflux, which is favorable for CNS penetration.

**15. Binding Affinity:** Ligand A (-8.5 kcal/mol) has a significantly stronger binding affinity than Ligand B (-7.7 kcal/mol). This >1.5 kcal/mol difference is substantial and can outweigh some ADME drawbacks.

**Overall Assessment:**

Despite Ligand A's poor logP, solubility, and BBB penetration, its *much* stronger binding affinity (-8.5 vs -7.7 kcal/mol) is a major advantage. The negative values for Cl_mic and t1/2 are unusual and suggest extremely high stability. While BBB penetration is a significant concern for a CNS target, the strong affinity might compensate if sufficient concentrations can reach the brain through other mechanisms or with formulation strategies. Ligand B has better ADME properties (TPSA, BBB, DILI), but its weaker binding affinity is a substantial drawback.

Given the strong emphasis on affinity for GPCRs, and the significant difference in binding strength, I would choose Ligand A for further investigation, despite its ADME liabilities.

Output:
0
2025-04-17 09:01:27,621 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (350.459 and 361.222 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (66.92) is better than Ligand B (69.44). Both are below the 90 A^2 threshold for CNS targets, which is good.

**3. logP:** Ligand A (1.991) is optimal (1-3), while Ligand B (4.369) is slightly high, potentially leading to solubility issues or off-target interactions.

**4. H-Bond Donors:** Both have 0 HBD, which is acceptable.

**5. H-Bond Acceptors:** Both have 4 HBA, which is acceptable (<=10).

**6. QED:** Ligand A (0.562) is significantly better than Ligand B (0.267), indicating a more drug-like profile.

**7. DILI:** Ligand A (30.748) has a much lower DILI risk than Ligand B (82.823). This is a significant advantage.

**8. BBB:** Both ligands have good BBB penetration (Ligand A: 73.672, Ligand B: 70.26). Both are above the 70% threshold, which is important for CNS targets.

**9. Caco-2 Permeability:** Both have negative values, indicating poor permeability. Ligand A (-4.481) is slightly better than Ligand B (-4.578), but both are concerning.

**10. Aqueous Solubility:** Ligand A (-2.342) is better than Ligand B (-5.809), indicating better solubility.

**11. hERG Inhibition:** Ligand A (0.295) has a lower hERG risk than Ligand B (0.642).

**12. Microsomal Clearance:** Ligand A (71.137) has higher clearance than Ligand B (61.459), meaning it's less metabolically stable.

**13. In vitro Half-Life:** Ligand B (29.202) has a significantly longer half-life than Ligand A (-9.274). This is a major advantage for Ligand B.

**14. P-gp Efflux:** Ligand A (0.172) has lower P-gp efflux than Ligand B (0.289), meaning it's less likely to be pumped out of the brain.

**15. Binding Affinity:** Ligand B (-9.8 kcal/mol) has a significantly stronger binding affinity than Ligand A (-6.9 kcal/mol). This is a substantial advantage, potentially outweighing some of its ADME drawbacks.

**Overall Assessment:**

Ligand B has a significantly better binding affinity and a longer half-life. However, it has a higher logP, higher DILI risk, and lower solubility. Ligand A has better solubility, lower DILI risk, lower hERG risk, and lower P-gp efflux. The difference in binding affinity is significant (>1.5 kcal/mol), and for a GPCR, BBB penetration is already acceptable for both. Considering the importance of potency for GPCRs, the stronger binding affinity of Ligand B is the deciding factor. While its ADME profile isn't ideal, optimization could potentially address the higher logP and DILI risk.

Output:
1
2025-04-17 09:01:27,621 - INFO - Batch 498 complete. Total preferences: 7968
2025-04-17 09:01:27,621 - INFO - Processing batch 499/512...
2025-04-17 09:02:08,152 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (347.459 and 363.889 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (70.67) is significantly better than Ligand B (81.99). For CNS targets, we want TPSA <= 90, and A is comfortably within that range, while B is approaching the upper limit.

**logP:** Ligand A (0.666) is a bit low, potentially hindering permeability. Ligand B (3.148) is optimal. This is a point in favor of B.

**H-Bond Donors/Acceptors:** Both have 2 HBD and a reasonable number of HBA (4 and 3 respectively). This isn't a major differentiating factor.

**QED:** Both ligands have good QED scores (0.717 and 0.76), indicating drug-likeness.

**DILI:** Both ligands have low DILI risk (32.261 and 32.299), which is excellent.

**BBB:** Ligand B (60.76) has a better BBB percentile than Ligand A (44.591), but both are below the desirable >70 for CNS targets. This is a weakness for both, but less so for B.

**Caco-2 Permeability:** Ligand A (-4.903) has very poor Caco-2 permeability, while Ligand B (-4.799) is slightly better, but still poor.

**Aqueous Solubility:** Ligand A (-1.732) has better solubility than Ligand B (-4.433).

**hERG:** Both ligands have low hERG inhibition liability (0.318 and 0.451), which is good.

**Microsomal Clearance:** Ligand A (-8.381) has much lower (better) microsomal clearance than Ligand B (57.816), indicating better metabolic stability.

**In vitro Half-Life:** Ligand A (2.242 hours) has a shorter half-life than Ligand B (13.982 hours).

**P-gp Efflux:** Ligand A (0.045) has significantly lower P-gp efflux than Ligand B (0.134), which is highly desirable for CNS penetration.

**Binding Affinity:** Ligand B (-8.5 kcal/mol) has a slightly better binding affinity than Ligand A (-7.3 kcal/mol). This 1.2 kcal/mol difference is significant and could outweigh some ADME drawbacks.

**Overall Assessment:**

Ligand B has a better logP, BBB, and binding affinity. However, Ligand A has a much better TPSA, P-gp efflux, and microsomal clearance. The low TPSA and P-gp efflux of Ligand A are particularly important for CNS penetration, even with a suboptimal logP. While Ligand B's affinity is better, the difference isn't enormous. The poor Caco-2 permeability for both is a concern, but less critical for a CNS target. Considering the GPCR-specific priorities, the combination of lower TPSA and P-gp efflux for Ligand A, coupled with acceptable DILI and hERG, makes it a slightly more promising candidate despite the lower logP and affinity.

Output:
0
2025-04-17 09:02:08,153 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (375.447 and 369.527 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (99.96) is higher than the preferred <90 for CNS targets, while Ligand B (48) is well within the range. This is a significant advantage for Ligand B.

**3. logP:** Ligand A (0.411) is quite low, potentially hindering membrane permeability. Ligand B (2.497) is within the optimal 1-3 range. This favors Ligand B.

**4. H-Bond Donors:** Both have 0 HBD, which is acceptable.

**5. H-Bond Acceptors:** Ligand A has 8 HBA, and Ligand B has 5. Both are within the acceptable limit of <=10.

**6. QED:** Both ligands have good QED scores (0.636 and 0.673), indicating drug-like properties.

**7. DILI:** Ligand A (65.568) has a higher DILI risk than Ligand B (32.648). This is a clear advantage for Ligand B.

**8. BBB:** Ligand A (61.613) has a moderate BBB penetration, while Ligand B (83.366) has excellent BBB penetration. This is a crucial advantage for Ligand B, given DRD2 is a CNS target.

**9. Caco-2:** Both have negative Caco-2 values which is unusual, and difficult to interpret without knowing the scale.

**10. Solubility:** Both have negative solubility values which is unusual, and difficult to interpret without knowing the scale.

**11. hERG:** Ligand A (0.127) has a slightly lower hERG risk than Ligand B (0.504), but both are relatively low.

**12. Cl_mic:** Ligand A (84.836) has a higher microsomal clearance than Ligand B (79.31), suggesting lower metabolic stability. This favors Ligand B.

**13. t1/2:** Ligand B (9.04) has a significantly longer in vitro half-life than Ligand A (-7.183). This is a strong advantage for Ligand B.

**14. Pgp:** Ligand A (0.168) has lower P-gp efflux liability than Ligand B (0.292), which is favorable for CNS penetration.

**15. Binding Affinity:** Ligand B (-7.4 kcal/mol) has a slightly better binding affinity than Ligand A (-6.3 kcal/mol). While the difference is not huge, it contributes to the overall preference for Ligand B.

**Overall Assessment:**

Ligand B consistently outperforms Ligand A across several critical parameters for a CNS-targeting GPCR ligand. Specifically, its superior TPSA, logP, BBB penetration, DILI risk, metabolic stability (lower Cl_mic, longer t1/2), and slightly better binding affinity make it a much more promising drug candidate. While Ligand A has a slight edge in Pgp efflux, the other advantages of Ligand B outweigh this.

Output:
1
2025-04-17 09:02:08,153 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (356.46 and 367.49 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (40.62) is significantly better than Ligand B (61.44). For CNS targets, we want TPSA <= 90, and ideally closer to 60. Ligand A is much closer to this ideal.

**logP:** Ligand A (3.47) is optimal (1-3), while Ligand B (1.73) is on the lower end, potentially impacting permeability.

**H-Bond Donors/Acceptors:** Ligand A (0 HBD, 2 HBA) is preferable to Ligand B (2 HBD, 4 HBA). Lower counts generally improve permeability.

**QED:** Both ligands have good QED scores (0.655 and 0.687, respectively), indicating good drug-like properties.

**DILI:** Ligand A (42.89) has a slightly higher DILI risk than Ligand B (36.49), but both are below the concerning threshold of 60.

**BBB:** Ligand A (96.32) has a *much* higher BBB penetration percentile than Ligand B (71.00). This is a critical advantage for a CNS target like DRD2.

**Caco-2 Permeability:** Ligand A (-4.25) is worse than Ligand B (-5.07), indicating lower intestinal absorption. However, for a CNS target, intestinal absorption is less crucial than BBB penetration.

**Aqueous Solubility:** Both ligands have poor aqueous solubility (-3.02 and -2.93 respectively).

**hERG:** Both ligands have low hERG inhibition risk (0.61 and 0.53 respectively).

**Microsomal Clearance:** Ligand B (61.51) has a higher microsomal clearance than Ligand A (52.34), suggesting faster metabolism and potentially lower *in vivo* exposure.

**In vitro Half-Life:** Ligand B (23.47) has a significantly longer half-life than Ligand A (-24.12). This is a positive for Ligand B.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.26 and 0.10 respectively).

**Binding Affinity:** Ligand A (-8.1 kcal/mol) has a significantly stronger binding affinity than Ligand B (-6.9 kcal/mol). This difference of 1.2 kcal/mol is substantial and can outweigh some of the ADME drawbacks.

**Conclusion:**

Despite Ligand B's better half-life, Ligand A is the superior candidate. The significantly better BBB penetration (96.32% vs 71.00%) and substantially stronger binding affinity (-8.1 vs -6.9 kcal/mol) are critical advantages for a CNS-targeting GPCR like DRD2. The TPSA is also much better for Ligand A. While Ligand A has slightly worse Caco-2 permeability and a slightly higher DILI risk, the benefits related to target engagement and CNS exposure outweigh these concerns.

Output:
1
2025-04-17 09:02:08,153 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (348.447 and 344.415 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (76.46) is significantly better than Ligand B (91.4).  For CNS targets, we want TPSA <= 90, so Ligand A is preferable.

**logP:** Ligand A (1.357) is within the optimal 1-3 range. Ligand B (0.595) is a bit low, potentially hindering permeability.

**H-Bond Donors/Acceptors:** Ligand A (1 HBD, 5 HBA) and Ligand B (2 HBD, 4 HBA) both have reasonable numbers of H-bond donors and acceptors, well within the guidelines.

**QED:** Ligand A (0.807) has a much better QED score than Ligand B (0.56), indicating a more drug-like profile.

**DILI:** Both ligands have acceptable DILI risk (Ligand A: 39.434, Ligand B: 32.261), below the 40 threshold.

**BBB:** Ligand A (76.813) has a significantly higher BBB percentile than Ligand B (60.876). This is *critical* for a CNS target like DRD2, where brain penetration is essential.

**Caco-2 Permeability:** Ligand A (-4.584) and Ligand B (-5.398) both have negative values, indicating poor permeability.

**Aqueous Solubility:** Both ligands have very poor aqueous solubility (-2.28 and -2.135). This is a concern for formulation, but can sometimes be overcome.

**hERG:** Both ligands have very low hERG inhibition risk (0.172 and 0.08).

**Microsomal Clearance:** Ligand A (21.024) has a higher, less favorable, microsomal clearance than Ligand B (-5.8). This suggests Ligand B is more metabolically stable.

**In vitro Half-Life:** Ligand A (5.294) has a longer half-life than Ligand B (-3.209).

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.046 and 0.018).

**Binding Affinity:** Ligand B (-8.1 kcal/mol) has a slightly better binding affinity than Ligand A (-7.6 kcal/mol). However, the difference is less than 1.5 kcal/mol, so it isn't a decisive factor on its own.

**Overall Assessment:**

Ligand A is superior despite the slightly weaker binding affinity. Its significantly better TPSA, QED, and *especially* BBB penetration make it the more promising candidate for a CNS-targeting drug like a DRD2 ligand. The better half-life also contributes. While both have poor solubility and Caco-2 permeability, these issues can potentially be addressed with formulation strategies. Ligand B's lower logP and higher clearance are more significant drawbacks.



Output:
0
2025-04-17 09:02:08,153 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (351.447 Da) is slightly lower, which could be beneficial for permeability, but both are acceptable.

**TPSA:** Ligand A (71.11) is significantly better than Ligand B (58.64) for CNS penetration, falling well below the 90 A^2 threshold. Ligand B is also good, but A is preferable.

**logP:** Ligand A (0.712) is a bit low, potentially hindering permeation. Ligand B (2.222) is closer to the optimal 1-3 range. This favors Ligand B.

**H-Bond Donors/Acceptors:** Both ligands have acceptable HBD (1) and HBA (A: 5, B: 3) counts.

**QED:** Both ligands have good QED scores (A: 0.808, B: 0.758), indicating drug-likeness.

**DILI:** Ligand A (14.889) has a much lower DILI risk than Ligand B (25.436), which is a significant advantage.

**BBB:** Ligand B (85.459) has a substantially better BBB penetration percentile than Ligand A (65.839). This is a crucial factor for a CNS target like DRD2, strongly favoring Ligand B.

**Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and potentially indicates issues with the prediction method or the compounds themselves. However, they are very close (-4.857 vs -4.809).

**Aqueous Solubility:** Both ligands have poor aqueous solubility (-1.35 and -3.35). This is a concern, but can be addressed with formulation strategies.

**hERG Inhibition:** Ligand A (0.195) has a lower hERG inhibition risk than Ligand B (0.602), which is desirable.

**Microsomal Clearance:** Ligand A (-0.507) has a lower (better) microsomal clearance than Ligand B (15.968), indicating better metabolic stability.

**In vitro Half-Life:** Ligand B (2.625) has a longer half-life than Ligand A (-5.417), which is preferable.

**P-gp Efflux:** Ligand A (0.015) has a much lower P-gp efflux liability than Ligand B (0.142), which is a significant advantage for CNS penetration.

**Binding Affinity:** Ligand B (-9.3 kcal/mol) has a stronger binding affinity than Ligand A (-8.1 kcal/mol) by 1.2 kcal/mol. This is a substantial difference and a major factor.

**Overall Assessment:**

Ligand B excels in BBB penetration and binding affinity, which are critical for a CNS GPCR target. While its logP is better than Ligand A, and its half-life is longer, it suffers from higher DILI risk, higher P-gp efflux, and lower metabolic stability. Ligand A has better safety profiles (DILI, hERG, P-gp) and metabolic stability, but its BBB penetration is lower and affinity is weaker.

The 1.2 kcal/mol difference in binding affinity, combined with the significantly better BBB penetration, outweighs the drawbacks of Ligand B. The stronger binding increases the likelihood of efficacy, and the better BBB penetration ensures sufficient CNS exposure.

Output:
1
2025-04-17 09:02:08,154 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (385.837 Da) is slightly higher than Ligand B (346.391 Da), but both are acceptable.

**TPSA:** Ligand A (134.07) is borderline for CNS penetration, being slightly above the ideal <90. Ligand B (106.15) is well within the desirable range for CNS targets. This gives a slight edge to Ligand B.

**logP:** Ligand A (1.696) is within the optimal range (1-3). Ligand B (0.595) is a bit low, potentially hindering membrane permeability. Ligand A is favored here.

**H-Bond Donors:** Ligand A (4) is acceptable. Ligand B (1) is also good. No clear advantage.

**H-Bond Acceptors:** Both ligands have 7 HBA, which is within the acceptable limit of 10.

**QED:** Ligand B (0.849) has a significantly better QED score than Ligand A (0.337), indicating a more drug-like profile.

**DILI:** Ligand A (91.004) has a higher DILI risk than Ligand B (67.429), which is preferable.

**BBB:** Ligand B (66.499) has a better BBB penetration percentile than Ligand A (56.146), though both are not ideal (>70 is desired). This is a significant advantage for Ligand B given the CNS target.

**Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and problematic. It suggests poor permeability.

**Aqueous Solubility:** Both have negative solubility values, which is also problematic.

**hERG:** Both ligands have very low hERG inhibition liability (0.189 and 0.104), which is excellent.

**Microsomal Clearance:** Ligand B (16.139) has significantly lower microsomal clearance than Ligand A (42.488), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (32.621) has a longer half-life than Ligand B (0.433), which is generally desirable.

**P-gp Efflux:** Both have very low P-gp efflux liability (0.021 and 0.032), which is excellent.

**Binding Affinity:** Both ligands have very similar and strong binding affinities (-8.5 kcal/mol and -8.4 kcal/mol). The difference is negligible.

**Overall Assessment:**

Considering the GPCR-specific priorities, Ligand B is more promising. While Ligand A has a slightly better logP and half-life, Ligand B excels in TPSA, QED, DILI, and importantly, BBB penetration and metabolic stability (Cl_mic). The slightly lower logP of Ligand B is a manageable concern, especially given its other advantages. The poor Caco-2 and solubility values are concerning for both, but can be addressed through formulation strategies. The strong binding affinity is maintained in both.

Output:
1
2025-04-17 09:02:08,154 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (354.466 and 346.427 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (60.85) is significantly better than Ligand B (67.87). Both are below the 90 A^2 threshold for CNS targets, but A is closer to the ideal.

**logP:** Ligand A (2.293) is optimal (1-3), while Ligand B (0.725) is a bit low, potentially hindering permeability.

**H-Bond Donors/Acceptors:** Both have acceptable HBD (1) and HBA (3/4) counts, well within the guidelines.

**QED:** Both ligands have good QED scores (0.537 and 0.602), indicating drug-likeness.

**DILI:** Ligand A (11.516) has a much lower DILI risk than Ligand B (55.138), which is a significant advantage.

**BBB:** Ligand A (79.915) has a good BBB penetration percentile, while Ligand B (57.968) is lower. This is a critical factor for a CNS target like DRD2.

**Caco-2 Permeability:** Both have negative Caco-2 values which is unusual and suggests poor permeability.

**Aqueous Solubility:** Both have negative solubility values, which is also unusual and suggests poor solubility.

**hERG:** Both ligands have low hERG inhibition liability (0.558 and 0.274), which is good.

**Microsomal Clearance:** Ligand A (45.308) has higher microsomal clearance than Ligand B (23.851), indicating potentially lower metabolic stability.

**In vitro Half-Life:** Ligand B (-5.084) has a slightly better (less negative) in vitro half-life than Ligand A (-23.647), suggesting better stability.

**P-gp Efflux:** Ligand A (0.253) has lower P-gp efflux liability than Ligand B (0.087), which is desirable for CNS penetration.

**Binding Affinity:** Ligand A (-8.1 kcal/mol) has a significantly stronger binding affinity than Ligand B (-6.5 kcal/mol). This is a substantial advantage, potentially outweighing some of the ADME drawbacks.

**Overall Assessment:**

Ligand A is the stronger candidate. While it has higher microsomal clearance, its superior binding affinity, lower DILI risk, and better BBB penetration are critical advantages for a CNS-targeting GPCR like DRD2. Ligand B's lower logP and poorer BBB penetration are significant drawbacks. The large difference in binding affinity (-8.1 vs -6.5 kcal/mol) is a decisive factor.



Output:
1
2025-04-17 09:02:08,154 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (380.539 Da) is slightly higher than Ligand B (354.451 Da), but both are acceptable.

**TPSA:** Ligand A (65.54) is much better than Ligand B (99.77). For CNS targets, we want TPSA <= 90, and Ligand A is comfortably within this range, while Ligand B is close to the upper limit and less desirable.

**logP:** Ligand A (0.968) is borderline, potentially a little low for optimal permeability. Ligand B (0.229) is quite low, raising concerns about membrane permeability.

**H-Bond Donors/Acceptors:** Ligand A has 1 HBD and 6 HBA, which are reasonable. Ligand B has 3 HBD and 4 HBA, also acceptable, but slightly higher HBD count could be a minor drawback.

**QED:** Ligand B (0.57) has a slightly better QED score than Ligand A (0.453), suggesting a marginally more drug-like profile.

**DILI:** Both ligands have acceptable DILI risk, with Ligand A (40.403) being slightly higher than Ligand B (29.624), but both are below the concerning threshold of 60.

**BBB:** Ligand B (73.672) has a significantly better BBB penetration score than Ligand A (53.781). This is a critical factor for a CNS target like DRD2.

**Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and suggests poor permeability based on this metric. However, the scale is not specified, so this is difficult to interpret.

**Aqueous Solubility:** Both ligands have poor aqueous solubility (-1.936 and -1.04 respectively). This could pose formulation challenges.

**hERG Inhibition:** Both ligands show very low hERG inhibition risk (0.351 and 0.269 respectively).

**Microsomal Clearance:** Ligand B (-11.81) has a much lower (better) microsomal clearance than Ligand A (30.728), indicating greater metabolic stability.

**In vitro Half-Life:** Ligand B (3.144 hours) has a slightly longer half-life than Ligand A (-16.058 hours - negative value is concerning).

**P-gp Efflux:** Both ligands show very low P-gp efflux liability (0.052 and 0.008 respectively). This is good, as it suggests better CNS exposure.

**Binding Affinity:** Ligand B (-7.2 kcal/mol) has a significantly stronger binding affinity than Ligand A (-0.0 kcal/mol). This is a major advantage, potentially outweighing some of the ADME drawbacks.

**Overall Assessment:**

Ligand B is the stronger candidate. While it has a slightly higher TPSA and lower logP, its significantly better BBB penetration, much improved metabolic stability (lower Cl_mic), longer half-life, and *much* stronger binding affinity outweigh these concerns. The binding affinity difference is substantial. Ligand A's very weak binding affinity makes it unlikely to be a viable candidate, regardless of its other properties.

Output:
1
2025-04-17 09:02:08,154 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (340.358 and 342.355 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (80.04) is significantly better than Ligand B (108.46). For CNS targets, TPSA <= 90 is preferred, and A is comfortably within that range, while B is approaching the upper limit.

**3. logP:** Both ligands have good logP values (2.178 and 1.612), falling within the optimal 1-3 range.

**4. H-Bond Donors:** Ligand A (2) and Ligand B (1) are both acceptable, being <= 5.

**5. H-Bond Acceptors:** Ligand A (5) and Ligand B (6) are both acceptable, being <= 10.

**6. QED:** Both ligands have good QED values (0.746 and 0.799), indicating good drug-like properties.

**7. DILI:** Ligand A (83.133) has a higher DILI risk than Ligand B (73.982). Both are acceptable, but B is preferable.

**8. BBB:** Ligand A (44.591) has a significantly lower BBB penetration percentile than Ligand B (52.23). For a CNS target like DRD2, >70 is desirable, and while neither is ideal, B is better.

**9. Caco-2 Permeability:** Ligand A (-4.934) has better Caco-2 permeability than Ligand B (-4.932). However, both are negative values which is unusual and requires further investigation.

**10. Aqueous Solubility:** Both ligands have very poor aqueous solubility (-3.164 and -3.087). This is a significant drawback for both.

**11. hERG Inhibition:** Ligand A (0.488) has a slightly higher hERG inhibition liability than Ligand B (0.223). Lower is better, so B is preferable.

**12. Microsomal Clearance:** Ligand A (13.327) has a much lower microsomal clearance than Ligand B (58.557), indicating better metabolic stability. This is a major advantage for A.

**13. In vitro Half-Life:** Ligand A (9.505) has a better in vitro half-life than Ligand B (-22.004). This is a significant advantage for A.

**14. P-gp Efflux:** Ligand A (0.26) has a much lower P-gp efflux liability than Ligand B (0.069). Lower is better, especially for CNS targets, giving A a significant advantage.

**15. Binding Affinity:** Both ligands have excellent binding affinities (-10.0 and -8.0 kcal/mol). Ligand A is 2 kcal/mol better, which is a substantial advantage and can outweigh some of the ADME drawbacks.

**Overall Assessment:**

Despite Ligand B having a slightly better DILI and BBB profile, Ligand A is the stronger candidate. The significantly better metabolic stability (lower Cl_mic, higher t1/2), lower P-gp efflux, and superior binding affinity of Ligand A outweigh the slightly higher DILI risk and lower BBB. The TPSA is also more favorable for CNS penetration. The poor solubility is a concern for both, but can potentially be addressed with formulation strategies.

Output:
1
2025-04-17 09:02:08,154 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B based on the provided guidelines, prioritizing GPCR-specific properties (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (364.423 and 364.364 Da) fall within the ideal range of 200-500 Da.

**TPSA:** Ligand A (94.99) is slightly higher than Ligand B (87.66). Both are below the 90 A^2 threshold desirable for CNS targets, but Ligand B is preferable.

**logP:** Ligand A (1.529) is within the optimal range (1-3). Ligand B (0.595) is slightly below, which could potentially hinder permeation, but not drastically.

**H-Bond Donors/Acceptors:** Ligand A has 1 HBD and 4 HBA, while Ligand B has 3 HBD and 4 HBA. Both are within acceptable limits.

**QED:** Ligand A (0.878) has a higher QED score than Ligand B (0.624), indicating better overall drug-likeness.

**DILI:** Ligand B (35.789) has a significantly lower DILI risk than Ligand A (72.664), which is a substantial advantage.

**BBB:** Ligand A (59.946) has a better BBB penetration score than Ligand B (47.499), which is crucial for a CNS target like DRD2.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.033 and -5.061). This is unusual and suggests poor permeability. However, these values are on a scale where negative values are possible, and the absolute difference is small.

**Aqueous Solubility:** Both ligands have negative solubility values (-2.6 and -1.967). Again, this is unusual and suggests poor solubility. The difference is small.

**hERG Inhibition:** Ligand A (0.032) has a slightly lower hERG inhibition risk than Ligand B (0.281), which is preferable.

**Microsomal Clearance:** Ligand B (1.716) has a significantly lower microsomal clearance than Ligand A (26.043), indicating better metabolic stability.

**In vitro Half-Life:** Ligand B (-16.384) has a longer in vitro half-life than Ligand A (-12.943), which is desirable.

**P-gp Efflux:** Ligand A (0.021) has a lower P-gp efflux liability than Ligand B (0.03), which is beneficial for CNS exposure.

**Binding Affinity:** Ligand A (-8.1 kcal/mol) has a slightly better binding affinity than Ligand B (-6.9 kcal/mol). This 1.2 kcal/mol difference is significant and could potentially outweigh some of the ADME drawbacks of Ligand A.

**Overall Assessment:**

Ligand B has superior ADME properties (lower DILI, better metabolic stability, longer half-life) and a lower P-gp efflux liability, which are all crucial for CNS drug development. While Ligand A has a slightly better BBB score and binding affinity, the substantial advantages of Ligand B in ADME, particularly the lower DILI risk and improved metabolic stability, make it the more promising candidate. The affinity difference, while notable, may be overcome with further optimization.

Output:
1
2025-04-17 09:02:08,155 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight (MW):** Both ligands (364.555 and 366.487 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (49.41) is significantly better than Ligand B (86.95). For CNS targets, we want TPSA <= 90, and A is comfortably within that, while B is approaching the upper limit.

**3. logP:** Ligand A (3.561) is optimal (1-3). Ligand B (0.862) is a bit low, potentially hindering permeation.

**4. H-Bond Donors (HBD):** Both have 1 HBD, which is within the acceptable limit of <=5.

**5. H-Bond Acceptors (HBA):** Ligand A has 3 HBA, and Ligand B has 5. Both are within the acceptable limit of <=10.

**6. QED:** Ligand B (0.809) has a better QED score than Ligand A (0.476), indicating a more drug-like profile.

**7. DILI:** Ligand B (20.396) has a much lower DILI risk than Ligand A (36.758), which is a significant advantage.

**8. BBB:** Both ligands have good BBB penetration (A: 73.672, B: 71.772), exceeding the desirable threshold of >70 for CNS targets.

**9. Caco-2 Permeability:** Both have negative values (-5.03 and -5.244), which is unusual and suggests poor permeability. However, these values are on a scale where negative values are possible, and direct comparison is difficult without knowing the scale's specifics.

**10. Aqueous Solubility:** Both have negative values (-3.932 and -1.408), indicating poor aqueous solubility. Again, the scale is unclear.

**11. hERG Inhibition:** Both ligands show low hERG inhibition risk (A: 0.463, B: 0.303).

**12. Microsomal Clearance (Cl_mic):** Ligand B (-10.033) has significantly lower (better) microsomal clearance than Ligand A (86.613), suggesting better metabolic stability.

**13. In vitro Half-Life:** Both have similar in vitro half-lives (A: 4.179, B: 4.071).

**14. P-gp Efflux:** Both ligands have low P-gp efflux liability (A: 0.305, B: 0.019), which is good for CNS exposure. Ligand B is slightly better.

**15. Binding Affinity:** Ligand B (-7.3 kcal/mol) has a significantly stronger binding affinity than Ligand A (-6.5 kcal/mol). This >1.5 kcal/mol difference is substantial and can outweigh minor ADME drawbacks.

**Overall Assessment:**

While Ligand B has a better QED score, lower DILI risk, and significantly better metabolic stability (lower Cl_mic), the most important factor for a CNS GPCR target is the combination of BBB penetration and binding affinity. Both ligands have acceptable BBB penetration. However, Ligand B's binding affinity is 0.8 kcal/mol stronger, which is a crucial advantage. Ligand A has a better logP and TPSA, but the affinity difference and lower DILI risk of Ligand B are more important.

Output:
1
2025-04-17 09:02:08,155 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (362.421 and 360.351 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (104.53) is higher than the preferred <90 for CNS targets, while Ligand B (41.57) is excellent. This is a significant advantage for Ligand B.

**logP:** Both ligands have acceptable logP values (1.081 and 2.486), falling within the 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A has 3 HBD and 3 HBA, which is acceptable. Ligand B has 1 HBD and 3 HBA, also acceptable.

**QED:** Ligand A (0.602) has a better QED score than Ligand B (0.482), suggesting a more drug-like profile.

**DILI:** Ligand A (18.728) has a much lower DILI risk than Ligand B (31.02), indicating better predicted liver safety.

**BBB:** Ligand B (96.355) has a significantly higher BBB penetration score than Ligand A (84.025). This is a critical advantage for a CNS target like DRD2.

**Caco-2 Permeability:** Ligand A (-5.175) has a negative Caco-2 value, which is concerning, suggesting poor intestinal absorption. Ligand B (-4.451) is also negative, but less so.

**Aqueous Solubility:** Both ligands have poor aqueous solubility (-2.117 and -3.071). This could pose formulation challenges, but is less critical than BBB for a CNS drug.

**hERG Inhibition:** Ligand A (0.302) has a lower hERG inhibition liability than Ligand B (0.728), which is preferable.

**Microsomal Clearance:** Ligand A (-10.874) has a much lower (better) microsomal clearance than Ligand B (24.947), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (-19.909) has a longer in vitro half-life than Ligand B (8.592), which is desirable.

**P-gp Efflux:** Ligand A (0.008) has very low P-gp efflux liability, while Ligand B (0.098) is slightly higher but still low.

**Binding Affinity:** Ligand B (-7.8 kcal/mol) has a slightly better binding affinity than Ligand A (-8.0 kcal/mol). While the difference is small, it's still a factor.

**Overall Assessment:**

Ligand B excels in BBB penetration, a crucial factor for CNS GPCR targets. It also has a slightly better binding affinity. However, Ligand A demonstrates superior drug-likeness (QED), metabolic stability (Cl_mic, t1/2), lower DILI risk, and lower hERG liability. The poor Caco-2 permeability of both is a concern, but less critical for a CNS-focused drug. The significant advantage of Ligand B in BBB outweighs the benefits of Ligand A, making it the more promising candidate.

Output:
1
2025-04-17 09:02:08,155 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (346.289 and 348.443 Da) are within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (89.16) is better than Ligand B (76.66), both are below the 90 A^2 threshold for CNS targets.

**3. logP:** Both ligands (1.353 and 1.28) are within the optimal 1-3 range.

**4. H-Bond Donors:** Ligand A (0) is preferable to Ligand B (2), as fewer HBDs generally improve permeability.

**5. H-Bond Acceptors:** Ligand A (6) is preferable to Ligand B (4), but both are below the 10 threshold.

**6. QED:** Both ligands have good QED scores (0.737 and 0.785), indicating drug-likeness.

**7. DILI:** Ligand A (79.566) has a higher DILI risk than Ligand B (38.852). This is a significant drawback for Ligand A.

**8. BBB:** Both ligands have excellent BBB penetration (78.519 and 73.943, respectively), exceeding the >70% threshold for CNS targets.

**9. Caco-2 Permeability:** Ligand A (-4.123) is slightly better than Ligand B (-4.967), but both are negative values, which is unusual and requires further investigation.

**10. Aqueous Solubility:** Ligand A (-3.531) is slightly better than Ligand B (-3.046), but both are negative values, which is unusual and requires further investigation.

**11. hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.268 and 0.243).

**12. Microsomal Clearance:** Ligand A (73.277) has a higher microsomal clearance than Ligand B (18.901), indicating lower metabolic stability.

**13. In vitro Half-Life:** Ligand B (51.635) has a significantly longer in vitro half-life than Ligand A (-6.155).

**14. P-gp Efflux:** Both ligands have low P-gp efflux liability (0.305 and 0.021).

**15. Binding Affinity:** Both ligands have very similar and excellent binding affinities (-8.7 and -8.6 kcal/mol). The difference is negligible.

**Overall Assessment:**

Ligand B is the more promising candidate. While Ligand A has slightly better TPSA and Caco-2 permeability, Ligand B excels in critical areas: significantly lower DILI risk, much better metabolic stability (lower Cl_mic and higher t1/2), and a slightly lower P-gp efflux. The similar binding affinities make these ADME properties the deciding factors. The negative solubility and Caco-2 values for both compounds are concerning and would require experimental validation. However, given the importance of minimizing toxicity and maximizing metabolic stability for a CNS drug, Ligand B is the preferred choice.

Output:
1
2025-04-17 09:02:08,155 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (354.411 and 351.403 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (121.61) is slightly above the optimal <90 for CNS targets, but still reasonable. Ligand B (96.11) is excellent, well below 90.

**logP:** Ligand A (-0.059) is a bit low, potentially hindering permeability. Ligand B (1.139) is within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A (3 HBD, 7 HBA) is good. Ligand B (1 HBD, 6 HBA) is also good, potentially slightly better due to fewer hydrogen bonds.

**QED:** Both ligands have good QED scores (0.696 and 0.877), indicating drug-like properties.

**DILI:** Ligand A (38.581) has a lower DILI risk than Ligand B (51.725), which is preferable.

**BBB:** Both ligands have acceptable BBB penetration (61.613% and 63.862%). While >70 is desirable, these are not drastically low.

**Caco-2 Permeability:** Both have negative Caco-2 values (-4.921 and -4.86), which is unusual and suggests poor permeability. This is a significant concern for both.

**Aqueous Solubility:** Both have negative solubility values (-1.226 and -1.804), also unusual and concerning.

**hERG:** Both ligands have low hERG inhibition liability (0.072 and 0.233), which is good.

**Microsomal Clearance:** Ligand A (15.143) has lower microsomal clearance than Ligand B (29.474), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (-10.517) has a negative half-life, which is impossible. Ligand B (-20.877) also has a negative half-life, which is impossible. This suggests an error in the data or a very rapid degradation.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.013 and 0.143), which is excellent for CNS penetration.

**Binding Affinity:** Ligand B (-7.5 kcal/mol) has a significantly stronger binding affinity than Ligand A (-9.1 kcal/mol). This is a substantial advantage.

**Overall Assessment:**

Despite the issues with Caco-2 and solubility, the stronger binding affinity of Ligand B is a major advantage, especially for a GPCR target. The better logP and slightly better H-bond profile also favor Ligand B. The negative half-life values are concerning for both, but the difference in binding affinity is likely to outweigh the other drawbacks. Ligand A has a slightly better DILI score and clearance, but the affinity difference is too significant to ignore.

Output:
1
2025-04-17 09:02:08,156 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands fall within the ideal range (200-500 Da). Ligand A (471.291 Da) is at the higher end, while Ligand B (348.443 Da) is closer to the middle.

**TPSA:** Ligand A (55.4) is better than Ligand B (67.87). For CNS targets, we want TPSA <= 90, both are within this range, but A is preferable.

**logP:** Ligand A (3.941) is good, while Ligand B (1.259) is a bit low. Optimal logP is 1-3, so A is better. A low logP can hinder permeation.

**H-Bond Donors/Acceptors:** Both have acceptable HBD (1) and HBA (A: 3, B: 4) counts, well within the guidelines.

**QED:** Both are below 0.5, indicating less than ideal drug-like properties. Ligand A (0.438) is slightly better than Ligand B (0.367).

**DILI:** Ligand A (89.027) has a significantly higher DILI risk than Ligand B (17.255). This is a major concern for Ligand A.

**BBB:** Ligand A (63.746) and Ligand B (71.462) both have reasonable BBB penetration, but Ligand B is better, exceeding 70% which is desirable for CNS targets.

**Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and suggests poor permeability. Ligand A (-5.058) is worse than Ligand B (-4.814).

**Aqueous Solubility:** Both have negative solubility values, indicating poor aqueous solubility. Ligand A (-5.17) is worse than Ligand B (-1.787).

**hERG:** Ligand A (0.885) has a slightly higher hERG risk than Ligand B (0.34).

**Microsomal Clearance:** Ligand A (82.052) has higher clearance than Ligand B (11.991), indicating lower metabolic stability.

**In vitro Half-Life:** Ligand A (17.457) has a longer half-life than Ligand B (3.129), which is a positive.

**P-gp Efflux:** Ligand A (0.676) has lower P-gp efflux than Ligand B (0.054), which is favorable for CNS penetration.

**Binding Affinity:** Ligand A (-9.8 kcal/mol) has significantly stronger binding affinity than Ligand B (-7.4 kcal/mol). This is a substantial advantage. A difference of >1.5 kcal/mol can outweigh other drawbacks.

**Overall Assessment:**

Ligand A has a much stronger binding affinity, better logP and TPSA, and lower P-gp efflux. However, it suffers from significantly higher DILI risk, higher microsomal clearance, and worse solubility and Caco-2 permeability. Ligand B has a better safety profile (lower DILI, hERG), better BBB penetration, and slightly better solubility.

Despite the substantial affinity advantage of Ligand A, the high DILI risk is a major red flag. The affinity difference, while significant, might not be enough to overcome the potential for liver toxicity. Ligand B, while having weaker affinity, presents a more balanced profile with better predicted safety and CNS penetration. Given the CNS target and the importance of a favorable safety profile, Ligand B is the more viable candidate.

Output:
1
2025-04-17 09:02:08,156 - INFO - Reasoning:

Let's analyze Ligand A and Ligand B based on the provided guidelines, prioritizing GPCR-specific properties (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (348.422 and 352.523 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (76.02) is significantly better than Ligand B (50.6). For CNS targets, we want TPSA <= 90, and ideally lower. Ligand A is closer to the ideal range.

**logP:** Both ligands have acceptable logP values (1.49 and 2.758, respectively), falling within the optimal 1-3 range. Ligand B is slightly higher, which *could* indicate a potential for off-target interactions, but isn't a major concern.

**H-Bond Donors/Acceptors:** Ligand A has 2 HBD and 4 HBA, while Ligand B has 0 HBD and 5 HBA. Both are within acceptable limits (<=5 HBD and <=10 HBA).

**QED:** Ligand A (0.866) has a substantially better QED score than Ligand B (0.686), indicating a more drug-like profile.

**DILI:** Ligand A (49.399) has a slightly higher DILI risk than Ligand B (12.253), but both are below the concerning threshold of 60.

**BBB:** Both ligands exhibit good BBB penetration (Ligand A: 78.907, Ligand B: 81.194), exceeding the desirable 70% for CNS targets. Ligand B is slightly better here.

**Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and suggests a potential issue with intestinal absorption. However, these values are on a different scale and difficult to interpret directly without more context.

**Aqueous Solubility:** Both ligands have negative solubility values, indicating poor aqueous solubility. This is a concern for both, but may be mitigated by formulation strategies.

**hERG Inhibition:** Both ligands show low hERG inhibition liability (Ligand A: 0.375, Ligand B: 0.748).

**Microsomal Clearance:** Ligand A (-11.729) has *much* lower microsomal clearance than Ligand B (87.721), suggesting significantly better metabolic stability. This is a major advantage for Ligand A.

**In vitro Half-Life:** Ligand A (19.287 hours) has a reasonable in vitro half-life, while Ligand B (26.791 hours) is slightly longer.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (Ligand A: 0.061, Ligand B: 0.097), which is favorable for CNS penetration.

**Binding Affinity:** Ligand A (-7.9 kcal/mol) has a stronger binding affinity than Ligand B (-6.8 kcal/mol). This 1.1 kcal/mol difference is substantial and can outweigh minor ADME drawbacks.

**Overall Assessment:**

Ligand A is the superior candidate. While Ligand B has slightly better BBB penetration, Ligand A excels in several crucial areas: significantly better TPSA, a much higher QED score, dramatically lower microsomal clearance (better metabolic stability), and a considerably stronger binding affinity. The slightly higher DILI risk for Ligand A is less concerning than the poor metabolic stability of Ligand B. The binding affinity difference is significant enough to prioritize Ligand A despite the solubility concerns which can be addressed through formulation.



Output:
1
2025-04-17 09:02:08,156 - INFO - Batch 499 complete. Total preferences: 7984
2025-04-17 09:02:08,156 - INFO - Processing batch 500/512...
2025-04-17 09:02:50,676 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (366.531 and 346.431 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (55.89) is significantly better than Ligand B (76.46). For CNS targets, we want TPSA <= 90, and A is comfortably within that range, while B is approaching the upper limit.

**logP:** Both ligands have good logP values (2.361 and 1.238), falling within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Both have 1 HBD, which is good. Ligand A has 4 HBA, and Ligand B has 5. Both are acceptable, being <=10.

**QED:** Ligand A (0.869) has a much better QED score than Ligand B (0.539), indicating a more drug-like profile.

**DILI:** Ligand A (56.534) has a slightly higher DILI risk than Ligand B (40.054), but both are below the concerning threshold of 60.

**BBB:** Ligand A (76.309) has a significantly better BBB percentile than Ligand B (60.14). For a CNS target like DRD2, >70 is desirable, and A is closer to this target.

**Caco-2 Permeability:** Both have negative Caco-2 values (-4.531 and -4.897), which is unusual and suggests poor permeability. This is a significant drawback for both.

**Aqueous Solubility:** Both have negative solubility values (-3.542 and -1.701), indicating very poor aqueous solubility. This is a major concern for both compounds.

**hERG Inhibition:** Ligand A (0.898) has a slightly higher hERG risk than Ligand B (0.202), but both are relatively low.

**Microsomal Clearance:** Ligand B (23.8) has a lower microsomal clearance than Ligand A (13.857), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (11.198) has a longer half-life than Ligand B (5.579).

**P-gp Efflux:** Both have very low P-gp efflux liability (0.289 and 0.043), which is excellent for CNS penetration.

**Binding Affinity:** Ligand B (-7.7) has a significantly stronger binding affinity than Ligand A (0). This is a crucial advantage. A difference of >1.5 kcal/mol often outweighs other drawbacks.

**Overall Assessment:**

While Ligand A has better TPSA, QED, and BBB penetration, the significantly stronger binding affinity of Ligand B (-7.7 kcal/mol vs 0 kcal/mol) is a decisive factor. The poor Caco-2 and solubility of both are concerning, but these can potentially be addressed through formulation strategies. The better metabolic stability of Ligand B is also a plus. Given the GPCR target and the importance of affinity, Ligand B is the more promising candidate.

Output:
1
2025-04-17 09:02:50,677 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (342.458 and 341.43 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (41.13) is better than Ligand B (45.23). Both are below the 90 A^2 threshold for CNS targets, but A is closer to optimal.

**logP:** Both ligands have good logP values (4.004 and 3.305), falling within the 1-3 range. Ligand B is slightly more optimal.

**H-Bond Donors/Acceptors:** Ligand A (HBD=2, HBA=2) is slightly better than Ligand B (HBD=1, HBA=3) in terms of balancing solubility and permeability.

**QED:** Both ligands have good QED scores (0.723 and 0.911), indicating good drug-like properties. Ligand B is slightly better.

**DILI:** Ligand A (26.328) has a significantly lower DILI risk than Ligand B (52.695), which is a major advantage.

**BBB:** Ligand B (78.402) has a significantly better BBB penetration percentile than Ligand A (66.033). This is a critical factor for a CNS target like DRD2.

**Caco-2 Permeability:** Ligand A (-5.005) has worse Caco-2 permeability than Ligand B (-4.705).

**Aqueous Solubility:** Ligand A (-3.342) has worse aqueous solubility than Ligand B (-2.816).

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.926 and 0.862).

**Microsomal Clearance:** Ligand B (29.494) has significantly lower microsomal clearance than Ligand A (49.808), indicating better metabolic stability.

**In vitro Half-Life:** Ligand A (47.689) has a better in vitro half-life than Ligand B (-1.131).

**P-gp Efflux:** Ligand A (0.355) has lower P-gp efflux than Ligand B (0.408), which is beneficial for CNS penetration.

**Binding Affinity:** Ligand B (-9.5 kcal/mol) has a significantly stronger binding affinity than Ligand A (-8.3 kcal/mol). This is a substantial advantage, potentially outweighing some ADME drawbacks.

**Overall Assessment:**

Ligand B excels in BBB penetration and binding affinity, which are paramount for a CNS GPCR target. It also has better metabolic stability (lower Cl_mic) and a slightly better QED. While Ligand A has a lower DILI risk and better P-gp efflux, the superior binding affinity and BBB penetration of Ligand B are more crucial for DRD2 targeting. The difference in binding affinity (-9.5 vs -8.3) is >1.5 kcal/mol, making it a significant factor.

Output:
1
2025-04-17 09:02:50,677 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (347.459 and 353.354 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (84.23) is excellent, well below the 90 A^2 threshold for CNS targets. Ligand B (116.42) is higher but still potentially acceptable, though less optimal.

**logP:** Ligand A (2.444) is within the optimal 1-3 range. Ligand B (-0.802) is below 1, which could hinder permeability.

**H-Bond Donors/Acceptors:** Ligand A (HBD=2, HBA=4) and Ligand B (HBD=3, HBA=5) both have reasonable H-bond characteristics, within the suggested limits.

**QED:** Ligand A (0.756) has a strong drug-like profile, significantly better than Ligand B (0.438).

**DILI:** Ligand A (24.118) has a very low DILI risk, which is excellent. Ligand B (70.919) has a higher, though not critically high, DILI risk.

**BBB:** Ligand A (65.801) has a good BBB penetration percentile, though ideally >70. Ligand B (56.534) is lower, raising concerns about CNS exposure.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.251 and -5.178), which is unusual and suggests poor permeability. However, these values are on a log scale and are difficult to interpret without knowing the original units. We will proceed with caution.

**Aqueous Solubility:** Both ligands have negative solubility values (-1.724 and -1.331), again suggesting poor solubility. This is a concern for bioavailability.

**hERG:** Both ligands have very low hERG inhibition liability (0.185 and 0.178), which is positive.

**Microsomal Clearance:** Ligand A (48.238) has a moderate clearance, while Ligand B (-16.442) has a negative clearance, which is impossible. This is likely an error in the data, and we should disregard this value for Ligand B.

**In vitro Half-Life:** Ligand A (-15.461) has a negative half-life, which is impossible. Ligand B (-34.042) is also negative, indicating data errors for both.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.123 and 0.012), which is favorable for CNS penetration.

**Binding Affinity:** Both ligands have similar strong binding affinities (-8.3 and -8.0 kcal/mol). The difference is less than 1.5 kcal/mol, so affinity alone doesn't strongly favor one over the other.

**Overall Assessment:**

Considering the GPCR-specific priorities, Ligand A is significantly more promising. It has a better logP, QED, lower DILI risk, and a better (though still suboptimal) BBB percentile. The negative values for Caco-2 and half-life are concerning for both, but the errors in the data for Ligand B are more pronounced (negative clearance). While both have similar affinity, the superior ADME properties of Ligand A make it the more viable candidate.

Output:
1
2025-04-17 09:02:50,677 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (345.4 and 368.5 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (111.45) is slightly above the optimal <90 for CNS targets, while Ligand B (104.73) is closer but still slightly above. This is a minor concern for both.

**logP:** Both ligands have good logP values (1.195 and 1.45), falling within the 1-3 range.

**H-Bond Donors/Acceptors:** Both have 3 HBDs, which is acceptable. Ligand A has 5 HBAs, while Ligand B has 6. Both are within the acceptable limit of <=10.

**QED:** Both have reasonable QED scores (0.484 and 0.632), with Ligand B being slightly more drug-like.

**DILI:** Both have acceptable DILI risk (41.41 and 48.43 percentile), below the 60 threshold.

**BBB:** This is a critical parameter for CNS targets. Ligand B (65.22%) significantly outperforms Ligand A (39.28%). This is a major advantage for Ligand B.

**Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and suggests poor permeability. However, the scale is not specified, so it's hard to interpret.

**Aqueous Solubility:** Both have negative solubility values, indicating poor solubility. Again, the scale is unknown, making it difficult to assess.

**hERG:** Both have low hERG inhibition liability (0.429 and 0.123), which is favorable.

**Microsomal Clearance:** Ligand A (-3.492) has a negative clearance, which is unusual and likely indicates very high metabolic stability. Ligand B (56.252) has a high clearance, suggesting faster metabolism. This is a significant advantage for Ligand A.

**In vitro Half-Life:** Ligand A (7.925 hours) has a reasonable half-life, while Ligand B (-11.204 hours) has a negative half-life, which is impossible and likely an error.

**P-gp Efflux:** Both have very low P-gp efflux liability (0.043 and 0.07), which is excellent for CNS penetration.

**Binding Affinity:** Ligand B (-7.2 kcal/mol) has a slightly better binding affinity than Ligand A (-6.7 kcal/mol). The difference is 0.5 kcal/mol, which is significant.

**Overall Assessment:**

Ligand B has a much better BBB penetration (65.22% vs 39.28%) and slightly better binding affinity (-7.2 vs -6.7 kcal/mol). However, Ligand A has significantly better metabolic stability (negative clearance) and a reasonable half-life, while Ligand B has a problematic negative half-life. The negative values for Caco-2 and solubility are concerning for both, but the scale is unknown. Given the importance of BBB for a CNS target like DRD2, and the slight affinity advantage, Ligand B is more promising despite the metabolic concerns. The negative half-life for Ligand B is a major red flag, but the affinity difference could be worth investigating further with structural modifications to improve metabolic stability.

Output:
1
2025-04-17 09:02:50,677 - INFO - Reasoning:

Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight (MW):** Both ligands are within the ideal range (200-500 Da). Ligand A (349.308 Da) is slightly lower, which could be beneficial for permeability.

**2. TPSA:** Ligand A (46.61) is significantly better than Ligand B (93.01). For CNS targets, TPSA should be <= 90, so Ligand A is much more favorable.

**3. logP:** Both ligands have similar and optimal logP values (A: 2.891, B: 2.912), falling within the 1-3 range.

**4. H-Bond Donors (HBD):** Both are acceptable, with Ligand A having 0 and Ligand B having 2.

**5. H-Bond Acceptors (HBA):** Both ligands have 4 HBA, which is within the acceptable limit of <= 10.

**6. QED:** Both ligands have good QED scores (A: 0.629, B: 0.702), indicating drug-like properties.

**7. DILI:** Ligand A (76.464) has a higher DILI risk than Ligand B (16.44). This is a significant negative for Ligand A.

**8. BBB:** Ligand A (86.39) has a much better BBB penetration percentile than Ligand B (48.662). This is a crucial advantage for a CNS target like DRD2.

**9. Caco-2:** Both have negative values, which is unusual. Assuming these are percentile scores, Ligand A (-4.24) is slightly better than Ligand B (-4.901).

**10. Solubility:** Both have negative values, again assuming percentile scores, Ligand A (-4.566) is slightly better than Ligand B (-3.997).

**11. hERG:** Both ligands have low hERG inhibition liability (A: 0.492, B: 0.49), which is good.

**12. Cl_mic:** Ligand B (51.556) has a lower microsomal clearance than Ligand A (90.416), suggesting better metabolic stability.

**13. t1/2:** Ligand B (-9.155) has a negative in vitro half-life, which is concerning. Ligand A (22.885) has a much more reasonable half-life.

**14. Pgp:** Both ligands have low P-gp efflux liability (A: 0.646, B: 0.16). Ligand B is slightly better.

**15. Binding Affinity:** Ligand A (-8.5 kcal/mol) has a significantly stronger binding affinity than Ligand B (-6.5 kcal/mol). This is a substantial advantage, potentially outweighing some of the ADME drawbacks.

**Overall Assessment:**

Ligand A excels in TPSA, BBB, and binding affinity, all critical for a CNS-targeting GPCR. While it has a higher DILI risk, the strong binding affinity and good BBB penetration are compelling. Ligand B has better metabolic stability and lower Pgp efflux, but suffers from a much higher TPSA, poor BBB penetration, and weaker binding affinity.

Given the importance of CNS penetration and potency for DRD2, Ligand A is the more promising candidate, despite the higher DILI risk. Further optimization could focus on mitigating the DILI liability while preserving the favorable binding and BBB properties.

Output:
1
2025-04-17 09:02:50,678 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (348.531 and 374.853 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (41.57) is significantly better than Ligand B (77). For CNS targets, we want TPSA <= 90, and ideally closer to 60. Ligand A is well within this range, while Ligand B is approaching the upper limit and less favorable.

**logP:** Both ligands have a logP around 3.5, which is within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Both have 1 HBD, which is good. Ligand A has 3 HBA, and Ligand B has 6 HBA. Lower HBA is generally preferred, making Ligand A slightly better.

**QED:** Both ligands have QED values around 0.7-0.8, indicating good drug-likeness.

**DILI:** Ligand A (12.136) has a much lower DILI risk than Ligand B (89.802). This is a significant advantage for Ligand A.

**BBB:** Ligand A (86.041) has a very good BBB penetration percentile, exceeding the desirable >70 threshold for CNS targets. Ligand B (32.571) has poor BBB penetration, a major drawback.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values, which is unusual and suggests poor permeability. However, the scale isn't specified, so it's hard to interpret.

**Aqueous Solubility:** Both ligands have negative solubility values, which is also unusual and suggests poor solubility.

**hERG:** Both ligands have low hERG inhibition liability (0.716 and 0.32), which is good.

**Microsomal Clearance:** Ligand A (61.409) has higher microsomal clearance than Ligand B (41.91). Lower clearance is preferred for better metabolic stability, giving a slight edge to Ligand B.

**In vitro Half-Life:** Ligand A (11.318) has a longer half-life than Ligand B (-0.741). This is a significant advantage for Ligand A.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.264 and 0.258), which is good.

**Binding Affinity:** Ligand B (-8.8 kcal/mol) has a significantly stronger binding affinity than Ligand A (-7.2 kcal/mol). This is a substantial advantage for Ligand B, potentially outweighing some of its ADME drawbacks. The difference is >1.5 kcal/mol, making it a key factor.

**Overall Assessment:**

While Ligand A excels in ADME properties (DILI, BBB, t1/2, TPSA), Ligand B boasts a considerably stronger binding affinity. For a GPCR target like DRD2, strong binding is crucial. The poor BBB penetration of Ligand B is a concern, but the substantial affinity difference (-8.8 vs -7.2) might be overcome with formulation strategies or prodrug approaches to improve brain exposure. The lower DILI risk of Ligand A is also attractive, but the binding affinity is the most important factor here.

Output:
1
2025-04-17 09:02:50,678 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (344.365 and 345.451 Da) fall comfortably within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (51.85) is significantly better than Ligand B (93.68). For CNS targets, we want TPSA <= 90, and A is well within this, while B is slightly above. This is a substantial advantage for A.

**3. logP:** Both ligands have acceptable logP values (2.926 and 1.927, respectively), falling within the optimal 1-3 range.

**4. H-Bond Donors:** Both ligands have reasonable HBD counts (1 and 2, respectively), well below the threshold of 5.

**5. H-Bond Acceptors:** Ligand B (8) is higher than Ligand A (4), but both are below the 10 threshold.

**6. QED:** Both ligands have similar and acceptable QED values (0.774 and 0.675), indicating good drug-like properties.

**7. DILI:** Ligand A (70.841) has a higher DILI risk than Ligand B (47.732). This favors Ligand B.

**8. BBB:** Ligand A (85.459) has a significantly higher BBB penetration percentile than Ligand B (48.119). This is a *critical* advantage for a CNS target like DRD2.

**9. Caco-2 Permeability:** Ligand A (-4.712) has better Caco-2 permeability than Ligand B (-5.603), though both are negative values which is unusual.

**10. Aqueous Solubility:** Ligand A (-3.545) has better aqueous solubility than Ligand B (-1.861), which is beneficial for formulation.

**11. hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.654 and 0.233, respectively).

**12. Microsomal Clearance:** Ligand B (14.121) has a much higher microsomal clearance than Ligand A (6.43). Lower clearance is preferred for metabolic stability, favoring Ligand A.

**13. In vitro Half-Life:** Ligand A (11.4) has a longer in vitro half-life than Ligand B (8.578), which is desirable.

**14. P-gp Efflux:** Both ligands have low P-gp efflux liability (0.275 and 0.347, respectively).

**15. Binding Affinity:** Ligand B (-7.4) has a significantly stronger binding affinity than Ligand A (-10.1). This is a substantial advantage for Ligand B.

**Overall Assessment:**

While Ligand B has a better binding affinity and lower DILI risk, Ligand A is superior in several key areas for a CNS-targeting GPCR ligand. Specifically, its significantly better TPSA, BBB penetration, solubility, metabolic stability (lower Cl_mic), and longer half-life outweigh the affinity difference. The strong affinity of Ligand B is tempting, but the poor BBB penetration is a major drawback. The TPSA of Ligand B is also less ideal.

Output:
0
2025-04-17 09:02:50,678 - INFO - Reasoning:

Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (387.307 Da) is slightly higher than Ligand B (340.427 Da), but both are acceptable.

**2. TPSA:** Ligand A (50.8) is significantly better than Ligand B (78.09). For CNS targets, we want TPSA <= 90, and ideally closer to 60. Ligand A is much closer to this ideal.

**3. logP:** Ligand A (3.959) is optimal, while Ligand B (1.259) is on the lower side. A logP between 1-3 is preferred, and Ligand B's value might indicate potential permeability issues.

**4. H-Bond Donors:** Both ligands have acceptable HBD counts (Ligand A: 1, Ligand B: 2), well below the threshold of 5.

**5. H-Bond Acceptors:** Both ligands have acceptable HBA counts (Ligand A: 3, Ligand B: 3), well below the threshold of 10.

**6. QED:** Both ligands have similar and good QED values (Ligand A: 0.851, Ligand B: 0.81), indicating good drug-like properties.

**7. DILI:** Ligand A (47.421) has a better DILI score than Ligand B (30.826), indicating a lower risk of liver injury. Both are below the 40 threshold, which is good.

**8. BBB:** This is crucial for a CNS target like DRD2. Ligand A (92.904) has a *very* strong BBB penetration prediction, exceeding the desirable >70 threshold. Ligand B (61.497) is significantly lower, which is a major drawback.

**9. Caco-2 Permeability:** Ligand A (-4.451) and Ligand B (-5.197) both have negative values, which is unusual. This suggests poor Caco-2 permeability for both. However, the scale is not specified, so it's hard to interpret.

**10. Aqueous Solubility:** Ligand A (-4.484) and Ligand B (-2.09) both have negative values, which suggests poor solubility.

**11. hERG Inhibition:** Ligand A (0.732) has a better hERG score than Ligand B (0.228), indicating lower cardiotoxicity risk.

**12. Microsomal Clearance:** Ligand A (49.782) has higher clearance than Ligand B (17.872), meaning it is less metabolically stable.

**13. In vitro Half-Life:** Ligand B (-31.794) has a much longer half-life than Ligand A (18.471), which is a positive attribute.

**14. P-gp Efflux:** Ligand A (0.412) has lower P-gp efflux than Ligand B (0.08), which is favorable for CNS exposure.

**15. Binding Affinity:** Both ligands have excellent binding affinities (Ligand A: -9 kcal/mol, Ligand B: -8.9 kcal/mol). The difference is minor, and both are well below the -7 kcal/mol threshold.

**Overall Assessment:**

Ligand A is the superior candidate. While Ligand B has a longer half-life, Ligand A excels in critical areas for a CNS-targeting GPCR ligand: TPSA, logP, and, most importantly, BBB penetration. The significantly better BBB score of Ligand A outweighs the slightly higher clearance and shorter half-life. The better DILI and hERG scores also contribute to its favorability.



Output:
1
2025-04-17 09:02:50,679 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (338.415 and 367.475 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (79.97) is significantly better than Ligand B (95.07). For CNS targets, we want TPSA <= 90, so Ligand A is preferable.

**3. logP:** Both ligands have good logP values (2.94 and 2.419), falling within the optimal 1-3 range.

**4. H-Bond Donors:** Both have 1 HBD, which is acceptable.

**5. H-Bond Acceptors:** Ligand A has 7 HBAs, and Ligand B has 9. Both are within the acceptable limit of <=10, but Ligand A is slightly better.

**6. QED:** Ligand A (0.709) has a significantly better QED score than Ligand B (0.505), indicating a more drug-like profile.

**7. DILI:** Ligand B (77.588) has a higher DILI risk than Ligand A (63.164). Both are above the preferred <40, but Ligand A is better.

**8. BBB:** Ligand A (73.672) has a much better BBB percentile than Ligand B (43.815). This is *critical* for a CNS target like DRD2.

**9. Caco-2:** Both have negative Caco-2 values (-5.217 and -5.447), which is unusual and suggests poor permeability. This is a concern for both, but doesn't differentiate them significantly.

**10. Solubility:** Both have negative solubility values (-2.401 and -3.517), indicating poor aqueous solubility. This is a drawback for both.

**11. hERG:** Ligand A (0.805) has a slightly higher hERG risk than Ligand B (0.044). Ligand B is much better here.

**12. Cl_mic:** Ligand B (97.357) has a much higher microsomal clearance than Ligand A (19.212), indicating lower metabolic stability. Ligand A is significantly better.

**13. t1/2:** Ligand A (55.741) has a much longer in vitro half-life than Ligand B (23.029). This is a significant advantage for Ligand A.

**14. Pgp:** Ligand A (0.079) has a much lower P-gp efflux liability than Ligand B (0.252), which is crucial for CNS penetration.

**15. Binding Affinity:** Ligand A (-9.1 kcal/mol) has a significantly stronger binding affinity than Ligand B (-7.0 kcal/mol). This is a major advantage, potentially outweighing some of the ADME concerns.

**Overall Assessment:**

Ligand A is clearly superior. While both compounds have issues with solubility and Caco-2 permeability, Ligand A excels in the critical areas for a CNS-targeting GPCR: BBB penetration, metabolic stability (lower Cl_mic, longer t1/2), lower P-gp efflux, and significantly stronger binding affinity. The better QED and lower DILI risk further support choosing Ligand A. The hERG risk is slightly higher for Ligand A, but the substantial advantage in affinity and CNS penetration makes it the more promising candidate.

Output:
1
2025-04-17 09:02:50,679 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (348.45 and 369.45 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (76.46) is excellent, well below the 90 A^2 threshold for CNS targets. Ligand B (124.26) is higher, but still potentially acceptable, though less ideal.

**logP:** Ligand A (2.624) is optimal (1-3). Ligand B (-0.41) is significantly lower, which could hinder membrane permeability and CNS penetration.

**H-Bond Donors/Acceptors:** Ligand A (HBD=1, HBA=5) is favorable. Ligand B (HBD=3, HBA=5) is also reasonable, but the higher HBD count could slightly impact permeability.

**QED:** Both ligands have good QED scores (A: 0.907, B: 0.629), suggesting good drug-like properties.

**DILI:** Ligand A (32.997) has a much lower DILI risk than Ligand B (59.829), which is a significant advantage.

**BBB:** Ligand A (86.661) has a very good BBB percentile, exceeding the desirable >70% threshold for CNS targets. Ligand B (31.912) is poor, indicating limited brain penetration. This is a critical drawback for a DRD2 ligand.

**Caco-2 Permeability:** Ligand A (-4.45) and Ligand B (-5.536) both have negative values, which is unusual and suggests poor permeability. However, the scale is not specified, so it's hard to interpret.

**Aqueous Solubility:** Both have negative solubility values (-2.127 and -3.039), which is also unusual and problematic. Poor solubility can hinder absorption.

**hERG:** Both ligands have very low hERG risk (A: 0.253, B: 0.104).

**Microsomal Clearance:** Ligand A (43.798) has moderate clearance, while Ligand B (-1.053) has a negative value, which is not physically possible and suggests a data error or unusual experimental conditions.

**In vitro Half-Life:** Ligand A (-8.466) has a negative half-life, which is not physically possible and suggests a data error. Ligand B (-41.182) also has a negative half-life, indicating a data issue.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (A: 0.045, B: 0.01).

**Binding Affinity:** Both ligands have excellent binding affinity (-7.9 and -8.4 kcal/mol), with Ligand B being slightly stronger. However, the affinity difference is not large enough to overcome the significant ADME deficiencies of Ligand B.

**Conclusion:**

Considering all factors, especially the critical GPCR-specific properties for CNS targets, **Ligand A is the more promising candidate.** It has a favorable BBB score, good logP, lower DILI risk, and acceptable TPSA. While both ligands have issues with solubility and Caco-2 permeability, Ligand A's superior BBB penetration and lower DILI risk outweigh the slightly better affinity of Ligand B. The negative values for half-life and clearance in Ligand B are also concerning and suggest data quality issues.

Output:
0
2025-04-17 09:02:50,679 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (348.447) is slightly better positioned.

**TPSA:** Ligand A (107.5) is better than Ligand B (48.99). For CNS targets, we want TPSA <= 90, so Ligand B is significantly better.

**logP:** Ligand A (0.889) is suboptimal, being below the preferred 1-3 range. Ligand B (4.966) is too high, potentially causing solubility and off-target issues.

**H-Bond Donors:** Both have 1 HBD, which is good.

**H-Bond Acceptors:** Ligand A has 4 HBA, and Ligand B has 3. Both are within the acceptable range of <=10.

**QED:** Ligand A (0.769) is better than Ligand B (0.663), indicating a more drug-like profile.

**DILI:** Both have relatively high DILI risk (Ligand A: 17.449, Ligand B: 59.946), but Ligand A is considerably better.

**BBB:** Ligand B (77.898) is significantly better than Ligand A (60.566) in terms of BBB penetration, which is crucial for a CNS target like DRD2.

**Caco-2 Permeability:** Ligand A (-5.069) and Ligand B (-4.932) both have negative values, indicating poor permeability.

**Aqueous Solubility:** Ligand A (-1.881) is better than Ligand B (-5.123).

**hERG Inhibition:** Ligand A (0.299) is much better than Ligand B (0.823), indicating a lower risk of cardiotoxicity.

**Microsomal Clearance:** Ligand B (72.87) has a much higher clearance than Ligand A (4.42), meaning it's less metabolically stable.

**In vitro Half-Life:** Ligand B (22.315) has a longer half-life than Ligand A (-4.704).

**P-gp Efflux:** Ligand A (0.006) has much lower P-gp efflux liability than Ligand B (0.636), which is favorable for CNS exposure.

**Binding Affinity:** Ligand B (-7.7 kcal/mol) has a slightly better binding affinity than Ligand A (-7.1 kcal/mol). This 1.6 kcal/mol difference is significant and could outweigh some ADME drawbacks.

**Overall Assessment:**

Ligand B has a better BBB penetration and binding affinity, which are key for a CNS GPCR target. However, it suffers from a high logP, high P-gp efflux, and high microsomal clearance. Ligand A has a better overall ADME profile (lower DILI, better solubility, lower hERG, lower P-gp efflux, lower clearance), but its BBB penetration and logP are less ideal.

Given the importance of CNS penetration for DRD2, and the significant affinity advantage of Ligand B, I would lean towards **Ligand B** as the more promising candidate, *assuming* that the logP and P-gp efflux issues can be addressed through further optimization. The affinity difference is substantial enough to warrant prioritizing it despite the ADME concerns.

Output:
1
2025-04-17 09:02:50,679 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B based on the provided guidelines, prioritizing GPCR-specific properties (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (388.961 Da) is slightly higher than Ligand B (354.401 Da), but both are acceptable.

**TPSA:** Ligand A (67.43) is better than Ligand B (78.67). For CNS targets, we want TPSA <= 90, both are within this range, but A is preferable.

**logP:** Ligand A (4.595) is higher than Ligand B (1.619). While 4.595 is approaching the upper limit of optimal (1-3), it's still potentially manageable. Ligand B's logP is quite low, which could hinder permeability.

**H-Bond Donors/Acceptors:** Both have 2 HBD and a reasonable number of HBA (4 for A, 3 for B). This is acceptable for both.

**QED:** Both ligands have good QED scores (0.684 and 0.862), indicating good drug-like properties.

**DILI:** Ligand A (42.885) has a slightly higher DILI risk than Ligand B (33.23), but both are below the 40 threshold and considered low risk.

**BBB:** Both ligands have excellent BBB penetration (70.609% and 74.758%). This is crucial for CNS targets like DRD2 and both perform well.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.709 and -4.858). This is unusual and suggests poor permeability. However, these values are on a log scale, so even negative values can be comparable.

**Aqueous Solubility:** Both have very poor aqueous solubility (-4.6 and -1.564). This is a significant drawback for both.

**hERG Inhibition:** Ligand A (0.608) has a slightly higher hERG risk than Ligand B (0.487), but both are relatively low.

**Microsomal Clearance:** Ligand B (-11.353) has significantly lower (better) microsomal clearance than Ligand A (98.688). This suggests better metabolic stability for Ligand B.

**In vitro Half-Life:** Ligand B (16.15 hours) has a longer half-life than Ligand A (48.249 hours). This is a positive for Ligand B.

**P-gp Efflux:** Ligand A (0.32) has higher P-gp efflux than Ligand B (0.017). Lower P-gp efflux is preferred, making Ligand B better.

**Binding Affinity:** Ligand A (-7.6 kcal/mol) has a slightly better binding affinity than Ligand B (-0.0 kcal/mol). This is a substantial difference, and affinity is a primary driver for GPCR drug candidates.

**Overall Assessment:**

Ligand A has a better binding affinity and acceptable TPSA, but suffers from higher logP, higher DILI, higher P-gp efflux, and significantly worse microsomal clearance. Ligand B has better ADME properties (lower logP, better clearance, lower P-gp efflux), but a significantly weaker binding affinity.

Given the strong emphasis on binding affinity for GPCRs, and the relatively small difference in other parameters, the superior binding affinity of Ligand A outweighs its drawbacks. The negative Caco-2 and solubility are concerning, but optimization could potentially address these. The difference in affinity is large enough to make A the more promising candidate.

Output:
1
2025-04-17 09:02:50,680 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (355.395 and 371.507 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (118.81) is slightly above the optimal <90 for CNS targets, but still reasonable. Ligand B (89.35) is excellent, well within the desired range.

**logP:** Ligand A (0.384) is quite low, potentially hindering permeability. Ligand B (0.857) is also on the lower side, but better than A. Both are below the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A has 2 HBD and 8 HBA, which are acceptable. Ligand B has 1 HBD and 7 HBA, also acceptable.

**QED:** Both ligands have good QED scores (0.804 and 0.765), indicating good drug-like properties.

**DILI:** Ligand A (67.39) has a higher DILI risk than Ligand B (47.15), although both are reasonably acceptable.

**BBB:** Ligand B (67.08) has a better BBB percentile than Ligand A (48.197). While both are not ideal (>70), B is significantly better. This is a critical factor for a CNS target like DRD2.

**Caco-2 Permeability:** Ligand A (-4.507) has poor Caco-2 permeability, suggesting poor absorption. Ligand B (-5.403) is also poor, but slightly better than A.

**Aqueous Solubility:** Both ligands have very poor aqueous solubility (-1.687 and -1.539). This could pose formulation challenges.

**hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.078 and 0.48), which is excellent.

**Microsomal Clearance:** Ligand A (20.612) has a higher microsomal clearance than Ligand B (-6.955), suggesting lower metabolic stability. This is a significant drawback for A.

**In vitro Half-Life:** Ligand B (5.257) has a positive in vitro half-life, while Ligand A (-25.742) has a negative value, indicating very poor stability.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.045 and 0.257), which is favorable for CNS penetration.

**Binding Affinity:** Ligand B (-8.2 kcal/mol) has a significantly stronger binding affinity than Ligand A (-6.8 kcal/mol). This >1.5 kcal/mol difference is a major advantage for Ligand B, potentially outweighing some of its ADME drawbacks.

**Conclusion:**

Considering all factors, particularly the GPCR-specific priorities, **Ligand B is the more promising drug candidate.** Its superior binding affinity, better BBB penetration, lower DILI risk, and improved metabolic stability (lower Cl_mic, positive t1/2) outweigh the slightly lower logP and solubility compared to Ligand A. The poor Caco-2 permeability is a concern for both, but the strong affinity of Ligand B suggests it might still achieve sufficient target engagement *in vivo*.



Output:
1
2025-04-17 09:02:50,680 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, considering the provided guidelines and GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (336.355 and 346.387 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (86.86) is excellent, falling well below the 90 A^2 threshold for CNS targets. Ligand B (108.46) is still reasonable but less optimal.

**logP:** Both ligands have good logP values (1.342 and 1.031), falling within the 1-3 range.

**H-Bond Donors/Acceptors:** Both ligands have 1 HBD and a reasonable number of HBAs (7 and 6 respectively), satisfying the criteria.

**QED:** Both ligands have good QED scores (0.727 and 0.824), indicating good drug-likeness.

**DILI:** Ligand A (83.017) has a higher DILI risk than Ligand B (65.413), which is preferable.

**BBB:** Ligand B (60.14) has a significantly better BBB penetration percentile than Ligand A (35.867). This is *critical* for a CNS target like DRD2.

**Caco-2 Permeability:** Ligand A (-5.059) has a worse Caco-2 permeability than Ligand B (-4.694).

**Aqueous Solubility:** Both ligands have similar and poor aqueous solubility (-2.732 and -2.615). This could pose formulation challenges, but is less critical than BBB for a CNS target.

**hERG:** Both ligands have very low hERG inhibition risk (0.549 and 0.2).

**Microsomal Clearance:** Ligand B (30.724) has a lower microsomal clearance than Ligand A (41.614), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand B (-19.335) has a longer in vitro half-life than Ligand A (-27.626).

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.068 and 0.065).

**Binding Affinity:** Ligand A (-9.5 kcal/mol) has a significantly stronger binding affinity than Ligand B (-7.4 kcal/mol). This is a substantial advantage.

**Overall Assessment:**

While Ligand A has a superior binding affinity, the significantly better BBB penetration (60.14 vs 35.867), lower DILI risk, better metabolic stability, and longer half-life of Ligand B are crucial for a CNS-targeting drug. The difference in binding affinity (2.1 kcal/mol) is considerable, but can potentially be optimized in subsequent iterations of drug design. The poor solubility of both compounds is a concern, but secondary to CNS penetration for this target.

Output:
1
2025-04-17 09:02:50,680 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (352.475 and 349.45 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (76.66) is better than Ligand B (43.86). For CNS targets, TPSA should be <=90, both are within this range, but A is closer to the upper limit.

**logP:** Both ligands (1.795 and 1.302) are within the optimal 1-3 range.

**H-Bond Donors:** Ligand A has 2 HBD, and Ligand B has 0. Both are acceptable (<=5).

**H-Bond Acceptors:** Ligand A has 4 HBA, and Ligand B has 3. Both are acceptable (<=10).

**QED:** Both ligands have good QED scores (0.62 and 0.703), indicating good drug-like properties.

**DILI:** Ligand A (25.669) has a significantly lower DILI risk than Ligand B (15.316). Both are good, but A is preferable.

**BBB:** Ligand B (94.067) has a much higher BBB penetration percentile than Ligand A (66.266). This is a *critical* advantage for a CNS target like DRD2.

**Caco-2 Permeability:** Ligand A (-4.494) and Ligand B (-4.358) are both negative, indicating poor permeability. This is a concern for both, but not a deciding factor.

**Aqueous Solubility:** Ligand A (-2.832) and Ligand B (-2.194) are both negative, indicating poor solubility. This is a concern for both, but not a deciding factor.

**hERG:** Ligand A (0.151) has a slightly higher hERG risk than Ligand B (0.619), but both are low.

**Microsomal Clearance:** Ligand A (75.178) has higher microsomal clearance than Ligand B (38.034), indicating lower metabolic stability.

**In vitro Half-Life:** Ligand B (-4.778) has a longer in vitro half-life than Ligand A (-11.706). This is a significant advantage for B.

**P-gp Efflux:** Ligand A (0.127) has lower P-gp efflux than Ligand B (0.115), which is better for CNS exposure.

**Binding Affinity:** Ligand B (-8.7 kcal/mol) has a stronger binding affinity than Ligand A (-7.6 kcal/mol). This is a substantial advantage (1.1 kcal/mol difference), and can often outweigh minor ADME drawbacks.

**Overall Assessment:**

While Ligand A has better DILI and P-gp efflux, Ligand B excels in the most crucial areas for a CNS-targeting GPCR: **BBB penetration and binding affinity.** The significantly higher BBB value for Ligand B is a major advantage, and the stronger binding affinity further solidifies its potential. The longer half-life of Ligand B is also a positive. The slightly higher clearance of Ligand A is a concern, but the superior affinity and BBB penetration of Ligand B are more important.

Output:
1
2025-04-17 09:02:50,680 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 drug candidates, considering the provided guidelines and GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (366.849 Da) is slightly higher than Ligand B (345.487 Da), but both are acceptable.

**TPSA:** Ligand A (87.32) is closer to the upper limit for CNS targets (<=90), while Ligand B (63.13) is well within the optimal range. This favors Ligand B.

**logP:** Both ligands have good logP values (A: 2.486, B: 3.095), falling within the 1-3 range. Ligand B is slightly higher, which could be beneficial for membrane permeability, but not significantly.

**H-Bond Donors/Acceptors:** Both ligands have 2 HBD and 4/3 HBA, which are within acceptable limits (<=5 HBD, <=10 HBA).

**QED:** Both ligands have reasonable QED values (A: 0.42, B: 0.711). Ligand B's QED is significantly better, indicating a more drug-like profile.

**DILI:** Ligand A (59.519) has a higher DILI risk than Ligand B (28.887). This is a significant advantage for Ligand B.

**BBB:** Ligand B (65.801) has a much better BBB penetration percentile than Ligand A (44.668). This is *critical* for a CNS target like DRD2, making Ligand B strongly favored.

**Caco-2 Permeability:** Ligand A (-5.338) has a negative Caco-2 value which is unusual and suggests very poor permeability; Ligand B (-4.601) is also poor but better than A.

**Aqueous Solubility:** Both have very poor solubility (-3.191 and -3.133), which is a concern for both.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (A: 0.415, B: 0.342).

**Microsomal Clearance:** Ligand A (7.159) has a lower microsomal clearance than Ligand B (47.509), suggesting better metabolic stability. This favors Ligand A.

**In vitro Half-Life:** Ligand B (27.242) has a significantly longer in vitro half-life than Ligand A (-16.682). This is a major advantage for Ligand B.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (A: 0.092, B: 0.198).

**Binding Affinity:** Ligand B (-8.0 kcal/mol) has a slightly better binding affinity than Ligand A (-7.9 kcal/mol). While the difference is small, it's still a positive for Ligand B.

**Overall Assessment:**

Considering the GPCR-specific priorities, Ligand B is the superior candidate. Its significantly better BBB penetration, higher QED, lower DILI risk, and longer half-life outweigh Ligand A's slightly better metabolic stability. The small affinity difference is not enough to offset the other advantages of Ligand B. The poor solubility and Caco-2 permeability are concerns for both, but can be addressed with formulation strategies.

Output:
1
2025-04-17 09:02:50,681 - INFO - Batch 500 complete. Total preferences: 8000
2025-04-17 09:02:50,681 - INFO - Processing batch 501/512...
2025-04-17 09:03:32,341 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (354.43 & 356.40 Da) fall comfortably within the ideal 200-500 Da range.

**2. TPSA:** Both ligands have TPSA values (96.25 & 94.36) below the 140 A^2 threshold for oral absorption, and reasonably close to the 90 A^2 target for CNS penetration. Ligand B is slightly better here.

**3. logP:** Ligand A (0.393) is a bit low, potentially hindering permeability. Ligand B (-0.277) is even lower, raising concerns about membrane penetration. Both are below the optimal 1-3 range.

**4. H-Bond Donors:** Both ligands have acceptable HBD counts (3 and 2 respectively), below the threshold of 5.

**5. H-Bond Acceptors:** Both ligands have acceptable HBA counts (5 and 6 respectively), below the threshold of 10.

**6. QED:** Both ligands have good QED scores (0.598 and 0.703), indicating good drug-like properties.

**7. DILI:** Ligand A (29.624%) has a significantly lower DILI risk than Ligand B (43.66%), which is a substantial advantage.

**8. BBB:** Ligand B (77.937%) has a better BBB penetration percentile than Ligand A (65.529%). This is a critical factor for a CNS target like DRD2.

**9. Caco-2 Permeability:** Ligand A (-5.198) has a worse Caco-2 permeability than Ligand B (-4.795), indicating lower intestinal absorption.

**10. Aqueous Solubility:** Both ligands have poor aqueous solubility (-1.664 and -1.709).

**11. hERG Inhibition:** Both ligands have low hERG inhibition risk (0.173 and 0.387).

**12. Microsomal Clearance:** Ligand A (0.895) has significantly lower microsomal clearance than Ligand B (4.459), suggesting better metabolic stability.

**13. In vitro Half-Life:** Ligand A (2.616) has a slightly longer in vitro half-life than Ligand B (2.967).

**14. P-gp Efflux:** Ligand A (0.021) has much lower P-gp efflux liability than Ligand B (0.108), which is very important for CNS penetration.

**15. Binding Affinity:** Both ligands have very similar and excellent binding affinities (-8.2 and -8.1 kcal/mol). The difference is negligible.

**Overall Assessment:**

While Ligand B has better BBB penetration and Caco-2 permeability, Ligand A demonstrates superior ADME properties in terms of DILI risk, microsomal clearance, and P-gp efflux. The slightly lower logP of Ligand A is a concern, but the substantial improvements in safety (DILI) and CNS exposure (P-gp, BBB) outweigh this drawback. Given the importance of CNS penetration for a DRD2 ligand, and the relatively similar binding affinities, Ligand A is the more promising candidate due to its better overall ADME profile.

Output:
0
2025-04-17 09:03:32,341 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (356.511 and 369.412 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (76.12) is excellent for CNS penetration, well below the 90 A^2 threshold. Ligand B (36.44) is also very good.

**logP:** Ligand A (-0.148) is slightly low, potentially hindering membrane permeability. Ligand B (2.992) is optimal.

**H-Bond Donors/Acceptors:** Ligand A has 2 HBD and 5 HBA, which is acceptable. Ligand B has 0 HBD and 4 HBA, also acceptable.

**QED:** Both ligands have good QED scores (0.569 and 0.813), suggesting good drug-like properties.

**DILI:** Ligand A (3.063) has a very low DILI risk. Ligand B (42.109) has a moderate DILI risk, but not alarmingly high.

**BBB:** This is crucial for a CNS target. Ligand A (31.214) has a poor BBB penetration percentile. Ligand B (88.833) has excellent BBB penetration.

**Caco-2 Permeability:** Ligand A (-5.205) has poor Caco-2 permeability. Ligand B (-4.661) also has poor Caco-2 permeability.

**Aqueous Solubility:** Ligand A (0.117) has very poor aqueous solubility. Ligand B (-2.812) also has poor aqueous solubility.

**hERG Inhibition:** Ligand A (0.237) has a low hERG inhibition risk. Ligand B (0.738) has a slightly elevated, but still acceptable, hERG risk.

**Microsomal Clearance:** Ligand A (-10.261) has very low microsomal clearance, indicating high metabolic stability. Ligand B (27.48) has moderate clearance.

**In vitro Half-Life:** Ligand A (-0.343) has a very short half-life. Ligand B (2.227) has a longer half-life.

**P-gp Efflux:** Ligand A (0.005) has very low P-gp efflux, which is favorable for CNS penetration. Ligand B (0.174) also has low P-gp efflux.

**Binding Affinity:** Ligand B (-7.9 kcal/mol) has a slightly better binding affinity than Ligand A (-7.3 kcal/mol). While both are good, the 1.6 kcal/mol difference is significant.

**Overall Assessment:**

Ligand B is the more promising candidate. While both have issues with Caco-2 permeability and aqueous solubility, Ligand B's superior BBB penetration, optimal logP, better half-life, and slightly better binding affinity outweigh the moderate DILI risk. Ligand A's extremely poor BBB penetration is a major drawback for a CNS target, despite its excellent metabolic stability and low DILI. The slightly better affinity of Ligand B is also a plus.

Output:
1
2025-04-17 09:03:32,341 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 drug candidates, considering the provided guidelines and GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (349.431 Da) is slightly lower, which could be beneficial for permeability, while Ligand B (362.543 Da) is also well within range.

**TPSA:** Ligand A (89.43) is better than Ligand B (61.88) as it is closer to the optimal TPSA for CNS targets (<=90).

**logP:** Ligand A (1.383) is within the optimal range (1-3), while Ligand B (4.569) is higher. While not drastically high, Ligand B's logP could potentially lead to solubility issues or off-target interactions.

**H-Bond Donors/Acceptors:** Ligand A has 2 HBD and 5 HBA, while Ligand B has 1 HBD and 4 HBA. Both are within acceptable limits.

**QED:** Both ligands have similar QED values (0.728 and 0.748), indicating good drug-like properties.

**DILI:** Both ligands have similar DILI risk (59.442 and 56.689), indicating moderate risk.

**BBB:** Ligand B (70.609) significantly outperforms Ligand A (45.444) in BBB penetration. This is a crucial factor for a CNS target like DRD2.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.073 and -5.283), which is unusual and suggests poor permeability. However, these values are on a scale where negative values are possible and don't necessarily disqualify a compound.

**Aqueous Solubility:** Both ligands have negative solubility values (-2.002 and -3.973), indicating poor aqueous solubility. This is a concern, but can sometimes be overcome with formulation strategies.

**hERG Inhibition:** Ligand A (0.121) has a much lower hERG inhibition liability than Ligand B (0.774), making it safer from a cardiotoxicity perspective.

**Microsomal Clearance:** Ligand A (13.931) has a lower microsomal clearance than Ligand B (55.099), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand B (30.066) has a longer in vitro half-life than Ligand A (12.325), which is generally desirable.

**P-gp Efflux:** Ligand A (0.083) has lower P-gp efflux liability than Ligand B (0.758), which is beneficial for CNS exposure.

**Binding Affinity:** Ligand B (-7.2 kcal/mol) has a significantly stronger binding affinity than Ligand A (-0.0 kcal/mol). This is a major advantage, potentially outweighing some of the ADME drawbacks.

**Overall Assessment:**

Ligand B has a superior binding affinity and better BBB penetration, which are critical for a CNS GPCR target. Its longer half-life is also a plus. However, it has a higher logP, higher hERG risk, and higher P-gp efflux. Ligand A has better TPSA, lower hERG, lower P-gp efflux, and better metabolic stability, but its binding affinity is very weak and its BBB penetration is poor.

Given the strong emphasis on affinity for GPCRs, and the importance of BBB penetration for CNS targets, the significantly stronger binding affinity and better BBB penetration of Ligand B outweigh its other drawbacks. While the higher logP and hERG risk are concerns, these can potentially be addressed through further optimization. The extremely weak binding of Ligand A is a major hurdle that would be difficult to overcome.

Output:
1
2025-04-17 09:03:32,341 - INFO - Reasoning:

Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (346.431 Da) is slightly preferable as it's lower.

**2. TPSA:** Ligand A (89.16) is excellent for CNS penetration, being well below 90. Ligand B (117.75) is still acceptable but less optimal.

**3. logP:** Ligand A (2.694) is within the optimal range (1-3). Ligand B (0.961) is a bit low, potentially hindering membrane permeability.

**4. H-Bond Donors:** Both ligands have acceptable HBD counts (Ligand A: 2, Ligand B: 1).

**5. H-Bond Acceptors:** Both ligands have acceptable HBA counts (Ligand A: 5, Ligand B: 8).

**6. QED:** Ligand A (0.807) has a significantly better QED score than Ligand B (0.362), indicating a more drug-like profile.

**7. DILI:** Ligand B (88.057) has a higher DILI risk than Ligand A (56.146). This is a significant concern.

**8. BBB:** Both ligands have reasonable BBB penetration (Ligand A: 44.436, Ligand B: 42.769). However, ideally, we want >70% for CNS targets. Neither is outstanding, but the difference is minimal.

**9. Caco-2:** Both have negative Caco-2 values, which is unusual and suggests poor permeability. This is a concern for both.

**10. Solubility:** Both have negative solubility values, which is also unusual and suggests poor solubility. This is a concern for both.

**11. hERG:** Both ligands have very low hERG inhibition risk (Ligand A: 0.319, Ligand B: 0.059).

**12. Cl_mic:** Ligand B (8.595) has a much lower microsomal clearance than Ligand A (48.649), indicating better metabolic stability.

**13. t1/2:** Ligand A (58.335) has a significantly longer in vitro half-life than Ligand B (17.902).

**14. Pgp:** Ligand B (0.091) has lower P-gp efflux liability than Ligand A (0.119), which is favorable for CNS exposure.

**15. Binding Affinity:** Ligand A (-8.9 kcal/mol) has a significantly stronger binding affinity than Ligand B (-7.7 kcal/mol). This is a crucial advantage, exceeding the 1.5 kcal/mol threshold.

**Overall Assessment:**

Ligand A is the stronger candidate. While both have issues with Caco-2 and solubility, Ligand A's superior binding affinity, better QED, lower DILI risk, and longer half-life outweigh Ligand B's slightly better metabolic stability and P-gp efflux. The strong binding affinity of Ligand A is particularly important for a GPCR target and can potentially compensate for some of the ADME deficiencies. The TPSA is also very favorable for CNS penetration.

Output:
1
2025-04-17 09:03:32,342 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight (MW):** Both ligands are within the ideal range (200-500 Da). Ligand A (338.451) is slightly lower, which is generally favorable for permeability.

**2. TPSA:** Ligand A (44.12) is significantly better than Ligand B (71.09). For a CNS target like DRD2, TPSA should be <= 90, and A is comfortably within that range, while B is approaching the upper limit.

**3. logP:** Ligand A (4.841) is higher than the optimal range (1-3), potentially leading to solubility issues and off-target effects. Ligand B (3.0) is within the optimal range.

**4. H-Bond Donors (HBD):** Both ligands are acceptable (A: 0, B: 2), well below the threshold of 5.

**5. H-Bond Acceptors (HBA):** Both ligands are acceptable (A: 4, B: 4), below the threshold of 10.

**6. QED:** Both ligands have good QED scores (A: 0.752, B: 0.827), indicating good drug-like properties.

**7. DILI:** Ligand A (37.263) has a lower DILI risk than Ligand B (65.684), which is a significant advantage.

**8. BBB:** Ligand A (71.656) has a better BBB penetration percentile than Ligand B (61.497). While both are reasonably good, A is closer to the desirable >70 threshold for CNS targets.

**9. Caco-2 Permeability:** Ligand A (-4.675) has worse Caco-2 permeability than Ligand B (-4.819). Both are negative, indicating poor permeability, but B is slightly better.

**10. Aqueous Solubility:** Ligand A (-5.627) has worse aqueous solubility than Ligand B (-3.784). Solubility is a concern for Ligand A due to its higher logP.

**11. hERG Inhibition:** Both ligands have low hERG inhibition risk (A: 0.657, B: 0.139). Ligand B is slightly better.

**12. Microsomal Clearance:** Ligand A (115.102) has higher microsomal clearance than Ligand B (47.891), meaning it's less metabolically stable.

**13. In vitro Half-Life:** Ligand A (-22.7) has a shorter in vitro half-life than Ligand B (-3.524). This is another point in favor of Ligand B.

**14. P-gp Efflux:** Both ligands have low P-gp efflux liability (A: 0.755, B: 0.156). Ligand B is significantly better.

**15. Binding Affinity:** Both ligands have similar binding affinities (A: -9.7, B: -9.9). The difference is minimal.

**Overall Assessment:**

Ligand A has advantages in BBB and DILI, but suffers from poor solubility, higher clearance, shorter half-life, and worse Caco-2 permeability. Ligand B, while having a slightly higher logP, exhibits better ADME properties overall, especially regarding metabolic stability, P-gp efflux, and solubility. Given the GPCR-specific emphasis on BBB, logP, Pgp, TPSA, and affinity, and considering the relatively small difference in binding affinity, Ligand B appears to be the more promising drug candidate.

Output:
1
2025-04-17 09:03:32,342 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight (MW):** Both ligands (344.415 and 346.431 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (107.11) is higher than Ligand B (68.88). For CNS targets, TPSA should be <= 90. Ligand B is significantly better here.

**3. logP:** Ligand A (1.516) is within the optimal 1-3 range. Ligand B (0.418) is slightly below 1, which could potentially hinder permeation.

**4. H-Bond Donors (HBD):** Both ligands have acceptable HBD counts (4 and 1, respectively), well below the threshold of 5.

**5. H-Bond Acceptors (HBA):** Both ligands have acceptable HBA counts (4 each), below the threshold of 10.

**6. QED:** Both ligands have good QED scores (0.545 and 0.727), indicating good drug-like properties.

**7. DILI:** Ligand A (60.915) has a higher DILI risk than Ligand B (19.426). Ligand B is significantly better here.

**8. BBB:** Ligand B (55.176) has a substantially better BBB penetration percentile than Ligand A (26.134). This is a critical factor for a CNS target like DRD2.

**9. Caco-2 Permeability:** Both have negative values, which is unusual. However, the magnitude of negativity is similar, and this metric is less critical than others.

**10. Aqueous Solubility:** Both have negative values, which is unusual. However, the magnitude of negativity is similar, and this metric is less critical than others.

**11. hERG Inhibition:** Both ligands show low hERG inhibition risk (0.371 and 0.227).

**12. Microsomal Clearance (Cl_mic):** Ligand B (-10.905) has a lower (better) microsomal clearance than Ligand A (16.159), suggesting better metabolic stability.

**13. In vitro Half-Life:** Ligand B (0.683) has a very short half-life compared to Ligand A (30.419). This is a significant drawback for Ligand B.

**14. P-gp Efflux:** Both ligands show low P-gp efflux liability (0.052 and 0.01).

**15. Binding Affinity:** Both ligands have very similar and strong binding affinities (-8.1 and -8.0 kcal/mol). The difference is negligible.

**Overall Assessment:**

Ligand B excels in key properties for a CNS-targeting GPCR ligand: TPSA, DILI, BBB, and Cl_mic. While its in vitro half-life is very short, the other advantages, particularly the significantly better BBB penetration and lower DILI risk, outweigh this drawback. Ligand A's higher TPSA and DILI risk are concerning. The similar binding affinities make the ADME properties the deciding factor.

Output:
1
2025-04-17 09:03:32,342 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (345.407 and 345.443 Da) fall comfortably within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (138.68) is borderline for CNS penetration, slightly above the preferred <90, but potentially acceptable. Ligand B (78.51) is excellent, well below 90 and favorable for CNS penetration.

**3. logP:** Both ligands have similar logP values (0.65 and 0.668), which are a bit low. While not ideal, they aren't drastically outside the 1-3 range. This could potentially impact permeability.

**4. H-Bond Donors & Acceptors:** Ligand A has 4 HBD and 6 HBA, while Ligand B has 2 HBD and 3 HBA. Both are within acceptable limits (<=5 HBD and <=10 HBA). Ligand B is slightly better due to fewer potential issues with off-target interactions.

**5. QED:** Ligand B (0.719) has a better QED score than Ligand A (0.581), indicating a more drug-like profile.

**6. DILI:** Ligand B (23.575) has a significantly lower DILI risk than Ligand A (63.746). This is a major advantage for Ligand B.

**7. BBB:** Ligand B (52.385) has a much better BBB percentile than Ligand A (35.246). This is crucial for a CNS target like DRD2.

**8. Caco-2 Permeability:** Both have negative Caco-2 values (-5.915 and -5.067), which is unusual and suggests poor permeability. This is a concern for both.

**9. Aqueous Solubility:** Both have negative solubility values (-2.251 and -1.755), indicating poor aqueous solubility. This could pose formulation challenges.

**10. hERG Inhibition:** Both ligands have low hERG inhibition risk (0.198 and 0.129).

**11. Microsomal Clearance:** Ligand A has a very low Cl_mic (0.479), suggesting high metabolic stability. Ligand B has a higher Cl_mic (-11.683), indicating faster metabolism.

**12. In vitro Half-Life:** Ligand A has a very long in vitro half-life (-12.944), while Ligand B has a shorter one (3.274).

**13. P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.008 and 0.02).

**14. Binding Affinity:** Ligand A (-8.8 kcal/mol) has a slightly better binding affinity than Ligand B (-7.8 kcal/mol). However, the difference is not substantial enough to outweigh the significant ADME advantages of Ligand B.

**Overall Assessment:**

While Ligand A has slightly better binding affinity and metabolic stability, Ligand B is the superior candidate. Its significantly lower DILI risk, much better BBB penetration, and higher QED score are critical advantages for a CNS-targeting GPCR. The lower affinity is a manageable drawback, and the poor Caco-2 and solubility can be addressed with formulation strategies.

Output:
1
2025-04-17 09:03:32,342 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (342.439 Da and 354.535 Da) fall within the ideal range of 200-500 Da.

**TPSA:** Ligand A (49.85) is significantly better than Ligand B (69.64). For CNS targets, TPSA should be <= 90, and lower is preferred. Ligand A is much closer to the optimal range for CNS penetration.

**logP:** Ligand A (1.132) is within the optimal range (1-3), while Ligand B (3.107) is at the higher end, potentially leading to solubility issues.

**H-Bond Donors/Acceptors:** Ligand A (0 HBD, 3 HBA) and Ligand B (2 HBD, 3 HBA) both have acceptable numbers of H-bond donors and acceptors.

**QED:** Both ligands have reasonable QED values (0.723 and 0.668), indicating good drug-like properties.

**DILI:** Ligand A (31.989) has a much lower DILI risk than Ligand B (16.712), suggesting better hepatotoxicity potential.

**BBB:** Ligand A (78.868) has a significantly higher BBB percentile than Ligand B (63.048). This is a crucial factor for CNS targets like DRD2.

**Caco-2 Permeability:** Both ligands have similar, very poor Caco-2 permeability (-4.41 and -4.409). This suggests potential absorption issues.

**Aqueous Solubility:** Both ligands have poor aqueous solubility (-2.821 and -3.531).

**hERG:** Both ligands have low hERG inhibition liability (0.398 and 0.381).

**Microsomal Clearance:** Ligand B (87.752) has a much higher microsomal clearance than Ligand A (32.737), indicating lower metabolic stability.

**In vitro Half-Life:** Ligand A (-2.448) has a better (longer) in vitro half-life than Ligand B (-6.168).

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.089 and 0.336).

**Binding Affinity:** Ligand A (-8.2 kcal/mol) has a slightly better binding affinity than Ligand B (-7.5 kcal/mol). While both are good, the 0.7 kcal/mol difference is noticeable.

**Overall Assessment:**

Ligand A is the superior candidate. It excels in key areas for CNS GPCR targets: TPSA, BBB penetration, DILI risk, metabolic stability (lower Cl_mic, longer t1/2), and binding affinity. While both ligands have solubility and permeability issues, the better CNS properties of Ligand A outweigh these concerns. The higher binding affinity, even if only slightly, further supports this conclusion.

Output:
1
2025-04-17 09:03:32,342 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (365.377 and 348.399 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (99.18) is better than Ligand B (103.01). Both are reasonably close to the <90 target for CNS penetration, but A is preferable.

**3. logP:** Ligand A (-0.784) is slightly lower than optimal (1-3), potentially hindering permeation. Ligand B (0.583) is also on the lower side, but closer to the desired range.

**4. H-Bond Donors:** Ligand A (2) is better than Ligand B (3). Lower HBD is generally preferred for better permeability.

**5. H-Bond Acceptors:** Both ligands have 5 HBA, which is acceptable (<=10).

**6. QED:** Ligand B (0.739) has a higher QED score than Ligand A (0.522), indicating a more drug-like profile.

**7. DILI:** Both ligands have acceptable DILI risk (Ligand A: 31.563, Ligand B: 34.161), well below the 60 threshold.

**8. BBB:** This is crucial for a CNS target like DRD2. Ligand A (62.233) is significantly better than Ligand B (25.785). A BBB percentile >70 is desirable, and A is closer to this.

**9. Caco-2:** Both have negative values, which is unusual and makes direct comparison difficult. However, the magnitude suggests Ligand A (-4.868) might have slightly better permeability than Ligand B (-5.221).

**10. Solubility:** Both have negative solubility values, which is also unusual. Ligand A (-0.46) is slightly better than Ligand B (-1.232).

**11. hERG:** Both ligands show very low hERG inhibition liability (Ligand A: 0.221, Ligand B: 0.135), which is excellent.

**12. Cl_mic:** Ligand A (-2.916) has a *lower* (better) microsomal clearance than Ligand B (-14.313), suggesting greater metabolic stability.

**13. t1/2:** Ligand A (-10.183) has a more negative (and therefore longer) in vitro half-life than Ligand B (20.684). This is a significant advantage.

**14. Pgp:** Both ligands have low P-gp efflux liability (Ligand A: 0.015, Ligand B: 0.036).

**15. Binding Affinity:** Ligand B (-8.7 kcal/mol) has a significantly stronger binding affinity than Ligand A (-5.7 kcal/mol). This is a substantial advantage, potentially outweighing some of the ADME drawbacks.

**Overall Assessment:**

Ligand B has a superior binding affinity, a better QED score, and a more favorable logP. However, Ligand A has a significantly better BBB penetration, lower microsomal clearance, and longer half-life. Considering DRD2 is a CNS target, BBB penetration is paramount. While the affinity difference is substantial, the improved CNS exposure and metabolic stability of Ligand A are critical. The slightly lower logP of Ligand A is a concern, but might be addressable through further optimization.

Output:
0
2025-04-17 09:03:32,343 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (362.539 Da and 349.439 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (43.78) is significantly better than Ligand B (105.04). For CNS targets, we want TPSA <= 90, and A is comfortably within this range, while B is well above.

**logP:** Ligand A (4.412) is higher than the optimal 1-3 range, but still potentially acceptable. Ligand B (-0.443) is too low, which could hinder membrane permeability.

**H-Bond Donors/Acceptors:** Ligand A (HBD=1, HBA=3) and Ligand B (HBD=2, HBA=7) both have reasonable numbers of H-bond donors and acceptors.

**QED:** Both ligands have similar QED values (0.865 and 0.721), indicating good drug-likeness.

**DILI:** Ligand A (10.585) has a much lower DILI risk than Ligand B (30.71). This is a significant advantage.

**BBB:** Ligand A (85.731) has excellent BBB penetration, exceeding the desirable >70% threshold. Ligand B (46.452) is much lower and less favorable for a CNS target.

**Caco-2 Permeability:** Ligand A (-4.703) and Ligand B (-5.751) both have negative values, which is unusual and suggests poor permeability. However, the scale is not specified, so it's difficult to interpret.

**Aqueous Solubility:** Ligand A (-3.335) and Ligand B (-0.8) both have negative values, suggesting poor solubility.

**hERG Inhibition:** Ligand A (0.743) has a slightly higher hERG risk than Ligand B (0.047), but both are relatively low.

**Microsomal Clearance:** Ligand A (35.014) has a higher microsomal clearance than Ligand B (-18.769). A negative value for B suggests very high metabolic stability, which is a strong positive.

**In vitro Half-Life:** Ligand A (8.514) has a shorter half-life than Ligand B (16.125).

**P-gp Efflux:** Ligand A (0.471) has lower P-gp efflux than Ligand B (0.008), which is favorable for CNS penetration.

**Binding Affinity:** Ligand A (-9.0) has a significantly stronger binding affinity than Ligand B (-7.4). This is a substantial advantage, potentially outweighing some of its ADME drawbacks.

**Overall Assessment:**

Ligand A is the stronger candidate. While its logP is slightly high and solubility is poor, its superior BBB penetration, significantly lower DILI risk, and *much* stronger binding affinity are decisive advantages for a CNS-targeting GPCR like DRD2. Ligand B's low logP and poor BBB penetration are major drawbacks. The negative Caco-2 and solubility values for both are concerning, but the binding affinity difference is so large that it likely compensates for these issues.



Output:
1
2025-04-17 09:03:32,343 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (337.375 and 351.451 Da) are within the ideal 200-500 Da range.

**TPSA:** Ligand A (64.63) is excellent, well below the 90 A^2 threshold for CNS targets. Ligand B (128.32) is higher, but still potentially acceptable, though less ideal.

**logP:** Ligand A (2.831) is optimal (1-3). Ligand B (0.73) is a bit low, potentially hindering permeation.

**H-Bond Donors/Acceptors:** Ligand A (HBD=1, HBA=4) and Ligand B (HBD=3, HBA=4) both have reasonable H-bond characteristics, within the suggested limits.

**QED:** Ligand A (0.852) has a very strong drug-like profile. Ligand B (0.557) is acceptable, but less optimal.

**DILI:** Ligand A (55.409) has a moderate DILI risk. Ligand B (29.081) has a low DILI risk, which is a significant advantage.

**BBB:** Both ligands have good BBB penetration (Ligand A: 66.615, Ligand B: 68.127). However, >70 is desirable, and neither quite reaches that.

**Caco-2 Permeability:** Ligand A (-4.48) has poor Caco-2 permeability. Ligand B (-5.304) also has poor Caco-2 permeability, but is slightly worse.

**Aqueous Solubility:** Both ligands have poor aqueous solubility (Ligand A: -4.116, Ligand B: -1.982).

**hERG:** Both ligands have low hERG inhibition liability (Ligand A: 0.415, Ligand B: 0.473).

**Microsomal Clearance:** Ligand A (44.343) has moderate clearance. Ligand B (-9.502) has *negative* clearance, which is unusual and suggests very high metabolic stability (potentially due to a prediction error, but we'll take it at face value for now).

**In vitro Half-Life:** Ligand A (-15.39) has a negative half-life, which is not possible. This is likely a prediction error. Ligand B (4.523) has a short half-life.

**P-gp Efflux:** Both ligands have very low P-gp efflux (Ligand A: 0.178, Ligand B: 0.018), which is excellent for CNS penetration.

**Binding Affinity:** Ligand A (-10.5 kcal/mol) has significantly stronger binding affinity than Ligand B (0.0 kcal/mol). This is a major advantage.

**Overall Assessment:**

Ligand A has a superior binding affinity and a better QED score. However, it has poor Caco-2 permeability and a questionable half-life prediction. Ligand B has a better DILI score and significantly better metabolic stability, but its logP is low and its binding affinity is very weak.

Given the GPCR-specific priorities, *affinity is paramount*. The substantial difference in binding affinity (-10.5 vs 0.0 kcal/mol) overrides the other drawbacks of Ligand A, *assuming the negative half-life is a prediction error*. The TPSA is excellent, BBB is acceptable, and P-gp efflux is low, all favorable for CNS penetration. While the solubility and Caco-2 permeability are concerns, these can potentially be addressed through formulation strategies.

Output:
1
2025-04-17 09:03:32,343 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (346.471 and 341.331 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (69.64) is excellent, well below the 90 A^2 threshold for CNS targets. Ligand B (129.89) is higher, but still potentially acceptable, though less ideal.

**3. logP:** Ligand A (1.547) is within the optimal 1-3 range. Ligand B (0.031) is quite low, potentially hindering permeability.

**4. H-Bond Donors:** Both ligands have 2 HBD, which is within the acceptable limit of <=5.

**5. H-Bond Acceptors:** Ligand A has 3 HBA, and Ligand B has 8 HBA. Both are within the acceptable limit of <=10, but Ligand B is approaching the upper end.

**6. QED:** Ligand A (0.811) has a strong drug-like profile. Ligand B (0.478) is lower, indicating a less favorable overall drug-likeness.

**7. DILI:** Ligand A (14.696) has a very low DILI risk. Ligand B (83.792) has a significantly higher DILI risk, which is concerning.

**8. BBB:** Ligand A (44.901) has a moderate BBB penetration, which is not ideal for a CNS target. Ligand B (23.071) has a very low BBB penetration, making it unlikely to reach the target in the brain.

**9. Caco-2:** Ligand A (-4.958) and Ligand B (-5.849) both have negative Caco-2 values, which is unusual and suggests poor permeability.

**10. Solubility:** Both ligands have similar, very low aqueous solubility (-2.638 and -2.438). This could pose formulation challenges.

**11. hERG:** Both ligands have very low hERG inhibition risk (0.213 and 0.05).

**12. Cl_mic:** Both ligands have negative Cl_mic values (-16.595 and -16.173), which is not physically meaningful. It suggests very rapid clearance or a problem with the prediction method.

**13. t1/2:** Ligand A (11.655) has a reasonable in vitro half-life. Ligand B (14.026) has a slightly longer half-life.

**14. Pgp:** Both ligands have very low Pgp efflux liability (0.041 and 0.018).

**15. Binding Affinity:** Ligand A (-8.6 kcal/mol) has a slightly better binding affinity than Ligand B (-9.2 kcal/mol).

**Overall Assessment:**

Considering the GPCR-specific priorities, Ligand A is the more promising candidate. While its BBB penetration is not ideal, its significantly lower DILI risk, better QED, and slightly better affinity outweigh the drawbacks. Ligand B's very low logP and poor BBB penetration are major concerns for a CNS-targeting drug. The negative Cl_mic values for both are problematic and require further investigation, but they don't drastically change the relative ranking given the other significant differences.

Output:
0
2025-04-17 09:03:32,343 - INFO - Reasoning:

Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (370.475 and 368.79 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (93.65) is slightly above the optimal <90 for CNS targets, but still reasonable. Ligand B (50.7) is excellent, well below the threshold.

**3. logP:** Ligand A (1.531) is within the optimal range (1-3). Ligand B (3.811) is at the higher end, but still acceptable.

**4. H-Bond Donors:** Both ligands have 1 HBD, which is good.

**5. H-Bond Acceptors:** Ligand A has 7 HBAs, acceptable. Ligand B has 4 HBAs, also good.

**6. QED:** Both ligands have good QED scores (0.79 and 0.834), indicating drug-like properties.

**7. DILI:** Ligand A (63.086) has a slightly higher DILI risk than Ligand B (56.495), but both are still below the concerning threshold of 60.

**8. BBB:** This is crucial for a CNS target. Ligand B (88.096) has a significantly higher BBB penetration percentile than Ligand A (66.344). This is a major advantage for Ligand B.

**9. Caco-2 Permeability:** Both have negative values, which is unusual and suggests poor permeability. However, the scale isn't specified, so it's difficult to interpret.

**10. Aqueous Solubility:** Both have negative values, indicating poor solubility. Again, the scale is unknown, making interpretation difficult.

**11. hERG Inhibition:** Ligand A (0.05) has a very low hERG risk. Ligand B (0.332) is slightly higher, but still relatively low.

**12. Microsomal Clearance:** Ligand A (50.793) has higher clearance than Ligand B (25.114), suggesting lower metabolic stability.

**13. In vitro Half-Life:** Ligand B (3.298) has a much longer half-life than Ligand A (-28.841). This is a significant advantage.

**14. P-gp Efflux:** Ligand A (0.035) has very low P-gp efflux, which is excellent. Ligand B (0.204) is slightly higher, but still reasonably low.

**15. Binding Affinity:** Ligand B (-9.6 kcal/mol) has a substantially better binding affinity than Ligand A (-7.3 kcal/mol). This difference of 2.3 kcal/mol is significant and can outweigh some ADME drawbacks.

**Overall Assessment:**

Ligand B is the stronger candidate. While both ligands have acceptable MW, logP, HBD/HBA, and QED scores, Ligand B excels in the critical areas for a CNS-targeting GPCR: significantly better BBB penetration, a much longer half-life, and a substantially higher binding affinity. Although Ligand A has slightly better P-gp efflux and lower hERG risk, the superior affinity and BBB penetration of Ligand B are more important for CNS efficacy. The slightly higher DILI risk of Ligand A is also a concern.

Output:
1
2025-04-17 09:03:32,344 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (353.423 and 357.445 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (125.35) is slightly above the preferred <90 for CNS targets, but still reasonable. Ligand B (52.65) is excellent, well below the threshold.

**logP:** Ligand A (-0.902) is a bit low, potentially hindering membrane permeability. Ligand B (1.727) is within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A (4 HBD, 6 HBA) is acceptable. Ligand B (1 HBD, 3 HBA) is also good, potentially offering better permeability due to fewer hydrogen bonds.

**QED:** Both ligands have reasonable QED values (0.458 and 0.815), with Ligand B being significantly better.

**DILI:** Ligand A (37.224) has a low DILI risk, which is favorable. Ligand B (15.2) is even lower, indicating a very low risk of liver injury.

**BBB:** This is crucial for a CNS target. Ligand A (20.822) has a very poor BBB penetration percentile. Ligand B (81.039) is excellent, exceeding the desirable >70 threshold.

**Caco-2 Permeability:** Ligand A (-5.552) indicates poor permeability. Ligand B (-4.744) is also poor, but slightly better.

**Aqueous Solubility:** Both ligands have poor aqueous solubility (-1.219 and -1.481). This could pose formulation challenges.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.107 and 0.559).

**Microsomal Clearance:** Ligand A (12.115) has moderate clearance. Ligand B (-14.461) has *negative* clearance, which is unusual and likely an artifact of the prediction method, but suggests excellent metabolic stability.

**In vitro Half-Life:** Ligand A (23.39) has a moderate half-life. Ligand B (-6.411) has a negative half-life, again likely an artifact, suggesting very high stability.

**P-gp Efflux:** Both ligands have low P-gp efflux (0.01 and 0.041), which is good for CNS penetration.

**Binding Affinity:** Ligand B (-8.3 kcal/mol) has a slightly better binding affinity than Ligand A (-7.7 kcal/mol), though both are good. The difference is less than the 1.5 kcal/mol threshold that would strongly favor one over the other.

**Conclusion:**

Despite Ligand A's lower DILI risk, Ligand B is the superior candidate. The overwhelmingly positive factor is Ligand B's excellent BBB penetration (81.039%), which is critical for a DRD2 ligand targeting CNS disorders. It also has a better logP, QED, and slightly better affinity. While both have poor solubility, the superior BBB penetration and metabolic stability of Ligand B outweigh this drawback. The negative values for clearance and half-life for Ligand B are suspect, but still suggest a very stable molecule.

Output:
1
2025-04-17 09:03:32,344 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (388.333 Da) is slightly higher than Ligand B (342.439 Da), but both are acceptable.

**TPSA:** Ligand A (49.41) is excellent for CNS penetration, well below the 90 A^2 threshold. Ligand B (62.55) is still reasonable, but less optimal.

**logP:** Both ligands have good logP values (A: 3.439, B: 2.82), falling within the 1-3 range.

**H-Bond Donors/Acceptors:** Both have 1 HBD and 3 HBA, which are within acceptable limits.

**QED:** Both ligands have good QED scores (A: 0.79, B: 0.837), indicating good drug-like properties.

**DILI:** Ligand A (46.491) has a moderate DILI risk, but is still acceptable. Ligand B (15.51) has a very low DILI risk, which is a significant advantage.

**BBB:** Ligand A (89.066) has excellent BBB penetration, exceeding the 70% threshold. Ligand B (66.344) is below this threshold, which is a substantial drawback for a CNS target.

**Caco-2 Permeability:** Both have negative Caco-2 values (-4.873 and -4.89), which is unusual and suggests poor permeability. This is a concern for both.

**Aqueous Solubility:** Both ligands have negative solubility values (-3.593 and -2.772), indicating poor solubility. This is a concern for both, but might be less critical given the CNS target and potential for formulation strategies.

**hERG Inhibition:** Both ligands have very low hERG inhibition risk (A: 0.514, B: 0.177), which is excellent.

**Microsomal Clearance:** Ligand A (9.965) has lower microsomal clearance than Ligand B (37.767), indicating better metabolic stability.

**In vitro Half-Life:** Ligand B (12.221 hours) has a significantly longer half-life than Ligand A (-2.04 hours). This is a major advantage for Ligand B.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (A: 0.16, B: 0.102), which is good for CNS exposure.

**Binding Affinity:** Ligand A (-9.5 kcal/mol) has a slightly better binding affinity than Ligand B (-8.4 kcal/mol). This 1.1 kcal/mol difference is significant.

**Overall Assessment:**

Ligand A excels in BBB penetration and binding affinity, which are crucial for a CNS GPCR target. However, its negative in vitro half-life is a major concern. Ligand B has a much better half-life and lower DILI risk, but its BBB penetration is significantly lower. Considering the importance of CNS penetration for DRD2, and the relatively small affinity difference, the strong BBB score of Ligand A outweighs its other drawbacks. The negative half-life could potentially be addressed through structural modifications.

Output:
1
2025-04-17 09:03:32,344 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (351.403 Da) is slightly lower, which could be advantageous for permeability. Ligand B (385.291 Da) is also good.

**TPSA:** Ligand A (100.46) is better than Ligand B (55.57). For CNS targets, we want TPSA <= 90, so Ligand A is closer to that ideal.

**logP:** Ligand A (-0.343) is quite low, potentially hindering membrane permeability. Ligand B (4.464) is high, potentially causing solubility issues and off-target effects. The optimal range is 1-3, so both are suboptimal, but Ligand B is further off.

**H-Bond Donors/Acceptors:** Ligand A has 2 HBD and 6 HBA, which are reasonable. Ligand B has 0 HBD and 5 HBA, also acceptable.

**QED:** Both ligands have similar QED values (0.706 and 0.628), indicating good drug-likeness.

**DILI:** Ligand A (27.608) has a lower DILI risk than Ligand B (39.511), which is preferable.

**BBB:** This is critical for a CNS target. Ligand B (75.378) has a significantly better BBB percentile than Ligand A (54.246). This is a major advantage for Ligand B.

**Caco-2 Permeability:** Both have negative values, indicating poor permeability.

**Aqueous Solubility:** Both have negative values, indicating poor solubility.

**hERG Inhibition:** Ligand A (0.169) has a lower hERG risk than Ligand B (0.751), which is better.

**Microsomal Clearance:** Ligand A (-5.389) has a *negative* clearance, which is unusual and suggests very high metabolic stability. Ligand B (83.096) has a high clearance, indicating rapid metabolism. This is a significant advantage for Ligand A.

**In vitro Half-Life:** Ligand A (27.718 hours) has a much longer half-life than Ligand B (43.758 hours).

**P-gp Efflux:** Both ligands show low P-gp efflux liability (0.018 and 0.615 respectively).

**Binding Affinity:** Ligand B (-8.4 kcal/mol) has a stronger binding affinity than Ligand A (-9.0 kcal/mol). This is a substantial difference and a significant advantage for Ligand B.

**Overall Assessment:**

Ligand B excels in BBB penetration and binding affinity, crucial for a CNS GPCR target. However, it suffers from a high logP and high microsomal clearance. Ligand A has better TPSA, DILI, metabolic stability (negative clearance), and half-life, but its BBB penetration is significantly lower, and its logP is very low.

The strong binding affinity and good BBB penetration of Ligand B outweigh its drawbacks, especially considering the potential for optimization of its logP and metabolic stability. The negative clearance of Ligand A is concerning and may not be realistic.

Output:
1
2025-04-17 09:03:32,344 - INFO - Batch 501 complete. Total preferences: 8016
2025-04-17 09:03:32,345 - INFO - Processing batch 502/512...
2025-04-17 09:04:12,985 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (341.375 and 345.443 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (119.7) is better than Ligand B (69.72). Both are below the 90 A^2 threshold desirable for CNS targets, but A is closer to the upper limit.

**logP:** Ligand A (0.145) is quite low, potentially hindering membrane permeability. Ligand B (0.621) is better, but still on the lower side of the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A has 2 HBD and 6 HBA, while Ligand B has 1 HBD and 3 HBA. Both are within acceptable limits.

**QED:** Both ligands have good QED scores (0.802 and 0.763), indicating good drug-like properties.

**DILI:** Ligand A (73.982) has a higher DILI risk than Ligand B (37.999). This is a significant negative for Ligand A.

**BBB:** Ligand B (61.535) has a substantially better BBB penetration percentile than Ligand A (21.287). This is a critical advantage for a CNS target like DRD2.

**Caco-2 Permeability:** Ligand A (-5.389) has very poor Caco-2 permeability, while Ligand B (-4.457) is slightly better, but still poor.

**Aqueous Solubility:** Both ligands have poor aqueous solubility (-3.293 and -2.343).

**hERG:** Both ligands have very low hERG inhibition risk (0.299 and 0.258).

**Microsomal Clearance:** Ligand A (-10.422) has significantly lower (better) microsomal clearance than Ligand B (39.141), indicating greater metabolic stability.

**In vitro Half-Life:** Ligand A (0.947) has a very short half-life, while Ligand B (-28.177) has a very long half-life.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.023 and 0.056).

**Binding Affinity:** Ligand B (-7.6 kcal/mol) has a slightly better binding affinity than Ligand A (-8.4 kcal/mol). Although the difference is small, it's still a positive for Ligand B.

**Overall Assessment:**

Ligand B is the more promising candidate. Its significantly better BBB penetration is crucial for a CNS target. While its logP is still somewhat low, it's better than Ligand A's. The improved DILI score, longer half-life, and slightly better binding affinity further support choosing Ligand B. Ligand A's poor Caco-2 permeability and short half-life are major drawbacks. Although Ligand A has better metabolic stability, the CNS penetration and safety profile of Ligand B are more important in this context.

Output:
1
2025-04-17 09:04:12,986 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (352.425 and 353.369 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (42.43) is significantly better than Ligand B (60.5). For CNS targets, we want TPSA <= 90, and ideally closer to 60. Ligand A is much closer to the ideal range.

**3. logP:** Both ligands have good logP values (3.659 and 3.243), falling within the optimal 1-3 range.

**4. H-Bond Donors:** Both have 0 HBD, which is acceptable.

**5. H-Bond Acceptors:** Ligand A has 3 HBA, while Ligand B has 5. Both are acceptable (<=10).

**6. QED:** Ligand A (0.785) has a better QED score than Ligand B (0.513), indicating a more drug-like profile.

**7. DILI:** Ligand A (21.675) has a much lower DILI risk than Ligand B (41.024). This is a significant advantage.

**8. BBB:** Ligand A (93.253) has a substantially higher BBB penetration percentile than Ligand B (84.451). This is crucial for a CNS target like DRD2.

**9. Caco-2 Permeability:** Both are negative, which is unusual and suggests poor permeability. However, the scale is not specified, so it's hard to interpret.

**10. Aqueous Solubility:** Both are negative, again making interpretation difficult without knowing the scale.

**11. hERG Inhibition:** Both ligands have low hERG inhibition risk (0.715 and 0.627).

**12. Microsomal Clearance:** Ligand A (56.144) has lower microsomal clearance than Ligand B (71.501), suggesting better metabolic stability.

**13. In vitro Half-Life:** Ligand B (16.016) has a significantly longer half-life than Ligand A (-4.683). This is a positive for Ligand B.

**14. P-gp Efflux:** Both have low P-gp efflux liability (0.131 and 0.396).

**15. Binding Affinity:** Ligand B (-7.2 kcal/mol) has a slightly better binding affinity than Ligand A (-6.8 kcal/mol). While a 0.4 kcal/mol difference is noticeable, it might not outweigh other significant ADME differences.

**Overall Assessment:**

Ligand A is superior due to its significantly better TPSA, DILI risk, BBB penetration, QED, and metabolic stability. While Ligand B has a slightly better binding affinity and half-life, the improvements in ADME properties for Ligand A are more critical for a CNS-targeted GPCR like DRD2. The lower TPSA and higher BBB of Ligand A are particularly important for brain penetration.

Output:
1
2025-04-17 09:04:12,986 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (348.443 and 354.407 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (78.87) is significantly better than Ligand B (122.04). For CNS targets, we want TPSA <= 90, so Ligand A is much more favorable.

**3. logP:** Ligand A (1.157) is within the optimal range (1-3), while Ligand B (-0.553) is slightly below, potentially hindering permeation.

**4. H-Bond Donors:** Both have 2 HBD, which is acceptable.

**5. H-Bond Acceptors:** Ligand A has 4 HBA, and Ligand B has 5. Both are within the acceptable range of <=10.

**6. QED:** Both ligands have good QED values (0.706 and 0.605), indicating drug-like properties.

**7. DILI:** Both have relatively low DILI risk (25.281 and 30.826), suggesting minimal liver injury potential.

**8. BBB:** Ligand B (81.815) has a much better BBB penetration score than Ligand A (58.007). This is a crucial factor for a CNS target like DRD2.

**9. Caco-2 Permeability:** Ligand A (-4.874) has poor Caco-2 permeability, while Ligand B (-5.126) is also poor. This is not ideal, but not a dealbreaker if other properties are strong.

**10. Aqueous Solubility:** Both have negative solubility values (-2.035 and -1.315), indicating poor aqueous solubility. This could pose formulation challenges.

**11. hERG Inhibition:** Both have very low hERG inhibition risk (0.18 and 0.066).

**12. Microsomal Clearance:** Ligand A (39.082) has higher microsomal clearance than Ligand B (1.864), suggesting lower metabolic stability.

**13. In vitro Half-Life:** Ligand B (-25.622) has a significantly longer in vitro half-life than Ligand A (-1.974).

**14. P-gp Efflux:** Both have very low P-gp efflux liability (0.114 and 0.002).

**15. Binding Affinity:** Ligand B (-7.4) has a significantly stronger binding affinity than Ligand A (0.0). A difference of >1.5 kcal/mol is considered substantial.

**Overall Assessment:**

Ligand B is the stronger candidate. While both have solubility issues, Ligand B's superior BBB penetration, significantly stronger binding affinity, and longer half-life outweigh Ligand A's slightly better TPSA and logP. The improved metabolic stability (lower Cl_mic) is also a significant advantage. The affinity difference is large enough to compensate for the slightly higher TPSA and lower logP.

Output:
1
2025-04-17 09:04:12,986 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (342.433 and 352.425 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (24.92) is excellent, well below the 90 A^2 threshold for CNS targets. Ligand B (40.62) is still reasonable, but higher, potentially impacting BBB penetration slightly.

**logP:** Ligand A (4.839) is a bit high, potentially leading to solubility issues or off-target interactions. Ligand B (2.671) is within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A (HBD=1, HBA=2) and Ligand B (HBD=0, HBA=2) both have acceptable numbers of hydrogen bond donors and acceptors.

**QED:** Both ligands have similar QED values (0.812 and 0.78), indicating good drug-likeness.

**DILI:** Ligand A (28.965) has a slightly higher DILI risk than Ligand B (23.149), but both are below the 40 threshold and considered good.

**BBB:** Ligand B (95.425) has a significantly better BBB penetration percentile than Ligand A (82.164). This is a crucial advantage for a CNS target like DRD2.

**Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and suggests potential issues with permeability prediction. However, the values are similar.

**Aqueous Solubility:** Both ligands have very poor predicted aqueous solubility (-4.346 and -3.28). This is a concern, but can sometimes be mitigated with formulation strategies.

**hERG Inhibition:** Both ligands show low hERG inhibition risk (0.911 and 0.606).

**Microsomal Clearance:** Ligand A (31.545) and Ligand B (29.09) have similar microsomal clearance values, suggesting comparable metabolic stability.

**In vitro Half-Life:** Ligand B (7.402 hours) has a significantly longer in vitro half-life than Ligand A (32.21 hours). This is a positive attribute.

**P-gp Efflux:** Ligand A (0.572) shows lower P-gp efflux than Ligand B (0.108), which is favorable for CNS penetration.

**Binding Affinity:** Ligand B (-7.9 kcal/mol) has a substantially stronger binding affinity than Ligand A (-9.3 kcal/mol). This is a major advantage, potentially outweighing some of the other drawbacks.

**Conclusion:**

While Ligand A has lower P-gp efflux, Ligand B excels in the most critical areas for a CNS-targeting GPCR: BBB penetration and binding affinity. The significantly stronger binding affinity (-7.9 vs -9.3 kcal/mol) is a substantial benefit. The better BBB score (95.425 vs 82.164) is also a key factor. The slightly higher logP of Ligand A is a concern, and the longer half-life of Ligand A is overshadowed by the superior affinity of Ligand B.

Output:
1
2025-04-17 09:04:12,986 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (371.771 and 350.463 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (83.48) is better than Ligand B (95.42). For CNS targets, we want TPSA <= 90, so Ligand A is closer to the ideal.

**3. logP:** Ligand A (3.265) is optimal (1-3), while Ligand B (1.762) is on the lower side, potentially hindering permeation.

**4. H-Bond Donors:** Ligand A (3) and Ligand B (2) are both acceptable (<=5).

**5. H-Bond Acceptors:** Ligand A (4) and Ligand B (5) are both acceptable (<=10).

**6. QED:** Both ligands have similar QED values (0.704 and 0.67), indicating good drug-likeness.

**7. DILI:** Ligand A (83.133) has a higher DILI risk than Ligand B (32.377). This is a negative for Ligand A.

**8. BBB:** Ligand B (50.446) has a better BBB penetration percentile than Ligand A (36.371). Although both are below the desirable >70 for CNS targets, Ligand B is closer.

**9. Caco-2 Permeability:** Ligand A (-4.781) has slightly better Caco-2 permeability than Ligand B (-4.876), but both are very poor.

**10. Aqueous Solubility:** Ligand A (-4.096) has slightly better solubility than Ligand B (-1.455), but both are very poor.

**11. hERG Inhibition:** Both ligands have similar, low hERG inhibition risk (0.279 and 0.291).

**12. Microsomal Clearance:** Ligand A (39.065) has slightly higher microsomal clearance than Ligand B (36.031), indicating lower metabolic stability.

**13. In vitro Half-Life:** Ligand B (19.34) has a shorter half-life than Ligand A (56.736).

**14. P-gp Efflux:** Both ligands have similar P-gp efflux liability (0.095 and 0.054), indicating low efflux.

**15. Binding Affinity:** Ligand B (-7.5) has slightly better binding affinity than Ligand A (-7.4). While the difference is small, it's still a factor.

**Overall Assessment:**

Ligand B is better overall. While Ligand A has slightly better Caco-2 permeability and in vitro half-life, Ligand B excels in crucial areas for a CNS-targeting GPCR ligand: lower DILI risk, better BBB penetration, and slightly better binding affinity. The logP of Ligand A is optimal, but the superior BBB and safety profile of Ligand B outweigh this advantage.

Output:
1
2025-04-17 09:04:12,987 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (349.39 and 363.85 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (107.11) is higher than Ligand B (78.45). For CNS targets, TPSA should be <=90. Ligand B is preferable here.

**logP:** Ligand A (0.039) is quite low, potentially hindering membrane permeability. Ligand B (2.767) is within the optimal 1-3 range. Ligand B is significantly better.

**H-Bond Donors:** Both have 2 HBD, which is acceptable.

**H-Bond Acceptors:** Ligand A has 6 HBA, and Ligand B has 4. Both are within the acceptable limit of <=10.

**QED:** Both ligands have good QED scores (0.727 and 0.756), indicating good drug-like properties.

**DILI:** Ligand A (30.98) has a lower DILI risk than Ligand B (44.13), which is favorable.

**BBB:** Ligand A (40.33) has a slightly better BBB penetration percentile than Ligand B (37.65), but both are below the desirable >70 for CNS targets.

**Caco-2 Permeability:** Ligand A (-4.846) has worse Caco-2 permeability than Ligand B (-4.771), indicating lower intestinal absorption.

**Aqueous Solubility:** Ligand A (-1.646) has better aqueous solubility than Ligand B (-3.928).

**hERG Inhibition:** Ligand A (0.162) has a lower hERG inhibition risk than Ligand B (0.58).

**Microsomal Clearance:** Ligand B (33.79) has lower microsomal clearance than Ligand A (7.4), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand B (38.79) has a significantly longer in vitro half-life than Ligand A (12.30), which is desirable.

**P-gp Efflux:** Ligand A (0.037) shows lower P-gp efflux liability than Ligand B (0.285), which is beneficial for CNS penetration.

**Binding Affinity:** Ligand B (-7.5 kcal/mol) has a stronger binding affinity than Ligand A (-8.0 kcal/mol). While A is slightly better, the difference is small, and other factors are more important.

**Overall Assessment:**

Ligand B is the more promising candidate. While Ligand A has a slightly better DILI score and P-gp efflux, Ligand B excels in crucial areas for a CNS-targeting GPCR ligand: logP, TPSA, metabolic stability (Cl_mic and t1/2), and has a good binding affinity. The low logP of Ligand A is a significant concern for brain penetration, and the higher TPSA is also unfavorable. The better metabolic stability and longer half-life of Ligand B are also important advantages.



Output:
1
2025-04-17 09:04:12,987 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (438.631 Da) is slightly higher than Ligand B (343.471 Da), but both are acceptable.

**2. TPSA:** Ligand A (46.5) is excellent, well below the 90 Angstroms threshold for CNS targets. Ligand B (71.09) is higher but still reasonable, though less ideal for CNS penetration.

**3. logP:** Ligand A (4.85) is a bit high, potentially leading to solubility issues or off-target interactions. Ligand B (3.209) is within the optimal range (1-3).

**4. H-Bond Donors:** Ligand A (1) is good. Ligand B (2) is also acceptable.

**5. H-Bond Acceptors:** Both ligands have 3 HBA, which is within the acceptable limit of 10.

**6. QED:** Both ligands have good QED scores (Ligand A: 0.729, Ligand B: 0.833), indicating drug-like properties.

**7. DILI:** Ligand A (78.945) has a higher DILI risk than Ligand B (36.758). This is a significant drawback for Ligand A.

**8. BBB:** Ligand A (79.139) has a good BBB penetration percentile. Ligand B (63.746) is lower, which is a concern for a CNS target like DRD2.

**9. Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and difficult to interpret without further context. However, the magnitude suggests poor permeability for both.

**10. Aqueous Solubility:** Both ligands have very poor aqueous solubility (-5.723 and -3.567 respectively). This is a significant issue for both compounds.

**11. hERG Inhibition:** Both ligands show low hERG inhibition risk (0.545 and 0.524 respectively).

**12. Microsomal Clearance:** Ligand A (58.923) has higher microsomal clearance than Ligand B (25.449), suggesting lower metabolic stability.

**13. In vitro Half-Life:** Ligand A (24.751) has a longer half-life than Ligand B (1.242).

**14. P-gp Efflux:** Ligand A (0.595) shows lower P-gp efflux than Ligand B (0.19), which is favorable for CNS penetration.

**15. Binding Affinity:** Both ligands have excellent binding affinities (Ligand A: -9 kcal/mol, Ligand B: -8.9 kcal/mol). Ligand A is slightly better.

**Overall Assessment:**

Ligand A has a slightly better binding affinity and BBB penetration, and lower P-gp efflux. However, it suffers from higher DILI risk, higher microsomal clearance (lower metabolic stability), and a higher logP. Ligand B has a better logP, lower DILI risk, and lower clearance, but its BBB penetration is lower and its affinity is slightly weaker.

Given the importance of BBB penetration for a CNS target like DRD2, and the significant concern of DILI with Ligand A, **Ligand B** is the more promising candidate despite the slightly lower affinity and BBB. The solubility issues are a concern for both, but can be addressed with formulation strategies.

Output:
1
2025-04-17 09:04:12,987 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (365.857 Da) is slightly higher than Ligand B (354.495 Da), but both are acceptable.

**TPSA:** Ligand A (48.0) is excellent, well below the 90 Angstroms threshold for CNS targets. Ligand B (73.91) is higher, but still reasonable, though less ideal for CNS penetration.

**logP:** Ligand A (3.215) is within the optimal range (1-3). Ligand B (0.062) is significantly lower, which is a major concern. Low logP can hinder membrane permeability and reduce brain exposure.

**H-Bond Donors/Acceptors:** Ligand A (0 HBD, 4 HBA) is favorable. Ligand B (2 HBD, 5 HBA) is also acceptable.

**QED:** Both ligands have reasonable QED values (Ligand A: 0.807, Ligand B: 0.645), indicating good drug-like properties.

**DILI:** Ligand A (50.95) has a moderate DILI risk, while Ligand B (4.963) has a very low risk. This is a point in favor of Ligand B.

**BBB:** Ligand A (89.066) has excellent BBB penetration potential, exceeding the 70% threshold. Ligand B (49.205) is significantly lower, raising concerns about CNS exposure.

**Caco-2 Permeability:** Ligand A (-4.614) has poor Caco-2 permeability. Ligand B (-5.232) is also poor.

**Aqueous Solubility:** Ligand A (-3.607) has poor solubility. Ligand B (-0.966) is better, but still not great.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (Ligand A: 0.408, Ligand B: 0.392).

**Microsomal Clearance:** Ligand A (52.005) has moderate clearance. Ligand B (-17.975) has negative clearance, which is not physically possible and indicates an issue with the data or prediction method. This is a major red flag.

**In vitro Half-Life:** Ligand A (43.727) has a reasonable half-life. Ligand B (-25.237) has a negative half-life, again indicating a data issue.

**P-gp Efflux:** Both ligands have very low P-gp efflux (Ligand A: 0.45, Ligand B: 0.003), which is favorable for CNS penetration.

**Binding Affinity:** Ligand B (-7.7 kcal/mol) has significantly stronger binding affinity than Ligand A (-0.0 kcal/mol). This is a substantial advantage.

**Overall Assessment:**

Despite the strong affinity of Ligand B, the negative values for microsomal clearance and half-life are highly problematic and suggest serious issues with the data or the molecule's predicted metabolism. These values are physically impossible. Ligand A, while having weaker affinity, has more reasonable ADME properties, particularly a good BBB score and acceptable (though not ideal) clearance and half-life. The low logP of Ligand B is also a significant drawback for CNS penetration.

Considering the GPCR-specific priorities and the questionable ADME profile of Ligand B, Ligand A is the more viable drug candidate, despite its weaker binding affinity. Further optimization of Ligand A to improve its affinity would be a logical next step.

Output:
1
2025-04-17 09:04:12,987 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (355.385 and 354.407 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (82.53) is significantly better than Ligand B (108.13). For CNS targets, we want TPSA <= 90, and A is comfortably within that, while B is pushing the limit.

**3. logP:** Ligand A (2.189) is optimal (1-3), while Ligand B (-1.608) is below 1, which could hinder permeation.

**4. H-Bond Donors:** Both have 2 HBD, which is within the acceptable limit of <=5.

**5. H-Bond Acceptors:** Ligand A has 4 HBA, and Ligand B has 7. Both are below the limit of <=10, but A is preferable.

**6. QED:** Ligand A (0.848) has a higher QED than Ligand B (0.582), indicating a more drug-like profile.

**7. DILI:** Ligand A (34.82) has a lower DILI risk than Ligand B (21.598), both are good, but A is slightly better.

**8. BBB:** This is crucial for a CNS target. Ligand A (64.754) is significantly better than Ligand B (21.326). A score >70 is desirable, and A is closer to this threshold.

**9. Caco-2:** Ligand A (-4.769) and Ligand B (-5.081) have similar, very low Caco-2 permeability. This is a concern for both, but not a deciding factor given the other differences.

**10. Solubility:** Ligand A (-2.423) is better than Ligand B (0.465), indicating better aqueous solubility.

**11. hERG:** Both ligands have very low hERG inhibition risk (0.359 and 0.057), which is excellent.

**12. Cl_mic:** Ligand A (-6.325) has a lower (better) microsomal clearance than Ligand B (-13.269), suggesting greater metabolic stability.

**13. t1/2:** Ligand A (-29.231) has a longer in vitro half-life than Ligand B (8.882), which is desirable.

**14. Pgp:** Ligand A (0.019) has a lower P-gp efflux liability than Ligand B (0.01), both are very good.

**15. Binding Affinity:** Ligand A (-7.9) has a slightly better binding affinity than Ligand B (-7.1). While both are good, the 0.8 kcal/mol difference is significant.

**Overall Assessment:**

Ligand A consistently outperforms Ligand B across most critical parameters, especially those prioritized for GPCRs targeting the CNS. It has better TPSA, logP, BBB penetration, solubility, metabolic stability, and a slightly better binding affinity. While both have acceptable DILI and hERG profiles, Ligand A is superior overall.

Output:
1
2025-04-17 09:04:12,987 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (384.801 and 368.836 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (116.36) is higher than the preferred <90 for CNS targets, while Ligand B (58.64) is well within the optimal range. This is a significant advantage for Ligand B.

**logP:** Both ligands have logP values within the optimal range (2.335 and 3.001).

**H-Bond Donors/Acceptors:** Both ligands have acceptable HBD (1) and HBA (7/3) counts.

**QED:** Both ligands have reasonable QED scores (0.48 and 0.816), with Ligand B being significantly better.

**DILI:** Ligand A has a very high DILI risk (99.147 percentile), which is a major red flag. Ligand B's DILI risk (67.003) is still elevated but considerably lower.

**BBB:** Ligand B has a much higher BBB penetration percentile (83.715) than Ligand A (45.095). This is crucial for a CNS target like DRD2.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values, which is unusual and suggests poor permeability. However, the scale is not specified, so it's hard to interpret.

**Aqueous Solubility:** Both ligands have negative solubility values, which is also unusual and suggests poor solubility. Again, the scale is not specified.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.262 and 0.463).

**Microsomal Clearance:** Ligand B has a higher microsomal clearance (63.964) than Ligand A (21.634), indicating lower metabolic stability.

**In vitro Half-Life:** Both ligands have similar in vitro half-lives (29.022 and 28.784 hours).

**P-gp Efflux:** Ligand B has a lower P-gp efflux liability (0.406) than Ligand A (0.256), which is favorable for CNS penetration.

**Binding Affinity:** Ligand A has a significantly stronger binding affinity (-8.8 kcal/mol) than Ligand B (-0.0 kcal/mol). This is a substantial advantage for Ligand A.

**Overall Assessment:**

Despite the significantly better binding affinity of Ligand A, its extremely high DILI risk and poor BBB penetration are major concerns. Ligand B, while having a weaker binding affinity, exhibits much better ADME properties, particularly BBB penetration and lower DILI risk, which are critical for a CNS-targeting GPCR. The combination of acceptable logP, Pgp, and TPSA further supports Ligand B. The unusual negative values for Caco-2 and solubility are concerning, but the difference in binding affinity is not large enough to overcome the ADME liabilities of Ligand A.

Output:
1
2025-04-17 09:04:12,988 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B based on the provided guidelines, prioritizing GPCR-specific properties (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (341.386 and 348.443 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (62.3) is significantly better than Ligand B (70.08). For CNS targets, TPSA should be <= 90, both are under this, but A is preferable.

**logP:** Ligand A (2.62) is optimal (1-3), while Ligand B (0.638) is a bit low, potentially hindering permeation.

**H-Bond Donors/Acceptors:** Both have acceptable HBD (1) and HBA (3 for A, 4 for B) counts.

**QED:** Ligand A (0.93) has a superior QED score compared to Ligand B (0.74), indicating better overall drug-likeness.

**DILI:** Ligand A (53.354) has a higher DILI risk than Ligand B (9.965). This is a significant drawback for Ligand A.

**BBB:** Ligand A (81.698) has a much better BBB penetration percentile than Ligand B (55.642). This is crucial for a CNS target like DRD2.

**Caco-2 Permeability:** Ligand A (-4.767) is worse than Ligand B (-4.484), indicating lower intestinal absorption.

**Aqueous Solubility:** Ligand A (-3.263) is worse than Ligand B (-1.333).

**hERG:** Both ligands have low hERG inhibition liability (0.334 and 0.179, respectively), which is good.

**Microsomal Clearance:** Ligand A (20.587) has a higher microsomal clearance than Ligand B (13.214), suggesting lower metabolic stability.

**In vitro Half-Life:** Ligand B (5.093) has a longer in vitro half-life than Ligand A (-7.17), which is a positive attribute.

**P-gp Efflux:** Ligand A (0.137) has lower P-gp efflux liability than Ligand B (0.047), which is favorable for CNS penetration.

**Binding Affinity:** Ligand B (-7.6 kcal/mol) has a slightly better binding affinity than Ligand A (-10.3 kcal/mol). This difference is substantial.

**Overall Assessment:**

Ligand A excels in BBB penetration, P-gp efflux, and QED, but suffers from higher DILI risk, lower solubility, and higher clearance. Ligand B has better solubility, lower DILI, and a longer half-life, but its BBB penetration and logP are less favorable. The binding affinity of Ligand B is also stronger.

Considering the GPCR-specific priorities, the strong binding affinity and lower DILI risk of Ligand B, combined with acceptable (though not ideal) BBB penetration, make it a more promising candidate despite the slightly lower logP. The better ADME properties of B outweigh the affinity difference.

Output:
1
2025-04-17 09:04:12,988 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (347.463 and 354.479 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (89.38) is better than Ligand B (61.92), both are below the 90 A^2 threshold for CNS targets.

**logP:** Both ligands have good logP values (2.961 and 3.576), falling within the optimal 1-3 range. Ligand B is slightly higher, which could be a minor concern.

**H-Bond Donors:** Both ligands have 0 HBD, which is acceptable.

**H-Bond Acceptors:** Ligand A has 3 HBA, and Ligand B has 5. Both are below the 10 threshold.

**QED:** Ligand B (0.824) has a significantly better QED score than Ligand A (0.444), indicating a more drug-like profile.

**DILI:** Both ligands have similar, low DILI risk (30.71 and 31.989 percentile), which is good.

**BBB:** Ligand B (84.413) has a much better BBB penetration score than Ligand A (64.017). This is a critical advantage for a CNS target like DRD2.

**Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and suggests poor permeability. However, the scale is not specified, so it's hard to interpret.

**Aqueous Solubility:** Both have negative solubility values, which is also unusual and suggests poor solubility.

**hERG Inhibition:** Ligand A (0.26) has a lower hERG inhibition liability than Ligand B (0.718), which is preferable.

**Microsomal Clearance:** Ligand B (67.223) has a higher microsomal clearance than Ligand A (56.427), suggesting lower metabolic stability.

**In vitro Half-Life:** Ligand A (-20.171) has a negative half-life, which is not possible. Ligand B (14.296) has a reasonable half-life.

**P-gp Efflux:** Ligand A (0.182) has lower P-gp efflux liability than Ligand B (0.626), which is beneficial for CNS penetration.

**Binding Affinity:** Ligand B (-8.1 kcal/mol) has a significantly stronger binding affinity than Ligand A (0.0 kcal/mol). This is a major advantage, potentially outweighing some of its other drawbacks.

**Overall Assessment:**

Ligand B is the stronger candidate. While it has slightly higher logP and P-gp efflux, and lower metabolic stability, its significantly better BBB penetration and *much* stronger binding affinity are decisive. The QED score is also considerably better. The negative values for Caco-2 and Solubility are concerning but could be experimental artifacts or indicate issues that could be addressed through prodrug strategies or formulation. The negative half-life for Ligand A is a major red flag.

Output:
1
2025-04-17 09:04:12,988 - INFO - Reasoning:

Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (350.459 and 353.419 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (75.71) is better than Ligand B (88.27). For CNS targets, we want TPSA <= 90, and A is closer to the optimal value.

**3. logP:** Both ligands (1.586 and 1.824) are within the optimal 1-3 range.

**4. H-Bond Donors:** Both have 1 HBD, which is acceptable (<=5).

**5. H-Bond Acceptors:** Ligand A has 4 HBAs, and Ligand B has 7. Ligand A is better here, as we prefer <=10.

**6. QED:** Both ligands have good QED scores (0.708 and 0.762), indicating good drug-like properties.

**7. DILI:** Ligand A (18.651) has a significantly lower DILI risk than Ligand B (31.563). This is a major advantage for A.

**8. BBB:** Ligand A (73.245) has a better BBB penetration percentile than Ligand B (65.529). While both are reasonably good, A is closer to the desirable >70 for CNS targets.

**9. Caco-2 Permeability:** Both are negative, indicating poor permeability. This is a concern for both, but the scale is unclear, so we can't definitively say which is worse.

**10. Aqueous Solubility:** Both are negative, indicating poor solubility. Again, the scale is unclear, making direct comparison difficult.

**11. hERG Inhibition:** Both ligands have low hERG inhibition risk (0.31 and 0.487).

**12. Microsomal Clearance:** Ligand A (44.538) has lower microsomal clearance than Ligand B (55.067), suggesting better metabolic stability.

**13. In vitro Half-Life:** Both have negative half-lives (-22.892 and -23.628). This is concerning and suggests rapid metabolism.

**14. P-gp Efflux:** Both ligands have low P-gp efflux liability (0.081 and 0.3).

**15. Binding Affinity:** Ligand B (-7.2 kcal/mol) has a slightly better binding affinity than Ligand A (-8.8 kcal/mol). However, the difference is not substantial enough to outweigh the other significant advantages of Ligand A.

**Overall Assessment:**

Ligand A is the more promising candidate. It has a lower DILI risk, better BBB penetration, lower TPSA, fewer HBA, and better metabolic stability (lower Cl_mic). While Ligand B has slightly better binding affinity, the other ADME/Tox properties of Ligand A are significantly more favorable, especially considering the CNS target and the importance of BBB penetration. The poor Caco-2 and solubility are concerns for both, but can be addressed with formulation strategies.

Output:
1
2025-04-17 09:04:12,988 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (350.467 and 345.407 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (92.62) is better than Ligand B (108.8), both are below the 140 threshold for oral absorption, and Ligand A is closer to the desirable <90 for CNS targets.

**3. logP:** Ligand A (1.865) is optimal, while Ligand B (0.524) is a bit low, potentially hindering permeation.

**4. H-Bond Donors:** Ligand A (0) is preferable to Ligand B (2). Fewer HBDs generally improve permeability.

**5. H-Bond Acceptors:** Ligand A (4) is better than Ligand B (6).

**6. QED:** Ligand B (0.84) has a better QED score than Ligand A (0.43), indicating a more drug-like profile.

**7. DILI:** Ligand A (15.083) has a significantly lower DILI risk than Ligand B (51.997). This is a major advantage for Ligand A.

**8. BBB:** Ligand B (62.776) is slightly better than Ligand A (59.984), but both are below the desirable >70 for CNS targets.

**9. Caco-2:** Ligand A (-4.765) is better than Ligand B (-5.264), indicating better intestinal absorption.

**10. Solubility:** Ligand A (-1.239) is better than Ligand B (-2.201), indicating better aqueous solubility.

**11. hERG:** Both ligands have very low hERG inhibition liability (0.21 and 0.292 respectively), which is good.

**12. Cl_mic:** Ligand B (-11.166) has a significantly lower (better) microsomal clearance than Ligand A (3.828), suggesting better metabolic stability.

**13. t1/2:** Ligand B (-12.127) has a much longer in vitro half-life than Ligand A (1.466), which is a significant advantage.

**14. Pgp:** Both ligands have very low P-gp efflux liability (0.012 and 0.06 respectively), which is good.

**15. Binding Affinity:** Ligand B (-7.7 kcal/mol) has a stronger binding affinity than Ligand A (-6.6 kcal/mol), with a difference of 1.1 kcal/mol. This is a substantial advantage that can outweigh some ADME drawbacks.

**Overall Assessment:**

While Ligand A has better physicochemical properties (TPSA, logP, HBD/HBA, solubility, DILI) and Caco-2 permeability, Ligand B's significantly stronger binding affinity (-7.7 vs -6.6 kcal/mol) and longer half-life are crucial for a GPCR target. The improved QED of Ligand B is also beneficial. The slightly lower BBB penetration of Ligand B is a concern, but the strong affinity may compensate for that. The lower DILI risk of Ligand A is attractive, but the difference in binding affinity is more impactful for a CNS target like DRD2.

Output:
1
2025-04-17 09:04:12,988 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (341.411 Da) is slightly better, being closer to the lower end which can aid permeability.

**TPSA:** Ligand A (62.76) is excellent, well below the 90 A^2 threshold for CNS targets. Ligand B (98.58) is higher, but still acceptable, though less favorable.

**logP:** Ligand A (3.381) is optimal. Ligand B (0.741) is quite low, potentially hindering membrane permeability and CNS penetration.

**H-Bond Donors/Acceptors:** Ligand A (0 HBD, 5 HBA) is good. Ligand B (3 HBD, 7 HBA) is also acceptable, but slightly higher counts could affect permeability.

**QED:** Both ligands have similar and good QED values (A: 0.63, B: 0.677), indicating good drug-like properties.

**DILI:** Ligand A (38.697) has a lower DILI risk than Ligand B (58.976), which is preferable.

**BBB:** This is a critical parameter for a CNS target like DRD2. Ligand A has a very high BBB percentile (96.161), indicating excellent brain penetration potential. Ligand B's BBB percentile (43.505) is significantly lower, a major drawback.

**Caco-2 Permeability:** Ligand A (-4.817) has poor Caco-2 permeability. Ligand B (-5.26) is also poor, but slightly worse.

**Aqueous Solubility:** Both ligands have very poor aqueous solubility (-2.65 and -2.055 respectively). This could pose formulation challenges.

**hERG Inhibition:** Ligand A (0.978) has a slightly lower hERG risk than Ligand B (0.429).

**Microsomal Clearance:** Ligand A (-0.88) has a lower (better) microsomal clearance than Ligand B (21.768). This suggests better metabolic stability for Ligand A.

**In vitro Half-Life:** Ligand A (32.591) has a longer half-life than Ligand B (-24.001).

**P-gp Efflux:** Ligand A (0.536) has lower P-gp efflux than Ligand B (0.074), which is favorable for CNS exposure.

**Binding Affinity:** Ligand B (-7.9 kcal/mol) has a significantly stronger binding affinity than Ligand A (-9.4 kcal/mol). This is a substantial advantage.

**Overall Assessment:**

Ligand B has a superior binding affinity, which is a major positive. However, its low logP and poor BBB penetration are significant concerns for a CNS-targeting drug. The higher DILI risk and P-gp efflux are also less desirable. Ligand A, while having a weaker binding affinity, has excellent BBB penetration, a favorable logP, lower DILI risk, and better metabolic stability. Considering the GPCR-specific priorities for DRD2 (BBB, logP, Pgp, TPSA, and affinity), the excellent CNS penetration profile of Ligand A outweighs the affinity difference, especially given the substantial affinity of -9.4 kcal/mol. The poor solubility and Caco-2 permeability of both are concerning, but can potentially be addressed through formulation strategies.

Output:
0
2025-04-17 09:04:12,989 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (345.443 and 367.515 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (75.44) is slightly higher than the ideal <90 for CNS targets, but still reasonable. Ligand B (54.9) is excellent, well below 90.

**3. logP:** Both ligands have good logP values (2.54 and 2.247), falling within the optimal 1-3 range.

**4. H-Bond Donors:** Ligand A has 1 HBD, which is acceptable. Ligand B has 0, also acceptable.

**5. H-Bond Acceptors:** Ligand A has 4 HBA, within the limit of 10. Ligand B has 6, also within the limit.

**6. QED:** Both ligands have similar QED values (0.804 and 0.772), indicating good drug-likeness.

**7. DILI:** Ligand A (35.479) has a slightly higher DILI risk than Ligand B (28.693), but both are below the concerning threshold of 60.

**8. BBB:** Both ligands exhibit excellent BBB penetration (83.404 and 84.606), exceeding the desirable >70 threshold for CNS targets.

**9. Caco-2 Permeability:** Ligand A (-5.057) has poor Caco-2 permeability, while Ligand B (-4.478) is also poor, but slightly better.

**10. Aqueous Solubility:** Both ligands have very poor aqueous solubility (-2.55 and -2.138). This is a significant drawback.

**11. hERG Inhibition:** Both ligands show low hERG inhibition risk (0.306 and 0.551).

**12. Microsomal Clearance:** Ligand A (40.382) has lower microsomal clearance than Ligand B (56.695), suggesting better metabolic stability.

**13. In vitro Half-Life:** Ligand A (-18.047) has a very poor in vitro half-life, while Ligand B (-3.645) is also poor, but significantly better.

**14. P-gp Efflux:** Both ligands show low P-gp efflux liability (0.276 and 0.137), which is favorable for CNS penetration.

**15. Binding Affinity:** Ligand A (-8.1) has a significantly stronger binding affinity than Ligand B (-6.6), with a difference of 1.5 kcal/mol. This is a substantial advantage.

**Overall Assessment:**

While both compounds have good BBB penetration and acceptable logP values, Ligand A stands out due to its significantly higher binding affinity (-8.1 vs -6.6 kcal/mol). The affinity difference is large enough to potentially offset the poorer solubility, Caco-2 permeability, and half-life. Ligand B has slightly better metabolic stability and lower P-gp efflux, but the affinity is a critical factor for GPCRs. The poor solubility and permeability of both compounds are concerns that would need to be addressed through formulation or structural modification, but the stronger binding of Ligand A makes it a more promising starting point.

Output:
1
2025-04-17 09:04:12,989 - INFO - Batch 502 complete. Total preferences: 8032
2025-04-17 09:04:12,989 - INFO - Processing batch 503/512...
2025-04-17 09:04:54,495 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (344.411 and 343.427 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (75.71) is slightly higher than Ligand B (71.53). Both are below the 90 A^2 threshold desirable for CNS targets, which is good.

**3. logP:** Both ligands have good logP values (2.087 and 1.277), falling within the optimal 1-3 range. Ligand B is slightly lower, which *could* indicate a slightly better solubility profile, but isn't a major concern.

**4. H-Bond Donors:** Both have 1 HBD, which is within the acceptable limit of <=5.

**5. H-Bond Acceptors:** Both have 4 HBA, which is within the acceptable limit of <=10.

**6. QED:** Both have good QED scores (0.673 and 0.836), indicating drug-like properties. Ligand B is slightly better here.

**7. DILI:** Ligand B (33.695) has a significantly lower DILI risk than Ligand A (47.15). This is a substantial advantage for Ligand B.

**8. BBB:** Ligand A (77.239) has a better BBB penetration percentile than Ligand B (60.838). This is a critical factor for a CNS target like DRD2.

**9. Caco-2 Permeability:** Both have negative Caco-2 values (-4.444 and -4.702), which is unusual and suggests poor permeability. This is a concern for both, but the values are very similar.

**10. Aqueous Solubility:** Ligand B (-1.58) has a slightly better (less negative) solubility score than Ligand A (-3.631), suggesting it might be easier to formulate.

**11. hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.415 and 0.102).

**12. Microsomal Clearance:** Ligand B (18.982) has significantly lower microsomal clearance than Ligand A (54.388), indicating better metabolic stability.

**13. In vitro Half-Life:** Ligand B (-6.755) has a negative half-life, which is unusual and concerning. Ligand A (12.297) has a positive half-life, suggesting better stability.

**14. P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.071 and 0.027).

**15. Binding Affinity:** Both ligands have the same binding affinity (-8.3 kcal/mol), which is excellent.

**Overall Assessment:**

While Ligand A has a better BBB score, Ligand B demonstrates superior ADME properties overall. The lower DILI risk and significantly improved metabolic stability (lower Cl_mic) are major advantages. The slightly better solubility and QED of Ligand B are also beneficial. The negative half-life for Ligand B is a red flag, but the other benefits outweigh this concern. Given the GPCR-specific priorities, the combination of good affinity, acceptable TPSA/logP, and significantly improved safety/ADME profile makes Ligand B the more promising candidate.

Output:
1
2025-04-17 09:04:54,495 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (341.455 and 356.467 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (45.55) is excellent, well below the 90 A^2 threshold for CNS targets. Ligand B (133.55) is higher, but still potentially acceptable, though less ideal.

**logP:** Ligand A (2.741) is optimal (1-3). Ligand B (0.387) is low, potentially hindering permeation.

**H-Bond Donors/Acceptors:** Ligand A (0 HBD, 3 HBA) is favorable. Ligand B (5 HBD, 4 HBA) is acceptable, but the 5 HBD is approaching the upper limit.

**QED:** Ligand A (0.794) is excellent, indicating strong drug-likeness. Ligand B (0.382) is significantly lower, suggesting a less drug-like profile.

**DILI:** Ligand A (43.234) has a low DILI risk. Ligand B (10.818) also has a very low DILI risk.

**BBB:** Ligand A (71.229) has a good BBB percentile, exceeding the 70% threshold for CNS targets. Ligand B (58.666) is lower, which is a significant drawback for a CNS target.

**Caco-2 Permeability:** Ligand A (-4.796) is poor. Ligand B (-5.497) is also poor.

**Aqueous Solubility:** Ligand A (-2.986) is poor. Ligand B (-1.573) is also poor.

**hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.392 and 0.191).

**Microsomal Clearance:** Ligand A (71.535) is relatively high, suggesting faster metabolism. Ligand B (-2.684) is negative, which is unexpected and suggests very slow clearance/high metabolic stability.

**In vitro Half-Life:** Ligand A (38.533) is moderate. Ligand B (-6.087) is negative, suggesting a very long half-life.

**P-gp Efflux:** Ligand A (0.413) has moderate P-gp efflux. Ligand B (0.013) has very low P-gp efflux, which is beneficial for CNS penetration.

**Binding Affinity:** Ligand A (-8.0) has a slightly better binding affinity than Ligand B (-7.7). However, the difference is not substantial enough to overcome other significant drawbacks.

**Overall Assessment:**

Ligand A excels in TPSA, QED, BBB, and binding affinity. However, its Caco-2 permeability and aqueous solubility are poor, and its microsomal clearance is relatively high.

Ligand B has a lower logP, which is a concern, and a lower QED. However, it has excellent metabolic stability (negative Cl_mic), a very long half-life, very low P-gp efflux, and a low DILI risk. While its BBB is not ideal, it's still reasonable.

Considering the GPCR-specific priorities, **BBB penetration and P-gp efflux are critical for CNS targets like DRD2.** Ligand B's significantly lower P-gp efflux and better metabolic stability are more valuable than Ligand A's slightly better affinity, especially given the poor permeability and solubility of both.

Output:
1
2025-04-17 09:04:54,496 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (363.374 Da) is slightly higher than Ligand B (347.415 Da), but both are acceptable.

**TPSA:** Ligand A (109.0) is above the optimal <90 for CNS targets, while Ligand B (71.44) is well within the desired range. This is a significant advantage for Ligand B.

**logP:** Ligand A (2.487) is within the optimal 1-3 range. Ligand B (0.947) is slightly below, which *could* indicate permeability issues, but isn't a dealbreaker.

**H-Bond Donors/Acceptors:** Ligand A has 3 HBD and 5 HBA, which are acceptable. Ligand B has 0 HBD and 5 HBA, also acceptable.

**QED:** Both ligands have similar QED values (0.617 and 0.71), indicating good drug-likeness.

**DILI:** Ligand A has a DILI risk of 98.759, which is very high and concerning. Ligand B has a DILI risk of 39.201, which is much lower and acceptable. This is a major advantage for Ligand B.

**BBB:** Ligand A has a BBB penetration of 40.52%, which is below the desirable >70% for CNS targets. Ligand B has a BBB penetration of 70.648%, which is excellent for a CNS-targeting drug.

**Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and hard to interpret. However, the magnitude is similar.

**Aqueous Solubility:** Both have negative solubility values, also unusual. The magnitude is similar.

**hERG Inhibition:** Ligand A (0.723) shows a slightly higher hERG inhibition risk than Ligand B (0.086).

**Microsomal Clearance:** Ligand A (27.904) has a higher microsomal clearance than Ligand B (21.566), suggesting lower metabolic stability.

**In vitro Half-Life:** Ligand B (-23.943) has a *negative* half-life, which is impossible and indicates a data error or an unusual experimental result. Ligand A (49.551) has a reasonable half-life.

**P-gp Efflux:** Ligand A (0.097) has lower P-gp efflux than Ligand B (0.03), which is favorable for CNS penetration.

**Binding Affinity:** Both ligands have very similar and strong binding affinities (-8.9 kcal/mol and -8.0 kcal/mol). The difference of 0.9 kcal/mol is not substantial enough to override other significant differences.

**Overall Assessment:**

Ligand B is significantly better due to its superior TPSA, lower DILI risk, and excellent BBB penetration. While the negative half-life is concerning, the other advantages are substantial. Ligand A's high DILI risk and poor BBB penetration are major drawbacks for a CNS-targeting drug. The slightly better P-gp efflux for Ligand A is not enough to compensate for these issues.

Output:
1
2025-04-17 09:04:54,496 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (367.373 and 342.483 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (72.47) is higher than Ligand B (58.2). For a CNS target like DRD2, we ideally want TPSA <= 90, so both are acceptable, but B is better.

**3. logP:** Both ligands have good logP values (2.449 and 3.082), falling within the optimal 1-3 range.

**4. H-Bond Donors:** Ligand A (1) is better than Ligand B (2). Lower HBDs are generally preferred for better permeability.

**5. H-Bond Acceptors:** Ligand A (4) is higher than Ligand B (2). Both are within the acceptable limit of <= 10, but B is better.

**6. QED:** Both ligands have reasonable QED values (0.824 and 0.576), indicating good drug-like properties.

**7. DILI:** Ligand A (82.784) has a significantly higher DILI risk than Ligand B (31.64). This is a major concern for Ligand A.

**8. BBB:** Ligand A (57.193) has a better BBB penetration percentile than Ligand B (49.67), but both are below the desirable >70 for CNS targets.

**9. Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and suggests potential issues with the modeling or data. However, the values are similar (-4.65 and -4.703).

**10. Aqueous Solubility:** Both have negative solubility values, again suggesting potential issues with the modeling or data. The values are similar (-4.445 and -4.78).

**11. hERG Inhibition:** Both ligands show very low hERG inhibition liability (0.317 and 0.156).

**12. Microsomal Clearance:** Ligand A (59.443) has higher microsomal clearance than Ligand B (45.148), indicating lower metabolic stability.

**13. In vitro Half-Life:** Ligand B (-4.11) has a longer in vitro half-life than Ligand A (6.896).

**14. P-gp Efflux:** Both ligands show low P-gp efflux liability (0.466 and 0.185).

**15. Binding Affinity:** Both ligands have excellent binding affinities (-10.2 and -9.0 kcal/mol). The difference is 1.2 kcal/mol, which is significant but might be outweighed by other factors.

**Overall Assessment:**

Ligand B is significantly better due to its much lower DILI risk (31.64 vs 82.784). While Ligand A has slightly better BBB penetration, the DILI risk is a major red flag. Ligand B also has a longer half-life and lower clearance, which are desirable. The affinity difference, while noticeable, is likely less important than mitigating the potential for liver toxicity. Given the GPCR-specific priorities, and the importance of CNS penetration, the lower TPSA and Pgp efflux of Ligand B are also beneficial.



Output:
1
2025-04-17 09:04:54,496 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B based on the provided guidelines, prioritizing GPCR-specific properties (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (368.543 and 359.491 Da) fall within the ideal range of 200-500 Da.

**TPSA:** Ligand A (78.43) is better than Ligand B (42.68). For CNS targets, TPSA should be <=90, both are well within this range, but A is slightly higher.

**logP:** Ligand A (2.083) is optimal (1-3), while Ligand B (4.446) is slightly high, potentially leading to solubility issues or off-target interactions.

**H-Bond Donors:** Ligand A (3) is acceptable, while Ligand B (0) is also good.

**H-Bond Acceptors:** Both ligands (4) are within the acceptable limit of <=10.

**QED:** Both ligands have good QED scores (0.516 and 0.653, respectively), indicating drug-likeness.

**DILI:** Ligand A (11.128) has a much lower DILI risk than Ligand B (30.748), a significant advantage.

**BBB:** Ligand B (83.443) has a significantly better BBB penetration percentile than Ligand A (50.756). This is a crucial factor for CNS targets like DRD2.

**Caco-2 Permeability:** Ligand A (-5.563) has a lower Caco-2 permeability than Ligand B (-4.487), suggesting potentially poorer intestinal absorption.

**Aqueous Solubility:** Ligand A (-2.723) has better aqueous solubility than Ligand B (-5.214).

**hERG Inhibition:** Ligand A (0.423) has a lower hERG inhibition risk than Ligand B (0.829).

**Microsomal Clearance:** Ligand B (107.669) has a higher microsomal clearance than Ligand A (40.612), indicating lower metabolic stability.

**In vitro Half-Life:** Ligand B (48.753) has a longer in vitro half-life than Ligand A (-4.172), which is desirable.

**P-gp Efflux:** Ligand A (0.065) has lower P-gp efflux liability than Ligand B (0.78), which is beneficial for CNS exposure.

**Binding Affinity:** Both ligands have very similar and strong binding affinities (-7.6 and -7.7 kcal/mol). The difference is negligible.

**Overall Assessment:**

Ligand B excels in BBB penetration and in vitro half-life, which are important for a CNS target. However, it suffers from higher logP, higher DILI risk, higher P-gp efflux, and higher microsomal clearance. Ligand A has a better safety profile (lower DILI, hERG), better solubility, and lower efflux, but its BBB penetration is significantly lower.

Given the importance of BBB penetration for a CNS target like DRD2, and the relatively small difference in binding affinity, Ligand B is slightly favored. However, the higher DILI risk of Ligand B is a concern. Considering all factors, the better BBB penetration of Ligand B outweighs the other drawbacks.

Output:
1
2025-04-17 09:04:54,496 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 drug candidates, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (347.459 and 344.459 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (70.67) is significantly better than Ligand B (83.98). For CNS targets, TPSA should be <= 90, and A is closer to the optimal <= 60-70 range. B is pushing the upper limit.

**3. logP:** Both ligands have acceptable logP values (1.237 and 2.333), falling within the 1-3 optimal range.

**4. H-Bond Donors:** Both have 2 HBD, which is within the acceptable limit of <= 5.

**5. H-Bond Acceptors:** Both have 4 HBA, also within the acceptable limit of <= 10.

**6. QED:** Both ligands have similar QED values (0.537 and 0.532), indicating good drug-like properties.

**7. DILI:** Ligand A (17.642) has a much lower DILI risk than Ligand B (43.001). This is a significant advantage for A.

**8. BBB:** Ligand A (71.307) has a substantially better BBB penetration percentile than Ligand B (56.378).  A score >70 is desirable for CNS targets, and A is closer to that threshold.

**9. Caco-2 Permeability:** Both have negative values (-5.61 and -5.187), which is unusual and suggests poor permeability. However, the scale isn't specified, so it's difficult to interpret.

**10. Aqueous Solubility:** Both have negative values (-2.201 and -2.233), again suggesting poor solubility. Similar to Caco-2, the scale is unclear.

**11. hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.412 and 0.153).

**12. Microsomal Clearance:** Ligand A (-1.499) has a lower (better) microsomal clearance than Ligand B (47.641), indicating greater metabolic stability.

**13. In vitro Half-Life:** Ligand A (5.402) has a slightly better in vitro half-life than Ligand B (-4.997).

**14. P-gp Efflux:** Ligand A (0.017) has significantly lower P-gp efflux liability than Ligand B (0.095), which is crucial for CNS penetration.

**15. Binding Affinity:** Ligand B (-8.0) has a slightly better binding affinity than Ligand A (-7.5). However, the difference is only 0.5 kcal/mol.

**Overall Assessment:**

Considering the GPCR-specific priorities, Ligand A is the superior candidate. While Ligand B has a slightly better binding affinity, Ligand A excels in critical ADME properties for CNS drug development: significantly better BBB penetration, lower DILI risk, lower P-gp efflux, and improved metabolic stability. The TPSA value is also more favorable for Ligand A. The small affinity difference is likely outweighed by the substantial improvements in ADME properties.

Output:
1
2025-04-17 09:04:54,497 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (353.419 and 349.479 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (96.97) is slightly above the optimal <90 for CNS targets, while Ligand B (89.38) is within the desired range.

**logP:** Ligand A (-0.719) is a bit low, potentially hindering membrane permeability. Ligand B (3.064) is within the optimal 1-3 range. This is a significant advantage for Ligand B.

**H-Bond Donors/Acceptors:** Ligand A has 2 HBD and 5 HBA, which are acceptable. Ligand B has 0 HBD and 3 HBA, also acceptable.

**QED:** Ligand A (0.698) has a better QED score than Ligand B (0.401), suggesting a more drug-like profile overall.

**DILI:** Ligand A (34.432) has a slightly higher DILI risk than Ligand B (19.232), but both are below the concerning threshold of 60.

**BBB:** This is crucial for a CNS target like DRD2. Ligand B (78.829) has a much better BBB percentile than Ligand A (27.065). This is a major advantage for Ligand B.

**Caco-2 Permeability:** Ligand A (-5.339) has poor Caco-2 permeability, while Ligand B (-4.59) is somewhat better, but still not great.

**Aqueous Solubility:** Ligand A (-0.804) has poor solubility, while Ligand B (-2.08) is even worse. This could pose formulation challenges for both.

**hERG Inhibition:** Ligand A (0.093) shows very low hERG inhibition risk, which is excellent. Ligand B (0.322) also has a low risk, but slightly higher than A.

**Microsomal Clearance:** Ligand A (-11.378) has a very low (good) microsomal clearance, indicating high metabolic stability. Ligand B (44.508) has a much higher clearance, suggesting faster metabolism.

**In vitro Half-Life:** Ligand A (22.676) has a reasonable half-life. Ligand B (-2.39) has a very short half-life, which is a significant drawback.

**P-gp Efflux:** Ligand A (0.006) has very low P-gp efflux, which is ideal for CNS penetration. Ligand B (0.047) also has low P-gp efflux.

**Binding Affinity:** Ligand B (-6.8 kcal/mol) has a significantly stronger binding affinity than Ligand A (-0.0 kcal/mol). This is a huge advantage, potentially outweighing some of the ADME concerns.

**Overall Assessment:**

While Ligand A has better QED, lower DILI, better hERG, and superior metabolic stability, Ligand B excels in the most critical areas for a CNS-targeting GPCR ligand: **BBB penetration and binding affinity**. The significantly stronger binding affinity of Ligand B (-6.8 vs -0.0 kcal/mol) is a decisive factor. The better BBB penetration (78.83% vs 27.07%) is also a major advantage. The lower half-life and higher clearance of Ligand B are concerns, but these can potentially be addressed through structural modifications during lead optimization. The poor solubility of both compounds is a concern, but formulation strategies can be explored. The lower logP of Ligand A is a significant drawback.

Output:
1
2025-04-17 09:04:54,497 - INFO - Reasoning:

Let's analyze Ligand A and Ligand B based on the provided guidelines, prioritizing GPCR-specific properties (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (364.917 and 348.397 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (58.2) is better than Ligand B (51.02). Both are below the 90 A^2 threshold desirable for CNS targets, which is excellent.

**logP:** Ligand A (3.864) is slightly higher than Ligand B (2.933). Both are within the optimal 1-3 range, but Ligand A is approaching the upper limit, potentially raising concerns about off-target effects.

**H-Bond Donors/Acceptors:** Ligand A (2 HBD, 2 HBA) is preferable to Ligand B (0 HBD, 4 HBA). Lower HBD counts are generally favorable for BBB penetration.

**QED:** Ligand B (0.806) has a higher QED score than Ligand A (0.619), indicating a more drug-like profile overall.

**DILI:** Ligand A (20.24) has a significantly lower DILI risk than Ligand B (54.207). This is a substantial advantage for Ligand A.

**BBB:** Ligand B (91.508) has a much higher BBB penetration percentile than Ligand A (75.533). This is a critical advantage for a CNS target like DRD2.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.867 and -4.586), which is unusual and suggests poor permeability. This is a significant concern for both.

**Aqueous Solubility:** Both ligands have negative solubility values (-3.865 and -2.999), indicating very poor aqueous solubility. This is a major drawback for both.

**hERG:** Ligand A (0.646) has a slightly higher hERG inhibition liability than Ligand B (0.482), but both are relatively low risk.

**Microsomal Clearance:** Ligand B (26.371) has a lower microsomal clearance than Ligand A (44.915), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand B (1.248) has a shorter half-life than Ligand A (40.452). This is a significant advantage for Ligand A.

**P-gp Efflux:** Ligand A (0.274) has lower P-gp efflux liability than Ligand B (0.453), which is favorable for CNS exposure.

**Binding Affinity:** Ligand B (-8.9 kcal/mol) has a slightly stronger binding affinity than Ligand A (-8.4 kcal/mol). While the difference is small, it's still a positive for Ligand B.

**Overall Assessment:**

Ligand B excels in BBB penetration and binding affinity, both crucial for a CNS GPCR target. However, it suffers from a higher DILI risk and poorer metabolic stability. Ligand A has a much better safety profile (lower DILI), better metabolic stability (longer half-life), and lower P-gp efflux, but its BBB penetration is lower. The poor Caco-2 and solubility for both are concerning, but can potentially be addressed with formulation strategies.

Given the importance of CNS penetration for DRD2, and the relatively small difference in binding affinity, the superior BBB value of Ligand B is the deciding factor. While Ligand A has a better safety profile, the primary goal is to reach the target in the brain, and Ligand B is better positioned to do so.

Output:
1
2025-04-17 09:04:54,497 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (345.355 and 352.475 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (124.69) is slightly above the optimal <90 for CNS targets, but still reasonable. Ligand B (70.08) is excellent, well below 90.

**logP:** Ligand A (0.566) is quite low, potentially hindering membrane permeability. Ligand B (1.271) is better, falling within the 1-3 optimal range.

**H-Bond Donors/Acceptors:** Ligand A has 4 HBD and 6 HBA, both acceptable. Ligand B has 1 HBD and 4 HBA, also acceptable.

**QED:** Both ligands have good QED scores (0.628 and 0.809), indicating drug-like properties.

**DILI:** Ligand A (56.727) has a moderate DILI risk, while Ligand B (7.871) has a very low risk. This is a significant advantage for Ligand B.

**BBB:** Ligand A (12.059) has very poor predicted BBB penetration, a critical drawback for a CNS target. Ligand B (67.158) has much better, though not outstanding, BBB penetration.

**Caco-2 Permeability:** Ligand A (-5.863) has poor Caco-2 permeability, consistent with its low logP. Ligand B (-4.452) is better, but still not ideal.

**Aqueous Solubility:** Both ligands have very poor aqueous solubility (-2.327 and -1.114). This could pose formulation challenges.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.095 and 0.358).

**Microsomal Clearance:** Ligand A (-3.496) has a negative value, suggesting very low clearance and high metabolic stability. Ligand B (15.905) has a higher clearance, indicating faster metabolism.

**In vitro Half-Life:** Ligand A (-13.568) has a negative value, suggesting a very long half-life. Ligand B (1.533) has a short half-life.

**P-gp Efflux:** Ligand A (0.011) has very low P-gp efflux, which is excellent for CNS penetration. Ligand B (0.061) also has low P-gp efflux.

**Binding Affinity:** Both ligands have very good binding affinities (-8.9 and -8.3 kcal/mol). The difference of 0.6 kcal/mol is not substantial enough to override other significant differences.

**Overall Assessment:**

Ligand B is the more promising candidate. While both have good affinity, Ligand B's superior logP, lower DILI risk, and significantly better BBB penetration outweigh Ligand A's slightly better metabolic stability and half-life. The poor solubility of both is a concern, but can potentially be addressed with formulation strategies. Ligand A's extremely poor BBB penetration is a deal-breaker for a CNS target like DRD2.

Output:
1
2025-04-17 09:04:54,497 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (350.419 and 362.423 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (107.69) is better than Ligand B (134.19). For CNS targets, we want TPSA <= 90, so A is closer to the desired range.

**logP:** Ligand A (-0.483) is slightly below the optimal 1-3 range, potentially hindering permeation. Ligand B (-1.047) is even lower, raising more concerns.

**H-Bond Donors/Acceptors:** Ligand A (HBD=3, HBA=6) is better than Ligand B (HBD=4, HBA=7) in terms of balancing solubility and permeability. Both are acceptable, but A is slightly preferred.

**QED:** Ligand A (0.642) has a better QED score than Ligand B (0.364), indicating a more drug-like profile.

**DILI:** Both ligands have low DILI risk (A: 36.293, B: 32.183), both below the 40 threshold.

**BBB:** Ligand A (27.763) has a significantly better BBB percentile than Ligand B (23.42). While both are low, DRD2 is a CNS target, so BBB is critical.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.449 and -5.528), which is unusual and suggests poor permeability. This is a significant concern for both.

**Aqueous Solubility:** Both ligands have negative solubility values (-1.197 and -1.36), which is also unusual and suggests poor solubility.

**hERG Inhibition:** Both ligands have very low hERG inhibition risk (A: 0.033, B: 0.153), which is excellent.

**Microsomal Clearance:** Ligand A (-11.569) has a much lower (better) microsomal clearance than Ligand B (67.615), indicating better metabolic stability.

**In vitro Half-Life:** Ligand A (13.562 hours) has a better in vitro half-life than Ligand B (-19.32 hours).

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (A: 0.006, B: 0.042), which is favorable for CNS penetration.

**Binding Affinity:** Ligand A (-7.9 kcal/mol) has a slightly better binding affinity than Ligand B (-6.6 kcal/mol). While both are good, A has a 1.3 kcal/mol advantage.

**Overall Assessment:**

Ligand A is superior to Ligand B. While both have issues with Caco-2 and solubility, Ligand A excels in key areas for a CNS-targeting GPCR: better TPSA, significantly better BBB penetration, much lower microsomal clearance (better metabolic stability), longer half-life, and slightly better binding affinity. The better QED score also supports its drug-likeness. The slightly lower logP of A is a concern, but the overall profile is more promising.

Output:
1
2025-04-17 09:04:54,497 - INFO - Reasoning:

Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight (MW):** Both ligands (348.49 & 381.89 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (69.64) is better than Ligand B (71.53). Both are below the 90 A^2 threshold for CNS targets, which is good.

**3. logP:** Both ligands have similar logP values (2.247 & 2.253), falling within the optimal 1-3 range.

**4. H-Bond Donors (HBD):** Ligand A (2) is slightly higher than Ligand B (1), both are within the acceptable limit of <=5.

**5. H-Bond Acceptors (HBA):** Ligand A (3) is lower than Ligand B (5), both are within the acceptable limit of <=10.

**6. QED:** Both ligands have good QED scores (0.766 & 0.812), indicating good drug-like properties.

**7. DILI:** Ligand A (14.541) has a significantly lower DILI risk than Ligand B (61.031). This is a major advantage for Ligand A.

**8. BBB:** Ligand B (79.604) has a better BBB penetration percentile than Ligand A (65.025). This is a crucial factor for a CNS target like DRD2.

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.673 & -4.964), which is unusual and suggests poor permeability. This is a significant concern for both.

**10. Aqueous Solubility:** Both ligands have negative solubility values (-2.661 & -3.473), indicating poor aqueous solubility. This is also a concern for both.

**11. hERG Inhibition:** Both ligands have low hERG inhibition risk (0.162 & 0.335).

**12. Microsomal Clearance (Cl_mic):** Ligand B (21.256) has a lower Cl_mic than Ligand A (39.607), suggesting better metabolic stability.

**13. In vitro Half-Life:** Ligand A (-7.926) has a much longer in vitro half-life than Ligand B (0.271).

**14. P-gp Efflux:** Ligand A (0.054) has lower P-gp efflux liability than Ligand B (0.274), which is favorable for CNS penetration.

**15. Binding Affinity:** Ligand B (-8.3) has a slightly better binding affinity than Ligand A (-8.1), but the difference is relatively small (0.2 kcal/mol).

**Overall Assessment:**

While Ligand B has better BBB penetration and slightly better binding affinity, Ligand A is significantly better in terms of DILI risk, P-gp efflux, and in vitro half-life. The poor Caco-2 and solubility for both are concerning, but can potentially be addressed with formulation strategies. Given the importance of minimizing toxicity (DILI) and maximizing CNS exposure (P-gp, BBB) for a DRD2 ligand, Ligand A appears to be the more promising candidate. The small difference in binding affinity is unlikely to outweigh the advantages of Ligand A in ADME-Tox properties.

Output:
0
2025-04-17 09:04:54,498 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (351.363 and 358.467 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (115.65) is slightly above the optimal <90 for CNS targets, but still reasonable. Ligand B (74.33) is excellent, well below 90.

**logP:** Ligand A (-0.725) is a bit low, potentially hindering permeation. Ligand B (2.109) is within the optimal 1-3 range. This is a significant advantage for Ligand B.

**H-Bond Donors/Acceptors:** Ligand A (1 HBD, 8 HBA) and Ligand B (2 HBD, 4 HBA) both have acceptable numbers of H-bond donors and acceptors.

**QED:** Both ligands have good QED scores (0.711 and 0.86), indicating good drug-like properties.

**DILI:** Both ligands have relatively high DILI risk (76.425 and 77.472), but are comparable.

**BBB:** Ligand A (70.415) is at the threshold for desirable BBB penetration, while Ligand B (62.97) is below. However, the difference isn't drastic.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.999 and -4.774). This is unusual and suggests poor permeability.

**Aqueous Solubility:** Both ligands have negative solubility values (-2.712 and -2.666), also unusual and suggesting poor solubility.

**hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.042 and 0.143).

**Microsomal Clearance:** Ligand A (25.226) has lower clearance than Ligand B (34.127), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (-10.609) has a negative half-life, which is not possible. Ligand B (19.749) has a reasonable half-life.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.045 and 0.117), which is good for CNS penetration.

**Binding Affinity:** Ligand B (-9.2 kcal/mol) has a significantly stronger binding affinity than Ligand A (-7.0 kcal/mol). This is a >1.5 kcal/mol advantage, which can outweigh other drawbacks.

**Overall Assessment:**

Ligand B is the more promising candidate. While both have issues with Caco-2 and solubility, Ligand B's superior logP, significantly stronger binding affinity, and reasonable half-life outweigh Ligand A's slightly better metabolic stability and BBB. The negative half-life for Ligand A is a critical flaw. The TPSA of ligand B is also more favorable for CNS penetration.

Output:
1
2025-04-17 09:04:54,498 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 drug candidates, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (347.415 and 350.394 Da) are within the ideal 200-500 Da range.

**TPSA:** Ligand A (89.95) is better than Ligand B (75.63) as it is closer to the optimal value of <=90 for CNS targets.

**logP:** Ligand B (1.024) is slightly better than Ligand A (-0.94). Both are within the 1-3 range, but A is a bit low, potentially hindering permeation.

**H-Bond Donors/Acceptors:** Ligand A has 2 HBD and 4 HBA, while Ligand B has 0 HBD and 6 HBA. Both are within acceptable limits (<=5 HBD and <=10 HBA).

**QED:** Both ligands have good QED scores (0.607 and 0.738, respectively), indicating good drug-like properties.

**DILI:** Ligand A (11.09) has a significantly lower DILI risk than Ligand B (55.099). This is a major advantage for Ligand A.

**BBB:** Ligand B (92.168) has a much higher BBB penetration percentile than Ligand A (44.32). This is a critical advantage for a CNS target like DRD2.

**Caco-2 Permeability:** Ligand A (-5.117) and Ligand B (-4.327) both have negative values, which is unusual and suggests poor permeability. However, the scale is not specified, so it's difficult to interpret.

**Aqueous Solubility:** Both ligands have poor aqueous solubility (-1.355 and -1.621 respectively).

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.092 and 0.171).

**Microsomal Clearance:** Ligand A (-29.134) has a much lower (better) microsomal clearance than Ligand B (74.281), indicating better metabolic stability.

**In vitro Half-Life:** Ligand B (1.655) has a slightly longer half-life than Ligand A (0.295).

**P-gp Efflux:** Ligand A (0.003) has a much lower P-gp efflux liability than Ligand B (0.082), which is favorable for CNS penetration.

**Binding Affinity:** Ligand B (-8.6 kcal/mol) has a slightly better binding affinity than Ligand A (-7.9 kcal/mol). This difference is significant (0.7 kcal/mol).

**Overall Assessment:**

Ligand B excels in BBB penetration and binding affinity, two crucial factors for a CNS GPCR target. However, it suffers from a higher DILI risk and higher P-gp efflux. Ligand A has a much better safety profile (lower DILI) and lower P-gp efflux, and better metabolic stability, but its BBB penetration is significantly lower.

Considering the GPCR-specific priorities, the improved binding affinity and *particularly* the much higher BBB penetration of Ligand B outweigh its slightly higher DILI risk and P-gp efflux. The 0.7 kcal/mol difference in binding is substantial. While both have poor solubility and Caco-2 permeability, these can be addressed through formulation strategies.

Output:
1
2025-04-17 09:04:54,498 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (362.392 and 347.503 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (60.85) is significantly better than Ligand B (71.09). For CNS targets, we want TPSA <= 90, and ideally closer to 60. Ligand A is much closer to the ideal.

**3. logP:** Both ligands have good logP values (2.362 and 3.479), falling within the optimal 1-3 range. Ligand B is slightly higher, which could potentially lead to off-target effects, but it's not a major concern.

**4. H-Bond Donors:** Ligand A (1) is preferable to Ligand B (2). Lower HBD generally improves permeability.

**5. H-Bond Acceptors:** Both ligands have 3 HBA, which is acceptable.

**6. QED:** Ligand A (0.837) has a better QED score than Ligand B (0.756), indicating a more drug-like profile.

**7. DILI:** Ligand A (20.9) has a much lower DILI risk than Ligand B (31.563). This is a significant advantage for Ligand A.

**8. BBB:** Ligand A (75.727) has a better BBB penetration percentile than Ligand B (68.399). While both are reasonably good, exceeding 70 is desirable for CNS targets, and A is closer.

**9. Caco-2 Permeability:** Ligand A (-4.904) has better Caco-2 permeability than Ligand B (-4.78). Higher values are better.

**10. Aqueous Solubility:** Ligand A (-2.192) has better aqueous solubility than Ligand B (-4.033).

**11. hERG Inhibition:** Both ligands have low hERG inhibition risk (0.348 and 0.575).

**12. Microsomal Clearance:** Ligand A (-13.188) has significantly lower microsomal clearance than Ligand B (65.043), indicating better metabolic stability.

**13. In vitro Half-Life:** Ligand A (-19.679) has a longer in vitro half-life than Ligand B (34.208), which is desirable.

**14. P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.019 and 0.093).

**15. Binding Affinity:** Both ligands have similar and excellent binding affinities (-8.2 and -8.4 kcal/mol). The difference is negligible.

**Overall Assessment:**

Ligand A consistently outperforms Ligand B across most ADME-Tox properties, particularly DILI, BBB, microsomal clearance, and solubility. While both have good binding affinity and logP, Ligand A's superior ADME profile, especially its better predicted CNS penetration and reduced toxicity risk, makes it the more promising drug candidate for a CNS target like DRD2.

Output:
1
2025-04-17 09:04:54,498 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the acceptable range (200-500 Da). Ligand A (415.255 Da) is higher, but not excessively so. Ligand B (350.415 Da) is slightly preferred here.

**TPSA:** Ligand A (64.99) is excellent, falling well below the 90 A^2 threshold for CNS targets. Ligand B (88.1) is still reasonable, but less optimal. This favors Ligand A.

**logP:** Ligand A (3.658) is within the optimal range (1-3), while Ligand B (1.541) is at the lower end. For a GPCR, a slightly higher logP is often beneficial for membrane permeability and receptor engagement, giving an edge to Ligand A.

**H-Bond Donors/Acceptors:** Ligand A (HBD=1, HBA=5) and Ligand B (HBD=2, HBA=5) both have acceptable numbers of H-bond donors and acceptors. No significant difference here.

**QED:** Both ligands have good QED scores (Ligand A: 0.527, Ligand B: 0.728). Ligand B is slightly better, indicating a more drug-like profile.

**DILI:** Ligand A (60.682) is moderately risky, while Ligand B (22.14) is very low risk. This is a significant advantage for Ligand B.

**BBB:** Both ligands have good BBB penetration (Ligand A: 79.062, Ligand B: 70.997), exceeding the 70% threshold for CNS targets. Ligand A is slightly better.

**Caco-2 Permeability:** Both have negative Caco-2 values which is unusual. This suggests poor permeability in either case.

**Aqueous Solubility:** Both have negative solubility values which is also unusual.

**hERG Inhibition:** Ligand A (0.821) shows a slightly higher risk of hERG inhibition than Ligand B (0.266). This favors Ligand B.

**Microsomal Clearance:** Ligand A (100.061) has higher clearance, indicating lower metabolic stability, compared to Ligand B (38.013). This is a significant advantage for Ligand B.

**In vitro Half-Life:** Ligand A (93.673) has a significantly longer half-life than Ligand B (-13.762). This is a strong advantage for Ligand A.

**P-gp Efflux:** Ligand A (0.783) shows moderate P-gp efflux, while Ligand B (0.081) has very low efflux. Lower P-gp efflux is crucial for CNS penetration, favoring Ligand B.

**Binding Affinity:** Ligand B (-8.3 kcal/mol) has a slightly better binding affinity than Ligand A (-8.1 kcal/mol), although the difference is small.

**Overall Assessment:**

Ligand B excels in safety (DILI, hERG), metabolic stability (Cl_mic), and P-gp efflux. Ligand A has better TPSA, logP, and half-life. The binding affinity difference is minimal. Considering the GPCR-specific priorities, the lower P-gp efflux and DILI risk of Ligand B are particularly important for CNS drug development. While Ligand A's longer half-life is attractive, the safety and permeability advantages of Ligand B outweigh this benefit.

Output:
1
2025-04-17 09:04:54,499 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (344.419 and 348.531 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (103.01) is borderline for CNS penetration, being slightly above the preferred <90. Ligand B (40.62) is excellent, well below 90.

**3. logP:** Ligand A (0.805) is a bit low, potentially hindering membrane permeability. Ligand B (4.01) is at the upper end of the optimal range, potentially causing solubility issues, but acceptable.

**4. H-Bond Donors:** Ligand A (3) is within the acceptable limit of <=5. Ligand B (0) is also good.

**5. H-Bond Acceptors:** Ligand A (5) is within the acceptable limit of <=10. Ligand B (2) is also good.

**6. QED:** Both ligands have good QED scores (0.689 and 0.704), indicating drug-like properties.

**7. DILI:** Ligand A (25.165) has a significantly lower DILI risk than Ligand B (16.053), which is a positive attribute.

**8. BBB:** This is crucial for a CNS target. Ligand A (34.548) has a poor BBB percentile. Ligand B (83.831) has an excellent BBB percentile, a major advantage.

**9. Caco-2 Permeability:** Ligand A (-5.806) has poor Caco-2 permeability, which is concerning. Ligand B (-4.521) is also poor, but slightly better than A.

**10. Aqueous Solubility:** Both ligands have poor aqueous solubility (-1.249 and -2.887). This could pose formulation challenges, but is less critical than BBB for CNS drugs.

**11. hERG Inhibition:** Ligand A (0.242) has a very low hERG risk, which is excellent. Ligand B (0.678) is slightly higher, but still relatively low.

**12. Microsomal Clearance:** Ligand A (-20.093) has very low microsomal clearance, indicating high metabolic stability. Ligand B (76.778) has high clearance, suggesting faster metabolism.

**13. In vitro Half-Life:** Ligand A (11.455) has a moderate half-life. Ligand B (-14.859) has a very short half-life, which is a significant drawback.

**14. P-gp Efflux:** Ligand A (0.01) has very low P-gp efflux, which is ideal for CNS penetration. Ligand B (0.46) has moderate P-gp efflux.

**15. Binding Affinity:** Ligand A (-8.3) has a significantly stronger binding affinity than Ligand B (0.0). This is a substantial advantage.

**Overall Assessment:**

Despite Ligand A's superior binding affinity and lower DILI/P-gp efflux, its extremely poor BBB penetration and Caco-2 permeability are major liabilities. Ligand B, while having weaker affinity, exhibits excellent BBB penetration, acceptable logP, and a lower P-gp efflux compared to Ligand A. The combination of good BBB penetration and acceptable ADME properties makes Ligand B a more promising starting point for CNS drug development, even with the weaker binding. The affinity can be optimized later.

Output:
1
2025-04-17 09:04:54,499 - INFO - Batch 503 complete. Total preferences: 8048
2025-04-17 09:04:54,499 - INFO - Processing batch 504/512...
2025-04-17 09:05:39,318 - INFO - Reasoning:

Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (350.419 and 349.439 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (90.98) is excellent, falling below the 90 threshold for CNS targets. Ligand B (105.04) is slightly higher but still reasonable.

**3. logP:** Both ligands (-0.315 and -0.443) are a bit low. While not drastically outside the optimal 1-3 range, they could potentially hinder membrane permeability.

**4. H-Bond Donors:** Both ligands have 2 HBD, which is within the acceptable limit of <=5.

**5. H-Bond Acceptors:** Ligand A has 4 HBA, while Ligand B has 7. Both are within the acceptable limit of <=10, but Ligand A is preferable.

**6. QED:** Both ligands have similar QED values (0.727 and 0.721), indicating good drug-likeness.

**7. DILI:** Ligand A (43.932) has a slightly higher DILI risk than Ligand B (30.71), but both are below the concerning threshold of 60.

**8. BBB:** This is a crucial parameter for a CNS target. Ligand A has a BBB percentile of 59.325, while Ligand B has 46.452. Ligand A is significantly better in this regard, although ideally, we'd want >70.

**9. Caco-2 Permeability:** Ligand A (-4.645) has a worse Caco-2 permeability than Ligand B (-5.751).

**10. Aqueous Solubility:** Ligand A (-1.316) has slightly better solubility than Ligand B (-0.8).

**11. hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.069 and 0.047).

**12. Microsomal Clearance:** Ligand A (0.436) has significantly lower microsomal clearance than Ligand B (-18.769). This suggests better metabolic stability for Ligand A.

**13. In vitro Half-Life:** Ligand A (11.089 hours) has a shorter half-life than Ligand B (16.125 hours).

**14. P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.007 and 0.008).

**15. Binding Affinity:** Ligand A (-8.5 kcal/mol) has a slightly better binding affinity than Ligand B (-7.4 kcal/mol). This 1.1 kcal/mol difference is substantial and can outweigh some ADME drawbacks.

**Overall Assessment:**

Considering the GPCR-specific priorities, Ligand A is the more promising candidate. Its superior BBB penetration, lower microsomal clearance (better metabolic stability), and slightly better binding affinity are key advantages. While its logP is a bit low, the stronger binding and better CNS penetration are more critical for a DRD2 ligand. The slightly shorter half-life of Ligand A is a minor drawback that could potentially be addressed through structural modifications.

Output:
1
2025-04-17 09:05:39,318 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (349.391 Da) is slightly lower, which could be beneficial for permeability.

**TPSA:** Ligand A (105.56) is better than Ligand B (46.32) as it is closer to the ideal range for CNS targets (<=90). Ligand B is quite low, which could indicate poor interactions with the receptor.

**logP:** Ligand A (-0.576) is suboptimal, being below the preferred 1-3 range. This could hinder membrane permeability. Ligand B (4.067) is at the higher end of the optimal range, potentially leading to solubility issues or off-target interactions, but is still acceptable.

**H-Bond Donors/Acceptors:** Ligand A has 2 HBD and 6 HBA, which are within acceptable limits. Ligand B has 0 HBD and 7 HBA, also acceptable.

**QED:** Both ligands have reasonable QED values (Ligand A: 0.715, Ligand B: 0.514), suggesting good drug-like properties.

**DILI:** Both ligands have relatively high DILI risk (Ligand A: 49.864, Ligand B: 63.086), but Ligand A is lower, indicating a slightly better safety profile.

**BBB:** Both ligands have good BBB penetration (Ligand A: 65.529, Ligand B: 68.864), but Ligand B is slightly better. However, both are below the desirable >70 for CNS targets.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.158 and -5.47), which is unusual and suggests poor permeability.

**Aqueous Solubility:** Both ligands have negative solubility values (-1.472 and -3.561), indicating poor aqueous solubility.

**hERG Inhibition:** Ligand A (0.052) has a very low hERG risk, which is excellent. Ligand B (0.879) has a moderate hERG risk.

**Microsomal Clearance:** Ligand A (-7.841) has a much lower (better) microsomal clearance than Ligand B (50.288), suggesting greater metabolic stability.

**In vitro Half-Life:** Ligand A (-5.676) has a negative half-life, which is unusual. Ligand B (6.813) has a reasonable half-life.

**P-gp Efflux:** Both ligands have low P-gp efflux (0.004 and 0.709), which is favorable for CNS penetration.

**Binding Affinity:** Both ligands have similar and strong binding affinities (Ligand A: -8.0 kcal/mol, Ligand B: -7.9 kcal/mol). The difference is negligible.

**Overall Assessment:**

Considering the GPCR-specific priorities, Ligand A is the better candidate. While its logP is suboptimal, its significantly lower microsomal clearance, very low hERG risk, and better TPSA outweigh this drawback. Ligand B has a better logP and slightly better BBB, but its higher DILI risk, higher microsomal clearance, and moderate hERG risk are concerning. The negative Caco-2 and solubility values for both are problematic, but can be addressed with formulation strategies. The superior metabolic stability and safety profile of Ligand A make it the more promising candidate.

Output:
0
2025-04-17 09:05:39,319 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (357.443 and 365.499 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (135.6) is slightly above the optimal <90 for CNS targets, but still reasonable. Ligand B (91.32) is closer to the ideal range for CNS penetration.

**logP:** Both ligands (2.174 and 2.102) are within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A has 4 HBD and 7 HBA, while Ligand B has 3 HBD and 5 HBA. Both are within acceptable limits (<=5 HBD and <=10 HBA).

**QED:** Both ligands have good QED scores (0.534 and 0.585), indicating drug-like properties.

**DILI:** Ligand A (86.468) has a higher DILI risk than Ligand B (42.536). This is a significant negative for Ligand A.

**BBB:** Ligand B (54.595) has a considerably better BBB penetration score than Ligand A (35.014). This is a crucial advantage for a CNS target like DRD2.

**Caco-2 Permeability:** Ligand A (-5.819) has worse Caco-2 permeability than Ligand B (-4.92), suggesting lower intestinal absorption.

**Aqueous Solubility:** Both have poor aqueous solubility (-3.49 and -2.795), but this is less critical for CNS drugs that need to cross the BBB.

**hERG Inhibition:** Ligand A (0.684) has a slightly higher hERG inhibition liability than Ligand B (0.129).

**Microsomal Clearance:** Ligand A (-9.779) has significantly lower (better) microsomal clearance than Ligand B (29.738), indicating better metabolic stability.

**In vitro Half-Life:** Ligand A (47.802) has a longer in vitro half-life than Ligand B (-6.655), which is desirable.

**P-gp Efflux:** Ligand A (0.328) has lower P-gp efflux liability than Ligand B (0.1), which is favorable for CNS penetration.

**Binding Affinity:** Ligand B (-7.5) has a slightly better binding affinity than Ligand A (-8.5). While A is better, the difference is not substantial enough to overcome other issues.

**Overall Assessment:**

Ligand B is the stronger candidate. While Ligand A has better metabolic stability and half-life, Ligand B excels in the critical areas for a CNS GPCR target: BBB penetration, lower DILI risk, and lower hERG inhibition. The slightly better affinity of Ligand B also contributes to its favorability. The TPSA of Ligand B is also more favorable for CNS penetration.



Output:
1
2025-04-17 09:05:39,319 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 drug candidates, considering the provided guidelines and GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (341.411 Da) is slightly lower, which is generally favorable for permeability. Ligand B (369.571 Da) is also good.

**TPSA:** Ligand A (95.66) is better than Ligand B (49.77) for CNS penetration, being closer to the <90 threshold.

**logP:** Both ligands have good logP values (A: 1.909, B: 3.489), falling within the optimal 1-3 range. Ligand B is slightly higher, which *could* raise concerns about solubility and off-target effects, but is still acceptable.

**H-Bond Donors/Acceptors:** Ligand A has 3 HBD and 4 HBA, while Ligand B has 1 HBD and 4 HBA. Both are within acceptable limits (HBD <= 5, HBA <= 10).

**QED:** Both ligands have similar QED values (A: 0.748, B: 0.698), indicating good drug-like properties.

**DILI:** Ligand A (31.563) has a significantly lower DILI risk than Ligand B (9.849), which is a major advantage.

**BBB:** Ligand B (74.292) has a much better BBB penetration score than Ligand A (40.791). This is *critical* for a CNS target like DRD2.

**Caco-2 Permeability:** Ligand A (-5.325) has a more negative Caco-2 value, indicating *lower* intestinal absorption. Ligand B (-4.421) is better, but still negative.

**Aqueous Solubility:** Both ligands have negative solubility values (A: -2.195, B: -3.922), indicating poor aqueous solubility. This is a concern, but can sometimes be mitigated through formulation.

**hERG Inhibition:** Both ligands have low hERG inhibition liability (A: 0.647, B: 0.705), which is good.

**Microsomal Clearance:** Ligand A (-28.65) has a much lower (better) microsomal clearance than Ligand B (68.538), indicating greater metabolic stability.

**In vitro Half-Life:** Ligand A (31.918) has a significantly longer half-life than Ligand B (-3.499).

**P-gp Efflux:** Ligand A (0.084) has lower P-gp efflux liability than Ligand B (0.574), which is favorable for CNS exposure.

**Binding Affinity:** Ligand A (-8.6) has a significantly stronger binding affinity than Ligand B (-7.0). This is a substantial advantage, potentially outweighing some ADME drawbacks.

**Overall Assessment:**

Ligand A excels in binding affinity, DILI risk, metabolic stability (Cl_mic and t1/2), and P-gp efflux. However, it suffers from lower BBB penetration and Caco-2 permeability. Ligand B has a much better BBB score, but weaker affinity, higher DILI risk, poorer metabolic stability, and higher P-gp efflux.

Given the GPCR-specific priorities, BBB is paramount for a CNS target. However, the substantial affinity difference (-8.6 vs -7.0 kcal/mol) and the significantly better safety profile (DILI, metabolic stability, P-gp) of Ligand A are compelling. The lower BBB score of Ligand A is a concern, but could potentially be addressed through structural modifications during lead optimization. The strong binding affinity suggests a higher probability of achieving efficacy, and the better ADME properties (excluding solubility and Caco-2) contribute to a more favorable overall profile.

Output:
1
2025-04-17 09:05:39,319 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (398.432 Da) is slightly higher than Ligand B (360.443 Da), but both are acceptable.

**TPSA:** Ligand A (83.47) is better than Ligand B (101.8). For CNS targets, we want TPSA <= 90, and A is closer to this threshold.

**logP:** Both ligands have similar logP values (A: 1.178, B: 1.144), falling within the optimal range of 1-3.

**H-Bond Donors/Acceptors:** Ligand A (HBD=0, HBA=6) is preferable to Ligand B (HBD=2, HBA=7) as fewer hydrogen bond donors generally improve BBB penetration. Both are within acceptable limits.

**QED:** Both ligands have similar QED values (A: 0.761, B: 0.721), indicating good drug-like properties.

**DILI:** Both ligands have similar DILI risk (A: 57.348, B: 59.519), and are both acceptable (below 60).

**BBB:** This is a critical parameter for CNS targets. Ligand A (89.492) is significantly better than Ligand B (47.15). A value >70 is desirable, and A is much closer to this.

**Caco-2 Permeability:** Ligand A (-4.734) is better than Ligand B (-5.567), indicating better intestinal absorption.

**Aqueous Solubility:** Ligand A (-2.885) is better than Ligand B (-2.119).

**hERG Inhibition:** Both ligands have very low hERG inhibition risk (A: 0.263, B: 0.207), which is excellent.

**Microsomal Clearance:** Ligand A (15.909) is slightly higher than Ligand B (13.481), suggesting slightly lower metabolic stability.

**In vitro Half-Life:** Ligand A (-24.441) is significantly worse than Ligand B (13.736), indicating a much shorter half-life.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (A: 0.06, B: 0.12), which is good for CNS penetration.

**Binding Affinity:** Ligand B (-8.1) has a slightly better binding affinity than Ligand A (-7.9). However, the difference is only 0.2 kcal/mol, which is not substantial enough to outweigh the other advantages of Ligand A.

**Overall:**

Ligand A is superior due to its significantly better BBB penetration (89.492 vs 47.15), lower TPSA, better solubility, and better Caco-2 permeability. While Ligand B has a slightly better binding affinity and half-life, the improved CNS penetration properties of Ligand A are more critical for a DRD2 target. The slightly worse half-life of A could potentially be addressed through structural modifications.

Output:
1
2025-04-17 09:05:39,319 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B based on the provided guidelines, prioritizing GPCR-specific properties (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (345.487 and 352.387 Da) fall within the ideal range of 200-500 Da.

**TPSA:** Ligand A (43.86) is significantly better than Ligand B (106.87). For CNS targets, TPSA should be <=90, so Ligand A is much more favorable.

**logP:** Both ligands have acceptable logP values (1.605 and 0.973, respectively), falling within the 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A (0 HBD, 3 HBA) is preferable to Ligand B (2 HBD, 6 HBA) as lower counts generally improve permeability. Both are within acceptable limits.

**QED:** Both ligands have good QED scores (0.562 and 0.675), indicating drug-like properties.

**DILI:** Ligand A (6.592) has a much lower DILI risk than Ligand B (58.976), which is a significant advantage.

**BBB:** Both have good BBB penetration (61.613 and 69.446), but Ligand B is slightly better. However, the TPSA difference is more impactful.

**Caco-2 Permeability:** Both have negative Caco-2 values (-4.631 and -4.574), which is unusual and suggests poor permeability. This is a concern for both.

**Aqueous Solubility:** Both have negative solubility values (-0.968 and -2.865), indicating poor solubility. This is a drawback for both.

**hERG:** Both ligands show low hERG inhibition liability (0.307 and 0.24), which is good.

**Microsomal Clearance:** Ligand A (-10.9) has much lower (better) microsomal clearance than Ligand B (68.834), suggesting greater metabolic stability.

**In vitro Half-Life:** Ligand A (-4.708) has a negative half-life, which is unusual, but still better than Ligand B (1.935).

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.042 and 0.068), which is favorable for CNS penetration.

**Binding Affinity:** Ligand A (-7.5) has slightly better binding affinity than Ligand B (-7.3), although the difference is relatively small.

**Overall Assessment:**

Ligand A is the stronger candidate. Its significantly lower TPSA and DILI risk, coupled with its better metabolic stability (lower Cl_mic) and slightly better binding affinity, outweigh the slightly better BBB penetration of Ligand B. The poor Caco-2 and solubility are concerns for both, but can be addressed with formulation strategies. The TPSA is a critical factor for CNS penetration, and Ligand A's value is much closer to the ideal range.

Output:
1
2025-04-17 09:05:39,319 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (353.463 and 362.547 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (73.32) is better than Ligand B (68.52). Both are below the 90 A^2 threshold desirable for CNS targets, but A is closer to the ideal.

**logP:** Ligand A (-0.071) is suboptimal, being slightly below 1. Ligand B (3.228) is within the optimal 1-3 range. This is a significant advantage for Ligand B.

**H-Bond Donors:** Both have 1 HBD, which is acceptable.

**H-Bond Acceptors:** Ligand A has 5 HBA, and Ligand B has 7. Both are within the acceptable limit of 10.

**QED:** Both ligands have similar QED values (0.724 and 0.7), indicating good drug-likeness.

**DILI:** Ligand A (6.941) has a significantly lower DILI risk than Ligand B (53.625). This is a strong positive for Ligand A.

**BBB:** Ligand A (60.644) is better than Ligand B (49.128), but neither is above the desirable 70% threshold for CNS targets. However, for a CNS target, maximizing BBB is crucial, and A is better.

**Caco-2:** Both have negative Caco-2 values (-4.453 and -5.701), which is unusual and suggests poor permeability.

**Solubility:** Ligand A (0.06) has very poor solubility, while Ligand B (-3.07) is also poor.

**hERG:** Ligand A (0.222) has a lower hERG risk than Ligand B (0.41).

**Microsomal Clearance:** Ligand A (6.165) has lower clearance than Ligand B (53.347), indicating better metabolic stability.

**In vitro Half-Life:** Ligand A (0.256) has a very short half-life, while Ligand B (47.641) has a longer one.

**P-gp:** Ligand A (0.015) has significantly lower P-gp efflux liability than Ligand B (0.269). This is a major advantage for CNS penetration.

**Binding Affinity:** Ligand A (-7.5 kcal/mol) has a stronger binding affinity than Ligand B (-6.2 kcal/mol). This difference of 1.3 kcal/mol is substantial and can outweigh some ADME drawbacks.

**Overall Assessment:**

Ligand A excels in binding affinity, DILI risk, P-gp efflux, and metabolic stability. However, it suffers from poor solubility, a low BBB, and a very short half-life. Ligand B has a better logP and half-life, but has higher DILI risk, P-gp efflux, and a weaker binding affinity.

Given the GPCR-specific priorities, and the importance of CNS penetration for a DRD2 target, the stronger binding affinity of Ligand A, coupled with its lower P-gp efflux and DILI, make it the more promising candidate *despite* its solubility and BBB limitations. The affinity difference is significant enough to potentially overcome these issues with formulation strategies.

Output:
0
2025-04-17 09:05:39,320 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (358.479 and 352.475 Da) are within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (99.1) is slightly higher than Ligand B (87.66). Both are below the 140 threshold for oral absorption, but only Ligand B is closer to the preferred <90 for CNS targets.

**3. logP:** Ligand A (0.821) is a bit low, potentially hindering permeation. Ligand B (1.386) is better, falling within the optimal 1-3 range.

**4. H-Bond Donors:** Both ligands have 3 HBDs, which is acceptable.

**5. H-Bond Acceptors:** Ligand A has 5 HBAs, and Ligand B has 4. Both are within the acceptable limit of 10.

**6. QED:** Both ligands have good QED scores (0.567 and 0.604), indicating drug-like properties.

**7. DILI:** Ligand A (8.841) has a significantly lower DILI risk than Ligand B (18.922), which is a substantial advantage.

**8. BBB:** Both ligands have similar BBB penetration (42.962 and 44.203). Neither is above the desirable 70% threshold, but this is less critical if other properties are favorable.

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.954 and -5.11), which is unusual and suggests poor permeability. This is a significant concern for both.

**10. Aqueous Solubility:** Both ligands have negative solubility values (-0.914 and -2.166), indicating very poor aqueous solubility. This is a major drawback for both.

**11. hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.158 and 0.09).

**12. Microsomal Clearance:** Ligand A (16.571) has a lower microsomal clearance than Ligand B (35.882), suggesting better metabolic stability.

**13. In vitro Half-Life:** Ligand A (-7.856) has a longer in vitro half-life than Ligand B (-6.767).

**14. P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.024 and 0.007).

**15. Binding Affinity:** Both ligands have excellent binding affinity (-7.2 and -7.1 kcal/mol). The difference is minimal.

**Overall Assessment:**

While both ligands have good binding affinity and low hERG/P-gp liabilities, Ligand A is preferable due to its significantly lower DILI risk, better metabolic stability (lower Cl_mic, longer t1/2), and slightly better TPSA. The slightly lower logP of Ligand A is a minor concern compared to the DILI risk of Ligand B. Both suffer from poor predicted solubility and permeability, but these could potentially be addressed with formulation strategies. Given the CNS target, the lower DILI and better metabolic profile of Ligand A make it a more promising starting point.

Output:
0
2025-04-17 09:05:39,320 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (344.459 and 351.535 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (67.23) is slightly higher than Ligand B (52.65). For CNS targets, we want TPSA <= 90, so both are acceptable, but B is better.

**3. logP:** Both ligands have good logP values (2.419 and 2.818), falling within the optimal 1-3 range.

**4. H-Bond Donors:** Both have 1 HBD, which is within the acceptable limit of <=5.

**5. H-Bond Acceptors:** Ligand A has 4 HBAs, and Ligand B has 3. Both are below the acceptable limit of <=10.

**6. QED:** Both ligands have similar QED values (0.7 and 0.718), indicating good drug-likeness.

**7. DILI:** Ligand A (28.887) has a slightly higher DILI risk than Ligand B (6.437), but both are below the concerning threshold of 40.

**8. BBB:** Ligand B (79.256) has a significantly better BBB penetration percentile than Ligand A (71.888). This is a crucial factor for CNS targets like DRD2.

**9. Caco-2 Permeability:** Both have negative values (-4.642 and -4.627), which is unusual and suggests poor permeability. This is a red flag for both.

**10. Aqueous Solubility:** Both have negative values (-2.444 and -1.894), which is also unusual and suggests poor solubility.

**11. hERG Inhibition:** Both ligands have low hERG inhibition liability (0.48 and 0.614), which is good.

**12. Microsomal Clearance:** Ligand B (23.924) has significantly lower microsomal clearance than Ligand A (43.737), indicating better metabolic stability.

**13. In vitro Half-Life:** Ligand B (-10.998) has a slightly better (less negative) in vitro half-life than Ligand A (-13.649), suggesting slightly better stability.

**14. P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.104 and 0.034), which is favorable for CNS penetration.

**15. Binding Affinity:** Ligand B (-7.2 kcal/mol) has a slightly better binding affinity than Ligand A (-7.0 kcal/mol), although the difference is small.

**Overall Assessment:**

Considering the GPCR-specific priorities, Ligand B is the better candidate. It has a significantly better BBB percentile and lower microsomal clearance, both critical for CNS drug development. While both have issues with Caco-2 and solubility, the improved BBB and metabolic stability of Ligand B outweigh the slightly better affinity of Ligand A.

Output:
1
2025-04-17 09:05:39,320 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (385.421 Da) is slightly higher, but acceptable. Ligand B (350.459 Da) is also good.

**TPSA:** Ligand A (81.93) is borderline for CNS targets (ideally <90), while Ligand B (70.08) is well within the desired range. This favors Ligand B.

**logP:** Ligand A (2.892) is optimal. Ligand B (0.879) is a bit low, potentially hindering membrane permeability. This favors Ligand A.

**H-Bond Donors/Acceptors:** Both have acceptable HBD (1) and HBA (Ligand A: 8, Ligand B: 4) counts.

**QED:** Both ligands have good QED scores (Ligand A: 0.497, Ligand B: 0.772), suggesting reasonable drug-likeness. Ligand B is better here.

**DILI:** Ligand A (95.812) has a very high DILI risk, which is a significant concern. Ligand B (23.42) has a low DILI risk, a major advantage.

**BBB:** Ligand A (65.413) has a moderate BBB penetration, while Ligand B (43.815) is lower. While both aren't ideal (>70), Ligand A is better.

**Caco-2 Permeability:** Ligand A (-5.093) and Ligand B (-4.524) both have negative values, which is unusual and suggests poor permeability.

**Aqueous Solubility:** Both have poor aqueous solubility (-4.015 and -2.044 respectively).

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.452 and 0.353 respectively).

**Microsomal Clearance:** Ligand A (67.779) has higher clearance than Ligand B (42.125), indicating lower metabolic stability. Ligand B is favored.

**In vitro Half-Life:** Ligand A (4.29 hours) has a slightly longer half-life than Ligand B (2.667 hours).

**P-gp Efflux:** Both have low P-gp efflux liability (0.254 and 0.12 respectively).

**Binding Affinity:** Ligand B (-7.7 kcal/mol) has a significantly better binding affinity than Ligand A (-8.2 kcal/mol). A 0.5 kcal/mol difference is substantial.

**Overall Assessment:**

Ligand B is the more promising candidate. While its logP is a bit low and BBB is not ideal, its significantly lower DILI risk and superior binding affinity outweigh these drawbacks. The higher QED score also contributes to its favorability. Ligand A's extremely high DILI risk is a major red flag, making it less likely to progress despite its slightly better BBB and half-life. The binding affinity difference is also important, and favors Ligand B.



Output:
1
2025-04-17 09:05:39,320 - INFO - Reasoning:
Let's analyze both ligands against the provided guidelines, prioritizing GPCR-specific properties (BBB, logP, Pgp, TPSA, and affinity).

**Ligand A:**

*   **MW:** 349.431 Da - Good. Within the ideal range.
*   **TPSA:** 82.97 A<sup>2</sup> - Excellent. Well below the 90 A<sup>2</sup> threshold for CNS targets.
*   **logP:** 1.523 - Good. Within the optimal range.
*   **HBD:** 1 - Good. Low, suggesting good permeability.
*   **HBA:** 5 - Good. Within the acceptable range.
*   **QED:** 0.842 - Excellent. Highly drug-like.
*   **DILI:** 21.869 - Excellent. Very low risk of liver injury.
*   **BBB:** 58.123 - Moderate. Below the desirable 70% for CNS targets, a significant drawback.
*   **Caco-2:** -4.568 - Poor. Indicates poor intestinal absorption.
*   **Solubility:** -1.307 - Poor. Suggests low aqueous solubility.
*   **hERG:** 0.268 - Excellent. Very low risk of hERG inhibition.
*   **Cl_mic:** -3.641 - Excellent. Suggests high metabolic stability.
*   **t1/2:** -0.627 - Moderate.
*   **Pgp:** 0.022 - Excellent. Low P-gp efflux, which is beneficial for CNS penetration.
*   **Affinity:** -6.9 kcal/mol - Good. Strong binding affinity.

**Ligand B:**

*   **MW:** 352.399 Da - Good. Within the ideal range.
*   **TPSA:** 123.22 A<sup>2</sup> - Moderate. Above the ideal 90 A<sup>2</sup> for CNS targets, but still potentially acceptable.
*   **logP:** -0.973 - Poor. Below the optimal range, potentially hindering permeation.
*   **HBD:** 2 - Good.
*   **HBA:** 10 - Acceptable. At the upper limit.
*   **QED:** 0.523 - Moderate. Acceptable, but not exceptional.
*   **DILI:** 56.999 - Moderate. Higher than Ligand A, but still within an acceptable range.
*   **BBB:** 73.788 - Excellent. Very good BBB penetration, a key advantage for a CNS target.
*   **Caco-2:** -5.316 - Poor. Indicates poor intestinal absorption.
*   **Solubility:** -0.33 - Poor. Suggests low aqueous solubility.
*   **hERG:** 0.264 - Excellent. Very low risk of hERG inhibition.
*   **Cl_mic:** 36.667 - Poor. High microsomal clearance, indicating lower metabolic stability.
*   **t1/2:** 20.914 - Excellent. Long half-life.
*   **Pgp:** 0.11 - Good. Low P-gp efflux.
*   **Affinity:** -7.0 kcal/mol - Excellent. Slightly better affinity than Ligand A.

**Comparison & Decision:**

Both compounds have poor Caco-2 and solubility. However, for a CNS target like DRD2, BBB penetration is critical. Ligand B has a significantly higher BBB percentile (73.788) compared to Ligand A (58.123). While Ligand A has better metabolic stability (lower Cl_mic), Ligand B's slightly improved binding affinity (-7.0 vs -6.9 kcal/mol) and excellent BBB penetration outweigh this drawback. The longer half-life of Ligand B is also a positive. Ligand A's low BBB is a major concern for CNS activity.

Output:
1
2025-04-17 09:05:39,320 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (367.921 and 359.373 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (44.81) is excellent, well below the 90 A^2 threshold for CNS targets. Ligand B (93.87) is higher, but still potentially acceptable, though less ideal.

**logP:** Ligand A (3.086) is optimal (1-3). Ligand B (0.381) is quite low, which could hinder membrane permeability and CNS penetration.

**H-Bond Donors/Acceptors:** Both ligands have acceptable HBD (1) and HBA (A: 3, B: 5) counts, well within the guidelines.

**QED:** Both ligands have good QED scores (A: 0.729, B: 0.74), indicating good drug-like properties.

**DILI:** Ligand A (11.594) has a very low DILI risk. Ligand B (26.677) is also relatively low, but higher than A.

**BBB:** Ligand A (91.857) has excellent BBB penetration potential, exceeding the desirable >70% threshold. Ligand B (57.929) is significantly lower, raising concerns about CNS exposure.

**Caco-2 Permeability:** Both have negative values, which is unusual and suggests either poor permeability or an issue with the prediction method. However, the magnitude of the negative value for Ligand A (-4.214) is smaller than for Ligand B (-4.698), suggesting slightly better permeability.

**Aqueous Solubility:** Both have negative values, indicating poor aqueous solubility. Ligand A (-2.413) is slightly better than Ligand B (-0.904).

**hERG Inhibition:** Both ligands show low hERG inhibition risk (A: 0.802, B: 0.501).

**Microsomal Clearance:** Ligand A (42.81) has a moderate clearance, while Ligand B (-8.018) has a *negative* clearance, which is not physically possible and indicates a prediction error. This is a major red flag for Ligand B.

**In vitro Half-Life:** Ligand A (46.846) has a reasonable half-life. Ligand B (-19.347) has a negative half-life, also indicating a prediction error.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (A: 0.084, B: 0.031), which is favorable for CNS penetration.

**Binding Affinity:** Ligand A (-7.8 kcal/mol) has a significantly stronger binding affinity than Ligand B (-6.3 kcal/mol). This 1.5 kcal/mol difference is substantial and can outweigh minor ADME drawbacks.

**Conclusion:**

Considering all factors, especially the GPCR-specific priorities, **Ligand A is the far superior candidate.** It has excellent BBB penetration, optimal logP, good TPSA, strong binding affinity, and low DILI risk. While its solubility and Caco-2 permeability are not ideal, they are better than Ligand B's. Critically, Ligand B has physically impossible predictions for clearance and half-life, making it a highly unreliable candidate. The significantly better affinity of Ligand A further solidifies its advantage.

Output:
1
2025-04-17 09:05:39,321 - INFO - Okay, let's analyze these two ligands for their potential as DRD2 drug candidates. DRD2 is a GPCR in the CNS, so BBB penetration, logP, Pgp efflux, TPSA, and binding affinity are paramount.

**Ligand A:** [337.423, 58.38, 3.538, 0, 5, 0.835, 65.491, 73.827, -4.58, -5.488, 0.797, 86.717, 16.643, 0.406, 0]
**Ligand B:** [352.341, 80.37, 2.006, 1, 5, 0.893, 60.14, 55.797, -5.054, -2.146, 0.47, -15.749, 7.187, 0.036, -8.2]

**Step-by-step comparison:**

1. **MW:** Both ligands are within the ideal range (200-500 Da). A (337.423) is slightly preferred as it's lower.
2. **TPSA:** A (58.38) is excellent for CNS penetration (well below 90). B (80.37) is still acceptable but less ideal.
3. **logP:** A (3.538) is optimal. B (2.006) is a bit low, potentially hindering membrane permeability.
4. **HBD:** A (0) is good. B (1) is acceptable.
5. **HBA:** Both A (5) and B (5) are within the ideal range.
6. **QED:** Both A (0.835) and B (0.893) are excellent, indicating good drug-like properties.
7. **DILI:** A (65.491) is moderately high, a potential concern. B (60.14) is slightly better.
8. **BBB:** A (73.827) is very good, exceeding the 70% threshold for CNS targets. B (55.797) is significantly lower, a major drawback.
9. **Caco-2:** Both are negative, indicating poor permeability. This is unusual and requires further investigation, but we'll proceed assuming it's a data artifact or indicates active efflux.
10. **Solubility:** Both are negative, indicating poor solubility. This is also a concern.
11. **hERG:** A (0.797) is preferable to B (0.47), indicating lower cardiotoxicity risk.
12. **Cl_mic:** A (86.717) is high, suggesting rapid metabolism. B (-15.749) is *extremely* low, indicating excellent metabolic stability. This is a significant advantage for B.
13. **t1/2:** A (16.643) is reasonable. B (7.187) is shorter, potentially requiring more frequent dosing.
14. **Pgp:** A (0.406) is better than B (0.036), meaning A is less likely to be effluxed.
15. **Affinity:** B (-8.2) is *significantly* stronger than A (0). A difference of >1.5 kcal/mol is considered substantial.

**Overall Assessment:**

While Ligand A has better BBB penetration and Pgp properties, Ligand B's *much* stronger binding affinity and excellent metabolic stability (very low Cl_mic) are compelling advantages. The lower logP and BBB for B are concerns, but the binding affinity difference is so large that it could potentially overcome these issues. The DILI risk for both is moderate, but manageable. The poor Caco-2 and solubility are shared concerns that would need to be addressed in further optimization.

Given the importance of potency for GPCR ligands, and the substantial advantage in binding affinity for Ligand B, I would prioritize it for further development, despite its lower BBB and logP. These properties could be improved through medicinal chemistry efforts.

Output:
1
2025-04-17 09:05:39,321 - INFO - Reasoning:

Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (356.304 and 371.413 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (95.99) is slightly above the optimal <90 for CNS targets, but still reasonably acceptable. Ligand B (73.14) is excellent, well below 90.

**3. logP:** Both ligands have good logP values (1.767 and 2.507), falling within the 1-3 range.

**4. H-Bond Donors:** Ligand A has 3 HBD, which is acceptable. Ligand B has 0, which is also good.

**5. H-Bond Acceptors:** Ligand A has 4 HBA, acceptable. Ligand B has 7, which is still within the reasonable limit of 10.

**6. QED:** Both ligands have the same QED score of 0.713, indicating good drug-likeness.

**7. DILI:** Ligand A (65.568) has a higher DILI risk than Ligand B (41.295). This is a significant negative for Ligand A.

**8. BBB:** Ligand B (93.486) has a significantly better BBB penetration score than Ligand A (70.143). This is a crucial factor for a CNS target like DRD2.

**9. Caco-2 Permeability:** Both have negative values, which is unusual. However, the magnitude is more important. Ligand B (-4.36) is slightly better than Ligand A (-5.318).

**10. Aqueous Solubility:** Both have negative values, indicating poor solubility. Ligand B (-3.922) is slightly better than Ligand A (-4.164).

**11. hERG Inhibition:** Both ligands have low hERG inhibition risk (0.576 and 0.489).

**12. Microsomal Clearance:** Ligand A (1.711) has much lower microsomal clearance than Ligand B (48.668), suggesting better metabolic stability.

**13. In vitro Half-Life:** Ligand B (-3.597) has a negative half-life, which is concerning and likely an error or indicates very rapid degradation. Ligand A (10.743) has a reasonable half-life.

**14. P-gp Efflux:** Both have low P-gp efflux liability (0.32 and 0.218).

**15. Binding Affinity:** Ligand A (-9.4 kcal/mol) has a significantly stronger binding affinity than Ligand B (-6.7 kcal/mol). This is a substantial advantage.

**Overall Assessment:**

While Ligand A has a superior binding affinity, Ligand B presents a more favorable ADME profile, particularly regarding BBB penetration (critical for a CNS target), DILI risk, and *potentially* metabolic stability (although the negative half-life for B is a major concern). The significantly better BBB score and lower DILI risk of Ligand B, combined with acceptable logP and TPSA, outweigh the affinity difference. The negative half-life for Ligand B is a red flag, but the other properties are so much better that it warrants further investigation to determine if the half-life is an experimental error. Ligand A's higher DILI risk is a significant concern.

Output:
1
2025-04-17 09:05:39,321 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (365.377 Da) is slightly higher than Ligand B (344.375 Da), but both are acceptable.

**TPSA:** Ligand A (96.97) is excellent for CNS penetration, falling well below the 90 A^2 threshold. Ligand B (124.1) is still reasonable, but less optimal, being above 90 A^2.

**logP:** Ligand A (-0.474) is a bit low, potentially hindering membrane permeability. Ligand B (0.494) is better, falling within the optimal range of 1-3, though still on the lower end.

**H-Bond Donors/Acceptors:** Ligand A (HBD=2, HBA=5) and Ligand B (HBD=3, HBA=6) both have acceptable numbers of H-bond donors and acceptors.

**QED:** Both ligands have good QED scores (Ligand A: 0.403, Ligand B: 0.742), indicating reasonable drug-likeness. Ligand B is significantly better here.

**DILI:** Ligand A (31.718) has a much lower DILI risk than Ligand B (67.158), which is a significant advantage.

**BBB:** Ligand A (75.843) has a much better BBB penetration score than Ligand B (22.567). This is *critical* for a CNS target like DRD2.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.043 and -5.287), which is unusual and suggests poor permeability. However, these values are on a scale where negative values are possible and don't necessarily disqualify a compound.

**Aqueous Solubility:** Both ligands have negative solubility values (-1.431 and -3.144), indicating poor aqueous solubility. This could pose formulation challenges.

**hERG Inhibition:** Both ligands show low hERG inhibition risk (Ligand A: 0.324, Ligand B: 0.132).

**Microsomal Clearance:** Ligand A (1.298) has a lower (better) microsomal clearance than Ligand B (-0.171). This suggests better metabolic stability.

**In vitro Half-Life:** Both have very short in vitro half-lives (-29.277 and -37.632), which is a concern.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (Ligand A: 0.016, Ligand B: 0.025).

**Binding Affinity:** Ligand B (-8.6 kcal/mol) has a significantly stronger binding affinity than Ligand A (-6.9 kcal/mol). This is a substantial advantage, exceeding the 1.5 kcal/mol difference threshold.

**Overall Assessment:**

While Ligand B has a superior binding affinity, Ligand A is a better overall candidate due to its significantly better BBB penetration (75.843 vs 22.567), lower DILI risk (31.718 vs 67.158), and better metabolic stability (lower Cl_mic). For a CNS target like DRD2, BBB penetration is paramount. The difference in binding affinity, while significant, can potentially be overcome with further optimization, whereas poor BBB penetration is much harder to fix. The slightly lower logP of Ligand A is a concern, but less critical than the other factors.

Output:
0
2025-04-17 09:05:39,321 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (362.539 Da and 365.861 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (49.41) is excellent, well below the 90 A^2 threshold for CNS targets. Ligand B (81.67) is higher but still acceptable, though less favorable.

**logP:** Ligand A (4.522) is slightly high, potentially leading to solubility issues or off-target interactions. Ligand B (1.151) is quite low, which could hinder membrane permeability and CNS penetration.

**H-Bond Donors/Acceptors:** Ligand A (HBD=1, HBA=3) is optimal. Ligand B (HBD=3, HBA=4) is also reasonable.

**QED:** Both ligands have good QED scores (0.518 and 0.706), indicating good drug-like properties.

**DILI:** Both ligands have acceptable DILI risk (32.959 and 41.877, both <40).

**BBB:** This is crucial for a CNS target. Ligand A has a very good BBB percentile (88.29), while Ligand B is significantly lower (46.646).

**Caco-2 Permeability:** Ligand A (-4.9) is poor, suggesting limited intestinal absorption. Ligand B (-5.206) is also poor.

**Aqueous Solubility:** Ligand A (-3.701) is poor. Ligand B (-2.711) is slightly better, but still not ideal.

**hERG Inhibition:** Ligand A (0.707) has a low risk of hERG inhibition, which is favorable. Ligand B (0.208) is even lower, presenting an even better safety profile.

**Microsomal Clearance:** Ligand A (73.63) has moderate clearance, suggesting moderate metabolic stability. Ligand B (19.136) has low clearance, indicating good metabolic stability.

**In vitro Half-Life:** Ligand A (34.487) has a reasonable half-life. Ligand B (25.685) is shorter, which might necessitate more frequent dosing.

**P-gp Efflux:** Ligand A (0.658) has moderate P-gp efflux, which is acceptable. Ligand B (0.066) has very low P-gp efflux, which is highly desirable for CNS penetration.

**Binding Affinity:** Both ligands have excellent binding affinities (-7.6 and -7.5 kcal/mol). The difference (0.1 kcal/mol) is not substantial enough to outweigh other factors.

**Overall Assessment:**

Ligand A excels in BBB penetration and has a good safety profile (DILI, hERG). However, it suffers from poor Caco-2 permeability and solubility, and a higher logP. Ligand B has excellent metabolic stability (low Cl_mic) and very low P-gp efflux, but its BBB penetration is significantly lower, and its logP is too low.

Given the emphasis on BBB for CNS GPCR targets like DRD2, and the relatively small difference in binding affinity, **Ligand A is the more promising candidate** despite its slightly higher logP and lower solubility. The strong BBB penetration is a significant advantage.

Output:
0
2025-04-17 09:05:39,322 - INFO - Batch 504 complete. Total preferences: 8064
2025-04-17 09:05:39,322 - INFO - Processing batch 505/512...
2025-04-17 09:06:22,195 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (342.311 and 353.507 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (134.33) is borderline for CNS penetration, slightly above the preferred <90, but acceptable. Ligand B (70.67) is excellent, well below 90, suggesting good CNS penetration.

**logP:** Ligand A (3.089) is optimal. Ligand B (1.543) is a bit low, potentially hindering membrane permeability, but not drastically.

**H-Bond Donors/Acceptors:** Ligand A has 3 HBD and 6 HBA, which are reasonable. Ligand B has 2 HBD and 4 HBA, also good. Both are within acceptable limits.

**QED:** Both ligands have good QED scores (0.465 and 0.694), indicating drug-like properties. Ligand B is slightly better.

**DILI:** Ligand A has a DILI risk of 85.731, which is high and concerning. Ligand B has a much lower DILI risk of 5.235, a significant advantage.

**BBB:** Ligand A's BBB penetration (34.742) is poor, a major drawback for a CNS target. Ligand B's BBB penetration (72.043) is good, exceeding the 70% threshold.

**Caco-2 Permeability:** Both have negative Caco-2 values (-5.249 and -4.887), which is unusual and suggests poor permeability. This is a red flag for both, but the scale is not clearly defined, making it hard to interpret.

**Aqueous Solubility:** Both have negative solubility values (-5.32 and -1.682), again unusual and suggesting poor solubility. This is a concern for both, but less so for Ligand B.

**hERG:** Both ligands have low hERG inhibition risk (0.684 and 0.443).

**Microsomal Clearance:** Both have similar microsomal clearance values (25.51 and 25.256), suggesting comparable metabolic stability.

**In vitro Half-Life:** Ligand A (54.686) has a better in vitro half-life than Ligand B (2.621).

**P-gp Efflux:** Ligand A (0.317) has lower P-gp efflux, which is favorable for CNS penetration. Ligand B (0.005) has very low P-gp efflux, even more favorable.

**Binding Affinity:** Ligand A (-8.8 kcal/mol) has a significantly stronger binding affinity than Ligand B (-7.5 kcal/mol). This is a substantial advantage.

**Overall Assessment:**

Ligand A has a much stronger binding affinity and better half-life, but suffers from high DILI risk and poor BBB penetration. Its Caco-2 and solubility are also concerning. Ligand B has a lower affinity but exhibits a significantly better safety profile (low DILI), excellent BBB penetration, and very low P-gp efflux. Considering the GPCR-specific priorities, particularly BBB for a CNS target, and the critical importance of avoiding liver toxicity, Ligand B is the more promising candidate despite its slightly weaker binding. The affinity difference, while notable, might be overcome with further optimization, while mitigating the DILI and BBB issues of Ligand A would be far more challenging.

Output:
1
2025-04-17 09:06:22,196 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (340.383 and 389.279 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (79.54) is better than Ligand B (71.78). Both are below the 90 A^2 threshold desirable for CNS targets, which is excellent.

**3. logP:** Ligand A (1.58) is within the optimal 1-3 range. Ligand B (2.444) is also acceptable.

**4. H-Bond Donors:** Ligand A (0) is preferable to Ligand B (1). Fewer HBDs generally improve permeability.

**5. H-Bond Acceptors:** Ligand A (5) is better than Ligand B (4). Both are within the acceptable limit of 10.

**6. QED:** Ligand A (0.844) is significantly better than Ligand B (0.728), indicating a more drug-like profile.

**7. DILI:** Ligand A (49.632) has a slightly higher DILI risk than Ligand B (38.581), but both are well below the concerning threshold of 60.

**8. BBB:** Ligand A (83.986) has a significantly better BBB penetration percentile than Ligand B (74.913). This is a crucial factor for a CNS target like DRD2.

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.937 and -4.993), which is unusual and suggests poor permeability. This is a significant concern for both.

**10. Aqueous Solubility:** Both ligands have negative solubility values (-1.668 and -3.725), which is also unusual and suggests poor solubility. This is a significant concern for both.

**11. hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.348 and 0.423).

**12. Microsomal Clearance:** Ligand A (44.115) has higher microsomal clearance than Ligand B (31.561), indicating lower metabolic stability.

**13. In vitro Half-Life:** Ligand B (24.012) has a much longer in vitro half-life than Ligand A (3.718), which is a significant advantage.

**14. P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.014 and 0.106).

**15. Binding Affinity:** Both ligands have very similar and strong binding affinities (-8.5 and -8.1 kcal/mol). The difference is less than the 1.5 kcal/mol threshold.

**Overall Assessment:**

Ligand A is superior in terms of TPSA, QED, and crucially, BBB penetration. While Ligand B has a better half-life and slightly lower DILI risk, the significantly better BBB score for Ligand A outweighs these benefits for a CNS target like DRD2. The poor Caco-2 and solubility values are concerning for both, but can potentially be addressed with formulation strategies. The similar binding affinities mean that the ADME properties are the deciding factor.

Output:
0
2025-04-17 09:06:22,196 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (346.431 Da) is slightly lower, which could be beneficial for permeability.

**TPSA:** Ligand A (67.67) is significantly better than Ligand B (88.16). For CNS targets, TPSA should be <= 90, and A is comfortably within that range, while B is approaching the upper limit.

**logP:** Both ligands have acceptable logP values (A: 1.031, B: 1.721), falling within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A (HBD=0, HBA=5) is preferable to Ligand B (HBD=2, HBA=4). Lower HBD generally improves BBB penetration.

**QED:** Both ligands have similar QED values (A: 0.772, B: 0.692), indicating good drug-likeness.

**DILI:** Ligand A (26.483) has a much lower DILI risk than Ligand B (41.838), which is a significant advantage. Both are below the concerning threshold of 60, but A is clearly better.

**BBB:** Both ligands have good BBB penetration (A: 76.309, B: 74.292), exceeding the desirable 70% for CNS targets, though A is slightly better.

**Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and suggests a potential issue with the data or modeling. However, A (-4.839) is less negative than B (-5.283), potentially indicating slightly better permeability.

**Aqueous Solubility:** Both ligands have negative solubility values, which is also unusual. A (-0.741) is slightly better than B (-2.132).

**hERG:** Both ligands have very low hERG inhibition risk (A: 0.23, B: 0.225), which is excellent.

**Microsomal Clearance:** Ligand A (28.068) has a higher microsomal clearance than Ligand B (8.631), indicating lower metabolic stability. This is a drawback for A.

**In vitro Half-Life:** Ligand B (-18.905) has a significantly longer in vitro half-life than Ligand A (10.582), which is a major advantage.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (A: 0.057, B: 0.085), which is favorable for CNS penetration.

**Binding Affinity:** Both ligands have excellent binding affinity (A: -8.0 kcal/mol, B: -8.3 kcal/mol). B is slightly more potent, but the difference is relatively small.

**Overall Assessment:**

Ligand A excels in TPSA, DILI, and BBB, and has comparable logP, QED, hERG, and P-gp values. However, it suffers from higher microsomal clearance and a shorter half-life. Ligand B has a longer half-life and slightly better binding affinity, but has a higher TPSA and DILI risk.

Given the importance of BBB penetration and minimizing off-target effects (DILI) for a CNS target like DRD2, and the relatively small difference in binding affinity, **Ligand A** is the more promising candidate. The slightly lower metabolic stability of A could be addressed through structural modifications during lead optimization.

Output:
0
2025-04-17 09:06:22,196 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (350.459 and 367.515 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (95.5) is slightly above the preferred <90 for CNS targets, but still reasonably acceptable. Ligand B (54.9) is excellent, well below 90.

**logP:** Both ligands have good logP values (1.475 and 2.247), falling within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A has 3 HBD and 4 HBA, which are acceptable. Ligand B has 0 HBD and 6 HBA, also acceptable.

**QED:** Both ligands have reasonable QED scores (0.433 and 0.772), with Ligand B being significantly better.

**DILI:** Both ligands have low DILI risk (21.83 and 28.693), indicating a low potential for liver injury.

**BBB:** This is a critical parameter for CNS targets. Ligand A has a BBB percentile of 63.862, which is okay, but not ideal. Ligand B has a significantly higher BBB percentile of 84.606, which is very promising.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values, which is unusual and suggests poor permeability. However, these values can be unreliable and require experimental validation.

**Aqueous Solubility:** Both ligands have negative solubility values, which is also unusual. Again, experimental validation is needed.

**hERG Inhibition:** Both ligands show low hERG inhibition liability (0.077 and 0.551), which is favorable.

**Microsomal Clearance:** Ligand A has a lower Cl_mic (25.464) than Ligand B (56.695), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A has a significantly longer in vitro half-life (-32.316) than Ligand B (-3.645), indicating better stability.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.014 and 0.137), which is excellent for CNS penetration.

**Binding Affinity:** Ligand A (-8.0 kcal/mol) has a slightly better binding affinity than Ligand B (-6.6 kcal/mol). The difference of 1.4 kcal/mol is significant.

**Overall Assessment:**

Ligand B excels in BBB penetration (84.606 vs 63.862) and QED (0.772 vs 0.433). While Ligand A has better metabolic stability (lower Cl_mic, longer half-life) and slightly better binding affinity, the superior BBB penetration of Ligand B is crucial for a CNS-targeting drug. The slightly weaker affinity of Ligand B can potentially be optimized further. The unusual Caco-2 and solubility values for both compounds warrant further investigation, but the overall profile of Ligand B is more favorable for development as a DRD2 ligand.

Output:
1
2025-04-17 09:06:22,196 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (363.443 and 357.445 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (113.08) is slightly above the optimal <90 for CNS targets, but still reasonable. Ligand B (45.67) is excellent, well below 90.

**logP:** Both ligands have good logP values (1.619 and 3.113), falling within the 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A has 3 HBD and 6 HBA, which are acceptable. Ligand B has 0 HBD and 4 HBA, also acceptable.

**QED:** Both ligands have similar QED scores (0.696 and 0.681), indicating good drug-likeness.

**DILI:** Ligand A has a DILI risk of 90.733, which is high and concerning. Ligand B has a much lower DILI risk of 13.571, a significant advantage.

**BBB:** Ligand A has a BBB penetration of 50.679, which is below the desirable >70 for CNS targets. Ligand B has a very good BBB penetration of 92.4, a major advantage for a CNS-targeting drug.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.311 and -4.227). This is unusual and suggests poor permeability. However, these values are on a log scale and negative values are not uncommon, and may not be directly comparable.

**Aqueous Solubility:** Both ligands have negative solubility values (-2.922 and -1.743), indicating poor aqueous solubility.

**hERG Inhibition:** Ligand A (0.123) has a slightly lower hERG inhibition liability than Ligand B (0.747), which is preferable.

**Microsomal Clearance:** Ligand B (55.093) has a higher microsomal clearance than Ligand A (4.388), suggesting faster metabolism and potentially lower *in vivo* exposure.

**In vitro Half-Life:** Ligand A (41.396) has a longer half-life than Ligand B (8.419), which is generally desirable.

**P-gp Efflux:** Ligand A (0.062) has lower P-gp efflux liability than Ligand B (0.065), which is preferable for CNS penetration.

**Binding Affinity:** Ligand A (-9.2 kcal/mol) has a significantly stronger binding affinity than Ligand B (-6.4 kcal/mol). This is a substantial advantage, potentially outweighing some of the ADME drawbacks.

**Overall Assessment:**

While Ligand A boasts a superior binding affinity, its high DILI risk and suboptimal BBB penetration are major concerns for a CNS drug. Ligand B, despite a weaker binding affinity, exhibits a much more favorable safety profile (low DILI), excellent BBB penetration, and acceptable ADME properties. The difference in binding affinity (-2.8 kcal/mol) is significant, but the improved safety and CNS penetration of Ligand B are crucial for a DRD2-targeting drug.

Output:
1
2025-04-17 09:06:22,197 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (346.343 and 346.383 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (133.67) is slightly above the optimal <90 for CNS targets, but still reasonable. Ligand B (108.64) is better, falling comfortably below 90. This favors Ligand B.

**3. logP:** Ligand A (0.58) is quite low, potentially hindering permeability. Ligand B (1.469) is better, within the optimal 1-3 range. This is a significant advantage for Ligand B.

**4. H-Bond Donors:** Both ligands have acceptable HBD counts (4 and 3 respectively), below the threshold of 5.

**5. H-Bond Acceptors:** Both ligands have acceptable HBA counts (7 and 5 respectively), below the threshold of 10.

**6. QED:** Both ligands have good QED scores (0.601 and 0.716), indicating good drug-like properties.

**7. DILI:** Ligand A (77.549) has a higher DILI risk than Ligand B (61.07), though both are acceptable. This favors Ligand B.

**8. BBB:** Ligand A (30.05) has a very poor BBB percentile, making CNS penetration unlikely. Ligand B (36.371) is still low, but better than Ligand A. This is a critical disadvantage for Ligand A, given the CNS target.

**9. Caco-2:** Both ligands have negative Caco-2 values (-5.356 and -4.98), which is unusual and suggests poor permeability. However, these values are on a scale where negative values are possible, and direct comparison is difficult without knowing the scale's specifics.

**10. Solubility:** Both ligands have negative solubility values (-3.124 and -2.859), again suggesting poor solubility. Similar to Caco-2, interpretation is limited without knowing the scale.

**11. hERG:** Both ligands have very low hERG inhibition liability (0.28 and 0.057), which is excellent.

**12. Cl_mic:** Ligand A (19.341) has a higher microsomal clearance than Ligand B (4.568), indicating lower metabolic stability. This favors Ligand B.

**13. t1/2:** Ligand A (-26.305) has a very negative in vitro half-life, suggesting rapid metabolism. Ligand B (-14.433) is also negative, but less so. This favors Ligand B.

**14. Pgp:** Both ligands have very low P-gp efflux liability (0.019 and 0.041), which is good for CNS penetration.

**15. Binding Affinity:** Ligand B (-9.0) has a significantly stronger binding affinity than Ligand A (-8.4). This difference of 0.6 kcal/mol is substantial and can outweigh minor ADME drawbacks.

**Overall Assessment:**

Ligand B is clearly the superior candidate. It has better logP, TPSA, DILI, BBB, metabolic stability (lower Cl_mic and better t1/2), and significantly stronger binding affinity. While both ligands have issues with Caco-2 and solubility, the poor BBB penetration predicted for Ligand A is a deal-breaker for a CNS target like DRD2. The stronger binding affinity of Ligand B further solidifies its position as the more promising drug candidate.

Output:
1
2025-04-17 09:06:22,197 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (364.785 and 351.353 Da) are within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (108.49) is slightly above the preferred <90 for CNS targets, while Ligand B (82.53) is well within the range. This favors Ligand B.

**3. logP:** Both ligands have good logP values (1.913 and 1.604), falling within the optimal 1-3 range.

**4. H-Bond Donors:** Ligand A has 3 HBD, and Ligand B has 2. Both are acceptable (<=5).

**5. H-Bond Acceptors:** Both ligands have 4 HBA, which is also acceptable (<=10).

**6. QED:** Both ligands have similar and good QED values (0.725 and 0.79), indicating good drug-likeness.

**7. DILI:** Ligand A (89.841) has a higher DILI risk than Ligand B (54.556). This favors Ligand B.

**8. BBB:** This is a crucial parameter for a CNS target like DRD2. Ligand A has a BBB percentile of 26.638, which is poor. Ligand B has a much better BBB percentile of 59.248, though still not ideal (>70). This is a significant advantage for Ligand B.

**9. Caco-2 Permeability:** Both have negative values, which is unusual. However, the magnitude of the negative value for Ligand A (-5.549) is worse than that of Ligand B (-4.948), suggesting lower intestinal absorption for Ligand A.

**10. Aqueous Solubility:** Both have similar, very poor aqueous solubility (-3.232 and -3.255). This could pose formulation challenges for both.

**11. hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.033 and 0.252).

**12. Microsomal Clearance:** Ligand A has a much lower (better) microsomal clearance (-24.739) than Ligand B (7.101), indicating greater metabolic stability. This favors Ligand A.

**13. In vitro Half-Life:** Ligand A has a longer in vitro half-life (-17.296) than Ligand B (-1.362), which is desirable. This favors Ligand A.

**14. P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.043 and 0.024), which is good.

**15. Binding Affinity:** Ligand A (-9.6 kcal/mol) has a slightly better binding affinity than Ligand B (-8.4 kcal/mol). The difference is 1.2 kcal/mol, which is significant.

**Overall Assessment:**

While Ligand A has better binding affinity, metabolic stability, and half-life, Ligand B significantly outperforms it in crucial GPCR/CNS-specific parameters: TPSA and, most importantly, BBB penetration. The lower DILI risk for Ligand B is also a positive. The affinity difference, while notable, might be overcome with further optimization of Ligand B. Given the importance of CNS penetration for a DRD2 target, Ligand B is the more promising candidate.

Output:
1
2025-04-17 09:06:22,197 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (350.419 and 352.475 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (87.91) is better than Ligand B (67.87) as it is closer to the ideal range for CNS targets (<=90).

**3. logP:** Ligand B (1.891) is better than Ligand A (0.461). A logP between 1-3 is optimal, and Ligand A's value is quite low, potentially hindering membrane permeability.

**4. H-Bond Donors:** Both have 1 HBD, which is within the acceptable limit of <=5.

**5. H-Bond Acceptors:** Ligand A has 6 HBAs, and Ligand B has 4. Both are within the acceptable limit of <=10.

**6. QED:** Both ligands have acceptable QED values (0.83 and 0.767, both >=0.5).

**7. DILI:** Ligand B (31.989) has a lower DILI risk than Ligand A (38.736), both are good (<40).

**8. BBB:** Ligand B (68.786) has a significantly better BBB penetration percentile than Ligand A (55.138). For a CNS target like DRD2, >70 is desirable, but Ligand B is closer.

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.776 and -4.682), which is unusual and suggests poor permeability. This is a significant drawback for both.

**10. Aqueous Solubility:** Both ligands have negative solubility values (-1.322 and -1.26), also unusual and suggesting poor solubility.

**11. hERG Inhibition:** Both ligands have low hERG inhibition risk (0.265 and 0.192).

**12. Microsomal Clearance:** Ligand B (31.256) has a much higher microsomal clearance than Ligand A (0.43). Lower clearance is preferred for metabolic stability, so Ligand A is better here.

**13. In vitro Half-Life:** Ligand B (12.691) has a longer in vitro half-life than Ligand A (12.193). Longer half-life is generally desirable.

**14. P-gp Efflux:** Ligand B (0.036) has a lower P-gp efflux liability than Ligand A (0.026). Lower efflux is better for CNS exposure.

**15. Binding Affinity:** Ligand A (-8.2 kcal/mol) has a significantly stronger binding affinity than Ligand B (-0.0 kcal/mol). This is a crucial factor, and a difference of >1.5 kcal/mol can outweigh other drawbacks.

**Overall Assessment:**

Despite Ligand B's better BBB, logP, and P-gp efflux, Ligand A's *much* stronger binding affinity (-8.2 vs -0.0 kcal/mol) is the deciding factor. The affinity difference is substantial. While both have poor Caco-2 and solubility, the strong binding of Ligand A suggests it might still be a viable starting point for optimization, especially given the importance of affinity for GPCR ligands. The poor permeability and solubility can be addressed through structural modifications. Ligand B's affinity is too weak to be a promising candidate.

Output:
1
2025-04-17 09:06:22,197 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (352.435 and 366.483 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (90.98) is slightly above the preferred <90 for CNS targets, while Ligand B (75.71) is well within the range. This favors Ligand B.

**logP:** Ligand A (-1.192) is too low, potentially hindering membrane permeability. Ligand B (2.585) is within the optimal 1-3 range. This is a significant advantage for Ligand B.

**H-Bond Donors/Acceptors:** Ligand A has 2 HBD and 5 HBA, while Ligand B has 1 HBD and 5 HBA. Both are acceptable within the guidelines.

**QED:** Both ligands have good QED scores (0.607 and 0.785), indicating good drug-like properties.

**DILI:** Ligand A (8.53) has a very low DILI risk, significantly better than Ligand B (46.917). This is a positive for Ligand A.

**BBB:** Ligand B (82.474) has a much higher BBB penetration percentile than Ligand A (56.65). Given that DRD2 is a CNS target, this is a crucial advantage for Ligand B.

**Caco-2 Permeability:** Ligand A (-5.135) has poor Caco-2 permeability, while Ligand B (-4.618) is slightly better, but still not great.

**Aqueous Solubility:** Ligand A (-0.862) and Ligand B (-2.877) both have poor aqueous solubility.

**hERG Inhibition:** Both ligands show low hERG inhibition risk (0.163 and 0.368).

**Microsomal Clearance:** Ligand A (-17.823) has much lower microsomal clearance (better metabolic stability) than Ligand B (73.848). This is a significant advantage for Ligand A.

**In vitro Half-Life:** Ligand A (7.355) has a shorter half-life than Ligand B (12.707).

**P-gp Efflux:** Ligand A (0.002) has very low P-gp efflux, which is excellent for CNS penetration. Ligand B (0.14) is slightly higher, but still reasonable.

**Binding Affinity:** Ligand B (-7.9 kcal/mol) has a slightly better binding affinity than Ligand A (-7.3 kcal/mol). While the difference is not huge, it's enough to consider.

**Overall Assessment:**

Ligand B excels in BBB penetration and has a good logP value, both critical for CNS GPCR targets. Its binding affinity is also slightly better. However, it has a higher DILI risk and significantly higher microsomal clearance. Ligand A has a lower DILI risk, better metabolic stability, and lower P-gp efflux, but suffers from a poor logP and lower BBB penetration.

Considering the importance of CNS penetration for a DRD2 ligand, and the slightly better affinity of Ligand B, the benefits of Ligand B outweigh its drawbacks. The lower logP of Ligand A is a major concern, potentially limiting its ability to cross the blood-brain barrier despite the lower P-gp efflux.

Output:
1
2025-04-17 09:06:22,198 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (365.455 and 364.511 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (93.5) is slightly above the ideal <90 for CNS targets, but still reasonable. Ligand B (58.64) is excellent, well below the threshold.

**logP:** Both ligands have good logP values (2.73 and 1.948), falling within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A has 2 HBD and 6 HBA, which are acceptable. Ligand B has 1 HBD and 4 HBA, also acceptable.

**QED:** Ligand B (0.832) has a significantly better QED score than Ligand A (0.457), indicating a more drug-like profile.

**DILI:** Ligand B (36.293) has a much lower DILI risk than Ligand A (63.086), which is a significant advantage.

**BBB:** Both ligands have similar BBB penetration (61.923 and 61.613), which is okay but not outstanding. Ideally, we'd want >70 for a CNS target.

**Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and suggests poor permeability. This is a concern for both.

**Aqueous Solubility:** Both have negative solubility values, which is also a concern.

**hERG Inhibition:** Both ligands show low hERG inhibition liability (0.491 and 0.232), which is positive.

**Microsomal Clearance:** Ligand A (-5.716) has a much lower (better) microsomal clearance than Ligand B (45.216), indicating greater metabolic stability.

**In vitro Half-Life:** Ligand B (8.571) has a longer half-life than Ligand A (3.778), which is desirable.

**P-gp Efflux:** Both have very low P-gp efflux liability (0.187 and 0.112), which is good for CNS penetration.

**Binding Affinity:** Ligand B (-8.2 kcal/mol) has a slightly better binding affinity than Ligand A (-7.6 kcal/mol). While the difference is not huge, it is meaningful.

**Overall Assessment:**

Ligand B is the stronger candidate. It has a significantly better QED score and a much lower DILI risk. Its binding affinity is slightly better, and its in vitro half-life is longer. While both have concerning Caco-2 and solubility values, the other advantages of Ligand B outweigh these drawbacks. Ligand A has better metabolic stability, but the other properties of Ligand B are more favorable for a CNS-targeting GPCR ligand.

Output:
1
2025-04-17 09:06:22,198 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 drug candidates, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (365.415 and 349.523 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (109.32) is higher than the preferred <90 for CNS targets, while Ligand B (64.86) is well within the range. This is a significant advantage for Ligand B.

**3. logP:** Ligand A (-0.171) is quite low, potentially hindering membrane permeability. Ligand B (3.499) is near the upper end of the optimal range (1-3), but still acceptable.

**4. H-Bond Donors:** Ligand A (2) and Ligand B (1) are both within the acceptable limit of <=5.

**5. H-Bond Acceptors:** Ligand A (7) and Ligand B (6) are both within the acceptable limit of <=10.

**6. QED:** Both ligands have good QED scores (0.765 and 0.816), indicating good drug-like properties.

**7. DILI:** Ligand A (66.731) has a higher DILI risk than Ligand B (22.8), suggesting a potentially greater risk of liver injury.

**8. BBB:** Ligand A (24.932) has a very low BBB penetration percentile, making it unlikely to effectively reach its CNS target. Ligand B (82.396) has excellent BBB penetration, a crucial factor for DRD2.

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.257 and -5.405), which is unusual and suggests poor permeability. However, these values are on a log scale and a negative number indicates low permeability.

**10. Aqueous Solubility:** Both ligands have negative solubility values (-2.432 and -2.869), indicating poor aqueous solubility.

**11. hERG Inhibition:** Both ligands have low hERG inhibition risk (0.377 and 0.407).

**12. Microsomal Clearance:** Ligand A (-28.14) has a more negative clearance value, indicating lower clearance and potentially better metabolic stability. Ligand B (28.078) has a positive value, suggesting faster clearance.

**13. In vitro Half-Life:** Ligand A (10.138) has a longer half-life than Ligand B (-0.726).

**14. P-gp Efflux:** Ligand A (0.072) has lower P-gp efflux, which is favorable for CNS penetration. Ligand B (0.189) has slightly higher P-gp efflux.

**15. Binding Affinity:** Ligand A (-7.7) has a slightly better binding affinity than Ligand B (-7.3), but the difference is relatively small (0.4 kcal/mol).

**Overall Assessment:**

Despite Ligand A's slightly better binding affinity and metabolic stability, Ligand B is the more promising candidate. The critical factors driving this decision are:

*   **BBB Penetration:** Ligand B's significantly higher BBB penetration (82.396 vs. 24.932) is paramount for a CNS target like DRD2.
*   **TPSA:** Ligand B's lower TPSA (64.86 vs. 109.32) is also highly favorable for CNS penetration.
*   **DILI Risk:** Ligand B has a much lower DILI risk.
*   **logP:** Ligand B has a more favorable logP.

The small difference in binding affinity (0.4 kcal/mol) is unlikely to outweigh the substantial advantages of Ligand B in terms of ADME properties and CNS penetration.

Output:
1
2025-04-17 09:06:22,198 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (347.5) is slightly better, being closer to the lower end which can aid permeability.

**TPSA:** Ligand A (47.56) is excellent, well below the 90 A^2 threshold for CNS targets. Ligand B (114.18) is higher, but still potentially acceptable, though less ideal.

**logP:** Ligand A (3.149) is optimal. Ligand B (0.469) is quite low, potentially hindering membrane permeability and CNS penetration.

**H-Bond Donors/Acceptors:** Ligand A (1 HBD, 4 HBA) and Ligand B (2 HBD, 7 HBA) both fall within acceptable ranges.

**QED:** Both ligands have similar QED values (A: 0.776, B: 0.644), indicating good drug-likeness.

**DILI:** Ligand A (7.135) has a significantly lower DILI risk than Ligand B (57.58), a major advantage.

**BBB:** Ligand A (64.637) has a better BBB percentile than Ligand B (61.535), though both are somewhat marginal for a CNS target (ideally >70).

**Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and suggests poor permeability. However, the scale is not specified, so it's hard to interpret.

**Aqueous Solubility:** Both have negative solubility values, which is also unusual and suggests poor solubility. Again, the scale is not specified.

**hERG Inhibition:** Ligand A (0.612) has a slightly higher hERG risk than Ligand B (0.072), but both are relatively low.

**Microsomal Clearance:** Ligand B (-6.287) has a negative clearance, which is not physically possible and indicates a data error or unusual calculation. Ligand A (40.716) is reasonable.

**In vitro Half-Life:** Ligand B (-8.055) has a negative half-life, which is also not physically possible and indicates a data error. Ligand A (16.304) is reasonable.

**P-gp Efflux:** Ligand A (0.127) has a lower P-gp efflux liability than Ligand B (0.057), which is favorable for CNS penetration.

**Binding Affinity:** Ligand A (-9.4 kcal/mol) has a significantly stronger binding affinity than Ligand B (-7.7 kcal/mol), a difference of 1.7 kcal/mol, which is substantial.

**Overall Assessment:**

Ligand A is clearly the superior candidate. It has a better logP, significantly lower DILI risk, better BBB penetration, more reasonable ADME properties (clearance and half-life), lower P-gp efflux, and, most importantly, a much stronger binding affinity. The negative values for Caco-2 and solubility are concerning but could be due to the scale used. The issues with Ligand B's clearance and half-life are major red flags, suggesting data quality issues or fundamentally unfavorable properties. The substantial difference in binding affinity (-9.4 vs -7.7 kcal/mol) is enough to overcome any minor drawbacks Ligand A might have.

Output:
1
2025-04-17 09:06:22,198 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (339.395 Da) is slightly lower, which could be beneficial for permeability. Ligand B (366.49 Da) is also well within the range.

**TPSA:** Ligand A (71.53) is excellent, falling well below the 90 A^2 threshold for CNS targets. Ligand B (108.64) is higher, but still acceptable, though less ideal for CNS penetration.

**logP:** Ligand A (2.64) is optimal. Ligand B (1.554) is a bit low, potentially hindering permeability.

**H-Bond Donors/Acceptors:** Ligand A (HBD=1, HBA=4) is favorable. Ligand B (HBD=3, HBA=5) is also acceptable, but slightly higher counts could impact permeability.

**QED:** Ligand A (0.873) is excellent, indicating high drug-likeness. Ligand B (0.662) is still good, but lower than Ligand A.

**DILI:** Ligand A (67.739) has a moderate DILI risk, while Ligand B (47.77) has a lower risk. This favors Ligand B.

**BBB:** Ligand A (78.907) has a good BBB penetration percentile. Ligand B (46.219) is significantly lower, a major drawback for a CNS target like DRD2.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.536 and -4.93), which is unusual and suggests poor permeability *in vitro*. This is a concern for both.

**Aqueous Solubility:** Both ligands have negative solubility values (-3.505 and -3.954), also unusual and problematic. This suggests very poor aqueous solubility, which would hinder bioavailability.

**hERG Inhibition:** Ligand A (0.54) has a slightly higher hERG risk than Ligand B (0.139). This favors Ligand B.

**Microsomal Clearance:** Ligand A (100.044) has a high microsomal clearance, indicating rapid metabolism. Ligand B (41.674) has a lower clearance, suggesting better metabolic stability. This favors Ligand B.

**In vitro Half-Life:** Ligand A (6.508) has a shorter half-life than Ligand B (-26.129). This favors Ligand B, although the negative value for B is concerning.

**P-gp Efflux:** Ligand A (0.155) has lower P-gp efflux, which is good for CNS penetration. Ligand B (0.078) has even lower efflux, which is even better. This favors Ligand B.

**Binding Affinity:** Ligand A (-8.9 kcal/mol) has a significantly stronger binding affinity than Ligand B (-0.0 kcal/mol). This is a *major* advantage for Ligand A, potentially outweighing some of its ADME drawbacks.

**Overall Assessment:**

Despite the concerning solubility and permeability values for both, Ligand A stands out due to its significantly superior binding affinity (-8.9 kcal/mol vs -0.0 kcal/mol). The strong binding is critical for a GPCR ligand. While Ligand B has better ADME properties in several areas (DILI, clearance, P-gp efflux), the lack of affinity makes it unlikely to be a viable candidate. The BBB penetration of Ligand A is also acceptable. The poor solubility/permeability would need to be addressed through formulation strategies, but a strong starting point with high affinity is essential.

Output:
0
2025-04-17 09:06:22,199 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (347.459 and 344.371 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (62.83) is excellent, well below the 90 A^2 threshold for CNS targets. Ligand B (126.55) is higher, but still potentially acceptable, though less ideal.

**logP:** Ligand A (2.106) is optimal (1-3). Ligand B (-0.725) is below 1, which could hinder permeation.

**H-Bond Donors/Acceptors:** Ligand A (HBD=2, HBA=5) is good. Ligand B (HBD=3, HBA=6) is also acceptable.

**QED:** Ligand A (0.854) is excellent, indicating high drug-likeness. Ligand B (0.647) is also good, but slightly lower.

**DILI:** Ligand A (21.753) has a very low DILI risk. Ligand B (34.277) is higher, but still relatively low.

**BBB:** Ligand A (69.019) is good, approaching the desirable >70% for CNS targets. Ligand B (21.171) is significantly lower, raising concerns about CNS penetration.

**Caco-2 Permeability:** Ligand A (-4.825) is poor. Ligand B (-5.346) is also poor.

**Aqueous Solubility:** Both ligands have poor aqueous solubility (-1.949 and -2.339). This could present formulation challenges.

**hERG:** Both ligands have low hERG inhibition risk (0.719 and 0.157).

**Microsomal Clearance:** Ligand A (-1.674) suggests good metabolic stability (negative value). Ligand B (-34.326) indicates very high metabolic clearance, a significant drawback.

**In vitro Half-Life:** Ligand A (6.954) has a moderate half-life. Ligand B (17.223) has a longer half-life, which is positive.

**P-gp Efflux:** Ligand A (0.044) suggests low P-gp efflux, which is favorable for CNS penetration. Ligand B (0.003) also suggests low P-gp efflux.

**Binding Affinity:** Ligand B (-8.7 kcal/mol) has a significantly stronger binding affinity than Ligand A (-7.9 kcal/mol). This 0.8 kcal/mol difference is substantial.

**Overall Assessment:**

Ligand B has a superior binding affinity, and a longer half-life. However, its logP is suboptimal, BBB penetration is poor, and it exhibits very high microsomal clearance. Ligand A has a better logP, better BBB penetration, and better metabolic stability. While its affinity is lower, the other ADME properties are more favorable for a CNS-targeting GPCR ligand. The poor Caco-2 permeability for both is a concern, but less critical for a CNS target.

Considering the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity), and the fact that the affinity difference, while significant, isn't enormous, Ligand A appears to be the more promising candidate due to its better predicted CNS penetration and metabolic stability.

Output:
1
2025-04-17 09:06:22,199 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (346.471 and 351.491 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (62.55) is significantly better than Ligand B (70.67). For CNS targets, we want TPSA <= 90, both are within this range, but A is closer to the optimal <60 range.

**logP:** Ligand A (3.381) is optimal (1-3), while Ligand B (1.153) is on the lower end, potentially hindering permeation.

**H-Bond Donors/Acceptors:** Ligand A (HBD=1, HBA=3) is preferable to Ligand B (HBD=2, HBA=4) as it has fewer hydrogen bonding groups, potentially improving permeability. Both are within acceptable limits.

**QED:** Both ligands have similar QED values (0.785 and 0.722), indicating good drug-like properties.

**DILI:** Ligand A (23.885) has a much lower DILI risk than Ligand B (10.857), a significant advantage.

**BBB:** Ligand A (67.933) has a better BBB percentile than Ligand B (46.103). While >70 is desirable, 67.933 is a reasonable starting point, whereas 46.103 is concerning for a CNS target.

**Caco-2 Permeability:** Ligand A (-4.377) is better than Ligand B (-5.149), indicating better intestinal absorption.

**Aqueous Solubility:** Ligand A (-3.48) is better than Ligand B (-0.992), which is a significant advantage for formulation and bioavailability.

**hERG Inhibition:** Ligand A (0.396) has a lower hERG risk than Ligand B (0.141), which is preferable.

**Microsomal Clearance:** Ligand A (75.12) has a higher microsomal clearance than Ligand B (0.426), indicating lower metabolic stability. This is a drawback for Ligand A.

**In vitro Half-Life:** Ligand A (49.711) has a longer half-life than Ligand B (-0.226), which is a positive attribute.

**P-gp Efflux:** Ligand A (0.249) has lower P-gp efflux liability than Ligand B (0.013), which is beneficial for CNS exposure.

**Binding Affinity:** Ligand A (-8.3 kcal/mol) has a significantly stronger binding affinity than Ligand B (-7.7 kcal/mol). This 1.5 kcal/mol difference is substantial and can outweigh some ADME drawbacks.

**Overall Assessment:**

Ligand A is the stronger candidate. It has better TPSA, logP, DILI, BBB, Caco-2 permeability, solubility, hERG, and significantly better binding affinity. While its microsomal clearance is higher than Ligand B, its superior binding affinity and overall favorable ADME profile, particularly the better BBB penetration, make it the more promising drug candidate for a CNS target like DRD2.

Output:
1
2025-04-17 09:06:22,199 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (355.385 and 353.463 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (69.41) is significantly better than Ligand B (87.74). For CNS targets, we want TPSA <= 90, and A is comfortably within this range, while B is approaching the upper limit.

**3. logP:** Ligand A (3.584) is optimal (1-3), while Ligand B (0.683) is a bit low, potentially hindering membrane permeability.

**4. H-Bond Donors:** Ligand A (1) and Ligand B (2) are both acceptable, being <= 5.

**5. H-Bond Acceptors:** Ligand A (6) and Ligand B (4) are both acceptable, being <= 10.

**6. QED:** Both ligands have similar, good QED values (0.78 and 0.705, both >= 0.5).

**7. DILI:** Ligand A (42.924) has a much lower DILI risk than Ligand B (11.361). Both are below 60, but A is significantly better.

**8. BBB:** This is critical for a CNS target. Ligand A (80.264) is excellent (>70), while Ligand B (60.644) is below the desirable threshold.

**9. Caco-2 Permeability:** Ligand A (-4.684) and Ligand B (-5.056) are both negative, indicating poor permeability. However, the scale is not specified, so it's difficult to interpret the absolute difference.

**10. Aqueous Solubility:** Ligand A (-4.005) and Ligand B (-1.482) are both negative, indicating poor solubility. Again, the scale is not specified.

**11. hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.563 and 0.198).

**12. Microsomal Clearance:** Ligand B (-11.218) has significantly lower (better) microsomal clearance than Ligand A (35.795), suggesting greater metabolic stability.

**13. In vitro Half-Life:** Ligand A (4.465) has a slightly better half-life than Ligand B (-1.65).

**14. P-gp Efflux:** Ligand A (0.181) has a much lower P-gp efflux liability than Ligand B (0.01), which is highly desirable for CNS penetration.

**15. Binding Affinity:** Both ligands have very similar and excellent binding affinities (-8.2 and -8.1 kcal/mol). The difference is negligible.

**Overall Assessment:**

Ligand A is clearly superior. While Ligand B has better metabolic stability (lower Cl_mic), Ligand A excels in crucial properties for CNS penetration: TPSA, logP, BBB, and P-gp efflux. The lower DILI risk for Ligand A is also a significant advantage. The similar binding affinities mean the ADME properties are the deciding factors.

Output:
1
2025-04-17 09:06:22,199 - INFO - Batch 505 complete. Total preferences: 8080
2025-04-17 09:06:22,199 - INFO - Processing batch 506/512...
2025-04-17 09:07:05,818 - INFO - Reasoning:

Let's analyze Ligand A and Ligand B based on the provided guidelines, prioritizing GPCR-specific properties (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight (MW):** Both ligands (355.385 and 374.393 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (65.64) is better than Ligand B (75.71). For CNS targets, we want TPSA <= 90, both are within this range, but A is closer to the optimal value.

**3. logP:** Both ligands have good logP values (1.32 and 1.834), falling within the optimal 1-3 range.

**4. H-Bond Donors (HBD):** Both have 1 HBD, which is acceptable (<=5).

**5. H-Bond Acceptors (HBA):** Ligand A has 3 HBA, and Ligand B has 4. Both are within the acceptable range of <=10.

**6. QED:** Ligand A (0.886) has a significantly better QED score than Ligand B (0.52), indicating a more drug-like profile.

**7. DILI:** Ligand A (27.801) has a lower DILI risk than Ligand B (20.047), which is preferable. Lower percentile is better.

**8. BBB:** Both ligands have good BBB penetration (77.821 and 73.711), exceeding the desirable threshold of >70 for CNS targets. Ligand A is slightly better.

**9. Caco-2 Permeability:** Ligand A (-4.538) has better Caco-2 permeability than Ligand B (-4.703). Higher values indicate better absorption.

**10. Aqueous Solubility:** Ligand A (-2.515) has better aqueous solubility than Ligand B (-1.799). Higher values are preferred.

**11. hERG Inhibition:** Both ligands have low hERG inhibition liability (0.661 and 0.312), which is good.

**12. Microsomal Clearance (Cl_mic):** Ligand A (10.507) has slightly higher microsomal clearance than Ligand B (9.148), meaning it's cleared faster. Lower is better.

**13. In vitro Half-Life:** Ligand A (-26.738) has a longer in vitro half-life than Ligand B (-23.37). Longer is better.

**14. P-gp Efflux:** Ligand A (0.045) has lower P-gp efflux than Ligand B (0.051), which is desirable for CNS exposure.

**15. Binding Affinity:** Ligand B (-7.1) has a slightly better binding affinity than Ligand A (-7.4). However, the difference is small (0.3 kcal/mol), and other factors are more important.

**Overall Assessment:**

Ligand A is the better candidate. While Ligand B has a slightly better binding affinity, Ligand A excels in several crucial ADME properties, including QED, DILI, BBB, solubility, Caco-2 permeability, and P-gp efflux. The superior QED and lower DILI risk are particularly important. The small difference in binding affinity is outweighed by the more favorable ADME profile of Ligand A, especially considering this is a CNS target where BBB penetration and efflux are critical.

Output:
1
2025-04-17 09:07:05,819 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (356.438 and 368.503 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (78.87) is significantly better than Ligand B (96.11). For CNS targets, we want TPSA <= 90, so Ligand A is preferable.

**3. logP:** Both ligands (1.187 and 1.57) are within the optimal 1-3 range.

**4. H-Bond Donors:** Ligand A (2) and Ligand B (3) are both acceptable, being <=5.

**5. H-Bond Acceptors:** Ligand A (4) and Ligand B (5) are both acceptable, being <=10.

**6. QED:** Both ligands have similar QED values (0.64 and 0.615), indicating good drug-likeness.

**7. DILI:** Ligand A (13.3) has a much lower DILI risk than Ligand B (43.738). This is a significant advantage for Ligand A.

**8. BBB:** Ligand A (72.354) has a better BBB penetration percentile than Ligand B (62.97). While both are reasonably good, exceeding 70 is desirable for CNS targets, and A is closer.

**9. Caco-2 Permeability:** Ligand A (-4.694) and Ligand B (-5.263) both have negative values. Lower Caco-2 permeability is not ideal, but the difference isn't substantial enough to be a deciding factor.

**10. Aqueous Solubility:** Ligand A (-1.796) and Ligand B (-3.359) both have negative values. Lower solubility is not ideal, but the difference isn't substantial enough to be a deciding factor.

**11. hERG Inhibition:** Both Ligand A (0.279) and Ligand B (0.22) have low hERG inhibition risk.

**12. Microsomal Clearance:** Ligand A (23.301) has lower microsomal clearance than Ligand B (32.927), indicating better metabolic stability.

**13. In vitro Half-Life:** Ligand A (-11.294) has a much longer in vitro half-life than Ligand B (6.628). This is a significant advantage for Ligand A.

**14. P-gp Efflux:** Both Ligand A (0.047) and Ligand B (0.032) have low P-gp efflux liability.

**15. Binding Affinity:** Ligand B (-7.5) has a slightly better binding affinity than Ligand A (-7.3). However, the difference is only 0.2 kcal/mol, which is not a huge advantage, and can be overcome by better ADME properties.

**Overall Assessment:**

Ligand A is the better candidate. It excels in crucial ADME properties for a CNS-targeting GPCR ligand: lower DILI risk, better BBB penetration, lower microsomal clearance, and a longer half-life. While Ligand B has slightly better binding affinity, the improvements in ADME for Ligand A are more impactful for overall drug development potential. The TPSA value for Ligand A is also more favorable.

Output:
1
2025-04-17 09:07:05,819 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (379.964 and 380.495 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (64.11) is significantly better than Ligand B (97.55). For CNS targets, we want TPSA <= 90, so Ligand A is much more favorable.

**3. logP:** Ligand A (4.744) is a bit high, potentially leading to solubility issues or off-target interactions. Ligand B (1.756) is within the optimal range (1-3).

**4. H-Bond Donors:** Ligand A (1) and Ligand B (2) are both acceptable, being <= 5.

**5. H-Bond Acceptors:** Ligand A (5) and Ligand B (7) are both acceptable, being <= 10.

**6. QED:** Both ligands have good QED scores (0.6 and 0.842), indicating good drug-like properties.

**7. DILI:** Ligand A (70.299) and Ligand B (77.433) are both acceptable, with values below 80.

**8. BBB:** Ligand A (60.295) and Ligand B (65.258) are both moderately good, but ideally, we want >70 for CNS targets. Neither is exceptional, but Ligand B is slightly better.

**9. Caco-2:** Both ligands have negative Caco-2 values (-4.658 and -5.082), which is unusual and suggests poor permeability. This is a significant concern for both.

**10. Solubility:** Both ligands have negative solubility values (-5.877 and -2.933), indicating very poor aqueous solubility. This is a major drawback for both.

**11. hERG:** Ligand A (0.602) and Ligand B (0.387) both have low hERG inhibition liability, which is good.

**12. Cl_mic:** Ligand A (120.578) has a higher microsomal clearance than Ligand B (10.434), suggesting lower metabolic stability. Ligand B is significantly better here.

**13. t1/2:** Ligand A (93.236) has a much longer in vitro half-life than Ligand B (-9.37), which is a significant advantage.

**14. Pgp:** Ligand A (0.382) has lower P-gp efflux liability than Ligand B (0.095), which is favorable for CNS penetration.

**15. Binding Affinity:** Ligand B (-8.2 kcal/mol) has a substantially stronger binding affinity than Ligand A (0.0 kcal/mol). This difference in affinity is very significant.

**Overall Assessment:**

Despite both ligands having issues with Caco-2 and solubility, the significantly stronger binding affinity of Ligand B (-8.2 kcal/mol vs 0.0 kcal/mol) and its better metabolic stability (lower Cl_mic) are decisive. While Ligand A has a better TPSA and Pgp profile, the affinity difference is large enough to outweigh these advantages. The slightly better BBB for Ligand B is also a plus. The poor solubility and permeability are serious concerns for both, but can potentially be addressed with formulation strategies.

Output:
1
2025-04-17 09:07:05,819 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (350.503 and 371.591 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (58.64) is better than Ligand B (43.86). Both are below the 90 A^2 threshold for CNS targets, which is excellent.

**logP:** Both ligands have good logP values (2.903 and 2.699), falling within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A has 1 HBD and 3 HBA, while Ligand B has 0 HBD and 4 HBA. Both are within acceptable limits (<=5 HBD and <=10 HBA).

**QED:** Both ligands have acceptable QED scores (0.685 and 0.592), indicating good drug-like properties.

**DILI:** Ligand A (13.92) has a slightly higher DILI risk than Ligand B (11.09), but both are well below the concerning threshold of 60.

**BBB:** Both ligands exhibit excellent BBB penetration (80.38% and 83.56%), exceeding the desirable 70% threshold for CNS targets. Ligand B is marginally better.

**Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and suggests a potential issue with the data or modeling. However, since both are similarly affected, it doesn't strongly differentiate them.

**Aqueous Solubility:** Both ligands have negative solubility values, again suggesting a potential data issue. Similar to Caco-2, this doesn't strongly differentiate them.

**hERG:** Both ligands have low hERG inhibition liability (0.464 and 0.563), indicating a low risk of cardiotoxicity.

**Microsomal Clearance:** Ligand A (66.412) has a higher microsomal clearance than Ligand B (42.961), suggesting lower metabolic stability. This is a significant advantage for Ligand B.

**In vitro Half-Life:** Ligand B (12.993 hours) has a considerably longer in vitro half-life than Ligand A (-7.911 hours). This is a major advantage for Ligand B, as a longer half-life can lead to less frequent dosing.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.063 and 0.082), which is favorable for CNS exposure.

**Binding Affinity:** Ligand A (-7.9 kcal/mol) has a slightly better binding affinity than Ligand B (-7.2 kcal/mol). This 0.7 kcal/mol difference is significant.

**Overall Assessment:**

While Ligand A has a slightly better binding affinity, Ligand B demonstrates superior ADME properties, particularly in terms of metabolic stability (lower Cl_mic) and longer half-life. For a CNS target like DRD2, good BBB penetration is essential, and both ligands meet this criterion. However, the improved pharmacokinetic profile of Ligand B (lower clearance, longer half-life) outweighs the small difference in binding affinity.

Output:
1
2025-04-17 09:07:05,819 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 drug candidates, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (371.507) is slightly higher than Ligand B (337.471), but both are acceptable.

**TPSA:** Ligand A (89.35) is better than Ligand B (62.73) as it is closer to the optimal range for CNS targets (<=90). Ligand B is also good, but A has a slight edge.

**logP:** Ligand A (0.857) is a bit low, potentially hindering permeation, while Ligand B (3.739) is closer to the optimal range (1-3). This is a significant advantage for Ligand B.

**H-Bond Donors/Acceptors:** Ligand A (HBD=1, HBA=7) and Ligand B (HBD=2, HBA=5) both fall within acceptable limits.

**QED:** Both ligands have good QED scores (A: 0.765, B: 0.841), indicating drug-like properties.

**DILI:** Both ligands have similar DILI risk (A: 47.15, B: 48.623), and are both within the acceptable range (<60).

**BBB:** Ligand B (82.047) has a significantly better BBB percentile than Ligand A (67.08). This is crucial for a CNS target like DRD2.

**Caco-2 Permeability:** Ligand A (-5.403) has a very poor Caco-2 permeability, suggesting poor intestinal absorption. Ligand B (-4.93) is also poor, but slightly better than A.

**Aqueous Solubility:** Ligand A (-1.539) has very poor solubility, while Ligand B (-4.053) is also poor, but slightly better.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (A: 0.48, B: 0.722).

**Microsomal Clearance:** Ligand A (-6.955) has a lower (better) microsomal clearance than Ligand B (75.095), indicating greater metabolic stability.

**In vitro Half-Life:** Ligand B (36.36) has a significantly longer half-life than Ligand A (5.257). This is a positive attribute for dosing convenience.

**P-gp Efflux:** Ligand A (0.257) has lower P-gp efflux liability than Ligand B (0.171), which is favorable for CNS penetration.

**Binding Affinity:** Ligand B (-8.5) has a slightly better binding affinity than Ligand A (-8.2), although the difference is relatively small.

**Overall Assessment:**

Ligand B is the more promising candidate. While Ligand A has better metabolic stability (lower Cl_mic) and P-gp efflux, Ligand B excels in critical areas for a CNS-targeting GPCR: significantly better BBB penetration, a longer half-life, and a slightly improved binding affinity. Ligand B's logP is also more favorable. The poor Caco-2 and solubility for both are concerning, but can potentially be addressed with formulation strategies. The slightly lower metabolic stability of Ligand B is a manageable drawback compared to the CNS penetration advantage.

Output:
1
2025-04-17 09:07:05,820 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (374.491 and 367.808 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (76.14) is significantly better than Ligand B (93.43). For CNS targets, we want TPSA <= 90, so Ligand A is preferable.

**3. logP:** Both ligands (2.807 and 2.547) are within the optimal 1-3 range.

**4. H-Bond Donors:** Both have 2 HBD, which is acceptable.

**5. H-Bond Acceptors:** Ligand A has 6 HBA, and Ligand B has 4. Both are within the acceptable limit of <=10.

**6. QED:** Both ligands have good QED scores (0.629 and 0.782), indicating drug-like properties.

**7. DILI:** Ligand A (79.721) has a higher DILI risk than Ligand B (52.734). This favors Ligand B.

**8. BBB:** Ligand B (59.597) has a significantly better BBB penetration percentile than Ligand A (23.42). This is *critical* for a CNS target like DRD2, making Ligand B strongly favored.

**9. Caco-2 Permeability:** Ligand A (-4.953) has better Caco-2 permeability than Ligand B (-4.66), but both are negative values, suggesting poor permeability.

**10. Aqueous Solubility:** Ligand A (-4.032) has better aqueous solubility than Ligand B (-3.597), but both are negative values, suggesting poor solubility.

**11. hERG Inhibition:** Both ligands have similar hERG inhibition liability (0.452 and 0.583).

**12. Microsomal Clearance:** Ligand B (2.398) has much lower microsomal clearance than Ligand A (66.805), indicating better metabolic stability.

**13. In vitro Half-Life:** Ligand B (3.037) has a longer in vitro half-life than Ligand A (-4.396).

**14. P-gp Efflux:** Ligand A (0.325) has lower P-gp efflux liability than Ligand B (0.092), which is favorable for CNS penetration.

**15. Binding Affinity:** Both ligands have the same binding affinity (-7.7 kcal/mol), which is excellent.

**Overall Assessment:**

While Ligand A has slightly better Caco-2 permeability and P-gp efflux, Ligand B is significantly better in several crucial areas for a CNS-targeting GPCR: BBB penetration, DILI risk, and metabolic stability (lower Cl_mic and longer t1/2). The TPSA value of Ligand A is also preferable. Given the importance of BBB penetration for DRD2, Ligand B is the more promising candidate.

Output:
1
2025-04-17 09:07:05,820 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (353.491 and 352.519 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (36.44) is significantly better than Ligand B (60.85). For CNS targets, we want TPSA <= 90, and ideally lower. Ligand A is well within this range, while Ligand B is approaching the upper limit and is less desirable.

**logP:** Ligand A (3.539) is slightly higher than Ligand B (2.525), both within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A (0 HBD, 4 HBA) is preferable to Ligand B (1 HBD, 3 HBA). Lower numbers generally improve permeability.

**QED:** Both ligands have good QED scores (0.775 and 0.846), indicating good drug-like properties.

**DILI:** Ligand A (61.07) has a higher DILI risk than Ligand B (14.308). This is a significant drawback for Ligand A.

**BBB:** Ligand A (85.847) has a better BBB penetration percentile than Ligand B (64.327). This is a critical factor for a CNS target like DRD2.

**Caco-2 Permeability:** Ligand A (-4.92) is worse than Ligand B (-4.423). Higher values are better.

**Aqueous Solubility:** Ligand A (-3.044) is worse than Ligand B (-2.386). Higher values are better.

**hERG:** Ligand A (0.793) is slightly higher than Ligand B (0.467), indicating a slightly higher hERG inhibition liability. Lower is better.

**Microsomal Clearance:** Ligand A (59.762) has a higher microsomal clearance than Ligand B (46.033), indicating lower metabolic stability.

**In vitro Half-Life:** Ligand B (-18.875) has a significantly longer in vitro half-life than Ligand A (-8.355).

**P-gp Efflux:** Ligand A (0.603) has a lower P-gp efflux liability than Ligand B (0.274), which is favorable for CNS penetration.

**Binding Affinity:** Ligand A (-9.1 kcal/mol) has a significantly stronger binding affinity than Ligand B (-7.9 kcal/mol). This is a substantial advantage, potentially outweighing some ADME concerns.

**Overall Assessment:**

Ligand A excels in BBB penetration and, crucially, binding affinity. However, it suffers from higher DILI risk, lower solubility, higher clearance, and worse Caco-2 permeability. Ligand B has a better safety profile (lower DILI), better solubility, and longer half-life, but its BBB penetration and binding affinity are considerably weaker.

Given the importance of strong binding affinity for GPCRs, and the relatively high BBB penetration of Ligand A, the superior affinity likely outweighs the ADME liabilities, *provided* the DILI risk can be mitigated through further structural modifications. The difference in binding affinity (1.2 kcal/mol) is significant.

Output:
1
2025-04-17 09:07:05,820 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (358.379 and 346.515 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (107.21) is higher than the preferred <90 for CNS targets, but not drastically so. Ligand B (40.62) is excellent, well below the threshold. This favors Ligand B.

**logP:** Ligand A (1.952) is within the optimal 1-3 range. Ligand B (3.312) is slightly higher, but still acceptable.

**H-Bond Donors/Acceptors:** Ligand A has 1 HBD and 8 HBA, which are reasonable. Ligand B has 0 HBD and 2 HBA, also good.

**QED:** Both ligands have similar QED values (0.671 and 0.692), indicating good drug-likeness.

**DILI:** Ligand A (95.812) has a significantly higher DILI risk than Ligand B (9.965). This is a major concern for Ligand A.

**BBB:** Ligand B (82.086) has a much better BBB penetration percentile than Ligand A (45.134). This is crucial for a CNS target like DRD2 and strongly favors Ligand B.

**Caco-2 Permeability:** Ligand A (-4.864) has a negative Caco-2 value, which is unusual and suggests poor permeability. Ligand B (-4.445) is also negative, but less so.

**Aqueous Solubility:** Both ligands have very poor aqueous solubility (-3.007 and -2.871). This could pose formulation challenges, but is less critical than BBB penetration for a CNS target.

**hERG Inhibition:** Ligand A (0.246) has a slightly higher hERG risk than Ligand B (0.536).

**Microsomal Clearance:** Ligand B (42.686) has lower microsomal clearance than Ligand A (70.569), indicating better metabolic stability.

**In vitro Half-Life:** Ligand B (-3.49) has a better in vitro half-life than Ligand A (-14.603).

**P-gp Efflux:** Ligand A (0.062) has lower P-gp efflux than Ligand B (0.119), which is favorable for CNS penetration. However, the difference is small.

**Binding Affinity:** Ligand A (-9.0) has a significantly stronger binding affinity than Ligand B (-0.0). This is a substantial advantage.

**Overall Assessment:**

While Ligand A has a superior binding affinity, its high DILI risk, poor BBB penetration, and negative Caco-2 permeability are major drawbacks. Ligand B, despite weaker binding, exhibits a much more favorable ADME profile, particularly its excellent BBB penetration, low DILI risk, and better metabolic stability. For a CNS target like DRD2, achieving brain exposure is paramount. The significantly better ADME properties of Ligand B outweigh the affinity difference.

Output:
1
2025-04-17 09:07:05,820 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B based on the provided guidelines, prioritizing GPCR-specific properties (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (341.426 Da) is slightly better being closer to the lower bound, potentially aiding permeability.

**TPSA:** Ligand A (29.54) is excellent for CNS penetration, well below the 90 A^2 threshold. Ligand B (41.57) is still reasonable but less optimal.

**logP:** Both ligands have logP values (3.973 and 4.628) within the optimal range of 1-3, but Ligand B is approaching the upper limit, potentially raising solubility concerns.

**H-Bond Donors/Acceptors:** Ligand A (0 HBD, 2 HBA) and Ligand B (1 HBD, 3 HBA) both have acceptable counts.

**QED:** Both ligands have QED values (0.842 and 0.792) indicating good drug-likeness.

**DILI:** Both ligands have moderate DILI risk (50.989 and 58.666). Ligand A is slightly better.

**BBB:** Ligand A (82.047) has a significantly better BBB percentile than Ligand B (75.107). This is a crucial advantage for a CNS target like DRD2.

**Caco-2 Permeability:** Both have negative Caco-2 values which is unusual. Assuming these are logP values, both are poor.

**Aqueous Solubility:** Both ligands have very poor aqueous solubility (-4.445 and -4.497). This is a significant drawback for both.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.835 and 0.873).

**Microsomal Clearance:** Ligand B (104.797) has a higher microsomal clearance than Ligand A (82.832), indicating lower metabolic stability.

**In vitro Half-Life:** Ligand A (-11.503) has a negative half-life, which is not possible. Ligand B (78.603) has a more reasonable half-life.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.798 and 0.846), which is good for CNS penetration.

**Binding Affinity:** Ligand B (-8.4 kcal/mol) has a stronger binding affinity than Ligand A (-9.7 kcal/mol). This is a substantial advantage.

**Overall Assessment:**

While Ligand B has a better binding affinity, Ligand A has a significantly better BBB percentile, lower microsomal clearance, and slightly lower DILI risk. The strong affinity of Ligand B is attractive, but the poor solubility of both is a major concern. Given the CNS target, BBB penetration is paramount. Furthermore, the better metabolic stability of Ligand A is a plus. The negative half-life for Ligand A is concerning and suggests a data error. However, the other factors favor Ligand A.

Output:
1
2025-04-17 09:07:05,820 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B based on the provided guidelines, prioritizing GPCR-specific properties (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (353.463 and 362.539 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (78.95) is better than Ligand B (58.2). Both are below the 90 A^2 threshold desirable for CNS targets, but A is slightly higher.

**logP:** Ligand B (4.111) is higher than Ligand A (0.633). While a logP of 4.111 is approaching the upper limit, it's still within a potentially acceptable range. Ligand A's logP is quite low, which could hinder permeation.

**H-Bond Donors/Acceptors:** Ligand A (HBD=1, HBA=4) and Ligand B (HBD=2, HBA=3) both have acceptable numbers of H-bond donors and acceptors.

**QED:** Both ligands have similar QED values (0.786 and 0.615), indicating good drug-like properties.

**DILI:** Both ligands have relatively low DILI risk (31.563 and 38.348), both below the 40 threshold.

**BBB:** Ligand B (75.998) significantly outperforms Ligand A (52.268) in BBB penetration. This is a critical factor for a DRD2 ligand targeting CNS disorders, making B more promising.

**Caco-2 Permeability:** Ligand A (-4.561) has a negative Caco-2 value, which is concerning. Ligand B (-5.131) also has a negative value, but it's not significantly worse. Both suggest poor intestinal absorption.

**Aqueous Solubility:** Ligand A (-1.263) has slightly better solubility than Ligand B (-4.192), but both are quite poor.

**hERG Inhibition:** Ligand A (0.142) shows a lower hERG inhibition risk than Ligand B (0.658).

**Microsomal Clearance:** Ligand B (82.066) has a higher microsomal clearance than Ligand A (18.916), indicating faster metabolism and potentially lower in vivo exposure.

**In vitro Half-Life:** Ligand B (11.951) has a slightly longer half-life than Ligand A (9.668).

**P-gp Efflux:** Ligand A (0.013) exhibits much lower P-gp efflux than Ligand B (0.684), which is favorable for CNS exposure.

**Binding Affinity:** Ligand B (-8.1 kcal/mol) has a significantly stronger binding affinity than Ligand A (-6.3 kcal/mol). This >1.5 kcal/mol difference is substantial and can outweigh some ADME drawbacks.

**Conclusion:**

Despite Ligand A's slightly better TPSA, solubility, lower hERG risk, and P-gp efflux, Ligand B is the more promising candidate. The significantly higher BBB penetration and substantially stronger binding affinity are critical advantages for a CNS-targeting DRD2 ligand. While its logP is higher and clearance is faster, the strong affinity suggests it may still achieve sufficient occupancy.

Output:
1
2025-04-17 09:07:05,821 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (391.559 Da) is slightly higher than Ligand B (357.523 Da), but both are acceptable.

**TPSA:** Ligand A (95.58) is borderline for CNS targets, being slightly above the preferred <90. Ligand B (46.09) is excellent, well below the threshold. This favors Ligand B.

**logP:** Ligand A (0.241) is quite low, potentially hindering membrane permeability. Ligand B (4.428) is high, potentially causing solubility issues or off-target effects, but is still within a reasonable range. This favors Ligand A slightly, as extremely high logP is more problematic.

**H-Bond Donors/Acceptors:** Ligand A has 2 HBD and 6 HBA, which is acceptable. Ligand B has 0 HBD and 4 HBA, also acceptable. No clear advantage here.

**QED:** Both ligands have good QED scores (A: 0.547, B: 0.795), indicating good drug-like properties. Ligand B is better.

**DILI:** Both have low DILI risk (A: 23.885, B: 27.685), which is positive. No significant difference.

**BBB:** This is crucial for a CNS target. Ligand A has a BBB percentile of 43.156, which is below the desirable >70. Ligand B has a BBB percentile of 89.802, which is excellent. This is a major advantage for Ligand B.

**Caco-2 Permeability:** Ligand A (-5.823) has poor Caco-2 permeability, suggesting poor absorption. Ligand B (-4.766) is also poor, but slightly better than Ligand A.

**Aqueous Solubility:** Ligand A (-1.508) has poor solubility. Ligand B (-4.196) also has poor solubility, but is slightly better than Ligand A.

**hERG Inhibition:** Both ligands have very low hERG inhibition risk (A: 0.134, B: 0.417), which is excellent. No significant difference.

**Microsomal Clearance:** Ligand A (-14.867) has a very low (good) microsomal clearance, indicating high metabolic stability. Ligand B (72.435) has a high clearance, suggesting rapid metabolism. This is a significant advantage for Ligand A.

**In vitro Half-Life:** Ligand A (-8.676) has a very long in vitro half-life, which is desirable. Ligand B (-1.373) has a shorter half-life. This favors Ligand A.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (A: 0.007, B: 0.277), which is good for CNS penetration. No significant difference.

**Binding Affinity:** Both ligands have comparable binding affinities (A: -7.0 kcal/mol, B: -7.6 kcal/mol). Ligand B is slightly better, but the difference is not substantial enough to outweigh other factors.

**Overall Assessment:**

Ligand B excels in BBB penetration and QED, which are critical for a CNS GPCR target. However, it suffers from high microsomal clearance and relatively poor solubility and Caco-2 permeability. Ligand A has a lower BBB penetration, but compensates with excellent metabolic stability (low Cl_mic, long t1/2) and slightly better solubility and Caco-2 permeability. The low logP of Ligand A is a concern, but the strong binding affinity (-7.0 kcal/mol) might overcome this. Given the importance of metabolic stability and CNS exposure for DRD2 ligands, and the significant advantage Ligand A has in these areas, I believe it is the more promising candidate.

Output:
0
2025-04-17 09:07:05,821 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (346.471 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (78.43) is higher than Ligand B (49.85). For a CNS target like DRD2, TPSA < 90 is preferred. Both are under this threshold, but B is significantly better.

**3. logP:** Both ligands (A: 2.183, B: 2.527) are within the optimal 1-3 range.

**4. H-Bond Donors:** Ligand A has 3 HBD, while Ligand B has 0. Lower HBD is generally preferred for BBB penetration, giving a slight edge to B.

**5. H-Bond Acceptors:** Both ligands have 3 HBA, which is acceptable.

**6. QED:** Both ligands have good QED scores (A: 0.675, B: 0.735), indicating drug-like properties.

**7. DILI:** Ligand A (15.394) has a lower DILI risk than Ligand B (29.081), which is favorable.

**8. BBB:** This is a critical parameter for CNS targets. Ligand B (83.172) has a significantly higher BBB percentile than Ligand A (57.464). This is a major advantage for B.

**9. Caco-2 Permeability:** Ligand A (-4.687) and Ligand B (-4.416) both have negative values, suggesting poor permeability. This is a concern for both, but the difference is minimal.

**10. Aqueous Solubility:** Both ligands have negative solubility values (A: -2.255, B: -2.092), indicating poor aqueous solubility. This could pose formulation challenges.

**11. hERG Inhibition:** Both ligands show low hERG inhibition liability (A: 0.278, B: 0.331), which is good.

**12. Microsomal Clearance:** Both ligands have similar microsomal clearance (A: 32.173, B: 32.041), suggesting comparable metabolic stability.

**13. In vitro Half-Life:** Ligand B (6.955) has a much longer in vitro half-life than Ligand A (-0.909). This is a significant advantage for B, potentially leading to less frequent dosing.

**14. P-gp Efflux:** Both ligands have low P-gp efflux liability (A: 0.058, B: 0.112), which is favorable for CNS penetration.

**15. Binding Affinity:** Ligand B (-9.2 kcal/mol) has a slightly better binding affinity than Ligand A (-8.9 kcal/mol). While the difference is not huge, it's enough to be considered, especially given the other favorable properties of B.

**Overall Assessment:**

Ligand B is the more promising candidate. Its superior BBB penetration (83.172 vs 57.464), longer half-life (6.955 vs -0.909), and slightly better binding affinity (-9.2 vs -8.9) outweigh the slightly higher DILI risk. Both ligands have solubility and Caco-2 permeability concerns, but these can potentially be addressed through formulation strategies. Given the GPCR-specific priorities, the improved CNS penetration properties of Ligand B make it the better choice.

Output:
1
2025-04-17 09:07:05,821 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (347.415 Da) is slightly lower, which could be beneficial for permeability, while Ligand B (384.707 Da) is still well within the acceptable range.

**TPSA:** Ligand A (78.95) is significantly better than Ligand B (34.15) regarding TPSA. For CNS targets, we want TPSA <= 90, and ideally lower. Ligand A is comfortably within this range, while Ligand B is excellent.

**logP:** Ligand A (2.048) is optimal, falling within the 1-3 range. Ligand B (4.784) is higher, potentially leading to solubility issues and off-target interactions.

**H-Bond Donors/Acceptors:** Both ligands have 1 HBD and a reasonable number of HBAs (5 for A, 3 for B). This is acceptable.

**QED:** Both ligands have similar QED values (0.764 and 0.728), indicating good drug-likeness.

**DILI:** Ligand A (71.539) has a higher DILI risk than Ligand B (53.548), but both are below the concerning threshold of 60.

**BBB:** Ligand B (79.488) has a better BBB percentile than Ligand A (70.803). Both are above the desired 70% threshold for CNS targets, but Ligand B is preferable.

**Caco-2 Permeability:** Ligand A (-4.635) has a worse Caco-2 permeability than Ligand B (-4.564). Both are negative, indicating poor permeability.

**Aqueous Solubility:** Ligand A (-3.321) has better aqueous solubility than Ligand B (-4.94).

**hERG Inhibition:** Ligand A (0.244) has a lower hERG inhibition liability than Ligand B (0.796), which is favorable.

**Microsomal Clearance:** Ligand A (-2.444) has a much lower (better) microsomal clearance than Ligand B (43.342), suggesting greater metabolic stability.

**In vitro Half-Life:** Ligand A (14.294 hours) has a shorter half-life than Ligand B (23.075 hours).

**P-gp Efflux:** Ligand A (0.02) has significantly lower P-gp efflux liability than Ligand B (0.553), which is crucial for CNS penetration.

**Binding Affinity:** Ligand B (-8.9 kcal/mol) has a slightly better binding affinity than Ligand A (-8.1 kcal/mol). This difference is significant (0.8 kcal/mol) and could outweigh some ADME drawbacks.

**Overall Assessment:**

Ligand B has a better BBB, slightly better affinity, and a longer half-life. However, it suffers from a higher logP, higher P-gp efflux, and significantly higher microsomal clearance. Ligand A has a much better safety profile (lower DILI, lower hERG, lower P-gp efflux, lower Cl_mic), better solubility, and a more favorable TPSA. The slightly weaker affinity of Ligand A is likely outweighed by its superior ADME properties, especially considering the importance of BBB penetration and metabolic stability for a CNS target like DRD2.

Output:
0
2025-04-17 09:07:05,821 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (350.459 Da and 386.583 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Both ligands have TPSA values (78.87 and 78.43) below the 90 A^2 threshold for CNS targets, which is excellent.

**3. logP:** Ligand A (1.071) is slightly lower than optimal (1-3) but acceptable. Ligand B (2.302) is well within the optimal range.

**4. H-Bond Donors:** Ligand A (2) and Ligand B (3) are both within the acceptable limit of <=5.

**5. H-Bond Acceptors:** Ligand A (4) and Ligand B (5) are both within the acceptable limit of <=10.

**6. QED:** Ligand A (0.798) has a better QED score than Ligand B (0.558), suggesting a more drug-like profile.

**7. DILI:** Ligand A (12.214) has a significantly lower DILI risk than Ligand B (38.697), which is a major advantage.

**8. BBB:** Ligand A (56.34) has a better BBB percentile than Ligand B (43.699), although both are below the desirable >70 for CNS targets. This is a critical factor for DRD2.

**9. Caco-2 Permeability:** Ligand A (-4.751) and Ligand B (-5.561) both have negative Caco-2 values, indicating poor permeability.

**10. Aqueous Solubility:** Ligand A (-1.851) and Ligand B (-2.774) both have poor aqueous solubility.

**11. hERG Inhibition:** Both ligands have low hERG inhibition risk (0.174 and 0.205).

**12. Microsomal Clearance:** Ligand A (-5.574) has a much lower (better) microsomal clearance than Ligand B (41.84), indicating better metabolic stability.

**13. In vitro Half-Life:** Ligand A (20.412) has a longer in vitro half-life than Ligand B (-2.444).

**14. P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.014 and 0.162).

**15. Binding Affinity:** Ligand A (-9.4 kcal/mol) has a significantly stronger binding affinity than Ligand B (-7.9 kcal/mol). The difference of 1.5 kcal/mol is substantial and can outweigh some ADME drawbacks.

**Overall Assessment:**

While both compounds have issues with Caco-2 permeability and solubility, Ligand A is significantly better across several crucial parameters. Its superior binding affinity (-9.4 vs -7.9 kcal/mol), lower DILI risk, better BBB penetration, lower microsomal clearance, and longer half-life make it a more promising candidate. The stronger binding affinity is a particularly important advantage for a GPCR target like DRD2.

Output:
1
2025-04-17 09:07:05,821 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (356.419 and 343.475 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (105.17) is higher than Ligand B (68.77). For a CNS target like DRD2, TPSA should ideally be <=90. Ligand B is much closer to this threshold, giving it an advantage.

**3. logP:** Ligand A (-0.167) is quite low, potentially hindering membrane permeability. Ligand B (3.835) is within the optimal 1-3 range. This is a significant advantage for Ligand B.

**4. H-Bond Donors:** Ligand A (2) and Ligand B (1) are both acceptable, being <=5.

**5. H-Bond Acceptors:** Both ligands (6) are within the acceptable range of <=10.

**6. QED:** Both ligands have good QED scores (0.416 and 0.738), indicating reasonable drug-likeness. Ligand B is better.

**7. DILI:** Ligand A (17.642) has a lower DILI risk than Ligand B (41.024), which is a positive.

**8. BBB:** Ligand A (70.57) has a slightly better BBB percentile than Ligand B (68.554), but both are reasonably good, exceeding the 70% threshold.

**9. Caco-2 Permeability:** Both have negative values, which is unusual. Assuming these are logP-like scales, lower values indicate poorer permeability.

**10. Aqueous Solubility:** Both have negative values, indicating poor solubility.

**11. hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.162 and 0.169).

**12. Microsomal Clearance:** Ligand A (33.998) has lower microsomal clearance than Ligand B (42.749), suggesting better metabolic stability.

**13. In vitro Half-Life:** Ligand A (-15.332) has a negative half-life, which is not possible. This is a major red flag. Ligand B (22.304) is reasonable.

**14. P-gp Efflux:** Both ligands have low P-gp efflux liability (0.027 and 0.243).

**15. Binding Affinity:** Ligand B (-7.5 kcal/mol) has a significantly stronger binding affinity than Ligand A (-6.1 kcal/mol). This >1.5 kcal/mol difference is substantial and can outweigh minor ADME drawbacks.

**Overall Assessment:**

Ligand B is the stronger candidate. While Ligand A has a lower DILI risk and slightly better BBB penetration, its extremely low logP, negative in vitro half-life, and weaker binding affinity are major drawbacks. Ligand B's superior logP, significantly stronger binding affinity, and reasonable ADME properties make it the more promising drug candidate for targeting DRD2. The negative half-life for ligand A is a showstopper.

Output:
1
2025-04-17 09:07:05,822 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (364.515 and 342.443 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (75.19) is slightly higher than Ligand B (67.23). Both are below the 90 A^2 threshold for CNS targets, which is good.

**logP:** Both ligands have good logP values (2.608 and 1.856), falling within the optimal 1-3 range. Ligand B is slightly lower, which could marginally improve solubility.

**H-Bond Donors/Acceptors:** Both have 1 HBD and a reasonable number of HBAs (5 and 4 respectively), satisfying the <5 HBD and <10 HBA guidelines.

**QED:** Both ligands have high QED scores (0.807 and 0.871), indicating good drug-likeness.

**DILI:** Ligand A (36.603) has a slightly higher DILI risk than Ligand B (27.724), but both are below the concerning threshold of 60.

**BBB:** This is a critical parameter for a CNS target like DRD2. Ligand A has a significantly better BBB penetration percentile (75.223) compared to Ligand B (54.207). This is a major advantage for Ligand A.

**Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and suggests poor permeability. However, these values are on a log scale, and the absolute values are important. Since the scale is not specified, it's hard to interpret these values.

**Aqueous Solubility:** Both ligands have negative solubility values, indicating poor aqueous solubility.

**hERG Inhibition:** Both ligands show low hERG inhibition liability (0.119 and 0.238), which is favorable.

**Microsomal Clearance:** Ligand A (41.526) has a higher microsomal clearance than Ligand B (29.286), indicating potentially lower metabolic stability.

**In vitro Half-Life:** Ligand B has a significantly longer in vitro half-life (18.384 hours) compared to Ligand A (-13.004 hours). This is a substantial advantage for Ligand B.

**P-gp Efflux:** Both ligands show low P-gp efflux liability (0.086 and 0.033), which is good for CNS penetration.

**Binding Affinity:** Ligand B (-8.6 kcal/mol) has a stronger binding affinity than Ligand A (-7.1 kcal/mol). This is a significant advantage (1.5 kcal/mol difference).

**Overall Assessment:**

While Ligand A has a better BBB score, Ligand B excels in binding affinity and has a much better in vitro half-life. The stronger binding affinity of Ligand B is a significant advantage, potentially outweighing the slightly lower BBB score, especially considering the low P-gp efflux for both compounds. The longer half-life also contributes to a more favorable pharmacokinetic profile. The slightly higher DILI risk for Ligand A is also a minor concern.

Output:
1
2025-04-17 09:07:05,822 - INFO - Batch 506 complete. Total preferences: 8096
2025-04-17 09:07:05,822 - INFO - Processing batch 507/512...
2025-04-17 09:07:47,657 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (364.515 Da) is slightly lower, which is generally favorable for permeability.

**2. TPSA:** Both ligands have TPSA values below 140, suggesting reasonable oral absorption. However, for a CNS target like DRD2, we ideally want TPSA < 90. Ligand A (76.44) is better than Ligand B (82.94) in this regard.

**3. logP:** Both ligands have logP values within the optimal range (1-3). Ligand A (1.25) and Ligand B (1.3) are very similar.

**4. H-Bond Donors:** Both ligands have 1 HBD, which is within the acceptable limit of <=5.

**5. H-Bond Acceptors:** Ligand A has 5 HBAs and Ligand B has 6. Both are within the acceptable limit of <=10.

**6. QED:** Both ligands have good QED scores (A: 0.718, B: 0.81), indicating good drug-like properties.

**7. DILI:** Ligand A (16.712%) has a significantly lower DILI risk than Ligand B (54.323%). This is a substantial advantage.

**8. BBB:** Ligand A (57.154%) has a better BBB penetration score than Ligand B (48.158%), though both are below the desirable >70% for CNS targets. However, given the other properties, a higher BBB is more critical.

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.227 and -5.217), which is unusual and suggests poor permeability. This is a significant drawback for both.

**10. Aqueous Solubility:** Both ligands have negative solubility values (-2.247 and -2.02), indicating poor aqueous solubility. This could pose formulation challenges.

**11. hERG Inhibition:** Ligand A (0.486) has a slightly lower hERG inhibition liability than Ligand B (0.124), which is preferable.

**12. Microsomal Clearance:** Ligand A (34.975) has a higher microsomal clearance than Ligand B (1.415), meaning it's metabolized faster. This is a disadvantage for Ligand A.

**13. In vitro Half-Life:** Ligand A (-1.448) has a shorter in vitro half-life than Ligand B (17.87), which is a significant disadvantage.

**14. P-gp Efflux:** Ligand A (0.011) has much lower P-gp efflux liability than Ligand B (0.092), which is highly desirable for CNS penetration.

**15. Binding Affinity:** Ligand A (-7.4 kcal/mol) has a slightly better binding affinity than Ligand B (-0.0 kcal/mol). This is a major advantage, as a difference of >1.5 kcal/mol can outweigh other drawbacks.

**Overall Assessment:**

Ligand A is the better candidate despite its higher clearance and shorter half-life. The significantly lower DILI risk, better TPSA, and *much* stronger binding affinity, combined with lower P-gp efflux, outweigh the disadvantages. The poor Caco-2 and solubility are concerning for both, but can potentially be addressed with formulation strategies. The stronger affinity of Ligand A is particularly important for a GPCR target, and the lower P-gp efflux will aid CNS exposure.

Output:
0
2025-04-17 09:07:47,657 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (346.312 and 342.359 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (59.81) is excellent, well below the 90 A^2 threshold for CNS targets. Ligand B (93.45) is higher, but still potentially acceptable, though less ideal.

**logP:** Ligand A (3.352) is optimal (1-3). Ligand B (-0.042) is significantly low, which could hinder membrane permeability and brain penetration.

**H-Bond Donors/Acceptors:** Ligand A (1 HBD, 4 HBA) is good. Ligand B (0 HBD, 7 HBA) is also reasonable, though the higher number of HBAs might slightly reduce permeability.

**QED:** Both ligands (0.737 and 0.777) have good drug-likeness scores.

**DILI:** Both ligands have acceptable DILI risk (79.953 and 75.572 percentile), below the concerning 60 threshold.

**BBB:** Ligand A (70.221) has a good BBB penetration score, meeting the >70% desirable threshold for CNS targets. Ligand B (47.189) is considerably lower, raising concerns about reaching the target in the brain.

**Caco-2 Permeability:** Both have negative values (-4.682 and -4.474), which is unusual and requires further investigation. However, we can still compare them relatively. Ligand A is slightly better.

**Aqueous Solubility:** Both have negative values (-3.891 and -1.749). Again, relative comparison is needed. Ligand B is slightly better.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.789 and 0.189).

**Microsomal Clearance:** Ligand A (45.304) has moderate clearance, while Ligand B (28.465) has lower clearance, indicating better metabolic stability.

**In vitro Half-Life:** Ligand A (-3.43) has a negative half-life, which is not possible. Ligand B (-15.715) also has a negative half-life, which is also not possible.

**P-gp Efflux:** Ligand A (0.342) has lower P-gp efflux, which is favorable for CNS penetration. Ligand B (0.054) has even lower P-gp efflux, which is even more favorable.

**Binding Affinity:** Ligand A (-10.7 kcal/mol) has significantly stronger binding affinity than Ligand B (-8.1 kcal/mol). This is a substantial advantage.

**Overall Assessment:**

Considering the GPCR-specific priorities, Ligand A is the more promising candidate. While Ligand B has slightly better metabolic stability and P-gp efflux, Ligand A's superior BBB penetration, optimal logP, and *much* stronger binding affinity outweigh these minor advantages. The negative half-life values are concerning for both, but the affinity difference is substantial. The TPSA of Ligand A is also much more favorable for CNS penetration.

Output:
1
2025-04-17 09:07:47,657 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (350.503 and 352.475 Da) fall comfortably within the ideal 200-500 Da range.

**2. TPSA:** Both ligands have TPSA values (78.43 and 78.87) that are acceptable for oral absorption (<140) but a bit high for optimal CNS penetration (<90). This is a slight drawback for both, but not disqualifying.

**3. logP:** Ligand A (2.231) is within the optimal 1-3 range. Ligand B (1.317) is slightly below this, potentially impacting permeability.

**4. H-Bond Donors:** Ligand A has 3 HBD, which is acceptable. Ligand B has 2 HBD, also acceptable.

**5. H-Bond Acceptors:** Ligand A has 3 HBA, and Ligand B has 4 HBA. Both are within the acceptable limit of <=10.

**6. QED:** Both ligands have good QED scores (0.628 and 0.707), indicating drug-like properties.

**7. DILI:** Ligand A (12.524) has a significantly lower DILI risk than Ligand B (8.996), which is a substantial advantage.

**8. BBB:** Ligand B (62.699) has a better BBB percentile than Ligand A (56.65), which is important for a CNS target like DRD2.

**9. Caco-2 Permeability:** Both have negative Caco-2 values (-4.814 and -4.759), which is unusual and suggests poor permeability. This is a significant concern for both.

**10. Aqueous Solubility:** Both have negative solubility values (-3.23 and -1.808), indicating poor aqueous solubility. This is a concern for formulation.

**11. hERG Inhibition:** Both ligands show low hERG inhibition risk (0.292 and 0.464).

**12. Microsomal Clearance:** Ligand B (11.862) has lower microsomal clearance than Ligand A (29.118), suggesting better metabolic stability.

**13. In vitro Half-Life:** Ligand B (19.577) has a significantly longer in vitro half-life than Ligand A (1.293), which is a major advantage.

**14. P-gp Efflux:** Both ligands have low P-gp efflux liability (0.162 and 0.072), which is favorable for CNS exposure.

**15. Binding Affinity:** Ligand A (-8.7 kcal/mol) has a slightly better binding affinity than Ligand B (-8.1 kcal/mol). While the difference is not huge (less than 1.5 kcal/mol), it's still a positive for Ligand A.

**Overall Assessment:**

Ligand A has a better binding affinity and significantly lower DILI risk. However, Ligand B has a better BBB penetration, lower clearance, and a longer half-life. The poor Caco-2 and solubility for both are concerning. Given the GPCR-specific priorities, BBB penetration is crucial for CNS targets. The longer half-life of Ligand B is also a significant advantage, potentially leading to less frequent dosing. Although Ligand A's affinity is slightly better, the combination of better BBB, metabolic stability, and half-life makes Ligand B the more promising candidate.

Output:
1
2025-04-17 09:07:47,658 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (349.39 and 350.50 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (97.92) is higher than Ligand B (58.64). For CNS targets, TPSA should be <=90, so Ligand B is significantly better here.

**logP:** Ligand A (-0.07) is quite low, potentially hindering membrane permeability. Ligand B (2.737) is within the optimal 1-3 range. This is a substantial advantage for Ligand B.

**H-Bond Donors/Acceptors:** Ligand A has 3 HBD and 6 HBA, while Ligand B has 1 HBD and 3 HBA. Both are within acceptable limits (<=5 HBD and <=10 HBA).

**QED:** Both ligands have good QED scores (0.569 and 0.732), indicating drug-like properties.

**DILI:** Ligand A (55.76) has a moderate DILI risk, while Ligand B (4.46) has a very low risk. This is a significant advantage for Ligand B.

**BBB:** Ligand A (52.27) has a moderate BBB penetration, while Ligand B (81.70) has excellent BBB penetration. This is a critical advantage for a CNS target like DRD2.

**Caco-2 Permeability:** Ligand A (-5.56) has poor Caco-2 permeability, while Ligand B (-4.68) is slightly better, but still not great.

**Aqueous Solubility:** Both ligands have poor aqueous solubility (-1.37 and -2.1). This could pose formulation challenges, but is less critical than BBB and logP for CNS drugs.

**hERG Inhibition:** Ligand A (0.11) has a very low hERG risk, while Ligand B (0.51) has a slightly higher, but still acceptable, risk.

**Microsomal Clearance:** Ligand A (-0.13) has very low clearance, suggesting good metabolic stability. Ligand B (31.81) has higher clearance, indicating faster metabolism. This favors Ligand A.

**In vitro Half-Life:** Ligand A (-19.07) has a very long half-life, while Ligand B (-6.81) has a shorter half-life. This favors Ligand A.

**P-gp Efflux:** Ligand A (0.01) has very low P-gp efflux, while Ligand B (0.067) has slightly higher efflux. Lower is better for CNS penetration, favoring Ligand A.

**Binding Affinity:** Ligand B (-8.6 kcal/mol) has a slightly better binding affinity than Ligand A (-7.5 kcal/mol). While >1.5 kcal/mol advantage is significant, the difference here is not overwhelming.

**Overall Assessment:**

Ligand B excels in key GPCR/CNS-relevant properties: logP, BBB penetration, and DILI risk. While its metabolic stability and half-life are less favorable than Ligand A, the superior BBB penetration and logP are crucial for CNS drug development. Ligand A has better metabolic stability and half-life, but its poor logP and lower BBB penetration are significant drawbacks. The slightly better binding affinity of Ligand B also contributes to its favorability.

Output:
1
2025-04-17 09:07:47,658 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (341.298 and 349.431 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (89.86) is better than Ligand B (85.87), both are below the 90 A^2 threshold for CNS targets.

**logP:** Ligand A (2.606) is optimal (1-3), while Ligand B (0.928) is slightly low, potentially hindering permeation.

**H-Bond Donors/Acceptors:** Ligand A (HBD=1, HBA=7) and Ligand B (HBD=2, HBA=4) both meet the criteria of <=5 HBD and <=10 HBA.

**QED:** Ligand B (0.828) has a better QED score than Ligand A (0.574), indicating a more drug-like profile.

**DILI:** Ligand B (40.83) has a significantly lower DILI risk than Ligand A (87.01). This is a major advantage for Ligand B.

**BBB:** Ligand A (57.154) has a better BBB penetration percentile than Ligand B (29.74). This is a critical factor for a CNS target like DRD2.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values, which is unusual and suggests poor permeability. However, these values are on different scales and hard to interpret directly.

**Aqueous Solubility:** Both ligands have negative solubility values, which is also unusual.

**hERG:** Both ligands have low hERG inhibition liability (0.437 and 0.269, respectively), which is good.

**Microsomal Clearance:** Ligand A (95.739) has higher microsomal clearance than Ligand B (-2.941), meaning Ligand B is likely more metabolically stable.

**In vitro Half-Life:** Ligand B (-12.941) has a longer in vitro half-life than Ligand A (-32.667).

**P-gp Efflux:** Ligand A (0.359) has lower P-gp efflux than Ligand B (0.036), which is favorable for CNS exposure.

**Binding Affinity:** Both ligands have strong binding affinities (-9.3 and -8.0 kcal/mol, respectively). Ligand A has a 1.3 kcal/mol advantage, which is significant.

**Overall Assessment:**

Ligand A excels in binding affinity and BBB penetration, which are crucial for a CNS GPCR target. However, it has a high DILI risk and higher metabolic clearance. Ligand B has a much better safety profile (lower DILI), better metabolic stability, and a longer half-life, but its BBB penetration is significantly lower and logP is suboptimal.

Given the importance of CNS penetration for DRD2, and the substantial affinity difference, Ligand A is the more promising candidate despite the higher DILI risk. The DILI risk could potentially be mitigated through structural modifications. The lower logP of Ligand B is a more difficult property to improve without sacrificing affinity.

Output:
0
2025-04-17 09:07:47,658 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (390.527 and 355.869 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (93.64) is slightly above the optimal <90 for CNS targets, but still reasonable. Ligand B (45.23) is excellent, well below 90.

**logP:** Ligand A (1.847) is within the optimal 1-3 range. Ligand B (4.767) is a bit high, potentially leading to solubility issues and off-target interactions.

**H-Bond Donors/Acceptors:** Ligand A (0 HBD, 6 HBA) is good. Ligand B (1 HBD, 3 HBA) is also good. Both are within acceptable limits.

**QED:** Both ligands have good QED scores (0.779 and 0.804), indicating drug-like properties.

**DILI:** Both ligands have similar DILI risk (60.527 and 64.948), placing them in a moderate risk category. This isn't a major differentiating factor.

**BBB:** This is a crucial parameter for DRD2. Ligand A has a BBB percentile of 45.715, which is below the desirable >70 for CNS targets. Ligand B has a significantly better BBB percentile of 82.474, making it more likely to reach the brain.

**Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and suggests poor permeability. However, these values are on a strange scale, so it's hard to interpret.

**Aqueous Solubility:** Both ligands have very poor aqueous solubility (-4.137 and -4.555). This is a concern, but can potentially be addressed with formulation strategies.

**hERG Inhibition:** Ligand A (0.292) has a very low hERG risk, which is excellent. Ligand B (0.736) has a slightly higher, but still acceptable, hERG risk.

**Microsomal Clearance:** Ligand A (66.576) and Ligand B (61.482) have similar moderate microsomal clearance values.

**In vitro Half-Life:** Ligand A (-40.005) has a very poor in vitro half-life. Ligand B (68.489) has a much better half-life.

**P-gp Efflux:** Ligand A (0.072) has low P-gp efflux, which is favorable for CNS penetration. Ligand B (0.642) has moderate P-gp efflux, which could limit brain exposure.

**Binding Affinity:** Ligand A (-0.0) has weak binding affinity. Ligand B (-9.6) has a very strong binding affinity, exceeding the desirable < -7.0 kcal/mol. This is a significant advantage.

**Overall Assessment:**

Ligand B is the stronger candidate. While its logP is slightly elevated, its significantly better BBB penetration, much stronger binding affinity, and improved in vitro half-life outweigh the drawbacks. Ligand A's weak binding affinity and poor half-life are major liabilities. The solubility issues are a concern for both, but are more manageable than a lack of potency or inability to cross the BBB.

Output:
1
2025-04-17 09:07:47,658 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B against the provided guidelines, prioritizing GPCR-specific properties (BBB, logP, Pgp, TPSA, and affinity) for DRD2.

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (337.423 Da) is slightly lower, which could be advantageous for permeability.

**TPSA:** Ligand A (48.31) is significantly better than Ligand B (66.32). For a CNS target like DRD2, a TPSA <= 90 is desirable, and Ligand A is well within this range, while Ligand B is approaching the upper limit.

**logP:** Both ligands have logP values within the optimal range (1-3), with Ligand A (3.317) being slightly lower than Ligand B (4.259). While both are acceptable, Ligand B's higher logP could potentially lead to off-target interactions or solubility issues.

**H-Bond Donors/Acceptors:** Both ligands have acceptable HBD (1) and HBA (5/6) counts.

**QED:** Both ligands have good QED scores (0.685 and 0.705), indicating good drug-like properties.

**DILI:** Both ligands have low DILI risk (40.403 and 36.099), which is positive.

**BBB:** Ligand A (57.968) has a better BBB percentile than Ligand B (52.617), although both are below the desirable >70 for CNS targets. This is a critical factor for DRD2.

**Caco-2 Permeability:** Both have negative Caco-2 values which is unusual and suggests a potential issue with the data. However, we will proceed with the assumption that these are percentile scores, and lower values indicate lower permeability. Ligand A (-4.878) is slightly better than Ligand B (-4.963).

**Aqueous Solubility:** Both ligands have poor aqueous solubility (-3.332 and -4.079). This could pose formulation challenges.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.922 and 0.8), which is good.

**Microsomal Clearance:** Ligand A (38.377) has a lower microsomal clearance than Ligand B (64.579), indicating better metabolic stability.

**In vitro Half-Life:** Ligand B (61.404) has a significantly longer in vitro half-life than Ligand A (-33.482). This is a significant advantage.

**P-gp Efflux:** Ligand A (0.573) has lower P-gp efflux liability than Ligand B (0.626), which is favorable for CNS penetration.

**Binding Affinity:** Ligand A (-8.7 kcal/mol) has a substantially stronger binding affinity than Ligand B (-6.2 kcal/mol). This is a >1.5 kcal/mol advantage, which can outweigh minor ADME drawbacks.

**Overall Assessment:**

Considering the GPCR-specific priorities, Ligand A is the more promising candidate. Its superior TPSA, BBB, metabolic stability (lower Cl_mic), P-gp efflux, and *significantly* stronger binding affinity outweigh the longer half-life of Ligand B. While both have poor solubility, the higher affinity of Ligand A suggests it might be more effective at lower concentrations, potentially mitigating solubility issues. The slightly better Caco-2 permeability of Ligand A is also a minor positive.



Output:
0
2025-04-17 09:07:47,659 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (366.487 and 346.475 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (87.46) is better than Ligand B (78.09) as both are below the 90 A^2 threshold for CNS targets.

**3. logP:** Ligand B (2.36) is better than Ligand A (0.57). Ligand A's logP is quite low, potentially hindering membrane permeability. Ligand B is within the optimal 1-3 range.

**4. H-Bond Donors:** Both ligands have 2 HBD, which is acceptable (<=5).

**5. H-Bond Acceptors:** Ligand A has 6 HBA, and Ligand B has 3 HBA. Both are within the acceptable range (<=10).

**6. QED:** Both ligands have high QED scores (0.796 and 0.804), indicating good drug-like properties.

**7. DILI:** Both ligands have relatively low DILI risk (53.936 and 27.801 percentiles), suggesting acceptable hepatic safety. Ligand B is slightly better.

**8. BBB:** Ligand B (53.974) is significantly better than Ligand A (27.84). For a CNS target like DRD2, BBB penetration is crucial, and Ligand B is much more promising.

**9. Caco-2 Permeability:** Both have negative Caco-2 values (-5.268 and -5.167), which is unusual and suggests poor permeability. This is a significant concern for both.

**10. Aqueous Solubility:** Both ligands have negative solubility values (-2.367 and -2.389). This is also a concern, indicating poor aqueous solubility.

**11. hERG Inhibition:** Both ligands have low hERG inhibition risk (0.114 and 0.192).

**12. Microsomal Clearance:** Ligand A (19.428) has a higher clearance than Ligand B (14.575), suggesting lower metabolic stability. Ligand B is preferable.

**13. In vitro Half-Life:** Ligand B (-9.881) has a negative half-life, which is not possible. Ligand A (4.097) has a short half-life, but it is at least a positive value.

**14. P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.044 and 0.058), which is favorable for CNS penetration.

**15. Binding Affinity:** Ligand A (-7.1) has a slightly better binding affinity than Ligand B (-0.0). This is a substantial difference.

**Overall Assessment:**

Despite Ligand A's slightly better binding affinity, Ligand B is the more promising candidate. The critical factor is BBB penetration, where Ligand B significantly outperforms Ligand A. While both have issues with Caco-2 permeability and solubility, the superior BBB penetration of Ligand B, combined with better logP and metabolic stability, makes it a more viable starting point for optimization. The negative half-life for Ligand B is a data error that would need to be investigated. The large difference in binding affinity is also concerning, and would need to be verified experimentally.

Output:
1
2025-04-17 09:07:47,659 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (354.401 and 346.431 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (76.02) is excellent, well below the 90 A^2 threshold for CNS targets. Ligand B (84.3) is still acceptable, but less optimal.

**logP:** Ligand A (2.649) is within the optimal 1-3 range. Ligand B (1.103) is at the lower end, potentially impacting permeability.

**H-Bond Donors/Acceptors:** Ligand A (2 HBD, 4 HBA) and Ligand B (1 HBD, 5 HBA) both have reasonable numbers of H-bond donors and acceptors, falling within the guidelines.

**QED:** Both ligands have good QED scores (0.705 and 0.809), indicating drug-like properties.

**DILI:** Ligand A (52.85) has a slightly higher DILI risk than Ligand B (39.162), but both are below the concerning 60 percentile.

**BBB:** This is a crucial parameter for a CNS target like DRD2. Ligand A (85.498) has a significantly better BBB penetration score than Ligand B (70.182). This is a major advantage for Ligand A.

**Caco-2 Permeability:** Both have negative Caco-2 values (-4.744 and -4.905), which is unusual and suggests poor permeability. This is a potential concern for both, but the values are similar.

**Aqueous Solubility:** Both ligands have negative solubility values (-3.934 and -1.784). This is also unusual and indicates very poor aqueous solubility, which could pose formulation challenges. Ligand B is slightly better here.

**hERG:** Both ligands have very low hERG inhibition liability (0.241 and 0.145), which is excellent.

**Microsomal Clearance:** Ligand A (35.514) has a higher microsomal clearance than Ligand B (14.148), suggesting lower metabolic stability. This is a drawback for Ligand A.

**In vitro Half-Life:** Ligand B (-8.357) has a longer in vitro half-life than Ligand A (-1.328), indicating better stability.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.145 and 0.046), which is favorable for CNS penetration.

**Binding Affinity:** Both ligands have excellent binding affinities (-8.4 kcal/mol and -8.7 kcal/mol). Ligand B is slightly more potent. However, the difference is small and may not outweigh other factors.

**Overall Assessment:**

Ligand A excels in TPSA and, critically, BBB penetration. While its metabolic stability (Cl_mic) and half-life are less favorable than Ligand B, its superior BBB score is a significant advantage for a CNS-targeting drug. Ligand B has a slightly better logP, solubility, and half-life, but its lower BBB score is a major drawback. Given the GPCR-specific priorities, particularly BBB for CNS targets, Ligand A is the more promising candidate.

Output:
1
2025-04-17 09:07:47,659 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (347.379 Da) is slightly lower, which could be beneficial for permeability, while Ligand B (372.847 Da) is also well within the range.

**TPSA:** Ligand A (120.25) is better than Ligand B (51.97). For CNS targets, we want TPSA <= 90, so Ligand B is significantly better in this regard.

**logP:** Ligand A (-0.784) is suboptimal, being below the preferred 1-3 range. This could hinder membrane permeability. Ligand B (3.536) is excellent, falling comfortably within the optimal range.

**H-Bond Donors/Acceptors:** Ligand A has 2 HBD and 7 HBA, which are acceptable. Ligand B has 1 HBD and 5 HBA, also acceptable.

**QED:** Both ligands have similar QED values (0.727 and 0.648), indicating good drug-likeness.

**DILI:** Ligand A (69.872) has a higher DILI risk than Ligand B (43.622), although both are below the concerning threshold of 60.

**BBB:** Ligand B (70.531) has a significantly better BBB penetration percentile than Ligand A (34.975). This is a *critical* factor for a CNS target like DRD2.

**Caco-2 Permeability:** Ligand A (-5.321) has poor Caco-2 permeability, while Ligand B (-4.583) is also poor, but slightly better.

**Aqueous Solubility:** Ligand A (-1.293) has poor aqueous solubility, while Ligand B (-3.241) is even worse.

**hERG Inhibition:** Ligand A (0.066) has a very low hERG risk, which is excellent. Ligand B (0.868) is slightly higher, but still relatively low.

**Microsomal Clearance:** Ligand A (11.269) has lower microsomal clearance than Ligand B (29.68), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand B (73.121) has a much longer in vitro half-life than Ligand A (-18.955), which is a significant advantage.

**P-gp Efflux:** Ligand A (0.013) has very low P-gp efflux liability, which is excellent for CNS penetration. Ligand B (0.739) has moderate P-gp efflux, which is less desirable.

**Binding Affinity:** Both ligands have very similar binding affinities (-7.6 and -7.7 kcal/mol), which are both excellent. The difference is negligible.

**Overall Assessment:**

Ligand B is the superior candidate. While Ligand A has slightly better metabolic stability and P-gp efflux, Ligand B excels in the most critical areas for a CNS-targeting GPCR: BBB penetration, logP, and in vitro half-life. The lower TPSA of Ligand B is also a significant advantage. The slightly higher DILI and P-gp efflux are minor drawbacks compared to the benefits of improved CNS exposure. The poor solubility of both compounds would need to be addressed during formulation, but this is a common challenge.

Output:
1
2025-04-17 09:07:47,659 - INFO - Reasoning:

Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (351.757 and 346.427 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (98.48) is slightly above the optimal <90 for CNS targets, but still reasonable. Ligand B (75.71) is well within the desired range.

**3. logP:** Both ligands have good logP values (2.511 and 1.535), falling within the 1-3 range.

**4. H-Bond Donors:** Both have 1 HBD, which is acceptable.

**5. H-Bond Acceptors:** Ligand A has 7 HBAs, and Ligand B has 4. Both are below the 10 threshold.

**6. QED:** Both ligands have good QED scores (0.609 and 0.725), indicating good drug-like properties.

**7. DILI:** Ligand A has a very high DILI risk (99.806%), which is a major red flag. Ligand B has a much lower, and acceptable, DILI risk (30.826%).

**8. BBB:** Ligand A has a BBB penetration of 50.523%, which is below the desirable >70% for CNS targets. Ligand B has a significantly better BBB penetration (70.027%), meeting the threshold.

**9. Caco-2:** Both have negative Caco-2 values, which is unusual and suggests poor permeability. However, these values are on a different scale and difficult to interpret directly.

**10. Solubility:** Both ligands have negative solubility values, which is also unusual.

**11. hERG:** Both ligands have very low hERG inhibition risk (0.542 and 0.129).

**12. Cl_mic:** Ligand A has a lower microsomal clearance (58.432) than Ligand B (77.21), suggesting better metabolic stability.

**13. t1/2:** Ligand B has a negative in vitro half-life (-16.325), which is concerning and likely indicates rapid degradation. Ligand A has a more reasonable half-life (31.615).

**14. Pgp:** Ligand A has a very high Pgp efflux liability (0.145), which would limit CNS exposure. Ligand B has a very low Pgp efflux liability (0.048), which is favorable.

**15. Binding Affinity:** Ligand B has a significantly stronger binding affinity (-7.7 kcal/mol) compared to Ligand A (-10.1 kcal/mol). This is a substantial difference.

**Overall Assessment:**

Despite Ligand A having a slightly better metabolic stability and half-life, the extremely high DILI risk, poor BBB penetration, and high Pgp efflux make it a very poor candidate. Ligand B, while having a shorter half-life, excels in the critical GPCR-specific parameters: good logP, excellent Pgp profile, acceptable TPSA, good BBB penetration, and *significantly* stronger binding affinity. The lower DILI risk is also a major advantage. The negative Caco-2 and solubility values are concerning, but the affinity difference is large enough to prioritize Ligand B for further investigation and optimization.

Output:
1
2025-04-17 09:07:47,659 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (353.809 and 347.375 Da) fall within the ideal range of 200-500 Da.

**TPSA:** Ligand A (50.75) is significantly better than Ligand B (102.49). For CNS targets, we want TPSA <= 90, and A is comfortably within this range, while B exceeds it.

**logP:** Ligand A (4.454) is higher than the optimal range (1-3), but still potentially acceptable. Ligand B (0.242) is *very* low, which could severely hinder permeability and binding.

**H-Bond Donors/Acceptors:** Ligand A (0 HBD, 4 HBA) is preferable. Ligand B has 1 HBD and 7 HBA, which is higher and could impact permeability.

**QED:** Both ligands have good QED scores (0.498 and 0.803), indicating reasonable drug-likeness.

**DILI:** Ligand A (71.113) has a higher DILI risk than Ligand B (47.964), but both are below the concerning threshold of 60.

**BBB:** Ligand A (64.211) has a better BBB percentile than Ligand B (55.176), though ideally, we want >70 for CNS targets.

**Caco-2 Permeability:** Ligand A (-5.196) has a negative Caco-2 value, which is unusual and suggests poor permeability. Ligand B (-4.963) is also negative, but slightly less so.

**Aqueous Solubility:** Both ligands have very poor aqueous solubility (-3.907 and -2.297). This is a significant drawback.

**hERG Inhibition:** Ligand A (0.702) has a slightly higher hERG risk than Ligand B (0.139), but both are relatively low.

**Microsomal Clearance:** Ligand A (77.615) has a higher microsomal clearance than Ligand B (4.158), indicating lower metabolic stability.

**In vitro Half-Life:** Ligand A (96.773) has a much longer half-life than Ligand B (27.955).

**P-gp Efflux:** Ligand A (0.79) shows moderate P-gp efflux, while Ligand B (0.036) has very low P-gp efflux. This is a significant advantage for B, as it suggests better CNS penetration.

**Binding Affinity:** Ligand A (-9.6 kcal/mol) has a significantly stronger binding affinity than Ligand B (-8.0 kcal/mol). This is a substantial difference that could outweigh some of the ADME drawbacks.

**Overall Assessment:**

Despite the poor solubility and Caco-2 values for both, Ligand A is the stronger candidate. The significantly better binding affinity (-9.6 vs -8.0 kcal/mol) is a major advantage, especially for a GPCR target. While Ligand B has better P-gp efflux and lower DILI, the lower logP and higher TPSA are concerning for CNS penetration and overall drug-like properties. The longer half-life of Ligand A is also a plus. The negative Caco-2 values are a concern for both, and would need to be addressed through formulation or structural modification.

Output:
1
2025-04-17 09:07:47,660 - INFO - Reasoning:

Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (355.463 and 340.423 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (63.99) is better than Ligand B (73.58). Both are below the 90 A^2 threshold for CNS targets, but A is closer to optimal.

**3. logP:** Both ligands have good logP values (3.105 and 2.848), falling within the 1-3 range.

**4. H-Bond Donors:** Ligand A (1) is preferable to Ligand B (2), as lower HBD generally improves permeability.

**5. H-Bond Acceptors:** Both ligands have the same number of HBA (4), which is acceptable (<=10).

**6. QED:** Both ligands have similar QED values (0.765 and 0.775), indicating good drug-likeness.

**7. DILI:** Ligand B (30.012) has a significantly lower DILI risk than Ligand A (79.604). This is a major advantage for Ligand B.

**8. BBB:** Ligand B (70.997) has a better BBB penetration percentile than Ligand A (50.407). This is crucial for a CNS target like DRD2.

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.169 and -5.115), which is unusual and suggests poor permeability. However, these values are on a scale where higher is better, so these are both quite poor.

**10. Aqueous Solubility:** Both ligands have negative solubility values (-4.207 and -2.539), indicating poor aqueous solubility.

**11. hERG Inhibition:** Both ligands have low hERG inhibition risk (0.613 and 0.683).

**12. Microsomal Clearance:** Ligand B (-10.377) has a lower (better) microsomal clearance than Ligand A (42.825), indicating better metabolic stability.

**13. In vitro Half-Life:** Ligand B (36.299) has a longer in vitro half-life than Ligand A (-11.543).

**14. P-gp Efflux:** Ligand A (0.377) has lower P-gp efflux liability than Ligand B (0.14), which is favorable for CNS penetration.

**15. Binding Affinity:** Ligand B (-9.5 kcal/mol) has a slightly better binding affinity than Ligand A (-8.4 kcal/mol). While the difference is not huge, it's a positive factor.

**Overall Assessment:**

While Ligand A has a slightly better TPSA and P-gp efflux, Ligand B is significantly better across several critical parameters for a CNS-targeting GPCR: DILI risk, BBB penetration, microsomal clearance, and in vitro half-life. The slightly better binding affinity of Ligand B further strengthens its case. The poor Caco-2 and solubility for both are concerning, but can potentially be addressed with formulation strategies. Given the importance of CNS penetration and safety (DILI) for DRD2, Ligand B is the more promising candidate.

Output:
1
2025-04-17 09:07:47,660 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (343.402 Da) is slightly lower, which could be beneficial for permeability. Ligand B (352.435 Da) is also good.

**TPSA:** Ligand A (54.46) is excellent, well below the 90 A^2 threshold for CNS targets. Ligand B (107.18) is higher, but still potentially acceptable, though less ideal for CNS penetration.

**logP:** Ligand A (3.61) is within the optimal range (1-3). Ligand B (-1.522) is significantly outside the optimal range and is quite low, which raises concerns about permeability and potentially binding.

**H-Bond Donors/Acceptors:** Ligand A (1 HBD, 5 HBA) is good. Ligand B (2 HBD, 5 HBA) is also acceptable.

**QED:** Ligand A (0.841) has a very strong drug-like profile. Ligand B (0.625) is still reasonably good, but lower than Ligand A.

**DILI:** Ligand A (62.35) has a moderate DILI risk. Ligand B (5.312) has a very low DILI risk, which is a significant advantage.

**BBB:** Ligand A (82.086) has good BBB penetration potential. Ligand B (34.122) has poor BBB penetration potential, a major drawback for a CNS target like DRD2.

**Caco-2 Permeability:** Ligand A (-4.582) is concerningly low. Ligand B (-5.923) is even lower, indicating very poor intestinal absorption for both.

**Aqueous Solubility:** Ligand A (-4.677) is poor. Ligand B (-0.29) is slightly better, but still not ideal.

**hERG Inhibition:** Ligand A (0.774) has a moderate risk of hERG inhibition. Ligand B (0.152) has a very low risk, which is a significant advantage.

**Microsomal Clearance:** Ligand A (86.929) has high microsomal clearance, indicating poor metabolic stability. Ligand B (-23.004) has negative clearance, which is not physically possible and likely an artifact of the prediction method, but suggests very high metabolic stability.

**In vitro Half-Life:** Ligand A (28.651) has a moderate half-life. Ligand B (-26.986) has a negative half-life, which is not physically possible and suggests very high stability.

**P-gp Efflux:** Ligand A (0.425) has moderate P-gp efflux. Ligand B (0.002) has very low P-gp efflux, which is a significant advantage for CNS penetration.

**Binding Affinity:** Ligand A (-8.3 kcal/mol) has a very strong binding affinity. Ligand B (-7.7 kcal/mol) also has good binding affinity, but is 0.6 kcal/mol weaker.

**Overall Assessment:**

Ligand A has a superior binding affinity and better BBB penetration, but suffers from poor Caco-2 permeability, solubility, and metabolic stability. Ligand B has a lower binding affinity, but excels in ADME properties: very low DILI and hERG risk, very low P-gp efflux, and potentially excellent metabolic stability. The significantly better ADME profile of Ligand B, particularly the low P-gp efflux and improved metabolic stability, outweighs the slightly weaker binding affinity, especially considering the challenges of CNS drug development. The poor BBB penetration of Ligand B is a major concern, however.

Output:
1
2025-04-17 09:07:47,660 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (351.353 and 347.503 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (71.53) is better than Ligand B (73.2), both are below the 90 A^2 threshold for CNS targets, which is good.

**logP:** Ligand A (1.256) is optimal, while Ligand B (3.273) is approaching the upper limit of the optimal range.

**H-Bond Donors:** Both have 1 HBD, which is within the acceptable limit of <=5.

**H-Bond Acceptors:** Ligand A has 4 HBAs, and Ligand B has 3. Both are within the acceptable limit of <=10.

**QED:** Ligand A (0.886) has a significantly better QED score than Ligand B (0.685), indicating better overall drug-likeness.

**DILI:** Ligand A (53.625) has a higher DILI risk than Ligand B (19.349). This is a concern for Ligand A.

**BBB:** Ligand A (87.67) has a much better BBB penetration percentile than Ligand B (58.24). This is a critical advantage for a CNS target like DRD2.

**Caco-2 Permeability:** Ligand A (-4.457) has a worse Caco-2 permeability than Ligand B (-4.651).

**Aqueous Solubility:** Ligand A (-2.61) has a slightly better solubility than Ligand B (-3.073).

**hERG Inhibition:** Ligand A (0.398) has a lower hERG inhibition risk than Ligand B (0.619).

**Microsomal Clearance:** Ligand A (-7.833) has a significantly lower (better) microsomal clearance than Ligand B (42.313), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (8.159) has a much longer half-life than Ligand B (-0.567).

**P-gp Efflux:** Ligand A (0.023) has a much lower P-gp efflux liability than Ligand B (0.136), which is beneficial for CNS penetration.

**Binding Affinity:** Ligand A (-7.4 kcal/mol) has a slightly better binding affinity than Ligand B (0.0 kcal/mol).

**Overall Assessment:**

Ligand A is superior despite the slightly higher DILI risk. The key advantages of Ligand A are its significantly better BBB penetration, lower P-gp efflux, lower microsomal clearance, longer half-life, better QED, and slightly better binding affinity. These factors are particularly important for a CNS GPCR target like DRD2. While Ligand B has a lower DILI risk, the poor BBB penetration and high P-gp efflux severely limit its potential to reach the target in the brain. The difference in binding affinity is also substantial.

Output:
1
2025-04-17 09:07:47,660 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (350.463 and 360.489 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (107.11) is borderline for CNS penetration, being above the preferred <90, but not drastically so. Ligand B (49.41) is excellent, well below the threshold.

**logP:** Ligand A (1.599) is within the optimal range (1-3). Ligand B (3.849) is at the higher end, potentially raising concerns about solubility and off-target effects, but still acceptable.

**H-Bond Donors/Acceptors:** Ligand A has 4 HBD and 4 HBA, which are both reasonable. Ligand B has 1 HBD and 2 HBA, also reasonable.

**QED:** Both ligands have good QED scores (0.507 and 0.669), indicating good drug-like properties.

**DILI:** Both ligands have relatively low DILI risk (13.61 and 14.773), suggesting acceptable hepatic safety.

**BBB:** This is a critical parameter for a CNS target like DRD2. Ligand A has a BBB percentile of 29.12, which is quite low and a significant drawback. Ligand B has a much higher BBB percentile of 92.323, which is excellent.

**Caco-2 Permeability:** Ligand A (-5.426) shows poor permeability. Ligand B (-4.364) is better, but still not great.

**Aqueous Solubility:** Ligand A (-0.968) has poor solubility. Ligand B (-3.871) is even worse.

**hERG Inhibition:** Ligand A (0.237) has a very low hERG risk, which is excellent. Ligand B (0.751) is slightly higher, but still relatively low.

**Microsomal Clearance:** Ligand A (-18.144) has very low clearance, indicating good metabolic stability. Ligand B (72.219) has high clearance, suggesting rapid metabolism.

**In vitro Half-Life:** Ligand A (-22.326) has a very long half-life, which is desirable. Ligand B (1.263) has a very short half-life, which is a significant drawback.

**P-gp Efflux:** Ligand A (0.03) has very low P-gp efflux, which is excellent for CNS penetration. Ligand B (0.15) also has low P-gp efflux.

**Binding Affinity:** Ligand A (-8.3 kcal/mol) has a slightly better binding affinity than Ligand B (-7.6 kcal/mol), but the difference is not huge.

**Overall Assessment:**

Ligand A has better affinity, metabolic stability, and lower hERG risk, but suffers from poor BBB penetration, poor solubility, and poor Caco-2 permeability. Ligand B excels in BBB penetration, has a good QED, and acceptable DILI risk, but has poor solubility, poor Caco-2 permeability, and is rapidly metabolized.

Given the GPCR-specific priorities, particularly the importance of BBB penetration for a CNS target, **Ligand B is the more promising candidate**, despite its slightly weaker affinity and poorer metabolic stability. The excellent BBB penetration outweighs the other drawbacks, as these can potentially be addressed through formulation strategies or further chemical modifications. The poor metabolic stability can be improved through structural modifications.



Output:
1
2025-04-17 09:07:47,661 - INFO - Batch 507 complete. Total preferences: 8112
2025-04-17 09:07:47,661 - INFO - Processing batch 508/512...
2025-04-17 09:08:42,383 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight (MW):** Both ligands (388.961 and 366.506 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (49.85) is better than Ligand B (54.18). Both are below the 90 A^2 threshold for CNS targets, which is good.

**3. logP:** Both ligands have good logP values (3.623 and 3.078), falling within the optimal 1-3 range.

**4. H-Bond Donors (HBD):** Both ligands are low in HBDs (0 and 1 respectively), which is favorable for permeability.

**5. H-Bond Acceptors (HBA):** Ligand A (4) is better than Ligand B (6). Both are below the 10 threshold.

**6. QED:** Both ligands have good QED scores (0.638 and 0.818), indicating good drug-like properties.

**7. DILI:** Ligand A (52.85) has a higher DILI risk than Ligand B (8.104). This is a significant drawback for Ligand A.

**8. BBB:** Ligand A (74.796) has a slightly better BBB penetration percentile than Ligand B (71.345), but both are above the desirable 70% threshold for CNS targets.

**9. Caco-2 Permeability:** Ligand A (-4.636) has a worse Caco-2 permeability than Ligand B (-4.883). Lower values are less desirable.

**10. Aqueous Solubility:** Ligand A (-4.826) has worse aqueous solubility than Ligand B (-2.677).

**11. hERG Inhibition:** Both ligands have low hERG inhibition liability (0.893 and 0.77).

**12. Microsomal Clearance:** Ligand A (86.027) has a much higher microsomal clearance than Ligand B (15.043), indicating poorer metabolic stability.

**13. In vitro Half-Life:** Ligand B (-6.93) has a longer in vitro half-life than Ligand A (20.458).

**14. P-gp Efflux:** Ligand A (0.435) has lower P-gp efflux than Ligand B (0.309), which is favorable for CNS exposure.

**15. Binding Affinity:** Ligand B (-8.3 kcal/mol) has a slightly better binding affinity than Ligand A (-7.6 kcal/mol). While both are good, the difference is significant.

**Overall Assessment:**

Ligand B is the better candidate. While Ligand A has slightly better BBB penetration and P-gp efflux, Ligand B excels in crucial areas: significantly lower DILI risk, better metabolic stability (lower Cl_mic, longer t1/2), better solubility, and slightly better binding affinity. The lower DILI and improved metabolic stability are particularly important for a CNS drug. The slight difference in binding affinity is outweighed by the ADME advantages of Ligand B.

Output:
1
2025-04-17 09:08:42,384 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (345.487 Da) is slightly lower, which can be favorable for permeability. Ligand B (353.463 Da) is also good.

**TPSA:** Ligand A (52.65) is excellent, well below the 90 A^2 threshold for CNS targets. Ligand B (90.9) is at the upper limit for CNS penetration, potentially hindering BBB crossing.

**logP:** Ligand A (1.483) is within the optimal range (1-3). Ligand B (-0.121) is below 1, which could indicate poor membrane permeability.

**H-Bond Donors/Acceptors:** Ligand A (HBD=1, HBA=3) is favorable. Ligand B (HBD=3, HBA=5) is acceptable, but higher values can sometimes reduce permeability.

**QED:** Both ligands have reasonable QED values (A: 0.768, B: 0.566), indicating drug-like properties.

**DILI:** Both ligands have similar, low DILI risk (A: 6.941, B: 6.747), which is good.

**BBB:** This is a critical parameter for a CNS target. Ligand A has a significantly higher BBB percentile (69.794) than Ligand B (39.55). This is a major advantage for Ligand A.

**Caco-2 Permeability:** Ligand A (-4.759) has poor Caco-2 permeability, while Ligand B (-5.133) is also poor. This is a concern for both, but less critical given the focus on BBB penetration for a CNS target.

**Aqueous Solubility:** Both have negative solubility values, indicating poor solubility. Ligand A (-1.466) is slightly better than Ligand B (-0.647).

**hERG:** Both ligands have very low hERG risk (A: 0.244, B: 0.103).

**Microsomal Clearance:** Ligand A (0.568) has much lower clearance than Ligand B (7.417), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (-0.463) has a negative half-life, which is concerning. Ligand B (19.352) has a good half-life.

**P-gp Efflux:** Both have low P-gp efflux liability (A: 0.037, B: 0.004), which is favorable for CNS penetration.

**Binding Affinity:** Ligand B (-7.9 kcal/mol) has a slightly better binding affinity than Ligand A (-8.4 kcal/mol). However, the difference is small, and other factors are more important.

**Overall Assessment:**

Ligand A excels in TPSA, BBB, and metabolic stability (Cl_mic). While its Caco-2 permeability and in vitro half-life are concerning, the strong BBB penetration and lower clearance are crucial for a CNS-targeting GPCR like DRD2. Ligand B has a slightly better binding affinity and half-life, but suffers from a higher TPSA, lower BBB, and significantly higher clearance. Given the GPCR-specific priorities, especially BBB penetration, Ligand A is the more promising candidate.

Output:
0
2025-04-17 09:08:42,384 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (362.836 Da) is slightly higher than Ligand B (345.447 Da), but both are acceptable.

**TPSA:** Ligand A (57.26) is significantly better than Ligand B (88.91). For CNS targets, we want TPSA <= 90, and ideally closer to 60. Ligand A is much closer to the ideal range.

**logP:** Ligand A (3.839) is optimal (1-3), while Ligand B (2.038) is at the lower end of optimal. While still acceptable, a higher logP generally aids in membrane permeability for CNS drugs.

**H-Bond Donors/Acceptors:** Both have 2 HBDs, which is good. Ligand A has 3 HBAs, and Ligand B has 5 HBAs. Both are within the acceptable limit of <=10, but fewer is generally preferred.

**QED:** Ligand A (0.849) has a much better QED score than Ligand B (0.529), indicating a more drug-like profile.

**DILI:** Ligand A (74.99) has a higher DILI risk than Ligand B (49.709). While both are below 60 (good), Ligand B is preferable.

**BBB:** Ligand A (80.419) has a significantly better BBB penetration percentile than Ligand B (56.805). This is *critical* for a CNS target like DRD2.

**Caco-2 Permeability:** Ligand A (-4.777) and Ligand B (-5.243) both have negative values, which is unusual. This suggests poor permeability.

**Aqueous Solubility:** Ligand A (-5.126) and Ligand B (-2.473) both have negative values, which is also unusual and suggests poor solubility.

**hERG:** Ligand A (0.644) has a slightly higher hERG risk than Ligand B (0.043). Ligand B is much more favorable here.

**Microsomal Clearance:** Ligand A (51.949) and Ligand B (48.412) are similar. Lower is better, but these are acceptable.

**In vitro Half-Life:** Ligand A (53.839) has a much longer half-life than Ligand B (-13.645). This is a significant advantage.

**P-gp Efflux:** Ligand A (0.319) has lower P-gp efflux than Ligand B (0.026). Lower is better, meaning less efflux and better CNS exposure.

**Binding Affinity:** Ligand A (-9.6 kcal/mol) has a significantly stronger binding affinity than Ligand B (-7.7 kcal/mol). This is a substantial difference (over 1.5 kcal/mol) and can outweigh some of the ADME drawbacks.

**Overall Assessment:**

Ligand A excels in key areas for a CNS-targeting GPCR: TPSA, BBB, QED, and *especially* binding affinity. Its longer half-life and lower P-gp efflux are also beneficial. While its DILI risk is slightly higher and solubility/permeability are poor, the strong binding affinity and excellent BBB penetration are likely to be decisive. Ligand B has better DILI and hERG, but its weaker affinity and significantly lower BBB penetration make it less promising.

Output:
1
2025-04-17 09:08:42,384 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (349.479 Da) is slightly lower, which could be advantageous for permeability. Ligand B (363.805 Da) is also good.

**TPSA:** Ligand A (70.47) is excellent, well below the 90 A^2 threshold for CNS targets. Ligand B (105.21) is higher but still potentially acceptable, though less ideal.

**logP:** Both ligands have good logP values (A: 0.72, B: 1.346), falling within the optimal range of 1-3. Ligand B is slightly better.

**H-Bond Donors/Acceptors:** Ligand A (HBD=1, HBA=5) is better than Ligand B (HBD=3, HBA=7) in terms of balancing solubility and permeability.

**QED:** Ligand A (0.787) has a significantly higher QED score than Ligand B (0.585), indicating a more drug-like profile.

**DILI:** Ligand A (11.206) has a much lower DILI risk than Ligand B (77.782). This is a significant advantage for Ligand A.

**BBB:** Ligand A (55.797) has a better BBB percentile than Ligand B (43.893), though both are below the desirable >70 for CNS targets.

**Caco-2 Permeability:** Both have negative values, which is unusual. Assuming these are logP-like scales, lower values suggest poorer permeability. Ligand A (-5.066) appears to have worse Caco-2 permeability than Ligand B (-5.483).

**Aqueous Solubility:** Both have negative values, suggesting poor solubility. Ligand A (-0.237) is slightly better than Ligand B (-2.752).

**hERG Inhibition:** Both ligands show low hERG inhibition risk (A: 0.25, B: 0.331).

**Microsomal Clearance:** Ligand A (4.857) has a much lower microsomal clearance than Ligand B (28.641), indicating better metabolic stability.

**In vitro Half-Life:** Ligand B (104.27) has a significantly longer in vitro half-life than Ligand A (4.985).

**P-gp Efflux:** Both ligands show low P-gp efflux liability (A: 0.006, B: 0.06).

**Binding Affinity:** Ligand B (-8.8 kcal/mol) has a significantly stronger binding affinity than Ligand A (-7.2 kcal/mol). This is a substantial advantage, potentially outweighing some ADME drawbacks.

**Overall Assessment:**

Ligand B has a significantly better binding affinity, which is paramount for GPCR ligands. However, it suffers from higher DILI risk, poorer BBB penetration, and higher metabolic clearance. Ligand A has a better overall ADME profile (lower DILI, better BBB, better metabolic stability, higher QED), but weaker binding affinity.

Considering the GPCR-specific priorities, the stronger binding affinity of Ligand B is a major advantage. While its ADME properties are less favorable, the difference in binding affinity (-8.8 vs -7.2 kcal/mol) is substantial (>1.5 kcal/mol advantage). Optimization of Ligand B's ADME properties might be more feasible than significantly improving the affinity of Ligand A.

Output:
1
2025-04-17 09:08:42,384 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (373.559 and 351.372 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (63.68) is better than Ligand B (67.89). Both are below the 90 A^2 threshold desirable for CNS targets.

**logP:** Both ligands have good logP values (3.054 and 3.943), falling within the optimal 1-3 range. Ligand B is slightly higher, potentially increasing off-target interactions, but not drastically.

**H-Bond Donors/Acceptors:** Both ligands have a low number of HBDs (0) and acceptable HBAs (4 and 3 respectively), which is favorable for permeability.

**QED:** Both ligands have good QED scores (0.583 and 0.807), indicating good drug-like properties. Ligand B is better here.

**DILI:** Ligand A (39.938) has a slightly higher DILI risk than Ligand B (26.793), but both are below the concerning threshold of 60.

**BBB:** Both ligands have excellent BBB penetration (74.06 and 74.37), exceeding the 70% threshold for CNS targets.

**Caco-2 Permeability:** Ligand A (-4.796) has a worse Caco-2 permeability than Ligand B (-4.24).

**Aqueous Solubility:** Both ligands have poor aqueous solubility (-3.263 and -3.932). This could pose formulation challenges.

**hERG Inhibition:** Both ligands show low hERG inhibition risk (0.625 and 0.802).

**Microsomal Clearance:** Ligand A (45.153) has lower microsomal clearance than Ligand B (59.264), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (12.618) has a longer half-life than Ligand B (-9.547). This is a significant advantage.

**P-gp Efflux:** Both ligands show low P-gp efflux liability (0.521 and 0.175), which is good for CNS exposure. Ligand B is better here.

**Binding Affinity:** Ligand B (-7.2 kcal/mol) has a stronger binding affinity than Ligand A (-6.5 kcal/mol). This 0.7 kcal/mol difference is substantial and likely outweighs minor ADME drawbacks.

**Overall Assessment:**

Ligand B is the stronger candidate. While Ligand A has better metabolic stability and half-life, Ligand B's significantly improved binding affinity (-7.2 vs -6.5 kcal/mol) is the most important factor, especially for a GPCR target. The slight increase in logP for Ligand B is not a major concern given the good BBB penetration. The better QED and Pgp efflux also contribute to its favorability.

Output:
1
2025-04-17 09:08:42,385 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (361.431 and 339.508 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (134.92) is borderline, but acceptable for a CNS target, while Ligand B (9.72) is excellent, well below the 90 A^2 threshold.

**logP:** Ligand A (0.593) is quite low, potentially hindering membrane permeability. Ligand B (3.927) is near the upper end of the optimal range (1-3), but still acceptable.

**H-Bond Donors/Acceptors:** Ligand A has 4 HBD and 8 HBA, which are reasonable. Ligand B has 0 HBD and 4 HBA, which is also good.

**QED:** Both ligands have good QED scores (0.54 and 0.835, respectively), indicating drug-like properties.

**DILI:** Ligand A (65.103) has a higher DILI risk than Ligand B (49.166), though both are below the concerning 60 threshold.

**BBB:** This is critical for a CNS target. Ligand A (59.442) is moderately good, but Ligand B (99.031) is *excellent*, indicating very high brain penetration potential.

**Caco-2 Permeability:** Ligand A (-5.768) shows poor permeability, consistent with its low logP. Ligand B (-4.405) is better, but still not great.

**Aqueous Solubility:** Both ligands have very poor aqueous solubility (-2.71 and -3.404). This could pose formulation challenges.

**hERG Inhibition:** Ligand A (0.198) has a slightly higher hERG risk than Ligand B (0.984), but both are low.

**Microsomal Clearance:** Ligand A (-4.226) suggests lower metabolic clearance and better metabolic stability than Ligand B (-1.279).

**In vitro Half-Life:** Ligand A (12.124 hours) has a longer half-life than Ligand B (-8.056 hours).

**P-gp Efflux:** Ligand A (0.025) has very low P-gp efflux, which is highly desirable for CNS penetration. Ligand B (0.471) has moderate P-gp efflux.

**Binding Affinity:** Both ligands have excellent binding affinities (-9.0 and -8.6 kcal/mol), with Ligand A being slightly better. The affinity difference is less than 1.5 kcal/mol, so it's not a decisive factor on its own.

**Overall Assessment:**

Ligand B is the stronger candidate. While Ligand A has slightly better affinity and metabolic stability, Ligand B's *exceptional* BBB penetration (99.031) and lower P-gp efflux are crucial advantages for a CNS-targeting GPCR. The TPSA is also significantly better for Ligand B. The lower logP of Ligand A is a significant concern, potentially limiting its ability to cross cell membranes. While solubility is poor for both, this can be addressed with formulation strategies.



Output:
1
2025-04-17 09:08:42,385 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (338.411 and 348.531 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (64.68) is better than Ligand B (49.41) as it is closer to the ideal <90 for CNS targets.

**3. logP:** Ligand A (0.955) is suboptimal, being slightly below the preferred 1-3 range. Ligand B (3.894) is within the optimal range.

**4. H-Bond Donors:** Ligand A (2) and Ligand B (1) are both acceptable, being less than 5.

**5. H-Bond Acceptors:** Ligand A (3) and Ligand B (2) are both acceptable, being less than 10.

**6. QED:** Ligand A (0.804) is significantly better than Ligand B (0.39), indicating a more drug-like profile.

**7. DILI:** Ligand A (47.034) has a lower DILI risk than Ligand B (15.471), both are good, but A is better.

**8. BBB:** Ligand B (72.354) is significantly better than Ligand A (49.826) in terms of BBB penetration, a crucial factor for CNS targets like DRD2.

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.716 and -4.522), which is unusual and suggests poor permeability. This is a significant concern for both.

**10. Aqueous Solubility:** Both ligands have negative solubility values (-2.629 and -3.892), indicating very poor aqueous solubility. This is a major drawback.

**11. hERG Inhibition:** Ligand A (0.411) has a lower hERG inhibition liability than Ligand B (0.624), which is preferable.

**12. Microsomal Clearance:** Ligand A (-9.97) has a much lower (better) microsomal clearance than Ligand B (96.167), suggesting better metabolic stability.

**13. In vitro Half-Life:** Ligand A (-10.229) has a longer (better) in vitro half-life than Ligand B (-6.585).

**14. P-gp Efflux:** Ligand A (0.006) has significantly lower P-gp efflux liability than Ligand B (0.528), which is highly desirable for CNS penetration.

**15. Binding Affinity:** Ligand B (0.0) has a better binding affinity than Ligand A (-7.4).

**Overall Assessment:**

Ligand B has a significantly better BBB penetration and binding affinity. However, Ligand A has better QED, DILI, metabolic stability (lower Cl_mic and longer t1/2), lower P-gp efflux, and lower hERG inhibition. Both have poor solubility and permeability.

Given the GPCR-specific priorities, BBB penetration and affinity are critical. While Ligand A has a better ADME profile overall, the substantially better BBB and affinity of Ligand B outweigh the ADME advantages of Ligand A. The poor solubility and permeability are concerns for both, but can potentially be addressed with formulation strategies.

Output:
1
2025-04-17 09:08:42,385 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (353.463 and 349.475 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (78.95) is better than Ligand B (61.88) as it is closer to the <90 A^2 threshold for CNS targets.

**logP:** Ligand B (0.864) is slightly better than Ligand A (0.433). Both are a bit low, potentially hindering membrane permeability, but not drastically.

**H-Bond Donors:** Both ligands have 1 HBD, which is within the acceptable limit of <=5.

**H-Bond Acceptors:** Ligand A has 5 HBAs, and Ligand B has 4. Both are within the acceptable limit of <=10.

**QED:** Ligand B (0.693) has a better QED score than Ligand A (0.455), indicating a more drug-like profile.

**DILI:** Ligand B (8.53) has a significantly lower DILI risk than Ligand A (20.163), a major advantage.

**BBB:** Ligand A (74.06) has a substantially better BBB penetration score than Ligand B (45.56). This is *critical* for a CNS target like DRD2.

**Caco-2 Permeability:** Both ligands have very poor Caco-2 permeability (-4.794 and -4.795).

**Aqueous Solubility:** Both ligands have poor aqueous solubility (-0.799 and -0.868).

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.33 and 0.307).

**Microsomal Clearance:** Ligand B (-13.994) has a much lower (better) microsomal clearance than Ligand A (30.689), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand B (5.244) has a positive in vitro half-life, while Ligand A (-22.836) has a negative value, indicating faster degradation.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.027 and 0.013).

**Binding Affinity:** Ligand B (-7.3 kcal/mol) has a slightly better binding affinity than Ligand A (-6.8 kcal/mol). While the difference is less than the 1.5 kcal/mol threshold, it's still a positive factor.

**Overall Assessment:**

Ligand A excels in BBB penetration, which is paramount for a CNS target. However, it suffers from higher DILI risk, poorer metabolic stability (higher Cl_mic), and a shorter in vitro half-life. Ligand B has a better overall ADME profile (lower DILI, better metabolic stability, longer half-life, better QED), and slightly better binding affinity. The substantial advantage in BBB for Ligand A is tempting, but the ADME liabilities are concerning. Considering the overall balance, and the importance of metabolic stability and safety (DILI) for chronic CNS therapies, Ligand B is the more promising candidate.

Output:
1
2025-04-17 09:08:42,385 - INFO - Reasoning:

Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (336.439 and 349.479 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (77.81) is slightly higher than Ligand B (70.47). Both are below the 90 A^2 threshold desirable for CNS targets, but B is closer to optimal.

**3. logP:** Ligand A (4.049) is higher than the optimal range (1-3), potentially leading to solubility issues and off-target interactions. Ligand B (0.971) is slightly below the optimal range, which could hinder permeation, but is much more favorable than A.

**4. H-Bond Donors:** Ligand A (2) and Ligand B (1) are both within the acceptable limit of <=5.

**5. H-Bond Acceptors:** Ligand A (3) and Ligand B (5) are both within the acceptable limit of <=10.

**6. QED:** Both ligands have similar QED values (0.835 and 0.759), indicating good drug-like properties.

**7. DILI:** Ligand A (47.15) has a moderate DILI risk, while Ligand B (13.843) has a very low DILI risk, which is a significant advantage.

**8. BBB:** Ligand A (56.65) has a moderate BBB penetration, while Ligand B (63.474) has a better BBB penetration. Both are below the 70% threshold, but B is closer.

**9. Caco-2 Permeability:** Ligand A (-4.719) has poor Caco-2 permeability, while Ligand B (-5.045) also has poor Caco-2 permeability. Both are unfavorable.

**10. Aqueous Solubility:** Ligand A (-3.806) has poor aqueous solubility, while Ligand B (-0.196) has slightly better aqueous solubility.

**11. hERG Inhibition:** Ligand A (0.773) has a moderate hERG risk, while Ligand B (0.136) has a very low hERG risk, a major advantage.

**12. Microsomal Clearance:** Ligand A (9.067) has lower microsomal clearance than Ligand B (11.114), suggesting better metabolic stability.

**13. In vitro Half-Life:** Ligand A (58.412) has a longer in vitro half-life than Ligand B (12.125), which is favorable.

**14. P-gp Efflux:** Ligand A (0.079) has lower P-gp efflux than Ligand B (0.012), which is favorable for CNS penetration.

**15. Binding Affinity:** Ligand B (-7.9 kcal/mol) has a significantly stronger binding affinity than Ligand A (-9.4 kcal/mol). This is a substantial advantage, potentially outweighing some of the ADME drawbacks.

**Overall Assessment:**

While Ligand A has better metabolic stability and P-gp efflux, Ligand B is superior in almost all other critical aspects. Specifically, it has a much lower DILI risk, lower hERG risk, better BBB penetration, and a significantly stronger binding affinity. The higher logP of Ligand A is a concern, and its poor solubility and Caco-2 permeability are unfavorable. The substantial affinity difference (-7.9 vs -9.4 kcal/mol) is a key driver in the decision.

Output:
1
2025-04-17 09:08:42,386 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (340.423 and 354.451 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (71.34) is significantly better than Ligand B (96.35). For CNS targets, TPSA should be <=90, so Ligand A is preferable.

**logP:** Ligand A (2.632) is within the optimal 1-3 range. Ligand B (-1.92) is too low, potentially hindering permeation.

**H-Bond Donors/Acceptors:** Ligand A (HBD=2, HBA=3) and Ligand B (HBD=3, HBA=6) both have acceptable numbers, though Ligand B's HBA is higher.

**QED:** Both ligands have reasonable QED values (0.412 and 0.515), indicating drug-like properties. Ligand B is slightly better.

**DILI:** Ligand A (34.277) has a much lower DILI risk than Ligand B (6.863), a significant advantage.

**BBB:** Ligand A (54.634) has a better BBB percentile than Ligand B (9.965). This is *critical* for a CNS target like DRD2.

**Caco-2 Permeability:** Ligand A (-4.647) has worse Caco-2 permeability than Ligand B (-5.477), but both are poor.

**Aqueous Solubility:** Ligand A (-4.134) has slightly better solubility than Ligand B (-0.32).

**hERG:** Ligand A (0.323) has a lower hERG risk than Ligand B (0.12), which is preferable.

**Microsomal Clearance:** Ligand B (-8.994) has a *much* lower (better) microsomal clearance than Ligand A (33.404), indicating greater metabolic stability.

**In vitro Half-Life:** Ligand B (2.125) has a slightly longer half-life than Ligand A (1.078).

**P-gp Efflux:** Ligand A (0.281) has a lower P-gp efflux liability than Ligand B (0.002), which is beneficial for CNS penetration.

**Binding Affinity:** Ligand A (-7.9 kcal/mol) has a slightly better binding affinity than Ligand B (-7.3 kcal/mol). While both are good, the 0.6 kcal/mol difference is notable.

**Overall Assessment:**

Ligand A excels in crucial areas for a CNS-targeting GPCR ligand: TPSA, logP, BBB, DILI, and P-gp efflux. Its binding affinity is also slightly better. While Ligand B has better metabolic stability (lower Cl_mic) and a slightly longer half-life, these advantages are outweighed by its poor logP, low BBB penetration, and higher DILI risk. The improved CNS penetration profile of Ligand A is paramount for DRD2.

Output:
1
2025-04-17 09:08:42,386 - INFO - Reasoning:

Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (371.216 and 357.361 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (71.84) is significantly better than Ligand B (98.14). For CNS targets, we want TPSA <= 90, and A is comfortably within that, while B is slightly above.

**3. logP:** Ligand A (3.971) is optimal (1-3), while Ligand B (-0.039) is quite low, potentially hindering membrane permeability.

**4. H-Bond Donors:** Both have 2 HBD, which is acceptable (<=5).

**5. H-Bond Acceptors:** Ligand A has 4 HBA, and Ligand B has 6. Both are within the acceptable range (<=10).

**6. QED:** Both ligands have similar QED values (0.799 and 0.68), indicating good drug-likeness.

**7. DILI:** Ligand A (81.427) has a higher DILI risk than Ligand B (65.956). While both are above the preferred <40, B is better.

**8. BBB:** Ligand A (69.95) is lower than Ligand B (74.564). Both are reasonably good, but B is slightly better for CNS penetration.

**9. Caco-2:** Ligand A (-4.845) and Ligand B (-5.434) both have negative Caco-2 values, which is unusual and suggests poor permeability. However, the scale isn't specified, so it's hard to interpret.

**10. Solubility:** Ligand A (-4.777) and Ligand B (-1.564) both have negative solubility values, which is also unusual. Again, the scale is unclear.

**11. hERG:** Both ligands have very low hERG risk (0.416 and 0.145).

**12. Cl_mic:** Ligand A (19.796) has a higher microsomal clearance than Ligand B (-14.513). B's negative value suggests very high metabolic stability, which is a significant advantage.

**13. t1/2:** Ligand A (57.82) has a longer in vitro half-life than Ligand B (6.775). This is a positive for A.

**14. Pgp:** Both ligands have very low P-gp efflux liability (0.06 and 0.011).

**15. Binding Affinity:** Both ligands have excellent binding affinities (-9.7 and -9.2 kcal/mol). The difference of 0.5 kcal/mol is not substantial enough to outweigh other factors.

**Overall Assessment:**

Considering the GPCR-specific priorities, Ligand A's lower TPSA and longer half-life are positives. However, Ligand B's significantly better logP, lower DILI risk, and *much* better metabolic stability (Cl_mic) are more crucial for a CNS-targeting drug. The slightly better BBB for B is also a plus. The unusual negative values for Caco-2 and solubility are concerning for both, but the other advantages of B are more compelling.

Output:
1
2025-04-17 09:08:42,386 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (375.515 Da) is slightly higher than Ligand B (345.443 Da), but both are acceptable.

**TPSA:** Ligand A (63.24) is better than Ligand B (82.43). For CNS targets, we want TPSA <= 90, both are within this range, but A is preferable.

**logP:** Ligand A (3.836) is optimal (1-3), while Ligand B (1.77) is on the lower side. Lower logP can hinder permeation, making A more favorable.

**H-Bond Donors/Acceptors:** Both have 1 HBD and 4 HBA, which are within acceptable limits.

**QED:** Ligand A (0.833) has a significantly better QED score than Ligand B (0.646), indicating a more drug-like profile.

**DILI:** Ligand B (16.867) has a much lower DILI risk than Ligand A (77.743). This is a significant advantage for B.

**BBB:** Ligand B (71.229) has a better BBB penetration score than Ligand A (50.834). For a CNS target like DRD2, >70 is desirable, but B is significantly better than A.

**Caco-2 Permeability:** Ligand A (-5.217) has a worse Caco-2 permeability than Ligand B (-4.652). Higher values are better, so B is preferable.

**Aqueous Solubility:** Ligand A (-4.078) has a worse solubility than Ligand B (-2.31). Higher values are better, so B is preferable.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.15 and 0.275, respectively).

**Microsomal Clearance:** Ligand B (22.432) has a lower microsomal clearance than Ligand A (17.955), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (52.58) has a longer half-life than Ligand B (2.343). This is a positive for A.

**P-gp Efflux:** Ligand A (0.31) has lower P-gp efflux than Ligand B (0.01). Lower P-gp efflux is better, especially for CNS targets, making A more favorable.

**Binding Affinity:** Ligand A (-9.5 kcal/mol) has a significantly stronger binding affinity than Ligand B (-7.1 kcal/mol). This is a substantial advantage for A, potentially outweighing some of its ADME drawbacks. The difference of 2.4 kcal/mol is significant.

**Overall Assessment:**

Ligand A excels in binding affinity and P-gp efflux, and has a better half-life. However, it has concerningly high DILI risk, lower BBB penetration, and poorer solubility/permeability. Ligand B has a much better safety profile (lower DILI), better BBB penetration, solubility, and permeability, but weaker binding affinity.

Given the importance of BBB penetration for a CNS target like DRD2, and the substantial difference in binding affinity, the stronger binding affinity of Ligand A is likely to be the deciding factor. While the ADME properties of A are less ideal, optimization could potentially mitigate these issues. The 2.4 kcal/mol difference in binding is a large advantage that outweighs the ADME concerns.

Output:
1
2025-04-17 09:08:42,386 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (345.487 Da) is slightly lower, which is generally favorable for permeability. Ligand B (383.905 Da) is also acceptable.

**TPSA:** Ligand A (56.15) is excellent, well below the 90 A^2 threshold for CNS targets. Ligand B (88.91) is still reasonable, but less optimal.

**logP:** Ligand A (3.227) is optimal. Ligand B (2.391) is also within the acceptable range (1-3), but closer to the lower bound.

**H-Bond Donors/Acceptors:** Ligand A (HBD=1, HBA=5) is good. Ligand B (HBD=2, HBA=6) is also acceptable.

**QED:** Both ligands have good QED scores (A: 0.446, B: 0.718), indicating reasonable drug-likeness. Ligand B is better here.

**DILI:** Ligand A (12.602) has a much lower DILI risk than Ligand B (64.327), which is a significant advantage.

**BBB:** Ligand A (81.698) has a good BBB penetration percentile, exceeding the 70% threshold for CNS targets. Ligand B (46.568) is considerably lower and less desirable for a CNS target like DRD2.

**Caco-2 Permeability:** Ligand A (-4.956) has poor Caco-2 permeability, while Ligand B (-5.587) is also poor. This is a concern for both, but less critical given the focus on BBB penetration for a CNS drug.

**Aqueous Solubility:** Both ligands have poor aqueous solubility (-3.153 and -2.683 respectively). This could pose formulation challenges, but can sometimes be overcome.

**hERG Inhibition:** Ligand A (0.635) has a lower hERG risk than Ligand B (0.226), which is preferable.

**Microsomal Clearance:** Ligand A (70.754) has higher microsomal clearance than Ligand B (18.966), indicating lower metabolic stability.

**In vitro Half-Life:** Ligand B (31.448) has a significantly longer in vitro half-life than Ligand A (-2.314), which is a major advantage.

**P-gp Efflux:** Ligand A (0.449) has lower P-gp efflux than Ligand B (0.084), which is favorable for CNS penetration.

**Binding Affinity:** Both ligands have excellent binding affinities (-7.8 and -7.9 kcal/mol), with Ligand B being slightly better. The affinity difference is small and likely less important than the ADME differences.

**Overall Assessment:**

Ligand A excels in TPSA, logP, DILI, BBB, and P-gp efflux. However, it suffers from poor Caco-2 permeability, higher microsomal clearance, and a shorter half-life. Ligand B has a better QED, lower clearance, and a longer half-life, but has a higher DILI risk and significantly worse BBB penetration.

Given that DRD2 is a CNS target, **BBB penetration is paramount**. Ligand A's BBB percentile of 81.698 is far superior to Ligand B's 46.568. While Ligand B has a better half-life, the poor BBB penetration is a critical drawback. The slightly better affinity of Ligand B is unlikely to overcome the significant difference in CNS exposure.

Output:
0
2025-04-17 09:08:42,386 - INFO - Here's a step-by-step comparison of Ligand A and Ligand B, followed by my final decision:

**1. Molecular Weight (MW):**
*   Ligand A: 344.455 Da - Within the ideal range (200-500 Da).
*   Ligand B: 363.443 Da - Within the ideal range (200-500 Da).
*   *Both are acceptable.*

**2. Topological Polar Surface Area (TPSA):**
*   Ligand A: 58.64  - Excellent, well below the 90 A<sup>2</sup> threshold for CNS targets.
*   Ligand B: 111.21 - Above the preferred 90 A<sup>2</sup> for CNS targets, but not drastically so.
*   *Ligand A is significantly better.*

**3. Lipophilicity (logP):**
*   Ligand A: 2.043 - Optimal (1-3).
*   Ligand B: 0.659 - Below the optimal range, potentially hindering permeation.
*   *Ligand A is better.*

**4. H-Bond Donors (HBD):**
*   Ligand A: 1 - Acceptable (<=5).
*   Ligand B: 3 - Acceptable (<=5).
*   *Both are acceptable.*

**5. H-Bond Acceptors (HBA):**
*   Ligand A: 3 - Acceptable (<=10).
*   Ligand B: 6 - Acceptable (<=10).
*   *Both are acceptable.*

**6. Quantitative Estimate of Drug-likeness (QED):**
*   Ligand A: 0.794 - Excellent, well above the 0.5 threshold.
*   Ligand B: 0.723 - Good, above the 0.5 threshold.
*   *Ligand A is slightly better.*

**7. DILI Risk (DILI):**
*   Ligand A: 26.25 - Very low risk (below 40).
*   Ligand B: 66.848 - Moderate risk (above 60).
*   *Ligand A is significantly better.*

**8. Blood-Brain Barrier Penetration (BBB):**
*   Ligand A: 84.025 - Excellent, well above the 70% threshold for CNS targets.
*   Ligand B: 7.6 - Very poor BBB penetration.
*   *Ligand A is dramatically better.*

**9. Caco-2 Permeability:**
*   Ligand A: -4.841 - This is a negative value, which is unusual. Assuming this is a log scale, it suggests very poor permeability.
*   Ligand B: -5.531 - Also poor permeability, but slightly worse than Ligand A.
*   *Ligand A is slightly better.*

**10. Aqueous Solubility:**
*   Ligand A: -2.98 - Poor solubility.
*   Ligand B: -2.329 - Poor solubility, but slightly better than Ligand A.
*   *Ligand B is slightly better.*

**11. hERG Inhibition:**
*   Ligand A: 0.353 - Low risk.
*   Ligand B: 0.118 - Very low risk.
*   *Ligand B is slightly better.*

**12. Microsomal Clearance (Cl_mic):**
*   Ligand A: 39.236 mL/min/kg - Moderate clearance.
*   Ligand B: -7.828 mL/min/kg - Negative value is unusual, suggesting very low clearance/high metabolic stability.
*   *Ligand B is significantly better.*

**13. In vitro Half-Life:**
*   Ligand A: 14.809 hours - Good.
*   Ligand B: -8.373 hours - Negative value is unusual, suggesting very long half-life.
*   *Ligand B is significantly better.*

**14. P-gp Efflux:**
*   Ligand A: 0.168 - Low efflux, good.
*   Ligand B: 0.017 - Very low efflux, excellent.
*   *Ligand B is better.*

**15. Binding Affinity:**
*   Ligand A: -8.9 kcal/mol - Excellent.
*   Ligand B: -8.6 kcal/mol - Excellent, but slightly weaker than Ligand A.
*   *Ligand A is slightly better.*

**Overall Assessment:**

Given that this is a CNS target (DRD2, a GPCR), BBB penetration, TPSA, and logP are critical. Ligand A excels in BBB (84%) and TPSA (58.64), and has a good logP (2.043). While its Caco-2 permeability and solubility are poor, these are less critical for a CNS target. Ligand B has very poor BBB penetration (7.6%), which is a major drawback. Although Ligand B has better metabolic stability and lower P-gp efflux, the poor BBB penetration and higher DILI risk outweigh these benefits. Ligand A's slightly better affinity is also a plus.

Therefore, I recommend **Ligand A** as the more viable drug candidate.

1
2025-04-17 09:08:42,387 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 drug candidates, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (363.336 and 344.463 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (88.69) is better than Ligand B (81.66), both are below the 90 A^2 threshold for CNS targets.

**logP:** Ligand A (1.94) and Ligand B (2.833) are both within the optimal 1-3 range.

**H-Bond Donors:** Both ligands have 1 HBD, which is within the acceptable limit of <=5.

**H-Bond Acceptors:** Ligand A (6) and Ligand B (7) are both within the acceptable limit of <=10.

**QED:** Ligand A (0.883) has a significantly better QED score than Ligand B (0.714), indicating higher drug-likeness.

**DILI:** Ligand A (65.568) has a higher DILI risk than Ligand B (37.611). This is a negative for Ligand A.

**BBB:** Ligand A (88.872) has a better BBB penetration percentile than Ligand B (69.833). This is a significant advantage for a CNS target like DRD2.

**Caco-2 Permeability:** Ligand A (-4.388) has worse Caco-2 permeability than Ligand B (-5.59). Lower values indicate poorer permeability.

**Aqueous Solubility:** Both ligands have very poor aqueous solubility (-2.71 and -2.623). This is a concern for both, but not a deciding factor between them.

**hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.211 and 0.173).

**Microsomal Clearance:** Ligand A (19.081) has lower microsomal clearance than Ligand B (42.134), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (-22.602) has a much longer in vitro half-life than Ligand B (-8.086).

**P-gp Efflux:** Ligand A (0.041) has significantly lower P-gp efflux liability than Ligand B (0.344). This is crucial for CNS penetration.

**Binding Affinity:** Ligand A (-8.2 kcal/mol) has slightly better binding affinity than Ligand B (-7.7 kcal/mol). While the difference is not huge, it's still a positive for Ligand A.

**Overall Assessment:**

Ligand A is the better candidate. While it has a higher DILI risk, its advantages in BBB penetration, P-gp efflux, metabolic stability (lower Cl_mic, longer t1/2), QED, and binding affinity outweigh this drawback. The improved CNS penetration properties (BBB and P-gp) are particularly important for a DRD2 ligand. The slightly better binding affinity also contributes.

Output:
1
2025-04-17 09:08:42,387 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B against the provided guidelines, prioritizing GPCR-specific properties (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (361.423 and 349.406 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (111.55) is better than Ligand B (57). For CNS targets, TPSA should be <=90. Both are within this range, but A is closer to the upper limit.

**logP:** Both ligands have good logP values (1.036 and 1.386), falling within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A has 4 HBD and 6 HBA, while Ligand B has 0 HBD and 4 HBA. Both are within acceptable limits (<=5 HBD and <=10 HBA).

**QED:** Both ligands have good QED scores (0.614 and 0.81), indicating drug-like properties.

**DILI:** Ligand A (47.421) has a higher DILI risk than Ligand B (15.51). This is a significant advantage for Ligand B.

**BBB:** Ligand B (93.37) has a *much* higher BBB penetration percentile than Ligand A (16.363). This is a critical factor for a CNS target like DRD2.

**Caco-2 Permeability:** Ligand A (-5.691) has poor Caco-2 permeability, while Ligand B (-4.558) is slightly better, but still poor.

**Aqueous Solubility:** Both ligands have poor aqueous solubility (-2.493 and -2.017).

**hERG Inhibition:** Ligand A (0.082) has a very low hERG inhibition risk, better than Ligand B (0.488).

**Microsomal Clearance:** Ligand A (-4.258) has lower (better) microsomal clearance than Ligand B (4.371), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (-25.424) has a longer half-life than Ligand B (7.716).

**P-gp Efflux:** Ligand A (0.013) has very low P-gp efflux, significantly better than Ligand B (0.062). This is crucial for CNS penetration.

**Binding Affinity:** Ligand B (-9.7 kcal/mol) has a slightly better binding affinity than Ligand A (-8.9 kcal/mol). While A is good, B has a clear advantage.

**Overall Assessment:**

Ligand B is the stronger candidate. The overwhelmingly positive BBB score (93.37) is the deciding factor for a CNS target. The better DILI score and slightly improved binding affinity also contribute. While Ligand A has better P-gp efflux and metabolic stability, the BBB penetration of Ligand B is far superior and outweighs these advantages. Both have poor solubility and Caco-2 permeability, which would need to be addressed in further optimization, but these are less critical than CNS penetration for this target.

Output:
1
2025-04-17 09:08:42,387 - INFO - Batch 508 complete. Total preferences: 8128
2025-04-17 09:08:42,387 - INFO - Processing batch 509/512...
2025-04-17 09:09:23,344 - INFO - Reasoning:

Let's analyze Ligand A and Ligand B based on the provided guidelines, prioritizing GPCR-specific properties (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (332.407 and 343.391 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (80.9) is significantly better than Ligand B (88.41). For CNS targets, we want TPSA <= 90, and A is closer to the optimal range.

**logP:** Ligand A (3.158) is optimal (1-3), while Ligand B (0.866) is a bit low, potentially hindering permeation.

**H-Bond Donors/Acceptors:** Ligand A (2 HBD, 4 HBA) is preferable to Ligand B (1 HBD, 7 HBA) as it strikes a better balance.

**QED:** Both ligands have good QED scores (0.719 and 0.87), indicating drug-like properties.

**DILI:** Ligand A (77.782) is better than Ligand B (81.427), indicating a lower risk of drug-induced liver injury. Both are acceptable, but lower is always preferred.

**BBB:** Both ligands have excellent BBB penetration (71.966 and 73.672), exceeding the desirable >70 threshold for CNS targets.

**Caco-2 Permeability:** Ligand A (-5.489) and Ligand B (-4.826) both have negative values, which is unusual and suggests poor permeability. This is a concern for both, but the negative value is less severe for Ligand B.

**Aqueous Solubility:** Both ligands have poor aqueous solubility (-2.964 and -2.349). This is a drawback for both, potentially impacting bioavailability.

**hERG Inhibition:** Ligand A (0.72) is slightly higher than Ligand B (0.198), suggesting a marginally higher risk of hERG inhibition. Ligand B is much better here.

**Microsomal Clearance:** Ligand A (61.323) has a higher clearance than Ligand B (22.531), indicating lower metabolic stability. Ligand B is significantly better.

**In vitro Half-Life:** Ligand B (14.822 hours) has a significantly longer half-life than Ligand A (2.939 hours). This is a major advantage for Ligand B.

**P-gp Efflux:** Ligand A (0.414) has lower P-gp efflux liability than Ligand B (0.006), which is favorable for CNS exposure.

**Binding Affinity:** Ligand B (-7.9 kcal/mol) has a significantly stronger binding affinity than Ligand A (-10.4 kcal/mol). This is a substantial advantage, potentially outweighing some of the ADME drawbacks of Ligand B.

**Overall Assessment:**

While Ligand A has better TPSA and P-gp efflux, Ligand B excels in crucial areas for a CNS-targeting GPCR ligand: significantly stronger binding affinity, better metabolic stability (lower Cl_mic, longer t1/2), lower hERG risk, and acceptable BBB penetration. The slightly lower logP of Ligand B is a concern, but the substantial affinity advantage and improved metabolic properties are more important. The Caco-2 permeability is poor for both, but the other advantages of Ligand B are more compelling.

Output:
1
2025-04-17 09:09:23,344 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (347.419 and 346.435 Da) fall comfortably within the ideal 200-500 Da range.

**2. TPSA:** Both ligands have a TPSA around 93-94 A^2, which is acceptable but pushing the upper limit for CNS penetration (ideally <90 A^2).

**3. logP:** Both ligands have logP values around 1.07-1.33, which are within the optimal 1-3 range.

**4. H-Bond Donors:** Ligand A has 1 HBD, and Ligand B has 2. Both are acceptable (<=5).

**5. H-Bond Acceptors:** Both ligands have 6 HBAs, which is acceptable (<=10).

**6. QED:** Both have QED values > 0.7, indicating good drug-likeness.

**7. DILI:** Both ligands have similar DILI risk (around 39), which is good (low risk).

**8. BBB:** Ligand B (62.854%) has a slightly better BBB penetration percentile than Ligand A (57.193%), which is a crucial factor for a CNS target like DRD2.

**9. Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and problematic. Lower values indicate poor permeability.

**10. Aqueous Solubility:** Both ligands have negative solubility values, which is also problematic and suggests poor aqueous solubility.

**11. hERG Inhibition:** Both ligands have very low hERG inhibition liability (0.093 and 0.25), which is excellent.

**12. Microsomal Clearance:** Ligand B has a lower microsomal clearance (17.551 mL/min/kg) than Ligand A (32.172 mL/min/kg), suggesting better metabolic stability.

**13. In vitro Half-Life:** Ligand A has a slightly longer in vitro half-life (42.746 hours) than Ligand B (31.889 hours).

**14. P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.024 and 0.016), which is favorable for CNS penetration.

**15. Binding Affinity:** Both ligands have the same binding affinity (-8.1 kcal/mol), which is excellent and well below the -7.0 kcal/mol threshold.

**Overall Assessment:**

While both ligands have excellent binding affinity and acceptable drug-likeness properties, Ligand B is slightly more favorable due to its better BBB penetration (62.854% vs 57.193%) and lower microsomal clearance (17.551 vs 32.172). The negative Caco-2 and solubility values are concerning for both, but the stronger CNS penetration potential of Ligand B outweighs the slightly shorter half-life of Ligand B.

Output:
1
2025-04-17 09:09:23,344 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (339.439 and 351.451 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (64.11) is excellent, well below the 90 A^2 threshold for CNS targets. Ligand B (89.35) is still reasonable, but closer to the upper limit.

**3. logP:** Ligand A (4.304) is slightly high, potentially leading to solubility issues or off-target effects. Ligand B (0.981) is a bit low, which could hinder membrane permeability.

**4. H-Bond Donors:** Both ligands have 1 HBD, which is within the acceptable limit of <=5.

**5. H-Bond Acceptors:** Ligand A has 5 HBAs, and Ligand B has 6. Both are within the acceptable limit of <=10.

**6. QED:** Both ligands have similar QED values (0.823 and 0.791), indicating good drug-likeness.

**7. DILI:** Ligand A (44.591) has a lower DILI risk than Ligand B (61.109), which is preferable.

**8. BBB:** Ligand A (71.656) has a significantly better BBB penetration percentile than Ligand B (53.238). This is a crucial advantage for a CNS target like DRD2.

**9. Caco-2:** Ligand A (-4.467) and Ligand B (-5.221) both have negative Caco-2 values, which is unusual and suggests poor permeability. However, these values are on a different scale and hard to interpret directly.

**10. Solubility:** Ligand A (-5.341) has slightly better solubility than Ligand B (-1.475).

**11. hERG:** Both ligands have very low hERG inhibition liability (0.31 and 0.118), which is excellent.

**12. Cl_mic:** Ligand A (94.356) has a higher microsomal clearance than Ligand B (14.188), indicating faster metabolism and potentially lower *in vivo* exposure.

**13. t1/2:** Ligand B (0.634) has a slightly longer *in vitro* half-life than Ligand A (-0.87), which is desirable.

**14. Pgp:** Ligand A (0.102) has lower P-gp efflux liability than Ligand B (0.034), which is beneficial for CNS penetration.

**15. Binding Affinity:** Ligand B (-0.0 kcal/mol) has significantly weaker binding affinity than Ligand A (-9.1 kcal/mol). This is a major difference. A >1.5 kcal/mol advantage in binding affinity can often outweigh minor ADME drawbacks.

**Overall Assessment:**

Ligand A is the stronger candidate. While its logP is slightly elevated and its metabolic clearance is higher, its significantly superior binding affinity (-9.1 kcal/mol vs -0.0 kcal/mol) and much better BBB penetration (71.656% vs 53.238%) are critical advantages for a CNS-targeting GPCR like DRD2. The lower DILI risk is also a positive factor. The Caco-2 values are concerning for both, but the binding affinity difference is so substantial that it outweighs these concerns.

Output:
1
2025-04-17 09:09:23,345 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B based on the provided guidelines, prioritizing GPCR-specific properties (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (369.447 Da) is slightly lower, which could be beneficial for permeability, but both are acceptable.

**TPSA:** Ligand A (115.21) is better than Ligand B (37.38) for CNS penetration, being closer to the <90 A^2 target. Ligand B is quite low, which might suggest poor interactions with the receptor.

**logP:** Ligand A (-0.244) is suboptimal, being below the ideal 1-3 range. This could hinder membrane permeability. Ligand B (4.417) is high, potentially causing solubility issues and off-target effects, but within a tolerable range.

**H-Bond Donors/Acceptors:** Ligand A has 2 HBD and 8 HBA, which are reasonable. Ligand B has 0 HBD and 4 HBA, also acceptable.

**QED:** Both ligands have good QED scores (A: 0.48, B: 0.66), indicating reasonable drug-likeness.

**DILI:** Both have acceptable DILI risk (A: 74.176, B: 52.307), with Ligand B being slightly better.

**BBB:** Ligand B (76.115) significantly outperforms Ligand A (26.134) in BBB penetration, which is *critical* for a CNS target like DRD2.

**Caco-2 Permeability:** Both have negative Caco-2 values (-5.424 and -5.102), which is unusual and suggests poor permeability. However, these values are on a scale where negative values are possible, so it's difficult to interpret without knowing the scale's origin.

**Aqueous Solubility:** Both have negative solubility values (-2.454 and -4.492), again unusual. Similar to Caco-2, interpretation is limited without knowing the scale.

**hERG Inhibition:** Ligand A (0.048) has a very low hERG risk, which is excellent. Ligand B (0.961) has a higher, but still relatively low, hERG risk.

**Microsomal Clearance:** Ligand A (51.835) has lower clearance than Ligand B (62.763), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand B (66.904) has a much longer half-life than Ligand A (1.188), which is a significant advantage.

**P-gp Efflux:** Ligand A (0.007) has very low P-gp efflux, which is highly desirable for CNS penetration. Ligand B (0.739) has higher efflux, which could limit brain exposure.

**Binding Affinity:** Ligand B (-7.9 kcal/mol) has a substantially stronger binding affinity than Ligand A (-6.6 kcal/mol). This difference of 1.3 kcal/mol is significant and can outweigh some of the ADME drawbacks.

**Overall Assessment:**

Ligand B is the stronger candidate despite its higher logP and P-gp efflux. The significantly improved BBB penetration, substantially better binding affinity, and longer half-life are crucial advantages for a CNS-targeting GPCR. While Ligand A has better hERG and P-gp profiles, the affinity and BBB are more important for DRD2. The negative solubility and Caco-2 values are concerning for both, but the superior potency and CNS penetration of Ligand B make it the more promising candidate.

Output:
1
2025-04-17 09:09:23,345 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (331.379 Da) is slightly lower, which could be beneficial for permeability. Ligand B (367.877 Da) is also good.

**TPSA:** Ligand A (85.07) is excellent, falling well below the 90 A^2 threshold for CNS targets. Ligand B (64.43) is even better, suggesting improved BBB penetration potential.

**logP:** Both ligands have logP values within the optimal range (1-3), with Ligand A at 2.898 and Ligand B at 3.027. This is favorable for both permeability and solubility.

**H-Bond Donors/Acceptors:** Ligand A has 2 HBD and 6 HBA, which is acceptable. Ligand B has 0 HBD and 5 HBA, also acceptable.

**QED:** Both ligands have similar QED values (Ligand A: 0.767, Ligand B: 0.725), indicating good drug-like properties.

**DILI:** Ligand A has a higher DILI risk (84.025%) than Ligand B (40.791%). This is a significant concern for Ligand A.

**BBB:** Ligand B has a much better BBB penetration percentile (73.75%) than Ligand A (36.797%). This is a critical advantage for a CNS target like DRD2.

**Caco-2 Permeability:** Ligand A shows poor Caco-2 permeability (-5.312), suggesting poor intestinal absorption. Ligand B also shows poor Caco-2 permeability (-4.648), but is slightly better than Ligand A.

**Aqueous Solubility:** Both ligands have poor aqueous solubility (-4.624 and -3.185 respectively). This could pose formulation challenges.

**hERG Inhibition:** Ligand A has a slightly higher hERG inhibition risk (0.9) than Ligand B (0.292), but both are relatively low.

**Microsomal Clearance:** Both ligands have similar microsomal clearance values (Ligand A: 54.977, Ligand B: 54.155), indicating comparable metabolic stability.

**In vitro Half-Life:** Ligand B has a negative half-life (-2.996), which is unusual and suggests rapid degradation or a problem with the assay. Ligand A has a half-life of 12.602 hours, which is more reasonable.

**P-gp Efflux:** Ligand A has a slightly higher P-gp efflux liability (0.11) than Ligand B (0.36). Lower is better, so Ligand B is slightly favored.

**Binding Affinity:** Ligand A has a significantly stronger binding affinity (-8.9 kcal/mol) compared to Ligand B (-7.2 kcal/mol). This is a substantial advantage, potentially outweighing some of the ADME drawbacks.

**Overall Assessment:**

While Ligand A boasts a superior binding affinity, its high DILI risk, poor BBB penetration, and poor Caco-2 permeability are major concerns. Ligand B, despite having a slightly weaker affinity, presents a much more favorable ADME profile, particularly its excellent BBB penetration and lower DILI risk. The negative half-life for Ligand B is concerning, but could be an artifact of the assay. Given the CNS target and the importance of BBB penetration, Ligand B is the more promising candidate. The affinity difference, while significant, might be overcome with further optimization of Ligand B.

Output:
1
2025-04-17 09:09:23,345 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (345.403 and 346.387 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (93.26) is significantly better than Ligand B (129.43). For CNS targets, TPSA should be <= 90. Ligand A is close, while Ligand B exceeds this threshold, potentially hindering BBB penetration.

**3. logP:** Both ligands have good logP values (1.526 and 1.041), falling within the optimal 1-3 range.

**4. H-Bond Donors:** Ligand A (1) is preferable to Ligand B (2). Lower HBD generally improves permeability.

**5. H-Bond Acceptors:** Ligand A (6) is preferable to Ligand B (5). Both are within the acceptable limit of <= 10.

**6. QED:** Ligand A (0.907) has a substantially better QED score than Ligand B (0.795), indicating a more drug-like profile.

**7. DILI:** Both ligands have similar, acceptable DILI risk (38.697 and 39.473, both <40).

**8. BBB:** This is a critical parameter for a CNS target like DRD2. Ligand A (84.102) has a much higher BBB percentile than Ligand B (59.325). A value >70 is desirable, and Ligand A is closer to this target.

**9. Caco-2:** Both ligands have negative Caco-2 values (-5.018 and -5.278), which is unusual and difficult to interpret without further context. However, the values are similar.

**10. Solubility:** Both have negative solubility values (-2.635 and -3.294), also unusual. Again, values are similar.

**11. hERG:** Both ligands show low hERG inhibition liability (0.2 and 0.419), which is good.

**12. Cl_mic:** Ligand B (-18.754) has a significantly *lower* (better) microsomal clearance than Ligand A (12.295), suggesting greater metabolic stability.

**13. t1/2:** Ligand B (20.599) has a much longer in vitro half-life than Ligand A (-0.023), which is a significant advantage.

**14. Pgp:** Both ligands have low Pgp efflux liability (0.088 and 0.039).

**15. Binding Affinity:** Both ligands have excellent binding affinities (-9.0 and -8.3 kcal/mol). The difference of 0.7 kcal/mol is not large enough to outweigh other significant differences.

**Overall Assessment:**

Ligand A excels in TPSA, BBB, QED, and H-bond donor/acceptor counts, all critical for CNS penetration and drug-likeness. However, Ligand B demonstrates superior metabolic stability (lower Cl_mic) and a longer half-life. Considering the GPCR-specific priorities, the improved BBB penetration and drug-like properties of Ligand A are more crucial than the slightly better metabolic stability of Ligand B for a CNS target. The affinity difference is minimal.

Output:
1
2025-04-17 09:09:23,345 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (370.312 and 353.463 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (107.97) is slightly above the optimal <90 for CNS targets, but still reasonable. Ligand B (82.11) is well within the desired range.

**logP:** Ligand A (1.994) is optimal. Ligand B (-0.025) is slightly below the optimal range, which *could* hinder permeability, but isn't a major concern.

**H-Bond Donors/Acceptors:** Ligand A (HBD=3, HBA=5) and Ligand B (HBD=2, HBA=5) both have acceptable numbers of H-bond donors and acceptors.

**QED:** Both ligands have good QED scores (A: 0.596, B: 0.701), indicating drug-like properties.

**DILI:** Ligand A has a very high DILI risk (99.341), which is a significant red flag. Ligand B has a much lower, and acceptable, DILI risk (7.988).

**BBB:** Ligand A (37.301) has a poor BBB percentile, making CNS penetration unlikely. Ligand B (44.591) is better, but still not ideal (we want >70).

**Caco-2 Permeability:** Both have negative Caco-2 values (-5.655 and -5.129), which is unusual and suggests poor permeability. However, these values are on a log scale and could be interpreted as very low permeability.

**Aqueous Solubility:** Both ligands have negative solubility values (-2.86 and -1.232), indicating poor aqueous solubility.

**hERG:** Both ligands have very low hERG inhibition liability (A: 0.042, B: 0.356), which is excellent.

**Microsomal Clearance:** Ligand A (-14.658) has a very low (good) microsomal clearance, indicating high metabolic stability. Ligand B (-21.591) also has a low clearance, but is slightly higher than A.

**In vitro Half-Life:** Ligand A (-6.993) has a negative half-life, which is nonsensical. Ligand B (28.566) has a good in vitro half-life.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (A: 0.034, B: 0.01), which is favorable for CNS penetration.

**Binding Affinity:** Ligand A (-9.5 kcal/mol) has a significantly stronger binding affinity than Ligand B (-7.9 kcal/mol). The difference of 1.6 kcal/mol is substantial.

**Overall Assessment:**

Despite Ligand A's superior binding affinity, its extremely high DILI risk and poor BBB penetration are deal-breakers. The negative half-life is also concerning. Ligand B, while having a slightly weaker affinity, has a much better safety profile (low DILI), better BBB penetration, and a reasonable half-life. The solubility and permeability issues are shared by both, but could potentially be addressed with formulation strategies. Given the GPCR-specific priorities, and the importance of CNS penetration for DRD2, Ligand B is the more promising candidate.

Output:
1
2025-04-17 09:09:23,345 - INFO - Reasoning:

Let's analyze Ligand A and Ligand B for their potential as DRD2 drug candidates, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (354.491 and 348.382 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (78.87) is significantly better than Ligand B (93.96). For CNS targets, we want TPSA <= 90, so Ligand A is preferable.

**3. logP:** Both ligands have good logP values (1.563 and 1.489) within the optimal 1-3 range.

**4. H-Bond Donors:** Both have 2 HBD, which is acceptable.

**5. H-Bond Acceptors:** Ligand A has 4 HBA, while Ligand B has 7.  Lower HBA is generally preferred for better permeability, giving a slight edge to Ligand A.

**6. QED:** Both ligands have good QED scores (0.759 and 0.821), indicating good drug-like properties.

**7. DILI:** Both have relatively high DILI risk (7.794 and 76.425), but Ligand A is much lower. This is a significant advantage for Ligand A.

**8. BBB:** Ligand A (65.801) is better than Ligand B (60.45), but both are below the desirable >70 percentile for CNS targets. However, since we must choose between the two, Ligand A is better.

**9. Caco-2:** Ligand A (-4.542) is significantly better than Ligand B (-5.041). Higher Caco-2 values indicate better absorption.

**10. Solubility:** Ligand A (-1.784) is better than Ligand B (-2.587), although both are negative, indicating poor solubility.

**11. hERG:** Both ligands have very low hERG risk (0.304 and 0.063).

**12. Cl_mic:** Ligand B (14.79) has a much lower microsomal clearance than Ligand A (38.932), suggesting better metabolic stability. This is a significant advantage for Ligand B.

**13. t1/2:** Ligand B (-5.271) has a longer in vitro half-life than Ligand A (-11.382). This is another advantage for Ligand B.

**14. Pgp:** Ligand A (0.021) has a much lower P-gp efflux liability than Ligand B (0.088), which is crucial for CNS penetration.

**15. Binding Affinity:** Ligand B (-7.9) has a slightly better binding affinity than Ligand A (-7.6), a difference of 0.3 kcal/mol. While a 1.5 kcal/mol advantage is considered significant, 0.3 is less impactful, and can be offset by other factors.

**Overall Assessment:**

Ligand A excels in TPSA, DILI, Caco-2 permeability, solubility, and importantly, P-gp efflux. Ligand B has better metabolic stability (lower Cl_mic, longer t1/2) and slightly better affinity. However, the lower TPSA, DILI, and P-gp efflux of Ligand A are more critical for a CNS-targeting GPCR like DRD2. The slight affinity difference is outweighed by the more favorable ADME properties of Ligand A.

Output:
1
2025-04-17 09:09:23,345 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (345.443 and 367.877 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (70.49) is better than Ligand B (74.43). Both are below the 90 A^2 threshold for CNS targets, but A is closer to optimal.

**3. logP:** Both ligands (2.489 and 2.616) are within the optimal 1-3 range.

**4. H-Bond Donors:** Both have 2 HBD, which is acceptable.

**5. H-Bond Acceptors:** Ligand A has 5 HBA, while Ligand B has 3. Both are within the acceptable limit of <=10.

**6. QED:** Both ligands (0.757 and 0.727) have good drug-likeness scores (>0.5).

**7. DILI:** Ligand A (8.181) has a significantly lower DILI risk than Ligand B (46.297). This is a major advantage for Ligand A.

**8. BBB:** Ligand A (79.062) has a substantially better BBB penetration score than Ligand B (66.615). This is crucial for a CNS target like DRD2.

**9. Caco-2 Permeability:** Ligand A (-5.345) has worse Caco-2 permeability than Ligand B (-4.911). However, given the CNS target, intestinal absorption is less critical than BBB penetration.

**10. Aqueous Solubility:** Ligand A (-3.167) has slightly worse solubility than Ligand B (-4.03).

**11. hERG Inhibition:** Ligand A (0.904) has slightly higher hERG inhibition risk than Ligand B (0.416).

**12. Microsomal Clearance:** Ligand A (7.455) has lower microsomal clearance than Ligand B (10.469), indicating better metabolic stability.

**13. In vitro Half-Life:** Ligand A (-34.235) has a much longer in vitro half-life than Ligand B (10.461).

**14. P-gp Efflux:** Ligand A (0.079) has lower P-gp efflux liability than Ligand B (0.164), which is favorable for CNS exposure.

**15. Binding Affinity:** Ligand B (-7.9) has a slightly better binding affinity than Ligand A (-8.7). While affinity is important, the difference of 0.8 kcal/mol is not substantial enough to outweigh the significant advantages of Ligand A in other critical ADME properties, particularly for a CNS target.

**Overall Assessment:**

Ligand A is the superior candidate. It demonstrates a significantly better safety profile (lower DILI), much better BBB penetration, improved metabolic stability (lower Cl_mic, longer t1/2), and lower P-gp efflux. While Ligand B has slightly better affinity and Caco-2 permeability, these are less critical for a CNS-targeting GPCR like DRD2. The combination of favorable ADME properties makes Ligand A the more promising drug candidate.

Output:
1
2025-04-17 09:09:23,345 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (357.4) is slightly lower, which could be beneficial for permeability.

**TPSA:** Ligand A (79.38) is significantly better than Ligand B (82.7), falling comfortably under the 90 A^2 threshold for CNS targets. Ligand B is still reasonable, but less optimal.

**logP:** Ligand A (1.363) is within the optimal range (1-3). Ligand B (4.374) is higher, potentially leading to solubility issues and off-target interactions.

**H-Bond Donors/Acceptors:** Ligand A (HBD=2, HBA=6) and Ligand B (HBD=3, HBA=5) both have acceptable numbers of hydrogen bond donors and acceptors, well below the limits of 5 and 10 respectively.

**QED:** Ligand A (0.767) has a better QED score than Ligand B (0.595), indicating a more drug-like profile.

**DILI:** Ligand A (38.62) has a much lower DILI risk than Ligand B (84.839). This is a significant advantage for Ligand A.

**BBB:** Ligand A (86.274) has a substantially higher BBB penetration percentile than Ligand B (40.403). This is *critical* for a CNS target like DRD2.

**Caco-2 Permeability:** Ligand A (-4.828) and Ligand B (-5.316) both have negative Caco-2 permeability values, which is unusual and suggests poor permeability. However, the scale is not specified, so it's difficult to interpret.

**Aqueous Solubility:** Ligand A (-2.291) and Ligand B (-4.423) both have negative solubility values, which is also unusual and suggests poor solubility. Again, the scale is not specified.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (Ligand A: 0.486, Ligand B: 0.623).

**Microsomal Clearance:** Ligand A (4.774) has lower microsomal clearance than Ligand B (38.435), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand A (-11.805) has a negative half-life, which is not possible. This is a red flag. Ligand B (138.501) has a very long half-life, which is positive.

**P-gp Efflux:** Ligand A (0.018) has very low P-gp efflux liability, which is excellent for CNS penetration. Ligand B (0.409) has higher, but still relatively low, P-gp efflux.

**Binding Affinity:** Ligand B (-8.8 kcal/mol) has a slightly better binding affinity than Ligand A (-7.5 kcal/mol). However, the difference is not substantial enough to outweigh the significant ADME advantages of Ligand A.

**Overall Assessment:**

Ligand A is significantly better overall, particularly regarding CNS penetration (BBB, P-gp), metabolic stability (Cl_mic), and DILI risk. While the negative values for Caco-2 and Solubility are concerning and need further investigation, the substantial advantages in other key areas, especially for a CNS target, make Ligand A the more promising candidate. The negative half-life for Ligand A is a major concern and needs to be investigated. However, assuming this is a data error, Ligand A is still the better candidate.

Output:
1
2025-04-17 09:09:23,345 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (378.881 and 348.487 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (69.64) is slightly above the optimal <90 for CNS targets, but still reasonable. Ligand B (58.64) is well within the desired range.

**3. logP:** Both ligands have good logP values (2.965 and 2.657), falling within the 1-3 optimal range.

**4. H-Bond Donors:** Ligand A (2) and Ligand B (1) are both acceptable, below the threshold of 5.

**5. H-Bond Acceptors:** Ligand A (4) and Ligand B (3) are both acceptable, below the threshold of 10.

**6. QED:** Both ligands have similar, good QED values (0.807 and 0.803), indicating good drug-like properties.

**7. DILI:** Ligand A (47.344) has a better DILI score than Ligand B (15.859), indicating lower potential for liver injury.

**8. BBB:** Ligand B (78.441) has a significantly better BBB penetration score than Ligand A (69.213). This is a crucial advantage for a CNS target like DRD2.

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.768 and -4.742), which is unusual and suggests poor permeability. However, these values are on a scale where negative values are possible, and direct comparison is difficult without knowing the scale's specifics.

**10. Aqueous Solubility:** Both ligands have negative solubility values (-4.484 and -2.453), indicating poor aqueous solubility. This could present formulation challenges.

**11. hERG Inhibition:** Both ligands have low hERG inhibition risk (0.592 and 0.436).

**12. Microsomal Clearance:** Ligand A (14.361) has a lower microsomal clearance than Ligand B (63.027), suggesting better metabolic stability.

**13. In vitro Half-Life:** Ligand A (5.717) has a longer half-life than Ligand B (-2.273).

**14. P-gp Efflux:** Ligand A (0.453) has lower P-gp efflux liability than Ligand B (0.106), which is favorable for CNS penetration.

**15. Binding Affinity:** Ligand B (-7.5 kcal/mol) has a significantly stronger binding affinity than Ligand A (-9.1 kcal/mol). This is a substantial advantage, potentially outweighing some of the ADME drawbacks.

**Overall Assessment:**

While Ligand A has better DILI, metabolic stability, half-life, and P-gp efflux, Ligand B's significantly stronger binding affinity (-7.5 vs -9.1 kcal/mol) and superior BBB penetration (78.441 vs 69.213) are critical for a CNS-targeting GPCR like DRD2. The affinity difference is particularly important. The poor Caco-2 and solubility are concerns for both, but can potentially be addressed with formulation strategies.

Output:
1
2025-04-17 09:09:23,345 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (390.571 and 365.539 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (74.76) is better than Ligand B (49.77). Both are below the 90 A^2 threshold desirable for CNS targets, but Ligand A is pushing the upper limit.

**logP:** Ligand A (1.404) is within the optimal range (1-3), while Ligand B (3.751) is approaching the higher end. This could potentially lead to solubility issues for B.

**H-Bond Donors/Acceptors:** Ligand A has 0 HBD and 5 HBA, while Ligand B has 1 HBD and 4 HBA. Both are within acceptable limits.

**QED:** Both ligands have good QED scores (0.657 and 0.763, respectively), indicating good drug-like properties.

**DILI:** Ligand A (38.736) has a lower DILI risk than Ligand B (17.72), suggesting a better safety profile.

**BBB:** Ligand B (80.651) has a significantly better BBB penetration score than Ligand A (62.466). This is a crucial factor for a CNS target like DRD2.

**Caco-2 Permeability:** Ligand A (-5.129) shows poor Caco-2 permeability, while Ligand B (-4.625) is slightly better, but still not ideal.

**Aqueous Solubility:** Both ligands have very poor aqueous solubility (-2.3 and -3.012 respectively).

**hERG Inhibition:** Ligand A (0.185) has a lower hERG inhibition liability than Ligand B (0.751), a positive attribute.

**Microsomal Clearance:** Ligand B (73.211) has a significantly higher microsomal clearance than Ligand A (15.711), indicating faster metabolism and potentially lower in vivo exposure.

**In vitro Half-Life:** Ligand B (34.121) has a longer half-life than Ligand A (4.376), which is generally desirable.

**P-gp Efflux:** Ligand A (0.133) has lower P-gp efflux liability than Ligand B (0.827), which is beneficial for CNS penetration.

**Binding Affinity:** Ligand A (-7.1) has a slightly better binding affinity than Ligand B (-6.9). While both are good, the 0.2 kcal/mol difference isn't massive.

**Overall Assessment:**

Ligand B excels in BBB penetration and has a longer half-life. However, it suffers from higher logP, higher DILI risk, higher P-gp efflux, and significantly higher microsomal clearance. Ligand A has better DILI, hERG, P-gp, and clearance profiles, and a slightly better binding affinity. The poor Caco-2 permeability and solubility are concerning for both, but for a CNS target, BBB is paramount. While Ligand B's BBB is much better, the other ADME liabilities are significant drawbacks. The slightly better binding affinity of Ligand A, combined with its superior safety and metabolic stability profile, makes it the more promising candidate, despite the lower BBB score. Further optimization to improve BBB penetration for Ligand A would be a priority.

Output:
0
2025-04-17 09:09:23,346 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (351.491 Da) is slightly lower, which could be advantageous for permeability. Ligand B (386.901 Da) is also acceptable.

**TPSA:** Ligand A (61.88) is significantly better than Ligand B (92.34). For CNS targets, we want TPSA <= 90, so Ligand A is preferable.

**logP:** Both ligands have similar logP values (A: 1.415, B: 1.471), falling within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A (HBD=1, HBA=4) and Ligand B (HBD=2, HBA=4) both have reasonable H-bond characteristics, well within the guidelines.

**QED:** Both ligands have similar and good QED values (A: 0.735, B: 0.742), indicating good drug-like properties.

**DILI:** Ligand A (20.706) has a much lower DILI risk than Ligand B (65.491), which is a significant advantage.

**BBB:** Ligand A (62.156) has a better BBB percentile than Ligand B (43.001). While >70 is desirable, 62.156 is still a reasonable value and preferable to 43.001, especially given the CNS target.

**Caco-2 Permeability:** Ligand A (-4.659) and Ligand B (-5.516) both have negative values, which is unusual and suggests poor permeability. However, the scale isn't defined, so it's hard to interpret.

**Aqueous Solubility:** Both ligands have negative solubility values (A: -1.181, B: -2.823), indicating poor solubility. Ligand A is slightly better.

**hERG Inhibition:** Both ligands have very low hERG inhibition risk (A: 0.1, B: 0.102).

**Microsomal Clearance:** Ligand B (-9.323) has a *negative* microsomal clearance, which is impossible and suggests an error in the data. Ligand A (30.179) is a more reasonable value, indicating moderate clearance.

**In vitro Half-Life:** Ligand B (40.177) has a longer half-life than Ligand A (-19.628). However, the negative half-life for Ligand A is a clear error.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (A: 0.033, B: 0.114).

**Binding Affinity:** Ligand B (-9.2 kcal/mol) has a slightly better binding affinity than Ligand A (-7.4 kcal/mol). This is a 1.8 kcal/mol difference, which is significant.

**Overall Assessment:**

Despite the slightly better affinity of Ligand B, the numerous issues with its ADME profile make it a less attractive candidate. Specifically, the high DILI risk, poor BBB penetration, and the impossible negative microsomal clearance are major red flags. Ligand A, while having a slightly weaker affinity, has a much more favorable ADME profile, including lower DILI risk, better BBB penetration, and a reasonable (though moderate) microsomal clearance. The TPSA is also much better for CNS penetration. The negative values for Caco-2 and solubility are concerning for both, but the other factors favor Ligand A.

Output:
0
2025-04-17 09:09:23,346 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (362.411 and 349.475 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (122.53) is slightly above the optimal <90 for CNS targets, but still reasonable. Ligand B (69.72) is excellent, well below 90.

**logP:** Ligand A (0.65) is a bit low, potentially hindering permeability. Ligand B (1.566) is better, falling within the 1-3 optimal range.

**H-Bond Donors/Acceptors:** Ligand A has 3 HBD and 6 HBA, acceptable values. Ligand B has 1 HBD and 3 HBA, also acceptable and potentially preferable due to fewer hydrogen bonds.

**QED:** Both ligands have acceptable QED values (0.39 and 0.56), with Ligand B being slightly better.

**DILI:** Ligand A (61.768) has a moderate DILI risk, while Ligand B (14.618) has a very low risk, a significant advantage.

**BBB:** Ligand A (45.25) has a poor BBB penetration percentile, which is a major drawback for a CNS target. Ligand B (71.229) has a good BBB percentile, exceeding the >70 desirable threshold.

**Caco-2 Permeability:** Ligand A (-5.176) has poor Caco-2 permeability. Ligand B (-4.874) is also poor, but slightly better.

**Aqueous Solubility:** Both ligands have poor aqueous solubility (-2.841 and -1.838 respectively).

**hERG:** Both ligands have low hERG inhibition liability (0.172 and 0.27 respectively).

**Microsomal Clearance:** Ligand A (18.358) has lower microsomal clearance than Ligand B (56.43), indicating better metabolic stability.

**In vitro Half-Life:** Ligand A (10.935) has a shorter half-life than Ligand B (-14.682), which is unusual and potentially concerning.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.021 and 0.091 respectively).

**Binding Affinity:** Ligand B (-8.9 kcal/mol) has a significantly stronger binding affinity than Ligand A (-7.6 kcal/mol), exceeding the 1.5 kcal/mol advantage threshold.

**Overall Assessment:**

Ligand B is the superior candidate. While both have solubility issues, Ligand B excels in the critical areas for a CNS GPCR target: BBB penetration, lower DILI risk, and significantly higher binding affinity. The better logP and fewer hydrogen bonds also contribute to its favorability. Although Ligand A has better metabolic stability, the substantial benefits of Ligand B outweigh this advantage.

Output:
1
2025-04-17 09:09:23,346 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B based on the provided guidelines, prioritizing GPCR-specific properties (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (351.447 and 359.354 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (83.8) is significantly better than Ligand B (119.24). For CNS targets, TPSA should be <= 90, and A is comfortably within this range, while B is pushing the limit.

**logP:** Ligand A (0.629) is a bit low, potentially hindering permeation. Ligand B (-1.551) is even lower, raising more concerns about permeability. Both are below the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A (2 HBD, 5 HBA) and Ligand B (1 HBD, 6 HBA) both have acceptable numbers of H-bond donors and acceptors.

**QED:** Ligand A (0.719) has a better QED score than Ligand B (0.453), indicating a more drug-like profile.

**DILI:** Ligand B (44.552) has a lower DILI risk than Ligand A (20.24), which is favorable.

**BBB:** Ligand B (79.062) has a significantly better BBB penetration percentile than Ligand A (48.119). This is a *critical* advantage for a CNS target like DRD2.

**Caco-2 Permeability:** Both have negative Caco-2 values (-4.614 and -4.985), which is unusual and suggests poor permeability. However, these values are on a scale where negative values are possible and don't necessarily indicate a complete lack of permeability.

**Aqueous Solubility:** Both ligands have very poor aqueous solubility (-1.436 and -1.527). This is a significant drawback.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.091 and 0.171).

**Microsomal Clearance:** Ligand B (2.993) has a much lower microsomal clearance than Ligand A (13.12), indicating better metabolic stability.

**In vitro Half-Life:** Ligand B (-34.976) has a much longer in vitro half-life than Ligand A (8.766), which is highly desirable.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.061 and 0.026).

**Binding Affinity:** Ligand B (-7.7) has a slightly better binding affinity than Ligand A (-7.4), although the difference is relatively small (0.3 kcal/mol).

**Overall Assessment:**

While Ligand A has a better TPSA and QED, Ligand B excels in the most critical areas for a CNS GPCR target: BBB penetration, metabolic stability (lower Cl_mic, longer t1/2), and a slightly better binding affinity. The lower DILI risk for Ligand B is also a positive. The poor solubility and permeability (Caco-2) are concerns for both, but the superior CNS penetration profile of Ligand B outweighs the other drawbacks. The slightly lower logP of Ligand B is a concern, but the better BBB penetration suggests it can still reach the target.

Output:
1
2025-04-17 09:09:23,346 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (361.873 and 347.463 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (47.24) is excellent, well below the 90 A^2 threshold for CNS targets. Ligand B (90.12) is at the upper limit, but still acceptable.

**logP:** Ligand A (3.474) is optimal (1-3). Ligand B (1.105) is a bit low, potentially hindering permeability.

**H-Bond Donors/Acceptors:** Ligand A (0 HBD, 4 HBA) is favorable. Ligand B (3 HBD, 4 HBA) is also acceptable.

**QED:** Both ligands have good QED scores (0.818 and 0.719), indicating good drug-like properties.

**DILI:** Ligand A (49.632) has a moderate DILI risk, while Ligand B (10.585) has a very low risk. This favors Ligand B.

**BBB:** Ligand A (78.209) has a good BBB penetration percentile, desirable for a CNS target. Ligand B (60.644) is lower, which is a significant drawback.

**Caco-2 Permeability:** Ligand A (-4.334) has poor Caco-2 permeability. Ligand B (-5.66) is even worse. Both are problematic.

**Aqueous Solubility:** Ligand A (-3.98) has poor solubility. Ligand B (-1.489) is also poor, but slightly better.

**hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.256 and 0.238).

**Microsomal Clearance:** Ligand A (56.255) has moderate clearance. Ligand B (-21.345) has negative clearance, which is unusual and likely an error, but interpreted as very low clearance and thus high metabolic stability. This strongly favors Ligand B.

**In vitro Half-Life:** Ligand A (2.627 hours) has a short half-life. Ligand B (-22.519 hours) has a very long half-life, which is highly desirable.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.339 and 0.011), which is good. Ligand B is better.

**Binding Affinity:** Both ligands have very similar and excellent binding affinities (-8.7 kcal/mol and -8.5 kcal/mol). The difference is not substantial enough to override other factors.

**Overall Assessment:**

Ligand B is superior despite its slightly higher TPSA and lower logP. Its significantly lower DILI risk, much lower microsomal clearance (indicating better metabolic stability), and dramatically longer half-life are major advantages. While Ligand A has a better BBB score, the other ADME properties of Ligand B are far more compelling for a CNS-targeting drug candidate. The poor Caco-2 permeability of both is a concern that would need to be addressed in further optimization, but is less critical than metabolic stability and safety.

Output:
1
2025-04-17 09:09:23,346 - INFO - Batch 509 complete. Total preferences: 8144
2025-04-17 09:09:23,346 - INFO - Processing batch 510/512...
2025-04-17 09:10:06,819 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (366.622 and 355.523 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (49.41) is excellent, well below the 90 A^2 threshold for CNS targets. Ligand B (72.88) is still reasonable but higher, potentially impacting BBB penetration.

**logP:** Ligand A (3.894) is at the upper end of the optimal range (1-3), but acceptable. Ligand B (1.479) is a bit low, potentially hindering membrane permeability.

**H-Bond Donors/Acceptors:** Ligand A (HBD=1, HBA=2) and Ligand B (HBD=2, HBA=4) both have reasonable numbers of H-bond donors and acceptors, within the guidelines.

**QED:** Both ligands have similar QED values (0.75 and 0.657), indicating good drug-like properties.

**DILI:** Ligand A (26.755) has a much lower DILI risk than Ligand B (3.218), which is a significant advantage.

**BBB:** Ligand A (81.815) has a very good BBB penetration percentile, exceeding the desirable >70% threshold for CNS targets. Ligand B (52.811) is considerably lower, raising concerns about sufficient brain exposure.

**Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual. Assuming these are logP-like scales, lower values indicate lower permeability. Ligand B (-4.926) is worse than Ligand A (-4.493).

**Aqueous Solubility:** Both ligands have negative solubility values, which is also unusual. Assuming these are logS-like scales, lower values indicate lower solubility. Ligand B (-0.676) is slightly better than Ligand A (-4.493).

**hERG Inhibition:** Both ligands show very low hERG inhibition risk (0.458 and 0.427).

**Microsomal Clearance:** Ligand A (66.166) has a higher microsomal clearance than Ligand B (18.191), indicating faster metabolism and potentially lower in vivo exposure.

**In vitro Half-Life:** Ligand B (-0.157) has a slightly better in vitro half-life than Ligand A (-11.352).

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.228 and 0.019).

**Binding Affinity:** Ligand B (-6.4 kcal/mol) has a significantly stronger binding affinity than Ligand A (-0.0 kcal/mol). This is a substantial advantage, potentially outweighing some of the ADME concerns.

**Overall Assessment:**

Ligand B has a much better binding affinity, which is critical for GPCR targets. However, it suffers from lower BBB penetration, lower logP, and a slightly worse solubility. Ligand A has excellent BBB penetration and a lower DILI risk, but its binding affinity is very weak.

Given the importance of CNS penetration for a DRD2 ligand (involved in CNS disorders), and the substantial affinity difference, Ligand B is the more promising candidate *despite* its lower BBB score. The stronger binding affinity is likely to be more impactful than the moderate reduction in BBB penetration, and formulation strategies could be employed to mitigate solubility issues. The lower metabolic clearance of Ligand B is also favorable.



Output:
1
2025-04-17 09:10:06,819 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (357.5 and 349.5 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (82.11) is slightly higher than Ligand B (78.51), but both are below the 90 A^2 threshold desirable for CNS targets.

**logP:** Ligand A (1.018) is at the lower end of the optimal 1-3 range, while Ligand B (1.733) is better positioned. Lower logP can sometimes hinder permeation.

**H-Bond Donors/Acceptors:** Both have 2 HBDs, which is good. Ligand A has 5 HBAs, and Ligand B has 3. Both are within the acceptable limit of <=10.

**QED:** Both ligands have good QED scores (0.634 and 0.742), indicating drug-like properties.

**DILI:** Both have low DILI risk (23.77 and 20.40), which is favorable.

**BBB:** This is a critical parameter for a CNS target like DRD2. Ligand B (66.11) has a significantly better BBB percentile than Ligand A (30.59). This is a major advantage for Ligand B.

**Caco-2 Permeability:** Both have negative Caco-2 values (-5.039 and -5.179), which is unusual and suggests poor permeability. This is a concern for both, but doesn't necessarily disqualify either.

**Aqueous Solubility:** Both have negative solubility values (-1.577 and -2.752), indicating poor aqueous solubility. This could pose formulation challenges.

**hERG Inhibition:** Both have very low hERG inhibition risk (0.265 and 0.203).

**Microsomal Clearance:** Ligand A (14.197) has a higher microsomal clearance than Ligand B (3.456), suggesting lower metabolic stability.

**In vitro Half-Life:** Ligand A (-1.481) has a negative half-life, which is not possible. This is a red flag. Ligand B (0.84) has a short half-life, but it's a realistic value.

**P-gp Efflux:** Both have very low P-gp efflux liability (0.021 and 0.04).

**Binding Affinity:** Ligand B (-8.7 kcal/mol) has a significantly stronger binding affinity than Ligand A (-6.3 kcal/mol). This difference of 2.4 kcal/mol is substantial and can outweigh minor ADME drawbacks.

**Conclusion:**

Considering all factors, especially the crucial BBB penetration and binding affinity for a CNS GPCR target, **Ligand B is the more promising drug candidate**. Its superior BBB score, significantly stronger binding affinity, and better metabolic stability outweigh the slightly lower logP and solubility concerns. The negative half-life for Ligand A is a major issue.

Output:
1
2025-04-17 09:10:06,819 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 drug candidates, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (386.279 Da) is slightly higher than Ligand B (350.459 Da), but both are acceptable.

**TPSA:** Both ligands have TPSA values below 140, suggesting good oral absorption potential. However, for a CNS target like DRD2, we ideally want TPSA < 90. Ligand A (81.67) is better than Ligand B (89.87) in this regard.

**logP:** Both ligands have logP values within the optimal range (1-3). Ligand A (1.437) is slightly higher than Ligand B (0.829), which is preferable for CNS penetration.

**H-Bond Donors/Acceptors:** Both have 3 HBD and 4 HBA, which are within acceptable limits.

**QED:** Both ligands have QED values above 0.5, indicating good drug-likeness. Ligand A (0.734) is slightly better than Ligand B (0.655).

**DILI:** Ligand A (44.281) has a higher DILI risk than Ligand B (8.918). This is a significant drawback for Ligand A.

**BBB:** This is a crucial parameter for CNS targets. Ligand B (52.617) has a significantly higher BBB penetration percentile than Ligand A (24.855). This is a major advantage for Ligand B.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values, which is unusual and suggests poor permeability. However, the scale is not specified, so it's difficult to interpret.

**Aqueous Solubility:** Both have negative solubility values, again suggesting poor solubility. The scale is not specified, making interpretation difficult.

**hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.175 and 0.194), which is excellent.

**Microsomal Clearance:** Ligand A (-40.083) has a much lower (better) microsomal clearance than Ligand B (-0.986). This indicates better metabolic stability for Ligand A.

**In vitro Half-Life:** Ligand A (20.145 hours) has a significantly longer half-life than Ligand B (-3.966 hours). This is a substantial advantage for Ligand A.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.03 and 0.089), which is favorable for CNS exposure.

**Binding Affinity:** Ligand A (-8.8 kcal/mol) has a slightly better binding affinity than Ligand B (-7.7 kcal/mol). While both are good, the 1.1 kcal/mol difference is notable.

**Overall Assessment:**

Ligand A has advantages in binding affinity, metabolic stability (Cl_mic), and half-life. However, it suffers from a higher DILI risk and significantly lower BBB penetration. Ligand B excels in BBB penetration and has a much lower DILI risk, despite slightly weaker binding affinity and poorer metabolic stability.

Given the GPCR-specific priorities, particularly the importance of BBB penetration for CNS targets, **Ligand B is the more promising candidate.** The improved BBB penetration and lower DILI risk outweigh the slightly weaker binding affinity and poorer metabolic stability. The affinity of -7.7 kcal/mol is still considered good, and metabolic stability can be improved through further optimization.



Output:
1
2025-04-17 09:10:06,819 - INFO - Reasoning:

Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (354.328 and 346.431 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (59.59) is significantly better than Ligand B (99.23). For CNS targets, we want TPSA <= 90, and A is comfortably within this range, while B is above.

**3. logP:** Ligand A (4.382) is slightly higher than optimal (1-3), but still potentially acceptable. Ligand B (2.032) is well within the optimal range. However, for GPCRs, a slightly higher logP can be tolerated if other properties are favorable.

**4. H-Bond Donors:** Both ligands have acceptable HBD counts (2 and 1, respectively), well below the threshold of 5.

**5. H-Bond Acceptors:** Both ligands have acceptable HBA counts (3 and 5, respectively), below the threshold of 10.

**6. QED:** Both ligands have good QED scores (0.801 and 0.849), indicating good drug-like properties.

**7. DILI:** Ligand A (98.178) has a very high DILI risk, which is a major concern. Ligand B (31.989) has a much lower, and acceptable, DILI risk.

**8. BBB:** Both ligands have reasonable BBB penetration (64.831 and 61.535), but neither exceeds the desirable >70% for CNS targets.

**9. Caco-2:** Both ligands have negative Caco-2 values (-4.272 and -4.991). This is unusual and suggests poor permeability.

**10. Solubility:** Both ligands have negative solubility values (-5.341 and -2.491), indicating very poor aqueous solubility.

**11. hERG:** Ligand A (0.665) has a slightly higher hERG risk than Ligand B (0.233), but both are relatively low.

**12. Cl_mic:** Ligand A (92.556) has a higher microsomal clearance than Ligand B (32.576), suggesting lower metabolic stability.

**13. t1/2:** Ligand B (-19.787) has a negative in vitro half-life, which is not physically possible and indicates a very short half-life. Ligand A (31.77) has a more reasonable half-life.

**14. Pgp:** Ligand A (0.214) has lower P-gp efflux liability than Ligand B (0.077), which is favorable for CNS penetration.

**15. Binding Affinity:** Ligand A (-8.8 kcal/mol) has significantly stronger binding affinity than Ligand B (-7.9 kcal/mol). This is a substantial difference (>1.5 kcal/mol).

**Overall Assessment:**

Despite Ligand A's superior binding affinity, its extremely high DILI risk is a critical drawback. The poor solubility and Caco-2 permeability of both compounds are also concerning. Ligand B has a much better safety profile (DILI) and metabolic stability (Cl_mic), but its affinity is lower. The negative half-life for Ligand B is a showstopper.

Considering the GPCR-specific priorities, the strong affinity of Ligand A is attractive. However, the high DILI risk outweighs this benefit. Ligand B, while less potent, has a much more favorable safety profile.

Output:
0
2025-04-17 09:10:06,820 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (341.415 and 363.483 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (102.93) is slightly above the optimal <90 for CNS targets, but still reasonable. Ligand B (78.51) is excellent, well below 90.

**logP:** Both ligands (1.724 and 1.93) are within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A has 4 HBD and 5 HBA, which are acceptable. Ligand B has 2 HBD and 3 HBA, also acceptable and potentially slightly better for permeability.

**QED:** Both ligands have good QED scores (0.663 and 0.858), indicating good drug-like properties.

**DILI:** Both ligands have similar, acceptable DILI risk (45.328 and 44.552 percentile).

**BBB:** This is a critical parameter for a CNS target like DRD2. Ligand B (82.202) has a significantly higher BBB penetration percentile than Ligand A (39.007). This is a major advantage for Ligand B.

**Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and suggests a potential issue with the data or modeling. However, the values are similar.

**Aqueous Solubility:** Both ligands have negative solubility values, again suggesting a potential data issue. The values are similar.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (0.454 and 0.52).

**Microsomal Clearance:** Ligand A (-17.991) has a much lower (better) microsomal clearance than Ligand B (22.188). This suggests better metabolic stability for Ligand A.

**In vitro Half-Life:** Ligand A (17.452 hours) has a positive half-life, while Ligand B (-9.877 hours) has a negative half-life, which is concerning.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.014 and 0.078), which is favorable for CNS penetration.

**Binding Affinity:** Ligand B (-9.5 kcal/mol) has a slightly better binding affinity than Ligand A (-8.0 kcal/mol). The difference is 1.5 kcal/mol, which is significant enough to potentially outweigh some ADME drawbacks.

**Overall Assessment:**

Ligand B clearly wins on BBB penetration and binding affinity, both crucial for a CNS GPCR target. While Ligand A has better metabolic stability (lower Cl_mic and positive half-life), the superior BBB penetration and affinity of Ligand B are more important in this context. The negative solubility and Caco-2 values are concerning for both, but the difference in BBB and affinity is more decisive.

Output:
1
2025-04-17 09:10:06,820 - INFO - Reasoning:

Let's analyze Ligand A and Ligand B against the provided guidelines, prioritizing GPCR-specific properties (BBB, logP, Pgp, TPSA, and affinity) for DRD2.

**Molecular Weight:** Both ligands (354.451 and 312.442 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (90.98) is excellent for CNS penetration, being below 90. Ligand B (30.87) is also very good.

**logP:** Ligand A (0.037) is quite low, potentially hindering permeation. Ligand B (3.439) is within the optimal 1-3 range. This is a significant advantage for Ligand B.

**H-Bond Donors/Acceptors:** Ligand A has 2 HBD and 5 HBA, acceptable values. Ligand B has 1 HBD and 5 HBA, also acceptable.

**QED:** Both ligands have good QED scores (0.673 and 0.808), indicating drug-likeness.

**DILI:** Ligand A (15.083) has a very favorable DILI score, indicating low liver injury risk. Ligand B (66.305) is higher, suggesting a moderate risk.

**BBB:** Ligand A (49.515) has a moderate BBB penetration score, while Ligand B (94.572) is excellent, exceeding the desirable >70 threshold. This is a major advantage for Ligand B, given DRD2 is a CNS target.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values, which is unusual and requires further investigation. However, the magnitude of the negative value for Ligand A (-5.253) is more concerning than for Ligand B (-4.707).

**Aqueous Solubility:** Both ligands have negative solubility values, indicating poor aqueous solubility. Ligand A (-0.499) is slightly better than Ligand B (-3.765).

**hERG Inhibition:** Ligand A (0.144) shows very low hERG inhibition risk, while Ligand B (0.966) has a slightly elevated risk.

**Microsomal Clearance:** Ligand A (-57.626) has a very negative clearance, suggesting high metabolic stability. Ligand B (35.87) has a positive clearance, indicating faster metabolism.

**In vitro Half-Life:** Ligand A (-27.574) has a negative half-life, which is not possible and indicates an issue with the data. Ligand B (-18.94) also has a negative half-life, suggesting data quality concerns.

**P-gp Efflux:** Ligand A (0.002) has very low P-gp efflux, which is favorable for CNS penetration. Ligand B (0.633) has moderate P-gp efflux.

**Binding Affinity:** Ligand B (-8.2 kcal/mol) has a slightly better binding affinity than Ligand A (-7.4 kcal/mol), although both are good.

**Overall Assessment:**

Ligand B is the stronger candidate. While Ligand A has a better DILI score and slightly better hERG profile, Ligand B excels in crucial areas for a CNS-targeting GPCR ligand: significantly better BBB penetration, a more favorable logP, and slightly better binding affinity. The negative half-life values are concerning for both, but the other advantages of Ligand B outweigh this data quality issue. The lower logP of Ligand A is a significant drawback, potentially limiting its ability to cross cell membranes and reach the target in the brain.

Output:
1
2025-04-17 09:10:06,820 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (347.503 and 347.419 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (52.65) is significantly better than Ligand B (80.56). For CNS targets, we want TPSA <= 90, and ideally closer to 60. Ligand A is much closer to this ideal.

**3. logP:** Ligand A (2.713) is optimal (1-3). Ligand B (0.303) is quite low, potentially hindering permeation.

**4. H-Bond Donors:** Ligand A (1) is good. Ligand B (0) is also acceptable.

**5. H-Bond Acceptors:** Ligand A (3) is good. Ligand B (6) is acceptable, but higher.

**6. QED:** Both ligands have good QED values (0.687 and 0.765), indicating drug-like properties.

**7. DILI:** Both ligands have acceptable DILI risk (29.391 and 49.826), well below the concerning threshold of 60.

**8. BBB:** Ligand B (74.564) has a significantly better BBB penetration percentile than Ligand A (60.682). While both are reasonably good, >70 is desirable for CNS targets.

**9. Caco-2 Permeability:** Both have negative values, which is unusual. Assuming these are logP-scale values, lower values indicate lower permeability. Ligand A (-4.84) is worse than Ligand B (-4.637).

**10. Aqueous Solubility:** Both have negative values, which is unusual. Assuming these are logS-scale values, lower values indicate lower solubility. Ligand A (-3.868) is worse than Ligand B (-1.79).

**11. hERG Inhibition:** Both ligands show low hERG inhibition liability (0.513 and 0.105), which is good.

**12. Microsomal Clearance:** Ligand B (33.341) has lower microsomal clearance than Ligand A (43.368), suggesting better metabolic stability.

**13. In vitro Half-Life:** Ligand B (-6.015) has a longer in vitro half-life than Ligand A (5.063), which is favorable.

**14. P-gp Efflux:** Both ligands show low P-gp efflux liability (0.177 and 0.182).

**15. Binding Affinity:** Ligand B (-7.8 kcal/mol) has a slightly better binding affinity than Ligand A (-7.2 kcal/mol). This difference of 0.6 kcal/mol is significant, and can outweigh some ADME drawbacks.

**Overall Assessment:**

Ligand B excels in BBB penetration, metabolic stability (lower Cl_mic, longer t1/2), and binding affinity. While its logP is low, the superior affinity and BBB penetration are compelling for a CNS target like DRD2. Ligand A has a better TPSA and logP, but suffers from poorer BBB penetration and a less favorable metabolic profile. The slightly better affinity of Ligand B is also a key advantage. Given the GPCR-specific priorities, the improved CNS penetration and affinity of Ligand B make it the more promising candidate.

Output:
1
2025-04-17 09:10:06,820 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B based on the provided guidelines, prioritizing GPCR-specific properties (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (348.42 & 330.39 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (72.63) is better than Ligand B (58.03) as it is closer to the ideal <90 for CNS targets.

**logP:** Ligand A (2.323) is optimal (1-3). Ligand B (4.0) is slightly higher, potentially leading to solubility issues or off-target interactions.

**H-Bond Donors/Acceptors:** Both have acceptable HBD (1 & 2) and HBA (3 & 3) counts, well within the recommended limits.

**QED:** Both ligands have good QED scores (0.908 & 0.581), indicating drug-like properties.

**DILI:** Ligand A (21.481) has a significantly lower DILI risk than Ligand B (55.758), which is a substantial advantage.

**BBB:** Ligand A (94.223) has excellent BBB penetration, exceeding the desirable >70% threshold for CNS targets. Ligand B (49.787) is considerably lower and less favorable.

**Caco-2 Permeability:** Ligand A (-4.523) and Ligand B (-5.616) both have negative values, which is unusual. Assuming these are percentile scores, lower values indicate poorer permeability. Ligand A is slightly better.

**Aqueous Solubility:** Ligand A (-2.93) and Ligand B (-4.233) both have negative values, which is unusual. Assuming these are percentile scores, lower values indicate poorer solubility. Ligand A is slightly better.

**hERG:** Ligand A (0.578) has a lower hERG inhibition liability than Ligand B (0.878), which is preferable.

**Microsomal Clearance:** Ligand A (26.646) has higher microsomal clearance than Ligand B (12.951), indicating lower metabolic stability.

**In vitro Half-Life:** Ligand B (105.216) has a much longer in vitro half-life than Ligand A (-11.886), which is a significant advantage.

**P-gp Efflux:** Ligand A (0.074) has much lower P-gp efflux liability than Ligand B (0.569), which is crucial for CNS exposure.

**Binding Affinity:** Ligand B (-10.0) has a substantially stronger binding affinity than Ligand A (-8.7), a difference of 1.3 kcal/mol. This is a significant advantage that could outweigh some of the ADME drawbacks.

**Overall Assessment:**

While Ligand B boasts a superior binding affinity, Ligand A demonstrates a much more favorable ADME profile, particularly regarding BBB penetration, DILI risk, and P-gp efflux. For a CNS-targeting GPCR like DRD2, good brain penetration is paramount. The substantial difference in BBB (94.223 vs 49.787) and DILI risk (21.481 vs 55.758) heavily favor Ligand A. The better P-gp efflux of Ligand A further supports its potential for CNS exposure. Although Ligand B has a better half-life, the other factors make Ligand A the more promising candidate.

Output:
0
2025-04-17 09:10:06,820 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (384.483 Da) is slightly higher than Ligand B (338.382 Da), but both are acceptable.

**TPSA:** Ligand A (93.53) is borderline for CNS targets (<=90), while Ligand B (51.22) is well within the desired range. This is a significant advantage for Ligand B.

**logP:** Ligand A (0.672) is a bit low, potentially hindering membrane permeability. Ligand B (4.723) is high, potentially causing solubility issues and off-target interactions. However, for a CNS target, a higher logP can sometimes be tolerated to enhance BBB penetration, but it's a risk.

**H-Bond Donors/Acceptors:** Both ligands have a reasonable number of HBD (1) and HBA (Ligand A: 7, Ligand B: 3), falling within the acceptable limits.

**QED:** Both ligands have similar QED values (Ligand A: 0.757, Ligand B: 0.732), indicating good drug-likeness.

**DILI:** Ligand A (81.427) has a higher DILI risk than Ligand B (93.292). Lower is better, so Ligand B is preferable.

**BBB:** Ligand A (53.936) has a lower BBB penetration percentile than Ligand B (62.233). While neither are *excellent*, Ligand B is better suited for a CNS target.

**Caco-2 Permeability:** Ligand A (-5.394) has very poor Caco-2 permeability, while Ligand B (-4.617) is also poor, but slightly better.

**Aqueous Solubility:** Both have poor aqueous solubility (Ligand A: -2.511, Ligand B: -5.685). This is a concern for both, but Ligand B is worse.

**hERG Inhibition:** Ligand A (0.197) shows very low hERG inhibition risk, which is excellent. Ligand B (0.696) is slightly higher, but still relatively low.

**Microsomal Clearance:** Ligand A (28.22) has significantly lower microsomal clearance than Ligand B (113.382), suggesting better metabolic stability. This is a major advantage for Ligand A.

**In vitro Half-Life:** Ligand A (1.684) has a shorter half-life than Ligand B (57.293). This is a significant advantage for Ligand B.

**P-gp Efflux:** Ligand A (0.033) has very low P-gp efflux liability, which is excellent for CNS penetration. Ligand B (0.636) is higher, which could limit brain exposure.

**Binding Affinity:** Ligand B (-9.7 kcal/mol) has a significantly stronger binding affinity than Ligand A (-8.3 kcal/mol). This is a crucial factor, and the 1.4 kcal/mol difference is substantial.

**Overall Assessment:**

Ligand B has a stronger binding affinity and better BBB penetration, and a longer half-life. However, it suffers from a high logP, poor solubility, and higher P-gp efflux. Ligand A has better metabolic stability (lower Cl_mic), lower P-gp efflux, and a much lower hERG risk, but its affinity is weaker, and its BBB penetration is lower.

Given the importance of affinity for GPCRs, and the substantial difference (-9.7 vs -8.3 kcal/mol), Ligand B is more likely to be a viable drug candidate *despite* its drawbacks. The higher affinity could potentially be optimized through further medicinal chemistry to address the solubility and efflux issues. The lower affinity of Ligand A would likely require more extensive modification to achieve therapeutic efficacy.

Output:
1
2025-04-17 09:10:06,820 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B based on the provided guidelines, prioritizing GPCR-specific properties (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (354.407 Da) is slightly lower, which could be beneficial for permeability.

**TPSA:** Ligand A (102.75) is better than Ligand B (130.23). For CNS targets, we want TPSA <= 90, so Ligand A is closer to this threshold.

**logP:** Ligand A (-0.949) is suboptimal, being below the preferred 1-3 range. Ligand B (1.418) is within the optimal range. This favors Ligand B.

**H-Bond Donors/Acceptors:** Ligand A (HBD=1, HBA=6) is better than Ligand B (HBD=4, HBA=7) in terms of maintaining a balance between solubility and permeability.

**QED:** Both ligands have similar QED values (0.663 vs 0.579), indicating reasonable drug-likeness.

**DILI:** Ligand A (56.223) has a significantly lower DILI risk than Ligand B (79.333). This is a major advantage for Ligand A.

**BBB:** Ligand A (38.891) has a lower BBB penetration percentile than Ligand B (46.336). While both are below the desirable >70 for CNS targets, Ligand B is better.

**Caco-2 Permeability:** Both have negative values, indicating poor permeability. Ligand A (-4.957) is slightly better than Ligand B (-5.297).

**Aqueous Solubility:** Both have negative values, indicating poor solubility. Ligand A (-0.617) is slightly better than Ligand B (-4.371).

**hERG Inhibition:** Ligand A (0.066) has a much lower hERG inhibition liability than Ligand B (0.391). This is a significant advantage for Ligand A.

**Microsomal Clearance:** Ligand A (-1.929) has lower (better) microsomal clearance than Ligand B (8.381), suggesting greater metabolic stability.

**In vitro Half-Life:** Ligand A (-19.573) has a lower in vitro half-life than Ligand B (-16.782). This is a disadvantage for Ligand A.

**P-gp Efflux:** Ligand A (0.015) has much lower P-gp efflux liability than Ligand B (0.039), which is crucial for CNS penetration.

**Binding Affinity:** Ligand B (-8.2 kcal/mol) has a slightly better binding affinity than Ligand A (-7.2 kcal/mol). This is a 1.0 kcal/mol difference, which is significant, but needs to be weighed against other factors.

**Overall Assessment:**

Ligand A excels in safety parameters (DILI, hERG), metabolic stability (Cl_mic), and P-gp efflux. Its TPSA is also better. However, it suffers from poor logP and BBB penetration. Ligand B has a better logP and BBB, and slightly better affinity, but has significantly higher DILI and hERG risk, and higher P-gp efflux.

Given the CNS target and the importance of BBB penetration, the slightly better affinity of Ligand B is tempting. However, the substantial improvements in safety (DILI, hERG) and efflux (P-gp) with Ligand A, alongside its better TPSA and metabolic stability, are more critical. The poor logP of Ligand A could potentially be addressed with further optimization, while mitigating the high DILI/hERG risk of Ligand B would be more challenging.

Output:
0
2025-04-17 09:10:06,820 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (356.817 and 361.511 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (96.45) is slightly above the optimal <90 for CNS targets, but still reasonable. Ligand B (59.23) is excellent, well below 90.

**3. logP:** Both ligands have good logP values (3.063 and 4.579), falling within the 1-3 range, though Ligand B is pushing the upper limit.

**4. H-Bond Donors:** Ligand A has 2 HBD, which is acceptable. Ligand B has 0, also acceptable.

**5. H-Bond Acceptors:** Both ligands have 5 HBA, which is within the acceptable limit of <=10.

**6. QED:** Both ligands have similar QED values (0.748 and 0.756), indicating good drug-likeness.

**7. DILI:** Ligand A (88.639) has a higher DILI risk than Ligand B (41.14). This is a significant negative for Ligand A.

**8. BBB:** Ligand A (62.233) has a moderate BBB penetration, while Ligand B (84.606) has a very good BBB penetration. This is a crucial factor for a CNS target like DRD2, favoring Ligand B.

**9. Caco-2 Permeability:** Both have negative values, which is unusual. It suggests poor permeability. However, the scale is not specified, so it's hard to interpret.

**10. Aqueous Solubility:** Both ligands have very poor aqueous solubility (-3.851 and -5.409). This is a concern for both, but could be mitigated with formulation strategies.

**11. hERG Inhibition:** Ligand A (0.155) has a slightly higher hERG risk than Ligand B (0.552), but both are relatively low.

**12. Microsomal Clearance:** Ligand A (10.371) has lower microsomal clearance, suggesting better metabolic stability than Ligand B (99.586).

**13. In vitro Half-Life:** Ligand A (9.826) has a longer half-life than Ligand B (6.628).

**14. P-gp Efflux:** Ligand A (0.215) has lower P-gp efflux, which is beneficial for CNS penetration, compared to Ligand B (0.374).

**15. Binding Affinity:** Both ligands have excellent binding affinities (-8.4 and -8.1 kcal/mol). The difference of 0.3 kcal/mol is not substantial enough to override other factors.

**Overall Assessment:**

Ligand B is the more promising candidate. While both have poor solubility, Ligand B excels in crucial areas for a CNS-targeting GPCR: significantly better BBB penetration, lower DILI risk, and a more favorable TPSA. Ligand A has better metabolic stability (lower Cl_mic) and longer half-life, and lower P-gp efflux, but the higher DILI risk and lower BBB penetration are major drawbacks. The affinity difference is minimal.

Output:
1
2025-04-17 09:10:06,820 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (354.403 and 356.373 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (102.96) is better than Ligand B (107.11). Both are reasonably good for CNS penetration, being below the 140 A^2 threshold, and A is closer to the preferred <90 A^2 for CNS targets.

**3. logP:** Ligand A (0.741) is slightly lower than optimal (1-3), but still acceptable. Ligand B (1.106) is better within the optimal range.

**4. H-Bond Donors:** Ligand A (2) is preferable to Ligand B (4). Fewer HBDs generally improve permeability.

**5. H-Bond Acceptors:** Ligand A (6) is preferable to Ligand B (4). Fewer HBAs generally improve permeability.

**6. QED:** Both ligands have good QED scores (0.516 and 0.612), indicating good drug-like properties.

**7. DILI:** Ligand A (45.677) has a lower DILI risk than Ligand B (55.68), which is preferable.

**8. BBB:** Ligand A (67.584) has a slightly better BBB penetration percentile than Ligand B (61.962), though both are below the desirable >70 for CNS targets.

**9. Caco-2:** Ligand A (-4.767) has a worse Caco-2 permeability than Ligand B (-5.262). Lower values here indicate poor permeability.

**10. Solubility:** Ligand A (-2.44) has better solubility than Ligand B (-3.141).

**11. hERG:** Ligand A (0.123) has a significantly lower hERG inhibition risk than Ligand B (0.327), which is a major advantage.

**12. Cl_mic:** Ligand B (0.568) has significantly better metabolic stability (lower clearance) than Ligand A (50.781).

**13. t1/2:** Ligand B (-11.078) has a longer in vitro half-life than Ligand A (-18.1).

**14. Pgp:** Ligand A (0.014) has a much lower P-gp efflux liability than Ligand B (0.042), which is critical for CNS penetration.

**15. Binding Affinity:** Ligand B (-7.8) has a slightly better binding affinity than Ligand A (-7.1). This 1.5 kcal/mol difference is significant and can outweigh some ADME drawbacks.

**Overall Assessment:**

While Ligand B has a better binding affinity and metabolic stability, Ligand A has a significantly better safety profile (lower DILI and hERG) and better P-gp efflux liability, which is crucial for CNS penetration. The TPSA is also more favorable for Ligand A. The slightly lower affinity of Ligand A is less concerning given its improved safety and CNS penetration properties. Given the target is a CNS GPCR (DRD2), BBB penetration, Pgp efflux, and safety are paramount.

Output:
0
2025-04-17 09:10:06,821 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (357.479 and 348.447 Da) fall within the ideal range of 200-500 Da.

**2. TPSA:** Ligand A (49.05) is excellent, well below the 90 Angstroms threshold for CNS targets. Ligand B (88.67) is higher, but still potentially acceptable, though less ideal.

**3. logP:** Ligand A (3.751) is optimal. Ligand B (0.44) is significantly low, potentially hindering membrane permeability and CNS penetration.

**4. H-Bond Donors:** Ligand A (0) is good. Ligand B (3) is acceptable.

**5. H-Bond Acceptors:** Ligand A (5) is good. Ligand B (4) is good.

**6. QED:** Both ligands have reasonable QED scores (0.837 and 0.696), indicating good drug-like properties.

**7. DILI:** Ligand A (50.291) has a moderate DILI risk, while Ligand B (16.906) has a very low DILI risk.

**8. BBB:** Ligand A (86.08) has a very good BBB penetration percentile. Ligand B (20.24) has poor BBB penetration. This is a critical factor for a CNS target like DRD2.

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.226 and -5.472), which is unusual and suggests poor permeability. However, these values are on a scale where negative values are possible and don't necessarily disqualify a compound.

**10. Aqueous Solubility:** Both ligands have negative solubility values (-3.434 and -1.402), which is also unusual. This indicates very low solubility.

**11. hERG Inhibition:** Ligand A (0.872) has a slightly elevated hERG risk, but not alarming. Ligand B (0.368) has a very low hERG risk.

**12. Microsomal Clearance:** Ligand A (19.127) has moderate clearance. Ligand B (-30.781) has a negative clearance, which is not physically possible and likely an artifact of the prediction method. This is a significant red flag.

**13. In vitro Half-Life:** Ligand A (40.519) has a reasonable half-life. Ligand B (6.245) has a very short half-life.

**14. P-gp Efflux:** Ligand A (0.514) has moderate P-gp efflux. Ligand B (0.012) has very low P-gp efflux, which is favorable for CNS penetration.

**15. Binding Affinity:** Ligand A (-8.1 kcal/mol) has significantly stronger binding affinity than Ligand B (-0.0 kcal/mol). This is a major advantage.

**Overall Assessment:**

Ligand A is the stronger candidate despite some drawbacks. Its superior binding affinity, good TPSA, and excellent BBB penetration outweigh its moderate DILI risk and moderate P-gp efflux. Ligand B suffers from a very low logP, poor BBB penetration, a nonsensical negative clearance value, and a very weak binding affinity. The negative values for Caco-2 and solubility are concerning for both, but the affinity and BBB are paramount for a CNS GPCR target.

Output:
1
2025-04-17 09:10:06,821 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (367.519 Da) is slightly higher than Ligand B (350.547 Da), but both are acceptable.

**TPSA:** Ligand A (87.22) is better than Ligand B (49.41). For CNS targets, TPSA should be <=90, and ideally lower. Ligand B is significantly better in this regard, suggesting better BBB penetration potential.

**logP:** Ligand A (1.354) is within the optimal range (1-3). Ligand B (4.28) is above this range, potentially leading to solubility issues and off-target interactions.

**H-Bond Donors/Acceptors:** Ligand A has 2 HBD and 6 HBA, while Ligand B has 1 HBD and 2 HBA. Both are within acceptable limits.

**QED:** Both ligands have similar QED values (0.76 and 0.745), indicating good drug-likeness.

**DILI:** Ligand A (13.649) has a much lower DILI risk than Ligand B (21.791). This is a significant advantage for Ligand A.

**BBB:** Ligand B (83.288) has a substantially higher BBB penetration percentile than Ligand A (51.997). This is crucial for a CNS target like DRD2.

**Caco-2 Permeability:** Ligand A (-5.603) has a negative Caco-2 value, which is unusual and suggests poor permeability. Ligand B (-4.7) is also negative, but less so.

**Aqueous Solubility:** Ligand A (-1.432) has slightly better solubility than Ligand B (-4.246).

**hERG Inhibition:** Both ligands show very low hERG inhibition risk (0.078 and 0.62).

**Microsomal Clearance:** Ligand A (-25.058) has a much lower (better) microsomal clearance than Ligand B (75.869), indicating better metabolic stability.

**In vitro Half-Life:** Ligand A (6.585) has a shorter half-life than Ligand B (-4.847). A negative half-life is unusual and likely indicates a very rapid degradation.

**P-gp Efflux:** Ligand A (0.01) shows very low P-gp efflux, which is favorable for CNS penetration. Ligand B (0.444) shows slightly higher efflux.

**Binding Affinity:** Both ligands have very similar and strong binding affinities (-8.0 and -8.3 kcal/mol). The difference is minimal.

**Overall Assessment:**

Ligand B excels in BBB penetration, which is paramount for a CNS target. However, it suffers from a higher logP, higher DILI risk, and significantly worse metabolic stability (higher Cl_mic). Ligand A has a better safety profile (lower DILI), better metabolic stability, and lower P-gp efflux. While its BBB penetration is lower, its TPSA is more favorable. The negative Caco-2 values for both are concerning, but the overall profile of Ligand A is more promising, especially considering the strong binding affinity is comparable between the two. The poor half-life of Ligand A is a concern, but could potentially be addressed through structural modifications.

Output:
1
2025-04-17 09:10:06,821 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (349.431 and 368.503 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (93.11) is slightly above the optimal <90 for CNS targets, but still reasonable. Ligand B (87.32) is better, falling comfortably below 90.

**logP:** Ligand A (-0.036) is quite low, potentially hindering membrane permeability. Ligand B (1.92) is within the optimal 1-3 range. This is a significant advantage for Ligand B.

**H-Bond Donors/Acceptors:** Ligand A has 3 HBD and 5 HBA, which are acceptable. Ligand B has 2 HBD and 5 HBA, also acceptable.

**QED:** Both ligands have similar QED values (0.643 and 0.65), indicating good drug-likeness.

**DILI:** Ligand A (3.916) has a very low DILI risk, excellent. Ligand B (50.33) is higher, but still within an acceptable range, though it warrants monitoring.

**BBB:** Ligand A (9.616) has very poor predicted BBB penetration, a major drawback for a CNS target. Ligand B (51.725) is significantly better, though not exceptional, it's a substantial improvement.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.964 and -5.165), which is unusual and suggests poor permeability. However, these are percentile scores, and the negative values are likely indicating very low permeability.

**Aqueous Solubility:** Both ligands have negative solubility values (-1.187 and -3.283), indicating poor aqueous solubility. This is a concern for both.

**hERG Inhibition:** Ligand A (0.076) shows very low hERG inhibition risk, excellent. Ligand B (0.46) is slightly higher, but still relatively low.

**Microsomal Clearance:** Ligand A (-30.886) has very low microsomal clearance, indicating high metabolic stability, which is good. Ligand B (46.756) has higher clearance, suggesting faster metabolism.

**In vitro Half-Life:** Ligand A (-2.096) has a very short in vitro half-life, a significant drawback. Ligand B (-35.394) also has a short half-life, but is slightly better than Ligand A.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.003 and 0.051), which is favorable for CNS penetration.

**Binding Affinity:** Ligand A (-8.2 kcal/mol) has a significantly stronger binding affinity than Ligand B (-7.6 kcal/mol). This is a substantial advantage for Ligand A.

**Overall Assessment:**

Despite Ligand A's superior binding affinity, its extremely poor BBB penetration and short half-life are major concerns for a CNS-targeted GPCR. The low logP also hinders permeability. Ligand B, while having a slightly weaker affinity, possesses a much better predicted BBB penetration, a more favorable logP, and acceptable DILI and hERG risk profiles. The metabolic stability and half-life are worse for Ligand B, but the difference in binding affinity (0.6 kcal/mol) is less critical than the significant improvements in ADME properties crucial for CNS drug development.

Output:
1
2025-04-17 09:10:06,821 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (347.434 Da) is slightly preferred due to being lower in weight.

**TPSA:** Both ligands have TPSA values (62.3 and 64.86) that are acceptable for oral absorption and reasonably good for CNS penetration, being below the 90 A^2 threshold for CNS targets.

**logP:** Both ligands have logP values (2.71 and 3.021) within the optimal range (1-3).

**H-Bond Donors/Acceptors:** Both have 1 HBD, which is good. Ligand A has 3 HBA, while Ligand B has 6. Lower HBA is generally preferred for better permeability, giving a slight edge to Ligand A.

**QED:** Ligand A (0.833) has a significantly better QED score than Ligand B (0.632), indicating a more drug-like profile.

**DILI:** Ligand A (42.071) has a slightly higher DILI risk than Ligand B (28.383), but both are below the concerning threshold of 60.

**BBB:** Ligand A (83.831) has a better BBB percentile than Ligand B (79.682), which is crucial for a CNS target like DRD2.

**Caco-2 Permeability:** Ligand A (-4.542) has a higher Caco-2 permeability than Ligand B (-5.212), suggesting better intestinal absorption.

**Aqueous Solubility:** Both ligands have poor aqueous solubility (-3.051 and -3.535). This could pose formulation challenges, but is not a deciding factor here.

**hERG:** Both ligands have very low hERG inhibition liability (0.477 and 0.404).

**Microsomal Clearance:** Ligand A (55.853) has a higher microsomal clearance than Ligand B (43.147), indicating lower metabolic stability. Ligand B is preferred here.

**In vitro Half-Life:** Ligand B (18.075 hours) has a significantly longer in vitro half-life than Ligand A (-19.934 hours), which is a major advantage.

**P-gp Efflux:** Both have low P-gp efflux liability (0.12 and 0.488), which is good for CNS penetration.

**Binding Affinity:** Ligand B (-7.3 kcal/mol) has a better binding affinity than Ligand A (-8.6 kcal/mol). This is a significant advantage, as a >1.5 kcal/mol difference can outweigh other ADME drawbacks.

**Overall Assessment:**

While Ligand A has better QED, BBB, and Caco-2 permeability, Ligand B's superior binding affinity (-7.3 vs -8.6 kcal/mol) and significantly longer half-life are more critical for a CNS GPCR target. The slightly higher DILI risk for Ligand A is not a major concern given both are below 60. The better metabolic stability (lower Cl_mic) and longer half-life of Ligand B are also important.

Output:
1
2025-04-17 09:10:06,821 - INFO - Batch 510 complete. Total preferences: 8160
2025-04-17 09:10:06,821 - INFO - Processing batch 511/512...
2025-04-17 09:10:47,893 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (360.479 and 351.407 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (66.48) is excellent, well below the 90 A^2 threshold for CNS targets. Ligand B (137.65) is higher, approaching the limit for good oral absorption (140) and less ideal for CNS penetration.

**logP:** Ligand A (3.079) is optimal (1-3). Ligand B (0.203) is quite low, potentially hindering membrane permeability and CNS entry.

**H-Bond Donors/Acceptors:** Ligand A (1 HBD, 3 HBA) is favorable. Ligand B (4 HBD, 5 HBA) is acceptable, but slightly higher counts could impact permeability.

**QED:** Ligand A (0.824) is excellent, indicating high drug-likeness. Ligand B (0.471) is below the 0.5 threshold, suggesting a less favorable drug-like profile.

**DILI:** Ligand A (55.913) has a moderate DILI risk, acceptable. Ligand B (34.587) has a lower, and therefore better, DILI risk.

**BBB:** Ligand A (72.237) is good, exceeding the 70% threshold for CNS targets. Ligand B (56.029) is lower, which is concerning for a CNS target like DRD2.

**Caco-2 Permeability:** Ligand A (-4.762) is poor, indicating low intestinal absorption. Ligand B (-5.64) is also poor, but slightly worse than A.

**Aqueous Solubility:** Ligand A (-4.935) is very poor. Ligand B (-1.387) is also poor, but better than A.

**hERG Inhibition:** Both ligands show low hERG inhibition risk (0.632 and 0.123, respectively).

**Microsomal Clearance:** Ligand A (50.463) has moderate clearance. Ligand B (0.158) has very low clearance, suggesting good metabolic stability.

**In vitro Half-Life:** Ligand A (5.204 hours) is moderate. Ligand B (-7.74 hours) is excellent, indicating a long half-life.

**P-gp Efflux:** Ligand A (0.171) shows low P-gp efflux, which is favorable for CNS penetration. Ligand B (0.009) shows very low P-gp efflux, even more favorable.

**Binding Affinity:** Ligand A (-11.2 kcal/mol) has significantly stronger binding affinity than Ligand B (-7.5 kcal/mol). The difference of 3.7 kcal/mol is substantial and can outweigh many ADME drawbacks.

**Overall Assessment:**

While Ligand B has better metabolic stability (lower Cl_mic, longer t1/2), lower DILI risk, and lower P-gp efflux, Ligand A's superior binding affinity (-11.2 vs -7.5 kcal/mol) and acceptable BBB penetration (72.2%) are critical for a CNS GPCR target. The lower logP and solubility of Ligand B are significant drawbacks that could severely limit its ability to reach the brain. The TPSA of Ligand B is also less favorable. The strong binding affinity of Ligand A suggests it might overcome its moderate ADME liabilities.

Output:
1
2025-04-17 09:10:47,893 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (352.387 Da) is slightly lower, which could be advantageous for permeability. Ligand B (383.945 Da) is also well within range.

**TPSA:** Ligand A (117.87) is better than Ligand B (71.09) as it is closer to the ideal range for CNS targets (<=90). Ligand B is excellent.

**logP:** Ligand A (0.166) is quite low, potentially hindering membrane permeability. Ligand B (2.822) is within the optimal range (1-3). This is a significant advantage for Ligand B.

**H-Bond Donors/Acceptors:** Ligand A has 3 HBD and 6 HBA, while Ligand B has 2 HBD and 4 HBA. Both are within acceptable limits.

**QED:** Both ligands have good QED scores (Ligand A: 0.574, Ligand B: 0.724), indicating drug-like properties. Ligand B is slightly better.

**DILI:** Both have acceptable DILI risk (Ligand A: 49.477, Ligand B: 40.287), with Ligand B being slightly lower.

**BBB:** Both ligands show good BBB penetration (Ligand A: 52.268, Ligand B: 54.323). However, for a CNS target like DRD2, higher is better, and Ligand B is slightly better.

**Caco-2 Permeability:** Ligand A (-4.886) shows poor permeability, while Ligand B (-5.496) also shows poor permeability.

**Aqueous Solubility:** Both ligands show poor aqueous solubility (Ligand A: -1.655, Ligand B: -3.565).

**hERG Inhibition:** Both ligands have low hERG inhibition risk (Ligand A: 0.209, Ligand B: 0.314).

**Microsomal Clearance:** Ligand A (41.744) has a higher clearance than Ligand B (30.51), suggesting lower metabolic stability.

**In vitro Half-Life:** Ligand B (8.526 hours) has a longer half-life than Ligand A (4.047 hours).

**P-gp Efflux:** Both ligands show low P-gp efflux (Ligand A: 0.093, Ligand B: 0.146).

**Binding Affinity:** Ligand B (-8.5 kcal/mol) has a significantly stronger binding affinity than Ligand A (-7.4 kcal/mol). This 1.1 kcal/mol difference is substantial and can outweigh some ADME drawbacks.

**Conclusion:**

Considering the GPCR-specific priorities, Ligand B is the more promising candidate. While both have acceptable BBB penetration and low P-gp efflux, Ligand B excels in logP (optimal range), binding affinity (significantly stronger), metabolic stability (lower Cl_mic, longer t1/2), and QED. Ligand A's low logP and poorer metabolic stability are significant drawbacks. The superior binding affinity of Ligand B is a major advantage for a DRD2 ligand.

Output:
1
2025-04-17 09:10:47,893 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (341.386 and 359.817 Da) fall within the ideal range of 200-500 Da.

**TPSA:** Ligand A (62.3) is significantly better than Ligand B (80.55). For CNS targets, TPSA should be <= 90, and A is comfortably within this range, while B is approaching the upper limit.

**logP:** Both ligands have good logP values (2.316 and 3.064), falling within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A (HBD=1, HBA=3) is better than Ligand B (HBD=2, HBA=5) in terms of maintaining a balance between solubility and permeability.

**QED:** Both ligands have acceptable QED values (0.877 and 0.733), indicating good drug-like properties.

**DILI:** Ligand A (56.689) has a much lower DILI risk than Ligand B (89.802). This is a significant advantage.

**BBB:** Ligand A (79.566) has a substantially better BBB penetration score than Ligand B (61.962). This is *critical* for a CNS target like DRD2.

**Caco-2 Permeability:** Both have negative Caco-2 values (-4.882 and -4.844), which is unusual and suggests poor permeability. However, the scale isn't specified, so it's hard to interpret.

**Aqueous Solubility:** Both ligands have negative solubility values (-2.552 and -4.495), which is also unusual and suggests poor solubility. Again, the scale is unknown.

**hERG:** Both ligands have low hERG inhibition liability (0.551 and 0.603), which is good.

**Microsomal Clearance:** Ligand A (15.775) has a much lower microsomal clearance than Ligand B (83.803), indicating better metabolic stability.

**In vitro Half-Life:** Ligand A (-7.035) has a significantly longer in vitro half-life than Ligand B (32.142).

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.099 and 0.485), which is favorable for CNS penetration.

**Binding Affinity:** Both ligands have excellent binding affinities (-9.1 and -9.2 kcal/mol), with Ligand B being slightly better. However, the difference is minimal.

**Overall Assessment:**

Ligand A is significantly superior to Ligand B. While both have good affinity, Ligand A excels in crucial ADME properties for a CNS-targeting GPCR: TPSA, BBB, DILI, microsomal clearance, and in vitro half-life. The lower TPSA and higher BBB penetration are particularly important for DRD2. Although both have unusual negative values for Caco-2 and solubility, the other advantages of Ligand A outweigh this concern.

Output:
0
2025-04-17 09:10:47,893 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (354.378 and 345.443 Da) fall within the ideal range of 200-500 Da.

**TPSA:** Ligand A (99.1) is slightly higher than the ideal <90 for CNS targets, but still reasonable. Ligand B (71.53) is well within the desired range.

**logP:** Ligand A (2.798) is optimal. Ligand B (1.466) is a bit low, potentially impacting permeability, but not drastically.

**H-Bond Donors/Acceptors:** Ligand A (3 HBD, 5 HBA) and Ligand B (1 HBD, 4 HBA) both have acceptable numbers of H-bond donors and acceptors.

**QED:** Both ligands have good QED scores (0.769 and 0.812), indicating good drug-like properties.

**DILI:** Ligand A (47.693) has a moderate DILI risk, but is still acceptable. Ligand B (9.771) has a very low DILI risk, a significant advantage.

**BBB:** Ligand A (50.679) has a moderate BBB penetration, which is a concern for a CNS target. Ligand B (71.772) has a good BBB penetration, exceeding the >70% threshold. This is a major advantage.

**Caco-2 Permeability:** Both ligands have negative Caco-2 values (-5.113 and -4.797). These values are unusual and suggest poor permeability. However, these are likely experimental artifacts or indicate a need for further investigation.

**Aqueous Solubility:** Both ligands have negative solubility values (-3.457 and -0.897), which is also unusual. Again, these values are concerning and require further investigation.

**hERG:** Both ligands have very low hERG inhibition risk (0.111 and 0.156).

**Microsomal Clearance:** Ligand A (25.407 mL/min/kg) has a higher clearance than Ligand B (0.174 mL/min/kg), indicating lower metabolic stability. Ligand B is significantly more stable.

**In vitro Half-Life:** Ligand B (-6.426 hours) has a longer half-life than Ligand A (-2.334 hours).

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.01 and 0.017).

**Binding Affinity:** Both ligands have excellent binding affinity (-7.7 and -7.8 kcal/mol), which is comparable. The difference of 0.1 kcal/mol is negligible.

**Conclusion:**

While both ligands exhibit good binding affinity, Ligand B is the superior candidate. Its significantly better BBB penetration (71.772 vs 50.679), lower DILI risk (9.771 vs 47.693), and improved metabolic stability (lower Cl_mic and longer half-life) outweigh the slightly lower logP. The unusual solubility and Caco-2 values for both compounds are concerning and would require further investigation, but do not immediately disqualify Ligand B given its other favorable properties.

Output:
1
2025-04-17 09:10:47,893 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (348.49 and 352.51 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (67.43) is significantly higher than Ligand B (33.43). For CNS targets, TPSA should be <= 90, so both are acceptable, but B is much better.

**logP:** Ligand A (2.714) is within the optimal 1-3 range. Ligand B (4.637) is slightly above, potentially leading to solubility issues and off-target interactions, but not drastically so.

**H-Bond Donors/Acceptors:** Ligand A has 2 HBD and 3 HBA, which is reasonable. Ligand B has 0 HBD and 5 HBA, also acceptable.

**QED:** Both ligands have reasonable QED values (0.422 and 0.554), indicating drug-like properties. Ligand B is slightly better.

**DILI:** Ligand A (32.842) has a lower DILI risk than Ligand B (47.266), which is preferable.

**BBB:** This is crucial for a CNS target like DRD2. Ligand B (83.443) has a much higher BBB penetration percentile than Ligand A (57.619). This is a major advantage for Ligand B.

**Caco-2 Permeability:** Both have negative Caco-2 values (-4.731 and -4.95), which is unusual and suggests poor permeability. This is a concern for both, but doesn't differentiate them.

**Aqueous Solubility:** Both have negative solubility values (-3.055 and -4.194), suggesting poor solubility. Again, a concern for both, but doesn't differentiate them.

**hERG Inhibition:** Ligand A (0.389) has a lower hERG inhibition liability than Ligand B (0.712), which is preferable.

**Microsomal Clearance:** Ligand B (75.811) has a higher microsomal clearance than Ligand A (54.606), indicating faster metabolism and potentially lower in vivo exposure.

**In vitro Half-Life:** Ligand A (-9.644) has a longer in vitro half-life than Ligand B (-18.819), which is preferable.

**P-gp Efflux:** Ligand A (0.261) has lower P-gp efflux liability than Ligand B (0.56), which is better for CNS exposure.

**Binding Affinity:** Ligand B (-7.5 kcal/mol) has a slightly better binding affinity than Ligand A (-8.2 kcal/mol). While A is better, the difference is not huge.

**Overall Assessment:**

Ligand B excels in BBB penetration, a critical factor for CNS drug development. It also has a slightly better binding affinity and QED. However, it has higher DILI risk, higher P-gp efflux, and faster metabolic clearance. Ligand A has better DILI, P-gp, and metabolic stability, but its BBB penetration is significantly lower.

Considering the GPCR-specific priorities, the superior BBB penetration of Ligand B outweighs its other drawbacks, especially given the relatively small difference in binding affinity. The improved CNS exposure is likely to be more impactful for a DRD2 ligand than slightly better metabolic stability.

Output:
1
2025-04-17 09:10:47,894 - INFO - Reasoning:

Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (364.431 and 340.427 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (120.29) is slightly above the optimal <90 for CNS targets, but still reasonable. Ligand B (83.98) is excellent, well below 90.

**3. logP:** Both ligands have a logP of approximately 1.5, which is optimal.

**4. H-Bond Donors:** Ligand A has 1 HBD, within the acceptable limit. Ligand B has 2, also acceptable.

**5. H-Bond Acceptors:** Ligand A has 6 HBA, within the acceptable limit. Ligand B has 4, also acceptable.

**6. QED:** Ligand B (0.769) has a significantly better QED score than Ligand A (0.467), indicating a more drug-like profile.

**7. DILI:** Ligand A (62.233) has a higher DILI risk than Ligand B (44.552), though both are reasonably low.

**8. BBB:** Ligand A (55.099) has a lower BBB penetration percentile than Ligand B (48.662). Both are suboptimal for a CNS target, but Ligand B is slightly better.

**9. Caco-2 Permeability:** Ligand A (-5.119) and Ligand B (-4.886) both have negative Caco-2 values which is unusual and suggests poor permeability.

**10. Aqueous Solubility:** Both ligands have negative solubility values, which is also unusual and suggests poor solubility.

**11. hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.102 and 0.155).

**12. Microsomal Clearance:** Ligand B (15.243) has a lower microsomal clearance than Ligand A (20.754), suggesting better metabolic stability.

**13. In vitro Half-Life:** Ligand B (-18.296) has a negative half-life which is impossible. This is a major red flag. Ligand A (19.591) has a reasonable half-life.

**14. P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.039 and 0.024).

**15. Binding Affinity:** Ligand B (-8.1 kcal/mol) has a significantly stronger binding affinity than Ligand A (-7.3 kcal/mol). This is a substantial advantage.

**Overall Assessment:**

Despite the unusual negative solubility and Caco-2 values, Ligand B is the more promising candidate. The significantly stronger binding affinity (-8.1 vs -7.3 kcal/mol) is a major advantage that can outweigh some of the ADME concerns. The better QED and lower DILI risk also favor Ligand B. However, the negative in vitro half-life for Ligand B is a critical issue that needs to be investigated. Ligand A's half-life is more reasonable.

Considering the GPCR-specific priorities, the slightly better BBB and lower P-gp efflux of Ligand B are beneficial. The TPSA of Ligand B is also more favorable.

Output:
1
2025-04-17 09:10:47,894 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (379.964 and 371.84 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (64.11) is better than Ligand B (65.79), both are reasonably good for CNS penetration, being below the 90 A^2 threshold.

**logP:** Ligand B (1.942) is significantly better than Ligand A (4.744). Ligand A's logP is quite high, potentially leading to solubility issues and off-target interactions. Ligand B is within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Both have 1 HBD and are similar in HBA (5 vs 4). These are acceptable values.

**QED:** Ligand B (0.881) has a better QED score than Ligand A (0.6), suggesting a more drug-like profile.

**DILI:** Ligand B (33.889) has a much lower DILI risk than Ligand A (70.299), a significant advantage.

**BBB:** Both ligands have similar BBB penetration (60.295 and 61.846). While not exceptional (>70), they are acceptable.

**Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and suggests poor permeability. However, these values are on a strange scale and difficult to interpret directly.

**Aqueous Solubility:** Both have negative solubility values, again unusual and suggesting poor solubility.

**hERG:** Both ligands have low hERG risk (0.602 and 0.508).

**Microsomal Clearance:** Ligand B (-33.345) has *much* better metabolic stability than Ligand A (120.578). A negative value suggests very slow clearance.

**In vitro Half-Life:** Ligand B (11.107) has a better in vitro half-life than Ligand A (93.236).

**P-gp Efflux:** Ligand A (0.382) has a slightly better P-gp efflux profile than Ligand B (0.062), but both are very low, indicating significant efflux.

**Binding Affinity:** Ligand A (0.0) has a better binding affinity than Ligand B (-8.0). This is a substantial difference.

**Overall Assessment:**

Despite Ligand A's superior binding affinity, Ligand B is the more promising candidate. The significantly better logP, DILI, metabolic stability (Cl_mic and t1/2), and QED outweigh the affinity difference. The high logP of Ligand A is a major concern, potentially leading to poor solubility and increased off-target effects. While both have issues with Caco-2 and solubility, the other ADME properties of Ligand B are far more favorable. For a GPCR target like DRD2, a balance of properties is crucial, and Ligand B strikes that balance better.

Output:
1
2025-04-17 09:10:47,894 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B based on the provided guidelines, prioritizing GPCR-specific properties (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (331.379 Da) is slightly preferred as it's closer to the lower end, potentially aiding permeability.

**TPSA:** Ligand A (64.74) is excellent for CNS penetration, well below the 90 A^2 threshold. Ligand B (92.78) is higher, but still potentially acceptable, though less optimal.

**logP:** Ligand A (3.07) is optimal. Ligand B (0.603) is quite low, potentially hindering membrane permeability and CNS entry. This is a significant drawback.

**H-Bond Donors/Acceptors:** Both ligands have acceptable HBD (1) and HBA (5/6) counts.

**QED:** Both ligands have similar, acceptable QED values (0.625 and 0.61).

**DILI:** Ligand A (88.251) has a higher DILI risk than Ligand B (33.501), but both are reasonably acceptable.

**BBB:** Ligand A (73.556) has a significantly better BBB percentile than Ligand B (59.636). This is crucial for a CNS target like DRD2.

**Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and suggests a potential issue with the data or modeling. However, we can still compare the relative values. Ligand A (-5.134) is slightly better than Ligand B (-5.051).

**Aqueous Solubility:** Both have negative solubility values, again indicating a potential issue with the data. Ligand A (-4.499) is slightly better.

**hERG:** Ligand A (0.736) has a slightly higher hERG risk than Ligand B (0.212), but both are relatively low.

**Microsomal Clearance:** Ligand B (63.004) has slightly better metabolic stability (lower clearance) than Ligand A (60.02).

**In vitro Half-Life:** Ligand A (69.917) has a much longer half-life than Ligand B (-56.416). This is a significant advantage.

**P-gp Efflux:** Ligand A (0.554) has lower P-gp efflux liability than Ligand B (0.017), which is desirable for CNS penetration.

**Binding Affinity:** Ligand A (-9.0 kcal/mol) has a significantly stronger binding affinity than Ligand B (-7.5 kcal/mol). This is a substantial advantage, potentially outweighing some ADME drawbacks.

**Overall:**

Ligand A is clearly the stronger candidate. Its superior BBB penetration, significantly higher binding affinity, longer half-life, and lower P-gp efflux outweigh its slightly higher DILI and hERG risk. Ligand B's low logP is a major concern, likely hindering its ability to cross the blood-brain barrier effectively. The negative Caco-2 and solubility values are concerning for both, but the overall profile of Ligand A is far more promising for a CNS-targeting drug.

Output:
1
2025-04-17 09:10:47,894 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (344.386 & 345.399 Da) fall comfortably within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (60.85) is significantly better than Ligand B (93.46).  For CNS targets, we want TPSA <= 90, so Ligand A is much more favorable.

**3. logP:** Both ligands have good logP values (2.034 and 1.874), falling within the optimal 1-3 range.

**4. H-Bond Donors:** Ligand A (1) and Ligand B (2) are both acceptable, being <= 5.

**5. H-Bond Acceptors:** Ligand A (3) and Ligand B (5) are both acceptable, being <= 10.

**6. QED:** Both ligands have acceptable QED scores (0.903 and 0.762), exceeding the 0.5 threshold.

**7. DILI:** Both ligands have similar, acceptable DILI risk (53.819 and 56.34), well below the concerning 60 percentile.

**8. BBB:** This is a critical parameter for a CNS target like DRD2. Ligand A has a much higher BBB penetration percentile (81.698) compared to Ligand B (56.534).  A value >70 is desirable, and Ligand A clearly meets this, while Ligand B is borderline.

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.327 and -4.86). This is unusual and suggests poor intestinal absorption. However, for a CNS target, intestinal absorption is less critical than BBB penetration.

**10. Aqueous Solubility:** Both ligands have negative solubility values (-1.989 and -2.307), indicating poor aqueous solubility. This could pose formulation challenges, but is less critical given the CNS target.

**11. hERG Inhibition:** Both ligands show low hERG inhibition liability (0.778 and 0.329), which is good.

**12. Microsomal Clearance:** Ligand A (24.863) has a lower microsomal clearance than Ligand B (34.532), suggesting better metabolic stability.

**13. In vitro Half-Life:** Ligand A (10.709) has a shorter half-life than Ligand B (36.932). This is a drawback for Ligand A, but potentially offset by other factors.

**14. P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.341 and 0.045), which is excellent for CNS penetration.

**15. Binding Affinity:** Both ligands have excellent binding affinities (-9 and -8.6 kcal/mol). Ligand A is slightly better (-9 kcal/mol).

**Overall Assessment:**

Ligand A is the superior candidate. While Ligand B has a longer half-life, Ligand A excels in the most critical areas for a CNS-targeting GPCR ligand: TPSA, BBB penetration, and slightly better binding affinity. The lower TPSA and significantly higher BBB penetration of Ligand A are decisive advantages. The slightly lower metabolic stability (shorter half-life) of Ligand A is a manageable concern compared to the poor BBB penetration of Ligand B.

Output:
1
2025-04-17 09:10:47,894 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 drug candidates, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (356.354 Da and 389.905 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (119.51) is better than Ligand B (99.93). Both are below the 140 A^2 threshold for oral absorption and, critically, below 90 A^2 which is preferred for CNS targets.

**3. logP:** Both ligands have good logP values (1.401 and 1.787), falling within the optimal 1-3 range.

**4. H-Bond Donors:** Ligand A (2) is slightly higher than Ligand B (1), but both are acceptable (<=5).

**5. H-Bond Acceptors:** Ligand A (7) is higher than Ligand B (5), but both are within the acceptable range (<=10).

**6. QED:** Both ligands have similar and good QED values (0.739 and 0.747), indicating good drug-like properties.

**7. DILI:** Ligand B (52.617) has a significantly lower DILI risk than Ligand A (73.711). This is a substantial advantage for Ligand B.

**8. BBB:** Ligand A (76.076) has a better BBB penetration percentile than Ligand B (46.607). This is *critical* for a CNS target like DRD2.

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.427 and -4.665). These values are unusual and suggest poor permeability. However, the scale is not specified, so it's difficult to interpret.

**10. Aqueous Solubility:** Both ligands have negative solubility values (-3.052 and -2.325). Again, the scale is unclear, but negative values suggest poor solubility.

**11. hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.166 and 0.181).

**12. Microsomal Clearance:** Ligand B (24.079) has significantly lower microsomal clearance than Ligand A (85.2), indicating better metabolic stability.

**13. In vitro Half-Life:** Ligand B (20.442) has a much longer in vitro half-life than Ligand A (-25.873). This is a major advantage for Ligand B.

**14. P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.021 and 0.211).

**15. Binding Affinity:** Ligand A (-7.8 kcal/mol) has a significantly stronger binding affinity than Ligand B (-6.5 kcal/mol). This is a substantial advantage for Ligand A.

**Overall Assessment:**

The key trade-off is between binding affinity (Ligand A) and ADME properties (Ligand B). Ligand A has a much stronger binding affinity, which is highly desirable. However, Ligand B has significantly better DILI, metabolic stability (lower Cl_mic), and half-life. While Ligand A has a better BBB score, Ligand B's BBB is not terrible. Given the importance of metabolic stability and safety (DILI) for a CNS drug, and the fact that the affinity difference is substantial (1.3 kcal/mol), I lean towards Ligand A. The strong binding affinity may overcome the slightly less favorable ADME profile, especially if further optimization can improve metabolic stability.

Output:
0
2025-04-17 09:10:47,894 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (371.849 Da) is slightly higher than Ligand B (342.359 Da), but both are acceptable.

**TPSA:** Ligand A (62.3) is excellent for CNS penetration, well below the 90 A^2 threshold. Ligand B (93.45) is higher, but still potentially acceptable, though less ideal.

**logP:** Ligand A (4.327) is a bit high, potentially leading to solubility issues or off-target effects. Ligand B (-0.042) is significantly low, which could hinder membrane permeability and CNS penetration.

**H-Bond Donors/Acceptors:** Ligand A (1 HBD, 4 HBA) is favorable. Ligand B (0 HBD, 7 HBA) is also reasonable.

**QED:** Both ligands have good QED scores (A: 0.692, B: 0.777), indicating drug-like properties.

**DILI:** Ligand A (85.886) has a higher DILI risk than Ligand B (75.572), but both are within an acceptable range.

**BBB:** Ligand A (69.213) has a significantly better BBB penetration score than Ligand B (47.189). This is a crucial factor for a CNS target like DRD2.

**Caco-2 Permeability:** Both have negative Caco-2 values which is unusual and suggests issues with the prediction method.

**Aqueous Solubility:** Both have negative solubility values which is also unusual and suggests issues with the prediction method.

**hERG:** Ligand A (0.594) has a slightly higher hERG risk than Ligand B (0.189), but both are relatively low.

**Microsomal Clearance:** Ligand A (64.459) has higher clearance than Ligand B (28.465), suggesting lower metabolic stability.

**In vitro Half-Life:** Ligand B (-15.715) has a negative half-life which is impossible and suggests issues with the prediction method. Ligand A (62.893) is reasonable.

**P-gp Efflux:** Ligand A (0.417) has lower P-gp efflux liability than Ligand B (0.054), which is beneficial for CNS exposure.

**Binding Affinity:** Ligand A (-9.2 kcal/mol) has a significantly stronger binding affinity than Ligand B (-8.1 kcal/mol). This 1.1 kcal/mol difference is substantial and can outweigh some ADME drawbacks.

**Overall Assessment:**

Ligand A is the stronger candidate. While its logP is a bit high and DILI risk is slightly elevated, its superior BBB penetration, significantly better binding affinity, and lower P-gp efflux outweigh these concerns. Ligand B suffers from a very low logP, poor BBB penetration, and an impossible half-life prediction. The strong binding affinity of Ligand A is a major advantage for a GPCR target.

Output:
1
2025-04-17 09:10:47,894 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (345.483 and 357.841 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (66.4) is slightly higher than Ligand B (62.3), but both are below the 90 A^2 threshold desirable for CNS targets.

**3. logP:** Ligand A (4.48) is higher than the optimal 1-3 range, potentially causing solubility issues. Ligand B (3.2) is within the optimal range. This favors Ligand B.

**4. H-Bond Donors:** Ligand A (2) and Ligand B (1) are both acceptable, below the 5 threshold.

**5. H-Bond Acceptors:** Ligand A (2) and Ligand B (3) are both acceptable, below the 10 threshold.

**6. QED:** Both ligands have reasonably good QED values (0.845 and 0.774), indicating good drug-like properties.

**7. DILI:** Both ligands have similar DILI risk (51.105 and 54.323), and are both below the concerning 60 threshold.

**8. BBB:** Ligand A (47.809) and Ligand B (45.638) are both below the desirable >70 percentile for CNS targets. However, this is less critical if other properties are favorable.

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.864 and -4.906), which is unusual and suggests poor permeability. This is a significant drawback for both.

**10. Aqueous Solubility:** Both ligands have negative solubility values (-3.829 and -3.285), indicating very poor aqueous solubility. This is a major concern for both.

**11. hERG Inhibition:** Ligand A (0.056) has a much lower hERG inhibition risk than Ligand B (0.479). This is a significant advantage for Ligand A.

**12. Microsomal Clearance:** Ligand A (33.239) has lower microsomal clearance than Ligand B (62.129), suggesting better metabolic stability. This favors Ligand A.

**13. In vitro Half-Life:** Ligand A (-16.372) has a negative half-life, which is not physically possible. Ligand B (21.327) has a reasonable half-life. This is a major disadvantage for Ligand A.

**14. P-gp Efflux:** Ligand A (0.045) has lower P-gp efflux than Ligand B (0.144), which is favorable for CNS penetration.

**15. Binding Affinity:** Both ligands have very similar and strong binding affinities (-8.9 and -8.6 kcal/mol). The difference is less than 1.5 kcal/mol, so it's not a deciding factor.

**Overall Assessment:**

Ligand A has advantages in hERG inhibition, P-gp efflux, and microsomal clearance. However, it has a nonsensical negative in vitro half-life, and its logP is higher than ideal. Ligand B has a more reasonable half-life and a logP within the optimal range, but has a higher hERG risk and P-gp efflux. Given the importance of metabolic stability and CNS penetration for a DRD2 ligand, and the fact that the binding affinities are comparable, the lower hERG risk and better metabolic stability of Ligand A are slightly more appealing, *despite* the negative half-life value which is a data error.

Output:
0
2025-04-17 09:10:47,894 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (376.762 and 362.47 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (67.43) is slightly above the optimal <90 for CNS targets, but still reasonable. Ligand B (53.43) is well within the desired range.

**3. logP:** Ligand A (1.997) is within the optimal 1-3 range. Ligand B (4.375) is a bit high, potentially leading to solubility issues and off-target interactions.

**4. H-Bond Donors:** Ligand A (2) and Ligand B (1) are both acceptable, below the threshold of 5.

**5. H-Bond Acceptors:** Ligand A (3) and Ligand B (4) are both acceptable, below the threshold of 10.

**6. QED:** Both ligands have good QED scores (0.746 and 0.83), indicating good drug-like properties.

**7. DILI:** Ligand A (61.109) has a higher DILI risk than Ligand B (32.261). This is a significant drawback for Ligand A.

**8. BBB:** Ligand A (90.074) has a significantly better BBB penetration score than Ligand B (69.833). This is a crucial advantage for a CNS target like DRD2.

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 values, which is unusual and suggests poor permeability. However, the scale isn't defined, so it's hard to interpret.

**10. Aqueous Solubility:** Both ligands have negative solubility values, which is also unusual and suggests poor solubility.

**11. hERG Inhibition:** Both ligands have low hERG inhibition risk (0.652 and 0.628).

**12. Microsomal Clearance:** Ligand A (14.18) has lower microsomal clearance than Ligand B (90.067), indicating better metabolic stability.

**13. In vitro Half-Life:** Ligand A (12.03) has a longer half-life than Ligand B (-14.426), which is a positive attribute.

**14. P-gp Efflux:** Ligand A (0.145) has lower P-gp efflux liability than Ligand B (0.303), which is beneficial for CNS penetration.

**15. Binding Affinity:** Ligand B (-7.5 kcal/mol) has a significantly stronger binding affinity than Ligand A (-9.0 kcal/mol). This is a major advantage for Ligand B, potentially outweighing some of its ADME drawbacks.

**Overall Assessment:**

Ligand A has a better BBB score, lower P-gp efflux, better metabolic stability, and longer half-life. However, it has a higher DILI risk. Ligand B has a much stronger binding affinity and lower DILI risk, but its logP is higher, and its BBB penetration is lower.

Given the GPCR-specific priorities, *binding affinity is paramount*. The 1.5 kcal/mol difference in binding affinity is substantial. While Ligand A's BBB is better, the improved affinity of Ligand B, coupled with the lower DILI risk, makes it the more promising candidate. The slightly higher logP of Ligand B can potentially be addressed with further optimization.

Output:
1
2025-04-17 09:10:47,895 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (355.316 and 364.515 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (69.72) is significantly better than Ligand B (75.19). For CNS targets, we want TPSA <= 90, and A is closer to the optimal <=60 range.

**3. logP:** Both ligands have good logP values (2.985 and 2.721), falling within the 1-3 optimal range.

**4. H-Bond Donors:** Both have 1 HBD, which is acceptable.

**5. H-Bond Acceptors:** Ligand A has 3 HBAs, while Ligand B has 5. Both are within the acceptable limit of <=10, but A is preferable.

**6. QED:** Both ligands have high QED scores (0.848 and 0.872), indicating good drug-like properties.

**7. DILI:** Ligand A (78.325) has a higher DILI risk than Ligand B (51.881). This is a negative for Ligand A, but not a dealbreaker.

**8. BBB:** This is *critical* for a CNS target like DRD2. Ligand A has a very high BBB penetration percentile (93.137), while Ligand B is considerably lower (62.97). This is a major advantage for Ligand A.

**9. Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and suggests poor permeability. However, the scale is not specified, so it's hard to interpret.

**10. Aqueous Solubility:** Both have negative solubility values, which is also unusual. Again, the scale is unknown.

**11. hERG Inhibition:** Both ligands have low hERG inhibition risk (0.28 and 0.305), which is good.

**12. Microsomal Clearance:** Ligand B (59.641) has significantly higher microsomal clearance than Ligand A (10.176), indicating lower metabolic stability. This favors Ligand A.

**13. In vitro Half-Life:** Ligand A (20.018 hours) has a longer half-life than Ligand B (11.759 hours), which is preferable.

**14. P-gp Efflux:** Both ligands have low P-gp efflux liability (0.059 and 0.463), which is good.

**15. Binding Affinity:** Both ligands have excellent binding affinities (-8.5 and -8.0 kcal/mol). The difference of 0.5 kcal/mol is not substantial enough to outweigh other factors.

**Overall Assessment:**

Ligand A is the superior candidate. Its significantly better BBB penetration, lower TPSA, lower microsomal clearance, and longer half-life outweigh its slightly higher DILI risk. The binding affinity is comparable between the two. Given the CNS target, BBB is paramount, and Ligand A excels in this area.

Output:
1
2025-04-17 09:10:47,895 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (346.475 and 345.403 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (87.46) is excellent, falling well below the 90 A^2 threshold for CNS targets. Ligand B (112.91) is still reasonable but less optimal, being above 100.

**3. logP:** Both ligands have good logP values (1.885 and 1.62), falling within the optimal 1-3 range.

**4. H-Bond Donors:** Both have 3 HBD, which is within the acceptable limit of <=5.

**5. H-Bond Acceptors:** Ligand A has 4 HBA, and Ligand B has 5 HBA, both within the acceptable limit of <=10.

**6. QED:** Both ligands have good QED scores (0.596 and 0.736), indicating good drug-like properties.

**7. DILI:** Ligand A (28.577) has a significantly lower DILI risk than Ligand B (59.674). This is a major advantage for Ligand A.

**8. BBB:** Ligand A (71.307) has a much better BBB penetration percentile than Ligand B (43.583). This is *critical* for a CNS target like DRD2.

**9. Caco-2 Permeability:** Both have negative values, indicating poor permeability. However, the scale is not specified, so it's hard to interpret.

**10. Aqueous Solubility:** Both have negative values, indicating poor solubility. Again, the scale is not specified.

**11. hERG:** Both ligands have very low hERG inhibition liability (0.641 and 0.077), which is excellent.

**12. Microsomal Clearance:** Ligand A (-10.08) has a much lower (better) microsomal clearance than Ligand B (-12.688). This suggests better metabolic stability for Ligand A.

**13. In vitro Half-Life:** Ligand A (7.077) has a shorter half-life than Ligand B (24.946). This is a slight disadvantage for Ligand A, but could be mitigated by formulation.

**14. P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.032 and 0.086), which is favorable.

**15. Binding Affinity:** Ligand B (-8.5) has a slightly better binding affinity than Ligand A (-8.2), but the difference is only 0.3 kcal/mol. Given the other significant advantages of Ligand A, this difference is unlikely to be decisive.

**Overall Assessment:**

Ligand A is significantly better than Ligand B. It has a much lower DILI risk, substantially better BBB penetration, and better metabolic stability. While Ligand B has slightly better affinity and half-life, the improvements in ADME properties, especially BBB and DILI, make Ligand A the more promising candidate for a CNS-targeting drug like a DRD2 ligand.

Output:
1
2025-04-17 09:10:47,895 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (342.439 and 341.371 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (49.85) is significantly better than Ligand B (79.51). For CNS targets, TPSA should be <= 90, and A is comfortably within this range, while B is approaching the upper limit.

**3. logP:** Both ligands have acceptable logP values (2.155 and 0.783), falling within the 1-3 optimal range. Ligand A is slightly preferred.

**4. H-Bond Donors:** Both have 0 HBD, which is good.

**5. H-Bond Acceptors:** Ligand A has 3 HBA, and Ligand B has 6. Both are within the acceptable limit of <= 10, but A is better.

**6. QED:** Ligand A (0.827) has a better QED score than Ligand B (0.61), indicating higher drug-likeness.

**7. DILI:** Ligand A (49.283) has a lower DILI risk than Ligand B (62.737), making it safer.

**8. BBB:** Ligand A (73.943) has a significantly better BBB penetration percentile than Ligand B (63.552). This is *critical* for a CNS target like DRD2.

**9. Caco-2 Permeability:** Both have negative values (-4.373 and -4.843). This is unusual and suggests poor permeability. However, the scale is not specified, so it's hard to interpret.

**10. Aqueous Solubility:** Both have negative values (-2.08 and -1.574). Similar to Caco-2, the scale is unclear, making interpretation difficult.

**11. hERG Inhibition:** Both ligands have low hERG inhibition risk (0.514 and 0.351).

**12. Microsomal Clearance:** Ligand A (44.136) has higher microsomal clearance than Ligand B (26.659), suggesting lower metabolic stability. This is a negative for A.

**13. In vitro Half-Life:** Ligand B (-13.104) has a significantly longer in vitro half-life than Ligand A (5.113). This is a strong positive for B.

**14. P-gp Efflux:** Ligand A (0.298) has lower P-gp efflux liability than Ligand B (0.06), which is desirable for CNS penetration.

**15. Binding Affinity:** Both ligands have excellent binding affinities (-8.8 and -8.1 kcal/mol). Ligand A is slightly better, but the difference is relatively small.

**Overall Assessment:**

Ligand A is superior in most key areas for a CNS-targeting GPCR ligand: TPSA, QED, DILI, and crucially, BBB penetration and P-gp efflux. While Ligand B has better metabolic stability (lower Cl_mic and longer t1/2), the improved CNS penetration of Ligand A outweighs this drawback. The slightly better affinity of A also contributes to its favorability. The negative Caco-2 and solubility values are concerning for both, but the strong BBB score for A makes it more likely to overcome these issues.

Output:
1
2025-04-17 09:10:47,896 - INFO - Batch 511 complete. Total preferences: 8176
2025-04-17 09:10:47,896 - INFO - Processing batch 512/512...
2025-04-17 09:11:29,863 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (364.433 and 350.463 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (78.87) is significantly better than Ligand B (87.46). For CNS targets, we want TPSA <= 90, and A is closer to the ideal <= 60.

**3. logP:** Both ligands have good logP values (1.418 and 1.315), falling within the optimal 1-3 range.

**4. H-Bond Donors:** Both have 2 HBD, which is acceptable.

**5. H-Bond Acceptors:** Ligand A has 4 HBA, while Ligand B has 5. Both are within the acceptable range of <=10.

**6. QED:** Both ligands have good QED scores (0.649 and 0.74), indicating good drug-like properties.

**7. DILI:** Ligand A (11.361) has a much lower DILI risk than Ligand B (32.183). This is a significant advantage.

**8. BBB:** Ligand A (65.878) has a slightly better BBB penetration percentile than Ligand B (63.048), though both are reasonably good. Ideally, we want >70 for CNS targets, but these are acceptable starting points.

**9. Caco-2 Permeability:** Both have negative Caco-2 values (-4.823 and -4.878), which is unusual and suggests poor permeability. This is a concern for both.

**10. Aqueous Solubility:** Both have negative solubility values (-1.356 and -2.021), indicating poor aqueous solubility. This is a concern for both.

**11. hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.489 and 0.211).

**12. Microsomal Clearance:** Ligand A (24.631) has a significantly lower microsomal clearance than Ligand B (47.027), indicating better metabolic stability.

**13. In vitro Half-Life:** Both have negative half-life values (-6.011 and -6.263), which is not physically meaningful. This suggests the models may be unreliable for these compounds in this regard.

**14. P-gp Efflux:** Both have very low P-gp efflux liability (0.08 and 0.133), which is good for CNS penetration.

**15. Binding Affinity:** Ligand B (-7.8 kcal/mol) has a slightly better binding affinity than Ligand A (-7.6 kcal/mol), but the difference is small (0.2 kcal/mol).

**Overall Assessment:**

Ligand A is the more promising candidate. While both have issues with Caco-2 permeability and aqueous solubility, Ligand A excels in several critical areas: lower DILI risk, lower microsomal clearance (better metabolic stability), and a slightly better BBB percentile. The small difference in binding affinity is outweighed by these ADME advantages, especially considering the target is a CNS GPCR where BBB penetration and minimizing toxicity are paramount.

Output:
0
2025-04-17 09:11:29,863 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (348.491 and 346.471 Da) fall comfortably within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (67.23) is better than Ligand B (69.64). Both are below the 90 A^2 threshold desirable for CNS targets, but A is closer to the optimal range.

**3. logP:** Ligand A (2.49) is within the optimal 1-3 range. Ligand B (3.267) is slightly higher, but still acceptable.

**4. H-Bond Donors:** Ligand A (1) is preferable to Ligand B (2). Lower HBD generally improves permeability.

**5. H-Bond Acceptors:** Ligand A (4) is preferable to Ligand B (3).

**6. QED:** Both ligands have similar QED values (0.745 and 0.71), indicating good drug-like properties.

**7. DILI:** Both ligands have low DILI risk (19.155 and 18.922 percentile), which is excellent.

**8. BBB:** Ligand A (70.686) has a significantly better BBB penetration percentile than Ligand B (54.595). This is a *critical* advantage for a CNS target like DRD2.

**9. Caco-2 Permeability:** Ligand A (-4.791) is better than Ligand B (-4.535), indicating better intestinal absorption.

**10. Aqueous Solubility:** Ligand A (-1.749) is better than Ligand B (-2.859), suggesting better solubility.

**11. hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.275 and 0.632), which is positive.

**12. Microsomal Clearance:** Ligand A (57.886) has lower microsomal clearance than Ligand B (66.196), indicating better metabolic stability.

**13. In vitro Half-Life:** Ligand A (-4.721) has a much better in vitro half-life than Ligand B (31.138).

**14. P-gp Efflux:** Ligand A (0.158) has a lower P-gp efflux liability than Ligand B (0.211), which is favorable for CNS penetration.

**15. Binding Affinity:** Ligand B (-7.8) has a slightly better binding affinity than Ligand A (-7.6), but the difference is relatively small (0.2 kcal/mol). Given the superior ADME properties of Ligand A, this small difference in affinity is unlikely to be decisive.

**Overall Assessment:**

Ligand A consistently outperforms Ligand B across most crucial ADME properties, particularly BBB penetration, metabolic stability, and solubility. While Ligand B has slightly better binding affinity, the difference isn't substantial enough to outweigh the significant advantages of Ligand A in terms of drug-likeness and CNS penetration. For a GPCR target in the CNS, prioritizing BBB penetration and metabolic stability is crucial.

Output:
0
2025-04-17 09:11:29,863 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (367.515 and 349.37 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (91.32) is better than Ligand B (127.82). For CNS targets, we want TPSA <= 90, so Ligand A is closer to this threshold.

**logP:** Ligand A (1.741) is optimal (1-3), while Ligand B (0.262) is quite low, potentially hindering membrane permeability.

**H-Bond Donors:** Both have 3 HBD, which is within the acceptable limit of <=5.

**H-Bond Acceptors:** Ligand A has 5 HBA, and Ligand B has 7 HBA, both within the acceptable limit of <=10.

**QED:** Ligand A (0.653) is better than Ligand B (0.463), indicating a more drug-like profile.

**DILI:** Ligand A (33.812) has a much lower DILI risk than Ligand B (73.052). Both are below 60, but A is significantly better.

**BBB:** Ligand A (30.981) is better than Ligand B (55.603), but both are below the desirable threshold of >70 for CNS targets. This is a weakness for both, but less so for A.

**Caco-2 Permeability:** Both have negative Caco-2 values (-5.177 and -5.534), which is unusual and suggests poor permeability.

**Aqueous Solubility:** Both have negative solubility values (-1.94 and -2.719), which is also unusual and suggests poor solubility.

**hERG Inhibition:** Ligand A (0.079) has a lower hERG risk than Ligand B (0.651).

**Microsomal Clearance:** Ligand A (17.895) has lower microsomal clearance than Ligand B (19.134), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand B (16.018) has a longer half-life than Ligand A (9.961).

**P-gp Efflux:** Ligand A (0.028) has significantly lower P-gp efflux liability than Ligand B (0.073), which is crucial for CNS penetration.

**Binding Affinity:** Both have excellent binding affinity (-8.0 and -8.2 kcal/mol), with Ligand B being slightly better. However, the difference is small and may not outweigh other factors.

**Overall Assessment:**

Ligand A is superior due to its better TPSA, logP, QED, DILI risk, P-gp efflux, and hERG inhibition. While both have poor Caco-2 and solubility, and suboptimal BBB penetration, Ligand A's better ADME properties, particularly logP and P-gp efflux, make it more likely to achieve sufficient CNS exposure. The slightly better affinity of Ligand B is unlikely to compensate for its poorer ADME profile.

Output:
0
2025-04-17 09:11:29,863 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (441.332 Da) is higher, but still acceptable. Ligand B (360.445 Da) is slightly better.

**TPSA:** Ligand A (101.05) is borderline for CNS penetration, being above the preferred <90. Ligand B (75.27) is excellent, well below the threshold.

**logP:** Both ligands have good logP values (A: 3.179, B: 2.971), falling within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Both have acceptable HBD (2) and HBA (A: 6, B: 3) counts.

**QED:** Both ligands have similar and acceptable QED values (A: 0.648, B: 0.621).

**DILI:** Ligand A (95.192) has a significantly higher DILI risk than Ligand B (45.25). This is a major concern for Ligand A.

**BBB:** Ligand B (87.631) has a better BBB percentile than Ligand A (70.803), although both are above the 70% threshold.

**Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and suggests poor permeability. However, the scale is not specified, so it's hard to interpret.

**Aqueous Solubility:** Both have negative solubility values, which is also unusual. Again, the scale is not specified, making interpretation difficult.

**hERG Inhibition:** Both ligands have low hERG inhibition risk (A: 0.338, B: 0.36).

**Microsomal Clearance:** Ligand A (29.97) has a slightly higher microsomal clearance than Ligand B (27.778), indicating potentially lower metabolic stability.

**In vitro Half-Life:** Ligand B (-14.197) has a negative half-life, which is impossible. This is a significant red flag. Ligand A (141.393) has a good half-life.

**P-gp Efflux:** Both have low P-gp efflux liability (A: 0.353, B: 0.095), which is favorable for CNS penetration.

**Binding Affinity:** Both have very similar and strong binding affinities (A: -9.0 kcal/mol, B: -8.6 kcal/mol). The difference of 0.4 kcal/mol is not substantial enough to override other factors.

**Overall Assessment:**

Ligand B initially appears better due to its superior TPSA, lower DILI risk, and better BBB penetration. However, the negative in vitro half-life is a critical flaw. A negative half-life is physically impossible and indicates a problem with the data or the compound itself. Ligand A has a higher DILI risk and a slightly less favorable TPSA, but its half-life is reasonable.

Considering the importance of metabolic stability and the unphysical value for Ligand B, Ligand A is the more viable candidate, despite its higher DILI risk. The DILI risk could potentially be mitigated through structural modifications. The negative half-life of Ligand B is a showstopper.

Output:
1
2025-04-17 09:11:29,863 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (374.35 and 381.523 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (58.64) is significantly better than Ligand B (88.57). For CNS targets, TPSA should be <= 90, and A is comfortably within that range, while B is approaching the upper limit.

**logP:** Both ligands have acceptable logP values (2.352 and 2.913), falling within the optimal 1-3 range.

**H-Bond Donors & Acceptors:** Ligand A (HBD=1, HBA=3) is preferable to Ligand B (HBD=2, HBA=6) as it has fewer H-bonds, which generally improves permeability.

**QED:** Both ligands have good QED scores (0.696 and 0.77), indicating good drug-like properties.

**DILI:** Ligand A (31.02) has a much lower DILI risk than Ligand B (63.746). This is a significant advantage for A.

**BBB:** Ligand A (76.774) has a substantially better BBB penetration percentile than Ligand B (52.579). This is *critical* for a CNS target like DRD2.

**Caco-2 Permeability:** Ligand A (-4.528) has a better Caco-2 permeability than Ligand B (-5.299), indicating better intestinal absorption.

**Aqueous Solubility:** Ligand A (-2.104) has better aqueous solubility than Ligand B (-3.724).

**hERG:** Both ligands have low hERG inhibition liability (0.488 and 0.342), which is good.

**Microsomal Clearance:** Ligand A (23.818) has lower microsomal clearance than Ligand B (54.169), suggesting better metabolic stability.

**In vitro Half-Life:** Ligand B (65.289) has a longer in vitro half-life than Ligand A (-22.934). However, the negative value for A is concerning and suggests a very rapid degradation.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.035 and 0.151).

**Binding Affinity:** Ligand B (-7.3) has a slightly better binding affinity than Ligand A (-7.8). While a 0.5 kcal/mol difference is not negligible, the other ADME properties of Ligand A are far more favorable.

**Overall Assessment:**

Ligand A is the stronger candidate. Its superior BBB penetration, lower TPSA, lower DILI risk, better solubility, and lower clearance outweigh the slightly weaker binding affinity. The negative in vitro half-life for Ligand A is a concern, but could potentially be addressed through structural modifications. Ligand B's higher TPSA, DILI risk, and significantly lower BBB penetration make it less attractive, despite the slightly better affinity. For a CNS target, getting the molecule into the brain is paramount, and Ligand A is much better positioned to achieve that.

Output:
0
2025-04-17 09:11:29,863 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B based on the provided guidelines, prioritizing GPCR-specific properties (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (357.479 and 384.267 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (64.6) is significantly better than Ligand B (72.28). For CNS targets, we want TPSA <= 90, both are within this range, but A is closer to the ideal.

**logP:** Both ligands have good logP values (3.506 and 2.888), falling within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A has 3 HBD and 3 HBA, while Ligand B has 1 HBD and 5 HBA. Both are acceptable, but A is slightly more balanced.

**QED:** Both ligands have good QED scores (0.659 and 0.88), indicating good drug-like properties.

**DILI:** Ligand A (72.354) has a higher DILI risk than Ligand B (76.192). Both are acceptable, but B is slightly better.

**BBB:** Ligand B (65.607) has a significantly better BBB penetration percentile than Ligand A (31.485). This is a *critical* factor for a CNS target like DRD2.

**Caco-2 Permeability:** Ligand A (-5.103) has better Caco-2 permeability than Ligand B (-4.829).

**Aqueous Solubility:** Ligand A (-4.174) has better aqueous solubility than Ligand B (-3.182).

**hERG:** Both ligands have low hERG inhibition liability (0.361 and 0.225), which is good.

**Microsomal Clearance:** Ligand B (25.024) has lower microsomal clearance than Ligand A (33.908), indicating better metabolic stability.

**In vitro Half-Life:** Ligand A (48.236) has a longer in vitro half-life than Ligand B (26.129).

**P-gp Efflux:** Ligand A (0.202) has lower P-gp efflux than Ligand B (0.054), which is favorable for CNS penetration.

**Binding Affinity:** Ligand B (-9.0 kcal/mol) has a significantly stronger binding affinity than Ligand A (-7.2 kcal/mol). This is a substantial advantage, exceeding the 1.5 kcal/mol threshold.

**Overall Assessment:**

While Ligand A has better solubility, Caco-2 permeability, and half-life, Ligand B wins out due to its *significantly* superior BBB penetration and binding affinity. The stronger binding affinity (-9.0 vs -7.2 kcal/mol) is a major advantage that can compensate for slightly less favorable ADME properties. The higher BBB value (65.607 vs 31.485) is crucial for a CNS target. Lower Pgp efflux for ligand A is good, but the difference isn't large enough to overcome the other advantages of ligand B.

Output:
1
2025-04-17 09:11:29,863 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (353.419 and 348.447 Da) fall within the ideal range of 200-500 Da.

**TPSA:** Both ligands (104.81 and 102.3) are above the optimal <90 for CNS targets, but not drastically so. This is a moderate concern.

**logP:** Ligand A (-0.183) is quite low, potentially hindering permeability. Ligand B (0.95) is better, falling within the 1-3 range. This is a significant advantage for Ligand B.

**H-Bond Donors/Acceptors:** Both ligands have 2 HBD and around 4-5 HBA, which is acceptable.

**QED:** Both ligands have good QED scores (0.509 and 0.669), indicating drug-like properties.

**DILI:** Ligand A (36.758) has a slightly higher DILI risk than Ligand B (16.208), but both are below the concerning threshold of 60.

**BBB:** This is crucial for a CNS target. Ligand B (53.974) has a substantially better BBB percentile than Ligand A (36.603). This is a major advantage for Ligand B.

**Caco-2 Permeability:** Both have negative values (-5.013 and -5.221), which is unusual and suggests very poor permeability. This is a significant concern for both.

**Aqueous Solubility:** Both have negative values (-1.721 and -1.585), again suggesting poor solubility.

**hERG:** Both ligands show very low hERG inhibition liability (0.058 and 0.406), which is excellent.

**Microsomal Clearance:** Ligand A (32.488) has higher microsomal clearance than Ligand B (-19.562). This suggests Ligand B is more metabolically stable.

**In vitro Half-Life:** Ligand B (-1.939) has a slightly better (less negative) in vitro half-life than Ligand A (-3.357).

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.018 and 0.021), which is favorable for CNS penetration.

**Binding Affinity:** Ligand B (-7.8 kcal/mol) has a slightly better binding affinity than Ligand A (-7.1 kcal/mol). While both are good, the 0.7 kcal/mol difference is notable.

**Overall Assessment:**

Ligand B is the superior candidate. While both have issues with Caco-2 permeability and solubility, Ligand B excels in the critical areas for a CNS-targeting GPCR: better logP, significantly higher BBB penetration, improved metabolic stability (lower Cl_mic), slightly better half-life, and a slightly stronger binding affinity. The lower DILI risk is also a plus. Ligand A's low logP is a major drawback.

Output:
1
2025-04-17 09:11:29,863 - INFO - Reasoning:

Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (349.362 and 356.375 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (87.74) is excellent, falling well below the 90 A^2 threshold for CNS targets. Ligand B (134.19) is higher, but still potentially acceptable, though less ideal.

**logP:** Ligand A (2.026) is optimal (1-3). Ligand B (-1.925) is significantly lower, which could hinder membrane permeability and CNS penetration.

**H-Bond Donors/Acceptors:** Ligand A (HBD=2, HBA=4) is well within acceptable limits. Ligand B (HBD=4, HBA=7) is also within limits, but approaching the higher end.

**QED:** Ligand A (0.814) has a very strong drug-like profile. Ligand B (0.322) is considerably lower, indicating a less favorable overall drug-likeness.

**DILI:** Both ligands have similar DILI risk (65.529 and 64.482), both falling within the acceptable range (<60 is good, >60 is high risk).

**BBB:** Ligand A (60.644) shows moderate BBB penetration. Ligand B (23.187) is quite low, a major concern for a CNS target like DRD2.

**Caco-2 Permeability:** Ligand A (-4.556) is poor. Ligand B (-5.446) is also poor.

**Aqueous Solubility:** Ligand A (-3.619) is poor. Ligand B (-1.264) is also poor.

**hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.252 and 0.142).

**Microsomal Clearance:** Ligand A (-1.84) suggests good metabolic stability (negative value). Ligand B (24.151) indicates rapid metabolism, which is undesirable.

**In vitro Half-Life:** Ligand A (22.287) has a reasonable half-life. Ligand B (-16.363) has a negative half-life, which is not possible and likely indicates a data error or a very unstable compound.

**P-gp Efflux:** Both ligands have low P-gp efflux (0.07 and 0.089), which is good for CNS penetration.

**Binding Affinity:** Ligand A (-9.2 kcal/mol) has significantly stronger binding affinity than Ligand B (-7.0 kcal/mol). The difference of 2.2 kcal/mol is substantial and can outweigh minor ADME drawbacks.

**Overall Assessment:**

Ligand A is clearly superior. While both have poor Caco-2 and solubility, Ligand A excels in crucial areas for a CNS GPCR target: TPSA, logP, BBB, metabolic stability, and *especially* binding affinity. Ligand B's low logP and very poor BBB penetration are significant liabilities. The negative half-life for Ligand B is also a red flag. The substantial affinity difference between A and B is the deciding factor.

Output:
1
2025-04-17 09:11:29,864 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (348.531 and 345.399 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (40.62) is excellent, well below the 90 A^2 threshold for CNS targets. Ligand B (91.76) is higher, exceeding the ideal range, which could hinder BBB penetration.

**logP:** Ligand A (3.698) is within the optimal 1-3 range. Ligand B (0.347) is quite low, potentially causing permeability issues.

**H-Bond Donors/Acceptors:** Ligand A (0 HBD, 2 HBA) is favorable. Ligand B (2 HBD, 5 HBA) is acceptable, but higher HBA could slightly impact permeability.

**QED:** Both ligands have good QED scores (0.734 and 0.821), indicating good drug-like properties.

**DILI:** Ligand A (13.61) has a very low DILI risk, significantly better than Ligand B (46.142).

**BBB:** Ligand A (92.71) has excellent BBB penetration potential, exceeding the desirable >70 percentile. Ligand B (25.824) is poor for CNS penetration.

**Caco-2 Permeability:** Ligand A (-4.604) is negative, indicating poor permeability. Ligand B (-4.807) is also negative, indicating poor permeability.

**Aqueous Solubility:** Ligand A (-3.075) and Ligand B (-1.559) are both negative, indicating poor solubility.

**hERG:** Both ligands have low hERG risk (0.633 and 0.198).

**Microsomal Clearance:** Ligand A (75.343) has moderate clearance. Ligand B (9.568) has very low clearance, suggesting good metabolic stability.

**In vitro Half-Life:** Ligand A (-21.609) has a negative half-life, which is not interpretable. Ligand B (-2.682) also has a negative half-life, which is not interpretable.

**P-gp Efflux:** Both ligands have low P-gp efflux liability (0.288 and 0.017).

**Binding Affinity:** Ligand B (-9.0 kcal/mol) has a significantly stronger binding affinity than Ligand A (-8.2 kcal/mol). This is a >1.5 kcal/mol advantage, which is substantial.

**Overall Assessment:**

Despite Ligand B's superior binding affinity, Ligand A is the more promising candidate. The critical factor is the BBB penetration. Ligand A's 92.71 percentile BBB score is excellent for a CNS target like DRD2, while Ligand B's 25.824 percentile is very poor. Ligand A also has a much lower DILI risk. While both have poor Caco-2 and solubility, and Ligand B has better metabolic stability, the importance of CNS penetration for a DRD2 ligand outweighs these factors. The affinity difference, while significant, can potentially be optimized in later stages of drug development.

Output:
1
2025-04-17 09:11:29,864 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (374.463 and 358.435 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (130.13) is slightly above the optimal <90 for CNS targets, but still reasonable. Ligand B (113.96) is better, falling comfortably below 90.

**logP:** Both ligands (-0.315 and -0.16) are a bit low. While not drastically outside the 1-3 range, higher logP values are generally preferred for BBB penetration.

**H-Bond Donors/Acceptors:** Both ligands have 3 HBD and 6 HBA, which are within acceptable limits (<=5 and <=10 respectively).

**QED:** Both ligands have QED values above 0.5 (0.51 and 0.494), indicating good drug-like properties.

**DILI:** Ligand A (60.295) has a higher DILI risk than Ligand B (25.708). This is a significant negative for Ligand A.

**BBB:** Ligand B (53.121) has a considerably better BBB percentile than Ligand A (47.809). While both are not ideal (>70), Ligand B is closer.

**Caco-2 Permeability:** Both have negative values, which is unusual. Assuming these are percentile scores, Ligand B (-4.942) is slightly better than Ligand A (-5.47), indicating marginally better absorption.

**Aqueous Solubility:** Both have negative values, which is also unusual. Assuming these are percentile scores, Ligand B (-1.564) is slightly better than Ligand A (-2.219).

**hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.25 and 0.118).

**Microsomal Clearance:** Ligand A (-8.541) has a much lower (better) microsomal clearance than Ligand B (54.352), suggesting greater metabolic stability.

**In vitro Half-Life:** Ligand A (32.565) has a positive half-life, while Ligand B (-50.805) has a negative half-life. This is unusual and suggests a potential issue with the data for Ligand B.

**P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.169 and 0.041).

**Binding Affinity:** Ligand B (-6.8 kcal/mol) has a slightly better binding affinity than Ligand A (-8.0 kcal/mol). While A is stronger, the difference isn't huge enough to overcome other issues.

**Overall Assessment:**

Ligand B is the more promising candidate. While its logP is low, its significantly better BBB penetration, lower DILI risk, and slightly better binding affinity outweigh the advantages of Ligand A's metabolic stability and stronger binding. The negative half-life for Ligand B is concerning, but the other factors strongly favor it. The lower DILI risk is a major advantage, as is the better BBB score, critical for a CNS target like DRD2.

Output:
1
2025-04-17 09:11:29,864 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (346.471 Da) is slightly lower, which can be advantageous for permeability.

**2. TPSA:** Ligand A (49.85) is significantly better than Ligand B (60.77). For a CNS target like DRD2, a TPSA <= 90 is desired, and A is much closer to the optimal < 90 range.

**3. logP:** Both ligands have acceptable logP values (A: 2.482, B: 3.854), falling within the 1-3 range. B is a bit higher, which *could* lead to solubility issues, but isn't a major concern.

**4. H-Bond Donors:** Ligand A (0) is preferable to Ligand B (2). Fewer HBDs generally improve permeability.

**5. H-Bond Acceptors:** Ligand A (3) is preferable to Ligand B (4). Fewer HBAs generally improve permeability.

**6. QED:** Both ligands have similar, acceptable QED values (A: 0.786, B: 0.7), indicating good drug-like properties.

**7. DILI:** Ligand B (35.789) has a lower DILI risk than Ligand A (17.642), which is a positive for B. However, both are below the concerning threshold of 60.

**8. BBB:** Ligand A (84.141) has a significantly higher BBB penetration percentile than Ligand B (61.962). This is *critical* for a CNS target like DRD2. A value >70 is desirable, and A is much closer.

**9. Caco-2 Permeability:** Ligand A (-4.605) is better than Ligand B (-4.88). Higher values are better.

**10. Aqueous Solubility:** Ligand A (-2.21) is better than Ligand B (-4.142). Higher values are better.

**11. hERG Inhibition:** Both ligands have very low hERG inhibition risk (A: 0.283, B: 0.67).

**12. Microsomal Clearance:** Ligand A (29.196) has lower microsomal clearance than Ligand B (54.964), indicating better metabolic stability.

**13. In vitro Half-Life:** Ligand B (30.859) has a longer in vitro half-life than Ligand A (11.642), which is a positive for B.

**14. P-gp Efflux:** Ligand A (0.11) has lower P-gp efflux than Ligand B (0.808), which is a significant advantage for CNS exposure.

**15. Binding Affinity:** Ligand A (-8.8 kcal/mol) has a *much* stronger binding affinity than Ligand B (-0.0 kcal/mol). This is a decisive factor. A difference of >1.5 kcal/mol is considered significant, and here it's a massive 8.8 kcal/mol difference.



**Overall Assessment:**

Ligand A is the superior candidate. While Ligand B has a slightly better DILI score and in vitro half-life, Ligand A excels in almost all other critical parameters, especially those prioritized for GPCRs targeting the CNS. The dramatically stronger binding affinity (-8.8 vs -0.0 kcal/mol) and significantly better BBB penetration (84.141 vs 61.962) outweigh the minor advantages of Ligand B. The lower TPSA, HBD, HBA, P-gp efflux, and better solubility/permeability of A further solidify its position.

Output:
1
2025-04-17 09:11:29,864 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (349.431 and 365.455 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (87.74) is better than Ligand B (97.39). Both are below the 90 A^2 threshold desirable for CNS targets, but A is closer to the ideal.

**3. logP:** Ligand A (0.216) is quite low, potentially hindering permeation. Ligand B (0.775) is better, but still on the lower side of the optimal 1-3 range.

**4. H-Bond Donors:** Both ligands have 2 HBD, which is within the acceptable limit of <=5.

**5. H-Bond Acceptors:** Ligand A has 4 HBA, and Ligand B has 5. Both are within the acceptable limit of <=10.

**6. QED:** Ligand B (0.664) has a significantly better QED score than Ligand A (0.335), indicating better overall drug-likeness.

**7. DILI:** Ligand A (21.908) has a much lower DILI risk than Ligand B (47.15), which is a substantial advantage.

**8. BBB:** Ligand A (56.223) has a better BBB percentile than Ligand B (46.413), though both are below the desirable >70 for CNS targets. This is a critical factor for DRD2.

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.88 and -4.951), which is unusual and suggests poor permeability.

**10. Aqueous Solubility:** Both ligands have negative solubility values (-1.525 and -2.553), which is also unusual and suggests poor solubility.

**11. hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.145 and 0.151).

**12. Microsomal Clearance:** Ligand A (0.661) has significantly lower microsomal clearance than Ligand B (19.263), indicating better metabolic stability.

**13. In vitro Half-Life:** Ligand B (-43.522) has a longer in vitro half-life than Ligand A (-24.194), which is a positive.

**14. P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.019 and 0.021).

**15. Binding Affinity:** Ligand B (-8.2 kcal/mol) has a significantly stronger binding affinity than Ligand A (-7.0 kcal/mol). This >1.5 kcal/mol difference is a major advantage.

**Overall Assessment:**

Ligand B has a significantly better binding affinity and a longer half-life. However, Ligand A has a much lower DILI risk, better BBB penetration (though still suboptimal), and better metabolic stability. Ligand A's logP is concerningly low. Considering the GPCR-specific priorities, the stronger affinity of Ligand B is a major driver. While the BBB penetration isn't ideal for either, the difference isn't as significant as the affinity difference. The DILI risk of Ligand B is higher, but can potentially be addressed through further optimization.

Output:
1
2025-04-17 09:11:29,864 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands are within the ideal range (200-500 Da). Ligand A (335.407) is slightly lower, which could be beneficial for permeability, but both are acceptable.

**TPSA:** Both ligands have TPSA values (A: 56.27, B: 62.3) below the 90 A^2 threshold for CNS targets, which is good.

**logP:** Ligand A (4.137) is slightly above the optimal range (1-3), potentially leading to solubility issues or off-target interactions. Ligand B (2.928) is within the optimal range. This favors Ligand B.

**H-Bond Donors/Acceptors:** Both ligands have acceptable HBD (1) and HBA (A: 5, B: 4) counts.

**QED:** Both ligands have good QED scores (A: 0.734, B: 0.81), indicating drug-like properties.

**DILI:** Ligand A (74.99) has a higher DILI risk than Ligand B (26.561). This is a significant advantage for Ligand B.

**BBB:** Ligand A (78.907) has a better BBB penetration percentile than Ligand B (65.607), which is important for a CNS target like DRD2.

**Caco-2 Permeability:** Both have negative Caco-2 values, which is unusual and suggests poor permeability. However, the values are on the same scale, so this isn't a differentiating factor.

**Aqueous Solubility:** Both ligands have very poor aqueous solubility (-5.845 and -2.693 respectively).

**hERG Inhibition:** Ligand A (0.792) has a slightly higher hERG inhibition risk than Ligand B (0.346), favoring Ligand B.

**Microsomal Clearance:** Both ligands have similar microsomal clearance values (A: 63.632, B: 63.867), indicating comparable metabolic stability.

**In vitro Half-Life:** Ligand A (5.9) has a longer half-life than Ligand B (-1.262), which is desirable.

**P-gp Efflux:** Ligand A (0.667) has lower P-gp efflux liability than Ligand B (0.342), which is good for CNS penetration.

**Binding Affinity:** Both ligands have very similar and excellent binding affinities (-8.3 and -8.4 kcal/mol). The difference is negligible.

**Overall Assessment:**

Ligand B has several advantages: better logP, significantly lower DILI risk, and lower hERG inhibition. Ligand A has better BBB penetration and a longer half-life, but the DILI risk is a major concern. Given the GPCR-specific priorities, and the relatively similar binding affinities, the lower DILI and hERG risk of Ligand B make it the more promising candidate. The slightly better BBB of Ligand A is outweighed by the safety concerns.

Output:
1
2025-04-17 09:11:29,864 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (352.435 Da and 361.427 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Ligand A (96.69) is better than Ligand B (106.1), both are below the 140 A^2 threshold for oral absorption, and importantly, below the 90 A^2 threshold for CNS targets.

**3. logP:** Ligand B (1.128) is slightly better than Ligand A (0.411). Both are within the optimal 1-3 range, but A is a bit low, which could hinder permeation.

**4. H-Bond Donors:** Both ligands have 2 HBD, which is within the acceptable limit of <=5.

**5. H-Bond Acceptors:** Ligand A has 6 HBA, and Ligand B has 7. Both are within the acceptable limit of <=10.

**6. QED:** Both ligands have similar QED values (0.741 and 0.766), indicating good drug-like properties.

**7. DILI:** Ligand A (47.15) has a significantly lower DILI risk than Ligand B (69.484). This is a major advantage for Ligand A.

**8. BBB:** Ligand B (59.403) has a much better BBB penetration percentile than Ligand A (30.128). This is critical for a CNS target like DRD2.

**9. Caco-2 Permeability:** Both ligands have negative Caco-2 values (-4.927 and -4.97), which is unusual and suggests poor permeability. This is a concern for both.

**10. Aqueous Solubility:** Ligand A (-1.122) has better aqueous solubility than Ligand B (-3.664).

**11. hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.142 and 0.184).

**12. Microsomal Clearance:** Ligand A (22.792) has a lower microsomal clearance than Ligand B (58.375), indicating better metabolic stability.

**13. In vitro Half-Life:** Ligand A (7.934) has a better in vitro half-life than Ligand B (-25.897).

**14. P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.016 and 0.027).

**15. Binding Affinity:** Both ligands have excellent binding affinity (-8.0 and -8.3 kcal/mol). The difference is minimal.

**Overall Assessment:**

Ligand B has a significantly better BBB penetration (59.403 vs 30.128), which is paramount for a CNS target like DRD2. However, Ligand A excels in several other crucial areas: lower DILI risk, better solubility, better metabolic stability (lower Cl_mic and longer t1/2). While both have poor Caco-2 permeability, the other advantages of Ligand A, particularly the lower DILI and better metabolic profile, make it a more promising candidate. The slight advantage in BBB for Ligand B is not enough to overcome these other significant drawbacks.

Output:
0
2025-04-17 09:11:29,864 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**Molecular Weight:** Both ligands (360.435 and 338.411 Da) fall within the ideal 200-500 Da range.

**TPSA:** Ligand A (85.36) is better than Ligand B (78.09) as both are below the 90 A^2 threshold for CNS targets.

**logP:** Both ligands have good logP values (2.534 and 2.087), falling within the optimal 1-3 range.

**H-Bond Donors/Acceptors:** Ligand A (HBD=1, HBA=5) is slightly better than Ligand B (HBD=2, HBA=3) as it has a lower number of HBDs. Both are within acceptable limits.

**QED:** Both ligands have similar and good QED scores (0.8 and 0.82).

**DILI:** Ligand A (76.192) has a slightly better DILI score than Ligand B (63.397), indicating a lower risk of liver injury. Both are acceptable (<60 is good).

**BBB:** Ligand A (55.138) has a significantly better BBB percentile than Ligand B (38.581). This is a crucial factor for a CNS target like DRD2.

**Caco-2 Permeability:** Ligand B (-5.045) is better than Ligand A (-4.483), indicating better intestinal absorption. However, this is less critical for a CNS target where BBB penetration is more important.

**Aqueous Solubility:** Ligand B (-3.348) is better than Ligand A (-4.252), indicating better solubility.

**hERG Inhibition:** Ligand A (0.101) has a lower hERG inhibition liability than Ligand B (0.481), which is preferable.

**Microsomal Clearance:** Ligand B (17.522) has a significantly lower microsomal clearance than Ligand A (82.107), indicating better metabolic stability.

**In vitro Half-Life:** Ligand B (-11.092) has a longer in vitro half-life than Ligand A (-32.065).

**P-gp Efflux:** Ligand A (0.049) has a lower P-gp efflux liability than Ligand B (0.043), which is better for CNS exposure.

**Binding Affinity:** Both ligands have very similar and strong binding affinities (-9.7 and -8.8 kcal/mol). The difference of 0.9 kcal/mol is not substantial enough to override other ADME considerations.

**Overall Assessment:**

Ligand A excels in BBB penetration, DILI risk, and hERG inhibition, all critical for CNS drug development. While Ligand B has better Caco-2 permeability, solubility, metabolic stability, and half-life, the superior BBB score of Ligand A is the deciding factor for a DRD2 ligand. The slightly better P-gp efflux for Ligand A also contributes to its favorability.

Output:
0
2025-04-17 09:11:29,864 - INFO - Reasoning:
Let's analyze Ligand A and Ligand B for their potential as DRD2 ligands, keeping in mind the GPCR-specific priorities (BBB, logP, Pgp, TPSA, and affinity).

**1. Molecular Weight:** Both ligands (350.463 and 346.362 Da) fall within the ideal 200-500 Da range.

**2. TPSA:** Both ligands have a TPSA of 87.46, which is acceptable for oral absorption but slightly high for optimal CNS penetration (ideally <90).

**3. logP:** Both ligands have logP values within the optimal range (1.021 and 1.299).

**4. H-Bond Donors:** Both have 2 HBD, which is within the acceptable limit of <=5.

**5. H-Bond Acceptors:** Both have 5 HBA, also within the acceptable limit of <=10.

**6. QED:** Both ligands have high QED scores (0.83 and 0.877), indicating good drug-like properties.

**7. DILI:** Ligand A (39.356) has a lower DILI risk than Ligand B (53.276), which is preferable. Both are below the concerning threshold of 60.

**8. BBB:** Ligand B (58.55) has a significantly better BBB penetration percentile than Ligand A (34.238). This is a critical advantage for a CNS target like DRD2.

**9. Caco-2 Permeability:** Ligand A (-4.992) has slightly better Caco-2 permeability than Ligand B (-4.754), suggesting better intestinal absorption.

**10. Aqueous Solubility:** Both ligands have similar, very poor aqueous solubility (-2.429 and -2.4). This could be a formulation challenge.

**11. hERG Inhibition:** Both ligands have very low hERG inhibition risk (0.115 and 0.161).

**12. Microsomal Clearance:** Ligand B (-7.531) has significantly lower (better) microsomal clearance than Ligand A (53.973), indicating greater metabolic stability.

**13. In vitro Half-Life:** Ligand B (-22.412) has a significantly longer in vitro half-life than Ligand A (13.838), which is desirable.

**14. P-gp Efflux:** Both ligands have very low P-gp efflux liability (0.022 and 0.02).

**15. Binding Affinity:** Ligand B (-8.4 kcal/mol) has a slightly better binding affinity than Ligand A (-7.8 kcal/mol). While both are good, the 0.6 kcal/mol difference is meaningful.

**Overall Assessment:**

While Ligand A has slightly better Caco-2 permeability and DILI risk, Ligand B is superior overall, especially considering the GPCR-specific priorities. The significantly improved BBB penetration, metabolic stability (lower Cl_mic, longer t1/2), and slightly better binding affinity of Ligand B outweigh the minor advantages of Ligand A. The poor solubility is a concern for both, but can potentially be addressed through formulation strategies.

Output:
1
2025-04-17 09:11:29,865 - INFO - Batch 512 complete. Total preferences: 8192
2025-04-17 09:11:29,865 - INFO - LLM processing complete.
2025-04-17 09:11:30,041 - INFO - Saved final results to llm_preferecence_DRD2_6cm4.npz
2025-04-17 09:11:30,041 - INFO - --- Script finished in 8:45:41.901496 ---